PMID- 24786304 TI - Formation and phase transformation of Bi-containing QD-like clusters in annealed GaAsBi. AB - We report the formation and phase transformation of Bi-containing clusters in GaAs(1-x)Bi(x) epilayers upon annealing. The GaAs(1-x)Bi(x) layers were grown by molecular beam epitaxy under low (220 degrees C) and high (315 degrees C) temperatures and subsequently annealed using different temperatures and annealing times. Bi-containing clusters were identified only in the annealed samples that were grown at low temperature, revealing a relatively homogeneous size distribution. Depending on the annealing temperature and duration, the clusters show different sizes ranging from 5 to 20 nm, as well as different crystallographic phase, being coherently strained zincblende GaAs(1-x)Bi(x) (zb Bi-rich Ga(As, Bi)) clusters or rhombohedral pure Bi (rh-Bi) clusters. We found that: (1) the formation of the zb Bi-rich Ga(As, Bi) clusters is driven by the intrinsic tendency of the alloy to phase separately and is mediated by the native point defects present in the low temperature grown epilayers; (2) the phase transformation from zb Bi-rich Ga(As, Bi) to rh-Bi nucleates in zincblende {111} planes and grows until total consumption of Bi in the GaAs matrix. We propose a model accounting for the formation and phase transformation of Bi-containing clusters in this system. Furthermore, our study reveals the possibility to realize self-organized zb Bi-rich Ga(As, Bi) clusters that can exhibit QD-like features. PMID- 24786305 TI - Highly sensitive electrochemical aptasensor based on a ligase-assisted exonuclease III-catalyzed degradation reaction. AB - In this paper, we have proposed a new electrochemical aptasensor based on a novel ligase-assisted Exo III-catalyzed degradation reaction (LAECDR), which consists of DNA ligase-catalyzed ligation of thrombin-binding aptamer (TBA) with an extension strand (E-strand) and Exo III-catalyzed selective degradation of probe DNA, by using an improved target-induced strand displacement strategy. As a result of LAECDR, methylene blue (MB)-labeled mononucleotides can be released from the 3'-terminal of probe DNA and captured by cucurbit[7]uril-functionalized electrode to induce noticeable electrochemical response. Nevertheless, in the presence of the target protein, thrombin, the TBA that is partially complementary to probe DNA is preferentially binding with the target protein, thereby inhibiting LAECDR from taking place. The remaining intact probe DNA will prevent the terminal-attached MB from approaching to the electrode surface due to strong electrostatic repulsion, so the electrochemical response will be changed by thrombin. By tracing the electrochemical response of adsorbed MB, our aptasensor can exhibit high sensitivity for thrombin detection with a wide linear range from 100 fM to 1 nM and an extremely low detection limit of 33 fM, which can also easily distinguish thrombin in the complex serum samples with high specificity. Therefore, our aptasensor might have great potential in clinical applications in the future. PMID- 24786306 TI - Fourier transform infrared detection of a polarizable proton trapped between photooxidized tyrosine YZ and a coupled histidine in photosystem II: relevance to the proton transfer mechanism of water oxidation. AB - The redox-active tyrosine YZ (D1-Tyr161) in photosystem II (PSII) functions as an immediate electron acceptor of the Mn4Ca cluster, which is the catalytic center of photosynthetic water oxidation. YZ is also located in the hydrogen bond network that connects the Mn4Ca cluster to the lumen and hence is possibly related to the proton transfer process during water oxidation. To understand the role of YZ in the water oxidation mechanism, we have studied the hydrogen bonding interactions of YZ and its photooxidized neutral radical YZ(*) together with the interaction of the coupled His residue, D1-His190, using light-induced Fourier transform infrared (FTIR) difference spectroscopy. The YZ(*)-minus-YZ FTIR difference spectrum of Mn-depleted PSII core complexes exhibited a broad positive feature around 2800 cm(-1), which was absent in the corresponding spectrum of another redox-active tyrosine YD (D2-Tyr160). Analyses by (15)N and H/D substitutions, examination of the pH dependence, and density functional theory and quantum mechanics/molecular mechanics (QM/MM) calculations showed that this band arises from the N-H stretching vibration of the protonated cation of D1 His190 forming a charge-assisted strong hydrogen bond with YZ(*). This result provides strong evidence that the proton released from YZ upon its oxidation is trapped in D1-His190 and a positive charge remains on this His. The broad feature of the ~2800 cm(-1) band reflects a large proton polarizability in the hydrogen bond between YZ(*) and HisH(+). QM/MM calculations further showed that upon YZ oxidation the hydrogen bond network is rearranged and one water molecule moves toward D1-His190. From these data, a novel proton transfer mechanism via YZ(*) HisH(+) is proposed, in which hopping of the polarizable proton of HisH(+) to this water triggers the transfer of the proton from substrate water to the luminal side. This proton transfer mechanism could be functional in the S2 -> S3 transition, which requires proton release before electron transfer because of an excess positive charge on the Mn4Ca cluster. PMID- 24786307 TI - Handedness predicts motivation to switch from the status quo. AB - Degree of handedness is a correlate of structural brain asymmetries and predicts individual differences in episodic memory, belief updating and various biases in decision-making. We examined whether handedness moderated the status quo bias given previous research suggests that both constructs are related to loss aversion. Participants answered hypothetical scenarios in which they decided either to stay with the status quo or to switch. Results indicated that consistent and inconsistent right-handers both exhibited status quo bias (Experiment 1; N=180), but inconsistent right-handers were more (or less) likely to stick with the status quo when informed of a positive (or negative) past experience. When provided with more equivocal information about the quality of the status quo and alternative, consistent-handers (CH) were more likely to show a status quo bias (Experiment 2; N=222). Compared to CH, we argue that inconsistent-handers (IH) more readily update their beliefs in a manner consistent with how the status quo and alternative options are presented switching when finding a reason to favour the alternative and staying when the status quo is described more favourably. These handedness differences fit a motivational account explaining status quo bias rather than a loss aversion account. PMID- 24786308 TI - Making connections: interorganelle contacts orchestrate mitochondrial behavior. AB - Mitochondria are highly dynamic organelles. During their life cycle they frequently fuse and divide, and damaged mitochondria are removed by autophagic degradation. These processes serve to maintain mitochondrial function and ensure optimal energy supply for the cell. It has recently become clear that this complex mitochondrial behavior is governed to a large extent by interactions with other organelles. In this review, we describe mitochondrial contacts with the endoplasmic reticulum (ER), plasma membrane, and peroxisomes. In particular, we highlight how mitochondrial fission, distribution, inheritance, and turnover are orchestrated by interorganellar contacts in yeast and metazoa. These interactions are pivotal for the integration of the dynamic mitochondrial network into the architecture of eukaryotic cells. PMID- 24786310 TI - Evaluating Objective Structured Clinical Assessment (OSCA) in undergraduate nursing. AB - The aims of this mixed methods study were to gain insight into how individual assessors determine an Objective Structured Clinical Assessment (OSCA) result for undergraduate nursing students and identify whether individual assessor perceptions and professional characteristics have an impact on students' results. Results from 25 participants showed that although less than half (44%) of the participants were teaching in the course that they were assessing, the participants were highly experienced clinicians and nearly three-quarters (72%) had completed formal teaching qualifications. There were wide variations in pass rates (16.7-90%) between assessors. The widest disparity was observed between assessors with and those without critical care experience (66% versus 39%), as well as assessors who were teaching the course and those who were not (68% versus 49%). Qualitative analysis revealed three dominant themes within participants' transcripts. The themes focused on determining student safety, and the use of personal perceptions and clinical experience to determine competency. Findings indicate that assessors' individual perceptions and clinical experience have the potential to influence and determine undergraduate nursing students OSCA results. Development of criteria standards and objective assessment may be enhanced by greater involvement of assessors and thorough education and training within the context of student assessments. PMID- 24786311 TI - Oxygen incorporation in rubrene single crystals. AB - Single crystal rubrene is a model organic electronic material showing high carrier mobility and long exciton lifetime. These properties are detrimentally affected when rubrene is exposed to intense light under ambient conditions for prolonged periods of time, possibly due to oxygen up-take. Using photoelectron, scanning probe and ion-based methods, combined with an isotopic oxygen exposure, we present direct evidence of the light-induced reaction of molecular oxygen with single crystal rubrene. Without a significant exposure to light, there is no reaction of oxygen with rubrene for periods of greater than a year; the crystal's surface (and bulk) morphology and chemical composition remain essentially oxygen free. Grand canonical Monte Carlo computations show no sorbtion of gases into the bulk of rubrene crystal. A mechanism for photo-induced oxygen inclusion is proposed. PMID- 24786309 TI - NAD+ and sirtuins in aging and disease. AB - Nicotinamide adenine dinucleotide (NAD(+)) is a classical coenzyme mediating many redox reactions. NAD(+) also plays an important role in the regulation of NAD(+) consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD(+) biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD(+) levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD(+) by supplementing NAD(+) intermediates can dramatically ameliorate these age associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide. PMID- 24786312 TI - Signal-regulatory protein alpha from the NOD mouse binds human CD47 with an exceptionally high affinity-- implications for engraftment of human cells. AB - One common way to study human leucocytes and cancer cells in an experimental in vivo situation is to use mice that have been genetically engineered to lack an immune system and prevent human cell rejection. These mice lack CD132 and either RAG2 or the catalytic subunit of the DNA-dependent protein kinase, to make the mice deficient in lymphocytes and natural killer cells. The NOD mouse strain provides a better background for engraftment than other strains due to stronger engagement of the signal-regulatory protein-alpha (SIRPalpha) inhibitory receptor with human CD47 (hCD47) resulting in a 'don't-eat-me' signal. To determine the molecular parameters that determine this major functional effect in the NOD mouse we measured the affinity of hCD47 for SIRPalpha from various mouse strains. Human CD47 bound SIRPalpha from the NOD mouse with an affinity 65 times greater than SIRPalpha from other mouse strains. This is due mainly to the NOD SIRPalpha lacking two amino acids in domain 1 compared with other mouse strains. Remarkably the SIRPalpha(NOD) binds hCD47 with 10 times the affinity of the syngeneic hCD47/hSIRPalpha interaction. This affinity is outside the normal range for affinities for leucocyte surface protein interactions and raises questions as to what is the optimal affinity of this interaction for engraftment and what other xenogeneic interactions involved in homeostasis may also not be optimal. PMID- 24786313 TI - Development and characterization of acellular porcine pulmonary valve scaffolds for tissue engineering. AB - Currently available replacement heart valves all have limitations. This study aimed to produce and characterize an acellular, biocompatible porcine pulmonary root conduit for reconstruction of the right ventricular outflow tract e.g., during Ross procedure. A process for the decellularization of porcine pulmonary roots was developed incorporating trypsin treatment of the adventitial surface of the scraped pulmonary artery and sequential treatment with hypotonic Tris buffer (HTB; 10 mM Tris pH 8.0, 0.1% (w/v) EDTA, and 10 KIU aprotinin), 0.1% (w/v) sodium dodecyl sulfate in HTB, two cycles of DNase and RNase, and sterilization with 0.1% (v/v) peracetic acid. Histology confirmed an absence of cells and retention of the gross histoarchitecture. Immunohistochemistry further confirmed cell removal and partial retention of the extracellular matrix, but a loss of collagen type IV. DNA levels were reduced by more than 96% throughout all regions of the acellular tissue and no functional genes were detected using polymerase chain reaction. Total collagen levels were retained but there was a significant loss of glycosaminoglycans following decellularization. The biomechanical, hydrodynamic, and leaflet kinematics properties were minimally affected by the process. Both immunohistochemical labeling and antibody absorption assay confirmed a lack of alpha-gal epitopes in the acellular porcine pulmonary roots and in vitro biocompatibility studies indicated that acellular leaflets and pulmonary arteries were not cytotoxic. Overall the acellular porcine pulmonary roots have excellent potential for development of a tissue substitute for right ventricular outflow tract reconstruction e.g., during the Ross procedure. PMID- 24786314 TI - Evaluation of environmental scanning electron microscopy for analysis of Proteus mirabilis crystalline biofilms in situ on urinary catheters. AB - Proteus mirabilis is a common cause of catheter-associated urinary tract infections and frequently leads to blockage of catheters due to crystalline biofilm formation. Scanning electron microscopy (SEM) has proven to be a valuable tool in the study of these unusual biofilms, but entails laborious sample preparation that can introduce artefacts, undermining the investigation of biofilm development. In contrast, environmental scanning electron microscopy (ESEM) permits imaging of unprocessed, fully hydrated samples, which may provide much insight into the development of P. mirabilis biofilms. Here, we evaluate the utility of ESEM for the study of P. mirabilis crystalline biofilms in situ, on urinary catheters. In doing so, we compare this to commonly used conventional SEM approaches for sample preparation and imaging. Overall, ESEM provided excellent resolution of biofilms formed on urinary catheters and revealed structures not observed in standard SEM imaging or previously described in other studies of these biofilms. In addition, we show that energy-dispersive X-ray spectroscopy (EDS) may be employed in conjunction with ESEM to provide information regarding the elemental composition of crystalline structures and demonstrate the potential for ESEM in combination with EDS to constitute a useful tool in exploring the mechanisms underpinning crystalline biofilm formation. PMID- 24786315 TI - Enhanced susceptibility-weighted angiography (ESWAN) of cerebral arteries and veins at 1.5 Tesla. AB - OBJECTIVE: Enhanced susceptibility-weighted angiography (ESWAN) is a three dimensional (3D) multi-echo gradient-echo sequence which consists of both magnitude and phase images. This study aims to demonstrate the feasibility of ESWAN for the depiction of both cerebral arteries and veins at 1.5 T by comparing with time-of-flight (TOF) MR angiography (MRA) and MR venography (MRV). METHODS: 13 healthy volunteers underwent both ESWAN and 3D-TOF-MRA examinations. Among them, nine volunteers underwent an additional two-dimensional-TOF-MRV examination. With regard to the ESWAN sequence, both maximum intensity projection (MIP) and minimum intensity projection (mIP) images were reconstructed and compared with MIP reconstructions of the TOF MRA and the TOF MRV. RESULTS: Concerning the depiction of the constituent segments of the Circle of Willis, as well as A1, A2, A3 (segments of the anterior cerebral artery), M1, M2 (segments of the middle cerebral artery), P1 and P2 (segments of the posterior cerebral artery), the value of the ESWAN MIP was comparable to that of the TOF MRA without regard to visualization of branches, vessel homogeneity and wall irregularities or slight stenosis. ESWAN-mIP visualized more deep cerebral veins than TOF MRV in this study. CONCLUSION: By use of either mIP reconstruction of a long echo data set or MIP reconstruction of a short echo data set, ESWAN allows simultaneous visualization of both cerebral veins and proximal segments of intracerebral arteries at 1.5 T. ADVANCES IN KNOWLEDGE: ESWAN acquires multiple images at different echo times corresponding to different T2* weightings, wherein a short echo TOF-MRA data set and a long echo susceptibility-weighted imaging-MRV data set are obtained simultaneously. PMID- 24786316 TI - Audit of the job satisfaction levels of the UK radiography and physics workforce in UK radiotherapy centres 2012. AB - OBJECTIVE: Workforce planning reports identify a staff shortfall that jeopardizes the ability of UK radiotherapy centres to meet future demands. Obtaining an understanding of the work experiences of radiotherapy professionals will support the development of strategies to increase job satisfaction, productivity and effectiveness. METHODS: A quantitative survey assessed job satisfaction, attitudes to incident reporting, stress and burnout, opportunities for professional development, workload, retention and turnover. Clinical oncologists were not included, as the Royal College of Radiologists, London, UK, had recently assessed their members' satisfaction. All questions were taken from validated instruments or adapted from the "UK National Health Service Staff Survey". RESULTS: The survey yielded 658 completed responses (approximately 16% response rate), from public and private sectors. Over a third (36%) of respondents were classified as satisfied for job satisfaction with 11% dissatisfied and the remaining 53% ambivalent. A significant proportion of clinical staff (37.5%) report high emotional exhaustion. Presenteeism was an issue with 42.4% attending work despite feeling unable to fulfil their role. CONCLUSION: Radiotherapy professionals are prone to the effects of compassion fatigue and burnout. Attention must be paid to workload and its impact on practitioners' job satisfaction. Professional development that is supported and informed by a performance development review is a simple and effective means of enhancing satisfaction. Individuals have a responsibility to themselves and their colleagues as their behaviours and attitudes influence job satisfaction. ADVANCES IN KNOWLEDGE: This work identifies areas for future research to enhance the professional resilience of practitioners, in order to provide high-quality treatments. PMID- 24786317 TI - Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model. AB - Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFalpha. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. PMID- 24786318 TI - Traction force microscopy in rapidly moving cells reveals separate roles for ROCK and MLCK in the mechanics of retraction. AB - Retraction is a major rate-limiting step in cell motility, particularly in slow moving cell types that form large stable adhesions. Myosin II dependent contractile forces are thought to facilitate detachment by physically pulling up the rear edge. However, retraction can occur in the absence of myosin II activity in cell types that form small labile adhesions. To investigate the role of contractile force generation in retraction, we performed traction force microscopy during the movement of fish epithelial keratocytes. By correlating changes in local traction stress at the rear with the area retracted, we identified four distinct modes of retraction. "Recoil" retractions are preceded by a rise in local traction stress, while rear edge is temporarily stuck, followed by a sharp drop in traction stress upon detachment. This retraction type was most common in cells generating high average traction stress. In "pull" type retractions local traction stress and area retracted increase concomitantly. This was the predominant type of retraction in keratocytes and was observed mostly in cells generating low average traction stress. "Continuous" type retractions occur without any detectable change in traction stress, and are seen in cells generating low average traction stress. In contrast, to many other cell types, "release" type retractions occur in keratocytes following a decrease in local traction stress. Our identification of distinct modes of retraction suggests that contractile forces may play different roles in detachment that are related to rear adhesion strength. To determine how the regulation of contractility via MLCK or Rho kinase contributes to the mechanics of detachment, inhibitors were used to block or augment these pathways. Modulation of MLCK activity led to the most rapid change in local traction stress suggesting its importance in regulating attachment strength. Surprisingly, Rho kinase was not required for detachment, but was essential for localizing retraction to the rear. We suggest that in keratocytes MLCK and Rho kinase play distinct, complementary roles in the respective temporal and spatial control of rear detachment that is essential for maintaining rapid motility. PMID- 24786319 TI - Movement profiles of elite women soccer players during international matches and the effect of opposition's team ranking. AB - Abstract Movement patterns in elite men's soccer have been reported in depth, but less research exists for women's soccer. Aims of the study were to identify the movement profiles of elite women soccer players in international competition and examine the effect the level of opposition, based on Federation Internationale de Football Association (FIFA) rankings, had on the physical demands of the game. MinimaxX athlete tracking devices were used by 15 players during 13 international matches against opponent teams of varying ability. Total distance covered averaged 9292 +/- 175 m. There was a decrease in high-intensity running (HIR) in the 60- to 75-min and 75- to 90-min periods compared to the 0- to 15-min period of 22.4% and 26.1%, respectively (P = 0.022, P = 0.004) although sprint distances remained unchanged across game periods. HIR distances covered were significantly greater for midfielders versus defenders, while defenders had lower sprinting compared to both midfielders and attackers. Stronger opponents elicited less HIR and greater low-speed activity (LSA) compared to playing teams of similar or lower ranking. These results are important to coaches to prepare players for international competition and show the differing demands required depending on the ability of the opponents. PMID- 24786320 TI - Quasi-classical trajectory study of the vibrational and translational effects on the O((3)P) + CD4 reaction. AB - The effects of vibrational excitation and translational energy, connected to mode selectivity and Polanyi's rules, are important issues in dynamics studies. To analyze these effects on the O((3)P) + CD4 reaction, an exhaustive dynamics study was performed using quasi-classical trajectory calculations on a full-dimensional analytical potential energy surface. The independent excitation of the C-D symmetric or asymmetric stretch modes leads to reactions with similar reaction cross sections and product scattering distributions, mode selectivity being discarded. Finally, translational energy raises the reactivity more effectively than an equal amount of energy in vibration, thus indicating that for this "central barrier" reaction it is not clear how to apply the venerable Polanyi's rules. The strong coupling between vibrational modes is responsible for this behavior, which seems to be the general tendency in polyatomic systems. PMID- 24786321 TI - Biobanks and electronic medical records: enabling cost-effective research. AB - The use of electronic medical record data linked to biological specimens in health care settings is expected to enable cost-effective and rapid genomic analyses. Here, we present a model that highlights potential advantages for genomic discovery and describe the operational infrastructure that facilitated multiple simultaneous discovery efforts. PMID- 24786322 TI - Using humans to make a human leishmaniasis vaccine. AB - The cellular immune response to peptide pools from conserved Leishmania antigens in leishmaniasis-immune individuals identified epitopes for a human DNA vaccine (Das et al., this issue). PMID- 24786323 TI - A cell culture-derived MF59-adjuvanted pandemic A/H7N9 vaccine is immunogenic in adults. AB - A potentially deadly A/H7N9 avian-origin influenza virus is currently the cause of an ongoing outbreak in China. Preparedness plans have thus been initiated to preempt the spread of this virus, which appears to have substantial pandemic potential. To effectively prevent a pandemic from unfolding, rapid production of an immunogenic vaccine with an acceptable safety profile is critical. Given the significance to public health, we are reporting immunogenicity and safety results from a phase 1 study in healthy adults administered one of four inactivated A/H7N9 vaccine formulations. Three formulations contained increasing quantities of antigen and of an oil-in-water adjuvant, MF59, and one formulation contained only the maximum dose of antigen without adjuvant. All vaccine formulations were derived using a synthetic virus seed technology in combination with a cell culture approach; together, these techniques have been shown to expedite vaccine production compared to conventional methods. Higher responses were seen with the MF59-adjuvanted versus the nonadjuvanted A/H7N9 vaccine, with significant and potentially protective immune responses after two doses in most subjects with no preexisting immunity to the H7N9 virus. Further, despite increased injection site pain and other mild effects with MF59, all formulations were well tolerated. These encouraging immunogenicity and safety data on the A/H7N9 vaccine provide a strong rationale for further clinical development. By also using synthetic seed/cell culture technology, we are now one step closer to being able to rapidly and reliably respond to a potential H7N9 pandemic using a clinically tested A/H7N9 vaccine. PMID- 24786324 TI - Modular multiantigen T cell epitope-enriched DNA vaccine against human leishmaniasis. AB - The leishmaniases are protozoal diseases that severely affect large populations in tropical and subtropical regions. There are only limited treatment options and preventative measures. Vaccines will be important for prevention, control and elimination of leishmaniasis, and could reduce the transmission and burden of disease in endemic populations. We report the development of a DNA vaccine against leishmaniasis that induced T cell-based immunity and is a candidate for clinical trials. The vaccine antigens were selected as conserved in various Leishmania species, different endemic regions, and over time. They were tested with T cells from individuals cured of leishmaniasis, and shown to be immunogenic and to induce CD4(+) and CD8(+) T cell responses in genetically diverse human populations of different endemic regions. The vaccine proved protective in a rodent model of infection. Thus, the immunogenicity of candidate vaccine antigens in human populations of endemic regions, as well as proof of principle for induction of specific immune responses and protection against Leishmania infection in mice, provides a viable strategy for T cell vaccine development. PMID- 24786327 TI - Gender differences in the effect of adult amphetamine on cognitive functions of rats prenatally exposed to methamphetamine. AB - Psychostimulants have been shown to affect brain regions involved in the process of learning and memory consolidation. It has been shown that females are more sensitive to the effects of drugs than males. The aim of our study was to investigate how prenatal methamphetamine (MA) exposure and application of amphetamine (AMP) in adulthood would affect spatial learning of adult female and male rats. Mothers of the tested offspring were exposed to injections of MA (5mg/kg) or saline (SA) throughout the entire gestation period. Cognitive functions of adult rats were evaluated in the Morris Water Maze (MWM) tests. Adult offspring were injected daily with AMP (5mg/kg) or SA through the period of MWM testing. Our data from the MWM tests demonstrates the following. Prenatal MA exposure did not change the learning ability of adult male and female rats. However, AMP administration to adult animals affected cognitive function in terms of exacerbation of spatial learning (increasing the latency to reach the hidden platform, the distance traveled and the search error) only in female subjects. There were sex differences in the speed of swimming. Prenatal MA exposure and adult AMP treatment increased the speed of swimming in female groups greater than in males. Overall, the male subjects showed a better learning ability than females. Thus, our results indicate that the adult AMP treatment affects the cognitive function and behavior of rats in a sex-specific manner, regardless of prenatal exposure. PMID- 24786326 TI - An acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss. AB - Biologic scaffolds composed of naturally occurring extracellular matrix (ECM) can provide a microenvironmental niche that alters the default healing response toward a constructive and functional outcome. The present study showed similarities in the remodeling characteristics of xenogeneic ECM scaffolds when used as a surgical treatment for volumetric muscle loss in both a preclinical rodent model and five male patients. Porcine urinary bladder ECM scaffold implantation was associated with perivascular stem cell mobilization and accumulation within the site of injury, and de novo formation of skeletal muscle cells. The ECM-mediated constructive remodeling was associated with stimulus responsive skeletal muscle in rodents and functional improvement in three of the five human patients. PMID- 24786325 TI - Disease risk factors identified through shared genetic architecture and electronic medical records. AB - Genome-wide association studies have identified genetic variants for thousands of diseases and traits. We evaluated the relationships between specific risk factors (for example, blood cholesterol level) and diseases on the basis of their shared genetic architecture in a comprehensive human disease-single-nucleotide polymorphism association database (VARIMED), analyzing the findings from 8962 published association studies. Similarity between traits and diseases was statistically evaluated on the basis of their association with shared gene variants. We identified 120 disease-trait pairs that were statistically similar, and of these, we tested and validated five previously unknown disease-trait associations by searching electronic medical records (EMRs) from three independent medical centers for evidence of the trait appearing in patients within 1 year of first diagnosis of the disease. We validated that the mean corpuscular volume is elevated before diagnosis of acute lymphoblastic leukemia; both have associated variants in the gene IKZF1. Platelet count is decreased before diagnosis of alcohol dependence; both are associated with variants in the gene C12orf51. Alkaline phosphatase level is elevated in patients with venous thromboembolism; both share variants in ABO. Similarly, we found that prostate specific antigen and serum magnesium levels were altered before the diagnosis of lung cancer and gastric cancer, respectively. Disease-trait associations identify traits that could serve as future prognostics, if validated through EMR and subsequent prospective trials. PMID- 24786328 TI - Olfactory delayed matching to sample performance in mice: sex differences in the 5XFAD mouse model of Alzheimer's disease. AB - While olfactory delayed matching-to-sample tasks have been used to assess working memory in rats, no such tasks have been tested in mice. Olfactory delayed matching-to-sample learning was assessed in male and female 5XFAD mice, a model of Alzheimer's disease, and their wildtype (B6SJL F1) littermates at 6-7 months of age using an operant olfactometer. All 5XFAD and wildtype mice were able to learn the delayed olfactory matching-to-sample task at 2 and 5s delays. Fewer mice learned with a 10s delay and only one mouse learned with a 30s delay. Female mice showed higher levels of performance on the delayed matching-to-sample task than males, indicative of better working memory. These results demonstrate for the first time that mice are able to learn an olfactory delayed matching to sample task. PMID- 24786329 TI - Lasting downregulation of the lipid peroxidation enzymes in the prefrontal cortex of mice susceptible to stress-induced anhedonia. AB - Antioxidant enzymes and lipid peroxidation in the brain are involved in neuropsychiatric pathologies, including depression. 14- or 28-day chronic stress model induced a depressive syndrome defined by lowered reward sensitivity in C57BL/6J mice and changed gene expression of peroxidation enzymes as shown in microarray assays. We studied how susceptibility or resilience to anhedonia is related to lipid peroxidation in the prefrontal cortex (PFC). With 14-day stress, a comparison of the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX) and accumulation of malondialdehyde (MDA) revealed a decrease of the first two measures in susceptible, but not in resilient animals or in stressed mice chronically dosed with imipramine (7mg/kg/day). Acute stress elevated activity of CAT and SOD and dynamics of MDA accumulation in the PFC that was prevented by imipramine (30mg/kg). 28-day stress evoked anhedonia lasting two but not five weeks while behavioural invigoration was detected at the latter time point in anhedonic but not non-anhedonic mice; enhanced aggressive traits were observed in both groups. After two weeks of a stress-free period, CAT and SOD activity levels in the PFC were reduced in anhedonic animals; after five weeks, only CAT was diminished. Thus, in the present chronic stress depression paradigm, lasting alterations in brain peroxidation occur not only during anhedonia but also in the recovery period and are accompanied by behavioural abnormalities in mice. This mimics behavioural and neurochemical deficits observed in depressed patients during remission which could be used to develop remedies preventing their relapse. PMID- 24786330 TI - Gamma-hydroxybutyrate (GHB) induces cognitive deficits and affects GABAB receptors and IGF-1 receptors in male rats. AB - In recent years, the abuse of the club drug gamma-hydroxybutyrate (GHB) has become increasingly popular among adolescents. The drug induces euphoria but can also result in sedation, anaesthesia as well as short-term amnesia. In addition, the abuse of GHB causes cognitive impairments and the mechanism by which GHB induces these impairments is not clarified. The present study investigates the impact of GHB treatment on spatial learning and memory using a water maze (WM) test in rats. Furthermore, the behavioural data is combined with an autoradiographic analysis of the GABAB and the IGF-1 receptor systems. The results demonstrate that the animals administered with GHB display an impaired performance in the WM test as compared to controls. In addition, significant alterations in GABAB and IGF-1 receptor density as well as GABAB receptor functionality, were observed in several brain regions associated with cognitive functions e.g. hippocampus. To conclude, our findings suggest that GHB treatment can affect spatial learning and memory, and that this outcome at least to some extent is likely to involve both GABAB and IGF-1 receptors. PMID- 24786331 TI - Ligation of mouse L4 and L5 spinal nerves produces robust allodynia without major motor function deficit. AB - Spinal nerve L5/L6 ligation (SNL) in rats has become the standard for mechanistic studies of peripheral neuropathy and screening for novel analgesics. Conventional SNL in our hybrid mice resulted in a wide range of allodynia. Anatomical evaluation indicated that a variable number of lumbar vertebrae existed, resulting in L4/L5 or L5/L6 being ligated. Surprisingly, L4/L5 ligation did not result in ipsilateral hind limb paralysis and produced robust allodynia. Following a recent report that the mouse L4 neural segment is homologous with rat L5 we generated L4, L5 or both L4 and L5 (L4/L5) ligations in C57 mice after establishing a modified set of surgical landmarks. In contrast to rats, L4 ligation in these mice did not result in hind limb paralysis. Robust allodynia was observed in all three ligation groups. Nerve degeneration confirmed that L4 and L5, respectively, are primary contributors to the tibial and sural branches of the sciatic nerve in mice. A larger von Frey sensitive area reflected the wider distribution of Wallerian degeneration in the hindlimb of L4- compared to L5-ligated mice. Ligation of mouse L4 and L5 spinal nerves produces consistent, robust neuropathic pain behaviors and is suitable as a model for investigating mechanisms of neuropathic pain and for testing of novel analgesics. Gabapentin, used as a validation drug in neuropathic pain models and as a reference compound for novel analgesics, significantly reduced allodynia in the mice tested (L4/L5 ligations). Given the ease of surgery, robust allodynia, and larger von Frey sensitive area, we conclude that combined ligation of spinal nerves L4 and L5 optimizes the SNL model in mice. PMID- 24786332 TI - Selective modulation of left primary motor cortex excitability after continuous theta burst stimulation to right primary motor cortex and bimanual training. AB - Bimanual movement training (BMT) enhances the excitability of human preparatory premotor and primary motor (M1) cortices. We have shown that activity in M1 is enhanced after BMT involving simultaneous activation of homologous muscles (in phase). Potential neural mechanisms underlying this effect could be input from premotor areas (i.e. dorsal premotor cortex (PMd)) and/or the homologous M1 representation. Recently, we showed that increasing PMd activity using theta burst stimulation (TBS) followed by BMT enhanced the corticospinal excitability of M1 compared to BMT alone. The purpose of this study was to investigate the effects of continuous TBS (cTBS) to right hemisphere M1 (rM1) on the homologous wrist extensor representation in left M1 (lM1), and its potential combined effects when followed by BMT. We used transcranial magnetic stimulation (TMS) to measure cortical excitability of extensor carpi radialis (ECR) representation at multiple time points in three conditions: (1) BMT, (2) cTBS to rM1 or (3) cTBS to rM1 and BMT. The combination of cTBS to rM1 and BMT resulted in an increased shift in the centre of gravity (CoG) compared to either intervention alone, along with an increased muscle topographical representation up to 60 min when cTBS to rM1 was combined with BMT compared to cTBS to rM1 alone. These results suggest that modulation of M1 may reduce ongoing interhemispheric inhibition (or increase facilitation indirectly) to the opposite homologous M1 region in healthy individuals via transcallosal or subcortical connections. Critically, this work may guide rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury. PMID- 24786333 TI - Moderate prenatal alcohol exposure alters behavior and neuroglial parameters in adolescent rats. AB - Alcohol consumption by women during gestation has become increasingly common. Although it is widely accepted that exposure to high doses of ethanol has long lasting detrimental effects on brain development, the case for moderate doses is underappreciated, and benchmark studies have demonstrated structural and behavioral defects associated with moderate prenatal alcohol exposure in humans and animal models. This study aimed to investigate the influence of in utero exposure to moderate levels of ethanol throughout pregnancy on learning/memory, anxiety parameters and neuroglial parameters in adolescent offspring. Female rats were exposed to an experimental protocol throughout gestation up to weaning. After mating, the dams were divided into three groups and treated with only water (control), non-alcoholic beer (vehicle) or 10% (vv) beer solution (moderate prenatal alcohol exposure - MPAE). Adolescent male offspring were subjected to the plus-maze discriminative avoidance task to evaluate learning/memory and anxiety-like behavior. Hippocampi were dissected and slices were obtained for immunoquantification of GFAP, NeuN, S100B and the NMDA receptor. The MPAE group clearly presented anxiolytic-like behavior, even though they had learned how to avoid the aversive arm. S100B protein was increased in the cerebrospinal fluid (CSF) in the group treated with alcohol, and alterations in GFAP expression were also shown. This study indicates that moderate ethanol doses administered during pregnancy could induce anxiolytic-like effects, suggesting an increase in risk taking behavior in adolescent male offspring. Furthermore, the data show the possibility that glial cells are involved in the altered behavior present after prenatal ethanol treatment. PMID- 24786334 TI - The place of birth in Kafa Zone, Ethiopia. AB - In this qualitative study, I used an ethnographic approach to provide an understanding about the place of birth in rural and semiurban Kafa Zone, Ethiopia. I interviewed women about birth at home and asked what would happen if there were serious problems and a woman was taken to a health facility. The development of health services aimed at reducing maternal mortality implies that the place of birth must change from home to health facility, but the distance from international policy to its implementation is vast and the pathway is not a direct, linear route. PMID- 24786336 TI - Ethical management in the constitution of a European database for leukodystrophies rare diseases. AB - BACKGROUND: The EU LeukoTreat program aims to connect, enlarge and improve existing national databases for leukodystrophies (LDs) and other genetic diseases affecting the white matter of the brain. Ethical issues have been placed high on the agenda by pairing the participating LD expert research teams with experts in medical ethics and LD patient families and associations. The overarching goal is to apply core ethics principles to specific project needs and ensure patient rights and protection in research addressing the context of these rare diseases. AIM: This paper looks at how ethical issues were identified and handled at project management level when setting up an ethics committee. METHODS: Through a work performed as a co-construction between health professionals, ethics experts, and patient representatives, we expose the major ethical issues identified. RESULTS: The committee acts as the forum for tackling specific issues tied to data sharing and patient participation: the thin line between care and research, the need for a charter establishing the commitments binding health professionals and the information items to be delivered. Ongoing feedback on the database, including delivering global results in a broad-audience format, emerged as a key recommendation. Information should be available to all patients in the partner countries developing the database and should be scaled to different patient profiles. CONCLUSION: This work led to a number of recommendations for ensuring transparency and optimizing the partnership between scientists and patients. PMID- 24786337 TI - Metal-organic framework@microporous organic network: hydrophobic adsorbents with a crystalline inner porosity. AB - This work reports the synthesis and application of metal-organic framework (MOF)@microporous organic network (MON) hybrid materials. Coating a MOF, UiO-66 NH2, with MONs forms hybrid microporous materials with hydrophobic surfaces. The original UiO-66-NH2 shows good wettability in water. In comparison, the MOF@MON hybrid materials float on water and show excellent performance for adsorption of a model organic compound, toluene, in water. Chemical etching of the MOF results in the formation of hollow MON materials. PMID- 24786335 TI - Gene sequences regulating the production of apoE and cerebral palsy of variable severity. AB - BACKGROUND: The apoE protein is the most important lipid transporter in the brain and has also been shown to have several regulatory functions in the central nervous system. The production of apoE is regulated by a number of genes and increases under certain conditions such as cerebral injury in adults. AIMS: Our aim was to study whether variations in genes regulating the expression of the APOE gene were associated with severity of cerebral palsy (CP). METHODS: Children enrolled in the Cerebral Palsy Register of Norway (CPRN) were invited to participate in this cross-sectional study; 281 of the invited 703 children (40%) returned swabs with buccal cells collected by parents. Six genetic variations thought to affect the production of apoE were genotyped and correlated with clinical data recorded in the CPRN. RESULTS: Compared with children carrying the GG allele, children with genotype GT or TT in a specific genetic variation (rs59007384 located in the nearby TOMM40 gene) had excess risk for worse fine motor function (Odds ratio (OR): 1.82; 95% Confidence interval (CI): 1.10-2.99; p = 0.019) and epilepsy (OR: 2.32; CI: 1.17-4.61; p = 0.016). There was no association between severity of CP and any of the other five genetic variations analyzed. CONCLUSION: Our findings suggest that genetic variations in one of the sequences regulating the expression of APOE, may be associated with worse clinical outcome in children with cerebral palsy. PMID- 24786338 TI - From shadow to light: visualization of extrahepatic bile ducts using image enhanced laparoscopy. AB - BACKGROUND: Correct recognition of the extrahepatic bile ducts is thought to be crucial to reduce the risk of bile duct injuries during various laparoscopic procedures. Image-enhanced laparoscopy techniques, utilizing various optical modalities other than white light, may help in detecting structures "hidden" underneath connective tissue. METHODS: A systematic literature search was conducted of studies describing image-enhanced laparoscopy techniques for visualization of the extrahepatic bile ducts. RESULTS: In all, 29 articles met inclusion criteria. They describe various techniques in the animal or human setting, including autofluorescence imaging, drug-enhanced fluorescence imaging, infrared thermography, and spectral imaging. This review describes these various techniques and their results. CONCLUSION: Image-enhanced laparoscopy techniques for real-time visualization of extrahepatic bile ducts are still in its infancy. Out of the techniques currently described, indocyanine green-enhanced near infrared fluorescence laparoscopy has the most mature results, but other techniques also appear promising. It can be expected that in the future, image enhanced laparoscopy might become a routine adjunct to any white-light laparoscopic operation near the hepatic hilum. PMID- 24786340 TI - Deployed research. AB - The Role 3 Medical Treatment Facility (Field Hospital) in Camp Bastion (R3 Bastion) is acknowledged to be one of the busiest dedicated trauma facilities in the world. Casualties typically present with severe injuries and in physiological extremis. These casualties form a unique cohort representing the most relevant population to evaluate the effectiveness of treating battlefield injuries as academic clinicians and scientists interested in trauma seek to improve outcomes for such patients in the future. This article describes four separate but related research projects that have been undertaken in Camp Bastion, Afghanistan, over the last year. They traverse the spectrum of clinical research, ranging from data collection to a randomised control trial. The aim is to discuss some of the problems encountered and the solutions that made it possible to undertake research in a theatre of operations, thereby providing a starting point for others who may wish to initiate research in a similar environment. PMID- 24786341 TI - Comparative study of total hydroperoxides and antioxidant defense system in the Indian tropical tasar silkworm, Antheraea mylitta, in diapausing and non diapausing generations. AB - In the present study, the total hydroperoxides, catalase, glutathione-s transferase, and ascorbic acid contents were determined in different developmental stages of the non-diapause and the diapause generation of the tropical tasar silkworm, Antheraea mylitta Drury (Lepidoptera: Saturniidae). The results showed stage-specific significantly higher levels of total hydroperoxides, catalase, and ascorbic acid contents in the non-diapause as compared to the diapause generation (p < 0.05). However, a significantly enhanced level of glutathione-S-transferase activity was observed in mature 5th instar larvae of the diapause generation (p < 0.05). In the case of pupae, significantly higher levels of total hydroperoxides, catalase, and glutathione-s-transferase activity were observed in the non-diapause generation (p < 0.05). These results could be the effect of intensive metabolic transformation that takes place in tissues of the non-diapause generation and causes increased production of reactive oxygen species, such as hydroperoxides. The results suggest that antioxidants play an important role in protecting cells against reactive oxygen species. PMID- 24786342 TI - Activating the antimicrobial activity of an anionic singlet-oxygen sensitizer through surfactant complexation. AB - Cationic oligo-p-phenylene ethynylenes have shown much promise as broad-spectrum light-activated antimicrobial compounds against both Gram-positive and Gram negative bacteria. The anionic varieties, however, have weak biocidal activity. In this study, a complex is formed between a weakly biocidal anionic oligomer and a cationic surfactant, and the effects on their biocidal activity against Gram negative E. coli and Gram-positive S. aureus are explored. The enhancement in biocidal activity that is observed when the complex is irradiated suggests that interfacial surfactant gives the complex a net-positive charge, allowing it to associate strongly with the bacterial membrane. The results of this study demonstrate a method for the enhancement of biocidal activity of singlet-oxygen sensitizers and corroborate the use of surfactants as trans-membrane drug delivery agents. PMID- 24786343 TI - Radiopacity, pH and antimicrobial activity of Portland cement associated with micro- and nanoparticles of zirconium oxide and niobium oxide. AB - The aim of this study was to evaluate some properties of the calcium silicate materials Mineral Trioxide Aggregate (MTA) and Portland cement (PC) with microparticulated (micro) and nanoparticulated (nano) zirconium oxide (ZrO2) or niobium oxide (Nb2O5). The experimental materials: White PC (PC), MTA Angelus((r)) (MTA), PC+ZrO2micro, PC+ZrO2nano, PC+Nb2O5micro and PC+Nb2O5nano were submitted to radiopacity and pH evaluations. Furthermore, the antimicrobial activity against different microorganisms was assessed by agar diffusion test. MTA presented higher radiopacity than other materials. However, all materials except PC presented higher radiopacity than recommended by ISO/ADA. MTA promoted higher pH values in all analyzed periods (p<=0.05). At the initial periods, PC and PC+ZrO2micro showed pH similar to MTA. All materials showed antimicrobial activity against the evaluated microorganisms. In conclusion, ZrO2 and Nb2O5 could be alternative radiopacifiers to be added to calcium silicate materials. PMID- 24786344 TI - Inhibitory effect of Ti-Ag alloy on artificial biofilm formation. AB - Titanium-silver (Ti-Ag) alloy has been improved for machinability and mechanical properties, but its anti-biofilm properties have not been elucidated yet. Thus, this study aimed to evaluate the effects of Ti-Ag alloy on biofilm formation and bacterial viability in comparison with pure Ti, pure Ag and silver-palladium (Ag Pd) alloy. Biofilm formation on the metal plates was evaluated by growing Streptococcus mutans and Streptococcus sobrinus in the presence of metal plates. Bactericidal activity was evaluated using a film contact method. There were no significant differences in biofilm formation between pure Ti, pure Ag and Ag-Pd alloy, while biofilm amounts on Ti-20% Ag and Ti-25% Ag alloys were significantly lower (p<0.05). In addition, Ti-Ag alloys and pure Ti were not bactericidal, although pure Ag and Ag-Pd alloy killed bacteria. These results suggest that Ti 20% Ag and Ti-25% Ag alloys are suitable for dental material that suppresses biofilm formation without disturbing healthy oral microflora. PMID- 24786345 TI - A new method for fabricating zirconia copings using a Nd:YVO4 nanosecond laser. AB - The purpose of this work was to fabricate zirconia copings from fully sintered Y TZP blocks using a Nd:YVO4 nanosecond laser in order to avoid complicated procedures using conventional CAD/CAM systems. To determine the most appropriate power level of a Nd:YVO4 laser, cuboid fully sintered Y-TZP specimens were irradiated at six different average power levels. One-way ANOVAs for the average surface roughness and laser machining depth revealed that an average power level of 7.5 W generated a smooth machined surface with high machining efficiency. Y TZP copings were then machined using the proposed method with the most appropriate power level. As the number of machining iterations increased, the convergence angles decreased significantly (p<0.01). The accuracy of the machined copings was judged to be good based on 3D measurements and traditional metal die methods. The proposed method using the nanosecond laser was demonstrated to be useful for fabricating copings from fully sintered Y-TZP. PMID- 24786346 TI - Three-dimensional finite element analysis of Aramany Class IV obturator prosthesis with different clasp designs. AB - The purpose of this study was to evaluate the stress distribution on the alveolar bone surrounding abutment teeth and the displacement of the Aramany Class IV obturator prosthesis with two different clasp designs. Three-dimensional finite element models of an Aramany Class IV maxillary defect were constructed. Two different clasp designs on an obturator prosthesis (double Akers clasps and multiple Roach clasps) and two different load conditions (vertical and horizontal) were compared. Finite element analysis was used to calculate the equivalent stress. The difference in the clasp design of the Aramany Class IV obturator prosthesis affected the stress distribution of the alveolar bone surrounding the abutment teeth and the displacement of the obturator prosthesis. Multiple Roach clasps reduced the stress distribution on the alveolar bone surrounding the abutment teeth and the displacement of the Aramany Class IV obturator prosthesis compared to double Akers clasps. PMID- 24786347 TI - Interfacial adhesion of zirconia/veneer bilayers with different thermal characteristics. AB - The aim of this study was to investigate how changes in the thermal characteristics of veneer ceramics with almost identical chemical and mechanical properties but with different coefficients of thermal expansion (CTE) can modify their interfacial adhesion to zirconia. 48 bilayers made of one Y-TZP ceramic and four veneer ceramics were fabricated (n=12). Thermal residual stresses were calculated on the basis of the CTE and glass transition temperatures. After defined notching all specimens were loaded in a four-point bending test and the critical loads were recorded which induced stable crack extension at the adhesion interface. The strain energy release rate (G, J/m(2)) was calculated and was taken as a measure of interfacial adhesion. The CTE of the veneer ceramics were significantly correlated with their adhesion to Y-TZP (p<0.001). Interfacial adhesion in zirconia/veneer bilayers is predominantly affected by the thermal characteristics of the veneer ceramic. PMID- 24786348 TI - Evaluation of torque moment in a novel elastic bendable orthodontic wire. AB - The objective of the study was to measure the torque moment delivered by a novel elastic bendable wire, Ti-Nb wire, and to compare it with nickel-titanium (Ni-Ti) and titanium-molybdenum (Ti-Mo) alloy wires. Two sizes of Ti-Nb, Ni-Ti and Ti-Mo alloy wires and 0.022-inch slot stainless steel brackets were ligated with elastic modules or ligature wires. The torque moment delivered by the various wire-bracket combinations was measured using a torque gauge at the temperature and humidity of 37 degrees C and 50%, respectively. As the degree of applied torque and the inserted wire size increased, the torque moment gradually increased. The torque moment of Ti-Nb wires was smaller than those of Ni-Ti wires and Ti-Mo wires, at more than 20 degrees applied torque. The torque moment with wire ligation was significantly larger than those with elastic ligation. PMID- 24786349 TI - Effect of EDTA solution on corrosion fatigue of Ni-Ti files with different shapes. AB - This study aimed to evaluate the effect of EDTA solutions (3% and 10% EDTA*2Na) on corrosion fatigue of three Ni-Ti files with different shapes, in comparison with other solutions (6% NaClO, 3% H2O2, 0.9% NaCl and distilled water). Ni-Ti files were subjected to rotational bending in a bent glass tube (30 degrees and 60 degrees angles) filled with the solutions, and the number of rotations to failure was counted. At 30 degrees bent angle, files in the two EDTA solutions showed significantly lower resistance than those in distilled water, but no significant difference was found between the two EDTA solutions. Fatigue resistance of two tested files in the two EDTA solutions was not significantly different from those in the other three solutions, whereas one file in EDTA solutions showed significantly lower resistance than that in 3% H2O2. At 60 degrees bent angle, early failure within 1-2.5 min was observed for all tested files, and no significant difference was found among the six solutions. At both angles, significant differences in fatigue resistance were observed among the three tested files, which could be related to the difference in the cross sectional shapes of the files. PMID- 24786350 TI - Measurement of the remaining dentin thickness using optical coherence tomography for crown preparation. AB - This study aimed to investigate the maximum depth imaging and optical properties of the dentin near the pulp by using optical coherence tomography (OCT) and to explore the possibility of measuring the remaining dentin thickness (RDT). Human third molars were used. In experiment 1, the cuspal dentin blocks (0.50-mm to 1.75-mm thickness) were prepared. Each specimen was scanned using OCT. OCT images could be obtained for all specimens with 1.00-mm or less thicknesses. In experiment 2, dentin-pulp complex slices (0.50-mm and 1.00-mm RDT) were prepared. Each specimen was scanned using OCT and micro-computed tomography, and compared. The resulting length change rates of OCT images for the 0.50-mm RDTs were significantly lower than those of the 1.00-mm RDTs. Within the limitations of this study, OCT was effective for measuring the 1.00-mm or less RDT and preventing pulpal injury, while considering the length change rate of OCT image as a variable. PMID- 24786351 TI - Influence of post and core materials on distortion around 4-unit zirconia bridge margins. AB - The purpose of this study was to evaluate the surface strain of zirconia fixed partial denture frameworks and their abutment roots when restored with two types of post and core materials. Artificial mandibular first premolars and second molars were used as the abutment teeth. Posts and cores were of two types: resin composite with glass fiber posts (RC) and cast platinum gold alloy (MC). The cores and 4-unit zirconia frameworks were bonded to the specimens. Static loading was applied to the occlusal surfaces, and the surface strain of the frameworks and roots (distal premolar and mesial molar) was measured by strain gauge method. Premolar root showed a significantly higher magnitude of principal strain than molar root. RC showed a significantly higher magnitude of principal strain than MC. The results suggest that MC restrain the surface strain compared to RC when the missing teeth are replaced by a 4-unit zirconia framework. PMID- 24786352 TI - Cultural measures associated with sexual risk behaviors among Latino youth in Southern California: a longitudinal study. AB - CONTEXT: Cultural variables have been associated with sexual risk behaviors among Latino youth, but findings across studies are inconsistent. METHODS: A longitudinal study of acculturation patterns followed Latino youth in Southern California from 2005 to 2012. Data from 995 participants were used in logistic and ordered regression analyses to test whether cultural variables measured in high school were associated with sexual risk behaviors in emerging adulthood, and whether gender moderated these associations. RESULTS: The cultural value of respect for parents was negatively associated with participants' odds of reporting an earlier age at sexual debut (odds ratio, 0.8) and condom nonuse at most recent sexual intercourse (0.8). A measure of acculturation reflecting U.S. cultural practices was positively associated with the likelihood of being sexually experienced (1.2), having concurrent sexual partners (1.5) and, among males only, having a greater number of sexual partners (1.3). Second- and later generation immigrant youth had lower odds of not using a condom at most recent sexual intercourse than first-generation youth (0.6 and 0.5, respectively). Strength of endorsement of Latino cultural practices was negatively associated with females' lifetime number of partners (0.8), but positively associated with males' (1.4). CONCLUSIONS: The cultural measures associated with Latino youths' sexual behaviors differed across outcomes and by gender. Further understanding of these associations and their underlying mechanisms may help inform the development of culturally sensitive sexual health interventions. PMID- 24786353 TI - Liberibacter crescens gen. nov., sp. nov., the first cultured member of the genus Liberibacter. AB - The Gram-stain-negative, rod-shaped bacterial isolate BT-1(T) is the closest relative to the genus 'Candidatus Liberibacter' cultured to date. BT-1(T) was recovered from the phloem sap of a defoliating mountain papaya in Puerto Rico. The BT-1(T) 16S rRNA gene sequence showed that strain BT-1(T) is most closely related to members of the genus 'Ca. Liberibacter' sharing 94.7% 16S rRNA gene sequence similarity with 'Ca. Liberibacter americanus' and 'Ca. Liberibacter asiaticus'. Additionally, average nucleotide identity, 16S rRNA gene sequences and conserved protein sequences supported inclusion of the previously described species of the genus 'Ca. Liberibacter' in a genus with BT-1(T). The prominent fatty acids of isolate BT-1(T) were C18 : 1omega7c (77.2%), C16 : 0 OH (4.8%), C18 : 0 (4.4%) and C16 : 0 (3.5%). Both physiological and genomic characteristics support the creation of the genus Liberibacter, as well as the novel species Liberibacter crescens gen. nov., sp. nov. with type strain BT-1(T) ( = ATCC BAA 2481(T) = DSM 26877(T)). PMID- 24786354 TI - Rhizobium lemnae sp. nov., a bacterial endophyte of Lemna aequinoctialis. AB - Bacterial strain L6-16(T) was isolated from Lemna aequinoctialis. Cells were Gram stain-negative, rod-shaped and motile with monopolar flagella. The phylogenetic analysis of its nearly complete 16S rRNA gene sequence revealed that strain L6 16(T) was a member of the genus Rhizobium. Its closest relative was Rhizobium tarimense PL-41(T) with a 16S rRNA gene sequence similarity value of 98.3%. Sequence similarity analysis of the housekeeping recA and atpD genes showed low levels of sequence similarity (<93.9%) between strain L6-16(T) and other species of the genus Rhizobium. Strain L6-16(T) was able to grow between pH 5 and 11 (optimum 7.0) and at temperatures ranging from 20 to 41 degrees C (optimum 30 degrees C). It tolerated NaCl up to 1 % (w/v) (optimum 0.5%). C18 : 1omega7c and/or C18 : 1omega6c (summed feature 8; 79.5%) were found as predominant cellular fatty acids. The DNA G+C content of strain L6-16(T) was 58.1 mol% (Tm). Based on low levels of DNA-DNA relatedness, strain L6-16(T) was distinct from members of phylogenetically related species including R. tarimense PL-41(T) (38.3 +/- 0.8%), Rhizobium rosettiformans W3(T) (6.9 +/- 0.4%) and Rhizobium pseudoryzae J3-A127(T) (12.3 +/- 0.6 %). Strain L6-16(T) was unable to nodulate the roots of Phaseolus vulgaris, and nodC and nifH genes were not detected. The results obtained from phylogenetic analyses, phenotypic characterization and DNA DNA hybridization indicated that strain L6-16(T) represents a novel species of the genus Rhizobium, for which the name Rhizobium lemnae sp. nov. is proposed. The type strain is L6-16(T) ( = NBRC 109339(T) = BCC 55143(T)). PMID- 24786355 TI - Contrasting the ethical perspectives of biospecimen research among individuals with familial risk for hereditary cancer and biomedical researchers: implications for researcher training. AB - While ethical concerns about participating in biospecimen research have been previously identified, few studies have reported the concerns among individuals with familial risk for hereditary cancer (IFRs). At the same time, biomedical researchers often lack training in discussing such concerns to potential donors. This study explores IFRs' and biomedical researchers' perceptions of ethical concerns about participating in biobanking research. In separate focus groups, IFRs and biomedical researchers participated in 90-min telephone focus groups. Focus group questions centered on knowledge about laws that protect the confidentiality of biospecimen donors, understanding of informed consent and study procedures, and preferences for being recontacted about potential incidental discovery and also study results. A total of 40 IFRs and 32 biomedical researchers participated in the focus groups. Results demonstrated discrepancies between the perceptions of IFRs and researchers. IFRs' concerns centered on health information protection; potential discrimination by insurers and employers; and preferences for being recontacted upon discovery of gene mutations or to communicate study results. Researchers perceived that participants understood laws protecting donors' privacy and (detailed study information outlined in the informed consent process), study outcomes were used to create a training tool kit to increase researchers' understanding of IFRs' concerns about biobanking. PMID- 24786356 TI - Efficacy, safety, tolerability, and pharmacokinetic profile of evacetrapib administered as monotherapy or in combination with atorvastatin in Japanese patients with dyslipidemia. AB - The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia. PMID- 24786357 TI - Comparison of frequency of radial artery occlusion after 4Fr versus 6Fr transradial coronary intervention (from the Novel Angioplasty USIng Coronary Accessor Trial). AB - The frequency of radial artery occlusion was compared between patients receiving 4Fr versus 6Fr transradial coronary interventions (TRIs) in an open-label randomized trial (ClinicalTrials.gov identifier: NCT00815997). The primary outcome measure was radial artery occlusion on the day after TRI. The secondary outcome measures were the procedural success, major advanced cardiac events, access site-related complications, procedural times, fluoroscopy times, and contrast dye usage. A total of 160 patients were included. The procedure was successful in 79 of 80 patients (99%) in both groups. Whereas the 4Fr group showed no access site-related complications, the 6Fr developed 5 (6%), including 3 radial artery occlusions and 2 bleedings (1 radial artery perforation and 1 massive hematoma; p = 0.02). Although the radial artery occlusion rate was lower in the 4Fr versus the 6Fr groups, the difference was not significant (0% vs 4%, p = 0.08). The mean hemostasis time was significantly shorter in the 4Fr than in the 6Fr groups (237 +/- 105 vs 320 +/- 238 minutes, p = 0.007). In conclusion, these findings suggest that 4Fr TRI may become a less invasive alternative to 6Fr TRI in treating coronary artery diseases. PMID- 24786358 TI - Usefulness of tissue Doppler imaging to evaluate pulmonary capillary wedge pressure during exercise in patients with reduced left ventricular ejection fraction. AB - The early diastolic transmitral velocity/tissue Doppler imaging mitral annular early diastolic velocity (E/e') ratio is used to estimate left ventricular (LV) filling pressures at rest. However, there are only limited data that validate its use during exercise. Accordingly, the aim of this study was to test the ability of E/e' to estimate pulmonary capillary wedge pressure (PCWP) during symptom limited exercise in patients with LV systolic dysfunction. Forty patients with severe LV dysfunction and heart failure symptoms (54 +/- 12 years, 28 men) underwent simultaneous Doppler assessment of E/e' and right-sided cardiac catheterization at rest and during a symptom-limited exercise test, at steady state levels of 30%, 60%, and 90% of their maximal exercise capacity. During exercise, all 40 patients successfully completed stage 1, yielding 40 pairs of data for comparison. Eighteen patients also successfully completed stage 2, and 5 patients also made it through stage 3, yielding 23 additional data pairs. In total, there were thus 63 pairs of data available during exercise. With exercise, heart rate increased from 77 +/- 14 to 112 +/- 21 beats/min. Septal E/e' at rest correlated well with PCWP at rest (r = 0.75, p <0.01). PCWP at rest also correlated with resting mitral deceleration time (r = 0.32, p <0.01) and with the transmitral E/A ratio (r = 0.74, p <0.01). During exercise, the correlation between septal E/e' and PCWP was weaker (r = 0.57, p <0.01) and was shifted to the right. This rightward shift was observed in patients with both separated or merged E and A velocities. In conclusion, in patients with severe LV dysfunction, although E/e' allows accurate estimation of PCWP at rest, it appears less reliable for estimating LV filing pressure during exercise. PMID- 24786359 TI - The intriguing ultrastructure of lipid body organelles within activated macrophages. AB - Macrophages are widely distributed immune system cells with essential functions in tissue homeostasis, apoptotic cell clearance, and first defense in infections. A distinguishing feature of activated macrophages participating in different situations such as inflammatory and metabolic diseases is the presence of increased numbers of lipid-rich organelles, termed lipid bodies (LBs) or lipid droplets, in their cytoplasm. LBs are considered structural markers of activated macrophages and are involved in different functions such as lipid metabolism, intracellular trafficking, and synthesis of inflammatory mediators. In this review, we revisit the distinct morphology of LB organelles actively formed within macrophages in response to infections and cell clearance, taking into account new insights provided by ultrastructural studies. We also discuss the LB interactions within macrophages, revealed by transmission electron microscopy, with a focus on the remarkable LB-phagosome association and discuss potential links between structural aspects and function. PMID- 24786360 TI - An examination of obsessive-compulsive symptoms and dimensions using profile analysis via multidimensional scaling (PAMS). AB - Contemporary cognitive models of obsessive-compulsive disorder (OCD) emphasize the importance of various types of dysfunctional beliefs in contributing to OC symptoms, such as beliefs about excessive personal responsibility, perfectionism, and intolerance for uncertainty. The present study seeks to further our understanding of the role of these beliefs by identifying the common profiles of such beliefs, using profile analysis via multidimensional scaling (PAMS). In Study 1, a large student sample (N=4079) completed the 44-item obsessive beliefs questionnaire. One major profile, control of thoughts and perfectionism, was extracted. Study 2 examined profiles of the 87-item obsessive beliefs questionnaire in people with obsessive-compulsive disorder (OCD; n=398), other anxiety disorders (n=104), and a sample of undergraduate students (n=285). Inflated responsibility was a prominent subscale in the profiles of all three groups. Only control over thoughts was a unique subscale in the profile obtained for the OCD group, with this group having lower scores compared to the other groups. The results suggest that while inflated responsibility is a significant subscale in the profile of individuals with OCD, it is not a unique contributor; instead, control over thoughts is unique to OCD. The data, as well as recent research investigating obsessive beliefs, suggest the need to revise the contemporary cognitive model of OCD. PMID- 24786361 TI - Changes in trauma-potentiated startle with treatment of posttraumatic stress disorder in combat Veterans. AB - Emotional Processing Theory proposes that habituation to trauma-related stimuli is an essential component of PTSD treatment. However, the mechanisms underlying treatment-related habituation are not well understood. We examined one psychophysiological measure that holds potential for elucidating the biological processes involved in treatment response: trauma-potentiated startle response. Seventeen OEF/OIF combat Veterans participated in the study and completed three assessments using a trauma-potentiated startle paradigm over PTSD treatment. Results revealed different patterns of trauma-potentiated startle across treatment for responders and nonresponders, but no differences in within task habituation. Responders showed an increase followed by a decrease in trauma potentiated startle, whereas nonresponders showed a relatively flat response profile. Results suggested that PTSD patients who engage with emotional content as demonstrated by greater startle reactivity may be more likely to respond to PTSD treatment. Furthermore, trauma-potentiated startle shows promise as an objective measure of psychophysiological responses involved in PTSD recovery. PMID- 24786362 TI - Subcellular localization and transport kinetics of ruthenium organometallic anticancer compounds in living cells: a dose-dependent role for amino acid and iron transporters. AB - Ruthenium-based compounds are developed for anticancer treatment, but their mode of action including their import mechanism and subcellular localization remains elusive. Here, we used the intrinsic luminescent properties of cytotoxic organoruthenium (Ru(II)) compounds obtained with an anionic cyclometalated 2 phenylpyridine chelate and neutral aromatic chelating ligands (e.g., phenanthrolines) to follow their behavior in living cells. We established that the difference in sensitivity between cancer cells and noncancerous cells toward one of the compounds correlates with its import kinetics and follows a balance between active and passive transport. The active-transport mechanism involves iron and amino-acid transporters, which are transcriptionally regulated by the drug. We also demonstrated a correlation between the accumulation of these compounds in specific compartments (endoplasmic reticulum, nucleus, mitochondria) and the activation of specific cytotoxic mechanisms such as the mitochondrial stress pathway. Our study pinpoints a novel and complex mechanism of accumulation of ruthenium drugs in cancer cells. PMID- 24786363 TI - An in vitro comparison of irrigation using photon-initiated photoacoustic streaming, ultrasonic, sonic and needle techniques in removing calcium hydroxide. AB - AIM: To evaluate the effect of various techniques including photon-initiated photoacoustic streaming (PIPS), ultrasonic, sonic and needle irrigation on the removal of calcium hydroxide [Ca(OH)2 ] from artificial grooves created in root canals. METHODS: The root canals of 48 extracted single-rooted teeth with straight canals were prepared using ProTaper rotary instruments up to size 40. After the specimens had been split longitudinally, a standardized groove was prepared in the apical part of one segment that was filled with Ca(OH)2 powder mixed with distilled water. Each tooth was reassembled and the apices closed with wax. The specimens were irrigated for 60 s with one of the following techniques: needle irrigation using 17% EDTA, PIPS with 17% EDTA, ultrasonic irrigation using 17% EDTA and sonic irrigation (EndoActivator) using 17% EDTA. The root segments were then disassembled, and the amount of remaining Ca(OH)2 evaluated under a stereomicroscope at 25* magnification. A pixel count of Ca(OH)2 remaining on the artificially created grooves was recorded as a percentage of the overall groove surface. The data were evaluated statistically using one-way analysis of variance and the least significant difference post hoc tests at 95% confidence level (P = 0.05). RESULTS: Photon-initiated photoacoustic streaming was superior in removing Ca(OH)2 as compared to needle irrigation (P < 0.001), sonic irrigation (P < 0.001) and ultrasonic irrigation (P = 0.046). CONCLUSION: Photon-initiated photoacoustic streaming provided complete removal of Ca(OH)2 from artificial grooves in straight root canals. Ultrasonic irrigation enhanced the Ca(OH)2 removal capacity of irrigating solution but did not provide complete removal from artificial grooves. PMID- 24786364 TI - Cerebrospinal fluid inflammatory cytokines and chemokines in naturally occurring canine spinal cord injury. AB - Canine intervertebral disk herniation (IVDH) is a common, naturally occurring form of spinal cord injury (SCI) that is increasingly being used in pre-clinical evaluation of therapies. Although IVDH bears critical similarities to human SCI with respect to lesion morphology, imaging features, and post-SCI treatment, limited data are available concerning secondary injury mechanisms. Here, we characterized cerebrospinal fluid (CSF) cytokines, and chemokines in dogs with acute, surgically treated, thoracolumbar IVDH (n=39) and healthy control dogs (n=21) to investigate early inflammatory events after SCI. A bioplex system was used to measure interleukin (IL)-2, -6, -7, -8, -10, -15, and -18, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), keratinocyte chemoattractant (KC)-like protein, IFN-gamma-inducible protein-10, monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor alpha. Cytokine and chemokine concentrations in the CSF of healthy and SCI dogs were compared and, in SCI dogs, were correlated to the duration of SCI, behavioral measures of injury severity at the time of sampling, and neurological outcome 42 days post SCI as determined by a validated ordinal score. IL-8 concentration was significantly higher in SCI cases than healthy controls (p=0.0013) and was negatively correlated with the duration of SCI (p=0.042). CSF MCP-1 and KC-like protein were positively correlated with CSF microprotein concentration in dogs with SCI (p<0.0001 and p=0.004). CSF MCP-1 concentration was negatively associated with 42-day postinjury outcome (p<0.0001). Taken together, these data indicate that cytokines and chemokines present after SCI in humans and rodent models are associated with SCI pathogenesis in canine IVDH. PMID- 24786366 TI - Coaxial wet-spun yarn supercapacitors for high-energy density and safe wearable electronics. AB - Yarn supercapacitors have great potential in future portable and wearable electronics because of their tiny volume, flexibility and weavability. However, low-energy density limits their development in the area of wearable high-energy density devices. How to enhance their energy densities while retaining their high power densities is a critical challenge for yarn supercapacitor development. Here we propose a coaxial wet-spinning assembly approach to continuously spin polyelectrolyte-wrapped graphene/carbon nanotube core-sheath fibres, which are used directly as safe electrodes to assembly two-ply yarn supercapacitors. The yarn supercapacitors using liquid and solid electrolytes show ultra-high capacitances of 269 and 177 mF cm(-2) and energy densities of 5.91 and 3.84 MUWh cm(-2), respectively. A cloth supercapacitor superior to commercial capacitor is further interwoven from two individual 40-cm-long coaxial fibres. The combination of scalable coaxial wet-spinning technology and excellent performance of yarn supercapacitors paves the way to wearable and safe electronics. PMID- 24786367 TI - Advances in point-of-care ultrasound in pediatric emergency medicine. AB - PURPOSE OF REVIEW: Point-of-care ultrasound (POCUS) has become an integral part of emergency medicine practice. Research evaluating POCUS in the care of pediatric patients has improved the understanding of its potential role in clinical care. RECENT FINDINGS: Recent work has investigated the ability of pediatric emergency medicine (PEM) physicians to perform a wide array of diagnostic and procedural applications in POCUS ultrasound. Studies have demonstrated that PEM providers are able to identify an array of diseases, including intussusception, pyloric stenosis and appendicitis. Novel applications of ultrasound, such as a cardiac evaluation in the acutely ill patient or identification of skull fractures in the assessment of a patient with head injury, have shown excellent promise in recent studies. These novel applications have the potential to reshape pediatric diagnostic algorithms. SUMMARY: Key applications in PEM have been investigated in the recent publications. Further exploration of the ability to integrate ultrasound into routine practice will require larger-scale studies and continued growth of education in the field. The use of ultrasound in clinical practice has the potential to improve safety and efficiency of care in the pediatric emergency department. PMID- 24786368 TI - Nuking the radiation: minimizing radiation exposure in the evaluation of pediatric blunt trauma. AB - PURPOSE OF REVIEW: Our objective is to highlight recent literature investigating low-radiation diagnostic strategies in the evaluation of pediatric trauma. RECENT FINDINGS: In the area of minor head injury, research has focused on implementation of validated clinical decision rules into practice to reduce unnecessary computed tomography scans. Clinical observation may also serve as an adjunct to initial assessment and a potential substitute for computed tomography imaging. Subgroups of children with special needs or severe injury mechanisms may also be safely characterized by the clinical decision rule and spared radiation exposure. Physical examination techniques may be useful in diagnosing mandibular fractures. In addition, evidence suggests that plain radiography for evaluation of blunt thoracic trauma may be sufficient in many cases, and computed tomography could be reserved for those with abnormal radiographs, high-risk mechanisms, or abnormal physical findings. Clinical decision rules are able to predict intra abdominal injury with high sensitivity. Data suggest that skeletal surveys may be modified to limit radiation exposure in the case of suspected nonaccidental trauma. SUMMARY: More research is needed in development of pediatric-specific clinical decision rules and risk stratification and in testing low-radiation diagnostic modalities in the pediatric trauma population. PMID- 24786365 TI - Galectin-9 is rapidly released during acute HIV-1 infection and remains sustained at high levels despite viral suppression even in elite controllers. AB - Galectin-9 (Gal-9) is a beta-galactosidase-binding lectin that promotes apoptosis, tissue inflammation, and T cell immune exhaustion, and alters HIV infection in part through engagement with the T cell immunoglobulin mucin domain 3 (Tim-3) receptor and protein disulfide isomerases (PDI). Gal-9 was initially thought to be an eosinophil attractant, but is now known to mediate multiple complex signaling events that affect T cells in both an immunosuppressive and inflammatory manner. To understand the kinetics of circulating Gal-9 levels during HIV infection we measured Gal-9 in plasma during HIV acquisition, in subjects with chronic HIV infection with differing virus control, and in uninfected individuals. During acute HIV infection, circulating Gal-9 was detected as early as 5 days after quantifiable HIV RNA and tracked plasma levels of interleukin (IL)-10, tumor necrosis factor (TNF)-alpha, and IL-1beta. In chronic HIV infection, Gal-9 levels positively correlated with plasma HIV RNA levels (r=0.29; p=0.023), and remained significantly elevated during suppressive antiretroviral therapy (median: 225.3 pg/ml) and in elite controllers (263.3 pg/ml) compared to age-matched HIV-uninfected controls (54 pg/ml). Our findings identify Gal-9 as a novel component of the first wave of the cytokine storm in acute HIV infection that is sustained at elevated levels in virally suppressed subjects and suggest that Gal-9:Tim-3 crosstalk remains active in elite controllers and antiretroviral (ARV)-suppressed subjects, potentially contributing to ongoing inflammation and persistent T cell dysfunction. PMID- 24786369 TI - Child maltreatment: a review of key literature in 2013. AB - PURPOSES OF REVIEW: This review summarizes new findings in the field of maltreatment, addressing epidemiology, physical abuse, abusive head trauma, sexual abuse, sequelae, and prevention. RECENT FINDINGS: Many articles this year focus on establishing a framework for thinking about how to evaluate a child for maltreatment, the consequences of maltreatment, and the current understanding of prevention efforts. Interestingly, some research has helped to reinforce some concepts that were clinically appreciated, especially related to retinal hemorrhages. SUMMARY: The volume, quality, and breadth of research relating to child maltreatment continue to improve and expand our understanding of child abuse pediatrics. These authors summarize notable advances in our understanding of child maltreatment over the past year. PMID- 24786370 TI - A paradigm shift in the treatment of extreme prematurity: the artificial placenta. AB - PURPOSE OF REVIEW: Extremely low gestational age newborns (ELGANs), born at less than 28 weeks' estimated gestational age, suffer the greatest consequences of prematurity. There have been significant advances in their care over the last several decades, but the prospects for major advances within traditional treatment modalities appear limited. An artificial placenta using extracorporeal life support (ECLS) has been investigated in the laboratory as a new advance in the treatment of ELGANs. We review the concept of an artificial placenta, the purported benefits, and the most recent research efforts in this area. RECENT FINDINGS: For 50 years, researchers have attempted to develop an artificial placenta based on ECLS. Traditional artificial placenta strategies have been based on arteriovenous ECLS using the umbilical vessels with moderate success. Recently, the use of venovenous ECLS and miniaturization of ECLS components have shown potential for creating a next-generation artificial placenta. SUMMARY: ELGANs suffer the greatest morbidity and mortality of prematurity, and are poised to benefit from a paradigm shift in the treatment. Although challenges remain, the artificial placenta is feasible. An artificial placenta would not only protect ELGANs from the complications of mechanical ventilation, but also support their development until a stage of greater maturity, preparing them for a life free of the sequelae of prematurity. PMID- 24786371 TI - Childhood melanoma: an increasingly important health problem in the USA. AB - PURPOSE OF REVIEW: To inform pediatricians of the challenges of detection of melanoma in children and adolescents as well as to instruct on proper biopsy technique of suspicious lesions. RECENT FINDINGS: The incidence of melanoma in children and adolescents is on the rise with an average increase of 2% per year. Rates of change are higher in adolescent girls and locations with low UV-B exposure. Standard Amelanotic, Bleeding, Bump, Color uniformity, De novo, any Diameter (ABCD) detection criteria fail to detect most childhood melanomas. Tumor thickness and sentinel lymph node status are the most important prognostic factors. Artificial tanning use is prevalent among adolescent girls and likely contributes to the growing incidence of melanoma in this group. SUMMARY: Childhood melanoma is often amelanotic and may also appear as raised or ulcerated lesions commonly mistaken for warts or other benign skin conditions. Excision and full-thickness punch biopsies are indicated for suspicious lesions, whereas shaves and small punch biopsies are to be avoided. Pediatric patients more frequently have positive sentinel lymph nodes and increased tumor thickness, yet similar survival compared with adults. PMID- 24786372 TI - Range verification for eye proton therapy based on proton-induced x-ray emissions from implanted metal markers. AB - Metal fiducial markers are often implanted on the back of the eye before proton therapy to improve target localization and reduce patient setup errors. We aim to detect characteristic x-ray emissions from metal targets during proton therapy to verify the treatment range accuracy. Initially gold was chosen for its biocompatibility properties. Proton-induced x-ray emissions (PIXE) from a 15 mm diameter gold marker were detected at different penetration depths of a 59 MeV proton beam at the CATANA proton facility at INFN-LNS (Italy). The Monte Carlo code Geant4 was used to reproduce the experiment and to investigate the effect of different size markers, materials, and the response to both mono-energetic and fully modulated beams. The intensity of the emitted x-rays decreases with decreasing proton energy and thus decreases with depth. If we assume the range to be the depth at which the dose is reduced to 10% of its maximum value and we define the residual range as the distance between the marker and the range of the beam, then the minimum residual range which can be detected with 95% confidence level is the depth at which the PIXE peak is equal to 1.96 sigma(bkg), which is the standard variation of the background noise. With our system and experimental setup this value is 3 mm, when 20 GyE are delivered to a gold marker of 15 mm diameter. Results from silver are more promising. Even when a 5 mm diameter silver marker is placed at a depth equal to the range, the PIXE peak is 2.1 sigma(bkg). Although these quantitative results are dependent on the experimental setup used in this research study, they demonstrate that the real-time analysis of the PIXE emitted by fiducial metal markers can be used to derive beam range. Further analysis are needed to demonstrate the feasibility of the technique in a clinical setup. PMID- 24786373 TI - In vitro assessment of human nuclear hormone receptor activity and cytotoxicity of the flame retardant mixture FM 550 and its triarylphosphate and brominated components. AB - Firemaster((r)) 550 (FM 550) is a mixture of brominated and triarylphosphate flame retardants used in polyurethane foam-based products. The primary components are also used in numerous other applications and are thus common household and industrial contaminants. Our previous animal studies suggested that FM 550 exposure may alter metabolism and cause weight gain. Employing human nuclear receptor (NR) luciferase reporter assays, the goal of this study was to evaluate the agonist actions of FM 550 and its constituent compounds at NRs with known roles in establishing or regulating energy balance. FM 550 was found to have significant agonist activity only at the master regulator of adipocyte differentiation PPARgamma. As a result, the concentration response relationships and relative activities of FM 550 at PPARgamma were investigated in more detail with the contribution of each chemical component defined and compared to the activities of the prototypical PPARgamma environmental ligands triphenyltin and tributyltin. The resulting data indicated that the primary metabolic disruptive effects of FM 550 were likely mediated by the activity of the triarylphosphates at PPARgamma, and have identified TPP as a candidate metabolic disruptor that also acts as a cytotoxicant. PMID- 24786374 TI - Limitations of minimal incision technique for tibiotalocalcaneal arthrodesis. PMID- 24786375 TI - Author response. PMID- 24786377 TI - Distribution of coronary artery disease severity and risk factors in Afro Caribbeans. AB - BACKGROUND: Traditional risk factors are strong predictors of the incidence of coronary artery disease (CAD), but their association with disease severity remains controversial and could differ across ethnic groups. AIMS: In this study, we assessed the prevalence of cardiovascular risk factors (CRFs) in Afro Caribbean patients with documented CAD, and sought to identify which of these factors are related to disease severity. METHODS: We retrospectively studied 420 consecutive patients with CAD. Disease severity was determined from the results of invasive coronary angiography, based on the presence or absence of multiple (two or three) diseased vessels and the myocardial jeopardy (MJ) score. RESULTS: In the studied population (mean age 64.7 +/- 12.4 years), hypertension, diabetes and dyslipidaemia were the most frequent modifiable CRFs, present in 75.9, 47.8 and 37.8% of patients, respectively. Multiple logistic regression analysis showed that diabetes, male sex and personal cardiovascular history significantly increased the risk of multivessel CAD: odds ratios (ORs) of 1.53 (1.01-2.33; P=0.048), 1.61 (1.02-2.55; P=0.043) and 1.68 (1.11-2.56; P=0.015), respectively. Obesity was an independent negative predictor, with an OR of 0.48 (0.29-0.79; P=0.004). Other traditional CRFs (hypertension, dyslipidaemia, smoking, age and family history of vascular disease) were not associated with CAD severity. For high-risk lesions (MJ score >=8), both diabetes and hypertension were independent predictors of disease severity, whereas obesity was no longer a protective factor. CONCLUSION: Diabetes emerged as the strongest modifiable risk factor predictor of multivessel disease in Afro-Caribbean patients, whereas obesity was an independent protective factor. The underlying mechanisms of these associations should be relevant to disease prevention. PMID- 24786378 TI - An iterative evaluation of two shortened systematic review formats for clinicians: a focus group study. AB - OBJECTIVE: To conduct a series of focus groups with primary care physicians to determine the optimal format of a shortened, focused systematic review. MATERIALS AND METHODS: Prototypes for two formats of a shortened systematic review were developed and presented to participants during focus group sessions. Focus groups were conducted with primary care physicians who were in full- or part-time practice. An iterative process was used so that the information learned from the first set of focus groups (Round 1) influenced the material presented to the second set of focus groups (Round 2). The focus group discussions were recorded, transcribed verbatim, and analyzed. RESULTS: Each of the two rounds of testing included three focus groups. A total of 32 physicians participated (Round 1:16 participants; Round 2:16 participants). Analysis of the transcripts from Round 1 identified three themes including ease of use, clarity, and implementation. Changes were made to the prototypes based on the results so that the revised prototypes could be presented and discussed in the second round of focus groups. After analysis of transcripts from Round 2, four themes were identified, including ease of use, clarity, brevity, and implementation. Revisions were made to the prototypes based on the results. CONCLUSIONS: Primary care physicians provided input on the refinement of two prototypes of a shortened systematic review for clinicians. Their feedback guided changes to the format, presentation, and layout of these prototypes in order to increase usability and uptake for end users. PMID- 24786379 TI - Sustained improvement of reading symptoms following botulinum toxin A injection for convergence insufficiency. AB - INTRODUCTION: We evaluated the use of botulinum toxin A in adults with convergence insufficiency in whom prior treatment had failed. METHODS: We studied 8 patients (median age 36 years, range 17 to 77 years) with reading symptoms due to convergence insufficiency defined as an exodeviation greater at near, not exceeding 10 PD in the distance measured by prism and alternate cover test, and either convergence near point>6 cm or reduced fusional amplitudes. All patients were still symptomatic after prior treatment by convergence exercises (n=8), base in prism glasses (n=5) or strabismus surgery (n=2). Five patients received injection of 5 IU botulinum toxin in 0.1 ml saline to one lateral rectus muscle, two received 2.5 IU, and one received 2.5 IU to both lateral rectus muscles. RESULTS: At 1 month post injection, all patients had an initial reduction of exodeviation from baseline (median 9 PD, p=0.008) at near, although 2 patients had a temporary intermittent esotropia in the distance with diplopia associated with difficulty driving. At 6 months, when the pharmacological effect of botulinum toxin had completely worn off, patients still maintained a small reduction of exodeviation (median 4 PD, p=0.3) at near. Reading symptoms improved in 7 of 8 patients at 1-month post injection, and in all patients at 6 months. Two patients had health-related quality of life assessed with the Adult Strabismus 20 Questionnaire, showing improved Reading Function scores at 6 months. Interestingly, 3 patients reported improved reading despite returning to the baseline angle at 6 months, and 2 of 4 with 12-month follow-up still reported improvement. CONCLUSIONS: In adult convergence insufficiency, botulinum toxin injection to a lateral rectus muscle improves reading symptoms beyond the duration of the pure pharmacological effect. Botulinum toxin injection may be useful in management of adult convergence insufficiency, although repeat injections may be needed. PMID- 24786380 TI - Molecular dynamics simulation of mechanical behavior of osteopontin hydroxyapatite interfaces. AB - Bone is characterized with an optimized combination of high stiffness and toughness. The understanding of bone nanomechanics is critical to the development of new artificial biological materials with unique properties. In this work, the mechanical characteristics of the interfaces between osteopontin (OPN, a noncollagenous protein in extrafibrillar protein matrix) and hydroxyapatite (HA, a mineral nanoplatelet in mineralized collagen fibrils) were investigated using molecular dynamics method. We found that the interfacial mechanical behavior is governed by the electrostatic attraction between acidic amino acid residues in OPN and calcium in HA. Higher energy dissipation is associated with the OPN peptides with a higher number of acidic amino acid residues. When loading in the interface direction, new bonds between some acidic residues and HA surface are formed, resulting in a stick-slip type motion of OPN peptide on the HA surface and high interfacial energy dissipation. The formation of new bonds during loading is considered to be a key mechanism responsible for high fracture resistance observed in bone and other biological materials. PMID- 24786381 TI - Chorioamnionitis: epidemiology of newborn management and outcome United States 2008. AB - OBJECTIVE: Current American Academy of Pediatric recommendations call for the empirical use of antibiotics for all well-appearing term newborn infants born to women given a diagnosis of chorioamnionitis. The objective of this analysis was to determine among term infants (37-42 weeks gestation) the prevalence of exposure to clinical chorioamnionitis, intrapartum antibiotics, infant antibiotic use and neonatal intensive care unit (NICU) admission and the relationship of these risk factors to neonatal mortality. STUDY DESIGN: United States-linked infant birth and death certificate files for the year 2008 were used. Maternal demographic variables, labor and delivery risk factors and infant characteristics were analyzed for associations with a reported diagnosis of chorioamnionitis and neonatal death, NICU admission and antibiotic usage. RESULT: There were 2,281,386 births available with information on the diagnosis of chorioamnionitis. The prevalence of chorioamnionitis in this population was 9.7 per 1000 live births (LB) and the neonatal mortality rate for exposed infants was 1.40/1000 LB vs 0.81/1000 LB for infants without chorioamnionitis, odds ratio (OR)=1.72, 95% confidence interval 1.20-2.45. The OR for neonatal death for infants with chorioamnionitis exposure who received antibiotics vs those who did not was 0.69 (95% confidence interval=0.21-2.26). CONCLUSION: Exposure to chorioamnionitis is associated with an increased risk of neonatal mortality. Guidelines for treatment of infants exposed to chorioamnionitis with antibiotics are followed in only a small proportion of such cases. PMID- 24786382 TI - Aberrant upregulation of miR-21 in placental tissues of macrosomia. AB - OBJECTIVE: With China's rapid economic growth in the past 3 decades, an increase in rate of macrosomia has been reported in China. Fetal growth is a result of multiple factors including genetic potential for growth, maternal nutrition, maternal metabolism, endocrine factors and placental perfusion and function. However, the detailed mechanism of how macrosomia happened remains poorly known. Recent studies showed that the expression of a number of microRNAs (miRNAs) in placentas is involved in fetal growth. We hypothesized that aberrant expression of microRNA-21 (miR-21) and microRNA-16 (miR-16) in placenta is associated with macrosomia. STUDY DESIGN: Using quantitative real time PCR, we analyzed the expression level of miR-21 and miR-16 in terminal placentas of macrosomia pregnancies (n=35) and normal controls (n=35). Potential target genes of miRNA were predicted using TargetScan, miRanda and PicTar. Target genes were mapped to KEGG pathways using KEGG Mapper with an in-house Perl script with KEGG Gene IDs. RESULT: MiR-21 showed significant up-regulation in macrosomia (P=0.037). After controlling the potential confounders, multivariable logistic regression analysis suggested the risk of macrosomia increased, multivariable adjusted ORs of macrosomia for those in the highest tertile was 3.931 (95%CI: 1.049-14.736) compared with those in the lowest tertile in terms of miR-21 level. The target genes of miR-21 were involved in eight possible signaling pathways. They were pathways in P53 signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, TGF-beta signaling pathway and PI3K-Akt signaling pathway (P<0.001), Wnt signaling pathway, Jak-STAT signaling pathway and mTOR signaling pathway (P<0.05). CONCLUSION: Our study is the first to investigate the association between placental miRNA expression and macrosomia. Our results indicate that the expression level of miR-21 in placental tissue may be involved in the development of macrosomia. PMID- 24786383 TI - Perinatal outcomes in singleton and twin pregnancies following first-trimester bleeding. AB - OBJECTIVE: To investigate associations between first-trimester bleeding and perinatal outcomes. STUDY DESIGN: Registry-based survey of the period 2002 through 2010. Pregnancies with versus without first-trimester bleeding were compared using Student's t- and chi(2)-test. Multivariable logistic regression was used to control for potential confounders. RESULT: 9924 singleton and 275 twin pregnancies with first-trimester bleeding, and 160 099 singleton and 2710 twin pregnancies without bleeding were included. Bleeding increased the risk of preterm birth in singletons (odds ratio 1.48; 95% confidence interval 1.38-1.60). Risks were also increased for preterm premature rupture of membranes, abruption, previa, stillbirth and congenital anomalies, with a reduced risk of preeclampsia. The differences remained significant after adjustment for confounders. In twin pregnancies, bleeding was not significantly associated with prematurity (odds ratio 1.04; 95% confidence interval 0.81-1.34), nor with other outcomes. CONCLUSION: In singletons, but not in twins, the risk of perinatal complications is significantly increased after first-trimester bleeding. PMID- 24786384 TI - Blood gas values in clamped and unclamped umbilical cord at birth. AB - AIM: To determine the reliability of the cord blood gas analysis on the unclamped cord compared to the standard technique of sampling on double clamped cord. STUDY DESIGN: Prospective observational study conducted on 46 singleton neonates vaginally delivered at term. Matched pairs of umbilical artery and vein blood samples were collected from unclamped cord within 90s after birth and from the same cord after clamping, with the clamping occurring immediately after the first blood collection. A blood gas analysis was performed on each collected sample. OUTCOME MEASURES: Arterial and venous blood samples were analyzed for pH, PO2, pCO2, SaO2, hemoglobin concentration (ctHb) and base excess (BE). The values were compared between the two groups (clamped vs unclamped) using a Wilcoxon test. RESULTS: No significant difference was found in pH, PO2, pCO2, SaO2 and ctHb values on arterial blood between unclamped and clamped cord. The only significant difference was related to BE (p<0.001). For the venous blood, the values of pH, PO2, pCO2 were comparable between unclamped and clamped cord, while the values of SaO2, ctHb and BE were significantly different (p<0.05). CONCLUSION: No significant difference was found in almost all the arterial blood gas parameters and in the main venous blood gas parameters between unclamped and clamped cord. Sampling of cord blood for gas analysis may be performed on the unclamped cord right after birth without reducing the accuracy of the analysis. PMID- 24786385 TI - Management strategy in case of meconium stained amniotic fluid. PMID- 24786386 TI - Modified supramid brow suspension in paediatric ptosis. AB - PURPOSE: To understand the safety and complication profile of the modified supramid brow suspension surgery in the paediatric ptosis. DESIGN: Retrospective interventional case series. METHODS: Review of medical notes of 32 patients who underwent supramid brow suspension surgery of the upper lid. Surgery was performed by a single surgeon at Great Ormond Street Hospital, London during 2007 2012. Complication rates were analysed. RESULTS: Forty-six eyes of 32 patients underwent upper eye lid brow suspension surgery; 18 cases were unilateral and 14 bilateral. Mean follow-up period is 28 months after the surgery. Post-operative granulomatous reaction was noted in 6 eyes (13%) and prolonged exposure keratopathy in 2 eyes (4.3%). There were no cases of suture infection or exposure. No recurrence of ptosis was observed in any of the operated cases. Pupillary axis clearance was achieved in all eyes. CONCLUSION: Modified brow suspension surgery using supramid for upper eyelid ptosis is a safe and clinically useful procedure with low complication rate. PMID- 24786387 TI - Synthesis and biological evaluation of a unique heparin mimetic hexasaccharide for structure-activity relationship studies. AB - To date, the structure-activity relationship studies of heparin/heparan sulfate with their diverse binding partners such as growth factors, cytokines, chemokines, and extracellular matrix proteins have been limited yet provide early insight that specific sequences contribute to this manifold biological role. This has led to an impetus for the chemical synthesis of oligosaccharide fragments of these complex polysaccharides, which can provide an effective tool for this goal. The synthesis of three heparin mimetic hexasaccharides with distinct structural patterns is described herein, and the influence of the targeted substitution on their bioactivity profiles is studied using in vitro affinity and/or inhibition toward different growth factors and proteins. Additionally, the particularly challenging synthesis of an irregular hexasaccharide is reported, which, interestingly, in spite of being considerably structurally similar with its two counterparts, displayed a unique and remarkably distinct profile in the test assays. PMID- 24786388 TI - Evaluation of sex differences in health-related quality of life outcomes associated with child abuse: Results from the Ontario Child Health Study. AB - AIMS: Despite the advances in child maltreatment research, there is still the need for comprehensive information about how abuse affects a broad range of categories of young adult functioning, and the extent to which these vary by sex. We examined the associations between child physical abuse (PA) and sexual abuse (SA) and six areas of functioning (mental health, physical health, life satisfaction, illegal substance use, alcohol problems and daily smoking). METHODS: Data were obtained from the 1983 Ontario Child Health Study and follow up in 2000/2001 (n = 1893). Multilevel regression estimated the adjusted associations for PA (with severity) and SA with each of the outcomes. Estimates with an entire sample were presented with sex-by-abuse interactions to examine sex differences and then presented separately by sex. RESULTS: In the adjusted model, severe PA and SA were associated with impairment in mental health, and both forms of PA (severe and non-severe) and SA were associated with low life satisfaction. In addition, severe PA was associated with illegal substance use. Child abuse variables were not associated with poor physical health, alcohol problems or smoking. Although sex-stratified analyses revealed different patterns, there was no significant sex difference in the integrated sample. CONCLUSIONS: This is among the first community-based studies to show a strong association between child PA and SA and low life satisfaction in young adults. The abuse effects were similar for both sexes. PMID- 24786389 TI - Higher expression of HSP70 and LOX-1 in the placental tissues of pre-eclampsia pregnancies. AB - BACKGROUND: Pre-eclampsia, a hypertensive disorder of pregnancy is the main cause of fetal and maternal morbidity and mortality. Growing evidences suggest that placental oxidative stress involves in the pathogenesis of pre-eclampsia. The HSP70 is a novel marker of oxidative stress which binds with high avidity to LOX 1. The aim of this study was to evaluate the co-expression of HSP70 and LOX-1 in the placental tissues of normotensive and pre-eclamptic pregnancies. MATERIALS AND METHODS: The placental tissues were collected from 35 healthy women with normal pregnancies and 33 women with pre-eclampsia disorder. Expression of HSP70 and LOX-1 on the placental tissues was examined by using immunohistochemistry technique. The intensity of the molecules' expression was determined by semi quantitative scoring. RESULTS: The 34.3% and 37.1% of the healthy women did not express the HSP70 and LOX-1 on their placenta, respectively. All pre-eclamptic patients expressed HSP70 and LOX-1 with various scores. Indeed, the majority of the pre-eclamptic subjects had >=3+ scores of the expression of HSP70 and LOX-1 on their placenta (60.6% and 66.7%, respectively). The percentage of the >=3+ scores of the expression of HSP70 and LOX-1 was significantly higher in patients than those in healthy women (p<0.0001 for both). Similarly, the majority of the pre-eclamptic subjects had >=3+ scores of the co-expression of HSP70 and LOX-1 molecules (57.6%) which was significantly higher in patients than those in control group (p=0.0001). CONCLUSIONS: These results showed higher expression of HSP70 and LOX-1 in the placental tissues of pre-eclampsia patients which represent the possible contribution of these molecules in the disease pathogenesis. Further studies need to clarify their role in the pathogenesis of preeclampsia disorder. PMID- 24786390 TI - Improving ion mobility measurement sensitivity by utilizing helium in an ion funnel trap. AB - Ion mobility instruments that utilize nitrogen as buffer gas are often preceded by an ion trap and accumulation region that also uses nitrogen, and for different inert gases, no significant effects upon performance are expected for ion mobility spectrometry (IMS) of larger ions. However, we have observed significantly improved performance for an ion funnel trap upon adding helium; the signal intensities for higher m/z species were improved by more than an order of magnitude compared to using pure nitrogen. The effect of helium upon IMS resolving power was also studied by introducing a He/N2 gas mixture into the drift cell, and in some cases, a slight improvement was observed compared to pure N2. The improvement in signal can be largely attributed to faster and more efficient ion ejection into the drift tube from the ion funnel trap. PMID- 24786391 TI - The role of epigenetics in the biology of multiple myeloma. AB - Several recent studies have highlighted the biological complexity of multiple myeloma (MM) that arises as a result of several disrupted cancer pathways. Apart from the central role of genetic abnormalities, epigenetic aberrations have also been shown to be important players in the development of MM, and a lot of research during the past decades has focused on the ways DNA methylation, histone modifications and noncoding RNAs contribute to the pathobiology of MM. This has led to, apart from better understanding of the disease biology, the development of epigenetic drugs, such as histone deacetylase inhibitors that are already used in clinical trials in MM with promising results. This review will present the role of epigenetic abnormalities in MM and how these can affect specific pathways, and focus on the potential of novel 'epidrugs' as future treatment modalities for MM. PMID- 24786392 TI - Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML. AB - Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34(+)/CD33(-) progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34(+)/CD33(+) progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role. PMID- 24786394 TI - Differential expression of selected candidate genes in bovine embryos produced in vitro and cultured with chemicals modulating lipid metabolism. AB - Lipid accumulated in embryos produced in vitro has been linked to reductions in both quality and postcryopreservation viability. Therefore, the objective of the present study was to investigate the influence of lipid-reducing chemicals on embryo development, quality, and postcryopreservation viability, in addition to expression profiles of selected lipid metabolism-regulating genes. Bovine cumulus oocyte complexes were matured and fertilized in vitro; eight-cell stage embryos were cultured in IVC medium supplemented with phenazine ethosulfate (PES), L carnitine (LC), PES + LC, or no supplementation (control). Culturing embryos in medium with LC increased (P < 0.05) blastocyst rate (38.8%) compared with the other groups (control = 28.1%, PES = 27.1%, PES + LC = 26.3%). Embryos cultured with supplements had greater total cell number and fewer apoptotic cells than the control. Cytoplasmic lipid content was reduced, whereas mitochondria density was increased in embryos treated with culture supplements; this was linked to altered expression profiles of selected genes regulating lipid metabolism. For example, transcript abundance of transmembrane lipid gene (SGPP1) was greater in LC- and PES-treated embryos, and they had increased postcryopreservation hatching ability (indicative of embryo cryotolerance). In conclusion, the two lipid metabolism regulators added to the culture media had improved embryo quality and cryotolerance, but embryo development rate and downstream lipid metabolism regulating genes were more influenced with LC supplementation. PMID- 24786393 TI - T-cell receptor Vbeta skewing frequently occurs in refractory cytopenia of childhood and is associated with an expansion of effector cytotoxic T cells: a prospective study by EWOG-MDS. AB - Immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A, is effective in refractory cytopenia of childhood (RCC), suggesting that, similar to low-grade myelodysplastic syndromes in adult patients, T lymphocytes are involved in suppressing hematopoiesis in a subset of RCC patients. However, the potential role of a T-cell-mediated pathophysiology in RCC remains poorly explored. In a cohort of 92 RCC patients, we prospectively assessed the frequency of T-cell receptor (TCR) beta-chain variable (Vbeta) domain skewing in bone marrow and peripheral blood by heteroduplex PCR, and analyzed T-cell subsets in peripheral blood by flow cytometry. TCRVbeta skewing was present in 40% of RCC patients. TCRVbeta skewing did not correlate with bone marrow cellularity, karyotype, transfusion history, HLA-DR15 or the presence of a PNH clone. In 28 patients treated with IST, TCRVbeta skewing was not clearly related with treatment response. However, TCRVbeta skewing did correlate with a disturbed CD4(+)/CD8(+) T-cell ratio, a reduction in naive CD8(+) T cells, an expansion of effector CD8(+) T cells and an increase in activated CD8(+) T cells (defined as HLA-DR(+), CD57(+) or CD56(+)). These data suggest that T lymphocytes contribute to RCC pathogenesis in a proportion of patients, and provide a rationale for treatment with IST in selected patients with RCC. PMID- 24786395 TI - Progesterone regulates chicken embryonic germ cell meiotic initiation independent of retinoic acid signaling. AB - The signaling molecule retinoic acid (RA) is known to trigger germ cells to enter meiosis. However, RA may not be the only secreted inducer of meiosis. Our previous data indicate that luteinizing hormone also promotes germ cell meiotic initiation by upregulating 3betaHSDII transcription. Here, using chicken embryos, we investigate the role of progesterone (P4) in regulating germ cell meiotic initiation. Progesterone treatment at embryonic Day 9.5 accelerated germ cell meiosis entry in the female chicken embryos. However, P4 treatment in vivo did no influence on testicular germ cells but triggered their meiotic initiation in the cultured testes. As treatment with an RA receptor (RAR) inhibitor did not block the stimulatory effect of P4 on germ cell meiotic initiation, this P4 stimulatory effect seems to be independent of RAR-mediated signaling. The abundance of RA metabolism-related enzymes and RAR (RARbeta) mRNAs did not differ significantly between P4-treated and control individuals. The RA concentration in the ovaries remained unchanged by P4 treatment in vivo. Because no inhibition by the P4 receptor (PR) nuclear receptor antagonist mifepristone on P4 effect was observed in either in vitro or in vivo experiments, the effect of P4 on germ cell meiotic initiation is probably mediated by membrane PRs (mPR). The mPRalpha, mPRbeta, and mPRgamma mRNAs were all expressed in the embryonic ovaries. The expression of mPRalpha and mPRbeta was higher than that of mPRgamma. Immunohistochemical results showed that mPRalpha-positive cells were mainly scattered in the ovarian cortex area where most germ cells were distributed. The mPRbeta-positive cells were widely distributed in the ovaries, and positive cells were clustered with a similar morphology to that of germ cell clusters. In conclusion, P4 may regulate embryonic germ cell meiotic initiation independent of RA signaling through the membrane PRs. This study provides a new insight into the mechanisms of germ cell meiotic initiation in the chicken. PMID- 24786396 TI - The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. AB - c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD. PMID- 24786397 TI - Conditioned medium derived from mesenchymal stem cells overexpressing HPV16 E6E7 dramatically improves ischemic limb. AB - Mesenchymal stem cells (MSCs) have been shown to secrete cytokines and growth factors required for angiogenesis. Previously, we demonstrated that MSCs expressing HPV16 E6E7 mRNA (E6E7-MSCs) increase life span and differentiation potential and maintain without neoplastic transformation. Whether E6E7-MSCs are sources of molecules for enhancing angiogenesis is unknown. We demonstrated that E6E7-MSC-derived conditioned medium (E6E7-CM) enhanced endothelial cell migration and tube formation compared to primary MSC-derived conditioned medium (primary CM). Moreover, E6E7-MSCs increased AKT activation and enhanced the release of Interleukin-1beta (IL-1beta) and vascular endothelial growth factor A (VEGFA). Neutralization of E6E7-CM with antibodies against IL-1beta or VEGFA abrogated its effect in enhancing endothelial migration and tube formation. Primary-CM, added with IL-1beta and VEGFA, enhanced its ability to increase endothelial migration and tube formation. E6E7-CM was shown to increase the ability to improve blood perfusion in a mouse limb ischemia model. Histological analysis revealed that E6E7-CM prohibited muscle loss or fibrosis and increased endothelial cell counts compared to primary-CM. Similarly, the effects of E6E7-CM in improving perfusion in ischemic limb were also contributed by the increase of IL-1beta or VEGFA levels. These results suggest that E6E7-MSCs increase the ability to secrete angiogenic factors via AKT activation, and E6E7-CM is abundant in IL-1beta and VEGFA levels and thereby increases the ability to improve blood perfusion and prohibit muscle loss or fibrosis in a mouse limb ischemia model. PMID- 24786398 TI - Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. AB - RATIONALE: An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3(+) CD4(+) regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI. OBJECTIVE: Our aim was to study the functional role of Treg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation. METHODS AND RESULTS: Using a model of genetic Treg-cell ablation (Foxp3(DTR) mice), we depleted the Treg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, Treg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in Treg-cell-ablated mice could be confirmed in a mouse model of anti CD25 monoclonal antibody-mediated depletion. In contrast, therapeutic Treg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA-treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic Treg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing. CONCLUSIONS: Our data indicate that Treg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of Treg cells constitutes a novel approach to improve healing post-MI. PMID- 24786399 TI - Nonuniform and variable arrangements of ryanodine receptors within mammalian ventricular couplons. AB - RATIONALE: Single-tilt tomograms of the dyads in rat ventricular myocytes indicated that type 2 ryanodine receptors (RYR2s) were not positioned in a well ordered array. Furthermore, the orientation and packing strategy of purified type 1 ryanodine receptors in lipid bilayers is determined by the free Mg2+ concentration. These observations led us to test the hypothesis that RYR2s within the mammalian dyad have multiple and complex arrangements. OBJECTIVES: To determine the arrangement of RYR2 tetramers in the dyads of mammalian cardiomyocytes and the effects of physiologically and pathologically relevant factors on this arrangement. METHODS AND RESULTS: We used dual-tilt electron tomography to produce en-face views of dyads, enabling a direct examination of RYR2 distribution and arrangement. Rat hearts fixed in situ; isolated rat cardiomyocytes permeabilized, incubated with 1 mmol/L Mg2+, and then fixed; and sections of human ventricle, all showed that the tetramer packing within a dyad was nonuniform containing a mix of checkerboard and side-by-side arrangements, as well as isolated tetramers. Both phosphorylation and 0.1 mmol/L Mg2+ moved the tetramers into a predominantly checkerboard configuration, whereas the 4 mmol/L Mg2+ induced a dense side-by-side arrangement. These changes occurred within 10 minutes of application of the stimuli. CONCLUSIONS: The arrangement of RYR2 tetramers within the mammalian dyad is neither uniform nor static. We hypothesize that this is characteristic of the dyad in vivo and may provide a mechanism for modulating the open probabilities of the individual tetramers. PMID- 24786400 TI - Total and inorganic arsenic in fish samples from Norwegian waters. AB - The contents of total arsenic and inorganic arsenic were determined in fillet samples of Northeast Artic cod, herring, mackerel, Greenland halibut, tusk, saithe and Atlantic halibut. In total, 923 individual fish samples were analysed. The fish were mostly caught in the open sea off the coast of Norway, from 40 positions. The determination of total arsenic was carried out by inductively coupled plasma mass spectrometry following microwave-assisted wet digestion. The determination of inorganic arsenic was carried out by high-performance liquid chromatography-ICP-MS following microwave-assisted dissolution of the samples. The concentrations found for total arsenic varied greatly between fish species, and ranged from 0.3 to 110 mg kg(-1) wet weight. For inorganic arsenic, the concentrations found were very low (<0.006 mg kg(-1)) in all cases. The obtained results question the assumptions made by the European Food Safety Authority (EFSA) on the inorganic arsenic level in fish used in the recent EFSA opinion on arsenic in food. PMID- 24786401 TI - Dietary exposure assessment of streptomycin and tetracycline in food of animal origin on the Croatian market. AB - Residual antibacterials in food constitute a risk to human health, particularly because they can contribute to the transmission of antibiotic-resistant pathogenic bacteria through the food chain. This paper presents dietary exposure assessment of streptomycin and tetracycline, based on combining food consumption data in Croatia with data on the concentration of veterinary drugs in analysed samples of food of animal origin. According to the median values, the estimated daily intake of streptomycin and tetracycline through food is 11.9 and 0.7 ug/person/day, respectively. The largest contribution to streptomycin intake comes from meat (4.8 ug/person/day, i.e. 41%), but milk is the largest source for tetracycline (0.3 ug/person/day, i.e. 46%). The estimated dietary exposure to these veterinary drugs does not exceed relevant toxicological reference values and the level of exposure is assessed to be acceptable. PMID- 24786402 TI - Heavy metal content in different types of smoked meat in Serbia. AB - Concentrations of Fe, Cu, Ni, Cr, Pb, Mn, Zn and Cd in pork, beef, turkey and chicken samples were determined using inductively coupled plasma-optical emission spectrometry (ICP-OES). The mean concentration ranges in milligrams per 100 g of the studied metals in all samples were 0.6924-1.2154 for Fe, 0.6492-0.9831 for Cu, 0.0012-0.0027 for Pb, 0.041-0.0510 for Ni, 0.1186-0.1481 for Mn, 0.7257 5.2726 for Zn and 0.0042-0.0050 for Cd. The levels of analysed elements were in accordance with European standards for all metals except for manganese in all samples and for nickel in a certain number of samples. Zn level in beef was significantly higher compared to other samples, and Pb and Cd were found in concentrations well below the recommended daily intake. PMID- 24786403 TI - Heavy metals in meat of Finnish city rabbits. AB - Levels of cadmium, chromium, lead, copper, manganese and zinc in city rabbits were determined to evaluate the edibility of the meat. Mean concentrations of toxic metals were 0.011 mg/kg for cadmium and 0.037 mg/kg for lead. Cadmium and lead concentrations were below the admissible maximum levels set by the EU. Concentrations of toxic metals in the meat were sufficiently low as to assume that consumption of the meat does not pose a health risk for human health. Investigation of polycyclic aromatic hydrocarbons, pesticides and other environmental pollutants is required before the meat can be declared to be completely safe. PMID- 24786404 TI - Determination of nickel in Polish brands of margarines. AB - Nickel is used in the production of margarine as a catalyst for hydrogenation. This may lead to the presence of its residues in the products and could cause allergic reactions. Therefore, monitoring of this metal in foods is essential for consumers. The described liquid sampling AAS procedure allows product control. Nickel was determined in 10 brands of margarine, and only in 3 samples its content was below the acceptable limit of 0.2 mg kg(-1). PMID- 24786405 TI - Oxytetracycline residues in retail chicken eggs in Ibadan, Nigeria. AB - Oxytetracycline residues in chicken eggs from five markets within Ibadan metropolis were determined by high-performance liquid chromatography following solid-phase extraction. Recovery of oxytetracycline was 80.5%-87.8%, whereas 75.2% of the samples contained detectable oxytetracycline with an overall mean residue concentration of 479.0 ug kg(-1). Residue concentrations from Iwo Road, Apata, Challenge, Ojoo and Bodija markets were 421, 460, 468, 568 and 476 ug kg( 1), respectively. Eggs from Ojoo market had the highest levels, whereas 68.8% of the samples contained residues above the Codex Alimentarius Commission maximum residue limit. The results are of public health interest as they indicate that a greater proportion of eggs being consumed in Ibadan could contain residues above the maximum residue limit, for which unregulated access and indiscriminate use of antibiotics by poultry farmers could be responsible. National surveillance of eggs and other animal products for antibiotic residue and appropriate regulation of antibiotic is recommended to ensure food safety for consumers. PMID- 24786406 TI - Lead, cadmium and mercury levels in the 2010 Korean diet. AB - This study analysed the level of contamination of harmful heavy metals in 3820 food samples available in Korea in 2010. A total of 119 types of samples were collected, including corns, vegetables, fruits, fishes, mollusks, shellfish, crustaceans, seaweed, bean products, meats and eggs from seven major cities. These samples were analysed using ICP-MS after pre-treatment with a microwave digestion system. Results of lead, cadmium and mercury analyses were compared with the standard specifications of Korea Food Standards Codex. As a result, high levels of Pb, Cd and Hg were detected in "cockle," "dried-squid" and "shark meat." Acceptable intake for consumers was checked using provisional tolerable weekly intake values. Such results will be utilised as data on the exposure of human body through foods. In addition, satisfactory results were obtained through purchase and analysis of National Institute of Science and Technology-certified reference materials to obtain reliability on analysis results. PMID- 24786407 TI - Investigation of pesticide residues in vegetables and fruits grown in various regions of Hatay, Turkey. AB - In this study, 175 pesticide residues in various vegetable and fruit samples grown in different regions of Hatay, Turkey, were investigated. Residue analyses were performed using liquid chromatography-tandem mass spectrometry with the QuEChERS method. In tomato, plum and apricot samples, pesticide residues were below the limits of detection. In other samples, at least one pesticide residue was detected. Twelve pesticides (acetamiprid, carbendazim, chlorpyrifos, fenarimol, fludioxonil, hexythiazox, imidacloprid, metalaxyl, pyridaben, pyriproxyfen, thiabendozole, triadimenol) were found at levels between 0.003 and 0.759 mg kg(-1). Only in cucumber samples, acetamiprid residues were found at levels greater than the maximum acceptable limit in Turkish Food Codex and European Union maximum residue limits (EU MRLs). In other samples, the detected residue amounts are less than the MRLs declared in the Turkish Food Codex and EU MRLs. PMID- 24786408 TI - Determination of trace elements in goat and ovine milk from Calabria (Italy) by ICP-AES. AB - There are many sources of contamination to which milk could be exposed: grazing animals can ingest contaminants present in nature, such as lead in soil, or that have been deposited on grass, resulting from industrial emissions. Another possible route of contamination is represented by feed for animals, which may contain heavy and essential metals. The potential of high-resolution inductively coupled plasma spectrometry was evaluated to quantify reliably various toxic and essential elements (Fe, Zn, Pb, Cr, Ni, Cu, As, Se, Cd) in 47 samples of goat and ovine milk from various farms in Calabria (southern Italy). The results showed that concentrations of cadmium were below the limit of detection. Lead levels were below the maximum limits as set by the EC in almost all samples tested. The highest values were those of Zn followed by Fe, Cu and Se. PMID- 24786410 TI - Aflatoxin monitoring in Italian hazelnut products by LC-MS. AB - Hazelnut samples of different origin were collected in stores in Northern Italy and analysed for aflatoxin (AF) contamination by a sensitive chromatographic method on the basis of a tandem mass spectrometer with electrospray ionisation. The effects of two extracting solvent mixtures (methanol/water and acetonitrile/water) and different extraction times were tested and compared in terms of recovery. Analysis showed that 35 out of 93 samples (37.6%) were contaminated by AFs. The incidence of positive samples was higher in Turkish (66.7%) than in Italian samples (35.9%). Mean AF contamination was higher (p = 0.045, Kruskal-Wallis test) in the Turkish samples (0.33 ug kg(-1)) compared to the Italian (0.14 ug kg(-1)) ones. In both cases, however, a low level of total AF contamination was found in the positive samples (0.64 ug kg(-1)), both being far below the maximum limit set in European legislation. PMID- 24786409 TI - Metal levels in economically important bivalve species from Turkey. AB - Concentrations of eight heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb and Zn) were determined in economically important bivalve species: oyster (Ostrea edulis), wedge clam (Donax trunculus), manila clam (Ruditapes philippinarium) and warty clam (Venus verrucosa) from the Marmara and Aegean seas. Samples were collected seasonally between 2008 and 2009. Metal levels of bivalves were found in the following ranges: As 0.02-3.40, Cd 0.02-2.80, Cr 0.19-0.82, Cu 0.82-25.06, Hg < LOD-0.12, Ni 0.09-0.73, Pb 0.05-4.16 and Zn 6.85-899 mg kg(-1). The most abundant elements were Zn > Cu > As. In addition, the results showed that oysters had the highest concentrations of Zn in all seasons. The next abundant heavy metal detected was Cu in oyster and other clam species. It was concluded that in the future, these metals should be monitored regularly. PMID- 24786411 TI - Dietary intake of aflatoxins in the adult Malaysian population - an assessment of risk. AB - Exposure to aflatoxins in the adult Malaysian diet was estimated by analysing aflatoxins in 236 food composites prepared as "ready for consumption". Dietary exposure to aflatoxin B1 (AFB1) ranged from 24.3 to 34.00 ng/kg b.w./day (lower to upper bound), with peanuts being the main contributor. Estimated liver cancer risk from this exposure was 0.61-0.85 cancers/100,000 population/year, contributing 12.4%-17.3% of the liver cancer cases. Excluding AFB1 occurrence data higher than 15 ug/kg reduced exposure by 65%-91% to 2.27-11.99 ng/kg b.w./day, reducing the cancer risk to 0.06-0.30 cancers/100,000 population/year (contributing 1.2%-6.1% liver cancer cases). Reducing further the ML of AFB1 from 15 to 5 ug/kg yielded 3%-7% greater drop in the exposure to 0.47-10.26 ng/kg b.w./day with an estimated risk of 0.01-0.26 cancers/100,000 population/year (0.2%-5.1% liver cancer cases attributed to dietary AFB1). These findings indicate that current MLs are adequate in protecting Malaysians' health. PMID- 24786414 TI - A reciprocating twin-channel model for ABC transporters. AB - ABC transporters comprise a large, diverse, and ubiquitous superfamily of membrane active transporters. Their core architecture is a dimer of dimers, comprising two transmembrane (TM) domains that bind substrate, and two ATP binding cassettes, which use the cell's energy currency to couple substrate translocation to ATP hydrolysis. Despite the availability of over a dozen resolved structures and a wealth of biochemical and biophysical data, this field is bedeviled by controversy and long-standing mechanistic questions remain unresolved. The prevailing paradigm for the ABC transport mechanism is the Switch Model, in which the ATP-binding cassettes dimerize upon binding two ATP molecules, and thence dissociate upon sequential ATP hydrolysis. This cycle of nucleotide-binding domain (NBD) dimerization and dissociation is coupled to a switch between inward- or outward facing conformations of a single TM channel; this alternating access enables substrate binding on one face of the membrane and its release at the other. Notwithstanding widespread acceptance of the Switch Model, there is substantial evidence that the NBDs do not separate very much, if at all, and thus physical separation of the ATP cassettes observed in crystallographic structures may be an artefact. An alternative Constant Contact Model has been proposed, in which ATP hydrolysis occurs alternately at the two ATP-binding sites, with one of the sites remaining closed and containing occluded nucleotide at all times. In this model, the cassettes remain in contact and the active sites swing open in an alternately seesawing motion. Whilst the concept of NBD association/dissociation in the Switch Model is naturally compatible with a single alternating-access channel, the asymmetric functioning proposed by the Constant Contact model suggests an alternating or reciprocating function in the TMDs. Here, a new model for the function of ABC transporters is proposed in which the sequence of ATP binding, hydrolysis, and product release in each active site is directly coupled to the analogous sequence of substrate binding, translocation and release in one of two functionally separate substrate translocation pathways. Each translocation pathway functions 180 degrees out of phase. A wide and diverse selection of data for both ABC importers and exporters is examined, and the ability of the Switch and Reciprocating Models to explain the data is compared and contrasted. This analysis shows that not only can the Reciprocating Model readily explain the data; it also suggests straightforward explanations for the function of a number of atypical ABC transporters. This study represents the most coherent and complete attempt at an all-encompassing scheme to explain how these important proteins work, one that is consistent with sound biochemical and biophysical evidence. PMID- 24786412 TI - Aminocarminic acid in E120-labelled food additives and beverages. AB - An analytical method was developed for investigating aminocarminic acid occurrence in E120-labelled red-coloured-beverages and in E120 additives, with the aim of controlling the purity of the carmine additive in countries where the use of aminocarminic acid is forbidden. The carminic acid and the aminocarminic acid were separated by high-performance liquid chromatography-photodiode array tandem mass spectrography (HPLC-PDA-MS/MS). The method was statistically validated. The regression lines, ranging from 10 to 100 mg/L, showed r(2 )> 0.9996. Recoveries from 97% to 101% were obtained for the fortification level of 50 mg/L; the relative standard deviations did not exceed 3%. The LODs were below 2 mg/L, whereas the LOQs did not exceed 4 mg/L. The method was successfully applied to 27 samples of commercial E120-labelled red-coloured beverages and E120 additives, collected in Italy during quality control investigations conducted by the Ministry. The results demonstrated that more than 50% of the samples contained aminocarminic acid, evidencing the alarming illicit use of this semi synthetic carmine acid derivative. PMID- 24786415 TI - A preliminary study of the contribution of telemicroscopy to the diagnosis and management of skin tumours in teledermatology. AB - Dermatology images can be acquired using a miniature handheld digital microscope at magnifications of 10- to 30-fold. We investigated the contribution of telemicroscopy to the reliability and accuracy of teledermatology for skin tumours. In a retrospective study of the reliability of diagnosis and management plans, two dermatologists compared teledermatology with face-to-face assessment. We also measured the accuracy of diagnosis by comparing teledermatology with histopathological examination. Two dermatologists evaluated the clinical images and information for 120 randomly sorted cases and recorded a diagnosis and a management plan for each case. Two months later, the same dermatologists re evaluated the cases and suggested a new diagnosis and management plan for each case. The reliability of teledermatology diagnosis was not significantly different from face-to-face examination; it was significantly increased with the addition of microscopic images (P < 0.001). The reliability of teledermatology management plans was not significantly different from face-to-face examination; it was significantly increased with the addition of the microscopic images (P < 0.001). The accuracy of teledermatology was significantly increased with microscopic images (P = 0.05). Telemicroscopy appears to be a useful adjunct to teledermatology with a digital camera. Future studies with different magnifications should be performed to detect the optimum magnification for telemicroscopy. PMID- 24786416 TI - Editorial: The vulnerable physician-scientist. PMID- 24786419 TI - Introduction. PMID- 24786418 TI - Diagnosis and treatment monitoring of toenail onychomycosis by reflectance confocal microscopy: prospective cohort study in 58 patients. AB - BACKGROUND: The clinical presentation of onychomycosis is often nonspecific and can lead to inappropriate antifungal therapy. Available mycologic tests share many drawbacks. OBJECTIVE: We sought to evaluate the accuracy of reflectance confocal microscopy (RCM) for the diagnosis of onychomycosis compared with standard mycologic tests. METHODS: In all, 58 patients with suspected onychomycosis were enrolled prospectively. RCM, potassium hydroxide preparation, and fungal culture were performed at baseline and after treatment in patients with confirmed onychomycosis. RCM diagnosis of onychomycosis was based on the presence of filamentous and/or roundish structures in the nail plate, corresponding respectively to septate hyphae and/or arthroconidia. RESULTS: Of patients, 46 of 58 were correctly classified by RCM, with a diagnosis yield of 79.3%, sensitivity of 52.9%, specificity of 90.2%, positive predictive value of 69.2%, and negative predictive value of 82.2%. The use of a handheld RCM imager permitted a faster examination with the same accuracy. RCM performed after treatment in 9 patients showed a normal nail plate, and healing was confirmed by mycologic tests or by follow-up. LIMITATIONS: Existing RCM scanner heads are not intended for nail examination. CONCLUSION: RCM has excellent specificity and can be used as a rapid, office-based test to strengthen the prescription of antifungal therapy and for follow-up. Technical improvement could aid sensitivity. PMID- 24786420 TI - Yeah, you. PMID- 24786421 TI - Beauty mandates and the appearance obsession. AB - ABSTRACT This article examines the effects of appearance norms within lesbian communities, drawing both on the research literature and on direct interviews with lesbian and bisexual women. In particular, the authors assess the impact of heterosexual beauty mandates on women's communities and ask whether lesbian and bisexual women are affected by the dominant culture's beauty mandates to a similar or lesser degree than heterosexual women. In addition, the authors examine appearance mandates developed by women within lesbian subculture. The positive and negative effects of these various "styles" on members of different lesbian subcultures are discussed. PMID- 24786422 TI - Bisexual women and beauty norms. AB - ABSTRACT This article examines how coming out and gender of partner affect bisexual women's behavior, thoughts and feelings regarding beauty and appearance norms. Seventy-four bisexual women participated in a qualitative survey addressing these issues. Results showed that just under half (49%) of respondents felt that coming out as bisexual affected their beauty ideas and practices and over two-thirds (71%) felt that the gender of their partners affected their beauty ideas and practices. Most of the latter group (80%) felt more appearance pressures when involved with men than when involved with women. Themes from open ended responses are presented through specific examples and the implications of findings are discussed. PMID- 24786423 TI - Lesbians discuss beauty and aging. AB - ABSTRACT Two conversations with three aging lesbians are presented to identify and explore different definitions of beauty and how these definitions change and are influenced by age. The three women interviewed believe beauty is more than skin deep, yet they differ regarding specific components of beauty. Two believe that their definition of beauty has changed as they age and one believes that her definition has remained basically unchanged through the years. Topics of discussion include: beauty role models, the impact of the American beauty standard on their self-esteem, and what they look for in potential partners. Through these women's diverse opinions on how beauty is defined and experienced by older lesbians, we see that there is no one perspective representing all older women. PMID- 24786424 TI - Beauty on the borderland. AB - ABSTRACT Everyday identities are constructed and re-constructed. For persons with multiple identities as women, as Black, as queer, as budding scholars, etc., the conceptions they have of beauty and of attractiveness are colored by the identities they create and maintain. In this piece, three graduate students of color share their experiences and perspectives on the topic of lesbian beauty. Through their dialogue they examine the functions of beauty in their communities, what attractiveness means for them as women, as Black women and as Black lesbians, and the power of images in their everyday lives. In their conversations, we see how three Black women, in their attempt to remain unfettered, must navigate their way through many social roles. PMID- 24786425 TI - Doing beauty. AB - ABSTRACT Beauty is often formulated as a singular image, system, or narrative. Missing in these formulations are conceptualizations of personal desire, agency, and affiliation with community aesthetics. The following essay seeks to "complicate" current understandings of beauty -understandings that implicitly assume heterosexuality -by focusing on how lesbians do beauty to negotiate within and across four discourses. These discourses, we argue, function like cultural conversations that include verbal and visual messages, individual acts and media images, and dominant and community looks. Lesbians negotiate mixed responses to these discourses, in part, through lesbian styling. In the process, lesbianrs' assertions of agency allow for a reclaiming of beauty. To illustrate the ways lesbians re-frame and reclaim beauty in everyday life, we rely upon the voices and experiences of lesbians from Northern California. PMID- 24786426 TI - Listen to the roars and whispers of water. PMID- 24786428 TI - Invisible womon. PMID- 24786427 TI - Confessions of a butch straight woman. AB - ABSTRACT According to stereotypical homosexual images of the stone-faced woman stomping around in work boots, lesbians adopt a more masculine demeanor and style of dress after coming out. In this article the author debunks this notion by sharing her personal experience of how her appearance changed through the course of her coming out process. She contrasts her views about beauty and how she felt about her body when she lived as a straight woman to her newfound comfort and freedom as a lesbian expressing the feminine and masculine sides of herself. In an ironic twist, coming out allowed her to shed the heterosexual beauty prescriptions, reconnect with her feminine side, and come out as beautiful. PMID- 24786429 TI - Lesbians walk the tightrope of beauty. AB - ABSTRACT This research addressed how lesbians are influenced by and respond to beauty constructions of dominant culture while they simultaneously redefine and create their own meaning of beauty within lesbian communities. A sample of 181 lesbian and bisexual women from the Sacramento area completed a survey examining their reasons for exercising, amount and type of exercise, body image and satisfaction with weight, eating disorder symptoms, perceptions of lesbian health threats, degree of feminist identification, appearance as a form of lesbian identification, and change of appearance after coming out. Whereas feminism served as a buffer against negative body image, the body image results found lesbians to be bound to dominant culture's thinness expectations. Other findings, however, also suggest that lesbians define beauty in their own unique way. Moving beyond simply responding to traditional beauty pressures, lesbians in this study also used beauty markers as a creative strategy to find and identify each other, suggesting that one purpose of lesbian beauty is functional. PMID- 24786430 TI - The myth of the short-haired lesbian. AB - ABSTRACT A number of myths and misperceptions related to images of lesbian beauty surround hair length. Short hair has become a symbol of being a lesbian, and many lesbians with long hair have felt pressured to cut theirs when they come out. For this essay, seven white lesbians were interviewed regarding their long hair. They describe how, in choosing not to cut their hair, or to grow it long again, they are not recognized or taken seriously as lesbians, both by other lesbians and by heterosexuals. They feel that they are perceived as heterosexual or bisexual, questioning, just coming out, trying to pass as straight, or buying into male defined standards of female beauty. This is in part because many lesbians have rejected traditionally "feminine" images of beauty,Including long hair, and have placed a higher value on more "masculine" attributes,Including short hair. In doing so, however, lesbians are still reacting to male-defined images and standards, and may be internalizing and perpetuating sexism. As more and more different kinds of women are coming out as lesbian, it becomes necessary to avoid making assumptions based on a woman's hair length. The time has come to create new images of who and what lesbians are and can be, and new standards of lesbian beauty. PMID- 24786431 TI - Even My Hair Won't Grow Straight. AB - ABSTRACT The author narrates the experience of growing her hair long after years of keeping it short, and ponders the "the socioculturo-sexual implications of hair growth." While her lesbian friends respond with curiosity and doubt, the rest of the world,Including her grandmother, wants to see long hair as a return to traditional (straight) femininity. PMID- 24786432 TI - Beauty and the butch. AB - ABSTRACT This personal narrative describes the reactions of a "butch" lesbian to notions of "beauty." I grew up in a Southern culture that glorifies strength, courage, and honor for males and beauty, care-taking, and passivity for females. My interests and activities in childhood were almost exclusively masculine. Beauty was of little importance to me except as a characteristic of the desired other. Through adolescence and young adulthood I felt alienated, confused, and conflicted about sexuality, gender, and beauty. I lived my personal and professional lives independently of each other. As I grew older and as social attitudes changed, I eventually began to incorporate and integrate a more complete and complex sense of being. PMID- 24786433 TI - Secret torrent. PMID- 24786434 TI - Lesbians and the internalization of societal standards of weight and appearance. AB - ABSTRACT Findings from a study of body image, weight concern, and disordered eating in lesbians are presented. While lesbians were more critical of traditional social norms regarding the rights and roles of women in general than heterosexual controls, this difference disappeared in regard to norms concerning women's weight and appearance. Dieting was frequent, almost half of the participants were dissatisfied with their weight, and self-esteem was strongly influenced by body esteem. A large number of lesbians said that physical attractiveness was important in a partner. However, lesbians' conception of physical attractiveness had a more functional quality, related to physical condition, and less concern for conventional aspects related to "looks" than heterosexual women. Involvement in lesbian, but not feminist, activities was found to be a protective factor against low body esteem. These findings are discussed in terms of understanding lesbians' relationships to beauty norms, variations across subgroups, and risk for eating problems. PMID- 24786435 TI - Body image, compulsory heterosexuality, and internalized homophobia. AB - ABSTRACT Body dissatisfaction in lesbians is a subject which has traditionally been ignored in the psychological literature on body image and eating disorders. Early feminist theorists and researchers argued that body dissatisfaction in women developed as a way of dealing with the oppression and misogyny they are faced with on a daily basis. However, these theories failed to take issues of race, class, and sexual orientation into account, thereby excluding the experiences of a diversity of women. This article focuses specifically on the lesbian experience and explores how cultural messages about thinness, femininity, and heterosexuality shape lesbians' feelings about their sexuality and about their bodies. Through the inevitable process of internalizing homophobia and fat hatred, both of which are institutionalized ways of keeping heterosexuality and female oppression in place, lesbians may begin to believe that there is something inherently wrong with them and with their bodies. This article explores how the impact of racism, classism, sexism, and homophobia on women may provide a more comprehensive understanding of the cultural forces behind women's dissatisfaction with their bodies. PMID- 24786436 TI - Does feminism serve a protective function against eating disorders? AB - ABSTRACT Two hundred seventeen women completed the Kinsey Sexual Orientation Scale, the Feminist Identity Scale, and three questionnaires that measured eating attitudes and behaviors. Lesbian participants were significantly more likely than heterosexual participants to work actively to improve the status of women, and they were less likely than heterosexuals to report attitudes and behaviors that are associated with eating disorders. Older women were more committed to feminist activism than younger women. Although feminist identity scores did not directly predict eating attitudes and behaviors, evidence suggests that feminism may serve a protective function against eating disorders in lesbians. PMID- 24786439 TI - Dietary salt is a public health hazard that requires vigorous attack. AB - High blood pressure is the leading cause of premature mortality worldwide. Reducing salt intake lowers blood pressure and blood pressure-lowering reduces vascular disease. There is a very high likelihood that reducing dietary salt intake will prevent vascular disease and no evidence to suggest it will cause harm. With average population salt consumption levels typically 5-10 times greater than physiological requirements, even moderately effective community-wide salt reduction programs offer the potential for very large health gains. This opportunity has been recognized and adopted by the World Health Organization as a priority action to combat chronic diseases. PMID- 24786440 TI - The population risks of dietary salt excess are exaggerated. AB - Policy positions on salt consumption (based largely on the association of sodium and blood pressure [BP]) has remained unchanged since the 1970s, until recently. However, this is beginning to change as new evidence emerges. The evidence supports a strong association of sodium with BP and cardiovascular disease events in hypertensive individuals, the elderly, and those who consume > 6 g/d of sodium. However, there is no association of sodium with clinical events at 3 to 6 g/day and a paradoxical higher rate of events at < 3 g/day. Therefore, until new evidence emerges, the optimal range of sodium consumption should be considered to be between 3 and 6 g/d. Population-wide sodium reduction is not justified in countries such as Canada. PMID- 24786441 TI - Increasing appreciation for the role of single-pill combinations for the prevention of atherosclerotic disease: a pro-polypill polemic. AB - The polypill concept for atherosclerosis is based on the notion that a single pill containing multiple products that attack frequently encountered risk factors will provide important advantages as a preventive strategy, particularly in the developing world. Potential benefits include improved efficacy and greater compliance because of simplicity and reduced costs. Here, we briefly review the rationale for the polypill and the evidence supporting its value. We consider the polypill to be a major advance in combat against cardiovascular disease, with enormous benefits to global health to be expected from its use. PMID- 24786438 TI - The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. AB - Herein, updated evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in Canadian adults are detailed. For 2014, 3 existing recommendations were modified and 2 new recommendations were added. The following recommendations were modified: (1) the recommended sodium intake threshold was changed from <= 1500 mg (3.75 g of salt) to approximately 2000 mg (5 g of salt) per day; (2) a pharmacotherapy treatment initiation systolic blood pressure threshold of >= 160 mm Hg was added in very elderly (age >= 80 years) patients who do not have diabetes or target organ damage (systolic blood pressure target in this population remains at < 150 mm Hg); and (3) the target population recommended to receive low-dose acetylsalicylic acid therapy for primary prevention was narrowed from all patients with controlled hypertension to only those >= 50 years of age. The 2 new recommendations are: (1) advice to be cautious when lowering systolic blood pressure to target levels in patients with established coronary artery disease if diastolic blood pressure is <= 60 mm Hg because of concerns that myocardial ischemia might be exacerbated; and (2) the addition of glycated hemoglobin (A1c) in the diagnostic work-up of patients with newly diagnosed hypertension. The rationale for these recommendation changes is discussed. In addition, emerging data on blood pressure targets in stroke patients are discussed; these data did not lead to recommendation changes at this time. The Canadian Hypertension Education Program recommendations will continue to be updated annually. PMID- 24786442 TI - Evolution of the polypill concept and ongoing clinical trials. AB - Ischemic heart disease and stroke are the leading causes of death worldwide. What was once thought to be an endemic disease of high income countries has become a global epidemic, as low and middle income countries have adopted Western lifestyles, to the point that noncommunicable diseases are now the main cause of death in these regions, above and beyond communicable diseases, malnutrition, and injury. As a result, a large proportion of individuals at high 10-year risk of a cardiovascular event live in low- and middle-income countries, and the most of all cardiovascular events occur in developing countries. A large amount of evidence supports the use of pharmacological treatment for the prevention of cardiovascular death in this population, including antiplatelet drugs, beta blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, however, the efficacy of cardiovascular event prevention is hampered by several problems, including inadequate prescription of medication, poor adherence to treatment, limited availability of medications, and unaffordable cost of treatment. Here we examine the use of fixed-dose combination therapy, and how this therapy could improve adherence to treatment, reduce the cost, and improve treatment affordability in low-income countries. PMID- 24786443 TI - Hypertension in developing countries. AB - The past 2 decades have seen a considerable global increase in cardiovascular disease, with hypertension remaining by far the most common. More than one-third of adults in Africa are hypertensive; as in the urban populations of most developing countries. Being a condition that occurs with relatively few symptoms, hypertension remains underdetected in many countries; especially in developing countries where routine screening at any point of health care is grossly underutilized. Because hypertension is directly related to cardiovascular disease, this has led to hypertension being the leading cause of adverse cardiovascular outcomes, as a result of patients living, often unknowingly, with uncontrolled hypertension for prolonged periods of time. In Africa, hypertension is the leading cause of heart failure; whereas at global levels, hypertension is responsible for more than half of deaths from stroke, just less than half of deaths from coronary artery disease, and for more than one-tenth of all global deaths. In this review, we discuss the escalating occurrence of hypertension in developing countries, before exploring the strengths and weaknesses of different measures to control hypertension, and the challenges of adopting these measures in developing countries. On a broad level, these include steps to curb the ripple effect of urbanization on the health and disease profile of developing societies, and suggestions to improve loopholes in various aspects of health care delivery that affect surveillance and management of hypertension. Furthermore, we consider how the industrial sectors' contributions toward the burden of hypertension can also be the source of the solution. PMID- 24786444 TI - Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome. AB - Novel antiangiogenic cancer therapies, particularly agents that block vascular endothelial growth factor (VEGF) signalling, have improved outcomes in patients with cancers and are now used as first-line therapies for some tumours. However, with VEGF inhibitors (VEGFIs) are new complications, particularly hypertension. VEGFI-induced hypertension is a dose-dependent phenomenon due to on-target effects rather than off-target effects. Increased blood pressure occurs in almost 100% of patients who take VEGFIs, with a subset who develop severe hypertension. Molecular mechanisms underlying VEGFI-induced hypertension are unclear, but endothelial dysfunction and increased vascular resistance, due to impaired nitric oxide signalling, reduced prostacyclin production, endothelin-1 (ET-1) upregulation, oxidative stress, and rarefaction have been implicated. Treatment of hypertension should be aimed at reducing the risk of short-term morbidity associated with hypertension while maintaining effective dosing of antiangiogenic therapy for optimal cancer treatment. Although specific guidelines are not yet available for the management of VEGFI-induced hypertension, angiotensin converting enzyme inhibitors and dihydropyridine calcium channel blockers are commonly used. Severe hypertension might require reduction of VEGFI dosing, or in some cases, interruption of treatment. As more potent VEGFIs are developed and as more cancer patients are treated with VEGFIs, the burden of hypertension toxicity will increase. This will be further compounded as the use of antiangiogenic drugs broadens to include older patients and those with pre-existing cardiovascular disease. Here we focus on VEGF as a target for antiangiogenesis and how this affects increased blood pressure. Putative mechanisms underlying VEGFI-induced hypertension are highlighted and therapeutic strategies to manage such hypertension are discussed. PMID- 24786445 TI - Systemic implementation strategies to improve hypertension: the Kaiser Permanente Southern California experience. AB - The past decade has seen hypertension improving in the United States where control is approximately 50%. Kaiser Permanente has mirrored and exceeded these national advances in control. Integrated models of care such as Kaiser Permanente and the Veterans Administration health systems have demonstrated the greatest hypertension outcomes. We detail the story of Kaiser Permanente Southern California (KPSC) to illustrate the success that can be achieved with an integrated health system model that uses implementation, dissemination, and performance feedback approaches to chronic disease care. KPSC, with a large ethnically diverse population of more than 3.6 million, has used a stepwise approach to achieve control rates greater than 85% in those recognized with hypertension. This was accomplished through systemic implementations of specific strategies: (1) capturing hypertensive members into a hypertension registry; (2) standardization of blood pressure measurements; (3) drafting and disseminating an internal treatment algorithm that is evidence-based and is advocating of combination therapy; and (4) a multidisciplinary approach using medical assistants, nurses, and pharmacists as key stakeholders. The infrastructure, support, and involvement across all levels of the health system with rapid and continuous performance feedback have been pivotal in ensuring the follow-through and maintenance of these strategies. The KPSC hypertension program is continually evolving in these areas. With these high control rates and established infrastructure, they are positioned to take on different innovations and study models. Such potential projects are drafting strategies on resistant hypertension or addressing the concerns about overtreatment of hypertension. PMID- 24786446 TI - Cardiovascular risk in women: focus on hypertension. AB - Hypertension is a major concern in women, contributing to the risk for morbidity and mortality and the development of cardiovascular disease (CVD), heart attack, and stroke. A woman's risk for the development of hypertension increases with age. Although it also affects younger women, hypertension is prevalent in approximately 60% of women >65 years of age. In addition to age, there are specific risk factors and lifestyle contributors for the development of hypertension in women, including obesity, ethnicity, diabetes, and chronic kidney disease. Risk reduction strategies need to be used to help reduce hypertension; maintaining a healthy body weight through diet and exercise, reduced sodium intake, and lower alcohol intake are a few of the approaches for hypertension risk reduction in women. There are several proposed mechanisms for the development of hypertension that are unique to women and pertain to the aging related elevated risk for hypertension resulting from falling estrogen levels during menopause. Oral contraceptives, pre-eclampsia and polycystic ovary syndrome are special considerations concerning the development and progression of hypertension in women. There are significant awareness issues and care gaps in the treatment of hypertension in women. Therefore, these problems must be faced and efforts need to be taken to resolve the issues surrounding the treatment and control of hypertension in women. PMID- 24786447 TI - The contribution of nurse consultants in England to the public health leadership agenda. AB - AIMS AND OBJECTIVES: To examine the contribution of nurse consultants in relation to UK public health outcomes by contrasting the health and public health skills frameworks with a study of the role of nurse consultants. BACKGROUND: Nurse consultants are the most senior advanced nurse practitioners in the UK. They work clinically, lead, research, develop policy and disseminate knowledge. DESIGN: A synthesis of research and data from the UK professional skills frameworks with data from a mixed-methods study of the role of nurse consultants. METHOD: Data collected from nurse consultants and stakeholders in England (n = 10) were analysed to identify issues impacting on the skills, competencies and effectiveness of advanced nurses. This was contrasted with the skills and career frameworks for public health and advanced healthcare practice. RESULTS: Nurse consultants use their clinical expertise to lead practice, facilitate change and monitor effectiveness. Within healthcare organisations, they contribute servicewide to the implementation of public health policy, service delivery and policy development, mirroring expected competencies and improved health outcomes. Two barriers were identified. First, that there was little time or will for nurse consultants to undertake research, precluding them from demonstrating their value. Second, that a lack of interprofessional understanding and support of their roles meant that their worth was often not appreciated by decision-makers. CONCLUSIONS: Nurse consultants lead and influence public health on many levels and need support to develop needs-led and evidence-based local, national and international public health practice and policy development. RELEVANCE TO CLINICAL PRACTICE: This research contributes to the global discussion currently being held about the nomenclature of advanced nurse practitioner roles, their scope and influence. The challenge for nurses to contribute meaningfully to public health structures at an advanced level is a concern for all nations seeking the common goal of addressing public health needs within their populations and suggests that further development of our understanding of the potential contribution of advanced nurses is needed. PMID- 24786448 TI - Direct investigation of halogen bonds by solid-state multinuclear magnetic resonance spectroscopy and molecular orbital analysis. AB - Noncovalent interactions play a ubiquitous role in the structure, stability, and reactivity of a wide range of molecular and ionic cocrystals, pharmaceuticals, materials, and biomolecules. The halogen bond continues to be the focus of much attention, due in part to its strength and unique directionality. Here, we report a multifaceted experimental and computational study of halogen bonds in the solid state. A series of cocrystals of three different diiodobenzene molecules and various onium halide (Cl(-) or Br(-)) salts, designed to exhibit moderately strong halogen bonds (C-I...X(-)) in the absence of competing hydrogen bonds, has been prepared and characterized by single-crystal X-ray diffraction. Interestingly, a wide range of geometries about the halide anion are observed. (35/37)Cl and (79/81)Br solid-state NMR spectroscopy is applied to characterize the nuclear quadrupolar coupling constants (C(Q)) and asymmetry parameters (eta(Q)) for the halogen-bonded anions at the center of bonding environments ranging from approximately linear to distorted square planar to octahedral. The relationship between the halogen bond environment and the quadrupolar parameters is elucidated through a natural localized molecular orbital (NLMO) analysis in the framework of density functional theory (DFT). These calculations reveal that the lone pair type orbitals on the halogen-bonded anion govern the magnitude and orientation of the quadrupolar tensor as the geometry about the anion is systematically altered. In -C-I...X(-)...I-C- environments, the value of eta(Q) is well-correlated to the I...X(-)...I angle. (13)C NMR and DFT calculations show a correlation between chemical shifts and halogen bond strength (through the C-I distance) in o-diiodotetrafluorobenzene cocrystals. Overall, this work provides a chemically intuitive understanding of the connection between the geometry and electronic structure of halogen bonds and various NMR parameters with the aid of NLMO analysis. PMID- 24786449 TI - Biomimetic synthesis of active isorhapontigenin dimers. AB - Synthetic isorhapontigenin was treated with several kinds of inorganic reagents and peroxidase so as to prepare active stilbene dimers. Among them, silver acetate in methanol gave two new isorhapontigenin dimers 4 and 5, together with four known natural stilbene dimers 2, 3, 6, and 7. Their structures and relative configurations were determined on the basis of spectral analysis, and their possible formation mechanisms were discussed, respectively. Compounds 2, 6, and 7 were artificially synthesized for the first time. All the products were evaluated for anti-inflammatory activities. PMID- 24786450 TI - Case series of pregnancy following gastric bypass. PMID- 24786452 TI - FDG/PET in CLL today. AB - In this issue of Blood, Falchi et al present their experience with 2-deoxy-2 [18F] fluoroglucose/positron emission tomography (FDG/PET) in the management of patients with chronic lymphocytic leukemia (CLL) or Richter syndrome (RS) over a 10-year period at a referral center. The results of this study shed light on the potential role of FDG/PET in CLL. PMID- 24786451 TI - Omega-3 polyunsaturated fatty acids protect neural progenitor cells against oxidative injury. AB - The omega-3 polyunsaturated fatty acids (omega-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived mainly from fish oil, play important roles in brain development and neuroplasticity. Here, we reported that application of omega-3 PUFAs significantly protected mouse neural progenitor cells (NPCs) against H2O2-induced oxidative injury. We also isolated NPCs from transgenic mice expressing the Caenorhabditis elegans fat-1 gene. The fat-1 gene, which is absent in mammals, can add a double bond into an unsaturated fatty acid hydrocarbon chain and convert omega-6 to omega-3 fatty acids. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that a marked decrease in apoptotic cells was found in fat-1 NPCs after oxidative injury with H2O2 as compared with wild-type NPCs. Quantitative RT-PCR and Western blot analysis demonstrated a much higher expression of nuclear factor erythroid 2 related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes, in fat-1 NPCs. The results of the study provide evidence that omega-3 PUFAs resist oxidative injury to NPCs. PMID- 24786453 TI - Waldenstrom macroglobulinemia: genetics dictates clinical course. AB - In this issue of Blood, Treon and colleagues provide strong evidence that mutations in MYD88 and CXCR4 dictate clinical presentation and survival in Waldenstrom macroglobulinemia (WM). PMID- 24786454 TI - Hallway gossip between Ras and PI3K pathways. AB - In this issue of Blood, Goodwin et al investigate the pathogenesis of juvenile myelomonocytic leukemia (JMML), demonstrating that mutant Shp2 induces granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity and that the p110delta subunit of phosphatidylinositol 3-kinase (PI3K) further promotes this dysregulation PMID- 24786455 TI - Neutrophil energetics and oxygen sensing. AB - In this issue of Blood, Jun et al, through the study of neutrophils deficient in the glucose-6-phosphate transporter, describe a novel role for the peroxisome proliferator-activated receptor-gamma (PPARG) pathway in the regulation of key neutrophil functions and link this to concomitant hypoxia-inducible factor (HIF) 1alpha stabilization. PMID- 24786456 TI - Regulators help new immigrants settle down? AB - In this issue of Blood, Muller et al showed, using a nonmyeloablative conditioning regimen consisting of total lymphoid irradiation (TLI) and anti-T cell globulin (ATG), that donor long-term hematopoietic stem cell (LT-HSC) engraftment requires the presence of host regulatory T cells that promote host HSC cycling, which could potentially provide bone marrow niches to donor HSCs. PMID- 24786457 TI - The RHOA G17V gene mutation occurs frequently in peripheral T-cell lymphoma and is associated with a characteristic molecular signature. PMID- 24786458 TI - Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event. PMID- 24786459 TI - Tet2-mutated myeloid progenitors possess aberrant in vitro self-renewal capacity. PMID- 24786460 TI - Utility of factor X concentrate for the treatment of acquired factor X deficiency in systemic light-chain amyloidosis. PMID- 24786461 TI - Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever. AB - BACKGROUND: Mice lacking the type I interferon receptor (IFNAR-/- mice) reproduce relevant aspects of Crimean-Congo hemorrhagic fever (CCHF) in humans, including liver damage. We aimed at characterizing the liver pathology in CCHF virus infected IFNAR-/- mice by immunohistochemistry and employed the model to evaluate the antiviral efficacy of ribavirin, arbidol, and T-705 against CCHF virus. METHODOLOGY/PRINCIPAL FINDINGS: CCHF virus-infected IFNAR-/- mice died 2-6 days post infection with elevated aminotransferase levels and high virus titers in blood and organs. Main pathological alteration was acute hepatitis with extensive bridging necrosis, reactive hepatocyte proliferation, and mild to moderate inflammatory response with monocyte/macrophage activation. Virus-infected and apoptotic hepatocytes clustered in the necrotic areas. Ribavirin, arbidol, and T 705 suppressed virus replication in vitro by >=3 log units (IC50 0.6-2.8 ug/ml; IC90 1.2-4.7 ug/ml). Ribavirin [100 mg/(kg*d)] did not increase the survival rate of IFNAR-/- mice, but prolonged the time to death (p<0.001) and reduced the aminotransferase levels and the virus titers. Arbidol [150 mg/(kg*d)] had no efficacy in vivo. Animals treated with T-705 at 1 h [15, 30, and 300 mg/(kg*d)] or up to 2 days [300 mg/(kg*d)] post infection survived, showed no signs of disease, and had no virus in blood and organs. Co-administration of ribavirin and T-705 yielded beneficial rather than adverse effects. CONCLUSIONS/SIGNIFICANCE: Activated hepatic macrophages and monocyte-derived cells may play a role in the proinflammatory cytokine response in CCHF. Clustering of infected hepatocytes in necrotic areas without marked inflammation suggests viral cytopathic effects. T 705 is highly potent against CCHF virus in vitro and in vivo. Its in vivo efficacy exceeds that of the current standard drug for treatment of CCHF, ribavirin. PMID- 24786462 TI - Drosophila melanogaster Hox transcription factors access the RNA polymerase II machinery through direct homeodomain binding to a conserved motif of mediator subunit Med19. AB - Hox genes in species across the metazoa encode transcription factors (TFs) containing highly-conserved homeodomains that bind target DNA sequences to regulate batteries of developmental target genes. DNA-bound Hox proteins, together with other TF partners, induce an appropriate transcriptional response by RNA Polymerase II (PolII) and its associated general transcription factors. How the evolutionarily conserved Hox TFs interface with this general machinery to generate finely regulated transcriptional responses remains obscure. One major component of the PolII machinery, the Mediator (MED) transcription complex, is composed of roughly 30 protein subunits organized in modules that bridge the PolII enzyme to DNA-bound TFs. Here, we investigate the physical and functional interplay between Drosophila melanogaster Hox developmental TFs and MED complex proteins. We find that the Med19 subunit directly binds Hox homeodomains, in vitro and in vivo. Loss-of-function Med19 mutations act as dose-sensitive genetic modifiers that synergistically modulate Hox-directed developmental outcomes. Using clonal analysis, we identify a role for Med19 in Hox-dependent target gene activation. We identify a conserved, animal-specific motif that is required for Med19 homeodomain binding, and for activation of a specific Ultrabithorax target. These results provide the first direct molecular link between Hox homeodomain proteins and the general PolII machinery. They support a role for Med19 as a PolII holoenzyme-embedded "co-factor" that acts together with Hox proteins through their homeodomains in regulated developmental transcription. PMID- 24786464 TI - Is nanotechnology a boon for oral drug delivery? AB - The oral route for drug delivery is regarded as the optimal route for achieving therapeutic benefits owing to increased patient compliance. Despite phenomenal advances in injectable, transdermal, nasal and other routes of administration, the reality is that oral drug delivery remains well ahead of the pack as the preferred delivery route. Nanocarriers can overcome the major challenges associated with this route of administration: mainly poor solubility, stability and biocompatibility of drugs. This review focuses on the potential of various polymeric drug delivery systems in oral administration, their pharmacokinetics, in vitro and in vivo models, toxicity and regulatory aspects. PMID- 24786463 TI - A direct link between the global regulator PhoP and the Csr regulon in Y. pseudotuberculosis through the small regulatory RNA CsrC. AB - In this study we investigated the influence of the global response regulator PhoP on the complex regulatory cascade controlling expression of early stage virulence genes of Yersinia pseudotuberculosis via the virulence regulator RovA. Our analysis revealed the following novel features: (1) PhoP activates expression of the CsrC RNA in Y. pseudotuberculosis, leading to activation of RovA synthesis through the CsrABC-RovM cascade, (2) activation of csrC transcription is direct and PhoP is shown to bind to two separate PhoP box-like sites, (3) PhoP-mediated activation results in transcription from two different promoters closely downstream of the PhoP binding sites, leading to two distinct CsrC RNAs, and (4) the stability of the CsrC RNAs differs significantly between the Y. pseudotuberculosis strains YPIII and IP32953 due to a 20 nucleotides insertion in CsrC(IP32953), which renders the transcript more susceptible to degradation. In summary, our study showed that PhoP-mediated influence on the regulatory cascade controlling the Csr system and RovA in Y. pseudotuberculosis varies within the species, suggesting that the Csr system is a focal point to readjust and adapt the genus to different hosts and reservoirs. PMID- 24786465 TI - Stereospecific functionalization of iodoaziridines via unstabilized aziridinyllithiums generated by iodine-lithium exchange. AB - Lithium-iodine exchange on alkyl- or aryl-substituted N-tosyliodoaziridines afforded unstabilized aziridinyllithiums, which were subsequently trapped at low temperatures with a range of carbon and heteroatom electrophiles affording cis substituted aziridines exclusively. When using isocyanates as electrophiles, access to aziridine carboxamides or 1,3,5-trisubstituted hydantoins can be selected by control of reaction temperature. PMID- 24786466 TI - Synthesis of WO3 nanoblades by the dealloying of glancing angle deposited W-Fe nanocolumnar thin films. AB - Glancing angle co-deposition of well-separated W-Fe nanocolumns was carried out using a W oblique angle sputter source and a Fe confocal incidence source. As deposited nanocolumns with an overall composition of W64.6Fe35.4 (at.%) exhibited an average column width w nc of 77 +/- 15 nm with predominant growth in the beta W phase. With the aim of synthesizing highly porous nanostructures, the as deposited precursor W-Fe nanocolumnar thin films were immersed in aqueous HNO3 solution for various dealloying durations (t d ). Formation of nanoflake-, nanocactus-, and nanoblade-like structures were observed during the dealloying treatment, as a result of selective dissolution of Fe from the W-Fe precursor films and simultaneous oxidation of W adatoms. By increasing the dealloying duration, the Fe concentration within the film reduced drastically and the film thickness increased by about three times in comparison to the as-deposited film. The dealloyed film exhibited an overall composition of W95.6Fe4.4, where the effective surface area of the film increased substantially. It was found that W adatom diffusion and subsequent rearrangement are crucially important in determining the resultant thin film morphology. The morphological development, corresponding compositions and crystallographic properties of different nanostructures were found to be significantly dependent on the dealloying duration. For optimized processing parameters, the selective dissolution process led to formation of single crystal monoclinic WO3 nanoblades, with growth along [002] and [020] axes. PMID- 24786467 TI - Characterizing topological order in superconductors via entanglement. AB - We investigate/characterize topological order in superconducting systems using entanglement. Demonstrating/utilizing the directional dependence of the entanglement, results are shown for two-dimensional [Formula: see text] and [Formula: see text] +idxy spin-singlet superconductors, comparing the results to those for a spin-polarized px+ipy superconductor; we also discuss the topological properties of a one-dimensional spin-polarized p-wave superconductor threaded by a magnetic flux. In carrying out these investigations, we establish an efficient approach to investigate entanglement in superconductors or, more generally, in quadratic fermionic Hamiltonians with pairing interactions. PMID- 24786468 TI - PASTEC: an automatic transposable element classification tool. AB - SUMMARY: The classification of transposable elements (TEs) is key step towards deciphering their potential impact on the genome. However, this process is often based on manual sequence inspection by TE experts. With the wealth of genomic sequences now available, this task requires automation, making it accessible to most scientists. We propose a new tool, PASTEC, which classifies TEs by searching for structural features and similarities. This tool outperforms currently available software for TE classification. The main innovation of PASTEC is the search for HMM profiles, which is useful for inferring the classification of unknown TE on the basis of conserved functional domains of the proteins. In addition, PASTEC is the only tool providing an exhaustive spectrum of possible classifications to the order level of the Wicker hierarchical TE classification system. It can also automatically classify other repeated elements, such as SSR (Simple Sequence Repeats), rDNA or potential repeated host genes. Finally, the output of this new tool is designed to facilitate manual curation by providing to biologists with all the evidence accumulated for each TE consensus. AVAILABILITY: PASTEC is available as a REPET module or standalone software (http://urgi.versailles.inra.fr/download/repet/REPET_linux-x64-2.2.tar.gz). It requires a Unix-like system. There are two standalone versions: one of which is parallelized (requiring Sun grid Engine or Torque), and the other of which is not. PMID- 24786469 TI - Respiratory mechanics during NCPAP and HHHFNC at equal distending pressures. AB - OBJECTIVE: To compare the effect of heated, humidified, high-flow nasal cannula (HHHFNC) and nasal continuous positive airways pressure (NCPAP) on lung function and mechanics in preterm infants with respiratory distress syndrome (RDS) at the same level of retropharyngeal pressure (Prp). DESIGN: Randomised crossover trial. SETTING: Neonatal intensive care unit, Ospedale Maggiore Policlinico, Milan, Italy. PATIENTS: 20 preterm infants (gestational age: 31+/-1 wks) with mild moderate RDS requiring non-invasive respiratory support within 96 h after birth. INTERVENTIONS: Infants were exposed to a randomised sequence of NCPAP and HHHFNC at different settings (2, 4 and 6 cmH2O for NCPAP and 2, 4, 6 L/min for HHHFNC) to enable comparison at the same level of Prp. MAIN OUTCOME MEASURES: Tidal volume by respiratory inductance plethysmography, pleural pressure estimated by oesophageal pressure, and gas exchange were evaluated at each setting and used to compute breathing pattern parameters, lung mechanics and work of breathing (WOB). RESULTS: A poor linear regression between flow and Prp was found during HHHFNC (Prp=0.3+0.7*flow; r2=0.37). Only in 15 out of 20 infants it was possible to compare HHHFNC and NCPAP at a Prp of 2 and 4 cmH2O. No statistically significant differences were found in breathing pattern, gas exchange, lung mechanics and total WOB. Resistive WOB in the upper airways was slightly but significantly higher during HHHFNC (0.65 (0.49;1.09) vs 1.57 (0.85;2.09) cmH2O median (IQR)). CONCLUSIONS: Despite differing mechanisms for generating positive airway pressure, when compared at the same Prp, NCPAP and HHHFNC provide similar effects on all the outcomes explored. PMID- 24786470 TI - Non-invasive prenatal diagnosis: progress and potential. AB - Non-invasive prenatal diagnosis and testing by analysis of cell-free DNA in the maternal circulation is a rapidly evolving field. Current clinical applications include fetal sex determination, fetal rhesus D determination, the diagnosis of some single gene disorders, and a highly accurate screening test for aneuploidies. In the future it is likely to be used for the diagnosis of an increasing range of monogenic disorders, and may even be used to profile entire fetal genomes. The introduction of these tests into clinical practice brings clear benefits but also poses several ethical, social and service delivery challenges. Here, we discuss the current clinical applications, discuss some of the technical and ethical challenges, and look to what the future might bring as technology continues to evolve. PMID- 24786471 TI - MiR-489 regulates chemoresistance in breast cancer via epithelial mesenchymal transition pathway. AB - To investigate the role of microRNAs in the development of chemoresistance and related epithelial-mesenchymal transition (EMT), we examined the effect of miR 489 in adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM). MiR-489 was significantly suppressed in MCF-7/ADM cells compared with chemosensitive parental control MCF-7/WT cells. Forced-expression of miR-489 reversed chemoresistance. Furthermore, Smad3 was identified as the target of miR-489 and is highly expressed in MCF-7/ADM cells. Forced expression of miR-489 both inhibited Smad3 expression and Smad3 related EMT properties. Finally, the interactions between Smad3, miR-489 and EMT were confirmed in chemoresistant tumor xenografts and clinical samples, indicating their potential implication for treatment of chemoresistance. PMID- 24786472 TI - Variation in optoelectronic properties of azo dye-sensitized TiO2 semiconductor interfaces with different adsorption anchors: carboxylate, sulfonate, hydroxyl and pyridyl groups. AB - The optoelectronic properties of four azo dye-sensitized TiO2 interfaces are systematically studied as a function of a changing dye anchoring group: carboxylate, sulfonate, hydroxyl, and pyridyl. The variation in optoelectronic properties of the free dyes and those in dye/TiO2 nanocomposites are studied both experimentally and computationally, in the context of prospective dye-sensitized solar cell (DSSC) applications. Experimental UV/vis absorption spectroscopy, cyclic voltammetry, and DSSC device performance testing reveal a strong dependence on the nature of the anchor of the optoelectronic properties of these dyes, both in solution and as dye/TiO2 nanocomposites. First-principles calculations on both an isolated dye/TiO2 cluster model (using localized basis sets) and each dye modeled onto the surface of a 2D periodic TiO2 nanostructure (using plane wave basis sets) are presented. Detailed examination of these experimental and computational results, in terms of light harvesting, electron conversion and photovoltaic device performance characteristics, indicates that carboxylate is the best anchoring group, and hydroxyl is the worst, whereas sulfonate and pyridyl groups exhibit competing potential. Different sensitization solvents are found to affect critically the extent of dye adsorption achieved in the dye-sensitization of the TiO2 semiconductor, especially where the anchor is a pyridyl group. PMID- 24786474 TI - Structural investigations into the stereochemistry and activity of a phenylalanine-2,3-aminomutase from Taxus chinensis. AB - Phenylalanine-2,3-aminomutase (PAM) from Taxus chinensis, a 4-methylidene imidazole-5-one (MIO)-dependent enzyme, catalyzes the reversible conversion of (S)-alpha-phenylalanine into (R)-beta-phenylalanine via trans-cinnamic acid. The enzyme also catalyzes the direct addition of ammonia to trans-cinnamic acid, a reaction that can be used for the preparation of beta-amino acids, which occur as frequent constituents of bioactive compounds. Different hypotheses have been formulated to explain the stereochemistry of the PAM-catalyzed reaction, but structural evidence for these hypotheses is lacking. Furthermore, it remains unclear how the PAM MIO group is formed from the three-amino acid (A-S-G) sequence motif. For these reasons, we elucidated PAM three-dimensional (3D) structures with a bound (R)-beta-phenylalanine analogue and with bound trans cinnamic acid. In addition, 3D structures of the (inactive) Y322A and N231A mutants of PAM were elucidated, which were found to be MIO-less. We conclude that the stereochemistry of the PAM-catalyzed reaction originates from the enzyme's ability to bind trans-cinnamic acid in two different orientations, with either the si,si face or the re,re face directed toward the MIO group, as evidenced by two distinct carboxylate binding modes. The results also suggest that the N231 side chain promotes MIO group formation by increasing the nucleophilicity of the G177 N atom through acidification of the amide proton. PMID- 24786475 TI - Reasons for withdrawing belief in vivid autobiographical memories. AB - Previous studies have shown that many people hold personal memories for events that they no longer believe occurred. This study examines the reasons that people provide for choosing to reduce autobiographical belief in vividly recollected autobiographical memories. A body of non-believed memories provided by 374 individuals was reviewed to develop a qualitatively derived categorisation system. The final scheme consisted of 8 major categories (in descending order of mention): social feedback, event plausibility, alternative attributions, general memory beliefs, internal event features, consistency with external evidence, views of self/others, personal motivation and numerous sub-categories. Independent raters coded the reports and judged the primary reason that each person provided for withdrawing belief. The nature of each category, frequency of category endorsement, category overlap and phenomenological ratings are presented, following which links to related literature and implications are discussed. This study documents that a wide variety of recollective and non recollective sources of information influence decision-making about the occurrence of autobiographical events. PMID- 24786473 TI - Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer. AB - Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations. PMID- 24786476 TI - Gait adaptability training improves obstacle avoidance and dynamic stability in patients with cerebellar degeneration. AB - Balance and gait problems in patients with cerebellar degeneration lead to reduced mobility, loss of independence, and frequent falls. It is currently unclear, however, whether balance and gait capacities can be improved by training in this group of patients. Therefore, the aim of this study was to examine the effects of gait adaptability training on obstacle avoidance and dynamic stability during adaptive gait. Ten patients with degenerative cerebellar ataxia received 10 protocolized gait adaptability training sessions of 1 h each during 5 weeks. Training was performed on a treadmill with visual stepping targets and obstacles projected on the belt's surface. As the primary outcome, we used an obstacle avoidance task while walking on a treadmill. We determined avoidance success rates, as well as dynamic stability during the avoidance manoeuvre. Clinical ratings included the scale for the assessment of ataxia (SARA), 10 m walking test, timed up-and-go test, berg balance scale, and the obstacle subtask of the emory functional ambulation profile (EFAP). Following the intervention, success rates on the obstacle avoidance task had significantly improved compared to pre intervention. For successful avoidance, participants allowed themselves smaller stability margins in the sagittal plane in the (shortened) pre-crossing step. However, in the subsequent steps they returned to baseline stability values more effectively than before training. SARA scores and the EFAP obstacle subtask improved significantly as well. This pilot study provides preliminary evidence of a beneficial effect of gait adaptability training on obstacle avoidance capacity and dynamic stability in patients with cerebellar degeneration. PMID- 24786477 TI - Charging and discharging of single colloidal particles at oil/water interfaces. AB - The physical behavior of solid colloids trapped at a fluid-fluid interface remains in itself an open fundamental issue. Here, we show that the gradients of surface tension can induce particles to jet towards the oil/water interface with velocities as high as ~ 60 mm/s when particle suspensions come in contact with the interface. We hypothesize that rubbing between the particles and oil lead to the spontaneous accumulation of negative charges on the hemisphere of those interfacial particles that contact the oil phase by means of triboelectrification. The charging process is highly dependent on the sliding distances, and gives rise to long-ranged repulsions that protect interfacial particles from coagulating at the interface by the presence of electrolyte. These triboelectric charges, however, are compensated within several hours, which affect the stability of interfacial particles. Importantly, by charging different kinds of colloidal particles using various spreading solvents and dispersion methods, we have demonstrated that charging and discharging of single colloidal particles at oil/water interfaces impacts a broad range of dynamical behavior. PMID- 24786478 TI - Special structures of hoopoe eggshells enhance the adhesion of symbiont-carrying uropygial secretion that increase hatching success. AB - Animals live in a bacterial world, and detecting and exploring adaptations favouring mutualistic relationships with antibiotic-producing bacteria as a strategy to fight pathogens are of prime importance for evolutionary ecologists. Uropygial secretion of European hoopoes (Upupa epops, Linnaeus) contains antimicrobials from mutualistic bacteria that may be used to prevent embryo infection. Here, we investigated the microscopic structure of hoopoe eggshells looking for special features favouring the adhesion of antimicrobial uropygial secretions. We impeded female access to the uropygial gland and compared microscopic characteristics of eggshells, bacterial loads of eggs and of uropygial secretion, and hatching success of experimental and control females. Then, we explored the link between microbiological characteristics of uropygial secretion and these of eggs of hoopoes, as well as possible fitness benefits. The microscopic study revealed special structures in hoopoes' eggshells (crypts). The experimental prevention of females' gland access demonstrated that crypts are filled with uropygial secretion and that symbiotic enterococci bacteria on the eggshells come, at least partially, from those in the female's uropygial gland. Moreover, the experiment resulted in a higher permeability of eggshells by several groups of bacteria and in elimination of the positive relationships detected for control nests between hatching success and density of symbiotic bacteria, either in the uropygial secretion of females or on the eggshell. The findings of specialized crypts on the eggshells of hoopoes, and of video-recorded females smearing secretion containing symbiotic bacteria at a high density onto the eggshells strongly support a link between secretion and bacteria on eggs. Moreover, the detected associations between bacteria and hatching success suggest that crypts enhancing the adhesion of symbiont-carrying uropygial secretion likely protect embryos against infections. PMID- 24786479 TI - A motion analysis marker-based method of determining centre of pressure during two-legged hopping. AB - The fixed position of force plates has led researchers to pursue alternative methods of determining centre of pressure (CoP) location. To date, errors reported using alternative methods to the force plate during dynamic tasks have been high. The aim of this study was to investigate the accuracy of a motion analysis marker-based system to determine CoP during a two-legged hopping task. Five markers were attached to the left and right feet of eight healthy adults (5 females, 3 males, age: 25.0+/-2.8 years, height: 1.75+/-0.07m, mass: 71.3+/ 11.3kg). Multivariate forward stepwise and forced entry linear regression was used with data from five participants to determine CoP position during quiet standing and hopping at various frequencies. Maximum standard error of the estimate of CoP position was 12mm in the anteroposterior direction and 8mm in the mediolateral. Cross-validation was performed using the remaining 3 participants. Maximum root mean square difference between the force plate and marker method was 14mm for mediolateral CoP and 20mm for anteroposterior CoP during 1.5Hz hopping. Differences reduced to a maximum of 7mm (mediolateral) and 14mm (anteroposterior) for the other frequencies. The smallest difference in calculated sagittal plane ankle moment and timing of maximum moment was during 3.0Hz hopping, and largest at 1.5Hz. Results indicate the marker-based method of determining CoP may be a suitable alternative to a force plate to determine CoP position during a two legged hopping task at frequencies greater than 1.5Hz. PMID- 24786480 TI - Development of artemether and lumefantrine co-loaded nanostructured lipid carriers: physicochemical characterization and in vivo antimalarial activity. AB - CONTEXT: Artemether and lumefantrine combination therapy is well-accepted for uncomplicated malaria treatment. However, the current available formulation has several pharmacokinetic mismatches such as drug degradation in gastrointestinal tract, erratic absorption, etc. Hence, need of the hour is the injectable formulation, which can overcome the pharmacokinetic mismatch associated with current available formulation in the market. OBJECTIVE: To fabricate artemether and lumefantrine co-loaded injectable nanostructured lipid carriers (NLCs) formulation. MATERIALS AND METHODS: Artemether and lumefantrine co-loaded NLCs were fabricated using homogenization followed by ultra-sonication method. Fabricated NLCs were evalauated for their physicochemical characteristics, and suitability of the formulation for malaria treatment was evaluated using in vivo animal model (Plasmodium berghei-infected mice). Results, discussion and conclusion: Artemether and lumefantrine co-loaded NLCs had a hydrodynamic diameter of ~ 145 nm with the surface charge of -66 mV. Due to the lipophilic nature of both antimalarial drugs, both single drugs-loaded and co-loaded NLCs have shown high encapsulation efficiency, which is 84% for artemether and 79% for lumefantrine. In vitro drug release study has shown a biphasic drug release pattern, which has shown 63% artemether release and 45% of lumefantrine release over a time period of 30 h. Plasmodium berghei-infected mice treated with artemether and lumefantrine co-loaded NLCs showed better antimalarial activity with respect to parasitemia progression and survivability period. PMID- 24786481 TI - Effect of polydimethylsiloxane and ethylcellulose on in vitro permeation of centchroman from its transdermal patches. AB - This research aims at the development of controlled release contraceptive transdermal patches of centchroman using ethylcellulose (EC) as film-forming polymer, polydimethylsiloxane (PDMS) as pressure sensitive adhesive with propylene glycol and Di-n-butyl-phthalate for their penetration enhancer and plasticizing properties, respectively. The physicochemical compatibility of the drug and the polymers was performed by differential scanning calorimetry and Fourier transform infrared (FTIR) spectroscopic technique. Effects of EC and PDMS ratios on moisture uptake, moisture content, tensile strength (TS), Young's modulus, adhesive strength, water vapor transmission rate (WVTR) and in vitro permeation of centchroman through Sprague-Dawley rats abdominal skin using Franz's diffusion cell were evaluated. A 3(2) full factorial design was employed to observe the effect of independent variables; concentration of ethyl cellulose and PDMS on drug permeated after 32 h, which was selected as dependent variable. Compatibility studies suggested that there were no significant interaction between the drug and polymers used. It was found that incorporation of only EC resulted in too hard patches and addition of PDMS produced patches with lower TS, increased percentage elongation, WVTR and Young's modulus. Statistical analyses suggested that independent variables have a significant effect on the dependent variable. All formulation follows zero-order release kinetics with r(2) > 0.990. In conclusion, drug in adhesive transdermal patches can be successfully fabricated for non-steroidal contraceptive centchroman to obtain a zero-order release systems. PMID- 24786482 TI - Formulation development of novel in situ nanoemulgel (NEG) of ketoprofen for the treatment of periodontitis. AB - The aim of the present study was to formulate and evaluate in situ gelling syringeable nanoemulgels (NEGs) of ketoprofen for periodontal delivery. Application of 3-factor 3-level design was employed using the Box-Behnken experimental design for the optimization of nanoemulsion using three independent variables such as percent concentration (v/v) of oil (X1), S mix (mixture of surfactant and cosurfactant) (X2) and water (X3); while the particle size (nm) (Y1), polydispersity index (Y2) and zeta potential (mV) (Y3) were used as dependent variables. The NEG was evaluated based on their drug content, pH measurement, mucoadhesion on the goat buccal mucosa, syringeability and inverted sol-gel transition temperature. The drug release data were analyzed for curve fitting based on the Korsmeyer-Peppas law, and the n-values of optimized A5 and A8 formulations were found 0.3721 and 0.3932, respectively, confirmed that both the formulations followed pseudo Fickian diffusion (n < 0.43). The formulation A8 with the optimal drug release was identified as the best NEG formulation. Results of rheological, mucoadhesion and syringeability studies showed the suitability of desired sol-gel property for periodontal drug delivery. The Herschel-Bulkley model was the best fit model to explain the flow behavior of optimized formulation. Using the HET-CAM method, significantly lower in vitro toxicity was indicated the suitability of developed NEG for intra-pocket delivery. PMID- 24786483 TI - Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious, lymph duct-cannulated rats. AB - The present study examined the effects of lipid vehicle and intestinally based efflux processes on intestinal lymphatic transport of paclitaxel (PTX) in the mesenteric lymph duct-cannulated anesthetized rat model. PTX solution alone, PTX solution pretreated with the P-glycoprotein (P-gp) inhibitor verapamil and/or PTX and a 2:1 (w/w) mixture of linoleic acid:glycerol monooleate were administered intraduodenally to anesthetized rats. Coadministration of a mixture of linoleic acid-monoolein significantly increased the extent of intestinal lymphatic transport of PTX, but it had little impact on the absolute oral bioavailability of PTX. In contrast, pretreatment with verapamil increased both the extent of lymphatic transport (3.5-fold) and absolute oral bioavailability (1.8-fold). Further increase in the lymphatic transport (6.5-fold) and absolute oral bioavailability (1.8-fold) was achieved by the combination of pretreatment with verapamil and coadministration with the linoleic acid-monoolein mixture. These data indicate that the application of lipid vehicle holds promise for selectively targeted lymphatic delivery of PTX. P-gp inhibition can result in both increased intestinal lymphatic levels and absolute oral bioavailability of PTX. PMID- 24786484 TI - Lactobionic acid coupled liposomes: an innovative strategy for targeting hepatocellular carcinoma. AB - INTRODUCTION: Liver cancer or hepatocellular carcinoma (HCC) is a major cause of death worldwide. Targeted delivery of drug to the carcinoma cell can be achieved by conjugation of ligand on the carrier system. METHODS AND MATERIALS: In this study, oxaliplatin-loaded hepatoma-targeted liposome were designed and prepared using galactosylated distearoylphosphatidylethanolamine. The liposomes were prepared by cast film method and coupled with lactobionic acid (LA-LP) using 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide as a coupling agent. The coupling was confirmed by infrared spectroscopy. They were further characterized for various parameters such as vesicle shape and surface morphology, size, entrapment efficiency and in vitro release pattern. RESULTS AND DISCUSSION: The vesicle size of the uncoupled liposome (256 nm) was found to be less than LA-LP (310 nm). The uptake of LA-LP and uncoupled liposomes by BEL7402 HCC cell lines was visualized using fluorescence microscopy that revealed the dependence of liposomal recognition and higher uptake of the LA-LP. Organ distribution studies provided evidence that coupling of lactobionic acid on liposomal surface significantly enhanced the tumor uptake of drug, which is reflected by recovery of higher percentage of drug from tumor as compared to uncoupled liposomes or free drug. CONCLUSION: These studies suggest them as effective vectors for HCC targeting. PMID- 24786485 TI - Preparation, in vitro and in vivo evaluation of bexarotene nanocrystals with surface modification by folate-chitosan conjugates. AB - Bexarotene (Bex) is a synthetic retinoid that exhibits anti-tumor activities. However, the low solubility of the compound hinders its development. In this study, bexarotene nanocrystal was developed and its surface was modified to improve the dissolution and absorption of the drug. The nanocrystals were prepared via precipitation, high-pressure homogenization method, and modified by folate-chitosan (FA-CS), which relied on the charge interaction between the negatively charged nanocrystals and the positively charged FA-CS. The physical chemical properties in terms of particle size, size distribution, zeta potential, morphology and crystallinity were evaluated. The results showed that bexarotene nanocrystals with surface modification by folate-chitosan conjugates (FC-NC-Bex) with a mean particle size of 631.3 +/- 2.7 nm, a polydispersity index of 0.33 +/- 0.06 and a zeta potential of 24.6 +/- 1.9 mV was obtained. The result of differential scanning calorimetry (DSC) showed that the nanocrystals were still in crystalline state after the preparation procedure. In the in vitro dissolution test, FC-NC-Bex showed significant increase in dissolution rate compared to raw bexarotene (nearly 6.5-fold). Compared to bexarotene suspension, FC-NC-Bex exhibited significant increase in AUC0-infinity (approximately 3-fold) and Cmax (about 1.5-fold). Taken together, the results suggested that FC-NC-Bex may provide a potential opportunity in enhancing the dissolution rate of bexarotene and its gastrointestinal absorption. PMID- 24786486 TI - Baclofen novel gastroretentive extended release gellan gum superporous hydrogel hybrid system: in vitro and in vivo evaluation. AB - Baclofen is a centrally acting skeletal muscle relaxant with a short elimination half-life, which results in frequent daily dosing and subsequent poor patient compliance. The narrow absorption window of baclofen in the upper gastrointestinal tract limits its formulation as extended release dosage forms. In this study, baclofen extended release superporous hydrogel (SPH) systems, including conventional SPH, SPH composite and SPH hybrid (SPHH), were prepared aiming to increase the residence of baclofen at its absorption window. The applicability of different polymers, namely, gellan gum, guar gum, polyvinyl alcohol and gelatin, was investigated in preparation of SPHH systems. The prepared SPH systems were evaluated regarding weight and volume swelling ratio, porosity, mechanical properties, incorporation efficiency, degree of erosion and drug release. In vivo assessment was performed in dogs to evaluate gastric residence time by X-ray studies. In addition, the oral bioavailability of baclofen relative to commercially available Lioresal(r) immediate release tablets was also investigated. The novel baclofen gellan SPHH cross linked with calcium chloride was characterized by optimum mechanical properties, acceptable swelling properties as well as extended drug release. It also exhibited a prolonged plasma profile when compared to twice daily administered Lioresal(r). PMID- 24786487 TI - Development and characterization of a novel antiacne niosomal gel of rosmarinic acid. AB - The antibacterial and anti-inflammatory potential of rosemarinic acid (ROA), a naturally occurring ester of caffeic acid has been well reported. Antibacterial effect of ROA is attributed to nucleoid damage with an increase in spatial division and condensation of genetic material. ROA has been found dynamic against many human pathogenic bacterial strains but its inhibitory prospective has never been established against skin inflammations caused by Propionibacterium acne. The skin surface in acne prone areas is colonized with Staphylococcus aureus and Propionibacterium acnes which contribute to inflammation and acne. Resistance to current antimicrobial therapies suggested the need to explore new antimicrobial agents against acne. Present work included the preparation of ROA-loaded niosomes and their in vitro antimicrobial evaluation against P. acne and S. aureus. This work also included the development of niosomal gel of rosmarinic acid for sustained delivery to bacteria infected cells. Niosomes of rosmarinic acid were formulated by reverse phase evaporation method using different ratio of span 85 and cholesterol. The prepared formulations were evaluated for its vesicle size, entrapment efficiency, in vitro release study and antibacterial activity. In vivo study of developed formulation was conducted on Swiss albino mice in comparison with solution of plain drug and a marketed formulation of benzoyl peroxide. It was evident that niosomes are novel carrier for delivery of naturally occurring antimicrobial agents, in deeper tissues of skin. The results showed that drug loaded niosomes dispersed in the gelling agent are an effective delivery system for treatment of acne vulgaris. PMID- 24786488 TI - PEGylation alleviates the non-specific toxicities of Alpha-Momorcharin and preserves its antitumor efficacy in vivo. AB - Alpha-Momorcharin (alpha-MMC) is a ribosome inactivating protein from Momordica charantia with anti-tumor activity. Previously, we had observed that modification of alpha-MMC with polyethylene glycol (PEG) could reduce toxicity, but it also reduces its anti-tumor activity in vitro. This study aims to investigate whether the metabolism-extended properties of alpha-MMC resulting from PEGylation could preserve its anti-tumor efficacy in vivo through pharmacokinetics and antitumor experiments. The pharmacokinetics experiments were conducted in rats using the TCA (Trichloroacetic Acid) method. Antitumor activity in vivo was investigated in murine mammary carcinoma (EMT-6) and human mammary carcinoma (MDA-MB-231) transplanted tumor mouse models. The results showed that PEGylation increased the plasma half-life of alpha-MMC in rats from 6.2-7.5 h to 52-87 h. When administered at 1 mg/kg, alpha-MMC-PEG and alpha-MMC showed similar anti-tumor activities in vivo, with a T/C% of 38.56% for alpha-MMC versus 35.43% for alpha MMC-PEG in the EMT-6 tumor model and 36.30% for alpha-MMC versus 39.88% for alpha MMC-PEG in the MDA-MB-231 tumor model (p > 0.05). Importantly, at the dose of 3 mg/kg, all the animals treated with alpha-MMC died while the animals treated with alpha-MMC-PEG exhibited only moderate toxic reactions, and alpha-MMC-PEG exhibited improved anti-tumor efficacy with a T/C% (relative tumor growth rate) of 25.18% and 21.07% in the EMT-6 and MDA-MB-231 tumor models, respectively. The present study demonstrates that PEGylation extends the half-life of alpha-MMC and alleviates non-specific toxicity, thereby preserving its antitumor efficacy in vivo, and a higher lever of dosage can be used to achieve better therapeutic efficacy. PMID- 24786489 TI - Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route. AB - The aim of the present study was to prepare and evaluate a rasagiline-loaded chitosan glutamate nanoparticles (RAS-CG-NPs) by ionic gelation of CG with tripolyphosphate anions (TPP). RAS-loaded CG-NPs were characterized for particle size, size distribution, encapsulation efficiency and in vitro drug release. The mean particles size, polydispersity index (PDI) and encapsulation efficiency was found to be 151.1 +/- 10.31, 0.380 +/- 0.01 and 96.43 +/- 4.23, respectively. Biodistribution of RAS formulations in the brain and blood of mice following intranasal (i.n.) and intravenous (i.v.) administration was performed using HPLC analytical method. The drug concentrations in brain following the i.n. of CG-NPs were found to be significantly higher at all the time points compared to both drug (i.n.) and drug CG-NPs (i.v.). The Cmax (999.25 ng/ml) and AUC (2086.60 ng h/ml) of formulation CG-NPs (i.n) were found to be significantly higher than CG NPs (i.v.) and RAS solution (i.n.). The direct transport percentage (DTP%) values of RAS-loaded CG-NPs (i.n.) as compared to drug solution (i.n.) increased from 66.27 +/- 1.8 to 69.27 +/- 2.1%. The results showed significant enhancement of bioavailability in brain, after administration of the RAS-loaded CG-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson's disease therapy. PMID- 24786491 TI - Regulation of Epstein-Barr virus reactivation from latency. AB - The Epstein-Barr virus (EBV) is a human gamma-herpesvirus that is implicated in various types of proliferative diseases. Upon infection, it predominantly establishes latency in B cells and cannot ever be eradicated; it persists for the host's lifetime. Reactivation of the virus from latency depends on expression of the viral immediate-early gene, BamHI Z fragment leftward open reading frame 1 (BZLF1). The BZLF1 promoter normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O tetradecanoylphorbol-13-acetate, calcium ionophore, histone deacetylase inhibitor, or anti-Ig. Transcription from the BZLF1 promoter is activated by myocyte enhancer factor 2, specificity protein 1, b-Zip type transcription factors and mediating epigenetic modifications of the promoter, such as histone acetylation and H3K4me3. In contrast, repression of the promoter is mediated by transcriptional suppressors, such as ZEB, ZIIR-BP, and jun dimerization protein 2, causing suppressive histone modifications like histone H3K27me3, H3K9me2/3 and H4K20me3. Interestingly, there is little CpG DNA methylation of the promoter, indicating that DNA methylation is not crucial for suppression of BZLF1. This review will focus on the molecular mechanisms by which the EBV lytic switch is controlled and discuss the physiological significance of this switching for its survival and oncogenesis. PMID- 24786492 TI - Behavioral and anatomical consequences of repetitive mild thoracic spinal cord contusion injury in the rat. AB - Moderate and severe spinal cord contusion injuries have been extensively studied, yet much less is known about mild injuries. Mild contusions result in transient functional deficits, proceeding to near-complete recovery, but they may render the spinal cord vulnerable to future injuries. However, to date there have been no appropriate models to study the behavioral consequences, anatomical changes, and susceptibility of a mild contusion to repeated injuries, which may occur in children as well as adults during competitive sport activities. We have developed a novel mild spinal cord contusion injury model characterized by a sequence of transient functional deficits after the first injury and restoration to near complete motor and sensory function, which is then followed up by a second injury. This model can serve not only to study the effects of repeated injuries on behavioral and anatomical changes, but also to examine the relationship between successive tissue damage and recovery of function. In the present study, we confirmed that mild thoracic spinal cord contusion, utilizing the NYU impactor device, resulted in localized tissue damage, characterized by a cystic cavity and peripheral rim of spared white matter at the injury epicenter, and rapid functional recovery to near-normal levels utilizing several behavioral tests. Repeated injury after 3weeks, when functional recovery has been completed, resulted in worsening of both motor and sensory function, which did not recover to prior levels. Anatomical analyses showed no differences in the volumes of spared white matter, lesion, or cyst, but revealed modest extension of lesion area rostral to the injury epicenter as well as an increase in inflammation and apoptosis. These studies demonstrate that a mild injury model can be used to test efficacy of treatments for repeated injuries and may serve to assist in the formulation of policies and clinical practice regarding mild SCI injury and spinal concussion. PMID- 24786493 TI - beta sheets not required: combined experimental and computational studies of self assembly and gelation of the ester-containing analogue of an Fmoc-dipeptide hydrogelator. AB - In our work toward developing ester-containing self-assembling peptides as soft biomaterials, we have found that a fluorenylmethoxycarbonyl (Fmoc)-conjugated alanine-lactic acid (Ala-Lac) sequence self-assembles into nanostructures that gel in water. This process occurs despite Fmoc-Ala-Lac's inability to interact with other Fmoc-Ala-Lac molecules via beta-sheet-like amide-amide hydrogen bonding, a condition previously thought to be crucial to the self-assembly of Fmoc-conjugated peptides. Experimental comparisons of Fmoc-Ala-Lac to its self assembling peptide sequence analogue Fmoc-Ala-Ala using a variety of microscopic, spectroscopic, and bulk characterization techniques demonstrate distinct features of the two systems and show that while angstrom-scale self-assembled structures are similar, their nanometer-scale size and morphological properties diverge and give rise to different bulk mechanical properties. Molecular dynamics simulations were performed to gain more insight into the differences between the two systems. An analysis of the hydrogen-bonding and solvent-surface interface properties of the simulated fibrils revealed that Fmoc-Ala-Lac fibrils are stronger and less hydrophilic than Fmoc-Ala-Ala fibrils. We propose that this difference in fibril amphiphilicity gives rise to differences in the higher-order assembly of fibrils into nanostructures seen in TEM. Importantly, we confirm experimentally that beta sheet-type hydrogen bonding is not crucial to the self-assembly of short, conjugated peptides, and we demonstrate computationally that the amide bond in such systems may act mainly to mediate the solvation of the self-assembled single fibrils and therefore regulate a more extensive higher-order aggregation of fibrils. This work provides a basic understanding for future research in designing highly degradable self-assembling materials with peptide-like bioactivity for biomedical applications. PMID- 24786494 TI - Propagating fronts and morphological instabilities in a precipitation reaction. AB - Precipitation processes are essential in many natural systems, especially in biomineralization and in geological pattern formation. We observe temporal oscillations in the total mass of the precipitate, the formation of propagating and annihilating waves, and morphological instabilities in a thin precipitation layer in a two-side-fed gel reactor containing the AlCl3/NaOH reaction-diffusion system. Contrary to the standard Liesegang patterns, these structures form in the lateral direction at the meeting of the counterpropagating diffusion fronts of the electrolytes. The two main ingredients of the system are the amphoteric precipitate and the cross gradient of the chemicals due to the fixed boundary conditions. Simulations with a four-variable precipitation/redissolution model qualitatively reproduce the oscillations in the total mass of the precipitate and point out the stratified three-dimensional structure of the precipitate. PMID- 24786496 TI - Translating intracellular calcium signaling into models. AB - The rich experimental data on intracellular calcium has put theoreticians in an ideal position to derive models of intracellular calcium signaling. Over the last 25 years, a large number of modeling frameworks have been suggested. Here, I will review some of the milestones of intracellular calcium modeling with a special emphasis on calcium-induced calcium release (CICR) through inositol-1,4,5 trisphosphate and ryanodine receptors. I will highlight key features of CICR and how they are represented in models as well as the challenges that theoreticians face when translating our current understanding of calcium signals into equations. The selected examples demonstrate that a successful model provides mechanistic insights into the molecular machinery of the Ca2+ signaling toolbox and determines the contribution of local Ca2+ release to global Ca2+ patterns, which at the moment cannot be resolved experimentally. PMID- 24786495 TI - Type III interferon protects swine against foot-and-mouth disease. AB - In recent years, we have developed novel strategies to control foot-and-mouth disease (FMD), including the use of biotherapeutics such as interferons (IFN) delivered by a replication-defective human adenovirus type 5 (Ad5). Swine can be sterilely protected after vaccination with an Ad5 that encodes porcine type I IFN (poIFN-alpha), and cattle can be similarly protected or develop significantly reduced disease when treated with an Ad5 delivering bovine type III IFN (boIFN lambda3). Here, we have evaluated the efficacy of porcine IFN-lambda3 (poIFN lambda3) against FMD virus in vivo. Swine inoculated with different doses of Ad5 poIFN-lambda3 were protected against disease in a dose-dependent manner. Despite the absence of systemic antiviral activity, 7 out of 10 Ad5-poIFN-lambda3 inoculated animals did not develop disease or viremia, and the other 3 inoculated animals displayed delayed and milder disease by 7 days postchallenge as compared with control animals inoculated with an Ad5 control vector. While analysis of gene expression showed significant induction of IFN and IFN-stimulated genes in Ad5-poIFN-lambda3-treated cultured porcine epithelial kidney cells, there was limited gene induction in peripheral blood monocytes isolated from treated swine. These results suggest that treatment with Ad5-poIFN-lambda3 is an effective biotherapeutic strategy against FMD in swine. PMID- 24786497 TI - Analysis of apoptosis in Caenorhabditis elegans. AB - The nematode worm Caenorhabditis elegans has provided researchers with a wealth of information on the molecular mechanisms controlling programmed cell death (apoptosis). Its genetic tractability, optical clarity, and relatively short lifespan are key advantages for rapid assessment of apoptosis in vivo. The use of forward and reverse genetics methodology, coupled with in vivo imaging, has provided deep insights into how a multicellular organism orchestrates the self destruction of specific cells during development and in response to exogenous stresses. Strains of C. elegans carrying mutations in the core elements of the apoptotic pathway, or in tissue-specific regulators of apoptosis, can be used for genetic analyses to reveal conserved mechanisms by which apoptosis is regulated in the somatic and reproductive (germline) tissue. Here we present an introduction to the study of apoptosis in C. elegans, including current techniques for visualization, analysis, and screening. PMID- 24786498 TI - Exploring oscillations in a point model of the intracellular Ca2+ concentration. AB - Intracellular calcium (Ca2+) oscillations are a key signaling mechanism in most cell types. A prominent approach to modeling intracellular Ca2+ oscillations is the use of ordinary differential equations (ODEs), which treat the intracellular Ca2+ concentration as spatially homogenous. Although ODEs cannot account for the interaction of Ca2+ microdomains to form cell-wide Ca2+ patterns, modelers still choose ODEs because (a) the study of ODEs is computationally cheap, and a large body of techniques is available to investigate ODEs in great detail, or (b) sufficient experimental data are not available to develop a spatially extended model. Irrespective of the reason, analyzing ODEs is a key instrument in the toolbox of modelers. In this protocol, we look at a well-known model for Ca2+ oscillations, the De Young-Keizer model, along with the Li-Rinzel approximation of the De Young-Keizer model. The main emphasis of this protocol is the use of the open source software package XPPAUT to numerically study ODEs. The knowledge gained here can be directly transferred to other ODE systems and therefore may serve as a template for future studies. PMID- 24786499 TI - Time to blip--stochastic simulation of single channel opening. AB - The stochastic dynamics of the inositol-1,4,5-trisphosphate (IP3) receptor (IP3R) is key to understanding a wide range of observed calcium (Ca2+) signals. The stochastic nature results from the constant binding and unbinding of Ca2+ and IP3 to and from their respective binding sites and is especially important in the initiation of a Ca2+ puff (i.e., the release of Ca2+ through a cluster of IP3Rs). Once the first IP3R opens, the Ca2+ concentration rises significantly around the ion channel, increasing the open probability for neighboring IP3Rs. This opening may trigger the activation of further receptors, giving rise to a Ca2+ puff. In this protocol, we determine the time that it takes for a single IP3R to open from rest. We explicitly take into account the tetrameric structure of the IP3R and the fact that multiple subunits must be active before the channel opens. We develop code for a stochastic simulation of the IP3R and simulate it using the software package MATLAB. This protocol shows the basic form of a stochastic simulation algorithm and may serve as a starting point to investigate more complex gating dynamics. PMID- 24786500 TI - Limited mouse necropsy. AB - Procurement of mouse tissues or organs is essential for complete verification of almost any phenotype. A proper necropsy can yield information that is difficult to obtain by limited biopsy or surgical intervention. The protocol described here is for a limited autopsy involving the thorax and abdomen only, and does not include all organs. PMID- 24786501 TI - Mouse tissue fixation. AB - One of the primary goals of fixation is to stop postmortem changes that degrade the tissue and allow optimal preservation of morphologic and cytological detail as well as nucleic acid integrity. Following death, tissues soon undergo autolysis, and if organisms from the gastrointestinal, urinary, or respiratory tracts are present, their colonization can soon cause putrefaction. Time is of the essence because warmer temperatures accelerate both types of degradation. Placing the tissue into a fixative stops the postmortem changes. Fixatives have their effect on tissue by cross-linking, coagulation, or a combination of both. This article outlines the basic tissue fixation procedure and offers guidance on choosing an appropriate fixative, the timing and duration of fixation, sample storage, and quality issues. PMID- 24786502 TI - Immunostaining for markers of apoptosis in the Caenorhabditis elegans germline. AB - The transparency of Caenorhabditis elegans makes it an ideal organism for visualizing proteins by immunofluorescence microscopy; however, the tough cuticle of worms and the egg shell surrounding embryos pose challenges in achieving effective fixation so that antibodies can diffuse into cells. In this protocol, we describe immunostaining of apoptosis-related proteins in the C. elegans adult germline using fluorescent reagents. Protein localization and abundance can be determined in various mutant backgrounds and under a variety of conditions, such as exposure to genotoxic stress. The number of antibodies specific to C. elegans proteins is quite limited compared with other organisms, but there is a growing list of immunological reagents directed against proteins in other organisms that cross-react with the homologous C. elegans proteins. PMID- 24786503 TI - Visualizing spatiotemporal dynamics of multicellular cell-cycle progressions with fucci technology. AB - The visualization of cell-cycle behavior of individual cells within complex tissues presents an irresistible challenge to biologists studying multicellular structures. However, the transition from G1 to S in the cell cycle is difficult to monitor despite the fact that the process involves the critical decision to initiate a new round of DNA replication. Here, we use ubiquitination oscillators that control cell-cycle transitions to develop genetically encoded fluorescent probes for cell-cycle progression. Fucci (fluorescent ubiquitination-based cell cycle indicator) probes exploit the regulation of cell-cycle-dependent ubiquitination to effectively label individual nuclei in G1 phase red, and those in S/G2/M phases green. Cultured cells and transgenic mice constitutively expressing the probes have been generated, such that every cell nucleus shows either red or green fluorescence. This protocol details two experiments that use biological samples expressing Fucci probes. One experiment involves time-lapse imaging of cells stably expressing a Fucci derivative (Fucci2), which allows for the exploration of the spatiotemporal patterns of cell-cycle dynamics during structural and behavioral changes of cultured cells. The other experiment involves large-field, high-resolution imaging of fixed sections of Fucci transgenic mouse embryos, which provides maps that illustrate cell proliferation versus differentiation in various developing organs. PMID- 24786504 TI - Investigating physical chromatin associations across the Xenopus genome by chromatin immunoprecipitation. AB - Chromatin immunoprecipitation (ChIP) combined with genomic analysis techniques provide a global snapshot of protein-DNA interactions in the context of chromatin, yielding insights into which genomic loci might be regulated by the DNA-associated protein under investigation. This protocol describes how to perform ChIP on intact or dissected Xenopus embryos. The ChIP-isolated DNA fragments are suitable for high-throughput sequencing (ChIP-Seq) or for quantitative PCR (ChIP-qPCR). In this protocol, embryonic tissue is harvested from Xenopus tropicalis or Xenopus laevis at the developmental stage of interest, and DNA-associated proteins are immobilized to their endogenous genomic binding sites with formaldehyde. Nuclei are extracted from embryos and subjected to sonication so as to shear the chromatin to a size that allows sufficient positional resolution of protein binding to genomic DNA. Chromatin fragments bound by the protein of interest are immunoprecipitated using antibody-coupled beads, washed under high-stringency conditions, and stripped from the beads with anionic detergents. The chemical cross-links are reversed, and the coimmunoprecipitated DNA is purified. The resulting DNA fragments can be analyzed by qPCR or used to create a ChIP-Seq library. General advice for qPCR and for making ChIP-Seq libraries is offered, and approaches for analyzing ChIP-Seq data are outlined. PMID- 24786505 TI - Inducing RNAi in Drosophila cells by soaking with dsRNA. AB - RNA interference (RNAi) triggered by synthetic long double-stranded RNAs (dsRNAs) has been applied in many Drosophila cell lines to study the functions of individual genes or for genome-wide scans. One contributor to the popularity of this approach is that many fly cell lines spontaneously take up dsRNAs from media, obviating the need for assisted uptake methods such as transfection. In this protocol, RNAi is induced in Drosophila S2 cells by soaking with dsRNA. Cell lines other than S2 can also be used, although the ability of each line to passively take up dsRNA does vary. Therefore, the efficiency of passive uptake should be carefully verified for each line. PMID- 24786506 TI - Generation of transgenic Drosophila expressing shRNAs in the miR-1 backbone. AB - In Drosophila, long-term effects of RNA interference (RNAi) must be achieved by integrating into the genome a template from which an RNAi trigger is transcribed by cellular RNA polymerases, generally RNA polymerase II or III. With encoded triggers, not only can essentially permanent silencing be achieved, but control can also be exerted over the level of trigger expression, with a resulting variation in the degree to which the target is silenced. Knockdown can also be controlled in a temporal and cell-type-dependent fashion through the use of well established transgenic methodologies and well-tested promoters. The forms of encoded triggers vary. Long double-stranded RNAs can be expressed as extended inverted repeats. The nearest equivalent of a small interfering RNA is an artificial microRNA (miRNA) or short hairpin RNA (shRNA), where a natural miRNA backbone (also called a scaffold) is remodeled to produce a different small RNA or a small inverted repeat (<30 nucleotides) is simply expressed. This protocol describes creation of transgenic Drosophila carrying shRNA inserts in a remodeled endogenous miRNA backbone. The protocol applies to the use of miRNA-based shRNAs, but most of the vectors, principles of experimental design, and methods are also applicable to long inverted repeat transgenes. PMID- 24786507 TI - Coherent Raman tissue imaging in the brain. AB - Imaging in neuroscience has been dramatically impacted by the advent of multiphoton microscopy. Multiphoton-excited fluorescence (MPF) in combination with endogenous fluorophores or labeling by fluorescent molecules has proven to be particularly powerful. However, endogenous fluorescence is limited to relatively few molecular species, and practical labeling schemes do not exist for many classes of molecules. Coherent Raman scattering (CRS) techniques, including coherent anti-Stokes Raman scattering and stimulated Raman scattering, allow imaging without the need for staining or fluorescent labeling. Such label-free imaging is desirable in biomedical research, because labeling often perturbs the function of small metabolite and drug molecules and may be too toxic to use in vivo. CRS techniques have similar imaging parameters to MPF, making use of pulsed near-infrared lasers to deliver high-sensitivity, high spatial resolution in three dimensions and rapid image acquisition. In this introduction, we will discuss the basic principles of CRS imaging, present the instrumentation requirements for high-speed CRS imaging, and show an example of imaging brain tumors and healthy tissue based on their intrinsic vibrational signatures. This discussion is intended to introduce the benefits and tradeoffs associated with different CRS techniques and show one example of the powerful capabilities of label-free chemical imaging. PMID- 24786508 TI - Identification and staining of distinct populations of secretory organelles in astrocytes. AB - Increasing evidence indicates that astrocytes, the most abundant glial cell type in the brain, respond to an elevation in cytoplasmic calcium concentration ([Ca(2+)]i) by releasing chemical transmitters (also called gliotransmitters) via regulated exocytosis of heterogeneous classes of organelles. By this process, astrocytes exert modulatory influences on neighboring cells and are thought to participate in the control of synaptic circuits and cerebral blood flow. Studying the properties of exocytosis in astrocytes is a challenge, because the cell biological basis of this process is incompletely defined. Astrocytic exocytosis involves multiple populations of secretory vesicles, including synaptic-like microvesicles (SLMVs), dense-core granules (DCGs), and lysosomes. Here we summarize the available information for identifying individual populations of secretory organelles in astrocytes, including DCGs, SLMVs, and lysosomes, and present experimental procedures for specifically staining such populations. PMID- 24786509 TI - Imaging exocytosis and recycling of synaptic-like microvesicles in astrocytes. AB - Optical imaging techniques are well suited for following the dynamics of physiological processes in living cells. Total internal reflection fluorescence (TIRF) microscopy based on evanescent wave illumination (EWi) allows spectacular, real-time visualization of individual vesicle movements, fusions, and retrievals at the cell surface (i.e., within 100 nm of the plasma membrane). TIRF microscopy is an ideal approach for studying the properties of exocytosis and recycling in cultured astrocytes, particularly because these cells have a rather flat surface and contain secretory vesicles with sparse distribution. Among all populations of secretory vesicles, we focus here on synaptic-like microvesicles (SLMVs). We illustrate how TIRF microscopy using EWi is useful to study exocytosis and recycling of SLMVs at the single-vesicle level and, when combined with epifluorescence illumination (EPIi), can provide detailed information on the kinetics of exocytosis, endocytosis, and re-acidification at the whole-cell level. PMID- 24786510 TI - Confocal spot detection of presynaptic Ca2+ domains. AB - Advances in rapid imaging of fluorescence probes are crucial to the study of neuronal signaling and information processing within the nervous system. Fluorescence indicators of cellular signaling (e.g., Ca2+ or voltage) can report changes on the millisecond timescale and signals can be localized to submicrometer structures. There are significant methodological challenges, however, involved in making measurements at such high temporal and spatial resolution. I describe here the principle and implementation of a confocal spot detection method for rapid and localized detection of fluorescence changes, which we have used for the detection of action potential-induced presynaptic Ca2+ domains. PMID- 24786511 TI - Chronic calcium imaging of neurons in the mouse visual cortex using a troponin C based indicator. AB - This protocol describes the use of the genetically encoded troponin C-based calcium indicator TN-XXL to chronically monitor the functional properties of single neocortical neurons in the mouse visual cortex. A cranial window is implanted over the brain of a mouse expressing TN-XXL in pyramidal neurons of the cerebral cortex. Several days later, the visual cortex is mapped and photographed to facilitate repeated imaging of the same region using two-photon microscopy. Initial two-photon imaging may be done ~2 wk after the window is implanted. We show the application of this technique for long-term in vivo imaging of stimulus response properties. Beyond providing functional information, long-term imaging of TN-XXL-labeled neurons also enables the simultaneous monitoring of structural properties down to the level of single dendritic spines. PMID- 24786512 TI - Nucleoside kinases in adult Schistosoma mansoni: phosphorylation of pyrimidine nucleosides. AB - Competition studies and column chromatography demonstrated that adults Schistosoma mansoni contains three nucleoside kinases that can phosphorylate pyrimidine nucleosides; a non-specific deoxyriboside kinase (EC 2.7.1.145), a specific uridine kinase and a specific cytidine kinase. The non-specific deoxyriboside kinase can phosphorylate all naturally occurring pyrimidine and purine 2'-deoxyribosides. Uridine and cytidine kinases are specific for uridine and cytidine, respectively. Various nucleoside 5'-triphosphate act as phosphate donors for the three kinases albeit to different degrees. Nucleoside kinases are critical in the activation of potential anti-parasitic drugs which may be identified among the numerous available pyrimidine nucleoside analogues. The finding that S. mansoni have nucleoside kinases that differ from their host enzymes raises the possibilities that certain pyrimidine nucleoside analogues could be selectively toxic to schistosomes. PMID- 24786513 TI - Three-dimensional fiber segment orientation distribution using X-ray microtomography. AB - The orientation of fibers in assemblies such as nonwovens has a major influence on the anisotropy of properties of the bulk structure and is strongly influenced by the processes used to manufacture the fabric. To build a detailed understanding of a fabric's geometry and architecture it is important that fiber orientation in three dimensions is evaluated since out-of-plane orientations may also contribute to the physical properties of the fabric. In this study, a technique for measuring fiber segment orientation as proposed by Eberhardt and Clarke is implemented and experimentally studied based on analysis of X-ray computed microtomographic data. Fiber segment orientation distributions were extracted from volumetric X-ray microtomography data sets of hydroentangled nonwoven fabrics manufactured from parallel-laid, cross-laid, and air-laid webs. Spherical coordinates represented the orientation of individual fibers. Physical testing of the samples by means of zero-span tensile testing and z-directional tensile testing was employed to compare with the computed results. PMID- 24786514 TI - The influence of age and exercise modality on growth hormone bioactivity in women. AB - OBJECTIVE: Prior research has indicated that the loss of skeletal muscle mass and bone mineral density observed with aging is related to the prominent age-related decline in the concentration of serum growth hormone (GH). However, there is limited data on the effects of aging on GH responses to acute bouts of heavy resistance exercise (HRE) and aerobic exercise (AE). DESIGN: The present investigation examined the effects of a HRE protocol and an AE protocol on immunoreactive GH (IGH) and bioactive GH (BGH) in active young and old women. RESULTS: Older women had a diminished serum IGH response to both the HRE and AE protocols compared to the younger women, however a similar response was not observed in serum BGH. Additionally, the HRE protocol elicited a greater BGH response than the AE protocol exclusively in the younger group. CONCLUSIONS: Regardless of exercise mode, aging induces an increase in growth hormone polymerization that specifically results in a loss of serum growth hormone immunoreactivity without a concurrent loss of serum growth hormone bioactivity. The greater BGH response to the HRE protocol found in the younger group can be attributed to an unknown serum factor of molecular weight between 30 and 55kD that either potentiated growth hormone bioactivity in response to HRE or inhibited growth hormone bioactivity in response to AE. PMID- 24786515 TI - Gas permeation in a molecular crystal and space expansion. AB - A novel single-crystal membrane [Cu(II)2(4-F-bza)4(2-mpyz)]n (4-F-bza = 4 fluorobenzoate; 2-mpyz = 2-methylpyrazine) was synthesized and its identical permeability in any crystal direction in the correction for tortuosity proved that gas diffuses inside the channels without detour. H2 permeated by 1.18 * 10( 12) mol m m(-2) s(-1) Pa(-1) with a high selectivity (Falpha: 23.5 for H2/CO and 48.0 for H2/CH4) through its 2D-channels having a minimum diameter of 2.6 A, which is narrower than the Lennard-Jones diameter of H2 (2.827 A), CO (3.690 A), and CH4 (3.758 A). The high rate of permeation was well explained by a modified Knudsen diffusion model based on the space expansion effect, which agrees with the observed permselectivity enhanced for smaller gases in considering the expansion of a channel resulting from the collision of gas molecules or atoms onto the channel wall. An analysis of single-crystal X-ray data showed the expansion order to be H2 > Ar > CH4, which was expected from the permeation analysis. The permselectivity of a porous solid depends on the elasticity of the pores as well as on the diameter of the vacant channel and the size of the target gas. PMID- 24786516 TI - MicroRNA miR-320a modulates induction of HO-1, GCLM and OKL38 by oxidized phospholipids in endothelial cells. AB - OBJECTIVE: Oxidized phospholipids (OxPLs), which are highly abundant in atherosclerotic lesions, are known to induce electrophilic stress response (ESR). ESR induces cytoprotective genes via the NF-E2-related factor 2 (NRF2) transcription factor. In order to get further insight into the mechanisms of ESR, we studied the role of microRNA (miR)-320a in induction of NRF2-dependent genes by OxPLs. METHODS: Microarray profiling and qRT-PCR methods were used for measurements of mRNA and miRNA levels. miR-320a levels were changed by transfection with synthetic oligonucleotides. Protein analysis was performed by Western blotting. The functional activity of NRF2 was measured by DNA-binding ELISA. RESULTS: Oxidized palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) induced miR-320a in endothelial cells. Induction of HO-1, OKL38 and GCLM mRNAs by OxPAPC and sulforaphane was attenuated upon knockdown of miR-320a. In contrast, transfection of ECs with miR-320a mimic oligonucleotide potentiated the effects of OxPAPC and sulforaphane on induction of HO-1, OKL38 and GCLM mRNAs. OxPAPC induced p38 activation, levels of NRF2 protein and its ability to bind to consensus NRF2 DNA binding site were elevated in ECs transfected with miR-320a mimic. miR-320a positively regulated induction of VEGF mRNA by OxPAPC. Levels of miR-320a and HO-1 and OKL38 mRNAs were elevated in aortas of ApoE knockout mice fed with high fat diet. Manipulation of miR-320a level in ECs did not affect ability of OxPAPC to induce IL-8, COX-2 and MCP-1. CONCLUSION: miR-320a plays important role in induction of expression of HO-1, GCLM and OKL38 upon ESR induced either by OxPAPC or sulforaphane. These observations propose a general role of miR-320a in control of ESR induced by different electrophilic agents. PMID- 24786517 TI - Statistical modeling reveals the effect of absolute humidity on dengue in Singapore. AB - Weather factors are widely studied for their effects on indicating dengue incidence trends. However, these studies have been limited due to the complex epidemiology of dengue, which involves dynamic interplay of multiple factors such as herd immunity within a population, distinct serotypes of the virus, environmental factors and intervention programs. In this study, we investigate the impact of weather factors on dengue in Singapore, considering the disease epidemiology and profile of virus serotypes. A Poisson regression combined with Distributed Lag Non-linear Model (DLNM) was used to evaluate and compare the impact of weekly Absolute Humidity (AH) and other weather factors (mean temperature, minimum temperature, maximum temperature, rainfall, relative humidity and wind speed) on dengue incidence from 2001 to 2009. The same analysis was also performed on three sub-periods, defined by predominant circulating serotypes. The performance of DLNM regression models were then evaluated through the Akaike's Information Criterion. From the correlation and DLNM regression modeling analyses of the studied period, AH was found to be a better predictor for modeling dengue incidence than the other unique weather variables. Whilst mean temperature (MeanT) also showed significant correlation with dengue incidence, the relationship between AH or MeanT and dengue incidence, however, varied in the three sub-periods. Our results showed that AH had a more stable impact on dengue incidence than temperature when virological factors were taken into consideration. AH appeared to be the most consistent factor in modeling dengue incidence in Singapore. Considering the changes in dominant serotypes, the improvements in vector control programs and the inconsistent weather patterns observed in the sub-periods, the impact of weather on dengue is modulated by these other factors. Future studies on the impact of climate change on dengue need to take all the other contributing factors into consideration in order to make meaningful public policy recommendations. PMID- 24786519 TI - Porphyrin dyes on TiO2 surfaces with different orientations: a photophysical, photovoltaic, and theoretical investigation. AB - Porphyrin dyes with a triphenylamino group as an electron donor, para- or meta benzoic acids as electron acceptors, and hydrogen (H) or mesityl (M) substituents on the meso position as auxiliary groups were synthesized. Their photophysical properties and photovoltaic performance in dye-sensitized solar cells were investigated. All four porphyrins exhibited similar photophysical properties in the solution and dye-loading densities on the surface of TiO2 nanoparticles; however, the p-benzoic acid functionalized porphyrins, p-H(M)PZn, gave better photovoltaic performance than m-benzoic acid functionalized porphyrins, m H(M)PZn. Theoretical calculations indicated that the electron density on the frontier molecular orbital was more delocalized to p-benzoic acid than to m benzoic acid. Absorption spectra indicated the stronger H-aggregation in m H(M)PZn than that in p-H(M)PZn on the surface of TiO2 nanoparticles. The mesityl groups in the meso positions reduced the dye-loading density due to steric hindrance between dyes. As a result, the p-MPZn exhibited the best energy conversion efficiency among the four porphyrins studied. This efficiency was further enhanced when a complementary dye BET was used. PMID- 24786518 TI - Allelic expression of deleterious protein-coding variants across human tissues. AB - Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants. PMID- 24786521 TI - The high-speed sliding friction of graphene and novel routes to persistent superlubricity. AB - Recent experiments on microscopic graphite mesas demonstrate reproducible high speed microscale superlubricity, even under ambient conditions. Here, we explore the same phenomenon on the nanoscale, by studying a graphene flake sliding on a graphite substrate, using molecular dynamics. We show that superlubricity is punctuated by high-friction transients as the flake rotates through successive crystallographic alignments with the substrate. Further, we introduce two novel routes to suppress frictional scattering and achieve persistent superlubricity. We use graphitic nanoribbons to eliminate frictional scattering by constraining the flake rotation, an approach we call frictional waveguides. We can also effectively suppress frictional scattering by biaxial stretching of the graphitic substrate. These new routes to persistent superlubricity at the nanoscale may guide the design of ultra-low dissipation nanomechanical devices. PMID- 24786523 TI - Bridging physiological and evolutionary time-scales in a gene regulatory network. AB - Gene regulatory networks (GRNs) govern phenotypic adaptations and reflect the trade-offs between physiological responses and evolutionary adaptation that act at different time-scales. To identify patterns of molecular function and genetic diversity in GRNs, we studied the drought response of the common sunflower, Helianthus annuus, and how the underlying GRN is related to its evolution. We examined the responses of 32,423 expressed sequences to drought and to abscisic acid (ABA) and selected 145 co-expressed transcripts. We characterized their regulatory relationships in nine kinetic studies based on different hormones. From this, we inferred a GRN by meta-analyses of a Gaussian graphical model and a random forest algorithm and studied the genetic differentiation among populations (FST ) at nodes. We identified two main hubs in the network that transport nitrate in guard cells. This suggests that nitrate transport is a critical aspect of the sunflower physiological response to drought. We observed that differentiation of the network genes in elite sunflower cultivars is correlated with their position and connectivity. This systems biology approach combined molecular data at different time-scales and identified important physiological processes. At the evolutionary level, we propose that network topology could influence responses to human selection and possibly adaptation to dry environments. PMID- 24786524 TI - Patients' contribution to the development of a web-based plan for integrated care - a participatory design study. AB - AIMS AND OBJECTIVES: The aim was to explore how a participatory design (PD) approach involving adult patients and parents of children with disabilities could contribute to the development of an electronic "Individual Care Plan" (e-ICP) in Norway. The system was intended to simplify multi-disciplinary cross-sector documentation and collaboration between care professionals and patients in care planning. METHODS: The data in the study comprised semi-structured interviews with patients and parents, as well as field notes. Systematic text condensation (STC) in a stepwise analysis model was performed on the data. RESULTS: Testing through three phases resulted in system improvements and additional functionality according to the participating patients' needs and requests. PD was initially applied, enabling a constructive dialogue between developers and patients. System training and collecting patient expectations was a preliminary task. Patients then brought testing experiences to the system developers, focusing first on access to information and document filing. Later, finalizing testing towards a tool for interaction with care professionals was a main concern. CONCLUSION: Adult patients and parents participating in the study provided various insights and expectations that informed system improvements and resulted in new functionality. System development and testing in healthcare can successfully incorporate patient involvement. PMID- 24786526 TI - Prophylactic role of acetyl-l-carnitine on knee lesions and associated pain in a rat model of osteoarthritis. AB - AIMS: in the present study, our aim was to validate in vivo the prophylactic role of acetyl-l-carnitine (ALC) using an established knee osteoarthritis (OA) animal model which mimics the pathological changes of OA in humans, targeting cartilage and causing chondrocyte death. MAIN METHODS: animal model was obtained by an intra-articular injection of monosodium iodoacetate (MIA) into rat femorotibial joint space. Pain was measured in animals submitted to MIA model by paw pressure and compression behavioral tests in the presence or absence of ALC. KEY FINDINGS: morphological analysis of knee-joint from MIA and ALC co-treated rats showed that the total pathological score attributed to histological findings was dramatically lower in rats treated with MIA in the presence of ALC. OA chondrocyte overexpression of pathogenic collagenase matrix-metallopeptidase-13 (MMP13) could be decreased in knee-cartilage from MIA/ALC rats; whereas type II collagen (COL2) expression level could be partially increased to control value. ALC twice daily treatment was able to attenuate pain in OA rat knee as revealed by mechanical behavioral tests. SIGNIFICANCE: in our experiments, pain that is usually associated with OA, was correlated with the severity of histopathological findings. Our findings show that there is a place for ALC as chondroprotective agents in cartilage degradation and strongly support the prophylactic and therapeutic potentials of ALC in knee-OA patients. PMID- 24786527 TI - Multicenter evaluation of Seegene Anyplex TB PCR for the detection of Mycobacterium tuberculosis in respiratory specimens. AB - Culture is the gold standard for diagnosis of tuberculosis, but it takes 6 to 8 weeks to confirm the result. This issue is complemented by the detection method using polymerase chain reaction, which is now widely used in a routine microbiology laboratory. In this study, we evaluated the performance of the Seegene Anyplex TB PCR to assess its diagnostic sensitivity and specificity, and compared its results with the Roche Cobas TaqMan MTB PCR, one of the most widely used assays in the world. Five university hospitals located in the Chungcheong area in South Korea participated in the study. A total of 1,167 respiratory specimens ordered for acid-fast bacilli staining and culture were collected for four months, analyzed via the Seegene Anyplex TB PCR, and its results were compared with the Roche Cobas TaqMan MTB PCR. For detection of Mycobacterium tuberculosis, the diagnostic sensitivity and specificity of the Anyplex TB PCR were 87.5% and 98.2% respectively, whereas those of the Cobas TaqMan were 92.0% and 98.0% respectively (p value > 0.05). For smear-positive specimens, the sensitivity of the Anyplex TB PCR was 95.2%, which was exactly the same as that of the Cobas TaqMan. For smear-negative specimens, the sensitivity of the Anyplex TB PCR was 69.2%, whereas that of the Cobas TaqMan TB PCR was 84.6%. For detection of MTB, the Seegene Anyplex TB PCR showed excellent diagnostic performance, and high sensitivity and specificity, which were comparable to the Roche Cobas TaqMan MTB PCR. In conclusion, the Anyplex TB PCR can be a useful diagnostic tool for the early detection of tuberculosis in clinical laboratories. PMID- 24786528 TI - Production of marine microalgal biodiesel through interesterification using novel Bacillus lipase. AB - In this study, enzymatic interesterification is carried out using encapsulated lipase as biocatalyst with methyl acetate as acyl acceptor in a solvent free system. Lipase, isolated from a marine bacterial isolate. Bacillus sp.S23 (KF220659.1) was immobilized in a sodium alginate beads. This investigation elaborated on the effects of various parameters namely enzyme loading, temperature, water, molar ratio, reaction time and agitation for interesterification. The study resulted in the following optimal conditions- 1.5 g immobilised lipase, 1:12 molar ratio of oil to methyl acetate, 35 degrees C, 8 % water, 60 h reaction time, 250 rpm of agitation. With the standardized condition, the maximum conversion efficiency was 95.68%. The immobilized beads, even after 10 cycles of repeated usage showed high stability in the presence of methyl acetate and no loss of lipase activity. The microalgal biodiesel composition was analysed by Gas Chromatography. The current study was efficient in using immobilized lipase for interesterification process, as the method turned to be cost effective and ecofriendly, no solvent was involved and enzyme being encapsulated in a natural polymer. PMID- 24786529 TI - Synthesis of chlorogenic acid and p-coumaroyl shikimates from glucose using engineered Escherichia coli. AB - Chlorogenic acid and hydroxylcinnamoyl shikimates are major dietary phenolics as well as antioxidants, with recently discovered biological, activities including protection against chemotheraphy side effects and prevention of cardiovascular disease and cancer. Certain fruits and vegetables produce these compounds, although a microbial system can also be utilized for synthesis of chlorogenic acid and hydroxylcinnamoyl shikimates. In this study, we engineered Escherichia coli to produce chlorogenic acid and p-coumaroyl shikimates from glucose. For the synthesis of chlorogenic acid, two E. coli strains were used; one strain for the synthesis of caffeic acid from glucose and the other strain for the synthesis of chlorogenic acid from caffeic acid and quinic acid. The final yield of chlorogenic acid using this approach was approximately 78 mg/l. To synthesize p coumaroyl shikimates, wild-type E. coli as well as several mutants were tested. Mutant E. coli carrying deletions in three genes (tyrR, pheA, and aroL) produced 236 mg/l of p-coumaroyl shikimates. PMID- 24786530 TI - Lipoteichoic acid from Lactobacillus plantarum inhibits the expression of platelet-activating factor receptor induced by Staphylococcus aureus lipoteichoic acid or Escherichia coli lipopolysaccharide in human monocyte-like cells. AB - Platelet-activating factor receptor (PAFR) plays an important role in bacterial infection and inflammation. We examined the effect of the bacterial cell wall components lipopolysaccharide (LPS) and lipoteichoic acid (LTA) from Lactobacillus plantarum (pLTA) and Staphylococcus aureus (aLTA) on PAFR expression in THP-1, a monocyte-like cell line. LPS and aLTA, but not pLTA, significantly increased PAFR expression, whereas priming with pLTA inhibited LPSmediated or aLTA-mediated PAFR expression. Expression of Toll-like receptor (TLR) 2 and 4, and CD14 increased with LPS and aLTA treatments, but was inhibited by pLTA pretreatment. Neutralizing antibodies against TLR2, TLR4, and CD14 showed that these receptors were important in LPS-mediated or aLTA-mediated PAFR expression. PAFR expression is mainly regulated by the nuclear factor kappa B signaling pathway. Blocking PAF binding to PAFR using a PAFR inhibitor indicated that LPS-mediated or aLTA-mediated PAF expression affected TNF-alpha production. In the mouse small intestine, pLTA inhibited PAFR, TLR2, and TLR4 expression that was induced by heat-labile toxin. Our data suggested that pLTA has an anti inflammatory effect by inhibiting the expression of PAFR that was induced by pathogenic ligands. PMID- 24786531 TI - Switching antibiotics production on and off in actinomycetes by an IclR family transcriptional regulator from Streptomyces peucetius ATCC 27952. AB - Doxorubicin, produced by Streptomyces peucetius ATCC 27952, is tightly regulated by dnrO, dnrN, and dnrI regulators. Genome mining of S. peucetius revealed the presence of the IclR (doxR) type family of transcription regulator mediating the signal-dependent expression of operons at the nonribosomal peptide synthetase gene cluster. Overexpression of doxR in native strain strongly repressed the drug production. Furthermore, it also had a negative effect on the regulatory system of doxorubicin, wherein the transcript of dnrI was reduced to the maximum level in comparision with the other two. Interestingly, the overexpression of the same gene also had strong inhibitory effects on the production of actinorhodin (blue pigment) and undecylprodigiosin (red pigment) in Streptomyces coelicolor M145, herboxidiene production in Streptomyces chromofuscus ATCC 49982, and spinosyn production in Saccharopolyspora spinosa NRRL 18395, respectively. Moreover, DoxR exhibited pleiotropic effects on the production of blue and red pigments in S. coelicolor when grown in different agar media, wherein the production of blue pigment was inhibited in R2YE medium and the red pigment was inhibited in YEME medium. However, the production of both blue and red pigments from S. coelicolor harboring doxR was halted in ISP2 medium, whereas S. coelicolor produced both pigmented antibiotics in the same plate. These consequences demonstrate that the on and off production of these antibiotics was not due to salt stress or media compositions, but was selectively controlled in actinomycetes. PMID- 24786532 TI - Surgical retroperitoneoscopic and transperitoneoscopic access in varicocelectomy: duplex scan results in pediatric population. AB - OBJECTIVE: This is a retrospective study to compare duplex scan results of laparoscopic Palomo's technique through retroperitoneal and transperitoneal approach for varicocelectomy in children. We statistically analyzed recurrence, testicular volume growth and complications. PATIENTS AND METHODS: Surgical intervention was performed utilizing transperitoneoscopic (group A) or retroperitoneoscopic access (group B). Duplex scan control was performed after 12 months (T1), after 2 years (T2) and the last one at 18 years old in most patients. Statistical analysis was performed using the t-test for parametric data. Differences in proportions were evaluated using chi2 or Fisher's exact test. RESULTS: We treated 120 children (age range 10-17 years) who presented an asymptomatic IV grade of reflux, Coolsaet 1, associated with a left testicular hypotrophy in 36.6% of the cases (44 patients). No post-operative complications were verified. Duplex scan exam showed an increase of left testicular growth in both groups, with complete hypotrophy disappear in patients in both groups after 24 months. Hydrocele, diagnosed clinically and confirmed with duplex scan, was the most frequent post-operative complication (22/120 cases; 18.3%). CONCLUSIONS: This study showed the importance of duplex scan at all steps of this vascular pathology in children, and that there is no significantly difference in results between the two surgical techniques except for hydrocele in transperitoneoscopic access. PMID- 24786534 TI - COMT Val158Met and cognitive and functional outcomes after traumatic brain injury. AB - There is significant variability in long-term outcomes after traumatic brain injury (TBI), making accurate prognosis difficult. In seeking to enhance understanding of outcomes, this study aimed to investigate whether COMT Val(158)Met allele status was associated with performance on neuropsychological measures of attention and working memory, executive functioning, learning and memory, and speed of information processing in the early rehabilitation phase. The study also aimed to examine whether the COMT polymorphism was associated with longer-term functional outcomes. A total of 223 participants (71.3% male) with moderate-to-severe TBI were recruited as rehabilitation inpatients to participate in a prospective, longitudinal head injury outcome study. The three COMT genotype groups (Val/Val, Val/Met, and Met/Met) were well matched for estimated full-scale IQ, years of education, age at injury, and injury severity. Results showed no significant difference between genotypes on neuropsychological measures (all p>0.05) or functional outcome, as measured by the Glasgow Outcome Scale-Extended (GOS-E), after controlling for age, education, and severity of injury. The presence of frontal lobe pathology was also not associated with cognitive performance. Those with greater injury severity (i.e., longer duration of post traumatic amnesia) performed more poorly on measures of processing speed and verbal new learning and recall. It was concluded that there was little support for the influence of COMT Val(158)Met on cognitive function, or functional outcome measures, in the acute rehabilitation phase after TBI. PMID- 24786533 TI - Therapeutic efficacy of combining pegylated liposomal doxorubicin and radiofrequency (RF) ablation: comparison between slow-drug-releasing, non thermosensitive and fast-drug-releasing, thermosensitive nano-liposomes. AB - AIMS: To determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation. MATERIALS AND METHODS: Two nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes' solid ordered to liquid disordered phase transition (at 42 degrees C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intra-tumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies. RESULTS: Non-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin. CONCLUSION: Optimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic instances, especially in extra-hepatic tumors. PMID- 24786535 TI - The debate over weight- versus price-based taxation of snuff in the United States' state legislatures. AB - Discount snuff, known for its cheap price, high nicotine content, and popularity among youth, has increased substantially in market share in the United States. As a likely result, the leading manufacturer of premium snuff has supported legislation changing the basis for taxing snuff from price to weight. To determine which public health issues arose in legislative debates, we transcribed 17 of 52 bills from US state legislatures and coded for arguments broadly categorized into public health, fair taxation, tax revenue, tax efficiency, and anti-competitiveness. State legislators expressed frustration that equitable taxation, revenue generation, and prevention of youth tobacco use were frequently conflated in the debates. Public health advocates expressed concerns over youths' incentives to purchase low-weight snuff, but seldom discussed youths' growing preference for discount snuff. The evolving market of moist snuff is a critical consideration for US state legislators as well as policy makers from other countries who may evaluate taxation methods for alternate tobacco products. PMID- 24786537 TI - Commentary: how china protects workers' health and safety: a comparison with the United States. AB - This excellent article may need some context for Western readers. My commentary attempts to provide a brief background about working conditions and the occupational safety and health situation in China during the past 40 years. This is all within the framework of the political changes and the development of the Chinese 'economic miracle' of which so many in the West are enamoured. PMID- 24786536 TI - China's laws, rights, and administrative structures in occupational safety and health: a comparison with the United States. AB - China has achieved rapid economic development, but faces tremendous challenges in occupational safety and health (OSH). We describe China's laws, rights, and administrative structures in OSH and in workers' compensation. The article compares these with comparable laws, rights, and administrative structures in the United States. We hope this comparison may provide useful lessons for continued OSH development and improvement in China. PMID- 24786539 TI - Multiple blood samples in elite soccer players. Is it worthwhile? PMID- 24786538 TI - Trends in the epidemiology of pandemic and non-pandemic strains of Vibrio parahaemolyticus isolated from diarrheal patients in Kolkata, India. AB - A total of 178 strains of V. parahaemolyticus isolated from 13,607 acute diarrheal patients admitted in the Infectious Diseases Hospital, Kolkata has been examined for serovar prevalence, antimicrobial susceptibility and genetic traits with reference to virulence, and clonal lineages. Clinical symptoms and stool characteristics of V. parahaemolyticus infected patients were analyzed for their specific traits. The frequency of pandemic strains was 68%, as confirmed by group specific PCR (GS-PCR). However, the prevalence of non-pandemic strains was comparatively low (32%). Serovars O3:K6 (19.7%), O1:K25 (18.5%), O1:KUT (11.2%) were more commonly found and other serovars such as O3:KUT (6.7%), O4:K8 (6.7%), and O2:K3 (4.5%) were newly detected in this region. The virulence gene tdh was most frequently detected in GS-PCR positive strains. There was no association between strain features and stool characteristics or clinical outcomes with reference to serovar, pandemic/non-pandemic or virulence profiles. Ampicillin and streptomycin resistance was constant throughout the study period and the MIC of ampicillin among selected strains ranged from 24 to >256 ug/ml. Susceptibility of these strains to ampicillin increased several fold in the presence of carbonyl cyanide-m-chlorophenyldrazone. The newly reported ESBL encoding gene from VPA0477 was found in all the strains, including the susceptible ones for ampicillin. However, none of the strains exhibited the beta-lactamase as a phenotypic marker. In the analysis of pulsed-field gel electrophoresis (PFGE), the pandemic strains formed two different clades, with one containing the newly emerged pandemic strains in this region. PMID- 24786540 TI - Cochlear implantation in unilateral sudden deafness improves tinnitus and speech comprehension: meta-analysis and systematic review. AB - OBJECTIVE: In recent years, otologists have begun to place cochlear implants into nonfunctioning ears after sudden unilateral hearing loss. Patients in these trials demonstrate differing degrees of hearing loss in the unimplanted ear. Few studies have examined the role of implantation in patients with normal hearing in the unimplanted ear. To understand if this practice benefits these patients in terms of tinnitus, sound localization, and speech understanding, the available world literature is reviewed. DATA SOURCES: MEDLINE, Embase, and Cochrane databases were searched for publications from database inception to June 1, 2013, without restriction of language. STUDY SELECTION: A search of multiple medical databases was performed to identify articles reporting cases series of cochlear implantation for unilateral hearing loss. Subjects were included for analysis only if the course of hearing loss was acute and rapidly progressive, if the loss was severe to profound, and if the contralateral ear had normal hearing. DATA EXTRACTION AND SYNTHESIS: Nine appropriate articles were identified, in which 36 patients met our inclusion criteria. Three meta-analyses were performed: of tinnitus (22 patients); of the lowest signal-to-noise ratio, which still allowed 50% sentence understanding (16 patients); and of sentence understanding at a fixed signal-to-noise ratio (12 patients). These found that measures of tinnitus reduction and decreased signal-to-noise ratios to still allow 50% speech discrimination were statistically significantly reduced. Systematic review of subjective changes of tinnitus in 27 patients, speech understanding in 16 patients, and sound localization in 16 patients found 96%, 100%, and 87% were improved, respectively. CONCLUSION: Cochlear implantation in unilateral sudden hearing loss with a normal functioning contralateral ear might prove to be an effective therapy. Tinnitus is reduced as is the signal-to-noise ratio, which still allows 50% speech discrimination. All patients felt that they localized sound better, and most felt that they understood speech better. Further studies should be conducted to compare the success of hearing rehabilitation of cochlear rehabilitation and traditional modalities such as contralateral routing of signal and bone-anchored hearing aids. PMID- 24786541 TI - Jellyfish model for ototoxicity. AB - OBJECTIVE: Pharmacologic ototoxicity is well described in the medical literature, yet efficient screening models are lacking. Aurelia aurita ephyrae, transparent jellyfish with identifiable hair cells, could be an effective model. Structural changes readily manifest behaviorally, and hair cells are easily stained and observed. We treated ephyrae with various gentamicin concentrations, evaluated its motility, and quantified its hair cell loss. STUDY DESIGN: Baseline pulsing per minute (P), swimming (S), and orientation (O) values were recorded from cultured ephyrae. Ephyrae were transferred into test tubes containing artificial seawater (ASW), gentamicin, or penicillin. P, S, and O were scored at 0, 24, and 48 hours. Ephyrae were formalin fixed, phalloidin stained, and imaged with confocal microscopy, and hair cells were then counted. RESULTS: P was impaired by gentamicin in a dose-dependent fashion, whereas ASW controls maintained baseline P, S, and O values. Impairment of S and O occurred with 3.5 mmol/L gentamicin at 24 hours. For six experiments each using 40 ephyrae, at 24 hours, average P was reduced from 75.2 in ASW to 28.8, 12.3, and 1.9 for 1, 2, and 3.5 mmol/L gentamicin, respectively (p < 0.05 for all cases). Hair cell loss at 24 and 48 hours was significant (32% and 48% reduction compared with control, p < 0.05) and correlated with motility deficits. Deficits from penicillin exposure were not statistically significant. CONCLUSION: The ephyra model demonstrated functional and histologic gentamicin-mediated impairments, showing promise as a screening tool for ototoxic agents. The changes in ephyra motility after gentamicin exposure correlated significantly with hair cell loss. PMID- 24786542 TI - Huschke's anterior external auditory canal foramen: art before medicine? AB - During the Renaissance, several anatomic details were described with a degree of exactness, which would stand the test of time. One example is the foramen in the anteroinferior wall of the external auditory canal, eponymously named after the German anatomist, Emil Huschke, who described it in 1844. However, the first clearly medical observation of this foramen was published by the French physician Jean Riolan the Younger in 1648. After a short excursion into some paleopathologic findings of this foramen in skulls of the Early Bronze Age and of pre-Columbian Peruvian populations, this article follows the traces of the early medical descriptions and depictions of the foramen up until the 19th century. They are connected with the names of Duverney (1683), Cassebohm (1734), Lincke (1837), Huschke (1844); Humphry (1858), von Troeltsch (1860), and especially Buerkner (1878). Surprisingly, the earliest exact depiction of the foramen in the auditory canal of a skull was found in the oil painting Saint Jerome in his study by the Flemish artist Marinus Claeszon van Reymerswaele. He depicted the foramen in the period between 1521 and 1541, a hundred years before Riolan the Younger. PMID- 24786543 TI - A practical use of a 16-gauge peripheral angiocatheter as an aspiration cautery in endoscopic ear surgery. AB - OBJECTIVE: To define a technique for the practical use of a 16-gauge peripheral venous catheter as an insulated aspiration cautery in endoscopic ear surgery. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. MATERIALS AND METHODS: A 16-gauge intravenous catheter was prepared as a cauterization instrument with aspiration. After simple rearrangement of the exterior plastic portion, it was connected to a suction system. With the help of an unipolar cautery, aspiration of the blood and homeostasis was achieved. RESULTS: Hemorrhage of the external ear canal skin after incision can be easily coagulated with this instrument. During follow-up, there were no wound infection, facial nerve paresis, scar formation, and inadvertent burn of the external canal and auricular skin. CONCLUSION: With the help of this instrument, bleeding control during incision can be easily maintained. It is a simple, easily prepared, and alternative homeostasis technique in endoscopic ear surgery. PMID- 24786544 TI - Current topics in toxicology and environmental health in Brazil. PMID- 24786545 TI - Influence of the d orbital occupation on the structures and sequential binding energies of pyridine to the late first-row divalent transition metal cations: a DFT study. AB - The ground-state structures and sequential binding energies of the late first-row divalent transition metal cations to pyridine (Pyr) are determined using density functional theory (DFT) methods. Five late first-row transition metal cations in their +2 oxidation states are examined including: Fe(2+), Co(2+), Ni(2+), Cu(2+), and Zn(2+). Calculations at B3LYP, BHandHLYP, and M06 levels of theory using 6 31G* and 6-311+G(2d,2p) basis sets are employed to determine the structures and theoretical estimates for the sequential binding energies of the M(2+)(Pyr)x complexes, where x = 1-6, respectively. Structures of the Ca(2+)(Pyr)x complexes are compared to those for the M(2+)(Pyr)x complexes of Fe(2+), Co(2+), Ni(2+), Cu(2+), and Zn(2+) to further assess the effects of the d-orbital occupation on the preferred binding geometries. The B3LYP, BHandHLYP, and M06 levels of theory yield very similar geometries for the analogous M(2+)(Pyr)x complexes. The overall trends in the sequential BDEs for all five metal cations at all three levels of theory examined are highly parallel, and are determined by a balance of the effects of the valence electronic configuration and hybridization of the metal cation, but are also influenced by repulsive ligand-ligand interactions. Present results for the M(2+)(Pyr)x complexes are compared to the analogous complexes of the late first-row monovalent transition metal cations, Co(+), Ni(+), Cu(+), and Zn(+) previously investigated to assess the effect of the charge/oxidation state on the structures and sequential binding energies. Trends in the sequential binding energies of the M(2+)(Pyr)x complexes are also compared to the analogous M(2+)(water)x, M(2+)(imidazole)x, M(2+)(2,2'-bipyridine)x, and M(2+)(1,10-phenanthroline)x complexes. PMID- 24786546 TI - Seasonal expression of KiSS-1 and the pituitary gonadotropins LHbeta and FSHbeta in adult male Libyan jird (Meriones libycus). AB - The molecular mechanisms operating on a seasonal time-scale and regulating functions such as reproduction are poorly understood in animals living in desert environments. Kisspeptin, the product of the KiSS-1 gene, plays a critical role in control of the hypothalamic-pituitary-gonad axis that orchestrates the reproductive system in vertebrates. We report a sequence analysis of KiSS-1 and the pituitary luteinising hormone-beta (LHbeta) and follicle-stimulating hormone beta (FSHbeta) in the Libyan jird (Meriones libycus), a seasonal breeding rodent that is sexually active during spring and quiescent in fall. We also assessed gene expression by quantitative real-time reverse transcription-polymerase chain reaction during the non-breeding and breeding seasons. The KiSS-1 cDNA sequence analysis showed high homology between M. libycus and all other rodents (94%) and humans (92%). KiSS-1 expression was higher during the breeding season than that during the non-breeding season. In contrast, LHbeta and FSHbeta expression levels were higher during the non-breeding season in autumn and varied in an opposite manner with testicular, seminal vesicle weights and plasma testosterone levels. Our results extend the role for KiSS-1 in activating the HPG axis in this desert rodent in its natural biotope by relaying environmental cues as in other seasonal non-desert rodent models. PMID- 24786547 TI - A screen of suitable inducers for germline differentiation of chicken embryonic stem cells. AB - Differentiation of germ cells from embryonic stem cells in vitro could have great application for treating infertility and provide an excellent model for uncovering molecular mechanisms of germline generation. In this study, we aim to screen the suitable inducers that may prove the efficiency of driving chicken embryonic stem cells (ES cells) toward germ cells. The male ES cells were separeted into different groups: single retinoic acid (RA) treatment, co-cultured with sertoli cell feeder with RA induction, cultured on matrix proteins (fibronectin, laminin and collagen) with RA treatment, cultured on fibronectin with sertoli cell feeder and RA induction, and single bone morphogenetic protein 4 (BMP4) treatment. Quantitative RT-PCR and immunoourescence were performed to characterize the ES cells differentiation process. The results showed that spermatogonial stem cells (SSCs)-like were not detected in single RA and RA with collagen groups, but were observed in the other groups. The expression of ES specific genes (Nanog and Sox2) was decreased while SSCs marker genes (Dazl, Stra8, integrin alpha6, integrinbeta1 and C-kit) was remarkably increased. The multiple comparsion results showed that the expression of SSCs marker genes in RA with sertoli cells group was significantly higher than the other groups(P<0.05). Collectively, our results suggested that chicken ES cells possess the potency to differentiate into SSCs-like cells in vitro through RA, matrix proteins, sertoli cells and BMP4 induction, of which co-cultured with sertoli cell feeder with RA induction was proved to be the best. PMID- 24786548 TI - A simple route to alloyed quaternary nanocrystals Ag-In-Zn-S with shape and size control. AB - A convenient method of the preparation of alloyed quaternary Ag-In-Zn-S nanocrystals is elaborated, in which a multicomponent mixture of simple and commercially available precursors, namely, silver nitrate, indium(III) chloride, zinc stearate, 1-dodecanethiol, and sulfur, is used with 1-octadecene as a solvent. The formation of quaternary nanocrystals necessitates the use of an auxiliary sulfur precursor, namely, elemental sulfur dissolved in oleylamine, in addition to 1-dodecanethiol. Without this additional precursor binary ZnS nanocrystals are formed. The optimum reaction temperature of 180 degrees C was also established. In these conditions shape, size, and composition of the resulting nanocrystals can be adjusted in a controlled manner by changing the molar ratio of the precursors in the reaction mixture. For low zinc stearate contents anisotropic rodlike (ca.3 nm x 10 nm) and In-rich nanocrystals are obtained. This is caused by a significantly higher reactivity of the indium precursor as compared to the zinc one. With increasing zinc precursor content the reactivities of both precursors become more balanced, and the resulting nanocrystals are smaller (1.5-4.0 nm) and become Zn-rich as evidenced by transmission electron microscopy, X-ray diffraction, and energy-dispersive spectrometry investigations. Simultaneous increases in the zinc and sulfur precursor content result in an enlargement of nanocrystals (2.5 to 5.0 nm) and further increase in the molar ZnS content (up to 0.76). The prepared nanoparticles show stable photoluminescence with the quantum yield up to 37% for In and Zn-rich nanocrystals. Their hydrodynamic diameter in toluene dispersion, determined by dynamic light scattering, is roughly twice larger than the diameter of their inorganic core. PMID- 24786550 TI - Serotype distribution and antibiotic resistance of Salmonella in food-producing animals in Shandong province of China, 2009 and 2012. AB - The aims of this study were to investigate the serotype distribution, genetic relationships and antibiotic resistance of Salmonella from food-producing animals in Shandong province of China in 2009 and 2012. A total of 362 out of 1825 samples from chickens, 53 out of 445 samples from ducks, and 50 out of 692 samples from pigs were positive for Salmonella. Isolates were subjected to serotyping, antibiotic susceptibility testing (15 antibiotics) and pulsed-field gel electrophoresis (PFGE). The most common serotypes recovered in the chicken samples were Enteritidis (n=294, 81.2%) and Indiana (n=45, 12.4%). For ducks, Cremieu (n=25, 47.2%), Indiana (n=13, 24.5%) and Typhimurium (n=9, 17%) were frequently isolated. In the pig samples, Derby (n=29, 58%), Typhimurium (n=9, 18%), and Enteritidis (n=6, 12%) were the most common serovars. PFGE results indicated that clonal dissemination of each serovar was prevalent, and that the Salmonella found on the poultry carcasses was caused by cross-contamination in the abattoirs. More than 99% of the Salmonella isolates collected were resistant to at least one antibiotic. The Salmonella resistance rates for 15 antibiotics in 2012 were significantly higher than those in 2009. In 2012, the highest resistance was to nalidixic acid (95.9%), followed by sulphafurazole (78.2%) and ampicillin (72.3%); the lowest levels of resistance were to kanamycin (40.1%) and amikacin (38.7%). Additionally, 41.5% and 42.2% of the Salmonella were resistant to ciprofloxacin and ceftiofur, respectively. Noticeably, 25% of the serovar Enteritidis and all of the serovar Indiana were resistant to at least 10 antibiotics in 2012. The increasing trend of antibiotic resistance in Shandong province indicates the need for more careful use of antibiotics. PMID- 24786551 TI - Identification of the significant factors in food safety using global sensitivity analysis and the accept-and-reject algorithm: application to the cold chain of ham. AB - Deterministic models describing heat transfer and microbial growth in the cold chain are widely studied. However, it is difficult to apply them in practice because of several variable parameters in the logistic supply chain (e.g., ambient temperature varying due to season and product residence time in refrigeration equipment), the product's characteristics (e.g., pH and water activity) and the microbial characteristics (e.g., initial microbial load and lag time). This variability can lead to different bacterial growth rates in food products and has to be considered to properly predict the consumer's exposure and identify the key parameters of the cold chain. This study proposes a new approach that combines deterministic (heat transfer) and stochastic (Monte Carlo) modeling to account for the variability in the logistic supply chain and the product's characteristics. The model generates a realistic time-temperature product history , contrary to existing modeling whose describe time-temperature profile Contrary to existing approaches that use directly a time-temperature profile, the proposed model predicts product temperature evolution from the thermostat setting and the ambient temperature. The developed methodology was applied to the cold chain of cooked ham including, the display cabinet, transport by the consumer and the domestic refrigerator, to predict the evolution of state variables, such as the temperature and the growth of Listeria monocytogenes. The impacts of the input factors were calculated and ranked. It was found that the product's time temperature history and the initial contamination level are the main causes of consumers' exposure. Then, a refined analysis was applied, revealing the importance of consumer behaviors on Listeria monocytogenes exposure. PMID- 24786552 TI - Development of PMA real-time PCR method to quantify viable cells of Pantoea agglomerans CPA-2, an antagonist to control the major postharvest diseases on oranges. AB - Dilution plating is the quantification method commonly used to estimate the population level of postharvest biocontrol agents, but this method does not permit a distinction among introduced and indigenous strains. Recently, molecular techniques based on DNA amplification such as quantitative real-time PCR (qPCR) have been successfully applied for their high strain-specific detection level. However, the ability of qPCR to distinguish viable and nonviable cells is limited. A promising strategy to avoid this issue relies on the use of nucleic acid intercalating dyes, such as propidium monoazide (PMA), as a sample pretreatment prior to the qPCR. The objective of this study was to optimize a protocol based on PMA pre-treatment samples combined with qPCR to distinguish and quantify viable cells of the biocontrol agent P. agglomerans CPA-2 applied as a postharvest treatment on orange. The efficiency of PMA-qPCR method under the established conditions (30MUM PMA for 20min of incubation followed by 30min of LED light exposure) was evaluated on an orange matrix. Results showed no difference in CFU or cells counts of viable cells between PMA-qPCR and dilution plating. Samples of orange matrix inoculated with a mixture of viable/dead cells showed 5.59log10 CFU/ml by dilution plating, 8.25log10 cells/ml by qPCR, and 5.93log10 cells/ml by PMA-qPCR. Furthermore, samples inoculated with heat-killed cells were not detected by dilution plating and PMA-qPCR, while by qPCR was of 8.16log10 cells/ml. The difference in quantification cycles (Cq) among qPCR and PMA-qPCR was approximately 16cycles, which means a reduction of 65,536 fold of the dead cells detected. In conclusion, PMA-qPCR method is a suitable tool for quantify viable CPA-2 cells, which could be useful to estimate the ability of this antagonist to colonize the orange surface. PMID- 24786553 TI - Implantation and persistence of yeast inoculum in Pinot noir fermentations at three Canadian wineries. AB - Inoculated fermentations are practiced in most wine regions of the world. This type of fermentation involves adding a commercial Saccharomyces cerevisiae strain as an inoculant. It is often assumed that the inoculant maintains dominance throughout the fermentation; however, sometimes commercial or indigenous yeasts, which were not intentionally added, end up as the dominant yeast in the winery fermentation. The aim of this study was to compare implantation/persistence of inoculants among three Canadian wineries (Quails' Gate, Cedar Creek, and Road 13 wineries). In 2010, three inoculated fermentation tanks at each of three wineries were sampled at four stages of fermentation (pre-inoculation, early, mid, and end). In addition, results from the end stage of fermentation, from two of the three wineries, were compared among different vintages (resulting in a 4-year comparison at Quails' Gate winery and a 2-year comparison at Cedar Creek winery). Strains of S. cerevisiae were discriminated by microsatellite analysis and identified using commercial microsatellite databases, whereas DNA sequencing was used to identify non-Saccharomyces. The percent implantation/persistence of the inoculum was significantly lower at Quails' Gate and Cedar Creek wineries as compared with the Road 13 winery in the 2010 vintage. Relatively low persistence of the inoculum at Quails' Gate winery was also found in the 2009 vintage, but low values were not found at Quails' Gate winery in 2011 and 2012 or at Cedar Creek winery in 2012. In all tanks having <80% relative abundance of the inoculant, the commercial strain (Lalvin ICV-D254(r)/Fermol(r) Premier Cru) was the dominant or co-dominant yeast. Our findings highlight year-to-year variation in inoculum implantation/persistence and the idea that unless strain typing of S. cerevisiae is conducted at the winery, there are no obvious fermentation factors that would indicate a relatively low inoculum implantation/persistence. PMID- 24786554 TI - Resveratrol against Arcobacter butzleri and Arcobacter cryaerophilus: activity and effect on cellular functions. AB - The frequent isolation of Arcobacter butzleri and Arcobacter cryaerophilus from food samples makes it imperative to search for potential compounds able to inhibit the development of these bacteria. Taking this into consideration, this study focuses on the antimicrobial activity of resveratrol and its mechanism of action against A. butzleri and A. cryaerophilus. The activity of resveratrol was assessed by a microdilution method and time-kill curves. Resveratrol effect on cellular functions was assessed by flow cytometry evaluating intracellular DNA content and metabolic activity. Ethidium bromide (EtBr) accumulation in the presence of resveratrol was also evaluated, as well as the susceptibility to resveratrol in the presence of phenylalanine-arginine beta-naphthylamide (PAbetaN). Scanning electron microscopy (SEM) was used to further evaluate cell damage caused by resveratrol. Resveratrol presented MIC values of 100 and 50MUg/mL to A. butzleri and A. cryaerophilus, respectively. Based on the time kill curves, resveratrol exhibited bactericidal activity, leading to a >=3log10CFU/mL reduction of initial inoculums, for A. butzleri exponential phase cells incubated for 6h with 1* MIC or with 2* MIC after 24h for stationary phase cells. For A. cryaerophilus cells in exponential growth phase, 99.9% killing was achieved after 24h incubation with 2* MIC, whereas, for stationary phase cells, bactericidal activity was only detected after incubation with 4* MIC. Incubation with resveratrol led to a decrease in both intracellular DNA content and metabolic activity. An increase in the accumulation of EtBr was observed in the presence of resveratrol, and the efflux pump inhibitor PAbetaN reduced the MIC of resveratrol. SEM analysis revealed disintegration of A. butzleri cells treated with resveratrol, whereas no morphological alteration was observed for A. cryaerophilus cells. Resveratrol has a good anti-Arcobacter activity, and the results obtained suggest that this compound could act through several different mechanisms in the inhibition of this microorganism. The results encourage the use of this compound for the development of potential strategies to control Arcobacter in food products. PMID- 24786555 TI - Intramolecular aglycon delivery enables the synthesis of 6-deoxy-beta-D-manno heptosides as fragments of Burkholderia pseudomallei and Burkholderia mallei capsular polysaccharide. AB - Burkholderia pseudomallei and Burkholderia mallei are potential bioterrorism agents. They express the same capsular polysaccharide (CPS), a homopolymer featuring an unusual [->3)-2-O-acetyl-6-deoxy-beta-D-manno-heptopyranosyl-(1->] as the repeating unit. This CPS is known to be one of the main targets of the adaptive immune response in humans and therefore represents a crucial subunit candidate for vaccine development. Herein, the stereoselective synthesis of mono- and disaccharidic fragments of the B. pseudomallei and B. mallei CPS repeating unit is reported. The synthesis of 6-deoxy-beta-D-manno-heptosides was investigated using both inter- and intramolecular glycosylation strategies from thio-manno-heptose that was modified with 2-naphthylmethyl (NAP) at C2. We show here that NAP-mediated intramolecular aglycon delivery (IAD) represents a suitable approach for the stereocontrolled synthesis of 6-deoxy-beta-D-manno heptosides without the need for rigid 4,6-O-cyclic protection of the sugar skeleton. The IAD strategy is highly modular, as it can be applied to structurally diverse acceptors with complete control of stereoselectivity. Problematic hydrogenation of the acetylated disaccharides was overcome by using a microfluidic continuous flow reactor. PMID- 24786556 TI - An unexpected worm hanging over the cecum. PMID- 24786557 TI - Management of celiac disease: beyond the gluten-free diet. PMID- 24786559 TI - Severe diarrhea following bone marrow transplantation is not always caused by GVHD. PMID- 24786560 TI - An unusual familial, recurrent neoplasm. PMID- 24786561 TI - Ebf factors and MyoD cooperate to regulate muscle relaxation via Atp2a1. AB - Myogenic regulatory factors such as MyoD and Myf5 lie at the core of vertebrate muscle differentiation. However, E-boxes, the cognate binding sites for these transcription factors, are not restricted to the promoters/enhancers of muscle cell-specific genes. Thus, the specificity in myogenic transcription is poorly defined. Here we describe the transcription factor Ebf3 as a new determinant of muscle cell-specific transcription. In the absence of Ebf3 the lung does not unfold at birth, resulting in respiratory failure and perinatal death. This is due to a hypercontractile diaphragm with impaired Ca(2+) efflux-related muscle functions. Expression of the Ca(2+) pump Serca1 (Atp2a1) is downregulated in the absence of Ebf3, and its transgenic expression rescues this phenotype. Ebf3 binds directly to the promoter of Atp2a1 and synergises with MyoD in the induction of Atp2a1. In skeletal muscle, the homologous family member Ebf1 is strongly expressed and together with MyoD induces Atp2a1. Thus, Ebf3 is a new regulator of terminal muscle differentiation in the diaphragm, and Ebf factors cooperate with MyoD in the induction of muscle-specific genes. PMID- 24786562 TI - L-mimosine increases the production of vascular endothelial growth factor in human tooth slice organ culture model. AB - AIM: To assess the pro-angiogenic and pro-inflammatory capacity of the dentine pulp complex in response to the prolyl hydroxylase inhibitor L-mimosine in a tooth slice organ culture model. METHODOLOGY: Human teeth were sectioned transversely into 600-MUm-thick slices and cultured in medium supplemented with serum and antibiotics. Then, pulps were stimulated for 48 h with L-mimosine. Pulps were subjected to viability measurements based on formazan formation in MTT assays. In addition, histological evaluation of pulps was performed based on haematoxylin and eosin staining. Culture supernatants were subjected to immunoassays for vascular endothelial growth factor (VEGF) to determine the pro angiogenic capacity and to immunoassays for interleukin (IL)-6 and IL-8 to assess the pro-inflammatory response. Interleukin-1 served as pro-inflammatory control. Echinomycin was used to inhibit hypoxia-inducible factor-1 (HIF-1) alpha activity. Data were analysed using Student's t-test and Mann-Whitney U test. RESULTS: Pulps within tooth slices remained vital upon L-mimosine stimulation as indicated by formazan formation and histological evaluation. L-mimosine increased VEGF production when normalized to formazan formation in the pulp tissue of the tooth slices (P < 0.05). This effect on VEGF was reduced by echinomycin (P < 0.01). Changes in normalized IL-6 and IL-8 levels upon treatment with L-mimosine did not reach the level of significance (P > 0.05), whilst treatment with IL-1, which served as positive control, increased IL-6 (P < 0.05) and IL-8 levels (P < 0.05). CONCLUSIONS: The prolyl hydroxylase inhibitor L-mimosine increased VEGF production via HIF-1 alpha in the tooth slice organ culture model whilst inducing no prominent increase in IL-6 and IL-8. Pre-clinical studies will reveal if these in vitro effects translate into dental pulp regeneration. PMID- 24786563 TI - Autism spectrum disorders: weighing the risk of SSRI exposure in pregnancy. AB - A possible link between prenatal exposure to the selective serotonin reuptake inhibitors (SSRIs) and development of autism spectrum disorders (ASDs), previously suggested by two case-control studies, was not confirmed by a recent cohort study that followed for 5-10 years more than 600,000 births. However, this study failed to demonstrate that SSRI exposure during pregnancy is safe in terms of child development outcomes, as an increased risk of ASDs cannot be completely ruled out. In the present article, the main strengths and weaknesses of this study are briefly analysed, including a possibility of confounding by indication. PMID- 24786564 TI - Different clinical courses of children exposed to a single incident of psychological trauma: a 30-month prospective follow-up study. AB - BACKGROUND: We investigated the distinct longitudinal trajectories of posttraumatic stress symptoms in a sample of 167 children, who witnessed death of two mothers of their schoolmates. METHODS: The cohort was followed-up at 2 days (T1), 2 months (T2), 6 months (T3), and 30 months (T4) after the traumatic event. The children's posttraumatic stress symptoms (T1-T4), depression (T1, T3 and T4), state anxiety (T1, T3 and T4), and quality of life (T4) were assessed, along with parental stress related to child rearing (T4). Different trajectory patterns of the children's posttraumatic stress symptoms were identified using growth mixture modeling (GMM). RESULTS: Four different patterns of symptom change were identified, which were consistent with the prototypical model, and were named Recovery (19.9%), Resilience (72.7%), Chronic Dysfunction (1.8%), and Delayed Reactions (5.6%). Significant differences were found in depression and anxiety scores, children's quality of life, and parental rearing stress according to the distinct longitudinal trajectories of posttraumatic stress symptoms. CONCLUSIONS: The present study suggests that individual differences should be taken into account in the clinical course and outcome of children exposed to psychological trauma. The two most common trajectories were the Resilience and the Recovery types, together suggesting that over 90% of children were evidenced with a favorable 30-month outcome. The latent classes were associated with significant mean differences in depression and anxiety scores, supporting the clinical validity of the distinct trajectories. PMID- 24786565 TI - In memoriam: Dr. Roland Meinert. PMID- 24786567 TI - In vivo applications of electrospun tissue-engineered vascular grafts: a review. AB - There is great clinical demand for synthetic vascular grafts with improved long term efficacy. The ideal vascular conduit is easily implanted, nonthrombogenic, biocompatible, resists aneurysmal dilatation, and ultimately degrades or is assimilated as the patient remodels the graft into tissue resembling native vessel. The field of vascular tissue engineering offers an opportunity to design the ideal synthetic graft, and researchers have evaluated a variety of methods and materials for use in graft construction. Electrospinning is one method that has received considerable attention within tissue engineering for constructing so called tissue scaffolds. Tissue scaffolds are temporary, porous structures which are commonly composed of bioresorbable polymers that promote native tissue ingrowth and have degradation kinetics compatible with a patient's rate of extracellular matrix production in order to successfully transit from synthetic conduits into neovessels. In this review, we summarize the history of tissue engineered vascular grafts (TEVG), focusing on scaffolds generated by the electrospinning process, and discuss in vivo applications. We review the materials commonly employed in this approach and the preliminary results after implantation in animal models in order to gauge clinical viability of the electrospinning process for TEVG construction. Scientists have studied electrospinning technology for decades, but only recently has it been orthotopically evaluated in animal models such as TEVG. Advantages of electrospun TEVG include ease of construction, favorable cellular interactions, control of scaffold features such as fiber diameter and pore size, and the ability to choose from a variety of polymers possessing a range of mechanical and chemical properties and degradation kinetics. Given its advantages, electrospinning technology merits investigation for use in TEVG, but an emphasis on long-term in vivo evaluation is required before its role in clinical vascular tissue engineering can be realized. PMID- 24786568 TI - Ferromagnetism in Mn-doped Sb(2)Te. AB - We report that Sb2Te, a natural superlattice phase consisting of two elemental Sb2 layers interleaved with single Sb2Te3 layers, becomes ferromagnetic at low temperatures on doping with small percentages of Mn. Ferromagnetism appears for Mn concentrations as low as Sb1.98Mn0.02Te, where a ferromagnetic Tc of ~8.6 K is observed. Tc decreases with increasing Mn content in the stoichiometric materials but increases with increasing Te excess in materials of the type Sb1.93 yMn0.07Te1+y, starting at ~3 K at y = 0 and reaching a Tc of ~8.9 K at y = 0.06. PMID- 24786569 TI - Batrachedra nuciferae, an inflorescence-feeding moth associated with coconut, Cocos nucifera, and palmiste, Roystonea oleracea, in Trinidad, West Indies. AB - In 2006, Batrachedra nuciferae Hodges (Lepidoptera: Batrachedridae) was the first phytophagous insect to be reported from inflorescences of coconut, Cocos nucifera L. (Arecales: Arecaceae), in Trinidad, West Indies. At that time, it was suggested to be an introduced species contributing to decreasing coconut yields on the island and potentially a threat to other palms. In this preliminary study, inflorescences of coconut, seven indigenous palms, and six exotic ornamental palms were surveyed in several areas of Trinidad. Caterpillars of more than 10 species of Lepidoptera were found and reared through to the adult stage. Batrachedra nuciferae was positively identified. It was concluded that the caterpillars of B. nuciferae feed on pollen in the male flowers of coconut and palmiste or royal palm, Roystonea oleracea (Jacquin) O.F. Cook. There was no evidence that B. nuciferae bred on any of the other palms surveyed, but it is not conclusive that they do not do so. A parasitoid, Apanteles (sensu lato) sp. (Hymenoptera: Braconidae), of B. nuciferae was reared. On available information, B. nuciferae is more likely to be an indigenous species that has hitherto been overlooked than an introduced species. In view of what is known about damage yield relationships and biological control agents, B. nuciferae is unlikely to cause yield losses to coconut, so control measures are not justified. PMID- 24786571 TI - Antibacterial activities of plants from Central Africa used traditionally by the Bakola pygmies for treating respiratory and tuberculosis-related symptoms. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The antibacterial activities of 18 plants from 10 different families were investigated for their antimicrobial efficacy, based on the traditional uses of these species by Bakola pygmies living in Central Africa, especially along the Ngoyang area in Cameroon for the treatment of respiratory and tuberculosis-related symptoms. The aim of the study is to test the antimicrobial efficacy of these plants against some pathogens associated with respiratory disease and to determine if there is any validation for the traditional use against Mycobacterium species. MATERIALS AND METHODS: Medium polar extracts were prepared in MeOH/DCM (1:1, v/v) from the plant parts of each species used traditionally and were assayed against pathogens associated with respiratory tract ailments [Staphylococcus aureus (ATCC 25923), Klebsiella pneumoniae (ATCC 13883) and Morexella cattarhalis (ATCC 14468)] using the minimum inhibitory concentration (MIC) method. Two additional faster growing Mycobacterium strains [Mycobacterium smegmatis (ATCC 23246) and Mycobacterium aurum (NCTC 10437)] were included in the assay as predictive test organisms for the more pathogenic strain Mycobacterium tuberculosis. RESULTS: Some plant species, such as Alchornea floribunda, Musanga cecropioides (both leaves and stem bark), Tetracera potatoria and Xylopia aethiopica (stem bark), were effective in inhibiting Morexella cattarhalis, having MIC values between 65 and 250 MUg/mL. Some noteworthy antimycobacterial inhibition (MIC<=200 MUg/mL and as low as MIC 6.5 ug/mL) for 54% of the extracts were observed. CONCLUSION: While moderate activity was shown for pathogens causing respiratory tract infections, these plant species seems to be selectively targeting Mycobacteria spp. suggesting that the traditional use for treating tuberculosis related symptoms may be indeed be accurate. PMID- 24786572 TI - European medicinal polypores--a modern view on traditional uses. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In particular five polypore species, i.e. Laetiporus sulphureus, Fomes fomentarius, Fomitopsis pinicola, Piptoporus betulinus, and Laricifomes officinalis, have been widely used in central European folk medicines for the treatment of various diseases, e.g. dysmenorrhoea, haemorrhoids, bladder disorders, pyretic diseases, treatment of coughs, cancer, and rheumatism. Prehistoric artefacts going back to over 5000 years underline the long tradition of using polypores for various applications ranging from food or tinder material to medicinal-spiritual uses as witnessed by two polypore species found among items of Otzi, the Iceman. The present paper reviews the traditional uses, phytochemistry, and biological activity of the five mentioned polypores. MATERIALS AND METHODS: All available information on the selected polypore taxa used in traditional folk medicine was collected through evaluation of literature in libraries and searches in online databases using SciFinder and Web of Knowledge. RESULTS: Mycochemical studies report the presence of many primary (e.g. polysaccharides) and secondary metabolites (e.g. triterpenes). Crude extracts and isolated compounds show a wide spectrum of biological properties, such as anti-inflammatory, cytotoxic, and antimicrobial activities. CONCLUSIONS: The investigated polypores possess a longstanding ethnomycological tradition in Europe. Here, we compile biological results which highlight their therapeutic value. Moreover, this work provides a solid base for further investigations on a molecular level, both compound- and target-wise. PMID- 24786573 TI - Effects of total lignans from Eucommia ulmoides barks prevent bone loss in vivo and in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The present study systematically investigate the in vivo and in vitro effect of total lignans (TL) extracted from Eucommia ulmoides Oliv. barks on bone formation using ovariectomy rat model and primary cultures of rat osteoblasts. MATERIALS AND METHODS: Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17alpha-ethinylestradiol (E2, 25 MUg/kg/day); OVX with TL of graded doses (20, 40, or 80 mg/kg/day). The treatment began 4 weeks after the surgery and lasted for 16 weeks. in vitro experiments were performed to determine the potential mechanisms of the anti-osteoporotic effect of TL. RESULTS: Treatment with TL significantly prevent OVX-induced decrease in biomechanical quality of femur such as maximum stress and Young's modulus. The mechanical changes were associated with the prevention of a further BMD decrease or even with some improvements in microarchitecture. TL inhibited BMD decrease in the femur caused by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers. MUCT analysis of the femoral metaphysis showed how to prevent the deterioration of trabecular microarchitecture. TL induced primary osteoblastic cell proliferation and differentiation, inhibition of osteoclastogenesis through an increase in osteoprotegrin (OPG) and a decrease in NF-kappaB ligand (RANKL) expression in vitro. CONCLUSIONS: We concluded that TL treatment can effectively suppress the loss of bone mass induced by OVX and in vitro evidence suggests this could be through actions on both osteoblasts and osteoclasts. PMID- 24786574 TI - Anti-inflammatory activity of compounds from Boesenbergia longiflora rhizomes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The rhizomes of Boesenbergia longiflora (Wall.) Kuntze have been traditionally used in treatment of inflammatory bowel disease, ulcerative colitis, aphthous ulcer and abscess. Our previous study indicated that CHCl3 fractions of Boesenbergia longiflora had potential on anti-inflammatory properties. In the present study, we investigated the active constituents of this plant for anti-inflammatory activity in order to support its traditional use. MATERIAL AND METHODS: The CHCl3 fraction was isolated using chromatographic techniques. Isolated compounds were tested using relevant in vitro anti inflammatory assays against LPS-induced NO and TNF-alpha releases as well as their mechanisms in transcription levels in murine macrophage RAW264.7 cells. RESULTS: The isolation of the CHCl3 fraction from Boesenbergia longiflora rhizomes led to the isolation of three new daucane sesquiterpenes, which were identified as 8-hydroxy-dauca-9, 11-diene-7-one (longiferone A; 1), dauca-8, 11 diene-7-one (longiferone B; 2) and dauca-8, 11-diene-7, 10-dione (longiferone C; 3); together with four known flavonoids, six known diarylheptanoids as well as one sterol. The longiferone B (2) and longiferone C (3) showed anti-inflammatory activity against NO release with IC50 values of 21.0 and 31.3uM, respectively. Longiferone B (2) also suppressed the iNOS and COX-2 mRNA expression. Moreover, the flavonoids and diarylheptanoids inhibited NO and TNF-alpha production in a dose dependent manner. CONCLUSION: This study demonstrated that sesquiterpenes, diarylheptanoids and some methoxyflavonoids found in Boesenbergia longiflora are responsible for anti-inflammatory activity. PMID- 24786576 TI - U- versus n-serrated immunofluorescence pattern distinguishes EBA from BP. Letter to the editor regarding "linear arrangement of neutrophils along the basal layer in bullous pemphigoid: a unique histological finding". PMID- 24786575 TI - Comparative "in vitro" evaluation of the antiresorptive activity residing in four Ayurvedic medicinal plants. Hemidesmus indicus emerges for its potential in the treatment of bone loss diseases. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Four Indian plants, traditionally used in Ayurvedic medicine: Asparagus racemosus Willd., Emblica officinalis Gaertn., Hemidesmus indicus R. Br., and Rubia cordifolia L. were selected on the basis of their ethnobotanical use and of scientific evidence that suggests a potential efficacy in the treatment of bone-loss diseases. The antiresorptive properties of the four plants have been investigated. The aim was to provide adequate evidence for the exploitation of natural compounds as alternative therapeutics for the treatment of diseases caused by increased osteoclast activity. MATERIALS AND METHODS: Decoctions were prepared from dried plant material according to the traditional procedure and standardization by HPLC was performed using marker compounds for each species. Total polyphenols, flavonoids and radical scavenging activity of the decoctions were also determined. The bioactivity of the plant decoctions was evaluated in subsequent phases. (1) A cytotoxicity screening was performed on the mouse monocytic RAW 264.7 cell line to define the concentrations that could be utilized in the following step. (2) The antiresorptive properties of plant decoctions were compared with that of a "gold standard" drug (alendronate) by measuring osteoclastogenesis inhibition and osteoclast apoptosis. (3) The toxic effect on bone forming cells was excluded by evaluating the impact on the proliferation of osteogenic precursors (mesenchymal stem cells, MSC). RESULTS: All the decoctions inhibited osteoclastogenesis similarly to alendronate at the highest doses, but Hemidesmus indicus and Rubia cordifolia were also effective at lower concentrations. Apoptosis increased significantly when cells were exposed to the highest concentration of Emblica officinalis, Hemidesmus indicus, and Rubia cordifolia. All concentrations of Emblica officinalis tested inhibited the proliferation of osteogenic precursors, while only the highest doses of Asparagus racemosus and Rubia cordifolia were toxic. On the contrary, Hemidesmus indicus did not affect osteogenic precursor growth at any concentration tested. CONCLUSION: Among the medicinal plants included in the study, Hemidesmus indicus showed the greatest antiosteoclastic activity without toxic effect on osteogenic precursors. Therefore, Hemidesmus indicus exhibits the properties of an antiresorptive drug and represents the ideal candidate for further clinical investigations. PMID- 24786577 TI - Morphological diversity of trichodiscomas and fibrofolliculomas. AB - Trichodiscomas (TDs) and fibrofolliculomas (FFs) are hamartomatous tumors, which are usually small facial papules; they are frequently a disease marker for Birt Hogg-Dube syndrome, their recognition is important because of this association. Some believe that TD and FF is the same lesion, others have proposed the term "mantleoma" to include the morphological continuum of both of these lesions. Recently, some variants (eg, spindle cell TD, TD with lipomatous metaplasia) have been described. The authors attempt to describe a review of cases with combined features of TF and FF, as well as the recently described variants, and variants not previously described to our knowledge (myxoid/mucin predominant, pseudocartilaginous, sclerotic/fibrotic, prominent apocrine/eccrine, leiomyoma like, with vascular proliferation). It has been hypothesized that the hair bulge stem cells may be responsible for the broad spectrum of histological variation in these tumors. PMID- 24786578 TI - Necrobiosis lipoidica with elastophagocytosis on an unusual location. AB - Necrobiosis lipoidica (NL) is a granulomatous disease of collagen degeneration classically affecting the lower extremities. Elastophagocytosis is a histological finding, whereby multinucleate macrophages demonstrate phagocytosis of elastic fibers commonly associated with sun-damaged skin. Elastophagocytosis is not typically described in NL. The authors present a patient who presented with reddish-yellow plaques on both his forearms. Skin biopsy revealed extensive palisaded granulomas consistent with NL and features of elastophagocytosis in the upper dermis. The unusual site of presentation is a diagnostic pitfall, further complicated by the histological features of elastophagocytosis, for which the differential diagnosis of actinic granuloma needs to be considered. This case highlights the importance of clinicopathological correlation to arrive at a definitive diagnosis in situations where unexpected features on physical examination and histology may confound the clinical picture. PMID- 24786580 TI - An unusual infiltrative basal cell carcinoma with osteoclastic stromal changes mimicking carcinosarcoma: a case report. AB - A 91-year-old man presented with an ulcerated nodule on his left lower eyelid. The tumor showed an epithelial component composed of basaloid and clear cells and a stroma that contained many osteoclastic giant cells. Strong, diffuse expression for cytokeratin 17 and p63 was noted in the epithelial component, whereas no staining was present in the sarcomatoid stroma, suggesting that the osteoclast rich stromal component represented an unusual benign stromal reaction to the carcinoma rather than a manifestation of carcinosarcoma. Further supporting this interpretation was the absence of mitotic figures and low Ki-67 proliferation index (of approximately 1%) in the stromal cells. We herein reported a case of unusual infiltrative basal cell carcinoma, accompanied by a clear cell carcinomatous features and concurrent benign osteoclastic stromal changes. PMID- 24786579 TI - Ultrastructural Examination of a Case of Pagetoid Bowen Disease Exhibiting Immunohistochemical Features in Common With Extramammary Paget Disease. AB - A panel of immunohistochemical markers may be used to differentiate between pagetoid Bowen disease (PBD) and primary extramammary Paget disease (EMPD) in selected cases. Although diffuse staining with cytokeratin 7 (CK7), CAM5.2, carcinoembryonic antigen, epithelial membrane antigen (EMA), and gross cystic disease fluid protein 15 generally supports diagnosis of EMPD, cases have been reported where PBD also expressed CK7, EMA, and CAM5.2. Based on these findings, some authors suggested that the 2 entities may arise from the same multipotent stem cell, capable of further differentiation toward squamous and secretory lines. To the best of our knowledge, this issue has never been investigated by comparing PBD and EMPD at the ultrastructural level. We performed the first ultrastructural study of a case of PBD exhibiting common immunohistochemical features with EMPD. The lesion displayed some ultrastructural features often observed in Bowen disease and some that are typically found in EMPD. These findings indicate the presence of a bidirectional differentiation--secretory and squamous--within the same lesion, thus supporting the hypothesis that PBD and primary EMPD may arise from a common progenitor cell. PMID- 24786581 TI - Clinical practice breastfeeding recommendations for primary care: applying a tri core breastfeeding conceptual model. AB - Promotional practice efforts are needed in primary care to support and foster breastfeeding as the first and natural choice of nutrition for all infants regardless of race, ethnicity, educational, or income demographics in the United States. Societal awareness is increasing with regard to the significant protective qualities that human milk bestows upon public health. An estimated 75% of American mothers attempt to breastfeed, but according to the Centers for Disease Control and Prevention, just 13% are able to exclusively breastfeed by 6 months. Early identification of lactation issues is crucial to establishing and sustaining breastfeeding for the first 6 to 12 months of the child's life and beyond. We propose a set of primary care guidelines, applying a Tri-Core Model approach, to promote and foster breastfeeding efforts in the postpartum period. Breastfeeding promotion is a fundamental public health endeavor, and pediatric nurse practitioners and other advanced practice registered nurses (APRNs) are uniquely qualified to become specialists and experts in lactation care and management. Lactation support, which should be an integral facet of an APRN's practice and education, will aid in improving national breastfeeding rates and patient care outcomes. Application of the Tri-Core Model approach will help APRNs develop and implement evidence-based practice efforts that incorporate the mother baby dyad and other multiprofessionals who are vested in successful breastfeeding outcomes. The goal of pediatric health care is provide safe and effective health care to all infants, children, and adolescents, and lactation care is an integral and crucial component of this effort. PMID- 24786582 TI - Development of a positive psychology intervention to improve adherence in adolescents with type 1 diabetes. AB - INTRODUCTION: Novel interventions are needed to improve adherence to treatment in adolescents with type 1 diabetes. In this article, we describe the development, feasibility, and acceptability of a positive psychology intervention for this population. METHOD: Adolescents and their parents (n = 39) were randomly assigned to either a positive psychology intervention or an attention control group. Quantitative and qualitative data were collected on feasibility and acceptability. Descriptive and content analysis methods were used. RESULTS: Recruitment was successful, participation and satisfaction were high in both groups, and retention was excellent over 6 months. In the positive psychology group, adolescents and their parents noted benefits related to increased positive communication and thinking more about diabetes care. We also identified challenges to implementation. DISCUSSION: Although more research is indicated, a positive psychology framework emphasizing positive emotions and strengths, rather than problems, may be beneficial to adolescents living with a complex chronic illness. PMID- 24786583 TI - Conversations with children about DNA and genes using an original children's book. AB - INTRODUCTION: The purpose of this evaluation was to compare parent and nurse use of an original children's book about deoxyribonucleic acid (DNA) function as a potential aid in the assent process in research. We also appraised parent's knowledge about DNA and the use of genetic testing results. METHOD: We used mixed qualitative and quantitative methods. Parent-child dyads were recruited at an urban pediatric hospital. Knowledge of genetic concepts was assessed in adults with use of the Genetic Knowledge Index. Participants read the book What DNA Does with a nurse or alone and participated in interviews with investigators. The content of field notes from interviews was analyzed. RESULTS: Parent and child knowledge of DNA and gene function was generally poor but improved in most cases, particularly after reading with the nurse. DISCUSSION: The evaluated book is appropriate as a teaching aid in the child assent process in research or prior to genetic testing but should be presented by clinicians in most cases. PMID- 24786585 TI - Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl) 1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-beta type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. AB - A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6 methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-beta type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin 6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 MUM in a kinase assay and with IC50 values of 0.0165 and 0.0121 MUM in HaCaT (3TP luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b.HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng * h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b. PMID- 24786584 TI - GOLPH3 is essential for contractile ring formation and Rab11 localization to the cleavage site during cytokinesis in Drosophila melanogaster. AB - The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein has been described as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is also known as a potent oncogene, commonly amplified in several human tumors. However, the molecular pathways through which the oncoprotein GOLPH3 acts in malignant transformation are largely unknown. GOLPH3 has never been involved in cytokinesis. Here, we characterize the Drosophila melanogaster homologue of human GOLPH3 during cell division. We show that GOLPH3 accumulates at the cleavage furrow and is required for successful cytokinesis in Drosophila spermatocytes and larval neuroblasts. In premeiotic spermatocytes GOLPH3 protein is required for maintaining the organization of Golgi stacks. In dividing spermatocytes GOLPH3 is essential for both contractile ring and central spindle formation during cytokinesis. Wild type function of GOLPH3 enables maintenance of centralspindlin and Rho1 at cell equator and stabilization of Myosin II and Septin rings. We demonstrate that the molecular mechanism underlying GOLPH3 function in cytokinesis is strictly dependent on the ability of this protein to interact with PI(4)P. Mutations that abolish PI(4)P binding impair recruitment of GOLPH3 to both the Golgi and the cleavage furrow. Moreover telophase cells from mutants with defective GOLPH3-PI(4)P interaction fail to accumulate PI(4)P-and Rab11 associated secretory organelles at the cleavage site. Finally, we show that GOLPH3 protein interacts with components of both cytokinesis and membrane trafficking machineries in Drosophila cells. Based on these results we propose that GOLPH3 acts as a key molecule to coordinate phosphoinositide signaling with actomyosin dynamics and vesicle trafficking during cytokinesis. Because cytokinesis failures have been associated with premalignant disease and cancer, our studies suggest novel insight into molecular circuits involving the oncogene GOLPH3 in cytokinesis. PMID- 24786586 TI - Pregnancy at late premenopausal age: outcome of pregnancies at 45 years and older in Flanders, Belgium. AB - To describe the obstetric outcome in women at ages >= 45. A retrospective cohort study on a large existing database covering all deliveries in the Flanders region, Belgium, was performed, comparing obstetric outcomes at age 25, 35, 40 and 45 or older, for the period 2005-2010. In the period studied, 421 women gave birth at maternal age >= 45 vs 3,405, 15,206, 22,586 at ages 40, 35 and 25, respectively. With advancing maternal age, a significant linear increase for low birth weight (< 2,500 g) and preterm delivery (< 37, < 35 weeks and < 29 weeks), maternal hypertension and diabetes, both primary and secondary caesarean section, was noted. Between ages 40 and >= 45, both fetal and early neonatal death demonstrated a significant rise from 4.9/1,000 and 1.8/1,000 to 26/1,000 and 9.5/1,000, respectively. With advancing maternal age, a gradual but not statistically significant decline in the proportion of male fetuses was noted, from 51.6% at 25, to 47.2% in the oldest group. Multivariate analysis confirmed advanced maternal age to be a significant factor in low birth weight, preterm delivery, hypertension, diabetes, caesarean section and perinatal mortality. In Flanders, mothers at age 45 and older have a significantly increased risk for low birth weight, preterm delivery, hypertension, diabetes, caesarean section and perinatal mortality. PMID- 24786588 TI - A simple method for the assessment of arterial stiffness in pre-eclamptic patients. AB - BACKGROUND: Arterial stiffness (AS), the term describes the rigidity of arterial walls, and its hemodynamic results have been shown to be associated with increase in future cardiovascular events. Women with pre-eclampsia in their past pregnancies have a higher risk of developing cardiovascular disease later in life. The goal of this study was to assess AS using a non-invasive and simple oscillometric method in pregnant women with and without pre-eclampsia. METHODS: Ninety pregnant women, forty-five of which had pre-eclampsia, were included in the study. The vascular measurements were performed with a Mobil-O-Graph 24 h PWA Monitor, an automatic oscillometric device. Statistical analysis was performed using the Chi-square, independent sample t-test or the Mann-Whitney U test, Pearson correlation, and linear regression tests. RESULTS: All the vascular function parameters were significantly higher in the patients with pre-eclampsia. The pulse wave velocity (PWV) values found in the pre-eclampsia group were positively correlated with gestational age, maternal age, glucose level, creatinine level, augmentation index, and central blood pressure. Using linear regression analysis, the PWV values were confirmed to be positively correlated with gestational age, maternal age, and central systolic blood pressure. The women with severe pre-eclampsia had significantly higher blood pressures, PWV values, augmentation indices, and cardiac outputs when compared with the patients with mild pre-eclampsia. CONCLUSION: Oscillometric PWV measurement is already accepted as the most reproducible quick, simple, and inexpensive non-invasive method for the assessment of large artery stiffness. It can be applied to evaluate the AS and also aid in detecting future cardiovascular risk of patients with pre-eclampsia. PMID- 24786587 TI - In vitro evaluation of a soluble Leishmania promastigote surface antigen as a potential vaccine candidate against human leishmaniasis. AB - PSA (Promastigote Surface Antigen) belongs to a family of membrane-bound and secreted proteins present in several Leishmania (L.) species. PSA is recognized by human Th1 cells and provides a high degree of protection in vaccinated mice. We evaluated humoral and cellular immune responses induced by a L. amazonensis PSA protein (LaPSA-38S) produced in a L. tarentolae expression system. This was done in individuals cured of cutaneous leishmaniasis due to L. major (CCLm) or L. braziliensis (CCLb) or visceral leishmaniasis due to L. donovani (CVLd) and in healthy individuals. Healthy individuals were subdivided into immune (HHR-Lm and HHR-Li: Healthy High Responders living in an endemic area for L. major or L. infantum infection) or non immune/naive individuals (HLR: Healthy Low Responders), depending on whether they produce high or low levels of IFN-gamma in response to Leishmania soluble antigen. Low levels of total IgG antibodies to LaPSA-38S were detected in sera from the studied groups. Interestingly, LaPSA-38S induced specific and significant levels of IFN-gamma, granzyme B and IL-10 in CCLm, HHR-Lm and HHR-Li groups, with HHR-Li group producing TNF-alpha in more. No significant cytokine response was observed in individuals immune to L. braziliensis or L. donovani infection. Phenotypic analysis showed a significant increase in CD4+ T cells producing IFN-gamma after LaPSA-38S stimulation, in CCLm. A high positive correlation was observed between the percentage of IFN gamma-producing CD4+ T cells and the released IFN-gamma. We showed that the LaPSA 38S protein was able to induce a mixed Th1 and Th2/Treg cytokine response in individuals with immunity to L. major or L. infantum infection indicating that it may be exploited as a vaccine candidate. We also showed, to our knowledge for the first time, the capacity of Leishmania PSA protein to induce granzyme B production in humans with immunity to L. major and L. infantum infection. PMID- 24786590 TI - Two new steroidal glycosides from Cynanchum wallichii. AB - Two new C21 steroidal glycosides were isolated from Cynanchum wallichii Wight. Their structures were elucidated as caudatin-3-O-beta-d-glucopyranosyl-(1 -> 4) beta-d-oleandropyranosyl-(1 -> 4)-beta-d-cymaropyranosyl-(1 -> 4)-beta-d digitoxopyranoside (1) and caudatin-3-O-beta-d-glucopyranosyl-(1 -> 4)-beta-d cymaropyranosyl-(1 -> 4)-beta-d-oleandropyranosyl-(1 -> 4)-beta-d-cymaropyranosyl (1 -> 4)-beta-d-digitoxopyranoside (2) by spectroscopic methods including 1D and 2D NMR experiments. PMID- 24786589 TI - Regulation of transcription by 6S RNAs: insights from the Escherichia coli and Bacillus subtilis model systems. AB - Whereas, the majority of bacterial non-coding RNAs and functional RNA elements regulate post-transcriptional processes, either by interacting with other RNAs via base-pairing or through binding of small ligands (riboswitches), 6S RNAs affect transcription itself by binding to the housekeeping holoenzyme of RNA polymerase (RNAP). Remarkably, 6S RNAs serve as RNA templates for bacterial RNAP, giving rise to the de novo synthesis of short transcripts, termed pRNAs (product RNAs). Hence, 6S RNAs prompt the enzyme to act as an RNA-dependent RNA polymerase (RdRP). Synthesis of pRNAs exceeding a certain length limit (~13 nt) persistently rearrange the 6S RNA structure, which in turn, disrupts the 6S RNA:RNAP complex. This pRNA synthesis-mediated "reanimation" of sequestered RNAP molecules represents the conceivably fastest mechanism for resuming transcription in cells that enter a new exponential growth phase. The many different 6S RNAs found in a wide variety of bacteria do not share strong sequence homology but have in common a conserved rod-shaped structure with a large internal loop, termed the central bulge; this architecture mediates specific binding to the active site of RNAP. In this article, we summarize the overall state of knowledge as well as very recent findings on the structure, function, and physiological effects of 6S RNA examples from the two model organisms, Escherichia coli and Bacillus subtilis. Comparison of the presently known properties of 6S RNAs in the two organisms highlights common principles as well as diverse features. PMID- 24786591 TI - Reply: To PMID 24727638. PMID- 24786592 TI - Evolution and communication of subcellular compartments: An integrated approach. AB - Compartmentation is a fundamental feature of eukaryotic cells and the basis for metabolic complexity. We recently reported on the protein compartmentation in the moss Physcomitrella patens. This study utilized a combination of quantitative proteomics, comparative genomics, and single protein tagging and provided data on the postendosymbiotic evolution of plastids and mitochondria, on organellar communication, as well as on inter- and intracellular heterogeneity of organelles. We highlight potential organelle interaction hubs with specific protein content such as plastid stromules, and report on the plasticity of protein targeting to organelles. PMID- 24786593 TI - Falls in the elderly were predicted opportunistically using a decision tree and systematically using a database-driven screening tool. AB - OBJECTIVE: To identify risk factors for falls and generate two screening tools: an opportunistic tool for use in consultation to flag at risk patients and a systematic database screening tool for comprehensive falls assessment of the practice population. STUDY DESIGN AND SETTING: This multicenter cohort study was part of the quality improvement in chronic kidney disease trial. Routine data for participants aged 65 years and above were collected from 127 general practice (GP) databases across the UK, including sociodemographic, physical, diagnostic, pharmaceutical, lifestyle factors, and records of falls or fractures over 5 years. Multilevel logistic regression analyses were performed to identify predictors. The strongest predictors were used to generate a decision tree and risk score. RESULTS: Of the 135,433 individuals included, 10,766 (8%) experienced a fall or fracture during follow-up. Age, female sex, previous fall, nocturia, anti-depressant use, and urinary incontinence were the strongest predictors from our risk profile (area under the receiver operating characteristics curve = 0.72). Medication for hypertension did not increase the falls risk. Females aged over 75 years and subjects with a previous fall were the highest risk groups from the decision tree. The risk profile was converted into a risk score (range -7 to 56). Using a cut-off of >=9, sensitivity was 68%, and specificity was 60%. CONCLUSION: Our study developed opportunistic and systematic tools to predict falls without additional mobility assessments. PMID- 24786594 TI - Five comorbidities reflected the health status in patients with chronic obstructive pulmonary disease: the newly developed COMCOLD index. AB - OBJECTIVE: This study aimed to identify those comorbidities with greatest impact on patient-reported health status in patients with chronic obstructive pulmonary disease (COPD) and to develop a comorbidity index that reflects their combined impact. STUDY DESIGN AND SETTING: We included 408 Swiss and Dutch primary care patients with COPD from the International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts (ICE COLD ERIC) in this cross-sectional analysis. Primary outcome was the Feeling Thermometer, a patient reported health status instrument. We assessed the impact of comorbidities at five cohort assessment times using multiple linear regression adjusted for FEV1, retaining comorbidities with associations P <= 0.1. We developed an index that reflects strength of association of comorbidities with health status. RESULTS: Depression (prevalence: 13.0%; regression coefficient: -9.00; 95% CI: -13.52, 4.48), anxiety (prevalence: 11.8%; regression coefficient: -5.53; 95% CI -10.25, 0.81), peripheral artery disease (prevalence: 6.4%; regression coefficient: 5.02; 95% CI-10.64, 0.60), cerebrovascular disease (prevalence: 8.8%; regression coefficient: -4.57; 95% CI -9.43, 0.29), and symptomatic heart disease (prevalence: 20.3%; regression coefficient: -3.81; 95% CI -7.23, -0.39) were most strongly associated with the Feeling Thermometer. These five comorbidities, weighted, compose the COMorbidities in Chronic Obstructive Lung Disease (COMCOLD) index. CONCLUSION: The COMCOLD index reflects the combined impact of five important comorbidities from patients' perspective and complements existing comorbidity indices that predict death. It may help clinicians focus on comorbidities affecting patients' health status the most. PMID- 24786595 TI - Response to Keriel-Gascou et al.: higher efficiency and other alleged advantages are not inherent to the stepped wedge design. PMID- 24786596 TI - The right indicator for the job: different levels of rigor may be appropriate for the development of quality indicators. Comment on Stelfox and Straus. PMID- 24786597 TI - Eye movements as a probe of corollary discharge function in schizophrenia. AB - Nearly every movement made by every animal is accompanied by a corollary discharge, a signal sent from the motor to sensory regions of its brain. Corollary discharges are a crucial mechanism by which the brain monitors its own actions, and there is some evidence that they are impaired in people with schizophrenia. Here, I briefly review this evidence and suggest that eye movements are a particularly valuable tool for assessing the role of corollary discharges in schizophrenia. PMID- 24786598 TI - Companions: tests and drug for better healthcare. PMID- 24786599 TI - Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy. AB - BACKGROUND: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. METHODS: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. RESULTS: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05). CONCLUSIONS: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients. PMID- 24786600 TI - Global methylation levels in peripheral blood leukocyte DNA by LUMA and breast cancer: a case-control study in Japanese women. AB - BACKGROUND: Global hypomethylation has been suggested to cause genomic instability and lead to an increased risk of cancer. We examined the association between the global methylation level of peripheral blood leukocyte DNA and breast cancer among Japanese women. METHODS: We conducted a hospital-based case-control study of 384 patients aged 20-74 years with newly diagnosed, histologically confirmed invasive breast cancer, and 384 matched controls from medical checkup examinees in Nagano, Japan. Global methylation levels in leukocyte DNA were measured by LUminometric Methylation Assay. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between global hypomethylation and breast cancer were estimated using a logistic regression model. RESULTS: Compared with women in the highest tertile of global methylation level, ORs for the second and lowest tertiles were 1.87 (95% CI=1.20-2.91) and 2.86 (95% CI=1.85-4.44), respectively. Global methylation levels were significantly lower in cases than controls, regardless of the hormone receptor status of the cancer (all P values for trend <0.05). INTERPRETATION: These findings suggest that the global methylation level of peripheral blood leukocyte DNA is low in patients with breast cancer and may be a potential biomarker for breast cancer risk. PMID- 24786601 TI - Clinical prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer. AB - BACKGROUND: Tumour aggressiveness might be related to the degree of main cancer hallmark acquirement of tumour cells, reflected by expression levels of specific biomarkers. We investigated the expression of Aldh1, Survivin, and EpCAM, together reflecting main cancer hallmarks, in relation to clinical outcome of colorectal cancer (CRC) patients. METHODS: Immunohistochemistry was performed using a tumour tissue microarray of TNM (Tumour, Node, Metastasis)-stage I-IV CRC tissues. Single-marker expression or their combination was assessed for associations with the clinical outcome of CRC patients (N=309). RESULTS: Increased expression of Aldh1 or Survivin, or decreased expression of EpCAM was each associated with poor clinical outcome, and was therefore identified as clinically unfavourable expression. Analyses of the combination of all three markers showed worse clinical outcome, specifically in colon cancer patients, with an increasing number of markers showing unfavourable expression. Hazard ratios ranged up to 8.3 for overall survival (P<0.001), 36.6 for disease-specific survival (P<0.001), and 27.1 for distant recurrence-free survival (P<0.001). CONCLUSIONS: Our data identified combined expression levels of Aldh1, Survivin, and EpCAM as strong independent prognostic factors, with high hazard ratios, for survival and tumour recurrence in colon cancer patients, and therefore reflect tumour aggressiveness. PMID- 24786602 TI - Discriminating metastasised from non-metastasised seminoma based on transcriptional changes in primary tumours using NGS. AB - BACKGROUND: We aimed to better discriminate (occult) metastasised from non metastasised seminoma based on transcriptional changes of small RNAs in the primary tumour. METHODS: Total RNAs including small RNAs were isolated from five testicular tumours of each, lymphogenic, occult and non-metastasised patients. Next-generation sequencing (SOLID, Life Technologies) was used to examine transcriptional changes. Small RNAs showing ?50 reads and a significant ?2-fold difference using non-metastasised tumours as the reference group were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines. RESULTS: On average, 1.3 * 10(7), 1.4 * 10(7) and 1.7 * 10(7) small RNA reads were detectable in non-metastasised, occult and lymphogenic metastasised seminoma, respectively, of which 30-32% remained after trimming. Between 59 and 68% represented annotated reads and between 8.6 and 11% were annotated small RNA tags. Of them, 137 small RNAs showed>50 reads and a two-fold difference to the reference. In univariate analysis, 32-38 small RNAs significantly discriminated lymphogenic/occult from non-metastasised seminoma, and among these different comparisons, it were the same small RNAs in 51-88%. Many combinations of two of these small RNAs allowed a complete discrimination of metastasised from non-metastasised seminoma irrespective of the metastasis subtype. CONCLUSIONS: Metastasised and non metastasised seminoma can be completely discriminated with a combination of two small RNAs. PMID- 24786603 TI - Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma. AB - BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1 5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings. PMID- 24786604 TI - Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC). AB - BACKGROUND: In order to improve therapy for HNSCC patients, novel methods to predict and combat local and/or distant tumour relapses are urgently needed. This study has been dedicated to the hypothesis that Rac1, a Rho GTPase, is implicated in HNSCC insensitivity to chemo-radiotherapy resulting in tumour recurrence development. METHODS: Parental and radiation-resistant (IRR) HNSCC cells were used to support this hypothesis. All cells were investigated for their sensitivity to ionising radiation and cisplatin, Rac1 activity, its intracellular expression and subcellular localisation. Additionally, tumour tissues obtained from 60 HNSCC patients showing different therapy response were evaluated for intratumoral Rac1 expression. RESULTS: Radiation-resistant IRR cells also revealed resistance to cisplatin accompanied by increased expression, activity and trend towards nuclear translocation of Rac1 protein. Chemical inhibition of Rac1 expression and activity resulted in significant improvement of HNSCC sensitivity to ionising radiation and cisplatin. Preclinical results were confirmed in clinical samples. Although Rac1 was poorly presented in normal mucosa, tumour tissues revealed increased Rac1 expression. The most pronounced Rac1 presence was observed in HNSCC patients with poor early or late responses to chemo-radiotherapy. Tissues taken at recurrence were characterised not only by enhanced Rac1 expression but also increased nuclear Rac1 content. CONCLUSIONS: Increased expression, activity and subcellular localisation of Rac1 could be associated with lower early response rate and higher risk of tumour recurrences in HNSCC patients and warrants further validation in larger independent studies. Inhibition of Rac1 activity can be useful in overcoming treatment resistance and could be proposed for HNSCC patients with primary or secondary chemo radioresistance. PMID- 24786605 TI - Diabetes and pancreatic cancer survival: a prospective cohort-based study. AB - BACKGROUND: Diabetes is a risk factor for pancreatic cancer but its association with survival from pancreatic cancer is poorly understood. Our objective was to investigate the association of diabetes with survival among pancreatic cancer patients in a prospective cohort-based study where diabetes history was ascertained before pancreatic cancer diagnosis. METHODS: We evaluated survival by baseline (1993-2001) self-reported diabetes history (n=62) among 504 participants that developed exocrine pancreatic cancer within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using Cox proportional hazards model, adjusted for age, sex, body mass index, race, smoking, and tumour stage (local, locally advanced, and metastatic). RESULTS: The multivariable-adjusted HR for mortality comparing participants with diabetes to those without was 1.52 (95% CI=1.14-2.04, P-value <0.01). After excluding those diagnosed with pancreatic cancer within 3 years of study enrolment, HR for mortality among those with diabetes was 1.45 (95% CI=1.06-2.00, P-value=0.02). CONCLUSIONS: Using prospectively collected data, our findings indicate that diabetes is associated with worse survival among patients with pancreatic cancer. PMID- 24786606 TI - A new mouse model for female genital schistosomiasis. AB - BACKGROUND: Over 112 million people worldwide are infected with Schistosoma haematobium, one of the most prevalent schistosome species affecting humans. Female genital schistosomiasis (FGS) occurs when S. haematobium eggs are deposited into the female reproductive tract by adult worms, which can lead to pelvic pain, vaginal bleeding, genital disfigurement and infertility. Recent evidence suggests co-infection with S. haematobium increases the risks of contracting sexually transmitted diseases such as HIV. The associated mechanisms remain unclear due to the lack of a tractable animal model. We sought to create a mouse model conducive to the study of immune modulation and genitourinary changes that occur with FGS. METHODS: To model FGS in mice, we injected S. haematobium eggs into the posterior vaginal walls of 30 female BALB/c mice. A control group of 20 female BALB/c mice were injected with uninfected LVG hamster tissue extract. Histology, flow cytometry and serum cytokine levels were assessed at 2, 4, 6, and 8 weeks post egg injection. Voiding studies were performed at 1 week post egg injection. RESULTS: Vaginal wall injection with S. haematobium eggs resulted in synchronous vaginal granuloma development within 2 weeks post-egg injection that persisted for at least 6 additional weeks. Flow cytometric analysis of vaginal granulomata revealed infiltration by CD4+ T cells with variable expression of the HIV co-receptors CXCR4 and CCR5. Granulomata also contained CD11b+F4/80+ cells (macrophages and eosinophils) as well as CXCR4+MerTK+ macrophages. Strikingly, vaginal wall-injected mice featured significant urinary frequency despite the posterior vagina being anatomically distant from the bladder. This may represent a previously unrecognized overactive bladder response to deposition of schistosome eggs in the vagina. CONCLUSION: We have established a new mouse model that could potentially enable novel studies of genital schistosomiasis in females. Ongoing studies will further explore the mechanisms by which HIV target cells may be drawn into FGS-associated vaginal granulomata. PMID- 24786607 TI - Multimodality characterization of microstructure by the combination of diffusion NMR and time-domain diffuse optical data. AB - Combining datasets with a model of the underlying physics prior to mapping of tissue provides a novel approach improving the estimation of parameters. We demonstrate this approach by merging near infrared diffuse optical signal data with diffusion NMR data to inform a model describing the microstructure of a sample. The study is conducted on a homogeneous emulsion of oil in a dispersion medium of water and proteins. The use of a protein based background, rich in collagen, introduces a similarity to real tissues compared to other models such as intralipids. The sample is investigated with the two modalities separately. Then, the two datasets are used to inform a combined model, and to estimate the size of the microstructural elements and the volume fraction. The combined model fits the microstructural properties by minimizing the difference between experimental and modelled data. The experimental results are validated with confocal laser scanning microscopy. The final results demonstrate that the combined model provides improved estimates of microstructural parameters compared to either individual model alone. PMID- 24786608 TI - Burden of AIDS in a Brazilian state. AB - BACKGROUND: To estimate the burden of a disease implies the simultaneous quantification of the impact of early mortality and the health problems that affect the individual's quality of life, and this evaluation can be particularly important in a disease such as AIDS that has become a long-term disease. The purpose of this study was to determine the burden of disease due to AIDS in the Brazilian Southern State of Santa Catarina. METHODS: An ecological designed study was performed using death and AIDS notifications data for 2009. The disability adjusted life years (DALYs) were estimated by the sum of years of life lost (YLL) and the years lived with disability (YLD). The YLL was estimated as the difference between the life expectancy from birth and the age at death with the application of a discount rate of 3% per year. The YLD was estimated as the product of the Burden of Disease Study's weight for AIDS of 0.167 and its average duration of 108 months in Brazil for the incident cases. The YLL, YLD and DALY rates were calculated per 100,000 inhabitants by sex and age groups. RESULTS: There were 2034 notified cases and 689 deaths due to AIDS reported. There were 15,756.5 YLLs estimated, resulting in 257.5 YLLs/100,000 inhabitants, and 4554.1 YLDs were estimated, resulting in 74.4 YLDs/100,000 inhabitants. The DALY was estimated at 20,310.6, with a rate of 331.9 DALYs/100,000 inhabitants. The highest rates were observed in males in the age groups 30-44 and 45-59 years. CONCLUSIONS: The burden of AIDS was high and was observed mainly in adults, with a predominance in males. PMID- 24786609 TI - Comparison of medical service use and human papillomavirus vaccination rates among Somali and white/non-Hispanic girls. AB - OBJECTIVE: This study aimed to determine if there is a relationship between medical use patterns and human papillomavirus (HPV) vaccination rates among a previously studied population of Somali and white/non-Hispanic girls in Rochester, MN. MATERIALS AND METHODS: With the use of a previously identified group of Somali and white/non-Hispanic girls with known HPV vaccination status, the number, type, and age at provider visits were abstracted. Abstraction was blinded to vaccination status and ethnic designation. chi and Student t tests were performed for descriptive analysis of parametric data. For nonparametric data, Wilcoxon rank sum test was performed. RESULTS: Somali girls had fewer provider visits (median = 7, interquartile range [IQR] = 3-12.25) compared with white/non-Hispanic girls (median = 12, IQR = 6-18) (p < .001). Among those who completed the HPV vaccine series, Somali girls had more well-child visits (median = 2, IQR = 1-2) compared with the white/non-Hispanic group (median = 1, IQR = 1 2) (p = .028). There was no difference in the number of emergency department visits or inpatient hospitalization between groups. CONCLUSIONS: White/non Hispanic girls had higher HPV vaccine completion rates and more provider visits. However, this increase in number of encounters is due to an increase in specialty visits. This is unlikely to account for the increase in HPV vaccination completion rates. Community-based research will likely provide greater insight into the cause(s) of reduced vaccine rates among Somali adolescent girls. PMID- 24786610 TI - Distal pedal bypasses combined with free microsurgical flaps in chronic limb ischaemia for problematic wounds. PMID- 24786612 TI - Improvement of Al2O3 films on graphene grown by atomic layer deposition with pre H2O treatment. AB - We improve the surface of graphene by atomic layer deposition (ALD) without the assistance of a transition layer or surface functionalization. By controlling gas solid physical adsorption between water molecules and graphene through the optimization of pre-H2O treatment and two-step temperature growth, we directly grew uniform and compact Al2O3 films onto graphene by ALD. Al2O3 films, deposited with 4-cycle pre-H2O treatment and 100-200 degrees C two-step growing process, presented a relative permittivity of 7.2 and a breakdown critical electrical field of 9 MV/cm. Moreover, the deposition of Al2O3 did not introduce any detective defects or disorders in graphene. PMID- 24786611 TI - Chromatin structure and gene expression changes associated with loss of MOP1 activity in Zea mays. AB - Though the mechanisms governing nuclear organization are not well understood, it is apparent that epigenetic modifications coordinately modulate chromatin organization as well as transcription. In maize, MEDIATOR OF PARAMUTATION1 (MOP1) is required for 24 nt siRNA-mediated epigenetic regulation and transcriptional gene silencing via a putative Pol IV- RdDM pathway. To elucidate the mechanisms of nuclear chromatin organization, we investigated the relationship between chromatin structure and transcription in response to loss of MOP1 function. We used a microarray based micrococcal nuclease sensitivity assay to identify genome wide changes in chromatin structure in mop1-1 immature ears and observed an increase in chromatin accessibility at chromosome arms associated with loss of MOP1 function. Within the many genes misregulated in mop1 mutants, we identified one subset likely to be direct targets of epigenetic transcriptional silencing via Pol-IV RdDM. We found that target specificity for MOP1-mediated RdDM activity is governed by multiple signals that include accumulation of 24 nt siRNAs and the presence of specific classes of gene-proximal transposons, but neither of these attributes alone is sufficient to predict transcriptional misregulation in mop1-1 homozygous mutants. Our results suggest a role for MOP1 in regulation of higher order chromatin organization where loss of MOP1 activity at a subset of loci triggers a broader cascade of transcriptional consequences and genome-wide changes in chromatin structure. PMID- 24786613 TI - Clinical efficacy, safety, and costs of percutaneous occlusive balloon catheter assisted ureteroscopic lithotripsy for large impacted proximal ureteral calculi: a prospective, randomized study. AB - PURPOSE: To evaluate the clinical efficacy, safety, and costs of percutaneous occlusive balloon catheter-assisted ureteroscopic lithotripsy (POBC-URSL) for large impacted proximal ureteral calculi. PATIENTS AND METHODS: 156 patients with impacted proximal ureteral stones >=1.5 cm in size were randomized to ureteroscopic lithotripsy (URSL), POBC-URSL, and percutaneous nephrolithotomy (PNL) group between May 2010 and May 2013. For URSL, the calculi were disintegrated with the assistance of anti-retropulsion devices. POBC-URSL was performed with the assistance of an 8F percutaneous occlusive balloon catheter. PNL was finished with the combination of an ultrasonic and a pneumatic lithotripter. A flexible ureteroscope and a 200 MUm laser fiber were used to achieve stone-free status to a large extent for each group. Variables studied were mean operative time, auxiliary procedure, postoperative hospital stay, operation-related complications, stone clearance rate, and treatment costs. RESULTS: The mean lithotripsy time for POBC-URSL was shorter than URSL, but longer than PNL (42.6+/-8.9 minutes vs 66.7+/-15.3 minutes vs 28.1+/-6.3 minutes, p=0.014). The auxiliary procedure rate and postoperative fever rate for POBC-URSL were significantly lower than URSL and comparable to PNL (p<0.01, p=0.034). POBC URSL was superior to URSL with regard to the stone clearance rate at 3 days postoperatively, and as good as PNL (98.1% vs 75.0% vs 96.2%, p<0.01). The postoperative hospital stay and hematuria rate were lower in POBC-URSL group than PNL group and similar to URSL group (p=0.016, p<0.01). The treatment costs were lowest in POBC-URSL group ($1205.0+/-$113.9 vs $1731.7+/-$208.1 vs $2446.4+/ $166.4, p=0.004). CONCLUSIONS: For large impacted proximal ureteral calculi, POBC URSL was associated with a higher stone clearance rate, fewer complications and costs. POBC-URSL combined the advantages of URSL and PNL. PMID- 24786614 TI - Australian practice nursing: collaboration in context. AB - AIMS AND OBJECTIVES: To explore whether or not the context of Australian practice nursing supports collaborative decision-making about organisation and delivery of patient care. BACKGROUND: Positive patient outcomes depend on Australian practice nurses participating in collaborative and interprofessional services, particularly for patients with chronic disease(s). It is unclear whether Australian practice nurses have the opportunity to collaborate in decision-making or how traditional organisational structures may support or hinder collaboration. DESIGN: This is a descriptive exploratory study. Semi-structured interviews were conducted using a purposive sample of practice nurses (n = 15). Thematic analysis was used to provide meaningful and contextual insights into how practice nurses participate in decision-making. METHOD: An interview tool, based on available literature, was developed and consisted of thirty open-ended questions to direct discussion during telephone interviews. Transcribed data were imported into NVivo(tm) for analysis and interpretation. The collection, analysis and thematic interpretation of data were an iterative process. FINDINGS: Participants fostered trusting interprofessional relationships, which enabled them to influence medical decision-making and thereby advocate for patient need. Trusting interprofessional relationships were perceived to alter the relative roles of the medical practitioner and practice nurse and enhance the opportunities for collaborative decision-making. CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: Collaborative interprofessional care in Australian general practice must occur if increased demands for care are to be met. It is timely to consider how government policy, financial regulations and the organisation of Australian general practice can better support and enhance a collaborative contribution to care by practice nurses. PMID- 24786615 TI - Augmentation of lateral tarsorrhaphy in lagophthalmos. AB - Lagophthalmos, the inability to close the eyelids completely, is a serious condition caused by orbicularis oculi muscle paresis or paralysis. The standard lateral tarsorrhaphy may leave the eye open with corneal exposure. In those cases, we suggest that better approximation of the upper and lower eyelids will be achieved when the lower lid is retracted laterally and the upper lid medially. This yields satisfactory closure of the eyelids. I report herein four patients who were successfully treated with permanent lateral tarsorrhaphy with this approximation of the upper and lower eyelids with effective, satisfactory outcomes. PMID- 24786616 TI - Electrical properties of nanofibers and structural characterization of DNA Au(III) complexes. AB - In order to realize deoxyribonucleic acid (DNA)-based molecular electronics, chemical modifications of DNA are needed to improve electrical conductivity. We developed a novel method utilizing the incorporation of Au(III) ions into DNA bases to alter their electronic properties. When Au(III) ions were incorporated proportionally into DNA bases, conductance increased up to an Au(III) content of 0.42 Au(III) ion/nucleotide. Surprisingly, electron paramagnetic resonance signals of Au(II) ions were detected at g ~1.98, and the calculated spin number of Au(II) ions ranged from ~10(13) to ~10(15). The structural deformation of the DNA helix occurred when complexed with Au(III); simultaneously, the conductance of DNA-Au(III) complexes decreased when the content of Au(III) was higher than 0.42 atom/nucleotide. This observation implies that the maintenance of helical structure in the Au(III) doped state of DNA molecules is very important to the enhancement of the carrier mobility of DNA. PMID- 24786617 TI - Occurrence of ochratoxin A in domestic beers and wines from Tunisia by immunoaffinity clean-up and liquid chromatography. AB - A survey on the occurrence of ochratoxin A (OTA) in wines and beers produced in Tunisia was carried out. Wines and beers were analysed using immunoaffinity column clean-up and high-performance liquid chromatography coupled to a fluorometric detector. OTA was detected in 29 wine samples, with an incidence of contamination of 85%. The OTA levels ranged between 0.09 and 1.5 ug/L. Neither of the studied samples showed levels above the European regulatory limit (2 ug/L). OTA was detected in 17 beer samples with an incidence of contamination of 45%. The OTA levels ranged between 0.04 and 0.35 ug/L. The OTA dietary intake by the consumption of wine and beer may be considered as negligible. The obtained results showed high incidence of OTA in Tunisian wines and beers; however, there are no toxicological risks for Tunisian consumers through their consumption of such processed products using cereals and grapes. PMID- 24786618 TI - Determination of nitrate, nitrite and perchlorate anions in meat, milk and their products consumed in Hatay region in Turkey. AB - Nitrates and nitrites added to food can cause formation of cancerous N-nitroso compounds, whereas exposure to perchlorate is especially emphasised as an important risk factor for newborns' health. In this study, nitrate, nitrite and perchlorate concentrations in meat and milk products consumed in the Hatay region of Turkey were determined. Nitrate and nitrite were analysed with a spectrophotometric method, and perchlorate analysed via ion chromatography. The detected sodium nitrate and nitrite amounts in meat consumed in the Hatay region are less than the maximum levels as declared in the Turkish Food Codex. The amount of perchlorate was considered not to pose a threat as well. However, in 50% of the cheese samples, sodium nitrate amounts were found to be more than the maximum acceptable level in the Turkish Food Codex. PMID- 24786619 TI - Survey of neonicotinoids and fipronil in corn seeds for agriculture. AB - Recently, legislative decisions withdrew or temporarily suspended the use of neonicotinoids and fipronil as seeds tanning in many countries because of their endocrine-disrupting activity imputable to the bees' toxicity. In this study, the occurrence of acetamiprid, fipronil, clothianidin, flonicamid, imidacloprid, nitenpyram, thiacloprid and thiamethoxam was detected in 66 samples of commercial treated corn seeds, collected in the Italian market in the frame of ministerial institutional quality control activity. Because of the lack of a validated analytical protocol for neonicotinoid detection in seeds, a routinely suitable liquid chromatography-tandem mass spectroscopy (LC-MS/MS) analytical method was developed and statistically validated on fortified corn seeds. Survey results demonstrated that 88% of the investigated seed samples showed the presence of residues of clothianidin, fipronil, thiamethoxam and thiacloprid, either individually or simultaneously, with values that ranged from about 0.002 to 20 mg kg(-1), which evidenced the alarming illicit use of these pesticides in seed treatments. PMID- 24786620 TI - Aflatoxin contamination in food commodities in Bangladesh. AB - During September 2009, we performed a rapid cross-sectional study to investigate the extent of aflatoxin contamination among common Bangladeshi foods. We collected eight common human food commodities (rice, lentils, wheat flour, dates, betelnut, red chili powder, ginger and groundnuts) and poultry feed samples from two large markets in each of three cities in Bangladesh. We quantified aflatoxin levels from pooled subsamples using fluorescence high-performance liquid chromatography. Aflatoxin levels were highest in dates and groundnuts (maximum 623 and 423 ng/g), respectively. Samples of betelnut (mean 30.6 ng/g), lentils (mean 21.2 ng/g) and red chili powder (>20 ng/g) also had elevated levels. The mean aflatoxin level among poultry feed samples was 73.0 ng/g. Aflatoxin levels were above the US maximum regulatory levels of 20 ng/g in five of eight commonly ingested human food commodities tested. PMID- 24786621 TI - Iodine content in commonly consumed food in Hong Kong and its changes due to cooking. AB - Levels of iodine of foods found in Hong Kong were analysed in 271 samples from 11 groups, including (i) cereals and grain products, (ii) legumes and vegetables, (iii) meat and poultry, (iv) egg and egg products, (v) milk and milk products, (vi) fish, (vii) crustaceans and mollusks, (viii) non-alcoholic beverages, (ix) condiments and sauces, (x) sashimi and (xi) seaweeds. All food samples were analysed individually as purchased. The iodine in all samples ranged from undetectable to 2.9 g kg(-1). Seaweeds, iodised salt, seafood, milk and milk products as well as egg and egg products were rich sources of iodine. To estimate the influence of cooking on iodine levels in foods, a total of 15 individual samples were analysed as raw and respective cooked food. The influence of cooking on the iodine level was minimal, except for boiling, as iodine dissolved into the soup. PMID- 24786622 TI - Toxic and essential elements in conventional and home-produced eggs by ICP-MS analysis. AB - Concentrations of As, Ba, Cd, Co, Mn, Pb, Se, Sr, V, Cu, Fe, Mg, Zn and Mo were determined in conventional and home-produced eggs as sold in Brazil. Thirty-four conventional and 21 home-produced samples were obtained in different Brazilian cities. Elements were determined by inductively coupled plasma mass spectrometry (ICP-MS). Concentrations of Ba, Cd, Co, Pb, Se, Fe, Zn and Mo in conventional and home-produced eggs differed (statistically significant). Correlations were found among the other elements in both production systems. The estimated daily intake for toxic elements based on Brazilian egg consumption did not exceed the toxicological reference values. The results clearly demonstrated that eggs are an important source of essential elements such as Mo, Fe, Se and Zn. PMID- 24786623 TI - Heavy metals in spices and herbs from wholesale markets in Malaysia. AB - As, Cd, Pb and Hg were analysed in commonly consumed spices and herbs in Malaysia. The range of As, Cd, Pb and Hg content was 0.24-2.54, 0.23-8.07, 1.54 8.94 and 0.06-0.52 ug g(-1), respectively. The highest concentration of Cd, Pb and Hg in spices and herbs exceeded the maximum permitted proportion, which are 1, 2 and 0.05 ug g(-1), respectively. This study suggests further monitoring of Cd, Pb and Hg on daily consumption of spices and herbs and its toxicological implication for consumers since only the amount of As was lower than the permitted concentration. PMID- 24786624 TI - Nitrate and nitrite content in bottled beverages by ion-pair high-performance liquid chromatography. AB - Nitrate and nitrite levels in six types of beverages--total of 292 individual samples from 73 brands (four bottles each)--from Guangzhou city in China were evaluated by ion-pair high-performance liquid chromatography. All samples contained nitrate. Nitrate and nitrite ranges were 0.43-46.08 and <0.005-0.501 mg/L, respectively. The highest nitrate levels were detected in tea drinks (46.08 mg/L). For nitrite, the highest levels were found in fruit juice drinks (0.501 mg/L). Three brands of fruit juice drinks exceeded the Joint FAO/WHO Expert Committee on Food Additives provisional guideline value of 0.2 mg/L for nitrite and were considered to be hazardous for public health. This study supplies useful information on safety of Chinese bottled beverages. PMID- 24786625 TI - Sorbic and benzoic acid in non-preservative-added food products in Turkey. AB - Sorbic acid (SA) and benzoic acid (BA) were determined in yoghurt, tomato and pepper paste, fruit juices, chocolates, soups and chips in Turkey by using high pressure liquid chromatography (HPLC). Levels were compared with Turkish Food Codex limits. SA was detected only in 2 of 21 yoghurt samples, contrary to BA, which was found in all yoghurt samples but one, ranging from 10.5 to 159.9 mg/kg. Both SA and BA were detected also in 3 and 6 of 23 paste samples in a range of 18.1-526.4 and 21.7-1933.5 mg/kg, respectively. Only 1 of 23 fruit juices contained BA. SA was not detected in any chips, fruit juice, soup, or chocolate sample. Although 16.51% of the samples was not compliant with the Turkish Food Codex limits, estimated daily intake of BA or SA was below the acceptable daily intake. PMID- 24786626 TI - Evaluation of trace elements in selected foods and dietary intake by young children in Thailand. AB - Elemental concentrations in rice, animal products, eggs, vegetables, fruits, infant formulas and drinking water were determined in 667 food samples randomly collected from local markets, big supermarkets and grocery stores in Bangkok, Thailand, during the period October 2005-August 2008. Samples were digested with nitric acid and analysed by inductively coupled plasma-mass spectrometry. Arsenic and cadmium levels in most foods were below the maximum levels as set by international organisations. Filtered and bottled drinking water, rice, vegetables and banana contained low concentrations of arsenic, cadmium and lead. Non-polished rice had higher magnesium, calcium, manganese, iron and selenium concentrations than polished rice. Banana was a major source for manganese and selenium. Pig kidney and liver contained high levels of arsenic and cadmium. Manganese, cadmium, lead and aluminium concentrations in soybean milk could also be of concern. With respect to food safety for children, the amounts of arsenic and cadmium ingested with poultry, pig liver or rice corresponded to high weekly or monthly intake. PMID- 24786627 TI - Aflatoxins in sunflower and safflower seeds from Iran. AB - Aflatoxin content of 173 sunflower and safflower seeds was determined by HPLC with immunoaffinity column (IAC) clean-up and fluorometric detection. Aflatoxin B1 contamination was found in 111 samples: in 8 of the sunflower seed samples (16%) at a mean level of 40.68 ng g(-1) and in 103 safflower seed samples (83.7%) at a mean level of 2.81 +/- 0.44 ng g(-1). In 5 sunflower seed samples and 1 safflower seed sample, aflatoxin B1 levels were higher than the maximum levels of AFB1 under Iran regulations (5 ng g(-1)). Aflatoxin B1 levels in 5 sunflower and 2 safflower seed samples were higher than the European Union maximum limit (2 ng g(-1)). PMID- 24786628 TI - Effects of chemopreventive natural products on non-homologous end-joining DNA double-strand break repair. AB - Double-strand breaks (DSBs) may result from endogenous (e.g., reactive oxygen species, variable (diversity) joining, meiotic exchanges, collapsed replication forks, nucleases) or exogenous (e.g., ionizing radiation, chemotherapeutic agents, radiomimetic compounds) events. DSBs disrupt the integrity of DNA and failed or improper DSBs repair may lead to genomic instability and, eventually, mutations, cancer, or cell death. Non-homologous end-joining (NHEJ) is the major pathway used by higher eukaryotic cells to repair these lesions. Given the complexity of NHEJ and the number of proteins and cofactors involved, secondary metabolites from medicinal or food plants might interfere with the process, activating or inhibiting repair. Twelve natural products, arbutin, curcumin, indole-3-carbinol, and nine flavonoids (apigenin, baicalein, chalcone, epicatechin, genistein, myricetin, naringenin, quercetin, sakuranetin) were chosen for their postulated roles in cancer chemoprevention and/or treatment. The effects of these compounds on NHEJ were investigated with an in vitro protocol based on plasmid substrates. Plasmids were linearized by a restriction enzyme, generating cohesive ends, or by a combination of enzymes, generating incompatible ends; plasmids were then incubated with a nuclear extract prepared from normal human small-intestinal cells (FHS 74 Int), either treated with these natural products or untreated (controls). The NHEJ repair complex from nuclear extracts ligates linearized plasmids, resulting in plasmid oligomers that can be separated and quantified by on-chip microelectrophoresis. Some compounds (chalcone, epicatechin, myricetin, sakuranetin and arbutin) clearly activated NHEJ, whereas others (apigenin, baicalein and curcumin) significantly reduced the repair rate of both types of plasmid substrates. Although this in vitro protocol is only partly representative of the in vivo situation, the natural products appear to interfere with NHEJ repair and warrant further investigation. PMID- 24786629 TI - Left ventricular ejection fraction and volumes: it depends on the imaging method. AB - BACKGROUND AND METHODS: In order to provide guidance for using measurements of left ventricular (LV) volume and ejection fraction (LVEF) from different echocardiographic methods a PubMed review was performed on studies that reported reference values in normal populations for two-dimensional (2D ECHO) and three dimensional (3D ECHO) echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR). In addition all studies (2 multicenter, 16 single center) were reviewed, which included at least 30 patients, and the results compared of noncontrast and contrast 2D ECHO, and 3D ECHO with those of CMR. RESULTS: The lower limits for normal LVEF and the normal ranges for end-diastolic (EDV) and end-systolic (ESV) volumes were different in each method. Only minor differences in LVEF were found in studies comparing CMR and 2D contrast echocardiography or noncontrast 3D echocardiography. However, EDV and ESV measured with all echocardiographic methods were smaller and showed greater variability than those derived from CMR. Regarding agreement with CMR and reproducibility, all studies showed superiority of contrast 2D ECHO over noncontrast 2D ECHO and 3D ECHO over 2D ECHO. No final judgment can be made about the comparison between contrast 2D ECHO and noncontrast or contrast 3D ECHO. CONCLUSION: Contrast 2D ECHO and noncontrast 3D ECHO show good reproducibility and good agreement with CMR measurements of LVEF. The agreement of volumes is worse. Further studies are required to assess the clinical value of contrast 3D ECHO as noncontrast 3D ECHO is only reliable in patients with good acoustic windows. PMID- 24786630 TI - Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. AB - BACKGROUND: Few human studies have examined bisphenol A (BPA) exposure in relation to semen quality and reproductive hormones in men, and results are divergent. OBJECTIVES: We examined associations between urinary BPA concentration and reproductive hormones, as well as semen quality, in young men from the general population. METHODS: Our study population consisted of 308 young men from the general population. Urinary BPA concentration was measured by isotope dilution TurboFlow-liquid chromatography-tandem mass spectrometry. We used multiple linear regression analysis to estimate associations between BPA concentration and reproductive hormones and semen quality, adjusting for confounding factors. RESULTS: We found that 98% of the men had detectable urinary levels of BPA. Median (5th-95th percentiles) BPA concentration was 3.25 ng/mL (0.59-14.89 ng/mL). Men with BPA concentrations above the lowest quartile had higher concentrations of serum testosterone, luteinizing hormone (LH), estradiol, and free testosterone compared with the lowest quartile (p trend <= 0.02). Men in the highest quartile of BPA excretion had on average 18% higher total testosterone (95% CI: 8, 28%), 22% higher LH (95% CI: 6, 39%), and 13% higher estradiol (95% CI: 4, 24%) compared with lowest quartile. Men in the highest quartile of BPA also had significantly lower percentage progressive motile spermatozoa compared with men in the lowest quartile (-6.7 percentage points, 95% CI: -11.76, -1.63). BPA was not associated with other semen parameters. Adjusting for dietary patterns did not influence the results. CONCLUSIONS: The pattern of associations between BPA and reproductive hormones could indicate an antiandrogenic or antiestrogenic effect, or both, of BPA on the hypothalamic pituitary-gonadal hormone feedback system, possibly through a competitive inhibition at the receptor level. However, additional research is needed to confirm our findings and to further test the suggested potential mechanisms. PMID- 24786631 TI - Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease. AB - Mild cognitive impairment (MCI) represents a cognitive state intermediate between normal aging and early Alzheimer's disease (AD). To investigate if the molecular signature of MCI parallels the clinical picture, we use microarrays to extensively profile gene expression in 4 cortical brain regions (entorhinal cortex, hippocampus, superior frontal gyrus, post-central gyrus) using the postmortem tissue from cognitively normal aged controls, MCI, and AD cases. Our data reveal that gene expression patterns in MCI are not an extension of aging, and for the most part, are not intermediate between aged controls and AD. Functional enrichment analysis of significant genes revealed prominent upregulation in MCI brains of genes associated with anabolic and biosynthetic pathways (notably transcription, protein biosynthesis, protein trafficking, and turnover) as well as mitochondrial energy generation. In addition, many synaptic genes showed altered expression in MCI, predominantly upregulation, including genes for central components of the vesicle fusion machinery at the synapse, synaptic vesicle trafficking, neurotransmitter receptors, and synaptic structure and stabilization. These data suggest that there is a rebalancing of synaptic transmission in the MCI brain. To investigate if synaptic gene expression levels in MCI were related to cognitive function, Pearson correlation coefficient between the Mini Mental State Examination (MMSE) and region-specific messenger RNA expression were computed for MCI cases. A number of synaptic genes showed strong significant correlations (r > 0.8, p < 0.01) most notably in the entorhinal cortex, with fewer in the hippocampus, and very few in neocortical regions. The synaptic genes with highly significant correlations were predominantly related to synaptic transmission and plasticity, and myelin composition. Unexpectedly, we found that gene expression changes that facilitate synaptic excitability and plasticity were overwhelmingly associated with poorer MMSE, and conversely that gene expression changes that inhibit plasticity were positively associated with MMSE. These data suggest that there are excessive excitability and apparent plasticity in limbic brain regions in MCI, that is associated with impaired synaptic and cognitive function. Such changes would be predicted to contribute to increased excitability, in turn leading to greater metabolic demand and ultimately progressive degeneration and AD, if not controlled. PMID- 24786632 TI - Clinical correlations of microstructural changes in progressive supranuclear palsy. AB - In patients with progressive supranuclear palsy (PSP), previous reports have shown a severe white matter (WM) damage involving supra and infratentorial regions including cerebellum. In the present study, we investigated potential correlations between WM integrity loss and clinical-cognitive features of patients with PSP. By using magnetic resonance imaging and diffusion tensor imaging with tract based spatial statistic analysis, we analyzed WM volume in 18 patients with PSP and 18 healthy controls (HCs). All patients and HCs underwent a detailed clinical and neuropsychological evaluation. Relative to HCs, patients with PSP showed WM changes encompassing supra and infratentorial areas such as corpus callosum, fornix, midbrain, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior cerebellar peduncle, superior longitudinal fasciculus, uncinate fasciculus, cingulate gyrus, and cortico-spinal tract bilaterally. Among different correlations between motor-cognitive features and WM structural abnormalities, we detected a significant association between fronto cerebellar WM loss and executive cognitive impairment in patients with PSP. Our findings, therefore, corroborate the hypothesis that cognitive impairment in PSP may result from both "intrinsic" and "extrinsic" frontal lobe dysfunction, likely related to cerebellar disconnection. PMID- 24786633 TI - Microstructural analysis of Au/TiO2-SBA-15 nanocomposite. AB - Properties of gold nanoparticles (AuNPs) are very different from bulk gold, in particular, highly dispersed AuNPs exhibit high catalytic activities on metal oxide supports. Catalytic activities of AuNPs are strongly dependent on: (i) size and morphology; (ii) synthesis methods; (iii) nature of the support; (iv) interaction between AuNPs and the support; and (v) oxidation state of AuNPs in the synthesized catalysts. A goal is to maintain the size and to prohibit aggregation of AuNPs, since aggregations deteriorate catalytic activities. Some strong interactions are therefore required between AuNPs and their supports to prevent the movement of AuNPs. SBA-15 is a promising material for the support of AuNPs since it has ordered two-dimensional hexagonal pore channels, uniform pore size ranging from 5 to 30 nm, narrow pore size distribution, thick amorphous walls ranging from 3 to 6 nm, and high surface area. In this study, SBA-15, TiO2 SBA-15 and TiO2-SBA-15-AuNP nanocomposites were synthesized by the sol-gel method and microstructural characterizations were carried out by both X-ray diffraction analysis and electron microscopy. PMID- 24786634 TI - From metal-organic framework to nitrogen-decorated nanoporous carbons: high CO2 uptake and efficient catalytic oxygen reduction. AB - High-surface-area N-decorated nanoporous carbons have been successfully synthesized using the N-rich metal-organic framework ZIF-8 as a template and precursor along with furfuryl alcohol and NH4OH as the secondary carbon and nitrogen sources, respectively. These carbons exhibited remarkable CO2 adsorption capacities and CO2/N2 and CO2/CH4 selectivities. The N-decoration in these carbons resulted in excellent activity for the oxygen reduction reaction. Samples NC900 and NC1000 having moderate N contents, high surface areas, and large numbers of mesopores favored the four-electron reduction pathway, while sample NC800 having a high N content, a moderate surface area, and a large number of micropores favored the two-electron reduction process. PMID- 24786635 TI - A highly efficient asymmetric synthesis of vernakalant. AB - A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction. PMID- 24786637 TI - Narrative organisation at encoding facilitated children's long-term episodic memory. AB - This study examined the effect of narrative organisation at encoding on long-term episodic memory in a sample of five- to seven-year-old children (N = 113). At an initial interview, children were asked to narrate a story from a picture book. Six months later, they were interviewed again and asked to recall the story and answer a series of direct questions about the story. Children who initially encoded more information in narrative and produced more complete, complex, cohesive and coherent narratives remembered the story in greater detail and accuracy following the six-month interval, independent of age and verbal skills. The relation between narrative organisation and memory was consistent across culture and gender. These findings provide new insight into the critical role of narrative in episodic memory. PMID- 24786636 TI - Metal-free cAMP-dependent protein kinase can catalyze phosphoryl transfer. AB - X-ray structures of several ternary product complexes of the catalytic subunit of cAMP-dependent protein kinase (PKAc) have been determined with no bound metal ions and with Na(+) or K(+) coordinated at two metal-binding sites. The metal free PKAc and the enzyme with alkali metals were able to facilitate the phosphoryl transfer reaction. In all studied complexes, the ATP and the substrate peptide (SP20) were modified into the products ADP and the phosphorylated peptide. The products of the phosphotransfer reaction were also found when ATP gammaS, a nonhydrolyzable ATP analogue, reacted with SP20 in the PKAc active site containing no metals. Single turnover enzyme kinetics measurements utilizing (32)P-labeled ATP confirmed the phosphotransferase activity of the enzyme in the absence of metal ions and in the presence of alkali metals. In addition, the structure of the apo-PKAc binary complex with SP20 suggests that the sequence of binding events may become ordered in a metal-free environment, with SP20 binding first to prime the enzyme for subsequent ATP binding. Comparison of these structures reveals conformational and hydrogen bonding changes that might be important for the mechanism of catalysis. PMID- 24786639 TI - On what scale does it benefit the patients if uterine arteries were preserved during ART? AB - OBJECTIVE: To guarantee a better perfusion, the preservation of the uterine arteries during ART has sometimes been performed but has seldom been tested. We share the results of our tests to provoke a potentially different point of view on such uses of ART. METHODS: Using computed tomography angiography (CTA), we identified the uterine blood supply in patients who underwent ART with uterine artery preserved and sacrificed. RESULTS: We included 26 consecutive post-ART patients from the outpatient service. The uterine arteries were preserved in 16 patients (61.5%) and ligated in 10 patients (38.5%). Out of the 26 patients studied, 17 (65.4%) were supplied by only the ovarian arteries; seven (26.9%) by one uterine artery and the contralateral ovarian artery; and only 2 (7.6%) by the uterine artery supply alone. No recanalization of the ligated uterine artery or other newly formed compensatory circulation was observed. Among the 16 patients who had preserved uterine arteries, only two (12.5%) showed identifiable bilateral uterine arteries, whereas seven (43.6%) had unilateral uterine artery occlusion and another seven (43.6%), bilateral occlusion. We had three obstetric outcomes, two of which came from the ovarian artery supplying group and one from the hybrid supplying group. CONCLUSIONS: The ovarian artery became the dominant supplying vessel after ART. The anatomically preserved uterine artery had an 87.5% chance of occlusion after the procedure. Moreover, the contributing uterine artery did not show any functional superiority. Thus, the benefit of preserving the uterine arteries during ART is probably very limited. PMID- 24786638 TI - Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer. AB - OBJECTIVE: Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined. METHODS: Nine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, also termed VS-6062) from 0.1 to 1 MUM for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown. RESULTS: Greater than 50% inhibition of OVCAR8, HEY, and ID8-IP ovarian carcinoma cell growth occurred with 0.1 MUM PF-271 in anchorage independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3 IP, A2780, and 5009-MOVCAR was not affected by 0.1 MUM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition. CONCLUSIONS: Differential responsiveness to FAK inhibitor treatment was observed. Intrinsic low merlin protein level correlated with PF-271-mediated anchorage independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials. PMID- 24786640 TI - Online oxygen kinetic isotope effects using membrane inlet mass spectrometry can differentiate between oxidases for mechanistic studies and calculation of their contributions to oxygen consumption in whole tissues. AB - The reduction chemistry of molecular oxygen underpins the energy metabolism of multicellular organisms, liberating free energy needed to catalyze a plethora of enzymatic reactions. Measuring the isotope signatures of (16)O and (18)O during O2 reduction can provide insights into both kinetic and equilibrium isotope effects. However, current methods to measure O2 isotope signatures are time consuming and disruptive. This paper describes the application of membrane inlet mass spectrometry to determine the oxygen isotope discrimination of a range of O2 consuming reactions, providing a rapid and convenient method for determining these values. A survey of oxygenase and oxidase reactions provides new insights into previously uncharacterized amino acid oxidase enzymes. Liquid and gas phase measurements show the ease of assays using this approach for purified enzymes, biological extracts and intact tissues. PMID- 24786641 TI - Genome-wide profiling of Hfq-binding RNAs uncovers extensive post-transcriptional rewiring of major stress response and symbiotic regulons in Sinorhizobium meliloti. AB - The RNA chaperone Hfq is a global post-transcriptional regulator in bacteria. Here, we used RNAseq to analyze RNA populations from the legume symbiont Sinorhizobium meliloti that were co-immunoprecipitated (CoIP-RNA) with a FLAG tagged Hfq in five growth/stress conditions. Hfq-bound transcripts (1315) were largely identified in stressed bacteria and derived from small RNAs (sRNAs), both trans-encoded (6.4%) and antisense (asRNAs; 6.3%), and mRNAs (86%). Pull-down with Hfq recovered a small proportion of annotated S. meliloti sRNAs (14% of trans-sRNAs and 2% of asRNAs) suggesting a discrete impact of this protein in sRNA pathways. Nonetheless, Hfq selectively stabilized CoIP-enriched sRNAs, anticipating that these interactions are functionally significant. Transcription of 26 Hfq-bound sRNAs was predicted to occur from promoters recognized by the major stress sigma factors sigma(E2) or sigma(H1/2). Recovery rates of sRNAs in each of the CoIP-RNA libraries suggest a large impact of Hfq-assisted riboregulation in S. meliloti osmoadaptation. Hfq directly targeted 18% of the predicted S. meliloti mRNAs, which encode functionally diverse proteins involved in transport and metabolism, sigma(E2)-dependent stress responses, quorum sensing, flagella biosynthesis, ribosome, and membrane assembly or symbiotic nitrogen fixation. Canonical targeting of the 5' regions of two of the ABC transporter mRNAs by the homologous Hfq-binding AbcR1 and AbcR2 sRNAs leading to inhibition of protein synthesis was confirmed in vivo. We therefore provide a comprehensive resource for the systems-level deciphering of hitherto unexplored S. meliloti stress and symbiotic post-transcriptional regulons and the identification of Hfq-dependent sRNA-mRNA regulatory pairs. PMID- 24786642 TI - The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia. AB - Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias and deciphering their molecular bases has contributed to the understanding of this complex process. Here, we report a homozygous mutation in the mitochondria-associated granulocyte macrophage colony stimulating factor signaling gene (MAGMAS) in a novel and severe spondylodysplastic dysplasia. MAGMAS, also referred to as PAM16 (presequence translocase-associated motor 16), is a mitochondria-associated protein involved in preprotein translocation into the matrix. We show that MAGMAS is specifically expressed in trabecular bone and cartilage at early developmental stages and that the mutation leads to an instability of the protein. We further demonstrate that the mutation described here confers to yeast strains a temperature-sensitive phenotype, impairs the import of mitochondrial matrix pre-proteins and induces cell death. The finding of deleterious MAGMAS mutations in an early lethal skeletal dysplasia supports a key role for this mitochondrial protein in the ossification process. PMID- 24786643 TI - A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma. AB - CONTEXT: Inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies including carboplatin is implicated in their failure to improve prognosis for patients with glioblastoma. Convection-enhanced delivery (CED) of carboplatin has the potential to improve outcomes by facilitating bypass of the BBB. OBJECTIVE: We report the first use of an implantable CED system incorporating a novel transcutaneous bone-anchored port (TBAP) for intermittent CED of carboplatin in a patient with recurrent glioblastoma. MATERIALS AND METHODS: The CED catheter system was implanted using a robot-assisted surgical method. Catheter targeting accuracy was verified by performing intra-operative O arm imaging. The TBAP was implanted using a skin-flap dermatome technique modeled on bone-anchored hearing aid surgery. Repeated infusions were performed by attaching a needle administration set to the TBAP. Drug distribution was monitored with serial real-time T2-weighted magnetic resonance imaging (MRI). RESULTS: All catheters were implanted to within 1.5 mm of their planned target. Intermittent infusions of carboplatin were performed on three consecutive days and repeated after one month without the need for further surgical intervention. Infused volumes of 27.9 ml per day were well tolerated, with the exception of a single seizure episode. Follow-up MRI at eight weeks demonstrated a significant reduction in the volume of tumor enhancement from 42.6 ml to 24.6 ml, and was associated with stability of the patient's clinical condition. CONCLUSION: Reduction in the volume of tumor enhancement indicates that intermittent CED of carboplatin has the potential to improve outcomes in glioblastoma. The novel technology described in this report make intermittent CED infusion regimes an achievable treatment strategy. PMID- 24786644 TI - The CAPITA study of protein-conjugate pneumococcal vaccine and its implications for use in adults in developed countries. AB - Until 1990, Hemophilus influenzae type b (HITB) was a major cause of morbidity and mortality in toddlers and young children. A vaccine consisting of purified polyribosyl ribitol phosphate (PRP), the capsular polysaccharide (CPS) of HITB, had been shown to be ineffective as an antigen in the population at risk, and this vaccine was withdrawn from the market within a few years of its introduction. By contrast, the discovery that PRP, when covalently bound to an antigenic protein, stimulated antibody production in infants and toddlers, (1) led to the development of a vaccine that has all but eradicated HITB infection and brought about a near-disappearance of this organism in the United States. PMID- 24786646 TI - Growth-mortality relationships in pinon pine (Pinus edulis) during severe droughts of the past century: shifting processes in space and time. AB - The processes leading to drought-associated tree mortality are poorly understood, particularly long-term predisposing factors, memory effects, and variability in mortality processes and thresholds in space and time. We use tree rings from four sites to investigate Pinus edulis mortality during two drought periods in the southwestern USA. We draw on recent sampling and archived collections to (1) analyze P. edulis growth patterns and mortality during the 1950s and 2000s droughts; (2) determine the influence of climate and competition on growth in trees that died and survived; and (3) derive regression models of growth mortality risk and evaluate their performance across space and time. Recent growth was 53% higher in surviving vs. dying trees, with some sites exhibiting decades-long growth divergences associated with previous drought. Differential growth response to climate partly explained growth differences between live and dead trees, with responses wet/cool conditions most influencing eventual tree status. Competition constrained tree growth, and reduced trees' ability to respond to favorable climate. The best predictors in growth-mortality models included long-term (15-30 year) average growth rate combined with a metric of growth variability and the number of abrupt growth increases over 15 and 10 years, respectively. The most parsimonious models had high discriminatory power (ROC>0.84) and correctly classified ~ 70% of trees, suggesting that aspects of tree growth, especially over decades, can be powerful predictors of widespread drought-associated die-off. However, model discrimination varied across sites and drought events. Weaker growth-mortality relationships and higher growth at lower survival probabilities for some sites during the 2000s event suggest a shift in mortality processes from longer-term growth-related constraints to shorter-term processes, such as rapid metabolic decline even in vigorous trees due to acute drought stress, and/or increases in the attack rate of both chronically stressed and more vigorous trees by bark beetles. PMID- 24786645 TI - Immunogenicity of a killed bivalent (O1 and O139) whole cell oral cholera vaccine, Shanchol, in Haiti. AB - BACKGROUND: Studies of the immunogenicity of the killed bivalent whole cell oral cholera vaccine, Shanchol, have been performed in historically cholera-endemic areas of Asia. There is a need to assess the immunogenicity of the vaccine in Haiti and other populations without historical exposure to Vibrio cholerae. METHODOLOGY/PRINCIPAL FINDINGS: We measured immune responses after administration of Shanchol, in 25 adults, 51 older children (6-17 years), and 47 younger children (1-5 years) in Haiti, where cholera was introduced in 2010. A>=4-fold increase in vibriocidal antibody titer against V. cholerae O1 Ogawa was observed in 91% of adults, 74% of older children, and 73% of younger children after two doses of Shanchol; similar responses were observed against the Inaba serotype. A>=2-fold increase in serum O-antigen specific polysaccharide IgA antibody levels against V. cholerae O1 Ogawa was observed in 59% of adults, 45% of older children, and 61% of younger children; similar responses were observed against the Inaba serotype. We compared immune responses in Haitian individuals with age- and blood group-matched individuals from Bangladesh, a historically cholera endemic area. The geometric mean vibriocidal titers after the first dose of vaccine were lower in Haitian than in Bangladeshi vaccinees. However, the mean vibriocidal titers did not differ between the two groups after the second dose of the vaccine. CONCLUSIONS/SIGNIFICANCE: A killed bivalent whole cell oral cholera vaccine, Shanchol, is highly immunogenic in Haitian adults and children. A two dose regimen may be important in Haiti, and other populations lacking previous repeated exposures to V. cholerae. PMID- 24786647 TI - Size-dependent strength of dental adhesive systems. AB - OBJECTIVE: The aim of this study is to explain the influence of peripheral interface stress singularities on the testing of tensile bond strength. The relationships between these theoretically predicted singularities and the effect of specimen size on the measured bond strength are evaluated. METHODS: Finite element method (FEM) and boundary element method (BEM) analyses of microtensile bond strength test specimens were performed and the presence of localized high stress concentrations and singularities was analyzed. The specimen size effect predicted by the models was compared to previously published experimental data. RESULTS: FEM analysis of single-material trimmed hour-glass versus cast cylindrical specimens showed different theoretical stress distributions, with the dumbbell or cylindrical specimens showing a more homogeneous distribution of the stress on the critical symmetry plane. For multi-material specimens, mathematical singularities at the free edge of the bonded interface posed a computational challenge that resulted in mesh-dependence in the standard FEM analysis. A specialized weighted-traction BEM analysis, designed to eliminate mesh-dependence by capturing the effect of the singularity, predicted a specimen size effect that corresponds to that published previously in the literature. SIGNIFICANCE: The results presented here further support the attention to specimen dimensions that has already broadened the empirical use of the microtensile test methods. FEM and BEM analyses that identify stress concentrations and especially marginal stress singularities must be accounted for in reliable bonding strength assessments. Size-dependent strength variations generally attributed to the effects of flaw distributions throughout the interfacial region are not as relevant as the presence of singularities at bonded joint boundaries - as revealed by both FEM and BEM analyses, when interpreted from a generalized fracture mechanics perspective. Furthermore, this size-dependence must be considered when evaluating or designing dental adhesive systems. PMID- 24786648 TI - Patient activation and use of an electronic patient portal. AB - PRIMARY OBJECTIVE: Electronic patient portals give patients access to personal medical data, potentially creating opportunities to improve knowledge, self efficacy, and engagement in healthcare. The combination of knowledge, self efficacy, and engagement has been termed activation. Our objective was to assess the relationship between patient activation and outpatient use of a patient portal. RESEARCH DESIGN: Survey. METHODS AND PROCEDURES: A telephone survey was conducted with 180 patients who had been given access to a portal, 113 of whom used it and 67 of whom did not. The validated patient activation measure (PAM) was administered along with questions about demographics and behaviors. RESULTS: Portal users were no different from nonusers in patient activation. Portal users did have higher education level and more frequent Internet use, and were more likely to have precisely 2 prescription medications than to have more or fewer. CONCLUSION: Patients who chose to use an electronic patient portal were not more highly activated than nonusers, although they were more educated and more likely to be Internet users. PMID- 24786649 TI - Removing singular refractive indices with sculpted surfaces. AB - The advent of Transformation Optics established the link between geometry and material properties, and has resulted in a degree of control over electromagnetic fields that was previously impossible. For waves confined to a surface it is known that there is a simpler, but related, geometrical equivalence between the surface shape and the refractive index, and here we demonstrate that conventional devices possessing a singularity - that is, the requirement of an infinite refractive index - can be realised for waves confined to an appropriately sculpted surface. In particular, we redesign three singular omnidirectional devices: the Eaton lens, the generalized Maxwell Fish-Eye, and the invisible sphere. Our designs perfectly reproduce the behaviour of these singular devices, and can be achieved with simple isotropic media of low refractive index contrast. PMID- 24786650 TI - Magnetic properties of Fe(x)Co(1-x) nanochains on Pt(1 1 1) surfaces. AB - The magnetic properties of FexCo1-x nanochains on Pt(1 1 1) were studied using the first-principles real-space linear muffin-tin orbital-atomic sphere approximation (RS-LMTO-ASA) method within the density functional theory. The relative amounts of Fe and Co atoms in a chosen nanochain were varied and several possible arrangements of the atomic species were taken into account. The results of the exchange interaction demonstrates ferromagnetic coupling for the nanowires. Our calculations of Fe and Co average magnetic moments reveal a large enhancement of both spin and orbital moments compared to Fe-Co films deposited on a Pt(1 1 1) surface. The trend for the orbital moments with respect to stoichiometry differs from all previous higher-dimensional Fe-Co alloys on Pt(1 1 1) studies. PMID- 24786651 TI - Chiral beta-cyclodextrin functionalized polymer monolith for the direct enantioselective reversed phase nano liquid chromatographic separation of racemic pharmaceuticals. AB - 2,3,6-Tris(phenylcarbamoyl)-beta-cyclodextrin-6-methacrylate was prepared and used as a functional monomer for the preparation of new beta-cyclodextrin (beta CD) functionalized polymer monoliths. The polymer monoliths were prepared via the copolymerization of beta-CD methacrylate and ethylene glycol dimethacrylate in different ratios in situ in fused silica capillary (internal diameter 150 MUm). The effect of functional monomer/cross linker concentration on the chiral separation of different classes of pharmaceuticals namely; alpha- and beta blockers, antiinflammatory drugs, antifungal drugs, dopamine antagonists, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, diuretics, antihistaminics, anticancer drugs and antiarrhythmic drugs was investigated. Baseline separation was achieved for propranolol, ifosfamide, alprenolol, tertalol, 1-indanol, tebuconazole, o-methoxymandelic acid, celiprolol and cizolertine under reversed phase conditions with mobile phase composed of methanol and water, using nano liquid chromatography. The method provides more economical analysis under environmentally benign conditions. The prepared capillary columns showed good mechanical stability and good repeatability (run-to run and batch-to batch). PMID- 24786652 TI - Capability measurement of size-exclusion chromatography with a light-scattering detection method in a stability study of bevacizumab using the process capability indices. AB - In this study, we investigated if the size-exclusion chromatography coupled with light-scattering and refractive index detection (SEC/LS/RI) method is fitted for its intended purpose and checked if the analytical method is able to provide enough conforming results. For this, the process capability indices Cp, Cpk, and Cpm were computed. The traditional X-chart and moving range (MR) chart were used by the same analyst to monitor the equipment in the laboratory over a 1-year period. For this, a bovine serum albumin (BSA) sample (0.3 mg mL(-1)) with a nominal Mw of 66.4 kDa was analyzed each working day. The results confirmed that the analytical method is in-control and stable. To determine whether the given process meets the present capability requirement and runs under the desired quality conditions, the Pearn and Shu (2003) method based on the lower confidence bound C on Cpm was used. The estimator Cpm was 1.81, and the lower confidence bound C was 1.40. We therefore conclude that the true value of the method capability Cpm is no less than 1.40 with a 95% level of confidence. This result indicates that the method is satisfactory and no stringent precision control is required. The usefulness of this method was applied in the characterization of bevacizumab commercial pharmaceutical preparations stored under different conditions that lead to aggregation. In this case, the computed Cpm index was 0.98 (0.70, 1.26), which indicates that the method does not comply with the specification limits and needs to be revised. The quality improvement effort should: (1) reduce the uncertainty in the absolute Mw determination; (2) either move the process mean closer to the target value or reduce the process variation, i.e. improve the method accuracy (MU-T) and precision (sigma(2)). On this point, the Bayesian posterior distribution of the mean and standard deviation pointed out the need to control the precision but specially accuracy in order to reduce the overall uncertainty of analytical method and thus, the method is capable. PMID- 24786653 TI - Multiple monolithic fiber solid-phase microextraction: a new extraction approach for aqueous samples. AB - A novel multiple monolithic fiber solid-phase microextraction (MMF-SPME) was designed and prepared. Two steps were involved in the preparation of MMF-SPME. Firstly, single thin fiber (0.5mm in diameter) was prepared by co-polymerization of vinylimidazole and ethylene dimethacrylate. Secondly, several thin fibers were bound together to obtain the MMF assembly. The extraction and desorption dynamics of MMF-SPME with different numbers of fibers were studied in detail. In order to demonstrate the usability of the new MMF-SPME, the extraction performance of MMF SPME for 2-chlorophenol, 2,4-dichlorophenol, 2,4,6-trichlorophenol and pentachlorophenol was investigated in direct SPME mode. Results indicated that aqueous samples could form convection effectively within MMF-SPME because there were gaps between fibers. The extraction procedure was accelerated by the convection. At the same time, the MMF-SPME possessed high extraction capacity because more sorbent was employed. Under the optimized extraction conditions, low detection limits (S/N=3) and quantification limits (S/N=10) for the target analytes were achieved within the range of 0.13-0.29 MUg/L and 0.44-0.98 MUg/L, respectively. The MMF-SPME also showed a very long lifespan and good repeatability. Finally, the MMF-SPME was successfully applied to the analysis of tap, lake and ground water samples with spiked recoveries in the range of 73.8 101%. PMID- 24786654 TI - Magnetic nanoparticles-nylon 6 composite for the dispersive micro solid phase extraction of selected polycyclic aromatic hydrocarbons from water samples. AB - In this article, the easy synthesis of magnetic nanoparticles-nylon 6 composite is presented, characterized and applied in the microextraction field. The one step synthesis of the composite is performed by a solvent changeover playing with the different solubility of the polymeric network in formic acid and water. The new material has been characterized by different techniques including infrared spectroscopy, transmission and scanning microscopy. The extraction performance of the composite under a dispersive micro solid phase extraction format has been evaluated by determining four polycyclic aromatic hydrocarbons (benzo[b]fluoranthene, fluoranthene, indeno[1,2,3-cd]pyrene and phenanthrene) in water using ultra performance liquid chromatography (UPLC) combined with photo diode array detection. The developed methodology allows the determination of the analytes with limits of detection in the range from 0.05 MUg/L (benzo[b]fluoranthene) to 0.58 MUg/L (phenanthrene). The repeatability of the method was better than 6.9% at the limit of quantification level. The relative recoveries varied in the interval 80-111%. PMID- 24786655 TI - A chemometric approach toward the detection and quantification of coffee adulteration by solid-phase microextraction using polymeric ionic liquid sorbent coatings. AB - Solid-phase microextraction (SPME) using cross-linked polymeric ionic liquid (PIL)-based sorbent coatings was used to extract volatile aroma-related compounds from coffee samples. Several PIL-based coatings were screened alongside a commercial poly(acrylate) (PA) SPME coating. The best performing PIL-based SPME fiber, poly(1-vinyl-3-hexadecylimidazolium bis[(trifluoromethyl)sulfonylimide]) with 50% (w/w) 1,12-di(3-vinylbenzylimidazolium)dodecane dibis[(trifluoromethyl)sulfonyl]imide incorporated cross-linker, was used to isolate the volatile fraction of Arabica coffee. To illustrate the importance of trace analyte isolation, a method for the detection and quantification of coffee adulteration is described. Chromatographic profiles obtained by gas chromatography/mass spectrometry (GC/MS) were used to create the chemometric model. Partial least squares (PLS) regression was employed to correlate the aroma related chemical fingerprint to the degree of adulteration. The proposed method successfully detected fraud down to 1% (w/w) of adulterant and accurately determined the degree of coffee adulteration (i.e, root mean square error of calibration and prediction of 0.54% and 0.83% (w/w), respectively). Finally, important aroma-related compounds including furans, methoxyphenols, pyrazines, and ketones were identified. PMID- 24786656 TI - Preparation and evaluation of a novel monolithic column containing double octadecyl chains for reverse-phase micro high performance liquid chromatography. AB - A novel reverse-phase monolithic stationary phase containing double long alkyl chains was prepared based on the thermally initiated co-polymerization of 3 methylacryloyl-3-oxapropyl-3-(N,N-dioctadecylcarbamoyl)-propionate (AOD) and ethylene glycol dimethacrylate (EDMA) in the presence of 2-methyl-1-propanol and 1,4-butanediol as the selected porogens. The polymerization was carefully optimized and good permeability, stability and column efficiency were observed for the final monolithic columns. The column also showed good long term stability and reproducibility. The methylene selectivity demonstrates typical reversed phase characteristics. The optimized poly (AOD-co-EDMA) monolith exhibited good selectivity for a range of non-polar test analytes such as PAHs, tocopherols and alkylphenones. A good separation of intact proteins was also observed. PMID- 24786657 TI - Recent advances of ionic liquids and polymeric ionic liquids in capillary electrophoresis and capillary electrochromatography. AB - Ionic liquids (ILs) and polymeric ionic liquids (PILs) with unique and fascinating properties have drawn considerable interest for their use in separation science, especially in chromatographic techniques. In this article, significant contributions of ILs and PILs in the improvement of capillary electrophoresis and capillary electrochromatography are described, and a specific overview of the most relevant examples of their applications in the last five years is also given. Accordingly, some general conclusions and future perspectives in these areas are discussed. PMID- 24786658 TI - Validated ultra high performance liquid chromatography-tandem mass spectrometry method for quantitative analysis of total and free thyroid hormones in bovine serum. AB - Thyroid hormones are essential hormones for regulating growth and development. Methods to accurately monitor low-levels (ppb-ppt) of these hormones in serum are needed to assess overall health, both from a clinical perspective as from environmental contaminant or drug exposures. In general, the separation of the free thyroid hormone fraction from animal sera is performed through labour intensive equilibrium dialysis, while detection of total and free thyroid hormone fractions in animals is done with commercially available radioimmunoassays (RIAs). This study reports newly developed analysis methods for both the total and free fractions of triiodothyronine (T3), reverse-triiodothyronine (rT3) and thyroxin (T4) from bovine serum, with a much higher specificity and selectivity than commercially available RIAs. The bovine serum extraction procedures of total and free T3, rT3, T4 were optimised with fractional factorial designs and consisted of, respectively, deproteinisation followed by liquid-liquid extraction, 30 kDA ultracentrifugation and solid phase extraction. Both free and total thyroid hormone UHPLC-HESI-MS/MS based analysis methods were successfully validated. The limits of quantification for T4, rT3 and T3 amounted respectively 0.04 ng mL(-1), 0.05 ng mL(-1), 0.03 ng mL(-1) for the total fraction, and 6.6 pg mL(-1), 2.6 pg mL(-1) and 2.7 pg mL(-1) for the free fraction. Individual recoveries of total and free thyroid hormone fractions ranged between 95.6 and 106.3% and 92.1 and 106.5%. Good results for repeatability and intra-laboratory reproducibility (RSD%) were observed, i.e. respectively <=8.0% and <=7.3% for the total and free fractions. Excellent linearity (R(2)>=0.99) and lack-of-fit was proven for both fractions. In conclusion, these methods show excellent in-house performance and possibilities for elaboration to application in other animal sera (e.g. feline, canine, equine). PMID- 24786659 TI - Robust and selective nano cavities for protein separation: an interpenetrating polymer network modified hierarchically protein imprinted hydrogel. AB - In the present work, we report a novel method for the reinforcement of hierarchically structured molecularly imprinted polymer (MIP) for the separation of human serum albumin (HSA) and immunoglobulin G (IgG) proteins under pressure driven flow conditions. The template proteins (HSA or IgG) were first physically adsorbed at their isoelectric point on the surface of wide pore silica particles. Thereafter, the pore system was filled with a monomer solution and polymerized to form a lightly crosslinked polyacrylamide network covering the protein template. In order to enhance the rigidity of the hydrogels, different type of crosslinkers such as ethylene glycol dimethacrylate (EGDMA), 3,4-dihydroxyphenethylamine (DA) and methylene-bis-acrylamide (MBA), at least partially interpenetrated into the initially made acrylamide base hydrogel leading to formation of an interpenetrating polymer network (IPN). Then the silica matrix was removed to leave highly porous and reinforced MIP. TGA together with FT-IR and TEM analysis supported the interpenetration of the secondary crosslinkers in the initially formed polymer matrix. The compression property of the modified hydrogels as a function of degree of swelling was in the following order: DA>EGDMA>MBA-IPN modified hydrogel. Batch binding assay verified the capability of the IPN modified MIPs to capture the target proteins. Moreover, solid phase extraction, HPLC and SDS-PAGE revealed that the EGDMA modified MIP could selectively capture and separate the proteins from human serum or fermentation broth. PMID- 24786660 TI - Clinical and economic consequences of post-operative infections following major elective surgery in U.S. hospitals. AB - BACKGROUND: The incidence and consequences of post-operative infections in patients undergoing major elective surgery is not well understood. METHODS: Using a large U.S. healthcare claims database, we identified all patients who underwent major elective surgery between January 1, 2007, and December 31, 2009. For each such patient, date of the first-noted surgery during this period was designated as the index date. Patients who developed infections within 30 d of their index date were matched to those who did not using propensity score matching. We compared hospital readmissions, mortality, and total healthcare cost during the 30-d period following index date between patients who developed post-operative infections versus those who did not. RESULTS: A total of 327,618 patients met all selection criteria. At 30 d following major elective surgery, 10.9% of patients had evidence of post-operative infections, 39% of which occurred during the index admission. In propensity-matched analyses, patients with post-operative infections were about five times as likely to be readmitted to hospital (11.3% vs. 2.1%) and more than twice as likely to die (0.8% vs. 0.3%) in the 30-d period following surgery; their average total healthcare cost was $8,417 higher ($29,229 vs. $20,812) (all comparisons, p<0.01). CONCLUSION: Approximately one in 10 patients undergoing major elective surgery develop post-operative infections by day 30. Post-operative infections are associated with significantly worse clinical outcomes and higher total healthcare cost. PMID- 24786661 TI - The influence of situational variables on ball possession in the English Premier League. AB - Abstract The aims of this study were twofold: (1) to examine the influence of situational variables on ball possession in elite soccer and (2) to quantify the variables that discriminate between high or low percentage ball possession teams (HPBPT and LPBPT) across different playing positions. Match performance data were collected from English Premier League matches using a multiple-camera system. Data were examined using linear regression, a 2 * 5 factorial analysis of variance and discriminant analysis. Playing against weak opposition was associated with an increase (P < 0.01) in time spent in possession while playing away decreased (P < 0.01) the time spent in possession by ~3%. Possession was increased (P < 0.01) when losing than winning or drawing. Finally, the better the ranking of a team, the higher (P < 0.01) the time spent in possession. The playing position effect was significant for all variables (P < 0.05); however, there were only interactions with team ball possession in some cases. The discriminant analysis identified functions for all five playing positions (P < 0.01). The variables that discriminated performance between HPBPT and LPBPT were different for various playing positions, although the number of successful passes was the most common discriminating variable. The results demonstrate that HPBPT and LPBPT developed different possession strategies during matches and that selected variables such as successful passes were identified to explain these data trends across various playing positions. Combinations of variables could be used to develop a probabilistic model for predicting time spent in possession by teams. PMID- 24786662 TI - Does the control of negative emotions influence blood pressure control and its variability? AB - The aim was to assess the control of negative emotions in treated patients with hypertension in comparison with normotensive individuals and to evaluate the association between suppression of negative emotions, control of blood pressure (BP) on ambulatory blood pressure monitoring (ABPM) and blood pressure variability (BPV). We studied 195 patients (women/men: 89/106); mean age 45.4 +/- 15.9 years. All patients had ABPM and completed the Courtauld Emotional Control Scale (CECS). The total CECS score and scores for subscales for anger, depression and anxiety were analyzed together with mean BP values from ABPM, and their SD and coefficient of variation as BPV measures. The mean CECS score was 54 +/- 12 in all subjects; highest in uncontrolled hypertension 56 +/- 11, intermediate 53 +/- 12 in controlled hypertension and lowest 48 +/- 12 in normotensive subjects. The reference value for the Polish population is 50 +/- 11. Significant differences of mean CECS scores among groups were observed (p = 0.0165) also in multivariate analysis. The difference between uncontrolled hypertension and normotension was significant (p = 0.0262). Few significant, weak correlations were observed between CECS score or its subscales and ABPM derivates in all subjects. Conclusion. Suppression of negative emotions may adversely affect BP control in treated hypertensive patients and it should be considered a cause of uncontrolled hypertension. PMID- 24786663 TI - Preliminary analysis for integration of spot-scanning proton beam therapy and real-time imaging and gating. AB - PURPOSE: Spot-scanning proton beam therapy (PBT) can create good dose distribution for static targets. However, there exists larger uncertainty for tumors that move due to respiration, bowel gas or other internal circumstances within the patients. We have developed a real-time tumor-tracking radiation therapy (RTRT) system that uses an X-ray linear accelerator gated to the motion of internal fiducial markers introduced in the late 1990s. Relying on more than 10 years of clinical experience and big log data, we established a real-time image gated proton beam therapy system dedicated to spot scanning. MATERIALS AND METHODS: Using log data and clinical outcomes derived from the clinical usage of the RTRT system since 1999, we have established a library to be used for in-house simulation for tumor targeting and evaluation. Factors considered to be the dominant causes of the interplay effects related to the spot scanning dedicated proton therapy system are listed and discussed. RESULTS/CONCLUSIONS: Total facility design, synchrotron operation cycle, and gating windows were listed as the important factors causing the interplay effects contributing to the irradiation time and motion-induced dose error. Fiducial markers that we have developed and used for the RTRT in X-ray therapy were suggested to have the capacity to improve dose distribution. Accumulated internal motion data in the RTRT system enable us to improve the operation and function of a Spot-scanning proton beam therapy (SSPT) system. A real-time-image gated SSPT system can increase accuracy for treating moving tumors. The system will start clinical service in early 2014. PMID- 24786664 TI - Proton range monitoring with in-beam PET: Monte Carlo activity predictions and comparison with cyclotron data. AB - GOAL: Proton treatment monitoring with Positron-Emission-Tomography (PET) is based on comparing measured and Monte Carlo (MC) predicted beta(+) activity distributions. Here we present PET beta(+) activity data and MC predictions both during and after proton irradiation of homogeneous PMMA targets, where protons were extracted from a cyclotron. METHODS AND MATERIALS: PMMA phantoms were irradiated with 62 MeV protons extracted from the CATANA cyclotron. PET activity data were acquired with a 10 * 10 cm(2) planar PET system and compared with predictions from the FLUKA MC generator. We investigated which isotopes are produced and decay during irradiation, and compared them to the situation after irradiation. For various irradiation conditions we compared one-dimensional activity distributions of MC and data, focussing on Deltaw50%, i.e., the distance between the 50% rise and 50% fall-off position. RESULTS: The PET system is able to acquire data during and after cyclotron irradiation. For PMMA phantoms the difference between the FLUKA MC prediction and our data in Deltaw50% is less than 1 mm. The ratio of PET activity events during and after irradiation is about 1 in both data and FLUKA, when equal time-frames are considered. Some differences are observed in profile shape. CONCLUSION: We found a good agreement in Deltaw50% and in the ratio between beam-on and beam-off activity between the PET data and the FLUKA MC predictions in all irradiation conditions. PMID- 24786665 TI - Substituent Effects in the Noncovalent Bonding of SO2 to Molecules Containing a Carbonyl Group. The Dominating Role of the Chalcogen Bond. AB - The SO2 molecule is paired with a number of carbonyl-containing molecules, and the properties of the resulting complexes are calculated by high-level ab initio theory. The global minimum of each pair is held together primarily by a S...O chalcogen bond wherein the lone pairs of the carbonyl O transfer charge to the pi* antibonding SO orbital, supplemented by smaller contributions from weak CH...O H-bonds. The binding energies vary between 4.2 and 8.6 kcal/mol, competitive with even some of the stronger noncovalent forces such as H-bonds and halogen bonds. The geometrical arrangement places the carbonyl O atom above the plane of the SO2 molecule, consistent with the disposition of the molecular electrostatic potentials of the two monomers. This S...O bond differs from the more commonly observed chalcogen bond in both geometry and origin. Substituents exert their influence via inductive effects that change the availability of the carbonyl O lone pairs as well as the intensity of the negative electrostatic potential surrounding this atom. PMID- 24786667 TI - Body mass index influences the outcome of acute pancreatitis: an analysis based on the Japanese administrative database. AB - OBJECTIVE: This study aimed to investigate the relationship between body mass index (BMI) and risk of death in patients with acute pancreatitis (AP) using a Japanese national administrative database. METHODS: We analyzed a total of 6002 patients with AP. We collected patient information, including sex, age, BMI, severity of AP based on the Japan Pancreas Society scoring system, and prognosis. We classified BMI into 5 categories (underweight [BMI, <18.5], normal range [18.5 24.9], preobese [25-29.9], obese class I [30-34.9], and obese class II/III [>35]) and investigated the relationship between each category and risk of death in AP. RESULTS: There was a good correlation between the Japanese AP severity score and in-hospital mortality. Overall mortality of severe pancreatitis was 7.0% (n = 2245). Mortality in each BMI category was as follows: underweight, 6.4%; normal range, 3.6%; preobese, 2.4%; obese class I, 3.2%; and obese class II/III, 5.7%. Underweight and obese class II/III patients had significantly higher relative risk (RR) of death in AP compared with preobese patients after adjusting for sex, age, and severity of AP (RR, 2.7; 95% confidence interval, 1.6-4.5; and RR, 6.4; 95% confidence interval, 1.9-20.9, respectively). CONCLUSIONS: Underweight or overweight was the independent risk factor for mortality in AP. PMID- 24786666 TI - A longitudinal diffusion tensor imaging study assessing white matter fiber tracts after sports-related concussion. AB - The extent of structural injury in sports-related concussion (SRC) is central to the course of recovery, long-term effects, and the decision to return to play. In the present longitudinal study, we used diffusion tensor imaging (DTI) to assess white matter (WM) fiber tract integrity within 2 days, 2 weeks, and 2 months of concussive injury. Participants were right-handed male varsity contact-sport athletes (20.2+/-1.0 years of age) with a medically diagnosed SRC (no loss of consciousness). They were compared to right-handed male varsity non-contact-sport athletes serving as controls (19.9+/-1.7 years). We found significantly increased radial diffusivity (RD) in concussed athletes (n=12; paired t-test, tract-based spatial statistics; p<0.025) at 2 days, when compared to the 2-week postinjury time point. The increase was found in a cluster of right hemisphere voxels, spanning the posterior limb of the internal capsule (IC), the retrolenticular part of the IC, the inferior longitudinal fasciculus, the inferior fronto occipital fasciculus (sagittal stratum), and the anterior thalamic radiation. Post-hoc, univariate, between-group (controls vs. concussed), mixed-effects analysis of the cluster showed significantly higher RD at 2 days (p=0.002), as compared to the controls, with a trend in the same direction at 2 months (p=0.11). Results for fractional anisotropy (FA) in the same cluster showed a similar, but inverted, pattern; FA was decreased at 2 days and at 2 months postinjury, when compared to healthy controls. At 2 weeks postinjury, no statistical differences between concussed and control athletes were found with regard to either RD or FA. These results support the hypothesis of increased RD and reduced FA within 72 h postinjury, followed by recovery that may extend beyond 2 weeks. RD appears to be a sensitive measure of concussive injury. PMID- 24786668 TI - Health risks among travelers to Brazil: implications for the 2014 FIFA World Cup and 2016 Olympic Games. PMID- 24786670 TI - Analysis of the functional morphology of mouthparts of the beetle Priacma serrata, and a discussion of possible food sources. AB - With the help of scanning electron microscopy, high resolution X-ray tomography (uCT), and finite element analysis, the mechanical and functional properties of the mandibles and associated muscles of the beetle Priacma serrata (LeConte) (Coleoptera: Archostemata) were studied. The combination of these techniques allowed for studying mechanical properties of the headmandible- system without using living animals. The uCT analysis delivered precise volumetric data of the geometry of the system to be studied. Dimensions of the cuticle of the parts involved could be readily deduced from the uCT-data. Thus, an exact representation of the specimen without significant artifacts like deformations and misalignments, usually resulting from histological sectioning, could be reconstructed. A virtual 3D model built from these data allowed for investigating different stress scenarios with finite element analysis. Combining these methods showed that P. serrata most likely uses its robustly-built mandibles for cutting hard material. In combination with available information on its habitat, possible food sources are discussed. PMID- 24786669 TI - IFN-lambda4: the paradoxical new member of the interferon lambda family. AB - Interferons (IFNs) are generally considered antiviral cytokines, yet the newly discovered IFN-lambda4 is linked with the failure to clear hepatitis C virus (HCV) infection either spontaneously or in response to treatment. IFN-lambda4 can be generated only by individuals who carry the IFNL4-DeltaG allele (rs368234815), which is the strongest known host factor for predicting clearance of HCV. The ancestral IFNL4-DeltaG allele is the major variant in Africans while the minor variant in Asians, suggesting very strong negative genetic selection for this allele-most likely driven by an infectious agent other than HCV. IFN-lambda4 most closely resembles IFN-lambda3, but these proteins share only 29% amino-acid identity, and, in contrast to IFN-lambda3, IFN-lambda4 is only weakly secreted. Nevertheless, IFN-lambda4 signals through the IFN-lambda receptor complex and induces expression of IFN-stimulated genes via the Janus kinase-signal transducer and activator of transcription signaling pathway. Although the IFNL4-DeltaG variant is strongly associated with the failure to clear HCV infection, HCV infected patients who carry this allele have lower baseline HCV RNA levels in the absence of treatment. Resolving the paradoxical functions of IFN-lambda4, which appears to induce antiviral activity yet impair effective clearance of HCV, may yield critical new insights into the immunologic response to HCV infection and IFN biology. PMID- 24786671 TI - Mechanisms of brain evolution: regulation of neural progenitor cell diversity and cell cycle length. AB - In the last few years, several studies have revisited long-held assumptions in the field of brain development and evolution providing us with a fundamentally new vision on the mechanisms controlling its size and shape, hence function. Among these studies, some described hitherto unforeseeable subtypes of neural progenitors while others reinterpreted long-known observations about their cell cycle in alternative new ways. Most remarkably, this knowledge combined has allowed the generation of mammalian model organisms in which brain size and folding has been selectively increased giving us the means to understand the mechanisms underlying the evolution of the most complex and sophisticated organ. Here we review the key findings made in this area and make a few conjectures about their evolutionary meaning including the likelihood of Martians conquering our planet. PMID- 24786672 TI - Explaining numeracy development in weak performing kindergartners. AB - Gaining better insight into precursors of early numeracy in young children is important, especially in those with inadequate numeracy skills. Therefore, in the current study, visual and verbal working memory, non-symbolic and symbolic comparison skills, and specific math-related language were used to explain early numeracy performance and development of weak performing children throughout kindergarten. The early numeracy ability of both weak performers and typical performers was measured at four time points during 2 years of kindergarten to compare growth rates. Results show a significant faster development of early numeracy in the weak performers. The development of weak performers' numeracy was influenced by verbal working memory, symbolic comparison skills, and math language, whereas only math language was positively related to the slope of typical performers' numeracy. In the weak performers, visual working memory, non symbolic comparison skills, and math language showed an effect on the initial early numeracy level of these children. The intercept of the typical performers was predicted by five covariates, all except non-symbolic comparison. PMID- 24786673 TI - A scientific registry of transplant recipients bayesian method for identifying underperforming transplant programs. AB - In response to recommendations from a recent consensus conference and from the Committee of Presidents of Statistical Societies, the Scientific Registry of Transplant Recipients explored the use of Bayesian hierarchical, mixed-effects models in assessing transplant program performance in the United States. Identification of underperforming centers based on 1-year patient and graft survival using a Bayesian approach was compared with current observed-to-expected methods. Fewer small-volume programs (<10 transplants per 2.5-year period) were identified as underperforming with the Bayesian method than with the current method, and more mid-volume programs (10-249 transplants per 2.5-year period) were identified. Simulation studies identified optimal Bayesian-based flagging thresholds that maximize true positives while holding false positive flagging rates to approximately 5% regardless of program volume. Compared against previous program surveillance actions from the Organ Procurement and Transplantation Network Membership and Professional Standards Committee, the Bayesian method would have reduced the number of false positive program identifications by 50% for kidney, 35% for liver, 43% for heart and 57% for lung programs, while preserving true positives for, respectively, 96%, 71%, 58% and 83% of programs identified by the current method. We conclude that Bayesian methods to identify underperformance improve identification of programs that need review while minimizing false flags. PMID- 24786674 TI - Regional distribution and accumulation of lead in caprine brain tissues following a long-term oral dosing regimen. AB - It is well known that the brain is a key target organ for lead (Pb)-induced toxicity, with exposure potentially resulting in numerous adverse neurological effects. However, information on the distribution and accumulation of Pb within different brain regions is scarce. In this study, Pb uptake and accumulation were characterized in brain and related tissues obtained from a convenience sample of goats dosed with Pb. Tissues were harvested postmortem from 10 animals (9 dosed and 1 undosed) that are used to produce blood Pb pools for the New York State Department of Health's Proficiency Testing program. Whole brains were subdivided into 14 distinct anatomical regions to explore interregional differences. Related tissues included the olfactory epithelium and spinal cord. Where sufficient tissue mass permitted, further subdivision into smaller sections was carried out to examine intraregional Pb variability. Determination of Pb content in these tissues was accomplished using inductively coupled plasma mass spectrometry (ICP MS), with accuracy assessed using reference materials certified for Pb. Lead content (dry weight) varied from <10 ng/g, that is, below the method detection limit, to as much as 4.45 * 10(4) ng/g Pb. Olfactory epithelium Pb content was several orders of magnitude greater than found in other regions analyzed. Enrichment of Pb was also observed in the olfactory bulb and choroid plexus. Data for each region analyzed were pooled from all goats to identify regions with the greatest propensity for Pb accumulation. Data related to Pb content were also assessed individually within each goat and significant differences in Pb content between regions were determined. PMID- 24786675 TI - Nitration of protein without allergenic potential triggers modulation of antioxidant response in type II pneumocytes. AB - Inhalation of nitrogen and reactive oxygen species (ROS) is known to induce lung inflammation, which is prevented by enzymatic and nonenzymatic antioxidant systems. These agents form nitrated allergens that were shown to enhance allergenicity. The aim of this study was to examine the influence of nitrated proteins on inflammation and antioxidant status of the lung. Ovalbumin (OVA) in nitrated form (nOVA) was intraperitoneally (ip) injected in mice for sensitization and in nitrated or unmodified form for challenge to induce allergic bronchial inflammation. To study the allergen potential of unrelated protein and verify cross-reactivity, nitrated and unmodified keyhole limpet hemocyanin (nKLH, KLH) was used for challenge. Challenge with OVA or nOVA reduced lung function and increased eosinophilia and protein content in bronchoalveolar lavage fluid (BALF). Challenge with nitrated or native OVA or KLH elevated glutathione (GSH) ratio in type II pneumocytes. Reduced mRNA expression of glutathione peroxidase (GPX) 3, glutathione reductase (GR), superoxide dismutase (SOD) 2, and catalase (CAT) was most prominent after challenge with nitrated OVA and nitrated KLH, respectively. Challenge with nOVA enhanced SOD1 mRNA reduction. Immunostaining of GPX 3 and SOD2 increased after challenge with OVA or nOVA, while reactivity of GR and reactivity of SOD2 were reduced after challenge with KLH or nKLH. SOD1 immunostaining was diminished after challenge with nonnitrated OVA or KLH. CAT immunoreaction was similar in all groups. Nitrated proteins without allergenic potential triggered mRNA reduction of antioxidants in type II cells after sensitization with a nitrated allergen but did not induce bronchial inflammation. PMID- 24786676 TI - Measurement of the temporal transferability of indoxacarb to cotton gloves from spot-on treated dogs. AB - The objectives of the studies reported herein were to (1) determine the minimum number of petting simulations required to load the maximum amount of test substance (indoxacarb) residue onto cotton gloves (the sampling medium) from spot on treated dogs; and (2) using the number of petting simulations that resulted in maximal transfer, to conduct a second study that measured amount of residue dislodged via petting a dog as a function of the time interval after application. Maximal percent transfer of indoxacarb from spot-on treated dogs occurred after 10 repetitive petting simulations (consisting of 3 directional pet strokes each) and was approximately 1-2% of amount applied. Temporal measurements of mean indoxacarb transferability followed an exponential decay function, beginning at approximately 2% transfer on the day of application, and declining to 0.08% by d 30 post treatment. PMID- 24786677 TI - Alterations in cardiomyocyte function after pulmonary treatment with stainless steel welding fume in rats. AB - Welding fume is composed of a complex of different metal particulates. Pulmonary exposure to different welding fumes may exert a negative impact on cardiac function, although the underlying mechanisms remain unclear. To explore the effect of welding fumes on cardiac function, Sprague-Dawley rats were exposed by intratracheal instillation to 2 mg/rat of manual metal arc hard surfacing welding fume (MMA-HS) once per week for 7 wk. Control rats received saline. Cardiomyocytes were isolated enzymatically at d 1 and 7 postexposure. Intracellular calcium ([Ca(2+)]i) transients (fluorescence ratio) were measured on the stage of an inverted phase-contrast microscope using a myocyte calcium imaging/cell length system. Phosphorylation levels of cardiac troponin I (cTnI) were determined by Western blot. The levels of nonspecific inflammatory marker C reactive protein (CRP) and proinflammatory cytokine interleukin-6 (IL-6) in serum were measured by enzyme-linked immunosorbent assay (ELISA). Contraction of isolated cardiomyocytes was significantly reduced at d 1 and d 7 postexposure. Intracellular calcium levels were decreased in response to extracellular calcium stimulation at d 7 postexposure. Changes of intracellular calcium levels after isoprenaline hydrochloride (ISO) stimulation were not markedly different between groups at either time point. Phosphorylation levels of cTnI in the left ventricle were significantly lower at d 1 postexposure. The serum levels of CRP were not markedly different between groups at either time point. Serum levels of IL-6 were not detectable in both groups. Cardiomyocyte alterations observed after welding fume treatment were mainly due to alterations in intracellular calcium handling and phosphorylation levels of cTnI. PMID- 24786678 TI - Toxicity of 7-ketocholesterol on lethality, growth, reproduction, and germline apoptosis in the nematode Caenorhabditis elegans. AB - 7-Ketocholesterol is one of the most abundant cholesterol oxides, and is known to be cytotoxic to various types of cultured mammalian cells; however, little is known regarding its effects in vivo. With the use of the nematode Caenorhabditis elegans as model organism, in vivo toxicity of 7-ketocholesterol was investigated. The aim of the study was to examine the effects on life span, as well as short-term effects on reproduction, thermotolerance, germline apoptosis, and reactive oxygen species (ROS) generation resulting from C. elegans exposure to 7-ketocholesterol at concentrations ranging from 0 to 200 MUg/ml. Results indicated that 7-ketocholesterol reduced reproductive capacity, shortened the life span in a concentration-dependent manner, and impaired thermotolerance of the adult nematode. 7-Ketocholesterol also induced germline apoptotic cell death and increased ROS generation in adult worms. Thus, the model organism C. elegans is recommended for assessment of the safety and bioactivity of cholesterol oxides. PMID- 24786679 TI - Immunogenic proteins specific to different bird species in bird fancier's lung. AB - Bird fancier's lung (BFL) is a disease produced by exposure to avian proteins present in droppings, blooms, and serum of a variety of birds. Although serological test results are currently used to confirm clinical diagnosis of the disease, bird species specificity is poorly understood. This study aimed to contribute to a better understanding of the specificity of immunogenic proteins revealed from the droppings of three bird species. Sera from four patients with BFL and two controls without exposure were analyzed by Western blotting with antigens from droppings of two pigeon and budgerigar strains and two hen species. When the antigens from the droppings of the three bird species were compared, the profile of immunogenic proteins was different and there were similarities between strains of the same species. Only one 68-kD protein was common to pigeon and budgerigar droppings, while proteins of 200, 175, 140, 100, and 35 kD were detected as specific in one bird species. These results provide insight to further characterize these proteins, and to design new serological tests specific to different bird species. These tests may help to refine strategies of antigenic exclusion and also to allow a patient compensation in case of BFL of occupational origin. PMID- 24786680 TI - Low-dimensional behavior of Kuramoto model with inertia in complex networks. AB - Low-dimensional behavior of large systems of globally coupled oscillators has been intensively investigated since the introduction of the Ott-Antonsen ansatz. In this report, we generalize the Ott-Antonsen ansatz to second-order Kuramoto models in complex networks. With an additional inertia term, we find a low dimensional behavior similar to the first-order Kuramoto model, derive a self consistent equation and seek the time-dependent derivation of the order parameter. Numerical simulations are also conducted to verify our analytical results. PMID- 24786681 TI - The role of tissue diagnosis prior to neoadjuvant chemoradiotherapy for locally advanced rectal cancer. AB - AIM: Neoadjuvant chemoradiotherapy is the standard of care for locally advanced rectal cancer, with diagnostic work-up routinely including a biopsy confirming invasive carcinoma. For the occasional patient where initial biopsies reveal only dysplasia, or even normal epithelium, repeat biopsy is currently advised, but this may delay therapy and repeat biopsy has potential adverse effects. The study aimed to determine, in the setting of clinical findings and imaging demonstrating locally advanced rectal cancer, whether the absence of a tissue diagnosis prior to commencing chemoradiation compromises patient outcome. METHOD: A review was conducted of our database, including comprehensive treatment and outcome details, in which consecutive patients with colorectal cancer have been enrolled since 1997 at a single institution. All records for patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer were reviewed to identify patients for whom treatment was initiated before a tissue diagnosis was obtained, and to assess any consequences of this. RESULTS: Of 254 patients who had received neoadjuvant treatment for rectal cancer, 16 (6.3%) were found to have had neoadjuvant therapy without a tissue diagnosis of invasive cancer. Compared with cases where a tissue diagnosis had been obtained, median age (59 vs 63 years, P = 0.497), sex (75% vs 71.3% male, P = 0.955) and tumour location (56.3% vs 73.5% < 8 cm, P = 0.230) were similar. Of these, 14 (87.5%) had adenocarcinoma identified on histopathology review of the surgical specimen. Three patients were considered to have had complete pathological responses with mucin lakes within the muscularis propria (n = 2) or lymph nodes (n = 1) or fibrosis (n = 3). One of these had no mucin evident and only fibrosis; thus final pathological proof of invasive cancer was present in 15 (93.5%) patients. There were no local recurrences, but three of the 16 (18.8%) cases developed distant recurrence. CONCLUSION: For the small number of cases without a confirmatory tissue diagnosis before chemoradiation, no adverse consequences were identified. In particular the initial diagnosis was confirmed in 15 out of 16 cases following pathological examination of the operative specimen. We would suggest that, where clinical and radiological features support a diagnosis of locally advanced rectal cancer, proceeding directly to neoadjuvant chemoradiotherapy in the absence of a biopsy demonstrating invasive cancer may not be unreasonable, particularly where repeat biopsy would delay the commencement of treatment. PMID- 24786682 TI - Further evidence for the stabilization of U(V) within a tetraoxo core. AB - Two complex layered uranyl borates, K10[(UO2)16(B2O5)2(BO3)6O8].7H2O (1) and K13[(UO2)19(UO4)(B2O5)2(BO3)6(OH)2O5].H2O (2), were isolated from supercritical water reactions. Within these compounds, borate exists only as BO3 units and is found as either isolated BO3 triangles or B2O5 dimers, the latter being formed from corner sharing of two BO3 units. These anions, along with oxide and hydroxide, bridge between uranyl centers to create the complex layers in these compounds. U(VI) cations are found within uranyl, UO2(2+) units, that are bound by four or five oxygen atoms to create tetragonal and pentagonal bipyramidal environments. The most striking feature in this system is found in 2, where a [UO4(OH)2] unit exists that contains U(V) within a tetraoxo core with trans hydroxide anions; therefore, this compound is a mixed-valent U(VI)/U(V) borate. The presence of a 5f(1) uranium site within 2 leads to unusual optical properties. PMID- 24786683 TI - Investigation of iterative image reconstruction in low-dose breast CT. AB - There is interest in developing computed tomography (CT) dedicated to breast cancer imaging. Because breast tissues are radiation-sensitive, the total radiation exposure in a breast-CT scan is kept low, often comparable to a typical two-view mammography exam, thus resulting in a challenging low-dose-data reconstruction problem. In recent years, evidence has been found that suggests that iterative reconstruction may yield images of improved quality from low-dose data. In this work, based upon the constrained image total-variation minimization program and its numerical solver, i.e., the adaptive steepest descent-projection onto the convex set (ASD-POCS), we investigate and evaluate iterative image reconstructions from low-dose breast-CT data of patients, with a focus on identifying and determining key reconstruction parameters, devising surrogate utility metrics for characterizing reconstruction quality, and tailoring the program and ASD-POCS to the specific reconstruction task under consideration. The ASD-POCS reconstructions appear to outperform the corresponding clinical FDK reconstructions, in terms of subjective visualization and surrogate utility metrics. PMID- 24786684 TI - Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats. AB - 1. The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats. 2. Unlabeled fimasartan or radiolabeled [(14)C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological samples were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS. 3. After oral administration of [(14)C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8 +/- 14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7-49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation. 4. These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs. PMID- 24786685 TI - Protective effect of Ferula gummosa hydroalcoholic extract against nitric oxide deficiency-induced oxidative stress and inflammation in rats renal tissues. AB - Nitric oxide (NO) synthase inhibition increases hypertension and causes renal injury. Ferula gummosa is used in Iranian traditional medicine for treatment of several diseases and has been reported to exert a potent anti-inflammatory and antioxidant action. The aim of this investigation was to evaluate the renoprotective effects of hydroalcoholic extract of Ferula gummosa (HEG) on Nomega-nitro-L-arginine methyl ester (L-NAME)-induced oxidative stress and inflammation and explore the mechanisms that link NO deficiency with altered renal heat shock protein (HSP70). Rats were injected intraperitoneally with L NAME (10 mg/kg) to induce renal injury. Simultaneously, HEG (90 mg/kg) was administered by gastric gavage to L-NAME-treated rats for 6 days/week during an 8 week period. Renal thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), HSP70, plasma NO and total antioxidant capacity (TAC) were evaluated. The administration of L-NAME significantly increased renal TBARS, TNF-alpha, IL-6, HSP70 levels and decreased renal SOD activity, that these changes were accompanied by the reduced plasma NO and TAC levels. HEG administration decreased TBARS, HSP70, TNF-alpha and IL-6 levels and increased SOD activity in the kidney tissues of L-NAME treated rats (p<0.05). Also, plasma TAC level and NO bioavailability have been elevated after administration of HEG (p<0.05). These findings support that NO deficiency induces renal stress oxidative and inflammation, which markedly increased renal HSP70 and HEG could protect kidney against these damaging effects via its anti-oxidative, anti-inflammatory action and modulate renal HSP70. PMID- 24786686 TI - Suicidal behaviour and suicide prevention in later life. AB - Despite a general decline in late life suicide rates over the last 30 years, older people have the highest rates of suicide in most countries. In contrast, non-fatal suicidal behaviour declines with age and more closely resembles suicide than in younger age groups. There are difficulties in the detection and determination of pathological suicidal ideation in older people. Multiple factors increase suicide risk ranging from distal early and mid-life issues such as child abuse, parental death, substance misuse and traumatic life experiences to proximal precipitants in late life such as social isolation and health-related concerns. Clinical depression is the most frequently identified proximal mental health concern and in many cases is a first episode of major depression. Recent studies have identified changes on neuroimaging and neurocognitive factors that might distinguish suicidal from non-suicidal depression in older people. Strategies for suicide prevention need to be 'whole of life' and, as no single prevention strategy is likely to be successful alone, a multi-faceted, multi layered approach is required. This should include optimal detection and management of depression and of high risk individuals as available evidence indicates that this can reduce suicidal behaviour. How best to improve the quality of depression management in primary and secondary care requires further research. PMID- 24786687 TI - Mixed antimony(V) complexes with different sugars to modulate the oral bioavailability of pentavalent antimonial drugs. AB - Previous studies have shown that the association of the drug meglumine antimoniate (MA) with beta-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 degrees C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration. PMID- 24786688 TI - Evaluation of antioxidant and antimicrobial activities and phenolic profile for Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys. AB - This study was designed to examine the in vitro antioxidant and antimicrobial activities and to characterize the polyphenolic composition of the ethanolic extracts of Hyssopus officinalis, Ocimum basilicum and Teucrium chamaedrys. Qualitative and quantitative analysis of the major phenolic compounds were conducted using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). The total polyphenols, caffeic acid derivatives and flavonoids content was spectrophotometrically determined. The phenolic profile showed the presence of phenolic acid derivatives (caftaric, gentisic, caffeic, p coumaric, chlorogenic and ferulic acids), flavonoid glycosides (rutin, isoquercitrin and quercitrin) and free flavonoid aglycons (luteolin, quercetin), in different concentrations. DPPH radical scavenging assay, Trolox equivalent antioxidant capacity (TEAC) method, hemoglobin ascorbate peroxidase activity inhibition (HAPX) assay, and electron paramagnetic resonance (EPR) radicals detection were employed, revealing several aspects of the antioxidant activities of these species. The antimicrobial tests were performed using the disk diffusion assay. These extracts contained a large amount of the polyphenolic compounds (77.72, 175.57, and 243.65 mg/g, respectively), and they showed a good antioxidant activity, as witnessed by a number of methods. T. chamaedrys had a high antimicrobial activity. Besides their antioxidant activity, the antimicrobial effect of these extracts confirms the biological activities of these herbal medicinal products. PMID- 24786689 TI - Novel [99mTcN]2+ labeled EGFR inhibitors as potential radiotracers for single photon emission computed tomography (SPECT) tumor imaging. AB - The epidermal growth factor receptor (EGFR) is overexpressed in many cancers, including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors or metastases. To achieve this goal, 4-(2-aminoethylamino)-6,7-dimethoxyquinazoline (ADMQ) was synthesized based on a 4-aminoquinazoline core and then conjugated with N-mercapto- acetylglycine (MAG) and N-mercaptoacetyltriglycine (MAG3), respectively, to give compounds 1 and 2. The final complexes [99mTcN]-1 and [99mTcN]-2 were successfully obtained with radiochemical purities of >99% and >98% as measured by radio-HPLC. No decomposition of the two complexes at room temperature was observed over a period of 2 h. Their partition coefficients indicated they were hydrophilic and the electrophoresis results showed they were negatively charged. Biodistribution in tumor-bearing mice demonstrated that the two new complexes showed tumor accumulation, high tumor-tomuscle (T/M) ratios and fast clearance from blood and muscle. Between the two compounds, the 99mTcN-MAG3 ADMQ ([99mTcN]-2) showed the better characteristics, with the tumor/muscle and tumor/blood ratios reached 2.11 and 1.90 at 60 min post-injection, 4.20 and 1.10 at 120 min post-injection, suggesting it could be a promising radiotracer for SPECT tumor imaging. PMID- 24786690 TI - Improved metathesis lifetime: chelating pyridinyl-alcoholato ligands in the second generation Grubbs precatalyst. AB - Hemilabile ligands can release a free coordination site "on demand" of an incoming nucleophilic substrate while occupying it otherwise. This is believed to increase the thermal stability and activity of catalytic systems and therefore prevent decomposition via free coordination sites. In this investigation chelating pyridinyl-alcoholato ligands were identified as possible hemilabile ligands for incorporation into the second generation Grubbs precatalyst. The O,N alcoholato ligands with different steric bulk could be successfully incorporated into the precatalysts. The incorporation of the sterically hindered, hemilabile O,N-ligands improved the thermal stability, activity, selectivity and lifetime of these complexes towards the metathesis of 1-octene. A decrease in the activity of the second generation Grubbs precatalyst was additionally observed after incorporating a hemilabile O,N-ligand with two phenyl groups into the system, while increasing their lifetime. PMID- 24786691 TI - Pharmacokinetics, tissue distribution, excretion and plasma protein binding studies of wogonin in rats. AB - Wogonin is a natural anticancer candidate. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, excretion and plasma protein binding of wogonin in Sprague-Dawley rats. A rapid, sensitive, and specific LC-MS/MS method has been developed for the determination of wogonin in different rat biological samples. After i.v. dosing of wogonin at different levels (10, 20 and 40 mg/kg) the elimination half-life was approximately 14 min, the AUC0-infinity increased in a dose disproportional manner from 112.13 mg/L.min for 10 mg/kg to 758.19 mg/L.min for 40 mg/kg, indicating a non linear pharmacokinetic profile. After i.g. dosing at 100 mg/kg, plasma levels of wogonin peaked at 28 min with a Cmax value of 300 ng/mL and a very low oral bioavailability (1.10%). Following i.v. single dose (20 mg/kg), wogonin was detected in all examined tissues (including testis) with the highest levels in kidney and liver. Approximately 21% of the administered dose was excreted as unchanged drug (mainly via non-biliairy fecal route (16.33%). Equilibrium dialysis was used to evaluate plasma protein binding of wogonin at three concentrations (0.1, 0.5 and 2 ug/mL). Results indicated a very high protein binding degree (over 90%), reducing substantially the free fraction of the compound. PMID- 24786692 TI - In-silico analyses of sesquiterpene-related compounds on selected Leishmania enzyme-based targets. AB - A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve sesquiterpene-based drug design. The present in silico study allows us to make important observations about the molecular details of the binding modes of a set of antileishmanial sesquiterpenes against four drug-enzyme targets [pteridine reductase-1 (PTR1), N-myristoyl transferase (NMT), cysteine synthase (CS), trypanothione synthetase (TryS)]. Through molecular docking it was found that two sesquiterpene coumarins are promising leads for the PTR1 and TryS inhibition purposes, and some xanthanolides also exhibited better affinity towards PTR1 and CS binding. In addition, the affinity values were clustered by Principal Component Analysis and drug-like properties were analyzed for the strongest-docking sesquiterpenes. The results are an excellent starting point for future studies of structural optimization of this kind of compounds. PMID- 24786693 TI - A highly active and air-stable ruthenium complex for the ambient temperature anti Markovnikov reductive hydration of terminal alkynes. AB - The conversion of terminal alkynes to functionalized products by the direct addition of heteroatom-based nucleophiles is an important aim in catalysis. We report the design, synthesis, and mechanistic studies of the half-sandwich ruthenium complex 12, which is a highly active catalyst for the anti-Markovnikov reductive hydration of alkynes. The key design element of 12 involves a tridentate nitrogen-based ligand that contains a hemilabile 3 (dimethylamino)propyl substituent. Under neutral conditions, the dimethylamino substituent coordinates to the ruthenium center to generate an air-stable, 18 electron, kappa(3)-complex. Mechanistic studies show that the dimethylamino substituent is partially dissociated from the ruthenium center (by protonation) in the reaction media, thereby generating a vacant coordination site for catalysis. These studies also show that this substituent increases hydrogenation activity by promoting activation of the reductant. At least three catalytic cycles, involving the decarboxylation of formic acid, hydration of the alkyne, and hydrogenation of the intermediate aldehyde, operate concurrently in reactions mediated by 12. A wide array of terminal alkynes are efficiently processed to linear alcohols using as little as 2 mol % of 12 at ambient temperature, and the complex 12 is stable for at least two weeks under air. The studies outlined herein establish 12 as the most active and practical catalyst for anti Markovnikov reductive hydration discovered to date, define the structural parameters of 12 underlying its activity and stability, and delineate design strategies for synthesis of other multifunctional catalysts. PMID- 24786694 TI - Macromolecular structures probed by combining single-shot free-electron laser diffraction with synchrotron coherent X-ray imaging. AB - Nanostructures formed from biological macromolecular complexes utilizing the self assembly properties of smaller building blocks such as DNA and RNA hold promise for many applications, including sensing and drug delivery. New tools are required for their structural characterization. Intense, femtosecond X-ray pulses from X-ray free-electron lasers enable single-shot imaging allowing for instantaneous views of nanostructures at ambient temperatures. When combined judiciously with synchrotron X-rays of a complimentary nature, suitable for observing steady-state features, it is possible to perform ab initio structural investigation. Here we demonstrate a successful combination of femtosecond X-ray single-shot diffraction with an X-ray free-electron laser and coherent diffraction imaging with synchrotron X-rays to provide an insight into the nanostructure formation of a biological macromolecular complex: RNA interference microsponges. This newly introduced multimodal analysis with coherent X-rays can be applied to unveil nano-scale structural motifs from functional nanomaterials or biological nanocomplexes, without requiring a priori knowledge. PMID- 24786696 TI - Parental Concerns About Infant and Toddler Sleep Assessed by a Mobile App. AB - The aim of this study was to assess the primary concerns of parents/caregivers regarding their young child's sleep. A total of 1,287 consecutive sleep-related questions were analyzed from submissions to an Ask the Expert section of a publicly available iPhone-based application for sleep in young children. Questions regarding infants were most likely to be submitted (53.9%), followed by newborns (23.76%) and toddlers (17.8%), with an average age of 10.94 months. The primary concerns regarded night wakings, sleep schedules, and bedtime problems, accounting for almost 85% of all questions. Results align with common concerns noted in epidemiological studies. Understanding the types of concerns for which parents seek advice is beneficial in the continued development of resources for caregivers. PMID- 24786695 TI - Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. AB - This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients. PMID- 24786697 TI - Correct positioning of pedicle screws with a percutaneous minimal invasive system in spine trauma. AB - BACKGROUND: When performing minimally invasive spine surgery in trauma patients, a short operation time and a perfect positioning of pedicle screws are demanded. In this study, we show that a Minimally Invasive Pedicle Screw System allows both. METHODS: One hundred and twenty-one patients (131 fractures) with fractures between Th 3 and L 5 were treated. The most common fracture type was A3. We treated 52 females and 69 men with a mean age of 56.7 years. In 72% of the cases, the procedure was performed by two experienced spine surgeons. Postoperatively, all patients were examined using a CT-scan. In 61 patients, an anterior stabilization was additionally performed in 33 patients, vertebroplasty or cyphoplasty was performed. Fifteen patients underwent laminectomy. RESULTS: No patient postoperatively developed any additional neurological compromise. In total, 682 screws were placed. In the postoperative CT-scan, we found 16 screws (2.2%) in suboptimal position, 8 with medial and 8 with lateral deviation. DISCUSSION: With the Minimally Invasive Pedicle Screw System used in this study, spinal fractures can be treated in a short operation time with percutaneous stabilization and a correct positioning of the pedicle screws in almost 98%. In our study, no screw was so much malpositioned that revision surgery would have been necessary. LEVEL OF EVIDENCE: Level III - Case-control study. PMID- 24786698 TI - Examining the relationship between operative time and hospitalization time in minimally invasive and open urologic procedures. AB - OBJECTIVE: To explore the relationship between operative time, approach, and length of stay (LOS) in partial nephrectomy (PN), radical prostatectomy (RP), and adrenalectomy (AD). MATERIALS AND METHODS: Using the National Surgical Quality Improvement Program database, we identified all PN, RP, and AD from 2010 to 2012. Non-prostate cancer RP were excluded. The primary outcome was LOS. Descriptive comparisons were drawn between open and minimally invasive surgery (MIS) for each surgery. Multiple linear regression assessed the impact of open versus MIS and operative time on LOS when controlling for confounders. RESULTS: We identified 3760 PN (60% MIS), 12,081 RP (82% MIS), and 1684 AD (76% MIS) cases for inclusion. Differences in operative time were identified. In PN and RP, MIS mean operative time was 10 to 23 minutes longer (p<0.001 each); while for AD, open was 35 minutes longer (p<0.001). Open procedures had consistently longer median LOS (p<0.001 all). Results of the linear regression are given next. CONCLUSIONS: Operative time and surgical approach are directly associated with LOS, independent of complications and patient comorbidities. PMID- 24786699 TI - Y chromosome microdeletions and alterations of spermatogenesis, patient approach and genetic counseling. AB - Infertility affects 15% of couples at reproductive age and human male infertility appears frequently idiopathic. The main genetic causes of spermatogenesis defect responsible for non-obstructive azoospermia and severe oligozoospermia are constitutional chromosomal abnormalities and microdeletions in the azoospermia factor region of the Y chromosome. The improvement of the Yq microdeletion screening method gave new insights in the mechanism responsible for the genesis of Yq microdeletions and for the consequences of the management of male infertility and genetic counselling in case of assisted reproductive technology. PMID- 24786700 TI - Germ cell cancer risk in DSD patients. AB - The risk of germ cell cancer is elevated in many DSD patients, although not to the same extent. A number of risk factors have been identified recently, but their interplay and relative impact is currently not fully clear. Until the advent of reliable screening tools for the detection of pre-invasive cancer lesions, managing germ cell tumour risk focuses on the question if and when to perform biopsy or gonadectomy in most patients and how to interpret the histological findings. PMID- 24786701 TI - Cryptorchidism --disease or symptom? AB - Testes descend to the scrotum normally before birth. When they fail to do so, the boy is cryptorchid and has an increased risk for testicular germ cell cancer and subfertility later in life. Early correction of maldescent by orchiopexy operation improves the spermatogenetic capacity of the testis but does not return the testicular cancer risk to the control level. Testicular descent is regulated by testis-derived hormones testosterone and insulin-like peptide 3. Cryptorchidism can therefore be considered a symptom of impaired testicular function that may also be linked to other testicular diseases, such as germ cell cancer and subfertility. Early orchiopexy can alleviate the effects of cryptorchidism on spermatogenesis, but alertness for testicular cancer should be maintained. In searching the genetic and environmental reasons for these diseases, it is useful to consider their connection with each other. PMID- 24786702 TI - Klinefelter syndrome and TESE-ICSI. AB - Until few years ago, Klinefelter syndrome with a homogenous 47,XXY karyotype was considered a model of absolute male sterility. We will discuss first the potential fertility following Testicular Sperm Injection, then the physiopathology of spermatogenic failure and the origin of focal spermatogenesis and risk of aneuploidy in offspring, and third the advantage of searching spermatozoa earlier instead of adult age. The rate of positive sperm extraction seems to be better for younger patients. During childhood, there is a low rate of spermatogonia. The spermagonia, which completes the spermatogenesis, seems resulting from a rare clone of 46,XY gonia, having lost their extra X chromosome. Several arguments suggest that this focal spermatogenesis decreases with age. In addition, androgen treatment, frequently prescribed in case of Klinefelter syndrome, carries a risk of decreasing focal spermatogenesis by lowering gonadotropins. The question arises if it is necessary to expect the sperm cryopreservation before introducing androgen treatment. Further studies are necessary to determine the best age of sperm retrieval in case of Klinefelter syndrome. PMID- 24786703 TI - Can first trimester placental protein-13 and pregnancy-associated plasma protein A predict pre-eclampsia in Turkish women? AB - The aim of study was to evaluate placental protein-13 (PP-13) and pregnancy associated plasma protein-A (PAPP-A) in first trimester maternal serum, for predicting pre-eclampsia. A prospective case-control study included 30 pre eclampsia patients and 90 control pregnant women. Pre-eclampsia patients were divided into two subgroups: early- and late-onset (9 vs 21), and PP-13 and PAPP-A levels were compared between the groups and the comparison of risks for pre eclampsia were calculated. Results showed that there was a significant inverse correlation between PAPP-A and late pre-eclampsia (p = 0.003), with a cut-off value of 0.805 (ROC analysis area under curve = 0.751). There was a significant reverse correlation between PAPP-A and early pre-eclampsia (p = 0.02). There was no significant relationship between PP-13 and early pre-eclampsia, nor with late pre-eclampsia (p = 0.7, p = 0.6, respectively). It was concluded that neither of these markers can serve as a sufficient and reliable screening test of pre eclampsia because of inadequate sensitivity in the Turkish pregnant population. PMID- 24786704 TI - Early targets of lithium in rat kidney inner medullary collecting duct include p38 and ERK1/2. AB - Almost half of patients receiving lithium salts have nephrogenic diabetes insipidus. Chronic lithium exposure induces AQP2 downregulation and changes in the cellular composition of the collecting duct. In order to understand these pathophysiological events, we determined the earliest lithium targets in rat inner medullary collecting duct (IMCD) by examining changes in the IMCD phosphoproteome after acute lithium administration. IMCDs were isolated 9 h after lithium exposure, a time when urinary concentrating impairment was evident. We found 1093 unique phosphopeptides corresponding to 492 phosphoproteins identified and quantified by mass spectrometry. Label-free quantification identified 152 upregulated and 56 downregulated phosphopeptides in response to lithium. Bioinformatic analysis highlighted several signaling proteins including MAP kinases and cell-junction proteins. The majority of the upregulated phosphopeptides contained a proline-directed motif, a known target of MAPK. Four hours after lithium exposure, phosphorylation sites in the activation loops of ERK1/2 and p38 were upregulated. Increased expression of phospho-Ser261-AQP2 (proline-directed motif) was concomitant with the increase in urine output. Pretreatment with MAPK inhibitors reversed the increased Ser261-AQP2 phosphorylation. Thus, in IMCD, ERK1/2 and p38 are early targets of lithium and may play a role in the onset of lithium-induced polyuria. PMID- 24786705 TI - Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. AB - Toll-like receptor 4 (TLR4), a component of the innate immune system, is recognized to promote tubulointerstitial inflammation in overt diabetic nephropathy (DN). However, there is no information on immune activation in resident renal cells at an early stage of human DN. In order to investigate this, we studied TLR4 gene and protein expression and TLR4 downward signaling in kidney biopsies of 12 patients with type 2 diabetes and microalbuminuria, and compared them with 11 patients with overt DN, 10 with minimal change disease (MCD), and control kidneys from 13 patients undergoing surgery for a small renal mass. Both in microalbuminuria and in overt DN, TLR4 mRNA and protein were overexpressed 4- to 10-fold in glomeruli and tubules compared with the control kidney and in MCD. In addition, NF-kappaB signaling was about fourfold higher in the glomeruli. TNF alpha, IL6, CCR2, CCL5, and CCR5 mRNAs were markedly (about three- to fivefold) upregulated in microdissected glomeruli. While IL6, CCL2 and CCR5-mRNA, and CD68 were overexpressed in the tubulointerstitial compartment in clinical DN, they were not expressed in microalbuminuria. In a 6-year follow-up of microalbuminuric patients, glomerular TLR4 gene expression was associated with the subsequent loss of kidney function. Thus, innate immunity is activated in the glomeruli of patients with diabetic microalbuminuria. Enhanced TLR4 signaling may contribute to the progression occurring after the incipient, microalbuminuric form of nephropathy evolves to overt disease. PMID- 24786706 TI - Shifting paradigms in eligibility criteria for live kidney donation: a systematic review. AB - As the organ shortage increases, inherently the demand for donor kidneys continues to rise. Thus, live kidney donation is essential for increasing the donor pool. In order to create successful expansion, extended criteria live kidney donors should be considered. This review combines current guidelines with all available literature in this field, trying to seek and establish the optimal extended criteria. Comprehensive searches were carried out in major databases until November 2013 to search for articles regarding older age, overweight and obesity, hypertension, vascular anomalies/multiplicity, nulliparous women, and minors as donors. Of the 2079 articles found, 152 fell within the scope of the review. Five major guidelines were included and reviewed. Based on the literature search, live kidney donation in older donors (up to 70 years of age) seems to be safe as outcome is comparable to younger donors. Obese donors have comparable outcome to lean donors, in short- and mid-term follow-up. Since little literature is available proving the safety of donation of hypertensive donors, caution is advised. Vascular multiplicity poses no direct danger to the donor and women of childbearing age can be safely included as donors. Although outcome after donation in minors is shown to be comparable to adult donors, they should only be considered if no other options exist. We conclude that the analyzed factors above should not be considered as absolute contraindications for donation. PMID- 24786707 TI - An instrumental variable approach finds no associated harm or benefit with early dialysis initiation in the United States. AB - The estimated glomerular filtration rate (eGFR) at dialysis initiation has been rising. Observational studies suggest harm, but may be confounded by unmeasured factors. As instrumental variable methods may be less biased, we performed a retrospective cohort study of 310,932 patients who started dialysis between 2006 and 2008 and were registered in the United States Renal Data System in order to describe geographic variation in eGFR at dialysis initiation and determine its association with mortality. Patients were grouped into 804 health service areas (HSAs) by zip code. Individual eGFR at dialysis initiation averaged 10.8 ml/min per 1.73 m(2) but varied geographically. Only 11% of the variation in mean HSA level eGFR at dialysis initiation was accounted for by patient characteristics. We calculated demographic-adjusted mean eGFR at dialysis initiation in the HSAs using the 2006 and 2007 incident cohort as our instrument and estimated the association between individual eGFR at dialysis initiation and mortality in the 2008 incident cohort using the two-stage residual inclusion method. Among 89,547 patients starting dialysis in 2008 with eGFR 5-20 ml/min per 1.73 m(2), eGFR at initiation was not associated with mortality over a median of 15.5 months (hazard ratio, 1.025 per 1 ml/min per 1.73 m(2) for eGFR 5-14 ml/min per 1.73 m(2); and 0.973 per 1 ml/min per 1.73 m(2) for eGFR 14-20 ml/min per 1.73 m(2)). Thus, there was no associated harm or benefit with early dialysis initiation in the United States. PMID- 24786708 TI - Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes. AB - The incidence and prevalence of diabetes mellitus (DM) continue to grow markedly throughout the world, due primarily to the increase in type 2 DM (T2DM). Although improvements in DM and hypertension management have reduced the proportion of diabetic individuals who develop chronic kidney disease (CKD) and progress to end stage renal disease (ESRD), the sheer increase in people developing DM will have a major impact on dialysis and transplant needs. This KDIGO conference addressed a number of controversial areas in the management of DM patients with CKD, including aspects of screening for CKD with measurements of albuminuria and estimated glomerular filtration rate (eGFR); defining treatment outcomes; glycemic management in both those developing CKD and those with ESRD; hypertension goals and management, including blockers of the renin-angiotensin aldosterone system; and lipid management. PMID- 24786709 TI - An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes. AB - In vitro and ex vivo studies have elucidated the step-by-step process whereby some physicochemically abnormal light chains are processed by mesangial cells to form amyloid fibrils. Although crucial steps in the cascade of events have been determined, these findings have not been reproduced in vivo. This has led to some doubts as to the significance and clinical application of the information that has been deciphered. Here, we developed an animal model which uses mice injected with amyloidogenic light chains purified from the urine of patients with biopsy proven, light-chain-associated glomerular amyloidosis which validated in vitro/ex vivo findings. This animal model showed internalization of the light chains utilizing caveolae followed by trafficking to the mature lysosomal compartment where fibrils were formed. This model permits evaluation of mesangial amyloidogenesis for prolonged periods of time, is potentially useful to test maneuvers to modulate events that take place, and can be used to design novel therapeutic interventions. PMID- 24786710 TI - PAG1, a cotton brassinosteroid catabolism gene, modulates fiber elongation. AB - Cotton (Gossypium hirsutum) is the major source of natural textile fibers. Brassinosteroids (BRs) play crucial roles in regulating fiber development. The molecular mechanisms of BRs in regulating fiber elongation, however, are poorly understood. pagoda1 (pag1) was identified via an activation tagging genetic screen and characterized by genome walking and brassinolide (BL) supplementation. RNA-Seq analysis was employed to elucidate the mechanisms of PAG1 in regulating fiber development. pag1 exhibited dwarfism and reduced fiber length due to significant inhibition of cell elongation and expansion. BL treatment rescued its growth and fiber elongation. PAG1 encodes a homolog of Arabidopsis CYP734A1 that inactivates BRs via C-26 hydroxylation. RNA-Seq analyses showed that the constitutive expression of PAG1 downregulated the expression of genes involved in very-long-chain fatty acids (VLCFA) biosynthesis, ethylene-mediated signaling, response to cadmium, cell wall development, cytoskeleton organization and cell growth. Our results demonstrate that PAG1 plays crucial roles in regulating fiber development via controlling the level of endogenous bioactive BRs, which may affect ethylene signaling cascade by mediating VLCFA. Therefore, BR may be a critical regulator of fiber elongation, a role which may in turn be linked to effects on VLCFA biosynthesis, ethylene and cadmium signaling, cell wall- and cytoskeleton-related gene expression. PMID- 24786711 TI - Atrial tachycardia: when the going gets tough... PMID- 24786712 TI - Streptococcus moroccensis sp. nov. and Streptococcus rifensis sp. nov., isolated from raw camel milk. AB - Two catalase- and oxidase-negative Streptococcus-like strains, LMG 27682(T) and LMG 27684(T), were isolated from raw camel milk in Morocco. Comparative 16S rRNA gene sequencing assigned these bacteria to the genus Streptococcus with Streptococcus rupicaprae 2777-2-07(T) as their closest phylogenetic neighbour (95.9% and 95.7% similarity, respectively). 16S rRNA gene sequence similarity between the two strains was 96.7%. Although strains LMG 27682(T) and LMG 27684(T) shared a DNA-DNA hybridization value that corresponded to the threshold level for species delineation (68%), the two strains could be distinguished by multiple biochemical tests, sequence analysis of the phenylalanyl-tRNA synthase (pheS), RNA polymerase (rpoA) and ATP synthase (atpA) genes and by their MALDI-TOF MS profiles. On the basis of these considerable phenotypic and genotypic differences, we propose to classify both strains as novel species of the genus Streptococcus, for which the names Streptococcus moroccensis sp. nov. (type strain, LMG 27682(T) = CCMM B831(T)) and Streptococcus rifensis sp. nov. (type strain, LMG 27684(T) = CCMM B833(T)) are proposed. PMID- 24786713 TI - Does L-arginine availability during the early pregnancy alters the immune response of Trypanosoma cruzi infected and pregnant Wistar rats? AB - Chagas disease induces a strong immune response and L-arginine is an essential amino acid which plays an important role in homeostasis of the immune system. The aims of this study were to evaluate parasitemia, corticosterone levels, production of nitric oxide (NO), fetal morphological measurements, and histology of heart and placenta. Twenty pregnant Wistar rats (180-220 g) were grouped in: pregnant control (PC), pregnant control and L-arginine supplied (PCA), pregnant infected (PI), pregnant infected and L-arginine supplied (PIA). Females were infected with 1*10(5) trypomastigotes of the Y strain (3rd day of pregnancy). Animals were supplied with 21 mg of L-arginine/kg/day during 14 days. PIA showed significant decreased levels of corticosterone and parasitemia. For control groups, any alteration in NO production was found with L-arginine supplementation; for PIA, enhanced nitrite concentrations were observed as compared to PI. Weights and lengths of fetuses were higher in L-arginine treated and infected pregnant rats as compared to untreated ones. Placental weight from the PIA group was significantly increased when compared to PI. In L-arginine treated animals, cardiac tissue showed reduced amastigote burdens. PIA and PI displayed similar placental parasitism. Based on these results, L-arginine supplementation may be potentially useful for the protection against Trypanosoma cruzi during pregnancy. PMID- 24786714 TI - Outcomes and statistical power in adult critical care randomized trials. AB - RATIONALE: Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits. OBJECTIVES: Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials. METHODS: One hundred forty-six ICU based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied. MEASUREMENT AND MAIN RESULTS: Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%. CONCLUSIONS: ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates. PMID- 24786715 TI - Meta-analysis of the efficacy and safety of long-acting non-ergot dopamine agonists in Parkinson's disease. AB - A meta-analysis of randomized controlled trials (RCT) was performed to evaluate the efficacy and safety of long-acting non-ergot dopamine agonists (NEDA) versus placebo in Parkinson's disease (PD). A comprehensive literature search up to February 2013 was performed, and the weighted mean differences (WMD) and relative risks (RR) with 95% confidence intervals (CI) were calculated. Nine RCT (n=2857) which assessed the rotigotine transdermal patch, extended-release pramipexole, and ropinirole prolonged-release, were included. Compared with placebo, long acting NEDA achieved greater improvements in Unified Parkinson's Disease Rating Scale activities of daily living (ADL) score (WMD -1.77, 95% CI -2.13 to -1.41), motor score (WMD -4.18, 95% CI -4.94 to -3.43) and the ADL and motor subtotal score (WMD -5.12, 95% CI -6.16 to -4.07), as well as a reduction in "off" time (WMD -1.29, 95% CI -1.64 to -0.93) and an increase in "on" time without troublesome dyskinesia (WMD 1.55, 95% CI 1.06 to 2.04). Compared with placebo, long-acting NEDA were associated with a higher risk of nausea, but no difference was found in headache incidence. Higher risks of dizziness, somnolence, constipation, vomiting, and insomnia were only found in early PD while higher risks of dyskinesia and hallucination were only found in advanced PD. The results of our meta-analysis showed that the use of long-acting NEDA can reduce the symptoms of PD patients. However, long-acting NEDA were also associated with a higher incidence of adverse events, especially in early PD patients, compared with placebo. PMID- 24786716 TI - Delayed complications after Gamma Knife surgery for intractable epilepsy. AB - Despite the controversy concerning the clinical usefulness of Gamma Knife surgery (GKS; Elekta AB, Stockholm, Sweden) for intractable epilepsy, this treatment modality has attracted attention due to its low invasiveness. We report the long term outcomes of four patients, focusing particularly on the efficacy and complications of GKS. We reviewed the data of four patients with medically intractable epilepsy who underwent GKS between 1998 and 2000 at our hospital. The marginal dose to the 50% isodose line was 24 Gy in one patient and 20Gy in the remaining three patients. Two of the four patients were treated in the right temporal lobe, one was treated in the left parietal lobe, and one was treated in the right frontal lobe. The mean follow-up was 12.5 years (range 12-14 years). One patient was seizure free (Engel class IA) 24 months after GKS, and two patients failed to show any seizure reduction (Engel class IVA). However, a clear aggravation was evident in one patient (Engel class IVC). All four patients underwent resective surgery due to radiation necrosis (RN) 7, 10, 10 and 12 years after GKS. Three patients were seizure free (Engel class IA), and one was considered to have Engel class IB status following the resective surgery. GKS treatment resulted in insufficient seizure control and carried a significant risk of RN after several years. Drawbacks such as a delay in seizure control and the risk of RN should be considered when the clinical application of this treatment is evaluated. PMID- 24786717 TI - Anterior lumbar interbody surgery for spondylosis results from a classically trained neurosurgeon. AB - Anterior lumbar surgery for degenerative disc disease (DDD) is a relatively novel technique that can prevent damage to posterior osseous, muscular and ligamentous spinal elements. This study reports the outcomes and complications in 286 patients who underwent fusion - with artificial disc implants or combined fusion and artificial disc implants - by a single-operator neurosurgeon, with up to 24 months of follow-up. The visual analogue scale (VAS), Oswestry Disability Index (ODI), Short Form 36 (SF36) and prospective log of adverse events were used to assess the clinical outcome. Radiographic assessments of implant position and bony fusion were analysed. Intraoperative and postoperative complications were also recorded. Irrespective of pre-surgical symptoms (back pain alone or back and leg pain combined), workers' compensation status and type of surgical implant, clinically significant improvements in VAS, ODI and SF36 were primarily observed at 3 and/or 6 month follow-up, and improvements were maintained at 24 months after surgery. A 94% fusion rate was obtained; the overall complication was 9.8% which included 3.5% with vascular complications. The anterior lumbar approach can be used for treating DDD for both back pain and back and leg pain with low complication rates. With appropriate training, single-operator neurosurgeons can safely perform these surgeries. PMID- 24786718 TI - Clinical and electrophysiological features of Guillain-Barre syndrome in Iran. AB - We evaluated the clinical and electrophysiological characteristics of 121 consecutive patients admitted with Guillain-Barre syndrome (GBS) to a tertiary referral hospital in Tehran, Iran, from 1997 to 2007. The mean age of patients was 38.9 (standard deviation 19.7) years. The predominant subtype of GBS was the demyelinating form. Miller Fisher syndrome was present in 3.3% of patients. There was no significant seasonal clustering among the three subtypes, but axonal variants tend to occur in summer. In contrast with other subtypes, the majority of patients with acute motor-sensory axonal neuropathy (AMSAN) were female (72.3%). AMSAN patients also had significantly longer hospitalization time (p=0.002) and intensive care unit (ICU) admission (p=0.017), while none of the acute motor axonal neuropathy patients needed ICU admission. Involvement of cranial nerves and symmetry of signs were significantly detected in the demyelinating variant (p=0.021 and p=0.040, respectively). The overall mortality was 3.3%. PMID- 24786719 TI - 3D dense local point descriptors for mouse brain gene expression images. AB - Anatomical landmarks play an important role in many biomedical image analysis applications (e.g., registration and segmentation). Landmark detection can be computationally very expensive, especially in 3D images, because every single voxel in a region of interest may need to be evaluated. In this paper, we introduce two 3D local image descriptors which can be computed simultaneously for every voxel in a volume. Both our proposed descriptors are extensions of the DAISY descriptor, a popular descriptor that is based on the histograms of oriented gradients and was named after its daisy-flower-like configuration. Our experiments on mouse brain gene expression images indicate that our descriptors are discriminative and are able to reduce the detection errors of landmark points more than 30% when compared with SIFT-3D, an extension in 3D of SIFT (scale invariant feature transform). We also demonstrate that our descriptors are more computationally efficient than SIFT-3D and n-SIFT (an extension SIFT in n dimensions) for densely sampled points. Therefore, our descriptors can be used in applications that require computation of the descriptors at densely sampled points (e.g., landmark point detection or feature-based registration). PMID- 24786721 TI - Primary, orbital, malignant extra-renal, non-cerebral rhabdoid tumour. AB - Malignant rhabdoid tumour is a rare tumour outside the kidney and central nervous system. Orbital and intraocular malignant rhabdoid tumour is particularly rare with very few reports in published literature. Given the aggressiveness of this tumour and resistance to conventional chemotherapy, it is important to differentiate this tumour from other, less aggressive tumours that may have similar clinicoradiological or light microscopic features. We report one such case in a 6-week-old male child with its clinicoradiological and histopathologic features, differential diagnosis and also review the literature on the same. PMID- 24786720 TI - Fuzzy logic color detection: Blue areas in melanoma dermoscopy images. AB - Fuzzy logic image analysis techniques were used to analyze three shades of blue (lavender blue, light blue, and dark blue) in dermoscopic images for melanoma detection. A logistic regression model provided up to 82.7% accuracy for melanoma discrimination for 866 images. With a support vector machines (SVM) classifier, lower accuracy was obtained for individual shades (79.9-80.1%) compared with up to 81.4% accuracy with multiple shades. All fuzzy blue logic alpha cuts scored higher than the crisp case. Fuzzy logic techniques applied to multiple shades of blue can assist in melanoma detection. These vector-based fuzzy logic techniques can be extended to other image analysis problems involving multiple colors or color shades. PMID- 24786722 TI - Calf exercise-induced vasodilation is blunted in healthy older adults with increased walking performance fatigue. AB - Vascular aging as measured by central arterial stiffness contributes to slow walking speed in older adults, but the impact of age-related changes in peripheral vascular function on walking performance is unclear. The aim of this study was to test the hypothesis that calf muscle-specific vasodilator responses are associated with walking performance fatigue in healthy older adults. Forty five older (60-78yrs) adults performed a fast-paced 400m walk test. Twelve of these adults exhibited fatigue as defined by slowing of walking speed (>=0.02m/s) measured during the first and last 100m segments of the 400m test. Peak calf vascular conductance was measured following 10min of arterial occlusion using strain-gauge plethysmography. Superficial femoral artery (SFA) vascular conductance response to graded plantar-flexion exercise was measured using Doppler ultrasound. No difference was found for peak calf vascular conductance between adults that slowed walking speed and those that maintained walking speed (p>0.05); however, older adults that slowed walking speed had a lower SFA vascular conductance response to calf exercise (at highest workload: slowed group, 2.4+/-0.9 vs. maintained group, 3.6+/-0.9ml/kg/min/mmHg; p<0.01). Moreover, the initial increase in SFA vascular conductance from rest to exercise was positively correlated with the change in walking speed for all adults (rho=0.41, p=0.005). In conclusion, these results suggest that calf exercise hemodynamics are associated with walking performance fatigability in older adults. PMID- 24786723 TI - Trophic ecology of Lampanyctus crocodilus on north-west Mediterranean Sea slopes in relation to reproductive cycle and environmental variables. AB - This study examined the population structure, reproductive cycle and feeding pattern of the lanternfish Lampanyctus crocodilus in the Balearic Basin (north west Mediterranean Sea) from a depth of 450 to 1800 m and at a seasonal scale. Juveniles were mainly located at shallower depths, but also at deepest stations in autumn, while adults mostly inhabited intermediate depths with their centre of population density (CPD) located at 800-1000 m of depth. The migration of adults to deeper depths was detected in late summer to autumn, probably linked to the occurrence of nepheloid layers at c. 1200 m, which in turn enhances the biomass of the zooplankton prey. The diet was mainly based on euphausiids and mysids, with marked seasonal variations both on the upper (450-800 m) and lower (1000 1800 m), where suprabenthic gammariids and pelagic decapods were also dominant. Stomach fullness increased from winter to autumn on the US, while it had a maximum in spring on the LS, in parallel with high consumption of gelatinous zooplankton, which is probably more available after the phytoplankton bloom in late winter. Reproduction occurred in winter, confirmed by the higher percentage of mature females and high gonadosomatic indices (I(G)) at both depth ranges. Hepatosomatic indices (I(H)) showed an inverse trend to I(G) on the US, except in autumn, and was almost parallel on the LS, probably attributable to the migration of adults, which determined different temporal schemes in energy use and storage for reproduction on the US v. LS. Consistent with the different patterns observed at the two depth ranges, environmental drivers of fullness (i.e. feeding intensity) and I(G) (as a proxy of reproductive cycle) differed on the US and LS. The biomass of mysids and euphausiids was the greatest explanatory variables of fullness on the US and LS, pointing to the increasing feeding intensity when a resource was more available. I(H) also explained fullness, suggesting that greater feeding intensity in pre-reproductive periods enabled energy storage in the liver. I(G) was linked directly (i.e. mysids) or indirectly (i.e. surface primary production recorded 2 months before sampling) to food availability, implying a rapid response to vertical food inputs by deep-sea predators. Also, I(G) in L. crocodilus was related to population density, which suggests aggregations for reproduction. Estimates of L. crocodilus trophic levels, and of other accompanying mesopelagic fishes, indicated that the species feed through a continuum spanning the third trophic level, confirming the key role of mesopelagic fishes in transferring organic carbon between trophic levels. Trophic niche segregation among mesopelagic species was pronounced and non-overlapping groups could be distinguished because of the different vertical distribution and migratory behaviour. The study highlights the important role of the benthic boundary layer in sustaining benthopelagic communities in the deep Mediterranean Sea and the need to study the biology of a species throughout its whole depth range and not just at exploited depths (i.e. fishing grounds). PMID- 24786724 TI - Molecular-level changes of aqueous poly(N-isopropylacrylamide) in phase transition. AB - We report a Compton scattering study on the molecular-level structural changes of aqueous poly(N-isopropylacrylamide) (PNIPAM) across the conformational phase transition. PNIPAM is a thermoresponsive polymer that changes its conformation in water from the hydrophilic coil state to the collapsed hydrophobic globule state at 32 degrees C. Combined with density functional theory calculations, the Compton scattering experiments detect two type of changes in the phase transition. The amount of hydrogen bonds is found to reduce, and an elongation of the internal covalent bond lengths is observed. The elongation of the bonds indicates that not only the hydrogen bonding changes but there are other processes, most likely related to hydrophobic interaction, that should be taken into account in the phase transition. PMID- 24786725 TI - Characteristics of a large cohort of patients with diabetes having at-risk feet and outcomes in patients with foot ulceration referred to a tertiary care diabetes unit. AB - To identify in a large population cohort the clinical and biochemical characteristics of patients with diabetes at risk of foot ulceration and outcomes in those with foot ulcers. All patients with diabetes attending Baqai Institute of Diabetology and Endocrinology from January 2004 to April 2012 included in the study. Clinical, biochemical and socio-demographic data were collected and patients were categorised into those at no risk of ulceration, at risk of ulceration and those with foot ulcer, according to the University of Texas classification. Patients with foot ulceration followed for their final outcome, that is complete healing, persisted non-healed ulcer, lower extremity amputation, lost to follow-up or death. A total of 18 119 patients with diabetes underwent assessment, 3576 (19.7%) patients defined as at high risk for foot ulceration and 3731 (20.6%) presented with foot ulcer. Age, male gender, hypertension, higher glycated haemoglobin (HbA1c), history of smoking and presence of neuropathy were risk factors (P < 0.000) for foot ulceration. Amputation rate in patients with foot ulceration was significantly related to severity of ulceration at presentation. Preventive foot care practices were followed by 19.02% patients. One thousand eight hundred seventy three (50.2%) patients completely healed, 293 (11%) patients underwent amputation and 397 (10.1%) patients continued to be treated in the foot clinic. All patients with diabetes should be screened for neuropathy to identify those at risk of foot ulceration, as it is the major contributory factor for foot ulceration. The final outcome of foot ulceration was determined by the severity and grade of ulcer at presentation. PMID- 24786727 TI - Physiological and structural anorectal abnormalities in patients with systemic sclerosis and fecal incontinence. AB - OBJECTIVE: Fecal incontinence is common in systemic sclerosis (SSc), but the underlying mechanisms are not fully understood. The objectives of this study were to characterize anorectal physiological and morphological defects in SSc patients and to correlate the results with incontinence symptoms. MATERIALS AND METHODS: Twenty-five SSc patients underwent anorectal neurophysiological investigations, anal manometry, and ultrasound. RESULTS: Eleven patients (44%) reported incontinence to solid or liquid feces, but no patient reported diarrhea. Increased fiber density (FD) was recorded in 78% of patients with and in 86% of patients without fecal incontinence not significant (NS). Incontinent patients had lower squeeze pressure (SP; median 49.5 mm Hg) in the high-pressure zone (HPZ) than continent patients (median 72 mm Hg; p = 0.01). In two of the incontinent patients, sonographic abnormalities of the internal anal sphincter (IAS) and the external anal sphincter (EAS) were present, whereas in another two patients isolated IAS abnormalities were seen. These four individuals had lower resting pressure at 1 cm and in the HPZ, and lower SP at 2 cm than patients with normal anorectal sonographic findings (p < 0.05). CONCLUSION: Lower voluntary SP in incontinent patients and EAS sonographic abnormalities only in patients with incontinence suggest that the EAS is more important in maintaining fecal continence in SSc patients than has previously been reported. The finding of increased FD in most patients further supports involvement of the EAS function in SSc and could indicate previous nerve injury with consequent incomplete reinnervation. PMID- 24786726 TI - Sleep duration in midlife and later life in relation to cognition. AB - OBJECTIVES: To evaluate associations between sleep duration at midlife and later life and change in sleep duration over time and cognition in older women. DESIGN: Participants reported sleep duration in 1986 and 2000, and a subgroup of older participants began cognitive testing in 1995 to 2001; follow-up testing was conducted three times, at 2-year intervals. SETTING: Prospective Nurses' Health Study cohort. PARTICIPANTS: Female nurses aged 70 and older free of stroke and depression at the initial cognitive assessment (N = 15,385). MEASUREMENTS: Validated, telephone-based cognitive battery to measure cognitive function; four repeated assessments over 6 years were averaged to estimate overall cognition at older ages, and trajectories of cognitive change were evaluated over follow up. RESULTS: Extreme sleep durations in later life were associated with worse average cognition (P < .001 for the quadratic term for a global score averaging all six cognitive tests). For example, women sleeping 5 h/d or less had worse global cognition than those sleeping 7 h/d, as did women sleeping 9 h/d or more; differences were equivalent to nearly 2 additional years of age. Associations were similar, although slightly attenuated, for sleep duration in midlife. Women whose sleep duration changed by 2 h/d or more over time had worse cognition than women with no change in sleep duration (e.g., for the global score, P < .001 for the quadratic term). Sleep duration was not associated with trajectories of cognitive function over 6 years, which might be attributable to short follow-up for detecting cognitive decline. CONCLUSION: Extreme sleep durations at midlife and later life and extreme changes in sleep duration over time appear to be associated with poor cognition in older women. PMID- 24786728 TI - Griseorhodins D-F, neuroactive intermediates and end products of post-PKS tailoring modification in Griseorhodin biosynthesis. AB - The griseorhodins belong to a family of extensively modified aromatic polyketides that exhibit activities such as inhibition of HIV reverse transcriptase and human telomerase. The vast structural diversity of this group of polyketides is largely introduced by enzymatic oxidations, which can significantly influence the bioactivity profile. Four new compounds, griseorhodins D-F, were isolated from a griseorhodin producer, Streptomyces sp. CN48+, based upon their enhancement of calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, griseorhodins D1 and D2, were shown to be identical to the major, previously uncharacterized products of a grhM mutant in an earlier griseorhodin biosynthesis study. Their structures enabled the establishment of a more complete hypothesis for the biosynthesis of griseorhodins and related compounds. The other two compounds, griseorhodins E and F, represent new products of post-polyketide synthase tailoring in griseorhodin biosynthesis and showed significant binding activity in a human dopamine active transporter assay. PMID- 24786729 TI - A review of the currently recognised opecoelid cercariae, including the identification and emergence ecology of Cercaria capricornia XII (Digenea: Opecoelidae) from Nassarius olivaceus (Gastropoda: Nassariidae) in Central Queensland, Australia. AB - A new opecoelid cercaria, Cercaria capricornia XII, is reported from Nassarius olivaceus in Capricornia, Central Queensland, Australia. Combined molecular and morphological data indicate that this cercaria is a member of the subfamily Opecoelinae. Cercaria capricornia XII is the first known opecoeline cercaria reported from a nassariid gastropod. Cercaria capricornia XII can be distinguished from other opecoelid cercariae by the combination of the presence of a 2-pointed stylet, body length and width, and the size of the tail. The emergence pattern for C. capricornia XII in captivity was erratic; rapid emergences of thousands of cercariae were interspersed by periods that sometimes exceeded a month in which no emergence occurred. There was no detectable pattern to or stimulus of the emergence. The molluscan host range of opecoelids is analysed in detail. Gastropods from the Buccinoidea, Cerithioidea and Rissooidea are hosts to both opecoeline and plagioporine cercariae, but the dominant subfamily infecting the Cerithioidea and Rissooidea is the Plagioporinae. The dominant marine host gastropod superfamily for opecoeline cercariae is the Buccinoidea; the family Nassariidae is contained in the Buccinoidea. The range of gastropod superfamilies known as hosts of plagioporines is much broader than that for opecoelines, which may be explained by the relative size of the two opecoelid families and perhaps by indications that the Plagioporinae is polyphyletic. PMID- 24786730 TI - Hematological and histopathological changes in Rattus norvegicus (Wistar) experimentally infected by Angiostrongylus cantonensis (Chen, 1935). AB - Eosinophilic meningitis caused by Angiostrongylus cantonensis is a zoonosis endemic to Southeast Asia and the Pacific islands. It is considered an emerging disease because it has been expanding both geographically and in terms of the range of hosts. In South America, the first cases were reported in Brazil and were attributed to eating infected snails. In this study, 70 adult females of Rattus norvegicus (Wistar) were used to evaluate hematology, blood gases, cardiac markers and lung histopathology changes caused by this parasite. Of them, 60 were individually infected by orogastric gavage with 100 L(3) larvae and 10 uninfected animals formed the control group. The results obtained demonstrate that infection caused by A. cantonensis in R. norvegicus promotes significant hematological changes induced in the vertebrate host, manifested mainly in the form of regenerative anemia, thrombocytopenia and eosinophilia. Additionally, histopathological changes in the lung parenchyma demonstrated in rodents reveal the occurrence of areas of necrosis and extensive fibrosis, being directly related to the development of cellular hypoxia and enzyme cardiac changes. This study can contribute to a better understanding of the relationship between A. cantonensis and R. norvegicus. PMID- 24786731 TI - Molecular prevalence and genetic diversity of bovine Theileria orientalis in Myanmar. AB - Theileria orientalis is a causative agent of benign theileriosis in cattle and distributed in mainly Asian countries. In the present study, we examined the prevalence of T. orientalis infection by PCR based on the major piroplasm surface protein gene (MPSP) sequences in cattle in Myanmar, followed by phylogenetic analysis of the MPSP genes. The MPSP gene was amplified in 258 of 713 (36.2%) cattle blood DNA samples collected from five cities in different geographical regions of Myanmar. Phylogenetic analysis of MPSP sequences from 54 T. orientalis positive DNA samples revealed the presence of six allelic genotypes, including Types 1, 3, 4, 5, 7, and N-3. Types 5 and 7 were the predominant types detected. Sequences of the MPSP genes detected in Myanmar were closely related to those from Thailand, Vietnam or Mongolia. These findings suggest that movement of animals carrying T. orientalis parasites between Southeast Asian countries could be a reason for the similar genotype distribution of the parasites in Myanmar. PMID- 24786732 TI - Capitellar fractures-is open reduction and internal fixation necessary? AB - OBJECTIVE: The purpose of this retrospective study was to evaluate the medium term to longer-term results of type 1 displaced capitellar fractures treated with closed reduction. DESIGN: Retrospective case series. PATIENTS: Eight consecutive cases (7 adults; 1 child) with type 1 capitellar fractures. INTERVENTION: Closed reduction of type 1 capitellar fractures and 4 weeks of postreduction immobilization. OUTCOME MEASURES: Complications (including radiographic), Disabilities of the Arm, Shoulder, and Hand Score, and active elbow range of motion. RESULTS: Average follow-up was 41.6 months (range, 18-77 months). All 8 fractures were united. The patients obtained near full return of the range of motion when compared with the uninjured contralateral side. Mean average Disabilities of the Arm, Shoulder, and Hand Score scores were 4.36 (SD, 2.68; Range, 0-9). No complications were observed. CONCLUSIONS: This study demonstrated that type 1 capitellar fractures can be treated successfully with closed reduction and cast immobilization. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24786733 TI - Operative agreement on lateral compression-1 pelvis fractures. a survey of 111 OTA members. AB - OBJECTIVES: To better characterize operative agreement and disagreement among orthopaedic surgeons treating lateral compression type 1 (LC-1) pelvic fractures in an effort to improve communication between care providers and improve patient care. DESIGN: Decision analysis. SETTING: Level 1 trauma center. METHODS: Twenty seven LC-1 cases were selected to represent a wide array of LC-1 injuries. Each case was presented with 3 plain pelvic radiographs (anteroposterior, inlet, and outlet) and a scrollable computed tomography at the OTA national meeting. Attendees were queried whether they would perform operative stabilization "yes/no." Years of surgical practice (0-5, 6-10, and >10), annual pelvic fracture case volume (0-20, 21-50, and >50), and completion of a trauma fellowship (yes/no) were also collected. Fleiss' kappa (K) was used to measure operative agreement among survey respondents, where K = 0.21-0.40 was fair and K = 0.41 0.60 was moderate agreement. RESULTS: One hundred eleven surgeons completed the survey where the average tendency to operate across surveys was 40%. Of the 27 cases presented, only 9 cases (33%) showed substantial agreement. There were 4 cases where nearly everyone chose operative stabilization (93.1%-94.4%) and 5 cases where nearly no one chose operative stabilization (0%-8.7%). The overall agreement was fair with K = 0.39 [95% confidence interval (CI), 0.34-0.44]. Although there was a trend for surgeons with more years of surgical practice to have a lower tendency to operate, it did not achieve statistical significance (odds ratio for >10 years vs. 0-5 years = 0.73; 95% CI, 0.48-1.11). Annual case volume and completion of a trauma fellowship were not statistically significant predictors of operative tendency. CONCLUSIONS: Our results show only fair operative agreement (K = 0.39; 95% CI, 0.34-0.44) in a radiographic survey representing a broad range of LC-1 fracture morphologies among OTA surgeons. Only 9 of the 27 cases (33%) had substantial agreement. There was no difference in the decision to operate based on surgical volume, completion of a trauma fellowship, or time in practice. These results highlight the differing practice decisions among surgeons currently treating LC-1 injuries, and there is need for further studies to more fully understand stability after this injury pattern. PMID- 24786734 TI - Can the use of variable-angle volar locking plates compensate for suboptimal plate positioning in unstable distal radius fractures? A biomechanical study. AB - OBJECTIVE: To compare the biomechanical stability under load-to-failure conditions of optimally placed fixed-angle volar locking plates versus suboptimally placed variable-angle volar locking plates in unstable, intraarticular distal radius fractures. METHODS: A Melone type 1 (AO 23-C3) fracture was created in 25 sawbone radii and plated with either a fixed-angle or variable-angle Synthes plate with identical profile. Four plate positions were tested: distal ulnar (DU, positioned distally to obtain subchondral support and ulnar to hold the lunate facet fragments), distal radial (DR, 3 mm radial to DU), proximal ulnar (PU, 3 mm proximal to DU), and proximal radial (PR, 3 mm proximal and 3 mm radial to DU). The specimens were loaded until failure as defined by a 2 mm displacement of any fracture fragment. The fixed-angle plates were tested in the DU position, whereas the variable-angle plates were tested in all 4 positions. RESULTS: The dorsal lunate fragment was the first to fail in every group followed by the radial styloid and volar lunate fragments, respectively. Load-to-failure, from greatest to least, occurred at the DR (278 +/- 56 N), PR (277 +/- 68 N), DU fixed-angle (277 +/- 68 N), DU variable-angle (236 +/- 31 N), and PU (202 +/- 75 N) positions, respectively. Rigidity was calculated using the slope of the dorsal lunate force-displacement curve before failure (at loads 100 150 N). Rigidity was greatest at the PU position (126 +/- 60 N/mm) followed by PR (125 +/- 30 N/mm), DU fixed-angle (125 +/- 25 N/mm), DR (122 +/- 66 N/mm), and DU variable-angle (101 +/- 35) positions, respectively. Univariate analysis of rigidity and load-to-failure was not significantly different between groups. CONCLUSIONS: In this experimental model, variable-angle screws provided a leeway of 3 mm in both the sagittal and coronal directions without sacrificing construct strength, which may considerably facilitate fixation of these difficult fractures. PMID- 24786735 TI - Acetabular fractures converted to total hip arthroplasties in the elderly: how does function compare to primary total hip arthroplasty? AB - OBJECTIVES: Little data exist regarding the outcomes of total hip arthroplasty (THA) after acetabular fracture treatment failure. We hypothesize that these patients achieve a lower level of function than those who undergo primary THA for osteoarthritis (atraumatic). DESIGN: Retrospective review. Control group consisted of sequential patients who underwent a primary THA for osteoarthritis and were 60 years or older at the time of surgery. SETTING: Level I Academic Trauma Center. PATIENTS: One hundred seventy-one patients older than 60 years when they sustained an acetabular fracture were included in this study. Seventeen (10%) patients were converted to THA. Control patients were treated with primary THA for osteoarthritis. MAIN OUTCOME MEASURES: Musculoskeletal function assessment scores and Harris Hip scores were obtained after a minimum follow-up of 2 years. RESULTS: Thirteen patients underwent open reduction and internal fixation, 3 underwent nonoperative treatment, and 1 received an acute THA. The most common fracture patterns converted to THA were associated both column (n = 5) and posterior column with posterior wall (n = 5). The average time to conversion to THA was 35 months. When compared with controls, patients who had THA after an acetabular fracture had significantly higher Musculoskeletal Function Assessment scores and significantly lower Harris Hip scores, indicating worse level of function. CONCLUSIONS: Patients who undergo THA after acetabular fracture have significantly worse functional outcome scores when compared with patients who undergo a primary THA for osteoarthritis. LEVEL OF EVIDENCE: Prognostic level III. PMID- 24786736 TI - Tailored surface structure of LiFePO4/C nanofibers by phosphidation and their electrochemical superiority for lithium rechargeable batteries. AB - We offer a brand new strategy for enhancing Li ion transport at the surface of LiFePO4/C nanofibers through noble Li ion conducting pathways built along reduced carbon webs by phosphorus. Pristine LiFePO4/C nanofibers composed of 1 dimensional (1D) LiFePO4 nanofibers with thick carbon coating layers on the surfaces of the nanofibers were prepared by the electrospinning technique. These dense and thick carbon layers prevented not only electrolyte penetration into the inner LiFePO4 nanofibers but also facile Li ion transport at the electrode/electrolyte interface. In contrast, the existing strong interactions between the carbon and oxygen atoms on the surface of the pristine LiFePO4/C nanofibers were weakened or partly broken by the adhesion of phosphorus, thereby improving Li ion migration through the thick carbon layers on the surfaces of the LiFePO4 nanofibers. As a result, the phosphidated LiFePO4/C nanofibers have a higher initial discharge capacity and a greatly improved rate capability when compared with pristine LiFePO4/C nanofibers. Our findings of high Li ion transport induced by phosphidation can be widely applied to other carbon-coated electrode materials. PMID- 24786737 TI - Effects of additional external weight on posture and movement adaptations to fatigue induced by a repetitive pointing task. AB - Fatigue and additional weight are risk factors of injuries by falls. Posture and trunk movement changes occur with fatigue induced by a repetitive pointing task. These changes facilitate arm movement but they may also jeopardize postural stability. When equilibrium is challenged, e.g. with additional weight, strategies that represent less postural threat could develop with fatigue. Nineteen participants performed two sessions (without, with 20% body weight added load (Load)) of a repetitive pointing task until shoulder fatigue (8 on Borg CR 10). There was no difference in time to fatigue between the two sessions. Anterior deltoid, biceps and upper trapezius muscle activity significantly increased with fatigue. Peak medial-lateral center-of-pressure (CoP) velocity and the mean vertical position of the reaching shoulder were both significantly lower with fatigue, though these fatigue-induced decreases were smaller with the added load. Reach-to-reach variability in CoP displacement significantly increased with fatigue, and more so with the added load. With fatigue, significant contralateral shifts occurred at the reaching shoulder and elbow joints, and ranges of motion (RoM) significantly increased at most joints but not at the center-of-mass (CoM). Conversely, Load main effects were mostly seen in CoM dependent measures. Significantly increased variability in mean and range values was seen with fatigue and Load in most of our kinematic and CoP dependent measures, with the most notable effects on CoM dependent measures. Findings suggest that the postural control system adapts to combined perturbing factors of fatigue and added load, likely by using parallel control mechanisms. PMID- 24786738 TI - Introduction: choosing the main outcome of an infertility trial is harder than you think. AB - Clinical trials in infertility choose from a variety of outcomes including change in some surrogate marker of gamete quality to healthy live birth. Incomplete reporting of outcomes makes it difficult to compare studies and to determine the clinical impact of infertility treatments. In this Views and Reviews, we explore the merits of collecting various outcomes of interest in infertility trials from the vantage point of infertility specialists, an obstetrician, and a pediatrician. These articles support more complete reporting of maternal, paternal, fetal, and infant outcomes from infertility trials to improve patient care and ultimately public health. PMID- 24786739 TI - Ongoing pregnancy qualifies best as the primary outcome measure of choice in trials in reproductive medicine: an opinion paper. AB - The most appropriate primary outcome measure for reproductive medicine has been discussed frequently. In 2003 the European Society for Human Reproduction and Embryology recommended that the outcome measure of assisted reproductive technology (ART) and non-ART should be singleton live birth. Although live birth is indeed the aim of clinical practice, and there is no discussion that it should be reported in infertility trials, we hereby provide arguments that plead for using ongoing pregnancy as the primary outcome in such trials. We feel that ongoing pregnancy best serves the many purposes of a primary outcome and best reflects the effectiveness of a treatment. PMID- 24786740 TI - Live birth is the correct outcome for clinical trials evaluating therapy for the infertile couple. AB - Well-designed and -conducted clinical trials are needed to further advance the field for reproductive medicine. However, current reporting of outcomes of trials is ambiguous and disparate. In this review it is offered that the preferred outcome for clinical trials in reproductive medicine should be live birth. Multiple births should be listed, and it should be specified whether this is multiple births per couple or multiple births per conception. The unit of measure should be women (or couples) and not cycles. The duration of exposure should also be clearly identified (i.e., treatment was one cycle, a prespecified number of cycles, or a period of time). Pregnancy loss should be specified, and the denominator should be those who conceived. Although live birth is the primary outcome, complications should be defined and reported, including multiple births and other objective markers, such as preterm delivery, small-for-gestational age, or stillbirth. PMID- 24786741 TI - Infertility trial outcomes: healthy moms and babies. AB - Traditionally, the primary outcome of infertility trials has been a positive pregnancy test or a clinically recognized pregnancy. However, parents desire a healthy baby that grows up to be a healthy adult, rather than a positive pregnancy test. Too often results of infertility trials are lacking in crucial obstetric details. This is problematic because treatments for infertility have the capacity to increase the risk for a variety of adverse obstetric outcomes. This review will outline important obstetric variables that should be included when reporting infertility research. The rationale for including these data, precise definitions of the variables, and cost-effective strategies for obtaining these obstetric details will be highlighted. PMID- 24786742 TI - Outcomes from infancy to adulthood after assisted reproductive technology. AB - The outcomes of assisted reproductive technology (ART) should be not only the evaluation of successful initiation of pregnancy but also the birth of healthy infants and the evaluation of long-term outcomes of the offspring of the couple undergoing therapy. Maternal and neonatal outcomes are reported in another article in this series. This article will review the infant, childhood, adolescent, and young adult outcomes published after ART. The recent literature will be reviewed. PMID- 24786743 TI - Evidence is king, but reader beware: the misinterpretation of studies. PMID- 24786744 TI - Next-generation sequencing: the dawn of a new era for preimplantation genetic diagnostics. PMID- 24786745 TI - An engaging example of translational medicine: the Wnt/beta-catenin cellular pathway and pharmacological research in fibroid treatment. PMID- 24786746 TI - Calculating length of gestation from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database versus vital records may alter reported rates of prematurity. AB - OBJECTIVE: To compare length of gestation after assisted reproductive technology (ART) as calculated by three methods from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) and vital records (birth and fetal death) in the Massachusetts Pregnancy to Early Life Longitudinal Data System (PELL). DESIGN: Historical cohort study. SETTING: Database linkage analysis. PATIENT(S): Live or stillborn deliveries. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): ART deliveries were linked to live birth or fetal death certificates. Length of gestation in 7,171 deliveries from fresh autologous ART cycles (2004-2008) was calculated and compared with that of SART CORS with the use of methods: M1 = outcome date - cycle start date; M2 = outcome date - transfer date + 17 days; and M3 = outcome date - transfer date + 14 days + day of transfer. Generalized estimating equation models were used to compare methods. RESULT(S): Singleton and multiple deliveries were included. Overall prematurity (delivery <37 weeks) varied by method of calculation: M1 29.1%; M2 25.6%; M3 25.2%; and PELL 27.2%. The SART methods, M1-M3, varied from those of PELL by >= 3 days in >45% of deliveries and by more than 1 week in >22% of deliveries. Each method differed from each other. CONCLUSION(S): Estimates of preterm birth in ART vary depending on source of data and method of calculation. Some estimates may overestimate preterm birth rates for ART conceptions. PMID- 24786748 TI - Next-generation sequencing of southern African Crimean-Congo haemorrhagic fever virus isolates reveals a high frequency of M segment reassortment. AB - Crimean Congo haemorrhagic fever virus (CCHFV) is a bunyavirus with a single stranded RNA genome consisting of three segments (S, M, L), coding for the nucleocapsid protein, envelope glycoproteins and RNA polymerase, respectively. To date only five complete genome sequences are available from southern African isolates. Complete genome sequences were generated for 10 southern African CCHFV isolates using next-generation sequencing techniques. The maximum-likelihood method was used to generate tree topologies for 15 southern African plus 26 geographically distinct complete sequences from GenBank. M segment reassortment was identified in 10/15 southern African isolates by incongruencies in grouping compared to the S and L segments. These reassortant M segments cluster with isolates from Asia/Middle East, while the S and L segments cluster with strains from South/West Africa. The CCHFV M segment shows a high level of genetic diversity, while the S and L segments appear to co-evolve. The reason for the high frequency of M segment reassortment is not known. It has previously been suggested that M segment reassortment results in a virus with high fitness but a clear role in increased pathogenicity has yet to be shown. PMID- 24786750 TI - Temporary internal pacing. AB - Technology and insertion techniques for cardiac temporary internal pacing have experienced a remarkable development over the last few years. Despite this fact, the procedure continues to have potentially fatal associated complications. Temporary internal pacing is indicated for the treatment of bradyarrhythmias or tachyarrhythmias refractory to conventional treatment, or arrhythmias causing cardiovascular or clinical instability of the patient. On the other hand, the indications of temporary cardiac pacing are far less well defined than those of permanent pacing. Since the decision of implementing temporary pacing is complex and delicate, it should always be carefully considered, and over-indication should be avoided. We must base these decisions on robust knowledge of the arrhythmias that may benefit from temporary internal pacing, and should also acquire the habit of considering external temporary pacing among other less aggressive treatments, and to make the best use of new technologies such as echocardiography that add accuracy to the procedure. PMID- 24786747 TI - Human embryos secrete microRNAs into culture media--a potential biomarker for implantation. AB - OBJECTIVE: To determine whether human blastocysts secrete microRNA (miRNAs) into culture media and whether these reflect embryonic ploidy status and can predict in vitro fertilization (IVF) outcomes. DESIGN: Experimental study of human embryos and IVF culture media. SETTING: Academic IVF program. PATIENT(S): 91 donated, cryopreserved embryos that developed into 28 tested blastocysts, from 13 couples who had previously completed IVF cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relative miRNA expression in IVF culture media. RESULT(S): Blastocysts were assessed by chromosomal comparative genomic hybridization analysis, and the culture media from 55 single-embryo transfer cycles was tested for miRNA expression using an array-based quantitative real-time polymerase chain reaction analysis. The expression of the identified miRNA was correlated with pregnancy outcomes. Ten miRNA were identified in the culture media; two were specific to spent media (miR-191 and miR-372), and one was only present in media before the embryos had been cultured (miR-645). MicroRNA-191 was more highly concentrated in media from aneuploid embryos, and miR-191, miR-372, and miR-645 were more highly concentrated in media from failed IVF/non-intracytoplasmic sperm injection cycles. Additionally, miRNA were found to be more highly concentrated in ICSI and day-5 media samples when compared with regularly inseminated and day 4 samples, respectively. CONCLUSION(S): MicroRNA can be detected in IVF culture media. Some of these miRNA are differentially expressed according to the fertilization method, chromosomal status, and pregnancy outcome, which makes them potential biomarkers for predicting IVF success. PMID- 24786751 TI - [Mucormycosis in severe trauma patients]. PMID- 24786752 TI - Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons. AB - Novel hypotheses suggest that antidepressants, such as the selective serotonin reuptake inhibitor fluoxetine, induce neuronal structural plasticity, resembling that of the juvenile brain, although the underlying mechanisms of this reopening of the critical periods still remain unclear. However, recent studies suggest that inhibitory networks play an important role in this structural plasticity induced by fluoxetine. For this reason we have analysed the effects of a chronic fluoxetine treatment in the hippocampus and medial prefrontal cortex (mPFC) of transgenic mice displaying eGFP labelled interneurons. We have found an increase in the expression of molecules related to critical period plasticity, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), GAD67/65 and synaptophysin, as well as a reduction in the number of parvalbumin expressing interneurons surrounded by perineuronal nets. We have also described a trend towards decrease in the perisomatic inhibitory puncta on pyramidal neurons in the mPFC and an increase in the density of inhibitory puncta on eGFP interneurons. Finally, we have found that chronic fluoxetine treatment affects the structure of interneurons in the mPFC, increasing their dendritic spine density. The present study provides evidence indicating that fluoxetine promotes structural changes in the inhibitory neurons of the adult cerebral cortex, probably through alterations in plasticity-related molecules of neurons or the extracellular matrix surrounding them, which are present in interneurons and are known to be crucial for the development of the critical periods of plasticity in the juvenile brain. PMID- 24786753 TI - Dextran-peptide hybrid for efficient gene delivery. AB - Gene therapy has drawn significant interest in the past two decades since it provides a promising strategy to treat both genetic disorders and acquired diseases. However, the transfer of gene therapy to clinical applications is troubled with many difficulties, since many current systems are of toxicity, low transfection efficiency and low biodegradability. To address these challenges, we developed a dextran-peptide hybrid system as a safe and efficient vector for gene therapy and investigated the structure-function-cytotoxicity relationship of this dextran-peptide hybrid system. Dextrans (Dex10, Dex20, and Dex70) with different molecular weights (10, 20 and 70 kDa) were conjugated with a cationic peptide, R5H5, at various degrees of substitution. Gene expression and cytotoxicity mediated by this delivery system were evaluated against SKOV-3 human ovarian carcinoma cells and compared to 25 kDa branched poly(ethylenimine) (PEI). The results showed that Dex10-R5H5 and Dex20-R5H5 hybrids derived from low molecular weight dextrans induced higher gene expression and lower cytotoxicity than Dex70 R5H5 hybrid from higher molecular weight dextran. The best performance on gene expression was achieved by Dex10-R5H5 at 40% substitution of R5H5, which induced greater gene expression than PEI at a low N/P ratio of 5. Dex10-R5H5/DNA complexes at 40% substitution of R5H5 also showed much higher cell viability (93%) than PEI/DNA (66%) at the same N/P ratio. These results indicate that the Dex-R5H5 hybrid with the low molecular weight of dextran and the high degree of substitution of R5H5 is a very promising material for safe and efficient gene therapy. PMID- 24786754 TI - A quality improvement programme with a specialist nurse in a neurovascular clinic. AB - AIMS AND OBJECTIVES: To measure the impact of a quality improvement programme with a stroke specialist nurse and increased capacity at neurovascular clinics. BACKGROUND: Transient ischaemic attack and minor stroke are medical emergencies prompting urgent assessment and treatment. Delays in specialist assessment and management are frequent and may increase stroke risk. DESIGN: Pre- and post evaluation of intervention. METHODS: All patients referred to a neurovascular clinic were recorded during two phases: 2006-2008 and 2010-2012. For the 2010 2012 period, a stroke specialist nurse contacted all patients with appointment details, provided driving advice and asked for an eyewitness to attend the clinic. Diagnosis, delay in specialist assessment, prevalence of transient ischaemic attack/minor stroke as confirmed at the clinic and compliance with UK driving regulations were measured and compared before and after this intervention. RESULTS: A total of 1327 patients were assessed in the two study phases. Referrals to the neurovascular service increased without a decrease in the prevalence of transient ischaemic attack/minor stroke. Delays from clinical event to assessment were decreased for referrals from 36.5-13 days, and adherence to the UK driving restrictions improved for confirmed transient ischaemic attack/minor stroke patients from 61-94%. Fewer patients failed to attend a neurovascular appointment arranged by the stroke specialist nurse than those who failed a general neurology appointment arranged by partial booking. CONCLUSIONS: This quality improvement programme reduced delays for all referred patients, improved compliance with driving regulations and demonstrated efficient use of neurovascular clinic spaces. Increasing local capacity may unmask more transient ischaemic attack/minor stroke patients. RELEVANCE TO CLINICAL PRACTICE: A stroke nurse can help improve the efficiency of a neurovascular clinic and improve patient safety with driving advice. PMID- 24786755 TI - Visible-light organic photocatalysis for latent radical-initiated polymerization via 2e-/1H+ transfers: initiation with parallels to photosynthesis. AB - We report the latent production of free radicals from energy stored in a redox potential through a 2e(-)/1H(+) transfer process, analogous to energy harvesting in photosynthesis, using visible-light organic photoredox catalysis (photocatalysis) of methylene blue chromophore with a sacrificial sterically hindered amine reductant and an onium salt oxidant. This enables light-initiated free-radical polymerization to continue over extended time intervals (hours) in the dark after brief (seconds) low-intensity illumination and beyond the spatial reach of light by diffusion of the metastable leuco-methylene blue photoproduct. The present organic photoredox catalysis system functions via a 2e(-)/1H(+) shuttle mechanism, as opposed to the 1e(-) transfer process typical of organometallic-based and conventional organic multicomponent photoinitiator formulations. This prevents immediate formation of open-shell (radical) intermediates from the amine upon light absorption and enables the "storage" of light-energy without spontaneous initiation of the polymerization. Latent energy release and radical production are then controlled by the subsequent light independent reaction (analogous to the Calvin cycle) between leuco-methylene blue and the onium salt oxidant that is responsible for regeneration of the organic methylene blue photocatalyst. This robust approach for photocatalysis-based energy harvesting and extended release in the dark enables temporally controlled redox initiation of polymer syntheses under low-intensity short exposure conditions and permits visible-light-mediated synthesis of polymers at least 1 order of magnitude thicker than achievable with conventional photoinitiated formulations and irradiation regimes. PMID- 24786757 TI - Scope and limitations of 2-deoxy- and 2,6-dideoxyglycosyl bromides as donors for the synthesis of beta-2-deoxy- and beta-2,6-dideoxyglycosides. AB - It is shown that 2-deoxy- and 2,6-dideoxyglycosyl bromides can be prepared in high yield (72-94%) and engaged in glycosylation reactions with beta:alpha selectivities >=6:1. Yields of product are 44-90%. Fully armed 2-deoxyglycoside donors are viable, while 2,6-dideoxyglycosides require one electron-withdrawing substituent for high efficiency and beta-selectivity. Equatorial C-3 ester protecting groups decrease beta-selectivity, and donors bearing an axial C-3 substituent are not suitable. The method is compatible with azide-containing donors and acid-sensitive functional groups. PMID- 24786756 TI - Mammalian O-mannosylation pathway: glycan structures, enzymes, and protein substrates. AB - The mammalian O-mannosylation pathway for protein post-translational modification is intricately involved in modulating cell-matrix interactions in the musculature and nervous system. Defects in enzymes of this biosynthetic pathway are causative for multiple forms of congenital muscular dystophy. The application of advanced genetic and biochemical technologies has resulted in remarkable progress in this field over the past few years, culminating with the publication of three landmark papers in 2013 alone. In this review, we will highlight recent progress focusing on the dramatic expansion of the set of genes known to be involved in O mannosylation and disease processes, the concurrent acceleration of the rate of O mannosylation pathway protein functional assignments, the tremendous increase in the number of proteins now known to be modified by O-mannosylation, and the recent progress in protein O-mannose glycan quantification and site assignment. Also, we attempt to highlight key outstanding questions raised by this abundance of new information. PMID- 24786758 TI - Source and destination memory: two sides of the same coin? AB - Whereas source memory involves remembering from whom you have heard something, destination memory involves remembering to whom you have told something. Despite its practical relevance, destination memory has been studied little. Recently, two reports suggested that generally destination memory should be poorer than source memory, and that it should be particularly difficult for older people. We tested these predictions by having young and older participants read sentences to two examiners (destination encoding) and listen to sentences read by two examiners (source encoding), under intentional (Experiment 1) or incidental encoding (Experiments 2 and 3). Only in Experiment 3 (in which cognitive demands during destination encoding were increased) was destination memory significantly poorer than source memory. In none of the experiments were older adults inferior to the young on destination or source memory. Destination- and source-memory scores were significantly correlated. Item memory was consistently superior for sentences that had been read out loud (during destination encoding) versus those that had been heard (during source encoding). Destination memory needs not always be poorer than source memory, appears not to be particularly impaired by normal ageing and may depend on similar processes to those supporting source memory. PMID- 24786759 TI - Does smoking within an individual's peer group affect intervention effectiveness? An evaluation of the Smoke-Free Class Competition among Swiss adolescents. AB - OBJECTIVE: The aim of this study is to test whether participation in the Smoke Free Class Competition (SFC), a classroom-based smoking prevention program, reduced smoking and increased smoking-related knowledge among those with and without smoking peers compared to control groups. METHOD: Including smoking peers as a moderator in multilevel models, a quasi-experimental design with a post-test at seven months was used to analyze data from 1035 students in Switzerland (2011; mean age 13.3, 53.2% female). RESULTS: Completing the SFC decreased smoking prevalence (OR=0.7; CI=0.5-1.0; ns) and increased smoking-related knowledge (b=1.0; p<.01) compared to control classes. However, the former effect was only significant among those without smoking peers (OR=0.3; CI=0.2-0.5; p<.001). With smoking peers, smoking prevalence was even higher at post-test (OR=3.7; CI=1.7 8.2; p<.01) in the classes that completed SFC compared to controls. No effect was found in classes that started SFC but had to pull out. CONCLUSIONS: The results indicate that SFC should be applied early in adolescence, when individuals are less likely to have classmates who smoke and are therefore less likely to have to pull out of the program. This is particularly important because SFC was only effective among those who completed the program and did not have smoking peers. PMID- 24786760 TI - Self-reported mental health in youth with cerebral palsy and associations to recurrent musculoskeletal pain. AB - PURPOSE: To explore self-reports on emotional, conduct, hyperactivity and peer problems and on prosocial behaviour in youth with cerebral palsy (CP), compare the reports to normative data and to mothers' reports and to analyse if recurrent CP-related musculoskeletal pain (RMP) influence the self-reports. METHODS: Eighty one youth with CP (mean age 14.2 years, 40 boys) were assessed by clinical examination, interview and the questionnaire Strengths and Difficulties Questionnaire (SDQ) filled in by the youths and their mothers. Gross motor function (GMFCS) was: level I 43%, level II 41%, level III 12% and level IV-V 4%. RESULTS: Compared to normative data, youth with CP reported similar levels of peer problems, less conduct problems (p < 0.01), less hyperactivity problems (p < 0.01) and more prosocial behaviour (p < 0.01). Compared to the mothers' reports, youth with CP reported lower levels of peer problems (p < 0.01). Twenty-six boys (65%) and 28 girls (68%) had RMP. Girls, but not boys with RMP reported a higher level of peer problems (p = 0.02) than youth without RMP. CONCLUSION: Self-report on mental health in addition to parental proxy-report is important because it yields additional information. Peer acceptance and the impact of pain on peer problems and participation are candidate topics for further research. PMID- 24786762 TI - Parental knowledge of coeliac disease. AB - AIM: Little information exists regarding parental knowledge of CD at diagnosis. We aimed for assessment of parental information at disease diagnosis to help us develop a tailored coeliac information package. METHODS: Children and teenagers referred for endoscopy and duodenal biopsy, with the sole indication for the diagnosis of CD, were prospectively recruited to the study. Parents were asked information and concerns regarding use of GFD. RESULTS: Sixty-three children (median 6.9 yrs (IQR 3.71-10.94)) and families were prospectively recruited in the study. The parents were very knowledgeable with an impressive 98% of the parents understanding that GFD is the treatment of CD; 95% knowing that this treatment is for life. However, specific dietary information was lacking with one third correctly identifying all the Gluten containing foods. Internet (70.6%) was the most common source of information. Knowing someone with CD (p = 0.038), particularly in the same household in the family (p = 0.013) and researching about the disease (p = 0.001) rather than level of parental education (p = ns) was predictive of better parental knowledge. CONCLUSION: Internet is a major influence to parental knowledge in today's age but there is a continued need for hospitals regarding provision of accurate information and alleviating anxieties regarding use of GFD. PMID- 24786761 TI - Imaging of influenza virus sialidase activity in living cells. AB - Influenza virus is rich in variation and mutations. It would be very convenient for virus detection and isolation to histochemically detect viral infection regardless of variation and mutations. Here, we established a histochemical imaging assay for influenza virus sialidase activity in living cells by using a new fluorescent sialidase substrate, 2-(benzothiazol-2-yl)-4-bromophenyl 5 acetamido-3,5-dideoxy-alpha-D-glycero-D-galacto-2-nonulopyranosidonic acid (BTP3 Neu5Ac). The BTP3-Neu5Ac assay histochemically visualized influenza virus infected cells regardless of viral hosts and subtypes. Influenza virus neuraminidase-expressed cells, viral focus formation, and virus-infected locations in mice lung tissues were easily, rapidly, and sensitively detected by the BTP3-Neu5Ac assay. Histochemical visualization with the BTP3-Neu5Ac assay is extremely useful for detection of influenza viruses without the need for fixation or a specific antibody. This novel assay should greatly improve the efficiency of detection, titration, and isolation of influenza viruses and might contribute to research on viral sialidase. PMID- 24786764 TI - The ELPA library: scalable parallel eigenvalue solutions for electronic structure theory and computational science. AB - Obtaining the eigenvalues and eigenvectors of large matrices is a key problem in electronic structure theory and many other areas of computational science. The computational effort formally scales as O(N(3)) with the size of the investigated problem, N (e.g. the electron count in electronic structure theory), and thus often defines the system size limit that practical calculations cannot overcome. In many cases, more than just a small fraction of the possible eigenvalue/eigenvector pairs is needed, so that iterative solution strategies that focus only on a few eigenvalues become ineffective. Likewise, it is not always desirable or practical to circumvent the eigenvalue solution entirely. We here review some current developments regarding dense eigenvalue solvers and then focus on the Eigenvalue soLvers for Petascale Applications (ELPA) library, which facilitates the efficient algebraic solution of symmetric and Hermitian eigenvalue problems for dense matrices that have real-valued and complex-valued matrix entries, respectively, on parallel computer platforms. ELPA addresses standard as well as generalized eigenvalue problems, relying on the well documented matrix layout of the Scalable Linear Algebra PACKage (ScaLAPACK) library but replacing all actual parallel solution steps with subroutines of its own. For these steps, ELPA significantly outperforms the corresponding ScaLAPACK routines and proprietary libraries that implement the ScaLAPACK interface (e.g. Intel's MKL). The most time-critical step is the reduction of the matrix to tridiagonal form and the corresponding backtransformation of the eigenvectors. ELPA offers both a one-step tridiagonalization (successive Householder transformations) and a two-step transformation that is more efficient especially towards larger matrices and larger numbers of CPU cores. ELPA is based on the MPI standard, with an early hybrid MPI-OpenMPI implementation available as well. Scalability beyond 10,000 CPU cores for problem sizes arising in the field of electronic structure theory is demonstrated for current high-performance computer architectures such as Cray or Intel/Infiniband. For a matrix of dimension 260,000, scalability up to 295,000 CPU cores has been shown on BlueGene/P. PMID- 24786763 TI - Tetraspecific ligand for tumor-targeted delivery of nanomaterials. AB - The polygenetic nature of most cancers emphasizes the necessity of cancer therapies that target multiple essential signaling pathways. However, there is a significant paucity of targeting ligands with multi-specificities for targeted delivery of biomaterials. To address this unmet need, we generated a tetraspecific targeting ligand that recognizes four different cancer biomarkers, including VEGFR2, alphavbeta3 integrin, EGFR, and HER2 receptors, which have been implicated in numerous malignant tumors. The tetraspecific targeting ligand was constructed by sequentially connecting four targeting ligand subunits via flexible linkers, yielding a fusion protein that can be highly expressed in Escherichia coli and readily purified to near homogeneity. Surface Plasmon Resonance (SPR), Bio-Layer Interferometry (BLI) studies and extensive cellular binding analyses indicated that all the targeting ligand subunits in the tetraspecific fusion protein recognized their target receptors proximately to the corresponding monospecific ligands. The resulting tetraspecific targeting ligand was applied for the delivery of nanomaterials such as gold nanoparticles (AuNPs) for targeted hyperthermic killing of various cancer cell lines with biomarkers of interest expressed. We demonstrate that the tetraspecific ligand can be facilely introduced on the surface of AuNPs and efficient target-dependent killing of cancer cells can be achieved only when the AuNPs are conjugated with the tetraspecific ligand. Significantly, the tetraspecific ligand simultaneously interacts with more than one receptors, such as EGFR and HER2 receptors, when they are expressed on the surface of the same cell, as demonstrated by in vitro binding assays and cell binding analyses. Our results demonstrate that the tetraspecific ligand, through multivalency and synergistic binding, can be readily used to generate various 'smart' biomaterials with greatly broadened tumor targeting range for simultaneous targeting of multiple signaling pathways on many different cancer types. PMID- 24786765 TI - The development of future thinking: young children's ability to construct event sequences to achieve future goals. AB - Previous studies suggest that the ability to think about and act on the future emerges between 3 and 5 years of age. However, it is unclear what underlying processes change during the development of early future-oriented behavior. We report three experiments that tested the emergence of future thinking ability through children's ability to explicitly maintain future goals and construct future scenarios. Our main objectives were to examine the effects of goal structure and the effects of working memory demands on children's ability to construct future scenarios and make choices to satisfy future goals. The results indicate that 4-year-olds were able to successfully accomplish two temporally ordered goals even with high working memory demands and a complex goal structure, whereas 3-year-olds were able to accomplish two goals only when the working memory demands were low and the goal structure did not involve additional demands from inferential reasoning and contingencies between the temporally ordered goals. Results are discussed in terms of the development of future thinking in conjunction with working memory, inferential reasoning ability, and goal maintenance abilities. PMID- 24786766 TI - Transpulmonary atrial pacing: an approach to transvenous pacemaker implantation after extracardiac conduit Fontan surgery. AB - INTRODUCTION: Patients with prior extracardiac (EC) conduit Fontan surgery are considered ineligible for transvenous atrial pacemaker implantation due to lack of venous access to the atrial myocardium. A new technique for atrial lead placement in the setting of this surgical anatomy is proposed. METHODS AND RESULTS: A 30-year-old female with prior EC Fontan surgery, incessant supraventricular tachycardia, sinus node dysfunction, and multi-organ failure was admitted to our hospital. After placement of a transvenous lead in the left pulmonary artery (LPA) for temporary pacing with ensuing clinical improvement, the patient was taken back to the catheterization laboratory for definitive treatment. After ablation of the supraventricular tachycardia and 3D mapping of the common atrium, a puncture through the LPA and into the left-sided atrium was performed. A transvenous lead was then attached to the base of the left-sided appendage where excellent pacing and sensing characteristics were observed. Follow-up transesophageal echocardiography revealed stable lead placement and absence of pericardial effusion. The patient was discharged to home several days later on warfarin therapy. CONCLUSIONS: Transpulmonary access to the left-sided atrium for patients with prior EC Fontan surgery is a feasible strategy for transvenous atrial pacing. Lead placement in this location is associated with excellent pacing characteristics and involves a limited segment of lead within the pulmonary venous atrium. The approach is technically straightforward and avoids the need for surgical pacemaker placement. PMID- 24786767 TI - "If you bring an alarm, we will destroy it," said Brucella to the host cell. PMID- 24786768 TI - Infection of a Rathke cleft cyst: a rare cause of pituitary abscess. AB - BACKGROUND: Only 20 cases of abscess formation within a Rathke cleft cyst have been reported. METHODS: Case report and review of the English-language literature. RESULTS: A 64-year-old female was admitted with a 12-mo history of headache and decreased visual acuity and had bilateral papilledema and bitemporal hemianopsia with impairment of visual acuity. Magnetic resonance imaging demonstrated a sellar and suprasellar mass measuring 2*2*2 cm. The lesion was removed using a transsphenoidal approach. The abscess was drained, and gram stain revealed polymorphonuclear cells and gram-positive cocci. The postoperative course was uneventful. Ceftriaxone and metronidazole were continued for 6 wks. The patient also received hydrocortisone and continued thyroid hormone replacement. During a 6-mo follow up, the patient's headaches disappeared, and the bitemporal hemianopsia and impaired visual acuity abated. CONCLUSION: Predisposing factors for pituitary abscesses in primary lesions include immunosuppression and pituitary irradiation, surgery, or infarction. Approximately one-third of pituitary abscesses arise within other lesions. The clinical manifestations are non-specific. Magnetic resonance imaging shows a cystic lesion with central low intensity and rim enhancement after administration of contrast. When a pituitary abscess is diagnosed, surgical procedures should be performed promptly via a transsphenoidal (preferably) or transcranial approach. PMID- 24786769 TI - Exploring athletic identity in elite-level English youth football: a cross sectional approach. AB - This study is the first empirical investigation that has explored levels of athletic identity in elite-level English professional football. The importance of understanding athletes' psychological well-being within professional sport has been well documented. This is especially important within the professional football industry, given the high attrition rate (Anderson, G., & Miller, R. M. (2011). The academy system in English professional football: Business value or following the herd? University of Liverpool, Management School Research Paper Series. Retrieved from http://www.liv.ac.uk/managementschool/research/working%20papers/wp201143.pdf ) and distinct occupational practices (Roderick, M. (2006). The work of professional football. A labour of love? London: Routledge). A total of 168 elite youth footballers from the English professional football leagues completed the Athletic Identity Measurement Scale (AIMS). Multilevel modelling was used to examine the effect of playing level, living arrangements and year of apprentice on the total AIMS score and its subscales (i.e., social identity, exclusivity and negative affectivity). Football club explained 30% of the variance in exclusivity among players (P = .022). Mean social identity was significantly higher for those players in the first year of their apprenticeship compared to the second year (P = .025). All other effects were not statistically significant (P > .05). The novel and unique findings have practical implications in the design and implementation of career support strategies with respect to social identity. This may facilitate the maintenance of motivation over a 2-year apprenticeship and positively impact on performance levels within the professional football environment. PMID- 24786770 TI - Drosha promotes splicing of a pre-microRNA-like alternative exon. AB - The ribonuclease III enzyme Drosha has a central role in the biogenesis of microRNA (miRNA) by binding and cleaving hairpin structures in primary RNA transcripts into precursor miRNAs (pre-miRNAs). Many miRNA genes are located within protein-coding host genes and cleaved by Drosha in a manner that is coincident with splicing of introns by the spliceosome. The close proximity of splicing and pre-miRNA biogenesis suggests a potential for co-regulation of miRNA and host gene expression, though this relationship is not completely understood. Here, we describe a cleavage-independent role for Drosha in the splicing of an exon that has a predicted hairpin structure resembling a Drosha substrate. We find that Drosha can cleave the alternatively spliced exon 5 of the eIF4H gene into a pre-miRNA both in vitro and in cells. However, the primary role of Drosha in eIF4H gene expression is to promote the splicing of exon 5. Drosha binds to the exon and enhances splicing in a manner that depends on RNA structure but not on cleavage by Drosha. We conclude that Drosha can function like a splicing enhancer and promote exon inclusion. Our results reveal a new mechanism of alternative splicing regulation involving a cleavage-independent role for Drosha in splicing. PMID- 24786771 TI - Phosphorylation-dephosphorylation cycle of HP1alpha governs accurate mitotic progression. AB - Heterochromatin protein 1alpha (HP1alpha), a bona fide factor of silent chromatin, is required for establishing as well as maintaining the higher-order chromatin structure in eukaryotes. HP1alpha is decorated with several post translational modifications, and many of these are critical for its cellular functions. HP1alpha is heavily phosphorylated; however, its physiological relevance had remained to be completely understood. We have recently demonstrated that human HP1alpha is a mitotic target for NDR kinase, and the phosphorylation at the hinge region of HP1alpha at the G 2/M phase of the cell cycle is crucial for mitotic progression and Sgo1 loading at mitotic centromeres (Chakraborty et al., 2014). We now demonstrate that the dephosphorylation of HP1alpha within its hinge domain occurs during mitosis, specifically soon after prometaphase. In the absence of the hinge-specific HP1alpha phosphorylation, either as a consequence of depleting NDR1 or in cells expressing a non-phosphorylatable HP1alpha mutant, the cells arrest in prometaphase with several mitotic defects. In this study we show that NDR1-depleted cells expressing hinge-specific phosphomimetic HP1alpha mutant rescues the prometaphase arrest but displays defects in mitotic exit, suggesting that the dephosphorylation of HP1alpha is required for the completion of cytokinesis. Taken together, our results reveal that the phosphorylation dephosphorylation cycle of HP1alpha orchestrates accurate progression of cells through mitosis. PMID- 24786772 TI - Integrated genetic approaches identify the molecular mechanisms of Sox4 in early B-cell development: intricate roles for RAG1/2 and CK1epsilon. AB - Commitment of hematopoietic stem cells to B lineage precursors and subsequent development of B lineage precursors into mature B cells is stringently controlled by stage-specific transcription factors. In this study, we used integrated genetic approaches and systematically determined the role of Sry-related high mobility group box (Sox) 4 and the underlying molecular mechanisms in early B cell development. We found that Sox4 coordinates multilevel controls in the differentiation of early stage B cells. At the molecular level, Sox4 orchestrates a unique gene regulatory program, and its function was predominantly mediated through a conventional Sox4-binding motif as well as an unconventional GA-binding protein alpha chain binding motif. Our integrated gene network and functional analysis indicated that Sox4 functions as a bimodular transcription factor and ensures B lineage precursor differentiation through 2 distinct mechanisms. It positively induces gene rearrangements at immunoglobulin heavy chain gene loci by transcriptionally activating the Rag1 and Rag2 genes and negatively regulates Wnt signaling, which is critical for self-renewal, by inducing the expression of casein kinase 1 epsilon. Our findings illustrate that Sox4 mediates critical fine tuning of the 2 opposing forces in early B-cell development and also set forth a model for characterization of critical genes whose deficiency, like Sox4 deficiency, is detrimental to this process. PMID- 24786773 TI - The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. AB - Analyses of the bleeding tendency by means of the bleeding score (BS) have been proposed until now to confirm diagnosis but not to predict clinical outcomes in patients with inherited von Willebrand disease (VWD). We prospectively followed up, for 1 year, 796 Italian patients with different types of VWD to determine whether the previous BS of European VWD1 is useful to predict the occurrence of spontaneous bleeds severe enough to require replacement therapy with desmopressin (DDAVP) and/or von Willebrand factor (VWF)/factor VIII concentrates. Among the 796 patients included, 75 (9.4%) needed treatment of 232 spontaneous bleeding events. BS >10 and VWF:ristocetin cofactor activity <10 U/dL were associated with the risk of bleeding, but only a BS >10 remained highly associated in a multivariable Cox proportional hazard model (adjusted hazard ratio: 7.27 [95% confidence interval, 3.83-13.83]). Although the bleeding event-free survival was different in VWD types, only a BS >10 could predict for each type which patient had bleeding events severe enough to require treatment with DDAVP and/or concentrates. Therefore, BS can be considered a simple predictor of clinical outcomes of VWD and may identify patients needing intensive therapeutic regimens. PMID- 24786774 TI - Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. AB - Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT 199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, 2 missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded ABT-199 binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of proapoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results anticipate the potential development of such mutations in patients treated with ABT-199, providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance. PMID- 24786775 TI - From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. AB - Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the JAK2 (V617F) mutation was identified in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in all myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials. PMID- 24786776 TI - Trans-spliced heat shock protein 90 modulates encystation in Giardia lamblia. AB - BACKGROUND: Hsp90 from Giardia lamblia is expressed by splicing of two independently transcribed RNA molecules, coded by genes named HspN and HspC located 777 kb apart. The reasons underlying such unique trans-splicing based generation of GlHsp90 remain unclear. PRINCIPLE FINDING: In this study using mass spectrometry we identify the sequence of the unique, junctional peptide contributed by the 5' UTR of HspC ORF. This peptide is critical for the catalytic function of Hsp90 as it harbours an essential "Arg" in its sequence. We also show that full length GlHsp90 possesses all the functional hall marks of a canonical Hsp90 including its ability to bind and hydrolyze ATP. Using qRT-PCR as well as western blotting approach we find the reconstructed Hsp90 to be induced in response to heat shock. On the contrary we find GlHsp90 to be down regulated during transition from proliferative trophozoites to environmentally resistant cysts. This down regulation of GlHsp90 appears to be mechanistically linked to the encystation process as we find pharmacological inhibition of GlHsp90 function to specifically induce encystation. SIGNIFICANCE: Our results implicate the trans spliced GlHsp90 from Giardia lamblia to regulate an essential stage transition in the life cycle of this important human parasite. PMID- 24786777 TI - Psychosocial stress but not hypertensive status associated with angiogenesis in Africans. AB - AIM: Increased angiogenic factors [vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2)] have been associated with vascular dysfunction and hypertension. Black Africans undergoing rapid urbanization present with elevated blood pressure (BP) and we aimed to determine whether angiogenic factors are elevated in urban versus rural Africans with normal and elevated BP. METHODS AND MATERIALS: Africans (n = 272), matched for gender and age, were recruited from rural and urban communities in South Africa. Omron HEM-757 BP data were obtained and angiogenic markers in plasma and serum were determined. RESULTS: Urban African men displayed a higher (43.90%) hypertension prevalence compared with their rural counterparts (18.52%) and disturbed angiongenic factors. Adjusted VEGF-A concentrations were higher in urban men and women compared with their rural counterparts. Similar VEGF-A levels were observed in rural and urban hypertensives. Logistic regression analysis demonstrated that VEGF-A and Ang-2 levels were associated with psychosocial stress but not with hypertensive status in Africans [odds ratios 1.01-1.09 (95% CI 1.01-1.15), p <= 0.05]. CONCLUSION: Psychosocial stress per se was associated with disturbed VEGF-A and Ang-2. We suggest that hyperkinetic BP may act as compensatory mechanism when chronic psychosocial stress prevails, affecting vascular functioning and subsequent increased cardiovascular disease risk. PMID- 24786778 TI - Developing an interactive mobile phone self-report system for self-management of hypertension. Part 2: content validity and usability. AB - Self-management support tools using technology may improve adherence to hypertension treatment. There is a need for user-friendly tools facilitating patients' understanding of the interconnections between blood pressure, wellbeing and lifestyle. This study aimed to examine comprehension, comprehensiveness and relevance of items, and further to evaluate the usability and reliability of an interactive hypertension-specific mobile phone self-report system. Areas important in supporting self-management and candidate items were derived from five focus group interviews with patients and healthcare professionals (n = 27), supplemented by a literature review. Items and response formats were drafted to meet specifications for mobile phone administration and were integrated into a mobile phone data-capture system. Content validity and usability were assessed iteratively in four rounds of cognitive interviews with patients (n = 21) and healthcare professionals (n = 4). Reliability was examined using a test-retest. Focus group analyses yielded six areas covered by 16 items. The cognitive interviews showed satisfactory item comprehension, relevance and coverage; however, one item was added. The mobile phone self-report system was reliable and perceived easy to use. The mobile phone self-report system appears efficiently to capture information relevant in patients' self-management of hypertension. Future studies need to evaluate the effectiveness of this tool in improving self management of hypertension in clinical practice. PMID- 24786779 TI - Effect of antihypertensive treatments on insulin signalling in lympho-monocytes of essential hypertensive patients: a pilot study. AB - It was previously demonstrated that metabolic syndrome in humans is associated with an impairment of insulin signalling in circulating mononuclear cells. At least in animal models of hypertension, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) may correct alterations of insulin signalling in the skeletal muscle. In the first study, we investigated the effects of a 3-month treatment with an ARB with additional PPARgamma agonist activity, telmisartan, or with a dihydropyridine calcium channel blocker, nifedipine, on insulin signalling in patients with mild-moderate essential hypertension. Insulin signalling was evaluated in mononuclear cells by isolating them through Ficoll-Paque density gradient centrifugation and protein analysis by Western Blot. An increased expression of mTOR and of phosphorylated (active) mTOR (p-mTOR) was observed in patients treated with telmisartan, but not in those treated with nifedipine, while both treatments increased the cellular expression of glucose transporter type 4 (GLUT-4). We also investigated the effects of antihypertensive treatment with two drug combinations on insulin signalling and oxidative stress. Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine. Then they were treated for 6 months with lercanidipine + enalapril or lercanidipine + hydrochlorothiazide. An increased expression of insulin receptor, GLUT-4 and an increased activation of p70S6K1 were observed during treatment with lercanidipine + enalapril but not with lercanidipine + hydrochlorothiazide. In conclusion, telmisartan and nifedipine are both effective in improving insulin signalling in human hypertension; however, telmisartan seems to have broader effects. The combination treatment lercanidipine + enalapril seems to be more effective than lercanidipine + hydrochlorothiazide in activating insulin signalling in human lympho-monocytes. PMID- 24786781 TI - Effect of Proton Substitution by Alkali Ions on the Fluorescence Emission of Rhodamine B Cations in the Gas Phase. AB - The photophysics of chromophores is strongly influenced by their environment. Solvation, charge state, and adduct formation significantly affect ground and excited state energetics and dynamics. The present study reports on fluorescence emission of rhodamine B cations (RhBH+) and derivatives in the gas phase. Substitution of the acidic proton of RhBH+ by alkali metal cations, M+, ranging from lithium to cesium leads to significant and systematic blue shifts of the emission. The gas-phase structures and singlet transition energies of RhBH+ and RhBM+, M = Li, Na, K, Rb, and Cs, were investigated using Hartree-Fock theory, density functional methods, second-order Moller-Plesset perturbation theory, and the second-order approximate coupled-cluster model CC2. Comparison of experimental and theoretical results highlights the need for improved quantum chemical methods, while the hypsochromic shift observed upon substitution appears best explained by the Stark effect due to the inhomogeneous electric field generated by the alkali ions. PMID- 24786780 TI - Population-based hospitalization burden of influenza a virus subtypes and antigenic drift variants in children in Hong Kong (2004-2011). AB - OBJECTIVES: We aim to document and analyze influenza hospitalization burden in light of antigenic changes in circulating influenza viruses in Hong Kong. METHODS: The pediatric age-specific rates of influenza A hospitalization in Hong Kong for 2004-2011 which encompassed the emergence of H1N1pdm09 were extrapolated from admissions to 2 hospitals that together catered for 72.5% of all pediatric admissions on Hong Kong Island. Influenza A was detected by immunofluorescence, culture and/or PCR on nasopharyngeal aspirates. RESULTS: Influenza A caused high rates of hospitalization in children with year to year fluctuations. The highest hospitalization burden was seen with H1N1pdm09 in 2009. Additional factors affecting hospitalization were the proportion of viral circulation among different subtypes, and antigenic drifts. Taking these into effect, an H3N2 dominated year was not always associated with more hospitalizations than a 'seasonal' H1N1 year. Hospitalization burden was higher in seasons when drifted viruses of H1N1 or H3N2 dominated. No hospitalization was documented in infants <6 months of age during years when an undrifted virus circulated (2006 for H1N1 and 2008 for H3N2) but significant hospitalization was observed with a drifted or shifted virus (2004, 2005, 2007 and 2010 for H3N2, and 2009 for H1N1pdm09). CONCLUSIONS: We documented a consistently high pediatric hospitalization burden of influenza A. Knowledge of antigenic changes and their proportion of circulation aids in the interpretation of impact of the subtypes. Year-to-year variation in hospitalization rates in young infants appeared to correlate with antigenic variation, lending support to the role of protection from maternal antibodies. PMID- 24786782 TI - Electroconvulsive therapy for catatonia in juvenile neuropsychiatric lupus. AB - Neuropsychiatric manifestations are serious and frequent complications of systemic lupus erythematous (SLE). Catatonia is a neuropsychiatric disorder characterized by motor disturbance (including waxy flexibility and catalepsy), stupor, excitement, negativism, mutism, echopraxia and echolalia. Catatonia associated with SLE has been only rarely reported, especially in children. Here we present a case of a 14-year-old patient encountered in consultation-liaison psychiatry who presented catatonia associated with SLE. Her catatonia was refractory to treatment with pulse methylprednisolone, intravenous cyclophosphamide and rituximab. The patient responded to a combined therapy of electroconvulsive therapy and benzodiazepines. The present case suggests that although rarely reported, catatonia seen in the background of SLE should be promptly identified and treated to reduce the morbidity. PMID- 24786783 TI - Burden of corticosteroid use in patients with systemic lupus erythematosus: results from a Delphi panel. AB - Corticosteroid-related adverse events (AEs) are commonly reported in systemic lupus erythematosus (SLE), but are often under-represented in claims data. The most common corticosteroid-related AEs are not necessarily the most costly. The present study aimed to examine corticosteroid-related AE rates and identify the associated cost consequences in patients with SLE from the perspective of rheumatologists treating SLE in the United States (US). A modified Delphi process and RAND Appropriateness Method was used to estimate corticosteroid-related AEs and costs based on data from SLE-treating US rheumatologists and estimates from alternative sources. The panel (n=10) participated in two web-based questionnaires, covering disease severity, corticosteroid use, corticosteroid related AEs, and resource utilization associated with treatment of the AEs. Eight members of the panel then participated in a guided discussion by interactive teleconference, in which the costs associated with specific corticosteroid related AEs were also discussed. Consensus was achieved in the teleconference when a single response category (consensus values from 1 to 4 [4=strongly agree, 1=strongly disagree]) accounted for >=80% of responses. Thirteen consensus statements were developed following two Delphi rounds. Costs were estimated for eight corticosteroid-associated AEs from the panel of rheumatologists. In the patients with SLE treated by these physicians, 41.5% were considered to have mild disease, 36.5% moderate disease, and 22.0% severe disease. The number of specialist visits, corticosteroid use, and corticosteroid dose increased with disease severity. The estimated rates of all AEs (except for cataracts) were at least doubled in patients receiving corticosteroid doses>20 mg/day compared with <=20 mg/day. The highest estimated mean total costs of an event (for the required treatment duration for one patient) were for avascular necrosis ($14,460) and serious infection ($11,660). The costs of more common AEs, such as osteoporosis, obesity, diabetes, and fractures, ranged from $1190 to $8220. Ten rheumatologists concluded that as disease severity increases, corticosteroid doses increased. Greater utilization of resources is needed to manage patients and corticosteroid related AEs. PMID- 24786784 TI - Synovitis with pitting edema as the presenting manifestation of systemic lupus erythematosus. AB - Rheumatologists are increasingly aware of the entity synovitis with pitting edema. The remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome has been reported with an array of conditions that include polymyalgia rheumatica, rheumatoid arthritis, Sjogren's syndrome and psoriatic arthropathy. Synovitis with pitting edema is now being increasingly recognized with systemic lupus erythematosus (SLE). We report a patient who presented with edema of hands and feet and was diagnosed eventually with definite SLE. With magnetic resonance imaging, joint effusions and tenosynovitis were confirmed to be associated with the otherwise-unexplained extremity edema. PMID- 24786785 TI - Serum free light chains, interferon-alpha, and interleukins in systemic lupus erythematosus. AB - OBJECTIVE: Interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-alpha (IFN alpha), and free light chains (FLCs: lambda, kappa) have all been noted to be of importance in systemic lupus erythematosus (SLE). Herein, we quantified and explored the relationship between these inflammatory mediators and disease activity in SLE; and stratified by their current anti-dsDNA antibody status. METHODS: Seventy-seven SLE patients underwent assessment of disease activity using the SLE disease activity index (SLEDAI). Serum FLC (lambda, kappa, and total), IL-6, IL-10, and IFN-alpha were quantified. Demographics of disease characteristics were determined by chart reviews. Statistical analyses included Mann-Whitney test, chi square, and linear regression analyses. RESULTS: Mean (SD) age of the patients was 44.9 +/- 12.7 years; SLEDAI (mean +/- SD) was 3.4 +/- 4.0. Serum lambda FLC levels had a moderate correlation (r = 0.46 with physician global assessment, 0.44 with SLEDAI) and the strongest correlation with disease activity as compared with other inflammatory mediators including current dsDNA antibody status. After adjusting for prednisone use, the correlation of lambda FLC with PGA (r = 0.48) and SLEDAI (r = 0.52) was better than of current dsDNA antibody status with PGA (r = 0.33) and adjusted SLEDAI (r = 0.24), respectively. IL-10 and IFN-alpha activity did not correlate with disease activity. Serum FLC and IL-6 levels could differentiate between active and inactive SLE patients. Serum lambda FLC and IL-6 levels differed significantly among patients with and without current dsDNA antibodies. Serum lambda FLC levels accounted for 31% of variance in SLEDAI scores. CONCLUSION: Serum FLC and IL-6 are potentially useful biomarkers of disease activity in SLE. Further studies, with larger study sample and longitudinal design, are indicated. PMID- 24786786 TI - Loss of the polycomb mark from bivalent promoters leads to activation of cancer promoting genes in colorectal tumors. AB - In colon tumors, the transcription of many genes becomes deregulated by poorly defined epigenetic mechanisms that have been studied mainly in established cell lines. In this study, we used frozen human colon tissues to analyze patterns of histone modification and DNA cytosine methylation in cancer and matched normal mucosa specimens. DNA methylation is strongly targeted to bivalent H3K4me3- and H3K27me3-associated promoters, which lose both histone marks and acquire DNA methylation. However, we found that loss of the Polycomb mark H3K27me3 from bivalent promoters was accompanied often by activation of genes associated with cancer progression, including numerous stem cell regulators, oncogenes, and proliferation-associated genes. Indeed, we found many of these same genes were also activated in patients with ulcerative colitis where chronic inflammation predisposes them to colon cancer. Based on our findings, we propose that a loss of Polycomb repression at bivalent genes combined with an ensuing selection for tumor-driving events plays a major role in cancer progression. PMID- 24786787 TI - Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. AB - The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGFbeta and IL10 production in these cells. TGFbeta and IL10 favored generation of T regulatory cells (Treg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. Depletion of CD8(+) T cells abolished this beneficial effect, suggesting that CD8(+) T cells were responsible for the effects of C5aR inhibition. In contrast to previous findings, we observed that C5aR signaling promoted Treg generation and suppressed T-cell responses in organs where metastases arose. Overall, our findings indicated that the immunomodulatory functions of C5aR are highly context dependent. Furthermore, they offered proof of-concept for complement-based immunotherapies to prevent or reduce cancer metastasis. PMID- 24786788 TI - Oncogenic protein MTBP interacts with MYC to promote tumorigenesis. AB - Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of Mdm2-binding protein (MTBP), a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared with MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer. PMID- 24786789 TI - Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase. AB - Glycolytic enzyme phosphoglycerate mutase (PGAM) plays an important role in coordinating energy production with generation of reducing power and the biosynthesis of nucleotide precursors and amino acids. Inhibition of PGAM by small RNAi or small molecule attenuates cell proliferation and tumor growth. PGAM activity is commonly upregulated in tumor cells, but how PGAM activity is regulated in vivo remains poorly understood. Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. Increased levels of reactive oxygen species stimulate PGAM2 deacetylation and activity by promoting its interaction with SIRT2. Substitution of endogenous PGAM2 with an acetylation mimetic mutant K100Q reduces cellular NADPH production and inhibits cell proliferation and tumor growth. These results reveal a mechanism of PGAM2 regulation and NADPH homeostasis in response to oxidative stress that impacts cell proliferation and tumor growth. PMID- 24786791 TI - Exploring contextual factors and patient activation: evidence from a nationally representative sample of patients with depression. AB - Patient activation has been considered as a "blockbuster drug of the century." Patients with mental disorders are less activated compared to patients with other chronic diseases. Low activation due to mental disorders can affect the efficiency of treatment of other comorbidities. Contextual factors are significantly associated with mental health care access and utilization. However, evidence of their association with patient activation is still lacking. Using data from the Health Tracking Household Survey 2007 and Area Health Resource File 2008, we examine the association between contextual factors and self-reported activation levels among patients with depression. We investigate two types of contextual factors--(a) site of usual source of care and (b) community characteristics, measured by mental health care resources availability, population demographics, and socioeconomic characteristics at the county level. Results show significant variation in activation levels by contextual factors. The availability of community mental health centers, lower proportion of foreign born individuals, and higher income in the local community are associated with higher patient activation. Our results also show that depressed patients having a usual source of care at a physician's office have significantly higher patient activation levels than those with a usual source of care in the emergency department or hospital outpatient clinics. Results suggest that primary care setting is critical to having a sustained relationship between patients and physicians in order to enhance patient engagement in mental health care. Interventions in communities with low income and high immigrant populations are necessary. PMID- 24786792 TI - Process evaluation of an intervention to increase provision of adolescent vaccines at school health centers. AB - BACKGROUND: Vaccination programs in school health centers (SHCs) may improve adolescent vaccine coverage. We conducted a process evaluation of an intervention to increase SHC-located vaccination to better understand the feasibility and challenges of such interventions. METHOD: Four SHCs participated in an intervention to increase provision of recommended vaccines to 2,975 adolescents. We reviewed program materials and SHC staff reports, and interviewed parents to assess implementation fidelity and reactions to materials. RESULTS: Ten percent of parents returned forms with consent to at least one vaccine. Of these, 79% checked the box consenting for "all recommended" vaccines, rather than indicating individual vaccines. SHCs sent supplemental mailings to some parents that clarified (a) vaccination costs or (b) human papillomavirus vaccine recommendation for boys and required parents to reconsent. This process resulted in loss of initial consent, primarily due to nonresponse. In interviews, parents who consented to vaccination indicated that intervention materials were clear and persuasive, but needed greater detail about costs and clinic processes. CONCLUSIONS: With limited additional investment, it appears feasible for SHCs to achieve a modest increase in the number of vaccinated adolescents. Providing a checkbox to indicate global consent for all recommended vaccinations, and close collaboration among individuals involved in intervention development, may facilitate vaccination efforts. PMID- 24786790 TI - Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. AB - Breast cancer stem-like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance, and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness, and tumorigenicity, defining it as a key target of miR200c, which is known to be a critical regulator in BCSC. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial-mesenchymal transition. Conversely, genetic or pharmacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR200c-resistant Pin1 rescued the BCSC defect in miR200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells, freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells freshly isolated from clinical samples inhibited the expansion, self-renewal activity, and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC. PMID- 24786793 TI - Colorectal cancer screening among Latinos in three communities on the Texas Mexico border. AB - OBJECTIVE: To assess colorectal cancer screening (CRCS) prevalence and psychosocial correlates of CRCS among Latinos in South Texas. METHOD: Using multivariable analyses, we examined the association of perceived susceptibility, self-efficacy, pros and cons, subjective norms, knowledge and fatalism on CRCS among 544 Latinos (50 years and older). RESULTS: In this socioeconomically disadvantaged population, 40% had never heard of any CRCS test, only 34% reported ever completing any type of CRCS, and only 25% were adherent to CRCS guidelines. Insurance status, gender, perceived cons, CRCS self-efficacy, and CRCS norms were significantly associated with CRCS. CONCLUSION: CRCS interventions in this population should focus on improving access, increasing self-efficacy and perceived norms, and decreasing negative perceptions of CRCS. PMID- 24786794 TI - Does concern motivate behavior change? Exploring the relationship between physical activity and body mass index among low-income housing residents. AB - OBJECTIVE: To explore relationships between concerns and physical activity and body mass index (BMI) among a racially/ethnically diverse low-income population. METHOD: A cross-sectional survey documented behavioral risks among racially/ethnically diverse low-income residents in the Boston area (2005-2009). Multivariable logistic regressions were conducted in 2012 for each concern, using SAS version 9.2. RESULTS: Those very/moderately concerned about weight were more likely to have higher BMIs, be in the preparation/action stage, received behavioral counseling, participated in a weight management program, and be interested in participating in one in the future. Those very/moderately concerned about physical activity were more likely to have higher BMIs, received behavioral counseling, and participated in a physical activity program. CONCLUSION: Individuals with elevated BMIs or low levels of physical activity are concerned. While level of concern is important, these findings suggest that it is not likely to be a sufficient catalyst to behavior change. PMID- 24786795 TI - Effectiveness of the surviving the Teens(r) suicide prevention and depression awareness program: an impact evaluation utilizing a comparison group. AB - Youth suicide is a serious public health issue in the United States. It is currently the third leading cause of death for youth aged 10 to 19. School-based prevention programs may be an effective method of educating youth and enhancing their help-seeking. Most school-based suicide prevention programs have not been rigorously evaluated for their effectiveness. This evaluation employs a comparison group to measure whether program group participants differed significantly from comparison group participants on pretest-posttest measures while assessing the immediate impact of the Surviving the Teens(r) Suicide Prevention and Depression Awareness Program. Findings indicate several positive outcomes in program group students' suicide and depression knowledge, attitudes, confidence, and behavioral intentions compared with the comparison group. Suicide prevention specialists and prevention planners may benefit from study findings. PMID- 24786796 TI - Re: "Body mass and weight change in adults in relation to mortality risk". PMID- 24786798 TI - Three authors reply. PMID- 24786797 TI - Overweight in early adulthood, adult weight change, and risk of type 2 diabetes, cardiovascular diseases, and certain cancers in men: a cohort study. AB - The relative importance of overweight after childhood and excess weight gain during adulthood remains unclear. In 39,909 male participants of the Health Professionals Follow-Up Study who were 40-75 years of age in 1986 and were followed until 2008, we documented 8,755 incident cases of obesity-related chronic diseases (type 2 diabetes mellitus, cardiovascular diseases, and colorectal, renal, pancreatic, and esophageal cancers). We calculated composite and cause-specific hazard ratios using a model that included body mass index (BMI; weight (kg)/height (m)(2)) at 21 years of age, weight change since age 21 years, smoking, alcohol consumption, and family histories of myocardial infarction, colon cancer, and diabetes. Compared with a BMI at 21 years of 18.5 22.9, the composite hazard ratio for a BMI of 23-24.9 was 1.22 (95% confidence interval (CI): 1.16, 1.29), that for a BMI of 25.0-27.4 was 1.57 (95% CI: 1.48, 1.67), that for a BMI of 27.5-29.9 was 2.40 (95% CI: 2.17, 2.65), and that for a BMI >=30.0 was 3.15 (95% CI: 2.76, 3.60). The composite hazard ratios for adult weight gain compared with a stable weight were 1.12 (95% CI: 1.03, 1.22) for a gain of 2.5-4.9 kg, 1.41 (95% CI: 1.31, 1.52) for a gain of 5-9.9 kg, 1.72 (95% CI: 1.59, 1.86) for a gain of 10-14.9 kg, and 2.45 (95% CI: 2.27, 2.63) for a gain >=15 kg. Adiposity in early adulthood and adult weight gain were both associated with marked increases in the risk of major chronic diseases in middle aged and older men, and these associations were already apparent at modest levels of overweight and weight gain. PMID- 24786799 TI - Loud noise exposure and acoustic neuroma. AB - The results from studies of loud noise exposure and acoustic neuroma are conflicting. A population-based case-control study of 451 acoustic neuroma patients and 710 age-, sex-, and region-matched controls was conducted in Sweden between 2002 and 2007. Occupational exposure was based on historical measurements of occupational noise (321 job titles summarized by a job exposure matrix) and compared with self-reported occupational noise exposure. We also evaluated self reported noise exposure during leisure activity. Conditional logistic regression was used to estimate odds ratios. There was no statistically significant association between acoustic neuroma and persistent occupational noise exposure, either with or without hearing protection. Exposure to loud noise from leisure activity without hearing protection was more common among acoustic neuroma cases (odds ratio = 1.47, 95% confidence interval: 1.06, 2.03). Statistically significant odds ratios were found for specific leisure activities including attending concerts/clubs/sporting events (odds ratio = 1.82, 95% confidence interval: 1.09, 3.04) and participating in workouts accompanied by loud music (odds ratio = 2.84, 95% confidence interval: 1.37, 5.89). Our findings do not support an association between occupational exposure to loud noise and acoustic neuroma. Although we report statistically significant associations between leisure-time exposures to loud noise without hearing protection and acoustic neuroma, especially among women, we cannot rule out recall bias as an alternative explanation. PMID- 24786800 TI - Identifying postelimination trends for the introduction and transmissibility of measles in the United States. AB - The continued elimination of measles requires accurate assessment of its epidemiology and a critical evaluation of how its incidence is changing with time. National surveillance of measles in the United States between 2001 and 2011 provides data on the number of measles introductions and the size of the resulting transmission chains. These data allow inference of the effective reproduction number, Reff, and the probability of an outbreak occurring. Our estimate of 0.52 (95% confidence interval: 0.44, 0.60) for Reff is smaller than prior results. Our findings are relatively insensitive to the possibility that as few as 75% of cases were detected. Although we confirm that measles remains eliminated, we identify an increasing trend in the number of measles cases with time. We show that this trend is likely attributable to an increase in the number of disease introductions rather than a change in the transmissibility of measles. However, we find that transmissibility may increase substantially if vaccine coverage drops by as little as 1%. Our general approach of characterizing the case burden of measles is applicable to the epidemiologic assessment of other weakly transmitting or vaccine-controlled pathogens that are either at risk of emerging or on the brink of elimination. PMID- 24786801 TI - Obstetric anaesthesia and peripartum management. AB - Anaesthetists play a key role in the management of parturients with cardiac disease. Pregnant women with cardiac disease should be seen antenatally in a high risk obstetric anaesthesia clinic, and a comprehensive management plan formulated. Most women with cardiac disease can have a vaginal delivery, and early epidural analgesia is frequently considered beneficial. No evidence exists to definitively support either regional or general anaesthesia for caesarean section, and much depends on the urgency of the procedure and the severity of disease. Women with the most severe forms of cardiac disease should be managed by a consultant anaesthetic team, with experience of both cardiac and obstetric anaesthesia. PMID- 24786802 TI - Abnormal white matter integrity related to head impact exposure in a season of high school varsity football. AB - The aim of this study was to determine whether the cumulative effects of head impacts from a season of high school football produce magnetic resonance imaging (MRI) measureable changes in the brain in the absence of clinically diagnosed concussion. Players from a local high school football team were instrumented with the Head Impact Telemetry System (HITSTM) during all practices and games. All players received pre- and postseason MRI, including diffusion tensor imaging (DTI). Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) was also conducted. Total impacts and risk-weighted cumulative exposure (RWE), including linear (RWELinear), rotational (RWERotational), and combined components (RWECP), were computed from the sensor data. Fractional, linear, planar, and spherical anisotropies (FA, CL, CP, and CS, respectively), as well as mean diffusivity (MD), were used to determine total number of abnormal white matter voxels defined as 2 standard deviations above or below the group mean. Delta (post-preseason) ImPACT scores for each individual were computed and compared to the DTI measures using Spearman's rank correlation coefficient. None of the players analyzed experienced clinical concussion (N=24). Regression analysis revealed a statistically significant linear relationship between RWECP and FA. Secondary analyses demonstrated additional statistically significant linear associations between RWE (RWECP and RWELinear) and all DTI measures. There was also a strong correlation between DTI measures and change in Verbal Memory subscore of the ImPACT. We demonstrate that a single season of football can produce brain MRI changes in the absence of clinical concussion. Similar brain MRI changes have been previously associated with mild traumatic brain injury. PMID- 24786803 TI - Single measurement of serum N-terminal pro-brain natriuretic peptide: the best predictor of long-term mortality in patients with chronic systolic heart failure. AB - BACKGROUND: Although high serum natriuretic peptide (NP) has long been associated with mortality prediction, it was usually tested under acute heart failure (HF) conditions and periods of analysis were short. This may explain the lack of consensus when its routine measurement for mortality prediction is contemplated. Here we evaluated, at the first clinic visit of chronic systolic HF patients, the usefulness of a single serum NP assessment for long-term mortality prediction. METHODS: In 279 consecutive patients with chronic systolic HF, serum NT-proBNP was routinely measured once during the first clinic visit. We analyzed correlations between recorded mortality and the NT-proBNP finding, along with several known clinical echocardiographic, electrocardiographic and laboratory parameters recorded at that visit. RESULTS: During average follow-up of 34+/ 21months 59 (21%) patients died. Serum NT-proBNP was the strongest of the tested predictors of mortality [hazard ratio 3.76, 95% Cl (1.20-11.80), p=0.008]. Nearly seven years later, mortality was still higher in patients with higher initial serum NT-proBNP (p<0.001). CONCLUSIONS: Compared to many other traditional prognostic parameters tested at the same time, the single serum NT-proBNP finding was the strongest predictor of long-term mortality. These results may justify its routine use for this purpose. PMID- 24786804 TI - Balancing act: optimal care in the real world. PMID- 24786805 TI - Critical care needs nurses with advanced degrees at the bedside. PMID- 24786808 TI - Adherence to institution-specific ventilator-associated pneumonia prevention guidelines. AB - BACKGROUND: Various institution-specific guidelines have been developed to prevent ventilator-associated pneumonia. However, the availability of guidelines does not ensure adherence to recommended strategies. OBJECTIVE: To identify factors that influence adherence to guidelines for prevention of ventilator associated pneumonia, with a focus on oral hygiene, head-of-bed elevation, and spontaneous breathing trials. METHODS: A cross-sectional descriptive study of critical care nurses at 8 hospitals in Northern California was conducted. A survey was created to gather information on possible facilitators of and barriers to adherence to institution-specific guidelines for preventing ventilator associated pneumonia. User factors, guideline qualities, and contextual factors were explored and tested for possible relationships. RESULTS: A total of 576 critical care nurses participated in the survey. Each hospital had unique guidelines for preventing ventilator-associated pneumonia. In general, nurses had positive attitudes and reported adhering to the guidelines always or most of the time. Factors associated with adherence differed according to the intervention implemented. The score on the user attitude scale was the strongest and most consistent predictor of adherence across interventions (odds ratio, 3.49-4.75). Time availability (odds ratio, 1.54) and the level of prioritization (odds ratio, 1.86) were also significant predictors. CONCLUSION: The most consistent facilitator of adherence to guidelines for prevention of ventilator-associated pneumonia was nurses' positive attitude toward the guidelines. PMID- 24786807 TI - Comparison of airway management practices between registered nurses and respiratory care practitioners. AB - BACKGROUND: Airway management, an essential component of care for patients receiving mechanical ventilation, is multifaceted and includes oral hygiene and suctioning, endotracheal suctioning, and care of endotracheal tubes. Registered nurses and respiratory care personnel often share responsibilities for airway management. Knowledge of current practices can help facilitate evidence-based practices to optimize care of patients receiving mechanical ventilation. OBJECTIVES: To describe current practices for airway management of intubated patients and determine if practices differ between registered nurses and respiratory care practitioners. METHODS: A descriptive, comparative design was used. Registered nurses and respiratory care practitioners who provided direct care to intubated patients receiving mechanical ventilation were recruited to complete an online survey of self-reported practices. RESULTS: A total of 85 participants completed the survey. Most were experienced caregivers with a bachelor's degree and certification or registration in their field. Selected practices have improved, including increasing oxygen saturation before endotracheal suctioning, maintaining pressure of endotracheal tube cuffs, and providing oral hygiene and suctioning. The practices of registered nurses and respiratory care practitioners differed in many ways. The nurses assumed responsibility for oral antisepsis, whereas the respiratory care practitioners managed the endotracheal tube. The 2 groups shared responsibility for oral and endotracheal suctioning. Knowledge of current guidelines for endotracheal suctioning was lacking. CONCLUSIONS: Practices in airway management have improved, but opportunities exist to develop shared policies and procedures based on current evidence. PMID- 24786809 TI - Discovery of unexpected pain in intubated and sedated patients. AB - BACKGROUND: The perceptions of patients who are restrained and sedated while being treated with mechanical ventilation in the intensive care unit are not well understood. The effectiveness of sedation used to aid in recovery and enhance comfort during intubation is unknown. OBJECTIVE: To explore the perceptions of patients who were intubated and receiving pain medication while sedated and restrained in the intensive care unit, in particular, their experience and their memories of the experience. METHODS: In a phenomenological study, 14 patients who were intubated and receiving pain medication while sedated and restrained were interviewed at the bedside. A semistructured interview guide was used. Data were analyzed by using an inductive method consistent with qualitative research. RESULTS: Three major themes were identified from the data: lack of memory of being restrained; a perception of being intubated as horrific; nursing behaviors that were helpful and comforting. An unexpected discovery was that sedation may be interfering with pain assessment and management. CONCLUSION: Being intubated can be painful and traumatic despite administration of sedatives and analgesics. Sedation may mask uncontrolled pain for intubated patients and prevent them from communicating this condition to a nurse. Nurses may need to evaluate current interventions in order to provide maximum comfort and promote optimal positive outcomes for intensive care patients who are intubated. PMID- 24786810 TI - Barriers to calling for urgent assistance despite a comprehensive pediatric rapid response system. AB - BACKGROUND: Rapid response systems (RRSs) aim to identify and rescue hospitalized patients whose condition is deteriorating before respiratory or cardiac arrest occurs. Previous studies of RRS implementation have shown variable effectiveness, which may be attributable in part to barriers preventing staff from activating the system. OBJECTIVE: To proactively identify barriers to calling for urgent assistance that exist despite recent implementation of a comprehensive RRS in a children's hospital. METHODS: Qualitative study using open-ended, semistructured interviews of 27 nurses and 30 physicians caring for patients in general medical and surgical care areas. RESULTS: The following themes emerged: (1) Self-efficacy in recognizing deteriorating conditions and activating the medical emergency team (MET) were considered strong determinants of whether care would be appropriately escalated for children in a deteriorating condition. (2) Intraprofessional and interprofessional hierarchies were sometimes challenging to navigate and led to delays in care for patients whose condition was deteriorating. (3) Expectations of adverse interpersonal or clinical outcomes from MET activations and intensive care unit transfers could strongly shape escalation-of-care behavior (eg, reluctance among subspecialty attending physicians to transfer patients to the intensive care unit for fear of inappropriate management). CONCLUSIONS: The results of this study provide an in-depth description of the barriers that may limit RRS effectiveness. By recognizing and addressing these barriers, hospital leaders may be able to improve the RRS safety culture and thus enhance the impact of the RRS on rates of cardiac arrest, respiratory arrest, and mortality outside the intensive care unit. PMID- 24786812 TI - Collaborative practice and patient safety. PMID- 24786811 TI - Delivering interprofessional care in intensive care: a scoping review of ethnographic studies. AB - BACKGROUND: The sustained clinical and policy interest in the United States and worldwide in quality and safety activities initiated by the release of To Err Is Human has resulted in some high-profile successes and much disappointment. Despite the energy and good intentions poured into developing new protocols and redesigning technical systems, successes have been few and far between, leading some to argue that more attention should be given to the context of care. OBJECTIVE: To examine the insights provided by qualitative studies of interprofessional care delivery in intensive care. METHODS: A total of 532 article abstracts were reviewed. Of these, 24 met the inclusion criteria. RESULTS: Articles focused on the nurse-physician relationship, patient safety, patients' families and end-of-life care, and learning and cognition. The findings indicated the complexities and nuances of interprofessional life in intensive care and also that much needs to be learned about team processes. CONCLUSION: The fundamental insight that interprofessional interactions in intensive care do not happen in a historical, social, and technological vacuum must be brought to bear on future research in intensive care if patient safety and quality of care are to be improved. PMID- 24786813 TI - Effectiveness of an electromagnetic feeding tube placement device in detecting inadvertent respiratory placement. AB - BACKGROUND: Use of technology capable of electromagnetically tracking advancement of a feeding tube on a monitoring screen during insertion may enable detection of deviation of the tube from the midline as it advances through the chest, possibly indicating entry of the tube into the right or left main bronchus. PURPOSES: To describe (1) published peer-reviewed studies that report on the detection of malpositioned tubes inserted by an electromagnetic tube placement device, and (2) events reported to the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database regarding use of such a device. METHODS: An Ovid MEDLINE search was conducted to locate peer-reviewed studies published between 2007 and 2012 that referred to use of an electromagnetic tube placement device to detect inadvertent respiratory placements of feeding tubes. In addition, an online search of the MAUDE database was conducted for the years 2007 through 2012. RESULTS: The Ovid MEDLINE search yielded 6 studies that referred to respiratory placements; no cases of pneumothorax were reported. The MAUDE database search yielded 21 adverse events associated with use of an electromagnetic tube placement device (including 17 cases of pneumothorax and 2 deaths). As the MAUDE database relies on voluntary reports, this number should not be construed as the incidence of malpositioned tubes during this period. CONCLUSIONS: The ability of clinicians to place feeding tubes correctly by using an electromagnetic tube placement device varies. Thus, it is reasonable to question the wisdom of eliminating radiographic confirmation of tube position before starting feedings. PMID- 24786814 TI - Glycemic control in cardiac surgery: implementing an evidence-based insulin infusion protocol. AB - BACKGROUND: Acute hyperglycemia following cardiac surgery increases the risk of deep sternal wound infection, significant early morbidity, and mortality. Insulin infusion protocols that target tight glycemic control to treat hyperglycemia have been linked to hypoglycemia and increased mortality. Recently published studies examining glycemic control in critical illness and clinical practice guidelines from professional organizations support moderate glycemic control. OBJECTIVES: To measure critical care nurses' knowledge of glycemic control in cardiac surgery before and after education. To evaluate the safety and effectiveness of an evidence-based insulin infusion protocol targeting moderate glycemic control in cardiac surgery patients. METHODS: This evidence-based practice change was implemented in the cardiovascular unit in a community teaching hospital. Nurses completed a self-developed questionnaire to measure knowledge of glycemic control. Blood glucose data, collected (retrospectively) from anesthesia end time through 11:59 PM on postoperative day 2, were compared from 2 months before to 2 months after the practice change. RESULTS: Nurses' knowledge (test scores) increased significantly after education (pretest mean = 53.10, SD = 11.75; posttest mean = 79.10, SD = 12.02; t54 = -8.18, P < .001). Mean blood glucose level after implementation was 148 mg/dL. The incidence of hypoglycemia, 2.09% before and 0.22% after the intervention, was significantly reduced ( $${?hbox{ ?chi }}_{1}^{2}$$ [n = 29] = 13.9, P < .001). The percentage of blood glucose levels less than 180 mg/dL was 88.30%. CONCLUSIONS: Increasing nurses' knowledge of glycemic control and implementing an insulin infusion protocol targeting moderate glycemic control were effective for treating acute hyperglycemia following cardiac surgery with decreased incidence of hypoglycemia. PMID- 24786815 TI - Brain death: lessons from the McMath case. PMID- 24786816 TI - Brain death: what health professionals should know. PMID- 24786817 TI - Chest pain after acute illness. PMID- 24786818 TI - Pseudo-ventricular tachycardia mimicking malignant arrhythmia in a patient with rapid atrial fibrillation. AB - Artifacts can simulate arrhythmias such as atrial flutter, atrial fibrillation, and ventricular tachycardia. A case of pseudo-ventricular tachycardia is outlined in a patient with newly diagnosed atrial fibrillation, which made the diagnosis a special challenge. Characteristic signs of pseudo-ventricular tachycardia are described. This case reinforces the importance of recognizing artifacts to avoid unnecessary interventions, especially in the telemetry and critical care units. PMID- 24786821 TI - Solution-processed white organic light-emitting diodes with enhanced efficiency by using quaternary ammonium salt doped conjugated polyelectrolyte. AB - Solution-processed white organic light emitting diodes (WOLEDs) with quaternary ammonium salt doped water/alcohol soluble conjugated polyelectrolyte, poly[(9,9 bis(3'-((N,N-dimethyl)-N-ethylammonium)-propyl)-2,7-fluorene)-alt-2,7-(9,9 dioctylfluoren)] dibromide (PFNBr), as electron transport material has been fabricated. Compared with the undoped devices, the performances of such devices with a doped electron transport layer have been dramatically improved to be nearly twice high in luminous efficiency and nearly one-third in response time when the weight ratio of PFNBr to tetraethylammonium bromide (TEAB) was 10:3. Four kinds of quaternary ammonium salts have been investigated to be dopants in the conjugated polyelectrolyte electron transport layer. It has been shown that both the anions and the cations of quaternary ammonium salts can influence the device performance. The dopant who has both a smaller anion and a smaller cation size can exhibit a better device performance. In addition, ultraviolet photoelectron spectroscopy measurement and single-carrier device testing have been employed to investigate the reason why such quaternary ammonium salt dopants can make an obvious improvement in the device performance of WOLEDs. These findings will be beneficial to the progress in design and fabrication of solution processed WOLEDs suitable for lighting. PMID- 24786820 TI - Attitudes and practices related to clinical alarms. AB - BACKGROUND: The number of devices with alarms has multiplied in recent years, causing alarm fatigue in bedside clinicians. Alarm fatigue is now recognized as a critical safety issue. OBJECTIVE: To determine if attitudes and practices related to clinical alarms have changed since 2005. METHODS: The Healthcare Technology Foundation's Clinical Alarms Committee developed an online survey for hospital personnel that addressed attitudes and practices related to clinical alarms. They administered it in 2005-2006 and in 2011 and compared the results. RESULTS: Respondents were asked about their level of agreement with 19 statements about alarms. Many of the statements revealed no significant differences between the 2 survey years, although some differences were apparent. Respondents to the 2011 survey were significantly more likely to agree with statements about alarm sounds differentiating the priority of alarm and the helpfulness of central alarm management. Respondents in 2011 were significantly less likely to feel that nuisance alarms occur frequently and disrupt patient care. Respondents also ranked the importance of 9 different alarm issues. In both years, they ranked frequent false alarms as the most important. In response to a new question in the 2011 survey, 18% of respondents reported patients' experiencing adverse events related to alarms at their institutions. CONCLUSIONS: Since 2005-2006 when the first survey was conducted, not much has changed. False alarms continue to contribute to a noisy hospital environment, and sentinel events related to alarm fatigue persist. Alarm hazards are a significant patient safety issue. PMID- 24786822 TI - Push-pull effects of three plant secondary metabolites on oviposition of the potato tuber moth, Phthorimaea operculella. AB - The push-pull effects of three plant secondary metabolites, azadirachtin, eucalyptol, and heptanal, on the oviposition choices of potato tubers by the potato tuber moth, Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae) were tested in the laboratory. Azadirachtin at concentrations from 1.5 to 12 mg/L had a significant repellent effect on oviposition. Eucalyptol at concentrations from 3 to 12 mg/L promoted oviposition. Heptanal promoted oviposition at low concentrations from 0.1875 to 3.0 mg/L but repelled it at higher concentrations from 12 to 24 mg/L. The combination of azadirachtin (12 mg/L) with eucalyptol (3.0 mg/L) resulted in a significant pushpull effect of 56.3% on oviposition. The average maximum push-pull effects occurred with the combinations of azadirachtin with heptanal (12 and 0.375 mg/L, respectively; 38.7% push-pull effect), heptanal with eucalyptol (12 and 6 mg/L, respectively; 31.4% push-pull effect), and heptanal (high concentration) with heptanal (low concentration) (12.0 and 0.375 mg/L, respectively; 25% push-pull effect). PMID- 24786823 TI - Discovery and characterization of RecA protein of thermophilic bacterium Thermus thermophilus MAT72 phage Tt72 that increases specificity of a PCR-based DNA amplification. AB - The recA gene of newly discovered Thermus thermophilus MAT72 phage Tt72 (Myoviridae) was cloned and overexpressed in Escherichia coli. The 1020-bp gene codes for a 339-amino-acid polypeptide with an Mr of 38,155 which shows 38.7% positional identity to the E. coli RecA protein. When expressed in E. coli, the Tt72 recA gene did not confer the ability to complement the ultraviolet light (254nm) sensitivity of an E. coli recA mutant. Tt72 RecA protein has been purified with good yield to catalytic and electrophoretic homogeneity using a three-step chromatography procedure. Biochemical characterization indicated that the protein can pair and promote ATP-dependent strand exchange reaction resulting in formation of a heteroduplex DNA at 60 degrees C under conditions otherwise optimal for E. coli RecA. When the Tt72 RecA protein was included in a standard PCR-based DNA amplification reaction, the specificity of the PCR assays was significantly improved by eliminating non-specific products. PMID- 24786824 TI - Directed evolution of stereoselective enzymes based on genetic selection as opposed to screening systems. AB - Directed evolution of stereoselective enzymes provides a means to generate useful biocatalysts for asymmetric transformations in organic chemistry and biotechnology. Almost all of the numerous examples reported in the literature utilize high-throughput screening systems based on suitable analytical techniques. Since the screening step is the bottleneck of the overall procedure, researchers have considered the use of genetic selection systems as an alternative to screening. In principle, selection would be the most elegant and efficient approach because it is based on growth advantage of host cells harboring stereoselective mutants, but devising such selection systems is very challenging. They must be designed so that the host organism profits from the presence of an enantioselective variant. Progress in this intriguing research area is summarized in this review, which also includes some examples of display systems designed for enantioselectivity as assayed by fluorescence-activated cell sorting (FACS). Although the combination of display systems and FACS is a powerful approach, we also envision innovative ideas combining metabolic engineering and genetic selection systems with protein directed evolution for the development of highly selective and efficient biocatalysts. PMID- 24786825 TI - Application of a phosphite dehydrogenase gene as a novel dominant selection marker for yeasts. AB - The use of antibiotic resistance markers in the commercial application of genetically modified microorganisms is limited due to restrictions on the release of antibiotics and their resistance genes to the environment. To avoid contamination by other microorganisms, the development of a dominant selection marker with low environmental risks is still needed. Here we demonstrated a new selection system for Schizosaccharomyces pombe and Saccharomyces cerevisiae using a bacterial phosphite dehydrogenase gene (ptxD). A Sz. pombe transformant carrying ptxD under a strong promoter or on a multicopy plasmid grew on a minimal medium containing phosphite (Pt) as a sole source of phosphorus. To adapt this system to S. cerevisiae strains, codon optimization of ptxD was necessary. The codon-optimized ptxD system appeared effective in not only laboratorial but also industrial S. cerevisiae strains that are diploid or polyploid. Since Pt is a safe and inexpensive chemical, ptxD could be used as a novel dominant selection marker applicable on an industrial scale. PMID- 24786826 TI - Origin of contact line forces during the retraction of dilute polymer solution drops. AB - The forced dewetting of water and dilute poly(ethylene oxide) solution (PEO) drops is investigated for syringe-driven flow. Comparisons are made with the free dewetting observed during drop impact. We provide strong evidence that during droplet retraction, polymer deposited on the substrate results in a velocity dependent force at the contact line. These findings are in stark contrast to previous studies which attributed dissipation to bulk viscoelastic effects or normal stress effects at the contact line. PMID- 24786827 TI - ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation. AB - Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt -748 to -585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients. PMID- 24786828 TI - The TORC1 inhibitors Nprl2 and Nprl3 mediate an adaptive response to amino-acid starvation in Drosophila. AB - Target of rapamycin complex 1 (TORC1) is a master regulator of metabolism in eukaryotes that integrates information from multiple upstream signaling pathways. In yeast, the Nitrogen permease regulators 2 and 3 (Npr2 and Npr3) mediate an essential response to amino-acid limitation upstream of TORC1. In mammals, the Npr2 ortholog, Nprl2, is a putative tumor suppressor gene that inhibits cell growth and enhances sensitivity to numerous anticancer drugs including cisplatin. However, the precise role of Nprl2 and Nprl3 in the regulation of metabolism in metazoans remains poorly defined. Here we demonstrate that the central importance of Nprl2 and Nprl3 in the response to amino-acid starvation has been conserved from single celled to multicellular animals. We find that in Drosophila Nprl2 and Nprl3 physically interact and are targeted to lysosomes and autolysosomes. Using oogenesis as a model system, we show that Nprl2 and Nprl3 inhibit TORC1 signaling in the female germline in response to amino-acid starvation. Moreover, the inhibition TORC1 by Nprl2/3 is critical to the preservation of female fertility during times of protein scarcity. In young egg chambers the failure to downregulate TORC1 in response to amino-acid limitation triggers apoptosis. Thus, our data suggest the presence of a metabolic checkpoint that initiates a cell death program when TORC1 activity remains inappropriately high during periods of amino-acid and/or nutrient scarcity in oogenesis. Finally, we demonstrate that Nprl2/3 work in concert with the TORC1 inhibitors Tsc1/2 to fine tune TORC1 activity during oogenesis and that Tsc1 is a critical downstream effector of Akt1 in the female germline. PMID- 24786829 TI - PKClambda/iota signaling promotes triple-negative breast cancer growth and metastasis. AB - Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2 directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKClambda/iota, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKClambda/iota signaling as a potential therapeutic target for TNBC. Our observations indicated that PKClambda/iota signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKClambda/iota expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKClambda/iota significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKClambda/iota-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFbeta and IL1beta could activate PKClambda/iota signaling in TNBC cells and depletion of PKClambda/iota impairs NF-kappaB p65 (RelA) nuclear localization. We observed that cytokine-PKClambda/iota-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKClambda/iota promote TNBC growth, invasion and metastasis. Thus, targeting PKClambda/iota signaling could be a therapeutic option for breast cancer, including the TNBC subtype. PMID- 24786830 TI - The plant metacaspase AtMC1 in pathogen-triggered programmed cell death and aging: functional linkage with autophagy. AB - Autophagy is a major nutrient recycling mechanism in plants. However, its functional connection with programmed cell death (PCD) is a topic of active debate and remains not well understood. Our previous studies established the plant metacaspase AtMC1 as a positive regulator of pathogen-triggered PCD. Here, we explored the linkage between plant autophagy and AtMC1 function in the context of pathogen-triggered PCD and aging. We observed that autophagy acts as a positive regulator of pathogen-triggered PCD in a parallel pathway to AtMC1. In addition, we unveiled an additional, pro-survival homeostatic function of AtMC1 in aging plants that acts in parallel to a similar pro-survival function of autophagy. This novel pro-survival role of AtMC1 may be functionally related to its prodomain-mediated aggregate localization and potential clearance, in agreement with recent findings using the single budding yeast metacaspase YCA1. We propose a unifying model whereby autophagy and AtMC1 are part of parallel pathways, both positively regulating HR cell death in young plants, when these functions are not masked by the cumulative stresses of aging, and negatively regulating senescence in older plants. PMID- 24786831 TI - Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53 mediated DNA damage response. AB - Proline-, glutamic acid- and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or gamma-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression. PMID- 24786832 TI - JunB protects beta-cells from lipotoxicity via the XBP1-AKT pathway. AB - Diets rich in saturated fats may contribute to the loss of pancreatic beta-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes beta-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated beta-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to beta-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient beta-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPdelta during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic beta-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to beta-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to beta-cell apoptosis. In conclusion, JunB modulates the beta-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic beta cell death. These findings elucidate novel beta-cell-protective signal transduction in type 2 diabetes. PMID- 24786833 TI - Ubiquitination by SAG regulates macrophage survival/death and immune response during infection. AB - The checkpoint between the life and death of macrophages is crucial for the host's frontline immune defense during acute phase infection. However, the mechanism as to how the immune cell equilibrates between apoptosis and immune response is unclear. Using in vitro and ex vivo approaches, we showed that macrophage survival is synchronized by SAG (sensitive to apoptosis gene), which is a key member of the ubiquitin-proteasome system (UPS). When challenged by pathogen-associated molecular patterns (PAMPs), we observed a reciprocal expression profile of pro- and antiapoptotic factors in macrophages. However, SAG knockdown disrupted this balance. Further analysis revealed that ubiquitination of Bax and SARM (sterile alpha- and HEAT/armadillo-motif-containing protein) by SAG-UPS confers survival advantage to infected macrophages. SAG knockdown caused the accumulation of proapoptotic Bax and SARM, imbalance of Bcl-2/Bax in the mitochondria, induction of cytosolic cytochrome c and activation of caspase-9 and -3, all of which led to disequilibrium between life and death of macrophages. In contrast, SAG-overexpressing macrophages challenged with PAMPs exhibited upregulation of protumorigenic cytokines (IL-1beta, IL-6 and TNF-alpha), and downregulation of antitumorigenic cytokine (IL-12p40) and anti-inflammatory cytokine (IL-10). This suggests that SAG-dependent UPS is a key switch between immune defense and apoptosis or immune overactivation and tumorigenesis. Altogether, our results indicate that SAG-UPS facilitates a timely and appropriate level of immune response, prompting future development of potential immunomodulators of SAG-UPS. PMID- 24786835 TI - Changing our prior assumptions: adapting to new bayesian transplant center report cards. PMID- 24786834 TI - Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). AB - OBJECTIVE: Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on serum electrolytes were evaluated using pooled data from studies of patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Analyses were performed using two datasets, each including four placebo-controlled studies: Population 1 (N = 2215), patients with baseline estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m(2) (mean = 89.6 mL/min/1.73 m(2)) and Population 2 (N = 721), patients with baseline eGFR >=45 and <60 mL/min/1.73 m(2) (mean = 53.3 mL/min/1.73 m(2)). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651. MAIN OUTCOME MEASURES: Mean percent changes from baseline in serum electrolytes (potassium, sodium, magnesium, bicarbonate, phosphate, calcium) and outlier analyses were assessed in patients receiving canagliflozin 100 and 300 mg or placebo. Potassium changes were further evaluated based on baseline therapy with anti-hypertensive agents that interfere with potassium excretion (renin angiotensin aldosterone system-acting agents and/or potassium-sparing diuretics). RESULTS: Mean percent changes from baseline in potassium with canagliflozin 100 and 300 mg and placebo were 0.6%, 1.0%, and 0.5%, respectively (Week 26; Population 1); and 1.7%, 2.8%, and 0.7%, respectively (Week 18/26; Population 2). The proportion of patients who had potassium elevations meeting pre-defined outlier criteria (>5.4 mmol/L [5.4 mEq/L] and >15% increase from baseline) with canagliflozin 100 and 300 mg and placebo was 4.5%, 6.8%, and 4.7% (Population 1); and 5.2%, 9.1%, and 5.5% (Population 2). In both populations, potassium elevations were usually <6.5 mmol/L for patients treated with canagliflozin or placebo; elevations >=6.5 mmol/L were rare but more frequent in patients taking anti-hypertensive agents that affect potassium excretion in both the canagliflozin and placebo groups. Small mean percent changes in sodium, bicarbonate, and calcium were seen across groups in both populations; small mean percent increases in magnesium and phosphate were seen with canagliflozin vs placebo, but without an increase in patients meeting outlier criteria. Adverse events related to changes in electrolytes were low across groups. CONCLUSIONS: In patients with T2DM, canagliflozin was generally associated with small mean percent changes in serum electrolytes. Infrequent episodes of potassium elevation occurred with canagliflozin 300 mg, but occurred more often in patients with reduced eGFR. PMID- 24786836 TI - Eating disorder risk and body dissatisfaction based on muscularity and body fat in male university students. AB - OBJECTIVE: To investigate the relationship between risk of eating disorders, body dissatisfaction, and perceptual attractiveness in male university students. PARTICIPANTS: Research was conducted January-April 2012 and involved 339 male and 441 female students. METHODS: Eating disorder risk was assessed with the Eating Attitudes Test (EAT) and body dissatisfaction and perceptual attractiveness determined with the Bodybuilder Image Grid (BIG). RESULTS: There was a positive correlation (r=.16, p<.01) between the EAT and fat dissatisfaction and a negative correlation (r=-.14, p<.05) for muscle dissatisfaction, 28% of the males had an EAT score indicating that they were at risk for an eating disorder. Males chose a significantly more muscular and leaner body type than what females chose to be attractive. CONCLUSION: College-aged males may be at risk for eating disorders based on distortions in their perceived ideal body image, both for fat and muscle. PMID- 24786837 TI - The colo-anal pull-through procedure. PMID- 24786838 TI - Mechanistic investigations on E-N bond-breaking and ring expansion for N heterocyclic carbene analogues containing the group 14 elements (E). AB - The potential-energy surfaces for the ring-expansion reactions (i)Pr N(CH)2N((i)Pr)E :(Rea-E) + SiH2Ph2 -> six-membered ring heterocyclcic product (E = C, Si, Ge, Sn, and Pb) and (i)Pr N(CH)2N((i)Pr)C :(Rea-C) + EH2Ph2 -> six membered ring heterocyclcic product are studied at the M06-2X/Def2-TZVP level of theory. These theoretical investigations suggest that for a given SiH2Ph2, the relative reactivity of Rea-E toward the ring-ring expansion reaction decreases as the atomic weight of the central atom E increases, that is, in the order Rea-C ? Rea-Si > Rea-Ge > Rea-Sn > Rea-Pb. However, for a given Rea-C, these theoretical observations demonstrate that the reactivity of the EH2Ph2 molecule that undergoes the ring-expansion reaction decreases in the order SiH2Ph2 ~ GeH2Ph2 ~ SnH2Ph2 > PbH2Ph2 ? CH2Ph2. This theoretical study indicates that both the electronic structure and steric effects play a crucial role in determining their reactivities. The model conclusions are consistent with available experimental findings. Furthermore, a valence bond state correlation diagram model can be used to rationalize the computational results. These results allow a number of predictions to be made. PMID- 24786839 TI - Diffusion tensor imaging reveals acute subcortical changes after mild blast induced traumatic brain injury. AB - Mild blast-induced traumatic brain injury (mbTBI) poses special diagnostic challenges due to its overlapping symptomatology with other neuropsychiatric conditions and the lack of objective outcome measures. Diffusion tensor imaging (DTI) can potentially provide clinically relevant information toward a differential diagnosis. In this study, we aimed to determine if single and repeated (5 total; administered on consecutive days) mild blast overpressure exposure results in detectable structural changes in the brain, especially in the hippocampus. Fixed rat brains were analyzed by ex vivo DTI at 2 h and 42 days after blast (or sham) exposure(s). An anatomy-based region of interest analysis revealed significant interactions in axial and radial diffusivity in a number of subcortical structures at 2 h only. Differences between single- and multiple injured rats were largely in the thalamus but not the hippocampus. Our findings demonstrate the value and the limitations of DTI in providing a better understanding of mbTBI pathobiology. PMID- 24786840 TI - Association of N-terminal pro-brain natriuretic peptide and hemodynamic parameters measured by impedance cardiography in patients with essential hypertension. AB - The aim of this study was to evaluate the association of NT-proBNP with clinical and hemodynamic assessment in 156 patients with arterial hypertension. NT-proBNP correlated positively with, i.e. age (r=0.310, p=0.00008), mean blood pressure (MBP; r=0.199, p=0.0136), Heather index (HI; r=0.375, p<0.00001) and negatively with thoracic fluid content (TFC; r=-0.300, p=0.0002). The patients with higher NT-proBNP were older (46.1 versus 40.6 years, p=0.001), with higher MBP (102.6 versus 98.5 mm Hg, p=0.0043), HI (14.54 versus 11.93 Ohm s2, p=0.009) and lower TFC (27.5 versus 29.4 1/kOhm, p=0.0032). The independent predictors of higher NT proBNP were: age, MBP and HI. PMID- 24786841 TI - A novel method to quantify and compare anatomical shape: application in cervix cancer radiotherapy. AB - Adaptive radiation therapy (ART) had been proposed to restore dosimetric deficiencies during treatment delivery. In this paper, we developed a technique of Geometric reLocation for analyzing anatomical OBjects' Evolution (GLOBE) for a numerical model of tumor evolution under radiation therapy and characterized geometric changes of the target using GLOBE. A total of 174 clinical target volumes (CTVs) obtained from 32 cervical cancer patients were analyzed. GLOBE consists of three main steps; step (1) deforming a 3D surface object to a sphere by parametric active contour (PAC), step (2) sampling a deformed PAC on 642 nodes of icosahedron geodesic dome for reference frame, and step (3) unfolding 3D data to 2D plane for convenient visualization and analysis. The performance was evaluated with respect to (1) convergence of deformation (iteration number and computation time) and (2) accuracy of deformation (residual deformation). Based on deformation vectors from planning CTV to weekly CTVs, target specific (TS) margins were calculated on each sampled node of GLOBE and the systematic (Sigma) and random (sigma) variations of the vectors were calculated. Population based anisotropic (PBA) margins were generated using van Herk's margin recipe. GLOBE successfully modeled 152 CTVs from 28 patients. Fast convergence was observed for most cases (137/152) with the iteration number of 65 +/- 74 (average +/- STD) and the computation time of 13.7 +/- 18.6 min. Residual deformation of PAC was 0.9 +/ 0.7 mm and more than 97% was less than 3 mm. Margin analysis showed random nature of TS-margin. As a consequence, PBA-margins perform similarly to ISO margins. For example, PBA-margins for 90% patients' coverage with 95% dose level is close to 13 mm ISO-margins in the aspect of target coverage and OAR sparing. GLOBE demonstrates a systematic analysis of tumor motion and deformation of patients with cervix cancer during radiation therapy and numerical modeling of PBA-margin on 642 locations of CTV surface. PMID- 24786843 TI - Photocurrent generation enhanced by charge delocalization over stacked perylenediimide chromophores assembled within DNA. AB - We now report the photocurrent generation and charge transfer dynamics of stacked perylenediimide (PDI) molecules within a pi-stack array of DNA. The cofacially stacked PDI dimer and trimer were found to strongly enhance the photocurrent generation compared to an isolated PDI monomer. Femtosecond time-resolved transient absorption experiments revealed that the excitation of the stacked PDI dimer and trimer provided the broad transient absorption band, which was attributed to the charge delocalization of a negative charge over the PDI chromophores. The lifetime of the charge delocalization of the PDI dimer and trimer (nearly 1 ns) was much longer than that of the charge separated state of the PDI monomer. A comparison between the photocurrent measurements and time resolved transient absorption measurements demonstrated that the cofacially stacked structure could possibly lead to the charge delocalization and increase the lifetime of the charge-separated state that is essential to enhancing the photocurrent generation. PMID- 24786842 TI - Gestational weight gain and exposure of newborns to persistent organic pollutants. AB - BACKGROUND: Exposure to persistent organic pollutants (POPs) during fetal development can increase the risk of adverse health effects during childhood. Maternal characteristics and physiological changes during gestation, such as gestational weight gain (GWG), may have an influence in the overall burden of POPs in neonates. However, the associations between GWG and POP concentrations are still not well established. OBJECTIVE: We examined the association of GWG with cord serum POPs concentrations after adjusting for prepregnancy maternal body mass index (BMI) and other potential determinants of the transfer of POPs into newborns. The GWG values were evaluated after grouping by the reference guidelines of the Institute of Medicine (IOM). METHODS: We measured levels of 14 organochlorine pesticides, 7 polychlorobiphenyls (PCBs), and 14 polybrominated diphenyl ethers (PBDEs) in 325 cord serum samples from a Spanish birth cohort. Multivariable models were used to estimate associations of GWG, prepregnancy BMI, and other maternal determinants on cord serum concentrations of POPs. RESULTS: Neonatal concentrations of POPs were inversely associated with GWG after adjustment for age, prepregnancy BMI, educational level, and fish consumption. On average, neonates of women with IOM-recommended GWG have lower POP concentrations than do neonates of mothers with inadequate GWG. CONCLUSIONS: The present findings suggest an association between neonatal exposure to POPs and inadequate GWG during pregnancy. Encouraging pregnant women to meet the recommended IOM guidelines for GWG may reduce the accumulation of POPs in newborns. PMID- 24786844 TI - Fatty acids as a tool to understand microbial diversity and their role in food webs of Mediterranean temporary ponds. AB - Temporary Mediterranean ponds are complex ecosystems which support a high diversity of organisms that include heterotrophic microorganisms, algae, crustaceans, amphibians and higher plants, and have the potential to supply food and a resting place to migratory birds. The role of heterotrophs at the base of the food web in providing energy to the higher trophic levels was studied in temporary ponds in Central and Southern Portugal. The relative quantification of the hetero and autotrophic biomass at the base of the food web in each pond was derived from the polar fatty acid (PLFA) composition of seston through the application of the matrix factorization program CHEMTAX that used specific PLFA and their relative proportion as markers for e.g., classes of bacteria, algae and fungi. The species composition of the culturable microbial communities was identified through their fatty acid profiles. The biomass in the lower trophic level of some ponds presented an even proportion of auto to heterotrophic organisms whilst either bacteria or algae dominated in others. In a selected subset of ponds, the incorporation of bacterial fatty acids was observed to occur in potentially herbivorous zooplankton crustacean. Zooplankton consumed and incorporated bacterial fatty acids into their body tissues, including into their phospholipids, which indicates that energy of heterotrophic origin contributes to the aquatic food webs of temporary ponds. PMID- 24786845 TI - Non-conventional methodologies in the synthesis of 1-indanones. AB - 1-Indanones have been successfully prepared by means of three different non conventional techniques, namely microwaves, high-intensity ultrasound and a Q tubeTM reactor. A library of differently substituted 1-indanones has been prepared via one-pot intramolecular Friedel-Crafts acylation and their efficiency and "greenness" have been compared. PMID- 24786846 TI - miRNAs for the detection of multidrug resistance: overview and perspectives. AB - The goal of the present paper is to establish and validate the link between cancer diagnosis and therapy by microRNAs detection. The induction in vitro of some specific microRNAs after treatment with MDR ligands has been outlined. Starting from the results obtained by in vitro induction of MDCK and MDCK-MDR1 cells treated by a MDR1 ligand, a new scenario in the early diagnosis and chemotherapy could be disclosed. To corroborate this perspective a short overview on pancreatic cancer diagnosis and chemotherapeutic treatment has been reported. PMID- 24786847 TI - Effects of piperine on the intestinal permeability and pharmacokinetics of linarin in rats. AB - Although linarin possesses diverse pharmacological activities, its poor oral bioavailability has been a concern for further development. The present study aimed to demonstrate the feasibility of improving the oral absorption of linarin in rats with a bioenhancer-piperine. First, the intestinal permeability of linarin in the presence and absence of verapamil or piperine was investigated using an in situ single-pass rat intestinal perfusion method. A significant increase in the Peff when co-perfused with verapamil or piperine indicated that piperine effectively inhibited P-glycoprotein mediated efflux of linarin. Then, the pharmacokinetic profiles of linarin in rats after oral administration of linarin (50 mg/kg) alone and in combination with piperine (20 mg/kg) were determined using a validated LC-MS/MS method. The results showed that piperine increased the plasma exposure (AUC) of linarin by 381% along with an increase in the Cmax by 346% and the Tmax from 0.05 h to 0.2 h. The present study revealed that piperine significantly enhanced the oral absorption of linarin in rats by inhibiting P-glycoprotein mediated cellular efflux during the intestinal absorption and likely simultaneously by inhibiting the metabolism of linarin. PMID- 24786848 TI - beta-asarone reverses chronic unpredictable mild stress-induced depression-like behavior and promotes hippocampal neurogenesis in rats. AB - In this study, we investigated the influence of beta-asarone, the major ingredient of Acorus tatarinowii Schott, on depressive-like behavior induced by the chronic unpredictable mild stresses (CUMS) paradigm and to clarify the underlying mechanisms. The results show that beta-asarone treatment partially reversed the CUMS-induced depression-like behaviors in both the forced swim and sucrose preference tests. The behavioral effects were associated with increased hippocampal neurogenesis indicated by bromodeoxyuridine (BrdU) immunoreactivity. beta-Asarone treatment significantly increased the expression of brain-derived neurotrophic factor (BDNF) at levels of transcription and translation. Moreover, CUMS caused significant reduction in ERK1/2 and CREB phosphorylation, both of which were partially attenuated by beta-asarone administration. It is important to note that beta-asarone treatment had no effect on total levels or phosphorylation state of any of the proteins examined in ERK1/2-CREB pathway in no stress rats, suggesting that beta-asarone acts in a stress-dependent manner to block ERK1/2-CREB signaling. We did not observe a complete reversal of depression like behaviors to control levels by beta-asarone. To our knowledge, the present study is the first to demonstrate that adult neurogenesis is involved in the antidepressant-like behavioral effects of beta-asarone, suggesting that beta asarone is a promising candidate for the treatment of depression. PMID- 24786849 TI - Chemical profile analysis and comparison of two versions of the classic TCM formula Danggui Buxue Tang by HPLC-DAD-ESI-IT-TOF-MSn. AB - Danggui Buxue Tang (DBT) is a Traditional Chinese Medicine (TCM) formula primarily used to treat symptoms associated with menopause in women. Usually, DBT is composed of one portion of Radix Angelicae Sinensis (RAS) and five portions of Radix Astragali (RA). Clinically, Radix Hedysari (RH) is sometimes used by TCM physicians to replace RA in DBT. In order to verity whether the chemical constituents of the DBT1 (RA:RAS = 5:1, w/w) and DBT2 (RH:RAS = 5:1, w/w) share similarities the chemical profiles of the two DBTs crude extracts and urine samples were analyzed and compared with the aid of HPLC-DAD-ESI-IT-TOF-MSn, which determines the total ion chromatogram (TIC) and multi-stage mass spectra (MSn). Then, the DBT1 and DBT2 were identified and compared on the basis of the TIC and the MSn. In the first experiment (with crude extracts), 69 compounds (C1-C69) were identified from the DBT1; 46 compounds (c1-c46) were identified from the DBT2. In the second experiment(with urine samples), 44 compounds (M1-M44) were identified from the urine samples of rats that had been administered DBT1, and 34 compounds (m1-m34) were identified from the urine samples of rats that had been administered DBT2. Identification and comparison of the chemical compositions were carried out between the DBT1 and DBT2 of the crude extracts and urine samples respectively. Our results showed that the two crude extracts of the DBTs have quite different chemical profiles. The reasons for their differences were that the special astragalosides in DBT1 and the isoflavonoid glycosides formed the malonic acid esters undergo single esterification and acetyl esters undergo acetylation in DBT1. In contrast, the urine from DBT1-treated rats strongly resembled that of DBT2-treated rats. These metabolites originate mainly from formononetin, calycosin and their related glycosides, and they were formed mainly by the metabolic process of reduction, deglycosylation, demethylation, hydrogenation and sulfation. The HPLC-DAD-ESI-IT-TOF-MSn method was successfully applied for the rapid chemical profiles evaluation of two DBTs and their related urine samples. PMID- 24786850 TI - The Roles of ACE Inhibitors in Lower Extremity Peripheral Artery Disease. AB - Peripheral artery disease (PAD) is an age-dependent atherosclerotic disorder associated with an increased prevalence of cardiovascular morbidity and mortality. Approximately 35% of patients with PAD complain of lower extremity claudication, which may worsen to impair daily function. ACE inhibitors may possess vasoactive properties that improve symptoms of claudication. We designed a meta-analysis to quantify the effectiveness of ACE inhibitors on walking capacities in patients with lower extremity PAD. We reviewed MEDLINE and Cochrane databases from 1966 to 2013, in addition to relevant bibliographies to obtain our clinical trials. From the original findings, 4 randomized, placebo-controlled, double-blind studies qualified for inclusion. Using a random-effects model, ACE inhibitors were associated with an increase of 126 m [95% confidence interval (CI), -95 to 346] (P = 0.264) in maximal walking distance and a rise in Ankle Brachial Index of 0.09 (95% CI, 0.024-0.205) (P = 0.12). However, pain-free walking distance was significantly increased by 86 m (95% CI, 13-156) (P = 0.021). Contradictions in study outcomes between more recent and earlier trials of ACE inhibitors in claudication impeded the interpretation of effectiveness. Early trials failed to demonstrate improvement in walking capacities, possibly because of omissions in patient enrollment criteria and inadequate sample size. Recent guidelines recommend consideration of ACE inhibitors in patients with PAD for cardioprotective effects. Although ACE inhibitors were well tolerated, vigilance for clinical predictors of renal arterial stenosis and renal instability after initiation will ensure safe administration in all patients with PAD. PMID- 24786851 TI - Thrombolysis for Right Atrial Thrombus-in-Transit in a Patient With Massive Pulmonary Embolism. AB - Right atrial thrombus is a rare entity frequently encountered in patients with pulmonary embolism. Although the existing guidelines do not offer a clear statement for the management of right atrial thrombus and pulmonary embolism, this condition is associated with worse outcomes. We present a case of a 79-year old patient presenting with signs suggestive of massive pulmonary embolism who was found to have a right atrial thrombus on transthoracic echocardiogram and was successfully treated with systemic thrombolysis. Despite the lack of data from randomized studies, right atrial thombi in transit should be considered a severe form of thromboembolic disease often requiring aggressive treatment, particularly in patients with severe right ventricular dysfunction. PMID- 24786852 TI - Using Caenorhabditis elegans as a Model for Obesity Pharmacology Development. AB - The Caenorhabditis elegans model is a rapid and inexpensive method to address pharmacologic questions. We describe the use of C. elegans to explore 2 pharmacologic questions concerning candidate antiobesity drugs and illustrate its potential usefulness in pharmacologic research: (1) to determine a ratio of betahistine-olanzapine that blocks the olanzapine-induced intestinal fat deposition (IFD) as detected by Nile red staining and (2) to identify the mechanism of action of a pharmaceutical candidate AB-101 that reduces IFD. Olanzapine (53 MUg/mL) increased the IFD (12.1 +/- 0.1%, P < 0.02), which was blocked by betahistine (763 MUg/mL, 39.3 +/- 0.01%, P < 0.05) in wild-type C. elegans (N2). AB-101 (1.0%) reduced the IFD in N2 (P < 0.05), increased the pharyngeal pumping rate (P < 0.05), and reversed the elevated IFD induced by protease inhibitors atazanavir and ritonavir (P < 0.05). AB-101 did not affect IFD in a ACS null mutant strain acs-4(ok2872) III/hT2[bli-4(e937) let-?(q782) qIs48](I;III) suggesting an involvement of the lipid oxidation pathway and an upregulation of CPT-1. Our studies suggest that C. elegans may be used as a resource in pharmacologic research. This article is intended to stimulate a greater appreciation of its value in the development of new pharmaceutical interventions. PMID- 24786854 TI - Photochemically colour-tuneable white fluorescence illuminants consisting of conjugated polymer nanospheres. AB - pi-Conjugated aromatic polymers have attracted much interest due to their semi conducting and luminescent properties, and are therefore regarded as promising materials for next-generation optoelectronic devices. Especially, it is considered as one of the indispensable steps for advanced function to control the optoelectronic properties by external stimuli. Herein, we show photochemically fluorescent colour-tuneable systems consisting of photoresponsive conjugated polymer nanospheres. We design and synthesize photoresponsive conjugated polymers with red, green and blue (RGB) fluorescence by introducing photoisomeric dithienylethene moieties in the side chains. A mixture of the red-, green- and blue-fluorescent polymer nanospheres exhibits photoswitchable white fluorescence between emission and quenching by irradiating external lights in both the nanosphere solution and film state. In addition, reversible change in fluorescent colour between white and RGB is also achieved by replacing a photoresponsive polymer with a non-photoresponsive analogue in the mixture. Thus, we successfully demonstrate 'photoresponsive polymer illuminant' systems bearing photochemically colour-tuneable white fluorescence. PMID- 24786853 TI - Stroke in a Young Woman as a Presenting Manifestation of Membranous Nephropathy. AB - Stroke is one of the most severe complications of nephrotic syndrome (NS), only a few cases have been reported in previous literature. Some of those cases are not clear about whether the stroke was purely caused by NS because they also had other risk factors for stroke, such as old age, hypertension. A recent study showed that serum albumin less than 2.8 g/dL is a risk factor for thromboembolic events (venous thromboembolic events). Anticoagulation is suggested for patients with NS with low albumin by KIDIGO guideline 2012. Here, we describe a case in which a young patient presented with stroke as an initial symptom of membranous nephropathy (MN). A 36-year-old woman with no medical history came to the emergency room for left side weakness. Computed tomography of head showed right middle cerebral artery infarct. She was healthy and had no history of hypertension or peripheral vascular disease. She was not taking any medication before admission and did not have any toxic habits. She had nephrotic range of proteinuria with no active sediment in urine analysis, serum albumin of 1.7 g/dL, normal renal function, elevated blood pressure on admission, and no signs of left ventricular hypertrophy. All coagulopathy workup was negative. The renal biopsy showed MN. She was started on Coumadin and treated with steroids and cyclophosphamide. Four months after the stroke, she still could not perform daily activity independently. This case illustrates that stroke can be an initial symptom of MN, and it is important we detect and anticoagulate this high-risk group of patients before their developing stroke. Urine analysis is an inexpensive screening tool for NS and should be considered as an initial workup for a young patient who presents with stroke. PMID- 24786855 TI - Fixed endothelial cells exhibit physiologically relevant nanomechanics of the cortical actin web. AB - It has been unknown whether cells retain their mechanical properties after fixation. Therefore, this study was designed to compare the stiffness properties of the cell cortex (the 50-100 nm thick zone below the plasma membrane) before and after fixation. Atomic force microscopy was used to acquire force indentation curves from which the nanomechanical cell properties were derived. Cells were pretreated with different concentrations of actin destabilizing agent cytochalasin D, which results in a gradual softening of the cell cortex. Then cells were studied 'alive' or 'fixed'. We show that the cortical stiffness of fixed endothelial cells still reports functional properties of the actin web qualitatively comparable to those of living cells. Myosin motor protein activity, tested by blebbistatin inhibition, can only be detected, in terms of cortical mechanics, in living but not in fixed cells. We conclude that fixation interferes with motor proteins while maintaining a functional cortical actin web. Thus, fixation of cells opens up the prospect of differentially studying the actions of cellular myosin and actin. PMID- 24786856 TI - Regioselective hydrothiolation of alkenes bearing heteroatoms with thiols catalyzed by palladium diacetate. AB - In sharp contrast to many examples of transition-metal-catalyzed hydrothiolation of alkynes, the corresponding catalytic addition of thiols to alkenes has remained undeveloped. However, a novel Pd-catalyzed addition of thiols to alkenes bearing a heteroatom, such as oxygen and nitrogen, is found to proceed under mild conditions to give the corresponding Markovnikov adducts, regioselectively, in good yields. PMID- 24786857 TI - Adolescents' sleep in low-stress and high-stress (exam) times: a prospective quasi-experiment. AB - This prospective quasi-experiment (N = 175; mean age = 15.14 years) investigates changes in adolescents' sleep from low-stress (regular school week) to high stress times (exam week), and examines the (moderating) role of chronic sleep reduction, baseline stress, and gender. Sleep was monitored over three consecutive weeks using actigraphy. Adolescents' sleep was more fragmented during the high-stress time than during the low-stress time, meaning that individuals slept more restless during stressful times. However, sleep efficiency, total sleep time, and sleep onset latency remained stable throughout the three consecutive weeks. High chronic sleep reduction was related to later bedtimes, later sleep start times, later sleep end times, later getting up times, and more time spent in bed. Furthermore, low chronic sleep reduction and high baseline stress levels were related to more fragmented sleep during stressful times. This study shows that stressful times can have negative effects on adolescents' sleep fragmentation, especially for adolescents with low chronic sleep reduction or high baseline stress levels. PMID- 24786858 TI - Beta-blocker usage and prostate cancer survival: a nested case-control study in the UK Clinical Practice Research Datalink cohort. AB - BACKGROUND: Recent laboratory and epidemiological evidence suggests that beta blockers could inhibit prostate cancer progression. METHODS: We investigated the effect of beta-blockers on prostate cancer-specific mortality in a cohort of prostate cancer patients. Prostate cancer patients diagnosed between 1998 and 2006 were identified from the UK Clinical Practice Research Database and confirmed by cancer registries. Patients were followed up to 2011 with deaths identified by the Office of National Statistics. A nested case-control analysis compared patients dying from prostate cancer (cases) with up to three controls alive at the time of their death, matched by age and year of diagnosis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. RESULTS: Post-diagnostic beta-blocker use was identified in 25% of 1184 prostate cancer-specific deaths and 26% of 3531 matched controls. There was little evidence (P=0.40) of a reduction in the risk of cancer-specific death in beta-blocker users compared with non-users (OR=0.94 95% CI 0.81, 1.09). Similar results were observed after adjustments for confounders, in analyses by beta-blocker frequency, duration, type and for all-cause mortality. CONCLUSIONS: Beta-blocker usage after diagnosis was not associated with cancer-specific or all cause mortality in prostate cancer patients in this large UK study. PMID- 24786859 TI - Longitudinal epigenetic drift in mice perinatally exposed to lead. AB - An understanding of the natural change in DNA methylation over time, defined as "epigenetic drift," will inform the study of environmental effects on the epigenome. This study investigates epigenetic drift in isogenic mice exposed perinatally to lead (Pb) acetate at four concentrations, 0 ppm (control), 2.1 ppm (low), 16 ppm (medium), and 32 ppm (high) prior to conception through weaning, then followed until 10 months of age. Absolute values of DNA methylation in a transposon-associated metastable locus, Cdk5-activator binding protein (Cabp(IAP)), and three imprinted loci (Igf2, Igf2r, and H19) were obtained from tail tissue in paired samples. DNA methylation levels in the controls increased over time at the imprinted Igf2 and Igf2r loci (both P = 0.0001), but not at the imprinted H19 locus or the Cabp(IAP) metastable epiallele. Pb exposure was associated with accelerated DNA hypermethylation in Cabp(IAP) (P = 0.0209) and moderated hypermethylation in Igf2r (P = 0.0447), and with marginally accelerated hypermethylation at H19 (P = 0.0847). In summary, the presence and magnitude of epigenetic drift was locus-dependent, and enhancement of drift was mediated by perinatal Pb exposure, in some, but not all, loci. PMID- 24786861 TI - Aortic valve morphology determines the presentation and surgical approach to acute type A aortic dissection. AB - BACKGROUND: Data on acute type A aortic dissection in patients with bicuspid aortic valve (BAV) syndrome are limited. This investigation evaluated the clinical details in patients with type A dissection stratified according to aortic valve morphology. METHODS: Between 1993 and 2013, 629 patients (median age 61 years [50; 73], 64% men) underwent surgical procedures for type A dissection. Forty-one patients with BAV were compared with 588 patients with tricuspid aortic valve (TAV). RESULTS: The BAV patients were younger (55 years [46; 67] vs 61 years [51; 73] years; p < 0.001), presented more frequently with moderate or severe aortic insufficiency (51% vs 34%; p = 0.039), cardiogenic shock (37 vs 21%; p = 0.029), and had larger ascending aorta diameters (5.5 cm [5.1; 6.4] vs 4.8 cm [4.4; 5.5] cm; p < 0.001). The BAV patients more frequently required aortic root replacement (81% vs 14%; p < 0.001). Total arch replacement was performed in 5% of the BAV patients and 4% of the TAV patients. In-hospital mortality (14.6% vs 13.1%; p = 1.0) and survival at 5, 10, and 15 years (56% +/- 8%, 46% +/- 10%, and 37% +/- 11% vs 68% +/- 2%, 49% +/- 3%, and 36% +/- 4%; log rank, p = 0.4) were similar in the BAV and TAV patients. Twenty (3%) TAV and no BAV patients underwent proximal reoperations (p = 0.6) at a median follow-up time of 4.1 years (range, 0.8 to 6.9 years). CONCLUSIONS: BAV patients experience dissection at a younger age and at a greater ascending aortic diameter. Extensive aortic root repair in BAV patients is not associated with higher in-hospital mortality and prevents the need for later proximal redo operation. PMID- 24786862 TI - The European Society of Cardiology Webinars. PMID- 24786860 TI - Fontan conversion: identifying the high-risk patient. AB - BACKGROUND: Patients with atriopulmonary Fontan tend to undergo conversion to total cavopulmonary connections secondary to arrhythmias or poor flow dynamics. However, the ideal candidate is unknown. METHODS: Between December 1994 and May 2011, 70 patients (40 males [57%]) underwent Fontan conversion. Median age was 23 years (range, 4 to 46 years). Excluded were 1.5 ventricle conversions. The most common diagnoses included tricuspid atresia in 34 patients (49%) and double-inlet left ventricle in 16 (23%). Atrial tachyarrhythmia was present in 62 patients (89%), 41 (59%) had atrioventricular valve (AVV) regurgitation, and 32 (46%) were in New York Heart Association class III or IV. Atriopulmonary Fontan was the original connection in 58 patients (83%), whereas the Bjork modification was performed in 8 (11%). RESULTS: Fontan was performed with an intraatrial conduit in 41 patients, an extracardiac conduit in 18, and a lateral tunnel in 11. Forty nine patients (70%) underwent concomitant arrhythmia operations. Early death occurred in 10 patients (14%). Multivariate analysis revealed age older than 27 years (p = 0.009), AVV regurgitation (p = 0.016), lack of arrhythmia operation (p = 0.04), and male sex (p = 0.02) were predictors of perioperative death. Mean follow-up was 5 years (maximum, 17 years). Overall survival at 1, 5, and 10 years was 81%, 70%, and 67%, respectively, and 84% of patients were in New York Heart Association class I or II. CONCLUSIONS: Proper selection of Fontan conversion candidates is critical. Concomitant arrhythmia operations may be associated with improved survival. Older age and AVV regurgitation increase the risk of poor outcome, and cardiac transplantation may be a better option. PMID- 24786863 TI - A clinical dilemma: pregnancy with asymptomatic elevated total serum bile acid levels. PMID- 24786864 TI - Virus discovery: are we scientists or genome collectors? AB - Some scientists now proclaim that future pandemics can be successfully forecasted, allowing the planning of useful intervention strategies for pandemic preparedness. We underline the fundamental importance of performing dedicated investigations when viruses are discovered, to guarantee public health authorities the availability of nonerroneous information about potential upcoming threats. PMID- 24786865 TI - Poplar PdC3H17 and PdC3H18 are direct targets of PdMYB3 and PdMYB21, and positively regulate secondary wall formation in Arabidopsis and poplar. AB - Wood biomass is mainly made of secondary cell walls, whose formation is controlled by a multilevel network. The tandem CCCH zinc finger (TZF) proteins involved in plant secondary wall formation are poorly understood. Two TZF genes, PdC3H17 and PdC3H18, were isolated from Populus deltoides and functionally characterized in Escherichia coli, tobacco, Arabidopsis and poplar. PdC3H17 and PdC3H18 are predominantly expressed in cells of developing wood, and the proteins they encode are targeted to cytoplasmic foci. Transcriptional activation assays showed that PdMYB2/3/20/21 individually activated the PdC3H17 and PdC3H18 promoters, but PdMYB3/21 were most significant. Electrophoretic mobility shift assays revealed that PdMYB3/21 bound directly to the PdC3H17/18 promoters. Overexpression of PdC3H17/18 in poplar increased secondary xylem width and secondary wall thickening in stems, whereas dominant repressors of them had the opposite effects on these traits. Similar alteration in secondary wall thickening was observed in their transgenic Arabidopsis plants. qRT-PCR results showed that PdC3H17/18 regulated the expression of cellulose, xylan and lignin biosynthetic genes, and several wood-associated MYB genes. These results demonstrate that PdC3H17 and PdC3H18 are the targets of PdMYB3 and PdMYB21 and are an additional two components in the regulatory network of secondary xylem formation in poplar. PMID- 24786866 TI - Narrowing with prematurity-what is the mechanism? PMID- 24786868 TI - Putting the glomerulus back together: per aspera ad astra ("a rough road leads to the stars"). PMID- 24786869 TI - SYMPLICITY: not all that simple. PMID- 24786870 TI - Onconephrology: the need and the emergence of a subspecialty in nephrology. PMID- 24786872 TI - ANO1: an additional key player in cyst growth. AB - Chloride secretion driven by calcium-dependent chloride channels has a major impact on cyst enlargement in polycystic kidney disease. Buchholz et al. studied the functional role of anoctamin 1 (ANO1), a recently identified calcium activated chloride channel, in kidney cyst growth, using principal-like cells forming cysts within a collagen matrix and an embryonic kidney cyst model. Their results support a potential role for this chloride channel in cyst generation. PMID- 24786873 TI - Special deLIVERy: podocyte injury promotes renal angiotensin II generation from liver-derived angiotensinogen. AB - The role of the circulating renin-angiotensin system (RAS) in regulating systemic blood pressure and sodium balance is well established. More recently, researchers have turned their focus to the local generation of angiotensin II (Ang II) in specific tissues. Matsusaka et al. revisit the renal RAS and provide evidence that liver-derived angiotensinogen (AGT) is a major determinant of renal Ang II levels in a model of podocyte injury. PMID- 24786874 TI - The heterogeneous mononuclear phagocyte system of the kidney. AB - The kidney has a diverse repertoire of cells that make up the mononuclear phagocyte system (MPS). Wu et al. identify a population of CD8alphaalpha+CD11c+MHC-II+ blood precursors that display dendritic cell-like characteristics in the glomeruli. These cells show increased recruitment in a rat anti-glomerular basement membrane glomerulonephritis model and were able to attenuate disease. This study highlights the importance of the MPS in kidney disease and the need to better understand it to develop immunotherapeutics translatable to the renal patient. PMID- 24786875 TI - The Ebf1 knockout mouse and glomerular maturation. AB - Mice deficient in the transcription factor early B-cell factor 1 (Ebf1) lack mature B lymphocytes but have additional phenotypes suggesting functions outside the hematopoietic system. Fretz et al. report that these mice also exhibit quantitative and qualitative developmental renal defects and develop progressive podocyte foot process effacement. The findings not only suggest that Ebf1 may be pivotal to the transcriptional podocyte network, but also illustrate the importance of distinguishing cell-autonomous and non-autonomous inputs to podocyte maturation and integrity. PMID- 24786876 TI - Donor kidney biopsies: pathology matters, and so does the pathologist. AB - Histologic scoring of pre-implantation biopsies of expanded-criteria donor (ECD) kidneys has proven useful for predicting post-implantation allograft performance and guiding transplant clinicians as to which kidneys to discard. However, there is considerable interobserver variability in scoring these biopsies, as well as disagreements between studies examining the value of different histologic parameters in predicting graft function. Azancot and co-workers demonstrate that these biopsies' prognostic value is highly dependent on their being examined by an experienced renal pathologist. PMID- 24786877 TI - Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better. AB - Atypical hemolytic uremic syndrome (HUS) secondary to anti-factor H autoantibodies has a poor prognosis. The study by Sinha et al. of a large cohort of Indian children makes a substantial contribution to improved management of this form of HUS by showing that standardized titration of anti-factor H autoantibodies is applicable worldwide and that early treatment initiation and guidance of maintenance treatment by autoantibody titer monitoring significantly improve outcomes. PMID- 24786878 TI - Fibroblast growth factor 23 and uremic vascular calcification: is it time to escalate from biomarker status to pathogenic agent? AB - Although epidemiologic associations have been informative, the elucidation of the role of fibroblast growth factor 23 (FGF23) in chronic kidney disease (CKD) requires testing with robust experimental models. Jimbo et al. used animal and cell-culture models to query whether FGF23 is a direct 'vasculotoxin.' We discuss the interpretation of their findings. At this juncture, much remains unanswered about the significance of FGF23 elevation in CKD. PMID- 24786879 TI - Update to hepatitis C review. PMID- 24786880 TI - The urinary metabolome of chronic kidney disease. PMID- 24786881 TI - The authors reply:. PMID- 24786882 TI - Acceptable mortality after living kidney donation. PMID- 24786883 TI - The importance of selecting controls in kidney donor outcome studies. PMID- 24786884 TI - The authors reply:. PMID- 24786885 TI - JC polyoma virus and kidney disease. PMID- 24786886 TI - The authors reply:. PMID- 24786887 TI - The Author's Reply:. PMID- 24786888 TI - A nephrologist's point of view on sodium-glucose linked transporter-2 inhibitors: not all that glitters is gold. PMID- 24786889 TI - Localized bladder amyloidosis mimicking bladder carcinoma. PMID- 24786890 TI - Emphysematous pyelonephritis: disappearing kidneys. PMID- 24786891 TI - The case: renal failure in a bodybuilder athlete. Diagnosis: Nephrocalcinosis secondary to exogenous vitamin D intoxication. PMID- 24786892 TI - Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection. AB - BACKGROUND & AIMS: Helicobacter pylori infection is a risk factor for gastric cancer. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in nontumorous gastric epithelium with H pylori infection. METHODS: We performed whole-exome sequencing of gastric tumors, noncancerous tissues with gastritis, and peripheral lymphocytes from 5 patients. We performed additional deep sequencing analyses of selected tumor-related genes using 34 gastritis mucosal samples from patients with or without gastric cancer. We also performed deep sequencing analyses of gastric mucosal tissues from mice that express transgenic human TP53 and constitutively express activation-induced cytidine deaminase (AICDA or AID) (human TP53 knock-in/AID-transgenic mice). RESULTS: Whole-exome sequencing revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep-sequencing analyses of tissues from regions of gastritis confirmed nonsynonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutations that accumulated in gastric mucosal tissues with H pylori-induced gastritis, as well as gastric tumors, were predominantly C:G>T:A transitions in GpCpX motifs-a marker of cytidine deamination induced by AID. Constitutive expression of AID in the gastric mucosa of mice led to mutations in the human TP53, at amino acid coding positions identical to those detected in human gastric cancers. CONCLUSIONS: Studies of gastric tumors and tissues from humans and mice indicate that somatic mutations accumulate in various genes in gastric mucosal tissues with H pylori infection. Increased cytidine deaminase activity in these tissues appears to promote the accumulation of these mutations and might promote gastric carcinogenesis in patients with H pylori infection. PMID- 24786893 TI - Cyclophilin inhibitors reduce phosphorylation of RNA-dependent protein kinase to restore expression of IFN-stimulated genes in HCV-infected cells. AB - BACKGROUND & AIMS: Cyclophilin inhibitors are being developed for treatment of hepatitis C virus (HCV) infection. They are believed to inhibit the HCV replication complex. We investigated whether cyclophilin inhibitors interact with interferon (IFN) signaling in cultured cells infected with HCV. METHODS: We used immunoblot assays to compare expression of IFN-stimulated genes (ISGs) and of components of IFN signaling in HCV-infected and uninfected cells. RESULTS: Incubation with IFN alfa induced expression of ISGs in noninfected cells and, to a lesser extent, in HCV-infected cells; addition of the cyclophilin inhibitor SCY 635 restored expression of ISG products in HCV-infected cells. SCY-635 reduced phosphorylation of double-strand RNA-dependent protein kinase (PKR) and its downstream factor eIF2alpha; the phosphorylated forms of these proteins are negative regulators of ISG translation. Cyclophilin A interacted physically with PKR; this interaction was disrupted by SCY-635. SCY-635 also suppressed PKR mediated formation of stress granules. Cyclophilin inhibitors were found to inhibit PKR phosphorylation and stress granule formation in HCV-infected and uninfected cells. CONCLUSIONS: In cultured cells, cyclophilin inhibitors reverse the attenuation of the IFN response by HCV, in addition to their effects on HCV replication complex. Cyclophilin A regulation of PKR has been proposed as a mechanism for observed effects of cyclophilin inhibitors on IFN signaling. We found that cyclophilin inhibitors reduce phosphorylation of PKR and eIF2alpha during HCV infection to allow for translation of ISG products. Proteins in this pathway might be developed as targets for treatment of HCV infection. PMID- 24786894 TI - Race, ethnicity, and sex affect risk for polyps >9 mm in average-risk individuals. AB - BACKGROUND & AIMS: Colorectal cancer risk differs based on patient demographics. We aimed to measure the prevalence of significant colorectal polyps in average risk individuals and to determine differences based on age, sex, race, or ethnicity. METHODS: In a prospective study, colonoscopy data were collected, using an endoscopic report generator, from 327,785 average-risk adults who underwent colorectal cancer screening at 84 gastrointestinal practice sites from 2000 to 2011. Demographic characteristics included age, sex, race, and ethnicity. The primary outcome was the presence of suspected malignancy or large polyp(s) >9 mm. The benchmark risk for age to initiate screening was based on white men, 50 54 years old. RESULTS: Risk of large polyps and tumors increased progressively in men and women with age. Women had lower risks than men in every age group, regardless of race. Blacks had higher risk than whites from ages 50 through 65 years and Hispanics had lower risk than whites from ages 50 through 80 years. The prevalence of large polyps was 6.2% in white men 50-54 years old. The risk was similar among the groups of white women 65-69 years old, black women 55-59 years old, black men 50-54 years old, Hispanic women 70-74 years old, and Hispanic men 55-59 years old. The risk of proximal large polyps increased with age, female sex, and black race. CONCLUSIONS: There are differences in the prevalence and location of large polyps and tumors in average-risk individuals based on age, sex, race, and ethnicity. These findings could be used to select ages at which specific groups should begin colorectal cancer screening. PMID- 24786895 TI - Xpert MTB/RIF as a measure of sputum bacillary burden. Variation by HIV status and immunosuppression. AB - RATIONALE: Xpert MTB/RIF cycle threshold values are a measure of sputum mycobacterial burden. Data on the impact of HIV infection and immunosuppression on this measure are limited. OBJECTIVES: Examine the impact of HIV status and level of immunosuppression on the distribution of mean cycle threshold values, and the correlation of cycle threshold values and smear microscopy grade with time to culture positivity. METHODS: Paired sputum samples from 2,406 individuals with suspected pulmonary tuberculosis in South Africa were tested by Xpert MTB/RIF, concentrated smear microscopy, and liquid culture to quantify bacterial burden using cycle threshold values, smear grading, and time to culture positivity. MEASUREMENTS AND MAIN RESULTS: Cycle threshold values were lower in HIV-uninfected versus HIV-infected individuals (22.9 vs. 26.6; P < 0.001). Among HIV-infected, CD4 count was an independent predictor of cycle threshold value, with an average increase of 1.50 cycles for CD4 count greater than or equal to 200 (P 0.071) and 3.66 cycles for CD4 count less than 200 (P < 0.001) compared with HIV-uninfected individuals. Correlation between cycle threshold value and time to culture positivity was similar to that between smear status and time to culture positivity (both Spearman rho 0.58). The strength of correlation between measures decreased as the level of immunosuppression increased. A cycle threshold value cutoff of 28 had good predictive value for smear positivity. CONCLUSIONS: We observed decreasing bacillary burden with increasing level of immunosuppression as measured by Xpert MTB/RIF cycle threshold values. A cycle threshold value of 28 can be used as a measure of bacterial burden and smear status in a high HIV burden setting. PMID- 24786896 TI - The cognitive psychology of Internet gaming disorder. AB - Internet gaming disorder (IGD) has received nomenclatural recognition as a potential mental health disorder, despite evident variability in its core psychopathology and psychometric assessment. Although cognitive-behavioural therapy (CBT) is considered an efficacious treatment for IGD, the underlying cognitions of the disorder are not well understood. This review aimed to synthesise research evidence on Internet gaming cognition toward identification of cognitive factors underlying IGD. A systematic review of 29 quantitative studies on Internet gaming cognition and 7 treatment studies employing cognitive therapy for IGD was conducted. Four cognitive factors underlying IGD were identified. Factors included (a) beliefs about game reward value and tangibility, (b) maladaptive and inflexible rules about gaming behaviour, (c) over-reliance on gaming to meet self-esteem needs, and (d) gaming as a method of gaining social acceptance. It is proposed that IGD-related cognition may be more complex than "preoccupation" (i.e., criterion A of IGD). IGD cognition may involve the persistent overvaluation of video gaming rewards, activities, and identities, combined with a need to adhere to maladaptive rules governing use and completion of video games. Greater understanding of the proposed cognitive factors may advance clinical research agendas on identification of individuals with IGD, as well as the expansion and improvement of cognitive therapies for the disorder. PMID- 24786897 TI - A meta-analytic review of psychodynamic therapies for anxiety disorders. AB - Recent randomized controlled trials (RCTs) suggest that psychodynamic therapy (PDT) may be useful in the treatment of anxiety disorders. This paper presents the most comprehensive meta-analysis to date examining the controlled effects of PDT for anxiety disorders. 14 RCTs totaling 1073 patients were included. PDT was found to be significantly more effective than control conditions (g=0.64). PDT did not differ significantly from alternative treatments at post-treatment (g=0.02), follow-up (FU) up to a year (g=-0.11), and FU past a year (g=-0.26). Medium-to-high levels of heterogeneity were detected, indicating significant differences between studies. Nevertheless, our findings remained unchanged when heterogeneity outliers were removed (termination g=-0.06/short FU g=-0.01/long FU g=-0.10). Power analyses indicated that large or medium effect size differences between PDT and other active treatments could be detected even with high heterogeneity. Exploratory moderator analyses found few significant predictors of effect (e.g., relative risk of dropout). No differences were found examining remission rates or relative risk of dropout. Overall, PDT was shown to be as efficacious as other active treatments that have been studied for anxiety disorders. PMID- 24786898 TI - Altered subcellular localization of IL-33 leads to non-resolving lethal inflammation. AB - Non-resolving inflammation is a major contributor to chronic disease pathogenesis, including that of cancer, chronic obstructive pulmonary disease, asthma, arthritis, inflammatory bowel disease, multiple sclerosis and obesity. Some cytokines, such as IL-1alpha and IL-33, may act as endogenous alarmins that contribute to non-resolving inflammation. These cytokines are constitutively expressed in the nucleus and are thought to promote inflammation only upon release during tissue damage or cell necrosis. However, the importance of their nuclear localization in immune homeostasis is not fully understood. We describe herein a novel mouse model in which the nuclear localization signal of IL-33 is abolished and demonstrate for the first time that, alone, altered subcellular localization of IL-33 dramatically affects immune homeostasis. Heterozygous IL33(tm1/+) mice display elevated serum IL-33 levels, indicating that IL-33 is constitutively released when not actively targeted to the nucleus. IL33(tm1/+) mice succumb to lethal inflammation characterized by eosinophil-dominated immune cell infiltration of multiple organs. The profound inflammatory phenotype is dependent on mediators downstream of ST2 as ST2-null mice are protected in spite of high serum IL-33 levels. Importantly, IL-33 transcript levels in this knock-in mouse model remain under endogenous control. We adopt the term "nuclear alarmin" to describe a danger signal that is primarily regulated by nuclear compartmentalization in this fashion. PMID- 24786899 TI - Green electrochemical template synthesis of CoPt nanoparticles with tunable size, composition, and magnetism from microemulsions using an ionic liquid (bmimPF6). AB - Electrodeposition from microemulsions using ionic liquids is revealed as a green method for synthesizing magnetic alloyed nanoparticles, avoiding the use of aggressive reducing agents. Microemulsions containing droplets of aqueous solution (electrolytic solution containing Pt(IV) and Co(II) ions) in an ionic liquid (bmimPF6) define nanoreactors in which the electrochemical reduction takes place. Highly crystalline hcp alloyed CoPt nanoparticles, in the 10-120 nm range with a rather narrow size distribution, have been deposited on a conductive substrate. The relative amount of aqueous solution to ionic liquid determines the size of the nanoreactors, which serve as nanotemplates for the growth of the nanoparticles and hence determine their size and distribution. Further, the stoichiometry (Pt(x)Co(1-x)) of the particles can be tuned by the composition of the electrolytic solution inside the droplets. The control of the size and composition of the particles allows tailoring the room-temperature magnetic behavior of the nanoparticles from superparaparamagnetic to hard magnetic (with a coercivity of HC = 4100 Oe) in the as-obtained state. PMID- 24786900 TI - Development of target system for intense neutron source of p-Li reaction. AB - A target cooling system was developed for an intense neutron source of p-Li reaction. The system consists of target cooling devices and protection devices for lithium evaporation. A pin-structure cooling device was developed to enhance cooling power. Functional graded material was utilized for the evaporation of lithium. Test experiments were performed by using the neutron exposure accelerator system for biological effect experiments (NASBEE) at the National Institute of Radiological Sciences (NIRS) in Japan. The target system was confirmed to be applicable for accelerator-based boron neutron capture therapy. PMID- 24786902 TI - Virtual-reality simulation to assess performance in hip fracture surgery. AB - BACKGROUND AND PURPOSE: Internal fixation of hip fractures is a common and important procedure that orthopedic surgeons must master early in their career. Virtual-reality training could improve initial skills, and a simulation-based test would make it possible to ensure basic competency of junior surgeons before they proceed to supervised practice on patients. The aim of this study was to develop a reliable and valid test with credible pass/fail standards. METHODS: 20 physicians (10 untrained novices and 10 experienced orthopedic surgeons) each performed 3 internal fixation procedures of an undisplaced femoral neck fracture: 2 hook-pins, 2 screws, and a sliding hip screw. All procedures were preformed on a trauma simulator. Performance scores for each procedure were obtained from the predefined metrics of the simulator. The inter-case reliability of the simulator metrics was explored by calculation of intra-class correlation coefficient. Validity was explored by comparison between novices' and experts' scores using independent-samples t-test. A pass/fail standard was set by the contrasting groups method and the consequences were explored. RESULTS: The percentage of maximum combined score (PM score) showed an inter-case reliability of 0.83 (95% CI: 0.65-0.93) between the 3 procedures. The mean PM score was 30% (CI: 7-53) for the novices and 76% (CI: 68-83) for the experienced surgeons. The pass/fail standard was set at 58%, resulting in none of the novices passing the test and a single experienced surgeon failing the test. INTERPRETATION: The simulation-based test was reliable and valid in our setting, and the pass/fail standard could discriminate between novices and experienced surgeons. Potentially, training and testing of future junior surgeons on a virtual-reality simulator could ensure basic competency before proceeding to supervised practice on patients. PMID- 24786901 TI - Differential expression of genes related to mitochondrial biogenesis and bioenergetics in fatigued prostate cancer men receiving external beam radiation therapy. AB - OBJECTIVES: This prospective study explored relationships between expression changes of genes related to mitochondrial biogenesis/bioenergetics and fatigue in men with prostate cancer receiving external beam radiation therapy (EBRT). METHODS: Fatigue and gene expression were measured before (Day 0), at midpoint (Days 19-21), and at completion (Days 38-42) of EBRT using the seven-item Patient Reported Outcomes Measurement Information System-Fatigue short form and from whole blood cell RNA, respectively. The human mitochondria RT2 Profiler PCR Array System was used to identify differential expression of mitochondrial biogenesis/bioenergetics-related genes. Mixed linear modeling estimated the changes in fatigue and gene expression over time and determined significant associations between gene expression and fatigue. RESULTS: Subjects were 50 men with prostate cancer (scheduled for EBRT = 25, active surveillance as matched controls = 25). The mean Patient-Reported Outcomes Measurement Information System Fatigue T-score (mean = 50 +/- 10 in a general population) for study subjects was 44.87 +/- 5.89 and for controls was 43.5 +/- 2.8 at baseline. Differential expression of two genes inside the mitochondria involved in critical mitochondrial complexes: BCS1L (beta = 1.30), SLC25A37 (beta = -2.44), and two genes on the outer mitochondrial membrane vital for mitochondrial integrity: BCL2L1 (beta = -1.68) and FIS1 (beta = -2.35) were significantly associated with changes in fatigue scores of study subjects during EBRT. CONCLUSION: Genes related to oxidative phosphorylation, energy production, and mitochondrial membrane integrity are associated with worsening fatigue during EBRT. Further investigation of the pathways involved with this association may explain mechanisms behind the development of fatigue in this population. PMID- 24786903 TI - Tibial fractures in children. A retrospective 27-year follow-up study. AB - BACKGROUND: Tibial fracture is the third most common long-bone fracture in children. Traditionally, most tibial fractures in children have been treated non operatively, but there are no long-term results. METHODS: 94 children (64 boys) were treated for a tibial fracture in Aurora City Hospital during the period 1980 89 but 20 could not be included in the study. 58 of the remaining 74 patients returned a written questionnaire and 45 attended a follow-up examination at mean 27 (23-32) years after the fracture. RESULTS: 89 children had been treated by manipulation under anesthesia and cast-immobilization, 4 by skeletal traction, and 1 with pin fixation. 41 fractures had been re-manipulated. The mean length of hospital stay was 5 (1-26) days. Primary complications were recorded in 5 children. The childrens' memories of treatment were positive in two-thirds of cases. The mean subjective VAS score (range 0-10) for function appearance was 9. Leg-length discrepancy (5-10 mm) was found clinically in 10 of 45 subjects and rotational deformities exceeding 20 degrees in 4. None of the subjects walked with a limp. None had axial malalignment exceeding 10 degrees . Osteoarthritis of the hip and/or knee was seen in radiographs from 2 subjects. INTERPRETATION: The long-term outcome of tibial fractures in children treated non-operatively is generally good. PMID- 24786904 TI - Dissatisfied patients after total knee arthroplasty: a registry study involving 114 patients with 8-13 years of followup. AB - BACKGROUND AND PURPOSE: In 2003, an enquiry by the Swedish Knee Arthroplasty Register (SKAR) 2-7 years after total knee arthroplasty (TKA) revealed patients who were dissatisfied with the outcome of their surgery but who had not been revised. 6 years later, we examined the dissatisfied patients in one Swedish county and a matched group of very satisfied patients. PATIENTS AND METHODS: 118 TKAs in 114 patients, all of whom had had their surgery between 1996 and 2001, were examined in 2009-2010. 55 patients (with 58 TKAs) had stated in 2003 that they were dissatisfied with their knees and 59 (with 60 TKAs) had stated that they were very satisfied with their knees. The patients were examined clinically and radiographically, and performed functional tests consisting of the 6-minute walk and chair-stand test. All the patients filled out a visual analog scale (VAS, 0-100 mm) regarding knee pain and also the Hospital and Anxiety and Depression scale (HAD). RESULTS: Mean VAS score for knee pain differed by 30 mm in favor of the very satisfied group (p < 0.001). 23 of the 55 patients in the dissatisfied group and 6 of 59 patients in the very satisfied group suffered from anxiety and/or depression (p = 0.001). Mean range of motion was 11 degrees better in the very satisfied group (p < 0.001). The groups were similar with regard to clinical examination, physical performance testing, and radiography. INTERPRETATION: The patients who reported poor response after TKA continued to be unhappy after 8-13 years, as demonstrated by VAS pain and HAD, despite the absence of a discernible objective reason for revision. PMID- 24786905 TI - Histology of 8 atypical femoral fractures: remodeling but no healing. AB - BACKGROUND AND PURPOSE: The pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues. PATIENTS AND METHODS: Between 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology. RESULTS: Incomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 um. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption. INTERPRETATION: Atypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival. PMID- 24786906 TI - The annual number of hip fractures in Sweden will double from year 2002 to 2050: projections based on local and nationwide data. AB - BACKGROUND AND PURPOSE: The incidence and annual number of hip fractures have increased worldwide during the past 50 years, and projections have indicated a further increase. During the last decade, however, a down-turn in the incidence of hip fracture has been seen in the western world. We predicted the development of hip fractures in Sweden until the year 2050. METHODS: We reviewed surgical records for the period 2002-2012 in the city of Malmo, Sweden, and identified patients aged 50 years or more with a hip fracture. We estimated incidence rates by using official population figures as denominator and applied the rates to population projections each year until 2050. We also made projections based on our previously published nationwide Swedish hip fracture rates for the period 1987-2002. Since the projections are based on estimates, no confidence limits are given. RESULTS: During the period 2002-2012, there were 7,385 hip fractures in Malmo. Based on these data, we predicted that there would be approximately 30,000 hip fractures in Sweden in the year 2050. Use of nationwide rates for 2002 in the predictive model gave similar results, which correspond to an increase in the number of hip fractures by a factor of 1.9 (1.7 for women and 2.3 for men) compared to 2002. INTERPRETATION: The annual number of hip fractures will almost double during the first half of the century. Time trends in hip fractures and also changes in population size and age distribution should be continuously monitored, as such changes will influence the number of hip fractures in the future. Our results indicate that we must optimize preventive measures for hip fractures and prepare for major demands in resources. PMID- 24786907 TI - Corticosteroid administration within 2 weeks after renal transplantation affects the incidence of femoral head osteonecrosis. AB - BACKGROUND AND PURPOSE: It has been suggested that avascular osteonecrosis (AVN) of the femoral head occurs early after systemic steroid administration. The purpose of this study was to investigate the risks regarding development of AVN at a very early stage after renal transplantation. METHODS: The presence or absence of AVN was determined by MRI at 4 weeks, at 6-12 weeks, at 24 weeks, and at 12 months after renal transplantation in 286 patients (183 males) with a mean age of 39 (16-65) years. The relationship between AVN and age, sex, absence or presence of acute rejection (AR), type of transplanted kidney (living or cadaveric), type of immune suppressor, and total dose of orally administered steroids given in the 2-week period after transplantation was investigated. RESULTS: There were no statistically significant correlations between the development of AVN and age, sex, absence or presence of AR, type of transplanted kidney, or type of immune suppressor. A significant dose-response relationship was found between development of AVN and the total dose of steroid administered in the first 2 weeks after surgery. INTERPRETATION: We found a relationship between AVN development and steroid dose in the early postoperative period, and we also showed a dose-response relationship. PMID- 24786908 TI - Age- and health-related quality of life after total hip replacement: decreasing gains in patients above 70 years of age. AB - BACKGROUND: While age is a common confounder, its impact on health-related quality of life (HRQoL) after total hip replacement is uncertain. This could be due to improper statistical modeling of age in previous studies, such as treating age as a linear variable or by using age categories. We hypothesized that there is a non-linear association between age and HRQoL. METHODS: We selected a nationwide cohort from the Swedish Hip Arthroplasty Register of patients operated with total hip replacements due to primary osteoarthritis between 2008 and 2010. For estimating HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group that consits or 2 parts: the EQ-5D index and the EQ VAS estimates. Using linear regression, we modeled the EQ-5D index and the EQ VAS against age 1 year after surgery. Instead of using a straight line for age, we applied a method called restricted cubic splines that allows the line to bend in a controlled manner. Confounding was controlled by adjusting for preoperative HRQoL, sex, previous contralateral hip surgery, pain, and Charnley classification. RESULTS: Complete data on 27,245 patients were available for analysis. Both the EQ-5D index and EQ VAS showed a non-linear relationship with age. They were fairly unaffected by age until the patients were in their late sixties, after which age had a negative effect. INTERPRETATION: There is a non linear relationship between age and HRQoL, with improvement decreasing in the elderly. PMID- 24786910 TI - Eco-evolutionary dynamics induced by massive mortality events. AB - An eco-genetic model tuned on a population of marble trout Salmo marmoratus subject to periodic flood events was used to explore how the evolution of growth rates interacting with density-dependent processes can modify size at age and population structure and in turn influence the resilience of populations. Fish with greater growth potential were assumed to have higher mortality rates. The results of simulations were compared between two scenarios, one in which populations may evolve growth rates and the other one in which the distribution of growth rates within a population is kept fixed. Evolving populations had a greater proportion of age 1 year individuals in the population, greater median length at age 3 years (the typical age at sexual maturity for S. marmoratus) and lower population sizes. The slightly smaller population sizes did not affect realized extinction risk. Resilience, defined as the number of years necessary to rebound from flood-induced population collapse, was on average from 2 to 3 years in both scenarios, with no significant difference between them. Moderate heritability of growth, relaxation of density-dependent processes at low densities and rapid recovery to a safe population size combine to limit the capacity to evolve faster recovery after flood-induced population collapses via changing growth rates. PMID- 24786911 TI - Molecular orientational order of nitroxide radicals in liquid crystalline media. AB - The orientational distribution of a set of stable nitroxide radicals in aligned liquid crystals 5CB (nematic) and 8CB (smectic A) was studied in detail by numerical simulation of EPR spectra. The order parameters up to the 10th rank were measured. The directions of the principal orientation axes of the radicals were determined. It was shown that the ordering of the probe molecules is controlled by their interaction with the matrix molecules more than the inherent geometry of the probes themselves. The rigid fused phenanthrene-based (A5) and 2 azaphenalene (A4) nitroxides as well as the rigid core elongated C11 and 5alpha cholestane (CLS) nitroxides were found to be most sensitive to the orientation of the liquid crystal matrixes. PMID- 24786909 TI - Shared common variants in prostate cancer and blood lipids. AB - BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors. METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR. RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B. CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting. PMID- 24786912 TI - Drug-induced peripheral neuropathy. AB - Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN. PMID- 24786913 TI - New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. AB - OBJECTIVES: To evaluate the efficacy and safety of new oral anticoagulants (NOACs) in elderly adults. DESIGN: Meta-analyses of randomized clinical trials (RCTs). SETTING: PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 1, 2001, through March 30, 2013. PARTICIPANTS: Elderly population (>= 75) in RCTs comparing NOACs (rivaroxaban, apixaban, and dabigatran) with conventional therapy. MEASUREMENTS: Two authors reviewed the trials, and odds ratios (ORs) were calculated using a random effects model. RESULTS: Ten RCTs included 25,031 elderly participants. Risk of major or clinically relevant bleeding was not significantly different between NOACs and conventional therapy in elderly adults (OR = 1.02, 95% confidence interval = 0.73 1.43). Similar results were observed when comparing NOACs and pharmacologically active agents. In atrial fibrillation (AF) trials, NOACs were more effective than conventional therapy in prevention of stroke or systemic embolism in an elderly population with AF. In non-AF trials, NOACs also had a significantly lower risk of venous thromboembolism (VTE) or VTE-related death than conventional therapy in elderly adults. Analysis for individual NOACs showed that the NOAC was noninferior or more effective than conventional therapy for efficacy and safety outcomes. CONCLUSION: In participants of clinical trials aged 75 and older, NOACs did not cause excess bleeding and were associated with equal or greater efficacy than conventional therapy. PMID- 24786914 TI - Development and validation of a computational model of the knee joint for the evaluation of surgical treatments for osteoarthritis. AB - A three-dimensional (3D) knee joint computational model was developed and validated to predict knee joint contact forces and pressures for different degrees of malalignment. A 3D computational knee model was created from high resolution radiological images to emulate passive sagittal rotation (full extension to 65 degrees -flexion) and weight acceptance. A cadaveric knee mounted on a six-degree-of-freedom robot was subjected to matching boundary and loading conditions. A ligament-tuning process minimised kinematic differences between the robotically loaded cadaver specimen and the finite element (FE) model. The model was validated by measured intra-articular force and pressure measurements. Percent full scale error between FE-predicted and in vitro-measured values in the medial and lateral compartments were 6.67% and 5.94%, respectively, for normalised peak pressure values, and 7.56% and 4.48%, respectively, for normalised force values. The knee model can accurately predict normalised intra articular pressure and forces for different loading conditions and could be further developed for subject-specific surgical planning. PMID- 24786915 TI - Cytotoxic alkylated hydroquinone, phenol, and cyclohexenone derivatives from Aspergillus violaceofuscus Gasperini. AB - New alkylated hydroquinones violaceoid A (1), violaceoid B (2), and violaceoid C (3), an alkylated phenol violaceoid D (4), and a cyclohexenoid violaceoid E (5) were isolated from a culture broth of Aspergillus violaceofuscus Gasperini isolated from moss. The structures were identified by interpretation of spectroscopic data (1D and 2D NMR, MS, and IR). Two known compounds, the cyclohexenoid 6 and eupenoxide (7), were also isolated. Compound 6 was isolated for the first time as a natural product and named violaceoid F. Isolated compounds were tested for cytotoxic activity against five human cancer cell lines and a mouse macrophage cell line. Violaceoid A was the most potent of the seven compounds against all cell lines. Violaceoid C and D exhibited cytotoxicity against the leukemia cell lines with LD50 values 5.9-8.3 MUM, while violaceoid F was found to be cytotoxic against HCT116 and RAW264.7 with LD50 values of 6.4 and 6.5 MUM, respectively. These results demonstrate that violaceoid derivatives are a new class of cytotoxic hydroquinones with a hydroxymethyl and a linear alkyl substituent. PMID- 24786916 TI - From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation. AB - Eotaxin-1 (CCL-11) is a potent eosinophil chemoattractant that is considered a major contributor to tissue eosinophilia. Elevated eotaxin-1 levels have been described in various pathologic conditions, ranging from airway inflammation, to Hodgkin lymphoma, obesity and coronary artery disease. The main receptor for eotaxin-1 is CCR3; however, recent evidence indicates that eotaxin-1 may also bind to other receptors expressed by various cell types, suggesting a more widespread regulatory role for eotaxin-1 beyond the recruitment of eosinophils. Eotaxin-1 is also strongly associated with various gastrointestinal (GI) disorders. Although the etiology of inflammatory bowel disease (IBD) is still unknown, eotaxin-1 may play a key role in the development of mucosal inflammation. In this review, we summarize the biological context and effects of eotaxin-1, as well as its potential role as a therapeutic target, with a special focus on gastrointestinal inflammation. PMID- 24786917 TI - Filaggrin-insufficiency in keratinocytes influences responsiveness of allergen specific T cells to cognate antigen and compounds barrier function deficiency. PMID- 24786918 TI - Deep Needle Procedures: Improving Safety With Ultrasound Visualization. AB - Promoting patient safety and increasing health care quality have dominated the health care landscape during the last 15 years. Health care regulators and payers are now tying patient safety outcomes and best practices to hospital reimbursement. Many health care leaders are searching for new technologies that not only make health care for patients safer but also reduce overall health care costs. New advances in ultrasonography have made this technology available to health care providers at the patient's bedside. Point-of-care ultrasound assistance now aids providers with real-time diagnosis and with visualization for procedural guidance. This is especially true for common deep needle procedures such as central venous catheter insertion, thoracentesis, and paracentesis.There is now mounting evidence that clinician-performed point-of-care ultrasound improves patient safety, enhances health care quality, and reduces health care cost for deep needle procedures. Furthermore, the miniaturization, ease of use, and the evolving affordability of ultrasound have now made this technology widely available. The adoption of point-of-care ultrasonography has reached a tipping point and should be seriously considered the safety standard for all hospital based deep needle procedures. PMID- 24786919 TI - Enhanced electrode performance of Fe2O3 nanoparticle-decorated nanomesh graphene as anodes for lithium-ion batteries. AB - Nanostructured Fe2O3-nanomesh graphene (NMG) composites containing ~3 nm Fe2O3 nanoparticles (NPs) uniformly distributed in the nanopores of NMG are synthesized by an adsorption-precipitation process. As anodes for Li ion batteries (LIBs), the 10%Fe2O3-NMG composite exhibits an upward trend in the capacity and delivers a reversible specific capacity of 1567 mA h g(-1) after 50 cycles at 150 mA g( 1), and 883 mA h g(-1) after 100 cycles at 1000 mA g(-1), much higher than the corresponding values for the NMG electrode. The significant capacity enhancement of the 10%Fe-NMG composite is attributed to the positive synergistic effect between NMG and Fe2O3 NPs due to the catalytic activity of Fe2O3 NPs for decomposition of the solid electrolyte interface film. Our results indicate that decoration of ultrasmall Fe2O3 NPs can significantly change the surface condition of graphene. This synthesis strategy is simple, effective, and broadly applicable for constructing other electrode materials for LIBs. PMID- 24786920 TI - A quantitative risk assessment model for Vibrio parahaemolyticus in raw oysters in Sao Paulo State, Brazil. AB - A risk assessment of Vibrio parahaemolyticus associated with raw oysters produced and consumed in Sao Paulo State was developed. The model was built according to the United States Food and Drug Administration framework for risk assessment. The outcome of the exposure assessment estimated the prevalence and density of pathogenic V. parahaemolyticus in raw oysters from harvest to consumption. The result of the exposure step was combined with a Beta-Poisson dose-response model to estimate the probability of illness. The model predicted that the average risks per serving of raw oysters were 4.7*10(-4), 6.0*10(-4), 4.7*10(-4) and 3.1*10(-4) for spring, summer, fall and winter, respectively. Sensitivity analyses indicated that the most influential variables on the risk of illness were the total density of V. parahaemolyticus at harvest, transport temperature, relative prevalence of pathogenic strains and storage time at retail. Only storage time under refrigeration at retail showed negative correlation with the risk of illness. PMID- 24786921 TI - Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling. AB - Melatonin is known to exert antitumour activity in several types of human cancers, but the underlying mechanisms as well as the efficacy of different doses of melatonin are not well defined. Here, we test the hypothesis whether melatonin in the nanomolar range is effective in exerting antitumour activity in vivo and examine the correlation with the hypoxia signalling mechanism, which may be a major molecular mechanism by which melatonin antagonizes cancer. To test this hypothesis, LNCaP human prostate cancer cells were xenografted into seven-wk-old Foxn1nu/nu male mice that were treated with melatonin (18 i.p. injections of 1 mg/kg in 41 days). Saline-treated mice served as control. We found that the melatonin levels in plasma and xenografted tissue were 4* and 60* higher, respectively, than in control samples. Melatonin tended to restore the redox imbalance by increasing expression of Nrf2. As part of the phenotypic response to these perturbations, xenograft microvessel density was less in melatonin-treated animals, indicative of lower angiogenesis, and the xenograft growth rate was slower (P < 0.0001). These changes were accompanied by a reduced expression of Ki67, elevated expression of HIF-1alpha and increased phosphorylation of Akt in melatonin than saline-treated mice. We conclude that the beneficial effect of melatonin in reducing cancer growth in vivo was evident at melatonin plasma levels as low as 4 nm and was associated with decreased angiogenesis. Higher HIF 1alpha expression in xenograft tissue indicates that the antitumour effect cannot be due to a postulated antihypoxic effect, but may stem from lower angiogenesis potential. PMID- 24786922 TI - Childhood-onset Takayasu arteritis -- experience from a tertiary care center in South India. AB - OBJECTIVE: To study the clinical profile and outcome of Asian Indian children with childhood-onset Takayasu arteritis (c-TA). METHODS: Records were studied of patients with c-TA onset prior to age 16. Disease Extent Index-Takayasu (DEI.TAK), Indian Takayasu Arteritis Score 2010, and Takayasu Arteritis Damage Score (TADS) were calculated retrospectively from electronic records. Cumulative incidence of sustained remission was estimated using the Kaplan-Meier curve. RESULTS: There were 40 patients with c-TA, with median age of onset of 12.5 years (range 1-16) and median diagnostic delay of 11.3 months (range 1-60). The most common presenting features were hypertension, headache, malaise, and fever. Pulseless disease was observed in 25 cases (62.5%). The majority (n = 28) had active disease with raised inflammatory markers, high baseline median DEI.TAK score of 10 (range 3-24), and high median TADS of 7 (range 1-14). Of the 34 patients followed for 21.5 months (range 3-192), remission was attained in 30. However, cumulative sustained remission was achieved in only 29% of them at 5 years. Median period of sustained remission was 22.5 months (95% CI 17.1-26.8). New areas of vessel involvement were observed in 13 patients (38%). Disease progression was arrested in the majority (n = 22, 66%) through aggressive medical management and endovascular intervention. All 11 patients with an increment in TADS of >= 4 during followup had persistently active or relapsing disease. There was a single fatality. CONCLUSION: Despite aggressive immunosuppression, damage progressed in one-third of patients with c-TA in association with persistent inflammation, warranting surveillance with clinical instruments and followup imaging. PMID- 24786923 TI - Comparison of labial minor salivary gland biopsies from childhood Sjogren syndrome and age-matched controls. AB - OBJECTIVE: To determine an appropriate focus score cutoff for childhood Sjogren syndrome (SS). METHODS: Labial salivary gland tissue from specimens from children with SS and age-matched controls was retrospectively identified and reviewed by a blinded oral pathologist. RESULTS: The presence of any focal sialadenitis (focus score > 0 foci/4 mm(2)) was common among childhood SS samples but present in only 1 of 8 control samples. CONCLUSION: The presence of any focal lymphocytic sialadenitis in minor labial salivary gland tissue is suggestive of childhood SS and should be included in future childhood SS-specific diagnostic or classification criteria. PMID- 24786924 TI - Higher expression of whole blood microRNA-21 in patients with ankylosing spondylitis associated with programmed cell death 4 mRNA expression and collagen cross-linked C-telopeptide concentration. AB - OBJECTIVE: Bone loss is a recognized feature of ankylosing spondylitis (AS). The binding of microRNA-21 (miR-21) to programmed cell death 4 (PDCD4) could inhibit the expression of PDCD4 and further induce the activation of osteoclasts. In the present study, we compared the difference in miR-21 expression between patients with AS and healthy controls, and evaluated the relationships of miR-21, PDCD4 mRNA, and bone erosion in patients with AS. The influences of nonsteroidal antiinflammatory drugs (NSAID) and disease-modifying antirheumatic drugs (DMARD) on the expressions of miR-21 and PDCD4 mRNA in patients with AS were also assessed. METHODS: Whole blood miR-21 and PDCD4 mRNA expression were evaluated by quantitative real-time PCR among 122 patients with AS and 122 healthy controls. The serum level of collagen cross-linked C-telopeptide (CTX) was measured using ELISA. RESULTS: When compared to controls, patients with AS had significantly higher levels of miR-21, PDCD4 mRNA, and CTX. MiR-21 expression was negatively correlated with PDCD4 mRNA expression in patients with AS who were taking neither NSAID nor DMARD. Interestingly, significantly positive correlations between miR 21 expression with PDCD4 mRNA expression (r = 0.33, p = 0.01) and CTX level (r = 0.44, p < 0.01) were observed in patients with AS who were taking sulfasalazine. Positive correlations of miR-21 and CTX level were also observed in AS patients with disease duration < 7.0 years (r = 0.36, p = 0.004) and active disease (r = 0.42, p = 0.001). CONCLUSION: The expression of miR-21 might have a role in the development of AS. PMID- 24786925 TI - Longterm safety, efficacy, and inhibition of structural damage progression over 5 years of treatment with abatacept in patients with rheumatoid arthritis in the abatacept in inadequate responders to methotrexate trial. AB - OBJECTIVE: Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). METHODS: Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (~10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received >= 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores. RESULTS: Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5, respectively. Disease Activity Score 28 C-reactive protein (DAS28-CRP) < 2.6 and <= 3.2 were achieved by 25.4% and 44.1% of patients at Year 1 (n = 370), and 33.7% and 54.7% at Year 5 (n = 267), respectively. Mean changes in DAS28-CRP and Health Assessment Questionnaire-Disability Index at Year 1 [-2.83 (n = 365) and -0.68 (n = 369)] were maintained at Year 5 [-3.14 (n = 264) and -0.77 (n = 271)] for patients continuing treatment. Of them, 59.5% (n = 291) and 45.1% (n = 235) remained free from radiographic progression at years 1 and 5, respectively. CONCLUSION: In MTX-refractory patients with RA, longterm ABA treatment was well tolerated and provided consistent safety and sustained efficacy, with high patient retention. Radiographic progression continued to be inhibited with ongoing treatment. PMID- 24786926 TI - Interleukin 18: a biomarker for differential diagnosis between adult-onset Still's disease and sepsis. AB - OBJECTIVE: The differential diagnosis between rheumatic diseases and infectious conditions is a great challenge in clinical practice. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory syndrome that shares several clinical and laboratory variables with sepsis. Interleukin (IL)-18 is overexpressed in AOSD, suggesting a possible role as a disease biomarker. The aim of our study was to detect IL-18 serum levels in a cohort of patients with AOSD and sepsis and to address its possible role as a biomarker for differential diagnosis. METHODS: A group of unselected patients with AOSD diagnosed according to the Yamaguchi criteria and consecutive patients with sepsis diagnosed according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference criteria were enrolled. The clinical and laboratory data were collected. In the AOSD group, disease activity was assessed by Pouchot's and Rau's criteria. IL-18 serum levels were detected by ELISA. RESULTS: Thirty-nine patients with AOSD and 18 patients with sepsis were enrolled. Two out of 18 patients with sepsis (11.1%) also fulfilled the Yamaguchi criteria. A significant difference was found in IL-18 serum levels between patients with active and inactive disease (p < 0.001), and it positively correlated with disease activity (p = 0.0003), ferritin serum level (p = 0.016), and erythrocyte sedimentation rate (p = 0.041). IL-18 was significantly increased in patients with AOSD when compared with sepsis (p = 0.014). For a cutoff of 148.9 pg/ml, this test had a specificity of 78.3% and a sensitivity of 88.6%. CONCLUSION: We have demonstrated that IL-18 can be a biomarker for differential diagnosis between AOSD and sepsis. PMID- 24786927 TI - Arthritis in idiopathic inflammatory myopathy: clinical features and autoantibody associations. AB - OBJECTIVE: To determine the prevalence, distribution, and clinical manifestations of arthritis in a cohort of patients with idiopathic inflammatory myopathies (IIM). Associations with autoantibody status and HLA genetic background were also explored. METHODS: Consecutive patients with IIM treated in a single center were included in this cross-sectional study (n = 106). History of arthritis, 68-joint and 66-joint tender and swollen joint index, clinical features of IIM, and autoantibody profiles were obtained by clinical examination, personal interview, and review of patient records. High-resolution genotyping in HLA-DRB1 and HLA DQB1 loci was performed in 71 and 73 patients, respectively. RESULTS: A combination of patients' medical history and cross-sectional physical examination revealed that arthritis at any time during the disease course had occurred in 56 patients (53%). It was present at the beginning of the disease in 39 patients (37%) including 23 cases (22%) with arthritis preceding the onset of muscle weakness. On physical examination, 29% of patients had at least 1 swollen joint. The most frequently affected areas were wrists, and metacarpophalangeal and proximal interphalangeal joints. Twenty-seven out of the 29 anti-Jo1-positive patients had arthritis at any time during the course of their illness; this prevalence was significantly higher compared to patients without the anti-Jo1 autoantibody (p < 0.0001). No association of arthritis with individual HLA alleles was found. CONCLUSION: Our data suggest that arthritis is a common feature of myositis. It is frequently present at the onset of disease and it may even precede muscular manifestations of IIM. The most common presentation is a symmetrical, nonerosive polyarthritis affecting particularly the wrists, shoulders, and small joints of the hands. We have confirmed a strong association of arthritis with the presence of the anti-Jo1 antibody. PMID- 24786928 TI - Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors. AB - OBJECTIVE: To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). METHODS: Eighty five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. RESULTS: Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. CONCLUSION: Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430. PMID- 24786929 TI - Discrepancy between clinical and radiological responses to tocilizumab treatment in patients with systemic-onset juvenile idiopathic arthritis. AB - OBJECTIVE: Tocilizumab (TCZ), an antiinterleukin-6 receptor monoclonal antibody, is clinically beneficial in patients with systemic-onset juvenile idiopathic arthritis (sJIA). We investigated the clinical and radiological outcomes of TCZ therapy in patients with sJIA. METHODS: We retrospectively evaluated 2 clinical trials (NCT00144599 and NCT00144612) involving 40 patients with sJIA who received intravenous TCZ (8 mg/kg) every 2 weeks. Clinical data and radiographs of the hands and large joints were assessed before and during TCZ treatment. The Poznanski score, modified Larsen scores of the hands and large joints, and Childhood Arthritis Radiographic Score of the Hip (CARSH) were recorded. RESULTS: After a mean duration of 4.5 years of TCZ treatment, clinical data had improved significantly, the mean Poznanski score improved from -1.5 to -1.1, the mean Larsen score of the hands deteriorated from 7.0 to 10.0, the mean Larsen score for the large joints deteriorated from 5.9 to 6.8, and the CARSH worsened from 3.9 to 6.2. The Larsen score for the large joints improved in 11 cases (28%), remained unchanged in 8 cases (20%), and worsened in 21 cases (52%). Matrix metalloproteinase 3 (MMP-3) levels remained significantly higher (278 mg/dl) in patients with worsened Larsen scores than in patients with improved or unchanged scores (65 mg/dl). Logistic regression analysis showed that older age at disease onset was a significant risk factor for radiographic progression. CONCLUSION: The modified Larsen score of the large joints deteriorated in half the patients who had high MMP-3 levels during TCZ treatment and who were significantly older at disease onset. PMID- 24786930 TI - Resistive home exercise in patients with recent-onset polymyositis and dermatomyositis -- a randomized controlled single-blinded study with a 2-year followup. AB - OBJECTIVE: To evaluate the outcome of resistive home exercise and its possible longterm influence on health, disability, and disease activity in patients with active polymyositis (PM) or dermatomyositis (DM). METHODS: Nineteen patients with recent-onset PM/DM were included after introduction of high-dose prednisolone. They were assessed by independent assessors as to perceived health, muscle performance, aerobic capacity, and serum creatine phosphokinase (CPK) at baseline and after 24 weeks, including repeated muscle biopsies at 24 weeks (single blinded randomized controlled study), and in an open-label followup at 52, 78, and 104 weeks. Patients were randomized to 12 weeks, 5 days/week resistive home exercise with telephone support and encouragement for another 12 weeks of twice-a week home or gym exercise (EG, n = 10) or to 24 weeks, 5 days/week range of motion exercise (CG, n = 9). Patients in the CG group without inflammatory infiltrates in muscle biopsies at 24 weeks were invited to the 12-week resistive home exercises. RESULTS: At baseline, the EG had poorer perceived health, but otherwise the groups were comparable. At 24 weeks, both groups improved in muscle performance and aerobic capacity (p < 0.001 to < 0.05) with no signs of increased inflammation assessed by CPK levels or muscle biopsies. Both groups improved in muscle performance and aerobic capacity up to 52 weeks (p < 0.05) lasting to 104 weeks in the EG (p < 0.05) and presented minor improvements in perceived health. CONCLUSION: Our study supports the safety of resistive exercise in patients with active PM/DM but did not reveal any between-group differences in exercise effects. An individually adapted physical therapist-supervised home exercise program might be recommended in early active PM/DM, with regular evaluation of muscle performance and health. PMID- 24786931 TI - The effect of intravenous golimumab on health-related quality of life in rheumatoid arthritis: 24-week results of the phase III GO-FURTHER trial. AB - OBJECTIVE: To evaluate the effects of intravenous (IV) golimumab 2 mg/kg + methotrexate (MTX) on patient-reported measures of health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA) despite prior MTX therapy. METHODS: In this randomized, multicenter, double-blind, placebo controlled, phase III trial, adults with RA were randomly assigned to receive IV placebo (n = 197) or golimumab 2 mg/kg (n = 395) infusions at Week 0, Week 4, and every 8 weeks thereafter. All patients continued stable oral MTX (15-25 mg/wk). HRQOL assessments included Health Assessment Questionnaire-Disability Index (HAQ DI; physical function), Medical Outcomes Study Short Form-36 questionnaire physical/mental component summary (SF-36 PCS/MCS) scores, EQ-5D assessment of current health state, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, and disease effect on productivity [10-cm visual analog scale (VAS)]. RESULTS: Mean HAQ-DI improvements from baseline were significantly greater with golimumab + MTX than placebo + MTX at Week 14 and Week 24 (p < 0.001). Significantly greater improvements in all 8 individual SF-36 subscores and both the SF-36 PCS and MCS scores (p < 0.001) also accompanied golimumab + MTX therapy. Improved EQ-5D and EQ-5D VAS (p < 0.001) and FACIT Fatigue (p < 0.001) scores were also observed for golimumab + MTX-treated patients at Week 12, Week 16, and Week 24, and greater proportions of golimumab + MTX-treated patients had clinically meaningful improvements in these measures. Greater reductions in disease effect on productivity were observed with golimumab + MTX versus placebo + MTX at Week 24 (p < 0.001). Improvements in physical function, HRQOL, fatigue, and productivity significantly correlated with disease activity improvement. CONCLUSION: In active RA, IV golimumab + MTX significantly improved physical function, HRQOL, fatigue, and productivity using multiple measurement tools; all correlated with improvements in disease activity (NCT00973479, EudraCT 2008-006064-11). PMID- 24786932 TI - Discordance in global assessments between patient and estimator in patients with newly diagnosed rheumatoid arthritis: associations with progressive joint destruction and functional impairment. AB - OBJECTIVE: Factors relevant to the discordance between the patient global assessment (PGA) and estimator global assessment (EGA) in patients newly diagnosed with rheumatoid arthritis (RA) were examined. METHODS: Seventy-five consecutive newly diagnosed patients with RA were prospectively enrolled. We used 3 models in which discordance between PGA and EGA at 12 months was set at 5 mm, 10 mm, or 20 mm. We adopted 10 mm as representative and examined time course changes in clinical variables over 12 months. RESULTS: No significant difference was found between the concordance and the higher PGA groups regarding baseline characteristics and treatment. At 12 months, EGA, swollen joint count, and inflammatory marker values were not different, but pain visual analog scale and tender joint count were significantly higher in the higher PGA group, and the Health Assessment Questionnaire improved less. In the 10 mm and 20 mm models, the structural remission rate was significantly lower in the higher PGA group and the rapid radiological progression rate significantly higher. The discrepancy was already significant at 3 months. CONCLUSION: In newly diagnosed RA, PGA at 12 months may be more sensitive for indicating progressive joint destruction and functional impairment when compared with EGA, and there is a discrepancy directed toward a worse assessment by patients. PMID- 24786933 TI - Multivariate analysis of factors affecting the immunogenicity of trivalent inactivated influenza vaccine in school-age children. AB - We examined factors affecting the immunogenicity of trivalent inactivated influenza vaccination (TIV) in children using the antibody titres of children participating in a Hong Kong community-based study. Antibody titres of strains included in the 2009-2010 northern hemisphere TIV [seasonal A(H1N1), seasonal A(H3N2) and B (Victoria lineage)] and those not included in the TIV [2009 pandemic A(H1N1) and B (Yamagata lineage)] were measured by haemagglutination inhibition immediately before and 1 month after vaccination. Multivariate regression models were fitted in a Bayesian framework to characterize the distribution of changes in antibody titres following vaccination. Statistically significant rises in geometric mean antibody titres were observed against all strains, with a wide variety of standard deviations and correlations in rises observed, with the influenza type B antibodies showing more variability than the type A antibodies. The dynamics of antibody titres after vaccination can be used in more complex models of antibody dynamics in populations. PMID- 24786935 TI - Directly observed therapy for chronic hepatitis C: a randomized clinical trial in the prison setting. AB - BACKGROUND: The diagnosis and treatment of chronic hepatitis C are major concerns in prisons. OBJECTIVES: The aim of this randomized clinical trial was to determine the extent to which directly observed therapy (DOT) improved the efficacy of the standard treatment for chronic hepatitis C in the prison setting. PATIENTS AND METHODS: A randomized clinical trial was carried out to evaluate the efficacy of a DOT compared with a self-administered therapy in prison inmates who underwent standard treatment for chronic hepatitis C (based on pegylated interferon alpha-2a and ribavirin). RESULTS: A total of 252 inmates were randomized, of which 244 were analyzed: 109 in the DOT group and 135 in the non DOT group. The mean age was 35.88 years (SD 6.54), 94.3% were men, 72.1% reported intravenous drug use, 21.3% were HIV co-infected, and 55.3% had genotype 1 or 4. The patients received the study treatment for a median time of 33.9 weeks in the overall sample. Sustained virological response was achieved in 60.6% (95% CI, 51.17-69.22) of the DOT group and in 65.9% (95% CI, 57.59-73.38) of the standard therapy group (risk ratio=0.92; 95% CI, 0.76-1.12). The mean proportion of patients continuing the treatment was 83% (SD=31). Adverse events were reported in 93.4% of the patients, and serious adverse events were reported in 8.2%, with no significant differences between groups. CONCLUSIONS: Sustained virological response was remarkably high, although there were no differences between groups, probably due to high treatment adherence. PMID- 24786936 TI - [Ileocolonic invagination in an human immunodeficiency virus-positive man]. PMID- 24786937 TI - Functional and social limitations after facial palsy: expanded and independent validation of the Italian version of the facial disability index. AB - BACKGROUND: The Facial Disability Index (FDI) is widely used for self-assessment of functional impairment and quality of life in patients with facial palsy. OBJECTIVE: The study aim was to complete the validation of the FDI by generating an Italian version (IT-FDI) and evaluating its clinimetric properties. DESIGN: This was a longitudinal, observational measurement study. METHODS: The questionnaire was translated, cross-culturally adapted, and administered to 100 consecutive participants (outpatients) with facial palsy. The clinical severity of facial palsy, impairments in physical and social function, and quality of life were evaluated with the Sunnybrook Facial Grading System, IT-FDI, and 12-Item Short-Form Health Survey. RESULTS: The IT-FDI showed excellent test-retest reliability for every item and for total scores (intraclass correlation coefficients of .93 and .84 for physical function subscale and social/well-being function subscale, respectively). The IT-FDI confirmed the high internal consistency of the original version, with theta coefficients of .82 for the physical function subscale and .78 for the social/well-being function subscale. The physical function subscale correlated with the Sunnybrook Facial Grading System composite score (r=.44), and the social/well-being function subscale correlated with the 12-Item Short-Form Health Survey mental component (r=.55). The IT-FDI confirmed the good responsiveness of the original version, as expressed by effect size, standardized response mean, and responsiveness ratio of, respectively, 1, 1.03, and 1.21 for the physical function subscale and 0.75, 0.83, and 1.15 for the social/well-being function subscale. LIMITATIONS: Responsiveness was evaluated with a limited number of participants. CONCLUSIONS: The results demonstrated the test-retest reliability for all items of the FDI and confirmed its internal consistency, construct validity, and responsiveness with an independent and larger clinical subset. This study completes the validation of the FDI and provides the first validated questionnaire in Italian for assessment of disability and quality of life specifically in patients with facial palsy. PMID- 24786938 TI - Response to pediatric physical therapy in infants with positional preference and skull deformation. AB - BACKGROUND: Pediatric physical therapy seems to reduce skull deformation in infants with positional preference. However, not all infants show improvement. OBJECTIVE: The study objective was to determine which infant and parent characteristics were related to responses to pediatric physical therapy in infants who were 2 to 4 months old and had positional preference, skull deformation, or both. DESIGN: This was a prospective cohort study. METHODS: Infants who were 2 to 4 months old and had positional preference, skull deformation, or both were recruited by pediatric physical therapists at the start of pediatric physical therapy. The primary outcome was a good response or a poor response (moderate or severe skull deformation) at 4.5 to 6.5 months of age. Potential predictors for responses to pediatric physical therapy were assessed at baseline with questionnaires, plagiocephalometry, and the Alberta Infant Motor Scale. Univariate and multiple logistic regression analyses with a stepwise backward elimination method were performed. RESULTS: A total of 657 infants participated in the study. At follow-up, 364 infants (55.4%) showed a good response to therapy, and 293 infants (44.6%) showed a poor response. Multiple logistic regression analysis resulted in the identification of several significant predictors for a poor response to pediatric physical therapy at baseline: starting therapy after 3 months of age (adjusted odds ratio [aOR]=1.50, 95% confidence interval [95% CI]=1.04-2.17), skull deformation (plagiocephaly [aOR=2.64, 95% CI=1.67-4.17] or brachycephaly [aOR=3.07, 95% CI=2.09-4.52]), and a low parental satisfaction score (aOR=2.64, 95% CI=1.67-4.17). A low parental satisfaction score indicates low parental satisfaction with the infant's head shape. LIMITATIONS: Information about pediatric physical therapy was collected retrospectively and included general therapy characteristics. Because data were collected retrospectively, no adjustment in therapy for individual participants could be made. CONCLUSIONS: Several predictors for responses to pediatric physical therapy in infants who were 2 to 4 months old and had positional preference, skull deformation, or both were identified. Health care professionals can use these predictors in daily practice to provide infants with more individualized therapy, resulting in a better chance for a good outcome. PMID- 24786939 TI - Early intervention post-hospital discharge for infants born preterm. PMID- 24786940 TI - Effects of whole-body vibration therapy on body functions and structures, activity, and participation poststroke: a systematic review. AB - BACKGROUND: Whole-body vibration (WBV) has gained increasing popularity in rehabilitation. Recent studies have investigated the application of WBV in individuals with chronic illnesses, including stroke. PURPOSE: The purpose of this study was to compare WBV exercise with the same exercise condition without WBV and with other types of physical exercise in enhancing body functions and structures, activity, and participation in individuals with stroke and examine its safety. DATA SOURCE: Electronic searches were conducted on MEDLINE, CINAHL, PEDro, PubMed, PsycINFO, and Science Citation Index. STUDY SELECTION: Randomized controlled trials (RCTs) that investigated the effects of WBV among individuals with stroke were identified by 2 independent researchers. Ten articles (9 studies, totaling 333 study participants) satisfied the selection criteria and were included in this review. DATA EXTRACTION: The methodological quality was rated using the PEDro scale. The results were extracted by 2 independent researchers and confirmed with the principal investigator. DATA SYNTHESIS: Only 2 RCTs were considered as demonstrating level 1 evidence (PEDro score >=6 and sample size >50). Two RCTs examined the effects of a single WBV session, and 7 RCTs examined the effects of WBV programs spanning 3 to 12 weeks. No consistent benefits on bone turnover, leg motor function, balance, mobility, sensation, fall rate, activities of daily living, or societal participation were found, regardless of the nature of the comparison group. Adverse events were minor. LIMITATIONS: A broad approach was used, with stroke as an inclusion criterion for review. No solid evidence was found concerning the effects of WBV on subgroups of people with specific stroke-related deficits due to the heterogeneity of patient groups. CONCLUSIONS: Based on the review, there is insufficient evidence to support clinical use of WBV in enhancing body functions and structures, activity, and participation after stroke. PMID- 24786941 TI - Experiences of exercise during pregnancy among women who perform regular resistance training: a qualitative study. AB - BACKGROUND: Women who are pregnant and healthy are recommended to do 30 minutes or more of light to moderate exercise a day on most, if not all, days of the week. However, only 1 of 6 pregnant women in the United States and northern Europe follows these recommendations. Little attention has been given to the experience of exercise in pregnancy. OBJECTIVES: The aim of the study was to describe experiences of exercise during pregnancy among women who performed regular resistance training. DESIGN: This was a qualitative, inductive content analysis study. METHODS: Seventeen pregnant women who exercised on a regular basis participated in individual semistructured, face-to-face interviews that were recorded, transcribed, coded, and condensed into subcategories and categories. RESULTS: Four categories emerged (subcategories within parentheses): (1) positive impact on body and mind (reduced pregnancy-related problems, increased self-confidence and sense of control, immediate positive feedback, and effects on lifestyle and quality of life); (2) expected benefits and facilitators (knowledge of health benefits, part of one's lifestyle, preventing pregnancy related problems, social support, staying in good shape, and healthy living with regard to the fetus); (3) new exercise barriers (physical limitations, taking care not to harm oneself or the fetus, uncertainty or lack of knowledge, sense of exclusion at the fitness center, lack of understanding on the part of others, and the pregnancy itself provided an easy excuse); and (4) overcoming exercise barriers (lowering the intensity of exercise, modifying the type of exercise, changing exercise goals, and being extra attentive during exercise). CONCLUSION: Pregnant women strived to exercise if the exercise facilitators outweighed the barriers. As the study described facilitators, barriers, and strategies for how to overcome exercise barriers, the results can be useful in exercise promotion in healthy pregnancy. PMID- 24786942 TI - Identifying items to assess methodological quality in physical therapy trials: a factor analysis. AB - BACKGROUND: Numerous tools and individual items have been proposed to assess the methodological quality of randomized controlled trials (RCTs). The frequency of use of these items varies according to health area, which suggests a lack of agreement regarding their relevance to trial quality or risk of bias. OBJECTIVE: The objectives of this study were: (1) to identify the underlying component structure of items and (2) to determine relevant items to evaluate the quality and risk of bias of trials in physical therapy by using an exploratory factor analysis (EFA). DESIGN: A methodological research design was used, and an EFA was performed. METHODS: Randomized controlled trials used for this study were randomly selected from searches of the Cochrane Database of Systematic Reviews. Two reviewers used 45 items gathered from 7 different quality tools to assess the methodological quality of the RCTs. An exploratory factor analysis was conducted using the principal axis factoring (PAF) method followed by varimax rotation. RESULTS: Principal axis factoring identified 34 items loaded on 9 common factors: (1) selection bias; (2) performance and detection bias; (3) eligibility, intervention details, and description of outcome measures; (4) psychometric properties of the main outcome; (5) contamination and adherence to treatment; (6) attrition bias; (7) data analysis; (8) sample size; and (9) control and placebo adequacy. LIMITATION: Because of the exploratory nature of the results, a confirmatory factor analysis is needed to validate this model. CONCLUSIONS: To the authors' knowledge, this is the first factor analysis to explore the underlying component items used to evaluate the methodological quality or risk of bias of RCTs in physical therapy. The items and factors represent a starting point for evaluating the methodological quality and risk of bias in physical therapy trials. Empirical evidence of the association among these items with treatment effects and a confirmatory factor analysis of these results are needed to validate these items. PMID- 24786944 TI - Clinical experience using a 5-week treadmill training program with virtual reality to enhance gait in an ambulatory physical therapy service. AB - BACKGROUND: Current literature views safe gait as a complex task, relying on motor and cognitive resources. The use of virtual reality (VR) in gait training offers a multifactorial approach, showing positive effects on mobility, balance, and fall risk in elderly people and individuals with neurological disorders. This form of training has been described as a viable research tool; however, it has not been applied routinely in clinical practice. Recently, VR was used to develop an adjunct training method for use by physical therapists in an ambulatory clinical setting. OBJECTIVE: The aim of this article is to describe the initial clinical experience of applying a 5-week VR clinical service to improve gait and mobility in people with a history of falls, poor mobility, or postural instability. DESIGN: A retrospective data analysis was conducted. METHODS: The clinical records of the first 60 patients who completed the VR gait training program were examined. Training was provided 3 times per week for 5 weeks, with each session lasting approximately 1 hour and consisting of walking on a treadmill while negotiating virtual obstacles. Main outcome measures were compared across time and included the Timed "Up & Go" Test (TUG), the Two-Minute Walk Test (2MWT), and the Four Square Step Test (FSST). RESULTS: After 5 weeks of training, time to complete the TUG decreased by 10.3%, the distance walked during the 2MWT increased by 9.5%, and performance on the FSST improved by 13%. LIMITATIONS: Limitations of the study include the use of a retrospective analysis with no control group and the lack of objective cognitive assessment. CONCLUSIONS: Treadmill training with VR appears to be an effective and practical tool that can be applied in an outpatient physical therapy clinic. This training apparently leads to improvements in gait, mobility, and postural control. It, perhaps, also may augment cognitive and functional aspects. PMID- 24786943 TI - Can change in prolonged walking be inferred from a short test of gait speed among older adults who are initially well-functioning? AB - BACKGROUND: The ability to walk for short and prolonged periods of time is often measured with separate walking tests. It is unclear whether decline in the 2 minute walk coincides with decline in a shorter 20-m walk among older adults. OBJECTIVE: The aim of this study was to describe patterns of change in the 20-m walk and 2-minute walk over 8 years among a large cohort of older adults. Should change be similar between tests of walking ability, separate retesting of prolonged walking may need to be reconsidered. DESIGN: A longitudinal, observational cohort study was conducted. METHODS: Data were from 1,893 older adults who were well-functioning (>=70 years of age). The 20-m walk and 2-minute walk were repeatedly measured over 8 years to measure change during short and prolonged periods of walking, respectively. Change was examined using a dual group-based trajectory model (dual model), and agreement between walking trajectories was quantified with a weighted kappa statistic. RESULTS: Three trajectory groups for the 20-m walk and 2-minute walk were identified. More than 86% of the participants were in similar trajectory groups for both tests from the dual model. There was high chance-corrected agreement (kappa=.84; 95% confidence interval=.82, .86) between the 20-m walk and 2-minute walk trajectory groups. LIMITATIONS: One-third of the original Health, Aging and Body Composition (Health ABC) study cohort was excluded from analysis due to missing clinic visits, followed by being excluded for health reasons for performing the 2-minute walk, limiting generalizability to healthy older adults. CONCLUSIONS: Patterns of change in the 2-minute walk are similar to those in the 20-m walk. Thus, separate retesting of the 2-minute walk may need to be reconsidered to gauge change in prolonged walking. PMID- 24786945 TI - Effects of the Fitkids exercise therapy program on health-related fitness, walking capacity, and health-related quality of life. AB - BACKGROUND: Children with disabilities have an increased risk for reduced fitness and reduced health-related quality of life (HRQoL). Fitkids, a nationwide exercise therapy program in the Netherlands, was developed to improve fitness and HRQoL in children with disabilities. OBJECTIVE: The study objective was to determine the effects of the Fitkids program on health-related fitness, walking capacity, and HRQoL in children with disabilities or chronic conditions. DESIGN: This was a quasi-experimental single-group longitudinal study. METHODS: Fifty-two children and adolescents who were referred to the Fitkids program participated in this study. Participants received a graded exercise training program for 6 months, with frequencies of 1 hour 2 times per week in the first 3 months and 1 hour per week during months 4 to 6. Health-related fitness (aerobic fitness, anaerobic fitness, and muscle strength), walking capacity, and HRQoL were evaluated at baseline and after 3 and 6 months of training. Multilevel modeling was used to quantify the contributions of repeated measures, participants, and Fitkids centers to variations in health-related fitness, walking capacity, and HRQoL during the intervention period. The models were adjusted for sex, height, and weight. RESULTS: After 6 months of training, significant intervention effects were found for aerobic fitness, anaerobic fitness, and muscle strength. A significant effect also was found for walking capacity. On the HRQoL measure, significant improvements were found for the self-reported and parent-reported physical and emotion domains and for the parent-reported total score for HRQoL. LIMITATIONS: No control group was included in this study. CONCLUSIONS: The Fitkids exercise therapy program has significantly improved health-related fitness, walking capacity, and HRQoL in children and adolescents with chronic conditions or disabilities. PMID- 24786947 TI - Measurement properties of gait-related outcomes in youth with neuromuscular diagnoses: a systematic review. AB - BACKGROUND: Sound measurement properties of outcome tools are essential when evaluating outcomes of an intervention, in clinical practice and in research. PURPOSE: The purpose of this study was to review the evidence on reliability, measurement error, and responsiveness of measures of gait function in children with neuromuscular diagnoses. DATA SOURCES: The MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched up to June 15, 2012. STUDY SELECTION: Studies evaluating reliability, measurement error, or responsiveness of measures of gait function in 1- to 18-year-old children and youth with neuromuscular diagnoses were included. DATA EXTRACTION: Quality of the studies was independently rated by 2 raters using a modified COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. Studies with a fair quality rating or better were considered for best evidence synthesis. DATA SYNTHESIS: Regarding the methodological quality, 32 out of 35 reliability studies, all of the 13 measurement error studies, and 5 out of 10 responsiveness studies were of fair or good quality. Best evidence synthesis revealed moderate to strong evidence for reliability for several measures in children and youth with cerebral palsy (CP) but was limited or unknown in other diagnoses. The Functional Mobility Scale (FMS) and the Gross Motor Function Measure (GMFM) dimension E showed limited positive evidence for responsiveness in children with CP, but it was unknown or controversial in other diagnoses. No information was reported on the minimal important change; thus, evidence on measurement error remained undetermined. LIMITATIONS: As studies on validity were not included in the review, a comprehensive appraisal of the best available gait-related outcome measure per diagnosis is not possible. CONCLUSIONS: There is moderate to strong evidence on reliability for several measures of gait function in children and youth with CP, whereas evidence on responsiveness exists only for the FMS and the GMFM dimension E. PMID- 24786946 TI - Build better bones with exercise: protocol for a feasibility study of a multicenter randomized controlled trial of 12 months of home exercise in women with a vertebral fracture. AB - BACKGROUND: Our goal is to conduct a multicenter randomized controlled trial (RCT) to investigate whether exercise can reduce incident fractures compared with no intervention among women aged >=65 years with a vertebral fracture. OBJECTIVES: This pilot study will determine the feasibility of recruitment, retention, and adherence for the proposed trial. DESIGN: The proposed RCT will be a pilot feasibility study with 1:1 randomization to exercise or attentional control groups. SETTING: Five Canadian sites (1 community hospital partnered with an academic center and 4 academic hospitals or centers affiliated with an academic center) and 2 Australian centers (1 academic hospital and 1 center for community primary care, geriatric, and rehabilitation services). PARTICIPANTS: One hundred sixty women aged >=65 years with vertebral fracture at 5 Canadian and 2 Australian centers will be recruited. INTERVENTION: The Build Better Bones With Exercise (B3E) intervention includes exercise and behavioral counseling, delivered by a physical therapist in 6 home visits over 8 months, and monthly calls; participants are to exercise >=3 times weekly. Controls will receive equal attention. MEASUREMENTS: Primary outcomes will include recruitment, retention, and adherence. Adherence to exercise will be assessed via calendar diary. Secondary outcomes will include physical function (lower extremity strength, mobility, and balance), posture, and falls. Additional secondary outcomes will include quality of life, pain, fall self-efficacy, behavior change variables, intervention cost, fractures, and adverse events. Analyses of feasibility objectives will be descriptive or based on estimates with 95% confidence intervals, where feasibility will be assessed relative to a priori criteria. Differences in secondary outcomes will be evaluated in intention-to-treat analyses via independent Student t tests, chi-square tests, or logistic regression. The Bonferroni method will be used to adjust the level of significance for secondary outcomes so the overall alpha level is .05. LIMITATIONS: No assessment of bone mineral density will be conducted. The proposed definitive trial will require a large sample size. CONCLUSIONS: The viability of a large-scale exercise trial in women with vertebral fractures will be evaluated, as well as the effects of a home exercise program on important secondary outcomes. PMID- 24786950 TI - Complete genome sequences of the first reported california h16 influenza a viruses. AB - Two reassortant H16 influenza A viruses were isolated from gulls in California. Seven of the eight segments were most closely related to H16 and H13 isolates from eastern North America and Iceland. Of note is a C-terminal truncation of the nonstructural 1 (NS1) protein in one of the isolates that is usually found in swine H1N1 virus. PMID- 24786949 TI - Toward an optimal docking and free energy calculation scheme in ligand design with application to COX-1 inhibitors. AB - Cyclooxygenase-1 (COX-1) is one of the main targets of most pain-relieving pharmaceuticals. Although the enzyme is well characterized, it is known to be a difficult target for automated molecular docking and scoring. We collected from the literature a structurally diverse set of 45 nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2-selective inhibitors (coxibs) with a wide range of binding affinities for COX-1. The binding of this data set to a homology model of human COX-1 was analyzed with different combinations of molecular docking algorithms, scoring functions, and the linear interaction energy (LIE) method for estimating binding affinities. It is found that the computational protocols for estimation of binding affinities are extremely sensitive to the initial orientations of the ligands in the binding pocket. To overcome this limitation, we propose a systematic exploration of docking poses using the LIE calculations as a postscoring function. This scheme yields predictions in excellent agreement with experiment, with a mean unsigned error of 0.9 kcal/mol for binding free energies and structures of high quality. A significant improvement of the results is also seen when averaging over experimental data from several independent measurements. PMID- 24786948 TI - GRIK1 genotype moderates topiramate's effects on daily drinking level, expectations of alcohol's positive effects and desire to drink. AB - We (Kranzler et al., 2014) reported that topiramate 200 mg/day reduced heavy drinking days and increased abstinent days in 138 heavy drinkers whose treatment goal was to reduce drinking to safe levels. In that 12-week, placebo-controlled study, we measured drinking using the Timeline Follow-back method at each treatment visit. In addition to the intent-to-treat effects of topiramate, we found that a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the GluK1 subunit of the kainate receptor, moderated the treatment effect in European Americans (EAs; n = 122). Topiramate reduced heavy drinking only in rs2832407*C allele homozygotes. Here, we augment those analyses by using patients' daily reports obtained using interactive voice response technology; (a) to validate the interactive effects of GRIK1 and topiramate as predictors of drinking level; and, (b) to examine changes in expected positive effects of drinking (i.e. positive outcome expectancies) and desire to drink. We found that rs2832407*C allele homozygotes treated with topiramate drank less overall during treatment than those receiving placebo, validating our earlier findings for heavy drinking days (Kranzler et al., 2014). There was also a study day * medication group * genotype group interaction that predicted both positive alcohol expectancies and desire to drink, with rs2832407*C-allele homozygotes treated with topiramate showing the largest decreases in these outcomes during the study period. Changes in positive alcohol expectancies or desire to drink did not mediate the effects on drinking. These findings validate and extend our previous pharmacogenetic findings with topiramate. PMID- 24786951 TI - Draft Genome Sequence of Fervidicella metallireducens Strain AeBT, an Iron Reducing Thermoanaerobe from the Great Artesian Basin. AB - The genome sequence of Fervidicella metallireducens strain AeB(T), a curved, heterotrophic, thermoanaerobic, and iron-reducing bacterium isolated from a gray microbial mat colonizing the free-flowing waters of a Great Artesian Basin (GAB) bore well located in outback Queensland, Australia, is reported here. The analysis of the 2.9-Mb sequence indicates that the attributes of the genome are consistent with its physiological and phenotypic traits. PMID- 24786952 TI - Identification of a novel single-stranded circular DNA virus in pig feces. AB - Porcine stool-associated circular virus 5 (PoSCV5) was detected in the feces of a pig with diarrhea. The complete 3,062-nucleotide genome contains two bidirectionally transcribed open reading frames (ORFs). Phylogenetic analysis of the deduced replication initiator protein (Rep) places PoSCV5 alone on a deep branch among the small circular Rep-encoding single-stranded DNA viruses. PMID- 24786953 TI - High-Quality Draft Whole-Genome Sequences of 162 Salmonella enterica subsp. enterica Serovar Enteritidis Strains Isolated from Diverse Sources in Canada. AB - We report the high-quality draft genome sequences of 162 strains of Salmonella enterica subsp. enterica serovar Enteritidis representing diverse phage types and pulsed-field gel electrophoresis (PFGE) profiles. The analysis of these genomes will enable the identification of markers that are useful for differentiating strains of this highly clonal serovar and will provide insights into the evolution, virulence, and epidemiology of the strains. PMID- 24786954 TI - Draft Genome Sequence of Mycobacterium mageritense DSM 44476T. AB - We report the draft genome sequence of Mycobacterium mageritense strain DSM 44476(T) (CIP 104973), a nontuberculosis species responsible for various infections. The genome described here is composed of 7,966,608 bp, with a G+C content of 66.95%, and contains 7,675 protein-coding genes and 120 predicted RNA genes. PMID- 24786955 TI - Draft Genome Sequence of Photorhabdus luminescens Strain BA1, an Entomopathogenic Bacterium Isolated from Nematodes Found in Egypt. AB - Photorhabdus luminescens strain BA1 is an entomopathogenic bacterium that forms a symbiotic association with Heterorhabditis nematodes. We report here a 5.0-Mbp draft genome sequence for P. luminscens strain BA1, with a G+C content of 42.46% and 4,250 candidate protein-coding genes. PMID- 24786956 TI - Complete Genome Sequence of Trueperella pyogenes, an Important Opportunistic Pathogen of Livestock. AB - Here, we report the complete genome sequence of Trueperella pyogenes TP6375, a strain isolated from the uterus of a dairy cow affected with metritis. The complete circular genome is 2,338,390 bp and contains several genes needed for pathogenicity. PMID- 24786957 TI - Genome Sequences of Three Frequently Used Listeria monocytogenes and Listeria ivanovii Strains. AB - We present the complete de novo assembled genome sequences of Listeria monocytogenes strains WSLC 1001 (ATCC 19112) and WSLC 1042 (ATCC 23074) and Listeria ivanovii WSLC 3009, three strains frequently used for the propagation and study of bacteriophages because they are presumed to be free of inducible prophages. PMID- 24786958 TI - Draft Genome Sequence of Fusobacterium necrophorum subsp. funduliforme Bovine Liver Abscess Isolate B35. AB - Fusobacterium necrophorum is a Gram-negative anaerobic bacterium that causes foot rot and liver abscesses in cattle. F. necrophorum subsp. necrophorum and the less virulent organism F. necrophorum subsp. funduliforme are recognized. We present here a draft genome sequence of the bovine liver abscess isolate F. necrophorum subsp. funduliforme strain B35, which affords a genomic perspective of virulence and bovine adaptation. PMID- 24786959 TI - Draft Genome Sequence of the Gluconobacter oxydans Strain DSM 2003, an Important Biocatalyst for Industrial Use. AB - Gluconobacter oxydans strain DSM 2003 can efficiently produce some industrially important building blocks, such as (R)-lactic acid and (R)-2-hydroxybutyric acid. Here, we present a 2.94-Mb assembly of its genome sequence, which might provide further insights into the molecular mechanism of its biocatalysis in order to further improve its biotechnological applications. PMID- 24786960 TI - Molecular characterization of the full kobuvirus genome in a cat. AB - Kobuviruses, which belong to the family Picornaviridae, have been detected in fecal samples from infected animals with or without diarrhea. Here, we report the first complete genome sequence of a feline kobuvirus (FKoV) strain, FK-13, identified from the feces of a cat with diarrhea in South Korea in 2011. PMID- 24786961 TI - Genome Sequence of the Nonpathogenic Pseudomonas aeruginosa Strain ATCC 15442. AB - Pseudomonas aeruginosa ATCC 15442 is an environmental strain of the Pseudomonas genus. Here, we present a 6.77-Mb assembly of its genome sequence. Besides giving insights into characteristics associated with the pathogenicity of P. aeruginosa, such as virulence, drug resistance, and biofilm formation, the genome sequence may provide some information related to biotechnological utilization of the strain. PMID- 24786962 TI - Major difficulties and information needs recognised by nurses in applying graduated compression stocking and intermittent pneumatic compression for deep vein thrombosis prophylaxis. PMID- 24786963 TI - Oriented mesoporous nanopyramids as versatile plasmon-enhanced interfaces. AB - We developed a facile interfacial oriented growth and self-assembly process to fabricate three-dimensional (3D) aligned mesoporous iron oxide nanopyramid arrays (NPAs). The unique NPAs possess a 3D mesostructure with multiple features, including high surface area (~175 m(2)/g), large pore size (~20 nm), excellent flexibility (bent over 150 times), and scalability at the foot scale for practical applications. More importantly, these NPAs structures enable versatile enhancement of localized surface plasmon resonance and photoelectrochemical conversion. The integration of plasmonic gold with 3D NPAs remarkably improves the performance of photoelectrochemical conversion, leading to ~6- and 83-fold increases of the photocurrent under simulated solar and visible-light illumination, respectively. The fabrication and investigation of NPAs provide a new paradigm for preparing unconventional mesoporous oriented thin films and further suggest a new strategy for designing plasmonic metal/semiconductor systems for effective solar energy harvesting. PMID- 24786964 TI - Continuous-flow synthesis of trimethylsilylphenyl perfluorosulfonate benzyne precursors. AB - 2-(Trimethylsilyl)phenyl perfluorosulfonated aryne precursors may now be accessed using flow chemistry, enabling the fast preparation of pure compounds with no requirement for low temperature lithiation or column chromatography. The process has been adapted to novel nonaflate precursors, utilizing the cheaper and more user-friendly nonaflyl fluoride reagent. The resultant nonaflates are shown to successfully participate in a range of aryne reaction classes. PMID- 24786966 TI - The use of cue familiarity during retrieval failure is affected by past versus future orientation. AB - Cue familiarity that is brought on by cue resemblance to memory representations is useful for judging the likelihood of a past occurrence with an item that fails to actually be retrieved from memory. The present study examined the extent to which this type of resemblance-based cue familiarity is used in future-oriented judgments made during retrieval failure. Cue familiarity was manipulated using a previously-established method of creating differing degrees of feature overlap between the cue and studied items in memory, and the primary interest was in how these varying degrees of cue familiarity would influence future-oriented feeling of-knowing (FOK) judgments given in instances of cued recall failure. The present results suggest that participants do use increases in resemblance-based cue familiarity to infer an increased likelihood of future recognition of an unretrieved target, but not to the extent that they use it to infer an increased likelihood of past experience with an unretrieved target. During retrieval failure, the increase in future-oriented FOK judgments with increasing cue familiarity was significantly less than the increase in past-oriented recognition judgments with increasing cue familiarity. PMID- 24786965 TI - Analysis of SecA dimerization in solution. AB - The Sec pathway mediates translocation of protein across the inner membrane of bacteria. SecA is a motor protein that drives translocation of preprotein through the SecYEG channel. SecA reversibly dimerizes under physiological conditions, but different dimer interfaces have been observed in SecA crystal structures. Here, we have used biophysical approaches to address the nature of the SecA dimer that exists in solution. We have taken advantage of the extreme salt sensitivity of SecA dimerization to compare the rates of hydrogen-deuterium exchange of the monomer and dimer and have analyzed the effects of single-alanine substitutions on dimerization affinity. Our results support the antiparallel dimer arrangement observed in one of the crystal structures of Bacillus subtilis SecA. Additional residues lying within the preprotein binding domain and the C-terminus are also protected from exchange upon dimerization, indicating linkage to a conformational transition of the preprotein binding domain from an open to a closed state. In agreement with this interpretation, normal mode analysis demonstrates that the SecA dimer interface influences the global dynamics of SecA such that dimerization stabilizes the closed conformation. PMID- 24786967 TI - Development of a new tool to evaluate work support needs and guide vocational rehabilitation: the work-ability support scale (WSS). AB - PURPOSE: This article outlines our overall approach, qualitative work, and pilot testing to develop a tool to facilitate identification of level of support needs and assist in planning for vocational rehabilitation interventions. METHODS: A set of foundation principles drawn from literature and previous critiques of work ability assessment tools were used to guide a set of studies to develop a new tool. A review of the literature regarding factors that influence work-ability, qualitative interviews and focus groups with a range of stakeholders in the return-to-work process, and pilot testing in different settings were used to develop the Work-ability Support Scale (WSS) to a stage where it had face validity, usability and acceptability for a range of key stakeholders and was ready for further testing. RESULTS: Qualitative work and pilot testing enhanced the proposed tool with a series of changes and refinements to the content, structure and scoring framework. The current version of the tool is presented. Inter-rater reliability is presented elsewhere. CONCLUSION: Core principles and stakeholders' views (injured or sick workers, employers, case managers and health professionals) support current tool design. Although further testing is required, the WSS appears to hold potential for use in the assessment of vocational rehabilitation needs. PMID- 24786968 TI - "It's fun, but ..." Children with cerebral palsy and their experiences of participation in physical activities. AB - PURPOSE: To explore the experiences of children with cerebral palsy (CP) regarding participation in physical activities, and to describe facilitators and barriers. METHODS: Sixteen children with CP 8-11 years old who varied in gross motor, cognitive and communicative function participated in either an individual interview or a focus group. RESULTS: Two categories and 10 sub-categories emerged from the content analysis. The category "Being physically active, because ..." describes facilitators for being physically active divided into the sub categories "Enjoying the feeling", "Being capable", "Feeling of togetherness", "Being aware it is good for me", and "Using available opportunities". The second category "Being physically active, but ..." describes barriers to being physically active, divided into the sub-categories "Getting tired and experiencing pain", "Something being wrong with my body", "Being dependent on others", "Not being good enough" and "Missing available opportunities". CONCLUSIONS: Asking children with CP about the physical activities they enjoy, and giving them the opportunity of trying self-selected activities with the right support is important for facilitating an increased participation in physical activities. Having fun with family and friends when being physically active, and enjoying the sensation of speed should be taken into consideration when designing interventions. When supporting children to become and remain physically active, attention should be paid to pain, fatigue and the accessibility of activities and locations. Implications for Rehabilitation Children want to be physically active together with friends or others. Children want to have fun and enjoy the sensation of speed when being physically active. Self-selected physical activities and the opportunity of trying new activities with the right support is essential for facilitating an increased participation in physical activities. Service planning and design may be facilitated by asking children about the physical activities they enjoy. PMID- 24786970 TI - DeafSpace and the principles of universal design. AB - PURPOSE: Recent debates about the epistemological origins of Universal Design (UD) have questioned how far universalist design approaches can address the particularities and diversities of the human form through a series of standardised, technical responses. This article contributes to these debates by discussing an emergent architectural paradigm known as DeafSpace, which articulates a set of design principles originating from the d/Deaf community in the US. METHOD: Commentary. RESULTS: DeafSpace has emerged as a design paradigm rooted in an expression of d/Deaf cultural identity based around sign language, rather than as a response designed to compensate for, or minimise, impairment. It distinguishes itself from UD by articulating a more user-centred design process, but its principles are arguably rooted in notions of d/Deaf identity based around consensus and homogeneity, with less attention paid to the socio-political contexts which shape diverse experiences of d/Deafness and the exclusion(s) of d/Deaf people from the built environment. CONCLUSIONS: While proponents of DeafSpace argue that UD and DeafSpace are not mutually exclusive, nor DeafSpace principles applicable only to d/Deaf people, questions remain about the type of spaces DeafSpace creates, most notably whether they lead to the creation of particularist spaces of and for the d/Deaf community, or reflect a set of design principles which can be embedded across a range of different environments. Implications for Rehabilitation UD as a basis for rehabilitation has been critiqued on the basis that creates "standardised", or universal solutions, thus negating the particularities of the human form. DeafSpace is an architectural paradigm rooted in socio-linguistic understandings of Deafness and the cultural identity of the Deaf community. It challenges UD's technocratic emphasis on minimising impairment and asserts design which is rooted in a more qualitative understanding of individuals' relationship with their environment. DeafSpace seeks to place the user more centrally in the design process and draw on the experiential knowledge of (Deaf) users. However, it has less to say about the often exclusionary socio-political relations which underlie the built environment and shape the diverse experience of deafness. DeafSpace raises questions about how the needs of particular groups can be met through UD principles and in turn whether DeafSpace principles lead to the creation of separate spaces for the D/deaf community. PMID- 24786969 TI - Gender perspective on fear of falling using the classification of functioning as the model. AB - PURPOSE: To investigate associations between fear of falling (FOF) and recurrent falls among women and men, and gender differences in FOF with respect to International Classification of Functioning (ICF). METHODS: Community-dwelling people (n = 230, 75-93 years, 72% women) were included and followed 1 year regarding falls. Data collection included self-reported demographics, questionnaires, and physical performance-based tests. FOF was assessed with the question "Are you afraid of falling?". RESULTS were discussed with a gender relational approach. RESULTS: At baseline 55% women (n = 92) and 22% men (n = 14) reported FOF. During the follow-up 21% women (n = 35) and 30% men (n = 19) experienced recurrent falls. There was an association between gender and FOF (p = 0.001), but not between FOF and recurrent falls (p = 0.79), or between gender and recurrent falls (p = 0.32). FOF was related to Personal factors and Activity and Participation. The relationship between FOF and Personal factors was in opposite directions for women and men. CONCLUSIONS: Results did not support the prevailing paradigm that FOF increases rate of recurrent falls in community-dwelling people, and indicated that the answer to "Are you afraid of falling?" might be highly influenced by gendered patterns. PMID- 24786971 TI - Patterns of interaction between factors that enhance or inhibit recovery from chronic low back pain. AB - PURPOSE: This interview study aimed to capture an account of change in low back pain over time and understand the interaction of known bio-psychosocial risk factors. METHODS: Thirty-four participants from the Back Skills Training (BeST) U.K. trial, evaluating a cognitive behavioural approach intervention for LBP, gave 61 interviews. Semi-structured interviews taken once or twice post intervention explored participants' experiences of LBP and the intervention received. Initial thematic analysis of the data gave themes, which participants spoke about in an integrated way. Rereading of whole transcripts identified interactions between themes, which we classified as helpful or unhelpful to recovery. The team also explored whether there were correlations with Roland and Morris Disability Questionnaire (RMDQ) scores from the main trial. RESULTS: Web diagrams gave a graphic representation of the interactions between factors, which were highly individual and time specific. We identified three categories of webs; dense web (mostly unhelpful), open web (helpful and unhelpful) and sparse web (mostly helpful). These categories correlated with (RMDQ) scores. CONCLUSIONS: Facilitators as well as potential barriers to recovery give added insight when considering psychosocial risk factors. Web categories highlight patterns of interaction between psychosocial factors, which underlie levels of disability. These patterns of interaction may help to guide clinicians in their choice of treatment approaches. PMID- 24786972 TI - Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer. AB - Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored. PMID- 24786973 TI - Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. AB - RATIONALE: Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation. OBJECTIVE: Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction. METHODS AND RESULTS: Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ~1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3+/-3.4%, whereas heart macrophages showed a much lower chimerism of 2.7+/-0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1+/-0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7+/-1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation. CONCLUSIONS: In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure. PMID- 24786975 TI - Comments on "defining professionalism in medical education: a systematic review". PMID- 24786974 TI - Aqueous two-phase system patterning of detection antibody solutions for cross reaction-free multiplex ELISA. AB - Accurate disease diagnosis, patient stratification and biomarker validation require the analysis of multiple biomarkers. This paper describes cross reactivity-free multiplexing of enzyme-linked immunosorbent assays (ELISAs) using aqueous two-phase systems (ATPSs) to confine detection antibodies at specific locations in fully aqueous environments. Antibody cross-reactions are eliminated because the detection antibody solutions are co-localized only to corresponding surface-immobilized capture antibody spots. This multiplexing technique is validated using plasma samples from allogeneic bone marrow recipients. Patients with acute graft versus host disease (GVHD), a common and serious condition associated with allogeneic bone marrow transplantation, display higher mean concentrations for four multiplexed biomarkers (HGF, elafin, ST2 and TNFR1) relative to healthy donors and transplant patients without GVHD. The antibody co localization capability of this technology is particularly useful when using inherently cross-reactive reagents such as polyclonal antibodies, although monoclonal antibody cross-reactivity can also be reduced. Because ATPS-ELISA adapts readily available antibody reagents, plate materials and detection instruments, it should be easily transferable into other research and clinical settings. PMID- 24786976 TI - Regulatory neuropeptides (ghrelin, obestatin and nesfatin-1) levels in serum and reproductive tissues of female and male rats with fructose-induced metabolic syndrome. AB - Although, the exact mechanisms underlying the development of the metabolic syndrome (MetS) are not still completely understood, obesity, circulated peptide hormone levels and their interaction with genetic factors are considered largely responsible. The purpose of this study is to explore how the levels of ghrelin, obestatin (OBS) and NUCB2/nesfatin-1 (NES)/NUCB2 change in serum and the reproductive tissues of female and male rats with fructose-induced metabolic syndrome, and whether the levels of each hormone is correlated with the hormones involved with fertility. Experiments were conducted on 5-week-old Sprague-Dawley male and female rats assigned to either a control group or a MetS group. Controls were fed standard rat food and water ad libitum, while the MetS group was fed standard food with 10% (v/v) fructose solution added to their drinking water for 12 weeks with a 12/12h photoperiod circle. Then, all animals were sacrificed after a one night fast. Peptides levels in the serum and reproductive tissues of rats were studied using the ELISA method while the immunoreactivity of reproductive system peptide hormones were shown by immunohistochemical staining method. Furthermore, the other biochemical parameters were measured using Konelab 60 equipment and infertility hormones were measured with Immulite2000. Fasting serum insulin, glucose, triglyceride, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels were statistically significantly higher, and the amount of high density lipoprotein cholesterol (HDL-C) was significantly lower, in the MetS groups. Serum and tissue supernatant NES levels were significantly higher in the rats with MetS than the control group. Ghrelin, OBS and NES were expressed in the cytoplasm, concentrated around the apical parts of the epithelial cells in the reproductive tissues of the rats. The amounts of ghrelin were lower in the reproductive tissues of the animals with MetS, while NES levels in the same tissues increased. Obestatin also decreased, though not in the seminal glands. PMID- 24786977 TI - Angiotensin II inhibits uptake of transferrin-bound iron but not non-transferrin bound iron by cultured astrocytes. AB - The existence of all components of the renin-angiotensin system (RAS) and the iron metabolism system, and the recent findings on the functions of angiotensin II (ANGII) in peripheral iron metabolism imply that ANGII might play a role in iron homeostasis by regulating expression of iron transport proteins in the brain. Here, we investigated effects of ANGII on uptake and release of iron as well as expression of cell iron transport proteins in cultured astrocytes. We demonstrated that ANGII could significantly inhibit transferrin-bound iron (Tf Fe) uptake and iron release as well as the expression of transferrin receptor 1 (TfR1) and the iron exporter ferroportin 1 (Fpn1) in cultured astrocytes. This indicated that the inhibitory role of ANGII on Tf-Fe uptake and iron release is mediated by its negative effect on the expression of TfR1 and Fpn1. We also provided evidence that ANGII had no effect on divalent metal transporter 1 (DMT1) expression as well as non-transferrin-bound iron (NTBI) uptake in the cells. Our findings showed that ANGII has a role to affect expression of iron transport proteins in astrocytes in vitro and also suggested that ANGII might have a physiological function in brain iron homeostasis. PMID- 24786978 TI - Zitterbewegung of electrons in carbon nanotubes created by laser pulses. AB - We describe a possibility of creating non-stationary electron wave packets in zigzag carbon nanotubes (CNT) illuminated by short laser pulses. After the disappearance of the pulse the packet experiences a trembling motion (Zitterbewegung, ZB). The band structure of CNT is calculated using the tight binding approximation generalized for the presence of radiation. By employing realistic pulse and CNT parameters we obtain the ZB oscillations with interband frequencies corresponding to specific pairs of energy bands. A choice of optimal parameters is presented in order to observe the phenomenon of ZB experimentally. The use of Gaussian wave packets to trigger the electron Zitterbewegung, as used in the literature, is critically reexamined. PMID- 24786979 TI - Left ventricular pacing threshold and outcome in MADIT-CRT. AB - INTRODUCTION: High left ventricular (LV) pacing threshold (PT) may in some cases indicate the presence of scarred myocardium, a predictor of poor outcome in cardiac resynchronization therapy (CRT) treated patients. We hypothesized that intraoperative LVPT can be used to determine echocardiographic and clinical responses to CRT. METHODS AND RESULTS: The study comprised 975 patients enrolled in the CRT-D arm of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Multivariate regression analysis was performed to evaluate the relationship between LVPT and percent reduction in LV end-systolic volume (ESV) and left atrial volume (LAV) 1 year after CRT. Cox proportional hazards analysis was used to evaluate the relationship between LVPT and heart failure (HF) events or death (primary endpoint) and all-cause death (secondary endpoint). An increasing LVPT was inversely related to percent reduction in both LVESV (P = 0.02) and LAV (P<0.01). Patients with LVPT in the highest quartile (>1.8 V) were less likely to achieve reverse LV remodeling (>=15% LVESV reduction from baseline) than those with LVPT in the lower quartiles (hazard ratios [HR] OR 0.56, P = 0.02). Mean percent reduction in LAV and LVESV was also significantly greater among those with lowest quartile LVPT. Multivariate analysis showed borderline significant 13% (P = 0.06) and significant 22% (P = 0.03) increase in the risk of HF/death and death alone, respectively, per 1 volt increase in LVPT. CONCLUSION: High intraoperative LVPT is associated with significantly lower echocardiographic and clinical response to CRT-D. PMID- 24786980 TI - Not just full of hot air: hyperbaric oxygen therapy increases survival in cases of necrotizing soft tissue infections. AB - BACKGROUND: The utility of hyperbaric oxygen therapy (HBOT) in the treatment of necrotizing soft tissue infections (NSTIs) has not been proved. Previous studies have been subject to substantial selection bias because HBOT is not available universally at all medical centers, and there is often considerable delay associated with its initiation. We examined the utility of HBOT for the treatment of NSTI in the modern era by isolating centers that have their own HBOT facilities. METHODS: We queried all centers in the University Health Consortium (UHC) database from 2008 to 2010 that have their own HBOT facilities (n=14). Cases of NSTI were identified by International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, which included Fournier gangrene (608.83), necrotizing fasciitis (728.86), and gas gangrene (040.0). Status of HBOT was identified by the presence (HBOT) or absence (control) of ICD-9 procedure code 93.95. Our cohort was risk-stratified and matched by UHC's validated severity of illness (SOI) score. Comparisons were then made using univariate tests of association and multivariable logistic regression. RESULTS: There were 1,583 NSTI cases at the 14 HBOT-capable centers. 117 (7%) cases were treated with HBOT. Univariate analysis showed that there was no difference between HBOT and control groups in hospital length of stay, direct cost, complications, and mortality across the three less severe SOI classes (minor, moderate, and major). However, for extreme SOI the HBOT group had fewer complications (45% vs. 66%; p<0.01) and fewer deaths (4% vs. 23%; p<0.01). Multivariable analysis showed that patients who did not receive HBOT were less likely to survive their index hospitalization (odds ratio, 10.6; 95% CI 5.2-25.1). CONCLUSION: At HBOT-capable centers, receiving HBOT was associated with a significant survival benefit. Use of HBOT in conjunction with current practices for the treatment of NSTI can be both a cost effective and life-saving therapy, in particular for the sickest patients. PMID- 24786981 TI - Effects of age, maturity and body dimensions on match running performance in highly trained under-15 soccer players. AB - The aim of the present study was to compare, in 36 highly trained under-15 soccer players, the respective effects of age, maturity and body dimensions on match running performance. Maximal sprinting (MSS) and aerobic speeds were estimated. Match running performance was analysed with GPS (GPSport, 1 Hz) during 19 international friendly games (n = 115 player-files). Total distance and distance covered >16 km h(-1) (D > 16 km h(-1)) were collected. Players advanced in age and/or maturation, or having larger body dimensions presented greater locomotor (Cohen's d for MSS: 0.5-1.0, likely to almost certain) and match running performances (D > 16 km h(-1): 0.2-0.5, possibly to likely) than their younger, less mature and/or smaller teammates. These age-, maturation- and body size related differences were of larger magnitude for field test measures versus match running performance. Compared with age and body size (unclear to likely), maturation (likely to almost certainly for all match variables) had the greatest impact on match running performance. The magnitude of the relationships between age, maturation and body dimensions and match running performance were position dependent. Within a single age-group in the present player sample, maturation had a substantial impact on match running performance, especially in attacking players. Coaches may need to consider players' maturity status when assessing their on-field playing performance. PMID- 24786983 TI - Effects of genotype, season, and nitrogen nutrition on gene expression and protein accumulation in wheat grain. AB - Six commercial U.K. cultivars of winter wheat selected to represent different abilities to partition nitrogen into grain protein were grown in replicated field trials at five different sites over three seasons. The proportion of LMW glutenin subunits decreased and the proportion of gliadins increased during grain development and in response to N application. Differences were observed between the proportions of LMW glutenin subunits and gliadins in low- and high-protein grain, these two fractions being decreased and increased, respectively. There was little effect of grain protein content on the proportions of either the HMW glutenin subunits or large glutenin polymers, which are enriched in these subunits, with the latter increasing during development in all cultivars. The proportion of total protein present in polymers in the mature grain decreased with increasing N level. Correlations were also observed between the abundances of gliadin protein transcripts and the corresponding proteins. PMID- 24786982 TI - Decoy receptor 3 polymorphisms are not associated with the risk of esophageal cancer in a Chinese population. AB - Esophageal cancer (EC) is the sixth most common cancer worldwide, and esophageal squamous-cell carcinoma (ESCC) accounts for more than 90% of ECs. We hypothesized that genetic factors might play an important role in ESCC carcinogenesis. We conducted a hospital-based case-control study to evaluate the association between two single nucleotide polymorphisms of decoy receptor 3 (DcR3), namely, rs2297441 G > A and rs2257440 T > C, on the ESCC risk. In all, 629 ESCC cases and 686 controls were included. Genotypes were determined using the ligation detection reaction method. When the DcR3 rs2297441 GG homozygote genotype was used as the reference group, the GA genotype showed no association with the ESCC risk (GA versus GG: adjusted OR = 1.11, 95% CI = 0.88-1.40, p = 0.396); similarly, even the TT genotype showed no association with the ESCC risk (AA versus GG: adjusted OR = 0.80, 95% CI = 0.55-1.18, p = 0.268). Logistic regression analyses revealed that the DcR3 rs2257440 T > C polymorphism was not associated with the ESCC risk. DcR3 rs2297441 G > A and DcR3 rs2257440 T > C polymorphisms may not contribute to the ESCC risk, and additional, larger studies are required to confirm our results. PMID- 24786984 TI - [Community resources prescription for self-care improvement in chronic illnesses. Clinical case management in Primary Health Care]. AB - A case is presented of a 52 year-old male seen in a Primary Care nursing clinic for a type 2 diabetes mellitus metabolic control. The frequency of the visits increased due to perceived difficulties caused by changing the medical treatment. A focused interview was conducted under functional health patterns framework. The patient was unable to write or read, had not worked for the last 25 years, and expressed a lack of control over his self-care. An action plan was prepared, prioritizing Ineffective Health Maintenance, Powerlessness, and Impaired Social Interaction NANDA-I nursing diagnoses. The goals were set at improving knowledge and control over his disease and participating in leisure activities. To achieve these, the social health resources in the area were contacted, and agreed that the patient could attend activities that could improve his self-care and his quality of life. An improvement in his diabetes control was observed in the following evaluations, with an increase in his level of knowledge and self-care. The Primary Health care nurse should consider available community resources by using a comprehensive approach to chronic diseases for their therapeutic benefit and management, especially in those patients with adverse sociocultural conditions. PMID- 24786985 TI - [Variability in the rate of episiotomies and its relation to severe perineal tears and neonatal morbility]. AB - OBJECTIVE: To determine the variability in the use of episiotomy among midwives and its relation to third and fourth-degree tears, and the impact on neonatal morbidity. METHOD: A study was conducted on historical groups from a total of 2,366 eutocic births with a single live fetus greater than or equal to 37 weeks gestation and 18 midwives over a three year period (2009, 2010 and 2011) in "Mancha-Centro" Hospital (Alcazar de San Juan).The outcomes variables for this analysis were the incidence of episiotomy, perineal lacerations, and neonatal morbidity. RESULTS: The variability in the use of episiotomy ranged from 19.5% to 50.1% among the 18 midwives in the study, with an average rate of 34.9% (824). Grouped at intervals, 22.1% (524) had a rate of <=25%, 26.1% (621) between 26 35%, 38% (898) between 36-44%, and 13.7% (323) a rate of >=45%, with homogeneity between the groups for all the confounding factors. There was no statistical association between higher rates of episotomy and pH of umbilical artery<7.10, Apgar score after 5 min<7, and the level of neonatal resuscitation type iii and iv. There was also no relationship between the rate of episiotomy with perineal integrity and third and fourth-degree tears. DISCUSSION: The variability in the rate of episiotomy is high, and it is not related to the increased presence of third and fourth-degree tears or increased neonatal morbidity. Episiotomy rates should not be greater than 25%, in order to prevent perineal trauma or loss of fetal well-being. PMID- 24786988 TI - Elevated lidocaine serum levels following the use of a needle free device in healthy adult volunteers. AB - There is increased concern regarding circulating levels of lidocaine immediately after the use of a needle-free device with buffered lidocaine. As a result, we conducted a prospective study to assess lidocaine circulation after the use of a needle-free device for the delivery of a local anesthetic in 10 healthy adult subjects. After informed consent, 2 peripheral intravenous catheters were placed in the antecubital fossa of each arm. Two milligrams of 1% buffered lidocaine was administered by the study physician via the needle-free device on the dorsum of the subject's hand. Within 2 minutes, a third intravenous catheter was placed in the location of the lidocaine administration and 5 mL of blood was collected from all 3 sites. If blood samples returned positive for lidocaine, they were also collected 1 hour and 2 hours after administration. Toxic levels of lidocaine were found in blood drawn from 2 subjects immediately after lidocaine administration. Results also showed that certain subjects had increasing levels of lidocaine over time. Other subjects also had increasing lidocaine serum levels from blood drawn on the arm opposite the administration site. We concluded that there may be systemic lidocaine levels with the administration of the needle-free device and that these levels may reach the toxic range in adults. Further investigation will be required to determine whether this finding has clinical significance, especially considering the smaller body mass of children. PMID- 24786987 TI - Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 * 10(-4)) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke. PMID- 24786989 TI - Fracture of the anterior arch of atlas after minor trauma of the immature spine postlaminectomy. AB - Torticollis is a common complaint in the pediatric emergency department. Here, we report what we believe to be the first example in a young child of a fracture of the anterior arch of the atlas associated with an acquired, postsurgical defect of the posterior arch. A brief review of pediatric cervical spine injuries and fractures is presented. Atlas laminectomy may predispose patients to isolated atlas fractures even with minor trauma. Those fractures, however, are stable and treated by hard cervical orthosis. PMID- 24786986 TI - From the cytoplasm into the cilium: bon voyage. AB - The primary cilium compartmentalizes a tiny fraction of the cell surface and volume, yet many proteins are highly enriched in this area and so efficient mechanisms are necessary to concentrate them in the ciliary compartment. Here we review mechanisms that are thought to deliver protein cargo to the base of cilia and are likely to interact with ciliary gating mechanisms. Given the immense variety of ciliary cytosolic and transmembrane proteins, it is almost certain that multiple, albeit frequently interconnected, pathways mediate this process. It is also clear that none of these pathways is fully understood at the present time. Mechanisms that are discussed below facilitate ciliary localization of structural and signaling molecules, which include receptors, G-proteins, ion channels, and enzymes. These mechanisms form a basis for every aspect of cilia function in early embryonic patterning, organ morphogenesis, sensory perception and elsewhere. PMID- 24786990 TI - Carnitine palmitoyl transferase II deficiency in an adolescent presenting with rhabdomyolysis and acute renal failure. AB - The most common cause of recurrent rhabdomyolysis in childhood is inherited metabolic disorders. Carnitine palmitoyl transferase II (CPT II) deficiency is a lipidosis and is a common cause of inherited recurrent myoglobinuria. The disease is inherited in autosomal recessive trait, and the clinical phenotype ranges from a severe and multisystemic infantile form to a milder muscle form, which is characterized with rhabdomyolysis and myoglobinuria. Exercise, infection, fasting, and cold are the most important triggering factors of rhabdomyolysis in CPT II deficiency. The severity of attacks is highly variable and some of these attacks may be complicated by acute renal failure. We report a case of a 13-year old girl with recurrent rhabdomyolysis due to CPT II deficiency whose last attack was complicated by acute renal failure. PMID- 24786991 TI - Arachnoid cysts with subdural hematoma or intracystic hemorrhage in children. AB - Arachnoid cyst (AC) is a common congenital intracranial lesion in children. It may be complicated by subdural hematoma (SDH) and intracystic hemorrhage (ICH) to cause intracranial hypertension after minor head injury or spontaneously. However, because most bleeding after trauma is delayed, it is often overlooked. At the same time, it remains controversial for treatment of ACs complicated with SDH and ICH. So far, it lacks review, especially for pediatric patients who have ACs with SDH or ICH. Here, we report 3 pediatric cases in our department from 2010 to 2011. At the same time, we review 41 pediatric patients reported in the last 20 years. We conclude that a child with AC should be regularly followed up after minor head injury, and that therapy for children with complicated ACs should be more aggressive than for adults. The cyst wall should be resected, and communication between cyst and cerebral cistern should be established. PMID- 24786992 TI - Rapunzel syndrome: diagnosis via radiograph and history. AB - Rapunzel syndrome is defined as a gastric trichobezoar with a tail that extends distally into the small intestine. It is extremely rare and found more often in premenarchal girls with psychiatric comorbidities. Symptoms can be vague and linger for years. However, prolonged intake of indigestible material can lead to gastric outlet obstruction, which may present similarly to a small bowel obstruction. The standard imaging modality of choice to make a presurgical diagnosis is via computed tomography (CT) scan of the abdomen. However, the risk of radiation-induced malignancy associated with a CT scan is an important consideration when managing children. We report a case of Rapunzel syndrome in a 6-year-old girl who was diagnosed presurgically without the use of a CT scan. PMID- 24786993 TI - Three unique presentations of atraumatic spinal cord infarction in the pediatric emergency department. AB - Nontraumatic spinal cord infarction is especially rare in children. Although diagnosis is easily made with magnetic resonance imaging, the typical presenting signs and symptoms and etiology remain elusive. Evidence-based treatment courses are not available. We assess a series of 3 unique patients with nontraumatic spinal cord infarction who presented to our emergency department over the course of 2 years. We consider their presentation, etiology, and treatment course to provide other emergency department physicians with the ability to better identify and evaluate these patients. We also note the need for further research on nontraumatic spinal cord infarction because these patients' outcomes can be quite devastating. PMID- 24786994 TI - Intra-articular lidocaine for reduction of shoulder dislocation. AB - Anterior shoulder dislocation is the most common joint dislocation seen in the emergency department. Although emergency medicine providers use several techniques for reduction, each method is associated with potential discomfort for the patient. In addition, pain from the dislocated shoulder causes muscle spasm that impedes reduction. Therefore, both analgesia and procedural sedation are often used to reduce pain and enable reduction. Intra-articular injection of lidocaine has demonstrated efficacy in reduction of pain and facilitation of shoulder reduction compared with analgesia and sedation. Intra-articular lidocaine may also reduce time to successful reduction of shoulder dislocations. PMID- 24786996 TI - Rapid evaluation of an inguinal mass in a female infant using point-of-care ultrasound. AB - A 35-day-old female infant presents to the pediatric emergency department with increased crying and persistent fullness in the right groin. On examination, the infant was noted to have increased fullness and a nonreducible mass in the right mons pubis. Point-of-care ultrasound was used to help diagnose an incarcerated ovary, allowing for expedited care while waiting for confirmatory imaging. The infant underwent surgery with salvage of the ovary. PMID- 24786997 TI - Intentional insertion of a foreign body in the tongue in a patient with polyembolokoilamania. PMID- 24786998 TI - ECGs in the ED. PMID- 24786999 TI - Sedation dilemmas for computed tomography with oral contrast in children. PMID- 24787002 TI - Stability of bivariate GWAS biomarker detection. AB - Given the difficulty and effort required to confirm candidate causal SNPs detected in genome-wide association studies (GWAS), there is no practical way to definitively filter false positives. Recent advances in algorithmics and statistics have enabled repeated exhaustive search for bivariate features in a practical amount of time using standard computational resources, allowing us to use cross-validation to evaluate the stability. We performed 10 trials of 2-fold cross-validation of exhaustive bivariate analysis on seven Wellcome-Trust Case Control Consortium GWAS datasets, comparing the traditional [Formula: see text] test for association, the high-performance GBOOST method and the recently proposed GSS statistic (Available at http://bioinformatics.research.nicta.com.au/software/gwis/). We use Spearman's correlation to measure the similarity between the folds of cross validation. To compare incomplete lists of ranks we propose an extension to Spearman's correlation. The extension allows us to consider a natural threshold for feature selection where the correlation is zero. This is the first reported cross validation study of exhaustive bivariate GWAS feature selection. We found that stability between ranked lists from different cross-validation folds was higher for GSS in the majority of diseases. A thorough analysis of the correlation between SNP-frequency and univariate [Formula: see text] score demonstrated that the [Formula: see text] test for association is highly confounded by main effects: SNPs with high univariate significance replicably dominate the ranked results. We show that removal of the univariately significant SNPs improves [Formula: see text] replicability but risks filtering pairs involving SNPs with univariate effects. We empirically confirm that the stability of GSS and GBOOST were not affected by removal of univariately significant SNPs. These results suggest that the GSS and GBOOST tests are successfully targeting bivariate association with phenotype and that GSS is able to reliably detect a larger set of SNP-pairs than GBOOST in the majority of the data we analysed. However, the [Formula: see text] test for association was confounded by main effects. PMID- 24787003 TI - Cystic fibrosis in children and adults: supplement to Paediatric Respiratory Reviews. PMID- 24787004 TI - Progress in preventing injuries: a content analysis of national policies in Europe. AB - The aim of this paper is to provide a content analysis of national policies to address violence and injury prevention in the World Health Organization (WHO) European Region so as to inform where future improvements can be made. Multiple search methods were used to identify national policies for violence and injury prevention. Application of a framework based on a WHO guide was used for policy analysis. A multiple correspondence analysis (MCA) was additionally conducted. One hundred and twenty-three national policies were identified; of these, 80 were available in English language and analysed further. Most national policies had been developed after 2003. The majority of policies fulfilled most of the WHO criteria for effective policy-making. Policy areas requiring improvement include quantifying objectives, targeting the socio-economic gap in injury burden and increased focus on primary prevention. Results from the MCA confirmed the ones obtained with the descriptive statistics. Encouraging progress is being made in formulating national policy for violence and injury prevention within the WHO European Region. There are specific areas that warrant increasing attention in future policy development. PMID- 24787001 TI - Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide. AB - BACKGROUND: Leishmaniasis is increasingly reported among travellers. Leishmania species vary in sensitivity to available therapies. Fast and reliable molecular techniques have made species-directed treatment feasible. Many treatment trials have been designed poorly, thus developing evidence-based guidelines for species directed treatment is difficult. Published guidelines on leishmaniasis in travellers do not aim to be comprehensive or do not quantify overall treatment success for available therapies. We aimed at providing comprehensive species directed treatment guidelines. METHODOLOGY/PRINCIPAL FINDINGS: English literature was searched using PubMed. Trials and observational studies were included if all cases were parasitologically confirmed, the Leishmania species was known, clear clinical end-points and time points for evaluation of treatment success were defined, duration of follow-up was adequate and loss to follow-up was acceptable. The proportion of successful treatment responses was pooled using mixed effects methods to estimate the efficacy of specific therapies. Final ranking of treatment options was done by an expert panel based on pooled efficacy estimates and practical considerations. 168 studies were included, with 287 treatment arms. Based on Leishmania species, symptoms and geography, 25 clinical categories were defined and therapy options ranked. In 12/25 categories, proposed treatment agreed with highest efficacy data from literature. For 5/25 categories no literature was found, and in 8/25 categories treatment advise differed from literature evidence. For uncomplicated cutaneous leishmaniasis, combination of intralesional antimony with cryotherapy is advised, except for L. guyanensis and L. braziliensis infections, for which systemic treatment is preferred. Treatment of complicated (muco)cutaneous leishmaniasis differs per species. For visceral leishmaniasis, liposomal amphotericin B is treatment of choice. CONCLUSIONS/SIGNIFICANCE: Our study highlights current knowledge about species directed therapy of leishmaniasis in returning travellers and also demonstrates lack of evidence for treatment of several clinical categories. New data can easily be incorporated in the presented overview. Updates will be of use for clinical decision making and for defining further research. PMID- 24787005 TI - Clinical relevance of ground glass opacity in 105 patients with miliary tuberculosis. AB - BACKGROUND: After the application of chest computed tomography (CT), ground glass opacity (GGO) was introduced as one of major accompanying findings of miliary tuberculosis (MT) in addition to miliary nodules. However, little is known about whether GGO is associated with the clinical manifestations and outcomes of MT. Therefore, the present study examined the clinical relevance of GGO in patients with MT. METHODS: Chest radiographs and CT scans of MT patients were retrospectively reviewed. Clinical manifestations and outcomes were compared in terms of the extent of GGO revealed by chest CT. RESULTS: Confirmed 105 MT patients were included. GGO was observed in 70 (67%) patients. MT patients with an extent of GGO >50% (n = 21) had symptoms of shorter duration, more frequent dyspnea, and more pronounced changes in the levels of acute phase reactants. Miliary nodules were less discernible on CT in those with an extent of GGO >50%. MT patients with an extent of GGO >50% were significantly associated with a longer hospital stay (p = 0.02) and with acute respiratory failure (p < 0.001) than those with an extent of GGO <= 50%. However, mortality among MT patients was not associated with the extent of GGO. CONCLUSION: MT patients with an extent of GGO >50% had more rapidly progressive manifestations and a greater potential for delayed diagnosis and poorer prognosis. Nevertheless, mortality was not higher in confirmed MT patients with an extent of GGO >50% than in those with an extent of GGO <= 50%. PMID- 24787006 TI - miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. AB - We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed zeta-chain associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome. PMID- 24787008 TI - Type and distribution of sensilla in the antennae of the red clover root borer, Hylastinus obscurus. AB - In order to determine the type, distribution, and structures of sensilla, the antennae of the red clover root borer, Hylastinus obscurus Marsham (Coleoptera: Curculionidae: Scolytinae), were examined by light and electron microscopy (both scanning and transmission). Four different types of sensilla were identified in the club, and one type of chaetica was found in the scape and funicle of both male and female individuals. Chaetica and basiconica were the most abundant sensilla types in the club. They were present in the three sensory bands described, totaling approximately 80% of sensilla in the antennal club of H. obscurus. Chaetica were predominantly mechanoreceptors, although gustatory function could not be excluded. Basiconica forms showed characteristics typical of olfactory sensilla. Trichoidea were not found in the proximal sensory band, and they exhibited abundant pores, suggesting olfactory function. Styloconica were the least abundant sensillum type, and their shape was similar to that reported as having hygro- and thermoreceptor functions. There was no difference in the relative abundance of antennal sensilla between males and females. Finally, the sensillar configuration and abundance of receptors in the H. obscurus antennae suggest that these sensilla have chemoreceptive and other functions. PMID- 24787007 TI - Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia. AB - Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor alpha (IL7R) or cytokine receptor-like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias. Here we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays showed that these are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells in vitro and are transforming in vivo. Protein fragment complementation assays suggest that despite the absence of cysteines, the mechanism of activation is through ligand independent dimerization. Mutagenesis experiments and ConSurf calculations suggest that the mutations stabilize the homodimeric conformation, positioning the cytosolic kinases in predefined orientation to each other, thereby inducing spontaneous receptor activation independently of external signals. Hence, type I cytokine receptors may be activated in leukemia through 2 types of transmembrane somatic dimerizing mutations. PMID- 24787009 TI - Identification of apoptotic cells in the thymus of piglets infected with highly pathogenic porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome (PRRS) is an immunosuppressive disease that is characterized by respiratory distress and poor growth in piglets and by severe reproductive failure in sows. PRRS was first recognized in the 1990s in Europe and the United States. In 2006, highly pathogenic (HP)-PRRS caused enormous economic losses in China. Our previous studies demonstrated that the HP-PRRS virus (HP-PRRSV) induced the apoptosis of numerous thymocytes in infected piglets, leading to severe thymus atrophy. To further identify the subset of apoptotic cells in thymus of HP-PRRSV-infected piglets, different cell types, apoptotic cells, and HP-PRRSV were marked with the corresponding markers. Results of the colocalization demonstrated that the apoptotic cells were not infected by HP-PRRSV, and most of them were CD3(+) T cells. No apoptosis was observed in the epithelial cells, and only few CD14(+) cells were apoptotic. HP PRRSV was only found in CD14(+) cells, and epithelial cells and CD3(+) cells were not infected by HP-PRRSV. This is the first study to report the apoptotic and infected cells in the thymuses of HP-PRRSV-infected piglets. PMID- 24787010 TI - Ordered packing of emulsion droplets toward the preparation of adjustable photomasks. AB - Monodisperse emulsion droplets with a high volume fraction form crystalline phases that can potentially serve as adjustable photomasks in photolithography. Such photomasks were prepared using a microfluidic device in which a flow focusing junction, side channels, and a reservoir were connected in series. Transparent oil droplets were generated in a dye-containing continuous water phase at the flow-focusing junction. The droplets were then concentrated through the selective removal of the continuous phase using the side channels. This process led to the formation of a regular array of droplets in the reservoir with a configuration that depended on the relative height of the reservoir to the droplet diameter. The configurations could be selected among a single-layered hexagonal array, a bilayered square array, and a bilayered hexagonal array. The droplet arrays were used as a photomask to create hexagonal or square arrays of microdots. The transmittance profile of the ultraviolet (UV) light from each droplet was parabolic, which enabled the dot size to be tuned by controlling the UV irradiation time. This mask effect is otherwise difficult to achieve using conventional photomasks. The dot size and array periodicity could be adjusted by the in-situ control of the droplet size at the flow-focusing droplet maker. The combination of droplet size adjustments and the UV irradiation time provided independent control over the dot size and array periodicity to enable the preparation of a series of hexagonal microarrays with a wide spectrum of array parameters using a single microfluidic device. PMID- 24787013 TI - Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases. AB - Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA 4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53 deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53 mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated. PMID- 24787014 TI - Nerve growth factor-mediated inhibition of apoptosis post-caspase activation is due to removal of active caspase-3 in a lysosome-dependent manner. AB - Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal cells that can inhibit apoptotic cell death upstream of mitochondrial outer membrane permeabilisation. Here we addressed the question of whether NGF can also protect against apoptosis downstream of caspase activation. NGF treatment promoted a rapid reduction in the level of the p17 subunit of active caspase-3 in PC12 cells that had been induced to undergo apoptosis by various cytotoxins. The mechanism involved TrkA-dependent activation of extracellular signal-regulated kinase (ERK1/2) but not phosphatidylinositol 3 kinase (PI3K)/Akt, and de novo protein synthesis. Involvement of inhibitor of apoptosis proteins (IAPs) and proteasomal degradation were ruled out. In contrast, inhibition of lysosome function using chloroquine and concanamycin A reversed NGF-induced removal of p17. Moreover, in NGF-treated cells, active caspases were found to be localised to lysosomes. The involvement of macroautophagy and chaperone-mediated autophagy were ruled out. Taken together, these findings suggest an anti-apoptotic mechanism by which NGF induces removal of active caspase-3 in a lysosome-dependent manner. PMID- 24787015 TI - High throughput screening for inhibitors of the HECT ubiquitin E3 ligase ITCH identifies antidepressant drugs as regulators of autophagy. AB - Inhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto-ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine--a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologs of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologs might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications. PMID- 24787016 TI - Quantitative multi-parametric evaluation of centrosome declustering drugs: centrosome amplification, mitotic phenotype, cell cycle and death. AB - Unlike normal cells, cancer cells contain amplified centrosomes and rely on centrosome clustering mechanisms to form a pseudobipolar spindle that circumvents potentially fatal spindle multipolarity (MP). Centrosome clustering also promotes low-grade chromosome missegregation, which can drive malignant transformation and tumor progression. Putative 'centrosome declustering drugs' represent a cancer cell-specific class of chemotherapeutics that produces a common phenotype of centrosome declustering and spindle MP. However, differences between individual agents in terms of efficacy and phenotypic nuances remain unexplored. Herein, we have developed a conceptual framework for the quantitative evaluation of centrosome declustering drugs by investigating their impact on centrosomes, clustering, spindle polarity, cell cycle arrest, and death in various cancer cell lines at multiple drug concentrations over time. Surprisingly, all centrosome declustering drugs evaluated in our study were also centrosome-amplifying drugs to varying extents. Notably, all declustering drugs induced spindle MP, and the peak extent of MP positively correlated with the induction of hypodiploid DNA containing cells. Our data suggest acentriolar spindle pole amplification as a hitherto undescribed activity of some declustering drugs, resulting in spindle MP in cells that may not have amplified centrosomes. In general, declustering drugs were more toxic to cancer cell lines than non-transformed ones, with some exceptions. Through a comprehensive description and quantitative analysis of numerous phenotypes induced by declustering drugs, we propose a novel framework for the assessment of putative centrosome declustering drugs and describe cellular characteristics that may enhance susceptibility to them. PMID- 24787018 TI - Retraction. High-mobility group A1 protein inhibits p53-mediated intrinsic apoptosis by interacting with Bcl-2 at mitochondria. PMID- 24787017 TI - Prognostic significance of low DICER expression regulated by miR-130a in cervical cancer. AB - Dicer is crucial for the maturation of microRNAs (miRNAs) and its dysregulation may contribute to tumor initiation and progression. The study explored the clinical implications of Dicer and its post-transcriptional regulation by microRNAs in cervical cancer. qRT-PCR and immunohistochemistry investigated Dicer mRNA and protein levels in cervical cancer tissues. The relationship between Dicer expression and survival was analyzed. MiRNA target prediction identified miRNAs that might target Dicer. Luciferase reporter and gain- or loss-of-function assays were performed. The results showed that 36.7% of cervical cancer cases showed low expression of Dicer mRNA and 63.3% cases showed high expression. At the protein level, 51% cases showed negative expression and 49% cases showed positive expression. Dicer mRNA and protein expressions were significantly associated with distant metastasis and recurrence in cervical cancer (P=0.002 and P=0.012, respectively). Multivariate Cox analysis indicated that low Dicer expression (P=0.016) and tumor stage (P=0.047) were independent predictors. Among the miRNAs predicted to target Dicer, 10 were detected by RT-PCR; their expressions were significantly higher in cervical cancers with lower Dicer expression than in those with higher Dicer expression and were negatively correlated with Dicer expression level (P<0.05). In vitro experiments demonstrated that miR-130a directly targeted Dicer mRNA to enhance migration and invasion in SiHa cells. Finally, survival analysis indicated that higher expression of miR-130a was significantly associated with poor disease-free survival. Taken together, Dicer expression regulated by miR-130a is an important potential prognostic factor in cervical cancer. PMID- 24787019 TI - Evaluation of the organizational cultural competence of a community health center: a multimethod approach. AB - Cultural competence is an important component of client-centered care in health promotion and community health services, especially considering the changing demographics of North America. Although a number of tools for evaluating cultural competence have been developed, few studies have reported on the results of organizational cultural competence evaluations in health care or social services settings. This article aims to fill this gap by providing a description of a cultural competence evaluation of a community health center serving a diverse population. Data collection included reviewing documents, and surveying staff, management, and the Board of Directors. The organization fully met 28 of 53 standards of cultural competence, partially met 21 standards, and did not meet 2 standards, and 2 standards could not be assessed due to missing information. The advantages and lessons learned from this organizational cultural competence evaluation are discussed. PMID- 24787020 TI - Religious involvement and health-related behaviors among Black Seventh-Day Adventists in Canada. AB - BACKGROUND: Most studies that involve Black Seventh-Day Adventists (SDAs) have been conducted in the United States. We sought to examine the association between religious involvement and lifestyle practices among Black SDAs in Canada. METHOD: A convenience sample of 509 Black SDA church members 18 years and older completed a self-administered questionnaire, assessing religious involvement and seven lifestyle practices promoted by the SDA church: diet, physical activity, water intake, exposure to sunlight, alcohol use, caffeine and tobacco use, and rest. RESULTS: Compliance with lifestyle practices ranged from a low of 10% meeting fitness guidelines to a high of 99% abstaining from tobacco products. Religious involvement and lifestyle were positively related (rs = .11, p < .05). Multivariate analyses indicated that private religious practice (beta = .16, p =.003), importance of the health principles (beta = .17, p = .003), and acceptance of health principles (beta = .65, p = .00001) significantly predicted the number of behaviors practiced. CONCLUSION: Greater religious involvement is associated with positive lifestyle practices but is not an independent predictor of lifestyle practices for Black Canadian SDAs. PMID- 24787022 TI - B7-H3 was highly expressed in human primary hepatocellular carcinoma and promoted tumor progression. AB - B7-H3 has been detected in different cancers and correlated to tumor progression and outcome in cancer patients. In this study, we investigated the expression of B7-H3 in tissues and cells of primary hepatocellular carcinoma (PHC) patients. The research showed that B7-H3 is aberrantly expressed in PHC tissues and cells, and its high expression on HepG2 cells significantly promotes cell proliferation, adhesion, migration, and invasion capacity; moreover, it inhibits the proliferation of CD8(+) T cells. Thus, B7-H3 may have a critical role in PHC and it may enhance tumor escape from the immune surveillance of CD8(+) T cells. PMID- 24787021 TI - Intimate partner violence and sexual health: voices and images of Latina immigrant survivors in southwestern United States. AB - Intimate partner violence (IPV), which describes physical and/or sexual assault of a spouse or sexually intimate companion, is a common health care issue across the globe. However, existing health outcomes studies are limited. Additionally, no study to our knowledge has specifically focused on the relationship between IPV and sexual health among Latina immigrants in southwestern United States. Through the use of photovoice methodology and a community-based participatory research approach, we assessed these types of relationships drawing on data gathered from 22 Latina survivors of IPV and 20 community stakeholders in El Paso, Texas. Participants identified two major themes: the different expressions of domestic violence and the need for access to sexual and reproductive health services. Community stakeholders and participants identified practical and achievable recommendations and actions including the development of a promotora training program on IPV and sexual health. This assessment extends beyond HIV and STI risk behaviors and highlights disease prevention within a wellness and health promotion framework. PMID- 24787023 TI - Turkey versus guinea pig red blood cells: hemagglutination differences alter hemagglutination inhibition responses against influenza A/H1N1. AB - For influenza hemagglutination inhibition (HAI) assays, species selection of red blood cells (RBCs) is critical to determine antibody titers to influenza viruses reliably. We compared pandemic influenza virus A/H1N1 (pdH1N1) HAI titers using turkey or guinea pig RBCs. Turkey RBCs appear to be the more appropriate species choice for influenza A/pH1N1 HAI assays. PMID- 24787024 TI - Response to Mroczkowski (2014): Lost in translation, or overestimating administrative data for outcome control in colorectal surgery. PMID- 24787025 TI - Reactivity of biomimetic iron(II)-2-aminophenolate complexes toward dioxygen: mechanistic investigations on the oxidative C-C bond cleavage of substituted 2 aminophenols. AB - The isolation and characterization of a series of iron(II)-2-aminophenolate complexes [(6-Me3-TPA)Fe(II)(X)](+) (X = 2-amino-4-nitrophenolate (4-NO2-HAP), 1; X = 2-aminophenolate (2-HAP), 2; X = 2-amino-3-methylphenolate (3-Me-HAP), 3; X = 2-amino-4-methylphenolate (4-Me-HAP), 4; X = 2-amino-5-methylphenolate (5-Me HAP), 5; X = 2-amino-4-tert-butylphenolate (4-(t)Bu-HAP), 6 and X = 2-amino-4,6 di-tert-butylphenolate (4,6-di-(t)Bu-HAP), 7) and an iron(III)-2-amidophenolate complex [(6-Me3-TPA)Fe(III)(4,6-di-(t)Bu-AP)](+) (7(Ox)) supported by a tripodal nitrogen ligand (6-Me3-TPA = tris(6-methyl-2-pyridylmethyl)amine) are reported. Substituted 2-aminophenols were used to prepare the biomimetic iron(II) complexes to understand the effect of electronic and structural properties of aminophenolate rings on the dioxygen reactivity and on the selectivity of C-C bond cleavage reactions. Crystal structures of the cationic parts of 5.ClO4 and 7.BPh4 show six-coordinate iron(II) centers ligated by a neutral tetradentate ligand and a monoanionic 2-aminophenolate in a bidentate fashion. While 1.BPh4 does not react with oxygen, other complexes undergo oxidative transformation in the presence of dioxygen. The reaction of 2.ClO4 with dioxygen affords 2-amino-3H phenoxazin-3-one, an auto-oxidation product of 2-aminophenol, whereas complexes 3.BPh4, 4.BPh4, 5.ClO4 and 6.ClO4 react with O2 to exhibit C-C bond cleavage of the bound aminophenolates. Complexes 7.ClO4 and 7(Ox).BPh4 produce a mixture of 4,6-di-tert-butyl-2H-pyran-2-imine and 4,6-di-tert-butyl-2-picolinic acid. Labeling experiments with (18)O2 show the incorporation of one oxygen atom from dioxygen into the cleavage products. The reactivity (and stability) of the intermediate, which directs the course of aromatic ring cleavage reaction, is found to be dependent on the nature of ring substituent. The presence of two tert butyl groups on the aminophenolate ring in 7.ClO4 makes the complex slow to cleave the C-C bond of 4,6-di-(t)Bu-HAP, whereas 4.BPh4 containing 4-Me-HAP displays fastest reactivity. Density functional theory calculations were conducted on [(6-Me3-TPA)Fe(III)(4-(t)Bu-AP)](+) (6(Ox)) to gain a mechanistic insight into the regioselective C-C bond cleavage reaction. On the basis of the experimental and computational studies, an iron(II)-2-iminobenzosemiquinonate intermediate is proposed to react with dioxygen resulting in the oxidative C-C bond cleavage of the coordinated 2-aminophenolates. PMID- 24787027 TI - SiH/TiO2 and GeH/TiO2 heterojunctions: promising TiO2-based photocatalysts under visible light. AB - We use hybrid density functional calculations to find that the monolayer silicane (SiH) and the anatase TiO2(101) composite (i.e. the SiH/TiO2 heterojunction) is a promising TiO2-based photocatalyst under visible light. The band gap of the SiH/TiO2(101) heterojunction is 2.082 eV, which is an ideal material for the visible-light photoexcitation of electron-hole pairs. Furthermore, the SiH/TiO2(101) heterojunction has a favorable type-II band alignment and thus the photoexcited electron can be injected to the conduction band of anatase TiO2 from that of silicane. Finally, the proper interface charge distribution facilitates the carrier separation in the SiH/TiO2(101) interface region. The electron injection and carrier separation can prevent the recombination of electron-hole pairs. Our calculation results suggest that such electronic structure of SiH/TiO2(101) heterojunction has significant advantages over these of doped TiO2 systems for visible-light photocatalysis. PMID- 24787026 TI - Bayesian methods for assessing transplant program performance. AB - Based on recommendations from a recent consensus conference and a report commissioned by the Centers for Medicare & Medicaid Services to the Committee of Presidents of Statistical Societies, the Scientific Registry of Transplant Recipients (SRTR) plans to adopt Bayesian methods for assessing transplant program performance. Current methods for calculating program-specific reports (PSRs) often generate implausible point estimates of program performance, wide confidence intervals and underpowered conventional statistical tests. Although technically correct, these methods produce statistical summaries that are prone to misinterpretation. The Bayesian approach assumes that performance of most programs is about average and few programs perform much better or much worse than average; thus, strong evidence is required to conclude that performance is extremely good or poor. In Bayesian statistics, inference is performed via a posterior probability distribution, which reflects both the available data and prior beliefs about what model parameter values are most likely. In the PSRs, the posterior distribution of a program-specific hazard ratio will show whether a program is likely to be performing better or worse than average. Bayesian-derived PSRs will be available for preview by programs on the private SRTR website in mid 2014 and will likely replace current methods for public reporting in early 2015. PMID- 24787028 TI - Elevated blood pressure at the first measurement predicts cardiovascular disease independently from the subsequent second reading in men, but not in women. AB - BACKGROUND AND METHODS: There have been no investigations concerning the association of each blood pressure (BP) reading with future cardiovascular disease (CVD) when multiple measurements are taken on one occasion. This community-based, prospective cohort study (n = 23 344, mean age = 62.4 years) investigated the associations between the BP obtained from the first and second of two consecutive measurements on one occasion and future cardiovascular events in men and women. RESULTS: During the mean follow-up of 5.5 years, 624 CVD events were identified. On the Cox regression analysis of age- and BP-adjusted models, the increased CVD risk of a hypertensive first measurement (systolic BP >= 140 mmHg) was independent from the second measurement in men. Even in subjects without a hypertensive second measurement, the CVD risk of the hypertensive first measurement was increased in men. In women, despite a hypertensive first measurement, subjects with a systolic BP < 130 mmHg on the second measurement showed a significantly reduced risk for CVD compared with subjects who retained a hypertensive level during the two measurements. CONCLUSIONS: An elevated BP on the first measurement should not be disregarded for CVD risk estimation in men, even if the second BP moves to the normal range. In women, elevated BP on the first measurement may have relatively less meaning for CVD prediction if the second BP shifts to a normal range. PMID- 24787029 TI - Purple discoloration of the colon found during autopsy: Identification of betanin, its aglycone and metabolites by liquid chromatography-high-resolution mass spectrometry. AB - During autopsy of a 38-year-old man the forensic pathologist noted an atypical purple discoloration of the colon membrane. Hypothesis was that the discoloration could have been caused by ingestion of red beetroot. In order to exclude other toxicological causes for this finding and to analytically verify this hypothesis, colon membrane, blood and urine were screened not only for the typical forensically relevant substances but also for the main chromophoric beetroot compounds employing liquid chromatography-high-resolution mass spectrometry (LC HRMS). Betanin (m/z 551.1495) and its aglycone betanidin (m/z 389.0973) were found in the extracts of colon membrane and urine. Betanin was detected in whole blood, and urinary analysis additionally revealed two metabolites: betanidin glucuronide (m/z 565.1294) and betanidin sulfate (m/z 469.0541) - showing the same fragmentation pattern as betanidin after the characteristic neutral loss of m/z 176.0315 and m/z 79.9554 for glucuronic acid and sulfate, respectively. This is the first time that betacyanins could be analytically confirmed as cause for a purple discoloration of the colon. Urine analysis further revealed that besides betanin itself betanidin phase II metabolites could be detected in human urine. PMID- 24787030 TI - Study of the PTW microLion chamber temperature dependence. AB - The use of liquid ionization chambers in radiotherapy has grown during the past few years. While for air ionization chambers the k(TP) correction for air mass density due to pressure and temperature variations is well known, less work has been done on the case of liquid ionization chambers, where there is still the need to take into account the influence of temperature in the free ion yield. We have measured the PTW microLion isooctane-filled ionization chamber temperature dependence in a ~ +/-10 degrees C interval around the standard 20 degrees C room temperature for three operation voltages, including the manufacturer recommended voltage, and two beam qualities, (60)Co and 50 kV x-rays. Within the measured temperature range, the microLion signal exhibits a positive linear dependence, which is around 0.24% K(-1) at 800 V with (60)Co irradiation. This effect is of the same order of magnitude as the T dependence found in air ionization chambers, but its nature is completely different and its sign opposite to that of an air chamber. Onsager theory has been used to model the results and is consistent with this linear behaviour. However, some inconsistencies in the modelling of the 50 kV x-ray results have been found that are attributed to the failure of Onsager's isolated pair assumption for such radiation quality. PMID- 24787032 TI - Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. AB - Vitamin C (VitC) has several roles in the brain acting both as a specific and non specific antioxidant. The brain upholds a very high VitC concentration and is able to preferentially retain VitC even during deficiency. The accumulation of brain VitC levels much higher than in blood is primarily achieved by the sodium dependent VitC transporter (SVCT2). This study investigated the effects of chronic pre-and postnatal VitC deficiency as well as the effects of postnatal VitC repletion, on brain SVCT2 expression and markers of oxidative stress in young guinea pigs. Biochemical analyses demonstrated significantly decreased total VitC and an increased percentage of dehydroascorbic acid, as well as increased lipid oxidation (malondialdehyde), in the brains of VitC deficient animals (p < 0.0001) compared to controls. VitC repleted animals were not significantly different from controls. No significant changes were detected in either gene or protein expression of SVCT2 between groups or brain regions. In conclusion, chronic pre-and postnatal VitC deficiency increased brain redox imbalance but did not increase SVCT2 expression. Our findings show potential implications for VitC deficiency induced negative effects of redox imbalance in the brain and provide novel insight to the regulation of VitC in the brain during deficiency. PMID- 24787031 TI - Pre-exercise nutrition: the role of macronutrients, modified starches and supplements on metabolism and endurance performance. AB - Endurance athletes rarely compete in the fasted state, as this may compromise fuel stores. Thus, the timing and composition of the pre-exercise meal is a significant consideration for optimizing metabolism and subsequent endurance performance. Carbohydrate feedings prior to endurance exercise are common and have generally been shown to enhance performance, despite increasing insulin levels and reducing fat oxidation. These metabolic effects may be attenuated by consuming low glycemic index carbohydrates and/or modified starches before exercise. High fat meals seem to have beneficial metabolic effects (e.g., increasing fat oxidation and possibly sparing muscle glycogen). However, these effects do not necessarily translate into enhanced performance. Relatively little research has examined the effects of a pre-exercise high protein meal on subsequent performance, but there is some evidence to suggest enhanced pre exercise glycogen synthesis and benefits to metabolism during exercise. Finally, various supplements (i.e., caffeine and beetroot juice) also warrant possible inclusion into pre-race nutrition for endurance athletes. Ultimately, further research is needed to optimize pre-exercise nutritional strategies for endurance performance. PMID- 24787033 TI - Vascular disease and risk factors are associated with cognitive decline in the alzheimer disease spectrum. AB - We investigated the relationship between vascular disease and risk factors versus cognitive decline cross-sectionally and longitudinally in normal older control, mild cognitive impairment, and mild Alzheimer disease (AD) dementia subjects. A total of 812 participants (229 normal older control, 395 mild cognitive impairment, 188 AD) underwent cognitive testing, brain magnetic resonance imaging, and clinical evaluations at baseline and over a period of 3 years. General linear, longitudinal mixed-effects, and Cox proportional hazards models were used. Greater homocysteine level and white matter hyperintensity volume were associated with processing speed impairment (homocysteine: P=0.02; white matter hyperintensity: P<0.0001); greater Vascular Index score was associated with memory impairment (P=0.007); and greater number of apolipoprotein E epsilon4 (APOE4) alleles was associated with global cognitive impairment (P=0.007) at baseline. Apolipoprotein E epsilon4 was associated with greater rate of increase in global cognitive impairment (P=0.002) and processing speed impairment (P=0.001) over time, whereas higher total cholesterol was associated with greater rate of increase in global cognitive impairment (P=0.02) and memory impairment (P=0.06) over time. These results suggest a significant association of increased vascular disease and risk factors with cognitive impairment at baseline and over time in the AD spectrum in a sample that was selected to have low vascular burden at baseline. PMID- 24787035 TI - Ferroelastic domain switching dynamics under electrical and mechanical excitations. AB - In thin film ferroelectric devices, switching of ferroelastic domains can significantly enhance electromechanical response. Previous studies have shown disagreement regarding the mobility or immobility of ferroelastic domain walls, indicating that switching behaviour strongly depends on specific microstructures in ferroelectric systems. Here we study the switching dynamics of individual ferroelastic domains in thin Pb(Zr0.2,Ti0.8)O3 films under electrical and mechanical excitations by using in situ transmission electron microscopy and phase-field modelling. We find that ferroelastic domains can be effectively and permanently stabilized by dislocations at the substrate interface while similar domains at free surfaces without pinning dislocations can be removed by either electric or stress fields. For both electrical and mechanical switching, ferroelastic switching is found to occur most readily at the highly active needle points in ferroelastic domains. Our results provide new insights into the understanding of polarization switching dynamics as well as the engineering of ferroelectric devices. PMID- 24787034 TI - Performance of multi-city land use regression models for nitrogen dioxide and fine particles. AB - BACKGROUND: Land use regression (LUR) models have been developed mostly to explain intraurban variations in air pollution based on often small local monitoring campaigns. Transferability of LUR models from city to city has been investigated, but little is known about the performance of models based on large numbers of monitoring sites covering a large area. OBJECTIVES: We aimed to develop European and regional LUR models and to examine their transferability to areas not used for model development. METHODS: We evaluated LUR models for nitrogen dioxide (NO2) and particulate matter (PM; PM2.5, PM2.5 absorbance) by combining standardized measurement data from 17 (PM) and 23 (NO2) ESCAPE (European Study of Cohorts for Air Pollution Effects) study areas across 14 European countries for PM and NO2. Models were evaluated with cross-validation (CV) and hold-out validation (HV). We investigated the transferability of the models by successively excluding each study area from model building. RESULTS: The European model explained 56% of the concentration variability across all sites for NO2, 86% for PM2.5, and 70% for PM2.5 absorbance. The HV R2s were only slightly lower than the model R2 (NO2, 54%; PM2.5, 80%; PM2.5 absorbance, 70%). The European NO2, PM2.5, and PM2.5 absorbance models explained a median of 59%, 48%, and 70% of within-area variability in individual areas. The transferred models predicted a modest-to-large fraction of variability in areas that were excluded from model building (median R2: NO2, 59%; PM2.5, 42%; PM2.5 absorbance, 67%). CONCLUSIONS: Using a large data set from 23 European study areas, we were able to develop LUR models for NO2 and PM metrics that predicted measurements made at independent sites and areas reasonably well. This finding is useful for assessing exposure in health studies conducted in areas where no measurements were conducted. PMID- 24787036 TI - ZnO nanorod-templated well-aligned ZrO2 nanotube arrays for fibroblast adhesion and proliferation. AB - Cellular responses to porous tubular structures have recently been investigated in highly ordered ZrO2 nanotube arrays fabricated with anodization. However, the potential applications of the nanotube arrays are hindered by instrument requirements and substrate limitations, as well as by the complicated processes needed for synthesis. In this work, ZrO2 nanotube arrays were synthesized by in situ hydrolysis of zirconium propoxide with a zinc oxide nanorod array-based template. Fibroblast cells were able to grow on the nanotube array surface with produced elongated filopodia. Studies of the capability of cell growth and the expression of adhesion- and proliferation-related genes reveal that ZrO2 nanotube arrays may provide a better environment for cell adhesion and growth than a flat titanium surface. These findings not only provide fundamental insight into cell response to nanostructures but also provide an opportunity to use a unique approach to fabricate ZrO2 nanotube array structures for potential implant applications. PMID- 24787037 TI - Mechanisms of the PtCl2-catalyzed intramolecular cyclization of o-isopropyl substituted aryl alkynes for the synthesis of indenes and comparison of three sp3 C-H bond activation modes. AB - Chatani and He respectively reported an efficient way to synthesize indenes through PtCl2 catalyzed sp(3) C-H bond activation. Interestingly, the R group (R = H or Br) in the alkyne moiety of the substrates in Chatani's experiments migrates to the C3 position in indenes, whereas the R group (R = Ar) stays in the original C2 position of final indenes in He's experiments. DFT calculations indicated that there are two competing pathways a and c for the cyclization reaction. Pathway a involves [1,2]-R migration, [1,5]-H shift, and 4pi electrocyclization, giving the indenes with the R group at the C3 position. Pathway c takes place through irreversible [1,5]-H shift/cyclization and [1,2]-H shift, generating indenes with the R group at the C2 position. DFT calculations found that, when R = H or Br, pathway a is favored. When R = alkyl group, the [1,2]-R migration is difficult and pathway c is preferred. When R = Ar, DFT calculations predicted and experiments verified that both pathways a and c occur to give two indene products. Comparison of different models of sp(3) C-H activations has been presented to guide further understanding and prediction of new C-H bond activations. PMID- 24787038 TI - Direct electrochemical synthesis of reduced graphene oxide (rGO)/copper composite films and their electrical/electroactive properties. AB - Electrical contact materials with excellent performances are crucial for the development and safe use of electrical contacts in different applications. In our work, reduced graphene oxide (rGO)/copper (Cu) composite films, as potential electrical contact materials, have been synthesized on copper foil with one-step electrochemical reduction deposition method. Cyclic voltammetry (CV) was used to define the deposition conditions, and confocal Raman microscopy (CRM), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) were used to characterize the chemical compositions, molecular and micro- and nano structures of the composite films. Atomic force microscopy/scanning Kelvin probe force microscopy (AFM/SKPFM), conductive AFM (C-AFM) as well as impedance analysis were employed to evaluate the electroactive/electrical properties of the prepared composite films, respectively. The CRM and XPS results suggest that the rGO/Cu composite films can be synthesized through one-step electrochemical codeposition using suitable precursor solutions. Within a short deposition period, the growth of discrete nanograins in the composite film predominates, whereas pine-tree-leaf nanostructures are formed in the composite film when the deposition period is long, due to the chelating role of GO or rGO to regulate the growth rate of metallic copper nanograins. The electrical resistivity of the composite films is lower than the polished Cu foil and the electrodeposited Cu film, probably due to the higher conductivity (enhanced transfer of charge carriers) of the rGO incorporated in the composite films. The Volta potential variation in the rGO/Cu composite film is quite different from that in the electrodeposited Cu film. The electroactivity of the rGO/Cu composite films is higher than the electrodeposited Cu film, but lower than polished Cu foil, and the underlying mechanisms have been discussed. PMID- 24787039 TI - Totally robotic Roux-en-Y gastric bypass (with video). PMID- 24787040 TI - Ligation of the intersphincteric fistula tract or LIFT procedure (with video). PMID- 24787041 TI - The effects of sleep deprivation on brain functioning in older adults. AB - Few studies have examined the effects of total sleep deprivation (TSD) on cognitive performance and brain activation using functional MRI (fMRI) in older adults. The current study examines blood oxygen level-dependent (BOLD) activation in older adults and younger adults during the sustained attention (GO) and response inhibition (NOGO) portions of a GO-NOGO cognitive task following 36 hr of total sleep deprivation. No significant performance differences were observed between the groups on the behavioral outcome measures of total hits and false alarms. Neuroimaging results, however, revealed a significant interaction between age-group and sleep-deprivation status. Specifically, older adults showed greater BOLD activation as compared to younger adults after 36 hours total sleep deprivation in brain regions typically associated with attention and inhibitory processes. These results suggest in order for older adults to perform the GO-NOGO task effectively after sleep deprivation, they rely on compensatory recruitment of brain regions that aide in the maintenance of cognitive performance. PMID- 24787042 TI - Glenohumeral Contact Pressure With Simulated Anterior Labral and Osseous Defects in Cadaveric Shoulders Before and After Soft Tissue Repair. AB - BACKGROUND: Glenoid rim fractures and erosion can result from traumatic and repeated shoulder dislocations, leading to glenoid bone loss. Traditional instability surgery includes Bankart repair to restore soft tissue anatomy, although a recent trend is to address glenoid bone deficiency when appropriate with a bone block procedure. HYPOTHESIS/PURPOSE: The purpose of this study was to quantify glenohumeral joint contact pressures as a function of anterior labral detachment, progressive anterior glenoid bone loss, and labral repair. The hypothesis was that a critical glenoid defect size exists whereby labral repair alone cannot restore joint contact pressures, therefore favoring bone block augmentation over soft tissue repair. STUDY DESIGN: Controlled laboratory study. METHODS: Eight fresh-frozen cadaveric shoulders were tested under a 440-N compressive load simulating glenohumeral abduction positions of 30 degrees and 60 degrees in neutral rotation and 60 degrees with 90 degrees of external rotation. Glenohumeral joint contact pressures were recorded with a Tekscan pressure sensor system in these configurations: (1) intact specimen, (2) Bankart lesion, (3) 10% anterior rim bone defect, (4) 10% bone defect with labral repair, (5) 20% bone defect, (6) 20% bone defect with labral repair, (7) 30% bone defect, and (8) 30% bone defect with labral repair. The joint contact pressures were compared at all configurations. RESULTS: The Bankart lesion and 10%, 20%, and 30% glenoid defects showed significant (P < .05) increases in mean contact pressures over baseline values. Labral repair at 10% bone loss reduced mean contact pressures to below the intact state, and labral repair of 20% defects demonstrated normalized mean contact pressures. However, mean contact pressures remained statistically elevated compared with baseline values after labral repair of 30% glenoid defects. CONCLUSION: Glenohumeral joint contact pressures were restored to baseline values after labral repair of 10% and 20% anterior glenoid bone defects. Conversely, labral repair at 30% glenoid bone loss did not restore glenohumeral contact mechanics, yielding elevated contact pressures despite repair. Further study is warranted to investigate the stability (resistance to dislocations) of the glenohumeral joint after labral repair and bone block augmentation. CLINICAL RELEVANCE: A critical glenoid defect size exists in which labral repair alone does not restore normal glenohumeral contact pressures. Surgeons should carefully evaluate glenoid bone loss before selecting a surgical treatment for shoulder instability. PMID- 24787043 TI - The Relation Between Testing Environment and Baseline Performance in Child and Adolescent Concussion Assessment. AB - BACKGROUND: Previous research has demonstrated differences in cognitive performance when baseline concussion assessment is performed in a group versus an individual setting. Accurate baseline assessment is imperative when such data are used to make clinical decisions regarding cognitive and symptom recovery after concussion. HYPOTHESIS: The use of similar standardized test administration procedures and test conditions across group and individual settings results in no differences in cognitive performance or symptom reporting. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 939 participants (aged 5-18 years), including 313 tested individually and 626 tested in a group setting, matched on age, sex, and attention-deficit/hyperactivity disorder status, were administered concussion baseline assessment using the desktop version of the Immediate Post-Concussion Assessment and Cognitive Testing and a new pediatric measure, the Multimodal Assessment of Cognition & Symptoms for Children. Cognitive performance, symptom reports, and rates of invalid performance were compared between settings. RESULTS: No significant differences were found between individual and group testing settings for the age-based Learning and Memory Accuracy composite and Response Speed composite standard scores on the Multimodal Assessment of Cognition & Symptoms for Children. Accounting for age and sex, adolescents' performance on the Immediate Post-Concussion Assessment and Cognitive Testing revealed no differences between settings on the 4 composite raw scores (Verbal Memory, Visual Memory, Visual Motor Speed, and Reaction Time). Furthermore, symptom reporting was similar between settings on both measures. Rates of invalid performance did not differ between the 2 administration groups for either age group. There was an interaction effect for invalid performance between attention-deficit/hyperactivity disorder and setting in younger children (aged 5-12 years), with higher rates of invalid performance for children in the group setting with attention-deficit/hyperactivity disorder compared with those without, although there were no differences in the individual setting. CONCLUSION: In this sample, children given a baseline assessment in a group setting performed no differently than children tested individually when standardized administration procedures were used by trained test administrators. Previous evidence suggesting differences between settings may be attributable to the variability in test administration and supervision rather than the environment itself. The importance of standardized procedures and proper supervision during baseline concussion assessment is supported by these findings. PMID- 24787044 TI - Effect of Anticipation on Lower Extremity Biomechanics During Side- and Cross Cutting Maneuvers in Young Soccer Players. AB - BACKGROUND: Less mature athletes exhibit biomechanical parameters during cutting maneuvers that may place these athletes at greater risk for injury than their more mature counterparts, especially if the maneuvers are unanticipated. However, most studies on risk factors for anterior cruciate ligament (ACL) injury have focused on neuromuscular and knee kinematic differences between the sexes, not on the biomechanical parameters between specific sporting maneuvers. HYPOTHESES: (1) Anticipation will have a greater effect than the type of cutting maneuver (side- vs cross-cutting) in terms of the biomechanical risk factors for ACL injuries, and (2) the biomechanical risk factors will be different between the 2 types of maneuvers. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-seven young, male middle school soccer players participated in this study. Three dimensional motion analysis featuring ground-reaction force and electromyography of the right leg was used. Kinematics, kinetics, and electromyography data for each athlete were analyzed during anticipated and unanticipated side- and cross cutting maneuvers. The differences between anticipated and unanticipated states as well as between side- and cross-cutting maneuvers were calculated and compared. RESULTS: After unanticipated side-cutting, the time to peak ground reaction force was longer and peak values were smaller compared with anticipated side-cutting. Flexion, valgus, and internal rotations in the knee joint were larger, and greater flexion and valgus moments were observed. The vastus lateralis and vastus medialis showed lower activity, and the lateral gastrocnemius showed higher activity after unanticipated side-cutting maneuvers. With unanticipated cross-cutting, the time to peak ground-reaction force was longer and peak values were smaller compared with anticipated cross-cutting, and the lateral gastrocnemius showed higher activity. Differences in the peak values of the mediolateral and vertical forces were smaller in the cross-cutting maneuver than in side-cutting. Changes in flexion and adduction of the hip joint, flexion of the knee joint, and inversion of the ankle joint were larger during side-cutting. CONCLUSION: Although there were some interactions between direction and anticipation, anticipating a cutting maneuver generally had a greater effect than the type of maneuver when there was no significant interaction. CLINICAL RELEVANCE: Increases in the valgus angle and moment of the knee joint and higher lateral gastrocnemius activity during the late period showed an association with ACL injury risk factors during side-cutting, and higher lateral gastrocnemius activity during the early period showed an association with injury risk factors during cross-cutting. PMID- 24787045 TI - Sex-Based Differences in the Clinical Presentation of Patients With Symptomatic Hip Labral Tears. AB - BACKGROUND: An increasing body of literature describes the clinical presentation and demographics of patients with hip labral tears. The differences in pelvic structure and joint laxity between sexes have been described; however, no study has evaluated differences in the clinical presentation of patients with symptomatic labral tears between sexes. PURPOSE: To describe the differences between sexes in demographics, clinical history, physical examination, and intraoperative findings in patients with symptomatic labral tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were prospectively collected between February 2008 and February 2013 on 1401 patients who had symptomatic labral tears and underwent arthroscopic surgery. Hips with previous pathologic disorders were excluded. Data on demographics and clinical history were gathered, and a physical examination was performed. Preoperative pain was estimated on the visual analog scale (VAS), and 4 hip-specific patient-reported outcomes (PROs) were administered to evaluate functional status. Intraoperative findings were recorded. RESULTS: A total of 654 patients met our inclusion/exclusion criteria, with 320 males and 334 females. The median age for males was 38.3 years (range, 15.0-69.6 years) and for females 40.4 years (range, 13.1-66.8 years). Male patients had a higher incidence of acute injury than females (39.6% vs 27.6%, respectively; P < .05) and a higher incidence of workers' compensation status (14.1% vs 4.5%, respectively; P < .05). Females had increased range of motion compared with males, which was statistically significant for all range of motion measurements (P < .05). The anterior impingement test was positive in 94.4% of females and 92.9% of males, the flexion/abduction/external rotation test was positive in 59.5% of females and 61.5% of males, and the lateral impingement test was positive in 55.0% of females and 59.2% of males, but there was no statistically significant difference between sexes in any of the tests. Pain with palpation over the greater trochanter was positive in 22.0% of males and 36.9% of females (P < .0001). Females had lower PROs; however, VAS scores were similar. CONCLUSION: Male and female patients differ in their hip structure, biomechanics, and operative findings of symptomatic labral tears. However, they do not differ substantially in clinical presentation, except that males are more likely to report an acute injury and females are more likely to be evaluated with increased range of motion. PMID- 24787047 TI - New protein kinase inhibitors in breast cancer: afatinib and neratinib. AB - INTRODUCTION: Human epidermal growth factor receptor (HER) 2 is overexpressed in 20 - 25% of breast cancers, and has historically been a poor prognostic marker. The introduction of trastuzumab, the first fully humanized monoclonal antibody targeting HER2, has drastically changed the outcomes of metastatic breast cancers. However, despite initial response, most patients develop resistance. Recent data suggest that strategies targeting more than one member of HER family may circumvent trastuzumab resistance and confer synergistic effects. AREAS COVERED: Following a literature search on PubMed, national meetings and clinicaltrials.gov using 'afatinib', 'neratinib', 'HER2' and 'breast cancer' as keywords, we critically analyzed the different HER2-targeted therapies for their drug development and evidence-based therapeutic strategies. Afatinib and neratinib, two second-generation tyrosine kinase inhibitors (TKIs) that irreversibly inhibit more than one HER family member, are being actively investigated in clinical trials either as monotherapy or in combination. We reviewed the efficacy and optimal use of these agents in various settings, such as systemic therapy for advanced breast cancer including brain metastases, and neoadjuvant therapy in early-stage breast cancer. EXPERT OPINION: HER2-targeted therapies have been widely used and greatly improved the outcome of HER2-positive breast cancer. Despite the accelerated advancement in recent years, several crucial questions remain unanswered, such as how to treat a prior resistance or affect a sanctuary site, that is, CNS metastasis. The novel next-generation TKIs, afatinib and neratinib, were rationally designed to overcome the resistance by targeting multiple HER family members and irreversibly binding the targets. In spite of the encouraging results of the afatinib and neratinib monotherapies, they have not been proven more efficacious in the combination therapies yet, even though multicenter international trials are still ongoing. The key tasks in the future are to study resistance pathways, design novel strategies to more efficiently test combinations for synergistic effects and identify biomarkers and novel imaging tools to guide individualized therapies. PMID- 24787049 TI - Fungal nutrient allocation in common mycorrhizal networks is regulated by the carbon source strength of individual host plants. AB - Common mycorrhizal networks (CMNs) of arbuscular mycorrhizal (AM) fungi in the soil simultaneously provide multiple host plants with nutrients, but the mechanisms by which the nutrient transport to individual host plants within one CMN is controlled are unknown. Using radioactive and stable isotopes, we followed the transport of phosphorus (P) and nitrogen (N) in the CMNs of two fungal species to plants that differed in their carbon (C) source strength, and correlated the transport to the expression of mycorrhiza-inducible plant P (MtPt4) and ammonium (1723.m00046) transporters in mycorrhizal roots. AM fungi discriminated between host plants that shared a CMN and preferentially allocated nutrients to high-quality (nonshaded) hosts. However, the fungus also supplied low-quality (shaded) hosts with nutrients and maintained a high colonization rate in these plants. Fungal P transport was correlated to the expression of MtPt4. The expression of the putative ammonium transporter 1723.m00046 was dependent on the fungal nutrient supply and was induced when the CMN had access to N. Biological market theory has emerged as a tool with which the strategic investment of competing partners in trading networks can be studied. Our work demonstrates how fungal partners are able to retain bargaining power, despite being obligately dependent on their hosts. PMID- 24787048 TI - Elevated brain lesion volumes in older adults who use calcium supplements: a cross-sectional clinical observational study. AB - Recent studies have implicated Ca supplements in vascular risk elevation, and therefore these supplements may also be associated with the occurrence of brain lesions (or hyperintensities) in older adults. These lesions represent damage to brain tissue that is caused by ischaemia. In the present cross-sectional clinical observational study, the association between Ca-containing dietary supplement use and lesion volumes was investigated in a sample of 227 older adults (60 years and above). Food and supplemental Ca intakes were assessed with the Block 1998 FFQ; participants with supplemental Ca intake above zero were categorised as supplement users. Lesion volumes were determined from cranial MRI (1.5 tesla) scans using a semi-automated technique; volumes were log-transformed because they were non-normal. ANCOVA models revealed that supplement users had greater lesion volumes than non-users, even after controlling for food Ca intake, age, sex, race, years of education, energy intake, depression and hypertension (Ca supplement use: beta = 0.34, SE 0.10, F(1,217)= 10.98, P= 0.0011). The influence of supplemental Ca use on lesion volume was of a magnitude similar to that of the influence of hypertension, a well-established risk factor for lesions. Among the supplement users, the amount of supplemental Ca was not associated with lesion volume (beta = - 0.000035, SE 0.00 015, F(1,139)= 0.06, P= 0.81). The present study demonstrates that the use of Ca-containing dietary supplements, even low dose supplements, by older adults may be associated with greater lesion volumes. Evaluation of randomised controlled trials is warranted to determine whether this relationship is a causal one. PMID- 24787050 TI - An innovative three-dimensional model of normal human skin to study the proinflammatory psoriatic effects of tumor necrosis factor-alpha and interleukin 17. AB - BACKGROUND: Among all cytokines involved in the pathogenesis and in the progression of psoriasis, Tumor Necrosis Factor (TNF)-alpha and interleukin (IL) 17 play a pivotal role. OBJECTIVE: The aim of the present study was to mimic a psoriatic microenvironment and to investigate the early effects of TNF-alpha and IL-17 in a three-dimensional model of organotypic normal human skin. METHODS: Human skin explants were obtained from plastic aesthetic surgery of healthy young women 20-40years old (n=7). The study was approved by the Institutional Review Board and written informed consent was obtained from all subjects. Bioptic fragments were cultured at the air-liquid interface overnight in a Transwell system and further divided before adding either 50ng/ml IL-17 or 100ng/ml TNF alpha or a combination of both cytokines. For each subject, a control sample was cultured without any cytokine. Samples were harvested 24 or 48h after cytokine incubation. At both time points and for all cytokine treatments a bioptic fragment obtained from each patient was processed. Epidermal proliferation, expressions of terminal differentiation (keratin 10, K10, and 14, K14) and of intercellular adhesion (occludin for tight junctions and E-cadherin for adherens junctions) biomarkers were investigated by indirect immunofluorescence. RESULTS: IL-17 and TNF-alpha induced an early and statistically significant inhibition of keratinocyte proliferation (more than 80% compared with their respective controls). At 24h, the combination of both cytokines did not further reduce cell proliferation. Starting from 24h of incubation, a non-continuous occludin expression in the granular layer was observed after both IL-17 and TNF-alpha exposure. Immunolabelling for E-cadherin in adherens junctions, for K10 in the suprabasal layers, and for K14 in the basal layer was similar in all experimental groups and unaffected after cytokine treatment. CONCLUSIONS: These results suggest that in this experimental model IL-17 and TNF-alpha induced an early alteration of the homeostasis of the inner proliferative layer and of the upper granular layer, as shown by cell proliferation inhibition and occludin expression. PMID- 24787051 TI - The relationship between TGFbeta, low oxygen and the outgrowth of extravillous trophoblasts from anchoring villi during the first trimester of pregnancy. AB - BACKGROUND: During the first trimester of human pregnancy, specialised placental cells called extravillous trophoblasts (EVTs) grow out from anchoring villi, invade the maternal decidua and remodel the uterine spiral arteries. Inadequate EVT invasion is associated with pregnancy complications including intrauterine growth restriction (IUGR) and pre-eclampsia. During early pregnancy, the placenta exists in a physiologically normal low oxygen environment, which may regulate EVT outgrowth. One potential oxygen responsive regulator of EVTs is the transforming growth factor-beta (TGFbeta) family of cytokines. This work aimed to determine the role of TGFbeta1, beta2 and beta3 in regulating EVT outgrowth in the low oxygen environment of early pregnancy. RESULTS: Using a quantitative high throughput first trimester villous explant model of EVT outgrowth we demonstrated no significant difference in the frequency of EVT outgrowth between explants treated with TGFbeta1, beta2 or beta3. However, explants treated with TGFbeta2, but not beta1 or beta3, produced EVT outgrowths with a significantly smaller area in comparison to untreated controls (p=0.03). When explants were cultured in 1.5% oxygen, TGFbeta2, but not beta1 or beta3, in the conditioned medium of explants that produced EVT outgrowth was significantly reduced in comparison to 8% oxygen (p<0.05). There was no significant difference in the concentration of TGFbeta2 or TGFbeta3 from isolated primary EVTs cultured in 1.5% or 8% oxygen. CONCLUSIONS: TGFbeta2 inhibits EVT outgrowth expansion from first trimester anchoring villi. As TGFbeta2 secretion from anchoring villi is down-regulated in low oxygen, these findings suggest that the low oxygen environment in early pregnancy may be important to allow EVT outgrowth expansion and promote adequate placentation. PMID- 24787052 TI - Long-range DNA interactions at the IL-1/IL-36/IL-37 gene cluster (2q13) are induced by activation of monocytes. AB - The interleukin-1 gene cluster occupies a 360kb region of chromosome 2q13 and contains nine homologous genes. These include agonists and antagonists of the parallel IL-1 and IL-36 systems, and IL1F7, the gene encoding IL-37. As the genes of the cluster are structurally and functionally related and have similar mRNA kinetics, we have sought evidence for gene induction-specific looping of chromatin in the IL-1 cluster by chromatin conformation capture (3C). We show here that IL1A, IL1B and IL1F7 regulatory regions come in close proximity in LPS stimulated cells but not in resting human monocytes. This suggests that IL1A, IL1B and IL1F7 are likely transcribed by the same transcription factory. One cardinal function of transcriptional Locus Control Region (LCR) is bringing map distant activated genes into close physical proximity within the transcription factory. Our data show distant intergenic DNA segments are also in close proximity to the regulatory regions of the three genes. This may indicate that they are co-regulated and raise the possibility of a LCR within the cluster. PMID- 24787053 TI - Ocular cytokinome is linked to clinical characteristics in ocular toxoplasmosis. AB - PURPOSE: To determine the cytokine levels in aqueous humor (AH) of Colombian patients with active ocular toxoplasmosis (OT), and to correlate them with their clinical characteristics. METHODS: 27 Cytokines/chemokines were assayed in 15 AH samples (nine patients with diagnosis of OT biologically-confirmed and six controls that underwent cataract surgery). Correlations were assessed between cytokine/chemokine levels, type of inflammatory response (Th1, Th2, Th17, Treg), and clinical characteristics. RESULTS: Th2 predominant response was related to more severe clinical features. The presence of VEGF and IL-5 was related to higher number of recurrences. Growth factors (VEGF, FGF, PDGF-beta), were related to higher number of lesions. Patients infected by type-I/III strains had a particular intraocular cytokine-pattern. CONCLUSIONS: Th2 response was related to more severe clinical characteristics in patients infected by Type I/III strains. IL-5 and VEGF were associated with recurrences. We correlate for the first time, specific cytokine-patterns with clinical characteristics and with the infecting Toxoplasma strain. PMID- 24787054 TI - CD4(+) T cells from food allergy model are resistant to TCR-dependent apoptotic induction. AB - BACKGROUND: CD4(+) T cell polarization plays a critical role in the pathogenesis of allergy. How to modulate the skewed CD4(+) T cell polarization is less clear. The specific immunotherapy (SIT) is the only specific remedy for the treatment of allergic diseases; the therapeutic effect is to be improved. OBJECTIVES: This study aims to investigate the role of interleukin (IL)-18 in enhancing the therapeutic effect of SIT. METHODS: A peanut allergy mouse model was developed and treated with SIT or/and IL-18. CD4(+) T cell apoptosis was assessed by flow cytometry. The expression of Fas ligand (FasL) was observed by quantitative real time RT-PCR and Western blotting. Interferon-gamma in the culture medium was determined by enzyme-linked immunosorbent assay. The fasL gene promoter methylation in CD4(+) T cells was assessed by methylation specific PCR. RESULTS: The results showed that lower levels of IL-18 were detected in allergic mice; administration of IL-18 significantly enhanced the therapeutic effect of SIT on suppressing the allergic inflammation in the mouse intestine. In the cell culture studies, IL-18 increased the TCR-dependent CD4(+) T cell apoptosis, the expression of FasL in CD4(+) T cells, the production of Interferon-gamma and the demethylation of the FasL promoter in CD4(+) T cells. CONCLUSIONS: Administration of IL-18 enhances the effect of SIT on suppressing allergic inflammation in the mouse intestine via enhancing the TCR-dependent CD4(+) T cell apoptosis. PMID- 24787055 TI - Expansion of the Litopenaeus vannamei and Penaeus monodon peptidomes using transcriptome shotgun assembly sequence data. AB - The shrimp Litopenaeus vannamei and Penaeus monodon are arguably the most important commercially farmed crustaceans. While expansion of their aquaculture has classically relied on improvements to rearing facilities, these options have largely been exhausted, and today a shift in focus is occurring, with increased investment in manipulating the shrimp themselves. Hormonal control is one strategy for increasing aquaculture output. However, to use it, one must first understand an animal's native hormonal systems. Here, transcriptome shotgun assembly (TSA) data were used to expand the peptidomes for L. vannamei and P. monodon. Via an established bioinformatics workflow, 41 L. vannamei and 25 P. monodon pre/preprohormone-encoding transcripts were identified, allowing for the prediction of 158 and 106 distinct peptide structures for these species, respectively. The identified peptides included isoforms of allatostatin A, B and C, as well as members the bursicon, CAPA, CCHamide, crustacean cardioactive peptide, crustacean hyperglycemic hormone, diuretic hormone 31, eclosion hormone, FLRFamide, GSEFLamide, intocin, leucokinin, molt-inhibiting hormone, myosuppressin, neuroparsin, neuropeptide F, orcokinin, orcomyotropin, pigment dispersing hormone, proctolin, red pigment concentrating hormone, RYamide, SIFamide, short neuropeptide F and tachykinin-related peptide families. While some of the predicted peptides are known L. vannamei and/or P. monodon isoforms (which vet the structures of many peptides identified previously via mass spectrometry and other means), most are described here for the first time. These data more than double the extant catalogs of L. vannamei and P. monodon peptides and provide platforms from which to launch future physiological studies of peptidergic signaling in these two commercially important species. PMID- 24787056 TI - Ocular surface changes in glaucomatous patients treated with and without preservatives beta-blockers. AB - PURPOSE: To determine whether there were ocular surface changes in glaucomatous patients treated with preservatives beta-blockers who switched to preservative free beta-blockers. METHODS: This was a prospective, longitudinal, open-labeled study. One hundred thirty-two patients with primary open angle glaucoma treated with a preserved beta-blocker were enrolled. All the patients underwent perimetric and gonioscopic examination, complete ophthalmologic examination, intraocular pressure (IOP) measurements, evaluation of ocular surface, Schirmer's test, blood pressure and heart rate at baseline and 1-3 months after changing the medical treatment to a preservative-free timolol 0.1% (Timogel 0.1; Thea). At baseline, after 1 month and at the end of the study (3 months), all patients underwent a questionnaire on the visual quality and symptoms and on the quality of life (QoL). Data were analyzed by t-test when the distribution of the data was normal, by Mann-Whitney when the distribution was not normal. RESULTS: No significant difference was found for IOP before switching from preserved beta blockers to preservative-free ones. No significant difference was found in blood pressure and heart rate. However, a statistically significant difference was found for abnormal fluorescein staining of the cornea and conjunctiva, eyelid erythema, conjunctival hyperemia, and follicular hyperplasia. A significant difference was found for break-up time (from 9.38+/-4.7 s at baseline to 10.64+/ 4.7 s after 3 months) and Schirmer's test (from 12.9+/-5.96 mm at baseline to 14.2+/-5.87 mm after 3 months). The questionnaire showed that the patient improved the dryness and foreign body sensation. CONCLUSION: In glaucomatous patients, preservative-free 0.1 timolol treatment improved their QoL. Similar dry eye signs or symptoms improved after 3 months of treatment reducing dryness, hyperemia, follicular hyperplasia, and foreign body sensation. PMID- 24787058 TI - Unusual closed loop stimulator responsive pacing in a patient with severe pulmonary hypertension. PMID- 24787057 TI - Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association. AB - 25-Hydroxyvitamin D (25(OH)D) deficits have been associated with schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown, vitamin D is a potent transcriptional modulator and can regulate proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia. We investigated the relationship between 25(OH)D and schizophrenia, comparing fasting plasma 25(OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(OH)D and schizophrenia. 25(OH)D levels were significantly lower in patients, and 25(OH)D insufficiency associated with schizophrenia (OR 2.1, adjusted p=0.044, 95% CI: 1.02-4.46). Moreover, 25(OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p=0.035, 95% CI: 1.08-8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(OH)D insufficiency on schizophrenia risk. This study presents a mechanism by which 25(OH)D insufficiency confers risk of schizophrenia; via proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support vitamin D supplementation in patients, particularly for those with elevated proline, who may represent a large subgroup of the schizophrenia population. PMID- 24787059 TI - Discrete Ramanujan transform for distinguishing the protein coding regions from other regions. AB - Based on the study of Ramanujan sum and Ramanujan coefficient, this paper suggests the concepts of discrete Ramanujan transform and spectrum. Using Voss numerical representation, one maps a symbolic DNA strand as a numerical DNA sequence, and deduces the discrete Ramanujan spectrum of the numerical DNA sequence. It is well known that of discrete Fourier power spectrum of protein coding sequence has an important feature of 3-base periodicity, which is widely used for DNA sequence analysis by the technique of discrete Fourier transform. It is performed by testing the signal-to-noise ratio at frequency N/3 as a criterion for the analysis, where N is the length of the sequence. The results presented in this paper show that the property of 3-base periodicity can be only identified as a prominent spike of the discrete Ramanujan spectrum at period 3 for the protein coding regions. The signal-to-noise ratio for discrete Ramanujan spectrum is defined for numerical measurement. Therefore, the discrete Ramanujan spectrum and the signal-to-noise ratio of a DNA sequence can be used for distinguishing the protein coding regions from the noncoding regions. All the exon and intron sequences in whole chromosomes 1, 2, 3 and 4 of Caenorhabditis elegans have been tested and the histograms and tables from the computational results illustrate the reliability of our method. In addition, we have analyzed theoretically and gotten the conclusion that the algorithm for calculating discrete Ramanujan spectrum owns the lower computational complexity and higher computational accuracy. The computational experiments show that the technique by using discrete Ramanujan spectrum for classifying different DNA sequences is a fast and effective method. PMID- 24787060 TI - Can the blues make it harder to breathe? PMID- 24787061 TI - What is the right dose of systemic corticosteroids for intensive care unit patients with chronic obstructive pulmonary disease exacerbations? A question in search of a definitive answer. PMID- 24787062 TI - Acute kidney injury: still deadly 10 years later. PMID- 24787063 TI - Right from wrong: the effect of traffic-related pollution on the right heart. PMID- 24787064 TI - Predictors of specific airway resistance during childhood. PMID- 24787065 TI - Update in pediatric lung disease 2013. PMID- 24787066 TI - Update in environmental and occupational lung diseases 2013. PMID- 24787067 TI - YKL-40 in pediatric asthma, MUC5B promoter polymorphism in idiopathic pulmonary fibrosis, and esmolol in septic shock. PMID- 24787068 TI - Mounier-Kuhn syndrome presenting as cough. PMID- 24787069 TI - Keratin-14 expression in pneumocytes as a marker of lung regeneration/repair during diffuse alveolar damage. PMID- 24787070 TI - Mechanistic classification of the systemic capillary leak syndrome: Clarkson disease. PMID- 24787071 TI - Lung clearance index in primary ciliary dyskinesia and bronchiectasis. PMID- 24787072 TI - Reply: lung clearance index in primary ciliary dyskinesia and bronchiectasis. PMID- 24787073 TI - Specialty status of intensive care medicine in Ireland. PMID- 24787075 TI - Pulmonary tuberculosis presenting as organizing pneumonia. PMID- 24787076 TI - Patient information series. Obesity hypoventilation syndrome. PMID- 24787077 TI - Quality and safety in healthcare revisited: a challenge to anaesthetists. PMID- 24787078 TI - Suction among pickers: jaw mechanics, dietary breadth and feeding behaviour in beach-spawning Leuresthes spp. compared with their relatives. AB - Jaw mechanics and dietary breadth in California grunion Leuresthes tenuis and Gulf grunion Leuresthes sardina were compared with three other members of the tribe Atherinopsini to test whether these two species have evolved a novel jaw protrusion that might be associated with feeding narrowly on abundant prey near spawning beaches. Quantitative comparison of cleared-and-stained specimens of five members of the atherinopsine clade showed that, compared with false grunion Colpichthys regis, topsmelt Atherinops affinis and jacksmelt Atherinopsis californiensis, L. tenuis and L. sardina have longer, more downwardly directed premaxillary protrusion, expanded dentary and premaxillary bones, greater lower jaw rotation and larger premaxilla-vomer separation. Leuresthes tenuis showed greater differences than L. sardina in these features. Comparison of the gut contents of L. tenuis and A. affinis with zooplankton samples collected simultaneously with these fishes in the water column within 1 km of shore showed that, as predicted, L. tenuis fed predominantly on mysid crustaceans and had a narrower diet than A. affinis. High-speed video analysis showed that L. tenuis exhibits a mean time to maximum jaw protrusion c. 2.5 times shorter than that of A. affinis. The grunion sister species, especially L. tenuis, have evolved suction feeding that may allow efficient feeding on common, evasive prey near spawning sites. The morphological traits seen in both species of Leuresthes signify a marked difference from their closest relatives in prey capture and suggest a type of jaw protrusion not yet seen in cyprinodontiforms or perciforms. PMID- 24787079 TI - Fast and early mandibular osteodistraction (FEMOD) in severe Pierre Robin Sequence. AB - Pierre Robin Sequence (PRS) is a congenital abnormality characterized by mandibular hypoplasia, glossoptosis and often secondary palate cleft. It may be an isolated or part of a most complicated syndrome. The genetic syndrome that most frequently co-occurs is Stickler syndrome characterized by skeletal abnormalities, joint pain, congenital myopia and retinal detachment. The authors describe their fast and early mandibular osteodistraction (FEMOD) protocol in severe cases of PRS airway obstruction. PMID- 24787080 TI - Obwegeser II osteotomy (transoral angle osteotomy) for open bite with skeletal class III deformity. AB - INTRODUCTION: This study evaluated postoperative stability after Obwegeser II osteotomy (transoral angle osteotomy, first reported by Obwegeser 1973) for severe open bite with mandibular prognathism. PATIENTS AND METHODS: This retrospective study reviewed 20 consecutive patients who underwent only mandibular Obwegeser II osteotomy to correct open bite and mandibular prognathism. Lateral cephalograms were evaluated preoperatively (T1), immediate postoperatively (T2) and at least 6 months after the surgery (T3). Surgical and postsurgical changes in cephalometric measurements were evaluated statistically. RESULTS: Open bite with skeletal class III malocclusion was corrected by the Obwegeser II osteotomy alone. After an average of 9.9 +/- 5.2 mm of mandibular setback with open bite closure (T2-T1, over-bite change, 5.7 +/- 2.4 mm) by counter-clockwise rotation of the mandible, the patients showed 0.8 +/- 1.7 mm of horizontal relapse (p > 0.05), 1.1 +/- 1.7 mm of vertical relapse at the B point (p = 0.011) and -0.2 +/- 1.6 mm of over-bite change postoperatively (T3-T2). DISCUSSION: With the adequate control of the condylar position with rigid internal fixation, Obwegeser II osteotomy showed acceptable stability after the correction of open bite with mandibular prognathism without a simultaneous maxillary osteotomy. An isolated Obwegeser II osteotomy can be considered a reliable option in cases with moderate to severe open bite with mandibular prognathism when the maxillary osteotomy is not needed if the patients have a well-positioned maxilla. PMID- 24787081 TI - Presence of mandibular third molars during bilateral sagittal split osteotomy increases the possibility of bad split but not the risk of other post-operative complications. AB - Timing of third molar removal in relation to bilateral sagittal split osteotomy (BSSO) is controversial, especially with regard to post-operative complications. We investigated the influence of mandibular third molar presence on complications after BSSO with sagittal splitters and separators, by a retrospective record review of 251 patients (502 surgical sites). Mandibular third molars were present during surgery at 169 sites and removed at least 6 months preoperatively in 333 sites. Bad splits occurred at 3.0 % (5/169) and 1.5% (5/333) of the respective sites. Presence of mandibular third molars significantly increased the risk of bad splits (OR 1.08, CI 1.02-1.13, p < 0.01). The mean incidences of permanent neurosensory disturbances, post-operative infection, and symptomatic removal of the osteosynthesis material were 5.4% (OR, 0.89; 95% CI, 0.79-1.00; p = 0.06), 8.2% (OR, 1.09; 95% CI, 0.99-1.20; p = 0.63), and 3.4% (OR, 0.97; 95% CI, .92 1.03; p = 0.35) per site, respectively, without a significant influence of mandibular third molar status. In conclusion, the presence of mandibular third molars during surgery increases the possibility of bad split but does not affect the risk of other complications. Therefore, third molars can be removed concomitantly with BSSO using sagittal splitters and separators. PMID- 24787082 TI - Midcheek mass: 10 year of clinical experience. AB - This is a literature review and retrospective chart review of ten years experience on the treatment of midcheek masses in our department. The purpose of this study is to provide the reader with an overview of the pathology of this complex anatomic area focusing the attention on the differential diagnosis and the recent surgical strategies. From May 2002 to December 2012 we enrolled 22 consecutive patients studied for masses located in the midcheek area. Only four studies were found in the literature describing the experience of individual centres reporting few cases of midcheek masses. Combined with the previously reported 37 cases, we describe 22 lesions for a total of 59 cases. Patients were evaluated with a head and neck clinical and instrumental examination. Apart from 4 cases treated with intramuscular infiltration of botulinum toxin for masseter hypertrophy, surgical approach to the lesions was varied: 10 patients received an external approach (standard parotidectomy approach or face-lift-type approach); 6 patients had the lesion removed through an intraoral approach; in 2 cases a direct skin incision was performed. In our series we found a significant rate (55.5%) of temporary complications in all the procedures performed (external, intraoral, direct skin approach). This study aims to emphasize the role of endoscope assisted surgery as a possible alternative to the traditional approaches for the management of well selected benign midcheek masses. It would be advisable to increase the study of the endoscopic anatomy of the midcheek area in order to standardize the procedure and better define the surgical indications. PMID- 24787083 TI - Versatility of the buccinator myomucosal flap in atypical palate reconstructions. AB - Initially described for the treatment of cleft palate, the anatomical bases of the buccinator myomucosal flap were described by Bozola et al. (1989). A meticulous search found several reports of its use for the correction of post palatoplasty oronasal fistulas, with only a few reports of its use for other palate-related pathologies. A retrospective analysis was undertaken of patients treated by the Plastic Surgery Units at the Rio de Janeiro Federal University Hospital (HU-UFRJ) and the Sao Paulo University Hospital (HC-USP), suffering from palatal lesions not associated with a cleft palate and treated through the use of buccinator myomucosal flaps. The average age was 47 years, with 70% of the patients being male. Assorted aetiologies were noted for palatal defects. When there was significant damage to the soft palate, a superior base pharyngeal flap was used. Of this total, in 71% of the cases only the buccinator myomucosal flap was used. In all cases, the flaps were unilateral, adequately covering the defects in question. The buccinator myomucosal flap is a good option for reconstructing medium to large palate defects, as it is a flap with good vascularization and dimension, in addition to an ample arc of rotation, with primary closure of the donor site, without adding significant morbidity. PMID- 24787084 TI - Fractures of the mandibular coronoid process: a two centres study. AB - The aim of this study was to assess the characteristics of patients with coronoid fractures treated in two European centres over 10 years and to briefly review the literature. This study is based on 2 systematic computer-assisted databases that have continuously recorded patients hospitalized with maxillofacial fractures and surgically treated in two European centres between 2001 and 2010. During the 10 years, 1818 patients and 523 patients with maxillofacial fractures were admitted to the two centres respectively: 21 patients (16 males, 5 females) were admitted with 21 coronoid fractures and 28 associated maxillofacial fractures. A mean age of 42.1 years was observed. The fractures were mainly the result of motor vehicle accidents, followed by assaults and falls. The most frequently observed associated maxillofacial fracture was a zygomatic fracture (13 fractures). In both centres, mandibular coronoid fractures are treated unless a severe dislocation of the fractured coronoid is observed or a functional mandibular impairment is encountered. Conservative treatment can be used, together with the open reduction and internal fixation of associated fractures. The crucial point is to prevent ankylosis, which may be prevented by correct and early postoperative physiotherapy and mandibular function. PMID- 24787088 TI - Abstracts of the 13th Annual Meeting of the International Society for the Study of Women's Sexual Health, February 20-23, 2014, San Diego, USA. PMID- 24787089 TI - Who uses a prescription drug monitoring program and how? Insights from a statewide survey of Oregon clinicians. AB - Prescription drug monitoring programs (PDMPs) are relatively new but potentially useful tools to enhance prudent prescribing of controlled substances. However, little is known about the types of clinicians who make the most use of PDMPs, how these programs are incorporated into clinicians' work flow, or how clinicians and patients respond to the information. We therefore surveyed a random sample of Oregon providers, with 1,065 respondents. Clinicians in emergency medicine, primary care, and pain and addiction specialties were the largest number of registrants, but many frequent prescribers of controlled substances were not registered to use the PDMP. Among users, 95% reported accessing the PDMP when they suspected a patient of abuse or diversion, but fewer than half would check it for every new patient or every time they prescribe a controlled drug. Nearly all PDMP users reported that they discuss worrisome PDMP data with patients; 54% reported making mental health or substance abuse referrals, and 36% reported sometimes discharging patients from the practice. Clinicians reported frequent patient denial or anger and only occasional requests for help with drug dependence. More research is needed to optimize how clinicians use PDMPs across settings and how clinicians and patients respond to the data. PERSPECTIVE: This study examined differences between PDMP users and nonusers and how clinicians in various specialties use PDMPs in practice. A better understanding of effective PDMP use will facilitate access to treatment for patients with pain while curbing the prescription drug epidemic and may ultimately reduce abuse, misuse, and overdose death. PMID- 24787090 TI - Enrichment of ventilation air methane (VAM) with carbon fiber composites. AB - Treatment of ventilation air methane (VAM) with cost-effective technologies has been an ongoing challenge due to its high volumetric flow rate with low and variable methane concentrations. In this work, honeycomb monolithic carbon fiber composites were developed and employed to capture VAM with a large-scale test unit at various conditions such as VAM concentration, ventilation air (VA) flow rate, temperature, and purging fluids. Regardless of inlet VAM concentrations, methane was captured at almost 100%. To regenerate the composites, the initial vacuum swing followed by combined temperature and vacuum swing adsorption (TVSA) was applied. It was found that initial vacuum swing is a control step for the final methane concentration having 5 or 11 times the VAM enrichment by one-step adsorption, which is, to our knowledge, the best performance achieved in VAM enrichment technologies worldwide. Five-time enriched VAM can be utilized as a principle fuel for lean burn turbine. Also, it can be further enriched by second step adsorption to more than 25% which then can be used for commercially available gas engines. In this way, the final product can be out of the methane explosive range (5-15%). PMID- 24787091 TI - Comparative study of the folding/unfolding dynamics of poly(glutamic acid) in light and heavy water. AB - The folding/unfolding equilibrium is investigated in poly(glutamic acid) (PGA) by two complementary sets of experiments: temperature-dependent steady-state circular dichroism spectra on the one hand and time-resolved circular dichroism measurements coupled with a T-jump experiment on the other hand. The experiments are performed for PGA dissolved in water for various pH values, as well as in heavy water. The kinetic and thermodynamic parameters extracted from these measurements are shown to be markedly different between light and heavy water, which is assigned to the difference in hydrogen bond energies in both solvents. PMID- 24787092 TI - Infantile hypertrophic pyloric stenosis: closing in on the cause. PMID- 24787074 TI - An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. AB - BACKGROUND: Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS: An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS: We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS: Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed. PMID- 24787093 TI - Seasonal vitamin D status of healthy schoolchildren and predictors of low vitamin D status. AB - OBJECTIVES: The aim of the study was to assess seasonal prevalence of vitamin D deficiency according to sex and to determine the relations between serum levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) and sociodemographic characteristics in otherwise healthy schoolchildren during spring and autumn. METHODS: In a cross-sectional study, 746 healthy students aged between 11 and 18 years were recruited during spring (n = 375) and autumn (n = 371). Sociodemographic data were collected by a questionnaire. Serum 25(OH)D, PTH, calcium, phosphate, and alkaline phosphatase were measured. Serum 25(OH)D levels were categorized as <50 nmol/L (vitamin D deficiency) and <25 nmol/L (severe deficiency). RESULTS: Mean +/- standard deviation 25(OH)D levels were 22.3 +/- 10.5 nmol/L in girls and 28.5 +/- 17.0 nmol/L in boys during spring (P < 0.001) and 36.5 +/- 20.3 nmol/L in girls and 45.0 +/- 18.5 nmol/L in boys during autumn (P < 0.001). The prevalence of vitamin D deficiency was 93% during spring and 71% during autumn. There was a negative correlation between 25(OH)D and PTH levels (P < 0.01). We determined a cutoff point of serum 25(OH)D in which the mean serum PTH concentration began to increase as 35.8 nmol/L (P < 0.0001). The age, sex, and calcium level were found to be independent predictors for vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is prevalent among healthy schoolchildren. It is noteworthy that 25(OH)D levels were significantly lower in girls and during autumn. We recommend vitamin D supplementation for children in addition to more time spent for outdoor activities for sensible sunlight exposure. PMID- 24787094 TI - Trabecular bone adaptation to low-magnitude high-frequency loading in microgravity. AB - Exposure to microgravity causes loss of lower body bone mass in some astronauts. Low-magnitude high-frequency loading can stimulate bone formation on earth. Here we hypothesized that low-magnitude high-frequency loading will also stimulate bone formation under microgravity conditions. Two groups of six bovine cancellous bone explants were cultured at microgravity on a Russian Foton-M3 spacecraft and were either loaded dynamically using a sinusoidal curve or experienced only a static load. Comparable reference groups were investigated at normal gravity. Bone structure was assessed by histology, and mechanical competence was quantified using MUCT and FE modelling; bone remodelling was assessed by fluorescent labelling and secreted bone turnover markers. Statistical analyses on morphometric parameters and apparent stiffness did not reveal significant differences between the treatment groups. The release of bone formation marker from the groups cultured at normal gravity increased significantly from the first to the second week of the experiment by 90.4% and 82.5% in response to static and dynamic loading, respectively. Bone resorption markers decreased significantly for the groups cultured at microgravity by 7.5% and 8.0% in response to static and dynamic loading, respectively. We found low strain magnitudes to drive bone turnover when applied at high frequency, and this to be valid at normal as well as at microgravity. In conclusion, we found the effect of mechanical loading on trabecular bone to be regulated mainly by an increase of bone formation at normal gravity and by a decrease in bone resorption at microgravity. Additional studies with extended experimental time and increased samples number appear necessary for a further understanding of the anabolic potential of dynamic loading on bone quality and mechanical competence. PMID- 24787095 TI - Quantification of trabecular spatial orientation from low-resolution images. AB - No accepted methodology exists to assess trabecular bone orientation from clinical CT scans. The aim of this study was to test the hypothesis that the distribution of grey values in clinical CT images is related to the underlying trabecular architecture and that this distribution can be used to identify the principal directions and local anisotropy of trabecular bone. Fourteen trabecular bone samples were extracted from high-resolution (30 MUm) micro-CT scans of seven human femoral heads. Trabecular orientations and local anisotropy were calculated using grey-level deviation (GLD), a novel method providing a measure of the three dimensional distribution of image grey values. This was repeated for different image resolutions down to 300 MUm and for volumes of interest (VOIs) ranging from 1 to 7 mm. Outcomes were compared with the principal mechanical directions and with mean intercept length (MIL) as calculated for the segmented 30-MUm images. For the 30-MUm images, GLD predicted the mechanical principal directions equally well as MIL. For the 300-MUm images, which are resolutions that can be obtained in vivo using clinical CT, only a small increase (3 degrees -6 degrees ) in the deviation from the mechanical orientations was found. VOIs of 5 mm resulted in a robust quantification of the orientation. We conclude that GLD can quantify structural bone parameters from low-resolution CT images. PMID- 24787096 TI - Differences in immunohistochemical biomarkers between intra- and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. AB - BACKGROUND AND AIM: Cholangiocarcinomas of different locations differ in growth patterns, symptoms, treatment response, and survival. Still, they are regarded in many studies as a uniform malignancy. Because intra- (iCCA) and extrahepatic (eCCA) cholangiocarcinoma display such differences, we performed a systematic review and meta-analysis to analyze differences in the immunohistochemical profile of these tumors. METHODS: In February 2014, we searched the two main medical literature databases MEDLINE and EMBASE. We extracted risk ratios and 95% confidence intervals from the identified studies and performed random-effects model meta-analyses in accordance with PRISMA and REMARK guidelines. RESULTS: A total of 54 cohort studies, including 4458 patients and studying 102 individual markers met the inclusion criteria. Of the 57 markers that were evaluated in more than 30 iCCA and eCCA patients, 18 showed a statistically significant difference in expression between iCCA and eCCA. Biomarkers expressed differently between iCCA and eCCA included potential targets of therapy: EGFR, c-erbB-2 and VEGF-A. Several markers showed no statistical difference but large 95% confidence intervals, suggesting insufficient sample size. CONCLUSIONS: This systematic review shows differences in marker expression between iCCA and eCCA. Consequently, patients with iCCA and eCCA may benefit from different treatment strategies. PMID- 24787097 TI - For more than four decades, the Robert Wood Johnson Foundation Clinical Scholars program has fostered the development of physicians: introduction. PMID- 24787098 TI - The surgical specialties and the Robert Wood Johnson Clinical Scholars Program. PMID- 24787099 TI - Accountability for end-stage organ care: implications of geographic variation in access to kidney transplantation. AB - BACKGROUND: The provision of effective surgical care for end-stage renal disease (ESRD) requires efficient evaluation and transplantation. Prior assessments of transplant access have focused primarily on waitlisted patients rather than the overall populations served by "accountable" providers of transplant services. METHODS: Novel transplant referral regions (TRRs) were defined using United Network for Organ Sharing registry data for 301,092 kidney transplant listings to assign zip codes to "accountable" transplant programs. Subsequently, risk adjusted observed to expected (O:E) rates of listing and transplant procedures were calculated for each TRR. Finally, the impact of variation in TRR listing and transplant rates on mortality was assessed for ESRD patients <60 years old diagnosed between 2000 and 2008. RESULTS: In total, 113 TRRs were defined, 51% of which included >1 transplant center. The likelihood of being evaluated and listed for transplant varied significantly between TRRs (risk-adjusted O:E, 0.58-1.95). Variation was greater for the overall transplant rate (0.62-2.19), living donor transplantation (0.36-3.08), and donation after cardiac death transplant (0-15.4) than for standard criteria donors (0.64-2.86). Mortality was decreased for ESRD patients living in TRRs in the highest tertile of listings (hazard ratio, 0.89; P < .0001) and transplantation (0.90; P < .0001). CONCLUSION: Residence in a TRR with care delivery systems that increase access to transplant services is associated with significant, risk-adjusted decreases in ESRD-related mortality. Transplant centers should continue to focus on improving access to care within the communities they serve. PMID- 24787100 TI - Hospital-based, acute care after ambulatory surgery center discharge. AB - BACKGROUND: As a measure of quality, ambulatory surgery centers have begun reporting rates of hospital transfer at discharge. This process, however, may underestimate the acute care needs of patients after care. We conducted this study to determine rates and evaluate variation in hospital transfer and hospital based, acute care within 7 days among patients discharged from ambulatory surgery centers. METHODS: Using data from the Healthcare Cost and Utilization Project, we identified adult patients who underwent a medical or operative procedure between July 2008 and September 2009 at ambulatory surgery centers in California, Florida, and Nebraska. The primary outcomes were hospital transfer at the time of discharge and hospital-based, acute care (emergency department visits or hospital admissions) within 7-days expressed as the rate per 1,000 discharges. At the ambulatory surgery center level, rates were adjusted for age, sex, and procedure mix. RESULTS: We studied 3,821,670 patients treated at 1,295 ambulatory surgery centers. At discharge, the hospital transfer rate was 1.1 per 1,000 discharges (95% confidence interval 1.1-1.1). Among patients discharged home, the hospital based, acute care rate was 31.8 per 1,000 discharges (95% confidence interval 31.6-32.0). Across ambulatory surgery centers, there was little variation in adjusted hospital transfer rates (median = 1.0/1,000 discharges [25th-75th percentile = 1.0-2.0]), whereas substantial variation existed in adjusted, hospital-based, acute care rates (28.0/1,000 [21.0-39.0]). CONCLUSION: Among adult patients undergoing ambulatory care at surgery centers, hospital transfer at time of discharge from the ambulatory care center is a rare event. In contrast, the rate of need for hospital-based, acute care in the first week afterwards is nearly 30-fold greater, varies across centers, and may be a more meaningful measure for discriminating quality. PMID- 24787101 TI - Identification of modifiable factors for reducing readmission after colectomy: a national analysis. AB - BACKGROUND: Rates of hospital readmission are currently used for public reporting and pay for performance. Colectomy procedures account for a large number of readmissions among operative procedures. Our objective was to compare the importance of 3 groups of clinical variables (demographics, preoperative risk factors, and postoperative complications) in predicting readmission after colectomy procedures. METHODS: Patient records (2005-2008) from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) were linked to Medicare inpatient claims. Patient demographics (n = 2), preoperative risk factors (n = 23), and 30-day postoperative complications (n = 17) were identified from ACS-NSQIP, whereas 30-day postoperative readmissions and costs were determined from Medicare. Multivariable logistic regression models were used to examine risk-adjusted predictors of colectomy readmission. RESULTS: Among 12,981 colectomy patients, the 30-day postoperative readmission rate was 13.5%. Readmitted patients had slightly greater rates of comorbidities and indicators of clinical severity and substantially greater rates of complications than non-readmitted patients. After risk adjustment, patients with a complication were 3.3 times as likely to be readmitted as patients without a complication. Among individual complications, progressive renal failure and organ-space surgical site infection had the highest risk-adjusted relative risks of readmission (4.6 and 4.0, respectively). Demographic, preoperative risk factor, and postoperative complication variables increased the ability to discriminate readmissions (reflected by the c-statistic) by 5.3%, 23.3%, and 35.4%, respectively. CONCLUSION: Postoperative complications after colectomy are more predictive of readmission than traditional risk factors. Focusing quality improvement efforts on preventing and managing postoperative complications may be the most important step toward reducing readmission rates. PMID- 24787102 TI - The RWJ Clinical Scholars Program: how health services research and this alumna were helped from the fringe to the mainstream in general surgery. PMID- 24787103 TI - The impact of unplanned postprocedure visits in the management of patients with urinary stones. AB - BACKGROUND: Unplanned follow-up care is the focus of intense health policy interest, as evidenced by recent financial penalties imposed under the Affordable Care Act. To date, however, unplanned postoperative care remains poorly characterized, particularly for patients with kidney stones. Our objective was to describe the frequency, variation, and financial impact of unplanned, high acuity, follow-up visits in the treatment of patients with urinary stone disease. METHODS: We identified privately insured patients undergoing percutaneous nephrostolithotomy, ureteroscopy, or shock-wave lithotripsy for stone disease. The primary outcome was occurrence of an emergency department visit or hospital admission within 30 days of the procedure. Multivariable models estimated the odds of an unplanned visit and the incremental cost of those visits, controlling for important covariates. RESULTS: We identified 93,523 initial procedures to fragment or remove stones. Overall, 1 in 7 patients had an unplanned postprocedural visit. Unplanned visits were least common after shock-wave lithotripsy (12%) and occurred with similar frequency after ureteroscopy and percutaneous nephrostolithotomy (15%). Procedures at high-volume facilities were substantially less likely to result in an unplanned visit (odds ratio 0.80, 95% confidence interval [95% CI] 0.74-0.87, P < .001). When an unplanned visit occurred, adjusted incremental expenditures per episode were greater after shock wave lithotripsy ($32,156 [95% CI $30,453-33,859]) than after ureteroscopy ($23,436 [95% CI $22,281-24,590]). CONCLUSION: Patients not infrequently experience an unplanned, high-acuity visit after low-risk procedures to remove urinary stones, and the cost of these encounters is substantial. Interventions are indicated to identify and reduce preventable unplanned visits. PMID- 24787104 TI - For-profit hospital ownership status and use of brachytherapy after breast conserving surgery. AB - BACKGROUND: Little is known about the relationship between operative care for breast cancer at for-profit hospitals and subsequent use of adjuvant radiation therapy (RT). Among Medicare beneficiaries, we examined whether hospital ownership status is associated with the use of breast brachytherapy--a newer and more expensive modality--as well as overall RT. METHODS: We conducted a retrospective study of female Medicare beneficiaries who received breast conserving surgery for invasive breast cancer in 2008 and 2009. We assessed the relationship between hospital ownership and receipt of brachytherapy or overall RT by using hierarchical generalized linear models. RESULTS: The sample consisted of 35,118 women, 8.0% of whom had breast-conserving operations at for-profit hospitals. Among patients who received RT, those who underwent operation at for profit hospitals were more likely to receive brachytherapy (20.2%) than patients treated at not-for-profit hospitals (15.2%; odds ratio [OR] for for-profit versus not-for-profit: 1.50; 95% confidence interval [95% CI] 1.23-1.84; P < .001). Among women aged 66-79 years, there was no relationship between hospital ownership status and overall use of RT. Among women ages 80-94 years of age--the group least likely to benefit from RT due to shorter life expectancy--undergoing breast-conserving operations at a for-profit hospital was associated with greater overall use of RT (OR 1.22; 95% CI 1.03-1.45, P = .03) and brachytherapy use (OR 1.66; 95% CI 1.18-2.34, P = .003). CONCLUSION: Operative care at for-profit hospitals was associated with increased use of the newer and more expensive RT modality, brachytherapy. Among the oldest women who are least likely to benefit from RT, operative care at a for-profit hospital was associated with greater overall use of RT, with this difference largely driven by the use of brachytherapy. PMID- 24787105 TI - User-centered design of quality of life reports for clinical care of patients with prostate cancer. AB - BACKGROUND: Primary treatment of localized prostate cancer can result in bothersome urinary, sexual, and bowel symptoms. Yet clinical application of health-related quality-of-life (HRQOL) questionnaires is rare. We employed user centered design to develop graphic dashboards of questionnaire responses from patients with prostate cancer to facilitate clinical integration of HRQOL measurement. METHODS: We interviewed 50 prostate cancer patients and 50 providers, assessed literacy with validated instruments (Rapid Estimate of Adult Literacy in Medicine short form, Subjective Numeracy Scale, Graphical Literacy Scale), and presented participants with prototype dashboards that display prostate cancer-specific HRQOL with graphic elements derived from patient focus groups. We assessed dashboard comprehension and preferences in table, bar, line, and pictograph formats with patient scores contextualized with HRQOL scores of similar patients serving as a comparison group. RESULTS: Health literacy (mean score, 6.8/7) and numeracy (mean score, 4.5/6) of patient participants was high. Patients favored the bar chart (mean rank, 1.8 [P = .12] vs line graph [P < .01] vs table and pictograph); providers demonstrated similar preference for table, bar, and line formats (ranked first by 30%, 34%, and 34% of providers, respectively). Providers expressed unsolicited concerns over presentation of comparison group scores (n = 19; 38%) and impact on clinic efficiency (n = 16; 32%). CONCLUSION: Based on preferences of prostate cancer patients and providers, we developed the design concept of a dynamic HRQOL dashboard that permits a base patient-centered report in bar chart format that can be toggled to other formats and include error bars that frame comparison group scores. Inclusion of lower literacy patients may yield different preferences. PMID- 24787106 TI - Learning to see the forest through the trees. PMID- 24787107 TI - Patient expectations and patient-reported outcomes in surgery: a systematic review. AB - BACKGROUND: Recent events in health care reform have brought national attention to integrating patient experiences and expectations into quality metrics. Few studies have comprehensively evaluated the effect of patient expectations on patient-reported outcomes (PROs) after surgery. The purpose of this study is to systematically review the available literature describing the relationship between patient expectations and postoperative PROs. METHODS: We performed a search of the literature published before November 1, 2012. Articles were included in the review if (1) primary data were presented, (2) patient expectations regarding a surgical procedure were measured, (3) PROs were measured, and (4) the relationship between patient expectations and PROs was specifically examined. PROs were categorized into 5 subgroups: Satisfaction, quality of life (QOL), disability, mood disorder, and pain. We examined each study to determine the relationship between patient expectations and PROs as well as study quality. RESULTS: From the initial literature search yielding 1,708 studies, 60 articles were included. Fulfillment of expectations was associated with improved PROs among 24 studies. Positive expectations were correlated with improved PROs for 28 studies (47%), and poorer PROs for 9 studies (15%). Eighteen studies reported that fulfillment of expectations was correlated with improved patient satisfaction, and 10 studies identified that positive expectations were correlated with improved postoperative. Finally, patients with positive preoperative expectations reported less pain (8 studies) and disability (15 studies) compared with patients with negative preoperative expectations. CONCLUSION: Patient expectations are inconsistently correlated with PROs after surgery, and there is no accepted method to capture perioperative expectations. Future efforts to rigorously measure expectations and explore their influence on postoperative outcomes can inform clinicians and policymakers seeking to integrate PROs into measures of surgical quality. PMID- 24787109 TI - The quality of surgical care in safety net hospitals: a systematic review. AB - OBJECTIVE: The quality of surgical care in safety net hospitals (SNHs) is not well understood owing to sparse data that have not yet been analyzed systematically. We hypothesized that on average, SNHs provide a lesser quality of care for surgery patients than non-SNHs. STUDY DESIGN: We performed a systematic review of published literature on quality of surgical care in SNHs in accordance with guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We searched within the PubMed, CINAHL, and Scopus online databases, and included peer-reviewed, English-language, scientific papers published between 1995 and 2013 that analyzed primary or secondary data on >=1 of the domains of quality (safety, effectiveness, efficiency, timeliness, patient centeredness, and equity) of surgical care in a US hospital or system that met the Institute of Medicine definition of a SNH. Each article was reviewed independently by >=2 co-investigators. A data abstraction tool was used to record the eligibility, purpose, design, results, conclusion, and overall quality of each article reviewed. Disagreements over eligibility and data were resolved by group discussion. The main results and conclusions abstracted from the included articles were then analyzed and presented according to the quality domains addressed most clearly by each article. PRINCIPAL FINDINGS: Our initial search identified 1,556 citations, of which 86 were potentially eligible for inclusion. After complete review and abstraction, only 19 of these studies met all inclusion criteria. SNHs performed significantly worse than non-SNHs in measures of timeliness and patient centeredness. Surgical care in SNHs tended to be less equitable than in non-SNHs. Data on the safety of surgical care in SNHs were inconsistent. CONCLUSION: Although data are limited, there seems to be need for improvement in particular aspects of the quality of surgical care provided in SNHs. Thus, SNHs should be priority settings for future quality improvement interventions in surgery. Such initiatives could have disproportionately greater impact in these lower-performing settings and would address directly any health care disparities among the poor, underserved, and most vulnerable populations in the United States. PMID- 24787108 TI - A qualitative analysis of acute care surgery in the United States: it's more than just "a competent surgeon with a sharp knife and a willing attitude". AB - BACKGROUND: Since acute care surgery (ACS) was conceptualized a decade ago, the specialty has been adopted widely; however, little is known about the structure and function of ACS teams. METHODS: We conducted 18 open-ended interviews with ACS leaders (representing geographic [New England, Northeast, Mid-Atlantic, South, West, Midwest] and practice [Public/Charity, Community, University] diversity). Two independent reviewers analyzed transcribed interviews using an inductive approach (NVivo qualitative analysis software). RESULTS: All respondents described ACS as a specialty treating "time-sensitive surgical disease" including trauma, emergency general surgery (EGS), and surgical critical care (SCC); 11 of 18 combined trauma and EGS into a single clinical team; 9 of 18 included elective general surgery. Emergency orthopedics, emergency neurosurgery, and surgical subspecialty triage were rare (1/18 each). Eight of 18 ACS teams had scheduled EGS operating room time. All had a core group of trauma and SCC surgeons; 13 of 18 shared EGS due to volume, human resources, or competition for revenue. Only 12 of 18 had formal signout rounds; only 2 of 18 had prospective EGS data registries. Streamlined access to EGS, evidence-based protocols, and improved education were considered strengths of ACS. ACS was described as the "last great surgical service" reinvigorated to provide "timely," cost-effective EGS by experts in "resuscitation and critical care" and to attract "young, talented, eager surgeons" to trauma/SCC; however, there was concern that ACS might become the "wastebasket for everything that happens at inconvenient times." CONCLUSION: Despite rapid adoption of ACS, its implementation varies widely. Standardization of scope of practice, continuity of care, and registry development may improve EGS outcomes and allow the specialty to thrive. PMID- 24787110 TI - Expanding the research experience. PMID- 24787112 TI - Referring physicians' decision making for pediatric anti-reflux procedures. AB - BACKGROUND: Rates of anti-reflux procedures (ARP) vary greatly among pediatric hospitals. How pediatric subspecialists make referral decisions for ARPs has not been described. The aim of this study was to characterize pediatric subspecialists' decision making for referring children for ARPs. METHODS: Pediatric subspecialists at a single children's hospital were interviewed about their decision making when referring for ARPs. Qualitative analysis was performed on clinicians' perceptions of the risks and benefits of the treatment options. Clinical algorithms were derived from each interview and were compared using the Clinical Algorithm Nosology. Clinical Algorithm Structural Analysis (CASA) scores were calculated to assess algorithm complexity. Clinical Algorithm Patient Abstraction (CAPA) scores on a scale from 0 (different) to 10 (identical) were generated based on algorithm agreement. RESULTS: The interviews yielded 15 algorithms. There was substantial variation in the providers' perceived risks and benefits of the treatment options. CASA scores ranged from 8 to 28 and CAPA scores ranged from 0 to 5.7 (median, 0), indicating great variation in both complexity and patient management. Management variation included testing (33% of algorithms incorporated pH probe test, 67% upper gastrointestinal, and 47% small bowel follow-through), procedure contraindications (33% considered history of gagging a contraindication to ARP), and use of gastrojejunostomy tubes (20% using gastrojejunostomy tube before ARP). CONCLUSION: No standards exist for the decision to refer children with gastroesophageal reflux disease for ARP. There is great variation among pediatric subspecialists in their decision making. Differences in providers' perception of the risks and benefits of these procedures contribute to this variation. PMID- 24787111 TI - The effect of complications on the patient-surgeon relationship after colorectal cancer surgery. AB - BACKGROUND: Trust in physicians is an essential part of therapeutic relationships. Complications are common after colorectal cancer procedures, but little is known of their effect on patient-surgeon relationships. We hypothesized that unexpected complications impair trust and communication between patients and surgeons. METHODS: We performed a population-based survey of surgically diagnosed stage III colorectal cancer patients in the Surveillance Epidemiology and End Results registries for Georgia and Metropolitan Detroit between August 2011 and October 2012. Using published survey instruments, we queried subjects about trust in and communication with their surgeon. The primary predictor was the occurrence of an operative complication. We examined patient factors associated with trust and communication then compared the relationship between operative complications and patient-reported trust and communication with their surgeons. RESULTS: Among 622 preliminary respondents (54% response rate), 25% experienced postoperative complications. Those with complications were less likely to report high trust (73% vs 81%, P = .04) and high-quality communication (80% vs 95%, P < .001). Complications reduced trust among only 4% of patient-surgeon dyads with high quality communication, whereas complications diminished patients' trust in 50% with poorer communication (P < .001). After controlling for communication ratings, we found there was no residual effect of complications on trust (P = .96). CONCLUSION: Most respondents described trust in and communication with their surgeons as high. Complications were common and were associated with lower trust and poorer communication. However, the relationship between complications and trust was modified by communication. Trust remained high, even in the presence of complications, among respondents who reported high levels of patient centered communication with their surgeons. PMID- 24787114 TI - Back to the future: the renaissance of whole-blood transfusions for massively hemorrhaging patients. PMID- 24787113 TI - Implementation of a "real-world" learning health care system: Washington State's Comparative Effectiveness Research Translation Network (CERTAIN). AB - BACKGROUND: Learning health care systems apply the experiences of prior patients to inform care and help to guide decision making for current patients. These systems should help to deliver more effective, efficient, and appropriate care. Most examples of learning systems derive from integrated care delivery systems and examples of such systems in the community at large have been lacking. METHODS: The comparative effectiveness research translation network (CERTAIN) is a learning system bringing together hospitals and outpatient clinics across Washington State. CERTAIN leverages existing medical record-based data collection taking place at nearly all statewide hospitals and links this data collection with patient-reported information about function and quality of life. RESULTS: We have described the components of the CERTAIN infrastructure, the elements of a pilot project evaluating treatments of claudication, and the opportunities and challenges of developing and implementing a "real world" learning system. Examples in the areas of vascular disease, spine care, gastrointestinal disease, and urology. CONCLUSION: Learning health care systems face many operational challenges but hold great promise for discovery and implementation of more effective clinical practices. PMID- 24787115 TI - Arterial resection at the time of pancreatectomy for cancer. AB - BACKGROUND: Tumor-induced arterial abutment/encasement has been traditionally a contraindication to surgery in patients with localized pancreatic cancer (PC). One recent meta-analysis reported greater mortality rates in this setting. We report herein a series of planned arterial resections in carefully selected patients who responded favorably to combined modality therapy for localized PC. METHODS: We reviewed all patients with PC and arterial encasement treated between May 2011 and September 2013; all patients received an extensive course of neoadjuvant therapy before surgery. RESULTS: Of 15 patients taken to surgery, 2 had peritoneal disease at laparoscopy, and therefore, laparotomy was not performed. Pancreatectomy (pancreaticoduodenectomy, 3; distal, 8; central pancreatectomy, 1; total, 1) was performed in the remaining 13, 10 of whom required arterial resection. The most common operation was an Appleby procedure. Of 10 patients who underwent combined pancreatectomy and arterial resection, their median age was 62 years (range, 33-75), median operative time was 7.5 hours, and median blood loss was 725 mL. Complications occurred in 3 of 15 patients with no perioperative mortality. Median duration of hospital stay was 9 days (range, 5-19). An R0 resection was achieved in 11 (85%) of 13 patients. At a median follow-up of 21 months, 8 of these 13 resected patients (62%) are alive without disease. CONCLUSION: Planned arterial resection at the time of pancreatectomy can be performed with acceptable morbidity and mortality; patient selection and induction therapy are likely critically important variables that seem to impact patient outcome. Those patients with stable or responding disease after induction therapy represent the subset of patients with potentially favorable tumor biology in whom extended resections may enhance survival duration. PMID- 24787117 TI - [Differences between decreased glomerular filtration rate and renal failure: risks of the association of both concepts in the healthy elderly]. PMID- 24787118 TI - Diterpenoids from the flowers of Rhododendron molle. AB - A new seco-kalmane-type diterpenoid, seco-rhodomollone (1), five new grayanane type diterpenoids, rhodomollein XXI (2), 6-O-acetylrhodomollein XXI (3), 6,14-di O-acetylrhodomollein XXI (4), rhodomollein XXII (5), and 2-O-methylrhodomollein XI (6), and two new kalmane-type diterpenoids, rhodomolleins XXIII (7) and XXIV (8), together with seven known compounds, were isolated from the flowers of Rhododendron molle collected in Guangxi Province, China. The absolute configurations of 1 and 3 were defined by single-crystal X-ray diffraction experiments. Compound 1 possesses an unprecedented 1,5-seco-kalmane skeleton presumably derived by cleavage of the C-1-C-5 bond of the kalmane skeleton. Compounds 2-4 represent the first examples from a natural source of grayanane type diterpenoids with a chlorine substituent. PMID- 24787119 TI - Fear of falling in robust community-dwelling older people: results of a cross sectional study. AB - AIMS AND OBJECTIVES: To identify the prevalence and risk factors for fear of falling among robust community-dwelling older people. BACKGROUND: Different models including various risk factors emerged when previous studies attempted to explore the factors' multivariate associations with fear of falling. Attempting to detect fear of falling by a single question in some previous studies may not have been sufficiently sensitive, particularly in a robust population. Although some studies used a validated instrument to detect participants' fear of falling, their self-perceived efficacy in performing various activities was seldom reported. Information to provide an insight into the planning of well-targeted interventions to reduce fear of falling has been lacking. DESIGN: A cross sectional study of 445 robust community-dwelling older people aged >=65. METHODS: Besides their demographic and fall-related background, participants' fear of falling level was assessed using the Chinese Fall Efficacy Scale-International. Other instruments included the timed up and go test, the Chinese Geriatric Depression Scale-Short Form, the Chinese Anxiety Disorder Scale, the Chinese Lubben Social Network Scale and the Chinese Personal Wellbeing Index, which were used to assess different variables that may be associated with fear of falling. RESULTS: Of the 64.73% of participants who had fear of falling, 65.63% had no history of fall but still had fear of falling. This result was higher than in most previous studies. Participants' main concerns were walking on slippery/uneven surfaces, in crowded places and up/down a slope. Multivariate analyses showed that being female, suffering from poor vision and arthritis, poor performance in the timed up and go test, expressing more depressive and anxiety symptoms and low self-perceived well-being are multiply associated with fear of falling. CONCLUSION: Fear of falling is prevalent among robust community-dwelling older people regardless of their fall history. They showed lack of self-perceived efficacy in performing various outdoor activities. RELEVANCE TO CLINICAL PRACTICE: The findings can assist in developing multidimensional strategies for reducing fear of falling in robust community-dwelling older people. PMID- 24787120 TI - Quantitative understanding of the optical properties of a single, complex-shaped gold nanoparticle from experiment and theory. AB - We report on a combined study of Rayleigh and Raman scattering spectroscopy, 3D electron tomography, and discrete dipole approximation (DDA) calculations of a single, complex-shaped gold nanoparticle (NP). Using the exact reconstructed 3D morphology of the NP as input for the DDA calculations, the experimental results can be reproduced with unprecedented precision and detail. We find that not only the exact NP morphology but also the surroundings including the points of contact with the substrate are of crucial importance for a correct prediction of the NP optical properties. The achieved accuracy of the calculations allows determining how many of the adsorbed molecules have a major contribution to the Raman signal, a fact that has important implications for analyzing experiments and designing sensing applications. PMID- 24787122 TI - A real-time microfluidic multiplex electrochemical loop-mediated isothermal amplification chip for differentiating bacteria. AB - This report shows that loop-mediated isothermal amplification (LAMP) of nucleic acid can be integrated on a laser etched indium tin oxide (ITO) electrode-based multiplex microfluidic chip for real-time quantitative differentiation of bacteria; we call this technique microfluidic multiplex electrochemical LAMP (MUME-LAMP) system. Three important acute upper respiratory tract infections (URTI) related bacteria, namely Mycobacterium tuberculosis (MTB), Haemophilus influenza (HIN), and Klebsiella pneumonia (KPN) were chosen for this study. We monitored the amplification process by measuring and analyzing the electrochemical signal of methylene blue (MB) through eight etched ITO electrochemical reactors. The results indicated that this assay with the ability of analyzing multiple genes qualitatively and quantitatively is highly specific, operationally simple, and cost/time effective. It exhibits high sensitivity with detection limits of 28, 17, and 16 copies MUL(-1) for MTB, HIN, and KPN, respectively. The whole differentiation can be finished in a short time of 45 min, which has the potential to apply in clinical diagnosis. PMID- 24787124 TI - Silicon nanowire field-effect-transistor based biosensors: from sensitive to ultra-sensitive. AB - Silicon nanowire field effect transistors (SiNW-FETs) have shown great promise as biosensors in highly sensitive, selective, real-time and label-free measurements. While applications of SiNW-FETs for detection of biological species have been described in several publications, less attention has been devoted to summarize the conjugating methods involved in linking organic bio-receptors with the inorganic transducer and the strategies of improving the sensitivity of devices. This article attempts to focus on summarizing the various organic immobilization approaches and discussing various sensitivity improving strategies, that include (I) reducing non-specific binding, (II) alignment of the probes, (III) enhancing signals by charge reporter, (IV) novel architecture structures, and (V) sensing in the sub-threshold regime. PMID- 24787123 TI - An ion-exchange nanomembrane sensor for detection of nucleic acids using a surface charge inversion phenomenon. AB - We present a novel low-cost biosensor for rapid, sensitive and selective detection of nucleic acids based on an ionic diode feature of an anion exchange nanoporous membrane under DC bias. The ionic diode feature is associated with external surface charge inversion on the positively charged anion exchange nanomembrane upon hybridization of negatively charged nucleic acid molecules to single-stranded oligoprobes functionalized on the membrane surface resulting in the formation of a cation selective monolayer. The resulting bipolar membrane causes a transition from electroconvection-controlled to water-splitting controlled ion conductance, with a large ion current signature that can be used to accurately quantify the hybridized nucleic acids. The platform is capable of distinguishing two base-pair mismatches in a 22-base pairing segment of microRNAs associated with oral cancer, as well as serotype-specific detection of dengue virus. We also show the sensor' capability to selectively capture target nucleic acids from a heterogeneous mixture. The limit of detection is 1 pM for short 27 base target molecules in a 15-min assay. Similar hybridization results are shown for short DNA molecules as well as RNAs from Brucella and Escherichia coli. The versatility and simplicity of this low-cost biosensor should enable point-of-care diagnostics in food, medical and environmental safety markets. PMID- 24787125 TI - Enzymatic cascade based fluorescent DNAzyme machines for the ultrasensitive detection of Cu(II) ions. AB - A novel enzymatic cascade based fluorescent DNAzyme machine has been developed for the amplified detection of copper (Cu(2+)) ions. This is the first attempt to carry out the combination of the self-cleaving DNAzyme and the polymerase/endonuclease reaction cycles involving cleaved substrate extension. In the presence of Cu(2+) ions, the enzyme strand carries out catalytic reactions to hydrolytic cleavage of the substrate strand. The cleaved DNAzyme substrates act as primers and trigger the Klenow Fragment polymerization. Nb.BbvCI endonuclease cuts the double-stranded niking site and thus opens a new site for a new replication. The replication regenerates the complete dsDNA to initiate another cycle of nicking, polymerization and displacement. Finally the fluorescence dye, SG, inserts into the DNA double helix to generate a distinguishable fluorescence enhancement. The Cu(2+) ions act as the activator for enzymatic cascade amplification generating multiple duplex structures in the nascent product. An increasing fluorescence is observed with increasing Cu(2+) ions concentration. A good nonlinear correlation (R=0.9997) was obtained between fluorescence intensity and the cubic logarithm of the Cu(2+) ions concentration over the range 0.50-200 nM. This nonlinear response phenomenon results in an efficient improvement of the sensitivity of our current proposed assay. The activation of such enzymatic cascades through analyte-DNAzyme interactions is not only valuable to activate the cooperation of enzyme networks, but also has a substantial impact on the development of amplified DNAzyme sensors. PMID- 24787126 TI - Electrochemical immunosensor for detecting the spore wall protein of Nosema bombycis based on the amplification of hemin/G-quadruplex DNAzyme concatamers functionalized Pt@Pd nanowires. AB - In this work, an ultrasensitive electrochemical immunosensor for detecting the Pebrine disease related spore wall protein of Nosema bombycis (SWP N.b) was fabricated based on the amplification of hemin/G-quadruplex functionalized Pt@Pd nanowires (Pt@PdNWs). The synthesized Pt@PdNWs possessed large surface area, which could effectively improve the immobilization amount of hemin/G-quadruplex DNAzyme concatamers produced via hybridization chain reaction (HCR). In the presence of SWP N.b, the hemin/G-quadruplex labeled Pt@PdNWs bioconjugations was captured on electrode surface and thus obtained electrochemical signal. After the addition of NADH into the electrolytic cell, hemin/G-quadruplex firstly acted as an NADH oxidase to locally produce H2O2 in the presence of dissolved O2. Then, the generated H2O2 would be quickly reduced via hemin/G-quadruplex as a horseradish peroxidase mimicking (HRP-mimicking) DNAzyme, which finally promoted the self-redox reaction of hemin/G-quadruplex and a greatly enhanced electrochemical signal was obtained. Furthermore, Pt@PdNWs with excellent electrocatalytic performance could also amplify electrochemical signal. With these amplification factors, the electrochemical immunosensor exhibited a wide linear range from 0.001 ng mL(-1) to 100 ng mL(-1) with a detection limit (LOD) of 0.24 pg mL(-1), providing a new promise for the diagnosis of Pebrine disease. PMID- 24787127 TI - Monomer priming of denture teeth and its effects on the bond strength of composite resin. AB - STATEMENT OF PROBLEM: The bond strength of acrylic resin denture teeth used as pontics in fiber-reinforced composite fixed dental prostheses needs to be improved. PURPOSE: The purpose of this study was to assess the influence of various chemical surface-conditioning monomers on the ridge-lap surface of acrylic resin denture teeth by determining the strength of their bonding to a composite resin and changes in surface hardness. MATERIAL AND METHODS: Acrylic resin denture teeth of 2 different brands (Artic 8 and Vitapan Cuspiform) (n=120) were tested. Four monomer systems were used as surface primers (conditioning): a flowable composite resin, methylmethacrylate 99%, composite primer, and a photopolymerizable dimethacrylate resin. Five surface-conditioning exposure times were used: no conditioning, 1, 5, 15, and 60 minutes. Surface microhardness measurements were made after the application of the monomer systems. Shear bond strength tests were subsequently performed, followed by a new surface microhardness indentation after the application of the load. The evaluation of the changes on specimen surfaces was performed with a scanning electron microscope. The differences between the shear bond strength and the surface hardness were evaluated for statistical significance by using a 3-way ANOVA. RESULTS: Tooth brand, monomer used, exposure time, and their 2- and 3-way interactions had a significant effect on the shear bond strength and hardness before and after testing, except for the 3-way interaction effect on hardness before testing. CONCLUSIONS: The chemical pretreatment of the ridge-lap surface of acrylic resin denture teeth increased the shear bond strength and influenced the surface hardness. The monomer systems caused dissolution on the denture surfaces. PMID- 24787128 TI - Effects of cigarette smoke and denture cleaners on the surface roughness and color stability of different denture teeth. AB - STATEMENT OF PROBLEM: Denture teeth have the most effect on the esthetics of complete dentures. However, extrinsic factors can change their roughness and color. PURPOSE: The purpose of this study was to investigate the effects of smoking and denture cleaners on the roughness and color (CIE [Commission International de I'Eclairage] L*a*b*) of denture teeth. MATERIAL AND METHODS: Maxillary central incisors made of acrylic resin, high-strength acrylic resin, and porcelain (Acrylux, SR, Orthosit PE-O, and Enta) were divided into 4 groups (n=10): control, denture cleaner, cigarette smoke, and cigarette smoke and denture cleaner. The dental cleaner group and cigarette smoke and dental cleaner group were immersed in denture cleaner (Protefix; Queisser Pharma) for 15 minutes; the cigarette smoke group and cigarette smoke and dental cleaner group were exposed to smoke from 20 cigarettes for 10 minutes per cigarette. The roughness was measured with a profilometer, and the color was measured with a colorimeter. The CIE L*a*b* values were recorded. The data were analyzed with a 3 way ANOVA and the Fisher least significant difference test (alpha=.05). RESULTS: The roughness of Acrylux, SR Orthosit PE-O (P<.001), and Enta (P<.01) was significantly higher in the cigarette smoke group and dental cleaner group than in the control group. Immersion in denture cleaner after exposure to cigarette smoke decreased the roughness of Acrylux, SR Orthosit PE-O (P<.001), and Enta (P<.01). The greatest color change (7.94) was observed in Acrylux in the cigarette smoke group, whereas the smallest color change (0.24) was in Enta in the control group. The color change of all of the teeth in the cigarette smoke group decreased after exposure to denture cleaner (P<.05). The L* decreased, and the a* and b* increased after exposure to smoke (P<.05). CONCLUSIONS: Smoking and denture cleaner increased the roughness and discolored the teeth, whereas denture cleaners after exposure to smoke decreased the roughness. PMID- 24787129 TI - Accuracy of a self-perforating impression tray for dental implants. AB - STATEMENT OF PROBLEM: Difficulties are involved in impression making with conventional open impression trays. PURPOSE: The purpose of this study was to evaluate the accuracy of transferring implant impressions with a self-perforating impression tray. MATERIAL AND METHODS: A reference model of a mandible was fabricated, and 4 implants were placed in the regions of the first premolars and lateral incisors (implants 1, 2, 3, 4). Ten impressions of the reference model with polyvinyl siloxane were made for each group; control (conventional open impression tray) and test (self-perforating impression tray; Miratray Implant). A metal bar was screw-retained on implant 1, and the gaps generated at the vestibular face of implants 3 and 4 were measured by optical microcopy. The 2-way ANOVA and least square difference post hoc test were used (alpha=.05). RESULTS: Higher mean (+/-SD) values were obtained for the test group than for the control group for both implants: implant 3: 150 +/-84 MUm for the test group, 73 +/-63 MUm for the control group (P=.019); implant 4: 129 +/-65 MUm for the test group, 62 +/-61 MUm for the control group (P=.04). CONCLUSION: The self-perforating impression tray provided less accuracy than the conventional open tray. PMID- 24787130 TI - Influence of reverse torque values in abutments with or without internal hexagon indexes. AB - STATEMENT OF PROBLEM: The mechanical stability of the implant-abutment connection is of fundamental importance for successful implant-supported restorations. Therefore, understanding removal torque values is essential. PURPOSE: The purpose of this study was to evaluate the reverse torque values of indexed and nonindexed abutments of the Morse Taper system. MATERIAL AND METHODS: Twelve Morse taper implants with their respective abutments were divided into 2 groups (n=6): group NI, nonindexed abutments; and group IN, indexed abutments. Each abutment received a sequence of 2 consecutive torques for insertion (15 Ncm) at an interval of 10 minutes, and 1 reverse torque, all measured with a digital torque wrench. The Student t test with a 5% significance level was used to evaluate the data. RESULTS: Statistical analysis showed no significant difference in reverse torque values between nonindexed and indexed abutments (P=.57). When comparing insertion torque and reverse torque values between the groups, group NI presented a mean torque loosening percentage of 8% (P=.013), whereas group IN presented a loosening of 15.33% (P<.001). CONCLUSION: The use of indexed abutments for the Morse taper system presented similar biomechanical stability when compared with nonindexed abutments, both with a significant reduction in reverse torque values. PMID- 24787131 TI - Influence of different conditioning methods on immediate and delayed dentin sealing. AB - STATEMENT OF PROBLEM: Data are needed to evaluate the effect of various conditioning methods on immediate and delayed dentin sealing. PURPOSE: The purpose of this study was to test bond strength and surface configuration of immediate and delayed dentin sealing surfaces after applying different surface conditioning methods. MATERIAL AND METHODS: A total of 96 premolars were allocated to the immediate and delayed groups. The groups differed in the timing of dentin sealing. The immediate-group specimens were sealed with a self-etching adhesive immediately after preparation. The delayed-group specimens were sealed before the final ceramic restoration bonding. Provisional restorations were cemented on immediate-group and delayed-group specimens for 1 week. Four conditioning methods were used: polishing with fluoride-free pumice paste, airborne-particle abrasion with silicoated aluminum oxide, glycin, or calcium carbonate. After 24-hour storage, the shear bond strength was tested. The fractured specimens were optically inspected with a stereomicroscope. An optical 3-dimensional surface analysis was performed for quantitative and qualitative evaluation. A 2-way ANOVA with post hoc Tukey honestly significant difference tests for significant effects was performed to investigate effects of the 2 factors, sealing and conditioning, and their interaction (alpha=.05). RESULTS: Two-way ANOVA found significant differences between the sealing and conditioning groups. The immediate group had significantly lower bond strengths than the delayed group. In all groups, surface polishing produced the highest bond strengths, and airborne-particle abrasion with calcium carbonate produced the lowest. Fracture analysis found more failures in the adhesive layers in the immediate groups and a prevalence of mixed failures in the delayed groups. The surface analysis found significant abrasion and roughness when airborne-particle abrasion with silicoated aluminum oxide was used for immediate and delayed dentin sealing surfaces. CONCLUSIONS: Polishing and airborne-particle abrasion with silicoated aluminum oxide or glycin are efficient methods in conditioning immediate and delayed dentin sealing surfaces. Airborne-particle abrasion with silicoated aluminum oxide leaves significant surface alterations on both types of surfaces. PMID- 24787132 TI - Immediate loading and implant-bar overdenture. AB - Immediate loaded implants may be used with an implant-bar overdenture to provide fixed splinting. This is a relatively new system that provides for immediate implant placement and restoration. PMID- 24787133 TI - Insight into the allosteric inhibition of Abl kinase. AB - Abl kinase inhibitors targeting the ATP binding pocket are currently used as a front-line therapy for the treatment of chronic myelogenous leukemia (CML), but their use has significant limitation because of the development of drug resistance (especially due to the T315I mutation). Two compounds (GNF-2 and BO1) have been found able to inhibit the Abl activity through a peculiar mechanism of action. Particularly, GNF-2 acts as allosteric inhibitor against Bcr-Abl wild type (wt), but it has no activity against the gatekeeper mutant T315I. Its activity against the last mutant reappears when used together with an ATP competitive inhibitor such as Imatinib or Nilotinib. A crystal structure of GNF-2 bound to the Abl myristoyl pocket (MP) has been released. On the contrary, BO1 shows an ATP-competitive/mixed mechanism of action against the wt, while it acts as an allosteric inhibitor against T315I. In order to better understand the mechanism of Abl allosteric inhibition, MD simulations and MM/GBSA analysis were performed on Abl wt and T315I in complex with GNF-2 and BO1, and the results were compared to those found for the natural myristoyl ligand. Similarly to that observed for the myristoyl group, the binding of an allosteric inhibitor to the MP promotes the formation of a compact and inhibited conformation of the wt protein, characterized by the stabilization of the intramolecular interactions that occur between SH2-SH3 and kinase domains. Conversely, an overall higher flexibility was observed with the Abl T315I mutant, especially in the case of GNF 2. Our analysis highlighted differences in the dynamic behavior of GNF-2 and BO1 which could explain the different biological profiles of the two allosteric inhibitors against the T315I mutant. PMID- 24787134 TI - The use of mini-CEX in UK foundation training six years following its introduction: lessons still to be learned and the benefit of formal teaching regarding its utility. PMID- 24787135 TI - Flashbulb memories of the Pope's resignation: explicit and implicit measures across differing religious groups. AB - In the present paper, we aimed to provide evidence in support of the idea tested in a recent study by Lanciano and colleagues that flashbulb memories (FBMs) are a special class of autobiographical memories that can be assessed through the autobiographical implicit association test (aIAT). FBMs and event memories (EMs) for the news of the resignation of Pope Benedict XVI were evaluated in three samples of churchgoer Catholic, non-churchgoer Catholic and Evangelical Italian participants through the traditional self-report measures (specificity/accuracy, confidence, consistency) and aIAT indices. Results confirmed the strength of the association between FBM and true information. The aIAT effect was stronger for FBMs than for EM details, and for Catholic respondents who were the group most concerned by the original event. Furthermore, the use of implicit measures for memory assessment concurs with the traditional self-report indices of FBMs. The present evidence supports the idea that FBMs are special autobiographical memories which remain detailed, certain and consistent over time. PMID- 24787136 TI - Learning from the design and development of the NHS Safety Thermometer. AB - QUALITY ISSUE: Research indicates that 10% of patients are harmed by healthcare but data that can be used in real time to improve safety are not routinely available. INITIAL ASSESSMENT: We identified the need for a prospective safety measurement system that healthcare professionals can use to improve safety locally, regionally and nationally. CHOICE OF SOLUTION: We designed, developed and implemented a national tool, named the NHS Safety Thermometer (NHS ST) with the goal of measuring the prevalence of harm from pressure ulcers, falls, urinary tract infection in patients with catheters and venous thromboembolism on one day each month for all NHS patients. IMPLEMENTATION: The NHS ST survey instrument was developed in a learning collaborative involving 161 organizations (e.g. hospitals and other delivery organizations) using a Plan, Do, Study, Act method. EVALUATION: Testing of operational definitions, technical capability and use were conducted and feedback systems were established by site coordinators in each participating organization. During the 17-month pilot, site coordinators reported a total of 73,651 patient entries. LESSONS LEARNED: It is feasible to obtain national data through standardized reporting by site coordinators at the point of care. Some caution is required in interpreting data and work is required locally to ensure data collection systems are robust and data collectors were trained. Sampling is an important strategy to optimize efficiency and reduce the burden of measurement. PMID- 24787137 TI - R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. AB - Friedreich ataxia (FRDA) and Fragile X syndrome (FXS) are among 40 diseases associated with expansion of repeated sequences (TREDs). Although their molecular pathology is not well understood, formation of repressive chromatin and unusual DNA structures over repeat regions were proposed to play a role. Our study now shows that RNA/DNA hybrids (R-loops) form in patient cells on expanded repeats of endogenous FXN and FMR1 genes, associated with FRDA and FXS. These transcription dependent R-loops are stable, co-localise with repressive H3K9me2 chromatin mark and impede RNA Polymerase II transcription in patient cells. We investigated the interplay between repressive chromatin marks and R-loops on the FXN gene. We show that decrease in repressive H3K9me2 chromatin mark has no effect on R-loop levels. Importantly, increasing R-loop levels by treatment with DNA topoisomerase inhibitor camptothecin leads to up-regulation of repressive chromatin marks, resulting in FXN transcriptional silencing. This provides a direct molecular link between R-loops and the pathology of TREDs, suggesting that R-loops act as an initial trigger to promote FXN and FMR1 silencing. Thus R-loops represent a common feature of nucleotide expansion disorders and provide a new target for therapeutic interventions. PMID- 24787139 TI - Hyperfine local probe study of alkaline-earth manganites SrMnO3 and BaMnO3. AB - We report perturbed angular correlation measurements with (111m)Cd/(111)Cd and (111)In/(111)Cd probes, at the ISOLDE-CERN facility, in the manganite compounds BaMnO3, with the 6H and 15R polymorphs, and SrMnO3, with the 4H polymorph. The electric field gradient (EFG) is measured, and found approximately constant in a large temperature range for all the compounds. The EFG is also calculated from first principles with density functional theory, and compared with experimental results by considering diluted substitutional Cd impurities. Based on the results, we assign as sites for the probes the Ba (for BaMnO3-6H, 15R) and Sr (for SrMnO3-4H) sites, apart from fractions of undetermined origin in the case of BaMnO3-6H. We predict the hyperfine parameters in the recently synthesized multiferroic manganite Sr(0.5)Ba(0.5)MnO3, and its variation with the structure and electric polarization, which is found to be very small. PMID- 24787141 TI - Design and synthesis of photoactive ionic liquids. AB - Two ionic liquids with photoisomerizable p-hydroxycinnamic acid moieties were synthesized and characterized by X-ray crystallography and DSC, and their photochemistry was studied in solution and neat conditions. Irradiation at absorption maxima led to trans-cis photoisomerization and resulted in significant reduction of melting temperatures of the ionic liquids. X-ray structures of both compounds show an intricate network of supramolecular interactions before irradiation. Physical and chemical transformations are completely reversible upon irradiation at lower wavelengths of ionic liquid solutions in acetonitrile. PMID- 24787140 TI - Defining the stoichiometry and cargo load of viral and bacterial nanoparticles by Orbitrap mass spectrometry. AB - Accurate mass analysis can provide useful information on the stoichiometry and composition of protein-based particles, such as virus-like assemblies. For applications in nanotechnology and medicine, such nanoparticles are loaded with foreign cargos, making accurate mass information essential to define the cargo load. Here, we describe modifications to an Orbitrap mass spectrometer that enable high mass analysis of several virus-like nanoparticles up to 4.5 MDa in mass. This allows the accurate determination of the composition of virus-like particles. The modified instrument is utilized to determine the cargo load of bacterial encapsulin nanoparticles that were engineered to encapsulate foreign cargo proteins. We find that encapsulin packages from 8 up to 12 cargo proteins, thereby quantifying cargo load but also showing the ensemble spread. In addition, we determined the previously unknown stoichiometry of the three different splice variants of the capsid protein in adeno-associated virus (AAV) capsids, showing that symmetry is broken and assembly is heterogeneous and stochastic. These results demonstrate the potential of high-resolution mass analysis of protein based nanoparticles, with widespread applications in chemical biology and nanotechnology. PMID- 24787138 TI - Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures. AB - Environmental exposure to manganese (Mn) leads to a neurodegenerative disease that has shared clinical characteristics with Parkinson's disease (PD). Mn induced neurotoxicity is time- and dose-dependent, due in part to oxidative stress. We ascertained the molecular targets involved in Mn-induced neurodegeneration using astrocyte culture as: (1) Astrocytes are vital for information processing within the brain, (2) their redox potential is essential in mitigating reactive oxygen species (ROS) levels, and (3) they are targeted early in the course of Mn toxicity. We first tested protein levels of Mn superoxide dismutase -2 (SOD-2) and glutathione peroxidase (GPx-1) as surrogates of astrocytic oxidative stress response. We assessed levels of the forkhead winged-helix transcription factor O (FoxO) in response to Mn exposure. FoxO is highly regulated by the insulin-signaling pathway. FoxO mediates cellular responses to toxic stress and modulates adaptive responses. We hypothesized that FoxO is fundamental in mediating oxidative stress response upon Mn treatment, and may be a biomarker of Mn-induced neurodegeneration. Our results indicate that 100 or 500 uM of MnCl2 led to increased levels of FoxO (dephosphorylated and phosphorylated) compared with control cells (P<0.01). p-FoxO disappeared from the cytosol upon Mn exposure. Pre-treatment of cultured cells with (R)-(-)-2 oxothiazolidine-4-carboxylic acid (OTC), a cysteine analog rescued the cytosolic FoxO. At these concentrations, MAPK phosphorylation, in particular p38 and ERK, and PPAR gamma coactivator-1 (PGC-1) levels were increased, while AKT phosphorylation remained unchanged. FoxO phosphorylation level was markedly reduced with the use of SB203580 (a p38 MAPK inhibitor) and PD98059 (an ERK inhibitor). We conclude that FoxO phosphorylation after Mn exposure occurs in parallel with, and independent of the insulin-signaling pathway. FoxO levels and its translocation into the nucleus are part of early events compensating for Mn induced neurotoxicity and may serve as valuable targets for neuroprotection in the setting of Mn-induced neurodegeneration. PMID- 24787142 TI - Gas gangrene: need for aggressive management in delayed presentation. PMID- 24787144 TI - Red wine tannins fluidify and precipitate lipid liposomes and bicelles. A role for lipids in wine tasting? AB - Sensory properties of red wine tannins are bound to complex interactions between saliva proteins, membranes taste receptors of the oral cavity, and lipids or proteins from the human diet. Whereas astringency has been widely studied in terms of tannin-saliva protein colloidal complexes, little is known about interactions between tannins and lipids and their implications in the taste of wine. This study deals with tannin-lipid interactions, by mimicking both oral cavity membranes by micrometric size liposomes and lipid droplets in food by nanometric isotropic bicelles. Deuterium and phosphorus solid-state NMR demonstrated the membrane hydrophobic core disordering promoted by catechin (C), epicatechin (EC), and epigallocatechin gallate (EGCG), the latter appearing more efficient. C and EGCG destabilize isotropic bicelles and convert them into an inverted hexagonal phase. Tannins are shown to be located at the membrane interface and stabilize the lamellar phases. These newly found properties point out the importance of lipids in the complex interactions that happen in the mouth during organoleptic feeling when ingesting tannins. PMID- 24787143 TI - A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. AB - The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18-65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 (10 mg: p < 0.0001) and -6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms. PMID- 24787145 TI - Validation of three geolocation strategies for health-facility attendees for research and public health surveillance in a rural setting in western Kenya. AB - Understanding the spatial distribution of disease is critical for effective disease control. Where formal address networks do not exist, tracking spatial patterns of clinical disease is difficult. Geolocation strategies were tested at rural health facilities in western Kenya. Methods included geocoding residence by head of compound, participatory mapping and recording the self-reported nearest landmark. Geocoding was able to locate 72.9% [95% confidence interval (CI) 67.7 77.6] of individuals to within 250 m of the true compound location. The participatory mapping exercise was able to correctly locate 82.0% of compounds (95% CI 78.9-84.8) to a 2 * 2.5 km area with a 500 m buffer. The self-reported nearest landmark was able to locate 78.1% (95% CI 73.8-82.1) of compounds to the correct catchment area. These strategies tested provide options for quickly obtaining spatial information on individuals presenting at health facilities. PMID- 24787146 TI - Estimating energy expenditure from heart rate in older adults: a case for calibration. AB - BACKGROUND: Accurate measurement of free-living energy expenditure is vital to understanding changes in energy metabolism with aging. The efficacy of heart rate as a surrogate for energy expenditure is rooted in the assumption of a linear function between heart rate and energy expenditure, but its validity and reliability in older adults remains unclear. OBJECTIVE: To assess the validity and reliability of the linear function between heart rate and energy expenditure in older adults using different levels of calibration. DESIGN: Heart rate and energy expenditure were assessed across five levels of exertion in 290 adults participating in the Baltimore Longitudinal Study of Aging. Correlation and random effects regression analyses assessed the linearity of the relationship between heart rate and energy expenditure and cross-validation models assessed predictive performance. RESULTS: Heart rate and energy expenditure were highly correlated (r=0.98) and linear regardless of age or sex. Intra-person variability was low but inter-person variability was high, with substantial heterogeneity of the random intercept (s.d. =0.372) despite similar slopes. Cross-validation models indicated individual calibration data substantially improves accuracy predictions of energy expenditure from heart rate, reducing the potential for considerable measurement bias. Although using five calibration measures provided the greatest reduction in the standard deviation of prediction errors (1.08 kcals/min), substantial improvement was also noted with two (0.75 kcals/min). CONCLUSION: These findings indicate standard regression equations may be used to make population-level inferences when estimating energy expenditure from heart rate in older adults but caution should be exercised when making inferences at the individual level without proper calibration. PMID- 24787147 TI - Prevalence and serological diagnosis of relapse in paracoccidioidomycosis patients. AB - A review of 400 clinical records of paracoccidioidomycosis (PCM) patients, 93 with the acute/subacute (AF) and 307 with the chronic form (CF), attended from 1977 to 2011, selected as to the schedule of release for study by the Office of Medical Records at the University Hospital of the Faculdade de Medicina de Botucatu-Sao Paulo State University--UNESP, was performed to detect cases in relapse. The control of cure was performed by clinical and serological evaluation using the double agar gel immunodiffusion test (DID). In the diagnosis of relapse, DID, enzyme-linked immunosorbent assay (ELISA) and immunoblotting assay (IBgp70 and IBgp43) were evaluated. Out of 400 patients, 21 (5.2%) went through relapse, 18 of them were male and 3 were female, 6?1 male/female ratio. Out of the 21 patients in relapse, 15 (4.8%) showed the CF, and 6 (6.4%) the AF (p>0.05). The sensitivity of DID and ELISA before treatment was the same (76.1%). DID presented higher sensitivity in pre-treatment (80%) than at relapse (45%; p = 0.017), while ELISA showed the same sensitivity (80% vs 65%; p = 0.125). The serological methods for identifying PCM patients in relapse showed low rates of sensitivity, from 12.5% in IBgp70 to 65.0% in IBgp43 identification and 68.8% in ELISA. The sensitivity of ELISA in diagnosing PCM relapse showed a strong tendency to be higher than DID (p = 0.06) and is equal to IBgp43 (p = 0.11). In sum, prevalence of relapse was not high in PCM patients whose treatment duration was based on immunological parameters. However, the used methods for serological diagnosis present low sensitivity. While more accurate serological methods are not available, we pay special attention to the mycological and histopathological diagnosis of PCM relapse. Hence, direct mycological, cytopathological, and histopathological examinations and isolation in culture for P. brasiliensis must be appropriately and routinely performed when the hypothesis of relapse is considered. PMID- 24787149 TI - Compensation of elemental image using multiple view vectors for off-axis integral floating system. AB - A novel method is proposed to compensate the distortion caused by the off-axis structure in integral floating with a concave mirror. The proposed method of this paper can generate the elemental image that is integrated into the multiple predistortion images for the corresponding multiview directions, which cannot be performed by the predistortion method using a single-view vector. The fundamental concept of the proposed method is that the predistortion images can be generated for more than two view vectors, which are defined by each set of corresponding elemental lens and subimage, and captured onto the subimage. In addition, the subimage can be divided into the several segments to increase the number of view vectors, so that the predistortion images generated by more view vectors can enhance the degree of compensation. The proper number of the view vectors per subimage is discussed and analyzed based on the small-angle approximation. Experiments to verify the feasibility of the proposed method are performed. PMID- 24787150 TI - Initial design method based on an iterative calculation of aberration and its application to an objective lens for imaging spectrometer. AB - An initial optical design method based on an iterative calculation of third-order aberration is presented to overcome the problems of the conventional method. The aberrations of each lens group in the optical system are calculated individually and iteratively under the constraint that aberrations of one group compensate for those of the other groups. The stabilities of initial design results have been confirmed and the iterative design method has been applied for the design of optical system with an external entrance pupil for imaging spectrometer. The designed lens corresponds to an objective lens with the aperture of F/1.5 and the focal length of 30 mm. PMID- 24787151 TI - Pulsed Yb3+-doped fiber laser operating at 1011 nm by intra-cavity phase modulation. AB - A 1011 nm pulsed Yb3+-doped fiber laser is experimentally demonstrated by employing a commercially available LiNbO3 phase modulator (PM) in the linear cavity. The resonator is built up with a section of normal single-cladding Yb3+ doped fiber, a PM, and a pair of fiber Bragg gratings. Active mode-locked stable trains of pulses with 2 and 1.4 ns are generated at repetition rates of 30.2478 and 60.4956 MHz, respectively. The maximum average output power is 10.6 mW at pump power of 200 mW, with the slope efficiency of 13.3%. Relaxation-oscillation modulated pulses with width of 2 MUs are obtained at a repetition rate of 27.778 kHz. PMID- 24787152 TI - Optical characterization of gold-cuprous oxide interfaces for terahertz emission applications. AB - We show that the interface between gold and thermally formed cuprous oxide, which emits terahertz radiation when illuminated with ultrafast femtosecond lasers, is in fact an AuCu/Cu2O interface due to the formation of the thermal diffusion alloy AuCu. The alloy enables the formation of a Schottky-barrier-like electric field near the interface which is essential to explain the THz emission from these samples. We confirm the formation of this AuCu layer by x-ray diffraction measurements, ellipsometry, and visual inspection. We determined the frequency dependent complex refractive indices of the Cu2O and AuCu layer and verified them using reflection spectroscopy measurements. These refractive indices can be used for optimizing the thickness of Cu2O for maximum THz emission from these interfaces. PMID- 24787148 TI - Insights into the mechanism of deubiquitination by JAMM deubiquitinases from cocrystal structures of the enzyme with the substrate and product. AB - AMSH, a conserved zinc metallo deubiquitinase, controls downregulation and degradation of cell-surface receptors mediated by the endosomal sorting complexes required for transport (ESCRT) machinery. It displays high specificity toward the Lys63-linked polyubiquitin chain, which is used as a signal for ESCRT-mediated endosomal-lysosomal sorting of receptors. Herein, we report the crystal structures of the catalytic domain of AMSH orthologue Sst2 from fission yeast, its ubiquitin (product)-bound form, and its Lys63-linked diubiquitin (substrate) bound form at 1.45, 1.7, and 2.3 A, respectively. The structures reveal that the P-side product fragment maintains nearly all the contacts with the enzyme as seen with the P portion (distal ubiquitin) of the Lys63-linked diubiquitin substrate, with additional coordination of the Gly76 carboxylate group of the product with the active-site Zn(2+). One of the product-bound structures described herein is the result of an attempt to cocrystallize the diubiquitin substrate bound to an active site mutant presumed to render the enzyme inactive, instead yielding a cocrystal structure of the enzyme bound to the P-side ubiquitin fragment of the substrate (distal ubiquitin). This fragment was generated in situ from the residual activity of the mutant enzyme. In this structure, the catalytic water is seen placed between the active-site Zn(2+) and the carboxylate group of Gly76 of ubiquitin, providing what appears to be a snapshot of the active site when the product is about to depart. Comparison of this structure with that of the substrate-bound form suggests the importance of dynamics of a flexible flap near the active site in catalysis. The crystal structure of the Thr319Ile mutant of the catalytic domain of Sst2 provides insight into structural basis of microcephaly capillary malformation syndrome. Isothermal titration calorimetry yields a dissociation constant (KD) of 10.2 +/- 0.6 MUM for the binding of ubiquitin to the enzyme, a value comparable to the KM of the enzyme catalyzing hydrolysis of the Lys63-linked diubiquitin substrate (~20 MUM). These results, together with the previously reported observation that the intracellular concentration of free ubiquitin (~20 MUM) exceeds that of Lys63-linked polyubiquitin chains, imply that the free, cytosolic form of the enzyme remains inhibited by being tightly bound to free ubiquitin. We propose that when AMSH associates with endosomes, inhibition would be relieved because of ubiquitin binding domains present on its endosomal binding partners that would shift the balance toward better recognition of polyubiquitin chains via the avidity effect. PMID- 24787153 TI - W-band Pancharatnam half-wave plate based on negative refractive index metamaterials. AB - Electromagnetic metamaterials, made from arrangements of subwavelength-sized structures, can be used to manipulate radiation. Designing metamaterials that have a positive refractive index along one axis and a negative refractive index along the orthogonal axis can result in birefringences, Deltan>1. The effect can be used to create wave plates with subwavelength thicknesses. Previous attempts at making wave plates in this way have resulted in very narrow usable bandwidths. In this paper, we use the Pancharatnam method to increase the usable bandwidth. A combination of finite element method and transmission line models was used to optimize the final design. Experimental results are compared with the modeled data. PMID- 24787154 TI - Refractive index sensor based on plastic optical fiber with tapered structure. AB - This work reports a refractive index sensor made of plastic optical fiber (POF) with tapered structure. Transmission loss is measured when the external environment's refractive index changes from 1.33 to 1.41. Three wavelengths (532, 633, and 780 nm) are used to evaluate the sensitivity of the sensor, and results indicate that 633 nm is the best sensing wavelength due to the increased levels of sensitivity achieved at this wavelength. A biconical sensing structure is designed to enhance the sensitivity of the sensor. A sensitivity of 950 MUW/RIU at 633 nm is obtained for a biconical sensing structure when launched power is 1 mW. Due to its sensitivity to the refractive index and simple construction, POF with tapered structure has potential applications in the biosensing field. PMID- 24787155 TI - Multiplex path for magnetorheological jet polishing with vertical impinging. AB - We report a way to shape surfaces by optimizing the path instead of changing the removal function of a polishing tool for magnetorheological jet polishing (MJP). The M-shaped removal function of MJP generates a track with a W-shaped profile along one path. However, applying two parallel paths with appropriate line spacing can obtain a track with V-shaped profile, which has a removal distribution similar to that by using the Gaussian removal function along one path. Based on this, a multiplex path applying an M-shaped removal function is constructed in an actual process. A transformation model describing the relationship between the M-shaped removal function and the Gaussian removal function is established, which is crucial to determine the velocity function on the multiplex path. By using the M-shaped removal function, we have planned new processing steps by applying the multiplex path and the velocity function for full aperture polishing. Polishing performance is designed and demonstrated on two K9 work-pieces with different multiplex paths. The form error on 23 mm diameter is decreased from 0.256lambda PV (lambda=632.8 nm) and 0.068lambda RMS to 0.038lambda PV and 0.005lambda RMS with scanning multiplex path. Results indicate that this method of path optimization is suitable for optical manufacturing. PMID- 24787156 TI - Beam smoothing characteristics of multi-central frequency and multi-color smoothing by spectral dispersion. AB - A multi-central frequency and multi-color smoothing by spectral dispersion (SSD) scheme is presented for better beam smoothing than conventional SSD. One of the difficulties in conventional SSD is the narrow bandwidth limited by efficiency frequency conversion. The new scheme has overcome this problem by using multi central frequency laser sources and a multi-color beam smoothing system. The multi-central frequency laser sources are incoherent combinations of several pulses in the time domain, each with different central frequencies and independent sinusoidal frequency-modulated components. Then, the laser beams from the multi-central frequency laser sources transmit in the multi-color smoothing system, spatially separated and independently spectrally dispersed by gratings array, independently achieve the third harmonic generation in KDP array with independent phase-matching for efficient conversion. Moreover, by adjusting the dispersion direction of the gratings to be perpendicular to each other, it is an effective way to achieve a 2D beam smoothing effect on the focal plane. Simulation results show that the novel beam smoothing scheme performs better than the conventional SSD. PMID- 24787157 TI - Liquid crystal Fresnel zone lens based on single-side-patterned photoalignment layer. AB - In this article, we disclose a method to fabricate a liquid crystal (LC) Fresnel zone lens (FZL) with high efficiency. The LCFZL, based on patterned planar aligned regions, has been prepared by means of a two-step photoalignment technique. The proposed binary-phase LCFZL manifests 39% diffraction efficiency at the focal point, which is close to the theoretical limit, 41%. Moreover, because of a lower driving voltage and faster response time, these elements could find application in many modern devices. PMID- 24787158 TI - InGaN diode pumped actively Q-switched intracavity frequency doubling Pr:LiYF4 261 nm laser. AB - We demonstrate actively Q-switched deep ultraviolet laser operation at 261 and 320 nm by intracavity frequency doubling of an InGaN laser diode-pumped Pr:LiYF4 laser. We obtain a maximum peak power of 61.6 W (8.7 MUJ/pulse at 7.7 kHz) and 594 W (19.0 MUJ/pulse at 7.7 kHz) with a pulse width of 142 and 35 ns at 261 and 320 nm, respectively. The conversion efficiency from the fundamental laser energy at 639 nm to the second-harmonic generation is 88%. Good agreement is obtained with prediction by a rate equation model. PMID- 24787159 TI - Dual-view integral imaging 3D display using polarizer parallax barriers. AB - We propose a dual-view integral imaging (DVII) 3D display using polarizer parallax barriers (PPBs). The DVII 3D display consists of a display panel, a microlens array, and two PPBs. The elemental images (EIs) displayed on the left and right half of the display panel are captured from two different 3D scenes, respectively. The lights emitted from two kinds of EIs are modulated by the left and right half of the microlens array to present two different 3D images, respectively. A prototype of the DVII 3D display is developed, and the experimental results agree well with the theory. PMID- 24787160 TI - Arithmetic of focused vortex beams in three-dimensional optical lattice arrays. AB - In this work, we present a method to generate a 3D lattice of vortex beams. We apply phase look-up tables (LUTs) designed to generate gratings having an arbitrary content of diffraction orders. This phase LUT can be applied to a variety of diffraction optical elements, such as linear phase gratings, blazed diffractive lenses, and spiral phase patterns. We concentrate on combinations of all of these to create 3D structures of vortex beams. In particular, we generate all of these elements in the first output quadrant and eliminate the zero-order diffraction that often unavoidably accompanies these patterns. We discuss different ways of producing these 3D vortex gratings, and how the various output beams are related to the arithmetic of the 3D distribution of topological charges. Experimental results are provided by means of a liquid crystal spatial light modulator. PMID- 24787161 TI - Orthonormal polynomials for elliptical wavefronts with an arbitrary orientation. AB - We generalize the analytical form of the orthonormal elliptical polynomials for any arbitrary aspect ratio to arbitrary orientation and give expression for them up to the 4th order. The utility of the polynomials is demonstrated by obtaining the expansion up to the 8th order in two examples of an off-axis wavefront exiting from an optical system with a vignetted pupil. PMID- 24787162 TI - Off-axis digital holographic microscopy: practical design parameters for operating at diffraction limit. AB - The utilization of microscope objectives (MOs) in digital holographic microscopy (DHM) has associated effects that are not present in conventional optical microscopy. The remaining phase curvature, which can ruin the quantitative phase imaging, is the most evident and analyzed. As phase imaging is considered, this interest has made possible the development of different methods of overcoming its undesired consequences. Additionally to the effects in phase imaging, there exist a set of less obvious conditions that have to be accounted for as MOs are utilized in DHM to achieve diffraction-limit operation. These conditions have to be considered even in the case in which only amplitude or intensity imaging is of interest. In this paper, a thorough analysis of the physical parameters that control the appropriate utilization of MOs in DHM is presented. A regular DHM system is theoretically modeled on the basis of the imaging theory. The Fourier spectrum of the recorded hologram is analyzed to evaluate the performance of the DHM. A set of the criteria that consider the microscope features and the recording parameters to achieve DHM operation at the diffraction limit is derived. Numerical modeling and experimental results are shown to validate our findings. PMID- 24787163 TI - Two-shot common-path phase-shifting interferometer with a four-step algorithm and an unknown phase shift. AB - This paper presents a two-shot common-path phase-shifting interferometer that consists of a 4f optical system with two windows in the input plane and a Ronchi grating in the Fourier plane, and generates two adjacent interferograms using only diffraction orders 0 and +1 and 0 and -1. Four phase-shifted interferograms can be obtained in two shots by modulating two linear polarizers with angle difference of pi/4 and translating the grating with only an unknown phase shift. An algorithm similar to the standard four-step algorithm is used to retrieve the phase of a specimen, and it requires no knowledge of the phase shift introduced by translation of the grating. The validity and repeatability of the proposed method is proved through simulations and experiments. PMID- 24787164 TI - Smeared star spot location estimation using directional integral method. AB - Image smearing significantly affects the accuracy of attitude determination of most star sensors. To ensure the accuracy and reliability of a star sensor under image smearing conditions, a novel directional integral method is presented for high-precision star spot location estimation to improve the accuracy of attitude determination. Simulations based on the orbit data of the challenging mini satellite payload satellite were performed. Simulation results demonstrated that the proposed method exhibits high performance and good robustness, which indicates that the method can be applied effectively. PMID- 24787165 TI - Faraday rotation of cobalt ferrite nanoparticle polymer composite films at cryogenic temperatures. AB - This paper investigates the behavior of the Verdet constant for cobalt ferrite (CoFe2O4) nanoparticles polymer composite films at low temperatures using a 532 nm laser source. An experimental setup for Faraday rotation (FR) at low temperatures is introduced and FRs were measured at various temperatures. Verdet constants were deduced from the paramagnetic model for terbium gallium garnet glass where ~4* improvement was observed at 40 degrees K for CoFe2O4 composite film. PMID- 24787167 TI - Birefringence measurement using rotating analyzer approach and quadrature cross points. AB - A new technique for birefringence measurement and extracting the coefficients of the dispersion relation such as Cauchy or Sellmeier equations is proposed. The main principle of the technique is based on finding accurately the wavelengths that the birefringent plate operates as a quarter-wave plate (QWP) and measuring the birefringence at these points. As the projections of the ordinary and extraordinary beams on the analyzer axis interfere, the setup is a form of common path interferometer and these QWP points are the quadrature points at which the sensitivity of the interferometer is optimum. An algorithm is developed to find these crossing points precisely. Implementation of this technique has been done on two different kinds of nematic liquid crystal wave plates made of Merck E44 and BL036. PMID- 24787166 TI - Resonantly pumped acousto-optic Q-switched Er:YAG lasers at 1617 and 1645 nm. AB - Resonantly pumped acousto-optic Q-switched Er:YAG lasers at 1617 and 1645 nm are demonstrated. An etalon was used to obtain 1617 nm output. Laser pulses with 4.02 mJ energy at 1617 nm and 5.64 mJ energy at 1645 nm were generated, with pulse duration more than 400 ns at a pulse repetition rate of 1000 Hz. PMID- 24787168 TI - Fresnel diffraction of fractal grating and self-imaging effect. AB - Based on the self-similarity property of fractal, two types of fractal gratings are produced according to the production and addition operations of multiple periodic gratings. Fresnel diffractions of fractal grating are analyzed theoretically, and the general mathematic expressions of the diffraction intensity distributions of fractal grating are deduced. The gray-scale patterns of the 2D diffraction distributions of fractal grating are provided through numerical calculations. The diffraction patterns take on the periodicity along the longitude and transverse directions. The 1D diffraction distribution at some certain distances shows the same structure as the fractal grating. This indicates that the self-image of fractal grating is really formed in the Fresnel diffraction region. The experimental measurement of the diffraction intensity distribution of fractal grating with different fractal dimensions and different fractal levels is performed, and the self-images of fractal grating are obtained successfully in experiments. The conclusions of this paper are helpful for the development of the application of fractal grating. PMID- 24787169 TI - Analysis of the propagation dynamics and Gouy phase of Airy beams using the fast Fresnel transform algorithm. AB - There is great interest in Airy beams because they appear to propagate in a curved path. These beams are usually generated by inserting a cubic phase mask onto the input plane of a Fourier transform system. Here, we utilize a fast Fresnel diffraction algorithm to easily derive both the propagation dynamics and the Gouy phase shift for these beams. The trajectories of these beams can be modified by adding additional linear and quadratic phase terms onto the cubic phase mask. Finally, we have rewritten the equations regarding the propagating Airy beams completely in laboratory coordinates for use by experimentalists. Experimental results are included. We expect that these results will be of great importance in applications of Airy beams. PMID- 24787170 TI - Estimation of the effective phase function of bulk diffusing materials with the inverse adding-doubling method. AB - The accuracy of optical simulations including bulk diffusors is heavily dependent on the accuracy of the bulk scattering properties. If no knowledge on the physical scattering effects is available, an iterative procedure is usually used to obtain the scattering properties, such as the inverse Monte Carlo method or the inverse adding-doubling (AD) method. In these methods, a predefined phase function with one free parameter is usually used to limit the number of free parameters. In this work, three predefined phase functions (Henyey-Greenstein, two-term Henyey-Greenstein, and Gegenbauer kernel (GK) phase function) are implemented in the inverse AD method to determine the optical properties of two strongly diffusing materials: low-density polyethylene and TiO2 particles. Using the presented approach, an estimation of the effective phase function was made. It was found that the use of the GK phase function resulted in the best agreement between calculated and experimental transmittance, reflectance, and scattered radiant intensity distribution for the LDPE sample. For the TiO2 sample, a good agreement was obtained with both the two-term Henyey-Greenstein and the GK phase function. PMID- 24787171 TI - Thermal stability studies of short period Sc/Cr and Sc/B4C/Cr multilayers. AB - The stability of short period Sc/Cr and Sc/B4C/Cr multilayers was investigated over a large temperature range. The aim was to find a stable reflective coating for an off-axis parabola for focusing x rays from a soft x-ray free-electron laser. Normal incidence reflectivity, surface roughness, and intrinsic stress were investigated as a function of annealing temperature and two samples were also studied with a high-resolution transmission electron microscope (TEM), a scanning TEM, and through electron energy loss spectroscopy (EELS). Interface engineered Sc/B4C/Cr multilayers showed increased thermal stability and higher reflectivity as compared to pure Sc/Cr multilayers. PMID- 24787172 TI - Fiber-optic combined FPI/FBG sensors for monitoring of radiofrequency thermal ablation of liver tumors: ex vivo experiments. AB - We present a biocompatible, all-glass, 0.2 mm diameter, fiber-optic probe that combines an extrinsic Fabry-Perot interferometry and a proximal fiber Bragg grating sensor; the probe enables dual pressure and temperature measurement on an active 4 mm length, with 40 Pa and 0.2 degrees C nominal accuracy. The sensing system has been applied to monitor online the radiofrequency thermal ablation of tumors in liver tissue. Preliminary experiments have been performed in a reference chamber with uniform heating; further experiments have been carried out on ex vivo porcine liver, which allowed the measurement of a steep temperature gradient and monitoring of the local pressure increase during the ablation procedure. PMID- 24787173 TI - Use of signal decomposition to compensate for respiratory disturbance in mainstream capnometer. AB - End-tidal carbon dioxide (P(ET)CO2) monitoring has become an important tool in clinical monitoring, but there are still limitations in practice. Low-frequency modulation was used to reliably acquire respiratory information. Then the disturbances of humidity and flow rate were removed by signal decomposition. Finally, the real-time concentration of CO2 was calculated and displayed by an adjusted calibration function. Targeted experiments confirm that a period of 180 ms and a depth of 50% was the optimal choice. In this case, the effects of humidity and flow rate reflected by different components were removed effectively from the capnography. This capnometer obtains capnography with excellent accuracy and stability in long-term continuous monitoring. PMID- 24787174 TI - Plasmonic metal-dielectric-metal stack structure with subwavelength metallic gratings for improving sensor sensitivity and signal quality. AB - In this study, we investigated the performance improvement of a localized surface plasmon resonance (LSPR) biosensor by incorporating a metal-dielectric-metal (MDM) stack structure and subwavelength metallic nanograting. The numerical results showed that the LSPR substrate with a MDM stack can provide not only a better sensitivity by more than five times but also a notably improved signal quality. While the gold nanogratings on a gold film inevitably lead to a broad and shallow reflectance curve, the presence of a MDM stack can prevent propagating surface plasmons from interference by locally enhanced fields excited at the gold nanogratings, finally resulting in a strong and deep absorption band at resonance. Therefore, the proposed LSPR structure could potentially open a new possibility of enhanced detection for monitoring biomolecular interactions of very low molecular weights. PMID- 24787175 TI - Loop-locked coherent population trapping magnetometer based on a fiber electro optic modulator. AB - We have set up a coherent population trapping (CPT)-based magnetometer prototype with the D1 line of 87Rb atoms. The dichromatic light field is derived from a fiber electro-optic modulator (FEOM) connected to an external cavity laser diode. A CPT resonance signal with a 516 Hz linewidth is observed. By feeding back the derivative of the resonance curve to the FEOM with a proportional integral controller, of which the voltage output is directly converted to the measured magnetic field intensity, the resonance peak is locked to the environmental magnetic field. The measurement data we have achieved are well matched with the data measured by a commercial fluxgate magnetometer within 2 nT, and the sensitivity is better than 8 pT/?Hz in a parallel B field. PMID- 24787176 TI - Phase locking of slab laser amplifiers via square wave dithering algorithm. AB - An active phase locking of slab laser amplifiers via square wave dithering algorithm is demonstrated experimentally. The MPD technique based on dual-level square wave phase modulation, time division multiplexing, and single detector can achieve the phase error signal of amplifiers, but without coherent demodulation process. The experimental investigation on the 208 W coherent beam combining of two slab amplifiers shows that the whole system in a closed loop performs well over a long time observation. The contrast of the coherent combined beam profile is about 87% and the combining efficiency is nearly 90.4%. The beam steering with three kinds of steering angles based on coherent beam combining using square wave dithering algorithm is demonstrated numerically. PMID- 24787177 TI - Quantification of total carbon in soil using laser-induced breakdown spectroscopy: a method to correct interference lines. AB - The C cycle in the Brazilian forests is very important, mainly for issues addressed to climate changes and soil management. Assessing and understanding C dynamics in Amazonian soils can help scientists to improve models and anticipate scenarios. New methods that allow soil C measurements in situ are a crucial approach for this kind of region, due to the costs for collecting and sending soil samples from the rainforest to the laboratory. Laser-induced breakdown spectroscopy (LIBS) is a multielemental atomic emission spectroscopy technique that employs a highly energetic laser pulse for plasma production and requires neither sample preparation nor the use of reagents. As LIBS takes less than 10 s per sample measurement, it is considered a promising technique for in situ soil analyses. One of the limitations of portable LIBS systems, however, is the common overlap of the emission lines that cannot be spectrally resolved. In this study a method was developed capable of separating the Al interference from the C emission line in LIBS measurements. Two typical forest Brazilian soils rich in Al were investigated: a spodosol (Amazon Forest) and an oxisol (Atlantic Forest). Fifty-three samples were collected and analyzed using a low-resolution LIBS apparatus to measure the intensities of C lines. In particular, two C lines were evaluated, at 193.03 and 247.86 nm. The line at 247.86 nm showed very strong interference with Fe and Si lines, which made quantitative analysis difficult. The line at 193.03 nm showed interference with atomic and ionic Al emission lines, but this problem could be solved by applying a correction method that was proposed and tested in this work. The line at 247.86 was used to assess the proposed model. The strong correlation (Pearson's coefficient R=0.91) found between the LIBS values and those obtained by a reference technique (dry combustion by an elemental analyzer) supported the validity of the proposed method. PMID- 24787178 TI - Set of Sellmeier equations for GaS and GaSe and its applications to the nonlinear optics in GaS(x)Se(1-x). AB - This paper reports a set of Sellmeier equations for GaS and GaSe that provide excellent reproduction of the phase-matching conditions for second- to sixth harmonic generation of CO2 laser radiation at 10.5910 MUm in GaS(0.4)Se(0.6) at 20 degrees C. In addition, this set of Sellmeier equations is found to reproduce well the phase-matching angles for second-harmonic generation of a Ti:Al2O3 laser pumped BaB2O4 optical parametric generator at 2.14-2.9 MUm and CO2 laser radiation at 9.2(9.2007)-10.7(10.6746) MUm measured by Kang et al. [Appl. Phys. B 108, 545 (2012)] in GaS(0.09)Se(0.91) and GaS(0.41)Se(0.59). PMID- 24787179 TI - Achieving high levels of color uniformity and optical efficiency for a wedge shaped waveguide head-mounted display using a photopolymer. AB - We developed a head-mounted display (HMD) that achieved high levels of color uniformity and optical efficiency. The full-color holographic volume grating (HVG) attached on the specially designed wedge-shaped waveguide HMD system provided a 17 degrees horizontal field of view (FOV). Theoretical analyses showed that the proposed waveguide resolved the problems of thickness and limited FOV. In this system, the HVG was recorded using a special sequential recording process on single photopolymer unit with 633, 532, and 473 nm wavelengths. The results confirm that the designed and fabricated waveguide can be employed in future commercial HMS. PMID- 24787180 TI - Comparison of fiber lasers based on distributed side-coupled cladding-pumped fibers and double-cladding fibers. AB - We compare both analytically and numerically the distributed side-coupled cladding-pumped (DSCCP) fiber lasers and double cladding fiber (DCF) lasers. We show that, through optimization of the coupling and absorbing coefficients, the optical-to-optical efficiency of DSCCP fiber lasers can be made as high as that of DCF lasers. At the same time, DSCCP fiber lasers are better than the DCF lasers in terms of thermal management. PMID- 24787181 TI - Computationally efficient scalar nonparaxial modeling of optical wave propagation in the far-field. AB - We present a scalar model to overcome the computation time and sampling interval limitations of the traditional Rayleigh-Sommerfeld (RS) formula and angular spectrum method in computing wide-angle diffraction in the far-field. Numerical and experimental results show that our proposed method based on an accurate nonparaxial diffraction step onto a hemisphere and a projection onto a plane accurately predicts the observed nonparaxial far-field diffraction pattern, while its calculation time is much lower than the more rigorous RS integral. The results enable a fast and efficient way to compute far-field nonparaxial diffraction when the conventional Fraunhofer pattern fails to predict correctly. PMID- 24787182 TI - Fast fluorescent imaging-based Thai jasmine rice identification with polynomial fitting function and neural network analysis. AB - With our single-wavelength spectral-imaging-based Thai jasmine rice identification system, we emphasize here that a combination of an appropriate polynomial fitting function on the determined chain code and a well-trained neural network configuration is highly sufficient in achieving a low false acceptance rate (FAR) and a low false rejection rate (FRR). Experimental demonstration shows promising results in identifying our desired Thai jasmine rice from six unwanted rice varieties with FAR and FRR values of 6.2% and 7.1%, respectively. Additional key performances include a much faster identification time of 30.5 s, chemical-free analysis, robustness, and adaptive learning. PMID- 24787183 TI - Beam shaping characteristics of an unstable-waveguide hybrid resonator. AB - The unstable-waveguide hybrid resonator emits a rectangular, simple astigmatic beam with a large number of high-spatial-frequency oscillations in the unstable direction. To equalize the beam quality, in this paper, a beam shaping system with a spatial filter for the hybrid resonator was investigated by numerical simulation and experimental method. The high-frequency components and fundamental mode of the output beam of the hybrid resonator in the unstable direction are separated by a focus lens. The high-frequency components of the beam are eliminated by the following spatial filter. A nearly Gaussian-shaped beam with approximately equal beam propagation factor M2 in the two orthogonal directions was obtained. The effects of the width of the spatial filter on the beam quality, power loss, and intensity distribution of the shaped beam were investigated. The M2 factor in the unstable direction is changed from 1.6 to 1.1 by optimum design. The power loss is only 9.5%. The simulation results are in good agreement with the experimental results. PMID- 24787184 TI - Dynamic characteristics analysis of a large-aperture rotating prism with adjustable radial support. AB - Support elements as key components in performing the opto-mechanical function have been an important topic for optical system development. Focusing on a rotation prism with a large aperture and asymmetric loading, a radial multi segment support is developed to solve the dynamic mounting issue. In order to explore the actual surface deformations over the full rotation, a novel dynamic analysis method to extract the transient load spectrum is established to access the surface deformations, including dynamic load extraction to connect varying loads with corresponding rotation positions, typical position analysis to obtain maximum deformation values, and vibration analysis. The results show that a maximum peak-to-valley value on the plane side reaches 103.16 nm when the prism rotates to 159.84 degrees , and that of the wedge side is 74.38 nm when the prism rotates to 213.84 degrees , both of which are less than lambda/4 (lambda=632.8 nm). However, when excited by the external loads with response frequency, the surface deformations become more serious. Because the dynamic characteristics obtained can reflect the actual usage situation, the proposed method is preferable for system development. PMID- 24787185 TI - Flat-top picosecond pulses generated by chirped spectral modulation from a Nd:YLF regenerative amplifier for pumping few-cycle optical parametric amplifiers. AB - In this paper we present an optically synchronized Nd:YLF regenerative amplifier optimized for use as a preamplifier in a few-cycle optical parametric chirped pulse amplification pump laser. In the pump amplification process we employ a combination of spectral modulation and chirping in order to control and optimize the temporal shape of the pulses. We report on a comparative study of two methods for generating near-flat-top or custom real-time variable-shaped pump pulses using either controlled chirp and shaping of the spectrum of the pulses seeding a regenerative amplifier or intracavity spectral filtering to broaden the gain bandwidth of the system. We show that in addition to minimizing gain narrowing and B-integral, the efficiency of the cascaded nonlinear processes of the parametric amplifiers can be increased. PMID- 24787186 TI - Mueller matrix microscope with a dual continuous rotating compensator setup and digital demodulation. AB - In this paper we describe a new Mueller matrix (MM) microscope that generalizes and makes quantitative the polarized light microscopy technique. In this instrument all the elements of the MU are simultaneously determined from the analysis in the frequency domain of the time-dependent intensity of the light beam at every pixel of the camera. The variations in intensity are created by the two compensators continuously rotating at different angular frequencies. A typical measurement is completed in a little over one minute and it can be applied to any visible wavelength. Some examples are presented to demonstrate the capabilities of the instrument. PMID- 24787187 TI - Deployment and evaluation of a dual-sensor autofocusing method for on-machine measurement of patterns of small holes on freeform surfaces. AB - This paper presents and evaluates an active dual-sensor autofocusing system that combines an optical vision sensor and a tactile probe for autofocusing on arrays of small holes on freeform surfaces. The system has been tested on a two-axis test rig and then integrated onto a three-axis computer numerical control (CNC) milling machine, where the aim is to rapidly and controllably measure the hole position errors while the part is still on the machine. The principle of operation is for the tactile probe to locate the nominal positions of holes, and the optical vision sensor follows to focus and capture the images of the holes. The images are then processed to provide hole position measurement. In this paper, the autofocusing deviations are analyzed. First, the deviations caused by the geometric errors of the axes on which the dual-sensor unit is deployed are estimated to be 11 MUm when deployed on a test rig and 7 MUm on the CNC machine tool. Subsequently, the autofocusing deviations caused by the interaction of the tactile probe, surface, and small hole are mathematically analyzed and evaluated. The deviations are a result of the tactile probe radius, the curvatures at the positions where small holes are drilled on the freeform surface, and the effect of the position error of the hole on focusing. An example case study is provided for the measurement of a pattern of small holes on an elliptical cylinder on the two machines. The absolute sum of the autofocusing deviations is 118 MUm on the test rig and 144 MUm on the machine tool. This is much less than the 500 MUm depth of field of the optical microscope. Therefore, the method is capable of capturing a group of clear images of the small holes on this workpiece for either implementation. PMID- 24787188 TI - Nonimaging optical concentrators using graded-index dielectric. AB - A new generation of inhomogeneous nonimaging optical concentrators is proposed, able to achieve simultaneously high optical efficiency and acceptance solid angle at a given geometrical concentration factor. General design methods are given, and concentrators are numerically investigated and optimized. PMID- 24787189 TI - Precise determination of full matrix of piezo-optic coefficients with a four point bending technique: the example of lithium niobate crystals. AB - A recently proposed technique representing a combination of digital imaging laser interferometry with a classical four-point bending method is applied to a canonical nonlinear optical crystal, LiNbO3, to precisely determine a full matrix of its piezo-optic coefficients (POCs). The contribution of a secondary piezo optic effect to the POCs is investigated experimentally and analyzed theoretically. Based on the POCs thus obtained, a full matrix of strain-optic coefficients (SOCs) is calculated and the appropriate errors are estimated. A comparison of our experimental errors for the POCs and SOCs with the known reference data allows us to claim the present technique as the most precise. PMID- 24787190 TI - Acoustic and elastic anisotropy of acousto-optic Pb2P2Se6 crystals. AB - We have determined experimentally the acoustic wave velocities for Pb2P2Se6 crystals and obtained complete matrices of the elastic stiffness and elastic compliance coefficients on this basis. The anisotropy of the acoustic wave velocities has been analyzed, and the spatial directions of propagation and polarization of the slowest acoustic waves have been determined. In the case of acousto-optic (AO) interaction with these waves, the AO figure of merit can reach extremely high values, thus making Pb2P2Se6 a promising AO material for the infrared spectral range. PMID- 24787191 TI - Optical and photoluminescence properties of ZnO(1-x)Se(x) thin films. AB - ZnO(1-x)Se(x) (0<=x<=0.11) thin films have been grown on sapphire (c-Al2O3) substrates at the temperature of 350 degrees C by means of the radio-frequency magnetron sputtering technique. The optical transmission, reflectance, and luminescence spectra at room temperature were analyzed. Using the lambda modulation method gives the possibility to reveal the main features of the energy band structure and the nature of the radiative transitions that cause ultraviolet luminescence. PMID- 24787192 TI - Magneto-optical properties of terbium iron borate. AB - The Faraday effect induced by an external magnetic field in TbFe3(BO3)4 and TbAl3(BO3)4 borates at a wavelength 633 nm has been investigated. It was found that the terbium subsystem brings the dominant magnetic contribution to the Faraday rotation at low temperatures in borate TbFe3(BO3)4. For both TbFe3(BO3)4 and TbAl3(BO3)4 the magneto-optical coefficients of the terbium subsystem were determined. PMID- 24787193 TI - Laser speckle probes of relaxation dynamics in soft porous media saturated by near-critical fluids. AB - Speckle correlation analysis was applied to study the relaxation dynamics in soft porous media saturated by near-critical carbon dioxide. The relaxation of soft matrix deformation was caused by a stepwise change in the fluid pressure. It was found that the deformation rate in the course of relaxation and the relaxation time strongly depend on the temperature of the system. The values of relaxation time reach their maximal values in the vicinity of the critical point of saturating fluid. The contributions of hydrodynamic relaxation of the fluid density and viscoelastic relaxation of the porous matrix to its creeping are analyzed. PMID- 24787194 TI - 11th International Conference "Correlation Optics": Propolis films for hybrid biomaterial-inorganic electronics and optoelectronics. AB - We report on the analysis of optical, polarimetric, and electrical properties of propolis films and hybrid biomaterial-inorganic heterojunctions based on them. It was shown that the material of the propolis films belongs to wide-bandgap optically active substances with the light-scattering centers, which possess complex optical properties. The values of the specific resistance rho(P)=1.9.107 Omega.cm and dielectric constant epsilon(P)=19.5 of the propolis film were determined from the spectral distribution of the real and imaginary components of its impedance at room temperature, respectively. The dominating current transport mechanisms through the hybrid bioinorganic heterojunction propolis/p-CdTe were established to be the interface-states-assisted generation-recombination within the depletion region via deep energy levels at forward bias as well as the leakage current through the shunt resistance at reverse bias. PMID- 24787195 TI - Two wavelength Mueller matrix reconstruction of blood plasma films polycrystalline structure in diagnostics of breast cancer. AB - The model of a Mueller matrix description of mechanisms of optical anisotropy typical for polycrystalline films of blood plasma--optical activity, birefringence, as well as linear and circular dichroism--is suggested. On this basis, the algorithms of reconstruction of parameters distribution (polarization plane rotations, phase shifts, coefficients of linear and circular dichroism) of the indicated types of anisotropy were found for different spectrally selective ranges. Within the statistical analysis of such distributions, the objective criteria of differentiation of films of blood plasma taken from healthy women and breast cancer patients were determined. From the point of view of probative medicine, the operational characteristics (sensitivity, specificity and accuracy) of the method of Mueller matrix reconstruction of optical anisotropy parameters were found, and its efficiency in diagnostics of breast cancer was demonstrated. PMID- 24787196 TI - Robustness properties of hill-climbing algorithm based on Zernike modes for laser beam correction. AB - A modified hill-climbing algorithm based on Zernike modes is used for laser beam correction. The algorithm adopts the Zernike mode coefficients, instead of the deformable mirror actuators' voltages in a traditional hill-climbing algorithm, as the adjustable variables to optimize the object function. The effect of the mismatches between the laser beam and the deformable mirror both in the aperture size and the center position was analyzed numerically and experimentally to test the robustness of the algorithm. Both simulation and experimental results show that the mismatches have almost no influence on the laser beam correction, unless the laser beam exceeds the effective aperture of the deformable mirror, which indicates the good robustness of the algorithm. PMID- 24787197 TI - Correlation properties of the vector signal representation for speckle pattern. AB - In one-dimensional (1D) signal analysis, the complex analytic signal built from a real-valued signal and its Hilbert transform is an important tool providing a mathematical foundation for 1D statistical analysis. For a natural extension beyond 1D signal, Riesz transform has been applied to high-dimensional signal processing as a generalized Hilbert transform to construct a vector signal representation and therefore, to enlarge the traditional analytic signal concept. In this paper, we introduce the vector correlations as new mathematical tools for vector calculus for statistical speckle analysis. Based on vector correlations of a real-valued speckle pattern, we present the associated correlation properties, which can be regarded as mathematical foundation for the vector analysis in speckle metrology. PMID- 24787198 TI - Laser generation of shock waves in a water suspension with light-absorbing particles. AB - We report the generation of shock waves in a disperse medium with absorbing particles of black pigment in the water using continuous laser radiation. As a result of the experimental investigation it was found that the illuminating beam diameter growth at the constant laser power results in the decrease of the signals' modulation frequencies, improving their stability and increasing their amplitudes. In turn, the decrease of the signal's modulation frequency is caused by the growth of time, which is needed for heating the medium to the critical temperature of cavitation. Improving the stability and the increase of optical and acoustic signal amplitudes take place, due to the growth of the medium volume and hence the number of pigment particles that participate in cavitation. PMID- 24787199 TI - Cement hydration investigation by method of piezoelectric photoacoustics. AB - The piezoelectric photoacoustics application possibility for polycrystalline structure formation has been considered. The accent was on research and transient modeling with pulse laser irradiation. A mathematical model for the given setup with a single laser impulse was developed. The results of mathematical modeling were experimentally tested on cement samples. PMID- 24787200 TI - Moment domain representation of nonblind image deblurring. AB - In this paper, we propose the use of geometric moments to the field of nonblind image deblurring. Using the developed relationship of geometric moments for original and blurred images, a mathematical formulation based on the Euler Lagrange identity and variational techniques is proposed. It uses an iterative procedure to deblur the image in moment domain. The theoretical framework is validated by a set of experiments. A comparative analysis of the results obtained using the spatial and moment domains are evaluated using a quality assessment method known as the Blind/Reference-less Image Spatial Quality Evaluator (BRISQUE). The results show that the proposed method yields a higher quality score when compared with the spatial domain method for the same number of iterations. PMID- 24787201 TI - Spatial-frequency selection of complex degree of coherence of laser images of blood plasma in diagnostics and differentiation of pathological states of human organism of various nosology. AB - The theoretical background of correlation and phase analysis of laser images of human blood plasma with the spatial-frequency selection of the manifestations of mechanisms of linear and circular birefringence of albumin and globulin is presented. The comparative results of measuring the coordinate distributions of the module of complex degree of coherence (CDC) of laser images of blood plasma taken from the patients of three groups--healthy patients (donors), the patients suffering from the rheumatoid arthritis, and those with stomach cancer (adenocarcinoma)--are shown. The values and ranges of change of the statistical (moments of the first-fourth orders), correlation (excess of autocorrelation functions), and fractal (slopes of approximating curves and dispersion of the extremes of logarithmic dependencies of power spectra) parameters of CDC coordinate distributions are studied. The objective criteria of diagnostics of the pathology and differentiation of the inflammation and oncological state are determined. PMID- 24787202 TI - Laser polarization autofluorescence of endogenous porphyrins of optically anisotropic biological tissues and fluids in diagnostics of necrotic and pathological changes of human organs. AB - This research presents the results of investigation of laser polarization fluorescence of biological layers (histological sections, cytological smears). The polarization structural properties of autofluorescent images of human biological tissues layers and fluids were found and investigated. A model describing the formation of polarizationally heterogeneous images of optically anisotropic biological layers is suggested. On this basis, the practical method of polarization-variable autofluorescence is analytically substantiated and experimentally tested. The efficiency of applying this method to various tasks of medical diagnostics is analyzed: objectification of histological conclusions, defining and differentiating of various forms of cancer (dysplasia--microinvasive cancer) of the cervix uteri, and forensic medical express-differentiation of cause of death. The objective criteria (statistical moments) of differentiation of autofluorescent images of histological sections of myocardium biopsy and endometrium and cytological smears of its mucous tunic are defined. The operational characteristics (sensitivity, specificity, accuracy) of this method are determined concerning the positions of probative medicine, and the clinical efficiency of the technique is demonstrated. PMID- 24787203 TI - Medium for polarization-sensitive diffraction gratings. AB - New polymers applicable for optoelectronics are developed and investigated. The ability to form photoinduced anisotropy in the media based on the films of these polymers is demonstrated. The media can be used for recording of polarization sensitive diffraction gratings. PMID- 24787204 TI - Features of optical image jitter in a random medium with a finite outer scale. AB - For more than 40 years, we have studied the effect of the low-frequency spectral range of atmospheric turbulence on optical characteristics. We also have looked at the influence of the turbulence models as well as an outer scale of turbulence on the parameters of telescopes and systems of laser beam formations. This question is important mainly for ground-based astronomy. Here we propose what we believe is a new optical method that uses the phase fluctuations of optical image jitter to estimate both the integral (along an atmospheric path) value of the structure parameter of atmospheric turbulence and effective outer scales of turbulence. PMID- 24787205 TI - Fourier-domain Jones-matrix mapping of a complex degree of mutual anisotropy in differentiation of biological tissues' pathological states. AB - This article presents the theoretical background of an azimuthally stable method of Jones-matrix mapping of histological sections of a uterine wall biopsy on the basis of spatial-frequency selection of the mechanisms of linear and circular birefringence. The diagnostic application of a new correlation parameter--a complex degree of mutual anisotropy--is analytically substantiated. The method of measuring coordinate distributions of a complex degree of mutual anisotropy with further spatial filtration of their high- and low-frequency components is developed. The interconnections of such distributions with linear and circular birefringence parameters of the uterine-wall-endometrium histological sections are found. The comparative results of measuring the coordinate distributions of a complex degree of mutual anisotropy formed by fibrillar networks of myosin and collagen fibrils of uterus wall tissue of different pathological states--pre cancer (dysplasia) and cancer (adenocarcinoma)--are shown. The values and ranges of change of the statistical (moments of the first to fourth orders) parameters of complex degree of mutual-anisotropy coordinate distributions are studied. The objective criteria of diagnosing the pathology and differentiation of its severity degree are determined. PMID- 24787206 TI - Denoising and extracting background from fringe patterns using midpoint-based bidimensional empirical mode decomposition. AB - We propose a 2D generalization to the midpoint-based empirical mode decomposition algorithm (MBEMD). Unlike with the regular bidimensional empirical mode decomposition algorithm (BEMD), we do not interpolate the upper and lower envelopes, but rather directly find the mean envelope, utilizing well-defined points between two extrema of different kinds (midpoints). This approach has several advantages, such as improved spectral selectivity and better time performance over the regular BEMD process. The MBEMD algorithm is then applied to the task of the interferometric fringe pattern analysis, to identify its distinct components. This allows separating the oscillatory pattern component, which is of interest, from the background, noise, and possibly other spurious interferometric patterns. Such an enhancement is meant to aid further phase demodulation and reduce its errors. Flexibility of the adaptive method allows for processing correlation fringe patterns met in the digital speckle pattern interferometry as well as the regular interferometric fringe patterns without any special tuning of the algorithm. PMID- 24787207 TI - Magneto-optical Faraday rotation of semiconductor nanoparticles embedded in dielectric matrices. AB - Faraday rotation has been studied for CdS, CdTe, and CdS:Mn semiconductor nanoparticles synthesized by colloidal chemistry methods. Additionally these materials were prepared in a form of semiconductor nanoparticles embedded in polyvinyl alcohol films. Transmission electron microscopy and atomic force microscopy analyses served as confirmation of nanocrystallinity and estimation of the average size of the nanoparticles. Spectral dependence of the Faraday rotation for the studied nanocrystals and nanocomposites is correlated with a blueshift of the absorption edge due to the confinement effect in zero dimensional structures. Faraday rotation spectra and their temperature behavior in Mn-doped nanocrystals demonstrates peculiarities, which are associated with s, p-d exchange interaction between Mn2+ ions and band carriers in diluted magnetic semiconductor nanostructures. PMID- 24787208 TI - Bottlenecks of the wavefront sensor based on the Talbot effect. AB - Physical constraints and peculiarities of the wavefront sensing technique, based on the Talbot effect, are discussed. The limitation on the curvature of the measurable wavefront is derived. The requirements to the Fourier spectrum of the periodic mask are formulated. Two kinds of masks are studied for their performance in the wavefront sensor. It is shown that the boundary part of the mask aperture does not contribute to the initial data for wavefront restoration. It is verified by experiment and computer simulation that the performance of the Talbot sensor, which meets established conditions, is similar to that of the Shack-Hartmann sensor. PMID- 24787209 TI - Comparison of Kolmogorov's and coherent turbulence. AB - Features of optical wave fluctuations while propagating through a randomly inhomogeneous turbulent medium with a finite outer scale are considered, including conditions when areas with dominating influence of one large-scale coherent structure are observed in the atmosphere, for which the spectrum of atmospheric turbulence can differ significantly from the Kolmogorov model spectrum. Using an approximate model of the spectrum for coherent turbulence, described earlier in our works, the variance of jitter of an optical image is calculated (under the applicability condition for the smooth perturbation method). The comparison of these equations with known similar equations for Kolmogorov turbulence has shown that the variance of fluctuations is significantly weaker in coherent turbulence than in the Kolmogorov theory under similar conditions. This means that phase fluctuations of optical radiation decrease significantly in coherent turbulence. The importance of this conclusion is noted for interpretation of the results of optical sounding of atmospheric turbulence. PMID- 24787210 TI - Ultrasmooth metal nanolayers for plasmonic applications: surface roughness and specific resistivity. AB - The future of plasmonic devices depends on effective reduction of losses of surface plasmon-polariton waves propagating along metal-dielectric interfaces. Energy dissipation is caused by resistive heating at the skin-deep-thick outer layer of metal and scattering of surface waves on rough metal-dielectric interfaces. Fabrication of noble metal nanolayers with a smooth surface still remains a challenge. In this paper, Ag layers of 10, 30, and 50 nm thickness deposited directly on fused-silica substrates and with a 1 nm wetting layer of Ge, Ti, and Ni are examined using an atomic-force microscope and four-probe resistivity measurements. In the case of all three wetting layers, the specific resistivity of silver film decreases as the thickness increases. The smallest, equal 0.4 nm root mean squared roughness of Ag surface of 10 nm thickness is achieved for Ge interlayer; however, due to Ge segregation the specific resistivity of silver film in Ag/Ge/SiO2 structures is about twice higher than that in Ag/Ti/SiO2 and Ag/Ni/SiO2 sandwiches. PMID- 24787211 TI - Information media based on electron donor oligomers with different structures. AB - Information properties of recording media for photothermoplastic techniques were investigated. The films consisted of oligomer composites based on carbazole containing co-oligomers of linear and radial structures with branching centers on silicon and germanium atoms. It was ascertained that the media based on the radial oligomers possessed high holographic sensitivity because of the high plasticity and its ability to accumulate volume electric charge during the exposure. Examples of practical applications of the investigated recording media are presented. PMID- 24787212 TI - Dynamics of three-Airy beams carrying optical vortices. AB - We study numerically and demonstrate experimentally a novel type of singular optical beams formed by the phase imprinting of an optical vortex into the structure of the three-Airy beams. In contrast to a vortex-free product of three Airy beams, in this type of singular-Airy beam, the vortex in the beam axis causes a twist in the beam transverse intensity profile with propagation. Such a new type of singular beams appears especially attractive for applications in optical micromanipulation. PMID- 24787213 TI - Moving average process underlying the holographic-optical-tweezers experiments. AB - We study the statistical properties of recordings that contain time-dependent positions of a bead trapped in optical tweezers. Analysis of such a time series indicates that the commonly accepted model, i.e., the autoregressive process of first-order, is not sufficient to fit the data. We show the presence of a first order moving average part in the dynamical model of the system. We explain the origin of this part as an influence of the high-frequency CCD camera on the measurements. We show that this influence evidently depends on the applied exposure time. The proposed autoregressive moving average model appears to reflect perfectly all statistical features of the high-frequency recording data. PMID- 24787214 TI - Transverse energy circulation and the edge diffraction of an optical vortex beam. AB - Edge diffraction of a circular Laguerre-Gaussian beam represents an example of the optical vortex symmetry breakdown in which the hidden "vortex" energy circulation is partially transformed into the visible "asymmetry" form. The diffracted beam evolution is studied in terms of the irradiance moments and the moment-based parameters. In spite of the limited applicability of the moment based formalism, we show that the "vortex" and "asymmetry" parts of the orbital angular momentum can still be reasonably defined for the hard-edge diffracted beams and retain their physical role of quantifying the corresponding forms of the transverse energy circulation. PMID- 24787215 TI - Angular momentum of an incoherent Gaussian beam. AB - The relations for the components of the Poynting vector of a quasi-monochromatic wave are obtained. It is shown that in this case the behavior of the transversal Poynting component may be defined similarly to that in the coherent case. The total angular momentum of the quasi-monochromatic wave may be divided into the orbital and spin parts. The example of a Gaussian beam shows that the value of the spin angular momentum is connected to the coherence characteristics of the beam. Experimental results are presented. PMID- 24787216 TI - Interconnection of polarization properties and coherence of optical fields. AB - Theoretical and experimental approaches to diagnosing internal spin and orbital optical flows and the corresponding optical forces caused by these flows are offered. These approaches are based on the investigation of the motion of the particles tested in the formed optical field. The dependence of the above mentioned forces upon the size and optical properties of the particles is demonstrated. The possibility of using kinematic values defining the motion dynamics of particles of the Rayleigh light scattering mechanism to make a quantitative assessment of the degree of coherence of mutually orthogonal waves that are linearly polarized in the incidence plane is demonstrated. The feasibility of using the above mentioned approach, its shortcomings, and its advantages over the interfering method for estimating the degree of coherence are analyzed. PMID- 24787217 TI - Effects of symbol modulation coding on readout fidelity of shift-multiplexed holographic digital data page storage in a photopolymerizable nanoparticle-(thiol ene)polymer composite film. AB - We report on shift-multiplexed holographic storage of 250 digital data pages in a photopolymerizable SiO2 nanoparticle-polymer composite film being capable of step growth thiol-ene polymerization in the green. Various two-dimensional symbol modulation codes for the digital data page format were employed to examine the dependence of the readout fidelity on modulation coding schemes. It is found that, as compared to 1:2 and 2:4 modulation codes, higher-order 5:9, 9:16, and 13:25 modulation codes possessing reduced white rates and higher coding efficiencies give lower symbol-error rates of ~1*10-3 and higher signal-to-noise ratios (>4). PMID- 24787218 TI - Generation of double-charged optical vortices on the basis of electro-optic Kerr effect. AB - We show that double-charged optical vortices can be generated with the help of Kerr electro-optic effect in either single crystals or isotropic media, including gaseous and liquid ones. We analyze possibilities for the vortex generation via the Kerr effect for different point groups of symmetry and formulate the appropriate conditions. We prove that the crystals, textures, and the isotropic media most suitable for the generation of double-charged optical vortices should belong to the symmetry groups 622, 6mm, 6/mmm, 6, 6/m, infinity/m, infinity, infinity2, infinitymm, infinity/mmm, infinity/infinity/mmm, and infinity/infinity2. PMID- 24787219 TI - Determination of U contours in simulated speckle fields. AB - The behavior of vector singularities in partially coherent inhomogeneously polarized optical beams, such as U contours with zero degree of polarization, is investigated by computer simulation for the most important cases of incoherent mixing of orthogonally polarized components (speckle fields and plane waves). Vector singularities in partially coherent combined beams are considered within the notion of the complex degree of polarization, with representation in the Stokes space. The dependences of U singularities on the intensity ratio obtained by simulation are compared with obtained early qualitative experimental results. PMID- 24787220 TI - Optical absorption spectra as a useful tool to find parameters of deep impurity centers in semiconductors. AB - We analyze physical models accounting for deep-level conduction band transitions to describe impurity absorption spectra in tetrahedral-structured semiconductors. The investigations were carried out for ZnSe crystals doped with transition metals (Ti, V, Cr, Mn, Fe, Co, Ni) from a vapor phase. It was shown that the impurities provide acceptor centers with ground state energy offset by 0.3-0.6 eV from the edge of the conduction band, forming long-wave bands in the absorption spectra of the materials studied. PMID- 24787221 TI - Skew projectors and generalized observables in polarization optics: a biorthogonal analyses [Invited]. AB - This paper constitutes an application of the polarization optics in the problem of quantum measurement. The non-Hermitian operators of the nonorthogonal multilayer optical polarizers represent observables in the sense of the generalized quantum theory of measurement. The intimate spectral structure of these polarizers can be disclosed in the frame of skew-angular vector bases and biorthonormal vector systems. We show that these polarizers correspond to skew projectors; their operators are "generated" by skew projectors in the sense of the spectral theorem of linear operators theory. Thus the common feature of all the polarizers (Hermitian and non-Hermitian) is that their "nuclei" are (orthogonal or skew) projectors--the generating projectors. PMID- 24787222 TI - Interrelations between technology for obtaining quantum dots and optoelectronic properties of semiconductors [Invited]. AB - The mechanism and kinetics of growth of nanocrystals considered as quantum dots (those used as electronic blocks in optoelectronic devices) is investigated for the case when the growth and solving of them is controlled in parallel by diffusion (surface of volume) and by the rate of chemical reaction at surface of the nanocrystals (Wagner's mechanism of growth). It is shown that the total flow to and from the nanocrystal consists of two parts, viz. the diffusion and kinetic ones. Depending on the ratio x of the two parts of the total flow, the diffusion or Wagner's mechanism of growth predominates. For that, the size distribution function is determined for the specified x either by the curve corresponding to the generalized Chakraverty-Wagner distribution or from the generalized Lifshitz Slyozov-Wagner distribution. Comparison of theoretically computed distributions with the experimentally obtained histograms is carried out. PMID- 24787223 TI - Dynamics of speckles with a small number of scattering events: specific features of manifestation of the Doppler effect. AB - Spectra of intensity fluctuations of dynamic non-Gaussian speckles formed with a small number of scattering events have been studied theoretically and experimentally. A new type of manifestation of the Doppler effect has been observed. The dependence of frequency position of the Doppler peak and the shape of the Doppler spectrum on the number of scatterers has been analyzed. PMID- 24787224 TI - Correlation optics in progress: introduction to the feature issue. AB - This feature issue of Applied Optics contains a series of selected papers reflecting recent progress of correlation optics and showing, in part, the trend from micro-optics to nano-optics. PMID- 24787225 TI - A universal small molecule, inorganic phosphate, restricts the substrate specificity of Dicer-2 in small RNA biogenesis. AB - The enzyme Dicer is central to the production of small silencing RNAs such as microRNAs (miRNAs) and small interfering RNAs (siRNAs). Like other insects, Drosophila melanogaster uses different Dicers to make siRNAs and miRNAs: Dicer-1 produces miRNAs from pre-miRNAs, whereas Dicer-2 generates siRNAs from long double-stranded RNA (dsRNA). How do the 2 Dicers achieve their substrate specificity? Here, we review recent findings that inorganic phosphate restricts the substrate specificity of Dicer-2 to long dsRNA. Inorganic phosphate inhibits Dicer-2 from binding and cleaving pre-miRNAs, without affecting the processing of long dsRNA. Crystal structures of a fragment of human Dicer in complex with an RNA duplex identify a phosphate-binding pocket that recognizes both the 5' monophosphate of a substrate RNA and inorganic phosphate. We propose that inorganic phosphate occupies the phosphate-binding pocket in the fly Dicer-2, blocking binding of pre-miRNA and restricting pre-miRNA processing to Dicer-1. Thus, a small molecule can alter the substrate specificity of a nucleic acid processing enzyme. PMID- 24787226 TI - MR imaging techniques for nano-pathophysiology and theranostics. AB - The advent of nanoparticle DDSs (drug delivery systems, nano-DDSs) is opening new pathways to understanding physiology and pathophysiology at the nanometer scale. A nano-DDS can be used to deliver higher local concentrations of drugs to a target region and magnify therapeutic effects. However, interstitial cells or fibrosis in intractable tumors, as occurs in pancreatic or scirrhous stomach cancer, tend to impede nanoparticle delivery. Thus, it is critical to optimize the type and size of nanoparticles to reach the target. High-resolution 3D imaging provides a means of "seeing" the nanoparticle distribution and therapeutic effects. We introduce the concept of "nano-pathophysiological imaging" as a strategy for theranostics. The strategy consists of selecting an appropriate nano-DDS and rapidly evaluating drug effects in vivo to guide the next round of therapy. In this article we classify nano-DDSs by component carrier materials and present an overview of the significance of nano-pathophysiological MRI. PMID- 24787227 TI - Evaluation of ZAR1 and SFRP4 methylation status as potentials biomarkers for diagnosis in cervical cancer: exploratory study phase I. AB - CONTEXT: Aberrant hypermethylation of promoter region of tumor suppressor genes could be used as cancer biomarkers. OBJECTIVE: To test methylation status of ZAR1 and SFRP4 promoter regions as potentials biomarkers for diagnosis of preneoplastic and neoplastic lesions of cervix. MATERIALS AND METHODS: Cytobrush samples were evaluated by Methylation specific PCR (MSP) and quantitative MSP (qMSP). RESULTS: ZAR1 and SFRP4 methylation frequency increased as the grade of lesion increased and the differences between normal and cervical cancer (CC) are statistically significant (p < 0.0001). qMSP showed higher ZAR1 and SFRP4 methylation levels in cancer than normal epithelia (p < 0.001) and preneoplastics lesions (p < 0.01). DISCUSSION: qMSP quantify methylation levels and have high sensitivity and specificity. CONCLUSION: ZAR1 and SFRP4 qMSP could be used as potential biomarker for CC diagnosis. PMID- 24787229 TI - Extraventricular neurocytoma and ganglioneurocytoma: advanced MR imaging, histopathological, and chromosomal findings. AB - Extraventricular neurocytoma and ganglioneurocytoma are rare intra-axial brain neoplasms that are now recognized as distinct entities in the 2007 WHO classification of brain tumors. We describe the conventional MR imaging, perfusion MRI, proton MR spectroscopy (1H MRS), histopathology, immunohistochemistry, and chromosomal analysis in two cases of these tumors, with some features which have not been previously well described. Both tumor types demonstrated markedly elevated cerebral blood volume on perfusion MRI and had 1p19q chromosomal codeletions. Both tumor types showed an elevated Cho/Cr ratio, but extraventricular ganglioneurocytoma showed a preserved NAA/Cr ratio. These tumors should be considered in the differential diagnosis of intra-axial brain tumors. PMID- 24787230 TI - Pilot phase I/II personalized therapy trial for metastatic colorectal cancer: evaluating the feasibility of protein pathway activation mapping for stratifying patients to therapy with imatinib and panitumumab. AB - This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms. PMID- 24787228 TI - Report of the NIH Task Force on research standards for chronic low back pain. AB - Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. PERSPECTIVE: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. PMID- 24787231 TI - Long term follow-up of BEAM-autologous and BEAM-alemtuzumab allogeneic stem cell transplantation in relapsed advanced stage follicular lymphoma. AB - This is an analysis in 171 patients comparing BEAM-Auto and BEAM-Allo (alemtuzumab)-hematopoietic stem cell transplantation in relapsed follicular lymphoma. BEAM-Allo group had a lower 10 years cumulative incidence of relapse(31.4% vs 55.1%, p=0.042), a trend to a plateau in survival but no statistical differences in OS or DFS, and a TRM of 24%. When transplanted in CR BEAM-Allo patients had better OS and DFS. Incidence of acute and chronic GVHD was 16.6% and 22%. 29% of BEAM-Allo patients received DLI (all but two remain in CR and alive). Our data supports Allo-HSCT as a potential curative treatment for selected patients with FL. PMID- 24787233 TI - Nutritional practices associated with low energy availability in Division I female soccer players. AB - The purpose of this study was to examine macronutrient intake, energy density and energy intake distribution that may be associated with low energy availability (EA) in Division I female soccer players. The energy intake, exercise energy expenditure and EA of 19 participants (18-21 years) was assessed during the pre-, mid- and postseasons. Repeated measures analysis of variance was performed to examine the changes across the season. Chi-square analysis was performed to examine the distribution of participants meeting the American College of Sports Medicine recommendations for carbohydrate and protein consumption. Independent t tests were used to compare differences between groups. The proportion of athletes who did not meet the American College of Sports Medicine recommendations for carbohydrate intake (6-10 g . kg(-1) BW) was significantly greater in the low (<30 kcal . kg(-1) LBM) than higher (>= 30 kcal . kg(-1) LBM) EA group (chi(2) (1) = 7.5; P = 0.006). Participants with low compared to higher EA consumed a lower energy dense dinner (0.8 +/- 0.1 vs. 1.4 +/- 0.1 kcal . g(-1); P = 0.004) after a soccer match during midseason. No differences in the percentage (%) of kilocalories from food (84.5 +/- 2.0% vs. 84.7 +/- 2.6%), sports drinks (7.3 +/- 1.4% vs. 6.0 +/- 3.2%), other drinks (7.6 +/- 1.5 % vs. 6.0 +/- 1.5%) or bars/gels/beans (1.7 +/- 0.6 vs. 3.0 +/- 1.5) were observed in participants with low compared to higher EA (P > 0.05) during the pre- and midseasons. Identifying inadequate carbohydrate intake and the practice of consuming lower energy dense meals may be important in preventing low EA conditions and consequently the Female Athlete Triad. PMID- 24787232 TI - Bcl-xL is necessary for neurite outgrowth in hippocampal neurons. AB - AIMS: B-cell lymphoma-extra large (Bcl-xL) protects survival in dividing cells and developing neurons, but was not known to regulate growth. Growth and synapse formation are indispensable for neuronal survival in development, inextricably linking these processes. We have previously shown that, during synaptic plasticity, Bcl-xL produces changes in synapse number, size, activity, and mitochondrial metabolism. In this study, we determine whether Bcl-xL is required for healthy neurite outgrowth and whether neurite outgrowth is necessary for survival in developing neurons in the presence or absence of stress. RESULTS: Depletion of endogenous Bcl-xL impairs neurite outgrowth in hippocampal neurons followed by delayed cell death which is dependent on upregulation of death receptor 6 (DR6), a molecule that regulates axonal pruning. Under hypoxic conditions, Bcl-xL-depleted neurons demonstrate increased vulnerability to neuronal process loss and to death compared with hypoxic controls. Endogenous DR6 expression and upregulation during hypoxia are associated with worsened neurite damage; depletion of DR6 partially rescues neuronal process loss, placing DR6 downstream of the effects of Bcl-xL on neuronal process outgrowth and protection. In vivo ischemia produces early increases in DR6, suggesting a role for DR6 in brain injury. INNOVATION: We suggest that DR6 levels are usually suppressed by Bcl-xL; Bcl-xL depletion leads to upregulation of DR6, failure of neuronal outgrowth in nonstressed cells, and exacerbation of hypoxia-induced neuronal injury. CONCLUSION: Bcl-xL regulates neuronal outgrowth during development and protects neurites from hypoxic insult, as opposed by DR6. Factors that enhance neurite formation may protect neurons against hypoxic injury or neurodegenerative stimuli. PMID- 24787234 TI - Conditionality and risk for the pedestrian: modelling with the Bayesian networks. AB - The conditional script questionnaire (CSQ) makes possible to study the conditions under which drivers find it legitimate to transgress the Highway Code. In this paper, we propose to analyse conditional respect towards the pedestrian with a new methodology based on Bayesian networks (BN). This methodology is designed to give a useful decision support tool for the analyst. Starting from data encoded in the CSQ, we use structure learning algorithms in order to build a BN. Then, we exploit it for two purposes: to extract new knowledge about the main topics expressed in the CSQ and to make inferences. This methodology helps to better understand the behaviour of drivers interacting with pedestrians and what might be the cause of their decisions of legitimate transgressions. The efficiency of the methodology proposed here is illustrated and a context-dependent 'mapping' of the legitimate transgressions established. PMID- 24787236 TI - Joint contractures in the intensive care unit: quality of life and function 3.3 years after hospital discharge. AB - PURPOSE: To investigate the mortality, quality of life and functional limitations of intensive care unit (ICU) patients with and without joint contractures 3.3 years after discharge from the hospital. METHODS: 155 consecutive patients admitted to a primary care referral centre ICU for 2 or more weeks with information on joint range of motion formed a retrospective cohort. The EuroQol and a Joint Contracture Questionnaire were administered to the cohort survivors. RESULTS: Fifty patients returned the questionnaires, 57 did not return the questionnaire, and 48 were deceased. The patients who had died presented significantly more joint contractures in the ICU than the respondents and the non respondents (p = 0.003 and p = 0.006, respectively). More respondents who reported limitations in their mobility on the EuroQol had joint contractures in ICU 13/18 (72.2%) compared to respondents who did not have contractures 7/21 (33.3%; p = 0.02). CONCLUSIONS: Joint contractures in ICU were associated with higher mortality. Patients who spent 2 weeks or more in ICU and developed joint contractures identified more difficulty with mobility 3.3 years after discharge; joint contractures may impose irreversible disability. A strategy to identify and treat joint contractures in ICU may prevent long-term functional limitations. PMID- 24787235 TI - Early cytokine dysregulation and viral replication are associated with mortality during lethal influenza infection. AB - Infection with influenza A virus (IAV) leads to acute lung injury and possibly fatal complications, especially in immunocompromised, elderly, or chronically infected individuals. Therefore, it is important to study the factors that lead to pathology and mortality in infected hosts. In this report, we analyze immune responses to infection at a sublethal (0.1 LD(50)) and lethal (1 LD(50)) dose of the highly pathogenic IAV A/Puerto Rico/8/34 (PR8). Our experiments revealed that infection with a 1 LD(50) dose induced peak viral titers at day 2 compared to day 4 in the 0.1 LD(50) dose. Moreover, early cytokine dysregulation was observed in the lethal dose with significantly elevated levels of IFN-alpha, TNF-alpha, CXCL9, IL-6, and MCP-1 produced at day 2. Early inflammatory responses following infection with 1 LD(50) correlated with a greater influx of neutrophils into the lung. However, depletion of neutrophils enhanced morbidity following IAV infection. Though no differences in CD8+ cell function were observed, CD4+ effector responses were impaired in the lungs 8 days after infection with 1 LD(50). Histological analysis revealed significant pathology in lethally infected mice at day 2 and day 6 postinfection, when viral titers remained high. Treating lethally infected mice with oseltamivir inhibited viral titers to sublethal levels, and abrogated the pathology associated with the lethal dose. Together, these results suggest that early cytokine dysregulation and viral replication play a role in pulmonary damage and high mortality in lethally infected mice. PMID- 24787237 TI - Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre. AB - INTRODUCTION: Ambrisentan is an oral selective endothelin receptor antagonist licensed for use in pulmonary arterial hypertension (PAH). There are few data on clinical use and long-term tolerability in a wider range of patients with pulmonary hypertension (PH). METHODS: All patients treated with ambrisentan over a 4-year period were identified. Baseline characteristics, liver function test (LFT) results and World Health Organization (WHO) functional class were retrieved from hospital databases. RESULTS: 272 patients received ambrisentan between March 2009 and June 2013 (32% idiopathic PAH, 36% connective tissue disease PAH, 11% congenital heart disease PAH, 6% portopulmonary hypertension, 1% HIV PAH, 4% PH in association with lung disease, 8% chronic thromboembolic PH and 2% PH in association with sarcoidosis). 33.5% of patients received ambrisentan as monotherapy and 12% received ambrisentan as their initial PH therapy. 18% stopped treatment due to side effects and 12% stopped due to lack of efficacy. Oedema was the most common side effect leading to cessation of therapy, which occurred in 7% of patients. 57% of patients who discontinued ambrisentan due to side effects also discontinued other PAH therapies due to side effects previously or subsequently. Ambrisentan was discontinued in two (<1%) patients due to abnormal LFTs. The 3-year survival in congenital heart disease PAH, idiopathic PAH and systemic sclerosis-associated PAH was 80%, 62%, and 38%, respectively (p = 0.003). Survival was superior in patients in whom WHO functional class improved in response to therapy. CONCLUSION: Ambrisentan is used as an initial therapy and as monotherapy in a minority of patients in a large UK PH referral centre. Discontinuation due to side effects, and especially oedema, was higher than reported in previous studies while discontinuation due to abnormal LFTs was very uncommon. A majority of patients who discontinued therapy due to side effects also previously or subsequently discontinued other PAH therapies. Improvement in WHO functional class was associated with superior survival. PMID- 24787238 TI - Taxonomic approach to the tachinid flies Dinera carinifrons (Fallen) (Diptera: Tachinidae) and Dinera fuscata Zhang and Shima using molecular and morphometric data. AB - Molecular phylogenetic and traditional morphometric methods were applied to examine six Palaearctic taxa of the taxonomically difficult tachinid fly genus Dinera Robineau-Desvoidy (Diptera: Tachinidae), with particular reference to D. carinifrons (Fallen) and D. fuscata Zhang and Shima. Results of a phylogenetic analysis based on the mitochondrial markers 12S and 16S rDNA and multivariate statistical analyses of 19 morphometric characters were used to delimit both species. A lectotype was designated for D. carinifrons to stabilize the nomenclature in the group. Dinera carinifrons has a transpalaearctic distribution and is present in Central Europe, especially in high altitudes of the Alps. It differs from the similar and closely related D. fuscata in that it has a slightly larger body size, a dense greyish microtrichosity on the body, and different head proportions. Dinera fuscata, as delimited here, is widespread in the Palaearctic region, including Europe. Slight differences in both molecular and morphometric characters were found between western (Europe and Iran) and eastern (China and Japan) populations of D. fuscata, which are interpreted as an intraspecific variation. Differential diagnosis between D. carinifrons and D. fuscata is provided in the form of a revised portion of the determination key to the Palaearctic Dinera by Zhang and Shima (2006). PMID- 24787240 TI - Regulation of aggregation behavior and neurotoxicity of prion neuropeptides by platinum complexes. AB - Prion diseases belong to a group of infectious, fatal neurodegenerative disorders. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion disease pathology. PrP106-126 resembles PrP(Sc) in some physicochemical and biological characteristics, such as apoptosis induction in neurons, fibrillar formation, and mediation of the conversion of native cellular PrP(C) to PrP(Sc). Numerous studies have been conducted to explore the inhibiting methods on the aggregation and neurotoxicity of prion neuropeptide PrP106-126. We showed that PrP106-126 aggregation, as assessed by fluorescence assay and atomic force microscopy, is inhibited by platinum complexes cisplatin, carboplatin, and Pt(bpy)Cl2. ESI-MS and NMR assessments of PrP106-126 and its mutant peptides demonstrate that platinum complexes bind to the peptides in coordination and nonbonded interactions, which rely on the ligand properties and the peptide sequence. In peptides, methionine residue is preferred as a potent binding site over histidine residue for the studied platinum complexes, implying a typical thiophile characteristic of platinum. The neurotoxicity induced by PrP106-126 is better inhibited by Pt(bpy)Cl2 and cisplatin. Furthermore, the ligand configuration contributes to both the binding affinity and the inhibition of peptide aggregation. The pursuit of novel platinum candidates that selectively target prion neuropeptide is noteworthy for medicinal inorganic chemistry and chemical biology. PMID- 24787241 TI - A novel de novo duplication mutation of PAX6 in a Chinese family with aniridia and other ocular abnormalities. AB - Aniridia is a congenital panocular disorder caused by the mutations of the paired box gene-6 (PAX6). To investigate the clinical characterization and the underlying genetic defect in a Chinese family with aniridia and other ocular abnormalities, we recruited the family members who underwent ophthalmic examination. Two patients in this family, the proband and his affected son, both have bilateral aniridia, foveal hypoplasia and nystagmus. Moreover, the proband also had presenile cataracts, but his affected son did not show cataracts at the time of examination. Sequencing PAX6 revealed that a heterozygous duplication mutation c.95_105dup11, predicted to generate non-functional truncated protein at position Gly36 (p.G36X), was found in the affected individuals but not in any of the unaffected family members including the parents of the proband. Haplotype analysis showed that the proband and his affected son shared a common disease related haplotype, which was arisen from the proband's unaffected father through crossing-over. In conclusion, we identified a novel de novo duplication mutation of PAX6 in the aniridia and other ocular abnormalities family. This mutation has occurred de novo on a paternal chromosome by direct duplication, which presumably results from replication slippage or unequal non-sister chromatids exchange during spermatogenesis. PMID- 24787242 TI - Inferior alveolar and mental nerve injuries associated with open reduction and internal fixation of mandibular fractures: a Seven Year retrospective study. AB - PURPOSE: To document adverse neurosensory changes in the inferior alveolar nerve (IAN) and mental nerve (MN) after surgical mandibular fracture treatment and to identify risk factors associated with these changes. MATERIALS AND METHODS: A retrospective study of patients surgically treated for mandibular fractures. The primary study variable was the postoperative change in IAN/MN neurosensory examination after fracture fixation. Risk factors were categorized as demographic, anatomic, experience of the operator, fracture displacement and number of miniplates placed at each fracture site. Appropriate statistics were computed. RESULTS: 209 patients with 293 fractures were analysed. One hundred twenty fractures (41%) were located between the lingula and mental foramen, and 173 fractures (59%) were located distal to the mental foramen. Two hundred seventeen (41%) were displaced by 5 mm or more. In 38 fractures (13%), the IAN/MN neurosensory status worsened after treatment. In a multivariate model, fracture displacement, operator inexperience and two plate fixation were associated with a statistically significant risk (P <= 0.05) for postoperative deterioration of IAN/MN sensation. CONCLUSION: Fixation with two miniplates, fracture displacement of 5 mm or more and operator inexperience were associated with an increased risk for deterioration of the IAN/MN neurosensory status after treatment of mandibular fractures. PMID- 24787239 TI - Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer. AB - Although mortality from colorectal cancer (CRC) is decreasing, CRC is still the second highest cause of cancer-related deaths in America. Chemotherapy and radiation therapy now have central roles in our strategies to fight cancer, although we continue to lack novel strategies overcoming therapeutic resistance. Molecular mechanisms of therapeutic resistance in CRC continue to be under intense investigation. In this review, we highlight the recent evidence linking epithelial-to-mesenchymal transition (EMT) with aggressive tumor biology as well as with the cancer stem cells (CSCs) across multiple organ systems including colon cancer. Furthermore, in the era of neo-adjuvant treatment, the clinical implications are concerning that our treatments may have the potential to induce more aggressive cancer cells through EMT, perhaps even generating CSCs more capable of metastasis and further resistant to treatment. This concern and potential reality highlights the critical need for further understanding the impact of clinical therapy on the pathobiology of cancer and further supports the need to therapeutically target the CSC. Besides serving as potential biomarkers for aggressive tumor biology and therapeutic resistance, EMT and CSC molecular pathways may highlight novel therapeutic targets as strategies for improving the response to conventional anti-neoplastic agents translating into improved oncologic outcomes. PMID- 24787243 TI - Dual redox responsive coassemblies of diselenide-containing block copolymers and polymer lipids. AB - A general approach is reported to fabricate a stimuli responsive system via coassembly of diselenide-containing block copolymers with polymer lipids, which integrates the stimuli-responsiveness of diselenide chemistry and the biocompatibility of polymer lipids. By using dynamic light scattering, transmission electron microscopy, and zeta potential analyzer, coassembly behavior of these two kinds of polymers and responsiveness of coassemblies have been investigated. These coassemblies can exhibit redox-responsiveness inheriting from the diselenide-containing block copolymers. In the presence of low concentration of hydrogen peroxide or glutathione, the coassemblies can be disrupted. PMID- 24787245 TI - Passivation of aluminum nanoparticles by plasma-enhanced chemical vapor deposition for energetic nanomaterials. AB - We have produced passivating coatings on 80-nm aluminum particles by plasma enhanced chemical vapor deposition (PECVD). Three organic precursors--isopropyl alcohol, toluene, and perfluorodecalin--were used to fabricate thin films with thicknesses ranging from 5 nm to 30 nm. The coated samples and one untreated sample were exposed to 85% humidity at 25 degrees C for two months, and the active Al content was determined by thermogravimetric analysis (TGA) in the presence of oxygen. The results were compared with an uncoated sample stored in a glovebox under argon for the same period. We find that all three coatings provide protection against humidity, compared to the control, and their efficacy ranks in the following order: isopropyl alcohol < toluene < perfluorodecalin. This order also correlates with increasing water contact angle of the three solid coatings. The amount of heat released in the oxidation, measured by differential scanning calorimetry (DSC), was found to increase in the same order. Perfluorodecalin resulted in providing the best protection, and it produced the maximum enthalpy of combustion, DeltaH = 4.65 kJ/g. This value is higher than that of uncoated aluminum stored in the glovebox, indicating that the coatings promote more complete oxidation of the core. Overall, we conclude that the plasma polymer coatings of this study are suitable passivating thin film for aluminum nanoparticles by providing protection against oxidation while facilitating the complete oxidation of the metallic core at elevated temperature. PMID- 24787246 TI - Supporting parents and parenting: an overview of data-based papers recently published in contemporary nurse. PMID- 24787244 TI - Cytokine induction of VCAM-1 but not IL13Ralpha2 on glioma cells: a tale of two antibodies. AB - The interleukin-13 receptor alpha2 (IL13Ralpha2) is a cell surface receptor that is over-expressed by a subset of high-grade gliomas, but not expressed at significant levels by normal brain tissue. For both malignant and non-malignant cells, IL13Ralpha2 surface expression is reported to be induced by various cytokines such as IL-4 or IL-13 and tumor necrosis factor (TNF). Our group has developed a therapeutic platform to target IL13Ralpha2-positive brain tumors by engineering human cytotoxic T lymphocytes (CTLs) to express the IL13-zetakine chimeric antigen receptor. We therefore sought to investigate the potential of cytokine stimulation to induce IL13Ralpha2 cell surface expression, and thereby increase susceptibility to IL13Ralpha2-specific T cell killing. In the course of these experiments, we unexpectedly found that the commercially available putative IL13Ralpha2-specific monoclonal antibody B-D13 recognizes cytokine-induced VCAM-1 on glioblastoma. We provide evidence that the induced receptor is not IL13Ralpha2, because its expression does not consistently correlate with IL13Ralpha2 mRNA levels, it does not bind IL-13, and it is not recognized by IL13 zetakine CTL. Instead we demonstrate by immunoprecipitation experiments and mass spectrometry that the antigen recognized by the B-D13 antibody following cytokine stimulation is VCAM-1, and that VCAM-1, but not IL13Ralpha2, is induced on glioma cells by TNF alone or in combination with IL-13 or IL-4. Further evaluation of several commercial B-D13 antibodies revealed that B-D13 is bi-specific, recognizing both IL13Ralpha2 and VCAM-1. This binding is non-overlapping based on soluble receptor competition experiments, and mass spectrometry identifies two distinct heavy and light chain species, providing evidence that the B-D13 reagent is di-clonal. PE-conjugation of the B-D13 antibody appears to disrupt IL13Ralpha2 recognition, while maintaining VCAM-1 specificity. While this work calls into question previous studies that have used the B-D13 antibody to assess IL13Ralpha2 expression, it also suggests that TNF may have significant effects on glioma biology by up-regulating VCAM-1. PMID- 24787247 TI - The Cochrane collaboration - a 20-year celebration. PMID- 24787248 TI - The reality of hospitalisation: stories from family members of their hospital experience for adolescents and young adults living with and dying from cancer. AB - BACKGROUND: Adolescents and Young Adults (AYAs) with cancer are being disadvantaged within the present health care system. Some of the factors identified as leading to this disadvantage include medical issues specific to AYAs with cancer, delay in diagnosis, fragmented services, lack of access to clinical trials and psychosocial life stage issues. OBJECTIVE: A major study investigated the experience that accompanies the stages of diagnosis, treatment, dying and death of an AYA from the perspective of family members. This paper discusses the major theme of the reality of hospitalisation. METHODS: Narrative inquiry was the methodology for this study. The participants were a self-selected purposeful sample of 26 family members. Open-ended interviews were conducted to obtain a story of the experience of having an AYA family member live with and die of cancer. A meta-narrative of the family member's experience was developed by NVivo8. RESULTS: In amongst the mass of data this study produced, a major theme to emerge was the experience 'of the reality of hospitalisation'. Within this theme issues regarding: The place of treatment; the hospital experience; not fitting in; and, confronting illness and death were revealed. CONCLUSION: While on the whole the cancer was treated with state of the art medicine, the experiences of the hospitalisation repeated consistently throughout this narrative reveals a failure to meet the higher order needs specific to adolescents and young adults and their families As a result this cohort were exposed to a landscape which did not facilitate a therapeutic experience, as well as would be expected for children and older adults. PMID- 24787249 TI - Building trust to work with children after a severe traumatic accident. AB - Trust is integral to nursing; yet little is known about how nurses establish trust when working with patients. This grounded theory study explored nurses' perspectives of how to build trust with a child and family in the context of paediatric acute health care. Seven paediatric acute care nurses were asked what they did when they cared for a child admitted to an acute care ward from emergency department or intensive care unit following a severe traumatic accident. Building trust emerged as the basic social process for an effective working relationship between a nurse and family to promote the rehabilitation of the child. This paper argues that building trust is critical to nurses developing a working relationship with both child and family to promote optimal health, and enables nurses to effectively step out and handover the care of the child to the family. PMID- 24787250 TI - Intimate partner violence and women's health and wellbeing: impacts, risk factors and responses. AB - Women have approximately a one in four chance of experiencing intimate partner violence (IPV). Those who do are at increased risk of developing physical and mental health problems including traumatic brain injury, chronic pain, gastrointestinal disorders, depression, post-traumatic stress disorder, and substance-related disorders. Nurses, in whatever situation they work, are therefore highly likely to encounter women who are victims of IPV. This paper explores the prevalence of physical and mental health issues for women with an experience of IPV. Factors that influence a woman's experience of IPV such as culture, remaining in an abusive relationship, and childhood sexual abuse as a risk factor of IPV are also examined. Recommended responses for women with an experience of IPV are discussed. PMID- 24787251 TI - Piloting of an oral health education programme and knowledge test for midwives. AB - Research shows limited emphasis being placed on oral health by midwives in Australia and the need for further education in this area. The study aim was to pilot a midwifery oral health education programme and knowledge test and identify any flaws in its content and design. Twenty-two midwives from an antenatal ward in South-Western Sydney completed the programme and 12 feedback forms/knowledge tests were returned. Data was analysed using descriptive statistics and content analysis. Feedback data showed all midwives appreciated that the programme was available online and self-paced. Most found the programme extremely informative and following completion were more confident in promoting maternal oral health. The mean correct responses in the knowledge test was 79% (SD = 12.3) which suggests most items were suitable for assessing knowledge improvement. However, in three items midwives had low correct responses. Various aspects that could be improved or clarified were identified and suggestions discussed. PMID- 24787252 TI - Differences in the perceptions of self-care, health education barriers and educational needs between diabetes patients and nurses. AB - This study examined the differing perceptions of diabetic patients and their nurses regarding the completion of self-care activities, barriers to participation in diabetes health education, and diabetic patients' educational needs to promote better health care for patients with diabetes in Taiwan. This study employed a cross-sectional survey. The data were collected during 2009. Questionnaires were developed to collect data on a convenience sample of 312 patients with type 2 diabetes and 202 nurses recruited from diabetes clinics in Taiwan. Perceptions of self-care behavior were statistically significantly different between patients and nurses (t = -5.05, P < 0.000). The patients perceived themselves to be more successful at completing self-care tasks whereas nurses perceived patients to be less successful at completing self-care tasks. Nurses perceived patients to experience greater difficulties in diabetes health education (t = 18.36, P < 0.000). Nurses perceived there to be a greater need for health education as compared with patients (t = 9.03, P < 0.000). PMID- 24787253 TI - A narrative inquiry: how do nurses respond to patients' use of humour? AB - In today's healthcare system where technical instruments and test results are used to implement care it is easy to lose the human aspect of nursing. Personal interaction can get lost and nurses sometimes miss humorous attempts made by patients. Humour is a very personal concept, what one person thinks is funny does not necessarily make another person smile, or might even be hurtful. Humour is an important communication tool for patients as it humanises the nurses, creates a bond and opens communication lines. Humour has the potential to change the hospital experience for patients. The aim of this paper is to highlight the importance of humour in the therapeutic relationship between patient and nurse. Semi-structured interviews were held with four registered nurses and narrative inquiry was used to analyse and present the findings because of its ability to capture human interaction and experience. PMID- 24787254 TI - Critical care nurses' perception of nursing error and its causes: a qualitative study. AB - Nurses' perceptions of nursing error could affect their professional practice. The aim of the study was to explore critical care nurses' perceptions of nursing error and its causes. This was a qualitative study in which 12 critical care nurses were recruited through purposive sampling. The data were collected via in depth interviews and analyzed through qualitative content analysis method (Elo & Kyngas, 2008). Nursing error was deemed as an unavoidable issue which consisted of the lack of congruence with standards, doing extra-nursing tasks and giving care against the agreed-upon routines. Five categories emerged as the causes of error: individual reasons, work pressure, caring blindly, the uniqueness of caring environment and the lack of coordination among health care team members. The perception of nursing error is sort of unique; hence, managers should provide support for critical care nurses and pave the way for the prevention of errors. PMID- 24787255 TI - Clinical teaching competence inventory for nursing preceptors: instrument development and testing. AB - The aim of the study was to develop and test the psychometric properties of an instrument which measures clinical teaching competencies of nursing preceptors. It is necessary to investigate what kinds of teaching competencies are required in modern, more student-centered higher education teaching contexts. Nurses need to possess teaching competence to perform the role of preceptor properly. However, empirical studies exploring teaching competence are rare. Psychometric testing was conducted on a sample of 389 clinical nursing preceptors from three hospitals in 2010. Exploratory factor analysis and reliability testing were conducted on the 53-item Clinical Teaching Competencies Scale. Results indicated that principal axis factoring extraction identified four factors through a promax rotation: Student evaluation, goal setting and individual teaching, teaching strategies, and demonstration of organized knowledge. The Cronbach's alpha values for the four factors ranged from 0.82-0.87. The Clinical Teaching Competence Inventory was found to have adequate construct validity and internal consistency of reliability for clinical nursing preceptors to assess clinical teaching behaviors in practice settings. PMID- 24787256 TI - Creativity and power: a qualitative, exploratory study of student learning acquired in a community nursing setting that is applied in future settings. AB - Nursing students undertake clinical placements in a wide range of clinical areas as part of their preparation for professional practice, offering students the opportunity to learn about the clinical context and the work that nurses do. This descriptive study explores the implicit learnings that occur for students in a community nursing placement and whether they transfer the knowledge they gain in the community setting into practice in other settings. Participants in this research study described implicit learning from a community nursing context which they were able to utilise in their current practice. Three major themes emerged. Firstly, participants recognised that power relationships manifest differently in a community based setting. This manifest in a recognition of patient autonomy and a creative approach to enhancing the patient's power. The second, related theme involved the enabling of self-determination through collaborative decision making between nurse and the person receiving care. The third theme was the development of an understanding of self-management which manifest in appropriate referrals and what the participants considered high quality discharge planning. This recognition of practice beyond technical, rationalist manifestations suggests that students grasped the unarticulated, implicit dimensions of the community nurse role through their experiences in a community nursing placement. PMID- 24787257 TI - Do practice nurses have the knowledge to provide diabetes self-management education? AB - PURPOSE: Practice nurses are ideally positioned to provide key aspects of self management education to a large majority of people with diabetes within a primary care setting. However, practice nurses have seldom had comprehensive training in this field and consequently their role may have limitations. A study was designed to determine the diabetes related knowledge levels of practice nurses in a regional/rural setting in Australia. METHODS: A cross-sectional study was undertaken using a questionnaire to identify the knowledge of practice nurses. A convenience sample of PNs (N = 52) was drawn from a Division of General Practice in a regional/rural area of NSW. Data was collected using a 14 item knowledge survey from the National Association of Diabetes Centres. RESULTS: Twenty-nine PNs (55%) responded to the survey; primarily the participants were registered nurses (89.6%), only one had completed a postgraduate qualification in diabetes, although 76% had recently completed one or more short courses in diabetes management. Pathophysiology related knowledge was strong (M = 88%) as was knowledge concerning blood glucose monitoring (87%). Less strong was dietary knowledge (79.5%), although one particular question relating to sources of carbohydrate contributed to the lower score. The weakest knowledge area was medication management, with PNs scoring a mean score of only 54%. CONCLUSION: These findings suggest that PNs have deficits in the knowledge required for DSME and therefore, this must be addressed through targetting continuing professional development. PMID- 24787258 TI - N2E: Envisioning a process to support transition from nurse to educator. AB - Rising health inequities, continuing nursing shortages, and overlooked professional development needs of nurse educators are three important issues facing nursing in Australia. This paper argues for an innovative and proactive strategy that could transform the nurse education workforce into one that is repopulated, reinvigorated and refocused. The problem facing nurse educators, and subsequently affecting nurses' preparation for practice and longevity in the profession, was identified by drawing on findings from the literature, extensive educational experience, and an exploratory study of nurse educators working in universities, colleges and health services. A solution has been devised by drawing together the tenets of critical social theory, transformative learning, communities of practice and social media. Nursing educators, refocused around a social justice agenda, may be the remedy that the Australian Health Care System requires to embark on effective action that can benefit everyone, from the health service staff to our most vulnerable groups in society. This refocusing can be achieved in a structured and strategic process that builds confidence and professional capabilities. PMID- 24787259 TI - Home is where I want to die: Kelly's journey. AB - The definition of a 'good death' is centred on being peaceful, dignified and pain free. The preferred place of death has also been highlighted as an important concept in defining a good death (Cox, Almack, Pollack, & Seymour, 2011). Seventy percent of Australians express the desire to spend their last days at home. In reality only 16% of people die at home (Preferred Place of Death, 2008). With 10% of Australians dying in residential aged care facilities and approximately 20% in hospices, the rest die in hospitals (Parish et al., 2006). Family support and the family's care giving ability play a major role in determining whether a person is able to die at home. Other factors include the availability of medical and nursing care. This story has been written with the consent of Kelly's husband. All efforts have been made to maintain privacy and confidentiality: Pseudonyms have been used. PMID- 24787260 TI - Providing culturally congruent care for Saudi patients and their families. AB - This article aims to increase an awareness of caring for Saudi families by non Saudi nurses to improve their understanding of culturally competent care from a Saudi perspective. Healthcare providers have a duty of a care to deliver holistic and culturally specific health care to their patients. As a consequence of 'duty of care' obligations, healthcare providers must facilitate culturally congruent care for patients of diverse cultural backgrounds. For the Saudi family considerable cultural clashes may arise when Saudi patients are hospitalized and receive care from healthcare professionals who do not understand Islamic principles and Saudi cultural beliefs and values. The healthcare workforce in Saudi Arabia is a unique multicultural workforce that is mix of Saudi and significant other nationalities. Saudi nurses for example represent only 36.3% of the workforce in the different health sectors. Whilst the different ethnic and cultural background expatriate nurses represent 63.7% (Ministry of Health, 2010). This article also could increase the awareness of healthcare professionals caring for Arab and Muslims patients in another context in the world. PMID- 24787261 TI - Older Arab migrants in Australia: between the hammer of prejudice and the anvil of social isolation. PMID- 24787262 TI - Single rapamycin administration induces prolonged downward shift in defended body weight in rats. AB - Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy. PMID- 24787264 TI - Quantum spin ice: a search for gapless quantum spin liquids in pyrochlore magnets. AB - The spin ice materials, including Ho2Ti2O7 and Dy2Ti2O7, are rare-earth pyrochlore magnets which, at low temperatures, enter a constrained paramagnetic state with an emergent gauge freedom. Spin ices provide one of very few experimentally realized examples of fractionalization because their elementary excitations can be regarded as magnetic monopoles and, over some temperature range, spin ice materials are best described as liquids of these emergent charges. In the presence of quantum fluctuations, one can obtain, in principle, a quantum spin liquid descended from the classical spin ice state characterized by emergent photon-like excitations. Whereas in classical spin ices the excitations are akin to electrostatic charges with a mutual Coulomb interaction, in the quantum spin liquid these charges interact through a dynamic and emergent electromagnetic field. In this review, we describe the latest developments in the study of such a quantum spin ice, focusing on the spin liquid phenomenology and the kinds of materials where such a phase might be found. PMID- 24787265 TI - Distinct expression patterns of alveolar "alarmins" in subtypes of chronic lung allograft dysfunction. AB - The long-term success of lung transplantation is limited by chronic lung allograft dysfunction (CLAD). The purpose of this study was to investigate the alveolar alarmin profiles in CLAD subtypes, restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). Bronchoalveolar lavage (BAL) samples were collected from 53 recipients who underwent double lung or heart-lung transplantation, including patients with RAS (n = 10), BOS (n = 18) and No CLAD (n = 25). Protein levels of alarmins such as S100A8, S100A9, S100A8/A9, S100A12, S100P, high-mobility group box 1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in BAL fluid were measured. RAS and BOS showed higher expressions of S100A8, S100A8/A9 and S100A12 compared with No CLAD (p < 0.0001, p < 0.0001, p < 0.0001 in RAS vs. No CLAD, p = 0.0006, p = 0.0044, p = 0.0086 in BOS vs. No CLAD, respectively). Moreover, RAS showed greater up regulation of S100A9, S100A8/A9, S100A12, S100P and HMGB1 compared with BOS (p = 0.0094, p = 0.038, p = 0.041, p = 0.035 and p = 0.010, respectively). sRAGE did not show significant difference among the three groups (p = 0.174). Our results demonstrate distinct expression patterns of alveolar alarmins in RAS and BOS, suggesting that RAS and BOS may represent biologically different subtypes. Further refinements in biologic profiling will lead to a better understanding of CLAD. PMID- 24787263 TI - Language Production in Children With and At Risk for Delay: Mediating Role of Parenting Skills. AB - The current study examined the effect of Parent-Child Interaction Therapy (PCIT), a parent-training intervention for child behavior problems, on child language production. Participants were 46 children (ages 20-70 months) with externalizing behavior problems and with or at risk for developmental delay. Parent-child dyads were randomly assigned to a waitlist control or immediate treatment group. Parenting skills learned during PCIT (i.e., "do skills") and children's word tokens and word types were measured at baseline and 4 months later. Findings suggest an indirect effect of parent do skills on the relation between group and child word types, such that more parent do skills predicted more child word types for families receiving PCIT. The present study found that mothers' use of child directed skills played an important role in the growth and improvement of child language. Results suggest that parent-training interventions targeting child behavior problems may also foster child language production. PMID- 24787266 TI - Ischemic preconditioning provides no additive clinical value in liver resection of cirrhotic and non-cirrhotic patients under portal triad clamping: a prospective randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: The clinical value of ischemic preconditioning (IP) on patients undergoing hepatectomy under portal triad clamping (PTC) is uncertain, especially for patients with liver cirrhosis. Hence, we conducted a prospective randomized controlled trial to test whether IP could protect liver against ischemic reperfusion (IR) injury after hepatectomy under PTC. METHOD: One hundred patients, including 67 with cirrhosis, undergoing hepatectomy with PTC were randomly divided into IP and control groups. Liver function tests at postoperative days 1, 3, and 7 as well as postoperative morbidity, mortality, and duration of hospitalization were compared between the two groups. RESULTS: The general clinical characteristics between both groups were comparable. The duration of the operation, the amount of intraoperative blood loss, and the need and amount of perioperative blood transfusion were similar in both groups. The postoperative levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and albumin were not statistically different between the two groups. In addition, the morbidity and mortality rates and the duration of hospitalization were similar in both groups. CONCLUSIONS: IP did not improve liver tolerance to IR injury after hepatectomy under PTC. Therefore, the clinical use of IP cannot be recommended as a standard procedure before PTC. PMID- 24787267 TI - Diastereoselective synthesis of dihydroisoindolo[2,1-a]quinolin-11-ones by solvent-free AMCell-SO3H-catalyzed imino Diels-Alder/intramolecular amide cyclization cascade reactions. AB - Nineteen bioactive highly functionalized 6,6a-dihydroisoindolo[2,1-a]quinolin 11(5H)-one derivatives were easily prepared in good yield without solvent using catalytic amorphous milled cellulose sulfonic acid (AMCell-SO3H), substituted anilines, propenyl-phenols, and phthaldehydic acid. The cascade reaction gave high regioselectivity and diastereoselectivity. PMID- 24787268 TI - Response to: 'pelvic floor reconstruction with a biological mesh after extralevator abdominoperineal excision leads to few perineal hernias and acceptable wound complication rates with minor movement limitations'. PMID- 24787269 TI - Phenolic lipids affect the activity and conformation of acetylcholinesterase from Electrophorus electricus (Electric eel). AB - Phenolic lipids were isolated from rye grains, cashew nutshell liquid (CNSL) from Anacardium occidentale, and fruit bodies of Merrulius tremellosus, and their effects on the electric eel acetylcholinesterase activity and conformation were studied. The observed effect distinctly depended on the chemical structure of the phenolic lipids that were available for interaction with the enzyme. All of the tested compounds reduced the activity of acetylcholinesterase. The degree of inhibition varied, showing a correlation with changes in the conformation of the enzyme tested by the intrinsic fluorescence of the Trp residues of the protein. PMID- 24787270 TI - Hypoxic ischemic encephalopathy in a case of intranuclear rod myopathy without any prenatal sentinel event. AB - Intranuclear rod myopathy (IRM), a variant of nemaline myopathy, is characterized by the presence of nemaline bodies in myonuclei. We report a case of IRM presenting with hypoxic ischemic encephalopathy (HIE). There were no prenatal complications caused by fetal brain injury. Although no nemaline bodies were observed in the cytoplasm, intranuclear rods were observed in some fibers under light and electron microscopy. Molecular analysis identified a heterozygous variant, c.449C>T (p.Thr150Ile), in ACTA1. On magnetic resonance imaging at 9days of age, injuries to the basal ganglia, thalamus, and brainstem consistent with perinatal HIE were seen. Respiratory insufficiency at birth was strongly suspected to be the cause of HIE. Our case highlights that a patient with a congenital neuromuscular disorder who presents with severe respiratory dysfunction requiring substantial resuscitative efforts at birth can be complicated by HIE without any prenatal sentinel event. Prenatal detection of neuromuscular disorders, careful management of delivery, and neonatal resuscitation and adequate respiratory management are important in preventing irreversible brain injury in these patients. PMID- 24787271 TI - Prognostic factors for acute encephalopathy with bright tree appearance. AB - OBJECTIVE: To determine the prognostic factors for encephalopathy with bright tree appearance (BTA) in the acute phase through retrospective case evaluation. METHODS: We recruited 10 children with encephalopathy who presented with BTA and classified them into 2 groups. Six patients with evident regression and severe psychomotor developmental delay after encephalopathy were included in the severe group, while the remaining 4 patients with mild mental retardation were included in the mild group. We retrospectively analyzed their clinical symptoms, laboratory data, and magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings. RESULTS: Patients in the severe group developed subsequent complications such as epilepsy and severe motor impairment. Univariate analysis revealed that higher maximum lactate dehydrogenase (LDH) levels (p=0.055) were a weak predictor of poor outcome. Maximum creatinine levels were significantly higher (p<0.05) and minimal platelet counts were significantly lower (p<0.05) in the severe group than in the mild group. Acute renal failure was not observed in any patient throughout the study. MRS of the BTA lesion during the BTA period showed elevated lactate levels in 5 children in the severe group and 1 child in the mild group. MRI performed during the chronic phase revealed severe brain atrophy in all patients in the severe group. CONCLUSIONS: Higher creatinine and LDH levels and lower platelet counts in the acute phase correlated with poor prognosis. Increased lactate levels in the BTA lesion during the BTA period on MRS may predict severe physical and mental disability. PMID- 24787272 TI - Chemodiversity of dissolved organic matter in lakes driven by climate and hydrology. AB - Despite the small continental coverage of lakes, they are hotspots of carbon cycling, largely due to the processing of terrestrially derived dissolved organic matter (DOM). As DOM is an amalgam of heterogeneous compounds comprising gradients of microbial and physicochemical reactivity, the factors influencing DOM processing at the molecular level and the resulting patterns in DOM composition are not well understood. Here we show, using ultrahigh-resolution mass spectrometry to unambiguously identify 4,032 molecular formulae in 120 lakes across Sweden, that the molecular composition of DOM is shaped by precipitation, water residence time and temperature. Terrestrially derived DOM is selectively lost as residence time increases, with warmer temperatures enhancing the production of nitrogen-containing compounds. Using biodiversity concepts, we show that the molecular diversity of DOM, or chemodiversity, increases with DOM and nutrient concentrations. The observed molecular-level patterns indicate that terrestrially derived DOM will become more prevalent in lakes as climate gets wetter. PMID- 24787273 TI - Orientational time correlation functions for vibrational sum-frequency generation. 2. Propionitrile. AB - Molecular dynamics (MD) simulations of propionitrile have been performed to assess the influence of reorientation on vibrational sum-frequency-generation (VSFG) spectra at the liquid/vapor (LV) and liquid/silica (LS) interfaces. Orientational time-correlation functions (TCFs) are derived for the VSFG spectroscopy of the symmetric and asymmetric stretches of functional groups such as methylene groups and rotationally hindered methyl groups. The MD simulations are used to compute VSFG orientational TCFs for the methyl, methylene, and cyanide groups of propionitrile at the LV and LS interfaces. Although propionitrile exhibits relatively fast reorientation in the bulk liquid, we find that for symmetric stretching modes at these interfaces, reorientation only plays a significant role in VSFG spectra under SPS polarization conditions. For asymmetric stretches, reorientation affects the VSFG spectra significantly under all polarization conditions. Azimuthal dynamics tend to dominate the orientational TCFs. PMID- 24787275 TI - A systematic description of MLL fusion gene formation. AB - Rearrangements of the MLL gene involve multiple partners and are implicated in both therapy related acute leukemia [tAL] and infant acute leukemia. For these diseases, recently compiled clinical data confirms an elevated frequency of such breakpoints within a 4 kb tract between exon 11 and a region of structural instability adjacent to exon 12. Linked primarily to cases of tAL, interference with topoisomerase II activity may either contribute to the initial DNA lesion directly or indirectly by, for example, providing a physical block to transcription progression. Alternatively, sites of fragmentation may be mis repaired, guided by intergenic spliced transcripts of the participating genes. Co transcription of MLL and potential fusion partners may provide the localization that enhances the probability of gene interaction. An indirect role for the leukemogenic activity of topoisomerase II inhibitors would imply that the negative consequences of their use may be separated from their therapeutic effects. PMID- 24787274 TI - Establishment and maintenance of a PBMC repository for functional cellular studies in support of clinical vaccine trials. AB - A large repository of cryopreserved peripheral blood mononuclear cells (PBMCs) samples was created to provide laboratories testing the specimens from human immunodeficiency virus-1 (HIV-1) vaccine clinical trials the material for assay development, optimization, and validation. One hundred thirty-one PBMC samples were collected using leukapheresis procedure between 2007 and 2013 by the Comprehensive T cell Vaccine Immune Monitoring Consortium core repository. The donors included 83 human immunodeficiency virus-1 (HIV-1) seronegative and 32 HIV 1 seropositive subjects. The samples were extensively characterized for the ability of T cell subsets to respond to recall viral antigens including cytomegalovirus, Epstein-Barr virus, influenza virus, and HIV-1 using Interferon gamma (IFN-gamma) enzyme linked immunospot (ELISpot) and IFN-gamma/interleukin 2 (IL-2) intracellular cytokine staining (ICS) assays. A subset of samples was evaluated over time to determine the integrity of the cryopreserved samples in relation to recovery, viability, and functionality. The principal results of our study demonstrate that viable and functional cells were consistently recovered from the cryopreserved samples. Therefore, we determined that this repository of large size cryopreserved cellular samples constitutes a unique resource for laboratories that are involved in optimization and validation of assays to evaluate T, B, and NK cellular functions in the context of clinical trials. PMID- 24787276 TI - Pacemakers at the elective replacement indicator with a normal magnet rate on transtelephonic monitoring. PMID- 24787277 TI - Heat-related morbidity in brisbane, australia: spatial variation and area-level predictors. AB - BACKGROUND: Extreme heat is a leading weather-related cause of illness and death in many locations across the globe, including subtropical Australia. The possibility of increasingly frequent and severe heat waves warrants continued efforts to reduce this health burden, which could be accomplished by targeting intervention measures toward the most vulnerable communities. OBJECTIVES: We sought to quantify spatial variability in heat-related morbidity in Brisbane, Australia, to highlight regions of the city with the greatest risk. We also aimed to find area-level social and environmental determinants of high risk within Brisbane. METHODS: We used a series of hierarchical Bayesian models to examine city-wide and intracity associations between temperature and morbidity using a 2007-2011 time series of geographically referenced hospital admissions data. The models accounted for long-term time trends, seasonality, and day of week and holiday effects. RESULTS: On average, a 10 degrees C increase in daily maximum temperature during the summer was associated with a 7.2% increase in hospital admissions (95% CI: 4.7, 9.8%) on the following day. Positive statistically significant relationships between admissions and temperature were found for 16 of the city's 158 areas; negative relationships were found for 5 areas. High-risk areas were associated with a lack of high income earners and higher population density. CONCLUSIONS: Geographically targeted public health strategies for extreme heat may be effective in Brisbane, because morbidity risk was found to be spatially variable. Emergency responders, health officials, and city planners could focus on short- and long-term intervention measures that reach communities in the city with lower incomes and higher population densities, including reduction of urban heat island effects. PMID- 24787278 TI - The effects of sex, tissue type, and dietary components on stable isotope discrimination factors (Delta13C and Delta15N) in mammalian omnivores. AB - We tested the effects of sex, tissue, and diet on stable isotope discrimination factors (Delta(13)C and Delta(15)N) for six tissues from rats fed four diets with varied C and N sources, but comparable protein quality and quantity. The Delta(13)C and Delta(15)N values ranged from 1.7-4.10/00 and 0.4-4.30/00, respectively. Females had higher Delta(15)N values than males because males grew larger, whereas Delta(13)C values did not differ between sexes. Differences in Delta(13)C values among tissue types increased with increasing variability in dietary carbon sources. The Delta(15)N values increased with increasing dietary delta(15)N values for all tissues except liver and serum, which have fast stable isotope turnover times, and differences in Delta(15)N values among tissue types decreased with increasing dietary animal protein. Our results demonstrate that variability in dietary sources can affect Delta(13)C values, protein source affects Delta(15)N values even when protein quality and quantity are controlled, and the isotope turnover rate of a tissue can influence the degree to which diet affects Delta(15)N values. PMID- 24787279 TI - Metabolomic shifts in Brassica napus lines with enhanced BnPLC2 expression impact their response to low temperature stress and plant pathogens. AB - Phosphatidylinositol-specific phospholipase C2 (PLC2) is a signaling enzyme with hydrolytic activity against membrane-bound phosphoinositides. It catalyzes the cleavage of phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P 2) into two initial second messengers, myo-inositol-1,4,5-trisphosphate (InsP 3) and diacylglycerol (DAG). The former, as well as its fully phosphorylated derivative, myo-inositol-1,2,3,4,5,6-hexakisphosphate (InsP 6), play a major role in calcium signaling events within the cell, while DAG may be used in the regeneration of phospholipids or as a precursor for phosphatidic acid (PA) biosynthesis, an important signaling molecule involved in both biotic and abiotic types of stress tolerance. Overexpression of the gene for Brassica napus phospholipase C2 (BnPLC2) in Brassica napus has been shown to enhance drought tolerance, modulate multiple genes involved in different processes and favorably affect hormonal levels in different tissues. We, therefore, undertook the current study with a view to examining, at the metabolome level, its effect on both abiotic (low temperature) and biotic (stem white rot disease) types of stress in canola. Thus, while transgenic plants exhibited a significant rise in maltose levels and a concomitant elevation in some unsaturated free fatty acids (FFAs), glycerol, and glycerol 3-phosphate under subzero temperatures, they accumulated high levels of raffinose, stachyose and other sugars as well as some flavonoids under acclimatization conditions. Collectively, overexpression of BnPLC2 appears to have triggered different metabolite patterns consistent with its abiotic and, to a limited extent, biotic stress tolerance phenotypes. PMID- 24787280 TI - Pressure-volume curves: revisiting the impact of negative turgor during cell collapse by literature review and simulations of cell micromechanics. AB - The Scholander-Hammel pressure chamber has been used in thousands of papers to measure osmotic pressure, pic , turgor pressure, Pt , and bulk modulus of elasticity, epsilon, of leaf cells by pressure-volume (PV) curve analysis. PV analysis has been questioned in the past. In this paper we use micromechanical analysis of leaf cells to examine the impact on PV curve analysis of negative turgor in living cells (Pt ). Models predict negative Pt (-0.1 to -1.8 MPa) depending on leaf cell size and shape in agreement with experimental values reported by J. J. Oertli. Modeled PV curves have linear regions even when Pt is quite negative, contrary to the arguments of M.T. Tyree. Negative Pt is totally missed by PV curve analysis and results in large errors in derived pic and Pt but smaller errors in epsilon. A survey of leaf cell sizes vs habitat (arid, temperate, and rainforest), suggests that the majority of published PV curves result in errors of 0.1-1.8 MPa in derived pic and Pt , whereby the error increases with decreasing cell size. We propose that small cell size in leaves is an ecological adaptation that permits plants to endure negative values of water potential with relatively little water loss. PMID- 24787281 TI - Long-term changes in the fish assemblage of a neotropical hydroelectric reservoir. AB - The changes in the fish assemblage of the Capivara Reservoir, Brazil, were assessed over a 20 year period. Of 50 native fishes present in the initial samples, 27 were no longer present in the final samples, but there had been an addition of 11 invasive fishes, suggesting the occurrence of substantial shifts in fish diversity and abundance. PMID- 24787282 TI - Enhanced photocatalytic removal of sodium pentachlorophenate with self-doped Bi2WO6 under visible light by generating more superoxide ions. AB - In this study, we demonstrate that the photocatalytic sodium pentachlorophenate removal efficiency of Bi2WO6 under visible light can be greatly enhanced by bismuth self-doping through a simple soft-chemical method. Density functional theory calculations and systematical characterization results revealed that bismuth self-doping did not change the redox power of photogenerated carriers but promoted the separation and transfer of photogenerated electron-hole pairs of Bi2WO6 to produce more superoxide ions, which were confirmed by photocurrent generation and electron spin resonance spectra as well as superoxide ion measurement results. We employed gas chromatography-mass spectrometry and total organic carbon analysis to probe the degradation and the mineralization processes. It was found that more superoxide ions promoted the dechlorination process to favor the subsequent benzene ring cleavage and the final mineralization of sodium pentachlorophenate during bismuth self-doped Bi2WO6 photocatalysis by producing easily decomposable quinone intermediates. This study provides new insight into the effects of photogenerated reactive species on the degradation of sodium pentachlorophenate and also sheds light on the design of highly efficient visible-light-driven photocatalysts for chlorophenol pollutant removal. PMID- 24787283 TI - Controlling carbon nanotube photoluminescence using silicon microring resonators. AB - We report on coupling between semiconducting single-wall carbon nanotubes (s SWNT) photoluminescence and silicon microring resonators. Polyfluorene extracted s-SWNT deposited on such resonators exhibit sharp emission peaks, due to interaction with the cavity modes of the microring resonators. Ring resonators with radius of 5 MUm and 10 MUm were used, reaching quality factors up to 4000 in emission. These are among the highest values reported for carbon nanotubes coupled with an integrated cavity on silicon platform, which open up the possibility to build s-SWNT based efficient light source on silicon. PMID- 24787284 TI - The prognostic role of various indices and ratios of Doppler velocimetry in patients with pre-eclampsia. AB - Doppler velocimetry is a non-invasive method to monitor pregnancies complicated by pre-eclampsia. We aimed to assess the predictive value of adverse perinatal or maternal outcome of three ratios, i.e. middle cerebral to umbilical arteries pulsatility indices (PI), middle cerebral to uterine arteries PI and uterine to umbilical arteries PI, compared with that of uterine and umbilical arteries PI in pre-eclamptic patients. This is a cohort study on 168 singleton pregnancies between January 2010 and June 2013. Doppler velocimetry was performed at the diagnosis of pre-eclampsia. Logistic regression analysis was performed and receiver-operating characteristics (ROC) curves were calculated to determine the predictive ability of each Doppler index. Multivariate analysis was run to adjust results for confounding parameters. Seventy-eight cases were complicated by adverse perinatal outcome, 79 by maternal one, 49 by both. Considering perinatal outcome, area under ROC curve was 0.730 for uterine arteries PI, 0.691 for umbilical artery PI and 0.834 for middle cerebral to uterine arteries PI ratio, while for maternal one 0.720 for uterine arteries PI, 0.686 for umbilical artery PI and 0.817 for middle cerebral to uterine arteries PI ratio. At multivariate analysis, only middle cerebral to uterine arteries PI ratio remain statistically significant for both outcomes (p = 0.001). The cited ratio appeared more accurate than all other considered indices in predicting perinatal and maternal outcomes in patients affected by pre-eclampsia. PMID- 24787285 TI - Biocomputional construction of a gene network under acid stress in Synechocystis sp. PCC 6803. AB - Acid stress is one of the most serious threats that cyanobacteria have to face, and it has an impact at all levels from genome to phenotype. However, very little is known about the detailed response mechanism to acid stress in this species. We present here a general analysis of the gene regulatory network of Synechocystis sp. PCC 6803 in response to acid stress using comparative genome analysis and biocomputational prediction. In this study, we collected 85 genes and used them as an initial template to predict new genes through co-regulation, protein protein interactions and the phylogenetic profile, and 179 new genes were obtained to form a complete template. In addition, we found that 11 enriched pathways such as glycolysis are closely related to the acid stress response. Finally, we constructed a regulatory network for the intricate relationship of these genes and summarize the key steps in response to acid stress. This is the first time a bioinformatic approach has been taken systematically to gene interactions in cyanobacteria and the elaboration of their cell metabolism and regulatory pathways under acid stress, which is more efficient than a traditional experimental study. The results also provide theoretical support for similar research into environmental stresses in cyanobacteria and possible industrial applications. PMID- 24787286 TI - Tofogliflozin: the road goes ever on. AB - Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but few patients achieve and maintain glycaemic control without weight gain and hypoglycaemias. Sodium glucose co-transporter 2 (SGLT-2) inhibitors are an emerging class of drugs with an original mechanism of action involving inhibition of renal glucose reabsorption. Two agents of this class, dapagliflozin and canagliflozin, have already been approved, although we need more data on cardiovascular outcomes along with bladder and breast cancer. Tofogliflozin is a further SGLT-2 inhibitor, which exhibits the highest selectivity for SGLT-2, the most potent antidiabetic action and a reduced risk of hypoglycaemia. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has shown that tofogliflozin exhibits adequate safety and efficacy as monotherapy or as add-on treatment in patients suboptimally controlled with oral agents. Despite the very promising characteristics of this new drug, important questions remain to be answered, mainly additional data on safety outcomes and potential beneficial effects of tofogliflozin, for instance in prediabetes and diabetic nephropathy. Moreover, it would be welcome to examine the utility of its therapeutic use in combination with insulin and metformin. PMID- 24787287 TI - Losing sight of our primary target: curing cancer. PMID- 24787288 TI - Tumor microenvironment: introduction. PMID- 24787289 TI - Animal models and the tumor microenvironment: studies of tumor-host symbiosis. AB - The contributions of murine models to elucidation of processes central to tumor growth are reviewed. Localized acidosis, increased interstitial pressure, perturbations in structure and function of the extracellular matrix, hypoxia, angiogenesis, and co-optation of the immune response are all phenomena that promote tumor survival and metastasis. The use of animal models is critical to understanding the pathophysiology of these processes and the development of more effective cancer therapies. PMID- 24787291 TI - Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. AB - Immune evasion is a hallmark of cancer. While there are multiple different mechanisms that cancer cells employ, myeloid-derived suppressor cells (MDSCs) are one of the key drivers of tumor-mediated immune evasion. MDSCs begin as myeloid cells recruited to the tumor microenvironment, where they are transformed into potent immunosuppressive cells. However, our understanding of the clinical relevance of MDSCs in cancer patients has significantly lagged behind the preclinical literature in part due to the absence of a cognate molecule present in mice, as well as to the considerable heterogeneity of MDSCs. However, if one evaluates the clinical literature through the filter of clinically robust endpoints, such as overall survival, three important phenotypes emerge: promyelocytic, monocytic, and granulocytic. Based on these studies, MDSCs have clear prognostic importance in multiple solid tumors, and emerging data support the utility of circulating MDSCs as a predictive marker for cancer immunotherapy, and even as an early leading marker for predicting clinical response to systemic chemotherapy in patients with advanced solid tumors. More recent preclinical data in immunosuppressed murine models suggest that MDSCs play an important role in tumor progression and the metastatic process that is independent of their immunosuppressive properties. Consequently, targeting MDSCs either in combination with cancer immunotherapy or independently as part of an approach to inhibit the metastatic process appears to be a very clinically promising strategy. We review different approaches to target MDSCs that could potentially be tested in future clinical trials in cancer patients. PMID- 24787292 TI - Macro- and micro-environmental factors in clinical hepatocellular cancer. AB - We previously developed a network phenotyping strategy (NPS), a graph theory based transformation of clinical practice data, for recognition of two primary subgroups of hepatocellular cancer (HCC), called S and L, which differed significantly in their tumor masses. In the current study, we have independently validated this result on 641 HCC patients from another continent. We identified the same HCC subgroups with mean tumor masses 9 cm x n (S) and 22 cm x n (L), P<10(-14). The means of survival distribution (not available previously) for this new cohort were also significantly different (S was 12 months, L was 7 months, P<10(-5)). We characterized nine unique reference patterns of interactions between tumor and clinical environment factors, identifying four subtypes for S and five subtypes for L phenotypes, respectively. In L phenotype, all reference patterns were portal vein thrombosis (PVT)-positive, all platelet/alpha fetoprotein (AFP) levels were high, and all were chronic alcohol consumers. L had phenotype landmarks with worst survival. S phenotype interaction patterns were PVT-negative, with low platelet/AFP levels. We demonstrated that tumor-clinical environment interaction patterns explained how a given parameter level can have a different significance within a different overall context. Thus, baseline bilirubin is low in S1 and S4, but high in S2 and S3, yet all are S subtype patterns, with better prognosis than in L. Gender and age, representing macro environmental factors, and bilirubin, prothrombin time, and AST levels representing micro-environmental factors, had a major impact on subtype characterization. Clinically important HCC phenotypes are therefore represented by complete parameter relationship patterns and cannot be replaced by individual parameter levels. PMID- 24787293 TI - Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. AB - Metabolic synergy or metabolic coupling between glycolytic stromal cells (Warburg effect) and oxidative cancer cells occurs in human breast cancers and promotes tumor growth. The Warburg effect or aerobic glycolysis is the catabolism of glucose to lactate to obtain adenosine triphosphate (ATP). This review summarizes the main findings on this stromal metabolic phenotype, and the associated signaling pathways, as well as the critical role of oxidative stress and autophagy, all of which promote carcinoma cell mitochondrial metabolism and tumor growth. Loss of Caveolin 1 (Cav-1) and the upregulation of monocarboxylate transporter 4 (MCT4) in stromal cells are novel markers of the Warburg effect and metabolic synergy between stromal and carcinoma cells. MCT4 and Cav-1 are also breast cancer prognostic biomarkers. Reactive oxygen species (ROS) are key mediators of the stromal Warburg effect. High ROS also favors cancer cell mitochondrial metabolism and tumorigenesis, and anti-oxidants can reverse this altered stromal and carcinoma metabolism. A pseudo-hypoxic state with glycolysis and low mitochondrial metabolism in the absence of hypoxia is a common feature in breast cancer. High ROS induces loss of Cav-1 in stromal cells and is sufficient to generate a pseudo-hypoxic state. Loss of Cav-1 in the stroma drives glycolysis and lactate extrusion via HIF-1alpha stabilization and the upregulation of MCT4. Stromal cells with loss of Cav-1 and/or high expression of MCT4 also show a catabolic phenotype, with enhanced macroautophagy. This catabolic state in stromal cells is driven by hypoxia-inducible factor (HIF)-1alpha, nuclear factor kappaB (NFkappaB), and JNK activation and high ROS generation. A feed-forward loop in stromal cells regulates pseudo-hypoxia and metabolic synergy, with Cav-1, MCT4, HIF-1alpha, NFkappaB, and ROS as its key elements. Metabolic synergy also may occur between cancer cells and cells in distant organs from the tumor. Cancer cachexia, which is due to severe organismal metabolic dysregulation in myocytes and adipocytes, shares similarities with stromal-carcinoma metabolic synergy, as well. In summary, metabolic synergy occurs when breast carcinoma cells induce a nutrient-rich microenvironment to promote tumor growth. The process of tumor metabolic synergy is a multistep process, due to the generation of ROS, and the induction of catabolism with autophagy, mitophagy and glycolysis. Studying epithelial-stromal interactions and metabolic synergy is important to better understand the ecology of cancer and the metabolic role of different cell types in tumor progression. PMID- 24787290 TI - Interferons and their stimulated genes in the tumor microenvironment. AB - Constitutive expression of interferons (IFNs) and activation of their signaling pathways have pivotal roles in host responses to malignant cells in the tumor microenvironment. IFNs are induced by the innate immune system and in tumors through stimulation of Toll-like receptors (TLRs) and through other signaling pathways in response to specific cytokines. Although in the oncologic context IFNs have been thought of more as exogenous pharmaceuticals, the autocrine and paracrine actions of endogenous IFNs probably have even more critical effects on neoplastic disease outcomes. Through high-affinity cell surface receptors, IFNs modulate transcriptional signaling, leading to regulation of more than 2,000 genes with varying patterns of temporal expression. Induction of the gene products by both unphosphorylated and phosphorylated STAT1 after ligand binding results in alterations in tumor cell survival, inhibition of angiogenesis, and augmentation of actions of T, natural killer (NK), and dendritic cells. The interferon-stimulated gene (ISG) signature can be a favorable biomarker of immune response but, in a seemingly paradoxical finding, a specific subset of the full ISG signature indicates an unfavorable response to DNA-damaging interventions such as radiation. IFNs in the tumor microenvironment thus can alter the emergence, progression, and regression of malignancies. PMID- 24787294 TI - Tumor microenvironment in head and neck squamous cell carcinoma. AB - The tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC) is comprised of cancer-associated fibroblasts (CAFs), immune cells, and other supporting cells. Genetic changes in the carcinoma cells, such as alterations to TP53, NOTCH1, and specific gene expression profiles, contribute to derangements in cancer and microenvironment cells such as increased ROS, overproduction of cytokines, and epithelial to mesenchymal transition (EMT). CAFs are among the most critical elements of the TME contributing to proliferation, invasion, and metastasis. The adaptive immune response is suppressed in HNSCC through overexpression of cytokines, triggered apoptosis of T cells, and alterations in antigen processing machinery. Overexpression of critical cytokines, such as transforming growth factor-beta (TGF-beta), contributes to EMT, immune suppression, and evolution of CAFs. Inflammation and hypoxia are driving forces in angiogenesis and altered metabolism. HNSCC utilizes glycolytic and oxidative metabolism to fuel tumorigenesis via coupled mechanisms between cancer cell regions and cells of the TME. Increased understanding of the TME in HNSCC illustrates that the long-held notion of "condemned mucosa" reflects a process that extends beyond the epithelial cells to the entire tissue comprised of each of these elements. PMID- 24787295 TI - Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond. AB - Our understanding of the dynamic tumor microenvironment (TME) has improved exponentially over the last few decades. In addition to traditional cytotoxic agents, anti-cancer strategies now include numerous molecular-targeted drugs that modulate distinct elements of the TME. Angiogenesis is an underlying promoter of tumor growth, invasion, and metastases. From traditional and emerging angiogenic cytokines and their receptors to novel immune checkpoint inhibitors, regulation of the tumor microenvironment is potentially key in countering tumor progression. In this article, an overview of the architecture of the TME and the orchestration of angiogenesis within the TME is provided. Additionally, traditional and novel angiogenic targets of current interest within the TME are reviewed. PMID- 24787296 TI - Association of abnormal plasma bilirubin with aggressive hepatocellular carcinoma phenotype. AB - Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness. PMID- 24787298 TI - Tumor microenvironment and metabolism in prostate cancer. AB - Prostate cancer is no longer viewed mostly as a disease of abnormally proliferating epithelial cells, but rather as a disease affecting the complex interactions between the cells of the prostate epithelial compartment and the surrounding stromal compartment in which they live. Indeed, the microenvironment in which tumor cells evolve towards an aggressive phenotype is highly heterogeneous, as it is composed of different cell populations such as endothelial cells, fibroblasts, macrophages, and lymphocytes, either resident or trans-differentiated by bone marrow-derived mesenchymal stem cells recruited at the tumor site. Cancer-associated fibroblasts, the most abundant population within this microenvironment, exert a mandatory role in prostate cancer progression as they metabolically sustain cancer cell survival and growth, recruit inflammatory and immune cells, and promote cancer cells stemness and epithelial mesenchymal transition, thereby favoring metastatic dissemination of aggressive cancers. The interruption of this two-compartment crosstalk, together with the idea that stromal cells are mostly vulnerable, being drug-sensitive, could lead to the development of anticancer therapies that target tumor stromal elements. PMID- 24787297 TI - Melanoma tumor cell heterogeneity: a molecular approach to study subpopulations expressing the embryonic morphogen nodal. AB - As the frequency of melanoma increases, current treatment strategies are struggling to significantly impact patient survival. One of the critical issues in designing efficient therapies is understanding the composition of heterogeneous melanoma tumors in order to target cancer stem cells (CSCs) and drug-resistant subpopulations. In this review, we summarize recent findings pertinent to the reemergence of the embryonic Nodal signaling pathway in melanoma and its significance as a prognostic biomarker and therapeutic target. In addition, we offer a novel molecular approach to studying the functional relevance of Nodal-expressing subpopulations and their CSC phenotype. PMID- 24787300 TI - T2 muscle-invasive bladder cancer. PMID- 24787301 TI - Validity and reliability of the iPhone to measure rib hump in scoliosis. AB - STUDY DESIGN: This was a prospective blinded validity and reliability analysis. OBJECTIVE: The aim of this study was validation and reliability evaluation of the Scoligauge iPhone app. BACKGROUND: The scoliometer is used to clinically measure the rib hump in scoliosis as a means to evaluate the axial trunk rotation. The increasing availability of smartphone with built-in accelerometer led to the development of a vast number of applications to measure angles. Of these, the Scoligauge mimics a scoliometer. The aim of this study was to compare the validity of the Scoligauge iPhone application without an associated adapter with the traditional scoliometer and to test the reliability of the application in a clinical setting. METHODS: Two observers measured the rib hump deformity on 34 consecutive patients with idiopathic scoliosis with an average Cobb angle of 24.2 +/- 13.5 degrees (range, 4 to 65 degrees). Measurements were made with an iPhone without the adapter and with a scoliometer. The validity as well as the interobserver and intraobserver reliability were calculated using the intraclass coefficient (ICC) and the Bland-Altman test. RESULTS: The mean difference between the scoliometer and the Scoligauge application was 0.4 degrees [95% confidence interval (CI) of +/- 3.1 degrees] with an ICC of 0.947 (P < 0.001). The intraobserver and interobserver ICC were 0.961 (P < 0.001) and 0.901 (P < 0.001), respectively. The mean intraobserver difference was 0.0 degrees (95% CI of +/- 2.7 degrees) and the mean interobserver difference was 0.1 degrees (95% CI of +/- 4.4 degrees). CONCLUSIONS: The intraobserver and interobserver reliability of the Scoligauge iPhone app, as well as its validity compared with the scoliometer, are excellent. The mean differences between measurements are small and clinically not significant. Thus, the Scoligauge application is valid for clinical evaluation even without special adapter. LEVEL OF EVIDENCE: Level I (Diagnostic Study). PMID- 24787299 TI - Tumor macroenvironment and metabolism. AB - In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%-20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient's outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described. PMID- 24787302 TI - Outcomes of long-arm casting versus double-sugar-tong splinting of acute pediatric distal forearm fractures. AB - INTRODUCTION: The traditional treatment after closed reduction of distal radius (DR) and distal both bone (DBB) forearm fractures has been application of a long arm cast (LAC) or a short-arm cast (SAC). Splinting is another option that avoids the potential complications associated with casting. The purpose of this study is to evaluate the maintenance of reduction of DR or DBB fractures placed in a double-sugar-tong splint (DSTS) compared with a LAC in a pediatric population. METHODS: This is an IRB-approved, prospective, randomized trial. Patients aged 4 to 12 years with DR or DBB fractures treated at a single institution between 2010 and 2012 were enrolled. After reduction, fractures were placed into either a LAC or a DSTS. Radiographs were reviewed at initial injury, postreduction, and at set intervals for angulation, displacement, and apposition, as well as cast index and 3-point index. The DSTS was overwrapped into a cast after week 1. The immobilization device was changed to a SAC at week 4 or 6. Total duration of immobilization was 6 to 8 weeks. RESULTS: Seventy-one patients were enrolled with 37 in the LAC and 34 in the DSTS. Average age was 8.73 years (range, 4 to 12) with 43 being males. There were 28 isolated DR and 43 DBB fractures. There were no week-to-week differences between the 2 groups in regards to sagittal alignment, coronal alignment, apposition, or displacement. Sagittal alignment at immediate postreduction and week 2 showed that the DSTS was slightly better (average 2.0 vs. 5.0 degrees, respectively, P=0.04). For the entire treatment period there was an increased risk of loss of reduction of >=10 degrees in the LAC group versus the DSTS group (7 patients vs. 2 patients, respectively, P=0.0001), and of meeting the criteria for remanipulation (10 patients vs. 5 patients, respectively, P=0.01). At cast removal, there was no difference between groups. CONCLUSIONS: Although there were significant differences between the 2 groups with regards to risk of reduction loss, the DSTS and LAC were comparable in maintenance of reduction at the time of cast removal. Both the DSTS and LAC are appropriate immobilization devices for these pediatric fractures. LEVEL OF EVIDENCE: Level II-prospective, comparative study. PMID- 24787303 TI - The medial dye pool revisited: correlation between arthrography and MRI In closed reductions for DDH. AB - BACKGROUND: Closed reduction (CR) and spica casting is performed using arthrography to assess the adequacy of reduction based in part on the width of medial dye pool (MDP); however, the amount of MDP that is acceptable and its correlation to the actual anatomic position of the femoral head within the acetabulum has been poorly delineated. The purpose of this study was to determine this correlation and to explore the potential limits of acceptable MDP measurements. METHODS: We retrospectively reviewed a consecutive series of patients with DDH treated at our institution by CR and immediate postoperative magnetic resonance imaging (MRI) and found 20 patients (23 hips) meeting inclusion criteria. We measured the MDP and femoral head area on the best reduced arthrographic image, the immediate postoperative mid-coronal MRI, and on 3 planes (neutral, 30-degree anterior, and 30-degree posterior) of the mid-axial MRI and compared MDP values from both imaging modalities using the Pearson correlation coefficient (R). To provide useful data for establishing intraoperative thresholds, MDP was also expressed as a percentage of femoral head width to control for fluoroscopic magnification. RESULTS: Twenty-two of the 23 hips were reduced on postoperative MRI; the one persistently dislocated hip was excluded from our analysis. The Pearson correlation coefficient was R = 0.73 comparing arthrography and coronal MRI, indicating excellent correlation. Correlation was even stronger between arthrography and axial MRI (neutral R = 0.73; 30-degree anterior, R = 0.81; 30-degree posterior, R = 0.81). The mean fluoroscopic MDP in the successful, fully concentric, CRs was 4.2% of the femoral head width (range, 0.6% to 15.8%). CONCLUSIONS: There is very strong correlation between MDP measurements on arthrography and immediate postoperative MRI in both the axial and coronal planes. On the basis of our data, an arthrographic MDP between 0.6% and 15.8% of the femoral head width always resulted in an excellent reduction, suggesting that an MDP of <= 16% of femoral head width may be a useful intraoperative criterion for determining the adequacy of CR. LEVEL OF EVIDENCE: Level I Diagnostic Study. PMID- 24787304 TI - Satisfactory patient-based outcomes after surgical treatment for idiopathic clubfoot: includes surgeon's individualized technique. AB - INTRODUCTION: Treatment of idiopathic clubfoot has shifted towards Ponseti technique, but previously surgical management was standard. Outcomes of surgery have varied, with many authors reporting discouraging results. Our purpose was to evaluate a single surgeon's series of children with idiopathic clubfoot treated with a la carte posteromedial and lateral releases using the Pediatric Outcomes Data Collection Instrument (PODCI) with a minimum of 2-year follow-up. METHODS: A total of 148 patients with idiopathic clubfoot treated surgically by a single surgeon over 15 years were identified, and mailed PODCI questionnaires. Fifty percent of the patients were located and responded, resulting in 74 complete questionnaires. Median age at surgery was 10 months (range, 5.3 to 84.7 mo), male sex 53/74 (71.6%), bilateral surgery 31/74 (41.9%), and average follow-up of 9.7 years. PODCI responses were compared with previously published normal healthy controls using t test for each separate category. Included in the methods is the individual surgeon's operative technique. RESULTS: In PODCIs where a parent reports for their child or adolescent, there was no difference between our data and the healthy controls in any of the 5 categories. In PODCI where an adolescent self-reports, there was no difference in 4 of 5 categories; significant difference was only found between our data (mean = 95.2; SD = 7.427) and normal controls (mean = 86.3; SD = 12.5) in Happiness Scale (P = 0.0031). DISCUSSION: In this group of idiopathic clubfoot patients, treated with judicious posteromedial release by a single surgeon, primarily when surgery was treatment of choice for clubfoot, patient-based outcomes are not different from their normal healthy peers through childhood and adolescence. While Ponseti treatment has since become the treatment of choice for clubfoot, surgical treatment, in some hands, has led to satisfactory results. LEVEL OF EVIDENCE: Level III. PMID- 24787305 TI - A line drawn along the radial shaft misses the capitellum in 16% of radiographs of normal elbows. AB - BACKGROUND: The radiocapitellar line (RCL) is a routinely referenced radiographic measurement for evaluating injury of the pediatric elbow, such as a Monteggia fracture. It is most commonly described as a line drawn along the radius that should intercept the center of the capitellum in a normal elbow. However, the RCL has not been rigorously defined or validated in young children. METHODS: The RCL was drawn out on the anteroposterior and lateral radiographs of 116 normal pediatric elbows by 3 examiners. On each radiograph, lines were drawn along the longitudinal center of the radial neck as well as the radial shaft. The distance from each of these lines to the center of the capitellum was defined as the line capitellar distance (LCD). The LCD was standardized to the patient size and correlated with patient variables. RESULTS: Of the 2052 RCLs drawn, 50% (1029/2052) fell outside the middle third of the capitellum and 8.6% (176/2052) missed the capitellum completely. Lines drawn along the radial neck in the anteroposterior and lateral views missed the capitellum less frequently (1.2% vs. 12.7%, P<0.0001) and passed through its central third less (77.8% vs. 44.7%, P<0.0001) when compared with lines drawn using the radial shaft. Lines along the radial neck intersected the capitellum significantly more often on the lateral view than on the anteroposterior view (98.8% vs. 96.8%, P=0.06) and were more likely to pass through the center third of the capitellum (77.8% vs. 55.5%, P<0.0001). With both techniques of drawing the RCL, the percent of measurements falling within the middle third of the capitellum was higher in patients above 5 years of age (P<0.001). The RCL is more reliable in older patients and shows considerable variation in infants. CONCLUSIONS: The RCL does not invariably bisect or fall within the middle third of the capitellum in normal pediatric elbows. Therefore, an abnormal RCL is suggestive but not pathognomonic for injury such as Monteggia fracture. An RCL drawn along the radial shaft will miss the capitellum in 15.6% of elbows. The most consistent RCL is drawn along the radial neck on the lateral view. Patient variables such as age and sex should be considered in the ability of the RCL to identify elbow injury. LEVEL OF EVIDENCE: Diagnostic Level 3. PMID- 24787306 TI - Legg-Calve-perthes disease: quality of life, physical activity, and behavior pattern. AB - BACKGROUND: Legg-Calve-Perthes disease (LCPD) is a disease in children leading to deformation of the femoral head and can be a promoter for early dysfunction of the hip and early osteoarthritis of the hip. The study of health-related quality of life, physical activity, and behavior patterns in patients with LCPD can reveal its consequences later in life and also contribute to a better understanding of the etiology of the disease. PATIENTS AND METHODS: We identified 145 patients with LCPD diagnosed and treated at Uppsala University Hospital between 1978 and 1995. A total of 116 patients answered questionnaires regarding health-related quality of life (EQ-5D-3L), physical activity [International Physical Activity Questionnaire (IPAQ)], and hyperactive/inattentive behavior pattern [ADHD self-reporting symptom checklist (ASRS v1.1)] by interview. Patients were asked to report on fractures or soft-tissue injuries that required medical care. Medical charts were reviewed to determine age at onset of LCPD and treatment received. RESULTS: Patients with LCPD had significantly lower EQ-5D-3L and EQ VAS scores than the Swedish general population in all age groups. A total of 28% of our patient group had ASRS scores indicating they are likely or highly likely to have an ADHD diagnosis. A lower EQ-5D-3L score was significantly correlated with a higher total ASRS v1.1 score (rho=-0.309**). Over 90% of our patient group was physically active on a moderate or high level, despite 52% reporting either some or severe problems with pain according to the EQ-5D-3L questionnaire. Patients with high ASRS v1.1 scores (>16) had a significantly higher incidence of soft-tissue injuries than those with lower ASRS v1.1 scores. CONCLUSION: The consequence of LCPD in adulthood was expressed in a lower quality of life compared with the Swedish general population. Despite this, the patients in our study reported a higher level of physical activity than the general population. A tendency toward hyperactive behavior pattern and high physical activity level may be present even in childhood and could contribute to the etiology of LCPD. LEVEL OF EVIDENCE: A retrospective study, level II. PMID- 24787307 TI - Incidence and etiology of unplanned cast changes for fractures in the pediatric population. AB - BACKGROUND: The majority of pediatric fractures are treated in casts due to the child's ability to heal rapidly and remodel. Unplanned cast changes are a time and economic burden with potentially adverse effects on fracture management. The purpose of this study is to document the incidence, etiology, and complications related to unplanned cast changes. METHODS: A prospective study was conducted over a 6-month period to determine the incidence of unplanned cast changes. All casts applied were nonwaterproof. Data collected include the reason for cast placement, type of cast placed, duration of wear before the unplanned change, reason for the unplanned change, experience level of the original cast applicator, and cast-related complications. RESULTS: A total of 1135 casts were placed with 58% placed by a resident, 38% by a cast technician, 2% by a physician's assistant, and 2% by an attending physician. Sixty casts (5.3%) required an unplanned change including 19 short-arm casts, 18 short-leg casts, 17 long-arm casts, 4 thumb spica casts, and 2 long-leg casts. The average duration from cast application until the unplanned change was 13 days. Twenty-eight (47%) were changed for wetness, 20 (33%) for wear/breakage, 2 (3%) for skin irritation, and 10 (17%) for other reasons including objects in the cast and patient self removal. Two patients had superficial skin infections requiring oral antibiotics. No fracture reductions were lost secondary to an unplanned cast change. The need for an unplanned cast change did not correlate with the level of experience of the applicator. CONCLUSIONS: Most unplanned cast changes were the result of patient nonadherence to instructions and not related to cast application technique. Improved patient and family education regarding cast care may reduce the frequency of unplanned cast changes, thus reducing an economic and time burden on the health care system. LEVEL OF EVIDENCE: Level II--prognostic study. PMID- 24787308 TI - Effect of asymmetrical configuration of pins in the TSF external fixator used for tibial lengthening in a pediatric population. AB - BACKGROUND: The Taylor Spatial Frame (TSF) is a relatively new circular external fixator linked with a computer program used in limb reconstruction surgery. It is routinely used in our unit (Royal Manchester Children's Hospital) for pediatric tibial lengthening. METHODS: The case notes and radiographs of 17 children who underwent 18 tibial lengthenings were reviewed. The TSF was attached to the tibia using a hybrid fixation method in the safe zone with two 1.8 mm tensioned smooth wires and 2 anteriorly placed hydroxyapatite-coated pins. Mechanical compression testing of our TSF construct was performed and compared with a double-ring Ilizarov frame construct fixed with only tensioned wires. RESULTS: Out of the 18 tibiae lengthened 14 (77.8%) had a significant anterior angulation (>10 degrees) at the end of the distraction period that was corrected with a residual TSF program, with no known long-term consequences. The mechanical tests showed that the Ilizarov frame showed a more symmetrical distribution of loading in compression when compared with the TSF. With increasing load the TSF had the tendency to angulate anteriorly, that is, the apex of the angulation was pointing toward the 2 pins. CONCLUSIONS: The problem of anterior angulation observed in our clinical and mechanical studies is due to instability of the fixation of the proximal part of the frame. Surgical techniques that can improve the stability of the proximal fixation and promote symmetrical loading are discussed. PMID- 24787309 TI - Higher levels of melatonin in early stages of adolescent idiopathic scoliosis: toward a new scenario. AB - BACKGROUND: The melatonin deficiency hypothesis as a central mechanism in the pathogenesis of adolescent idiopathic scoliosis (AIS) is certainly intriguing. However, the actual role of melatonin remains unclear. The aim of this study was to assess the potential clinical value of melatonin serum level in the pathogenesis and the prognosis of AIS progression in patients who were treated nonoperatively. METHODS: Two groups of patients were enrolled. The study group consisted of patients with AIS aged below 14 years who were treated conservatively. In the second group, that is, the control group, age-matched, weight-matched, and height-matched healthy individuals were enrolled. Blood samples were collected from all patients on visit 1 and the serum levels of melatonin were evaluated with the enzyme-linked immunosorbent assay (ELISA) method. The blood sampling procedure was repeated exactly 1 year later (visit 2). RESULTS: Forty-two patients formed the study group (with AIS) and 29 served as the control group. The mean serum value of melatonin on visit 1 was 19.32 pg/mL for the AIS group and 12.23 pg/mL for the control group. This difference was statistically significant (P = 0.014). One year later, 34 patients from the AIS group and 23 from the control group were reevaluated and the mean serum levels of melatonin were 52.43 and 68.44 pg/mL, respectively. No statistically significant difference was found between the 2 groups (P = 0.235). Statistical analysis of the serum melatonin levels of patients with progressing AIS (>5 degrees of the Cobb angle in 1 y) when compared with patients with stable AIS (P = 0.387) or the control group (P = 0.727) failed to show that the deficiency of melatonin may be associated with the progression of AIS. CONCLUSIONS: Higher melatonin levels were observed in conservatively treated patients with AIS, whereas melatonin deficiency was not associated with AIS progression in this study. LEVEL OF EVIDENCE: Level III-case-control study. PMID- 24787310 TI - Kirschner wire infections in pediatric orthopaedic surgery. AB - BACKGROUND: Few studies have described the presentation, bacteriology, risk factors, and complications of Kirschner wire infections in pediatrics. The purpose of this study is to describe these factors to better understand, prevent, and treat infectious complications of smooth wires. METHODS: A retrospective review was performed to identify all patients (birth to 16 y) who were hospitalized for Kirschner wire infection from 1995 to 2012. Presentation, hospital course, bacteriology, outcomes, and complications were recorded. A management algorithm was developed from the experience. RESULTS: Kirschner wire infections were present in 12 patients: 5 supracondylar fractures, 3 lateral humeral condylar fractures, a distal tibia physeal fracture, a great toe open fracture, a distal radius fracture, and an elective osteotomy for hallux valgus. The patients presented with cellulitis in 3 cases, soft-tissue abscess in 4 cases, osteomyelitis in 4 cases, and 1 case of toxic shock syndrome. A history of missed appointments or wet dressing was present in 60% of cases. Reoperation was required in 5 patients with abscess, septic arthritis, or osteomyelitis. Methicillin-sensitive Staphylococcus aureus (MSSA) was the most common pathogen followed by Pseudomonas aeruginosa. Methicillin-resistant S. aureus was not seen. Complications were present in 5 patients and included: loss of range of motion, joint destruction, wound breakdown, catheter migration, and toxic shock syndrome. CONCLUSIONS: Infected Kirschner wires are rare and may be maintained in a nonunited bone if the infection is superficial. Infections in this series commonly had a history of missed appointments and wet dressings, which suggests that improved postoperative education may reduce the risk. Osteomyelitis was often preceded by pin-site drainage and failed oral antibiotic therapy. MSSA and Pseudomonas were most commonly cultured and should be considered when empiric antibiotic therapy is necessary. LEVEL OF EVIDENCE: Prognostic level IV. PMID- 24787311 TI - Chronic anterior monteggia lesions in children: report of 4 cases treated with closed reduction by ulnar osteotomy and external fixation. AB - BACKGROUND: Chronic, subacute, and chronic Monteggia fracture dislocations of the elbow are challenging problems. The literature generally recommends complex open reconstructive procedures. We present an alternative, minimally invasive, percutaneous method with external fixation. METHODS: This was a retrospective review of 4 cases presenting with chronic Monteggia lesions with anterior dislocation of the radial head. RESULTS: Reduction of the radiocapitellar joint was successfully achieved in all patients after ulnar osteotomy and gradual correction using the Ilizarov external fixation. Open reduction or reconstruction of the radio-ulnar-capitellar joint and/or ligament was not undertaken. The patients were between 9 and 11 years of age at the time of injury. The time from injury to treatment was between 3 and 56 months. At follow-up of an average of 3.5 years (range, 2 to 6 y), all patients had full movement of the elbow and normal function of the forearm. Radiographically, all radial heads were well reduced and the ulnar osteotomy showed remodeling. CONCLUSIONS: The technique is relatively simple and avoids the risks and technical challenges of open osteotomies, open reduction, and ligament reconstruction. Gradual reduction of the radial head with the aid of an external fixation is a safe and effective method of treatment for chronic Monteggia lesions. PMID- 24787312 TI - A randomized clinical trial comparing reported and measured wear rates in clubfoot bracing using a novel pressure sensor. AB - BACKGROUND: The treatment of clubfoot by the Ponseti method requires the utilization of a foot abduction orthosis (FAO) after manipulation and casting. Adherence to this protocol, specifically FAO wear rates, has been postulated to improve treatment outcomes. Our hypothesis was that caregiver-reported wear rates were significantly less than actual wear rates in these braces. METHODS: A randomized prospective study of 67 children, aged 0 to 3 years old with idiopathic clubfoot, treated using the Ponseti technique for idiopathic clubfoot, was undertaken after IRB approval. Participants were randomized into 3 groups: a functioning pressure-based sensor (group FPS) attached to the FAO (21 patients), a nonfunctioning sensor (NFPS group) attached to the FAO (24 patients), or no sensor (NS group) (22 patients). All caregivers filled out a diary of subjective wear rates. Reported and actual wear rates were recorded as a percentage of the entire day and compared. RESULTS: In the FPS group, the average actual wear rate for months 1, 2, and 3 were 91.7% (15 patients; 72.7% to 97.0%), 86.8% (9 patients; 60.5% to 96.3%), and 77.1% (7 patients; 52.6% to 95.8%), respectively. The average self-reported wear rate in the FPS group in months 1, 2, and 3 were 94.9% (13 patients; 93.1% to 98.7%), 95.6% (10 patients; 92.3% to 99.4%), and 94.8% (11 patients; 82.8% to 99.6%), respectively. The most predictive factor in determining a patient's decrease in the overall wear rate was a drop in the wear rate between months 1 and 2 (P<0.001). The reported wear rates were not statistically different between any of the 3 groups (P<0.01). CONCLUSIONS: By using a novel method of pressure measurement, which documented FAO wear, we have shown a significant decline in wear rates from months 1 to 3. These actual FAO wear rates did not match their reported rates, thus putting into question previous assumptions about reported brace compliance. The largest drop in wear rates occurred from months 2 to 3. This study provides the first objective measurement of FAO brace wear in patients undergoing the Ponseti method of treatment. LEVELS OF EVIDENCE: Level II. PMID- 24787313 TI - Congenital constriction band syndrome with limb defects. AB - BACKGROUND: The purpose of this study was to clarify the spectrum of congenital constriction band syndrome (CBS) and associated anomalies and mortality in Finland. METHODS: Register-based data were analyzed for children with congenital constriction bands in upper and lower extremities as a part of an ongoing study on 419 upper limb defects and 171 lower limb defects occurring among 753,342 births in Finland during 1993 to 2005. RESULTS: A total of 71 cases with limb CBS were identified during the 13-year study period. The birth prevalence was 0.9 per 10 000 births (1:10 600). Infant mortality was 4.6% (3/65) and perinatal mortality 12.7% (9/71). In 35 cases (49%) only upper limbs were affected and in 13 cases (18%) there were constriction defects only in lower limbs. In 23 cases (32%) both upper and lower limbs were involved. None of the cases associated with a known syndrome. However, in 21 cases (30%) the child had other anomalies associated with constriction rings: pes equinovarus in 8/21, cleft palate in 5/21, congenital heart defect in 6/21, and other anomalies in 14/21. Eighteen (25%) had low birth weight, 22 (31%) were born preterm, and 8 children (11%) were small for gestational age. Children with associated anomalies showed higher mortality, shorter duration of gestation, and lower birth weight. CONCLUSIONS: CBS is rare and comprises approximately 12% of all congenital upper limb defects and 14% of lower limb defects. Other skeletal and nonskeletal anomalies are present in 30% of the affected children, suggesting a possible genetic etiology. More detailed characterization of the children with associated anomalies may shed light to the pathogenetic mechanisms of this syndrome. LEVEL OF EVIDENCE: Population-based register study/II. PMID- 24787314 TI - Exposed versus buried intramedullary implants for pediatric forearm fractures: a comparison of complications. AB - BACKGROUND: The purpose of this study was to compare the rate of complications between buried and exposed intramedullary implants after fixation of pediatric forearm fractures. METHODS: A retrospective comparative cohort study of 339 children treated with intramedullary fixation for displaced forearm fractures between 2004 and 2009 was performed. Implants were left exposed in 128 patients (37.8%) and buried beneath the skin in 208 patients (61.4%); 3 patients had buried and exposed hardware (0.9%). Data on demographics, injury, surgical technique, and complications were analyzed. RESULTS: The buried implant group was older (mean 10.3 vs. 8.5 y; P < 0.001), heavier (mean 38.6 vs. 31.9 kg; P < 0.001), and had fewer open injuries (23% vs. 41%; P < 0.001) than the exposed implant group. The buried group had their implants removed later than the exposed group (median 3.5 vs. 1.2 mo; P < 0.001). There was no difference between time to removal for patients with refracture and those without (median 1.3 vs. 2.0 mo; P = 0.78). A total of 36.2% of exposed implants were successfully removed in the office. Complications were seen in 56 patients (16.5%). There were 16 patients (4.7%) with refracture and 12 patients (3.5%) with infection. The buried and exposed implant groups did not differ significantly with respect to refracture (3.1% vs. 7.0%; P = 0.20), infection (3.5% vs. 2.3%; P = 0.66), or overall complications (14.5% vs. 17.2%; P = 0.87). There was also no difference between groups with respect to loss of reduction, nondelayed or delayed union, loss of motion, hypertrophic granuloma, or tendon rupture. Buried implants were also associated with penetration through the skin (3.9%). Injury to the dominant arm and need for open reduction were significant predictors of complication (OR = 1.01; 95% CI, 1.001-1.012; P = 0.02 and OR = 0.51; 95% CI, 0.264-0.974; P = 0.04, respectively). CONCLUSIONS: There were no significant differences seen in number of infections, refractures, or overall complications based on whether implants were left exposed or buried beneath the skin after surgery. LEVEL OF EVIDENCE: Level III, therapeutic. PMID- 24787316 TI - Production of fumaric acid from biodiesel-derived crude glycerol by Rhizopus arrhizus. AB - This work investigated the capability of Rhizopus arrhizus to assimilate biodiesel-derived crude glycerol and convert it into fumaric acid. After optimizing the initial glycerol concentration, spore inoculum and yeast extract concentration, smaller pellets (0.7 mm) and higher biomass (3.11 g/L) were obtained when R. arrhizus grew on crude glycerol. It was found that crude glycerol was more suitable than glucose for smaller R. arrhizus pellet forming. When 80 g/L crude glycerol was used as carbon source, the fumaric acid production of 4.37 g/L was obtained at 192 h. With a highest concentration of 22.81 g/L achieved in the co-fermentation of crude glycerol (40 g/L) and glucose (40 g/L) at 144 h, the fumaric acid production was enhanced by 553.6%, compared to the fermentation using glycerol (80 g/L) as sole carbon source. Moreover, the production cost of fumaric acid in co-fermentation was reduced by approximately 14% compared to glucose fermentation. PMID- 24787315 TI - The effective photoinduction of Haematococcus pluvialis for accumulating astaxanthin with attached cultivation. AB - As the optimal source of astaxanthin, Haematococcus pluvialis was cultured for commercial production of astaxanthin through two continuous phases: cell growth and astaxanthin induction. In this study, the efficiency of an attached system for producing astaxanthin from H. pluvialis was investigated and compared to that of the suspended system (bubble column bioreactor) under various conditions. Results showed that this attached system is more suitable for photoinduction of H. pluvialis than the suspended bioreactor. Under the optimal conditions, the astaxanthin productivity of the attached system was 65.8 mg m(-2)d(-1) and 2.4 fold of that in the suspended system. This attached approach also offers other advantages over suspended systems, such as, producing astaxanthin under a wide range of light intensities and temperatures, saving water, ease to harvest cells, resisting contamination. Therefore, the attached approach can be considered an economical, environmentally friendly and highly-efficient technology for producing astaxanthin from H. pluvialis. PMID- 24787317 TI - Parameters characterization and optimization of activated carbon (AC) cathodes for microbial fuel cell application. AB - Activated carbon (AC) is employed as a cost-effective catalyst for cathodic oxygen reduction in microbial fuel cells (MFC). The fabrication protocols of AC based cathodes are conducted at different applied pressures (175-3500 psi) and treatment temperatures (25-343 degrees C). The effects of those parameters along with changes in the surface morphology and chemistry on the cathode performances are comprehensively examined. The cathodes are tested in a three-electrode setup and explored in single chamber membraneless MFCs (SCMFCs). The results show that the best performance of the AC-based cathode is achieved when a pressure of 1400 psi is applied followed by heat treatment of 150-200 degrees C for 1h. The influence of the applied pressure and the temperature of the heat treatment on the electrodes and SCMFCs is demonstrated as the result of the variation in the transfer resistance, the surface morphology and surface chemistry of the AC-based cathodes tested. PMID- 24787318 TI - Trichoderma longibrachiatum acetyl xylan esterase 1 enhances hemicellulolytic preparations to degrade corn silage polysaccharides. AB - Supplementation of a Trichoderma longibrachiatum preparation to an industrial Aspergillus niger/Talaromyces emersonii enzyme mixture demonstrated synergy for the saccharification of corn silage water-unextractable solids (WUS). Sub fractions of the crude T. longibrachiatum preparation obtained after chromatography were analyzed regarding their hydrolytic activity. An acetyl xylan esterase 1 [Axe1, carbohydrate esterase (CE) family 5]-enriched sub-fraction closely mimicked the hydrolytic gain as obtained by supplementation of the complete, crude enzyme mixture (increase of 50%, 62% and 29% for Xyl, Ara and Glc, respectively). The acetic acid released from model polysaccharides (WUS) and oligosaccharides [neutral (AcXOS) and acidic (AcUXOS) xylo-oligosaccharides] by Axe1 was two and up to six times higher compared to the acetic acid released by acetyl xylan esterase A (AxeA, CE 1). Characterization of Axe1 treated AcXOS and AcUXOS revealed deacetylation of oligosaccharides that were not deacetylated by AxeA or the A. niger/T. emersonii preparation. PMID- 24787319 TI - Energy efficiency and environmental performance of bioethanol production from sweet sorghum stem based on life cycle analysis. AB - Life cycle analysis method was used to evaluate the energy efficiency and environmental performance of bioethanol production from sweet sorghum stem in China. The scope covers three units, including plant cultivation, feedstock transport, and bioethanol conversion. Results show that the net energy ratio was 1.56 and the net energy gain was 8.37 MJ/L. Human toxicity was identified as the most significant negative environmental impact, followed by eutrophication and acidification. Steam generation in the bioethanol conversion unit contributed 82.28% and 48.26% to total human toxicity and acidification potential, respectively. Fertilizers loss from farmland represented 67.23% of total eutrophication potential. The results were significantly affected by the inventory allocation methods, vinasse reusing approaches, and feedstock yields. Reusing vinasse as fuel for steam generation and better cultivation practice to control fertilizer loss could significantly contribute to enhance the energy efficiency and environmental performance of bioethanol production from sweet sorghum stem. PMID- 24787320 TI - Potential of duckweed in the conversion of wastewater nutrients to valuable biomass: a pilot-scale comparison with water hyacinth. AB - The application potential of duckweed (Lemna japonica 0234) and water hyacinth (Eichhornia crassipes) were compared in two pilot-scale wastewater treatment systems for more than one year. The results indicated duckweed had the same total nitrogen (TN) recovery rate as water hyacinth (0.4 g/m(2)/d) and a slightly lower total phosphorus (TP) recovery rate (approximately 0.1g/m(2)/d) even though its biomass production was half that of water hyacinth. The higher content of crude protein (33.34%), amino acids (25.80%), starch (40.19%), phosphorus (1.24%), flavonoids (2.91%) and lower fiber content provided duckweed with more advantages in resource utilization. Additionally, microbial community discovered by 454 pyrosequencing indicated that less nitrifying bacteria and more nitrogen-fixing bacteria in rhizosphere of duckweed provided it with higher nitrogen recovery efficiency (60%) than water hyacinth (47%). Under the presented condition, duckweed has more application advantages than water hyacinth because it more effectively converted the wastewater nutrients into valuable biomass. PMID- 24787321 TI - Anoxic phases are the main N2O contributor in partial nitritation reactors treating high nitrogen loads with alternate aeration. AB - Partial nitritation (PN) reactors treating complex industrial wastewater can be operated by alternating anoxic-aerobic phases to promote heterotrophic denitrification via NO2(-). However, denitrification under stringent conditions can lead to high N2O production. In this study, the suitability of including anoxic phases in a PN-SBR treating real industrial wastewater was assessed in terms of process performance and N2O production. The PN-SBR was operated successfully and, when the HCO3(-):NH4(+) molar ratio was adjusted, produced a suitable effluent for a subsequent anammox reactor. 10-20% of the total influent nitrogen was removed. N2O production accounted for 3.6% of the NLR and took place mainly during the anoxic phases (60%). Specific denitrification batch tests demonstrated that, despite the availability of biodegradable COD, NO2(-) denitrification advanced at a faster rate than N2O denitrification, causing high N2O accumulation. Thus, the inclusion of anoxic phases should be avoided in PN reactors treating industrial wastewaters with high nitrogen loads. PMID- 24787322 TI - Simultaneous saccharification and fermentation of cassava to succinic acid by Escherichia coli NZN111. AB - In this study, the production of succinic acid from cassava starch and raw cassava instead of glucose by Escherichia coli NZN111 was investigated. During the two-stage fermentation, simultaneous saccharification and fermentation (SSF) was applied in the anaerobic stage. The results showed that both the productivity and specific productivity in the process conducted at 40 degrees C were higher than those in the cultivation conducted at 37 degrees C. The yield of succinic acid based on the amount of added starch reached the highest level 0.86 g/g and cassava starch was almost totally hydrolyzed in the SSF process. With the improved cell density, 127.13 g/L of succinic acid was obtained. When the liquefied crude cassava powder was used directly in SSF, 106.17 g/L of succinic acid was formed. The result showed that crude cassava powder could be another cheap raw material for succinic acid formation. PMID- 24787323 TI - Hydrotreating of wheat straw in toluene and ethanol. AB - In the present work, wheat straw was hydroliquefied at a temperature of 300 degrees C for 4h in ethanol or toluene in order to obtain bio-components which are useful for fuel purposes. The experiments were performed in a 100mL batch reactor under hydrogen pressure of 70 bar. Typically, 2g of straw and 0.1g of catalyst (66%Ni/SiO2-Al2O3) were dispersed in 15 g of solvent. The main compounds of the oil produced during the liquefaction of hemicellulose, cellulose and lignin of wheat straw in both solvents are: tetrahydrofuran-2-methanol, 1,2 butanediol and butyrolactone. Besides the mentioned compounds, ethanol favoured the decomposition of bigger molecules to short-chain alcohols such as 1-butanol, 1,2-propanediol and 1,2-ethanediol. Toluene contributes to the production of furans and other cyclic compounds. The light fractions distilled together with the solvent also contain the following: 1-propanol, 2-methyl-cyclopentanone, acetic acid and ethyl acetate. PMID- 24787324 TI - Shunting for hydrocephalus: analysis of techniques and failure patterns. AB - BACKGROUND: Hydrocephalus is characterized by ventricular dilatation because of progressive accumulation of cerebrospinal fluid. Normal pressure hydrocephalus (NPH) affects a subset of patients representing a reversible clinical triad of gait disturbance, urinary incontinence, and dementia with normal cerebrospinal fluid pressure and composition. Various shunting procedures have been used for treatment, but techniques and outcomes remain under debate. The objective of this study was to evaluate the clinical outcomes of 232 patients with and without NPH after the first-time Ventriculoperitoneal shunt placement and assessed patterns of failure between December 2004 and December 2012. RESULTS: Mean age was 54.7 y in non-NPH and 71.9 y in NPH patients. We used open technique in 34.3% and laparoscopic technique in 65.7% of NPH patients and 32.7% and 67.3% of the non NPH patients, respectively. A total of 36 of 232 patients displayed shunt failure, 16.4% in NPH and 15.2% in non-NPH patients. Twenty-three of 155 patients failed after laparoscopic and 13 of 77 failed after open placement. Proximal shunt failure was more frequent in the non-NPH cohort. Distal failures accounted for 13 of 232 cases, and the difference between laparoscopic (six of 155) and open failures (seven of 77) was profound, but not between NPH- and non-NPH patients. CONCLUSIONS: Shunt failures are related to the placement method. Non NPH patients showed more proximal failures. NPH patients showed fewer proximal failures. Less distal failures were observed after laparoscopic ventriculoperitoneal shunt placement without significant differences between NPH and non-NPH patients. Beyond this, laparoscopic surgery carries distinct advantages such as shorter operating room times and hospital stays, which should translate into less use of pain medications, earlier mobilization, and a lower incidence of ileus. PMID- 24787325 TI - Maintaining, restoring, and improving the health of our nation. AB - We need to start a conversation about Health. A conversation with our patients, our peers in the health care professions, and our communities across this nation. In the view of US Army Surgeon General LTG Patricia D. Horoho, our American health care system today, including military medicine, is focused on disease rather than Health. That's understandable--but it has to change. PMID- 24787326 TI - Perspectives for patients. Knee pain: safely strengthening your thigh muscles. AB - Quadriceps are the muscles on the front of your thigh that help you straighten your knee. When these muscles are not strong, you may feel pain under your kneecap. Quadriceps can be strengthened by performing squats and leg extensions. However, when you do not perform these exercises properly, you may also feel knee pain. Understanding the load and stress under the kneecap when you execute squats and leg extensions can help you perform these exercises better and with less pain while you strengthen your quadriceps. A study published in the May 2014 issue of JOSPT provides information intended to help physical therapists and their patients use these exercises to strengthen thigh muscles while minimizing the load under the kneecap. PMID- 24787327 TI - Fracture of the radial head. AB - The patient was a 22-year-old man who was currently serving in a military special operations training program. He was referred to a physical therapist for a chief complaint of left elbow pain that currently prevented him from performing routine upper extremity exercise activities. Due to the traumatic nature of the patient's injury, inability to fully extend his elbow, and palpation findings, there was concern for a radial head fracture. Therefore, the physical therapist ordered radiographs of the left elbow, which revealed an intra-articular fracture involving the radial head that extended through the neck of the radius. PMID- 24787328 TI - Key enablers to facilitate healthy behavior change: workshop summary. AB - The increases in preventable chronic diseases and the rising costs of health care are unsustainable. The US Army Surgeon General's vision to transition from a health care system to a system of health requires the identification of key health enablers to facilitate the adoption of healthy behaviors. In support of this vision, the US Army Telemedicine and Advanced Technology Research Center hosted a workshop in April 2013 titled "Incentives to Create and Sustain Change for Health." Members of government and academia participated to identify key health enablers that could ultimately be leveraged by technology. The key health enablers discussed included (1) public health messaging, (2) changing health habits and the environmental influence on health, (3) goal setting and tracking, (4) the role of incentives in behavior-change intervention, and (5) the role of peer and social networks on change. This report summarizes leading evidence and the group consensus on evidence-based practices with respect to the key enablers in creating healthy behavior change. PMID- 24787329 TI - Perspectives for patients. Health and wellness: making the healthy choice the easy choice. AB - Our lifestyle choices play a key role in keeping us from getting hurt or sick. Limited sleep, inactivity, and poor nutrition can increase the risk of injury and disease. Also, increasing our sleep, activity, and the quality of what we eat and drink can speed recovery from a disease or illness. Less than 70% of adults get enough sleep. Poor sleep-less than 7 to 8 hours each night-is related to depression, work-related injuries, and weight gain. In addition, less than 45% of adults get the recommended 30 to 60 minutes of physical activity daily. Inactivity is tied to chronic disease, weight gain, and poor sleep. Finally, only 30% of Americans are at a healthy weight. Poor nutrition-too much sugar and fat and not enough fruits and vegetables-is linked to disease, depression, and inadequate sleep. Recently, a panel of 36 experts from academia, government, and the military gathered to discuss how to make the healthy choice the easy choice. A summary of this meeting was published in the May 2014 issue of JOSPT. PMID- 24787330 TI - Carpal tunnel syndrome diagnosis. AB - Carpal tunnel syndrome (CTS) is a common median nerve compression syndrome and the most common peripheral mononeuropathy. The clinical syndrome is diagnosed by history and physical examination. Electrodiagnostic testing is the objective method used to measure median nerve dysfunction at the wrist and confirm the clinical diagnosis of CTS. Neuromuscular ultrasound imaging of the carpal tunnel provides supportive diagnostic information by revealing pathologic nerve swelling in CTS, and other anatomic anomalies that compress the median nerve. These tests cannot be used to make the diagnosis in the absence of history that includes CTS symptom criteria and excludes other causes. PMID- 24787331 TI - Two novel nonsurgical treatments of carpal tunnel syndrome. AB - This article describes 2 nonsurgical approaches to the treatment of carpal tunnel syndrome that are not routinely offered, probably due to a lack of awareness. Osteopathic manipulative treatment (OMT) is commonly used for many medical problems, including musculoskeletal issues. OMT of the carpal tunnel is well described and researched, and can be clinically used by a skilled practitioner. The second treatment strategy is a more recent development. The use of ultrasound for guidance of injection is established, but a newer technique using sonographically guided percutaneous needle release of the transverse carpal ligament has shown promising results. PMID- 24787332 TI - Challenging pain syndromes: Parsonage-Turner syndrome. AB - Parsonage-Turner syndrome (PTS) is a rare disorder typically characterized by an abrupt onset of upper extremity pain followed by progressive neurologic deficits, including weakness, atrophy, and occasionally sensory abnormalities. The exact cause and pathophysiology of PTS are complex and incompletely understood. Autoimmune, genetic, infectious, and mechanical processes have all been implicated. No specific treatments have been proven to reduce neurologic impairment or improve the prognosis of PTS. Most patients with PTS are treated with a multidisciplinary approach that includes both physical therapy and pharmacologic treatment, often with multiple agents. Further research is needed. PMID- 24787333 TI - Greater trochanteric pain syndrome diagnosis and treatment. AB - Lateral hip pain, or greater trochanteric pain syndrome, is a commonly seen condition; in this article, the relevant anatomy, epidemiology, and evaluation strategies of greater trochanteric pain syndrome are reviewed. Specific attention is focused on imaging of this syndrome and treatment techniques, including ultrasound-guided interventions. PMID- 24787334 TI - Complex regional pain syndrome: diagnosis and treatment. AB - This article discusses the diagnostic criteria, clinical course, and complications of complex regional pain syndrome. Multidisciplinary treatment including physical and occupational therapy, psychological evaluation and treatment, pharmacologic management, and more aggressive options including sympathetic blocks, sympathectomy, and spinal cord stimulation are also reviewed. PMID- 24787335 TI - Discogenic low back pain. AB - Most lumbar disk herniations improve over time with or without medical treatment. Disk herniations and annular tears may not be symptomatic and are shown to exist in patients without any symptoms. In some patients, chronic low back pain may result from the syndrome of internal disk disruption. Treatment of chronic pain of diskal cause can be challenging and have varying results in terms of success. The diagnosis, cause, and treatment options are reviewed in this article. PMID- 24787336 TI - The failed back surgery syndrome: pitfalls surrounding evaluation and treatment. AB - This article describes the costs and risk factors for failed back surgery syndrome and reviews the diagnosis and treatment strategies commonly used to address this syndrome. The purpose of this review is to describe some of the treatment pitfalls associated with these approaches from a physiatric perspective. PMID- 24787337 TI - Diagnosis of myofascial pain syndrome. AB - Myofascial pain is one of the most common causes of pain. The diagnosis of myofascial pain syndrome (MPS) is made by muscle palpation. The source of the pain in MPS is the myofascial trigger point, a very localized region of tender, contracted muscle that is readily identified by palpation. The trigger point has well-described electrophysiologic properties and is associated with a derangement of the local biochemical milieu of the muscle. A proper diagnosis of MPS includes evaluation of muscle as a cause of pain, and assessment of associated conditions that have an impact on MPS. PMID- 24787338 TI - Myofascial pain syndrome treatments. AB - Myofascial pain syndrome (MPS) is a regional pain disorder caused by taut bands of muscle fibers in skeletal muscles called myofascial trigger points. MPS is a common disorder, often diagnosed and treated by physiatrists. Treatment strategies for MPS include exercises, patient education, and trigger point injection. Pharmacologic interventions are also common, and a variety of analgesics, antiinflammatories, antidepressants, and other medications are used in clinical practice. This review explores the various treatment options for MPS, including those therapies that target myofascial trigger points and common secondary symptoms. PMID- 24787339 TI - Opioid syndrome: failed opioid therapy for chronic noncancer pain. AB - Treatment of chronic noncancer pain (CNCP) with high-dose opioids (HDOs) has burgeoned over the past 2 decades in the United States. Characteristic domains and features of the failed CNCP management patient using long-term HDOs are described herein as the/an opioid syndrome (Schreiber AL, personal communication. 2013). Reversing or even modulating HDO use in patients with CNCP requires a paradigm shift on the part of physician, patient, and the societal "quick fix" medical culture. This review offers measures, agents, and strategies to consider in management of this pervasive, erosive medical and societal challenge. PMID- 24787340 TI - Spinal cord injury pain. AB - Chronic pain associated with traumatic spinal cord injury (SCI) can be quite challenging to the physiatrist. This highly prevalent condition within the SCI population requires an appropriate evaluative approach including a thorough history, a targeted physical examination, and appropriate use of diagnostic testing. The International Spinal Cord Injury Pain Classification allows for a reasonable categorization of the various pain syndromes and may assist in selecting a reasoned treatment strategy. A multitude of management approaches exist including nonpharmacologic, pharmacologic, and interventional approaches. This article provides an overview of the epidemiology, classification, evaluation, and management of SCI-associated pain. PMID- 24787341 TI - Hemiplegic shoulder pain: an approach to diagnosis and management. AB - Stroke is a significant source of mortality and long-term disability in the United States. Of persons who survive a stroke, approximately 50% will have hemiplegia, half of whom will live with a nonfunctional arm. Hemiplegic shoulder pain (HSP), which occurs in most patients with hemiplegia, reduces participation and worsens outcomes in rehabilitation. Management of HSP is challenging because its causes are multifactorial and there is limited, conflicting, or nonspecific evidence in support of most treatments. This article develops an effective approach for diagnosis and treatment using the best available evidence to aid practitioners in obtaining optimal results. PMID- 24787342 TI - Cancer pain and current theory for pain control. AB - This article discusses current trends in managing cancer pain, with specific regard to opioid transmission, descending pathway inhabitation, and ways to facilitate the endogenous antinociceptive chemicals in the human body. Various techniques for opioid and nonopioid control of potential pain situations of patients with cancer are discussed. The benefits of using pharmacogenetics to assess the appropriate medications are addressed. Finally, specific treatment of abdominal cancer pain using radiofrequency lesioning is discussed. PMID- 24787343 TI - Side effects of commonly prescribed analgesic medications. AB - Analgesics, including opioids, steroidal and nonsteroidal anti-inflammatory drugs, aspirin, acetaminophen, antiepileptics, and serotonin-norepinephrine reuptake inhibitors, are medications commonly used to treat many forms of pain. However, all of these agents may have significant adverse side effects. Adverse effects may occasionally be inseparable from desired effects. Side effects are often dose dependent and time dependent. It is critical that the prescribing practitioner and the dispensing pharmacist provide a thorough, understandable review of the potential side effects to all patients before these drugs are administered. Proper monitoring and follow-up during therapy are crucial. PMID- 24787345 TI - Challenging pain syndromes. PMID- 24787344 TI - Epidural steroid injections for radicular lumbosacral pain: a systematic review. AB - Most clinical guidelines do not recommend routine use of epidural steroid injections for the management of chronic low back pain. However, many clinicians do not adhere to these guidelines. This comprehensive evidence overview concluded that off-label epidural steroid injections provide small short-term but not long- term leg-pain relief and improvement in function; injection of steroids is no more effective than injection of local anesthetics alone; post-procedural complications are uncommon, but the risk of contamination and serious infections is very high. The evidence does not support routine use of off-label epidural steroid injections in adults with benign radicular lumbosacral pain. PMID- 24787346 TI - Challenging pain syndromes. PMID- 24787347 TI - Person-centred ward climate as experienced by mentally lucid residents in long term care facilities. AB - AIMS AND OBJECTIVES: To assess the content validity and reliability of the Person centred Climate Questionnaire-Patient version in long-term care facilities, to describe residents' perceptions of the extent to which their ward climate was person-centred and to explore whether person-centredness was associated with facility and resident characteristics, such as facility and ward size, having a sensory garden and having a primary caregiver. BACKGROUND: The importance of the physical environment to persons with dementia has been investigated. However, research is lacking regarding the extent to which mentally lucid residents experience their physical and psycho-social ward climate as person-centred and the factors influencing their experience. DESIGN: Cross-sectional survey design. METHODS: The Person-centred Climate Questionnaire-Patient version was translated into Norwegian with forward and backward translation. The content validity index for scales was assessed. The Person-centred Climate Questionnaire -Patient version was completed by 145 mentally lucid residents in 17 Norwegian long-term care facilities. Reliability was assessed by Cronbach's alpha and item-total correlations. Test-retest reliability was assessed by paired samples t-test and Spearman's correlation. To explore differences based on facility and resident characteristics, independent-samples t-test and one-way anova were used. RESULTS: The content validity index for scales was satisfactory. The Person-centred Climate Questionnaire-Patient version was internally consistent and had satisfactory test-retest reliability. The climate was experienced as highly person-centred. No significant differences were found, except that residents in larger facilities experienced the climate as more person-centred in relation to everyday activities (subscale 2) than residents in smaller facilities. CONCLUSION: The Norwegian version of the Person-centred Climate Questionnaire Patient version can be regarded as reliable in a long-term care facility context. Perceived degree of person-centredness was not associated with facility or resident characteristics, such as the number of residents, having a sensory garden or knowing that one has a primary caregiver. RELEVANCE TO CLINICAL PRACTICE: A person-centred climate can be attained in different kinds of long term care facilities. PMID- 24787348 TI - Allele-specific genome-wide profiling in human primary erythroblasts reveal replication program organization. AB - We have developed a new approach to characterize allele-specific timing of DNA replication genome-wide in human primary basophilic erythroblasts. We show that the two chromosome homologs replicate at the same time in about 88% of the genome and that large structural variants are preferentially associated with asynchronous replication. We identified about 600 megabase-sized asynchronously replicated domains in two tested individuals. The longest asynchronously replicated domains are enriched in imprinted genes suggesting that structural variants and parental imprinting are two causes of replication asynchrony in the human genome. Biased chromosome X inactivation in one of the two individuals tested was another source of detectable replication asynchrony. Analysis of high resolution TimEX profiles revealed small variations termed timing ripples, which were undetected in previous, lower resolution analyses. Timing ripples reflect highly reproducible, variations of the timing of replication in the 100 kb-range that exist within the well-characterized megabase-sized replication timing domains. These ripples correspond to clusters of origins of replication that we detected using novel nascent strands DNA profiling methods. Analysis of the distribution of replication origins revealed dramatic differences in initiation of replication frequencies during S phase and a strong association, in both synchronous and asynchronous regions, between origins of replication and three genomic features: G-quadruplexes, CpG Islands and transcription start sites. The frequency of initiation in asynchronous regions was similar in the two homologs. Asynchronous regions were richer in origins of replication than synchronous regions. PMID- 24787349 TI - Patterns of sexual arousal in young, heterosexual men who experience condom associated erection problems (CAEP). AB - INTRODUCTION: Condom-associated erection problems (CAEPs) are reported by a substantial number of young men and are associated with inconsistent and/or incomplete condom use. The underlying mechanisms of CAEP are not well understood, and research examining the possibility that men who report CAEP differ from other men in their sexual responsivity is lacking. AIM: This study used psychophysiological methods to examine whether men who report CAEP have a higher threshold for sexual arousal, a stronger need for tactile stimulation, and/or more easily lose their sexual arousal due to neutral distractors or performance related demands. METHODS: A total of 142 young, heterosexual men (53% reporting CAEP) were presented with four 3-minute erotic film clips. Three film clips were combined with one of the following manipulations: (i) distraction; (ii) performance demand; or (iii) vibrotactile stimulation. One erotic film clip was presented with no further instructions or manipulations. MAIN OUTCOME MEASURES: Average penile circumference changes during the first, second, and third minute (time) of the erotic film stimuli (condition) were submitted to a mixed-model analysis of variance with condition and time as within-subjects factors and group (CAEP/no-CAEP) as between-subjects factor. RESULTS: Significant main effects of condition and time and a significant interaction of group * time were found. No significant interactions involving condition were found. Men who reported CAEP had smaller erectile responses during the first minute, regardless of film condition, than men who reported no CAEP (F(1,141) = 8.64, P < 0.005). CONCLUSION: The findings suggest that men with and without CAEP differ in the ease with which they become sexually aroused. Men reporting CAEP needed more time and/or more intense stimulation to become aroused. To our knowledge, this study is the first to use psychophysiological methods to assess sexual responsivity in men who report CAEP. PMID- 24787350 TI - Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia. AB - BACKGROUND: The diagnosis of acute life-threatening allergic reactions during anesthesia relies on clinical signs, histamine and/or tryptase measurements, and allergic testing. In patients who die after the reaction, skin tests cannot be performed, and the effect of resuscitation manoeuvres on mediator concentrations is unknown. The authors compared plasma histamine and tryptase concentrations in patients with severe allergic reactions during anesthesia with those measured in patients with shock due to other causes. METHODS: Patients with life-threatening allergic reactions were retrieved from a previous database (Group ALLERGY). All had positive allergy tests to administered agents. Patients with severe septic/cardiogenic shock or cardiac arrest (Group CONTROL) had histamine and tryptase measurements during resuscitation manoeuvres. Receiver operating characteristics curves were built to calculate the optimal mediator thresholds differentiating allergic reactions from others. RESULTS: One hundred patients were included, 75 in Group ALLERGY (cardiovascular collapse, 67; cardiac arrest, 8) and 25 in Group CONTROL (shock, 11; cardiac arrest, 14). Mean histamine and tryptase concentrations remained unchanged throughout resuscitation in Group CONTROL and were significantly higher in Group ALLERGY. The optimal thresholds indicating an allergic mechanism were determined as 6.35 nmol/l for histamine (sensitivity: 90.7% [95% CI, 81.7 to 96.1]; specificity: 91.7% [73.0 to 98.9]) and 7.35 MUg/l for tryptase (sensitivity: 92% [83.4 to 97.0]; specificity: 92% [73.9 to 99.0]). CONCLUSIONS: Resuscitation manoeuvres by themselves did not modify mediator concentrations. Virtually all life-threatening reactions during anesthesia associated with mediator concentrations exceeding the thresholds were allergic events. These findings have potential forensic interest when a patient dies during anesthesia. PMID- 24787351 TI - Reflections from armenia. PMID- 24787353 TI - Anesthesiology and poetry. PMID- 24787352 TI - Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3beta activation in young mice. AB - BACKGROUND: Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane is a commonly used anesthetic in children. Tau phosphorylation contributes to cognitive dysfunction. The authors therefore assessed the effects of sevoflurane on Tau phosphorylation and the underlying mechanisms in young mice. METHODS: Six-day-old wild-type and Tau knockout mice were exposed to sevoflurane. The authors determined the effects of sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6 and postsynaptic density protein-95 in hippocampus, and cognitive function in both young wild-type and Tau knockout mice. RESULTS: Anesthesia with 3% sevoflurane 2 h daily for 3 days induced Tau phosphorylation (257 vs. 100%, P = 0.0025, n = 6) and enhanced activation of glycogen synthase kinase 3beta, which is the kinase related to Tau phosphorylation in the hippocampus of postnatal day-8 wild-type mice. The sevoflurane anesthesia decreased hippocampus postsynaptic density protein-95 levels and induced cognitive impairment in the postnatal day-31 mice. Glycogen synthase kinase 3beta inhibitor lithium inhibited the sevoflurane induced glycogen synthase kinase 3beta activation, Tau phosphorylation, increased levels of interleukin-6, and cognitive impairment in the wild-type young mice. Finally, the sevoflurane anesthesia did not induce an increase in interleukin-6 levels, reduction in postsynaptic density protein-95 levels in hippocampus, or cognitive impairment in Tau knockout young mice. CONCLUSIONS: These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3beta activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relation of these effects. PMID- 24787355 TI - A systematic review of low back pain and sciatica patients' expectations and experiences of health care. AB - BACKGROUND CONTEXT: Previous systematic reviews of patients' experience of health services have used mixed qualitative and quantitative studies. This review focused on qualitative studies, which are more suitable for capturing experience, using modern methods of synthesis of qualitative studies. PURPOSE: To describe the experience of health care of low back pain and sciatica patients and the sources of satisfaction or dissatisfaction with special reference to patients who do not receive a diagnosis. STUDY DESIGN: A systematic review of qualitative studies. SAMPLE: Primary qualitative studies identified from Medline, Embase, CINAHL, and Psychinfo databases. OUTCOME MEASURES: Conceptual themes of patients' experiences. METHOD: Data collection and analysis were through thematic content analysis. Two reviewers independently screened titles and collected and analyzed data. The authors were in receipt of a Primary Care Research Bursary from National Health Service Suffolk and Norfolk Research Departments, a not-for profit organization. RESULTS: Twenty-eight articles met the inclusion criteria. Most studies were of high quality. Nine themes emerged: the process and content of care, relationships and interpersonal skills, personalized care, information, the outcome of care, the importance of a diagnosis, delegitimation, recognizing the expert, and service matters. How care was given mattered greatly to patients, with importance given to receiving a perceived full assessment, consideration for the individual's context, good relationships, empathy, and the sharing of information. These aspects of care facilitated the acceptance by some of the limitations of health care and were spread across disciplines. Not having a diagnosis made coping more difficult for some but for others led to delegitimation, a feeling of not being believed. Service matters such as cost and waiting time received little mention. CONCLUSIONS: Although much research into the development of chronic low back pain (LBP) has focused on the patient, this review suggests that research into aspects of care also warrant research. The benefits of generic principles of care, such as personalization and communication, are important to patients with LBP and sciatica; so, practitioners may help their patients by paying as much attention to them as to specific interventions. When neither cure nor a diagnostic label is forthcoming, generic skills remain important for patient satisfaction. PMID- 24787356 TI - Overcoming barriers to undergraduate research: potential usefulness of a facilitated peer mentoring programme? PMID- 24787357 TI - An etiological model of perfectionism. AB - OBJECTIVE: Perfectionism has been recognized as a transdiagnostic factor that is relevant to anxiety disorders, eating disorders and depression. Despite the importance of perfectionism in psychopathology to date there has been no empirical test of an etiological model of perfectionism. METHOD: The present study aimed to address the paucity of research on the etiology of perfectionism by developing and testing an etiological model using a sample of 311 clients seeking treatment. RESULTS: Structural equation modeling showed a direct relationship between high Parental Expectations and Criticism, and Perfectionism. There was also an indirect relationship between Parental Bonding and Perfectionism that was mediated by core schemas of disconnection and rejection. Finally, it was found that Neuroticism had both an indirect relationship, which was mediated by core schemas, and a direct relationship with perfectionism. CONCLUSIONS: The study provided the first direct test of an etiological model of perfectionism to date. Clinical implications include investigating whether the inclusion of etiological factors in the understanding and treatment of perfectionism is effective. PMID- 24787358 TI - Assessment of an efficient xeno-free culture system of human periodontal ligament stem cells. AB - The possibility of transplanting adult stem cells into damaged organs has opened new prospects for the treatment of several human pathologies. The purpose of this study was to develop a culture system for the expansion and production of human Periodontal Ligament Stem Cells (hPDLSCs) using a new xeno-free media formulation and ensuring the maintenance of the stem cells features comprising the multiple passage expansion, mesengenic lineage differentiation, cellular phenotype, and genomic stability, essential elements for conforming to translation to cell therapy. Somatic stem cells were isolated from the human periodontium using a minimally invasive periodontal access flap surgery in healthy donors. Expanded hPDLSCs in a xeno-free culture showed the morphological features of stem cells, expressed the markers associated with pluripotency, and a normal karyotype. Under appropriate culture conditions, hPDLSCs presented adipogenic and osteogenic potential; indeed, a very high accumulation of lipid droplets was evident in the cytoplasm of adipogenic-induced cells, and indisputable evidence of osteogenic differentiation, investigated by transmission electron microscopy, and analyzed for gene expression analysis has been shown. Based on these data, the novel xeno free culture method might provide the basis for Good Manufacturing Procedure culture of autologous stem cells, readily accessible from human periodontium, and can be a resource to facilitate their use in human clinical studies for potential therapeutic regeneration. PMID- 24787359 TI - Physical capability in mid-life and survival over 13 years of follow-up: British birth cohort study. AB - OBJECTIVES: To examine associations between three commonly used objective measures of physical capability assessed at age 53 and a composite score of these measures and all cause mortality; to investigate whether being unable to perform these tests is associated with mortality. DESIGN: Cohort study. SETTING: MRC National Survey of Health and Development in England, Scotland, and Wales. PARTICIPANTS: 1355 men and 1411 women with data on physical capability at age 53 who were linked to the National Health Service (NHS) central register for death notification. MAIN OUTCOME MEASURE: All cause mortality between ages 53 (1999) and 66 (2012). RESULTS: For each of the three measures of physical capability (grip strength, chair rise speed, and standing balance time) those participants unable to perform the test and those in the lowest performing fifth were found to have higher mortality rates than those in the highest fifth. Adjustment for baseline covariates partially attenuated associations but in fully adjusted models the main associations remained. For example, the fully adjusted hazard ratio of all cause mortality for the lowest compared with the highest fifth of a composite score of physical capability was 3.68 (95% confidence interval 2.03 to 6.68). Those people who could not perform any of the tests had considerably higher rates of death compared with those people able to perform all three tests (8.40, 4.35 to 16.23). When a series of models including different combinations of the measures were compared by using likelihood ratio tests, all three measures of physical capability were found to improve model fit, and a model including all three measures produced the highest estimate of predictive ability (Harrell's C index 0.71, 95% confidence interval 0.65 to 0.77). There was some evidence that standing balance time was more strongly associated with mortality than the other two measures. CONCLUSIONS: Lower levels of physical capability at age 53 and inability to perform capability tests are associated with higher rates of mortality. Even at this relatively young age these measures identify groups of people who are less likely than others to achieve a long and healthy life. PMID- 24787362 TI - The effect of surgeon experience on the detection of metastatic lymph nodes in the central compartment and the pathologic features of clinically unapparent metastatic lymph nodes: what are we missing when we don't perform a prophylactic dissection of central compartment lymph nodes in papillary thyroid cancer? AB - BACKGROUND: Prophylactic central neck dissection (PCND) for papillary thyroid cancer (PTC) is controversial. Recent publications suggest that the number and size of nodes and the presence of extranodal extension (ENE) are important features for risk stratification of lymph node metastases. We analyzed these features in clinically unapparent nodes that would not otherwise be removed. We also investigated the impact of surgeon experience on the ability to detect metastatic lymph nodes intraoperatively. METHODS: Forty-seven patients with well differentiated PTC, with no preoperative evidence of central metastases, were included in this study. Intraoperatively, clinically apparent disease was determined by inspection and palpation by the senior surgeon and a fellow/senior resident, and recorded in a blinded fashion. Rate of occult metastases based on intraoperative evaluation were tabulated for each group of surgeons. Histopathologic features of occult nodes were analyzed to determine what clinicians would be missing by foregoing a PCND, and how that would have impacted the patient management. RESULTS: The rate of occult metastases, based on senior surgeon assessment, was 26%, and did not differ significantly from fellow/senior resident assessment. The level of agreement between these two surgeon groups was moderate (k=0.665). Analysis of the false negative cases revealed that the size of the largest undetected node ranged from 0.1 to 1.3 cm; 36% of patients with occult metastases demonstrated five or more positive nodes, and 27% showed ENE. DISCUSSION: Clinical assessment based on intraoperative inspection and palpation had poor sensitivity and specificity in identifying metastatic central nodes, regardless of the level of experience of the surgeon. There was moderate agreement between surgeons of different experience levels. Sensitivity improved significantly with larger size of positive nodes, but not with the presence of multiple positive nodes or presence of ENE. In foregoing PCND in this patient population, our results suggest that treating clinicians miss potentially virulent disease with a large number of occult positive central nodes and occult nodes with ENE. This is the first report to address the pathologic features of clinically nonevident central nodes showing a high incidence of clinically relevant, adverse histologic features, as well as the impact of surgeon experience in performing the important intraoperative determination of whether there are clinically evident nodes that require removal. PMID- 24787361 TI - Memory and comprehension for health information among older adults: distinguishing the effects of domain-general and domain-specific knowledge. AB - While there is evidence that knowledge influences understanding of health information, less is known about the processing mechanisms underlying this effect and its impact on memory. We used the moving window paradigm to examine how older adults varying in domain-general crystallised ability (verbal ability) and health knowledge allocate attention to understand health and domain-general texts. Participants (n = 107, age: 60-88 years) read and recalled single sentences about hypertension and about non-health topics. Mixed-effects modelling of word-by-word reading times suggested that domain-general crystallised ability increased conceptual integration regardless of text domain, while health knowledge selectively increased resource allocation to conceptual integration at clause boundaries in health texts. These patterns of attentional allocation were related to subsequent recall performance. Although older adults with lower levels of crystallised ability were less likely to engage in integrative processing, when they did, this strategy had a compensatory effect in improving recall. These findings suggest that semantic integration during reading is an important comprehension process that supports the construction of the memory representation and is engendered by knowledge. Implications of the findings for theories of text processing and memory as well as for designing patient education materials are discussed. PMID- 24787363 TI - Synthetic supercontainers exhibit distinct solution versus solid state guest binding behavior. AB - The phase-dependent host-guest binding behavior of a new family of synthetic supercontainers has been probed in homogeneous solution and at liquid-liquid, solid-liquid, and solid-gas interfaces. The synthetic hosts, namely, type II metal-organic supercontainers (MOSCs), are constructed from the assembly of divalent metal ions, 1,4-benzenedicarboxylate (BDC) linker, and sulfonylcalix[4]arene-based container precursors. One member of the MOSCs, MOSC II-tBu-Ni, which is derived from Ni(II), BDC, and p-tert butylsulfonylcalix[4]arene (TBSC), crystallizes in the space group R3 and adopts pseudo face-centered cubic (fcc) packing, whereas other MOSCs, including TBSC analogue MOSC-II-tBu-Co, p-tert-pentylsulfonylcalix[4]arene (TPSC) analogues MOSC II-tPen-Ni/Co, and p-tert-octylsulfonylcalix[4]arene (TOSC) analogues MOSC-II-tOc Ni/Mg/Co, all crystallize in the space group I4/m and assume a pseudo body centered cubic (bcc) packing mode. This solid-state structural diversity is nevertheless not reflected in their solution host-guest chemistry, as evidenced by the similar binding properties of MOSC-II-tBu-Ni and MOSC-II-tBu-Co in solution. Both MOSCs show comparable binding constants and adsorb ca. 7 equiv of methylene blue (MB) and ca. 30 equiv of aspirin in chloroform. In contrast, the guest-binding behavior of the MOSCs in solid state reveals much more variations. At the solid-liquid interface, MOSC-II-tBu-Co adsorb ca. 5 equiv of MB from an aqueous solution at a substantially faster rate than MOSC-II-tBu-Ni does. However, at the solid-gas interface, MOSC-II-tBu-Ni has higher gas uptake than MOSC-II-tBu-Co, contradicting their overall porosity inferred from the crystal structures. This discrepancy is attributed to the partial collapse of the solid state packing of the MOSCs upon solvent evacuation. It is postulated that the degree of porosity collapse correlates with the molecular size of the MOSCs, i.e., the larger the MOSCs, the more severe they suffer from the loss of porosity. The same principle can rationalize the negligible N2 and O2 adsorption seen in the larger MOSC-II-tPen-Co and MOSC-II-tOC-Ni/Mg/Co molecules. MOSC-II tPen-Ni features an intermediate molecular size and endures a partial structural collapse in such a way that the resulting pore dimension permits the inclusion of kinetically smaller O2 (3.46 A) but excludes larger N2 (3.64 A), explaining the observed remarkable O2/N2 adsorption selectivity. PMID- 24787364 TI - Total syntheses of (-)-spirooliganones A and B. AB - The enantioselective syntheses of (-)-spirooliganones A and B have been accomplished in eight steps from commercially available starting materials. Noteworthy transformations include a three-component hetero-Diels-Alder cycloaddition to construct the tetracyclic core of spirooliganones, a Sharpless asymmetric dihydroxylation, and a tandem oxidative dearomatization/cyclization to build the oxa-spiro cyclohexadienone skeleton. The straightforward syntheses were performed without protecting groups. PMID- 24787365 TI - Pro-neurogenesis and anti-dementia properties of tetradecyl 2,3-dihydroxybenzoate through TrkA receptor-mediated signalling pathways. AB - Tetradecyl 2,3-dihydroxybenzoate, termed ABG001, has been reported to enhance neurite outgrowth of PC12 cells. Herein, we report that oral administration of ABG001 for five days to adult male mice could dose-dependently enhance survival and neurite growth of newborn cells in hippocampal dentate gyrus (DG) without changes in cell proliferation and differentiation of progenitor cells. The ABG001 administration (0.5 mg/kg) enhanced the phosphorylation of tyrosine kinase A (TrkA) receptor, which induced increases in the levels of ERK, Akt and mTOR phosphorylation in hippocampus. The pro-neurogenesis of ABG001 was blocked by the TrkA receptor inhibitor K252a. By contrast, the ERK inhibitor U0126 attenuated only the ABG001-increased number of newborn cells, while the PI3K inhibitor LY294002 prevented mainly the ABG001-enhanced neurite growth. In comparison with control mice, the mice treated with ABG001 showed a more preferential spatial cognitive function as assessed by Morris water maze and Y maze tests, which was sensitive to the blockade of TrkA receptor. In addition, a single injection (i.c.v.) of 'aggregated' Abeta 25-35 in adult male mice (Abeta 25-35-mice) impaired spatial memory, survival and neurite growth of newborn cells in the DG with reduced phosphorylation of Akt and mTOR. The treatment of Abeta 25-35-mice with ABG001 could protect the survival and neurite growth of newborn cells through increasing TrkA receptor-induced phosphorylation of Akt and mTOR, which was accompanied by the improvement of spatial cognitive performance. PMID- 24787366 TI - Aerobic exercise and not a diet supplemented with jussara acai (Euterpe edulis Martius) alters hepatic oxidative and inflammatory biomarkers in ApoE-deficient mice. AB - The pulp of jussara acai (Euterpe edulis Martius) fruit is rich in anthocyanins that exert antioxidant and anti-inflammatory effects similar to those exerted by aerobic exercise. In the present study, we investigated the effects of jussara acai fruit pulp consumption, either alone or in combination with aerobic exercise, on the hepatic oxidative and inflammatory status of ApoE-deficient (ApoE - / - ) mice. Male mice were divided into four groups (control (C), control plus acai, exercise plus acai (EXA) and exercise (EX)) and fed the AIN-93M diet or the AIN-93M diet formulated to contain 2 % freeze-dried acai pulp. Mice in the EX and EXA groups were subjected to a progressive running programme (5 d/week, 60 min/d, 16 m/min) for 12 weeks. Mice that were made to exercise exhibited reduced (40.85 %; P< 0.05) hepatic superoxide dismutase activity when compared with the C mice, independent of the acai diet. Mice in the EX group exhibited a lower (42 %; P< 0.05) mRNA expression of monocyte chemotactic protein-1 in the liver compared with the C mice. Mice in the EXA and EX groups had lower percentages of hepatic lipid droplets (70 % and 56 %, respectively; P< 0.05) when compared with the C mice. Mice in the EX group had smaller (58 %; P< 0.05) area of lesions in the aorta when compared with the C mice. Serum lipid profile was not affected (P>0.05). In conclusion, aerobic exercise training rather than acai fruit pulp consumption or a combination of both enhances the hepatic oxidative and inflammatory status of ApoE - / - mice. PMID- 24787367 TI - Human papillomavirus and vaccine-related perceptions among men who have sex with men: a systematic review. AB - BACKGROUND: Targeted human papillomavirus (HPV) vaccine could prevent HPV-related cancers and genital warts among men who have sex with men (MSM). In order to develop effective vaccination programmes for MSM, it is crucial to understand their knowledge, beliefs about HPV and attitudes towards HPV vaccine. METHODS: A systematic search of 10 databases examined articles investigating HPV knowledge and HPV-related perceptions among MSM. Each paper was assessed to identify potential research directions in the context of targeted HPV vaccination for MSM. RESULTS: We identified 16 studies that included 5185 MSM and conducted mainly in North America. Generally, participants were over 26 years old, had poor-to moderate knowledge about HPV and were not concerned about HPV-related diseases. Over a half of MSM were willing to accept HPV vaccine, if offered. However, there was large variability in HPV vaccine acceptability, partially due to inconsistencies in methods of ascertainment but also different levels of HPV vaccine awareness. CONCLUSIONS: Despite several misconceptions and poor knowledge of HPV infection, MSM might be receptive to HPV vaccination. However, further research is needed to identify which factors contribute to potential vaccine uptake in hypothetical MSM-targeted HPV vaccination. Future studies need to target those MSM with little sexual experience, who would benefit most from HPV vaccination. PMID- 24787368 TI - Pitfalls in the diagnosis and management of inguinal lymphogranuloma venereum: important lessons from a case series. AB - Current lymphogranuloma venereum (LGV) guidelines mainly focus on anorectal infections. Inguinal LGV infections have been rare in the current epidemic among men who have sex with men (MSM), but might require a different approach not yet recommended in current guidelines for the treatment and diagnosis of LGV. We describe 4 inguinal LGV cases. Three MSM developed inguinal LGV infection several weeks after a previous consultation, of which two had received azithromycin after being notified for LGV. Three failed the recommended 21 days doxycycline treatment. These inguinal LGV cases highlight 3 pitfalls in the current standard management of LGV: (1) Urethral chlamydia infections in MSM can be caused by LGV biovars that in contrast to non-LGV biovars require prolonged antibiotic therapy. (2) The recommended one gram azithromycin contact treatment seems insufficient to prevent established infections. (3) Inguinal LGV may require prolonged courses of doxycycline, exceeding the currently advised 21 days regimen. PMID- 24787360 TI - Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm. AB - Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, (iv) accessibility of binding sites and cellular response to their engagement, (v) role of cell phenotype and microenvironment in targeting, (vi) optimization of targeting by lowering carrier avidity, (vii) endocytosis of multivalent carriers via molecules not implicated in internalization of their ligands, and (viii) modulation of cellular uptake and trafficking by selection of specific epitopes on the target determinant, carrier geometry, and hydrodynamic factors. Refinement of these aspects and improving our understanding of vascular biology and pathology is likely to enable the clinical translation of vascular endothelial targeting of nanocarriers. PMID- 24787369 TI - Investigation of thermoelectric properties of half-metallic Co2MnGe by using first principles calculations. AB - By combining the electronic structures obtained from first principles calculations with Boltzmann transport theory we have investigated the electronic, magnetic and transport properties of the Co2MnGe Heusler compound. The density of state plots, dispersion curves and the total energy of paramagnetic and ferromagnetic (FM) phases clearly show the half-metallic FM ground state for the compound, with an indirect band gap of about 400 meV in the minority spin channel. It has an integer value of the magnetic moment equal to 5 MU(B). In the FM phase a very large value (~ 550 uV K(-1)) of the Seebeck coefficient (S) is obtained for down-spin electrons due to the existence of an almost flat conduction band along X in the Gamma direction. The two-current model has been used to find the total S and the obtained value is about 10 uV K(-1). The calculated values of the Seebeck coefficient, resistivity and electronic thermal conductivity show nice agreement with the experimental results. PMID- 24787370 TI - Quality and safety in healthcare revisited: a challenge accepted. PMID- 24787373 TI - Abstracts of the SAEM 2014 Annual Meeting, May 13-17, 2014, Dallas, Texas. PMID- 24787375 TI - Copper stable isotopes to trace copper behavior in wetland systems. AB - Wetlands are reactive zones of the landscape that can sequester metals released by industrial and agricultural activities. Copper (Cu) stable isotope ratios (delta(65)Cu) have recently been used as tracers of transport and transformation processes in polluted environments. Here, we used Cu stable isotopes to trace the behavior of Cu in a stormwater wetland receiving runoff from a vineyard catchment (Alsace, France). The Cu loads and stable isotope ratios were determined in the dissolved phase, suspended particulate matter (SPM), wetland sediments, and vegetation. The wetland retained >68% of the dissolved Cu and >92% of the SPM bound Cu, which represented 84.4% of the total Cu in the runoff. The dissolved Cu became depleted in (65)Cu when passing through the wetland (Delta(65)Cuinlet outlet from 0.030/00 to 0.770/00), which reflects Cu adsorption to aluminum minerals and organic matter. The delta(65)Cu values varied little in the wetland sediments (0.04 +/- 0.100/00), which stored >96% of the total Cu mass within the wetland. During high-flow conditions, the Cu flowing out of the wetland became isotopically lighter, indicating the mobilization of reduced Cu(I) species from the sediments and Cu reduction within the sediments. Our results demonstrate that the Cu stable isotope ratios may help trace Cu behavior in redox-dynamic environments such as wetlands. PMID- 24787374 TI - Hantavirus infection in rodents and haemorrhagic fever with renal syndrome in Shaanxi province, China, 1984-2012. AB - The transmission of haemorrhagic fever with renal syndrome (HFRS) is deeply influenced by the reservoir and hantavirus prevalence rate. In this study, a surveillance on human HFRS cases, relative rodent abundance, and hantavirus infection prevalence was conducted in Shaanxi province, China, during 1984-2012. A generalized linear model with Poisson-distributed residuals and a log link was used to quantify the relationship between reservoir, virus and HFRS cases. The result indicated that there was a significant association of HFRS incidence with relative rodent density and the prevalence rate. This research provides evidence that the changes of infection prevalence in the reservoir could lead directly to the emergence of a new epidemic. It was concluded that the measurement of a number of these variables could be used in disease surveillance to give useful advance warning of potential disease epidemics. PMID- 24787376 TI - Junctions and inflammation in the skin. AB - The skin forms a life-sustaining barrier between the organism and physical environment. The physical barrier of skin is mainly localized in the stratum corneum (SC); however, nucleated epidermis also contributes to the barrier through tight, gap, and adherens junctions (AJs), as well as through desmosomes and cytoskeletal elements. Many inflammatory diseases, such as atopic dermatitis (AD) and psoriasis, are associated with barrier dysfunction. It is becoming increasingly clear that the skin barrier function is not only affected by inflammatory signals but that defects in structural components of the barrier may be the initiating event for inflammatory diseases. This view is supported by findings that mutations in filaggrin, a key structural epidermal barrier protein, cause the inflammatory skin disease AD, and that a loss of AJ components, namely epidermal p120 catenin or alpha-catenin results in skin inflammation. PMID- 24787377 TI - Inflammation induced by human papillomavirus in cervical cancer and its implication in prevention. AB - Many pathological conditions including most cancers show an exacerbated activation of the inflammatory pathways and their sustained maintenance. In cervical carcinogenesis, the hyperactivation of the inflammatory pathways plays an important role in tumorigenesis, progression of the disease from low-grade lesions to invasive cervical cancer as well as in the initiation of other infections such as HIV. Cyclooxygenase-2 (COX-2) is the inducible isoform of cyclooxygenases regulated by growth factors and cytokines, hence overexpressed under inflammatory conditions. Higher levels of COX-2 expression are closely related to a higher incidence of parametrial invasion and lymph node metastases in early-stage uterine cervical cancer. The principal products of COX-2 enzyme, prostanoids, are released from cells and act locally in autocrine and paracrine modes, activating diverse intracellular pathways, which in turn induce cellular proliferation, antiapoptotic activity, angiogenesis, and increased metastasis. In the current review, we focus on the role of the viral oncogenic proteins in activation of the COX-2/PGE2 pathway and their clinical implications, a better understanding of which would be helpful in designing newer and more effective therapeutic and preventive strategies for the disease. PMID- 24787378 TI - Health-related lifestyle factors and mammography screening attendance in a Swedish cohort study. AB - To determine whether health-related lifestyle factors are associated with attendance at a population-based invitational mammography screening program in southern Sweden, data on health-related lifestyle factors (smoking, alcohol use, physical activity, BMI, diet, self-rated health, and stress) were obtained from the Malmo Diet and Cancer Study and linked to the Malmo mammography register (Sweden, 1992-2009). Women (n=11 409) who were free from breast cancer at study entry were included in the cohort, and mammography attendance was followed from cohort entry to 31 December 2009. Generalized estimating equations were used to account for repeated measures within patients. Adjusted odds ratios (OR) and 95% confidence intervals (CI) are reported. Nonattendance occurred in 8% of the 69 746 screening opportunities that were observed. Nonattendance was more common among women who were current or former smokers [OR=1.60 (1.45-1.76) and OR=1.15 (1.05-1.28)], had not used alcohol in the past year [OR=1.55 (1.32-1.83)], were less physically active outside of work [OR=1.10 (1.00-1.20)], had high physical activity at work (OR=1.13, 95% CI: 1.00-1.28), were vegetarians or vegans [OR=1.49 (1.11-1.99)], had not used dietary supplements [OR=1.11 (1.01-1.21)], had poor self-rated health [OR=1.24 (1.14-1.36)], and were experiencing greater stress [OR=1.25 (1.14-1.36)]. In this cohort, nonattendance was associated with smoking, alcohol abstinence, physical activity, poor self-rated health, stress, and following a vegetarian/vegan diet. These findings generally support the notion that women with less healthy lifestyles are less likely to engage in mammography screening. PMID- 24787380 TI - Folate intake and breast cancer prognosis: a meta-analysis of prospective observational studies. AB - Some studies have investigated the association between folate intake and breast cancer prognosis, but the results have been far from conclusive. Thus, a meta analysis was carried out to explore this association. We performed a comprehensive search of the PubMed, Web of Knowledge, and Cochrane databases from inception to May 2013. The summary hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a random effects model. Prespecified stratified analyses, sensitivity analyses, and dose-response analysis were also carried out. Five studies, with a total of 7299 participants, were included in the meta-analysis. The pooled HR (95% CI) of the five studies on the association of dietary folate intake (highest vs. lowest) with all-cause mortality was 0.74 (0.60-0.92). Stratified analyses suggested that the inverse association of dietary folate and all-cause mortality was more easily detected in studies that focused on prediagnosis diets, included more patients (>1000), had longer follow up periods (>7 years), used structured interviews, or had more categories of folate intake (>3). However, none of these differences was statistically significant. No significant association was found between total (dietary and supplementary) folate intake and all-cause mortality, or dietary folate intake and breast cancer-specific mortality, with pooled HRs (95% CI) of 0.93 (0.75 1.15) and 0.79 (0.61-1.01), respectively. Sensitivity analyses confirmed the robustness of the findings by excluding studies that poorly represented the cohort. Our findings suggest a significant inverse association between dietary folate intake and all-cause mortality, but not between total folate intake and all-cause mortality. PMID- 24787379 TI - Screening history of cervical cancers in Emilia-Romagna, Italy: defining priorities to improve cervical cancer screening. AB - Most invasive cervical cancers in industrialized countries are due to the lack of Pap test coverage, very few are due to screening failures. This study aimed at quantifying the proportion of invasive cancers occurring in nonscreened or underscreened women and that in women with a previous negative screening, that is, screening failure, during the first two screening rounds (1996-2002) and in the following rounds (2003-2008) in the Emilia-Romagna region. All cases of invasive cancers registered in the regional cancer registry between 1996 and 2008 were classified according to screening history through a record linkage with the screening programme registry. The incidence significantly decreased from 11.6/100 000 to 8.7/100 000; this decrease is due to a reduction in squamous cell cancers (annual percentage change -6.2; confidence interval: -7.8, -4.6) and advanced cancers (annual percentage change -6.6; confidence interval: -8.8, -4.3), whereas adenocarcinomas and microinvasive cancers were essentially stable. The proportion of cancers among women not yet invited and among nonresponders decreased over the two periods, from 45.5 to 33.3%. In contrast, the proportion of women with a previous negative Pap test less than 5 years and 5 years or more before cancer incidence increased from 5.7 to 13.3% and from 0.3 to 5.5%, respectively. Although nonattendance of the screening programme remains the main barrier to cervical cancer control, the introduction of a more sensitive test, such as the human papillomavirus DNA test, could significantly reduce the burden of disease. PMID- 24787382 TI - Diagnosis of infection after splenectomy for trauma should be based on lack of platelets rather than white blood cell count. AB - BACKGROUND: There is a lack of evidence-based criteria to assist the diagnosis of infection following trauma splenectomy (TS). However, the literature suggests that white blood cell count (WBC) is associated with infection in patients who undergo TS. We sought to find whether there exist key differences in laboratory and clinical parameters that can assist the diagnosis of infection after TS. METHODS: We evaluated all consecutive trauma patients who had undergone TS at a Level 1 trauma center from 2005 to 2011 for the development of infection. To do this, we compared the values of demographic, laboratory, and clinical variables of infected and non-infected patients on odd post-operative days (POD) in the period from 1-15 days after TS. RESULTS: Of 127 patients who underwent TS, 25 died within 48 h after the procedure and were excluded from our analysis, leaving, 102 patients for investigation. In the 41 (40%) patients who developed an infection, the mean day for the first infectious episode was POD 7 (range, POD 4-14). The three most common infections were pneumonia (51%), urinary tract infection (24%), and bacteremia (20%). An evaluation of laboratory and clinical parameters showed no differences in the WBC of the patients who did and did not develop infections at any time in the 15 d after TS. However, the platelet count was statistically significantly higher in non-infected patients on POD 3-9 and on POD 13, and maximal body temperature was statistically significantly higher in the infected group of patients during the first week after TS. Differences in laboratory and clinical values of the infected and non-infected patients were greatest on POD 5. CONCLUSIONS: Patients who undergo TS have high rates of infectious complications. The WBC is not a reliable predictor of infection in these patients in the 2 wks following TS. However, patients who do not develop infection after TS have statistically significantly higher absolute platelet counts and rates of change in their daily platelet counts than those who develop infection. PMID- 24787381 TI - Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein. AB - Prostate cancer frequently metastasizes to the skeleton but the underlying mechanism remains largely undefined. Discoidin domain receptor 2 (DDR2) is a member of receptor tyrosine kinase (RTK) family and is activated by collagen binding. This study aimed to investigate the function and detailed mechanism of DDR2 in prostate cancer bone dissemination. Herein we found that DDR2 was strongly expressed in bone-metastatic prostate cancer cells and tissues compared to that in normal controls. Enhanced expression of constitutively activated DDR2 led to elevation in motility and invasiveness of prostate cancer cells, whereas knockdown of DDR2 through specific shRNA caused a dramatic repression. Knockdown of DDR2 in prostate cancer cells resulted in significant decrease in the proliferation, differentiation and function of osteoblast. Over-expression of DDR2 in prostate cancer cells resulted in notable acceleration of osteoclast differentiation and bone resorption, whereas knockdown of DDR2 exhibited the opposite effects. An intrabone injection bone metastasis animal model demonstrated that DDR2 promoted osteolytic metastasis in vivo. Molecular evidence demonstrated that DDR2 regulated the expression, secretion, and promoter activity of parathyroid hormone-related protein (PTHrP), via modulating Runx2 phosphorylation and transactivity. DDR2 was responsive to TGF-beta and involved in TGF-beta-mediated osteoclast activation and bone resorption. In addition, DDR2 facilitated prostate cancer cells adhere to type I collagen. This study reveals for the first time that DDR2 plays an essential role in prostate cancer bone metastasis. The mechanism disclosure may provide therapeutic targets for the treatment of prostate cancer. PMID- 24787383 TI - Fast closure of N-terminal long loops but slow formation of beta strands precedes the folding transition state of Escherichia coli adenylate kinase. AB - The nature of the earliest steps of the initiation of the folding pathway of globular proteins is still controversial. To elucidate the role of early closure of long loop structures in the folding transition, we studied the folding kinetics of subdomain structures in Escherichia coli adenylate kinase (AK) using Forster type resonance excitation energy transfer (FRET)-based methods. The overall folding rate of the AK molecule and of several segments that form native beta strands is 0.5 +/- 0.3 s(-1), in sharp contrast to the 1000-fold faster closure of three long loop structures in the CORE domain. A FRET-based "double kinetics" analysis revealed complex transient changes in the initially closed N terminal loop structure that then opens and closes again at the end of the folding pathway. The study of subdomain folding in situ suggests a hierarchic ordered folding mechanism, in which early and rapid cross-linking by hydrophobic loop closure provides structural stabilization at the initiation of the folding pathway. PMID- 24787384 TI - Long-term outcome of foveolar internal limiting membrane nonpeeling for myopic traction maculopathy. AB - PURPOSE: To investigate the long-term results of a novel technique to preserve the foveolar cone without peeling off the foveolar internal limiting membrane (ILM) during myopic traction maculopathy surgery. METHODS: Nineteen patients (19 eyes) were retrospectively studied and divided into 2 groups by the extent of ILM peeled and followed for more than 3 years. Group 1: foveolar ILM nonpeeling group (FN) (12 eyes) and Group 2: total peeling of foveal ILM group (TP) (7 eyes). A donut-shaped ILM was peeled off, leaving a 400-MUm diameter ILM over foveola with a sharp margin in FN group. RESULTS: Macular hole was developed in 2 of the 7 eyes (28.6%) in the TP group and none in the FN group. Long-term central fovea thickness thinning and decrease of vision were found in the TP group, but not in the FN group (P < 0.05). Inner segment/outer segment line recovered in 75% of the 12 eyes in the FN group, but in only 14.3% of the 7 eyes in the TP group. CONCLUSION: Preservation of the foveolar cone by foveola nonpeeling surgery correlates with better anatomical and visual results than total peel, prevents long-term foveolar retinal thinning, and successfully saves the fovea from macular hole formation. PMID- 24787385 TI - Diagnostic and therapeutic challenges. PMID- 24787386 TI - Conserved noncoding elements follow power-law-like distributions in several genomes as a result of genome dynamics. AB - Conserved, ultraconserved and other classes of constrained elements (collectively referred as CNEs here), identified by comparative genomics in a wide variety of genomes, are non-randomly distributed across chromosomes. These elements are defined using various degrees of conservation between organisms and several thresholds of minimal length. We here investigate the chromosomal distribution of CNEs by studying the statistical properties of distances between consecutive CNEs. We find widespread power-law-like distributions, i.e. linearity in double logarithmic scale, in the inter-CNE distances, a feature which is connected with fractality and self-similarity. Given that CNEs are often found to be spatially associated with genes, especially with those that regulate developmental processes, we verify by appropriate gene masking that a power-law-like pattern emerges irrespectively of whether elements found close or inside genes are excluded or not. An evolutionary model is put forward for the understanding of these findings that includes segmental or whole genome duplication events and eliminations (loss) of most of the duplicated CNEs. Simulations reproduce the main features of the observed size distributions. Power-law-like patterns in the genomic distributions of CNEs are in accordance with current knowledge about their evolutionary history in several genomes. PMID- 24787387 TI - Rapid and efficient isolation of high-quality small RNAs from recalcitrant plant species rich in polyphenols and polysaccharides. AB - Small RNAs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), are important regulators of plant development and gene expression. The acquisition of high-quality small RNAs is the first step in the study of its expression and function analysis, yet the extraction method of small RNAs in recalcitrant plant tissues with various secondary metabolites is not well established, especially for tropical and subtropical plant species rich in polysaccharides and polyphenols. Here, we developed a simple and efficient method for high quality small RNAs extraction from recalcitrant plant species. Prior to RNA isolation, a precursory step with a CTAB-PVPP buffer system could efficiently remove compounds and secondary metabolites interfering with RNAs from homogenized lysates. Then, total RNAs were extracted by Trizol reagents followed by a differential precipitation of high-molecular-weight (HMW) RNAs using polyethylene glycol (PEG) 8000. Finally, small RNAs could be easily recovered from supernatant by ethanol precipitation without extra elimination steps. The isolated small RNAs from papaya showed high quality through a clear background on gel and a distinct northern blotting signal with miR159a probe, compared with other published protocols. Additionally, the small RNAs extracted from papaya were successfully used for validation of both predicted miRNAs and the putative conserved tasiARFs. Furthermore, the extraction method described here was also tested with several other subtropical and tropical plant tissues. The purity of the isolated small RNAs was sufficient for such applications as end-point stem-loop RT-PCR and northern blotting analysis, respectively. The simple and feasible extraction method reported here is expected to have excellent potential for isolation of small RNAs from recalcitrant plant tissues rich in polyphenols and polysaccharides. PMID- 24787389 TI - Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. AB - OBJECTIVE: To investigate the effect of homocysteine (Hcy) on intestinal permeability in rats with TNBS/ethanol-induced colitis and elucidate its mechanism. METHODS: Sprague-Dawley rats were divided into four groups: normal, normal + Hcy injection, TNBS model, and TNBS model + Hcy injection. Experimental colitis was induced by trinitrobenzene sulfonic acid (TNBS) in 50% ethanol; rats were injected subcutaneously with Hcy from the first day after the induction of experimental colitis on 30 consecutive days. To determine the severity of colitis, the disease activity index (DAI) was evaluated; colon tissues were collected for the detection of the activity of myeloperoxidase (MPO) and the contents of MDA, IL-1beta, IL-6, TNF-alpha, MMP-2, and MMP-9. Intestinal epithelial permeability was assessed with Evans blue (EB) dye. The levels of Hcy in plasma and colon mucosa were measured by high-performance liquid chromatography-fluorescence detection (HPLC-FD). RESULTS: Compared with the normal group, the DAI scoring and MPO activity, contents of MDA, IL-1beta, IL-6, TNF-alpha, MMP-2, MMP-9 in the colon and EB in the small intestine were significantly increased in the TNBS group (P < 0.01). Compared with the TNBS model group, the DAI scoring, plasma and colonic mucosa Hcy levels, MPO activity and contents of MDA, IL-1beta, IL-6, TNF-alpha, MMP-2, MMP-9 in colon and EB in small intestine were significantly increased in the TNBS-induced colitis rats with simultaneous Hcy injection (P < 0.01). CONCLUSION: Hcy can increase intestinal permeability and aggravate inflammatory damage in rats with TNBS induced colitis, the underlying mechanisms of which may be attributed to its effects of promoting the expression of MMP-2 and MMP-9, leading to injury of the intestinal barrier. PMID- 24787390 TI - Sengstaken-Blakemore tube for non-variceal distal esophageal bleeding refractory to endoscopic treatment: a case report & review of the literature. AB - Non-variceal upper-gastrointestinal bleeding (NVUGIB) refractory to therapeutic endoscopy is a challenging situation. The following details a novel use for the Sengstaken-Blakemore tube in a case of severe ulcerative esophagitis after failure of conventional medical and endoscopic treatment. A 77-year-old man with a history of peptic ulcer disease developed massive hematemesis during a hospital admission. Initial gastroscopy revealed an adherent blood clot occupying the distal esophagus, extending to the gastric cardia and proximal fundus. Epinephrine was injected into and surrounding the clot; however, following the endoscopy the patient was hemodynamically unstable, requiring aggressive resuscitation. Repeat gastroscopy, following saline lavage, revealed active bleeding within severely ulcerated esophageal mucosa, immediately proximal to the gastro-esophageal (GE) junction. Despite apparent hemostasis following injection of epinephrine and electrocautery, the patient displayed clinical signs of continued bleeding. Furthermore, surgical and radiological interventions were precluded by the patient's hemodynamic instability. In an attempt to tamponade blood supply to the GE junction, a Sengstaken-Blakemore tube was inserted and placed under tension. Successful hemostasis was subsequently achieved and the patient remained stable. This is the first case to describe use of a Sengstaken Blakemore tube in severe ulcerative esophagitis refractory to standard endoscopic management. PMID- 24787392 TI - The positive role of religion and religious communities in child protection. PMID- 24787391 TI - Suicide gene-mediated sequencing ablation revealed the potential therapeutic mechanism of induced pluripotent stem cell-derived cardiovascular cell patch post myocardial infarction. AB - AIMS: This study is designed to assess the protective cardiac effects after myocardial infarction (MI) of (i) cardiovascular progenitor cells (PC) differentiated directly into cardiomyocytes (CM) and endothelial cells (ECs) at the injury site, as separable from the effects of (ii) paracrine factors released from PC. RESULTS: In vivo: bi-cell patch containing induced pluripotent stem cell (iPSC)-derived CM and EC (BIC) was transplanted onto the infarcted heart. BIC were transduced with herpes simplex virus thymidine kinase "suicide" gene driven by cardiac NCX1 or endothelial vascular endothelium-cadherin promoter. IGF-1alpha and VEGF levels released from ischemic tissues were significantly enhanced in the BIC patch treatment group. Heart function, infarction size, and vessel density were significantly improved after BIC patch treatment. These effects were completely abolished in the group given ganciclovir (GCV) at week 1 as a suicide gene activator, and partially abolished in the group given GCV at week 3 as compared with the untreated cell patch group. INNOVATION: This study was designed to distinguish between cell-based and noncell-based therapeutic effects of PC lineages after MI. PCs derived from iPSC were genetically modified to express "suicide" gene. iPSC-derived CM and EC were then ablated in situ at week 1 and 3 by intraperitoneal administration of GCV. This enabled direct assessment of the effects of iPSC transplantation on myocardial function and tissue regeneration potential. CONCLUSIONS: Data support a mechanism in which iPSC-derived cardiovascular lineages contribute directly to improved cardiac performance and attenuated remodeling. Paracrine factors provide additional support to the restoration of heart function. PMID- 24787393 TI - Refractive index and geometrical thickness measurement of a transparent pellicle in air by Gaussian beam defocusing. AB - We demonstrate that it is possible to measure the local geometrical thickness and the refractive index of a transparent pellicle in air by combining the diffractive properties of a Gaussian beam with the analytical equations of the light that propagates through a thin layer. We show that our measurement technique is immune to inherent piston-like vibrations present in the pellicle. As our measurements are based on characterizing properly the Gaussian beam in a plane of detection, a homodyne technique for this purpose is devised and described. The feasibility of our proposal is confirmed by measuring local geometrical thicknesses and the refractive index of a commercially available stretch film. PMID- 24787394 TI - Ground-based airglow imaging interferometer. Part 2: forward model and inverse method. AB - The ground-based airglow imaging interferometer (GBAII) observes the nighttime airglow of the O2(0-1) 867.7 nm line, peaked at 94 km altitude, to measure the upper atmospheric wind and temperature field. Its forward model, a code package in interactive data language (IDL), is developed to simulate the expected imaging interference fringes. It includes eight modules to simulate the light source, the atmospheric radiation transmission, the wide-angle Michelson interferometer, the interference filter, the optical system decay function, the responsivity, the imaging CCD, and the noises. The inverse method is also developed for obtaining the rest phase calibration, temperature, and wind. By means of both theoretical tools, we carry out a comparison of theoretical results with a field observation case. The apparent quantities J(1-p) from the forward model has the deviation of 1.5%-2.5% compared with that from the observation image. The temperature falls mainly in the range of 167-196 K with the precision of 2 K. The zonal and meridional winds are mainly in the region of 5.1 to 46.5 m/s and 12.5 to 48.3 m/s respectively, with errors of 13.2 to 21.5 m/s. The consistent trends between the observation results and standard models (MSISE90 and HWM93) suggest that the forward model and inverse method are suitable for GBAII. PMID- 24787395 TI - Undersea laser communication using polarization and wavelength modulation. AB - We report a technique to increase the data rate of a free-space all-undersea laser communication link using polarization and wavelength modulation. Measurements were made at various background light levels to estimate the required power increase as a function of bits per pulse. Transmission measurements were made of laser light through a 2-m-long tube filled with a mixture of Maalox and water to simulate ocean-water conditions for several receiver field-of-view (FOV) angles. A degree of polarization greater than 98% was measured at FOVs up to 100 mrad at an attenuation of 14 extinction lengths. PMID- 24787396 TI - Propagation analysis of Ince-Gaussian beams in turbulent atmosphere. AB - We analyze the properties of Ince-Gaussian beams propagating in turbulent atmosphere. Due to analytic difficulties, this analysis is done with the aid of a random phase screen setup. Intensity profile, beam size, and the kurtosis parameter are evaluated against the changes in beam orders, propagation distance, and turbulence levels. It is found that when propagating in turbulence, Ince Gaussian beams will no longer keep their beam profile invariant like in free space but will experience beam profile changes. These changes will cause additional beam spreading, as well as an increase in beam size and the kurtosis parameter. PMID- 24787397 TI - Total variation regularization cost function for demodulating phase discontinuities. AB - We introduce a method based on the minimization of a total variation regularization cost function for computing discontinuous phase maps from fringe patterns. The performance of the method is demonstrated by numerical experiments with both synthetic and real data. PMID- 24787398 TI - Coherent chirped pulse laser network with Mickelson phase conjugator. AB - The mechanisms of nonlinear phase-locking of a large fiber amplifier array are analyzed. The preference is given to the most suitable configuration for a coherent coupling of thousands of fundamental spatial mode fiber beams into a single smooth beam ready for chirped pulse compression. It is shown that a Michelson phase-conjugating configuration with double passage through an array of fiber amplifiers has the definite advantage compared to a one-way fiber array coupled in a Mach-Zehnder configuration. Regardless of the amount of synchronized fiber amplifiers, the Michelson phase-conjugating interferometer is expected to do a perfect compensation of the phase-piston errors and collimation of backwardly amplified fiber beams on an entrance/output beam splitter. In both configurations, the nonlinear transformation of the stretched pulse envelope, due to gain saturation, is capable of randomizing the position of chirp inside an envelope; thus it may reduce the visibility of the interference pattern at an output beam splitter. Certain advantages are inherent to the sech-form temporal envelope because of the exponential precursor and self-similar propagation in gain medium. The Gaussian envelope is significantly compressed in a deep gain saturation regime, and the frequency chirp position inside pulse envelope is more deformed. PMID- 24787399 TI - Large-aperture fast multilevel Fresnel zone lenses in glass and ultrathin polymer films for visible and near-infrared imaging applications. AB - The ability to fabricate 4-level diffractive structures with 1 um critical dimensions has been demonstrated for the creation of fast (~f/3.1 at 633 nm) Fresnel zone lenses (FZLs) with >60% diffraction efficiency into the -1 focusing order and nearly complete suppression of 0 and +1 orders. This is done using tooling capable of producing optics with 800 mm apertures. A 4-level grating fabricated in glass at 300 mm aperture is shown to have <15 nm rms holographic phase error. Glass FZLs have also been used as mandrels for casting zero-thermal expansion, 20 um thick polymer films created with the 4-level structure as a route to mass replication of efficient diffractive membranes for ultralight segmented space-based telescope applications. PMID- 24787400 TI - Improvement in the synchronization between the radio frequency signal and the image detector in an acousto-optic tunable filter imaging spectrometer. AB - An improved synchronization between the radio frequency (RF) signal and the image detector in an acousto-optic tunable filter (AOTF) imaging spectrometer is proposed to optimize power consumption and eliminate image smear. The RF signal is controlled on and off alternately to match the exposure of the image sensor. This scheme reduces the RF power and rejects the light illumination on the image sensor in the interval of charge transfer. An experiment using a visible AOTF, a frame transfer charge-coupled device camera, and an incandescent lamp is conducted for demonstration. The average RF power decreases 7.6%, and the image smear is eliminated. PMID- 24787401 TI - Optical roughness BRDF model for reverse Monte Carlo simulation of real material thermal radiation transfer. AB - Optical roughness was introduced into the bidirectional reflectance distribution function (BRDF) model to simulate the reflectance characteristics of thermal radiation. The optical roughness BRDF model stemmed from the influence of surface roughness and wavelength on the ray reflectance calculation. This model was adopted to simulate real metal emissivity. The reverse Monte Carlo method was used to display the distribution of reflectance rays. The numerical simulations showed that the optical roughness BRDF model can calculate the wavelength effect on emissivity and simulate the real metal emissivity variance with incidence angles. PMID- 24787402 TI - Application of the windowed-Fourier-transform-based fringe analysis technique for investigating temperature and concentration fields in fluids. AB - The present work is concerned with the development and application of a novel fringe analysis technique based on the principles of the windowed-Fourier transform (WFT) for the determination of temperature and concentration fields from interferometric images for a range of heat and mass transfer applications. Based on the extent of the noise level associated with the experimental data, the technique has been coupled with two different phase unwrapping methods: the Itoh algorithm and the quality guided phase unwrapping technique for phase extraction. In order to generate the experimental data, a range of experiments have been carried out which include cooling of a vertical flat plate in free convection conditions, combustion of mono-propellant flames, and growth of organic as well as inorganic crystals from their aqueous solutions. The flat plate and combustion experiments are modeled as heat transfer applications wherein the interest is to determine the whole-field temperature distribution. Aqueous-solution-based crystal growth experiments are performed to simulate the mass transfer phenomena and the interest is to determine the two-dimensional solute concentration field around the growing crystal. A Mach-Zehnder interferometer has been employed to record the path-integrated quantity of interest (temperature and/or concentration) in the form of interferometric images in the experiments. The potential of the WFT method has also been demonstrated on numerically simulated phase data for varying noise levels, and the accuracy in phase extraction have been quantified in terms of the root mean square errors. Three levels of noise, i.e., 0%, 10%, and 20% have been considered. Results of the present study show that the WFT technique allows an accurate extraction of phase values that can subsequently be converted into two-dimensional temperature and/or concentration distribution fields. Moreover, since WFT is a local processing technique, speckle patterns and the inherent noise in the interferometric data do not affect the resultant phase values. Brief comparisons of the accuracy of the WFT with other standard techniques such as conventional Fourier-filtering methods are also presented. PMID- 24787404 TI - Frequency switched narrow linewidth microwave signal photonic generation based on a double-Brillouin-frequency spaced fiber laser. AB - A simple photonic approach to generate microwave frequency switched microwave signal is proposed and experimentally demonstrated. In this scheme, a Brillouin fiber laser with double-Brillouin-frequency spacing is used. The Brillouin ring configuration suppresses incoming Brillouin pump and even-order Stokes signals in the cavity. In addition, it also allows propagation of the odd-order Brillouin Stokes signals from configuration to output coupler. A dual-wavelength optical signal is heterodyned at the high-speed photodetector to produce a microwave signal. Frequency switched microwave signals, at 10.75 and 21.39 GHz, respectively, can be obtained through adjusting the polarization controller (PC) and loss of the variable optical attenuator (VOA). PMID- 24787403 TI - Synthesis of dye conjugates to visualize the cancer cells using fluorescence microscopy. AB - The clinical diagnosis of most cancers is based on evaluation of histology microscopic slides to view the size and shape of cellular nuclei and morphological structure of tissue. To achieve this goal for in vivo and in-deep tissues, near infrared dyes-bovine serum albumin and immunoglobulin G conjugates were synthesized. The spectral study shows that the absorption and fluorescence of the dye conjugates are in the "tissue optical window" spectral ranges between 650 and 900 nm. The internalization and pinocytosis of the synthesized compounds were investigated at cell level using fluorescence microscopy to obtain the optimal concentration and staining time. PMID- 24787405 TI - Validity of scalar diffraction theory and effective medium theory for analysis of a blazed grating microstructure at oblique incidence. AB - The accuracy of scalar diffraction theory (SDT) and effective medium theory (EMT) for analyzing a blazed grating is quantitatively demonstrated by making a comparison of diffraction efficiencies calculated by the two simplified methods to exact results from the Fourier modal method (FMM). It is found that when the normalized period is more than fivefold wavelength of incident light at normal incidence and is more than about tenfold wavelength at larger incident angle, SDT can be used to easily analyze effectively the transmittance characteristics of a blazed grating with divergence less than 1%. Particularly, for zeroth-order diffraction when the groove depth is less than threefold wavelength, the transmittance calculated by SDT with refractive index of 1.5 and normalized period of 5.0 agrees well with that of FMM at normal incidence. But, for +/-1 orders, the validity of SDT is degraded from that for zeroth order. Generally, the deviation of transmittances between the SDT and the FMM increases as the incident angle and refractive index augment. Furthermore, when higher diffraction orders other than zeroth order are not propagating, the EMT is valid to evaluate the transmittance of a blazed grating at normal incidence. Similarly, the error of transmittances between the EMT and the FMM increases with the increase of incident angle and refractive index. The effectiveness of the SDT and the EMT for analyzing a blazed grating in the range of the normalized period far more than and less than the wavelength of incident light, respectively, is dependent on the parameters including incident angle, refractive index, normalized period, and normalized groove depth. PMID- 24787406 TI - Scanning laser-line source technique for nondestructive evaluation of cracks in human teeth. AB - This paper describes the first application of a remote nondestructive laser ultrasonic (LU) system for clinical diagnosis of cracks in human teeth, to our knowledge. It performs non-contact cracks detection on small-dimension teeth samples. Two extracted teeth with different types of cracks (cracked tooth and craze lines), which have different crack depths, are used as experimental samples. A series of ultrasonic waves were generated by a scanning laser-line source technique and detected with a laser-Doppler vibrometer on the two samples. The B-scan images and peak-to-peak amplitude variation curves of surface acoustic waves were obtained for evaluating the cracks' position and depth. The simulation results calculated by finite element method were combined with the experimental results for accurately measuring the depth of crack. The results demonstrate that this LU system has been successfully applied on crack evaluation of human teeth. And as a remote, nondestructive technique, it has great potential for early in vivo diagnosis of cracked tooth and even the future clinical dental tests. PMID- 24787407 TI - Optically controllable switch for light propagation based on triple coupled quantum dots. AB - A switch is proposed for controlling the subluminal and superluminal light propagation through the triple coupled quantum dots system. The steady-state and transient behavior of the absorption and the dispersion of a probe pulse through a triple quantum dots molecule are investigated. We demonstrate that the group velocity of a light pulse can be controlled from subluminal to superluminal or vice versa by controlling the rates of incoherent pumping and tunneling between electronic levels. Switching time is calculated by discussing the dependency of optical transient properties on the incoherent pumping and inter-dot tunneling rates. We introduce three controlling parameters that make it possible to control the wave propagation electrically or even optically in such coupled quantum dot systems. PMID- 24787408 TI - Class of resonator for slab waveguide lasers. AB - We describe a class of laser resonator, incorporating a feedback collimator (FBC), that provides feedback that is mode-matched onto a higher-order lateral mode of a slab waveguide laser. In addition, this same resonator, in outcoupling, converts the stabilized higher-order lateral mode into an essentially laterally collimated output beam with a width that exceeds twice the width of the laser active region. This output beam should have excellent beam quality. Here, we develop the FBC resonator design principles and describe both refractive and reflective versions. Finally, we compare the efficiencies and thresholds of an FBC resonator and an angled-ridge resonator applied to a broad-ridge quantum cascade laser. PMID- 24787409 TI - Compact polarization rotator for silicon-based slot waveguide structures. AB - A compact polarization rotator (PR) for silicon-based slot waveguides is proposed, where the slot region including the upper claddings is filled with liquid crystals (LCs). With the anisotropic features of the LCs, the transverse field components of eigenmodes have almost identical amplitudes, leading to a high modal hybridness. As a result, the TE (TM) polarization can be rotated efficiently to the TM (TE) polarization within a short length. The numerical results show that a PR 11.3 MUm in length at an operating wavelength of 1.55 MUm is achieved with an extinction ratio (ER) (insertion loss) of 12.6 (0.22) dB for TE-to-TM and 11.5 (0.30) dB for TM-to-TE. Moreover, the optical bandwidth for TE to-TM (TM-to-TE) mode must be ~64(~29) nm to keep the ER over 12 (10) dB. In addition, fabrication tolerances to the structural parameters are investigated, and field evolution along the propagation distance through the PR is also demonstrated. PMID- 24787410 TI - Holodiagram: elliptic visualizing interferometry, relativity, and light-in flight. AB - In holographic interferometry, there is usually a static distance separating the point of illumination and the point of observation. In Special Relativity, this separation is dynamic and is caused by the velocity of the observer. The corrections needed to compensate for these separations are similar in the two fields. We use the ellipsoids of the holodiagram for measurement and in a graphic way to explain and evaluate optical resolution, gated viewing, radar, holography, three-dimensional interferometry, Special Relativity, and light-in-flight recordings. Lorentz contraction together with time dilation is explained as the result of the eccentricity of the measuring ellipsoid, caused by its velocity. The extremely thin ellipsoid of the very first light appears as a beam aimed directly at the observer, which might explain the wave or ray duality of light and entanglement. Finally, we introduce the concept of ellipsoids of observation. PMID- 24787411 TI - Optical role of randomness for structured surfaces. AB - It has long been known that random height variations of a repeated nanoscale structure can give rise to smooth angular color variations instead of the well known diffraction pattern experienced if no randomization is present. However, until now there have been few publications trying to explain this and similar phenomena taking outset in electromagnetic theory. This paper presents a method for analyzing far-field reflection from a surface constructed by translated instances of a given structure. Several examples of the effect of random translations are given. PMID- 24787412 TI - Rigorous investigation of the array-tilt aberration for hexagonal, optical phased arrays. AB - An investigation of the array-tilt aberration for hexagonal, optical phased arrays is presented. The investigation begins with theoretical derivations of the far-zone radiated field, the array factor, and the far-field radiated power for the seven-element hexagonal array with array tilt present. Physical insights gained from this analysis are discussed. An analytical treatment of correlation based array-tilt estimators is also undertaken. Two novel array-tilt estimation techniques are developed from the analysis. The new techniques are shown to be significantly more efficient computationally than the traditional estimation approach. Simulation and experimental results are presented to validate the new array-tilt estimation methods. PMID- 24787413 TI - Optical activities of large-area SU8 microspirals fabricated by multibeam holographic lithography. AB - We report on the fabrication of large-area microspirals in SU8 photoresist using a 6+1 beam holographic lithography (HL) technique involving the interference of six linearly polarized side beams and one circularly polarized central beam. In contrast to common photoresist-substrate (glass) configuration, the spirals are fabricated on a substrate with a precured thin SU8 photoresist. This SU8-SU8 glass configuration strengthens the attachment of the spirals to the substrate, and hence enhances the quality of the fabricated spirals. The fabricated SU8 microspirals exhibit large optical activities with a polarization rotation close to 10 deg and a circular dichroism of about 0.5 in the visible range. Our precured substrate method could lift the limitations of the HL method in fabricating large and uniform microstructures or nanostructures. PMID- 24787414 TI - Wavelength-selective infrared Salisbury screen absorber. AB - Experimental long wavelength infrared spectral response characterization of a narrowband Salisbury screen absorber suitable for use in microbolometer focal plane arrays is presented. We have demonstrated a microfabricated germanium dielectric support structure layer that replaces the usual silicon nitride structural layer in microbolometers. The fabricated Salisbury screen absorber consists of a chromium resistive sheet as an absorber layer above a germanium dielectric/air-gap/interference structure. In order to produce wavelength selective narrowband absorption, the general design rules for the germanium dielectric supported Salisbury screen show that the thickness of the air gap should be a half wavelength thick and the optical thickness of the germanium layer a quarter dielectric wavelength thick. PMID- 24787415 TI - Statistics of remote roll angle measurement. AB - Remote measurement of object orientation is used in various scientific fields, such as robotics, optics, and biology (e.g., optical tweezers). Roll angle is one of the three angles that describe the orientation of an object in space. A common method to measure the roll angle is based on analyzing the polarization of the backreflection of a beam. The accuracy of the measurement is degraded by low signal-to-noise ratio (SNR). The low SNR is the result of the large distance between the measurement device and the object, or due to the small backreflection cross section. We perform a laboratory experiment and derive a mathematical model for the probability density function of the measured roll angle and its expectation value. This model makes it possible to calculate the accuracy of the roll angle measurement at low SNRs. Experiments and theoretical analysis using our model were performed and good agreement between the two approaches has been found. PMID- 24787416 TI - Polarization filter characteristics of photonic crystal fibers with square lattice and selectively filled gold wires. AB - A novel design of Au-filled photonic crystal fiber (PCF) with square lattice has been proposed in this paper. The resonance strength of the surface plasmon mode and the impacts of structural parameters of the PCF on the polarization filter characteristics are studied through the finite element method. Numerical results show that the sizes of Au wires and the symmetry of the air holes near the fiber core have a great effect on the polarization filter characteristics. In the optimization process, it was found that the resonance strengths can reach 279.10 and 399.18 dB/cm at wavelengths of 1.02 MUm and 1.55 MUm, respectively, which can be applied in many polarization filter devices. PMID- 24787417 TI - High-precision topography measurement through accurate in-focus plane detection with hybrid digital holographic microscope and white light interferometer module. AB - High-precision topography measurement of micro-objects using interferometric and holographic techniques can be realized provided that the in-focus plane of an imaging system is very accurately determined. Therefore, in this paper we propose an accurate technique for in-focus plane determination, which is based on coherent and incoherent light. The proposed method consists of two major steps. First, a calibration of the imaging system with an amplitude object is performed with a common autofocusing method using coherent illumination, which allows for accurate localization of the in-focus plane position. In the second step, the position of the detected in-focus plane with respect to the imaging system is measured with white light interferometry. The obtained distance is used to accurately adjust a sample with the precision required for the measurement. The experimental validation of the proposed method is given for measurement of high numerical-aperture microlenses with subwavelength accuracy. PMID- 24787418 TI - Modified subaperture tool influence functions of a flat-pitch polisher with reverse-calculated material removal rate. AB - Numerical simulation of subaperture tool influence functions (TIF) is widely known as a critical procedure in computer-controlled optical surfacing. However, it may lack practicability in engineering because the emulation TIF (e-TIF) has some discrepancy with the practical TIF (p-TIF), and the removal rate could not be predicted by simulations. Prior to the polishing of a formal workpiece, opticians have to conduct TIF spot experiments on another sample to confirm the p TIF with a quantitative removal rate, which is difficult and time-consuming for sequential polishing runs with different tools. This work is dedicated to applying these e-TIFs into practical engineering by making improvements from two aspects: (1) modifies the pressure distribution model of a flat-pitch polisher by finite element analysis and least square fitting methods to make the removal shape of e-TIFs closer to p-TIFs (less than 5% relative deviation validated by experiments); (2) predicts the removal rate of e-TIFs by reverse calculating the material removal volume of a pre-polishing run to the formal workpiece (relative deviations of peak and volume removal rate were validated to be less than 5%). This can omit TIF spot experiments for the particular flat-pitch tool employed and promote the direct usage of e-TIFs in the optimization of a dwell time map, which can largely save on cost and increase fabrication efficiency. PMID- 24787419 TI - Eye-safe single-frequency single-mode polarized all-fiber pulsed laser with peak power of 361 W. AB - An all-fiber, single-frequency, single-mode linearly polarized, high peak power pulsed laser at 1540 nm for coherent Doppler wind lidar is demonstrated. A narrow linewidth seed laser is pulse modulated by an acousto-optic modulator and then amplified by two-stage cascade amplifiers. An 0.8 m long erbium/ytterbium co doped polarization-maintaining fiber with a core diameter of 10 MUm is used as the gain fiber of a power amplifier, and longitudinally varied strains are applied on the gain fiber to realize approximately 3.4 times enhancement of the stimulated Brillouin scattering threshold. Peak power of 361 W pulse width of 200 ns at 10 kHz repetition rate is achieved with transform-limited linewidth and diffraction-limited beam quality. To the best of our knowledge, it is the highest peak power of an eye-safe, single-mode narrow-linewidth pulsed fiber laser based on 10 MUm core diameter silica fiber. PMID- 24787420 TI - Creation of tunable multiple 3D dark spots with cylindrical vector beam. AB - We present a method to generate multiple three-dimensional (3D) dark focal spots along the optical axis by focusing a cylindrical vector beam. The formation of uniform 3D dark spots is determined by optimizing three parameters of the pupil filter in the wavefront of the lens and the polarized state of the incident cylindrical vector beam. By adjusting the three parameters of the pupil filter, the number and position of dark spots can be controlled willingly, and the uniformity of dark spots can be adjusted by modulating the polarized state of the incident cylindrical vector beam. A single dark spot with uniform surrounding intensity is formed and double dark spots are also obtained with the proper parameters and can be separated with an equal distance away from the geometric focus. Moreover, multiple dark spots numbering up to six are formed along the optical axis. The size of each 3D dark spot is almost the same, and the central light intensity of the dark spots is nearly zero while the light intensity surrounding around is almost uniform. This work may find valuable application in particle trapping, microscopes, optical engineering, and so on. PMID- 24787421 TI - Diffractive optics calibrator: measurement of etching variations for binary computer-generated holograms. AB - We present a new device, the diffractive optics calibrator (DOC), for measuring etching variations of computer-generated holograms (CGHs). The intensity distribution of the far-field diffraction pattern is captured and fitted to a parametric model to obtain local etching parameters such as the duty cycle, etching depth, and grating period. The sensitivity of each etching parameter is analyzed, and design choices are provided. For the wavefront created by the CGH, the DOC is capable of measuring variations in these parameters that cause 1 nm peak-to-valley phase errors. System performance is verified by measurements from a phase shift Fizeau interferometer. This device will be used primarily for quality control of the CGHs. The measurement results can be used to evaluate the fabrication performance and guide future design. DOC is also capable of generating an induced phase error map for calibration. Such calibration is essential for measuring free-form aspheric surfaces with 1 nm root-mean-square accuracy. PMID- 24787422 TI - Influence of local densification on microscopic morphology evolution during ion beam sputtering of fused-silica surfaces. AB - Morphology evolution at microscopic scales has an inseparable relationship with surface material behaviors, especially during ultrasmooth surface fabrication. In this work, the influence of initially existing local densification on ion nanopatterning of a fused-silica surface is investigated. Our research results indicate that fused-silica surfaces will easily densify permanently under a compressive load, exhibiting an anisotropic surface at the nanoscale. During the subsequent ion-beam sputtering process, the densification-dependent sputtering would influence and even dominate surface morphology evolution, which is identified as being an important evolution mechanism. However, ion-induced relaxation mechanisms will overcome surface roughening in the absence of local densification, and an ultrasmooth surface with root mean square roughness down to 0.06 nm is obtained in our experiment. PMID- 24787423 TI - Theoretical analysis of coma aberration measurement for aerial image sidelobe peaks. AB - By analyzing aerial images, we characterize the lowest order coma aberration measurements for the projection optics of a microlithography exposure apparatus based on scalar diffraction theory. Our developed method for measuring the coma aberration exploits the intensity difference between the sidelobe peaks appearing near the boundaries of the bright field ("negative") single-line or plural-line patterns. Our method further demonstrates linearity between the intensity difference of the sidelobe peaks and the amount of residual lowest order coma aberration. We analyze the coma aberration sensitivity formula and determine the duty ratio of the line-and-space pattern that realizes the highest aberration sensitivity. PMID- 24787424 TI - Effective emissivity of a blackbody cavity formed by two coaxial tubes. AB - A blackbody cavity is developed for continuously measuring the temperature of molten steel, which consists of a cylindrical outer tube with a flat bottom, a coaxial inner tube, and an aperture diaphragm. The ray-tracing approach based on the Monte Carlo method was applied to calculate the effective emissivity for the isothermal cavity with the diffuse walls. And the dependences of the effective emissivity on the inner tube relative length were calculated for various inner tube radii, outer tube lengths, and wall emissivities. Results indicate that the effective emissivity usually has a maximum corresponding to the inner tube relative length, which can be explained by the impact of the inner tube relative length on the probability of the rays absorbed after two reflections. Thus, these results are helpful to the optimal design of the blackbody cavity. PMID- 24787425 TI - Performance evaluation of a metal-insulator-metal surface plasmon resonance optical gas sensor under the effect of Gaussian beams. AB - In this work, the performance of a nonconventional IR surface plasmon resonance (SPR) gas sensor structure based on the use of a metal-insulator-metal (MIM) structure is studied. This MIM-based sensor structure gives enhanced performance five times better than the conventional MI SPR optical gas sensors. The performance of the SPR gas sensors is studied under the effect of oblique incident Gaussian beams with different spot sizes, and the performance enhancement of the MIM structure is confirmed for different spot sizes. The simulation technique used to generate the results is also verified by comparing them to actual experimental results available in the literature. PMID- 24787426 TI - Analysis of optical properties in injection-molded and compression-molded optical lenses. AB - Numerical mold-flow simulations and experimental measurements for injection molded lenses have been investigated in form accuracy on a two-cavity mold with various process conditions. First, form profiles of the molded lenses have been measured together with the corresponding simulated mold-temperature distribution and displacement distribution of the lens in the z direction. A flow-through type layout of cooling channels has been devised for balance of mold-temperature distribution in mold cavities with various parametric distances for assessments in uniformity of temperature distribution. Finally, a compression-molding process is proposed for the post-process of birefringence relaxation as well as adequate form accuracy of lenses. In conclusion, optimization of process parameters to achieve good form accuracy in a multicavity mold with symmetric geometry but nonuniform cooling conditions is difficult. A good design of cooling channels plus optimized process conditions could provide uniform mold-temperature distribution so that molded lenses of good quality would be possible. Then, the profile deviation of lenses could be further compensated by profile geometry corrections. In conclusion, the post-compression-molding process could make birefringence-free plastic lenses with good form accuracy. PMID- 24787427 TI - Diffraction light analysis method for a diffraction grating imaging lens. AB - We have developed a new method to analyze the amount and distribution of diffraction light for a diffraction grating lens. We have found that diffraction light includes each-order diffraction light and striped diffraction light. In this paper, we describe characteristics of striped diffraction light and suggest a way to analyze diffraction light. Our analysis method, which considers the structure of diffraction grating steps, can simulate the aberrations of an optical system, each-order diffraction light, and striped diffraction light simultaneously with high accuracy. A comparison between the simulation and experimental results is presented, and we also show how our analysis method can be used to optimize a diffraction grating lens with low flare light. PMID- 24787428 TI - Thermoresponsive layer-by-layer assemblies for nanoparticle-based drug delivery. AB - Layer-by-layer (LbL) capsules, known for their versatility and smart response to environmental stimuli, have attracted great interest in drug delivery applications. However, achieving a desired drug delivery system with sustained and tunable drug release is still challenging. Here, a thermoresponsive drug delivery system of solid dexamethasone nanoparticles (DXM NPs, 200 +/- 100 nm) encapsulated in a model LbL assembly of tunable thickness consisting of strong polyelectrolytes poly(diallyldimethylammonium chloride)/poly(styrenesulfonate) (PDAC/PSS) is constructed. The influence of various parameters on drug release, such as number of layers, ionic strength of the adsorption solution, temperature, and outermost layer, is investigated. Increasing the number of layers results in a thicker encapsulating nanoshell and decreases the rate of dexamethasone release. LbL assemblies created in the absence of salt are most responsive to temperature, yielding the greatest contrast in drug release. Relationships between drug release and LbL architecture are attributed to the size and concentration of free volume cavities within the assemblies. By tailoring the properties of those cavities, a thermoresponsive drug delivery system may be obtained. This work provides a promising example of how LbL assemblies may be implemented as temperature-gated materials for the controlled release of drug, thus providing an alternative approach to the delivery of therapeutics with reduced toxic effects. PMID- 24787429 TI - Determinants of iron accumulation in deep grey matter of multiple sclerosis patients. AB - BACKGROUND: Iron accumulation in deep grey matter (GM) structures is a consistent finding in multiple sclerosis (MS) patients. This study focused on the identification of independent determinants of iron accumulation using R2* mapping. SUBJECTS AND METHODS: Ninety-seven MS patients and 81 healthy controls were included in this multicentre study. R2* mapping was performed on 3T MRI systems. R2*in deep GM was corrected for age and was related to disease duration, disability, T2 lesion load and brain volume. RESULTS: Compared to controls, R2* was increased in all deep GM regions of MS patients except the globus pallidus and the substantia nigra. R2* increase was most pronounced in the progressive stage of the disease and independently predicted by disease duration and disability. Reduced cortical volume was not associated with iron accumulation in the deep GM with the exception of the substantia nigra and the red nucleus. In lesions, R2* was inversely correlated with disease duration and higher total lesion load. CONCLUSION: Iron accumulation in deep GM of MS patients is most strongly and independently associated with duration and severity of the disease. Additional associations between cortical GM atrophy and deep GM iron accumulation appear to exist in a region specific manner. PMID- 24787431 TI - SLE mimicking infectious myelitis. PMID- 24787430 TI - Emerging infectious diseases in free-ranging wildlife-Australian zoo based wildlife hospitals contribute to national surveillance. AB - Emerging infectious diseases are increasingly originating from wildlife. Many of these diseases have significant impacts on human health, domestic animal health, and biodiversity. Surveillance is the key to early detection of emerging diseases. A zoo based wildlife disease surveillance program developed in Australia incorporates disease information from free-ranging wildlife into the existing national wildlife health information system. This program uses a collaborative approach and provides a strong model for a disease surveillance program for free-ranging wildlife that enhances the national capacity for early detection of emerging diseases. PMID- 24787432 TI - Targeted proteomics pipeline reveals potential biomarkers for the diagnosis of metastatic lung cancer in pleural effusion. AB - The ability to discriminate lung cancer malignant pleural effusion (LC-MPE) from benign pleural effusion has profound implications for the therapy and prognosis of lung cancer. Here, we established a pipeline to verify potential biomarkers for this purpose. In the discovery phase, label-free quantification was performed for the proteome profiling of exudative pleural effusion in order to select 34 candidate biomarkers with significantly elevated levels in LC-MPE. In the verification phase, signature peptides for 34 candidates were first confirmed by accurate inclusion mass screening (AIMS). To quantify the candidates in PEs, multiple reaction monitoring mass spectrometry (MRM-MS) with stable isotope labeled standards (SIS) peptides was performed for the 34 candidate biomarkers using the QconCAT approach for the generation of the SIS peptides. The results of the MRM assay were used to prioritize candidates based on their discriminatory power in 82 exudative PE samples. The five potential biomarkers (ALCAM, CDH1, MUC1, SPINT1, and THBS4; AUC > 0.7) and one three-marker panel (SPINT1/SVEP1/THBS4; AUC = 0.95) were able to effectively differentiate LC-MPE from benign PE. Collectively, these results demonstrate that our pipeline is a feasible platform for verifying potential biomarkers for human diseases. PMID- 24787433 TI - Exploiting cancer's antioxidative weakness through p53 with nanotoxicology. PMID- 24787434 TI - Nanoparticles and antigen delivery: understanding the benefits and drawbacks of different delivery platforms. PMID- 24787435 TI - Mesoporous silica nanoparticles: a potential platform for generation of induced pluripotent stem cells? PMID- 24787437 TI - Research Highlights: highlights from the latest articles in nanomedicine. PMID- 24787438 TI - Europe as leaders in nanomedicine: let's go for it! PMID- 24787439 TI - Of nanobacteria, nanoparticles, biofilms and their role in health and disease: facts, fancy and future. AB - Nanobacteria have been at the center of a major scientific controversy in recent years owing to claims that they represent not only the smallest living microorganisms on earth but also new emerging pathogens associated with several human diseases. We and others have carefully examined these claims and concluded that nanobacteria are in fact nonliving mineralo-organic nanoparticles (NPs) that form spontaneously in body fluids. We have shown that these mineral particles possess intriguing biomimetic properties that include the formation of cell- and tissue-like morphologies and the possibility to grow, proliferate and propagate by subculture. Similar mineral NPs (bions) have now been found in both physiological and pathological calcification processes and they appear to represent precursors of physiological calcification cycles, which may at times go awry in disease conditions. Furthermore, by functioning at the nanoscale, these mineralo-organic NPs or bions may shed light on the fate of nanomaterials in the body, from both nanotoxicological and nanopathological perspectives. PMID- 24787440 TI - Therapeutic application of electrospun nanofibrous meshes. AB - Fabricating tissue architecture-mimicking scaffolds is one of the major challenges in the field of tissue engineering. Electrospun nanofibers have been considered as potent techniques for fabricating fibrous scaffolds biomimicking extracellular frameworks. Therapeutic agent-incorporated nanofibrous meshes have widely served as excellent substrates for adhesion, proliferation and differentiation. Many drugs, proteins and nucleic acids were incorporated into the scaffolds for regeneration of skin, musculoskeletal, neural and vascular tissue engineering in aims to control the release of the therapeutic agents. In the current article, we focus on introducing various fabrication techniques for electrospun nanofiber-based scaffolds and subsequent functionalization of nanofibers for therapeutic purposes. We also detail how the therapeutic nanofibrous meshes can be employed in the field of tissue engineering. PMID- 24787441 TI - Porous silicon nanoparticles for nanomedicine: preparation and biomedical applications. AB - The research on porous silicon (PSi) materials for biomedical applications has expanded greatly since the early studies of Leigh Canham more than 25 years ago. Currently, PSi nanoparticles are receiving growing attention from the scientific biomedical community. These nanostructured materials have emerged as promising multifunctional and versatile platforms for nanomedicine in drug delivery, diagnostics and therapy. The outstanding properties of PSi, including excellent in vivo biocompatibility and biodegradability, have led to many applications of PSi for delivery of therapeutic agents. In this review, we highlight current advances and recent efforts on PSi nanoparticles regarding the production properties, efficient drug delivery, multidrug delivery, permeation across biological barriers, biosafety and in vivo tracking for biomedical applications. The constant boost on successful preclinical in vivo data reported so far makes this the 'golden age' for PSi, which is expected to finally be translated into the clinic in the near future. PMID- 24787442 TI - Match analysis in football: a systematic review. AB - Abstract The main focus of this paper was to review the available literature on match analysis in adult male football. The most common research topics were identified, their methodologies described and the evolutionary tendencies of this research area systematised. A systematic review of Institute for Scientific Information (ISI) Web of Knowledge database was performed according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines. The following keywords were used: football and soccer, each one associated with the terms: match analysis, performance analysis, notational analysis, game analysis, tactical analysis and patterns of play. Of 2732 studies initially identified, only 53 were fully reviewed, and their outcome measures abstracted and analysed. Studies that fit all inclusion criteria were organised according to their research design as descriptive, comparative or predictive. Results showed that 10 studies focused predominantly on a description of technical, tactical and physical performance variables. From all comparative studies, the dependent variables more frequently used were "playing position" and "competitive level". Even though the literature stresses the importance of developing predictive models of sports performance, only few studies (n = 8) have focused on modelling football performance. Situational variables like game location, quality of opposing teams, match status and match half have been progressively included as object of research, since they seem to work as effective covariables of football performance. Taking into account the limitations of the reviewed studies, future research should provide comprehensive operational definitions for the studied variables, use standardised categories and description of activities and participants, and consider integrating the situational and interactional contexts into the analysis of football performance. PMID- 24787443 TI - Rapid removal and separation of iron(II) and manganese(II) from micropolluted water using magnetic graphene oxide. AB - A novel two-dimensional carbon-based magnetic nanomaterial, magnetic graphene oxide (MGO), was prepared and then used as an efficient adsorbent. MGO showed rapid and complete removal of iron(II) (Fe) and manganese(II) (Mn) from micropolluted water bodies over a wide pH range. After saturated adsorption, MGO could be rapidly separated from water under an external magnetic field. Results of the adsorption equilibrium study indicated that the adsorption of Fe and Mn by MGO took place via monolayer heterogeneous and spontaneous processes resulting from the heterogeneity of the MGO surface as well as from the electrostatic interactions between surface acidic groups of MGO and metal ions. In addition, both the Fe and Mn uptake of MGO was very slightly affected by NaCl, although it decreased with increased humic acid in solutions. In an Fe/Mn binary aqueous system, both metal ions can be efficiently removed at low concentrations, but MGO showed preferential adsorption of Fe in a concentrated aqueous mixture. The adsorption behavior in the binary system was due to different affinities of surface oxygen-containing functional groups on MGO to Fe and Mn. Finally, unlike traditional approaches in recycling and reusing an adsorbent, the Fe- and Mn loaded MGO can be directly applied as a new adsorbent to achieve the efficient removal of fluoride from aqueous solutions. PMID- 24787444 TI - An ontology-based, mobile-optimized system for pharmacogenomic decision support at the point-of-care. AB - BACKGROUND: The development of genotyping and genetic sequencing techniques and their evolution towards low costs and quick turnaround have encouraged a wide range of applications. One of the most promising applications is pharmacogenomics, where genetic profiles are used to predict the most suitable drugs and drug dosages for the individual patient. This approach aims to ensure appropriate medical treatment and avoid, or properly manage, undesired side effects. RESULTS: We developed the Medicine Safety Code (MSC) service, a novel pharmacogenomics decision support system, to provide physicians and patients with the ability to represent pharmacogenomic data in computable form and to provide pharmacogenomic guidance at the point-of-care. Pharmacogenomic data of individual patients are encoded as Quick Response (QR) codes and can be decoded and interpreted with common mobile devices without requiring a centralized repository for storing genetic patient data. In this paper, we present the first fully functional release of this system and describe its architecture, which utilizes Web Ontology Language 2 (OWL 2) ontologies to formalize pharmacogenomic knowledge and to provide clinical decision support functionalities. CONCLUSIONS: The MSC system provides a novel approach for enabling the implementation of personalized medicine in clinical routine. PMID- 24787445 TI - To pass or not to pass: a mathematical model for competitive interactions in rugby union. AB - Predicting behavior has been a main challenge in human movement science. An important step within the theory of coordination dynamics is to find out the rules that govern human behavior by defining order parameters and control parameters that support mathematical models to predict the behavior of a system. Models to describe human coordination have been focused on interlimb coordination and on interpersonal coordination in affiliative tasks but not on competitive tasks. This article aims to present a formal model with two attractors to describe the interactive behavior on a 2v1 system in rugby union. Interpersonal distance and relative velocity critical values were empirically identified and were included as task constraints that define the attractor landscape. It is shown that using relative velocity as a control parameter the model offers reasonable prediction concerning the decision-making process. The model has the plasticity to adapt to other settings where interpersonal distances and relative velocities amongst system components act as significant task constraints. PMID- 24787447 TI - Metalloporphyrinic framework containing multiple pores for highly efficient and selective epoxidation. AB - Metalloporphyrin Mn(III)Cl-5,10,15,20-tetrakis(3,5-biscarboxylphenyl)porphyrin, having eight carboxylate groups in multiple coordination modes, connects with paddle-wheel Zn2(COO)4 units for the construction of an interesting porous porphyrinic framework that demonstrates high efficiency and stability upon epoxidation of olefins with excellent substrate size selectivity. PMID- 24787446 TI - Nearly perfect spin filter, spin valve and negative differential resistance effects in a Fe4-based single-molecule junction. AB - The spin-polarized transport in a single-molecule magnet Fe4 sandwiched between two gold electrodes is studied, using nonequilibrium Green's functions in combination with the density-functional theory. We predict that the device possesses spin filter effect (SFE), spin valve effect (SVE), and negative differential resistance (NDR) behavior. Moreover, we also find that the appropriate chemical ligand, coupling the single molecule to leads, is a key factor for manipulating spin-dependent transport. The device containing the methyl ligand behaves as a nearly perfect spin filter with efficiency approaching 100%, and the transport is dominated by transmission through the Fe4 metal center. However, in the case of phenyl ligand, the spin filter effect seems to be reduced, but the spin valve effect is significantly enhanced with a large magnetoresistance ratio, reaching 1800%. This may be attributed to the blocking effect of the phenyl ligands in mediating transport. Our findings suggest that such a multifunctional molecular device, possessing SVE, NDR and high SFE simultaneously, would be an excellent candidate for spintronics of molecular devices. PMID- 24787448 TI - The staphylococcal elastin-binding protein regulates zinc-dependent growth/biofilm formation. AB - Staphylococcus aureus is one of the most important human pathogens because it is a common cause of nosocomial infections. The elastin-binding protein of Staphylococcus aureus (EbpS) is an adhesin that is responsible for attachment to host cells via its binding to elastin. Despite its relatively weak contribution to adhesion, the ebpS gene is highly conserved among S. aureus isolates, suggesting that EbpS may have other crucial functions. Here, we found that EbpS binds Zn(2+) with its N-terminal region, which leads to local conformational changes that result in the assembly of the EbpS protein. The growth rate of the EbpS-deficient strain was considerably decreased. Zn(2+) chelation decreased the growth rate of the wild-type strain but did not alter that of the EbpS-deficient strain. Furthermore, biofilm formation by the EbpS-deficient strain was abnormally enhanced in the Zn(2+) concentration-dependent manner. All the results suggest that ebpS deficiency led to a zinc concentration-dependent inability to modulate the growth/biofilm maturation phase appropriately. Given the high conservation of ebpS and that appropriate regulation of biofilm formation is thought to be essential for effective staphylococcal infection, inhibition of EbpS binding to Zn(2+) could lead to the development of novel therapeutic strategies for controlling S. aureus infections. PMID- 24787449 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia (AHA) induced by a number of drugs. We provide guidance as to which G6PD genotypes are associated with G6PD deficiency in males and females. Rasburicase is contraindicated in G6PD-deficient patients due to the risk of AHA and possibly methemoglobinemia. Unless preemptive genotyping has established a positive diagnosis of G6PD deficiency, quantitative enzyme assay remains the mainstay of screening prior to rasburicase use. The purpose of this article is to help interpret the results of clinical G6PD genotype tests so that they can guide the use of rasburicase. Detailed guidelines on other aspects of the use of rasburicase, including analyses of cost effectiveness, are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on https://www.pharmgkb.org/page/cpic to reflect new developments in the field. PMID- 24787450 TI - Expression of tumor necrosis factor alpha and its correlation with severity of oral submucous fibrosis: a case-control study. AB - OBJECTIVE: The objective of this case-control study was to evaluate the plasma tumor necrosis factor alpha (TNF-alpha) levels in patients with oral submucous fibrosis and to determine the relation of plasma TNF-alpha levels with the severity of oral submucous fibrosis. STUDY DESIGN: Blood samples were collected from 25 patients who were diagnosed with oral submucous fibrosis and from 25 age- and sex-matched control participants. The plasma was isolated by centrifugation of blood samples. The levels of plasma TNF-alpha were estimated using enzyme linked immunosorbent assay. RESULTS: A total of 19 out of 25 patients had detectable plasma TNF-alpha levels ranging from 0.1 to 106.4 pg/mL (mean, 23.46 pg/mL), whereas only 12 out of 25 control participants had detectable plasma TNF alpha levels ranging from 0.1 to 33.3 pg/mL (mean, 6.93 pg/mL). The difference between the TNF-alpha levels of patients and controls was statistically significant (P = .015) according to the Mann-Whitney test. CONCLUSIONS: Patients with oral submucous fibrosis had significantly increased TNF-alpha levels compared with controls. PMID- 24787451 TI - A new species and new records for the subfamily Aleocharinae from Turkey. AB - In this study, a new Aleocharinae (Coleoptera: Staphylinidae) species from Turkey, Gyrophaena cagatay sp. n. (Aksaray), is described and illustrated. In addition, new records are presented for seven species: Atheta hygrotopora (Kraatz, 1856), Atheta incognita (Sharp, 1869), Atheta ripicola Hanssen, 1932, Brachyusa concolor Erichson, 1839, Ischnopoda leucopus (Marsham, 1802), Ischnopoda subaenea Eppelsheim, 1890, and Liogluta granigera Kiesenwetter, 1850. Photographs of the habitus of male and female specimens are presented. The 8(th) tergite and aedeagus of the male and the spermatheca of the female are also illustrated for the new species. Differential diagnosis guidelines are given for comparisons with Gyrophaena rousi Dvorak, 1966. PMID- 24787452 TI - Parent-teacher agreement on children's problems in 21 societies. AB - Parent-teacher cross-informant agreement, although usually modest, may provide important clinical information. Using data for 27,962 children from 21 societies, we asked the following: (a) Do parents report more problems than teachers, and does this vary by society, age, gender, or type of problem? (b) Does parent teacher agreement vary across different problem scales or across societies? (c) How well do parents and teachers in different societies agree on problem item ratings? (d) How much do parent-teacher dyads in different societies vary in within-dyad agreement on problem items? (e) How well do parents and teachers in 21 societies agree on whether the child's problem level exceeds a deviance threshold? We used five methods to test agreement for Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF) ratings. CBCL scores were higher than TRF scores on most scales, but the informant differences varied in magnitude across the societies studied. Cross-informant correlations for problem scale scores varied moderately across societies studied and were significantly higher for Externalizing than Internalizing problems. Parents and teachers tended to rate the same items as low, medium, or high, but within-dyad item agreement varied widely in every society studied. In all societies studied, both parental noncorroboration of teacher-reported deviance and teacher noncorroboration of parent-reported deviance were common. Our findings underscore the importance of obtaining information from parents and teachers when evaluating and treating children, highlight the need to use multiple methods of quantifying cross informant agreement, and provide comprehensive baselines for patterns of parent teacher agreement across 21 societies. PMID- 24787453 TI - Atom-by-atom assembly. AB - Atomic manipulation using a scanning tunneling microscope (STM) tip enables the construction of quantum structures on an atom-by-atom basis, as well as the investigation of the electronic and dynamical properties of individual atoms on a one-atom-at-a-time basis. An STM is not only an instrument that is used to 'see' individual atoms by means of imaging, but is also a tool that is used to 'touch' and 'take' the atoms, or to 'hear' their movements. Therefore, the STM can be considered as the 'eyes', 'hands' and 'ears' of the scientists, connecting our macroscopic world to the exciting atomic world. In this article, various STM atom manipulation schemes and their example applications are described. The future directions of atomic level assembly on surfaces using scanning probe tips are also discussed. PMID- 24787455 TI - Relationship between echocardiographic LV mass and ECG based left ventricular voltages in an adolescent population: related or random? AB - BACKGROUND: In attempts to detect diseases that may place adolescents at risk for sudden death, some have advocated for population-based screening. Controversy exists over electrocardiography (ECG) screening due to the lack of specificity, cost, and detrimental effects of false positive or extraneous outcomes. OBJECTIVES: Analyze the relationship between precordial lead voltage on ECG and left ventricle (LV) mass by echocardiogram in adolescent athletes. METHODS: Retrospective cohort analysis of a prospectively obtained population of self identified adolescent athletes during sports screening with ECG and echocardiogram. Correlation between ECG LV voltages (R wave in V6 [RV6] and S wave in lead V1 [SV1]) was compared to echocardiogram-based measurements of left ventricular mass. Potential effects on ECG voltages by body anthropometrics, including weight, body mass index (BMI), and body surface area were analyzed, and ECG voltages indexed to BMI were compared to LV mass indices to analyze for improved correlation. RESULTS: A total of 659 adolescents enrolled in this study (64% male). The mean age was 15.4 years (14-18). The correlations between LV mass and RV6, SV1, and RV6 + SV1 were all less than 0.20. The false positive rate for abnormal voltages was relatively high (5.5%) but improved if abnormal voltages in both RV6 and SV1 were mandated simultaneously (0%). Indexing ECG voltages to BMI significantly improved correlation to LV mass, though false positive findings were increased (12.9%). CONCLUSION: There is poor correlation between ECG precordial voltages and echocardiographic LV mass. This relationship is modified by BMI. This finding may contribute to the poor ECG screening characteristics. PMID- 24787454 TI - Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. AB - The large surface area for gas exchange makes the respiratory system particularly susceptible to oxidative stress-mediated injury. Both endogenous and exogenous pro-oxidants (e.g. cigarette smoke) trigger activation of leukocytes and host defenses. These mechanisms interact in a "multilevel cycle" responsible for the control of the oxidant/antioxidant homeostasis. Several studies have demonstrated the presence of increased oxidative stress and decreased antioxidants (e.g. reduced glutathione [GSH]) in subjects with chronic obstructive pulmonary disease (COPD), but the contribution of oxidative stress to the pathophysiology of COPD is generally only minimally discussed. The aim of this review was to provide a comprehensive overview of the role of oxidative stress in the pathogenesis of respiratory diseases, particularly COPD, and to examine the available clinical and experimental evidence on the use of the antioxidant N-acetylcysteine (NAC), a precursor of GSH, as an adjunct to standard therapy for the treatment of COPD. The proposed concept of "multilevel cycle" helps understand the relationship between respiratory diseases and oxidative stress, thus clarifying the rationale for using NAC in COPD. Until recently, antioxidant drugs such as NAC have been regarded only as mucolytic agents. Nevertheless, several clinical trials indicate that NAC may reduce the rate of COPD exacerbations and improve small airways function. The most plausible explanation for the beneficial effects observed in patients with COPD treated with NAC lies in the mucolytic and antioxidant effects of this drug. Modulation of bronchial inflammation by NAC may further account for these favorable clinical results. PMID- 24787456 TI - Orbital control of western North America atmospheric circulation and climate over two glacial cycles. AB - The now arid Great Basin of western North America hosted expansive late Quaternary pluvial lakes, yet the climate forcings that sustained large ice age hydrologic variations remain controversial. Here we present a 175,000 year oxygen isotope record from precisely-dated speleothems that documents a previously unrecognized and highly sensitive link between Great Basin climate and orbital forcing. Our data match the phasing and amplitudes of 65 degrees N summer insolation, including the classic saw-tooth pattern of global ice volume and on time terminations. Together with the observation of cold conditions during the marine isotope substage 5d glacial inception, our data document a strong precessional-scale Milankovitch forcing of southwestern paleoclimate. Because the expansion of pluvial lakes was associated with cold glacial conditions, the reappearance of large lakes in the Great Basin is unlikely until ca. 55,000 years into the future as climate remains in a mild non-glacial state over the next half eccentricity cycle. PMID- 24787457 TI - Local excision of T1 and T2 rectal cancer: proceed with caution. AB - AIM: This study aimed to compare the clinical outcome between local excision (LE) and total mesorectal excision (TME) for early rectal cancer. METHOD: After Institutional Review Board approval, charts of patients with T1 or T2 N0M0 rectal adenocarcinoma treated by curative LE or TME without preoperative radiotherapy from 2004 to 2012 were reviewed. Categorical and continuous variables were compared using chi-square analysis and the ANOVA test. Kaplan-Meier analysis compared survival rates. RESULTS: The study included 153 patients: 79 underwent TME and 74 LE. Postoperative infection was more common after TME (P = 0.009). There was tumour involvement of the margins in 13.5% after LE compared with 0% after TME (P = 0.001). Of the patients treated initially by LE, 13.5% had additional surgery for unfavourable histological findings and 4.1% had residual tumour. Median follow up was 35 (17-96) months. No deaths were recorded in 56 patients with a pT1 lesion. There was no significant difference in local recurrence (P = 0.332) or 3-year disease-free survival (DFS; P = 0.232) between patients having LE or TME. The 68 patients with a T2 lesion had higher local recurrence (P = 0.025) and lower DFS following LE compared with TME (P = 0.044). There was no difference in overall survival (P = 0.351). CONCLUSION: LE of early rectal cancer is associated with higher local recurrence and decreased DFS. These disadvantages are significant for T2 lesions. PMID- 24787458 TI - Synthesis, Radiolabelling and In Vitro Characterization of the Gallium-68-, Yttrium-90- and Lutetium-177-Labelled PSMA Ligand, CHX-A''-DTPA-DUPA-Pep. AB - Since prostate-specific membrane antigen (PSMA) has been identified as a diagnostic target for prostate cancer, many urea-based small PSMA-targeting molecules were developed. First, the clinical application of these Ga-68 labelled compounds in positron emission tomography (PET) showed their diagnostic potential. Besides, the therapy of prostate cancer is a demanding field, and the use of radiometals with PSMA bearing ligands is a valid approach. In this work, we describe the synthesis of a new PSMA ligand, CHX-A''-DTPA-DUPA-Pep, the subsequent labelling with Ga-68, Lu-177 and Y-90 and the first in vitro characterization. In cell investigations with PSMA-positive LNCaP C4-2 cells, KD values of <=14.67 +/- 1.95 nM were determined, indicating high biological activities towards PSMA. Radiosyntheses with Ga-68, Lu-177 and Y-90 were developed under mild reaction conditions (room temperature, moderate pH of 5.5 and 7.4, respectively) and resulted in nearly quantitative radiochemical yields within 5 min. PMID- 24787459 TI - [Pluridisciplinary meetings and concertations on thrombosis and cancer]. PMID- 24787460 TI - Rate and mechanistic investigation of Eu(OTf)2-mediated reduction of graphene oxide at room temperature. AB - We describe a fast, efficient, and mild approach to prepare chemically reduced graphene oxide (rGO) at room temperature using divalent europium triflate {Eu(OTf)2}. The characterization of solution-processable reduced graphene oxide has been carried out by various spectroscopic (FT-IR, UV-visible absorption, and Raman), microscopic (TEM and AFM), and powder X-ray diffraction (XRD) techniques. Kinetic study indicates that the bimolecular rate constants for the reduction of graphene oxide are 13.7 +/- 0.7 and 5.3 +/- 0.1 M(-1) s(-1) in tetrahydrofuran (THF)-water and acetonitrile (ACN)-water mixtures, respectively. The reduction rate constants are two orders of magnitude higher compared to the values obtained in the case of commonly used reducing agents such as the hydrazine derivative, sodium borohydride, and a glucose-ammonia mixture. The present work introduces a feasible reduction process for preparing reduced graphene oxide at ambient conditions, which is important for bulk production of GO. More importantly, the study explores the possibilities of utilizing the unique chemistry of divalent lanthanide complexes for chemical modifications of graphene oxide. PMID- 24787461 TI - Ring expansion of 1,2,3,4-tetrahydroisoquinolines to dibenzo[c,f]azonines. An unexpected [1,4]-sigmatropic rearrangement of nitrile-stabilized ammonium ylides. AB - When the products of a Strecker reaction of 1,2,3,4-tetrahydroisoquinolines with aromatic aldehydes are quaternized with alkyl triflates and subsequently treated with base, a ring expansion to 6,7,8,13-tetrahydro-5H-dibenzo[c,f]azonine-5 carbonitriles takes place. The nine-membered cyclic products can be obtained in good yields (78-89%) in a process involving the [1,4]-sigmatropic rearrangement of a nitrile-stabilized ammonium ylide. The reaction sequence provides a new, simple, and efficient method for the synthesis of these unusual N-heterocycles. PMID- 24787462 TI - Fish consumption and blood mercury levels. PMID- 24787464 TI - Tuning topological edge states of Bi(111) bilayer film by edge adsorption. AB - Based on first-principles and tight-binding calculations, we report that the topological edge states of zigzag Bi(111) nanoribbon can be significantly tuned by H edge adsorption. The Fermi velocity is increased by 1 order of magnitude, as the Dirac point is moved from the Brillouin zone boundary to the Brillouin zone center, and the real-space distribution of Dirac states are made twice more delocalized. These intriguing changes are explained by an orbital filtering effect of edge H atoms, which pushes certain components of the p orbital of edge Bi atoms out of the band gap regime that reshapes the topological edge states. In addition, the spin texture of the Dirac states is also modified, which is described by introducing an effective Hamiltonian. Our findings not only are of fundamental interest but also have practical implications in potential applications of topological insulators. PMID- 24787463 TI - Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. AB - Claudins are a family of transmembrane proteins that are required for tight junction formation. Claudin (CLDN)-18.1, the only known lung-specific tight junction protein, is the most abundant claudin in alveolar epithelial type (AT) 1 cells, and is regulated by lung maturational agonists and inflammatory mediators. To determine the function of CLDN18 in the alveolar epithelium, CLDN18 knockout (KO) mice were generated and studied by histological, biochemical, and physiological approaches, in addition to whole-genome microarray. Alveolar epithelial barrier function was assessed after knockdown of CLDN18 in isolated lung cells. CLDN18 levels were measured by quantitative PCR in lung samples from fetal and postnatal human infants. We found that CLDN18 deficiency impaired alveolar epithelial barrier function in vivo and in vitro, with evidence of increased paracellular permeability and architectural distortion at AT1-AT1 cell junctions. Although CLDN18 KO mice were born without evidence of a lung abnormality, histological and gene expression analysis at Postnatal Day 3 and Week 4 identified impaired alveolarization. CLDN18 KO mice also had evidence of postnatal lung injury, including acquired AT1 cell damage. Human fetal lungs at 23-24 weeks gestational age, the highest-risk period for developing bronchopulmonary dysplasia, a disease of impaired alveolarization, had significantly lower CLDN18 expression relative to postnatal lungs. Thus, CLDN18 deficiency results in epithelial barrier dysfunction, injury, and impaired alveolarization in mice. Low expression of CLDN18 in human fetal lungs supports further investigation into a role for this tight junction protein in bronchopulmonary dysplasia. PMID- 24787465 TI - Serum cytokines are increased and circulating micronutrients are not altered in subjects with early compared to advanced knee osteoarthritis. AB - Knee osteoarthritis (OA) is a leading cause of physical disability. At the early stage of knee OA, the increase in synovial fluid cytokine concentrations could contribute to the pathogenesis of OA by degrading articular cartilage. It is unknown, however, if inflammatory cytokines increase systemically at the early or advanced stage of knee OA. The systemic increase of inflammatory cytokines could be detrimental to the endogenous status of micronutrients that protect against excessive inflammation and cytokine-mediated events. The purpose of this study was to test the hypothesis that an increase in serum cytokines associate with a decrease in circulating micronutrients in subjects with early compared to advanced knee OA. Advanced knee OA subjects (n=14) displayed radiographic, pain, and muscular weakness symptoms of knee OA. Early knee OA subjects (n=14) were matched (age, gender, and body mass index) to the advanced OA group and displayed one or two of the aforementioned symptoms of knee OA. Inflammatory cytokines, vitamins C (ascorbic acid), D (25-hydroxyvitamin D), and E (alpha- and gamma tocopherols), and beta-carotene were measured in fasting blood samples. In the early OA group, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-5, IL 6, IL-12, and IL-13 concentrations were significantly (all p<0.05) increased. Circulating ascorbic acid, 25-hydroxyvitamin D, alpha- and gamma-tocopherol's, and beta-carotene concentrations were not significantly different between groups. Based on these preliminary results, we conclude that the systemic increase of inflammatory cytokines is not associated with a decrease in circulating micronutrients in subjects with early compared to advanced knee OA. PMID- 24787466 TI - Estimation of Kd of lead and (210)Po in 11 soils from India. AB - The fate of contaminant transport is often estimated using the distribution (partition) coefficient, Kd. It is a measure of sorption of contaminants to soil. As Kd is element, soil type and ground water dependent, chemical characterization of soil and ground water of the particular site is essential. In this study, soil and ground water samples from different locations around India were collected. The soil samples were physically characterized and pH, CaCO3, cation exchange capacity (CEC), organic matter and organic carbon were determined. Equilibration time for lead and (210)Po were estimated with respect to contact time and were found to be 28 and 72 h respectively. The Kd of lead varied from 6700 to 31,000 L/kg with a geometric mean of 15,200 L/kg, and for (210)Po from 1400 to 8700 L/kg with a geometric mean of 3700 L/kg. PMID- 24787467 TI - Diurnal variations of (218)Po, (214)Pb, and (214)Po and their effect on atmospheric electrical conductivity in the lower atmosphere at Mysore city, Karnataka State, India. AB - The short-lived radon daughters ((218)Po, (214)Pb, (214)Bi and (214)Po) are natural tracers in the troposphere, in particular near the ground surface. They are electrically charged particles and are chemically reactive. As soon as they are formed they get attached to the aerosol particles of the atmosphere. The behavior of radon daughters is similar to that of aerosols with respect to their growth, transport and removal processes in the atmosphere. The electrical conductivity of the atmosphere is mainly due to the presence of highly mobile ions. Galactic cosmic rays are the main source of ionization in the planetary boundary layer; however, near the surface of the earth, ions are produced mainly by decays of natural radioactive gases emanating from the soil surface and by radiations emitted directly from the surface. Hence the electrical conductivity of air near the surface of the earth is mainly due to radiations emitted by (222)Rn, (218)Po, (214)Pb, (214)Bi and (214)Po, and depends on aerosol concentrations and meteorological parameters. In the present work the diurnal and seasonal variations of radon and its progeny concentrations are studied using Low Level Radon Detection System and Airflow Meter respectively. Atmospheric electrical conductivity of both positive and negative polarities is measured using a Gerdien Condenser. All the measurements were carried out simultaneously at one location in Mysore city (12 degrees N, 76 degrees E), India. The diurnal variation of atmospheric electrical conductivity was found to be similar to that of ion pair production rate estimated from radon and its progeny concentrations with a maximum in the early morning hours and minimum during day time. The annual average concentrations of (222)Rn, (218)Po, (214)Pb, and (214)Po at the study location were found to be 21.46, 10.88, 1.78 and 1.80 Bq m(-3) respectively. The annual average values of positive and negative atmospheric electrical conductivity were found to be 18.1 and 16.6 f S m(-1) respectively. The radon and its progeny concentrations are higher in winter than in summer and rainy season. PMID- 24787468 TI - Concept Analysis: Alzheimer's Caregiver Stress. AB - AIM: The aim of this article was to analyze the concept of caregiver stress in the context of caring for a person with Alzheimer's disease and related dementias. BACKGROUND: Currently, there are more than 15 million unpaid caregivers for persons suffering from Alzheimer's disease and related dementias. This unpaid care can be stressful for caregivers due to the chronic nature of the disease process, as well as other factors. METHOD: The paper incorporates the modified method of Wilson's concept analysis procedure to analyze the concept of caregiver stress. DATA SOURCES: A review of the literature was undertaken using the Cumulative Index to Nursing and Allied Health Literature, Google Scholar, and PubMed. RESULTS: A theoretical definition of caregiver stress is provided, and the defining attributes, related concepts, antecedents, and consequences of caregiver stress are proposed, and case studies are presented. CONCLUSIONS: The analysis demonstrates that caregiver stress is the unequal exchange of assistance among people who stand in close relationship to one another, which results in emotional and physical stress on the caregiver. Implications for future nursing research and practice conclude the paper. PMID- 24787469 TI - Effects of sex on coronary microvascular dysfunction and cardiac outcomes. AB - BACKGROUND: Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown. METHODS AND RESULTS: We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5-2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75-086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049-0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041). CONCLUSIONS: CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions. PMID- 24787470 TI - The prevalence of microvascular dysfunction, its role among men, and links with adverse outcomes: noninvasive imaging reveals the tip of the iceberg. PMID- 24787472 TI - Ca(2+) homeostasis in sealed t-tubules of mouse ventricular myocytes. AB - We have recently shown that in mouse ventricular myocytes, t-tubules can be quickly and tightly sealed during the resolution of hyposmotic shock of physiologically relevant magnitude. Sealing of t-tubules is associated with trapping extracellular solution inside the myocytes but the ionic homeostasis of sealed t-tubules and the consequences of potential transtubular ion fluxes remain unknown. In this study we investigated the dynamics of Ca(2+) movements associated with sealing of t-tubules. The data show that under normal conditions sealed t-tubules contain Ca(2+) at concentrations below 100MUM. However, blockade of voltage-dependent Ca(2+) channels with 10MUM nicardipine, or increasing extracellular concentration of K(+) from 5.4mM to 20mM led to several fold increase in concentration of t-tubular Ca(2+). Alternatively, the release of Ca(2+) from sarcoplasmic reticulum using 10mM caffeine led to the restoration of t-tubular Ca(2+) towards extracellular levels within few seconds. Sealing of t tubules in the presence of extracellular 1.5mM Ca(2+) and 5.4mM extracellular K(+) led to occasional and sporadic intracellular Ca(2+) transients. In contrast, sealing of t-tubules in the presence of 10mM caffeine was characterized by a significant long lasting increase in intracellular Ca(2+). The effect was completely abolished in the absence of extracellular Ca(2+) and significantly reduced in pre-detubulated myocytes but was essentially preserved in the presence of mitochondrial decoupler dinitrophenol. This study shows that sealed t-tubules are capable of highly regulated transport of Ca(2+) and present a major route for Ca(2+) influx into the cytosol during sealing process. PMID- 24787473 TI - A pharmacologic activator of endothelial KCa channels enhances coronary flow in the hearts of type 2 diabetic rats. AB - Endothelial dysfunction is a common early pathogenic event in patients with type 2 diabetes (T2D) who exhibit cardiovascular disease. In the present study, we have examined the effect of SKA-31, a positive modulator of endothelial Ca(2+) activated K(+) (KCa) channels, on total coronary flow in isolated hearts from Goto-Kakizaki rats, a non-obese model of T2D exhibiting metabolic syndrome. Total coronary flow and left ventricular developed pressure were monitored simultaneously in isolated, spontaneously beating Langendorff-perfused hearts. Acute administrations of bradykinin (BK) or adenosine (ADO) increased coronary flow, but responses were significantly blunted in diabetic hearts at 10-12 and 18 20weeks of age compared with age-matched Wistar controls, consistent with the presence of endothelial dysfunction. In contrast, SKA-31 dose-dependently (0.01 5MUg) increased total coronary flow to comparable levels in both control and diabetic rat hearts at both ages. Flow responses to sodium nitroprusside were not different between control and diabetic hearts, suggesting normal arterial smooth muscle function. Importantly, exposure to a sub-threshold concentration of SKA-31 (i.e. 0.3MUM) rescued the impaired BK and ADO-evoked vasodilatory responses in diabetic hearts. Endothelial KCa channel activators may thus help to preserve coronary flow in diabetic myocardium. PMID- 24787474 TI - Does the persistence of pulsatile antegrade pulmonary blood flow following bidirectional Glenn procedure affect long term outcome? AB - OBJECTIVES: To evaluate outcomes of the Glenn procedure with or without pulsatile antegrade pulmonary blood flow during palliation of patients with functionally single ventricles. METHODS: The clinical records of 111 consecutive patients who underwent a bidirectional Glenn procedure for palliation of single ventricle morphologies at our institution between 1997 and 2010 were reviewed. We specifically excluded infants with the diagnosis of hypoplastic left heart syndrome. Following the Glenn procedure, there were 57 patients (Group 1) with and 54 (Group 2) without antegrade pulmonary blood flow. We reviewed their long term data from our database to determine whether the presence of forward flow after the Glenn procedure affected outcome. RESULTS: There was 1 early hospital death (in Group 1). The mean SaO2 at discharge was higher in Group 1 (83%+/-2 vs 78%+/-4; P<0.001). There was no difference in duration of chest drain insertion, length of intensive care and hospital stay between the two groups. The median follow-up time was 7.1 years (range, 1.7-14.9 years). Sixty-five patients underwent Fontan completion (35 from Group 1) a median of 3.6 years (Group 1) and 3.3 (Group 2) after the Glenn procedure. Three patients died following Fontan completion (1 from Group 1). The 5- and 10-year survival (95% CI) was 96% (84 98%) and 96% (84-98%) in Group 1, and 88% (74-94%) and 82% (66-91%) in Group 2, respectively (log-rank; P=0.03). There was no significant difference in SaO2 levels, or incidence of systemic atrioventricular valve regurgitation or ventricular dysfunction in survivors between groups at the last follow-up. CONCLUSIONS: We conclude that leaving antegrade flow following a Glenn procedure improves oxygen saturation significantly and while it does not impact on short term outcome or hospital stay, long-term outcome is significantly better. PMID- 24787475 TI - Reply to Patel and Hunt. PMID- 24787476 TI - Coronary revascularization in heart failure-old lessons relearnt: patient outcomes are paramount in the stenting era. PMID- 24787477 TI - The evidence for routine anti-arrhythmic prophylaxis in patients undergoing pulmonary resection surgery. PMID- 24787471 TI - Extravirgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED (Prevencion con Dieta Mediterranea) trial. AB - BACKGROUND: The PREDIMED (Prevencion con Dieta Mediterranea) randomized primary prevention trial showed that a Mediterranean diet enriched with either extravirgin olive oil or mixed nuts reduces the incidence of stroke, myocardial infarction, and cardiovascular mortality. We assessed the effect of these diets on the incidence of atrial fibrillation in the PREDIMED trial. METHODS AND RESULTS: Participants were randomly assigned to 1 of 3 diets: Mediterranean diet supplemented with extravirgin olive oil, Mediterranean diet supplemented with mixed nuts, or advice to follow a low-fat diet (control group). Incident atrial fibrillation was adjudicated during follow-up by an events committee blinded to dietary group allocation. Among 6705 participants without prevalent atrial fibrillation at randomization, we observed 72 new cases of atrial fibrillation in the Mediterranean diet with extravirgin olive oil group, 82 in the Mediterranean diet with mixed nuts group, and 92 in the control group after median follow-up of 4.7 years. The Mediterranean diet with extravirgin olive oil significantly reduced the risk of atrial fibrillation (hazard ratio, 0.62; 95% confidence interval, 0.45-0.85 compared with the control group). No effect was found for the Mediterranean diet with nuts (hazard ratio, 0.89; 95% confidence interval, 0.65 1.20). CONCLUSIONS: In the absence of proven interventions for the primary prevention of atrial fibrillation, this post hoc analysis of the PREDIMED trial suggests that extravirgin olive oil in the context of a Mediterranean dietary pattern may reduce the risk of atrial fibrillation. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639. PMID- 24787478 TI - Historical trauma: politics of a conceptual framework. AB - The concept of historical trauma (HT) is compelling: Colonialism has set forth cumulative cycles of adversity that promote morbidity and mortality at personal and collective levels, with especially strong mental health impacts. Yet as ongoing community-based as well as scholarly discussions attest, lingering questions continue to surround HT as a framework for understanding the relationships between colonialism and indigenous mental health. Through an overview of 30 recent peer-reviewed publications that aim to clarify, define, measure, and interpret how HT impacts American Indian and Alaska Native (AIAN) mental health, this paper examines how the conceptual framework of HT has circulated in ways shaped by interactions among three prominent research approaches: evidence-based, culturally relevant, and decolonizing. All define current approaches to AIAN mental health research, but each sets forth different conceptualizations of the connections between colonialism and psychological distress. The unfolding trajectory of research about HT reflects persistent tensions in how these frameworks interact, but also possibilities for better integrating them. These considerations aim to advance conversations about the politics of producing knowledge about AIAN mental health, and support ongoing calls for greater political pluralism in mental health research. PMID- 24787479 TI - Genetic diversity of upper Lake Constance whitefish Coregonus spp. under the influence of fisheries: a DNA study based on archived scale samples from 1932, 1975 and 2006. AB - This investigation examined changes in the genetic diversity of pelagic upper Lake Constance (ULC) whitefish Coregonus wartmanni population before and after the alteration of fishery methods and management from 1932 to 2006. The study spans a period of pronounced changes in trophic status of the lake and transitions from traditional relatively unselective pelagic seine (Klusgarn) fishing to highly size-selective nylon gillnet techniques. In addition, supportive breeding and stocking became most popular during the phase of eutrophication in the 1970s. The main hypothesis is that size-selective fisheries and breeding lead to an overall decrease in genetic variability over time. A total of 215 archived C. wartmanni scale samples from 1932, 1975 and 2006 were analysed by genotyping 11 microsatellite loci. A comparison of population genetic parameters, including allelic richness, observed and expected heterozygosities, and estimates of effective population sizes, suggests that the genetic diversity of C. wartmanni population has not decreased. The appearance of new alleles in the gene pool in 1975 and 2006 may be indicative of admixture with other forms in the lake or with stocked allochthonous forms. Overall, the fisheries management practice in ULC, including the effects of size-selective fisheries, supportive breeding and stocking, have not significantly altered the genetic diversity of Coregonus spp. over an 80 year period. PMID- 24787480 TI - Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease. AB - Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease. PMID- 24787481 TI - Preserving the efficacy of front-line fluoroquinolones through selective use to optimise clinical outcomes. AB - As antibiotic resistance is increasing worldwide, it is important to prescribe fluoroquinolone (FQ) antibiotics appropriately for a given infection to preserve class efficacy. Clinical studies reveal good efficacy and tolerability of the currently approved FQs (ciprofloxacin, levofloxacin and moxifloxacin) in a wide range of community- and hospital-acquired infections. However, certain features supporting their clinical efficacy suggest a rationale for inclusion of moxifloxacin and ciprofloxacin with complementary clinical benefit on a formulary rather than levofloxacin alone; it may also be more cost-effective. Ciprofloxacin has advantages over levofloxacin in the treatment of Gram-negative infections, whilst moxifloxacin has certain efficacy and ease of use advantages over levofloxacin in respiratory tract infections. To preserve the potential of FQs and to minimise the risk of resistance selection, agents with the highest in vitro activity and supportive pharmacokinetic/pharmacodynamic profiles should be used first-line, as appropriate for local guidelines and prescribing information. PMID- 24787482 TI - Biofuels from pyrolysis in perspective: trade-offs between energy yields and soil carbon additions. AB - Coproduction of biofuels with biochar (the carbon-rich solid formed during biomass pyrolysis) can provide carbon-negative bioenergy if the biochar is sequestered in soil, where it can improve fertility and thus simultaneously address issues of food security, soil degradation, energy production, and climate change. However, increasing biochar production entails a reduction in bioenergy obtainable per unit biomass feedstock. Quantification of this trade-off for specific biochar-biofuel pathways has been hampered by lack of an accurate-yet simple model for predicting yields, product compositions, and energy balances from biomass slow pyrolysis. An empirical model of biomass slow pyrolysis was developed and applied to several pathways for biochar coproduction with gaseous and liquid biofuels. Here, we show that biochar production reduces liquid biofuel yield by at least 21 GJ Mg(-1) C (biofuel energy sacrificed per unit mass of biochar C), with methanol synthesis giving this lowest energy penalty. For gaseous-biofuel production, the minimum energy penalty for biochar production is 33 GJ Mg(-1) C. These substitution rates correspond to a wide range of Pareto optimal system configurations, implying considerable latitude to choose pyrolysis conditions to optimize for desired biochar properties or to modulate energy versus biochar yields in response to fluctuating price differentials for the two commodities. PMID- 24787483 TI - Diagnosis of Kikuchi-Fujimoto disease: a comparison between open biopsy and minimally invasive ultrasound-guided core biopsy. AB - Kikuchi-Fujimoto disease (KFD) is a self-limited disease without any need of surgical treatments. Sampling of tissue is the only invasive procedure during the clinical course. However, the standard sampling procedure with accuracy, minimal invasiveness, and esthetic maintenance has not been established yet. In this study, a retrospective review of clinical utility and pathological presentations of the ultrasound-guided core biopsy (USCB) and the open biopsy (OB) in consecutive KFD patients. From 2010 to 2012, 34 consecutive patients were enrolled. USCB was performed in 11 patients, and OB was done in 26 patients. KFD was confirmed in 82% cases by USCB. Similar pathological presentations were found both in the specimens of USCB and OB. In the three patients who had received both USCB and OB, KFD was confirmed by USCB in one case, while two by OB. Sampling errors were found both in USCB and OB. For diagnosing KFD, USCB can serve as the first-line diagnostic tool. OB can be applied only in the failed cases of USCB. PMID- 24787484 TI - Functional evaluation of ES-somatic cell hybrids in vitro and in vivo. AB - Embryonic stem cells (ESCs) have previously been reported to reprogram somatic cells following fusion. The resulting ES-somatic cell hybrids have been shown to adopt the transcriptional profile of ESCs, suggesting that the pluripotent program is dominant. ES-somatic cell hybrids have most characteristics of pluripotent cells in vitro; however, it remains unclear whether the somatic genome is an active partner in the hybrid cells or simply retained predominately as silent cargo. Furthermore, the functional properties of ES-somatic cell hybrids in vivo have been limited to studies on their contribution to teratomas and developing embryos/chimeras. The extent of their pluripotency remains largely unclear. Here we determined that the somatic genome is actively transcribed by generating ES-somatic cell hybrids using Rag2-deficient ESCs fused to autologous wild-type somatic cells. Rag2 expression was detected during in vitro differentiation, suggesting that the somatic genome follows the correct temporal cues during differentiation. Furthermore, ES-somatic cell hybrids maintain their tetraploid state following 4 weeks of differentiation in vivo and are immune tolerated when transferred into matched individuals. The ES-somatic cell hybrids can efficiently differentiate into hematopoietic precursors in both myeloid and lymphoid lineages in vitro, suggesting that the somatic genome is actively transcribed following cell fusion based reprogramming. However, the ES-somatic cell hybrids showed an altered hematopoietic potential following in vitro differentiation and were unable to show hematopoietic engraftment in a mouse model. PMID- 24787486 TI - Selective progesterone receptor modulators: an update. AB - INTRODUCTION: Several selective progesterone receptor modulators (SPRMs) show promise in several areas of medicine and this work has been summarized by us in 2008. AREAS COVERED: Since the publication of our reviews, several developments have taken place in the field of reproductive medicine. The first is emergency contraception (EC). Two SPRMs are clinically utilized today: mifepristone (MFP) and ulipristal acetate (UPA). MFP is available for EC in up to 120 h following unprotected intercourse. A dose of 10 mg is significantly more effective than levonorgestrel (LNG). In a metanalysis of the use of UPA versus LNG up to 72 h after unprotected intercourse, failure rates of 1.4 versus 2.2% were reported. The second is contraception. A daily dose of 2 mg MFP can block ovulation and several MFP regimens are being tested, including a vaginal ring releasing MFP. The third is the preoperative administration in women harboring leiomyomas, where clinical testing of several SPRM has shown that they can decrease uterine leiomyomas' size and substantially reduce uterine bleeding. SPRM can induce unusual, specific endometrial appearances. Many believe that these changes should not cause concern, but the issue remains controversial. EXPERT OPINION: SPRMs are very effective in EC and for the preoperative treatment of uterine leiomyomas. PMID- 24787487 TI - Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. AB - Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL 3), IL-7, tumor necrosis factor-alpha, transforming growth factor-beta (TGF-beta) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-beta signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction. PMID- 24787485 TI - Frontal midline theta reflects anxiety and cognitive control: meta-analytic evidence. AB - Evidence from imaging and anatomical studies suggests that the midcingulate cortex (MCC) is a dynamic hub lying at the interface of affect and cognition. In particular, this neural system appears to integrate information about conflict and punishment in order to optimize behavior in the face of action-outcome uncertainty. In a series of meta-analyses, we show how recent human electrophysiological research provides compelling evidence that frontal-midline theta signals reflecting MCC activity are moderated by anxiety and predict adaptive behavioral adjustments. These findings underscore the importance of frontal theta activity to a broad spectrum of control operations. We argue that frontal-midline theta provides a neurophysiologically plausible mechanism for optimally adjusting behavior to uncertainty, a hallmark of situations that elicit anxiety and demand cognitive control. These observations compel a new perspective on the mechanisms guiding motivated learning and behavior and provide a framework for understanding the role of the MCC in temperament and psychopathology. PMID- 24787488 TI - Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL. AB - Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q- and 17p-). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy. PMID- 24787489 TI - Is restricted fetal growth associated with later adiposity? Observational analysis of a randomized trial. AB - BACKGROUND: Several recent "developmental origins" studies have reported increased long-term risks of adiposity, especially truncal adiposity, among children born small for gestational age (SGA). OBJECTIVE: We assessed the effects of SGA birth and weight gain in early infancy on adiposity at age 11.5 y. DESIGN: From a cluster-randomized breastfeeding promotion trial in 17,046 Belarusian children, we measured height, weight, waist and hip circumferences, triceps and subscapular skinfold thicknesses, and bioimpedance measures of percentage body fat at age 11.5 y. Children born SGA (birth weight <10th percentile) and those born large for gestational age (LGA; >90th percentile for gestational age) were compared with those born appropriate for gestational age (AGA). Weight gain from birth to 6 mo was categorized as high (>0.67-SD increase in weight-for-age), low (>0.67-SD decrease in weight-for-age), or normal. Multilevel statistical models accounted for clustered measurement and controlled for maternal and paternal height and body mass index (BMI), maternal education, geographic region, urban compared with rural residence, and the child's exact age at follow-up. RESULTS: Children born SGA had a significantly lower BMI, percentage body fat, and fat mass index than did those born AGA, with a dose-response effect across 2 subcategories of SGA (P < 0.001 for all comparisons). No difference was observed in waist-to-hip ratio, although the subscapular-to-triceps skinfold ratio was slightly but significantly (P < 0.001) higher in children born SGA. Differences among the study groups continued to increase since the previous follow-up at 6.5 y. SGA infants with catch-up growth in the first 3-6 mo had growth and adiposity measures intermediate between those born SGA without catch-up and those born AGA. Opposite effects of similar magnitude were observed in children born LGA. CONCLUSION: The 11.5-y-old Belarusian children born SGA were shorter, were thinner, and had less body fat than their non-SGA peers, irrespective of postnatal weight gain. The Promotion of Breastfeeding Intervention Trial was registered at www.isrctn.org as ISRCTN-37687716. PMID- 24787490 TI - Measuring exposure to the polyphenol metabolome in observational epidemiologic studies: current tools and applications and their limits. AB - Much experimental evidence supports a protective role of dietary polyphenols against chronic diseases such as cardiovascular diseases, diabetes, and cancer. However, results from observational epidemiologic studies are still limited and are often inconsistent. This is largely explained by the difficulties encountered in the estimation of exposure to the polyphenol metabolome, which is composed of ~500 polyphenols distributed across a wide variety of foods and characterized by diverse biological properties. Exposure to the polyphenol metabolome in epidemiologic studies can be assessed by the use of detailed dietary questionnaires or the measurement of biomarkers of polyphenol intake. The questionnaire approach has been greatly facilitated by the use of new databases on polyphenol composition but is limited by bias as a result of self-reporting. The use of polyphenol biomarkers holds much promise for objective estimation of polyphenol exposure in future metabolome-wide association studies. These approaches are reviewed and their advantages and limitations discussed by using examples of epidemiologic studies on polyphenols and cancer. The current improvement in these techniques, along with greater emphasis on the intake of individual polyphenols rather than polyphenols considered collectively, will help unravel the role of these major food bioactive constituents in disease prevention. PMID- 24787491 TI - Performance of the Automated Self-Administered 24-hour Recall relative to a measure of true intakes and to an interviewer-administered 24-h recall. AB - BACKGROUND: The Automated Self-Administered 24-hour Recall (ASA24), a freely available Web-based tool, was developed to enhance the feasibility of collecting high-quality dietary intake data from large samples. OBJECTIVE: The purpose of this study was to assess the criterion validity of ASA24 through a feeding study in which the true intake for 3 meals was known. DESIGN: True intake and plate waste from 3 meals were ascertained for 81 adults by inconspicuously weighing foods and beverages offered at a buffet before and after each participant served him- or herself. Participants were randomly assigned to complete an ASA24 or an interviewer-administered Automated Multiple-Pass Method (AMPM) recall the following day. With the use of linear and Poisson regression analysis, we examined the associations between recall mode and 1) the proportions of items consumed for which a match was reported and that were excluded, 2) the number of intrusions (items reported but not consumed), and 3) differences between energy, nutrient, food group, and portion size estimates based on true and reported intakes. RESULTS: Respondents completing ASA24 reported 80% of items truly consumed compared with 83% in AMPM (P = 0.07). For both ASA24 and AMPM, additions to or ingredients in multicomponent foods and drinks were more frequently omitted than were main foods or drinks. The number of intrusions was higher in ASA24 (P < 0.01). Little evidence of differences by recall mode was found in the gap between true and reported energy, nutrient, and food group intakes or portion sizes. CONCLUSIONS: Although the interviewer-administered AMPM performed somewhat better relative to true intakes for matches, exclusions, and intrusions, ASA24 performed well. Given the substantial cost savings that ASA24 offers, it has the potential to make important contributions to research aimed at describing the diets of populations, assessing the effect of interventions on diet, and elucidating diet and health relations. This trial was registered at clinicaltrials.gov as NCT00978406. PMID- 24787493 TI - Healthy diets for a healthy planet. PMID- 24787492 TI - Amount, type, and sources of carbohydrates in relation to ischemic heart disease mortality in a Chinese population: a prospective cohort study. AB - BACKGROUND: The relation between carbohydrate intake and risk of ischemic heart disease (IHD) has not been fully explored in Asian populations known to have high carbohydrate diets. OBJECTIVE: We assessed whether intakes of total carbohydrates, different types of carbohydrates, and their food sources were associated with IHD mortality in a Chinese population. DESIGN: We prospectively examined the association of carbohydrate intake and IHD mortality in 53,469 participants in the Singapore Chinese Health Study with an average follow-up of 15 y. Diet was assessed by using a semiquantitative food-frequency questionnaire. HRs and 95% CIs were calculated by using a Cox proportional hazards analysis. RESULTS: We documented 1660 IHD deaths during 804,433 person-years of follow-up. Total carbohydrate intake was not associated with IHD mortality risk [men: HR per 5% of energy, 0.97 (95% CI: 0.92, 1.03); women: 1.06 (95% CI: 0.99, 1.14)]. When types of carbohydrates were analyzed individually, starch intake was associated with higher risk [men: 1.03 (95% CI: 0.99, 1.08); women: 1.08, (95% CI: 1.02, 1.14)] and fiber intake with lower risk of IHD mortality [men: 0.94 (95% CI: 0.82, 1.08); women: 0.71 (95% CI: 0.60, 0.84)], with stronger associations in women than men (both P-interaction < 0.01). In substitution analyses, the replacement of one daily serving of rice with one daily serving of noodles was associated with higher risk (difference in HR: 26.11%; 95% CI: 10.98%, 43.30%). In contrast, replacing one daily serving of rice with one of vegetables (-23.81%; 95% CI: -33.12%, -13.20%), fruit (-11.94%; 95% CI: -17.49%, -6.00%), or whole wheat bread (-19.46%; 95% CI: -34.28%, -1.29%) was associated with lower risk of IHD death. CONCLUSIONS: In this Asian population with high carbohydrate intake, the total amount of carbohydrates consumed was not substantially associated with IHD mortality. In contrast, the shifting of food sources of carbohydrates toward a higher consumption of fruit, vegetables, and whole grains was associated with lower risk of IHD death. PMID- 24787495 TI - Sucrose compared with artificial sweeteners: a clinical intervention study of effects on energy intake, appetite, and energy expenditure after 10 wk of supplementation in overweight subjects. AB - BACKGROUND: There is a lack of appetite studies in free-living subjects supplying the habitual diet with either sucrose or artificially sweetened beverages and foods. Furthermore, the focus of artificial sweeteners has only been on the energy intake (EI) side of the energy-balance equation. The data are from a subgroup from a 10-wk study, which was previously published. OBJECTIVE: The objective was to investigate changes in EI and energy expenditure (EE) as possible reasons for the changes in body weight during 10 wk of supplementation of either sucrose or artificial sweeteners in overweight subjects. DESIGN: Supplements of sucrose-sweetened beverages and foods (2 g/kg body weight; n = 12) or similar amounts containing artificial sweeteners (n = 10) were given single blind in a 10-wk parallel design. Beverages accounted for 80% and solid foods for 20% by weight of the supplements. The rest of the diet was free choice. Indirect 24-h whole-body calorimetry was performed at weeks 0 and 10. At week 0 the diet was a weight-maintaining standardized diet. At week 10 the diet consisted of the supplements and ad libitum choice of foods. Visual analog scales were used to record appetite. RESULTS: Body weight increased in the sucrose group and decreased in the sweetener group during the intervention. The sucrose group had a 3.3-MJ higher EI but felt less full and had higher ratings of prospective food consumption than did the sweetener group at week 10. Basal metabolic rate was increased in the sucrose group, whereas 24-h EE was increased in both groups at week 10. Energy balance in the sucrose group was more positive than in the sweetener group at the stay at week 10. CONCLUSION: The changes in body weight in the 2 groups during the 10-wk intervention seem to be attributable to changes in EI rather than to changes in EE. PMID- 24787494 TI - Effect of the glycemic index of the diet on weight loss, modulation of satiety, inflammation, and other metabolic risk factors: a randomized controlled trial. AB - BACKGROUND: Low-glycemic index (GI) diets have been proven to have beneficial effects in such chronic conditions as type 2 diabetes, ischemic heart disease, and some types of cancer, but the effect of low-GI diets on weight loss, satiety, and inflammation is still controversial. OBJECTIVE: We assessed the efficacy of 2 moderate-carbohydrate diets and a low-fat diet with different GIs on weight loss and the modulation of satiety, inflammation, and other metabolic risk markers. DESIGN: The GLYNDIET study is a 6-mo randomized, parallel, controlled clinical trial conducted in 122 overweight and obese adults. Participants were randomly assigned to one of the following 3 isocaloric energy-restricted diets for 6 mo: 1) a moderate-carbohydrate and high-GI diet (HGI), 2) a moderate-carbohydrate and low-GI diet (LGI), and 3) a low-fat and high-GI diet (LF). RESULTS: At weeks 16 and 20 and the end of the intervention, changes in body mass index (BMI; in kg/m(2)) differed significantly between intervention groups. Reductions in BMI were greater in the LGI group than in the LF group, whereas in the HGI group, reductions in BMI did not differ significantly from those in the other 2 groups (LGI: -2.45 +/- 0.27; HGI: -2.30 +/- 0.27; LF: -1.43 +/- 0.27; F = 4.616, P = 0.012; pairwise comparisons: LGI compared with HGI, P = 1.000; LGI compared with LF, P = 0.016; HGI compared with LF, P = 0.061). The decrease in fasting insulin, homeostatic model assessment of insulin resistance, and homeostatic model assessment of beta cell function was also significantly greater in the LGI group than in the LF group (P < 0.05). Despite this tendency for a greater improvement with a low-GI diet, the 3 intervention groups were not observed to have different effects on hunger, satiety, lipid profiles, or other inflammatory and metabolic risk markers. CONCLUSION: A low-GI and energy-restricted diet containing moderate amounts of carbohydrates may be more effective than a high-GI and low-fat diet at reducing body weight and controlling glucose and insulin metabolism. This trial was registered at Current Controlled Trials (www.controlled-trials.com) as ISRCTN54971867. PMID- 24787498 TI - The affordable care act and state coverage of clinical preventive health services for working-age adults. AB - Significant public health challenges facing the United States stem from preventable disease. The Patient Protection and Affordable Care Act dedicated substantial resources toward prevention. Among other reforms, the Affordable Care Act requires Medicaid and private health insurers to cover clinical preventive services for adults, pursuant to recommendations by the U.S. Preventive Service Task Force. This article examines the infrastructure upon which these recommendations are based, the requirements related to risk factors for leading causes of preventable disease in adults associated with tobacco and alcohol use, unhealthy diet, and inactivity, and coverage requirements for private plans and Medicaid. The article provides and assesses data comparing the health statuses of populations in and preventive services offered by states taking the Affordable Care Act Medicaid expansion versus those in states declining to expand coverage. The article suggests legislative and other methods to increase preventive clinical service requirements and notes outstanding issues for future research. PMID- 24787496 TI - Glycemic index, glycemic load, and risk of type 2 diabetes: results from 3 large US cohorts and an updated meta-analysis. AB - BACKGROUND: Epidemiologic evidence for the relation between carbohydrate quality and risk of type 2 diabetes (T2D) has been mixed. OBJECTIVE: We prospectively examined the association of dietary glycemic index (GI) and glycemic load (GL) with T2D risk. DESIGN: We prospectively followed 74,248 women from the Nurses' Health Study (1984-2008), 90,411 women from the Nurses' Health Study II (1991 2009), and 40,498 men from the Health Professionals Follow-Up Study (1986-2008) who were free of diabetes, cardiovascular disease, and cancer at baseline. Diet was assessed by using a validated questionnaire and updated every 4 y. We also conducted an updated meta-analysis, including results from our 3 cohorts and other studies. RESULTS: During 3,800,618 person-years of follow-up, we documented 15,027 cases of incident T2D. In pooled multivariable analyses, those in the highest quintile of energy-adjusted GI had a 33% higher risk (95% CI: 26%, 41%) of T2D than those in the lowest quintile. Participants in the highest quintile of energy-adjusted GL had a 10% higher risk (95% CI: 2%, 18%) of T2D. Participants who consumed a combination diet that was high in GI or GL and low in cereal fiber had an ~50% higher risk of T2D. In the updated meta-analysis, the summary RRs (95% CIs) comparing the highest with the lowest categories of GI and GL were 1.19 (1.14, 1.24) and 1.13 (1.08, 1.17), respectively. CONCLUSION: The updated analyses from our 3 cohorts and meta-analyses provide further evidence that higher dietary GI and GL are associated with increased risk of T2D. PMID- 24787497 TI - Effect of weight loss, exercise, or both on cognition and quality of life in obese older adults. AB - BACKGROUND: Obesity impairs cognition and health-related quality of life (HRQOL) in older adults; however, the appropriate treatment of obese older adults remains controversial. OBJECTIVE: The objective was to determine the independent and combined effects of weight loss and exercise on cognition, mood, and HRQOL in obese older adults. DESIGN: One hundred seven frail, obese older adults were randomly assigned to a control, weight-management (diet), exercise, or weight management-plus-exercise (diet-exercise) group for 1 y. In this secondary analysis, main outcomes were Modified Mini-Mental State Examination (3MS) and total Impact of Weight on Quality of Life-Lite (IWQOL) scores. Other outcomes included Word Fluency Test, Trail Making Test Parts A and B, and Geriatric Depression Scale (GDS) scores. RESULTS: Scores on the 3MS improved more in the diet (mean +/- SE: 1.7 +/- 0.4), exercise (2.8 +/- 0.4), and diet-exercise (2.9 +/- 0.4) groups than in the control group (0.1 +/- 0.4) (between-group P = 0.0001 0.04); scores in the diet-exercise group improved more than in the diet group but not more than in the exercise group. Scores on the Word Fluency Test improved more in the exercise (4.1 +/- 0.8) and diet-exercise (4.2 +/- 0.7) groups than in the control group (-0.8 +/- 0.8; both P = 0.001). For the Trail Making Test Part A, scores in the diet-exercise group (-11.8 +/- 1.9) improved more than in the control group (-0.8 +/- 1.9) (P = 0.001); a similar finding was observed for the Trail Making Test Part B. Scores on the IWQOL improved more in the diet (7.6 +/- 1.6), exercise (10.1 +/- 1.6), and diet-exercise (14.0 +/- 1.4) groups than in the control group (0.3 +/- 1.6) (P = 0.0001-0.03); scores in the diet-exercise group improved more than in the diet group but not more than in the exercise group. In the diet-exercise group, peak oxygen consumption and strength changes were independent predictors of 3MS changes; weight and strength changes were independent predictors of IWQOL changes. GDS scores did not change. CONCLUSIONS: Weight loss and exercise each improve cognition and HRQOL, but their combination may provide benefits similar to exercise alone. These findings could inform practice guidelines with regard to optimal treatment strategies for obese older adults. This trial was registered atclinicaltrials.govas NCT00146107. PMID- 24787499 TI - Impaired oral fatty acid chemoreception is associated with acute excess energy consumption. AB - Excessive consumption of dietary fat is implicated with development of obesity. Impaired oral and gastrointestinal chemoreception to the breakdown products of dietary fat, fatty acids, may be associated with increased energy consumption. The objective of this study was to determine if impaired oral fatty acid chemoreception influences energy intake and perceived satiety. Subjects (n = 24) attended six laboratory sessions. Impaired fatty acid chemoreception was defined as subjects who could not identify >3.8 mM oleic acid (C18:1). Subjects participated in a blinded crossover study and consumed each of three high macronutrient breakfasts (high fat, high protein, high carbohydrate) and a balanced macronutrient breakfast on four separate days. Following breakfast, subjects were required to consume a buffet-style lunch until comfortably full. The amount consumed (MJ and g) was measured, as was perceived satiety prior to and following meals. Following the high fat breakfast, subjects with impaired fatty acid chemoreception (n = 10) consumed significantly more energy (2.1 +/- 0.8 MJ) and grams (237.70 +/- 46.37 g) of food at lunch compared to other subjects (P < 0.05). There were no significant differences in energy, grams of food consumed at lunch and perceived satiety, between subjects for the other breakfasts (P > 0.05). Impaired oral fatty acid chemoreception was associated with excess energy consumption following a high fat meal. PMID- 24787500 TI - Photomask-based integration process of low-defect suspended carbon nanotubes into SOI MEMS. AB - A fully-developed photomask-based integration process is reported. The process can integrate suspended carbon nanotubes (CNTs) into micro-structures on silicon on-insulator chips. The process features batch-compatible fabrication and post growth metallization of suspended CNTs, which has never been demonstrated by any other processes. The post-growth metallization avoids deterioration of the metals at the elevated CNT growth temperature and enables mechanically robust double clamped configuration. Two key steps ensure a significant reduction of the risk for damage or contamination of the CNTs during post-growth processing. SiO2 bridges were fabricated to physically support CNTs during the wet processing, and a protective Al2O3 layer (~40 nm) was deposited to prevent resist contamination during lithography. The combination of these two steps enables the removal of the unprotected suspended segments of unwanted CNTs by oxygen plasma ashing, improving device yield by a factor of six. The electrically interfaced suspended CNT device possessed high CNT quality (D/G(+) intensity ratio of 1/224 in Raman spectroscopy) and good electrical properties, such as low device resistances as low as 105 kOmega and reduced gate hysteresis as low as 65 mV in ambient air. Measurements of eights devices indicate that the release step did not have a systematic influence on the device resistances. PMID- 24787502 TI - Interactive effect of brassinosteroids and cytokinins on growth, chlorophyll, monosaccharide and protein content in the green alga Chlorella vulgaris (Trebouxiophyceae). AB - Interaction between brassinosteroids (BRs) (brassinolide, BL; 24-epibrassinolide, 24-epiBL; 28-homobrassinolide, 28-homoBL; castasterone, CS; 24-epicastasterone, 24-epiCS; 28-homocastasterone, 28-homoCS) and adenine- (trans-zeatin, tZ; kinetin, Kin) as well as phenylurea-type (1,3-diphenylurea, DPU) cytokinins (CKs) in the regulation of cell number, phytohormone level and the content of chlorophyll, monosaccharide and protein in unicellular green alga Chlorella vulgaris (Trebouxiophyceae) were examined. Chlorella vulgaris exhibited sensitivity to CKs in the following order of their stimulating properties: 10 nM tZ > 100 nM Kin >1 MUM DPU. Exogenously applied BRs possessed the highest biological activity in algal cells at concentration of 10 nM. Among the BRs, BL was characterized by the highest activity, while 28-homoCS - by the lowest. The considerable increase in the level of all endogenous BRs by 27-46% was observed in C. vulgaris culture treated with exogenous 10 nM tZ. It can be speculated that CKs may stimulate BR activity in C. vulgaris by inducing the accumulation of endogenous BRs. CKs interacted synergistically with BRs increasing the number of cells and endogenous accumulation of proteins, chlorophylls and monosaccharides in C. vulgaris. The highest stimulation of algal growth and the contents of analyzed biochemical parameters were observed for BL applied in combination with tZ, whereas the lowest in the culture treated with both 28-homoCS and DPU. However, regardless of the applied mixture of BRs with CKs, the considerable increase in cell number and the metabolite accumulation was found above the level obtained in cultures treated with any single phytohormone in unicellular green alga C. vulgaris. PMID- 24787501 TI - Bcl-2 suppresses activation of VPEs by inhibiting cytosolic Ca2+ level with elevated K+ efflux in NaCl-induced PCD in rice. AB - Bcl-2 is one of the most important antiapoptotic members in mammals and prevents many forms of apoptosis in a variety of cell types. Our previous study revealed that overexpression of Bcl-2 significantly suppressed H2O2/NaCl-induced programmed cell death via inhibiting the transcriptional activation of OsVPE2 and OsVPE3 in transgenic rice. However, Ca(2+) and K(+) homeostasis of this process remains largely unknown. In the present study, we investigate whether nonselective cation channels (NSCC) blockers affect Bcl-2 function in rice under salt stress and how Bcl-2 affects ion homeostasis in salt stress-induced PCD. The results showed that overexpression of Bcl-2 significantly decreased transient elevations in the cytosolic Ca(2+) levels, inhibited NaCl-induced K(+) efflux but not H(+) efflux across the plasma membrane, and further suppressed the expression levels of OsVPE2 and OsVPE3, leading to the inhibition of salt-induced PCD and increase of tolerance to salt stress in transgenic rice. During the NaCl-induced PCD, the effects of a NSCC blocker La(3+) on ion homeostasis and VPEs expression in wild-type were similar to the effects of Bcl-2 overexpression in transgenic line. However, a synergistic effect of Bcl-2 and La(3+) was not obviously detectable. Our results suggested that Bcl-2 played an important role in suppression of NaCl-induced PCD by disruption of ion homeostasis, providing an insight into the mechanistic study of plant VPEs, cytosolic Ca(2+) level and K(+) efflux. PMID- 24787503 TI - Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt-Jakob disease: proposed staging of cerebral cortical pathology. AB - In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex. PMID- 24787504 TI - Activation of spinal GABAB receptors normalizes N-methyl-D-aspartate receptor in diabetic neuropathy. AB - N-methyl-D-aspartate receptor (NMDAR) activity is increased, while GABAB receptor is downregulated in the spinal cord dorsal horn in diabetic neuropathy. In this study, we determined the interaction of NMDARs and GABAB receptors in streptozotocin (STZ)-induced diabetic neuropathy. The paw withdrawal threshold (PWT) was significantly lower in STZ-treated rats than in vehicle-treated rats. Intrathecal injection of baclofen, a GABAB receptor agonist, significantly increased the PWT in STZ-treated rats, an effect that was abolished by pre administration of the GABAB receptor specific antagonist CGP55845. Spinal NR2B, an NMDA receptor subunit, protein and mRNA expression levels were significantly higher in STZ-treated rats than in vehicle-treated rats. Intrathecal baclofen significantly reduced the NR2B protein and mRNA expression levels in STZ-treated rats. Intrathecal administration of CGP55845 eliminated baclofen-induced reduction of NR2B protein and mRNA levels in STZ-treated rats. In addition, the phosphorylated cAMP response element-binding (CREB) protein level was significantly higher in the spinal cord dorsal horn in STZ-treated rats compared with vehicle-treated rats. Intrathecal injection of baclofen significantly decreased phosphorylated CREB protein level in STZ-treated rats; an effect was blocked by CGP55845. These data suggest that activation of GABAB receptors in the spinal cord dorsal horn normalizes NMDAR expression level in diabetic neuropathic pain. PMID- 24787505 TI - Lifestyle intervention in prevention of type 2 diabetes in women with a history of gestational diabetes mellitus: one-year results of the FIN-D2D project. AB - BACKGROUND: Lifestyle interventions are effective in preventing type 2 diabetes (T2D). Women with history of gestational diabetes mellitus (GDM) may have barriers to lifestyle changes, and the previous results of lifestyle interventions are contradictory reporting either favorable outcomes or no significant beneficial effects. Our aim was to compare cardio-metabolic risk profile and responses to a 1-year lifestyle intervention program in women with and without history of GDM. METHODS: The Implementation Project of the Program for Prevention of Type 2 Diabetes (FIN-D2D) was conducted in Finland in five hospital districts. Altogether 1,661 women aged <=45 years participated in the program. One-year follow-up was available for 393 women who did not have screen detected T2D at baseline, and 265 of them had at least one intervention visit [115 (43.4%) women with history of GDM and 150 (56.6%) without history of GDM]. RESULTS: At baseline, women with GDM had similar baseline glucose tolerance but better anthropometric characteristics, blood pressure, and lipid profile than women without GDM after adjustment for age. Beneficial changes in cardiovascular risk profile existed among women with and without GDM during follow-up and the effect of lifestyle intervention was similar between the groups, except that low density lipoprotein cholesterol improved only in women with GDM. Altogether, 4.0% of those with GDM and 5.0% of those without GDM developed T2D (p=0.959 adjustment for age). CONCLUSIONS: The effect of a 1-year lifestyle intervention in primary healthcare setting was similar regardless of history of GDM, both women with and without GDM benefitted from participation in the lifestyle intervention. PMID- 24787506 TI - Helicopter emergency medical services and weather-related accidents. PMID- 24787507 TI - Response to large civilian air medical jets: implications for Australian disaster health. PMID- 24787508 TI - Experience matters. PMID- 24787509 TI - A 47-year-old woman with an intracerebral hemorrhage. PMID- 24787510 TI - Hemodynamic monitoring: part 1. PMID- 24787511 TI - Hitech novice. PMID- 24787512 TI - Helicopter emergency medical service utilization for scene trauma: an evidence based guideline. PMID- 24787513 TI - Nonurgent commercial air travel after nonhemorrhagic cerebrovascular accident. AB - Nonurgent commercial air travel in patients who have experienced a nonhemorrhagic cerebrovascular accident (CVA) may occur, particularly in the elderly traveling population. A recent CVA, particularly occurring during a person's travel, presents a significant challenge to the patient, companions, family, and health care team. Specific medical recommendation, based on accumulated scientific data and interpreted by medical experts, is needed so that travel health care professionals can appropriately guide the patient. Unfortunately, such recommendations are almost entirely lacking despite the relative frequency of CVA and air travel. This article reviews the existing recommendations with conclusions based on both these limited data and rationale conjecture. PMID- 24787514 TI - Air travel of patients with abdominal aortic aneurysm: urgent air medical evacuation and nonurgent commercial air repatriation. AB - Abdominal aortic aneurysm (AAA) presents across a spectrum of severity. Although some resources suggest a theoretic risk for rupture related to air travel, this claim remains unproven. In fact, there are little data from which to make evidence-based recommendations. Air medical evacuation of a patient with either an AAA at risk of imminent rupture or status post recent rupture can be performed, assuming that local surgical care is not available and that transfer is taking the patient to a higher level of medical intervention. Furthermore, medical opinion suggests that patients with asymptomatic and/or surgically corrected AAA can safely travel by commercial aircraft for nonurgent reasons, assuming that other issues including postoperative needs are appropriately addressed. In this discussion, answers to the following issues are sought: flight safety for urgent evacuation and nonurgent repatriation scenarios, waiting time to fly nonurgently after AAA diagnosis, and the need for medical accompaniment. PMID- 24787515 TI - Evaluation of Dutch Helicopter Emergency Medical Services in transporting children. AB - OBJECTIVE: In the Netherlands, helicopter emergency medical services (HEMS) function as an adjunct to paramedic ambulance service delivering hospital-level medical care to a prehospital location. The main goal of Dutch HEMS is to provide on-scene medical expertise and not primarily to serve as transport. The transportation of patients to specialized hospitals is sometimes mandatory, especially in cases of critically ill or wounded children. In the literature, no support can be found to support the safety of transportation by helicopter. We retrospectively evaluated the safety of this type of transportation and if any problems were encountered transporting children by helicopter. METHODS: We reviewed our local HEMS database for all children (, 16 years) transported by helicopter to a level 1 trauma center between January 2007 and December 2012. RESULTS: A total number of 430 patients were transported by helicopter to a hospital (0-87 years, mean 5 31.6 years). Of these patients, 83 (19%) were younger than 16 years (0-15.7 years, mean 5 6.6 years). Causes for HEMS transport in children varied, but the main groups were road traffic accidents (40%), cardiopulmonary arrests (15%), falls from height (12%), and horse riding accidents (7%). In the children group, 1 accidental extubation of the orotracheal tube was noted while lifting the patient (10 years old) into the helicopter. This was immediately noticed, and the patient was reintubated without complications. No further adverse events were encountered during transportation time. The accidental extubation is not a specific complication of helicopter transportation but is inextricably linked with moving severely injured and intubated patients/children. CONCLUSION: We conclude that transporting children by helicopter is a safe method of transportation for critically ill children to adequately equipped medical centers. PMID- 24787516 TI - Ankylosing spondylitis in a military aviator: air medical considerations. AB - Rheumatologic diseases are a challenging diagnosis when it comes to air medical disposition decision making because many of these diseases overlap and their initial presentation is insidious and relapsing remitting in future scope. Many rheumatologic diseases have musculoskeletal and other organ complications. One of these diagnoses is spondyloarthritides. These disorders include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis and spondylitis, enteropathic arthritis and spondylitis, juvenile-onset spondyloarthritis, and undifferentiated spondyloarthritis. The prevalence of spondyloarthropathy is estimated to be between 0.1% and 2.5%,(1) although figures vary from 1 study to another. In this article, we report the case of a military pilot diagnosed with AS who had a favorable response to treatment with etanercept therapy. PMID- 24787518 TI - Testosterone, cardiovascular risk, and hormonophobia. AB - INTRODUCTION: A public outcry against testosterone (T) therapy has suddenly occurred based on two reports suggesting treatment was associated with increased cardiovascular (CV) risks. AIM: To analyze scientific and social bases for concerns regarding T therapy. METHODS: Analysis of recent articles regarding CV risks with T and comparison with events surrounding publication of results of the Women's Health Initiative in 2002. RESULTS: In the first study, the percentage of individuals with an adverse event was lower by half in men who received T compared with untreated men (10.1% vs. 21.2%). However, an opposite conclusion was reached via complex statistics. The second study reported minor increased rate of nonfatal myocardial infarction (MI) up to 90 days after receiving a T prescription compared with the prior 12 months. However, there was no control group, so it is unknown whether this MI rate was increased, reduced, or unchanged compared with untreated men. Neither study provided substantive evidence of risk, yet these were lauded as proof of dangers, despite a substantial literature to the contrary. Similar events followed the publication of the Women's Health Initiative in 2002 when a media frenzy over increased risks with female hormone replacement therapy obscured the fact that the reported excess risk was clinically meaningless, at two events per 1,000 person-years. Stakeholders driving concerns regarding hormone risks are unlikely to be clinicians with real world patient experience. CONCLUSIONS: The use of weak studies as proof of danger indicates that cultural (i.e., nonscientific) forces are at play. Negative media stories touting T's risks appear fueled by antipharma sentiment, anger against aggressive marketing, and antisexuality. This stance is best described as "hormonophobia." As history shows, evidence alone may be insufficient to alter a public narrative. The true outrage is that social forces and hysteria have combined to deprive men of a useful treatment without regard for medical science. PMID- 24787519 TI - Effects of contaminant exposure and food restriction on hepatic autophagic lysosomal parameters in Herring Gull (Larus argentatus) chicks. AB - Lysosomal autophagic responses, such as lysosomal membrane stability, neutral lipids (NL), lipofuscin (LF), and malondialdehyde (MDA) levels, are valuable measures of cellular early-onset effects induced by environmental stress factors, such as contaminant exposure and fasting. In this study, these parameters were analysed and related to levels of halogenated organic contaminants (HOCs) in 40 Herring Gull (Larus argentatus) chicks. Chicks were experimentally exposed to HOCs through diet and went through a period of nutrient deprivation at the end of the experiment. HOC exposure and fasting were conducted separately and in combination. NL storages were depleted, and lysosomal membranes were destabilised after HOC exposure and nutrient deprivation. These responses were not related specifically to one type of stress or the extent of the treatment. No synergistic or additive effects from the combination of HOC exposure and fasting were observed. LF accumulated, and MDA levels increased as a result of fasting, but were unaffected by HOC exposure. LF accumulation was strongly associated with the percent weight change in the chicks. Large weight loss was associated with high LF levels, and slight weight gain was associated with low LF levels. Hence, food deprivation affected all the measured parameters, and HOC exposure decreased NL levels and lysosomal membrane stability in HG chick liver. Furthermore, autophagic lysosomal parameters have frequently been applied as biomarkers of cellular health status in previous studies of marine and terrestrial invertebrates, and this study suggests that these parameters may be good candidates for biomarkers of cellular health status in seabirds as well. PMID- 24787520 TI - Splenic injury during resection for esophageal cancer: risk factors and consequences. AB - OBJECTIVE: Esophageal cancer surgery carries a risk of splenic injury, which may require splenectomy, but predictors of such events remain uncertain. Moreover, the hypothesis that incidental splenectomy carries a worse prognosis deserves attention. DESIGN: A population-based, nationwide cohort study was conducted on 1679 patients who underwent resection for esophageal cancer in Sweden in 1987 to 2010, with follow-up until February 2012. Predictors of splenic injury and incidental splenectomy were analyzed using multivariable logistic regression, providing odds ratios (ORs) with 95% confidence intervals (CIs). Associations between incidental splenectomy and risk of mortality and severe infections were analyzed using multivariable Cox regression, providing hazard ratios (HRs) with 95% CIs. RESULTS: Higher surgeon volume of esophageal cancer resection decreased the risk of splenic injury and incidental splenectomy (OR: 0.58; 95% CI: 0.41 0.80; and OR: 0.41; 95% CI: 0.25-0.66, respectively, comparing the highest to lowest category). In patients with splenic injury, progression to incidental splenectomy decreased by 92% during the study period. Sex, age, tumor stage, previous abdominal surgery, neoadjuvant therapy, and surgical radicality did not influence these risks. Incidental accidental splenectomy increased the overall risk of mortality (HR: 1.29; 95% CI: 1.03-1.61) and severe infections (HR: 2.79; 95% CI: 1.35-5.79). CONCLUSION: The inverse association between surgeon volume and splenic injury supports centralization of esophageal cancer surgery. The increased risk of mortality and severe infections after incidental splenectomy should be kept in mind during surgery, and we should encourage efforts to preserve an injured spleen and stress the relevance of vaccination after splenectomy. PMID- 24787521 TI - Twelve tips for providing effective student support in undergraduate medical education. AB - Medical students often require high levels of specialised institutional and personal support to facilitate success. Contributory factors may include personality type, course pressures and financial hardship. Drawing from research literature and the authors' experience, 12 tips are listed under five subheadings: policy and systems; people and resources; students; delivering support; limits of support. The 12 tips provide guidance to organisations and individual providers that encourages implementation of good practice and helps them better visualise their role within the system. By following the tips, medical schools can make more effective provisions for the expected, diverse and sometimes specialist needs of their students. Schools must take a proactive, anticipatory approach to provide appropriately for their entire student body. This ensures that students receive the best quality support, are more likely to succeed and are adequately prepared for their medical careers. PMID- 24787522 TI - Twelve tips to guide effective participant recruitment for interprofessional education research. AB - BACKGROUND: The success of research in interprofessional education is largely due to the participation of students. Their recruitment is, however, perhaps the most challenging part of any study, and, yet, is a key determinant of the results. AIM: The aim of this article is to provide a "how to guide" for medical education researchers to facilitate the recruitment of students across health professions. RESULTS: The 12 tips are (1) establish clear expectations with your research team from the start; (2) do your homework: invest time and energy in pre-recruitment preparation; (3) develop a plan: be realistic about your resources; (4) create a "Buzz" about your interprofessional research; (5) prepare multiple communication methods - can't just rely on one! (6) engage volunteers across professions to participate; (7) address the participant's willingness to take part in the research; (8) demonstrate good interpersonal skills; (9) be diligent in tracking participants; (10) show appreciation and share results; (11) consider participant incentives: are they really important? (12) maintain tenacity - no one said interprofessional recruitment was easy! CONCLUSIONS: Interprofessional studies offer numerous logistical, administrative and scheduling challenges; the 12 tips are provided to help medical education researchers develop and manage the successful recruitment of students across the health professions. PMID- 24787523 TI - A snapshot of the status of problem-based learning (PBL) in Chinese medical schools. AB - INTRODUCTION: In North America, where it was born, problem-based learning (PBL) has seen dips and rises in its popularity, but its inherent strengths have led to its spread to medical schools all over the world. Although its use at medical schools in some Western countries has already been examined, no one has looked at its status in many other countries, including China. The aim of this study is to determine the number of schools currently using PBL in China, the degree to which they use it, and the reasoning behind such usage. METHODS: We used survey and internet search to examine PBL usage at Chinese medical schools. We were able to collect data from 43 first-class Chinese medical schools that are geographically diverse and thus representative of medical schools all across China. RESULTS: 34 (79.1%) of the 43 medical schools use PBL in the preclinical curriculum. Of the 34, data were collected from 24 (70.6%) medical schools regarding the extent of their PBL usage. Nine (37.5%) schools use PBL for less than 10% of preclinical hours, 14 (58.3%) schools use PBL for 10-50% of preclinical hours, and one (4.2%) school uses PBL for more than 50% of preclinical hours. CONCLUSION: In our sample of Chinese medical institutions, a large majority of schools use PBL, however, most schools use it for less than 50% of total preclinical curricular hours. Our results suggest that schools are interested in increasing the number of curricular hours devoted to PBL but are constrained by resources. PMID- 24787524 TI - The hidden curriculum: is it time to re-consider the concept? PMID- 24787525 TI - Unprofessional behavior by specialty: a qualitative analysis of six years of student perceptions of medical school faculty. AB - BACKGROUND: Unprofessional behavior has well documented negative effects both on the clinical care environment and on the learning environment. If unprofessional behavior varies by department or specialty, this has implications both for faculty development and for undergraduate and graduate level training. AIMS: We sought to learn which unprofessional behaviors were endemic in our school, and which were unique to particular departments. METHODS: Students graduating from medical school between 2007 and 2012 were asked to complete a questionnaire naming the most professional and least professional faculty members they encountered in during school. For the least professional faculty members, they were also asked to provide information about the unprofessional behavior. RESULTS: Students noted several types of unprofessional behavior regardless of the department faculty were in; however, there were some behaviors only noted in individual departments. The unprofessional behavior profiles for Surgery and Obstetrics/Gynecology were markedly similar, and were substantially different from all other specialties. CONCLUSION: Undergraduate, graduate, and faculty education focused on unprofessional behavior that may occur in various learning environments may provide a feasible, practical, and an effective approach to creating a culture of professional behavior throughout the organization. PMID- 24787526 TI - Electives in undergraduate medical education: AMEE Guide No. 88. AB - This Guide outlines the scope and potential roles an elective can contribute to undergraduate medical training and identifies ways to maximize learning opportunities, including within global health. The types of educational activity available for electives range from meeting individual educational need through to exploration of potential career pathways, with many factors influencing choice. Key areas of organization underpinning a successful elective before, during and after the placement include developing clarity of the intended educational outcomes as well as addressing practicalities such as travel and accommodation. Risk management including the implications for the participating schools as well as the student and their elective supervisors is crucial. This Guide would not be complete without some discussion around ethics and professional conduct during an elective, with consideration of the impact of elective placements, particularly in low-middle income countries. PMID- 24787527 TI - How we developed eForms: an electronic form and data capture tool to support assessment in mobile medical education. AB - Mobile learning technologies are being introduced and adopted by an increasing number of medical schools. Following the implementation of these devices, institutions are tasked with the challenge of their integration into curriculum delivery and presented with the opportunity to facilitate data collection from large student cohorts. Since 2011, Manchester Medical School (MMS) has undertaken the largest deployment of iPads within UK Higher Education. Working towards the more efficient collation of students' compulsory workplace-based assessment data led us to evaluate how existing information management software could replace previously paper-based systems. Following an evaluation of six, and a trial of one, commercially available packages, the existing software solutions were found to be inflexible and unfit for purpose. This resulted in the development of a new digital solution that addressed the limitations of the previous system. "University of Manchester (UoM) eForms" consists of an app and a web-based administration system that respectively permit high volume data collection and management. UoM eForms has now replaced the preceding paper-based and electronic systems within MMS for workplace-based assessment administration, due to the improved usability and dynamicity built into its interface and infrastructure. This new system has found many further useful applications, including research data collection, feedback, placement evaluations, quality assurance and interview marking. PMID- 24787528 TI - Faculty development through international exchange: the IMEX initiative. AB - BACKGROUND: Faculty development is often local and international experiences are usually limited to conferences and courses. In 2006, five schools across the globe decided to enhance international faculty experiences through an exciting new collaboration: the International Medical Educators Exchange (IMEX) initiative. METHOD: Twice a year, one of the five schools in the Netherlands, Canada, Sweden and the UK organizes a week of faculty development activities for experienced medical educators from each school, including group discussions, short presentations, observations and active engagement in local education, one on-one meetings with local faculty members, and many opportunities for in-depth discussion. We administered a survey to evaluate the impact of this international exchange. RESULTS: By August 2013, 31 IMEX scholars had attended at least one of the 14 site visits held; most of them (29) had attended 3-5 site visits. Responding IMEX alumni (55%, N = 16) felt that their experiences impacted their personal competence and international orientation, and to some extent their career, their daily work and their institution. Most features of the IMEX program were valued as highly important and highly successful. DISCUSSION: IMEX has established itself as an important additional faculty development opportunity for those medical educators who wish to develop and pursue a career in education. PMID- 24787529 TI - Pointing and tracing gestures may enhance anatomy and physiology learning. AB - BACKGROUND: Currently, instructional effects generated by Cognitive load theory (CLT) are limited to visual and auditory cognitive processing. In contrast, "embodied cognition" perspectives suggest a range of gestures, including pointing, may act to support communication and learning, but there is relatively little research showing benefits of such "embodied learning" in the health sciences. AIM: This study investigated whether explicit instructions to gesture enhance learning through its cognitive effects. METHODS: Forty-two university educated adults were randomly assigned to conditions in which they were instructed to gesture, or not gesture, as they learnt from novel, paper-based materials about the structure and function of the human heart. Subjective ratings were used to measure levels of intrinsic, extraneous and germane cognitive load. RESULTS: Participants who were instructed to gesture performed better on a knowledge test of terminology and a test of comprehension; however, instructions to gesture had no effect on subjective ratings of cognitive load. CONCLUSIONS: This very simple instructional re-design has the potential to markedly enhance student learning of typical topics and materials in the health sciences and medicine. PMID- 24787530 TI - Weighting checklist items and station components on a large-scale OSCE: is it worth the effort? AB - BACKGROUND: Past research suggests that the use of externally-applied scoring weights may not appreciably impact measurement qualities such as reliability or validity. Nonetheless, some credentialing boards and academic institutions apply differential scoring weights based on expert opinion about the relative importance of individual items or test components of Observed Structured Clinical Examinations (OSCEs). AIMS: To investigate the impact of simplified scoring models that make little to no use of differential weighting on the reliability of scores and decisions on a high stakes OSCE required for medical licensure in Canada. METHOD: We applied four different weighting models of various complexities to data from three administrations of the OSCE. We compared score reliability, pass/fail rates, correlations between the scores and classification decision accuracy and consistency across the models and administrations. RESULTS: Less complex weighting models yielded similar reliability and pass rates as the more complex weighting model. Minimal changes in candidates' pass/fail status were observed and there were strong and statistically significant correlations between the scores for all scoring models and administrations. Classification decision accuracy and consistency were very high and similar across the four scoring models. CONCLUSIONS: Adopting a simplified weighting scheme for this OSCE did not diminish its measurement qualities. Instead of developing complex weighting schemes, experts' time and effort could be better spent on other critical test development and assembly tasks with little to no compromise in the quality of scores and decisions on this high-stakes OSCE. PMID- 24787531 TI - Scaffolding reflective learning in clinical practice: a comparison of two types of reflective activities. AB - BACKGROUND: The development of reflective learning skills is a continuous process that needs scaffolding. It can be described as a continuum, with the focus of reflection differing in granularity from recent, concrete activities to global competency development. AIM: To explore learners' perceptions regarding the effects of two reflective writing activities designed to stimulate reflection at different degrees of granularity during clinical training. METHODS: Totally 142 respondents (students and recent graduates) completed a questionnaire. Quantitative and qualitative data were triangulated. RESULTS: Immediate reflection-on-action was perceived to be more valuable than delayed reflection-on competency-development because it facilitated day-to-day improvement. Delayed reflection was perceived to facilitate overall self-assessment, self-confidence and continuous improvement, but this perception was mainly found among graduates. Detailed reflection immediately after a challenging learning experience and broad reflection on progress appeared to serve different learning goals and consequently require different arrangements regarding feedback and timing. CONCLUSIONS: Granularity of focus has consequences for scaffolding reflective learning, with immediate reflection on concrete events and reflection on long term progress requiring different approaches. Learners appeared to prefer immediate reflection-on-action. PMID- 24787532 TI - The emergence of humanistic anatomy. PMID- 24787533 TI - A speed-dating agency for writers and non-writers? PMID- 24787534 TI - Assessors for communication skills: SPs or healthcare professionals? AB - INTRODUCTION: The complexity of modern medicine creates more challenges for teaching and assessment of communication skills in undergraduate medical programme. This research was conducted to study the level of communication skills among undergraduate medical students and to determine the difference between simulated patients and clinical instructors' assessment of communication skills. METHODS: This comparative study was conducted for three months at the Clinical Skills and Simulation Centre of the International Medical University in Malaysia. The modified Calgary-Cambridge checklist was used to assess the communication skills of 50 first year and 50 second year medical students (five-minutes pre recorded interview videos on the scenario of sore throat). These videos were reviewed and scored by simulated patients (SPs), communication skills instructors (CSIs) and non-communication skills instructors (non-CSIs). RESULTS: Better performance was observed among the undergraduate medical students, who had formal training in communication skills with a significant difference in overall scores detected among the first and second year medical students (p = 0.0008). A non significant difference existed between the scores of SPs and CSIs for Year 1 (p = 0.151). CONCLUSIONS: The SPs could be trained and involved in assessment of communication skills. Formal training in communication skills is necessary in the undergraduate medical programme. PMID- 24787535 TI - Foundation doctors working at night: what training opportunities exist? AB - INTRODUCTION: Foundation Training is designed for doctors in their first two years of post-graduation. The number of foundation doctors (FD) in the UK working nights has reduced because of a perception that clinical supervision at night is unsatisfactory and that minimal training opportunities exist. We aimed to assess the value of night shifts to FDs and hypothesised that removing FDs from nights may be detrimental to training. METHODS: Using a survey, we assessed the number of FDs working nights in London, FDs views on working nights and their supervision at night. We evaluated whether working at night, compared to daytime working provided opportunities to achieve foundation competencies. RESULTS: 83% (N = 2157/2593) of FDs completed the survey. Over 90% of FDs who worked nights felt that the experience they gained improved their ability to prioritise, make decisions and plan. FDs who worked nights reported higher scores for achieving competencies in history taking (2.67 vs. 2.51; p = 0.00), examination (2.72 vs. 2.59; p = 0.01) and resuscitation (2.27 vs. 1.96; p = 0.00). The majority (65%) felt adequately supervised. CONCLUSIONS: Our survey has demonstrated that FDs find working nights a valuable experience, providing important training opportunities, which are additional to those encountered during daytime working. PMID- 24787536 TI - Competing interests and medical education. PMID- 24787537 TI - Subungual exostosis. PMID- 24787538 TI - Further evidence for botulinum toxin A in cerebral palsy. PMID- 24787539 TI - Bicuspid aortic valve in association with Schmitt Gillenwater Kelly syndrome. PMID- 24787540 TI - Highly active and stable hydrogen evolution electrocatalysts based on molybdenum compounds on carbon nanotube-graphene hybrid support. AB - Highly active and stable electrocatalysts for hydrogen evolution have been developed on the basis of molybdenum compounds (Mo2C, Mo2N, and MoS2) on carbon nanotube (CNT)-graphene hybrid support via a modified urea-glass route. By a simple modification of synthetic variables, the final phases are easily controlled from carbide, nitride to sulfide with homogeneous dispersion of nanocrystals on the CNT-graphene support. Among the prepared catalysts, Mo2C/CNT graphene shows the highest activity for hydrogen evolution reaction with a small onset overpotential of 62 mV and Tafel slope of 58 mV/dec as well as an excellent stability in acid media. Such enhanced catalytic activity may originate from its low hydrogen binding energy and high conductivity. Moreover, the CNT-graphene hybrid support plays crucial roles to enhance the activity of molybdenum compounds by alleviating aggregation of the nanocrystals, providing a large area to contact with electrolyte, and facilitating the electron transfer. PMID- 24787541 TI - No dual-task practice effect in Alzheimer's disease. AB - Diagnosis of Alzheimer's disease (AD) requires evidence of progressive decline in cognitive function. However, many tests used to assess cognitive function suffer from considerable practice effects, reducing their reliability. Several studies have reported that the ability to do two things at once, or dual tasking, is impaired in AD, but unaffected by healthy ageing. The apparent specificity of this impairment suggests that this assessment may be particularly useful in the early diagnosis of AD, but the reliability of this assessment remains unknown. Therefore, this study investigated simultaneous performance of digit recall and tracking tasks across six testing sessions in eight people with AD, eight healthy older adults and eight healthy younger adults. The results found that dual-task performance was unaffected by healthy ageing, but significantly impaired in AD, with no effect of repeated exposure. The absence of any improvements in performance despite increased familiarity with the task's demands suggests that not only is the dual-task assessment well suited for monitoring progression over time, but also that dual tasking involves a specific cognitive function which is impaired in the AD brain. PMID- 24787543 TI - X-ray snapshot observation of palladium-mediated aromatic bromination in a porous complex. AB - Pd-mediated aromatic bromination is intriguing to synthetic and organometallic chemists due to both its synthetic utility and, more importantly, a proposed mechanism involving an uncommon Pd(IV)/Pd(II) catalytic cycle. Here, we report an X-ray snapshot observation of a Pd reaction center during a Pd-mediated aromatic bromination in a single crystal of a porous coordination network crystalline scaffold. Upon treatment of a single crystal with N-bromosuccinimide, sequential X-ray snapshots revealed that the aryl-Pd(II)-L species embedded in the network pores was converted to the brominated aryl product through a transient aryl Pd(II)-Br species, which is normally unobservable because of its rapid dimerization into insoluble Pd2(MU-Br)2 species. Though the reaction pathway may be biased by the crystalline state, the new X-ray snapshot method relies on crystalline flasks to provide important mechanistic insight. PMID- 24787544 TI - Eating more fibre increases survival after myocardial infarction. PMID- 24787542 TI - Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naive schizophrenia: evidence for differential susceptibility? AB - BACKGROUND: Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naive schizophrenia patients in comparison with healthy controls. METHODOLOGY: We examined antipsychotic-naive schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. RESULTS: Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. CONCLUSION: Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naive schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a "differential susceptibility" effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin. PMID- 24787545 TI - The BRAF(V600E) mutation influences the short- and medium-term outcomes of classic papillary thyroid cancer, but is not an independent predictor of unfavorable outcome. AB - INTRODUCTION: The prognostic usefulness of BRAF(V600E) evaluation in papillary thyroid cancer (PTC) has been analyzed in many studies, with controversial conclusions. AIM: To analyze the clinical relevance of BRAF(V600E) measurement in a homogenous series of PTC patients followed in a single institution. METHODS: One hundred three classical variant PTC patients who underwent total thyroidectomy in the 3-year period between 2005 and 2008 were retrospectively selected, and BRAF(V600E) assessment was performed using paraffin-embedded archival specimens in 2013. All patients were actively followed at our medical center, with an average follow-up of 55+/-13 months. RESULTS: BRAF(V600E) mutation-positive cancers (55.3%) were more frequently associated with lymph node metastasis (p=0.01) and advanced TNM stage (III-IV) (p=0.03). These findings were also confirmed in the subset of 42 microcarcinomas. BRAF(V600E)-positive patients were also at a higher risk of persistent disease (OR 3.5 [95% confidence interval {CI} 1.2-10.3], p=0.03) in univariate but not multivariate analysis (OR 2.8 [CI 0.7-11.8], p=0.2). Lymph node involvement was an independent predictor of persistent disease (OR 30.9 [CI 6.0-159.0], p<0.0001). Kaplan-Meier curves confirmed a higher percentage of persistent/recurrent disease in BRAF(V600E) positive patients (p=0.02). However, the BRAF(V600E) mutation did not change the recurrence rate of PTC in subgroup analyses on the basis of other established risk factors (p=0.2). CONCLUSIONS: BRAF(V600E)-positive tumors were at higher risk of developing more aggressive behavior and were associated with less favorable outcomes in the short and medium term, but the BRAF(V600E) mutation was not an independent predictor of unfavorable outcome. Therefore, its use as a prognostic marker in clinical practice is not advisable. PMID- 24787546 TI - An approach for rapid increase in molecular complexity: atom economic routes to fused polycyclic ring systems. AB - A protocol for the asymmetric trimethylenemethane (TMM) [3 + 2] cycloaddition reaction of alkynyl-substituted TMM donors and unsaturated N-acyl pyrroles employing a chiral bisdiamidophosphite ligand has been developed. This process generates alkynyl-substituted cyclopentanes in high yields and diastereo- and enantioselectivities. These chiral precursors are employed for the atom economic assembly of fused polycyclic hydrocarbons with hydroindene, hydroazulene, and hydrocyclopentanaphthalene scaffolds by consecutive cycloaddition reactions. PMID- 24787548 TI - Effect of dietary alpha-lipoic acid on the mRNA expression of genes involved in drug metabolism and antioxidation system in rat liver. AB - In the present study, the mRNA levels of hepatic proteins involved in the drug metabolism of rats fed alpha-lipoic acid were evaluated by DNA microarray and real-time PCR analyses. Experimental diets containing 0, 0.1, 0.25 and 0.5 % (w/w) alpha-lipoic acid were fed to four groups of rats consisting of seven animals each for 21 d. DNA microarray analysis revealed that the diet containing 0.5 % alpha-lipoic acid significantly (P< 0.05) increased the mRNA levels of various phase I drug-metabolising enzymes up to 15-fold and phase II enzymes up to 52-fold in an isoenzyme-specific manner. alpha-Lipoic acid also up-regulated the mRNA levels of some members of the ATP-binding cassette transporter superfamily, presumed to be involved in the exportation of xenobiotics, up to 6.6 fold. In addition, we observed that alpha-lipoic acid increased the mRNA levels of many proteins involved in antioxidation, such as members of the thiol redox system (up to 5.5-fold), metallothioneins (up to 12-fold) and haeme oxygenase 1 (1.5-fold). These results were confirmed using real-time PCR analysis, and alpha lipoic acid dose dependently increased the mRNA levels of various proteins involved in drug metabolism and antioxidation. Consistent with these observations, alpha-lipoic acid dose dependently increased the hepatic concentration of glutathione and the activities of glutathione reductase and glutathione transferase measured using 1-chloro-2,4-dinitrobenzene and 1,2 dichloro-4-nitrobenzene as substrates, but decreased the hepatic and serum concentrations of malondialdehyde. In conclusion, the present study unequivocally demonstrated that alpha-lipoic acid increases the mRNA expression of proteins involved in drug metabolism and antioxidation in the liver. PMID- 24787547 TI - Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model. AB - Alteration in normal hippocampal (HPC) function attributed to reduced parvalbumin (PV) expression has been consistently reported in schizophrenia patients and in animal models of schizophrenia. However, it is unclear whether there is an overall loss of interneurons as opposed to a reduction in activity-dependent PV content. Co-expression of PV and the constitutively expressed substance P (SP) receptor protein has been utilized in other models to ascertain the degree of cell survival, as opposed to reduction in activity-dependent PV content, in the HPC. The present study measured the co-expression of PV and SP-receptors in the dentate and dorsal and ventral CA3 subregions of the HPC in the methylazoymethanol acetate (MAM) rat neurodevelopmental model of schizophrenia. In addition, these changes were compared at the post-natal day 27 (PND27) and post-natal day 240 (PND > 240) time points. Brains from PND27 and PND > 240 MAM (n = 8) and saline (SAL, n = 8) treated offspring were immunohistochemically processed for the co-expression of PV and SP-receptors. The dorsal dentate, dorsal CA3 and ventral CA3 subregions of PND27 and PND > 240 MAM rats demonstrated significant reductions in PV but not SP-receptor expression, signifying a loss of PV-content. In contrast, in the ventral dentate the co expression of PV and SP-receptors was significantly reduced only in PND > 240 MAM animals, suggesting a reduction in cell number. While MAM-induced reduction of PV content occurs in CA3 of dorsal and ventral HPC, the most substantial loss of interneuron number is localized to the ventral dentate of PND > 240 animals. The disparate loss of PV in HPC subregions likely impacts intra-HPC network activity in MAM rats. PMID- 24787550 TI - Characterization of anomalous pair currents in Josephson junction networks. AB - Measurements performed on superconductive networks shaped in the form of planar graphs display anomalously large currents when specific branches are biased. The temperature dependences of these currents evidence that their origin is due to Cooper pair hopping through the Josephson junctions connecting the superconductive islands of the array. The experimental data are discussed in terms of theoretical models which predict, for the system under consideration, an inhomogeneous Cooper pair distribution on the superconductive islands of the network as a consequence of a Bose-Einstein condensation phenomenon. PMID- 24787549 TI - Co-sensitization to silkworm moth (Bombyx mori) and 9 inhalant allergens among allergic patients in Guangzhou, Southern China. AB - OBJECTIVES: This study aimed to investigate the profile of sensitization to silkworm moth (Bombyx mori) and other 9 common inhalant allergens among patients with allergic diseases in southern China. METHODS: A total of 175 patients were tested for serum sIgE against silkworm moth in addition to combinations of other allergens: Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia tropicalis, Blattella germanica, Periplaneta americana, cat dander, dog dander, Aspergillus fumigatus and Artemisia vulgaris by using the ImmunoCAP system. Correlation between sensitization to silkworm moth and to the other allergens was analyzed. RESULTS: Of the 175 serum samples tested, 86 (49.14%) were positive for silkworm moth sIgE. With high concordance rates, these silkworm moth sensitized patients were concomitantly sensitized to Dermatophagoides pteronyssinus (94.34%), Dermatophagoides farinae (86.57%), Blomia tropicalis (93.33%), Blattella germanica (96.08%), and Periplaneta americana (79.41%). Moreover, there was a correlation in serum sIgE level between silkworm moth and Dermatophagoides pteronyssinus (r = 0.518), Dermatophagoides farinae (r = 0.702), Blomia tropicalis (r = 0.701), Blattella germanica (r = 0.878), and Periplaneta americana (r = 0.531) among patients co-sensitized to silkworm moth and each of these five allergens. CONCLUSION: In southern Chinese patients with allergic diseases, we showed a high prevalence of sensitization to silkworm moth, and a co sensitization between silkworm moth and other five common inhalant allergens. Further serum inhibition studies are warranted to verify whether cross-reactivity exists among these allergens. PMID- 24787551 TI - Necrolytic acral erythema following hepatitis B vaccination. PMID- 24787552 TI - "Killer coronary artery" and aortic valve stenosis: A tricky case. AB - Anomalous origin of the left main coronary artery from the right coronary sinus is rarely diagnosed in elderly patients. We report such an anomaly in a 75-year old lady presenting with chest pain and syncope. Preoperative screening revealed that her aortic valve was moderately stenotic. The patient underwent a successful unroofing procedure combined with aortic valve replacement. The outcome was uncomplicated and the patient remained asymptomatic at one year postoperatively. PMID- 24787553 TI - Role of surgery in the management and prognosis of limited-stage small cell carcinoma of the esophagus. AB - Small cell carcinoma of the esophagus (SCCE) is a rare, highly aggressive tumor characterized by early dissemination and a poor prognosis. Surgery, chemotherapy, and radiotherapy have been used alone or in combination for the treatment of this rare disease. The aim of this retrospective study was to analyze the role of surgery in the management of limited-stage SCCE at a high-volume center. We retrospectively evaluated 73 patients with limited-stage SCCE who received an esophagectomy at our center from January 1994 to December 2011. The clinical characteristics, median survival times (MSTs), overall survival (OS), and relevant prognostic factors were analyzed. The overall MST was 23.0 months, and the 1-, 2-, 3-, and 5-year OS rates were 61.6%, 47.9%, 22.7%, and 10.6%, respectively. The MST for patients without lymph node involvement (33.0 months) was greater than the MST for patients with lymph node involvement (17.0 months) (P = 0.014). Similarly, patients who underwent radical resection had a greater MST (25.0 months) than patients who underwent palliative resection (7.0 months) (P = 0.004). Patients who received chemotherapy had a greater MST (27.0 months) than patients who did not receive chemotherapy (13.0 months) (P = 0.021). Survival analysis confirmed that a radical operation, chemotherapy, and lymph node involvement were independent prognostic factors. This study suggests that radical resection combined with chemotherapy should be recommended for patients with limited-stage SCCE, especially patients with negative regional lymph nodes. A lack of lymph node metastasis was a good prognostic factor because patients without lymph node involvement had greater OS. PMID- 24787554 TI - Preponderance of toxigenic Escherichia coli in stool pathogens correlates with toxin detection in accessible drinking-water sources. AB - Since early detection of pathogens and their virulence factors contribute to intervention and control strategies, we assessed the enteropathogens in diarrhoea disease and investigated the link between toxigenic strains of Escherichia coli from stool and drinking-water sources; and determined the expression of toxin genes by antibiotic-resistant E. coli in Lagos, Nigeria. This was compared with isolates from diarrhoeal stool and water from Wisconsin, USA. The new Luminex xTAG GPP (Gastroplex) technique and conventional real-time PCR were used to profile enteric pathogens and E. coli toxin gene isolates, respectively. Results showed the pathogen profile of stool and indicated a relationship between E. coli toxin genes in water and stool from Lagos which was absent in Wisconsin isolates. The Gastroplex technique was efficient for multiple enteric pathogens and toxin gene detection. The co-existence of antibiotic resistance with enteroinvasive E. coli toxin genes suggests an additional prognostic burden on patients. PMID- 24787555 TI - Reproductive history and risk of colorectal adenocarcinoma. AB - BACKGROUND: Sex hormones may be associated with colorectal adenocarcinoma, although the association of pregnancy history and risk of colorectal cancer is not consistent. METHODS: We conducted a population-based nested case-control study of persons born between 1932 and 2008 who are in the Swedish Multi Generation Register. In total, 12,915 women and 15,519 men with colorectal adenocarcinoma were identified during follow-up in the Swedish Cancer Register; 10 age- and sex-matched controls were selected for each case. Number of children and age at first and last birth were analyzed in relation to the risk of colorectal adenocarcinoma, using conditional logistic regression, to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Compared with women without children, women with 1 or 2 children had an OR of 1.02 (95% CI = 0.93-1.13) of developing adenocarcinoma in the proximal colon; those with 3 or 4 children, 1.18 (1.06-1.32); and those with >=5 children, 1.30 (1.05-1.61) (test for trend P < 0.01). The corresponding associations in men were 0.92 (0.84-1.00), 1.02 (0.92-1.13), and 0.97 (0.78-1.20), respectively (test for trend P = 0.13). CONCLUSIONS: Higher parity in women was associated with the risk of adenocarcinoma of the proximal colon, although not the distal colon or rectum. A similar risk with family size was not seen for fathers. Still, the influence of lifestyle factors cannot be ruled out. PMID- 24787556 TI - Residential proximity to major roads and term low birth weight: the roles of air pollution, heat, noise, and road-adjacent trees. AB - BACKGROUND: Maternal residential proximity to roads has been associated with adverse pregnancy outcomes. However, there is no study investigating mediators or buffering effects of road-adjacent trees on this association. We investigated the association between mothers' residential proximity to major roads and term low birth weight (LBW), while exploring possible mediating roles of air pollution (PM(2.5), PM(2.5-10), PM(10), PM(2.5) absorbance, nitrogen dioxide, and nitrogen oxides), heat, and noise and buffering effect of road-adjacent trees on this association. METHODS: This cohort study was based on 6438 singleton term births in Barcelona, Spain (2001-2005). Road proximity was measured as both continuous distance to and living within 200 m from a major road. We assessed individual exposures to air pollution, noise, and heat using, respectively, temporally adjusted land-use regression models, annual averages of 24-hour noise levels across 50 m and 250 m, and average of satellite-derived land-surface temperature in a 50-m buffer around each residential address. We used vegetation continuous fields to abstract tree coverage in a 200-m buffer around major roads. RESULTS: Living within 200 m of major roads was associated with a 46% increase in term LBW risk; an interquartile range increase in heat exposure with an 18% increase; and third-trimester exposure to PM(2.5), PM(2.5-10), and PM10 with 24%, 25%, and 26% increases, respectively. Air pollution and heat exposures together explained about one-third of the association between residential proximity to major roads and term LBW. Our observations on the buffering of this association by road adjacent trees were not consistent between our 2 measures of proximity to major roads. CONCLUSION: An increased risk of term LBW associated with proximity to major roads was partly mediated by air pollution and heat exposures. PMID- 24787557 TI - Characterization and compatibility of hydroxyethyl starch-polyethylenimine copolymers for DNA delivery. AB - Hydroxyethyl starch (HES) has been proposed as a biodegradable polymer for shielding of DNA polyplexes, where the feasibility of this approach was shown both in vitro and in vivo. In this study, we report on the physicochemical characterization, the in vitro cytocompatibility and hemotoxicity of HES decorated polyplexes. For this purpose, various HES molecules were coupled to a 22 kDa linear polyethylenimine (LPEI22) to produce a library of nine different HES-PEI conjugates. Particle analysis using dynamic light scattering showed that, neither the molar mass of HES nor the amount of HES in the polyplexes affected the particle diameter, as it was consistently around 70-80 nm. Imaging using atomic force microscopy and transmission electron microscopy showed that, both naked and HESylated polyplexes were in the same size range and had a spherical morphology. Meanwhile, the HES-mediated particle-shielding effect, manifested as reduction in the surface charge, strongly correlated with the molar mass of HES, where the charge decreased linearly with the increase in molar mass. Ethidium bromide binding assay showed that HES-PEI did not negatively affect DNA condensation at N/P ratios higher than 4. HES conjugation also showed a stabilizing effect against salt-induced particle disassembly, and particle aggregation in protein-containing media. Compatibility tests included cellular viability, as well as erythrocyte aggregation and hemolysis assays. HES-PEI conjugates showed lower cytotoxicity, no aggregation, and much lower hemolysis compared to unmodified PEI. In conclusion, these results show that the HES-PEI conjugates are promising gene delivery polymers with favorable physicochemical properties and compatibility profile. PMID- 24787558 TI - An innovative pediatric chest tube insertion task trainer simulation: a technical report and pilot study. AB - INTRODUCTION: Iatrogenic complications associated with chest tube insertion (CTI) could be related to the gaps in the procedural fidelity of the current CTI training models and their insufficiency to support training of procedural mastery. A CTI bench model simulation developed with reference to preexisting curriculum increases trainees' exposure and practice of this clinical skill. Newly developed training models need to be recognized by trainees as a usable learning device. In this report, we describe the development of a novel CTI model, based on curriculum, and survey its usability as a training model among pediatric trainees. METHODS: Based on the acute trauma life support curriculum for CTI and expert interview, a pediatric CTI task trainer (PCTITT) model was developed, piloted, and then implemented for usability by volunteer pediatric residents and pediatric emergency fellows in 2 procedural training courses. Participants responded to 11 questions designed to capture self-reported attitudes toward the usability of the PCTITT as a training model for CTI. Results were obtained using a subjective 5-point Likert scale. RESULTS: Of the 32 participants, we achieved a response rate of 75%. Of these respondents, 92% had some kind of CTI hands-on training in the past, and 50% had experience with a real patient. Of these respondents, 91% recommended this model for training, and 80% stated that this model was superior to previous models. CONCLUSIONS: A PCTITT is an easy to create and feasible bench top task trainer to teach CTI skills, which integrates with other simulations currently in use the process of teaching CTI. Trainees recognized it as usable and superior to previous models. Future work needs to focus on the improvement of model fidelity, skills transferability, and tool validation. PMID- 24787559 TI - Evaluation of the impact of a simulation-enhanced breaking bad news workshop in pediatrics. AB - INTRODUCTION: Our goal was to develop and evaluate the effectiveness of a simulation-based workshop for teaching pediatric trainees' communication skills in breaking bad news. METHODS: A simulation-based workshop was developed to teach skills in breaking bad news. After a classroom-based introduction, small groups of residents participated in 3 scenarios, each starting with a simulated resuscitation, followed by 2 conversations with the patient's parent, played by actors. Each conversation was observed through a 1-way mirror and was followed by a debriefing. After the workshop, the residents completed workshop evaluations and a self-assessment. Before and after the workshop, residents were evaluated in Objective Structured Clinical Examination stations where they were required to give bad news. Two physician experts and 2 parents who personally experienced receiving bad news about their child evaluated resident performance using a previously validated communication evaluation tool. RESULTS: Residents' ratings of the workshop were very high for all items, and 100% of the residents reported improvement in their ability to deliver bad news after the workshop. Statistically significant improvement was found in 14 of 17 items of the evaluation tool used by experts and parents, with the parents reporting greater improvement than the experts. CONCLUSIONS: This reflective, simulation-based workshop successfully improved pediatric trainees' skills in having difficult conversations with families, as evaluated by the participants, by physician experts, and, most importantly, by parents who have experienced these conversations in real life. PMID- 24787560 TI - Easy-to-implement oral cavity modification to expand simulation-based training in airway management. AB - INTRODUCTION: Injuries to the oral cavity and teeth can occur during routine intubation and general anesthesia but often occur in emergency situations when the priority of securing the airway supersedes preanesthetic evaluation. This study demonstrates the feasibility of modifying the oral cavity to increase the dental fidelity during emergency airway management. METHODS: A Laerdal Manikin was used to manipulate the preexisting Polyester (hard) and the Vinyl (flexible) dentition sets that are interchangeable among the Laerdal family of manikins. Items easily available in a dental laboratory such as dental acrylic and dental impression material were used to create modifications. RESULTS: Laerdal dentition sets were altered to simulate common dental (tooth-related) trauma encountered during intubation such as a fracture, luxation, or avulsion injuries. Anatomic variations such as carious (decayed) teeth, loose teeth, and class II malocclusion (overbite) were also fabricated. Tooth luxation was engineered to occur with pressure by a laryngoscope, and bleeding teeth were also created to demonstrate excessive pressure applied during direct laryngoscopy. It is feasible to improve the realism of the Laerdal family of manikins with simple modifications. CONCLUSIONS: This project proves the concept of feasibly fabricating anatomic variations to increase the fidelity of existing simulation manikins. Other anatomic variations present challenges to airway management, and future research will aim at creating additional modifications. In addition, future research will seek to quantify the improvement in airway management skills by anesthesia and emergency medicine providers by training on manikins with variable oral cavity anatomy. PMID- 24787561 TI - Immediate and 1-year chest compression quality: effect of instantaneous feedback in simulated cardiac arrest. AB - INTRODUCTION: Several studies have demonstrated subpar chest compression (CC) performance by trained health care professionals. The objective of this study was to determine the immediate and sustained effect of instantaneous audiovisual feedback on CC quality. METHODS: A prospective, randomized, crossover study measuring the effect of audiovisual feedback training on the performance of CCs by health care providers and medical students in a simulated cardiopulmonary arrest scenario was performed. Compression rate, hand placement, depth, and recoil were collected using 60-second epochs of CC on a simulation mannequin. RESULTS: Data from 200 initial enrollments and 100 tested 1 year later were analyzed by evaluators using standard criterion. At initial testing, feedback trainees demonstrated significantly improved depth compliance, recoil compliance, and accuracy of hand placement. One year later, the previous year's control group now receiving feedback demonstrated immediate improvement in depth, hand placement, and rate. In the feedback group, the only statistically significant improvement from initial baseline to the baseline 1 year later was an 18% improvement in depth compliance. However, the same improvement rate was seen in the control group. Improved depth compliance performance was correlated to the number of cardiopulmonary resuscitation training sessions received external to the study. CONCLUSIONS: Instantaneous audiovisual feedback training on CC quality produces immediate improvements in compression rate, hand placement, as well as depth and recoil compliance. These improvements, however, are not retained 1 year later. Improved depth performance may be correlated to an increased training frequency. PMID- 24787562 TI - Low-hanging fruit: a clementine as a simulation model for advanced laparoscopy. AB - INTRODUCTION: Low-cost, high-fidelity models for training in advanced laparoscopic surgery techniques are not currently available. The objective of this study was to evaluate a model and assessment protocol for developing associated fine, precise laparoscopic dissection skills with accompanying surgical decision making. METHODS: Novice to expert laparoscopists (n = 41) were asked to remove the peel of a clementine in as few pieces as possible, separate and remove all albedo from and between all fruit segments, and return the clementine to as close to its natural state as possible with completely closed skin (sutured). Clinical decision making included deciding when unacceptable segment damage would result by removing difficult-to-extract albedo, analogous to treating lesions or metastases through other methods, rather than risking damage to vital anatomic structures. Faculty assessed deidentified video-recorded performances. Data analyses included analysis of variance with Bonferroni post hoc. RESULTS: A single-performance construct (operative ability) with 2 scoring dimensions (surgical skills and clinical judgment) was confirmed through factor analysis. There were significant performance differences between all experience levels (F2,41 = 59.175, P < 0.000). There were no statistical time differences between the groups. CONCLUSIONS: Validation of this low-cost, easily facilitated model for developing advanced laparoscopic surgical skills may support the preparation of residents and fellows and provide a platform for skill acquisition, assessment, and basic critical thinking for performing laparoscopic tasks. PMID- 24787563 TI - Acute retinal pigment epitheliitis: spectral-domain optical coherence tomography findings in 18 cases. AB - PURPOSE: To describe the imaging characteristics and to investigate the prognostic factors of acute retinal pigment epitheliitis. METHODS: In this retrospective observational case series, a total of 18 patients (18 eyes) with acute retinal pigment epitheliitis were included. The features of acute retinal pigment epitheliitis were analyzed by spectral-domain optical coherence tomography (SD-OCT). RESULTS: Spectral domain-OCT images obtained at baseline revealed abnormal reflectivity in the RPE inner layer in every case (18 eyes, 100%). The line corresponding to the RPE inner layer, the inner segment ellipsoid (ISe), showed abnormal reflectivity in 16 cases (89%). Among patients with ISe abnormalities, three eyes (17%) also showed external limiting membrane (ELM) disruption and two expanded abnormal reflectivity in the outer nuclear layer (ONL). With time, SD-OCT images showed disappearance and gradual resolution of the ONL hyperreflectivity, and disruption of the ELM or ISe. Sixteen eyes (89%) fully recovered their BCVA within 2 months. However, two eyes (11%) with involvement of the ELM or ONL at baseline, with BCVA of less than 20/70 at baseline, showed incomplete BCVA recovery after more than 1 year of follow-up. CONCLUSIONS: Spectral domain-OCT findings indicated that the initial lesion in acute retinal pigment epitheliitis is located at the junction between the photoreceptor outer segments and the apical sides of the RPE cells. Poor visual acuity at baseline and involvement of the ELM or ONL on SD-OCT at baseline were associated with the incomplete recovery of visual acuity. PMID- 24787564 TI - Comparison of conventional pattern and novel navigated panretinal photocoagulation in proliferative diabetic retinopathy. AB - PURPOSE: To compare the laser spot quality between the conventional slit lamp pattern laser (PASCAL) and the navigated pattern laser (NAVILAS) for panretinal photocoagulation (PRP). METHODS: Prospective randomized interventional trial of 73 eyes (51 patients) with high-risk proliferative diabetic retinopathy. Eyes underwent PRP using 30-ms pulse duration with either PASCAL (16 eyes) or NAVILAS laser (21 eyes), or 100-ms pulse duration with either PASCAL (16 eyes) or NAVILAS laser (20 eyes). Fundus color images of all quadrants were taken 5 minutes after treatment. Laser burn size (major and minor diameter and area) and ellipticity (ratio of minor to major axis) were analyzed across the retina. Treatment time and pain were compared between both groups. RESULTS: The burn size variation in navigated laser 30 ms, 100 ms, and conventional pattern 30 ms and single-spot 100 ms laser was 22%, 24%, 21%, and 35%, respectively. The variation of the laser burn area near the arcade for NAVILAS and for PASCAL was 29% and 22%, respectively (P < 0.01). Closer to the equator, burns from the NAVILAS showed even smaller variation of 15% compared with 25% with PASCAL (P < 0.005). Laser spots from PASCAL exhibited an increasing elliptical shape toward the periphery, whereas NAVILAS laser spots tended to be more uniform all over the retina. Average treatment duration and pain experience was less with navigated laser compared with pattern laser (P <= 0.05). CONCLUSIONS: Navigated laser treatment achieves more uniform laser burns with less pain during shorter treatment duration in comparison with conventional pattern laser. PMID- 24787565 TI - Analysis of the intraocular jet flows and pressure gradients induced by air and fluid infusion: mechanism of focal chorioretinal damage. AB - PURPOSE: To comprehend the mechanism of focal chorioretinal damage by analysis of the pressure distribution and dynamic pressure induced by infused air during fluid-air exchange. METHODS: A precise simulation featuring a model eye and a fluid circuit was designed to analyze fluid-air exchange. The pressure distribution, flow velocity, and dynamic pressure induced by infusion of air into an air-filled eye were analyzed using an approach based on fluid dynamics. The size of the port and the infusion pressure were varied during simulated iterations. We simulated infusion of an air-filled eye with balanced salt solution (BSS) to better understand the mechanism of chorioretinal damage induced by infused air. RESULTS: Infused air was projected straight toward a point on the retina contralateral to the infusion port (the "vulnerable point"). The highest pressure was evident at the vulnerable point, and the lowest pressure was recorded on most retinal areas. Simulations using greater infusion pressure and a port of larger size were associated with elevations in dynamic pressure and the pressure gradient. The pressure gradients were 2.8 and 5.1 mm Hg, respectively, when infusion pressures of 30 and 50 mm Hg were delivered through a 20-gauge port. The pressure gradient associated with BSS infusion was greater than that created by air, but lasted for only a moment. CONCLUSIONS: Our simulation explains the mechanism of focal chorioretinal damage in numerical terms. Infused air induces a prolonged increase in focal pressure on the vulnerable point, and this may be responsible for visual field defects arising after fluid-air exchange. PMID- 24787566 TI - Development of a chinese version of the ocular comfort index. AB - PURPOSE: Dry eye is common in Asian populations, but there are limited validated instruments available to assess ocular symptoms within these populations. This study aimed to develop and assess the psychometric properties of a Chinese version of the ocular comfort index (OCI-C). METHODS: The OCI was translated and back translated by 32 bilingual volunteers and a preliminary OCI-C was produced for analysis; 165 bilingual volunteers completed both the OCI and the preliminary OCI-C. The item scores for preliminary OCI-C were compared with the OCI using Cronbach's alpha. Repeatability of the total score of OCI-C was evaluated in a subgroup of 20 participants after a week by calculating the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) for the OCI-C score; 322 subjects, including 81 dry eye subjects, completed the OCI-C to verify the sensitivity in dry eye diagnosis. Rasch analysis was used to estimate interval measures from ordinal Likert score and assess psychometric property of item-fit, category function, targeting of items to subjects, and person separation reliability. RESULTS: Cronbach's alpha for all items was above 0.85. The CoR was +/- 5.84 and the ICC was 0.96 (95% confidence interval 0.91-0.98). The total score of OCI-C was able to differentiate dry eye (40.0) with non-dry eye (30.2) (P < 0.0001). In the Rasch analysis model, the OCI-C showed robust psychometric properties for item-fit and category calibration: person-separation reliability: 2.47 and item reliability: 8.42. CONCLUSIONS: The psychometric properties of the OCI-C are comparable with the OCI and the instrument is appropriate as a diagnostic tool and to determine the severity of dry eye in this population. PMID- 24787567 TI - Corneal sensory nerve activity in an experimental model of UV keratitis. AB - PURPOSE: To produce in guinea pigs a UV-induced keratitis, to analyze the effects of this pathology on corneal nerve activity. METHODS: In anesthetized animals, one eye was exposed to 254 nm UV-C radiation (500-1000 mJ/cm(2)), excised 24 to 48 hours later and superfused in vitro. Nerve impulse activity was recorded in ciliary nerve filaments or in corneal sensory terminals of intact and UV irradiated eyes. Impulse activity in response to mechanical (von Frey hairs), chemical (98.5% CO2 gas jets), and thermal stimulation (cooling from 34 degrees C to 20 degrees C; heating to 50 degrees C) was analyzed. Duration of eyelid closure and blinking and tearing rates were evaluated in control and in UV irradiated eyes, before and after application of TRPV1, TRPA1, and TRPM8 agonists (100 MUM capsaicin; 10 mM AITC, and 200 MUM menthol, respectively). RESULTS: After irradiation, mechanical threshold of mechano-nociceptor corneo-scleral fibers was reduced (0.59 +/- 0.4 vs. 0.27 +/- 0.07 mN; P < 0.05) while polymodal nociceptors increased their response to chemical stimulation (1.7 +/- 0.2 vs. 3.4 +/- 0.5 imps/s; P < 0.05). In contrast, cold thermoreceptors showed a significantly lower ongoing activity at 34 degrees C (8.6 +/- 0.5 vs. 6.1 +/- 0.9 imp/s; P < 0.05) and a reduced responsiveness to cooling pulses (peak frequency = 29.8 +/- 1.3 vs. 18.9 +/- 1.8 imp/s; P < 0.001). Blinking but not tearing rate was significantly higher; behavioral responses to topical capsaicin and AITC, but not to menthol were enhanced in UV-irradiated animals. CONCLUSIONS: Sensitization of nociceptor and depression of cold thermoreceptor activity following UV radiation appear to result from an action of inflammatory mediators on TRP channels selectively expressed by sensory nerve terminals. Changes in nerve activity possibly underlie discomfort sensations associated with corneo conjunctival inflammation induced by UV exposure. PMID- 24787568 TI - Morphology of retinal vessels in patients with optic nerve head drusen and optic disc edema. AB - PURPOSE: We quantitatively investigated the peripapillary vascular morphology in patients with optic nerve head drusen (ONHD) and optic disc edema (ODE). METHODS: Computer-based fundus analysis was used to investigate peripapillary vascular morphology, including length, branching, and diameter of arteries and veins calibrated by optical coherence tomography. RESULTS: Patients with ONHD showed significantly larger diameters of arteries without branching (P = 0.05), and arteries after primary/before secondary branching (P = 0.04) and secondary venous branching started closer to the optic disc (P = 0.03) compared to healthy controls. The ODE patients had significantly reduced number of small peripapillary veins and larger number of veins without branching compared to ONHD and controls (P = 0.02). Anomalous branching with arterial and venous trifurcation presented in the ODE and ONHD groups, with significant higher prevalence in ODE patients for venous trifurcations compared to ONHD and controls (P = 0.02). CONCLUSIONS: The diameter of vessels in ONHD patients were significantly larger in arteries without branching (P = 0.05), after primary branching (P = 0.04), and venous branching closer to the disc area (P = 0.03) compared to controls. The ODE patients demonstrated widening of the small peripapillary veins measured by a significantly larger number of veins without branching (P = 0.001 and P = 0.02, compared to controls and ONHD, respectively) and less small veins (P = 0.001 and P = 0.04, compared to controls and ONHD, respectively). PMID- 24787569 TI - Human trabecular meshwork sphingolipid and ceramide profiles and potential latent fungal commensalism. AB - PURPOSE: We determined the profiles of sphingomyelin, sphingoid base, sphingoid base-1-phosphate, and ceramide, and their quantitative differences between control and glaucomatous trabecular meshwork (TM) derived from human donors. METHODS: Control and primary open angle glaucoma (POAG) TM samples were collected from cadaver donors. In addition, POAG TM surgical specimens also were procured. Lipid extraction was performed using suitable modifications of the Bligh and Dyer method. Protein concentrations were determined using Bradford's method. Lipids, identified using standardized class-specific lipid mass spectrometry, were quantified using a two-step ratiometric process. Gomori methenamine silver (GMS) staining was performed for detection of presence of Fusarium in the anterior eye tissue sections. PCR analyses were performed for detection of Fusarium species in the donor TM samples. RESULTS: Several species of sphingomyelin, sphingoid base, sphingoid base-1-phosphate, and ceramide were common between control and POAG TM. Only a subset of species in some of these classes were identified uniquely either in controls or in POAG TM. Several lipid species of fungal origin (many from Fungi imperfecti, Fusarium species) were found to be common between control and POAG TM. The GMS staining and PCR analyses showed presence of DNA belonging to Fusarium species suggesting latent commensalism. CONCLUSIONS: Most sphingolipids and ceramides (except a few unique to a specific donor TM group) were found to be common in the control and POAG TM. Latent commensalism by Fusarium was suggested by identification of Fusarium-specific lipids, which was supported further by PCR amplification and sequencing of DNA. PMID- 24787570 TI - A comparative effectiveness analysis of visual field outcomes after projected glaucoma screening using SD-OCT in African American communities. AB - PURPOSE: To assess the impact on visual function of community glaucoma screening in an African American population using spectral-domain optical coherence tomography (SD-OCT). METHODS: Using a Monte Carlo microsimulation model with a 10 year time horizon, we analyzed the efficacy of SD-OCT screening on visual field outcomes in a population of African Americans who are not otherwise seeking office-based care. Outcomes included classification of visual field severity, quality-adjusted life years, and direct health care costs. RESULTS: Assuming a 60% follow-up rate, screening decreased the prevalence of undiagnosed glaucoma from 75% to 38%, and decreased the prevalence of severe visual field loss in patients with glaucoma from 29.1% to 23.9%. Conversely, screening increased the prevalence of mild visual field loss in patients with glaucoma from 9.2% to 18.7%. From initial screening through confirmatory eye examination, the screening program ("screen only") cost $98 per screened individual, and $2561 per new diagnosis of glaucoma. When considering the costs of initial screening though the resultant treatment, the screening program ("screen and treat") had an average annual cost of $79 and $2138, respectively, over a 10-year time period. The cost of one quality-adjusted life year (QALY) gained by screening, including management and treatment, in comparison with opportunistic case finding, ranged from $46,416 to $67,813. CONCLUSIONS: Our findings suggest that community SD-OCT screening in an African American population will minimize glaucoma-related visual morbidity. Ideally, strategies to maximize treatment efficacy through improved medication adherence and improved compliance with follow-up should be identified and implemented before instituting a screening program. PMID- 24787571 TI - Auditing a breast MRI practice: performance measures for screening and diagnostic breast MRI. AB - PURPOSE: Breast MRI is increasingly used for both screening and diagnostic purposes. Although performance benchmarks for screening and diagnostic mammography have been published, performance benchmarks for breast MRI have yet to be established. The purpose of this study was to comprehensively evaluate breast MRI performance measures, stratified by screening and diagnostic indications, from a single academic institution. METHODS: Institutional review board approval was acquired for this HIPAA-compliant study. Informed consent was not required. Retrospective review of the institutional database identified all breast MRI examinations performed from April 1, 2007, to March 31, 2008. After application of exclusion criteria, the following performance measures for screening and diagnostic indications were calculated: cancer detection rate, positive predictive value (PPV), and abnormal interpretation rates. RESULTS: The study included 2,444 examinations, 1,313 for screening and 1,131 for diagnostic indications. The cancer detection rates were 14 per 1,000 screening breast MRI examinations and 47 per 1,000 diagnostic examinations (P < .00001). The abnormal interpretation rate was 12% (152 of 1,313) for screening and 17% (194 of 1,131) for diagnostic indications (P = .00008). The PPVs of MRI were lower for screening [PPV1 (abnormal findings) = 12%, PPV2 (biopsy recommended) = 24%, PPV3 (biopsy performed) = 27%] compared with diagnostic indications (PPV1 (abnormal findings) = 28%, PPV2 (biopsy recommended) = 36%, PPV3 (biopsy performed) = 38%]. CONCLUSIONS: Breast MRI performance measures differ significantly between screening and diagnostic MRI indications. Medical audits for breast MRI should calculate performance measures for screening and diagnostic breast MRI separately, as recommended for mammography. PMID- 24787572 TI - Can hospital-based cellular phones improve on-call communication? PMID- 24787573 TI - Bundled payment. AB - Bundled payment (BP) is defined as a single aggregate payment for all health care services for clinically defined episodes of care. Some results suggest that transitioning from a fee-for-service model to BP resulted in a <10% decline in spending and a 5% to 15% decrease in the utilization of services in the bundle. However, future BPs will need to account for how individual providers will be compensated for their services, and acceptance of BP as a viable health care payment model will depend on the ability of payers and providers to collaborate in a new way to address several operational and implementation challenges. PMID- 24787574 TI - The opportunity for the medical physicist in quality improvement. PMID- 24787576 TI - Landscape factors facilitating the invasive dynamics and distribution of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), after arrival in the United States. AB - The brown marmorated stink bug, Halyomorpha halys, a native of Asia, has become a serious invasive pest in the USA. H. halys was first detected in the USA in the mid 1990s, dispersing to over 41 other states. Since 1998, H. halys has spread throughout New Jersey, becoming an important pest of agriculture, and a major nuisance in urban developments. In this study, we used spatial analysis, geostatistics, and Bayesian linear regression to investigate the invasion dynamics and colonization processes of this pest in New Jersey. We present the results of monitoring H. halys from 51 to 71 black light traps that were placed on farms throughout New Jersey from 2004 to 2011 and examined relationships between total yearly densities of H. halys and square hectares of 48 landscape/land use variables derived from urban, wetland, forest, and agriculture metadata, as well as distances to nearest highways. From these analyses we propose the following hypotheses: (1) H. halys density is strongly associated with urban developments and railroads during its initial establishment and dispersal from 2004 to 2006; (2) H. halys overwintering in multiple habitats and feeding on a variety of plants may have reduced the Allee effect, thus facilitating movement into the southernmost regions of the state by railroads from 2005 to 2008; (3) density of H. halys contracted in 2009 possibly from invading wetlands or sampling artifact; (4) subsequent invasion of H. halys from the northwest to the south in 2010 may conform to a stratified-dispersal model marked by rapid long-distance movement, from railroads and wetland rights-of-way; and (5) high densities of H. halys may be associated with agriculture in southern New Jersey in 2011. These landscape features associated with the invasion of H. halys in New Jersey may predict its potential rate of invasion across the USA and worldwide. PMID- 24787578 TI - Donnan potentials in aqueous phase-separated polymer mixtures. AB - A promising approach to texturize water is by the addition of mutually incompatible polymers, leading to phase separation. Here, we demonstrate that the phase stability of aqueous polymer solutions is affected not only by chemical differences between the polymers but also by their electric charge. Direct electrochemical measurements are performed of the electric potential difference between two coexisting phases in aqueous solutions of the charged protein fish gelatin (nongelling) and the uncharged polysaccharide dextran. Charge counteracts demixing because of the entropic cost of confining the counterions to one phase, resulting in a strong shift of the critical point upon an increase of the charge on one of the polymers. Upon phase separation, the charged polymer is spatially confined, and due to the Donnan effect, an interfacial electric potential is developed. A direct proportionality is found between this Donnan potential and the difference in gelatin concentration in the two phases, for which we propose a theoretical explanation. The electrostatics may provide a new handle in the development of stable water-in-water emulsions. PMID- 24787575 TI - Bifidobacterium breve attenuates murine dextran sodium sulfate-induced colitis and increases regulatory T cell responses. AB - While some probiotics have shown beneficial effects on preventing or treating colitis development, others have shown no effects. In this study, we have assessed the immunomodulating effects of two probiotic strains, Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) on T cell polarization in vitro, using human peripheral blood mononuclear cells (PBMC), and in vivo, using murine dextran sodium sulfate (DSS) colitis model. With respect to the latter, the mRNA expression of T cell subset-associated transcription factors and cytokines in the colon was measured and the T helper type (Th) 17 and regulatory T cell (Treg) subsets were determined in the Peyer's patches. Both L. rhamnosus and B. breve incubations in vitro reduced Th17 and increased Th2 cell subsets in human PBMCs. In addition, B. breve incubation was also able to reduce Th1 and increase Treg cell subsets in contrast to L. rhamnosus. In vivo intervention with B. breve, but not L. rhamnosus, significantly attenuated the severity of DSS-induced colitis. In DSS-treated C57BL/6 mice, intervention with B. breve increased the expression of mRNA encoding for Th2- and Treg-associated cytokines in the distal colon. In addition, intervention with B. breve led to increases of Treg and decreases of Th17 cell subsets in Peyer's patches of DSS treated mice. B. breve modulates T cell polarization towards Th2 and Treg cell associated responses in vitro and in vivo. In vivo B. breve intervention ameliorates DSS-induced colitis symptoms and this protective effect may mediated by its effects on the T-cell composition. PMID- 24787579 TI - Magneto-optic surface plasmon polariton modulator based on refractive index variations. AB - In this paper, we have proposed a magneto-optic (MO) surface plasmon polariton (SPP) modulator based on variations of refractive index. For description of modulator operation, we have analyzed the MO effects in the insulator-metal insulator (IMI) SPP slab waveguides in a transversal configuration in which the applied magnetic field is parallel to the interfaces and normal to the wave propagation direction. We have derived an exact dispersion relation by considering MO effects for one of the side layers by the separation of variables method. The cut-off conditions have been studied for the SPP modes guided by IMI structures as a function of the variations of the dielectric constants of the side layers. We have shown that the SPP modes always propagate in a symmetric structure and the SPP odd modes do not have a cut-off dielectric constant in an asymmetric structure. Also, we have shown that in an asymmetric IMI configuration, the SPP even mode has a cut-off effective dielectric constant for all metal layer thicknesses. These configurations can be used to design active devices, such as switches and modulators to be used in photonic integrated circuits. PMID- 24787580 TI - Holographic fabrication of functionally graded photonic lattices through spatially specified phase patterns. AB - In this paper, we present a method for the mathematically formulated phase engineering of interfering laser beams through a spatial light modulator for a holographic fabrication of graded photonic lattices. The desired phases can be programmed at specific locations by assigning gray levels in cellular structures. The method is demonstrated by embedding single-lattice structures or missing lattices in dual-lattice periodic photonic structures. The demonstrated method can be potentially combined with the coordinate transformation technique in transformation optics for the fabrication of graded photonic devices. PMID- 24787581 TI - Multilevel anisotropic diffractive optical elements fabricated by means of stepping photo-alignment technique using photo-cross-linkable polymer liquid crystals. AB - Multilevel anisotropic diffractive optical elements (DOEs), in which digitized spatial patterns of optical birefringence are fabricated by means of stepping photoalignment technique, has been demonstrated using photo-cross-linkable polymer liquid crystals (PCLCs). The polarization state of incident light is converted into a different polarization state by diffracting light in the practical, i.e., transparent in visible region and thermally stable, multilevel anisotropic DOEs, and both polarization azimuth and ellipticity can be widely controlled by their birefringence patterns. Theoretical considerations for such polarization conversion were also performed using the Jones calculus and diffraction theory and well-explained experimental observations. PMID- 24787582 TI - Wafer-based aberration metrology for lithographic systems using overlay measurements on targets imaged from phase-shift gratings. AB - In this paper, a new methodology is presented to derive the aberration state of a lithographic projection system from wafer metrology data. For this purpose, new types of phase-shift gratings (PSGs) are introduced, with special features that give rise to a simple linear relation between the PSG image displacement and the phase aberration function of the imaging system. By using the PSGs as the top grating in a diffraction-based overlay stack, their displacement can be measured as an overlay error using a standard wafer metrology tool. In this way, the overlay error can be used as a measurand based on which the phase aberration function in the exit pupil of the lithographic system can be reconstructed. In practice, the overlay error is measured for a set of different PSG targets, after which this information serves as input to a least-squares optimization problem that, upon solving, provides estimates for the Zernike coefficients describing the aberration state of the lithographic system. In addition to a detailed method description, this paper also deals with the additional complications that arise when the method is implemented experimentally and this leads to a number of model refinements and a required calibration step. Finally, the overall performance of the method is assessed through a number of experiments in which the aberration state of the lithographic system is intentionally detuned and subsequently estimated by the new method. These experiments show a remarkably good agreement, with an error smaller than 5 mlambda, among the requested aberrations, the aberrations measured by the on-tool aberration sensor, and the results of the new wafer-based method. PMID- 24787583 TI - Three-dimensional super-resolution: theory, modeling, and field test results. AB - Many flash lidar applications continue to demand higher three-dimensional image resolution beyond the current state-of-the-art technology of the detector arrays and their associated readout circuits. Even with the available number of focal plane pixels, the required number of photons for illuminating all the pixels may impose impractical requirements on the laser pulse energy or the receiver aperture size. Therefore, image resolution enhancement by means of a super resolution algorithm in near real time presents a very attractive solution for a wide range of flash lidar applications. This paper describes a super-resolution technique and illustrates its performance and merits for generating three dimensional image frames at a video rate. PMID- 24787584 TI - Dynamic characteristics of photonic crystal quantum dot lasers. AB - In this paper, we analyze the dynamic characteristics of quantum dot (QD) photonic crystal lasers by solving Maxwell equations coupled to rate equations through linear susceptibility of QDs. Here, we study the effects of the quality factor of the microcavity and temperature on the delay, relaxation oscillation frequency, and output intensity of the lasers. Moreover, we investigate the dependence of the Purcell factor on temperature. We show that when the quality factor of the microcavity is so high that we can consider its linewidth as a delta function in comparison with QDs, the Purcell factor significantly drops with increasing temperature. PMID- 24787585 TI - Sparse phase-stepping in two-dimensional x-ray phase contrast imaging. AB - We have developed a sparse phase-stepping (SPS) method for x-ray Talbot-Lau interferometry, which first constructs a SPS intensity pattern of fewer images than the conventional phase-stepping (PS) method and then fills the data gap with neighboring pixels for phase retrieval. The SPS method is highly beneficial in practice since the fundamental difference in spatial resolution between the SPS and PS methods becomes negligible due to the blur caused by an interferometer. The concept of the SPS method has been proved by the experiment using a small effective source size. Furthermore, the experiment using a large effective source size has verified that in practical situations the SPS method can reduce the required number of images for phase retrieval and still offer the retrieved images with as high a spatial resolution as the PS method. PMID- 24787586 TI - Robust cladding light stripper for high-power fiber lasers using soft metals. AB - In this paper we present a novel method to reliably strip the unwanted cladding light in high-power fiber lasers. Soft metals are utilized to fabricate a high power cladding light stripper (CLS). The capability of indium (In), aluminum (Al), tin (Sn), and gold (Au) in extracting unwanted cladding light is examined. The experiments show that these metals have the right features for stripping the unwanted light out of the cladding. We also find that the metal-cladding contact area is of great importance because it determines the attenuation and the thermal load on the CLS. These metals are examined in different forms to optimize the contact area to have the highest possible attenuation and avoid localized heating. The results show that sheets of indium are very effective in stripping unwanted cladding light. PMID- 24787587 TI - Design and fabrication of stress-compensated optical coatings: Fabry-Perot filters for astronomical applications. AB - The performance of optical coatings may be negatively affected by the deleterious effects of mechanical stress. In this work, we propose an optimization tool for the design of optical filters taking into account both the optical and mechanical properties of the substrate and of the individual deposited layers. The proposed method has been implemented as a supplemental module in the OpenFilters open source design software. It has been experimentally validated by fabricating multilayer stacks using e-beam evaporation, in combination with their mechanical stress assessment performed as a function of temperature. Two different stress compensation strategies were evaluated: (a) design of two complementary coatings on either side of the substrate and (b) implementing the mechanical properties of the individual materials in the design of the optical coating on one side only. This approach has been tested by the manufacture of a Fabry-Perot etalon used in astronomy while using evaporated SiO2 and TiO2 films. We found that the substrate curvature can be decreased by 85% and 49% for the first and second strategies, respectively. PMID- 24787588 TI - Spatiotemporal structure of a laser beam at a path length of 144 km: comparative analysis of spatial and temporal spectra. AB - We present an analysis of spatial and temporal spectra of the observations of scintillations in a laser beam (532 nm, ~200 mW power) traveling along a 144 km path at an altitude of 2-2.4 km above sea level, just above the atmospheric boundary layer, between the islands of La Palma and Tenerife. The observations were performed during nighttime on July 18 and 21, 2011, by means of a telescope with an aperture diameter of 1 m. Strong scintillations were observed. We compared the temporal and spatial spectra of the scintillations. For the temporal spectra, we performed the correction for the aliasing effect due to the low frame rate. The 2D spatial spectra of the scintillations in the observation plane were found to be close to isotropic. This allowed for transforming them into 1D spectra. We found a good agreement between the temporal and 1D spatial spectra. This corroborates the applicability of the Taylor hypothesis of frozen turbulence for finite-size laser beams and strong scintillations. PMID- 24787589 TI - Laser frequency offset locking via tripod-type electromagnetically induced transparency. AB - We have demonstrated laser frequency offset locking via the Rb87 tripod-type double-dark resonances electromagnetically induced transparency (EIT) system. The influence of coupling fields' power and detuning on the tripod-type EIT profile is studied in detail. In a wide coupling field's detuning range, the narrower EIT dip has an ultranarrow linewidth of ~590 kHz, which is about one order narrower than the natural linewidth of Rb87. Without the additional frequency stabilization of the coupling lasers, we achieve the relative frequency fluctuation of 60 kHz in a long time of ~2000 s, which is narrower than the short-time linewidth of each individual laser. PMID- 24787590 TI - Fabrication of a laser patterned flexible organic light-emitting diode on an optimized multilayered barrier. AB - The fast-growing market of organic electronics stimulates the development of versatile technologies for structuring thin-film materials. Ultraviolet lasers have proven their full potential for patterning organic thin films, but only a few studies report on interaction with thin-film barrier layers. In this paper, we present an approach in which the laser patterning process is optimized together with the barrier film, leading to a highly selective patterning technology without introducing barrier damage. This optimization is crucial, as the barrier damage would lead to moisture and oxygen ingress, with accelerated device degradation as a result. Following process optimization, a laser processed flexible organic LED has been fabricated and thin-film encapsulated and its operation is shown for the first time in atmospheric conditions. PMID- 24787591 TI - Efficient broadband 400 nm noncollinear second-harmonic generation of chirped femtosecond laser pulses in BBO and LBO. AB - We report on 400 nm broadband type I frequency doubling in a noncollinear geometry with pulse-front-tilted and chirped femtosecond pulses (lambda =800 nm; Fourier transform limited pulse duration, 45 fs). With moderate power densities (2 to 10 GW/cm2) thus avoiding higher-order nonlinear phenomena, the energy conversion efficiency was up to 65%. Second-harmonic pulses of Fourier transform limited pulse duration shorter than the fundamental wave were generated, exhibiting good beam quality and no pulse-front tilt. High energy (20 mJ/pulse) was produced in a 40 mm diameter and 6 mm thick LBO crystal. To the best of our knowledge, this is the first demonstration of this optical configuration with sub 100-fs pulses. Good agreement between experimental results and simulations is obtained. PMID- 24787592 TI - Detection of drilling-induced delamination in aeronautical composites by noncontact laser ultrasonic method. AB - A novel application of the laser ultrasonic technique for the detection of drilling-induced delamination in composite components of aircrafts is proposed. Numerous key components of aircrafts are made of composite materials, and drilling is often a final operation during assembly. Drilling-induced delamination significantly reduces the structural reliability, and it is rather difficult to be detected effectively and automatically. The laser ultrasonic technique is a promising method to solve the problem. This paper investigates the characterization of drilling-induced delamination in composites by a noncontact laser ultrasonic method. A carbon fiber reinforced plastic laminate with drilling holes is prepared as a specimen. The characterization of drilling-induced delamination with laser-generated ultrasonic waves is investigated theoretically and experimentally, and the morphology features of the delamination are obtained by laser ultrasonic C-scan testing. The results prove that the laser ultrasonic technique is effective for the detection of drilling-induced delamination in composite components, and it is a feasible solution for evaluating the drilling quality during assembly. PMID- 24787593 TI - 2 * 2 arrayed and passively Q-switched Nd:YVO4 laser under Dammann-arrayed pumping. AB - We reported our proof-of-concept investigation in developing an arrayed and passively Q-switched Nd:YVO4 laser. In the investigation, we used a Dammann grating to diffract the pumping light from a 808 nm laser diode into 2*2 pump beam array, and then used this pump array to pump a monolithic Nd:YVO4 laser crystal standing with a Cr4+:YAG saturable absorber inside a simple plano-plano resonator. As a result, 2*2 arrayed and nanosecond laser pulses were emitted. The laser-diode-pumped monolithic solid-state laser incorporated with a Dammann grating is promising for application in high-peak-power and multipoint pulse ignition of an automobile engine. PMID- 24787594 TI - Full-range Fourier domain Doppler optical coherence tomography based on sinusoidal phase modulation. AB - A novel full-range Fourier domain Doppler optical coherence tomography (full range FD-DOCT) using sinusoidal phase modulation for B-M scan is proposed. In this sinusoidal B-M scan, zero optical path difference (OPD) position does not move corresponding to lateral scanning points in contrast to linear B-M scan. Since high phase sensitivity arises around the zero OPD position, the proposed full-range FD-DOCT can achieve easily high velocity sensitivity without mirror image around the zero OPD position. Velocity sensitivity dependent on the OPD and the interval of scanning points is examined, and flow velocity detection capability is verified through Doppler imaging of a flow phantom and an in vivo biological sample. PMID- 24787595 TI - Zernike analysis of all-sky night brightness maps. AB - All-sky night brightness maps (calibrated images of the night sky with hemispherical field-of-view (FOV) taken at standard photometric bands) provide useful data to assess the light pollution levels at any ground site. We show that these maps can be efficiently described and analyzed using Zernike circle polynomials. The relevant image information can be compressed into a low dimensional coefficients vector, giving an analytical expression for the sky brightness and alleviating the effects of noise. Moreover, the Zernike expansions allow us to quantify in a straightforward way the average and zenithal sky brightness and its variation across the FOV, providing a convenient framework to study the time course of these magnitudes. We apply this framework to analyze the results of a one-year campaign of night sky brightness measurements made at the UCM observatory in Madrid. PMID- 24787596 TI - Electrically modulated diffraction gratings in organic chromophore thin films. AB - An electrically modulated diffraction grating has been demonstrated in poled polymer thin films containing the organic nonlinear optical chromophore, PYR-3 (2 {3-Cyano-4-[3-(1-decyl-1 H-pyridin-4-ylidene)-propenyl]-5,5-dimethy l-5 H-furan-2 ylidene}-malononitrile), and amorphous polycarbonate. A dc electric field induced change in the diffraction efficiency of up to 9% was observed. The diffraction efficiency modulation was likely due to an electric field induced change in the film thickness via a piezoelectric effect rather than via an electronic linear electro-optic effect. PMID- 24787597 TI - Up-taper-based Mach-Zehnder interferometer for temperature and strain simultaneous measurement. AB - A novel all-fiber sensing configuration for simultaneous measurements of temperature and strain based on the up-taper Mach-Zehnder interferometer (MZI) with an in-line embedded fiber Bragg grating (FBG) is proposed and experimentally demonstrated. This configuration consists of two up-tapers fabricated by an excessive fusion splicing method and a short segment of inscribed FBG. Due to the different responses of the up-taper MZI and the FBG to the uniform variation of temperature and strain, the simultaneous measurement for these two variables could be achieved by real-time monitoring the transmission spectrum. For 0.01 nm wavelength resolution, a resolution of 0.311 degrees C in temperature can be achieved, and the average strain resolution is 10.07 MUepsilon. PMID- 24787598 TI - Semi-open cavity in-fiber Mach-Zehnder interferometer for temperature measurement with ultra-high sensitivity. AB - We demonstrate a semi-open cavity in-fiber Mach-Zehnder interferometer based on optical fiber tube (OFT) for temperature measurement with high sensitivity. The interferometer is composed of an OFT sandwiched between two multimode fibers, with lateral offset. The air hole of the OFT was not completely sealed and liquid is poured into the air hole through the unsealed gap. Light from the multimode fiber is split into two beams: one beam transmits directly through the silica tube while the other travels along the liquid-filled cavity. The device has ultra high temperature sensitivity due to the much larger thermo-optic coefficient of the liquid compared with that of silica. Experimental results show that the temperature sensitivity is 6.35 nm/ degrees C for an ethanol-filled structure. PMID- 24787599 TI - Spectroscopic diagnostics of morphological changes arising in thermal processing of polypropylene. AB - Polypropylene is considered as a representative thermoplastic matrix for advanced composite materials that have some advantages in various engineering applications. Wide-range infrared optical properties of polypropylene are important for combined heat transfer modeling in these composite materials, which are semitransparent in a considerable part of the whole spectral range. This study is focused on optical properties of polypropylene in the visible and near infrared ranges because the measurements in these ranges exhibit a stronger effect of the processing temperature used in the material manufacturing. The experimental study is based on spectral measurements of both the normal hemispherical reflectance and transmittance of polypropylene samples. The main characteristics of volumetric absorption and scattering are identified using the inverse problem solution based on the modified two-flux approximation, which is sufficiently accurate to determine the hemispherical characteristics of the radiation field in the range of the problem parameters. In particular, the effect of a relatively strong scattering is observed at the absorption peaks in the near infrared range. An approximate theoretical model based on spectroscopic data is developed to estimate morphological changes arising in thermal processing of polypropylene at different temperatures. PMID- 24787600 TI - Development of solar concentrators for high-power solar-pumped lasers. AB - We have developed unique solar concentrators for solar-pumped solid-state lasers to improve both efficiency and laser output power. Natural sunlight is collected by a primary concentrator which is a 2 m*2 m Fresnel lens, and confined by a cone-shaped hybrid concentrator. Such solar power is coupled to a laser rod by a cylinder with coolant surrounding it that is called a liquid light-guide lens (LLGL). Performance of the cylindrical LLGL has been characterized analytically and experimentally. Since a 14 mm diameter LLGL generates efficient and uniform pumping along a Nd:YAG rod that is 6 mm in diameter and 100 mm in length, 120 W cw laser output is achieved with beam quality factor M2 of 137 and overall slope efficiency of 4.3%. The collection efficiency is 30.0 W/m2, which is 1.5 times larger than the previous record. The overall conversion efficiency is more than 3.2%, which can be comparable to a commercial lamp-pumped solid-state laser. The concept of the light-guide lens can be applied for concentrator photovoltaics or other solar energy optics. PMID- 24787601 TI - Topology optimization for optical projection lithography with manufacturing uncertainties. AB - This article presents a topology optimization approach for micro- and nano devices fabricated by optical projection lithography. Incorporating the photolithography process and the manufacturing uncertainties into the topology optimization process results in a binary mask that can be sent directly to manufacturing without additional optical proximity correction (OPC). The performance of the optimized device is robust toward the considered process variations. With the proposed unified approach, the design for photolithography is achieved by considering the optimal device performance and manufacturability at the same time. Only one optimization problem is solved instead of two as in the conventional separate procedures by (1) blueprint design and (2) OPC. A micro gripper design example is presented to demonstrate the potential of this approach. PMID- 24787602 TI - One-mirror and two-mirror three-dimensional optical scanners--position and accuracy of laser beam spot. AB - This article presents several fundamental formulas for ray tracing in optical systems used in 3D optical scanners. A procedure for numerical modeling of one mirror and two-mirror optical systems is presented, and the calculation of positioning and accuracy of the laser beam spot in a detection plane is carried out. Finally, a point position and accuracy depending on a transit time is evaluated. PMID- 24787603 TI - Tunable terahertz Kerr switching based on nonlinear polarization rotation in silicon waveguide. AB - A compact and widely tunable terahertz (THz) all-optical Kerr switching using nonlinear polarization rotation generated by cross-phase modulation in a silicon waveguide is theoretically proposed. A switching efficiency of 83% is obtained when a pi-phase shift difference between the TE and TM polarization components of the continuous-wave THz signal is achieved. Moreover, the tuning range of the THz switching is from 7.69 to 10 THz through changing the pump power. This THz all optical switching has potential applications in THz communications and other THz switchable devices. PMID- 24787604 TI - Sensitive birefringent temperature sensor based on a waveguide ring resonator. AB - A sensitive birefringent thermometer based on a SiO2 waveguide ring resonator is demonstrated in this paper. It can be used to fabricate a terahertz thermal detector. The temperature sensitivity is enhanced by the resonances of two polarization modes in the waveguide ring resonator. A high degree of common rejection exists for external influence. A linear temperature range from 6 degrees C to 40 degrees C has been detected with resolution of 0.025 degrees C. PMID- 24787606 TI - [Operative risk related to tobacco in gynecology]. AB - If tobacco has been recognized for many years as a major risk factor for cardiovascular, lung diseases and cancer in the general population, women are insufficiently aware of the consequences and the specific gynecological operative risks related to this intoxication. Thus, a regular tobacco consumption increases the risk for many gynecological conditions may require surgical treatment with in addition a significant negative impact on the healing process and the risk of postoperative complications. The operative risk must be explained by surgeons in daily practice gynecological, pelvic surgery or breast screening. The issue of smoking cessation should precede surgery has been established by a consensus conference of experts on perioperative smoking held in 2005. The implementation of these recommendations during the preoperative period requires improvement of staff training and better practices to allow smoking cessation effective and sustainable. It is lawful in this context to delay scheduled surgery of 6 to 8 weeks to allow an optimal smoking cessation and to continue smoking cessation for the time necessary for healing to reduce the excess operative risk associated with smoking. PMID- 24787607 TI - [Real time virtual sonography: a new approach in the evaluation of fetal cerebral structures?]. AB - If ultrasonography is the first intention exam in the evaluation of fetal cerebral structures, MR is the second intention exam the indications of which are well defined. Both techniques are complementary but still independent and the retrospective synthesis of these exams allows optimal analysis of fetal cerebral anomalies. Real time virtual sonography can synchronize a sonographic image and MRI multiplanar image of the same section in real time. This technique can be performed in the evaluation of fetal cerebral structures and synchronous recognition of anatomic structures and has many advantages especially on the pedagogic plan. However, this technique is currently limited to the research area. PMID- 24787605 TI - Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature. AB - AIMS: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation. RESULTS: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naive Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin. INNOVATION: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans. CONCLUSION: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans. PMID- 24787608 TI - [Toxoplasmic infections in pregnancy: about 94 cases diagnosed at the Pasteur Institute of Tunis]. AB - OBJECTIVES: The objectives of this study were to estimate the risk of maternal fetal transmission of toxoplasmosis and its consequences on the fetus and to emphasize the importance of follow-up of newborns in Tunisia. PATIENTS AND METHODS: It was a retrospective study of 94 cases of pergravidic toxoplasmic seroconversion who were diagnosed and followed in the Laboratory of Parasitology of Pasteur Institute of Tunis between 2005 and 2010. RESULTS: In our series, amniocentesis was performed for 60 parturients. Among the amniotic fluid tested, research of toxoplasmosis DNA by PCR was positive in 12 cases (12/60, 20 %). Twenty-six cases of congenital toxoplasmosis were diagnosed with 14 postnatal cases. The rate of maternal-fetal transmission of Toxoplasma gondii was 27.6 % (26/94). This risk increases with gestational age, from 19 % at seroconversion of the 1st quarter to 29.4 % in the 2nd quarter and 44.4 % in the 3rd trimester. Monitoring of newborns with congenital toxoplasmosis showed that only 3 children were symptomatic. There were 2 cases of toxoplasmic chorioretinitis and a case of brain damage. Under serological monitoring of newborns, 21 cases were lost to follow-up and monitoring was stopped for 29 after decrease of anti-toxoplasmic IgG. DISCUSSION AND CONCLUSION: The prenatal diagnosis allowed to decrease the severe forms of congenital toxoplasmosis in Tunisia. Nevertheless, it is always necessary to raise the problem of the significant number of newborn children whose follow-up is incomplete. PMID- 24787609 TI - [Fusion imaging, a modern symbol of collaboration between obstetricians and radiologists]. PMID- 24787610 TI - [S. de Lambilly and P. Panel in reply to the article by F. Flory et al]. PMID- 24787611 TI - [C. Jamin in reply to the article by F. Flory et al]. PMID- 24787612 TI - Prevalence of the hospitalisation of mentally ill offenders in the Forensic Unit of the Clinic of Psychiatry in Pristina over a three-year period and long-term strategy implications for the management of the Forensic Mental Health System Service. AB - BACKGROUND: As a new field in our country, forensic psychiatry needs strategies for management and rehabilitation programmes. AIM: The aim of this study was to evaluate the sociodemographic characteristics of psychiatrically diagnosed inpatients who were hospitalised in the three years from January 2009 to December 2011 and the prevalence of such diagnoses. The specific objectives of this study were to use our results to identify rehabilitation programmes for the treatment of patients and to identify the specific training needs of mental-health professionals. METHODS: In this retrospective study, we collected data about the sociodemographics and violent behaviour of all forensic inpatients who underwent court-ordered psychiatric forensic evaluation and assessment. We reviewed and studied the documented diagnoses based on the following criteria and sources: the ICD-10 criteria for mental disorders, the Structured Clinical Interview (SCID), recidivism rates, criminal data, court records and other hetero-anamnesis data. The data were analysed using a descriptive approach. RESULTS: The subjects were referred for forensic psychiatric evaluation, diagnosis and treatment either directly from prison (23.2%) or from the court (76.8%). The majority of the offenders (85.7%) were currently on trial, and charges of physically threatening others were more common than charges of domestic violence or murder. The prevalence of psychiatric diagnosis was 94.6%, and the most common diagnosis was psychosis (69.1%). Drug abuse and personality disorders, including high-risk behaviours, were also common. The overall relapse rate for aggressive behaviour was 48.9%. CONCLUSION: Rehabilitation programmes for treatment and management are needed that specifically focus on psychotic disorders, severe personality disorders and drug abuse. PMID- 24787613 TI - Exercise performance and cardiovascular health variables in 70-year-old male soccer players compared to endurance-trained, strength-trained and untrained age matched men. AB - The aim was to investigate performance variables and indicators of cardiovascular health profile in elderly soccer players (SP, n = 11) compared to endurance trained (ET, n = 8), strength-trained (ST, n = 7) and untrained (UT, n = 7) age matched men. The 33 men aged 65-85 years underwent a testing protocol including measurements of cycle performance, maximal oxygen uptake (VO2max) and body composition, and muscle fibre types and capillarisation were determined from m. vastus lateralis biopsy. In SP, time to exhaustion was longer (16.3 +/- 2.0 min; P < 0.01) than in UT (+48%) and ST (+41%), but similar to ET (+1%). Fat percentage was lower (P < 0.05) in SP (-6.5% points) than UT but not ET and ST. Heart rate reserve was higher (P < 0.05) in SP (104 +/- 16 bpm) than UT (+21 bpm) and ST (+24 bpm), but similar to ET (+2 bpm), whereas VO2max was not significantly different in SP (30.2 +/- 4.9 ml O2 . min(-1) . kg(-1)) compared to UT (+14%) and ST (+9%), but lower (P < 0.05) than ET (-22%). The number of capillaries per fibre was higher (P < 0.05) in SP than UT (53%) and ST (42%) but similar to ET. SP had less type IIx fibres than UT (-12% points). In conclusion, the exercise performance and cardiovascular health profile are markedly better for lifelong trained SP than for age-matched UT controls. Incremental exercise capacity and muscle aerobic capacity of SP are also superior to lifelong ST athletes and comparable to endurance athletes. PMID- 24787614 TI - Epidemic contact tracing via communication traces. AB - Traditional contact tracing relies on knowledge of the interpersonal network of physical interactions, where contagious outbreaks propagate. However, due to privacy constraints and noisy data assimilation, this network is generally difficult to reconstruct accurately. Communication traces obtained by mobile phones are known to be good proxies for the physical interaction network, and they may provide a valuable tool for contact tracing. Motivated by this assumption, we propose a model for contact tracing, where an infection is spreading in the physical interpersonal network, which can never be fully recovered; and contact tracing is occurring in a communication network which acts as a proxy for the first. We apply this dual model to a dataset covering 72 students over a 9 month period, for which both the physical interactions as well as the mobile communication traces are known. Our results suggest that a wide range of contact tracing strategies may significantly reduce the final size of the epidemic, by mainly affecting its peak of incidence. However, we find that for low overlap between the face-to-face and communication interaction network, contact tracing is only efficient at the beginning of the outbreak, due to rapidly increasing costs as the epidemic evolves. Overall, contact tracing via mobile phone communication traces may be a viable option to arrest contagious outbreaks. PMID- 24787615 TI - Highly regenerable mussel-inspired Fe3O4@polydopamine-Ag core-shell microspheres as catalyst and adsorbent for methylene blue removal. AB - We report a facile method to synthesize Fe3O4@polydopamine (PDA)-Ag core-shell microspheres. Ag nanoparticles (NPs) are deposited on PDA surfaces via in situ reduction by mussel-inspired PDA layers. High catalytic activity and fast adsorption of a model dye methylene blue (MB) at different pH values are achieved mainly due to the presence of monodisperse Ag NPs and electrostatic interactions between PDA and MB. The as-prepared Fe3O4@PDA-Ag microspheres also show high cyclic stability (>27 cycles), good acid stability, and fast regeneration ability, which can be achieved efficiently within several minutes by using NaBH4 as the desorption agent, showing great potentials in a wide range of applications. PMID- 24787616 TI - The sine wave protocol: decrease movement time without increasing errors. AB - Practice tracking a sine wave template has been shown (J. B. Boyle, D. Kennedy, & C. H. Shea, 2012) to greatly enhance performance on a difficult Fitts task of the same amplitude. The purpose of the experiment was to replicate this finding and determine whether enhancements related to the sine wave practice are specific to the amplitude experienced during the sine wave practice. Following sine wave or Fitts task practice with amplitudes of 16 degrees or 24 degrees , participants were tested under the conditions they had practiced under (Test 1) and then all groups were tested under Fitts task conditions (Test 2; ID = 6, amplitude = 16 degrees ). Participants who practiced with the sine wave templates were able to move faster on Test 2 where a 16 degrees amplitude Fitts task was used than participants that had practiced either the 16 degrees or 24 degrees amplitude Fitts tasks. The movements produced by the sine groups on Test 2 were not only faster than the movements of the Fitts groups on Test 2, but dwell time was lower with percent time to peak velocity and harmonicity higher for the Sine groups than for the Fitts groups. The decreased movement times for the sine groups on Test 2 were accomplished with hits or endpoint variability similar to that of the Fitts group. PMID- 24787617 TI - Manipulating nonlinear emission and cooperative effect of CdSe/ZnS quantum dots by coupling to a silver nanorod complex cavity. AB - Colloidal semiconductor quantum dots have three-dimensional confined excitons with large optical oscillator strength and gain. The surface plasmons of metallic nanostructures offer an efficient tool to enhance exciton-exciton coupling and excitation energy transfer at appropriate geometric arrangement. Here, we report plasmon-mediated cooperative emissions of approximately one monolayer of ensemble CdSe/ZnS quantum dots coupled with silver nanorod complex cavities at room temperature. Power-dependent spectral shifting, narrowing, modulation, and amplification are demonstrated by adjusting longitudinal surface plasmon resonance of silver nanorods, reflectivity and phase shift of silver nanostructured film, and mode spacing of the complex cavity. The underlying physical mechanism of the nonlinear excitation energy transfer and nonlinear emissions are further investigated and discussed by using time-resolved photoluminescence and finite-difference time-domain numerical simulations. Our results suggest effective strategies to design active plasmonic complex cavities for cooperative emission nanodevices based on semiconductor quantum dots. PMID- 24787618 TI - Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis. AB - Spermatogenesis in mammals is characterized by two waves of piRNA expression: one corresponds to classic piRNAs responsible for silencing retrotransponsons and the second wave is predominantly derived from nontransposon intergenic regions in pachytene spermatocytes, but the function of these pachytene piRNAs is largely unknown. Here, we report the involvement of pachytene piRNAs in instructing massive mRNA elimination in mouse elongating spermatids (ES). We demonstrate that a piRNA-induced silencing complex (pi-RISC) containing murine PIWI (MIWI) and deadenylase CAF1 is selectively assembled in ES, which is responsible for inducing mRNA deadenylation and decay via a mechanism that resembles the action of miRNAs in somatic cells. Such a highly orchestrated program appears to take full advantage of the enormous repertoire of diversified targeting capacity of pachytene piRNAs derived from nontransposon intergenic regions. These findings suggest that pachytene piRNAs are responsible for inactivating vast cellular programs in preparation for sperm production from ES. PMID- 24787620 TI - Population-genetic inference from pooled-sequencing data. AB - Although pooled-population sequencing has become a widely used approach for estimating allele frequencies, most work has proceeded in the absence of a proper statistical framework. We introduce a self-sufficient, closed-form, maximum likelihood estimator for allele frequencies that accounts for errors associated with sequencing, and a likelihood-ratio test statistic that provides a simple means for evaluating the null hypothesis of monomorphism. Unbiased estimates of allele frequencies [Formula: see text] (where N is the number of individuals sampled) appear to be unachievable, and near-certain identification of a polymorphism requires a minor-allele frequency [Formula: see text]. A framework is provided for testing for significant differences in allele frequencies between populations, taking into account sampling at the levels of individuals within populations and sequences within pooled samples. Analyses that fail to account for the two tiers of sampling suffer from very large false-positive rates and can become increasingly misleading with increasing depths of sequence coverage. The power to detect significant allele-frequency differences between two populations is very limited unless both the number of sampled individuals and depth of sequencing coverage exceed 100. PMID- 24787619 TI - Dissecting vancomycin-intermediate resistance in staphylococcus aureus using genome-wide association. AB - Vancomycin-intermediate Staphylococcus aureus (VISA) is currently defined as having minimal inhibitory concentration (MIC) of 4-8 ug/ml. VISA evolves through changes in multiple genetic loci with at least 16 candidate genes identified in clinical and in vitro-selected VISA strains. We report a whole-genome comparative analysis of 49 vancomycin-sensitive S. aureus and 26 VISA strains. Resistance to vancomycin was determined by broth microdilution, Etest, and population analysis profile-area under the curve (PAP-AUC). Genome-wide association studies (GWAS) of 55,977 single-nucleotide polymorphisms identified in one or more strains found one highly significant association (P = 8.78 E-08) between a nonsynonymous mutation at codon 481 (H481) of the rpoB gene and increased vancomycin MIC. Additionally, we used a database of public S. aureus genome sequences to identify rare mutations in candidate genes associated with VISA. On the basis of these data, we proposed a preliminary model called ECM+RMCG for the VISA phenotype as a benchmark for future efforts. The model predicted VISA based on the presence of a rare mutation in a set of candidate genes (walKR, vraSR, graSR, and agrA) and/or three previously experimentally verified mutations (including the rpoB H481 locus) with an accuracy of 81% and a sensitivity of 73%. Further, the level of resistance measured by both Etest and PAP-AUC regressed positively with the number of mutations present in a strain. This study demonstrated 1) the power of GWAS for identifying common genetic variants associated with antibiotic resistance in bacteria and 2) that rare mutations in candidate gene, identified using large genomic data sets, can also be associated with resistance phenotypes. PMID- 24787622 TI - Retracted: Molecular phylogeny of sequenced saccharomycetes reveals polyphyly of the alternative yeast codon usage. PMID- 24787621 TI - Two new fern chloroplasts and decelerated evolution linked to the long generation time in tree ferns. AB - We report the chloroplast genomes of a tree fern (Dicksonia squarrosa) and a "fern ally" (Tmesipteris elongata), and show that the phylogeny of early land plants is basically as expected, and the estimates of divergence time are largely unaffected after removing the fastest evolving sites. The tree fern shows the major reduction in the rate of evolution, and there has been a major slowdown in the rate of mutation in both families of tree ferns. We suggest that this is related to a generation time effect; if there is a long time period between generations, then this is probably incompatible with a high mutation rate because otherwise nearly every propagule would probably have several lethal mutations. This effect will be especially strong in organisms that have large numbers of cell divisions between generations. This shows the necessity of going beyond phylogeny and integrating its study with other properties of organisms. PMID- 24787625 TI - AAg2(M'(1/3)M(2/3))[VO4]2: synthesis, magnetic properties, and lattice dynamics of honeycomb-type lattices. AB - The magnetic honeycomb lattice series of compounds, AAg2(M'1/3M2/3)[VO4]2 with A = Ba(2+), Sr(2+), M' = Mg(2+), Zn(2+), and M = Mn(2+), Co(2+), and Ni(2+), have been synthesized and their physical properties are reported. This series of compounds contains the M' and M cations in a 1:2 ratio on a single crystallographic site. In an ordered arrangement, this could generate a magnetic honeycomb-type lattice. Presented X-ray diffraction data, spectroscopic measurements of lattice dynamics, along with ab initio calculations, magnetic, and specific heat data for these compounds clearly point toward the formation of magnetic honeycomb-type lattices. PMID- 24787624 TI - Regime shift in fertilizer commodities indicates more turbulence ahead for food security. AB - Recent human population increase has been enabled by a massive expansion of global agricultural production. A key component of this "Green Revolution" has been application of inorganic fertilizers to produce and maintain high crop yields. However, the long-term sustainability of these practices is unclear given the eutrophying effects of fertilizer runoff as well as the reliance of fertilizer production on finite non-renewable resources such as mined phosphate- and potassium-bearing rocks. Indeed, recent volatility in food and agricultural commodity prices, especially phosphate fertilizer, has raised concerns about emerging constraints on fertilizer production with consequences for its affordability in the developing world. We examined 30 years of monthly prices of fertilizer commodities (phosphate rock, urea, and potassium) for comparison with three food commodities (maize, wheat, and rice) and three non-agricultural commodities (gold, nickel, and petroleum). Here we show that all commodity prices, except gold, had significant change points between 2007-2009, but the fertilizer commodities, and especially phosphate rock, showed multiple symptoms of nonlinear critical transitions. In contrast to fertilizers and to rice, maize and wheat prices did not show significant signs of nonlinear dynamics. From these results we infer a recent emergence of a scarcity price in global fertilizer markets, a result signaling a new high price regime for these essential agricultural inputs. Such a regime will challenge on-going efforts to establish global food security but may also prompt fertilizer use practices and nutrient recovery strategies that reduce eutrophication. PMID- 24787626 TI - Promoting adolescent behavioral adjustment in violent neighborhoods: supportive families can make a difference! AB - This study examined the moderating effects of family cohesion on the relationship between community violence and child internalizing and externalizing problems at age 18. The study sample consisted of 728 children and families who were part of the Infant Health and Development Program, an intervention study for low birthweight, preterm infants. Six of eight sites in the Infant Health and Development Program were in large metropolitan areas; two served rural and urban areas. About half of the sample was African American. Research teams collected data from caregivers multiple times in the first 3 years of the target child's life, and at 4, 5, 61/2, 8, and 18 years. Caregivers reported on community violence, neighborhood problems with (a) drug users/sellers; (b) delinquent gangs; and (c) crime, assaults, and burglaries reports when children were 4, 5, and 8 years of age. Family cohesion was assessed twice, at ages 61/2 and 8 years, using caregiver reports on the Family Environment Scale. Adolescent self-report of Internalizing and Externalizing Behavior Problems at age 18 were assessed using the Behavior Problems Index. In this study, the association between adolescent psychosocial outcomes and community violence were moderated by family cohesion and gender such that being in a highly cohesive family as a child protected male children from the negative effects of community violence. Findings demonstrate the long-term protective effects of family cohesion on child behavioral development for male children but suggest a need to examine additional supports for females exposed to community violence during childhood. PMID- 24787627 TI - Faunistic composition, ecological properties, and zoogeographical composition of the Elateridae (Coleoptera) family in the Western Black Sea region of Turkey. AB - The main aim of this study was to understand the faunistic composition, ecological properties, and zoogeographical composition of the family Elateridae (Coleoptera) of the Western Black Sea region of Turkey. As a result, 44 species belonging to 5 subfamilies and 19 genera were identified. After adding species reported in the literature to the analysis, the fauna in the research area consists of 6 subfamilies, 23 genera and 72 species. Most of the Elateridae fauna of the Western Black Sea region were classified in the subfamilies Elaterinae and Dendrometrinae. The genus Athous was the most species-rich genus. The species composition of the Elateridae fauna of the Western Black Sea region partially overlaps with the known Elateridae fauna of Turkey. The Western Black Sea region shares the most species with the European part of the Western Palaearctic region, including many of those in the Elateridae family, compared to other regions. Comparisons of the three geographical regions of Turkey show that fauna composition, ecological properties, and zoogeographical compositions of the Middle and Western Black Sea regions are more similar to each other than to those of the Central Anatolian region. PMID- 24787628 TI - Biphasic hemodynamic effects of LDL-apheresis in common carotid artery. AB - OBJECTIVE: Heparin-induced Extracorporeal Low Density Lipoprotein Precipitation (HELP) Apheresis gives beneficial reductions in Low Density Lipoprotein (LDL) cholesterol levels; otherwise, extracorporeal circulation settings might elicit inflammation and platelet aggregation. The net effect of these variations on carotid hemodynamic has not been established. Aim of the present study was to investigate periprocedural variations of common carotid artery wall shear stress, circumferential wall tension, and Peterson's elastic modulus. METHODS: Measurements were sequentially performed on 22 procedures: immediately before apheresis (T1), within one hour after (T2), after 24 (T3) and 48 hours (T4). In order to confirm acute effects, in additional 30 procedures measurements were performed at T1 and T2. RESULTS: Mean shear stress was decreased at T2, with an improvement at T4. Mean circumferential wall tension showed an improvement at T4; arterial stiffness showed the same trend, but only close to statistical significance. The following 30 procedures, where measurements were performed at T1 and T2 only, confirmed previous results, showing a deep wall shear stress decrease at T2 (-21%). CONCLUSION: LDL apheresis seems to have a biphasic effect on common carotid hemodynamics: the acute worsening of shear stress, probably mediated by extracorporeal circulation, was followed by its improvement, possibly driven by LDL cholesterol reduction. PMID- 24787629 TI - Effect of specific surface microstructures on substrate endothelialisation and thrombogenicity: Importance for stent design. AB - BACKGROUND: In coronary artery disease, highly stenosed arteries are frequently treated by stent implantation, which thereafter necessitates a dual-antiplatelet therapy (DAPT) in order to prevent stent-thrombosis. We hypothesized that specific patterns of microstructures on stents can accelerate endothelialisation thereby reducing their thrombogenicity and the DAPT duration. METHODS: Differently designed, 2-5 MUm high elevations or hollows were lithographically etched on silicon plates, subsequently coated with silicon carbide. Smooth silicon plates and bare metal substrates were used as controls. To assess attachment and growth of human umbilical vein endothelial cells under static or flow conditions, actin cytoskeleton was visualised with green phalloidin. Endothelial migration was assessed in a modified barrier assay. To investigate surface thrombogenicity, platelets were incubated on the structured surfaces in static and flow conditions, and visualised with fluorescein-conjugated P-selectin antibody. Images were taken with incident-light fluorescent microscope for non transparent objects. RESULTS: Compared to smooth surface, flat cubic elevations (5 MUm edge length) improved endothelial cell attachment and growth under static and dynamic conditions, whereas smaller, spiky structures (2 MUm edge length) had a negative influence on endothelialisation. Endothelial cell migration was fastest on flat cubic elevations, hollows, and smooth surfaces, whereas spiky structures and bare metal had a negative effect on endothelial migration. Thrombogenicity assays under static and flow conditions showed that platelet adhesion was reduced on the flat elevations and the smooth surface, as compared to the spiky structures, the hollow design and the bare metal substrates. CONCLUSION: Surface microstructures strongly influence endothelialisation of substrates. Designing stents with surface topography which accelerates endothelialisation and reduces thrombogenicity may be of clinical benefit by improving the safety profile of coronary interventions. PMID- 24787630 TI - A generalized non-local optical response theory for plasmonic nanostructures. AB - Metallic nanostructures exhibit a multitude of optical resonances associated with localized surface plasmon excitations. Recent observations of plasmonic phenomena at the sub-nanometre to atomic scale have stimulated the development of various sophisticated theoretical approaches for their description. Here instead we present a comparatively simple semiclassical generalized non-local optical response theory that unifies quantum pressure convection effects and induced charge diffusion kinetics, with a concomitant complex-valued generalized non local optical response parameter. Our theory explains surprisingly well both the frequency shifts and size-dependent damping in individual metallic nanoparticles as well as the observed broadening of the crossover regime from bonding-dipole plasmons to charge-transfer plasmons in metal nanoparticle dimers, thus unravelling a classical broadening mechanism that even dominates the widely anticipated short circuiting by quantum tunnelling. We anticipate that our theory can be successfully applied in plasmonics to a wide class of conducting media, including doped semiconductors and low-dimensional materials such as graphene. PMID- 24787631 TI - Heart Rhythm Society members' views on pacemaker and implantable cardioverter defibrillator reuse. AB - BACKGROUND: Reuse of cardiac implantable electronic devices (CIEDs) may help address the unmet need among patients in low- and middle-income countries (LMICs). METHODS: To examine Heart Rhythm Society (HRS) physicians' opinions regarding CIED reuse, an online survey eliciting attitudes toward CIED reuse was sent to all 3,380 HRS physician members. RESULTS: There were 429 responses (response rate 13%). A large majority of respondents agreed or strongly agreed that resterilization of devices for reimplantation in patients who cannot afford new devices may be safe (370, 87%) and, if proven to be safe, would be ethical (375, 88%). A total of 340 (81%) respondents would be comfortable asking their patients to consider donating their device, and 353 (84%) would be willing to reimplant a resterilized device if it were legal. The most commonly cited concerns about device reuse were infection (270, 64%) and device malfunction (125, 29%). Respondents from the United States and Canada had more favorable impressions of device reuse than respondents from other high-income countries (P < 0.05 for three of five positive statements regarding reuse), and were less likely to cite ethical concerns (P < 0.001). However, when responses from all high-income countries were compared with lower- and upper-middle income countries, there were no significant differences in the rates of approval. CONCLUSIONS: HRS survey respondents support the concept of CIED reuse for patients in LMICs who cannot afford new devices. Studies are needed to demonstrate the clinical efficacy and safety of this practice and to identify potential barriers to adoption among physicians. PMID- 24787632 TI - The effect of 4-week rehabilitation on heart rate variability and QTc interval in patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease negatively affects the autonomic nervous system and increases risks of arrhythmias and sudden cardiac death. Electrocardiogram (ECG) recordings were used to compare parameters of heart rate variability and QTc interval in patients with COPD and healthy individuals. The effects of a 4-week program of rehabilitation in patients with COPD were also evaluated by comparing pre- and post-rehabilitation ECGs with age- and sex matched control COPD patients not participating in the program. Heart rate, average NN, SDNN, RMSSD, pNN50, TP, LF, HF, LF/HF, and QTc were analyzed. Rehabilitation effects were evaluated using the St. George's respiratory questionnaire (SGRQ), the 6-min walk test (6MWT), and the incremental shuttle walking test (ISWT). In comparison with the healthy individuals, the patients with COPD had higher heart rate (p < 0.05) and reduced average NN, SDNN, RMSSD, pNN50, HF, LF, and TP (all p < 0.05) but similar QTc interval (p = 0.185). During rehabilitation, SDNN and TP (p < 0.05 for both) increased, as did the results for 6MWT, ISWT, and SGRQ (all p < 0.05). No significant change of QTc interval was observed within or between the two groups of patients with COPD. Change in SDNN correlated with a clinically relevant difference in SGRQ (r = 0.538, p = 0.021). It is concluded that patients with COPD demonstrate reduced parameters of heart rate variability and that these can be improved in a rehabilitation program, thus improving health-related quality of life. PMID- 24787633 TI - Antibiotic resistance in adult female patients hospitalized for acute pyelonephritis: rates and predicting factors. AB - INTRODUCTION: The empiric treatment of acute pyelonephritis (APN) with third generation cephalosporins (3GC) or fluoroquinolones (FQ) has been challenged by Escherichia coli resistance reported by community surveillance networks. But these could overestimate resistance because they do not discriminate between uncomplicated and complicated, or between community and care-related infections. OBJECTIVES: We had for aim to: quantify resistance rates in hospitalized patients presenting with APN; identify subgroups with resistance <10% that could still be treated empirically with FQ or 3GC. PATIENTS AND METHODS: We retrospectively analyzed files of patients presenting with documented APN, hospitalized in an Infectious Diseases Department from October 2010 to December 2012. RESULTS: Hundred and fifty-six female patients (median age: 66, interquartile range: 37), were admitted for uncomplicated APN (36%) or APN (64%) at risk of complications by 1 (46%), 2 (40%), or 3 or more (14%) risk factors. Bacteremia was associated in 44% of uncomplicated and 8% of APN at risk of complications. E. coli was predominant (82%), resistant to 3GC in 6% of patients (including 4% ESBL) and to FQ in 15% of patients. The rate of resistance to FQ increased with the number of risk factors for complication, from 6% in uncomplicated APN, to 25% in patients with >=3 risk factors. No enterobacteria was resistant to either 3GC or aminoglycosides. CONCLUSION: The resistance rates of 3GC and aminoglycosides were <10% in patients hospitalized for APN. FQ resistance rates reached 15% but only 6% in uncomplicated APN. Hence, FQ empiric regimen should now be restricted to the treatment of uncomplicated APN without severe sepsis. PMID- 24787634 TI - [Contribution of PET/CT for the management of hepatosplenic candidiasis in hematology]. PMID- 24787635 TI - The effects of intravenous romifidine on intraocular pressure in clinically normal horses and horses with incidental ophthalmic findings. AB - DESIGN: Original study. OBJECTIVE: To evaluate the effect of sedation with romifidine hydrochloride 1% (Sedivet: Boehringer-Ingelheim) on intraocular pressure (IOP) in the normal horse and horses with incidental ophthalmic findings as measured by applanation tonometry. ANIMALS: Nineteen clinically normal horses (13 geldings, six mares) and eight horses (three geldings, five mares) with incidental ophthalmic findings were included in this study. PROCEDURES: All horses underwent complete ophthalmic examination with pharmacologic mydriasis a minimum of 2 weeks prior to IOP evaluation. Baseline intraocular pressure values were obtained following auriculopalpebral nerve block and topical anesthetic. Immediately thereafter, romifidine was administered intravenously (75 ug/kg) and the IOP recorded at 5, 15, 30, 45 and 60 min postsedation in both eyes. Five successive readings were obtained at each time point, the low and high value discarded, and three remaining readings averaged for a mean. RESULTS: The changes with time were consistent between eyes and OD and OS results were pooled. The mean IOP at baseline was 26.35 +/- 5.57 mmHg. Mean IOP values were significantly lower than baseline at 5 (P < 0.0001), 15 (P < 0.0001), 30 (P = 0.0003), 45 (P < 0.0001) and 60 (P = 0.0005) minutes. The largest change from baseline (16.7%) was noted at t = 15 min. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of romifidine significantly decreased the IOP from baseline at all time points measured. The greatest decline in IOP was noted at 15 min postsedation. Results are consistent with other studies noting a decline in IOP with administration of alpha-2 agonists. PMID- 24787636 TI - Muecas: a multi-sensor robotic head for affective human robot interaction and imitation. AB - This paper presents a multi-sensor humanoid robotic head for human robot interaction. The design of the robotic head, Muecas, is based on ongoing research on the mechanisms of perception and imitation of human expressions and emotions. These mechanisms allow direct interaction between the robot and its human companion through the different natural language modalities: speech, body language and facial expressions. The robotic head has 12 degrees of freedom, in a human-like configuration, including eyes, eyebrows, mouth and neck, and has been designed and built entirely by IADeX (Engineering, Automation and Design of Extremadura) and RoboLab. A detailed description of its kinematics is provided along with the design of the most complex controllers. Muecas can be directly controlled by FACS (Facial Action Coding System), the de facto standard for facial expression recognition and synthesis. This feature facilitates its use by third party platforms and encourages the development of imitation and of goal based systems. Imitation systems learn from the user, while goal-based ones use planning techniques to drive the user towards a final desired state. To show the flexibility and reliability of the robotic head, the paper presents a software architecture that is able to detect, recognize, classify and generate facial expressions in real time using FACS. This system has been implemented using the robotics framework, RoboComp, which provides hardware-independent access to the sensors in the head. Finally, the paper presents experimental results showing the real-time functioning of the whole system, including recognition and imitation of human facial expressions. PMID- 24787637 TI - Assessment of the kinetic trajectory of the median nerve in the wrist by high frequency ultrasound. AB - Carpal tunnel syndrome (CTS) is typically diagnosed by physical examination or nerve conduction measurements. With these diagnostics however it is difficult to obtain anatomical information in the carpal tunnel. To further improve the diagnosis of CTS, an attempt using 30 MHz high-frequency ultrasound to noninvasively detect the local anatomical structures and the kinetic trajectory of the median nerve (MN) in the wrist was explored. Measurements were performed on the right wrist of 14 asymptomatic volunteers. The kinetic trajectory of the MN corresponding to flexion (from 0 degrees to 90 degrees ) and extension (from 90 degrees to 0 degrees ) movements of the fingers were detected by a cross correlation-based motion tracking technique. The average displacements of the MN according to finger movements were measured to be 3.74 and 2.04 mm for male and female subjects, respectively. Moreover, the kinetic trajectory of the MN in both the ulnar-palmar and total directions generally follows a sigmoidal curve tendency. This study has verified that the use of high-frequency ultrasound imaging and a motion tracking technique to sensitively detect the displacement and kinetic trajectory of the MN for the assessment of CTS patients is feasible. PMID- 24787638 TI - Design and implementation of practical bidirectional texture function measurement devices focusing on the developments at the University of Bonn. AB - Understanding as well as realistic reproduction of the appearance of materials play an important role in computer graphics, computer vision and industry. They enable applications such as digital material design, virtual prototyping and faithful virtual surrogates for entertainment, marketing, education or cultural heritage documentation. A particularly fruitful way to obtain the digital appearance is the acquisition of reflectance from real-world material samples. Therefore, a great variety of devices to perform this task has been proposed. In this work, we investigate their practical usefulness. We first identify a set of necessary attributes and establish a general categorization of different designs that have been realized. Subsequently, we provide an in-depth discussion of three particular implementations by our work group, demonstrating advantages and disadvantages of different system designs with respect to the previously established attributes. Finally, we survey the existing literature to compare our implementation with related approaches. PMID- 24787639 TI - A multipoint correction method for environmental temperature changes in airborne double-antenna microwave radiometers. AB - This manuscript describes a new type Ka-band airborne double-antenna microwave radiometer (ADAMR) designed for detecting atmospheric supercooled water content (SCWC). The source of the measurement error is investigated by analyzing the model of the system gain factor and the principle of the auto-gain compensative technique utilized in the radiometer. Then, a multipoint temperature correction method based on the two-point calibration method for this radiometer is proposed. The multipoint temperature correction method can eliminate the effect of changes in environmental temperature by establishing the relationship between the measurement error and the physical temperatures of the temperature-sensitive units. In order to demonstrate the feasibility of the correction method, the long term outdoor temperature experiment is carried out. The multipoint temperature correction equations are obtained by using the least square regression method. The comparison results show that the measuring accuracy of the radiometer can be increased more effectively by using the multipoint temperature correction method. PMID- 24787641 TI - Unit cell structure of water-filled monoolein into inverted hexagonal (H(II)) mesophase modeled by molecular dynamics. AB - The study investigates the unit cell structure of inverted hexagonal (H(II)) mesophase composed of monoolein (1-monoolein, GMO) and water using atomistic molecular dynamics methods without imposing any restraints on lipid and water molecules. Statistically meaningful and very contrast images of the radial mass density distribution, scrutinizing also the separate components water, monoolein, the polar headgroups of the lipids, the double bond, and the termini of the hydrocarbon chain (the tail), are obtained. The lipid/water interface structure is analyzed based on the obtained water density distribution, on the estimated number of hydrogen bonds per monoolein headgroup, and on the headgroup-water radial distribution functions. The headgroup mass density distribution demonstrates hexagonal shape of the monoolein/water interface that is well defined at higher water/monoolein ratios. Water interacts with the headgroups by forming a three-layer diffusive mass density distribution, and each layer's shape is close to hexagonal, which is an indication of long-range structural interactions. It is found that the monoolein headgroups form a constant number of hydrogen bonds leaving an excessive amount of water molecules outside the first lipid coordination sphere. Furthermore, the quantity of water at the monoolein/water interface increases steadily upon extension of the unit cell, so the interface should have a very dynamic structure. Investigation of the hydrocarbon residues reveals high compression and well-expressed structuring of the tails. The tails form a very compressed and constrained structure of defined layers across the unit cell with properties corresponding to a more densely packed nonpolar liquid (oil). Due to the hexagonal shape the 2D packing frustration is constant and does not depend on the water content. All reported structural features are based on averaging of the atomic coordinates over the time-length of the simulation trajectories. That kind of processing allows the observation of the water/GMO interface shape and its stability and mobility at a time scale close to the ones of the intermolecular interactions. PMID- 24787640 TI - Seamless tracing of human behavior using complementary wearable and house embedded sensors. AB - This paper presents a multimodal system for seamless surveillance of elderly people in their living environment. The system uses simultaneously a wearable sensor network for each individual and premise-embedded sensors specific for each environment. The paper demonstrates the benefits of using complementary information from two types of mobility sensors: visual flow-based image analysis and an accelerometer-based wearable network. The paper provides results for indoor recognition of several elementary poses and outdoor recognition of complex movements. Instead of complete system description, particular attention was drawn to a polar histogram-based method of visual pose recognition, complementary use and synchronization of the data from wearable and premise-embedded networks and an automatic danger detection algorithm driven by two premise- and subject related databases. The novelty of our approach also consists in feeding the databases with real-life recordings from the subject, and in using the dynamic time-warping algorithm for measurements of distance between actions represented as elementary poses in behavioral records. The main results of testing our method include: 95.5% accuracy of elementary pose recognition by the video system, 96.7% accuracy of elementary pose recognition by the accelerometer-based system, 98.9% accuracy of elementary pose recognition by the combined accelerometer and video based system, and 80% accuracy of complex outdoor activity recognition by the accelerometer-based wearable system. PMID- 24787642 TI - Direct amidation of 2'-aminoacetophenones using I2-TBHP: a unimolecular domino approach toward isatin and iodoisatin. AB - Synthesis of isatin and iodoisatin from 2'-aminoacetophenone was achieved via oxidative amido cyclization of the sp(3) C-H bond using I2-TBHP as the catalytic system. The reaction proceeds through sequential iodination, Kornblum oxidation, and amidation in one pot. This method is simple, atom economic, and works under metal- and base-free conditions. PMID- 24787643 TI - Fish consumption and blood mercury levels: Golding et al. respond. PMID- 24787644 TI - High-density lipoproteins potentiate alpha1-antitrypsin therapy in elastase induced pulmonary emphysema. AB - Several studies report that high-density lipoproteins (HDLs) can carry alpha1 antitrypsin (AAT; an elastase inhibitor). We aimed to determine whether injection of exogenous HDL, enriched or not in AAT, may have protective effects against pulmonary emphysema. After tracheal instillation of saline or elastase, mice were randomly treated intravenously with saline, human plasma HDL (75 mg apolipoprotein A1/kg), HDL-AAT (75 mg apolipoprotein A1-3.75 mg AAT/kg), or AAT alone (3.75 mg/kg) at 2, 24, 48, and 72 hours. We have shown that HDL-AAT reached the lung and prevented the development of pulmonary emphysema by 59.3% at 3 weeks (alveoli mean chord length, 22.9 +/- 2.8 MUm versus 30.7 +/- 4.5 MUm; P < 0.001), whereas injection of HDL or AAT alone only showed a moderate, nonsignificant protective effect (28.2 +/- 4.2 MUm versus 30.7 +/- 5 MUm [P = 0.23] and 27.3 +/- 5.66 MUm versus 30.71 +/- 4.96 MUm [P = 0.18], respectively). Indeed, protection by HDL-AAT was significantly higher than that observed with HDL or AAT (P = 0.006 and P = 0.048, respectively). This protective effect was associated (at 6, 24, and 72 h) with: (1) a reduction in neutrophil and macrophage number in the bronchoalveolar lavage fluid; (2) decreased concentrations of IL-6, monocyte chemoattractant protein-1, and TNF-alpha in both bronchoalveolar lavage fluid and plasma; (3) a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-9 activities; and (4) a reduction in the degradation of fibronectin, a marker of tissue damage. In addition, HDL-AAT reduced acute cigarette smoke-induced inflammatory response. Intravenous HDL-AAT treatment afforded a better protection against elastase-induced pulmonary emphysema than AAT alone, and may represent a significant development for the management of emphysema associated with AAT deficiency. PMID- 24787645 TI - HPLC analysis of harringtonine and homoharringtonine in the needles of Cephalotaxus griffithii alkaloid fraction and cytotoxic activity on chronic myelogenous leukaemia K562 cell. AB - Harringtonine (HT) and homoharringtonine (HHT) are Cephalotaxus alkaloids with considerable antileukaemic activity. The objectives of this research were to (1) determine the content of HT and HHT present in Cephalotaxus griffithii needles alkaloid fraction (CGAF) and (2) compare the antiproliferative activity of CGAF, with that of HT and HHT on chronic myelogenous leukaemia K562 cell. The concentration of HT and HHT was found to be 122.14 and 16.79 mg/g of CGAF, respectively. Treatment of K562 cells with CGAF, HT and HHT decreased the viable cells in a dose- and time-dependent manner. Interestingly, the maximum cell death was found in CGAF, with IC50 value which was 3- to 4.6-fold lower than those of HT and HHT. Our results indicate that HT content in the needles of C. griffithii is higher than HHT, and alkaloids other than HT and HHT in CGAF are predominantly responsible for K562 cell death. PMID- 24787646 TI - Supramolecular halogen bond passivation of organic-inorganic halide perovskite solar cells. AB - Organic-inorganic halide perovskites, such as CH3NH3PbX3 (X = I(-), Br(-), Cl( )), are attracting growing interest to prepare low-cost solar cells that are capable of converting sunlight to electricity at the highest efficiencies. Despite negligible effort on enhancing materials' purity or passivation of surfaces, high efficiencies have already been achieved. Here, we show that trap states at the perovskite surface generate charge accumulation and consequent recombination losses in working solar cells. We identify that undercoordinated iodine ions within the perovskite structure are responsible and make use of supramolecular halogen bond complexation to successfully passivate these sites. Following this strategy, we demonstrate solar cells with maximum power conversion efficiency of 15.7% and stable power output over 15% under constant 0.81 V forward bias in simulated full sunlight. The surface passivation introduces an important direction for future progress in perovskite solar cells. PMID- 24787647 TI - Quality of life, psychological wellbeing and treatment needs of trauma and head and neck cancer patients. AB - There is increasing evidence that patients treated for trauma or cancer of the head and neck may go on to experience psychological distress. We aimed to measure the impact of this on their quality of life (QoL) and to explore their willingness to be referred for psychological support. A total of 96 patients with facial injuries and 124 with cancer of the head and neck completed a self reported questionnaire to identify psychological distress (Hospital Anxiety and Depression Scale (HADS) and the Acute Stress Disorder (ASD) Scale), quality of life (WHOQoL-BREF), satisfaction with treatment, and willingness to accept psychological support. Thirty-nine percent of patients showed high levels of depressive symptoms and 43% reported high levels of anxiety; 43% in the trauma group and 12% in the cancer group had high ASD scores. Patients with high scores on the HADS reported poorer QoL, and 40% of those with high levels of psychological distress were willing to consider psychological support. Despite the fact that patients report high levels of satisfaction with their medical and surgical care, many have psychological problems and have needs that are not being met. A large proportion would use psychological support services. PMID- 24787648 TI - Choosing to use compared to taking medication: the meaning of medication as described by people who experience schizophrenia. AB - PURPOSE: The use of medication is an important aspect within the experience of schizophrenia. DESIGN AND METHODS: Interviews with 14 people with schizophrenia were analyzed using van Kaam's psychophenomenological method, and findings revealed two opposing and important attitudes toward medication. FINDINGS: Adopting an attitude of choosing to use prescribed medication means autonomously self-managing medication and taking prescribed medication means feeling challenged and being under external pressure through being told or forced by others and therefore having no personal connection to the details or purpose of medication. PRACTICE IMPLICATIONS: Nurses need to actively work in partnership to support consumers to take an active stance toward choosing to use medication rather than ensuring consumers take medication. PMID- 24787649 TI - A closer look on the polyhydroxybutyrate- (PHB-) negative phenotype of Ralstonia eutropha PHB-4. AB - The undefined poly(3-hydroxybutyrate)- (PHB-) negative mutant R. eutropha PHB-4 was generated in 1970 by 1-nitroso-3-nitro-1-methylguanidine (NMG) treatment. Although being scientific relevant, its genotype remained unknown since its isolation except a recent first investigation. In this study, the mutation causing the PHA-negative phenotype of R. eutropha PHB-4 was confirmed independently: sequence analysis of the phaCAB operon identified a G320A mutation in phaC yielding a stop codon, leading to a massively truncated PhaC protein of 106 amino acids (AS) in R. eutropha PHB-4 instead of 589 AS in the wild type. No other mutations were observed within the phaCAB operon. As further mutations probably occurred in the genome of mutant PHB-4 potentially causing secondary effects on the cells' metabolism, the main focus of the study was to perform a 2D PAGE-based proteome analysis in order to identify differences in the proteomes of the wild type and mutant PHB-4. A total of 20 differentially expressed proteins were identified which provide valuable insights in the metabolomic changes of mutant PHB-4. Besides excretion of pyruvate, mutant PHB-4 encounters the accumulation of intermediates such as pyruvate and acetyl-CoA by enhanced expression of the observed protein species: (i) ThiJ supports biosynthesis of cofactor TPP and thereby reinforces the 2-oxoacid dehydrogenase complexes as PDHC, ADHC and OGDHC in order to convert pyruvate at a higher rate and the (ii) 3 isopropylmalate dehydrogenase LeuB3 apparently directs pyruvate to synthesis of several amino acids. Different (iii) acylCoA-transferases enable transfer reactions between organic acid intermediates, and (iv) citrate lyase CitE4 regenerates oxaloacetate from citrate for conversion with acetyl-CoA in the TCC in an anaplerotic reaction. Substantial amounts of reduction equivalents generated in the TCC are countered by (v) synthesis of more ubiquinones due to enhanced synthesis of MenG2 and MenG3, thereby improving the respiratory chain which accepts electrons from NADH and succinate. PMID- 24787651 TI - Are in vitro estimates of cell diffusivity and cell proliferation rate sensitive to assay geometry? AB - Cells respond to various biochemical and physical cues during wound-healing and tumour progression. in vitro assays used to study these processes are typically conducted in one particular geometry and it is unclear how the assay geometry affects the capacity of cell populations to spread, or whether the relevant mechanisms, such as cell motility and cell proliferation, are somehow sensitive to the geometry of the assay. In this work we use a circular barrier assay to characterise the spreading of cell populations in two different geometries. Assay 1 describes a tumour-like geometry where a cell population spreads outwards into an open space. Assay 2 describes a wound-like geometry where a cell population spreads inwards to close a void. We use a combination of discrete and continuum mathematical models and automated image processing methods to obtain independent estimates of the effective cell diffusivity, D, and the effective cell proliferation rate, lambda. Using our parameterised mathematical model we confirm that our estimates of D and lambda accurately predict the time-evolution of the location of the leading edge and the cell density profiles for both assay 1 and assay 2. Our work suggests that the effective cell diffusivity is up to 50% lower for assay 2 compared to assay 1, whereas the effective cell proliferation rate is up to 30% lower for assay 2 compared to assay 1. PMID- 24787652 TI - Superior H2 production by hydrophilic ultrafine Ta2O5 engineered covalently on graphene. AB - A H2O2-mediated hydrothermal method was developed for the fabrication of hydrophilic Ta2O5/graphene composite. The composite shows a superior H2 productivity, up to 30 mmol g(-1) h(-1) when used as a photocatalyst for water splitting, corresponding to an apparent quantum efficiency of 33.8% at 254 nm. This superior performance is due to the hydrophilic nature of the composite and more importantly due to the ultrafine Ta2O5 nanoparticles (about 4.0 +/- 1.5 nm) which are covalently bonded with the conductive graphene. The hydrophilic property of the composite is attributed to the use of H2O2 in the hydrothermal process. The ultrafine size of the Ta2O5 particles which are covalently bonded with the graphene sheets is attributed to the use of sonication in the synthesis process. Furthermore, the hydrophilic Ta2O5/Gr composite is durable, which is beneficial to long term photocatalysis. The strategy reported here provides a new approach to designing photocatalysts with superior performance for H2 production. PMID- 24787650 TI - Protein thermodynamics can be predicted directly from biological growth rates. AB - Life on Earth is capable of growing from temperatures well below freezing to above the boiling point of water, with some organisms preferring cooler and others hotter conditions. The growth rate of each organism ultimately depends on its intracellular chemical reactions. Here we show that a thermodynamic model based on a single, rate-limiting, enzyme-catalysed reaction accurately describes population growth rates in 230 diverse strains of unicellular and multicellular organisms. Collectively these represent all three domains of life, ranging from psychrophilic to hyperthermophilic, and including the highest temperature so far observed for growth (122 degrees C). The results provide credible estimates of thermodynamic properties of proteins and obtain, purely from organism intrinsic growth rate data, relationships between parameters previously identified experimentally, thus bridging a gap between biochemistry and whole organism biology. We find that growth rates of both unicellular and multicellular life forms can be described by the same temperature dependence model. The model results provide strong support for a single highly-conserved reaction present in the last universal common ancestor (LUCA). This is remarkable in that it means that the growth rate dependence on temperature of unicellular and multicellular life forms that evolved over geological time spans can be explained by the same model. PMID- 24787654 TI - Characterization and bioactivity of hepcidin-2 in zebrafish: dependence of antibacterial activity upon disulfide bridges. AB - Hepcidin is an antimicrobial peptide and iron-regulatory molecule with highly conserved disulfide bridges among vertebrates, but structural insights into the function in fish remains largely missing. We demonstrate here that recombinant hepcidin-2 from zebrafish is capable of inhibiting the growth of the Gram negative bacteria Escherichia coli and Vibrio anguillarum, and the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis with minimum inhibitory concentrations (MICs) of 18, 15, 13 and 9MUM, respectively. We also show by TEM examination that recombinant hepcidin-2 is directly cidal to the cells of E. coli and S. aureus. Moreover, we find that hepcidin-2 displays affinity to LPS, LTA and PGN. All these data indicate that hepcidin-2 is both a pattern recognition molecule, capable of identifying LPS, LTA and PGN, and an antibacterial effector, capable of inhibiting the growth of bacteria. The data also show that the antibacterial activity of hepcidin-2 depends upon the disulfide bridges. PMID- 24787655 TI - Preoperative plasma leptin levels predict delirium in elderly patients after hip fracture surgery. AB - Leptin is considered to be a modulator of the immune response. Hypoleptinemia increases the risk for Alzheimer's disease and vascular dementia. The present study aimed to investigate the ability of plasma leptin level to predict delirium in elderly patients after hip fracture surgery. Postoperative delirium (pod) was evaluated using the Confusion Assessment Method. Prolonged postoperative delirium (ppod) was defined as delirium lasting more than 4 weeks. Plasma leptin levels of 186 elderly patients and 186 elderly controls were measured by an enzyme-linked immunosorbent assay. Plasma leptin level was substantially lower in patients than in controls (4.6+/-2.2ng/ml vs. 7.5+/-1.8ng/ml, P<0.001). It was identified as an independent predictor for pod [odds ratio, 0.385; 95% confidence interval (CI), 0.286-0.517; P<0.001] and ppod (odds ratio, 0.283; 95% CI, 0.152-0.527; P<0.001) using a multivariate analysis, and had high area under receiver operating characteristic curve for pod [area under curve (AUC), 0.850; 95% CI, 0.790-0.898] and ppod (AUC, 0.890; 95% CI, 0.836-0.931). The predictive value of leptin was markedly bigger than that of age for pod (AUC, 0.705; 95% CI, 0.634-0.770; P=0.002) and ppod (AUC, 0.713; 95% CI, 0.642-0.777; P=0.019). In a combined logistic-regression model, leptin improved the AUC of age to 0.890 (95% CI, 0.836 0.931) (P<0.001) for pod and 0.910 (95% CI, 0.860-0.947) (P=0.005) for ppod. Thus, preoperative plasma leptin level may be a useful, complementary tool to predict delirium and also prolonged delirium in elderly patients after hip fracture surgery. PMID- 24787656 TI - Seeing the forest for the trees: how "one health" connects humans, animals, and ecosystems. PMID- 24787657 TI - Understanding androgen action in adipose tissue. AB - Androgens play an important role in regulation of body fat distribution in humans. They exert direct effects on adipocyte differentiation in a depot specific manner, via the androgen receptor (AR), leading to modulation of adipocyte size and fat compartment expansion. Androgens also impact directly on key adipocyte functions including insulin signalling, lipid metabolism, fatty acid uptake and adipokine production. Androgen excess and deficiency have implications for metabolic health in both males and females, and these metabolic effects may be mediated through adipose tissue via effects on fat distribution, adipocyte function and lipolysis. Research into the field of androgen metabolism in human and animal adipose tissue has produced inconsistent results; it is important to take into account the sex-, depot- and organism-specific effects of androgens in fat. In general, studies point towards a stimulatory effect on lipolysis, with impairment of adipocyte differentiation, insulin signalling and adipokine generation. Observed effects are frequently gender-specific. Adipose tissue is an important organ of pre-receptor androgen metabolism, through which local androgen availability is rigorously controlled. Adipose androgen exposure is tightly controlled by isoenzymes of AKR1C, 5alpha-reductase and others, but regulation of the balance between generation and irreversible inactivation remains poorly understood. In particular, AKR1C2 and AKR1C3 are crucial in the regulation of local androgen bioavailability within adipose tissue. These isoforms control the balance between activation of androstenedione (A) to testosterone (T) by the 17beta-hydroxysteroid dehydrogenase activity (17beta-HSD) of AKR1C3, or inactivation of 5alpha-dihydrotestosterone (DHT) to 5alpha androstane-3alpha,17beta-diol by the 3alpha-hydroxysteroid dehydrogenase (3alpha HSD) activity of AKR1C2. Most studies suggest that androgen inactivation is the predominant reaction in fat, particularly in the abdominal subcutaneous (SC) depot. Modulation of local adipose androgen availability may afford future therapeutic options to improve metabolic phenotype in disorders of androgen excess and deficiency. PMID- 24787658 TI - Maternal protein restriction during gestation and lactation programs offspring ovarian steroidogenesis and folliculogenesis in the prepubertal gilts. AB - Maternal malnutrition may disrupt ovarian functions in adult offspring. Steroidogenesis and folliculogenesis in the offspring ovary appear to be the major targets of nutritional programming. Nevertheless, the mechanism by which maternal low-protein diet affects the offspring steroidogenesis and folliculogenesis, and the possible pathway linking these two processes remain unclear. In this study, Landrace*Yorkshire crossbred sows were fed either standard (SP) or low-protein (LP, 50% of the SP) diets throughout gestation and lactation. Female offspring were fed the same diet after weaning until 6 months of age. LP offspring had higher serum 17beta-estradiol level (P<0.01), which was accompanied by lower mRNA (P<0.05) but higher protein (P<0.05) expression of cytochrome P450 aromatase (CYP19A1) in the ovary. CYP19A1 protein up-regulation was associated with lower ovarian expression of drosha (P<0.05) and miRNAs targeting CYP19A1 (P<0.05). LP offspring had less graafian follicles with more apoptotic granulosa cells (P<0.05), as well as higher caspase 3 activity (P<0.05) and FasL expression (P<0.05) in the ovary. FasL gene up-regulation was associated with higher ERalpha protein expression (P<0.05) and binding to FasL gene promoter. These results suggest that a maternal LP diet in pregnancy and lactation elevated serum 17beta-estradiol level by activating CYP19A1 through miRNA-mediated mechanism, and induced granulosa apoptosis in graafian follicles through ER-activated Fas/FasL-caspase 3 pathway. PMID- 24787659 TI - Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats. AB - INTRODUCTION: Estetrol (E4), a naturally occurring estrogen only produced by the human fetal liver, is being evaluated in human studies for potential use in contraception and menopausal care. The present study was designed to profile E4 in the central nervous system, to assess the in vivo effects of E4 administration on allopregnanolone (AP) synthesis in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated AP synthesis. MATERIAL AND METHODS: Intact female adult rats received different doses of E4, and ovariectomized OVX rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of AP were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, anterior pituitary, and serum. RESULTS: E4 did not alter AP in intact animals in any region. E4 at a dosage of 5mg/kg/day increased AP levels in different brain areas and in the serum of OVX animals. However, in the presence of estradiol, E4 showed an estrogen antagonistic effect on the brain and serum levels of AP. CONCLUSION: E4 increases the CNS and peripheral levels of AP, behaving as a weak estrogen-agonist in OVX rats. The antagonistic effect observed with E2V co-administration further profile E4 as a natural SERM. PMID- 24787660 TI - Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling. AB - Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with a mean patient survival of 13-15 months despite surgical resection, radiation therapy and standard-of-care chemotherapy. We investigated the chemotherapeutic effects of the hormone progesterone (P4) on the growth of human GBM in four genetically different cell lines (U87MG, U87dEGFR, U118MG, LN-229) in vitro and in a U87MG subcutaneous xenograft mouse model. At high concentrations (20, 40, and 80 MUM), P4 significantly (P<0.05) decreased tumor cell viability in all cell lines except LN-229. This effect was not blocked by the P4 receptor antagonist RU468. Conversely, at low physiological concentrations (0.1, 1, and 5 MUM) P4 showed a proliferative effect in all cell lines which was blocked by RU486. In nude mice, P4 (100 and 200 mg/kg) inhibited tumor growth significantly (P<0.05) over 5 weeks of treatment and extended survival time of tumor-bearing mice by 60% without signs of systemic toxicity. P4 suppressed tumor vascularization as indicated by the expression of CD31, vascular endothelial growth factor and matrix metalloproteinase-9. Apoptosis in tumor tissue was detected by the expression of cleaved caspase-3, BCl-2, BAD and p53 proteins and confirmed by TUNEL assay. P4 treatment also suppressed PI3K/Akt/mTOR signaling, which regulates tumor growth, as demonstrated by the suppression of proliferating cell nuclear antigen. Our data can be interpreted to suggest that P4 suppresses the growth of human GBM cells both in vitro and in vivo and enhances survival time in mice without any demonstrable side effects. This article is part of a Special Issue entitled 'Sex steroids and brain disorders'. PMID- 24787661 TI - Modulation of ovarian steroidogenesis by adiponectin during delayed embryonic development of Cynopterus sphinx. AB - The aim of present study was to evaluate role of adiponectin in ovarian steroidogenesis during delayed embryonic development of Cynopterus sphinx. This study showed significantly low circulating adiponectin level and a decline in expression of adiponectin receptor 1 (AdipoR1) in the ovary during the period of delayed embryonic development as compared with the normal development. The adiponectin treatment in vivo during the period of delayed development caused significantly increased in circulating progesterone and estradiol levels together with increased expression of AdipoR1 in the ovary. The in vitro study confirmed the stimulatory effect of adiponectin on progesterone synthesis. Both in vivo and in vitro studies showed that the effects of adiponectin on ovarian steroidogenesis were mediated through increased expression of luteinizing hormone receptor, steroidogenic acute regulatory protein and 3beta-hydroxyl steroid dehydrogenase enzyme. The adiponectin treatment may also promote progesterone synthesis by modulating ovarian angiogenesis, cell survival and rate of apoptosis. PMID- 24787662 TI - Repetitive hyperbaric oxygen therapy provides better effects on brain inflammation and oxidative damage in rats with focal cerebral ischemia. AB - BACKGROUND/PURPOSE: Repetitive hyperbaric oxygen (HBO2) therapy may cause excessive generation of reactive oxygen species. This study assessed whether repetitive or 2-4-day trials of HBO2 therapy (2 treatments daily for 2-4 consecutive days) provides better effects in reducing brain inflammation and oxidative stress caused by middle cerebral artery occlusion (MCAO) in rats than did a 1-day trial of HBO2 therapy (2 treatments for 1 day). METHODS: Rats were randomly divided into four groups: sham; MCAO without HBO2 treatment; MCAO treated with 1-day trial of HBO2; and MCAO treated with 2-4-day trials of HBO2. One treatment of HBO2 (100% O2 at 253 kPa) lasted for 1 hour in a hyperbaric chamber. RESULTS: Therapy with the 2-4-day trials of HBO2 significantly and dose dependently attenuated the MCAO-induced cerebral infarction and neurological deficits more than the 1-day trial of HBO2 therapy. The beneficial effects of repetitive HBO2 therapy were associated with: (1) reduced inflammatory status in ischemic brain tissues (evidenced by decreased levels of tumor necrosis factor alpha, interleukin-1beta, and myeloperoxidase activity); (2) decreased oxidative damage in ischemic brain tissues (evidenced by decreased levels of reactive oxygen and nitrogen species, lipid peroxidation, and enzymatic pro-oxidants, but increased levels of enzymatic antioxidant defenses); and (3) increased production of an anti-inflammatory cytokine, interleukin-10. CONCLUSION: The results provide the apparently contradictory finding that heightened oxygen tension reduced oxidative stress (and inflammation), which was reflected by increased antioxidant and decreased oxidant contents under focal cerebral ischemia. PMID- 24787663 TI - Chronic kidney disease in Taiwan's aging population: something far more than a distant ship's smoke on the horizon. PMID- 24787664 TI - Examining the diagnostic criteria for Internet addiction: Expert validation. AB - BACKGROUND/PURPOSE: Internet addiction is the coming problem around the world. The diagnostic criteria for Internet addiction among adolescents (DC-IA-A) has become a widely used measure for assessing the presence of Internet addiction in Taiwan. This study examined the diagnosis criteria for Internet addiction in adolescents by expert evaluation. METHODS: Twenty psychiatrists rated the adequacy of each criterion in DC-IA-A. The content validity and homogeneity reliability proposed by Aiken were calculated. RESULTS: The coefficients content validity and homogeneity reliability showed twenty psychiatrists agreed on each of DC-IA-A as relevant to the diagnosis of Internet addiction, though several criteria need improvements. Two criteria "excessive time spent on Internet activities and leaving the Internet" and "excessive effort spent on activities necessary to obtain access to the Internet" should be omitted, and the criteria of "tolerance" should be modified. CONCLUSION: The diagnostic criteria for Internet addiction among adolescents should be revised to meet the real condition of this population. PMID- 24787665 TI - External review of the National Tuberculosis Program and the development of strategy and targets post 2015 in Taiwan. PMID- 24787666 TI - Systematic lymph node dissection is necessary for T1a non-small cell lung cancer. AB - AIM: With the development of computed tomography, the number of surgical interventions for small-sized lung cancer has increased. It still remains controversial whether a systematic lymph node dissection is necessary in such cases. METHODS: From 2004 to 2010, a total of 138 patients with non-small cell lung cancer (NSCLC) of 2 cm or less in diameter were operated on in our institution. The clinical data were retrospectively analyzed using the Kaplan Meier method and compared using the log-rank test in surgical approaches, lymph node involvement, histology and survival rates. RESULTS: Lymph node metastasis was found in 24 of 138 (17%) patients. The 5-year survival rate for patients without lymph node metastasis was 83%, whereas it was 75 and 48% for those with pN1 and pN2 disease (P=0.001). Patients receiving lobectomy had a significantly better survival rate than patients receiving limited resection (P=0.02). The 5 year survival rates for patients with stage I, stage II and stage III were 90, 78 and 43%, respectively (P<0.001). Lymph node metastasis was found in 1 of 11 (9%) patients with tumors sized less than 1 cm, 7 of 39 (18%) patients with tumors sized from 1.1 to 1.5 cm, and 16 of 64 (25%) patients with a tumor larger than 1.5 cm (statistically not significant). CONCLUSION: The survival of patients with small-sized lung cancer is closely related to the nodal involvement, stage of disease and surgical approaches. Our study supports that systematic lymph node dissection should be performed in patients with T1a NSCLC. PMID- 24787667 TI - Isthmus-dependent atrial flutter with unusual activation pattern. PMID- 24787668 TI - Immobilized synthetic pathway for biodegradation of toxic recalcitrant pollutant 1,2,3-trichloropropane. AB - The anthropogenic compound 1,2,3-trichloropropane (TCP) has recently drawn attention as an emerging groundwater contaminant. No living organism, natural or engineered, is capable of the efficient aerobic utilization of this toxic industrial waste product. We describe a novel biotechnology for transforming TCP based on an immobilized synthetic pathway. The pathway is composed of three enzymes from two different microorganisms: engineered haloalkane dehalogenase from Rhodococcus rhodochrous NCIMB 13064, and haloalcohol dehalogenase and epoxide hydrolase from Agrobacterium radiobacter AD1. Together, they catalyze consecutive reactions converting toxic TCP to harmless glycerol. The pathway was immobilized in the form of purified enzymes or cell-free extracts, and its performance was tested in batch and continuous systems. Using a packed bed reactor filled with the immobilized biocatalysts, 52.6 mmol of TCP was continuously converted into glycerol within 2.5 months of operation. The efficiency of the TCP conversion to the intermediates was 97%, and the efficiency of conversion to the final product glycerol was 78% during the operational period. Immobilized biocatalysts are suitable for removing TCP from contaminated water up to a 10 mM solubility limit, which is an order of magnitude higher than the concentration tolerated by living microorganisms. PMID- 24787669 TI - Introduced American eels Anguilla rostrata in European waters: life-history traits in a non-native environment. AB - This study investigated growth, condition and development of American eels Anguilla rostrata that were introduced into a European river to estimate their competitive potential in a non-native habitat. Results demonstrate that A. rostrata develops normally in European waters and successfully competes with the native European eel Anguilla anguilla. In addition, A. rostrata appears to be more susceptible to the Asian swimbladder nematode Anguillicola crassus than A. anguilla and could support the further propagation of this parasite. Detected differences in fat content and gonad mass between Anguilla species are assumed to reflect species-specific adaptations to spawning migration distances. This study indicates that A. rostrata is a potential competitor for the native fauna in European fresh waters and suggests strict import regulations to prevent additional pressure on A. anguilla and a potential further deterioration of its stock situation. PMID- 24787671 TI - A new method for estimating the coefficients of diffusion and emanation of radon in the soil. AB - This paper describes a new method for determining the basic parameters of soil - diffusion and emanation coefficients related to the transfer of radon in the soil matrix, which are very useful for testing models, based on diffusion and characteristics of various soil matrices regarding the dangers of radon. The method is based on the measurement of radon in soil air on two small depths, differing twice. The paper presents the results of the determination of the parameters for covering loams and clays of Tomsk (Russian Federation), obtained by this method. PMID- 24787672 TI - Isodose mapping of terrestrial gamma radiation dose rate of Selangor state, Kuala Lumpur and Putrajaya, Malaysia. AB - A terrestrial gamma radiation survey for the state of Selangor, Kuala Lumpur and Putrajaya was conducted to obtain baseline data for environmental radiological health practices. Based on soil type, geological background and information from airborne survey maps, 95 survey points statistically representing the study area were determined. The measured doses varied according to geological background and soil types. They ranged from 17 nGy h(-1) to 500 nGy h(-1). The mean terrestrial gamma dose rate in air above the ground was 182 +/- 81 nGy h(-1). This is two times higher than the average dose rate of terrestrial gamma radiation in Malaysia which is 92 nGy h(-1) (UNSCEAR 2000). An isodose map was produced to represent exposure rate from natural sources of terrestrial gamma radiation. PMID- 24787670 TI - FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene. AB - PURPOSE: Alveolar rhabdomyosarcoma that harbors the PAX3-FOXO1 fusion gene (t ARMS) is a common and lethal subtype of this childhood malignancy. Improvement in clinical outcomes in this disease is predicated upon the identification of novel therapeutic targets. EXPERIMENTAL DESIGN: Robust mouse models were used for in vivo analysis, and molecular studies were performed on xenografts treated in parallel. Two independent patient sets (n = 101 and 124) of clinically annotated tumor specimens were used for analysis of FANCD2 levels and its association with clinical and molecular characteristics and outcomes. RESULTS: Our xenograft studies reveal a selective suppression of FANCD2 by m-TOR kinase inhibition and radiosensitization of the t-ARMS line only. In the initial patient set, we show that FANCD2 transcript levels are prognostic in univariate analysis, and are significantly associated with metastatic disease and that the copresence of the translocation and high expression of FANCD2 is independently prognostic. We also demonstrate a significant and nonrandom enrichment of mTOR-associated genes that correlate with FANCD2 gene expression within the t-ARMS samples, but not within other cases. In the second patient set, we show that on a protein level, FANCD2 expression correlates with PAX3-FOXO1 fusion gene and is strongly associated with phospho-P70S6K expression in cases with the fusion gene. CONCLUSIONS: Our data demonstrate that FANCD2 may have a significant role in the radiation resistance and virulence of t-ARMS. Indirectly targeting this DNA repair protein, through mTOR inhibition, may represent a novel and selective treatment strategy. PMID- 24787673 TI - Current developments in nucleoside/nucleotide analogues for hepatitis B. AB - There had been remarkable development in nucleos(t)ide analogues (NAs) and evolution in treatment strategies in last 15 years. Currently, there are five NAs available for chronic hepatitis B treatment, namely lamivudine, telbivudine and entecavir (nucleoside analogues), adefovir dipivoxil and tenofovir disoproxil fumarate (nucleotide analogues). The advantages of relatively infrequent side effects and easy administration per oral make NAs popular treatment options. The major drawback of earlier generation NAs is the risk of emergence of drug resistance. Current international guidelines recommend the use of more potent agents with high genetic barriers to resistance including entecavir and tenofovir as first line chronic hepatitis B treatment. However, there is no consensus regarding the subsequent treatment regimens in patients with suboptimal responses to NAs. De novo combination therapy of two NAs, response-guided therapy and roadmap concept in NAs with subsequent switch or add-on therapy can also potentially improve treatment efficacy and avoid resistance. PMID- 24787674 TI - Association of the weekly practice of guided physical activity with the reduction of falls and symptoms of fibromyalgia in adult women. AB - The purpose of this study was to evaluate the effects of weekly physical activity on the risk of falls and the impact of fibromyalgia (FM) symptoms on daily function in Spanish women. Fibromyalgia is a common widespread pain condition that has been linked to an increased risk of falling and a low amount of guided physical activity, defined as regular participation in moderate-intensity exercise. Before the development of fall-risk reduction interventions, it is essential to understand the context of falls and fall-related experiences in patients with FM. Ours was a descriptive longitudinal study, wherein 140 women participated, all aged 28-73 years and belonging to AFIXA (Asociacion Provincial de Fibromialgia y Sindrome de Fatiga Cronica), the Fibromyalgia Association of Jaen (Andalusia, Spain). The study took place during 2013; data were collected through fall diaries, interviews, and questionnaires. Results showed that weekly physical activity can explain up to 12% of the variance in the fear of falling and 18% of the number of falls per year in patients with FM. However, the weekly physical activity prediction against the perceived impact of FM yielded R values below 10% in the 3 factors and in the total score of the Revised Fibromyalgia Impact Questionnaire (FIQ-R). Inactive women were proven to have a significantly higher number of falls per year than active ones (1.86 +/- 1.46 vs. 0.69 +/- 0.43, p < 0.001), but their fear of falling was similar (p > 0.05). In addition, physically active women had a significantly lower intensity in the symptoms of their condition (FIQ-R symptoms: 30.87 +/- 8.58 vs. 34.78 +/- 7.58 arbitrary units [a.u.], p = 0.014), and lower scores in the total score of the FIQ-R (54.33 +/- 21.50 vs. 65.19 +/- 19.27 a.u., p = 0.004). Results show that, with at least 1 hour per session of guided physical activity, a higher weekly number of sessions reduced the fear of falling in patients with FM and the total number of falls per year, and is associated with less severe symptoms (FIQ-R3). PMID- 24787675 TI - The development of a new stop'n'go reactive-agility test. AB - The main objective of this study was to evaluate the reliability and the validity of a newly constructed reactive-agility test that can be used to define the reactive-agility performance in sports that employ repeated scenarios of "stop'n'go" agility. Measuring is done by original hardware based on the ATMEL microcontroller AT89C51RE2. A total of 36 college-aged male athletes (age, 22.1 +/- 2.4 years; body height, 182.45 +/- 5.19 cm; body mass, 80.67 +/- 7.69 kg) and 21 college-aged female athletes (age, 21.4 +/- 2.5 years; body height, 171.45 +/- 6.81 cm; body mass, 61.95 +/- 6.70 kg) were evaluated for a stop'n'go reactive agility test (SNG-RAT), stop'n'go change of direction speed (SNG-CODS), countermovement jump, and anthropometrics. The reliability analyses suggested a high consistency for the applied tests (SNG-CODS, intraclass correlation coefficient [ICC] = 0.87 and 0.92; SNG-RAT, ICC = 0.81 and 0.86, for men and women, respectively). The SNG-RAT and SNG-CODS shared <40% of the common variance. The longer version of the SNG-RAT, which included 5 unpredictable changes of direction, was found to be valid among men. At the same time, the shorter version of the SNG-RAT (3 unpredictable changes of direction) is suggested for women because it better discriminates more agile from less agile athletes. Because the SNG-RAT and SNG-CODS were performed on the same course, we believe that simultaneously performing both tests can be beneficial when defining "stop'n'go" agility. This implies that the calculated SNG-CODS to SNG-RAT ratio will allow strength and conditioning coaches to indirectly determine the perceptual and reaction capacities of their athletes. PMID- 24787676 TI - Enhancement of peak and mean power in concentric phase of resistance exercises. AB - The study compares the differences in peak and mean power of concentric-only and countermovement resistance exercises (DeltaP) with different weights. A group of 27 fit men randomly performed 3 repetitions of either barbell bench presses or barbell squats on different days. The initial weight of 20 kg was increased by 10 or 5 kg (at higher loads) up to at least 85% of a previously established 1 repetition maximum (1RM). A computer-based system FiTRO Dyne Premium was used to monitor force and velocity and to calculate power. The peak values and mean values of power during the entire concentric phase of lifting and during the acceleration phase were analyzed. Results showed that maximal DeltaP calculated from the peak and mean values in the acceleration phase of bench presses was achieved at lower weights (118.4 +/- 19.0 W at 47% of 1RM and 116.2 +/- 15.3 W at 48% of 1RM, respectively) than the one calculated from mean values in the entire concentric phase of lifting (114.8 +/- 14.8 W at 57% 1RM). Likewise, maximal DeltaP calculated from the peak and mean values in the acceleration phase of squats was achieved at lower weights (127.7 +/- 20.4 W at 67% of 1RM and 124.3 +/ 22.1 W at 69% of 1RM, respectively) than the one calculated from the mean values in the entire concentric phase of lifting (125.0 +/- 19.2 W at 77% of 1RM). This fact has to be taken into account when training efficiency is evaluated, namely, in sports requiring the production of maximal force in a short time. PMID- 24787677 TI - A Methodological Approach to Quantifying Plyometric Intensity. AB - Jarvis, MM, Graham-Smith, P, and Comfort, P. A Methodological approach to quantifying plyometric intensity. J Strength Cond Res 30(9): 2522-2532, 2016-In contrast to other methods of training, the quantification of plyometric exercise intensity is poorly defined. The purpose of this study was to evaluate the suitability of a range of neuromuscular and mechanical variables to describe the intensity of plyometric exercises. Seven male recreationally active subjects performed a series of 7 plyometric exercises. Neuromuscular activity was measured using surface electromyography (SEMG) at vastus lateralis (VL) and biceps femoris (BF). Surface electromyography data were divided into concentric (CON) and eccentric (ECC) phases of movement. Mechanical output was measured by ground reaction forces and processed to provide peak impact ground reaction force (PF), peak eccentric power (PEP), and impulse (IMP). Statistical analysis was conducted to assess the reliability intraclass correlation coefficient and sensitivity smallest detectable difference of all variables. Mean values of SEMG demonstrate high reliability (r >= 0.82), excluding ECC VL during a 40-cm drop jump (r = 0.74). PF, PEP, and IMP demonstrated high reliability (r >= 0.85). Statistical power for force variables was excellent (power = 1.0), and good for SEMG (power >=0.86) excluding CON BF (power = 0.57). There was no significant difference (p > 0.05) in CON SEMG between exercises. Eccentric phase SEMG only distinguished between exercises involving a landing and those that did not (percentage of maximal voluntary isometric contraction [%MVIC] = no landing -65 +/- 5, landing 140 +/- 8). Peak eccentric power, PF, and IMP all distinguished between exercises. In conclusion, CON neuromuscular activity does not appear to vary when intent is maximal, whereas ECC activity is dependent on the presence of a landing. Force characteristics provide a reliable and sensitive measure enabling precise description of intensity in plyometric exercises. The present findings provide coaches and scientists with an insightful and precise method of measuring intensity in plyometrics, which will allow for greater control of programming variables. PMID- 24787678 TI - CSM enhances the filtration bleb survival in rabbit model of experimental glaucoma surgery. AB - PURPOSE: The aim of this study is to investigate whether CS-g-MMCs conjugate (CSM) could be a new agent to prevent the post-operative fibrosis in a rabbit model of experimental glaucoma filtration surgery. MATERIALS AND METHODS: In a randomized, controlled, masked-observer study, 40 New Zealand White rabbits underwent trabeculectomy in the right eyes and randomly received subconjunctival injection of phosphate buffered saline, chitosan (CS), CSM (100 ug/ml), CSM (200 ug/ml) or Mitomycin C (100 ug/ml). Bleb characteristics and anterior chamber depth were evaluated by slit-lamp examination. The animals were killed on day 14 and 28. Histopathology and immunohistochemistry were performed to determine the amount of the scarring and fibrosis. Ocular toxicity was assessed by histopathology and electron microscope. RESULTS: We found that the five groups were similar with respect to intraocular pressure and anterior chamber depth. The medians for survival days were: 5.5, 8, 17.5, 28 and 16 in the PBS, CS, CSM100, CSM200 and MMC groups, respectively. Both the CSM200 and the MMC group showed a significantly larger bleb area than the CSM100, CS and the PBS group. Less scarring was seen on day 14 and 28 in CSM200 and MMC group than in the PBS, CS and CSM100 group by histology and immunohistochemistry assessment. No damages were found in the rabbit eyes in each group. CONCLUSIONS: Subconjunctival injection of CSM postoperatively can improve the filtration bleb survival in the rabbit model. It can be a safe and effective antimetabolite in glaucoma surgery. PMID- 24787679 TI - Contrasting genetic diversity patterns in two sister kelp species co-distributed along the coast of Brittany, France. AB - We investigated patterns of genetic structure in two sister kelp species to explore how distribution width along the shore, zonation, latitudinal distribution and historical factors contribute to contrasting patterns of genetic diversity. We implemented a hierarchical sampling scheme to compare patterns of genetic diversity and structure in these two kelp species co-distributed along the coasts of Brittany (France) using a total of 12 microsatellites, nine for Laminaria hyperborea and 11 for Laminaria digitata, of which eight amplified in both species. The genetic diversity and connectivity of L. hyperborea populations were greater than those of L. digitata populations in accordance with the larger cross-shore distribution width along the coast and the greater depth occupied by L. hyperborea populations in contrast to L. digitata populations. In addition, marginal populations showed reduced genetic diversity and connectivity, which erased isolation-by-distance patterns in both species. As L. digitata encounters its southern range limit in southern Brittany (SBr) while L. hyperborea extends down to mid-Portugal, it was possible to distinguish the effect of habitat continuity from range edge effects. We found that L. digitata did not harbour high regional diversity at its southern edge, as expected in a typical rear edge, suggesting that refuges from the last glacial maximum for L. digitata were probably not located in SBr, but most likely further north. For both species, the highest levels of genetic diversity were found in the Iroise Sea and Morlaix Bay, the two regions in which they are being currently harvested. Preserving genetic diversity of these two foundation species in these areas should, thus, be a priority for the management of this resource in Brittany. PMID- 24787680 TI - Contraceptive provision in the VA healthcare system to women who report military sexual trauma. AB - BACKGROUND: Women Veterans who suffered military sexual trauma (MST) may be at high risk for unintended pregnancy and benefit from contraceptive services. The objective of this study is to compare documented provision of contraceptives to women Veterans using the Department of Veterans Affairs (VA) health system who report or deny MST. METHODS: This retrospective cohort study included women Veterans aged 18-45 years who served in Operation Enduring or Iraqi Freedom and had at least one visit to a VA medical center between 2002 and 2010. Data were obtained from VA administrative and clinical databases. Chi-squared tests and logistic regression were conducted to evaluate the association between MST, ascertained by routine clinical screening, and first documented receipt of hormonal or long-acting contraception. RESULTS: Of 68,466 women Veterans, 13% reported, 59% denied and 28% had missing data for the MST screen. Among the entire study cohort, 30% of women had documented receipt of a contraceptive method. Women reporting MST were significantly more likely than those denying MST to receive a method of contraception (adjusted odds ratio [aOR] 1.12, 95% confidence interval [CI] 1.07-1.18) including an intrauterine device (odds ratio [OR] 1.29, 95% CI 1.17-1.41) or contraceptive injection (OR 1.17, 95% CI 1.05 1.29). Women who were younger, unmarried, seen at a women's health clinic, or who had more than one visit were more likely to receive contraception. CONCLUSIONS: A minority of women Veterans of reproductive age receive contraceptive services from the VA. Women Veterans who report MST, and particularly those who seek care at VA women's health clinics, are more likely to receive contraception. PMID- 24787681 TI - [Uncommon lipodystrophic syndromes]. PMID- 24787682 TI - [Chronotherapy with anti-hypertensive drugs to improve blood pressure control and reduce the vascular risk]. PMID- 24787683 TI - [Epidemiologic and public-health issues of progressive fibrodysplasia ossificans in Spain]. PMID- 24787684 TI - [Pneumomediastinum and subcutaneous emphysema due to ribs fractures]. PMID- 24787685 TI - [Attention deficit hyperactivity disorder]. AB - Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders and can persist into the adulthood. ADHD has important social, academic and occupational consequences. ADHD diagnosis is based on the fulfillment of several clinical criteria, which can vary depending on the diagnostic system used. The clinical presentation can show great between-patient variability and it has been related to a dysfunction in the fronto-striatal and meso-limbic circuits. Recent investigations support a model in which multiple genetic and environmental factors interact to create a neurobiological susceptibility to develop the disorder. However, no clear causal association has yet been identified. Although multimodal treatment including both pharmacological and psychosocial interventions is usually recommended, no convincing evidence exists to support this recommendation. Pharmacological treatment has fundamentally shown to improve ADHD symptoms in the short term, while efficacy data for psychosocial interventions are scarce and inconsistent. Yet, drug treatment is increasingly popular and the last 2 decades have witnessed a sharp increase in the prescription of anti-ADHD medications coinciding with the marketing of new drugs to treat ADHD. PMID- 24787686 TI - [Treatment of cryoglobulinemic vasculitis associated with hepatitis C virus infection]. AB - Cryoglobulinemia is a heterogeneous systemic autoimmune disease with a wide variety of causes, symptoms and outcomes, and different etiopathogenic pathways involved in the vasculitic organ damage. The discovery of the hepatitis C virus (HCV) in 1989 changed radically the focus of research of the so-called "essential" cryoglobulinemia. Cryoglobulins can be detected in 25-30% of patients with HCV, overwhelmingly representing mixed cryoglobulins. However, only 10-15% of patients present with cryoglobulinemic vasculitis, with a broad spectrum of symptoms including mild or life-threatening manifestations. Consequently, not all patients can be uniformly treated. The key therapeutic points in HCV+ patients with cryoglobulinemic vasculitis cover different aspects. The first is to treat the underlying cause of cryoglobulinemia whenever possible, hence the use of antiviral therapies must always be considered in these patients. An individualized diagnostic approach to assess the number of organs involved and the severity of organ involvement is also essential in the therapeutic planning. This complex clinical scenario leads to an equally complex therapeutic scenario. There are three main treatment strategies for HCV-associated cryoglobulinemic vasculitis: conventional immunosuppression, antiviral treatment and biological therapies. The most recent studies are suggesting a change from the classical therapeutic approach (monotherapeutic regimens) to combination/sequential regimens, including treatments targeting the virus and those directed against the induced autoimmune disease, with the aim of blocking the various etiopathogenic pathways involved. PMID- 24787687 TI - Peptides from the variable region of specific antibodies are shared among lung cancer patients. AB - Late diagnosis of lung cancer is still the main reason for high mortality rates in lung cancer. Lung cancer is a heterogeneous disease which induces an immune response to different tumor antigens. Several methods for searching autoantibodies have been described that are based on known purified antigen panels. The aim of our study is to find evidence that parts of the antigen binding-domain of antibodies are shared among lung cancer patients. This was investigated by a novel approach based on sequencing antigen-binding-fragments (Fab) of immunoglobulins using proteomic techniques without the need of previously known antigen panels. From serum of 93 participants of the NELSON trial IgG was isolated and subsequently digested into Fab and Fc. Fab was purified from the digested mixture by SDS-PAGE. The Fab containing gel-bands were excised, tryptic digested and measured on a nano-LC-Orbitrap-Mass-spectrometry system. Multivariate analysis of the mass spectrometry data by linear canonical discriminant analysis combined with stepwise logistic regression resulted in a 12 antibody-peptide model which was able to distinguish lung cancer patients from controls in a high risk population with a sensitivity of 84% and specificity of 90%. With our Fab-purification combined Orbitrap-mass-spectrometry approach, we found peptides from the variable-parts of antibodies which are shared among lung cancer patients. PMID- 24787688 TI - A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies. AB - BACKGROUND: Many women diagnosed with varying psychiatric disorders take antipsychotic medications during pregnancy. The safety of antipsychotic medications in pregnancy is largely unknown. METHODS: We established the National Register of Antipsychotic Medications in Pregnancy in 2005. Women who are pregnant and taking an antipsychotic medication are interviewed every 6 weeks during pregnancy and then followed until their babies are one year old. The baby's progress is closely followed for the first year of life. FINDINGS: As of April 18 2012, 147 pregnancies had been followed through to completion. There were 142 live births and data is available for 100 one year old babies. 18% of babies were born preterm, with a higher dose of antipsychotic medication correlating to an increased likelihood of premature delivery; 43% of babies required special care nursery or intensive care after birth; 37% had any degree of respiratory distress and 15% of babies developed withdrawal symptoms. Congenital anomalies were seen in eight babies. Most pregnancies resulted in the birth of live, healthy babies. The use of mood stabilisers or higher doses of antipsychotics during pregnancy increased the likelihood of babies experiencing respiratory distress or admission to Special Care Nursery or Neonatal Intensive Care Units. CONCLUSION: There is a great need for safety and efficacy information about the use of antipsychotic medications in pregnancy. Live, healthy babies are the most common outcome following the use of antipsychotic medication in pregnancy, but clinicians should be particularly mindful of neonatal problems such as respiratory distress. PMID- 24787689 TI - Cell labeling via membrane-anchored lipophilic MR contrast agents. AB - Cell tracking in vivo with MR imaging requires the development of contrast agents with increased sensitivity that effectively label and are retained by cells. Most clinically approved Gd(III)-based contrast agents require high incubation concentrations and prolonged incubation times for cellular internalization. Strategies to increase contrast agent permeability have included conjugating Gd(III) complexes to cell penetrating peptides, nanoparticles, and small molecules which have greatly improved cell labeling but have not resulted in improved cellular retention. To overcome these challenges, we have synthesized a series of lipophilic Gd(III)-based MR contrast agents that label cell membranes in vitro. Two of the agents were synthesized with a multiplexing strategy to contain three Gd(III) chelates (1 and 2) while the third contains a single Gd(III) chelate (3). These new agents exhibit significantly enhanced labeling and retention in HeLa and MDA-MB-231-mcherry cells compared to agents that are internalized by cells (4 and Prohance). PMID- 24787691 TI - Preparation and properties of biocompatible PS-PEG/calcium phosphate nanospheres. AB - A facile room-temperature method was used to prepare phosphatidylserine (PS) poly(ethylene glycol) (PEG)/calcium phosphate (CaP) nanospheres (PS-poly(ethylene glycol) methyl ether/CaP nanospheres). Transmission electron microscopy (TEM) results confirmed that the PS-PEG/CaP porous nanospheres were spherical with a diameter of 8-12 nm. X-ray and thermo-gravimetric analysis (TGA) results also confirmed that the PS-PEG micelle was packed in the CaP shell. PS-PEG/CaP nanospheres exhibited little effect on the hemolysis, coagulation characteristics of blood and inflammatory response, demonstrating a negligible cytotoxicity response in LO2 liver cells. Experiments performed in zebrafish demonstrated that the PS-PEG/CaP nanospheres had a long circulatory residence time and did not induce apoptosis in zebrafish. Taken together, these results suggest that the PS PEG/CaP nanospheres have great potential to be used as a drug carrier. PMID- 24787690 TI - ALDH expression characterizes G1-phase proliferating beta cells during pregnancy. AB - High levels of aldehyde dehydrogenase (ALDH) activity have been detected in various progenitor and stem cells. Thus, Aldefluor fluorescence, which represents precisely the ALDH activity, has been widely used for the identification, evaluation, and isolation of stem and progenitor cells. Recently, ALDH activity was detected in embryonic and adult mouse pancreas, specifically in adult centroacinar and terminal duct cells supposed to harbor endocrine and exocrine progenitor cells in the adult pancreas. Nevertheless, ALDH activity and aldeflour fluorescence have not been examined in beta cells. Here, we report a dynamic increase in the number of aldeflour+ beta cells during pregnancy. Interestingly, nearly all these aldeflour+ beta cells are positive for Ki-67, suggesting that they are in an active cell cycle (G1, S and M phases). To determine precisely at which phase beta cells activate ALDH activity and thus become aldeflour+, we co stained insulin with additional proliferation markers, phosphohistone3 (PHH3, a marker for M-phase proliferating cells) and Bromodeoxyuridine (BrdU, a marker for S-phase proliferating cells). Our data show little aldeflour+ beta cells that were positive for either PHH3, or BrdU, suggesting that beta cells activate ALDH and become Aldefluor+ when they enter G1-phase of active cell cycle, but may downregulate ALDH when they leave G1-phase and enter S phase. Our data thus reveal a potential change in ALDH activity of proliferating beta cells during pregnancy, which provides a novel method for isolation and analysis of proliferating beta cells. Moreover, our data also suggest that caution needs to be taken on interpretation of Aldefluor lineage-tracing data in pancreas. PMID- 24787692 TI - The state-led large scale public private partnership 'Chiranjeevi Program' to increase access to institutional delivery among poor women in Gujarat, India: How has it done? What can we learn? AB - BACKGROUND: Many low-middle income countries have focused on improving access to and quality of obstetric care, as part of promoting a facility based intra-partum care strategy to reduce maternal mortality. The state of Gujarat in India, implements a facility based intra-partum care program through its large for profit private obstetric sector, under a state-led public-private-partnership, the Chiranjeevi Yojana (CY), under which the state pays accredited private obstetricians to perform deliveries for poor/tribal women. We examine CY performance, its contribution to overall trends in institutional deliveries in Gujarat over the last decade and its effect on private and public sector deliveries there. METHODS: District level institutional delivery data (public, private, CY), national surveys, poverty estimates, census data were used. Institutional delivery trends in Gujarat 2000-2010 are presented; including contributions of different sectors and CY. Piece-wise regression was used to study the influence of the CY program on public and private sector institutional delivery. RESULTS: Institutional delivery rose from 40.7% (2001) to 89.3% (2010), driven by sharp increases in private sector deliveries. Public sector and CY contributed 25-29% and 13-16% respectively of all deliveries each year. In 2007, 860 of 2000 private obstetricians participated in CY. Since 2007, >600,000 CY deliveries occurred i.e. one-third of births in the target population. Caesareans under CY were 6%, higher than the 2% reported among poor women by the DLHS survey just before CY. CY did not influence the already rising proportion of private sector deliveries in Gujarat. CONCLUSION: This paper reports a state-led, fully state-funded, large-scale public-private partnership to improve poor women's access to institutional delivery - there have been >600,000 beneficiaries. While caesarean proportions are higher under CY than before, it is uncertain if all beneficiaries who require sections receive these. Other issues to explore include quality of care, provider attrition and the relatively low coverage. PMID- 24787693 TI - Vascular relaxation induced by C-type natriuretic peptide involves the ca2+/NO synthase/NO pathway. AB - AIMS: C-type natriuretic peptide (CNP) and nitric oxide (NO) are endothelium derived factors that play important roles in the regulation of vascular tone and arterial blood pressure. We hypothesized that NO produced by the endothelial NO synthase (NOS-3) contributes to the relaxation induced by CNP in isolated rat aorta via activation of endothelial NPR-C receptor. Therefore, the aim of this study was to investigate the putative contribution of NO through NPR-C activation in the CNP induced relaxation in isolated conductance artery. MAIN METHODS: Concentration-effect curves for CNP were constructed in aortic rings isolated from rats. Confocal microscopy was used to analyze the cytosolic calcium mobilization induced by CNP. The phosphorylation of the residue Ser1177 of NOS was analyzed by Western blot and the expression and localization of NPR-C receptors was analyzed by immunohistochemistry. KEY FINDINGS: CNP was less potent in inducing relaxation in denuded endothelium aortic rings than in intact ones. L NAME attenuated the potency of CNP and similar results were obtained in the presence of hydroxocobalamin, an intracellular NO0 scavenger. CNP did not change the phosphorylation of Ser1177, the activation site of NOS-3, when compared with control. The addition of CNP produced an increase in [Ca2+]c in endothelial cells and a decrease in [Ca2+]c in vascular smooth muscle cells. The NPR-C-receptors are expressed in endothelial and adventitial rat aortas. SIGNIFICANCE: These results suggest that CNP-induced relaxation in intact aorta isolated from rats involves NO production due to [Ca2+]c increase in endothelial cells possibly through NPR-C activation expressed in these cells. The present study provides a breakthrough in the understanding of the close relationship between the vascular actions of nitric oxide and CNP. PMID- 24787694 TI - Maternal and neonatal mortality in south-west Ethiopia: estimates and socio economic inequality. AB - INTRODUCTION: Ethiopia has achieved the fourth Millennium Development Goal by reducing under 5 mortality. Nevertheless, there are challenges in reducing maternal and neonatal mortality. The aim of this study was to estimate maternal and neonatal mortality and the socio-economic inequalities of these mortalities in rural south-west Ethiopia. METHODS: We visited and enumerated all households but collected data from those that reported pregnancy and birth outcomes in the last five years in 15 of the 30 rural kebeles in Bonke woreda, Gamo Gofa, south west Ethiopia. The primary outcomes were maternal and neonatal mortality and a secondary outcome was the rate of institutional delivery. RESULTS: We found 11,762 births in 6572 households; 11,536 live and 226 stillbirths. There were 49 maternal deaths; yielding a maternal mortality ratio of 425 per 100,000 live births (95% CI:318-556). The poorest households had greater MMR compared to richest (550 vs 239 per 100,000 live births). However, the socio-economic factors examined did not have statistically significant association with maternal mortality. There were 308 neonatal deaths; resulting in a neonatal mortality ratio of 27 per 1000 live births (95% CI: 24-30). Neonatal mortality was greater in households in the poorest quartile compared to the richest; adjusted OR (AOR): 2.62 (95% CI: 1.65-4.15), headed by illiterates compared to better educated; AOR: 3.54 (95% CI: 1.11-11.30), far from road (>=6 km) compared to within 5 km; AOR: 2.40 (95% CI: 1.56-3.69), that had three or more births in five years compared to two or less; AOR: 3.22 (95% CI: 2.45-4.22). Households with maternal mortality had an increased risk of stillbirths; OR: 11.6 (95% CI: 6.00-22.7), and neonatal deaths; OR: 7.2 (95% CI: 3.6-14.3). Institutional delivery was only 3.7%. CONCLUSION: High mortality with socio-economic inequality and low institutional delivery highlight the importance of strengthening obstetric interventions in rural south-west Ethiopia. PMID- 24787695 TI - Survival after intervention in patients with low gradient severe aortic stenosis and preserved left ventricular function. AB - OBJECTIVE: The outcome of aortic valve replacement for patients with low gradient severe aortic stenosis and preserved ejection fraction has been debated. The aim of the present study was to evaluate the effect of aortic valve intervention on survival in that group. METHODS: A cohort of 416 consecutive patients with low gradient severe aortic stenosis (aortic valve area, <= 1 cm(2); mean pressure gradient, <40 mm Hg) and preserved ejection fraction (>= 50%) were identified from the Sheba Medical Center echocardiography database. Clinical data, aortic valve intervention, and death were recorded. RESULTS: During an average follow-up of 28 months, of 416 study patients (mean age, 76 +/- 14 years, 42% men), 97 (23%) underwent aortic valve intervention and 140 (32%) died. Mantel-Byar analysis showed that the cumulative probability of survival was significantly greater after aortic valve intervention. Multivariate analysis revealed a 49% reduction in the risk of death after surgery (P < .05). The survival benefit of aortic valve intervention was comparable with adjustment to older age, aortic valve area <= 0.8 cm(2), and a low (<= 35 cm(2)/m(2)) or normal (>35 cm(2)/m(2)) stroke volume index. CONCLUSIONS: Our findings suggest that aortic valve intervention is associated with improved survival among patients with low gradient severe aortic stenosis and preserved left ventricular function. The presence of either a low or normal stroke volume index did not affect the mortality benefit. PMID- 24787696 TI - Nature of the underlying heart disease affects survival in pediatric patients undergoing extracorporeal cardiopulmonary resuscitation. AB - OBJECTIVE: To describe the use of extracorporeal membrane oxygenation (ECMO) in acute resuscitation after cardiac arrest in pediatric patients with heart disease, with reference to patient selection and predictors of outcome. METHODS: A retrospective medical record review was performed of all patients aged <=21 years with heart disease who had undergone ECMO for cardiopulmonary resuscitation (ECPR) at Texas Children's Hospital from January 2005 to December 2012. The most recent Pediatric Overall Performance Category score was determined from the patients' medical records. RESULTS: During the study period, 62 episodes of ECPR occurred in 59 patients, with 27 (46%) surviving to hospital discharge and 25 (43%) alive at the most recent follow-up visit. The overall survival to discharge for patients with myocardial failure (myocarditis, cardiomyopathy, or after transplantation) and structural heart disease was similar (40% vs 50%, P=.6). No patient with restrictive cardiomyopathy survived; 1 patient (13%) in ECPR group after late cardiac graft failure survived to discharge. Survival to discharge was greater for patients who were intubated (70%) at cardiac arrest (P=.001). The presence of pre-existing acute kidney injury at cardiac arrest (62%) was associated with greater mortality (P=.059). A Pediatric Overall Performance Category score of <=2 (indicating good neurologic performance) was present in 68% of the survivors; 7 patients (87%) with a score>2 had abnormal imaging findings (P=.01). CONCLUSIONS: ECPR was associated with modest survival in pediatric patients with heart disease; however, this was associated in part with the underlying disease and pre-existing comorbidities, including the presence of acute kidney injury. PMID- 24787697 TI - A novel approach for the accurate prediction of thoracic surgery workforce requirements in Canada. AB - OBJECTIVE: To develop a microsimulation model of thoracic surgery workforce supply and demand to forecast future labor requirements. METHODS: The Canadian Community Health Survey and Canadian Census data were used to develop a microsimulation model. The demand component simulated the incidence of lung cancer; the supply component simulated the number of practicing thoracic surgeons. The full model predicted the rate of operable lung cancers per surgeon according to varying numbers of graduates per year. RESULTS: From 2011 to 2030, the Canadian national population will increase by 10 million. The lung cancer incidence rates will increase until 2030, then plateau and decline. The rate will vary by region (12.5% in Western Canada, 37.2% in Eastern Canada) and will be less pronounced in major cities (10.3%). Minor fluctuations in the yearly thoracic surgery graduation rates (range, 4-8) will dramatically affect the future number of practicing surgeons (range, 116-215). The rate of operable lung cancer varies from 35.0 to 64.9 cases per surgeon annually. Training 8 surgeons annually would maintain the current rate of operable lung cancer cases per surgeon per year (range, 32-36). However, this increased rate of training will outpace the lung cancer incidence after 2030. CONCLUSIONS: At the current rate of training, the incidence of operable lung cancer will increase until 2030 and then plateau and decline. The increase will outstrip the supply of thoracic surgeons, but the decline after 2030 will translate into an excess future supply. Minor increases in the rate of training in response to short-term needs could be problematic in the longer term. Unregulated workforce changes should, therefore, be approached with care. PMID- 24787698 TI - Multiparameter approach to evaluate elderly patients undergoing aortic valve replacement. PMID- 24787699 TI - Clinical performance of a sutureless aortic bioprosthesis: five-year results of the 3f Enable long-term follow-up study. AB - OBJECTIVE: Sutureless valves are designed to facilitate surgical implantation, including less-invasive techniques in aortic valve replacement, by maintaining surgical precision of implantation compared with transcatheter techniques. Long term clinical experience with sutureless valves is lacking. We report the 5-year follow-up results of an international, prospective, multicenter study evaluating the clinical performance and safety of the 3f Enable valve (Medtronic Inc, Minneapolis, Minn). METHODS: Between March 2007 and December 2009, 141 patients (54 male; mean age, 76.1+/-5.7 years) undergoing aortic valve replacement with the 3f Enable valve were enrolled in 10 European sites. The mean follow-up was 2.76 years (range, 2 days to 5.1 years; total, 388.7 patient-years). Echocardiographic valvular hemodynamic and morphologic analyses were performed by an independent core laboratory. RESULTS: The mean systolic gradient was 10.4+/ 4.4 mm Hg at discharge and 7.7+/-4.1 mm Hg at 5 years. The mean effective orifice area was 1.7+/-0.5 cm2 at discharge and 1.6+/-0.2 cm2 at 5 years. Freedom from all-cause and valve-related mortality was 87.6%+/-2.9% and 96.8%+/-1.6% at 1 year (113 patients at risk) and 77.0%+/-7.5% and 93.8%+/-4.8% at 5 years (24 patients at risk), respectively. Six patients underwent reoperation (4 because of major paravalvular leakage and 2 because of endocarditis). Freedom from reoperation was 95.4%+/-1.9% at 1 year and 95.4%+/-6.1% at 5 years. No structural valve deterioration occurred during the follow-up period. CONCLUSIONS: The sutureless 3f Enable valve represents a safe and effective treatment for aortic valve stenosis, providing an excellent hemodynamic profile. This study represents the longest follow-up study for a sutureless bioprosthesis. Sutureless valves may become an option for all patients with indicated biological aortic valve replacement. PMID- 24787700 TI - Synthesis of alpha,beta-unsaturated aldehydes based on a one-pot phase-switch dehydrogenative cross-coupling of primary alcohols. AB - An efficient one-pot ruthenium-catalyzed hydrogen-transfer strategy for a direct access to alpha,beta-unsaturated aldehydes has been developed. The employment of enolates prepared in situ from alcohols avoided handling unstable aldehydes and provided a very appealing route to different cinnamaldehydes substituted in position 2. A silica-grafted amine was used as phase-switch tag leading to a selective one-pot process in favor of cross-dehydrogenative coupling products. PMID- 24787701 TI - Development of a new multidimensional individual and interpersonal resilience measure for older adults. AB - OBJECTIVES: Develop an empirically grounded measure that can be used to assess family and individual resilience in a population of older adults (aged 50-99). METHODS: Cross-sectional, self-report data from 1006 older adults were analyzed in two steps. The total sample was split into two subsamples and the first step identified the underlying latent structure through principal component exploratory factor analysis (EFA). The second step utilized the second half of the sample to validate the derived latent structure through confirmatory factor analysis (CFA). RESULTS: EFA produced an eight-factor structure that appeared clinically relevant for measuring the multidimensional nature of resilience. Factors included self-efficacy, access to social support network, optimism, perceived economic and social resources, spirituality and religiosity, relational accord, emotional expression and communication, and emotional regulation. CFA confirmed the eight-factor structure previously achieved with covariance between each of the factors. Based on these analyses we developed the multidimensional individual and interpersonal resilience measure, a broad assessment of resilience for older adults. CONCLUSION: This study highlights the multidimensional nature of resilience and introduces an individual and interpersonal resilience measure developed for older adults which is grounded in the individual and family resilience literature. PMID- 24787702 TI - Echocardiographic integrated backscatter for the differentiation between aortic valve calcification and valvular myxoid degeneration in rats. AB - AIMS: Calcification is an independent predictor of mortality in aortic valve (AV) stenosis. Echocardiographic calibrated integrated backscatter (cIB) is a promising parameter for quantifying AV calcification. However, the ability of cIB to differentiate between calcification and valvular thickening has been questioned. Therefore, we aimed to use cIB to study AV calcification compared with non-calcified AV thickening in rats, with histology as reference. METHODS AND RESULTS: Twenty male Wistar rats were studied. Group 1 (N = 6) received subcutaneous (SC) serotonin injections (60 mg/kg/day) for 12 weeks to induce myxoid non-calcified AV thickening. Group 2 (N = 7) received vitamin D3 (25,000 UI/kg/day) SC to induce AV calcification, and Group 3 (N = 7) received only vehicle SC for 10 weeks. cIB of the AV was calculated at the end of the study, followed by measurement of the percentage of the histological AV calcification. At the end of the study, cIB values and calcification percentages were significantly higher in vitamin D3-injected rats compared with serotonin-injected rats and controls. There was no significant difference in cIB values between serotonin-injected rats and controls (vitamin D3: 21.5 +/- 3.0 dB*; serotonin: 11.8 +/- 3.1 dB; control: 10.3 +/- 3.4 dB; *P < 0.05). The percentage of histological calcification was significantly higher in the vitamin D3 group compared with the other groups. Serotonin-injected rats developed significant AV thickening. CONCLUSION: Increased cIB values of the AV are related to increased calcification at histology and not to myxoid non-calcified valvular thickening. Therefore, cIB may be considered as a sensitive technique to quantify calcification of AV rather than for detecting non-calcified valvular thickening. PMID- 24787703 TI - Goal attainment scaling in brain injury rehabilitation: strengths, limitations and recommendations for future applications. AB - There is increasing emphasis on the need to identify, work with and evaluate rehabilitation outcomes in ways that are personally relevant to individuals with brain injury, whether this be at a global or individual client level. This paper focuses on the use of one such method, Goal Attainment Scaling (GAS). It provides a general review of GAS and discusses what we found to be the strengths and limitations of using GAS to assess functional improvements in a rehabilitation study. Strengths included enabling the measurement of goal accomplishment on meaningful daily activities, capturing improvement on relevant functional tasks more effectively than broad measures of impairment, and facilitating collaborative goal-setting. Limitations included the time required to identify goals that could be broken down into five GAS outcome levels and defining the five levels, and compromised assessment of goal attainment due to poorly constructed GAS scales. Recommendations for minimising these potential limitations in future applications of GAS are also discussed. They include setting GAS baseline levels consistently across all scales, assigning GAS weights based on the client's ratings of importance, reviewing GAS weightings prior to each measurement phase, and using a suggested checklist to minimise the likelihood of poorly constructed scales. PMID- 24787704 TI - Folding wings like a cockroach: a review of transverse wing folding ensign wasps (Hymenoptera: Evaniidae: Afrevania and Trissevania). AB - We revise two relatively rare ensign wasp genera, whose species are restricted to Sub-Saharan Africa: Afrevania and Trissevania. Afrevania longipetiolata sp. nov., Trissevania heatherae sp. nov., T. hugoi sp. nov., T. mrimaensis sp. nov. and T. slideri sp. nov. are described, males and females of T. anemotis and Afrevania leroyi are redescribed, and an identification key for Trissevaniini is provided. We argue that Trissevania mrimaensis sp. nov. and T. heatherae sp. nov. populations are vulnerable, given their limited distributions and threats from mining activities in Kenya. We hypothesize that these taxa together comprise a monophyletic lineage, Trissevaniini, tr. nov., the members of which share the ability to fold their fore wings along two intersecting fold lines. Although wing folding of this type has been described for the hind wing of some insects four plane wing folding of the fore wing has never been documented. The wing folding mechanism and the pattern of wing folds of Trissevaniini is shared only with some cockroach species (Blattodea). It is an interesting coincidence that all evaniids are predators of cockroach eggs. The major wing fold lines of Trissevaniini likely are not homologous to any known longitudinal anatomical structures on the wings of other Evaniidae. Members of the new tribe share the presence of a coupling mechanism between the fore wing and the mesosoma that is composed of a setal patch on the mesosoma and the retinaculum of the fore wing. While the setal patch is an evolutionary novelty, the retinaculum, which originally evolved to facilitate fore and hind wing coupling in Hymenoptera, exemplifies morphological exaptation. We also refine and clarify the Semantic Phenotype approach used in previous taxonomic revisions and explore the consequences of merging new with existing data. The way that semantic statements are formulated can evolve in parallel, alongside improvements to the ontologies themselves. PMID- 24787706 TI - The role of theory and culture in child and adolescent prevention science: introduction to the special section. PMID- 24787705 TI - Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular degeneration. AB - BACKGROUND AND PURPOSE: The present treatment for choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) is not sufficient. Hence, we examined the therapeutic efficacy of reducing histamine H4 receptor expression on CNV in mice. EXPERIMENTAL APPROACH: H4 receptor expression was examined in CNVs from patients with AMD. In mice, laser photocoagulation was performed in the retina to induce experimental CNV (laser CNV). Protein and mRNA expression levels were determined and CNV volume measured in wild-type and Hrh4( /-) mice with laser CNV. The effects of JNJ7777120, an H4 receptor antagonist, administered intravitreously, on CNV volume and pathological vessel leakage were determined in mice with laser CNV and controls. Fundus imaging, retinal histology and electroretinography were performed on eyes injected with JNJ7777120 to evaluate retinal toxicity. KEY RESULTS: Human H4 receptors were only confirmed in CNV samples from AMD patients and not in the other subretinal tissues. Mouse H4 receptors were expressed in retinal pigment epithelium only after inducing laser CNV in wild-type mice, and were co-localized with the macrophage marker F4/80. Laser CNV volume was reduced in Hrh4(-/-) mice compared with that in wild-type mice, and JNJ7777120 suppressed laser-induced CNV volume and pathological CNV leakage in wild-type mice. Also eyes injected with JNJ7777120 did not show retinal degeneration. CONCLUSIONS AND IMPLICATIONS: H4 receptors are expressed in macrophages that accumulate around CNVs. Suppressing H4 receptor expression prevented the pathological vessel leakage without showing retinal toxicity, indicating that the H4 receptor has potential as a novel therapeutic target in AMD. PMID- 24787709 TI - High-pressure synthesis and structural characterization of the type II clathrate compound Na(30.5)Si(136) encapsulating two sodium atoms in the same silicon polyhedral cages. AB - Single crystals of sodium containing silicon clathrate compounds Na8Si46 (type I) and NaxSi136 (type II) were prepared from the mixtures of NaSi and Si under high pressure and high-temperature conditions of 5 GPa at 600-1000 degrees C. The type II crystals were obtained at relatively low-temperature conditions of 700 800 degrees C, which were found to have a Na excess composition Na30.5Si136 in comparison with the compounds NaxSi136 (x <= 24) obtained by a thermal decomposition of NaSi under vacuum. The single crystal study revealed that the Na excess type II compound crystallizes in space group Fd3m with a lattice parameter of a = 14.796(1) A, slightly larger than that of the ambient phase (Na24Si136), and the large silicon hexakaidecahedral cages (@Si28) are occupied by two sodium atoms disordered in the two 32e sites around the center of the @Si28 cages. At temperatures <90 K, the crystal symmetry of the compound changes from the face centered to the primitive cell with space group P213, and the Na atoms in the @Si28 cages are aligned as Na2 pairs. The temperature dependence of the magnetic susceptibility of Na30.5Si136 suggests that the two Na ions (2 Na(+)) in the cage are changed to a Na2 molecule. The Na atoms of Na30.5Si136 can be deintercalated from the cages topochemically by evacuation at elevated temperatures. The single crystal study of the deintercalated phases NaxSi136 (x = 25.5 and 5.5) revealed that only excess Na atoms have disordered arrangements. PMID- 24787707 TI - The development and implementation of theory-driven programs capable of addressing poverty-impacted children's health, mental health, and prevention needs: CHAMP and CHAMP+, evidence-informed, family-based interventions to address HIV risk and care. AB - This article describes a program of prevention and intervention research conducted by the CHAMP (Collaborative HIV prevention and Adolescent Mental health Project; McKay & Paikoff, 2007 ) investigative team. CHAMP refers to a set of theory-driven, evidence-informed, collaboratively designed, family-based approaches meant to address the prevention, health, and mental health needs of poverty-impacted African American and Latino urban youth who are either at risk for HIV exposure or perinatally infected and at high risk for reinfection and possible transmission. CHAMP approaches are informed by theoretical frameworks that incorporate an understanding of the critical influences of multilevel contextual factors on youth risk taking and engagement in protective health behaviors. Highly influential theories include the triadic theory of influence, social action theory, and ecological developmental perspectives. CHAMP program delivery strategies were developed via a highly collaborative process drawing upon community-based participatory research methods in order to enhance cultural and contextual sensitivity of program content and format. The development and preliminary outcomes associated with a family-based intervention for a new population, perinatally HIV-infected youth and their adult caregivers, referred to as CHAMP+, is described to illustrate the integration of theory, existing evidence, and intensive input from consumers and healthcare providers. PMID- 24787708 TI - Oncogenic functions of the cancer-testis antigen SSX on the proliferation, survival, and signaling pathways of cancer cells. AB - SSX is a transcription factor with elusive oncogenic functions expressed in a variety of human tumors of epithelial and mesenchymal origin. It has raised substantial interest as a target for cancer therapy since it elicits humoral responses and displays restricted expression to cancer, spermatogonia and mesenchymal stem cells. Here, we investigated the oncogenic properties of SSX by employing a RNA interference to knock-down the endogenous expression of SSX in melanoma and osteosarcoma cell lines. Depletion of SSX expression resulted in reduced proliferation with cells accumulating in the G1 phase of the cell cycle. We found that the growth promoting and survival properties of SSX are mediated in part though modulation of MAPK/Erk and Wnt signaling pathways, since SSX silencing inhibited Erk-mediated signaling and transcription of cMYC and Akt-1. We also found that SSX forms a transient complex with beta-catenin at the G1-S phase boundary resulting in the altered expression of beta-catenin target genes such as E-cadherin, snail-2 and vimentin, involved in epithelial-mesenchymal transitions. Importantly the silencing of SSX expression in in vivo significantly impaired the growth of melanoma tumor xenografts. Tumor biopsies from SSX silenced tumors displayed reduced cyclin A staining, indicative of low proliferation and predominantly cycloplasmic beta-catenin compared to SSX expressing tumors. The present study demonstrates a previously unknown function of SSX, that as an oncogene and as a tumor target for the development of novel anti-cancer drugs. PMID- 24787710 TI - Paediatric pharmacovigilance: use of pharmacovigilance data mining algorithms for signal detection in a safety dataset of a paediatric clinical study conducted in seven African countries. AB - BACKGROUND: Pharmacovigilance programmes monitor and help ensuring the safe use of medicines which is critical to the success of public health programmes. The commonest method used for discovering previously unknown safety risks is spontaneous notifications. In this study we examine the use of data mining algorithms to identify signals from adverse events reported in a phase IIIb/IV clinical trial evaluating the efficacy and safety of several Artemisinin-based combination therapies (ACTs) for treatment of uncomplicated malaria in African children. METHODS: We used paediatric safety data from a multi-site, multi country clinical study conducted in seven African countries (Burkina Faso, Gabon, Nigeria, Rwanda, Uganda, Zambia, and Mozambique). Each site compared three out of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL) or chlorproguanil/dapsone and artesunate (CD+A). We examine two pharmacovigilance signal detection methods, namely proportional reporting ratio and Bayesian Confidence Propagation Neural Network on the clinical safety dataset. RESULTS: Among the 4,116 children (6-59 months old) enrolled and followed up for 28 days post treatment, a total of 6,238 adverse events were reported resulting into 346 drug-event combinations. Nine signals were generated both by proportional reporting ratio and Bayesian Confidence Propagation Neural Network. A review of the manufacturer package leaflets, an online Multi-Drug Symptom/Interaction Checker (DoubleCheckMD) and further by therapeutic area experts reduced the number of signals to five. The ranking of some drug-adverse reaction pairs on the basis of their signal index differed between the two methods. CONCLUSIONS: Our two data mining methods were equally able to generate suspected signals using the pooled safety data from a phase IIIb/IV clinical trial. This analysis demonstrated the possibility of utilising clinical studies safety data for key pharmacovigilance activities like signal detection and evaluation. This approach can be applied to complement the spontaneous reporting systems which are limited by under reporting. PMID- 24787711 TI - The tertiary origin of the allosteric activation of E. coli glucosamine-6 phosphate deaminase studied by sol-gel nanoencapsulation of its T conformer. AB - The role of tertiary conformational changes associated to ligand binding was explored using the allosteric enzyme glucosamine-6-phosphate (GlcN6P) deaminase from Escherichia coli (EcGNPDA) as an experimental model. This is an enzyme of amino sugar catabolism that deaminates GlcN6P, giving fructose 6-phosphate and ammonia, and is allosterically activated by N-acetylglucosamine 6-phosphate (GlcNAc6P). We resorted to the nanoencapsulation of this enzyme in wet silica sol gels for studying the role of intrasubunit local mobility in its allosteric activation under the suppression of quaternary transition. The gel-trapped enzyme lost its characteristic homotropic cooperativity while keeping its catalytic properties and the allosteric activation by GlcNAc6P. The nanoencapsulation keeps the enzyme in the T quaternary conformation, making possible the study of its allosteric activation under a condition that is not possible to attain in a soluble phase. The involved local transition was slowed down by nanoencapsulation, thus easing the fluorometric analysis of its relaxation kinetics, which revealed an induced-fit mechanism. The absence of cooperativity produced allosterically activated transitory states displaying velocity against substrate concentration curves with apparent negative cooperativity, due to the simultaneous presence of subunits with different substrate affinities. Reaction kinetics experiments performed at different tertiary conformational relaxation times also reveal the sequential nature of the allosteric activation. We assumed as a minimal model the existence of two tertiary states, t and r, of low and high affinity, respectively, for the substrate and the activator. By fitting the velocity-substrate curves as a linear combination of two hyperbolic functions with Kt and Kr as KM values, we obtained comparable values to those reported for the quaternary conformers in solution fitted to MWC model. These results are discussed in the background of the known crystallographic structures of T and R EcGNPDA conformers. These results are consistent with the postulates of the Tertiary Two-States (TTS) model. PMID- 24787712 TI - Effect of oat intake on glycaemic control and insulin sensitivity: a meta analysis of randomised controlled trials. AB - The present meta-analysis of randomised controlled trials (RCT) aimed to investigate the effect of oat intake on glycaemic control and insulin sensitivity. A literature search was carried out in PubMed, ScienceDirect Online and The Cochrane Library (up to October 2013) for RCT that assessed the effect of oat intake on glucose control and insulin sensitivity. A total of fifteen articles with 673 subjects met the inclusion criteria. A random-effects model was used when the overall pooled studies exhibited significant heterogeneity. Otherwise, a fixed-effects model was used. Compared with controls, oat intake significantly reduced the concentrations of fasting insulin by - 6.29 (95 % CI - 12.32, - 0.27) pmol/l (P= 0.04) and the values of glucose AUC (GAUC; 0-120 min) by - 30.23 (95 % CI - 43.65, - 16.81) min * mmol/l (P< 0.0001). There was a slight decrease in fasting glucose concentrations, glycated Hb concentrations and homeostatic model assessment-insulin resistance values in subjects who consumed oats, but the difference was not significant. In conclusion, oat intake significantly lowers fasting insulin concentrations and GAUC values. To further investigate the effect of oat intake on fasting glucose concentrations, additional long-term and high-quality RCT with a parallel design are required. PMID- 24787713 TI - Malaria parasite infection compromises control of concurrent systemic non typhoidal Salmonella infection via IL-10-mediated alteration of myeloid cell function. AB - Non-typhoidal Salmonella serotypes (NTS) cause a self-limited gastroenteritis in immunocompetent individuals, while children with severe Plasmodium falciparum malaria can develop a life-threatening disseminated infection. This co-infection is a major source of child mortality in sub-Saharan Africa. However, the mechanisms by which malaria contributes to increased risk of NTS bacteremia are incompletely understood. Here, we report that in a mouse co-infection model, malaria parasite infection blunts inflammatory responses to NTS, leading to decreased inflammatory pathology and increased systemic bacterial colonization. Blunting of NTS-induced inflammatory responses required induction of IL-10 by the parasites. In the absence of malaria parasite infection, administration of recombinant IL-10 together with induction of anemia had an additive effect on systemic bacterial colonization. Mice that were conditionally deficient for either myeloid cell IL-10 production or myeloid cell expression of IL-10 receptor were better able to control systemic Salmonella infection, suggesting that phagocytic cells are both producers and targets of malaria parasite-induced IL 10. Thus, IL-10 produced during the immune response to malaria increases susceptibility to disseminated NTS infection by suppressing the ability of myeloid cells, most likely macrophages, to control bacterial infection. PMID- 24787715 TI - Drivers' and non-drivers' performance in a change detection task with static driving scenes: is there a benefit of experience? AB - The 'looked-but-failed-to-see' phenomenon is crucial to driving safety. Previous research utilising change detection tasks related to driving has reported inconsistent effects of driver experience on the ability to detect changes in static driving scenes. Reviewing these conflicting results, we suggest that drivers' increased ability to detect changes will only appear when the task requires a pattern of visual attention distribution typical of actual driving. By adding a distant fixation point on the road image, we developed a modified change blindness paradigm and measured detection performance of drivers and non-drivers. Drivers performed better than non-drivers only in scenes with a fixation point. Furthermore, experience effect interacted with the location of the change and the relevance of the change to driving. These results suggest that learning associated with driving experience reflects increased skill in the efficient distribution of visual attention across both the central focus area and peripheral objects. PRACTITIONER SUMMARY: This article provides an explanation for the previously conflicting reports of driving experience effects in change detection tasks. We observed a measurable benefit of experience in static driving scenes, using a modified change blindness paradigm. These results have translational opportunities for picture-based training and testing tools to improve driver skill. PMID- 24787716 TI - Using metallic noncontact atomic force microscope tips for imaging insulators and polar molecules: tip characterization and imaging mechanisms. AB - We demonstrate that using metallic tips for noncontact atomic force microscopy (NC-AFM) imaging at relatively large (>0.5 nm) tip-surface separations provides a reliable method for studying molecules on insulating surfaces with chemical resolution and greatly reduces the complexity of interpreting experimental data. The experimental NC-AFM imaging and theoretical simulations were carried out for the NiO(001) surface as well as adsorbed CO and Co-Salen molecules using Cr coated Si tips. The experimental results and density functional theory calculations confirm that metallic tips possess a permanent electric dipole moment with its positive end oriented toward the sample. By analyzing the experimental data, we could directly determine the dipole moment of the Cr-coated tip. A model representing the metallic tip as a point dipole is described and shown to produce NC-AFM images of individual CO molecules adsorbed onto NiO(001) in good quantitative agreement with experimental results. Finally, we discuss methods for characterizing the structure of metal-coated tips and the application of these tips to imaging dipoles of large adsorbed molecules. PMID- 24787714 TI - Relationship between working hours and power of attention, memory, fatigue, depression and self-efficacy one year after diagnosis of clinically isolated syndrome and relapsing remitting multiple sclerosis. AB - The role of cognitive domain dysfunction with respect to vocational changes in persons with Clinically Isolated Syndrome (CIS) and early Relapsing Remitting Multiple Sclerosis (eRRMS) is insufficiently known. We investigated thirty-three patients--14 CIS, 19 eRRMS -, mean (standard deviation [SD]) time since diagnosis 13.5 (4.8) months and mean (SD) Expanded Disability Status Scale (EDSS) score 1.3 (1.1). Patients were assessed on the CDR System, a set of automated tests of cognitive function, which yielded scores for Power of Attention (ms), Continuity of Attention (#), Working Memory (SI), Episodic Memory (#) and Speed of Memory (ms). Work-related items and the confounding variables fatigue, depression, disease impact and self-efficacy, were assessed by self-report questionnaires. Patients had poorer Power of Attention compared to normative data (1187 [161.5] vs. 1070 [98.6]; P<0.0001) and slower Speed of Memory (4043 [830.6]) vs. 2937 [586.1]; P<0.0001). Power of Attention (Pearson r = -0.42; P<0.04), Working Memory (r = 0.42; P<0.04) and depression r = -0.41; P<0.05) correlated with number of days worked per week. Fatigue (r = -0.56; P<0.005), self-efficacy (r = 0.56; P<0.005) and disease impact (r = -0.46; P<0.05) correlated with number of hours worked per week. Persons who wished to work less had poorer Power of Attention (1247 vs. 1116 ms; P<0.02), those who wished to change job had poorer Episodic Memory (1.35 vs. 1.57; p<0.03). People who reduced working hours within 12 months after diagnosis had higher fatigue and disease impact, and lower self efficacy. The findings of this pilot study indicate that one year after the diagnosis of CIS and RRMS Power of Attention and Speed of Memory are reduced, that Power of Attention and Memory are associated with a capability of working less hours, and that fatigue, depression and disease impact may negatively, and self-efficacy positively affect working hours. PMID- 24787717 TI - EuNiGe3, an anisotropic antiferromagnet. AB - Single crystals of EuNiGe3, crystallizing in the non-centrosymmetric BaNiSn3-type structure, were grown using In flux, enabling us to explore the anisotropic magnetic properties, which was not possible with previously reported polycrystalline samples. The EuNiGe3 single crystalline sample is found to order antiferromagnetically at 13.2 K, as revealed from the magnetic susceptibility, heat capacity and electrical resistivity data. The low temperature magnetization M (H) is distinctly different for the field parallel to the ab-plane and c-axis; the ab-plane magnetization varies almost linearly with the field before the occurrence of an induced ferromagnetic (FM) phase (spin-flip) at 6.2 Tesla. On the other hand M (H) along the c-axis is accompanied by two metamagnetic transitions followed by a spin-flip at 4.1 T. A model including anisotropic exchange and dipole-dipole interactions reproduces the main features of magnetization plots but falls short of full representation. (H,T) phase diagrams have been constructed for the field applied along the principal directions. From the (151)Eu Mossbauer spectra, we determine that the 13.2 K transition leads to an incommensurate antiferromagnetic (AFM) intermediate phase followed by a transition near 10.5 K to a commensurate AFM configuration. PMID- 24787719 TI - Attempting to successfully treat the elite level throwing athlete. Preface. PMID- 24787718 TI - Comparative analysis of the effectiveness of three immunization strategies in controlling disease outbreaks in realistic social networks. AB - The high incidence of emerging infectious diseases has highlighted the importance of effective immunization strategies, especially the stochastic algorithms based on local available network information. Present stochastic strategies are mainly evaluated based on classical network models, such as scale-free networks and small-world networks, and thus are insufficient. Three frequently referred stochastic immunization strategies-acquaintance immunization, community-bridge immunization, and ring vaccination-were analyzed in this work. The optimal immunization ratios for acquaintance immunization and community-bridge immunization strategies were investigated, and the effectiveness of these three strategies in controlling the spreading of epidemics were analyzed based on realistic social contact networks. The results show all the strategies have decreased the coverage of the epidemics compared to baseline scenario (no control measures). However the effectiveness of acquaintance immunization and community bridge immunization are very limited, with acquaintance immunization slightly outperforming community-bridge immunization. Ring vaccination significantly outperforms acquaintance immunization and community-bridge immunization, and the sensitivity analysis shows it could be applied to controlling the epidemics with a wide infectivity spectrum. The effectiveness of several classical stochastic immunization strategies was evaluated based on realistic contact networks for the first time in this study. These results could have important significance for epidemic control research and practice. PMID- 24787720 TI - The biomechanics of throwing: simplified and cogent. AB - The majority of shoulder injuries occur due to repetitive overhead movements, with baseball pitching being the most common mechanism for overuse injury. Before studying the treatment of these shoulder injuries, it is paramount that the health professional have an understanding of the etiology of and the underlying mechanisms for shoulder pathology. The act of overhead throwing is an eloquent full-body motion that requires tremendous coordination from the time of force generation to follow-through. The shoulder complex is a crucial component of the upper body kinetic chain as it transmits force created in the lower body to the arm and hand to produce velocity and accuracy with ball release. The focus of this article is on the biomechanics of the throwing motion, with emphasis on the kinematics of the shoulder. The established phases of the throwing motion will be reviewed in a stepwise manner and the contributions of osseous and soft-tissue structures to the successful completion of each phase will be discussed. PMID- 24787721 TI - The role of the scapula in throwing disorders. AB - Shoulder injuries in the thrower can prove a challenge to diagnose and treat. Overhead throwing is an intricate motion that places considerable torque on the shoulder. The complex interplay of the scapula with the glenohumeral joint and its surrounding musculature allows elite pitchers to achieve speeds >95 miles per hour. An understanding of scapular motion is integral to diagnose and treat shoulder pathology in these athletes. Treatment is aimed at addressing the underlying cause with a physical rehabilitation program. Although nonoperative care is the most predictable and useful treatment, occasionally operative treatment is necessary. This chapter will outline normal scapular motion during throwing, the effects of common shoulder disorders on throwing mechanics, and the prevention, diagnosis, and treatment of these conditions. PMID- 24787722 TI - Acquired and adaptive changes in the throwing athlete: implications on the disabled throwing shoulder. AB - The throwing shoulder continues to be one of the most actively studied and poorly understood aspects of sports medicine. The act of throwing itself transfers tremendous power throughout the kinetic chain, resulting in forces experienced in the shoulder that can exceed its physiologic limits. These forces over time lead to many adaptive changes in the bone, capsule, and muscular structures of the shoulder girdle. An understanding of these acquired changes is critical to differentiate between normal or protective adaptation and pathologic change. The purposes of this article were to elucidate the adaptive and acquired changes, which commonly develop in the throwing shoulder, to explain how these changes contribute in both protective and pathologic roles, and to apply these principles into a deeper understanding of the care of the disabled throwing shoulder. PMID- 24787723 TI - Comprehensive history and physical examination of the throwing shoulder. AB - The shoulder is subject to tremendous stress during the throwing motion, which creates the opportunity for injury and disability. Understanding the potential causes of injury in the overhead athlete can be challenging in and of itself; however, placing those diagnoses in the clinical context of an injured athlete can be even more challenging. In a world of advancing technology and increasing dependence on magnetic resonance imaging, the art of history taking and physical examination can be easily forgotten. PMID- 24787724 TI - Rotator cuff tears in the throwing athlete. AB - Tears of the rotator cuff, both partial, and less commonly, full thickness, are relatively common in the throwing athlete. The rotator cuff is subjected to enormous stresses during repetitive overhead activity. The supraphysiological strains, especially when combined with pathology elsewhere in the kinetic chain, can lead to compromise of the cuff fabric, most commonly on the undersurface where tensile overload occurs. Exacerbation by a tight posterior capsular, anterior instability, and internal impingement render the cuff progressively compromised, with intrinsic shear stresses and undersurface fiber failure. Advances in imaging technology, including contrast magnetic resonance imaging, dynamic ultrasound, and arthroscopic visualization have enhanced our understanding of cuff pathology in this athletic population. Unfortunately, this has not yet translated into how to best approach these athletes to return them to their previous level of activity. Nonoperative management remains the mainstay for most throwers, with arthroscopic debridement an effective surgical option for those with refractory symptoms. Despite technological advances in cuff repair in the general population, comparable outcomes have not been achieved in high-level throwers. Widespread appreciation that securing the cuff operatively will likely end an athletes' throwing career has led to adopting a surgical approach that emphasizes debridement over repair for nearly all partial and full-thickness tears. Whether advances in surgical technique will ultimately permit definitive and lasting repairs that allow overhead throwers to return to their previous level of sports remains unknown at this time. PMID- 24787725 TI - SLAP lesions in the overhead athlete. AB - The diagnosis and management of SLAP lesions in the overhead athlete remains a challenge for the sports medicine specialist due to variable anatomy, changes with aging, concomitant pathology, lack of dependable physical findings on examination, and lack of sensitivity and specificity with imaging studies. This article presents a comprehensive review of the epidemiology, relevant anatomy, proposed pathogenesis, diagnostic approach, and outcomes of nonoperative and operative management of SLAP lesions in the overhead athlete. PMID- 24787726 TI - Anterior instability in the throwing shoulder. AB - The disabled throwing shoulder is a multifactorial problem. Laxity of the glenohumeral joint is necessary to achieve a satisfactory velocity. Normal wear and tear with throwing may convert this normal amount of excessive translation into instability. Instability in the throwing athlete manifests itself in 2 forms: traumatic anterior instability that happens to occur in a throwing athlete and excessive anterior subluxation because of overuse that occurs in conjunction with the disabled throwing shoulder. In most cases, it is difficult to determine by physical examination or imaging how much laxity is too much; therefore, the managing physician should always err on the side of caution. A trial of rest and rehabilitation should always be attempted before any consideration of surgery. The multifactorial issues in the disabled throwing athlete should be corrected during this phase of treatment, including assessment and treatment of hip abnormalities, restoration of satisfactory core strength, correction of scapular dyskinesis, and an evaluation and correction of any biomechanical abnormalities in the throwing mechanism. Surgical management of anterior instability in the throwing shoulder depends on the mechanism of injury. The traumatic anterior instability patient is managed by acute surgical repair without a shift, utilizing mattress sutures to prevent suture chondromalacia on the humeral head or glenoid. The anterior laxity management centers on the posterior superior labrum, although occasionally the anterior labrum or capsule may be involved as well. Overall, symptomatic anterior instability is less common in the throwing shoulder. Jobe and colleagues are credited with the first successful technique for the correction of anterior instability in the throwing athlete, the anterior capsulolabral reconstruction by a subscapularis split. The success of this technique paved the way for the adoption of the current arthroscopic techniques that are utilized to correct instability in the throwing athlete. PMID- 24787727 TI - Symptomatic internal impingement of the shoulder in overhead athletes. AB - The term "internal impingement" describes the normal physiological contact that occurs between the posterosuperior glenoid and the greater tuberosity in positions of hyperabduction and external rotation. This physiological contact can become symptomatic when repeated overhead motion results in partial articular sided posterosuperior rotator cuff tears and lesions of the posterosuperior glenoid labrum. The precise pathophysiology involved with the development of symptomatic internal impingement has been debated extensively over the past few decades. However, current literature suggests that symptomatic internal impingement may result from a combination of multiple factors involving repetitive overhead activity, physiological remodeling of the throwing shoulder, posterior capsule contracture, and scapular dyskinesis, among other factors. These can all lead to scapulohumeral hyperangulation and associated pathologic findings. The purpose of this article is to review the relevant anatomy, pathophysiology, diagnosis, and management of symptomatic internal impingement through a critical review of current evidence. PMID- 24787728 TI - Decision making in the throwing athlete. AB - The throwing athlete represents a very interesting and challenging patient population to treat. Few other athletes require the unique combination of stability combined with inherent laxity to allow them to achieve peak performance. Treatment of them and their injuries necessitates an understanding of this phenomenon, recognition of common pathologies encountered, and experience in the process. In this section, we will review several of the most common entities that we encounter in the care of throwing athletes and the current literature on these topics as well as describing our approach to the decision making process with regards to their treatment. We will also review our surgical techniques for each of these when nonoperative care has failed or acute intervention is deemed necessary. PMID- 24787729 TI - Nonoperative and postoperative rehabilitation for injuries of the throwing shoulder. AB - The repetitive overhead motion involved in throwing is responsible for unique and sport-specific patterns of injury to the shoulder joint. Specific strengthening and flexibility plays a vital role in the ultimate function and injury prevention in the overhead-throwing athlete. The clinician must achieve a delicate balance between mobility and stability, which often presents as a significant challenge. Most shoulder injuries in the overhead thrower can be successfully treated nonoperatively to allow the athlete to return to competition. A well-structured, in-season strengthening program that is designed to maintain the athlete's strength, power, and endurance while not inhibiting with the athlete's ability to compete on a regular basis is critical. PMID- 24787730 TI - Midlife metabolic syndrome and neurocognitive function in a mixed Asian sample. AB - BACKGROUND: An association between metabolic syndrome (MetS) and disturbances in neurocognitive function has been identified in Caucasians but the nature and extent of impaired cognition in Asian MetS patients, who may be at greater risk of degenerative cognitive decline, remains unspecified. METHODS: A cross sectional study was conducted at the National University Hospital of Singapore. Participants were recruited from a diabetes clinic at the National University Hospital. Fifty-three patients who met MetS criteria and 44 clinical controls were recruited. All participants were 55 years and above and community ambulant. Neurocognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). CANTAB performances between MetS and control groups were examined with analysis of variance (ANOVA) and the relative contributions of vascular risk, and intrademographic factors on CANTAB scores were dilineated with stepwise regression analyses. RESULTS: Participants with MetS consistently performed significantly worse than controls across all CANTAB subtests. Education and Chinese race were found to be potential protective factors. CONCLUSIONS: Executive and memory impairment is present in Asian patients with midlife MetS who may be particularly vulnerable to the detrimental impact of MetS in midlife. PMID- 24787731 TI - Epidemiology of injuries in First Division Spanish football. AB - The aim was to examine the injuries sustained by Spanish football players in the First Division and to compare injury-related variables in the context of both competition and training. The injury data were prospectively collected from 16 teams (427 players) using a specific web-based survey during the 2008/2009 season. A total of 1293 injuries were identified (145 were recurring injuries). The overall injury incidence was 5.65 injuries per 1000 h of exposure. Injuries were much more common during competition than during training (43.53 vs. 3.55 injuries per 1000 h of exposure, P < 0.05). Most of the injuries (89.6%) involved the lower extremities, and overuse (65.7%) was the main cause. Muscle and tendon injuries were the most common types of injury (53.8%) among the players. The incidence of training injuries was greater during the pre-season and tended to decrease throughout the season, while the incidence of competition injuries increased throughout the season (all P < 0.05). In conclusion, the results of this study suggest the need for injury prevention protocols in the First Division of the Spanish Football League to reduce the number of overuse injuries in the muscles and tendons in the lower extremities. In addition, special attention should be paid during the pre-season and the competitive phase II (the last four months of the season) in order to prevent training and competition injuries, respectively. PMID- 24787732 TI - Probiotic Bifidobacterium animalis subsp. lactis Bi-07 alleviates bacterial translocation and ameliorates microinflammation in experimental uraemia. AB - AIM: Uraemia is characterized by intestinal bacterial translocation, which contributes to the development of microinflammation. Probiotics enhance the intestinal barrier and overall health of the host. The present study investigated whether the probiotic Bifidobacterium animalis subsp. lactis Bi-07 alleviates bacterial translocation and ameliorates microinflammation in experimental uraemia. METHODS: Sixty Sprague-Dawley rats were divided into three groups of 20 rats each: the sham group, which underwent only laparotomy; the uraemia group, which underwent 5/6 nephrectomy; and the uraemia + probiotic group, which underwent 5/6 nephrectomy and daily intragastric administration of B. animalis subsp. lactis Bi-07 for 4 weeks. Bacterial translocation was evaluated by polymerase chain reaction amplification of the green fluorescent protein (GFP) gene from oral GFP-labelled Escherichia coli in the peripheral blood, mesenteric lymph nodes, liver, and spleen. Intestinal permeability, plasma inflammatory biomarker levels, and endotoxin levels were measured. Jejunum, ileum, and colon specimens were removed for histological examination. RESULTS: Uraemic rats exhibited a significantly higher incidence of bacterial translocation (70%) than did sham rats (10%). Probiotic treatment resulted in a decrease in bacterial translocation (20%). Intestinal permeability, inflammatory biomarker levels, and endotoxin levels in uraemic rats were significantly higher than those in the sham group. After treatment with the probiotic, inflammatory biomarker levels significantly decreased. Uraemic rats demonstrated superficial mucosal erosion and inflammatory cell infiltration in the small intestine, and administration of the probiotic alleviated these lesions. CONCLUSION: The probiotic B. animalis subsp. lactis Bi-07 alleviate bacterial translocation and ameliorate microinflammation through the recovery of intestinal mucosal integrity. PMID- 24787733 TI - The protective effect of dietary Arthrospira (Spirulina) maxima against mutagenicity induced by benzo[alpha]pyrene in mice. AB - Benzo[alpha]pyrene (B[alpha]P) was used to test the possible antimutagenic effects of Arthrospira (Spirulina) maxima (SP) on male and female mice. SP was orally administered at 0, 200, 400, or 800 mg/kg of body weight to animals of both sexes for 2 weeks before starting the B[alpha]P (intraperitoneal injection) at 125 mg/kg of body weight for 5 consecutive days. For the male dominant lethal test, each male was caged with two untreated females per week for 3 weeks. For the female dominant lethal test, each female was caged for 1 week with one untreated male. All the females were evaluated 13-15 days after mating for incidence of pregnancy, total corpora lutea, total implants and pre- and postimplant losses. SP protected from B[alpha]P-induced pre- and postimplant losses in the male dominant lethal test, and from B[alpha]P-induced postimplantation losses in treated females. Moreover, SP treatment significantly reduced the detrimental effect of B[alpha]P on the quality of mouse semen. Our results illustrate the protective effects of SP in relation to B[alpha]P-induced genetic damage to germ cells. We conclude that SP, owing mainly to the presence of phycocyanin, could be of potential clinical interest in cancer treatment or prevention of relapse. PMID- 24787734 TI - Simultaneous deletion of floxed genes mediated by CaMKIIalpha-Cre in the brain and in male germ cells: application to conditional and conventional disruption of Goalpha. AB - The Cre/LoxP system is a well-established approach to spatially and temporally control genetic inactivation. The calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKIIalpha) promoter limits expression to specific regions of the forebrain and thus has been utilized for the brain-specific inactivation of the genes. Here, we show that CaMKIIalpha-Cre can be utilized for simultaneous inactivation of genes in the adult brain and in male germ cells. Double transgenic Rosa26(+/stop-lacZ)::CaMKIIalpha-Cre(+/Cre) mice generated by crossing CaMKIIalpha-Cre(+/Cre) mice with floxed ROSA26 lacZ reporter (Rosa26(+/stop lacZ)) mice exhibited lacZ expression in the brain and testis. When these mice were mated to wild-type females, about 27% of the offspring were whole body blue by X-gal staining without inheriting the Cre transgene. These results indicate that recombination can occur in the germ cells of male Rosa26(+/stop lacZ)::CaMKIIalpha-Cre(+/Cre) mice. Similarly, when double transgenic Gnao(+/f)::CaMKIIalpha-Cre(+/Cre) mice carrying a floxed Go-alpha gene (Gnao(f/f)) were backcrossed to wild-type females, approximately 22% of the offspring carried the disrupted allele (Gnao(Delta)) without inheriting the Cre transgene. The Gnao(Delta/Delta) mice closely resembled conventional Go-alpha knockout mice (Gnao(-/-)) with respect to impairment of their behavior. Thus, we conclude that CaMKIIalpha-Cre mice afford recombination for both tissue- and time controlled inactivation of floxed target genes in the brain and for their permanent disruption. This work also emphasizes that extra caution should be exercised in utilizing CaMKIIalpha-Cre mice as breeding pairs. PMID- 24787735 TI - Patterns of genome-wide VDR locations. AB - The genome-wide analysis of the binding sites of the transcription factor vitamin D receptor (VDR) is essential for a global appreciation the physiological impact of the nuclear hormone 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). Genome-wide analysis of lipopolysaccharide (LPS)-polarized THP-1 human monocytic leukemia cells via chromatin immunoprecipitation sequencing (ChIP-seq) resulted in 1,318 high-confidence VDR binding sites, of which 789 and 364 occurred uniquely with and without 1,25(OH)2D3 stimulation, while only 165 were common. We re-analyzed five public VDR ChIP-seq datasets with identical peak calling settings (MACS, version 2) and found, using a novel consensus summit identification strategy, in total 23,409 non-overlapping VDR binding sites, 75% of which are unique within the six analyzed cellular models. LPS-differentiated THP-1 cells have 22% more genomic VDR locations than undifferentiated cells and both cell types display more overlap in their VDR locations than the other investigated cell types. In general, the intersection of VDR binding profiles of ligand-stimulated cells is higher than those of unstimulated cells. De novo binding site searches and HOMER screening for binding motifs formed by direct repeats spaced by three nucleotides (DR3) suggest for all six VDR ChIP-seq datasets that these sequences are found preferentially at highly ligand responsive VDR loci. Importantly, all VDR ChIP seq datasets display the same relationship between the VDR occupancy and the percentage of DR3-type sequences below the peak summits. The comparative analysis of six VDR ChIP-seq datasets demonstrated that the mechanistic basis for the action of the VDR is independent of the cell type. Only the minority of genome wide VDR binding sites contains a DR3-type sequence. Moreover, the total number of identified VDR binding sites in each ligand-stimulated cell line inversely correlates with the percentage of peak summits with DR3 sites. PMID- 24787736 TI - Spread of viral infection to family members from influenza patients treated with a neuraminidase inhibitor. AB - We compared the incidence rates of household secondary infection among influenza patients prescribed laninamivir, oseltamivir, or zanamivir (neuraminidase inhibitors), based on health-insurance claims data owned by Japan Medical Data Center (JMDC) which was consisting of medical information on patients who were prescribed an anti-influenza drug and their family members between October 2010 and July 2011. The date when an index case patient was prescribed laninamivir, oseltamivir or zanamivir for the first time was defined as "Day 1". If other members in the same family were prescribed laninamivir, oseltamivir, zanamivir, or peramivir during Days 3-8, we assumed any household secondary infection had occurred. The incidence rate was 11.0%, 14.3%, and 11.6% in index case patients prescribed laninamivir, oseltamivir, and zanamivir, respectively. The results of the logistic regression analysis revealed a significant difference between laninamivir and oseltamivir, while no significant difference was observed between laninamivir and zanamivir. PMID- 24787737 TI - Efficacy and safety of levofloxacin in patients with bacterial pneumonia evaluated according to the new "Clinical Evaluation Methods for New Antimicrobial Agents to Treat Respiratory Infections (Second Version)". AB - The guideline for the "Clinical Evaluation Methods for New Antimicrobial Agents to Treat Respiratory Infections (Second Version)," published by the Japanese Society of Chemotherapy in January 2012, was proposed to achieve consistency with FDA guidelines based on the concept of clinical evaluation used in Japan. We assessed the clinical efficacy of levofloxacin (LVFX) in patients with bacterial pneumonia according to this new set of guidelines for the first time. The clinical efficacy of LVFX in patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) at the test of cure (TOC) was 87.5% (56/64) and 85.7% (6/7), respectively, with an overall efficacy of 87.3% (62/71). The clinical efficacy of LVFX at TOC was as follows: intravenous 81.5% (22/27), oral 88.9% (24/27), switchover from intravenous to oral administration 100% (10/10), respectively. The bacterial eradication rate in the patients with CAP and HCAP and overall efficacy at the end of therapy (EOT) was 95.3% (41/43), 100.0% (4/4) and 95.7% (45/47), respectively. The frequent causative bacterial strains included Streptococcus pneumoniae (18), Haemophilus influenzae (14) and Moraxella catarrhalis (6). The incidence of adverse reactions in the patients whose safety was evaluated was 15.7% (14/89), similar to that previously reported. The clinical efficacy of LVFX at the early phase, EOT and TOC of CAP, as assessed according to the new and former guidelines, was 70.4% (38/54) and 27.8% (15/54), 87.0% (60/69) and 79.1% (53/67), 87.5% (56/64) and 88.1% (59/67), respectively, with no significant differences. Therefore, the new efficacy evaluation method can be used in exchange for the former evaluation method. PMID- 24787738 TI - Efficacy and safety of intravenous azithromycin followed by oral azithromycin for the treatment of acute pelvic inflammatory disease and perihepatitis in Japanese women. AB - Pelvic inflammatory disease (PID) is mainly caused by ascending infection from the vaginal flora including the sexually transmitted organisms, Neisseria gonorrhoeae and Chlamydia trachomatis, and lower genital tract endogenous anaerobes, leading to serious consequences including infertility and ectopic pregnancy. To evaluate the efficacy and safety of azithromycin in the treatment of PID that requires initial intravenous therapy, we conducted a multicenter, unblinded, non-comparative phase 3 trial. Intravenous azithromycin (500 mg, once daily) for 1 or 2 days followed by oral azithromycin (250 mg once daily) to complete a total of 7 days treatment was administered to 60 Japanese women with acute PID. The clinical and bacteriological responses were assessed at the end of treatment, and on Days 15 and 29. The most commonly detected baseline causative pathogens were C. trachomatis (12 strains), Prevotella bivia (10 strains), Streptococcus agalactiae (7 strains), N. gonorrhoeae and Peptostreptococcus anaerobius (6 strains each). The clinical success rate on Day 15 was 94.1% (48/51 subjects including perihepatitis). The clinical efficacy and bacterial eradication rates against C. trachomatis and N. gonorrhoeae (including 2 quinolone-resistant strains) were both 100%. Common treatment-related adverse events were diarrhoea, injection site pain, and nausea. All adverse events were mild or moderate in severity. Azithromycin intravenous-to-oral switch therapy demonstrated excellent clinical and bacteriological effects for PID caused by various etiologic agents including quinolone-resistant strains and strains with low susceptibility to azithromycin at in vitro testing. The therapy was well tolerated in the treatment of PID in Japanese women. REGISTRATION NUMBER: NCT00871494. PMID- 24787739 TI - The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis. AB - EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF) leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism. PMID- 24787740 TI - Observations and models of highly intermittent phytoplankton distributions. AB - The measurement of phytoplankton distributions in ocean ecosystems provides the basis for elucidating the influences of physical processes on plankton dynamics. Technological advances allow for measurement of phytoplankton data to greater resolution, displaying high spatial variability. In conventional mathematical models, the mean value of the measured variable is approximated to compare with the model output, which may misinterpret the reality of planktonic ecosystems, especially at the microscale level. To consider intermittency of variables, in this work, a new modelling approach to the planktonic ecosystem is applied, called the closure approach. Using this approach for a simple nutrient phytoplankton model, we have shown how consideration of the fluctuating parts of model variables can affect system dynamics. Also, we have found a critical value of variance of overall fluctuating terms below which the conventional non-closure model and the mean value from the closure model exhibit the same result. This analysis gives an idea about the importance of the fluctuating parts of model variables and about when to use the closure approach. Comparisons of plot of mean versus standard deviation of phytoplankton at different depths, obtained using this new approach with real observations, give this approach good conformity. PMID- 24787741 TI - Mitochondrial changes in platelets are not related to those in skeletal muscle during human septic shock. AB - Platelets can serve as general markers of mitochondrial (dys)function during several human diseases. Whether this holds true even during sepsis is unknown. Using spectrophotometry, we measured mitochondrial respiratory chain biochemistry in platelets and triceps brachii muscle of thirty patients with septic shock (within 24 hours from admission to Intensive Care) and ten surgical controls (during surgery). Results were expressed relative to citrate synthase (CS) activity, a marker of mitochondrial density. Patients with septic shock had lower nicotinamide adenine dinucleotide dehydrogenase (NADH)/CS (p = 0.015), complex I/CS (p = 0.018), complex I and III/CS (p<0.001) and complex IV/CS (p = 0.012) activities in platelets but higher complex I/CS activity (p = 0.021) in triceps brachii muscle than controls. Overall, NADH/CS (r2 = 0.00; p = 0.683) complex I/CS (r(2) = 0.05; p = 0.173), complex I and III/CS (r(2) = 0.01; p = 0.485), succinate dehydrogenase (SDH)/CS (r(2) = 0.00; p = 0.884), complex II and III/CS (r(2) = 0.00; p = 0.927) and complex IV/CS (r(2) = 0.00; p = 0.906) activities in platelets were not associated with those in triceps brachii muscle. In conclusion, several respiratory chain enzymes were variably inhibited in platelets, but not in triceps brachii muscle, of patients with septic shock. Sepsis-induced mitochondrial changes in platelets do not reflect those in other organs. PMID- 24787742 TI - Automatic and reproducible positioning of phase-contrast MRI for the quantification of global cerebral blood flow. AB - Phase-Contrast MRI (PC-MRI) is a noninvasive technique to measure blood flow. In particular, global but highly quantitative cerebral blood flow (CBF) measurement using PC-MRI complements several other CBF mapping methods such as arterial spin labeling and dynamic susceptibility contrast MRI by providing a calibration factor. The ability to estimate blood supply in physiological units also lays a foundation for assessment of brain metabolic rate. However, a major obstacle before wider applications of this method is that the slice positioning of the scan, ideally placed perpendicular to the feeding arteries, requires considerable expertise and can present a burden to the operator. In the present work, we proposed that the majority of PC-MRI scans can be positioned using an automatic algorithm, leaving only a small fraction of arteries requiring manual positioning. We implemented and evaluated an algorithm for this purpose based on feature extraction of a survey angiogram, which is of minimal operator dependence. In a comparative test-retest study with 7 subjects, the blood flow measurement using this algorithm showed an inter-session coefficient of variation (CoV) of 4.07 +/- 3.03%. The Bland-Altman method showed that the automatic method differs from the manual method by between -8% and 11%, for 95% of the CBF measurements. This is comparable to the variance in CBF measurement using manually-positioned PC MRI alone. In a further application of this algorithm to 157 consecutive subjects from typical clinical cohorts, the algorithm provided successful positioning in 89.7% of the arteries. In 79.6% of the subjects, all four arteries could be planned using the algorithm. Chi-square tests of independence showed that the success rate was not dependent on the age or gender, but the patients showed a trend of lower success rate (p = 0.14) compared to healthy controls. In conclusion, this automatic positioning algorithm could improve the application of PC-MRI in CBF quantification. PMID- 24787743 TI - The effect of XPD polymorphisms on digestive tract cancers risk: a meta-analysis. AB - BACKGROUND: The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer. METHODS: We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. RESULTS: The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01-1.24, P = 0.029, P heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01-1.63, P = 0.045, P heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous. CONCLUSIONS: Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations. PMID- 24787745 TI - The effect of acupressure application on chemotherapy-induced nausea, vomiting, and anxiety in patients with breast cancer. AB - OBJECTIVE: The purpose of this study was to determine the effect of acupressure applied to the pericardium 6 (P6 or neiguan) acupuncture point on chemotherapy induced nausea, vomiting, and anxiety in patients with breast cancer. METHOD: The study was conducted using a quasi-experimental model with a control group. It included a total of 64 patients with stages 1-3 breast cancer who received cycle two and more advanced chemotherapy in an ambulatory chemotherapy unit. There were 32 patients in the experimental group and 32 patients in the control group. Acupressure was applied to the P6 acupuncture point of patients in the experimental group with the help of a wristband. A Patient Information Form, the Beck Anxiety Inventory, and the Index of Nausea, Vomiting and Retching were employed to collect the data. RESULTS: It was determined that the mean nausea, vomiting, and retching scores, the total (experience, occurrence, and distress) scores, and the mean anxiety scores for patients to whom acupressure was applied at the P6 acupuncture point were statistically significantly lower compared with the scores of patients in the control group. SIGNIFICANCE OF RESULTS: The efficacy of applying acupressure was demonstrated. We determined that applying acupressure at the P6 point is effective in decreasing chemotherapy-induced nausea, vomiting, and anxiety in patients with breast cancer. Further research with more subjects is needed. PMID- 24787744 TI - Particle deposition in a child respiratory tract model: in vivo regional deposition of fine and ultrafine aerosols in baboons. AB - To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols ([d16-d84], equal to [0.15 um-0.5 um], [0.25 um 1 um], or [1 um-9 um]). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 um-9 um] aerosol (72% +/- 17%). The [0.15 um-0.5 um] aerosol was associated almost exclusively with thoracic region deposition (84% +/- 4%). Airborne particles in the range of [0.25 um-1 um] showed an intermediate deposition pattern, with 49% +/- 8% in the extrathoracic region and 51% +/- 8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 um-9 um] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes. PMID- 24787746 TI - No catalyst addition and highly efficient dissociation of H2O for the reduction of CO2 to formic acid with Mn. AB - The "greenhouse effect" caused by the increasing atmospheric CO2 level is becoming extremely serious, and thus, the reduction of CO2 emissions has become an extensive, urgent, and long-term task. The dissociation of water for CO2 reduction with solar energy is regarded as one of the most promising methods for the sustainable development of the environment and energy. However, a high solar to-fuel efficiency keeps a great challenge. In this work, the first observation of a highly effective, highly selective, and robust system of dissociating water for the reduction of carbon dioxide (CO2) into formic acid with metallic manganese (Mn) is reported. A considerably high formic acid yield of more than 75% on a carbon basis from NaHCO3 was achieved with 98% selectivity in the presence of simple commercially available Mn powder without the addition of any catalyst, and the proposed process is exothermic. Thus, this study may provide a promising method for the highly efficient dissociation of water for CO2 reduction by combining solar-driven thermochemistry with the reduction of MnO into Mn. PMID- 24787747 TI - Smartphone interventions for long-term health management of chronic diseases: an integrative review. AB - INTRODUCTION: Long-term health management is challenging for the rapidly growing number of patients with chronic diseases. Smartphone interventions offer promising solutions. This article presents features of smartphone interventions for long-term chronic condition management, illustrating how these applications benefit patients with chronic diseases. MATERIALS AND METHODS: Systematic searches for smartphone health interventions were conducted in five publication databases. Articles were included only if (1) the smartphone application (app) was exclusively developed for patients with chronic diseases and (2) the article incorporated a defined outcome measurement to evaluate the effects of the implemented intervention. Sixteen articles were included in the final review, including studies in diabetes, mental health problems, overweight, cancer, and chronic obstructive pulmonary disease. RESULTS: These studies found that the smartphone intervention was a completely or at least partially effective tool to assist in managing some chronic diseases. With the help of health-related smartphone apps, patients with chronic conditions (1) felt secure in the knowledge that their illnesses were closely monitored, (2) participated in their own health management more effectively, and (3) felt that they had not been forgotten by their doctors and were taken good care of even outside the hospital/clinic. CONCLUSIONS: However, there are limited smartphone apps for the long-term health management of chronic diseases. More smartphone apps need to be developed to help people manage chronic diseases. PMID- 24787748 TI - Changes in leptin production/secretion induced in response to septic doses of lipopolysaccharides in gonadally intact and ovariectomized female rats. AB - In addition to its role as a regulator of energy homeostasis, leptin plays a pivotal role in certain immune/inflammatory responses. It has been reported that the synthesis and secretion of leptin are increased during immune stress in male experimental animals, whereas the changes in leptin synthesis and secretion induced by immune stress in females have not been fully elucidated. In this study, we found that during lipopolysaccharide (LPS)-induced immune stress the synthesis and secretion of leptin were decreased in gonadally intact female rats, but increased in ovariectomized rats. However, the LPS-induced increase in the serum leptin level observed in the ovariectomized rats was partially attenuated by estradiol supplementation. These results suggest that the changes in leptin synthesis and secretion induced in response to immune stress in females are affected by the gonadal steroid milieu and that estradiol and other factors are involved in these alterations. PMID- 24787749 TI - Seeking high reliability in primary care: Leadership, tools, and organization. AB - BACKGROUND: Leaders in health care increasingly recognize that improving health care quality and safety requires developing an organizational culture that fosters high reliability and continuous process improvement. For various reasons, a reliability-seeking culture is lacking in most health care settings. Developing a reliability-seeking culture requires leaders' sustained commitment to reliability principles using key mechanisms to embed those principles widely in the organization. PURPOSE: The aim of this study was to examine how key mechanisms used by a primary care practice (PCP) might foster a reliability seeking, system-oriented organizational culture. METHODOLOGY: A case study approach was used to investigate the PCP's reliability culture. The study examined four cultural artifacts used to embed reliability-seeking principles across the organization: leadership statements, decision support tools, and two organizational processes. To decipher their effects on reliability, the study relied on observations of work patterns and the tools' use, interactions during morning huddles and process improvement meetings, interviews with clinical and office staff, and a "collective mindfulness" questionnaire. The five reliability principles framed the data analysis. FINDINGS: Leadership statements articulated principles that oriented the PCP toward a reliability-seeking culture of care. Reliability principles became embedded in the everyday discourse and actions through the use of "problem knowledge coupler" decision support tools and daily "huddles." Practitioners and staff were encouraged to report unexpected events or close calls that arose and which often initiated a formal "process change" used to adjust routines and prevent adverse events from recurring. Activities that foster reliable patient care became part of the taken-for-granted routine at the PCP. PRACTICE IMPLICATIONS: The analysis illustrates the role leadership, tools, and organizational processes play in developing and embedding a reliable-seeking culture across an organization. Progress toward a reliability-seeking, system oriented approach to care remains ongoing, and movement in that direction requires deliberate and sustained effort by committed leaders in health care. PMID- 24787750 TI - How best practices are copied, transferred, or translated between health care facilities: A conceptual framework. AB - INTRODUCTION: In spite of significant investment in quality programs and activities, there is a persistent struggle to achieve quality outcomes and performance improvements within the constraints and support of sociopolitical parsimonies. Equally, such constraints have intensified the need to better understand the best practice methods for achieving quality improvements in health care organizations over time.This study proposes a conceptual framework to assist with strategies for the copying, transferring, and/or translation of best practice between different health care facilities. PURPOSE: Applying a deductive logic, the conceptual framework was developed by blending selected theoretical lenses drawn from the knowledge management and organizational learning literatures. FINDINGS: The proposed framework highlighted that (a) major constraints need to be addressed to turn best practices into everyday practices and (b) double-loop learning is an adequate learning mode to copy and to transfer best practices and deuteron learning mode is a more suitable learning mode for translating best practice. We also found that, in complex organizations, copying, transferring, and translating new knowledge is more difficult than in smaller, less complex organizations. We also posit that knowledge translation cannot happen without transfer and copy, and transfer cannot happen without copy of best practices. Hence, an integration of all three learning processes is required for knowledge translation (copy best practice-transfer knowledge about best practice translation of best practice into new context). In addition, the higher the level of complexity of the organization, the more best practice is tacit oriented and, in this case, the higher the level of K&L capabilities are required to successfully copy, transfer, and/or translate best practices between organizations. PRACTICE IMPLICATIONS: The approach provides a framework for assessing organizational context and capabilities to guide copy/transfer/translation of best practices. A roadmap is provided to assist managers and practitioners to select appropriate learning modes for building success and positive systemic change. PMID- 24787752 TI - Analyzing personalized policies for online biometric verification. AB - Motivated by India's nationwide biometric program for social inclusion, we analyze verification (i.e., one-to-one matching) in the case where we possess similarity scores for 10 fingerprints and two irises between a resident's biometric images at enrollment and his biometric images during his first verification. At subsequent verifications, we allow individualized strategies based on these 12 scores: we acquire a subset of the 12 images, get new scores for this subset that quantify the similarity to the corresponding enrollment images, and use the likelihood ratio (i.e., the likelihood of observing these scores if the resident is genuine divided by the corresponding likelihood if the resident is an imposter) to decide whether a resident is genuine or an imposter. We also consider two-stage policies, where additional images are acquired in a second stage if the first-stage results are inconclusive. Using performance data from India's program, we develop a new probabilistic model for the joint distribution of the 12 similarity scores and find near-optimal individualized strategies that minimize the false reject rate (FRR) subject to constraints on the false accept rate (FAR) and mean verification delay for each resident. Our individualized policies achieve the same FRR as a policy that acquires (and optimally fuses) 12 biometrics for each resident, which represents a five (four, respectively) log reduction in FRR relative to fingerprint (iris, respectively) policies previously proposed for India's biometric program. The mean delay is [Formula: see text] sec for our proposed policy, compared to 30 sec for a policy that acquires one fingerprint and 107 sec for a policy that acquires all 12 biometrics. This policy acquires iris scans from 32-41% of residents (depending on the FAR) and acquires an average of 1.3 fingerprints per resident. PMID- 24787754 TI - Fabrication of vertical light emitting diode based on thermal deformation of nanoporous GaN and removable mechanical supporter. AB - A GaN vertical light emitting diode (LED) based on the novel lift-off method was demonstrated by high temperature regrowth over nanoporous (NP) GaN template formed by electrochemical (EC) etching. A two-step EC etching process was employed on a SiO2 patterned GaN surface to fabricate a nanoporous template with a controlled porosity profile, which enabled better structural stability than a single NP GaN. During the regrowth of LED structures, the high porosity GaN layer produced large coalesced voids due to the thermal deformation of nanopores. LED layers were then separated from the sapphire substrate and transferred to a Mo substrate by the removal of the SiO2 mechanical supporters that held the LED structure to suppress cracks and damage during the process. The vertical LEDs fabricated using this technique showed improved optical power emission as well as low series resistance. PMID- 24787755 TI - Factors limiting the enzymatic hydrolysis of wheat gluten. AB - The enzymatic hydrolysis of wheat gluten for the production of seasonings using mixtures of endo- and exopeptidases results in yields typically below 40%. Possible limiting parameters, such as an increasing product inhibition, autopeptidolysis of the enzymes, and lack of cleavage sites, were studied using novel peptidases from Flammulina velutipes or the commercial Flavourzyme preparation. Seven intermittent electrodialysis steps (10 g/L gluten and 10 kaU/mL) for the in situ removal of amino acids minimized the product inhibition. During 16 h, hydrolysis progressed nearly linearly. Compared to the batch control, a 3-fold yield of amino acids released was obtained indicating that an integrated product removal alleviates the problem of product inhibition. Autopeptidolysis, as shown using sodium dodecyl sulfate polyacrylamide gel electrophoresis and enzyme activity assays, was suppressed with increasing concentrations of competing gluten substrate. Peptidases of F. velutipes showed product inhibition only, whereas a combined effect of product inhibition and lack of cleavage sites was observed for Flavourzyme. PMID- 24787753 TI - Transcription control pathways decode patterned synaptic inputs into diverse mRNA expression profiles. AB - Synaptic plasticity requires transcription and translation to establish long-term changes that form the basis for long term memory. Diverse stimuli, such as synaptic activity and growth factors, trigger synthesis of mRNA to regulate changes at the synapse. The palette of possible mRNAs is vast, and a key question is how the cell selects which mRNAs to synthesize. To address this molecular decision-making, we have developed a biochemically detailed model of synaptic activity triggered mRNA synthesis. We find that there are distinct time-courses and amplitudes of different branches of the mRNA regulatory signaling pathways, which carry out pattern-selective combinatorial decoding of stimulus patterns into distinct mRNA subtypes. Distinct, simultaneously arriving input patterns that impinge on the transcriptional control network interact nonlinearly to generate novel mRNA combinations. Our model combines major regulatory pathways and their interactions connecting synaptic input to mRNA synthesis. We parameterized and validated the model by incorporating data from multiple published experiments. The model replicates outcomes of knockout experiments. We suggest that the pattern-selectivity mechanisms analyzed in this model may act in many cell types to confer the capability to decode temporal patterns into combinatorial mRNA expression. PMID- 24787756 TI - Like-charge attraction of molecular cations in water: subtle balance between interionic interactions and ionic solvation effect. AB - Despite strong electrostatic repulsion, like-charged ions in aqueous solution can effectively attract each other via ion-water interactions. In this paper we investigate such an effective interaction of like-charged ions in water by using the 3D-RISM-SCF method (i.e., electronic structure theory combined with three dimensional integral equation theory for molecular solvents). Free energy profiles are calculated at the CCSD(T) level for a series of molecular ions including guanidinium (Gdm(+)), alkyl-substituted ammonium, and aromatic amine cations. Polarizable continuum model (PCM) and mean-field QM/MM free energy calculations are also performed for comparison. The results show that the stability of like-charged ion pairs in aqueous solution is determined by a very subtle balance between interionic interactions (including dispersion and pi stacking interactions) and ionic solvation/hydrophobic effects and that the Gdm(+) ion has a rather favorable character for like-charge association among all the cations studied. Furthermore, we investigate the like-charge pairing in Arg Ala-Arg and Lys-Ala-Lys tripeptides in water and show that the Arg-Arg pair has a contact free-energy minimum of about -6 kcal/mol. This result indicates that arginine pairing observed on protein surfaces and interfaces is stabilized considerably by solvation effects. PMID- 24787757 TI - Caudate dopaminergic denervation and visual hallucinations: evidence from a 123I FP-CIT SPECT study. AB - OBJECTIVE: The pathogenesis of visual hallucinations (VHs) in Parkinson's disease (PD) has been considered multifactorial. In the pathophysiology of VHs a combination of impaired visual processing and attention has been reported. Imaging studies evidenced a role of the primary visual system and visual association areas as well as a dysfunctional activation of frontal areas in the occurrence of VHs. Due to the functional connections between basal ganglia and frontal areas, a role of basal ganglia and of the fronto-striatal circuits in the pathogenesis of VHs may be postulated. Aim of this study is to unveil whether a presynaptic dopamine deficiency at baseline may predict the development of VHs. METHODS: A group of 18 non demented PD patients with VHs was matched with 18 non demented PD patients without VHs as regards age of onset of disease, disease duration and severity and levodopa equivalent dose. We retrospectively analyzed the (123)I-FP CIT SPECT performed on the two groups at the onset of their disease. The striatal uptake values in the two groups were examined, in order to evaluate nigrostriatal differences between the groups with different behavioral phenotype. RESULTS: The group of patients with VHs had a significant reduction (p < 0.05) in right caudate uptake values at baseline when compared with patients without VHs. No significant differences were found between the groups regarding left caudate and putaminal uptake values. CONCLUSIONS: The frontal impairment reported in PD patients with VHs may be due to a right caudate dysfunction, as it is connected to the frontal brain areas via neuronal loops. PMID- 24787758 TI - Surface EMG activity during REM sleep in Parkinson's disease correlates with disease severity. AB - OBJECTIVES: Over 40% of individuals with Parkinson's disease (PD) have rapid eye movement sleep behavior disorder (RBD). This is associated with excessive sustained (tonic) or intermittent (phasic) muscle activity instead of the muscle atonia normally seen during REM sleep. We examined characteristics of manually quantitated surface EMG activity in PD to ascertain whether the extent of muscle activity during REM sleep is associated with specific clinical features and measures of disease severity. METHODS: In a convenience sample of outpatients with idiopathic PD, REM sleep behavior disorder was diagnosed based on clinical history and polysomnogram, and severity was measured using the RBD sleep questionnaire. Surface EMG activity in the mentalis, extensor muscle group of the forearms, and anterior tibialis was manually quantitated. Percentage of REM time with excessive tonic or phasic muscle activity was calculated and compared across PD and RBD characteristics. RESULTS: Among 65 patients, 31 had confirmed RBD. In univariate analyses, higher amounts of surface EMG activity were associated with longer PD disease duration (srho = 0.34; p = 0.006) and greater disease severity (p < 0.001). In a multivariate regression model, surface EMG activity was significantly associated with RBD severity (p < 0.001) after adjustment for age, PD disease duration, PD severity and co-morbid sleep abnormalities. CONCLUSION: Surface EMG activity during REM sleep was associated with severity of both PD and RBD. This measure may be useful as a PD biomarker and, if confirmed, may aid in determining which PD patients warrant treatment for their dream enactment to reduce risk of injury. PMID- 24787759 TI - Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity? AB - BACKGROUND: We describe the clinical characteristics of a Swedish family with autosomal dominant cerebellar ataxia, sensory and autonomic neuropathy, additional neurological features and unknown genetic cause. METHODS: Fourteen affected family members were identified. Their disorder was characterized by neurological examination, MRI, electroneurography, electromyography, MIBG scintigraphy, and tilt-testing. RESULTS: The disorder presented as a balance and gait disturbance starting between 16 and 47 years of age. Cerebellar ataxia progressed slowly over the course of decades, and MRI showed mild to moderate cerebellar atrophy. Sensory axonal polyneuropathy was the most prominent additional feature and occurred in all patients examined. Autonomic neuropathy caused pronounced orthostatic dysregulation in at least four patients. Several affected members showed muscle wasting, and mild upper or lower motor neuron signs were documented. Patients had no nystagmus but slow or hypometric horizontal saccades and ocular motor apraxia. Cognition remained unimpaired, and there were no non-neurological disease manifestations. The disorder affected men and women in successive generations in a pattern compatible with autosomal dominant inheritance without evidence of anticipation. A second family where 7 members had very similar symptoms was identified and its origin traced back to the same village in southern Sweden as that of the first family's ancestors. All relevant known genetic causes of cerebellar ataxia were excluded by a novel next generation sequencing approach. CONCLUSION: We present two probably related Swedish families with a characteristic and novel clinical syndrome of cerebellar ataxia and sensory polyneuropathy. The study serves as a basis for the mapping of the underlying genetic cause. PMID- 24787760 TI - Troponin I and NT-proBNP and the association of systolic blood pressure with outcomes in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study. AB - BACKGROUND: There is uncertainty regarding treatment of hypertension in hemodialysis patients due to the observed J-shaped association between blood pressure (BP) and death. We hypothesized that this association reflects confounding by cardiovascular disease (CVD) and that stratification by CVD biomarkers, cardiac troponin I (cTnI) and N-terminal fragment of prohormone brain natriuretic peptide (NT-proBNP), might change this association. STUDY DESIGN: National prospective cohort study. SETTING & PARTICIPANTS: 446 incident hemodialysis patients. PREDICTOR: Predialysis systolic BP. OUTCOMES: Mortality (all-cause and CVD) and first CVD event assessed using Cox regression adjusted for demographics, comorbid conditions, and clinical factors. MEASUREMENTS: Participants with cTnI level >=0.1 ng/mL or NT-proBNP level >=9,252 pg/mL were classified as the high-biomarker group; remaining participants were included in the low-biomarker group. RESULTS: Participants in the high-biomarker group (n=138 [31%]) were older (61 vs. 57 years) and had a higher prevalence of CVD (67% vs. 23%), but similar baseline BPs (152 vs. 153 mm Hg). There were 323 deaths (143 from CVD) and 271 CVD events. The high-biomarker group had a higher risk of mortality than the low-biomarker group (HR, 1.75; 95% CI, 1.37-2.24). The association between BP and outcomes differed between the 2 biomarker groups (P for interaction=0.01, 0.2, and 0.07 for all-cause mortality, CVD mortality, and first CVD event, respectively). In the low-biomarker group, BP was associated with greater risk of outcomes: HR per 10 mm Hg higher BP was 1.07 (95% CI, 1.01 1.14), 1.10 (95% CI, 0.96-1.25), and 1.04 (95% CI, 0.96-1.13) for all-cause mortality, CVD mortality, and first CVD event, respectively. Importantly, lower BP was not associated with increased risk of outcomes in stratified models, including for those in high biomarker group. LIMITATIONS: BP measurements not standardized. CONCLUSIONS: The observed J-shaped association between BP and outcomes in hemodialysis patients is due to confounding by subclinical CVD. A stratification approach based on cTnI and NT-proBNP levels has the potential to inform BP treatment in hemodialysis patients. PMID- 24787761 TI - Exercise capacity in polycystic kidney disease. AB - BACKGROUND: Reports about exercise performance in autosomal dominant polycystic kidney disease (ADPKD) are scarce. We aimed to evaluate exercise capacity and levels of nitric oxide and asymmetric dimethylarginine (ADMA) in normotensive patients with ADPKD. STUDY DESIGN: Prospective controlled cohort study. SETTING & PARTICIPANTS: 26 patients with ADPKD and 30 non-ADPKD control participants (estimated glomerular filtration rate>60 mL/min/1.73 m2, aged 19-39 years, and blood pressure [BP]<140/85 mmHg). We excluded smokers, obese people, and individuals with associated diseases. PREDICTOR: ADPKD versus control. OUTCOMES: Exercise capacity and nitric oxide and ADMA levels in response to exercise. MEASUREMENTS: Cardiopulmonary exercise testing and serum and urinary nitric oxide, plasma ADMA, and BP levels before and after exercise. RESULTS: Mean basal systolic and diastolic BP, estimated glomerular filtration rate, and age did not differ between the ADPKD and control groups (116+/-12 vs. 110+/-11 mmHg, 76+/-11 vs 71+/-9 mmHg, 113+/-17 vs. 112+/-9.6 mL/min/1.73 m2, and 30+/-8 vs. 28.9+/-7.3 years, respectively). Peak oxygen uptake and anaerobic threshold were significantly lower in the ADPKD group than in controls (22.2+/-3.3 vs. 31+/-4.8 mL/kg/min [P<0.001] and 743.6+/-221 vs. 957.4+/-301 L/min [P=0.01], respectively). Postexercise serum and urinary nitric oxide levels in patients with ADPKD were not significantly different from baseline (45+/-5.1 vs. 48.3+/ 4.6 MUmol/L and 34.7+/-6.5 vs. 39.8+/-6.8 MUmol/mg of creatinine, respectively), contrasting with increased postexercise values in controls (63.1+/-1.9 vs. 53.9+/ 3.1 MUmol/L [P=0.01] and 61.4+/-10.6 vs. 38.7+/-5.6 MUmol/mg of creatinine [P=0.01], respectively). Similarly, whereas postexercise ADMA level did not change in the ADPKD group compared to those at rest (0.47+/-0.04 vs. 0.45+/-0.02 MUmol/L [P=0.6]), it decreased in controls (0.39+/-0.02 vs. 0.47+/-0.02 MUmol/L [P=0.006]), as expected. A negative correlation between nitric oxide and ADMA levels after exercise was found in only the control group (r = -0.60; P<0.01). LIMITATIONS: Absence of measurements of flow-mediated dilatation and oxidative status. CONCLUSIONS: We found lower aerobic capacity in young normotensive patients with ADPKD with preserved kidney function and inadequate responses of nitric oxide and ADMA levels to acute exercise, suggesting the presence of early endothelial dysfunction in this disease. PMID- 24787762 TI - Impact of estimated GFR reporting on late referral rates and practice patterns for end-stage kidney disease patients: a multilevel logistic regression analysis using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). AB - BACKGROUND: Late referral for renal replacement therapy (RRT) leads to worse outcomes. In 2005, estimated glomerular filtration rate (eGFR) reporting began in Australasia, with an aim of substantially increasing earlier disease detection. STUDY DESIGN: Observational cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data. SETTING & PARTICIPANTS: All patients commencing RRT in Australasia between January 1, 1999, and December 31, 2010. We excluded the period between December 31, 2004, and January 1, 2007, to allow for practice change. FACTOR: Introduction of eGFR reporting. OUTCOMES: Primary outcome was late referral defined as commencing RRT within 3 months of nephrology referral. Secondary outcomes included initial RRT modality and prepared access at hemodialysis therapy initiation. MEASUREMENTS: Late referral rates per era were determined and multilevel logistic regression was used to identify late referral predictors. RESULTS: We included 25,009 patients. Overall, 3,433 (25.3%) patients were referred late in the pre-eGFR era compared with 2,464 (21.6%) in the post-eGFR era, for an absolute reduction of 3.7% (95% CI, 2.7% 4.8%; P<0.001). After adjustments for age, body mass index, race, comorbid conditions, and primary kidney disease, adjusted late referral rates were 25.8% (95% CI, 23.3%-28.3%) and 21.8% (95% CI, 19.2%-24.4%) in the pre- and post-eGFR eras, respectively, for a difference of 4.0% (95% CI, 1.2%-6.8%; P=0.005). Late referral risk was attenuated significantly post-eGFR reporting (OR, 1.30; 95% CI, 1.12-1.51) compared to pre-eGFR reporting (OR, 2.15; 95% CI, 1.88-2.46) for indigenous patients. Late referral rates decreased for older patients but increased slightly for younger patients (P=0.001 for interaction between age and era). There was no impact on initial RRT modality or prepared access rates at hemodialysis therapy initiation between eras. LIMITATIONS: Residual confounding could not be excluded. CONCLUSIONS: eGFR reporting was associated with small reductions in late referral, but more than 1 in 5 patients are still referred late. Other initiatives to increase timely referral warrant investigation. PMID- 24787764 TI - Calciphylaxis: a rare but fatal delayed complication of Roux-en-Y gastric bypass surgery. AB - Gastric bypass is a commonly used surgical procedure that has shown impressive health benefits for patients with morbid obesity. However, mineral bone abnormalities (hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism) and micronutrient (e.g., iron) deficiencies are common complications after gastric bypass surgery due to alterations in the digestive anatomy. These abnormalities, their treatments, and a number of other factors associated with obesity can set up a perfect storm to induce calciphylaxis, a rare but highly fatal condition with severe comorbid conditions. We present a fatal case of nonuremic calciphylaxis coincident with symptomatic hypocalcemia in a morbidly obese man with a history of Roux-en-Y gastric bypass surgery. PMID- 24787766 TI - Outcomes for professional health care chaplaincy: an international call to action. PMID- 24787763 TI - Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis. AB - BACKGROUND: It is controversial whether proteinuria is a valid surrogate end point for randomized trials in chronic kidney disease. STUDY DESIGN: Meta analysis of individual patient-level data. SETTING & POPULATION: Individual patient data for 9,008 patients from 32 randomized trials evaluating 5 intervention types. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least 1 further year of follow-up for the clinical outcome. PREDICTOR: Early change in proteinuria. OUTCOMES: Doubling of serum creatinine level, end-stage renal disease, or death. RESULTS: Early decline in proteinuria was associated with lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from -7.0% (95%CI, -40.6% to 26.7%) to 43.9% (95%CI, 25.3% to 62.6%) across 5 intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the 2 end points agreeing for 4 of the 5 intervention types. The pooled treatment effects on both end points were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine whether differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies. LIMITATIONS: Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials. CONCLUSIONS: These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate end point, but do not provide sufficient evidence to establish its validity in all settings. PMID- 24787767 TI - Restore: the journey toward self-forgiveness: a randomized trial of patient education on self-forgiveness in cancer patients and caregivers. AB - The present study evaluated "Restore: The Journey Toward Self-Forgiveness," a brief psycho-spiritual curriculum for encouraging self-forgiveness. This was a randomized, wait-list controlled trial including 83 cancer patients and caregivers. Restore encourages self-acceptance, self-improvement, and commitment using prayer/meditation, reflection, and expressive writing in a workbook format. Measures of self-forgiveness, acceptance, self-improvement, and optimism/pessimism were collected before and after participation. Using Analysis of Covariance to control initial levels, post-session levels showed that Restore participants scored higher than wait-list controls on self-forgiveness (F(1,78) = 9.85, p < .001), acceptance (F(1,77) = 4.84, p < .05), and self-improvement (F(1,79) = 5.28, p < .05) and lower than wait-list controls on pessimism (F(1,77) = 5.01, p < .05). Changes in acceptance, self-improvement, and pessimism mediate the Restore effect on self-forgiveness (Beta = -.08, p < .05). This is the first known brief, evidence-based program for facilitating self-forgiveness in patients with self-forgiveness issues. PMID- 24787768 TI - Fundamentals of measurement in health care research. AB - This article discusses levels of measurement and their application to research and practice in health care. The concept of levels of measurement was codified in a seminal article by S. S. Stevens in 1946 that defined four levels of measurement: nominal scales, which label and classify cases (objects and individuals) and assign them to categories; ordinal scales, which rank cases on some attribute; interval scales, which have equal intervals for measuring attributes; and ratio scales, which have equal intervals and a natural zero point. The rules that apply to each level of measurement are presented and the mathematical operations that can be performed on them are explained. The similarities and differences among the four types of scales are discussed and examples of their use in health care and other contexts are described. PMID- 24787765 TI - Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. AB - NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, alphabeta and gammadelta T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1-6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12-US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family. PMID- 24787769 TI - Operational definitions in research on religion and health. AB - This article summarizes the historical development of operational definitions and discusses their application to research on religion and health, and their importance for research, in general. The diversity of religious concepts that have been operationalized is described, as well as the development of multi dimensional self-report measures of religion specifically designed for use in health research. The operational definitions of a variety of health concepts are also described, including the development of multi-dimensional self-report measures of health. Some of the most consistently observed salutary relationships between religion and health are mentioned. The rising interest in spirituality in health research is discussed, along with problems with the current operational definitions of spirituality in healthcare research. The levels of measurement used in various, operationally defined religious and healthcare concepts are highlighted. PMID- 24787771 TI - NMR based metabolomics reveals acute hippocampal metabolic fluctuations during cranial irradiation in murine model. AB - Cranial irradiation is widely used as a treatment modality or prophylactic treatment in cancer patients, but it is frequently related to neurocognitive impairment in cancer survivors. Though most of radiation-induced changes occur during early and late delayed phase of radiation sickness, recent reports have supported the evidence of impaired neurogenesis within 24-48 h of radiation exposure that may implicate changes in acute phase as well. Inspection of these acute changes could be considered important as they may have long lasting effect on cognitive development and functions. In the present study, (1)H NMR spectroscopy based metabolomic approach was used to obtain comprehensive information of hippocampus metabolic physiology during acute phase of radiation sickness in a mouse model for single dose 8 Gy cranial irradiation. The analysis demonstrated reduced metabolic activity in irradiated animals compared to controls, typically evident in citric acid cycle intermediates, glutamine/glutamate and ketone bodies metabolism thus providing strong indication that the hippocampus is metabolically responsive to radiation exposure. The data suggested reduced glucose utilization, altered intermediary and neurotransmitter metabolism in hippocampus tissue extract. To the best of our knowledge this is the first metabolomic study to document cranial irradiation induced acute metabolic changes using in vitro(1)H NMR spectroscopy. PMID- 24787772 TI - Dynamic optical frequency domain reflectometry. AB - We describe a dynamic Optical Frequency Domain Reflectometry (OFDR) system which enables real time, long range, acoustic sensing at high sampling rate. The system is based on a fast scanning laser and coherent detection scheme. Distributed sensing is obtained by probing the Rayleigh backscattered light. The system was tested by interrogation of a 10 km communication type single mode fiber and successfully detected localized impulse and sinusoidal excitations. PMID- 24787773 TI - Violet-green excitation for NIR luminescence of Yb3+ ions in Bi2O3-B2O3-SiO2 Ga2O3 glasses. AB - 60Bi(2)O(3)-20B(2)O(3)-10SiO(2)-10Ga(2)O(3) glasses doped with 1-9 mol% Yb(2)O(3) were prepared and investigated mainly on their violet-green excitation for the typical NIR emission of Yb(3+), generally excited in the NIR. Two violet excitation bands at 365 nm and 405 nm are related to Yb(2+) and Bi(3+). 465 nm excitation band and 480 nm absorption band in the blue-green are assigned to Bi(0) metal nanoparticles/grains. Yb-content-dependence of the excitation and absorption means that Bi(0) is the reduced product of Bi(3+), but greatly competed by the redox reaction of Yb(2+) <-> Yb(3+). It is proved that the violet green excitations result in the NIR emission of Yb(3+). On the energy transfer, the virtual level of Yb(3+)-Yb(3+) as well as Bi(0) dimers probably plays an important role. An effective and controllable way is suggested to achieve nano optical applications by Bi(0) metal nanoparticles/grains and Yb(3+). PMID- 24787774 TI - Hydrogen induced optically-active defects in silicon photonic nanocavities. AB - We demonstrate intense room temperature photoluminescence (PL) from optically active hydrogen- related defects incorporated into crystalline silicon. Hydrogen was incorporated into the device layer of a silicon on insulator (SOI) wafer by two methods: hydrogen plasma treatment and ion implantation. The room temperature PL spectra show two broad PL bands centered at 1300 and 1500 nm wavelengths: the first one relates to implanted defects while the other band mainly relates to the plasma treatment. Structural characterization reveals the presence of nanometric platelets and bubbles and we attribute different features of the emission spectrum to the presence of these different kind of defects. The emission is further enhanced by introducing defects into photonic crystal (PhC) nanocavities. Transmission electron microscopy analyses revealed that the isotropicity of plasma treatment causes the formation of a higher defects density around the whole cavity compared to the ion implantation technique, while ion implantation creates a lower density of defects embedded in the Si layer, resulting in a higher PL enhancement. These results further increase the understanding of the nature of optically active hydrogen defects and their relation with the observed photoluminescence, which will ultimately lead to the development of intense and tunable crystalline silicon light sources at room temperature. PMID- 24787775 TI - Broad-band Mach-Zehnder interferometers as high performance refractive index sensors: theory and monolithic implementation. AB - Broad-band Mach-Zehnder interferometry is analytically described and experimentally demonstrated as an analytical tool capable of high accuracy refractive index measurements over a wide spectral range. Suitable photonic engineering of the interferometer sensing and reference waveguides result in sinusoidal TE and TM spectra with substantially different eigen-frequencies. This allows for the instantaneous deconvolution of multiplexed polarizations and enables large spectral shifts and noise reduction through filtering in the Fourier Transform domain. Due to enhanced sensitivity, optical systems can be designed that employ portable spectrum analyzers with nm range resolution without compromising the sensor analytical capability. Practical detection limits in the 10(-6)-10(-7) RIU range are achievable, including temperature effects. Finally, a proof of concept device is realized on a silicon microphotonic chip that monolithically integrates broad-band light sources and single mode silicon nitride waveguides. Refractive index detection limits rivaling that of ring resonators with externally coupled laser sources are demonstrated. Sensitivities of 20 MUm/RIU and spectral shifts in the tens of a pm are obtained. PMID- 24787776 TI - Focal-plane irradiance tailoring using the concept of Woofer-Tweeter deformable mirrors. AB - Deformable mirror (DM) is a common-used active freeform optical element. We introduce the concept of Woofer-Tweeter DM system for controlling focal-plane irradiance profiles. We firstly determine a freeform reflective surface for transforming a given incident laser beam into the desired focal-plane irradiance distribution by numerically solving a standard Monge-Ampere equation. Then, we use a low-bandwidth Woofer DM to approximate the required freeform reflective surface and a high-bandwidth Tweeter DM to compensate the residual error. Simulation results show that, compared with single DMs, the Woofer-Tweeter DM system brings the best focal-plane irradiance performances. PMID- 24787777 TI - Range clusters based time-of-flight 3D imaging obstacle detection in manifold space. AB - A new obstacle detection method using time-of-flight 3D imaging sensor based on range clusters is proposed. To effectively reduce the influence of outlier and noise in range images, we utilize intensity images to estimate noise deviation of the range images and a weighted local linear smoothing is used to project the data into a new manifold surface. The proposed method divides the 3D imaging data into range clusters with different shapes and sizes according to the distance ambient relation between the pixels, and some regulation criterions are set to adjust the range clusters into optimal shape and size. Experiments on the SwissRanger sensor data show that, compared to the traditional obstacle detection methods based on regular data patches, the proposed method can give more precious detection results. PMID- 24787778 TI - Optical absorption of hyperbolic metamaterial with stochastic surfaces. AB - We investigate the absorption properties of planar hyperbolic metamaterials (HMMs) consisting of metal-dielectric multilayers, which support propagating plane waves with anomalously large wavevectors and high photonic-density-of states over a broad bandwidth. An interface formed by depositing indium-tin-oxide nanoparticles on an HMM surface scatters light into the high-k propagating modes of the metamaterial and reduces reflection. We compare the reflection and absorption from an HMM with the nanoparticle cover layer versus those of a metal film with the same thickness also covered with the nanoparticles. It is predicted that the super absorption properties of HMM show up when exceedingly large amounts of high-k modes are excited by strong plasmonic resonances. In the case that the coupling interface is formed by non-resonance scatterers, there is almost the same enhancement in the absorption of stochastically perturbed HMM compared to that of metal. PMID- 24787779 TI - Terahertz radiation from an ultra-relativistic charge exiting the open end of a waveguide with a dielectric layer. AB - We analyze radiation produced by an ultrarelativistic charge as it exits the open end of a cylindrical waveguide with a dielectric lining. The end of the waveguide can be either orthogonal to the structure axis or skewed. To obtain terahertz radiation from waveguides with centimeter or millimeter radii, we consider high order TM(0m) modes driven by the beam. We obtain an integral representation which describes the radiation produced by a single waveguide mode in the Fraunhofer zone. We perform a series of numerical calculations for structures which look promising for generation of THz radiation. It is shown that for a mode with large mode number, the aperture of the vacuum channel gives the main contribution to the field if the skew angle of the waveguide aperture is not too small. Simple expressions for the angle of the main pattern lobe maximum are obtained. PMID- 24787780 TI - The influence of optical fiber bundle parameters on the transmission of laser speckle patterns. AB - Laser speckle imaging (LSI) techniques provide important functional information about tissue perfusion and mechanical properties. To perform LSI in vivo, laser speckle patterns are transmitted via optical fiber bundles incorporated within small-diameter endoscopes. Inter-fiber crosstalk due to mode coupling in fiber bundles can result in erroneous speckle statistics and therefore reduces the accuracy of LSI analysis. In this paper, we investigate the influence of multiple parameters that influence crosstalk between neighboring cores within optical fiber bundles and govern the modulation of transmitted laser speckle patterns. Our results show that in addition to large core-to-core separation, large refractive index contrast between core and cladding material, reduced number of propagating modes and variability in core size are essential parameters for accurate speckle pattern transmission to conduct endoscopic LSI. PMID- 24787781 TI - Silver nanoparticle piezoresistive sensors fabricated by roll-to-roll slot-die coating and laser direct writing. AB - In this study, we propose new fusion technology to overcome the limitations of the current printing process for printed electronics. The combinative slot-die coating and laser direct writing on a roll-to-roll (R2R) basis was studied and applied to the fabrication of piezoresistive strain gauges. Piezoresistive sensors were fabricated for the first time by this developed fusion technology. A parametric study was performed for the R2R process, followed by a comparison of the fabricated functional devices with commercial products, which confirmed a 40% increase in the gauge factor of the fabricated sensors over the commercial product. The combinative manufacturing process for functional device fabrication will open a new chapter in the future of printed electronics due to its large area capacity at low cost. PMID- 24787782 TI - A transparent thin-film sensor for multi-focal image reconstruction and depth estimation. AB - We present a fully transparent and flexible light-sensing film that, based on a single thin-film luminescent concentrator layer, supports simultaneous multi focal image reconstruction and depth estimation without additional optics. Together with the sampling of two-dimensional light fields propagated inside the film layer under various focal conditions, it allows entire focal image stacks to be computed after only one recording that can be used for depth estimation. The transparency and flexibility of our sensor unlock the potential of lensless multilayer imaging and depth sensing with arbitrary sensor shapes--enabling novel human-computer interfaces. PMID- 24787783 TI - Detection of chemical vapor with high sensitivity by using the symmetrical metal cladding waveguide-enhanced Goos-Hanchen shift. AB - We present a novel and simple optical structure, i.e., the symmetrical metal cladding waveguide, in which a polymer layer is added into the guiding layer, for sensitive detection of chemical vapor by using the enhanced Goos-Hanchen (GH) shift (nearly a millimeter scale). Owing to the high sensitivity of the excited ultrahigh-order modes, the vapor-induced effect (swelling effect and refractive index change) in the polymer layer will lead to a dramatic variation of the GH shift. The detected GH shift signal is irrelevant to the power fluctuation of the incident light. The detection limit of 9.5 ppm for toluene and 28.5 ppm for benzene has been achieved. PMID- 24787784 TI - Multipole and plane wave expansions of diverging and converging fields. AB - This paper presents and compares two basis systems, spherical harmonics and plane waves, for studying diverging and converging beams in an optical system. We show a similarity between a converging field and the time reversed field of a radiation field. We present and analyze the differences between the Debye-Wolf diffraction integral and the multipole theory for focusing of polarized light. The Debye-Wolf diffraction integral gives a well-known anomalous behavior on the optical axis and at the edge of the focused beam that can be avoided by using the multipole theory. PMID- 24787785 TI - Harnessing the fiber fuse for sensing applications. AB - A simple refractive index sensor based on a small section of fiber damaged by the fiber fuse is proposed and demonstrated with a sensitivity of 350.58 nm/refractive index unit (RIU). For comparison, a hetero-core structure fiber sensor composed of a short no-core fiber (NCF) sandwiched between two pieces of single-mode fibers is demonstrated with a sensitivity of 157.29 nm/RIU. The fiber fuse technique can allow mass production of sensors by incorporating small sections of the damaged fiber of any type into each device. We believe this is the first application of the periodic damage tracks in optical fibers formed by the fiber fuse. PMID- 24787786 TI - Counterfactual entanglement distribution without transmitting any particles. AB - To date, all schemes for entanglement distribution needed to send entangled particles or a separable mediating particle among distant participants. Here, we propose a counterfactual protocol for entanglement distribution against the traditional forms, that is, two distant particles can be entangled with no physical particles travel between the two remote participants. We also present an alternative scheme for realizing the counterfactual photonic entangled state distribution using Michelson-type interferometer and self-assembled GaAs/InAs quantum dot embedded in a optical microcavity. The numerical analysis about the effect of experimental imperfections on the performance of the scheme shows that the entanglement distribution may be implementable with high fidelity. PMID- 24787788 TI - Nanowire Terahertz detectors with a resonant four-leaf-clover-shaped antenna. AB - We report on the development of an innovative class of nanowire-based Terahertz (THz) detectors in which the metamaterial properties of an antenna have been imported in the detection scheme of an overdamped plasma-wave field-effect transistor making its response resonant to THz radiation. Responsivities of ~105 V/W at 0.3 THz, with noise equivalent power levels ~ 10(-10) W/?Hz, detectivities ~2 . 10(8) cm?Hz/W and quantum efficiencies ~1.2 . 10(-5) are reached at room temperature. The resonant nature of the detection scheme provided by the four leaf-clover-shaped geometry and the possibility to extend this technology to large multi-pixel arrays opens the path to demanding applications for ultra sensitive metrology, spectroscopy and biomedicine. PMID- 24787787 TI - In vivo imaging of middle-ear and inner-ear microstructures of a mouse guided by SD-OCT combined with a surgical microscope. AB - We developed an augmented-reality system that combines optical coherence tomography (OCT) with a surgical microscope. By sharing the common optical path in the microscope and OCT, we could simultaneously acquire OCT and microscope views. The system was tested to identify the middle-ear and inner-ear microstructures of a mouse. Considering the probability of clinical application including otorhinolaryngology, diseases such as middle-ear effusion were visualized using in vivo mouse and OCT images simultaneously acquired through the eyepiece of the surgical microscope during surgical manipulation using the proposed system. This system is expected to realize a new practical area of OCT application. PMID- 24787789 TI - Wavefront metrology measurements at SACLA by means of X-ray grating interferometry. AB - The knowledge of the X-ray wavefront is of importance for many experiments at synchrotron sources and hard X-ray free-electron lasers. We will report on metrology measurements performed at the SACLA X-ray Free Electron Laser by means of grating interferometry which allows for an at-wavelength, in-situ, and single shot characterization of the X-ray wavefront. At SACLA the grating interferometry technique was used for the study of the X-ray optics installed upstream of the end station, two off-set mirror systems and a double crystal monochromator. The excellent quality of the optical components was confirmed by the experimental results. Consequently grating interferometry presents the ability to support further technical progresses in X-ray mirror manufacturing and mounting. PMID- 24787790 TI - Bidirectional laser triggering of planar device based on vanadium dioxide thin film. AB - By incorporating a 1550 nm laser diode, bidirectional laser triggering was investigated in a two-terminal planar device based on vanadium dioxide (VO2) thin film grown by sol-gel method. A specific bias voltage range enabling the bidirectional laser triggering was experimentally found from the current-voltage characteristics of the VO2-based device, which was measured in a current controlled mode. At a bias voltage selected within the range, 10 mA bidirectional triggering was implemented with a maximum amplitude switching ratio of ~68.2, and the transient responses of light-triggered currents were also analyzed. PMID- 24787791 TI - Sub-diffraction resolution pump-probe microscopy with shot-noise limited sensitivity using laser diodes. AB - We demonstrate the use of intensity-modulated laser diodes to implement pump probe microscopy and achieved sub-diffraction resolution imaging with shot-noise limited sensitivity with a scheme of balanced detection. This technique has several applications for various types of induced transmission change, including excited-state absorption, ground state absorption bleaching and stimulated emission. By using our technique, biological imaging of mouse T cells and the axons of neurons in the cerebral cortex was demonstrated. PMID- 24787792 TI - Compression of a pyramidal absorber using multiple discrete coordinate transformation. AB - The discrete coordinate transformation (DCT), as a unique technique to control the electromagnetic waves, has been applied for creating all-dielectric devices recently. To extend the applicability of this technique, we propose the concept of multiple discrete coordinate transformation, which serves to deal with more complicated geometries in the transformation domain. As an example, an all dielectric absorber is created by compressing a pyramidal absorber to a third of its original thickness using the multiple DCT technique. The Finite-Difference Time-Domain (FDTD) method based numerical simulations demonstrate the broadband performance of the transformation absorber from 2 GHz to 20 GHz. PMID- 24787793 TI - Measuring isotropic subsurface light transport. AB - Subsurface light transport can affect the visual appearance of materials significantly. Measuring and modeling this phenomenon is crucial for accurately reproducing colors in printing or for rendering translucent objects on displays. In this paper, we propose an apparatus to measure subsurface light transport employing a reference material to cancel out adverse signals that may bias the results. In contrast to other approaches, the setup enables improved focusing on rough surfaces (e.g. uncoated paper). We derive a measurement equation that may be used to deduce the point spread function (PSF) of subsurface light transport. Main contributions are the usage of spectrally-narrowband exchangeable LEDs allowing spectrally-resolved measurements and an approach based on quadratic programming for reconstructing PSFs in the case of isotropic light transport. PMID- 24787794 TI - 2D IR spectroscopy with phase-locked pulse pairs from a birefringent delay line. AB - We introduce a new scheme for two-dimensional IR spectroscopy in the partially collinear pump-probe geometry. Translating birefringent wedges allow generating phase-locked pump pulses with exceptional phase stability, in a simple and compact setup. A He-Ne tracking scheme permits to scan continuously the acquisition time. For a proof-of-principle demonstration we use lithium niobate, which allows operation up to 5 MUm. Exploiting the inherent perpendicular polarizations of the two pump pulses, we also demonstrate signal enhancement and scattering suppression. PMID- 24787796 TI - Switchable reflective lens based on cholesteric liquid crystal. AB - We demonstrated a switchable reflective lens based on choleteric liquid crystal (CLC) with a plano-convex shape. The plano-convex CLC lens was fabricated by assembling a planar substrate and a concave substrate. The reflective CLC lens exhibits wavelength selectivity and handedness sensitivity like the conventional CLC cell. The plano-convex CLC lens acts as a biconvex lens with the same curvature due to the Bragg reflection of the CLC layer. In addition, the reflective CLC lens was defocused by applying external voltage. PMID- 24787795 TI - A 10 * 10 Gb/s DFB laser diode array fabricated using a SAG technique. AB - We present a ten-channel distributed feedback laser diode array (DFB-LDA) developed for the transmission of 100-Gb/s (10 * 10 Gb/s) signals separated by an 8 nm wavelength grid at a center wavelength of 1.55 MUm. For the fabrication of this type of laser array, a selective area growth (SAG) technique, electron-beam lithography, and a reverse-mesa ridge waveguide LD processing technique were adopted to offer a tailored gain spectrum to each channel, providing both accurate lasing-wavelength control and excellent single-mode yield over all channels, and reducing the fabrication cost and electrical and thermal resistances. To evaluate the operational performance of the fabricated chip systematically, we also developed a sub-assembly module containing a ten-channel lambda/4-shifted DFB-LDA, ten matching resistors, flexible printed circuit board (FPCB) wiring, and a thermistor on a metal optical bench. The static and dynamic properties of all channels of the fabricated array are examined in this paper. The developed sub-assembly module shows a side-mode suppression ratio (SMSR) of > 50 dB, a modulation bandwidth of > 10 GHz, and a clear eye-opening before and after a 2-km transmission with dynamic extinction ratio of > 5 dB. PMID- 24787797 TI - Duality between noise and spatial resolution in linear systems. AB - It is shown that in a broad class of linear systems, including general linear shift-invariant systems, the spatial resolution and the noise satisfy a duality relationship, resembling the uncertainty principle in quantum mechanics. The product of the spatial resolution and the standard deviation of output noise in such systems represents a type of phase-space volume that is invariant with respect to linear scaling of the point-spread function, and it cannot be made smaller than a certain positive absolute lower limit. A corresponding intrinsic "quality" characteristic is introduced and then evaluated for the cases of some popular imaging systems, including computed tomography, generic image convolution and phase-contrast imaging. It is shown that in the latter case the spatial resolution and the noise can sometimes be decoupled, potentially leading to a substantial increase in the imaging quality. PMID- 24787798 TI - Displacement sensor based on Kerr induced phase-modulation of orthogonally polarized sinusoidal optical signals. AB - We present a novel short, medium, and long range displacement sensor using a Kerr phase-interrogator. Displacement induces relative phase variation between two orthogonally polarized sinusoidal optical signals. The Kerr phase-interrogator converts the phase variation into power variation through Kerr induced phase modulation. Displacement sensing over a range of 12 mm with micron level resolution around the quadrature points is demonstrated. PMID- 24787799 TI - Nd:YAG waveguide laser Q-switched by evanescent-field interaction with graphene. AB - We report on the Q-switched laser operation by the evanescent-field interaction with the graphene layers deposited on a Nd:YAG surface planar waveguide, which was fabricated by the 15 MeV carbon ion irradiation. Based on the simple and compact design of the cavity with saturable-absorber features, the Q-switched pulsed waveguide laser operation was achieved at the wavelength of 1064 nm through the interaction between the graphene layer and the evanescent-field of the waveguide mode. The maximum output pulse repetition rate was ~29 kHz with the pulse duration of ~9.8 us. PMID- 24787800 TI - Mu and epsilon near zero metamaterials for perfect coherence and new antenna designs. AB - Wave interference is a fundamental physical phenomenon. Traditionally, the coherent effect of two identical point sources only takes place when the optical path is an integer number of wavelengths. In this paper, we show that mu and epsilon near zero (MENZ) metamaterials can be used to realize a perfectly constructive and isotropic interference. No matter how many point sources are embedded in the MENZ region, the wavefronts overlap perfectly. This translates into a total relaxation of the conventional condition for coherence enabled by the apparent infinite wavelength of the fields within MENZ metamaterials. Furthermore, we investigate crucial parameters such as the shape and size of the MENZ region. We demonstrate that flat sided geometries give rise to constructive interference beams serving as a powerful design mean. We also reveal the importance of relying on deeply sub-wavelength MENZ volumes as larger sizes increase the impedance and therefore reduce the output power of the device. The proposed concepts bear significance for current trends in antenna design which are inspired by the recent developments of electromagnetic metamaterials. Moreover, the perfect coherence effect can be appealing for power combiners, especially in the terahertz where sources are dim, as the irradiation intensity scales with the square of the number of embedded sources. PMID- 24787802 TI - 30.4 Tb/s transmission over transpacific distance using 200 Gb/s and dual wavelength 400 Gb/s 16QAM at 6.0 b/s/Hz spectral efficiency. AB - Using single-stage C-band EDFAs equalized to 41 nm, we transmit 152 x 200 Gb/s PDM 16QAM channels with 6.0 b/s/Hz spectral efficiency over 9,748 km enabled by Nyquist spectral shaping and digital back propagation. 76 x 400 Gb/s channels are also transmitted over 8,665 km detecting two 200 Gb/s channels simultaneously using a single wideband receiver. Digital back propagation benefit versus channel pre-emphasis, transmission distance and wavelength are experimentally investigated. PMID- 24787803 TI - Spectrogenic imaging: a novel approach to multispectral imaging in an uncontrolled environment. AB - Increasing the number of imaging channels beyond the conventional three has been shown to be beneficial for a wide range of applications. However, it is mostly limited to imaging in a controlled environment, where the capture environment (illuminant) is known a priori. We propose here a novel system and methodology for multispectral imaging in an uncontrolled environment. Two images of a scene, a normal RGB and a filtered RGB are captured. The illuminant under which an image is captured is estimated using a chromagenic based algorithm, and the multispectral system is calibrated automatically using the estimated illuminant. A 6-band multispectral image of a scene is obtained from the two RGB images. The spectral reflectances of the scene are then estimated using an appropriate spectral estimation method. The proposed concept and methodology is generic one, as it is valid in whatever way we acquire the two images of a scene. A system that can acquire two images of a scene can be realized, for instance in two shots using a digital camera and a filter, or in a single shot using a stereo camera, or a custom color filter array design. Simulation experiments using a stereo camera based system confirms the effectiveness of the proposed method. This could be useful in many imaging applications and computer vision. PMID- 24787804 TI - Precise calibration of binocular vision system used for vision measurement. AB - Binocular vision calibration is of great importance in 3D machine vision measurement. With respect to binocular vision calibration, the nonlinear optimization technique is a crucial step to improve the accuracy. The existing optimization methods mostly aim at minimizing the sum of reprojection errors for two cameras based on respective 2D image pixels coordinate. However, the subsequent measurement process is conducted in 3D coordinate system which is not consistent with the optimization coordinate system. Moreover, the error criterion with respect to optimization and measurement is different. The equal pixel distance error in 2D image plane leads to diverse 3D metric distance error at different position before the camera. To address these issues, we propose a precise calibration method for binocular vision system which is devoted to minimizing the metric distance error between the reconstructed point through optimal triangulation and the ground truth in 3D measurement coordinate system. In addition, the inherent epipolar constraint and constant distance constraint are combined to enhance the optimization process. To evaluate the performance of the proposed method, both simulative and real experiments have been carried out and the results show that the proposed method is reliable and efficient to improve measurement accuracy compared with conventional method. PMID- 24787805 TI - Metal-semiconductor-metal ion-implanted Si waveguide photodetectors for C-band operation. AB - Metal-semiconductor-metal Si waveguide photodetectors are demonstrated with responsivities of greater than 0.5 A/W at a wavelength of 1550 nm for a device length of 1mm. Sub-bandgap absorption in the Si waveguide is achieved by creating divacancy lattice defects via Si(+) ion implantation. The modal absorption coefficient of the ion-implanted Si waveguide is measured to be ~ 185 dB/cm, resulting in a detector responsivity of ~ 0.51 A/W at a 50 V bias. The frequency response of a typical 1mm-length detector is measured to be 2.6 GHz, with simulations showing that a frequency response of 9.8 GHz is achievable with an optimized contact configuration and bias voltage of 15 V. Due to the ease with which these devices can be fabricated, and their potential for high performance, these detectors are suitable for various applications in Si-based photonic integrated circuits. PMID- 24787806 TI - Shot-noise limited localization of single 20 nm gold particles with nanometer spatial precision within microseconds. AB - Single-particle tracking (SPT) is a powerful approach to investigate dynamics without ensemble average. Continuing effort has been made to track smaller particles with better spatial precision at higher speed. In this work, we demonstrate SPT of 20 nm gold nanoparticle (GNP) with 2 nm spatial precision up to 500 kHz by using microsecond interferometric scattering (MUs-iSCAT) microscopy. The linear scattering signal from single GNPs is detected by a high speed CMOS camera via interference. Through this homodyne detection, shot-noise limited sensitivity, and therefore optimal localization precision are achieved at high speed where considerable electronic noise is present. Using MUs-iSCAT microscopy, we observe anomalous diffusion of GNPs labeled to lipid molecules in a supported bilayer membrane prepared on a glass substrate. The combination of nanometer spatial precision and microsecond temporal resolution provides the opportunity to study rapid motions of nano-objects on molecular scale with unprecedented clarity. PMID- 24787807 TI - Photosensitive and all-optically fast-controllable photonic bandgap device and laser in a dye-doped blue phase with a low-concentration azobenzene liquid crystal. AB - This work demonstrates the feasibility of a novel photosensitive and all optically fast-controllable photonic bandgap (PBG) device based on a dye-doped blue phase (DDBP), embedded with a low-concentration azobenzene liquid crystal (azo-LC). PBG of the DDBP can be reversibly fast-tuned off and on with the successive illumination of a weak UV and green beams. UV irradiation can transform the trans azo-LCs into bend cis isomers, which can easily disturb LCs at the boundary between the double twisting cylinders (DTCs) and the disclinations, and, then, quickly destabilize BPI to become a BPIII-like texture with randomly-oriented DTCs. Doing so may quickly destroy the BP PBG structure. However, with the successive illumination of a green beam, the BPI PBG device can be fast-turned on, owing to the fast disappearance of the disturbance of the azo LCs on the boundary LCs via the green-beam-induced cis -> trans back isomerization. The response time and irradiated energy density for turning off (on) the BP PBG device under the UV (green) beam irradiation are only 120 ms (120 ms) and 0.764 mJ/cm(2) (2.12 mJ/cm(2)), respectively, which are a thousand-fold reduction in photoswitching a traditional cholesteric LC (CLC) PBG device based on similar experimental conditions (i.e., materials used, azo-LC concentration (1 wt%), spectral position of PBG peak, sample thickness, and temperature difference for a working temperature lower than the clearing one). The BP PBG device can significantly contribute to efforts to develop a photosensitive and all-optically fast-controlling LC laser. PMID- 24787808 TI - Optical continuous-variable quadratic phase gate via Faraday interaction. AB - The continuous-variable (CV) quadratic phase gate is one of the most fundamental CV quantum gates for universal CV quantum computation, while its experimental realization still remains a challenge. Here we propose a novel and experimentally feasible scheme to realize optical CV quadratic phase gate via Faraday interaction in an atomic ensemble. The gate is performed by simply sending an optical beam three times through an atomic medium prepared in coherent spin state. The fidelity of the gate can ideally run up to one. We show that the scheme also works well as a device to generate optical polarization squeezing. Considering the noise effects due to atomic decoherence and light losses, we find that the observed fidelities of gate operation and the attainable degree of polarization squeezing are still quite high. PMID- 24787809 TI - Design method of freeform off-axis reflective imaging systems with a direct construction process. AB - In this paper, a novel method is proposed to design the freeform off-axis reflective imaging systems. A special algorithm is demonstrated to calculate the data points on the unknown freeform surface using the rays from multiple fields and different pupil coordinates. These points are used to construct the multiple three-dimensional freeform surfaces in an imaging system which works for a certain object size and a certain width of light beam. An unobscured design with freeform surfaces can be obtained directly with this method, and it can be taken as a good starting point for further optimization. The benefit of this design method is demonstrated by designing a freeform off-axis three-mirror imaging system with high performance and system specifications. The final system operates at F/1.49 with a 64mm entrance pupil diameter and an 8 degrees * 9 degrees field-of-view (FOV). The performance of the system is diffraction limited at LWIR (long-wavelength-infrared). PMID- 24787810 TI - Single-mode chirally-coupled-core fibers with larger than 50 um diameter cores. AB - In this paper, we report an advance in increasing core size of effective single mode chirally-coupled-core (CCC) Ge-doped and Yb-doped double-clad fibers into 55 um to 60 um range, and experimentally demonstrate their robust single-mode performance. Theoretical and numerical description of CCC fibers structures with multiple side cores and polygon-shaped central core is consistent with experimental results. Detailed experimental characterization of 55 um-core CCC fibers based on spatially and spectrally resolved broadband measurements (S(2) technique) shows that modal performance of these large core fibers well exceeds that of standard 20 MUm core step-index large mode area fibers. PMID- 24787811 TI - Boundary-artifact-free phase retrieval with the transport of intensity equation: fast solution with use of discrete cosine transform. AB - The transport of intensity equation (TIE) is a two-dimensional second order elliptic partial differential equation that must be solved under appropriate boundary conditions. However, the boundary conditions are difficult to obtain in practice. The fast Fourier transform (FFT) based TIE solutions are widely adopted for its speed and simplicity. However, it implies periodic boundary conditions, which lead to significant boundary artifacts when the imposed assumption is violated. In this work, TIE phase retrieval is considered as an inhomogeneous Neumann boundary value problem with the boundary values experimentally measurable around a hard-edged aperture, without any assumption or prior knowledge about the test object and the setup. The analytic integral solution via Green's function is given, as well as a fast numerical implementation for a rectangular region using the discrete cosine transform. This approach is applicable for the case of non uniform intensity distribution with no extra effort to extract the boundary values from the intensity derivative signals. Its efficiency and robustness have been verified by several numerical simulations even when the objects are complex and the intensity measurements are noisy. This method promises to be an effective fast TIE solver for quantitative phase imaging applications. PMID- 24787812 TI - Unconstrained splitting ratios in compact double-MMI couplers. AB - A novel guided-wave optical power coupler is presented, based on two 2x2 50/50 multimode interference splitters connected with tapered waveguides that play the role of a phase shifter. By simply changing the length of this phase shifter, these double-MMI couplers can be easily designed to get any desired splitting ratio. Results of simulations are discussed and compared with the characterizations of devices fabricated on micron-scale SOI wafers, to highlight pros and cons of the proposed solution. The fabricated splitters have been found to have average losses about 0.4 +/- 0.5 dB and splitting ratios ranging from 56/44 to 96/4. PMID- 24787813 TI - Pulse-analysis-pulse investigation of femtosecond laser-induced periodic surface structures on silicon in air. AB - A new approach to experimentally investigate laser-induced periodic surface structures (LIPSSs) is introduced. Silicon was iteratively exposed to femtosecond laser pulses at lambda = 800 nm and normal incidence in ambient air and at a fluence slightly over the single-pulse modification threshold. After each laser pulse, the topography of the surface was inspected by confocal microscopy. Subsequently, the sample was reproducibly repositioned in the laser setup, to be exposed to the next laser pulse. By this approach, the initiation and spatial evolution ("growth") of the LIPSSs were analyzed as function of the number of pulses applied. It was found that, after the first laser pulses, the ridges of the LIPSSs elevate, and valleys between the ridges deepen, by a few tens of nanometers relative to the initial surface. An electromagnetic model, discussed in earlier works, predicted that the spatial periodicity of LIPSSs decreases with the number of laser pulses applied. This implies material transport and reorganization of the irradiated material on the surface, due to each laser pulse. However, our experiments show a negligible shift of the lateral positions of the LIPSSs on the surface. PMID- 24787814 TI - Transparent near-infrared reflector metasurface with randomly dispersed silver nanodisks. AB - We present large-area ultrathin metasurfaces that transmit visible light and reflect near-infrared (NIR) wavelengths. These visible-transparent metasurfaces consist of 10 nm-thick monolayer of randomly dispersed silver nanodisks, that is only lambda/90 thickness at the reflection peak wavelength. Calculated optical properties of the structure show that the reflectance for NIR wavelengths increases monotonically as a function of increasing nanodisk density, while the absorption saturates and scattering of visible light decreases. We demonstrate that the proposed structure is easy to fabricate with chemically synthesized silver particles using the bottom-up method and has industrially applications. PMID- 24787815 TI - Resonant grating polarizers made with silicon nitride, titanium dioxide, and silicon: design, fabrication, and characterization. AB - We present the design, fabrication, and characterization of guided-mode resonance (GMR) linear polarizers that operate in the optical communications C-band near a wavelength of 1550 nm. We provide theoretical and experimental spectra using resonant elements fashioned in three material systems. In particular, we investigate silicon nitride resonant gratings and titanium dioxide gratings on glass substrates as well as silicon-on-quartz gratings. These materials exhibit very low losses and are capable of high diffraction efficiencies and extinction ratios; thus, high-power laser applications may be enabled. We present the methods applied to fabricate these GMR devices as well as means to ascertain their fabricated physical parameters. We quantify increased polarizer bandwidth with increased grating refractive-index modulation. The numerical results obtained with the fabricated-device parameters agree well with the experimental measured spectra. PMID- 24787816 TI - Reconfigurable two-mode mux/demux device. AB - A reconfigurable two-mode mux/demux device in planar waveguide was proposed. The simulated mux/demux extinction ratio was >= 35 dB with <= 0.4 dB excess loss. The device was realized in polymer materials using the thermo-optic effect. It was characterized via a tunable laser source at 1550 nm. Its mux/demux performance in both routes was demonstrated and compared with the theoretical prediction. The device is easy to implement and has applications in future multimode optical communication systems to further extend transmission capacity. PMID- 24787817 TI - Sensitive and rapid laser diagnostic for shock tube kinetics studies using cavity enhanced absorption spectroscopy. AB - We report the first application of cavity-enhanced absorption spectroscopy (CEAS) using a coherent light source for sensitive and rapid gaseous species time history measurements in a shock tube. Off-axis alignment and fast scanning of the laser wavelength were used to minimize coupling noise in a low-finesse cavity. An absorption gain factor of 83 with a measurement time resolution of 20 us was demonstrated for C2H2 detection using a near-infrared transition near 1537 nm, corresponding to a noise-equivalent detection limit of 20 ppm at 296 K and 76 ppm at 906 K at 50 kHz. This substantial gain in signal, relative to conventional single-pass absorption, will enable ultra-sensitive species detection in shock tube kinetics studies, particularly useful for measurements of minor species and for studies of dilute reactive systems. PMID- 24787818 TI - Dual-band unidirectional circular polarizer with opposite handedness filtration using hybridized metamaterial. AB - We theoretically propose a unidirectional dual-band circular polarizer using a subwavelength hybridized metamaterial. By fulfilling the critical requirements of left-/right-handed circular polarizer design at each band, the polarization handedness filtration can be flipped in the same structure at different operation frequency band. The physics behind this exotic performance is further explained by a simple analytical model. Our investigation expands the capabilities of metamaterials in getting intriguing optical properties. The proposed metamaterial polarizer is helpful in effective and fruitful optical polarization manipulation and is highly valuable for the development of nanophotonic devices. PMID- 24787819 TI - Heterodyne detection and transmission of 60-Gbaud PDM-QPSK signal with SE of 4b/s/Hz. AB - We experimentally demonstrate 8 * 240-Gb/s super-Nyquist wavelength-division multiplexing (WDM) polarization-division-multiplexing quadrature-phase-shift keying (PDM-QPSK) signal transmission on a 50-GHz grid with a net spectral efficiency (SE) of 4b/s/Hz adopting hardware-efficient simplified heterodyne detection. 9-ary quadrature-amplitude-modulation-like (9QAM-like) processing based on multi-modulus blind equalization (MMBE) is adopted to reduce analog-to digital converter (ADC) bandwidth requirement and improve receiver sensitivity. The transmission distance at the soft-decision forward-error-correction (SD-FEC) threshold of 2 * 10(-2) is 2 * 420 km based on digital post filtering while largely extended to over 5 * 420 km based on 9QAM-like processing, which well illustrates 9QAM-like processing is more efficient for heterodyne coherent WDM system. Moreover, only two ADC channels are needed for simplified heterodyne detection of one 60-Gbaud PDM-QPSK WDM channel, and thus only one commercial oscilloscope (OSC) with two input ports can work well for each WDM channel. PMID- 24787820 TI - Plenoptic wavefront sensor with scattering pupil. AB - We consider a wavefront sensor combining scattering pupil with a plenoptic imager. Such a sensor utilizes the same reconstruction principle as the Hartmann Shack sensor, however it is free from the ambiguity of the spot location caused by the periodic structure of the sensor matrix, and allows for wider range of measured aberrations. In our study, sensor with scattering pupil has demonstrated a good match between the introduced and reconstructed aberrations, both in the simulation and experiment. The concept is expected to be applicable to optical metrology of strongly distorted wavefronts, especially for measurements through dirty, distorted, or scattering windows and pupils, such as cataract eyes. PMID- 24787821 TI - Retroreflector for GRACE follow-on: Vertex vs. point of minimal coupling. AB - The GRACE Follow-On mission will monitor fluctuations in Earth's geoid using, for the first time, a Laser Ranging Interferometer to measure intersatellite distance changes. We have investigated the coupling between spacecraft rotation and the intersatellite range measurement that is incurred due to manufacturing and assembly tolerances of the Triple Mirror Assembly (TMA), a precision retroreflector to ensure alignment between in- and outgoing laser beams. The three TMA mirror planes intersect in a virtual vertex to which satellite displacements are referenced. TMA manufacturing tolerances degrade this ideal vertex, however, a Point of Minimal Coupling (PMC) between spacecraft rotation and displacement exists. This paper presents the experimental location of the PMC under pitch and yaw rotations for a prototype TMA. Rotations are performed using a hexapod, while displacements are monitored with heterodyne laser interferometry to verify the PMC position. Additionally, the vertex of the three TMA mirror planes is measured using a Coordinate Measuring Machine and compared to the PMC position. In the pitch and yaw axes, the biggest deviation between TMA vertex and PMC was 50 +/- 64 MUm. Thus, within the measurement uncertainties, no difference between TMA vertex and PMC could be observed. This is a key piece of information for integration of the TMA into the spacecraft: It is sufficient to use the readily-available TMA vertex location to ensure minimal rotation-to-displacement coupling during the mission. PMID- 24787822 TI - Efficient design of polarization insensitive polymer optical waveguide devices considering stress-induced effects. AB - We present an approach for the efficient design of polarization insensitive polymeric optical waveguide devices considering stress-induced effects. In this approach, the stresses induced in the waveguide during the fabrication process are estimated first using a more realistic model in the finite element analysis. Then we determine the perturbations in the material refractive indices caused by the stress-optic effect. It is observed that the stresses cause non-uniform optical anisotropy in the waveguide materials, which is then incorporated in the modal analysis considering a multilayer structure of waveguide. The approach is exploited in the design of a Bragg grating on strip waveguide. Excellent agreement between calculated and published experimental results confirms the feasibility of our approach in the accurate design of polarization insensitive polymer waveguide devices. PMID- 24787823 TI - Timing, carrier frequency and phase recovery for OFDM and Nyquist signals using a mean modulus algorithm. AB - Efficient algorithms for timing, carrier frequency and phase recovery of Nyquist and OFDM signals are introduced and experimentally verified. The algorithms exploit the statistical properties of the received signals to efficiently derive the optimum sampling time, the carrier frequency offset, and the carrier phase. Among the proposed methods, the mean modulus algorithm (MMA) shows a very robust performance at reduced computational complexity. This is especially important for optical communications where data rates can exceed 100 Gbit/s per wavelength. All proposed algorithms are verified by simulations and by experiments using optical M-ary QAM Nyquist and OFDM signals with data rates up to 84 Gbit/s. PMID- 24787824 TI - Generation of vector beams in planar photonic crystal cavities with multiple missing-hole defects. AB - We propose a novel method to generate vector beams in planar photonic crystal cavities with multiple missing-hole defects. Simulating the resonant modes in the cavities, we observe that the optical fields in each defect have different phase and polarization state distributions, which promise the compositions of vector beams by the scattered light from the defects. The far-field radiation patterns of the cavity modes calculated via the Sommerfeld diffraction theory present vector beams possessing hollow intensity profiles and polarization singularities. In addition, the extraction efficiencies of the vector beams from the cavities could be improved by modifying the air-holes surrounding the defects. This planar photonic crystal cavity-based vector beam generator may provide useful insights for the on-chip controlling of vector beams in their propagations and interactions with matter. PMID- 24787825 TI - Laser Doppler holographic microscopy in transmission: application to fish embryo imaging. AB - We have extended Laser Doppler holographic microscopy to transmission geometry. The technique is validated with living fish embryos imaged by a modified upright bio-microcope. By varying the frequency of the holographic reference beam, and the combination of frames used to calculate the hologram, multimodal imaging has been performed. Doppler images of the blood vessels for different Doppler shifts, images where the flow direction is coded in RGB colors or movies showing blood cells individual motion have been obtained as well. The ability to select the Fourier space zone that is used to calculate the signal, makes the method quantitative. PMID- 24787826 TI - Optical phase imaging using a synthetic aperture phase retrieval technique. AB - Optical phase imaging enables visualization of transparent samples, numerical refocusing, and other computational processing. Typically phase is measured quantitatively using interferometric techniques such as digital holography. Researchers have demonstrated image enhancement by synthetic aperture imaging based on digital holography. In this work we introduce a novel imaging technique that implements synthetic aperture imaging using phase retrieval, a non interferometric technique. Unlike digital holography, phase retrieval obviates the need for a reference arm and provides a more compact, less expensive, and more stable experimental setup. We call this technique synthetic aperture phase retrieval. PMID- 24787827 TI - Low-loss and low-crosstalk 8 * 8 silicon nanowire AWG routers fabricated with CMOS technology. AB - Low-loss and low-crosstalk 8 * 8 arrayed waveguide grating (AWG) routers based on silicon nanowire waveguides are reported. A comparative study of the measurement results of the 3.2 nm-channel-spacing AWGs with three different designs is performed to evaluate the effect of each optimal technique, showing that a comprehensive optimization technique is more effective to improve the device performance than a single optimization. Based on the comprehensive optimal design, we further design and experimentally demonstrate a new 8-channel 0.8 nm channel-spacing silicon AWG router for dense wavelength division multiplexing (DWDM) application with 130 nm CMOS technology. The AWG router with a channel spacing of 3.2 nm (resp. 0.8 nm) exhibits low insertion loss of 2.32 dB (resp. 2.92 dB) and low crosstalk of -20.5~-24.5 dB (resp. -16.9~-17.8 dB). In addition, sophisticated measurements are presented including all-input transmission testing and high-speed WDM system demonstrations for these routers. The functionality of the Si nanowire AWG as a router is characterized and a good cyclic rotation property is demonstrated. Moreover, we test the optical eye diagrams and bit error-rates (BER) of the de-multiplexed signal when the multi-wavelength high speed signals are launched into the AWG routers in a system experiment. Clear optical eye diagrams and low power penalty from the system point of view are achieved thanks to the low crosstalk of the AWG devices. PMID- 24787828 TI - Generalization and modularization of two-dimensional adaptive coordinate transformations for the Fourier modal method. AB - The Fourier modal method (FMM) has advanced greatly by using adaptive coordinates and adaptive spatial resolution. The convergence characteristics were shown to be improved significantly, a construction principle for suitable meshes was demonstrated and a guideline for the optimal choice of the coordinate transformation parameters was found. However, the construction guidelines published so far rely on a certain restriction that is overcome with the formulation presented in this paper. Moreover, a modularization principle is formulated that significantly eases the construction of coordinate transformations in unit cells with reappearing shapes and complex sub-structures. PMID- 24787830 TI - Generation of 150-fs pulses from a diode-pumped Yb:KYW nonlinear regenerative amplifier. AB - Generation of sub-150-fs-level pulses has been obtained from an Yb-doped crystal based regenerative amplifier by applying an innovative amplification scheme. This scheme is based on optimization of the linear and non-linear phase during the amplification process inside the regenerative amplifier cavity. This technique with Yb:KYW allows to achieve pulse durations from diode-pumped Yb-doped regenerative amplifiers that were up to now only accessible with more complex Ti:sapphire amplifiers. With this Yb-doped tungstate crystal used in regenerative amplifiers, 145 fs pulses centered at 1026 nm with a spectral bandwidth of 14 nm at 50 kHz for an average power of 1.6 W have been generated. PMID- 24787831 TI - Nyquist-shaped dispersion-precompensated subcarrier modulation with direct detection for spectrally-efficient WDM transmission. AB - The use of single-sideband subcarrier modulation (SCM) with Nyquist (N) pulse shaping for cost-effective spectrally-efficient wavelength division multiplexed transmission with direct detection is described. Transmission of digitally pre compensated 7 * 11 GHz-spaced QPSK SCM channels at 14 Gb/s per channel is experimentally demonstrated over distances of up to 800 km of uncompensated standard single-mode fiber (SSMF) (13440 ps/nm chromatic dispersion). PMID- 24787832 TI - Fast, compact, autonomous holographic adaptive optics. AB - We present a closed-loop adaptive optics system based on a holographic sensing method. The system uses a multiplexed holographic recording of the response functions of each actuator in a deformable mirror. By comparing the output intensity measured in a pair of photodiodes, the absolute phase can be measured over each actuator location. From this a feedback correction signal is applied to the input beam without need for a computer. The sensing and correction is applied to each actuator in parallel, so the bandwidth is independent of the number of actuator. We demonstrate a breadboard system using a 32-actuator MEMS deformable mirror capable of operating at over 10 kHz without a computer in the loop. PMID- 24787833 TI - Uncertainty propagation algorithm from the radiometric calibration to the restored earth observation radiance. AB - The uncertainty of the radiometric calibration affects the accuracy of the earth observation (EO) radiance restored from the remote sensing digital number (DN) data. However, it has not been intensively analyzed whether they are equivalent to each other. The algorithm to deduce the uncertainty of the restored EO radiance in the solar-reflective spectral range (400-2500 nm) along the uncertainty propagation chain in the radiometric calibration process is proposed. It was validated compared with the traditional calibration uncertainty algorithm through an example of calibrating an imaging spectrometer. The interval about the real EO radiance and the corresponding level of confidence was reported as a result, which shows the possibility to accurately expressing the quality of the restored EO radiance following the rules used in the field of metrology. PMID- 24787834 TI - Simulation method for resonant light scattering of exciton confined to arbitrary geometry. AB - We develop an electromagnetic (EM) simulation method based on a finite-element method (FEM) for an exciton confined to a semiconductor nanostructure. The EM field inside the semiconductor excites two transverse exciton polariton and a single longitudinal exciton at a given frequency. Established EM simulation methods cannot be applied directly to semiconductor nanostructures because of this multimode excitation; however, the present method overcomes this difficulty by introducing an additional boundary condition. To avoid spurious solutions and enhance the precision, we propose a hybrid edge-nodal element formulation in which edge and nodal elements are employed to represent the transverse and longitudinal polarizations, respectively. We apply the developed method to the EM field scattering and distributions of exciton polarizations of spherical and hexagonal-disk quantum dots. PMID- 24787835 TI - Optical independent-sideband modulation for bandwidth-economic coherent transmission. AB - We proposed and implemented a bandwidth-economic coherent optical transmission technology using optical independent-sideband (O-ISB) modulation. Generation of two software-defined, 30-GBd O-ISB channels per wavelength sharing one set of transmitter hardware was demonstrated, which was made possible by digital single sided up-conversion, channel pre-equalization and optical IQ modulation with precise amplitude and delay matching between driving signals. With 120-Gb/s PM QPSK per O-ISB channel, we successfully delivered 16 O-ISB channels in 8 wavelengths at 3.86-bits/s/Hz over 2100 km SSMF. In addition, the system performance was evaluated by using regular and enhanced Rx DSP, respectively. For metro and regional network applications where small footprint, low power consumption and low cost are required features, the proposed two-channels-per wavelength O-ISB modulation may be considered an economic option. PMID- 24787836 TI - Robust source and mask optimization compensating for mask topography effects in computational lithography. AB - Mask topography effects need to be taken into consideration for a more accurate solution of source mask optimization (SMO) in advanced optical lithography. However, rigorous 3D mask models generally involve intensive computation and conventional SMO fails to manipulate the mask-induced undesired phase errors that degrade the usable depth of focus (uDOF) and process yield. In this work, an optimization approach incorporating pupil wavefront aberrations into SMO procedure is developed as an alternative to maximize the uDOF. We first design the pupil wavefront function by adding primary and secondary spherical aberrations through the coefficients of the Zernike polynomials, and then apply the conjugate gradient method to achieve an optimal source-mask pair under the condition of aberrated pupil. We also use a statistical model to determine the Zernike coefficients for the phase control and adjustment. Rigorous simulations of thick masks show that this approach provides compensation for mask topography effects by improving the pattern fidelity and increasing uDOF. PMID- 24787837 TI - Design and optimization of mechanically down-doped terahertz fiber directional couplers. AB - We present a thorough practical design optimization of broadband low loss, terahertz (THz) photonic crystal fiber directional couplers in which the two cores are mechanically down-doped with a triangular array of air holes. A figure of merit taking both the 3-dB bandwidth and loss of the coupler into account, is used for optimization of the structure parameters, given by the diameter and pitch of the cladding (d and Lambda) and of the core (d(c) and Lambdac) air-hole structure. The coupler with Lambda = 498.7 um, d = 324.2 um, Lambdac = 74.8 um, and d(c) = 32.5 um is found to have the best performance at a center frequency of 1THz, with a bandwidth of 0.25 THz and a total device loss of 9.2 dB. The robustness of the optimum coupler to structural changes is investigated. PMID- 24787838 TI - High power NIR fiber-optic femtosecond Cherenkov radiation and its application on nonlinear light microscopy. AB - We reported a record high power (>250 mW) and compact near-infrared fiber-optic femtosecond Cherenkov radiation source and its new application on nonlinear light microscopy for the first time (to our best knowledge). The high power femtosecond Cherenkov radiation was generated by 1.03 MUm femtosecond pulses from a portable diode-pumped laser and a photonic crystal fiber as a compact, flexible, and highly efficient wavelength convertor. Sectioned nonlinear light microscopy images from mouse brain blood vessel network and rat tail tendon were then performed by the demonstrated light source. Due to the advantages of its high average output power (>250 mW), high pulse energy (>4 nJ), excellent wavelength conversion efficiency (>40%), compactness, simplicity in configuration, and turn key operation, the demonstrated femtosecond Cherenkov radiation source could thus be widely applicable as an alternative excitation source to mode-locked Ti:Sapphire lasers for future clinical nonlinear microscopy or other applications requiring synchronized multi-wavelength light sources. PMID- 24787839 TI - Copper nanorod array assisted silicon waveguide polarization beam splitter. AB - We present the design of a three-dimensional (3D) polarization beam splitter (PBS) with a copper nanorod array placed between two silicon waveguides. The localized surface plasmon resonance (LSPR) of a metal nanorod array selectively cross-couples transverse electric (TE) mode to the coupler waveguide, while transverse magnetic (TM) mode passes through the original input waveguide without coupling. An ultra-compact and broadband PBS compared to all-dielectric devices is achieved with the LSPR. The output ports of waveguides are designed to support either TM or TE mode only to enhance the extinction ratios. Compared to silver, copper is fully compatible with complementary metal-oxide-semiconductor (CMOS) technology. PMID- 24787841 TI - Rigorous characterization of acoustic-optical interactions in silicon slot waveguides by full-vectorial finite element method. AB - For the first time detailed interactions between optical and acoustic modes in a silicon slot waveguide are presented. A new computer code has been developed by using a full-vectorial formulation to study the acoustic modes in optical waveguides. The results have shown that the acoustic modes in an optical slot waveguide are not purely longitudinal or transverse but fully hybrid in nature. The model allows the effects of Stimulated Brillouin Scattering and the associated frequency shift due to the interaction of these hybrid acoustic modes with the fully hybrid optical mode also to be presented. PMID- 24787840 TI - Optically-sectioned two-shot structured illumination microscopy with Hilbert Huang processing. AB - We introduce a fast, simple, adaptive and experimentally robust method for reconstructing background-rejected optically-sectioned images using two-shot structured illumination microscopy. Our innovative data demodulation method needs two grid-illumination images mutually phase shifted by pi (half a grid period) but precise phase displacement between two frames is not required. Upon frames subtraction the input pattern with increased grid modulation is obtained. The first demodulation stage comprises two-dimensional data processing based on the empirical mode decomposition for the object spatial frequency selection (noise reduction and bias term removal). The second stage consists in calculating high contrast image using the two-dimensional spiral Hilbert transform. Our algorithm effectiveness is compared with the results calculated for the same input data using structured-illumination (SIM) and HiLo microscopy methods. The input data were collected for studying highly scattering tissue samples in reflectance mode. Results of our approach compare very favorably with SIM and HiLo techniques. PMID- 24787842 TI - Experimental performance evaluation of software defined networking (SDN) based data communication networks for large scale flexi-grid optical networks. AB - Software defined networking (SDN) has become the focus in the current information and communication technology area because of its flexibility and programmability. It has been introduced into various network scenarios, such as datacenter networks, carrier networks, and wireless networks. Optical transport network is also regarded as an important application scenario for SDN, which is adopted as the enabling technology of data communication networks (DCN) instead of general multi-protocol label switching (GMPLS). However, the practical performance of SDN based DCN for large scale optical networks, which is very important for the technology selection in the future optical network deployment, has not been evaluated up to now. In this paper we have built a large scale flexi-grid optical network testbed with 1000 virtual optical transport nodes to evaluate the performance of SDN based DCN, including network scalability, DCN bandwidth limitation, and restoration time. A series of network performance parameters including blocking probability, bandwidth utilization, average lightpath provisioning time, and failure restoration time have been demonstrated under various network environments, such as with different traffic loads and different DCN bandwidths. The demonstration in this work can be taken as a proof for the future network deployment. PMID- 24787843 TI - New model for subsurface irradiance reflectance in clear and turbid waters. AB - Modeling of subsurface irradiance reflectance fields especially in turbid coastal, harbor and lagoon waters has important applications in ecology, engineering and optical remote sensing. The present study aims at exploring many possible causes of variation in the proportionality factor f and analyzing its effect on the subsurface irradiance reflectance in different waters. A new model is then developed to estimate this optical property as a function of the absorption coefficient (a), backscattering coefficient (bb), incident illumination condition, and other wavelength-depth dependent factors. Implementation of this new model is examined for five types of waters with varying turbidity and chlorophyll. Model results are verified with in situ measurements data and compared with the results from existing models. Formulas already proposed for estimating R in the previous studies and generally expressed by R = 0.33(bb/(a + bb)) or R = f (bb/(a + bb)) where f = 0.975-0.629 MU(0) (MU(0) is the incident photons just below the sea surface) work fairly well in clear oceanic waters, but yield large errors in turbid coastal and lagoon waters due to the use of a constant value ~0.33 or the dimensionless parameter f which does not account for certain processes in the model (e.g., multiple scattering, depth-dependent changes in the diffuse components of solar radiation, and spectral variation in f). By contrast, the new model estimates the reflectances having good agreement with in situ data from just below the water surface and throughout the water column. The improved performance of the present model is because it includes a parameterization of the proportionality factor f which varies with wavelength and depends on the sun angle, inherent optical properties, and diffuse attenuation coefficients. Knowledge related to interrelationships between inherent optical properties and apparent optical properties can be used to study the variability of the subsurface reflectance in homogeneous and stratified coastal waters with respect to many possible causes of its variations. PMID- 24787844 TI - Watt-level optical parametric amplifier at 42 MHz tunable from 1.35 to 4.5 MUm coherently seeded with solitons. AB - We report on an optical parametric amplifier at high repetition rate of 41.7 MHz seeded by an optical soliton from a tapered fiber. Gap-free signal tuning from 1.35 MUm to 1.95 MUm with corresponding idler wavelengths from 2.2 MUm to 4.5 MUm is demonstrated. The system provides up to 1.8 W average power at 1.4 MUm, more than 1.1 W up to 1.7 MUm, and more than 400 mW up to 4.0 MUm with a signal pulse duration of 200 to 300 fs. It is directly pumped by a solid-state oscillator providing up to 7.4 W at 1.04 MUm wavelength with 425 fs pulse duration. Soliton seeding is shown to lead to excellent pulse-to-pulse stability, but it introduces a timing-jitter on the millisecond timescale. Using a two-stage concept the timing-jitter is efficiently suppressed due to the passive synchronization of both conversion stages. PMID- 24787845 TI - Optical isolation via ?? ?? -symmetric nonlinear Fano resonances. AB - We show that Fano resonances created by two ?? ?? -symmetric nonlinear micro resonators coupled to a waveguide, have line-shape and resonance position that depends on the direction of the incident light. We utilize these features in order to induce asymmetric transport, up to 47 dBs, in the optical C-window. Our theoretical proposal requires low input power and does not compromise the power or frequency characteristics of the output signal. PMID- 24787846 TI - Generation of biphoton correlation trains through spectral filtering. AB - We demonstrate the generation of two-photon correlation trains based on spectral filtering of broadband biphotons. Programmable amplitude filtering is employed to create biphoton frequency combs, which when coupled with optical dispersion allows us to experimentally verify the temporal Talbot effect for entangled photons. Additionally, an alternative spectral phase-filtering approach is shown to significantly improve the overall efficiency of the generation process when a comb-like spectrum is not required. Our technique is ideal for the creation of tunable and high-repetition-rate biphoton states. PMID- 24787847 TI - Latching operation in a tunable wavelength filter using Si sampled grating waveguide with ferroelectric liquid crystal cladding. AB - A tunable wavelength filter fabricated with a latching function is proposed. The proposed tunable wavelength filter consists of a silicon sampled grating waveguide and ferro-electric liquid crystal (FLC) cladding. The sampled grating waveguide in a silicon-on-insulator (SOI) wafer achieved narrower stop bands than that with the conventional uniform grating structure. Enhanced wavelength shift was also obtained due to the increased effect in FLC by using a thinner silicon core. Bistable switching operation with the fabricated device, which was latching without state-sustaining power, was successfully demonstrated. Its switching and latching characteristics are also reported. PMID- 24787848 TI - Effect of surface roughness on self-assembled monolayer plasmonic ruler in nonlocal regime. AB - Recently, self-assembled monolayers (SAMs) have been used for plasmonic rulers to measure the nonlocal influence on the Au nanoparticle - metal film resonance wavelength shift and probe the ultimate field enhancement. Here we examine the influence of surface roughness on this plasmonic ruler in the nonlocal regime by comparing plasmonic resonance shifts for as-deposited and for ultra-flat Au films. It is shown that the resonance shift is larger for ultra-flat films, suggesting that there is not the saturation from nonlocal effects previously reported for the spacer range from 0.7 nm to 1.6 nm. We attribute the previously reported saturation to the planarization of the as-deposited films by thinner SAMs, as measured here by atomic-force microscopy. This work is of interest both in probing the ultimate limits of plasmonic enhancement with SAMs for applications in Raman and nonlinear optics, but also in the study of SAMs planarization as a function surface roughness. PMID- 24787849 TI - Chirped time-resolved CARS microscopy with square-pulse excitation. AB - Time-resolved coherent anti-Stokes Raman scattering (T-CARS) microscopy is a technique known for suppressing non-resonant background by utilizing the different temporal responses of virtual electronic transitions and Raman transitions. However, the previous use of femtosecond excitations in T-CARS microscopy has led to low spectral resolution and difficulty in selectively exciting a single Raman band. Here, we report an improved T-CARS imaging technique with chirped pump and Stokes excitations, and the Stokes pulses were shaped into square pulses. Using a femtosecond probe, we acquired T-CARS images with a high spectral resolution, suppressed non-resonant background, and high resonant signal level. We experimentally demonstrated the selective excitation of two close Raman bands of polystyrene at 1005 cm(-1) and 1035 cm(-1) using our technique; conventional T-CARS would inevitably excite them both with little selectivity. Our novel technique could become an ideal method for high sensitivity, background-free imaging of single Raman bands for a wide variety of samples. PMID- 24787850 TI - Design constraints of optical parametric chirped pulse amplification based on chirped quasi-phase-matching gratings. AB - Chirped quasi-phase-matching (QPM) gratings offer efficient, ultra-broadband optical parametric chirped pulse amplification (OPCPA) in the mid-infrared as well as other spectral regions. Only recently, however, has this potential begun to be realized [1]. In this paper, we study the design of chirped QPM-based OPCPA in detail, revealing several important constraints which must be accounted for in order to obtain broad-band, high-quality amplification. We determine these constraints in terms of the underlying saturated nonlinear processes, and explain how they were met when designing our mid-IR OPCPA system. The issues considered include gain and saturation based on the basic three-wave mixing equations; suppression of unwanted non-collinear gain-guided modes; minimizing and characterizing nonlinear losses associated with random duty cycle errors in the QPM grating; avoiding coincidentally-phase-matched nonlinear processes; and controlling the temporal/spectral characteristics of the saturated nonlinear interaction in order to maintain the chirped-pulse structure required for OPCPA. The issues considered place constraints both on the QPM devices as well as the OPCPA system. The resulting experimental guidelines are detailed. Our results represent the first comprehensive discussion of chirped QPM devices operated in strongly nonlinear regimes, and provide a roadmap for advancing and experimentally implementing OPCPA systems based on these devices. PMID- 24787851 TI - Adiabatically widened silicon microrings for improved variation tolerance. AB - We show that silicon microrings with adiabatically widened bends are more tolerant to dimensional variations than conventional microring designs with uniform waveguide widths. Through wafer-scale measurements of test structures fabricated in the IMEC Standard Passives process (193 nm DUV lithography, 200 mm SOI wafer), improvements in the intra-die and wafer-scale variation of the resonance wavelength are demonstrated. A 2.1* reduction in the standard deviation of the resonance wavelength across the wafer was observed. PMID- 24787852 TI - Towards nonlinear conversion from mid- to near-infrared wavelengths using Silicon Germanium waveguides. AB - We demonstrate the design, fabrication and characterization of a highly nonlinear graded-index SiGe waveguide for the conversion of mid-infrared signals to the near-infrared. Using phase-matched four-wave mixing, we report the conversion of a signal at 2.65 um to 1.77 um using a pump at 2.12 um. PMID- 24787853 TI - Analysis of interchannel crosstalk in multimode parallel optical waveguides using the beam propagation method. AB - We theoretically analyze the origin of inter-channel crosstalk in densely aligned multimode parallel optical waveguides for on-board interconnects using the Beam Propagation Method. In this paper, we demonstrate that the inter-channel crosstalk due to mode coupling is very low in graded-index (GI) circular-core waveguides because the propagation constants of the propagating modes are discrete. Additionally, it is also found that the waveguides with GI-type circular cores is sensitive to the optical confinement in the cladding: low-power cladding modes largely decrease the mode conversion. PMID- 24787854 TI - Unrepeatered DPSK transmission over 360 km SMF-28 fibre using URFL based amplification. AB - Unrepeatered 42.7 Gb/s per channel RZ-DPSK transmission over standard SMF-28 fibre with novel URFL based amplification using fibre Bragg gratings is investigated. OSNR and gain performance are studied experimentally and through simulations. Error free transmission for 16 channels across the full C-band with direct detection was experimentally demonstrated for 280 km span length, as well as 6-channel transmission at 340 km and single-channel transmission up to 360 km (75 dB) without employing ROPA or specialty fibres. PMID- 24787855 TI - Accurate full-field optical displacement measurement technique using a digital camera and repeated patterns. AB - In this study, a novel, fast, and accurate in-plane displacement distribution measurement method is proposed that uses a digital camera and arbitrary repeated patterns based on the moire methodology. The key aspect of this method is the use of phase information of both the fundamental frequency and the high-order frequency components of the moire fringe before and after deformations. Compared with conventional displacement methods and sensors, the main advantages of the method developed herein are its high resolution, accuracy, speed, low cost, and easy implementation. The effectiveness is confirmed by a simple in-plane displacement measurement experiment, and the experimental results indicate that an accuracy of 1/1000 of the pitch can be achieved for various repeated patterns. This method is useful for various applications ranging from the study of displacement and strain distributions in materials science, the biomimetics field, and mechanical material testing, to secure the integrity of infrastructures. PMID- 24787856 TI - Thermally resilient Tm-doped large mode area photonic crystal fiber with symmetry free cladding. AB - The design of a Tm-doped photonic crystal fiber with ~ 80 MUm core diameter and robust single-mode guiding is proposed. State-of-art modal discrimination is obtained through the suppression of the inner cladding C(6nu) symmetry, which fosters the delocalization of the LP(11)-like mode. The effects of thermally induced refractive index change are investigated by means of a computationally efficient thermal model, and the possibility to obtain wide-band single-mode propagation and effective area exceeding 2500 MUm(2) under a heat load of over 300 W/m is demonstrated. PMID- 24787857 TI - Snapshot coherence-gated direct wavefront sensing for multi-photon microscopy. AB - Deep imaging in turbid media such as biological tissue is challenging due to scattering and optical aberrations. Adaptive optics has the potential to compensate the tissue aberrations. We present a wavefront sensing scheme for multi-photon scanning microscopes using the pulsed, near-infrared light reflected back from the sample utilising coherence gating and a confocal pinhole to isolate the light from a layer of interest. By interfering the back-reflected light with a tilted reference beam, we create a fringe pattern with a known spatial carrier frequency in an image of the back-aperture plane of the microscope objective. The wavefront aberrations distort this fringe pattern and thereby imprint themselves at the carrier frequency, which allows us to separate the aberrations in the Fourier domain from low spatial frequency noise. A Fourier analysis of the modulated fringes combined with a virtual Shack-Hartmann sensor for smoothing yields a modal representation of the wavefront suitable for correction. We show results with this method correcting both DM-induced and sample-induced aberrations in rat tail collagen fibres as well as a Hoechst-stained MCF-7 spheroid of cancer cells. PMID- 24787858 TI - Characterization and control of peak intensity distribution at the focus of a spatiotemporally focused femtosecond laser beam. AB - We report on experimental examination of two-photon fluorescence excitation (TPFE) at the focus of a spatially chirped femtosecond laser beam, which reveals an unexpected tilted peak intensity distribution in the focal spot. Our theoretical calculation shows that the tilting of the peak intensity distribution originates from the fact that along the optical axis of objective lens, the spatiotemporally focused pulse reaches its shortest duration exactly at the focal plane. However, when moving away from the optical axis along the direction of spatial chirp of the incident pulse, the pulse reaches its shortest duration either before or after the focal plane, depending on whether the pulse duration is measured above or below the optical axis as well as the sign of the spatial chirp. The tilting of the peak intensity distribution in the focal spot of the spatiotemporally focused femtosecond laser beam can play important roles in applications such as femtosecond laser micromachining and bio-imaging. PMID- 24787859 TI - Fiber-coupled balanced optical cross-correlator using PPKTP waveguides. AB - We present a fiber-coupled balanced optical cross-correlator using waveguides in periodically-poled KTiOPO(4) (PPKTP). The normalized conversion efficiency of the waveguide device is measured to be eta(0) = 1.02% / [W . cm(2)], which agrees well with theory and simulation. This result represents an expected improvement of a factor of 20 over previous bulk-optic devices. The sensitivity of the cross correlator is characterized and shown to be comparable to the free-space bulk optic version, with the potential for significant performance enhancements in the future. PMID- 24787860 TI - Electrically switchable cholesteric gratings based on slit electrodes. AB - An electrically switchable diffraction grating (ESDG) based on cholesteric liquid crystal (CLC) filled into the cell with slit electrodes is demonstrated in this study. On one hand, with low voltage, the ESDG has high second order diffraction efficiency because of the alternating planar and fingerprint textures. With high voltage, on the other hand, the ESDG has high first order diffraction efficiency because of the alternating planar and homeotropic textures. The first and second order diffraction efficiencies of ESDG are electrically swapped. The maximum diffraction efficiency of the ESDG is approximately 32% at each grating mode. PMID- 24787862 TI - Compressive holographic two-dimensional localization with 1/30(2) subpixel accuracy. AB - We propose the use of compressive holography for two-dimensional (2D) subpixel motion localization. Our approach is based on computational implementation of edge-extraction using a Fourier-plane spiral phase mask, followed by compressive reconstruction of the edge of the object. Using this technique and relatively low cost computer and piezo motion stage to establish ground truth for the motion, we demonstrated localization within 1/30th of a camera pixel in each linear dimension. PMID- 24787861 TI - Measurement of wavefront aberrations and lens deformation in the accommodated eye with optical coherence tomography-equipped wavefront system. AB - To quantitatively approach the relationship between optical changes in an accommodated eye and the geometrical deformation of its crystalline lens, a long scan-depth anterior segment OCT equipped wavefront sensor was developed and integrated with a Badal system. With this system, accommodation was stimulated up to 6.0D in the left eye and also measured in the same eye for three subjects. High correlations between the accommodative responses of refractive power and the radius of the anterior lens surface were found for the three subjects (r>0.98). The change in spherical aberration was also highly correlated with the change in lens thickness (r>0.98). The measurement was very well repeated at a 2nd measurement session on the same day for the three subjects and after two weeks for one subject. The novelty of incorporating the Badal system into the OCT equipped wavefront sensor eliminated axial misalignment of the measurement system with the test eye due to accommodative vergence, as in the contralateral paradigm. The design also allowed the wavefront sensor to capture conjugated sharp Hartmann-Shack images in accommodated eyes to accurately analyze wavefront aberrations. In addition, this design extended the accommodation range up to 10.0D. By using this system, for the first time, we demonstrated linear relationships of the changes between the refractive power and the lens curvature and also between the spherical aberration and the lens thickness during accommodation in vivo. This new system provides an accurate and useful technique to quantitatively study accommodation. PMID- 24787863 TI - Adaptive 84.44-190 Mbit/s phosphor-LED wireless communication utilizing no blue filter at practical transmission distance. AB - We propose and experimentally demonstrate a white-light phosphor-LED visible light communication (VLC) system with an adaptive 84.44 to 190 Mbit/s 16 quadrature-amplitude-modulation (QAM) orthogonal-frequency-division-multiplexing (OFDM) signal utilizing bit-loading method. Here, the optimal analogy pre equalization design is performed at LED transmitter (Tx) side and no blue filter is used at the Rx side. Hence, the ~1 MHz modulation bandwidth of phosphor-LED could be extended to 30 MHz. In addition, the measured bit error rates (BERs) of < 3.8 * 10(-3) [forward error correction (FEC) threshold] at different measured data rates can be achieved at practical transmission distances of 0.75 to 2 m. PMID- 24787864 TI - Numerical analysis on current and optical confinement of III-nitride vertical cavity surface-emitting lasers. AB - We report on the numerical analysis of the electrical and optical properties of current-injected III-nitride based vertical-cavity surface-emitting lasers (VCSELs) with three types of current confinement schemes: the conventional planar indium tin oxide (ITO) type, the AlN-buried type without ITO, and the hybrid type. The proposed hybrid structure, which combines an ITO layer and an intracavity AlN aperture, exhibits not only uniform current distribution but also enhanced lateral optical confinement. Thus, the hybrid type design shows remarkably better performance including lower threshold current and series resistance compared with the planar-ITO type and the AlN-buried type. Furthermore, the multi-transverse mode lasing behavior induced by strong index guiding of the AlN aperture is suppressed to single transverse mode operation by reducing the aperture size. Such design provides a powerful solution for the high performance III-N based VCSELs and is also viable by using current state of the art processing techniques. PMID- 24787865 TI - Multifocal spot array generated by fractional Talbot effect phase-only modulation. AB - We propose an approach for generating a multifocal spot array (MSA) with a high numerical aperture (NA) objective. The MSA is generated by using a special designed phase-only modulation at the back aperture of an objective. Without using any iteration algorithm, the modulated phase pattern is directly obtained by the simple analytical expressions based on the fractional Talbot effect. It is shown that the number of the spots in the focal region depends solely on the fractional Talbot parameter. By engineering the phase pattern with a large fractional Talbot parameter, a large number of focal spots can be created. Furthermore, the intensity distribution of each focal spot can be manipulated by introducing a composite spatially shifted vortex beam (CSSVB) as the incident field, leading to creation of various kinds of specific shaped spots. Consequently, the MSA composed of multiple individual spots with specific shape is created by focusing the CSSVB combined with the multifocal phase-only modulation. These kinds of MSAs may be found applications in parallel optical micromanipulation, multifocal multiphoton microscopic imaging, and parallel laser printing nanofabrication. PMID- 24787866 TI - A circuit model for plasmonic resonators. AB - Simple circuit models provide valuable insight into the properties of plasmonic resonators. Yet, it is unclear how the circuit elements can be extracted and connected in the model in an intuitive and accurate manner. Here, we present a detailed treatment for constructing such circuits based on energy and charge oscillation considerations. The accuracy and validity of this approach was demonstrated for a gold nanorod, and extended for a split-ring resonator with varying gap sizes, yielding good intuitive and quantitative agreement with full electromagnetic simulations. PMID- 24787867 TI - Time-sequential autostereoscopic 3-D display with a novel directional backlight system based on volume-holographic optical elements. AB - A novel directional backlight system based on volume-holographic optical elements (VHOEs) is demonstrated for time-sequential autostereoscopic three-dimensional (3 D) flat-panel displays. Here, VHOEs are employed to control the direction of light for a time-multiplexed display for each of the left and the right view. Those VHOEs are fabricated by recording interference patterns between collimated reference beams and diverging object beams for each of the left and right eyes on the volume holographic recording material. For this, self-developing photopolymer films (Bayfol(r) HX) were used, since those simplify the manufacturing process of VHOEs substantially. Here, the directional lights are similar to the collimated reference beams that were used to record the VHOEs and create two diffracted beams similar to the object beams used for recording the VHOEs. Then, those diffracted beams read the left and right images alternately shown on the LCD panel and form two converging viewing zones in front of the user's eyes. By this he can perceive the 3-D image. Theoretical predictions and experimental results are presented and the performance of the developed prototype is shown. PMID- 24787868 TI - Localization and quantification of reflective events along an optical fiber using a bi-directional TRA technique. AB - We report on the theory and the implementation of a novel approach for the detection and localization of a reflective event along a fiber link. By launching a continuous-wave signal into both fiber ends and by analyzing the transmitted and reflected/backscattered optical powers, it is possible to localize an optical event and to quantify the induced insertion and return losses simultaneously. The novel idea of utilizing bi-directional measurement allows the localization of both reflective and non-reflective events. Theoretical and experimental studies show that for a 10 km-long single mode fiber, the localization accuracy can be in the range of 5.0 m. PMID- 24787869 TI - A method for super-resolved CARS microscopy with structured illumination in two dimensions. AB - We propose a structured illumination scheme for achieving widefield coherent anti Stokes Raman scattering (CARS) microscopy with a resolution surpassing the diffraction limit in two dimensions (2D). By acquiring a set of coherent images of a sample with third-order nonlinear susceptibility illuminated by the phase matched excitation field of square lattice patterns, a 2D super-resolution CARS image can be reconstructed. We derive a theoretical framework to describe the coherent image formation and reconstruction scheme for this structured illumination CARS imaging system and carry out numerical simulations to investigate its imaging performance. The results demonstrate that our method promises a particular benefit on CARS microscopy by adding the super-resolution capability to improve its 2D spatial resolution by a factor of approximately three. PMID- 24787870 TI - Detection and compensation of basis deviation in satellite-to-ground quantum communications. AB - Basis deviation is the reference-frame deviation between a sender and receiver caused by satellite motion in satellite-to-ground quantum communications. It increases the quantum-bit error ratio of the system and must be compensated for to guarantee reliable quantum communications. We present a new scheme for compensating for basis deviation that employs a BB84 decoding module to detect basis deviation and half-wave plate to provide compensation. Based on this detection scheme, we design a basis-deviation compensation approach and test its feasibility in a voyage experiment. Unlike other polarization-correction schemes, this compensation scheme is simple, convenient, and can be easily implemented in satellite-to-ground quantum communications without increased burden to the satellite. PMID- 24787871 TI - Adaptive fringe-pattern projection for image saturation avoidance in 3D surface shape measurement. AB - In fringe-projection 3D surface-shape measurement, image saturation results in incorrect intensities in captured images of fringe patterns, leading to phase and measurement errors. An adaptive fringe-pattern projection (AFPP) method was developed to adapt the maximum input gray level in projected fringe patterns to the local reflectivity of an object surface being measured. The AFPP method demonstrated improved 3D measurement accuracy by avoiding image saturation in highly-reflective surface regions while maintaining high intensity modulation across the entire surface. The AFPP method can avoid image saturation and handle varying surface reflectivity, using only two prior rounds of fringe-pattern projection and image capture to generate the adapted fringe patterns. PMID- 24787872 TI - Fabrication of water-cooled laser silicon mirror by direct laser sintering. AB - Coppery heat sink with micro pores and Sub-millimeter channel has been fabricated by direct laser sintering on the back of the silicon mirror. To verify the heat dissipation capability of the fabricated heat sink, a Twyman-Green interferometer was employed to measure the thermal deformation of the silicon mirror radiated by a high power laser. It is shown that the thermal deformation of the mirror increases with the irradiating time and laser intensity. The heat balance can be achieved after several seconds of laser irradiation even when the net absorbed laser power density is up to 5.3 * 10(5) W/m(2). The time for reaching the heat balance also increases with the laser intensity. The maximum thermal deformation of the mirror is 0.65 um if the net absorbed laser power density is 5.3 * 10(5) W/m(2). PMID- 24787873 TI - Asymmetric band-pass plasmonic nanodisk filter with mode inhibition and spectrally splitting capabilities. AB - A compact wavelength band-pass filter based on metal-insulator-metal (MIM) nanodisk cavity is proposed and numerically investigated by using Finite Difference Time-Domain (FDTD) simulations. It is found that the transmission characteristics of the filter can be easily adjusted by changing the geometrical parameters of the radius of the nanodisk and coupling distance between the nanodisk and waveguide. By extending the length of input/output waveguides, the filter shows the resonant mode inhibition function. Basing on this characteristic, a two-port wavelength demultiplexer is designed, which can separate resonant modes inside the nanodisk with high transmission up to 70%. The waveguide filter may become a potential application for the design of devices in highly integrated optical circuits. PMID- 24787874 TI - Correcting vortex splitting in higher order vortex beams. AB - We demonstrate a general method for the first order compensation of singularity splitting in a vortex beam at a single plane. By superimposing multiple forked holograms on the SLM used to generate the vortex beam, we are able to compensate vortex splitting and generate beams with desired phase singularities of order l = 0, 1, 2, and 3 in one plane. We then extend this method by application of a radial phase, in order to simultaneously compensate the observed vortex splitting at two planes (near and far field) for an l = 2 beam. PMID- 24787875 TI - Mode competition of two bandedge lasing from dye doped cholesteric liquid crystal laser. AB - Mode competition of two-lasing modes at the photonic bandedge from dye-doped cholesteric liquid crystal lasing was studied by the alternation of temperatures. The increase or decrease of the wavelengths from photonic bandedges versus the alternation of temperature is attributed to the variation of helical twist power (HTP) and thus it shows the completely different result by choosing two of different nematic liquid crystals (MDA-981602 and MDA-3970). At certain temperature, the intensity contrast and slope efficiency between long and short emission lasing peaks were dominated from the experienced gain or loss of laser for the position of the photonic bandedge. By the linear combination of these two lasing modes with different emission wavelengths and intensity contrast at distinct temperature, the wide tuning of the output colors can be revealed from the CIE chromaticity diagram and thus it has opportunity to be used in the display technology in the near future. PMID- 24787876 TI - Acousto-optically cavity dumped Tm:YAG laser with 54 ns pulses at 200 kHz repetition rate. AB - In this paper, a cavity dumped Tm:YAG laser was obtained for the first time, whose output pulse width was constant at 54 ns. Maximum repetition rate was 200 kHz, and wavelength was 2013 nm. Its average output power was 595 mW. The laser cavity length was 208 mm with an inserted acousto-optic modulator. Pulses were coupled out of the lateral surface of the cavity when Radio Frequency was added into the modulator. And lens was used to compensate the thermal focal length of Tm:YAG crystal. Numerical calculation of pulse was done. PMID- 24787877 TI - Negligible nonlinear absorption in hydrogenated amorphous silicon at 1.55 MUm for ultra-fast nonlinear signal processing. AB - Three-photon absorption (3PA) has been observed as the dominant mechanism for nonlinear absorption in wide-bandgap hydrogenated amorphous silicon (a-Si:H-W) at 1.55 MUm. The nonlinear index n2 and 3PA coefficient were measured to be 22 * 10( 17)m(2)/W and 5.0 * 10(-26) m(3)/W(2) respectively at 1.55 MUm by using the z scan method. This indicates that the figure of merit (FOM) of this material is intensity dependent. A value FOM>60 is predicted at intensities below 0.5 GW/cm(2) which is the maximum practical intensity for high-bit-rate (>160 GB/s) alloptical signal processing. The nonlinear phase change in a-Si:H-W has been compared with other common nonlinear materials (c-Si, As(2)S(3), Ge(11.5)As(24)Se(64.5)) for a 2 cm long waveguide with a-Si:H-W showing the greatest potential for integrated devices for all-optical processing with a high nonlinear index and negligible nonlinear absorption at intensities < 0.5 GW/cm(2). PMID- 24787878 TI - Expanded all-optical programmable logic array based on multi-input/output canonical logic units. AB - We present an expanded all-optical programmable logic array (O-PLA) using multi input and multi-output canonical logic units (CLUs) generation. Based on four wave mixing (FWM) in highly nonlinear fiber (HNLF), two-input and three-input CLUs are simultaneously achieved in five different channels with an operation speed of 40 Gb/s. Clear temporal waveforms and wide open eye diagrams are successfully observed. The effectiveness of the scheme is validated by extinction ratio and optical signal-to-noise ratio measurements. The computing capacity, defined as the total amount of logic functions achieved by the O-PLA, is discussed in detail. For a three-input O-PLA, the computing capacity of the expanded CLUs-PLA is more than two times as large as that of the standard CLUs PLA, and this multiple will increase to more than three and a half as the idlers are individually independent. PMID- 24787879 TI - The spectral shift between near- and far-field resonances of optical nano antennas. AB - Within the past several years a tremendous progress regarding optical nano antennas could be witnessed. It is one purpose of optical nano-antennas to resonantly enhance light-matter interactions at the nanoscale, e.g. the interaction of an external illumination with molecules. In this specific, but in almost all schemes that take advantage of resonantly enhanced electromagnetic fields in the vicinity of nano-antennas, the precise knowledge of the spectral position of resonances is of paramount importance to fully exploit their beneficial effects. Thus far, however, many nano-antennas were only optimized with respect to their far-field characteristics, i.e. in terms of their scattering or extinction cross sections. Although being an emerging feature in many numerical simulations, it was only recently fully appreciated that there exists a subtle but very important difference in the spectral position of resonances in the near-and the far-field. With the purpose to quantify this shift, Zuloaga et al. suggested a Lorentzian model to estimate the resonance shift. Here, we devise on fully analytical grounds a strategy to predict the resonance in the near-field directly from that in the far-field and disclose that the issue is involved and multifaceted, in general. We outline the limitations of our theory if more sophisticated optical nano-antennas are considered where higher order multipolar contributions and higher order antenna resonances become increasingly important. Both aspects are highlighted by numerically studying relevant nano-antennas. PMID- 24787880 TI - Compensation of anisotropy effects in the generation of two-photon light. AB - We analyse a method to compensate for anisotropy effects in the spatial distribution of parametric down-conversion (PDC) radiation in bulk crystals. In this method, a single nonlinear crystal is replaced by two consecutive crystals with opposite transverse walk-off directions. We implement a simple numerical model to calculate the spatial distribution of intensity and correlations, as well as the Schmidt mode structure, with an account for the anisotropy. Experimental results are presented which prove the validity of both the model and the method. PMID- 24787881 TI - A full-duplex lightwave transmission system with an innovative VCSEL-based PM-to IM converter. AB - A full-duplex lightwave transmission system employing innovative VCSEL-based PM to-IM converters to deliver intensity-modulated CATV/phase-modulated RoF/intensity-remodulated RoF signals over two 40-km SMFs links is proposed and demonstrated. To be the first one of employing VCSEL-based PM-to-IM converters in full-duplex lightwave transmission systems, the downstream light is successfully intensity-remodulated with RoF signal for up-link transmission. Good performances of CNR/CSO/CTB are achieved for downstream CATV signal transmission, and low BER values are obtained for both downstream and upstream RoF signals transmissions. Our proposed systems present brilliant performances in delivering hybrid CATV and RoF signals. Such a full-duplex lightwave transmission system would be very attractive for fiber trunk applications to provide broadband integrated services. PMID- 24787882 TI - An optimized watermarking scheme using an encrypted gyrator transform computer generated hologram based on particle swarm optimization. AB - In this paper, a novel secure optimal image watermarking scheme using an encrypted gyrator transform computer generated hologram (CGH) in the contourlet domain is presented. A new encrypted CGH technique, which is based on the gyrator transform, the random phase mask, the three-step phase-shifting interferometry and the Fibonacci transform, has been proposed to produce a hologram of a watermark first. With the huge key space of the encrypted CGH, the security strength of the watermarking system is enhanced. To achieve better imperceptibility, an improved quantization embedding algorithm is proposed to embed the encrypted CGH into the low frequency sub-band of the contourlet transformed host image. In order to obtain the highest possible robustness without losing the imperceptibility, particle swarm optimization algorithm is employed to search the optimal embedding parameter of the watermarking system. In comparison with other method, the proposed watermarking scheme offers better performances for both imperceptibility and robustness. Experimental results demonstrate that the proposed image watermarking is not only secure and invisible, but also robust against a variety of attacks. PMID- 24787883 TI - All-optical helicity dependent magnetic switching in Tb-Fe thin films with a MHz laser oscillator. AB - We demonstrate all-optical magnetic switching (AOS) in an amorphous Tb30Fe70 thin film, triggered by a 5.1 MHz laser oscillator. The magnetic layer is grown on SiO2/Si substrate. An identical magnetic film deposited on a microscope glass slide reveals no AOS but solely thermally induced demagnetization. This effect is due to heat accumulation by multiple laser pulses because of the low thermal conductivity of the glass substrate. In contrast, the use of a proper heat sink (e.g. SiO2/Si) avoids the need for low repetitive laser amplifier systems to induce AOS and paves the way for a cheap and simple technical implementation using conventional laser oscillators. PMID- 24787884 TI - Ultraviolet electroluminescence from hetero p-n junction between a single ZnO microsphere and p-GaN thin film. AB - We report ultraviolet electroluminescence from a hetero p-n junction between a single ZnO microsphere and p-GaN thin film. ZnO microspheres, which have high crystalline quality, have been synthesized by ablating a ZnO sintered target. It was found that synthesized ZnO microspheres had a high-optical property and exhibit the laser action in the whispering gallery mode under pulsed optical pumping. A hetero p-n junction was formed between the single ZnO microsphere/ p GaN thin film, and a good rectifying property with a turn-on voltage of approximately 6 V was observed in I-V characteristic across the junction. Ultraviolet and visible electroluminescence were observed under forward bias. PMID- 24787885 TI - Prediction of radiation pressure force exerted on moving particles by the two level skeletonization. AB - A fast full-wave method for computing radiation pressure force (RPF) exerted by shaped light beams on moving particles is presented. The problem of evaluating RPF exerted on a moving particle by a single excitation beam is converted into that of computing RPF's exerted on a static particle by multiple beams. The discretization of different beams leads to distinct right hand sides (RHS's) for the matrix system. To avoid solving each RHS by the brute-force manner, the algorithm conducts low-rank decomposition on the excitation matrix consisting of all RHS's to figure out the so-called skeleton light beams by interpolative decomposition (ID). The peak memory requirement of the skeletonization is a bottle-neck if the particle is large. A two-level skeletonization scheme is proposed to solve this problem. Some numerical experiments on arbitrarily shaped homogeneous particles are performed to illustrate the performance and capability of the developed method. PMID- 24787886 TI - Texture analysis microscopy: quantifying structure in low-fidelity images of dense fluids. AB - Optical images are often corrupted by noise, low contrast, uneven illumination and artefacts, which may pose significant challenges to image analysis, particularly for dense fluids. Traditionally, noise removal and contrast enhancement are achieved by global arithmetic operations on the image as a whole, and/or by image convolution with various kernels. However, these methods work under very limited conditions and can compromise detail within the image. Here, we develop a new technique, texture analysis microscopy (TAM), to overcome these challenges based on the method of image correlation. TAM recasts an image by the statistical similarities between a raw image and a template feature (e.g. a Gaussian) that best approximates features in the image. We demonstrate the superiority of TAM by applying it to low-fidelity images under conditions where traditional methods fail or have deteriorative performance, for analyses including structural correlations, particle identification and sizing. PMID- 24787887 TI - Multi-polarization fringe projection imaging for high dynamic range objects. AB - Traditional fringe-projection three-dimensional (3D) imaging techniques struggle to estimate the shape of high dynamic range (HDR) objects where detected fringes are of limited visibility. Moreover, saturated regions of specular reflections can completely block any fringe patterns, leading to lost depth information. We propose a multi-polarization fringe projection (MPFP) imaging technique that eliminates saturated points and enhances the fringe contrast by selecting the proper polarized channel measurements. The developed technique can be easily extended to include measurements captured under different exposure times to obtain more accurate shape rendering for very HDR objects. PMID- 24787888 TI - Fiber-integrated optical nano-tweezer based on a bowtie-aperture nano-antenna at the apex of a SNOM tip. AB - We propose a new concept of fiber-integrated optical nano-tweezer on the basis of a single bowtie-aperture nano-antenna (BNA) fabricated at the apex of a metal coated SNOM tip. We demonstrate 3D optical trapping of 0.5 micrometer latex beads with input power which does not exceed 1 mW. Optical forces induced by the BNA on tip are then analyzed numerically. They are found to be 10(3) times larger than the optical forces of a circular aperture of the same area. Such a fiber nanostructure provides a new path for manipulating nano-objects in a compact, flexible and versatile architecture and should thus open promising perspectives in physical, chemical and biomedical domains. PMID- 24787889 TI - Orthogonal dispersive spectral-domain optical coherence tomography. AB - Ultrahigh depth range spectral domain optical coherence tomography (SDOCT) can be realized based on the orthogonal dispersive spectrometer consisted by a high spectral resolution virtually-imaged phased array (VIPA) and a low spectral resolution grating. However, two critical issues result in the challenge of obtaining desirable one-dimensional (1-D) spectra from the recorded two dimensional (2-D) orthogonal spectra for high-quality OD-SDOCT imaging. One is the wavenumber mapping errors and the other is the periodic intensity modulations. The paper proposes a method for desirable reconstruction of 1-D spectra from the recorded 2-D orthogonal spectra. A sample etalon with identical parameters to the dispersive VIPA is used to determine the free spectrum range (FSR) of the VIPA, and spectral phases from two reflecting mirrors are further applied for broadband wavenumber calibration. The cascading of column spectra are performed from interval of four lines of column spectra, and four records of cascaded 1-D spectra are obtained and then averaged to alleviate the periodic intensity modulations. Broadband 1-D spectra are thus reconstructed with an ultrahigh spectral resolution. To demonstrate the feasibility of the proposed method, three typical samples are imaged by the OD-SDOCT system. PMID- 24787890 TI - Hollow antiresonant fibers with low bending loss. AB - We first use numerical simulations to show that bending losses of hollow antiresonant fibers are a strong function of their geometrical structure. We then demonstrate this by fabricating a hollow antiresonant fiber which presents a bending loss as low as 0.25 dB/turn at a wavelength of 3.35 MUm and a bend radius of 2.5 cm. This fiber has a relatively low attenuation (<200 dB/km) over 600 nm mid-infrared spectral range. PMID- 24787891 TI - Inhibition of very late antigen-4 and leukocyte function-associated antigen-1 in experimental autoimmune uveoretinitis. AB - B10.RIII mice were immunized with interphotoreceptor retinoid binding protein peptide to induce uveitis. Mice were injected intraperitoneally with anti-very late antigen-4 (VLA-4), anti-leukocyte function-associated antigen-1 (LFA-1), or a control Ab every other day from Day 5 to Day 13 post-immunization. The eyes and spleens were harvested on Day 14 or 28. The eyes were used for histologic/cytokine mRNA expression analyses. The spleens were used for Ag-recall cytokine production assays and intracellular cytokine assays. Treatment with both Abs led to a profoundly significant reduction in severity of uveitis and cytokine mRNA expression in the eye. However, cytokine production by splenocytes was significantly upregulated. Discontinuation of Ab treatment led to an increase in uveitis severity and cytokine mRNA expression in the eye, but led to a decrease in cytokine production and intracellular IFN-gamma(+) and IL-17A(+)cytokine profile by splenocytes. Thus, blockade of these molecules using specific Abs may be a therapeutic option for patients with uveitis; however, such treatment must be continued. PMID- 24787892 TI - A meta-analysis of pulmonary function with pulsatile perfusion in cardiac surgery. AB - The aim of this study was to determine whether pulsatile or nonpulsatile perfusion had a greater effect on pulmonary dysfunction in randomized controlled trials. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were used to identify available articles published before April 13, 2013. A meta analysis was conducted on the effects of pulsatile perfusion on postoperative pulmonary function, intubation time, and the lengths of intensive care unit (ICU) and hospital stays. Eight studies involving 474 patients who received pulsatile perfusion and 496 patients who received nonpulsatile perfusion during cardiopulmonary bypass (CPB) were considered in the meta-analysis. Patients receiving pulsatile perfusion had a significantly greater PaO2 /FiO2 ratio 24 h and 48 h post-operation (P < 0.00001, both) and significantly lower chest radiograph scores at 24 h and 48 h post-operation (P < 0.00001 and P = 0.001, respectively) compared with patients receiving nonpulsatile perfusion. The incidence of noninvasive ventilation for acute respiratory insufficiency was significantly lower (P < 0.00001), and intubation time and ICU and hospital stays were shorter (P = 0.004, P < 0.00001, and P < 0.00001, respectively) in patients receiving pulsatile perfusion during CPB compared with patients receiving nonpulsatile perfusion. In conclusion, our meta-analysis suggests that the use of pulsatile flow during CPB results in better postoperative pulmonary function and shorter ICU and hospital stays. PMID- 24787893 TI - Antidyslipidemic effects of a farnesoid X receptor antagonist in primates. AB - AIMS: We investigated antidyslipidemic effects of a farnesoid X receptor antagonist compound-T3 in non-human primates as a novel treatment approach for dyslipidemia. MAIN METHODS: Cynomolgus monkeys were fed a high-fat diet over 3 weeks. Drugs were administered to the monkeys for a week, and their plasma and fecal lipid parameters were measured. KEY FINDINGS: Compound-T3 dose-dependently decreased the plasma non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B levels in high-fat diet-fed cynomolgus monkeys. The plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7alpha-hydroxylase activity, and total fecal bile acid levels increased, suggesting that the hypocholesterolemic effects would be dependent on the activation of cholesterol catabolism in the liver. Compound-T3 significantly increased the plasma levels of HDL cholesterol and apolipoprotein A-I. In this condition, the cholesterol absorption inhibitor ezetimibe significantly decreased the plasma non-HDL cholesterol levels and increased the fecal cholesterol levels without affecting plasma HDL cholesterol and triglyceride levels. Bile acid sequestrant cholestyramine tended to decrease plasma non-HDL cholesterol and increase fecal bile acid levels. The cholesteryl ester transfer protein inhibitor torcetrapib significantly increased plasma HDL cholesterol levels without affecting plasma non-HDL cholesterol and fecal cholesterol levels. SIGNIFICANCE: The results of ezetimibe, cholestyramine, and torcetrapib treatments indicate that our high-fat diet fed monkey model would be a preferred animal model for studying non-statin type antidyslipidemic drugs. Compound-T3 significantly decreased non-HDL cholesterol levels and increased HDL cholesterol levels in the monkey model, suggesting that a farnesoid X receptor antagonist could be a therapeutic option in human dyslipidemia. PMID- 24787894 TI - Mechanically and chemically tunable cell culture system for studying the myofibroblast phenotype. AB - Cell culture systems for studying the combined effects of matrix proteins and mechanical forces on the behavior of soft tissue cells have not been well developed. Here, we describe a new biomimetic cell culture system that allows for the study of mixtures of matrix proteins while controlling mechanical stiffness in a range that is physiological for soft tissues. This system consists of layer by-layer (LbL)-assembled films of native matrix proteins atop mechanically tunable soft supports. We used hepatic stellate cells, which differentiate to myofibroblasts in liver fibrosis, for proof-of-concept studies. By culturing cells on collagen and lumican LbL-modified hydrogels, we demonstrate that this system is noncytotoxic and offers a valid control substrate, that the hydrogel determines the overall system mechanics, and that the addition of lumican to collagen influences the stellate cell phenotype. LbL-modified hydrogels offer the potential to study the influence of complex environmental factors on soft-tissue cells in culture. PMID- 24787895 TI - Deterministic cold cathode electron emission from carbon nanofibre arrays. AB - The ability to accurately design carbon nanofibre (CN) field emitters with predictable electron emission characteristics will enable their use as electron sources in various applications such as microwave amplifiers, electron microscopy, parallel beam electron lithography and advanced Xray sources. Here, highly uniform CN arrays of controlled diameter, pitch and length were fabricated using plasma enhanced chemical vapour deposition and their individual emission characteristics and field enhancement factors were probed using scanning anode field emission mapping. For a pitch of 10 um and a CN length of 5 um, the directly measured enhancement factors of individual CNs was 242, which was in excellent agreement with conventional geometry estimates (240). We show here direct empirical evidence that in regular arrays of vertically aligned CNs the overall enhancement factor is reduced when the pitch between emitters is less than half the emitter height, in accordance to our electrostatic simulations. Individual emitters showed narrow Gaussian-like field enhancement distributions, in excellent agreement with electric field simulations. PMID- 24787896 TI - Axonal transport plays a crucial role in mediating the axon-protective effects of NmNAT. AB - Deficits in axonal transport are thought to contribute to the pathology of many neurodegenerative diseases. Expressing the slow Wallerian degeneration protein (Wld(S)) or related nicotinamide mononucleotide adenyltransferases (NmNATs) protects axons against damage from a broad range of insults, but the ability of these proteins to protect against inhibition of axonal transport has received little attention. We set out to determine whether these proteins can protect the axons of cultured hippocampal neurons from damage due to hydrogen peroxide or oxygen-glucose deprivation (OGD) and, in particular, whether they can reduce the damage that these agents cause to the axonal transport machinery. Exposure to these insults inhibited the axonal transport of both mitochondria and of the vesicles that carry axonal membrane proteins; this inhibition occurred hours before the first signs of axonal degeneration. Expressing a cytoplasmically targeted version of NmNAT1 (cytNmNAT1) protected the axons against both insults. It also reduced the inhibition of transport when cells were exposed to hydrogen peroxide and enhanced the recovery of transport following both insults. The protective effects of cytNmNAT1 depend on mitochondrial transport. When mitochondrial transport was inhibited, cytNmNAT1 was unable to protect axons against either insult. The protective effects of mitochondrially targeted NmNAT also were blocked by inhibiting mitochondrial transport. These results establish that NmNAT robustly protects the axonal transport system following exposure to OGD and reactive oxygen species and may offer similar protection in other disease models. Understanding how NmNAT protects the axonal transport system may lead to new strategies for neuroprotection in neurodegenerative diseases. PMID- 24787897 TI - PSD-93 deletion inhibits Fyn-mediated phosphorylation of NR2B and protects against focal cerebral ischemia. AB - Modification of N-methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity appears to be a potential target in the treatment of ischemic stroke. Postsynaptic density protein-93 (PSD-93) specifically binds the C-terminal tails of the NMDAR, which is critical to couple NMDAR activity to specific intracellular signaling. This study is to investigate whether PSD-93 disruption displays neuroprotection in a focal ischemic stroke model of adult mice and, if it does, to explore possible mechanisms. It was found that, following middle cerebral artery occlusion (MCAO), PSD-93 knockout (KO) mice manifested significant reductions in infarcted volume, neurological deficits and number of degenerated neurons. PSD-93 deletion also reduced cultured cortical neuronal death caused by glucose and oxygen deprivation (OGD). Ischemic long term potentiation (i-LTP) could not be induced in the PSD-93 KO group and wild type (WT) groups pretreated with either AP-5 (NMDAR inhibitor) or PP2 (Src family inhibitor). PSD-93 KO decreased the phosphorylation of the NR2B at Tyr1472 and the interaction between NR2B and Fyn after MCAO. Together, our study demonstrated that PSD-93 KO confers profound neuroprotection against ischemic brain injury, which probably links to the inhibitory effect on Fyn-mediated phosphorylation of NR2B caused by PSD-93 deletion. These findings may provide a novel avenue for the treatment of ischemic stroke. PMID- 24787898 TI - Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration. AB - Ca(2+) and Zn(2+) have both been implicated in the induction of acute ischemic neurodegeneration. We recently examined changes in intracellular Zn(2+) and Ca(2+) in CA1 pyramidal neurons subjected to oxygen glucose deprivation (OGD), and found that Zn(2+) rises precede and contribute to the onset of terminal Ca(2+) rises ("Ca(2+) deregulation"), which are causatively linked to a lethal loss of membrane integrity. The present study seeks to examine the specific role of intramitochondrial Zn(2+) accumulation in ischemic injury, using blockers of the mitochondrial Ca(2+) uniporter (MCU), through which both Zn(2+) and Ca(2+) appear able to enter the mitochondrial matrix. In physiological extracellular Ca(2+), treatment with the MCU blocker, Ruthenium Red (RR), accelerated the Ca(2+) deregulation, most likely by disrupting mitochondrial Ca(2+) buffering and thus accelerating the lethal cytosolic Ca(2+) overload. However, when intracellular Ca(2+) overload was slowed, either by adding blockers of major Ca(2+) entry channels or by lowering the concentration of Ca(2+) in the extracellular buffer, Ca(2+) deregulation was delayed, and under these conditions either Zn(2+) chelation or MCU blockade resulted in similar further delays of the Ca(2+) deregulation. In parallel studies using the reactive oxygen species (ROS) indicator, hydroethidine, lowering Ca(2+) surprisingly accelerated OGD induced ROS generation, and in these low Ca(2+) conditions, either Zn(2+) chelation or MCU block slowed the ROS generation. These studies suggest that, during acute ischemia, Zn(2+) entry into mitochondria via the MCU induces mitochondrial dysfunction (including ROS generation) that occurs upstream of, and contributes to the terminal Ca(2+) deregulation. PMID- 24787899 TI - Dipterans associated with a decomposing animal carcass in a rainforest fragment in Brazil: notes on the early arrival and colonization by necrophagous species. AB - This study aimed to provide the first checklist of forensically-important dipteran species in a rainforest environment in Northeastern Brazil, a region exposed to high rates of homicides. Using a decomposing pig, Sus scrofa L. (Artiodactyla: Suidae), carcass as a model, adult flies were collected immediately after death and in the early stages of carcass decomposition. To confirm actual colonization of the carcass, insects that completed their larval development on the resource were also collected and reared until adult stage. A diverse assemblage of dipterans composed of at least 28 species from seven families with necrophagous habits was observed within minutes after death. Besides Calliphoridae and Sarcophagidae, species from forensically-important families such as Phoridae, Anthomyiidae, and Fanniidae were also registered. Eleven species were shown to complete their development on the carcass. The majority of individuals emerged from larvae collected at the dry stage of decomposition. Hemilucilia segmentaria Fabricius (Diptera: Calliphoridae), H. semidiaphana (Rondani), and Ophyra chalcogaster (Wiedemann) (Muscidae) were the dominant species among the colonizers, which supports their importance as forensic evidence in Brazil. PMID- 24787900 TI - Application of carbon nanocatalysts in upgrading heavy crude oil assisted with microwave heating. AB - Heavy crude oil can be upgraded to lighter oil using several techniques. However, current methods usually require high temperatures, long reaction duration, and cause serious environmental pollution. This study shows that by using carbon nanocatalysts, heavy crude oil can be efficiently upgraded to lighter oil at a relatively low temperature of about 150 degrees C. The temperature of crude oil was increased by microwave heating. The technique proposed in this study has the following advantages: (1) great viscosity reduction ratio over 96%, (2) short reaction time (less than 1 h), (3) low required temperature, and (4) long viscosity regression time. Because of these advantages, upgrading heavy crude oil to light oil can be cheaper and more environment-friendly. PMID- 24787901 TI - Evaluation of potassium-clavulanate-supplemented modified charcoal-cefoperazone deoxycholate agar for enumeration of Campylobacter in chicken carcass rinse. AB - Potassium-clavulanate-supplemented modified charcoal-cefoperazone-deoxycholate agar (C-mCCDA) that was described in our previous study was compared with original mCCDA for the enumeration of Campylobacter in pure culture and chicken carcass rinse. The quantitative detection of viable Campylobacter cells from a pure culture, plated on C-mCCDA, is statistically similar (P > 0.05) to mCCDA. In total, 120 chickens were rinsed using 400 mL buffered peptone water. The rinses were inoculated onto C-mCCDA and mCCDA followed by incubation at 42 degrees C for 48 h. There was no statistical difference between C-mCCDA (45 of 120 plates; mean count, 145.5 CFU/mL) and normal mCCDA (46 of 120 plates; mean count, 160.8 CFU/mL) in the isolation rate and recovery of Campylobacter (P > 0.05) from chicken carcass rinse. The Pearson correlation coefficient value for the number of Campylobacter cells recovered in the 2 media was 0.942. However, the selectivity was much better on C-mCCDA than on mCCDA plates (P < 0.05). Significantly fewer C-mCCDA plates (33 out of 120 plates; mean count, 1.9 CFU/mL) were contaminated with non-Campylobacter cells than the normal mCCDA plates (67 out of 120 plates; mean count, 27.1 CFU/mL). The C-mCCDA may provide improved results for enumeration of Campylobacter in chicken meat alternative to mCCDA with its increased selectivity the modified agar possess. PMID- 24787902 TI - Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish. AB - We previously reported a fusion protein NUP98-IQCG in an acute leukaemia, which functions as an aberrant regulator of transcriptional expression, yet the structure and function of IQCG have not been characterized. Here we use zebrafish to investigate the role of iqcg in haematopoietic development, and find that the numbers of haematopoietic stem cells and multilineage-differentiated cells are reduced in iqcg-deficient embryos. Mechanistically, IQCG binds to calmodulin (CaM) and acts as a molecule upstream of CaM-dependent kinase IV (CaMKIV). Crystal structures of complexes between CaM and IQ domain of IQCG reveal dual CaM binding footprints in this motif, and provide a structural basis for a higher CaM IQCG affinity when deprived of calcium. The results collectively allow us to understand IQCG-mediated calcium signalling in haematopoiesis, and propose a model in which IQCG stores CaM at low cytoplasmic calcium concentrations, and releases CaM to activate CaMKIV when calcium level rises. PMID- 24787903 TI - Functional characterization of duplicated Suppressor of Overexpression of Constans 1-like genes in petunia. AB - Flowering time is strictly controlled by a combination of internal and external signals that match seed set with favorable environmental conditions. In the model plant species Arabidopsis thaliana (Brassicaceae), many of the genes underlying development and evolution of flowering have been discovered. However, much remains unknown about how conserved the flowering gene networks are in plants with different growth habits, gene duplication histories, and distributions. Here we functionally characterize three homologs of the flowering gene Suppressor Of Overexpression of Constans 1 (SOC1) in the short-lived perennial Petunia hybrida (petunia, Solanaceae). Similar to A. thaliana soc1 mutants, co-silencing of duplicated petunia SOC1-like genes results in late flowering. This phenotype is most severe when all three SOC1-like genes are silenced. Furthermore, expression levels of the SOC1-like genes Unshaven (UNS) and Floral Binding Protein 21 (FBP21), but not FBP28, are positively correlated with developmental age. In contrast to A. thaliana, petunia SOC1-like gene expression did not increase with longer photoperiods, and FBP28 transcripts were actually more abundant under short days. Despite evidence of functional redundancy, differential spatio temporal expression data suggest that SOC1-like genes might fine-tune petunia flowering in response to photoperiod and developmental stage. This likely resulted from modification of SOC1-like gene regulatory elements following recent duplication, and is a possible mechanism to ensure flowering under both inductive and non-inductive photoperiods. PMID- 24787904 TI - Diastereoselective three-component synthesis of beta-amino carbonyl compounds using diazo compounds, boranes, and acyl imines under catalyst-free conditions. AB - Diazo compounds, boranes, and acyl imines undergo a three-component Mannich condensation reaction under catalyst-free conditions to give the anti beta-amino carbonyl compounds in high diastereoselectivity. The reaction tolerates a variety of functional groups, and an asymmetric variant was achieved using the (-) phenylmenthol as chiral auxiliary in good yield and selectivity. These beta-amino carbonyl compounds are valuable intermediates, which can be transformed to many potential bioactive molecules. PMID- 24787905 TI - Central body fat changes in men affected by post-surgical hypogonadotropic hypogonadism undergoing testosterone replacement therapy are modulated by androgen receptor CAG polymorphism. AB - BACKGROUND AND AIMS: Little is known about the effect of androgen receptor (AR) gene CAG repeat polymorphism in conditioning body composition changes after testosterone replacement therapy (TRT). In this study, we aimed to clarify this aspect by focussing our attention on male post-surgical hypogonadotropic hypogonadism, a condition often associated with partial or total hypopituitarism. METHODS AND RESULTS: Fourteen men affected by post-surgical hypogonadotropic hypogonadism and undergoing several replacement hormone therapies were evaluated before and after TRT. Dual-energy X-ray absorptiometry (DEXA)-derived body composition measurements, pituitary-dependent hormones and AR gene CAG repeat polymorphism were considered. While testosterone and insulin-like growth factor-1 (IGF-1) levels increased after TRT, cortisol concentration decreased. No anthropometric or body composition parameters varied significantly, except for abdominal fat decrease. The number of CAG triplets was positively and significantly correlated with this abdominal fat decrease, while the opposite occurred between the latter and Delta-testosterone. No correlation of IGF-1 or cortisol variation (Delta-) with Delta-abdominal fat was found. At multiple linear regression, after correction for Delta-testosterone, the positive association between CAG triplet number and abdominal fat change was confirmed. CONCLUSIONS: In male post-surgical hypogonadotropic hypogonadism, shorter length of AR CAG repeat tract is independently associated with a more marked decrease of abdominal fat after TRT. PMID- 24787906 TI - Cardiometabolic and immune factors associated with increased common carotid artery intima-media thickness and cardiovascular disease in patients with systemic lupus erythematosus. AB - BACKGROUND AND AIM: Patients with systemic lupus erythematosus (SLE) have a higher prevalence of subclinical atherosclerosis and higher risk of cardiovascular (CV) events compared to the general population. The relative contribution of CV-, immune- and disease-related risk factors to accelerated atherogenesis in SLE is unclear. METHODS AND RESULTS: Fifty SLE patients with long-lasting disease (mean age 44 +/- 10 years, 86% female) and 50 sex- and age matched control subjects were studied. Common carotid artery intima-media thickness (CCA-IMT) was used as a surrogate marker of atherosclerosis. We evaluated traditional and immune- and disease-related factors, assessed multiple T-cell subsets by 10-parameter-eight-colour polychromatic flow cytometry and addressed the effect of pharmacological therapies on CCA-IMT. In SLE patients, among several cardiometabolic risk factors, only high-density lipoprotein levels (HDL) and their adenosine triphosphate-binding cassette transporter 1 (ABCA-1) dependent cholesterol efflux capacity were markedly reduced (p < 0.01), whereas the CCA-IMT was significantly increased (p = 0.03) compared to controls. CCA-IMT correlated with systolic blood pressure, low-density lipoprotein (LDL) cholesterol and body mass index (BMI), but not with disease activity and duration. The activated CD4(+)HLA-DR(+) and CCR5(+) T-cell subsets were expanded in SLE patients. Patients under hydroxychloroquine (HCQ) therapy showed lower CCA IMT (0.62 +/- 0.08 vs. 0.68 +/- 0.10 mm; p = 0.03) and better risk-factor profile and presented reduced circulating pro-atherogenic effector memory T-cell subsets and a parallel increased percentage of naive T-cell subsets. CONCLUSION: HDL represents the main metabolic parameter altered in SLE patients. The increased CCA-IMT in SLE patients may represent the net result of a process in which 'classic' CV risk factors give a continuous contribution, together with immunological factors (CD4(+)HLA-DR(+) T cells) which, on the contrary, could contribute through flares of activity of various degrees over time. Patients under HCQ therapy present a modified metabolic profile, a reduced T-cell activation associated with decreased subclinical atherosclerosis. PMID- 24787907 TI - Mediterranean dietary pattern, inflammation and endothelial function: a systematic review and meta-analysis of intervention trials. AB - BACKGROUND: High adherence to a Mediterranean diet (MD) is associated with reduced all-cause and cardiovascular mortality risk. To our knowledge, there is no systematic review and meta-analysis of randomized controlled trials that has compared the effects of an MD on outcomes of endothelial function and inflammation. METHODS AND RESULTS: Literature search was performed using the electronic databases MEDLINE, EMBASE, and the Cochrane Trial Register. Inclusion criteria were: randomized controlled trials, 19 + years of age, and minimum intervention period of 12 weeks. Study specific weighted mean differences (WMD) were pooled using a random effect model. Seventeen trials including 2300 subjects met the objectives. MD regimens resulted in a significantly more pronounced increase in flow mediated dilatation [WMD: 1.86%, 95% CI 0.23 to 3.48, p = 0.02; I(2) = 43%], and adiponectin [WMD: 1.69 MUg/ml, 95% CI 0.27 to 3.11, p = 0.02; I(2) = 78%], while high-sensitive C reactive protein [WMD: -0.98 mg/l, 95% CI 1.48 to -0.49, p < 0.0001; I(2) = 91%], interleukin-6 [WMD: -0.42 pg/ml, 95% CI 0.73 to -0.11, p = 0.008; I(2) = 81%], and intracellular adhesion molecule-1 [WMD: -23.73 ng/ml, 95% CI -41.24 to -6.22 p = 0.008; I(2) = 34%] turned out to be significantly more decreased. CONCLUSION: The results of the present meta analysis provide evidence that an MD decreases inflammation and improves endothelial function. PMID- 24787908 TI - Effects of six months of vitamin D supplementation in patients with heart failure: a randomized double-blind controlled trial. AB - BACKGROUND AND AIM: Low plasma vitamin D levels have been associated with heart failure (HF). This research attempts to explain the role of vitamin D supplementation on myocardial function in elderly patients with HF. METHODS AND RESULTS: Twenty-three chronic HF patients were randomized in a small parallel group, double-blind, placebo-controlled trial. All patients, with a mean age of 74 years and vitamin D levels <30 ng/mL, received 800,000 IU (4000 IU/daily) of cholecalciferol or placebo for 6 months. The outcomes measured at baseline and after 6 months were ejection fraction (EF) and other echocardiography parameters, carboxyterminal propeptide of procollagen type I (PIP), natriuretic peptides, lipid profile, renin, parathyroid hormone, blood pressure, and body mass index (BMI). In 13 patients under active treatment for 6 months, mean plasma 25-hydroxy vitamin D concentrations (15.51 vs. -1.40 ng/mL, p < 0.001) and plasma calcium (from 9.3 to 9.6 mmol/L, p < 0.05) increased significantly. However, other biomarkers of bone metabolism did not differ between the treatment and placebo groups. EF increased significantly in the intervention group (6.71 vs. -4.3%; p < 0.001), and the serum concentration of PIP increased only in the placebo group after 6 months (1140.98 vs. -145 mcg/L; p < 0.05). Systolic blood pressure was lower after 6 months of cholecalciferol treatment (from 129.6 to 122.7 mm Hg, p < 0.05). No significant variations were observed for other parameters. CONCLUSIONS: Six months of vitamin D supplementation significantly improves EF in elderly patients with HF and vitamin D deficiency. PMID- 24787909 TI - Workflow interruptions, cognitive failure and near-accidents in health care. AB - Errors are frequent in health care. A specific model was tested that affirms failure in cognitive action regulation to mediate the influence of nurses' workflow interruptions and safety conscientiousness on near-accidents in health care. One hundred and sixty-five nurses from seven Swiss hospitals participated in a questionnaire survey. Structural equation modelling confirmed the hypothesised mediation model. Cognitive failure in action regulation significantly mediated the influence of workflow interruptions on near-accidents (p < .05). An indirect path from conscientiousness to near-accidents via cognitive failure in action regulation was also significant (p < .05). Compliance with safety regulations was significantly related to cognitive failure and near accidents; moreover, cognitive failure mediated the association between compliance and near-accidents (p < .05). Contrary to expectations, compliance with safety regulations was not related to workflow interruptions. Workflow interruptions caused by colleagues, patients and organisational constraints are likely to trigger errors in nursing. Work redesign is recommended to reduce cognitive failure and improve safety of nurses and patients. PMID- 24787910 TI - Development of three-dimensional shoulder kinematic and electromyographic exposure variation analysis methodology in violin musicians. AB - A total of 11 male and 19 female violinists performed 30-second random-ordered slow and fast musical repertoire while right shoulder three-dimensional kinematic, and upper trapezius and serratus anterior surface electromyography (EMG) data were summarised using exposure variation analysis (EVA), a bivariate distribution of work time spent at categories of signal amplitude, and duration spent at a fixed category of amplitude. Sixty-two per cent of intraclass correlation coefficients [1,1] for all kinematic and EMG variables exceeded 0.75, and 40% of standard error of the measurement results were below 5%, confirming EVA reliability. When fast repertoire was played, increases in odds ratios in short duration cells were seen in 23 of 24 possible instances, and decreases in longer duration cells were seen in 17 instances in all EVA arrays using multinomial logistic regression with random effects, confirming a shift towards shorter duration. A reliable technique to assess right shoulder kinematic and EMG exposure in violinists was identified. PRACTITIONER SUMMARY: A reliable method of measuring right shoulder motion and muscle activity exposure variation in violinists was developed which can be used to assess ergonomic risk in other occupations. Recently developed statistical methods enabled differentiation between fast and slow musical performance of standardised musical repertoire. PMID- 24787911 TI - Dementia and depression in older adults: a southeast European perspective: summary of a dementia psychogeriatric symposium held in Ohrid, Macedonia, 23 May 2013. AB - We present a report on the recent symposium on dementia and depression in older adults, held in Ohrid, Macedonia and discuss the urgent need for development of psychogeriatric and affiliated services in the Southeast European region. The limited epidemiological data from nine countries in this region suggest high variability of prevalence rates for mental health problems in older adults (>65 years of age). At the moment, there are over 520,000 older adults in the region living with dementia alone. The prevalence rates for dementia (%) are either similar to those of the developed countries (9-9.6% in build-up northern Greece and Albania, respectively) or substantially lower (3.6-4% in rural northern Greece and Montenegro, respectively). The latter may be due to either cultural diversity or lack of adequate medical health service provision and expertise to recognize and diagnose dementia. Indeed, there is a lack of organized specialized services for older adults with mental health problem in the region. The symposium raised the awareness of this problem in the region and called for networking between isolated individuals working in this field to improve the current situation and facilitate further development of adequate clinical services to meet the growing needs of the older adults in the countries of the Southeast Europe. PMID- 24787913 TI - Utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy as adjunct techniques for screening and predicting dementia due to Alzheimer's disease in clinical practice. AB - We validated the utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy (1H MRS) as an adjunct screening technique for dementia due to Alzheimer's disease (AD). We examined the posterior cingulate gyri of 228 subjects using VSRAD and 1H MRS in addition to conventional cerebrospinal fluid biomarkers at baseline. At the 3-year follow-up, the 228 subject were classified as follows: 93 healthy subjects, 42 MCI-non-converters (MCI-NC), 25 MCI converters to AD (MCI-C), 44 AD, 8 dementia with Lewy bodies (DLB), 5 normal pressure hydrocephalus, and 11 patients with other neurological diseases. Our results demonstrated that subjects with increased medial temporal atrophy (MTA) severity on VSRAD, increased Cho/Cr, MI/Cr ratio, and decreased NAA/Cr and NAA/MI ratio on 1H MRS at baseline were at risk of dementia due to AD. Receiver operating characteristic analysis showed that severity of MTA and the NAA/MI ratio distinguished patients with AD and MCI-C from controls. Furthermore, the 118 subjects without dementia and MTA showing only a decreased NAA/MI ratio at baseline developed to MCI-C, AD, and DLB 3 years later. 1H MRS detected biochemical abnormalities preceding brain atrophy and cognitive decline. VSRAD combined with 1H MRS may be routinely applied to screen for MCI/AD and prodromal AD in clinical practice. PMID- 24787912 TI - Ordered subset analysis of copy number variation association with age at onset of Alzheimer's disease. AB - Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer's disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor that facilitates amyloid-beta1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets. PMID- 24787914 TI - Antipsychotic polypharmacy among a nationwide sample of community-dwelling persons with Alzheimer's disease. AB - BACKGROUND: Antipsychotic polypharmacy (APP) is not recommended in treatment of behavioral and psychological symptoms of dementia (BPSD). There is lack of studies concerning prevalence of APP among persons with dementia. OBJECTIVES: The objective of our study was to describe prevalence and risk factors associated with antipsychotic polypharmacy among antipsychotic users with Alzheimer's disease (AD). METHODS: Data from nationwide MEDALZ-2005 cohort including all community-dwelling persons diagnosed with AD in Finland was utilized. Register based data included prescriptions, comorbidities, and hospital discharge diagnoses. Users of antipsychotics during 2006-2009 were included (n = 9,803). The risk of starting antipsychotic polypharmacy was evaluated with Cox proportional hazards model. RESULTS: Prevalence of antipsychotic polypharmacy was 8% (n = 750) among antipsychotic users (n = 9,803). Quetiapine and risperidone was the most common combination of two antipsychotics followed by combination of quetiapine and haloperidol. Antipsychotic polypharmacy was associated with younger age (HR 1.35 [Confidence Interval, CI, 1.16-1.56]), male gender (HR 1.18 [CI 1.02-1.38]), and history of psychiatric disorder (HR 1.50 [CI 1.26-1.78]) in the adjusted model. CONCLUSIONS: In conclusion, we found higher prevalence of APP than previously reported among older populations. This is concerning since effectiveness of APP has not been demonstrated and APP is not recommended in the treatment of BPSD. Clinicians should pay more attention to avoid APP and use of antipsychotics to other indications than BPSD among persons with AD. PMID- 24787915 TI - Alzheimer's disease and methanol toxicity (part 1): chronic methanol feeding led to memory impairments and tau hyperphosphorylation in mice. AB - Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (~10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology. PMID- 24787916 TI - Cognitive training enhances pre-attentive neurophysiological responses in older adults 'at risk' of dementia. AB - BACKGROUND: With predicted increases in dementia incidence, interventions targeting neuroplasticity and neuroprotection are required. Cognitive Training (CT) is an intervention which has been shown to improve aspects of cognition, but the pathophysiological mechanisms contributing to its efficacy are unknown. OBJECTIVE: We aimed to explore the neurobiological correlates of CT using Mismatch Negativity (MMN), a neurophysiological marker of pre-attentive information processing, which in turn, is postulated to underpin higher-order cognitive processes. METHODS: As part of a larger randomized controlled trial, forty 'at risk' (i.e., mild cognitive impairment or late-life depression) participants aged 51-79 years underwent neurophysiological, neuropsychological, and psychiatric assessments before and after a multi-faceted seven-week CT program or a 'treatment-as-usual' seven-week waitlist period. RESULTS: The treatment group demonstrated significantly increased fronto-central MMN responses (p < 0.05), as well as improved phonemic verbal fluency (p < 0.05) and decreased self-rated memory difficulties (p < 0.05) following CT, in comparison to the waitlist control group. However, there were no significant correlations between enhanced MMN and cognitive/psychosocial outcomes. CONCLUSIONS: Results from this preliminary investigation indicate that CT is associated with enhanced neurophysiological mechanisms suggestive of improved pre-attentive processing, which may reflect alterations in underlying neurobiology. Further research is warranted to confirm these findings, to explicate whether CT is associated with restorative or compensatory neuroplastic processes and to determine whether MMN is a useful biomarker for treatment response. PMID- 24787917 TI - Alzheimer's disease and methanol toxicity (part 2): lessons from four rhesus macaques (Macaca mulatta) chronically fed methanol. AB - A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology. PMID- 24787918 TI - Region-specific expression of tau, amyloid-beta protein precursor, and synaptic proteins at physiological condition or under endoplasmic reticulum stress in rats. AB - Region-specific neurodegeneration was reported in brains of Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we studied the expression of some AD-associated proteins in temporal cortex, frontal cortex, cerebellum, and hippocampus of 4-month-old male Sprague-Dawley rats. Levels of the phosphorylated tau at Thr231, Ser396, and Ser202/Thr205, phosphorylated amyloid beta protein precursor (AbetaPP) and amyloid-beta, synapse-associated proteins glutamate receptors 2, N-methyl-D-aspartic receptors 1 (NR1), NR2A, NR2B, and postsynaptic density protein 95 were much lower in cerebellum, while the levels of total tau, phosphorylated tau at Thr205, Ser214, Ser262, and Ser198/199/202 epitopes, and total AbetaPP were similar in the four brain regions. As endoplasmic reticulum (ER) stress was reported in the early stage of AD, we injected tunicamycin, an ER stress inducer, into the lateral ventricular of rats and 48 hours later found in the other three brain regions but not cerebellum, increasing of binding immunoglobulin protein with the increased phosphorylation of pancreatic ER kinase, inositol-requiring enzyme 1, and activating transcription factor 6. Simultaneously, levels of phosphorylated tau at all of the above sites were significantly increased with the activation of glycogen synthase kinase-3beta in temporal cortex, frontal cortex, and/or hippocampus, but not cerebellum. The synapse-associated proteins, GluR2, PSD95, and synapsin1, were found decreased in the hippocampus after tunicamycin exposure. These data together may partially explain why the AD-like neuropathology, such as formation of neurofibrillary tangles, was rarely detected in cerebellum. PMID- 24787919 TI - Age-dependent alterations of the hippocampal cell composition and proliferative potential in the hAbetaPPSwInd-J20 mouse. AB - The J20 mouse expresses human mutant amyloid-beta protein precursor (hAbetaPPSwInd) and is an established transgenic model of Alzheimer's disease (AD). From the age of 5 months, amyloid-beta (Abeta) deposits appear in the hippocampus with concomitant increase of AD-associated features. Although changes occurring after the appearance of Abeta deposits have been extensively studied, very little is known about alterations that occur prior to 5 months. The present study aimed to identify changes in the cellular composition and proliferative potential of the J20 hippocampus using 1-18-month-old mice. Neuronal, non neuronal, Ki-67+, and TUNEL+ cell numbers were counted with the isotropic fractionator method. Age-dependent changes of the expression of microglia-, astrocyte-, and neurogenesis-specific markers were sought in the entire hippocampus. Several transgene-associated changes were revealed before the appearance of Abeta deposits. The number of proliferating cells decreased whereas the number of microglia clusters increased as early as 4 weeks of age. The neurogenesis was also impaired in the dentate gyrus of 7-11-week-old J20 mice. A statistically significant negative correlation was found between the number of proliferating cells and age in both populations, but the time course of the age dependence was steeper in wild-type than in J20 mice. Negative age-dependence was noted when the number of cells committed to apoptosis was examined. Our results indicate that overexpression of mutant hAbetaPP initiates a cascade of pathologic events well before the appearance of visible Abeta plaques. Accordingly, early signs of AD include reduced cell proliferation, impaired neurogenesis, and increased activity of microglia in the hippocampus. PMID- 24787920 TI - Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIalpha and CREB. AB - Inheritance of the apolipoprotein E genotype epsilon4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 MUg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 MUg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIalpha (p-CaMKIIalpha) and phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIalpha and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIalpha and CREB are important intracellular targets of the neurotoxic ApoE4. PMID- 24787921 TI - Is amyloid-beta an innocent bystander and marker in Alzheimer's disease? Is the liability of multivalent cation homeostasis and its influence on amyloid-beta function the real mechanism? AB - Two decades of the amyloid-beta (Abeta) hypothesis in Alzheimer's disease (AD) and the prominence of Abeta-targeting strategies have yet to meet the levels of original expectation. Disappointing results in numerous Phase II/III studies have called for a re-examination of the validity of the Abeta-targeting approaches as an intervention strategy in AD. The mid-life onset of chronic conditions (e.g., hypertension, diabetes, insulin intolerance, and depression nominated as risk factors for the later development of AD) points to the possibility that each condition could involve mechanisms, which while relatively modest over a short term, could have significant accumulative effects. What may also not be fully appreciated is that a number of these conditions involve potential disturbances to multivalent cations (MC) levels through various mechanisms such as autophagy, oxidative stress, and apoptosis. Furthermore, some MCs have intimate associations with the mechanisms by which Abeta pathology manifests. Considering various lines of evidence and incorporating statistical analysis on Disability-Adjusted Life Years (DALYs) data of both causes of and prevalence of multifactorial risk factors in different world regions, we propose an MC hypothesis for AD. More specifically, we suggest that MC imbalance marks many chronic conditions and because of their involvement with Abeta pathology, could reflect that Abeta may be a vital manifestation and marker of underlying MC imbalance. Thus, careful targeting of MC imbalance may provide an alternative or complementary interventional approach to current Abeta treatment strategies. PMID- 24787923 TI - Valuing volunteers. PMID- 24787922 TI - Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. AB - GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range. PMID- 24787931 TI - Emphasis on the problems of ageing detracts from the joy. PMID- 24787932 TI - Should health and social care services be merged into a single budget? PMID- 24787937 TI - Not just a 'funny turn'. PMID- 24787941 TI - Practice question. PMID- 24787942 TI - The drive to refer more NHS 111 callers to community nursing teams. AB - Cutting emergency department admission rates has been a health service priority. The NHS 111 free telephone-based service was created for people who require urgent care or advice for conditions that are not life threatening. Callers may be given advice on self-management or directed to a GP, walk-in centre or pharmacist. However, some policy experts argue that opportunities to divert large numbers of patients who call community nursing teams are being missed. Two senior nurses in London community services with higher referral rates explain how they achieve these by using integrated pathways. PMID- 24787943 TI - Developing advanced nursing skills for frail older people. AB - Improving hospital care for frail older people requires expertise, leadership and resources as these patients have multiple complex needs. One innovative solution to providing the skilled care necessary is to train experienced nurses to become advanced nurse practitioners (ANPs). Such roles encompass activity previously undertaken by medical staff, together with leadership, teaching, research and service development. Skills specific to caring for older people, such as comprehensive geriatric assessment, are also required. This article discusses the need for ANPs in this clinical area, a pilot that is under way in one acute trust to develop these roles, and the potential benefits and challenges that may accompany this development. PMID- 24787944 TI - Use of doll therapy for people with dementia: an overview. AB - Over the past decade, dolls have been used increasingly as a therapeutic device for people with dementia. While there has not been much empirical research carried out on the topic, current evidence suggests that engagement with dolls can promote wellbeing. This has been described in the literature as a reduction in challenging behaviour, greater engagement with others and even increased dietary intake. Providing people with dementia with dolls has supporters and critics. This article seeks to supply healthcare professionals with a synopsis of the phenomenon as well as illuminating some of the pertinent debates associated with this therapy. PMID- 24787945 TI - Introducing on-ward volunteers to work with patients with dementia. AB - This article reports on an evaluation of the effect of an on-ward volunteer service in an acute orthopaedic ward with a number of dementia patients. A mixed methods evaluation was undertaken in 2012. This included interviews with individuals who have strategic, management, operational and clinical roles in the voluntary organisation and the NHS trust, focus group discussions with volunteers, non-participant observations of practice and focused conversations with ward staff. The service had a positive effect on patient experience. Patients were engaged through a variety of activities and enjoyed the volunteers' presence. Staff valued the initiative because they could see the difference that it made to patients and their own working lives. The lessons learned from the evaluation can inform the development of similar initiatives elsewhere and are relevant, given the emphasis in healthcare policy to improve patient experience. PMID- 24787946 TI - Sharing skills in dementia care with staff overseas. AB - More than 35 million people worldwide are living with dementia. In some countries the existence of a health and social welfare state offers a level of support to those affected, but in many others resources are limited and inadequate, with responsibility for care lying primarily with relatives and friends. Significant efforts are being made by low and middle income nations to respond to the health needs of patients and carers, yet insufficient numbers of professionals and lack of specialist training opportunities are barriers that are difficult to overcome. Based on the author's volunteering experience in Sri Lanka, this article explores the role of UK trained nurses in supporting the development of dementia care services in countries where resources are limited. It discusses the contribution that nurses can make to the creation of services and reflects on the benefits that such exchanges can have on nursing practice in the UK. PMID- 24787947 TI - Life down under. PMID- 24787948 TI - Simple sample processing enhances malaria rapid diagnostic test performance. AB - Lateral flow immunochromatographic rapid diagnostic tests (RDTs) are the primary form of medical diagnostic used for malaria in underdeveloped nations. Unfortunately, many of these tests do not detect asymptomatic malaria carriers. In order for eradication of the disease to be achieved, this problem must be solved. In this study, we demonstrate enhancement in the performance of six RDT brands when a simple sample-processing step is added to the front of the diagnostic process. Greater than a 4-fold RDT signal enhancement was observed as a result of the sample processing step. This lowered the limit of detection for RDT brands to submicroscopic parasitemias. For the best performing RDTs the limits of detection were found to be as low as 3 parasites per MUL. Finally, through individual donor samples, the correlations between donor source, WHO panel detection scores and RDT signal intensities were explored. PMID- 24787950 TI - Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala. AB - BACKGROUND: Recognition of specific individuals is fundamental to mammalian social behavior and is mediated in most mammals by the main and accessory olfactory systems. Both these systems innervate the medial amygdala (MeA), where activity of the neuropeptide oxytocin is thought to mediate social recognition memory (SRM). The specific contribution of the MeA to SRM formation and the specific actions of oxytocin in the MeA are unknown. METHODS: We used the social discrimination test to evaluate short-term and long-term SRM in adult Sprague Dawley male rats (n = 38). The role of protein synthesis in the MeA was investigated by local application of the protein synthesis blocker anisomycin (n = 11). Synaptic plasticity was assessed in vivo by recording the MeA evoked field potential responses to stimulation of the main (n = 21) and accessory (n = 56) olfactory bulbs before and after theta burst stimulation. Intracerebroventricular administration of saline, oxytocin, or oxytocin receptor antagonist was used to measure the effect of oxytocin on synaptic plasticity. RESULTS: Anisomycin application to the MeA prevented the formation of long-term SRM. In addition, the responses of MeA neurons underwent long-term depression (LTD) after theta burst stimulation of the accessory olfactory bulb, but not the main accessory bulb, in an oxytocin-dependent manner. No LTD was found in socially isolated rats, which are known to lack long-term SRM. Finally, accessory olfactory bulb stimulation before SRM acquisition blocked long-term SRM, supporting the involvement of LTD in the MeA in formation of long-term SRM. CONCLUSIONS: Our results indicate that long-term SRM in rats involves protein synthesis and oxytocin-dependent LTD in the MeA. PMID- 24787949 TI - Cancer stem cell marker Musashi-1 rs2522137 genotype is associated with an increased risk of lung cancer. AB - Gene single nucleotide polymorphisms (SNPs) have been extensively studied in association with development and prognosis of various malignancies. However, the potential role of genetic polymorphisms of cancer stem cell (CSC) marker genes with respect to cancer risk has not been examined. We conducted a case-control study involving a total of 1000 subjects (500 lung cancer patients and 500 age matched cancer-free controls) from northeastern China. Lung cancer risk was analyzed in a logistic regression model in association with genotypes of four lung CSC marker genes (CD133, ALDH1, Musashi-1, and EpCAM). Using univariate analysis, the Musashi-1 rs2522137 GG genotype was found to be associated with a higher incidence of lung cancer compared with the TT genotype. No significant associations were observed for gene variants of CD133, ALDH1, or EpCAM. In multivariate analysis, Musashi-1 rs2522137 was still significantly associated with lung cancer when environmental and lifestyle factors were incorporated in the model, including lower BMI; family history of cancer; prior diagnosis of chronic obstructive pulmonary disease, pneumonia, or pulmonary tuberculosis; occupational exposure to pesticide; occupational exposure to gasoline or diesel fuel; heavier smoking; and exposure to heavy cooking emissions. The value of the area under the receiver-operating characteristic (ROC) curve (AUC) was 0.7686. To our knowledge, this is the first report to show an association between a Musashi 1 genotype and lung cancer risk. Further, the prediction model in this study may be useful in determining individuals with high risk of lung cancer. PMID- 24787951 TI - Evolutionary basis of mitonuclear discordance between sister species of mole salamanders (Ambystoma sp.). AB - Distinct genetic markers should show similar patterns of differentiation between species reflecting their common evolutionary histories, yet there are increasing examples of differences in the biogeographic distribution of species-specific nuclear (nuDNA) and mitochondrial DNA (mtDNA) variants within and between species. Identifying the evolutionary processes that underlie these anomalous patterns of genetic differentiation is an important goal. Here, we analyse the putative mitonuclear discordance observed between sister species of mole salamanders (Ambystoma barbouri and A. texanum) in which A. barbouri-specific mtDNA is found in animals located within the range of A. texanum. We test three hypotheses for this discordance (undetected range expansion, mtDNA introgression, and hybridization) using nuDNA and mtDNA data analysed with methods that varied in the parameters estimated and the timescales measured. Results from a Bayesian clustering technique (structure), bidirectional estimates of gene flow (migrate-n and IMa2) and phylogeny-based methods (*beast, bucky) all support the conclusion that the discordance is due to geographically restricted mtDNA introgression from A. barbouri into A. texanum. Limited data on species-specific tooth morphology match this conclusion. Significant differences in environmental conditions exist between sites where A. texanum with and without A. barbouri-like mtDNA occur, suggesting a possible role for selection in the process of introgression. Overall, our study provides a general example of the value of using complimentary analyses to make inferences of the directionality, timescale, and source of mtDNA introgression in animals. PMID- 24787953 TI - Hydrothermal synthesis, structure investigation, and oxide ion conductivity of mixed Si/Ge-based apatite-type phases. AB - Apatite-type oxides ([A(I)4][A(II)6][(BO4)6]O2), particularly those of the rare earth silicate and germanate systems, are among the more promising materials being considered as alternative solid oxide fuel cell electrolytes. Nonstoichiometric lanthanum silicate and germanate apatites display pure ionic conductivities exceeding those of yttria-stabilized zirconia at moderate temperatures (500-700 degrees C). In this study, mixed Si/Ge-based apatites were prepared by hydrothermal synthesis under mild conditions rather than the conventional solid-state method at high temperatures. Single-phase and highly crystalline nanosized apatite powders were obtained with the morphology changing across the series from spheres for the Si-based end member to hexagonal rods for the Ge-based end member. Powder X-ray and neutron analysis found all of these apatites to be hexagonal (P63/m). Quantitative X-ray microanalysis established the partial (<15 at%) substitution of La(3+) by Na(+) (introduced from the NaOH hydrothermal reagent), which showed a slight preference to enter the A(I) 4f framework position over the A(II) 6h tunnel site. Moreover, retention of hydroxide (OH(-)) was confirmed by IR spectroscopy and thermogravimetric analysis, and these apatites are best described as oxyhydroxyapatites. To prepare dense pellets for conductivity measurements, both conventional heat treatment and spark plasma sintering methods were compared, with the peculiar features of hydrothermally synthesized apatites and the influence of sodium on the ionic conductivity considered. PMID- 24787952 TI - The coexistence of coping resources and specific coping styles in stress: evidence from full information item bifactor analysis. AB - BACKGROUND: Knowledge of coping styles is useful in clinical diagnosis and suggesting specific therapeutic interventions. However, the latent structures and relationships between different aspects of coping styles have not been fully clarified. A full information item bifactor model will be beneficial to future research. OBJECTIVE: One goal of this study is identification of the best fit statistical model of coping styles. A second goal is entails extended analyses of latent relationships among different coping styles. In general, such research should offer greater understanding of the mechanisms of coping styles and provide insights into coping with stress. METHODS: Coping Styles Questionnaire (CSQ) and Generalized Self-Efficacy Scale (GSES) were administrated to officers suffering from military stress. Confirmatory Factor Analyses was performed to indentify the best fit model. A hierarchical item response model (bifactor model) was adopted to analyze the data. Additionally, correlations among coping styles and self efficacy were compared using both original and bifactor models. RESULTS: Results showed a bifactor model best fit the data. Item loadings on general and specific factors varied among different coping styles. All items loaded significantly on the general factor, and most items also had moderate to large loadings on specific factors. The correlation between coping styles and self-efficacy and the correlation among different coping styles changed significantly after extracting the general factor of coping stress using bifactor analysis. This was seen in changes from positive (r = 0.714, p<0.01) correlation to negative (r = -0.335, p<0.01) and also from negative (r = -0.296, p<0.01) to positive (r = 0.331, p<0.01). CONCLUSION: Our results reveal that coping styles have a bifactor structure. They also provide direct evidence of coexisting coping resources and styles. This further clarifies that dimensions of coping styles should include coping resources and specific coping styles. This finding has implications for measurement of coping mechanisms, health maintenance, and stress reduction. PMID- 24787954 TI - Using unnatural amino acids to probe the energetics of oxyanion hole hydrogen bonds in the ketosteroid isomerase active site. AB - Hydrogen bonds are ubiquitous in enzyme active sites, providing binding interactions and stabilizing charge rearrangements on substrate groups over the course of a reaction. But understanding the origin and magnitude of their catalytic contributions relative to hydrogen bonds made in aqueous solution remains difficult, in part because of complexities encountered in energetic interpretation of traditional site-directed mutagenesis experiments. It has been proposed for ketosteroid isomerase and other enzymes that active site hydrogen bonding groups provide energetic stabilization via "short, strong" or "low barrier" hydrogen bonds that are formed due to matching of their pKa or proton affinity to that of the transition state. It has also been proposed that the ketosteroid isomerase and other enzyme active sites provide electrostatic environments that result in larger energetic responses (i.e., greater "sensitivity") to ground-state to transition-state charge rearrangement, relative to aqueous solution, thereby providing catalysis relative to the corresponding reaction in water. To test these models, we substituted tyrosine with fluorotyrosines (F-Tyr's) in the ketosteroid isomerase (KSI) oxyanion hole to systematically vary the proton affinity of an active site hydrogen bond donor while minimizing steric or structural effects. We found that a 40-fold increase in intrinsic F-Tyr acidity caused no significant change in activity for reactions with three different substrates. F-Tyr substitution did not change the solvent or primary kinetic isotope effect for proton abstraction, consistent with no change in mechanism arising from these substitutions. The observed shallow dependence of activity on the pKa of the substituted Tyr residues suggests that the KSI oxyanion hole does not provide catalysis by forming an energetically exceptional pKa-matched hydrogen bond. In addition, the shallow dependence provides no indication of an active site electrostatic environment that greatly enhances the energetic response to charge accumulation, consistent with prior experimental results. PMID- 24787955 TI - Mid Staffs hospital is fined L200,000 over "avoidable" death of diabetic patient in 2007. PMID- 24787956 TI - In silico docking of forchlorfenuron (FCF) to septins suggests that FCF interferes with GTP binding. AB - Septins are GTP-binding proteins that form cytoskeleton-like filaments, which are essential for many functions in eukaryotic organisms. Small molecule compounds that disrupt septin filament assembly are valuable tools for dissecting septin functions with high temporal control. To date, forchlorfenuron (FCF) is the only compound known to affect septin assembly and functions. FCF dampens the dynamics of septin assembly inducing the formation of enlarged stable polymers, but the underlying mechanism of action is unknown. To investigate how FCF binds and affects septins, we performed in silico simulations of FCF docking to all available crystal structures of septins. Docking of FCF with SEPT2 and SEPT3 indicated that FCF interacts preferentially with the nucleotide-binding pockets of septins. Strikingly, FCF is predicted to form hydrogen bonds with residues involved in GDP-binding, mimicking nucleotide binding. FCF docking with the structure of SEPT2-GppNHp, a nonhydrolyzable GTP analog, and SEPT7 showed that FCF may assume two alternative non-overlapping conformations deeply into and on the outer side of the nucleotide-binding pocket. Surprisingly, FCF was predicted to interact with the P-loop Walker A motif GxxxxGKS/T, which binds the phosphates of GTP, and the GTP specificity motif AKAD, which interacts with the guanine base of GTP, and highly conserved amino acids including a threonine, which is critical for GTP hydrolysis. Thus, in silico FCF exhibits a conserved mechanism of binding, interacting with septin signature motifs and residues involved in GTP binding and hydrolysis. Taken together, our results suggest that FCF stabilizes septins by locking them into a conformation that mimics a nucleotide-bound state, preventing further GTP binding and hydrolysis. Overall, this study provides the first insight into how FCF may bind and stabilize septins, and offers a blueprint for the rational design of FCF derivatives that could target septins with higher affinity and specificity. PMID- 24787957 TI - The safety and treatment response of combination therapy of radioimmunotherapy and radiofrequency ablation for solid tumor: a study in vivo. AB - OBJECTION: To investigate the safety and treatment response of radioimmunotherapy (RIT) in combination with radiofrequency ablation (RFA) for the treatment of VX2 tumor on rabbit. MATERIALS AND METHODS: A total of 36 rabbits bearing VX2 tumor on the thigh were randomly assigned into 3 groups (group I: 1-2 cm; group II: 2-3 cm; group III: 3-4 cm) and 4 subgroups (A: as control, just puncture the tumor using the RFA electrode without power output; B: RFA alone; C: 131I-chTNT intratumoral injection alone; D: RFA+131I-chTNT intratumoral injection 3 days later). The variation of blood assay, weight and survival among different groups and subgroups were used to assess the treatment safety. Ultrasound (US) was used to monitor and assess the tumor response after treatment. RESULTS: According to the results of the weight and the blood assay among different groups, subgroups, and at two time points (one day before and the 16th day after treatment), no damages to the liver, kidney function and myelosuppression resulting from the treatment were found. No significant differences in survivals among the four subgroups (p = 0.087) were found. In addition, 131I-chTNT did not show significant inhibition effect on VX2 tumor progression according to US measurements. CONCLUSION: 131I-chTNT intratumoral injection alone or in combination with RFA is relatively safe for rabbit without significant toxicity and shows no significant effect on the survival. The treatment response is not as satisfactory as anticipated. PMID- 24787958 TI - MicroRNA-195 inhibits colorectal cancer cell proliferation, colony-formation and invasion through targeting CARMA3. AB - MicroRNA (miR)-195 has been reported to be a tumor suppressor. Downregulation of miR-195 has been shown to correlate with lymph node metastasis and poor prognosis in colorectal cancer. However, the specific regulatory role of miR-195 in colorectal cancer cells is yet to be elucidated. In the present study, miR-195 expression was significantly reduced in colorectal cancer tissues. Furthermore, CARMA3 was identified as a novel target of miR-195, which was observed to be upregulated in colorectal cancer. In addition, downregulation of miR-195 increased CARMA3 protein expression, whereas miR-195 upregulation suppressed CARMA3 protein expression in SW480 and HT29 colorectal cancer cells. Moreover, overexpression of miR-195 downregulated cell proliferation, colony-formation and invasion in SW480 and HT29 cells, which was reversed upon CARMA3 overexpression. In conclusion, the findings of the present study suggest that miR-195 has a suppressive role in colorectal cancer cells through directly targeting CARMA3. Therefore, CARMA3 may be a potential target for the treatment of colorectal cancer. PMID- 24787959 TI - A journey to support environmental change in early childhood. PMID- 24787960 TI - Regulatory role of nucleophosmin during the differentiation of human liver cancer cells. AB - Nucleophosmin (NPM, also known as B23), mainly localized in the nucleolus, has been reported to be overexpressed in many types of human cancer, including colon, ovarian, prostate and gastric cancer. NPM was identified while screening the differential nuclear matrix proteins during HMBA-induced differentiation of human liver cancer cells. We investigated the aberrant expression and subcellular localization of NPM in clinical liver cancer tissues and a cell line with the aim of providing more evidence for revealing the roles of NPM on regulating liver cancer cell proliferation and differentiation. In addition, we studied the potential interaction between NPM and several important proteins. Our results revealed that NPM protein was overexpressed in cancer cells, which was in accordance with the overexpressed mRNA in cancer tissues compared to the corresponding non-cancer tissues. We also found a decrease of NPM in protein and mRNA levels upon treatment with the differentiation reagent HMBA. We focused on the aberrant localization of NPM. Immunochemistry and immunofluorescence revealed aberrant cytoplasmic and nucleoplasm localization of NPM in liver cancer tissues and its colocalization with c-Myc, c-Fos, P53 and Rb in the SMMC-7721 cell line. The interactions between NPM and the above proteins were confirmed by GST pull down assay and co-immunoprecipitation assay. These findings indicate that NPM plays a regulatory role in liver cancer, which deserves in-depth investigation. PMID- 24787961 TI - Frequency of lymph node metastasis according to the size of tumors in resected pulmonary adenocarcinoma with a size of 30 mm or smaller. AB - BACKGROUND: This study analyzed the relation between the tumor size and the lymph node metastasis in adenocarcinoma of the lung with a size of 30 mm or smaller. METHODS: Four hundred thirteen patients who had undergone curative resection for lung adenocarcinoma were enrolled. If the tumor presented ground-glass opacities on the preoperative high-resolution computed tomography, both the total size including ground-glass opacities and the solid size alone were measured. To calculate the rates of lymph node metastasis by the tumor size, the tumors were divided into six groups by their sizes: 5 mm or less, 6 to 10 mm, 11 to 15 mm, 16 to 20 mm, 21 to 25 mm, and 26 to 30 mm. RESULTS: The average numbers of dissected lymph nodes and dissected lymph node stations were 17 and 5, respectively. Seventy-five patients (18%) were postoperatively discovered to have positive nodes. The rates of node metastasis in each total size group were 0/1 (0%), 0/29 (0%), 5/77 (7%), 17/121 (14%), 27/101 (27%), and 26/84 (31%), respectively. The rates of node metastasis in each solid size group were 0/37 (0%), 1/53 (2%), 9/88 (10%), 17/104 (16%), 23/78 (30%), and 25/53 (47%), respectively. The area under the curve of receiver operating characteristic curves for the total size was measured as 0.701, and that for the solid size was measured as 0.777. By multivariate analysis, solid size, maximum standardized uptake value, and lymphovascular invasion were independent significant predictive factors. CONCLUSIONS: Solid size, maximum standardized uptake value, and lymphovascular invasion were independent predictors for lymph node metastasis of lung adenocarcinoma. The size of the solid component explained the relation between the tumor size and the lymph node metastasis more accurately than that explained by the total tumor size on high-resolution computed tomography. PMID- 24787962 TI - Human papillomavirus shows highly variable prevalence in esophageal squamous cell carcinoma and no significant correlation to p16INK4a overexpression: a systematic review. AB - INTRODUCTION: This review investigates the role of p16(INK4a) as a marker of transcriptionally active human papillomavirus (HPV) in esophageal squamous cell carcinoma (ESCC) and the regional prevalence of HPV in ESCC. METHODS: PubMed, EMBASE, and the Cochrane Library were systematically searched with the purpose of identifying all studies published between January 1980 and July 2013 reporting both HPV and p16 results in a minimum of five human ESCC specimens. RESULTS: Twelve studies were identified, providing data on a total of 1383 ESCC specimens collected between 1987 and 2009 from 10 different countries. HPV DNA was detected in 12.0% (n = 161) of 1347 specimens, and p16(INK4a) was detected in 33.9% (n = 209) of 617 specimens. The HPV presence varied from 0% to 70% among the studies. The prevalence of p16(INK4a) overexpression in HPV-positive and HPV-negative specimens demonstrated no statistically significant difference, neither for the combined data (p = 0.7507) nor for any individual study, and detection of p16(INK4a) overexpression did not affect the odds of tumors being HPV positive (odds ratio = 1.0666 with 95% confidence interval 0.7040-1.6157). In a pooled analysis, the sensitivity of p16(INK4a) overexpression as a marker of HPV DNA presence was 0.35, the specificity 0.67, and the positive predictive value 0.25. CONCLUSIONS: This systematic review reports great regional variation in the prevalence of HPV in ESCC and suggests that p16(INK4a) is not a reliable marker of HPV status in ESCC. PMID- 24787963 TI - Primary tumor standardized uptake value measured on F18-Fluorodeoxyglucose positron emission tomography is of prediction value for survival and local control in non-small-cell lung cancer receiving radiotherapy: meta-analysis. AB - INTRODUCTION: The 2-[18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) has become an imaging tool for clinical assessment of tumor, node, metastasis in non-small-cell lung cancer (NSCLC). Primary tumor maximum standardized uptake value (SUV(max)) on (18)F-FDG PET/CT before and after radiation therapy (RT) has been studied as a potential prognostic factor for NSCLC patients receiving radiotherapy. However, the sample sizes of most studies were small, and the results of the prediction value of SUV(max) remained undetermined, which lead us to perform a meta-analysis to improve the precision in estimating its effect. METHODS: We performed a meta-analysis of published literature for primary tumor SUV(max)-based biomarkers of the outcome of NSCLC receiving radiotherapy. The required data for estimation of individual hazard ratios (HRs) to compare patients with a low and a high SUV(max) were extracted from each publication. A combined HR was calculated by Stata statistical software (Version 11). All of the results were verified by two persons to ensure its accuracy. RESULTS: Thirteen studies were finally included into this meta analysis; data are available in 13 studies for pre-RT primary tumor SUV(max) and in five studies for post-RT. For overall survival, the combined HR estimate was 1.05 (95% confidence interval [CI], 1.02-1.08) and 1.32 (95% CI, 1.15-1.51) for pre-RT SUV(max) and post-RT SUV(max), respectively; 1.26 (95% CI, 1.05-1.52) and 2.01 (95% CI, 1.16-3.46) for local control (LC). In stereotactic body radiotherapy (SBRT) group, HR for LC was 1.11 (95% CI, 1.06-1.18) and 2.19 (95% CI, 1.34-3.60) for pre-SBRT SUV(max) and post-SBRT SUV(max), respectively. CONCLUSION: Both pre-RT and post-RT primary tumor SUV(max) can predict the outcome of patients with NSCLC treated with radiotherapy. Patients with high levels of pre-RT SUV(max) seemed to have poorer overall survival and LC. PMID- 24787964 TI - Meta-analysis of first-line therapies in advanced non-small-cell lung cancer harboring EGFR-activating mutations. AB - INTRODUCTION: Tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib have been compared with chemotherapy as first-line therapies for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor activating mutations. This meta-analysis compares gefitinib, erlotinib, afatinib, and chemotherapy. METHODS: Literature search was performed using relevant keywords. Direct and indirect meta-estimates were generated using log-linear mixed-effects models, with random effects for study. Study-to-study heterogeneity was summarized using I statistics and predictive intervals (PIs). RESULTS: Literature search yielded eight randomized phase 3 clinical trials comparing gefitinib, erlotinib, or afatinib with chemotherapy as first-line therapy in patients with advanced non-small-cell lung cancer during the last 5 years. Hazard ratio meta-estimates for progression-free survival were for gefitinib versus chemotherapy 0.44 (95% confidence interval [CI] 0.31-0.63; 95% PI, 0.22-0.88), erlotinib versus chemotherapy 0.25 (95% CI, 0.15-0.42; 95% PI, 0.11-0.55), afatinib versus chemotherapy 0.44 (95% CI, 0.26-0.75; 95% PI, 0.20-0.98), erlotinib versus gefitinib 0.57 (95% CI, 0.30-1.08; 95% PI, 0.24-1.36), afatinib versus gefitinib 1.01 (95% CI, 0.53-1.92; 95% PI, 0.41-2.42), and erlotinib versus afatinib 0.56 (95% CI, 0.27-1.18; 95% PI, 0.22-1.46). Results for overall response rate and disease control rate were similar. There was no evidence that gefitinib, erlotinib, or afatinib improved overall survival compared with chemotherapy. CONCLUSION: Gefitinib, erlotinib, and afatinib out-performed chemotherapy in terms of progression-free survival, overall response rate, and disease control rate. Differences among gefitinib, erlotinib, and afatinib were not statistically significant. PMID- 24787965 TI - A comparison of immunohistochemical assays and FISH in detecting the ALK translocation in diagnostic histological and cytological lung tumor material. AB - INTRODUCTION: Detection of the ALK rearrangement in a solid tumor gives these patients the option of crizotinib as an oral form of anticancer treatment. The current test of choice is fluorescence in situ hybridization (FISH), but various cheaper and more convenient immunohistochemical (IHC) assays have been proposed as alternatives. METHODS: Fifteen FISH-positive cases from patients, seven with data on crizotinib therapy and clinical response, were evaluated for the presence of ALK protein using three different commercially available antibodies: D5F3, using the proprietary automated system (Ventana), ALK1 (Dako), and 5A4 (Abcam). A further 14 FISH-negative and three uncertain (<15% rearrangement detected) cases were also retrieved. Of the total 32 specimens, 17 were excisions and 15 were computed tomography-guided biopsies or cytological specimens. All three antibodies were applied to all cases. Antibodies were semiquantitatively scored on intensity, and the proportion of malignant cells stained was documented. Cutoffs were set by receiver operating curve analysis for positivity to optimize correct classification. RESULTS: All three IHC assays were 100% specific but sensitivity did vary: D5F3 86%, ALK 79%, 5A4 71%. Intensity was the most discriminating measure overall, with a combination of proportion and intensity not improving the test. No FISH-negative IHC-positive cases were seen. Two FISH positive cases were negative with all three IHC assays. One of these had been treated with crizotinib and had failed to show clinical response. The other harbored a second driving mutation in the EGFR gene. CONCLUSIONS: IHC with all three antibodies is especially highly specific (100%) although variably sensitive (71%-86%), specifically in cases with scanty material. D5F3 assay was most sensitive in these latter cases. Occasional cases are IHC-positive but FISH negative, suggesting either inaccuracy of one assay or occasional tumors with ALK rearrangement that do not express high levels of ALK protein. PMID- 24787967 TI - Maximum tumor diameter and the risk of prostate-specific antigen recurrence after radical prostatectomy. AB - INTRODUCTION/BACKGROUND: The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. PATIENTS AND METHODS: The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. RESULTS: After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.23 6.10; P = .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA <= 4 ng/mL (P = .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P = .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score >= 8) was present at RP (P = .01; 5-year estimate: 46.6% vs. 100%) versus none (P = .09; 5-year estimate: 93.4% vs. 98.9%). CONCLUSION: Men with a low MTD (<= 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART. PMID- 24787966 TI - First-line Mammalian target of rapamycin inhibition in metastatic renal cell carcinoma: an analysis of practice patterns from the International Metastatic Renal Cell Carcinoma Database Consortium. AB - INTRODUCTION/BACKGROUND: Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. PATIENTS AND METHODS: We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients. CONCLUSION: Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made. PMID- 24787968 TI - Response to subsequent docetaxel in a patient cohort with metastatic castration resistant prostate cancer after abiraterone acetate treatment. AB - INTRODUCTION/BACKGROUND: Docetaxel or AA are therapeutic options for mCRPC. We retrospectively analyzed clinical outcomes with subsequent docetaxel in patients with mCRPC after disease progression (DP) with AA to evaluate cross resistance between these therapies. PATIENTS AND METHODS: Patients with chemotherapy-naive mCRPC who were treated with AA in previously reported phase I to III trials, who had DP, and were subsequently treated (not on study) with docetaxel, were included. Acquired AA resistance was defined as: PSA decline > 50% from baseline or radiographically stable disease for >= 8 months, with subsequent DP. All other patients were defined as having primary AA resistance. Efficacy outcomes after docetaxel therapy were analyzed. RESULTS: We identified 23 patients who were treated with docetaxel after DP with AA, including 14 (61%) with acquired and 9 (39%) with primary AA resistance. Median duration between discontinuation of AA and docetaxel initiation was 2.7 months (range, 0.2-14.7 months). Subsequent docetaxel therapy led to >= 30% PSA decline in 15 patients (65%) and >= 50% PSA decline in 11 patients (48%). Median OS from date of first docetaxel dose was 12.4 months (95% confidence interval, 8.2-19.6). Patients with previous primary versus acquired AA resistance had similar outcomes with subsequent docetaxel therapy. CONCLUSION: In this retrospective analysis, the type of AA resistance did not appear to affect outcomes with subsequent docetaxel. The PSA response rates observed suggest a lack of cross-resistance between docetaxel and AA, but prospective studies are needed to evaluate for potential cross-resistance and optimize sequences of therapy in patients with mCRPC. PMID- 24787969 TI - Penile metastases from bladder and prostate cancer detected by PET/CT: a report of 3 cases and a review of literature. PMID- 24787970 TI - Metastatic large-cell neuroendocrine prostate carcinoma: successful treatment with androgen deprivation therapy. PMID- 24787971 TI - Concurrent chemoradiotherapy for men with locally advanced penile squamous cell carcinoma. AB - BACKGROUND: Outcomes with concurrent chemoradiotherapy for penile squamous cell carcinoma (PSCC) are unclear, and only anecdotal reports have been published. This study was a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. PATIENTS AND METHODS: Individual patient level data were obtained from 5 institutions for outcomes with concurrent chemoradiotherapy for PSCC. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors on progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was <= III in 9 patients (36%) and stage IV in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients, and the median (range) of external beam radiotherapy administered was 4900 cGy (range, 1800-7000 cGy). The median OS was 6.9 months (95% CI, 5-14), and the median PFS was 5.1 months (95% CI, 2.5-7.0). When excluding patients with M1 disease, the remaining patients (n = 21) had a median OS and PFS of 10.0 months (95% CI, 5-14) and 6.0 months (95% CI, 2.0-7.0), respectively. Baseline neutrophil to lymphocyte ratio (NLR) was significantly associated with survival, and visceral metastasis showed a trend for association with OS. CONCLUSIONS: Concurrent chemoradiotherapy demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted. PMID- 24787973 TI - A new world order: tailored gene targeting and regulation using CRISPR. PMID- 24787972 TI - Interim fluorine-18 fluorodeoxyglucose positron emission tomography for early metabolic assessment of therapeutic response to chemotherapy for metastatic transitional cell carcinoma. AB - BACKGROUND: The prognostic impact of early metabolic response by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) after 2 cycles of first line chemotherapy is still unrecognized in metastatic transitional cell carcinoma (TCC). PATIENTS AND METHODS: Patients with metastatic TCC receiving the modified combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), according to institutional protocol, underwent computed tomography (CT) and FDG PET imaging at baseline, a restaging with PET imaging after 2 cycles only (PET2), and a CT (+/- FDG-PET) scan at the end of treatment and during follow-up. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method; univariate (UVA) and multivariate (MVA) Cox models were fitted. Prespecified variables were the presence of visceral metastases, nodal or soft tissue disease, and early PET response. RESULTS: In the period from May 2010 to October 2012, 31 patients with Eastern Cooperative Oncology Group performance status 0 received the modified MVAC regimen every 3 weeks. In all, 6 patients (19.3%) had a complete response (CR) and 17 (54.8%) a partial metabolic response (PR), 4 had stable disease (SD), and 4 progressed. PET2 responders had a median PFS of 8 months (95 % CI, 7-11 mo) compared with 3 months (95 % CI, 2-5 mo) of patients without response (P = .024). They also had a significant benefit in 8 month PFS (P < .001 via Klein test) and 15-month OS (P = .016). PET2 response was significant for PFS in both UVA and MVA Cox models (P = .027 and P = .023, respectively). CONCLUSION: PET response after 2 cycles of first-line chemotherapy, compared with detection by early CT, was associated with longer PFS and OS in advanced TCC and warrants further investigation in the field. PMID- 24787976 TI - Clarifying misconceptions about myoblast transplantation in myology. PMID- 24787977 TI - The other face of chimeric antigen receptors. PMID- 24787979 TI - Synthesis of orderly nanoporous aluminophosphate and zirconium phosphate materials and their catalytic applications. AB - Amorphous alumino phosphate (AP) and zirconium phosphate (ZP) materials possessing an ordered nanoporosity have been successfully synthesized by a hydrothermal method using a P123 block co-polymer as the structure directing agent. The materials exhibited excellent catalytic activity towards selective alkylation of phenol with cyclohexanol, where AP showed as high as 100% selectivity to produce the industrially important O-alkylation product, while the corresponding ZP selectively produced a C-alkylation product (93% selectivity). PMID- 24787980 TI - Distributions of iron, phosphorus and sulfur along trichomes of the cyanobacteria Trichodesmium. AB - The nonheterocystous cyanobacterium Trichodesmium fixes C and N concurrently during the light period in tropical and subtropical oceans. Synchrotron mapping of Fe, P and S in trichomes of Trichodesmium erythraeum Erhenberg IMS 101 (CCMP 1985) collected during exponential and senescent growth revealed that 16% of trichomes contained sections of up to 25 cells with ca. 2-fold elevated Fe and S but ca. 2-fold lowered P in comparison to neighboring trichome sections. The correlation between Fe and S in these trichomes was moderate to strongly positive (R > 0.35), while the correlation between Fe and P was moderate to strongly negative (R < 0.35). Higher Fe in theses trichome sections might indicate the presence of nitrogenase. Increase in S in conjunction with Fe is likely driven by other S-containing compounds in addition to Fe-S proteins. Furthermore, the concurrent increase in S and decrease in P in these Fe-rich trichome sections might indicate a switch from P- to S-containing compounds. Diurnal changes and growth phase-related differences in the correlation between Fe and P both point to Trichodesmium's ability to re-allocate elements depending on their physiological need. Concurrent P depletion and Fe and S enrichment in trichome sections is a strong indication that Trichodesmium is able to develop special trichome regions consisting of multiple cells with a unique chemical composition. Whether these cells are uniquely dedicated to N2-fixation (i.e., diazocytes) is an open question. PMID- 24787982 TI - Scanning laser ophthalmoscopy and optical coherence tomography imaging of spectacular ecdysis in the corn snake (Pantherophis guttatus) and the California king snake (Lampropeltis getulus californiae). AB - PURPOSE: One of the singularities of the eyes of snakes is the presence of the spectacle, a transparent and vascularized integument covering the cornea. The spectacle is completely renewed during ecdysis. Combined scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and conventional macrophotography were used to image this phenomenon. MATERIAL AND METHODS: A spectral OCT/SLO examination and macrophotography were performed in four healthy adult corn snakes (Pantherophis guttatus) and one healthy adult California king snake (Lampropeltis getulus californiae) the day before the start of ecdysis and then daily during ecdysis. RESULTS: In all animals, ecdysis lasted 5 days. The spectacle was hardly visible at baseline, but became obvious at day one, while the subspectacular space became larger and the superficial cornea presented a hyperechoic band. At day two, eye surface became translucent, and at the same time, vascularization of the spectacle was visible using SLO. At day 3, the vascularization was no longer visible, while the subspectacular space increased and the eye surface remained translucent. At day 4, the eye surface was transparent and the superficial hyperechoic band started to become less bright. At day 5, the old spectacle was shed and all the parameters returned to baseline. CONCLUSION: We hypothesize that the echogenicity modifications of the anterior cornea correspond to major metabolic activity associated with new spectacle formation. This increased metabolic activity may contribute to the neovascularization and play an important role in the accumulation of fluid in the subspectacular space, facilitating the shedding of the old spectacle. PMID- 24787983 TI - Size-selective catalytic growth of nearly 100% pure carbon nanocoils with copper nanoparticles produced by atomic layer deposition. AB - In this paper, Cu nanoparticles with narrow size distribution are synthesized by reduction of CuO films produced by atomic layer deposition (ALD), which are used as catalysts for the catalytic growth of carbon nanostructures. By properly adjusting the ALD cycle numbers, the size of produced Cu nanoparticles can be well controlled. Uniform carbon nanocoils with near 100% purity can be obtained by using 50-80 nm Cu nanoparticles, while thin straight fibers and thick straight fibers are produced by applying 5-35 and 100-200 nm Cu nanoparticles, respectively. The mechanism of the particle size-dependent growth of the carbon nanostructure was analyzed based on the experimental results and theoretical simulation. Our results can provide important information for the preparation of helical carbon nanostructures with high purity. Moreover, this work also demonstrates that ALD is a viable technique for synthesizing nanoparticles with highly controllable size and narrow size distribution suitable for studying particle size-dependent catalytic behavior and other applications. PMID- 24787986 TI - Bidirectional cytoplasmic incompatibility induced by cross-order transfection of Wolbachia: implications for control of the host population. AB - Wolbachia are widespread endosymbionts in arthropods and some nematodes. This genus of bacteria is known to manipulate host reproduction by inducing cytoplasmic incompatibility (CI). This important phenotype is implicated in the control of host populations since Wolbachia can suppress host populations through the induction of CI in a way similar to the sterile insect technique. Here, we identified a candidate CI-inducing Wolbachia strain from the parasitic wasp Scleroderma guani (wSguBJ) by sequencing and phylogenetic analysis. This Wolbachia strain was then isolated, purified, and artificially transfected into the new whitefly host Bemisia tabaci through nymphal microinjection. Infection frequency monitoring by molecular detection showed that 60-80 % of the offspring from transfected whitefly populations was infected with wSguBJ six generations after the transfer. Laboratory rearing experiments indicated that the artificial transfection caused no significant difference in the numbers of offspring between the transfected and naturally infected populations and had no significant detrimental effects on the development of transfected males, although the development of transfected females was delayed. Reciprocal crossings revealed that bidirectional CI was induced between the transfected and naturally infected whiteflies. These data indicated that the cross-order transfer of the heterologous Wolbachia strain by nymphal microinjection was successful. Mass release of the transfected males that could stably carry the heterologous Wolbachia without significant compromise of fecundity/development may provide an alternative approach to control of host populations. PMID- 24787988 TI - Voting with your fondaparinux. PMID- 24787987 TI - Exo-metabolome of Pseudovibrio sp. FO-BEG1 analyzed by ultra-high resolution mass spectrometry and the effect of phosphate limitation. AB - Oceanic dissolved organic matter (DOM) is an assemblage of reduced carbon compounds, which results from biotic and abiotic processes. The biotic processes consist in either release or uptake of specific molecules by marine organisms. Heterotrophic bacteria have been mostly considered to influence the DOM composition by preferential uptake of certain compounds. However, they also secrete a variety of molecules depending on physiological state, environmental and growth conditions, but so far the full set of compounds secreted by these bacteria has never been investigated. In this study, we analyzed the exo metabolome, metabolites secreted into the environment, of the heterotrophic marine bacterium Pseudovibrio sp. FO-BEG1 via ultra-high resolution mass spectrometry, comparing phosphate limited with phosphate surplus growth conditions. Bacteria belonging to the Pseudovibrio genus have been isolated worldwide, mainly from marine invertebrates and were described as metabolically versatile Alphaproteobacteria. We show that the exo-metabolome is unexpectedly large and diverse, consisting of hundreds of compounds that differ by their molecular formulae. It is characterized by a dynamic recycling of molecules, and it is drastically affected by the physiological state of the strain. Moreover, we show that phosphate limitation greatly influences both the amount and the composition of the secreted molecules. By assigning the detected masses to general chemical categories, we observed that under phosphate surplus conditions the secreted molecules were mainly peptides and highly unsaturated compounds. In contrast, under phosphate limitation the composition of the exo-metabolome changed during bacterial growth, showing an increase in highly unsaturated, phenolic, and polyphenolic compounds. Finally, we annotated the detected masses using multiple metabolite databases. These analyses suggested the presence of several masses analogue to masses of known bioactive compounds. However, the annotation was successful only for a minor part of the detected molecules, underlining the current gap in knowledge concerning the biosynthetic ability of marine heterotrophic bacteria. PMID- 24787989 TI - Cerebral venous thrombosis and myeloproliferative neoplasms: results from two large databases. AB - INTRODUCTION: Myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs are prone to develop arterial and venous thrombosis either at diagnosis or during follow-up; in particular splancnic vein is strongly associated with MPN. Conversely, presence of MPN is uncommon in patients with deep vein thrombosis of the lower extremities and with pulmonary embolism. Only few studies with conflicting results have evaluated the prevalence of an underlying MPN in patients with cerebral venous thrombosis (CVT), and limited evidence exists on the incidence of CVT in patients with established MPN. METHODS: We assessed the frequency of MPNs in a series of 706 patients with cerebral vein thrombosis (CVT) and the frequency of CVT in a cohort of 2,143 MPNs patients. RESULTS: Twenty seven CVT patients (3.8%) were diagnosed with MPN: 9 before CVT (1.3%), 4 concomitantly (0.6%), and 14 after CVT (2.0%). Nine CVT cases (0.4%) were diagnosed in the MPN cohort, with a slightly higher frequency in PV (five of 735, 0.7%) than in ET (three of 964, 0.3%) and in PMF (one of 444, 0.2%). CONCLUSION: Considering the analyses of these databases jointly, the results obtained suggest a weak association between CVT and MPNs and ultimately suggest that a thorough investigation looking for an underlying MPN may not be warranted in all the patients with CVT without overt myeloproliferative features. PMID- 24787990 TI - Functional characterization of a novel missense mutation, His147Arg, in A1 domain of FV protein causing type II deficiency. AB - INTRODUCTION: Congenital factor V (FV) deficiency is a rare inherited disorder. Three compound heterozygous missense mutations, Asp68His, His147Arg, and Arg2074Cys, were observed in a Taiwanese patient with moderately severe FV deficiency. METHOD: The novel His147Arg mutation in the A1 domain was investigated by protein modeling, followed by in vitro expression studies in COS 1 cells, to elucidate the molecular pathology associated with FV deficiency. RESULTS: The His147Arg mutation was associated with normal antigen levels, both in cell lysates and conditioned media, whereas FV activity was significantly reduced to 63.5 +/- 17.0%. These observations correspond to a type II FV deficiency mutation. Protein modeling by short-duration molecular dynamics (MD) simulation showed that the His147Arg mutation was associated with a conformational change, which could disrupt the stability of FVa by interfering with His1817 coordination of the copper ion. In functional activation assays, the His147Arg mutation did not affect FV protein activation by thrombin; however, reduced cofactor activity of the FVa protein, due to an increased rate of dissociation of heavy and light chains, was observed. CONCLUSION: Our results show that the His147Arg mutation in the A1 domain of FV does not impair synthesis or procoagulant activity. Instead, the His147Arg mutation appears to disrupt the stability of FVa, providing a potential explanation for the functional deficiency. PMID- 24787991 TI - Inhibitory effects of LDL-associated tissue factor pathway inhibitor. AB - INTRODUCTION: Tissue factor pathway inhibitor (TFPI) is present in plasma as full length free TFPI (TFPIalpha) and as C-terminally degraded forms mainly associated with low-density lipoprotein particles (LDL-TFPI). Addition of TFPIalpha to plasma induces a prolongation of the clotting time when tested in a diluted prothrombin time (dPT) assay, whereas no prolongation is observed with LDL-TFPI or truncated recombinant TFPI (TFPI 1-161). The aim was to further characterize kinetic properties of purified LDL-TFPI in thrombin generation and chromogenic activity assays. MATERIALS AND METHODS: LDL-TFPI was purified from human plasma by sequential flotation ultracentrifugation. Thrombin generation was measured in human plasma or in FVIII-immunodepleted plasma using either 1 pM tissue factor and 4 MUM phospholipids or 0.5 nM factor Xa (FXa) and 4 MUM phospholipids, respectively. RESULTS: TFPIalpha prolonged the lag-phase and decreased the thrombin peak in tissue factor-induced thrombin generation, whereas LDL-TFPI exclusively decreased the peak height of thrombin without effecting the lag phase. Steady-state and transient kinetics showed that LDL-TFPI was a more potent inhibitor of FXa than TFPIalpha and TFPI 1-161, indicating that FXa inhibition was not rate determining for the lag phase, whereas it appeared to affect thrombin generation during the propagation phase. This was supported by FXa induced thrombin generation showing that LDL-TFPI, compared with TFPIalpha, more actively decreased the peak height. CONCLUSIONS: Our results suggest that LDL TFPI affects thrombin generation during the propagation phase, and is kinetically different from TFPI 1-161. It may therefore play a more prominent physiological role in vivo than hereto anticipated from dPT measurements. PMID- 24787992 TI - The Effect of Microneedle Thickness on Pain During Minimally Invasive Facial Procedures: A Clinical Study. AB - BACKGROUND: Minimally invasive procedures are becoming increasingly popular because they require minimal downtime and are effective for achieving a more youthful appearance. The choice of needle for minimally invasive procedures can be a major factor in the patient's comfort level, which in turn affects the physician's comfort level. OBJECTIVES: In this comparative study, the authors assessed levels of pain and bruising after participants were injected with 30 gauge or 33-gauge (G) microneedles, which are commonly used for minimally invasive injection procedures. METHODS: Twenty healthy volunteers were recruited for this prospective study. Eight injection points (4 on each side of the face) were determined for each patient. All participants received injections of saline with both microneedles in a randomized, blinded fashion. Levels of pain and bruising were assessed and analyzed for significance. RESULTS: The highest level of pain was in the malar region, and the lowest level was in the glabella. Although all pain scores were lower for the 33-G microneedle, the difference was significant only for the forehead. Because most minimally invasive procedures require multiple injections during the same sitting, the overall procedure was evaluated as well. Assessment of the multiple-injection process demonstrated a significant difference in pain level, favoring the 33-G needle. Although the difference in bruising was not statistically significant between the 2 needles, the degree of bruising was lower with the 33-G needle. CONCLUSIONS: For procedures that involve multiple injections to the face (such as mesotherapy and injection of botulinum toxin A), thinner needles result in less pain, making the overall experience more comfortable for the patient and the physician. LEVEL OF EVIDENCE: 3. PMID- 24787993 TI - Restricted puckering of mineralized RNA-like riboses. AB - The pseudorotational motions of highly hydroxylated pentafuranose sugars in the free state and tethered to hydroxyapatite have been compared. The conformation pentafuranose ring remains restricted at the North region of the pseudorotational wheel, which is the one typically observed for nucleosides and nucleotides in the double helix A-RNA, when the phosphate-bearing sugar is anchored to the mineral surface. Results indicate that the severe restrictions imposed by the mineral are responsible of the double helix preservation when DNA and RNA are encapsulated in crystalline nanorods. PMID- 24787994 TI - Peroxisome proliferator-activated receptor gamma ligands inhibit VEGF-mediated vasculogenic mimicry of prostate cancer through the AKT signaling pathway. AB - Vasculogenic mimicry (VM) describes functional vascular channels composed only of tumor cells and its presence predicts a poor prognosis for patients with prostate cancer. The present study demonstrated that prostate cancer PC-3 cells were able to form a patterned matrix or tubular VM in 3D cultures in vitro and rosiglitazone (RSG), the ligand of peroxisome proliferator-activated receptor gamma (PPARgamma) and effectively inhibited the formation of VM structures in a dose- and PPARgamma-dependent manner. In addition, RSG significantly inhibited prostate cancer cell migration and invasion. The inhibitory effect of RSG on VM formation could be at least partially explained by an RSG-driven downregulation of vascular endothelial growth factor (VEGF) levels and phosphorylation of AKT, which is known to be important in VM. Furthermore, the present study highlighted that VEGF and the phosphoinositide 3-kinase/AKT pathway exert a positive feedback regulation in the process of VM formation. These findings reveal new therapeutic potential for PPARgamma ligands in anti-cancer therapy. PMID- 24787995 TI - Overtime work and prevalence of diabetes in Japanese employees: Japan epidemiology collaboration on occupational health study. AB - OBJECTIVE: Epidemiologic evidence on long working hour and diabetes has been conflicting. We examined the association between overtime work and prevalence of diabetes among Japanese workers. METHODS: The subjects were 40,861 employees (35,170 men and 5,691 women), aged 16 to 83 years, of 4 companies in Japan. Hours of overtime were assessed using self-reported questionnaires. Diabetes was defined as a fasting plasma glucose >=126 mg/dl (7.0 mmol/l), hemoglobin A1c >=6.5% (48 mmol/mol), or current use of anti-diabetic drug. Multiple logistic regression analysis was used to calculate odds ratio of diabetes for each category of overtime. RESULTS: After adjustment for age, sex, company, smoking, and BMI, there was a suggestion of U-shaped relationship between overtime work and prevalence of diabetes (P for quadratic trend = 0.07). Compared with those who worked <45 hours of overtime per month, the adjusted odds ratios (95% confidence interval) of diabetes were 0.86 (0.77-0.94), 0.69 (0.53-0.89), and 1.03 (0.72-1.46) for those who worked 45-79, 80-99, and >=100 hours of overtime per month, respectively. In one company (n = 33,807), where other potential confounders including shift work, job position, type of department, alcohol consumption, sleep duration, leisure time physical activity, and family history of diabetes was additionally adjusted for, similar result was obtained (P for quadratic trend = 0.05). CONCLUSIONS: Long hours of overtime work may not be associated with increased prevalence of diabetes among Japanese workers. PMID- 24787996 TI - Fluorescent polyion complex nanoparticle that incorporates an internal standard for quantitative analysis of protein kinase activity. AB - We demonstrate a polyion complex (PIC) nanoparticle that contains both a responsive fluorophore and an "internal standard" fluorophore for quantitative measurement of protein kinase (PK) activity. The PK-responsive fluorophore becomes more fluorescent with PK-catalyzed phosphorylation of substrate peptides incorporated in the PIC, while fluorescence from the internal standard remains unchanged during phosphorylation. This new concept will be useful for quantitative PK assays and the discovery of PK inhibitors. PMID- 24787998 TI - Phylogeography and phylodynamics of European genotype 3 hepatitis E virus. AB - Hepatitis E virus is classified into four genotypes that have different geographical and host distributions. The main cause of sporadic autochthonous type E acute hepatitis in developed countries is genotype 3, which has a worldwide distribution and widely infects pigs. The aim of this study was to make hypotheses concerning the origin and global dispersion routes of this genotype by reconstructing the spatial and temporal dynamics of 208 HEV genotype 3 ORF-2 sequences (retrieved from public databases) isolated in different geographical areas. The evolutionary rates, time of the most recent common ancestors (tMRCAs), epidemic growth and phylogeography of HEV-3 were co-estimated using a MCMC Bayesian method. The maximum clade credibility tree showed the existence of two distinct main clades: clade A, which consists of only European subtypes (HEV-3e and 3f), and clade B, which consists of European subtype 3c and all of the Asian subtypes (3a, 3b and 3d) sharing a common ancestor, which most probably existed in Asia in 1920s. All of the North American isolates belonged to Asian subtype 3a. On the basis of our time-scaled phylogeographical reconstruction, we hypothesise that after originating in the early 1800s in Europe, HEV reached Asia in the first decades of 1900, and then moved to America probably in the 1970s 1980s. Analysis of the skyline plot showed a sharp increase of the number of infections between the 1980s and 2005, thus suggesting the intervention of new and highly efficient routes of transmission possibly related to changes in the pig industry. PMID- 24788000 TI - U exon variability as a discriminatory tool for Bayesian analysis of adenoviruses. AB - Members of the family Adenoviridae are divided into five genera and infect a wide variety of vertebrates with a narrow host range, usually restricted to one species. Due to the high genetic diversity and distinct genomic organization, classification of adenoviruses is difficult to achieve and often performed by phylogenetic analysis. The most commonly used region for phylogenetic inference of adenoviruses is the DNA polymerase (AdPol) gene carried out at amino acid level. In this paper we investigated the suitability of the U exon to discriminate adenoviruses. The tree based on this genus-common feature, obtained with 23 short amino acid sequences, offered a clearest discrimination of the members of the adenovirus family (Adenoviridae) than the trees generated with the complete or partial polymerase protein sequences. Therefore, our results demonstrate that the U exon is an effective tool for a refined phylogenetic inference and genus classification of the Adenoviridae family. PMID- 24787999 TI - Lyme disease risk not amplified in a species-poor vertebrate community: similar Borrelia burgdorferi tick infection prevalence and OspC genotype frequencies. AB - The effect of biodiversity declines on human health is currently debated, but empirical assessments are lacking. Lyme disease provides a model system to assess relationships between biodiversity and human disease because the etiologic agent, Borrelia burgdorferi, is transmitted in the United States by the generalist black legged tick (Ixodes scapularis) among a wide range of mammalian and avian hosts. The 'dilution effect' hypothesis predicts that species-poor host communities dominated by white-footed mice (Peromyscus leucopus) will pose the greatest human risk because P. leucopus infects the largest numbers of ticks, resulting in higher human exposure to infected I. scapularis ticks. P. leucopus-dominated communities are also expected to maintain a higher frequency of those B. burgdorferi outer surface protein C (ospC) genotypes that this host species more efficiently transmits ('multiple niche polymorphism' hypothesis). Because some of these genotypes are human invasive, an additive increase in human disease risk is expected in species-poor settings. We assessed these theoretical predictions by comparing I. scapularis nymphal infection prevalence, density of infected nymphs and B. burgdorferi genotype diversity at sites on Block Island, RI, where P. leucopus dominates the mammalian host community, to species-diverse sites in northeastern Connecticut. We found no support for the dilution effect hypothesis; B. burgdorferi nymphal infection prevalence was similar between island and mainland and the density of B. burgdorferi infected nymphs was higher on the mainland, contrary to what is predicted by the dilution effect hypothesis. Evidence for the multiple niche polymorphism hypothesis was mixed: there was lower ospC genotype diversity at island than mainland sites, but no overrepresentation of genotypes with higher fitness in P. leucopus or that are more invasive in humans. We conclude that other mechanisms explain similar nymphal infection prevalence in both communities and that high ospC genotype diversity can be maintained in both species-poor and species-rich communities. PMID- 24788001 TI - A one-pot C-H insertion/olefination sequence for the formation of alpha alkylidene-gamma-butyrolactones. AB - A one-pot C-H insertion/olefination sequence for the conversion of alpha-diazo alpha-(dialkoxyphosphoryl)acetates into alpha-alkylidene-gamma-butyrolactones is reported. The key C-H insertion process is achieved using a catalytic amount of a dirhodium carboxylate catalyst, using operationally simple conditions. The size and electronic properties of the attached substituents were found to influence the regio- and diastereoselectivity of the process. The utility of the process is demonstrated by the synthesis of a known Staphylococcus aureus (MRSA) virulence inhibitor. PMID- 24788002 TI - Palladium(II)-catalysed total synthesis of naturally occurring pyrano[3,2 a]carbazole and pyrano[2,3-b]carbazole alkaloids. AB - Seven naturally occurring pyranocarbazole alkaloids (pyrayafoline A-E, O methylmurrayamine A and O-methylmahanine) have been obtained by total synthesis using a palladium(II)-catalysed oxidative cyclisation of a diarylamine to an orthogonally diprotected 2,7-dihydroxycarbazole as key step. PMID- 24788003 TI - Na+,HCO3- -cotransport is functionally upregulated during human breast carcinogenesis and required for the inverted pH gradient across the plasma membrane. AB - Metabolic and biochemical changes during breast carcinogenesis enhance cellular acid production. Extrusion of the acid load from the cancer cells raises intracellular pH, while it decreases extracellular pH creating an inverted pH gradient across the plasma membrane compared to normal cells and promoting cancer cell metabolism, proliferation, migration, and invasion. We investigated the effects of breast carcinogenesis on the mechanisms of cellular pH control using multicellular epithelial organoids freshly isolated from human primary breast carcinomas and matched normal breast tissue. Intracellular pH was measured by fluorescence microscopy, while protein expression was investigated by immunofluorescence imaging and immunoblotting. We found that cellular net acid extrusion increased during human breast carcinogenesis due to enhanced Na(+),HCO3 (-)-cotransport, which created an alkaline shift (~0.3 units of magnitude) in steady-state intracellular pH of human primary breast carcinomas compared to normal breast tissue. Na(+)/H(+)-exchange activity and steady-state intracellular pH in the absence of CO2/HCO3 (-) were practically unaffected by breast carcinogenesis. These effects were evident under both acidic (pH 6.8, representative of the tumor microenvironment) and physiological (pH 7.4) extracellular conditions. Protein expression of the Na(+),HCO3 (-)-cotransporter NBCn1 (SLC4A7), which has been linked to breast cancer susceptibility in multiple genome-wide association studies, was twofold higher in human breast carcinomas compared to matched normal breast tissue. Protein expression of the Na(+)/H(+) exchanger NHE1 (SLC9A1) was markedly less affected. We propose that upregulated NBCn1 during human breast carcinogenesis contributes to the characteristic acid distribution within human breast carcinomas and thereby plays a pathophysiological role for breast cancer development and progression. PMID- 24788004 TI - Competence in metered dose inhaler technique among dispensers in Mekelle. AB - BACKGROUND: Inhaled medications are the cornerstone of asthma therapy. Metered dose inhaler technique is a widely used technique to administer medications like corticosteroids. Meanwhile, the health professionals and patients knowledge and practice towards this metered dose inhaler is quite deficient but arguably understood by policy makers or education expertise. OBJECTIVE: This study tried to assess the pharmacists and druggists competency on MDI who are the professionals at the front line to demonstrate and teach the technique for patients. METHOD: A cross sectional study was conducted among registered pharmacists and druggists from different public and private pharmacies and drug stores in Mekelle Town, Ethiopia from March to June, 2013. Evaluation tool was adapted from the National Asthma Education and Prevention Programmes of America (NAEPP) step criteria for the administration of a metered dose inhaler to score the knowledge/proficiency of use of MDIs by the subjects using two evaluators. RESULT: The mean score given by evaluators was 4.34 and 4.28 by evaluator I and II respectively. Of the 106 professionals took part in this research, based on the competency on essential steps for optimum therapeutic value of MDI, only 2 (1.9%) and 1 (0.9%) study participants had adequate competency in metered dose inhaler according to evaluator I and evaluator II respectively. The rest, irrespective of their age, sex, educational status and experience, did not achieve adequate score on MDI technique. Of the essential steps, only 25 (23.6%) and 16 (15.1%) participants breathed in and actuating the canister together according to evaluators I and II respectively. CONCLUSION: Very poor MDI technique was very common in this sample of healthcare providers. Despite involvement of all participants in patient counselling on inhalers, none of them were able to perform all steps correctly, which shows that patient may not have adequate instruction. PMID- 24788005 TI - Response to Vinciguerra et al. PMID- 24788006 TI - Spontaneous relocation of a trapped retrolenticular slow-release dexamethasone implant (Ozurdex) in a silicone oil-filled eye of a pseudophakic patient. PMID- 24788008 TI - A woman with bilateral maculopathy and acquired vitamin B12 deficiency. PMID- 24788007 TI - Images created in a model eye during simulated cataract surgery can be the basis for images perceived by patients during cataract surgery. AB - PURPOSE: To evaluate the images created in a model eye during simulated cataract surgery. PATIENTS AND METHODS: This study was conducted as a laboratory investigation and interventional case series. An artificial opaque lens, a clear intraocular lens (IOL), or an irrigation/aspiration (I/A) tip was inserted into the 'anterior chamber' of a model eye with the frosted posterior surface corresponding to the retina. Video images were recorded of the posterior surface of the model eye from the rear during simulated cataract surgery. The video clips were shown to 20 patients before cataract surgery, and the similarity of their visual perceptions to these images was evaluated postoperatively. RESULTS: The images of the moving lens fragments and I/A tip and the insertion of the IOL were seen from the rear. The image through the opaque lens and the IOL without moving objects was the light of the surgical microscope from the rear. However, when the microscope light was turned off after IOL insertion, the images of the microscope and operating room were observed by the room illumination from the rear. Seventy percent of the patients answered that the visual perceptions of moving lens fragments were similar to the video clips and 55% reported similarity with the IOL insertion. Eighty percent of the patients recommended that patients watch the video clip before their scheduled cataract surgery. CONCLUSIONS: The patients' visual perceptions during cataract surgery can be reproduced in the model eye. Watching the video images preoperatively may help relax the patients during surgery. PMID- 24788009 TI - How many people in England and Wales are registered partially sighted or blind because of age-related macular degeneration? AB - PURPOSE: The purpose of the study was to determine what proportion of new certifications between 1 April 2007 and 31 March 2008 could be attributed to age related macular degeneration (AMD) and to describe the AMD-certified population in England and Wales. METHODS: An electronic version of the Certificate of Vision Impairment form (CVI), the ECVI, was used at the certifications office to transfer information from the paper-based certificates into a database. The electronic certifications data set was queried for all certificates completed between 1 April 2007 and 31 March 2008 with the main cause of certifiable visual loss being AMD or with the main cause of certifiable visual loss being multiple pathology but a contributory cause being AMD. The electronic data set was adapted so that a distinction could be made between geographic atrophy (GA) and neovascular AMD (nAMD). RESULTS: The Certifications Office received 23 185 CVIs between April 2007 and March 2008, of whom 9823 (42%) were people registered severely sight impaired (SSI) and 12 607 (52%) were certified as sight impaired (SI). AMD contributed to 13 000 causes of registration on the CVI forms during this period and was the main cause in 11 015 people. In these 11 015 people, GA accounted for 49.3%, nAMD 35.1%, and AMD not specified 15.7%. CONCLUSIONS: The data in this report provide detailed information on CVI registration due to AMD before the widespread adoption of ranibizumab therapy in NHS practice and provide an insight into the burden of vision loss due to AMD at a time of great change in the management of nAMD. PMID- 24788010 TI - Comment on, 'Factors affecting outcomes of corneal collagen crosslinking treatment'. PMID- 24788011 TI - Response to Nesmith et al. PMID- 24788012 TI - Influence of image compression on the interpretation of spectral-domain optical coherence tomography in exudative age-related macular degeneration. AB - PURPOSE: To evaluate the effect of image compression of spectral-domain optical coherence tomography (OCT) images in the examination of eyes with exudative age related macular degeneration (AMD). METHODS: Thirty eyes from 30 patients who were diagnosed with exudative AMD were included in this retrospective observational case series. The horizontal OCT scans centered at the center of the fovea were conducted using spectral-domain OCT. The images were exported to Tag Image File Format (TIFF) and 100, 75, 50, 25 and 10% quality of Joint Photographic Experts Group (JPEG) format. OCT images were taken before and after intravitreal ranibizumab injections, and after relapse. The prevalence of subretinal and intraretinal fluids was determined. Differences in choroidal thickness between the TIFF and JPEG images were compared with the intra-observer variability. RESULTS: The prevalence of subretinal and intraretinal fluids was comparable regardless of the degree of compression. However, the chorio-scleral interface was not clearly identified in many images with a high degree of compression. In images with 25 and 10% quality of JPEG, the difference in choroidal thickness between the TIFF images and the respective JPEG images was significantly greater than the intra-observer variability of the TIFF images (P=0.029 and P=0.024, respectively). CONCLUSIONS: In OCT images of eyes with AMD, 50% of the quality of the JPEG format would be an optimal degree of compression for efficient data storage and transfer without sacrificing image quality. PMID- 24788013 TI - Live Brugia malayi in the anterior chamber: a case report from India. PMID- 24788014 TI - Is accelerated corneal collagen cross-linking for keratoconus the way forward? No. PMID- 24788015 TI - High intraocular pressure in four vitrectomized eyes with intravitreal C3F8 without high altitude travel. AB - IMPORTANCE: It is well known that altitude ascent with intravitreal gas can cause expansion of gas and intraocular pressure (IOP) elevation. According to Boyle's law, the gas bubble will not expand unless a higher altitude than the gas insertion site has been reached. We report four cases in which intravitreal gas was injected at an altitude of 790 m (Jerusalem). All four cases developed high IOP even though they did not reach a higher altitude in their post-operative period. OBSERVATIONS: A report of four patients following vitrectomy with 12% mixture of perfluoropropane and air are presented. All four patients arrived with ocular pain following the ascent by car of 765-1100 m to Jerusalem where the vitrectomy and gas insertion was conducted. Upon examination, all four patients had high IOP (30-55 mm Hg). IOP was well controlled with IOP-lowering medications. None of the patients suffered from long-term complications. CONCLUSIONS AND RELEVANCE: Caution should be taken with altitude changes in patients with intravitreal gas even if there was no ascent from the altitude in which the vitrectomy was performed. PMID- 24788016 TI - Diagnostic accuracy of the Amsler grid and the preferential hyperacuity perimetry in the screening of patients with age-related macular degeneration: systematic review and meta-analysis. AB - OBJECTIVE: To clarify the screening potential of the Amsler grid and preferential hyperacuity perimetry (PHP) in detecting or ruling out wet age-related macular degeneration (AMD). EVIDENCE ACQUISITION: Medline, Scopus and Web of Science (by citation of reference) were searched. Checking of reference lists of review articles and of included articles complemented electronic searches. Papers were selected, assessed, and extracted in duplicate. EVIDENCE SYNTHESIS: Systematic review and meta-analysis. Twelve included studies enrolled 903 patients and allowed constructing 27 two-by-two tables. Twelve tables reported on the Amsler grid and its modifications, twelve tables reported on the PHP, one table assessed the MCPT and two tables assessed the M-charts. All but two studies had a case control design. The pooled sensitivity of studies assessing the Amsler grid was 0.78 (95% confidence intervals; 0.64-0.87), and the pooled specificity was 0.97 (95% confidence intervals; 0.91-0.99). The corresponding positive and negative likelihood ratios were 23.1 (95% confidence intervals; 8.4-64.0) and 0.23 (95% confidence intervals; 0.14-0.39), respectively. The pooled sensitivity of studies assessing the PHP was 0.85 (95% confidence intervals; 0.80-0.89), and specificity was 0.87 (95% confidence intervals; 0.82-0.91). The corresponding positive and negative likelihood ratios were 6.7 (95% confidence intervals; 4.6-9.8) and 0.17 (95% confidence intervals; 0.13-0.23). No pooling was possible for MCPT and M charts. CONCLUSION: Results from small preliminary studies show promising test performance characteristics both for the Amsler grid and PHP to rule out wet AMD in the screening setting. To what extent these findings can be transferred to a real clinic practice still needs to be established. PMID- 24788017 TI - The clinical course of recurrent intermittent exotropia following one or two surgeries over 24 months postoperatively. AB - PURPOSE: The aim of this study is to investigate the difference of the clinical course in recurrent intermittent exotropia after second surgery compared with both recurrent intermittent exotropia after its first of two surgeries and intermittent exotropia after only a single surgery. METHODS: We retrospectively reviewed the medical records of patients diagnosed with intermittent exotropia who underwent lateral rectus recession and medial rectus resection (R&R) between January 1992 and January 2011 at Yeungnam University Hospital. Repeated measure ANOVA (rmANOVA) was used to compare the clinical course of recurrent intermittent exotropia before and after a second surgery with that of intermittent exotropia with a single surgery. RESULTS: A total of 352 intermittent exotropia patients who underwent one R&R procedure and 77 recurrent intermittent exotropia patients who underwent a second R&R in the contralateral eye were included in this study. Although exodrift of recurrent intermittent exotropia was observed at 24 months of follow-up even after a second surgery, it was significantly lower than both intermittent exotropia with a single surgery and after its first of two surgeries (P<0.001, rmANOVA). CONCLUSION: The clinical course of recurrent intermittent exotropia after a second surgery was improved compared with both recurrent intermittent exotropia after its first of two surgeries and intermittent exotropia after a single surgery. PMID- 24788018 TI - The anatomical and functional benefit of bevacizumab in the treatment of macular edema associated with Purtscher-like retinopathy. PMID- 24788019 TI - Is accelerated corneal collagen cross-linking for keratoconus the way forward? Yes. PMID- 24788021 TI - Theory-assisted development of a robust and Z-selective olefin metathesis catalyst. AB - DFT calculations have predicted a new, highly Z-selective ruthenium-based olefin metathesis catalyst that is considerably more robust than the recently reported (SIMes)(Cl)(RS)RuCH(o-OiPrC6H4) (3a, SIMes = 1,3-dimesityl-4,5-dihydroimidazol-2 ylidene, R = 2,4,6-triphenylbenzene) [J. Am. Chem. Soc., 2013, 135, 3331]. Replacing the chloride of 3a by an isocyanate ligand to give 5a was predicted to increase the stability of the complex considerably, at the same time moderately improving the Z-selectivity. Compound 5a is easily prepared in a two-step synthesis starting from the Hoveyda-Grubbs second-generation catalyst 3. In agreement with the calculations, the isocyanate-substituted 5a appears to be somewhat more Z-selective than the chloride analogue 3a. More importantly, 5a can be used in air, with unpurified and non-degassed substrates and solvents, and in the presence of acids. These are traits that are unprecedented among highly Z selective olefin metathesis catalysts and also very promising with respect to applications of the new catalyst. PMID- 24788022 TI - Net platelet angiogenic activity (NPAA) correlates with progression and prognosis of non-small cell lung cancer. AB - Circulating platelets are abundant sources of angiogensis molecules for the tumor vasculature affecting tumor growth and metastasis. The relationship between non small cell lung cancer (NSCLC) and intra-platelet levels of VEGF, TSP-1 and net platelet angiogenic activity (NPAA) is unclear. The aim of this study was to better understand the role of these factors in the progression of NSCLC cancer and to assess its clinical significance. Platelet VEGF and TSP-1 and NPAA were measured preoperatively in 68 patients with NSCLC by ELISA or Capillary tube formation assay. VEGF, TSP-1 and NPAA distributions in cancer patients and healthy volunteers were compared using the Mann-Whitney U test. The Kaplan-Meier method, univariate and multivariate regression analysis was used to analyze the correlation between these factors and clinicopathological features, overall survival and disease-free survival. Mean intra-platelet TSP-1 level was slightly higher in patients than in healthy subjects (p = 0.092). Intra-platelet TSP-1 levels were significantly higher in patients with involvement greater than T2 or stage III, compared to other patients. Mean intra-platelet VEGF level was 40.8 pg/106 in patients compared to 21.9 ng/106 in healthy subjects (p = 0.041). Median value of NPAA in patients was significantly higher than that in healthy controls (p<0.001). Patients with high NPAA are more likely to exhibit aggressive clinical pathological features. NPAA greater than the median are associated with poor prognosis. The elevated NPAA have better correlation with tumor microvessel density (MVD) than platelet-derived VEGF. The areas under receiver operating curve (AUROC) of NPAA were higher than that of platelet derived VEGF in different groups. A multivariate analysis showed that NPAA are independent prognostic factors. These results indicated that NPAA may be a clinically useful indicator for diagnostic and prognostic evaluation in NSCLC patients. PMID- 24788023 TI - Larval intraspecific competition for food in the European grapevine moth Lobesia botrana. AB - Effective pest management with lower amounts of pesticides relies on accurate prediction of insect pest growth rates. Knowledge of the factors governing this trait and the resulting fitness of individuals is thus necessary to refine predictions and make suitable decisions in crop protection. The European grapevine moth, Lobesia botrana, the major pest of grapes in Europe, is responsible for huge economic losses. Larvae very rarely leave the grape bunch on which they were oviposited and thus cannot avoid intraspecific competition. In this study, we determined the impact of intraspecific competition during the larval stage on development and adult fitness in this species. This was tested by rearing different numbers of larvae on an artificial diet and measuring developmental and reproductive life history traits. We found that intraspecific competition during larval development has a slight impact on the fitness of L. botrana. The principal finding of this work is that larval density has little effect on the life history traits of survivors. Thus, the timing of eclosion, duration of subsequent oviposition, fecundity appears to be more uniform in L. botrana than in other species. The main effect of larval crowding was a strong increase of larval mortality at high densities whereas the probability of emergence, sex ratio, pupal mass, fecundity and longevity of mated females were not affected by larval crowding. Owing to increased larval mortality at high larval densities, we hypothesized that mortality of larvae at high densities provided better access to food for the survivors with the result that more food was available per capita and there were no effect on fitness of survivors. From our results, larval crowding alters the reproductive capacity of this pest less than expected but this single factor should now be tested in interaction with limited resources in the wild. PMID- 24788024 TI - Immunoreactivity of protein tyrosine phosphatase A (PtpA) in sera from sheep infected with Mycobacterium avium subspecies paratuberculosis. AB - Evasion of host defense mechanisms and survival inside infected host macrophages are features of pathogenic mycobacteria including Mycobacterium avium subspecies paratuberculosis, the causative agent of Johne's disease in ruminants. Protein tyrosine phosphatase A (PtpA) has been identified as a secreted protein critical for survival of mycobacteria within infected macrophages. The host may mount an immune response to such secreted proteins. In this study, the humoral immune response to purified recombinant M. avium subsp. paratuberculosis PtpA was investigated using sera from a cohort of sheep infected with M. avium subsp. paratuberculosis and compared with uninfected healthy controls. A significantly higher level of reactivity to PtpA was observed in sera collected from M. avium subspecies paratuberculosis infected sheep when compared to those from uninfected healthy controls. PtpA could be a potential candidate antigen for detection of humoral immune responses in sheep infected with M. avium subspecies paratuberculosis. PMID- 24788025 TI - Effect of haptic supplementation on postural control of younger and older adults in an unstable sitting task. AB - Standing postural control is known to be altered during aging, but age-related changes in sitting postural control have scarcely been explored. The present experiment studied the roles of visual and haptic information in a sitting task in both young and older adults. Fifteen young and fifteen older adults participated in this study. Six experimental conditions were performed with eyes open and eyes closed: quiet sitting, rocker-board sitting, and 4 conditions of haptic supplementation, provided by a hand-held pen, during rocker-board sitting. Classical variables were extracted from the center of pressure (COP) and pen trajectories, and the stabilogram diffusion analysis was performed on the COP data. Three-way ANOVAs (Group*Vision*Condition) were carried out. Postural instability was strongly attenuated by haptic supplementation in both age groups. Furthermore, instability due to visual deprivation was compensated by haptic supplementation. Long- and short-term diffusion coefficients were smaller in conditions of haptic supplementation. The present study confirmed the effect of haptic supplementation on both open-loop and closed-loop mechanisms of postural control and extended it to unstable sitting in young and older adults despite the complex biomechanical systems involved in sitting postural tasks. PMID- 24788026 TI - Insight into the function of the obturator internus muscle in humans: observations with development and validation of an electromyography recording technique. AB - There are no direct recordings of obturator internus muscle activity in humans because of difficult access for electromyography (EMG) electrodes. Functions attributed to this muscle are based on speculation and include hip external rotation/abduction, and a role in stabilization as an "adjustable ligament" of the hip. Here we present (1) a technique to insert intramuscular EMG electrodes into obturator internus plus (2) the results of an investigation of obturator internus activity relative to that of nearby hip muscles during voluntary hip efforts in two hip positions and a weight-bearing task. Fine-wire electrodes were inserted with ultrasound guidance into obturator internus, gluteus maximus, piriformis and quadratus femoris in ten participants. Participants performed ramped and maximal isometric hip efforts (open kinetic chain) into flexion/extension, abduction/adduction, and internal/external rotation, and hip rotation to end range in standing. Analysis of the relationship between activity of the obturator internus and the other hip muscles provided evidence of limited contamination of the recordings with crosstalk. Obturator internus EMG amplitude was greatest during hip extension, then external rotation then abduction, with minimal to no activation in other directions. Obturator internus EMG was more commonly the first muscle active during abduction and external rotation than other muscles. This study describes a viable and valid technique to record obturator internus EMG and provides the first evidence of its activation during simple functions. The observation of specificity of activation to certain force directions questions the hypothesis of a general role in hip stabilisation regardless of force direction. PMID- 24788027 TI - Essential oil composition and antimicrobial activity of Angelica archangelica L. (Apiaceae) roots. AB - In this paper, the chemical composition and the antimicrobial activity of the essential oil of Angelica archangelica L. (Apiaceae) roots from central Italy were analyzed. The major constituents of the oil were alpha-pinene (21.3%), delta 3-carene (16.5%), limonene (16.4%) and alpha-phellandrene (8.7%). The oil shows a good antimicrobial activity against Clostridium difficile, Clostridium perfringens, Enterococcus faecalis, Eubacterium limosum, Peptostreptococcus anaerobius, and Candida albicans with minimum inhibitory concentration (MIC) values of 0.25, 0.25, 0.13, 0.25, 2.25, and 0.50% v/v, respectively. A weaker antimicrobial activity against bifidobacteria and lactobacilli-very useful in the intestinal microflora-has also been shown with MIC values >4.0% v/v. PMID- 24788028 TI - Characteristics of community mental health clinics associated with treatment engagement. AB - OBJECTIVES: Past literature documents many individual predictors of treatment engagement among mental health clients in community settings, but few studies have examined clinic characteristics that may be associated with treatment engagement. With data from a patient activation and self-management trial, this study examined the variation in demographic and clinic characteristics across community mental health clinics and whether this variation predicted differences in treatment engagement in mental health services. METHODS: Chart reviews were conducted for 638 clients of 12 community mental health clinics. Client attendance records were collected for a one-year period to examine engagement (defined as the ratio of kept versus scheduled appointments). Adjusting for client variability, the investigators examined which clinic-level characteristics were associated with treatment engagement. RESULTS: Clinics varied significantly in their clients' demographic characteristics and engagement in mental health care. Providing case management and offering transportation vouchers or free parking at the clinic were associated with lower engagement. However, offering outreach was associated with greater engagement. CONCLUSIONS: The results of this study suggest that certain clinic characteristics are associated with engagement in mental health services. These results demonstrate the difficulties faced by community mental health clinics in reducing no-show rates even in the face of strong efforts to improve engagement. PMID- 24788029 TI - A medical illusion from Pinocchio. PMID- 24788030 TI - Translation and cross-cultural adaptation of the Scleroderma Health Assessment Questionnaire to Brazilian Portuguese. AB - CONTEXT AND OBJECTIVE: Systemic sclerosis is an autoimmune disease characterized by abnormalities of vascularization that may cause fibrosis of the skin and other organs and lead to dysfunction. It is therefore essential to have tools capable of evaluating function in individuals with this condition. The aim of this study was to translate the Scleroderma Health Assessment Questionnaire (SHAQ) into Portuguese, adapt it to Brazilian culture and test its validity and reliability. DESIGN AND SETTING: The validation of SHAQ followed internationally accepted methodology, and was performed in university outpatient clinics. METHODS: SHAQ was translated into Portuguese and back-translated. In the cultural adaptation phase, it was applied to 20 outpatients. Items not understood by 20% of the patients were modified and applied to another 20 outpatients. Twenty patients were interviewed on two different occasions to determine the validity and reliability of the questionnaire: two interviewers on the first occasion and one interviewer 14 days later. To determine the external validity, comparisons were made with Health Assessment Questionnaire (HAQ), Disabilities of the Arm, Shoulder and Hand (DASH) and short form-36 (SF-36). RESULTS: In the interobserver evaluation, Pearson's correlation coefficient and the intraclass correlation coefficient were both 0.967. In the intraobserver evaluation, Pearson's correlation coefficient was 0.735 and the intraclass correlation coefficient was 0.687. Regarding external validity, SHAQ scores were statistically correlated with all measurements, except the general health domain of SF-36 and the work related score (Q2) of DASH. CONCLUSION: The Brazilian version of SHAQ proved to be valid and reliable for assessing function in patients with diffuse systemic sclerosis. PMID- 24788031 TI - Methods of cognitive function investigation in the Longitudinal Study on Adult Health (ELSA-Brasil). AB - CONTEXT AND OBJECTIVE: Many uncertainties concerning risk factors and evolution of cognitive disorders remain. We describe the methods and preliminary results from the investigation of the cognitive function in the Longitudinal Study on Adult Health (ELSA-Brasil). DESIGN AND SETTING: Multicenter cohort study on public employees at six public teaching and research institutions. METHODS: The participants were interviewed and examined to obtain a broad range of social, clinical and environmental characteristics. The following standardized tools were used to assess memory, language and visuospatial and executive functions: words or figure memory test; semantic (animals) and phonemic (letter F) verbal fluency tests; and trail test B. RESULTS: 15,101 out of 15,105 participants took the cognitive tests: 54% were women; the mean age was 51 years; and 52% had a university degree. 14,965 participants (99%) did the word test and 136 (1%) did the figure test due to low schooling level. The scores from the semantic verbal fluency tests (mean = 18.42 +/- 5.29; median = 18 words) were greater than the scores from the phonemic verbal fluency tests (mean = 12.46 +/- 4.5; median = 12 words). The median time taken to perform the trail test was 1.6 minutes. CONCLUSION: The large cohort size, of young age, and the extensive amount of clinical and epidemiological data available will make it possible to investigate the prognostic value of biological, behavioral, environmental, occupational and psychosocial variables over the short and medium terms in relation to cognitive decline, among adults and elderly people. PMID- 24788032 TI - Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement. AB - CONTEXT AND OBJECTIVE: Case-control studies are important in developing clinical and public health knowledge. The STROBE statement (STrengthening the Reporting of OBservational Studies in Epidemiology) was developed to establish a checklist of items that should be included in articles reporting observational studies. Our aim was to analyze whether the psychiatric case-control articles published in Brazilian journals with CAPES Qualis rating B1/B2 in 2009 conformed with the STROBE statement. DESIGN AND SETTING: Descriptive study on psychiatric papers published in Brazilian journals, within the Postgraduate Medical Program on Psychiatry, at Universidade Federal do Rio Grande do Sul. METHODS: All psychiatric case-control studies from Brazilian Qualis B1/B2 journals of psychiatry, neurology and public health in 2009 were analyzed. The four most specific items of the STROBE statement were used to evaluate whether these studies fitted within the case-control parameters: 1) selection of cases and controls; 2) controlling for bias; 3) statistical analysis; and 4) presentation of results. RESULTS: Sixteen case-control studies were identified, of which eleven (68.75%) were in psychiatry-focused journals. From analysis using the STROBE statement, all of the articles conformed with item 1; two (12.5%) completely conformed with item 2; none completely conformed with item 3; and only three (18.8%) conformed with item 4. CONCLUSION: The case-control studies analyzed here did not completely conform with the four STROBE statement items for case-control design. In view of the inadequate methodology of the published studies, these findings justify focusing on research and methodology and expanding the investigations on adherence of studies to their designs. PMID- 24788033 TI - Hemorrhagic shock secondary to button battery ingestion. AB - CONTEXT: Button battery ingestion is a frequent pediatric complaint. The serious complications resulting from accidental ingestion have increased significantly over the last two decades due to easy access to gadgets and electronic toys. Over recent years, the increasing use of lithium batteries of diameter 20 mm has brought new challenges, because these are more detrimental to the mucosa, compared with other types, with high morbidity and mortality. The clinical complaints, which are often nonspecific, may lead to delayed diagnosis, thereby increasing the risk of severe complications. CASE REPORT: A five-year-old boy who had been complaining of abdominal pain for ten days, was brought to the emergency service with a clinical condition of hematemesis that started two hours earlier. On admission, he presented pallor, tachycardia and hypotension. A plain abdominal x-ray produced an image suggestive of a button battery. Digestive endoscopy showed a deep ulcerated lesion in the esophagus without active bleeding. After this procedure, the patient presented profuse hematemesis and severe hypotension, followed by cardiorespiratory arrest, which was reversed. He then underwent emergency exploratory laparotomy and presented a new episode of cardiorespiratory arrest, which he did not survive. The battery was removed through rectal exploration. CONCLUSION: This case describes a fatal evolution of button battery ingestion with late diagnosis and severe associated injury of the digestive mucosa. A high level of clinical suspicion is essential for preventing this evolution. Preventive strategies are required, as well as health education, with warnings to parents, caregivers and healthcare professionals. PMID- 24788035 TI - Remote science support during MARS2013: testing a map-based system of data processing and utilization for future long-duration planetary missions. AB - MARS2013 was an integrated Mars analog field simulation in eastern Morocco performed by the Austrian Space Forum between February 1 and 28, 2013. The purpose of this paper is to discuss the system of data processing and utilization adopted by the Remote Science Support (RSS) team during this mission. The RSS team procedures were designed to optimize operational efficiency of the Flightplan, field crew, and RSS teams during a long-term analog mission with an introduced 10 min time delay in communication between "Mars" and Earth. The RSS workflow was centered on a single-file, easy-to-use, spatially referenced database that included all the basic information about the conditions at the site of study, as well as all previous and planned activities. This database was prepared in Google Earth software. The lessons learned from MARS2013 RSS team operations are as follows: (1) using a spatially referenced database is an efficient way of data processing and data utilization in a long-term analog mission with a large amount of data to be handled, (2) mission planning based on iterations can be efficiently supported by preparing suitability maps, (3) the process of designing cartographical products should start early in the planning stages of a mission and involve representatives of all teams, (4) all team members should be trained in usage of cartographical products, (5) technical problems (e.g., usage of a geological map while wearing a space suit) should be taken into account when planning a work flow for geological exploration, (6) a system that helps the astronauts to efficiently orient themselves in the field should be designed as part of future analog studies. PMID- 24788034 TI - Determinants of highly active antiretroviral therapy duration in HIV-1-infected children and adolescents in Madrid, Spain, from 1996 to 2012. AB - OBJECTIVES: To investigate the duration of sequential HAART regimens and predictors of first-line regimen discontinuation among HIV-1 vertically infected children and adolescents. DESIGN: Multicentre survey of antiretroviral-naive patients enrolled in the HIV-Paediatric Cohor,t CoRISpeS-Madrid Cohort, Spain. METHODS: Patients with a follow-up of >= 1 month spent on HAART, with available baseline CD4 count and HIV-viral load (VL) were included. Time spent on sequential HAART regimens was estimated and multivariable regression was used to identify predictors of time to first-line regimen discontinuation. RESULTS: 104 patients were followed for a median 8 years after starting HAART among 1996-2012; baseline %CD4 was 21.5 (12.3-34.0)and viral load was 5.1 (4.6-5.6) log10 copies/mL. Patients received a mean of 1.9 regimens. Median time on first-line HAART (n = 104) was 64.5 months; second HAART (n = 56) 69.8 months; and third HAART (n = 21) 66.5 months. Eleven (11%) patients were lost to follow-up while on first-line HAART and 54% discontinued (cumulative incidence of 16% and 38% by 1 and 3-year, respectively). The main predictor of first-line regimen discontinuation was suboptimal adherence to antiretrovirals (AHR: 2.60; 95% CI: 1.44-4.70). CONCLUSIONS: Adherence to therapy was the main determinant of the duration of the first-line HAART regimen in children. It is important to identify patients at high risk for non-adherence, such as very young children and adolescents, in provide special care and support to those patients. PMID- 24788036 TI - Combined radiofrequency ablation and ethanol injection with a multipronged needle for the treatment of medium and large hepatocellular carcinoma. AB - OBJECTIVE: To evaluate the efficacy and safety of combined radiofrequency ablation (RFA) and ethanol injection with a multipronged needle in the treatment of medium (3.1-5.0 cm) and large (5.1-7.0 cm) hepatocellular carcinoma (HCC). METHODS: A total of 65 patients with 67 HCC nodules were enrolled in this prospective study. All of them received the treatment of combined RFA and multipronged ethanol injection percutaneously. RESULTS: The average volume of injected ethanol was 14.4 +/- 4.1 ml (range, 9-30 ml). The average number of RFA electrode insertions was 1.7 +/- 0.8 (range, 1-4). The rate of initial local complete response (CR) was 94.0 % (63/67). After additional treatment, technical success was achieved in all HCC nodules. There were no treatment-related deaths, and major complications were observed in 3 (4.6%) patients. After a mean follow up of 20.0 +/- 7.6 months, local tumour progression was observed in 10 (10/67, 14.9%) tumours, whereas distant recurrence developed in 32 (32/65, 49.2%) patients. The 1-year and 2-year survival rates were 93.1% and 88.1%, respectively. CONCLUSION: The combination of RFA and multipronged ethanol injection in the treatment of medium and large HCC is safe and effective with a high rate of local tumour control. KEY POINTS: * Combined radiofrequency ablation and multipronged ethanol injection is a new therapeutic strategy * Treatment is safe and effective for medium and large hepatocellular carcinoma (HCC) * A multipronged needle allows for a homogeneous ethanol distribution. PMID- 24788037 TI - Diagnostic accuracy of dual-echo (in- and opposed-phase) T1-weighted gradient recalled echo for detection and grading of hepatic iron using quantitative and visual assessment. AB - OBJECTIVES: Detection and quantification of hepatic iron with dual-echo gradient recalled echo (GRE) has been proposed as a rapid alternative to other magnetic resonance imaging (MRI) techniques. Co-existing steatosis and T1 weighting are limitations. This study assesses the accuracy of routine dual-echo GRE. METHODOLOGY: Between 2010 and 2013, 109 consecutive patients underwent multi-echo (ME) MRI and dual-echo GRE for quantification of hepatic iron. Liver iron concentration (LIC) was calculated from ME-MRI. Relative signal intensity (RSI) and fat signal fraction (FSF) were calculated from dual-echo GRE. Four radiologists subjectively evaluated dual-echo GRE (+/-subtraction). Diagnostic accuracy was compared between techniques and correlated with biopsy using Fisher's exact test, Spearman correlation and regression. RESULTS: The sensitivity of visual detection of iron ranged from 48 to 55%. Subtraction did not increase sensitivity (p < 0.001). Inter-observer variability was substantial (kappa = 0.72). The specificity of visual detection of iron approached 100% with false-positive diagnoses observed using subtraction. LIC showed a higher correlation with histopathological iron grade (r = 0.94, p < 0.001) compared with RSI (r = 0.65, p = 0.02). Univariate regression showed an association between RSI and LIC (B = 0.98, p < 0.001, CI 0.73-1.23); however, the association was not significant with multi-variate regression including FSF (p = 0.28). CONCLUSIONS: Dual-echo GRE has low sensitivity for hepatic iron. Subtraction imaging can result in false-positive diagnoses. KEY POINTS: * Routine liver MRI studies cannot effectively screen patients for iron overload. * Concomitant hepatic steatosis and iron limits diagnostic accuracy of routine liver MRI. * Dual-echo GRE subtraction imaging causes false-positive diagnoses of iron overload. * Dedicated MRI techniques should be used to diagnose and quantify iron overload. PMID- 24788038 TI - Intravoxel incoherent motion diffusion-weighted MR imaging in differentiation of lung cancer from obstructive lung consolidation: comparison and correlation with pharmacokinetic analysis from dynamic contrast-enhanced MR imaging. AB - OBJECTIVES: To test whether parameters derived from intravoxel incoherent motion (IVIM) can be used to distinguish lung cancer from obstructive pulmonary consolidation by comparing them with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived parameters and to evaluate the correlation between these quantitative parameters. METHODS: A total of 31 lung cancer patients, confirmed by pathology and obstructive consolidations confirmed by positron emission tomography/computed tomography (PET-CT), were recruited. All of them were assessed with structural MRI and IVIM and 17 of them underwent additional DCE-MRI examinations. Parameters derived from IVIM and DCE-MRI in the tumour and consolidation were analysed, and the optimal cut-off values in differential diagnosis were obtained. RESULTS: ADC(total), D and f values were lower (P < 0.05), while IAUC60 was higher in lung cancers (P = 0.013) compared with obstructive pulmonary consolidations. According to the ROC curve, ADC(total) outperformed other perfusion and diffusion parameters with the optimal cut-off value of 1.409 * 10(-3) mm(2)/s (AUC = 0.95). Poor correlations were found between parameters derived from IVIM and DCE-MRI. CONCLUSIONS: IVIM-MRI is potentially useful in the differentiation of lung cancer and obstructive pulmonary consolidation. ADC(total), D and f may be reliable independent discriminating markers, but D* is variable with low diagnostic accuracy. KEY POINTS: * Lung cancer and consolidation differentiation is essential for treatment decision-making. * Perfusion and diffusion characteristics of lesions could help differential diagnosis. * IVIM can separate reflection of tissue diffusivity and microcapillary perfusion. * The relationship between perfusion quantified by IVIM and DCE-MRI is controversial. PMID- 24788039 TI - Spatial covariance reconstructive (SCORE) super-resolution fluorescence microscopy. AB - Super-resolution fluorescence microscopy has become a powerful tool to resolve structural information that is not accessible to traditional diffraction-limited imaging techniques such as confocal microscopy. Stochastic optical reconstruction microscopy (STORM) and photoactivation localization microscopy (PALM) are promising super-resolution techniques due to their relative ease of implementation and instrumentation on standard microscopes. However, the application of STORM is critically limited by its long sampling time. Several recent works have been focused on improving the STORM imaging speed by making use of the information from emitters with overlapping point spread functions (PSF). In this work, we present a fast and efficient algorithm that takes into account the blinking statistics of independent fluorescence emitters. We achieve sub diffraction lateral resolution of 100 nm from 5 to 7 seconds of imaging. Our method is insensitive to background and can be applied to different types of fluorescence sources, including but not limited to the organic dyes and quantum dots that we demonstrate in this work. PMID- 24788040 TI - Probiotics in inflammatory bowel disease: is it fair to lump them into a one size that fits all? PMID- 24788041 TI - Reply to Mardini and Grigorian. PMID- 24788042 TI - Processing of heparanase is mediated by syndecan-1 cytoplasmic domain and involves syntenin and alpha-actinin. AB - Heparanase activity plays a decisive role in cell dissemination associated with cancer metastasis. Cellular uptake of heparanase is considered a pre-requisite for the delivery of latent 65-kDa heparanase to lysosomes and its subsequent proteolytic processing and activation into 8- and 50-kDa protein subunits by cathepsin L. Heparan sulfate proteoglycans, and particularly syndecan, are instrumental for heparanase uptake and activation, through a process that has been shown to occur independent of rafts. Nevertheless, the molecular mechanism underlying syndecan-mediated internalization outside of rafts is unclear. Here, we examined the role of syndecan-1 cytoplasmic domain in heparanase processing, utilizing deletion constructs lacking the entire cytoplasmic domain (Delta), the conserved (C1 or C2), or variable (V) regions. Heparanase processing was markedly increased following syndecan-1 over-expression; in contrast, heparanase was retained at the cell membrane and its processing was impaired in cells over expressing syndecan-1 deleted for the entire cytoplasmic tail. We have next revealed that conserved domain 2 (C2) and variable (V) regions of syndecan-1 cytoplasmic tail mediate heparanase processing. Furthermore, we found that syntenin, known to interact with syndecan C2 domain, and alpha actinin are essential for heparanase processing. PMID- 24788044 TI - Decreased expression of Sox7 correlates with the upregulation of the Wnt/beta catenin signaling pathway and the poor survival of gastric cancer patients. AB - Sox7 is a tumor suppressor gene that plays an important role in the inhibition and progression of cancer. In the present study, we sought to investigate Sox7 expression in gastric cancer (GC) and its association with the Wnt/beta-catenin signaling pathway. We also wished to determine its clinicopathological significance and prognostic implications. Sox7 expression and its effects on the Wnt/beta-catenin signaling in vitro were assessed by reverse transcription polymerase chain reaction using the AGS, MKN-45 and GES-1 gastric cell lines. We also used immunohistochemistry on paraffin-embedded tissue samples and western blot analysis on fresh tissue samples from patients with GC. The results revealed that Sox7 expression was significantly lower in the GC samples than in distal normal tissues, which was in accordance with our results obtained from our in vitro experiments on the cell lines. However, the expression levels of beta catenin were significantly higher. Sox7 and beta-catenin expression significantly correlated with the depth of invasion, lymph node metastasis, distant metastasis and the TNM stage. Patient samples that were Sox7-negative correlated with a significantly shorter survival time. Multivariate survival analysis revealed that Sox7 and beta-catenin had an independent effect on the survival of GC patients. Sox7 and beta-catenin expression in GC had a negative liner correlation with each other. Our findings suggest that Sox7 plays an important role in inhibiting tumorigenesis and progression, and may be a potential marker for predicting the prognosis of patients with GC. PMID- 24788045 TI - Perceived challenges and supports experienced by the family caregiver of the older adult: a photovoice study. AB - As the older adult population in the United States grows in number, the need for family caregivers will also rise. Results from quantitative studies mostly provide evidence of caregiver burden, not caregiver support, and qualitative studies are needed. This study used a community-based participatory action research methodology called photovoice to explore challenges and supports experienced by family caregivers of the older adult. Photovoice incorporates the use of photographs to facilitate the elucidation of an experience by populations or groups. Using photovoice, study participants self-identified 5 challenges and 5 supports experienced in the caregiver role. PMID- 24788043 TI - NHE3 phosphorylation via PKCeta marks the polarity and orientation of directionally migrating cells. AB - Endogenous electric fields (EF) may provide an overriding cue for directional cell migration during wound closure. Perceiving a constant direction requires active sodium-hydrogen exchanger (pNHE3) at the leading edge of HEK 293 cells but its activation mechanism is not yet fully understood. Because protein kinase C (PKC) is required in electrotaxis, we asked whether NHE3 is activated by PKC during wound healing. Using pharmacological (pseudosubstrate and edelfosine) inhibition, we showed that inhibition of PKCeta isoform impairs directional cell migration in HEK 293 cells in the presence of a persistent directional cue (0.25 0.3 V/mm of EF for 2 h). Further, we found that pNHE3 forms complexes with both PKCeta and gamma-tubulin, suggesting that these molecules may regulate the microtubule-organizing center. In addition, cellular pNHE3 content was reduced significantly when PKCeta was inhibited during directional cell migration. Taken together, these data suggest that PKCeta-dependent phosphorylation of NHE3 and the formation of pNHE3/PKCeta/gamma-tubulin complexes at the leading edge of the cell are required for directional cell migration in an EF. PMID- 24788046 TI - University students' knowledge and attitudes toward emergency contraception pills. AB - The purpose of this study was to assess university students' knowledge and attitudes toward emergency contraception pills (ECPs). A written survey was administered to a convenience sample at a university. Study findings showed favorable student attitudes toward ECP and poor knowledge levels. Knowledge and attitude scores were not influenced by gender. Students who reported receiving health care provider ECP counseling had more positive attitudes toward ECP than those who did not receive counseling, but no knowledge level difference existed. More research is needed on methods to educate students on ECP and on the relationship between knowledge, attitudes and ECP utilization. PMID- 24788047 TI - A new participative, family-oriented health counseling approach for children and their families: a comparative qualitative analysis. AB - Health counseling is an essential part of health promotion and there is a need for new, family-oriented health counseling methods. The objective of this study was to describe the differences in physical activity conversations from the perspective of family-oriented care between child health visits using the Weighty Matter Toolkit and those using normal protocol. In total, 35 health visits were analyzed. The results indicate that the Weighty Matter Toolkit offers the child, and other family members, a better opportunity to participate to conversations, and the focus of the conversation is more diverse and based on the family's perception regarding physical activity compared to the normal protocol. Thus, the Weighty Matter Toolkit is a promising method for family-oriented health counseling. PMID- 24788048 TI - Homeless health needs: shelter and health service provider perspective. AB - The effects of homelessness on health are well documented, although less is known about the challenges of health care delivery from the perspective of service providers. Using data from a larger health needs assessment, the purpose of this study was to describe homeless health care needs and barriers to access utilizing qualitative data collected from shelter staff (n = 10) and health service staff (n = 14). Shelter staff members described many unmet health needs and barriers to health care access, and discussed needs for other supportive services in the area. Health service providers also described multiple health and service needs, and the need for a recuperative care setting for this population. Although a variety of resources are currently available for homeless health service delivery, barriers to access and gaps in care still exist. Recommendations for program planning are discussed and examined in the context of contributing factors and health care reform. PMID- 24788049 TI - A collaborative communitywide health fair: the process and impacts on the community. AB - The purpose of this article is to describe the process of conducting a collaborative communitywide health fair, and the impacts of such health intervention programs on community members. A community health fair addresses the health access needs of underserved populations. The success or effectiveness of such community-based programs requires systematic approach to assessment, planning, implementation, and evaluation. The PRECEDE~PROCEED model was used as the guiding framework. The health fair described in this article was coordinated by nurses and drew resources from multiple health providers and organizations. The fair provided opportunities for vulnerable populations to access and utilize appropriate and comprehensive health services, resources and education. PMID- 24788052 TI - Rapid response: email, immediacy, and medical humanitarianism in Aceh, Indonesia. AB - After more than 20 years of sporadic separatist insurgency, the Free Aceh Movement and the Indonesian government signed an internationally brokered peace agreement in August 2005, just eight months after the Indian Ocean tsunami devastated Aceh's coastal communities. This article presents a medical humanitarian case study based on ethnographic data I collected while working for a large aid agency in post-conflict Aceh from 2005 to 2007. In December 2005, the agency faced the first test of its medical and negotiation capacities to provide psychiatric care to a recently amnestied political prisoner whose erratic behavior upon returning home led to his re-arrest and detention at a district police station. I juxtapose two methodological approaches-an ethnographic content analysis of the agency's email archive and field-based participant-observation-to recount contrasting narrative versions of the event. I use this contrast to illustrate and critique the immediacy of the humanitarian imperative that characterizes the industry. Immediacy is explored as both an urgent moral impulse to assist in a crisis and a form of mediation that seemingly projects neutral and transparent transmission of content. I argue that the sense of immediacy afforded by email enacts and amplifies the humanitarian imperative at the cost of abstracting elite humanitarian actors out of local and moral context. As a result, the management and mediation of this psychiatric case by email produced a bureaucratic model of care that failed to account for complex conditions of chronic political and medical instability on the ground. PMID- 24788055 TI - Characterization of indeterminate spleen lesions in primary CT after blunt abdominal trauma: potential role of MR imaging. AB - The purpose of this study was to determine the value of magnetic resonance imaging (MRI) for characterization of indeterminate spleen lesions in primary computed tomography (CT) of patients with blunt abdominal trauma. Twenty-five consecutive patients (8 female, 17 male, mean age 51.6 +/- 22.4 years) with an indeterminate spleen lesion diagnosed at CT after blunt abdominal trauma underwent MRI with T2- and T1-weighted images pre- and post-contrast material administration. MRI studies were reviewed by two radiologists. Age, gender, injury mechanism, injury severity score (ISS), management of patients, time interval between CT and MRI, and length of hospital stay were included into the analysis. Patient history, clinical history, imaging, and 2-month clinical outcome including review of medical records and telephone interviews served as reference standard. From the 25 indeterminate spleen lesions in CT, 11 (44 %) were traumatic; nine (36 %) were non-traumatic (pseudocysts, n=5; hemangioma, n=4) and five proven to represent artifacts in CT. The ISS (P<0.001) and the length of hospital stay (P=0.03) were significantly higher in patients with spleen lesions as compared with those without. All other parameters were similar among groups (all, P>0.05). The MRI features ill-defined lesion borders, variable signal intensity on T1- and T2-weighted images depending on the age of the hematoma, focal contrast enhancement indicating traumatic pseudoaneurysm, perilesional contrast enhancement, and edema were most indicative for traumatic spleen lesions. As compared with CT (2/25), MRI (5/25) better depicted thin subcapsular hematomas as indicator of traumatic spleen injury. In conclusion, MRI shows value for characterizing indeterminate spleen lesions in primary CT after blunt abdominal trauma. PMID- 24788056 TI - Provision of cardiovascular genetic counseling services: current practice and future directions. AB - Cardiovascular genetic counseling has emerged as a specialty critical to the care of patients with heritable cardiovascular disease. Current strategies to meet the growing demand are not clear. We sought to characterize practice patterns of cardiac genetic counseling by developing a novel survey distributed to the National Society of Genetic Counselors (NSGC) Listserv to assess clinical practice, cardiovascular training, and education. Descriptive statistics were used to summarize clinical practice; Fisher's exact test and the Cochran-Armitage trend test were used to compare the practice of cardiovascular genetic counselors (CVGCs) to those who did not identify cardiology as a specialty (non-CVGCs). A total of 153 individuals completed the survey. Of the 105 participants who reported seeing a cardiac genetics patient, 42 (40%) identified themselves as a CVGC. The most common conditions for which genetic counseling was provided were hypertrophic cardiomyopathy (HCM) (71% of participants), dilated cardiomyopathy (DCM) (61%), long QT syndrome (LQTS) (56%), and genetic syndromes with cardiovascular disease (55%). CVGCs were significantly more confident than non CVGCs in providing genetic counseling for seven cardiovascular diseases (2.3 * 10(-6) <= p <= 0.021). Eighty-six percent of genetic counselors sought additional education related to cardiovascular genetics and listed online courses as the most desirable method of learning. These data suggest a growing interest in cardiovascular genetic counseling and need for additional training resources among the NSGC membership. PMID- 24788057 TI - It is time: a commentary on "An exploration of genetic counselors' needs and experiences with prenatal chromosomal microarray testing". PMID- 24788058 TI - Potential of decursin to inhibit the human cytochrome P450 2J2 isoform. AB - CYP2J2 enzyme is highly expressed in human tumors and carcinoma cell lines, and epoxyeicosatrienoic acids, CYP2J2-mediated metabolites, have been implicated in the pathologic development of human cancers. To identify a CYP2J2 inhibitor, 50 natural products obtained from plants were screened using astemizole as a CYP2J2 probe substrate in human liver microsomes. Of these, decursin noncompetitively inhibited CYP2J2-mediated astemizole O-demethylation and terfenadine hydroxylation activities with Ki values of 8.34 and 15.8MUM, respectively. It also showed cytotoxic effects against human hepatoma HepG2 cells in a dose dependent manner while it did not show cytotoxicity against mouse hepatocytes. The present data suggest that decursin is a potential candidate for further evaluation for its CYP2J2 targeting anti-cancer activities. Studies are currently underway to test decursin as a potential therapeutic agent for cancer. PMID- 24788059 TI - Camel's milk ameliorates TNBS-induced colitis in rats via downregulation of inflammatory cytokines and oxidative stress. AB - Current treatment strategies for inflammatory bowel diseases (IBD) are associated with several adverse effects, and thus, the search for effective agents with minimal side effects merits attention. Camel's milk (CM) is endowed with antioxidant/anti-inflammatory features and has been reported to protect against diabetes and hepatic injury, however, its effects on IBD have not been previously explored. In the current study, we aimed to investigate the potential alleviating effects of CM against TNBS-induced colitis in rats. CM (10 ml/kg b.i.d. by oral gavage) effectively suppressed the severity of colon injury as evidenced by amelioration of macroscopic damage, colon weight/length ratio, histopathological alterations, leukocyte influx and myeloperoxidase activity. Administration of CM mitigated the colonic levels of TNF-alpha and IL-10 cytokines. The attenuation of CM to colon injury was also associated with suppression of oxidative stress via reduction of lipid peroxides and nitric oxide along with boosting the antioxidant defenses through restoration of colon glutathione and total anti-oxidant capacity. In addition, caspases-3 activity, an apoptotic marker, was inhibited. Together, our study highlights evidences for the promising alleviating effects of CM in colitis. Thus, CM may be an interesting complementary approach for the management of IBD. PMID- 24788060 TI - DNA recombination in somatic plant cells: mechanisms and evolutionary consequences. AB - In somatic cells, recombination is a means of DNA damage repair. The most severe type of damage in nuclear DNA is double-strand breaks (DSBs) which may be repaired via either non-homologous end joining (NHEJ) or homologous recombination (HR). In this review, we will summarize the basic features, the mechanisms, and the key players of both repair modes in plants with a focus on the model plant Arabidopsis thaliana. NHEJ may result in insertion of sequences from elsewhere in the genome but is much more often associated with deletions. If more than one DSB is processed simultaneously via NHEJ, besides deletions, inversions or translocations may also arise. As the germ line is only set aside late in plant development, somatic changes may be transferred to the next generation. Thus, NHEJ might influence the evolution of plant genomes and indeed seems to be an important factor of genome shrinking. Deletions may also be due to DSB-induced recombination between tandem duplicated homologous sequences by single-strand annealing (SSA). Moreover, conservative HR using the synthesis-dependent strand annealing (SDSA) mechanism operates in somatic plant cells. The efficiency of SDSA is dependent on the genomic template used as matrix for the repair of the DSB. Besides DSBs, stalled replication forks may also be processed via HR. Several DNA processing enzymes are involved in the regulation of replication initiated HR, mostly in its suppression, and we summarize the current knowledge of these processes in plants. PMID- 24788062 TI - A rare complication with Edwards Sapien: aortic valve embolization in TAVI. AB - One of the problems is valve embolization at the time of transcatheter aortic valve implantation, which is a rare but serious complication. In this case, we have shown balloon expandable aortic valve embolization TAVI which is a rare complication and we managed with second valve without surgery. Although there is not enough experience in the literature, embolized valve was re-positioned in the arch aorta between truncus brachiocephalicus and left common carotid artery. PMID- 24788063 TI - Carotid false aneurysm after carotid stent fracture: report of a surgical solution. AB - Stent fracture has been well documented in the Literature and in the majority of cases arises from the exposition of the stent to unfavourable stresses and biomechanical forces. We report a case of carotid false aneurysm after stent placement for post-surgery restenosis. Stent fracture is a clinical reality that sometimes should be considered prior to stent deployment and may require monitoring or treatment after occurrence. PMID- 24788061 TI - Polyploidy in the Arabidopsis genus. AB - Whole genome duplication (WGD), which gives rise to polyploids, is a unique type of mutation that duplicates all the genetic material in a genome. WGD provides an evolutionary opportunity by generating abundant genetic "raw material," and has been implicated in diversification, speciation, adaptive radiation, and invasiveness, and has also played an important role in crop breeding. However, WGD at least initially challenges basic biological functions by increasing cell size, altering relationships between cell volume and DNA content, and doubling the number of homologous chromosome copies that must be sorted during cell division. Newly polyploid lineages often have extensive changes in gene regulation, genome structure, and may suffer meiotic or mitotic chromosome mis segregation. The abundance of species that persist in nature as polyploids shows that these problems are surmountable and/or that advantages of WGD might outweigh drawbacks. The molecularly especially tractable Arabidopsis genus has several ancient polyploidy events in its history and contains several independent more recent polyploids. This genus can thus provide important insights into molecular aspects of polyploid formation, establishment, and genome evolution. The ability to integrate ecological and evolutionary questions with molecular and genetic understanding makes comparative analyses in this genus particularly attractive and holds promise for advancing our general understanding of polyploid biology. Here, we highlight some of the findings from Arabidopsis that have given us insights into the origin and evolution of polyploids. PMID- 24788064 TI - Restenosis and symptom recurrence after endovascular therapy for claudication: does duplex ultrasound correlate with recurrent claudication? AB - After endovascular therapy, duplex ultrasound surveillance to detect restenosis guides clinical decisions and defines treatment failure. However, the correlation between duplex ultrasound and symptom recurrence remains unclear. We reviewed our institutional experience (2007-2010) to identify patients undergoing endovascular therapy for claudication. The association between post-intervention systolic velocity ratio and patient-reported symptom recurrence was determined. We analyzed 183 follow-up visits following treatment in 88 limbs (femoropopliteal (56%) or iliac (44%) arteries). After femoropopliteal intervention, median systolic velocity ratio was higher in patients with symptom recurrence (2.99 symptomatic vs. 1.69 asymptomatic; p<0.001). Elevated systolic velocity ratio or occlusion correlated with symptom recurrence (area under receiver operator characteristic curve=0.82 [95% CI 0.74-0.83]), and systolic velocity ratio>2.5 was 71% sensitive and 72% specific for symptom recurrence. After femoropopliteal endovascular therapy for claudication, duplex ultrasound-detected restenosis is highly associated with clinical deterioration. This validates objective criteria for treatment failure in claudicants and suggests that symptom status can serve as a primary indicator of anatomic restenosis. PMID- 24788065 TI - Molecular characterization of HIV-1 subtype C gp-120 regions potentially involved in virus adaptive mechanisms. AB - The role of variable regions of HIV-1 gp120 in immune escape of HIV has been investigated. However, there is scant information on how conserved gp120 regions contribute to virus escaping. Here we have studied how molecular sequence characteristics of conserved C3, C4 and V3 regions of clade C HIV-1 gp120 that are involved in HIV entry and are target of the immune response, are modulated during the disease course. We found an increase of "shifting" putative N glycosylation sites (PNGSs) in the alpha2 helix (in C3) and in C4 and an increase of sites under positive selection pressure in the alpha2 helix during the chronic stage of disease. These sites are close to CD4 and to co-receptor binding sites. We also found a negative correlation between electric charges of C3 and V4 during the late stage of disease counteracted by a positive correlation of electric charges of alpha2 helix and V5 during the same stage. These data allow us to hypothesize possible mechanisms of virus escape involving constant and variable regions of gp120. In particular, new mutations, including new PNGSs occurring near the CD4 and CCR5 binding sites could potentially affect receptor binding affinity and shield the virus from the immune response. PMID- 24788067 TI - Proteomics to study adaptations in marine organisms to environmental stress. AB - Comparisons of proteomic responses of closely related congeners and populations have shown which cellular processes are critical to adapt to environmental stress. For example, several proteomic species comparisons showed that increasing abundances of oxidative stress proteins indicate that reactive oxygen species (ROS) represent a ubiquitous signal and possible co-stressor of warm and cold temperature, acute hyposaline and low pH stress, possibly causing a shift from pro-oxidant NADH-producing to anti-oxidant NADPH-producing and -consuming metabolic pathways. Changes in cytoskeletal and actin-binding proteins in response to several stressors, including ROS, suggest that both are important structural and functional elements in responding to stress. Disruption of protein homeostasis, e.g., increased abundance of molecular chaperones, was severe in response to acute heat stress, inducing proteolysis, but was also observed in response to chronic heat and cold stress and was concentrated to the endoplasmic reticulum during hyposaline stress. Small GTPases affecting vesicle formation and transport, Ca(2+)-signaling and ion transport responded to salinity stress in species- and population-specific ways. Aerobic energy metabolism was in general down-regulated in response to temperature, hypoxia, hyposalinity and low pH stress, but other metabolic pathways were activated to respond to increased oxidative stress or to switch metabolic fuels. Thus, comparative proteomics is a powerful approach to identify functionally adaptive variation. This article is part of a Special Issue entitled: Proteomics of non-model organisms. PMID- 24788066 TI - Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: in vitro and in vivo evaluation. AB - The purpose of the present study was to develop and assess a novel sustained release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 ug BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system for glaucoma management. PMID- 24788068 TI - Are the 10 meter and 6 minute walk tests redundant in patients with spinal cord injury? AB - OBJECTIVE: To evaluate the relationship and redundancy between gait speeds measured by the 10 Meter Walk Test (10MWT) and 6 Minute Walk Test (6MWT) after motor incomplete spinal cord injury (iSCI). To identify gait speed thresholds supporting functional ambulation as measured with the Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI). DESIGN: Prospective observational cohort. SETTING: Seven outpatient rehabilitation centers from the Christopher and Dana Reeve Foundation NeuroRecovery Network (NRN). PARTICIPANTS: 249 NRN patients with American Spinal Injury Association Impairment Scale (AIS) level C (n = 20), D (n = 179) and (n = 50) iSCI not AIS evaluated, from February 2008 through April 2011. INTERVENTIONS: Locomotor training using body weight support and walking on a treadmill, overground and home/community practice. MAIN OUTCOME MEASURE(S): 10MWT and 6MWT collected at enrollment, approximately every 20 sessions, and upon discharge. RESULTS: The 10MWT and 6MWT speeds were highly correlated and the 10MWT speeds were generally faster. However, the predicted 6MWT gait speed from the 10MWT, revealed increasing error with increased gait speed. Regression lines remained significantly different from lines of agreement, when the group was divided into fast (>=0.44 m/s) and slow walkers (<0.44 m/s). Significant differences between 6MWT and 10MWT gait speeds were observed across SCI-FAI walking mobility categories (Wilcoxon sign rank test p<.001), and mean speed thresholds for limited community ambulation differed for each measure. The smallest real difference for the 6MWT and 10MWT, as well as the minimally clinically important difference (MCID) values, were also distinct for the two tests. CONCLUSIONS: While the speeds were correlated between the 6MWT and 10MWT, redundancy in the tests using predictive modeling was not observed. Different speed thresholds and separate MCIDs were defined for community ambulation for each test. PMID- 24788069 TI - Distal limb perfusion: Achilles' heel in peripheral venoarterial extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is a temporary mechanical circulatory assist method that offers circulatory as well as respiratory support efficiently via peripheral access; however, it is liable to complications. Limb ischemia is one of the notorious complications of ECMO but can be avoided utilizing a proper distal limb perfusion method. A retrospective study of patients undergoing peripheral venoarterial (VA) ECMO for various reasons between June 2010 and December 2012 was performed. All patients were evaluated by our multidisciplinary team for suitability as candidates for ECMO. A peripheral VA-ECMO circuit was implanted via groin: inflow cannula in the femoral vein, an outflow cannula and distal-perfusion cannula, or an introducer sheath in the femoral artery. During the study period, 83 patients underwent various types of ECMO; 45 received peripheral VA-ECMO. Distal limb perfusion was achieved with an introducer sheath (6-8 Fr) in 13 cases and with a distal-perfusion cannula (10-12 Fr) in 32 cases. Nine (20%) patients developed signs of ischemia; five (11.2%) were treated conservatively, while four (8.8%) required surgical intervention. One patient required a below-knee amputation. The incidences of limb ischemia and limb ischemia requiring surgical intervention were significantly higher for the introducer sheath compared with the cannula (30.6 vs. 15.6% and 15.4 vs. 6.25%, respectively). Moreover, the patients supported on ECMO with a distal-perfusion cannula spent a significantly longer time on ECMO compared with the ones in whom an introducer sheath was used (11.9 +/- 9.1 vs. 7.7 +/- 4.3 days). The mean cannula size was significantly greater than the mean introducer sheath size (11.1 +/- 1.3 vs. 7.0 +/- 1.1 Fr). Use of a distal-perfusion cannula is a most reliable method of limb perfusion in peripheral VA-ECMO. The cannula can ensure adequate and smooth perfusion of the limb owing to its large caliber, its less turbulent flow, the ability it provides to monitor the flow, and the option to attach a side port. PMID- 24788070 TI - Circulating lipid levels and risk of coronary artery disease in a large group of patients undergoing coronary angiography. AB - A main underlying pathology of coronary artery disease is the deposition of cholesterol in the arteries supplying blood to the heart that leads to stenosis and myocardial infarction. We tested if dyslipidemia is a risk factor for coronary artery disease in the Lebanese population, and studied the role of the total cholesterol/HDL cholesterol (TC/HDL-C) ratio as a biological marker of coronary artery disease. We recruited 6,180 Lebanese patients undergoing cardiac catheterization. We conducted a cross-sectional association study between TC/HDL C ratio and the number and type of vessels occluded in catheterized patients by controlling for confounding effects. The TC/HDL-C ratio >=4 significantly predicts >=50 % stenosis in all vessels individually with the odds ratio (OR) ranging from 1.22 to 1.92. The OR increased with increasing number of >=50 % stenotic vessels (1.39 for 2 vessels and 1.64 for 3-4 vessels), as did risk due to diabetes, CAD family history, gender, and age. The younger than average age of onset subgroup shows a pronounced increase in risk for occlusion of the left main coronary artery due to TC/HDL-C >=4 (OR 3.26). In conclusion, low levels of HDL cholesterol and high levels TC/HDL-C ratio are strong biological markers of disease occurrence and severity in the Lebanese population. PMID- 24788071 TI - Management of pulmonary arterial hypertension associated to thalassemia: when pulmonary endarterectomy is the best therapeutical option? A case report. AB - Pulmonary arterial hypertension (PAH) has been reported with nearly all forms of the inherited as well as the acquired hemolytic anemias. Although screening studies suggested that PAH has emerged as major complication of thalassemia patients, its impact on survival is unknown; the pathophysiology of the PAH in these patients is multifactorial, and a thorough diagnostic evaluation is essential. Understanding the PAH pathogenesis, diagnostic options, prevention is critical for clinicians who care for the thalassemic patients; there are virtually no high-quality data on the safety/efficacy of PAH treatment strategy in this patient population. We are reporting the case of a thalassemic patient suffering from progressive severe PAH, not responding to medical treatment and related to chronic thromboembolic disease. After carefully considering all the options, we decided to proceed with vascular disobliteration by pulmonary endarterectomy (PEA), the first line choice in these cases. This intervention led to a significant improvement in the clinical status and in the functional parameters. Therefore, even if haemolytic anemia-associated-PAH is included in the group I of the Dana-point classification, an individualized approach is recommended as well as a particular management with disease-specific measures and a comprehensive evaluation of other causes of PAH; this current report supports the feasibility and effectiveness of PEA also in the thalassemic patients with surgically accessible chronic thromboembolic pulmonary hypertension. PMID- 24788072 TI - Response to comment on: semi-automatic assessment of skin capillary density: proof of principle and validation. PMID- 24788073 TI - gamma-Irradiated cord blood MNCs: different paracrine effects on mature and progenitor endothelial cells. AB - Cell-based therapies have been employed to promote neovascularization mainly through the release of paracrine factors inhibiting apoptosis and supporting migration and proliferation of resident differentiated cells. We tested in vitro pro-angiogenic effects of apoptotic cord blood-derived mononuclear cells (CB MNCs) and their conditioned medium (CM) on mature endothelial cells (HUVECs) and peripheral blood-derived endothelial progenitor cells (ECFCs). CB-MNCs were gamma irradiated to induce apoptosis and cultured for 72 h to obtain the release of CM. MNCs viability, evaluated by flow cytometry, decreased progressively after gamma irradiation reaching 41% at 72 h. gamma-Irradiated MNCs (gammaMNCs) released increasing amounts of EGF, PDGF-AB and VEGF in their CM over time, as assessed by ELISA. gamma-MNCs and their CM enhanced capillary-like network formation (in a dose-dependent and time-persistent manner), proliferation and migration of HUVECs in vitro, while they primed capillary-like network formation (dose-independent and not time-persistent) and induced migration but did not support proliferation of ECFCs. Our data support the hypothesis of paracrine mechanism as prevalent in regenerative medicine and demonstrate the efficacy of MNCs secretome in inducing neovascularization. To our knowledge, this is the first paper highlighting differential pro-angiogenic effects of CM on mature and progenitor endothelial cells, adding a tile in the understanding of mechanisms involved in neovascularization. PMID- 24788075 TI - Relative indexes of cutaneous blood perfusion measured by real-time laser Doppler imaging (LDI) in healthy volunteers. AB - We used real-time LDI to study regional variations in microcirculatory perfusion in healthy candidates to establish a new methodology for global perfusion body mapping that is based on intra-individual perfusion index ratios. Our study included 74 (37 female) healthy volunteers aged between 22 and 30 years (mean 24.49). Imaging was performed using a recent microcirculation-imaging camera (EasyLDI) for different body regions of each volunteer. The perfusion values were reported in Arbitrary Perfusion Units (APU). The relative perfusion indexes for each candidate's body region were then obtained by normalization with the perfusion value of the forehead. Basic parameters such as weight, height, and blood pressure were also measured and analyzed. The highest mean perfusion value was reported in the forehead area (259.21APU). Mean perfusion in the measured parts of the body correlated positively with mean forehead value, while there was no significant correlation between forehead blood perfusion values and room temperature, BMI, systolic blood pressure and diastolic blood pressure (p=0.420, 0.623, 0.488, 0.099, respectively). Analysis of the data showed that perfusion indexes were not significantly different between male and female volunteers except for the ventral upper arm area (p=.001). LDI is a non-invasive, fast technique that opens several avenues for clinical applications. The mean perfusion indexes are useful in clinical practice for monitoring patients before and after surgical interventions. Perfusion values can be predicted for different body parts for patients only by taking the forehead perfusion value and using the perfusion index ratios to obtain expected normative perfusion values. PMID- 24788074 TI - Characterization of nanoparticle delivery in microcirculation using a microfluidic device. AB - This work focuses on the characterization of particle delivery in microcirculation through a microfluidic device. In microvasculature the vessel size is comparable to that of red blood cells (RBCs) and the existence of blood cells largely influences the dispersion and binding distribution of drug loaded particles. The geometry of the microvasculature leads to non-uniform particle distribution and affects the particle binding characteristics. We perform an in vitro study in a microfluidic chip with micro vessel mimicking channels having a rectangular cross section. Various factors that influence particle distribution and delivery such as the vessel geometry, shear rate, blood cells, particle size, particle antibody density are considered in this study. Around 10% higher particle binding density is observed at bifurcation regions of the mimetic microvasculature geometry compared to straight regions. Particle binding density is found to decrease with increased shear rates. RBCs enhance particle binding for both 210 nm and 2 MUm particles for shear rates between 200-1600 s(-1) studied. The particle binding density increases about 2-3 times and 6-10 times when flowing in whole blood at 25% RBC concentration compared to the pure particle case, for 210 nm and 2 MUm particles respectively. With RBCs, the binding enhancement is more significant for 2 MUm particles than that for 210 nm particles, which indicates an enhanced size dependent exclusion of 2 MUm particles from the channel centre to the cell free layer (CFL). Increased particle antibody coating density leads to higher particle binding density for both 210 nm and 2 MUm particles. PMID- 24788076 TI - Interfacial structure of immobilized antibodies and perdeuterated HSA in model pregnancy tests measured with neutron reflectivity. AB - Experimental studies of antibody adsorption and antigen binding that mimicked pregnancy test immunoassays have been performed using neutron reflectivity studies of a model antibody/antigen system immobilized on the silica/water interface. The study revealed the nature of the antibody/antigen interaction and also the importance of a blocking protein, in this case human serum albumin (HSA), that enhances the immunoassay's specificity and efficiency. Of central importance to this study has been the use of a perdeuterated human serum albumin (d-HSA), providing contrast that highlights the orientation and position of the blocking agent within the adsorbed layer. It was found that the adsorbed HSA filled the gaps between the preadsorbed antibodies on the substrate, with decreased adsorption occurring as a function of increased antibody surface coverage. In addition, the antigen binding capacity of the adsorbed antibodies was investigated as a function of antibody surface coverage. The amount of specifically bound antigen was found to saturate at approximately 0.17 mg/m(2) and became independent of the antibody surface coverage. The ratio of bound antigen to immobilized antibody decreased with increased antibody surface coverage. These results are of importance for a full understanding of immunoassay systems that are widely used in clinical tests and in the detection of environmental contaminants. PMID- 24788077 TI - Volumetric quantification of the effect of aging and hormone replacement therapy on breast composition from digital mammograms. AB - OBJECTIVE: To assess the physiological changes in breast composition with aging using volumetric breast composition measurement from digital mammograms and to assess the effect of hormone replacement therapy (HRT). METHODS: A total of 764 consecutive mammograms of 208 non-HRT using women and 508 mammograms of 134 HRT using women were analyzed using a volumetric breast composition assessment software (QuantraTM, Hologic Inc.). Fibroglandular tissue volume (FTV), breast volume (BV), and percent density (PD) were measured. For statistical analysis, women were divided into a premenopausal (<46 years), a perimenopausal (46-55 years), and a postmenopausal (>55 years) age group. More detailed graphical analysis was performed using smaller age brackets. Women using HRT were compared to age-matched controls not using HRT. RESULTS: Women in the postmenopausal age group had a significantly lower FTV and PD and a significantly higher BV than women in the premenopausal age group (FTV: 77 vs. 120 cm(3), respectively; PD: 16% vs. 28%, respectively; BV 478 vs. 406 cm(3), respectively; p<0.01 for all). Median FTV was nearly stable in consecutive mammograms in the premenopausal and postmenopausal age groups, but declined at a rate of 3.9% per year in the perimenopausal period. Median PD was constant in the premenopausal and postmenopausal age groups and declined at a rate of 0.57% per year in the perimenopausal age group. BV continuously increased with age. Women using HRT throughout the study had a 5% higher PD than women not using HRT (22% vs. 17%, respectively; p<0.001). CONCLUSIONS: Accurate knowledge of normal changes in breast composition are of particular interest nowadays due to the importance of breast density for breast cancer risk evaluation. FTV and PD change significantly during the perimenopausal period but remain relatively constant before and thereafter. Median total breast volume consistently increases with age and further contributes to changes in breast density. HRT use is associated with a significantly higher PD. PMID- 24788078 TI - Detection and distribution of opioid peptide receptors in porcine myocardial tissue. AB - There is growing evidence that opioid peptide receptors (OPRs) play an important role in cardiovascular function. Many studies have been conducted in swine, in view of their anatomic and physiologic similarities to humans. Until now, the presence and particularly distribution of OPRs has been unclear. Porcine myocardial tissue was obtained from both the left and right atria and ventricles. Expression of mRNA for MU-, delta- and kappa-OPR was determined by reverse transcription PCR. OPR proteins were detected by Western blot, distribution and cellular location were identified using immunohistochemistry. Homogenous expression of mRNA and protein for delta- and kappa-OPRs were demonstrated in all porcine myocardial tissue tested, whereas expression of MU-OPR mRNA was not demonstrated in any of the tissues tested. This study demonstrates the expression of delta- and kappa-OPRs in porcine myocardial tissue. No differences in distribution of delta- and kappa-OPRs were found between the four heart cavities. Modulation of cardiac function by delta- and kappa-OPR agonists or antagonists is therefore possible, while MU-OPR-mediated direct cardiac effects appear unlikely, due to nonexpression of the receptor. This study demonstrates that porcine studies can further elucidate the role of OPRs in cardiac (patho-)physiology. PMID- 24788079 TI - Hydrogen sulfide attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation. AB - Endogenously produced hydrogen sulfide (H2S) may have multiple functions in the brain including potent anti-inflammatory effects. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic injuries in the developing brain. The aim of this study is to investigate the potential role of H2S in altering hypoxia-induced neurotoxicity via its anti-inflammatory actions as examined in vitro and in vivo models. Using the BV-2 microglial cell line, we found that sodium hydrosulfide (NaHS), a H2S donor, significantly inhibited hypoxia-induced microglial activation and suppressed subsequent pro-inflammatory factor release. In addition, treating murine primary cortical neurons with conditioned medium (CM) from hypoxia stimulated microglia induced neuronal apoptosis, an effect that was reversed by CM treated with NaHS. Further, NaHS inhibited phosphorylation of the p65 subunit of NF-kappaB, phosphorylation of ERK and p38 but not JNK MAPK in these hypoxia induced microglia. When administered in vivo to neonatal mice subjected to hypoxia, NaHS was found to attenuate neuron death, an effect that was associated with suppressed microglial activation, pro-inflammatory cytokines and NO levels. Taken together, H2S exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effect in microglia. This effect appears to be attributable to inhibition of iNOS, NF-kappaB, ERK and p38 MAPK signaling pathways. Our results suggest a potential therapeutic application of H2S releasing drugs in hypoxic brain damage treatment. PMID- 24788080 TI - Developmental toxicity of diclofenac and elucidation of gene regulation in zebrafish (Danio rerio). AB - Environmental pollution by emerging contaminants, e.g. pharmaceuticals, has become a matter of widespread concern in recent years. We investigated the membrane transport of diclofenac and its toxic effects on gene expression and the development of zebrafish embryos. The association of diclofenac with the embryos conformed to the general partition model at low concentration, the partition coefficient being 0.0033 ml per embryo. At high concentration, the interaction fitted the Freundlich model. Most of the diclofenac remained in the extracellular aqueous solution with less than 5% interacting with the embryo, about half of which was adsorbed on the membranes while the rest entered the cytoplasm. Concentrations of diclofenac over 10.13 MUM were lethal to all the embryos, while 3.78 MUM diclofenac was teratogenic. The development abnormalities at 4 day post treatment (dpt) include shorter body length, smaller eye, pericardial and body edema, lack of liver, intestine and circulation, muscle degeneration, and abnormal pigmentation. The portion of the diclofenac transferred into the embryo altered the expression of certain genes, e.g. down-regulation of Wnt3a and Gata4 and up-regulation of Wnt8a. The alteration of expression of such genes or the regulation of downstream genes could cause defects in the cardiovascular and nervous systems. PMID- 24788081 TI - Accuracy of endoscopic ultrasound in the diagnosis of T2N0 esophageal cancer. AB - BACKGROUND: Accurate staging of esophageal carcinoma (EC) is important since it directs further management. Endoscopic ultrasound (EUS) is the best tool available in the locoregional staging of EC; however, differentiating depth of tumor invasion (T) and nodal involvement (N) can be challenging. Accurate staging is particularly important to differentiate T1-2 N0 cancers, which can proceed directly to surgical resection versus TXN1 or T3N0/1 cancers, which benefit from induction chemoradiation prior to surgery. We report the accuracy of EUS staging for cT2N0 lesions. PATIENTS AND INTERVENTIONS: Six hundred six patients underwent EUS for staging of EC between October 2003 and February 2013 by a single interventional endoscopist specially trained in endoscopic ultrasound. Thirty eight patients were diagnosed with T2N0 tumors and underwent surgical resection without preoperative chemoradiation. EUS staging was compared to surgical pathology to evaluate accuracy. Patient follow-up was obtained from a retrospective chart review. RESULTS: Thirty-eight patients (34 men, mean age 65.8 +/- 10.5 years) with cT2N0 tumors by EUS underwent surgical resection of EC without chemoradiation after a mean of 22.4 +/- 13.7 days post-EUS. When compared with final pathologic outcomes, 12 (32%) were understaged by EUS and 18 (47%) were overstaged. Understaging occurred due to tumor depth (T) in two patients (17%), nodal disease (N) in six (50%), and both in four (33%). Overstaging occurred due to pathology consistent with pT1b tumors instead of T2 tumors in all 17 cases. Based on EUS, 74% were referred for appropriate therapy. CONCLUSION: While EUS is highly accurate in staging EC, it is less accurate in staging tumors which are not on either ends of the spectrum (mucosally based or clearly transmural). In this challenging group of patients, EUS understaged EC in 32% of cases resulting in surgical resection when neoadjuvant chemoradiation may have been beneficial. We suspect that newer generation EUS systems, which provide better imaging, will result in improved accuracy in staging this group of patients. PMID- 24788082 TI - Association between HBsAg positivity and pancreatic cancer: a meta-analysis. AB - BACKGROUND: Several studies have proposed an association between hepatitis B and pancreatic cancer. Although the spectrum of serological tests varied between studies, hepatitis B virus (HBV) surface antigen (HBsAg) test results were consistently reported. This meta-analysis evaluates the association between HBsAg positivity and pancreatic cancer. METHODS: A systematic literature search was performed from inception through September 2013 for English language studies using the following terms: "hepatitis B," "HBsAg," "pancreatic cancer," and "pancreatic adenocarcinoma." Studies that have not reported cumulative odds ratio for the association of interest were excluded. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CI) were calculated using a random effects model. Statistical heterogeneity and publication bias were addressed using the I2 statistic and Egger's weighted regression statistics, respectively. RESULTS: We included two case-control studies and one cohort study, involving 1,636 patients with pancreatic cancer. The OR of developing pancreatic cancer was 1.50 (95% CI 1.21 to 1.87) for individuals who were HBsAg-positive. The type of study, case-control versus cohort, did not appear to influence the results. Only two of the three studies reported the association between anti-HBc positivity and pancreatic cancer. Our analysis revealed a nonsignificant increased risk of cancer in patients with positive anti-HBc status (OR 1.23, 95% CI 0.95-1.59). No statistically significant heterogeneity or publication bias was noted. CONCLUSION: HBsAg positivity is associated with an increased risk of pancreatic cancer. Additional studies are needed to clearly define the association between chronic hepatitis B infection and pancreatic cancer. This could have important implications for both primary prevention and treatment of pancreatic cancer. PMID- 24788083 TI - Gastric metastasis in a patient with lobular breast carcinoma 6 years after diagnosis. PMID- 24788084 TI - Insights of Chinese medicine syndrome study: from current status to future prospects. AB - Syndrome differentiation is a key feature of Chinese medicine (CM) system. With CM receiving more and more attention from the mainstream medical systems, researchers from both traditional medical systems and the Western medical system are putting more effort into studying why and how the CM system works, particularly about CM syndromes. This paper reviews the current status of syndrome study and its future development. The major aspects include: (1) Usage of syndrome differentiation in clinical practice; (2) Formalization of syndrome diagnostic criteria; (3) Evidence-based determination of the common syndrome(s) of a disease; (4) Systems biology study of syndromes; and (5) Usage of syndrome in randomized controlled trials. It is expected to integrate the syndrome concept into the main stream medical system, in terms of diagnosis, treatment and prevention. PMID- 24788085 TI - Designing clinical studies that take into account traditional East Asian medicine's systems and methods - with focus on pattern identification. AB - This article is based on two presentations held at Chinese medicine conference in Rothenburg (2013), Germany and at the 19th Anniversary of Korean Institute of Oriental Medicine (KIOM) International Symposium of Current Research Trends in Traditional Medicine - Pattern of Identification (2013). In designing clinical studies, it is a research question that leads to appropriate study design. However, they are mostly diagnostic procedures and techniques that are the key points to reflect the application of systems and methods in all forms of medicine - traditional East Asian medicine (TEAM) is no exception. The challenges within TEAM based on research reflect in different systems of medicine/theories such as traditional Japanese acupuncture, traditional Korean acupuncture and traditional Chinese acupuncture. This diversity of medical systems and methods applied in East Asia seems to have been fruitful within the different countries and traditional medicines have found their places within the respective countries health systems. The existing diversity, from a clinician's point of view, may be viewed as a treasure when dealing with patients in the 'real world'. On the other hand, this diversity seems to challenge the scientific mind worldwide, especially when it comes to research. Hence, there is a gap between clinical practice and research. PMID- 24788086 TI - Traditional East Asian medicine: how to understand and approach diagnostic findings and patterns in a modern scientific framework? AB - Research into the diagnostic methods and patterns of traditional East Asian medical (TEAM) systems of practice such as acupuncture and herbal medicine face certain challenges due to the nature of thinking in TEAM and the subjective basis of judgments made in practice. The TEAM-based diagnosis can take into account various findings and signs such as the appearance of the tongue, palpable qualities of the radial pulses, palpable qualities and findings on the abdomen, the complexion of the patient and so on. Both diagnostic findings and the patterns of diagnosis cannot be assumed to have objective bases or to be causally related to the complaints of the patient. However, the diagnoses of TEAM based acupuncture and herbal medicine have tended to look at pictures of the whole patient and rather than focus on a particular symptom, they have looked across a myriad of signs and symptoms to decide or identify the 'pattern' of diagnosis according to the theory in question. Although open for selective and subjective biases each diagnosis pattern always comes with a prescribed treatment tailored to the pattern. Further, the same research requirements needed for the validation of the diagnoses are needed also for these clinical observations and judgments. Hence, it is necessary, albeit challenging for research on TEAM diagnoses to first address these issues before proceeding to more complex investigations such as the development of instruments for making diagnostic observations, instruments for forming diagnostic conclusions or studies investigating the physiological bases of the diagnostic patterns. Preliminary work has started and instruments have been made, but we suggest that any instrumentation must necessarily be first validated by matching of the calibrated or scaled observations or judgments to observations made and agreed upon by relevant experts. Reliability of all observations and judgments are needed before any other tool, technology or more advanced approach can proceed and also whenever the natural system of diagnosis treatment is applied in clinical trials. In this paper the authors highlight the core problems and describe a step wise process for addressing them. PMID- 24788088 TI - Distinct temporal expression of 5-HT(1A) and 5-HT(2A) receptors on cerebellar granule cells in mice. AB - Serotonin plays an important role of controlling the physiology of the cerebellum. However, serotonin receptor expression has not been fully studied in the developing cerebellum. We have recently shown that cerebellar granule cells transiently express 5-HT3 receptors. In the present study, we investigate expression of 5-HT1 and 5-HT2 receptors in the mouse cerebellum both during postnatal development and in juvenile mice. Here, we show for the first time that 5-HT1A and 5-HT2A receptors are present on cerebellar granule cells with a distinct temporal expression pattern: 5-HT1A receptors are expressed only during the first 2 weeks, while 5-HT2A receptor expression persists until at least 8 weeks after birth. Because of its prolonged expression pattern, we investigated the electrophysiological properties of the 5-HT2A receptor. 5-HT2A receptors expressed by cerebellar granule cells promote stability by reducing variability of the synaptic response, and they modulate the paired-pulse ratio of the parallel fibre-Purkinje cell synapse. Furthermore, pharmacological block of 5 HT2A receptors enhances short-term synaptic plasticity at the parallel fibre Purkinje cell synapse. We thus show a novel role for serotonin in controlling function of the cerebellum via 5-HT2A receptors expressed by cerebellar granule cells. PMID- 24788087 TI - Knockdown of acid-sensing ion channel 1a (ASIC1a) suppresses disease phenotype in SCA1 mouse model. AB - The mutated ataxin-1 protein in spinocerebellar ataxia 1 (SCA1) targets Purkinje cells (PCs) of the cerebellum and causes progressive ataxia due to loss of PCs and neurons of the brainstem. The exact mechanism of this cellular loss is still not clear. Currently, there are no treatments for SCA1; however, understanding of the mechanisms that regulate SCA1 pathology is essential for devising new therapies for SCA1 patients. We previously established a connection between the loss of intracellular calcium-buffering and calcium-signalling proteins with initiation of neurodegeneration in SCA1 transgenic (Tg) mice. Recently, acid sensing ion channel 1a (ASIC1a) have been implicated in calcium-mediated toxicity in many brain disorders. Here, we report generating SCA1 Tg mice in the ASIC1a knockout (KO) background and demonstrate that the deletion of ASIC1a gene expression causes suppression of the SCA1 disease phenotype. Loss of the ASIC1a channel in SCA1/ASIC1a KO mice resulted in the improvement of motor deficit and decreased PC degeneration. Interestingly, the expression of the ASIC1 variant, ASIC1b, was upregulated in the cerebellum of both SCA1/ASIC1a KO and ASIC1a KO animals as compared to the wild-type (WT) and SCA1 Tg mice. Further, these SCA1/ASIC1a KO mice exhibited translocation of PC calcium-binding protein calbindin-D28k from the nucleus to the cytosol in young animals, which otherwise have both cytosolic and nuclear localization. Furthermore, in addition to higher expression of calcium-buffering protein parvalbumin, PCs of the older SCA1/ASIC1a KO mice showed a decrease in morphologic abnormalities as compared to the age matched SCA1 animals. Our data suggest that ASIC1a may be a mediator of SCA1 pathogenesis and targeting ASIC1a could be a novel approach to treat SCA1. PMID- 24788089 TI - Preliminary evidence for color stimuli discrimination in the Asian small-clawed otter (Aonyx cinerea). AB - Color discrimination ability can be determined through anatomy or perceptual ability. In this study we tested perceptual ability. Three Asian small-clawed otters (Aonyx cinerea), one male and two females, were trained via operant conditioning to discriminate stimuli within a training task. If they passed criteria for this task, they were tested on as many as six delayed matching-to sample experimental tasks. These experimental tasks involved comparing varying saturations of the colors blue, green, and red against varying shades of gray, as well as against each other. The male reached criterion on five of the experimental tasks, indicating an ability to discriminate the stimuli. One female participated in only two tasks and did not achieve the criteria as set. The second female did not pass the training task, and thus was not experimentally tested. This study overall showed some early evidence that Asian small-clawed otters may have the ability to learn to discriminate different stimuli on the basis of color cues. Sensory studies conducted on two other otter species and the results of this study indicate that color vision may be a common trait across Lutrinae species. PMID- 24788090 TI - Prophenoloxidase activation is required for survival to microbial infections in Drosophila. AB - The melanization reaction is a major immune response in Arthropods and involves the rapid synthesis of melanin at the site of infection and injury. A key enzyme in the melanization process is phenoloxidase (PO), which catalyzes the oxidation of phenols to quinones, which subsequently polymerize into melanin. The Drosophila genome encodes three POs, which are primarily produced as zymogens or prophenoloxidases (PPO). Two of them, PPO1 and PPO2, are produced by crystal cells. Here we have generated flies carrying deletions in PPO1 and PPO2. By analyzing these mutations alone and in combination, we clarify the functions of both PPOs in humoral melanization. Our study shows that PPO1 and PPO2 are responsible for all the PO activity in the hemolymph. While PPO1 is involved in the rapid early delivery of PO activity, PPO2 is accumulated in the crystals of crystal cells and provides a storage form that can be deployed in a later phase. Our study also reveals an important role for PPO1 and PPO2 in the survival to infection with Gram-positive bacteria and fungi, underlining the importance of melanization in insect host defense. PMID- 24788091 TI - Synthesis of diverse nitrogen-enriched heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions. AB - Five elegant and switchable three-component reactions which enable access to a new series of nitrogen-containing heterocycles are reported. A novel one-step addition of an isocyanide to a hydrazine derived Schiff base affords unique six membered pyridotriazine scaffolds (A and E). With slight modification of reaction conditions and replacement of the nucleophilic isocyanide moiety with different electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides) five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step. Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and tolerate a diverse collection of reactants, and as such, it is expected that the new scaffolds and associated chemistry will garner high interest from medicinal chemists involved in either file enhancement or specific target-related drug discovery campaigns. PMID- 24788092 TI - An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. AB - The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the tri-snRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. High-resolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products. PMID- 24788093 TI - Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy. AB - Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with self-renewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1 colocalizes with CSCs in vitro and in vivo. Furthermore, Gremlin1 blocks prodifferentiation effects of BMPs, and overexpression of Gremlin1 in non-CSCs decreases their endogenous BMP signaling to promote stem-like features. Consequently, Gremlin1-overexpressing cells display increased growth and tumor formation abilities. Targeting Gremlin1 in CSCs results in impaired growth and self-renewal. Transcriptional profiling demonstrated that Gremlin1 effects were associated with inhibition of p21(WAF1/CIP1), a key CSC signaling node. This study establishes CSC-derived Gremlin1 as a driving force in maintaining glioblastoma tumor proliferation and glioblastoma hierarchies through the modulation of endogenous prodifferentiation signals. PMID- 24788095 TI - Perceived quality of the parental relationship and divorce effects on sexual behaviour in Spanish adolescents. AB - Parental divorce has been linked to some risky sexual behaviour in previous studies. Here we examine whether the sexual behaviour of adolescents is related more to the perceived quality of the interparental relationship or to the parents' divorce in a sample from Spain, the country that has experienced the greatest recent increase in marital break-ups in the European Union. Participants were 801 adolescents aged between 14 and 17, who completed questionnaires anonymously. Adolescents who perceive high conflict in their parents' marriages have more sexual activity and engage in more risk practices in some sexual behaviours compared to adolescents with divorced parents and low interparental conflict. When adolescents perceive low conflict, those with divorced parents are more sexually active than adolescents with married parents, but they do not engage in more risk practices. The perceived quality of the parental relationship has a greater negative impact on adolescents than does the type of family structure. The study highlights the need to address the parents' marital relationship in the implementation of prevention programmes of sexual risk behaviours in Spanish adolescents. PMID- 24788094 TI - Global microRNA depletion suppresses tumor angiogenesis. AB - MicroRNAs delicately regulate the balance of angiogenesis. Here we show that depletion of all microRNAs suppresses tumor angiogenesis. We generated microRNA deficient tumors by knocking out Dicer1. These tumors are highly hypoxic but poorly vascularized, suggestive of deficient angiogenesis signaling. Expression profiling revealed that angiogenesis genes were significantly down-regulated as a result of the microRNA deficiency. Factor inhibiting hypoxia-inducible factor 1 (HIF-1), FIH1, is derepressed under these conditions and suppresses HIF transcription. Knocking out FIH1 using CRISPR/Cas9-mediated genome engineering reversed the phenotypes of microRNA-deficient cells in HIF transcriptional activity, VEGF production, tumor hypoxia, and tumor angiogenesis. Using multiplexed CRISPR/Cas9, we deleted regions in FIH1 3' untranslated regions (UTRs) that contain microRNA-binding sites, which derepresses FIH1 protein and represses hypoxia response. These data suggest that microRNAs promote tumor responses to hypoxia and angiogenesis by repressing FIH1. PMID- 24788096 TI - Programmable transdermal clonidine delivery through voltage-gated carbon nanotube membranes. AB - Oral dosage forms and traditional transdermal patches are inadequate for complex clonidine therapy dosing schemes, because of the variable dose/flux requirement for the treatment of opioid withdrawal symptoms. The purpose of this study was to evaluate the in vitro transdermal flux changes of clonidine in response to alterations in carbon nanotube (CNT) delivery rates by applying various electrical bias. Additional skin diffusion studies were carried out to demonstrate the therapeutic feasibility of the system. This study demonstrated that application of a small electrical bias (-600 mV) to the CNT membrane on the skin resulted in a 4.7-fold increase in clonidine flux as compared with no bias (0 mV) application. The high and low clonidine flux values were very close to the desired variable flux of clonidine for the treatment of opioid withdrawal symptoms. Therapeutic feasibility studies demonstrated that CNT membrane served as the rate-limiting step to clonidine diffusion and lag and transition times were suitable for the clonidine therapy. Skin elimination studies revealed that clonidine depletion from the skin would not negatively affect clonidine therapy. Overall, this study showed that clonidine administration difficulties associated with the treatment of opiate withdrawal symptoms can be reduced with the programmable CNT membrane transdermal system. PMID- 24788099 TI - SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability. AB - The SWI/SNF chromatin-remodeling family contains various protein complexes, which regulate gene expression during cellular development and influence DNA damage response in an ATP- and complex-dependent manner, of which details remain elusive. Recent human genome sequencing of various cancer cells revealed frequent mutations in SWI/SNF factors, especially ARID1A, a variant subunit in the BRG1 associated factor (BAF) complex of the SWI/SNF family. We combined live-cell analysis and gene-suppression experiments to show that suppression of either ARID1A or its paralog ARID1B led to reduced nonhomologous end joining activity of DNA double-strand breaks (DSB), decreased accumulation of KU70/KU80 proteins at DSB, and sensitivity to ionizing radiation, as well as to cisplatin and UV. Thus, in contrast to transcriptional regulation, both ARID1 proteins are required for cellular resistance to various types of DNA damage, including DSB. The suppression of other SWI/SNF factors, namely SNF5, BAF60a, BAF60c, BAF155, or BAF170, exhibits a similar phenotype. Of these factors, ARID1A, ARID1B, SNF5, and BAF60c are necessary for the immediate recruitment of the ATPase subunit of the SWI/SNF complex to DSB, arguing that both ARID1 proteins facilitate the damage response of the complex. Finally, we found interdependent protein stability among the SWI/SNF factors, suggesting their direct interaction within the complex and the reason why multiple factors are frequently lost in parallel in cancer cells. Taken together, we show that cancer cells lacking in the expression of certain SWI/SNF factors, including ARID1A, are deficient in DNA repair and potentially vulnerable to DNA damage. PMID- 24788098 TI - An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer. AB - Bone metastasis will impact most men with advanced prostate cancer. The vicious cycle of bone degradation and formation driven by metastatic prostate cells in bone yields factors that drive cancer growth. Mechanistic insights into this vicious cycle have suggested new therapeutic opportunities, but complex temporal and cellular interactions in the bone microenvironment make drug development challenging. We have integrated biologic and computational approaches to generate a hybrid cellular automata model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model accurately reproduces the basic multicellular unit bone coupling process, such that introduction of a single prostate cancer cell yields a vicious cycle similar in cellular composition and pathophysiology to models of prostate-to-bone metastasis. Notably, the model revealed distinct phases of osteolytic and osteogenic activity, a critical role for mesenchymal stromal cells in osteogenesis, and temporal changes in cellular composition. To evaluate the robustness of the model, we assessed the effect of established bisphosphonate and anti-RANKL therapies on bone metastases. At approximately 100% efficacy, bisphosphonates inhibited cancer progression while, in contrast with clinical observations in humans, anti-RANKL therapy fully eradicated metastases. Reducing anti-RANKL yielded clinically similar results, suggesting that better targeting or dosing could improve patient survival. Our work establishes a computational model that can be tailored for rapid assessment of experimental therapies and delivery of precision medicine to patients with prostate cancer with bone metastases. PMID- 24788100 TI - Blocking and randomization to improve molecular biomarker discovery. AB - Randomization and blocking have the potential to prevent the negative impacts of nonbiologic effects on molecular biomarker discovery. Their use in practice, however, has been scarce. To demonstrate the logistic feasibility and scientific benefits of randomization and blocking, we conducted a microRNA study of endometrial tumors (n = 96) and ovarian tumors (n = 96) using a blocked randomization design to control for nonbiologic effects; we profiled the same set of tumors for a second time using no blocking or randomization. We assessed empirical evidence of differential expression in the two studies. We performed simulations through virtual rehybridizations to further evaluate the effects of blocking and randomization. There was moderate and asymmetric differential expression (351/3,523, 10%) between endometrial and ovarian tumors in the randomized dataset. Nonbiologic effects were observed in the nonrandomized dataset, and 1,934 markers (55%) were called differentially expressed. Among them, 185 were deemed differentially expressed (185/351, 53%) and 1,749 not differentially expressed (1,749/3,172, 55%) in the randomized dataset. In simulations, when randomization was applied to all samples at once or within batches of samples balanced in tumor groups, blocking improved the true-positive rate from 0.95 to 0.97 and the false-positive rate from 0.02 to 0.002; when sample batches were unbalanced, randomization was associated with the true positive rate (0.92) and the false-positive rate (0.10) regardless of blocking. Normalization improved the detection of true-positive markers but still retained sizeable false-positive markers. Randomization and blocking should be used in practice to more fully reap the benefits of genomics technologies. PMID- 24788101 TI - Molecular pathways: harnessing E2F1 regulation for prosenescence therapy in p53 defective cancer cells. AB - Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1-CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1-CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53 deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. PMID- 24788102 TI - A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. AB - PURPOSE: Racotumomab-alum is an anti-idiotype vaccine targeting the NeuGcGM3 tumor-associated ganglioside. This clinical trial was conducted to provide a preliminary estimate of efficacy and safety of racotumomab as switch maintenance for patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with stage IIIb/IV NSCLC who have at least stable disease after first-line chemotherapy were randomized 1:1 to racotumomab-alum (5 immunizations every 2 weeks and re-immunizations every 4 weeks) or placebo. Treatment was administered beyond progressive disease, until severe performance status worsening or toxicity. At progression, only five patients per group received further anticancer therapy. The primary endpoint was overall survival (OS). RESULTS: One-hundred and seventy-six patients were randomized to racotumomab-alum (n = 87) and placebo (n = 89). Median OS was 8.23 and 6.80 months, respectively [HR, 0.63; 95% confidence interval (CI), 0.46-0.87; P = 0.004]. Median progression-free survival (PFS) in vaccinated patients was 5.33 versus 3.90 months for placebo (HR, 0.73; 95% CI 0.53-0.99; P = 0.039). The most common adverse events in the racotumomab-alum arm were burning and pain at the injection site, bone pain, and asthenia. A high antibody response of IgM and IgG isotype against the NeuGcGM3 ganglioside was obtained. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 cell line. Patients who developed anti-NeuGcGM3 antibodies capable to bind and kill >=30% L1210 cells showed longer median survival times. CONCLUSIONS: Switch maintenance with racotumomab-alum is an effective and a well-tolerated treatment option for patients with advanced NSCLC. PMID- 24788103 TI - The association of media exposure and media literacy with adolescent alcohol and tobacco use. AB - This study examined the relationship of media exposure and media literacy to alcohol and tobacco use among adolescents in Taiwan. A total of 2992 10th-grade students recruited from 26 high schools in Taipei, Taiwan, completed a questionnaire in 2010. The multivariable analysis results indicated that the students with higher alcohol and tobacco media exposure were more likely to use alcohol and tobacco and have intentions to drink and smoke, while students with higher media literacy were less likely to use alcohol and have intentions to drink and smoke. PMID- 24788104 TI - Hypnotherapy for disability-related pain: A meta-analysis. AB - Hypnotherapy can address the biopsychosocial aspects of disability-related pain, although the available evidence is limited in quality and quantity. Meta-analytic techniques were utilised to evaluate 10 controlled studies. Hypnotherapy produced significant short-term improvements in fatigue, pain experience and affect. However, a lack of significance was noted at 3- to 6-month follow-up. A beneficial effect size (d(w)= 0.53; confidence interval = 0.28-0.84) in comparison to control conditions was reported, although comparability with other cognitive-behavioural treatments could not be confirmed across the few studies reporting this data (d(w)= 0.06; confidence interval = -0.33 to 0.45). The findings highlight the need for further controlled and longitudinal research in this area. PMID- 24788105 TI - Lifestyle and treatment adherence among overweight adolescents. AB - This study evaluated the influence of overweight adolescents' lifestyle on the adherence to weight control, and identifies their predictors. Participants were 94 adolescents, aged 12-18 years, attending a Paediatric Obesity Clinic. Lifestyle was assessed using the "Adolescent Lifestyle Profile" and treatment adherence through the "Therapeutic Adherence to Weight Control Questionnaire." Adherence to weight control was associated with various lifestyle domains. Several predictors were identified for lifestyle and adherence to weight control among overweight adolescents. A broad array of inter-correlations and predictors were identified and should be taken into account when designing adolescent weight control interventions. PMID- 24788106 TI - ComQXPA quorum sensing systems may not be unique to Bacillus subtilis: a census in prokaryotic genomes. AB - The comQXPA locus of Bacillus subtilis encodes a quorum sensing (QS) system typical of Gram positive bacteria. It encodes four proteins, the ComQ isoprenyl transferase, the ComX pre-peptide signal, the ComP histidine kinase, and the ComA response regulator. These are encoded by four adjacent genes all situated on the same chromosome strand. Here we present results of a comprehensive census of comQXPA-like gene arrangements in 2620 complete and 6970 draft prokaryotic genomes (sequenced by the end of 2013). After manually checking the data for false-positive and false-negative hits, we found 39 novel com-like predictions. The census data show that in addition to B. subtilis and close relatives, 20 comQXPA-like loci are predicted to occur outside the B. subtilis clade. These include some species of Clostridiales order, but none outside the phylum Firmicutes. Characteristic gene-overlap patterns were observed in comQXPA loci, which were different for the B. subtilis-like and non-B. subtilis-like clades. Pronounced sequence variability associated with the ComX peptide in B. subtilis clade is evident also in the non-B. subtilis clade suggesting grossly similar evolutionary constraints in the underlying quorum sensing systems. PMID- 24788107 TI - Capillary electrophoresis and herbicide analysis: present and future perspectives. AB - The aim of this article is to provide an overview on the potential of the CE herbicides binomial. To this end, the methods proposed so far are discussed: their characteristics, types of samples and analytes to which the methods have been applied, sample preparation steps, if required (e.g. cleanup preconcentration, derivatization steps), and type of detection in each case. Also, the methods are compared with counterparts based on LC, when appropriate. The role of MS detection in present and future analytical research in this field (both for identification and quantitation) are commented. The foreseeable and desirable trends in analysis of herbicides are also outlined in the light of the present trends in metabolomics as a way of knowing the pathways, the intermediate and final degradation products that can influence the crops and the food chain of humans and other animals, as a result. PMID- 24788108 TI - Effect of taxoid and nontaxoid site microtubule-stabilizing agents on axonal transport of mitochondria in untransfected and ECFP-htau40-transfected rat cortical neurons in culture. AB - An important aspect of synaptic plasticity in the brain is axonal transport of essential components such as mitochondria from the soma to the synapse. For uninterrupted transport of cellular cargo down the axon, functional microtubules are required. Altered microtubule dynamics induced by changes in expression of microtubule-associated tau protein affects normal microtubule function and interferes with axonal transport. Here we investigate the effects of the nontaxoid-binding-site microtubule-stabilizing agents peloruside A (PelA) and laulimalide, compared with the taxoid-site-binding agents paclitaxel (Ptx) and ixabepilone, on axonal transport of mitochondria in 1-day-old rat pup cerebral cortical neuron cultures. The differences in effects of these two types of compound on mitochondrial trafficking were specifically compared under conditions of excess tau expression. PelA and laulimalide had no adverse effects on their own on mitochondrial transport compared with Ptx and ixabepilone, which inhibited mitochondrial run length at higher concentrations. PelA, like Ptx, was able to partially reverse the blocked mitochondrial transport seen in ECFP-htau40 overexpressing neurons, although at higher concentrations of microtubule stabilizing agent, the PelA response was improved over the Ptx response. These results support a neuroprotective effect of microtubule stabilization in maintaining axonal transport in neurons overexpressing tau protein and may be beneficial in reducing the severity of neurodegenerative diseases such as Alzheimer's disease. PMID- 24788109 TI - Porin involvement in cephalosporin and carbapenem resistance of Burkholderia pseudomallei. AB - BACKGROUND: Burkholderia pseudomallei (Bps) is a Gram-negative bacterium that causes frequently lethal melioidosis, with a particularly high prevalence in the north and northeast of Thailand. Bps is highly resistant to many antimicrobial agents and this resistance may result from the low drug permeability of outer membrane proteins, known as porins. PRINCIPAL FINDINGS: Microbiological assays showed that the clinical Bps strain was resistant to most antimicrobial agents and sensitive only to ceftazidime and meropenem. An E. coli strain defective in most porins, but expressing BpsOmp38, exhibited considerably lower antimicrobial susceptibility than the control strain. In addition, mutation of Tyr119, the most prominent pore-lining residue in BpsOmp38, markedly altered membrane permeability, substitution with Ala (mutant BpsOmp38Y119A) enhanced uptake of the antimicrobial agents, while substitution with Phe (mutant BpsOmp38Y119F) inhibited uptake. Channel recordings of BpsOmp38 reconstituted in a planar black lipid membrane (BLM) suggested that the higher permeability of BpsOmp38Y119A was caused by widening of the pore interior through removal of the bulky side chain. In contrast, the lower permeability of BpsOmp38Y119F was caused by introduction of the hydrophobic side chain (Phe), increasing the 'greasiness' of the pore lumen. Significantly, liposome swelling assays showed no permeation through the BpsOmp38 channel by antimicrobial agents to which Bps is resistant (cefoxitin, cefepime, and doripenem). In contrast, high permeability to ceftazidime and meropenem was observed, these being agents to which Bps is sensitive. CONCLUSION/SIGNIFICANCE: Our results, from both in vivo and in vitro studies, demonstrate that membrane permeability associated with BpsOmp38 expression correlates well with the antimicrobial susceptibility of the virulent bacterium B. pseudomallei, especially to carbapenems and cephalosporins. In addition, substitution of the residue Tyr119 affects the permeability of the BpsOmp38 channel to neutral sugars and antimicrobial agents. PMID- 24788110 TI - Suicide ideation, dementia and mental disorders among a community sample of older people in Mexico. AB - Data on the prevalence of and risk factors for suicide ideation among older people in developing countries is lacking. OBJECTIVE: This study aimed to estimate if dementia and other mental disorders are associated with suicide ideation among the older people controlling for demographic and other suspected risk factors. METHODS: We report on the Mexican study of dementia, part of the 10/66 international dementia research group, a series of cross-sectional population-based surveys in low and middle income countries. A survey was conducted to all residents aged 65 years and older from urban and rural catchment areas in Mexico City and Morelos (January 2006 to June 2007). RESULTS: After 18 months of field work, a total of 2003 completed interviews were obtained, with a response rate of 85.1%. We found a lifetime prevalence of suicide ideation of 13.5% and a 2-week prevalence of 4.2%. The common factors associated with both lifetime and 2-week prevalence were having a large number of physical disorders (lifetime prevalence ratio = PR and 95% confidence interval = CI; PR = 2.23, CI = 1.63-3.06), depression (PR = 1.92, CI = 1.36-2.70) and anxiety (PR = 2.23, CI = 1.68-2.97) and screening positive for psychosis (PR = 1.64, CI = 1.15-2.34). CONCLUSION: Dementia plays a minor role on suicide ideation after the other aforementioned variables were taken into account and its effect, if any, could be concentrated among those elders with lower severity scores of dementia. These results show the great challenges that Mexico faces in providing services for the older people with suicidality. As the population in the country ages, suicidality will constitute an additional challenge to the healthcare system. PMID- 24788111 TI - Attitudes to vaccination: a critical review. AB - This paper provides a consolidated overview of public and healthcare professionals' attitudes towards vaccination in Europe by bringing together for the first time evidence across various vaccines, countries and populations. The paper relies on an extensive review of empirical literature published in English after 2009, as well as an analysis of unpublished market research data from member companies of Vaccines Europe. Our synthesis suggests that hesitant attitudes to vaccination are prevalent and may be increasing since the influenza pandemic of 2009. We define hesitancy as an expression of concern or doubt about the value or safety of vaccination. This means that hesitant attitudes are not confined only to those who refuse vaccination or those who encourage others to refuse vaccination. For many people, vaccination attitudes are shaped not just by healthcare professionals but also by an array of other information sources, including online and social media sources. We find that healthcare professionals report increasing challenges to building a trustful relationship with patients, through which they might otherwise allay concerns and reassure hesitant patients. We also find a range of reasons for vaccination attitudes, only some of which can be characterised as being related to lack of awareness or misinformation. Reasons that relate to issues of mistrust are cited more commonly in the literature than reasons that relate to information deficit. The importance of trust in the institutions involved with vaccination is discussed in terms of implications for researchers and policy-makers; we suggest that rebuilding this trust is a multi stakeholder problem requiring a co-ordinated strategy. PMID- 24788112 TI - Social class differences in BMI among Danish women: applying Cockerham's health lifestyles approach and Bourdieu's theory of lifestyle. AB - Research on social class differences in obesity and weight-related outcomes has highlighted the need to consider how such class differences reflect the unequally distributed constellations of economic, cultural, and social resources that enable and constrain health-related habits and practices or health lifestyles. Motivated by this need, the present study applies a theoretical perspective that integrates Cockerham's (2005) health lifestyles theory with Bourdieu's (1984) theoretical scholarship on social class, lifestyles, and the body to analyzing class-based differences in body mass index (BMI) among adult female respondents of a 2007 Danish national survey (n = 1376). We test hypotheses concerning how respective levels of economic, cultural, and social capital that constitute women's social class membership are associated with BMI directly and via their influence on respondent's dietary-related values, preferences, behaviors, and exercise activities. Our analyses indicate that cultural and economic capital were both directly associated with BMI. Mediation analyses revealed that greater cultural and social capital were linked to higher BMI via interest in cooking; while all three forms of capital were associated with lower BMI via greater frequency of exercise. These findings provide evidence for the many-and sometimes contradictory-ways that social class can influence body weight. Identifying such patterns can inform the design of more effective population health interventions. PMID- 24788113 TI - Social class and body weight among Chinese urban adults: the role of the middle classes in the nutrition transition. AB - While a plethoric empirical literature addresses the relationship between socio economic status and body weight, little is known about the influence of social class on nutritional outcomes, particularly in developing countries. The purpose of this article is to contribute to the analysis of the social determinants of adult body weight in urban China by taking into account the influence of social class. More specifically, we propose to analyse the position of the Chinese urban middle class in terms of being overweight or obese. The empirical investigations conducted as part of this research are based on a sample of 1320 households and 2841 adults from the China Health and Nutrition Survey for 2009. For the first step, we combine an economic approach and a sociological approach to identify social classes at household level. First, households with an annual per capita income between 10,000 Yuan and the 95th income percentile are considered as members of the middle class. Second, we strengthen the characterization of the middle class using information on education and employment. By applying clustering methods, we identify four groups: the elderly and inactive middle class, the old middle class, the lower middle class and the new middle class. For the second step, we implement an econometric analysis to assess the influence of social class on adult body mass index and on the probability of being overweight or obese. We use multinomial treatment regressions to deal with the endogeneity of the social class variable. Our results show that among the four subgroups of the urban middle class, the new middle class is the only one to be relatively well-protected against obesity. We suggest that this group plays a special role in adopting healthier food consumption habits and seems to be at a more advanced stage of the nutrition transition. PMID- 24788114 TI - Impacts of Child Development Accounts on maternal depressive symptoms: evidence from a randomized statewide policy experiment. AB - This study examines the impact of Child Development Accounts (CDAs)-asset building accounts created for children at birth-on the depressive symptoms of mothers in a statewide randomized experiment conducted in the United States. The experiment identified the primary caregivers of children born in Oklahoma during 2007, and 2704 of the caregivers completed a baseline interview before random assignment to the treatment (n = 1358) or the control group (n = 1346). To treatment participants, the experiment offered CDAs built on the existing Oklahoma 529 College Savings Plan. The baseline and follow-up surveys measured the participants' depressive symptoms with a shortened version of the Center for Epidemiologic Studies Depression Scale (CES-D). In models that control for baseline CES-D scores, the mean follow-up score of treatment mothers is .17 lower than that of control mothers (p < .05). Findings suggest that CDAs have a greater impact among subsamples that reported lower income or lower education. Although designed as an economic intervention for children, CDAs may improve parents' psychological well-being. Findings also suggest that CDAs' impacts on maternal depressive symptoms may be partially mediated through children's social-emotional development. PMID- 24788115 TI - The impact of fiscal austerity on suicide: on the empirics of a modern Greek tragedy. AB - Suicide rates in Greece (and other European countries) have been on a remarkable upward trend following the global recession of 2008 and the European sovereign debt crisis of 2009. However, recent investigations of the impact on Greek suicide rates from the 2008 financial crisis have restricted themselves to simple descriptive or correlation analyses. Controlling for various socio-economic effects, this study presents a statistically robust model to explain the influence on realised suicidality of the application of fiscal austerity measures and variations in macroeconomic performance over the period 1968-2011. The responsiveness of suicide to levels of fiscal austerity is established as a means of providing policy guidance on the extent of suicide behaviour associated with different fiscal austerity measures. The results suggest (i) significant age and gender specificity in these effects on suicide rates and that (ii) remittances have suicide-reducing effects on the youth and female population. These empirical regularities potentially offer some guidance on the demographic targeting of suicide prevention measures and the case for 'economic' migration. PMID- 24788116 TI - Hierarchically designed SiOx/SiOy bilayer nanomembranes as stable anodes for lithium ion batteries. AB - Hierarchically designed SiOx /SiOy rolled-up bilayer nanomembranes are used as anodes for lithium-ion batteries. The functionalities of the SiO(x,y) layers can be engineered by simply controlling the oxygen content, resulting in anodes that exhibit a reversible capacity of about 1300 mA h g(-1) with an excellent stability of over 100 cycles, as well as a good rate capability. PMID- 24788117 TI - Excretory/secretory products from Trichinella spiralis adult worms ameliorate DSS induced colitis in mice. AB - BACKGROUND: Many evidences show the inverse correlation between helminth infection and allergic or autoimmune diseases. Identification and characterization of the active helminth-derived products responsible for the beneficial effects on allergic or inflammatory diseases will provide another feasible approach to treat these diseases. METHODS AND FINDINGS: Colitis was induced in C57BL/6 mice by giving 3% DSS orally for 7 days. During this period, the mice were treated daily with the excretory/secretory products from T. spiralis adult worms (AES) intraperitoneally. The severity of colitis was monitored by measuring body weight, stool consistency or bleeding, colon length and inflammation. To determine the T. spiralis AES product-induced immunological response, Th1, Th2, Th17 and regulatory cytokine profiles were measured in lymphocytes isolated from colon, mesenteric lymph nodes (MLN), and the spleen of treated mice. The CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) were also measured in the spleens and MLN of treated mice. Mice treated with AES significantly ameliorated the severity of the DSS-induced colitis indicated by the reduced disease manifestations, improved macroscopic and microscopic inflammation correlated with the up-regulation of Treg response (increased regulatory cytokines IL-10, TGF-beta and regulatory T cells) and down-regulation of pro inflammatory cytokines (IFN-gamma, IL-6 and IL-17) in the spleens, MLN and colon of treated mice. CONCLUSIONS: Our results provide direct evidences that T. spiralis AES have a therapeutic potential for alleviating inflammatory colitis in mice. This effect is possibly mediated by the immunomodulation of regulatory T cells to produce regulatory and anti-inflammatory cytokines and inhibit pro inflammatory cytokines. PMID- 24788118 TI - CTNNB1 S45F mutation predicts poor efficacy of meloxicam treatment for desmoid tumors: a pilot study. AB - We hypothesized that patterns of CTNNB1 (beta-catenin) mutations would affect the outcome of conservative therapy in patients with desmoid tumors. This study aimed to determine the significance of CTNNB1 (beta-catenin) mutations in predicting the treatment outcome in patients with desmoid tumors treated with meloxicam, a cyclooxygenase-2 (COX-2) selective inhibitor. Between 2003 and 2012, consecutive thirty-three patients with extra-peritoneal sporadic desmoid tumors were prospectively treated with meloxicam as the initial systemic medical therapy. The efficacy of meloxicam was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). DNA was isolated from frozen tissue or formalin-fixed materials. CTNNB1 mutation analysis was performed by direct sequencing. Positivity of nuclear beta-catenin staining by immunohistochemistry was compared with the status of CTNNB1 mutations. The correlation between the efficacy of meloxicam treatment and status of CTNNB1 mutations was analyzed. Of the 33 patients with meloxicam treatment, one showed complete remission (CR), 7 partial remission (PR), 12 stable disease (SD), and 13 progressive disease (PD). The following 3 point mutations were identified in 21 of the 33 cases (64%): T41A (16 cases), S45F (4 cases) and S45P (one case). The nuclear expression of beta catenin correlated significantly with CTNNB1 mutation status (p = 0.035); all four cases with S45F mutation exhibited strong nuclear expression of beta catenin. S45F mutation was significantly associated with a poor response (all cases; PD) (p = 0.017), whereas the other mutations had no impact on efficacy. The CTNNB1 mutation status was of significant prognostic value for meloxicam treatment in patients with sporadic desmoid tumors. PMID- 24788119 TI - Factors influencing disability due to low back pain using the Oswestry Disability Questionnaire and the Quebec Back Pain Disability Scale. AB - OBJECTIVES: The aim of this research was to compare the difference in disability caused by back pain using scores from the Oswestry Disability Questionnaire (ODQ) and the Quebec Back Pain Disability Scale (QUE) according to gender, acute and chronic low back pain (LBP) groups, specific and nonspecific LBP groups and to identify the factors influencing the degree of LBP disability. METHODS: One hundred and thirty-three patients with LBP participated in this study. The Visual Analogue Scale (VAS) of ODQ and QUE were used to compare the differences between men and women, acute and chronic and specific and nonspecific LBP groups. We identified the factors influencing the disability of LBP using a stepwise multiple regression. RESULTS: In comparison with the nonspecific LBP group, the VAS, ODQ and QUE scores were significantly higher and the pain duration was significantly longer in the specific LBP group (P < 0.05). A multiple regression equation with VAS and LBP classification explained the 45.4% variance in ODQ and an equation with VAS, LBP classification, pain duration and gender explained 31.1% of the variance in QUE. CONCLUSIONS: The degree of disability from back pain assessed using the ODQ score was influenced by a pain severity and LBP type. Also, QUE score was influenced by a pain severity, LBP type, pain duration and gender. To assess the disability caused by back pain accurately using the ODQ and QUE, various factors affecting the scores of the questionnaire must be considered. PMID- 24788120 TI - A DNA-scaffolded silver nanocluster/Cu2+ ensemble as a turn-on fluorescent probe for histidine. AB - A new type of rapid, sensitive, and selective fluorescence turn-on assay was developed for detection of histidine using a DNA-scaffolded silver nanocluster/Cu(2+) ensemble (DNA-AgNC/Cu(2+)). Cu(2+) was first bound to nucleic acids of the DNA-AgNCs forming a DNA-AgNC/Cu(2+) ensemble and then liberated into solution via the highly specific interaction between histidine and Cu(2+) in the presence of other amino acids. The fluorescence of DNA-AgNCs was greatly quenched with the addition of Cu(2+), and then the DNA-AgNC/Cu(2+) ensemble exhibited marvelous fluorescent enhancement in the presence of histidine, which showed the possibility for constructing a turn-on chemosensor of histidine. Compared to other methods, this approach promises high sensitivity, simplicity in design, convenient operation, and minimized use of organic solvents. The ultra-high selectivity demonstrated the feasibility of the assay for detecting histidine in sophisticated physical environments. The fitting range of the proposed assay is from 0 to 100 MUM, with a detection limit of 1.4 MUM (S/N = 3) in artificial urine samples. The protocol was evaluated by analysis of artificial urine samples with good recoveries and showed great potential for practical applications. PMID- 24788121 TI - Global DNA methylation of ischemic stroke subtypes. AB - Ischemic stroke (IS), a heterogeneous multifactorial disorder, is among the leading causes of mortality and long-term disability in the western world. Epidemiological data provides evidence for a genetic component to the disease, but its epigenetic involvement is still largely unknown. Epigenetic mechanisms, such as DNA methylation, change over time and may be associated with aging processes and with modulation of the risk of various pathologies, such as cardiovascular disease and stroke. We analyzed 2 independent cohorts of IS patients. Global DNA methylation was measured by luminometric methylation assay (LUMA) of DNA blood samples. Univariate and multivariate regression analyses were used to assess the methylation differences between the 3 most common IS subtypes, large-artery atherosclerosis (LAA), small-artery disease (SAD), and cardio-aortic embolism (CE). A total of 485 IS patients from 2 independent hospital cohorts (n = 281 and n = 204) were included, distributed across 3 IS subtypes: LAA (78/281, 59/204), SAD (97/281, 53/204), and CE (106/281, 89/204). In univariate analyses, no statistical differences in LUMA levels were observed between the 3 etiologies in either cohort. Multivariate analysis, adjusted by age, sex, hyperlipidemia, and smoking habit, confirmed the lack of differences in methylation levels between the analyzed IS subtypes in both cohorts. Despite differences in pathogenesis, our results showed no global methylation differences between LAA, SAD, and CE subtypes of IS. Further work is required to establish whether the epigenetic mechanism of methylation might play a role in this complex disease. PMID- 24788122 TI - Epithelial-mesenchymal transition and apoptosis of renal tubular epithelial cells are associated with disease progression in patients with IgA nephropathy. AB - The aim of the present study was to examine the effects of epithelial-mesenchymal transition (EMT) and apoptosis of renal tubular epithelial cells on the prognosis of immunoglobulin A (IgA) nephropathy. Renal biopsy tissues from 74 cases of IgA nephropathy were divided into a mild mesangial proliferation group (27 cases), a focal hyperplasia group (28 cases) and a proliferative sclerosis group (19 cases). The blood pressure, serum creatinine and 24 h urinary protein excretion of all patients were detected. To define EMT, alpha-smooth muscle actin (alpha SMA), vimentin and collagen fibers were assessed. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The blood pressure, serum creatinine and 24 h urinary protein excretion of patients with IgA nephropathy altered with increasing pathological grade. All clinical indices of patients in the proliferative sclerosis group were higher than those of the other two groups, and the 24 h urinary protein excretion of the focal hyperplasia group was statistically higher than that of the mild mesangial proliferation group. The expression of tubular interstitial alpha-SMA, vimentin and collagen fibers increased with the pathological grade and was closely correlated with clinical indices, including collagen fibers and 24 h urinary protein excretion. TUNEL-positive cells increased with the exacerbation of pathological changes. The EMT and apoptosis of renal tubular epithelial cells reflected the clinical severity of IgA nephropathy. alpha-SMA, vimentin and the apoptotic index may be used as important markers for evaluating the prognosis of IgA nephropathy. PMID- 24788123 TI - Stem cell adhesion and proliferation on hydrolyzed poly(butylene succinate)/beta tricalcium phosphate composites. AB - Although poly(butylene succinate)/beta-tricalcium phosphate (PBSu/TCP) composites are biocompatible and allow the growth and osteogenic differentiation of stem cells, cell attachment and adhesion to the PBSu-based substrates is often limited. To enhance cell adhesion and proliferation, we used a sodium hydroxide (NaOH) hydrolysis technique to generate a different degree of roughness on PBSu/TCP substrates with different PBSu:TCP ratios. The results showed that NaOH hydrolysis increased surface roughness of PBSu/TCP substrates in a concentration dependent manner. Substrates with higher ratios of TCP:PBSu provided more porous topography after NaOH hydrolysis, with a substrate containing 40 wt % TCP (PBSu/TCP-6040) hydrolyzed with 1.5M NaOH (HPBSu/TCP-6040-1.5) showing the highest degree of roughness. As with the roughness, PBSu/TCP surface hydrophilicity was positively affected by the increasing NaOH concentration and TCP incorporation. Stem cells adhered best on HPBSu/TCP-6040-1.5 with three dimensionally elongated cell extensions. Moreover, the HPBSu/TCP-6040-1.5 substrate most significantly facilitated stem cell actin cytoskeleton reorganization and vinculin-positive focal adhesion formation when compared with the other substrates tested. HPBSu/TCP-6040-1.5 also demonstrated the greatest increase in cell proliferation when compared with the other substrates studied. In conclusion, the results have shown that among various substrates tested, HPBSu/TCP-6040-1.5 provided the best support for stem cell adhesion and proliferation, suggesting its potential use in bone engineering. PMID- 24788124 TI - Evaluation of ?2-pioglitazone, an analogue of pioglitazone, on colon cancer cell survival: Evidence of drug treatment association with autophagy and activation of the Nrf2/Keap1 pathway. AB - Thiazolidinediones have been shown to exhibit anti-proliferative effects against cancer cells derived from diverse tissue origins both in vivo and in vitro. We studied the anti-proliferative impact of 5-{4-(2-(5-ethyl-pyridin-2-yl)-ethoxy) benzylidene}-thiazolidine-2,4-dione (?2-pioglitazone), an analogue of pioglitazone, which binds to the nuclear peroxisome proliferator activated receptor-gamma without activating it, on human adenocarcinoma-derived HT29 and HCT116 cells. In HTC116 cells, exposure to ?2-pioglitazone reduced cell growth, but HT29 cells reached the plateau phase of growth after three days. ?2 pioglitazone treatment did not trigger cells to enter apoptosis but enhanced the autophagy process. The effect of ?2-pioglitazone treatment was related to the increase of oxygen and nitric oxide-derived species production and decreased glutathione content. Moreover, pre-treatment with an antioxidant before addition of ?2-pioglitazone limited cell growth inhibition, reduced the production of reactive species and attenuated autophagy within the cells. The impact of the drug was associated with activation of the Nrf2/Keap1 pathway as demonstrated by the increased protein content of several antioxidant enzymes, notably heme oxygenase-1. PMID- 24788125 TI - A single pipeline embolization device is sufficient for treatment of intracranial aneurysms. AB - BACKGROUND AND PURPOSE: The Pipeline Embolization Device has emerged as an important treatment option for intracranial aneurysms. The number of devices needed to treat an aneurysm is uncertain and is the subject of vigorous debate. The purpose of this study was to compare rates of complications, aneurysm occlusion, and outcome in patients treated with a single-versus-multiple Pipeline Embolization Devices. MATERIAL AND METHODS: One hundred seventy-eight patients were treated with the Pipeline Embolization Device at our institution. Patients were divided into 2 groups: a single-device group (n = 126) and a multiple-device group (n = 52). RESULTS: There was no statistically significant difference between the 2 groups with respect to baseline characteristics except for age and aneurysm size (higher with multiple Pipeline Embolization Devices). Complications occurred more frequently with multiple (15%) versus a single device (5%, P = .03). In multivariate analysis, the use of multiple devices independently predicted complications. A similar proportion of patients achieved adequate aneurysm obliteration at follow-up in the single-device (84%) and the multiple device groups (87%, P = .8). In multivariate analysis, age and follow-up time predicted obliteration. At follow-up, a significantly higher proportion of patients treated with a single device (97%) achieved a favorable outcome compared with those treated with multiple devices (89%, P = .03). In multivariate analysis, there was a strong trend for the use of a single device to predict favorable outcomes (P = .06). CONCLUSIONS: Treatment with a single Pipeline Embolization Device provides similar occlusion rates with less complications and better overall outcomes. These findings suggest that a single Pipeline Embolization Device is sufficient for treatment of most intracranial aneurysms. PMID- 24788126 TI - Variation in anisotropy and diffusivity along the medulla oblongata and the whole spinal cord in adolescent idiopathic scoliosis: a pilot study using diffusion tensor imaging. AB - BACKGROUND AND PURPOSE: Disturbed somatosensory evoked potentials have been demonstrated in patients with adolescent idiopathic scoliosis (but this functional delay was found to originate above the C5-6 level, while the lower cord level was unaffected). Together with MR imaging observation of tonsillar ectopia and a relatively tethered cord, we hypothesized that there is disturbed mean diffusivity integrity along the spinal cord. In this study, advanced DTI was used to evaluate whether there was underlying decreased WM integrity within the brain stem and spinal cord in adolescent idiopathic scoliosis and any relationship to cerebellar tonsillar ectopia. Clinical impact on balance testing was also correlated. MATERIALS AND METHODS: Thirteen girls with adolescent idiopathic scoliosis with right thoracic curves were compared with 13 age-matched healthy girls. DTI of the brain and whole spinal cord was performed. ROIs were manually defined for the medulla oblongata and along each intervertebral segment of the cord. Mean values of fractional anisotropy and mean diffusivity were computed at the defined regions. Between-group comparisons were performed by 1 way ANOVA. RESULTS: Significantly decreased fractional anisotropy values and increased mean diffusivity values were found at the medulla oblongata and C1-2, C2-3, C3-4, and C4-5 segments in patients with adolescent idiopathic scoliosis compared with healthy subjects. No significant difference was found in the lower cord levels. Significant correlation was found between the tonsillar level and fractional anisotropy value at the C4-5 level in patients with adolescent idiopathic scoliosis only. CONCLUSIONS: The findings from this study are in agreement with previous findings showing abnormal somatosensory evoked potential readings occurring only above the C5-6 level in patients with adolescent idiopathic scoliosis; these findings might partially explain the pathophysiology of the neural pathway involved. PMID- 24788127 TI - Large-volume blood patch to multiple sites in the epidural space through a single catheter access site for treatment of spontaneous intracranial hypotension. AB - BACKGROUND AND PURPOSE: Spontaneous intracranial hypotension can be a therapeutic challenge to the treating physician. In this study, we present our experience with the administration of a large-volume blood patch to multiple sites in the epidural space through a single-catheter access site. MATERIALS AND METHODS: A retrospective review was conducted of patients with spontaneous intracranial hypotension who underwent a large-volume blood patch to multiple sites in the epidural space through a single-catheter access site from 2010 to 2012. Patient demographic data, clinical charts, indications for treatment, radiographic images, procedure notes, and postprocedure hospital course were reviewed. RESULTS: Overall, 9 patients were identified who underwent 20 blood patch procedures. Patients were selected to undergo the large-volume procedure either because they had a failed site-directed epidural blood patch or if imaging demonstrated multiple possible leak sites. There were 6 women and 3 men, with an average age of 33.5 years. The mean volume of blood injected per procedure was 54.1 mL (median=55 mL; range=38-70 mL). All patients had an orthostatic headache as one of their presenting symptoms; 22% also presented with neurocognitive decline and behavioral changes; 89% of patients had improvement or resolution of their symptoms; and 80% of patients who had a previously failed site-directed epidural blood or fibrin glue patch improved with a large volume catheter directed blood patch. CONCLUSIONS: Our experience supports the use of a large volume blood patch to multiple sites in the epidural space through a single catheter access site for the treatment of spontaneous intracranial hypotension. Additionally, our results indicate a role for this procedure in refractory cases of spontaneous intracranial hypotension. PMID- 24788128 TI - Acute myelopathy or cauda equina syndrome in HIV-positive adults in a tuberculosis endemic setting: MRI, clinical, and pathologic findings. AB - BACKGROUND AND PURPOSE: Cape Town is the center of an HIV-tuberculosis coepidemic. This study's aim was to highlight the importance and to describe the MR imaging features of tuberculosis in acute myelopathy and cauda equina syndrome in HIV-positive adults. To accomplish this we retrospectively reviewed the MR imaging and clinico-pathologic findings of HIV-positive patients presenting to our hospital with recent onset paraplegia and sphincter dysfunction over a 4-year period, 2008-2011. MATERIALS & METHODS: MR imaging, CD4 count, and CSF analysis and pathology were correlated in 216 cases. RESULTS: Fifty-eight percent (127) of subjects were female. The mean age was 37 years. The median CD4 count was 185 cells/MUL. Twenty-five percent (54) of patients were on antiretroviral therapy. MR imaging showed spondylitis in 30% (65). The median CD4 count in these patients was significantly higher than in the remainder. Disk destruction was common and 10% had synchronous spondylitis elsewhere in the spinal column. Thirty percent (64) had features of myelitis/arachnoiditis. Twenty-five percent (55) had no MR imaging abnormality. In 123 (57%) of cases with a definitive etiology on CSF culture or biopsy, 84 (68%) were attributable to tuberculosis including all spondylitis cases and 40% of nonspondylitis cases. Twelve (10%) were due to nontuberculous infection and 12 (10%) had HIV-associated tumors including 2 rare Epstein-Barr-related tumors. CONCLUSIONS: In our setting, acute onset myelopathy/cauda equina syndrome in HIV-positive patients is largely attributable to tuberculosis with nonspondylitic forms being more common than spondylitis and associated with a lower CD4 count. PMID- 24788129 TI - Cerebrovascular reactivity mapping: an evolving standard for clinical functional imaging. AB - SUMMARY: This review article explains the methodology of breath-hold cerebrovascular reactivity mapping, both in terms of acquisition and analysis, and reviews applications of this method to presurgical mapping, particularly with respect to blood oxygen level-dependent fMRI. Its main application in clinical fMRI is for the assessment of neurovascular uncoupling potential. Neurovascular uncoupling is potentially a major limitation of clinical fMRI, particularly in the setting of mass lesions in the brain such as brain tumors and intracranial vascular malformations that are associated with alterations in regional hemodynamics on either an acquired or congenital basis. As such, breath-hold cerebrovascular reactivity mapping constitutes an essential component of quality control analysis in clinical fMRI, particularly when performed for presurgical mapping of eloquent cortex. Exogenous carbon dioxide challenges used for cerebrovascular reactivity mapping will also be discussed, and their applications to the evaluation of cerebrovascular reserve and cerebrovascular disease will be described. PMID- 24788130 TI - Complex hemodynamic insult in combination with wall degeneration at the apex of an arterial bifurcation contributes to generation of nascent aneurysms in a canine model. AB - BACKGROUND AND PURPOSE: The detailed mechanisms of cerebral aneurysm generation remain unclear. Our aim was to investigate whether specific hemodynamic insult in combination with arterial wall degeneration leads to the development of aneurysms in a canine model. MATERIALS AND METHODS: New branch points in the common carotid artery were created in 18 dogs. Nine animals subsequently received elastase insult at the arterial bifurcation apex (elastase-treated bifurcation group); the control bifurcation group (n=9) received saline, and 3 dogs received an elastase insult to both straight common carotid arteries (elastase-treated straight group). Angiographic and hemodynamic analysis was performed immediately and 12 and 24 weeks' postsurgery; histologic response was evaluated at 12 and 24 weeks. RESULTS: Angiography revealed nascent aneurysms (mean, 3.2+/-0.4 mm) at the arterial bifurcation apices in 5/9 models of the elastase-treated bifurcation group (versus 0 in the control bifurcation group and elastase-treated straight group) without any observed aneurysm rupture. Histologic analysis revealed internal elastic lamina discontinuity, elastic fiber disruption, a thinner muscular layer, reduced smooth-muscle cell proliferation, increased inflammatory cell (macrophage) infiltration, and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in the media of the elastase-treated bifurcation group compared with that in either the control bifurcation group or the elastase treated straight group (P<.001). Hemodynamic analysis after surgery indicated that the apex experienced extremely low wall shear stress and flow velocity and the highest relative and total pressure in the elastase-treated bifurcation group, while the values returned to normal after arterial wall remodelling. CONCLUSIONS: In our study, combined hemodynamic insult and arterial wall degeneration at arterial bifurcations are required for the generation of aneurysms in a canine model. PMID- 24788131 TI - Brain changes in Kallmann syndrome. AB - BACKGROUND AND PURPOSE: Kallmann syndrome is a rare inherited disorder due to defective intrauterine migration of olfactory axons and gonadotropin-releasing hormone neurons, leading to rhinencephalon hypoplasia and hypogonadotropic hypogonadism. Concomitant brain developmental abnormalities have been described. Our aim was to investigate Kallmann syndrome-related brain changes with conventional and novel quantitative MR imaging analyses. MATERIALS AND METHODS: Forty-five male patients with Kallmann syndrome (mean age, 30.7 years; range, 9 55 years) and 23 age-matched male controls underwent brain MR imaging. The MR imaging study protocol included 3D-T1, FLAIR, and diffusion tensor imaging (32 noncollinear gradient-encoding directions; b-value=800 s/mm2). Voxel-based morphometry, sulcation, curvature, and cortical thickness analyses and tract based spatial statistics were performed by using Statistical Parametric Mapping 8, FreeSurfer, and the fMRI of the Brain Software Library. RESULTS: Corpus callosum partial agenesis, multiple sclerosis-like white matter abnormalities, and acoustic schwannoma were found in 1 patient each. The total amount of gray and white matter volume and tract-based spatial statistics measures (fractional anisotropy and mean, radial, and axial diffusivity) did not differ between patients with Kallmann syndrome and controls. By specific analyses, patients with Kallmann syndrome presented with symmetric clusters of gray matter volume increase and decrease and white matter volume decrease close to the olfactory sulci; reduced sulcal depth of the olfactory sulci and deeper medial orbital frontal sulci; lesser curvature of the olfactory sulcus and sharper curvature close to the medial orbital-frontal sulcus; and increased cortical thickness within the olfactory sulcus. CONCLUSIONS: This large MR imaging study on male patients with Kallmann syndrome featured significant morphologic and structural brain changes, likely driven by olfactory bulb hypo-/aplasia, selectively involving the basal forebrain cortex. PMID- 24788132 TI - Brain white matter involvement in hereditary spastic paraplegias: analysis with multiple diffusion tensor indices. AB - BACKGROUND AND PURPOSE: The hereditary spastic paraplegias are a group of genetically heterogeneous neurodegenerative disorders, characterized by progressive spasticity and weakness of the lower limbs. Although conventional brain MR imaging findings are normal in patients with pure hereditary spastic paraplegia, microstructural alteration in the cerebral WM can be revealed with DTI. Concomitant investigation of multiple intrinsic diffusivities may shed light on the neurobiologic substrate of the WM degeneration pattern in patients with pure hereditary spastic paraplegia across the whole brain. MATERIALS AND METHODS: Tract-based spatial statistics analysis was performed to compare fractional anisotropy and mean, axial, and radial diffusivities of the WM skeleton in a group of 12 patients with pure hereditary spastic paraplegia and 12 healthy volunteers. Data were analyzed counting age and sex as nuisance covariates. The threshold-free cluster-enhancement option was applied, and the family-wise error rate was controlled by using permutation tests for nonparametric statistics. RESULTS: In pure hereditary spastic paraplegia, group widespread fractional anisotropy decreases and radial diffusivity and mean diffusivity increases (P < .05, corrected) were found. No voxelwise difference was observed for the axial diffusivity map. Percentage of voxels within the WM skeleton that passed the significance threshold were 51%, 41.6%, and 11.9%, respectively, for radial diffusivity, fractional anisotropy, and mean diffusivity clusters. An anteroposterior pattern with preferential decrease of fractional anisotropy in the frontal circuitry was detected. CONCLUSIONS: In patients with pure hereditary spastic paraplegia, alterations in multiple DTI indices were found. Radial diffusivity seems more sensitive to hereditary spastic paraplegia-related WM pathology and, in line with the lack of axial diffusivity changes, might indicate a widespread loss of myelin integrity. A decrease of fractional anisotropy alone in the frontal circuitry may reflect subtle disruption of the frontal connections. PMID- 24788133 TI - Antitumor properties and mechanisms of mitochondria-targeted Ag(I) and Au(I) complexes containing N-heterocyclic carbenes derived from cyclophanes. AB - Metal/N-heterocyclic carbene (NHC) complexes hold great opportunities for the development of novel antitumor metallodrugs. Herein, four Ag(I) and Au(I) complexes containing NHCs derived from cyclophanes have been prepared and characterized as potential anticancer agents. These complexes show higher cytotoxicity than cisplatin against several cancer cell lines including a cisplatin-resistant cell line. The Au(I) complexes display higher anticancer activity than the corresponding Ag(I) complexes. Moreover, all the complexes are less cytotoxic than cisplatin on the normal human liver cell line LO2. Intracellular distribution studies show that these complexes are selectively localized in the mitochondria, especially for the Au(I) complexes. Interestingly, although both Ag(I) and Au(I) complexes can influence mitochondrial integrity, they induce cancer cell death through different mechanisms. The Ag(I) complexes mainly induce caspase- and reactive oxygen species (ROS)-independent early apoptosis. However, Au(I) complexes induce both early apoptosis and late apoptosis through caspase- and ROS-dependent pathways. These studies may open up an avenue for a better understanding of the impact of metal centers on antitumor potentialities and mechanisms. PMID- 24788134 TI - External validation and comparison of three pediatric clinical dehydration scales. AB - OBJECTIVE: To prospectively validate three popular clinical dehydration scales and overall physician gestalt in children with vomiting or diarrhea relative to the criterion standard of percent weight change with rehydration. METHODS: We prospectively enrolled a non-consecutive cohort of children <= 18 years of age with an acute episode of diarrhea or vomiting. Patient weight, clinical scale variables and physician clinical impression, or gestalt, were recorded before and after fluid resuscitation in the emergency department and upon hospital discharge. The percent weight change from presentation to discharge was used to calculate the degree of dehydration, with a weight change of >= 5% considered significant dehydration. Receiver operating characteristics (ROC) curves were constructed for each of the three clinical scales and physician gestalt. Sensitivity and specificity were calculated based on the best cut-points of the ROC curve. RESULTS: We approached 209 patients, and of those, 148 were enrolled and 113 patients had complete data for analysis. Of these, 10.6% had significant dehydration based on our criterion standard. The Clinical Dehydration Scale (CDS) and Gorelick scales both had an area under the ROC curve (AUC) statistically different from the reference line with AUCs of 0.72 (95% CI 0.60, 0.84) and 0.71 (95% CI 0.57, 0.85) respectively. The World Health Organization (WHO) scale and physician gestalt had AUCs of 0.61 (95% CI 0.45, 0.77) and 0.61 (0.44, 0.78) respectively, which were not statistically significant. CONCLUSION: The Gorelick scale and Clinical Dehydration Scale were fair predictors of dehydration in children with diarrhea or vomiting. The World Health Organization scale and physician gestalt were not helpful predictors of dehydration in our cohort. PMID- 24788136 TI - Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape. AB - There are several challenges to successful implementation of a cell therapy for insulin dependent diabetes derived from human embryonic stem cells (hESC). Among these are development of functional insulin producing cells, a clinical delivery method that eliminates the need for chronic immunosuppression, and assurance that hESC derived tumors do not form in the patient. We and others have shown that encapsulation of cells in a bilaminar device (TheraCyte) provides immunoprotection in rodents and primates. Here we monitored human insulin secretion and employed bioluminescent imaging (BLI) to evaluate the maturation, growth, and containment of encapsulated islet progenitors derived from CyT49 hESC, transplanted into mice. Human insulin was detectable by 7 weeks post transplant and increased 17-fold over the course of 8 weeks, yet during this period the biomass of encapsulated cells remained constant. Remarkably, by 20 weeks post-transplant encapsulated cells secreted sufficient levels of human insulin to ameliorate alloxan induced diabetes. Further, bioluminescent imaging revealed for the first time that hESCs remained fully contained in encapsulation devices for up to 150 days, the longest period tested. Collectively, the data suggest that encapsulated hESC derived islet progenitors hold great promise as an effective and safe cell replacement therapy for insulin dependent diabetes. PMID- 24788135 TI - Cross talk between spliceosome and microprocessor defines the fate of pre-mRNA. AB - The spliceosome and the microprocessor complex (MPC) are two important processing machineries that act on precursor (pre)-mRNA. Both cleave the pre-mRNA to generate spliced mature transcripts and microRNAs (miRNAs), respectively. While spliceosomes identify in a complex manner correct splice sites, MPCs typically target RNA hairpins (pri-miRNA hairpins). In addition, pre-mRNA transcripts can contain pri-miRNA-like hairpins that are cleaved by the MPC without generating miRNAs. Recent evidence indicates that the position of hairpins on pre-mRNA, their distance from splice sites, and the relative efficiency of cropping and splicing contribute to determine the fate of a pre-mRNA. Depending on these factors, a pre-mRNA can be preferentially used to generate a miRNA, a constitutively or even an alternative spliced transcript. For example, competition between splicing and cropping on splice-site-overlapping miRNAs (SO miRNAs) results in alternative spliced isoforms and influences miRNA biogenesis. In several cases, the outcome of a pre-mRNA transcript and its final handling as miRNA or mRNA substrate can be frequently closely connected to the functional relationships between diverse pre-mRNA processing events. These events are influenced by both gene context and physiopathological conditions. PMID- 24788137 TI - Timing, frequency and environmental conditions associated with mainstem-tributary movement by a lowland river fish, golden perch (Macquaria ambigua). AB - Tributary and mainstem connections represent important links for the movement of fish and other biota throughout river networks. We investigated the timing, frequency and environmental conditions associated with movements by adult golden perch (Macquaria ambigua) between the mainstem of the mid-Murray River and a tributary, the Goulburn River, in south-eastern Australia, using acoustic telemetry over four years (2007-2011). Fish were tagged and released in autumn 2007-2009 in the mid-Murray (n = 42) and lower Goulburn (n = 37) rivers within 3 6 km of the mid-Murray-lower Goulburn junction. 38% of tagged fish undertook mainstem-tributary movements, characterised mostly by temporary occupation followed by return of fish to the original capture river. Approximately 10% of tagged fish exhibited longer-term shifts between the mainstem and tributary. Movement of fish from the tributary into the mainstem occurred primarily during the spawning season and in some years coincided with the presence of golden perch eggs/larvae in drift samples in the mainstem. Many of the tributary-to-mainstem movements occurred during or soon after changes in flow. The movements of fish from the mainstem into the tributary were irregular and did not appear to be associated with spawning. The findings show that golden perch moved freely across the mainstem-tributary interface. This demonstrates the need to consider the spatial, behavioural and demographic interdependencies of aquatic fauna across geographic management units such as rivers. PMID- 24788138 TI - Loss of function of TET2 cooperates with constitutively active KIT in murine and human models of mastocytosis. AB - Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM. PMID- 24788139 TI - Scale-free brain activity: past, present, and future. AB - Brain activity observed at many spatiotemporal scales exhibits a 1/f-like power spectrum, including neuronal membrane potentials, neural field potentials, noninvasive electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) signals. A 1/f-like power spectrum is indicative of arrhythmic brain activity that does not contain a predominant temporal scale (hence, 'scale-free'). This characteristic of scale-free brain activity distinguishes it from brain oscillations. Although scale-free brain activity and brain oscillations coexist, our understanding of the former remains limited. Recent research has shed light on the spatiotemporal organization, functional significance, and potential generative mechanisms of scale-free brain activity, as well as its developmental and clinical relevance. A deeper understanding of this prevalent brain signal should provide new insights into, and analytical tools for, cognitive neuroscience. PMID- 24788141 TI - Frequencies of inaudible high-frequency sounds differentially affect brain activity: positive and negative hypersonic effects. AB - The hypersonic effect is a phenomenon in which sounds containing significant quantities of non-stationary high-frequency components (HFCs) above the human audible range (max. 20 kHz) activate the midbrain and diencephalon and evoke various physiological, psychological and behavioral responses. Yet important issues remain unverified, especially the relationship existing between the frequency of HFCs and the emergence of the hypersonic effect. In this study, to investigate the relationship between the hypersonic effect and HFC frequencies, we divided an HFC (above 16 kHz) of recorded gamelan music into 12 band components and applied them to subjects along with an audible component (below 16 kHz) to observe changes in the alpha2 frequency component (10-13 Hz) of spontaneous EEGs measured from centro-parieto-occipital regions (Alpha-2 EEG), which we previously reported as an index of the hypersonic effect. Our results showed reciprocal directional changes in Alpha-2 EEGs depending on the frequency of the HFCs presented with audible low-frequency component (LFC). When an HFC above approximately 32 kHz was applied, Alpha-2 EEG increased significantly compared to when only audible sound was applied (positive hypersonic effect), while, when an HFC below approximately 32 kHz was applied, the Alpha-2 EEG decreased (negative hypersonic effect). These findings suggest that the emergence of the hypersonic effect depends on the frequencies of inaudible HFC. PMID- 24788140 TI - Novel natural mutations in the hepatitis B virus reverse transcriptase domain associated with hepatocellular carcinoma. AB - BACKGROUND/AIM: Hepatitis B Virus (HBV) mutations play a role in the development of hepatocellular carcinoma (HCC). However, the association between HBV polymerase gene mutations and HCC has not been reported. In this study, we conducted a multi-stage study to identify HCC-related mutations in the reverse transcriptase (RT) domain of the HBV polymerase gene. METHODS: A total of 231 HCCs and 237 non-HCC controls from Qidong, China, were included in this study. The entire sequence of HBV RT was first compared between 29 HCC and 35 non-HCC cases, and candidate mutations were then evaluated in two independent validation sets. RESULTS: There were 15 candidate mutations identified from the discovery set, with A799G and T1055A being consistently associated with HCC across all studies. A pooled analysis of samples revealed that A799G, A987G, and T1055A were independent risk factors for HCC, with adjusted odds ratios of 5.53 [95% confidence interval (CI), 1.69-18.10], 4.20 (95%CI, 1.15-15.35), and 3.78 (95%CI, 1.45-9.86), respectively. A longitudinal study showed that these mutations were detectable 4-5 years prior to HCC diagnosis. CONCLUSIONS: Our study provides evidence the first that HBV RT contains naturally occurring mutations that can be used as predictive markers for HCC. PMID- 24788142 TI - Total levels of hippocampal histone acetylation predict normal variability in mouse behavior. AB - BACKGROUND: Genetic, pharmacological, and environmental interventions that alter total levels of histone acetylation in specific brain regions can modulate behaviors and treatment responses. Efforts have been made to identify specific genes that are affected by alterations in total histone acetylation and to propose that such gene specific modulation could explain the effects of total histone acetylation levels on behavior - the implication being that under naturalistic conditions variability in histone acetylation occurs primarily around the promoters of specific genes. METHODS/RESULTS: Here we challenge this hypothesis by demonstrating with a novel flow cytometry based technique that normal variability in open field exploration, a hippocampus-related behavior, was associated with total levels of histone acetylation in the hippocampus but not in other brain regions. CONCLUSIONS: Results suggest that modulation of total levels of histone acetylation may play a role in regulating biological processes. We speculate in the discussion that endogenous regulation of total levels of histone acetylation may be a mechanism through which organisms regulate cellular plasticity. Flow cytometry provides a useful approach to measure total levels of histone acetylation at the single cell level. Relating such information to behavioral measures and treatment responses could inform drug delivery strategies to target histone deacetylase inhibitors and other chromatin modulators to places where they may be of benefit while avoiding areas where correction is not needed and could be harmful. PMID- 24788143 TI - Comparison of spa types, SCCmec types and antimicrobial resistance profiles of MRSA isolated from turkeys at farm, slaughter and from retail meat indicates transmission along the production chain. AB - The prevalence of MRSA in the turkey meat production chain in Germany was estimated within the national monitoring for zoonotic agents in 2010. In total 22/112 (19.6%) dust samples from turkey farms, 235/359 (65.5%) swabs from turkey carcasses after slaughter and 147/460 (32.0%) turkey meat samples at retail were tested positive for MRSA. The specific distributions of spa types, SCCmec types and antimicrobial resistance profiles of MRSA isolated from these three different origins were compared using chi square statistics and the proportional similarity index (Czekanowski index). No significant differences between spa types, SCCmec types and antimicrobial resistance profiles of MRSA from different steps of the German turkey meat production chain were observed using Chi-Square test statistics. The Czekanowski index which can obtain values between 0 (no similarity) and 1 (perfect agreement) was consistently high (0.79-0.86) for the distribution of spa types and SCCmec types between the different processing stages indicating high degrees of similarity. The comparison of antimicrobial resistance profiles between the different process steps revealed the lowest Czekanowski index values (0.42-0.56). However, the Czekanowski index values were substantially higher than the index when isolates from the turkey meat production chain were compared to isolates from wild boar meat (0.13-0.19), an example of a separated population of MRSA used as control group. This result indicates that the proposed statistical method is valid to detect existing differences in the distribution of the tested characteristics of MRSA. The degree of similarity in the distribution of spa types, SCCmec types and antimicrobial resistance profiles between MRSA isolates from different process stages of turkey meat production may reflect MRSA transmission along the chain. PMID- 24788148 TI - Allelic variation in a willow warbler genomic region is associated with climate clines. AB - Local adaptation is an important process contributing to population differentiation which can occur in continuous or isolated populations connected by various amounts of gene flow. The willow warbler (Phylloscopus trochilus) is one of the most common songbirds in Fennoscandia. It has a continuous breeding distribution where it is found in all forested habitats from sea level to the tree line and therefore constitutes an ideal species for the study of locally adapted genes associated with environmental gradients. Previous studies in this species identified a genetic marker (AFLP-WW1) that showed a steep north-south cline in central Sweden with one allele associated with coastal lowland habitats and the other with mountainous habitats. It was further demonstrated that this marker is embedded in a highly differentiated chromosome region that spans several megabases. In the present study, we sampled 2,355 individuals at 128 sites across all of Fennoscandia to study the geographic and climatic variables associated with the allele frequency distributions of WW1. Our results demonstrate that 1) allele frequency patterns significantly differ between mountain and lowland populations, 2) these allele differences coincide with extreme temperature conditions and the short growing season in the mountains, and milder conditions in coastal areas, and 3) the northern-allele or "altitude variant" of WW1 occurs in willow warblers that occupy mountainous habitat regardless of subspecies. Finally these results suggest that climate may exert selection on the genomic region associated with these alleles and would allow us to develop testable predictions for the distribution of the genetic marker based on climate change scenarios. PMID- 24788149 TI - Lipotoxic effect of p21 on free fatty acid-induced steatosis in L02 cells. AB - Nonalcoholic fatty liver disease (NAFLD) is increasingly regarded as a hepatic manifestation of metabolic syndrome. Though with high prevalence, the mechanism is poorly understood. This study aimed to investigate the effects of p21 on free fatty acid (FFA)-induced steatosis in L02 cells. We therefore analyzed the L02 cells with MG132 and siRNA treatment for different expression of p21 related to lipid accumulation and lipotoxicity. Cellular total lipid was stained by Oil Red O, while triglyceride content, cytotoxicity assays, lipid peroxidation markers and anti-oxidation levels were measured by enzymatic kits. Treatment with 1 mM FFA for 48 hr induced magnificent intracellular lipid accumulation and increased oxidative stress in p21 overload L02 cells compared to that in p21 knockdown L02 cells. By increasing oxidative stress and peroxidation, p21 accelerates FFA induced lipotoxic effect in L02 cells and might provide information about potentially new targets for drug development and treatments of NAFLD. PMID- 24788166 TI - Prefrontal cortex haemodynamics and affective responses during exercise: a multi channel near infrared spectroscopy study. AB - The dose-response effects of the intensity of exercise upon the potential regulation (through top-down processes) of affective (pleasure-displeasure) responses in the prefrontal cortex during an incremental exercise protocol have not been explored. This study examined the functional capacity of the prefrontal cortex (reflected by haemodynamics using near infrared spectroscopy) and affective responses during exercise at different intensities. Participants completed an incremental cycling exercise test to exhaustion. Changes (Delta) in oxygenation (O2Hb), deoxygenation (HHb), blood volume (tHb) and haemoglobin difference (HbDiff) were measured from bilateral dorsal and ventral prefrontal areas. Affective responses were measured every minute during exercise. Data were extracted at intensities standardised to: below ventilatory threshold, at ventilatory threshold, respiratory compensation point and the end of exercise. During exercise at intensities from ventilatory threshold to respiratory compensation point, DeltaO2Hb, DeltaHbDiff and DeltatHb were greater in mostly ventral than dorsal regions. From the respiratory compensation point to the end of exercise, DeltaO2Hb remained stable and DeltaHbDiff declined in dorsal regions. As the intensity increased above the ventilatory threshold, inverse associations between affective responses and oxygenation in (a) all regions of the left hemisphere and (b) lateral (dorsal and ventral) regions followed by the midline (ventral) region in the right hemisphere were observed. Differential activation patterns occur within the prefrontal cortex and are associated with affective responses during cycling exercise. PMID- 24788167 TI - The role of experienced and anticipated discrimination in the lives of people with first-episode psychosis. AB - OBJECTIVE: This study aimed to describe patterns of experienced and anticipated discrimination in a sample of persons experiencing a first episode of psychosis and to explore associations with clinical and psychosocial variables. METHODS: This cross-sectional survey was conducted within the context of the Psychosis Incident Cohort Outcome Study, a multisite naturalistic study examining first episode patients treated in public psychiatric services in the Veneto Region of Italy. The Discrimination and Stigma Scale was used to assess experienced and anticipated discrimination. RESULTS: Ninety-seven patients were interviewed. Experiences of discrimination were common in relationships with family members (43%), making friends (32%), relationships with neighbors (25%), keeping a job (25%), finding a job (24%), and intimate relationships (23%). In regard to anticipated discrimination, 37% had stopped seeking a close relationship and 34% had stopped looking for work, 58% felt the need to conceal their diagnosis, and 37% reported that other people avoided them. In regression analysis, a higher number of functioning needs together with higher anticipated discrimination were associated with a higher level of experienced discrimination. A higher level of experienced discrimination and greater illness awareness were associated with more anticipated discrimination. CONCLUSIONS: First-episode patients reported experiencing discrimination in several key life areas. Anticipated discrimination further limited their access to life opportunities. Patients' awareness of the negative consequences of symptoms and disabilities led them to more easily perceive discrimination. PMID- 24788150 TI - Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. AB - Deletion of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) envelope (E) gene attenuates the virus. E gene encodes a small multifunctional protein that possesses ion channel (IC) activity, an important function in virus-host interaction. To test the contribution of E protein IC activity in virus pathogenesis, two recombinant mouse-adapted SARS-CoVs, each containing one single amino acid mutation that suppressed ion conductivity, were engineered. After serial infections, mutant viruses, in general, incorporated compensatory mutations within E gene that rendered active ion channels. Furthermore, IC activity conferred better fitness in competition assays, suggesting that ion conductivity represents an advantage for the virus. Interestingly, mice infected with viruses displaying E protein IC activity, either with the wild-type E protein sequence or with the revertants that restored ion transport, rapidly lost weight and died. In contrast, mice infected with mutants lacking IC activity, which did not incorporate mutations within E gene during the experiment, recovered from disease and most survived. Knocking down E protein IC activity did not significantly affect virus growth in infected mice but decreased edema accumulation, the major determinant of acute respiratory distress syndrome (ARDS) leading to death. Reduced edema correlated with lung epithelia integrity and proper localization of Na+/K+ ATPase, which participates in edema resolution. Levels of inflammasome-activated IL-1beta were reduced in the lung airways of the animals infected with viruses lacking E protein IC activity, indicating that E protein IC function is required for inflammasome activation. Reduction of IL 1beta was accompanied by diminished amounts of TNF and IL-6 in the absence of E protein ion conductivity. All these key cytokines promote the progression of lung damage and ARDS pathology. In conclusion, E protein IC activity represents a new determinant for SARS-CoV virulence. PMID- 24788168 TI - Assaying NF-kappaB activation and signaling from TNF receptors. AB - Tumor necrosis factor (TNF)-mediated activation of the NF-kappaB family of transcription factors is mediated by two receptors, TNFR1 and TNFR2. These two receptors have unique roles in response to TNF and have been the focus of new therapeutic strategies in a variety of diseases with an immune or an inflammatory component. This chapter describes in vitro methods to functionally identify which TNF receptor is initiating NF-kappaB activation. This will include antibody mediated receptor blockade and RNAi-mediated gene silencing targeting the individual receptors. The NF-kappaB activation methods presented include standard, accepted assays for monitoring the sequential activation steps through the NF-kappaB signal transduction cascade, including IkappaBalpha degradation, NF kappaB nuclear translocation, and transcriptional activation of gene expression. PMID- 24788169 TI - Dissecting DR3 signaling. AB - Receptor signaling can be evaluated in multiple ways, including analysis of phosphorylation of downstream molecules and analysis of proteins that are recruited to the receptor upon ligand binding. Majority of studies on the mechanism of DR3 signaling were performed using overexpression systems that can often lead to artifacts. In this chapter we describe how to analyze DR3 downstream events with most attention being paid to endogenous immunoprecipitation. PMID- 24788170 TI - Modulation of FcepsilonRI-dependent mast cell response by OX40L. AB - OX40L is expressed by many cell types, including antigen presenting cells (APCs), T cells, vascular endothelial cells, mast cells (MCs), and natural killer cells. The importance of OX40L:OX40 interactions and the OX40L signaling is crucial for the homeostasis and for the modulation of the effector functions of the immune system. However, the lack of non-murine/non-IgG commercially available OX40L triggering antibodies and the potential signal cross-contamination caused by the binding to the FcgammaRs co-expressed by several immune cells have limited the study of the OX40L-signaling cascade. We recently characterized the functions and described the molecular events, which follow the engagement of OX40L in MCs, by the use of the soluble OX40 molecule, able to mimic the regulatory T cell-driven engagement of MC-OX40L. This molecule enables signaling studies in MCs with any requirement for OX40-expressing cells. Using this unique reagent, we determined the modality and the extent by which the engagement of OX40L in MCs influences the IgE-dependent MC degranulation. This tool may find a potential application for signaling studies of other OX40L-expressing populations other than MCs, mainly APCs, with similar approaches we reported for the study of OX40L cascade. PMID- 24788171 TI - Analyzing the signaling capabilities of soluble and membrane TWEAK. AB - TWEAK, like many other ligands of the TNF family, occurs naturally in two forms, as a type II transmembrane protein and as soluble ligand released from the latter by proteases of the furin family. Both TWEAK variants interact with high affinity with Fn14, an unusual small member of the TNF receptor family. TWEAK and Fn14 activate a variety of intracellular signaling pathways but regulation of TNF induced cell death and stimulation of the classical and alternative NFkappaB pathway are certainly the best understood ones. Intriguingly, soluble and membrane TWEAK significantly differ in their ability to trigger these responses. While activation of the alternative NFkappaB pathway and enhancement of TNF induced cell death are efficiently induced by both forms of TWEAK, membrane TWEAK has a much higher capacity than soluble TWEAK to stimulate the classical NFkappaB pathway. Importantly, soluble TWEAK gains a membrane TWEAK-like Fn14 stimulating activity upon oligomerization or artificial anchoring to the cell surface. On the example of NFkappaB signaling and enhancement of TNF-induced cell death, we summarize here protocols that allow the identification of signaling pathways/cellular responses that preferentially respond to membrane TWEAK. These protocols base either on the side-by-side analysis of soluble TWEAK and oligomerized or cell surface-anchorable TWEAK variants or on the use of transfectants expressing soluble and membrane TWEAK. PMID- 24788172 TI - Regulation of human dendritic cell functions by natural anti-CD40 antibodies. AB - Dendritic cells (DCs) are professional antigen presenting cells that play a pivotal role in the initiation of immune responses. DCs ingest antigens and then present these antigens to T cells to initiate T cell activation and polarization. DCs receive signals both from environment and from endogenous molecules. DCs in the immune system constantly interact with immunoglobulins (or antibodies) and a substantial amount of these immunoglobulins are natural. We found that natural antibodies have a key role in regulating the DC functions and that CD40-reactive natural antibodies constitute one of the endogenous molecules that provide maturation-associated signals to DCs in physiology. In this chapter, we describe the isolation of anti-CD40 natural antibodies from pooled normal immunoglobulin preparations (intravenous immunoglobulin, IVIg) and their biological effects on human DC maturation and functions. PMID- 24788173 TI - beta-actin in the signaling of transmembrane TNF-alpha-mediated cytotoxicity. AB - To study the role of beta-actin in the signaling of transmembrane TNF-alpha (tmTNF-alpha)-mediated cytotoxicity, we mainly used bioassay and apoptosis assay, detection of the visual changes in beta-actin and intracellular translocation of signal molecules in response to tmTNF-alpha, and analysis of the signal molecules coupled or uncoupled with TNFR2 complex. These protocols might also be used to investigate the signaling events mediated by other transmembrane cytokines or members of TNF superfamily, which have transmembrane and soluble forms, as well as the involvement of actin cytoskeleton in signal transduction pathways. PMID- 24788174 TI - Investigating the protective role of death receptor 3 (DR3) in renal injury using an organ culture model. AB - Death receptor 3 (DR3; also designated as Wsl-1, Apo3, LARD, TRAMP, TNFRSF25, and TR3) is a member of the tumor necrosis factor (TNF) receptor superfamily that has emerged as a major regulator of inflammation and autoimmune diseases. DR3 contains a homologous intracellular region called the death domain (DD) that can bind adaptor proteins, which also contain a DD, initiating cellular responses such as caspase activation and apoptotic cell death. However, in other circumstances DR3 can initiate induction of transcription genes and gene products that can prevent cell death from occurring. Our laboratory has reported an inducible expression of DR3 in human and mouse tubular epithelial cells in renal injury, but its function in these setting still remains unclear. To directly manipulate and evaluate the role of DR3 in vivo, I have used an in vitro organ culture (OC) model, which I have developed in our laboratory. In this chapter, I will describe in detail the OC model used to study the role of DR3 in renal injury and discuss its advantages and limitations. In my hands, the OC model has proven to be an efficient tool for studying human cell heterogeneity, basal and regulated receptor expression, signalling pathways, and various biological responses not readily achievable in traditional cell culture models. Various assays can be carried out on organ cultures including histology, biochemistry, cell biology, and molecular biology, which will not be described in detail in this chapter. PMID- 24788175 TI - Analysis of TNF-alpha-mediated cerebral pericyte remodeling. AB - As well as being a central regulator of inflammatory and immune-mediated events, TNF-alpha also influences vascular remodeling, resulting in alterations in the structure and function of blood vessels. In addition to endothelial cells, pericytes are another type of vascular cell that significantly contribute to the development, maturation, stabilization, and remodeling of blood vessels. To investigate the regulatory influence of different factors on pericyte behavior, we recently described a novel yet simple approach of isolating and culturing highly pure, high density cultures of mouse brain pericytes. In this chapter, we briefly describe this culture system, as well as methods for examining different aspects of pericyte behavior, including cell adhesion, cell migration, and cell proliferation. These assays can be used to examine the influence of TNF-alpha or any other factor on pericyte behavior. PMID- 24788176 TI - CD137 in chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (GVHD) occurs in recipients of allogeneic hematopoietic stem cell transplantation with a high frequency. Preclinical animal chronic GVHD models outlined in this chapter allow for the delineation of events that occur during chronic GVHD development. The DBA/2 -> (C56BL/6 * DBA/2)F1 (BDF1) model is characterized by systemic lupus erythematosus (SLE)-like phenotype. The B10.D2 -> Balb/c model presents many features of autoimmune scleroderma. The former model is useful in defining how alloreactive donor CD4(+) T cells break B-cell tolerance, whereas the latter model is suitable for dissecting the pathogenesis of organ fibrosis. Our laboratory has demonstrated that injection of a single dose of strong CD137 agonists can prevent or cure chronic GVHD in these two models. In general, these models are particularly suited to screening the immunomodulatory therapeutics. PMID- 24788177 TI - In vitro investigation of the roles of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 in murine osteoclastogenesis. AB - Whereas the monocyte/macrophage-colony stimulating factor (M-CSF) and the receptor activator of NF-kB ligand (RANKL) are essential and sufficient for osteoclastogenesis, a number of other cytokines including two proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 (IL-1), can exert profound effects on the osteoclastogenic process. However, the precise mode of action of TNF-alpha and IL-1 in osteoclastogenesis remains controversial. While some groups demonstrated that these two cytokines can promote murine osteoclastogenesis in vitro in the presence of M-CSF only, we and others showed that TNF-alpha-/IL-1-mediated osteoclastogenesis requires permissive levels of RANKL. This chapter describes the method that we have used to investigate the effects of TNF-alpha and IL-1 on osteoclast formation in in vitro osteoclastogenesis assays using primary murine bone marrow macrophages (BMMs). Detailed experimental conditions are provided and critical points are discussed to help the reader use the method to independently evaluate the roles of TNF alpha and IL-1 in osteoclastogenesis in vitro. Moreover, this method can be used to further elucidate the signaling mechanisms by which these two cytokines act in concert with RANKL or with each other to modulate osteoclastogenesis. PMID- 24788178 TI - Evasion of TNF-alpha-mediated apoptosis by hepatitis C virus. AB - Hepatitis C virus (HCV) often causes chronic infection in humans, although the mechanisms for viral chronicity are not clearly understood. Tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis is a key element in a host organism's defense inhibiting viral spread and persistence. HCV has evolved mechanisms that antagonize host cell death signals so that virus propagation can continue unabated in infected cells. HCV core protein blocks TNF-alpha-mediated apoptosis signaling and inhibits caspase-8 activation by sustaining the expression of cellular FADD-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory protein (c-FLIP). HCV core protein also blocks TNF-induced proteolytic cleavage of the death substrate poly (SDP-ribose) polymerase from its native 116-kDa protein to the characteristic 85-kDa polypeptide. A decrease in endogenous c-FLIP by specific small-interfering RNA induces TNF-alpha-mediated apoptotic cell death and caspase-8 activation. However, HCV core neither affects the association between TNF receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD) nor TRADD-Fas-associated death domain protein (FADD) and procaspase-8. Thus, HCV core protein appears to play a role in the inhibition of TNF-alpha-mediated cell death. This chapter describes methods to identify inhibitory mechanism of HCV for TNF-alpha-mediated apoptosis. PMID- 24788179 TI - TNF-alpha modulates TLR2-dependent responses during mycobacterial infection. AB - Multifunctional roles of tumor necrosis factor-alpha (TNF-alpha) during the mycobacterial pathogenesis make it an important molecule to understand and to examine the course of infection. Identification and analysis of TNF-alpha response can largely contribute to determine the potential host mediators for therapeutic intervention against tuberculosis. The current chapter describes several methods to assess the ability of TNF-alpha signaling to modulate toll like receptor (TLR)2 signaling, another key player in mycobacterial infection and its responses. Experiments involving neutralizing antibodies, antagonists, pharmacological inhibitors, and siRNA-mediated gene silencing are discussed in this chapter to establish the role of TNF-alpha signaling. The widely used protein and mRNA analysis readouts like enzyme-linked immunosorbent assay (ELISA), immunoblotting, fluorescence-activated cell sorting (FACS), and quantitative real-time RT-PCR are useful to estimate and confirm the mediators involved in TNF-alpha and TLR2 signaling. PMID- 24788180 TI - Experimental applications of TNF-reporter mice with far-red fluorescent label. AB - This chapter provides protocols for in vitro and in vivo analysis of TNF producing cells from a novel TNF reporter mouse. In these transgenic mice, genetic sequence encoding far-red reporter protein Katyushka (FRFPK) was placed under control of the same regulatory elements as TNF, thus providing the basis for detection, isolation, and visualization of TNF-producing cells. PMID- 24788181 TI - A solid-phase assay for studying direct binding of progranulin to TNFR and progranulin antagonism of TNF/TNFR interactions. AB - The discovery that TNF receptors (TNFR) serve as the binding receptors for progranulin (PGRN) reveals the significant role of PGRN in inflammatory and autoimmune diseases, including inflammatory arthritis. Herein we describe a simple, antibody-free analytical assay, i.e., a biotin-based solid-phase binding assay, to examine the direct interaction of PGRN/TNFR and the PGRN inhibition of TNF/TNFR interactions. Briefly, a 96-well high-binding microplate is first coated with the first protein (protein A), and after blocking, the coated microplate is incubated with the biotin-labeled second protein (protein B) in the absence or presence of the third protein (protein C). Finally the streptavidin conjugated with a detecting enzyme is added, followed by a signal measurement. Also discussed in this chapter are the advantages of the strategy, key elements to obtain reliable results, and discrepancies among various PGRN proteins in view of the binding activity with TNFR. PMID- 24788182 TI - Compartment-specific flow cytometry for the analysis of TNF-mediated recruitment and activation of glomerular leukocytes in murine kidneys. AB - Cytokines of the TNF superfamily, particularly TNF itself, are important mediators of inflammatory leukocyte recruitment and activation in parenchymal organs. In inflammatory kidney diseases, leukocytes accumulate in glomeruli and the tubulointerstitium, leading to glomerulonephritis and tubulointerstitial nephritis, respectively. In particular, glomeruli can be the target of organ threatening leukocyte-mediated inflammation. As microvasculatures of the glomerulus and the tubulointerstitium differ markedly in their structural and functional properties, recruitment and subsequent activation of leukocytes to these sites occur via distinct mechanisms. To understand the pathways and mediators of leukocyte-driven inflammation in the kidney it is therefore essential to analyze glomerular and tubulointerstitial leukocyte recruitment in a compartment-specific way. The protocol presented here describes an easy and rapid technique that allows compartment-specific quantitation and qualitative analysis of leukocytes present in glomeruli and tubulointerstitial tissue by flow cytometry after separation of these tissue compartments. PMID- 24788183 TI - Determination of soluble tumor necrosis factor receptor 2 produced by alternative splicing. AB - Soluble cytokine receptors have proven to be very useful biomarkers in a large variety of diseases, including cancer, infections, and chronic inflammatory diseases. These soluble receptors are produced by proteolytic cleavage or alternative splicing. Several cytokine receptors including tumor necrosis factor receptor 2 (TNFR2) can be generated by both mechanisms. However, the conventional ELISA systems do not differentiate between these two types of soluble receptors. We describe a sandwich ELISA to specifically quantify soluble TNFR2 protein generated by alternative splicing. This method requires the use of a capturing monoclonal antibody (mAb) specific of an epitope present in the soluble TNFR2 generated by alternatively splicing but absent in the proteolytically generated isoform. Here we present a detailed protocol for the production and validation of such a mAb. This method has the potential to be applied for measuring other soluble cell surface molecules generated by alternative splicing. PMID- 24788184 TI - Effective expression and purification of bioactive recombinant soluble LIGHT. AB - LIGHT (TNFSF14, CD258) is a member of the tumor necrosis factor (TNF) ligand superfamily, which is involved in innate and adaptive immune responses as well as in regulation of cell survival and proliferation. LIGHT forms a membrane-anchored homotrimeric complex on the cell surface and is often processed as a soluble protein. In this study, we established an effective strategy for producing bioactive soluble forms of human LIGHT (s-hLIGHT), which is an extracellular region (Ile(84)-Val(240)) of human LIGHT (hLIGHT), and soluble forms of mouse LIGHT (s-mLIGHT), which is an extracellular region (Asp(72)-Val(239)) of mouse LIGHT (mLIGHT). To enhance the refolding of s-hLIGHT from inclusion bodies in Escherichia coli, we added L-cysteine to the denaturation buffer, which significantly improved the refolding efficiency of s-hLIGHT. However, there was little information available about the biological activity of mLIGHT in the literature because of the difficulty in producing bioactive s-mLIGHT. We produced trimeric s-mLIGHT by fusing s-mLIGHT with a trimerization domain termed "foldon" from bacteriophage T4 fibritin (Foldon-mLIGHT). We further demonstrated that Foldon-mLIGHT inhibited the growth of mouse carcinoma cells at the picomolar range, indicating that trimerization of s-mLIGHT is essential for its biological activity. PMID- 24788185 TI - One of the TNF superfamily members: bifunctional protein, TNFR2-Fc-IL-1ra. AB - Many anti-inflammatory agents have been exploited for the treatment of inflammatory diseases by targeting the most potent proinflammatory cytokines including tumor necrosis factor (TNF) and interleukin-1 (IL-1). Theoretically, simultaneous neutralization or blocking two important inflammatory mediators might achieve a synergistic therapeutic effect. A recombinant fusion protein, TNFR2-Fc-IL-1ra (TFI), was developed as bifunctional inflammatory inhibitor. TFI was able to strongly neutralize TNF activity and to antagonize IL-1 receptor in the cell binding inhibition assays, suggesting that TFI could be used as a bifunctional ligand with enhanced anti-inflammatory effect. PMID- 24788186 TI - Tetraphosphonated thiophene ligand: mixing the soft and the hard. AB - The synthesis of ligand L(T)H8, based on a thiophene framework containing two bis(aminomethyldiphosphonate) functions in the ortho position to the central sulfur atom, is described, together with the characterization of the intermediate compounds. The physico-chemical properties of the ligand were first studied by means of potentiometry and UV-Vis absorption spectrophotometric titrations to determine its pK values. Six successive equilibrium constants were determined in aqueous solutions. The same means were then used to quantify the interactions of the ligand with Ni(II), Cu(II) and Zn(II). Following the conventional Irving Williams trend, L(T) was shown to have the highest affinity towards Cu(II) (log K(CuL(T)) = 16.11(3)), while Zn(II) and Ni(II) showed similar values (log K(ML(T)) = 10.81(8) and 10.9(1), respectively), revealing a large selectivity of L(T) toward Cu(II). Based on a combination of UV-Vis absorption spectroscopy and EPR measurements as a function of pH, along with DFT calculations, the coordination behavior of the hard phosphonate, medium amino and soft thiophene entities are questioned regarding their coordination to the Cu atom. PMID- 24788187 TI - Arthroscopic treatment of pigmented villonodular synovitis of the proximal tibiofibular joint. AB - Disorders of the proximal tibiofibular joint should be kept in mind in the evaluation of lateral knee pain. They include osteoarthrosis, rheumatic disease, traumatic subluxation or dislocation, ganglion or synovial cysts, synostosis, synovial chondromatosis, pigmented villonodular synovitis and hypomobility of the joint. Peroneal nerve can be at risk with pathologies of the joint either by compressive effect or formation of intra-neural ganglion. A case of pigmented villonodular synovitis of the proximal tibiofibular joint was reported which presented with lateral knee pain. It was successfully treated by arthroscopic synovectomy. Level of evidence V. PMID- 24788188 TI - Urologic manifestations of Erdheim-Chester disease. AB - OBJECTIVE: To describe the urologic manifestations of Erdheim-Chester disease (ECD). ECD is a rare multisystem disorder of non-Langerhans cell histiocytosis. In addition to classic long bone involvement, the retroperitoneum is a well established site of disease infiltration. Herein, we present the urologic manifestations and outcomes of ECD in a large series of patients. METHODS: We identified 47 patients diagnosed with ECD between 1996 and 2012 at our institution. The medical records and imaging for these patients were reviewed for urologic involvement, including perirenal soft tissue encasement, renal atrophy, hydronephrosis, chronic renal insufficiency, diabetes insipidus, and lower urinary tract symptoms. RESULTS: At diagnosis, the median patient age was 57 years (interquartile range 49, 68), and median follow-up after diagnosis was 3 years (interquartile range 1.8, 7.3). There were 31 male patients (66%) and 16 female patients (34%). The majority of these patients (37, 79%) demonstrated evidence of urologic involvement from ECD, requiring urologic surgery in 13 (28%). This urologic involvement included retroperitoneal infiltration (28, 60%), worsening lower tract urinary symptoms from diabetes insipidus (21, 45%), hydronephrosis (10, 21%), and chronic kidney disease (18, 38%). CONCLUSION: The incidence of urologic involvement with ECD is higher than previously reported in the published data. Urologists should be aware of this disorder, as it might mimic other retroperitoneal diseases and might contribute to lower urinary tract symptoms, hydronephrosis, renal atrophy, and chronic kidney disease. PMID- 24788190 TI - Influence of oxygen tension on dopaminergic differentiation of human fetal stem cells of midbrain and forebrain origin. AB - Neural stem cells (NSCs) constitute a promising source of cells for transplantation in Parkinson's disease (PD), but protocols for controlled dopaminergic differentiation are not yet available. Here we investigated the influence of oxygen on dopaminergic differentiation of human fetal NSCs derived from the midbrain and forebrain. Cells were differentiated for 10 days in vitro at low, physiological (3%) versus high, atmospheric (20%) oxygen tension. Low oxygen resulted in upregulation of vascular endothelial growth factor and increased the proportion of tyrosine hydroxylase-immunoreactive (TH-ir) cells in both types of cultures (midbrain: 9.1 +/- 0.5 and 17.1 +/- 0.4 (P<0.001); forebrain: 1.9 +/- 0.4 and 3.9 +/- 0.6 (P<0.01) percent of total cells). Regardless of oxygen levels, the content of TH-ir cells with mature neuronal morphologies was higher for midbrain as compared to forebrain cultures. Proliferative Ki67-ir cells were found in both types of cultures, but the relative proportion of these cells was significantly higher for forebrain NSCs cultured at low, as compared to high, oxygen tension. No such difference was detected for midbrain-derived cells. Western blot analysis revealed that low oxygen enhanced beta-tubulin III and GFAP expression in both cultures. Up regulation of beta-tubulin III was most pronounced for midbrain cells, whereas GFAP expression was higher in forebrain as compared to midbrain cells. NSCs from both brain regions displayed less cell death when cultured at low oxygen tension. Following mictrotransplantation into mouse striatal slice cultures predifferentiated midbrain NSCs were found to proliferate and differentiate into substantial numbers of TH-ir neurons with mature neuronal morphologies, particularly at low oxygen. In contrast, predifferentiated forebrain NSCs microtransplanted using identical conditions displayed little proliferation and contained few TH-ir cells, all of which had an immature appearance. Our data may reflect differences in dopaminergic differentiation capacity and region-specific requirements of NSCs, with the dopamine-depleted striatum cultured at low oxygen offering an attractive micro-environment for midbrain NSCs. PMID- 24788191 TI - Induction of E-cadherin+ human amniotic fluid cell differentiation into oocyte like cells via culture in medium supplemented with follicular fluid. AB - Pluripotent human amniotic fluid cells (HuAFCs) can differentiate into various types of somatic cell in vitro. However, their differentiation into oocyte-like cells has never been described to the best of our knowledge. In the present study, differentiation of E-cadherin+ and E-cadherin- HuAFC sub-populations into oocyte-like cells was induced via culture in medium containing bovine follicular fluid and beta-mercaptoethanol. The E-cadherin+ HuAFCs expressed DAZL highly. Post-induction, cells with an oocyte-like phenotype were found among the E cadherin+ HuAFCs, expressing markers specific to germ cells and oocytes (VASA, ZP3 and GDF9) and meiosis (DMC1 and SCP3). When specific small interfering RNA (siRNA) was used to suppress E-cadherin in the E-cadherin+ HuAFCs, the levels of DAZL expression were reduced. Post-induction, the morphology of the siRNA-E cadherin HuAFCs was poorer and the expression levels of germ cell-specific markers were lower compared with those of the siRNA-mock HuAFCs. Therefore, E cadherin+ HuAFCs could be more easily induced to differentiate into oocyte-like cells by bovine follicular fluid and beta-mercaptoethanol. In addition, the E cadherin+ HuAFCs exhibited potential characteristics of DAZL protein expression, and thus it was conjectured that bovine follicular fluid acts on DAZL protein and promotes E-cadherin+ HuAFC differentiation into oocyte-like cells. PMID- 24788192 TI - Effect of umbilical cord serum coated 3D PCL/alginate scaffold for mastoid obliteration. AB - OBJECTIVE: Human umbilical cord serum (hUCS) has a lot of growth factors. To date, there are no reports on stimulating effect of hUCS in osteogenesis. The purpose of this study is to evaluate enhancing effect of hUCS in osteogenesis by mastoid obliteration combined with bony scaffold. MATERIALS AND METHODS: The fabrication procedure for obtaining PCL/alginate/hUCS was performed. The bulla obliteration was done using PCL/alginate/hUCS in the experimental group and PCL in the control group. To assess the early active mineralization of new bone formation, guinea pigs of each group received an intraperitoneal infusion with alizarin red at 6 weeks post-surgery. The animals of each group were sacrificed 8 weeks post-surgery. Ex vivo microCT and histologic observation were performed. RESULTS: MicroCT finding shows more radiopaque change within the pores in the experimental group compared to the control group. Stereomicroscopic and SEM findings show new bone formation of the pores in the experimental group. However, the pores between strands almost all remained in the control group. Corresponding histological observations for the stimulatory effects of hUCS showed osteogenesis in the pores between the strands compared to the control group. CONCLUSION: Our data suggest that hUCS coated 3D porous PCL scaffold in mastoid obliteration provides enhanced osteogenesis. Therefore, we suggest that our hUCS coated 3D porous PCL could be used in mastoid obliteration in the future. PMID- 24788193 TI - [Direct anticoagulants for atrial fibrillation. Update 2014]. AB - For several decades vitamin K antagonists (VKA) were the standard for stroke prevention in atrial fibrillation. Because of inconvenience associated with their use (frequently VKA levels cannot be consistently maintained within the therapeutic range, e.g. due to food and drug interactions, which necessitates regular control of international normalized ratios) alternative compounds have recently been developed, the direct oral anticoagulants (DOACs) dabigatran (a direct antithrombin) as well as rivaroxaban, apixaban and edoxaban (direct factor Xa inhibitors). All these agents show a predictable pharmacokinetic profile making routine laboratory controls unnecessary. Moreover, DOACs do not only show a similar or even better efficacy, but also a more attractive safety profile in terms of similar or less major bleeding complications, where all DOACs significantly reduce the rate of intracranial bleeding when compared to VKAs. This review summarizes the pharmacological characteristics and clinical study results of DOACs that have been tested in phase 3 trials. PMID- 24788194 TI - Attitudes towards potentially carrying the FMR1 premutation: before vs after testing of non-carrier females with diminished ovarian reserve. AB - Diminished ovarian reserve (DOR) and premature ovarian failure are associated with elevated FMR1 CGG repeat alleles. We assessed pretest attitudes about potentially carrying the FMR1 premutation (FXP) (>55 CGG repeats) among reproductive age women compared with attitudes after learning their non-carrier status. Ninety-two women with DOR, regular menses and no family history of Fragile X Syndrome underwent FMR1 testing and completed attitudinal questionnaires before (T1) and 3 months after learning the test results (T2). The analysis utilized signed rank tests and alpha = 0.05. Very few women thought they were likely to have a FXP (6.6%). More participants thought FMR1 premutations were "serious" at T2 (62.9%) than at T1 (46.1%, p < 0.0003). When asked at T1 to "describe your feelings when you consider that you are potentially a carrier" of a FXP, 10% had negative feelings, 50% felt ambivalent, and 40% had positive feelings. At T2, feelings about not being a carrier were significantly more favorable (p < 0.0001): negative (0%), ambivalent (6.5%), positive (93%). Corroborating prior reports, few women had a negative view of FXP, perhaps anticipating that carrying the FXP explains their infertility. Perception of the seriousness of FXP increased after learning they did not carry the FXP, which would be predicted by health belief models. PMID- 24788195 TI - Barriers impacting the utilization of supervision techniques in genetic counseling. AB - Clinical supervision is an essential element in training genetic counselors. Although live supervision has been identified as the most common supervision technique utilized in genetic counseling, there is limited information on factors influencing its use as well as the use of other techniques. The purpose of this study was to identify barriers supervisors face when implementing supervision techniques. All participants (N = 141) reported utilizing co-counseling. This was most used with novice students (96.1%) and intermediate students (93.7%). Other commonly used techniques included live supervision where the supervisor is silent during session (98.6%) which was used most frequently with advanced students (94.0%), and student self-report (64.7%) used most often with advanced students (61.2%). Though no barrier to these commonly used techniques was identified by a majority of participants, the most frequently reported barriers included time and concern about patient's welfare. The remaining supervision techniques (live remote observation, video, and audio recording) were each used by less than 10% of participants. Barriers that significantly influenced use of these techniques included lack of facilities/equipment and concern about patient reactions to technique. Understanding barriers to implementation of supervisory techniques may allow students to be efficiently trained in the future by reducing supervisor burnout and increasing the diversity of techniques used. PMID- 24788196 TI - Client views and attitudes to non-invasive prenatal diagnosis for sickle cell disease, thalassaemia and cystic fibrosis. AB - In the near future the availability of non-invasive prenatal diagnosis (NIPD) for single gene disorders will change the prenatal diagnosis options available to couples who are carriers of conditions such as cystic fibrosis, sickle cell disorder and thalassaemia. Client opinions about NIPD are needed to inform the implementation of NIPD for single gene disorders. This qualitative study used two focus groups (n = 12) and one-to-one interviews (n = 16) with carriers and support group representatives of sickle cell disease, thalassaemia and cystic fibrosis. Discussions were digitally recorded, transcribed verbatim and analysed using thematic analysis. Opinions about NIPD were very positive and participants valued the opportunity to have safe and early testing. Uptake of prenatal testing is likely to increase as women who had previously declined invasive testing expressed interest in having NIPD. Participant concerns about NIPD centred on the need for accuracy to be high to be used for subsequent decision making about termination of pregnancy. Participants also raised concerns that less thought may be given to having a blood test compared to an invasive test and that the perceived ease of a blood test may bring increased pressure to have testing. Participants thought NIPD should be offered through existing specialist services to ensure appropriate genetic counseling and support. Maintaining all testing options is important as some people may prefer invasive testing over NIPD if invasive testing was more accurate or if invasive testing could give information about other conditions such as Down syndrome. PMID- 24788197 TI - Influence of molting and starvation on digestive enzyme activities and energy storage in Gammarus fossarum. AB - Among the many biological responses studied in ecotoxicology, energy-based biomarkers such as digestive enzyme activities and energy reserves appear to be useful predictive tools for detecting physiological disturbances in organisms. However, the use of these biological responses as biomarkers could be limited by the effects of confounding factors (biotic and abiotic) and physiological processes, such as the reproductive cycle. Thus, the optimal use of these biomarkers will be facilitated by understanding the effects of these factors on the energy metabolism of the sentinel species being studied. We considered abiotic factors (temperature and conductivity) in a previous study, whereas the present study investigated the effects of gender, the female reproductive stage, and food availability on the digestive enzyme activities and energy storage of Gammarus fossarum. The results indicated that, during the female reproductive cycle, the activities of digestive enzymes (amylase, cellulase, and trypsin) decreased significantly, whereas the levels of reserves (proteins, lipids, and sugar) increased until the last premolt stage. Restricted food diets only led to decreased amylase activities in both sexes. Food starvation also induced a decrease in the energy outcomes in females, whereas there were no effects in males. In general, the biochemical (digestive enzyme activities) and physiological (energy reserves) responses were more stable in males than in females. These results support the use of males fed ad libitum to limit the effects of confounding factors when using these energy biomarkers in Gammarus fossarum during biomonitoring programs. PMID- 24788198 TI - Increased periostin expression affects the proliferation, collagen synthesis, migration and invasion of keloid fibroblasts under hypoxic conditions. AB - Periostin, a secreted extracellular matrix protein, is involved in the wound healing and pathological process of various human cancers. Keloid scars are fibroproliferative tumor-like lesions and develop under local hypoxia. Using suppression subtractive hybridization, in a previous study, we found that periostin is overexpressed in keloids compared with hypertrophic scars. However, little is known about the regulation and function of periostin in keloids. In this study, we examined the effects of periostin on the bioactivity of keloid fibroblasts (KFs) in order to determine whether periostin is involved in hypoxia stimulated keloid pathogenesis by measuring the expression levels of periostin in KFs cultured under hypoxic conditions. We also investigated the association between periostin and hypoxia-inducible factor-1alpha (HIF-1alpha). The mRNA, intracellular protein and secreted protein level of periostin was examined by RT PCR (and quantitative PCR), western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. We also used shRNA targeting periostin to knockdown its expression in the KFs. We report that hypoxia (2% O(2)) upregulates both HIF 1alpha and periostin expression in KFs. In addition, hypoxia-upregulated periostin expression was regulated by HIF-1alpha. The inhibition of periostin by short hairpin RNA decreased the hypoxia-stimulated proliferation, collagen synthesis, migration and invasion of KFs and altered the cell cycle, but did not affect apoptosis; treatment with recombinant human periostin protein reversed these effects. Periostin also activated the alphavbeta3 integrin-PI3K/Akt pathway in the KFs. These findings suggest that hypoxia initiates hyperplasia of KFs and increases periostin expression under hypoxic conditions; periostin is involved in the pathogenesis of keloids, which indicates that periostin may be a novel therapeutic target for keloids and other fibroproliferative disorders. PMID- 24788199 TI - The effect of substrate elasticity and actomyosin contractility on different forms of endocytosis. AB - Substrate mechanical properties have emerged as potent determinants of cell functions and fate. We here tested the hypothesis that different forms of endocytosis are regulated by the elasticity of the synthetic hydrogels cells are cultured on. Towards this objective, we quantified cell-associated fluorescence of the established endocytosis markers transferrin (Tf) and cholera toxin subunit B (CTb) using a flow-cytometry based protocol, and imaged marker internalization using microscopy techniques. Our results demonstrated that clathrin-mediated endocytosis of Tf following a 10-minute incubation with a fibroblast cell line was lower on the softer substrates studied (5 kPa) compared to those with elasticities of 40 and 85 kPa. This effect was cancelled after 1-hour incubation revealing that intracellular accumulation of Tf at this time point did not depend on substrate elasticity. Lipid-raft mediated endocytosis of CTb, on the other hand, was not affected by substrate elasticity in the studied range of time and substrate elasticity. The use of pharmacologic contractility inhibitors revealed inhibition of endocytosis for both Tf and CTb after a 10-minute incubation and a dissimilar effect after 1 hour depending on the inhibitor type. Further, the internalization of fluorescent NPs, used as model drug delivery systems, showed a dependence on substrate elasticity, while transfection efficiency was unaffected by it. Finally, an independence on substrate elasticity of Tf and CTb association with HeLa cells indicated that there are cell-type differences in this respect. Overall, our results suggest that clathrin-mediated but not lipid-raft mediated endocytosis is potentially influenced by substrate mechanics at the cellular level, while intracellular trafficking and accumulation show a more complex dependence. Our findings are discussed in the context of previous work on how substrate mechanics affect the fundamental process of endocytosis and highlight important considerations for future studies. PMID- 24788200 TI - MicroPure imaging for the evaluation of microcalcifications in gouty arthritis involving the first metatarsophalangeal joint: a preliminary study. AB - OBJECTIVE: To assess the value of MicroPure, a new ultrasound image processing technique, in identifying microcalcifications (formed by monosodium urate crystals) in the first metatarsophalangeal joints attacked by gout compared to gray-scale ultrasound images. MATERIALS AND METHODS: Thirty-six patients who fulfilled the study inclusion criteria underwent gray-scale ultrasound and MicroPure examinations of the first metatarsophalangeal joints attacked by gout. Static images of the target areas were acquired using gray-scale ultrasound and MicroPure. Two independent and blinded investigators analyzed the images to determine the number of microcalcifications and to score for image quality and artifacts. RESULTS: The two investigators observed significantly more microcalcifications with MicroPure compared to gray-scale ultrasound (rho<0.001). The level of agreement between the investigators consistently increased from gray scale ultrasound to MicroPure imaging (gray-scale interclass correlation coefficient of 0.69 vs. MicroPure interclass correlation coefficient of 0.81). One investigator preferred the MicroPure image quality over gray-scale ultrasound (rho<0.001), but the other investigator disagreed (rho<0.001). Both investigators observed fewer artifacts with MicroPure than with gray-scale ultrasound (rho<0.009). CONCLUSION: MicroPure imaging identified significantly more microcalcifications than gray-scale ultrasound. PMID- 24788201 TI - Rectal mucosal prolapse in males: surgery is effective for fecal incontinence but not for obstructed defecation. AB - BACKGROUND: The aim of this prospective study was to evaluate the functional outcome of transanal surgery in male patients suffering from fecal incontinence, soiling, and obstructed defecation associated with rectal mucosal prolapse. METHODS: All male patients who underwent transanal surgery (either stapled or Delorme mucosectomy) for rectal mucosal prolapse associated with fecal incontinence and obstructed defecation were prospectively enrolled in the study. The recruitment phase was 17 months (April 2011 to August 2012). Symptom evaluation was based on the validated scores preoperatively and 12 months after surgery (Wexner incontinence score and Wexner constipation score). The primary end point was "success," which was defined as a 50 % reduction in symptoms. Using a decision-tree algorithm, patient groups with the highest and lowest chance of success were identified. RESULTS: Thirty-eight male patients (mean age 51 years) underwent transanal surgery for rectal mucosal prolapse. The predominant symptoms were fecal incontinence in 31 patients (82 %) and obstructed defecation in 7 (18 %). Stapled mucosectomy was performed in 34 patients and Delorme mucosectomy in 4 patients. No major morbidity occurred. Symptom resolution for soiling was 77 %, itching and mucus secretion were improved in 47 and 50 %, and bleeding resolved in 89 % of patients affected. Functional outcome was good in 90 % (28/31) of the patients with fecal incontinence but in only 28 % (2/7) for obstructed defecation. The Wexner incontinence score decreased significantly (11.1 vs. 3.9, p < 0.01), whereas the Wexner constipation score was not influenced (18.4 vs. 15.6, p > 0.05). Using a decision-tree algorithm, a success rate of 96 % was observed in patients with fecal incontinence associated with younger age (age <45 years) and no presence of fecal urgency prior to surgery. CONCLUSIONS: Transanal stapled mucosectomy for rectal mucosal prolapse in males is effective for fecal incontinence, but not for obstructed defecation. PMID- 24788202 TI - Development and application of serine/threonine ligation for synthetic protein chemistry. AB - Chemical synthesis of proteins, especially those with post-translational modifications, has offered new opportunities to study the protein structure function relationship. In the past four years, we have developed the serine/threonine ligation (STL), which involves the chemoselective reaction between peptide salicylaldehyde esters and peptides with N-terminal serine or threonine. The method has been successfully applied to the synthesis of both linear and cyclic peptides/proteins. PMID- 24788203 TI - Female reproductive aging is master-planned at the level of ovary. AB - The ovary receives a finite pool of follicles during fetal life. Atresia remains the major form of follicular expenditure at all stages since development of ovary. The follicular reserve, however, declines at an exponential rate leading to accelerated rate of decay during the years preceding menopause. We examined if diminished follicle reserve that characterizes ovarian aging impacts the attrition rate. Premature ovarian aging was induced in rats by intra-embryonic injection of galactosyltransferase-antibody on embryonic day 10. On post-natal day 35 of the female litters, either a wedge of fat (sham control) or a wild type ovary collected from 25-day old control rats, was transplanted under the ovarian bursa in both sides. Follicular growth and atresia, and ovarian microenvironment were evaluated in the follicle-deficient host ovary and transplanted ovary by real time RT-PCR analysis of growth differentiation factor-9, bone morphogenetic protein 15, and kit ligand, biochemical evaluation of ovarian lipid peroxidation, superoxide dismutase (SOD) and catalase activity, and western blot analysis of ovarian pro- and anti-apoptotic factors including p53, bax, bcl2, and caspase 3. Results demonstrated that the rate of follicular atresia, which was highly preponderant in the follicle-deficient ovary of the sham-operated group, was significantly prevented in the presence of the transplanted ovary. As against the follicle-deficient ovary of the sham-operated group, the follicle-deficient host ovary as well as the transplanted ovary in the ovary-transplanted group exhibited stimulated follicle growth with increased expression of anti-apoptotic factors and down regulation of pro-apoptotic factors. Both the host and transplanted ovaries also had significantly lower rate of lipid peroxidation with increased SOD and catalase activity. We conclude that the declining follicular reserve is perhaps the immediate thrust that increases the rate of follicle depletion during the final phase of ovarian life when the follicle reserve wanes below certain threshold size. PMID- 24788204 TI - Fine mapping of qRC10-2, a quantitative trait locus for cold tolerance of rice roots at seedling and mature stages. AB - Cold stress causes various injuries to rice seedlings in low-temperature and high altitude areas and is therefore an important factor affecting rice production in such areas. In this study, root conductivity (RC) was used as an indicator to map quantitative trait loci (QTLs) of cold tolerance in Oryza rufipogon Griff., Dongxiang wild rice (DX), at its two-leaf stage. The correlation coefficients between RC and the plant survival rate (PSR) at the seedling and maturity stages were -0.85 and -0.9 (P = 0.01), respectively, indicating that RC is a reliable index for evaluating cold tolerance of rice. A preliminary mapping group was constructed from 151 BC2F1 plants using DX as a cold-tolerant donor and the indica variety Nanjing 11 (NJ) as a recurrent parent. A total of 113 codominant simple-sequence repeat (SSR) markers were developed, with a parental polymorphism of 17.3%. Two cold-tolerant QTLs, named qRC10-1 and qRC10-2 were detected on chromosome 10 by composite interval mapping. qRC10-1 (LOD = 3.1, RM171-RM1108) was mapped at 148.3 cM, and qRC10-2 (LOD = 6.1, RM25570-RM304) was mapped at 163.3 cM, which accounted for 9.4% and 32.1% of phenotypic variances, respectively. To fine map the major locus qRC10-2, NJ was crossed with a BC4F2 plant (L188-3), which only carried the QTL qRC10-2, to construct a large BC5F2 fine-mapping population with 13,324 progenies. Forty-five molecular markers were designed to evenly cover qRC10-2, and 10 markers showed polymorphisms between DX and NJ. As a result, qRC10-2 was delimited to a 48.5-kb region between markers qc45 and qc48. In this region, Os10g0489500 and Os10g0490100 exhibited different expression patterns between DX and NJ. Our results provide a basis for identifying the gene(s) underlying qRC10-2, and the markers developed here may be used to improve low-temperature tolerance of rice seedling and maturity stages via marker-assisted selection (MAS). KEY MESSAGE: With root electrical conductivity used as a cold-tolerance index, the quantitative trait locus qRC10-2 was fine mapped to a 48.5-kb candidate region, and Os10g0489500 and Os10g0490100 were identified as differently expressed genes for qRC10-2. PMID- 24788206 TI - Patient-centered imaging: more relevant (and perhaps more elusive) than ever. PMID- 24788205 TI - A pre-breeding screening program for transgenic boars based on fluorescence in situ hybridization assay. AB - For efficient transgenic herd expansion, only the transgenic animals that possess the ability to transmit transgene into next generation are considered for breeding. However, for transgenic pig, practically lacking a pre-breeding screening program, time, labor and money is always wasted to maintain non transgenic pigs, low or null transgenic transmission pigs and the related fruitless gestations. Developing a pre-breeding screening program would make the transgenic herd expansion more economical and efficient. In this technical report, we proposed a three-step pre-breeding screening program for transgenic boars simply through combining the fluorescence in situ hybridization (FISH) assay with the common pre-breeding screening workflow. In the first step of screening, combined with general transgenic phenotype analysis, FISH is used to identify transgenic boars. In the second step of screening, combined with conventional semen test, FISH is used to detect transgenic sperm, thus to identify the individuals producing high quality semen and transgenic sperm. In the third step of screening, FISH is used to assess the in vitro fertilization embryos, thus finally to identify the individuals with the ability to produce transgenic embryos. By this three-step screening, the non-transgenic boars and boars with no ability to produce transgenic sperm or transgenic embryos would be eliminated; therefore only those boars could produce transgenic offspring are maintained and used for breeding and herd expansion. It is the first time a systematic pre-breeding screening program is proposed for transgenic pigs. This program might also be applied in other transgenic large animals, and provide an economical and efficient strategy for herd expansion. PMID- 24788207 TI - Single-center experience in prostate fiducial marker placement: technique and midterm follow-up. AB - PURPOSE: To describe the technique, technical success, and complications of prostate fiducial marker implantation using transrectal ultrasound (US) guidance in patients undergoing image-guided radiation therapy. MATERIALS AND METHODS: A retrospective review was performed of patients who underwent fiducial marker placement from January 2010-April 2013. In each case, gold markers were placed in the prostate using transrectal US guidance. Computed tomography (CT) was performed after the procedure and evaluated to confirm correct placement. Technical success, complications, and development of symptoms during radiotherapy were reviewed. RESULTS: Transrectal US-guided fiducial marker placement was performed on 75 patients (mean age, 62 y; range, 48-79 y) with a mean Gleason score of 7.25 (range, 6-10). Fiducial marker placement was confirmed in the intended location of the prostate or prostate bed for 297 of 300 markers (99%) on follow-up CT imaging. Two markers were placed just outside the prostate capsule, and one marker was lost. Complications included sepsis (n = 1; 1.3%), self limiting perirectal or intraprostatic hemorrhage (n = 3; 4%), nausea (n = 1; 1.3%), transient hypotension (n = 1; 1.3%), epididymitis (n = 1; 1.3%), and urinary tract infection (n = 1; 1.3%). Complications were seen more frequently in patients with high tumor grade (P = .001) and in patients who developed metastatic disease (P = .01). CONCLUSIONS: Transrectal US-guided implantation of fiducial markers is technically feasible, is well tolerated, and has a good safety profile. PMID- 24788208 TI - Health care reform in the United States: an opportunity for interventional radiologists. PMID- 24788209 TI - Comparison of polyvinyl alcohol microspheres and tris-acryl gelatin microspheres for uterine fibroid embolization: results of a single-center randomized study. AB - PURPOSE: To assess the efficacy of two embolic agents in the treatment of symptomatic uterine leiomyomas. MATERIALS AND METHODS: A randomized, prospective, single-center study enrolled 60 women with symptomatic uterine leiomyomas. Uterine artery embolization (UAE) with spherical polyvinyl alcohol (SPVA) microspheres (n = 30; 700-900 MUm and 900-1,200 MUm; near-stasis or stasis endpoint) and tris-acryl gelatin (TAG) microspheres (n = 30; 500-700 MUm; "pruned tree" endpoint) was performed. Infarction rates were calculated for the dominant tumor and for small (< 2 cm) and large (> 2 cm) nondominant tumors. The primary endpoint was tumor infarction at 24 hours measured by contrast-enhanced magnetic resonance imaging assessed by a blinded reviewer. RESULTS: Baseline characteristics were similar between groups. The primary endpoint was similar in both treatments (>= 91% dominant tumor infarction; SPVA. 86.2%; TAG, 93.3%, P = .35). Complete infarction (100%) was also similar between arms at 24 hours and 3 months. Symptom severity was reduced and quality of life improved equally at 3 and 12 months in each treatment group. Complications were minor in both groups. CONCLUSIONS: Uterine leiomyoma infarction at 24 hours and 3 months after treatment with SPVA or TAG microspheres was comparable when using near-stasis as a procedural endpoint with SPVA microspheres. Symptom relief was maintained for as long as 12 months for both embolic agents. PMID- 24788210 TI - Purposeful creation of a pneumothorax and chest tube placement to facilitate CT guided coil localization of lung nodules before video-assisted thoracoscopic surgical wedge resection. AB - PURPOSE: To evaluate the feasibility and efficacy of pneumothorax creation and chest tube insertion before computed tomography (CT)-guided coil localization of small peripheral lung nodules for video-assisted thoracoscopic surgical (VATS) wedge resection. MATERIALS AND METHODS: From May 2011 to October 2013, 21 consecutive patients (seven men; mean age, 62 y; range, 42-76 y) scheduled for VATS wedge resection required CT-guided coil localization for small, likely nonpalpable peripheral lung lesions at a single institution. Outcomes were evaluated retrospectively for technical success and complications. RESULTS: There were 12 nodules and nine ground-glass opacities. Mean lesion distance from the pleural surface was 15 mm (range, 5-35 mm), and average size was 13 mm (range, 7 30 mm). A pneumothorax was successfully created in all patients with a Veress needle, and a chest tube was inserted. All target lesions were marked successfully, leaving one end of the coil within/beyond the lesion and the other end of the coil in the pleural space. The inserted chest tube was used to insufflate air to widen the pleural space during coil positioning and to aspirate any residual air before transfer of the patient to the operating room holding area. Intraparenchymal hemorrhages smaller than 7 cm in diameter developed in two patients during coil placement. All lesions were successfully resected with VATS. Histologic examinaiton revealed 13 primary adenocarcinomas, four metastases, and four benign lesions. CONCLUSIONS: Pneumothorax creation and chest tube placement before CT-guided coil localization of peripheral lung nodules for VATS wedge resection facilitates the deployment of the peripheral end of the coil in the pleural space and provides effective management of procedure-related pneumothorax until surgery. PMID- 24788211 TI - Differential responses of the whitefly Bemisia tabaci symbionts to unfavorable low and high temperatures. AB - The whitefly Bemisia tabaci complex contains many cryptic species, of which the Middle East-Asia Minor 1 (MEAM1) and Mediterranean (MED) are notorious invasive pests. In our field-collected whitefly samples, MEAM1 harbors an obligate primary symbiont "Candidatus Portiera aleyrodidarum" and two secondary symbionts, "Candidatus Hamiltonella defensa" and Rickettsia sp., whereas MED has only "Ca. Portiera aleyrodidarum" and "Ca. Hamiltonella defensa." Both "Ca. Portiera aleyrodidarum" and "Ca. Hamiltonella defensa" are intracellular endosymbionts residing in the bacteriomes, whereas Rickettsia sp. has a scattered distribution throughout the host body cavity. We examined responses of these symbionts to adverse temperatures as well as survival of the host insects. After cold treatment at 5 or 10 degrees C or heat treatment at 35 or 40 degrees C for 24 h, respectively, the infection rates of all symbionts were not significantly decreased based on diagnosis PCR. However, quantitative PCR assays indicated significant reduction of "Ca. Hamiltonella defensa" at 40 degrees C, and the reduction became greater as the duration increased. Compared with "Ca. Hamiltonella defensa," "Ca. Portiera aleyrodidarum" was initially less affected in the first day but then showed more rapid reduction at days 3-5. The density of Rickettsia sp. fluctuated but was not reduced significantly at 40 degrees C. Meanwhile, the mortality rates of the host whiteflies elevated rapidly as the duration of exposure to heat treatment increased. The differential responses of various symbionts to adverse temperatures imply complex interactions among the symbionts inside the same host insect and highlight the importance of taking the whole bacterial community into account in studies of symbioses. PMID- 24788212 TI - Chemical castration of Danish sex offenders. PMID- 24788213 TI - Prognostic impact of the number of viable circulating cells with high telomerase activity in gastric cancer patients: a prospective study. AB - The identification of circulating tumor cells (CTCs) in peripheral blood is a useful approach to estimate prognosis, monitor disease progression and measure treatment effects in several types of malignancies. We have previously used OBP 401, a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein (GFP) gene. GFP-positive cells (GFP+ cells) were counted under a fluorescence microscope. Our results showed that the number of at least 7.735 um in diameter GFP+ cells (L-GFP+ cells) in the peripheral blood was a significant marker of prognosis in gastric cancer patients. However, tumor cells undergoing epithelial-mesenchymal transition (EMT) have been reported to be smaller in size than cells without EMT features; thus, CTCs undergoing EMT may escape detection with this technique. Therefore, in this study, we analyzed the relationship between patient outcome and the number of GFP+ cells of any size. We obtained peripheral blood samples from 65 patients with gastric cancer. After infection of OBP-401, GFP+ cells were counted and measured. The relationship between the number of GFP+ cells and surgical outcome was analyzed. The median follow-up period of the surviving patients was 36 months. A significant difference in overall survival was found between patients with 0-5 and patients with >=6 L-GFP+ cells. No clear relationship was established between the number of small-sized GFP+ cells and patient prognosis. The number of L-GFP+ cells was significantly related to overall survival in patients with gastric cancer. The detection of L-GFP+ cells using OBP-401 may be a useful prognostic marker in gastric cancer. PMID- 24788214 TI - Solvent-responsive properties of octadecyltrichlorosiloxane nanostructures investigated using atomic force microscopy in liquid. AB - An emerging challenge for nanoscale measurements is to capture and quantify the magnitude of structural changes in response to environmental changes. Certain environmental parameters can affect the nanoscale morphology of samples, such as changing the pH, solvent polarity, ionic strength, and temperature. We prepared test platforms of n-octadecyltrichlorosilane ring nanostructures to study surface morphology changes at the nanoscale in selected liquid media compared to dry conditions in air. Particle lithography combined with organosilane vapor deposition was used to fabricate nanostructures of regular dimensions. Multilayer nanostructures of OTS were used as a test platform for scanning probe studies of solvent-responsive properties where the sides of designed ring structures expose a 3D interface for studying the interaction of solvents with molecular side groups. In dry, ambient conditions, nanostructures of OTS were first imaged using contact mode atomic force microscopy (AFM). Next, ethanol or buffer was introduced to the sample cell, and images were acquired using the same probe. We observed substantial changes in the lateral and vertical dimensions of the ring nanostructures in AFM topography frames; the sizes of the rings were observed to swell by tens of nanometers. Even after heat treatment of samples to promote cross-linking, the samples still evidenced swelling in liquid media. This research will have consequences for studies of the properties of nanomaterials, such as solvent-responsive organic films and polymers. PMID- 24788215 TI - The effect of immunomodulators and biologics on indication for surgical bowel resection in children with Crohn's disease. AB - BACKGROUND: Despite advances in medical therapies, many children with Crohn's disease (CD) will require bowel resection. Although previous registry studies have attempted to identify risk factors for surgery, the effect of immunomodulators and biologics (IMB) on surgical indications has not been well characterized. METHODS: We reviewed a series of 125 children with CD who underwent bowel resection with reanastomosis between 1977 and 2011 and were followed up for at least 6 months. We compared patients who underwent surgery for perforating disease (abscess or internal fistula) and patients who were operated on for medically refractory or fibrostenosing disease. Between these 2 groups, we examined medications received before surgery. Other demographic and disease specific covariates were examined. RESULTS: Of the 82 patients who received IMB before surgery, only 19 patients (23%) required surgery for a perforating complication of CD, whereas 63 patients (77%) required surgery for strictures or medically refractory disease. In contrast, of the 43 patients who did not receive IMB preoperatively, 20 patients (45%) developed a perforating complication and 23 patients (53%) required surgery for strictures or refractory disease. These differences across groups were significant, with a lower rate of operation for perforating disease among patients receiving preoperative IMB therapy (P = 0.007). CONCLUSIONS: In our surgical cohort, children with CD who were treated with IMB were less likely to have surgery for perforating disease. This finding raises the possibility that the administration of IMB in children who require surgery may be associated with a difference in disease behavior. PMID- 24788217 TI - Inviting patients with inflammatory bowel disease to active involvement in their own care: a randomized controlled trial. AB - BACKGROUND: Inflammatory bowel diseases impose on patients a broad spectrum of somatic and psychosocial burden. We hypothesized that patients' self responsibility in planning and initiating adequate usually multimodal health care can be supported by self-assessment and proactive information, thus improving health-related quality of life and social participation. METHODS: We conducted a randomized controlled trial among a random sample of adult members of a German statutory health insurance with Crohn's disease or ulcerative colitis with at least 1 inflammatory bowel diseases-related hospital stay or sick leave in 2009 or 2010. Five hundred fourteen patients completed a postal screening questionnaire inquiring about 22 problems. The intervention group (IG) received an automated data analysis with individualized written advice on appropriate health services, and the control group received usual care. Main outcomes were health-related quality of life and social participation. Secondary outcomes included health care utilization, number of screened problems, and self management skills. RESULTS: After 12 months, small beneficial effects were seen for all primary outcomes in the IG: EuroQol visual analog scale score (difference between IG and control group: 4.4; 95% confidence interval, 7.7-1.0; P = 0.011), index for measuring participation restriction (IMET) score (difference between IG and control group: 0.4; 95% confidence interval, 0.07-0.62; P = 0.013). The number of disability days improved only in the IG. The IG reported significantly fewer outpatient visits, fewer disease-related problems, and improved self management skills (health education impact questionnaire scores) with no increase in disease activity, hospital stays, or consultations with allied health professionals. CONCLUSIONS: Our activation and information procedure is effective and beneficial. Further studies might show its usefulness in comprehensive management of patients with inflammatory bowel diseases. PMID- 24788216 TI - Utility of neutrophil Fcgamma receptor I (CD64) index as a biomarker for mucosal inflammation in pediatric Crohn's disease. AB - BACKGROUND: Neutrophil expression of the Fcgamma receptor I (CD64) is upregulated in adult patients with clinically active inflammatory bowel disease (IBD). We tested the relationship of CD64 with mucosal inflammation and clinical relapse in pediatric Crohn's disease (CD). METHODS: In a cohort of 208 newly diagnosed CD and 43 non-IBD controls, ileal expression of FcgammaRI/S100A9 was determined by RNA sequencing from biopsies obtained at ileocolonoscopy. In a second cohort, we tested for the peripheral blood polymorphonuclear neutrophil (PMN) CD64 index from 26 newly diagnosed CD, 30 non-IBD controls, and 83 children with established CD. RESULTS: Ileal FcgammaRIA mRNA expression was significantly elevated in CD at diagnosis compared with non-IBD controls (P < 0.001), and correlated with ileal S100A9 (calprotectin) expression (r = 0.83, P < 0.001). The median (range) PMN CD64 index for newly diagnosed CD was 2.3 (0.74-9.3) compared with 0.76 (0.39 1.2) for non-IBD controls (P < 0.001) with 96% sensitivity and 90% specificity at the cut point of 1.0. The PMN CD64 index significantly correlated with mucosal injury as measured by the simple endoscopic score for CD (r = 0.62, P < 0.001). Patients with CD in clinical remission receiving maintenance therapy with a PMN CD64 index <1.0 had a sustained remission rate of 95% over the following 12 months compared with 56% in those with a PMN CD64 index >1.0 (P < 0.01). CONCLUSIONS: An elevated PMN CD64 index is associated with both mucosal inflammation and an increased risk for clinical relapse in pediatric CD. The PMN CD64 index is a reliable marker for sustained remission in patients with CD receiving maintenance therapy. PMID- 24788218 TI - Fecal calprotectin testing can identify ineffective colorectal cancer surveillance procedures in patients with longstanding colitis. AB - BACKGROUND: Active colitis impairs neoplasia detection during colonoscopic surveillance for colorectal cancer in patients with inflammatory bowel disease. We investigated whether fecal calprotectin testing before surveillance colonoscopy might identify ineffective surveillance procedures. METHODS: All consecutive patients with Crohn's disease or ulcerative colitis scheduled for surveillance colonoscopy were asked to collect a stool sample before the start of bowel cleansing. Ineffective surveillance was defined as at least 1 colonic segment with moderate or severe inflammation. Calprotectin was analyzed using an enzyme-linked immunosorbent assay (Ridascreen; R-Biopharm). Receiver operator characteristics statistics were used to determine the optimal cutoff for calprotectin. RESULTS: A total of 176 surveillance colonoscopies were performed in 164 patients, of which 83 had Crohn's disease and 81 had ulcerative colitis or inflammatory bowel disease-unclassified. Complete endoscopic remission or mild inflammation categorized as effective surveillance was observed in 151 colonoscopies (86%), whereas moderate or severe inflammation categorized as ineffective surveillance was observed in 25 colonoscopies (14%). Median calprotectin levels for the effective and ineffective surveillance group were 84 mg/kg (range, 20-4609) and 1605 mg/kg (range, 66-26,336), respectively (P < 0.01). A cutoff of 539 mg/kg identified patients with ineffective surveillance with 84% sensitivity, 89% specificity, 55% positive predictive value, 97% negative predictive value, and an area under the curve of 0.89. CONCLUSIONS: Low fecal calprotectin accurately identifies inflammatory bowel disease patients without colonic inflammation in whom colorectal cancer surveillance is most effective. PMID- 24788219 TI - Incidence of pediatric inflammatory bowel disease in Saudi Arabia: a multicenter national study. AB - BACKGROUND: Pediatric inflammatory bowel disease (IBD) is increasingly recognized in developing countries; however, the incidence and trend over time have not been reported. METHODS: This retrospective study included children diagnosed with IBD in gastroenterology centers in the Kingdom of Saudi Arabia between 2003 and 2012. The date of birth, date and age at diagnosis, gender, and final diagnosis were collected on special forms. Clinical, laboratory, imaging, endoscopy, and histopathology results were reviewed to confirm the final diagnosis. Descriptive statistics were used to compare ulcerative colitis and Crohn's disease in different age groups, and significance was assessed by the chi-square test. Incidence rates and trend over time were analyzed with the assumption of Poisson distribution. The incidence rate over time was compared in 2 periods (2003-2007 and 2008-2012). A P value of <0.05 and 95% confidence intervals were used to assess the significance and precision of the estimates. RESULTS: A total of 340 Saudi Arabian children aged 0 to 14 years were diagnosed. The mean incidence rate per 100,000 individuals was 0.2, 0.27, and 0.47 for ulcerative colitis, Crohn's disease, and IBD, respectively. Except for the 0- to 4-year age group, there was a significant increase in incidence over time. CONCLUSIONS: Although the incidence of pediatric IBD in Saudi Arabian children is lower than suggested in the Western literature, there is a significantly increasing trend over time. However, decreased trend in the younger age group over time is identified. Prospective studies will be important to identify the risk factors for IBD in different age groups. PMID- 24788220 TI - Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. AB - BACKGROUND: Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. METHODS: Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time to-relapse was performed according to the baseline median level of each bacterial signal. RESULTS: Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001). CONCLUSIONS: In this work, we report that CD associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management. PMID- 24788221 TI - Tissue studies in screened first-degree relatives reveal a distinct Crohn's disease phenotype. AB - BACKGROUND: First-degree relatives of patients with Crohn's disease (CD) are at risk of developing the disease with 5% to 15% reported to be affected over time. Yet, a much greater proportion of them (>40%) shows features of "subclinical inflammation" with elevated intestinal inflammatory markers such as fecal calprotectin. The meaning of these findings is unclear in the absence of tissue data. METHODS: Thirty-eight asymptomatic first-degree relatives of patients with CD underwent ileocolonoscopy and other tests including fecal calprotectin. All known causes of intestinal inflammation were carefully excluded. Age and gender matched controls consisted of 10 individuals who underwent colonoscopy for other reasons. Histology was scored based on known methods. RESULTS: Compared with controls, the relatives had significantly greater median values for fecal calprotectin and histological scores. In relatives, endoscopy identified 3 different phenotypes: (1) normal, (2) with minor lesions (aphthae or small superficial erosions), and (3) with typical CD inflammation. Based on the histological scores, the clustering analysis produced 3 corresponding highly separated clusters (61%, 26%, and 13% of the total, respectively) with divisive coefficient D = 0.94. When followed up (on the average for 53 mo), individuals in the second cluster had histological scores similar to baseline values (P = 0.12). CONCLUSIONS: Tissue studies in first-degree relatives of patients with CD reveal 3 distinct groups: normal, with minimal inflammation, and with frank disease. The second cluster represents a novel phenotype, which does not seem to develop the disease over time. These findings explain previous observations of "subclinical inflammation" in such population. PMID- 24788222 TI - Antiproliferative effects of TRPV1 ligands on nonspecific and enteroantigen specific T cells from wild-type and Trpv1 KO mice. AB - BACKGROUND: Treatment with the TRPV1 agonist, capsaicin, was previously shown to protect against experimental colitis in the severe combined immunodeficiency (SCID) T-cell transfer model. Here, we investigate trpv1 gene expression in lymphoid organs and cells from SCID and BALB/c mice to identify a potential target for the anti-inflammatory effect of capsaicin. METHODS: The trpv1 expression was studied by real-time PCR in lymphoid tissues and gut of untreated and capsaicin-treated colitic SCID mice. Effects of capsaicin and a TRPV1 antagonist on T cells were studied in vitro. RESULTS: In contrast to BALB/c mice, spleen, lymph nodes, and rectum of colitic and noncolitic SCID mice express trpv1 mRNA. Capsaicin treatment in vivo attenuated T-cell transfer colitis and capsaicin in vitro also attenuated T-cell proliferation induced by enteroantigen, mitogen, and anti-CD3/CD28 beads in BALB/c, C57BL/6 mice, and B6.129X1 trpv1tm1Jul/J trpv1 knockout mice. Proliferation and cytokine secretion were fully comparable in mice with and without trpv1 expression. Likewise, enteroantigen- and mitogen-stimulated T cells from wild-type and trpv1 knockout mice were equally inhibited by capsaicin. Surprisingly, the TRPV1 antagonist BCTC also inhibited enteroantigen- and mitogen-induced T-cell proliferation. CONCLUSIONS: The trpv1 mRNA expression in lymphoid organs and the rectum of SCID mice suggests that the TRPV1 signaling in these organs could play a role in capsaicin-mediated attenuation of colitis. In addition, capsaicin-induced inhibition of T-cell proliferation of wild-type T cells lacking trpv1 expression suggests that capsaicin inhibits colitogenic T cells in a TRPV1 receptor independent way, which might be linked to its anti-inflammatory effect. PMID- 24788223 TI - Faecal calprotectin as a novel biomarker for differentiating between inflammatory bowel disease and irritable bowel syndrome. AB - The present study aimed to investigate faecal calprotectin as a diagnostic marker to differentiate between patients with inflammatory bowel disease (IBD) and those with irritable bowel syndrome (IBS). A total of 20 healthy control subjects, 26 patients with IBS and 58 patients with IBD, including 22 with ulcerative colitis (UC) and 36 with Crohn's disease (CD), were recruited for the present study. Calprotectin was analysed in stool samples, and C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were assessed in blood samples. CRP and calprotectin levels, and the ESR were observed to be significantly higher in patients with CD and UC compared with those of the healthy control subjects (P<0.0001). Furthermore, in patients with IBD and IBS, significant increases in faecal calprotectin and CRP levels were observed (694.8+/-685.0 ug/g in IBD vs. 85.8+/-136.1 ug/g in IBS and 0.851+/-1.200 mg/dl in IBD vs. 0.16+/-0.23 mg/dl in IBS, respectively; P<0.0001). Area under the receiver operating characteristic curve analysis revealed that, in patients with IBD, the levels of faecal calprotectin [0.931+/-0.029; 95% confidence interval (CI), 0.874-0.987] were significantly higher than that of CRP (0.865+/-0.041; 95% CI, 0.785-0.946) and the ESR (0.869+/-0.042; 95% CI, 0.786-0.952). These findings indicate that faecal calprotectin may represent a novel biomarker for diagnosing IBD and may be effective in distinguishing between IBD and IBS. PMID- 24788224 TI - ApoE-deficient promotes blood-brain barrier disruption in experimental autoimmune encephalomyelitis via alteration of MMP-9. AB - Disruption of the blood-brain barrier (BBB) is a surrogate marker of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Data from experiments suggest that apolipoprotein E (ApoE) plays an important role in the antiinflammatory and immunological process in MS/EAE. Recent researches have shown that lack of ApoE leads to loss of cerebrovascular integrity and BBB breakdown causing neuronal injury. Cerebrovascular effects of ApoE might be another important element resulting to more susceptibility to MS/EAE. However, there is no direct evidence that ApoE dependently contributes to maintaining BBB integrity in EAE. In this study, we induced EAE in ApoE-/- mice and wild-type mice. During EAE, our results show that lack of ApoE increased the Evan's blue (EB) permeability of BBB. Furthermore, deficiency of ApoE upregulated MMP-9 expression activity but decreased the expression of endothelial cell tight junction integral proteins claudin-5 and occludin. Our result also suggests that the protective role of ApoE in EAE by maintaining BBB integrity could be another interesting therapeutic target at MS/EAE. PMID- 24788225 TI - The role of LRRK2 in the regulation of monocyte adhesion to endothelial cells. AB - The leucine-rich repeat kinase 2 (LRRK2) gene was discovered to encode a member of an evolutionarily conserved family of proteins marked by GTPase domains usually in combination with kinase domains. Missense mutations in both the kinase and GTPase domains in LRRK2 have been found to cause late-onset Parkinson's disease (PD). In this study, we investigated the effects of the LRRK2 on endothelial inflammation. We first demonstrated that the LRRK2 is expressed in endothelial cells. We also report here that IL-1beta can possibly increase LRRK2 expression in human umbilical vein endothelial cells (HUVECs). Wild-type LRRK2 (LRRK2(wt)) expression induces expression of vascular cell adhesion molecule 1 (VCAM-1) which is further exacerbated in cells expressing PD-associated LRRK2 G2019S mutants (LRRK2(G2019S)). Importantly, induction of VCAM-1 is almost completely blocked in cells expressing the GTP-binding-deficient mutant K1347A of LRRK2 (LRRK2(K1347A)). In addition, overexpression of LRRK2(wt) and LRRK2(G2019S) were found to cause an increase in monocyte attachment to endothelial cells. Mechanistically, we found that LRRK2 increases the transcriptional activity of nuclear factor kappaB (NF-kappaB) by increasing phosphorylation levels of IkappaBalpha. These findings suggest that inhibition of LRRK2 kinase activity may be a potential target for treatment of endothelial dysfunction. PMID- 24788226 TI - The C-terminus of tau protein plays an important role in its stability and toxicity. AB - The identification of tau fragments generated by proteolysis in the neurons of AD patients and in neurofibrillary tangles encourages research on the toxicity of truncated tau. However, the detailed mechanism underlying the proteolysis-induced toxicity of tau is not clear and even controversial in some cases. In the present study, we used Drosophila as a model to evaluate the toxicity of a set of truncated tau fragments in vivo and found that the flies harboring C-terminal truncated tau exhibited less toxicity due to the unstable characteristic of C terminal-truncated tau fragments. Further study carried out in cultured Drosophila Kc cells revealed that C-terminal-truncated tau fragments degrade faster than full-length tau or N-terminal-truncated fragments. Collectively, our data implicate proteolysis of tau as an important pathway mediating tau degradation and neurotoxicity in vivo. PMID- 24788227 TI - State-trace analysis can be an appropriate tool for assessing the number of cognitive systems: a reply to Ashby (2014). AB - Ashby (2014) has argued that state-trace analysis (STA) is not an appropriate tool for assessing the number of cognitive systems, because it fails in its primary goal of distinguishing single-parameter and multiple-parameter models. We show that this is based on a misunderstanding of the logic of STA, which depends solely on nearly universal assumptions about psychological measurement and clearly supersedes inferences based on functional dissociation and the analysis of interactions in analyses of variance. We demonstrate that STA can be used to draw inferences concerning the number of latent variables mediating the effects of a set of independent variables on a set of dependent variables. We suggest that STA is an appropriate tool to use when making arguments about the number of cognitive systems that must be posited to explain behavior. However, no statistical or inferential procedure is able to provide definitive answers to questions about the number of cognitive systems, simply because the concept of a "system" is not defined in an appropriate way. PMID- 24788228 TI - Computer-aided evaluation as an adjunct to revised BI-RADS Atlas: improvement in positive predictive value at screening breast MRI. AB - OBJECTIVES: To investigate whether kinetic features via magnetic resonance (MR) computer-aided evaluation (CAE) can improve the positive predictive value (PPV) of morphological descriptors for suspicious lesions at screening breast MRI. METHODS: One hundred and sixteen consecutive, suspiciously enhancing lesions detected at contralateral breast MRI screening in 116 women with newly-diagnosed breast cancers were included. Morphological descriptors according to the revised BI-RADS Atlas and kinetic features from MR-CAE were analysed. The PPV of each descriptor was analysed to identify subgroups in which PPV could be improved by the addition of MR-CAE. RESULTS: When biopsy recommendations were downgraded to follow-up in cases where there were both the absence of enhancement at a 50% threshold and the absence of delayed washout, PPV increased from 0.328 (95% CI, 0.249-0.417) to 0.500 (95% CI, 0.387- 0.613). Two ductal carcinoma in situ (DCIS) non-mass enhancement (NME) lesions were missed. Application of downgrading criteria to foci or masses led to increased PPV from 0.310 (95% CI, 0.216-0.419) to 0.437 (95% CI, 0.331-0.547) without missing cancers. CONCLUSIONS: MR-CAE has the potential to improve the PPV of breast MR imaging by reducing the number of false positives. When suspicious mass lesions do not show enhancement at a 50% threshold nor delayed washout, follow-up rather than biopsy can be considered. KEY POINTS: * MR-CAE has the potential to increase PPV at breast MRI screening. * Lesions without enhancement at 50% threshold and washout might be downgraded. * DCIS non-mass lesions might be false-negative cases at MR-CAE. PMID- 24788229 TI - Computed tomography angiography of carotid and coronary artery via a single-bolus injection protocol: a feasibility study using 320-row multidetector CT. AB - OBJECTIVES: To investigate the feasibility of using a single-dose injection protocol in CT angiography (CTA) of the carotid and coronary artery with 320-row multidetector CT. METHODS: A total of 82 consecutive patients with suspected carotid artery disease underwent an original CTA protocol aiming at capturing the extra-cranial carotid arteries and coronary arteries simultaneously using 320-row MDCT. The image quality, attenuation, and CNRs of the carotid and coronary arteries were assessed. The lag time (between two separated volumetric acquisitions) was compared between patients with and without cardiac venous opacification (CVO). The contrast medium volume and radiation dose were recorded. RESULTS: The image quality was 99.4% diagnostic in carotid and 86.9% in coronary artery segments. The mean attenuation of carotid and coronary arteries ranged from 462.2 Hu to 533.7 Hu, 415.9 Hu to 454.7 Hu respectively. The mean CNR of the carotid and coronary artery ranged from 15.8 to 18.9 and 17.7 to 20.4 respectively. The lag time in patients with and without CVO was 5.75 +/- 1.64 s vs. 4.21 +/- 1.14 s (p < 0.05). The mean radiation dose was 6.6 +/- 4.1 mSv.The mean contrast media volume was 71.9 +/- 9.1 ml. CONCLUSIONS: The carotid and coronary artery can be imaged simultaneously via our original single-dose injection CTA protocol using 320-row CT with adequate image quality. KEY POINTS: * Carotid and coronary 320-row CTA can be achieved in a single-dose injection. * Longer coverage was achieved with two or more volumes using 320-row CT. * The single-dose protocol allows a reduced contrast agent dose of about 72 ml. PMID- 24788230 TI - A novel removable shield attached to C-arm units against scattered X-rays from a patient's side. AB - OBJECTIVES: We invented a drape-like shield against scattered X-rays that can safely come into contact with medical equipment or people during fluoroscopically guided procedures. The shield can be easily removed from a C-arm unit using one hand. We evaluated the use of the novel removable shield during the endoscopic retrograde cholangiopancreatography (ERCP) procedure. METHODS: We measured the dose rate of scattered X-rays around endoscopists with and without this removable shield and surveyed the occupational doses to the ERCP staff. We also examined the endurance of the shield. RESULTS: The removable shield reduced the dose rate of scattered X-rays to one-tenth and reduced the monthly dose to an endoscopist by at least two-fifths. For 2.5 years, there was no damage to the shield and no loosening of the seam. The bonding of the hook-and-loop fasteners did not weaken, although the powerful double-sided tapes made especially for plastic did. CONCLUSIONS: The removable shield can reduce radiation exposure to the ERCP staff and may contribute to reducing the exposure to the eye lenses of operators. It would also be possible to expand its use to other fluoroscopically guided procedures besides ERCP because it is a light, simple, and useful device. KEY POINTS: * We invented a shield that can be removed from C-arm units with one hand. * The removable shield reduces the dose rate of X-rays to one-tenth. * The removable shield reduces operator exposure by two-fifths. * The removable shield is durable, lasting for several years. * The drape-like removable shield is light, simple, and useful. PMID- 24788231 TI - Admission interview scores are associated with clinical performance in an undergraduate physiotherapy course: an observational study. AB - OBJECTIVE: The purpose of this study was to determine if there is an association between admission interview score and subsequent academic and clinical performance, in a four-year undergraduate physiotherapy course. DESIGN: Retrospective observational study. PARTICIPANTS: 141 physiotherapy students enrolled in two entry year groups. OUTCOME MEASURES: Individual student performance in all course units, practical examinations, clinical placements as well as year level and overall Grade Point Average. Predictor variables included admission interview scores, admission academic scores and demographic data (gender, age and entry level). RESULTS: Interview score demonstrated a significant association with performance in three of six clinical placements through the course. This association was stronger than for any other admission criterion although effect sizes were small to moderate. Further, it was the only admission score to have a significant association with overall Clinical Grade Point Average for the two year groups analysed (r=0.322). By contrast, academic scores on entry showed significant associations with all year level Grade Point Averages except Year 4, the clinical year. CONCLUSIONS: This is the first study to review the predictive validity of an admission interview for entry into a physiotherapy course in Australia. The results show that performance in this admission interview is associated with overall performance in clinical placements through the course, while academic admission scoring is not. These findings suggest that there is a role for both academic and non-academic selection processes for entry into physiotherapy. PMID- 24788233 TI - Metal-mediated DNA damage and cell death: mechanisms, detection methods, and cellular consequences. AB - The redox activity of metal ions can lead to the formation of highly reactive species that damage DNA, producing different oxidation products and types of damage depending upon the redox potentials of the DNA bases, formation of intermediate adducts, and identity of the reactive species. Other factors are also important in determining the degree of metal-mediated DNA damage, such as localization and redox chemistry of the metal ions or complexes and lifetimes of the reactive oxygen species generated. This review examines the types of DNA damage mediated by first-row transition metals under oxidative stress conditions, with emphasis on work published in the past ten years. Similarities and differences between DNA damage mechanisms of the first-row transition metals in vitro and in E. coli and human cells are compared and their relationship to disease development are discussed. Methods to detect this metal-mediated DNA damage, including backbone breakage, base oxidation, inter- and intra-strand crosslinking, and DNA-protein crosslinking are also briefly reviewed, as well as detection methods for reactive oxygen species generated by these metal ions. Understanding the conditions that cause metal-mediated DNA damage and metal generation of reactive oxygen species in vitro and in cells is required to develop effective drugs to prevent and treat chronic disease. PMID- 24788232 TI - Minichromosomes and artificial chromosomes in Arabidopsis. AB - Minichromosomes have been extensively used as tools for revealing the functional structures of eukaryotic chromosomes. However, the definition of a minichromosome is still ambiguous. Based on previous reports on various eukaryotes, minichromosomes are defined here to be chromosomes that are smaller than one third the size of the smallest chromosome in the given species. In Arabidopsis thaliana, therefore, chromosomes <8.5 Mb in length are classified as minichromosomes, although to date only six different minichromosomes have been found or created, probably due to their extremely small sizes that limit detection. Minichromosomes vary from 1.7 to 8.4 Mb in length and are much shorter than authentic chromosomes (25.3 to 38.0 Mb). Linear and circular minichromosomes have been identified, and both types are maintained as experimental lines. Most of the circular, ring-shaped minichromosomes in Arabidopsis are relatively stable at mitosis and transmissible to the next generation, regardless of the centromere form (dicentric or monocentric). Recently, a ring minichromosome was artificially generated by a combination of the Cre/LoxP and Ac/Ds systems. This artificial ring chromosome, AtARC1, has several advantages over the previously reported minichromosomes as a chromosome vector; therefore, this method of generating artificial ring chromosomes is expected to be improved for application to other plant species including important crops. PMID- 24788234 TI - Au(I)-catalyzed triple bond alkoxylation/dienolether aromaticity-driven cascade cyclization to naphthalenes. AB - A novel strategy for the synthesis of multisubstituted naphthalenes was developed via a Au(i)-catalyzed alkyne alkoxylation/dienolether aromaticity-driven cascade cyclization using 1,5-enyne substrates. The functional group toleration was examined by synthesizing a series of substrates and the mechanism was also studied based on intermediates isolated through deuterium labeling experiments. PMID- 24788235 TI - Female genital morphology in the secondarily haplogyne spider genus Glenognatha Simon, 1887 (Araneae, Tetragnathidae), with comments on its phylogenetic significance. AB - Female genital morphology of secondarily haplogyne spiders has been poorly studied, hampering the analysis of its possible phylogenetic significance. We conduct a comparative morphological study of 12 species of the secondarily haplogyne spider genus Glenognatha Simon, 1887 using scanning electron microscopy. Representatives of the closely related genera Pachygnatha Sundevall, 1823 and Dyschiriognatha Simon, 1893 were also examined. The female genitalia of Glenognatha, Dyschiriognatha, and Pachygnatha species examined are composed of a spiracle-shape gonopore, a membranous chamber, a pair of copulatory ducts (CD) leading to spermathecae and a large uterus externus (UE). The most significant variation among Glenognatha species, previously unregistered within Araneoidea, is related with the absence or presence of CD and spermathecae. In addition, several characters as the form and distribution of long stem gland ductules and compartmentalization of the UE may be important for phylogenetic inference at species and generic level. Our results corroborate the close relationship between Dyshiriognatha and Glenognatha. A table with potentially informative female genitalic characters for phylogenetic inference within Glenognatha is provided. Understanding the general structure of the female genitalia in secondarily haplogyne taxa is a crucial step in order to propose characters for phylogenetic inference and to understand its possible functional significance. PMID- 24788236 TI - Multimodal optical imaging can reveal changes in microcirculation and tissue oxygenation during skin wound healing. AB - BACKGROUND AND OBJECTIVE: Faster and better wound healing is a longstanding goal. Blood flow, angiogenesis, and tissue oxygenation are important parameters in evaluating the healing process. Optical microangiography (OMAG) allows 3D imaging of tissue vasculature and can provide quantitative blood flow information down to the capillary level of resolution. Dual wavelength laser speckle imaging (DW-LSI) can measure tissue oxygenation status. MATERIALS AND METHODS: Cutaneous wound healing of a mouse ear model using a multimodal imaging system that combines OMAG with DWLSI was studied. RESULTS: A complete microvasculature map of the ear in vivo was obtained. The imaging system revealed both hemodynamic and metabolic changes during acute stage wound healing. Blood flow velocity, blood flow direction, as well as changes in concentration of oxygenated hemoglobin (DeltaHbO) and deoxygenated hemoglobin (DeltaHb) were measured and quantified. In addition, capillary recruitment and angiogenesis were visualized during the chronic stage of repairing. CONCLUSIONS: The combination of DW-LSI and OMAG imaging technique may be a powerful tool to visualize and understand microvascular, hemodynamic, and metabolic changes during cutaneous wound healing. PMID- 24788237 TI - The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer. AB - Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), which could induce genome-wide retargeting of polycomb-repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes, is involved in development and progression of esophageal squamous cell carcinoma (ESCC). We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, ESCC risk. Therefore, we examined the association between three haplotype-tagging SNPs (htSNP) across the whole HOTAIR locus and ESCC risk as well as the functional relevance of an ESCC susceptibility SNP rs920778. Genotypes were determined in three independent case-control sets consisted of 2098 ESCC patients and 2150 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was investigated in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.37-fold, 1.78-fold and 2.08-fold increased ESCC risk in Jinan, Shijiazhuang and Huaian populations, respectively, compared with the CC carriers (P = 0.003, 7.7 * 10(-4) and 5.9 * 10(-4)). During inspecting functional relevance of the rs920778 SNP, we identified a novel intronic HOTAIR enhancer locating between +1719bp and +2353bp from the transcriptional start site through reporter assays. Moreover, there is an allelic regulation of rs920778 on HOTAIR expression via this enhancer in both ESCC cell lines and normal esophageal tissue specimens, with higher HOTAIR expression among T allele carriers. These results demonstrate that functional genetic variants influencing lncRNA regulation may explain a fraction of ESCC genetic basis. PMID- 24788238 TI - Use of tissue swabbing as an alternative to tissue dissection and lysis prior to nucleic acid extraction and real-time polymerase chain reaction detection of Bovine viral diarrhea virus and Porcine reproductive and respiratory syndrome virus. AB - The use of swabbing to sample tissue samples, prior to nucleic acid extraction and performance of a real-time polymerase chain reaction (PCR) assay, was investigated for the detection of the viral pathogens Bovine viral diarrhea virus (BVDV) and Porcine reproductive and respiratory syndrome virus (PRRSV). The tissue swabbing method involved swabbing recently cut tissues, eluting the swabbed material, and extracting nucleic acid from the eluate prior to PCR amplification. Parallel testing of this method with traditional nucleic acid extraction from tissues, where small pieces of tissue are dissected and digested (typically overnight) in lysis buffer prior to nucleic acid extraction, was carried out for 50 samples for each virus. The results demonstrated that equivalent PCR results were obtained with both methods. It was also shown on a smaller number of samples that equivalent PCR results were also obtained when the lysis step of the swabbing method was reduced to only 2 hr. The ability to remove the overnight step typically associated with processing tissue samples for PCR analysis offers the potential for same-day testing of tissue. Although the current study is preliminary in nature and further validation will be required before adoption for routine use, the results show that tissue swabbing is a promising approach. It offers a convenient, simpler, and less time-consuming alternative to tissue dissection and lysis and has potential advantages for routine laboratory operation and outbreak testing, including easier pooling and sampling of large areas of tissue and carcasses. PMID- 24788239 TI - Biowaiver monographs for immediate-release solid oral dosage forms: codeine phosphate. AB - The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the "highly soluble" criteria according to World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (US FDA). Codeine's fraction of dose absorbed in humans was reported to be high (>90%) based on cumulative urinary excretion of drug and drug-related material following oral administration. The permeability of codeine was also assessed to be high in both Caco-2 monolayers and rat intestinal perfusion studies. The main risks associated with codeine, that is, toxicity (attributed to CYP2D6 polymorphism) and its abuse potential, are present irrespective of the dosage form, and do not need to be taken into account for bioequivalence (BE) considerations. Taken together, codeine is a class 1 drug with manageable risk and is a good candidate for waiver of in vivo BE studies. PMID- 24788241 TI - The assessment, benefits and delivery of physical activity in people with schizophrenia: a survey of members of the International Organization of Physical Therapists in Mental Health. AB - BACKGROUND: People with schizophrenia typically die over a decade before members of the general population. Physical activity is a low cost and effective intervention that can have a multitude of beneficial effects on people with schizophrenia. Physical therapists lead in the delivery of physical activity in many of the commonly observed co-morbidities in schizophrenia, yet their role in the delivery of physical activity in patients with schizophrenia remains unclear. OBJECTIVE: This study aimed to establish an international consensus on physical therapists' beliefs, potential benefits and practices in the use of physical activity in schizophrenia. METHOD: All members of the International Organization of Physical Therapists in Mental Health were invited to take part in a cross sectional online survey. All data were analysed using descriptive statistics and quantitative content and/or thematic analysis. RESULTS: One hundred and fifty-one physical therapists from 31 countries responded. Almost all respondents (92%) felt that physical activity benefited patients with schizophrenia, and 75.2% and 22.5%, respectively, felt that it was very important and important that physical therapists oversee in the delivery of physical activity in psychiatric services. Resultant themes established that physical activity has a plethora of beneficial effects on people with schizophrenia including physical health benefits and biopsychosocial effects such as improved mental health, socialization and quality of life. In addition, participants felt they have the necessary theoretical knowledge and clinical skills required for leading and overseeing physical activity programmes in this complex patient group. CONCLUSION: Physical therapists identified that physical activity has a plethora of benefits for patients with schizophrenia and that they have the necessary knowledge and skills to lead and oversee the successful delivery of physical activity in patients with schizophrenia in clinical practice. PMID- 24788240 TI - Estrous cycle dependent fluctuations of regulatory neuropeptides in the lower urinary tract of female rats upon colon-bladder cross-sensitization. AB - Co-morbidity of bladder, bowel, and non-specific pelvic pain symptoms is highly prevalent in women. Little evidence is present on modulation of pelvic pain syndromes by sex hormones, therefore, the objective of this study was to clarify the effects of hormonal fluctuations within the estrous cycle on regulatory neuropeptides in female rats using a model of neurogenic bladder dysfunction. The estrous cycle in female rats (Sprague-Dawley, 230-250 g) was assessed by vaginal smears and weight of uterine horns. Neurogenic bladder dysfunction was induced by a single inflammatory insult to the distal colon. Protein expression of calcitonin gene related peptide (CGRP), substance P (SP), nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) in the pelvic organs, sensory ganglia and lumbosacral spinal cord was compared in rats in proestrus (high estrogen) vs diestrus (low estrogen). Under normal physiological conditions, concentration of SP and CGRP was similar in the distal colon and urinary bladder during all phases of the estrous cycle, however, acute colitis induced a significant up-regulation of CGRP content in the colon (by 63%) and urinary bladder (by 54%, p<=0.05 to control) of rats in proestrus. These changes were accompanied by a significant diminution of CGRP content in L6-S2 DRG after colonic treatment, likely associated with its release in the periphery. In rats with high estrogen at the time of testing (proestrus), experimental colitis caused a significant up-regulation of BDNF colonic content from 26.1+/-8.5 pg/ml to 83.4+/-32.5 pg/ml (N = 7, p<=0.05 to control) and also induced similar effects on BDNF in the urinary bladder which was also up-regulated by 5-fold in rats in proestrus (p<=0.05 to respective control). Our results demonstrate estrous cycle dependent fluctuations of regulatory neuropeptides in the lower urinary tract upon colon-bladder cross-sensitization, which may contribute to pain fluctuations in female patients with neurogenic bladder pain. PMID- 24788242 TI - Barraquer-Simons syndrome: a rare clinical entity. AB - The Barraquer-Simons syndrome or acquired parital lipodystrophy is a rare form of partial lipodystrophy characterized by gradual onset of bilaterally symmetrical subcutaneous fat loss from the face, neck, upper extremities, thorax, and abdomen but sparing the lower extremities. The patients gradually loose their subcutaneous fat in clearly demarcated, generally symmetric areas of the body over several years. Nephropathy, myopathy, deafness, epilepsy, and intellectual disability have also been described. Although the etiology is unknown, heterozygous mutations in the gene encoding one of the nuclear lamina proteins, lamin B2, have been reported in several patients. We here report on a young female patient affected by Barraquer-Simons syndrome, without accompanying renal or central nervous system involvement in whom DNA sequencing did not reveal any mutations in the genes LMNB2, LMNA, PPARG, AGPAT2, BSCL2, CAV1, PTRF, PLIN1, and CIDEC. PMID- 24788243 TI - DDX6 and its orthologs as modulators of cellular and viral RNA expression. AB - DDX6 (Rck/p54), a member of the DEAD-box family of helicases, is highly conserved from unicellular eukaryotes to vertebrates. Functions of DDX6 and its orthologs in dynamic ribonucleoproteins contribute to global and transcript-specific messenger RNA (mRNA) storage, translational repression, and decay during development and differentiation in the germline and somatic cells. Its role in pathways that promote mRNA-specific alternative translation initiation has been shown to be linked to cellular homeostasis, deregulated tissue development, and the control of gene expression in RNA viruses. Recently, DDX6 was found to participate in mRNA regulation mediated by miRNA-mediated silencing. DDX6 and its orthologs have versatile functions in mRNA metabolism, which characterize them as important post-transcriptional regulators of gene expression. PMID- 24788245 TI - Authors' reply to Dunning. PMID- 24788246 TI - Switch to diesel engines is significantly to blame for poor air quality in UK cities, experts say. PMID- 24788247 TI - FDA panel recommends banning "aversive" shock devices. PMID- 24788250 TI - Corrigendum. AB - Fleischut PM, Eskreis-Winkler JM, Gaber-Baylis LK, Giambrone GP, Faggiani SL, Dutton RP, Memtsoudis SG. Variability in anesthetic care for total knee arthroplasty: an analysis from the anesthesia quality institute [published online March 13, 2014]. Am J Med Qual. (Original doi:10.1177/1062860614525989). PMID- 24788249 TI - VIP regulates CFTR membrane expression and function in Calu-3 cells by increasing its interaction with NHERF1 and P-ERM in a VPAC1- and PKCepsilon-dependent manner. AB - Vasoactive intestinal peptide (VIP) is a topical airway gland secretagogue regulating fluid secretions, primarily by stimulating cystic fibrosis transmembrane conductance regulator (CFTR)-dependent chloride secretion that contributes to the airways innate defense mechanism. We previously reported that prolonged VIP stimulation of pituitary adenylate cyclase-activating peptide receptors (VPAC1) in airway cells enhances CFTR function by increasing its membrane stability. In the present study, we identified the key effectors in the VIP signaling cascade in the human bronchial serous cell line Calu-3. Using immunocytochemistry and in situ proximity ligation assays, we found that VIP stimulation increased CFTR membrane localization by promoting its colocalization and interaction with the scaffolding protein Na(+)/H(+) exchange factor 1 (NHERF1), a PDZ protein known as a positive regulator for CFTR membrane localization. VIP stimulation also increased phosphorylation, by protein kinase Cepsilon of the actin-binding protein complex ezrin/radixin/moesin (ERM) and its interaction with NHERF1 and CFTR complex. On the other hand, it reduced intracellular CFTR colocalization and interaction with CFTR associated ligand, another PDZ protein known to compete with NHERF1 for CFTR interaction, inducing cytoplasmic retention and lysosomal degradation. Reducing NHERF1 or ERM expression levels by specific siRNAs prevented the VIP effect on CFTR membrane stability. Furthermore, iodide efflux assays confirmed that NHERF1 and P-ERM are necessary for VIP regulation of the stability and sustained activity of membrane CFTR. This study shows the cellular mechanism by which prolonged VIP stimulation of airway epithelial cells regulates CFTR-dependent secretions. PMID- 24788248 TI - Type-2 pericytes participate in normal and tumoral angiogenesis. AB - Tissue growth and function depend on vascularization, and vascular insufficiency or excess exacerbates many human diseases. Identification of the biological processes involved in angiogenesis will dictate strategies to modulate reduced or excessive vessel formation. We examine the essential role of pericytes. Their heterogeneous morphology, distribution, origins, and physiology have been described. Using double-transgenic Nestin-GFP/NG2-DsRed mice, we identified two pericyte subsets. We found that Nestin-GFP(-)/NG2-DsRed(+) (type-1) and Nestin GFP(+)/NG2-DsRed(+) (type-2) pericytes attach to the walls of small and large blood vessels in vivo; in vitro, type-2, but not type-1, pericytes spark endothelial cells to form new vessels. Matrigel assay showed that only type-2 pericytes participate in normal angiogenesis. Moreover, when cancer cells were transplanted into Nestin-GFP/NG2-DsRed mice, type-1 pericytes did not penetrate the tumor, while type-2 pericytes were recruited during its angiogenesis. As inhibition of angiogenesis is a promising strategy in cancer therapy, type-2 pericytes may provide a cellular target susceptible to signaling and pharmacological manipulation in treating malignancy. This work also reports the potential of type-2 pericytes to improve blood perfusion in ischemic hindlimbs, indicating their potential for treating ischemic illnesses. PMID- 24788251 TI - Organizational factors and change strategies associated with medical home transformation. AB - There is limited information about how to transform primary care practices into medical homes. The research team surveyed leaders of the first 132 primary care practices in Minnesota to achieve medical home certification. These surveys measured priority for transformation, the presence of medical home practice systems, and the presence of various organizational factors and change strategies. Survey response rates were 98% for the Change Process Capability Questionnaire survey and 92% for the Physician Practice Connections survey. They showed that 80% to 100% of these certified clinics had 15 of the 18 organizational factors important for improving care processes and that 60% to 90% had successfully used 16 improvement strategies. Higher priority for this change (P = .001) and use of more strategies (P = .05) were predictive of greater change in systems. Clinics contemplating medical home transformation should consider the factors and strategies identified here and should be sure that such a change is indeed a high priority for them. PMID- 24788252 TI - The effect of organizational climate on patient-centered medical home implementation. AB - Organizational climate is a key determinant of successful adoption of innovations; however, its relation to medical home implementation is unknown. This study examined the association between primary care providers' (PCPs') perception of organization climate and medical home implementation in the Veterans Health Administration. Multivariate regression was used to test the hypothesis that organizational climate predicts medical home implementation. This analysis of 191 PCPs found that higher scores in 2 domains of organizational climate (communication and cooperation, and orientation to quality improvement) were associated with a statistically significantly higher percentage (from 7 to 10 percentage points) of PCPs implementing structural changes to support the medical home model. In addition, some aspects of a better organizational climate were associated with improved organizational processes of care, including a higher percentage of patients contacted within 2 days of hospital discharge (by 2 to 3 percentage points) and appointments made within 3 days of a patient request (by 2 percentage points). PMID- 24788253 TI - PTSD treatment for soldiers after combat deployment: low utilization of mental health care and reasons for dropout. AB - OBJECTIVE: Limited data exist on the adequacy of treatment for posttraumatic stress disorder (PTSD) after combat deployment. This study assessed the percentage of soldiers in need of PTSD treatment, the percentage receiving minimally adequate care, and reasons for dropping out of care. METHODS: Data came from two sources: a population-based cohort of 45,462 soldiers who completed the Post-Deployment Health Assessment and a cross-sectional survey of 2,420 infantry soldiers after returning from Afghanistan (75% response rate). RESULTS: Of 4,674 cohort soldiers referred to mental health care at a military treatment facility, 75% followed up with this referral. However, of 2,230 soldiers who received a PTSD diagnosis within 90 days of return from Afghanistan, 22% had only one mental health care visit and 41% received minimally adequate care (eight or more encounters in 12 months). Of 229 surveyed soldiers who screened positive for PTSD (PTSD Checklist score >=50), 48% reported receiving mental health treatment in the prior six months at any health care facility. Of those receiving treatment, the median number of visits in six months was four; 22% had only one visit, 52% received minimally adequate care (four or more visits in six months), and 24% dropped out of care. Reported reasons for dropout included soldiers feeling they could handle problems on their own, work interference, insufficient time with the mental health professional, stigma, treatment ineffectiveness, confidentiality concerns, or discomfort with how the professional interacted. CONCLUSIONS: Treatment reach for PTSD after deployment remains low to moderate, with a high percentage of soldiers not accessing care or not receiving adequate treatment. This study represents a call to action to validate interventions to improve treatment engagement and retention. PMID- 24788254 TI - A Comparison of Attitudes Toward Prisoners of Religious and Non-Religious College Students in Hong Kong. AB - While there have been numerous studies on the religious, namely, Christians', attitudes toward punishment, less attention has been devoted to the religious attitudes toward prisoners. This study aims to examine and compare religious affiliation and spirituality with respect to attitudes toward prisoners. Respondents were comprised of a sample of college students in Hong Kong divided into three groups: Buddhists, Christians, and those self-identified as non religious. Both Christians and Buddhists displayed more positive attitudes toward prisoners with respect to perceived bad character and perception of negative interaction compared with the non-religious. Likewise, Christians and Buddhists exhibited more positive attitudes toward prisoners with respect to empathy and perception that prisoners are normal compared with the non-religious. Spirituality, however, moderated these relationships as spirituality interacted with religious affiliation to produce more negative attitudes toward prisoners. Possible implications are discussed. PMID- 24788255 TI - Profiles of Maternal Parenting Practices: Exploring the Link With Maternal Delinquency, Offending, Mental Health, and Children's Physical Aggression. AB - Studies have often linked parenting to children's subsequent antisocial behavior; however, the circumstances under which this might occur are less clear. The current study explores patterns in mothers' parenting practices, and associated correlates including maternal delinquency and offending, mental health, and children's physical aggression. This study is based on the first wave of the ongoing Vancouver Longitudinal Study; the objective of this prospective study is to identify the early risk and protective factors for aggression and violence from the earliest developmental periods. Parenting practices of 287 mothers with preschoolers are examined using a series of latent class analyses. Three different patterns of parenting emerged: Positive, Negative, and Intermittent. Patterns identified are associated with several key criminogenic, socio demographic, historical, and developmental factors including current maternal adult offending, mothers' mental health, ethnicity, and frequency of children's physical aggression. Importantly, mothers who show parenting in line with the more negative classes also rely on a number of positive practices. Implications of the study suggest that parenting is influenced by mothers' immediate situations and contexts (e.g., current offending rather that past delinquency), which can be targeted for intervention. PMID- 24788256 TI - "I Don't See Myself as Prison Material": Motivations for Entering a Rural Drug Court. AB - Since the inception of drug court in the late 1980s, it has become a widely used alternative to incarcerating drug offenders. Previous research has detailed the effectiveness of programming on recidivism, participants' perceptions of the service delivery model, and cost-effectiveness. The scholarship related to drug offender motivations to participate in drug court has largely discussed family obligations and the sense of loss stemming from drug abuse, and only two studies have discussed the fear of prison as a primary motivator. This research utilized semi-structured interviews with former drug court participants from a rural county in California to ascertain their motivation for engaging in drug court (N = 29). The results show 79% of participants were trying to avoid prison or jail, while 62% were motivated to end the cycle of drug abuse in their lives. The conclusion has policy implications for future drug court design; however, additional research is needed. PMID- 24788258 TI - Introduction to biomedical literature text mining: context and objectives. AB - INFORMATION: If you are reading this, you know how important it is and almost certainly look to the biomedical literature for a large part of the information you need. We work hard to find more and more biomedical literature, seeking new content from multiple sources. But, can there be too much of a good thing? Most science is reductionist by nature. It is difficult enough finding the relevant nuggets of information from 1,000 documents. It is at least ten times harder to do so from 10,000 documents. And, with 25 million biomedical journal articles and many times that of other textual information sources, we are faced with significant challenges. In this introduction, we identify some of those challenges to prepare you for the remaining chapters. PMID- 24788257 TI - Dicer regulates differentiation and viability during mouse pancreatic cancer initiation. AB - miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation. PMID- 24788259 TI - Accessing biomedical literature in the current information landscape. AB - Biomedical and life sciences literature is unique because of its exponentially increasing volume and interdisciplinary nature. Biomedical literature access is essential for several types of users including biomedical researchers, clinicians, database curators, and bibliometricians. In the past few decades, several online search tools and literature archives, generic as well as biomedicine specific, have been developed. We present this chapter in the light of three consecutive steps of literature access: searching for citations, retrieving full text, and viewing the article. The first section presents the current state of practice of biomedical literature access, including an analysis of the search tools most frequently used by the users, including PubMed, Google Scholar, Web of Science, Scopus, and Embase, and a study on biomedical literature archives such as PubMed Central. The next section describes current research and the state-of-the-art systems motivated by the challenges a user faces during query formulation and interpretation of search results. The research solutions are classified into five key areas related to text and data mining, text similarity search, semantic search, query support, relevance ranking, and clustering results. Finally, the last section describes some predicted future trends for improving biomedical literature access, such as searching and reading articles on portable devices, and adoption of the open access policy. PMID- 24788260 TI - Mapping of biomedical text to concepts of lexicons, terminologies, and ontologies. AB - Concept mapping is a fundamental task in biomedical text mining in which textual mentions of concepts of interest are annotated with specific entries of lexicons, terminologies, ontologies, or databases representing these concepts. Though there has been a significant amount of research, there are still a limited number of practical, publicly available tools for concept mapping of biomedical text specified by the user as an independent task. In this chapter, several tools that can automatically map biomedical text to concepts from a wide range of terminological resources are presented, followed by those that can map to more restricted sets of these resources. This presentation is intended to serve as a guide to researchers without a background in biomedical concept mapping of text for the selection of an appropriate tool based on usability, scalability, configurability, balance between precision and recall, and the desired set of terminological resources with which to annotate the text. Only with effective automatic concept-mapping tools will systems be able to scalably analyze the biomedical literature and other large sets of documents as a fundamental part of more complex text-mining tasks such as information extraction and hypothesis evaluation and generation. PMID- 24788262 TI - Biological information extraction and co-occurrence analysis. AB - Nowadays, it is possible to identify terms corresponding to biological entities within passages in biomedical text corpora: critically, their potential relationships then need to be detected. These relationships are typically detected by co-occurrence analysis, revealing associations between bioentities through their coexistence in single sentences and/or entire abstracts. These associations implicitly define networks, whose nodes represent terms/bioentities/concepts being connected by relationship edges; edge weights might represent confidence for these semantic connections.This chapter provides a review of current methods for co-occurrence analysis, focusing on data storage, analysis, and representation. We highlight scenarios of these approaches implemented by useful tools for information extraction and knowledge inference in the field of systems biology. We illustrate the practical utility of two online resources providing services of this type-namely, STRING and BioTextQuest concluding with a discussion of current challenges and future perspectives in the field. PMID- 24788261 TI - Text mining for drug-drug interaction. AB - In order to understand the mechanisms of drug-drug interaction (DDI), the study of pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenetics (PG) data are significant. In recent years, drug PK parameters, drug interaction parameters, and PG data have been unevenly collected in different databases and published extensively in literature. Also the lack of an appropriate PK ontology and a well-annotated PK corpus, which provide the background knowledge and the criteria of determining DDI, respectively, lead to the difficulty of developing DDI text mining tools for PK data collection from the literature and data integration from multiple databases.To conquer the issues, we constructed a comprehensive pharmacokinetics ontology. It includes all aspects of in vitro pharmacokinetics experiments, in vivo pharmacokinetics studies, as well as drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three-level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK corpus was demonstrated by a drug interaction extraction text mining analysis.The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions. PMID- 24788263 TI - Roles for text mining in protein function prediction. AB - The Human Genome Project has provided science with a hugely valuable resource: the blueprints for life; the specification of all of the genes that make up a human. While the genes have all been identified and deciphered, it is proteins that are the workhorses of the human body: they are essential to virtually all cell functions and are the primary mechanism through which biological function is carried out. Hence in order to fully understand what happens at a molecular level in biological organisms, and eventually to enable development of treatments for diseases where some aspect of a biological system goes awry, we must understand the functions of proteins. However, experimental characterization of protein function cannot scale to the vast amount of DNA sequence data now available. Computational protein function prediction has therefore emerged as a problem at the forefront of modern biology (Radivojac et al., Nat Methods 10(13):221-227, 2013).Within the varied approaches to computational protein function prediction that have been explored, there are several that make use of biomedical literature mining. These methods take advantage of information in the published literature to associate specific proteins with specific protein functions. In this chapter, we introduce two main strategies for doing this: association of function terms, represented as Gene Ontology terms (Ashburner et al., Nat Genet 25(1):25-29, 2000), to proteins based on information in published articles, and a paradigm called LEAP-FS (Literature-Enhanced Automated Prediction of Functional Sites) in which literature mining is used to validate the predictions of an orthogonal computational protein function prediction method. PMID- 24788264 TI - Functional molecular units for guiding biomarker panel design. AB - The field of biomarker research has experienced a major boost in recent years, and the number of publications on biomarker studies evaluating given, but also proposing novel biomarker candidates is increasing rapidly for numerous clinically relevant disease areas. However, individual markers often lack sensitivity and specificity in the clinical context, resting essentially on the intra-individual phenotype variability hampering sensitivity, or on assessing more general processes downstream of the causative molecular events characterizing a disease term, in consequence impairing disease specificity. The trend to circumvent these shortcomings goes towards utilizing multimarker panels, thus combining the strength of individual markers to further enhance performance regarding both sensitivity and specificity. A way of identifying the optimal composition of individual markers in a panel approach is to pick each marker as representative for a specific pathophysiological (mechanistic) process relevant for the disease under investigation, hence resulting in a multimarker panel for covering the set of pathophysiological processes underlying the frequently multifactorial composition of a clinical phenotype.Here we outline a procedure of identifying such sets of disease-specific pathophysiological processes (units) delineated on the basis of disease-associated molecular feature lists derived from literature mining as well as aggregated, publicly available Omics profiling experiments. With such molecular units in hand, providing an improved reflection of a specific clinical phenotype, biomarker candidates can then be assigned to or novel candidates are to be selected from these units, subsequently resulting in a multimarker panel promising improved accuracy in disease diagnosis as well as prognosis. PMID- 24788265 TI - Mining biological networks from full-text articles. AB - The study of biological networks is playing an increasingly important role in the life sciences. Many different kinds of biological system can be modelled as networks; perhaps the most important examples are protein-protein interaction (PPI) networks, metabolic pathways, gene regulatory networks, and signalling networks. Although much useful information is easily accessible in publicly databases, a lot of extra relevant data lies scattered in numerous published papers. Hence there is a pressing need for automated text-mining methods capable of extracting such information from full-text articles. Here we present practical guidelines for constructing a text-mining pipeline from existing code and software components capable of extracting PPI networks from full-text articles. This approach can be adapted to tackle other types of biological network. PMID- 24788266 TI - Scientific collaboration networks using biomedical text. AB - The combination of scientific knowledge and experience is the key success for biomedical research. This chapter demonstrates some of the strategies used to help in identifying key opinion leaders with the expertise you need, thus enabling an effort to increase collaborative biomedical research. PMID- 24788267 TI - Predicting future discoveries from current scientific literature. AB - Knowledge discovery in biomedicine is a time-consuming process starting from the basic research, through preclinical testing, towards possible clinical applications. Crossing of conceptual boundaries is often needed for groundbreaking biomedical research that generates highly inventive discoveries. We demonstrate the ability of a creative literature mining method to advance valuable new discoveries based on rare ideas from existing literature. When emerging ideas from scientific literature are put together as fragments of knowledge in a systematic way, they may lead to original, sometimes surprising, research findings. If enough scientific evidence is already published for the association of such findings, they can be considered as scientific hypotheses. In this chapter, we describe a method for the computer-aided generation of such hypotheses based on the existing scientific literature. Our literature-based discovery of NF-kappaB with its possible connections to autism was recently approved by scientific community, which confirms the ability of our literature mining methodology to accelerate future discoveries based on rare ideas from existing literature. PMID- 24788269 TI - Integrative literature and data mining to rank disease candidate genes. AB - While the genomics-derived discoveries promise benefits to basic research and health care, the speed and affordability of sequencing following recent technological advances has further aggravated the data deluge. Seamless integration of the ever-increasing clinical, genomic, and experimental data and efficient mining for knowledge extraction, delivering actionable insight and generating testable hypotheses are therefore critical for the needs of biomedical research. For instance, high-throughput techniques are frequently applied to detect disease candidate genes. Experimental validation of these candidates however is both time-consuming and expensive. Hence, several computational approaches based on literature and data mining have been developed to identify the most promising candidates for follow-up studies. Based on "guilt by association" principle, most of these methods use prior knowledge about a disease of interest to discover and rank novel candidate genes. In this chapter, we provide a brief overview of recent advances made in literature- and data-mining based approaches for candidate gene prioritization. As a case study, we focus on a Web-based computational approach that uses integrated heterogeneous data sources including gene-literature associations for ranking disease candidate genes and explain how to run typical queries using this system. PMID- 24788268 TI - Mining emerging biomedical literature for understanding disease associations in drug discovery. AB - Systematically evaluating the exponentially growing body of scientific literature has become a critical task that every drug discovery organization must engage in in order to understand emerging trends for scientific investment and strategy development. Developing trends analysis uses the number of publications within a 3-year window to determine concepts derived from well-established disease and gene ontologies to aid in recognizing and predicting emerging areas of scientific discoveries relevant to that space. In this chapter, we describe such a method and use obesity and psoriasis as use-case examples by analyzing the frequency of disease-related MeSH terms in PubMed abstracts over time. We share how our system can be used to predict emerging trends at a relatively early stage and we analyze the literature-identified genes for genetic associations, druggability, and biological pathways to explore any potential biological connections between the two diseases that could be utilized for drug discovery. PMID- 24788270 TI - Role of text mining in early identification of potential drug safety issues. AB - Drugs are an important part of today's medicine, designed to treat, control, and prevent diseases; however, besides their therapeutic effects, drugs may also cause adverse effects that range from cosmetic to severe morbidity and mortality. To identify these potential drug safety issues early, surveillance must be conducted for each drug throughout its life cycle, from drug development to different phases of clinical trials, and continued after market approval. A major aim of pharmacovigilance is to identify the potential drug-event associations that may be novel in nature, severity, and/or frequency. Currently, the state-of the-art approach for signal detection is through automated procedures by analyzing vast quantities of data for clinical knowledge. There exists a variety of resources for the task, and many of them are textual data that require text analytics and natural language processing to derive high-quality information. This chapter focuses on the utilization of text mining techniques in identifying potential safety issues of drugs from textual sources such as biomedical literature, consumer posts in social media, and narrative electronic medical records. PMID- 24788271 TI - Systematic drug repurposing through text mining. AB - Drug development remains a time-consuming and highly expensive process with high attrition rates at each stage. Given the safety hurdles drugs must pass due to increased regulatory scrutiny, it is essential for pharmaceutical companies to maximize their return on investment by effectively extending drug life cycles. There have been many effective techniques, such as phenotypic screening and compound profiling, which identify new indications for existing drugs, often referred to as drug repurposing or drug repositioning. This chapter explores the use of text mining leveraging several publicly available knowledge resources and mechanism of action representations to link existing drugs to new diseases from biomedical abstracts in an attempt to generate biologically meaningful alternative drug indications. PMID- 24788272 TI - Mining the electronic health record for disease knowledge. AB - The growing amount and availability of electronic health record (EHR) data present enhanced opportunities for discovering new knowledge about diseases. In the past decade, there has been an increasing number of data and text mining studies focused on the identification of disease associations (e.g., disease disease, disease-drug, and disease-gene) in structured and unstructured EHR data. This chapter presents a knowledge discovery framework for mining the EHR for disease knowledge and describes each step for data selection, preprocessing, transformation, data mining, and interpretation/validation. Topics including natural language processing, standards, and data privacy and security are also discussed in the context of this framework. PMID- 24788273 TI - Axial knee radiographs: consistency across clinic sites. AB - PURPOSE: (1) Do radiographic protocols for knee axial images vary across different clinic locations? (2) Does variability between radiographic positioning protocols (knee flexion angle, beam positioning) yield different radiographic measurements that could influence clinical assumptions? METHODS: Radiographic positioning, including beam angle and knee flexion, was measured using a photograph taken of a phantom leg and (human) model set-up. An axial radiograph of a phantom leg was taken at seven different outpatients musculoskeletal clinics to assess patella position (lateral tilt/translation). The phantom leg patella was placed in an abnormal position for the radiographic image across all sites. RESULTS: Knee flexion<30 degrees was less accurate in obtaining requested knee flexion than higher knee flexion angles (phantom limb error averaged 6 degrees , range 4 degrees -7 degrees human model error averaged 15 degrees , range 11 degrees -25 degrees ). Of the five sites utilizing a 'Merchants' axial radiographs, the congruence angle varied from +12 degrees to +29 degrees , being normal at one site (+12 degrees ) and abnormal (>+16 degrees ) at three sites, and negative at one site (-15 degrees ). CONCLUSIONS: Radiographic protocols for knee axial imaging are inconsistent in radiographic positioning and imaging. This variability can lead to disparity in radiographic image results used for clinical decision-making. Standardization of radiographic positioning would yield more consistent imaging of patella position in early flexion, increasing clinical utility and accuracy. PMID- 24788275 TI - Effect of peroxisome proliferator-activated receptor gamma on the cholesterol efflux of peritoneal macrophages in inflammation. AB - Atherosclerosis, a chronic inflammatory disorder characterized by lipid and cholesterol accumulation, is the principal contributing factor to the pathology of cardiovascular disease. Macrophages contribute to plaque development by internalizing native and modified lipoproteins that convert them into cholesterol rich foam cells. With multiple factors, including hypercholesterolemia and inflammation, promoting atherosclerosis, it is of great significance to elucidate how the mechanism of cholesterol efflux from the macrophages changes and the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in these situations. Following isolation and culture of peritoneal macrophages from C57BL/6 mice in the present study, the cells were divided into three groups: The control group, the ciglitazone group and the PPARgamma antisense oligonucleotide group. The expression of PPARgamma and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaBalpha) in each group was observed through the levels of protein and mRNA, and then the cholesterol efflux of each group was investigated. In addition, the same experiments were repeated following stimulation of each group with lipopolysaccharide (LPS). No significant difference in the expression levels of PPARgamma between the control group and ciglitazone group was observed. The expression levels of PPARgamma in the PPARgamma antisense oligonucleotide group were evidently lower than those in the control group. Subsequent to stimulation with LPS, the expression levels of PPARgamma in the three groups were higher than those of each group prior to stimulation. The cholesterol efflux of the PPARgamma antisense oligonucleotide group was clearly suppressed following stimulation with LPS in comparison with that of the other groups. PPARgamma contributes to anti-inflammation by protecting IkappaBalpha from being phosphorylated and degraded and promoting cholesterol efflux from peritoneal macrophages in inflammation. PMID- 24788276 TI - "Psychological interventions for psychosis": theme and variations. PMID- 24788277 TI - A cognitive neuroscience trifecta. PMID- 24788278 TI - New serological evidence points toward an infectious route to bipolar disorder. PMID- 24788279 TI - Toward mapping altered trajectories of brain development in depression. PMID- 24788280 TI - DSM-5 and the research domain criteria: 100 years after Jaspers' General psychopathology. PMID- 24788281 TI - The global dissemination of psychological treatments: a road map for research and practice. PMID- 24788283 TI - Depression in a Latino man in New York. AB - This case illustrates some of the issues that may affect a Latino patient's presentation. Although the patient's constellation of symptoms are classically representative of major depression, the patient also raises themes regarding the process of immigration, subsequent challenges in acculturation and identification with the host culture versus the culture of origin, and culture-specific notions about causes of symptoms. In addition to some of the special features of stigma in Latino cultures, the prominence of physical concerns in the presentation and the use of traditional healers contribute to the complexity of selecting appropriate interventions for this young man. PMID- 24788282 TI - Coaching in healthy dietary practices in at-risk older adults: a case of indicated depression prevention. AB - Prevention of major depressive disorder is important because current treatments are only partially adequate in reducing symptom burden and promoting health related quality of life. Lifestyle interventions may be a desirable prevention strategy for reasons of patient preference, particularly among older patients from minority groups. Using evidence from a randomized depression prevention trial for older adults, the authors found that coaching in healthy dietary practices was potentially effective in protecting at-risk older adults from developing incident episodes of major depression. The authors describe the dietary coaching program (highlighted in a case example) as well as the feasibility and potential efficacy of the program within the context of evidence based interventions for preventing episodes of major depression and mitigating symptoms of depression. Older adults receiving dietary coaching experienced a low incidence of major depressive episodes and exhibited a 40%-50% decrease in depressive symptoms, as well as enhanced well-being, during the initial 6-week intervention; these gains were sustained over 2 years. The authors also describe why lifestyle interventions like coaching in healthy dietary practices may hold promise as effective, practical, nonstigmatizing interventions for preventing episodes of major depressive disorder in older adults with subsyndromal depressive symptoms. PMID- 24788284 TI - Angel of the Waters (Bethesda Fountain) by Emma Stebbins. PMID- 24788285 TI - Risk of upper gastrointestinal bleeding when taking SSRIs with NSAIDs or aspirin. PMID- 24788286 TI - Response to Kuo et al. PMID- 24788287 TI - Psychoanalytic psychotherapy or cognitive-behavioral therapy for bulimia nervosa. PMID- 24788288 TI - Response to Tasca et al. PMID- 24788289 TI - Genetic counseling for common psychiatric disorders: an opportunity for interdisciplinary collaboration. PMID- 24788296 TI - Resource document on risk management and liability issues in integrated care models. PMID- 24788299 TI - Extreme Anemia Causing Unusual "Black-out" of the Cerebral Vessels on Noncontrast Brain CT. PMID- 24788298 TI - Specificity of anti-tau antibodies when analyzing mice models of Alzheimer's disease: problems and solutions. AB - Aggregates of hyperphosphorylated tau protein are found in a group of diseases called tauopathies, which includes Alzheimer's disease. The causes and consequences of tau hyperphosphorylation are routinely investigated in laboratory animals. Mice are the models of choice as they are easily amenable to transgenic technology; consequently, their tau phosphorylation levels are frequently monitored by Western blotting using a panel of monoclonal/polyclonal anti-tau antibodies. Given that mouse secondary antibodies can recognize endogenous mouse immunoglobulins (Igs) and the possible lack of specificity with some polyclonal antibodies, non-specific signals are commonly observed. Here, we characterized the profiles of commonly used anti-tau antibodies in four different mouse models: non-transgenic mice, tau knock-out (TKO) mice, 3xTg-AD mice, and hypothermic mice, the latter a positive control for tau hyperphosphorylation. We identified 3 tau monoclonal antibody categories: type 1, characterized by high non-specificity (AT8, AT180, MC1, MC6, TG-3), type 2, demonstrating low non-specificity (AT270, CP13, CP27, Tau12, TG5), and type 3, with no non-specific signal (DA9, PHF-1, Tau1, Tau46). For polyclonal anti-tau antibodies, some displayed non-specificity (pS262, pS409) while others did not (pS199, pT205, pS396, pS404, pS422, A0024). With monoclonal antibodies, most of the interfering signal was due to endogenous Igs and could be eliminated by different techniques: i) using secondary antibodies designed to bind only non-denatured Igs, ii) preparation of a heat stable fraction, iii) clearing Igs from the homogenates, and iv) using secondary antibodies that only bind the light chain of Igs. All of these techniques removed the non-specific signal; however, the first and the last methods were easier and more reliable. Overall, our study demonstrates a high risk of artefactual signal when performing Western blotting with routinely used anti-tau antibodies, and proposes several solutions to avoid non-specific results. We strongly recommend the use of negative (i.e., TKO) and positive (i.e., hypothermic) controls in all experiments. PMID- 24788302 TI - Degradation of alpha-melanocyte-stimulating hormone photosensitized by pterin. AB - Oxidized pterins, efficient photosensitizers under UV-A irradiation, accumulate in the skin of patients suffering from vitiligo, a chronic depigmentation disorder. In this work, we have investigated the ability of pterin (Ptr), the parent compound of oxidized pterins, to photosensitize the oxidation of the peptide alpha-melanocyte-stimulating hormone (alpha-MSH), which stimulates the production and release of melanin by melanocytes in skin and hair. Our results showed that Ptr is able to photoinduce the degradation of alpha-MSH upon UV-A irradiation and that the reaction is initiated by an electron transfer from the peptide to the triplet excited state of Ptr. The photosensitized process produces chemical changes in at least two different amino acid residues: tryptophan and tyrosine (Tyr). It was shown that alpha-MSH undergoes dimerization and oxidation, the former process taking place after the formation of Tyr radicals. The present findings are analyzed in the context of the general behavior of pterins as photosensitizers and the biological implications are discussed. PMID- 24788304 TI - MyCases-a portable application for radiologic case collections. AB - Radiologists come across interesting patient cases almost every day. This work proposes a novel case database server for quick and easy storage of such cases including whole image series, patient data, and annotations. Cases can be added to the database by saving DICOM images into a predefined directory on the local network. The application automatically extracts patient and study data from the DICOM header and saves it in the database while images are stored as anonymized JPEG files. Users can mark their cases as private or public (visible to all users). Different data fields for annotations and categorization of a case are available. The user frontend also provides several retrieval mechanisms allowing for browsing the cases and performing different kinds of search queries. The stored series can be scrolled interactively in the form of scrollable image stacks. The project is realized as a web-based application using a portable web and database server software package (XAMPP). This makes the system very lightweight and easy to run on almost any desktop computer, even from a USB flash drive, without the need for deeper IT knowledge and administrative rights. PMID- 24788303 TI - Simvastatin modulates cellular components in influenza A virus-infected cells. AB - Influenza A virus is one of the most important health risks that lead to significant respiratory infections. Continuous antigenic changes and lack of promising vaccines are the reasons for the unsuccessful treatment of influenza. Statins are pleiotropic drugs that have recently served as anti-influenza agents due to their anti-inflammatory activity. In this study, the effect of simvastatin on influenza A-infected cells was investigated. Based on the MTT cytotoxicity test, hemagglutination (HA) assay and qPCR it was found that simvastatin maintained cell viability and decreased the viral load significantly as compared to virus-inoculated cells. The expression of important pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6 and interferon-gamma), which was quantified using ELISA showed that simvastatin decreased the expression of pro inflammatory cytokines to an average of 2-fold. Furthermore, the modulation of actin filament polymerization was determined using rhodamine staining. Endocytosis and autophagy processes were examined by detecting Rab and RhoA GTPase protein prenylation and LC3 lipidation using western blotting. The results showed that inhibiting GTPase and LC3 membrane localization using simvastatin inhibits influenza replication. Findings of this study provide evidence that modulation of RhoA, Rabs and LC3 may be the underlying mechanisms for the inhibitory effects of simvastatin as an anti-influenza compound. PMID- 24788305 TI - Effects of Affective and Anxiety Disorders on Outcome in Problem Gamblers Attending Routine Cognitive-Behavioural Treatment in South Australia. AB - This study evaluated the influence of 12-month affective and anxiety disorders on treatment outcomes for adult problem gamblers in routine cognitive-behavioural therapy. A cohort study at a state-wide gambling therapy service in South Australia. Primary outcome measure was rated by participants using victorian gambling screen (VGS) 'harm to self' sub-scale with validated cut score 21+ (score range 0-60) indicative of problem gambling behaviour. Secondary outcome measure was Work and Social Adjustment Scale (WSAS). Independent variable was severity of affective and anxiety disorders based on Kessler 10 scale. We used propensity score adjusted random-effects models to estimate treatment outcomes for sub-populations of individuals from baseline to 12 month follow-up. Between July, 2010 and December, 2012, 380 participants were eligible for inclusion in the final analysis. Mean age was 44.1 (SD = 13.6) years and 211 (56%) were males. At baseline, 353 (92.9%) were diagnosed with a gambling disorder using VGS. For exposure, 175 (46%) had a very high probability of a 12-month affective or anxiety disorder, 103 (27%) in the high range and 102 (27%) in the low to moderate range. For the main analysis, individuals experienced similar clinically significant reductions (improvement) in gambling related outcomes across time (p < 0.001). Individuals with co-varying patterns of problem gambling and 12 month affective and anxiety disorders who present to a gambling help service for treatment in metropolitan South Australia gain similar significant reductions in gambling behaviours from routine cognitive-behavioural therapy in the mid-term. PMID- 24788306 TI - Individuality and stability in male songs of cao vit gibbons (Nomascus nasutus) with potential to monitor population dynamics. AB - Vocal individuality and stability has been used to conduct population surveys, monitor population dynamics, and detect dispersal patterns in avian studies. To our knowledge, it has never been used in these kinds of studies among primates. The cao vit gibbon is a critically endangered species with only one small population living in a karst forest along China-Vietnam border. Due to the difficult karst terrain, an international border, long life history, and similarity in male morphology, detailed monitoring of population dynamics and dispersal patterns are not possible using traditional observation methods. In this paper, we test individuality and stability in male songs of cao vit gibbons. We then discuss the possibility of using vocal individuality for population surveys and monitoring population dynamics and dispersal patterns. Significant individuality of vocalization was detected in all 9 males, and the correct rate of individual identification yielded by discriminant function analysis using a subset of variables was satisfactory (>90%). Vocal stability over 2-6 years was also documented in 4 males. Several characters of cao vit gibbons allowed long term population monitoring using vocal recordings in both China and Vietnam: 1) regular loud calls, 2) strong individuality and stability in male songs, 3) stable territories, and 4) long male tenure. During the course of this research, we also observed one male replacement (confirmed by vocal analysis). This time- and labor-saving method might be the most effective way to detect dispersal patterns in this transboundary population. PMID- 24788307 TI - Disease-specific predictive formulas for energy expenditure in the dialysis population. AB - OBJECTIVE: Metabolic rate is poorly understood in advanced kidney disease because direct measurement is expensive and time-consuming. Predictive equations for resting energy expenditure (REE) are needed based on simple bedside parameters. Algorithms derived for normal individuals may not be valid in the renal population. We aimed to develop predictive equations for REE specifically for the dialysis population. DESIGN: Two-hundred subjects on maintenance dialysis underwent a comprehensive metabolic assessment including REE from indirect calorimetry. Parameters predicting REE were identified, and regression equations developed and validated in 20 separate subjects. RESULTS: Mean REE was 1,658 +/- 317 kCal/day (males) and 1,380 +/- 287 kCal/day (females). Weight and height correlated positively with REE (r(2) = 0.54 and 0.31) and negatively with age older than 65 years (r(2) = 0.18). The energy cost of a unitary kilogram of body weight increased nonlinearly for lower body mass index (BMI). Existing equations derived in normal individuals underestimated REE (bias 50-114 kCal/day for 3 equations). The novel derived equation was REE(kCal/day) = 2.497.Age.Factorage+0.011.height(2.023) + 83.573.Weight(0.6291) + 68.171.Factorsex, where Factorage = 1 if 65 years or older and 0 if younger than 65, and Factorsex = 1 if male and 0 if female. This algorithm performed at least as well as those developed for normals in terms of limits of agreement and reduced bias. In validation with the Bland-Altman technique, bias was not significant for our algorithm (-22 +/- 96 kCal/day). The 95% limits of agreement were +380 to -424 kCal/day. CONCLUSION: Existing equations for REE derived from normal individuals are not valid in the dialysis population. The relatively increased REE in those with low BMI implies the need for higher dialysis doses in this subgroup. This disease-specific algorithm may be useful clinically and as a research tool to predict REE. PMID- 24788308 TI - Relation between anxiety, depression, and physical activity and performance in maintenance hemodialysis patients. AB - OBJECTIVE: Maintenance hemodialysis (MHD) patients have a high prevalence of anxiety and depression and decreased daily physical activity (DPA) and exercise capacity. Because affective disorders may affect DPA and physical performance, we investigated possible relationships between anxiety or depression and DPA and physical performance in relatively healthy MHD patients. DESIGN AND METHODS: This cross-sectional study included 72 relatively healthy MHD patients and 39 normal adults. DPA was measured for 7 days with an Actigraph Activity Monitor(r). Physical performance was assessed using the 6-minute walk (6-MWT), sit-to-stand (STS), and stair-climbing tests. Subjects completed the Beck Anxiety Inventory (BAI), the Beck Depression Inventory-II (BDI), and the Hospital Anxiety and Depression Scale (HADS). Main outcome measures were physical activity counts (expressed as vector magnitude), in the 6-MWT, STS, stair-climbing test, BAI, BDI, and HADS scores. RESULTS: Anxiety and depression by BAI and BDI were identified in 43% and 33% of MHD patients and 2.5% and 5% of normals, respectively (P < .0001 for each comparison). MHD patients without anxiety or depression had decreased DPA and physical performance compared with normals, indicating that these disorders were also independent of anxiety or depression. MHD patients with anxiety and depression generally had the most impaired DPA and physical performance. Higher BAI and BDI scores were each associated with impaired physical performance. In fully adjusted analyses, DPA in MHD patients was negatively correlated with the BDI (r = -0.33, P = .01) but not with the BAI. DPA on the day of hemodialysis (P = .01), and day 1 (P = .03) and day 2 (P = .03) after dialysis each correlated negatively with degree of depression by BDI. In MHD patients, BAI was negatively correlated with 6-MWT (P = .03) and STS (P = .04). CONCLUSIONS: In relatively healthy adult MHD patients, anxiety and depression are common and are associated with impaired physical performance. There was a trend toward stronger negative associations between BDI scores and DPA than between BAI scores and DPA. PMID- 24788309 TI - Urinary phytate (Myo-inositol hexaphosphate) in healthy school children and risk of nephrolithiasis. AB - OBJECTIVE: Although the incidence of urolithiasis is lower in children than in adults, the number of children with urolithiasis is increasing. Phytate, a naturally occurring compound present in legumes, nuts, and whole meals, has antilithiasic activity. The aim of this study was to assess, for the first time, the urinary levels of phytate in children and to correlate these levels with other urinary parameters related to crystallization risk and to general dietary habits. DESIGN AND METHODS: This was a cohort study conducted from April 2012 to March 2013 in the Laboratory of Investigation in Renal Lithiasis and at Son Espases Universitary Hospital in Palma de Majorca, Spain. SUBJECTS: Subjects included 165 healthy schoolchildren aged 5 to 12 years. INTERVENTION: All subjects followed their habitual diet. Information on the main dietary habits of the study subjects was obtained by asking each child's parents to fill out a dietary questionnaire. MAIN OUTCOME MEASURE: Phytate and citrate concentration and excretion were measured in 2 urine samples (a spot sample and a 12-hour overnight sample) for each child. Furthermore, common urinary biochemical indicators of stone risk were measured in each sample. RESULTS: The urinary phytate concentrations were low in this child population because of low consumption of dietary phytate. The urinary concentrations of phytate and citrate were low in 27.5% of these children. CONCLUSION: Because both substances are important inhibitors of crystallization, these finding suggests that these children are at risk of crystallization. Moreover, their diets consisted of foods rich in animal protein, with insufficient consumption of vegetables, legumes, and fruits. PMID- 24788310 TI - Demographic associations of high estimated sodium intake and frequency of consumption of high-sodium foods in people with chronic kidney disease stage 3 in England. AB - OBJECTIVE: The objective of this study was to investigate sodium intake in a cohort of people with chronic kidney disease (CKD) Stage 3 in England to identify demographic characteristics of subgroups with high sodium intake and specific foods that contribute to excessive sodium intake. DESIGN AND METHODS: Study subjects (N = 1,729) included CKD patients from 32 general practices in the Renal Risk in Derby study. Patients had a glomerular filtration rate between 30 and 59 mL/min per 1.73 m(2) on 2 or more occasions at least 3 months apart before recruitment. Sodium excretion (assumed to be equal to intake) was estimated from early morning urine specimens using an equation validated for this study population. The frequency of intake of 12 salty foods was assessed by a food frequency questionnaire. RESULTS: The mean estimated urinary sodium excretion was 110.5 +/- 33.8 mmol/day; 60.1% had values above the National Kidney Foundation recommendation (<100 mmol/day). Subgroups with a greater percentage of participants having sodium excretion above the recommendation were as follows: men, those younger than 75 years of age, those with central obesity or diabetes, those with formal educational qualifications, and those who were previous or current smokers. In multivariable analysis, gender, younger age, waist-to-hip ratio, and diabetes mellitus status were the main independent determinants of excessive sodium excretion. Specific food items that contributed to excessive intake were table and cooking salt, salted snacks, hard cheeses, processed meat, and tinned fish. The most important source of sodium varied by subgroup. CONCLUSION: A high prevalence of sodium excretion above the recommended value was detected, and independent determinants were gender, age, waist-to-hip ratio, and diabetes mellitus. Specific food items that contributed to excessive intake were also identified and varied in different subgroups. These data will be helpful in informing strategies to target dietetic advice to those most likely to have high sodium intake and will allow dietitians to focus on the most likely sources of sodium in different subgroups. PMID- 24788311 TI - Intake and digestion of wethers fed with dwarf elephant grass hay with or without the inclusion of peanut hay. AB - The aim of this study was to evaluate the effect of the inclusion of peanut (Arachis pintoi cv. Amarillo) hay in diets based on dwarf elephant grass (DEG, Pennisetum purpureum Schum cv. Kurumi) hay of different regrowth ages on forage intake and digestibility in wether lambs. The experimental treatments consisted of DEG hay with an interval of regrowth of 30 or 45 days offered as the only feed or in mixture with peanut hay (300 g/kg of total dry matter (DM)), which were tested in eight Texel * Suffolk crossbred wethers in a replicated 4 * 4 Latin square experiment. Both organic matter (OM) and digestible OM intakes were higher (P < 0.05) in animals receiving the legume forage. Total apparent OM digestibility was higher (P < 0.05) at an increased grass regrowth age. Ruminal OM digestibility increased (P < 0.05) with legume inclusion and at a higher grass regrowth age. The nitrogen (N) intake was higher (P < 0.05) in legume treatments and lower (P < 0.05) as the grass regrowth age increased, but retention of N was not affected by treatments. Duodenal flow of both, non-ammonia N and microbial N, were not affected by legume inclusion and were lower (P < 0.05) as grass regrowth age increased. The efficiency of rumen microbial protein synthesis (ERMPS) was negatively affected (P < 0.05) by legume inclusion and was lower (P < 0.05) as the grass regrowth age increased. Supplementation of dwarf elephant grass hay cut at the vegetative stage with peanut legume hay improves nutritional supply to wethers due to an increase in the forage intake. PMID- 24788312 TI - Point mutations associated with organophosphate and carbamate resistance in Chinese strains of Culex pipiens quinquefasciatus (Diptera: Culicidae). AB - Acetylcholinesterase resistance has been well documented in many insects, including several mosquito species. We tested the resistance of five wild, Chinese strains of the mosquito Culex pipiens quinquefasciatus to two kinds of pesticides, dichlorvos and propoxur. An acetylcholinesterase gene (ace1) was cloned and sequenced from a pooled sample of mosquitoes from these five strains and the amino acids of five positions were found to vary (V185M, G247S, A328S, A391T, and T682A). Analysis of the correlation between mutation frequencies and resistance levels (LC50) suggests that two point mutations, G247S (r2 = 0.732, P = 0.065) and A328S (r2 = 0.891, P = 0.016), are associated with resistance to propoxur but not to dichlorvos. Although the V185M mutation was not associated with either dichlorvos or propoxur resistance, its RS genotype frequency was correlated with propoxur resistance (r2 = 0.815, P = 0.036). And the HWE test showed the A328S mutation is linked with V185M, also with G247S mutation. This suggested that these three mutations may contribute synergistically to propoxur resistance. The T682A mutation was negatively correlated with propoxur (r2 = 0.788, P = 0.045) resistance. Knowledge of these mutations may help design strategies for managing pesticide resistance in wild mosquito populations. PMID- 24788313 TI - A mutation in POLE predisposing to a multi-tumour phenotype. AB - Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase epsilon have been found in sporadic colorectal cancers (CRCs) and are most likely of importance in tumour development and/or progression. Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE. The highly penetrant mutation was associated with predisposition to CRC only and no extra-colonic tumours were observed. We have identified a mutation in a large family in which the carriers not only developed CRC, they also demonstrate a highly penetrant predisposition to extra-intestinal tumours such as ovarian, endometrial and brain tumours. The mutation, NM_006231.2:c.1089C>A, p.Asn363Lys, also located in the proofreading exonuclease domain is directly involved in DNA binding. Theoretical prediction of the amino acid substitution suggests a profound effect of the substrate binding capability and a more severe impairment of the catalytic activity compared to the previously reported germline mutation. A possible genotype to phenotype correlation for deleterious mutations in POLE might exist that needs to be considered in the follow-up of mutation carriers. PMID- 24788314 TI - Factors influencing primary health care professionals' physical activity promotion behaviors: a systematic review. AB - BACKGROUND: Despite the promising findings related to the efficacy of interventions aimed at promoting physical activity (PA) in primary health care (PHC), the translation of these interventions to PHC practice does not always happen as desired. PURPOSE: To help understand why efficacious PHC-based PA interventions are not effectively translated to practice, this study systematically reviewed the literature on factors influencing PHC professionals' PA promotion practices. METHOD: Literature searches were conducted in Web of Science, PubMed, and PsycINFO for peer-reviewed articles published in English from 1990 onwards. Studies were included that met the following criteria: (1) involving PHC-based PA interventions, and (2) reporting factors influencing PHC professionals' PA promotion behaviors. Two researchers independently screened studies and extracted data. A narrative synthesis using thematic analysis was conducted to identify factors. RESULTS: Of the 4,469 identified articles, 59 were included in the review. Factors were identified by qualitative methods, barrier/facilitator ratings, and the examination of the relationship between factors and PA promotion, and the effectiveness of introduction strategies. Many factors related to the development, delivery, and effects of the innovation, the sociopolitical and organizational culture, resources, and support, patient and PHC professional characteristics, and innovation strategies were identified as potential influences on PHC professionals' PA promotion practices. However, the lack of evidence on the relationship between factors and PA promotion indicated insufficient evidence on PA promotion determinants. CONCLUSION: This extensive overview of potential factors can inform intervention developers and implementers on which factors may play a role when introducing PA interventions in PHC. Future research should further investigate relationships between factors and PA promotion, which should be guided by qualitative in-depth knowledge on influencing factors. PMID- 24788315 TI - The fear-avoidance model of chronic pain: assessing the role of neuroticism and negative affect in pain catastrophizing using structural equation modeling. AB - BACKGROUND: Previous research on the fear-avoidance model (FAM) of chronic pain suggests that the personality traits of neuroticism and negative affect (NA) influence pain catastrophizing. However, the mechanisms of their influence on pain catastrophizing remain unclear. PURPOSE: This study examined four possible models of relationships between neuroticism, NA, and pain catastrophizing within the FAM framework using structural equation modeling. METHOD: A total of 401 patients with chronic musculoskeletal pain completed measures of neuroticism, NA, three core FAM components (pain catastrophizing, pain-related fear, and pain anxiety), and adjustment outcomes (pain-related disability and depression). RESULTS: Regression analyses refuted the possibility that neuroticism and NA moderated each other's effect on pain catastrophic thoughts (p > 0.05). Results of structural equation modeling (SEM) evidenced superior data-model fit for the collapsed models in which neuroticism and NA were two secondary traits underlying a latent construct, negative emotion (disability: comparative fit index (CFI) = 0.93; depression: CFI = 0.91). CONCLUSION: The results offer preliminary evidence that patients presenting with more neurotic symptom and heightened NA probably elicit more catastrophic thoughts about pain. PMID- 24788316 TI - Changing minds, changing lives from the top down: an investigation of the dissemination and adoption of a Canada-wide educational intervention to enhance health care professionals' intentions to prescribe physical activity. AB - PURPOSE: The purposes of the current study were to (1) describe the restructuring and dissemination of a Canada-wide intervention curriculum designed to enhance health care professionals' prescription of physical activity to patients with physical disabilities, and (2) examine interventionists' social cognitions for, and their acceptance and adoption of, the new curriculum. METHODS: A participatory curriculum development process was utilized, resulting in a theory- and evidence-based curriculum. Interventionists (N = 28) were trained in curriculum delivery and most (n = 22) completed measures of Theory of Planned Behavior (TPB) constructs assessing their cognitions for delivering the new curriculum at pre- and post-training and at 6-month follow-up. Interventionists also completed a Diffusion of Innovations (DOI) measure assessing their opinion of whether the new curriculum met characteristics that would facilitate its adoption and use. RESULTS: Interventionists reported strong TPB cognitions for curriculum use before training. Significant increases emerged for some TPB constructs (ps <= 0.025) from pre- to post-training, and significant decreases were seen in some TPB constructs (ps <= 0.024) between post-training and 6-month follow-up. The interventionists rated the new curriculum as high on all the DOI characteristics. CONCLUSION: The theory-driven, participatory development process facilitated interventionists' social cognitions towards and adoption of the new curriculum. Positive increases in TPB cognitions from pre- to post-training were not maintained at follow-up. Further research is needed to determine if these changes in cognitions are indicative of a curriculum "reinvention" process that facilitates long-term curriculum use. Understanding curriculum adoption and implementation is a crucial step to determining the potential population impact of the intervention. PMID- 24788317 TI - Altered regional and circuit resting-state activity associated with unilateral hearing loss. AB - The deprivation of sensory input after hearing damage results in functional reorganization of the brain including cross-modal plasticity in the sensory cortex and changes in cognitive processing. However, it remains unclear whether partial deprivation from unilateral auditory loss (UHL) would similarly affect the neural circuitry of cognitive processes in addition to the functional organization of sensory cortex. Here, we used resting-state functional magnetic resonance imaging to investigate intrinsic activity in 34 participants with UHL from acoustic neuroma in comparison with 22 matched normal controls. In sensory regions, we found decreased regional homogeneity (ReHo) in the bilateral calcarine cortices in UHL. However, there was an increase of ReHo in the right anterior insular cortex (rAI), the key node of cognitive control network (CCN) and multimodal sensory integration, as well as in the left parahippocampal cortex (lPHC), a key node in the default mode network (DMN). Moreover, seed-based resting-state functional connectivity analysis showed an enhanced relationship between rAI and several key regions of the DMN. Meanwhile, lPHC showed more negative relationship with components in the CCN and greater positive relationship in the DMN. Such reorganizations of functional connectivity within the DMN and between the DMN and CCN were confirmed by a graph theory analysis. These results suggest that unilateral sensory input damage not only alters the activity of the sensory areas but also reshapes the regional and circuit functional organization of the cognitive control network. PMID- 24788318 TI - HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of type 1 interferon. AB - Innate immune sensing of viral infection results in type I interferon (IFN) production and inflammasome activation. Type I IFNs, primarily IFN-alpha and IFN beta, are produced by all cell types upon virus infection and promote an antiviral state in surrounding cells by inducing the expression of IFN-stimulated genes. Type I IFN production is mediated by Toll-like receptor (TLR) 3 in HCV infected hepatocytes. Type I IFNs are also produced by plasmacytoid dendritic cells (pDC) after sensing of HIV and HCV through TLR7 in the absence of productive pDC infection. Inflammasomes are multi-protein cytosolic complexes that integrate several pathogen-triggered signaling cascades ultimately leading to caspase-1 activation and generation pro-inflammatory cytokines including interleukin (IL)-18 and IL-1beta. Here, we demonstrate that HIV and HCV activate the inflammasome, but not Type I IFN production, in monocytes and macrophages in an infection-independent process that requires clathrin-mediated endocytosis and recognition of the virus by distinct endosomal TLRs. Knockdown of each endosomal TLR in primary monocytes by RNA interference reveals that inflammasome activation in these cells results from HIV sensing by TLR8 and HCV recognition by TLR7. Despite its critical role in type I IFN production by pDCs stimulated with HIV, TLR7 is not required for inflammasome activation by HIV. Similarly, HCV activation of the inflammasome in monocytes does not require TLR3 or its downstream signaling adaptor TICAM-1, while this pathway leads to type I IFN in infected hepatocytes. Monocytes and macrophages do not produce type I IFN upon TLR8 or TLR7 sensing of HIV or HCV, respectively. These findings reveal a novel infection-independent mechanism for chronic viral induction of key anti-viral programs and demonstrate distinct TLR utilization by different cell types for activation of the type I IFN vs. inflammasome pathways of inflammation. PMID- 24788319 TI - Endoscopic therapy with 2-octyl-cyanoacrylate for the treatment of gastric varices. AB - BACKGROUND: Gastric variceal bleeding is associated with significant morbidity and mortality and limited endoscopic therapeutic options. AIM: The aim of this study was to evaluate the short- and long-term efficacy and safety of endoscopic therapy with 2-octyl-cyanoacrylate in patients with gastric variceal bleeding. METHODS: A single-center retrospective review of patients receiving endoscopic therapy for gastric variceal hemorrhage. Patient demographics, laboratory, and procedural data were collected. Patients were followed to death, liver transplantation, or last follow-up. Success rates were defined as immediate control of bleeding; early re-bleeding (1-7 days), short-term re-bleeding (1-12 weeks), overall survival, and serious procedure complications. RESULTS: A total of 41 patients (39 with cirrhosis) underwent 54 cyanoacrylate injections during study period. Mean age was 57 and 73 % were males. Twenty-four (58.5 %) patients had failed or were deemed ineligible for transjugular intra-hepatic portosystemic shunt, and 5 % were done for primary prophylaxis. Immediate hemostasis was achieved in five active bleeders. During a median survival time of 117 days, early re-bleeding was seen in 1 (2.4 %), short-term re-bleeding in five patients (12 %), and varices were eradicated in 15 (46.8 %) patients on follow-up. Mean MELD score at the time of the first injection was 17.1 +/- 7.8. Mean volume injected was 3.4 cc and median number of varices injected per session was one. Eight patients died during the long-term follow-up: metastatic cancer (2), infections (3), liver failure (1), and re-bleeding (2). There were no serious procedure-related complications. CONCLUSIONS: Endoscopic cyanoacrylate therapy appears effective and safe for treatment of patients with bleeding from gastric varices or high-risk stigmata. PMID- 24788320 TI - Antibiotic treatment of constipation-predominant irritable bowel syndrome. AB - BACKGROUND: The antibiotic rifaximin is used to treat non-constipated irritable bowel syndrome (IBS). Methane production is associated with constipation and its severity in constipation-predominant IBS (C-IBS). A previous retrospective study suggested that rifaximin and neomycin was superior to neomycin alone in improving symptoms in methane-positive subjects. AIMS: To determine the effectiveness of neomycin alone or with rifaximin in improving symptoms in methane-positive C-IBS subjects. METHODS: A double-blind, randomized, placebo-controlled trial was performed from 2010 to 2013 at three tertiary care centers. Subjects aged 18-65 with C-IBS (Rome II criteria) and breath methane (>3 ppm) meeting the inclusion and exclusion criteria were recruited. Subjects completed a baseline symptom questionnaire rating the severity of abdominal and bowel symptoms on a visual analog scale and were randomized to receive neomycin and placebo or neomycin and rifaximin for 14 days. Symptom severity was assessed by weekly questionnaire for 2 weeks of therapy and 4 additional weeks of follow-up. RESULTS: Thirty-one subjects (16 neomycin and placebo, 15 neomycin and rifaximin) were included in the intention-to-treat analysis. Constipation severity was significantly lower in the neomycin and rifaximin group (28.6 +/- 30.8) compared to neomycin alone (61.2 +/- 24.1) (P = 0.0042), with greater improvement in constipation (P = 0.007), straining (P = 0.017) and bloating (P = 0.020), but not abdominal pain. In the neomycin and rifaximin group, subjects with methane <3 ppm after treatment reported significantly lower constipation severity (30.5 +/- 21.8) than subjects with persistent methane (67.2 +/- 32.1) (P = 0.020). CONCLUSIONS: Rifaximin plus neomycin is superior to neomycin alone in improving multiple C-IBS symptoms. This effect is predicted by a reduction in breath methane. PMID- 24788321 TI - The prevalence of Clostridium difficile infection in pediatric and adult patients with inflammatory bowel disease. AB - OBJECTIVES: Adults with inflammatory bowel disease (IBD) have a high prevalence of Clostridium difficile infection (CDI). CDI in children with IBD may differ from adults. We aim to compare the prevalence of CDI in hospitalized pediatric and adult IBD patients and patients without IBD. METHODS: The rates of CDI per 1,000 IBD and non-IBD hospitalizations between 1993 and 2012 were examined using the Maryland Health Services Cost Review Commission database. Age, sex and calendar year adjusted incidence rate ratios comparing CDI in pediatrics and adults by type of IBD and with patients without IBD were calculated. p values for trend identifying changes in rates over time were calculated. RESULTS: Among children, the rate of CDI was over 12 times greater in IBD than non-IBD hospitalizations (p < 0.0001) and among adults, the rate of CDI was four times greater in IBD than non-IBD hospitalizations (p < 0.0001). In adults, CDI was significantly higher in ulcerative colitis (UC) than Crohn's disease (60.4 per 1,000 vs. 19.8 per 1,000, p < 0.0001) but in children there was no difference in CDI in UC compared with Crohn's disease (32 per 1,000 vs. 27 per 1,000, p = 0.45). The prevalence of CDI increased in pediatric and adult IBD patients, and patients without IBD, between 1993 and 2012 (p for trend <0.0001). CONCLUSIONS: CDI was more common in adult patients with UC, and no difference was found between CDI and IBD type in pediatrics. There may be different risk factors for CDI during hospitalization between adults and children with IBD. PMID- 24788322 TI - Role of SpyGlass peroral cholangioscopy in the evaluation of indeterminate biliary lesions. AB - BACKGROUND: Accurate diagnosis of indeterminate biliary lesions is essential for treatment planning. The currently available techniques have some limitations in evaluating indeterminate biliary lesions. SpyGlass single-operator peroral cholangioscopy system has been developed to overcome these limitations. AIM: The aim of this retrospective study was to evaluate the diagnostic accuracy of SpyGlass visual assessment and SpyBite biopsy in patients with indeterminate biliary lesions. METHODS: We conducted a retrospective analysis of data from 36 patients with indeterminate biliary strictures or filling defects who had inconclusive results on the cross-sectional imaging study from September 2010 to October 2013. Four patients were excluded because of the presence of a metastatic mass and an ampulla of Vater cancer. RESULTS: Thirty-two patients (19 men, mean age 63.7 years) with indeterminate biliary lesions underwent SpyGlass cholangioscopy. The cholangioscopy procedure with SpyGlass was technically successful in all of the cases except for one case because of the intraprocedural breakage of the SpyGlass optic probe (96.8%, 31/32). The biopsy specimens from nineteen patients were obtained using SpyBite forceps. The sensitivity, specificity, and overall accuracy of SpyGlass visual assessment and SpyBite biopsy for the diagnosis of malignancy were 100% (21/21) and 64.2% (9/14), 90% (9/10) and 100% (5/5), and 96.7% (30/31) and 73.6% (14/19), respectively. Procedure-related complications were noted in three cases; postsphincterotomy bleeding in one case and mild pancreatitis in two cases. CONCLUSIONS: SpyGlass cholangioscopy with SpyBite biopsy is highly accurate and safe for differentiating malignant lesions from benign lesions in patients with indeterminate biliary lesions. PMID- 24788323 TI - Analysis of residuals in contingency tables: another nail in the coffin of conditional approaches to significance testing. AB - Omnibus tests of significance in contingency tables use statistics of the chi square type. When the null is rejected, residual analyses are conducted to identify cells in which observed frequencies differ significantly from expected frequencies. Residual analyses are thus conditioned on a significant omnibus test. Conditional approaches have been shown to substantially alter type I error rates in cases involving t tests conditional on the results of a test of equality of variances, or tests of regression coefficients conditional on the results of tests of heteroscedasticity. We show that residual analyses conditional on a significant omnibus test are also affected by this problem, yielding type I error rates that can be up to 6 times larger than nominal rates, depending on the size of the table and the form of the marginal distributions. We explored several unconditional approaches in search for a method that maintains the nominal type I error rate and found out that a bootstrap correction for multiple testing achieved this goal. The validity of this approach is documented for two-way contingency tables in the contexts of tests of independence, tests of homogeneity, and fitting psychometric functions. Computer code in MATLAB and R to conduct these analyses is provided as Supplementary Material. PMID- 24788324 TI - Widely applicable MATLAB routines for automated analysis of saccadic reaction times. AB - Saccadic reaction time (SRT) is a widely used dependent variable in eye-tracking studies of human cognition and its disorders. SRTs are also frequently measured in studies with special populations, such as infants and young children, who are limited in their ability to follow verbal instructions and remain in a stable position over time. In this article, we describe a library of MATLAB routines (Mathworks, Natick, MA) that are designed to (1) enable completely automated implementation of SRT analysis for multiple data sets and (2) cope with the unique challenges of analyzing SRTs from eye-tracking data collected from poorly cooperating participants. The library includes preprocessing and SRT analysis routines. The preprocessing routines (i.e., moving median filter and interpolation) are designed to remove technical artifacts and missing samples from raw eye-tracking data. The SRTs are detected by a simple algorithm that identifies the last point of gaze in the area of interest, but, critically, the extracted SRTs are further subjected to a number of postanalysis verification checks to exclude values contaminated by artifacts. Example analyses of data from 5- to 11-month-old infants demonstrated that SRTs extracted with the proposed routines were in high agreement with SRTs obtained manually from video records, robust against potential sources of artifact, and exhibited moderate to high test retest stability. We propose that the present library has wide utility in standardizing and automating SRT-based cognitive testing in various populations. The MATLAB routines are open source and can be downloaded from http://www.uta.fi/med/icl/methods.html . PMID- 24788325 TI - Comment on Hoffman and Rovine (2007): SPSS MIXED can estimate models with heterogeneous variances. AB - Hoffman and Rovine (Behavior Research Methods, 39:101-117, 2007) have provided a very nice overview of how multilevel models can be useful to experimental psychologists. They included two illustrative examples and provided both SAS and SPSS commands for estimating the models they reported. However, upon examining the SPSS syntax for the models reported in their Table 3, we found no syntax for models 2B and 3B, both of which have heterogeneous error variances. Instead, there is syntax that estimates similar models with homogeneous error variances and a comment stating that SPSS does not allow heterogeneous errors. But that is not correct. We provide SPSS MIXED commands to estimate models 2B and 3B with heterogeneous error variances and obtain results nearly identical to those reported by Hoffman and Rovine in their Table 3. Therefore, contrary to the comment in Hoffman and Rovine's syntax file, SPSS MIXED can estimate models with heterogeneous error variances. PMID- 24788326 TI - Transformable facultative thermophile Geobacillus stearothermophilus NUB3621 as a host strain for metabolic engineering. AB - Metabolic engineers develop inexpensive enantioselective syntheses of high-value compounds, but their designs are sometimes confounded by the misfolding of heterologously expressed proteins. Geobacillus stearothermophilus NUB3621 is a readily transformable facultative thermophile. It could be used to express and properly fold proteins derived from its many mesophilic or thermophilic Bacillaceae relatives or to direct the evolution of thermophilic variants of mesophilic proteins. Moreover, its capacity for high-temperature growth should accelerate chemical transformation rates in accordance with the Arrhenius equation and reduce the risks of microbial contamination. Its tendency to sporulate in response to nutrient depletion lowers the costs of storage and transportation. Here, we present a draft genome sequence of G. stearothermophilus NUB3621 and describe inducible and constitutive expression plasmids that function in this organism. These tools will help us and others to exploit the natural advantages of this system for metabolic engineering applications. PMID- 24788327 TI - The C-terminal region of xylanase domain in Xyn11A from Paenibacillus curdlanolyticus B-6 plays an important role in structural stability. AB - Paenibacillus curdlanolyticus B-6 produces an extracellular multienzyme complex containing a major xylanase subunit, designated Xyn11A, which includes two functional domains belonging to glycosyl hydrolase family-11 (GH11) and carbohydrate binding module family-36 (CBM36) and possesses a glycine and asparagine-rich linker (linker). To clarify the roles of each functional domain, recombinant proteins XynXL and XynX (CBM36 deleted and CBM36 and linker deleted, respectively) were constructed. Their xylanase activities were similar toward soluble xylan, whereas XynXL showed decreased hydrolysis activity toward insoluble xylan while XynX had no xylanase activity. To determine the significance of the linker and its neighbor region, XynX was subjected to secondary structural alignments using circular dichroism (CD) spectroscopy and three-dimensional (3D) structural analysis. A seven amino acid (NTITIGG) neighbor linker sequence was highly conserved among GH11 xylanases of Paenibacillus species. Although XynX exhibited a typical GH11 xylanase structure, conformational gaps were observed in the beta6- and beta12-sheets and in CD spectra. Flipping of the Arg163 side chains in the subsite was also observed upon analysis of superimposed models. Docking analysis using xylohexaose indicated that flipping of the Arg163 side chains markedly affected substrate binding in the subsite. To identify the amino acids related to stabilizing the substrate binding site, XynX with an extended C-terminal region was designed. At least seven amino acids were necessary to recover substrate binding and xylanase activity. These results indicated that the seven amino acid neighbor Xyn11A linker plays an important role in the activity and conformational stability of the xylanase domain. PMID- 24788328 TI - Perspectives for the biotechnological production of ethyl acetate by yeasts. AB - Ethyl acetate is an environmentally friendly solvent with many industrial applications. The production of ethyl acetate currently proceeds by energy intensive petrochemical processes which are based on natural gas and crude oil without exception. Microbial synthesis of ethyl acetate could become an interesting alternative. The formation of esters as aroma compounds in food has been repeatedly reviewed, but a survey which deals with microbial synthesis of ethyl acetate as a bulk product is missing. The ability of yeasts for producing larger amounts of this ester is known for a long time. In the past, this potential was mainly of scientific interest, but in the future, it could be applied to large-scale ester production from renewable raw materials. Pichia anomala, Candida utilis, and Kluyveromyces marxianus are yeasts which convert sugar into ethyl acetate with a high yield where the latter is the most promising one. Special attention was paid to the mechanism of ester synthesis including regulatory aspects and to the maximum and expectable yield. Synthesis of much ethyl acetate requires oxygen which is usually supplied by aeration. Ethyl acetate is highly volatile so that aeration results in its phase transfer and stripping. This stripping process cannot be avoided but requires adequate handling during experimentation and offers a chance for a cost-efficient process integrated recovery of the synthesized ester. PMID- 24788329 TI - dsrAB-based analysis of sulphate-reducing bacteria in moving bed biofilm reactor (MBBR) wastewater treatment plants. AB - Sulphate-reducing bacteria (SRB) are important members of the sulphur cycle in wastewater treatment plants (WWTPs). In this study, we investigate the diversity and activity of SRB within the developing and established biofilm of two moving bed biofilm reactor (MBBR) systems treating municipal wastewater in New Zealand. The larger of the two WWTPs (Moa Point) generates high levels of sulphide relative to the smaller Karori plant. Clone libraries of the dissimilatory (bi)sulphite reductase (dsrAB) genes and quantitative real-time PCR targeting dsrA transcripts were used to compare SRB communities between the two WWTPs. Desulfobulbus (35-53 % of total SRB sequences) and genera belonging to the family Desulfobacteraceae (27-41 %) dominated the SRB fraction of the developing biofilm on deployed plastic carriers at both sites, whereas Desulfovibrio and Desulfomicrobium were exclusively found at Moa Point. In contrast, the established biofilms from resident MBBR carriers were largely dominated by Desulfomonile tiedjei-like organisms (58-100 % of SRB sequences). The relative transcript abundance of dsrA genes (signifying active SRBs) increased with biofilm weight yet remained low overall, even in the mature biofilm stage. Our results indicate that although SRB are both present and active in the microbial community at both MBBR study sites, differences in the availability of sulphate may be contributing to the observed differences in sulphide production at these two plants. PMID- 24788330 TI - Cloning, expression, and directed evolution of carbonyl reductase from Leifsonia xyli HS0904 with enhanced catalytic efficiency. AB - (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol ((R)-BTPE) is a valuable chiral intermediate for the synthesis of antiemetic drug Aprepitant and Fosaprepitant. A Leifsonia xyli HS0904-derived carbonyl reductase (LXCAR), an effective biocatalyst for the asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone (BTAP) to (R)-BTPE, was overexpressed in Escherichia coli BL21 (DE3). Bioinformatics analysis indicated that the amino acid sequence of recombinant LXCAR showed 89 % similarity to short-chain dehydrogenase/reductase. E. coli recombinant carbonyl reductase crude extract showed a specific activity of 1.54 U/mg, which was 62 times higher than that of L. xyli HS0904 crude extract. By using error-prone polymerase chain reaction and site-directed mutagenesis, the engineered LXCAR demonstrated superior catalytic activity toward BTAP, and the obtained mutant LXCAR-S154Y exhibited nearly 13-fold, 5.4-fold, and 2.3-fold increase in k cat/K m value, k cat value, and specific activity toward BTAP, respectively, compared to the recombinant LXCAR. Additionally, the reduction of BTAP by whole cells of mutant LXCAR-S154Y afforded a best yield of 99.6 % for (R) BTPE within 2 h at 200 mM BTAP, which was shortened by 28 and 2 h compared to those catalyzed by L. xyli HS0904 cells and recombinant E. coli cells expressing LXCAR, respectively. Moreover, a yield of 82.5 % for (R)-BTPE was achieved within 12 h at an increased BTAP concentration of up to 1,000 mM (256 g/l), representing a 1.9-fold increase over the recombinant LXCAR. Homology modeling and docking analysis revealed the molecular basis for the high catalytic activity of mutant LXCAR-S154Y toward BTAP. The results present here provide a promising alternative for economical and efficient production of chiral alcohols by engineered LXCAR. PMID- 24788331 TI - Monoglucosyl-rutin as a potential radioprotector in mammalian cells. AB - In the present study, the role of monoglucosyl-rutin as a potential radioprotector was investigated using mammalian cell culture models. Cell survival and DNA damage were assessed using colony formation, sister chromatid exchange and gammaH2AX assays. It was demonstrated that monoglucosyl-rutin was able to increase cell survival when exposed to ionizing radiation, possibly by decreasing the amount of base damage experienced by the cell. However, the present study also demonstrated that, despite monoglucosyl-rutin exhibiting radioprotective effects at low doses, high doses of monoglucosyl-rutin led to a decrease in plating efficiency and an increased doubling time. This effect may be due to double-strand breaks caused by high concentrations of monoglucosyl-rutin. PMID- 24788332 TI - Cognitive components of color vision in honey bees: how conditioning variables modulate color learning and discrimination. AB - Since the demonstration of color vision in honey bees 100 years ago by Karl von Frisch, appetitive conditioning to color targets has been used as the principal way to access behavioral aspects of bee color vision. Yet, analyses on how conditioning parameters affect color perception remained scarce. Conclusions on bee color vision have often been made without referring them to the experimental context in which they were obtained, and thus presented as absolute facts instead of realizing that subtle variations in conditioning procedures might yield different results. Here, we review evidence showing that color learning and discrimination in bees are not governed by immutable properties of their visual system, but depend on how the insects are trained and thus learn a task. The use of absolute or differential conditioning protocols, the presence of aversive reinforcement in differential conditioning and the degrees of freedom of motor components determine dramatic variations in color discrimination. We, thus, suggest top-down attentional modulation of color vision to explain the changes in color learning and discrimination reviewed here. We discuss the possible neural mechanisms of this modulation and conclude that color vision experiments require a careful consideration of how training parameters shape behavioral responses. PMID- 24788333 TI - Development and plasticity of mitochondria and electrical properties of the cell membrane in blowfly photoreceptors. AB - Blowfly photoreceptors are highly energy demanding sensory systems. Their information processing efficiency is enabled by the high temporal resolution of the cell membrane, requiring heavy metabolic support by the mitochondria. We studied the developmental changes of the mitochondrial apparatus and electrical properties of the photoreceptor membrane in the white eyed Calliphora vicina Chalky. Using in vivo microspectrophotometry and Western blot analysis, we found an age-dependent increase in the concentration of mitochondrial pigments. The maximal change occurred during the first week. The age-related changes were smaller in dark-bred than in light-bred flies. The mitochondrial pigment content increased after the switch from dark to light rearing and decreased after the switch from light to dark rearing. The electrical parameters of the photoreceptors were investigated with intracellular recordings. The resting membrane resistance and time constant decreased significantly after eclosion. The decrease was again most significant during the first week of adult life, paralleled with changes in the Na/K pump-dependent hyperpolarizing afterpotential. We conclude that the photoreceptor mitochondria exhibit remarkable ontogenetic and phenotypic plasticity, because the quantity of mitochondrial pigments tightly follows the development of the cell membrane as well as the energy demands of the photoreceptors under different rearing conditions. PMID- 24788335 TI - Social cognition and brain morphology: implications for developmental brain dysfunction. AB - The social-cognitive deficits associated with several neurodevelopmental and neuropsychiatric disorders have been linked to structural and functional brain anomalies. Given the recent appreciation for quantitative approaches to behavior, in this study we examined the brain-behavior links in social cognition in healthy young adults from a quantitative approach. Twenty-two participants were administered quantitative measures of social cognition, including the social responsiveness scale (SRS), the empathizing questionnaire (EQ) and the systemizing questionnaire (SQ). Participants underwent a structural, 3-T magnetic resonance imaging (MRI) procedure that yielded both volumetric (voxel count) and asymmetry indices. Model fitting with backward elimination revealed that a combination of cortical, limbic and striatal regions accounted for significant variance in social behavior and cognitive styles that are typically associated with neurodevelopmental and neuropsychiatric disorders. Specifically, as caudate and amygdala volumes deviate from the typical R > L asymmetry, and cortical gray matter becomes more R > L asymmetrical, overall SRS and Emotion Recognition scores increase. Social Avoidance was explained by a combination of cortical gray matter, pallidum (rightward asymmetry) and caudate (deviation from rightward asymmetry). Rightward asymmetry of the pallidum was the sole predictor of Interpersonal Relationships and Repetitive Mannerisms. Increased D-scores on the EQ-SQ, an indication of greater systemizing relative to empathizing, was also explained by deviation from the typical R > L asymmetry of the caudate.These findings extend the brain-behavior links observed in neurodevelopmental disorders to the normal distribution of traits in a healthy sample. PMID- 24788334 TI - Reliability of negative BOLD in ipsilateral sensorimotor areas during unimanual task activity. AB - Research using functional magnetic resonance imaging has for numerous years now reported the existence of a negative blood oxygenation level dependent (BOLD) response. Based on accumulating evidence, this negative BOLD signal appears to represent an active inhibition of cortical areas in which it is found during task activity. This particularly important with respect to motor function given that it is fairly well-established that, in younger adults, the ipsilateral sensorimotor cortex exhibits negative BOLD during unimanual movements in fMRI. This interhemispheric suppression of cortical activity may have useful implications for our understanding of both basic motor function and rehabilitation of injury or disease. However, to date, we are aware of no study that has tested the reliability of evoked negative BOLD in ipsilateral sensorimotor cortex in individuals across sessions. The current study employs a unimanual finger opposition task previously shown to evoke negative BOLD in ipsilateral sensorimotor cortex across three sessions. Reliability metrics across sessions indicates that both the magnitude and location of ipsilateral sensorimotor negative BOLD response is relatively stable over each of the three sessions. Moreover, the volume of negative BOLD in ipsilateral cortex was highly correlated with volume of positive BOLD activity in the contralateral primary motor cortex. These findings show that the negative BOLD signal can be reliably evoked in unimanual task paradigms, and that the signal dynamic could represent an active suppression of the ipsilateral sensorimotor cortex originating from the contralateral motor areas. PMID- 24788336 TI - Escin, a novel triterpene, mitigates chronic MPTP/p-induced dopaminergic toxicity by attenuating mitochondrial dysfunction, oxidative stress, and apoptosis. AB - Parkinson's disease (PD) is a common, chronic, and debilitating neurodegenerative disorder characterized by progressive loss of nigrostriatal dopaminergic neurons due to unknown factors. In the present study, we have evaluated if escin, a triterpene saponin from seeds of horse chestnut tree (Aesculus hippocastanum), offers neuroprotection against chronic 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid (MPTP/p)-induced toxicity using a mouse model. Chronic administration of MPTP/p deteriorated the loss of TH immunoreactivity in striatum. Subsequently, MPTP/p also enhanced oxidative stress by mitochondrial complex I inhibition, thereby ensuing dopaminergic denervation via modulation of Bcl-2, Bax, Cyto-C, and cleaved caspases expressions. However, we observed that pretreatment with escin (4 mg/kg) significantly attenuated MPTP/p-induced mitochondrial dysfunction, oxidative stress, and apoptosis. Furthermore, behavioral studies and ultrastructural analysis of mitochondria and intracellular components were in support of these findings. Therefore, we speculate that escin might be a promising candidate for the prevention of mitochondrial dysfunction induced apoptosis in neurodegenerative disorders such as PD. PMID- 24788337 TI - Altered desferrioxamine-mediated iron utilization is a common trait of bald mutants of Streptomyces coelicolor. AB - Streptomyces coelicolor is an important model organism for developmental studies of filamentous GC-rich actinobacteria. The genetic characterization of mutants of S. coelicolor blocked at the vegetative mycelium stage, the so-called bald (bld) mutants that are unable to erect spore-forming aerial hyphae, has opened the way to discovering the molecular basis of development in actinomycetes. Desferrioxamine (DFO) production and import of ferrioxamines (FO; iron-complexed DFO) are key to triggering morphogenesis of S. coelicolor and we show here that growth of S. coelicolor on the reference medium for Streptomyces developmental studies is fully dependent on DFO biosynthesis. UPLC-ESI-MS analysis revealed that all bld mutants tested are affected in DFO biosynthesis, with bldA, bldJ, and ptsH mutants severely impaired in DFO production, while bldF, bldK, crr and ptsI mutants overproduce DFO. Morphogenesis of bldK and bldJ mutants was recovered by supplying exogenous iron. Transcript analysis showed that the bldJ mutant is impaired in expression of genes involved in the uptake of FO, whereas transcription of genes involved in both DFO biosynthesis and FO uptake is increased in bldK mutants. Our study allows proposing altered DFO production and/or FO uptake as a novel phenotypic marker of many S. coelicolor bld mutants, and strengthens the role of siderophores and iron acquisition in morphological development of actinomycetes. PMID- 24788338 TI - Stac3 inhibits myoblast differentiation into myotubes. AB - The functionally undefined Stac3 gene, predicted to encode a SH3 domain- and C1 domain-containing protein, was recently found to be specifically expressed in skeletal muscle and essential to normal skeletal muscle development and contraction. In this study we determined the potential role of Stac3 in myoblast proliferation and differentiation, two important steps of muscle development. Neither siRNA-mediated Stac3 knockdown nor plasmid-mediated Stac3 overexpression affected the proliferation of C2C12 myoblasts. Stac3 knockdown promoted the differentiation of C2C12 myoblasts into myotubes as evidenced by increased fusion index, increased number of nuclei per myotube, and increased mRNA and protein expression of myogenic markers including myogenin and myosin heavy chain. In contrast, Stac3 overexpression inhibited the differentiation of C2C12 myoblasts into myotubes as evidenced by decreased fusion index, decreased number of nuclei per myotube, and decreased mRNA and protein expression of myogenic markers. Compared to wild-type myoblasts, myoblasts from Stac3 knockout mouse embryos showed accelerated differentiation into myotubes in culture as evidenced by increased fusion index, increased number of nuclei per myotube, and increased mRNA expression of myogenic markers. Collectively, these data suggest an inhibitory role of endogenous Stac3 in myoblast differentiation. Myogenesis is a tightly controlled program; myofibers formed from prematurely differentiated myoblasts are dysfunctional. Thus, Stac3 may play a role in preventing precocious myoblast differentiation during skeletal muscle development. PMID- 24788340 TI - Recalculating ... PMID- 24788339 TI - Implementation of adolescent-friendly voluntary medical male circumcision using a school based recruitment program in rural KwaZulu-Natal, South Africa. AB - BACKGROUND: Epidemiological data from South Africa demonstrate that risk of human immunodeficiency virus (HIV) infection in males increases dramatically after adolescence. Targeting adolescent HIV-negative males may be an efficient and cost effective means of maximising the established HIV prevention benefits of voluntary medical male circumcision (VMMC) in high HIV prevalence-, low circumcision practice-settings. This study assessed the feasibility of recruiting male high school students for VMMC in such a setting in rural KwaZulu-Natal. METHODS AND FINDINGS: Following community and key stakeholder consultations on the acceptability of VMMC recruitment through schools, information and awareness raising sessions were held in 42 high schools in Vulindlela. A three-phase VMMC demand-creation strategy was implemented in partnership with a local non governmental organization, ZimnadiZonke, that involved: (i) community consultation and engagement; (ii) in-school VMMC awareness sessions and centralized HIV counselling and testing (HCT) service access; and (iii) peer recruitment and decentralized HCT service access. Transport was provided for volunteers to the Centre for the AIDS Programme of Research in South Africa (CAPRISA) clinic where the forceps-guided VMMC procedure was performed on consenting HIV-negative males. HIV infected volunteers were referred to further care either at the CAPRISA clinic or at public sector clinics. Between March 2011 and February 2013, a total of 5165 circumcisions were performed, the majority (71%) in males aged between 15 and 19 years. Demand-creation strategies were associated with an over five-fold increase in VMMC uptake from an average of 58 procedures/month in initial community engagement phases, to an average of 308 procedures/month on initiation of the peer recruitment-decentralized service phase. Post-operative adverse events were rare (1.2%), mostly minor and self resolving. CONCLUSIONS: Optimizing a high volume, adolescent-targeted VMMC program was feasible, acceptable and safe in this setting. Adaptive demand creation strategies are required to sustain high uptake. PMID- 24788341 TI - The influential roles of antibiotics prophylaxis in cirrhotic patients with peptic ulcer bleeding after initial endoscopic treatments. AB - The influential roles of antibiotic prophylaxis on cirrhotic patients with peptic ulcer bleeding are still not well documented. The purpose of this study is to clarify these influential roles and to identify the risk factors associated with rebleeding, bacterial infection and in-hospital mortality. A cross-sectional, chart review study was conducted on 210 cirrhotic patients with acute peptic ulcer hemorrhage who underwent therapeutic endoscopic procedures. Patients were divided into group A (with prophylactic intravenous ceftriaxone, n = 74) and group B (without antibiotics, n = 136). The outcomes were length of hospital days, prevention of infection, rebleeding rate and in-hospital mortality. Our results showed that more patients suffered from rebleeding and infection in group B than group A (31.6% vs. 5.4%; p<0.001 and 25% vs. 10.8%; p = 0.014 respectively). The risk factors for rebleeding were active alcoholism, unit of blood transfusion, Rockall score, model for end-stage liver disease score and antibiotic prophylaxis. The risk factors for infection were active alcoholism, Child-Pugh C, Rockall score and antibiotic prophylaxis. Rockall score was the predictive factor for in-hospital mortality. In conclusions, antibiotic prophylaxis in cirrhotic patients after endoscopic interventions for acute peptic ulcer hemorrhage reduced infections and rebleeding rate but not in-hospital mortality. Rockall score was the predictive factor of in-hospital mortality. PMID- 24788343 TI - Captive rearing experiments confirm song development without learning in a tracheophone suboscine bird. AB - The origin of vocal learning in animals has long been the subject of debate, but progress has been limited by uncertainty regarding the distribution of learning mechanisms across the tree of life, even for model systems such as birdsong. In particular, the importance of learning is well known in oscine songbirds, but disputed in suboscines. Members of this diverse group (~1150 species) are generally assumed not to learn their songs, but empirical evidence is scarce, with previous studies restricted to the bronchophone (non-tracheophone) clade. Here, we conduct the first experimental study of song development in a tracheophone suboscine bird by rearing spotted antbird (Hylophylax naevioides) chicks in soundproofed aviaries. Individuals were raised either in silence with no tutor or exposed to standardized playback of a heterospecific tutor. All individuals surviving to maturity took a minimum of 79 days to produce a crystallized version of adult song, which in all cases was indistinguishable from wild song types of their own species. These first insights into song development in tracheophone suboscines suggest that adult songs are innate rather than learnt. Given that empirical evidence for song learning in suboscines is restricted to polygamous and lek-mating species, whereas tracheophone suboscines are mainly monogamous with long-term social bonds, our results are consistent with the view that sexual selection promotes song learning in birds. PMID- 24788342 TI - The continuum of physiological impairment during treadmill walking in patients with mild-to-moderate COPD: patient characterization phase of a randomized clinical trial. AB - BACKGROUND: To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls. METHODS: Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study. Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise. All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests. RESULTS: Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104). Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups. Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001). Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls. Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001). CONCLUSIONS: Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort. Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01072396. PMID- 24788344 TI - Mitochondrial DNA variants in obesity. AB - Heritability estimates for body mass index (BMI) variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s) in the exclusively maternally inherited mitochondrial DNA (mtDNA) might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs) were available from genome-wide association study SNP arrays (Affymetrix 6.0). For discovery, we analyzed association in a case control (CC) sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI >= 30 kg/m2) and n = 2,373 normal weight and lean controls (BMI<25 kg/m2). SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger) in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002) located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039). These findings could not be confirmed independently. For two of the 252 identified D loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048). Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their offspring could not be substantiated by the findings of the present study. PMID- 24788345 TI - Fabrication of anti-aging TiO2 nanotubes on biomedical Ti alloys. AB - The primary objective of this study was to fabricate a TiO2 nanotubular surface, which could maintain hydrophilicity over time (resist aging). In order to achieve non-aging hydrophilic surfaces, anodization and annealing conditions were optimized. This is the first study to show that anodization and annealing condition affect the stability of surface hydrophilicity. Our results indicate that maintenance of hydrophilicity of the obtained TiO2 nanotubes was affected by anodization voltage and annealing temperature. Annealing sharply decreased the water contact angle (WCA) of the as-synthesized TiO2 nanotubular surface, which was correlated to improved hydrophilicity. TiO2 nanotubular surfaces are transformed to hydrophilic surfaces after annealing, regardless of annealing and anodization conditions; however, WCA measurements during aging demonstrate that surface hydrophilicity of non-anodized and 20 V anodized samples decreased after only 11 days of aging, while the 60 V anodized samples maintained their hydrophilicity over the same time period. The nanotubes obtained by 60 V anodization followed by 600 degrees C annealing maintained their hydrophilicity significantly longer than nanotubes which were obtained by 60 V anodization followed by 300 degrees C annealing. PMID- 24788346 TI - The role of stress in absenteeism: cortisol responsiveness among patients on long term sick leave. AB - OBJECTIVE: This study aimed to (1) See whether increased or decreased variation relate to subjective reports of common somatic and psychological symptoms for a population on long-term sick leave; and (2) See if this pattern in variation is correlated with autonomic activation and psychological appraisal. METHODS: Our participants (n = 87) were referred to a 3.5-week return-to-work rehabilitation program, and had been on paid sick leave >8 weeks due to musculoskeletal pain, fatigue and/or common mental disorders. An extensive survey was completed, addressing socio-demographics, somatic and psychological complaints. In addition, a physician and a psychologist examined the participants, determining baseline heart rate, medication use and SCID-I diagnoses. During the 3.5-week program, the participants completed the Trier Social Stress Test for Groups. Participants wore heart rate monitors and filled out Visual Analogue Scales during the TSST-G. RESULTS: Our participants presented a low cortisol variation, with mixed model analyses showing a maximal increase in free saliva cortisol of 26% (95% CI, 0.21 0.32). Simultaneously, the increase in heart rate and Visual Analogue Scales was substantial, indicating autonomic and psychological activation consistent with intense stress from the Trier Social Stress Test for Groups. CONCLUSIONS: The current findings are the first description of a blunted cortisol response in a heterogeneous group of patients on long-term sick leave. The results suggest lack of cortisol reactivity as a possible biological link involved in the pathway between stress, sustained activation and long-term sick leave. PMID- 24788349 TI - Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells. AB - Melittin is a water-soluble toxic peptide derived from the venom of the bee. Although many studies show the anti-tumor activity of melittin in human cancer including glioma cells, the underlying mechanisms remain elusive. Here the effect of melittin on human hepatocelluar carcinoma HepG2 cell proliferation in vitro and further mechanisms was investigated. We found melittin could inhibit cell proliferation in vitro using Flow cytometry and MTT method. Besides, we discovered that melittin significantly downregulated the expressions of CyclinD1 and CDK4. Results of western Blot and Real-time PCR analysis indicated that melittin was capable to upregulate the expression of PTEN and attenuate histone deacetylase 2 (HDAC2) expression. Further studies demonstrated that knockdown of HDAC2 completely mimicked the effects of melittin on PTEN gene expression. Conversely, it was that the potential utility of melittin on PTEN expression was reversed in cells treated with a recombinant pEGFP-C2-HDAC2 plasmid. In addition, treatment with melittin caused a downregulation of Akt phosphorylation, while overexpression of HDAC2 promoted Akt phosphorylation. These findings suggested that the inhibitory of cell growth by melittin might be led by HDAC2-mediated PTEN upregulation, Akt inactivation, and inhibition of the PI3K/Akt signaling pathways. PMID- 24788350 TI - Abnormal brain magnetic resonance imaging in two patients with Smith-Magenis syndrome. AB - Smith-Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome ascribed to an interstitial deletion in chromosome 17p11.2. Seventy percent of SMS patients have a common deletion interval spanning 3.5 megabases (Mb). Clinical features of SMS include characteristic mild dysmorphic features, ocular anomalies, short stature, brachydactyly, and hypotonia. SMS patients have a unique neurobehavioral phenotype that includes intellectual disability, self injurious behavior and severe sleep disturbance. Little has been reported in the medical literature about anatomical brain anomalies in patients with SMS. Here we describe two patients with SMS caused by the common deletion in 17p11.2 diagnosed using chromosomal microarray (CMA). Both patients had a typical clinical presentation and abnormal brain magnetic resonance imaging (MRI) findings. One patient had subependymal periventricular gray matter heterotopia, and the second had a thin corpus callosum, a thin brain stem and hypoplasia of the cerebellar vermis. This report discusses the possible abnormal MRI images in SMS and reviews the literature on brain malformations in SMS. Finally, although structural brain malformations in SMS patients are not a common feature, we suggest baseline routine brain imaging in patients with SMS in particular, and in patients with chromosomal microdeletion/microduplication syndromes in general. Structural brain malformations in these patients may affect the decision-making process regarding their management. PMID- 24788351 TI - Host responses to sepsis vary in different low-lethality murine models. AB - INTRODUCTION: Animal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research. In particular, recent studies have suggested that at the level of the leukocyte transcriptome, murine models of burns, trauma and endotoxemia markedly differ from their human equivalents, and are only weakly similar amongst themselves. We compared the plasma cytokine and leukocyte transcriptome responses between two different low-lethality murine models of polymicrobial intra-abdominal sepsis. METHODS: Six to ten week male C57BL/6j mice underwent either the 'gold standard' cecal ligation and puncture (CLP) model of intra-abdominal sepsis or administration of a cecal slurry (CS), where cecal contents are injected intraperitoneally. Surviving mice were euthanized at two hours, one or three days after sepsis. RESULTS: The murine leukocyte transcriptomic response to the CLP and CS models of sepsis was surprisingly dissimilar at two hours, one, and three days after sepsis. The Pearson correlation coefficient for the maximum change in expression for the entire leukocyte transcriptome that changed significantly over time (n = 19,071) was R = 0.54 (R2 = 0.297). The CS model resulted in greater magnitude of early inflammatory gene expression changes in response to sepsis with associated increased production of inflammatory chemokines and cytokines. Two hours after sepsis, CLP had more significant expression of genes associated with IL-10 signaling pathways, whereas CS had greater expression of genes related to CD28, apoptosis, IL-1 and T-cell receptor signaling. By three days, the changes in gene expression in both sepsis models were returning to baseline in surviving animals. CONCLUSION: These analyses reveal that the murine blood leukocyte response to sepsis is highly dependent on which model of intra abdominal sepsis is employed, despite their similar lethality. It may be difficult to extrapolate findings from one murine model to another, let alone to human sepsis. PMID- 24788352 TI - KNDC1 knockdown protects human umbilical vein endothelial cells from senescence. AB - KNDC1 (kinase noncatalytic C-lobe domain containing 1), a brain-specific Ras guanine nucleotide exchange factor, controls the negative regulation of neuronal dendrite growth. However, the effect of KNDC1 on cellular senescence remains to be elucidated. The present study investigated the impact of KNDC1 knockdown on human endothelial cell senescence and the mechanisms underlying this effect. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as a model of biological aging. Senescence-associated beta-galactosidase staining was used to detect cellular senescence and flow cytometry was employed to determine cell cycle progression. Quantitative polymerase chain reaction (qPCR) and western blot analysis were utilized to investigate mRNA transcription and protein expression. In the HUVECs, a senescence-like phenotypes developed with increasing passage number in vitro, which were associated with a progressive increase in the transcription and expression of KNDC1. KNDC1 knockdown promoted cell proliferation and partially reversed cellular senescence and cell cycle arrest in the G0/G1 phase in aging HUVECs. Investigations into the mechanism underlying this effect demonstrated that KNDC1 knockdown promoted HUVEC proliferation via the extracellular signal-regulated kinase signaling pathway and delayed HUVEC senescence by inhibiting the p53-p21-p16 transduction cascade. In addition, the promotion of the capillary tube network formation and the increased expression of endothelial nitric oxide synthase revealed that the activity and function of endothelial cells were enhanced. In conclusion, KNDC1 knockdown delayed endothelial cell senescence and promoted HUVEC activity and function. These results demonstrated that KNDC1 may be a novel therapeutic target for the development of agents to extend human life. PMID- 24788353 TI - Should clinical trial research of psychotropic medication in autism control for gastrointestinal symptoms? AB - Recent research has established that many children and adult diagnosed with autism experience gastrointestinal symptoms. Furthermore, research has demonstrated that gastrointestinal symptoms can impact drug availability and absorption. In this paper we explore the presence of gastrointestinal symptoms in autism and put forth a call for a formal evaluation of the potential relationship between gastrointestinal symptoms and psychotropic medication effectiveness in individuals with autism. PMID- 24788355 TI - Report of two never treated adult sisters with aromatic L-amino Acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype? AB - Two sisters were diagnosed in their adulthood with aromatic L-amino acid decarboxylase (AADC) deficiency (OMIM#608643). They experienced early myasthenia like manifestations, myoclonic jerks, oculogyric crises, tremors, and developmental delay during childhood; clinical stabilization afterwards; and spontaneous improvement during adolescence and young adulthood. Two novel pathogenic mutations on DDC gene [p.Tyr37Thrfs*5 (c.105delC) and p.F237S (c.710 T>C)] were associated with undetectable enzyme activity in plasma and only a mild reduction of biogenic amines in cerebrospinal fluid (CSF). The increase of both 3 O-methyldopa and 5-hydroxytryptophan on CSF was the most relevant biochemical alteration denoting AADC defect in these subjects. Transdermal rotigotine remarkably improved their gross motor functions and the asthenic status they complained. The present cases broaden the phenotypic spectrum of AADC deficiency and suggest that (1) AADC defect is not a progressive neurological disease and behaves rather as a neurodevelopmental disorder that improves during the second decade of life; (2) treatment-naive adults can still respond well to neurotransmitter therapy; and (3) the possibility of a mild presentation of AADC deficiency should be considered when examining young adults with asthenic and parkinsonian symptoms. PMID- 24788354 TI - NanoClusters surface area allows nanoparticle dissolution with microparticle properties. AB - Poorly water-soluble drugs comprise the majority of new drug molecules. Nanoparticle agglomerates, called NanoClusters, can increase the dissolution rate of poorly soluble compounds by increasing particle surface area. Budesonide and danazol, two poorly soluble steroids, were studied as model compounds. NanoCluster suspensions were made using a Netzsch MiniCer media mill with samples collected between 5 and 15 h and lyophilized. Differential scanning calorimetry (DSC) and powder X-ray Diffraction were used to evaluate the physicochemical properties of the powders, and Brunauer, Emmett and Teller (BET) analysis was used to determine surface area. Scanning electron microscopy confirmed NanoClusters were between 1 and 5 MUm. NanoCluster samples showed an increase in dissolution rate compared with the micronized stock and similar to a dried nanoparticle suspension. BET analysis determined an increase in surface area of eight times for budesonide NanoClusters and 10-15 times for danazol NanoClusters compared with the micronized stock. Melting temperatures decreased with increased mill time of NanoClusters by DSC. The increased surface area of NanoClusters provides a potential micron-sized alternative to nanoparticles to increase dissolution rate of poorly water-soluble drugs. PMID- 24788357 TI - Acculturative stress and influential factors among international students in China: a structural dynamic perspective. AB - Stress represents a prominent aspect of modern life and is associated with numerous negative health consequences. International students are a key force in shaping globalization. However, these students often experience acculturative stress, influencing their health and well-being. The growing number of international students in China emerges as a new global health challenge and presents an opportunity to advance our understanding of acculturative stress. This study aims to investigate the acculturative stress of international students in China, and verify the mechanism and influential factors of acculturative stress. We analyzed survey data from 567 international students attending universities in Wuhan, China. We used a network-based analytical approach to assess the structure of the Acculturative Stress Scale for International Students and used regression analysis to assess the relationships between acculturative stress and theoretically related factors. We found that higher levels of acculturative stress were reported by students from Asia and Africa than from other regions (Europe/America/Oceania). Lower acculturative stress was reported by unmarried students than others and by students well prepared than not well prepared. We verified seven acculturative stress subconstructs: rejection, identity threat, opportunity deprivation, self-confidence, value conflict, cultural competence, and homesickness; and discovered a three-dimensional network structure of these subconstructs. Our results suggest that acculturative stress was more common among international students in China than in developed countries. Acculturative stress was also more common among international students who did not well prepared, married, and belonged to an organized religion. African and Asian students' stress was higher than that for students from other regions. Acculturative stress prevention programs should seek to improve preparedness of the international students for studying abroad and pay extra attention to the high risk subgroups. PMID- 24788358 TI - Characterization of complete genome sequence of genotype VI and VII velogenic Newcastle disease virus from Japan. AB - The complete genome sequences of three strains of Newcastle disease virus (NDV) isolated from vaccinated commercial layer flocks in Japan in the span of three decades were characterized. All strains had genome lengths of 15,192 nucleotides consisting of six genes in the order of 3'-NP-P/V/W-M-F-HN-L-5'. The general genomic characteristics of the Japanese field strains were consistent with previously characterized class II NDV, except for those belonging to early genotypes (genotype I-IV), which lack the six nucleotide insertion at nucleotide positions 1,648-1,653 of the nucleoprotein (NP) gene. Phylogenetic analysis showed that the Japanese strains could be classified into genotypes VIc and VIIe using the complete genome sequence and the complete coding sequence of the fusion (F) gene according to the unified NDV classification system. Characterization of functional domains and neutralizing epitopes of the F and hemagglutinin neuraminidase (HN) proteins of Japanese field strains revealed a total of 31 amino acid substitutions, as compared to vaccine strains Ishii and B1, which were widely used in Japan. Although virus neutralization (VN) test showed that poor flock immunity due to vaccination failure or partial and non-uniform immunization maybe the major factors involved in the mechanism of breakthrough infection of the Japanese field strains, approximately two to threefold decrease in the VN titers of the field NDV strains possessing a point mutation (E347K or E347G) at the linear epitope of the HN protein was observed, as compared to vaccine strain B1 and field strain 2440/69, which lack the point mutation. This study may be a useful reference in characterizing future ND outbreaks in vaccinated chickens and as a genetic map for future investigations regarding vaccine designs, reverse genetics systems, and development of molecular diagnostic tools to prevent future ND outbreaks in vaccinated poultry flocks. PMID- 24788362 TI - Comparison of eating habits in obese and non-obese Filipinas living in an urban area of Japan. AB - This study compares eating habits among obese and non-obese Filipinas living in an urban area of Japan. We used self-report questionnaires to study 635 Filipinos. Body mass index (BMI) and eating/lifestyle habits were noted. Obesity was defined as BMI >=25 kg/m(2). Seventeen percent (24/140) were obese. Results of the age-adjusted multiple logistic regression analysis show that the following responses were associated with obesity: "frequency of eating high green and yellow vegetables" (every day: 0, not every day: 1) [OR 4.9; 95% confidence interval (CI) 1.6-14.8] and "frequency of eating high fruits" (every day: 0, not every day: 1) (OR .2; 95% CI .1-.7). We suggest strategies to prevent obesity and improve eating habits among this Filipina population. PMID- 24788363 TI - Meaning in Life and Suicidal Tendency Among Immigrant (Ethiopian) Youth and Native-Born Israeli Youth. AB - The impact of meaning in life, or lack thereof, on suicidal tendencies among populations at greater risk-youth born to immigrants from developing countries, in this case Ethiopia-in comparison to native-born Israeli youth was examined among 277 adolescents-162 of Israeli origin and 115 of Ethiopian origin-aged 15 18. (1) Overall significant negative correlation between meaning in life and suicidal tendencies was found; (2) no difference was found in meaning in life between immigrant and native-born youth; (3) higher suicidal tendency, anxiety and depression were found among immigrants, with boys displaying more anxiety than girls. No difference in depression was detected between Ethiopian boys and girls. Meaning in life is crucial to minimizing suicidal tendencies among youth, native-born and immigrant alike. Establishment of prevention, intervention and therapy plans in the age range crucial for suicide. Such programs should be based upon finding meaning in life. PMID- 24788365 TI - Catabolism of terbuthylazine by mixed bacterial culture originating from s triazine-contaminated soil. AB - The s-triazine herbicide terbuthylazine (TERB) has been used as the main substitute of atrazine in many EU countries for more than 10 years. However, the ecological consequences of this substitution are still not fully understood. Since the fate of triazine herbicides is primarily dependent on microbial degradation, in this paper, we investigated the ability of a mixed bacterial culture, M3-T, originating from s-triazine-contaminated soil, to degrade TERB in liquid culture and soil microcosms. The M3-T culture grown in mineral medium with TERB as the N source and citrate as the C source degraded 50 mg L(-1) of TERB within 3 days of incubation. The culture was capable of degrading TERB as the sole C and N source, though at slower degradation kinetics. A thorough LC-MS analysis of the biodegradation media showed the formation of hydroxyterbuthylazine (TERB-OH) and N-t-butylammelide (TBA) as major metabolites, and desethylterbuthylazine (DET), hydroxydesethylterbuthylazine (DET-OH) and cyanuric acid (CA) as minor metabolites in the TERB degradation pathway. TBA was identified as a bottleneck in the catabolic pathway leading to its transient accumulation in culture media. The supplementation of glucose as the exogenous C source had no effect on TBA degradation, whereas citrate inhibited its disappearance. The addition of M3-T to sterile soil artificially contaminated with TERB at 3 mg kg(-1) of soil resulted in an accelerated TERB degradation with t 1/2 value being about 40 times shorter than that achieved by the native microbial community. Catabolic versatility of M3-T culture makes it a promising seed culture for accelerating biotransformation processes in s-triazine contaminated environment. PMID- 24788366 TI - Levator ani defect scores and pelvic organ prolapse: is there a threshold effect? AB - INTRODUCTION AND HYPOTHESIS: The goal of this study was to use a well-described system of quantifying levator ani defect (LAD) severity using magnetic resonance imaging (MRI) to examine the relationship between defect severity and the presence or absence of prolapse. METHODS: This is a secondary analysis of two case-control studies comparing 284 cases (with prolapse) to 219 controls (normal support) defined by using Pelvic Organ Prolapse Quantification (POP-Q) exams. LAD were assessed on MRI, with scores from 0 (no defects) to 6 (complete, bilateral defects). The number of cases and controls at each score were compared. Logistic regression and receiver operating characteristic (ROC) analyses were used to quantify relationships between LAD and prolapse. RESULTS: The proportion of cases exceeds the overall prolapse rate in this study at LAD scores >=3, with higher rates of prolapse at higher LAD scores (p < 0.0000001). Prolapse risk stratifies into low risk at LAD scores 0-2, moderate at 3-5, and high at 6. ROC analysis for classification of prolapse based on LAD scores has an area under the curve of 69.9% (p < 0.001), suggesting LAD alone can discriminate between normal support and prolapse for nearly 70% of patients. Logistic regression identified higher parity and higher LAD scores as independent predictors of prolapse. CONCLUSIONS: There are three clusters of prolapse risk: low (0-2), moderate (3-5), and high (6). Although LAD have a dose-response-like effect for prolapse, other factors are clearly involved. PMID- 24788367 TI - Binary role of an ylide in formation of a terminal methylidene complex of niobium. AB - The first structurally characterized niobium(v) complex possessing a terminal methylidene ligand is reported in high yield from the reaction of [(Ar'O)2Nb(CH3)2Cl] (Ar' = (2,6-CHPh2)2-4-tBu-C6H2) and two equivalents of H2CPPh3. PMID- 24788368 TI - National prevalence of receipt of antidepressant prescriptions by persons without a psychiatric diagnosis. AB - OBJECTIVE: The study addressed recent concerns regarding increasing prescription of antidepressant drugs to patients with no recorded psychiatric diagnosis. METHODS: Records from ten large integrated health systems in the Mental Health Research Network were used to examine diagnoses received by 1,011,946 health plan members who filled at least one antidepressant prescription in 2010. RESULTS: Among individuals filling antidepressant prescriptions, psychiatric diagnoses recorded during the year were depressive disorders (48%), anxiety disorders (27%), bipolar disorders (3%), and attention deficit disorders (3%). The proportion of those filling prescriptions who had no psychiatric diagnosis was 39%, which fell to 27% after the analysis excluded prescriptions for antidepressants often prescribed for nonpsychiatric indications (tricyclic antidepressants, trazodone, and bupropion). CONCLUSIONS: Prescription of antidepressants to patients without an appropriate diagnosis appears to be less common than previously reported. PMID- 24788370 TI - Detection of breast surgical margins with optical coherence tomography imaging: a concept evaluation study. AB - This study aimed to evaluate the concept of using high-resolution optical coherence tomography (OCT) imaging to rapidly assess surgical specimens and determine if cancer positive margins were left behind in the surgical bed. A mouse model of breast cancer was used in this study. Surgical specimens from 30 animals were investigated with OCT and automated interpretation of the OCT images was performed and tested against histopathology findings. Specimens from 10 animals were used to build a training set of OCT images, while the remaining 20 specimens were used for a validation set of images. The validation study showed that automated interpretation of OCT images can differentiate tissue types and detect cancer positive margins with at least 81% sensitivity and 89% specificity. The findings of this pilot study suggest that OCT imaging of surgical specimens and automated interpretation of OCT data may enable in the future real-time feedback to the surgeon about margin status in patients with breast cancer, and potentially with other types of cancers. Currently, such feedback is not provided and if positive margins are left behind, patients have to undergo another surgical procedure. Therefore, this approach can have a potentially high impact on breast surgery outcome. PMID- 24788369 TI - Noninvasive optical cytochrome c oxidase redox state measurements using diffuse optical spectroscopy. AB - A major need exists for methods to assess organ oxidative metabolic states in vivo. By contrasting the responses to cyanide (CN) poisoning versus hemorrhage in animal models, we demonstrate that diffuse optical spectroscopy (DOS) can detect cytochrome c oxidase (CcO) redox states. Intermittent decreases in inspired O2 from 100% to 21% were applied before, during, and after CN poisoning, hemorrhage, and resuscitation in rabbits. Continuous DOS measurements of total hemoglobin, oxyhemoglobin, deoxyhemoglobin, and oxidized and reduced CcO from muscle were obtained. Rabbit hemorrhage was accomplished with stepwise removal of blood, followed by blood resuscitation. CN treated rabbits received 0.166 mg/min NaCN infusion. During hemorrhage, CcO redox state became reduced concurrently with decreases in oxyhemoglobin, resulting from reduced tissue oxygen delivery and hypoxia. In contrast, during CN infusion, CcO redox state decreased while oxyhemoglobin concentration increased due to CN binding and reduction of CcO with resultant inhibition of the electron transport chain. Spectral absorption similarities between hemoglobin and CcO make noninvasive spectroscopic distinction of CcO redox states difficult. By contrasting physiological perturbations of CN poisoning versus hemorrhage, we demonstrate that DOS measured CcO redox state changes are decoupled from hemoglobin concentration measurement changes. PMID- 24788371 TI - Comparison of super-resolution algorithms applied to retinal images. AB - A critical challenge in biomedical imaging is to optimally balance the trade-off among image resolution, signal-to-noise ratio, and acquisition time. Acquiring a high-resolution image is possible; however, it is either expensive or time consuming or both. Resolution is also limited by the physical properties of the imaging device, such as the nature and size of the input source radiation and the optics of the device. Super-resolution (SR), which is an off-line approach for improving the resolution of an image, is free of these trade-offs. Several methodologies, such as interpolation, frequency domain, regularization, and learning-based approaches, have been developed over the past several years for SR of natural images. We review some of these methods and demonstrate the positive impact expected from SR of retinal images and investigate the performance of various SR techniques. We use a fundus image as an example for simulations. PMID- 24788372 TI - Simultaneous measurement of breathing rate and heart rate using a microbend multimode fiber optic sensor. AB - We propose and demonstrate the feasibility of using a highly sensitive microbend multimode fiber optic sensor for simultaneous measurement of breathing rate (BR) and heart rate (HR). The sensing system consists of a transceiver, microbend multimode fiber, and a computer. The transceiver is comprised of an optical transmitter, an optical receiver, and circuits for data communication with the computer via Bluetooth. Comparative experiments conducted between the sensor and predicate commercial physiologic devices showed an accuracy of +/-2 bpm for both BR and HR measurement. Our preliminary study of simultaneous measurement of BR and HR in a clinical trial conducted on 11 healthy subjects during magnetic resonance imaging (MRI) also showed very good agreement with measurements obtained from conventional MR-compatible devices. PMID- 24788373 TI - Microcirculation assessment using an individualized model for diffuse reflectance spectroscopy and conventional laser Doppler flowmetry. AB - Microvascular assessment would benefit from co-registration of blood flow and hemoglobin oxygenation dynamics during stimulus response tests. We used a fiber optic probe for simultaneous recording of white light diffuse reflectance (DRS; 475-850 nm) and laser Doppler flowmetry (LDF; 780 nm) spectra at two source detector distances (0.4 and 1.2 mm). An inverse Monte Carlo algorithm, based on a multiparameter three-layer adaptive skin model, was used for analyzing DRS data. LDF spectra were conventionally processed for perfusion. The system was evaluated on volar forearm recordings of 33 healthy subjects during a 5-min systolic occlusion protocol. The calibration scheme and the optimal adaptive skin model fitted DRS spectra at both distances within 10%. During occlusion, perfusion decreased within 5 s while oxygenation decreased slowly (mean time constant 61 s; dissociation of oxygen from hemoglobin). After occlusion release, perfusion and oxygenation increased within 3 s (inflow of oxygenized blood). The increased perfusion was due to increased blood tissue fraction and speed. The supranormal hemoglobin oxygenation indicates a blood flow in excess of metabolic demands. In conclusion, by integrating DRS and LDF in a fiber-optic probe, a powerful tool for assessment of blood flow and oxygenation in the same microvascular bed has been presented. PMID- 24788374 TI - Feasibility of interstitial near-infrared radiance spectroscopy platform for ex vivo canine prostate studies: optical properties extraction, hemoglobin and water concentration, and gold nanoparticles detection. AB - The canine prostate is a close match for the human prostate and is used in research of prostate cancers. Determining accurately optical absorption and scattering properties of the gland in a wide spectral range (preferably in a minimally invasive way), linking optical properties to concentrations of major endogenous chromophores, and detecting the presence of localized optical inhomogeneities like inclusions of gold nanoparticles for therapeutic and diagnostic purposes, are among the major challenges for researchers. The goal of the article is to demonstrate a feasibility of the multifunctional radiance spectroscopy platform in providing the required information. For ex vivo canine prostate, extraction of the effective attenuation and diffusion coefficients using relative cw radiance measurements was demonstrated in the 650- to 900-nm range. The derived absorption coefficient was decomposed to contributions from 9.0 MUM HbO2, 29.6 MUM Hb, and 0.47 fractional volume of H2O. Detection of a localized inclusion containing ~1.5.1010 gold nanorods (0.8 MUg Au) at 10 mm distance from the urethra was achieved with the detector in the urethra and the light source in a virtual rectum position. The platform offers the framework for a systematic study of various chromophores in the prostate that can be used as comprehensive diagnostic markers. PMID- 24788377 TI - Effects of anesthesia with sevoflurane and propofol on the cytokine/chemokine production at the airway epithelium during esophagectomy. AB - Post-operative pulmonary complications such as pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are closely associated with morbidity and mortality after esophagectomy. One lung ventilation (OLV) is commonly used during esophagectomy. However, the effect of the anesthetic agents on the inflammatory response induced by OLV has yet to be evaluated, particularly during esophagectomy, which causes several complications in the lung. The aim of the present study was to determine the effects of anesthetic agents, such as sevoflurane or propofol, on the inflammatory reactions at the airway. Twenty patients undergoing esophagectomy were randomized to receive either sevoflurane (n=10) or propofol (n=10) as a main anesthetic agent. Epithelial lining fluid (ELF) was obtained from ventilated-dependent lung (DL) and collapsed non dependent lung (NDL) by a bronchoscopic microsampling method. The levels of inflammatory cytokines and chemokine [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12p70] in the ELF were measured using multiplexed bead-based immunoassays before and after OLV. The results indicated that the levels of IL-6 in ELF were significantly increased in both the ventilated DL and collapsed NDL after OLV compared with the levels prior to OLV in the sevoflurane group. By contrast, there was no significant change in the IL 6 levels in the propofol group in the ventilated DL and collapsed NDL before and after OLV. Similarly, IL-8 levels were markedly increased in the ventilated DL and collapsed NDL after OLV compared with those before OLV in the sevoflurane group, whereas there was no significant change in IL-8 levels in the propofol group in the ventilated DL and collapsed NDL before and after OLV. In contrast to the changes in IL-6 and IL-8 levels, levels of IL-10, an anti-inflammatory cytokine, were not obviously changed in both the ventilated DL and collapsed NDL before and after OLV in the sevoflurane group. However, IL-10 levels in the propofol group were increased in the ventilated DL and collapsed NDL after OLV compared with those before OLV. Of note, the levels of TNF-alpha, IL-1beta and IL 12p70 in ELF were below the detection limits. These observations suggested that propofol anesthesia more potently suppresses the surgical stress-induced inflammatory perturbation at the local milieu of the airway during esophagectomy compared with sevoflurane anesthesia. PMID- 24788378 TI - Improved FK506 production by the precursors and product-tolerant mutant of Streptomyces tsukubaensis based on genome shuffling and dynamic fed-batch strategies. AB - FK506, a secondary metabolite produced by Streptomyces tsukubaensis, is well known for its immunosuppressant properties to prevent rejection of transplanted organs and treat autoimmune diseases. However, the low titer of FK506 in the original producer strain limits the further industrialization efforts and restricts its clinical applications. To address this issue, a highly efficient method combined genome shuffling and dynamic fed-batch strategies was systematically performed in this work. Firstly, after five rounds of genome shuffling based on precursors and product resistances, a higher yielding strain TJ-P325 was successfully acquired, whose production reached 365.6 mg/L, 11-fold increase compared with the original strain. Then, the possible mechanism of different production capabilities between TJ-P325 and the wild type was explored through comparative gene expression analysis of key genes. Results showed that the transcription level of key genes was altered significantly in the mutant. Moreover, precursors addition enhanced the FK506 production by 28 %, as well as reduced the by-products biosynthesis. Finally, the disodium malonate and disodium methylmalonate dynamic fed-batch strategies dramatically led to the production of 514.5 mg/L in a 7.5-L bioreactor. These results demonstrated that genome shuffling and dynamic fed-batch strategies could be successfully applied to generate high-yield strains with value-added natural products during industrial microbial fermentation. PMID- 24788379 TI - Production of 3-hydroxypropionic acid from glycerol by acid tolerant Escherichia coli. AB - The biological production of 3-hydroxypropionic acid (3-HP) has attracted significant attention because of its industrial importance. The low titer, yield and productivity, all of which are related directly or indirectly to the toxicity of 3-HP, have limited the commercial production of 3-HP. The aim of this study was to identify and select a 3-HP tolerant Escherichia coli strain among nine strains reported to produce various organic acids efficiently at high titer. When transformed with heterologous glycerol dehydratase, reactivase and aldehyde dehydrogenase, all nine E. coli strains produced 3-HP from glycerol but the level of 3-HP production, protein expression and activities of the important enzymes differed significantly according to the strain. Two E. coli strains, W3110 and W, showed higher levels of growth than the others in the presence of 25 g/L 3-HP. In the glycerol fed-batch bioreactor experiments, the recombinant E. coli W produced a high level of 3-HP at 460 +/- 10 mM (41.5 +/- 1.1 g/L) in 48 h with a yield of 31 % and a productivity of 0.86 +/- 0.05 g/L h. In contrast, the recombinant E. coli W3110 produced only 180 +/- 8.5 mM 3-HP (15.3 +/- 0.8 g/L) in 48 h with a yield and productivity of 26 % and 0.36 +/- 0.02 g/L h, respectively. This shows that the tolerance to and the production of 3-HP differ significantly among the well-known, similar strains of E. coli. The titer and productivity obtained with E. coli W were the highest reported thus far for the biological production of 3 HP from glycerol by E. coli. PMID- 24788380 TI - The oncoprotein hepatitis B X-interacting protein promotes the migration of ovarian cancer cells through the upregulation of S-phase kinase-associated protein 2 by Sp1. AB - Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein. We have previously reported that HBXIP promotes the proliferation and migration of breast cancer cells. S-phase kinase-associated protein 2 (Skp2) is another oncoprotein which is important for migration. In this study, we investigated whether Skp2 is involved in the migration enhanced by HBXIP in ovarian cancer. The expression of HBXIP and Skp2 in ovarian cancer tissues was examined by immunohistochemistry using tissue microarrays. The role of HBXIP and Skp2 in the migration of ovarian cancer cells was investigated by wound-healing assay and Transwell migration assay. The effect of HBXIP on Skp2 was assessed by reverse transcription polymerase chain reaction (RT-PCR), western blot analysis, luciferase reporter gene assays and chromatin immunoprecipitation in ovarian cancer cells (SKOV3 and CAOV3). We found that both HBXIP and Skp2 were highly expressed in ovarian cancer tissues. We observed that the overexpression of HBXIP enhanced the migration of ovarian cancer cells, while Skp2 siRNAs decreased the cell migration enhanced by HBXIP. The HBXIP siRNAs inhibited ovarian cancer cell migration and Skp2 rescued the migration inhibition induced by HBXIP siRNA. HBXIP could upregulate Skp2 at the levels of mRNA and protein in ovarian cancer cells. Moreover, HBXIP increased the activity of Skp2 promoter via binding to the transcription factor Sp1. HBXIP is highly expressed in ovarian cancer tissues. HBXIP enhances the migration of ovarian cancer cells. HBXIP was able to stimulate the activity of Skp2 promoter via transcription factor Sp1 thus promoting the migration of ovarian cancer cells. PMID- 24788381 TI - Synthesis and properties of chemiluminescent acridinium ester labels with fluorous tags. AB - Acridinium dimethylphenyl esters are highly sensitive chemiluminescent labels that are used in clinical diagnostics. Light emission from these labels is triggered with alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride (CTAC). CTAC compresses emission times of these labels to <5 seconds and also increases overall light yield 3-4 fold. The observed enhancement in acridinium ester chemiluminescence (light yield) is quite sensitive to the polarity of the micellar interface. In the current study, we report the synthesis of new acridinium ester labels with fluorous tags of varying fluorine content and their chemiluminescence in the presence of cationic micelles of CTAC, anionic micelles of sodium perfluorooctanoate (SPFO) as well as mixed micelles of CTAC and SPFO. These studies indicate that in the presence of the mixed micelle system of CTAC and SPFO and at low mole fractions of SPFO, polarity of the mixed micelle interface is lower than that of CTAC leading to a greater enhancement of chemiluminescence for both fluorinated acridinium esters as well as a structurally analogous but non-fluorinated acridinium ester. Chemiluminescence stability of the fluorinated acridinium esters was either comparable to or better than the stability of the non-fluorinated acridinium ester. Non-specific binding to paramagnetic microparticles was higher for fluorinated acridinium esters requiring a surfactant wash to reduce their non specific binding to the same extent as that observed for the non-fluorinated acridinium ester. PMID- 24788382 TI - Insight into the heterogeneity of prostate cancer through PSA-PSMA prostate clones: mechanisms and consequences. AB - A major clinical challenge is posed by the current inability to readily distinguish indolent from aggressive tumors in prostate cancer patients. Research efforts are dedicated to overcome this problem by understanding the molecular basis of the transition from normal, benign cells to prostatic intraepithelial neoplasia (PIN), localized carcinoma, and metastatic cancer. Combined with the evidence of the phenotypic heterogeneity of benign prostate hyperplasia, primary tumors and metastases, it is conceivable that several prostate clones emerge progressively during tumor progression. We have identified several PSA-PSMA prostate clones during prostate cancer progression. In this paper we focus on the susceptibilities of these PSA-PSMA prostate clones to factors that promote prostate hyperplastic, neoplastic and metastatic development and their consequences in disease outcome. PMID- 24788383 TI - A new method of producing casts for anatomical studies. AB - The objective of the present study was to verify if polyurethane foam is a suitable material to make accurate casts of vessels and viscera, and to develop a method based on its use for anatomical studies. This new technique has been tested primarily on the lungs of different animals, but also on the renal, intestinal and equine digital vessels. It consisted of three steps: specimen preparation, injection of the foam and corrosion of the cast. All structures injected with foam were properly filled. The bronchial tree and the vessels could be observed up to their finer branches. The method is inexpensive, simple and requires no special equipment. The pre-casting procedure does not require perfusion of the specimens with formalin, or prolonged flushing with carbon dioxide gas or air for drying. The polyurethane foam does not need a catalyst. It is simply diluted with acetone, which does not cause shrinkage of the cast due to evaporation during hardening. The foam naturally expands into the cavities without high pressure of the inoculum, and hardens in just 2 or 3 h at room temperature. Only two drawbacks were observed. The first is the fact that multiple injections cannot be made in the same cavity since the foam solidifies quickly; the second is the slight brittleness of the cast, due to the low elasticity of polyurethane foam. In conclusion, polyurethane foam was a suitable material for producing accurate casts of vessels and viscera. PMID- 24788384 TI - Excited-state dynamics of pentacene derivatives with stable radical substituents. AB - The excited-state dynamics of pentacene derivatives with stable radical substituents were evaluated in detail through transient absorption measurements. The derivatives showed ultrafast formation of triplet excited state(s) in the pentacene moiety from a photoexcited singlet state through the contributions of enhanced intersystem crossing and singlet fission. Detailed kinetic analyses for the transient absorption data were conducted to quantify the excited-state characteristics of the derivatives. PMID- 24788385 TI - Emotion based attentional priority for storage in visual short-term memory. AB - A plethora of research demonstrates that the processing of emotional faces is prioritised over non-emotive stimuli when cognitive resources are limited (this is known as 'emotional superiority'). However, there is debate as to whether competition for processing resources results in emotional superiority per se, or more specifically, threat superiority. Therefore, to investigate prioritisation of emotional stimuli for storage in visual short-term memory (VSTM), we devised an original VSTM report procedure using schematic (angry, happy, neutral) faces in which processing competition was manipulated. In Experiment 1, display exposure time was manipulated to create competition between stimuli. Participants (n = 20) had to recall a probed stimulus from a set size of four under high (150 ms array exposure duration) and low (400 ms array exposure duration) perceptual processing competition. For the high competition condition (i.e. 150 ms exposure), results revealed an emotional superiority effect per se. In Experiment 2 (n = 20), we increased competition by manipulating set size (three versus five stimuli), whilst maintaining a constrained array exposure duration of 150 ms. Here, for the five-stimulus set size (i.e. maximal competition) only threat superiority emerged. These findings demonstrate attentional prioritisation for storage in VSTM for emotional faces. We argue that task demands modulated the availability of processing resources and consequently the relative magnitude of the emotional/threat superiority effect, with only threatening stimuli prioritised for storage in VSTM under more demanding processing conditions. Our results are discussed in light of models and theories of visual selection, and not only combine the two strands of research (i.e. visual selection and emotion), but highlight a critical factor in the processing of emotional stimuli is availability of processing resources, which is further constrained by task demands. PMID- 24788386 TI - Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase. AB - The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so called "mepacrine binding site". The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi. PMID- 24788387 TI - High-throughput phenotypic assessment of cardiac physiology in four commonly used inbred mouse strains. AB - Mice with genetic alterations are used in heart research as model systems of human diseases. In the last decade there was a marked increase in the recognition of genetic diversity within inbred mouse strains. Increasing numbers of inbred mouse strains and substrains and analytical variation of cardiac phenotyping methods require reproducible, high-throughput methods to standardize murine cardiovascular physiology. We describe methods for non-invasive, reliable, easy and fast to perform echocardiography and electrocardiography on awake mice. This method can be used for primary screening of the murine cardiovascular system in large-scale analysis. We provide insights into the physiological divergence of C57BL/6N, C57BL/6J, C3HeB/FeJ and 129P2/OlaHsd mouse hearts and define the expected normal values. Our report highlights that compared to the other three strains tested C57BL/6N hearts reveal features of heart failure such as hypertrophy and reduced contractile function. We found several features of the mouse ECG to be under genetic control and obtained several strain-specific differences in cardiac structure and function. PMID- 24788388 TI - RNA-seq analysis of synovial fibroblasts in human rheumatoid arthritis. AB - The aim of the present study was to identify differentially expressed genes (DEGs) between individuals with rheumatoid arthritis (RA) and healthy controls, in order to provide a theoretical foundation for RA diagnosis and targeted gene therapy. Illumina mRNA sequence data (RNA-Seq) corresponding to RA and control samples were downloaded from the Sequence Read Archive (SRA) database. Gene Ontology (GO) enrichment analysis was performed with the GOstat tool in order to identify over-represented biological functions among DEGs, and the related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified using the KEGG Automatic Annotation Server (KAAS). A total of 293 DEGs were identified, among which 16 DEGs have been previously shown to associate with RA, such as those encoding matrix metalloproteinase-1 (MMP-1), interleukin-1 receptor type 1 (IL1R1), and chemokine (C-X3-C motif) ligand 1 (CX3CL1). GO functional annotation and enrichment analysis showed that the DEGs are enriched for 309 GO terms, mainly protein-protein interactions, membrane formation and stability. KEGG pathway analysis demonstrated that these DEGs are involved in 131 pathways, including Wnt and calcium signaling, and cell adhesion molecule (CAM)-related pathways. In conclusion, the results provide both expansive and detailed insights into the molecular pathogenesis of RA, particularly with regards to the development of therapeutic targets, and may inspire further experimentation aiming to identify new strategies for RA treatment. PMID- 24788389 TI - Authors' reply to Mark Jones's second critique of the study by Muthuri and colleagues reported in The BMJ. PMID- 24788390 TI - Donor-acceptor chemistry in the main group. AB - This Perspective article summarizes recent progress from our laboratory in the isolation of reactive main group species using a general donor-acceptor protocol. A highlight of this program is the use of carbon-based donors in combination with suitable Lewis acidic acceptors to yield stable complexes of parent Group 14 element hydrides (e.g. GeH2 and H2SiGeH2). It is anticipated that this strategy could be extended to include new synthetic targets from throughout the Periodic Table with possible applications in bottom-up materials synthesis and main group element catalysis envisioned. PMID- 24788391 TI - The consequences of migration to the United States for short-term changes in the health of Mexican immigrants. AB - Although many studies have attempted to examine the consequences of Mexico-U.S. migration for Mexican immigrants' health, few have had adequate data to generate the appropriate comparisons. In this article, we use data from two waves of the Mexican Family Life Survey (MxFLS) to compare the health of current migrants from Mexico with those of earlier migrants and nonmigrants. Because the longitudinal data permit us to examine short-term changes in health status subsequent to the baseline survey for current migrants and for Mexican residents, as well as to control for the potential health selectivity of migrants, the results provide a clearer picture of the consequences of immigration for Mexican migrant health than have previous studies. Our findings demonstrate that current migrants are more likely to experience recent changes in health status-both improvements and declines-than either earlier migrants or nonmigrants. The net effect, however, is a decline in health for current migrants: compared with never migrants, the health of current migrants is much more likely to have declined in the year or two since migration and not significantly more likely to have improved. Thus, it appears that the migration process itself and/or the experiences of the immediate post-migration period detrimentally affect Mexican immigrants' health. PMID- 24788393 TI - Laparoscopic sleeve gastrectomy using 42-French versus 32-French bougie. PMID- 24788392 TI - Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. AB - Covering: 2006 to 2013. Investigations on the chemistry and biology of rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species during the period 2006-2013 are reviewed. Included are new phytochemical studies of naturally occurring rocaglamide derivatives, an update on synthetic methods for cyclopenta[b]benzofurans, and a description of the recent biological evaluation and mechanism-of-action studies on compounds of this type. PMID- 24788394 TI - Laparoscopic sleeve gastrectomy using 42-French versus 32-French bougie. PMID- 24788395 TI - Patient preferences and bariatric surgery procedure selection; the need for shared decision-making. AB - BACKGROUND: Bariatric surgery is the most effective treatment for patients suffering from obesity-related comorbidities. There is little data regarding how patients choose one particular bariatric procedure over another. This study aimed to better define the relationship between preferences of patients considering bariatric surgery and the procedure patients undergo. METHODS: A bilingual questionnaire was administered to all prospective patients seen between March 1 and August 31, 2012. The questionnaire assessed basic knowledge of bariatric surgery (based on the information seminar) as well as patient preferences of the various outcomes and complications for sleeve gastrectomy, gastric bypass, and gastric banding. RESULTS: One hundred seventy-two patients completed the questionnaire. Fifty-eight percent of patients chose "maximum weight loss" as the most important outcome, and 65 % chose "leak" as the most concerning complication. Subgroup analysis of patients with diabetes revealed that 58 % chose "curing diabetes" as the most important outcome. Nineteen percent of patients were either not sure which procedure they wanted or changed their decision after consultation with the surgeon. CONCLUSIONS: The decision to choose one bariatric procedure over another is complex and is based on factors beyond absolute patient preferences. Although maximum weight loss is a commonly reported preference for patients seeking bariatric surgery, patients with diabetes are more focused on diabetes remission. Most patients have already decided which procedure to undergo prior to surgeon consultation. Patients may benefit from shared decision making, which integrates patient values and preferences along with current medical evidence to assist in the complex bariatric surgery selection process. PMID- 24788396 TI - The effect of exposure to a high-fat diet on microRNA expression in the liver of blunt snout bream (Megalobrama amblycephala). AB - Blunt snout bream (Megalobrama amblycephala) are susceptible to hepatic steatosis when maintained in modern intensive culture systems. The aim of this study was to investigate the potential roles of microRNAs (miRNAs) in diet-induced hepatic steatosis in this species. MiRNAs, small non-coding RNAs that regulate gene expression at the posttranscriptional level, are involved in diverse biological processes, including lipid metabolism. Deep sequencing of hepatic small RNA libraries from blunt snout bream fed normal-fat and high-fat diets identified 202 (193 known and 9 novel) miRNAs, of which 12 were differentially expressed between the normal-fat and high-fat diet groups. Quantitative stem-loop reverse transcriptase-polymerase chain reaction analyses confirmed the upregulation of miR-30c and miR-30e-3p and the downregulation of miR-145 and miR-15a-5p in high fat diet-fed fish. Bioinformatics tools were used to predict the targets of these verified miRNAs and to explore potential downstream gene ontology biological process categories and Kyoto Encyclopedia of Genes and Genomes pathways. Six putative lipid metabolism-related target genes (fetuin-B, Cyp7a1, NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2, 3-oxoacid CoA transferase 1b, stearoyl-CoA desaturase, and fatty-acid synthase) were identified as having potential important roles in the development of diet-induced hepatic steatosis in blunt snout bream. The results presented here are a foundation for future studies of miRNA-controlled lipid metabolism regulatory networks in blunt snout bream. PMID- 24788399 TI - Poly(trifluoromethyl)azulenes: structures and acceptor properties. AB - Six new poly(trifluoromethyl)azulenes prepared in a single high-temperature reaction exhibit strong electron accepting properties in the gas phase and in solution and demonstrate the propensity to form regular pi-stacked columns in donor-acceptor crystals when mixed with pyrene as a donor. PMID- 24788398 TI - Update on the molecular diagnosis and targeted therapy of thyroid cancer. AB - Thyroid cancer (TC) is the most common endocrine malignancy with steadily increasing incidence over the past few decades. Although standard strategies for the management of TC offer optimal outcomes in TC patients with favorable histological types at early stage, challenges arising from diagnosis and therapy still exist during clinical practice. A number of genetic alterations have been described in thyroid cancer, which provides an unprecedented opportunity for the identification of novel diagnostic and prognostic molecular markers as well as novel therapeutic targets. Molecular-targeted therapies, which have been investigated recently with increasing success, may prove to be a breakthrough in patients with advanced, radioiodine-refractory thyroid cancers. This review summarizes the latest progression in molecular diagnosis and targeted therapy of TC. PMID- 24788397 TI - Anthrax lethal factor as an immune target in humans and transgenic mice and the impact of HLA polymorphism on CD4+ T cell immunity. AB - Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified. PMID- 24788400 TI - Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension. AB - OBJECTIVE: The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS). METHODS: Thirteen males age = (26 (sd 6)) years were exposed to normobaric hypoxia (12% O2 ) and normoxia (21% O2 ). After 2 and 10 hours, AMS symptoms were assessed alongside ventricular and venous vessel volumes, cerebral blood flow, regional brain volumes, and intracranial pressure, using high-resolution magnetic resonance imaging. RESULTS: In normoxia, neither lateral ventricular volume (R(2) = 0.07, p = 0.40) nor predominance of unilateral transverse venous sinus drainage (R(2) = 0.07, p = 0.45) was related to AMS symptoms. Furthermore, despite an increase in cerebral blood flow after 2 hours of hypoxia (hypoxia vs normoxia: Delta148ml/min(-1) , 95% confidence interval [CI] = 58 to 238), by 10 hours, when AMS symptoms had developed, cerebral blood flow was normal (Delta-51ml/min(-1) , 95% CI = -141 to 39). Conversely, at 10 hours brain volume was increased (Delta59ml, 95% CI = 8 to 110), predominantly due to an increase in gray matter volume (Delta73ml, 95% CI = 25 to 120). Therefore, cerebral spinal fluid volume was decreased (Delta-40ml, 95% CI = -67 to -14). The intracranial pressure response to hypoxia varied between individuals, and as hypothesized, the most AMS-symptomatic participants had the largest increases in intracranial pressure (AMS present, Delta7mmHg, 95% CI = -2.5 to 17.3; AMS not present, Delta-1mmHg, 95% CI = -3.3 to 0.5). Consequently, there was a significant relationship between the change in intracranial pressure and AMS symptom severity (R(2) = 0.71, p = 0.002). INTERPRETATION: The data provide the strongest evidence to date to support the hypothesis that the "random" nature of AMS symptomology is explained by a variable intracranial pressure response to hypoxia. PMID- 24788401 TI - Mucoperiosteal exostoses in the tympanic bulla of African lions (Panthera leo). AB - Mucoperiosteal exostoses (MpEs) of the tympanic bulla (TB), also referred as middle-ear otoliths, have been occasionally described in dogs and cats in association with clinical signs of otitis media or as an incidental finding, but they have not been recorded in other species. In this report, we describe the radiographic, gross, and histopathologic features of MpEs in 8 African lions (Panthera leo). All animals (5 males and 3 females) were adults that had been kept in captivity and had their skeletons conserved as part of an anatomic academic collection. A radiographic study revealed mineralized structures in the TB consistent with MpEs in 7 of the 16 examined TB; a computed tomography study identified MpEs in 12 of the 16 TB. Six TB from 4 lions were sectioned, and several MpEs were demineralized for histopathologic analysis. Grossly, MpEs appeared variable in number and shape. Some were globular structures that were loosely attached to the mucosal surface of the TB; others were isolated to coalescent bone spicules extending from the mucoperiosteum. Position was also variable, but MpEs frequently developed in the hypotympanum, especially on the ventromedial aspect of the TB wall. Microscopically, MpEs were composed of osteonal bone growing from the periosteum and not by dystrophic calcification of necrotic tissue debris, as is hypothesized in dogs. PMID- 24788402 TI - Mycobacterium fortuitum lipoid pneumonia in a dog. AB - A 1-year old female spayed German Shepherd dog was evaluated for acute onset of dyspnea. Pyogranulomatous inflammation and green globoid structures were present on aspirates of the affected lung. Impression smears and histopathology confirmed pyogranulomatous pneumonia, with large amounts of lipid corresponding to the green structures noted cytologically, and identified poorly staining bacterial rods within lipid vacuoles. Special stains confirmed the presence of acid-fast bacterial rods, and polymerase chain reaction and DNA sequencing identified the organism as Mycobacterium fortuitum. M. fortuitum pneumonia is well described in humans and has previously been reported in 4 dogs and 1 cat. Lipid was a prominent cytologic and histologic feature, as is often described in humans and in the single feline case report. Additionally, this case highlights the variable cytologic appearance of lipid, as well as Mycobacterium spp, which are classically nonstaining with Wright-Giemsa. PMID- 24788403 TI - Desolvation and dehydrogenation of solvated magnesium salts of dodecahydrododecaborate: relationship between structure and thermal decomposition. AB - Attempts to synthesize solvent-free MgB12H12 by heating various solvated forms (H2O, NH3, and CH3OH) of the salt failed because of the competition between desolvation and dehydrogenation. This competition has been studied by thermogravimetric analysis (TGA) and temperature-programmed desorption (TPD). Products were characterized by IR, solution- and solid-state NMR spectroscopy, elemental analysis, and single-crystal or powder X-ray diffraction analysis. For hydrated salts, thermal decomposition proceeded in three stages, loss of water to form first hexahydrated then trihydrated, and finally loss of water and hydrogen to form polyhydroxylated complexes. For partially ammoniated salts, two stages of thermal decomposition were observed as ammonia and hydrogen were released with weight loss first of 14 % and then 5.5 %. Thermal decomposition of methanolated salts proceeded through a single step with a total weight loss of 32 % with the release of methanol, methane, and hydrogen. All the gaseous products of thermal decomposition were characterized by using mass spectrometry. Residual solid materials were characterized by solid-state (11)B magic-angle spinning (MAS) NMR spectroscopy and X-ray powder diffraction analysis by which the molecular structures of hexahydrated and trihydrated complexes were solved. Both hydrogen and dihydrogen bonds were observed in structures of [Mg(H2O)6B12H12]?6 H2O and [Mg(CH3OH)6B12H12]?6 CH3OH, which were determined by single-crystal X-ray diffraction analysis. The structural factors influencing thermal decomposition behavior are identified and discussed. The dependence of dehydrogenation on the formation of dihydrogen bonds may be an important consideration in the design of solid-state hydrogen storage materials. PMID- 24788404 TI - Anaerobic gut fungi: Advances in isolation, culture, and cellulolytic enzyme discovery for biofuel production. AB - Anaerobic gut fungi are an early branching family of fungi that are commonly found in the digestive tract of ruminants and monogastric herbivores. It is becoming increasingly clear that they are the primary colonizers of ingested plant biomass, and that they significantly contribute to the decomposition of plant biomass into fermentable sugars. As such, anaerobic fungi harbor a rich reservoir of undiscovered cellulolytic enzymes and enzyme complexes that can potentially transform the conversion of lignocellulose into bioenergy products. Despite their unique evolutionary history and cellulolytic activity, few species have been isolated and studied in great detail. As a result, their life cycle, cellular physiology, genetics, and cellulolytic metabolism remain poorly understood compared to aerobic fungi. To help address this limitation, this review briefly summarizes the current body of knowledge pertaining to anaerobic fungal biology, and describes progress made in the isolation, cultivation, molecular characterization, and long-term preservation of these microbes. We also discuss recent cellulase- and cellulosome-discovery efforts from gut fungi, and how these interesting, non-model microbes could be further adapted for biotechnology applications. PMID- 24788406 TI - Biodegradable delivery system containing a peptide inhibitor of polyglutamine aggregation: a step toward therapeutic development in Huntington's disease. AB - Huntington's and eight other neurodegenerative diseases occur because of CAG repeat expansion mutation culminating into an expanded polyglutamine tract in respective protein. In Huntington's disease (HD), a number of CAG repeats beyond normal repeat length (>36) lead to the formation of mutant protein, the proteolytic cleavage of which induces aggregation in polyglutamine length dependent manner. The neurodegeneration in this disease is linked to aggregation, and its inhibition is a potential approach for therapeutic development. Although peptides and other molecules have been developed for inhibiting aggregation, peptides in general are susceptible to degradation in vivo conditions. To understand their clinical significance, they also need to be delivered through blood-brain barrier. Here, for the first time, we have synthesized poly-d,l lactide-co-glycolide nanoparticles containing a polyglutamine aggregation inhibitor peptide PGQ9 [P(2) ], by nanoprecipitation method. This process yielded less than 200 nm spherical nanoparticles with uniform distribution. Characterization studies by infrared spectroscopy-based and HPLC-based assays show the presence of PGQ9 [P(2) ] in nanoparticles. In vitro release kinetics demonstrates that nanoparticles release PGQ9 [P(2) ] by erosion and diffusion processes. When the PGQ9 [P(2) ]-loaded nanoparticles are incubated with aggregation-prone Q35 P10 peptide, representing N-terminal part of Huntingtin protein, it arrests the elongation phase of Q35 P10 aggregation. These findings propose the first step toward delivery of a peptide inhibitor against polyglutamine aggregation in HD. PMID- 24788405 TI - Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice. AB - Trisomy 21 results in gene-dosage imbalance during embryogenesis and throughout life, ultimately causing multiple anomalies that contribute to the clinical manifestations of Down syndrome. Down syndrome is associated with manifestations of variable severity (e.g., heart anomalies, reduced growth, dental anomalies, shortened life-span). Craniofacial dysmorphology and cognitive dysfunction are consistently observed in all people with Down syndrome. Mouse models are useful for studying the effects of gene-dosage imbalance on development. We investigated quantitative changes in the skull and brain of the Dp(16)1Yey Down syndrome mouse model and compared these mice to Ts65Dn and Ts1Cje mouse models. Three dimensional micro-computed tomography images of Dp(16)1Yey and euploid mouse crania were morphometrically evaluated. Cerebellar cross-sectional area, Purkinje cell linear density, and granule cell density were evaluated relative to euploid littermates. Skulls of Dp(16)1Yey and Ts65Dn mice displayed similar changes in craniofacial morphology relative to their respective euploid littermates. Trisomy based differences in brain morphology were also similar in Dp(16)1Yey and Ts65Dn mice. These results validate examination of the genetic basis for craniofacial and brain phenotypes in Dp(16)1Yey mice and suggest that they, like Ts65Dn mice, are valuable tools for modeling the effects of trisomy 21 on development. PMID- 24788407 TI - Atoh1 expression levels define the fate of rat cochlear nonsensory epithelial cells in vitro. AB - Atonal homolog 1 (Atoh1) is a basic helix-loop-helix transcription factor that is essential for inner ear hair cell differentiation. Previous studies have reported that Atoh1 gene transfer induces the production of ectopic hair cell-like cells (EHCLCs). In the present study, the effect of different Atoh1 expression levels and the duration of EHCLC formation on the lesser epithelial ridge (LER) of cochleae was examined using a human adenovirus serotype 5 (Ad5) vector encoding atoh1 and the reporter gene EGFP. Different Ad5-EGFP-atoh1/Ad5-EGFP virus titers were added to cultured cochlear explants and EHCLCs were detected in the LER at various time points. The results demonstrated that GFP alone did not induce EHCLCs. By contrast, Atoh1 expression induced EHCLCs as early as 2.5-5 days following EGFP-atoh1 infection in the LER and depending upon the viral titer, the number of EHCLCs increased with time. Higher Ad5-EGFP-atoh1 titers induced enhanced Atoh1 expression, resulting in an increase in EHCLCs. Lower Ad5-EGFP atoh1 titers required more time for EHCLC formation and very low titers of Ad5 EGFP-atoh1 induced only weak Atoh1 expression and did not trigger EHCLC formation. In conclusion, the present study utilized an appropriate Ad5-EGFP atoh1 titer range to induce Atoh1 expression and the subsequent production of EHCLCs. The results revealed that the Atoh1 expression level defined the fate of LER cells as either EHCLCs or nonsensory epithelial cells. This evidence may provide an important guideline for future studies into gene therapy strategies for the treatment of deafness. PMID- 24788408 TI - Effect of verapamil on the pharmacokinetics of pasireotide in healthy volunteers. AB - We evaluated the drug-drug interaction between pasireotide SC and verapamil, a known P-glycoprotein inhibitor. Subjects received pasireotide SC (single dose, 600 MUg) on day 1, and samples for pharmacokinetics evaluation were collected from days 1 to 8. Subjects received an oral dose of verapamil 240 mg/d for 10 days (days 15-24). On day 18, subjects also received pasireotide SC 600 MUg. Pharmacokinetic sampling for pasireotide SC and verapamil was done during days 18 to 25 and days 15 to 21, respectively. Safety evaluations were performed throughout the study period, including a 30-day post-treatment follow-up. Pharmacokinetic profiles of pasireotide SC alone and in combination with verapamil sustained-release (SR) were superimposable with the geometric mean ratios (90% confidence interval [CI]) of 0.98 (0.91-1.06) for C(max), 0.97 (0.90 1.04) for AUC(last), and 0.98 (0.92-1.05) for AUC(inf). Exploratory analyses showed a 17% (90% CI, 0.72-0.94) reduction in C(trough) and 31% (0.58-0.82) reduction in C(max) (8 hours post-dose) for verapamil SR with pasireotide SC versus verapamil alone. Pasireotide SC with or without verapamil was well tolerated. In conclusion, there was no change in the rate of pasireotide absorption and elimination or extent of exposure following concomitant administration with verapamil. PMID- 24788410 TI - The uncommon roles of common gene regulatory factors in the genomes of differentiating cells. AB - Viewed through the lens of comparative regulatory mechanisms in developmental processes, the article of Calero-Nieto et al (2014, this issue) is of particular interest. This work uncovers the causal combinatorial subtleties of the distinct enhancer occupancy profiles displayed by ten different transcription factors, which are expressed in common in two hematopoietic cell types, a stem cell-like precursor and primary mast cells. PMID- 24788409 TI - c-Src drives intestinal regeneration and transformation. AB - The non-receptor tyrosine kinase c-Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult Drosophila and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage-induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self-renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non-redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation in vivo. PMID- 24788411 TI - The ER under rapid fire. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to selective death of upper and lower motoneurons. Clinically, the ALS syndrome is linked to pathogenic mutations in superoxide dismutase 1 (SOD1), though actual molecular mechanisms remain ill understood. Two papers recently published in Cell Stem Cell and Cell Reports employ syngenic, iPSC-derived cell lines of one of the most severe SOD1 mutations to report mitochondrial and ER stress as causal for perturbed electrical activity in ALS neurons (Kiskinis et al, 2014; Wainger et al, 2014). PMID- 24788412 TI - Analyses of the temporal dynamics of fungal communities colonizing the healthy wood tissues of esca leaf-symptomatic and asymptomatic vines. AB - Esca, a Grapevine Trunk Disease (GTD), is of major concern for viticulture worldwide. Our study compares the fungal communities that inhabit the wood tissues of vines that expressed or not foliar esca-symptoms. The trunk and rootstock tissues were apparently healthy, whether the 10 year-old plants were symptomatic or not. The only difference was in the cordon, which contained white rot, a typical form of esca, in 79% of symptomatic plants. Observations over a period of one year using a fingerprint method, Single Strand Conformation Polymorphism (SSCP), and the ITS-DNA sequencing of cultivable fungi, showed that shifts occurred in the fungal communities colonizing the healthy wood tissues. However, whatever the sampling time, spring, summer, autumn or winter, the fungi colonizing the healthy tissues of asymptomatic or symptomatic plants were not significantly different. Forty-eight genera were isolated, with species of Hypocreaceae and Botryosphaeriaceae being the most abundant species. Diverse fungal assemblages, made up of potentially plant-pathogenic and -protective fungi, colonized these non-necrotic tissues. Some fungi, possibly involved in GTD, inhabited the non-necrotic wood of young plants, but no increase in necrosis areas was observed over the one-year period. PMID- 24788413 TI - Effect of added alkalizer and surfactant on dissolution and absorption of the potassium salt of a weakly basic poorly water-soluble drug. AB - Telcagepant potassium salt (MK-0974) is an oral calcitonin gene-related peptide receptor inhibitor investigated for the treatment of acute migraine. Under gastric pH conditions, the salt rapidly gels, then converts to an insoluble neutral form that creates an impervious shell on the tablet surface, resulting in a slow and variable release dissolution rate and poor bioavailability. Early attempts to develop a solid dosage form, including solid dispersion and nanosuspension formulations, resulted in low exposures in preclinical studies. Thus, a liquid-filled soft gelatin capsule (SGC) formulation (oblong 20) was used for clinical studies. However, a solid dosage form was desirable for commercialization. The slow dissolution of the tablet formulations was overcome by using a basifying agent, arginine, and inclusion of a nonionic surfactant, poloxamer 407. The combination of arginine and poloxamer in the formulation created a local transient basic microenvironment that promoted the dissolution of the salt and prevented rapid precipitation of the neutral form on the tablet surface to form the gel layer. The tablet formulation achieved fast absorption and comparable exposure to the SGC formulation. The final optimized 280 mg tablet formulation was successfully demonstrated to be bioequivalent to the 300 mg SGC formulation. PMID- 24788415 TI - Proteasomal degradation of O-GlcNAc transferase elevates hypoxia-induced vascular endothelial inflammatory response?. AB - AIMS: Hypoxia induces vascular inflammation by a mechanism not fully understood. Emerging evidence implicates O-GlcNAc transferase (OGT) in inflammation. This study explored the role of OGT in hypoxia-induced vascular endothelial inflammatory response. METHODS AND RESULTS: Hypoxia was either induced (1% O2 chamber) or mimicked by exposure to hypoxia-mimetic agents in cultured endothelial cells. Hypoxia increased hypoxia-inducible factor (HIF-1alpha) and inflammatory response (gene and protein expression of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and E-selectin) but, surprisingly, reduced OGT protein (not mRNA) levels. Hypoxia-mimetic CoCl2 failed to reduce OGT when proteasome inhibitors were present, suggesting proteasome involvement. Indeed, CoCl2 enhanced 26S proteasome functionality evidenced by diminished reporter (Ub(G76V)-GFP) proteins in proteasome reporter cells, likely due to increased chymotrypsin-like activities. Mechanistically, beta-TrCP1 mediated OGT degradation, since siRNA ablation of this E3 ubiquitin ligase stabilized OGT. Administration of the oxidative stress inhibitors reversed both proteasome activation and OGT degradation. Furthermore, up-regulation of OGT by stabilization, overexpression, or activation mitigated CoCl2-elicited inflammatory response. These observations were recapitulated in a mouse (C57BL/6J) model mimicking hypoxia, in which lung tissues presented higher levels of HIF-1alpha, proteasome activity, and inflammatory response, but lower levels of OGT (n = 5/group, hypoxia vs. normoxia, P < 0.05). However, administration of an activator of OGT (glucosamine: 1 mg/g/day, vehicle: saline, ip, 5 days) abolished the up-regulation of proteasome activity and inflammatory response (n = 5/group, the treated vs. untreated hypoxia groups, P < 0.05). CONCLUSIONS: 26S proteasome-mediated OGT reduction contributed to hypoxia-induced vascular endothelial inflammatory response. Modulation of OGT may represent a new approach to treat diseases characterized by hypoxic inflammation. PMID- 24788416 TI - Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis. AB - AIMS: Insulin resistance (IR) is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events are mainly due to rupture of unstable plaques, and the role of vascular smooth muscle cells (VSMCs) in this process in IR, Type 2 diabetes mellitus, and metabolic syndrome (T2DM/MetS) has not been fully addressed. Therefore, the role of VSMC survival in the generation of unstable plaques in T2DM/MetS and the involvement of inflammatory mediators was investigated. METHODS AND RESULTS: Defective insulin receptor substrate 2 (IRS2)-mediated signalling produced insulin-resistant VSMCs with reduced survival, migration, and higher apoptosis than control cells. Silencing of IRS2 or inhibition of the V-akt murine thymomaviral oncogene homologue kinase (AKT) extracellular signal-regulated kinase (ERK)-dependent pathway in VSMCs augmented expression of the inflammatory chemokine fractalkine (CX3CL1) and its receptor CX3CR1, previously involved in atheroma plaque vulnerability. Interestingly, treatment of VSMCs with CX3CL1 promoted apoptosis in the presence of other stimuli or when the AKT pathway was blocked. Analysis of a mouse model of IR-MetS and accelerated atherosclerosis, apoE-/-Irs2+/- mice, showed reduced VSMC survival, unstable plaques, and up-regulation of CX3CL1/CX3CR1 axis compared with apoE-/- mice. Human studies showed augmented soluble CX3CL1 plasma levels and CX3CR1 expression in monocytes from IR-MetS subjects compared with controls. A positive correlation between insulin levels, homeostatic model assessment (HOMA) index, carotid atherosclerosis, and CX3CR1 mRNA levels was also found in all patients. CONCLUSION: IR increases plaque vulnerability by augmenting the CX3CL1/CX3CR1 axis, which is mechanistically linked to reduced VSMC survival. Thus, modulation of IRS2-dependent signalling emerges as a potential therapeutic strategy to promote VSMC survival and atheroma plaque stability and to reduce inflammatory mediators in IR-MetS. PMID- 24788417 TI - Post-heparin LPL activity measurement using VLDL as a substrate: a new robust method for routine assessment of plasma triglyceride lipolysis defects. AB - BACKGROUND: Determination of lipoprotein lipase (LPL) activity is important for hyperchylomicronemia diagnosis, but remains both unreliable and cumbersome with current methods. Consequently by using human VLDL as substrate we developed a new LPL assay which does not require sonication, radioactive or fluorescent particles. METHODS: Post-heparin plasma was added to the VLDL substrate prepared by ultracentrifugation of heat inactivated normolipidemic human serums, diluted in buffer, pH 8.15. Following incubation at 37 degrees c, the NEFA (non esterified fatty acids) produced were assayed hourly for 4 hours. LPL activity was expressed as umol/l/min after subtraction of hepatic lipase (HL) activity, obtained following LPL inhibition with NaCl 1.5 mmol/l. Molecular analysis of LPL, GPIHBP1, APOA5, APOC2, APOE genes was available for 62 patients. RESULTS: Our method was reproducible (coefficient of variation (CV): intra-assay 5.6%, inter-assay 7.1%), and tightly correlated with the conventional radiolabelled triolein emulsion method (n = 26, r = 0.88). Normal values were established at 34.8 +/- 12.8 umol/l/min (mean +/- SD) from 20 control subjects. LPL activities obtained from 71 patients with documented history of major hypertriglyceridemia showed a trimodal distribution. Among the 11 patients with a very low LPL activity (<10 umol/l/min), 5 were homozygous or compound heterozygous for LPL or GPIHBP1 deleterious mutations, 3 were compound heterozygous for APOA5 deleterious mutations and the p.S19W APOA5 susceptibility variant, and 2 were free of any mutations in the usual candidate genes. No homozygous gene alteration in LPL, GPIHBP1 and APOC2 genes was found in any of the patients with LPL activity >10 umol/l/min. CONCLUSION: This new reproducible method is a valuable tool for routine diagnosis and reliably identifies LPL activity defects. PMID- 24788418 TI - The long non-coding HOTAIR is modulated by cyclic stretch and WNT/beta-CATENIN in human aortic valve cells and is a novel repressor of calcification genes. AB - Aortic valve calcification is a significant and serious clinical problem for which there are no effective medical treatments. Individuals born with bicuspid aortic valves, 1-2% of the population, are at the highest risk of developing aortic valve calcification. Aortic valve calcification involves increased expression of calcification and inflammatory genes. Bicuspid aortic valve leaflets experience increased biomechanical strain as compared to normal tricuspid aortic valves. The molecular pathogenesis involved in the calcification of BAVs are not well understood, especially the molecular response to mechanical stretch. HOTAIR is a long non-coding RNA (lncRNA) that has been implicated with cancer but has not been studied in cardiac disease. We have found that HOTAIR levels are decreased in BAVs and in human aortic interstitial cells (AVICs) exposed to cyclic stretch. Reducing HOTAIR levels via siRNA in AVICs results in increased expression of calcification genes. Our data suggest that beta-catenin is a stretch responsive signaling pathway that represses HOTAIR. This is the first report demonstrating that HOTAIR is mechanoresponsive and repressed by WNT beta-catenin signaling. These findings provide novel evidence that HOTAIR is involved in aortic valve calcification. PMID- 24788419 TI - Simulation-based teaching: resisting the allure of shiny new toys. PMID- 24788420 TI - Motivational interviewing workshop in a virtual world: learning as avatars. AB - BACKGROUND AND OBJECTIVES: Limited research has been done to understand outcomes of continuing medical education offered in three-dimensional, immersive virtual worlds. We studied a case of a virtual world workshop on motivational interviewing (MI) applied to smoking cessation counseling and its educational impact. METHODS: To facilitate content development and evaluation, we specified desired MI competencies. The workshop consisted of three sessions, which included lectures, practice with standardized patients, and chat interactions. Data were collected from 13 primary care physicians and residents through workshop observation, and pre- and 3-month post-workshop telephone/Skype interviews and interactions with standardized patients. Interactions with standardized patients were assessed by an expert using a validated MI tool and by standardized patients using a tool developed for this study. For 11 participants who attended two or three sessions, we conducted paired-samples t tests comparing mean differences between the competency scores before and after the workshop. RESULTS: Expert assessment showed significant improvement on six of seven MI competencies. All participants reported learning new knowledge and skills, and nine described incorporating new learning into their clinical practice. Practicing MI with standardized patients and/or observing others' practice appeared to be the most helpful workshop component. CONCLUSIONS: The evaluated workshop had positive impact on participants' competencies and practice as related to MI applied to smoking cessation counseling. Our findings support further exploration of three dimensional virtual worlds as learning environments for continuing medical education. PMID- 24788421 TI - A qualitative study of medical students in a rural track: views on eventual rural practice. AB - BACKGROUND: Rural tracks (RTs) exist within medical schools across the United States. These programs often target those students from rural areas and those with primary care career interests, given that these factors are robust predictors of eventual rural practice. However, only 26% to 64% of graduates from RTs enter eventual rural practice. METHODS: We conducted a qualitative, exploratory study of medical students enrolled in one school's RT, examining their interests in rural training, specialization, and eventual rural practice, via open coding of transcripts from focus groups and in-depth individual interviews, leading to identification of emerging themes. RESULTS: A total of 16 out of 54 eligible first- and second-year preclinical medical students participated in focus group sessions, and a total of seven out of 17 eligible third- and fourth-year medical students participated in individual interviews. Analyses revealed the recognition of a "Rural Identity," typical characteristics, and the importance of "Program Fit" and "Intentions for Practice" that trended toward family medicine specialization and rural practice. However, nuances within the comments reveal incomplete commitment to rural practice. In many cases, student preference for rural practice was driven largely by a disinterest in urban practice. CONCLUSIONS: Students with rural and primary care practice interests are often not perfectly committed to rural practice. However, RTs may provide a haven for such students within medical school. PMID- 24788422 TI - Citizenship documentation requirement for Medicaid eligibility: effects on Oregon children. AB - BACKGROUND AND OBJECTIVES: The Deficit Reduction Act (DRA) of 2005 mandated Medicaid beneficiaries to document citizenship. Using a prospective cohort (n=104,375), we aimed to (1) determine characteristics of affected children, (2) describe effects on health insurance coverage and access to needed health care, and (3) model the causal relationship between this new policy, known determinants of health care access, and receipt of needed health care. METHODS: We identified a stratified random sample of children shortly after the DRA was implemented and used state records and surveys to compare three groups: children denied Medicaid for inability to document citizenship, children denied for other reasons, and children accepted for coverage. To combat survey nonresponse, we used Medicaid records to identify differences between responders and nonrespondents and created survey weights to account for these differences. Weighted simple and multivariable logistic regression described the complete, originally identified population. RESULTS: Children denied Medicaid for inability to document citizenship were likely to be US citizens, were medically and socially more vulnerable than their peers, and went on to have gaps in health insurance coverage and unmet health care needs. The DRA led to persistent loss of insurance coverage, which decreased access to needed health care. Having a usual source of care was an effect modifier in this relationship. CONCLUSIONS: Our findings demonstrate the negative consequences of the DRA and support the use of automated methods of citizenship verification allowed under the Patient Protection and Affordable Care Act. PMID- 24788423 TI - Do ABFM board pass rates or additional curriculum activities affect match rates for family medicine residency programs? AB - BACKGROUND AND OBJECTIVES: While standard characteristics, such as location and size of family medicine residency programs, have been found to be significantly associated with initial Match rates, the association of characteristics potentially related to quality or non-Accreditation Council of Graduate Medical Education (ACGME) required curricular activities (NRCA) with initial Match rates has not been previously studied. The aim of this study is to examine the association between initial program Match rates and previously uninvestigated measures of potential quality and curriculum. METHODS: Using information from the American Academy of Family Physicians (AAFP), American Medical Association's (AMA) FRIEDA Online(r) database, and National Resident Matching Program (NRMP), program-specific information was obtained. Five-year aggregate initial Match rates and American Board of Family Medicine (ABFM) board pass rates were calculated. The relationship between program quality characteristics, such as accreditation cycle length, ABFM examination pass rate, and participation in NRCA (ie, specialized tracks, Preparing the Personal Physician for Practice (P4) initiative, integrative or alternative medicine curriculum, and opportunities for additional training through international experiences or training beyond accredited length), and initial program Match rates were analyzed. RESULTS: Fifty two percent of residency programs have ABFM board pass rates ? 90%. The initial Match rate for programs was significantly associated with regional location and program size. No significant difference in initial Match rates was found between programs with board pass rates ? or < 90% or those with reported additional curricula. CONCLUSIONS: The selected measures of program quality and reported non ACGME required curricular activities, as listed in the AMA FRIEDA Online(r) database, are not associated with initial Match rates. PMID- 24788424 TI - Innovating within the ACGME regulatory environment is not an oxymoron. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to describe the analysis of program citations and cycle length for reaccreditation in the 14 family medicine residencies participating in the P4 project. METHODS: An exploratory narrative analysis was conducted on all actions taken by the Review Committee for Family Medicine (RC-FM) between 2003 and 2012. The analysis included cycle length and types of citations associated with accreditation actions. Several validation steps were undertaken to confirm findings reported. RESULTS: Mean cycle length for all P4 programs was 4.0 before P4 (2007) and did not change significantly during P4. The average number of citations per program before P4 was 6.2, and during P4 the average was 6.8. The P4 averages were similar to national norms during the project period. The citations that most commonly decreased during the P4 project were: Continuity of Patient Care/Inpatient, FMC Patient Population/Patient Volume, Orthopedics or Sports Medicine Curriculum, Resident Final Evaluation, Resident Workload/Duty Hours, and Resident Attrition. The citations that most commonly increased during the P4 project were FMC Patient Population/Demographics, Certifying Exam Scores, and Management of Health Systems Curriculum. CONCLUSIONS: Innovation and redesign of residency training in the P4 programs appears not to have affected the average cycle length or number of citations per program. The current regulatory environment in family medicine residency education appears to allow for innovation and experimentation. PMID- 24788425 TI - Increase in residency scholarly activity as a result of resident-led initiative. AB - BACKGROUND AND OBJECTIVES: Scholarly activity (SA) is a fundamental component of family medicine residency training. Despite the variety of SA options, the output of resident presentations and publications remains disappointingly low, and many residents voice frustration with fulfilling the research requirements. A resident driven process improvement project was undertaken with the goal of achieving a 100% increase of peer-reviewed publications and scholarly presentations by residents with secondary goals of doubling the involvement of staff, residents, and visiting medical or physician assistant students. METHODS: This project involves (1) increasing awareness of conferences for scholarly submission, (2) assignment of residents in a resident research team to lead efforts, (3) pairing of interns/students with senior mentors with similar interests, (4) faculty to include one resident on all projects, and (5) monthly SA meetings to track research progress, share ideas, and troubleshoot areas of difficulty. Scholarly totals were compared between the 2011--2012 and 2012--2013 academic years. RESULTS: The SA goals were achieved on all fronts. The number of resident presentations increased from three to 28 (seven regional, 10 national, and 11 international presentations), and resident peer-reviewed publications increased from two to six when compared to the previous year. Scholarly participation doubled at all levels. CONCLUSIONS: The authors recommend that other residencies consider promoting increased resident-to-resident scholarly mentorship, early planning with scheduled timeline, and increasing awareness of SA opportunities yearly. PMID- 24788426 TI - Readability of American Academy of Family Physicians patient education materials. AB - BACKGROUND AND OBJECTIVES: Unfortunately, it is not uncommon for the reading demands of patient education materials (PEMs) to exceed the actual literacy abilities of the typical American adult. The purposes of this study were to (1) assess reading demands of English and Spanish language American Academy of Family Physicians (AAFP) PEMs and (2) examine whether reading demands of English language AAFP PEMs varied from 2004 to 2012. METHODS: In December 2012, matched English and Spanish language AAFP PEMs, available via http://www.familydoctor.org, were downloaded and printed in their entirety (n=200). Reading demands of PEMs were assessed using the Lexile(r) analyzer, an Internet-based program that uses a combination of sentence length and word frequency to determine text comprehension difficulty. RESULTS: Lexile scores of English language PEMs averaged 906.0 +/- 80.2 (range=700--1,080), while mean Lexile scores of Spanish language PEMs was 874.2 +/- 63.9 (range=700--1,060). Overall, reading demands of Spanish language PEMs were significantly lower than PEMs written in English (t=3.1, P<.01). In 2012, 59% of English language PEMs were written ?6th grade reading level, whereas in 2004 only 5% of PEMs were written ?6th grade reading level. CONCLUSIONS: The majority of currently available AAFP PEMS, in both English and Spanish, were written ?6th grade reading level. Since 2004, reading demands of AAFP PEMs have decreased substantially with the majority meeting recommended low-literacy guidelines. Future efforts should be used to revise and reformat all English and Spanish language AAFP PEMs to meet the established ?6th grade reading level. PMID- 24788427 TI - Curriculum changes to increase research in a family medicine residency program. AB - BACKGROUND AND OBJECTIVES: Scholarly activity is an important component of residency programs. Amidst many other professional obligations, finding time and support for resident research can be challenging. Thus, it is important to equip residents with the tools needed to perform scholarly activity both during and after residency. METHODS: We studied a series of curriculum initiatives on scholarly productivity at Naval Hospital Jacksonville. Educational interventions were rolled out in three parts. First, a faculty research coordinator (FRC) was established. Second, a scholarly activity point system was adapted from one published by Seehusen et al, along with research and conference tracking systems. Third, a resident research coordinator (RRC) position was created. The FRC and RRC acted as liaisons between residents, faculty, and non-faculty staff and created an annual scholarly activity workshop. Scholarly productivity was analyzed using descriptive statistics. RESULTS: Prior to the roll out of these curriculum changes, the number of resident scholarly projects per resident, defined as regional or higher posters/presentations and peer-reviewed publications, was 0.07 with four residents involved. In 2012, the research per resident was 0.91, with 26 residents involved. CONCLUSIONS: Our analysis reveals an association between these new curricular initiatives and increased research among residents, similar to growth demonstrated by the innovations of Seehusen et al. Limitations of this study include reliance on the accuracy of past records and a small sample size. We believe this is a model that could be implemented in other residency programs to support scholarly activity requirements. PMID- 24788428 TI - Family medicine residency program directors' plans to incorporate maintenance of certification into residency training: a CERA survey. AB - BACKGROUND AND OBJECTIVES: Participation in Maintenance of Certification for Family Physicians (MC-FP) is now a requirement for residents to take the American Board of Family Medicine (ABFM) certification examination. The objective of this study was to determine baseline use of MC-FP products prior to this requirement and assess how family medicine residency program directors (FMPD) intended to integrate MC-FP into residency education. METHODS: We used the CERA platform to survey FMPDs. In addition to the core CERA demographic questions, we asked about the use of MC-FP in residency, how FMPDs intended to incorporate MC-FP, and how useful they believe MC-FP will be for resident evaluation. Additionally, we compared select results with the ABFM administrative database. RESULTS: A total of 224 FMPDs responded, for a 50.6% response rate. There was agreement between CERA and ABFM data on the percentage of residencies already using Part 4 modules (39.3% versus 38.8%) but not Part 2 modules (24.7% versus 62.8%). Group MC-FP activities were the preferred method for both Part 2 (45.0%) and Part 4 (54.4%). Most FMPDs agreed that MC-FP will be effective in teaching quality improvement and assessing competencies. Respondents from dually accredited programs were more likely to have used Part 4, but not Part 2, activities prior to 2012. CONCLUSIONS: Prior to MC-FP becoming a requirement in residency, a sizeable minority of residencies were already using these tools for education. Assessment of competencies will be crucial in the Next Accreditation System, and MC-FP may help in tracking clinical development over a physician's career. PMID- 24788431 TI - A very special lady. PMID- 24788432 TI - Mouse spermatocytes express CYP2E1 and respond to acrylamide exposure. AB - Metabolism of xenobiotics by cytochrome P450s (encoded by the CYP genes) often leads to bio-activation, producing reactive metabolites that interfere with cellular processes and cause DNA damage. In the testes, DNA damage induced by xenobiotics has been associated with impaired spermatogenesis and adverse effects on reproductive health. We previously reported that chronic exposure to the reproductive toxicant, acrylamide, produced high levels of DNA damage in spermatocytes of Swiss mice. CYP2E1 metabolises acrylamide to glycidamide, which, unlike acrylamide, readily forms adducts with DNA. Thus, to investigate the mechanisms of acrylamide toxicity in mouse male germ cells, we examined the expression of the CYP, CYP2E1, which metabolises acrylamide. Using Q-PCR and immunohistochemistry, we establish that CYP2E1 is expressed in germ cells, in particular in spermatocytes. Additionally, CYP2E1 gene expression was upregulated in these cells following in vitro acrylamide exposure (1 uM, 18 h). Spermatocytes were isolated and treated with 1 uM acrylamide or 0.5 uM glycidamide for 18 hours and the presence of DNA-adducts was investigated using the comet assay, modified to detect DNA-adducts. Both compounds produced significant levels of DNA damage in spermatocytes, with a greater response observed following glycidamide exposure. A modified comet assay indicated that direct adduction of DNA by glycidamide was a major source of DNA damage. Oxidative stress played a small role in eliciting this damage, as a relatively modest effect was found in a comet assay modified to detect oxidative adducts following glycidamide exposure, and glutathione levels remained unchanged following treatment with either compound. Our results indicate that the male germ line has the capacity to respond to xenobiotic exposure by inducing detoxifying enzymes, and the DNA damage elicited by acrylamide in male germ cells is likely due to the formation of glycidamide adducts. PMID- 24788433 TI - Sources of variability in metabolite measurements from urinary samples. AB - BACKGROUND: The application of metabolomics in epidemiological studies would potentially allow researchers to identify biomarkers associated with exposures and diseases. However, within-individual variability of metabolite levels caused by temporal variation of metabolites, together with technical variability introduced by laboratory procedures, may reduce the study power to detect such associations. We assessed the sources of variability of metabolites from urine samples and the implications for designing epidemiologic studies. METHODS: We measured 539 metabolites in urine samples from the Navy Colon Adenoma Study using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectroscopy (GC-MS). The study collected 2-3 samples per person from 17 male subjects (age 38-70) over 2-10 days. We estimated between-individual, within individual, and technical variability and calculated expected study power with a specific focus on large case-control and nested case-control studies. RESULTS: Overall technical reliability was high (median intraclass correlation = 0.92), and for 72% of the metabolites, the majority of total variance can be attributed to between-individual variability. Age, gender and body mass index explained only a small proportion of the total metabolite variability. For a relative risk (comparing upper and lower quartiles of "usual" levels) of 1.5, we estimated that a study with 500, 1,000, and 5,000 individuals could detect 1.0%, 4.5% and 75% of the metabolite associations. CONCLUSIONS: The use of metabolomics in urine samples from epidemiological studies would require large sample sizes to detect associations with moderate effect sizes. PMID- 24788434 TI - Characterization of multidrug-resistant Salmonella enterica serovars Indiana and Enteritidis from chickens in Eastern China. AB - A total of 310 Salmonella isolates were isolated from 6 broiler farms in Eastern China, serotyped according to the Kauffmann-White classification. All isolates were examined for susceptibility to 17 commonly used antimicrobial agents, representative isolates were examined for resistance genes and class I integrons using PCR technology. Clonality was determined by pulsed-field gel electrophoresis (PFGE). There were two serotypes detected in the 310 Salmonella strains, which included 133 Salmonella enterica serovar Indiana isolates and 177 Salmonella enterica serovar Enteritidis isolates. Antimicrobial sensitivity results showed that the isolates were generally resistant to sulfamethoxazole, ampicillin, tetracycline, doxycycline and trimethoprim, and 95% of the isolates sensitive to amikacin and polymyxin. Among all Salmonella enterica serovar Indiana isolates, 108 (81.2%) possessed the blaTEM, floR, tetA, strA and aac (6') Ib-cr resistance genes. The detected carriage rate of class 1 integrons was 66.5% (206/310), with 6 strains carrying gene integron cassette dfr17-aadA5. The increasing frequency of multidrug resistance rate in Salmonella was associated with increasing prevalence of int1 genes (rs = 0.938, P = 0.00039). The int1, blaTEM, floR, tetA, strA and aac (6')-Ib-cr positive Salmonella enterica serovar Indiana isolates showed five major patterns as determined by PFGE. Most isolates exhibited the common PFGE patterns found from the chicken farms, suggesting that many multidrug-resistant isolates of Salmonella enterica serovar Indiana prevailed in these sources. Some isolates with similar antimicrobial resistance patterns represented a variety of Salmonella enterica serovar Indiana genotypes, and were derived from a different clone. PMID- 24788440 TI - Routine production of [(18)f]flumazenil from iodonium tosylate using a sample pretreatment method: a 2.5-year production report. AB - PURPOSE: [(18)F]Flumazenil, which has the advantage of a longer half-life than [(11)C]flumazenil, is well known for determining of the central benzodiazepine receptor concentrations. However, [(18)F]flumazenil has not been widely used because fluctuating and relatively low yields render automatic production insufficient for routine and multicenter clinical trials. Here, we describe the results of a 2.5-year production study of [(18)F]flumazenil using an iodonium tosylate precursor, which allowed us to overcome the limitations of low and fluctuating radiochemical yields. PROCEDURES: We developed a clinically applicable production system by modifying a commercial synthesizer for the reliable and reproducible production of [(18)F]flumazenil for routine clinical studies. [(18)F]Flumazenil was prepared at 150 degrees C for 5 min in the presence of 4-methylphenyl-mazenil iodonium tosylate (4 mg), a radical scavenger (TEMPO, 1 mg), and [(18)F]KF/kryptofix 2.2.2 complex in N,N-dimethylformamide (1 ml). In the purification step, the final mixture was pretreated using different cartridges before performing high-performance liquid chromatography (HPLC) separation. Finally, we measured the radiochemical yield and performed quality control assays on 94 batches. RESULTS: After carrying out additional purification before HPLC separation using a C18 plus Sep-Pak cartridge, the radiochemical yield of [(18)F]flumazenil increased from 34.4 +/- 9.7 % (without the pretreatment, n = 24) to 53.4 +/- 9.0 % (n = 94), and the lifetime of the semi preparative column was five times that of the column without the C18 plus Sep-Pak cartridge. The mean-specific activity of [(18)F]flumazenil was 572 +/- 116 GBq/MUmol at the end of synthesis, and the radiochemical purity was more than 99 %, as determined by analytical HPLC and radio-TLC. [(18)F]Flumazenil prepared using this method satisfied all quality-control test standards and was highly stable for up to 6 h after preparation. CONCLUSIONS: The results of the 2.5-year production study using an iodonium tosylate precursor indicate that [(18)F]flumazenil has commercial and routine clinical applicability. PMID- 24788435 TI - Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain. AB - Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy. PMID- 24788441 TI - Protective effect of Boerhaavia diffusa L. against mitochondrial dysfunction in angiotensin II induced hypertrophy in H9c2 cardiomyoblast cells. AB - Mitochondrial dysfunction plays a critical role in the development of cardiac hypertrophy and heart failure. So mitochondria are emerging as one of the important druggable targets in the management of cardiac hypertrophy and other associated complications. In the present study, effects of ethanolic extract of Boerhaavia diffusa (BDE), a green leafy vegetable against mitochondrial dysfunction in angiotensin II (Ang II) induced hypertrophy in H9c2 cardiomyoblasts was evaluated. H9c2 cells challenged with Ang II exhibited pathological hypertrophic responses and mitochondrial dysfunction which was evident from increment in cell volume (49.09+/-1.13%), protein content (55.17+/ 1.19%), LDH leakage (58.74+/-1.87%), increased intracellular ROS production (26.25+/-0.91%), mitochondrial superoxide generation (65.06+/-2.27%), alteration in mitochondrial transmembrane potential (DeltaPsim), opening of mitochondrial permeability transition pore (mPTP) and mitochondrial swelling. In addition, activities of mitochondrial respiratory chain complexes (I-IV), aconitase, NADPH oxidase, thioredoxin reductase, oxygen consumption rate and calcium homeostasis were evaluated. Treatment with BDE significantly prevented the generation of intracellular ROS and mitochondrial superoxide radicals and protected the mitochondria by preventing dissipation of DeltaPsim, opening of mPTP, mitochondrial swelling and enhanced the activities of respiratory chain complexes and oxygen consumption rate in H9c2 cells. Activities of aconitase and thioredoxin reductase which was lowered (33.77+/-0.68% & 45.81+/-0.71% respectively) due to hypertrophy, were increased in BDE treated cells (P<=0.05). Moreover, BDE also reduced the intracellular calcium overload in Ang II treated cells. Overall results revealed the protective effects of B. diffusa against mitochondrial dysfunction in hypertrophy in H9c2 cells and the present findings may shed new light on the therapeutic potential of B. diffusa in addition to its nutraceutical potentials. PMID- 24788442 TI - Management of septic arthritis following anterior cruciate ligament reconstruction: a review of current practices and recommendations. PMID- 24788443 TI - Traumatic atlanto-occipital dislocation in children. AB - Although once considered an invariably fatal injury, improvements in diagnosis and management have made atlanto-occipital dislocation (AOD) a survivable injury. MRI is the preferred imaging modality; occasionally, flexion/extension/distraction fluoroscopy may be required to determine craniovertebral stability. Early surgical stabilization is recommended for all children with AOD. Early occipitocervical fusion using screws in combination with a rod or plate, or sublaminar wires with a contoured rod, coupled with autograft bone, provide immediate stabilization and a high fusion rate. Halo immobilization and traction are contraindicated in the management of AOD in children because of the risk of displacement of the injured occipitocervical joint. Postoperative hydrocephalus is frequent and should be suspected when neurologic decline occurs after fixation. Nearly half of children who survive AOD will have residual neurologic deficits. PMID- 24788444 TI - Anterior glenohumeral instability: a pathology-based surgical treatment strategy. AB - The glenohumeral joint is the most frequently dislocated major joint, and most cases involve an anterior dislocation. Young male athletes competing in contact sports are at especially high risk of recurrent instability. Surgical timing and selection of surgical technique continue to be debated. Full characterization of the injury requires an accurate history and physical examination. Diagnostic imaging assists in identifying the underlying anatomic lesions, which range from no discernible lesion to significant bone loss of the glenoid or humeral head and/or capsulolabral stretching or avulsion from the glenoid or humerus. Historically, open Bankart repair has been considered to be the standard method of managing capsulolabral injuries, but comparable results have been achieved with arthroscopic techniques. In the setting of anterior glenoid bone loss >20% of the articular surface, iliac crest bone grafting or coracoid transfer via the Bristow or Latarjet procedures has demonstrated satisfactory outcomes. Favorable results have been reported with bone grafting or remplissage for engaging Hill Sachs lesions and those that affect >30% of the humeral circumference. PMID- 24788445 TI - Unicameral bone cysts: general characteristics and management controversies. AB - Unicameral bone cysts are benign bone lesions that are often asymptomatic and commonly develop in the proximal humerus and femur of skeletally immature patients. The etiology of these lesions remains unknown. Most patients present with a pathologic fracture, but these cysts can be discovered incidentally, as well. Radiographically, a unicameral bone cyst appears as a radiolucent lesion with cortical thinning and is centrally located within the metaphysis. Although diagnosis is frequently straightforward, management remains controversial. Because the results of various management methods are heterogeneous, no single method has emerged as the standard of care. New minimally invasive techniques involve cyst decompression with bone grafting and instrumentation. These techniques have yielded promising results, with low rates of complications and recurrence reported; however, prospective clinical trials are needed to compare these techniques with current evidence-based treatments. PMID- 24788446 TI - Combined acetabulum and pelvic ring injuries. AB - Combined fractures of the acetabulum and pelvic ring are more common than previously believed, with an incidence as high as 15.7%. Recent series that include combined injuries indicate that the incidence of lateral compression and anteroposterior compression pelvic ring injuries is similar and that transverse and both-column acetabular fractures are the most common acetabular fracture patterns. Combined injuries most often are the result of high-energy mechanisms, and, compared with patients who present with isolated pelvic or acetabular injury, patients with combined injury typically have higher injury severity scores, higher transfusion requirements, and lower systolic blood pressure, with reported mortality rates of 1.5% to 13%. Treatment requires a multidisciplinary approach. The first priority is resuscitation following the Advanced Trauma Life Support protocols. Once the patient is stable, acetabular fractures and pelvic ring injuries should be assessed individually, and the most appropriate treatment for each should be outlined. These treatments should then be integrated to develop the most appropriate overall treatment strategy. Although outcomes data are available for isolated acetabulum and pelvic ring disruptions, no such data currently exist for combined injuries. PMID- 24788447 TI - Ulnar collateral ligament injuries in the throwing athlete. AB - Repetitive valgus forces on the throwing elbow place significant stress on that joint. This stress can cause structural damage and injury to the ulnar collateral ligament. Many acute injuries of the throwing elbow are caused by repetitive chronic wear. Although much work has been done on injury prevention in youth who are pitchers, overuse injury in throwing sports constitutes an epidemic. Failing nonsurgical management, ulnar collateral ligament reconstruction is a viable option to return the throwing athlete to competition. PMID- 24788448 TI - Occupational hazards for pregnant or lactating women in the orthopaedic operating room. AB - Pregnant or lactating staff working in the orthopaedic operating room may be at risk of occupational exposure to several hazards, including blood-borne pathogens, anesthetic gases, methylmethacrylate, physical stress, and radiation. Because the use of proper personal protective equipment is mandatory, the risk of contamination with blood-borne pathogens such as hepatitis B, hepatitis C, and HIV is low. Moreover, effective postexposure prophylactic regimens are available for hepatitis B and HIV. In the 1960s, concerns were raised about occupational exposure to harmful chemicals in the operating room such as anesthetic gases and methylmethacrylate. Guidelines on safe levels of exposure to these chemicals and the use of personal protective equipment have helped to minimize the risks to pregnant or lactating staff. Short periods of moderate physical activity are beneficial for pregnant women, but prolonged strenuous activity can lead to increased pregnancy complications. The risk of prenatal radiation exposure during orthopaedic procedures is of concern, as well. However, proper lead protection and contamination control can minimize the risk of occupational exposure to radiation. PMID- 24788449 TI - Anterior ankle impingement: diagnosis and treatment. AB - Anterior ankle impingement is a common clinical condition characterized by chronic anterior ankle pain that is exacerbated on dorsiflexion. Additional symptoms include instability; limited ankle motion; and pain with squatting, sprinting, stair climbing, and hill climbing. Diagnosis is typically confirmed with plain radiographs. Nonsurgical management includes physical therapy, strengthening exercises, activity modification, bracing, and anti-inflammatory medication. Although arthroscopic treatment is sufficient in some patients, most require an open approach to address related pathology. We advocate aggressive range of motion as well as weight bearing postoperatively. Further study is needed to confirm current understanding of anterior ankle impingement and to better define treatment options and prevention strategies. PMID- 24788450 TI - Heart motion uncertainty compensation prediction method for robot assisted beating heart surgery - Master-slave Kalman Filters approach. AB - Robot Assisted Coronary Artery Bypass Graft (CABG) allows the heart keep beating in the surgery by actively eliminating the relative motion between point of interest (POI) on the heart surface and surgical tool. The inherited nonlinear and diverse nature of beating heart motion gives a huge obstacle for the robot to meet the demanding tracking control requirements. In this paper, we novelty propose a Master-slave Kalman Filter based on beating heart motion Nonlinear Adaptive Prediction (NAP) algorithm. In the study, we describe the beating heart motion as the combination of nonlinearity relating mathematics part and uncertainty relating non-mathematics part. Specifically, first, we model the nonlinearity of the heart motion via quadratic modulated sinusoids and estimate it by a Master Kalman Filter. Second, we involve the uncertainty heart motion by adaptively change the covariance of the process noise through the slave Kalman Filter. We conduct comparative experiments to evaluate the proposed approach with four distinguished datasets. The results indicate that the new approach reduces prediction errors by at least 30 MUm. Moreover, the new approach performs well in robustness test, in which two kinds of arrhythmia datasets from MIT-BIH arrhythmia database are assessed. PMID- 24788451 TI - The real-world problem of care coordination: a longitudinal qualitative study with patients living with advanced progressive illness and their unpaid caregivers. AB - OBJECTIVES: To develop a model of care coordination for patients living with advanced progressive illness and their unpaid caregivers, and to understand their perspective regarding care coordination. DESIGN: A prospective longitudinal, multi-perspective qualitative study involving a case-study approach. METHODS: Serial in-depth interviews were conducted, transcribed verbatim and then analyzed through open and axial coding in order to construct categories for three cases (sites). This was followed by continued thematic analysis to identify underlying conceptual coherence across all cases in order to produce one coherent care coordination model. PARTICIPANTS: Fifty-six purposively sampled patients and 27 case-linked unpaid caregivers. SETTINGS: Three cases from contrasting primary, secondary and tertiary settings within Britain. RESULTS: Coordination is a deliberate cross-cutting action that involves high-quality, caring and well informed staff, patients and unpaid caregivers who must work in partnership together across health and social care settings. For coordination to occur, it must be adequately resourced with efficient systems and services that communicate. Patients and unpaid caregivers contribute substantially to the coordination of their care, which is sometimes volunteered at a personal cost to them. Coordination is facilitated through flexible and patient-centered care, characterized by accurate and timely information communicated in a way that considers patients' and caregivers' needs, preferences, circumstances and abilities. CONCLUSIONS: Within the midst of advanced progressive illness, coordination is a shared and complex intervention involving relational, structural and information components. Our study is one of the first to extensively examine patients' and caregivers' views about coordination, thus aiding conceptual fidelity. These findings can be used to help avoid oversimplifying a real-world problem, such as care coordination. Avoiding oversimplification can help with the development, evaluation and implementation of real-world coordination interventions for patients and their unpaid caregivers in the future. PMID- 24788453 TI - Success rates for computed tomography-guided musculoskeletal biopsies performed using a low-dose technique. AB - OBJECTIVE: To evaluate the success rate of a low-dose (50% mAs reduction) computed tomography (CT) biopsy technique. This protocol was adopted based on other successful reduced-CT radiation dose protocols in our department, which were implemented in conjunction with quality improvement projects. MATERIALS AND METHODS: The technique included a scout view and initial localizing scan with standard dose. Additional scans obtained for further guidance or needle adjustment were acquired by reducing the tube current-time product (mAs) by 50%. The radiology billing data were searched for CT-guided musculoskeletal procedures performed over a period of 8 months following the initial implementation of the protocol. These were reviewed for the type of procedure and compliance with the implemented protocol. The compliant CT-guided biopsy cases were then retrospectively reviewed for patient demographics, tumor pathology, and lesion size. Pathology results were compared to the ultimate diagnoses and were categorized as diagnostic, accurate, or successful. RESULTS: Of 92 CT-guided procedures performed during this period, two were excluded as they were not biopsies (one joint injection and one drainage), 19 were excluded due to non compliance (operators neglected to follow the protocol), and four were excluded due to lack of available follow-up in our electronic medical records. A total of 67 compliant biopsies were performed in 63 patients (two had two biopsies, and one had three biopsies). There were 32 males and 31 females with an average age of 50 (range, 15-84 years). Of the 67 biopsies, five were non-diagnostic and inaccurate and thus unsuccessful (7%); five were diagnostic but inaccurate and thus unsuccessful (7%); 57 were diagnostic and accurate thus successful (85%). These results were comparable with results published in the radiology literature. CONCLUSIONS: The success rate of CT-guided biopsies using a low-dose protocol is comparable to published rates for conventional dose biopsies. The implemented low dose protocol did not change the success rate of CT-guided musculoskeletal biopsies. PMID- 24788454 TI - The return on investment of postdischarge follow-up calls for suicidal ideation or deliberate self-harm. AB - OBJECTIVE: Transitions of care are critical for individuals at risk of suicide. This study determined the return on investment (ROI) for providing postdischarge follow-up calls to patients at risk of suicide who are discharged from a hospital or an emergency department. METHODS: Claims data were from the 2006-2011 Truven Health MarketScan Commercial Claims and Encounters Database and Multi-State Medicaid Database. Cost estimates were from eight call centers that provide postdischarge follow-up calls. The ROI was estimated for the 30 days after discharge and was calculated from a payer's perspective (return gained for every $1 invested). One-way and probabilistic sensitivity analyses were used to examine the influence of variations of ROI model inputs. RESULTS: Under base case assumptions, the estimated ROI was $1.76 for commercial insurance and $2.43 for Medicaid for patients discharged from a hospital and $1.70 for commercial insurance and $2.05 for Medicaid for those discharged from an emergency department. Variation in the effect size of postdischarge contacts on reducing readmission had the largest effect on the ROI, producing a range from $0 to $4.11. The ROI would be greater than $1 for both payers and across both discharge settings as long as postdischarge contact could reduce readmission by at least 13.3%. Sensitivity analyses indicated a 77% probability (commercial) and an 88% probability (Medicaid) that the ROI would be greater than $1 among hospital discharges; the probabilities among emergency department discharges were 74% (commercial) and 82% (Medicaid). CONCLUSIONS: The study supports the business case for payers, particularly Medicaid, to invest in postdischarge follow-up calls. PMID- 24788455 TI - Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus. AB - The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA>=31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed. PMID- 24788457 TI - Increased CB2 mRNA and anandamide in human blood after cessation of cannabis abuse. AB - In previous studies, long-term cannabis use led to alterations of the endocannabinoid system including an increase in CB1 and/or CB2 receptor messenger RNA (mRNA) in blood cells and an increase in the serum level of the endocannabinoid 2-arachidonoyl glycerol. However, in those studies, cannabis use was stopped only few days before testing or not interrupted at all. Therefore, one cannot decide whether the alterations are due to long-term cannabis abuse or are confounded by acute effects of cannabis. Blood was sampled from donors that had smoked marijuana >=20 times in their lives but had abstained from cannabis for >=6 months (high-frequency users, HFU) and from controls (cannabis use <=5 times lifetime). CB1 and CB2 mRNA was determined in peripheral mononuclear blood cells using the reverse transcriptase polymerase chain reaction. Serum anandamide level was assayed using electrospray tandem mass spectrometry. CB2 mRNA was increased by 45 % in HFU when compared to controls, whereas CB1 mRNA did not differ. The anandamide level in HFU exceeded that in controls by 90 %. Tobacco smoking could be excluded as a confounding factor. In conclusion, marijuana users that had smoked marijuana >=20 times in their lives and stopped cannabis use at least 6 months before the study show an increase in CB2 receptor mRNA in the blood and in serum anandamide level. These alterations resemble those obtained for marijuana smokers that had stopped cannabis use only few days before testing and may be implicated in the pathogenesis of disorders associated with long-term cannabis use. PMID- 24788458 TI - Efficient myoblast expansion for regenerative medicine use. AB - Cellular therapy using expanded autologous myoblasts is a treatment modality for a variety of diseases. In the present study, we compared the commercial skeletal muscle cell growth medium-2 (SKGM-2) with a medium designed by our group for the expansion of skeletal myoblasts. The use of an in-house medium [DMEM/F12 medium supplemented with EGF, bFGF, HGF, insulin and dexamethasone (DFEFH)] resulted in a greater number of myoblast colonies (>50%) and a 3-, 4- and 9-fold higher proliferation rate, eventually resulting in a 3-, 7- and 87-fold greater number of cells at the 1st, 2nd and 3rd passage, respectively, compared with the cells grown in SKGM-2 medium. The average CD56 expression level was higher in the myoblasts cultured in DFEFH than in those culturd in SKGM-2 medium. At the 3rd passage, lower expression levels of myostatin and considerably higher expression levels of myogenin were observed in the cells that were grown in DFEFH medium. The results of our study indicated that myoblasts cultured in both medium types displayed fusogenic potential at the 3rd passage. Furthermore, it was shown that cells cultured in DFEFH medium created myotubes with a considerably higher number of nuclei. Additionally, we observed that the fusion potential of the cells markedly decreased with the subsequent passages and that the morphology of the myoblasts differed between the 2 cultured media. Our data demonstrate that culture in the DFEFH medium leads to an approximately 90-fold greater number of myoblasts, with improved morphology and greater fusion potential, compared with culture in the commercial SKGM-2 medium. PMID- 24788459 TI - Evaluation of electrochemically treated bulk electrodes for a retinal prosthesis by examination of retinal intrinsic signals in cats. AB - PURPOSE: Our goal was to determine the feasibility of using electrochemically treated bulk platinum electrodes with large charge injection capacity for a retinal prosthesis. METHODS: Seven eyes of seven cats were studied. Small retinal areas were focally stimulated with electrochemically treated bulk electrodes (phi = 500 um) placed in a scleral pocket. Fundus images with near-infrared (800-880 nm) light were recorded, and a 2D map of the reflectance changes elicited by the electrical currents was constructed by subtracting the images taken before stimulation from those taken after stimulation. The impedance of each electrode was measured at 1 kHz. The degree of retinal elevation by the electrode was measured by optical coherence tomography. Scleral thickness where the electrode array was inserted was measured in histologic sections. RESULTS: The diameter of reflectance changes (full width at half maximum) was 0.42 +/- 0.22 mm [mean +/- standard deviation (SD)] in minor axes and 1.46 +/- 0.82 mm in major axes. The threshold current decreased with a reduction in the residual scleral thickness (R (2) = 0.9215; P = 0.0002); it also decreased with an increase in retinal elevation (R (2) = 0.6259; P = 0.0111).The threshold current also decreased with an increase in electrode impedance (R (2) = 0.2554; P = 0.0147). CONCLUSIONS: Electrochemically treated porous platinum electrodes can stimulate localized retinal areas. The threshold current necessary to stimulate the retina was influenced by residual scleral thickness and the electrode tightness of fit against the sclera. PMID- 24788460 TI - Subunits of the Drosophila actin-capping protein heterodimer regulate each other at multiple levels. AB - The actin-Capping Protein heterodimer, composed of the alpha and beta subunits, is a master F-actin regulator. In addition to its role in many cellular processes, Capping Protein acts as a main tumor suppressor module in Drosophila and in humans, in part, by restricting the activity of Yorkie/YAP/TAZ oncogenes. We aimed in this report to understand how both subunits regulate each other in vivo. We show that the levels and capping activities of both subunits must be tightly regulated to control F-actin levels and consequently growth of the Drosophila wing. Overexpressing capping protein alpha and beta decreases both F actin levels and tissue growth, while expressing forms of Capping Protein that have dominant negative effects on F-actin promote tissue growth. Both subunits regulate each other's protein levels. In addition, overexpressing one of the subunit in tissues knocked-down for the other increases the mRNA and protein levels of the subunit knocked-down and compensates for its loss. We propose that the ability of the alpha and beta subunits to control each other's levels assures that a pool of functional heterodimer is produced in sufficient quantities to restrict the development of tumor but not in excess to sustain normal tissue growth. PMID- 24788462 TI - Radiography versus magnetic resonance imaging (MRI) in juvenile spondyloarthritis: is the MR image everything? PMID- 24788461 TI - An intramolecular cascade cyclization of 2-aryl indoles: efficient methods for the construction of 2,3-functionalized indolines and 3-indolinones. AB - Efficient intramolecular N/O-nucleophilic cyclization of 2-aryl indoles has been developed to afford the corresponding 2-aza-3-oxaindolines and 3-indolinones in 80-95% yield. The methods provided convenient access to fused imidazo[1,2 c]oxazolidinone, oxazolidine, or tetrahydro-1,3-oxazine cores under mild conditions. PMID- 24788463 TI - The current and future status of biomarkers in osteoarthritis. PMID- 24788464 TI - Optical coherence tomographic imaging in a patient with granulomatosis with polyangiitis presenting with acute myocardial infarction. PMID- 24788465 TI - Spacing of toes reveals rheumatoid nodulosis. PMID- 24788466 TI - Updating the OMERACT filter at OMERACT 11. AB - The Outcome Measures in Rheumatology (OMERACT) community strives to develop core outcome sets for rheumatologic conditions to specify, for each condition, the minimum set of outcomes necessary to provide consistent estimates of the benefits of an intervention. The original and successful OMERACT filter of "truth, discrimination, and feasibility" requires development and updating because of application to a widening range of conditions by an expanding group, particularly patients. It should more explicitly identify the relevant core outcomes that might be universal to all randomized controlled trials within rheumatology. Working from first principles, comparing proposals against actual procedures adopted by OMERACT working groups, and seeking a broad consensus over several major sessions at the OMERACT 11 meeting, a new version has emerged, OMERACT Filter 2.0, which will form the central theme of the intended OMERACT handbook and offers an approach to core outcome set development in many areas of healthcare. PMID- 24788467 TI - A false-positive antineutrophil cytoplasmic antibody proteinase 3 test in a patient with pulmonary-renal syndrome. PMID- 24788469 TI - Therapeutic effects of sorafenib on the A549/DDP human lung adenocarcinoma cell line in vitro. AB - The aim of the present study was to observe the effects of sorafenib on the proliferation, apoptosis and invasion of A549/DDP cisplatin-resistant lung adenocarcinoma cells cultured in vitro. The A549/DDP cisplatin-resistant lung adenocarcinoma cell strain was cultured in vitro, the cell culture group incubated in culture medium only was set as the control group (Group S0) and the four concentration gradients of sorafenib were added to the culture groups as the experimental groups: S1, 2 umol/l; S2, 4 umol/l; S3, 8 umol/l; and S4, 16 umol/l. The MTT assay was used to determine the growth inhibition rate of the cells, which were respectively subjected to sorafenib treatment for 24, 48 and 72 h. Flow cytometry was used to determine the rate of apoptosis of cells in each group following sorafenib treatment for 72 h. Furthermore, the Transwell invasion experiment was used to determine the effect on A549/DDP cell invasion following sorafenib treatment for 24 h. Based on the MTT assay, it was found that the inhibition rates of A549/DDP cisplatin-resistant lung adenocarcinoma cells in groups S1-4 following sorafenib treatment for 24 h were 4.58+/-2.82, 14.93+/ 2.62, 37.58+/-7.13 and 58.39+/-8.15%, respectively. For 48 h, inhibition rates in S1-4 were 14.98+/-2.93, 26.28+/-7.31, 63.00+/-3.05 and 78.84+/-3.96%, respectively, and for 72 h, inhibition rates were 18.80+/-2.82, 32.71+/-2.55, 75.51+/-4.73 and 87.50+/-3.36%, respectively. The difference in the inhibition rates of cells among the experimental groups for the same incubation time showed statistical significance (P<0.05). Flow cytometric analysis indicated that the rate of apoptosis in the control group was 8.88+/-0.81% following sorafenib treatment for 72 h, and the rates of apoptosis in groups S1-4 were, 12.84+/-0.24, 17.27+/-0.78, 21.98+/-0.75 and 49.67+/-1.38%, respectively. The rate of apoptosis in each experimental group was higher compared with that in the control group (P<0.05). The difference in the rate of apoptosis among the experimental groups was statistically significant (P<0.05). The Transwell assay showed that the number of cells permeating the septum in the control group was 82.7+/-2.3/high power lens (HP), while the average number of cells permeating septum in groups S1 4 following treatment with sorafenib for 24 h was 58.2+/-2.5, 41.3+/-1.3, 22.6+/ 2.1 and 14.7+/-1.1/HP, which was significantly lower compared with the control group. The number of cells permeating the septum in each experimental group decreased with the enhancement of the concentration gradient. The differences were statistically significant (P<0.05). In conclusion, sorafenib inhibits the proliferation of A549/DDP cisplatin-resistant lung adenocarcinoma cells in a time and concentration-dependent manner. In addition, sorafenib induces apoptosis in A549/DDP cisplatin-resistant lung adenocarcinoma cells, thus reducing their invasiveness. PMID- 24788471 TI - Launch of International Care Ethics (ICE) Observatory. PMID- 24788470 TI - Changes in the harmonic components of the flicker electroretinogram during light adaptation. AB - PURPOSE: To evaluate the nature and extent of changes in the fundamental and harmonic components of the 31-Hz flicker electroretinogram (ERG) during light adaptation. METHODS: Full-field ERGs were recorded from five visually normal subjects (ages 21-60 years). Following 30 min of dark adaptation, the subjects were exposed to a uniform adapting field of 50 cd/m(2). The field, which was presented for approximately 15 min, was intermittently modulated sinusoidally at 31.25 Hz. The ERG was recorded during the sinusoidal modulation, and Fourier analysis was used to obtain the amplitude and phase of the fundamental (F), second (2F), and third (3F) harmonic response components. RESULTS: F amplitude increased by almost a factor of two over approximately 6 min (time constant, tau, of 3.0 min). The 2F amplitude increased by a smaller amount, a factor of 1.4, and the time-course was approximately eight times faster than that of F (tau = 0.4 min). The 3F amplitude increased by a factor of 4.6, an increase that was larger than F or 2F, with a time-course that was between that of F and 2F (tau = 1.4 min). F phase was unaffected by light adaptation, whereas the 2F and 3F phases both increased by approximately 45 degrees over similar time-courses (tau = 2.0 min). CONCLUSIONS: Light adaptation had different effects on the fundamental, second, and third harmonic components of the 31-Hz flicker ERG, which resulted in a change in waveform shape during light adaptation. The previously reported flicker ERG amplitude growth is driven primarily, but not entirely, by changes in the fundamental. PMID- 24788472 TI - Authorship dispute of a doctoral thesis publication. PMID- 24788473 TI - Why editors should never be "ghost" or "gift" authors. PMID- 24788475 TI - Copper-chelating azides for efficient click conjugation reactions in complex media. AB - The concept of chelation-assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I) catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper-chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements. PMID- 24788479 TI - Towards a comprehensive understanding of the chemical vapor deposition of titanium nitride using Ti(NMe2)4: a density functional theory approach. AB - A gas phase mechanistic investigation of the chemical vapor deposition (CVD) of titanium nitride (TiN) from the decomposition of Ti(NMe2)4, tetrakis(dimethylamido)titanium (TDMAT) as a single source precursor as well as from the reaction of Ti(NMe2)4 with NH3, i.e., the ammonia assisted mechanism is carried out and reported herein within the framework of density functional theory. Contrary to the theoretical result reported previously for a model TDMAT, metallacycle formation and beta-H elimination pathways are found to be the major decomposition pathways responsible for the decomposition of TDMAT, and this finding is in accord with the experimental observation. Interestingly, agostic interaction is found to play a key role in promoting beta-H elimination in the decomposition of TDMAT. A new additional pathway of decomposition of TDMAT has been identified theoretically in this present study. Exploration of the complex gas phase mechanism and thereby a detailed identification of the reaction intermediates enable us in realizing the origin of incorporation of carbon contamination in TiN films produced from TDMAT alone and then how the contamination is removed in the presence of ammonia. The ammonia assisted mechanism is found to proceed through the formation of a pre-equilibrium complex. The computed barrier height of 7.3 kcal mol(-1) for the initial transamination process associated with the Ti(NMe2)4 + NH3 reaction is found to be in very good agreement with the experimental activation energy. The total rate constant ktot for the ammonia assisted mechanism is calculated to be 1.28 * 10(-51) cm(3) molecule(-1) s(-1) at 298.15 K. PMID- 24788476 TI - Cardiac thin filament regulation and the Frank-Starling mechanism. AB - The heart has an intrinsic ability to increase systolic force in response to a rise in ventricular filling (the Frank-Starling law of the heart). It is widely accepted that the length dependence of myocardial activation underlies the Frank Starling law of the heart. Recent advances in muscle physiology have enabled the identification of the factors involved in length-dependent activation, viz., titin (connectin)-based interfilament lattice spacing reduction and thin filament "on-off" regulation, with the former triggering length-dependent activation and the latter determining the number of myosin molecules recruited to thin filaments. Patients with a failing heart have demonstrated reduced exercise tolerance at least in part via depression of the Frank-Starling mechanism. Recent studies revealed that various mutations occur in the thin filament regulatory proteins, such as troponin, in the ventricular muscle of failing hearts, which consequently alter the Frank-Starling mechanism. In this article, we review the molecular mechanisms of length-dependent activation, and the influence of troponin mutations on the phenomenon. PMID- 24788478 TI - Novel curcumin analogue IHCH exhibits potent anti-proliferative effects by inducing autophagy in A549 lung cancer cells. AB - Curcumin is a natural polyphenolic compound that exhibits strong antioxidant and anticancer activities; however, low bioavailability has restricted its application in chemotherapeutic trials. The present study aimed to investigate the anticancer effect of the novel curcumin derivative 2E,6E-2-(1H-indol-3-yl) methylene)-6-(4-hydroxy-3-methoxy benzylidene)-cyclohexanone (IHCH) on A549 lung cancer cells. Cells were treated with IHCH at different concentrations (1-40 uM) for different time periods (1-36 h). Microscopic analysis revealed that IHCH inhibited A549 cell growth and induced the formation of characteristic autophagolysosomes in a dose- and time-dependent manner. Furthermore, the inhibitory rate of IHCH (40 uM) on A549 cell viability was 77.34% after 36 h of treatment. Acridine orange staining revealed an increase in autophagic vacuoles in the IHCH-treated A549 cells. Monodansylcadaverine staining was used to analyze autophagy rate. Immunocytochemistry revealed an increase in light chain (LC) 3 protein expression in the IHCH-treated cells and western blot analysis detected the conversion of LC3-I to LC3-II, as well as the recruitment of LC3 to autophagosomes in the cytoplasmatic compartment, suggesting the occurrence of autophagy. These findings show that IHCH induced autophagy in A549 cells, which is a novel cell death mechanism induced by curcumin derivatives. PMID- 24788480 TI - Synthesis of purine and 7-deazapurine nucleoside analogues of 6-N-(4 Nitrobenzyl)adenosine; inhibition of nucleoside transport and proliferation of cancer cells. AB - Human equilibrative nucleoside transporter 1 (hENT1) is a prototypical nucleoside transporter protein ubiquitously expressed on the cell surface of almost all human tissue. Given the role of hENT1 in the transport of nucleoside drugs, an important class of therapeutics in the treatment of various cancers and viral infections, efforts have been made to better understand the mechanisms by which hENT1 modulates nucleoside transport. To that end, we report here the design and synthesis of novel tool compounds for the further study of hENT1. The 7 deazapurine nucleoside antibiotic tubercidin was converted into its 4-N-benzyl and 4-N-(4-nitrobenzyl) derivatives by alkylation at N3 followed by a Dimroth rearrangement to the 4-N-isomer or by fluoro-diazotization followed by SN Ar displacement of the 4-fluoro group by a benzylamine. The 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin antibiotics were prepared by the alkylation approach. Cross-membrane transport of labeled uridine by hENT1 was inhibited to a weaker extent by the 4-nitrobenzylated tubercidin and sangivamycin analogues than was observed with 6-N-(4-nitrobenzyl)adenosine. Type-specific inhibition of cancer cell proliferation was observed at micromolar concentrations with the 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin, and also with 4-N-benzyltubercidin. Treatment of 2',3',5'-O-acetyladenosine with aryl isocyanates gave the 6-ureido derivatives but none of them exhibited inhibitory activity against cancer cell proliferation or hENT1. PMID- 24788481 TI - Refusal bias in the estimation of HIV prevalence. AB - In 2007, UNAIDS corrected estimates of global HIV prevalence downward from 40 million to 33 million based on a methodological shift from sentinel surveillance to population-based surveys. Since then, population-based surveys are considered the gold standard for estimating HIV prevalence. However, prevalence rates based on representative surveys may be biased because of nonresponse. This article investigates one potential source of nonresponse bias: refusal to participate in the HIV test. We use the identity of randomly assigned interviewers to identify the participation effect and estimate HIV prevalence rates corrected for unobservable characteristics with a Heckman selection model. The analysis is based on a survey of 1,992 individuals in urban Namibia, which included an HIV test. We find that the bias resulting from refusal is not significant for the overall sample. However, a detailed analysis using kernel density estimates shows that the bias is substantial for the younger and the poorer population. Nonparticipants in these subsamples are estimated to be three times more likely to be HIV-positive than participants. The difference is particularly pronounced for women. Prevalence rates that ignore this selection effect may be seriously biased for specific target groups, leading to misallocation of resources for prevention and treatment. PMID- 24788482 TI - Twin-driven thermoelectric figure-of-merit enhancement of Bi2Te3 nanowires. AB - Thermoelectric figure-of-merits (ZT) are enhanced or degraded by crystal defects such as twins and excess atoms that are correlated with thermal conductivity (k) and carrier concentration (n). For Bi2Te3, it is unclear whether the crystal defects can enhance ZT without a degradation in the thermopower factor. In the present study, n-type Bi2Te3 nanowires (NWs) are electrochemically synthesized to have twin-free (TF) or twin-containing (TC) microstructures with a ZT of 0.10 and 0.08, respectively, at 300 K. The ZTs of TF and TC NWs remarkably increase up to 0.21 and 0.31, when heat-treatments cause n-reduction and twins induce phonon scattering, as follows: first, the enhancement of the Seebeck coefficient from 70 to -98 MUV K(-1) for TF NWs and from -57 to -143 MUV K(-1) for TC NWs, by virtue of n-reduction; secondly, twin-driven k-reduction from 1.9 to 1.4 W m(-1) K(-1) of TC NWs, while the k of TF NWs increases from 2.3 to 2.6 W m(-1) K(-1) due to the enhanced carrier mobility. The lattice thermal conductivities of TC NW are lowered from 1.1 to 0.8 W m(-1) K(-1) by phonon scattering at twins. Density functional theory calculations indicate that twins do not significantly influence the Seebeck coefficient of Bi2Te3. It is strongly recommended that twins be incorporated with an optimum carrier concentration to enhance the ZT of Bi2Te3. PMID- 24788483 TI - Gender differences in the expression and cellular localization of lipin 1 in the hearts of fructose-fed rats. AB - To give new insight to alterations of cardiac lipid metabolism accompanied by a fructose-rich diet (FRD), rats of both sexes were exposed to 10 % fructose in drinking water during 9 weeks. The protein level and subcellular localization of the main regulators of cardiac lipid metabolism, such as lipin 1, peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1alpha), carnitine palmitoyltransferase I (CPTI), and CD36 were studied. Caloric intake in fructose fed rats (FFR) of both sexes was increased. Circulating triacylglyceroles (TAG) and non-esterified fatty acids were increased in male FFR, while females increased visceral adiposity and blood TAG. Total expression of lipin 1 in cardiac cell lysate and its cytosolic and microsomal level were increased in the hearts of male FFR. PPARalpha and PGC-1alpha content were decreased in the nuclear extract. In addition, cardiac deposition of TAG in male FFR was elevated, as well as inhibitory phosphorylation of insulin receptor substrate 1 (IRS-1). In contrast, in female FFR, lipin 1 level was increased in nuclear extract only, while overall CPTI expression and phosphorylation of IRS-1 at serine 307 were decreased. The results of our study suggest that fructose diet causes gender dependent alterations in cardiac lipid metabolism. Potentially detrimental effects of FRD seem to be limited to male rats. Most of the observed changes might be a consequence of elevated expression and altered localization of lipin 1. Increased inhibitory phosphorylation of IRS-1 is possible link between cardiac lipid metabolism and insulin resistance in FFR. PMID- 24788484 TI - Fetal subcutaneous tissue measurements in pregnancy as a predictor of neonatal total body composition. AB - OBJECTIVE: The purpose of this study was to examine the relationship between prenatal measures of subcutaneous tissue as surrogate markers of fetal nutritional status and correlate them with neonatal total body composition. METHODS: This prospective longitudinal study of 62 singleton pregnancies obtained serial biometry and subcutaneous tissue measurements at 28, 33 and 38 weeks gestation. These measurements were then correlated with neonatal body composition, which was analysed using the PEAPODTM Infant Body Composition System (Cosmed USA, Concord, CA, USA). RESULTS: At 38 weeks gestation, fetal abdominal subcutaneous tissue (FAST) in millimetres was significantly associated with infant fat mass at delivery (+64 g per mm of FAST, p < 0.001). Thigh fat (TF) at 28 weeks gestation was associated with infant fat mass at delivery (+79 g/mm TF, p = 0.023). TF at 38 weeks gestation was associated with infant fat mass (+63/mm TF, p = 0.004). TF and FAST at 38 weeks were also predictive of both birth weight and increased abdominal circumference (AC) (p = 0.001) with FAST measurement predicting an additional 5.7 mm in AC per millimetre of FAST (p = 0.002) and TF predicting an additional 6.9 mm per mm of TF (p = 0.002). CONCLUSION: We believe that this study further validates the use of prenatal measures of subcutaneous tissue and may help to highlight fetuses at risk of newborn adiposity and metabolic syndrome. PMID- 24788485 TI - Authors' reply to Mark Jones's critique of the study by Muthuri and colleagues reported in The BMJ. PMID- 24788486 TI - Using orthopaedic journals for continuing professional development. AB - Continuing professional development (CPD) refers to the ongoing participation in activities that keep a doctor up to date and fit to practise once they have completed formal training. It is something that most will do naturally to serve their patients and to enable them to run a safe and profitable practice. Increasingly, regulators are formalising the requirements for evidence of CPD, often as part of a process of revalidation or relicensing. This paper reviews how orthopaedic journals can be used as part of the process of continuing professional development. PMID- 24788487 TI - Salvage hip surgery in severe cerebral palsy: some answers, more questions? PMID- 24788488 TI - Nanotechnology: current concepts in orthopaedic surgery and future directions. AB - Nanotechnology is the study, production and controlled manipulation of materials with a grain size < 100 nm. At this level, the laws of classical mechanics fall away and those of quantum mechanics take over, resulting in unique behaviour of matter in terms of melting point, conductivity and reactivity. Additionally, and likely more significant, as grain size decreases, the ratio of surface area to volume drastically increases, allowing for greater interaction between implants and the surrounding cellular environment. This favourable increase in surface area plays an important role in mesenchymal cell differentiation and ultimately bone-implant interactions. Basic science and translational research have revealed important potential applications for nanotechnology in orthopaedic surgery, particularly with regard to improving the interaction between implants and host bone. Nanophase materials more closely match the architecture of native trabecular bone, thereby greatly improving the osseo-integration of orthopaedic implants. Nanophase-coated prostheses can also reduce bacterial adhesion more than conventionally surfaced prostheses. Nanophase selenium has shown great promise when used for tumour reconstructions, as has nanophase silver in the management of traumatic wounds. Nanophase silver may significantly improve healing of peripheral nerve injuries, and nanophase gold has powerful anti inflammatory effects on tendon inflammation. Considerable advances must be made in our understanding of the potential health risks of production, implantation and wear patterns of nanophase devices before they are approved for clinical use. Their potential, however, is considerable, and is likely to benefit us all in the future. PMID- 24788489 TI - Litigation relating to conditions affecting the shoulder and elbow: an analysis of claims against the National Health Service. AB - We present a review of claims made to the NHS Litigation Authority (NHSLA) by patients with conditions affecting the shoulder and elbow, and identify areas of dissatisfaction and potential improvement. Between 1995 and 2012, the NHSLA recorded 811 claims related to the shoulder and elbow, 581 of which were settled. This comprised 364 shoulder (64%), and 217 elbow (36%) claims. A total of L18.2 million was paid out in settled claims. Overall diagnosis, mismanagement and intra-operative nerve injury were the most common reasons for litigation. The highest cost paid out resulted from claims dealing with incorrect, missed or delayed diagnosis, with just under L6 million paid out overall. Fractures and dislocations around the shoulder and elbow were common injuries in this category. All 11 claims following wrong-site surgery that were settled led to successful payouts. This study highlights the diagnoses and procedures that need to be treated with particular vigilance. Having an awareness of the areas that lead to litigation in shoulder and elbow surgery will help to reduce inadvertent risks to patients and prevent dissatisfaction and possible litigation. PMID- 24788490 TI - Three-dimensional morphology and bony range of movement in hip joints in patients with hip dysplasia. AB - To confirm whether developmental dysplasia of the hip has a risk of hip impingement, we analysed maximum ranges of movement to the point of bony impingement, and impingement location using three-dimensional (3D) surface models of the pelvis and femur in combination with 3D morphology of the hip joint using computer-assisted methods. Results of computed tomography were examined for 52 hip joints with DDH and 73 normal healthy hip joints. DDH shows larger maximum extension (p = 0.001) and internal rotation at 90 degrees flexion (p < 0.001). Similar maximum flexion (p = 0.835) and external rotation (p = 0.713) were observed between groups, while high rates of extra-articular impingement were noticed in these directions in DDH (p < 0.001). Smaller cranial acetabular anteversion (p = 0.048), centre-edge angles (p < 0.001), a circumferentially shallower acetabulum, larger femoral neck anteversion (p < 0.001), and larger alpha angle were identified in DDH. Risk of anterior impingement in retroverted DDH hips is similar to that in retroverted normal hips in excessive adduction but minimal in less adduction. These findings might be borne in mind when considering the possibility of extra-articular posterior impingement in DDH being a source of pain, particularly for patients with a highly anteverted femoral neck. PMID- 24788491 TI - Patient-reported outcome is influenced by surgical approach in total hip replacement: a study of the Swedish Hip Arthroplasty Register including 42,233 patients. AB - The effects of surgical approach in total hip replacement on health-related quality of life and long-term pain and satisfaction are unknown. From the Swedish Hip Arthroplasty Register, we extracted data on all patients that had received a total hip replacement for osteoarthritis through either the posterior or the direct lateral approach, with complete pre- and one-year post-operative Patient Reported Outcome Measures (PROMs). A total of 42 233 patients met the inclusion criteria and of these 4962 also had complete six-year PROM data. The posterior approach resulted in an increased mean satisfaction score of 15 (sd 19) vs. 18 (sd 22) (p < 0.001) compared with the direct lateral approach. The mean pain score was 13 (sd 17) vs. 15 (sd 19) (p < 0.001) and the proportion of patients with no or minimal pain was 78% vs. 74% (p < 0.001) favouring the posterior approach. The patients in the posterior approach group reported a superior mean EQ-5D index of 0.79 (sd 0.23) vs. 0.77 (sd 0.24) (p < 0.001) and mean EQ score of 76 (sd 20) vs. 75 (sd 20) (p < 0.001). All observed differences between the groups persisted after six years follow-up. Although PROMs after THR in general are very good regardless of surgical approach, the results indicate that some patients operated by the direct lateral approach report an inferior outcome compared with the posterior approach. The large number of procedures and the seemingly sustained differences make it likely these findings are clinically relevant. PMID- 24788492 TI - An analysis of the best method for evaluating anteversion of the acetabular component after total hip replacement on plain radiographs. AB - Several radiological methods of measuring anteversion of the acetabular component after total hip replacement (THR) have been described. These studies used different definitions and reference planes to compare methods, allowing for misinterpretation of the results. We compared the reliability and accuracy of five current methods using plain radiographs (those of Lewinnek, Widmer, Liaw, Pradhan, and Woo and Morrey) with CT measurements, using the same definition and reference plane. We retrospectively studied the plain radiographs and CT scans in 84 hips of 84 patients who underwent primary THR. Intra- and inter-observer reliability were high for the measurement of inclination and anteversion with all methods on plain radiographs and CT scans. The measurements of inclination on plain radiographs were similar to the measurements using CT (p = 0.043). The mean difference between CT measurements was 0.6 degrees (-5.9 degrees to 6.8 degrees ). Measurements using Widmer's method were the most similar to those using CT (p = 0.088), with a mean difference between CT measurements of -0.9 degrees (-10.4 degrees to 9.1 degrees ), whereas the other four methods differed significantly from those using CT (p < 0.001). This study has shown that Widmer's method is the best for evaluating the anteversion of the acetabular component on plain radiographs. PMID- 24788493 TI - Continuous distal migration and internal rotation of the C-stem prosthesis without any adverse clinical effects: an RSA study of 33 primary total hip arthroplasties followed for up to ten years. AB - In 2005, we demonstrated that the polished triple-tapered C-stem at two years had migrated distally and rotated internally. From that series, 33 patients have now been followed radiologically, clinically and by radiostereometric analysis (RSA) for up to ten years. The distal migration within the cement mantle had continued and reached a mean of 2 mm (0.5 to 4.0) at ten years. Internal rotation, also within the cement mantle, was a mean 3.8 degrees (external 1.6 degrees to internal 6.6 degrees ) The cement mantle did not show any sign of migration or loosening in relation to the femoral bone. There were no clinical or radiological signs indicating that the migration or rotation within the cement mantle had had any adverse effects for the patients. PMID- 24788494 TI - Functional outcome and alignment in computer-assisted and conventionally operated total knee replacements: a multicentre parallel-group randomised controlled trial. AB - We performed a randomised controlled trial comparing computer-assisted surgery (CAS) with conventional surgery (CONV) in total knee replacement (TKR). Between 2009 and 2011 a total of 192 patients with a mean age of 68 years (55 to 85) with osteoarthritis or arthritic disease of the knee were recruited from four Norwegian hospitals. At three months follow-up, functional results were marginally better for the CAS group. Mean differences (MD) in favour of CAS were found for the Knee Society function score (MD: 5.9, 95% confidence interval (CI) 0.3 to 11.4, p = 0.039), the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales for 'pain' (MD: 7.7, 95% CI 1.7 to 13.6, p = 0.012), 'sports' (MD: 13.5, 95% CI 5.6 to 21.4, p = 0.001) and 'quality of life' (MD: 7.2, 95% CI 0.1 to 14.3, p = 0.046). At one-year follow-up, differences favouring CAS were found for KOOS 'sports' (MD: 11.0, 95% CI 3.0 to 19.0, p = 0.007) and KOOS 'symptoms' (MD: 6.7, 95% CI 0.5 to 13.0, p = 0.035). The use of CAS resulted in fewer outliers in frontal alignment (> 3 degrees malalignment), both for the entire TKR (37.9% vs. 17.9%, p = 0.042) and for the tibial component separately (28.4% vs 6.3%, p = 0.002). Tibial slope was better achieved with CAS (58.9% vs. 26.3%, p < 0.001). Operation time was 20 minutes longer with CAS. In conclusion, functional results were, statistically, marginally in favour of CAS. Also, CAS was more predictable than CONV for mechanical alignment and positioning of the prosthesis. However, the long-term outcomes must be further investigated. PMID- 24788496 TI - Assessing treatment outcomes using a single question: the net promoter score. AB - Satisfaction with care is important to both patients and to those who pay for it. The Net Promoter Score (NPS), widely used in the service industries, has been introduced into the NHS as the 'friends and family test'; an overarching measure of patient satisfaction. It assesses the likelihood of the patient recommending the healthcare received to another, and is seen as a discriminator of healthcare performance. We prospectively assessed 6186 individuals undergoing primary lower limb joint replacement at a single university hospital to determine the Net Promoter Score for joint replacements and to evaluate which factors contributed to the response. Achieving pain relief (odds ratio (OR) 2.13, confidence interval (CI) 1.83 to 2.49), the meeting of pre-operative expectation (OR 2.57, CI 2.24 to 2.97), and the hospital experience (OR 2.33, CI 2.03 to 2.68) are the domains that explain whether a patient would recommend joint replacement services. These three factors, combined with the type of surgery undertaken (OR 2.31, CI 1.68 to 3.17), drove a predictive model that was able to explain 95% of the variation in the patient's recommendation response. Though intuitively similar, this 'recommendation' metric was found to be materially different to satisfaction responses. The difference between THR (NPS 71) and TKR (NPS 49) suggests that no overarching score for a department should be used without an adjustment for case mix. However, the Net Promoter Score does measure a further important dimension to our existing metrics: the patient experience of healthcare delivery. PMID- 24788495 TI - Clinical outcomes following re-admission for non-infectious wound complications after primary total knee replacement. AB - Haematomas, drainage, and other non-infectious wound complications following total knee replacement (TKR) have been associated with long-term sequelae, in particular, deep infection. However, the impact of these wound complications on clinical outcome is unknown. This study compares results in 15 patients re admitted for wound complications within 90 days of TKR to 30 matched patients who underwent uncomplicated total knee replacements. Patients with wound complications had a mean age of 66 years (49 to 83) and mean body mass index (BMI) of 37 (21 to 54), both similar to that of patients without complications (mean age 65 years and mean BMI 35). Those with complications had lower mean Knee Society function scores (46 (0 to 100 vs. 66 (20 to 100), p = 0.047) and a higher incidence of mild or greater pain (73% vs. 33%, p = 0.01) after two years compared with the non re-admitted group. Expectations in patients with wound complications following TKR should be tempered, even in those who do not develop an infection. PMID- 24788497 TI - The risk of surgical site infection and re-admission in obese patients undergoing total joint replacement who lose weight before surgery and keep it off post operatively. AB - This study evaluated whether obese patients who lost weight before their total joint replacement and kept it off post-operatively were at lower risk of surgical site infection (SSI) and re-admission compared with those who remained the same weight. We reviewed 444 patients who underwent a total hip replacement and 937 with a total knee replacement who lost weight pre-operatively and sustained their weight loss after surgery. After adjustments, patients who lost weight before a total hip replacement and kept it off post-operatively had a 3.77 (95% confidence interval (CI) 1.59 to 8.95) greater likelihood of deep SSIs and those who lost weight before a total knee replacement had a 1.63 (95% CI 1.16 to 2.28) greater likelihood of re-admission compared with the reference group. These findings raise questions about the safety of weight management before total replacement of the hip and knee joints. PMID- 24788498 TI - A case-control study of surgical site infection following operative fixation of fractures of the ankle in a large U.K. trauma unit. AB - Most of the literature on surgical site infections following the surgical treatment of fractures of the ankle is based on small series of patients, focusing on diabetics or the elderly. None have described post-operative functional scores in those patients who develop an infection. We performed an age and gender-matched case-control study to identify patient- and surgery-related risk factors for surgical site infection following open reduction and internal fixation of a fracture of the ankle. Logistic regression analysis was used to identify significant risk factors for infection and to calculate odds ratios (OR). Function was assessed using the Olerud and Molander Ankle Score. The incidence of infection was 4% (29/717) and 1.1% (8/717) were deep infections. The median ankle score was significantly lower in the infection group compared with the control group (60 vs 90, Mann-Whitney test p < 0.0001). Multivariate regression analysis showed that diabetes (OR = 15, p = 0.031), nursing home residence (OR = 12, p = 0.018) and Weber C fractures (OR = 4, p = 0.048) were significant risk factors for infection. A low incidence of infection following open reduction and internal fixation of fractures of the ankle was observed. Both superficial and deep infections result in lower functional scores. PMID- 24788499 TI - A prospective study of the incidence and outcomes of incidental dural tears in microendoscopic lumbar decompressive surgery. AB - Little information is available about the incidence and outcome of incidental dural tears associated with microendoscopic lumbar decompressive surgery. We prospectively examined the incidence of dural tears and their influence on the outcome six months post-operatively in 555 consecutive patients (mean age 47.4 years (13 to 89)) who underwent this form of surgery. The incidence of dural tears was 5.05% (28/555). The risk factors were the age of the patient and the procedure of bilateral decompression via a unilateral approach. The rate of recovery of the Japanese Orthopaedic Association score in patients with dural tears was significantly lower than that in those without a tear (77.7% vs. 87.6%; p < 0.02), although there were no significant differences in the improvement of the Oswestry Disability Index between the two groups. Most dural tears were small, managed by taking adequate care of symptoms of low cerebrospinal fluid pressure, and did not require direct dural repair. Routine MRI scans were undertaken six months post-operatively; four patients with a dural tear had recurrent or residual disc herniation and two had further stenosis, possibly because the dural tear prevented adequate decompression and removal of the fragments of disc during surgery; as yet, none of these patients have undergone further surgery. PMID- 24788500 TI - A new morphological classification for greater tuberosity fractures of the proximal humerus: validation and clinical implications. AB - In this study, we describe a morphological classification for greater tuberosity fractures of the proximal humerus. We divided these fractures into three types: avulsion, split and depression. We retrospectively reviewed all shoulder radiographs showing isolated greater tuberosity fractures in a Level I trauma centre between July 2007 and July 2012. We identified 199 cases where records and radiographs were reviewed and included 79 men and 120 women with a mean age of 58 years (23 to 96). The morphological classification was applied to the first 139 cases by three reviewers on two occasions using the Kappa statistic and compared with the AO and Neer classifications. The inter- and intra-observer reliability of the morphological classification was 0.73 to 0.77 and 0.69 to 0.86, respectively. This was superior to the Neer (0.31 to 0.35/0.54 to 0.63) and AO (0.30 to 0.32/0.59 to 0.65) classifications. The distribution of avulsion, split and depression type fractures was 39%, 41%, and 20%, respectively. This classification of greater tuberosity fractures is more reliable than the Neer or AO classifications. These distinct fracture morphologies are likely to have implications in terms of pathophysiology and surgical technique. PMID- 24788501 TI - the Targon femoral neck hip screw versus cannulated screws for internal fixation of intracapsular fractures of the hip: a randomised controlled trial. AB - We compared a new fixation system, the Targon Femoral Neck (TFN) hip screw, with the current standard treatment of cannulated screw fixation. This was a single centre, participant-blinded, randomised controlled trial. Patients aged 65 years and over with either a displaced or undisplaced intracapsular fracture of the hip were eligible. The primary outcome was the risk of revision surgery within one year of fixation. A total of 174 participants were included in the trial. The absolute reduction in risk of revision was of 4.7% (95% CI 14.2 to 22.5) in favour of the TFN hip screw (chi-squared test, p = 0.741), which was less than the pre-specified level of minimum clinically important difference. There were no significant differences in any of the secondary outcome measures. We found no evidence of a clinical difference in the risk of revision surgery between the TFN hip screw and cannulated screw fixation for patients with an intracapsular fracture of the hip. PMID- 24788502 TI - Post-operative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy. AB - Management of bisphosphonate-associated subtrochanteric fractures remains opinion or consensus-based. There are limited data regarding the outcomes of this fracture. We retrospectively reviewed 33 consecutive female patients with a mean age of 67.5 years (47 to 91) who were treated surgically between May 2004 and October 2009. The mean follow-up was 21.7 months (0 to 53). Medical records and radiographs were reviewed to determine the post-operative ambulatory status, time to clinical and radiological union and post-fixation complications such as implant failure and need for second surgery. The predominant fixation method was with an extramedullary device in 23 patients. 25 (75%) patients were placed on wheelchair mobilisation or no weight-bearing initially. The mean time to full weight-bearing was 7.1 months (2.2 to 29.7). The mean time for fracture site pain to cease was 6.2 months (1.2 to 17.1). The mean time to radiological union was 10.0 months (2.2 to 27.5). Implant failure was seen in seven patients (23%, 95 confidence interval (CI) 11.8 to 40.9). Revision surgery was required in ten patients (33%, 95 CI 19.2 to 51.2). A large proportion of the patients required revision surgery and suffered implant failure. This fracture is associated with slow healing and prolonged post-operative immobility. PMID- 24788503 TI - Is limb salvage surgery safe for bone sarcomas identified after a previous surgical procedure? AB - Bone sarcomas are rare cancers and orthopaedic surgeons come across them infrequently, sometimes unexpectedly during surgical procedures. We investigated the outcomes of patients who underwent a surgical procedure where sarcomas were found unexpectedly and were subsequently referred to our unit for treatment. We identified 95 patients (44 intra-lesional excisions, 35 fracture fixations, 16 joint replacements) with mean age of 48 years (11 to 83); 60% were males (n = 57). Local recurrence arose in 40% who underwent limb salvage surgery versus 12% who had an amputation. Despite achieving local control, overall survival was worse for patients treated with amputation rather than limb salvage (54% vs 75% five-year survival). Factors that negatively influenced survival were invasive primary surgery (fracture fixation, joint replacement), a delay of greater than two months until referral to our oncology service, and high-grade tumours. Survival in these circumstances depends mostly on factors that are determined prior to definitive treatment by a tertiary orthopaedic oncology unit. Limb salvage in this group of patients is associated with a higher rate of inadequate marginal surgery and, consequently, higher local recurrence rates than amputation, but should still be attempted whenever possible, as local control is not the primary determinant of survival. PMID- 24788504 TI - Monostotic fibrous dysplasia of the proximal femur: natural history and predisposing factors for disease progression. AB - Monostotic fibrous dysplasia of the proximal femur has a variable clinical course, despite its reported limited tendency to progress. We investigated the natural history and predisposing factors for progression of dysplasia in a group of 76 patients with a mean follow-up of 8.5 years (2.0 to 15.2). Of these, 31 (41%) presented with an asymptomatic incidental lesion while 45 (59%) presented with pain or a pathological fracture. A group of 23 patients (30%) underwent early operative treatment for pain (19: 25%) or pathological fracture (4: 5%). Of the 53 patients who were initially treated non-operatively, 45 (85%) remained asymptomatic but eight (15%) needed surgery because of pain or fracture. The progression-free survival of the observation group was 81% (sd 6.4%) at five years follow-up. An initial presentation of pain (p < 0.001), a limp (p < 0.001), radiological evidence of microfracture (p = 0.001) and younger age (< 17 years) (p = 0.016) were significant predisposing factors for disease progression. The risk of experiencing pain or pathological fracture is considerable in monostotic fibrous dysplasia of the proximal femur. Patients presenting with pain, a limp or radiological evidence of microfracture have a high chance of needing surgical treatment. PMID- 24788505 TI - The distribution of heat in bone during radiofrequency ablation of an ex vivo bovine model of osteoid osteoma. AB - Osteoid osteoma is treated primarily by radiofrequency (RF) ablation. However, there is little information about the distribution of heat in bone during the procedure and its safety. We constructed a model of osteoid osteoma to assess the distribution of heat in bone and to define the margins of safety for ablation. Cavities were drilled in cadaver bovine bones and filled with a liver homogenate to simulate the tumour matrix. Temperature-sensing probes were placed in the bone in a radial fashion away from the cavities. RF ablation was performed 107 times in tumours < 10 mm in diameter (72 of which were in cortical bone, 35 in cancellous bone), and 41 times in cortical bone with models > 10 mm in diameter. Significantly higher temperatures were found in cancellous bone than in cortical bone (p < 0.05). For lesions up to 10 mm in diameter, in both bone types, the temperature varied directly with the size of the tumour (p < 0.05), and inversely with the distance from it. Tumours of > 10 mm in diameter showed a trend similar to those of smaller lesions. No temperature rise was seen beyond 12 mm from the edge of a cortical tumour of any size. Formulae were developed to predict the expected temperature in the bone during ablation. PMID- 24788506 TI - Interscapulothoracic resection of tumours of shoulder with a note on reconstruction. AB - We retrospectively reviewed the outcomes of 33 consecutive patients who had undergone an extra-articular, total or partial scapulectomy for a malignant tumour of the shoulder girdle between 1 July 2001 and 30 September 2013. Of these, 26 had tumours which originated in the scapula or the adjacent soft tissue and underwent a classic Tikhoff-Linberg procedure, while seven with tumours arising from the proximal humerus were treated with a modified Tikhoff-Linberg operation. We used a Ligament Advanced Reinforcement System for soft-tissue reconstruction in nine patients, but not in the other 24. The mean Musculoskeletal Tumor Society score (MSTS) was 17.6 (95% confidence interval (CI) 15.9 to 19.4); 17.6 (95% CI 15.5 to 19.6) after the classic Tikhoff-Linberg procedure and 18.1 (95% CI 13.8 to 22.3) after the modified Tikhoff-Linberg procedure. Patients who had undergone a LARS soft-tissue reconstruction had a mean score of 18.6 (95% (CI) 13.9 to 22.4) compared with 17.2 (95% CI 15.5 to 19.0) for those who did not. The Tikhoff-Linberg procedure is a useful method for wide resection of a malignant tumour of the shoulder girdle which helps to preserve hand and elbow function. The method of soft-tissue reconstruction has no effect on functional outcome. PMID- 24788507 TI - Supracondylar osteotomy for the treatment of cubitus varus in children: a systematic review. AB - Cubitus varus is the most frequent complication following the treatment of supracondylar humeral fractures in children. We investigated data from publications reporting on the surgical management of cubitus varus found in electronic searches of Ovid/MEDLINE and Cochrane Library databases. In 894 children from 40 included studies, the mean age at initial injury was 5.7 years (3 to 8.6) and 9.8 years (4 to 15.7) at the time of secondary correction. The four osteotomy techniques were classified as lateral closing wedge, dome, complex (multiplanar) and distraction osteogenesis. A mean angular correction of 27.6o (18.5 degrees to 37.0 degrees ) was achieved across all classes of osteotomy. The meta-analytical summary estimate for overall rate of good to excellent results was 87.8% (95% CI 84.4 to 91.2). No technique was shown to significantly affect the surgical outcome, and the risk of complications across all osteotomy classes was 14.5% (95% CI 10.6 to 18.5). Nerve palsies occurred in 2.53% of cases (95% CI 1.4 to 3.6), although 78.4% were transient. No one technique was found to be statistically safer or more effective than any other. PMID- 24788508 TI - Proximal femoral resection without post-operative traction for the painful dislocated hip in young patients with cerebral palsy: a review of 79 cases. AB - Proximal femoral resection (PFR) is a proven pain-relieving procedure for the management of patients with severe cerebral palsy and a painful displaced hip. Previous authors have recommended post-operative traction or immobilisation to prevent a recurrence of pain due to proximal migration of the femoral stump. We present a series of 79 PFRs in 63 patients, age 14.7 years (10 to 26; 35 male, 28 female), none of whom had post-operative traction or immobilisation. A total of 71 hips (89.6%) were reported to be pain free or to have mild pain following surgery. Four children underwent further resection for persistent pain; of these, three had successful resolution of pain and one had no benefit. A total of 16 hips (20.2%) showed radiographic evidence of heterotopic ossification, all of which had formed within one year of surgery. Four patients had a wound infection, one of which needed debridement; all recovered fully. A total of 59 patients (94%) reported improvements in seating and hygiene. The results are as good as or better than the historical results of using traction or immobilisation. We recommend that following PFR, children can be managed without traction or immobilisation, and can be discharged earlier and with fewer complications. However, care should be taken with severely dystonic patients, in whom more extensive femoral resection should be considered in combination with management of the increased tone. PMID- 24788510 TI - Photoinduced color change and photomechanical effect of naphthalene diimides bearing alkylamine moieties in the solid state. AB - Photoinduced color change of naphthalene diimides (NDIs) bearing alkylamine moieties has been observed in the solid state. The color change is attributed to the generation of a NDI radical-anion species, which may be formed through a photoinduced electron-transfer process from the alkylamine moiety to the NDI. The photosensitivity of NDIs is highly dependent on the structures of the alkylamine moieties. Crystallographic analysis, kinetic analysis, UV/Vis/NIR spectroscopic measurements, and analysis of the photoproduct suggested that a radical anion was formed through an irreversible process initiated by proton abstraction between an amine radical cation and the neutral amine moiety. The radical anions formed stacks including mixed-valence stacks and radical-anion stacks, as shown by the broad absorption bands in near-IR spectra. These photosensitive NDIs also showed crystal bending upon photoirradiation, which may be associated with a change in the intermolecular distance of the NDI stacks by the formation of monomeric radical anions, mixed-valence stacks, and radical-anion stacks. PMID- 24788511 TI - Stroke risk after nonstroke emergency department dizziness presentations: a population-based cohort study. AB - OBJECTIVE: Acute stroke is a serious concern in emergency department (ED) dizziness presentations. Prior studies, however, suggest that stroke is actually an unlikely cause of these presentations. Lacking are data on short- and long term follow-up from population-based studies to establish stroke risk after presumed nonstroke ED dizziness presentations. METHODS: From May 8, 2011 to May 7, 2012, patients >=45 years of age presenting to EDs in Nueces County, Texas, with dizziness, vertigo, or imbalance were identified, excluding those with stroke as the initial diagnosis. Stroke events after the ED presentation up to October 2, 2012 were determined using the BASIC (Brain Attack Surveillance in Corpus Christi) study, which uses rigorous surveillance and neurologist validation. Cumulative stroke risk was calculated using Kaplan-Meier estimates. RESULTS: A total of 1,245 patients were followed for a median of 347 days (interquartile range [IQR] = 230-436 days). Median age was 61.9 years (IQR = 53.8 74.0 years). After the ED visit, 15 patients (1.2%) had a stroke. Stroke risk was 0.48% (95% confidence interval [CI] = 0.22-1.07%) at 2 days, 0.48% (95% CI = 0.22 1.07%) at 7 days, 0.56% (95% CI = 0.27-1.18%) at 30 days, 0.56% (95% CI = 0.27 1.18%) at 90 days, and 1.42% (95% CI = 0.85-2.36%) at 12 months. INTERPRETATION: Using rigorous case ascertainment and outcome assessment in a population-based design, we found that the risk of stroke after presumed nonstroke ED dizziness presentations is very low, supporting a nonstroke etiology to the overwhelming majority of original events. High-risk subgroups likely exist, however, because most of the 90-day stroke risk occurred within 2 days. Vascular risk stratification was insufficient to identify these cases. PMID- 24788512 TI - NADH plays the vital role for chiral pure D-(-)-2,3-butanediol production in Bacillus subtilis under limited oxygen conditions. AB - Compared with traditional pathogenic producers, Bacillus subtilis as a Class I microorganism offers many advantages for industrial-scale 2,3-butanediol production. Unlike previous reports in which two stereoisomers (with a ratio of 3:2) were produced, we first found that wild type B. subtilis 168 generates only D-(-)-2,3-butanediol (purity >99%) under low oxygen conditions. The total high yield of 2,3-butanediol and acetoin, and acetoin reductase enzyme assay indicate that it is the high level of NADH availability, instead of high acetoin reductase activity, contributes more to 2,3-butanediol production in B. subtilis. The strategy for increasing the pool of NADH availability, the key factor for 2,3 butanediol production, was designed through low dissolved oxygen control, adding reducing substrates and rationally metabolic engineering. A transhydrogenase encoded by udhA was introduced to provide more NADH from NADPH and allowed enhanced 2,3-butanediol production. Finally, BSF20 produced 49.29 g/L D(-)-2,3 butanediol. These results demonstrated that B. subtilis is a competitive producer for chiral 2,3-butanediol production. PMID- 24788513 TI - Productivity in the barents sea--response to recent climate variability. AB - The temporal and spatial dynamics of primary and secondary biomass/production in the Barents Sea since the late 1990s are examined using remote sensing data, observations and a coupled physical-biological model. Field observations of mesozooplankton biomass, and chlorophyll a data from transects (different seasons) and large-scale surveys (autumn) were used for validation of the remote sensing products and modeling results. The validation showed that satellite data are well suited to study temporal and spatial dynamics of chlorophyll a in the Barents Sea and that the model is an essential tool for secondary production estimates. Temperature, open water area, chlorophyll a, and zooplankton biomass show large interannual variations in the Barents Sea. The climatic variability is strongest in the northern and eastern parts. The moderate increase in net primary production evident in this study is likely an ecosystem response to changes in climate during the same period. Increased open water area and duration of open water season, which are related to elevated temperatures, appear to be the key drivers of the changes in annual net primary production that has occurred in the northern and eastern areas of this ecosystem. The temporal and spatial variability in zooplankton biomass appears to be controlled largely by predation pressure. In the southeastern Barents Sea, statistically significant linkages were observed between chlorophyll a and zooplankton biomass, as well as between net primary production and fish biomass, indicating bottom-up trophic interactions in this region. PMID- 24788514 TI - LINking microRNAs, kidney development, and Wilms tumors. AB - In this issue of Genes & Development, Urbach and colleagues (pp. 971-982) provide compelling data suggesting a role for LIN28 in the pathogenesis of a significant percentage of Wilms tumors. These data extend our insights in the genetics underlying Wilms tumor development and emphasize the importance of stemness and microRNA-mediated processes in the origins of these tumors. PMID- 24788515 TI - Dual views of SRF: a genomic exposure. AB - Esnault and colleagues (pp. 943-958) take a genomics approach to investigate the role of SRF (serum response factor) in the serum response of fibroblasts. The well-established dual role of SRF with alternative cofactors and responsiveness to two signaling pathways is illustrated at the genome-wide level, yet new insight comes from this global picture. PMID- 24788516 TI - Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. AB - The subunits of the nonspecific lethal (NSL) complex, which include the histone acetyltransferase MOF (males absent on the first), play important roles in various cellular functions, including transcription regulation and stem cell identity maintenance and reprogramming, and are frequently misregulated in disease. Here, we provide the first biochemical and structural insights into the molecular architecture of this large multiprotein assembly. We identified several direct interactions within the complex and show that KANSL1 acts as a scaffold protein interacting with four other subunits, including WDR5, which in turn binds KANSL2. Structural analysis of the KANSL1/WDR5/KANSL2 subcomplex reveals how WDR5 is recruited into the NSL complex via conserved linear motifs of KANSL1 and KANSL2. Using structure-based KANSL1 mutants in transgenic flies, we show that the KANSL1-WDR5 interaction is required for proper assembly, efficient recruitment of the NSL complex to target promoters, and fly viability. Our data clearly show that the interactions of WDR5 with the MOF-containing NSL complex and MLL/COMPASS histone methyltransferase complexes are mutually exclusive. We propose that rather than being a shared subunit, WDR5 plays an important role in assembling distinct histone-modifying complexes with different epigenetic regulatory roles. PMID- 24788517 TI - Coordination of tRNA transcription with export at nuclear pore complexes in budding yeast. AB - tRNAs are encoded by RNA polymerase III-transcribed genes that reside at seemingly random intervals along the chromosomes of budding yeast. Existing evidence suggests that the genes congregate together at the nucleolus and/or centromeres. In this study, we re-examined spatial and temporal aspects of tRNA gene (tDNA) expression. We show that tDNA transcription fluctuates during cell cycle progression. In M phase, when tRNA synthesis peaks, tDNAs localize at nuclear pore complexes (NPCs). Docking of a tDNA requires the DNA sequence of the contacted gene, nucleoporins Nup60 and Nup2, and cohesin. Characterization of mutants that block NPC localization revealed that docking is a consequence of elevated tDNA transcription. NPC-tDNA contact falters in the absence of the principal exportin of nascent tRNA, Los1, and genetic assays indicate that gating of tDNAs at NPCs favors cytoplasmic accumulation of functional tRNA. Collectively, the data suggest that tDNAs associate with NPCs to coordinate RNA polymerase III transcription with the nuclear export of pre-tRNA. The M-phase specificity of NPC contact reflects a regulatory mechanism that may have evolved, in part, to avoid collisions between DNA replication forks and transcribing RNA polymerase III machinery at NPCs. PMID- 24788518 TI - Loss of beta-catenin triggers oxidative stress and impairs hematopoietic regeneration. AB - Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. beta-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking beta-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double strand breaks after radiation. Consistent with the impaired response to radiation, beta-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on beta-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage. PMID- 24788519 TI - PI3K-mediated PDGFRalpha signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways. AB - Previous studies have identified phosphatidylinositol 3-kinase (PI3K) as the main downstream effector of PDGFRalpha signaling during murine skeletal development. Autophosphorylation mutant knock-in embryos in which PDGFRalpha is unable to bind PI3K (Pdgfra(PI3K/PI3K)) exhibit skeletal defects affecting the palatal shelves, shoulder girdle, vertebrae, and sternum. To identify proteins phosphorylated by Akt downstream from PI3K-mediated PDGFRalpha signaling, we immunoprecipitated Akt phosphorylation substrates from PDGF-AA-treated primary mouse embryonic palatal mesenchyme (MEPM) lysates and analyzed the peptides by nanoliquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS). Our analysis generated a list of 56 proteins, including 10 that regulate cell survival and proliferation. We demonstrate that MEPM cell survival is impaired in the presence of a PI3K inhibitor and that Pdgfra(PI3K/PI3K)-derived MEPMs do not proliferate in response to PDGF-AA treatment. Several of the identified Akt phosphorylation targets, including Ybox1, mediate cell survival through regulation of p53. We show that Ybox1 binds both the Trp53 promoter and the p53 protein and that expression of Trp53 is significantly decreased upon PDGF-AA treatment in MEPMs. Finally, we demonstrate that introduction of a Trp53-null allele attenuates the vertebral defects found in Pdgfra(PI3K/PI3K) neonates. Our findings identify p53 as a novel effector downstream from PI3K-engaged PDGFRalpha signaling that regulates survival and proliferation during skeletal development in vivo. PMID- 24788521 TI - Hepatic lesions in 90 captive nondomestic felids presented for autopsy. AB - Hepatic lesions in nondomestic felids are poorly characterized. The purpose of this study was to evaluate hepatic lesions in 90 captive, nondomestic felids including tigers, cougars, and lions. Hepatic lesions were histologically characterized as vacuolar change (lipidosis or glycogenosis), biliary cysts, biliary hyperplasia, hepatitis, necrosis, neoplasia, fibrosis, veno-occlusive disease, cholestasis, hematoma, congestion, or hemorrhage. Stepwise logistic regression analyses were performed for vacuolar change, benign biliary lesions, hepatitis, lipogranulomas, extramedullary hematopoiesis, and hepatic stellate cell hypertrophy and hyperplasia, with species as the outcome variable. Ninety cats met the inclusion criteria. Seventy livers (78%) contained 1 or more lesions. Hepatocellular vacuolar change (41/90 [46%]) was the most common lesion overall. Extramedullary hematopoiesis, lipogranulomas, and hepatic stellate cell hyperplasia were also common. One snow leopard had veno-occlusive disease. Tigers were more likely than other felids to have no significant hepatic histologic lesions (odds ratio [OR], 12.687; P = .002), and lions were more likely to have biliary cysts (OR, 5.97; P = .021). Six animals (7%) died of hepatic disease: cholangiocellular carcinoma (n = 2) and 1 each of hepatic lipidosis, hepatocellular necrosis, pyogranulomatous hepatitis, and suppurative cholecystitis. Hepatocellular iron and copper accumulations were present in 72 of 90 (80%) and 10 of 90 (11%) sections, respectively. Sinusoidal fibrosis was common (74/90 [82%]) and primarily centrilobular (65/74 [88%]). Hepatocellular iron, copper, and fibrosis were not significantly associated with hepatic lesions. Primary hepatic disease was not a common cause of death in nondomestic felids in this study. PMID- 24788520 TI - Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARgamma-driven enhancers. AB - Rosiglitazone (rosi) is a powerful insulin sensitizer, but serious toxicities have curtailed its widespread clinical use. Rosi functions as a high-affinity ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), the adipocyte-predominant nuclear receptor (NR). The classic model, involving binding of ligand to the NR on DNA, explains positive regulation of gene expression, but ligand-dependent repression is not well understood. We addressed this issue by studying the direct effects of rosi on gene transcription using global run-on sequencing (GRO-seq). Rosi-induced changes in gene body transcription were pronounced after 10 min and correlated with steady-state mRNA levels as well as with transcription at nearby enhancers (enhancer RNAs [eRNAs]). Up-regulated eRNAs occurred almost exclusively at PPARgamma-binding sites, to which rosi treatment recruited coactivators, including MED1, p300, and CBP. In contrast, transcriptional repression by rosi involved a loss of coactivators from eRNA sites devoid of PPARgamma and enriched for other transcription factors, including AP-1 factors and C/EBPs. Thus, rosi activates and represses transcription by fundamentally different mechanisms that could inform the future development of anti-diabetic drugs. PMID- 24788522 TI - Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer's disease and obesity. AB - Deviations from normal body weight are observed prior to and after the onset of Alzheimer's disease (AD). Midlife obesity confers increased AD risk in later life, whereas late-life obesity is associated with decreased AD risk. The role of underweight and weight loss for AD risk is controversial. Based on the hypothesis of shared genetic variants for both obesity and AD, we analyzed the variants identified for AD or obesity from genome-wide association meta-analyses of the GERAD (AD, cases = 6,688, controls = 13,685) and GIANT (body mass index [BMI] as measure of obesity, n = 123,865) consortia. Our cross-disorder analysis of genome wide significant 39 obesity SNPs and 23 AD SNPs in these two large data sets revealed that: (1) The AD SNP rs10838725 (pAD = 1.1 * 10(-08)) at the locus CELF1 is also genome-wide significant for obesity (pBMI = 7.35 * 10(-09) ). (2) Four additional AD risk SNPs were nominally associated with obesity (rs17125944 at FERMT2, pBMI = 4.03 * 10(-05), pBMI corr = 2.50 * 10(-03) ; rs3851179 at PICALM; pBMI = 0.002, rs2075650 at TOMM40/APOE, pBMI = 0.024, rs3865444 at CD33, pBMI = 0.024). (3) SNPs at two of the obesity risk loci (rs4836133 downstream of ZNF608; pAD = 0.002 and at rs713586 downstream of RBJ/DNAJC27; pAD = 0.018) were nominally associated with AD risk. Additionally, among the SNPs used for confirmation in both studies the AD risk allele of rs1858973, with an AD association just below genome-wide significance (pAD = 7.20 * 10(-07)), was also associated with obesity (SNP at IQCK/GPRC5B; pBMI = 5.21 * 10(-06) ; pcorr = 3.24 * 10(-04)). Our first GWAS based cross-disorder analysis for AD and obesity suggests that rs10838725 at the locus CELF1 might be relevant for both disorders. PMID- 24788523 TI - A natural bacterial-derived product, the metalloprotease arazyme, inhibits metastatic murine melanoma by inducing MMP-8 cross-reactive antibodies. AB - The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent. PMID- 24788525 TI - Large scale conformational transitions in beta-structural motif of gramicidin A: kinetic analysis based on CD and FT-IR data. AB - Gramicidin A (gA) is a polypeptide antibiotic, which forms dimeric channels specific for monovalent cations in artificial and biological membranes. It is a polymorphic molecule that adopts a unique variety of helical conformations, including antiparallel double-stranded ??beta5.6 or ??beta7.2 helices (number of residues per turn) and a single-stranded beta6.3 helix (the 'channel form'). The behavior of gA-Cs(+) complex in the micelles of TX-100 was studied in this work. Transfer of the complex into the micelles activates a cascade of sequential conformational transitions monitored by CD and FT-IR spectroscopy: [Formula: see text] At the first step after Cs(+) removal, the RH ??beta5.6 helix is formed, which has been discussed so far only hypothetically. Kinetics of the transitions was measured, and the activation parameters were determined. The activation energies of the ??beta5.6 -> beta-helical monomer transition in dioxane and dioxane/water solutions were also measured for comparison. The presence of water raises the transition rate constant ~10(3) times but does not lead to crucial fall of the activation energy. All activation energies were found in the 20-25 kcal/mol range, i.e. much lower than would be expected for unwinding of the double helix (when 28 H-bonds are broken simultaneously). These results can be accounted for in the light of local unfolding (or 'cracking') model for large scale conformational transitions developed by the P. G.Wolynes team [Miyashita O, Onuchic JN, Wolynes PG. Proc. Natl. Acad. Sci. USA 2003; 100: 12570-12575.]. PMID- 24788526 TI - Classical and Operatic Musicians Presented by Surgical Pathology. PMID- 24788524 TI - Dual-site phosphorylation of the control of virulence regulator impacts group a streptococcal global gene expression and pathogenesis. AB - Phosphorylation relays are a major mechanism by which bacteria alter transcription in response to environmental signals, but understanding of the functional consequences of bacterial response regulator phosphorylation is limited. We sought to characterize how phosphorylation of the control of virulence regulator (CovR) protein from the major human pathogen group A Streptococcus (GAS) influences GAS global gene expression and pathogenesis. CovR mainly serves to repress GAS virulence factor-encoding genes and has been shown to homodimerize following phosphorylation on aspartate-53 (D53) in vitro. We discovered that CovR is phosphorylated in vivo and that such phosphorylation is partially heat-stable, suggesting additional phosphorylation at non-aspartate residues. Using mass spectroscopy along with targeted mutagenesis, we identified threonine-65 (T65) as an additional CovR phosphorylation site under control of the serine/threonine kinase (Stk). Phosphorylation on T65, as mimicked by the recombinant CovR T65E variant, abolished in vitro CovR D53 phosphorylation. Similarly, isoallelic GAS strains that were either unable to be phosphorylated at D53 (CovR-D53A) or had functional constitutive phosphorylation at T65 (CovR-T65E) had essentially an identical gene repression profile to each other and to a CovR inactivated strain. However, the CovR-D53A and CovR-T65E isoallelic strains retained the ability to positively influence gene expression that was abolished in the CovR-inactivated strain. Consistent with these observations, the CovR-D53A and CovR-T65E strains were hypervirulent compared to the CovR-inactivated strain in a mouse model of invasive GAS disease. Surprisingly, an isoalleic strain unable to be phosphorylated at CovR T65 (CovR-T65A) was hypervirulent compared to the wild-type strain, as auto-regulation of covR gene expression resulted in lower covR gene transcript and CovR protein levels in the CovR-T65A strain. Taken together, these data establish that CovR is phosphorylated in vivo and elucidate how the complex interplay between CovR D53 activating phosphorylation, T65 inhibiting phosphorylation, and auto-regulation impacts streptococcal host pathogen interaction. PMID- 24788527 TI - Well-differentiated follicular patterned tumors of the thyroid with high-grade features can metastasize in the absence of capsular or vascular invasion: report of a case. AB - We report a case of an encapsulated, noninvasive, follicular thyroid neoplasia with high-grade features in a 59-year-old man who developed multiple metastases. The 5-cm lesion was originally categorized by thyroid fine-needle aspiration as "suspicious for a follicular lesion" and as a "follicular adenoma" on the subsequent hemithyroidectomy specimen. The high-grade features were represented by foci of solid, trabecular, and insular pattern (10% of the tumor), necrosis (< 5% of the tumor), and up to 14 mitoses per 10 high-power fields in the solid areas. No immunohistochemical and molecular markers associated to thyroid malignancy were observed. Although encapsulated noninvasive follicular tumors are usually regarded as benign lesions that never metastasize or recur, our case was characterized mainly by an elevated number of mitoses, and the patient progressed to widespread metastatic disease. This uncommon lesion should most likely be considered as an early form of poorly differentiated thyroid carcinoma with a dismal prognosis. PMID- 24788528 TI - Melanoma with rhabdomyosarcomatous differentiation: two further cases of a rare pathologic pitfall. AB - We describe 2 new cases of malignant melanoma with divergent rhabdomyoblastic differentiation occurring in adult patients. The patients were women aged 67 and 51 years with primary cutaneous and uterine cervical melanoma, respectively. Rhabdomyoblastic differentiation in melanoma is very rare in adult patients, and to our knowledge, only 7 such cases have been described in the world literature, of which only 4 have conclusive documentation of the presence of rhabdomyoblastic differentiation. We present the fifth and sixth cases of adult melanomas with conclusive divergent rhabdomyoblastic differentiation, including the first noncutaneous (cervical) case; we also review the literature and highlight the potential for underrecognition of this phenomenon. PMID- 24788529 TI - Gastric adenocarcinoma in common variable immunodeficiency: features of cancer and associated gastritis may be characteristic of the condition. AB - Common variable immunodeficiency (CVID) is associated with an increased risk of gastric cancer. The aim of the study was to determine the morphological features of CVID-associated gastric adenocarcinoma (CAGA) and of the background gastritis. The population of gastric cancer patients with CVID of Mayo Clinic in the period 2000-2010 was studied; 6 cases of CVID (2 males, 4 females, average age 47 years, age range 26-71 years) were found in 5793 patients with gastric cancer in the study period. Each patient underwent gastric resection for which histology slides were reviewed. Chronic gastritis variables, CVID-related findings, and features of the adenocarcinoma were recorded. CAGA was of intestinal type, with high number of intratumoral lymphocytes (ITLs). Cancer was diagnosed in younger patients than in the overall population of gastric cancer. Severe atrophic metaplastic pangastritis with extensive dysplasia was present in the background in 4 cases, with features of lymphocytic gastritis in 2 cases. Features of CVID (plasma cells paucity in 4 of 6 cases, lymphoid nodules prominent in four cases) could be detected. In summary, gastric adenocarcinoma at young age with ITLs, accompanied by atrophic metaplastic pangastritis, should alert the pathologist of the possibility of CAGA. It follows that, in presence of those characteristics, the search of CVID-associated abnormalities should be undertaken in the nonneoplastic tissues. PMID- 24788530 TI - Immunohistochemical analysis of expressions of RB1, CDK4, HSP90, cPLA2G4A, and CHMP2B is helpful in distinction between myxofibrosarcoma and myxoid liposarcoma. AB - The role and diagnostic efficacy of gene and protein products RB1, CDK4, CHMP2B, HSP90, and cPLA2G4A, all previously shown to be involved in tumor genesis and cell proliferation, were examined by immunohistochemical techniques in 32 cases of myxofibrosarcomas and 29 myxoid liposarcomas (all diagnosis had been confirmed by fluorescence in situ hybridization). HSP90 demonstrated strong nuclear and cytoplasmic positivity in all myxoid liposarcoma cases, while only 4 myxofibrosarcomas showed scattered HSP90 positivity. All but 4 cases of myxofibrosarcoma displayed strong positivity for cPLA2G4A, while only 2 myxoid liposarcoma cases were cPLA2G4A positive and both were CHMP2B negative. Overexpression of both cPLA2G4A and CHMP2B also suggested higher tumor grade. In conclusion, HSP90 and cPLA2G4A immunohistochemical stains are useful markers to distinguish myxofibrosarcoma from myxoid liposarcoma. PMID- 24788531 TI - "Dominant" myelolipoma encasing adrenal cortical carcinoma: an unusual variation of myelolipoma occurring as a synchronous and predominant neoplasm. AB - Although myelolipomas of the adrenal glands are detected with increasing frequency with advances in imaging, the occurrence of myelolipoma with adrenal cortical carcinoma remains very rare. We present a case of combined myelolipoma with adrenal cortical carcinoma in a 47-year-old man. In previously reported cases of adrenal cortical carcinoma and myelolipoma, the latter occurred as incidental foci within or peripheral to the carcinoma, perhaps representing "myelolipomatous metaplasia" rather than true neoplasia. We describe a new finding, in which the myelolipomatous component consisted of a large mass adjacent and dominant to the carcinoma. The presence of these 2 defined and apparently independent tumors suggests, in this case, the occurrence of collision or synchronous neoplastic events, rather than of metaplasia. PMID- 24788532 TI - ASAP1 mediates the invasive phenotype of human laryngeal squamous cell carcinoma to affect survival prognosis. AB - ASAP1 helps regulate cellular structures such as actin cytoskeletal remodeling and focal adhesions that have a pivotal function in tumor progression. Overexpression of ASAP1 has proven to be a malignant indicator for a variety of tumors. To further determine the potential involvement of ASAP1 in laryngeal squamous cell carcinoma (LSCC), we evaluated the expression levels of ASAP1 by quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry in tissue samples of 64 LSCC patients. We then analyzed and correlated the results with clinicopathological features. Furthermore, we used small interfering RNA (siRNA) to inhibit ASAP1 expression in vitro. The potential function of ASAP1 in invasiveness was evaluated in the Hep-2 LSCC cell line. Kaplan-Meier method was utilized to determine the association of ASAP1 expression with survival of patients. We showed that ASAP1 was upregulated in primary LSCC tumors and was correlated with lymph node metastasis and clinical tumor stage. Similarly, higher levels of ASAP1 were detected in the Hep-2 cell line compared to the 16 human bronchial epithelial (16HBE) cell line. ASAP1 expression was downregulated by lentiviral vector transfection containing siRNA in vitro. The invasive potential of these cells was found to be significantly suppressed, while expression levels of Rac1 and Cdc42 positively correlated with the inhibition of ASAP1 expression. In Kaplan-Meier overall survival curves, higher ASAP1 mRNA levels were found to be associated with a shorter progression free survival trend. Based on these results, ASAP1 appears to contribute to the malignant mechanism of LSCC and may represent a significant prognostic marker for LSCC patients. PMID- 24788533 TI - Prediction of polymorphic transformations of paracetamol in solid dispersions. AB - A novel approach employing variable-temperature X-ray powder diffraction (VTXRPD) was used to exploit its suitability as an off-line predictive tool to study the polymorphic transformations of paracetamol (PMOL) in melt-extruded hydrophilic polymer matrices. Physical mixtures (PMs) and extruded formulations of PMOL with either polyvinyl caprolactam graft copolymer (Soluplus(r)) or vinylpyrrolidone vinyl acetate copolymer (Kollidon(r)) in the solid state were characterized by using differential scanning calorimetry, hot-stage microscopy, and scanning electron microscopy. The experimental findings from VTXRPD showed that the stable Form I (monoclinic) of PMOL transformed to the metastable polymorph Form II (orthorhombic) at temperatures varying from 112 degrees C to 120 degrees C, in both the PMs and extrudates suggesting an effect of both temperature and identity of the polymers. The findings obtained from VTXRD analysis for both the PMs and the extruded formulations were confirmed by in-line near-infrared (NIR) monitoring during the extrusion processing. In the NIR study, PMOL underwent the same pattern of polymorphic transformations as those detected using VTXPRD. The results of this study suggest that VTXRPD can be used to predict the polymorphic transformation of drugs in polymer matrices during extrusion processing and provides a better understanding of extrusion processing parameters. PMID- 24788534 TI - Liver X receptor gene polymorphisms in tuberculosis: effect on susceptibility. AB - OBJECTIVES: The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis. METHODS: We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes. RESULTS: The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly "protective" (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease. CONCLUSIONS: Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in additional areas. PMID- 24788536 TI - The position of DNA cleavage by TALENs and cell synchronization influences the frequency of gene editing directed by single-stranded oligonucleotides. AB - With recent technological advances that enable DNA cleavage at specific sites in the human genome, it may now be possible to reverse inborn errors, thereby correcting a mutation, at levels that could have an impact in a clinical setting. We have been developing gene editing, using single-stranded DNA oligonucleotides (ssODNs), as a tool to direct site specific single base changes. Successful application of this technique has been demonstrated in many systems ranging from bacteria to human (ES and somatic) cells. While the frequency of gene editing can vary widely, it is often at a level that does not enable clinical application. As such, a number of stimulatory factors such as double-stranded breaks are known to elevate the frequency significantly. The majority of these results have been discovered using a validated HCT116 mammalian cell model system where credible genetic and biochemical readouts are available. Here, we couple TAL-Effector Nucleases (TALENs) that execute specific ds DNA breaks with ssODNs, designed specifically to repair a missense mutation, in an integrated single copy eGFP gene. We find that proximal cleavage, relative to the mutant base, is key for enabling high frequencies of editing. A directionality of correction is also observed with TALEN activity upstream from the target base being more effective in promoting gene editing than activity downstream. We also find that cells progressing through S phase are more amenable to combinatorial gene editing activity. Thus, we identify novel aspects of gene editing that will help in the design of more effective protocols for genome modification and gene therapy in natural genes. PMID- 24788538 TI - Land-applied goat manure as a source of human Q-fever in the Netherlands, 2006 2010. AB - Studies have shown a link between Q-fever positive farms (QFPFs) and community cases of human Q-fever. Our study is the first to investigate the potential role of contaminated land-applied manure in human Q-fever, based on a large set of nationwide notification and farm management data. Time between manure application and disease onset in geographically linked notified human cases coincided with the incubation period of Q-fever. Proximity of contaminated land parcels predicted human cases better than proximity of QFPFs (80% vs. 58%, 0-5 km in 2009). Incidence around QFPFs and contaminated land parcels decreased with distance, but not around non-contaminated land parcels. Incidence was higher around contaminated land parcels than non-contaminated land parcels (RR = [10],95%CI = [7], [1]-[14,2]). Our findings deliver evidence that, apart from QFPFs, land-applied contaminated manure may be another source of human Q-fever. PMID- 24788539 TI - Quality in gastrointestinal endoscopy. PMID- 24788540 TI - Prior hysterectomy and discomfort during colonoscopy: a retrospective cohort analysis. AB - BACKGROUND AND STUDY AIMS: Discomfort during colonoscopy may affect acceptability of the procedure. The study aim was to determine factors, including prior hysterectomy and gender, associated with higher levels of patient discomfort during colonoscopy to help with procedural planning such as choice of instrument and sedation. METHODS: A retrospective cohort study of colonoscopies (n = 1098) performed between February 2007 and March 2012 at the Tees Bowel Cancer Screening Centre within the English Bowel Cancer Screening Programme (BCSP). Determinants of moderate/severe discomfort assessed using the Gloucester Scale were explored, using logistic regression with a range of participant and procedural variables. RESULTS: Rates of moderate/severe discomfort varied significantly among men, women without hysterectomy, and women with hysterectomy (5.8 %, 10.4 %, and 17.8 %, respectively; P < 0.001). In an unadjusted model, women with hysterectomy were significantly more likely to experience moderate/severe discomfort than those without (odds ratio [OR]1.87, 95 % confidence interval [95 %CI] 1.05 - 3.32, P = 0.005). The very strong influence of sedation on discomfort level precluded an adjusted model. In subgroup analysis of participants receiving sedation, adjusted comparison again showed increased odds for moderate/severe discomfort for women with hysterectomy, compared with women without (OR 1.70, 95 %CI 1.03 - 2.80, P = 0.036). CONCLUSIONS: Prior hysterectomy is associated with greater levels of moderate/severe discomfort in women undergoing colonoscopy. Minimizing participant discomfort is desirable in any screening or surveillance program. This should be considered in preprocedural counseling and in selecting equipment, sedation, and analgesia. Further studies should examine methods to minimize discomfort in those with prior hysterectomy. PMID- 24788541 TI - Up-regulating CYP3A4 expression in C3A cells by transfection with a novel chimeric regulator of hPXR-p53-AD. AB - Most hepatoma cell lines lack proper expression and induction of CYP3A4 enzyme, which limits their use for predicting drug metabolism and toxicity. Nuclear receptor pregnane X receptor (PXR) has been well recognized for its critical role in regulating expression of CYP3A4 gene. However, its physiological activity of binding to the particular site of promoter is significantly weakened in hepatic cell lines. To address this problem, we created "chimeric PXR" constructs by appending a strong activation domain (AD) from p53 subunit to either N- or C- termini of the human PXR (hPXR), that is, hPXR-p53 and p53-hPXR. C3A, a hepatoma cell line, was used as the cell model to test the regulation effect of chimeric hPXR over wild type (WT) hPXR on CYP3A4 expression at gene, protein, and metabolism levels, respectively. Compared with C3A cells transiently transfected with WT hPXR, the activity of CYP3A4.XREM.luc reporter gene in C3A cells transfected with hPXR-p53 or p53-hPXR increased 5- and 9-fold respectively, and the levels of CYP3A4 mRNA expression increased 3.5- and 2.6-fold, respectively. C3A cells stably transfected with hPXR-p53-AD exhibited an improved expression of CYP3A4 at both gene (2-fold) and protein (1.5-fold) levels compared to WT C3A cells. Testosterone, a CYP3A4-specific substrate, was used for detecting the metabolism activity of CYP3A4. No testosterone metabolite could be detected in microsomes from WT C3A cells and WT C3A cells-based array, while the formation of 6beta-hydroxytestosterone metabolite in the transfected cells was 714 and 55 pmol/mg protein/min, respectively. In addition, all the above expression levels in the transfected cell models could be further induced with additional treatment of Rifampicin, a specific inducer for CYP3A4. In conclusion, our study established a proof-of-principle example that genetic modification with chimeric hPXR-p53-AD could improve CYP3A4 metabolism ability in hepatic cell line. PMID- 24788542 TI - Time-dependent effects of training on cardiovascular control in spontaneously hypertensive rats: role for brain oxidative stress and inflammation and baroreflex sensitivity. AB - Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-kappaB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172+/-3 mmHg), pressure variability and heart rate (358+/-7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-kappaB activity and increased TNF-alpha and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04+/-0.31 vs. 2.31+/ 0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (-13%) at the 4th week, and, by reduced vasomotor component of pressure variability (-28%) and decreased mean arterial pressure (-7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall. PMID- 24788543 TI - A comparative study of classroom and online distance modes of official vocational education and training. AB - The study discussed in this paper had two principal objectives. The first was to evaluate the distance model of official vocational education and training offered by means of a virtual learning platform. The second was to establish that both on site classroom and online distance modes of vocational education and training can be seen as complementary in terms of responding to the majority of modern educational needs. We performed a comparative study using data and results gathered over the course of eleven academic years for 1,133 of our students enrolled in an official vocational education and training program, leading to the awarding of a certificate as an Administrative Management Expert. The classes were offered by the Alfonso de Avellaneda Vocational Education and Training School, located in the city of Alcala de Henares near Madrid, Spain. We offered classes both in traditional classroom mode and through online distance learning. This paper begins with a descriptive analysis of the variables we studied; inferential statistical techniques are subsequently applied in order to study the relationships that help form the basis for the conclusions reached. This study's results provide evidence that a broad offering of vocational education and training opportunities will facilitate access to such learning for students who require it, regardless of their age, employment status, or personal circumstances, with the online distance mode playing a fundamental role while also yielding results equivalent to those observed for classroom instruction. PMID- 24788544 TI - Commentary--Project Towards No Drug Abuse: an evidence-based drug abuse prevention program. AB - Project Towards No Drug Abuse (Project TND) is a research-based program that has been examined over seven group-randomized controlled trials. In all trials, an effect has been found on hard drug use. An effect has been found on alcohol use in four trials, and on cigarettes and marijuana in two trials. (Arguably, an effect is found on marijuana in three trials.) Program effects on violence related behavior were established in earlier trials, though such effects were not assessed in later trials. Certainly, as in most scientific studies, there are limitations in the interpretation of the effects obtained, particularly regarding cigarette and marijuana use and violence-related behavior, and more empirical work is needed. For Project TND, however, numerous trial replications have been completed, and the effects within each trial could not have been obtained by chance alone more than 10 % of the time (two-tailed). These results suggest that Project TND is indeed evidence-based. To be evidence-based means that evidence has accumulated to suggest that the program is likely to work, at least under conditions that are comparable to those in which it has been tested. PMID- 24788545 TI - Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw. PMID- 24788547 TI - Tarsal navicular bone size in diabetics: radiographic assessment. AB - OBJECTIVE: To test the anecdotal observation that isolated navicular collapse is associated with diabetes mellitus, we quantified the size of the tarsal navicular bone in subjects with and without diabetes and tested for association of size with age, height, weight, body mass index (BMI), gender, smoking, bone mineral density (BMD), duration, and level of control of diabetes. MATERIALS AND METHODS: Ankle radiographs of 200 patients (122 female; 78 male; mean age 58 years [27 89]), 100 with type II diabetes and 100 age- and gender-matched controls were selected and reviewed. The anteroposterior (AP) dimension of the mid-navicular bone was measured from lateral radiographs. For standardization, the supero inferior (SI) dimension of the calcaneal was measured and the navicular-calcaneus ratio calculated. Statistical evaluation included independent sample t tests and linear regression analyses. RESULTS: Diabetic subjects had a significantly smaller navicular AP dimension and navicular-calcaneus ratio compared with controls (p = 0.02 and p = 0.0001 respectively). Age, gender, height and duration of diabetes had no association with the navicular-calcaneus ratio. The navicular calcaneus ratio was inversely correlated with weight (p = 0.01) and BMI (p < 0.001) and directly correlated with smoking (p = 0.04). Reliability of the radiographic measurements was excellent (ICC 0.80-0.97; SEM 0.3-1.7 mm). CONCLUSION: The anteroposterior dimension of the navicular is smaller in type II diabetic subjects than in age- and gender-matched controls. We hypothesize that this might be due to navicular collapse of multifactorial causes. PMID- 24788549 TI - Reducing the trauma of hospitalization. PMID- 24788552 TI - MicroRNA-26a involved in Toll-like receptor 9-mediated lung cancer growth and migration. AB - Toll-like receptor 9 (TLR9) has been shown to have a significant role in cancer. MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are involved in the development and progression of human cancers. The present study was undertaken to determine the roles of TLR9 on lung cancer and whether miR-26a is involved in TLR9-mediated lung cancer growth and migration. The lung cancer models were elicited by injecting human lung cancer cells into the left ventricle. The expression of TLR9 and miR-26a in lung cancer tissues obtained from lung cancer patients was increased. TLR9 ligand CpG oligodeoxynucleotides (CpG-ODN) caused an increase in the mean tumor weight and the size of tumor mass in nude mice, and the proliferation and migration of H460 human lung cancer cells. CpG-ODN also induced an increase in the expression of miR-26a in H460 cells. The overexpression of miR-26a increased the weight and size of the tumor mass in the nude mice, and the proliferation and migration of H460 cells. Expression of phosphoinositide 3 kinase (PI3K) and phosphorylation of protein kinase B (Akt) was increased after miR-26a overexpression in the H460 cells. PI3K inhibitor wortmannin (WM) or Akt inhibitor triciribine hydrate (TCN) eliminated the increase in the proliferation and migration induced by the overexpression of miR-26a in H460 cells. These results suggested that miR-26a is involved in the TLR9-mediated growth and migration of lung cancer through the PI3K-Akt signaling pathway. PMID- 24788550 TI - Protein kinase C theta regulates the phenotype of murine CD4+ Th17 cells. AB - Protein kinase C theta (PKCtheta) is involved in signaling downstream of the T cell antigen receptor (TCR) and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCtheta in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures) and in vivo (experimental autoimmune encephalomyelitis model, EAE) techniques, we demonstrated that PKCtheta-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORgammat), accompanied by enhanced production of the Th1 typical markers such as interferon gamma (IFN-gamma) and transcription factor T bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCtheta-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCtheta-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCtheta is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-gamma/T-bet axis at the onset of differentiation. PMID- 24788553 TI - Laboratory selection quickly erases historical differentiation. AB - The roles of history, chance and selection have long been debated in evolutionary biology. Though uniform selection is expected to lead to convergent evolution between populations, contrasting histories and chance events might prevent them from attaining the same adaptive state, rendering evolution somewhat unpredictable. The predictability of evolution has been supported by several studies documenting repeatable adaptive radiations and convergence in both nature and laboratory. However, other studies suggest divergence among populations adapting to the same environment. Despite the relevance of this issue, empirical data is lacking for real-time adaptation of sexual populations with deeply divergent histories and ample standing genetic variation across fitness-related traits. Here we analyse the real-time evolutionary dynamics of Drosophila subobscura populations, previously differentiated along the European cline, when colonizing a new common environment. By analysing several life-history, physiological and morphological traits, we show that populations quickly converge to the same adaptive state through different evolutionary paths. In contrast with other studies, all analysed traits fully converged regardless of their association with fitness. Selection was able to erase the signature of history in highly differentiated populations after just a short number of generations, leading to consistent patterns of convergent evolution. PMID- 24788554 TI - MH-3: evidence for non-competitive antagonism towards the low-affinity site of beta1-adrenoceptors. AB - beta-Adrenoceptor antagonists are important drugs for the treatment of cardiovascular diseases and some of those drugs also block the so-called low affinity site of beta1-adrenoceptors although at much higher concentrations. This low-affinity site, also identified in vivo and in human tissue, may come into play under certain pathophysiological situations including arrhythmias. The aim of our study was to determine the potency of 14 compounds chemically related to bupranolol or bevantolol and two xanthone derivatives at the low-affinity site of the beta1-adrenoceptor. The potency of the compounds at the low- and high affinity site of beta1-adrenoceptors (beta1L and beta1H; both increasing heart rate) was compared in the pithed rat. One compound was also studied in the isolated rat heart and its alpha1-adrenolytic effect determined in the isolated rat mesenteric artery. In the pithed rat, four compounds blocked the beta1L adrenoceptor at a >=10-fold lower potency than the beta1H-adrenoceptor whereas the xanthone derivative (-)-MH-3 was equipotent. In the spontaneously beating right atrium (-)-MH-3 was a non-competitive antagonist of comparable potency at either receptor; its apparent pD'2 value for the beta1L-adrenoceptor ranged from 5.6 to 6.4 under various conditions, including the Langendorff preparation. Its apparent pA2 at the alpha1-adrenoceptor in the mesenteric artery was 8.4. (-)-MH 3 is the first compound with virtually the same potency at the low- and high affinity site of beta1-adrenoceptors in vivo; it appears to be a non-competitive antagonist at either site in vitro. PMID- 24788556 TI - Radiofrequency ablation of hepatic metastases: factors influencing local tumor progression. AB - BACKGROUND: Although radiofrequency ablation (RFA) of nonresectable hepatic metastases has gained wide acceptance by showing survival benefit in selected patients, scattered reports are available regarding risk factors of local control of percutaneous RFA. The purpose of this study was to prospectively evaluate the factors influencing local tumor progression after percutaneous RFA of hepatic metastases. METHODS: Sixty-nine hepatic metastatic lesions in 54 patients were treated by percutaneous RFA. Efficacy was evaluated by contrast-enhanced computed tomography or magnetic resonance imaging at 1 month after ablation, then at 3 month intervals for the first year and biannually thereafter. RESULTS: The results of the log-rank test showed that tumor size of <3 cm (p = 0.024) and the absence of tumor contiguous with large vessels (p = 0.002) significantly correlated with local control for hepatic metastases. Cox regression analysis showed that the tumor size <3 cm and the absence of tumor contiguous with large vessels were independent factors (p = 0.055 and 0.009, respectively). The results of the log-rank test showed that neither the threshold post-ablation margin of 1.8 cm (p = 0.064) nor the presence of a tumor with subcapsular location (p = 0.134) correlated with the success of local control. CONCLUSIONS: Percutaneous RFA is more effective in achieving local control in patients with hepatic metastases when the tumor size is <3 cm and not contiguous with large vessels. PMID- 24788555 TI - Local recurrence rates are low in high-risk neoadjuvant breast cancer in the I SPY 1 Trial (CALGB 150007/150012; ACRIN 6657). AB - BACKGROUND: Increasingly, women with stage 2 and 3 breast cancers receive neoadjuvant therapy, after which many are eligible for breast-conserving surgery (BCS). The question often arises as to whether BCS, if achievable, provides adequate local control. We report the results of local recurrence (LR) from the I SPY 1 Trial in the setting of maximal multidisciplinary treatment where approximately 50 % of patients were treated with BCS. METHODS: We analyzed data from the I-SPY 1 Trial. Women with tumors >=3 cm from nine clinical breast centers received neoadjuvant doxorubicin, cyclophosphamide and paclitaxel followed by definitive surgical therapy, and radiation at physician discretion. LR following mastectomy and BCS were analyzed in relation to clinical characteristics and response to therapy as measured by residual cancer burden. RESULTS: Of the 237 patients enrolled in the I-SPY 1 Trial, 206 were available for analysis. Median tumor size was 6.0 cm, and median follow-up was 3.9 years. Fourteen patients (7 %) had LR and 45 (22 %) had distant recurrence (DR). Of the 14 patients with LR, nine had synchronous DR; one had DR > 2 years later. Only four (2 % of evaluable patients) had LR alone. The rate of LR was low after mastectomy and after BCS, even in the setting of significant residual disease. CONCLUSIONS: Overall, these patients at high risk for early recurrence, treated with maximal multidisciplinary treatment, had low LR. Recurrence was associated with aggressive biological features such as more advanced stage at presentation, where LR occurs most frequently in the setting of DR. PMID- 24788557 TI - Aqueous synthesis of highly luminescent surface Mn2+-doped CdTe quantum dots as a potential multimodal agent. AB - Mn(2+)-doped CdTe quantum dots (QDs) were synthesized directly via a facile surface doping strategy in aqueous solution. The best optical property emerged when the added amount of Mn(2+) was 5% compared to Cd(2+) in the CdTe nanoparticles and the reaction temperature was 60 degrees C. The fluorescence and magnetic properties of the QDs were studied. The as-prepared Mn(2+)-doped CdTe QDs have high quantum yield (48.13%) and a narrow distribution with an average diameter of 3.7 nm. The utility of biological imaging was also studied. Depending on the high quantum yield, cells in culture were illuminated and made more distinct from each other compared to results obtained with normal QDs. They also have a prominent longitudinal relaxivity value (r1= 4.2 mM(-1) s(-1)), which could indicate that the Mn(2+)-doped CdTe QDs can be used as a potential multimodal agent for fluorescence and magnetic resonance imaging. PMID- 24788558 TI - Rhodium(III)-catalyzed formal oxidative [4 + 1] cycloaddition of benzohydroxamic acids and alpha-diazoesters. A facile synthesis of functionalized benzolactams. AB - A Rh(III)-catalyzed oxidative [4 + 1] cycloaddition of benzohydroxamic acids and alpha-diazoesters is achieved to afford benzolactams in up to 93% yields. With the N-OAc amido moiety as a directing group, the ortho-C-H is selectively functionalized and the catalytic reaction exhibits excellent tolerance to different functional substituents. A notable rhodacyclic complex is isolated and structurally characterized, suggesting that C-H/N-H cyclometallation is a key step in the catalytic cycle. PMID- 24788559 TI - Climate and land use controls on soil organic carbon in the loess plateau region of China. AB - The Loess Plateau of China has the highest soil erosion rate in the world where billion tons of soil is annually washed into Yellow River. In recent decades this region has experienced significant climate change and policy-driven land conversion. However, it has not yet been well investigated how these changes in climate and land use have affected soil organic carbon (SOC) storage on the Loess Plateau. By using the Dynamic Land Ecosystem Model (DLEM), we quantified the effects of climate and land use on SOC storage on the Loess Plateau in the context of multiple environmental factors during the period of 1961-2005. Our results show that SOC storage increased by 0.27 Pg C on the Loess Plateau as a result of multiple environmental factors during the study period. About 55% (0.14 Pg C) of the SOC increase was caused by land conversion from cropland to grassland/forest owing to the government efforts to reduce soil erosion and improve the ecological conditions in the region. Historical climate change reduced SOC by 0.05 Pg C (approximately 19% of the total change) primarily due to a significant climate warming and a slight reduction in precipitation. Our results imply that the implementation of "Grain for Green" policy may effectively enhance regional soil carbon storage and hence starve off further soil erosion on the Loess Plateau. PMID- 24788560 TI - Genetic polymorphism of interferon regulatory factor 5 (IRF5) correlates with allograft acute rejection of liver transplantation. AB - BACKGROUND: Although liver transplantation is one of the most efficient curative therapies of end stage liver diseases, recipients may suffer liver graft loss opst-operation. IRF-5, a member of Interferon Regulatory Factors, functions as a key regulator in TLR4 cascade, and is capable of inducing inflammatory cytokines. Although TLR4 has been proved to contribute to acute allograft rejection, including after liver transplantation, the correlation between IRF5 gene and acute rejection has not been elucidated yet. METHODS: The study enrolled a total of 289 recipients, including 39 females and 250 males, and 39 recipients developed acute allograft rejection within 6 months post-transplantation. The allograft rejections were diagnosed by liver biopsies. Genome DNA of recipients was extracted from pre-operative peripheral blood. Genotyping of IRF-5, including rs3757385, rs752637 and rs11761199, was performed, followed by SNP frequency and Hardy-Weinberg equilibrium analysis. RESULTS: The genetic polymorphism of rs3757385 was found associated with acute rejection. G/G homozygous individuals were at higher risk of acute rejection, with a P value of 0.042 (OR = 2.34 (1.07 5.10)). CONCLUSIONS: IRF5, which transcriptionally activates inflammatory cytokines, is genetically associated with acute rejection and might function as a risk factor for acute rejection of liver transplantations. PMID- 24788561 TI - Hepatoprotective effects of erythropoietin on D-galactosamine/lipopolysaccharide induced fulminant hepatic failure in mice. AB - Fulminant hepatic failure is a severe clinical syndrome associated with a high rate of patient mortality. Recent studies have shown that in addition to its hematopoietic effect, erythropoietin (EPO) has multiple protective effects and exhibits antiapoptotic, antioxidant and anti-inflammatory activities. The present study aimed to determine the hepatoprotective effect of EPO and to elucidate the underlying mechanisms using a D-galactosamine (D-GalN)/lipopolysaccharide (LPS) induced model of acute liver injury. Experimental groups of mice were administered with various doses of EPO (1,000, 3,000 or 10,000 U/kg, intraperitoneal) once per day for 3 days, prior to injection with D-GalN (700 mg/kg)/LPS (10 ug/kg). Mice were sacrificed 8 h after treatment with D-GalN/LPS. Liver function and histopathology, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and EPO receptor (EPOR) and phosphatidylinositol 3-kinase (PI3K) mRNA expression were evaluated. D-GalN/LPS administration markedly induced liver injury, as evidenced by elevated levels of serum aminotransferases, as well as histopathological changes. Compared with the D-GalN/LPS group, pretreatment with EPO significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase and MDA, and increased the activities of SOD and GSH-Px. Furthermore, the protective effects of EPO were paralleled by an upregulation in the mRNA expression of EPOR and PI3K. These data suggest that EPO can ameliorate D-GalN/LPS-induced acute liver injury by reducing oxidative stress and upregulating the mRNA expression of EPOR and PI3K. PMID- 24788562 TI - Design of informative renal impairment studies: evaluation of the impact of design stratification on bias, precision and dose adjustment error. AB - PURPOSE: Renal impairment (RI) studies are conducted to estimate the impact of RI on pharmacokinetics (PK). In some disease areas, these studies can be difficult to conduct, for instance due to the limited number of eligible patients. The objective of this analysis was to evaluate bias and precision of population PK parameters, and the dose adjustment error (DAE) for RI studies i) with different levels of study design imbalance in the stratification of subjects across RI categories, and ii) that include additional patients in the control arm of RI studies, that may be available from previously conducted PK studies. METHODS: Study designs were simulated and re-estimated using a hypothetical 2 compartmental PK model with varying magnitude of the fraction of renal elimination (FR) and magnitude of between-subject variability (BSV). The DAE was computed based on the difference between the theoretical necessary dose adjustment versus the empirical estimated dose adjustment to reach a similar exposure as controls. RESULTS: Although some design imbalance may still lead to DAEs of acceptable magnitude (DAE < -11.05-14.44 inter-quartile range, IQR), at least some patients are necessary in the more severe RI groups. When 100 additional patients with normal renal function were included in a sub-informative design, the DAE changed from < -7.63-16.64 IQR to < -8.89-8.69 IQR. CONCLUSIONS: We quantified the impact of study design imbalance on bias and precision of PK parameters and DAE, as may occur for RI studies in some indications. Adding additional data from earlier studies to the analysis dataset improves the bias and precision of PK parameters. PMID- 24788564 TI - Analgesic, sedative, antipsychotic, and neuromuscular blocker use in Canadian intensive care units: a prospective, multicentre, observational study. AB - PURPOSE: Our aim was to describe analgo-sedation and antipsychotic and neuromuscular blocking drug (NMBD) use in critically ill patients, management strategies, and variables associated with these practice patterns. METHODS: This prospective observational study in 51 intensive care units (ICUs) included all patients who underwent invasive mechanical ventilation (MV) over a two-week period during 2008-2009. RESULTS: We included 712 patients representing 3,620 patient-days. Median MV duration was 3.0 days (interquartile range 2-6). During MV, 92% of patients received analgo-sedation, 32% an adjunct agent (e.g., acetaminophen), 18% NMBDs, and 10% antipsychotics. Opioids were used more frequently than benzodiazepines or propofol (84.8% vs 62.2% vs 10.1% patients, respectively, P < 0.0001). Independent predictors of opioid and benzodiazepine use were a longer MV duration, assessment scales, physical restraints, and university-affiliated hospital. Although more than 50% of ICUs reported that assessment tools, protocols, and daily sedation interruption (DSI) were available for use, application was modest: sedation scale 53.0%, pain scale 19.1%, delirium scale 5.2%, protocol 25.0%, DSI 42.1%. Accidental device removal occurred in 4.6% of patients, with 75.8% of events during DSI. Daily sedation interruption was associated with protocol use, physical restraints, university-affiliated hospital, and short-duration MV. Variables associated with protocol use included assessment scales, longer MV duration, lack of physical restraints, and admission to a community hospital. CONCLUSION: Nearly all MV patients received analgo sedation. Opioids were used more often than sedatives despite infrequent use of pain scales. Few patients received antipsychotic therapy, but physical restraint was common. Protocol use was poor compared to DSI. Duration of MV predicted the use of either. PMID- 24788565 TI - Aberrant expression of CD227 is correlated with tumor characteristics and invasiveness of breast carcinoma. AB - PURPOSE: Increasing evidences demonstrate that CD227 plays a crucial role in the development and progression of breast cancer. However, the function of CD227 in breast carcinoma was still controversial and the investigation on CD227 in Asian race was scarce. METHODS: To investigate the relationship between CD227 and tumor characteristics of breast carcinoma, CD227, estrogen receptor (ER), progesterone receptor (PR), Her2/neu and Ki-67 were detected by immunohistochemistry in a series of 227 patients. The Kaplan-Meier method and log-rank tests were used to estimate the correlation between CD227 expression and patients' prognosis. Furthermore, in vitro invasion assay was performed to examine the effect of CD227 on the invasiveness of breast carcinoma cells after transfection with CD227 cDNA or antisense phosphorothioate oligodeoxynucleotides (ASODN) against CD227 mRNA. RESULTS: Our data demonstrate that the cytoplasm staining and high expression of CD227 were positively related to the aggressiveness of breast cancer. Both circumferential membrane staining and cytoplasm staining were associated with lymph node metastasis. Moreover, the cytoplasm staining and overexpression of CD227 were found to be related to Her-2/neu positivity, higher Ki-67 positivity and poorer survival of patients. We further demonstrated that the invasion ability of breast carcinoma cells could be enhanced or inhibited by CD227 cDNA or ASODN, respectively. CONCLUSIONS: We conclude that the aberrant expression of CD227, especially cytoplasm staining could be predictive for tumor aggressiveness, lymph node metastasis, poorer outcome of patients with breast cancers. And CD227 could promote the invasion ability of breast cancer cells, suggesting a potential role of CD227 as an oncogene in breast carcinoma. PMID- 24788563 TI - A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients. AB - BACKGROUND: Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. METHODS: Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1-12) and 2 in arm B (range 1 9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p = 0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9-6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. CONCLUSIONS: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688. PMID- 24788566 TI - Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery. AB - The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 ug versus 0.3 ug) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use. PMID- 24788567 TI - Cerebral oxygenation and hemodynamic measurements during craniosynostosis surgery with near-infrared spectroscopy. AB - INTRODUCTION: Focal pressure-related changes in brain perfusion and metabolism are discussed in single-suture craniosynostosis and brachycephalic cases (bicoronal synostosis). Raised intracranial pressure levels could be measured in some cases. In order to find possible loco-regional brain tissue changes during plastic surgery, we investigated oxygenation and perfusion parameters using non invasive near-infrared spectroscopy (NIRS) probes. METHODS: Twenty-two consecutively operated cases (mean age 7 months) with single-suture craniosynostosis were prospectively investigated using a NIRS probe (LEA((c)), O2C, white light 500-800 nm, laser NIR). Measurements for oxygen saturation (SO(2)), relative quantity of hemoglobin (rHb), blood flow, and blood flow velocity of the bilateral frontal, temporal, and parietal cortices were taken transosseously (prior to decompression) and epidurally directly after decompression as well as 15 and 30 min after decompression and before closure. RESULTS: Twenty-two patients with scaphocephaly (11), trigonocephaly (6), anterior plagiocephaly (3), and brachycephaly (2) were investigated. SO(2) was improving in all patient subgroups, showing the highest levels in the fronto temporal region; rHb improved in scaphocephalic, trigonocephalic, and brachycephalic children. Again, the highest values were found not only in the temporal but also in the frontal region and in brachycephalic patients also in the parietal cortex. CONCLUSION: These preliminary results of a new technology for brain tissue oxygenation and blood flow measurements suggest a regional compromise of cortical metabolism and circulation in patients with craniosynostosis. PMID- 24788568 TI - Interventions for treating fingertip entrapment injuries in children. AB - BACKGROUND: Fingertip entrapment injuries, which involve lacerations to the pulp and nail and often a fracture of the underlying bone, commonly occur in children, usually as the result of a crushing injury. Treatment is either conservative (wound cleaning and fingertip dressing)or surgical (repair of lacerations, reduction and stabilisation of fractures); however, no consensus currently exists regarding the most appropriate treatment modality. OBJECTIVES: To assess the effects (benefits and harms) of surgical and conservative interventions for fingertip entrapment injuries in children. We aimed to compare: different methods of conservative treatment; surgical versus conservative treatment; different methods of surgical treatment; and different methods of management after initial conservative or surgical treatment. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, the World Health Organization Clinical Trials Registry Platform and reference lists of articles up to 30 April 2013. We did not apply any restrictions based on language or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing interventions for treating fingertip entrapment injuries in children.The primary outcomes were fingertip function, nail growth, nail deformity and adverse events such as infection. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for inclusion, assessed the risk of bias in each included trial and extracted data.We resolved disagreements through discussion. MAIN RESULTS: We included two RCTs examining a total of 191 young children, 180 of whom were included in the analyses. The two trials tested different comparisons. Both trials were at high risk of bias, particularly from lack of blinding of participants and personnel, and of outcome assessment. The trials did not record fingertip function, nail growth or nail deformity. The quality of the evidence for the reported outcomes was judged to be 'low' using the GRADE approach (i.e. further research is very likely to have an important impact on our confidence in the estimate of the effect and is likely to change the estimate).One trial compared a seven-day course of antibiotics with no antibiotics after formal surgical repair of fingertip entrapment injuries.One child in each group had an infection at day seven (1/66 antibiotic group versus 1/69 no antibiotic group; RR 1.05, 95% CI 0.07 to 16.37). Both participants with infections had a more severe injury (partial fingertip amputation).The other trial compared two different dressings (silicone net and paraffin gauze) for use after either surgical or initial conservative management of fingertip entrapment injuries. It reported that two of 20 children in the silicone group versus one of 25 in the paraffin group had complications of wound infection (RR 2.50, 95% CI 0.24 to 25.63) and that one of 20 children in the silicone group versus two of 25 in the paraffin group had skin necrosis (RR 0.63, 95% CI 0.06 to 6.41). All complications healed with conservative treatment. The results for mean healing times and mean number of dressing changes were similar between groups but benefits of either silicone or paraffin dressings could not be excluded (silicone mean 4.1 weeks versus paraffin mean 4.0 weeks;MD 0.10 weeks, 95% CI-0.61 to 0.81); (silicone mean 4.3 dressing changes versus paraffin mean 4.2 dressing changes; MD 0.10, 95% CI -0.57 to 0.77). The trial found that a silicone dressing was less likely to adhere to the wound or cause distress for the child at the one week dressing change. AUTHORS' CONCLUSIONS: There is a lack of evidence from RCTs to inform all key treatment decisions for the management of fingertip entrapment injuries in children.Given that the quality of evidence is low from one trial, we do not have conclusive evidence that prophylactic use of antibiotics after surgical repair fails to reduce risk of infection. The two children who experienced infection had more severe wounds.Similarly, the low quality evidence from one trial has not enabled us to draw firm conclusions regarding the effect on healing time or complications (infection, skin necrosis) at four-week follow up between a silicone net dressing and a paraffin gauze dressing when applied post-surgery or after simple wound irrigation; however, the silicone net dressing may be easier to remove in the first week.Further RCTs are required in this area, preferably comparing surgical with conservative methods of managing fingertip entrapment injuries. Outcome assessment should include fingertip function, nail growth and nail deformity for a minimum of three months posttreatment. PMID- 24788569 TI - Clinical and pathological features of patients with nemaline myopathy. AB - Nemaline myopathy (NM) is a rare congenital myopathy of great heterogeneity, characterized by the presence of rods in the cytoplasm of muscle fibers. This study aimed to summarize and analyze retrospectively the clinicopathological features of 28 patients with NM. Among the 28 patients, 15 were classified as of the typical congenital type, manifested as lower- or four-limb weakness as the first symptom and slowly progressive course. Six patients were classified as of childhood onset type, with lower-limb weakness and progressive course. Seven patients were classified as of the adult onset type, with rapidly progressive course and obvious muscle atrophy. Patient's 1, 16 and 23 had rapid clinical progression. On follow up, the three patients showed respiratory failure. Limb weakness in all patients was proximal-dominant. Hypotonia was observed in most patients. High arched feet were also observed as dysmorfic features. In all patients, the creatine kinase (CK) level was normal or mildly elevated, and electromyography revealed myogenic changes. Nemaline bodies were observed under a light microscope in more than half of the patients' muscle fibers, and especially in type I fibers. All patients showed fiber type I predominance and atrophy. Modified Gomori trichrome staining showed characteristic purple-colored rods. Muscle electron microscopy revealed the presence of high electron-dense nemaline bodies around the nucleus, and of a disorganized myofibrillar apparatus, with broken myofilaments and irregular myofibrils and Z lines. The 28 patients with NM shared a number of clinical features, such as proximal limb weakness, reduced deep tendon reflex and dysmorfic features. Differences were also observed between the three types of patients, with regards to course progression, disease severity and respiratory failure. In conclusion, patients with NM showed great clinical heterogeneity. The diagnosis of NM was mainly based on the muscle biopsy. PMID- 24788570 TI - Zeolite films as building blocks for antireflective coatings and vapor responsive Bragg stacks. AB - Zeolite films (LTL, BEA and MFI) are prepared with a thickness in the range 50 170 nm through a multistep spin-on deposition method. The optical properties of the zeolite films including refractive index, extinction coefficient and thickness are determined from the reflectance spectra using a nonlinear curve fitting method. The total free pore volume of the films using the Bruggeman effective medium theory is calculated. The potential of the zeolite films for broadband antireflection (AR) application is demonstrated. Five times reduction of the reflectance of a silicon substrate covered with the double AR films comprising of MFI type zeolite (120 nm) deposited on Nb2O5 (60 nm) is achieved. Additionally, the MFI zeolite film is used as a building block of vapor responsive Bragg stacks with a strong response towards acetone. The reversible response of the Bragg stacks towards acetone without additional annealing opens up the possibility of preparing sensors with optical read-out by incorporation of sensitive and transducer elements into a single device. PMID- 24788571 TI - Observational study on dipeptidyl peptidase-4 inhibitors: a real-life analysis on 360 patients from the ASL VCO territory in Italy. AB - BACKGROUND AND OBJECTIVES: Diabetes mellitus is a complex, progressive disease that can lead to complications if it is not strictly controlled. The literature suggests that only 50 % of Italian patients with type 2 diabetes mellitus (T2DM) achieve guideline-recommended levels of glycaemic control, suggesting that treatment regimens need to be improved. The present study aimed to evaluate the effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of glycaemic control, body weight and lipid profile in a series of patients with T2DM attending a diabetes outpatient facility. METHODS: This was an observational retrospective study performed on a series of patients with T2DM attending our three outpatient clinics. The study included 360 patients with T2DM of both sexes, aged between 30 and 85 years, with a body mass index (BMI) of 22-45 kg/m(2) who were uncontrolled [glycated haemoglobin (HbA(1c)) 7.1-10 %] despite dietary restrictions or treatment with pharmacological therapy. Patients included in the analysis received therapy with a DPP-4 inhibitor (sitagliptin, n = 244; vildagliptin, n = 97; saxagliptin, n = 19). RESULTS: Vildagliptin reduced HbA(1c) by 1.2 % compared with sitagliptin and saxagliptin (-0.9 %) from a baseline of 8 % (similar in all groups). The greatest decrease in fasting plasma glucose was seen with vildagliptin (-37 mg/dL) compared with sitagliptin and saxagliptin (-20 and -29 mg/dL, respectively). A greater reduction in total cholesterol was achieved with vildagliptin (-24 mg/dL) than with sitagliptin (-11 mg/dL) and saxagliptin (-3.6 mg/dL). Effectiveness was maintained in all age groups, provided disease duration was short (~5 to 6 years). Adverse effects were mild and transient and did not require treatment discontinuation. CONCLUSIONS: DPP-4 inhibitors are a viable option in patients with T2DM not adequately controlled by existing therapy. They demonstrate comparable efficacy to other antidiabetic medicines with regard to HbA(1c) reduction. The positive changes in the lipid profile make DPP-4 inhibitors a particularly interesting class of drugs; however, further studies are needed to confirm their true impact on cardiovascular risk in a real-world setting. PMID- 24788572 TI - The changing face of obesity: exposure to and acceptance of obesity. AB - OBJECTIVE: Adiposity has started to become the norm in many western countries. The current studies tested the hypothesis that exposure to heavier body weights will increase the acceptance of obesity, which could further propagate rises in body weight. METHODS: Across three experiments we examined the effect that exposing participants to photographs of either obese or healthy weight males had on later judgments about an obese male. We also tested how obesity exposure impacted upon visual preferences and how accepting participants were of obesity, to examine the mechanisms by which exposure to obesity increases acceptance of heavier body weights. RESULTS: In Experiment 1, obesity exposure resulted in an obese male being judged more positively, than after exposure to healthy weights. Experiment 2 replicated the effect that obesity exposure had on acceptability and demonstrated this effect was mediated by obesity exposure increasing how much participants liked the way an obese person looked. In Experiment 3, exposure to obesity resulted in participants being more likely to believe that an obese person did not need to lose weight. CONCLUSIONS: Findings across these three studies were consistent and suggest that exposure to adiposity results in an increased acceptance of obesity, by altering visual preferences towards heavier body weights. PMID- 24788573 TI - Introduction to the special online issue: Eat, sleep, exercise. PMID- 24788574 TI - Volumes and bouts of sedentary behavior and physical activity: associations with cardiometabolic health in obese children. AB - OBJECTIVE: To examine associations of volumes and bouts of sedentary behavior (SED) and moderate-to-vigorous physical activity (MVPA) with individual and clustered cardio-metabolic outcomes in overweight/obese children. METHODS: Cross sectional data from 120 overweight/obese children (8.3 +/- 1.1 years, 62% girls, 74% obese) with SED and MVPA assessed using accelerometry. Children were categorized into quartiles of mean bouts per day of SED (10, 20, and 30 min) and MVPA (5, 10, and 15 min). Associations with triglycerides, HDL cholesterol, glucose, insulin, systolic/diastolic blood pressure, and clustered cardio metabolic risk (cMet) were examined using linear regression, adjusted for confounders. RESULTS: Independent of MVPA, SED volume was inversely associated with HDL cholesterol (beta [95% CI] = -0.29 [-0.52, -0.05]). MVPA volume was inversely associated with diastolic blood pressure, independent of SED (beta = 0.22 [-0.44, -0.001]), and cMet (beta = -0.19 [-0.36, -0.01]) although not after adjustment for SED (beta = -0.14 [-0.33, 0.06]). Independent of MVPA and SED volumes, participants in the highest quartile of 30 min bouts per day of SED had 12% lower HDL cholesterol than those in the lowest quartile (d = 0.53, P = 0.046, Ptrend = 0.11). CONCLUSIONS: In addition to increasing MVPA, targeting reduced SED and limiting bouts of SED to <30 min may contribute to improved HDL cholesterol levels and cardio-metabolic health in overweight/obese children. PMID- 24788575 TI - Update on vaccines for high-risk melanoma. AB - The management of high-risk melanoma has historically included primary surgical resection with or without lymphadenectomy followed by an array of adjuvant options including radiation therapy or immunomodulatory therapies such as interferon-alpha, granulocyte macrophage colony-stimulating factor, and a multitude of vaccines. There has been a long-standing interest in the development of vaccines in high-risk and metastatic melanoma, and clinical trials have been ongoing for decades. Given that melanoma is identified as one of the most immunogenic solid tumors, there is continued hope that vaccine therapies will improve clinical outcomes. Despite intense interest in this field, few clinical trials to-date have demonstrated significant benefit from melanoma vaccines in high-risk disease. Several trials have even documented a detrimental effect on outcomes after vaccine administration. While the role of vaccines in the adjuvant setting of high-risk melanoma presently remains unclear, recent advances in immunotherapy for melanoma including development of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) monoclonal antibodies have demonstrated meaningful clinical responses. With further study and focus on mechanisms of immune regulation, there remains promise for the role of vaccines in combination with other immune-stimulatory agents in high-risk melanoma. PMID- 24788576 TI - Giant cell tumor of bone: current treatment options. AB - OPINION STATEMENT: Giant cell tumor of bone (GCTB) comprises up to 20 % of benign bone tumors in the US. GCTB are typically locally aggressive, but metastasize to the lung in ~5 % of cases. Malignant transformation occurs in a small percentage of cases, usually following radiation therapy. Historically, GCTB have been treated primarily with surgery. When the morbidity of surgery would be excessive, radiation therapy may achieve local control. In most cases the primary driver of the malignant cell appears to be a mutation in H3F3A leading to a substitution of Gly34 to either Trp or Leu in Histone H3.3. This change presumably alters the methylation of the protein, and thus, its effect on gene expression. The malignant stromal cells of GCTB secrete RANKL, which recruits osteoclast precursors to the tumor and stimulates their differentiation to osteoclasts. The elucidation of the biology of GCTB led to trials of the anti-RANKL monoclonal antibody denosumab in this disease, with a clear demonstration of beneficial clinical effect. Surgery remains the primary treatment of localized GCTB. When surgery is not possible or would be associated with excessive morbidity, denosumab is a good treatment option. The optimal length of treatment and schedule of denosumab is unknown, but recurrences after apparent complete responses have been observed after stopping denosumab, and long-term follow-up of denosumab treatment may reveal unrecognized effects. The role of denosumab in the preoperative or adjuvant setting will require clinical trials. In some cases local radiation therapy may be useful, although long term effects should be considered. PMID- 24788578 TI - Analysis of cellular responses of macrophages to zinc ions and zinc oxide nanoparticles: a combined targeted and proteomic approach. AB - Two different zinc oxide nanoparticles, as well as zinc ions, are used to study the cellular responses of the RAW 264 macrophage cell line. A proteomic screen is used to provide a wide view of the molecular effects of zinc, and the most prominent results are cross-validated by targeted studies. Furthermore, the alteration of important macrophage functions (e.g. phagocytosis) by zinc is also investigated. The intracellular dissolution/uptake of zinc is also studied to further characterize zinc toxicity. Zinc oxide nanoparticles dissolve readily in the cells, leading to high intracellular zinc concentrations, mostly as protein bound zinc. The proteomic screen reveals a rather weak response in the oxidative stress response pathway, but a strong response both in the central metabolism and in the proteasomal protein degradation pathway. Targeted experiments confirm that carbohydrate catabolism and proteasome are critical determinants of sensitivity to zinc, which also induces DNA damage. Conversely, glutathione levels and phagocytosis appear unaffected at moderately toxic zinc concentrations. PMID- 24788577 TI - Simultaneous quantitative and qualitative analysis of aliskiren, enalapril and its active metabolite enalaprilat in undiluted human urine utilizing LC-ESI MS/MS. AB - The benefit-risk ratio of combined blocking by the direct renin inhibitor aliskiren and an angiotensin-converting enzyme inhibitor (e.g. enalapril) on the renin-angiotensin-aldosterone system is discussed. No method was available for simultaneous determination of both drugs in urine. A novel sensitive method for simultaneous quantification in undiluted human urine was developed which enables systematic pharmacokinetic investigations, especially in poorly investigated populations like children. Matrix effects were clearly reduced by applying solid phase extraction followed by a chromatographic separation on Xselect(TM) C18 CSH columns. Mobile phase consisted of methanol and water, both acidified with formic acid. Under gradient conditions and a flow rate of 0.4 mL/min the column effluent was monitored by tandem mass spectrometry with electrospray ionization. Calibration curves were constructed in the range of 9.4-9600 ng/mL regarding aliskiren, 11.6-12000 ng/mL for enalapril and 8.8-9000 ng/mL for enalaprilat. All curves were analyzed utilizing 1/x(2) -weighted quadratic squared regression. Intra-run and inter-run precision were 3.2-5.8% and 6.1-10.3% for aliskiren, 2.4 6.1% and 3.9-7.9% for enalapril as well as 3.1-9.4% and 4.7-12.7% regarding enalaprilat. Selectivity, accuracy and stability results comply with current international bioanalysis guidelines. The fully validated method was successfully applied to a pharmacokinetic investigation in healthy volunteers. PMID- 24788579 TI - Recognition of free tryptophan in water by synthetic pseudopeptides: fluorescence and thermodynamic studies. AB - Pseudopeptidic receptors containing an acridine unit have been prepared and their fluorescence response to a series of amino acids was measured in water. Free amino acids, not protected either at the C or the N terminus, were used for this purpose. The prepared receptors display a selective response to tryptophan (Trp) versus the other assayed amino acids under acidic conditions. The macrocyclic nature of the receptor is important as the fluorescence quenching is higher for the macrocyclic compound than for the related open-chain receptor. Notably, under the experimental acidic conditions used, both the receptor and guest are fully protonated and positively charged; thus, the experimental results suggest the formation of supramolecular species that contain two positively charged organic molecular components in proximity stabilized through aromatic-aromatic interactions and a complex set of cation-anion-cation interactions. The selectivity towards Trp seems to be based on the existence of a strong association between the indole ring of the monocharged amino acid and the acridinium fragment of the triprotonated form of the receptor, which is established to be assisted by the interaction of the cationic moieties with hydrogen sulfate anions. PMID- 24788580 TI - Caregiver-mediated intervention can improve physical functional recovery of patients with chronic stroke: a randomized controlled trial. AB - Background and Purpose. Patients with chronic stroke may benefit from continuing rehabilitation training after hospital discharge. This study examined whether caregiver-mediated, home-based intervention (CHI) could improve physical functioning and social participation in these patients. Methods. A single-blind, randomized, controlled 12-week trial conducted with 51 patients from 3 hospitals in Taiwan who had chronic stroke (>6 months; Brunnstrom recovery stages III-V). Patients and their caregivers in the intervention arm (n = 25) were given weekly personalized CHI trainings designed by a physical therapist. Patients in the control arm (n = 26) received visits from the therapist without intervention. All were evaluated for physical recovery through the Stroke Impact Scale, Berg Balance Scale, 10-Meter Walk Test, 6-Minute Walk Test, and Barthel Index at baseline and endpoint. Caregivers were evaluated with the Caregiver Burden Scale. Results were analyzed through Mann-Whitney U test. Results. CHI significantly improved scores of the Stroke Impact Scale: strength (control vs intervention, respectively: 1.4 vs 15.5; P = .002), mobility (-0.5 vs 13.7; P < .001), composite physical (-0.7 vs 11.2; P < .001), and general recovery domain (0.2 vs 17.4; P < .001). CHI also significantly improved free-walking velocity (-1.4 vs 7.5 cm/s; P = .006), 6-minute walk distance (-10.5 vs 15.8 m; P = .003), Berg Balance Scale score (-0.8 vs 4.5; P = .006), and Barthel Index score (0.6 vs 7.2; P = .008). CHI did not significantly increase caregiver burden at endpoint. Conclusion. CHI can improve physical functional recovery and, possibly, social participation in patients with chronic stroke. PMID- 24788582 TI - Obatoclax induces G1/G0-phase arrest via p38/p21(waf1/Cip1) signaling pathway in human esophageal cancer cells. AB - Pan-Bcl-2 family inhibitor obatoclax has been demonstrated to be effective against various cancers, of which the mechanism of action is not fully understood. In this study, we demonstrate that obatoclax suppressed esophageal cancer cell viability with concomitant G1/G0-phase cell cycle arrest. At the tested concentrations (1/2 IC50 and IC50), obatoclax neither induced PARP cleavage nor increased the Annexin V-positive population, suggesting G1/G0-phase arrest rather than apoptosis accounts for most of the reduction of cell viability produced by obatoclax. Double knockdown of Bak and Bax by small interference RNA failed to block obatoclax-induced G1/G0-phase arrest, implying its role in cell cycle progression is Bak/Bax-independent. The cell cycle arresting effect of obatoclax was associated with up-regulation of p21(waf1/Cip1). Knockdown of p21(waf1/Cip1) significantly attenuated obatoclax-induced G1/G0-phase arrest. Although obatoclax stimulated phosphorylation of Erk, p38, and JNK, pharmacological inhibition of p38 but not Erk or JNK blocked obatoclax-induced G1/G0-phase arrest. Moreover, knockdown of p38 abolished the cell cycle arresting effect of obatoclax. In consistent with this finding, inhibition of p38 blocked obatoclax-induced p21(waf1/Cip1) expression while inhibition of Erk or JNK failed to exert similar effect. To conclude, these findings suggest that obatoclax induced cell cycle arrest via p38/p21(waf1/Cip1) signaling pathway. This study may shed a new light on the anti-cancer activity of obatoclax in relation to cell cycle arrest. PMID- 24788581 TI - Multistimulation group therapy in Alzheimer's disease promotes changes in brain functioning. AB - Background. The growing social emergency represented by Alzheimer's disease (AD) and the lack of medical treatments able to modify the disease course have kindled the interest in nonpharmacological therapies. Objective. We introduced a novel nonpharmacological approach for people with AD (PWA) named Multidimensional Stimulation group Therapy (MST) to improve PWA condition in different disease domains: cognition, behavior, and motor functioning. Methods. Enrolling 60 PWA in a mild to moderate stage of the disease, we evaluated the efficacy of MST with a randomized-controlled study. Neuropsychological and neurobehavioral measures and functional magnetic resonance imaging (fMRI) data were considered as outcome measures. Results. The following significant intervention-related changes were observed: reduction in Neuropsychiatric Inventory scale score, improvement in language and memory subscales of Alzheimer's Disease Assessment Scale-Cognitive subscale, and increased fMRI activations in temporal brain areas, right insular cortex, and thalamus. Conclusions. Cognitive-behavioral and fMRI results support the notion that MST has significant effects in improving PWA cognitive-behavioral status by restoring neural functioning. PMID- 24788583 TI - Evolution of "The Guideline Advantage": Lessons learned from the front lines of outpatient performance measurement. PMID- 24788584 TI - Mark Jones's reply to Myles and Leonardi-Bee's response to his critique of their paper reported in The BMJ. PMID- 24788585 TI - Rapid and sensitive detection of Sclerotium rolfsii associated with collar rot disease of Amorphophallus paeoniifolius by species-specific polymerase chain reaction assay. AB - Collar rot disease caused by Sclerotium rolfsii is an economically important disease prevailing in all Amorphophallus growing areas. The pathogen propagules surviving in soil and planting material are the major sources of inoculum. A nested PCR assay has been developed for specific detection of S. rolfsii in soil and planting material. The PCR detection limit was 10 pg in conventional assay whereas 0.1 pg in nested assay. The primers designed were found to be highly specific and could be used for accurate identification of pathogen up to species level. The protocol was standardized for detection of the pathogen in artificially and naturally infected field samples. PMID- 24788586 TI - Cellular internalization and detailed toxicity analysis of protein-immobilized iron oxide nanoparticles. AB - Iron oxide nanoparticles (IONPs) have been extensively used for biomedical applications like in the diagnosis and treatment of various diseases, as contrast agents in magnetic resonance imaging, and in targeted drug delivery. Despite several attempts, there is a dearth of information with respect to the cellular response and in-depth toxicity analysis of the nanoparticles. Considering the potential benefits of IONPs, there is a need to study the potential cellular damage associated with IONPs. The size and surface of the particles are some critical factors that should be analyzed when evaluating cytotoxicity. Therefore, in this study, we synthesized and characterized bare (7-9 nm) and protein-coated IONPs of diameter 50-70 nm, and evaluated their toxicity on membrane integrity, intracellular accumulation of reactive oxygen species, and mitochondrial activity in mouse fibroblast cell line by lactate dehydrogenase, 2',7'-dichlorofluorescein diacetate, and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assays, respectively. Our extensive cytotoxicity analysis demonstrated that the size of the IONPs and their surface coating are the critical determinants of cellular response and potential mechanism toward cytotoxicity. The study of the interactions and assessment of potential toxicity of the nanoparticles with cells/tissues is a key determinant when considering their translation in biomedical applications. PMID- 24788587 TI - Frontal white matter alterations in short-term medicated panic disorder patients without comorbid conditions: a diffusion tensor imaging study. AB - The frontal cortex might play an important role in the fear network, and white matter (WM) integrity could be related to the pathophysiology of panic disorder (PD). A few studies have investigated alterations of WM integrity in PD. The aim of this study was to determine frontal WM integrity differences between patients with PD without comorbid conditions and healthy control (HC) subjects by using diffusion tensor imaging. Thirty-six patients with PD who had used medication within 1 week and 27 age- and sex-matched HC subjects participated in this study. Structural brain magnetic resonance imaging was performed on all participants. Panic Disorder Severity Scale and Beck Anxiety Inventory (BAI) scores were assessed. Tract-based spatial statistics (TBSS) was used for image analysis. TBSS analysis showed decreased fractional anisotropy (FA) in frontal WM and WM around the frontal lobe, including the corpus callosum of both hemispheres, in patients with PD compared to HC subjects. Moreover, voxel-wise correlation analysis revealed that the BAI scores for patients with PD were positively correlated with their FA values for regions showing group differences in the FA of frontal WM of both hemispheres. Altered integrity in frontal WM of patients with PD without comorbid conditions might represent the structural pathophysiology in these patients, and these changes could be related to clinical symptoms of PD. PMID- 24788588 TI - One-step strategy for the synthesis of a derivatized cyclodextrin-based monolithic column. AB - Derivatized beta-cyclodextrin (beta-CD) functionalized monolithic columns were prepared by a "one-step" strategy using click chemistry. First, the intended derivatized beta-CD monomers were synthesized by a click reaction between propargyl methacrylate and mono-6-azido-beta-CD and then sulfonation or methylation was carried out. Finally, monolithic columns were prepared through a one-step in situ copolymerization of the derivatized beta-CD monomer and ethylene glycol dimethacrylate. The sulfated beta-CD-based monolith was successfully applied to the hydrophilic interaction liquid chromatography separation of nucleosides and small peptides, while the methylated beta-CD-functionalized monolith was useful for the separation of nonpolar compounds and drug enantiomers in capillary reversed-phase liquid chromatography. The structures of the monomers were characterized by Fourier transform infrared spectroscopy and mass spectrometry. The physicochemical properties and column performance of monoliths were evaluated by scanning electron microscopy and micro high performance liquid chromatography. This strategy has considerable prospects for the preparation of other derivatized CD-functionalized methacrylate monoliths. PMID- 24788589 TI - Effects of antenatal yoga on maternal anxiety and depression: a randomized controlled trial. AB - BACKGROUND: Antenatal depression and anxiety are associated with adverse obstetric and mental health outcomes, yet practicable nonpharmacological therapies, particularly for the latter, are lacking. Yoga incorporates relaxation and breathing techniques with postures that can be customized for pregnant women. This study tested the efficacy of yoga as an intervention for reducing maternal anxiety during pregnancy. METHODS: Fifty-nine primiparous, low-risk pregnant women completed questionnaires assessing state (State Trait Anxiety Inventory; STAI-State), trait (STAI-Trait), and pregnancy-specific anxiety (Wijma Delivery Expectancy Questionnaire; WDEQ) and depression (Edinburgh Postnatal Depression Scale; EPDS) before randomization (baseline) to either an 8-week course of antenatal yoga or treatment-as-usual (TAU); both groups repeated the questionnaires at follow-up. The yoga group also completed pre- and postsession state anxiety and stress hormone assessments at both the first and last session of the 8-week course. RESULTS: A single session of yoga reduced both subjective and physiological measures of state anxiety (STAI-S and cortisol); and this class induced reduction in anxiety remained at the final session of the intervention. Multiple linear regression analyses identified allocation to yoga as predictive of greater reduction in WDEQ scores (B = -9.59; BCa 95% CI = -18.25 to -0.43; P = .014; d = -0.57), while allocation to TAU was predictive of significantly increased elevation in EPDS scores (B = -3.06; BCa 95% CI = -5.9 to -0.17; P = .042; d = -0.5). No significant differences were observed in state or trait anxiety scores between baseline and follow-up. CONCLUSION: Antenatal yoga seems to be useful for reducing women's anxieties toward childbirth and preventing increases in depressive symptomatology. PMID- 24788590 TI - Clinicopathologic characteristics and prognostic significance of EGFR and p53 mutations in surgically resected lung adenocarcinomas <=2 cm in maximal dimension. AB - BACKGROUND AND OBJECTIVES: Small lung adenocarcinomas are detected more frequently than in the past. However, the clinicopathologic characteristics and prognostic significance of EGFR/p53 mutations in these tumors remains unclear. METHODS: We evaluated the correlation of EGFR/p53 mutations with clinicopathologic characteristics and tumor relapse in 172 surgically resected lung adenocarcinomas <=2 cm in maximal dimension. EGFR/p53 mutational analysis was performed on DNA extracted from paraffin-embedded tumors. RESULTS: EGFR and p53 mutations were identified in 104 (60.5%) and 36 (20.9%) small adenocarcinomas, respectively. EGFR/p53 mutations were associated with tumor size >1 cm, whereas p53 mutations were frequently observed in moderately differentiated tumors. Disease-free survival analysis showed that p53 mutation, presence of visceral pleural surface invasion, elevated preoperative serum carcinoembryonic antigen, and moderate histologic differentiation were significantly correlated with tumor relapse in patients with stage I disease. The 5-year survival rate was higher in relapsed patients with EGFR-mutated tumors who were treated with tyrosine kinase inhibitor (TKI) than in those who were not treated with TKI. CONCLUSIONS: p53 mutation was significantly correlated with tumor progression, and our findings may provide a rationale for the selective use of adjuvant chemotherapy in stage IB patients with p53 mutations. EGFR mutation was a predictor of EGFR TKI response in relapsed patients. PMID- 24788591 TI - Achieving professional success in US government, academia, and industry: an EMGS commentary. AB - One of the goals of the EMGS is to help members achieve professional success in the fields they have trained in. Today, there is greater competition for jobs in genetic toxicology, genomics, and basic research than ever before. In addition, job security and the ability to advance in one's career is challenging, regardless of whether one works in a regulatory, academic, or industry environment. At the EMGS Annual Meeting in Monterey, CA (September, 2013), the Women in EMGS Special Interest Group held a workshop to discuss strategies for achieving professional success. Presentations were given by three speakers, each representing a different employment environment: Government (Miriam C. Poirier), Academia (Jeffrey L. Schwartz), and Industry (Marilyn J. Aardema). Although some differences in factors or traits affecting success in the three employment sectors were noted by each of the speakers, common factors considered important for advancement included networking, seeking out mentors, and developing exceptional communication skills. PMID- 24788592 TI - MRI hemodynamic markers of progressive bicuspid aortic valve-related aortic disease. AB - PURPOSE: To determine the reproducibility of MRI aortic hemodynamic markers and to assess their relationship to aortic growth in a cohort of patients with bicuspid aortic valves (BAV). MATERIALS AND METHODS: Twenty-five patients previously studied with four-dimensional (4D) Flow imaging who had at least two separate cross-sectional imaging studies to assess for aortic growth were included: tricuspid aortic valve (TAV) controls without valvular disease (n = 12) and patients with BAV (n = 13). Flow data from the ascending aorta was used for calculation of peak velocity, normalized flow displacement, maximum wall shear stress (WSS), mean WSS, and minimal WSS. Pearson's correlation was used to evaluate interobserver agreement, and linear regression to evaluate the correlation between the different hemodynamic markers and growth. Patient informed consent was waived by the institutional review board that approved the study. RESULTS: Peak velocity and flow displacement were very reproducible (r = 0.90-1.0 and r = 0.91-0.98, respectively). The range of WSS parameters was largely reproducible (0.47 < r < 0.96) with the greatest variability at the data extraction stage of analysis (0.47 < r < 0.85). Flow displacement best correlated with interval aortic growth (r = 0.65), peak velocity was moderately correlated (r = 0.35), but the WSS parameters did not correlate well with growth (r < 0.17). CONCLUSION: Flow displacement is a simple and reproducible hemodynamic marker that shows good correlation with aortic growth in patients with bicuspid aortic valves. PMID- 24788593 TI - Evaluation of non-extracted genital swabs for real-time HSV PCR. AB - Nucleic acid extraction of clinical samples is accepted as a key requirement in molecular diagnostics. At Barts Health NHS Trust, swabs taken from patients with clinical suspicion of HSV infection were routinely extracted on the Qiagen MDx BioRobot prior to testing with a real-time triplex PCR for HSV1, HSV2, and VZV. The aim of this study was to adapt an existing HSV1/HSV2/VZV real-time PCR by replacing VZV with phocine herpesvirus 1 (PhHV) as an internal control (IC) and evaluate whether this adapted assay required the nucleic acid extraction step for predominantly genital swabs. First 313 non-extracted and extracted swabs were tested in parallel with the existing triplex HSV1/HSV2/VZV real-time PCR. The second stage involved testing 176 non-extracted swabs using a triplex real-time PCR for HSV1, HSV2, and PhHV and comparing the results with the samples extracted and tested by the original triplex assay. The results correlated well when the existing assay was used, with only three non-extracted samples that would have been reported as negative compared to the extracted sample result (Cq s 33, 39, 35-two samples HSV1, one sample HSV2). In the evaluation using the adapted assay containing the IC, two of 176 samples were discordant, where a HSV negative non extracted sample result would have been reported differently to the extracted sample result (Cq s 32, 33-both HSV1). This study demonstrated that it is feasible to test non-extracted swabs for HSV in a real-time PCR that includes an IC. J. Med. Virol. 87: 125-129, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 24788596 TI - Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines. AB - Metformin is an oral anti-hyperglycemic agent of the biguanide family, which is used first-line for type II diabetes with few side-effects. A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients showed that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients, demonstrating the potential value of metformin in ICC management. In the present study, we firstly showed that metformin exhibited a dose- and time-dependent anti proliferation effect on ICC cell lines, by mechanisms including apoptosis induction and cell cycle arrest. Metformin targeted the AMPK/mTORC1 pathway in ICC cells. Furthermore, metformin sensitized ICC cells to certain chemotherapeutic agents, such as sorafenib, 5-fluorouracil and As2O3 by targeting the AMPK/mTOR/HIF-1alpha/MRP1 pathway and ERK. As it is an inexpensive and widely used antidiabetic drug without severe adverse effects, metformin may be a prospective chemotherapeutic agent or a chemosensitizer in future ICC treatment. PMID- 24788597 TI - In situ back-side illumination fluorescence XAFS (BI-FXAFS) studies on platinum nanoparticles deposited on a HOPG surface as a model fuel cell: a new approach to the Pt-HOPG electrode/electrolyte interface. AB - We measured the in situ polarization-dependent X-ray absorption fine structure of platinum nanoparticles (PtNPs) deposited on a flat highly oriented pyrolytic graphite (HOPG) substrate under electrochemical conditions using a back-side illumination method. In this method, the thin HOPG substrate with PtNPs deposited on one side was used as a window for incident and fluorescent X-rays, as well as an electrode. A bent crystal Laue analyzer (BCLA) was applied to the extraction of the Pt Lalpha fluorescent X-ray signals from strong scattered X-rays. Pt L3 edge XAFS spectra were observed for various electrode potentials and polarization directions. PMID- 24788598 TI - Secondary triage in prehospital emergency ambulance services: a systematic review. AB - OBJECTIVE: Secondary telephone triage to divert low-acuity patients to alternative non-ambulance services before ambulance arrival has been trialled in the UK and USA as a management strategy to cope with the increase in ambulance demand. The objective of this systematic review was to examine the literature on the structure, safety and success of secondary triage systems. METHODS: For inclusion in the study, the telephone triage system had to be a secondary process, receiving referred patients who had already been categorised as low priority by a primary triage process. Two independent reviewers conducted the search to identify relevant studies. Six articles and one report were identified. RESULTS: The major theme of the papers was the safety and accuracy of secondary telephone triage in identifying low-acuity patients. Two studies also discussed patient satisfaction. There was a low incidence of adverse events, as expected as these patients had already been subjected to primary telephone triage. In the studies identifying ambulance dispatch as a potential final disposition, at least half of the patients were diverted away from ambulance dispatch. In the studies that identified self/home care as a final disposition, a maximum of 31% of patients were categorised to this outcome. Otherwise all patients were recommended for assessment by a healthcare professional other than ambulance clinicians. Patients appeared to be satisfied with secondary telephone triage on follow-up. CONCLUSIONS: These results suggest that, while secondary triage of these patients is safe, further research is required to determine its most appropriate structure and its effect on ambulance demand. PMID- 24788599 TI - A survey of college-bound high school graduates regarding circadian preference, caffeine use, and academic performance. AB - BACKGROUND: This study examines the relationships between circadian preference and caffeine use with academic performance and hours spent studying for recent high school graduates entering their first year of college. METHOD: Entering first-year college students enrolled at 90 baccalaureate-level institutions across the USA were invited to complete the Beginning College Survey of Student Engagement (BCSSE) and the Composite Scale of Morningness (CSM) as well as answer questions regarding caffeine consumption. Surveys were administered on each campus during the summer months of 2013. Only those that graduated from a US high school in the spring of 2013 were included in this study. The final sample for this study included 25,200 students that completed the BCSSE, CSM, and questions regarding caffeine consumption. RESULTS: Evening types (E-types) were significantly less likely to report earning A/A-'s in high school and less likely to study 16 or more hours per week compared to intermediate or morning types (M types) (p < 0.05). Overall, entering first-year students reported an average of 1.1 servings of caffeine per day, with 39 % reporting no caffeine consumption. M types were more likely to consume no caffeine (54 %) compared to E-types that also indicated no daily caffeine (31 %) (p < 0.05). However, E-types were approximately 2.5 times more likely to consume three or more daily servings of caffeine (18 %) compared to M-types that consume the same amount (7 %) (p < 0.05). M-types that consumed no caffeine reported the highest grades with nearly 64 % reporting they earned mostly A's or A-'s in high school. However, the apparent advantage that morning types had over evening types regarding high school grades was completely ameliorated once three or more servings of caffeine were consumed per day. CONCLUSIONS: This study provides additional information to educators and health professionals to create programs and provide resource to help adolescents better understand the impact of their sleep behaviors and use of caffeine on their academic performance. PMID- 24788600 TI - A nasal epithelial receptor for Staphylococcus aureus WTA governs adhesion to epithelial cells and modulates nasal colonization. AB - Nasal colonization is a major risk factor for S. aureus infections. The mechanisms responsible for colonization are still not well understood and involve several factors on the host and the bacterial side. One key factor is the cell wall teichoic acid (WTA) of S. aureus, which governs direct interactions with nasal epithelial surfaces. We report here the first receptor for the cell wall glycopolymer WTA on nasal epithelial cells. In several assay systems this type F scavenger receptor, termed SREC-I, bound WTA in a charge dependent manner and mediated adhesion to nasal epithelial cells in vitro. The impact of WTA and SREC I interaction on epithelial adhesion was especially pronounced under shear stress, which resembles the conditions found in the nasal cavity. Most importantly, we demonstrate here a key role of the WTA-receptor interaction in a cotton rat model of nasal colonization. When we inhibited WTA mediated adhesion with a SREC-I antibody, nasal colonization in the animal model was strongly reduced at the early onset of colonization. More importantly, colonization stayed low over an extended period of 6 days. Therefore we propose targeting of this glycopolymer-receptor interaction as a novel strategy to prevent or control S. aureus nasal colonization. PMID- 24788601 TI - Potential role of IL-17-producing iNKT cells in type 1 diabetes. AB - We explored in this study the status and potential role of IL-17-producing iNKT cells (iNKT17) in type 1 diabetes (T1D) by analyzing these cells in patients with T1D, and in NOD mice, a mouse model for T1D. Our analysis in mice showed an increase of iNKT17 cells in NOD vs control C57BL/6 mice, partly due to a better survival of these cells in the periphery. We also found a higher frequency of these cells in autoimmune-targeted organs with the occurrence of diabetes, suggesting their implication in the disease development. In humans, though absent in fresh PMBCs, iNKT17 cells are detected in vitro with a higher frequency in T1D patients compared to control subjects in the presence of the proinflammatory cytokine IL-1beta, known to contribute to diabetes occurrence. These IL-1beta stimulated iNKT cells from T1D patients keep their potential to produce IFN gamma, a cytokine that drives islet beta-cell destruction, but not IL-4, with a reverse picture observed in healthy volunteers. On the whole, our results argue in favour of a potential role of IL-17-producing iNKT cells in T1D and suggest that inflammation in T1D patients could induce a Th1/Th17 cytokine secretion profile in iNKT cells promoting disease development. PMID- 24788602 TI - Improving the power of GWAS and avoiding confounding from population stratification with PC-Select. AB - Using a reduced subset of SNPs in a linear mixed model can improve power for genome-wide association studies, yet this can result in insufficient correction for population stratification. We propose a hybrid approach using principal components that does not inflate statistics in the presence of population stratification and improves power over standard linear mixed models. PMID- 24788604 TI - [Cross-linking and neurodermitis: prolonged re-epithelisation with severe corneal vascularisation after cross-linking in a patient with neurodermitis and keratoconus]. AB - This case report describes a patient with keratoconus and neurodermitis suffering from a significantly prolonged postoperative time interval to re-epithelisation after corneal cross-linking. The development of corneal calcifications and vascularisations additionally inhibited proper re-epithelisation. Therefore the patient received four subsequent subconjunctival injections of Bevacizumab and an additional keratectomy to remove the calcifications. This therapeutic scheme led to a significant reduction of corneal vascularisation and finally a full rehabilitation of the epithelium. PMID- 24788603 TI - Gene-flow in a mosaic hybrid zone: is local introgression adaptive? AB - Genome-wide scans of genetic differentiation between hybridizing taxa can identify genome regions with unusual rates of introgression. Regions of high differentiation might represent barriers to gene flow, while regions of low differentiation might indicate adaptive introgression-the spread of selectively beneficial alleles between reproductively isolated genetic backgrounds. Here we conduct a scan for unusual patterns of differentiation in a mosaic hybrid zone between two mussel species, Mytilus edulis and M. galloprovincialis. One outlying locus, mac-1, showed a characteristic footprint of local introgression, with abnormally high frequency of edulis-derived alleles in a patch of M. galloprovincialis enclosed within the mosaic zone, but low frequencies outside of the zone. Further analysis of DNA sequences showed that almost all of the edulis allelic diversity had introgressed into the M. galloprovincialis background in this patch. We then used a variety of approaches to test the hypothesis that there had been adaptive introgression at mac-1. Simulations and model fitting with maximum-likelihood and approximate Bayesian computation approaches suggested that adaptive introgression could generate a "soft sweep," which was qualitatively consistent with our data. Although the migration rate required was high, it was compatible with the functioning of an effective barrier to gene flow as revealed by demographic inferences. As such, adaptive introgression could explain both the reduced intraspecific differentiation around mac-1 and the high diversity of introgressed alleles, although a localized change in barrier strength may also be invoked. Together, our results emphasize the need to account for the complex history of secondary contacts in interpreting outlier loci. PMID- 24788605 TI - [Entropion: objective and subjective evaluation of two different surgical procedures]. AB - BACKGROUND: The aim of this study was to compare two different surgical techniques for the therapy of senile entropion. PATIENTS AND METHODS: Our retrospective case series study included patients who were operated on for a senile entropion, either according to the technique described by Quickert or by surgery of the lateral tarsal strip in combination with resection of a part of the hypertrophic orbicularis muscle. All patients who had undergone entropion surgery according to one of the two procedures between 2008 and 2010 were contacted. Main outcome measures were patients' satisfaction and recurrence of entropion. RESULTS: The study included 38 patients (age: 75.5 +/- 7.7 years) who could be contacted and who were able to perform a telephone interview; 13 of these patients were additionally examined clinically. Mean follow-up after surgery was 43.1 +/- 5.6 months. 83 % were happy to do the operation again. There was no statistical difference in patients' satisfaction with the operations. The clinical examination showed two recurrences of entropion in the Quickert group and none in the lateral tarsal strip group. CONCLUSIONS: Quickert's operation and the lateral tarsal strip procedure in combination with resection of a part of the hypertrophic orbicularis muscle are efficient procedures for therapy of an entropion. PMID- 24788606 TI - [Initial clinical experience in the treatment of vitreomacular traction and macular holes with ocriplasmin]. AB - BACKGROUND: The introduction and approval of Ocriplasmin as an intravitreally applicable drug in the pharmocological treatment of vitreomacular traction represents a new therapeutic approach possibly avoiding vitreoretinal surgery. With our article we report our first experience wih Ocriplasmin in clinical practice. METHODS: The indication for intravitreal therapy with Ocriplasmin was provided for symptomatic VMT or macular hole with VMT in 20 patients since March 2013. Surgery was planned in cases with remaining symptoms. Before IVI we performed SD-OCT. Best visual acuity (BCVA) was evaluated preoperatively, 7 and 28 days after treatment and finally every month in 14 treated eyes. SD-OCT images were analysed before treatment and later on with every follow-up examination. In addition to functional and morphological changes we analysed all side effects. RESULTS: The mean BCVA at the beginning of treatment was 0.3 and 0.4 before injection. The indications for treatment were as follows: symptomatic VMT in 10 patients and 4 patients suffering from full thickness macular hole stage 2. In 3 patients spontaneous regression of VMT could be observed with increasing of vision from 0.3 to 0.5. In one patient his macular hole was closed and BCVA increased from 0.2 to 0.6 within 7 days. Two patients showed significant enlargement of their macular holes after 7 days and finally underwent surgery. A massive cystoid macular oedema occurred in one patient. No change in the SD-OCT image could be observed 28 days after treatment. The mean visual acuity improved to 0.6 during a follow-up period of 90 days. Photopsia and disturbing vitreous opacities up to 28 days post injection could be regarded as minor side effects. CONCLUSION: Our first clinical experience with intravitreous injection of Ocriplasmin were performed to confirm the presumed therapeutic effect in patients suffering from VMT. Small macular holes could frequently be closed. The possibility of special side effects must be taken in consideration just as the possibility of spanteous improvement before performing IVI with Ocriplasmin. Further prospective studies must be recommended to be right about Ocriplasmin injections. PMID- 24788607 TI - Frontal sinus and naso-orbital-ethmoid fractures. AB - IMPORTANCE: Frontal sinus and naso-orbital-ethmoid (NOE) fractures are among the most challenging injuries in the treatment of maxillofacial trauma. OBJECTIVE: To summarize the current knowledge regarding frontal sinus and NOE fractures and to present some of the more recent, evidence-based literature to support current treatment recommendations. EVIDENCE REVIEW: A PubMed search of articles from 1990 through 2013 was performed. Search terms included frontal sinus fracture, NOE fracture, naso-orbito-ethmoid fracture, naso-ethmoid-orbital fracture, and nasoethmoid fracture. FINDINGS: Advances in sophisticated imaging and evolution in minimally invasive surgical techniques are introducing more conservative options that may provide better patient outcomes while minimizing the risks and morbidity associated with more traditional treatment approaches. CONCLUSIONS AND RELEVANCE: The treatment of frontal sinus and NOE fractures is challenging, given the complex anatomy and associated pattern of injuries. Traditional treatment paradigms are evolving and support the role of more conservative treatment algorithms in selected patients. PMID- 24788614 TI - Spiritual Needs of Polish Patients with Chronic Diseases. AB - In a cross-sectional survey using standardized questionnaires such as the Spiritual Needs Questionnaire (SpNQ), we analyze unmet spiritual needs of 275 patients with chronic diseases from Catholic Poland. The factorial structure of SpNQ's Polish version is similar to the primary version and has good internal consistency (Cronbach's alpha = 0.89). Here, not only Inner Peace needs and Giving/Generativity needs were of relevance, but also Religious Needs and Existential Needs. These needs were not significantly associated with life satisfaction, but with interpretations of illness. To address such unmet needs, multi-professional teams should care for patients' multifaceted needs. PMID- 24788615 TI - The Role of Religion in the Recovery from Alcohol and Substance Abuse Among Jordanian Adults. AB - The purpose of this study is to understand religious factors role during recovery period among Jordanian receiving treatment for alcohol and substances abuse. Participants were asked to answer open-ended questions related to role of religion on their recovery from alcohol and substances abuse. Content analysis was used to explore the role of religion on their recovery process. One hundred and forty-six clients from two treatment centers participated with two main themes that emerged from the analysis: role of religion and role of religious men. Religion not only helps during the recovery process, but also is considered as a protector from drug and alcohol abuse in the future. PMID- 24788613 TI - First line treatment response in patients with transmitted HIV drug resistance and well defined time point of HIV infection: updated results from the German HIV 1 seroconverter study. AB - BACKGROUND: Transmission of drug-resistant HIV-1 (TDR) can impair the virologic response to antiretroviral combination therapy. Aim of the study was to assess the impact of TDR on treatment success of resistance test-guided first-line therapy in the German HIV-1 Seroconverter Cohort for patients infected with HIV between 1996 and 2010. An update of the prevalence of TDR and trend over time was performed. METHODS: Data of 1,667 HIV-infected individuals who seroconverted between 1996 and 2010 were analysed. The WHO drug resistance mutations list was used to identify resistance-associated HIV mutations in drug-naive patients for epidemiological analysis. For treatment success analysis the Stanford algorithm was used to classify a subset of 323 drug-naive genotyped patients who received a first-line cART into three resistance groups: patients without TDR, patients with TDR and fully active cART and patients with TDR and non-fully active cART. The frequency of virologic failure 5 to 12 months after treatment initiation was determined. RESULTS: Prevalence of TDR was stable at a high mean level of 11.9% (198/1,667) in the HIV-1 Seroconverter Cohort without significant trend over time. Nucleotide reverse transcriptase inhibitor resistance was predominant (6.0%) and decreased significantly over time (OR = 0.92, CI = 0.87-0.98, p = 0.01). Non-nucleoside reverse transcriptase inhibitor (2.4%; OR = 1.00, CI = 0.92 1.09, p = 0.96) and protease inhibitor resistance (2.0%; OR = 0.94, CI = 0.861.03, p = 0.17) remained stable. Virologic failure was observed in 6.5% of patients with TDR receiving fully active cART, 5,6% of patients with TDR receiving non-fully active cART and 3.2% of patients without TDR. The difference between the three groups was not significant (p = 0.41). CONCLUSION: Overall prevalence of TDR remained stable at a rather high level. No significant differences in the frequency of virologic failure were identified during first line cART between patients with TDR and fully-active cART, patients with TDR and non-fully active cART and patients without TDR. PMID- 24788616 TI - Effect of Religion on End-of-Life Care Among Trauma Patients. AB - Evidence suggests that religiousness is associated with more aggressive end-of life (EOL) care among terminally ill patients. The effect of religion on care in more acutely life-threatening diseases is not well studied. This study examines the association of religious affiliation and request for chaplain visit with aggressive EOL care among critically injured trauma patients. We conducted a retrospective review of all trauma patients surviving at least 2 days but dying within 30 days of injury over a 3-year period at a major academic trauma center. Time until death was used as a proxy for intensity of life-prolonging therapy. Controlling for social factors, severity of injury, and medical comorbidities, religious affiliation was associated with a 43 % increase in days until death. Controlling for these same variables, chaplain request was associated with a 24 % decrease in time until death. These results suggest that religious patients receive more aggressive, and ultimately futile, EOL care and that pastoral care may reduce the amount of futile care consumed. PMID- 24788618 TI - Expanded genetic codes in next generation sequencing enable decontamination and mitochondrial enrichment. AB - We have developed a PCR method, coined Deja vu PCR, that utilizes six nucleotides in PCR with two methyl specific restriction enzymes that respectively digest these additional nucleotides. Use of this enzyme-and-nucleotide combination enables what we term a "DNA diode", where DNA can advance in a laboratory in only one direction and cannot feedback into upstream assays. Here we describe aspects of this method that enable consecutive amplification with the introduction of a 5th and 6th base while simultaneously providing methylation dependent mitochondrial DNA enrichment. These additional nucleotides enable a novel DNA decontamination technique that generates ephemeral and easy to decontaminate DNA. PMID- 24788619 TI - Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial. AB - OBJECTIVES: To compare 1-year clinical efficacy of (1) initial triple disease modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis. METHODS: In a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression. RESULTS: 281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively -2.39 (95% CI -4.77 to -0.00) and -1.67 (95% CI -3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications. The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time. No differences were seen between the two GC bridging therapies. Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year. Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM. CONCLUSIONS: Treatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM. However, no difference in radiographic progression is seen. Both GC bridging therapies are equally effective and, therefore, both can be used. TRIAL REGISTRATION NUMBER: ISRCTN26791028. PMID- 24788627 TI - Depletion of RhoGDI2 expression inhibits the ability of invasion and migration in pancreatic carcinoma. AB - Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of tumor metastasis, although its role in tumor progression remains controversial. In this study, we examined the expression of RhoGDI2 in PC tissues and cell lines. To investigate the function of RhoGDI2 in PC cells, RhoGDI2 expression was depleted in PANC-1 and Patu8988 cells by small interfering RNA (siRNA). RhoGDI2 was found to be overexpressed in pancreatic carcinoma (PC) tissues and PC cell lines. Additionally, the results showed that depletion of RhoGDI2 significantly inhibited cell motility and invasion in vitro, but did not affect cell proliferation. The clinical study together with the experimental data confirmed that RhoGDI2 modulated the expression of matrix metalloproteinase 2 (MMP2). Taken together, findings of the present study indicated that RhoGDI2 is involved in pancreatic tumor malignancy and metastasis. Thus, RhoGDI2 is a potential target for the gene therapy of PC. PMID- 24788626 TI - Protective effect of DNA vaccine encoding pseudomonas exotoxin A and PcrV against acute pulmonary P. aeruginosa Infection. AB - Infections with Pseudomonas aeruginosa have been a long-standing challenge for clinical therapy because of complex pathogenesis and resistance to antibiotics, thus attaching importance to explore effective vaccines for prevention and treatment. In the present study, we constructed a novel DNA vaccine by inserting mutated gene toxAm encoding Pseudomonas Exotoxin A and gene pcrV encoding tip protein of the type III secretion system into respective sites of a eukaryotic plasmid pIRES, named pIRES-toxAm-pcrV, and next evaluated the efficacy of the vaccine in murine acute Pseudomonas pneumonia models. Compared to DNA vaccines encoding single antigen, mice vaccinated with pIRES-toxAm-pcrV elicited higher levels of antigen-specific serum immunoglobulin G (IgG), enhanced splenic cell proliferation and cytokine secretion in response to Pseudomonas aeruginosa antigens, additionally PAO1 challenge in mice airway resulted in reduced bacteria burden and milder pathologic changes in lungs. Besides, it was observed that immunogenicity and protection could be promoted by the CpG ODN 1826 adjuvant. Taken together, it's revealed that recombinant DNA vaccine pIRES-toxAm-pcrV was a potential candidate for immunotherapy of Pseudomonas aeruginosa infection and the CpG ODN 1826 a potent stimulatory adjuvant for DNA vaccination. PMID- 24788628 TI - Medial opening wedge distal femoral osteotomy for post-traumatic secondary knee osteoarthritis. AB - Osteoarthritis of the knee secondary to femoral fracture is difficult to treat. There are some surgical options, such as total knee arthroplasty or correction osteotomy. Opening wedge high tibial osteotomy is an established treatment of gonarthrosis. However, few reports are available on the effectiveness of a medial opening wedge distal femoral osteotomy. We present a case of a medial opening wedge distal femoral osteotomy on gonarthrosis secondary to a malunited femoral fracture with varus deformity and leg length discrepancy. This osteotomy was performed at the deformed femur, with locking plate fixation and autologous bone graft. Six months after the surgery, the osteotomy site was filled with bridging callus. Two years later, the Knee Society Score improved from 45 to 90 points. Medial opening wedge distal femoral osteotomy can be a useful method to treat knee osteoarthritis associated with distal femoral deformity. PMID- 24788629 TI - Chemical injury caused by acute alendronic acid aspiration. AB - A 79-year-old woman was prescribed bisphosphonates 3 years ago for osteoporosis. At the time of first prescription, she received counselling directions on how to take her medication, which she stringently adhered to. However, she accidentally aspirated an alendronic acid tablet and subsequently developed respiratory tract symptoms. An emergency bronchoscopy was performed. We describe the marked bronchoscopic changes following aspiration of alendronic acid. PMID- 24788630 TI - Renal cell carcinoma needle biopsy: sowing the seed for later complications? AB - Pathological examination of a radical nephrectomy for papillary renal cell carcinoma showed tumour present within the perinephric fat, with a morphology indicative of iatrogenic tumour cell tracking caused by previous biopsy of the mass. This is a rare complication of percutaneous biopsy, and as this procedure is becoming more common in investigating renal masses, it is important that the professionals are aware of the potential risks posed by renal mass biopsy. PMID- 24788631 TI - Non-operative management of a grade IV pancreatic injury. AB - Isolated pancreatic transection with ductal disruption in blunt abdominal trauma is extremely rare. We report the case of a 14-year-old boy who suffered pancreatic transection at the junction of body and head of the pancreas; yet remarkably recovered after initial conservative management. He was periodically examined clinically and underwent regular abdominal ultrasonography. Nearly 6 months later, endoscopic retrograde cholangiopancreatography with pancreatic duct stenting, pancreatic sphincterotomy and cystogastrostomy for the pseudocyst diagnosed during the follow-up period was performed. Acute surgical management of pancreatic transection is fraught with high mortality and morbidity. Through this effort, we highlight the successful role of non-operative management of a haemodynamically stable patient with grade IV pancreatic injury, thereby avoiding radical surgery in the acute stage and preserving exocrine and endocrine function. PMID- 24788632 TI - An idiopathic congenital chylothorax: surgery or conservative management? AB - A 3-month-old infant was admitted to the respiratory unit for dyspnoea and vomiting after her second DTaP-Polio vaccine shot. The chest X-rays showed a white right lung with a left mediastinal shift. A pleural aspiration assessed the diagnosis of chylothorax. A conservative treatment was initiated with a fat-free diet and pleural aspirations. As this treatment was ineffective, a total parenteral nutrition was started at day 11, plus increasing doses of Octreotide. As the chylothorax persisted at day 50, a pleuroperitoneal shunting was performed but a pleurodesis was finally necessary. The child was discharged from the hospital 6 weeks after the surgery. Ten months later, her physical and biological conditions were normal and her chest X-rays dramatically improved. This case highlights the difficult management of infant chylothorax. Although conservative treatment has to be tried first, surgical procedures as pleuroperitoneal shunting and rarely pleurodesis have to be discussed. PMID- 24788633 TI - Spectrum of left atrial thrombus in rheumatic heart disease. PMID- 24788634 TI - Isolated and severe left main coronary stenosis in the young: a rare angiographic entity. PMID- 24788635 TI - Down-regulation of CD9 by methylation decreased bortezomib sensitivity in multiple myeloma. AB - Bortezomib therapy has been proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM). However, both intrinsic and acquired resistance has already been observed. In this study, we explored the relationship between CD9 expression and bortezomib sensitivity in MM. We found that down regulation of CD9 by methylation decreased bortezomib sensitivity in multiple myeloma. CD9 expression obviously increased bortezomib sensitivity through inducing apoptosis, significantly inhibiting U266 cells' adhesion to HS-5 and primary bone marrow stromal cells, but increasing U266 cells' adhesion to fibronectin. CD9 expression also significantly inhibited U266 cell migration. The mechanisms may include: the endoplasmic reticulum stress pathway, cell adhesion related signaling pathway and osteoclast differentiation related signaling pathway. Combination therapy with de-methylation reagent 5-Aza-2-deoxycytidine may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients. PMID- 24788636 TI - Robust data driven model order estimation for independent component analysis of FMRI data with low contrast to noise. AB - Independent component analysis (ICA) has been successfully utilized for analysis of functional MRI (fMRI) data for task related as well as resting state studies. Although it holds the promise of becoming an unbiased data-driven analysis technique, a few choices have to be made prior to performing ICA, selection of a method for determining the number of independent components (nIC) being one of them. Choice of nIC has been shown to influence the ICA maps, and various approaches (mostly relying on information theoretic criteria) have been proposed and implemented in commonly used ICA analysis packages, such as MELODIC and GIFT. However, there has been no consensus on the optimal method for nIC selection, and many studies utilize arbitrarily chosen values for nIC. Accurate and reliable determination of true nIC is especially important in the setting where the signals of interest contribute only a small fraction of the total variance, i.e. very low contrast-to-noise ratio (CNR), and/or very focal response. In this study, we evaluate the performance of different model order selection criteria and demonstrate that the model order selected based upon bootstrap stability of principal components yields more reliable and accurate estimates of model order. We then demonstrate the utility of this fully data-driven approach to detect weak and focal stimulus-driven responses in real data. Finally, we compare the performance of different multi-run ICA approaches using pseudo-real data. PMID- 24788637 TI - Using our knowledge of typical language development. AB - PURPOSE: In this column, the editor introduces the articles in the April issue of LSHSS (Volume 45, Issue 2). All are part of a Clinical Forum, with a thought provoking lead article by Alan Kamhi and several response articles by Kamhi's colleagues. In this introduction to the April issue, Marilyn A. Nippold summarizes Kamhi's main points, directs readers to the various perspectives presented by authors of the other articles in this Clinical Forum, and speaks to the importance of the ideas presented-and their potential relevance to clinicians. Nippold reminds readers that this Clinical Forum provides a stimulating platform for discussion and debate among clinicians and researchers. PMID- 24788638 TI - Prologue: improving clinical practice from the inside out. AB - PURPOSE: This prologue introduces a clinical forum entitled "Reflections on Improving Clinical Practice" and orients the reader to the scope of articles included within it. METHOD: The purpose of the clinical forum is described, its lead article is introduced, and brief summaries of the 7 response articles are provided. CONCLUSIONS: The commentaries in this clinical forum draw on scientific evidence and assert that current intervention services for children and adolescents who have language and learning disorders could be improved. Authors describe rationales for doing so and provide practical suggestions that could promote better intervention outcomes. PMID- 24788639 TI - Improving clinical practices for children with language and learning disorders. AB - PURPOSE: This lead article of the Clinical Forum addresses some of the gaps that exist between clinical practice and current knowledge about instructional factors that influence learning and language development. METHOD: Topics reviewed and discussed include principles of learning, generalization, treatment intensity, processing interventions, components of language therapy, grammar goals, and goal prioritization for students with language and learning difficulties. CONCLUSION: The gaps that exist between current knowledge about learning, language development, and clinical practice often do not receive as much attention as the gaps in the evidence base that addresses the efficacy and effectiveness of language intervention practices and service delivery models. Fortunately, clinicians do not have to wait for future intervention studies to apply their knowledge of learning and language development to clinical practices. PMID- 24788640 TI - Clinical scientists improving clinical practices: in thoughts and actions. AB - PURPOSE: In this article, the author comments on aspects of Kamhi's (2014) article, which caused the author to think more deeply about definitions of language, theories of learning, and how these two core components of intervention prepare clinical scientists as they search the literature for new knowledge. Interprofessional collaborative practice as a model for team-based intervention in school settings is also discussed. METHOD: The article addresses aspects of Kamhi's article that aligned or did not align with the author's definition of language and theory of learning and explains why considering these alignments is important for clinical scientists. Two challenges to staying current with the research base are also described, and suggestions are offered for addressing these challenges. Finally, the article provides an overview of interprofessional collaborative practice. CONCLUSION: Clinical scientists should continue to strive to use their knowledge of what language is and how it is learned, combined with the best available scientific information, to best serve their clients. Combining their thoughts and actions, they undoubtedly will continuously improve their clinical practices. PMID- 24788641 TI - Approaching early grammatical intervention from a sentence-focused framework. AB - PURPOSE: In this response to Kamhi (2014), a sentence-focused framework is presented to help clinicians select treatment targets as part of a comprehensive approach to early grammatical intervention. METHOD: The literature on the relationship between lexical verbs, sentence structure, and tense/agreement morphemes is reviewed, and developmental expectations are summarized for each. CONCLUSION: Given that the sentence is the basic unit of grammar, the author concludes that early grammatical intervention should promote sentence development for young children at risk for language disorders. Recommendations for selecting and facilitating grammatical objectives in early childhood are provided. PMID- 24788642 TI - What works in therapy: further thoughts on improving clinical practice for children with language disorders. AB - PURPOSE: In this response to Kamhi (2014), the author reviewed research about what does and does not help children with language impairment (LI) to learn grammatical features and considered how that research might inform clinical practice. METHOD: The author reviewed studies about therapy dose (the number of learning episodes per session) and dose frequency (how learning episodes are spaced over time) and also reviewed studies about dose form, including input characteristics and therapy strategies. CONCLUSION: Although the research is limited, it offers implications for how clinicians do therapy. Children with LI need many learning episodes clustered together within sessions but spread out over time across sessions. Input must be grammatical and consistent while providing varied exemplars of the target features. Learning episodes should actively engage children in producing utterances with the target form, but only after they have had the chance to hear some utterances with that feature. The author suggests a session plan that starts with a structured activity and then incorporates the target form into an embedded activity such as storytelling. PMID- 24788643 TI - Improving clinical practice: a school-age and school-based perspective. AB - PURPOSE: In this article, the author presents a conceptual framework for intervention at school-age levels reflecting upon a number of aspects raised by Kamhi (2014) in the lead article of this forum. The focus is on the persistence of traditional practices, components of language intervention, and prioritizing goals for students with language learning difficulties. Weaving together learning and generalization challenges, the author considers advanced levels of language that move beyond preschool and early elementary grade goals and objectives with a focus on comprehension and meta-abilities. METHOD: Using a 3-tiered macrostructure, the author demonstrates how integrating students' background knowledge into intervention, helping them develop an awareness of structure and content interactions, and addressing the increasing demands of the curriculum provide a roadmap for improving clinical practices at school-age levels. CONCLUSION: Reiterating some of Kamhi's notions, the author addresses gaps that exist between available and, often, exciting research in language, literacy, and current practices in schools. Professionals are challenged by the persistence of approaches and techniques that defy what they know about children and adolescents with language learning disabilities. Nonetheless, there are reasons to remain optimistic about the future. PMID- 24788644 TI - Improving clinical services: be aware of fuzzy connections between principles and strategies. AB - PURPOSE: This article is a response to Alan Kamhi's treatise on improving clinical practices for children with language and learning disorders by focusing on what is known about learning (see Kamhi, 2014, article in this issue). METHOD: Descriptive methods are used to discuss general learning principles and the fact that they do not always translate readily into effective language intervention practices. The authors give examples of 2 instances in which popular intervention strategies should have worked but did not. The authors also summarize what they learned about their own approach to contextualized language intervention for teaching priority goals related to narration and the Common Core State Standards (CCSS; National Governors Association Center for Best Practices, & Council of Chief State School Officers, 2010). CONCLUSION: Even theoretically sound, well intentioned, and carefully implemented interventions can result in equivocal outcomes. When they do, careful attention to the evidence and willingness to rethink strategy often serves to right the course. PMID- 24788645 TI - One size does not fit all: improving clinical practice in older children and adolescents with language and learning disorders. AB - PURPOSE: In the lead article for this clinical forum, Kamhi (2014) suggests ways that current knowledge on instructional practices in learning and language can be applied to clinical practice in language disorders. I propose that Kamhi's suggestions are in need of fine-tuning for older children and adolescents with language disorders. A one-size-fits-all approach to language intervention across a broad age range is untenable due to unique needs and capabilities of this older population. METHOD: Three intervention goal priorities for older students are presented with supporting research: complex (multiclausal) sentences, verb structure, and expository text. Methodologies for teaching complex sentences are discussed next, including topics of content/form balance and treatment intensity. These goals and methods are designed to assist students with language disorders in the comprehension and production of complex language they encounter in school. CONCLUSION: Guidance for high-priority language intervention goals with older students comes from a consideration of language needs in academic settings and language weaknesses that persist in this population. Although current research offers support for these goals, less is known about methodological variables such as treatment intensity. PMID- 24788646 TI - Language intervention at the middle school: complex talk reflects complex thought. AB - PURPOSE: In this article, the author discusses 2 points raised by Kamhi (2014) in his lead article to this clinical forum: (a) the need for speech-language pathologists to consider typical language development as they plan intervention and (b) the importance of addressing complex syntax. METHOD: A hypothetical scenario of a 7th grade English class assignment is presented, and aspects of the assignment that would be quite challenging to middle school adolescents with language impairments are highlighted. The author then describes strategies that a speech-language pathologist could use to enhance students' success with the assignment. This approach emphasizes the importance of collaborating with the classroom teacher and reading specialist, having knowledge of the Common Core State Standards and the language demands of the classroom, and understanding later language development and the reasons why speakers and writers use complex syntax. CONCLUSION: When language intervention incorporates these points, adolescents with language impairments can acquire skills that will help them make meaningful progress in the classroom. PMID- 24788647 TI - Characteristics of bone turnover in the long bone metaphysis fractured patients with normal or low Bone Mineral Density (BMD). AB - The incidence of osteoporotic fractures increases as our population ages. Until now, the exact biochemical processes that occur during the healing of metaphyseal fractures remain unclear. Diagnostic instruments that allow a dynamic insight into the fracture healing process are as yet unavailable. In the present matched pair analysis, we study the time course of the osteoanabolic markers bone specific alkaline phosphatase (BAP) and transforming growth factor beta1 (TGFbeta1), as well as the osteocatabolic markers crosslinked C-telopeptide of type-I-collagen (beta-CTX) and serum band 5 tartrate-resistant acid phosphatase (TRAP5b), during the healing of fractures that have a low level of bone mineral density (BMD) compared with fractures that have a normal BMD. Between March 2007 and February 2009, 30 patients aged older than 50 years who suffered a metaphyseal fracture were included in our study. BMDs were verified by dual energy Xray absorptiometry (DXEA) scans. The levels of BTMs were examined over an 8-week period. Osteoanabolic BAP levels in those with low levels of BMD were significantly different from the BAP levels in those with normal BMD. BAP levels in the former group increased constantly, whereas the latter group showed an initial strong decrease in BAP followed by slowly rising values. Osteocatabolic beta-CTX increased in the bone of the normal BMD group constantly, whereas these levels decreased significantly in the bone of the group with low BMD from the first week. TRAP5b was significantly reduced in the low level BMD group. With this work, we conduct first insights into the molecular biology of the fracture healing process in patients with low levels of BMD that explains the mechanism of its fracture healing. The results may be one reason for the reduced healing qualities in bones with low BMD. PMID- 24788652 TI - Control of angiogenesis by galectins involves the release of platelet-derived proangiogenic factors. AB - Platelets contribute to vessel formation through the release of angiogenesis modulating factors stored in their alpha-granules. Galectins, a family of lectins that bind beta-galactoside residues, are up-regulated in inflammatory and cancerous tissues, trigger platelet activation and mediate vascularization processes. Here we aimed to elucidate whether the release of platelet-derived proangiogenic molecules could represent an alternative mechanism through which galectins promote neovascularization. We show that different members of the galectin family can selectively regulate the release of angiogenic molecules by human platelets. Whereas Galectin (Gal)-1, -3, and -8 triggered vascular endothelial growth factor (VEGF) release, only Gal-8 induced endostatin secretion. Release of VEGF induced by Gal-8 was partially prevented by COX-1, PKC, p38 and Src kinases inhibitors, whereas Gal-1-induced VEGF secretion was inhibited by PKC and ERK blockade, and Gal-3 triggered VEGF release selectively through a PKC-dependent pathway. Regarding endostatin, Gal-8 failed to stimulate its release in the presence of PKC, Src and ERK inhibitors, whereas aspirin or p38 inhibitor had no effect on endostatin release. Despite VEGF or endostatin secretion, platelet releasates generated by stimulation with each galectin stimulated angiogenic responses in vitro including endothelial cell proliferation and tubulogenesis. The platelet angiogenic activity was independent of VEGF and was attributed to the concerted action of other proangiogenic molecules distinctly released by each galectin. Thus, secretion of platelet-derived angiogenic molecules may represent an alternative mechanism by which galectins promote angiogenic responses and its selective blockade may lead to the development of therapeutic strategies for angiogenesis-related diseases. PMID- 24788653 TI - Flow injection analysis of thiamazole based on strong Ru(bpy)3 (2+) co-reactant electrochemiluminescence. AB - Based on the strong electrochemiluminescence (ECL) reaction between thiamazole and tris(2,2'-bipyridine)ruthenium(II) (Ru(bpy)3 (2+) ), a sensitive, simple and rapid flow injection analysis method for the determination of thiamazole was developed. When a Pt working electrode was maintained at a potential of +1.50 V (vs Ag/AgCl) in pH 12.0 H3 PO4 -NaOH solution containing thiamazole and Ru(bpy)3 (2+) at a flow rate of 1.0 mL/min, a linear range of 2.0 * 10(-7) -1.0 * 10(-4) mol/L with a detection limit of 5.0 * 10(-8) mol/L was obtained for the detection of thiamazole. The method showed good reproducibility with a relative standard deviation (RSD) of 0.75%. The method has been successfully applied to the determination of thiamazole in spiked animal feeds. In addition, a co reactant ECL mechanism was proposed for the thiamazole-Ru(bpy)3 (2+) system. PMID- 24788654 TI - Chiral derivatives of 1,2-benzenedisulfonimide as efficient Bronsted acid catalysts in the Strecker reaction. AB - Two chiral derivatives of 1,2-benzenedisulfonimide, namely 4-methyl-3,6-bis(o tolyl)-1,2-benzenedisulfonimide and 4,5-dimethyl-3,6-bis(o-tolyl)-1,2 benzenedisulfonimide, have been easily synthesized in good overall yields (respectively 34% and 41%) by means of an eleven-step synthetic protocol from commercially available 2-methyl-6-nitroaniline or 2,3-dimethyl-6-nitroaniline. 4,5-Dimethyl-3,6-bis(1-naphthyl)-1,2-benzenedisulfonimide was also synthesized, but the overall yield from 2,3-dimethyl-6-nitroaniline was lower (9%). The atropisomers of these compounds have been resolved and (-)atropisomers have been demonstrated to be efficient chiral catalysts in the Strecker reaction. PMID- 24788648 TI - Tissue engineering and regenerative repair in wound healing. AB - Wound healing is a highly evolved defense mechanism against infection and further injury. It is a complex process involving multiple cell types and biological pathways. Mammalian adult cutaneous wound healing is mediated by a fibroproliferative response leading to scar formation. In contrast, early to mid gestational fetal cutaneous wound healing is more akin to regeneration and occurs without scar formation. This early observation has led to extensive research seeking to unlock the mechanism underlying fetal scarless regenerative repair. Building upon recent advances in biomaterials and stem cell applications, tissue engineering approaches are working towards a recapitulation of this phenomenon. In this review, we describe the elements that distinguish fetal scarless and adult scarring wound healing, and discuss current trends in tissue engineering aimed at achieving scarless tissue regeneration. PMID- 24788655 TI - MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer. AB - OBJECTIVE: Triple-negative breast cancer (TNBC) patients with truly chemosensitive disease still represent a minority among all TNBC patients. The aim of the present study is to identify microRNAs (miRNAs) that correlate with TNBC chemoresistance. METHODS: In this study, we conducted miRNAs profile comparison between triple-negative breast cancer (TNBCs) and normal breast tissues by microRNA array. Quantitative real-time PCR (qRT-PCR) was utilized to confirm the specific deregulated miRNAs change trend. We used starBase 2.1 and GOrilla to predict the potential targets of the specific miRNAs. Cells viability and apoptosis assays were employed to determine the effect of alteration of the specific miRNAs in TNBC cells on the chemosensitivity. RESULTS: We identified 11 specific deregulated miRNAs, including 5 up-regulated miRNAs (miR-155-5p, miR-21 3p, miR-181a-5p, miR-181b-5p, and miR-183-5p) and 6 down-regulated miRNAs (miR 10b-5p, miR-451a, miR-125b-5p, miR-31-5p, miR-195-5p and miR-130a-3p). Thereafter, this result was confirmed by qRT-PCR. We predicted the potential targets of the candidate miRNAs and found that they are involved in cancer associated pathways. For the first time, we found that miR-130a-3p and miR-451a were down-regulated in TNBC. 9 of the 11 specific deregulated miRNAs were found to be associated with chemoresistance. In vitro assays, we found that up regulation of either miR-130a-3p or miR-451a in MDA-MB-231 cells significantly changed the cells sensitivity to doxorubicin. The results suggest that TNBC chemotherapy might be affected by a cluster of miRNAs. CONCLUSION: The abnormal expression miRNAs in TNBC are mainly chemoresistance related. This might be part of reason that TNBC likely to evade from chemotherapy resulting in early relapse and high risk of death. To alter their expression status might be a potential therapeutic strategy to improve the outcome of chemotherapy for TNBC patients. PMID- 24788656 TI - Support for the EUCAST and revised CLSI fluconazole clinical breakpoints by Sensititre(r) YeastOne(r) for Candida albicans: a prospective observational cohort study. AB - OBJECTIVES: Species-specific clinical breakpoints (CBPs) for Candida spp. were established following consideration of clinical outcomes in patients with oesophageal candidiasis. We sought to further determine the validity of the current CBPs based on data from a prospective candidaemia study. PATIENTS AND METHODS: All Candida albicans candidaemia episodes in patients enrolled in the Australian Candidaemia Study and who were treated with fluconazole monotherapy were included. Fluconazole MICs were established using Sensititre((r)) YeastOne((r)). RESULTS: Two hundred and seventeen evaluable episodes were identified, 93.5% of which occurred in adult patients. Fluconazole was commenced within 72 h of blood culture positivity in 96.3% (209/217) of episodes. Fluconazole doses were appropriate in 89.9% (195/217) of episodes and the median duration of therapy was 14 days (IQR 8-21 days) for the whole cohort. The all cause 30 day mortality was 19.8% (43/217), with 37.2% (16/43) of deaths attributed to candidaemia. Classification and regression tree (CART) analysis identified a fluconazole MIC target of >=2 mg/L for infection-related mortality and >=4 mg/L for overall 30 day mortality. Overall mortality was no different in episodes with isolates above or below the identified MIC target, although there was a trend towards significance (P = 0.051). On univariate analysis, infection related mortality was significantly increased in C. albicans episodes with an MIC >=2 mg/L compared with those below this MIC target (20.6% versus 4.9%; P = 0.001). This target remained an independent predictor of infection-related mortality (OR 8.2; 95% CI 2.3-29.7; P = 0.001). CONCLUSIONS: We observed a direct relationship between infection-related mortality and rising fluconazole MIC for C. albicans candidaemia; overall, the data support the EUCAST and revised CLSI fluconazole clinical breakpoints. PMID- 24788658 TI - Drug resistance in the HIV-1-infected paediatric population worldwide: a systematic review. AB - BACKGROUND: Drug resistance monitoring of the paediatric HIV-1-infected population is required to optimize treatment success and preserve future treatment options. OBJECTIVES: To explore the current knowledge of HIV drug resistance (HIVDR) in naive and pretreated HIV-1-infected paediatric populations across diverse settings and sampling time periods. METHODS: PubMed database screened until May 2013. We selected publications including data on transmitted (TDR) and acquired drug resistance mutation (DRM) rates and/or pol sequences for HIVDR testing in paediatric patients. We recorded the children's country, age, study period, number of children with pol sequences, presence or absence of antiretroviral treatment (ART) at sampling time, viral region sequenced, HIVDR rate to the three main drug classes (single, double or triple), the considered resistance mutation list and performed assay, specimen type, HIV-1 variants and subtyping methodology when available. RESULTS: Forty-one selected studies showed HIVDR data from 2538 paediatric HIV-1-infected patients (558 naive and 1980 pretreated) from 30 countries in Africa (11), Asia (6), America (10) and Europe (3). Both TDR and DRM prevalence were reported in 9 studies, only TDR in 6 and only DRM in 26. HIVDR prevalence varied across countries and periods. Most studies used in-house resistance assays using plasma or infected cells. HIV-1 non B variants were prevalent in 18 paediatric cohorts of the 24 countries with reported subtypes. Only five countries (Uganda, Spain, the UK, Brazil and Thailand) presented resistance data in >=200 patients. CONCLUSIONS: Systematic and periodic studies among infected children are crucial to design a more suitable first- or second-line therapy. PMID- 24788657 TI - Zero tolerance for healthcare-associated MRSA bacteraemia: is it realistic? AB - BACKGROUND: The term 'zero tolerance' has recently been applied to healthcare associated infections, implying that such events are always preventable. This may not be the case for healthcare-associated infections such as methicillin resistant Staphylococcus aureus (MRSA) bacteraemia. METHODS: We combined information from an epidemiological investigation and bacterial whole-genome sequencing to evaluate a cluster of five MRSA bacteraemia episodes in four patients in a specialist hepatology unit. RESULTS: The five MRSA bacteraemia isolates were highly related by multilocus sequence type (ST) (four isolates were ST22 and one isolate was a single-locus variant, ST2046). Whole-genome sequencing demonstrated unequivocally that the bacteraemia cases were unrelated. Placing the MRSA bacteraemia isolates within a local and global phylogenetic tree of MRSA ST22 genomes demonstrated that the five bacteraemia isolates were highly diverse. This was consistent with the acquisition and importation of MRSA from the wider referral network. Analysis of MRSA carriage and disease in patients within the hepatology service demonstrated a higher risk of both initial MRSA acquisition compared with the nephrology service and a higher risk of progression from MRSA carriage to bacteraemia, compared with patients in nephrology or geriatric services. A root cause analysis failed to reveal any mechanism by which three of five MRSA bacteraemia episodes could have been prevented. CONCLUSIONS: This study illustrates the complex nature of MRSA carriage and bacteraemia in patients in a specialized hepatology unit. Despite numerous ongoing interventions to prevent MRSA bacteraemia in healthcare settings, these are unlikely to result in a zero incidence in referral centres that treat highly complex patients. PMID- 24788660 TI - Sepedonium intra-abdominal infection: a case report and review of an emerging fungal infection. PMID- 24788659 TI - HIV-2 viral tropism influences CD4+ T cell count regardless of viral load. AB - BACKGROUND: HIV-2 infection is characterized by low plasma viraemia and slower progression to AIDS in comparison with HIV-1 infection. However, antiretroviral therapy in patients with HIV-2 is less effective and often fails to provide optimal CD4 recovery. METHODS: We examined viral tropism in persons with HIV-2 infection enrolled in the HIV-2 Spanish cohort. Viral tropism was estimated based on V3 sequences obtained from plasma RNA and/or proviral DNA. RESULTS: From a total of 279 individuals with HIV-2 infection recorded in the Spanish national register, 58 V3 sequences belonging to 42 individuals were evaluated. X4 viruses were recognized in 14 patients (33%). Patients with X4 viruses had lower median CD4+ cell counts than patients with R5 viruses [130 (17-210) versus 359 (180-470) cells/mm(3); P = 0.007]. This was true even considering only the subset of 19 patients on antiretroviral therapy [94 (16-147) versus 184 (43-368) cells/mm(3); P = 0.041]. In multivariate analysis, significant differences in CD4+ cell counts between patients with X4 and R5 viruses remained after adjusting for age, gender, antiretroviral therapy and viral load. CONCLUSIONS: The presence of X4-tropic viruses in HIV-2 infection is associated with low CD4+ cell counts, regardless of antiretroviral treatment. Along with CD4+ cell counts, viral tropism testing may assist decisions about when to initiate antiretroviral therapy in HIV-2-infected individuals. PMID- 24788661 TI - ABCC2*1C and plasma tenofovir concentration are correlated to decreased glomerular filtration rate in patients receiving a tenofovir-containing antiretroviral regimen. AB - OBJECTIVES: To study the correlations of genetic variants of tenofovir tubular transporters, plasma tenofovir concentrations and clinical factors with decreased glomerular filtration rate in HIV-infected patients who received tenofovir. METHODS: A total of 117 HIV-1-infected patients were administered antiretroviral therapy with tenofovir/lamivudine/efavirenz. Two single nucleotide polymorphisms (SNPs), ABCC2*1C c.-24C>T and ABCB1*6 c.3435C>T, were genotyped. At week 24, plasma tenofovir concentration at 12 h after drug intake was measured. Serum creatinine and estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease study formula were measured every 24 weeks until 96 weeks. RESULTS: Overall, mean +/- SD age was 37 +/- 9 years. Mean +/- SD baseline eGFR was 130.3 +/- 35.0 mL/min/1.73 m(2). The frequencies of wild type/heterozygous/homozygous mutants of ABCC2*1C were 57%/39%/4% and those of ABCB1*6 were 28%/51%/21%. Mean +/- SD plasma tenofovir concentration at 24 weeks was 105 +/- 46 ng/mL. At week 48, m-ean +/- SD eGFR of ABCC2*1C CC versus CT/TT was 96 versus 108 mL/min (P = 0.005) and m-ean +/- SD eGFR of ABCB1*6 CC versus CT/TT was 106 versus 99 mL/min (P = 0.157). Mean +/- SD tenofovir concentration in ABCC2*1C genotype CC versus CT/TT was 113 +/- 47 versus 93 +/- 44 ng/mL, respectively (P = 0.018). By multivariate analysis I, decreased eGFR at week 48 was correlated to ABCC2*1C genotype CC (P = 0.001), low eGFR at baseline (P = 0.006) and older age (P = 0.048). By multivariate analysis II, decreased eGFR at week 48 was correlated to high plasma tenofovir concentration (P = 0.001) and low eGFR at baseline (P = 0.019). CONCLUSIONS: HIV-infected patients who carry ABCC2*1C genotype CC at position -24 or have high plasma tenofovir concentration are at risk of decreased glomerular filtration rate. PMID- 24788662 TI - Comparison of planktonic and biofilm-associated communities of Clostridium difficile and indigenous gut microbiota in a triple-stage chemostat gut model. AB - BACKGROUND: Biofilms are characteristic of some chronic or recurrent infections and this mode of growth tends to reduce treatment efficacy. Clostridium difficile infection (CDI) is associated with a high rate of recurrent symptomatic disease. The presence and behaviour of C. difficile within intestinal biofilms remains largely unexplored, but may factor in recurrent infection. METHODS: A triple stage chemostat gut model designed to facilitate the formation of intestinal biofilm was inoculated with a pooled human faecal emulsion. Bacterial populations were allowed to equilibrate before simulated CDI was induced by clindamycin (33.9 mg/L, four times daily, 7 days) and subsequently treated with vancomycin (125 mg/L, four times daily, 7 days). Indigenous gut microbiota, C. difficile total viable counts, spores, cytotoxin and antimicrobial activity in planktonic and biofilm communities were monitored during the 10 week experimental period. RESULTS: Vancomycin successfully treated the initial episode of simulated CDI, but ~18 days after therapy cessation, recurrent infection occurred. Germination, proliferation and toxin production were evident within planktonic communities in both initial and recurrent CDI. In contrast, sessile C. difficile remained in dormant spore form for the duration of the experiment. The effects of and recovery from clindamycin and vancomycin exposure for sessile populations was delayed compared with responses for planktonic bacteria. CONCLUSIONS: Intestinal biofilms provide a potential reservoir for C. difficile spore persistence, possibly facilitating their dispersal into the gut lumen after therapeutic intervention, leading to recurrent infection. Therapeutic options for CDI could have increased efficacy if they are more effective against sessile C. difficile. PMID- 24788664 TI - Prognostic value of PPM1D in 800 gastric cancer patients. AB - Protein phosphatase magnesium-dependent 1 delta (PPM1D) has recently been associated with tumor biology. However, the expression pattern and clinical significance of PPM1D in gastric cancer (GC) have yet to be elucidated. The present study aimed to investigate the clinical and prognostic significance of PPM1D in GC. PPM1D expression was assessed in 800 patients with GC using immunohistochemistry and tissue samples were divided into a PPM1D-positive and negative group. The correlation between PPM1D expression and clinicopathological parameters or prognosis was investigated. PPM1D expression was significantly higher in GC tissue than in adjacent normal tissue (48 versus 9.5%; P<0.001). PPM1D positivity was significantly correlated with nodal status, distant metastasis and vascular invasion. Survival analysis indicated that the five-year survival rate in the PPM1D-positive group was significantly lower than that in the PPM1D-negative group (41 versus 72%; p=0.0012). Furthermore, the association between PPM1D positivity and survival rate was still significant following regulation of other prognostic markers in a multivariate analysis [hazard ratio (HR), 6.572; 95% confidence interval (CI), 3.108-13.471; P=0.0018]. In conclusion, the present study suggested that PPM1D positivity is associated with GC invasion and metastasis, and proposed PPM1D positivity as an indicator of unfavorable prognosis in patients with GC. PMID- 24788663 TI - Bioenergetics and gene silencing approaches for unraveling nucleotide recognition by the human EIF2C2/Ago2 PAZ domain. AB - Gene silencing and RNA interference are major cellular processes that control gene expression via the cleavage of target mRNA. Eukaryotic translation initiation factor 2C2 (EIF2C2, Argonaute protein 2, Ago2) is considered to be the major player of RNAi as it is the core component of RISC complexes. While a considerable amount of research has focused on RNA interference and its associated mechanisms, the nature and mechanisms of nucleotide recognition by the PAZ domain of EIF2C2/Ago2 have not yet been characterized. Here, we demonstrate that the EIF2C2/Ago2 PAZ domain has an inherent lack of binding to adenine nucleotides, a feature that highlights the poor binding of 3'-adenylated RNAs with the PAZ domain as well as the selective high trimming of the 3'-ends of miRNA containing adenine nucleotides. We further show that the PAZ domain selectively binds all ribonucleotides (except adenosine), whereas it poorly recognizes deoxyribonucleotides. In this context, the modification of dTMP to its ribonucleotide analogue gave a drastic improvement of binding enthalpy and, hence, binding affinity. Additionally, higher in vivo gene silencing efficacy was correlated with the stronger PAZ domain binders. These findings provide new insights into the nature of the interactions of the EIF2C2/Ago2 PAZ domain. PMID- 24788665 TI - Biocatalytic self-assembly of supramolecular charge-transfer nanostructures based on n-type semiconductor-appended peptides. AB - The reversible in situ formation of a self-assembly building block (naphthalenediimide (NDI)-dipeptide conjugate) by enzymatic condensation of NDI functionalized tyrosine (NDI-Y) and phenylalanine-amide (F-NH2) to form NDI-YF NH2 is described. This coupled biocatalytic condensation/assembly approach is thermodynamically driven and gives rise to nanostructures with optimized supramolecular interactions as evidenced by substantial aggregation induced emission upon assembly. Furthermore, in the presence of di-hydroxy/alkoxy naphthalene donors, efficient charge-transfer complexes are produced. The dynamic formation of NDI-YF-NH2 and electronic and H-bonding interactions are analyzed and characterized by different methods. Microscopy (TEM and AFM) and rheology are used to characterize the formed nanostructures. Dynamic nanostructures, whose formation and function are driven by free-energy minimization, are inherently self-healing and provide opportunities for the development of aqueous adaptive nanotechnology. PMID- 24788667 TI - A positive correlation between mercury and oxidative stress-related gene expression (GPX3 and GSTM3) is measured in female Double-crested Cormorant blood. AB - Mercury (Hg) is a widespread contaminant that has been shown to induce a wide range of adverse health effects in birds including reproductive, physiological and neurological impairments. Here we explored the relationship between blood total Hg concentrations ([THg]) and oxidative stress gene induction in the aquatic piscivorous Double-crested Cormorants (Phalacrocorax auritus) using a non lethal technique, i.e., blood gene expression analysis. P. auritus blood was sampled at five sites across the Great Lakes basin, Ontario, Canada and was analyzed for [THg]. To assess cellular stress, the expression of glutathione peroxidases 1 and 3 (GPX1, GPX3), superoxide dismutase 1 (SOD1), heat-shock protein 70 kd-8 (HSP70-8) and glutathione S-transferase u3 (GSTM3) were measured in whole blood samples using real-time RT-PCR. Results showed a significantly positive correlation between female blood [THg] and both GPX3 and GSTM3 expression. Different levels of oxidative stress experienced by males and females during the breeding season may be influencing the differential oxidative stress responses to blood [THg] observed in this study. Overall, these results suggest that Hg may lead to oxidative stress as some of the cellular stress-related genes were altered in the blood of female P. auritus and that blood gene expression analysis is a successful approach to assess bird health condition. PMID- 24788670 TI - Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. AB - BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In April 2014, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. The initial search also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. No new trials were eligible in 2014. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome.Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36).Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38).Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73).Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17beta-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI 0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods.We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal). PMID- 24788671 TI - Dose-response meta-analysis of poultry intake and colorectal cancer incidence and mortality. AB - PURPOSE: Poultry intake has been inconsistently associated with incidence or mortality of colorectal cancer (CRC) in epidemiologic studies. The purpose of this study was to assess their relationships by performing a dose-response meta analysis. METHODS: We conducted a search of PubMed database between January 1966 and July 2013 for prospective studies that reported relative risks (RRs) with 95 % confidence interval (CIs) of CRC for at least three categories of poultry intake. Dose-response relationships were examined with the generalized least squares trend estimation. Study-specific results were pooled with a random effects model. Subgroup, sensitivity, and meta-regression analyses were also conducted to explore heterogeneity. RESULTS: Sixteen studies on poultry intake and CRC incidence, and four studies regarding poultry intake and CRC mortality were identified. These studies involved a total of 13,949 incident CRC cases and 983 CRC deaths. The RRs of CRC for higher compared with lower intake of poultry were reported in these studies, and the reported levels of poultry intake varied substantially. Results of the dose-response meta-analysis conferred a RR of 0.89 (95 % CI 0.81-0.97) for an increase in poultry intake of 50 g/day. The results were not sensitive to any individual studies and were similar for colon and rectal cancer. Poultry intake was not associated with CRC mortality (RR for 50 g/day = 0.97, 95 % CI 0.79-1.20). CONCLUSIONS: This meta-analysis indicates that poultry intake may be moderately associated with reduced incidence of CRC. PMID- 24788672 TI - A systematic review of the safety of lisdexamfetamine dimesylate. AB - BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants. PMID- 24788673 TI - Growth hormone protects colorectal cancer cells from radiation by improving the ability of DNA damage repair. AB - The present study aimed to examine the effects of recombinant human growth hormone (rhGH) on the sensitivity of a colorectal cancer cell line to radiotherapy, and to investigate its association with DNA damage and repair. Flow cytometry and immunofluorescence were employed to detect growth hormone receptor (GHR) expression in nine human colorectal cancer cell lines. A colony forming assay was performed to measure the colorectal cancer cell proliferation post radiotherapy, as an indicator of radiotherapy sensitivity. The comet assay results were interpreted as an indicator of radiotherapy-induced DNA damage, and growth arrest and DNA damage 45 (GADD45) and apurinic/apyrimidinic endonuclease (APEN) protein expression were quantified with western blot analysis from the same cell lines. The results demonstrated that the colony-forming efficiency (CFE) was significantly increased in HCT-8 cells subject to radiotherapy and rhGH pretreatment compared with the cells treated with radiotherapy alone, in a dose dependent manner (0-100 mg/l). This effect was enhanced under high doses of radiation (8 Gy; 52.1+/-2.9 vs. 21.0+/-2.7; P<0.001) and was ameliorated with GHR neutralizing antibody exposure. By contrast, rhGH pre-incubation did not change the colony formation rate in GHR(-) LOVO cells. rhGH intervention reduced the early HCT-8 cell DNA damage (21.53+/-2.88 vs. 36.56+/-3.93; P=0.003) as well as the following plateau phase, compared with cells treated with radiotherapy alone (5.5+/-0.42 vs. 9.07+/-0.84; P=0.012). rhGH upregulated GADD45 and APEN protein expression, which is associated with cellular stress responses and DNA damage repair (P=0.007). The results suggest that rhGH is able to protect colorectal cancer cells from radiation through the interaction with GHR, which is associated with the promotion of DNA damage repair activity. PMID- 24788675 TI - Reduction of C,N-chelated chloroborane: straightforward formation of the unprecedented 1H-2,1-benzazaborolyl potassium salt. AB - Reduction of C,N-chelated chloroborane [2-(CH=NtBu)C6H4]BPhCl () with the potassium metal afforded (3,3')-bis(1-Ph-2-tBu-1H-2,1-benzazaborole) (2). Compound 2 is formed via C-C reductive coupling reaction. Subsequent reduction of 2 with two equivalents of the potassium metal produced orange crystals of 1Ph 2tBu-1H-2,1-benzazaborolyl (Bab) potassium salt K(THF)(Bab) (3). Compound 3 is able to react with simple electrophiles (MeI or Me3SiCl) resulting in the formation of substituted 1H-2,1-benzazaboroles. PMID- 24788674 TI - Identification of O-GlcNAc modification targets in mouse retinal pericytes: implication of p53 in pathogenesis of diabetic retinopathy. AB - Hyperglycemia is the primary cause of the majority of diabetes complications, including diabetic retinopathy (DR). Hyperglycemic conditions have a detrimental effect on many tissues and cell types, especially the retinal vascular cells including early loss of pericytes (PC). However, the mechanisms behind this selective sensitivity of retinal PC to hyperglycemia are undefined. The O-linked beta-N-acetylglucosamine (O-GlcNAc) modification is elevated under hyperglycemic condition, and thus, may present an important molecular modification impacting the hyperglycemia-driven complications of diabetes. We have recently demonstrated that the level of O-GlcNAc modification in response to high glucose is variable in various retinal vascular cells. Retinal PC responded with the highest increase in O-GlcNAc modification compared to retinal endothelial cells and astrocytes. Here we show that these differences translated into functional changes, with an increase in apoptosis of retinal PC, not just under high glucose but also under treatment with O-GlcNAc modification inducers, PUGNAc and Thiamet-G. To gain insight into the molecular mechanisms involved, we have used click-It chemistry and LC-MS analysis and identified 431 target proteins of O-GlcNAc modification in retinal PC using an alkynyl-modified GlcNAc analog (GlcNAlk). Among the O-GlcNAc target proteins identified here 115 of them were not previously reported to be target of O-GlcNAc modification. We have identified at least 34 of these proteins with important roles in various aspects of cell death processes. Our results indicated that increased O-GlcNAc modification of p53 was associated with an increase in its protein levels in retinal PC. Together our results suggest that post-translational O-GlcNAc modification of p53 and its increased levels may contribute to selective early loss of PC during diabetes. Thus, modulation of O GlcNAc modification may provide a novel treatment strategy to prevent the initiation and progression of DR. PMID- 24788676 TI - HPLC-DAD for the determination of three different classes of antifungals: method characterization, statistical approach, and application to a permeation study. AB - This study describes and characterizes methods for high-performance liquid chromatography diode array detection (HPLC-DAD) analysis of formulations containing molecules with antifungal activity of three different classes: terbinafine and butenafine (allylamines), miconazole and fluconazole (azoles), and geraniol, neral and geranial (monoterpenes). All methods used the same chromatographic column (RP18 ), enabling the analysis to be performed in a single batch. The specificity was extensively discussed through the establishment of purity peak methods. The analytical parameters (linearity, precision and accuracy) were calculated and discussed in detail using specific statistical approaches. All substances showed satisfactory results for chromatographic and analytical parameters. Limits of 1.3% to mean repeatability and 2.0% for intermediate precision are suggested as acceptance criteria in validation of methods by HPLC-DAD, in situations where there is no extensive pretreatment of the samples. The methods proved to be robust and significant factors were discussed regarding their influence on chromatographic parameters (retention time, resolution, tailing factor and column efficiency). Finally, the application of the developed methods was demonstrated by the results of a permeation study of the antifungal agents through bovine hoof membranes. PMID- 24788678 TI - Spectral selectivity of 3D magnetophotonic crystal film fabricated from single butterfly wing scales. AB - 3D magnetophotonic crystal (3D-MPC) film is an excellent platform for tailoring the magneto-optical response of magnetic materials. However, its fabrication is a great challenge due to the limitation of commonly used artificial synthesis methods. Inspired by the unique structures of biospecies, we hereby manipulate the pristine single wing scales of Morpho didius precisely and successfully fabricate Fe3O4 films with photonic structure. The synthesis strategy involves the fabrication of Fe2O3 film from a single wing scale using an improved sol-gel method followed by a subsequent reduction. The intrinsic hierarchical photonic structures as well as the anisotropic optical properties of the pristine butterfly wing scale have been retained in the obtained Fe2O3 and Fe3O4 films. When investigated under an external magnetic field, a spectral blue shift about 43 nm is observed in the designated orientation of the Fe3O4 film, which is useful for the design and creation of novel magnetic-optical modulator devices. Furthermore, these single scales can be used as building blocks to fabricate designable and more complicated assembled nano systems. This biomimetic technique combined with the variety of structures of butterfly wing scales provides an effective approach to produce magneto-photonic films with desired structure, paving a new way for theoretical research and practical applications. PMID- 24788677 TI - Association between urinary albumin excretion and intraocular pressure in type 2 diabetic patients without renal impairment. AB - BACKGROUND: To assess the relationship between urinary albumin excretion and intraocular pressure (IOP) in type 2 diabetes patients without renal impairment. METHODS: We explored the effects of albuminuria on high IOP in 402 non glaucomatous type 2 diabetes without renal impairment who participated in the 2011 Korean National Health and Nutrition Examination Survey (KNHANES). Multiple logistic regression analysis was used to assess the relationship between log transformed albumin/creatinine ratio (ACR) tertiles and an IOP of >= 18 mmHg after adjusting for age, gender, hypertension, body mass index, triglycerides, area of residence, and education level. RESULTS: Subjects with a high IOP >= 18 mmHg were more likely to be current smokers (P = 0.038), heavy drinkers (P = 0.006), and to have high systolic blood pressure (P = 0.016), triglycerides (P = 0.008), and a higher log-transformed ACR (P = 0.022).In multivariate regression analysis, ACR tertile was associated with the prevalence of high IOP significantly (P = 0.022). The associations between ACR tertiles and high IOP were significant in overweight patients and those with abdominal obesity (P = 0.003 and 0.003, respectively). In contrast, there were no associations in the subgroup of patients who were not overweight and those without abdominal obesity (P = 0.291 and 0.561, respectively). CONCLUSIONS: Urinary albumin excretion is associated with high IOP in the type 2 diabetes population without renal insufficiency. The effect of the albuminuria on IOP was evident in a subgroup of patients with components of metabolic syndrome. PMID- 24788679 TI - Long-term stability for cobalt-based dye-sensitized solar cells obtained by electrolyte optimization. AB - A significant improvement in the long-term stability for cobalt-based dye sensitized solar cells (DSCs) under light-soaking conditions has been achieved by optimization of the composition of tris(2,2'-bipyridine) Co(ii)/Co(iii) electrolytes. The effects of component exchanges and changes were also studied during the optimization process. PMID- 24788680 TI - Electrochemically generated nanoparticles of halogen-bridged mixed-valence binuclear metal complex chains. AB - Spherical nanoparticles composed of MMX chains can be made by a polymerization strategy driven by electrochemical processes. In particular, the [Pt2(MeCS2)4I2] (MMI2) dimetal subunit is employed as a monomer for the formation of [Pt2(MeCS2)4I]n spherical nanostructures on surfaces. We have paid particular attention to elucidating the general mechanism of the deposition process on the basis of in situ electrochemical measurements. The reduction of MMI2 to give the electrodeposition of nanostructures agrees well with formation of the reduced [MMI2](-) species followed by a disproportionation mechanism mediated by iodide anions. The chemical composition of the particles was determined by energy dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS) to reveal the MMI2 polymer. PMID- 24788681 TI - Risk factors of nocturia (two or more voids per night) in Chinese people older than 40 years. AB - AIMS: To explore the risk factors of nocturia in Chinese inhabitants aged >=40 years. METHODS: A randomized, community-based, cross-sectional study was performed on 10,160 inhabitants >=40 years old in mainland China, via a stratified sampling approach. A questionnaire, including socio-demographics, lifestyle factors and medical history, was completed. Nocturia was defined as a threshold of two or more voids per night. Differences in prevalence between age and gender groups were ascertained by the chi-squared test. Gender-related factors were evaluated by multivariate logistic regression analysis. P < 0.05 was considered to be statistically significant. RESULTS: Data on 9,637 (94.9%) people aged 59.6 +/- 9.7 years qualified for final statistical analysis. The overall prevalence of nocturia was 31.7% (3,053/9,637), and this increased with age (P < 0.001). Nocturia was significantly associated with cardiovascular disease and overactive bladder symptom score (OABSS) (P < 0.05), while sporting activities were protective (P < 0.001). Diabetes mellitus (DM) was significantly correlated with nocturia in men (P < 0.05), whereas hypertension was correlated with nocturia in women (P < 0.05). No correlation was found between nocturia and education level, occupation, civil status, tea consumption, body mass index (BMI), female birth history, and International Prostate Symptom Score. CONCLUSIONS: In Chinese people aged >=40 years, nocturia is associated with aging, OABSS, cardiovascular disease, hypertension, and DM. Sporting activities are negatively associated with nocturia. PMID- 24788682 TI - Heme oxygenase-2 suppress TNF-alpha and IL6 expression via TLR4/MyD88-dependent signaling pathway in mouse cerebral vascular endothelial cells. AB - Heme oxygenase (HO) represents an intrinsic antiinflammatory system based on its ability to inhibit expression of proinflammatory cytokines. The constitutive isoform heme oxygenase-2 (HO-2) has high expression and activity in cerebral microvascular endothelial cells (CMVEC). This study was undertaken to evaluate the role of HO-2 in regulation of TLR4/MyD88-dependent signaling and to study the effect of HO-2 on the expression and secretion of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and Interleukin-6 (IL6) in CMVEC. HO-2 short hairpin RNA (shRNA) and HO-2 overexpression plasmids were used to observe the effect of HO-2 on proinflammatory cytokines in CMVEC in vitro, and the results showed that the messenger RNA (mRNA) and protein levels of TNF-alpha and IL6 were increased and decreased, respectively, compared with control groups. LPS stimulated TNF-alpha and IL6 mRNA and protein were also reduced in CMVEC treated with an inhibitor of TLR4 signaling, CLI-095, or HO-2 overexpression. CLI-095 and HO-2 overexpression both reduced TLR4 expression in CMVEC, and HO-2 shRNA blocked these effects of CLI-095. CLI-095 and HO-2 overexpression potently suppressed TLR4/MyD88-dependent proinflammatory cytokine expression in CMVEC. These results suggest that HO-2 plays an important role in protecting CMVEC against cytokine mediated inflammation. PMID- 24788683 TI - Increase of zinc finger protein 179 in response to CCAAT/enhancer binding protein delta conferring an antiapoptotic effect in astrocytes of Alzheimer's disease. AB - Reactive astrogliosis is a cellular manifestation of neuroinflammation and occurs in response to all forms and severities of the central nervous system (CNS)'s injury and disease. Both astroglial proliferation and antiapoptotic processes are aspects of astrogliosis. However, the underlying mechanism of this response remains poorly understood. In addition, little is known about why activated astrocytes are more resistant to stress and inflammation. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor found in activated astrocytes that surround beta-amyloid plaques. In this study, we found that astrocytes activation was attenuated in the cortex and hippocampus of APPswe/PS1 E9 (AppTg)/Cebpd (-/-)mice. Furthermore, an increase in apoptotic astrocytes was observed in AppTg/Cebpd (-/-)mice, suggesting that CEBPD plays a functional role in enhancing the antiapoptotic ability of astrocytes. We found that Zinc Finger Protein 179 (ZNF179) was a CEBPD-regulated gene that played an antiapoptotic, but not proliferative, role in astrocytes. The transcriptions of the proapoptotic genes, insulin-like growth factor binding protein 3 (IGFBP3) and BCL2-interacting killer (BIK), were suppressed by ZNF179 via its interaction with the promyelocytic leukemia zinc finger (PLZF) protein in astrocytes. This study provides the first evidence that ZNF179, PLZF, IGFBP3, and BIK contributed to the novel CEBPD-induced antiapoptotic feature of astrocytes. PMID- 24788685 TI - Linoleic acid derivative DCP-LA ameliorates stress-induced depression-related behavior by promoting cell surface 5-HT1A receptor translocation, stimulating serotonin release, and inactivating GSK-3beta. AB - Impairment of serotonergic neurotransmission is the major factor responsible for depression and glycogen synthase kinase 3beta (GSK-3beta) participates in serotonergic transmission-mediated signaling networks relevant to mental illnesses. In the forced-swim test to assess depression-like behavior, the immobility time for mice with restraint stress was significantly longer than that for nonstressed control mice. Postsynaptic cell surface localization of 5-HT1A receptor, but not 5-HT2A receptor, in the hypothalamus for mice with restraint stress was significantly reduced as compared with that for control mice, which highly correlated to prolonged immobility time, i.e., depression-like behavior. The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl] octanoic acid (DCP-LA) restored restraint stress-induced reduction of cell surface 5-HT1A receptor and improved depression-like behavior in mice with restraint stress. Moreover, DCP-LA stimulated serotonin release from hypothalamic slices and cancelled restraint stress-induced reduction of GSK-3beta phosphorylation at Ser9. Taken together, the results of the present study indicate that DCP-LA could ameliorate depression-like behavior by promoting translocation of 5-HT1A receptor to the plasma membrane on postsynaptic cells, stimulating serotonin release, and inactivating GSK-3beta. PMID- 24788684 TI - Transcription, epigenetics and ameliorative strategies in Huntington's Disease: a genome-wide perspective. AB - Transcriptional dysregulation in Huntington's disease (HD) is an early event that shapes the brain transcriptome by both the depletion and ectopic activation of gene products that eventually affect survival and neuronal functions. Disruption in the activity of gene expression regulators, such as transcription factors, chromatin-remodeling proteins, and noncoding RNAs, accounts for the expression changes observed in multiple animal and cellular models of HD and in samples from patients. Here, I review the recent advances in the study of HD transcriptional dysregulation and its causes to finally discuss the possible implications in ameliorative strategies from a genome-wide perspective. To date, the use of genome-wide approaches, predominantly based on microarray platforms, has been successful in providing an extensive catalog of differentially regulated genes, including biomarkers aimed at monitoring the progress of the pathology. Although still incipient, the introduction of combined next-generation sequencing techniques is enhancing our comprehension of the mechanisms underlying altered transcriptional dysregulation in HD by providing the first genomic landscapes associated with epigenetics and the occupancy of transcription factors. In addition, the use of genome-wide approaches is becoming more and more necessary to evaluate the efficacy and safety of ameliorative strategies and to identify novel mechanisms of amelioration that may help in the improvement of current preclinical therapeutics. Finally, the major conclusions obtained from HD transcriptomics studies have the potential to be extrapolated to other neurodegenerative disorders. PMID- 24788686 TI - Drug release from calcium sulfate-based composites. AB - To help reduce the need for autografts, calcium sulfate (CS)-based bone graft substitutes are being developed to provide a stable platform to aid augmentation while having the ability to release a broad range of bioactive agents. CS has an excellent reputation as a biocompatible and osteoconductive substance, but addition of bioactive agents may further enhance these properties. Samples were produced with either directly loaded small, hydrophobic molecule (i.e., simvastatin), directly loaded hydrophilic protein (i.e., lysozyme), or 1 and 10 wt % of fast-degrading poly(beta-amino ester) (PBAE) particles containing protein. Although sustained release of directly loaded simvastatin was achieved, direct loading of small amounts of lysozyme resulted in highly variable release. Direct loading of a larger amount of protein generated a large burst, 65% of total loading, followed by sustained release of protein. Release of lysozyme from 1 wt % of PBAE particles embedded into CS was more controllable than when directly loaded, and for 10 wt % of protein-loaded PBAE particles, a higher burst was followed by sustained release, comparable to the results for the high direct loading. Compression testing determined that incorporation of directly loaded drug or drug-loaded PBAE particles weakened CS. In particular, PBAE particles had a significant effect on the strength of the composites, with a 25 and 80% decrease in strength for 1 and 10 wt % particle loadings, respectively. CS-based composites demonstrated the ability to sustainably release both macromolecules and small molecules, supporting the potential for these materials to release a range of therapeutic agents. PMID- 24788687 TI - Speciation analysis of orthophosphate and myo-inositol hexakisphosphate in soil- and plant-related samples by high-performance ion chromatography combined with inductively coupled plasma mass spectrometry. AB - A novel method based on high-performance ion chromatography inductively coupled plasma mass spectrometry employing strong anion exchange chromatography with HNO3 gradient elution for simultaneous analysis of orthophosphate and myo-inositol hexakisphosphate (IP6 ) in soil solution and plant extracts is presented. As inductively coupled plasma mass spectrometry analysis of phosphorus at m/z 31 is hampered by N-based interferences, (31)P was measured as (31)P(16)O(+) at m/z 47 employing dynamic reaction cell technique with O2 as reaction gas. Orthophosphate and IP6 were separated within a total chromatographic run-time of 12 min revealing a limit of detection of 0.3 MUmol/L. The coefficients of determination obtained in a working range of 1-100 and 1-30 MUmol/L were 0.9991 for orthophosphate and 0.9968 for IP6, respectively. The method was successfully applied to extracts from three different soils as well as root and shoot extracts of Brassica napus L. The precision of three independently prepared soil extracts was in the range of 4-10% relative standard deviation for PO4 (3-) and 3-8% relative standard deviation for IP6. Soil adsorption/desorption kinetics for IP6/orthophosphate were performed for investigating the sorption behavior of the two P species in the experimental soils. PMID- 24788688 TI - Peer victimization during adolescence and risk for anxiety disorders in adulthood: a prospective cohort study. AB - BACKGROUND: Peer victimization is ubiquitous across schools and cultures, and has been suggested as one developmental pathway to anxiety disorders. However, there is a dearth of prospective studies examining this relationship. The purpose of this cohort study was to examine the association between peer victimization during adolescence and subsequent anxiety diagnoses in adulthood. A secondary aim was to investigate whether victimization increases risk for severe anxiety presentations involving diagnostic comorbidity. METHODS: The sample comprised 6,208 adolescents from the Avon Longitudinal Study of Parents and Children who were interviewed about experiences of peer victimization at age 13. Maternal report of her child's victimization was also assessed. Anxiety disorders at age 18 were assessed with the Clinical Interview Schedule-Revised. Multivariable logistic regression was used to examine the association between victimization and anxiety diagnoses adjusted for potentially confounding individual and family factors. Sensitivity analyses explored whether the association was independent of diagnostic comorbidity with depression. RESULTS: Frequently victimized adolescents were two to three times more likely to develop an anxiety disorder than nonvictimized adolescents (OR = 2.49, 95% CI: 1.62-3.85). The association remained after adjustment for potentially confounding individual and family factors, and was not attributable to diagnostic overlap with depression. Frequently victimized adolescents were also more likely to develop multiple internalizing diagnoses in adulthood. CONCLUSIONS: Victimized adolescents are at increased risk of anxiety disorders in later life. Interventions to reduce peer victimization and provide support for victims may be an effective strategy for reducing the burden associated with these disorders. PMID- 24788689 TI - Conservative surgery for ipsilateral breast tumor recurrence. AB - The surgical and radiotherapeutic management of patients who develop an ipsilateral breast recurrence after primary conservative therapy remains controversial. Although current guidelines indicate the need for mastectomy for all recurrences, some reports in the literature suggest that a new conserving procedure (including repeat lumpectomy and second sentinel node biopsy) may be oncologically safe in selected patients. The rationale and current evidence for an appropriate second conservative approach are reviewed and discussed. PMID- 24788690 TI - Chemoenzymatic approach to optically active 4-hydroxy-5-alkylcyclopent-2-en-1-one derivatives: an application of a combined circular dichroism spectroscopy and DFT calculations to assignment of absolute configuration. AB - A series of representative optically active derivatives of 4-hydroxy-5 alkylcyclopent-2-en-1-one were prepared from the respective 2-furyl methyl carbinols via the Piancatelli rearrangement followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (experimental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD] spectra) to determine the absolute configuration of both stereogenic centers in 4-hydroxy-5-methylcyclopent-2-en-1-one was demonstrated. It was also demonstrated that the concurrent application of ECD and VCD spectroscopy can be used for the determination of the configuration of two stereogenic centers. PMID- 24788691 TI - Perfect spin filtering and large spin thermoelectric effects in organic transition-metal molecular junctions. AB - We present ab initio studies of spin-polarized transport properties and thermospin effects in cyclopentadienyl-iron molecular junctions. It is found that the spin-up transmission coefficient at the Fermi level shows an odd-even oscillating behaviour, while the spin-down transmission coefficient has an exponential decay with the molecule length. The spin polarization at the Fermi level rapidly tends toward a saturation value close to 100% with the molecule length. This is ascribed to the existence of different orbital states for different spin components at the Fermi level. In addition, we find that the spin up Seebeck coefficient oscillates between positive and negative values, while the spin-down Seebeck coefficient always has a positive value and monotonically increases with the molecule length. Therefore in some cases, the spin Seebeck coefficient is even larger than the corresponding charge Seebeck effect. Finally, we also provide a possibility of utilizing cyclopentadienyl-iron molecular junctions to achieve the pure spin current without an accompanying charge current at about room temperature. PMID- 24788692 TI - Potential adverse effects of negative publicity surrounding antivirals for influenza. PMID- 24788693 TI - Evidence of distinct populations of hepatitis C virus in the liver and plasma of patients co-infected with HIV and HCV. AB - Viral diversity is an important predictor of hepatitis C virus (HCV) treatment response and may influence viral pathogenesis. HIV influences HCV variability in the plasma; however, limited data on viral variability are available from distinct tissue/cell compartments in patients co-infected with HIV and HCV. Thus, this exploratory study evaluated diversity of the hypervariable region 1 (HVR1) of HCV in the plasma and liver for 14 patients co-infected with HIV and HCV. Median intra-patient genetic distances and entropy values were similar in the plasma and liver compartments. Positive immune selection pressure was observed in the plasma for five individuals and in the liver for three individuals. Statistical evidence supporting viral compartmentalization was found in five individuals. Linear regression identified ALT (P = 0.0104) and AST (P = 0.0130) as predictors of viral compartmentalization. A total of 12 signature amino acids that distinguish liver from plasma E1/HVR1 were identified. One signature amino acid was shared by at least two individuals. These findings suggest that HCV compartmentalization is relatively common among patients co-infected with HIV and HCV. These data also imply that evaluating viral diversity, including drug resistance patterns, in the serum/plasma only may not adequately represent viruses replicating with in the liver and, thus, deserves careful consideration in future studies. PMID- 24788694 TI - A modular, prospective, semi-automated drug safety monitoring system for use in a distributed data environment. AB - PURPOSE: The aim of this study was to develop and test a semi-automated process for conducting routine active safety monitoring for new drugs in a network of electronic healthcare databases. METHODS: We built a modular program that semi automatically performs cohort identification, confounding adjustment, diagnostic checks, aggregation and effect estimation across multiple databases, and application of a sequential alerting algorithm. During beta-testing, we applied the system to five databases to evaluate nine examples emulating prospective monitoring with retrospective data (five pairs for which we expected signals, two negative controls, and two examples for which it was uncertain whether a signal would be expected): cerivastatin versus atorvastatin and rhabdomyolysis; paroxetine versus tricyclic antidepressants and gastrointestinal bleed; lisinopril versus angiotensin receptor blockers and angioedema; ciprofloxacin versus macrolide antibiotics and Achilles tendon rupture; rofecoxib versus non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and myocardial infarction; telithromycin versus azithromycin and hepatotoxicity; rosuvastatin versus atorvastatin and diabetes and rhabdomyolysis; and celecoxib versus ns NSAIDs and myocardial infarction. RESULTS: We describe the program, the necessary inputs, and the assumed data environment. In beta-testing, the system generated four alerts, all among positive control examples (i.e., lisinopril and angioedema; rofecoxib and myocardial infarction; ciprofloxacin and tendon rupture; and cerivastatin and rhabdomyolysis). Sequential effect estimates for each example were consistent in direction and magnitude with existing literature. CONCLUSIONS: Beta-testing across nine drug-outcome examples demonstrated the feasibility of the proposed semi-automated prospective monitoring approach. In retrospective assessments, the system identified an increased risk of myocardial infarction with rofecoxib and an increased risk of rhabdomyolysis with cerivastatin years before these drugs were withdrawn from the market. PMID- 24788695 TI - Downregulation of glutathione peroxidase 3 is associated with lymph node metastasis and prognosis in cervical cancer. AB - Glutathione peroxidase 3 (GPX3) is a member of the glutathione peroxidase family of selenoproteins and is one of the key defensive enzymes against oxidative damages to host cells. Downregulation of GPX3 due to its promoter hypermethylation has been documented in several different types of cancer, indicating that GPX3 functions as a possible tumor suppressor. In the present study, we showed that GPX3 is also significantly downregulated in cervical cancer tissues compared to normal cervical tissues by qRT-PCR analyses and immunohistostainings. GPX3 expression was significantly related to lymph node metastasis and prognosis in cervical cancer patients. Treatment of cervical cancer cells with 5-aza-2'-deoxycytidine restored the expression of GPX3 and methylation-specific PCR (MSP) confirmed the CpG methylation of the GPX3 gene. Our results indicate that promoter methylation is one of the major causes of GPX3 downregulation in cervical cancer and GPX3 could serve as a predictive biomarker for lymph node metastasis and prognosis of cervical cancer. PMID- 24788696 TI - Treatment of elderly patients with snoring and obstructive sleep apnea using a mandibular advancement device. AB - INTRODUCTION: The simplicity of oral appliance therapy in the treatment of adult patients with snoring and obstructive sleep apnea (OSA) has resulted in a worldwide interest for this treatment modality. Mandibular advancement devices (MADs) that hold the lower jaw forward during sleep are mainly indicated for patients with milder OSA and those with CPAP intolerance. There has been minor attention on age when suggesting treatment alternatives for patients with OSA. Some studies indicate that there is a weak negative relationship between treatment success from MADs and higher age, but no studies have stratified their samples with respect to age. OBJECTIVE: The present aim was to compare the effects and side effects from MADs between an elderly group of patients (>65 years of age) and a younger age group that were extracted from two of our previous studies. RESULTS: The results showed no difference between the elderly and the younger patients in success rate or the degree of bite changes from MAD treatment. CONCLUSION: These findings indicate that MADs represent an alternative to CPAP irrespective of the age of the patient. PMID- 24788697 TI - The role of BRCA status on the prognosis of patients with epithelial ovarian cancer: a systematic review of the literature with a meta-analysis. AB - OBJECTIVE: The role of BRCA dysfunction on the prognosis of patients with epithelial ovarian cancer (EOCs) remains controversial. This systematic review tried to assess the role of BRCA dysfunction, including BRCA1/2 germline, somatic mutations, low BRCA1 protein/mRNA expression or BRCA1 promoter methylation, as prognostic factor in EOCs. METHODS: Studies were selected for analysis if they provided an independent assessment of BRCA status and prognosis in EOC. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a modified quality scale. RESULTS: Of 35 evaluable studies, 23 identified BRCA dysfucntion status as a favourable prognostic factor. No significant differences were detected in the global score of quality assessment. The aggregated hazard ratio (HR) of overall survival (OS) of 34 evaluable studies suggested that BRCA dysfunction status had a favourable impact on OS (HR = 0.69, 95% CI 0.61-0.79), and when these studies were categorised into BRCA1/2 mutation and low protein/mRNA expression of BRCA1 subgroups, all of them demonstrated positive results (HR = 0.67, 95% CI: 0.57-0.78; HR = 0.62, 95% CI: 0.51-0.75; and HR = 0.51, 95% CI: 0.33-0.78, respectively), except for the subgroup of BRCA1 promoter methylation (HR = 1.59, 95% CI: 0.72-3.50). The meta analysis of progression-free survival (PFS), which included 18 evaluable studies, demonstrated that BRCA dysfunction status was associated with a longer PFS in EOC (HR = 0.69, 95% CI: 0.63-0.76). CONCLUSIONS: Patients with BRCA dysfunction status tend to have a better outcome, but further prospective clinical studies comparing the different BRCA statuses in EOC is urgently needed to specifically define the most effective treatment for the separate patient groups. PMID- 24788698 TI - Indications, Hospital Course, and Complexity of Patients Undergoing Tracheostomy at a Tertiary Care Pediatric Hospital. AB - OBJECTIVE: The purpose of this study was to review inpatients undergoing tracheostomies at a tertiary care pediatric hospital in a 24-month period and to identify the indications, comorbidities, hospital course, patient complexity, and predischarge planning for tracheostomy care. The goal was to analyze these factors to highlight potential areas for improvement. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care pediatric hospital. SUBJECTS: Ninety five inpatients at Boston Children's Hospital requiring a primary or revision tracheostomy during the 24-month period encompassing 2010 to 2011. METHODS: Inpatients undergoing tracheostomy during the study period were identified using 2 different databases: the Boston Children's Hospital Department of Otolaryngology and Communication Enhancement database and institution-specific information from the Child Health Corporation of America's Pediatric Health Information System (PHIS). We extracted the specified metrics from the inpatient charts. RESULTS: Patients undergoing tracheostomy are complex, with an average of 3.4 comorbidities and 13.6 services involved in their care. The tracheostomy was mentioned in 97.9% of physician and 69.5% of nurse discharge notes, and 42.5% of physician discharge notes contained a plan or appointment for follow-up. Of the patients, 33.7% were discharged home (27.3% of the nonanatomic group and 52.4% of the anatomic group). Overall, 8.4% of tracheostomy patients died before discharge. CONCLUSION: The complexity of pediatric tracheostomy patients presents challenges and opportunities for optimizing quality of care for these children. Future directions include the introduction and assessment of multidisciplinary tracheostomy care teams, tracheostomy nurse specialists, and tracheostomy care plans in the pediatric setting. PMID- 24788699 TI - Evaluation of a Telerobotic System for Transnasal Surgery of the Larynx and Airways in Cadavers. AB - OBJECTIVES: Minimally invasive, transnasal endoscopic approaches to the larynx have been utilized but are limited by the precision and accuracy afforded to the surgeon. The objective of this study is to analyze the feasibility of a rapidly deployable telerobotic system for enabling transnasal microsurgery of the larynx and upper airways, specifically injection laryngoplasty. STUDY DESIGN: This is a feasibility study. SETTING: This study was conducted at a laboratory in the Department of Mechanical Engineering at Vanderbilt University. SUBJECTS AND METHODS: A feasibility study was conducted in which a telerobotic system was transnasally inserted in both a human intubation trainer mannequin and a cadaver. A flexible needle was passed through an instrumentation port and targeted specific areas of the vocal folds of our models to simulate injection laryngoplasty. The experiments were recorded with both still and video photography. Average forces exerted on surrounding tissue and times of deployment were measured. RESULTS: Our robot was able to expeditiously gain access to the glottis with an average manual insertion time of 5.87 seconds while exerting minimal forces on the surrounding tissues with an average force of 4.45 Newtons. The onboard fiberoptic endoscope conveyed images of adequate quality for the completion of a simulated injection medialization laryngoplasty. The experiment was successfully completed in both mannequin and cadaveric models. CONCLUSION: This telerobotic system proved to be capable of being rapidly deployed to the upper airways while exerting minimal forces to the surrounding structures and successfully simulated injection medialization laryngoplasty. PMID- 24788700 TI - High-efficiency targeted editing of large viral genomes by RNA-guided nucleases. AB - A facile and efficient method for the precise editing of large viral genomes is required for the selection of attenuated vaccine strains and the construction of gene therapy vectors. The type II prokaryotic CRISPR-Cas (clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas)) RNA-guided nuclease system can be introduced into host cells during viral replication. The CRISPR-Cas9 system robustly stimulates targeted double-stranded breaks in the genomes of DNA viruses, where the non-homologous end joining (NHEJ) and homology directed repair (HDR) pathways can be exploited to introduce site-specific indels or insert heterologous genes with high frequency. Furthermore, CRISPR-Cas9 can specifically inhibit the replication of the original virus, thereby significantly increasing the abundance of the recombinant virus among progeny virus. As a result, purified recombinant virus can be obtained with only a single round of selection. In this study, we used recombinant adenovirus and type I herpes simplex virus as examples to demonstrate that the CRISPR-Cas9 system is a valuable tool for editing the genomes of large DNA viruses. PMID- 24788701 TI - Transcriptome profiling of human ulcerative colitis mucosa reveals altered expression of pathways enriched in genetic susceptibility loci. AB - Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P = 1.49 * 10(-19)). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process. PMID- 24788702 TI - Cancer stem-like cells and thyroid cancer. AB - Thyroid cancer is one of the most rapidly increasing malignancies. The reasons for this increase is not completely known, but increases in the diagnosis of papillary thyroid microcarcinomas and follicular variant of papillary thyroid carcinomas along with the enhanced detection of well-differentiated thyroid carcinomas are probably all contributing factors. Although most cases of well differentiated thyroid carcinomas are associated with an excellent prognosis, a small percentage of patients with well-differentiated thyroid carcinomas as well as most patients with poorly differentiated and anaplastic thyroid carcinomas have recurrent and/or metastatic disease that is often fatal. The cancer stem like cell (CSC) model suggests that a small number of cells within a cancer, known as CSCs, are responsible for resistance to chemotherapy and radiation therapy, as well as for recurrent and metastatic disease. This review discusses current studies about thyroid CSCs, the processes of epithelial-to-mesenchymal transition (EMT), and mesenchymal-to-epithelial transition that provide plasticity to CSC growth, in addition to the role of microRNAs in CSC development and regulation. Understanding the biology of CSCs, EMT and the metastatic cascade should lead to the design of more rational targeted therapies for highly aggressive and fatal thyroid cancers. PMID- 24788703 TI - Diagnosing the Correct Site of Obstruction in Newly Diagnosed Obstructive Sleep Apnea. AB - HYPOTHESIS: Upper airway evaluation identifies the correct site of obstruction in newly diagnosed obstructive sleep apnea. PMID- 24788704 TI - Are aortic valve reoperations after primary replacement with stentless heart valve prostheses more demanding than after stented biological prostheses? AB - OBJECTIVE: Reoperations after aortic valve replacement (AVR) with stentless valve prostheses are believed to be surgically more difficult than after stented prostheses. METHODS: Between January 1996 and December 2006, 1,340 of 3,785 patients with AVR in a single institution received a stentless valve prosthesis in aortic position (Medtronic Freestyle, Medtronic GmbH, Meerbusch, Germany). Reoperations after stentless AVR occurred in 27 patients (2.0%). Twenty-four of these patients were compared with another 24 patients having redo surgery after a primary stented bioprosthesis after carrying out propensity score matching. RESULTS: After matching, stentless valve redo patients had a similar preoperative risk profile regarding EuroSCORE (stentless 10 +/- 3 points/stented 11 +/- 3 points; p = 0.37), preoperative active endocarditis (stentless 37.5%/stented 16.7%; p = 0.081), and amount of concomitant procedures (stentless 37.5%/stented 16.7%; p = 0.222). Thirty-day mortality after reoperation was 20.8% (5 patients) in the stentless and 4.2% (1 patient) in the stented group (p = 0.081), and reintubation rate was 16.7% in the stentless and 0% in the stented group (p = 0.037). Aortic clamping time (stentless 90 +/- 25 min/stented 86 +/- 34 min; p = 0.208) and extracorporeal circulation time (stentless 151 +/- 59 min/stented 132 +/- 52 min; p = 0.55) were similar in both groups. CONCLUSION: Our data do not show that the technical difficulty of reoperations after stentless AVR is higher than that of reoperations after stented AVR. The clinically visible, but not statistically significant, higher early mortality rate of our stentless group is mainly due to more active valve prosthesis endocarditis cases and a higher amount of concomitant procedures. PMID- 24788705 TI - Need for psychosocial assistance in patients undergoing cardiothoracic surgery evaluated by a seven-item questionnaire. AB - BACKGROUND: Cardiothoracic surgery can have adverse effects on the patients' psychosocial well-being which may influence the overall prognosis. In this study, we tested the use of a seven-item screening instrument for the preoperative identification of need for psychosocial assistance in cardiothoracic patients. Methods and RESULTS: A total of 297 consecutive patients (69% male) with a median age of 70 years (59;75) completed the seven-item Hornheide Screening Instrument (HSI) on the day of admission. According to questionnaire scores predefined in the literature (cutoff >= 4), 130 patients (44%) exhibited a need for psychosocial support. We found female patients to have significantly higher need for psychosocial support than male patients, irrespective of their age, New York Heart Association classification or Canadian Cardiovascular Society classification, and the type of surgery they were undergoing (53 vs. 41%, p=0.034). In addition, we found that preoperative need for psychosocial support, using the predefined cutoff criterion as well as a higher absolute score, was associated with a prolonged length of hospitalization (p<0.05). CONCLUSION: We found the HSI to be a suitable tool to identify psychosocial need in cardiothoracic patients. The relatively high incidence of these patients in our study concurs with previous studies, which generally used more complex instruments. In addition, we found that preoperative scores were associated with prolonged length of stay. Therefore, the use of this questionnaire could represent an alternative, more rapid tool for the psychosocial assessment of cardiothoracic patients in daily routine. PMID- 24788706 TI - Restrictive Atrial Septum Defect Becomes a Risk Factor for Norwood Palliation of Hypoplastic Left Heart Syndrome Only When It Is Combined with Mitral or Aortic Atresia. AB - BACKGROUND: Restrictive atrial septal defect (ASD) is described as risk factor for Norwood procedure because of elevated pulmonary resistance. We hypothesized that it invariably could not cause pulmonary hypertension, unless it was combined with mitral valve or aortic valve atresia. We investigated how restrictive ASD influenced survival of patients with hypoplastic left heart syndrome (HLHS) who underwent Norwood operation. PATIENTS AND METHODS: A total of 118 HLHS patients who underwent surgery between January 2005 and December 2012 were grouped into three groups. Group 1 included 31 patients with restrictive ASD combined with mitral or aortic atresia; Group 2 composed of 12 patients with restrictive ASD and mitral and aortic stenosis; Group 3 (n = 75) had no ASD restriction. Survival was determined for each group. Multivariate analysis was conducted to test risk factors for mortality. RESULTS: Mean follow-up was 26.3 +/- 24.1 months. Survival was 78.7% +/- 4.2% at 30-month interval and onward after Norwood procedure for the whole cohort; it was 43.8% +/- 10.0%, 91.7% +/- 8.0%, and 77.3% +/- 5.0% for Group 1, 2, and 3, respectively. The difference was significant between Group 1 and Group 2 and 3: p < 0.001. Survival was similar for Group 2 and Group 3: p = 0.45. Combination of restrictive ASD and mitral or aortic atresia was found to be the sole risk factor for early and late mortality (odds ratio: 3.5, 95% confidence interval: 1.8-7.1, p < 0.001). CONCLUSION: Restrictive ASD only affects survival of HLHS patients following Norwood procedure if it is associated with mitral or aortic atresia. PMID- 24788707 TI - Optimal lung inflation techniques in a rat lung transplantation model: a revisit. AB - BACKGROUND: Most of the experimental work assessing optimal lung inflation during lung graft preservation was performed in the late 1990s. Since that time, lung preservation before transplantation has been more standardized, and the optimal lung inflation techniques used during lung preservation in the current clinical setting remain undefined. Nonetheless, lung inflation during storage may play a pivotal role in optimal lung preservation. MATERIALS AND METHODS: Lewis rat lungs were perfused with and stored in cold, low-potassium dextran solution (Perfadex, Vitrolife, Goteborg, Sweden) for 6 hours at different levels of lung inflation (25, 50, 75, or 100% of vital capacity [VC]). Orthotopic left lung transplantation using cuff techniques was performed in syngeneic Lewis rats. Posttransplant allograft function, expression of proinflammatory mediators, and expression of lung surfactants were evaluated. RESULTS: Lungs inflated to 75 or 100% VC showed a significantly better oxygenation in blood gas analysis than lungs inflated to 25 or 50% VC. The levels of mRNAs for tumor necrosis factor alpha, pro-interleukin-1beta, intracellular adhesion molecule 1 were attenuated in lungs inflated to 75 or 100% VC as compared with deflated lungs, suggesting reduced ischemia/reperfusion injury. In addition, transmission electron microscopy demonstrated better preserved lung surfactants in the alveolar space in the lungs inflated to 75 or 100% VC. CONCLUSIONS: Inflating lungs to 75 or 100% VC during preservation may be beneficial and result in better posttransplant allograft function through attenuated reperfusion injury and better preserved lung surfactants. PMID- 24788708 TI - 72 hours standby time of wet-primed cardiopulmonary bypass circuits: a microbiological quality assurance study. AB - In a microbiological sample study of 15 wet-primed cardiopulmonary bypass circuits in standby mode for 72 hours under regular clinical conditions, no contamination of the priming fluid or the connectors could be detected. Hand contact surfaces of the machines demonstrated environmental microorganisms. These findings indicate the safe use of primed cardiopulmonary bypass circuits in standby mode for 72 hours. A surface disinfection of hand contact surfaces immediately before use is recommended. PMID- 24788709 TI - Bernoulli in the operating room: from the perspective of a cardiac surgeon. AB - The Bernoullis were one of the most distinguished families in the history of science. It was Daniel Bernoulli who applied mathematical physics to medicine to further his understanding of physiological mechanisms that have an impact even in today's high-end medicine. His masterwork was the analysis of fluid dynamics, which resulted in Bernoulli's law. Most important for cardiac surgery, it describes how a centrifugal pump works within an extracorporeal circulation, lays the basis for measuring a gradient over a stenotic heart valve, and explains how to measure the transit time flow within a bypass graft. PMID- 24788710 TI - Women's representation in 60 occupations from 1972 to 2010: more women in high status jobs, few women in things-oriented jobs. AB - To explore factors associated with occupational sex segregation in the United States over the past four decades, we analyzed U.S. Bureau of Labor Statistics data for the percent of women employed in 60 varied occupations from 1972 to 2010. Occupations were assessed on status, people-things orientation, and data ideas orientation. Multilevel linear modeling (MLM) analyses showed that women increasingly entered high-status occupations from 1972 to 2010, but women's participation in things-oriented occupations (e.g., STEM fields and mechanical and construction trades) remained low and relatively stable. Occupations' data ideas orientation was not consistently related to sex segregation. Because of women's increased participation in high-status occupations, occupational status became an increasingly weak predictor of women's participation rates in occupations, whereas occupations' people-things orientation became an increasingly strong predictor over time. These findings are discussed in relation to theories of occupational sex segregation and social policies to reduce occupational sex segregation. PMID- 24788712 TI - Spectral-domain optical coherence tomography of the rodent eye: highlighting layers of the outer retina using signal averaging and comparison with histology. AB - Spectral-Domain Optical Coherence Tomography (SD-OCT) is a widely used method to observe retinal layers and follow pathological events in human. Recently, this technique has been adapted for animal imaging. This non-invasive technology brings a cross-sectional visualization of the retina, which permits to observe precisely each layer. There is a clear expansion of the use of this imaging modality in rodents, thus, a precise characterization of the different outer retinal layers observed by SD-OCT is now necessary to make the most of this technology. The identification of the inner strata until the outer nuclear layer has already been clearly established, while the attribution of the layers observed by SD-OCT to the structures corresponding to photoreceptors segments and retinal pigment epithelium is much more questionable. To progress in the understanding of experimental SD-OCT imaging, we developed a method for averaging SD-OCT data to generate a mean image allowing to better delineate layers in the retina of pigmented and albino strains of mice and rats. It allowed us to locate precisely the interface between photoreceptors and retinal pigment epithelium and to identify unambiguously four layers corresponding to the inner and outer parts of photoreceptors segments. We show that the thickness of the various layers can be measured as accurately in vivo on SD-OCT images, than post-mortem by a morphometric analysis of histological sections. We applied SD-OCT to different models and demonstrated that it allows analysis of focal or diffuse retinal pathological processes such as mutation-dependent damages or light-driven modification of photoreceptors. Moreover, we report a new method of combined use of SD-OCT and integration to quantify laser-induced choroidal neovascularization. In conclusion, we clearly demonstrated that SD-OCT represents a valuable tool for imaging the rodent retina that is at least as accurate as histology, non-invasive and allows longitudinal follow-up of the same animal. PMID- 24788713 TI - Older Women Discuss Planning for Future Care Needs: An Explanatory Framework. AB - OBJECTIVE: This study expands upon existing narrative data concerning health care preparation by developing a multi-theme framework of plans for future care needs. METHOD:: Inductive content analysis was conducted on 185 interviews with European American and African American older women. RESULTS:: An explanatory framework emerged of five themes, describing varied approaches to planning for future care needs: (a) Autonomous Care Planners, (b) Externally Reliant Planners, (c) Aware of Preference, (d) Wishful Thinkers, and (e) Avoidant. A distinct group included women performing only end-of-life planning. Barriers to planning included low perceived vulnerability, financial constraints, being uninformed of needed actions, and fear of burdening. DISCUSSION:: Although the majority undertook active steps to prepare for future care needs, many missed key steps or achievement of planning goals recommended by experts. Findings may be applied to long-term care planning research by providing added, rich detail on how aging women construct their options, make choices, and address this important area for future well-being. PMID- 24788715 TI - Hearing Loss in Older Persons: Does the Rate of Decline Affect Psychosocial Health? AB - OBJECTIVE: This study investigates whether the rate of decline in older persons' hearing status is associated with the rate of decrease in their psychosocial health and explores moderation by baseline hearing status, health-related factors, and sociodemographic factors. METHOD: Multilevel analyses were applied to data of 1,178 older participants from the Longitudinal Aging Study Amsterdam (LASA), covering 3 to 7 years of follow-up. RESULTS: Faster decrease in speech-in noise recognition was significantly associated with more increase in loneliness for persons with a moderate baseline speech-in-noise recognition (emotional and social loneliness) and for persons who recently lost their partner (emotional loneliness). No relationship was found with depression. DISCUSSION: The results indicate that faster hearing decline results in more increase in loneliness in specific subgroups of older persons: in persons with an already impaired hearing and in widow(er)s. Monitoring older persons' hearing seems important and may be a relevant starting point for targeted loneliness prevention efforts. PMID- 24788716 TI - Waist circumference and health-related quality of life by sex in the Korean elderly. AB - OBJECTIVE: This study aims to explore the impact of differential degrees of obesity on health-related quality of life (HRQL) by sex in the Korean elderly. METHOD: We analyzed data on those aged between 65 and 74 years from the Korean National Health and Nutrition Examination Survey (KNHANES) using multiple regression analysis. RESULTS: Compared with the lowest waist circumference (WC) quintile, the women in the fourth and fifth quintiles demonstrated significantly lower unadjusted HRQL but not the men in any quintiles. Whereas higher WC quintiles impaired mobility, usual activities, and pain/discomfort in women, the fourth WC quintile improved usual activities in men. After adjustment, only the women of the highest WC quintile reported impaired mobility. DISCUSSION: Extreme obesity worsens mobility, and comorbidity in combination with obesity worsens HRQL in elderly women. Monitoring and controlling comorbidity and maintaining adequate WC decreases the risks of lowered HRQL in Korean elderly women. PMID- 24788717 TI - Use of Quality Indicators in Nursing Homes in Victoria, Australia: A Cross Sectional Descriptive Survey. AB - OBJECTIVE: This study aimed to characterize the use of mandated quality indicators (QIs) in public sector nursing homes by describing their adherence to established principles of measurement and whether nursing homes respond to QI data to improve care. METHOD: Data were collected from a descriptive cross sectional quantitative study using a confidential survey questionnaire distributed electronically to senior staff in all public sector nursing homes in Victoria, Australia. RESULTS: Staff from 113 of 196 facilities completed the survey (58%). Adherence to principles of measurement was suboptimal, with variation in applying QI definitions and infrequent random audits of data (n = 54, 48%). QI data triggered reviews of individual residents (62%-79%), staff practice (44%-65%), and systems of care (45%-55%). Most facilities (58%-75%) reported that beneficial changes in care occurred as a result of using QIs. DISCUSSION: QI performance data are positively received and used to improve care. Standardization of data collection, analysis, and reporting should strengthen the program's utility. PMID- 24788714 TI - How design of places promotes or inhibits mobility of older adults: realist synthesis of 20 years of research. AB - OBJECTIVE: The objective of this study was to determine the environmental features that best support aging in place. METHOD: We conducted a realist synthesis, a theory-driven interpretive method of evidence synthesis, of 120+ articles (published 1991-2011) that attempts to explain how place may influence older adults' decisions about mobility (e.g., physical activity). We developed an initial program theory, reviewed the literature, identified outcomes, analyzed and synthesized patterns, and created a final program theory. RESULTS: Safety was a central mechanism, serving as one of the bridges between environmental components (e.g., connectivity, aesthetics, retail and services) and decisions about mobility. Population density, sidewalk presence, and park proximity did not emerge as key factors. DISCUSSION: Safety considerations are one of the most prominent influences of older adults' decisions about mobility. Street connectivity, pedestrian access and transit, and retail and services were also important. These factors are amenable to change and can help promote mobility for older adults. PMID- 24788718 TI - Short-Term Impact of Anemia on Mortality: Evidence From a Sample of Mexican Older Adults. AB - OBJECTIVE: To estimate the short-term (14 months) impact of anemia on mortality among Mexican older adults (OAs). METHOD: Longitudinal analyses using data from a quasi-experimental study in a non-contributory pension program in Mexico with a sample of 3,621 OAs aged 65 to 74 years. Data on health, nutrition, life conditions, and mortality were gathered at both baseline and follow-up. Logistic regression model was used to estimate the impact of anemia and hemoglobin quintiles on mortality. RESULTS: Overall mortality rate was 2.1%. Both mild anemia and moderate/severe anemia increased mortality risk at 14 months (odds ratio [OR] = 2.04, 95% confidence interval [CI] = [1.1, 4.1]; and OR = 6, 95% CI = [2.1, 16.9], respectively). DISCUSSION: In the short term, degree of severity of anemia is an independent predictor of mortality risk. Because anemia is a modifiable factor, further research is required to better understand this condition in terms of main causes, prevention, treatment, and impact on OAs' survival. PMID- 24788719 TI - Distribution, cleavage and lipidation of Atg8 fusion proteins in Spodoptera litura Sl-HP cells. AB - Atg8 proteins fused with tags are commonly used to detect autophagy. The expression patterns of Lepidopteran insect Atg8 are relatively well documented. However, the influence of protein tags on characterization of Atg8 is still not very clear. Our results showed that endogenous Spodoptera litura Atg8 and HA tagged Atg8 driven by the baculovirus ie2 promoter were enriched in cytoplasm. The recombinant plasmid pEGFP-Atg8(EGFP) in which Atg8 contained a stop codon was constructed and expressed. Green fluorescence was accumulated in cytoplasm. However, red fluorescence was located in both cytoplasm and nucleoplasm in most cells transfected with the recombinant plasmid pmCherry-Atg8(EGFP). In contrast to pEGFP-Atg8(EGFP), green fluorescence was also located in both cytoplasm and nucleoplasm in most cells transfected with the recombinant plasmid pie2/EGFP-Atg8 driven by the baculovirus ie2 promoter in which the CMV promoter and EGFP nucleotide sequences were removed, and the high level of the EGFP-Atg8 expression significantly increased its abundance in nucleoplasm. HA-Atg8 expressed at high level through baculovirus under the control of polyherin promoter was also localized in cytoplasm and nucleoplasm. The cleavage of mCherry-Atg8 was different from that of EGFP-Atg8. Both the mutant mCherry-Atg8F77/79A resulting in non-cleavage of the Atg8 and the mutant mCherry-Atg8G exposing its glycine residue at the end of C-terminus were also localized in cytoplasm and nucleoplasm. The increase of autophagosomes decreased the abundance of mCherry Atg8 in nucleoplasm. In addition, the ratio of HA-Atg8-PE/HA-Atg8 was less than that of endogenous Atg8-PE/Atg8. These results demonstrated that the Atg8 is located in both nucleus and cytoplasm when expressed at high level and exported to the cytoplasm when autophagy is activated, and the fusion tags of Atg8 might have influence on the processing of Atg8 fusion proteins. PMID- 24788720 TI - Insect leaf-chewing damage tracks herbivore richness in modern and ancient forests. AB - The fossil record demonstrates that past climate changes and extinctions significantly affected the diversity of insect leaf-feeding damage, implying that the richness of damage types reflects that of the unsampled damage makers, and that the two are correlated through time. However, this relationship has not been quantified for living leaf-chewing insects, whose richness and mouthpart convergence have obscured their value for understanding past and present herbivore diversity. We hypothesized that the correlation of leaf-chewing damage types (DTs) and damage maker richness is directly observable in living forests. Using canopy access cranes at two lowland tropical rainforest sites in Panama to survey 24 host-plant species, we found significant correlations between the numbers of leaf chewing insect species collected and the numbers of DTs observed to be made by the same species in feeding experiments, strongly supporting our hypothesis. Damage type richness was largely driven by insect species that make multiple DTs. Also, the rank-order abundances of DTs recorded at the Panama sites and across a set of latest Cretaceous to middle Eocene fossil floras were highly correlated, indicating remarkable consistency of feeding-mode distributions through time. Most fossil and modern host-plant pairs displayed high similarity indices for their leaf-chewing DTs, but informative differences and trends in fossil damage composition became apparent when endophytic damage was included. Our results greatly expand the potential of insect-mediated leaf damage for interpreting insect herbivore richness and compositional heterogeneity from fossil floras and, equally promisingly, in living forests. PMID- 24788722 TI - Long-term citizen-collected data reveal geographical patterns and temporal trends in lake water clarity. AB - We compiled a lake-water clarity database using publically available, citizen volunteer observations made between 1938 and 2012 across eight states in the Upper Midwest, USA. Our objectives were to determine (1) whether temporal trends in lake-water clarity existed across this large geographic area and (2) whether trends were related to the lake-specific characteristics of latitude, lake size, or time period the lake was monitored. Our database consisted of >140,000 individual Secchi observations from 3,251 lakes that we summarized per lake-year, resulting in 21,020 summer averages. Using Bayesian hierarchical modeling, we found approximately a 1% per year increase in water clarity (quantified as Secchi depth) for the entire population of lakes. On an individual lake basis, 7% of lakes showed increased water clarity and 4% showed decreased clarity. Trend direction and strength were related to latitude and median sample date. Lakes in the southern part of our study-region had lower average annual summer water clarity, more negative long-term trends, and greater inter-annual variability in water clarity compared to northern lakes. Increasing trends were strongest for lakes with median sample dates earlier in the period of record (1938-2012). Our ability to identify specific mechanisms for these trends is currently hampered by the lack of a large, multi-thematic database of variables that drive water clarity (e.g., climate, land use/cover). Our results demonstrate, however, that citizen science can provide the critical monitoring data needed to address environmental questions at large spatial and long temporal scales. Collaborations among citizens, research scientists, and government agencies may be important for developing the data sources and analytical tools necessary to move toward an understanding of the factors influencing macro-scale patterns such as those shown here for lake water clarity. PMID- 24788721 TI - Gene expression profile and toxic effects in human bronchial epithelial cells exposed to zearalenone. AB - Zearalenone (ZEA), a mycoestrogen produced by Fusarium fungal species, is mainly found in cereal crops such as maize, wheat and barley. Although ZEA has been reported to be present in air, little is known about the health risk or the molecular basis of action when lung cells are exposed to ZEA. As ZEA has a similar structure to estrogen, its potential risk as an endocrine disrupting chemical (EDC) has thus aroused both environmental and public health concerns. The purpose of this study is to identify the responses and underlying molecular changes that occur when human bronchial epithelial BEAS-2B cells are exposed to ZEA. Differential gene expression profiles were identified in cells that were treated with 40 uM ZEA for 6 h and 24 h by high-throughput microarray analysis using Affymetrix Human Gene 2.0 GeneChip. The array results showed that after ZEA treatment, 262 genes at 6 h and 1073 genes at 24 h were involved in the differential regulation. Pathway analysis revealed that diverse cellular processes were affected when lung cells were exposed to ZEA resulting in impaired response to DNA damage, cell cycle arrest, down-regulation of inflammatory responses and alterations of epigenetic marks. Results of further experiments indicated that 40 uM ZEA decreased cell viability, induced apoptosis and promoted reactive oxygen species (ROS) generation in a time-dependent manner. Immuno suppressive effects of ZEA were further revealed through the suppression of lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, IL-8 and IL-1beta). Interestingly, the level of global DNA methylation was markedly decreased after 24 h exposure to ZEA. Collectively, these observations suggested that a broad range of toxic effects are elicited by ZEA. Particularly, ROS may play a pivotal role in ZEA-induced cell death. These adverse effects observed in lung cells suggest that exposure to ZEA may increase susceptibility of lung cells to diseases and required further investigations. PMID- 24788723 TI - Membrane connexin 43 acts as an independent prognostic marker in oral squamous cell carcinoma. AB - The aim of the present study was to evaluate the expression and localization of connexin (Cx) 26, -43 and -45 in a group of 35 patients with primary oral squamous cell carcinoma (OSCC) with the objective of making a more accurate disease prognosis. We analysed the expression of connexins in tissue samples of primary OSCC, matching oral mucosa free of dysplasia, and its associated lymph node metastases (LNM) by semi-quantitative immunohistochemistry of membrane, cytoplasmic and nuclear connexin expression. The levels of expression were correlated with the overall survival time (OS). Cx43 was overexpressed in tumour cells compared to epithelia in dysplasia-free mucosa. High membrane expression of Cx43 on tumour cells was the only statistically significant and independent prognostic factor of short OS (P=0.0088). Membrane expression of Cx43 in matching dysplasia-free mucosa acted similarly, but did not reach statistical significance (P=0.059). No correlation was found between the Cx26, Cx45 expression and OS. We conclude that Cx43 expression in dysplasia-free mucosa may indicate a very early stage of tumour promotion. Although overexpression of Cx43 is found in invasive tumours we only found membrane Cx43 expression to correlate with OS. This observation suggests that cytoplasmic Cx43 serves as storage and only membrane translocation may promote the formation of gap junctions and gap junctional intercellular communication (GJIC) with prognostic relevance. PMID- 24788724 TI - Diagnostic accuracy of the PURE-LAMP test for pulmonary tuberculosis at the county-level laboratory in China. AB - BACKGROUND: Early and effective detection of Mycobacterium tuberculosis (MTB), particularly in smear-negative tuberculosis (TB), is a priority for global TB control. Loop-mediated isothermal amplification with a procedure for ultra rapid DNA extraction (PURE-LAMP) can detect TB in sputum samples rapidly and with high sensitivity and specificity. However, the PURE-LAMP test has not been effectively evaluated, especially in resource-limited laboratories. In this study, we evaluated the performance of the PURE-LAMP test for TB detection in TB suspects from two county-level TB dispensaries in China. METHODOLOGY/PRINCIPAL FINDINGS: From April 2011 to February 2012, patients with suspected TB were continuously enrolled from two county-level TB laboratories in China. Three sputum samples (spot, night, and morning sputum) were collected from each recruited patient. Detection of MTB by PURE-LAMP was compared to a reference standard L-J culture. The results showed that the sensitivity of the PURE-LAMP test based on spot sputum for MTB detection was 70.67%, while the sensitivity of the PURE-LAMP test based on spot sputum for MTB detection in smear positive and culture positive patients and smear negative and culture positive patients was 92.12% and 53.81%, respectively. The specificity of PURE-LAMP based on spot sputum for MTB detection was 98.32%. The sensitivity and specificity of the PURE-LAMP test based on three sputa combination for MTB detection was 88.80% and 96.86%, respectively. The results also showed that the PURE-LAMP test had a significantly lower contamination rate than did solid culture. CONCLUSIONS/SIGNIFICANCE: The study suggested that, in peripheral-level TB laboratories in China, the PURE-LAMP test showed high sensitivity and specificity for TB detection in TB suspects, making it a more effective, rapid, and safe method worthy of broader use in the future. PMID- 24788725 TI - Murder or not? Cold temperature makes criminals appear to be cold-blooded and warm temperature to be hot-headed. AB - Temperature-related words such as cold-blooded and hot-headed can be used to describe criminal behavior. Words associated with coldness describe premeditated behavior and words associated with heat describe impulsive behavior. Building on recent research about the close interplay between physical and interpersonal coldness and warmth, we examined in a lab experiment how ambient temperature within a comfort zone influences judgments of criminals. Participants in rooms with low temperature regarded criminals to be more cold-blooded than participants in rooms with high temperature. Specifically, they were more likely to attribute premeditated crimes, ascribed crimes resulting in higher degrees of penalty, and attributed more murders to criminals. Likewise, participants in rooms with high temperature regarded criminals to be more hot-headed than participants in rooms with low temperature: They were more likely to attribute impulsive crimes. Results imply that cognitive representations of temperature are closely related to representations of criminal behavior and attributions of intent. PMID- 24788726 TI - Selective expression of tumor necrosis factor-related apoptosis-inducing ligand mediated by microRNA suppresses renal carcinoma growth. AB - Renal cell carcinoma (RCC) is the most common types among kidney cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) strongly induces apoptosis in RCC. However, TRAIL therapy also leads to hepatotoxicity. To improve the biosafety, we inserted miRNA response elements (MREs) of miR-138, miR-199, and miR-122 into an adenoviral vector, Ad-TRAIL-3MREs, to restrict TRAIL expression within RCC cells. Luciferase assays showed that MREs can regulate the expression of exogenous gene in RCC cells. Ad-TRAIL-3MREs selectively expressed TRAIL and induce apoptosis in RCC cells, but not in normal cells. MTT assays revealed that Ad-TRAIL-3MREs reduced viability of RCC cells without cytotoxicity to normal cells. Ad-TRAIL-3MREs suppressed the growth of ACHN tumors and exerted no hepatotoxicity in vivo. Collectively, we generated a TRAIL-expressing adenoviral vector under the regulation of MREs. This miRNA-based gene therapy may be a promising strategy for RCC treatment. PMID- 24788727 TI - PIPKIIalpha is widely expressed in hematopoietic-derived cells and may play a role in the expression of alpha- and gamma-globins in K562 cells. AB - Characterized for the first time in erythrocytes, phosphatidylinositol phosphate kinases (PIP kinases) belong to a family of enzymes that generate various lipid messengers and participate in several cellular processes, including gene expression regulation. Recently, the PIPKIIalpha gene was found to be differentially expressed in reticulocytes from two siblings with hemoglobin H disease, suggesting a possible relationship between PIPKIIalpha and the production of globins. Here, we investigated PIPKIIalpha gene and protein expression and protein localization in hematopoietic-derived cells during their differentiation, and the effects of PIPKIIalpha silencing on K562 cells. PIPKIIalpha silencing resulted in an increase in alpha and gamma globins and a decrease in the proliferation of K562 cells without affecting cell cycle progression and apoptosis. In conclusion, using a cell line model, we showed that PIPKIIalpha is widely expressed in hematopoietic-derived cells, is localized in their cytoplasm and nucleus, and is upregulated during erythroid differentiation. We also showed that PIPKIIalpha silencing can induce alpha and gamma globin expression and decrease cell proliferation in K562 cells. PMID- 24788728 TI - Expression of oxidored nitro domain-containing protein 1(NOR1) impairs nasopharyngeal carcinoma cells adaptation to hypoxia and inhibits PDK1 expression. AB - Hypoxia is a characteristic pathophysiological property of locally advanced solid tumors and a relevant factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Tumors alter their metabolic pathways to survive in nutrient and oxygen poor microenvironments by a process known as the "Warburg Effect." The current studies identify a novel tumor suppressor gene, termed oxidored nitro domain-containing protein 1 (NOR1) which alters hypoxia cellular response in nasopharyngeal carcinoma. NOR1 expression causes apoptosis of tumor cells in hypoxia by altering the expression of PDK1 expression and mitochondrial Bax-Bcl2 balance thus suppress tumor cell adaptation to hypoxia. Although the importance of hypoxia cellular response is well documented in tumor progression, this is the first demonstration of a human tumor suppressor which functions by regulating mitochondrial apoptotic pathways to suppress tumor survival in oxygen poor microenvironments. PMID- 24788729 TI - Lycopene inhibits neointimal hyperplasia through regulating lipid metabolism and suppressing oxidative stress. AB - The present study aimed to investigate the possible mechanism(s) through which lycopene inhibits neointimal hyperplasia in restenosis models. A total of 32 white rabbits were randomly divided into the following four groups: A sham group, a model group, a model group treated with apocynin and a model group treated with lycopene. Immunohistochemistry and transmission electron microscopy (TEM) were used to detect the carotid structures in these groups. Quantitative polymerase chain reaction (qPCR) and western blot analysis were performed to detect the mRNA and protein expression levels of the proteins involved in cell proliferation and oxidative stress, including anti-proliferating cell nuclear antigen, extracellular signal-regulated kinase, nicotinamide adenine dinucleotide phosphate oxidase 1, hydroxymethyl glutaric acyl coenzyme A reductase, adenosine triphosphate-binding cassette transporter A1 and human neutrophil cytochrome b light chain. Immunohistochemistry and TEM indicated that lycopene treatment significantly reduced the intima/media ratios, the accumulation of lipids and the formation of foam cells in carotid plaques in rabbit restenosis models. Furthermore, lycopene regulated the blood lipid levels and suppressed the oxidative stress in these models. In addition, qPCR and western blot analyses revealed that lycopene significantly decreased the expression levels of cell proliferation-associated proteins, as well as proteins involved in lipid synthesis and transportation. The results suggest that lycopene may regulate lipid metabolism and suppress oxidative stress, and thus, represents a promising therapeutic against neointimal hyperplasia. PMID- 24788730 TI - Association of a TNIP1 polymorphism with Vogt-Koyanagi-Harada syndrome but not with ocular Behcet's disease in Han Chinese. AB - OBJECTIVES: The aim of the study was to investigate the association of TNFalpha induced protein 3 interacting with protein 1 (TNIP1) gene polymorphisms with Vogt Koyanagi-Harada (VKH) syndrome and Behcet's disease (BD) in a Han Chinese population. METHODS: A total of 656 BD patients, 961 VKH syndrome patients and 1534 healthy controls were included in this two-stage case control study. Seven SNPs, including rs17728338, rs7708392, rs10036748, rs3762999, rs999556, rs4958881 and rs3792783, belonging to TNIP1 were genotyped and analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The data were analyzed by using the chi2 or Fisher's exact test and corrected for multiple comparisons by the Bonferroni method. RESULTS: A significantly increased frequency of the GG genotype and a decreased frequency of the AG genotype of rs17728338 were found in VKH patients (Pc = 0.038 OR = 1.934, 95% CI = 1.438 ~ 2.601). No significant difference was noted in allele or genotype frequencies of rs7708392, rs10036748, rs3762999, rs999556, rs4958881 and rs3792783, between VKH patients and healthy controls (Pc>0.05). No significant difference was noted in allele or genotype frequencies of the tested 7 SNPs between BD patients and healthy controls. Analysis of extraocular clinical findings, did not reveal an association of the TNIP1 gene polymorphisms with BD or VKH syndrome subgroups. CONCLUSION: A TNIP1 polymorphism may be a risk factor for VKH syndrome in Han Chinese. PMID- 24788731 TI - Dopamine release dynamics change during adolescence and after voluntary alcohol intake. AB - Adolescence is associated with high impulsivity and risk taking, making adolescent individuals more inclined to use drugs. Early drug use is correlated to increased risk for substance use disorders later in life but the neurobiological basis is unclear. The brain undergoes extensive development during adolescence and disturbances at this time are hypothesized to contribute to increased vulnerability. The transition from controlled to compulsive drug use and addiction involve long-lasting changes in neural networks including a shift from the nucleus accumbens, mediating acute reinforcing effects, to recruitment of the dorsal striatum and habit formation. This study aimed to test the hypothesis of increased dopamine release after a pharmacological challenge in adolescent rats. Potassium-evoked dopamine release and uptake was investigated using chronoamperometric dopamine recordings in combination with a challenge by amphetamine in early and late adolescent rats and in adult rats. In addition, the consequences of voluntary alcohol intake during adolescence on these effects were investigated. The data show a gradual increase of evoked dopamine release with age, supporting previous studies suggesting that the pool of releasable dopamine increases with age. In contrast, a gradual decrease in evoked release with age was seen in response to amphetamine, supporting a proportionally larger storage pool of dopamine in younger animals. Dopamine measures after voluntary alcohol intake resulted in lower release amplitudes in response to potassium-chloride, indicating that alcohol affects the releasable pool of dopamine and this may have implications for vulnerability to addiction and other psychiatric diagnoses involving dopamine in the dorsal striatum. PMID- 24788732 TI - Fetal alcohol exposure among African Americans. PMID- 24788734 TI - Datapoints: U.S. out-of-pocket health care expenses for mental disorders, 1996 2011. PMID- 24788735 TI - Integrated care: nonfasting screening for cardiovascular risk among individuals taking second-generation antipsychotics. AB - Ischemic heart disease (IHD) is the leading cause of mortality among adults with severe mental illness. Although gains in reducing mortality from IHD through screening, risk reduction, and early intervention have been realized for the general public, rates of recognition and treatment among individuals with mental illness continue to be poor. Obtaining blood samples from patients who have been fasting for eight to 12 hours is challenging for adults with severe mental illness and presents an additional obstacle to screening and treatment. This column outlines newer guidelines for cholesterol and diabetes screening that provide valid alternatives to fasting blood draws, thereby significantly reducing this common barrier to recognition of leading risk factors for IHD. PMID- 24788736 TI - Engaging U.S. veterans with PTSD in online therapy. PMID- 24788737 TI - Schizophrenia treatment satisfaction in Nigeria. PMID- 24788738 TI - Dis-ease and disease. PMID- 24788739 TI - Dis-ease and disease: in reply. PMID- 24788740 TI - Conflicts among CMHC clinicians over the role of urine drug testing. PMID- 24788741 TI - Report estimates substantial economic impact of integrated care. PMID- 24788750 TI - Metal-free aerobic oxidative C-N bond cleavage of tertiary amines for the synthesis of N-heterocycles with high atom efficiency. AB - An efficient metal-free aerobic oxidative C-N bond cleavage of tertiary amines has been developed to construct N-heterocycles using molecular oxygen as the sole oxidant with high atom efficiency, in which all of the three alkyl groups in tertiary amines can be utilized and transformed into N-heterocycles. PMID- 24788751 TI - A case-control study of the protective effect of alcohol, coffee, and cigarette consumption on Parkinson disease risk: time-since-cessation modifies the effect of tobacco smoking. AB - The aim of this study was to investigate the possible reduced risk of Parkinson Disease (PD) due to coffee, alcohol, and/or cigarette consumption. In addition, we explored the potential effect modification by intensity, duration and time since-cessation of smoking on the association between cumulative pack-years of cigarette smoking (total smoking) and PD risk. Data of a hospital based case control study was used including 444 PD patients, diagnosed between 2006 and 2011, and 876 matched controls from 5 hospitals in the Netherlands. A novel modeling method was applied to derive unbiased estimates of the potential modifying effects of smoking intensity, duration, and time-since-cessation by conditioning on total exposure. We observed no reduced risk of PD by alcohol consumption and only a weak inverse association between coffee consumption and PD risk. However, a strong inverse association of total smoking with PD risk was observed (OR=0.27 (95%CI: 0.18-0.42) for never smokers versus highest quartile of tobacco use). The observed protective effect of total smoking was significantly modified by time-since-cessation with a diminishing protective effect after cessation of smoking. No effect modification by intensity or duration of smoking was observed indicating that both intensity and duration have an equal contribution to the reduced PD risk. Understanding the dynamics of the protective effect of smoking on PD risk aids in understanding PD etiology and may contribute to strategies for prevention and treatment. PMID- 24788752 TI - Functional characterization of the rice UDP-glucose 4-epimerase 1, OsUGE1: a potential role in cell wall carbohydrate partitioning during limiting nitrogen conditions. AB - Plants grown under inadequate mineralized nitrogen (N) levels undergo N and carbon (C) metabolic re-programming which leads to significant changes in both soluble and insoluble carbohydrate profiles. However, relatively little information is available on the genetic factors controlling carbohydrate partitioning during adaptation to N-limitation conditions in plants. A gene encoding a uridine-diphospho-(UDP)-glucose 4-epimerase (OsUGE-1) from rice (Oryza sativa) was found to be N-responsive. We developed transgenic rice plants to constitutively over-express the OsUGE-1 gene (OsUGE1-OX1-2). The transgenic rice lines were similar in size to wild-type plants at the vegetative stage and at maturity regardless of the N-level tested. However, OsUGE1-OX lines maintained 18 24% more sucrose and 12-22% less cellulose in shoots compared to wild-type when subjected to sub-optimal N-levels. Interestingly, OsUGE1-OX lines maintained proportionally more galactose and glucose in the hemicellulosic polysaccharide profile of plants compared to wild-type plants when grown under low N. The altered cell wall C-partitioning during N-limitation in the OsUGE1-OX lines appears to be mediated by OsUGE1 via the repression of the cellulose synthesis associated genes, OsSus1, OsCesA4, 7, and 9. This relationship may implicate a novel control point for the deposition of UDP-glucose to the complex polysaccharide profiles of rice cell walls. However, a direct relationship between OsUGE1 and cell wall C-partitioning during N-limitation requires further investigation. PMID- 24788753 TI - Risk factors for venous thromboembolism in 1.3 million pregnancies: a nationwide prospective cohort. AB - OBJECTIVE: To quantify risk factors for venous thromboembolism during pregnancy and the puerperal period. DESIGN: In a nationwide prospective cohort study we followed pregnant and puerperal women in Denmark from 1995 to 2009 for venous thromboembolism. Information on risk factors and confounders was retrieved from national registries. The diagnosis of venous thromboembolism was confirmed through medical charts. We calculated adjusted incidence rates per 10,000 women years and used Poisson regression to estimate effects during pregnancy and the puerperal period. RESULTS: We studied 1,297,037 pregnancies and related puerperal periods, during which there were 748 venous thromboembolisms. The incidence rate for venous thromboembolism during a pregnancy with and without hospitalization for hyperemesis was 15.2/10,000 yr and 6.3/10,000 yr, respectively, (adjusted rate ratio: 2.5 (95%-confidence interval; 1.4-4.5)). The incidence rate among women with multiple pregnancies was 18.2/10,000 yr and 6.3/10,000 yr in singletons (adjusted rate ratio: 2.8 (1.9-4.2)). Increased risk was found with hospitalization during pregnancy or the puerperal period with incidence rates of 42.1/10.000 and 54.7/10.000, respectively, (rate ratios: 12.2 (8.7-17) and 5.9 (4.0-8.8)). Women hospitalized with infections during pregnancy had incidence rates of 25.9/10,000 yr and 29.3/10,000 yr during pregnancy and the puerperal period, respectively, and of 62.7/10,000 yr if hospitalized with infection in the puerperal period. Puerperal venous thromboembolism was associated with hospitalization for preeclampsia and intrauterine growth restriction/fetal death with incidence rates of 45.8/10,000 yr and 18.3/10,000 yr, respectively (rate ratio: 5.0 (3.1-7.8) and 1.9 (0.9-4.4)). Additionally puerperal venous thromboembolism was associated with obesity, elective and acute caesarean sections and major postpartum bleeding with incidence rates of 25.5/10,000 yr, 23.2/10,000 yr, 34.0/10,000 yr and 20.3/10,000 yr, respectively (rate ratios 1.7 (1.1-2.7), 2.1 (1.4-3.1), 3.0 (2.3-4.0) and 1.4 (1.0-2.1)). CONCLUSIONS: Important risk factors for venous thromboembolism during pregnancy or the puerperal period were hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, caesarean section, major postpartum bleeding, and intrauterine growth restriction or fetal death. PMID- 24788754 TI - PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling. AB - Protein Tyrosine Kinase 6 (PTK6) is a non-receptor type tyrosine kinase that may be involved in some cancers. However, the biological role and expression status of PTK6 in pancreatic cancer is unknown. Therefore in this study, we evaluated the functional role of PTK6 on pancreatic cancer invasion. Five pancreatic cancer cell lines expressed PTK6 at varying levels. PTK6 expression was also observed in human pancreatic adenocarcinomas. PTK6 suppression by siRNA significantly reduced both cellular migration and invasion (0.59/0.49 fold for BxPC3, 0.61/0.62 for Panc1, 0.42/0.39 for MIAPaCa2, respectively, p<0.05 for each). In contrast, forced overexpression of PTK6 by transfection of a PTK6 expression vector in Panc1 and MIAPaCa2 cells increased cellular migration and invasion (1.57/1.67 fold for Panc1, 1.44/1.57 for MIAPaCa2, respectively, p<0.05). Silencing PTK6 reduced ERK1/2 activation, but not AKT or STAT3 activation, while PTK6 overexpression increased ERK1/2 activation. U0126, a specific inhibitor of ERK1/2, completely abolished the effect of PTK6 overexpression on cellular migration and invasion. These results suggest that PTK6 regulates cellular migration and invasion in pancreatic cancer via ERK signaling. PTK6 may be a novel therapeutic target for pancreatic cancer. PMID- 24788755 TI - The survival effect in memory: does it hold into old age and non-ancestral scenarios? AB - The survival effect in memory refers to the memory enhancement for materials encoded in reference to a survival scenario compared to those encoded in reference to a control scenario or with other encoding strategies. The current study examined whether this effect is well maintained in old age by testing young (ages 18-29) and older adults (ages 65-87) on the survival effect in memory for words encoded in ancestral and/or non-ancestral modern survival scenarios relative to a non-survival control scenario. A pilot study was conducted to select the best matched comparison scenarios based on potential confounding variables, such as valence and arousal. Experiment 1 assessed the survival effect with a well-matched negative control scenario in both young and older adults. The results showed an age-equivalent survival effect across an ancestral and a non ancestral modern survival scenario. Experiment 2 replicated the survival effect in both age groups with a positive control scenario. Taken together, the data suggest a robust survival effect that is well preserved in old age across ancestral and non-ancestral survival scenarios. PMID- 24788756 TI - Stress exacerbates infectivity and pathogenicity of Blastocystis hominis: in vitro and in vivo evidences. AB - BACKGROUND: Stress alters the oxidant-antioxidant state and immune cell responses which disrupts its function to combat infection. Blastocystis hominis, a common intestinal protozoan has been reported to be opportunistic in immunocompromised patients namely cancer. B. hominis infectivity in other altered immune system conditions especially stress is unknown. We aimed to demonstrate the stress effects towards the susceptibility and pathogenicity of B. hominis infection. METHODS/FINDINGS: Three-week-old Wistar rats were divided into four groups: (a)control; (b)stress-induced; (c)B. hominis infected; (d)stress-induced with B. hominis infection; (n = 20 respectively). Stress was induced for an hour daily (30 days) using a Belly Dancer Shaker. Weight gain was monitored, stool samples were collected for B. hominis screening and blood for the determination of differential count, levels of immunoglobulin, oxidative damage, and peripheral blood mononuclear cell (PBMC) proliferation upon induction with solubilized antigen of B. hominis (Blasto-Ag). Group (b) exhibited the highest level of weight gain. Group (d) had higher levels of parasite cyst count in stools, serum IgE, oxidized protein and lipid compared to the group (c). Levels of monocyte and antioxidant in group (d) were decreased and their PBMCs showed highest inhibition of proliferation level when exposed to Blasto-Ag. Monocyte level in Group (b) showed insignificant difference compared to group (a) but was significantly lower compared to group (c). Antioxidant levels in group (c) were generally lower compared to group (a) and (b). Inhibition level exhibited by Blasto-Ag treated PBMCs of group (c) was higher compared to group (a) and (b). CONCLUSION: The pathogenicity and augmentation of B. hominis infection is enhanced when stress is present. Lifestyles today are becoming increasingly stressed and the present findings suggest that the parasite which has been reported to be one of the most common organisms seen in stool surveys, namely in developing countries, may tend to be more pathogenic in stressful situations. PMID- 24788757 TI - Hemostatic effects of microbubble-enhanced low-intensity ultrasound in a liver avulsion injury model. AB - OBJECTIVES: Microbubble-enhanced therapeutic ultrasound (MEUS) can block the blood flow in the organs. The aim of this study was to evaluate the hemostatic effect of microbubble-enhanced pulsed, low-intensity ultrasound in a New Zealand White rabbit model of avulsion trauma of the liver. The therapeutic ultrasound (TUS) transducer was operated with the frequency of 1.2 MHz and an acoustic pressure of 3.4 MPa. Microbubble-(MB) enhanced ultrasound (MEUS) (n = 6) was delivered to the distal part of the liver where the avulsion was created. Livers were treated by TUS only (n = 4) or MB only (n = 4) which served as controls. Bleeding rates were measured and contrast enhanced ultrasound (CEUS) was performed to assess the hemostatic effect, and liver hemoperfusion before and after treatment. Generally, bleeding rates decreased more than 10-fold after the treatment with MEUS compared with those of the control group (P<0.05). CEUS showed significant declines in perfusion. The peak intensity value and the area under the curve also decreased after insonation compared with those of the control group (P<0.05). Histological examination showed cloudy and swollen hepatocytes, dilated hepatic sinusoids, perisinusoidal spaces with erythrocyte accumulation in small blood vessels, obvious hemorrhage around portal areas and scattered necrosis in liver tissues within the insonation area of MEUS Group. In addition, necrosis was found in liver tissue 48 h after insonation. We conclude that MEUS might provide an effective hemostatic therapy for serious organ trauma such as liver avulsion injury. PMID- 24788759 TI - A human blood-brain barrier transcytosis assay reveals antibody transcytosis influenced by pH-dependent receptor binding. AB - We have adapted an in vitro model of the human blood-brain barrier, the immortalized human cerebral microvascular endothelial cells (hCMEC/D3), to quantitatively measure protein transcytosis. After validating the receptor mediated transport using transferrin, the system was used to measure transcytosis rates of antibodies directed against potential brain shuttle receptors. While an antibody to the insulin-like growth factor 1 receptor (IGF1R) was exclusively recycled to the apical compartment, the fate of antibodies to the transferrin receptor (TfR) was determined by their relative affinities at extracellular and endosomal pH. An antibody with reduced affinity at pH5.5 showed significant transcytosis, while pH-independent antibodies of comparable affinities at pH 7.4 remained associated with intracellular vesicular compartments and were finally targeted for degradation. PMID- 24788758 TI - Follicular helper T cells promote liver pathology in mice during Schistosoma japonicum infection. AB - Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice. PMID- 24788761 TI - Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. AB - BACKGROUND: Amifostine is the most clinical used chemical radioprotector, but its effect in patients treated with radiation is not consistent. METHODS: By searching Medline, CENTRAL, EMBASE, ASCO, ESMO, and CNKI databases, the published randomized controlled trials (RCTs) about the efficacy of amifostine in HNSCC patients treated with radiotherapy were collected. The pooled efficacy and side effects of this drug were calculated by RevMan software. RESULTS: Seventeen trials including a total of 1167 patients (604 and 563 each arm) were analyzed in the meta-analysis. The pooled data showed that the use of amifostine significantly reduce the risk of developing Grade 3-4 mucositis (relative risk [RR],0.72; 95% confidence interval [CI],0.54-0.95; p<0.00001), Grade 2-4 acute xerostomia (RR,0.70; 95%CI,0.52-0.96; p = 0.02), or late xerostomia (RR,0.60; 95%CI,0.49-0.74; p<0.00001) and Grade 3-4 dysphagia (RR,0.39; 95%CI,0.17-0.92; p = 0.03). However, subgroup analysis demonstrated that no statistically significant reduction of Grade 3-4 mucositis (RR,0.97; 95% CI,0.74-1.26; p = 0.80), Grade 2-4 acute xerostomia (RR,0.35; 95%CI,0.02-5.44; p = 0.45), or late xerostomia (RR,0.40; 95%CI,0.13-1.24; p = 0.11) and Grade 3-4 dysphagia (RR,0.23; 95%CI,0.01-4.78; p = 0.35) was observed in patients treated with concomitant chemoradiotherapy. Compared with placebo or observation, amifostine does not show tumor protective effect in complete response (RR,1.02; 95%CI,0.89-1.17; p = 0.76) and partial response (RR,0.90; 95%CI, 0.56-1.44; p = 0.66). For the hematologic side effect, no statistical difference of Grade 3-4 leucopenia (RR,0.60; 95%CI,0.35-1.05; p = 0.07), anemia (RR,0.80; 95%CI, 0.42-1.53; p = 0.50) and thrombocytopenia (RR,0.43; 95%CI,0.16-1.15; p = 0.09) were found between amifostine and control groups. The most common amifostine related side effects were nausea, emesis, hypotension and allergic with an average incidence rate (Grade 3-4) of 5%, 6%, 4% and 4% respectively. CONCLUSION: This systematic review showed that amifostine significantly reduce the serious mucositis, acute/late xerastomia and dysphagia without protection of the tumor in HNSCC patients treated with radiotherapy. And the toxicities of amifostine were generally acceptable. PMID- 24788762 TI - The continuous incorporation of carbon into existing Sassafras albidum fine roots and its implications for estimating root turnover. AB - Although understanding the timing of the deposition of recent photosynthate into fine roots is critical for determining root lifespan and turnover using isotopic techniques, few studies have directly examined the deposition and subsequent age of root carbon. To gain a better understanding of the timing of the deposition of root carbon, we labeled four individual Sassafras albidum trees with 99% 13C CO2. We then tracked whether the label appeared in roots that were at least two weeks old and no longer elongating, at the time of labeling. We found that not only were the non-structural carbon pools (soluble sugars and starch) of existing first-order tree roots incorporating carbon from current photosynthate, but so were the structural components of the roots, even in roots that were more than one year old at the time of labeling.Our findings imply that carbon used in root structural and nonstructural pools is not derived solely from photosynthate at root initiation and have implications regarding the determination of root age and turnover using isotopic techniques. PMID- 24788768 TI - Single versus combination intravenous antibiotic therapy for people with cystic fibrosis. AB - BACKGROUND: Choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. OBJECTIVES: To assess the effectiveness of single compared to combination intravenous antibiotic therapy for treating people with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search of the Group's Trials Register: 22 August 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a single intravenous antibiotic with a combination of that antibiotic plus a second antibiotic in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: We identified 43 trials, of which eight trials (356 participants) comparing a single agent to a combination of the same antibiotic and one other, were included.There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam aminoglycoside combination. These two groups of trials were analysed as separate subgroups.There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. The meta analysis did not demonstrate any significant differences between monotherapy and combination therapy, in terms of lung function; symptom scores; adverse effects; and bacteriological outcome measures.These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor. AUTHORS' CONCLUSIONS: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials. PMID- 24788769 TI - Enhanced production of docosahexaenoic acid in mammalian cells. AB - Docosahexaenoic acid (DHA), one of the important polyunsaturated fatty acids (PUFA) with pharmaceutical and nutraceutical effects, may be obtained through diet or synthesized in vivo from dietary a-linolenic acid (ALA). However, the accumulation of DHA in human body or other mammals relies on the intake of high dose of DHA for a certain period of time, and the bioconversion of dietary ALA to DHA is very limited. Therefore the mammalian cells are not rich in DHA. Here, we report a new technology for increased production of DHA in mammalian cells. By using transient transfection method, Siganus canaliculatus Delta4 desaturase was heterologously expressed in chinese hamster ovary (CHO) cells, and simultaneously, mouse Delta6-desaturase and Delta5-desaturase were overexpressed. The results demonstrated that the overexpression of Delta6/Delta5-desaturases significantly enhanced the ability of transfected cells to convert the added ALA to docosapentaenoic acid (DPA) which in turn get converted into DHA directly and efficiently by the heterologously expressed Delta4 desaturase. This technology provides the basis for potential utility of these gene constructs in the creation of transgenic livestock for increased production of DHA/related products to meet the growing demand of this important PUFA. PMID- 24788770 TI - Prognostic significance of the neutrophil-to-lymphocyte ratio in primary liver cancer: a meta-analysis. AB - The neutrophil-to-lymphocyte ratio (NLR) is a useful biomarker that reflects systemic inflammation responses. However, the prognostic value of the NLR in patients with primary liver cancer (PLC) remains controversial. We performed a meta-analysis of 26 studies (comprising 4,461 patients) to evaluate the association between the pre-treatment NLR and clinical outcomes of overall survival (OS) and disease-free survival (DFS) in patients with PLC. The correlation between NLR and tumor characteristics or other inflammation-related parameters was also assessed. Data were synthesized using the random-effects model of DerSimonian and Laird, and the hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was used to estimate effect size. Our analysis indicated that a high NLR predicted poor OS (HR, 2.102; 95% CI: 1.741-2.538) and DFS (HR, 2.474; 95% CI: 1.855-3.300) for PLC. A high NLR was associated with the presence of tumor vascular invasion (OR: 1.889, 95% CI: 1.487-2.400; p<0.001) and an elevated alpha-fetoprotein level (OR: 1.536; 95% CI: 1.152-2.048; p = 0.003). Thus, we conclude that a high NLR indicates a poor prognosis for patients with PLC and may also be predictive for PLC invasion and metastasis. Subgroup analysis suggested that the predictive role of NLR in cholangiocarcinoma is limited, and a further large study to confirm these findings is warranted. PMID- 24788772 TI - Diverse gastropod hosts of Angiostrongylus cantonensis, the rat lungworm, globally and with a focus on the Hawaiian Islands. AB - Eosinophilic meningitis caused by the parasitic nematode Angiostrongylus cantonensis is an emerging infectious disease with recent outbreaks primarily in tropical and subtropical locations around the world, including Hawaii. Humans contract the disease primarily through ingestion of infected gastropods, the intermediate hosts of Angiostrongylus cantonensis. Effective prevention of the disease and control of the spread of the parasite require a thorough understanding of the parasite's hosts, including their distributions, as well as the human and environmental factors that contribute to transmission. The aim of this study was to screen a large cross section of gastropod species throughout the main Hawaiian Islands to determine which act as hosts of Angiostrongylus cantonensis and to assess the parasite loads in these species. Molecular screening of 7 native and 30 non-native gastropod species revealed the presence of the parasite in 16 species (2 native, 14 non-native). Four of the species tested are newly recorded hosts, two species introduced to Hawaii (Oxychilus alliarius, Cyclotropis sp.) and two native species (Philonesia sp., Tornatellides sp.). Those species testing positive were from a wide diversity of heterobranch taxa as well as two distantly related caenogastropod taxa. Review of the global literature showed that many gastropod species from 34 additional families can also act as hosts. There was a wide range of parasite loads among and within species, with an estimated maximum of 2.8 million larvae in one individual of Laevicaulis alte. This knowledge of the intermediate host range of Angiostrongylus cantonensis and the range of parasite loads will permit more focused efforts to detect, monitor and control the most important hosts, thereby improving disease prevention in Hawaii as well as globally. PMID- 24788771 TI - Marine litter distribution and density in European seas, from the shelves to deep basins. AB - Anthropogenic litter is present in all marine habitats, from beaches to the most remote points in the oceans. On the seafloor, marine litter, particularly plastic, can accumulate in high densities with deleterious consequences for its inhabitants. Yet, because of the high cost involved with sampling the seafloor, no large-scale assessment of distribution patterns was available to date. Here, we present data on litter distribution and density collected during 588 video and trawl surveys across 32 sites in European waters. We found litter to be present in the deepest areas and at locations as remote from land as the Charlie-Gibbs Fracture Zone across the Mid-Atlantic Ridge. The highest litter density occurs in submarine canyons, whilst the lowest density can be found on continental shelves and on ocean ridges. Plastic was the most prevalent litter item found on the seafloor. Litter from fishing activities (derelict fishing lines and nets) was particularly common on seamounts, banks, mounds and ocean ridges. Our results highlight the extent of the problem and the need for action to prevent increasing accumulation of litter in marine environments. PMID- 24788773 TI - Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease. AB - The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane of brain neurons and is involved in endoplasmic reticulum-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid beta production associated with endoplasmic reticulum stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer's disease patients because of its insolubility. The mechanisms that affect HRD1 solubility are not well understood. We here show that HRD1 protein was insolubilized by oxidative stress but not by other Alzheimer's disease-related molecules and stressors, such as amyloid beta, tau, and endoplasmic reticulum stress. Furthermore, we raise the possibility that modifications of HRD1 by 4-hydroxy-2 nonenal, an oxidative stress marker, decrease HRD1 protein solubility and the oxidative stress led to the accumulation of HRD1 into the aggresome. Thus, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased amyloid beta production and amyloid beta-induced oxidative stress in Alzheimer's disease pathogenesis. PMID- 24788774 TI - Blinded by PRISMA: are systematic reviewers focusing on PRISMA and ignoring other guidelines? AB - BACKGROUND: PRISMA guidelines have been developed to improve the reporting of systematic reviews (SRs). Other reporting guidelines and techniques to assess methodological quality of SRs have been developed. We aimed to assess the frequency of the use of reporting and other guidelines in SRs to assess whether PRISMA is being used inappropriately as a substitute for other relevant guidelines. METHODS: Web of Knowledge was searched to identify articles citing the PRISMA guidelines over a 12-month period. The use of reporting guidelines (including PRISMA and MOOSE) and tools for assessing methodological quality (including QUADAS) was assessed. Factors associated with appropriate use of guidelines including review type, field of publication and involvement of a methodologist were investigated. RESULTS: Over the 12-month period, 701 SRs were identified. MOOSE guidelines were cited in just 17% of epidemiologic reviews; QUADAS or QUADAS-2 was referred to in just 40% of diagnostic SRs. In the multivariable analysis, medical field of publication and methodologist involvement (OR = 1.97, 95% CI: 1.37, 2.83) were significant predictors of appropriate use of guidelines. Inclusion of a meta-analysis resulted in 73% higher odds of appropriate usage of systematic review guidelines (OR = 1.73, 95% CI: 1.22, 2.35). CONCLUSIONS: Usage of SR reporting guidelines and tools for assessment of methodological quality other than PRISMA may be under-utilized with negative implications both for the reporting and methodological quality of systematic reviews. PMID- 24788775 TI - Mapping the homodimer interface of an optimized, artificial, transmembrane protein activator of the human erythropoietin receptor. AB - Transmembrane proteins constitute a large fraction of cellular proteins, and specific interactions involving membrane-spanning protein segments play an important role in protein oligomerization, folding, and function. We previously isolated an artificial, dimeric, 44-amino acid transmembrane protein that activates the human erythropoietin receptor (hEPOR) in trans. This artificial protein supports limited erythroid differentiation of primary human hematopoietic progenitor cells in vitro, even though it does not resemble erythropoietin, the natural ligand of this receptor. Here, we used a directed-evolution approach to explore the structural basis for the ability of transmembrane proteins to activate the hEPOR. A library that expresses thousands of mutants of the transmembrane activator was screened for variants that were more active than the original isolate at inducing growth factor independence in mouse cells expressing the hEPOR. The most active mutant, EBC5-16, supports erythroid differentiation in human cells with activity approaching that of EPO, as assessed by cell-surface expression of glycophorin A, a late-stage marker of erythroid differentiation. EBC5-16 contains a single isoleucine to serine substitution at position 25, which increases its ability to form dimers. Genetic studies confirmed the importance of dimerization for activity and identified the residues constituting the homodimer interface of EBC5-16. The interface requires a GxxxG dimer packing motif and a small amino acid at position 25 for maximal activity, implying that tight packing of the EBC5-16 dimer is a crucial determinant of activity. These experiments identified an artificial protein that causes robust activation of its target in a natural host cell, demonstrated the importance of dimerization of this protein for engagement of the hEPOR, and provided the framework for future structure function studies of this novel mechanism of receptor activation. PMID- 24788778 TI - Effects of Arginine concentration on the in vitro expression of Casein and mTOR pathway related genes in mammary epithelial cells from dairy cattle. AB - Arginine (Arg) is a conditionally-essential amino acid that is taken up by bovine mammary gland in excess of its output in milk. In this study we evaluated the effects of Arg concentration on the expression of casein and signaling pathway related genes in mammary epithelial cells. The treatments (applied for 24 h) were designed to be devoid of Arg 0X (control; 0.00 mg/L), resemble the profile of Arg in casein (Arg 1X; 278.00 mg/L), be deficient [Arg 0.25X (69.50 mg/L) and Arg 0.5X (139.00 mg/L)], or be in excess of the amount in casein [Arg 2X (556.00 mg/L), Arg 4X (1,112 mg/L), and Arg 8X (2,224 mg/L)]. The expression of CSN1S, CSN3 and mTOR in the experimental groups was higher than those of the control group (P<0.05). Except for Arg 0.25X and Arg 8X (P>0.05), the expression of CSN1S2, CSN2 and JAK2 in other experimental groups was higher (P<0.05) than those in the control group. Except for Arg 8X (P>0.05), the expression of STAT5 in the other experimental groups was higher than those of the control (P<0.05). It also was observed that except for Arg 0.5X, the S6K expression was higher in other experimental groups than the control (P<0.05). In contrast, except for Arg 0.25X the other experimental groups resulted in lower 4EBP1 expression than the control (P<0.05). Among groups, the expression of CSN1S1, CSN1S2, CSN2, CSN3, JAK2, STAT5, mTOR and S6K gene was highest with Arg 2X (P<0.05); the reverse was true for 4EBP1 gene, with the lowest expression in this group (P<0.05). Taken together, Arg appears to play an important role in the transcriptional regulation of casein genes and mTOR-related genes in bovine mammary epithelial cells. PMID- 24788776 TI - Sparstolonin B, a novel plant derived compound, arrests cell cycle and induces apoptosis in N-myc amplified and N-myc nonamplified neuroblastoma cells. AB - Neuroblastoma is one of the most common solid tumors and accounts for ~ 15% of all the cancer related deaths in the children. Despite the standard therapy for advanced disease including chemotherapy, surgery, and radiation, the mortality rate remains high for these patients. Hence, novel therapeutic agents are desperately needed. Here we examined the anticancer activity of a novel plant derived compound, sparstolonin B (SsnB; 8,5'-dihydroxy-4-phenyl-5,2' oxidoisocoumarin) using neuroblastoma cell lines of different genetics. SsnB was recently isolated from an aquatic Chinese herb, Sparganium stoloniferum, and tubers of this herb have been used in traditional Chinese medicine for the treatment of several inflammatory diseases and cancers. Our cell viability and morphological analysis indicated that SsnB at 10 uM concentration significantly inhibited the growth of both N-myc amplified (SK-N-BE(2), NGP, and IMR-32 cells) and N-myc nonamplified (SH-SY5Y and SKNF-1 cells) neuroblastoma cells. The flow cytometric analyses suggested that SsnB arrests the cell cycle progression at G2 M phase in all neuroblastoma cell lines tested. Exposure of SsnB inhibited the compact spheroid formation and reduced the tumorigenicity of SH-SY5Y cells and SK N-BE(2) cells in in vitro 3-D cell culture assays (anchorage-independent colony formation assay and hanging drop assay). SsnB lowers the cellular level of glutathione (GSH), increases generation of reactive oxygen species and activates the cleavage of caspase-3 whereas co-incubation of a GSH precursor, N acetylcysteine, along with SsnB attenuates the inhibitory effects of SsnB and increases the neuroblastoma cell viability. Our results for the first time demonstrate that SsnB possesses anticancer activity indicating that SsnB-induced reactive oxygen species generation promotes apoptotic cell death in neuroblastoma cells of different genetic background. Thus these data suggest that SsnB can be a promising drug candidate in neuroblastoma therapy. PMID- 24788779 TI - New therapy of skin repair combining adipose-derived mesenchymal stem cells with sodium carboxymethylcellulose scaffold in a pre-clinical rat model. AB - Lesions with great loss of skin and extensive burns are usually treated with heterologous skin grafts, which may lead rejection. Cell therapy with mesenchymal stem cells is arising as a new proposal to accelerate the healing process. We tested a new therapy consisting of sodium carboxymethylcellulose (CMC) as a biomaterial, in combination with adipose-derived stem cells (ADSCs), to treat skin lesions in an in vivo rat model. This biomaterial did not affect membrane viability and induced a small and transient genotoxicity, only at the highest concentration tested (40 mg/mL). In a rat wound model, CMC at 10 mg/mL associated with ADSCs increased the rate of cell proliferation of the granulation tissue and epithelium thickness when compared to untreated lesions (Sham), but did not increase collagen fibers nor alter the overall speed of wound closure. Taken together, the results show that the CMC is capable to allow the growth of ADSCs and is safe for this biological application up to the concentration of 20 mg/mL. These findings suggest that CMC is a promising biomaterial to be used in cell therapy. PMID- 24788781 TI - Tailored nutrition education and food assistance improve adherence to HIV antiretroviral therapy: evidence from Honduras. AB - Food insecurity and malnutrition negatively affect adherence to antiretroviral therapy (ART) and are associated with poor HIV clinical outcomes. We examined the effect of providing household food assistance and nutrition education on ART adherence. A 12-month prospective clinical trial compared the effect of a monthly household food basket (FB) plus nutrition education (NE) versus NE alone on ART adherence on 400 HIV patients at four clinics in Honduras. Participants had been receiving ART for an average of 3.7 years and were selected because they had suboptimal adherence. Primary outcome measures were missed clinic appointments, delayed prescription refills, and self-reported missed doses of ART. These three adherence measures improved for both groups over 12 months (p < 0.01), mostly within 6 months. On-time prescription refills improved for the FB plus NE group by 19.6 % more than the group receiving NE alone after 6 months (p < 0.01), with no further change at 12 months. Change in missed appointments and self-reported missed ART doses did not significantly differ by intervention group. PMID- 24788780 TI - Declining prevalence of probable depression among patients presenting for antiretroviral therapy in rural Uganda: the role of early treatment initiation. AB - Little is known about trends in depression at antiretroviral therapy (ART) initiation among people living with HIV (PLHIV) in low- and middle-income countries. We used data from an ongoing cohort of treatment-naive PLHIV in rural Uganda to estimate secular trends in depression among PLHIV at ART initiation. We fitted linear regression models with depression symptom severity as the outcome variable and year of cohort entry (2005-2012) as the explanatory variable, adjusting for socio-demographic variables and assessing physical health score, body mass index (BMI), and CD4 count as potential mediators of a secular trend in depression symptom severity. There was a statistically significant negative association between year of entry and depression symptom severity, suggesting a 3.1 % relative decline in the mean depression symptom severity score at ART initiation in each year of study recruitment after the first year. This trend remained statistically significant after inclusion of baseline socio-demographic characteristics to the model and appeared to be driven by improved physical health scores, but not CD4 count or BMI. PMID- 24788783 TI - State health system performance: a scorecard. PMID- 24788782 TI - Socialization patterns and their associations with unprotected anal intercourse, HIV, and syphilis among high-risk men who have sex with men and transgender women in Peru. AB - The association of socialization patterns with unprotected anal intercourse (UAI) and HIV/STI prevalence remains underexplored in men who have sex with men (MSM) and transgender women (TW) in developing country settings. We evaluated the correlation of UAI, HIV, and syphilis with MSM/TW venue attendance and social network size among high-risk MSM and TW in Peru according to self-reported sexual identity. Frequency of venue attendance and MSM/TW social network size were lowest among heterosexual MSM and highest among TW respondents. Attendance (frequent or occasional) at MSM/TW venues was associated with increased odds of insertive UAI among heterosexual participants. Frequent venue attendance was associated with increased odds of receptive UAI among gay/homosexual, bisexual, and TW participants. Further investigation of the differing socialization patterns and associations with HIV/STI transmission within subgroups of Peruvian MSM and TW will enable more effective prevention interventions for these populations. PMID- 24788784 TI - Characterization and complete separation of major cyclolinopeptides in flaxseed oil by reversed-phase chromatography. AB - Organoleptic properties of flaxseed oil deteriorate during storage due to methionine oxidation in its major cyclolinopeptides. Cyclolinopeptide E was previously identified as being responsible for the manifestation of bitter taste with flaxseed oil ageing. We developed a chromatographic procedure to monitor the oxidation of major cyclic peptides in flaxseed oil. We also used liquid chromatography with mass spectrometry and high-efficiency core-shell reversed phase sorbents to study the separation of cyclolinopeptides in detail. The Kinetex(TM) family of stationary phases (C8, C18, phenyl-hexyl) was tested, along with the standard porous Luna(TM) C18(2) media. We found that only the phenyl hexyl stationary phase allows for complete resolution of major cyclolinopeptides, thus permitting direct UV monitoring of degree of conversion for cyclolinopeptide B into C and L into E. We also report, for the first time, a significant effect of peak splitting for some methionine S-oxide (Mso) containing cyclolinopeptides, which most likely appear due to diastereomerization. This results in poor separation efficiency for cyclolinopeptides F, G, and E, and gives baseline resolution of diastereomeric pairs for cyclolinopeptides I and P. Thus, a single oxidation of cyclolinopeptide N yields three distinct chromatographic peaks corresponding to cyclolinopeptide T (cyclo-MsoLMPFFWV, reported for the first time) and pair of cyclolinopeptide I (cyclo-MLMsoPFFWV) diastereomers. PMID- 24788785 TI - Bladder function development and its urodynamic evaluation in neonates and infants less than 2 years old. AB - AIMS: To understand the function development of bladder and its evaluation in neonates and infants less than 2 years old. METHODS: Literature on neonatal and infant bladder function development and urodynamic evaluation were collected and reviewed. RESULTS: Normal range of bladder volume, pressure during voiding and other parameters in neonates and infants less than 2 years old is far from set up, making interpretation of UDS findings difficult. This review provides insight into the bladder development process and problems of the lower urinary tract in this age group with special emphasis on the urodynamic evaluation. CONCLUSIONS: Further animal and human studies will increase our understanding of bladder development leading toward mature function. UDS are still important in providing information for early bladder dysfunction in newborns and infants. PMID- 24788786 TI - Comment on "(Au-Ag)144(SR)60 alloy nanomolecules" by C. Kumara and A. Dass, Nanoscale, 2011, 3, 3064. AB - A recent paper in this journal reported the synthesis and characterization via electrospray ionization mass spectroscopy and UV-vis spectroscopy of (Au Ag)144(SR)60 alloy nanomolecules with different compositions, ranging from 1 : 0 to 1 : 0.75 Au : Ag ratios. The UV-vis spectra of such systems were found to exhibit absorption peaks at 310 nm, 425 nm and 560 nm, interpreted as reminiscent of the silver surface plasmon resonance band due to simple atomic replacement of Au by Ag atoms in a fixed structural framework. On the basis of a comparison of experimentally observed and theoretically simulated optical absorption spectra, we conclude that the experimental situation must be more complicated, and that further work is needed to achieve atomistic insight into these fascinating systems. PMID- 24788787 TI - Trends and variations in the rates of hospital complications, failure-to-rescue and 30-day mortality in surgical patients in New South Wales, Australia, 2002 2009. AB - BACKGROUND: Despite the increased acceptance of failure-to-rescue (FTR) as an important patient safety indicator (defined as the percentage of deaths among surgical patients with treatable complications), there has not been any large epidemiological study reporting FTR in an Australian setting nor any evaluation on its suitability as a performance indicator. METHODS: We conducted a population based study on elective surgical patients from 82 public acute hospitals in New South Wales, Australia between 2002 and 2009, exploring the trends and variations in rates of hospital complications, FTR and 30-day mortality. We used Poisson regression models to derive relative risk ratios (RRs) after adjusting for a range of patient and hospital characteristics. RESULTS: The average rates of complications, FTR and 30-day mortality were 13.8 per 1000 admissions, 14.1% and 6.1 per 1000 admission, respectively. The rates of complications and 30-day mortality were stable throughout the study period however there was a significant decrease in FTR rate after 2006, coinciding with the establishment of national and state-level peak patient safety agencies. There were marked variations in the three rates within the top 20% of hospitals (best) and bottom 20% of hospitals (worst) for each of the four peer-hospital groups. The group comprising the largest volume hospitals (principal referral/teaching hospitals) had a significantly higher rate of FTR in comparison to the other three groups of smaller-sized peer hospital groups (RR = 0.78, 0.57, and 0.61, respectively). Adjusted rates of complications, FTR and 30-day mortality varied widely for individual surgical procedures between the best and worst quintile hospitals within the principal referral hospital group. CONCLUSIONS: The decrease in FTR rate over the study period appears to be associated with a wide range of patient safety programs. The marked variations in the three rates between- and within- peer hospital groups highlight the potential for further quality improvement intervention opportunities. PMID- 24788788 TI - An ancient Mediterranean melting pot: investigating the uniparental genetic structure and population history of sicily and southern Italy. AB - Due to their strategic geographic location between three different continents, Sicily and Southern Italy have long represented a major Mediterranean crossroad where different peoples and cultures came together over time. However, its multi layered history of migration pathways and cultural exchanges, has made the reconstruction of its genetic history and population structure extremely controversial and widely debated. To address this debate, we surveyed the genetic variability of 326 accurately selected individuals from 8 different provinces of Sicily and Southern Italy, through a comprehensive evaluation of both Y chromosome and mtDNA genomes. The main goal was to investigate the structuring of maternal and paternal genetic pools within Sicily and Southern Italy, and to examine their degrees of interaction with other Mediterranean populations. Our findings show high levels of within-population variability, coupled with the lack of significant genetic sub-structures both within Sicily, as well as between Sicily and Southern Italy. When Sicilian and Southern Italian populations were contextualized within the Euro-Mediterranean genetic space, we observed different historical dynamics for maternal and paternal inheritances. Y-chromosome results highlight a significant genetic differentiation between the North-Western and South-Eastern part of the Mediterranean, the Italian Peninsula occupying an intermediate position therein. In particular, Sicily and Southern Italy reveal a shared paternal genetic background with the Balkan Peninsula and the time estimates of main Y-chromosome lineages signal paternal genetic traces of Neolithic and post-Neolithic migration events. On the contrary, despite showing some correspondence with its paternal counterpart, mtDNA reveals a substantially homogeneous genetic landscape, which may reflect older population events or different demographic dynamics between males and females. Overall, both uniparental genetic structures and TMRCA estimates confirm the role of Sicily and Southern Italy as an ancient Mediterranean melting pot for genes and cultures. PMID- 24788789 TI - Routes of delivery for CpG and anti-CD137 for the treatment of orthotopic kidney tumors in mice. AB - We have found previously that the tumor cell lines, Renca (a renal cancer) and MC38 (a colon tumor) which had been injected subcutaneously in mice, could be successfully treated with a combination therapy of an oligodeoxynucleotide (CpG1826) (injected intratumorally) and anti-CD137 antibody (injected intraperitoneally). Thus the combination treatment was expected to initiate a "danger" signal via TLR9 on immune cells, and the anti-CD137 was expected to further activate T cells. In the present study, we found that several other tumor types injected subcutaneously could also be successfully treated with this combination therapy. In addition, we wished to determine if the treatment could work as effectively in an orthotopic metastatic model, which is more physiologically relevant to cancer in humans. Renca was selected as we were familiar with injecting this orthotopically into the outer cortex of the kidney in mice, and it spontaneously metastasizes to lung and abdominal sites. We tested various routes of delivery of CpG combined with intraperitoneal delivery of anti CD137. Orthotopic tumors were injected with CpG intratumorally, using ultrasound guided delivery on multiple occasions, combined with anti-CD137 intraperitoneally. A reduction in primary tumor size was observed following intratumoral injection of CpG compared to other treatments. We found that there was a statistically significant increase in survival of mice with orthotopic Renca tumor following intratumoral injection of CpG. However, we determined that the most effective route of delivery of CpG was intravenous, which led to further significantly enhanced survival of mice when combined with anti-CD137 intraperitoneally, likely due to inhibition of metastatic disease. Our data supports future development of this combination therapy for cancer. PMID- 24788790 TI - ModuleRole: a tool for modulization, role determination and visualization in protein-protein interaction networks. AB - Rapidly increasing amounts of (physical and genetic) protein-protein interaction (PPI) data are produced by various high-throughput techniques, and interpretation of these data remains a major challenge. In order to gain insight into the organization and structure of the resultant large complex networks formed by interacting molecules, using simulated annealing, a method based on the node connectivity, we developed ModuleRole, a user-friendly web server tool which finds modules in PPI network and defines the roles for every node, and produces files for visualization in Cytoscape and Pajek. For given proteins, it analyzes the PPI network from BioGRID database, finds and visualizes the modules these proteins form, and then defines the role every node plays in this network, based on two topological parameters Participation Coefficient and Z-score. This is the first program which provides interactive and very friendly interface for biologists to find and visualize modules and roles of proteins in PPI network. It can be tested online at the website http://www.bioinfo.org/modulerole/index.php, which is free and open to all users and there is no login requirement, with demo data provided by "User Guide" in the menu Help. Non-server application of this program is considered for high-throughput data with more than 200 nodes or user's own interaction datasets. Users are able to bookmark the web link to the result page and access at a later time. As an interactive and highly customizable application, ModuleRole requires no expert knowledge in graph theory on the user side and can be used in both Linux and Windows system, thus a very useful tool for biologist to analyze and visualize PPI networks from databases such as BioGRID. AVAILABILITY: ModuleRole is implemented in Java and C, and is freely available at http://www.bioinfo.org/modulerole/index.php. Supplementary information (user guide, demo data) is also available at this website. API for ModuleRole used for this program can be obtained upon request. PMID- 24788791 TI - Efficacy of a metalloproteinase inhibitor in spinal cord injured dogs. AB - Matrix metalloproteinase-9 is elevated within the acutely injured murine spinal cord and blockade of this early proteolytic activity with GM6001, a broad spectrum matrix metalloproteinase inhibitor, results in improved recovery after spinal cord injury. As matrix metalloproteinase-9 is likewise acutely elevated in dogs with naturally occurring spinal cord injuries, we evaluated efficacy of GM6001 solubilized in dimethyl sulfoxide in this second species. Safety and pharmacokinetic studies were conducted in naive dogs. After confirming safety, subsequent pharmacokinetic analyses demonstrated that a 100 mg/kg subcutaneous dose of GM6001 resulted in plasma concentrations that peaked shortly after administration and were sustained for at least 4 days at levels that produced robust in vitro inhibition of matrix metalloproteinase-9. A randomized, blinded, placebo-controlled study was then conducted to assess efficacy of GM6001 given within 48 hours of spinal cord injury. Dogs were enrolled in 3 groups: GM6001 dissolved in dimethyl sulfoxide (n = 35), dimethyl sulfoxide (n = 37), or saline (n = 41). Matrix metalloproteinase activity was increased in the serum of injured dogs and GM6001 reduced this serum protease activity compared to the other two groups. To assess recovery, dogs were a priori stratified into a severely injured group and a mild-to-moderate injured group, using a Modified Frankel Scale. The Texas Spinal Cord Injury Score was then used to assess long-term motor/sensory function. In dogs with severe spinal cord injuries, those treated with saline had a mean motor score of 2 (95% CI 0-4.0) that was significantly (P<0.05; generalized linear model) less than the estimated mean motor score for dogs receiving dimethyl sulfoxide (mean, 5; 95% CI 2.0-8.0) or GM6001 (mean, 5; 95% CI 2.0-8.0). As there was no independent effect of GM6001, we attribute improved neurological outcomes to dimethyl sulfoxide, a pleotropic agent that may target diverse secondary pathogenic events that emerge in the acutely injured cord. PMID- 24788792 TI - Genomic characterization of H14 subtype Influenza A viruses in new world waterfowl and experimental infectivity in mallards (Anas platyrhynchos). AB - Recent repeated isolation of H14 hemagglutinin subtype influenza A viruses (IAVs) in the New World waterfowl provides evidence to suggest that host and/or geographic ranges for viruses of this subtype may be expanding. In this study, we used genomic analyses to gain inference on the origin and evolution of H14 viruses in New World waterfowl and conducted an experimental challenge study in mallards (Anas platyrhynchos) to evaluate pathogenicity, viral replication, and transmissibility of a representative viral strain in a natural host species. Genomic characterization of H14 subtype IAVs isolated from New World waterfowl, including three isolates sequenced specifically for this study, revealed high nucleotide identity among individual gene segments (e.g. >=95% shared identity among H14 HA gene segments). In contrast, lower shared identity was observed among internal gene segments. Furthermore, multiple neuraminidase subtypes were observed for H14 IAVs isolated in the New World. Gene segments of H14 viruses isolated after 2010 shared ancestral genetic lineages with IAVs isolated from wild birds throughout North America. Thus, genomic characterization provided evidence for viral evolution in New World waterfowl through genetic drift and genetic shift since purported introduction from Eurasia. In the challenge study, no clinical disease or lesions were observed among mallards experimentally inoculated with A/blue-winged teal/Texas/AI13-1028/2013(H14N5) or exposed via contact with infected birds. Titers of viral shedding for mallards challenged with the H14N5 IAV were highest at two days post-inoculation (DPI); however shedding was detected up to nine DPI using cloacal swabs. The distribution of viral antigen among mallards infected with H14N5 IAV was largely restricted to enterocytes lining the villi in the lower intestinal tract and in the epithelium of the bursa of Fabricius. Characterization of the infectivity of A/blue-winged teal/Texas/AI13-1028/2013(H14N5) in mallards provides support for similarities in viral replication and shedding as compared to previously described waterfowl adapted, low pathogenic IAV strains in ducks. PMID- 24788794 TI - Validation of a French version of the quality of life "Celiac Disease Questionnaire". AB - BACKGROUND AND OBJECTIVE: Celiac disease (CD) is a common chronic autoimmune disorder. Both the manifestations of the disease and the burden of the compulsory life-long gluten-free diet (GFD) have been shown to be associated with impairment of health-related quality of life. The objectives of this study were to provide a cross-cultural adaptation of the specific quality of life "Celiac Disease Questionnaire" (CDQ) and to analyze its psychometric properties. MATERIALS AND METHODS: A cross-cultural French adaptation of the CDQ (F-CDQ) was obtained according to the revised international guidelines. The questionnaire was administered at baseline to 211 patients with biopsy proven CD followed-up in a single tertiary referral centre. The questionnaire was also administered after 7 days and 6 months. Reliability (intraclass correlation coefficients (ICC), Cronbach's alpha and Bland and Altman graphical analysis), validity (factorial structure and Rasch analysis, convergent validity), and responsiveness (effect size) of the F-CDQ were studied. RESULTS: The reliability of the F-CDQ was excellent with ICC and Cronbach's alpha coefficients being between 0.79 and 0.94 for the four subscales and the total score. The factorial structure and the Rasch analysis showed that the four dimensions of the original instrument were retained. Correlations with external measures (a generic measure of quality of life, an anxiety and depression instrument, a self-assessed disease severity, and clinical manifestations) were all in the expected direction confirming the validity of the instrument. Responsiveness was studied and effect sizes >= 0.20 were demonstrated for most of the subscales for patients who reported improvement or deterioration after 6 months. CONCLUSION: The F-CDQ retains the psychometric properties of the original instrument and should be useful in cross-national surveys and to assess outcome in clinical trials involving patients with CD. PMID- 24788795 TI - Multiple-locus variable number of tandem repeats analysis of Salmonella enterica serotype paratyphi A from Yuxi and comparison with isolates from the Chinese Medical Culture Collection Center. AB - The aim of the present study was to genotype Salmonella enterica serotype paratyphi A (SPA) isolated from Yuxi, China, in a multiple-locus variable number of tandem repeats (VNTRs) analysis (MLVA) and to compare them with isolates from the Chinese Medical Culture Collection Center (CMCC). Potential VNTRs were screened from the genomes of ATCC9150 and AKU_12601 using the Tandem Repeats Finder program. Nine VNTRs were established for MLVA typing of 195 SPA isolates from Yuxi and 20 isolates from CMCC. The dendogram for MLVA profiles and minimum spanning tree (MST) were drawn using the categorical coefficient calculated by BioNumerics software. A total of 23 MLVA types were identified in 215 SPA isolates and were grouped into six distinct cluster groups A, B, C, D, E and F. A total of 195 Yuxi SPA isolates were exclusively grouped into cluster C with nine MLVA genotypes. A total of 20 CMCC isolates were grouped in clusters A B, D, E and F with the other 14 MLVA types. The MLVA with nine VNTR loci, which was exploited in the present study, represents a successful strategy for genotyping SPA. Furthermore, the 195 Yuxi isolates appear to be closely related to each other and distinct from the 20 CMCC strains. PMID- 24788797 TI - Biophysical characteristics of successful oilseed embryo cryoprotection and cryopreservation using vacuum infiltration vitrification: an innovation in plant cell preservation. AB - Heterogeneity in morphology, physiology and cellular chemistry of plant tissues can compromise successful cryoprotection and cryopreservation. Cryoprotection is a function of exposure time * temperature * permeability for the chosen protectant and diffusion pathway length, as determined by specimen geometry, to provide sufficient dehydration whilst avoiding excessive chemical toxicity. We have developed an innovative method of vacuum infiltration vitrification (VIV) at 381 mm (15 in) Hg (50 kPa) that ensures the rapid (5 min), uniform permeation of Plant Vitrification Solution 2 (PVS2) cryoprotectant into plant embryos and their successful cryopreservation, as judged by regrowth in vitro. This method was validated on zygotic embryos/embryonic axes of three species (Carica papaya, Passiflora edulis and Laurus nobilis) up to 1.6 mg dry mass and 5.6 mm in length, with varying physiology (desiccation tolerances) and 80 degrees C variation in lipid thermal profiles, i.e., visco-elasticity properties, as determined by differential scanning calorimetry. Comparisons between the melting features of cryoprotected embryos and embryo regrowth indicated an optimal internal PVS2 concentration of about 60% of full strength. The physiological vigour of surviving embryos was directly related to the proportion of survivors. Compared with conventional vitrification, VIV-cryopreservation offered a ~ 10-fold reduction in PVS2 exposure times, higher embryo viability and regrowth and greater effectiveness at two pre-treatment temperatures (0 degrees C and 25 degrees C). VIV-cryopreservation may form the basis of a generic, high throughput technology for the ex situ conservation of plant genetic resources, aiding food security and protection of species from diverse habitats and at risk of extinction. PMID- 24788796 TI - A novel mechanism inducing genome instability in Kaposi's sarcoma-associated herpesvirus infected cells. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. Like other herpesviruses, KSHV has a biphasic life cycle and both the lytic and latent phases are required for tumorigenesis. Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. A surprising link has recently been suggested between mRNA export, genome instability and cancer development. Notably, aberrations in the cellular transcription and export complex (hTREX) proteins have been identified in high grade tumours and these defects contribute to genome instability. We have previously shown that the lytically expressed KSHV ORF57 protein interacts with the complete hTREX complex; therefore, we investigated the possible intriguing link between ORF57, hTREX and KSHV-induced genome instability. Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. Furthermore, we show that sequestration of the hTREX complex by the KSHV ORF57 protein leads to this double strand break response and significant DNA damage. Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. Importantly, the link between hTREX sequestration and DNA damage may be a common feature in herpesvirus infection, as a similar phenotype was observed with the herpes simplex virus 1 (HSV-1) ICP27 protein. Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX. PMID- 24788798 TI - Ultrastructural and histochemical study on the Paneth cells in the rat ascending colon. AB - Paneth cells (PCs) contribute to the host defense against indigenous bacteria in the small intestine. We found Paneth cell-like cells (PLCs) in the rat ascending colon, but the nature of PLCs is never clarified. Therefore, the present study aimed to clarify the cytological characteristics of PLCs and discuss their cellular differentiation. PLCs were localized in the bases of intestinal crypts, especially follicle-associated intestinal crypts in proximal colonic lymphoid tissue, but were very seldom found in the ordinary intestinal crypts of the ascending colon. PLCs possessed specific granules with highly electron-dense cores and haloes, as well as PCs in the small intestine. The secretory granules of PLCs were positive for PAS reaction, lysozyme and soluble phospholipase A2, but negative for Alcian blue staining, beta-defensin-1 and -2, as well as the ones of PCs. Furthermore, intermediate cells possessing both the PLC-specific granules and the mucus granules similar to those of goblet cells (GCs) were occasionally found in the vicinity of PLCs. Intermediate cells ranged from goblet cell-like cells rich in mucus granules to PLC-like cells with few mucus granules. The cellular condensation and fragmentation were exclusively found in PLCs but never seen in intermediate cells or GCs. The PLCs, which were identified as PC, were suggested to be transformed from GCs through intermediate cells and finally to die by apoptosis in intestinal crypts of proximal colonic lymphoid tissue in the rat ascending colon. PMID- 24788799 TI - Evaluation of fundamental transport properties of Li-excess garnet-type Li(5+2x)La(3)Ta(2-x)Y(x)O(12) (x = 0.25, 0.5 and 0.75) electrolytes using AC impedance and dielectric spectroscopy. AB - The fundamental electrical transport properties including ionic conductivity, dielectric constants, loss tangent, and relaxation time constants of Li-excess garnet-type cubic (space group Ia3d) Li5+2xLa3Ta2-xYxO12 (x = 0.25, 0.5 and 0.75) have been studied in the temperature range of -50 to 50 degrees C using electrochemical AC impedance spectroscopy. A correlation has been established between the excess Li content and the Li(+) ion migration pathways. The loss tangent (tan delta) for all samples exhibits a relaxation peak corresponding to the dielectric loss because of dipolar rotations due to Li(+) migration. Comparing the modulus analysis of Li-excess garnets with fluorite-type oxygen ion conductors, we propose the local migration of Li(+) ions between octahedral sites around the "immobile" Li(+) ions in tetrahedral (24d) sites. In the samples with x = 0.25 and 0.5, Li(+) ions seem to jump from one octahedral (96h) site to another bypassing the tetrahedral (24d) site between them (path A), both in local and long-range order migration processes, with activation energies of ~0.69 and 0.54 eV, respectively. For the x = 0.75 member, Li(+) ions exhibit mainly long range order migration, with an activation energy of 0.34 eV, where the Li hopping between two octahedral sites occurs through the edge which is shared between the two LiO6 octahedra and a LiO4 tetrahedron (path B). The present AC impedance analysis is consistent with the ab initio theoretical analysis of Li-excess garnets that showed two conduction paths (A and B) for Li ion conduction with different activation energies. PMID- 24788800 TI - Do not just do it, do it right: urinary metabolomics--establishing clinically relevant baselines. AB - Metabolomics is currently being adopted as a tool to understand numerous clinical pathologies. It is essential to choose the best combination of techniques in order to optimize the information gained from the biological sample examined. For example, separation by reverse-phase liquid chromatography may be suitable for biological fluids in which lipids, proteins and small organic compounds coexist in a relatively nonpolar environment, such as serum. However, urine is a highly polar environment and metabolites are often specifically altered to render them polar suitable for normal phase/hydrophilic interaction liquid chromatography. Similarly, detectors such as high-resolution mass spectrometry (MS) may negate the need for a pre-separation but specific detection and quantification of less abundant analytes in targeted metabolomics may require concentration of the ions by methods such an ion trap MS. In addition, the inherent variability of metabolomic profiles need to be established in appropriately large sample sets of normal controls. This review aims to explore various techniques that have been tried and tested over the past decade. Consideration is given to various key drawbacks and positive alternatives published by active research groups and an optimum combination that should be used for urinary metabolomics is suggested to generate a reliable dataset for baseline studies. PMID- 24788801 TI - Profile of adverse events in patients receiving treatment for malaria in urban Ghana: a cohort-event monitoring study. AB - BACKGROUND: Antimalarial treatment strategies have changed much in the last 15 years, resulting in an increased variety of medicines available. Active pharmacovigilance methods are important for continued safety surveillance of these medicines, particularly in environments in which there is variability in treatments prescribed and limited confirmatory diagnostic capacity as well as limited ability of spontaneous reporting pharmacovigilance systems to generate much needed safety information quickly and efficiently. OBJECTIVE: Our objective was to use the cohort-event monitoring (CEM) technique to gather drug utilization and adverse event data for patients prescribed antimalarial medicines in an outpatient setting. METHODS: The characteristics of a large urban African cohort of outpatients (n = 2,831) receiving antimalarial medications are described. The cohort was actively surveyed over the subsequent week to record adverse events, using follow-up phone calls, paper reports, and/or voluntary return clinic visits. Adverse events reported in the cohort were analysed overall and by clinically relevant age and medication groupings. RESULTS: At least one event was reported in 29.4 % of patients. Adverse events were more likely to be reported in subjects older than 12 years of age, and by patients prescribed an artesunate amodiaquine combination. A range of adverse events were reported, the most frequent higher level terms being asthenic conditions (10.1 % of total cohort), neurological signs and symptoms (4.5 %), headaches (3.1 %), appetite disorders (2.1 %), and disturbances in consciousness (1.6 %). There were three reports of possible extrapyramidal events (two cases of tremor "hand and back shaking all over" and one case of tongue protrusion), which may appear to be related to combinations including amodiaquine and an artemisinin. CONCLUSION: The CEM methodology is a useful tool for monitoring the safety of widely available and utilized medicines, particularly in an urban environment where spontaneous reporting yields poor results and where the availability of various regimens and high levels of medicine usage can give valuable 'real-life' safety data. The types and frequencies of events reported reflected the types of events expected in patients prescribed antimalarials and nearly all events reported are listed in the summary of product characteristics of the medicines involved. PMID- 24788802 TI - The 8th International Congress on Cutaneous Adverse Drug Reactions, Taiwan, 2013: focus on severe cutaneous adverse reactions. PMID- 24788804 TI - Effects of Patient Empowerment Programme (PEP) on clinical outcomes and health service utilization in type 2 diabetes mellitus in primary care: an observational matched cohort study. AB - BACKGROUND: To evaluate the effects of a large population-based patient empowerment programme (PEP) on clinical outcomes and health service utilization rates in type 2 diabetes mellitus (T2DM) patients in the primary care setting. RESEARCH DESIGN AND SUBJECTS: A stratified random sample of 1,141 patients with T2DM enrolled to PEP between March and September 2010 were selected from general outpatient clinics (GOPC) across Hong Kong and compared with an equal number of T2DM patients who had not participated in the PEP (non-PEP group) matched by age, sex and HbA1C level group. MEASURES: Clinical outcomes of HbA1c, SBP, DBP and LDL C levels, and health service utilization rates including numbers of visits to GOPC, specialist outpatient clinics (SOPC), emergency department (ED) and inpatient admissions, were measured at baseline and at 12-month post-recruitment. The effects of PEP on clinical outcomes and health service utilization rates were assessed by the difference-in-difference estimation, using the generalized estimating equation models. RESULTS: Compared with non-PEP group, PEP group achieved additional improvements in clinical outcomes over the 12-month period. A significantly greater percentage of patients in the PEP group attained HbA1C<=7% or LDL-C<=2.6 mmol/L at 12-month follow-up compared with the non-PEP group. PEP group had a mean 0.813 fewer GOPC visits in comparison with the non-PEP group. CONCLUSIONS: PEP was effective in improving the clinical outcomes and reduced the general outpatient clinic utilization rate over a 12-month period. Empowering T2DM patients on self-management of their disease can enhance the quality of diabetes care in primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01935349. PMID- 24788805 TI - The effect of age and NT-proBNP on the association of central obesity with 6 years cardiovascular mortality of middle-aged and elderly diabetic people: the population-based Casale Monferrato study. AB - BACKGROUND: Among people with type 2 diabetes the relationship between central obesity and cardiovascular mortality has not been definitely assessed. Moreover, NT-proBNP is negatively associated with central obesity, but no study has examined their combined effect on survival. We have examined these issues in a well-characterized population-based cohort. METHODS AND FINDINGS: Survival data of 2272 diabetic people recruited in 2000 who had no other chronic disease have been updated to 31 December 2006. NT-proBNP was measured in a subgroup of 1690 patients. Cox proportional hazards modeling was employed to estimate the independent associations between cardiovascular and all-cause mortality and waist circumference. Mean age was 67.9 years, 49.3% were men. Both age and NT-proBNP were negatively correlated with waist circumference (r = -0.11, p<0.001 and r = 0.07, p = 0.002). Out of 2272 subjects, 520 deaths (221 for CV mortality) occurred during a median follow-up of 5.4 years. Central obesity was not associated with CV mortality (hazard ratio, HR, adjusted for age, sex, diabetes duration, 1.14, 95% CI 0.86-1.52). NTproBNP was a negative confounder and age a strong modifier of this relationship (p for interaction<0.001): age<70 years, fully adjusted model HR = 3.52 (1.17-10.57) and age >=70 years, HR = 0.80 (0.46 1.40). Respective HRs for all-cause mortality were 1.86 (1.03-3.32) and 0.73 (0.51-1.04). CONCLUSIONS: In diabetic people aged 70 years and lower, central obesity was independently associated with increased cardiovascular mortality, independently of the negative effect of NT-proBNP. In contrast, no effect on 6 years survival was evident in diabetic people who have yet survived up to 70 years. PMID- 24788803 TI - Benefit-risk assessment of rosuvastatin in the treatment of atherosclerosis and related diseases. AB - Rosuvastatin has been marketed for approximately a decade. In this review we critically discuss available evidence on the benefits and risks from its use. In clinical trials using rosuvastatin, 'lowest is best' was relevant for on treatment low-density lipoprotein cholesterol levels. Targeting levels <50 mg/dl was associated with the greatest decrease in vascular morbidity/mortality in the primary prevention setting. Also, such reduction can induce atherosclerosis regression without increasing the risk of adverse effects. Pooled data suggest that the safety profile of rosuvastatin is not different from that of other statins. It was estimated that rosuvastatin-associated absolute hazards of muscle , liver- and renal-related adverse effects are lower than the corresponding vascular benefits in moderate vascular risk individuals. However, these data are subject to biases and need confirmation on a prospective basis. Significant liver enzyme elevations are rare. These often imply underlying non-alcoholic fatty liver disease (NAFLD), which is associated with increased vascular risk. Rosuvastatin can improve biochemical biomarkers and histological score of NAFLD. Whether this benefit is associated with vascular risk reduction should be assessed by prospective studies. Both chronic kidney disease and albuminuria independently predict vascular morbidity and mortality. Rosuvastatin improved the estimated glomerular filtration rate and decreased albuminuria in patients with moderately impaired kidney function. Also, vascular morbidity and mortality might be reduced in these patients. The same was not relevant in end-stage renal disease. Rosuvastatin-induced proteinuria appears to be of tubular origin, not relating to kidney injury. Rosuvastatin increases the risk of new-onset diabetes by dose-dependently impairing insulin sensitivity. Obese individuals with prediabetes appear to be predominantly affected. However, absolute vascular benefits of rosuvastatin may counterbalance this risk. Rosuvastatin is effective for the prevention and management of atherosclerotic vascular disease. Individualization of its use can maximize benefits and reduce the risk of adverse effects. PMID- 24788806 TI - Retinoic acid and GM-CSF coordinately induce retinal dehydrogenase 2 (RALDH2) expression through cooperation between the RAR/RXR complex and Sp1 in dendritic cells. AB - Retinoic acid (RA)-producing dendritic cells (DCs) play critical roles in gut immunity. Retinal dehydrogenase 2 (RALDH2) encoded by Aldh1a2 is a key enzyme for generating RA in DCs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) potently induces RALDH2 expression in DCs in an RA-dependent manner, and RA alone weakly induces the expression. However, how GM-CSF and RA induce RALDH2 expression remains unclear. Here, we show that GM-CSF-induced activation of the transcription factor Sp1 and RA-dependent signaling via the RA receptor (RAR)/retinoid X receptor (RXR) complex contribute to Aldh1a2 expression. The RAR antagonist LE540 and the Sp1 inhibitor mithramycin A inhibited GM-CSF-induced Aldh1a2 expression in fms-related tyrosine kinase 3 ligand-generated bone marrow derived DCs (BM-DCs). ERK and p38 MAPK inhibitors suppressed GM-CSF-induced nuclear translocation of Sp1 and Aldh1a2 expression. Sp1 and the RARalpha/RXRalpha complex bound to GC-rich Sp1-binding sites and an RA response element (RARE) half-site, respectively, near the TATA box in the mouse Aldh1a2 promoter. The DNA sequences around these sites were highly conserved among different species. In the presence of RA, ectopic expression of RARalpha/RXRalpha and Sp1 synergistically enhanced Aldh1a2 promoter-reporter activity. GM-CSF did not significantly induce Aldh1a2 expression in plasmacytoid DCs, peritoneal macrophages, or T cells, and the Aldh1a2 promoter in these cells was mostly unmethylated. These results suggest that GM-CSF/RA-induced RALDH2 expression in DCs requires cooperative binding of Sp1 and the RAR/RXR complex to the Aldh1a2 promoter, and can be regulated by a DNA methylation-independent mechanism. PMID- 24788807 TI - Does KRAS testing in metastatic colorectal cancer impact overall survival? A comparative effectiveness study in a population-based sample. AB - PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors are approved for treating metastatic colorectal cancer (CRC); KRAS mutation testing is recommended prior to treatment. We conducted a non-inferiority analysis to examine whether KRAS testing has impacted survival in CRC patients. PATIENTS AND METHODS: We included 1186 metastatic CRC cases from seven health plans. A cutpoint of July, 2008, was used to define two KRAS testing time period groups: "pre-testing" (n = 760 cases) and "post-testing" (n = 426 cases). Overall survival (OS) was estimated, and the difference in median OS between the groups was calculated. The lower bound of the one-sided 95% confidence interval (CI) for the difference in survival was used to test the null hypothesis of post-testing inferiority. Multivariable Cox regression models were constructed to adjust for covariates. RESULTS: The median unadjusted OS was 15.4 months (95% CI: 14.0-17.5) and 12.8 months (95% CI: 10.0-15.2) in the pre- and post-testing groups, respectively. The OS difference was -2.6 months with one-sided 95% lower confidence bound of -5.13 months, which was less than the non-inferiority margin (-5.0 months, unadjusted p = 0.06), leading to a failure to reject inferiority of OS in the post-testing period. In contrast, in the adjusted analysis, OS non-inferiority was identified in the post-testing period (p = 0.001). Sensitivity analyses using cutpoints before and after July, 2008, also met the criteria for non-inferiority. CONCLUSION: Implementation of KRAS testing did not influence CRC OS. Our data support the use of KRAS testing to guide administration of EGFR inhibitors for treatment of metastatic CRC without diminished OS. PMID- 24788808 TI - Categorization of natural dynamic audiovisual scenes. AB - This work analyzed the perceptual attributes of natural dynamic audiovisual scenes. We presented thirty participants with 19 natural scenes in a similarity categorization task, followed by a semi-structured interview. The scenes were reproduced with an immersive audiovisual display. Natural scene perception has been studied mainly with unimodal settings, which have identified motion as one of the most salient attributes related to visual scenes, and sound intensity along with pitch trajectories related to auditory scenes. However, controlled laboratory experiments with natural multimodal stimuli are still scarce. Our results show that humans pay attention to similar perceptual attributes in natural scenes, and a two-dimensional perceptual map of the stimulus scenes and perceptual attributes was obtained in this work. The exploratory results show the amount of movement, perceived noisiness, and eventfulness of the scene to be the most important perceptual attributes in naturalistically reproduced real-world urban environments. We found the scene gist properties openness and expansion to remain as important factors in scenes with no salient auditory or visual events. We propose that the study of scene perception should move forward to understand better the processes behind multimodal scene processing in real-world environments. We publish our stimulus scenes as spherical video recordings and sound field recordings in a publicly available database. PMID- 24788809 TI - Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. AB - Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or beta-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV. PMID- 24788810 TI - Reassessment of QTLs for late blight resistance in the tomato accession L3708 using a restriction site associated DNA (RAD) linkage map and highly aggressive isolates of Phytophthora infestans. AB - Tomato late blight caused by the oomycete pathogen Phytophthora infestans (Mont.) de Bary is a major threat to tomato production in cool and wet environments. Intensified outbreaks of late blight have been observed globally from the 1980s, and are associated with migration of new and more aggressive populations of P. infestans in the field. The objective of this study was to reassess late blight resistance in the wild tomato accession L3708 (Solanum pimpinellifolium L.) against pathogens of different aggressiveness. An F2:3 genetic mapping population was developed using L3708 as the paternal parent. Two isolates of P. infestans, Pi39A and Pi733, were used for inoculation. Pi733 is a highly aggressive genotype that defeats three known late blight resistance genes, Ph-1, Ph-2, and Ph-5t in tomato. In contrast, Pi39A is a less aggressive genotype that defeats only Ph-1. Restriction site Associated DNA Sequencing (RAD-Seq) technology was used to massively sequence 90 bp nucleotides adjacent to both sides of PstI restriction enzyme cutting sites in the genome for all individuals in the genetic mapping population. The RAD-seq data were used to construct a genetic linkage map containing 440 single nucleotide polymorphism markers. Quantitative trait locus (QTL) analysis identified a new disease-resistant QTL specific to Pi733 on chromosome 2. The Ph-3 gene located on chromosome 9 could be detected whichever isolates were used. This study demonstrated the feasibility and efficiency of RAD Seq technology for conducting a QTL mapping experiment using an F2:3 mapping population, which allowed the identification of a new late blight resistant QTL in tomato. PMID- 24788811 TI - Expression of a humanized viral 2A-mediated lux operon efficiently generates autonomous bioluminescence in human cells. AB - BACKGROUND: Expression of autonomous bioluminescence from human cells was previously reported to be impossible, suggesting that all bioluminescent-based mammalian reporter systems must therefore require application of a potentially influential chemical substrate. While this was disproven when the bacterial luciferase (lux) cassette was demonstrated to function in a human cell, its expression required multiple genetic constructs, was functional in only a single cell type, and generated a significantly reduced signal compared to substrate requiring systems. Here we investigate the use of a humanized, viral 2A-linked lux genetic architecture for the efficient introduction of an autobioluminescent phenotype across a variety of human cell lines. METHODOLOGY/PRINCIPAL FINDINGS: The lux cassette was codon optimized and assembled into a synthetic human expression operon using viral 2A elements as linker regions. Human kidney, breast cancer, and colorectal cancer cell lines were both transiently and stably transfected with the humanized operon and the resulting autobioluminescent phenotype was evaluated using common imaging instrumentation. Autobioluminescent cells were screened for cytotoxic effects resulting from lux expression and their utility as bioreporters was evaluated through the demonstration of repeated monitoring of single populations over a prolonged period using both a modified E SCREEN assay for estrogen detection and a classical cytotoxic compound detection assay for the antibiotic Zeocin. Furthermore, the use of self-directed bioluminescent initiation in response to target detection was assessed to determine its amenability towards deployment as fully autonomous sensors. In all cases, bioluminescent measurements were supported with traditional genetic and transcriptomic evaluations. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that the viral 2A-linked, humanized lux genetic architecture successfully produced autobioluminescent phenotypes in all cell lines tested without the induction of cytotoxicity. This autobioluminescent phenotype allowed for repeated interrogation of populations and self-directed control of bioluminescent activation with detection limits and EC50 values similar to traditional reporter systems, making the autobioluminescent cells amenable to automated monitoring and significantly reducing the time and cost required to perform bioluminescent workflows. PMID- 24788812 TI - Forensic comparison and matching of fingerprints: using quantitative image measures for estimating error rates through understanding and predicting difficulty. AB - Latent fingerprint examination is a complex task that, despite advances in image processing, still fundamentally depends on the visual judgments of highly trained human examiners. Fingerprints collected from crime scenes typically contain less information than fingerprints collected under controlled conditions. Specifically, they are often noisy and distorted and may contain only a portion of the total fingerprint area. Expertise in fingerprint comparison, like other forms of perceptual expertise, such as face recognition or aircraft identification, depends on perceptual learning processes that lead to the discovery of features and relations that matter in comparing prints. Relatively little is known about the perceptual processes involved in making comparisons, and even less is known about what characteristics of fingerprint pairs make particular comparisons easy or difficult. We measured expert examiner performance and judgments of difficulty and confidence on a new fingerprint database. We developed a number of quantitative measures of image characteristics and used multiple regression techniques to discover objective predictors of error as well as perceived difficulty and confidence. A number of useful predictors emerged, and these included variables related to image quality metrics, such as intensity and contrast information, as well as measures of information quantity, such as the total fingerprint area. Also included were configural features that fingerprint experts have noted, such as the presence and clarity of global features and fingerprint ridges. Within the constraints of the overall low error rates of experts, a regression model incorporating the derived predictors demonstrated reasonable success in predicting objective difficulty for print pairs, as shown both in goodness of fit measures to the original data set and in a cross validation test. The results indicate the plausibility of using objective image metrics to predict expert performance and subjective assessment of difficulty in fingerprint comparisons. PMID- 24788814 TI - Cytokine diversity in the Th1-dominated human anti-influenza response caused by variable cytokine expression by Th1 cells, and a minor population of uncommitted IL-2+IFNgamma- Thpp cells. AB - Within overall Th1-like human memory T cell responses, individual T cells may express only some of the characteristic Th1 cytokines when reactivated. In the Th1-oriented memory response to influenza, we have tested the contributions of two potential mechanisms for this diversity: variable expression of cytokines by a uniform population during activation, or different stable subsets that consistently expressed subsets of the Th1 cytokine pattern. To test for short term variability, in vitro-stimulated influenza-specific human memory CD4+ T cells were sorted according to IL-2 and IFNgamma expression, cultured briefly in vitro, and cytokine patterns measured after restimulation. Cells that were initially IFNgamma+ and either IL-2+ or IL-2- converged rapidly, containing similar proportions of IL-2-IFNgamma+ and IL-2+IFNgamma+ cells after culture and restimulation. Both phenotypes expressed Tbet, and similar patterns of mRNA. Thus variability of IL-2 expression in IFNgamma+ cells appeared to be regulated more by short-term variability than by stable differentiated subsets. In contrast, heterogeneous expression of IFNgamma in IL-2+ influenza-specific T cells appeared to be due partly to stable T cell subsets. After sorting, culture and restimulation, influenza-specific IL-2+IFNgamma- and IL-2+IFNgamma+ cells maintained significantly biased ratios of IFNgamma+ and IFNgamma- cells. IL 2+IFNgamma- cells included both Tbetlo and Tbethi cells, and showed more mRNA expression differences with either of the IFNgamma+ populations. To test whether IL-2+IFNgamma-Tbetlo cells were Thpp cells (primed but uncommitted memory cells, predominant in responses to protein vaccines), influenza-specific IL-2+IFNgamma- and IL-2+IFNgamma+ T cells were sorted and cultured in Th1- or Th2-generating conditions. Both cell types yielded IFNgamma-secreting cells in Th1 conditions, but only IL-2+IFNgamma- cells were able to differentiate into IL-4-producing cells. Thus expression of IL-2 in the anti-influenza response may be regulated mainly by short term variability, whereas different T cell subsets, Th1 and Thpp, may contribute to variability in IFNgamma expression. PMID- 24788816 TI - A role of Rab29 in the integrity of the trans-Golgi network and retrograde trafficking of mannose-6-phosphate receptor. AB - Rab29 (also referred as Rab7L1) is a novel Rab protein, and is recently demonstrated to regulate phagocytosis and traffic from the Golgi to the lysosome. However, its roles in membrane trafficking have not been investigated extensively. Our results in this study revealed that Rab29 is associated with the trans-Golgi network (TGN), and is essential for maintaining the integrity of the TGN, because inhibition of the activity of Rab29 or depletion of Rab29 resulted in fragmentation of the TGN marked by TGN46. Expression of the dominant negative form Rab29T21N or shRNA-Rab29 also altered the distribution of mannose-6 phosphate receptor (M6PR), and interrupted the retrograde trafficking of M6PR through monitoring the endocytosis of CD8-tagged calcium dependent M6PR (cdM6PR) or calcium independent M6PR (ciM6PR), but without significant effects on the anterograde trafficking of vesicular stomatitis virus G protein (VSV-G). Our results suggest that Rab29 is essential for the integrity of the TGN and participates in the retrograde trafficking of M6PRs. PMID- 24788815 TI - Mapping small-world properties through development in the human brain: disruption in schizophrenia. AB - Evidence from imaging studies suggests that the human brain has a small-world network topology that might be disrupted in certain brain disorders. However, current methodology is based on global graph theory measures, such as clustering, C, characteristic path length, L, and small-worldness, S, that lack spatial specificity and are insufficient to identify regional brain abnormalities. Here we propose novel ultra-fast methodology for mapping local properties of brain network topology such as local C, L and S (lC, lL and lS) in the human brain at 3 mm isotropic resolution from 'resting-state' magnetic resonance imaging data. Test-retest datasets from 40 healthy children/adolescents were used to demonstrate the overall good reliability of the measures across sessions and computational parameters (intraclass correlation > 0.5 for lC and lL) and their low variability across subjects (< 29%). Whereas regions with high local functional connectivity density (lFCD; local degree) in posterior parietal and occipital cortices demonstrated high lC and short lL, subcortical regions (globus pallidus, thalamus, hippocampus and amygdala), cerebellum (lobes and vermis), cingulum and temporal cortex also had high, lS, demonstrating stronger small world topology than other hubs. Children/adolescents had stronger lFCD, higher lC and longer lL in most cortical regions and thalamus than 74 healthy adults, consistent with pruning of functional connectivity during maturation. In contrast, lFCD, lC and lL were weaker in thalamus and midbrain, and lL was shorter in frontal cortical regions and cerebellum for 69 schizophrenia patients than for 74 healthy controls, suggesting exaggerated pruning of connectivity in schizophrenia. Follow up correlation analyses for seeds in thalamus and midbrain uncovered lower positive connectivity of these regions in thalamus, putamen, cerebellum and frontal cortex (cingulum, orbitofrontal, inferior frontal) and lower negative connectivity in auditory, visual, motor, premotor and somatosensory cortices for schizophrenia patients than for controls, consistent with prior findings of thalamic disconnection in schizophrenia. PMID- 24788817 TI - Second primary malignancies in patients with neuroendocrine tumors. AB - PURPOSE: An association between neuroendocrine tumors (NETs) and second primary malignancies (SPMs) has been reported. We have examined the incidence and etiology of SPMs in patients with NETs included in the Neuroendocrine Tumor Association of Andalusia (ATNEA) Registry. METHODS: Data on 111 patients were collected. Sex, age, NET site, chromogranin A levels, neuropeptide secretion and disease stage were compared between NETs with and without SPMs. RESULTS: SPMs were present in 21 patients (18.9 %): five colorectal tumors, four non-small-cell lung cancers, three gastric cancers, two tumors in the small intestine, one hepatocarcinoma, two ovarian tumors, one breast adenocarcinoma, one hypernephroma, one bladder cancer, and one neuroblastoma. SPMs were present in 18 % of patients with a gastrointestinal NET and 22 % of those with a non gastrointestinal NET. SPMs were found in 23 % of patients with elevated levels of serum chromogranin A, compared to 17 % of patients with normal levels, and in 22 % of patients with functional tumors, compared to 11 % of those with non functional tumors. Finally, SPMs were observed in 24 % of patients with a local or locoregional tumor but in only 13 % of those with a metastatic tumor. No other differences between patients with and without SPMs were observed. CONCLUSIONS: The percentage of patients with SPMs in the ATNEA Registry is similar to those reported in other series. In our registry, patients with functional NETs and local/locoregional tumors have higher probability of SPMs. The low number of patients, selection bias and other etiologic factors of SPMs may have influenced our results. PMID- 24788818 TI - Analysis of differentially expressed genes between rheumatoid arthritis and osteoarthritis based on the gene co-expression network. AB - The aim of the current study was to investigate disease-associated genes and related molecular mechanisms of osteoarthritis (OA) and rheumatoid arthritis (RA). Using GSE7669 datasets downloaded from Gene Expression Omnibus databases, the differentially expressed genes (DEGs) between RA and OA synovial fibroblasts (SFBs) (n=6 each) were screened. DEG-associated co-expression and topological properties were analyzed to determine the rank of disease-associated genes. Specifically, the fold change of differentially expressed genes, the clustering coefficient and the degree of differential gene co-expression were integrated to determine the disease-associated gene ranking. The underlying molecular mechanisms of these crucial disease-associated genes were investigated by gene ontology (GO) enrichment analysis. A total of 1313 DEGs, including 1068 upregulated genes and 245 downregulated genes were observed. The top 20 disease associated genes were identified, including proteoglycan 4, inhibin beta B, carboxypeptidase M, alcohol dehydrogenase 1C and integrin beta2. The major GO biological processes of these top 20 disease-associated genes were highly involved in the immune system, such as responses to stimuli, immune responses and inflammatory responses. This large-scale gene expression study observed disease associated genes and their associated GO function in RA and OA, which may provide opportunities for biomarker development and novel insights into the molecular mechanisms of these two diseases. PMID- 24788820 TI - A protic ionic liquid catalyzes CO2 conversion at atmospheric pressure and room temperature: synthesis of quinazoline-2,4(1H,3H)-diones. AB - The chemical fixation of CO2 under mild reaction conditions is of significance from a sustainable chemistry viewpoint. Herein a CO2-reactive protic ionic liquid (PIL), [HDBU(+)][TFE(-)], was designed by neutralization of the superbase 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) with a weak proton donor trifluoroethanol (TFE). As a bifunctional catalyst for simultaneously activating CO2 and the substrate, this PIL displayed excellent performance in catalyzing the reactions of CO2 with 2-aminobenzonitriles at atmospheric pressure and room temperature, thus producing a series of quinazoline-2,4(1H,3H)-diones in excellent yields. PMID- 24788819 TI - delta-Opioid receptors and inflammatory cytokines in hypoxia: differential regulation between glial and neuron-like cells. AB - Emerging evidence suggests that the delta-opioid receptor (DOR) is neuroprotective against hypoxic stress. Since inflammatory factors play an important role in hypoxic injury, we sought to determine if DOR modulates cellular inflammatory process in hypoxia. Since astrocytes produce inflammatory cytokines and play a major role in inflammatory response to hypoxia, we exposed cultured rat astrocytes to severe hypoxia (0.1% O2) for 3-6 h to examine if DOR activation altered hypoxia-induced expression of proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) along with cell viability. To examine a differential DOR-mediated modulation between glial and neuron-like cells, we also conducted the same experiments in differentiated PC-12 cells. We found that hypoxia reduced cell viability in both astrocytes and PC-12 cells, and DOR activation with UFP-512 (5 MUM) effectively protected both the cells against hypoxic insult. Hypoxia markedly increased TNF-alpha levels in the astrocytes (p < 0.05); however, the same hypoxic stress reduced TNF-alpha levels in the PC-12 cells. Exogenous addition of TNF-alpha to the culture media further worsened the hypoxia-induced damage in PC-12 cells. Hypoxia increased the DOR-expression in astrocytes but not in PC-12 cells. DOR-activation reversed the hypoxia-induced changes in TNF-alpha levels in both the cells. In contrast, the IL-1beta levels did not significantly alter in astrocytes and PC-12 cells when exposed to the same hypoxic conditions or following DOR activation. Our novel data suggest that DOR activation inhibits TNF-alpha mediated inflammatory processes following exposure to severe hypoxia with a differential regulation between glial vs. neuron-like cells. PMID- 24788822 TI - Crafting the brain - role of histone acetyltransferases in neural development and disease. AB - The human brain is a highly specialized organ containing nearly 170 billion cells with specific functions. Development of the brain requires adequate proliferation, proper cell migration, differentiation and maturation of progenitors. This is in turn dependent on spatial and temporal coordination of gene transcription, which requires the integration of both cell intrinsic and environmental factors. Histone acetyltransferases (HATs) are one family of proteins that modulate expression levels of genes in a space- and time-dependent manner. HATs and their molecular complexes are able to integrate multiple molecular inputs and mediate transcriptional levels by acetylating histone proteins. In mammals, 19 HATs have been described and are separated into five families (p300/CBP, MYST, GNAT, NCOA and transcription-related HATs). During embryogenesis, individual HATs are expressed or activated at specific times and locations to coordinate proper development. Not surprisingly, mutations in HATs lead to severe developmental abnormalities in the nervous system and increased neurodegeneration. This review focuses on our current understanding of HATs and their biological roles during neural development. PMID- 24788821 TI - Cutaneous neuropathy in Parkinson's disease: a window into brain pathology. AB - The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson's disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity. PMID- 24788823 TI - Laminin regulates the osteogenic differentiation of dental follicle cells via integrin-alpha2/-beta1 and the activation of the FAK/ERK signaling pathway. AB - Dental follicle cells (DFCs) are ideal for studies concerning the differentiation of dental precursor cells into alveolar osteoblasts and cementoblasts. Previous investigations have suggested that the extracellular matrix (ECM) protein laminin and the ECM receptor integrin-alpha2/-beta1 play regulatory roles during the osteogenic differentiation of DFCs. Our present data indicate that laminin impairs alkaline phosphatase (ALP) activity following osteogenic induction while inducing integrin-alpha2/-beta1 expression, osteogenic differentiation marker elevation, and DFC biomineralization. Integrin-alpha2/-beta1 facilitates the laminin-dependent expression of osteogenic differentiation markers and the laminin-dependent inhibition of ALP activity. Moreover, these laminin-dependent effects on the osteogenic differentiation of DFCs can be reversed by the inhibition of the FAK/ERK signaling pathway. Thus, laminin regulates the inhibition of early osteogenic differentiation markers and the induction of late osteogenic differentiation markers via integrin-alpha2/-beta1 and the activation of the FAK/ERK signaling pathway. PMID- 24788824 TI - A langevin canonical approach to the dynamics of chiral systems: thermal averages and heat capacity. AB - A Langevin canonical framework for a chiral two-level system coupled to a bath of harmonic oscillators was developed within a coupling scheme different from the well-known spin-boson model. Thermal equilibrium values were reached at asymptotic times by solving the corresponding set of nonlinear coupled equations in a Markovian regime. In particular, phase difference thermal values (or, equivalently, the so-called coherence factor) and heat capacity through energy fluctuations were obtained and are discussed in terms of tunneling rates and asymmetries. PMID- 24788825 TI - Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. AB - PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour necrosis factor (TNF) antibodies. METHODS: De novo malignancies in 666 thiopurine-treated and/or anti-TNF-treated IBD patients were analysed. Patients (n = 262) were treated with thiopurines alone and never exposed to anti-TNF antibodies (TP group). In addition, patients (n = 404) were exposed to anti-TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy. RESULTS: In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82-9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group >=50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age (p = 0.0008). In the TNF+ group, 6.5% of all patients >=50 years of age developed malignancies compared with 0.3% of all patients <50 years of age (p = 0.0007). In both groups combined, thiopurine treatment duration >=4 years was associated with the risk for skin cancer (p = 0.0024) and lymphoma (p = 0.0005). CONCLUSIONS: Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti-TNF antibodies with or without thiopurines. PMID- 24788826 TI - Plasma levels of IL-37 and correlation with TNF-alpha, IL-17A, and disease activity during DMARD treatment of rheumatoid arthritis. AB - The aim of this study was to assess the change of IL-37 concentrations in rheumatoid arthritis (RA) patients under Disease-modifying anti-rheumatic drug (DMARD) therapy, and to establish a correlation between Interleukin-37 and pro inflammatory cytokines in plasma and disease activity. The plasma level of IL-37 was determined using ELISA in 50 newly diagnosed RA patients and 30 healthy controls (HC). Plasma levels of IL-17A, IL-6 and TNF-alpha were measured using flow a cytometric bead array assay. We found that the concentrations of IL-37, as well as IL-17A, IL-6 and TNF-alpha, were higher in plasma of RA patients compared to HCs. Compared to patients who did not respond to DMARD treatment, treatment of patients responsive to DMARDs resulted in down-regulation of IL-17A, IL-6 and TNF alpha expression. The plasma level of the anti-inflammatory cytokine IL-37 was also decreased in drug responders after DMARD treatment. The plasma level of IL 37 in RA patients was positively correlated with pro-inflammatory cytokines (IL 17A, TNF-alpha) and disease activity (CRP, DAS28) in RA patients. IL-37 expression in RA and during DMARD treatment appears to be controlled by the level of pro-inflammatory cytokines. This results in a strong correlation between plasma levels of IL-37 and disease activity in RA patients. PMID- 24788827 TI - Nanoparticle-based pseudo hapten for target-responsive cargo release from a magnetic mesoporous silica nanocontainer. AB - A novel homogeneous immunoassay method is developed for sensitive monitoring of small molecular biotoxin by using a portable personal glucose meter (PGM) based on the target-responsive release of cargo (glucose) from a polystyrene microsphere-gated magnetic mesoporous nanocontainer. PMID- 24788828 TI - Self-reported pain intensity with the numeric reporting scale in adult dengue. AB - BACKGROUND: Pain is a prominent feature of acute dengue as well as a clinical criterion in World Health Organization guidelines in diagnosing dengue. We conducted a prospective cohort study to compare levels of pain during acute dengue between different ethnicities and dengue severity. METHODS: Demographic, clinical and laboratory data were collected. Data on self-reported pain was collected using the 11-point Numerical Rating Scale. Generalized structural equation models were built to predict progression to severe disease. RESULTS: A total of 499 laboratory confirmed dengue patients were recruited in the Prospective Adult Dengue Study at Tan Tock Seng Hospital, Singapore. We found no statistically significant differences between pain score with age, gender, ethnicity or the presence of co-morbidity. Pain score was not predictive of dengue severity but highly correlated to patients' day of illness. Prevalence of abdominal pain in our cohort was 19%. There was no difference in abdominal pain score between grades of dengue severity. CONCLUSION: Dengue is a painful disease. Patients suffer more pain at the earlier phase of illness. However, pain score cannot be used to predict a patient's progression to severe disease. PMID- 24788829 TI - First record of eocene bony fishes and crocodyliforms from Canada's Western Arctic. AB - BACKGROUND: Discovery of Eocene non-marine vertebrates, including crocodylians, turtles, bony fishes, and mammals in Canada's High Arctic was a critical paleontological contribution of the last century because it indicated that this region of the Arctic had been mild, temperate, and ice-free during the early - middle Eocene (~53-50 Ma), despite being well above the Arctic Circle. To date, these discoveries have been restricted to Canada's easternmost Arctic - Ellesmere and Axel Heiberg Islands (Nunavut). Although temporally correlative strata crop out over 1,000 km west, on Canada's westernmost Arctic Island - Banks Island, Northwest Territories - they have been interpreted as predominantly marine. We document the first Eocene bony fish and crocodyliform fossils from Banks Island. PRINCIPAL FINDINGS: We describe fossils of bony fishes, including lepisosteid (Atractosteus), esocid (pike), and amiid, and a crocodyliform, from lower - middle Eocene strata of the Cyclic Member, Eureka Sound Formation within Aulavik National Park (~76 degrees N. paleolat.). Palynology suggests the sediments are late early to middle Eocene in age, and likely spanned the Early Eocene Climatic Optimum (EECO). CONCLUSIONS/SIGNIFICANCE: These fossils extend the geographic range of Eocene Arctic lepisosteids, esocids, amiids, and crocodyliforms west by approximately 40 degrees of longitude or ~1100 km. The low diversity bony fish fauna, at least at the family level, is essentially identical on Ellesmere and Banks Islands, suggesting a pan-High Arctic bony fish fauna of relatively basal groups around the margin of the Eocene Arctic Ocean. From a paleoclimatic perspective, presence of a crocodyliform, gar and amiid fishes on northern Banks provides further evidence that mild, year-round temperatures extended across the Canadian Arctic during early - middle Eocene time. Additionally, the Banks Island crocodyliform is consistent with the phylogenetic hypothesis of a Paleogene divergence time between the two extant alligatorid lineages Alligator mississippiensis and A. sinensis, and high-latitude dispersal across Beringia. PMID- 24788830 TI - Quantitative T2* (T2 star) relaxation times predict site specific proteoglycan content and residual mechanics of the intervertebral disc throughout degeneration. AB - Degeneration alters the biochemical composition of the disc, affecting the mechanical integrity leading to spinal instability. Quantitative T2* MRI probes water mobility within the macromolecular network, a potentially more sensitive assessment of disc health. We determined the relationship between T2* relaxation time and proteoglycan content, collagen content, and compressive mechanics throughout the degenerative spectrum. Eighteen human cadaveric lumbar (L4-L5) discs were imaged using T2* MRI. The T2* relaxation time at five locations (nucleous pulposus or NP, anterior annulus fibrosis or AF, posterior AF, inner AF, and outer AF) was correlated with sulfated-glycosaminoglycan (s-GAG) content, hydroxyproline content, and residual stress and strain at each location. T2* relaxation times were significantly correlated with s-GAG contents in all test locations and were particularly strong in the NP (r = 0.944; p < 0.001) and inner AF (r = 0.782; p < 0.001). T2* relaxation times were also significantly correlated with both residual stresses and excised strains in the NP (r = 0.857; p < 0.001: r = 0.816; p < 0.001), inner AF (r = 0.535; p = 0.022: r = 0.516; p = 0.028), and outer AF (r = 0.668; p = 0.002: r = 0.458; p = 0.041). These strong correlations highlight T2* MRI's ability to predict the biochemical and mechanical health of the disc. T2* MRI assessment of disc health is a clinically viable tool showing promise as a biomarker for distinguishing degenerative changes. PMID- 24788831 TI - Expression of Ciona intestinalis variable region-containing chitin-binding proteins during development of the gastrointestinal tract and their role in host microbe interactions. AB - Variable region-containing chitin-binding proteins (VCBPs) are secreted, immune type molecules that have been described in both amphioxus, a cephalochordate, and sea squirt, Ciona intestinalis, a urochordate. In adult Ciona, VCBP-A, -B and -C are expressed in hemocytes and the cells of the gastrointestinal tract. VCBP-C binds bacteria in the stomach lumen and functions as an opsonin in vitro. In the present paper the expression of VCBPs has been characterized during development using in situ hybridization, immunohistochemical staining and quantitative polymerase chain reaction (qPCR) technologies. The expression of VCBP-A and -C is detected first in discrete areas of larva endoderm and becomes progressively localized during differentiation in the stomach and intestine, marking the development of gut tracts. In "small adults" (1-2 cm juveniles) expression of VCBP-C persists and VCBP-A gradually diminishes, ultimately replaced by expression of VCBP-B. The expression of VCBP-A and -C in stage 7-8 juveniles, at which point animals have already started feeding, is influenced significantly by challenge with either Gram-positive or -negative bacteria. A potential role for VCBPs in gut-microbiota interactions and homeostasis is indicated. PMID- 24788833 TI - [Three options for case presentation]. PMID- 24788832 TI - The human adenovirus E4-ORF1 protein subverts discs large 1 to mediate membrane recruitment and dysregulation of phosphatidylinositol 3-kinase. AB - Adenoviruses infect epithelial cells lining mucous membranes to cause acute diseases in people. They are also utilized as vectors for vaccination and for gene and cancer therapy, as well as tools to discover mechanisms of cancer due to their tumorigenic potential in experimental animals. The adenovirus E4-ORF1 gene encodes an oncoprotein that promotes viral replication, cell survival, and transformation by activating phosphatidylinositol 3-kinase (PI3K). While the mechanism of activation is not understood, this function depends on a complex formed between E4-ORF1 and the membrane-associated cellular PDZ protein Discs Large 1 (Dlg1), a common viral target having both tumor suppressor and oncogenic functions. Here, we report that in human epithelial cells, E4-ORF1 interacts with the regulatory and catalytic subunits of PI3K and elevates their levels. Like PI3K activation, PI3K protein elevation by E4-ORF1 requires Dlg1. We further show that Dlg1, E4-ORF1, and PI3K form a ternary complex at the plasma membrane. At this site, Dlg1 also co-localizes with the activated PI3K effector protein Akt, indicating that the ternary complex mediates PI3K signaling. Signifying the functional importance of the ternary complex, the capacity of E4-ORF1 to induce soft agar growth and focus formation in cells is ablated either by a mutation that prevents E4-ORF1 binding to Dlg1 or by a PI3K inhibitor drug. These results demonstrate that E4-ORF1 interacts with Dlg1 and PI3K to assemble a ternary complex where E4-ORF1 hijacks the Dlg1 oncogenic function to relocate cytoplasmic PI3K to the membrane for constitutive activation. This novel mechanism of Dlg1 subversion by adenovirus to dysregulate PI3K could be used by other pathogenic viruses, such as human papillomavirus, human T-cell leukemia virus type 1, and influenza A virus, which also target Dlg1 and activate PI3K in cells. PMID- 24788834 TI - [Assessment of fetal cardiac function--established and novel methods]. AB - Numerous maternal (diabetes, preeclampsia) and fetal pathologies (uteroplacental dysfunction, hydrops, infection, congenital heart disease) can lead to cardiac dysfunction in the fetus. This includes increase of pre- and afterload, compression of the heart, myocardial damage, hypoxia and hyperglycemia. Beside already established methods like m-mode and pulse-waved Doppler, new promising technologies like tissue Doppler and speckle tracking are available for monitoring fetal cardiac function. Some of these new techniques have not been part of clinical routine yet because no validation has been performed so far and/or the technique is too time-consuming. Other technologies are currently being tested and only part of research projects. Innovations like speckle tracking that have its seeds in adult cardiology, are still limited because of the smallness of the fetal heart, the higher heart rate, fetal and maternal moving artefacts and finally because of a missing fetal ECG signal. Therefore their application should be performed critically. PMID- 24788835 TI - [Maternal risks in pregnancies involving fetal surgery for TTTS and fetal malformations]. AB - The improvements in fetal diagnosis or imaging, maternal-fetal anaesthesia, and instrumentation have resulted in a wider application of fetal surgery for complex fetal diseases of the fetal patient in order to prevent death and to improve the quality of life for long-term survivors. However, for all decisions the maternal risks have to be balanced and considered in the informed consent process. Sometimes symptoms of the fetal disease may overlap with risks of the procedures. Maternal symptoms may even improve after fetal surgery in some cases. Here we aim at illustrating the short- and long-term consequences of different procedures of fetal surgery in order to improve the indication and informed consent process with the parents. Interdisciplinary team approaches help to illustrate the fetal, neonatal and maternal consequences when discussing and indicating fetal surgery and hopefully facilitate a long-term support for the family. PMID- 24788836 TI - Analysis of infants based on data from the German Perinatal Survey of the years 1994-2011 in Mecklenburg-Pomerania, Germany: new percentile values for anthropometric measures of infants. AB - BACKGROUND: This communication presents precise percentile values for birth weight, birth length and cranial circumference of infants in Mecklenburg Pomerania, Germany. MATERIAL AND METHODS: Based on data from the German Perinatal Survey of the years 1994-2011 in Mecklenburg-Pomerania, the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentile values for birth weight, birth length and head circumference are specified. The measurements of a total of 174,084 infants from non-multiple births are shown. RESULTS: The statistically calculated percentile values are presented in tabular and graph forms. The mean birth weight of the infants was 3,437.8 g. The average age of the mothers was 27.9 years. The average duration of pregnancy was 39.4 complete weeks. CONCLUSIONS: The insights gained from many years of data collection are presented as standardised, regional percentile values and curves for Mecklenburg-Pomerania for the first time. The differentiated presentation for the federal state opens the possibility for individually tailored consultations in clinical practice and may provide support for recognised national curves for these values. PMID- 24788837 TI - The factor time in fetal heart rate monitoring and the detection of acidosis using the WAS score. AB - BACKGROUND: Using the naked eye evaluation of fetal heart rate (fhr) patterns remains difficult and is not complete. Computer-aided analysis of the fhr offers the opportunity to analyze fhr patterns completely and to detect all changes due to hypoxia and acidosis. It was the goal of this study to analyze the factor time in fetal monitoring and to evaluate the association between the fhr and the actual pH values in arterial umbilical blood. METHODS: During a period of 11 years the FHR signals (i. e., the R-R interval of the F-ECG) of 646 fetuses were recorded with a CTG and simultaneously by a computer. The computer files were analyzed thereafter, i. e., the results did not influence our clinical management. To enter the study, all fetuses must have been delivered by the vaginal route--in consequence without a significant loss of fhr signals. During forceps and/or vacuum deliveries recordings were continued. If necessary a new electrode was inserted. In this study recordings of fetuses with chorioamnionitis, tracings of malformed neonates and tracings shorter than 30 min were excluded. Thus 484 recordings were left. We used our own computer programs written in MATLAB (USA). 3 parameters were determined electronically: 1) the mean fetal frequency [fhf, (bpm)], 2) the number of turning points (N/min) in the fhr, which we called 'microfluctuation' (micro) and 3) the oscillation amplitude, oamp (bpm). Measurements of the acid-base variables from arterial (UA) and venous (UV) blood were performed using RADIOMETER equipment (ABL500) and trained personnel. However, only the actual pHUA values were used in this study. To detect the influence of hypoxia and acidosis, all 484 cases were separated into 7 groups according to the actual pH(UA) value: 55 fetuses lying in a small non-acidotic "pH-window" (pH(UA)=7.290-7.310, mean=7.300+/-0.008) were used as 'controls'. RESULTS: In humans fhf, micro and the oamp behave differently during the last 30 min of delivery and with different fetal pHUA values: micro is early (at 0 min) decreased with fetal acidemia and is steadily deceasing (68-40 N/min) during vaginal delivery; the oamp--mainly due to decelerations--is increased from 35 up to 70 bpm during the last 30 min. Hypoxia and acidosis increase the amplitude and duration of decelerations; finally fhf shows only an insignificant reaction to acidemia but is decreased (from 135 to 110 bpm) overall with the course of time. Therefore the 3 characteristics of the fhr might be ranged according to their decreasing sensitivity to acidemia as follows: 1) fetal microfluctuation, 2) oscillation amplitude and 3) mean frequency. The 3 components of the fhr were used to invent and apply a score named the WAS score. This score increases the association between the actual pHUA values and the activity of the fetal heart. The 3 variables of the fhr mentioned above were rated differently; the 3 factors necessary to achieve this were computed electronically using an optimization program. The result is the WAS score: WAS=mean [frq*f(f)(v(j)) * micro*f(m)(v(j))/oamp*f(a)(v(j))](j=1,30). Using the last 30 min of delivery the correlation coefficient r of this score with pH(UA) reaches 0.645, P<< 0.001. The regression is linear in our 484 cases. CONCLUSIONS: Microfluctuation is the most sensible variable of the fetal heart followed by the oscillation amplitude and mean frequency. The WAS score offers the best correlation with the actual pH values measured in arterial umbilical blood. PMID- 24788838 TI - The trophic status of Suwalki Landscape Park lakes based on selected parameters (NE Poland). AB - This study describes changes in the trophic status of 12 lakes within Suwalki Landscape Park (SLP). All of the trophic classifications of the lakes were based on the trophic continuum division. Trophic status was determined by means of multiparameter indices using several diverse criteria. In this study, the assessment of the trophic status of lakes included water quality; abundance and biomass of bacterioplankton, phytoplankton, and zooplankton; and primary production of phytoplankton. The Carlson trophic state index (TSI) describes the level of water fertility and indicated the dominance of moderately eutrophic waters. Lakes Perty, Jeglowek, and Hancza have a trophic status that indicates mesotrophy (TSI <50). The trophic status of the studied lakes was determined based on the bacterial abundance and clearly showed a lack of oligotrophic lakes in SLP. Based on the number of bacteria, only Lake Szurpily can be classified as beta-mesotrophic, whereas Lake Linowek can be characterized as hypertrophic with some features typical for humic waters. The greatest value of gross primary production was observed in Lake Linowek (126.4 mg C/m(3)/h). The phytoplankton trophy index varied from 1.59 to 2.28, and its highest value, which indicated eutrophy, was determined for Lake Udziejek. In the case of Lakes Hancza, Szurpily, Perty, Jeglowek, and Kojle, the index ranged from 1.25 to 1.74, which indicated mesotrophy. The majority of the lakes were classified as mesoeutrophic (1.75-2.24). The highest trophic status was assessed for lakes with a marked dominance of cyanobacteria (Lake Przechodnie, Lake Krajwelek, Lake Udziejek, and Lake Pogorzalek), which is commonly recognized as an indicator of high trophic status. Considering all of the indices of trophic status, the analysis of rotifer community structure indicates that the studied group of lakes is mesoeutrophic or eutrophic. The values of crustacean zooplankton indices indicated that the trophic status of the studied lakes was close to that determined using a TSI. The parameters of zooplankton abundance and species structure allowed for the observance of changes in the tropic levels of lakes, which are difficult to detect by a chemical assay alone. PMID- 24788839 TI - Temporal and spatial variability of phytoplankton monitored by a combination of monitoring buoys, pigment analysis and fast screening microscopy in the Fehmarn Belt Estuary. AB - For 2 years, a baseline investigation was carried out to collect reference information of the present environmental status in the Fehmarn Belt and adjacent area. The temporal and spatial variability of phytoplankton was monitored by a combination of monitoring buoys, pigment analysis and fast screening microscopy. The overall phytoplankton succession in the Fehmarn Belt area was found to be influenced primarily by the seasonal changes, where various diatoms dominated the spring and autumn blooms and flagellates like Chrysochromulina sp., Dictyocha speculum and various dinoflagellates were occasionally abundant in late spring and summer. The phytoplankton groups were remarkably uniform horizontally in the investigation area while large differences in both biomasses and composition of individual phytoplankton groups were seen vertically in the water column, especially in the summer periods, in which the two-layer exchange flow between the North Sea and the Baltic Sea is showing a particularly strong stratification in the Fehmarn Belt. The chlorophyll a concentrations ranged continuously from 1 to 3 MUg/L at the three permanent buoy stations during the 2 years of monitoring, except for the spring and autumn blooms where chlorophyll a increased up to 18 MUg/L in the spring of 2010 and up to 8 MUg/L in the autumn of 2009. Recurrent blooms of filamentous cyanobacteria are common during the summer period in the Baltic Sea and adjacent areas, but excessive blooms of cyanobacteria did not occur in 2009 and 2010 in the Fehmarn Belt area. The combination of the HPLC pigment analysis method and monitoring buoys continuously measuring fluorescence at selected stations with fast screening of samples in the microscope proved advantageous for obtaining information on both the phytoplankton succession and dynamic and, at the same time, getting information on duration and intensity of the blooms as well as specific information on the dominant species present both temporally and spatially in the large Fehmarn Belt area. PMID- 24788840 TI - The use of a natural coagulant (Opuntia ficus-indica) in the removal for organic materials of textile effluents. AB - The goal of this study was to investigate the activity of the coagulant extracted from the cactus Opuntia ficus-indica (OFI) in the process of coagulation/flocculation of textile effluents. Preliminary tests of a kaolinite suspension achieved maximum turbidity removal of 95 % using an NaCl extraction solution. Optimization assays were conducted with actual effluents using the response surface methodology (RSM) based on the Box-Behnken experimental design. The responses of the variables FeCl3, dosage, cactus dosage, and pH in the removal of COD and turbidity from both effluents were investigated. The optimum conditions determined for jeans washing laundry effluent were the following: FeCl3 160 mg L(-1), cactus dosage 2.60 mg L(-1), and pH 5.0. For the fabric dyeing effluent, the optimum conditions were the following: FeCl3 640 mg L(-1), cactus dosage 160 mg L(-1), and pH 6.0. Investigation of the effects of the storage time and temperature of the cactus O. ficus-indica showed that coagulation efficiency was not significantly affected for storage at room temperature for up to 4 days. PMID- 24788841 TI - The relationship between maternal depressive, anxious, and stress symptoms during pregnancy and adult offspring behavioral and emotional problems. AB - BACKGROUND: Prenatal maternal depressive, anxious, and stress symptoms have been found to be associated with child and adolescent behavior problems. In this paper, we investigate their impact on behavior problems and depressive symptoms in adulthood. METHODS: Participants included 3,099 mother-offspring pairs from the Mater University Study of Pregnancy (MUSP), an Australian based, prebirth cohort study. We used latent class growth analysis (LCGA) with parallel processes to identify trajectories of maternal depressive, anxious, and stress symptoms over four time periods between the mothers' first clinic visit and 5 years postpregnancy. We fitted the estimates from the maternal trajectories in multivariate logistic regression models to predict internalizing and externalizing behavior at age 21. We adjusted for a wide range of prenatal and postnatal factors, including maternal life events, relationship quality, contact with the new born, as well as concurrent maternal depressive and anxious symptoms and father's history of mental health problem. RESULTS: LCGA found seven groups of mothers; one group of mothers exhibited high levels of depressive, anxious, and stress symptoms during pregnancy but not at later time points. Their offspring experienced increased levels of behavior problems and depressive symptoms. CONCLUSIONS: This paper provides the first evidence that high levels of maternal subjective depressive, anxious, and stress symptoms experienced in early pregnancy may predict internalizing and externalizing behavior problems and depressive symptoms in young adults. PMID- 24788842 TI - A "catch-and-release" protocol for alkyne-tagged molecules based on a resin-bound cobalt complex for peptide enrichment in aqueous media. AB - The development of new and mild protocols for the specific enrichment of biomolecules is of significant interest from the perspective of chemical biology. A cobalt-phosphine complex immobilised on a solid-phase resin has been found to selectively bind to a propargyl carbamate tag, that is, "catch", under dilute aqueous conditions (pH 7) at 4 degrees C. Upon acidic treatment of the resulting resin-bound alkyne-cobalt complex, the Nicholas reaction was induced to "release" the alkyne-tagged molecule from the resin as a free amine. Model studies revealed that selective enrichment of the alkyne-tagged molecule could be achieved with high efficiency at 4 degrees C. The proof-of-concept was applied to an alkyne tagged amino acid and dipeptide. Studies using an alkyne-tagged dipeptide proved that this protocol is compatible with various amino acids bearing a range of functionalities in the side-chain. In addition, selective enrichment and detection of an amine derived from the "catch and release" of an alkyne-tagged dipeptide in the presence of various peptides has been accomplished under highly dilute conditions, as determined by mass spectrometry. PMID- 24788843 TI - Detection and characterization of porcine caliciviruses in Italy. AB - Porcine noroviruses and sapoviruses have been sporadically reported in European countries, and more rarely in Italy. In this study, stools samples were collected from both asymptomatic and diarrheic pigs from northern Italy and were screened for caliciviruses by RT-PCR. Sapoviruses were detected frequently and were genetically related to both the GIII reference strain and the newly described porcine sapovirus genogroups. Porcine norovirus was detected in one asymptomatic pig (0.5%) and was genotyped as GII.11. This is the first detection of porcine norovirus in Italy. PMID- 24788844 TI - Genetic polymorphism of CCL2-2510 and susceptibility to enterovirus 71 encephalitis in a Chinese population. AB - The study was performed in 36 Chinese patients with enterovirus 71 (EV71) encephalitis and 141 patients with EV71-related hand, foot and mouth disease (HFMD) without encephalitis. Genotyping was done by the polymerase chain reaction restriction fragment length polymorphism technique. Patients with EV71 encephalitis had a significantly higher frequency of the CCL2-2510GG genotypes when compared to patients with EV71-related HFMD without encephalitis (66.7% vs. 41.8%, p=0.028). The frequency of CCL2-2510G alleles was also significantly higher among the patients with EV71 encephalitis than among patients with EV71 related HFMD without encephalitis (79.2% vs. 64.9%, OR=2.1, 95% CI=1.1-3.8, P=0.023). Significant differences were found in gender, age, fever days, white blood cell count, C-reactive protein level, blood glucose concentration, and CCL2 level among genotypes of CCL2-2510A/G in EV71-infected patients, but no significant differences were found in alanine aminotransferase, aspartate aminotransferase, or creatine kinase myocardial isozyme levels or in cerebrospinal fluid evaluations (except monocytes) in patients with EV71 encephalitis. These findings suggest that the CCL2-2510G allele is associated with susceptibility to EV71 encephalitis in Chinese patients. PMID- 24788845 TI - Downregulation of miR-101-3p by hepatitis B virus promotes proliferation and migration of hepatocellular carcinoma cells by targeting Rab5a. AB - RAB GTPase 5A (RAB5A), a member of the Rab subfamily of small GTPases, acts as an oncogene and has been associated with various key cellular functions, including cell growth, differentiation, apoptosis and angiogenesis. Recently, it has been reported that the Rab5a gene is involved in the progression of cancer. Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers, and it is usually associated with persistent hepatitis B virus (HBV) infections. Emerging evidence suggests that HBV alters microRNA (miRNA) expression profiles, but the mechanisms underlying this process have not yet been fully elucidated. Here, we examine how HBV affects the production of miR-101-1, which has been shown to be downregulated in HCC. We found that HBV could repress miR-101-3p by inhibiting its promoter activity. Downregulation of miR-101-3p promoted cancer cell growth and migration, and a specific miR-101-3p inhibitor was able to enhance proliferation and migration. Moreover, we identified Rab5a was one of the target genes of miR-101-3p in HBV-related HCC. Forced expression of miR-101-3p in liver cell lines resulted in a marked reduction of the expression of Rab5a at both the mRNA and protein level by directly targeting the 3'untranslated region of Rab5a. Overexpression of Rab5a resulted in a reversal of the suppression of proliferation and migration of SMMC-7721 cells mediated by miR-101-3p. Taken together, our data show that HBV can downregulate miR-101-3p expression by inhibiting its promoter activity and that downregulation of miR-101-3p promotes HCC cell proliferation and migration by targeting Rab5a. This provides new insights into the mechanisms of HBV-related HCC pathogenesis. PMID- 24788846 TI - Detection and genetic characterization of cosavirus in a pediatric patient with diarrhea. AB - Human cosavirus (HCoSV) is a newly discovered virus of the family Picornaviridae. A total of 411 fecal specimens were collected from children admitted to hospitals with acute gastroenteritis symptoms in Chiang Mai, Thailand, in 2010-2011 and screened for HCoSV by an RT-nested PCR method. HCoSV was found in a single specimen (CMH-N199-11) collected from a 3-year-old boy. This represents the first report of HCoSV infection in a pediatric patient with diarrhea in Thailand. Analysis of the complete coding sequence revealed that this HCoSV was most similar to the Chinese HCoSV-A reference strain SH1, and belonged to genotype A6. The data imply that HCoSVs detected in Thailand and China share the same evolutionary ancestor. Our results emphasize the need for further research to understand the distribution, genetic diversity, and association of the HCoSV with acute gastroenteritis in humans. PMID- 24788847 TI - Epidemiology of rotavirus diarrhoea in Albania. AB - The aim of the study was to estimate the prevalence of rotavirus disease in children<5 years old in Tirana, Albania, and to monitor and characterize the rotavirus genotypes. Rotavirus was detected in 21% of samples, more frequently in children under 2 years of age, which accounted for 80.8% of all positive cases. Among all rotavirus-positive samples collected, G4P[8] was the most prevalent genotype (38%), followed by G1P[8] (36.6%). The use of safe and effective rotavirus vaccines for the prevention of severe diarrhoea and the reduction of treatment costs will be of great importance for Albania. PMID- 24788848 TI - In vivo delivery of interleukin-35 relieves coxsackievirus-B3-induced viral myocarditis by inhibiting Th17 cells. AB - Interleukin (IL)-35 is a new member of the IL-12 cytokine family. The suppressive role of IL-35 in the immune response to parasitic and bacterial infections and in autoimmunity has been demonstrated in terms of its anti-inflammatory properties. However, the functional role of IL-35 in viral myocarditis has not been investigated. In this study, IL-35 expression was measured in heart tissues with coxsackievirus B3 (CVB3)-induced myocarditis. It was significantly reduced in the late stage of viral infection and correlated negatively with disease severity. To examine the therapeutic role of IL-35 in viral myocarditis, an IL-35-expressing plasmid (pIL-35-FC) was packaged with polyethyleneimine and delivered intraperitoneally to BALB/c male mice before and after CVB3 infection. The severity of myocarditis was assessed 7 days after infection. The in vivo delivery of IL-35 significantly ameliorated the severity of viral myocarditis, reflected in an increased survival rate and increased bodyweights, and reduced serum creatine kinase (CK) and CK-MB activities, cardiac pathological scores, and viral replication. We also show that the overexpression of IL-35 reduced splenic Th17 cells and Th17-related proinflammatory cytokines in heart tissues. In conclusion, our data indicate that IL-35 effectively protects the myocardium from the pathogenesis of CVB3-induced viral myocarditis, which may be attributable to reduced Th17 production. This suggests that supplementation with IL-35 could be a novel therapeutic treatment for viral myocarditis. PMID- 24788850 TI - A meta-analysis of health effects of randomized controlled worksite interventions: does social stratification matter? AB - OBJECTIVES: The aim of this review was to assess what types of socioeconomic positions (SEP) are being considered in randomized controlled intervention studies and estimate the moderation of SEP in workplace intervention effects on body mass index (BMI), fruit and vegetable consumption, musculoskeletal symptoms, and job stress. METHODS: A meta-analysis of randomized controlled workplace interventions was undertaken. Studies were classified by participants' SEP. The overall standardized mean difference (SMD) for each outcome was estimated with random-effects models. Additionally, a random-effects model with SEP as moderating variable was calculated in order to assess intervention effect modification (EM). RESULTS: This review covers 36 studies. Altogether 40 reports of intervention effects were considered. The overall mean differences in the models, without SEP as moderating variable, were significant for all outcomes. BMI, self-reported musculoskeletal symptoms, and self-reported job stress decreased [SMD -0.16, 95% confidence interval (95% CI) -0.29- -0.02, SMD -0.32, 95% CI -0.51- -0.14, and SMD -0.37, 95% CI -0.71- -0.04, respectively], whereas daily consumption of fruit and vegetables increased (SMD 0.12, 95% CI 0.01-0.22). There were no statistically significant differences between occupational classes for the health outcomes considered (SMD -0.102, 95% CI -0.264-0.060, EM -0.141, 95% CI -0.406-0.125; SMD 0.117, 95% CI -0.049-0.282, EM 0.000, 95% CI -0.230 0.231; SMD -0.301, 95% CI -0.494- -0.107, EM -0.369, 95% CI -1.169-0.430; and SMD -0.200, 95% CI -0.524-0.124, EM -0.598, 95% CI -1.208-0.012, respectively). CONCLUSIONS: Workplace interventions can achieve small positive effects on major health outcomes. We could not confirm whether these effects are moderated by occupational class. PMID- 24788849 TI - Altered resting-state functional connectivity of striatal-thalamic circuit in bipolar disorder. AB - Bipolar disorder is characterized by internally affective fluctuations. The abnormality of inherently mental state can be assessed using resting-state fMRI data without producing task-induced biases. In this study, we hypothesized that the resting-state connectivity related to the frontal, striatal, and thalamic regions, which were associated with mood regulations and cognitive functions, can be altered for bipolar disorder. We used the Pearson's correlation coefficients to estimate functional connectivity followed by the hierarchical modular analysis to categorize the resting-state functional regions of interest (ROIs). The selected functional connectivities associated with the striatal-thalamic circuit and default mode network (DMN) were compared between bipolar patients and healthy controls. Significantly decreased connectivity in the striatal-thalamic circuit and between the striatal regions and the middle and posterior cingulate cortex was observed in the bipolar patients. We also observed that the bipolar patients exhibited significantly increased connectivity between the thalamic regions and the parahippocampus. No significant changes of connectivity related to the frontal regions in the DMN were observed. The changed resting-state connectivity related to the striatal-thalamic circuit might be an inherent basis for the altered emotional and cognitive processing in the bipolar patients. PMID- 24788851 TI - Associations of traffic noise with self-rated health and psychotropic medication use. AB - OBJECTIVES: Road traffic noise is a common environmental nuisance, which has been thought to increase the risk of many types of health problems. However, population-level evidence often remains scarce. This study examined whether road traffic noise is associated with self-rated health and use of psychotropic medication in a cohort of public sector employees. METHODS: Data are from the Finnish Public Sector Study cohort. Geographical information system (GIS) was used to link modeled outdoor road traffic noise levels (L den) to residential addresses of 15 611 men and women with cross-sectional survey responses on self rated health and register-based information on the use of antidepressants, anxiolytics, and hypnotics. High trait anxiety scores were used to identify potentially vulnerable individuals. The analyses were run with logistic regression models adjusting for individual and area-level variables. All participants were blind to the aim of the study. RESULTS: Mean level of road traffic noise at participants' home addresses was 52 decibels (dB) (standard deviation 8.1). Noise level >60 dB versus <=45 dB was associated with poor self rated health in men [odds ratio (OR) 1.58, 95% confidence interval (95% CI) 1.14 2.21]. Further stratification revealed that the association was evident only among men with high trait anxiety scores (OR 2.23, 95% CI 1.28-3.89). No association was found with psychotropic medication use or among women. CONCLUSION: Exposure to road traffic noise was not associated with increased use of psychotropic medication, although it was associated with weakened self-rated health among men. PMID- 24788852 TI - Filtration improves the performance of a high-throughput screen for anti mycobacterial compounds. AB - The tendency for mycobacteria to aggregate poses a challenge for their use in microplate based assays. Good dispersions have been difficult to achieve in high throughput screening (HTS) assays used in the search for novel antibacterial drugs to treat tuberculosis and other related diseases. Here we describe a method using filtration to overcome the problem of variability resulting from aggregation of mycobacteria. This method consistently yielded higher reproducibility and lower variability than conventional methods, such as settling under gravity and vortexing. PMID- 24788853 TI - German second-opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice. AB - In 2006, the German Testicular Cancer Study Group initiated an extensive evidence based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project's effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson's chi2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice. PMID- 24788854 TI - Biocompatible cationic lipids for the formulation of liposomal DNA vectors. AB - Ethylphosphocholine lipids are highly biocompatible cationic amphiphiles that can be used for the formulation of liposomal DNA vectors, with negligible toxic effects on cells and organisms. Here we report the characterization of EDPPC (1,2 dipalmitoyl-sn-glycero-O-ethyl-3-phosphocholine chloride) liposomes, containing two different zwitterionic helper lipids, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine) and DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine). Depending on the nature of the helper lipid, a phase separation in the bilayer is found at room temperature, where domains enriched in the cationic component coexist in a relatively large temperature range with regions where the zwitterionic lipids are predominant. We studied DNA complexation, the internal structure of lipoplexes and their docking and fusogenic ability with model target bilayers. The structural and functional modifications caused by DNA binding were studied using Dynamic Light Scattering (DLS), zeta potential, and small and wide angle X-ray scattering (SAXS-WAXS) measurements, while the interaction with membranes was assessed by using Giant Unilamellar Vesicles (GUVs) as model target bilayers. The results presented establish a connection between the physicochemical properties of lipid bilayers, and in particular of lipid demixing, with the phase state of the complexes and their ability to interact with model membranes. PMID- 24788855 TI - Graphene oxide and metal-mediated base pairs based "molecular beacon" integrating with exonuclease I for fluorescence turn-on detection of biothiols. AB - A novel fluorescence turn-on strategy, based on the resistance of metal-mediated molecular-beacons (MBs) toward nuclease digestion and the remarkable difference in the affinity of graphene oxide (GO) with MBs and the mononucleotides, is designed for the biothiols assay. Specifically, the metal-mediated base pairs facilitate the dye labeled MBs to fold into a hairpin structure preventing the digestion by exonuclease I, and thus allow the fluorescence quenching. The competition binding by biothiols removes metal ions from the base pairs, causing the nuclease reaction, and less decrease in the fluorescence is obtained after incubating with GO due to the weak affinity of the product-mononucleotides to GO. Hg(2+)-mediated MBs were firstly designed for the biothiols detection, and glutathione (GSH) was applied as the model target. Under the optimal conditions, the approach exhibits high sensitivity to GSH with a detection limit of 1.53 nM. Ag(+)-mediated MBs based sensor was also constructed to demonstrate its versatility, and cysteine was studied as the model target. The satisfactory results in the determination of biothiols in serum demonstrate that the method possesses great potential for detecting thiols in biological fluids. This new approach is expected to promote the exploitation of metal-mediated base pairs based biosensors in biochemical and biomedical studies. PMID- 24788856 TI - Commentary on "combined alloplastic implant and autologous dermis graft for nasal augmentation rhinoplasty in asians". AB - Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24788857 TI - The skin-tightening effects of 1,444-nm Nd:YAG laser on human skin: an in vivo study. AB - BACKGROUND: The 1,444-nm Nd:YAG laser was developed to improve the removal of fat cells and to affect the underlying dermis with the aim of skin tightening. We conducted this study to evaluate whether this laser is effective in tightening the skin and causing histological alterations to dermal collagen fibers, fibroblasts, mucopolysaccharides, and elastin. METHODS: In a 38-year-old patient who was scheduled to undergo elective abdominoplasty, we subdermally performed laser-assisted treatment with the 1,444-nm Nd:YAG laser using different power settings over periods of 3 months and 1 month and prior to surgery. Postoperatively, we evaluated the skin-tightening effect through histopathologic examination. RESULTS: On histopathology examination, the thickness of the dermis had gradually increased following the 3-month treatment with laser irradiation. In the treatment groups on the abdomen, the collagen fibers were arranged in a more parallel pattern and became denser than those in the control group. Likewise, fibroblast proliferation and the levels of mucopolysaccharides and elastin were higher in the treatment groups than in the control group. CONCLUSIONS: The 1,444-nm Nd:YAG laser was effective in promoting the remodeling of the dermis and the regeneration of collagen fibers. As such, the 1,444-nm Nd:YAG laser could be used for skin tightening in addition to its function in lipolysis. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24788859 TI - Emergy-based comparative analysis on industrial clusters: economic and technological development zone of Shenyang area, China. AB - In China, local governments of many areas prefer to give priority to the development of heavy industrial clusters in pursuit of high value of gross domestic production (GDP) growth to get political achievements, which usually results in higher costs from ecological degradation and environmental pollution. Therefore, effective methods and reasonable evaluation system are urgently needed to evaluate the overall efficiency of industrial clusters. Emergy methods links economic and ecological systems together, which can evaluate the contribution of ecological products and services as well as the load placed on environmental systems. This method has been successfully applied in many case studies of ecosystem but seldom in industrial clusters. This study applied the methodology of emergy analysis to perform the efficiency of industrial clusters through a series of emergy-based indices as well as the proposed indicators. A case study of Shenyang Economic Technological Development Area (SETDA) was investigated to show the emergy method's practical potential to evaluate industrial clusters to inform environmental policy making. The results of our study showed that the industrial cluster of electric equipment and electronic manufacturing produced the most economic value and had the highest efficiency of energy utilization among the four industrial clusters. However, the sustainability index of the industrial cluster of food and beverage processing was better than the other industrial clusters. PMID- 24788860 TI - Influence of UV radiation on chlorophyll, and antioxidant enzymes of wetland plants in different types of constructed wetland. AB - A surface- and vertical subsurface-flow-constructed wetland were designed to study the response of chlorophyll and antioxidant enzymes to elevated UV radiation in three types of wetland plants (Canna indica, Phragmites austrail, and Typha augustifolia). Results showed that (1) chlorophyll content of C. indica, P. austrail, and T. augustifolia in the constructed wetland was significantly lower where UV radiation was increased by 10 and 20 % above ambient solar level than in treatment with ambient solar UV radiation (p < 0.05). (2) The malondialdehyde (MDA) content, guaiacol peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) activities of wetland plants increased with elevated UV radiation intensity. (3) The increased rate of MDA, SOD, POD, and CAT activities of C. indica, P. australis, and T. angustifolia by elevated UV radiation of 10 % was higher in vertical subsurface-flow-constructed wetland than in surface-flow constructed wetland. The sensitivity of MDA, SOD, POD, and CAT activities of C. indica, P. austrail, and T. augustifolia to the elevated UV radiation was lower in surface-flow-constructed wetland than in the vertical subsurface-flow constructed wetland, which was related to a reduction in UV radiation intensity through the dissolved organic carbon and suspended matter in the water. C. indica had the highest SOD and POD activities, which implied it is more sensitive to enhanced UV radiation. Therefore, different wetland plants had different antioxidant enzymes by elevated UV radiation, which were more sensitive in vertical subsurface-flow-constructed wetland than in surface-flow-constructed wetland. PMID- 24788861 TI - Variation of Microcystis and microcystins coupling nitrogen and phosphorus nutrients in Lake Erhai, a drinking-water source in Southwest Plateau, China. AB - Lake Erhai is the second largest lake of Southwest China and an important drinking water source. The lake is currently defined as the preliminary stage of eutrophic states, but facing a serious threat with transfer into intensive eutrophication. The present study examined the dynamics of Microcystis blooms and toxic Microcystis in Lake Erhai during 2010, based on quantitative real-time PCR method using 16S rRNA gene specific for Microcystis and microcystin systhesis gene (mcy), and chemical analysis on microcystin (MC) concentrations. Total Microcystis cell abundance at 16 sampling sites were shown as an average of 1.7 * 10(7) cells l(-1) (1.3 * 10(2)-3.8 * 10(9) cells l(-1)). Microcystin LR (MC-LR) and microcystin RR (MC-RR) were the main variants. The strong southwesterly winds, anticlockwise circular flows and geographical characteristics of lake and phytoplankton community succession impacted the distribution patterns of Chl a and MC in the lake. The concentration of Chl a and MC and abundances of total Microsytis and MC-producing Microsystis (MCM) were shown to be positively correlated with pH, DO and TP, negatively correlated with SD, NO3-N, TN/Chl a and TN/TP, and not correlated with NH4-N, TN, dissolved total nitrogen (DTN) and water temperatures. When TN/TP decrease, Microcystis tended to dominate and MC concentrations tended to increase, suggesting that the "TN/TP rule" can be partially applied to explain the correlation between the cyanobacterial blooms and nutrients N and P only within a certain nutrient level. It is speculated that N and P nutrients and the associated genes (e.g., mcy) may jointly drive MC concentration and toxigenicity of Microcystis in Lake Erhai. PMID- 24788862 TI - Biosequestration of lead using Bacillus strains isolated from seleniferous soils and sediments of Punjab. AB - The present study was conducted to isolate and explore bacterial strains with a potential to sequester lead (Pb) and tolerate other heavy metals from industrial effluents and sediments. Out of the six bacterial strains isolated from seleniferous sites of Punjab, three isolates (RS-1, RS-2, and RS-3) were screened out for further growth-associated lead sequestration and molecular characterization on the basis of their tolerance toward lead and other heavy metals. Biomass and cell-free supernatant were analyzed for lead contents using ICP-MS after growth-associated lead sequestration studies in tryptone soya broth (pH = 7.2 +/- 0.2) under aerobic conditions at 37 degrees C temperature. Almost 82 % and 70 % divalent lead was sequestered in cell pellets of RS-1 and RS-3, respectively while only 45 % of lead was found in cell pellet of RS-2 in the first 24 h. However, significant biosequestration of lead was observed in RS-2 after 48 h of incubation with concomitant increase in biomass. Simultaneously, morphological, biochemical, and physiological characterization of selected strains was carried out. 16S rRNA gene sequence of these isolates revealed their phylogenetic relationship with class Bacillaceae, a low G + C firmicutes showing 98 % homology with Bacillus sp. PMID- 24788863 TI - Influences of sediment properties and macrophytes on phosphorous speciation in the intertidal marsh. AB - Phosphorus (P) in wetlands is mainly bound to sediment in various species, which is essential to predict water column P levels. The purpose of this work is to understand the influences of sediment properties and vegetation types on P speciation. Sediments under four vegetation types in the tidal flat and offshore sandbar in Hangzhou Bay of China were collected seasonally. The rank order of P species in sediment based on concentration was exchangeable P (Exch-P) < iron/aluminum-bound P (Fe/Al-P) < organic P (Org-P) < calcium-bound P (Ca-P). Sediment total phosphorus (TP) and Fe/Al-P concentrations were lower in offshore sandbar than those of tidal flat, reflecting effects of anthropogenic contamination in the latter. Sediment particle size distribution strongly affected P speciation, as indicated by a significant correlation between them. Total phosphorus and Org-P concentrations in vegetated sediments were higher than those of bare mudflat. Additionally, there was a significant negative correlation between Ca-P and Org-P, and Fe/Al-P, indicating the presence of vegetation which may result in P speciation by converting Ca-P to soluble and active P and higher Org-P. Overall, sediment particle size distribution is the most fundamental physical property that affects P speciation, and vegetation types are important factors that influence Org-P concentration. PMID- 24788864 TI - Application of selection mapping to identify genomic regions associated with dairy production in sheep. AB - In Europe, especially in Mediterranean areas, the sheep has been traditionally exploited as a dual purpose species, with income from both meat and milk. Modernization of husbandry methods and the establishment of breeding schemes focused on milk production have led to the development of "dairy breeds." This study investigated selective sweeps specifically related to dairy production in sheep by searching for regions commonly identified in different European dairy breeds. With this aim, genotypes from 44,545 SNP markers covering the sheep autosomes were analysed in both European dairy and non-dairy sheep breeds using two approaches: (i) identification of genomic regions showing extreme genetic differentiation between each dairy breed and a closely related non-dairy breed, and (ii) identification of regions with reduced variation (heterozygosity) in the dairy breeds using two methods. Regions detected in at least two breeds (breed pairs) by the two approaches (genetic differentiation and at least one of the heterozygosity-based analyses) were labeled as core candidate convergence regions and further investigated for candidate genes. Following this approach six regions were detected. For some of them, strong candidate genes have been proposed (e.g. ABCG2, SPP1), whereas some other genes designated as candidates based on their association with sheep and cattle dairy traits (e.g. LALBA, DGAT1A) were not associated with a detectable sweep signal. Few of the identified regions were coincident with QTL previously reported in sheep, although many of them corresponded to orthologous regions in cattle where QTL for dairy traits have been identified. Due to the limited number of QTL studies reported in sheep compared with cattle, the results illustrate the potential value of selection mapping to identify genomic regions associated with dairy traits in sheep. PMID- 24788865 TI - A Case of Trigeminocardiac Reflex During Infrastructure Maxillectomy. AB - IMPORTANCE: The trigeminocardiac reflex refers to the sudden development of bradycardia or even asystole with arterial hypotension from manipulation of any sensory branches of the trigeminal nerve. Although it has only rarely been associated with morbidity and tends to be self-limited with removal of the stimulus, it is an important phenomenon for head and neck surgeons to recognize and respond to. OBSERVATIONS: We present the case of a woman in her late 60s with maxillary alveolar ridge squamous cell carcinoma who developed episodes of asystole and bradycardia during posterior maxillary manipulation for an infrastructure maxillectomy at a tertiary academic medical center. Administration of atropine and removal of the inciting stimulus sufficed to extinguish the episodes and allow procedure completion. CONCLUSIONS AND RELEVANCE: The trigeminocardiac reflex can be provoked by a number of head and neck and skull base procedures including parotidectomy and posterior maxillectomy. Surgeons and anesthesiologists should be wary of inciting the reflex during manipulation of trigeminal branches. Careful dissection for prevention and early intervention with stimulus removal and anticholinergic use as needed are paramount to ensure good outcomes. PMID- 24788866 TI - Biomechanical and histological evaluation of roughened surface titanium screws fabricated by electron beam melting. AB - BACKGROUND: Various fabrication methods are used to improve the stability and osseointegration of screws within the host bone. The aim of this study was to investigate whether roughened surface titanium screws fabricated by electron beam melting can provide better stability and osseointegration as compared with smooth titanium screws in sheep cervical vertebrae. METHODS: Roughened surface titanium screws, fabricated by electron beam melting, and conventional smooth surface titanium screws were implanted into sheep for 6 or 12 weeks (groups A and B, respectively). Bone ingrowth and implant stability were assessed with three dimensional imaging and reconstruction, as well as histological and biomechanical tests. RESULTS: No screws in either group showed signs of loosening. Fibrous tissue formation could be seen around the screws at 6 weeks, which was replaced with bone at 12 weeks. Bone volume/total volume, bone surface area/bone volume, and the trabecular number were significantly higher for a define region of interest surrounding the roughened screws than that surrounding the smooth screws at 12 weeks. Indeed, for roughened screws, trabecular number was significantly higher at 12 weeks than at 6 weeks. On mechanical testing, the maximum pullout strength was significantly higher at 12 weeks than at 6 weeks, as expected; however, no significant differences were found between smooth and roughened screws at either time point. The maximum torque to extract the roughened screws was higher than that required for the smooth screws. CONCLUSIONS: Electron beam melting is a simple and effective method for producing a roughened surface on titanium screws. After 12 weeks, roughened titanium screws demonstrated a high degree of osseointegration and increased torsional resistance to extraction over smooth titanium screws. PMID- 24788867 TI - Highly effective hot spots for SERS signatures of live fibroblasts. AB - Pre-formed silver-boron nanoparticles of 22 nm form pearl-like necklace nanostructures with interparticle junctions of less than 10 nm length in the matrix of polyethylene glycol (8000 Da). The silver necklace nanostructure is stable at 37 degrees C or 70 degrees C and also inside a live cell medium. A polyethylene glycol matrix with a shorter chain length (1000 Da) does not protect the nanoparticles against attraction, and random aggregates are formed. Silver necklace nanostructures exhibit strong Raman enhancement by more than ~10(9) which is much higher than for silver-citrate or random silver-boron aggregates. The polymeric matrix of 8000 Da contributes strongly to the electromagnetic field enhancement and removes the chemical contribution to the surface Raman scattering increase. The stable interparticle junctions act as local hot spots for strong Raman scattering signals collected from live fibroblasts and allow systematic in situ studies. PMID- 24788868 TI - Compositions and their application to the analysis of choice. AB - Descriptions of steady-state patterns of choice allocation under concurrent schedules of reinforcement have long relied on the "generalized matching law" (Baum, 1974), a log-odds power function. Although a powerful model in some contexts, a series of conflicting empirical results have cast its generality in doubt. The relevance and analytic relevance of matching models can be greatly expanded by considering them in terms of compositions (Aitchison, 1986). A composition encodes a set of ratios (e.g., 5:3:2) as a vector with a constant sum, and this constraint (called closure) restricts the data to a nonstandard sample space. By exploiting this sample space, unbiased estimates of model parameters can be obtained to predict behavior given any number of choice alternatives. Additionally, the compositional analysis of choice provides tools that can accommodate both violations of scale invariance and unequal discriminability of stimuli signaling schedules of reinforcement. In order to demonstrate how choice data can be analyzed using the compositional approach, data from three previously published studies are reanalyzed. Additionally, new data is reported comparing matching behavior given four, six, and eight response alternatives. PMID- 24788869 TI - Host control of symbiont natural product chemistry in cryptic populations of the tunicate Lissoclinum patella. AB - Natural products (secondary metabolites) found in marine invertebrates are often thought to be produced by resident symbiotic bacteria, and these products appear to play a major role in the symbiotic interaction of bacteria and their hosts. In these animals, there is extensive variation, both in chemistry and in the symbiotic bacteria that produce them. Here, we sought to answer the question of what factors underlie chemical variation in the ocean. As a model, we investigated the colonial tunicate Lissoclinum patella because of its rich and varied chemistry and its broad geographic range. We sequenced mitochondrial cytochrome c oxidase 1 (COXI) genes, and found that animals classified as L. patella fall into three phylogenetic groups that may encompass several cryptic species. The presence of individual natural products followed the phylogenetic relationship of the host animals, even though the compounds are produced by symbiotic bacteria that do not follow host phylogeny. In sum, we show that cryptic populations of animals underlie the observed chemical diversity, suggesting that the host controls selection for particular secondary metabolite pathways. These results imply novel approaches to obtain chemical diversity from the oceans, and also demonstrate that the diversity of marine natural products may be greatly impacted by cryptic local extinctions. PMID- 24788870 TI - Glutathione-S-transferase M1 and T1 null genotypes are associated with hypertension risk: a systematic review and meta-analysis of 12 studies. AB - Oxidative stress is known to be implicated in the pathogenesis of essential hypertension. Glutathione-S-transferase (GST) enzymes are key components of cellular defense against oxidative stress. The present study aimed to clarify the association between polymorphisms in GST and risk of essential hypertension using a meta-analysis of published studies. PubMed-Medline, Ovid-EMBASE, HuGE Navigator and SCOPUS databases were searched to identify case-control studies that examined the association of GST polymorphisms and hypertension. Data were extracted using standardized methods. Combined odds ratios (OR) with 95% confidence intervals (CI) for the association of polymorphisms with hypertension were calculated using a fixed effect approach and under dominant, recessive, additive and overdominant models of inheritance. A total of 12 studies comprising 2,040 cases and 2,462 controls fulfilled the inclusion criteria. GSTM1 (presence/null), GSTT1 (presence/null) and GSTP1 (Ile105Val; rs1695) polymorphisms were evaluated. Meta analysis revealed significant associations between the null genotypes of GSTM1 (OR: 1.22; 95% CI: 1.08-1.39; p=0.002) and GSTT1 (OR: 1.30; 95% CI: 1.13-1.50; p=0.0003) and risk of hypertension. The observed associations were robust in sensitivity analyses. However, no significant association was found for the rs1695 polymorphism under all assessed modes of inheritance. Findings of the present meta-analysis demonstrated that GSTM1 and GSTT1 null genotypes may serve as predisposing factors for essential hypertension. Further studies are warranted to validate this association, and also to explore if these null genotypes are in linkage with other hypertension susceptibility polymorphisms. PMID- 24788871 TI - Motility and trafficking in B-cell non-Hodgkin's lymphoma (Review). AB - B cell non-Hodgkin's lymphomas (B-NHLs) consist of a wide spectrum of entities and consequently have varied clinical courses. Like many other malignancies, each of the B-NHL depend on their microenvironment for growth and survival; therefore, understanding the factors involved in their tissue localisation is likely to have implications for therapies designed to treat B-NHL. This review summarises the chemokines, integrins and sphingosine-1 phosphate receptors involved in normal B cell location and distribution within the lymphoid tissues (lymph nodes, spleen and bone marrow). It also provides a precis of what is known about these factors in the disease state: i.e., in some subtypes of B-NHL. PMID- 24788872 TI - The early evolutionary history of belemnites: new data from Japan. AB - Belemnites (Order Belemnitida), a very successful group of Mesozoic coleoid cephalopods, dominated the world's oceans throughout the Jurassic and Cretaceous. According to the current view, the phylogenetically earliest belemnites are known from the lowermost Jurassic (Hettangian, 201-199 Ma) of northern Europe. They are of low diversity and have small sized rostra without clear grooves. Their distribution is restricted to this area until the Pliensbachian (191-183 Ma). Here we describe two new belemnite taxa of the Suborder Belemnitina from the Sinemurian (199-191 Ma) of Japan: Nipponoteuthis katana gen et sp. nov., which represents the new family Nipponoteuthidae, and Eocylindroteuthis (?) yokoyamai sp. nov. This is the first reliable report of Sinemurian belemnites outside of Europe and the earliest record of typical forms of Belemnitina in the world. The Sinemurian belemnites from Japan have small to large rostra with one deep and long apical groove. Morphologically these forms are completely different from coeval European genera of Hettangian-Sinemurian age. These new findings suggest that three groups of Belemnitina existed in the Hettangian-Sinemurian: 1) European small forms, 2) Japanese very large forms, and 3) the typical forms with a distinctive apical groove, reported here. The Suborder Belemnitina therefore did not necessarily originate in the Hettangian of northern Europe. The new material from Japan documents that the suborder Belemnitina had a much higher diversity in the early Jurassic than previously thought, and it also shows strong endemisms from the Sinemurian onwards. PMID- 24788874 TI - Pincer versus pseudopincer: isomerism in palladium(II) complexes bearing kappa(3)C,S,C ligands. AB - In NHC pincer complexes incorporating a hemilabile donor site, there exists an equilibrium between the true pincer form and a pseudopincer coordination isomer. The influence of the NHC moieties on this isomerism has been studied by DFT calculations. PMID- 24788873 TI - Admission lipoprotein-associated phospholipase A2 activity is not associated with long-term clinical outcomes after ST-segment elevation myocardial infarction. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is a biomarker predicting cardiovascular diseases in a real-world. However, the prognostic value in patients undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) on long-term clinical outcomes is unknown. METHODS: Lp-PLA2 activity was measured in samples obtained prior to pPCI from consecutive STEMI patients in a high-volume intervention center from 2005 until 2007. Five years all-cause mortality was estimated with the Kaplan-Meier method and compared among tertiles of Lp-PLA2 activity during complete follow-up and with a landmark at 30 days. In a subpopulation clinical endpoints were assessed at three years. The prognostic value of Lp-PLA2, in addition to the Thrombolysis In Myocardial Infarction or multimarker risk score, was assessed in multivariable Cox regression. RESULTS: The cohort (n = 987) was divided into tertiles (low <144, intermediate 144-179, and high >179 nmol/min/mL). Among the tertiles differences in baseline characteristics associated with long-term mortality were observed. However, no significant differences in five years mortality in association with Lp-PLA2 activity levels were found; intermediate versus low Lp-PLA2 (HR 0.97; CI 95% 0.68 1.40; p = 0.88) or high versus low Lp-PLA2 (HR 0.75; CI 95% 0.51-1.11; p = 0.15). Both in a landmark analysis and after adjustments for the established risk scores and selection of cases with biomarkers obtained, non-significant differences among the tertiles were observed. In the subpopulation no significant differences in clinical endpoints were observed among the tertiles. CONCLUSION: Lp-PLA2 activity levels at admission prior to pPCI in STEMI patients are not associated with the incidence of short and/or long-term clinical endpoints. Lp-PLA2 as an independent and clinically useful biomarker in the risk stratification of STEMI patients still remains to be proven. PMID- 24788875 TI - Improved protein deproteinization method for the determination of meloxicam in human plasma and application in pharmacokinetic study. AB - A simple, rapid, specific and reliable high-performance liquid chromatographic assay of meloxicam in human plasma has been developed using a C18 reversed-phase analytical column. Reversed-phase chromatography was conducted using a mobile phase of 0.02 potassium dihydrogen phosphate (adjusted to pH 2.7 with phosphoric acid)-acetonitrile-triethylamine (35:65:0.05, v/v) with UV detection at 354 nm. The drug in human plasma was deproteinized using a combination of methanol and chloroform. This method is simple, rapid and consistent with a high recovery of meloxicam in human plasma ranging from 93.29 to 111.09%. Regression analysis for the calibration plot for plasma standards obtained for the drug concentrations between (25-4000) ng/mL indicated excellent linearity (r >= 0.9997). The proposed method was applied to study the bioequivalence between Mobic (original) and Melocam (generic) products. The study was conducted on using two tablets (4 * 7.5 mg) of each of the commercial product and the reference standard in a two-way open randomized crossover design involving 20 volunteers. Area under the concentration-time curve, peak concentration (C(max)) and time to reach C(max) were 72,868.61 ng h/mL, 2133.93 ng/mL and 4.06 h for Mobic, and 78,352.52 ng h/mL, 2525.18 ng/mL and 3.61 h for Melocam. Two C(max) were discovered in the pharmacokinetic profiles which confirm enterohepatic recirculation. PMID- 24788876 TI - Role of macrophage sialoadhesin in host defense against the sialylated pathogen group B Streptococcus. AB - Several bacterial pathogens decorate their surfaces with sialic acid (Sia) residues within cell wall components or capsular exopolysaccharides. Sialic acid expression can promote bacterial virulence by blocking complement activation or by engagement of inhibitory sialic acid-binding immunoglobulin-like lectins (Siglecs) on host leukocytes. Expressed at high levels on splenic and lymph node macrophages, sialoadhesin (Sn) is a unique Siglec with an elongated structure that lacks intracellular signaling motifs. Sialoadhesin allows macrophage to engage certain sialylated pathogens and stimulate inflammatory responses, but the in vivo significance of sialoadhesin in infection has not been shown. We demonstrate that macrophages phagocytose the sialylated pathogen group B Streptococcus (GBS) and increase bactericidal activity via sialoadhesin-sialic acid-mediated recognition. Sialoadhesin expression on marginal zone metallophilic macrophages in the spleen trapped circulating GBS and restricted the spread of the GBS to distant organs, reducing mortality. Specific IgM antibody responses to GBS challenge were also impaired in sialoadhesin-deficient mice. Thus, sialoadhesin represents a key bridge to orchestrate innate and adaptive immune defenses against invasive sialylated bacterial pathogens. KEY MESSAGE: Sialoadhesin is critical for macrophages to phagocytose and clear GBS. Increased GBS organ dissemination in the sialoadhesin-deficient mice. Reduced anti-GBS IgM production in the sialoadhesin-deficient mice. PMID- 24788878 TI - Fluorescence spectroscopy of individual semiconductor nanoparticles in different ethylene glycols. AB - The optical properties of single colloidal semiconductor nanoparticles (NPs) are considerably influenced by the direct environment of the NPs. Here, the influence of different liquid and solid glycol matrices on CdSe-based NPs is investigated. Since the fluorescence of individual NPs varies from one NP to another, it is highly desirable to study the very same individual NPs in different matrices. This was accomplished by immobilizing NPs in a liquid cell sample holder or in microfluidic devices. The samples have been investigated by space-resolved wide field fluorescence microscopy and energy- and time-resolved confocal scanning fluorescence microscopy with respect to fluorescence intensities, emission energies, blinking behavior, and fluorescence decay dynamics of individual NPs. During the measurements the NPs were exposed to air, to liquid ethylene glycols H(OCH2CH2)nOH (also called EGn) with different chain lengths (1 <= n <= 7), to liquid 2-methylpentane-2,3-diol, or to solid polyethylene oxide. It was found that EG6-7 (also known as PEG 300) is very well suited as a liquid matrix or solvent for experiments that correlate chemical and physical modifications of the surface and of the immediate environment of individual NPs to their fluorescence properties since it leads to intense and stable fluorescence emission of the NPs. PMID- 24788877 TI - White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism. AB - The etiology of schizophrenia (SZ) is complex and largely unknown. Neuroimaging and postmortem studies have suggested white matter disturbances in SZ. In the present study, we tested the white matter deficits hypothesis of SZ using a mouse model of SZ induced by NMDA receptor antagonist MK-801. We found that mice with repeated chronic MK-801 administration showed increased locomotor activity in the open field test, less exploration of a novel environment in the hole-board test, and increased anxiety in the elevated plus maze but no impairments were observed in coordination or motor function on accelerating rota-rod. The total white matter volume and corpus callosum volume in mice treated with MK-801 were significantly decreased compared to control mice treated with saline. Myelin basic protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase were also significantly decreased in the mouse model of SZ. Furthermore, we observed degenerative changes of myelin sheaths in the mouse model of SZ. These results provide further evidence of white matter deficits in SZ and indicate that the animal model of SZ induced by MK-801 is a useful model to investigate mechanisms underlying white matter abnormalities in SZ. PMID- 24788879 TI - The rapid detection of microRNA based on p19-enhanced fluorescence polarization. AB - Via a molecular caliper p19 protein, we have developed an amplified fluorescence polarization method for rapid microRNA detection. This proposed assay has several intrinsic features including rapidity, simplicity, and accuracy. PMID- 24788880 TI - Aquamicrobium terrae sp. nov., isolated from the polluted soil near a chemical factory. AB - A Gram-negative, aerobic, non-motile bacterial strain hun6(T) isolated from the polluted soil near a chemical factory in northern Nanjing, China was investigated to clarify its taxonomic position. Growth of strain hun6(T) occurred between 10 and 45 degrees C (optimum, 30 degrees C) and between pH 6.0 and 8.0 (optimum, pH 7.0). No growth occurred at NaCl concentrations greater than 5 % (w/v). The 16S rRNA gene sequence analysis indicated that strain hun6(T) belongs to the genus Aquamicrobium. The sequence similarities of strain hun6(T) to other type strains of Aquamicrobium genus were all below 98.5 %. The presence of ubiquinone 10, the predominant fatty acid summed feature 8 (C18:1 omega7c and/or C18:1 omega6c) and C19:0 cyclo omega8c, a polar lipid pattern with phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, phosphatidylethanolamine and phophatidylmonomethylethanoamine were in accord with the characteristics of the genus Aquamicrobium. The G+C content of the genomic DNA was determined to be 63.5 mol%. The results of DNA-DNA hybridization, physiological and biochemical tests and chemotaxonomic properties allowed genotypic and phenotypic differentiation of strain hun6(T) from all known Aquamicrobium species. Therefore, strain hun6(T) can be assigned to a new species of this genus for which the name Aquamicrobium terrae sp. nov. is proposed. The type strain is hun6(T) (= CICC 10733(T) = DSM 27865(T)). PMID- 24788885 TI - Theophylline improves lipopolysaccharide-induced alveolarization arrest through inflammatory regulation. AB - Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased numbers of alveoli and increased airspace. BPD, frequently suffered by very low birth weight infants, has been closely associated with intrauterine infection. However, the underlying mechanisms of BPD remain unclear. In the present study, it was identified that administration of intra-amniotic lipopolysaccharide (LPS) to pregnant rats on embryonal day 16.5 (E16.5) induced significant alveolarization arrest similar to that of BPD in neonatal pups, and theophylline injected subcutaneously into the newborns improved the pathological changes. To further investigate the underlying mechanism of the morphogenesis amelioration of theophylline, cytokine antibody arrays were performed with the lung lysates of neonatal rats. The results indicated that LPS upregulated a series of pro-inflammatory cytokines and theophylline significantly attenuated the expression levels of pro-inflammatory cytokines tumor necrosis factor-alpha, macrophage inflammatory protein (MIP)-1alpha and MIP-2, and markedly elevated the production of tumor growth factor (TGF)-beta family members TGF-beta1, TGF-beta2 and TGF-beta3, which are anti-inflammatory cytokines. Accordingly, it was hypothesized that theophylline may protect against BPD and improve chorioamnionitis-induced alveolar arrest by regulating the balance between pro and anti-inflammatory cytokine expression. PMID- 24788884 TI - A Wickerhamomyces anomalus killer strain in the malaria vector Anopheles stephensi. AB - The yeast Wickerhamomyces anomalus has been investigated for several years for its wide biotechnological potential, especially for applications in the food industry. Specifically, the antimicrobial activity of this yeast, associated with the production of Killer Toxins (KTs), has attracted a great deal of attention. The strains of W. anomalus able to produce KTs, called "killer" yeasts, have been shown to be highly competitive in the environment. Different W. anomalus strains have been isolated from diverse habitats and recently even from insects. In the malaria mosquito vector Anopheles stephensi these yeasts have been detected in the midgut and gonads. Here we show that the strain of W. anomalus isolated from An. stephensi, namely WaF17.12, is a killer yeast able to produce a KT in a cell free medium (in vitro) as well as in the mosquito body (in vivo). We showed a constant production of WaF17.12-KT over time, after stimulation of toxin secretion in yeast cultures and reintroduction of the activated cells into the mosquito through the diet. Furthermore, the antimicrobial activity of WaF17.12-KT has been demonstrated in vitro against sensitive microbes, showing that strain WaF17.12 releases a functional toxin. The mosquito-associated yeast WaF17.12 thus possesses an antimicrobial activity, which makes this yeast worthy of further investigations, in view of its potential as an agent for the symbiotic control of malaria. PMID- 24788887 TI - Retention and selectivity of basic drugs on solid-phase extraction sorbents: application to direct determination of beta-blockers in urine. AB - Seven solid phase sorbent materials with reversed-phase, mixed-mode interactions (ion-exchange and reversed-phase), and molecularly imprinted polymers (MIP), namely Oasis HLB, Oasis MAX, Oasis MCX, Bond Elute Plexa, Bond Elute Plexa PAX, Bond Elute Plexa PCX, and SupelMIP sorbents, were investigated. The present study was focused on the retention and elution of pharmaceutically active substances based on several analyte-sorbent interaction properties. Basic drugs, such as beta-blockers (i.e., atenolol, pindolol, acebutolol, metoprolol, labetalol, and propranolol) were selected as the model compounds for this study. These compounds are frequently encountered in anti-doping tests. The extraction efficiencies of the individual sorbents were compared based on the recovery of known amounts of the targeted analytes in a metered elution volume (500 MUL) in three separate elution fractions. The elution efficiency of the total amount of the target analytes on various sorbents was not appreciably influenced by the volume of eluent required for complete elution. Based on the small matrix effects and clear baseline, SupelMIP was the most suitable sorbent for urine analysis. The relative analyte recoveries of the SPE-HPLC procedure proved satisfactory for the range from 94% to 105%, with an RSD ranging from 2% to 4%. The regression equations for all of the targeted compounds exhibited excellent linearity (r(2) > 0.9991) over the range of 10 to 1000 ng mL(-1). The limits of detection and quantification for the selected beta-blocker compounds in urine were in the ranges of 0.6 to 2.0 ng mL(-1) and 2.0 to 6.7 ng mL(-1), respectively. PMID- 24788889 TI - Highly sensitive determination of 68 psychoactive pharmaceuticals, illicit drugs, and related human metabolites in wastewater by liquid chromatography-tandem mass spectrometry. AB - The present work describes the development and validation of a highly sensitive analytical method for the simultaneous determination of 68 compounds, including illicit drugs (opiates, opioids, cocaine compounds, amphetamines, and hallucinogens), psychiatric drugs (benzodiazepines, barbiturates, anesthetics, antiepileptics, antipsychotics, antidepressants, and sympathomimetics), and selected human metabolites in influent and effluent wastewater (IWW and EWW) by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method involves a pre-concentration and cleanup step, carried out by solid-phase extraction (SPE) using the adsorbent Strata-XC, followed by the instrumental analysis performed by LC-MS/MS, using a Kinetex pentafluorophenyl (PFP) reversed phase fused-core column and electrospray ionization (ESI) in both positive and negative modes. A systematic optimization of mobile phases was performed to cope with the wide range of physicochemical properties of the analytes. The PFP column was also compared with two reversed-phase columns: fused-core C18 and XB-C18 (with a cross-butyl C18 ligand). SPE optimization and critical aspects associated with the trace level determination of the target compounds (e.g., matrix effects) have been also considered and discussed. Fragmentation patterns for all the classes were proposed. The validated method provides absolute recoveries between 75 and 120% for most compounds in IWW and EWW. Low method limits of detection were achieved (between 0.04 and 10.0 ng/L for 87% of the compounds), allowing a reliable and accurate quantification of the analytes at trace level. The method was successfully applied to the analysis of these compounds in five wastewater treatment plants in Santorini, a touristic island of the Aegean Sea, Greece. Thirty-two out of 68 compounds were detected in all IWW samples in the range between 0.6 ng/L (for nordiazepam) and 6,822 ng/L (for carbamazepine) and 22 out of 68 in all EWW samples, with values between 0.4 ng/L (for 9-OH risperidone) and 2,200 ng/L (for carbamazepine). The novel methodology described herein maximizes the information on the environmental analysis of these substances and also provides a first profile of 68 drugs in a Greek touristic area. PMID- 24788890 TI - Partial-filling affinity capillary electrophoresis and quartz crystal microbalance with adsorption energy distribution calculations in the study of biomolecular interactions with apolipoprotein E as interaction partner. AB - Adsorption energy distribution (AED) calculations were successfully applied to partial-filling affinity capillary electrophoresis (PF-ACE) to facilitate more detailed studies of biomolecular interactions. PF-ACE with AED calculations was employed to study the interactions between two isoforms of apolipoprotein E (apoE) and dermatan sulfate (DS), and a quartz crystal microbalance (QCM) was used in combination with AED calculations to examine the interactions of the 15 amino-acid peptide fragment of apoE with DS. The heterogeneity of the interactions was elucidated. Microscale thermophoresis was used to validate the results. The interactions studied are of interest because, in vivo, apolipoprotein E localizes on DS-containing regions in the extracellular matrix of human vascular subendothelium. Two-site binding was demonstrated for the isoform apoE3 and DS, but only one-site binding for apoE2-DS. Comparable affinity constants were obtained for the apoE2-DS, apoE3-D3, and 15-amino-acid peptide of apoE-DS using the three techniques. The results show that combining AED calculations with modern biosensing techniques can open up another dimension in studies on the heterogeneity and affinity constants of biological molecules. PMID- 24788888 TI - Comprehensive automation of the solid phase extraction gas chromatographic mass spectrometric analysis (SPE-GC/MS) of opioids, cocaine, and metabolites from serum and other matrices. AB - The analysis of opioids, cocaine, and metabolites from blood serum is a routine task in forensic laboratories. Commonly, the employed methods include many manual or partly automated steps like protein precipitation, dilution, solid phase extraction, evaporation, and derivatization preceding a gas chromatography (GC)/mass spectrometry (MS) or liquid chromatography (LC)/MS analysis. In this study, a comprehensively automated method was developed from a validated, partly automated routine method. This was possible by replicating method parameters on the automated system. Only marginal optimization of parameters was necessary. The automation relying on an x-y-z robot after manual protein precipitation includes the solid phase extraction, evaporation of the eluate, derivatization (silylation with N-methyl-N-trimethylsilyltrifluoroacetamide, MSTFA), and injection into a GC/MS. A quantitative analysis of almost 170 authentic serum samples and more than 50 authentic samples of other matrices like urine, different tissues, and heart blood on cocaine, benzoylecgonine, methadone, morphine, codeine, 6 monoacetylmorphine, dihydrocodeine, and 7-aminoflunitrazepam was conducted with both methods proving that the analytical results are equivalent even near the limits of quantification (low ng/ml range). To our best knowledge, this application is the first one reported in the literature employing this sample preparation system. PMID- 24788891 TI - A capillary electrophoresis procedure for the screening of oligosaccharidoses and related diseases. AB - The most widely used method for the biochemical screening of oligosaccharidoses is the analysis of the urinary oligosaccharide pattern by thin-layer chromatography on silica gel plates. However, this method is not always sensitive enough, and it is extremely time-consuming and laborious. In this work, the analysis of the urine oligosaccharide pattern was standardized for the first time by using capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection (Beckman P/ACE MDQ) with a 488-nm argon ion laser module. All of the analyses were conducted using the Carbohydrate Labeling and Analysis Kit (Beckman Coulter), which derivatizes samples with 8-aminopyrene-1,3,6-trisulfonate. Urine samples from 40 control subjects (age range, 1 week to 16 years) and from ten patients diagnosed with eight different lysosomal diseases (six of them included in the Educational Oligosaccharide Kit from ERNDIM EQA schemes) were analyzed. Two oligosaccharide excretion patterns were established in our control population according to age (younger or older than 1 year of age). Abnormal peaks with slower migration times than the tetrasaccharide position were observed for fucosidosis, alpha-mannosidosis, GM1 gangliosidosis, GM2 gangliosidosis variant 0, Pompe disease, and glycogen storage disease type 3. In conclusion, the first CE-LIF method to screen for oligosaccharidoses and related diseases, which also present oligosacchariduria, has been standardized. In all of the cases, the urine oligosaccharide analysis was strongly informative and showed abnormal patterns that were not present in any of the urine samples from the control subjects. Only urine from patients with aspartylglucosaminuria and Schindler disease displayed normal results. PMID- 24788893 TI - Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma. AB - Vitamin D analogues can reduce TGF-beta pro-fibrotic signaling in dermal fibroblasts, but they may also induce a potentially pro-fibrotic thymic stromal lymphopoietin (TSLP)-dependent Th2 cytokine local response. We have analyzed the net effect of topical vitamin D analogue calcipotriol (CPT) on the cytokine profile and the development of fibrosis in experimental model of bleomycin induced fibrosis. Mice were simultaneously treated with topical CPT or vehicle cream and skin fibrosis was measured by collagen deposition, Masson's trichrome staining and hydroxyproline content. Cytokine and TSLP gene expression was evaluated by quantitative RT-PCR. We showed that in bleomycin injected skin, CPT administration significantly enhanced TSLP and IL-13 gene expression, but did not modify the expression of other cytokines. Skin fibrosis and hydroxyproline content were significantly reduced in CPT compared to vehicle-treated mice. In normal skin, topical administration of CPT lacked a direct pro-fibrotic effect. Our results demonstrate that topical CPT superinduces the expression of the TSLP/IL-13 Th2 axis in fibrotic skin, but it has a net anti-fibrotic effect. These data support the therapeutic use of topical vitamin D analogues for skin fibrosis. PMID- 24788892 TI - Phenethyl isothiocyanate inhibits growth of human chronic myeloid leukemia K562 cells via reactive oxygen species generation and caspases. AB - Phenethyl isothiocyanate (PEITC), a potential cancer chemopreventive constituent of cruciferous vegetables, including watercress, has been reported to inhibit cancer cell growth by arresting the cell cycle and inducing apoptosis in various human cancer cell models. However, the role of PEITC in the inhibition of human chronic myeloid leukemia (CML) K562 cell growth and its underlying mechanisms have yet to be elucidated. In the present study, PEITC was found to induce cell death through the induction of reactive oxygen species (ROS) stress and oxidative damage. Heme oxygenase-1 (HO-1), which participates in the development of numerous tumors and the sensitivity of these tumors to chemotherapeutic drugs, plays a protective role by modulating oxidative injury. Therefore, the present study assessed the inhibitory effect of PEITC on K562 cells and whether HO-1 facilitated cell apoptosis and ROS generation. PEITC was found to suppress cell growth and cause apoptosis by promoting Fas and Fas ligand expression, increasing ROS generation and by the successive release of cytochrome c as well as the activation of caspase-9 and caspase-3. PEITC was also combined with the HO-1 inhibitor zinc protoporphyrin IX and the inducer hemin to assess whether HO-1 determines cell survival and ROS generation. The results of the present study suggest that PEITC may be a potential anti-tumor compound for CML therapy, and that HO-1 has a critical function in PEITC-induced apoptosis and ROS generation. PMID- 24788894 TI - Electrospun polyamide-polyethylene glycol nanofibers for headspace solid-phase microextration. AB - A solution of polyamide (PA) containing polyethylene glycol (PEG) as a side low molecular-weight polymer was electrospun. After synthesizing the PA-PEG nanofibers, the constituent was subsequently removed (modified PA) and confirmed by Fourier transform infrared spectroscopy. The scanning electron microscopy images showed an average diameter of 640 and 148 nm for PA and PA-PEG coatings, respectively, while the latter coating structure was more homogeneous and porous. The extraction efficiencies of PA, PA-PEG, and the modified PA fiber coatings were assayed by headspace solid-phase microextraction of a number of chlorophenols from real water samples followed by their determination by gas chromatography with mass spectrometry. To prepare the most appropriate coatings, the amounts and the flow rate of the electrospinning solution were investigated. Various extraction parameters, such as the salt content, desorption condition, extraction temperature, and time were optimized. The limits of detection of the method were in the range of 0.8-25 ng/L, while the RSDs at two concentration levels of 200 and 80 ng/L were between 2.1 and 12.2%. The analysis of real water samples led to relative recoveries between 85 and 98% with a linearity of 8-1500 ng/L. PMID- 24788895 TI - Epigenetic impact of curcumin on stroke prevention. AB - The epigenetic impact of curcumin in stroke and neurodegenerative disorders is curiosity-arousing. It is derived from Curcuma longa (spice), possesses anti oxidative, anti-inflammatory, anti-lipidemic, neuro-protective and recently shown to exhibit epigenetic modulatory properties. Epigenetic studies include DNA methylation, histone modifications and RNA-based mechanisms which regulate gene expression without altering nucleotide sequences. Curcumin has been shown to affect cancer by altering epigenetic changes but its role as an epigenetic agent in cerebral stroke has not been much explored. Although curcumin possesses remarkable medicinal properties, the bioavailability of curcumin has limited its success in epigenetic studies and clinical trials. The present review is therefore designed to look into epigenetic mechanisms that could be induced with curcumin during stroke, along with its molecular designing with different moieties that may increase its bioavailability. Curcumin has been shown to be encapsulated in exosomes, nano-vesicles (<200 nm), thereby showing its therapeutic effects in brain diseases. Curcumin delivered through nanoparticles has been shown to be neuroregenerative but the use of nanoparticles in brain has limitations. Hence, curcumin-encapsulated exosomes along with curcumin-primed exosomes (exosomes released by curcumin-treated cells) are much needed to be explored to broadly look into their use as a novel therapy for stroke. PMID- 24788896 TI - Neuroprotective effects of guanosine administration on behavioral, brain activity, neurochemical and redox parameters in a rat model of chronic hepatic encephalopathy. AB - It is well known that glutamatergic excitotoxicity and oxidative stress are implicated in the pathogenesis of hepatic encephalopathy (HE). The nucleoside guanosine exerts neuroprotective effects through the antagonism against glutamate neurotoxicity and antioxidant properties. In this study, we evaluated the neuroprotective effect of guanosine in an animal model of chronic HE. Rats underwent bile duct ligation (BDL) and 2 weeks later they were treated with i.p. injection of guanosine 7.5 mg/kg once a day for 1-week. We evaluated the effects of guanosine in HE studying several aspects: a) animal behavior using open field and Y-maze tasks; b) brain rhythm changes in electroencephalogram (EEG) recordings; c) purines and glutamate levels in the cerebral spinal fluid (CSF); and d) oxidative stress parameters in the brain. BDL rats presented increased levels of glutamate, purines and metabolites in the CSF, as well as increased oxidative damage. Guanosine was able not only to prevent these effects but also to attenuate the behavioral and EEG impairment induced by BDL. Our study shows the neuroprotective effects of systemic administration of guanosine in a rat model of HE and highlights the involvement of purinergic system in the physiopathology of this disease. PMID- 24788897 TI - Molecular analysis in X-linked adrenoleukodystrophy patients: identification of a novel mutation. AB - X linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease characterized by progressive demyelination of the central nervous system, adrenocortical insufficiency and elevated levels of very long chain fatty acids (VLCFAs). It is caused by mutations in ABCD1 gene located at Xq28. More than 1,300 mutations have been identified to date which is unique to each patient. In this study we report the mutational analysis of 2 X-ALD patients (1 male and 1 female) showing variable clinical spectrum. The mutation analysis of the female patient revealed IVS5-6delC (c.1489-6delC) and p. P543L variations in compound heterozygous state. The male patient was found to be hemizygous for a novel mutation, p. R104P. In conclusion, while defining a novel mutation, the cases presented herein may contribute to the mutation and clinical spectrum of X-ALD. PMID- 24788899 TI - Musicians are at increased risk of noise induced deafness, study finds. PMID- 24788898 TI - Safety, effectiveness and acceptability of the PrePex device for adult male circumcision in Kenya. AB - OBJECTIVE: To assess the safety, effectiveness and acceptability of the PrePex device for adult medical male circumcision (MMC) in routine service delivery in Kenya. METHODS: We enrolled 427 men ages 18-49 at one fixed and two outreach clinics. Procedures were performed by trained clinical officers and nurses. The first 50 enrollees were scheduled for six follow-up visits, and remaining men were followed at Days 7 and 42. We recorded adverse events (AEs) and time to complete healing, and interviewed men about acceptability and pain. RESULTS: Placement and removal procedures each averaged between 3 and 4 minutes. Self reported pain was minimal during placement but was fleetingly intense during removal. The rate of moderate/severe AEs was 5.9% overall (95% confidence interval [CI] 3.8%-8.5%), all of which resolved without sequelae. AEs included 5 device displacements, 2 spontaneous foreskin detachments, and 9 cases of insufficient foreskin removal. Surgical completion of MMC was required for 9 men (2.1%). Among the closely monitored first 50 participants, the probability of complete healing by Day 42 was 0.44 (95% CI 0.30-0.58), and 0.90 by Day 56. A large majority of men was favorable about their MMC procedure and would recommend PrePex to friends and family. CONCLUSIONS: The PrePex device was effective for MMC in Kenya, and well-accepted. The AE rate was higher than reported for surgical procedures there, or in previous PrePex studies. Healing time is longer than following surgical circumcision. Provider experience and clearer counseling on post-placement and post-removal care should lead to lower AE rates. TRIAL REGISTRATION: ClinicalTrials.gov NCT01711411. PMID- 24788900 TI - Accommodative intraocular lens versus standard monofocal intraocular lens implantation in cataract surgery. AB - BACKGROUND: Following cataract surgery and intraocular lens (IOL) implantation, loss of accommodation or postoperative presbyopia occurs and remains a challenge. Standard monofocal IOLs correct only distance vision; patients require spectacles for near vision. Accommodative IOLs have been designed to overcome loss of accommodation after cataract surgery. OBJECTIVES: To define (a) the extent to which accommodative IOLs improve unaided near visual function, in comparison with monofocal IOLs; (b) the extent of compromise to unaided distance visual acuity; c) whether a higher rate of additional complications is associated the use of accommodative IOLs. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 9), Ovid MEDLINE, Ovid MEDLINE in-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily Update, Ovid OLDMEDLINE (January 1946 to October 2013), EMBASE (January 1980 to October 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrial.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 October 2013. SELECTION CRITERIA: We include randomised controlled trials (RCTs) which compared implantation of accommodative IOLs to implantation of monofocal IOLs in cataract surgery. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, assessed risk of bias and extracted data. All included trials used the 1CU accommodative IOL (HumanOptics, Erlangen, Germany) for their intervention group. One trial had an additional arm with the AT-45 Crystalens accommodative IOL (Eyeonics Vision). We performed a separate analysis comparing 1CU and AT-45 IOL. MAIN RESULTS: We included four RCTs, including 229 participants (256 eyes), conducted in Germany, Italy and the UK. The age range of participants was 21 to 87 years. All studies included people who had bilateral cataracts with no pre-existing ocular pathologies. We judged all studies to be at high risk of performance bias. We graded two studies with high risk of detection bias and one study with high risk of selection bias.Participants who received the accommodative IOLs achieved better distance-corrected near visual acuity (DCNVA) at six months (mean difference (MD) -3.10 Jaeger units; 95% confidence intervals (CI) -3.36 to -2.83, 2 studies, 106 people, 136 eyes, moderate quality evidence). Better DCNVA was seen in the accommodative lens group at 12 to 18 months in the three trials that reported this time point but considerable heterogeneity of effect was seen, ranging from 1.3 (95% CI 0.98 to 1.68; 20 people, 40 eyes) to 6 (95% CI 4.15 to 7.85; 51 people, 51 eyes) Jaeger units and 0.12 (95% CI 0.05 to 0.19; 40 people, binocular) logMAR improvement (low quality evidence). The relative effect of the lenses on corrected distant visual acuity (CDVA) was less certain. At six months there was a standardised mean difference of -0.04 standard deviations (95% CI 0.37 to 0.30, 2 studies, 106 people, 136 eyes, low quality evidence). At long term follow-up there was heterogeneity of effect with 18-month data in two studies showing that CDVA was better in the monofocal group (MD 0.12 logMAR; 95% CI 0.07 to 0.16, 2 studies, 70 people,100 eyes) and one study which reported data at 12 months finding similar CDVA in the two groups (-0.02 logMAR units, 95% CI 0.06 to 0.02, 51 people) (low quality evidence).The relative effect of the lenses on reading speed and spectacle independence was uncertain, The average reading speed was 11.6 words per minute more in the accommodative lens group but the 95% confidence intervals ranged from 12.2 words less to 35.4 words more (1 study, 40 people, low quality evidence). People with accommodative lenses were more likely to be spectacle-independent but the estimate was very uncertain (risk ratio (RR) 8.18; 95% CI 0.47 to 142.62, 1 study, 40 people, very low quality evidence).More cases of posterior capsule opacification (PCO) were seen in accommodative lenses but the effect of the lenses on PCO was uncertain (Peto odds ratio (OR) 2.12; 95% CI 0.45 to 10.02, 91 people, 2 studies, low quality evidence). People in the accommodative lens group were more likely to require laser capsulotomy (Peto OR 7.96; 95% CI 2.49 to 25.45, 2 studies, 60 people, 80 eyes, low quality evidence). Glare was reported less frequently with accommodative lenses but the relative effect of the lenses on glare was uncertain (RR any glare 0.78; 95% CI 0.32 to 1.90, 1 study, 40 people, and RR moderate/severe glare 0.45; 95% CI 0.04 to 4.60, low quality evidence). AUTHORS' CONCLUSIONS: There is moderate-quality evidence that study participants who received accommodative IOLs had a small gain in near visual acuity after six months. There is some evidence that distance visual acuity with accommodative lenses may be worse after 12 months but due to low quality of evidence and heterogeneity of effect, the evidence for this is not clear-cut. People receiving accommodative lenses had more PCO which may be associated with poorer distance vision. However, the effect of the lenses on PCO was uncertain.Further research is required to improve the understanding of how accommodative IOLs may affect near visual function, and whether they provide any durable gains. Additional trials, with longer follow-up, comparing different accommodative IOLs, multifocal IOLs and monofocal IOLs, would help map out their relative efficacy, and associated late complications. Research is needed on control over capsular fibrosis postimplantation.Risks of bias, heterogeneity of outcome measures and study designs used, and the dominance of one design of accommodative lens in existing trials (the HumanOptics 1CU) mean that these results should be interpreted with caution. They may not be applicable to other accommodative IOL designs. PMID- 24788901 TI - Studies probe links between childhood asthma and obesity. PMID- 24788902 TI - Good news, bad news and issues to watch. PMID- 24788903 TI - Making mental health services accessible to people with an intellectual disability. PMID- 24788904 TI - Dissociative identity disorder: An empirical overview. AB - OBJECTIVE: Despite its long and auspicious place in the history of psychiatry, dissociative identity disorder (DID) has been associated with controversy. This paper aims to examine the empirical data related to DID and outline the contextual challenges to its scientific investigation. METHODS: The overview is limited to DID-specific research in which one or more of the following conditions are met: (i) a sample of participants with DID was systematically investigated, (ii) psychometrically-sound measures were utilised, (iii) comparisons were made with other samples, (iv) DID was differentiated from other disorders, including other dissociative disorders, (v) extraneous variables were controlled or (vi) DID diagnosis was confirmed. Following an examination of challenges to research, data are organised around the validity and phenomenology of DID, its aetiology and epidemiology, the neurobiological and cognitive correlates of the disorder, and finally its treatment. RESULTS: DID was found to be a complex yet valid disorder across a range of markers. It can be accurately discriminated from other disorders, especially when structured diagnostic interviews assess identity alterations and amnesia. DID is aetiologically associated with a complex combination of developmental and cultural factors, including severe childhood relational trauma. The prevalence of DID appears highest in emergency psychiatric settings and affects approximately 1% of the general population. Psychobiological studies are beginning to identify clear correlates of DID associated with diverse brain areas and cognitive functions. They are also providing an understanding of the potential metacognitive origins of amnesia. Phase-oriented empirically-guided treatments are emerging for DID. CONCLUSIONS: The empirical literature on DID is accumulating, although some areas remain under-investigated. Existing data show DID as a complex, valid and not uncommon disorder, associated with developmental and cultural variables, that is amenable to psychotherapeutic intervention. PMID- 24788905 TI - Towards a dimensional approach to common mental disorders in the ICD-11? PMID- 24788906 TI - Mental illness and the National Disability Insurance Scheme: lessons from Europe. PMID- 24788907 TI - Ester carbonyl vibration as a sensitive probe of protein local electric field. AB - The ability to quantify the local electrostatic environment of proteins and protein/peptide assemblies is key to gaining a microscopic understanding of many biological interactions and processes. Herein, we show that the ester carbonyl stretching vibration of two non-natural amino acids, L-aspartic acid 4-methyl ester and L-glutamic acid 5-methyl ester, is a convenient and sensitive probe in this regard, since its frequency correlates linearly with the local electrostatic field for both hydrogen-bonding and non-hydrogen-bonding environments. We expect that the resultant frequency-electric-field map will find use in various applications. Furthermore, we show that, when situated in a non-hydrogen-bonding environment, this probe can also be used to measure the local dielectric constant (epsilon). For example, its application to amyloid fibrils formed by Abeta(16-22) revealed that the interior of such beta-sheet assemblies has an epsilon value of approximately 5.6. PMID- 24788908 TI - The morphometry of soft tissue insertions on the tibial plateau: data acquisition and statistical shape analysis. AB - This study characterized the soft tissue insertion morphometrics on the tibial plateau and their inter-relationships as well as variabilities. The outlines of the cruciate ligament and meniscal root insertions along with the medial and lateral cartilage on 20 cadaveric tibias (10 left and 10 right knees) were digitized and co-registered with corresponding CT-based 3D bone models. Generalized Procrustes Analysis was employed in conjunction with Principal Components Analysis to first create a geometric consensus based on tibial cartilage and then determine the means and variations of insertion morphometrics including shape, size, location, and inter-relationship measures. Step-wise regression analysis was conducted in search of parsimonious models relating the morphometric measures to the tibial plateau width and depth, and basic anthropometric and gender factors. The analyses resulted in statistical morphometric representations for Procrustes-superimposed cruciate ligament and meniscus insertions, and identified only a few moderate correlations (R2: 0.37 0.49). The study provided evidence challenging the isometric scaling based on a single dimension frequently employed in related morphometric studies, and data for evaluating cruciate ligament reconstruction strategies in terms of re creating the native anatomy and minimizing the risk of iatrogenic injury. It paved the way for future development of computer-aided personalized orthopaedic surgery applications improving the quality of care and patient safety, and biomechanical models with a better population or average representation. PMID- 24788910 TI - Acute kidney injury during concomitant use of valacyclovir and loxoprofen: detecting drug-drug interactions in a spontaneous reporting system. AB - PURPOSE: Little is known about the effects of drug-drug interactions between valacyclovir and non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we analysed the adverse event 'acute kidney injury (AKI)' resulting from a possible interaction between loxoprofen (a non-selective NSAID) and valacyclovir in reports received by FDA Adverse Event Reporting System (AERS) database between January 2004 and June 2012. METHODS: Adverse event reports of elderly patients aged >=65 years old were included in the study. Exposure categories were divided into three index groups (only valacyclovir or loxoprofen was used, and both drugs were concomitantly used) and a reference group (neither valacyclovir nor loxoprofen were used). Case/non-case AKI reports associated with these drugs were recorded and analysed by the reporting odds ratio (ROR). RESULTS: In total, 447 002 reports were included in the study. The ROR, adjusted for year of reporting, age and sex, for an AKI in elderly patients who used only valacyclovir or loxoprofen compared with elderly patients who used neither valacyclovir nor loxoprofen was 4.6 (95%CI: 4.1-5.2) and 1.4 (95%CI: 1.2-1.6), respectively, while the adjusted ROR was 26.0 (95%CI: 19.2-35.3) when both drugs were concomitantly used. CONCLUSIONS: Case reports in AERS are suggestive that interactions between valacyclovir and loxoprofen resulting in AKI may occur, while this association needs to be analysed by other methods in more detail in order to determine the real strength of the relationship. PMID- 24788909 TI - Chaperonin CCT-mediated AIB1 folding promotes the growth of ERalpha-positive breast cancer cells on hard substrates. AB - Clinical observations have revealed a strong association between estrogen receptor alpha (ERalpha)-positive tumors and the development of bone metastases, however, the mechanism underlying this association remains unknown. We cultured MCF-7 (ERalpha-positive) on different rigidity substrates. Compared with cells grown on more rigid substrates (100 kPa), cells grown on soft substrates (10 kPa) exhibited reduced spreading ability, a lower ratio of cells in the S and G2/M cell cycle phases, and a decreased proliferation rate. Using stable isotope labeling by amino acids (SILAC), we further compared the whole proteome of MCF-7 cells grown on substrates of different rigidity (10 and 100 kPa), and found that the expression of eight members of chaperonin CCT increased by at least 2-fold in the harder substrate. CCT folding activity was increased in the hard substrate compared with the soft substrates. Amplified in breast cancer 1 (AIB1), was identified in CCT immunoprecipitates. CCT folding ability of AIB1 increased on 100-kPa substrate compared with 10- and 30-kPa substrates. Moreover, using mammalian two-hybrid protein-protein interaction assays, we found that the polyglutamine repeat sequence of the AIB1 protein was essential for interaction between CCTzeta and AIB1. CCTzeta-mediated AIB1 folding affects the cell area spreading, growth rate, and cell cycle. The expressions of the c-myc, cyclin D1, and PgR genes were higher on hard substrates than on soft substrate in both MCF-7 and T47D cells. ERalpha and AIB1 could up-regulate the mRNA and protein expression levels of the c-myc, cyclin D1, and PgR genes, and that 17 beta estradiol could enhance this effects. Conversely, 4-hydroxytamoxifen, could inhibit these effects. Taken together, our studies demonstrate that some ERalpha positive breast cancer cells preferentially grow on more rigid substrates. CCT mediated AIB1 folding appears to be involved in the rigidity response of breast cancer cells, which provides novel insight into the mechanisms of bone metastasis. PMID- 24788911 TI - Human amniotic fluid stem cells: neural differentiation in vitro and in vivo. AB - The successful integration of stem cells after their implantation into the brain has become a central issue in modern neuroscience. In this study, we test the neural differentiation potential of c-Kit(+)/Oct-4(+) human amniotic fluid stem cells (hAFSCs) in vitro and their survival and integration in vivo. hAFSCs were induced towards neural differentiation and specific markers (GFAP, beta-III tubulin, CNPase, MAP2, NeuN, synapsines, S100, PMP22) were detected by immunofluorescence and Western blot analysis. Glial proteins were expressed as early as 2 weeks after the initial differentiation stimulus, whereas neuronal markers started to appear from the third week of differentiation under culturing conditions of high cell density. This timeline suggested that glial cells possessed a promoting role in the differentiation of hAFSCs towards a neuronal fate. hAFSCs were then implanted into the lateral ventricle of the brain of 1-day old rats, since neuronal development occurs up to 1 month after birth in this animal model. Our data showed that hAFSCs survived for up to 6 weeks post implantation, were integrated into various areas of the central nervous system and migrated away from the graft giving rise to mature neurons and oligodendrocytes. We conclude that hAFSCs are able to differentiate and integrate into nervous tissue during development in vivo. PMID- 24788912 TI - Validity of Maternal-Reported Weight and Height of 2-5 Year Old Children. PMID- 24788913 TI - Adipsic diabetes insipidus in pediatric patients. AB - OBJECTIVE: To present symptoms, complications and proposition of management protocol in children diagnosed with adipsic diabetes insipidus (aDI). METHODS: Clinical and biochemical analysis of six pediatric patients diagnosed with aDI, four boys aged 5, 13, 16, and 17 y and two girls aged 2.5 and 10 y. The etiology of aDI was germinoma (n = 2), extensive surgery due to optic glioma (n = 1) and astrocytoma (n = 1), congenital brain malformations (n = 1) and complications secondary to bacterial meningitis (n = 1). Two patients had severely impaired vision and two had hemiparesis. RESULTS: In all the patients, loss of thirst reflex was observed. The serum electrolytes in all patients showed sodium concentration from 159 to 176.6 mmol/L with plasma osmolality from above 297 mOsmol/kg. Polyuria was absent in three most severely dehydrated patients on admission. In two patients in whom DDAVP (1-desamino-8-D-arginine vasopressin; Desmopressin) therapy was withdrawn based on lack of polyuria deep venous thrombosis developed. CONCLUSIONS: Lack of polydipsia and polyuria, the key symptoms of diabetes insipidus (DI), may delay the diagnosis of aDI and may lead to severe complications of chronic hyperosmolar status. The fluid intake in patients diagnosed with aDI need to be supervised daily based on calculated constant volume of oral fluids, daily measurements of fluid balance, body weight and sodium levels, especially in patients whose vision is compromised or who are physically unable to take care of themselves. PMID- 24788914 TI - Pertussis resurgence in a highly vaccinated population, Mazandaran, North of Iran 2008-2011: an epidemiological analysis. AB - OBJECTIVE: To describe the epidemiological characteristics of pertussis cases reported to Mazandaran Center for Diseases Control and Prevention (P-CDC) during the years 2008-2011 in Mazandaran, North of Iran. METHODS: The patients included were those who fulfilled the WHO definition for pertussis or those clinically diagnosed by physicians. The demographic features of cases, their vaccination status, the incidence rate per 100,000 population, the relative proportion of cases for each age group, and their relation to vaccination status of the patients were all determined. RESULTS: During the study period, a total of 518 cases of pertussis were reported; of which 43 were confirmed. The highest incidence rate and the largest proportion were 135.5 cases/100,000 and 37.7 %, respectively, observed in infants <12 mo of age. Almost 35.7 % of the cases were under vaccinated, however 54.4 % of them were fully vaccinated. CONCLUSIONS: Pertussis infection has re-emerged in Mazandaran. It has caused a significant health problem in the susceptible young infants, and also among completely vaccinated children. Implementing strategies to protect these vulnerable infants and studies to evaluate the immunogenicity and efficacy of pertussis vaccine in Iran is recommended. It was difficult to confirm pertussis in the majority of cases, therefore, providing and improving laboratory diagnostic methods seems to be an urgent requirement. PMID- 24788915 TI - Osteomyelitis in Kawasaki disease. AB - A child who was having all symptoms of Kawasaki disease (KD) was diagnosed with osteomyelitis. Very quick response was appreciated with intravenous immunoglobulin (IVIG) infusion for all the symptoms except osteomyelitis. Long term antibiotics were required to treat it. This kind of overlap between KD and pyogenic osteomyelits due to S. aureus, further supports relationship between these two. PMID- 24788916 TI - Donor site of toe transfer: is combined second and third toe transfer the better choice? A 31 years of long-term follow-up. PMID- 24788918 TI - Perceptions and psychosocial correlates of bullying among Lumbee Indian youth. AB - Although bullying has been linked to suicide among youth, little is known about bullying in American Indians, a population at high risk for suicide. Qualitative data from focus groups with Lumbee Indian youth (N = 31, 16 males, 15 females, 12 17 years of age) and in-depth interviews with gatekeepers in the Lumbee community revealed that bullying is common, and is perceived to contribute to depression and suicide. Youth expressed powerlessness to overcome bullying. Survey data (N = 79, 32 males, 47 females, 11-18 years of age) showed that bullied youth (11.5%) had lower self-esteem and higher levels of depressive symptoms. Interventions are needed to address this behavior that contributes to poor psychosocial health in Lumbee youth. PMID- 24788917 TI - Disrupted bone remodeling leads to cochlear overgrowth and hearing loss in a mouse model of fibrous dysplasia. AB - Normal hearing requires exquisite cooperation between bony and sensorineural structures within the cochlea. For example, the inner ear secretes proteins such as osteoprotegrin (OPG) that can prevent cochlear bone remodeling. Accordingly, diseases that affect bone regulation can also result in hearing loss. Patients with fibrous dysplasia develop trabecular bone overgrowth resulting in hearing loss if the lesions affect the temporal bones. Unfortunately, the mechanisms responsible for this hearing loss, which could be sensorineural and/or conductive, remain unclear. In this study, we used a unique transgenic mouse model of increased Gs G-protein coupled receptor (GPCR) signaling induced by expression of an engineered receptor, Rs1, in osteoblastic cells. These ColI(2.3)+/Rs1+ mice showed dramatic bone lesions that histologically and radiologically resembled fibrous dysplasia. We found that ColI(2.3)+/Rs1+ mice showed progressive and severe conductive hearing loss. Ossicular chain impingement increased with the size and number of dysplastic lesions. While sensorineural structures were unaffected, ColI(2.3)+/Rs1+ cochleae had abnormally high osteoclast activity, together with elevated tartrate resistant acid phosphatase (TRAP) activity and receptor activator of nuclear factor kappa-B ligand (Rankl) mRNA expression. ColI(2.3)+/Rs1+ cochleae also showed decreased expression of Sclerostin (Sost), an antagonist of the Wnt signaling pathway that normally increases bone formation. The osteocyte canalicular networks of ColI(2.3)+/Rs1+ cochleae were disrupted and showed abnormal osteocyte morphology. The osteocytes in the ColI(2.3)+/Rs1+ cochleae showed increased expression of matrix metalloproteinase 13 (MMP-13) and TRAP, both of which can support osteocyte-mediated peri-lacunar remodeling. Thus, while the ossicular chain impingement is sufficient to account for the progressive hearing loss in fibrous dysplasia, the deregulation of bone remodeling extends to the cochlea as well. Our findings suggest that factors regulating bone remodeling, including peri lacunar remodeling by osteocytes, may be useful targets for treating the bony overgrowths and hearing changes of fibrous dysplasia and other bony pathologies. PMID- 24788919 TI - The Wiidookowishin program: results from a qualitative process evaluation of a culturally tailored commercial tobacco cessation program. AB - Commercial tobacco use rates remain disproportionately high among American Indians (AIs). Tailored cessation programs such as the Wiidookowishin (Help Me) program implemented at the Fond du Lac Reservation in Minnesota have demonstrated that such programs can be successful and achieve quit rates similar to mainstream programs. This paper presents findings from a qualitative process evaluation of the Wiidookowishin program and discusses elements that underlie its success at recruiting and enrolling participants, including individualization, flexibility, accessibility, ongoing outreach, and inclusion of traditional tobacco teachings. Lessons learned can be applied to the development of tailored programs to reduce tobacco-related disparities among AIs. PMID- 24788920 TI - Drum-Assisted Recovery Therapy for Native Americans (DARTNA): results from a pretest and focus groups. AB - Drum-Assisted Recovery Therapy for Native Americans (DARTNA) is a substance abuse treatment intervention for American Indians/Alaska Natives (AI/ANs). This article provides results from 1) an initial pretest of DARTNA provided to 10 AI/AN patients with histories of substance use disorders, and 2) three subsequent focus groups conducted among AI/AN DARTNA pretest participants, substance abuse treatment providers, and the DARTNA Community Advisory Board. These research activities were conducted to finalize the DARTNA treatment manual; participants also provided helpful feedback which will assist toward this goal. Results suggest that DARTNA may be beneficial for AI/ANs with substance use problems. PMID- 24788921 TI - The impact of widespread regulatory neofunctionalization on homeolog gene evolution following whole-genome duplication in maize. AB - Whole-genome duplications are a widespread feature of plant genome evolution, having been detected in all flowering plant lineages. Despite the prevalence of these events, the extent to which duplicated genes (homeolog gene pairs) functionally diverge (neofunctionalization) is unclear. We present a genome-wide analysis of molecular evolution and regulatory neofunctionalization in maize (Zea mays L.). We demonstrate that 13% of all homeolog gene pairs in maize are regulatory neofunctionalized in leaves, and that regulatory neofunctionalized genes experience enhanced purifying selection. We show that significantly more genes have been regulatory neofunctionalized in foliar leaves than in husk leaves and that both leaf types have experienced selection for distinct functional roles. Furthermore, we demonstrate that biased subgenome expression dominance occurs only in the presence of regulatory neofunctionalization and that in nonregulatory neofunctionalized genes subgenome dominance is progressively acquired during development. Taken together, our study reveals several novel insights into the evolution of maize, genes, and gene expression, and provides a general model for gene evolution following whole-genome duplication in plants. PMID- 24788922 TI - Electric double-layer capacitors based on highly graphitized nanoporous carbons derived from ZIF-67. AB - Nanoporous carbons (NPCs) have large specific surface areas, good electrical and thermal conductivity, and both chemical and mechanical stability, which facilitate their use in energy storage device applications. In the present study, highly graphitized NPCs are synthesized by one-step direct carbonization of cobalt-containing zeolitic imidazolate framework-67 (ZIF-67). After chemical etching, the deposited Co content can be completely removed to prepare pure NPCs with high specific surface area, large pore volume, and intrinsic electrical conductivity (high content of sp(2) -bonded carbons). A detailed electrochemical study is performed using cyclic voltammetry and galvanostatic charge-discharge measurements. Our NPC is very promising for efficient electrodes for high performance supercapacitor applications. A maximum specific capacitance of 238 F g(-1) is observed at a scan rate of 20 mV s(-1) . This value is very high compared to previous works on carbon-based electric double layer capacitors. PMID- 24788923 TI - Occurrence, sources, and ecological risks of PBDEs, PCBs, OCPs, and PAHs in surface sediments of the Yangtze River Delta city cluster, China. AB - Polybrominated diphenyl ethers (PBDEs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) in 25 surface sediments in three cities (Nantong, Wuxi, and Suzhou) in the Yangtze River Delta, eastern China were measured. The mean concentrations were 378, 45.8, 1.98, 4,002 ng/g for PBDEs, OCPs, PCBs, and PAHs, respectively. Their levels in the sediments in the three cities were generally consistent with the city industrialization. PBDEs and OCPs were markedly dominated by deca-BDE (>90 %) and DDTs (>70 %). A principle component analysis of the analytes identified three major factors suggesting different sources of the contaminants in the sediments. PBDEs and the organic carbon in the sediments have common sources from industrial activities; whereas OCPs and PCBs, correlated with the second factor, were mainly from historical sources. The third factor with loadings of PAHs is indicative of various combustion sources. Ecological risk assessment indicated that the potential highest risk is from DDTs, for which 22 sites exceed the effects range low (ERL) values and three sites exceed the effects range median (ERM) value. PMID- 24788924 TI - Energy-dispersive X-ray fluorescence analysis of moss and soil from abandoned mining of Pb-Zn ores. AB - This research investigates heavy metal pollution around one of the most important mining areas in Turkey, the Sebinkarahisar (Giresun) lead-zinc mining, by means of analyzing moss and soil samples collected in the neighborhood of the copper mining at different distances. Energy dispersive X-ray fluorescence spectrometry (Epsilon 5, PANalytical, Almelo, The Netherlands) is utilized in the experiments. The results have indicated that the both moss and soil samples contain aluminum, vanadium, chromium, manganese, iron, nickel, copper, zinc, arsenic, barium, cerium, tungsten, and lead. The comparison of the heavy metal concentrations with the typical measurements in the world and with the limit values for the human health has revealed the critical heavy metal pollution levels in the region. The possible consequences of these results are briefly discussed from the point of potential hazards to ecology and human health. PMID- 24788926 TI - Carboxymethylcellulose hydrogels support central nervous system-derived tumor cell chemotactic migration: comparison with conventional extracellular matrix macromolecules. AB - The local microenvironment plays an important role in maintaining the dynamics of the extracellular matrix and the cell-extracellular matrix relationship. The extracellular matrix is a complex network of macromolecules with distinct mechanical and biochemical characteristics. Disruptions in extracellular matrix homeostasis are associated with the onset of cancer. The extracellular matrix becomes highly disorganized, and the cell-matrix relationship changes, resulting in altered cell-signaling processes and metastasis. Medulloblastoma is one of the most common malignant pediatric brain tumors in the United States. In order to gain a better understanding of the interplay between cell-extracellular matrix interactions and cell-migratory responses in tumors, eight different matrix macromolecule formulations were investigated using a medulloblastoma-derived cell line: poly-D-lysine, matrigel, laminin, collagen 1, fibronectin, a 10% blend of laminin-collagen 1, a 20% blend of laminin-collagen 1, and a cellulose-derived hydrogel, carboxymethylcellulose. Over time, the average changes in cell morphology were quantified in 2D and 3D, as was migration in the presence and absence of the chemoattractant, epidermal growth factor. Data revealed that carboxymethylcellulose allowed for a cell-extracellular matrix relationship typically believed to be present in tumors, with cells exhibiting a rounded, amoeboid morphology consistent with chemotactic migration, while the other matrices promoted an elongated cell shape as well as both haptotactic and chemotactic motile processes. Therefore, carboxymethylcellulose hydrogels may serve as effective platforms for investigating central nervous system-derived tumor-cell migration in response to soluble factors. PMID- 24788925 TI - Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. AB - Recent studies have shown high usage of the IGHV1-69 germline immunoglobulin gene for influenza hemagglutinin stem-directed broadly-neutralizing antibodies (HV1-69 sBnAbs). Here we show that a major structural solution for these HV1-69-sBnAbs is achieved through a critical triad comprising two CDR-H2 loop anchor residues (a hydrophobic residue at position 53 (Ile or Met) and Phe54), and CDR-H3-Tyr at positions 98+/-1; together with distinctive V-segment CDR amino acid substitutions that occur in positions sparse in AID/polymerase-eta recognition motifs. A semi-synthetic IGHV1-69 phage-display library screen designed to investigate AID/poleta restrictions resulted in the isolation of HV1-69-sBnAbs that featured a distinctive Ile52Ser mutation in the CDR-H2 loop, a universal CDR H3 Tyr at position 98 or 99, and required as little as two additional substitutions for heterosubtypic neutralizing activity. The functional importance of the Ile52Ser mutation was confirmed by mutagenesis and by BCR studies. Structural modeling suggests that substitution of a small amino acid at position 52 (or 52a) facilitates the insertion of CDR-H2 Phe54 and CDR-H3-Tyr into adjacent pockets on the stem. These results support the concept that activation and expansion of a defined subset of IGHV1-69-encoded B cells to produce potent HV1-69-sBnAbs does not necessarily require a heavily diversified V-segment acquired through recycling/reentry into the germinal center; rather, the incorporation of distinctive amino acid substitutions by Phase 2 long-patch error prone repair of AID-induced mutations or by random non-AID SHM events may be sufficient. We propose that these routes of B cell maturation should be further investigated and exploited as a pathway for HV1-69-sBnAb elicitation by vaccination. PMID- 24788927 TI - Reversion of P-glycoprotein-mediated multidrug resistance by diallyl trisulfide in a human osteosarcoma cell line. AB - Diallyl trisulfide (DATS), the main sulfuric compound in garlic, has been shown to have antitumor effects. The present study aimed to ascertain whether DATS reverses the drug resistance of human osteosarcoma cells in vitro and to investigate its potential mechanisms. Human osteosarcoma U2-OS cells were treated with different concentrations of DATS. Cell proliferation was measured by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while P glycoprotein (P-gp) expression and the proportion of apoptotic cells were measured by flow cytometry. Morphological changes were observed under an optical microscope. Nuuclear factor-kappaB (NF-kappaB) and inhibitor of NF-kappaB (IkappaB) activities were measured by PCR and western blot analysis. Results showed that the proliferation of U2-OS cells treated with different concentrations of DATS was significantly decreased in a concentration- and time dependent manner. DATS increased the toxic effect of adriamycin on U2-OS cells. Moreover, P-gp expression was decreased and the apoptosis rate was increased in a concentration-dependent manner following treatment of DATS. Additionally, NF kappaB activity was inhibited by DATS while expression of IkappaB was increased. Our data clearly suggest that DATS has significant anticancer effects on human osteosarcoma cells. The potential mechanisms include reducing the multidrug resistance and inducing apoptosis. NF-kappaB suppression may be involved in DATS induced inhibition of cell proliferation. PMID- 24788928 TI - Proton flows across the plasma membrane in microperforated characean internodes: tonoplast injury and involvement of cytoplasmic streaming. AB - Microperforation of characean cell wall with a glass micropipette in the absence of the tonoplast impalement was found to cause rapid alkalinization of the apoplast by 2-3 pH units, which may rigidify the cell wall structure, thus protecting the cell from further injury. A similar but a deeper insertion of a microneedle, associated with piercing the tonoplast and with an action potential generation, led to a considerable delay in the apoplast alkalinization without affecting the amplitude of the eventual increase in pH. The retardation by the mechanically elicited action potential of the incision-mediated pH transients in the apoplast contrasted sharply to the enhancement of these pH transients by the action potential triggered electrically before the microperforation. Hence, the delay of the apoplast alkalinization was not related to basic ionic mechanisms of plant action potentials. Measurements of the vacuolar pH after mechanical elicitation of an action potential indicate that the tonoplast piercing was accompanied by leakage of protons from the vacuole into the cytoplasm, which may strongly acidify the cytoplasm around the wounded area, thus collapsing the driving force for H(+) influx from the medium into the cytoplasm. The lag period preceding the onset of external alkalinization was found linearly related to the duration of temporal cessation of cytoplasmic streaming. The results suggest that the delayed alkalinization of the apoplast in the region of tonoplast wounding reflects the localized recovery of the proton motive force across the plasmalemma during replacement of the acidic cytoplasm with fresh portions of unimpaired cytoplasm upon restoration of cytoplasmic streaming. PMID- 24788929 TI - Effect of a fibromyalgia rehabilitation programme in warm versus cold climate: a randomized controlled study. AB - OBJECTIVE: To study the long-term effects on symptoms and physical function of a 4-week rehabilitation programme for patients with fibromyalgia, and to determine whether there are any differences if this programme is applied in a warm or cold climate. METHODS: A total of 132 patients with fibromyalgia were randomized to a rehabilitation programme in a warm or cold climate, or to a control group without intervention. Assessments were performed before and after intervention, and after 3 and 12 months. The main outcome measures were pain, measured by tender point count (TPC), and physical function, measured with the 6-min walk test (6MWT). RESULTS: There was no difference in any outcome variables at baseline. Persistent reduction in pain measured by TPC occurred only in the warm climatic setting. Mean difference (95% confidence interval (CI)) in TPC between warm and cold climate groups 1 year after the intervention was -1.7 (-2.9 to -0.5) and between the warm climate and the control group -2.2 (-3.3 to -1.0). Three months after the intervention the mean difference between the warm and cold climate groups in pain distribution (McGill mannequin) was -12 (-20 to -5) and between the warm climate and the control group -11 (-18 to -3). There were comparable improvements in physical function (6MWT) between the 2 intervention groups and the control group. The mean difference (95% CI) in 6MWT 1 year after the intervention between the warm climate and the control group was 33 (7-59) m. The corresponding value between the cold climate and the control group was 29 (3-55) m. Grip Strength (95% CI) was increased by 4.6 kg (2.3-6.4) in the warm climate and by 3.2 kg (0.9 5.5) in the cold climate compared with the control group 1 year after the intervention. CONCLUSION: A rehabilitation programme for fibromyalgia may have a long-term effect on pain, as measured by TPC and pain distribution, when applied in a warm climatic setting, and may improve physical function regardless of the climatic setting. PMID- 24788930 TI - Influence of activated carbon upon the photocatalytic degradation of methylene blue under UV-vis irradiation. AB - Photodegradation of methylene blue (MB) was studied on TiO2 in the presence of activated carbon (AC) prepared from the sawdust of a soft wood by physical activation under CO2 flow, by pyrolysis under N2 flow, and by chemical activation with ZnCl2 and H3PO4 under N2 flow. MB photodegradation was performed under UV and UV-visible irradiation to verify the scaling-up of the present TiO2-AC binary materials. It was verified that oxygenated surface groups on carbon were intrinsically photoactive, and a synergy effect between both solids has been estimated from the first-order apparent rate constants in the photodegradation of MB. This effect enhances the photoactivity of TiO2 up to a factor of about 9 under visible irradiation, and it was associated to the surface properties of AC. PMID- 24788931 TI - Atmospheric reactions of methylcyclohexanes with Cl atoms and OH radicals: determination of rate coefficients and degradation products. AB - As the result of biogenic and anthropogenic activities, large quantities of chemical compounds are emitted into the troposphere. Alkanes, in general, and cycloalkanes are an important chemical class of hydrocarbons found in diesel, jet and gasoline, vehicle exhaust emissions, and ambient air in urban areas. In general, the primary atmospheric fate of organic compounds in the gas phase is the reaction with hydroxyl radicals (OH). The oxidation by Cl atoms has gained importance in the study of atmospheric reactions because they may exert some influence in the boundary layer, particularly in marine and coastal environments, and in the Arctic troposphere. The aim of this paper is to study of the atmospheric reactivity of methylcylohexanes with Cl atoms and OH radicals under atmospheric conditions (in air at room temperature and pressure). Relative kinetic techniques have been used to determine the rate coefficients for the reaction of Cl atoms and OH radicals with methylcyclohexane, cis-1,4 dimethylcyclohexane, trans-1,4-dimethylcyclohexane, and 1,3,5 trimethylcyclohexane at 298 +/- 2 K and 720 +/- 5 Torr of air by Fourier transform infrared) spectroscopy and gas chromatography-mass spectrometry (GC-MS) in two atmospheric simulation chambers. The products formed in the reaction under atmospheric conditions were investigated using a 200-L Teflon bag and employing the technique of solid-phase microextraction coupled to a GC-MS. The rate coefficients obtained for the reaction of Cl atoms with the studied compounds are the following ones (in units of 10(-10) cm(3) molecule(-1) s(-1)): (3.11 +/- 0.16), (2.89 +/- 0.16), (2.89 +/- 0.26), and (2.61 +/- 0.42), respectively. For the reactions with OH radicals the determined rate coefficients are (in units of 10(-11) cm(3) molecule(-1) s(-1)): (1.18 +/- 0.12), (1.49 +/- 0.16), (1.41 +/- 0.15), and (1.77 +/- 0.23), respectively. The reported error is twice the standard deviation. A detailed mechanism for ring-retaining product channels is proposed to justify the observed reaction products. The global tropospheric lifetimes estimated from the reported OH- and Cl-rate coefficients show that the main removal path for the investigated methylcyclohexanes is the reaction with OH radicals. But in marine environments, after sunrise, Cl reactions become more important in the tropospheric degradation. Thus, the estimated lifetimes range from 16 to 24 h for the reactions of the OH radical (calculated with [OH] = 10(6) atoms cm(-3)) and around 7-8 h in the reactions with Cl atoms in marine environments (calculated with [Cl] = 1.3 * 10(5) atoms cm(-3)). The reaction of Cl atoms and OH radicals and methylcylohexanes can proceed by H abstraction from the different positions. PMID- 24788932 TI - Improvement of health risk factors after reduction of VOC concentrations in industrial and urban areas. AB - After reductions of fugitive and diffuse emissions by an industrial complex, a follow-up study was performed to determine the time variability of volatile organic compounds (VOCs) and the lifetime cancer risk (LCR). Passive samplers (3 M monitors) were placed outdoors (n = 179) and indoors (n = 75) in industrial, urban, and control areas for 4 weeks. Twenty-five compounds including n-alkanes, cycloalkanes, aromatics, chlorinated hydrocarbons, and terpenes were determined by GC/MS. The results show a significant decrease of all VOCs, especially in the industrial area and to a lesser extent in the urban area. The median outdoor concentration of benzene in the industrial area declined compared to the former study, around 85% and about 50% in the urban area, which in the past was strongly influenced by industrial emissions. Other carcinogenic compounds like styrene and tetrachloroethylene were reduced to approximately 60%. VOC concentrations in control areas remained nearly unchanged. According to the determined BTEX ratios and interspecies correlations, in contrast to the previous study, traffic was identified as the main emission source in the urban and control areas and showed an increased influence in the industrial area. The LCR, calculated for benzene, styrene, and tetrachloroethylene, shows a decrease of one order of magnitude in accordance to the decreased total VOC concentrations and is now acceptable according to values proposed by the World Health Organization. PMID- 24788933 TI - Abatement of spinosad and indoxacarb residues in pure water by photocatalytic treatment using binary and ternary oxides of Zn and Ti. AB - The photodegradation of indoxacarb, a broad spectrum foliar insecticide and spinosad, a natural insecticide containing two active ingredients, spinosyn A (major component) and spinosyn D (minor component), was studied in aqueous suspensions of binary (ZnO and TiO2) and ternary (Zn2TiO4 and ZnTiO3) oxides under artificial light (300-460 nm) irradiation. As expected, the influence of the semiconductor materials on the degradation of both was very significant in all cases. Photocatalytic experiments showed that the addition of semiconductors in tandem with Na2S2O8 as electron acceptor strongly improved the removal of indoxacarb and spinosad in water compared with the photolytic tests. The reaction rates significantly increased, especially for the ZnO/Na2S2O8 and TiO2/Na2S2O8 systems. The first-order equation (monophasic model) satisfactorily explained the disappearance process, although it offered no explanation for the small concentrations remaining in the process. PMID- 24788934 TI - Denitrification controls in urban riparian soils: implications for reducing urban nonpoint source nitrogen pollution. AB - The purpose of this research was to thoroughly analyze the influences of environmental factors on denitrification processes in urban riparian soils. Besides, the study was also carried out to identify whether the denitrification processes in urban riparian soils could control nonpoint source nitrogen pollution in urban areas. The denitrification rates (DR) over 1 year were measured using an acetylene inhibition technique during the incubation of intact soil cores from six urban riparian sites, which could be divided into three types according to their vegetation. The soil samples were analyzed to determine the soil organic carbon (SOC), soil total nitrogen (STN), C/N ratio, extractable NO3 (-)-N and NH4 (+)-N, pH value, soil water content (SWC), and the soil nitrification potential to evaluate which of these factors determined the final outcome of denitrification. A nitrate amendment experiment further indicated that the riparian DR was responsive to added nitrate. Although the DRs were very low (0.099 ~ 33.23 ng N2O-N g(-1) h(-1)) due to the small amount of nitrogen moving into the urban riparian zone, the spatial and temporal patterns of denitrification differed significantly. The extractable NO3 (-)-N proved to be the dominant factor influencing the spatial distribution of denitrification, whereas the soil temperature was a determinant of the seasonal DR variation. The six riparian sites could also be divided into two types (a nitrate-abundant and a nitrate-stressed riparian system) according to the soil NO3 (-)-N concentration. The DR in nitrate-abundant riparian systems was significantly higher than that in the nitrate-stressed riparian systems. The DR in riparian zones that were covered with bushes and had adjacent cropland was higher than in grass-covered riparian sites. Furthermore, the riparian DR decreased with soil depth, which was mainly attributed to the concentrated nitrate in surface soils. The DR was not associated with the SOC, STN, C/N ratio, and pH. Nitrate supply and temperature finally decided the spatiotemporal distribution patterns of urban riparian denitrification. Considering both the low DR of existing riparian soils and the significance of nonpoint source nitrogen pollution, the substantial denitrification potential of urban riparian soils should be utilized to reduce nitrogen pollution using proper engineering measures that would collect the polluted urban rainfall runoff and make it flow through the riparian zones. PMID- 24788935 TI - A statistical approach for arsenic adsorption onto Turkey clinoptilolite. AB - The present study investigated the optimization of arsenic adsorption onto natural clinoptilolite (NC-Na). Response surface methodology in combination with Box-Behnken design was used to optimize the parameters of the adsorption process. Solution pH, temperature, and initial arsenic concentration were chosen as the main process variables, and the amount of arsenic adsorbed was selected as the investigated response. The analysis of variance results of the response surface model for arsenate (As(V)) adsorption on NC-Na showed that the effects and the interactions of pH and temperature were highly significant according to the p values (p < 0.05). The optimum conditions were found to be the solution pH of 5.0, temperature of 45 degrees C, and initial concentration of 7.8 mg L(-1). The response surfaces derived from the models revealed that solution pH and temperature showed the greatest effect on the As(V) adsorption capacity of natural clinoptilolite. PMID- 24788936 TI - Involvement of proline oxidase (PutA) in programmed cell death of Xanthomonas. AB - Xanthomonas campestris strains have been reported to undergo programmed cell death (PCD) in a protein rich medium. Protein hydrolysates used in media such as nutrient broth comprise of casein digest with abundance of proline and glutamate. In the current study, X. campestris pv. campestris (Xcc) cells displayed PCD when grown in PCD inducing medium (PIM) containing casein tryptic digest. This PCD was also observed in PCD non-inducing carbohydrate rich medium (PNIM) fortified with either proline or proline along with glutamate. Surprisingly, no PCD was noticed in PNIM fortified with glutamate alone. Differential role of proline or glutamate in inducing PCD in Xcc cells growing in PNIM was studied. It was found that an intermediate product of this oxidation was involved in initiation of PCD. Proline oxidase also called as proline utilization A (PutA), catalyzes the two step oxidation of proline to glutamate. Interestingly, higher PutA activity was noticed in cells growing in PIM, and PCD was found to be inhibited by tetrahydro 2-furoic acid, a competitive inhibitor of this enzyme. Further, PCD was abolished in Xcc DeltaputA strain generated using a pKNOCK suicide plasmid, and restored in Xcc DeltaputA strain carrying functional PutA in a plasmid vector. Xanthomonas cells growing in PIM also displayed increased generation of ROS, as well as cell filamentation (a probable indication of SOS response). These filamented cells also displayed enhanced caspase-3-like activity during in situ labeling using a fluorescent tagged caspase-3 inhibitor (FITC-DEVD-FMK). The extent of PCD associated markers such as DNA damage, phosphatidylserine externalization and membrane depolarization were found to be significantly enhanced in wild type cells, but drastically reduced in Xcc DeltaputA cells. These findings thus establish the role of PutA mediated proline oxidation in regulating death in stressed Xanthomonas cells. PMID- 24788937 TI - Electro-driven extraction of inorganic anions from water samples and water miscible organic solvents and analysis by ion chromatography. AB - A simple electromembrane extraction (EME) procedure combined with ion chromatography (IC) was developed to quantify inorganic anions in different pure water samples and water miscible organic solvents. The parameters affecting extraction performance, such as supported liquid membrane (SLM) solvent, extraction time, pH of donor and acceptor solutions, and extraction voltage were optimized. The optimized EME conditions were as follows: 1-heptanol was used as the SLM solvent, the extraction time was 10 min, pHs of the acceptor and donor solutions were 10 and 7, respectively, and the extraction voltage was 15 V. The mobile phase used for IC was a combination of 1.8 mM sodium carbonate and 1.7 mM sodium bicarbonate. Under these optimized conditions, all anions had enrichment factors ranging from 67 to 117 with RSDs between 7.3 and 13.5% (n = 5). Good linearity values ranging from 2 to 1200 ng/mL with coefficients of determination (R(2) ) between 0.987 and 0.999 were obtained. The LODs of the EME-IC method ranged from 0.6 to 7.5 ng/mL. The developed method was applied to different samples to evaluate the feasibility of the method for real applications. PMID- 24788938 TI - Designing non-native iron-binding site on a protein cage for biological synthesis of nanoparticles. AB - In biomineralization processes, a supramolecular organic structure is often used as a template for inorganic nanomaterial synthesis. The E2 protein cage derived from Geobacillus stearothermophilus pyruvate dehydrogenase and formed by the self assembly of 60 subunits, has been functionalized with non-native iron mineralization capability by incorporating two types of iron-binding peptides. The non-native peptides introduced at the interior surface do not affect the self assembly of E2 protein subunits. In contrast to the wild-type, the engineered E2 protein cages can serve as size- and shape-constrained reactors for the synthesis of iron nanoparticles. Electrostatic interactions between anionic amino acids and cationic iron molecules drive the formation of iron oxide nanoparticles within the engineered E2 protein cages. The work expands the investigations on nanomaterial biosynthesis using engineered host-guest encapsulation properties of protein cages. PMID- 24788940 TI - Effects of disturbance associated with seismic exploration for oil and gas reserves in coastal marshes. AB - Anthropogenic disturbances in wetland ecosystems can alter the composition and structure of plant assemblages and affect system functions. Extensive oil and gas extraction has occurred in wetland habitats along the northern Gulf of Mexico coast since the early 1900s. Activities involved with three-dimensional (3D) seismic exploration for these resources cause various disturbances to vegetation and soils. We documented the impact of a 3D seismic survey in coastal marshes in Louisiana, USA, along transects established before exploration began. Two semi impounded marshes dominated by Spartina patens were in the area surveyed. Vegetation, soil, and water physicochemical data were collected before the survey, about 6 weeks following its completion, and every 3 months thereafter for 2 years. Soil cores for seed bank emergence experiments were also collected. Maximum vegetation height at impact sites was reduced in both marshes 6 weeks following the survey. In one marsh, total vegetation cover was also reduced, and dead vegetation cover increased, at impact sites 6 weeks after the survey. These effects, however, did not persist 3 months later. No effects on soil or water properties were identified. The total number of seeds that germinated during greenhouse studies increased at impact sites 5 months following the survey in both marshes. Although some seed bank effects persisted 1 year, these effects were not reflected in standing vegetation. The marshes studied were therefore resilient to the impacts resulting from 3D seismic exploration because vegetation responses were short term in that they could not be identified a few months following survey completion. PMID- 24788939 TI - The complex interplay between ERK1/2, TGFbeta/Smad, and Jagged/Notch signaling pathways in the regulation of epithelial-mesenchymal transition in retinal pigment epithelium cells. AB - Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells is a major pathologic change in the development of proliferative vitreoretinopathy (PVR), which leads to severe visual impairment. ERK1/2 pathway has been reported to play a key role in the carcinogenesis, cancer metastasis, and multiple fibrotic diseases. We hypothesized that ERK1/2 signaling could cross interact with transforming growth factor beta2 (TGFbeta2)/Smad and Notch signaling pathways in the regulation of EMT in RPE cells. Here, we demonstrated that ERK1/2 signaling was activated in TGFbeta2-induced EMT in human RPE cells, while blockade of the canonical TGFbeta2/Smad2/3 signaling with SB431542 could not inhibit TGFbeta2-induced the activation of ERK1/2. Meanwhile, blockade of ERK1/2 signaling with a specific MEK/ERK1/2 inhibitor U0126 strongly prevented TGFbeta2-induced the downregulation of P-cadherin, and the upregulation of alpha SMA, collagen type IV, N-cadherin and fibronectin in RPE cells. In addition, we also identified that blockade of ERK1/2 signaling could inhibit not only the canonical TGFbeta/Smad signaling, but also the Jagged/Notch pathway. Finally, we found that blockade of Notch pathway with a specific inhibitor DAPT could inhibit TGFbeta2-induced the activation of ERK1/2 pathway conversely. Therefore, our study provides evidence that ERK1/2 signaling can cross-interact with the canonical TGFbeta/Smad and the Jagged/Notch signaling pathways in RPE cells EMT. ERK1/2 inhibitor may have therapeutic value in the prevention and treatment of PVR and other fibrotic diseases. PMID- 24788941 TI - A common representation of spatial features drives action and perception: grasping and judging object features within trials. AB - Spatial features of an object can be specified using two different response types: either by use of symbols or motorically by directly acting upon the object. Is this response dichotomy reflected in a dual representation of the visual world: one for perception and one for action? Previously, symbolic and motoric responses, specifying location, has been shown to rely on a common representation. What about more elaborate features such as length and orientation? Here we show that when motoric and symbolic responses are made within the same trial, the probability of making the same symbolic and motoric response is well above chance for both length and orientation. This suggests that motoric and symbolic responses to length and orientation are driven by a common representation. We also show that, for both response types, the spatial features of an object are processed independently. This finding of matching object processing characteristics is also in agreement with the idea of a common representation driving both response types. PMID- 24788942 TI - Translational and rotational near-wall diffusion of spherical colloids studied by evanescent wave scattering. AB - In this article we extend recent experimental developments [Rogers et al., Phys. Rev. Lett., 2012, 109, 098305] by providing a suitable theoretical framework for the derivation of exact expressions for the first cumulant (initial decay rate) of the correlation function measured in Evanescent Wave Dynamic Light Scattering (EWDLS) experiments. We focus on a dilute suspension of optically anisotropic spherical Brownian particles diffusing near a planar hard wall. In such a system, translational and rotational diffusion are hindered by hydrodynamic interactions with the boundary which reflects the flow incident upon it, affecting the motion of colloids. The validity of the approximation by the first cumulant for moderate times is assessed by juxtaposition to Brownian dynamics simulations, and compared with experimental results. The presented method for the analysis of experimental data allows the determination of penetration-depth-averaged rotational diffusion coefficients of spherical colloids at low density. PMID- 24788943 TI - Surgical Evaluation in Obstructive Sleep Apnea: Climbing the Steep Part of the Learning Curve. PMID- 24788944 TI - Impact of chest radiography for children with lower respiratory tract infection: a propensity score approach. AB - BACKGROUND: Management of acute respiratory tract infection varies substantially despite this being a condition frequently encountered in pediatric emergency departments. Previous studies have suggested that the use of antibiotics was higher when chest radiography was performed. However none of these analyses had considered the inherent indication bias of observational studies. OBJECTIVE: The aim of this work was to assess the relationship between performing chest radiography and prescribing antibiotics using a propensity score analysis to address the indication bias due to non-random radiography assignment. METHODS: We conducted a prospective study of 697 children younger than 2 years of age who presented during the winter months of 2006-2007 for suspicion of respiratory tract infection at the Pediatric Emergency Department of an urban general hospital in France (Paris suburb). We first determined the individual propensity score (probability of having a chest radiography according to baseline characteristics). Then we assessed the relation between radiography and antibiotic prescription using two methods: adjustment and matching on the propensity score. RESULTS: We found that performing a chest radiography lead to more frequent antibiotic prescription that may be expressed as OR = 2.3, CI [1.3 4.1], or as an increased use of antibiotics of 18.6% [0.08-0.29] in the group undergoing chest radiography. CONCLUSION: Chest radiography has a significant impact on the management of infants admitted for suspicion of respiratory tract infection in a pediatric emergency department and may lead to unnecessary administration of antibiotics. PMID- 24788945 TI - Quantifying extinction probabilities from sighting records: inference and uncertainties. AB - Methods are needed to estimate the probability that a population is extinct, whether to underpin decisions regarding the continuation of a invasive species eradication program, or to decide whether further searches for a rare and endangered species could be warranted. Current models for inferring extinction probability based on sighting data typically assume a constant or declining sighting rate. We develop methods to analyse these models in a Bayesian framework to estimate detection and survival probabilities of a population conditional on sighting data. We note, however, that the assumption of a constant or declining sighting rate may be hard to justify, especially for incursions of invasive species with potentially positive population growth rates. We therefore explored introducing additional process complexity via density-dependent survival and detection probabilities, with population density no longer constrained to be constant or decreasing. These models were applied to sparse carcass discoveries associated with the recent incursion of the European red fox (Vulpes vulpes) into Tasmania, Australia. While a simple model provided apparently precise estimates of parameters and extinction probability, estimates arising from the more complex model were much more uncertain, with the sparse data unable to clearly resolve the underlying population processes. The outcome of this analysis was a much higher possibility of population persistence. We conclude that if it is safe to assume detection and survival parameters are constant, then existing models can be readily applied to sighting data to estimate extinction probability. If not, methods reliant on these simple assumptions are likely overstating their accuracy, and their use to underpin decision-making potentially fraught. Instead, researchers will need to more carefully specify priors about possible population processes. PMID- 24788946 TI - 3-D TiO2 nanoparticle/ITO nanowire nanocomposite antenna for efficient charge collection in solid state dye-sensitized solar cells. AB - TiO2 nanoparticle (NP)/ITO nanowire (NW) nanocomposites for use as photoelectrode materials were fabricated to improve the charge collection efficiency in solid state dye sensitized solar cells (ss-DSSCs). The average current density for ss DSSCs containing TiO2 NP/ITO NW arrays was 7.2 mA cm(-2) that was 98% higher than that for the conventional TiO2 NP ss-DSSCs. The intensity modulated photocurrent spectroscopy (IMPS) and intensity modulated photovoltage spectroscopy (IMVS) studies exhibited that the electron diffusion length of TiO2 NP/ITO-NW nanocomposite ss-DSSCs was in the range of 4.3-5.6 MUm, longer than that of TiO2 NP solar cells (2.6-4.1 MUm). The longer diffusion length was responsible for the boosted current densities of TiO2 NP/ITO NW nanocomposite ss-DSSCs. We also employed the TiO2 NP/ITO NW nanocomposite photoelectrode to inorganic-organic perovskite solar cells whose energy conversion efficiency was 7.5%. PMID- 24788947 TI - Effect of Gua Lou Gui Zhi decoction on focal cerebral ischemia-reperfusion injury through regulating the expression of excitatory amino acids and their receptors. AB - Gua Lou Gui Zhi decotion (GLGZD) has been reported to be an effective treatment for post-apoplectic limb spasm in the clinic. The present study aimed to investigate whether GLGZD had an affect on cerebral injuries induced by middle cerebral artery occlusion (MCAO) in rats and its possible mechanism. High performance liquid chromatography was performed to analyze GLGZD. Furthermore, a model was established to assess the efficacy of GLGZD. Neurological defect scores and screen tests were analyzed. Brain ischemic infarct volume was measured using 2,3,5-triphenyl tetrazolium chloride staining and glutamic acid (Glu), aspartic acid (Asp) and glycine (Gly) levels in the cerebrospinal fluid were measured using the Hitachi automatic amino acid analyzer. Immunohistochemistry was performed to determine the expression of the alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, and to analyze histopathological change. GLGZD was found to improve neurological performance and reduce infarct volumes in MCAO rats. In addition, GLGZD was observed to enhance motor performance, which was assessed using the screen test. Furthermore, GLGZD was found to reduce Glu, Asp and Gly levels in the cerebrospinal fluid and downregulate the protein expression of the AMPA and NMDA glutamate receptors. Thus, it was demonstrated that GLGZD may exert neuroprotective effects through the modulation of excitatory amino acids, and AMPA and NMDA receptor expression. PMID- 24788948 TI - Non-compressive disorders of the chiasm. AB - Chiasmal dysfunction produces a characteristic clinical picture, regardless of the mechanism. In most cases a compressive lesion is the cause. In occasional cases, however, no such extrinsic mass is found and other possible etiologies must be explored. In some of these cases, the pathologic process is identifiable with appropriate neuroimaging. For example, inflammation, infiltrative tumors, and radiation necrosis produce intrinsic chiasmal enhancement. Chiasmal ischemia may require specialized magnetic resonance (MR) sequences for diagnosis. Chiasmal hemorrhage, trauma and chiasmal herniation typically produce distinctive changes on noncontrasted imaging. In cases of metabolic insult, either toxic or hereditary, radiographic changes are typically absent. In each of these, the correct diagnosis can usually be made with a combination of clinical and radiographic features. PMID- 24788949 TI - Directions of chemical change: experimental characterization of the stereodynamics of photodissociation and reactive processes. AB - This perspective article aims at accounting for the versatility of some current experimental investigations for exploring novel paths in chemical reactions. It updates a previous one [Phys. Chem. Chem. Phys., 2005, 5, 291] and is limited to work by the authors. The use of advanced molecular beam techniques together with a combination of modern tools for specific preparation, selection and detection permits us to discover new trends in reactivity in the gas phase as well as at interfaces. We specifically discuss new facets of stereodynamics, namely the effects of molecular orientation and alignment on reactive and photodissociation processes. Further topics involve roaming paths and triple fragmentation in photodissociation probed by imaging techniques, chirality effects in collisions and deviations from Arrhenius behavior in the temperature dependence of chemical reactions. PMID- 24788951 TI - Negative cross resistance mediated by co-treated bed nets: a potential means of restoring pyrethroid-susceptibility to malaria vectors. AB - Insecticide-treated nets and indoor residual spray programs for malaria control are entirely dependent on pyrethroid insecticides. The ubiquitous exposure of Anopheles mosquitoes to this chemistry has selected for resistance in a number of populations. This threatens the sustainability of our most effective interventions but no operationally practicable way of resolving the problem currently exists. One innovative solution involves the co-application of a powerful chemosterilant (pyriproxyfen or PPF) to bed nets that are usually treated only with pyrethroids. Resistant mosquitoes that are unaffected by the pyrethroid component of a PPF/pyrethroid co-treatment remain vulnerable to PPF. There is a differential impact of PPF on pyrethroid-resistant and susceptible mosquitoes that is modulated by the mosquito's behavioural response at co-treated surfaces. This imposes a specific fitness cost on pyrethroid-resistant phenotypes and can reverse selection. The concept is demonstrated using a mathematical model. PMID- 24788950 TI - The health benefits of muscular fitness for children and adolescents: a systematic review and meta-analysis. AB - BACKGROUND: Physical fitness during childhood and adolescence has been identified as an important determinant of current and future health status. While research has traditionally focused on the association between cardio-respiratory fitness and health outcomes, the association between muscular fitness (MF) and health status has recently received increased attention. OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the potential physiological and psychological benefits associated with MF among children and adolescents. METHODS: A systematic search of six electronic databases (PubMed, SPORTDiscus, Scopus, EMBASE, PsycINFO and OVID MEDLINE) was performed on the 20th May, 2013. Cross-sectional, longitudinal and experimental studies that quantitatively examined the association between MF and potential health benefits among children and adolescents were included. The search yielded 110 eligible studies, encompassing six health outcomes (i.e., adiposity, bone health, cardiovascular disease [CVD] and metabolic risk factors, musculoskeletal pain, psychological health and cognitive ability). The percentage of studies reporting statistically significant associations between MF and the outcome of interest was used to determine the strength of the evidence for an association and additional coding was conducted to account for risk of bias. Meta-analyses were also performed to determine the pooled effect size if there were at least three studies providing standardised coefficients. RESULTS: Strong evidence was found for an inverse association between MF and total and central adiposity, and CVD and metabolic risk factors. The pooled effect size for the relationship between MF and adiposity was r = -0.25 (95% CI -0.41 to -0.08). Strong evidence was also found for a positive association between MF and bone health and self-esteem. The pooled effect size for the relationship between MF and perceived sports competence was r = 0.39 (95% CI 0.34-0.45). The evidence for an association between MF and musculoskeletal pain and cognitive ability was inconsistent/uncertain. Where evidence of an association was found, the associations were generally low to moderate. CONCLUSION: The findings of this review highlight the importance of developing MF in youth for a number of health-related benefits. PMID- 24788953 TI - A portable optic fiber aptasensor for sensitive, specific and rapid detection of bisphenol-A in water samples. AB - Bisphenol A (BPA) is a known endocrine disruptor and one of the most serious environmental contaminants, often present at low levels in various water sources. Therefore, it is very important and necessary to develop a fast, cost-effective, sensitive, and selective method for on-site detection of BPA. Herein, we developed a portable, evanescent, wave fiber-optic aptasensor for rapid, on-site detection of BPA with high sensitivity and selectivity. In this system, the probe DNA molecule, which is the complementary sequence of a small part of the BPA aptamer, was covalently immobilized onto the optical fiber sensor surface. Using an indirect competitive detection mode, samples containing different concentrations of bisphenol A were premixed with a given concentration of fluorescence-labeled BPA aptamer, which binds to bisphenol A with high specificity. Then, the sample mixture was pumped to the sensor surface, and a higher concentration of BPA led to less fluorescence-labeled BPA aptamer hybridized with surface immobilized probe DNA and thus to a lower fluorescence signal. The developed sensing system exhibits a sensitive response to BPA in the range of 2 nM to 100 nM with a low detection limit of 1.86 nM (0.45 ng ml(-1)) under the optimal conditions. The biosensors showed good reproducibility, stability, and selectivity for BPA detection. Finally, this proposed sensor was successfully employed to determine the presence of BPA in wastewater samples. PMID- 24788952 TI - The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma. AB - Bcl-2 and other anti-apoptotic proteins are associated with defective caspase dependent apoptotic pathways, resulting in chemoresistance. We have previously shown that ATN-224, a copper chelator drug, induces cell death in murine thymic lymphoma cells transfected with Bcl-2. In the current study, we tested whether ATN-224 was effective in diffuse large B cell lymphoma (DLBCL) cells, which have increased anti-apoptotic proteins through translocation or amplification. We found that nanomolar concentrations of ATN-224 induced cell death in DLBCL cells independent of Bcl-2, Bcl-xL or Mcl-1 status. ATN-224 treatment resulted in mitochondrial dysfunction, release of apoptosis-inducing factor (AIF) and induction of caspase-independent cell death. In addition, ATN-224 degraded Mcl-1 and enhanced the effect of the BH3 mimetic ABT-263. These findings indicate that ATN-224 has potential as a therapeutic for the treatment of DLBCL. Induction of caspase-independent cell death in apoptosis-resistant DLBCL would provide a therapeutic alternative for the treatment of refractory disease. PMID- 24788957 TI - Iodine mediated deprotection of N-tert-butanesulfinyl amines: a functional group compatible method. AB - In the presence of iodine, a functional group compatible method for the deprotection of tert-butanesulfinyl and p-toluenesulfinyl units was developed. PMID- 24788958 TI - Separation of phenylsuccinic acid enantiomers using biphasic chiral recognition high-speed countercurrent chromatography. AB - High-speed countercurrent chromatography (HSCCC) combined with biphasic chiral recognition was successfully applied to the resolution of phenylsuccinic acid enantiomers. D-Isobutyl tartrate and hydroxypropyl-beta-cyclodextrin were employed as lipophilic and hydrophilic selectors dissolved in the organic stationary phase and aqueous mobile phase, respectively. The two-phase solvent system was made up of n-hexane/methyl tert-butyl ether/water (0.5:1.5:2, v/v/v). Impacts of the type and concentration of chiral selectors, the pH value of the aqueous phase solution as well as the temperature on the separation efficiency were investigated. By means of preparative HSCCC, pure enantiomer was obtained by separating 810 mg of racemate with a purity >99.5% and a recovery rate between 82 and 85%. The experimental results indicate that biphasic recognition HSCCC provide a promising means for efficient separation of racemates. PMID- 24788959 TI - Promise and deceit: pharmakos, drug replacement therapy, and the perils of experience. AB - The problem of lying as a feature of medication compliance has been well documented in anthropological and clinical literatures. Yet the role of the lie its destabilizing effects on the continuity of drug treatment and therapy, as a technology of drug misuse, or as a way to understand the neuro-chemical processes of treatment (pharmacotherapy "tricking" or lying to the brain)-has been less considered, particularly in the context of opioid replacement therapy. The following paper is set against the backdrop of a three-year study of adolescents receiving a relatively new drug (buprenorphine) for the treatment of opiate dependency inside and outside of highly monitored treatment environments in the United States. Lies give order not only to the experience of addiction but also to the experience of therapy as well. In order to better understand this ordering of experience, the paper puts the widely discussed conceptual duality of the pharmakon (healing and poison) in conversation with a perilously overlooked subject in the critical study of pharmacotherapy, namely the pharmakos or the personification of sacrifice. The paper demonstrates how the patient-subject comes to represent therapeutic promise by allowing for the possibility of (and often performing) deceit. PMID- 24788960 TI - Oxidative DNA damage causes premature senescence in mouse embryonic fibroblasts deficient for Kruppel-like factor 4. AB - Kruppel-like factor 4 (KLF4) is a zinc-finger-containing transcription factor with tumor suppressor activity in various cancer types. Cells that sustain double strand breaks (DSBs) in their DNA due to high levels of reactive oxygen species (ROS) can develop genomic instability, which can result in cancer formation. One protective response to increased levels of ROS is the induction of cellular senescence. Recently, we found that mouse embryonic fibroblasts (MEFs) null for Klf4 are genetically unstable, as evidenced by the presence of DNA DSBs. However, it is yet unknown whether KLF4 is involved in regulating oxidative stress-induced DNA damage. Therefore, we sought to determine the mechanisms by which ROS induce genomic instability in Klf4-deficient MEFs. With SA-beta-Gal staining, we show that Klf4(-/-) MEFs enter senescence earlier than Klf4(+/+) MEFs, and western blot shows accumulation of p21 and p53 with increasing passages. In addition, immunostaining against gamma-H2AX indicates that the increased level of DNA damage in Klf4(-/-) MEFs positively correlates with ROS accumulation. Consistent with ROS as a source of DSB in Klf4(-/-) MEFs, treatment with NAC, reduces the accumulation of DNA damage. Our RT-PCR result demonstrates that Klf4(-/-) MEFs have decreased expression of the antioxidant gene, Gsta4. The downregulation of the Gsta4 correlates with significant levels of ROS accumulation, as shown by DCFDA and FACS analysis, and thus the oxidative stress-induced premature senescence. Together these findings suggest a mechanism by which KLF4 protects against DNA damage and oxidative stress at least in part through the regulation of Gsta4 and likely related genes. PMID- 24788961 TI - Electrodermal and behavioral responses of children with autism spectrum disorders to sensory and repetitive stimuli. AB - Parents frequently report that their children with autism spectrum disorders (ASD) respond atypically to sensory stimuli. Repetitive behaviors are also part of the ASD behavioral profile. Abnormal physiological arousal may underlie both of these symptoms. Electrodermal activity (EDA) is an index of sympathetic nervous system arousal. The goals of this study were twofold: (1) to pilot methods for collecting EDA data in young children and (2) to examine hypothesized relationships among EDA, and sensory symptoms and repetitive behaviors in children with ASD as compared with children with typical development. EDA was recorded on 54 young children with ASD and on 33 children with typical development (TD) during a protocol that included baseline, exposure to sensory and repetitive stimuli, and play. Parents completed standardized questionnaires regarding their child's sensory symptoms and repetitive behaviors. Frequency and type of repetitive behavior during play was coded offline. Comparisons between EDA data for ASD and TD groups indicated no significant between-group differences in any measures. Parents of children with ASD reported more abnormal responses to sensory stimuli and more repetitive behaviors, but scores on these measures were not significantly correlated with EDA or with frequency of observed repetitive behaviors. Parent report of frequency and severity of sensory symptoms was significantly correlated with reports of repetitive behaviors in both groups. Although parents of children with ASD report high levels of sensory symptoms and repetitive behaviors, these differences are not related to measured EDA arousal or reactivity. PMID- 24788963 TI - Sperm-associated antigen 9 promotes astrocytoma cell invasion through the upregulation of podocalyxin. AB - Podocalyxin (PODXL) has been found to increase the aggressive phenotype of a number of cancers, including astrocytoma. In addition, the progression of astrocytoma has been associated with sperm-associated antigen 9 (SPAG9), a recently characterized oncoprotein. In the present study, the association between SPAG9 and PODXL in human astrocytoma invasion and the underlying mechanisms were investigated for the first time, to the best of our knowledge. Overexpression and knockdown of SPAG9 were performed in SW1783 (grade III astrocytoma) and U87 (grade IV astrocytoma; glioblastoma) cells, respectively. PODXL expression at both the mRNA and the protein level, as well as the PODXL gene promoter activity, were significantly increased and decreased in parallel with the overexpression and knockdown of SPAG9 in astrocytoma cells; these effects were blocked by the selective c-Jun N-terminal kinase (JNK) inhibitor SP600125 (5 uM) and restored by the JNK agonist anisomycin (25 ng/ml), respectively. SPAG9 overexpression significantly increased cell invasion and matrix metalloproteinase-9 (MMP-9) expression in SW1783 cells, and this effect was reversed by knockdown of PODXL. In U87 cells, knockdown of SPAG9 markedly decreased cell invasion and MMP-9 expression, which was completely restored by overexpression of PODXL. In conclusion, it was demonstrated in the present study that SPAG9 upregulates PODXL expression in human astrocytoma cells at the PODXL gene promoter/transcriptional level through a JNK-dependent mechanism and that PODXL is a critical mediator of the promoting effect of SPAG9 on astrocytoma cell invasion, possibly through upregulation of MMP-9 expression. This study provides novel insights into the molecular mechanisms involved in astrocytoma invasion. PMID- 24788964 TI - Impact of transobturator tape procedure on female and their partner sexual function: it improves sexual function of couples. AB - AIM: To assess the impact of transobturator tape (TOT) procedure on female sexual function as well as their male partners. MATERIALS AND METHODS: Sexually active 28 women and their partners included for the study. Before TOT operation, the patients completed incontinence impact questionnaire (IIQ-7) and urogenital distress inventory (UDI-6) to assess the effect of surgery on incontinence. Also the women and their partners completed a self-administered questionnaire evaluating the female sexual function index (FSFI) and international index of erectile function (IIEF-5), respectively. Three months after TOT surgery, the women were asked to complete IIQ-7 and UDI-6 questionnaires to measure the success of TOT procedure. Also, FSFI and IIEF forms were completed by the women and their partners to assess TOT-related sexual life change. RESULTS: After TOT procedure, the mean value of IIQ-7 and UDI-6 questionnaires was lower than the mean scores that measured before treatment (p < 0.001). The mean values of FSFI scores before and 3 months after the operation were 23.15 +/- 8.21 vs. 30.01 +/- 9.13, respectively (p < 0.001). The mean values of IIEF before and 3 months after the operation were 50.14 +/- 5.21 vs. 60.96 +/- 10.03, respectively (p < 0.001). CONCLUSION: According to our results, both women and their partners' sexual life improved after TOT surgery for incontinence. PMID- 24788965 TI - Glatiramer acetate (copaxone) modulates platelet activation and inhibits thrombin induced calcium influx: possible role of copaxone in targeting platelets during autoimmune neuroinflammation. AB - BACKGROUND: Glatiramer acetate (GA, Copaxone, Copolymer-1) is an FDA approved drug for the treatment of MS and it is very effective in suppressing neuroinflammation in experimental autoimmune encephalitis (EAE), an animal model of MS. Although this drug was designed to inhibit pathogenic T cells, the exact mechanism of EAE/MS suppression by GA is still not well understood. Previously we presented evidence that platelets become activated and promote neuroinflammation in EAE, suggesting a possible pathogenic role of platelets in MS and EAE. We hypothesized that GA could inhibit neuroinflammation by affecting not only immune cells but also platelets. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of GA on the activation of human platelets in vitro: calcium influx, platelet aggregation and expression of activation markers. Our results in human platelets were confirmed by in-vitro and in-vivo studies of modulation of functions of platelets in mouse model. We found that GA inhibited thrombin induced calcium influx in human and mouse platelets. GA also decreased thrombin induced CD31, CD62P, CD63, and active form of alphaIIbbeta3 integrin surface expression and formation of platelet aggregates for both mouse and human platelets, and prolonged the bleeding time in mice by 2.7-fold. In addition, we found that GA decreased the extent of macrophage activation induced by co-culture of macrophages with platelets. CONCLUSIONS: GA inhibited the activation of platelets, which suggests a new mechanism of GA action in suppression of EAE/MS by targeting platelets and possibly preventing their interaction with immune cells such as macrophages. Furthermore, the reduction in platelet activation by GA may have additional cardiovascular benefits to prevent thrombosis. PMID- 24788967 TI - Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. AB - The aim of this updated guideline is to provide comprehensive and timely evidence based recommendations on the prevention of future stroke among survivors of ischemic stroke or transient ischemic attack. The guideline is addressed to all clinicians who manage secondary prevention for these patients. Evidence-based recommendations are provided for control of risk factors, intervention for vascular obstruction, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke. Recommendations are also provided for the prevention of recurrent stroke in a variety of specific circumstances, including aortic arch atherosclerosis, arterial dissection, patent foramen ovale, hyperhomocysteinemia, hypercoagulable states, antiphospholipid antibody syndrome, sickle cell disease, cerebral venous sinus thrombosis, and pregnancy. Special sections address use of antithrombotic and anticoagulation therapy after an intracranial hemorrhage and implementation of guidelines. PMID- 24788966 TI - Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN. AB - Virus-derived double-stranded RNAs (dsRNAs) are sensed in the cytosol by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs). These induce the expression of type I IFN and proinflammatory cytokines through signaling pathways mediated by the mitochondrial antiviral signaling (MAVS) protein. TNF receptor-associated factor (TRAF) family proteins are reported to facilitate the RLR-dependent expression of type I IFN by interacting with MAVS. However, the precise regulatory mechanisms remain unclear. Here, we show the role of FK506-binding protein 51 (FKBP51) in regulating the dsRNA-dependent expression of type I IFN. The binding of FKBP51 to TRAF6 was first identified by "in vitro virus" selection and was subsequently confirmed with a coimmunoprecipitation assay in HEK293T cells. The TRAF-C domain of TRAF6 is required for its interaction, although FKBP51 does not contain the consensus motif for interaction with the TRAF-C domain. Besides TRAF6, we found that FKBP51 also interacts with TRAF3. The depletion of FKBP51 reduced the expression of type I IFN induced by dsRNA transfection or Newcastle disease virus infection in murine fibroblasts. Consistent with this, the FKBP51 depletion attenuated dsRNA-mediated phosphorylations of IRF3 and JNK and nuclear translocation of RelA. Interestingly, dsRNA stimulation promoted the accumulation of FKBP51 in the mitochondria. Moreover, the overexpression of FKBP51 inhibited RLR-dependent transcriptional activation, suggesting a scaffolding function for FKBP51 in the MAVS-mediated signaling pathway. Overall, we have demonstrated that FKBP51 interacts with TRAF proteins and facilitates the expression of type I IFN induced by cytosolic dsRNA. These findings suggest a novel role for FKBP51 in the innate immune response to viral infection. PMID- 24788968 TI - Sickle cell disease and stroke. PMID- 24788969 TI - Complex atheromatous plaques in the descending aorta and the risk of stroke: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Proximal aortic plaques, especially in the aortic arch, have already been established as an important cause of stroke and peripheral embolism. However, aortic plaques situated in the descending thoracic aorta have recently been postulated as a potential embolic source in patients with cryptogenic cerebral infarction through retrograde aortic flow. The aim of the present study was to evaluate the potential association of descending aorta atheromatosis with cerebral ischemia. METHODS: We conducted a systematic review and meta-analysis of all available prospective observational studies reporting the prevalence of complex atheromatous plaques in the descending aorta in patients with stroke and in unselected populations undergoing examination with transesophageal echocardiography. RESULTS: We identified 11 eligible studies including a total of 4000 patients (667 patients with stroke and 3333 unselected individuals; mean age, 65 years; 55% men). On baseline transesophageal echocardiograpic examination, the prevalence of complex atheromatous plaques in the descending aorta was higher (P=0.001) in patients with stroke (25.4%; 95% confidence interval, 14.6-40.4%) compared with unselected individuals (6.1%; 95% confidence interval, 3.4-10%). However, no significant difference (P=0.059) in the prevalence of complex atheromatous plaques in the descending aorta was found between patients with cryptogenic (21.8%; 95% confidence interval, 17.5-26.9%) and unclassified (28.3%; 95% confidence interval, 23.9-33.1%) cerebral infarction. CONCLUSIONS: Our findings indicate that the presence of complex plaques in the descending aorta is presumably a marker of generalized atherosclerosis and high vascular risk. The present analyses do not provide any further evidence for a direct causal relationship between descending aorta atherosclerosis and cerebral embolism. PMID- 24788970 TI - Safety of thrombolysis in patients with acute ischemic stroke and cerebral cavernous malformations. AB - BACKGROUND AND PURPOSE: Data on safety of intravenous thrombolysis with recombinant tissue-type plasminogen activator for acute ischemic stroke in patients with coexisting cerebral cavernous malformations (CCMs) are scarce. We assessed the risk of thrombolysis-associated hemorrhage in these patients. METHODS: We searched our tertiary care hospital thrombolysis register for patients with CCM confirmed by MRI (3 T, Siemens, TimTrio) before thrombolysis for acute ischemic stroke. CCMs were graded into subtypes according to the Zabramski classification on the basis of their MRI appearance. The primary end point was symptomatic intracerebral hemorrhage according to European Cooperative Acute Stroke Study III (ECASS III) criteria. The secondary end point was any parenchymal hemorrhage. RESULTS: In a total of 350 patients (median age, 76 years; interquartile range, 68-84; median National Institutes of Health Stroke Scale score, 8; interquartile range, 5-14; 51.4% women), CCMs were found in 9 patients (2.6%). Seven patients had a single CCM, and 2 patients had multiple CCMs with a total number of 12 CCMs in all patients. The subtype of CCMs was type III in 9 cases and type I in 3 cases. Symptomatic intracerebral hemorrhage occurred in 1 of 9 patients with CCM versus 11 of 341 patients without CCM (P=0.27). Parenchymal hemorrhage occurred in 2 of 9 patients with CCM versus 27 of 341 patients (P=0.17) without CCM. CONCLUSIONS: Given the limitations of our study (mainly low number of patients with CCM), the risk of thrombolysis associated hemorrhage in patients with CCM remains uncertain. Although our data do not suggest an increased hazard from thrombolysis in patients with CCM, larger studies are necessary to determine definitively the influence of CCMs on parenchymal hemorrhage and symptomatic intracerebral hemorrhage. PMID- 24788972 TI - Long-term risk and predictors of recurrent stroke beyond the acute phase. AB - BACKGROUND AND PURPOSE: Previous studies have shown heterogeneous results on predictors and rates of stroke recurrence. This study set out to investigate the long-term risk and predictors of recurrent stroke in Northern Sweden 1995 to 2008. METHODS: In the population-based Monitoring Trends and Determinants of Cardiovascular Disease (MONICA) stroke incidence registry, stroke survivors of either ischemic stroke or intracerebral hemorrhage were followed for recurrent stroke or death. Cox regression was used to identify predictors of stroke recurrence. RESULTS: The study comprised 6700 patients and 26 597 person-years. During follow-up, 928 (13.9%) patients had a recurrent stroke. Comparison between the first time period (1995-1998) and the last (2004-2008) showed declined risk of stroke recurrence (hazard ratio, 0.64 [95% confidence interval, 0.52-0.78]). Previous myocardial infarction was less prevalent in the most recent cohort (P<0.001). Predictors of stroke recurrence were age (hazard ratio, 1.03 [95% confidence interval, 1.02-1.04]) and diabetes mellitus (hazard ratio, 1.34 [95% confidence interval, 1.15-1.57]). After an index intracerebral hemorrhage (n=815), a major part of recurrent events were ischemic (63%), and compared with the ischemic stroke group (n=5885), a tendency toward lower risk of recurrence was observed. CONCLUSIONS: Despite declining recurrence rates in this relatively young stroke population, almost one third are either dead or have experienced a second stroke in 5 years. PMID- 24788971 TI - Remote or extraischemic intracerebral hemorrhage--an uncommon complication of stroke thrombolysis: results from the safe implementation of treatments in stroke international stroke thrombolysis register. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage after treatment with intravenous recombinant tissue-type plasminogen activator for ischemic stroke can occur in local relation to the infarct, as well as in brain areas remote from infarcted tissue. We aimed to describe risk factors, 3-month mortality, and functional outcome in patients with the poorly understood complication of remote intracerebral hemorrhage, as well as local intracerebral hemorrhage. METHODS: In this study, 43 494 patients treated with intravenous recombinant tissue-type plasminogen activator, with complete imaging data, were enrolled in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) during 2002 to 2011. Baseline data were compared among 970 patients (2.2%) with remote parenchymal hemorrhage (PHr), 2325 (5.3%) with PH, 438 (1.0%) with both PH and PHr, and 39 761 (91.4%) without PH or PHr. Independent risk factors for all hemorrhage types were obtained by multivariate logistic regression. RESULTS: Previous stroke (P=0.023) and higher age (P<0.001) were independently associated with PHr, but not with PH. Atrial fibrillation, computed tomographic hyperdense cerebral artery sign, and elevated blood glucose were associated with PH, but not with PHr. Female sex had a stronger association with PHr than with PH. Functional independence at 3 months was more common in PHr than in PH (34% versus 24%; P<0.001), whereas 3-month mortality was lower (34% versus 39%; P<0.001). CONCLUSIONS: Differences between risk factor profiles indicate an influence of previous vascular pathology in PHr and acute large-vessel occlusion in PH. Additional research is needed on the effect of pre-existing cerebrovascular disease on complications of recanalization therapy in acute ischemic stroke. PMID- 24788973 TI - Varying correlation between 18F-fluorodeoxyglucose positron emission tomography and dynamic contrast-enhanced MRI in carotid atherosclerosis: implications for plaque inflammation. AB - BACKGROUND AND PURPOSE: (18)F-fluorodeoxyglucose positron emission tomography and dynamic contrast-enhanced MRI have been proposed to quantitatively assess plaque inflammation by probing macrophages and neovessels, respectively. We examined their correlation to study the in vivo relationship between macrophage and neovessel activities in atherogenesis. METHODS: Forty-one patients (34 men; aged 65+/-12 years) with a total of 68 carotid plaques (thickness >=2 mm on ultrasound; 20 symptomatic) were assessed by both (18)F-fluorodeoxyglucose positron emission tomography/computed tomography and dynamic contrast-enhanced MRI within 2 weeks, measured as target-to-background ratio and transfer constant (K(trans)), respectively. RESULTS: Overall, the correlation between target-to background ratio and K(trans) was weak and marginal (r=0.22; P=0.068). They were correlated in the symptomatic plaques (r=0.59; P=0.006) but not in the asymptomatic plaques (r=0.07; P=0.625; P=0.033 for difference in r). Neither target-to-background ratio nor K(trans) was significantly higher in the symptomatic plaques, but both showed an inverse relationship with time since last neurological event (r=-0.94 and -0.69 for target-to-background ratio and K(trans), respectively). CONCLUSIONS: The correlation between (18)F fluorodeoxyglucose positron emission tomography and dynamic contrast-enhanced MRI measurements varied with clinical conditions, pointing to a complex interplay between macrophages and neovessels under different pathophysiological conditions. The moderate correlation shown only in symptomatic plaques indicates the presence of acute plaque inflammation with increased metabolic activity and cytokine production by inflammatory cells. PMID- 24788974 TI - Activities of daily living is a critical factor in predicting outcome after carotid endarterectomy in asymptomatic patients. AB - BACKGROUND AND PURPOSE: Ability to perform basic daily activity represented by functional status (FNS) before surgery can be assessed in the clinic for determining health status of the patient. We sought to study the effect of FNS on postoperative outcomes after carotid endarterectomy (CEA) in a national data set. METHODS: National Surgical Quality Improvement Project is a national data set, which includes data from >300 hospitals. Patients who underwent CEA were identified by Current Procedural Terminology code and divided into 3 categories based on FNS: independent, partially dependent, and dependent. Thirty-day postoperative stroke, death, and other postoperative complications were identified as the study end point. We used multivariate logistic regression to estimate odds ratio for outcomes while controlling for sex, race, diabetes mellitus, cardiovascular disease, smoking, and other confounders. RESULTS: Of 19 748 CEAs, 19 348 (97.97%) were functionally independent, 377 (1.99%) were functionally partially dependent, and 23 (0.12%) were functionallydependent. In functionally independent group, there were 196 (1.01%) strokes, 84 (0.43%) deaths, and 1416 (7.17%) other complications, whereas in the functionally partially dependent group, there were 14 (3.71%) strokes, 10 (2.65%) deaths, and 80 (21.22%) other complications. In multivariable risk-adjusted model, using functionally independent as reference, functionally partially dependent was associated with death (odds ratio, 3.3; 95% confidence interval, 1.6-6.8; P<0.001), stroke (odds ratio, 3; 95% confidence interval, 1.7-5.4; P<0.001), and other complications (odds ratio, 2.5; 95% confidence interval, 1.9-3.2; P<0.001). CONCLUSIONS: In this national data set, patient's inability to perform basic activities of independent living is associated with adverse postoperative outcomes after CEA. Hence, FNS should be vigilantly assessed in clinic for risk stratification along with other objective factors for gauging risk of adverse outcomes after CEA. PMID- 24788975 TI - Long-term outcome of 106 consecutive pediatric ruptured brain arteriovenous malformations after combined treatment. AB - BACKGROUND AND PURPOSE: Childhood intracerebral hemorrhage is mainly attributable to underlying brain arteriovenous malformations (bAVMs). Multimodal treatment options for bAVMs include microsurgery and embolization, allowing an immediate cure, and radiosurgery, entailing longer obliteration times. Follow-up data on pediatric ruptured bAVMs are scarce, making it difficult to assess the risk of subsequent intracerebral hemorrhage. Our aim was to assess the clinical and angiographic outcome and to analyze risk factors for rebleeding during and after combined treatment of pediatric bAVMs. METHODS: A prospectively maintained database of children referred to our institution between January 1997 and October 2012 for bAVMs was retrospectively queried to identify all consecutive ruptured bAVMs treated by surgery, embolization, and radiosurgery. The impact of baseline clinical and bAVM characteristics on clinical outcome, rebleeding rate, annual bleeding rate, and bAVM obliteration was studied using univariate and multivariate Cox regression analysis. RESULTS: One hundred six children with ruptured bAVMs were followed up for a total of 480.5 patient-years (mean, 4.5 years). Thirteen rebleeding events occurred, corresponding to an annual bleeding rate of 2.71+/-1.32%, significantly higher in the first year (3.88+/-1.39%) than thereafter (2.22+/-1.38%; P<0.001) and in the case of associated aneurysms (relative risk, 2.68; P=0.004) or any deep venous drainage (relative risk, 2.97; P=0.002), in univariate and multivariate analysis. Partial embolization was associated with a higher annual bleeding rate, whereas initial surgery for intracerebral hemorrhage evacuation was associated with a lower risk of rebleeding. CONCLUSIONS: Associated aneurysms and any deep venous drainage are independent risk factors for rebleeding in pediatric ruptured bAVMs. Immediate surgery or total embolization might be advantageous for children harboring such characteristics, whereas radiosurgery might be targeted at patients without such characteristics. PMID- 24788978 TI - El Nino-Southern Oscillation is linked to decreased energetic condition in long distance migrants. AB - Predicting how migratory animals respond to changing climatic conditions requires knowledge of how climatic events affect each phase of the annual cycle and how those effects carry-over to subsequent phases. We utilized a 17-year migration dataset to examine how El Nino-Southern Oscillation climatic events in geographically different regions of the Western hemisphere carry-over to impact the stopover biology of several intercontinental migratory bird species. We found that migratory birds that over-wintered in South America experienced significantly drier environments during El Nino years, as reflected by reduced Normalized Difference Vegetation Index (NDVI) values, and arrived at stopover sites in reduced energetic condition during spring migration. During El Nino years migrants were also more likely to stopover immediately along the northern Gulf coast of the southeastern U.S. after crossing the Gulf of Mexico in small suboptimal forest patches where food resources are lower and migrant density often greater than larger more contiguous forests further inland. In contrast, NDVI values did not differ between El Nino and La Nina years in Caribbean-Central America, and we found no difference in energetic condition or use of coastal habitats for migrants en route from Caribbean-Central America wintering areas. Birds over-wintering in both regions had consistent median arrival dates along the northern Gulf coast, suggesting that there is a strong drive for birds to maintain their time program regardless of their overall condition. We provide strong evidence that not only is the stopover biology of migratory landbirds influenced by events during the previous phase of their life-cycle, but where migratory birds over-winter determines how vulnerable they are to global climatic cycles. Increased frequency and intensity of ENSO events over the coming decades, as predicted by climatic models, may disproportionately influence long-distance migrants over-wintering in South America. PMID- 24788977 TI - Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion. AB - BACKGROUND: Central retinal vein occlusion (CRVO) is a relatively common retinal vascular disorder in which macular oedema may develop, with a consequent reduction in visual acuity. Until recently there has been no treatment of proven benefit, but growing evidence supports the use of anti-vascular endothelial growth factor (anti-VEGF) agents. OBJECTIVES: To investigate the effectiveness and safety of anti-VEGF therapies for the treatment of macular oedema secondary to CRVO. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 10), Ovid MEDLINE (January 1950 to October 2013), EMBASE (January 1980 to October 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2013), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to October 2013), OpenGrey, OpenSIGLE (January 1950 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and Web of Science Conference Proceedings Citation Index-Science (CPCI-S). There were no language or date restrictions in the electronic search for trials. The electronic databases and clinical trials registers were last searched on 29th October 2013. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that compared intravitreal anti-VEGF agents of any dose or duration to sham injection or no treatment. We focused on studies that included individuals of any age or gender and a minimum of six months follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The primary outcome was the proportion of participants with a gain in best-corrected visual acuity (BCVA) from baseline of greater than or equal to 15 letters (3 lines) on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Secondary outcomes included the proportion of participants with a loss of 15 letters or more of BCVA, the mean change from baseline BCVA, the mean change in central retinal thickness (CRT), the number and type of complications or adverse outcomes, and the number of additional interventions administered. Where available, we also presented quality of life and economic data. MAIN RESULTS: We found six RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs included 937 participants and compared outcomes at six months to sham injection for four anti-VEGF agents: aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) and ranibizumab (Lucentis). Three trials were conducted in Norway, Sweden and the USA, and three trials were multicentre, one including centres in the USA, Canada, India, Israel, Argentina and Columbia, a second including centres in the USA, Australia, France, Germany, Israel, and Spain, and a third including centres in Austria, France, Germany, Hungary, Italy, Latvia, Australia, Japan, Singapore and South Korea. We performed meta-analysis on three key visual outcomes, using data from up to six trials. High-quality evidence from six trials revealed that participants receiving intravitreal anti-VEGF treatment were 2.71 times more likely to gain at least 15 letters of visual acuity at six months compared to participants treated with sham injections (risk ratio (RR) 2.71; 95% confidence intervals (CI) 2.10 to 3.49). High-quality evidence from five trials suggested anti-VEGF treatment was associated with an 80% lower risk of losing at least 15 letters of visual acuity at six months compared to sham injection (RR 0.20; 95% CI 0.12 to 0.34). Moderate-quality evidence from three trials (481 participants) revealed that the mean reduction from baseline to six months in central retinal thickness was 267.4 um (95% CI 211.4 um to 323.4 um) greater in participants treated with anti-VEGF than in participants treated with sham. The meta-analyses demonstrate that treatment with anti-VEGF is associated with a clinically meaningful gain in vision at six months. One trial demonstrated sustained benefit at 12 months compared to sham. No significant ocular or systemic safety concerns were identified in this time period. AUTHORS' CONCLUSIONS: Compared to no treatment, repeated intravitreal injection of anti-VEGF agents in eyes with CRVO macular oedema improved visual outcomes at six months. All agents were relatively well tolerated with a low incidence of adverse effects in the short term. Future trials should address the relative efficacy and safety of the anti-VEGF agents and other treatments, including intravitreal corticosteroids, for longer-term outcomes. PMID- 24788979 TI - Funding for GP out of hours in England has fallen by L65m since 2012. PMID- 24788980 TI - Acquired blue nevi in older individuals: retrospective case series from a Veterans Affairs population, 1991 to 2013. AB - IMPORTANCE: Apart from the atypical mole phenotype, development of new melanocytic nevi in older individuals is uncommon and considered worrisome for melanoma. We performed a retrospective case series in a Veterans Affairs population from 1991 to 2013 to characterize blue nevi (BN) by patient age at biopsy, location, self-reported duration, and relation to prior or subsequent development of cutaneous melanoma. OBSERVATIONS: A total of 204 BN were identified in 194 predominantly male patients (90.7%) who had a mean (SD) age of 62.8 (14.4) years. Clinical duration of 10 years or less was reported by 90.3% of patients with available data (32.0%). Histopathologic examination classified 74.0% of BN as common, 1.5% as cellular, and 24.5% as combined type. No malignant BN were identified; however, 18 primary melanomas were diagnosed, most (72.2%) prior to blue nevus biopsy, including 38.9% in situ and 61.1% with mean (SD) Breslow thickness of 1.02 (0.99) mm. CONCLUSIONS AND RELEVANCE: The later patient reported onset of BN suggests a potential alternative mechanism of nevogenesis compared with common acquired nevi and differs from prior reports of BN development in younger adults. The lack of association with melanoma in older individuals suggests that most benign-appearing BN may be safely observed, even in a cohort at higher risk for skin cancer. PMID- 24788981 TI - Significance of branching for transfection: synthesis of highly branched degradable functional poly(dimethylaminoethyl methacrylate) by vinyl oligomer combination. AB - A series of degradable branched PDMAEMA copolymers were investigated with the linear PDMAEMA counterpart as gene-delivery vectors. The branched PDMAEMA copolymers were synthesized by controlled radical cross-linking copolymerization based on the "vinyl oligomer combination" approach. Efficient degradation properties were observed for all of the copolymers. The degree of branching was found to have a big impact on performance in transfection when tested on different cell types. The product with the highest degree of branching and highest degree of functionality had a superior transfection profile in terms of both transfection capability and the preservation of cell viability. These branched PDMAEMA copolymers show high potential for gene-delivery applications through a combination of the simplicity of their synthesis, their low toxicity, and their high performance. PMID- 24788982 TI - Lungfish axial muscle function and the vertebrate water to land transition. AB - The role of axial form and function during the vertebrate water to land transition is poorly understood, in part because patterns of axial movement lack morphological correlates. The few studies available from elongate, semi-aquatic vertebrates suggest that moving on land may be powered simply from modifications of generalized swimming axial motor patterns and kinematics. Lungfish are an ideal group to study the role of axial function in terrestrial locomotion as they are the sister taxon to tetrapods and regularly move on land. Here we use electromyography and high-speed video to test whether lungfish moving on land use axial muscles similar to undulatory swimming or demonstrate novelty. We compared terrestrial lungfish data to data from lungfish swimming in different viscosities as well as to salamander locomotion. The terrestrial locomotion of lungfish involved substantial activity in the trunk muscles but almost no tail activity. Unlike other elongate vertebrates, lungfish moved on land with a standing wave pattern of axial muscle activity that closely resembled the pattern observed in terrestrially locomoting salamanders. The similarity in axial motor pattern in salamanders and lungfish suggests that some aspects of neuromuscular control for the axial movements involved in terrestrial locomotion were present before derived appendicular structures. PMID- 24788983 TI - Sun protection education for diverse audiences: need for skin cancer pictures. AB - Sun protection education is needed for kidney transplant recipients, whose increased risk of skin cancer could be ameliorated with sun protection. Cognitive interviews with 24 participants equally stratified among non-Hispanic White, non Hispanic Black, and Hispanic/Latino kidney transplant recipients were performed to evaluate a sun protection education workbook. Study participants were recruited over the phone using a registry of 700 kidney transplant recipients. Participants included 12 women and 12 men with a median age of 52. In 16 of the cognitive interviews with non-Hispanic Blacks and Hispanic/Latinos, pictures of skin cancer were requested by the participants in order to see the appearance of skin cancer. Kidney transplant recipients with skin of color did not consider themselves at risk to develop skin cancer and wanted to see examples of skin cancer occurring on people with skin of color. Based on these results, the workbook was modified to include pictures of squamous cell carcinoma on varying skin tones. Then, 8 participants evaluated the revised workbook in cognitive interviews and found the photographs acceptable and necessary to demonstrate the severity of skin cancer and personalize their risk of developing skin cancer. The participants progressed from having knowledge of skin cancer to believing that they could develop skin cancer because they observed skin cancers on people with their skin tone. Using pictures of skin cancers occurring on people with similar skin tone may heighten a kidney transplant recipients' sense of vulnerability and possibly improve the use of sun protection. PMID- 24788985 TI - Unravelling the matrix effect of fresh sampled cells for in vivo unbiased FTIR determination of the absolute concentration of total lipid content of microalgae. AB - Over the past years, the substitution of the classical biochemical quantification techniques by Fourier transform infrared (FTIR) spectroscopy has been widely studied on microalgae because of its tremendous application potential for bioprocess monitoring. In the present work, mandatory aspects that have never been approached by FTIR end-users working onto fresh biomass were assessed. We demonstrated first that fresh cells' FTIR spectra main characteristics could be severely and unspecifically altered when the properties of the sampled biomass were not monitored. Microscopy indicated that important cell reorganization could occur when diminishing the cells density of the sample. Molecular probing approach suggested that such a modification could provoke an alteration of the hydrogen-bonding network of the sample. The sample heterogeneity was found to impact also the shape and intensity of the recorded FTIR bands, participating then to a matrix effect uncharacterized until now. In the second part of our study, we selected FTIR spectra not influenced by this matrix effect and the corresponding accurate calibration data obtained by the whole cell analytical procedure to elaborate an optimized total lipid quantification PLS-R model. Results demonstrated that our strategy could provide a small volume sampling (1 mL of fresh culture), rapid (within minutes), robust (physiological condition independent), and accurate (as accurate as the reference method could be) FTIR absolute quantification method to determine the fresh microalgae intracellular total lipid content. To validate our unbiased FTIR approach, a photobioprocess monitoring pipeline was developed and allowed assessing the effect of light attenuation on total lipid production by the marine microalga Nannochloropsis oculata. PMID- 24788984 TI - Ventilation-induced increases in EGFR ligand mRNA are not altered by intra amniotic LPS or ureaplasma in preterm lambs. AB - Chorioamnionitis and mechanical ventilation are associated with bronchopulmonary dysplasia (BPD) in preterm infants. Mechanical ventilation at birth activates both inflammatory and acute phase responses. These responses can be partially modulated by previous exposure to intra-amniotic (IA) LPS or Ureaplasma parvum (UP). Epidermal growth factor receptor (EGFR) ligands participate in lung development, and angiotensin converting enzyme (ACE) 1 and ACE2 contribute to lung inflammation. We asked whether brief mechanical ventilation at birth altered EGFR and ACE pathways and if antenatal exposure to IA LPS or UP could modulate these effects. Ewes were exposed to IA injections of UP, LPS or saline multiple days prior to preterm delivery at 85% gestation. Lambs were either immediately euthanized or mechanically ventilated for 2 to 3 hr. IA UP and LPS cause modest changes in the EGFR ligands amphiregulin (AREG), epiregulin (EREG), heparin binding epidermal growth factor (HB-EGF), and betacellulin (BTC) mRNA expression. Mechanical ventilation greatly increased mRNA expression of AREG, EREG, and HB EGF, with no additional increases resulting from IA LPS or UP. With ventilation AREG and EREG mRNA localized to cells in terminal airspace. EGFR mRNA also increased with mechanical ventilation. IA UP and LPS decreased ACE1 mRNA and increased ACE2 mRNA, resulting in a 4 fold change in the ACE1/ACE2 ratio. Mechanical ventilation with large tidal volumes increased both ACE1 and ACE2 expression. The alterations seen in ACE with IA exposures and EGFR pathways with mechanical ventilation may contribute to the development of BPD in preterm infants. PMID- 24788986 TI - Measuring persistence to hormonal therapy in patients with breast cancer: accounting for temporary treatment discontinuation. AB - PURPOSE: Several studies have been conducted to estimate persistence to hormonal therapy among women with breast cancer (BC). Most studies focus on first treatment discontinuation. Patients, however, can have numerous periods of treatment discontinuation or treatment exposure. Our objective is to estimate persistence to tamoxifen in patients with BC while accounting for temporary treatment discontinuations and this by using multi-state (MS) models. METHODS: A cohort of 10,806 women with BC having received at least one prescription of tamoxifen between 1998 and 2008 was constituted from the UK General Practice Research Database. We fitted a semi-Markov model with three states to estimate the probability of being off treatment over a 5-year period while accounting for temporary treatment discontinuations (transition between on treatment and off treatment) and competing risks (recurrence of BC or death). RESULTS: Non persistence, as estimated from the MS model, ranged from 12.1% (95% confidence interval [95%CI]: 9.2-15.1) at 1 year to 14.9% (95%CI: 11.7-18.1) at 5 years. Estimations of non-persistence based on the Kaplan-Meier model were higher, i.e., 29.3% (95%CI: 28.1-30.6) at 5 years, as well as those obtained from a competing risk model, i.e., 24.0% (95%CI: 22.9-25.1). Most temporary discontinuations (94.7%) lasted less than 6 months. Temporary treatment discontinuations are frequent and should be accounted for when measuring adherence to treatment. MS models can provide a useful framework for this sort of analysis insofar as they help describe patients' complex behavior. This may help tailor interventions that improve persistence to hormonal therapy among women with BC. PMID- 24788987 TI - Rapid Management of Trigeminal Neuralgia and Comorbid Major Depressive Disorder With Duloxetine. AB - OBJECTIVE: To describe a case of a patient diagnosed with major depressive disorder whose trigeminal neuralgia was unexpectedly but rapidly and efficiently responsive to duloxetine. CASE SUMMARY: A 37-year-old woman was diagnosed with trigeminal neuralgia, and the initial treatment with carbamazepine 800 mg/d did not improve her pain. In the following 3 years, she was poorly responsive to the combination therapy with several medications, including carbamazepine, valproate, baclofen, diclofenac, and acetaminophen. The repeated gamma knife radiosurgery still did not relieve her symptoms. She developed clinically significant depressive symptoms, and a diagnosis of major depressive disorder was made. Duloxetine 30 mg/d was initiated for the management of depression, with the dose gradually increased to 60 mg/d. Unexpectedly, at the dose of 60 mg/d, the patient reported remarkable relief in her trigeminal neuralgia within the first week. Her depressed mood gradually improved in the following 3 weeks. At the 4-year follow up, she was gradually tapered off her medications, and her depression and trigeminal neuralgia were well managed on duloxetine 60 mg/d and carbamazepine 600 mg/d. DISCUSSION: The mechanisms may be related to duloxetine's ability to modulate norepinephrine and serotonin and antagonize N-methyl-d-aspartate (NMDA) receptors. The ignition hypothesis is a proposed etiology of trigeminal neuralgia, in that any individual hyperexcitable neuron can spread its discharge quickly to activate the entire population of neurons. We suggest that duloxetine exerts desynchronizing effects through its NMDA antagonism, modulating the hyperexcitable state of the trigeminal afferents. CONCLUSIONS: Duloxetine may be an adjuvant in treatment-resistant trigeminal neuralgia. PMID- 24788988 TI - Clinical significance of myeloid-derived suppressor cells in human renal transplantation with acute T cell-mediated rejection. AB - Myeloid-derived suppressor cells (MDSCs) are negative regulators of the immune response and are in part responsible for the inhibition of the T cell-mediated immune response. A recent paper indicated that MDSCs were involved in prolonged allograft survival in animal models of transplantation, but the significance of MDSCs in human renal transplantation is still unknown. In our study, 50 patients with biopsy-proven acute T cell-mediated rejection (ATCMR) were included. The ratio of MDSCs in peripheral blood mononuclear cell (PBMC) was evaluated with FACS, and the patients were divided into the MDSCs high group (MDSCs, >10 %) or the MDSCs low group (MDSCs, <10 %). We compared the allograft function, severity of tissue injury, and long-time survival between the two groups. In the MDSCs high group, allograft function was significantly increased compared with the MDSCs low group. Furthermore, we found that isolated MDSCs from transplant recipients are capable of expanding regulatory T cell (Treg), meanwhile, inhibiting production of IL-17 in vitro. We also found that the ratio between Foxp3(+) and IL-17-producing CD4(+) T cells positively correlated with MDSCs frequency in PBMC. In conclusion, we demonstrated a potential role for MDSCs in prolonging allograft survival after ATCMR, and this was associated with higher CD4(+)Foxp3(+)/CD4(+)IL-17(+) ratio in PBMC. PMID- 24788989 TI - The most stable isomers of giant fullerenes C102 and C104 captured as chlorides, C102(603)Cl18/20 and C104(234)Cl16/18/20/22. AB - The chlorination of HPLC fractions with pristine giant fullerenes, C102 and C104, followed by X-ray crystallographic study of chlorides, C102(603)Cl18/20 and C104(234)Cl16-22, confirmed the presence of the most stable IPR (IPR = Isolated Pentagon Rule) isomers, C102(603) and C104(234), in the fullerene soot. The discussion concerns the chlorination patterns of polychlorides and relative stability of pristine isomers of C102 and C104 fullerenes. PMID- 24788990 TI - Fatty acid metabolic enzyme acyl-CoA thioesterase 8 promotes the development of hepatocellular carcinoma. AB - Dysregulated metabolism is an emerging hallmark of cancer development, and upregulated lipid synthesis is one of the important tumor metabolic features. However, lipolysis may also contribute to cancer pathogenesis by altering free fatty acid (FFA) metabolism. In the present study, we investigated the importance of the lipolytic enzyme acyl-CoA thioesterase 8 (ACOT8) in hepatocellular carcinoma (HCC) development. Bioinformatic analysis of published microarrays regarding clinical specimens revealed that both ACOT8 gene copy number and mRNA expression were increased in HCC tissues when compared to these variables in non tumor tissues. ACOT8 silencing with specific shRNA stably expressed in Huh7 and Hep3B HCC cell lines showed that ACOT8 protein expression and overall thioesterase activity were reduced following ACOT8 knockdown. In vitro tumorigenic assays revealed that ACOT8 knockdown inhibited anchorage-dependent and -independent growth of HCC cell lines. This growth inhibition was partially rescued by addition of the FFA, myristic acid, indicating the importance of FFA in cancer metabolism. In summary, lipolytic enzyme ACOT8 is frequently upregulated in HCC clinical specimens. More importantly, ACOT8 silencing leads to inhibition of cell growth in HCC in vitro. PMID- 24788991 TI - Competitive formation of b(2) and c(2)-H2O ions from b(3) ions containing Asp residue during tandem mass spectrometry: the influence of neighboring Arg. AB - The fragmentation of b3 ions derived from protonated Arg-Xxx-Asp-Ala-Ala (Xxx = Ala, Asp, Glu, Cys) and Arg-Xxx-Glu-Ala-Ala was investigated by electrospray ionization tandem mass spectrometry (MS (n) ) with collision-induced dissociation. A particular ion, which is 1 Da less than b2 ion, is shown to be the c2-H2O ion. The mechanism for its formation involved the aspartic acid in the third position easily losing anhydride to form a c2 ion, which then lost water to form an eight-membered ring of azacyclooctane derivative under the participation of the guanidine of the N-terminal arginine. However, this phenomenon was not observed when the aspartic acid was replaced by glutamic acid. The Amber program was used to determine the conformation of the original c2 residue from the dynamic energy perspective, and then density functional theory-based calculations and changing N-terminal amino acid from arginine to phenylalanine supported this mechanism. PMID- 24788993 TI - Biologics and tuberculosis risk: the rise and fall of an old disease and its new resurgence. PMID- 24788992 TI - Clinically apparent and occult metastasized seminoma: almost indistinguishable on the transcriptional level. AB - PURPOSE: The aim of the present study was to examine the biological differences between seminomas with occult and clinically apparent metastases at the time of diagnosis of the primary tumor to gain insight into the biology of these tumors and facilitate the identification of novel predictors of seminoma metastasis. MATERIALS AND METHODS: Total RNA including small RNAs was isolated from testicular tumors of patients with pure seminoma presenting with lymphogenic metastasis (n = 5, clinical stage IIb/c) and occult metastasis (n = 5, clinical stage I). The regulation of biological processes was examined (1) throughout the mRNA transcriptome (whole genome microarrays, 8*60 K Array, Agilent with 4 samples/group) and (2) the miRNA transcriptome employing small RNA next generation sequencing (SOLID, Life Technologies with 5 samples/group). Protein coding genes (mRNAs) and small RNAs showing a significant (>=2-fold) difference between the groups were identified. Finally (3), we examined 95 candidate miRNAs in 36 apparent metastasized and another 5 occult metastasized seminoma using logistic regression analysis. RESULTS: Among 19,596 genes, on average 12,894 mRNAs appeared expressed (65.8%, SD+/-2.4; range, 62.0-69.3%) and 16.99*106/13.94*106 small RNA reads were identified for apparent/occult metastasized seminoma. These reads on average convert into 9,901/9,675 small RNAs including 422/404 mature microRNAs. None of these mRNAs/small RNAs met our selection criteria for candidate genes. From 95 candidate miRNAs 44 appeared expressed, with 3 of them showing weak but significant (p = 0.05) differences among both groups. CONCLUSIONS: Occult and apparent metastasized seminomas are biologically almost indistinguishable and probably represent no separate tumor entities. These findings may simplify future research on seminoma metastasis. PMID- 24788994 TI - Update on the epidemiology of tuberculosis in Italy. AB - As in many countries in Western Europe, in Italy tuberculosis (TB) is a relatively rare disease. In the last decade its incidence has remained constant at under 10 cases/100,000 inhabitants, the threshold considered to define a country as low prevalence. The epidemiological picture, however, is very different in the countries of Eastern Europe and in Africa, Asia, and Latin America, where the incidence of TB continues to increase and in some cases is accompanied by the emergence and spread of multidrug-resistant TB. The present review describes the epidemiology of TB in Italy. In 2008, the incidence rate was 3.8 cases per 100,000 for people born in Italy, and 50-60 cases per 100,000 for those born abroad. There was an increase in cases from Eastern Europe. The crude mortality rate for TB in 2006 was 0.7 deaths per 100,000 residents. Although TB is a low-prevalence disease in Italy, its epidemiology is changing. Since 1955, more than 160,000 people in Italy have died from this potentially preventable and curable disease. PMID- 24788995 TI - The spectrum of tuberculosis infection: new perspectives in the era of biologics. AB - The risk of developing active tuberculosis (TB) is higher in patients taking immunosuppressive drugs, either as a result of reactivation of a latent TB infection (LTBI) or following a new infection with Mycobacterium tuberculosis (Mtb). We discuss the pathogenesis and spectrum of Mtb infection in light of its implication for the management of patients following biologic regimens. Among recent findings, during LTBI, Mtb can persist in the host for decades, localizing in many tissues and assuming different metabolic states that protect the bacilli from the harsh host immune defenses. Despite the strong host T cell response against Mtb, the bacilli may also replicate and multiply in vivo, and any event impairing immune function may lead to active and uncontrolled bacteria replication and active disease. The classic dichotomy between active and latent disease is being reconsidered in favor of a continuous and dynamic spectrum extending from infection to disease that can coexist in the same individual. This TB spectrum results from the dynamic interaction between the host immune system and the bacilli and can be maintained in equilibrium for decades, although treatments affecting the host immune cells may result in disease reactivation. PMID- 24788996 TI - Cellular and humoral immune responses during tuberculosis infection: useful knowledge in the era of biological agents. AB - In this review, recent insights into innate and adaptive cellular and humoral immune response to Mycobacterium tuberculosis (Mtb) are discussed and the role of specific cytokines such as tumor necrosis factor-alpha (TNF-alpha) is highlighted. According to recent findings, the immune system plays a key role in avoiding mycobacteria dissemination. The importance of different cell types (macrophages, dendritic cells, interferon-gamma-producing T cells) as well as the production of proinflammatory cytokines such as interleukin 6 (IL-6), IL-12, and IL-23/IL-17 have been demonstrated. Alveolar macrophages are considered the first cells infected by Mtb during respiratory infection. Mtb proliferates within alveolar macrophages and dendritic cells and induces the release of cytokines such as TNF-alpha, IL-1, IL-6, and IL-12. Toll-like receptors-stimulated dendritic cells link innate and adaptive immunity by promoting polarization of effector T cells. The efficient induction of Th1 immunity is decisive in defense against Mtb. In fact, host effector immune response against Mtb is related to the presence of a Th1 response. The definition of the cellular and molecular mechanisms involved in the immune response to Mtb can be helpful in developing new preventive strategies to avoid infection relapse, particularly in patients treated with biological agents. PMID- 24788997 TI - Performance of the tuberculin skin test and interferon-gamma release assays: an update on the accuracy, cutoff stratification, and new potential immune-based approaches. AB - An association between biologic agents and reactivation of active disease from latent tuberculosis infection (LTBI) has been established. Screening for LTBI is, therefore, now recommended for candidates for biologic drugs. The tuberculin skin test (TST) and interferon-gamma release assays (IGRA) are the available commercial tests for detecting LTBI. We discuss their accuracy in immune competent subjects and patients with autoimmune diseases, as well as potential new approaches to immune diagnosis. IGRA seem to be more accurate than TST in bacillus Calmette-Guerin vaccinated subjects and patients with autoimmune diseases. However, longitudinal studies are needed to estimate the risk of progression to TB after IGRA-based and/or TST-based diagnosis of LTBI in these vulnerable patients. New tests are needed to identify those patients with LTBI who will develop active TB and need prophylaxis. PMID- 24788998 TI - Diagnostic accuracy of chest radiography for the diagnosis of tuberculosis (TB) and its role in the detection of latent TB infection: a systematic review. AB - In this systematic review we evaluate the role of chest radiography (CXR) in the diagnostic flow chart for tuberculosis (TB) infection, focusing on latent TB infection (LTBI) in patients requiring medical treatment with biological drugs. In recent findings, patients scheduled for immunomodulatory therapy with biologic drugs are a group at risk of TB reactivation and, in such patients, detection of LTBI is of great importance. CXR for diagnosis of pulmonary TB has good sensitivity, but poor specificity. Radiographic diagnosis of active disease can only be reliably made on the basis of temporal evolution of pulmonary lesions. In vivo tuberculin skin test and ex vivo interferon-gamma release assays are designed to identify development of an adaptive immune response, but not necessarily LTBI. Computed tomography (CT) is able to distinguish active from inactive disease. CT is considered a complementary imaging modality to CXR in the screening procedure to detect past and LTBI infection in specific subgroups of patients who have increased risk for TB reactivation, including those scheduled for medical treatment with biological drugs. PMID- 24788999 TI - Diagnosis of latent tuberculosis and prevention of reactivation in rheumatic patients receiving biologic therapy: international recommendations. AB - OBJECTIVE: To review the official international recommendations on the management of latent tuberculosis infection (LTBI) in patients with rheumatic diseases undergoing biologic therapy. METHODS: A systematic search of all clinical practice recommendations on the diagnosis and treatment of LTBI in rheumatic patients eligible for starting biologic drugs published between January 2002 and March 2013. RESULTS: For the diagnosis of LTBI, based on positivity of tuberculin skin test (TST), interferon-gamma release assay (IGRA) is also available. Most recommendations advise using both TST and IGRA, especially in case of Bacillus Calmette-Guerin vaccination, to screen patients before commencing biologic drugs. There is a general consensus that evaluation of the global risk of TB infection is a crucial point and that patients with LTBI must receive chemoprophylaxis prior to biologic therapy. However, recommendations on the need for rescreening for activation of LTBI or new TB infection while patients are being treated are inadequate. Nevertheless, the main concern is poor compliance with TB recommendations of rheumatologists in clinical practice, which seems to be the main cause of the occurrence of active TB in rheumatic patients receiving biologic therapy. CONCLUSION: Notwithstanding some differences, mainly related to regional TB incidence, international recommendations strongly suggest careful screening for LTBI before starting biologic therapy. However, the critical point is implementing dissemination and awareness of the recommendations among rheumatologists to improve adherence in real life. PMID- 24789000 TI - Adalimumab, etanercept, infliximab, and the risk of tuberculosis: data from clinical trials, national registries, and postmarketing surveillance. AB - This review evaluates the risk of tuberculosis (TB), adherence with recommendations for TB prevention, and host-related risk in patients with rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis receiving infliximab (IFX), adalimumab (ADA), and etanercept (ETN) through an analysis of phase III randomized controlled trials (RCT), postmarketing surveillance, and national registries. Ten (0.21%) TB cases occurred among 4590 patients in 16 RCT of IFX, 9 (0.12%) among 7009 patients in 21 RCT of ADA, and 4 (0.05%) among 7741 patients in 26 RCT of ETN. Overall, 19/23 (83%) TB cases occurred in patients with RA. Data from national registries and postmarketing surveillance showed an increased risk of TB in patients receiving any of the 3 anti-tumor necrosis factor (TNF) drugs, with a 3-4 times higher risk associated with IFX and ADA than with ETN. Deviations from recommended TB prevention procedures were observed in up to 80% of patients, and most registries did not include data on host-related risk factors for TB. TB occurrence was reduced in recent RCT but not in real-life practice. TB risk was lower for ETN than for monoclonal antibody anti-TNF agents. More complete data collection, including host-related TB risk factors, is advisable to avoid biased results. PMID- 24789001 TI - Tuberculosis risk in patients treated with non-anti-tumor necrosis factor-alpha (TNF-alpha) targeted biologics and recently licensed TNF-alpha inhibitors: data from clinical trials and national registries. AB - This review aimed to evaluate the risk of active tuberculosis (TB) occurrence in patients with rheumatic disorders receiving non-anti-tumor necrosis factor (TNF) targeted biologics anakinra (ANK), tocilizumab (TCZ), rituximab (RTX), abatacept (ABA), and recently approved anti-TNF golimumab (GOL), and certolizumab pegol (CTP). In recent findings, no cases of active TB were recorded in patients with rheumatoid arthritis (RA) and other rheumatic conditions treated with anti-CD20+ RTX and anti-CD28 ABA. No patient receiving anti-interleukin 1 (IL-1) ANK developed active TB, and an increased risk was excluded in a Canadian database. In contrast, 8 active TB cases were observed in 21 trials of patients with RA receiving anti-IL-6 TCZ, while no increased TB risk resulted from Japanese postmarketing surveillance. Among GOL-treated and CTP-treated patients, 8 and 10 active TB cases occurred, respectively, while no data are available from registries. However, all but 1 TB case recorded in patients treated with TCZ, GOL, and CTP occurred in TB-endemic countries. No TB risk resulted for ANK, RTX, and ABA, suggesting pretreatment screening procedures for latent TB infection detection are unnecessary. Because all TB cases occurred in countries at high risk for TB, where TB exposure could have occurred during treatment, no definitive conclusions can be drawn for TCZ, GOL, and CTP. PMID- 24789002 TI - Tuberculosis reactivation risk in dermatology. AB - The treatment of some dermatological diseases, especially psoriasis, has been revolutionized by the advent of biologic therapies that target various immune cells or cytokines. However, biologic therapies may affect the risk of active tuberculosis (TB). We review the published safety data about TB risk reactivation for biologic agents used in dermatology. According to recent findings, psoriasis itself could represent an independent risk factor for TB; a high prevalence of TB was found in patients with psoriasis (18.0%), even after adjusting for age, work, and other characteristics. Latent TB infection was more common in patients with psoriasis (50%) than in those with inflammatory bowel disease (24.2%). Risk of TB reactivation was also influenced by the type of agent used. Several structural and functional differences among biologic drugs could account for differences in risk of granulomatous infection. Different kinetics of currently available tumor necrosis factor (TNF) antagonists, leading to different TNF bioavailability in granulomatous tissue, may explain differences in TB reactivation among patients treated with biologics. One could argue that etanercept should be the first choice of anti-TNF agent in populations at high risk of TB. Risk of TB reactivation during treatment with other biologics is not yet well defined. PMID- 24789003 TI - Current treatment options for latent tuberculosis infection. AB - Treatment of latent tuberculosis infection (LTBI) is a key component in TB control strategies worldwide. However, as people with LTBI are neither symptomatic nor contagious, any screening decision should be weighed carefully against the potential benefit of preventing active disease in those who are known to be at higher risk and are willing to accept therapy for LTBI. This means that a targeted approach is desirable to maximize cost effectiveness and to guarantee patient adherence. We focus on LTBI treatment strategies in patient populations at increased risk of developing active TB, including candidates for treatment with tumor necrosis factor-alpha blockers. In the last 40 years, isoniazid (INH) has represented the keystone of LTBI therapy across the world. Although INH remains the first therapeutic option, alternative treatments that are effective and associated with increased adherence and economic savings are available. Current recommendations, toxicity, compliance, and cost issues are discussed in detail in this review. A balanced relationship between the patient and healthcare provider could increase adherence, while cost-saving treatment strategies with higher effectiveness, fewer side effects, and of shorter duration should be offered as preferred. PMID- 24789004 TI - Restarting biologics and management of patients with flares of inflammatory rheumatic disorders or psoriasis during active tuberculosis treatment. AB - Our aim was to review the evidence concerning optimal timing for restarting biologics in patients with active tuberculosis (TB), and the management of relapsing rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis during treatment for TB. Few or no indications are available for 2 important challenges for clinicians: the timing for restarting biologics in patients with TB reactivation and the management of the underlying disorder. In the absence of clear evidence, guidelines and experts suggest restarting anti-tumor necrosis factor-alpha (TNF-alpha) agents after completion of an active TB therapy course, but no indications are available on the appropriate management of patients with flares of underlying rheumatic disease or psoriasis. Among anti-TNF-alpha agents, etanercept is associated with the lowest risk of TB reactivation, and non-anti-TNF-alpha biologics and several nonbiologic drugs are associated with low/no risk of TB reactivation. Therefore, for patients with relapsing RA, PsA, AS, or psoriasis during TB treatment we propose a therapeutic schedule modulated by disease activity and individual single drug-related TB risk. PMID- 24789005 TI - Cost for tuberculosis care in developed countries: which data for an economic evaluation? AB - Tuberculosis (TB) seems to be eradicated in developed countries. However, current migration flows and increasing use of immunosuppressive and biologic drugs for rheumatic diseases are increasing the risk of latent TB and TB onset for citizens of developed countries. Because little is known about the economic burden of TB in developed countries, we set out to describe the order and dimension of the costs of TB care in developed countries. A review of the literature indicated that the cost for anti-TB therapy is about $2000 US per patient. Costs of drugs associated with standard therapy for active TB [2HRZE/4HR, i.e., 2 months of isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E), followed by 4 months of HR] are about $600. Standard therapy for latent TB care costs about $80 for 9H and $256 for 4R, respectively. However, these data are very limited because of the horizon of analysis and because data are strongly localized. It can be concluded that in developed countries, available data on TB care costs are insufficient for detailed analysis of the economic burden of TB. PMID- 24789006 TI - Integrating High-Content Analysis into a Multiplexed Screening Approach to Identify and Characterize GPCR Agonists. AB - G protein-coupled receptors (GPCRs) are one of the most popular and proven target classes for therapeutic intervention. The increased appreciation for allosteric modulation, receptor oligomerization, and biased agonism has led to the development of new assay platforms that seek to capitalize on these aspects of GPCR biology. High-content screening is particularly well suited for GPCR drug discovery given the ability to image and quantify changes in multiple cellular parameters, to resolve subcellular structures, and to monitor events within a physiologically relevant environment. Focusing on the sphingosine-1-phosphate (S1P1) receptor, we evaluated the utility of high-content approaches in hit identification efforts by developing and applying assays to monitor beta-arrestin translocation, GPCR internalization, and GPCR recycling kinetics. Using these approaches in combination with more traditional GPCR screening assays, we identified compounds whose unique pharmacological profiles would have gone unnoticed if using a single platform. In addition, we identified a compound that induces an atypical pattern of beta-arrestin translocation and GPCR recycling kinetics. Our results highlight the value of high-content imaging in GPCR drug discovery efforts and emphasize the value of a multiassay approach to study pharmacological properties of compounds of interest. PMID- 24789007 TI - The potential effect of the tumour necrosis factor-alpha inhibitors on vitamin D status in psoriatic patients. PMID- 24789009 TI - MS4A8B promotes cell proliferation in prostate cancer. AB - BACKGROUND: Prostate cancer cells must maintain or achieve the further ability of proliferation during the progression. The molecular mechanisms, however, remain poorly understood. We identified a novel oncogene, termed membrane-spanning 4 domains, subfamily A, member 8B (MS4A8B), over-expressed in prostate cancer. METHODS: We firstly detected MS4A8B mRNA in 13 types of paired human normal and cancer tissues by real-time polymerase chain reaction (RT-PCR). In 140 clinically localized prostate cancer samples from radical prostatectomy, immunohistochemical staining was performed to study MS4A8B and PCNA protein level as an index of proliferative activity, TUNEL staining as an index of apoptosis. As MS4A8B RNAi and cDNA transfection technologies were used, the effect of MS4A8B on cellular vitality was determined in vitro and in vivo. RESULTS: MS4A8B mRNA was over expressed specifically in prostate cancer. Positive ratios of MS4A8B protein expression were 1.94%, 5.92%, and 62.8% in benign, HPIN and prostate cancer, respectively. Moreover, MS4A8B was positively associated with Gleason score, the proliferation index. In vitro, MS4A8B knockdown resulted in G1 -S cell cycle arrest and descended vitality, MS4A8B over-expression with accelerated S phase entry, elevated vitality in prostate cancer cells. Moreover, it was also found that expression of MS4A8B led to changes of Cyclin D1 , Cyclin E1 and PCNA. LNCaP cells transfected with sh-MS4A8B lentivirus particles grew more slowly when subcutaneously injected into the flanks of nude mice. CONCLUSIONS: We conclude that the expression of MS4A8B expression promotes cell proliferation and plays an important role in carcinogenesis and progression of prostate cancer. PMID- 24789010 TI - Highly reliable ag nanowire flexible transparent electrode with mechanically welded junctions. AB - Deformation behavior of the Ag nanowire flexible transparent electrode under bending strain is studied and results in a novel approach for highly reliable Ag nanowire network with mechanically welded junctions. Bending fatigue tests up to 500,000 cycles are used to evaluate the in situ resistance change while imposing fixed, uniform bending strain. In the initial stages of bending cycles, the thermally annealed Ag nanowire networks show a reduction in fractional resistance followed by a transient and steady-state increase at later stages of cycling. SEM analysis reveals that the initial reduction in resistance is caused by mechanical welding as a result of applied bending strain, and the increase in resistance at later stages of cycling is determined to be due to the failure at the thermally locked-in junctions. Based on the observations from this study, a new methodology for highly reliable Ag nanowire network is proposed: formation of Ag nanowire networks with no prior thermal annealing but localized junction formation through simple application of mechanical bending strain. The non-annealed, mechanically welded Ag nanowire network shows significantly enhanced cyclic reliability with essentially 0% increase in resistance due to effective formation of localized wire-to-wire contact. PMID- 24789008 TI - Preservation of blood glucose homeostasis in slow-senescing somatotrophism deficient mice subjected to intermittent fasting begun at middle or old age. AB - Poor blood glucose homeostatic regulation is common, consequential, and costly for older and elderly populations, resulting in pleiotrophically adverse clinical outcomes. Somatotrophic signaling deficiency and dietary restriction have each been shown to delay the rate of senescence, resulting in salubrious phenotypes such as increased survivorship. Using two growth hormone (GH) signaling-related, slow-aging mouse mutants we tested, via longitudinal analyses, whether genetic perturbations that increase survivorship also improve blood glucose homeostatic regulation in senescing mammals. Furthermore, we institute a dietary restriction paradigm that also decelerates aging, an intermittent fasting (IF) feeding schedule, as either a short-term or a sustained intervention beginning at either middle or old age, and assess its effects on blood glucose control. We find that either of the two genetic alterations in GH signaling ameliorates fasting hyperglycemia; additionally, both longevity-inducing somatotrophic mutations improve insulin sensitivity into old age. Strikingly, we observe major and broad improvements in blood glucose homeostatic control by IF: IF improves ad libitum fed hyperglycemia, glucose tolerance, and insulin sensitivity, and reduces hepatic gluconeogenesis, in aging mutant and normal mice. These results on correction of aging-resultant blood glucose dysregulation have potentially important clinical and public health implications for our ever-graying global population, and are consistent with the Longevity Dividend concept. PMID- 24789012 TI - Investigator(r) Argus X-12 study on the population of Czech Republic: comparison of linked and unlinked X-STRs for kinship analysis. AB - DNA samples of 523 unrelated anonymized individuals (307 males and 216 females) born and living in the Czech Republic were genotyped using Investigator(r) Argus X-12 system in the following loci localized in four linkage groups: DXS10148, DXS10135, DXS8378, DXS7132, DXS10079, DXS10074, DXS10103, HPRTB, DXS10101, DXS10146, DXS10134, DXS742. Haplotype frequencies were calculated for each LG (Linkage Group). The frequency of most common haplotype was 0.016, 0.036, 0.042, and 0.023 for LG1, LG2, LG3, and LG4, respectively. The combined power of discrimination was more than 0.999999999 both for female and male samples. The mean exclusion chance was 0.99999999 (trios) and 0.999999 (duos). Informativity and suitability of Investigator(r) Argus X-12 for kinship determination was assessed by computing in several female-female duos using LR (Likelihood Ratio) determination for autosomal STR (PowerPlex ESI-17), linked (Investigator(r) Argus X-12 system), and unlinked (X-STR Decaplex) X-STR kits. Investigator(r) Argus X 12 proved to be very useful for sibship determination, since its LR values were relatively similar to LR for autosomal STR kit. This work presents the first population data for Investigator(r) Argus X-12 system in the Czech Republic. PMID- 24789011 TI - Combined systems approaches reveal highly plastic responses to antimicrobial peptide challenge in Escherichia coli. AB - Obtaining an in-depth understanding of the arms races between peptides comprising the innate immune response and bacterial pathogens is of fundamental interest and will inform the development of new antibacterial therapeutics. We investigated whether a whole organism view of antimicrobial peptide (AMP) challenge on Escherichia coli would provide a suitably sophisticated bacterial perspective on AMP mechanism of action. Selecting structurally and physically related AMPs but with expected differences in bactericidal strategy, we monitored changes in bacterial metabolomes, morphological features and gene expression following AMP challenge at sub-lethal concentrations. For each technique, the vast majority of changes were specific to each AMP, with such a plastic response indicating E. coli is highly capable of discriminating between specific antibiotic challenges. Analysis of the ontological profiles generated from the transcriptomic analyses suggests this approach can accurately predict the antibacterial mode of action, providing a fresh, novel perspective for previous functional and biophysical studies. PMID- 24789013 TI - Informed consent in surgery. PMID- 24789014 TI - Ethics in global surgery. AB - Global surgery, while historically a small niche, is becoming a larger part of the global health enterprise. This article discusses the burden of global surgery, emphasizing the importance of addressing surgical needs in low- and middle-income countries. It describes the barriers to surgical care in the developing world, the ethical challenges that these barriers create, and strategies to overcome these barriers. It emphasizes the crucial role of preparation for global surgical interventions as a way to maximize benefits as well as minimize harms and ethical challenges. It ends with the cautionary statement that preparation does not eliminate ethical problems, so surgical volunteers must be prepared not only for the technical challenges of global surgery but also for the ethical challenges. PMID- 24789015 TI - Current status of robotic thyroid surgery in South Korea: a web-based survey. AB - BACKGROUND: More than 8,000 cases of robotic thyroidectomy (RoT) were performed in South Korea from 2007 to 2011 using either a transaxillary approach (TAA) or a bilateral axillo-breast approach (BABA). However, there is no consensus regarding patient selection for RoT. This study used a web-based survey questionnaire to examine the current status of RoT in South Korea. METHODS: Thirty-two of 50 surgeons (64.0 %) who had performed RoT in South Korea participated in the web based survey in August 2011. The questionnaires comprised four main domains: surgeon characteristics, surgical approach, patient selection, and future prospects. RESULTS: In terms of surgical approach, 43.8 % respondents used the TAA method and 53.1 % used the BABA method. The main advantage cited by surgeons using the TAA method was that it made lateral lymph node dissection easier (35.7 %), whereas those using the BABA method cited more cosmesis (100 %) and ease of performing a contralateral thyroidectomy (88.2 %). Papillary thyroid cancer <=2 cm (65.3 %), intracapsular lesion (76.7 %), nonposterior location (53.6 %), and no clinical evidence of lateral lymph node metastasis (76.7 %) were cited as main indications for RoT. Of respondents, 87.5 % agreed that RoT would play a future role as a treatment modality for thyroid disease. CONCLUSIONS: Opinions differed regarding the advantages and disadvantages of two approaches for RoT. This may be due to differences in surgical procedure itself between two approach methods. Accumulation of RoT surgeon's experiences might establish consensus regarding patient selection and indications for the RoT will need to be further investigated. PMID- 24789016 TI - Primary laparotomy is effective and safe in the treatment of necrotizing enterocolitis. AB - INTRODUCTION: There is ongoing controversy regarding the surgical treatment of necrotizing enterocolitis (NEC) in infants with extremely low birth weight (ELBW). We hypothesize that primary laparotomy is a safe and effective treatment for all infants with surgical NEC. METHODS: We retrospectively compared a group of ELBW infants (<1,000 g, group A, n = 39) with preterm infants (>=1,000 g, group B, n = 18) with surgical NEC during a 4-year period (10/2008-09/2012). Indications for emergency operation were Bell stages IIIa or IIIb. The main outcome measure was survival. Data were analyzed using Chi squared test and Spearman's rank correlation coefficient. RESULTS: Fifty-seven patients were included with a gestational age from 24 to 30 weeks in group A and 27-38 weeks in group B. There were no significant differences in Bell stage (IIIa; IIIb) and NEC type (focal; segmental; pannecrosis). The operative techniques were not significantly different between the groups and included resection and stoma formation in 44 of 57 (77 %) patients; resection and anastomosis in 6 of 57 (11 %); and inspection only, followed by withdrawal of care, in 7 of 57 (12 %). Overall mortality was 10 of 57 (17 %) with no significant difference between the groups. The only significant correlation was observed between the length of necrotic bowel and mortality. In total, 7 of 57 infants required repeated surgery after initial treatment. We observed stoma complications in 36 % of the patients in group A and 21 % in group B without the need of stoma revision. All stomas were successfully closed at the time of the study. One of 44 patients with stoma closure required a relaparotomy due to bowel obstruction. CONCLUSIONS: Early primary laparotomy is safe and effective for the management of surgical NEC in ELBW infants. Outcome of affected infants is not influenced by age or weight at surgery but by the length of necrotic bowel. PMID- 24789017 TI - One role of hydration water in proteins: key to the "softening" of short time intraprotein collective vibrations of a specific length scale. AB - High resolution inelastic X-ray scattering (IXS) experiments show that the "phonon energy softening" and "phonon population enhancement" observed in a hydrated native protein when increasing the temperature from 200 K to physiological temperature are not directly related to the protein structure. Such phenomena were also observed in a denatured sample without a defined tertiary structure and with a limited residual secondary structure. However, in a dry sample, such "softening" is strongly suppressed. These facts suggest that the above-mentioned protein "softening" phenomenon is water-induced. In addition, increasing the hydration level can also induce "phonon energy softening" at room temperature, but not at 200 K. This change may be due to a qualitative difference in the dynamics of hydration water at 200 K and at room temperature. PMID- 24789018 TI - Cochlear Implantation in Meniere's Disease. AB - IMPORTANCE: Though the effects of cochlear implantation (CI) on patients with hearing loss has been well described, its effect on the auditory and vestibular symptoms in patients with Meniere's disease (MD) has not been firmly established. OBJECTIVES: To determine whether CI in patients with MD improves hearing performance as measured by standard post-CI audiometric testing and to describe the impact of CI on subjective auditory and vestibular quality-of-life measures. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of all patients with MD 18 years or older who met diagnostic criteria for definite MD and underwent CI at Wake Forest University Baptist Medical Center, a tertiary care academic medical center, from 2000 through 2012. INTERVENTIONS: Patients were invited to answer questions regarding their current hearing ability, subjective perception of symptoms, and functional status related to their MD before and after CI. Patient records were reviewed for pertinent information. Results were then analyzed for statistical significance. MAIN OUTCOMES AND MEASURES: Pre-CI and post-CI sentence testing scores, frequency and severity of MD vestibular and auditory symptoms via the MD Functional Level Scale (FLS), and hearing quality of life via the Hearing Handicap Index were reviewed. RESULTS: Eleven CIs were performed in 10 patients. Mean long-term follow-up was 41 months. The mean age at first implantation was 64 years. The mean sentence testing scores in quiet improved from 22.8% before CI to 77.0% after CI (P < .001) at the most recent follow-up. Mean (SD) pre-CI and post CI MD-FLS vestibular scores were similar: 3.9 (1.9) and 3.4 (1.9) (P = .52). CONCLUSIONS AND RELEVANCE: Patients with MD who undergo CI are capable of achieving substantial receptive communication improvement comparable to the gains experienced by patients without MD. Implantation seems to neither adversely alter the natural history of vestibular function nor notable exacerbate auditory symptoms. PMID- 24789019 TI - Catalyzed formation of alpha,beta-unsaturated ketones or aldehydes from propargylic acetates by a recoverable and recyclable nanocluster catalyst. AB - An active, recoverable, and recyclable nanocluster catalyst, Au25(SR)18(-), has been developed to catalyze the formation of alpha,beta-unsaturated ketones or aldehydes from propargylic acetates. The catalytic process has been proposed to be initialized by an SN2' addition of OH(-). Moreover, a dramatic solvent effect was observed, for which a rational explanation was provided. PMID- 24789020 TI - Prognostic significance of nemo-like kinase in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a highly metastatic malignancy, which is highly prevalent in Southeast Asia and North Africa. Recent studies implicated the critical role of nemo-like kinase (NLK) in tumor biology. However, the functional role of NLK in NPC has yet to be elucidated. In the present study, the significance of NLK positivity in NPC was examined. NLK expression was evaluated by immunohistochemistry in a relatively large sample of patients with NPC (n=352) from December 1, 2002 to December 1, 2009. The correlation between the NLK expression status and clinicopathological features and prognosis was investigated. Univariate and multivariate Cox regression models were developed to evaluate the association between the NLK status and the relative risks for relapse and mortality. In total, 54% (190/352) of NPC samples were identified as positive for NLK. By contrast, all 176 specimens of adjacent normal tissue were negative for NLK. NLK positivity was associated with tumor extent, regional lymph node status and distant metastases. A Kaplan-Meier survival analysis demonstrated that patients with NLK-positive NPC exhibited significantly shorter disease-free survival (DFS) and overall survival (OS). Furthermore, Cox regression analysis revealed that NLK positivity was an unfavorable prognostic indicator of DFS and OS in NPC, independent of other features. Additionally, NLK-positive patients with NPC without distant metastases were more likely to relapse compared with NLK negative patients with NPC without distant metastases. The present study indicates that NLK is a good prognostic marker for NPC. PMID- 24789022 TI - Respiratory care year in review 2013: neonatal respiratory care, pulmonary function testing, and pulmonary rehabilitation. AB - Respiratory care practice includes neonatal respiratory care, pulmonary function testing, and pulmonary rehabilitation. The purpose of this paper is to review the recent literature related to these topics in a manner that is most likely to have interest to the readers of Respiratory Care. PMID- 24789023 TI - Is extended-release guaifenesin no better than a placebo? PMID- 24789024 TI - Humidification in intensive care: are we there yet? PMID- 24789025 TI - Clinical practice trends in mechanical ventilation for acute asthma. PMID- 24789026 TI - Outcome of patients treated with noninvasive ventilation by a medical emergency team on the wards: is it really scarce monitoring? PMID- 24789027 TI - Outcome of patients treated with noninvasive ventilation by a medical emergency team on the wards: scarce and probably secure and resourceful monitoring in select subjects--reply. PMID- 24789028 TI - Management of H7N9 bird flu case. PMID- 24789029 TI - The management of elbow instability using an internal joint stabilizer: preliminary results. AB - BACKGROUND: Nonsurgical and surgical treatments such as immobilization, transarticular pinning, and hinged or nonhinged external fixation have been used to treat unstable elbows. These methods all have drawbacks. We thought that a bent Steinmann pin introduced through the axis of ulnohumeral rotation and attached to the ulna could provide an improved method of treatment and that this could result in the development of a proper internal joint fixator that may have widespread application. QUESTIONS/PURPOSES: Does a fully internal hinged fixator crafted intraoperatively by the surgeon from a Steinmann pin for patients undergoing surgery for severe elbow instability result in restoration of range of motion and elbow stability? Does it result in new complications? METHODS: We reviewed the first 10 patients treated with the method for elbow instability. Diagnoses included fracture-dislocations of the elbow that remain unstable after fracture repair and unstable elbows that result from release of contracture or ulnohumeral synostosis. During that time, all patients meeting these criteria who underwent surgery by this surgeon (JLO) were treated with this approach. Charts, radiographs, and therapy notes were assessed at a minimum of 14 months (mean, 32 months; range, 14-59 months); no patients were lost to followup. Data recorded included age, sex, and elbow and forearm range of motion as well as any complications and reoperations that occurred. The absence of elbow instability was determined initially by radiographically observing concentric reduction of the ulnohumeral and radiocapitellar joints and later by radiography plus the absence of clinical signs and symptoms of elbow instability. RESULTS: Mean range of motion at latest followup was flexion 134 degrees , extension -19 degrees , pronation 75 degrees , and supination 64 degrees . All elbows were clinically and radiographically stable. Complications resulting in additional procedures occurred in four patients, including one recurrent deep infection in a patient with a remote history of sepsis, one wound hematoma that resolved after a drainage procedure performed in the office, one prominent implant treated by partial removal, and one patient with heterotopic ossification treated with excision of the heterotopic bone. CONCLUSIONS: This technique restores elbow stability and permits motion without the use of transcutaneous pins. It seems promising for the treatment of patients with severe elbow instability but requires a second procedure for removal. Further investigation is needed to understand its place in the surgeon's toolbox and what drawbacks it may have. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24789031 TI - Vitamin D status: ready for guiding prostate cancer diagnosis and treatment? AB - Vitamin D deficiency is associated with increased risk of prostate cancer for those with elevated prostate-specific antigen (PSA) level or abnormal digital rectal examination. Vitamin D deficiency is also associated with aggressive prostate cancer. Vitamin D level could be added as an additional factor to consider before ordering a biopsy. Clin Cancer Res; 20(9); 2241-3. (c)2014 AACR. PMID- 24789032 TI - Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. AB - The development of targeted therapies has revolutionized the treatment of cancer patients. The identification of "druggable" oncogenic kinases and the creation of small-molecule inhibitors designed to specifically target these mutant kinases have become an important therapeutic paradigm across several different malignancies. Often these inhibitors induce dramatic clinical responses in molecularly defined cohorts. However, resistance to such targeted therapies is an inevitable consequence of this therapeutic approach. Resistance can be either primary (de novo) or acquired. Mechanisms leading to primary resistance may be categorized as tumor intrinsic factors or as patient/drug-specific factors. Acquired resistance may be mediated by target gene modification, activation of "bypass tracks" that serve as compensatory signaling loops, or histologic transformation. This brief review is a snapshot of the complex problem of therapeutic resistance, with a focus on resistance to kinase inhibitors in EGF receptor mutant and ALK rearranged non-small cell lung cancer, BRAF-mutant melanoma, and BCR-ABL-positive chronic myeloid leukemia. We describe specific mechanisms of primary and acquired resistance and then review emerging strategies to delay or overcome drug resistance. PMID- 24789033 TI - Vitamin D deficiency predicts prostate biopsy outcomes. AB - PURPOSE: The association between vitamin D and prostate biopsy outcomes has not been evaluated. We examine serum vitamin D levels with prostate biopsy results in men with an abnormal prostate-specific antigen and/or digital rectal examination. EXPERIMENTAL DESIGN: Serum 25-hydroxyvitamin D (25-OH D) was obtained from 667 men, ages 40 to 79 years, prospectively enrolled from Chicago urology clinics undergoing first prostate biopsy. Logistic regression was used to evaluate the associations between 25-OH D status and incident prostate cancer, Gleason score, and tumor stage. RESULTS: Among European American (EA) men, there was an association of 25-OH D <12 ng/mL with higher Gleason score >= 4+4 [OR, 3.66; 95% confidence interval (CI), 1.41-9.50; P = 0.008] and tumor stage [stage >= cT2b vs. <= cT2a, OR, 2.42 (1.14-5.10); P = 0.008]. In African American (AA) men, we find increased odds of prostate cancer diagnosis on biopsy with 25-OH D < 20 ng/mL [OR, 2.43 (1.20-4.94); P = 0.01]. AA men demonstrated an association between 25-OH D < 12 ng/mL and Gleason >= 4+4 [OR, 4.89 (1.59-15.07); P = 0.006]. There was an association with tumor stage >= cT2b vs. <= cT2a [OR, 4.22 (1.52 11.74); P = 0.003]. CONCLUSIONS: In AA men, vitamin D deficiency was associated with increased odds of prostate cancer diagnosis on biopsy. In both EA and AA men, severe deficiency was positively associated with higher Gleason grade and tumor stage. PMID- 24789035 TI - TGR analysis in phase I clinical trials--letter. PMID- 24789034 TI - Mesenchymal stem cells from human fat engineered to secrete BMP4 are nononcogenic, suppress brain cancer, and prolong survival. AB - PURPOSE: Glioblastoma is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes because of its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSC) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on glioblastoma and glioblastoma brain tumor-initiating cells (BTIC), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on glioblastoma. EXPERIMENTAL DESIGN: The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial coinjections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of glioblastoma cells as well as the differentiation of BTICs, and survival of glioblastoma-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial glioblastoma murine model. RESULTS: hAMSCs-BMP4 targeted both the glioblastoma tumor bulk and migratory glioblastoma cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of glioblastomas in vitro and in vivo. In addition, hAMSCs BMP4 significantly prolonged survival in a murine model of glioblastoma. We also demonstrate that the use of hAMSCs in vivo is safe. CONCLUSIONS: Both unmodified and engineered hAMSCs are nononcogenic and effective against glioblastoma, and hAMSCs-BMP4 are a promising cell-based treatment option for glioblastoma. PMID- 24789036 TI - TGR analysis in phase I clinical trials--response. PMID- 24789037 TI - Efficacy of vemurafenib in a trametinib-resistant stage IV melanoma patient- letter. PMID- 24789038 TI - The weak, fluctuating, dipole moment of membrane-bound hydrogenase from Aquifex aeolicus accounts for its adaptability to charged electrodes. AB - [NiFe] hydrogenases from Aquifex aeolicus (AaHase) and Desulfovibrio fructosovorans (DfHase) have been mainly studied to characterize physiological electron transfer processes, or to develop biotechnological devices such as biofuel cells. In this context, it remains difficult to control the orientation of AaHases on electrodes to achieve a fast interfacial electron transfer. Here, we study the electrostatic properties of these two proteins based on microsecond long molecular dynamics simulations that we compare to voltammetry experiments. Our calculations show weak values and large fluctuations of the dipole direction in AaHase compared to DfHase, enabling the AaHase to absorb on both negatively and positively charged electrodes, with an orientation distribution that induces a spread in electron transfer rates. Moreover, we discuss the role of the transmembrane helix of AaHase and show that it does not substantially impact the general features of the dipole moment. PMID- 24789040 TI - Cigarette smoking exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis: the Bogalusa Heart Study. AB - Age and metabolic syndrome are major risk factors for atherosclerosis. However, limited information is available regarding whether cigarette smoking, another major, modifiable risk factor, has synergistic effects with age and metabolic syndrome on subclinical atherosclerosis, particularly in young adults. This aspect was examined in 1,051 adults (747 whites and 304 blacks; aged 24-43 years) from the Bogalusa Heart Study. General linear models were used to examine the effects of cigarette smoking and its interactive effects with age and metabolic syndrome on carotid intima-media thickness (CIMT). After adjusting for age, race, and sex, current smokers had lower BMI (mean +/- SE: 27.4 +/- 0.4, 29.3 +/- 0.5, and 29.9 +/- 0.3 kg/m2 in current, former, and never smokers, respectively; p<0.0001) and lower levels of fasting glucose (82.8 +/- 0.9, 89.5 +/- 2.3, and 87.1 +/- 1.1 mg/dL, respectively; p = 0.001) and insulin (10.6 +/- 0.4, 14.2 +/- 1.0, 13.6 +/- 0. 6 uU/ml, respectively; p<0.0001). Despite being lean and having favorable levels of glucose and insulin, current smokers had greater CIMT (0.850 +/- 0.012, 0.808 +/- 0.011, and 0.801 +/- 0.006 mm, respectively; p = 0.0004). Importantly, cigarette smoking showed significant interactions with age and metabolic syndrome on CIMT: Age-related change in CIMT in current smokers was significantly greater (0.013 +/- 0.002 mm/year) than in nonsmokers (former and never smokers combined) (0.008 +/- 0.001 mm/year) (p for interaction = 0.005); the difference in CIMT between those with and without metabolic syndrome was significantly greater in current smokers (0.154 +/- 0.030 mm, p<0.0001) than in nonsmokers (0.031 +/- 0.014 mm, p = 0.03) (p for interaction<0.0001). In conclusion, cigarette smoking significantly exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis in young adults, which underscores the importance of prevention and cessation of cigarette smoking behavior in the young. PMID- 24789039 TI - Neandertal demise: an archaeological analysis of the modern human superiority complex. AB - Neandertals are the best-studied of all extinct hominins, with a rich fossil record sampling hundreds of individuals, roughly dating from between 350,000 and 40,000 years ago. Their distinct fossil remains have been retrieved from Portugal in the west to the Altai area in central Asia in the east and from below the waters of the North Sea in the north to a series of caves in Israel in the south. Having thrived in Eurasia for more than 300,000 years, Neandertals vanished from the record around 40,000 years ago, when modern humans entered Europe. Modern humans are usually seen as superior in a wide range of domains, including weaponry and subsistence strategies, which would have led to the demise of Neandertals. This systematic review of the archaeological records of Neandertals and their modern human contemporaries finds no support for such interpretations, as the Neandertal archaeological record is not different enough to explain the demise in terms of inferiority in archaeologically visible domains. Instead, current genetic data suggest that complex processes of interbreeding and assimilation may have been responsible for the disappearance of the specific Neandertal morphology from the fossil record. PMID- 24789041 TI - Comparison of the effects of air pollution on outpatient and inpatient visits for asthma: a population-based study in Taiwan. AB - BACKGROUND: A nationwide asthma survey on the effects of air pollution is lacking in Taiwan. The purpose of this study was to evaluate the time trend and the relationship between air pollution and health care services for asthma in Taiwan. METHODS: Health care services for asthma and ambient air pollution data were obtained from the National Health Insurance Research database and Environmental Protection Administration from 2000 through 2009, respectively. Health care services, including those related to the outpatient and inpatient visits were compared according to the concentration of air pollutants. RESULTS: The number of asthma-patient visits to health-care facilities continue to increase in Taiwan. Relative to the respective lowest quartile of air pollutants, the adjusted relative risks (RRs) of the outpatient visits in the highest quartile were 1.10 (P-trend = 0.013) for carbon monoxide (CO), 1.10 (P-trend = 0.015) for nitrogen dioxide (NO2), and 1.20 (P-trend <0.0001) for particulate matter with an aerodynamic diameter ? 10 um (PM10) in the child group (aged 0-18). For adults aged 19-44, the RRs of outpatient visits were 1.13 (P-trend = 0.078) for CO, 1.17 (P-trend = 0.002) for NO2, and 1.13 (P-trend <0.0001) for PM10. For adults aged 45-64, the RRs of outpatient visits were 1.15 (P-trend = 0.003) for CO, 1.19 (P trend = 0.0002) for NO2, and 1.10 (P-trend = 0.001) for PM10. For the elderly (aged >= 65), the RRs of outpatient visits in were 1.12 (P-trend = 0.003) for NO2 and 1.10 (P-trend = 0.006) for PM10. For inpatient visits, the RRs across quartiles of CO level were 1.00, 1.70, 1.92, and 1.86 (P-trend = 0.0001) in the child group. There were no significant linear associations between inpatient visits and air pollutants in other groups. CONCLUSIONS: There were positive associations between CO levels and childhood inpatient visits as well as NO2, CO and PM10 and outpatient visits. PMID- 24789042 TI - Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells. AB - Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3beta activation, while p38alpha phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors. PMID- 24789044 TI - Understanding nutrient biogeochemistry in agricultural catchments: the challenge of appropriate monitoring frequencies. AB - We evaluate different frequencies of riverine nutrient concentration measurement to interpret diffuse pollution in agricultural catchments. We focus on three nutrient fractions, nitrate-nitrogen (NO3-N), total reactive phosphorus (TRP) and total phosphorus (TP) observed using conventional remote laboratory-based, low frequency sampling and automated, in situ high-frequency monitoring. We demonstrate the value of low-frequency routine nutrient monitoring in providing long-term data on changes in surface water and groundwater nutrient concentrations. By contrast, automated high-frequency nutrient observations provide insight into the fine temporal structure of nutrient dynamics in response to a full spectrum of flow dynamics. We found good agreement between concurrent in situ and laboratory-based determinations for nitrate-nitrogen (Pearson's R = 0.93, p < 0.01). For phosphorus fractions: TP (R = 0.84, p < 0.01) and TRP (R = 0.79, p < 0.01) the relationships were poorer due to the underestimation of P fractions observed in situ and storage-related changes of grab samples. A detailed comparison between concurrent nutrient data obtained by the hourly in situ automated monitoring and weekly-to-fortnightly grab sampling reveals a significant information loss at the extreme range of nutrient concentration for low-frequency sampling. PMID- 24789043 TI - Induction of the CLOCK gene by E2-ERalpha signaling promotes the proliferation of breast cancer cells. AB - Growing genetic and epidemiological evidence suggests a direct connection between the disruption of circadian rhythm and breast cancer. Moreover, the expression of several molecular components constituting the circadian clock machinery has been found to be modulated by estrogen-estrogen receptor alpha (E2-ERalpha) signaling in ERalpha-positive breast cancer cells. In this study, we investigated the regulation of CLOCK expression by ERalpha and its roles in cell proliferation. Immunohistochemical analysis of human breast tumor samples revealed high expression of CLOCK in ERalpha-positive breast tumor samples. Subsequent experiments using ERalpha-positive human breast cancer cell lines showed that both protein and mRNA levels of CLOCK were up-regulated by E2 and ERalpha. In these cells, E2 promoted the binding of ERalpha to the EREs (estrogen-response elements) of CLOCK promoter, thereby up-regulating the transcription of CLOCK. Knockdown of CLOCK attenuated cell proliferation in ERalpha-positive breast cancer cells. Taken together, these results demonstrated that CLOCK could be an important gene that mediates cell proliferation in breast cancer cells. PMID- 24789045 TI - Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative. AB - Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10-25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients. So far, there is no targeted treatment for TNBC. To that end, here we show that c-Abl is one of several tyrosine kinases that phosphorylate and activate geminin's ability to promote TNBC. Analysis of >800 breast tumor samples showed that geminin is overexpressed in ~50% of all tumors. Although c-Abl is overexpressed in ~90% of all tumors, it is only nuclear in geminin overexpressing tumors. In geminin negative tumors, c-Abl is only cytoplasmic. Inhibiting c-Abl expression or activity (using imatinib or nilotinib) prevented geminin Y150 phosphorylation, inactivated the protein, and most importantly converted overexpressed geminin from an oncogene to an apoptosis inducer. In pre-clinical orthotopic breast tumor models, geminin-overexpressing cells developed aneuploid and invasive tumors, which were suppressed when c-Abl expression was blocked. Moreover, established geminin overexpressing orthotopic tumors regressed when treated with imatinib or nilotinib. Our studies support imatinib/nilotonib as a novel treatment option for patients with aggressive breast cancer (including a subset of TNBCs) overexpressing geminin and nuclear c-Abl. PMID- 24789046 TI - [Detection of lung nodules. New opportunities in chest radiography]. AB - BACKGROUND: Chest radiography still represents the most commonly performed X-ray examination because it is readily available, requires low radiation doses and is relatively inexpensive. However, as previously published, many initially undetected lung nodules are retrospectively visible in chest radiographs. STANDARD RADIOLOGICAL METHODS: The great improvements in detector technology with the increasing dose efficiency and improved contrast resolution provide a better image quality and reduced dose needs. METHODICAL INNOVATIONS: The dual energy acquisition technique and advanced image processing methods (e.g. digital bone subtraction and temporal subtraction) reduce the anatomical background noise by reduction of overlapping structures in chest radiography. Computer-aided detection (CAD) schemes increase the awareness of radiologists for suspicious areas. RESULTS: The advanced image processing methods show clear improvements for the detection of pulmonary lung nodules in chest radiography and strengthen the role of this method in comparison to 3D acquisition techniques, such as computed tomography (CT). ASSESSMENT: Many of these methods will probably be integrated into standard clinical treatment in the near future. Digital software solutions offer advantages as they can be easily incorporated into radiology departments and are often more affordable as compared to hardware solutions. PMID- 24789047 TI - [Management of subsolid pulmonary nodules]. AB - The finding of subsolid pulmonary nodules poses a frequent problem in the daily routine of the radiologist. The biological behavior of such subsolid lesions differs significantly from solid nodules. The risk of malignancy is significantly higher in subsolid nodules as compared to solid or purely ground glass opacities or nodules. The recommendations regarding the diagnostic management of subsolid nodules have been adapted according to the tendency of growth and the risk of malignancy. A benign etiology is also seen quite often in subsolid lesions and in this case they will show a reduction of size or disappear completely by the follow-up examination. Therefore, in many cases a short-term follow-up examination is primarily recommended. As the findings will often show no changes for a long period of time, further annual follow-up examinations over a longer, not yet specified period of time are recommended. Subsolid lesions that grow in size and/or show an increase in density or develop a solid part within a ground glass lesion should remain as suspected malignancies until proven otherwise. PMID- 24789048 TI - The role of mass media in adolescents' sexual behaviors: exploring the explanatory value of the three-step self-objectification process. AB - This longitudinal study (N = 730) explored whether the three-step process of self objectification (internalization of appearance ideals, valuing appearance over competence, and body surveillance) could explain the influence of sexual media messages on adolescents' sexual behaviors. A structural equation model showed that reading sexualizing magazines (Time 1) was related to the internalization of appearance ideals and valuing appearance over competence (Time 2). In turn, the internalization of appearance ideals was positively associated with body surveillance and valuing appearance over competence (all at Time 2). Valuing appearance over competence was also positively associated with body surveillance (all at Time 2). Lastly, body surveillance (Time 2) positively related to the initiation of French kissing (Time 3) whereas valuing appearance over competence (Time 2) positively related to the initiation of sexual intercourse (Time 3). No significant relationship was observed for intimate touching. The discussion focused on the explanatory role of self-objectification in media effects on adolescents' sexual behaviors. PMID- 24789049 TI - Sexual activity with romantic and nonromantic partners and psychosocial adjustment in young adults. AB - The present study examined whether positive or negative links occur between psychosocial adjustment and sexual activity with four types of partners-romantic partners, friends, acquaintances, and friends with benefits. We examined longitudinal associations and concurrent between-person and within-person associations. A representative sample of 185 participants (93 males, 92 females), their friends, and mothers completed questionnaires when the participants were 2.5, 4, and 5.5 years out of high school. Regardless of the type of partner, more frequent sexual activity relative to the sexual activity of other young adults was associated with more substance use and risky sexual behavior (i.e., between person effects). Similarly, for all types of nonromantic partners, more frequrent sexual activity relative to one's own typical sexual activity was associated with more substance use and risky sexual behavior (i.e., within-person effects). Differences in frequency of sexual activity with friends and acquaintances were associated with greater internalizing and externalizing symptoms as well as lower self-esteem. Follow-up analyses revealed the associations were particularly strong for friends with benefits. Women's sexual activity frequency with a nonromantic partner was more commonly associated with poorer psychosocial adjustment than such activity by men. More frequent sexual activity with a romantic partner was associated with higher self-esteem and lower internalizing symptoms. Few long-term effects were found for any type of sexual activity. The findings underscore the importance of examining relationship context and illustrate the value of using multiple analytic strategies for identifying the precise nature of associations. PMID- 24789050 TI - Marital infidelity and intimate partner violence in rural Malawi: a dyadic investigation. AB - Extramarital sexual partnerships are a common reason for intimate partner violence (IPV) in sub-Saharan Africa. Despite the fact that IPV requires an interaction between two partners, the majority of the research focuses on individuals rather than the broader relationship context where such violence takes place. Using a sample of 422 married couples from rural Malawi, this study examined the dyadic environment of marital infidelity and two types of IPV victimization: sexual coercion and physical abuse. We considered both self reported marital infidelity and perceived partner infidelity to assess how well partners knew each other and to compare their respective associations with IPV. Logistic regression was used to test for associations between self-reported marital infidelity and IPV. Multilevel logistic regression was used to examine actor and partner effects of perceived partner infidelity on an individual's and their partner's experience of IPV. The results show that self-reported marital infidelity was not significantly associated with IPV for men or women. However, the perception of a partner's infidelity was significantly associated with both an individual's and their partner's risk for sexual coercion and physical abuse. Contrary to the "sexual double standard" hypothesis, women were not significantly more likely than men to report being physically abused when their partners suspected infidelity. Future studies should continue to explore the relationship context of IPV in sub-Saharan Africa in order to understand how spouses mutually shape each other's experience of IPV and subsequent health outcomes. PMID- 24789051 TI - The design and synthesis of a hydrophilic core-shell-shell structured magnetic metal-organic framework as a novel immobilized metal ion affinity platform for phosphoproteome research. AB - In this work, polydopamine (PDA)-coated magnetic microspheres with surface modification of zirconium-based MOFs were synthesized for the first time. The as synthesized Fe3O4@PDA@Zr-MOF composites were successfully applied as a novel immobilized metal ion affinity platform for phosphoproteome research. PMID- 24789052 TI - Chitosan-coated gold nanorods for cancer therapy combining chemical and photothermal effects. AB - To develop a novel type of nanoparticle for cancer therapy, gold nanorods (GNRs) are coated with chitosan (CS) derivatives to combine chemical and photothermal effects. Thiol-modified chitosan derivatives chemically conjugated to doxorubicin (DOX) are successfully synthesized and their in vitro effect is evaluated. Functional nanocarriers (DOX-CS-GNR) with good biocompatibility and optical properties are prepared by conjugating chitosan derivatives to GNRs. Two types of structures with different molar ratios of chitosan derivatives and GNRs are successfully obtained. In in vitro studies, GNR-loaded nanoparticles show low cytotoxicity and high potential for anti-cancer effects. Under conditions of short exposure time and low light intensity, DOX-CS-GNR nanocarriers with a side by-side structure exhibit cytoxicity against tumor cells based on a combination of chemical and photothermal therapeutic effects. PMID- 24789054 TI - Infections, vaccinations, drugs and interactions. PMID- 24789053 TI - Application of drug-related problem (DRP) classification systems: a review of the literature. AB - BACKGROUND: For over 20 years, researchers wanting to record, discuss and compare drug-related problems (DRPs) have had the task of choosing between a multiplicity of classification systems offering a variable number of categories identified as causes of DRPs and DRPs. OBJECTIVE: To characterise studies which have reported DRPs through the use of a DRP classification system to determine types of classification systems chosen, factors influencing their choice, and methodological issues that may have affected their application. METHOD: A systematic search of MEDLINE, CINAHL, International Pharmaceutical Abstracts (Ovid), EMBASE and PubMed was performed. All English language studies reporting DRPs through the use of a classification system published between January 2000 and July 2013 were reviewed, with no limitation on the type of study. RESULTS: Of 2,774 articles screened, 268 met our inclusion criteria. We identified the use of 20 different types of DRP classification systems. Three quarters of studies modified an existing classification system or developed their own. Few studies stated reasons for choice of system. We identified issues such as variability in skills of data collectors, selective choice of patients and missing data, affecting application of classification systems and limiting quality, analysis and comparison of studies. CONCLUSION: There appeared to be no consensus on preference or structure of classification systems. Future studies should consider addressing or acknowledging the methodological issues identified. Through identification and discussion of these problems, recommendations for future studies and for practice have been made. PMID- 24789055 TI - Upregulation of KLF4 by methylseleninic acid in human esophageal squamous cell carcinoma cells: Modification of histone H3 acetylation through HAT/HDAC interplay. AB - Esophageal squamous cell carcinoma (ESCC) occurs at a very high frequency in certain areas of China. Supplementation with selenium-containing compounds was associated with a significantly lower cancer mortality rate in a study conducted in Linxia, China. Thus, selenium could be a potential anti-esophageal cancer agent. In this study, methylseleninic acid (MSA) could inhibit cell growth of ESCC cells in vitro and in vivo. Upon treated with MSA, the activity of histone deacetylases (HDACs) was decreased and general control nonrepressed protein 5 (GCN5) was upregulated in ESCC cells. Meanwhile, a significant increase of H3K9 acetylation (H3K9ac) was detected. Upregulation of Kruppel-like factor 4 (KLF4) was also observed after MSA treatment. Additionally, the acetylated histone H3 located more at KLF4 promoter region after MSA treatment, shown by chromatin immunoprecipitation (ChIP) assay. Moreover, knockdown of GCN5 decreased the protein level of both H3K9ac and KLF4, along with less cell growth inhibition. Taken all, our results indicated that MSA could inhibit ESCC cell growth, at least in part, by MSA-HDAC/GCN5-H3K9ac-KLF4 axis. To our best knowledge, this is the first report that MSA induced acetylation of histone H3 at Lys9, which might depend on the activities and the balance between HDACs and HATs. PMID- 24789056 TI - Structural findings of cinnolines as anti-schizophrenic PDE10A inhibitors through comparative chemometric modeling. AB - Schizophrenia is a complex psychiatric disorder associated with the distortion of striatopallidal neurotransmission of central nervous system. Phosphodiesterase10A (PDE10A) enzyme plays crucial role in cellular signaling pathways in schizophrenia. Inhibition of this enzyme may facilitate better treatment of this disease. 2D-QSAR, HQSAR, pharmacophore mapping, molecular docking, and 3D-QSAR analyses were performed on 81 cinnoline derivatives having PDE10A inhibitory activity. 2D-QSAR models were developed by multiple linear regression and partial least square analyses using both atom based and whole molecular descriptors. The best model, having considerable internal (q(2) = 0.812) and external (R(2)(pred) = 0.691) predictabilities, demonstrated importance of atom-based topological and whole molecular E-state as well as 3D topological indices. The best HQSAR model was also found to be statistically significant (q(2) = 0.664, R(2)(pred) = 0.513) and it highlighted some important structural features. PHASE-based pharmacophore hypothesis showed the importance of three hydrogen bond acceptor and one each of ring aromatic and hydrophobic features for higher activity. 3D-QSAR CoMFA and CoMSIA models were generated on two different types of alignment procedures-(1) pharmacophore (PHASE) based and (2) docking (GLIDE) based. GLIDE-based alignment produced better results for both CoMFA (Q(2) = 0.578; R(2)(pred) = 0.841) and CoMSIA (Q(2) = 0.610; R(2)(pred) = 0.824) methods. Molecular dynamics (MDs) simulations were performed for two ligand-receptor complexes and these simulations explored some crucial factors for higher activity. These findings of MD simulations were consistent with the interpretations obtained from other methods of analyses. The current study may help in designing new PDE10A inhibitors of this class. PMID- 24789060 TI - Tetramethylpyrazine promotes the proliferation and migration of brain endothelial cells. AB - The aim of the present study was to investigate the role of tetramethylpyrazine (TMP), one of the alkaloids isolated from the Chinese herb Chuanxiong, on the proliferation and migration of brain endothelial cells. A different dosage of TMP was employed to stimulate the mouse microvascular cell line bEnd.3 in vitro. TMP at lower concentrations (0.25 ng/ml), however not at high concentrations (100 ng/ml) could promote the proliferation and migration of endothelial cells, which was further enhanced if combined with soluble Fas ligand (sFasL). TMP alone, or combined with sFasL, increased the autocrine signaling of vascular endothelial growth factor (VEGF) by endothelial cells and TMP improved the expression of Fas on endothelial cells, which may explain the effect of the sFasL. These results provide insight into the underlying mechanisms of the effects of TMP on stroke and other vascular diseases. PMID- 24789057 TI - Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. AB - The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25-800 mg), 10 male volunteers received DMAU and two received placebo at two academic medical centres. DMAU was administered both fasting and after a high-fat meal (200-800 mg doses). Serial serum samples were collected over 24 h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800 mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200 mg DMAU and showed a dose incremental increase up to 800 mg, with peak levels 4-8 h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12 h after DMAU administration with food at doses above 200 mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high fat meal markedly improved DMAU/DMA pharmacokinetics. PMID- 24789061 TI - Horizontal VOR function shows frequency dynamics in vestibular schwannoma. AB - The objective of this retrospective study was to investigate the horizontal vestibulo-ocular reflex (hVOR) pathway with caloric test (low-frequency hVOR) and video head impulse test (vHIT) (high-frequency hVOR) in patients with sporadic vestibular schwannoma (69 patients, 27-86 years, mean age 58.1 years) and to compare both test methods in terms of their sensitivity and specificity to detect a retrocochlear lesion. Test results with a unilateral weakness (UWCaloric) >25 % (caloric test) or a Mean-GainvHIT <0.79/asymmetry ratio of Gain (AR-GainvHIT) >8.5 % and accompanied refixation saccades (vHIT) were considered abnormal. The overall sensitivity of the caloric test was 72 %. The evaluation of AR-GainvHIT detected more abnormal cases than did Mean-GainvHIT (44 vs. 36 %). In up to 4 %, a normal caloric test result was related to an abnormal vHIT. There was only a moderate correlation of UWCaloric and AR-GainvHIT (r = 0.54, p < 0.05) with a linear regression line intercept/slope of 32.2/0.9 (p < 0.05). Receiver operating characteristics curve analysis exhibited at a UWCaloric of 50 % a vHIT sensitivity/specificity/positive predictive value/negative predictive value of 0.45/0.9/0.94/0.42. Vestibular testing at varying frequencies provides deeper insights into hVOR function and is helpful in detecting a cerebello-pontine lesion. Whereas caloric test yields a high sensitivity for nerve dysfunction, vHIT test reveals a remaining function of hVOR in the high-frequency range. PMID- 24789062 TI - Treatment expectations and quality of life outcomes of patients with laryngeal cancer based on different treatment methods. AB - The treatment expectations of patients with laryngeal carcinoma and their quality of life after treatment were evaluated. We enrolled patients who were receiving treatment for epidermoid carcinoma of the larynx between January 2011 and January 2012. Their expectations from the treatment were evaluated using the visual analog scale (VAS) prior to and at the end of the treatment. Quality of life was assessed using the EORTC QLQ C 30 and EORTC H&N 35 questionnaires 3 months after completion of the treatment. In addition, the Beck Depression Inventory was used for mood assessment of the patients after treatment. As per the VAS scores pre treatment, no differences were found between treatment expectations of early and advanced-stage tumors groups in pre-treatment expectations, but post-treatment evaluation statistically found difference between two groups in terms of average VAS score. Emotional, cognitive, and social functions of the EORTC QLQ C 30 questionnaire were the most affected items in the advanced-stage tumor group. Sense and speech problems in the symptom scales of the EORTC H&N 35 questionnaire were found to be significantly higher in patients with advanced-stage tumors than in those with early stage tumors. The present study is the first to assess the treatment expectations of patients with laryngeal carcinoma by using the VAS. Although the treatment expectations of the patients with early and advanced-stage tumors did not differ according to VAS scores in pre-treatment evaluation, early stage groups had better score than advanced-stage group. VAS was an easy and a simple applicable method for evaluating treatment expectations. PMID- 24789063 TI - Interventions for improving modifiable risk factor control in the secondary prevention of stroke. AB - BACKGROUND: People with stroke or transient ischaemic attack (TIA) are at increased risk of future stroke and other cardiovascular events. Evidence-based strategies for secondary stroke prevention have been established. However, the implementation of prevention strategies could be improved. OBJECTIVES: To assess the effects of stroke service interventions for implementing secondary stroke prevention strategies on modifiable risk factor control, including patient adherence to prescribed medications, and the occurrence of secondary cardiovascular events. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (April 2013), the Cochrane Effective Practice and Organisation of Care Group Trials Register (April 2013), CENTRAL (The Cochrane Library 2013, issue 3), MEDLINE (1950 to April 2013), EMBASE (1981 to April 2013) and 10 additional databases. We located further studies by searching reference lists of articles and contacting authors of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated the effects of organisational or educational and behavioural interventions (compared with usual care) on modifiable risk factor control for secondary stroke prevention. DATA COLLECTION AND ANALYSIS: Two review authors selected studies for inclusion and independently extracted data. One review author assessed the risk of bias for the included studies. We sought missing data from trialists. MAIN RESULTS: This review included 26 studies involving 8021 participants. Overall the studies were of reasonable quality, but one study was considered at high risk of bias. Fifteen studies evaluated predominantly organisational interventions and 11 studies evaluated educational and behavioural interventions for patients. Results were pooled where appropriate, although some clinical and methodological heterogeneity was present. The estimated effects of organisational interventions were compatible with improvements and no differences in the modifiable risk factors mean systolic blood pressure (mean difference (MD) -2.57 mmHg; 95% confidence interval (CI) -5.46 to 0.31), mean diastolic blood pressure (MD -0.90 mmHg; 95% CI -2.49 to 0.68), blood pressure target achievement (OR 1.24; 95% CI 0.94 to 1.64) and mean body mass index (MD -0.68 kg/m(2); 95% CI -1.46 to 0.11). There were no significant effects of organisational interventions on lipid profile, HbA1c, medication adherence or recurrent cardiovascular events. Educational and behavioural interventions were not generally associated with clear differences in any of the review outcomes, with only two exceptions. AUTHORS' CONCLUSIONS: Pooled results indicated that educational interventions were not associated with clear differences in any of the review outcomes. The estimated effects of organisational interventions were compatible with improvements and no differences in several modifiable risk factors. We identified a large number of ongoing studies, suggesting that research in this area is increasing. The use of standardised outcome measures would facilitate the synthesis of future research findings. PMID- 24789064 TI - Autoantibodies and disease activity in patients with discoid lupus erythematosus. PMID- 24789065 TI - Wearable solar cells by stacking textile electrodes. AB - A new and general method to produce flexible, wearable dye-sensitized solar cell (DSC) textiles by the stacking of two textile electrodes has been developed. A metal-textile electrode that was made from micrometer-sized metal wires was used as a working electrode, while the textile counter electrode was woven from highly aligned carbon nanotube fibers with high mechanical strengths and electrical conductivities. The resulting DSC textile exhibited a high energy conversion efficiency that was well maintained under bending. Compared with the woven DSC textiles that are based on wire-shaped devices, this stacked DSC textile unexpectedly exhibited a unique deformation from a rectangle to a parallelogram, which is highly desired in portable electronics. This lightweight and wearable stacked DSC textile is superior to conventional planar DSCs because the energy conversion efficiency of the stacked DSC textile was independent of the angle of incident light. PMID- 24789066 TI - Time course transcriptome changes in Shewanella algae in response to salt stress. AB - Shewanella algae, which produces tetrodotoxin and exists in various seafoods, can cause human diseases, such as spondylodiscitis and bloody diarrhea. In the present study, we focused on the temporal, dynamic process in salt-stressed S. algae by monitoring the gene transcript levels at different time points after high salt exposure. Transcript changes in amino acid metabolism, carbohydrate metabolism, energy metabolism, membrane transport, regulatory functions, and cellular signaling were found to be important for the high salt response in S. algae. The most common strategies used by bacteria to survive and grow in high salt environments, such as Na+ efflux, K+ uptake, glutamate transport and biosynthesis, and the accumulation of compatible solutes, were also observed in S. algae. In particular, genes involved in peptidoglycan biosynthesis and DNA repair were highly and steadily up-regulated, accompanied by rapid and instantaneous enhancement of the transcription of large- and small-ribosome subunits, which suggested that the structural changes in the cell wall and some stressful responses occurred in S. algae. Furthermore, the transcription of genes involved in the tricarboxylic acid (TCA) cycle and the glycolytic pathway was decreased, whereas the transcription of genes involved in anaerobic respiration was increased. These results, demonstrating the multi-pathway reactions of S. algae in response to salt stress, increase our understanding of the microbial stress response mechanisms. PMID- 24789067 TI - Wise regulates bone deposition through genetic interactions with Lrp5. AB - In this study using genetic approaches in mouse we demonstrate that the secreted protein Wise plays essential roles in regulating early bone formation through its ability to modulate Wnt signaling via interactions with the Lrp5 co-receptor. In Wise-/- mutant mice we find an increase in the rate of osteoblast proliferation and a transient increase in bone mineral density. This change in proliferation is dependent upon Lrp5, as Wise;Lrp5 double mutants have normal bone mass. This suggests that Wise serves as a negative modulator of Wnt signaling in active osteoblasts. Wise and the closely related protein Sclerostin (Sost) are expressed in osteoblast cells during temporally distinct early and late phases in a manner consistent with the temporal onset of their respective increased bone density phenotypes. These data suggest that Wise and Sost may have common roles in regulating bone development through their ability to control the balance of Wnt signaling. We find that Wise is also required to potentiate proliferation in chondrocytes, serving as a potential positive modulator of Wnt activity. Our analyses demonstrate that Wise plays a key role in processes that control the number of osteoblasts and chondrocytes during bone homeostasis and provide important insight into mechanisms regulating the Wnt pathway during skeletal development. PMID- 24789068 TI - Rupture signs on computed tomography, treatment, and outcome of abdominal aortic aneurysms. AB - OBJECTIVES: Abdominal aortic aneurysm (AAA) rupture has a high mortality rate. Although the diagnosis of a ruptured AAA is usually straightforward, detection of impending rupture signs can be more challenging. Early diagnosis of impending AAA rupture can be lifesaving. Furthermore, differentiating between impending and complete rupture has important repercussions on patient management and prognosis. The purpose of this article is to classify and illustrate the entire spectrum of AAA rupture signs and to review current treatment options for ruptured AAAs. METHODS: Using medical illustrations supplemented with computed tomography (CT), this essay showcases the various signs of impending rupture and ruptured AAAs. Endovascular aneurysm repair (EVAR) and open surgical repair are also discussed as treatment options for ruptured AAAs. RESULTS: CT imaging findings of ruptured AAAs can be categorised according to location: intramural, luminal, and extraluminal. Intramural signs generally indicate impending AAA rupture, whereas luminal and extraluminal signs imply complete rupture. EVAR has emerged as an alternative and possibly less morbid method to treat ruptured AAAs. CONCLUSIONS: AAA rupture occurs at the end of a continuum of growth and wall weakening. This review describes the CT imaging findings that may help identify impending rupture prior to complete rupture. TEACHING POINTS: * AAA rupture occurs at the end of a continuum of growth and wall weakening. * Intramural imaging findings indicate impending AAA rupture. * Luminal and extraluminal imaging findings imply complete AAA rupture. * Some imaging findings are not specific to AAA ruptures and can be seen in other pathologies. * EVAR has emerged as an alternative and possibly less morbid method of treating ruptured AAAs. PMID- 24789069 TI - Purification and characterization of beta-glucosidase from greater wax moth Galleria mellonella L. (Lepidoptera: Pyralidae). AB - The greater wax moth, Galleria mellonella, is one of the most ruinous pests of honeycomb in the world. Beta-glucosidases are a type of digestive enzymes that hydrolytically catalyzes the beta-glycosidic linkage of glycosides. Characterization of the beta-glucosidase in G. mellonella could be a significant stage for a better comprehending of its role and establishing a safe and effective control procedure primarily against G. mellonella and also some other insect pests. Laboratory reared final instar stage larvae were randomly selected and homogenized for beta-glucosidase activity assay and subsequent analysis. The enzyme was purified to apparent homogeneity by salting out with ammonium sulfate and using sepharose-4B-l-tyrosine-1-naphthylamine hydrophobic interaction chromatography. The purification was 58-fold with an overall enzyme yield of 29%. The molecular mass of the protein was estimated as ca. 42 kDa. The purified beta glucosidase was effectively active on para/ortho-nitrophenyl-beta-d glucopyranosides (p-/o-NPG) with Km values of 0.37 and 1.9 mM and Vmax values of 625 and 189 U/mg, respectively. It also exhibits different levels of activity against para-nitrophenyl-beta-d-fucopyranoside (p-NPF), para/ortho-nitrophenyl beta-d-galactopyranosides (p-/o-NPGal) and p-nitrophenyl 1-thio-beta-d glucopyranoside. The enzyme was competitively inhibited by beta-gluconolactone and also was very tolerant to glucose against p-NPG as substrate. The Ki and IC50 values of delta-gluconolactone were determined as 0.021 and 0.08 mM while the enzyme was more tolerant to glucose inhibition with IC50 value of 213.13 mM for p NPG. PMID- 24789071 TI - Diabetic peripheral neuropathy in ambulatory patients with type 2 diabetes in a general hospital in a middle income country: a cross-sectional study. AB - AIM: We aimed to estimate the morbidity rate and associated factors for diabetic peripheral neuropathy (DPN) in a low-middle income country setting. METHODS: Cross-sectional study, data was gathered at Peru's Ministry of Health national specialized hospital for endocrinological conditions through standardized interviews, anthropometric measurements and blood tests for glycated haemoglobin (HbA1c). DPN was evaluated using two techniques: the Semmes-Weinstein monofilament test and the diabetic neuropathy symptom score. Overall prevalence and 95% confidence intervals (95% CI) were calculated. Potential factors related to DPN explored included body mass index, years with disease (<10 vs. >=10 years), glycaemic control (HbA1c <7% vs. >=7%), microalbuminuria, retinopathy, and current pharmacological treatment. Multivariable analysis was performed using Poisson analysis to calculate prevalence ratios. RESULTS: DPN was observed in 73/129 (56.6%) patients. In multivariable analysis adjusted by age and sex, the prevalence ratio of neuropathy was 1.4 times higher (95% CI 1.07-1.88) in patients who took insulin plus metformin compared to patients who used one treatment alone, and 1.4 higher (95% CI 1.02-1.93) in patients with >=10 years of disease compared to those with a shorter duration of disease. Also we found some characteristics in foot evaluation associated to neuropathy such as deformities (p<0.001), onychomycosis (p = 0.012), abnormal Achilles reflex (p<0.001), pain perception (p<0.001) and vibration perception (p<0.001). CONCLUSION: DPN is highly frequent among patients with diabetes in a national specialized facility from Peru. Associated factors to DPN included being a diabetic patient for over ten years, and receiving insulin plus metformin. PMID- 24789072 TI - A gateway for phylogenetic analysis powered by grid computing featuring GARLI 2.0. AB - We introduce molecularevolution.org, a publicly available gateway for high throughput, maximum-likelihood phylogenetic analysis powered by grid computing. The gateway features a garli 2.0 web service that enables a user to quickly and easily submit thousands of maximum likelihood tree searches or bootstrap searches that are executed in parallel on distributed computing resources. The garli web service allows one to easily specify partitioned substitution models using a graphical interface, and it performs sophisticated post-processing of phylogenetic results. Although the garli web service has been used by the research community for over three years, here we formally announce the availability of the service, describe its capabilities, highlight new features and recent improvements, and provide details about how the grid system efficiently delivers high-quality phylogenetic results. PMID- 24789073 TI - A generalized K statistic for estimating phylogenetic signal from shape and other high-dimensional multivariate data. AB - Phylogenetic signal is the tendency for closely related species to display similar trait values due to their common ancestry. Several methods have been developed for quantifying phylogenetic signal in univariate traits and for sets of traits treated simultaneously, and the statistical properties of these approaches have been extensively studied. However, methods for assessing phylogenetic signal in high-dimensional multivariate traits like shape are less well developed, and their statistical performance is not well characterized. In this article, I describe a generalization of the K statistic of Blomberg et al. that is useful for quantifying and evaluating phylogenetic signal in highly dimensional multivariate data. The method (K(mult)) is found from the equivalency between statistical methods based on covariance matrices and those based on distance matrices. Using computer simulations based on Brownian motion, I demonstrate that the expected value of K(mult) remains at 1.0 as trait variation among species is increased or decreased, and as the number of trait dimensions is increased. By contrast, estimates of phylogenetic signal found with a squared change parsimony procedure for multivariate data change with increasing trait variation among species and with increasing numbers of trait dimensions, confounding biological interpretations. I also evaluate the statistical performance of hypothesis testing procedures based on K(mult) and find that the method displays appropriate Type I error and high statistical power for detecting phylogenetic signal in high-dimensional data. Statistical properties of K(mult) were consistent for simulations using bifurcating and random phylogenies, for simulations using different numbers of species, for simulations that varied the number of trait dimensions, and for different underlying models of trait covariance structure. Overall these findings demonstrate that K(mult) provides a useful means of evaluating phylogenetic signal in high-dimensional multivariate traits. Finally, I illustrate the utility of the new approach by evaluating the strength of phylogenetic signal for head shape in a lineage of Plethodon salamanders. PMID- 24789074 TI - High-quality NMR structure of human anti-apoptotic protein domain Mcl-1(171-327) for cancer drug design. AB - A high-quality NMR solution structure is presented for protein hMcl-1(171-327) which comprises residues 171-327 of the human anti-apoptotic protein Mcl-1 (hMcl 1). Since this construct contains the three Bcl-2 homology (BH) sequence motifs which participate in forming a binding site for inhibitors of hMcl-1, it is deemed to be crucial for structure-based design of novel anti-cancer drugs blocking the Mcl1 related anti-apoptotic pathway. While the coordinates of an NMR solution structure for a corresponding construct of the mouse homologue (mMcl-1) are publicly available, our structure is the first atomic resolution structure reported for the 'apo form' of the human protein. Comparison of the two structures reveals that hMcl-1(171-327) exhibits a somewhat wider ligand/inhibitor binding groove as well as a different charge distribution within the BH3 binding groove. These findings strongly suggest that the availability of the human structure is of critical importance to support future design of cancer drugs. PMID- 24789075 TI - Cancer incidence and survival among adolescents and young adults in Korea. AB - BACKGROUND: In Korea, cancer is the third leading cause of death among adolescents and young adults (AYAs). However, cancer incidence and survival trends among AYAs (15-29 years) have never been studied in Korea. Therefore, this study aimed to investigate the incidence and relative survival rates and their trends among AYAs in Korea. MATERIALS AND METHODS: Cancer incidence data from 1999-2010 were obtained from the Korea Central Cancer Registry (KCCR). Each cancer was classified into subgroups according to the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) AYA site recode. Percent distributions, age-specific incidence rates, age-standardized incidence rates per million, and annual percent changes (APCs) were calculated for AYAs according to sex. Five-year relative survival rates were estimated for cases diagnosed between 1993 and 2010 and followed up to 2011. RESULTS: The age-standardized incidence rates of all cancers combined were 196.4 and 367.8 per million for males and females, respectively (male-to-female (M/F) ratio: 0.5). The age-standardized incidence rates increased from 208.7 per million in 1999 to 396.4 per million in 2010, and the APC was 6.3% (P<0.001). The five most common cancers among AYAs were thyroid carcinoma, non-Hodgkin lymphoma, stomach carcinoma, breast carcinoma, and acute myeloid leukemia. In males, the 5-year relative survival rate improved, from 46.5% in 1993-1995 to 75.9% in 2006-2010. In females, the 5 year relative survival rate also improved, from 66.7% in 1993-1995 to 89.1% in 2006-2010. CONCLUSIONS: Our study showed increases in cancer incidence and improvements in the 5-year relative survival rate among Korean AYAs. This study also provides additional data regarding temporal and geographic trends in cancer that may enhance future efforts to identify factors affecting cancer incidence and responses to treatment among AYAs. PMID- 24789076 TI - Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: a meta analysis. AB - PURPOSE: Serotonergic antidepressants (SADs) are one of the most widely prescribed group of drugs. Of late, the use of SADs is being associated with an increased risk of perioperative bleeding. However, the results are inconsistent. The present analysis was planned to evaluate the association between preoperative SADs use and the risk of bleeding/mortality in patients undergoing surgery. METHODS: Studies that had reported the effects of preoperative SADs use on the perioperative bleeding outcomes and/or mortality in adult patients undergoing surgical interventions were identified and evaluated for inclusion in the analysis. Outcomes evaluated were reoperation for bleeding event, requirement of blood/RBC transfusion and mortality. A meta-analysis was conducted, and a pooled estimate of odds ratio (OR) was calculated using the inverse variance method. RESULTS: Eight cohort studies, comprising a total of 79 976 SADs users and 485 336 non-antidepressant users were included in the final analysis. SADs use was not associated with increased risk of requirement of reoperation for bleeding event [OR = 1.48 (0.84-2.62)]. However, there was an increased requirement of transfusion [OR = 1.19(1.09-1.30)], which was not observed in the subgroup of patients undergoing coronary artery bypass graft (CABG) [OR = 1.06(0.90-1.24)]. SADs use was associated with a substantial increase in mortality [OR = 1.53 (1.15 2.04)] in patients undergoing CABG but not in the overall population [OR = 1.1 (0.99-1.22)]. CONCLUSIONS: Preoperative SADs use is associated with increased bleeding risk with respect to requirement of transfusion; nevertheless, the results should not be generalized to all surgical groups. The divergence between bleeding risk and mortality in CABG surgery patients needs further evaluation. PMID- 24789077 TI - Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A. AB - Chondrosarcoma is a malignant cartilage-forming cancer composed of cells derived from transformed cells that produce cartilage. Conventional chemotherapy and radiotherapy have very limited efficacy in patients with advanced chondrosarcoma. In the present study, we reported a novel therapeutic approach in the treatment of chondrosarcoma cells. We detected that lactate dehydrogenase-A (LDHA) is highly active in chondrosarcoma cells and chondrosarcoma patient samples compared with normal chondrocyte cell lines and primary human chondrocyte. Moreover, chondrosarcoma cells exhibited elevated levels of LDHA expression under doxorubicin treatment. To further explore the mechanisms, we generated doxorubicin-resistant cells from SW1353 chondrosarcoma cell line. Notably, the activity and expression of LDHA are upregulated in doxorubicin-resistant cells. Moreover, our data showed a strong correlation between glucose metabolism and doxorubicin resistance in chondrosarcoma cells; doxorubicin-resistant cells displayed highly activated glucose metabolism and depended more on glucose supply. Finally, we reported a synergistic effect produced by incorporating doxorubicin with glycolysis inhibitors-oxamate in the combined treatment of chondrosarcoma cells in vitro and in vivo. In summary, the present study may aid in the development of new approaches using the combination of chemotherapeutic agents for the treatment of chondrosarcoma patients. PMID- 24789078 TI - Asymmetric synthesis of tetrahydroquinolines through a [3+2] cycloaddition controlled by dienamine catalysis. AB - A dienamine-mediated enantioselective 1,3-dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C-1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities. PMID- 24789079 TI - Clinical and epidemiological characteristics of infectious keratitis in Paraguay. AB - To describe the clinical and epidemiological characteristics of patients with severe infectious keratitis in Asuncion, Paraguay between April 2009 and September 2011. All patients with the clinical diagnosis of severe keratitis (ulcer >=2 mm in size and/or central location) were included. Empiric treatment consisted of topical antibiotics and antimycotics; in cases of advanced keratitis, fortified antibiotics were used. After microbiological analysis, treatment was changed if indicated. In total 48 patients (62.5 % males, 25 % farmers) were included in the analysis. A central ulcer was found in 81.3 % (n = 39). The median delay between onset of symptoms and time of first presentation at our institution was 7 days (range 1-30 days). Fungal keratitis was diagnosed in 64.5 % (n = 31) of patients, of which Fusarium sp. (n = 17) was the most common. Twenty-one patients (43.8 %) reported previous trauma to the eye. The globe could be preserved in all cases. While topical therapy only was sufficient in most patients, a conjunctival flap was necessary in six patients suffering from fungal keratitis. The high rate of fungal keratitis in this series is remarkable, and microbiological analysis provided valuable information for the appropriate treatment. In this setting, one has to be highly suspicious of fungal causes of infectious keratitis. PMID- 24789080 TI - Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs. AB - Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (DeltaYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression. PMID- 24789081 TI - Finasteride treatment alters tissue specific androgen receptor expression in prostate tissues. AB - BACKGROUND: Normal and pathologic growth of the prostate is dependent on the synthesis of dihydrotestosterone (DHT) from testosterone by 5alpha-reductase. Finasteride is a selective inhibitor of 5alpha-reductase 2, one isozyme of 5alpha reductase found in abundance in the human prostate. The objective of this study was to investigate the effects of finasteride on androgen receptor expression and tissue morphology in human benign prostatic hyperplasia specimens. METHODS: Patients undergoing transurethral resection of the prostate and either treated or not treated with finasteride between 2004 and 2010 at the University of Wisconsin Hospital were retrospectively identified using an institutional database. Prostate specimens from each patient were triple-stained for androgen receptor, prostate-specific antigen, and basal marker cytokeratin 5. Morphometric analysis was performed using the multispectral imaging, and results were compared between groups of finasteride treated and non-treated patients. RESULTS: Epithelial androgen receptor but not stromal androgen receptor expression was significantly lower in patients treated with finasteride than in non-treated patients. Androgen receptor-regulated prostate-specific antigen was not significantly decreased in finasteride-treated patients. Significant luminal epithelial atrophy and basal cell hyperplasia were prevalent in finasteride treated patients. Epithelial androgen receptor expression was highly correlated to the level of luminal epithelial atrophy. CONCLUSIONS: In this study, finasteride decreased the expression of epithelial androgen receptor in a tissue specific manner. The correlation between epithelial androgen receptor and the extent of luminal epithelial atrophy suggests that epithelial androgen receptor may be directly regulating the atrophic effects observed with finasteride treatment. PMID- 24789082 TI - Distinct risk profiles for human infections with the Influenza A(H7N9) virus among rural and urban residents: Zhejiang Province, China, 2013. AB - OBJECTIVE: To identify the risk factors and source of infection leading to human infections with the Influenza A(H7N9) virus in urban and rural areas. METHODS: We conducted a case-control investigation to identify potential exposures and risk factors. Controls were randomly selected from the same community as the cases using random digit dialing. We used exact conditional logistic regression to evaluate the exposures and risk factors, stratified by urban and rural residence. RESULTS: Buying live or freshly slaughtered poultry from a market was significantly associated with illness onset among both urban [48% of 25 case patients and 12% of 125 control-persons, adjusted odds ratio (AOR) = 19, 95% CI: 2.3-929] and rural (33% of 18 case-patients and 8.9% of 90 control-persons, AOR = 13, 95% CI:1.5-infinity) residents. In rural area, tending to home-raised poultry (56% of 18 case-patients and 10% of 90 control-persons, AOR = 57, 95% CI: 7.5 infinity) and existence of a poultry farm in the vicinity of the residence (28% of 18 case-patients and 5.6% of 90 control-persons, AOR = 37, 95% CI: 3.8 infinity) were also significantly associated with disease onset. Presence of underlying medical conditions was a significant risk factor for urban residents (76% of 25 case-patients and 13% of 125 control-persons, AOR = 49, 95% CI: 7.1 2132). CONCLUSIONS: Buying live or freshly slaughtered poultry from a market is a risk factor for both urban and rural residents, tending to home-raised poultry and existence of a poultry farm in the vicinity of the residence are risk factors unique for rural residents. The virus might have been in stealth circulation in the poultry population before infecting humans. We recommend strict poultry market management and multisectoral collaboration to identify the extent of poultry infection in China. PMID- 24789083 TI - Pressurized CEC coupled with QTOF-MS for urinary metabolomics. AB - Pressurized CEC (pCEC) coupled with ESI-QTOF-MS using a sheathless interface was applied for metabolomics to develop an alternative analytical method for metabolic profiling of complex biofluid samples such as urine. The hyphenated system was investigated with mixed standards and pooled urine samples to evaluate its precision, repeatability, linearity, sensitivity, and selectivity. The applied voltage, mobile phase, and gradient elution were optimized and applied for the analysis of urinary metabolites. Multivariate data analysis was subsequently performed and used to distinguish lung cancer patients from healthy controls successfully. High separation efficiency has been achieved in pCEC due to the EOF. For metabolite identification, the pCEC-MS separation mechnism was helpful for discriminating the fragment ions of glutamine conjugates from co eluted metabolites. Three glutamine conjugates, including phenylacetylglutamine, acylglutamine C8:1, and acylglutamine C6:1 were identified among 16 differential urinary metabolites of lung cancer. Receiver-operating-characteristic analysis of acylglutamine C8:1 resulted in an area-under-curve value of 0.882. Overall, this work suggests that this pCEC-ESI-QTOF-MS method may provide a novel and useful platform for metabolomic studies due to its superior separation and identification. PMID- 24789084 TI - Configurable three-dimensional boron nitride-carbon architecture and its tunable electronic behavior with stable thermal performances. AB - Recent developments of 3D-graphene and 3D-boron-nitride have become of great interest owing to their potential for ultra-light flexible electronics. Here we demonstrate the first synthesis of novel 3D-BNC hybrids. By specifically controlling the compositions of C and BN, new fascinating properties are observed, such as highly tunable electrical conductivity, controllable EMI shielding properties, and stable thermal conductivity. This ultra-light hybrid opens up many new applications such as for electronic packaging and thermal interface materials (TIMs). PMID- 24789085 TI - Biodosimetry estimation using the ratio of the longest:shortest length in the premature chromosome condensation (PCC) method applying autocapture and automatic image analysis. AB - The combination of automatic image acquisition and automatic image analysis of premature chromosome condensation (PCC) spreads was tested as a rapid biodosimeter protocol. Human peripheral lymphocytes were irradiated with (60)Co gamma rays in a single dose of between 1 and 20 Gy, stimulated with phytohaemaglutinin and incubated for 48 h, division blocked with Colcemid, and PCC-induced by Calyculin A. Images of chromosome spreads were captured and analysed automatically by combining the Metafer 4 and CellProfiler platforms. Automatic measurement of chromosome lengths allows the calculation of the length ratio (LR) of the longest and the shortest piece that can be used for dose estimation since this ratio is correlated with ionizing radiation dose. The LR of the longest and the shortest chromosome pieces showed the best goodness-of-fit to a linear model in the dose interval tested. The application of the automatic analysis increases the potential use of the PCC method for triage in the event of massive radiation causalities. PMID- 24789086 TI - Acetylsalicylic acid (ASA) increases the solubility of cholesterol when incorporated in lipid membranes. AB - Cholesterol has been well established as a mediator of cell membrane fluidity. By interacting with lipid tails, cholesterol causes the membrane tails to be constrained thereby reducing membrane fluidity, well known as the condensation effect. Acetylsalicylic acid (ASA), the main ingredient in aspirin, has recently been shown to increase fluidity in lipid bilayers by primarily interacting with lipid head groups. We used high-resolution X-ray diffraction to study both ASA and cholesterol coexisting in model membranes of dimyristoylphosphatidylcholine (DMPC). While a high cholesterol concentration of 40 mol% cholesterol leads to the formation of immiscible cholesterol bilayers, as was reported previously, increasing the amount of ASA in the membranes between 0 to 12.5 mol% was found to significantly increase the fluidity of the bilayers and dissolve the cholesterol plaques. We, therefore, present experimental evidence for an interaction between cholesterol and ASA on the level of the cell membrane at elevated levels of cholesterol and ASA. PMID- 24789088 TI - Dark Brownish Cutaneous Mass in the Cavum Concha. PMID- 24789087 TI - Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help. AB - X linked lymphoproliferative disease (XLP) is an inherited immunodeficiency resulting from mutations in the gene encoding the slam associated protein (SAP). One of the defining characteristics of XLP is extreme susceptibility to infection with Epstein-Barr virus (EBV), a gammaherpesvirus belonging to the genus Lymphocryptovirus, often resulting in fatal infectious mononucleosis (FIM). However, infection of SAP deficient mice with the related Murine gammaherpesvirus 68 (MHV68), a gammaherpesvirus in the genus Rhadinovirus, does not recapitulate XLP. Here we show that MHV68 inefficiently establishes latency in B cells in SAP deficient mice due to insufficient CD4 T cell help during the germinal center response. Although MHV68 infected B cells can be found in SAP-deficient mice, significantly fewer of these cells had a germinal center phenotype compared to SAP-sufficient mice. Furthermore, we show that infected germinal center B cells in SAP-deficient mice fail to proliferate. This failure to proliferate resulted in significantly lower viral loads, and likely accounts for the inability of MHV68 to induce a FIM-like syndrome. Finally, inhibiting differentiation of T follicular helper (TFH) cells in SAP-sufficient C57Bl/6 mice resulted in decreased B cell latency, and the magnitude of the TFH response directly correlated with the level of infection in B cells. This requirement for CD4 T cell help during the germinal center reaction by MHV68 is in contrast with EBV, which is thought to be capable of bypassing this requirement by expressing viral proteins that mimic signals provided by TFH cells. In conclusion, the outcome of MHV68 infection in mice in the setting of loss of SAP function is distinct from that observed in SAP-deficient patients infected with EBV, and may identify a fundamental difference between the strategies employed by the rhadinoviruses and lymphocryptoviruses to expand B cell latency during the early phase of infection. PMID- 24789089 TI - Anti-inflammatory effects of triptolide by inhibiting the NF-kappaB signalling pathway in LPS-induced acute lung injury in a murine model. AB - Triptolide is one of the main active components in the Chinese herb Tripterygium wilfordii Hook F, which has been demonstrated to possess anti-inflammatory properties. The aim of this study was to investigate the effects of triptolide on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to explore the possible mechanisms. Mice were administered LPS intranasally to induce lung injury, and triptolide was administered intraperitoneally 1 h prior to the LPS challenge. Triptolide-treated mice exhibited significantly reduced levels of leukocytes, myeloperoxidase activity and edema of the lung, as well as tumour necrosis factor-alpha, interleukin (IL)-1beta and IL-6 production in the bronchoalveolar lavage fluid compared with LPS-treated mice. Additionally, western blot analysis showed that triptolide inhibited the LPS-induced phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells-p65 (NF-kappaB p65) and the expression of Toll-like receptor 4 (TLR4). In conclusion, the results from the present study suggest that the anti-inflammatory effect of triptolide against LPS-induced ALI may be due to its ability to inhibit the TLR4-mediated NF-kappaB signalling pathway. Triptolide may therefore be a promising potential therapeutic agent for ALI treatment, which may ultimately aid the clinical therapy for patients with ALI. PMID- 24789090 TI - Identifying sp-sp2 carbon materials by Raman and infrared spectroscopies. AB - Two-dimensional (2D) materials composed of sp and sp(2) carbon atoms (e.g., graphyne and graphdiyne) show many interesting properties. These materials can be constructed through alkyne homocoupling; however, the occurrence of various side reactions increases the difficulty of their synthesis and structural characterization. Here, we investigate the thermodynamic properties and vibrational spectra of several aryl-alkynes. Both homocoupling and side reactions are found to occur spontaneously at room temperature in terms of thermodynamics. The calculated Raman spectra of the homocoupling products show regular changes with increasing polymerization degree. By rationalizing the vibrational modes of various oligomers, the Raman spectrum of a 2D sp-sp(2) carbon sheet is predicted; it exhibits three sharp peaks at 2241, 1560, and 1444 cm(-1). Although the target and byproducts display similar vibrational modes, a combination of Raman and infrared spectroscopies can be used to differentiate them. The theoretical results are then used to analyze the structure of a synthesized sample and provide useful information. PMID- 24789092 TI - The FDA and 23andMe: violating the First Amendment or protecting the rights of consumers? PMID- 24789093 TI - John Ashton: Outspoken and impatient. PMID- 24789091 TI - Role of the sympathetic nervous system in hypertension and hypertension-related cardiovascular disease. AB - A number of cardiovascular disease have been shown to be characterized by a marked increase in sympathetic drive to the heart and the peripheral circulation. This is the case for essential hypertension, congestive heart failure, cardiac arrhythmias, obesity, metabolic syndrome, obstructive sleep apnea, and chronic renal disease. This review focuses on the most recent findings documenting the role of sympathetic neural factors in the development and progression of the hypertensive state as well as in the pathogenesis of hypertension-related target organ damage. It also reviews the role of sympathetic neural factors in the development of cardiovascular diseases not necessarily strictly related to the hypertensive state, such as congestive heart failure, cardiac arrhythmias, obesity, metabolic syndrome and renal failure. The paper will finally review the pharmacological and non-pharmacological interventions acting on the sympathetic drive. Emphasis will be given to the new approaches, such as renal nerves ablation and carotid baroreceptor stimulation, which have been shown to exert sympathoinhibitory effects. PMID- 24789094 TI - "Modernising Medical Careers" to "Shape of Training"--how soon we forget. PMID- 24789095 TI - Back to red: allowing specialists to provide primary care would be a step backward for Poland. PMID- 24789096 TI - Balance between GP and hospital doctor numbers may need to shift, says new NHS chief. PMID- 24789097 TI - Peroxiredoxin proteins protect MCF-7 breast cancer cells from doxorubicin-induced toxicity. AB - Peroxiredoxin (Prdx) proteins are thiol-specific antioxidants that protect cells from oxidative stress in many normal and disease states. There are six Prdx proteins expressed in mammals, each with a characteristic tissue expression, subcellular distribution and substrate specificity. Recent studies have revealed elevated Prdx levels in many cancers, suggesting a protective role for these proteins in cancer cell survival. The present study is the first to investigate the function of all six Prdx proteins in the MCF-7 breast cancer cell line. We show that these cells have both higher resistance to doxorubicin-induced toxicity and significantly elevated Prdx levels, compared to the non-cancer MCF-10A cells. Using transient siRNA transfections, we show that Prdx3 suppression leads to decreased MCF-7 cell survival in the absence of doxorubicin. We further demonstrate that individual suppression of four of six of the Prdx proteins leads to increased doxorubicin-induced toxicity by apoptosis. Finally, we show that clonal selection of a doxorubicin-resistant MCF-7 subline by 2-week culture in 0.1 uM doxorubicin resulted in a marked elevation in the expression of several Prdx proteins. Together, these data reveal a protective function for peroxiredoxins in MCF-7 cell survival, and suggest that Prdx overexpression in breast cancer may play a role in doxorubicin-resistance in these, and possibly other, breast cancer cells. This study is the first to investigate the function of the entire Prdx family in a breast cancer cell line. PMID- 24789098 TI - Protective effect of liquiritigenin against methylglyoxal cytotoxicity in osteoblastic MC3T3-E1 cells. AB - Methylglyoxal (MG), a reactive dicarbonyl compound, is a metabolic byproduct of glycolysis and elevated MG levels contribute to diabetic complications. Glycation reactions of MG with amino acids can induce oxidative stress, leading to subsequent cytotoxicity. In the present study, the effect of liquiritigenin on MG induced cytotoxicity was investigated using osteoblastic MC3T3-E1 cells. Pretreatment of MC3T3-E1 cells with liquiritigenin prevented the MG-induced cell death and production of protein adduct, intracellular reactive oxygen species, mitochondrial superoxide, cardiolipin peroxidation, and TNF-alpha in osteoblastic MC3T3-E1 cells. In addition, liquiritigenin increased the activity of glyoxalase I inhibited by MG. These findings suggest that liquiritigenin provides a protective action against MG-induced cell damage by reducing oxidative stress and by increasing MG detoxification. Pretreatment with liquiritigenin prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation and adenosine triphosphate loss. Additionally, the nitric oxide and PGC-1alpha levels were significantly increased by liquiritigenin, suggesting that liquiritigenin may induce mitochondrial biogenesis. Our findings indicate that liquiritigenin might exert its therapeutic effects via enhancement of glyoxalase I activity and mitochondrial function, and anti-oxidant and anti-inflammatory activities. Taken together, liquiritigenin has potential as a preventive agent against the development of diabetic osteopathy related to MG-induced oxidative stress in diabetes. PMID- 24789100 TI - Effect of intrinsic and extrinsic factors on global and regional cortical thickness. AB - Global and regional cortical thicknesses based on T1-weighted magnetic resonance images acquired at 1.5 T and 3 T were measured on a relatively large cohort of 295 subjects using FreeSurfer software. Multivariate regression analysis was performed using Pillai's trace test to determine significant differences in cortical thicknesses measured at these two field strengths. Our results indicate that global cortical thickness is not affected by the field strength or gender. In contrast, the regional cortical thickness was observed to be field dependent. Specifically, the cortical thickness in regions such as parahippocampal, superior temporal, precentral and posterior cingulate is thicker at 3 T than at 1.5 T. In contrast regions such as cuneus and pericalcarine showed higher cortical thickness at 1.5 T than at 3 T. These differences appear to be age-dependent. The differences in regional cortical thickness between field strengths were similar in both genders. Further, male vs. female differences in regional cortical thickness were observed only at 1.5 T and not at 3 T. Our results indicate that magnetic field strength has a significant effect on the estimation of regional, but not global, cortical thickness. In addition, the pulse sequence, scanner type, and spatial resolution do not appear to have significant effect on the measured cortical thickness. PMID- 24789099 TI - The chemokine fractalkine can activate integrins without CX3CR1 through direct binding to a ligand-binding site distinct from the classical RGD-binding site. AB - The chemokine domain of fractalkine (FKN-CD) binds to the classical RGD-binding site of alphavbeta3 and that the resulting ternary complex formation (integrin FKN-CX3CR1) is critical for CX3CR1 signaling and FKN-induced integrin activation. However, only certain cell types express CX3CR1. Here we studied if FKN-CD can activate integrins in the absence of CX3CR1. We describe that WT FKN-CD activated recombinant soluble alphavbeta3 in cell-free conditions, but the integrin-binding defective mutant of FKN-CD (K36E/R37E) did not. This suggests that FKN-CD can activate alphavbeta3 in the absence of CX3CR1 through the direct binding of FKN CD to alphavbeta3. WT FKN-CD activated alphavbeta3 on CX3CR1-negative cells (K562 and CHO) but K36E/R37E did not, suggesting that FKN-CD can activate integrin at the cellular levels in a manner similar to that in cell-free conditions. We hypothesized that FKN-CD enhances ligand binding to the classical RGD-binding site (site 1) through binding to a second binding site (site 2) that is distinct from site 1 in alphavbeta3. To identify the possible second FKN-CD binding site we performed docking simulation of alphavbeta3-FKN-CD interaction using alphavbeta3 with a closed inactive conformation as a target. The simulation predicted a potential FKN-CD-binding site in inactive alphavbeta3 (site 2), which is located at a crevice between alphav and beta3 on the opposite side of site 1 in the alphavbeta3 headpiece. We studied if FKN-CD really binds to site 2 using a peptide that is predicted to interact with FKN-CD in site 2. Notably the peptide specifically bound to FKN-CD and effectively suppressed integrin activation by FKN-CD. This suggests that FKN-CD actually binds to site 2, and this leads to integrin activation. We obtained very similar results in alpha4beta1 and alpha5beta1. The FKN binding to site 2 and resulting integrin activation may be a novel mechanism of integrin activation and of FKN signaling. PMID- 24789102 TI - GE covariance through phenotype to environment transmission: an assessment in longitudinal twin data and application to childhood anxiety. AB - We considered identification of phenotype (at occasion t) to environment (at occasion t + 1) transmission in longitudinal model comprising genetic, common and unique environmental simplex models (autoregressions). This type of transmission, which gives rise to genotype-environment covariance, is considered to be important in developmental psychology. Having established identifying constraints, we addressed the issue of statistical power to detect such transmission given a limited set of parameter values. The power is very poor in the ACE simplex, but is good in the AE model. We investigated misspecification, and found that fitting the standard ACE simplex to covariance matrices generated by an AE simplex with phenotype to E transmission produces the particular result of a rank 1 C (common environment) covariance matrix with positive transmission, and a rank 1 D (dominance) matrix given negative transmission. We applied the models to mother ratings of anxiety in female twins (aged 3, 7, 10, and 12 years), and obtained support for the positive effect of one twin's phenotype on the other twin's environment. PMID- 24789103 TI - Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families. AB - BACKGROUND: Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. Its four subtypes (a, b, c, and d) are defined based on variable phenotypes, but the responsible gene is yet to be identified. SD1-a has been mapped to chromosome 3p21.31 and SD1-b to 2q34-q36. SD1-c and SD1-d are very rare and, to our knowledge, no gene loci have been identified. METHODS AND RESULTS: In two Chinese families with SD1-c, linkage and haplotype analyses mapped the disease locus to 2q31-2q32. Copy number variation (CNV) analysis, using array-based comparative genomic hybridization (array CGH), excluded the possibility of microdeletion or microduplication. Sequence analyses of related syndactyly genes in this region identified c.917G>A (p.R306Q) in the homeodomain of HOXD13 in family A. Analysis on family B identified the mutation c.916C>G (p.R306G) and therefore confirmed the genetic homogeneity. Luciferase assays indicated that these two mutations affected the transcriptional activation ability of HOXD13. The spectrum of HOXD13 mutations suggested a close genotype-phenotype correlation between the different types of HOXD13-Syndactyly. Overlaps of the various phenotypes were found both among and within families carrying the HOXD13 mutation. CONCLUSIONS: Mutations (p.R306Q and p.R306G) in the homeodomain of HOXD13 cause SD1-c. There are affinities between SD1-c and synpolydactyly. Different limb malformations due to distinct classes of HOXD13 mutations should be considered as a continuum of phenotypes and further classification of syndactyly should be done based on phenotype and genotype. PMID- 24789104 TI - Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. AB - OBJECTIVE: Epithelial-mesenchymal transition (EMT) plays an important role in cancer tumorigenesis. However, the underlying mechanisms of EMT in lung adenocarcinoma, and how this process might be inhibited, remain to be explored. This study investigated the role of IL-6 in lung adenocarcinoma cell EMT and explored the potential effects of metformin on this process. METHODS: Invasion assay and MTT assay was performed to determine cell invasion and cell proliferation. Western blotting, immunofluorescence, real-time PCR, ELISA, and immunohistochemistry were performed to detect the expression of IL-6, E-cadherin, Vimentin, and p-STAT3. RESULTS: We discovered that IL-6, via STAT3 phosphorylation, could promote lung adenocarcinoma cell invasion via EMT in vitro. This was supported by the inverse correlation between E-cadherin and IL-6 expression, positive correlation between IL-6 and vimentin mRNA expression and between STAT3 phosphorylation and IL-6 expression in tumor tissues. Importantly, metformin inhibited tumor growth and distant metastases in tumor-bearing nude mice and reversed IL-6-induced EMT both in vitro and in vivo. Furthermore, we found that blockade of STAT3 phosphorylation might be the underlying mechanism of metformin inhibition of IL-6-induced EMT. CONCLUSIONS: Collectively, our present results show that enhanced IL-6 expression, via STAT3 phosphorylation, is a mechanism of EMT in lung adenocarcinoma. We found that metformin could inhibit IL 6-induced EMT possibly by blocking STAT3 phosphorylation. PMID- 24789105 TI - Human epidermal keratinocyte cell response on integrin-specific artificial extracellular matrix proteins. AB - Cell-matrix interactions play critical roles in regulating cellular behavior in wound repair and regeneration of the human skin. In particular, human skin keratinocytes express several key integrins such as alpha5beta1, alpha3beta1, and alpha2beta1 for binding to the extracellular matrix (ECM) present in the basement membrane in uninjured skin. To mimic these key integrin-ECM interactions, artificial ECM (aECM) proteins containing functional domains derived from laminin 5, type IV collagen, fibronectin, and elastin are prepared. Human skin keratinocyte cell responses on the aECM proteins are specific to the cell-binding domain present in each construct. Keratinocyte attachment to the aECM protein substrates is also mediated by specific integrin-material interactions. In addition, the aECM proteins are able to support the proliferation of keratinocyte stem cells, demonstrating their promise for use in skin tissue engineering. PMID- 24789107 TI - Phase transitions in the brominated ferroelectric tris-sarcosine calcium chloride. PMID- 24789106 TI - The HIV-Brazil cohort study: design, methods and participant characteristics. AB - BACKGROUND: The HIV-Brazil Cohort Study was established to analyze the effectiveness of combination antiretroviral therapy (cART) and the impact of this treatment on morbidity, quality of life (QOL) and mortality. The study design, patients' profiles and characteristics of cART initiation between 2003 and 2010 were described. METHODOLOGY/PRINCIPAL FINDINGS: Since 2003, the HIV-Brazil Cohort has been following HIV-infected adults receiving cART at 26 public health care facilities, using routine clinical care data and self-reported QOL questionnaires. When not otherwise available, data are obtained from national information systems. The main outcomes of interest are diseases related or unrelated to HIV; suppression of viral replication; adverse events; virological, clinical and immunological failures; changes in the cART; and mortality. For the 5,061 patients who started cART between 2003 and 2010, the median follow-up time was 4.1 years (IQR 2.2-5.9 years) with an 83.4% retention rate. Patient profiles were characterized by a predominance of men (male/female ratio 1.7?1), with a mean age of 36.9 years (SD 9.9 years); 55.2% had been infected with HIV via heterosexual contact. The majority of patients (53.4%) initiated cART with a CD4+ T-cell count <=200 cells/mm3. The medications most often used in the various treatment regimens were efavirenz (59.7%) and lopinavir/ritonavir (18.2%). The proportion of individuals achieving viral suppression within the first 12 months of cART use was 77.4% (95% CI 76.1-78.6). Nearly half (45.4%) of the patients presented HIV-related clinical manifestations after starting cART, and the AIDS mortality rate was 13.9 per 1,000 person-years. CONCLUSIONS/SIGNIFICANCE: Results from cART use in the daily practice of health services remain relatively unknown in low- and middle-income countries, and studies with the characteristics of the HIV-Brazil Cohort contribute to minimizing these shortcomings, given its scope and patient profile, which is similar to that of the AIDS epidemic in the country. PMID- 24789108 TI - A symmetrical fluorous dendron-cyanine dye-conjugated bimodal nanoprobe for quantitative 19F MRI and NIR fluorescence bioimaging. AB - (19)F MRI and optical imaging are two powerful noninvasive molecular imaging modalities in biomedical applications. (19)F MRI has great potential for high resolution in vivo imaging, while fluorescent probes enable ultracontrast cellular/tissue imaging with high accuracy and sensitivity. A bimodal nanoprobe is developed, integrating the merits of (19)F MRI and fluorescence imaging into a single synthetic molecule, which is further engineered into nanoprobe, by addressing shortcomings of conventional contrast agents to explore the quantitative (19)F MRI and fluorescence imaging and cell tracking. Results show that this bimodal imaging nanoprobe presents high correlation of (19)F MR signal and NIR fluorescence intensity in vitro and in vivo. Additionally, this nanoprobe enables quantitative (19)F MR analysis, confirmed by a complementary fluorescence analysis. This unique feature can hardly be obtained by traditional (19)F MRI contrast agents. It is envisioned that this nanoprobe can hold great potential for quantitative and sensitive multi-modal molecular imaging. PMID- 24789109 TI - Candidiasis: predisposing factors, prevention, diagnosis and alternative treatment. AB - Candidiasis is the most common opportunistic yeast infection. Candida species and other microorganisms are involved in this complicated fungal infection, but Candida albicans continues to be the most prevalent. In the past two decades, it has been observed an abnormal overgrowth in the gastrointestinal, urinary and respiratory tracts, not only in immunocompromised patients, but also related to nosocomial infections and even in healthy individuals. There is a widely variety of causal factors that contribute to yeast infection which means that candidiasis is a good example of a multifactorial syndrome. Due to rapid increase in the incidence in these infections, this is the subject of numerous studies. Recently, the focus of attention is the treatment and, above all, the prevention of those complications. The diagnosis of candidiasis could become quite complicated. Prevention is the most effective "treatment," much more than eradication of the yeast with antifungal agents. There are several aspects to consider in the daily routine that can provide a strength protection. However, a therapeutic approach is necessary when the infection is established, and therefore, other alternatives should be explored. This review provides an overview on predisposition factors, prevention and diagnosis of candidiasis, highlighting alternative approaches for candidiasis treatment. PMID- 24789110 TI - Th17 cells are associated with the Th1/Th2-cell balance during Echinococcus multilocularis infection. AB - The present study investigated the immunopathological effect of Echinococcus multilocularis (Em) using cytokine detection. Expression of the T-helper (Th) 17 cytokine, interleukin 17 (IL-17), was observed using immunohistochemical staining, and levels of cytokines, including IL-17, transforming growth factor beta1 (TGF-beta1), IL-6, interferon gamma (IFN-gamma) and IL-4, were assessed using ELISA at different stages of infection. IL-17 expression occurred in hepatic cells at 1 month post-infection, reached a maximum at 3 months post infection and then decreased gradually. Compared with the uninfected control, levels of the cytokines IL-17, TGF-beta1, IL-6, IFN-gamma and IL-4 exhibited different dynamic patterns when infected with Em. In the immune response during the whole infection period, Th17 cells play an important role by secreting IL-17, which may be involved in the Th1/Th2-cell balance during the immune response. Th17 cells are associated with immunopathology in Em infection. PMID- 24789113 TI - Expression patterns of micro-RNAs 146a, 181a, and 155 in subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis is caused by persistent brain infection of mutated virus, showing inflammation, neurodegeneration, and demyelination. Although many factors are emphasized in the pathogenesis of subacute sclerosing panencephalitis, the exact mechanism of neurodegeneration remains unknown. Micro RNAs are small, noncoding RNAs that regulate gene expression at the posttranscriptional levels. Micro-RNAs are essential for normal immune system development; besides they are also implicated in the pathogenesis of many chronic inflammatory disorders. The aim of this study is to investigate the expression patterns of micro-RNAs 146a, 181a, and 155 in peripheral blood mononuclear cells of patients with subacute sclerosing panencephalitis. We enrolled 39 patients with subacute sclerosing panencephalitis and 41 healthy controls. Quantitative analysis of micro-RNAs 146a, 181a, and 155 were performed using specific stem loop primers followed by real-time polymerase chain reaction. All of 3 micro-RNAs were upregulated in subacute sclerosing panencephalitis patients. In addition, the level of micro-RNA 155 expression was higher in stage 3 patients. But, micro RNA 146a and 181a expression levels showed no association or correlation with clinically relevant data. Alteration of peripheral blood mononuclear cell micro RNAs in subacute sclerosing panencephalitis may shed new light on the pathogenesis of disease and may contribute to the aberrant systemic rise in mRNA levels in subacute sclerosing panencephalitis. PMID- 24789114 TI - Evidence of the gluten-free and casein-free diet in autism spectrum disorders: a systematic review. AB - In autism spectrum disorders, many parents resort to alternative treatments and these are generally perceived as risk free. Among these, the most commonly used is the gluten-free, casein-free diet. The objective of this work was to conduct a systematic review of studies published from 1970 to date related to the gluten free, casein-free diet in autism spectrum disorder patients. Few studies can be regarded as providing sound scientific evidence since they were blinded randomized controlled trials, and even these were based on small sample sizes, reducing their validity. We observed that the evidence on this topic is currently limited and weak. We recommend that it should be only used after the diagnosis of an intolerance or allergy to foods containing the allergens excluded in gluten free, casein-free diets. Future research should be based on this type of design, but with larger sample sizes. PMID- 24789115 TI - Long-term clinical course of Glut1 deficiency syndrome. AB - Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment. PMID- 24789116 TI - Mitochondria DNA depletion syndrome in a infant with multiple congenital malformations, severe myopathy, and prolonged postoperative paralysis. AB - Mitochondrial DNA depletion syndromes are an important cause of mitochondrial cytopathies in both children and adults. We describe a newborn with multiple congenital malformations including a right aberrant subclavian artery and a trachea-oesophageal fistula in whom mitochondrial depletion syndrome was unmasked by perioperative muscle relaxation. After vecuronium infusion, the infant developed an irreversible postoperative paralysis, leading to death 32 days after surgery. The present case highlights (a) the clinical heterogeneity of mitochondrial depletion syndrome; (b) the importance of rigorous antemortem and postmortem investigations when the cause of a severe myopathy is uncertain; (c) the possible coexistence of mitochondrial depletion syndrome and congenital malformations as a result of a likely abnormal antenatal embryofetal development and (d) the importance of a careful anaesthetic management of children with mitochondrial depletion syndrome, which could be prone to complications related to the possible depressive effects on mitochondrial electron transport chain mediated by some anaesthetic agents. PMID- 24789117 TI - Quick genetic screening using targeted next-generation sequencing in patients with tuberous sclerosis. AB - Tuberous sclerosis complex is an autosomal dominant disorder characterized by hamartomas in multiple organ systems. Mutations in the 2 large genes TSC1 and TSC2 have been demonstrated to be associated with tuberous sclerosis complex by various mutation screening methods. Targeted next-generation sequencing for genetic analysis is performed in the current study and is proved to be less cost, labor, and time consuming compared with Sanger sequencing. Two de novo and 1 recurrent TSC2 mutation in patients with tuberous sclerosis complex were revealed. Clinical details of patients were described and the underlying mechanism of the 2 novel TSC2 mutations, c.245G>A(p.W82X) and c.5405_5408dupACTT(p.P1803Lfs*25), were discussed. These results added to variability of TSC mutation spectrum and suggest that targeted next-generation sequencing could be the primary choice over Sanger sequencing in future tuberous sclerosis complex genetic counseling. PMID- 24789119 TI - Mucolytics for bronchiectasis. AB - BACKGROUND: Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils.Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice without clear supportive evidence. OBJECTIVES: To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013. SELECTION CRITERIA: Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by two review authors. Study authors were contacted for confirmation. MAIN RESULTS: Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis.One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low.In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points.The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low. AUTHORS' CONCLUSIONS: Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non-cystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required.Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed. PMID- 24789120 TI - Further investigation into the risk of skin cancer associated with the use of UV nail lamps. PMID- 24789121 TI - A designed amide as an aldol donor in the direct catalytic asymmetric aldol reaction. AB - The direct catalytic asymmetric aldol reaction offers efficient access to beta hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of alpha-sulfanyl 7-azaindolinylamide, thus affording both aromatic and aliphatic beta-hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Bronsted base. PMID- 24789118 TI - Getting down to the core of histone modifications. AB - The identification of an increasing number of posttranslationally modified residues within histone core domains is furthering our understanding of how nucleosome dynamics are regulated. In this review, we first discuss how the targeting of specific histone H3 core residues can directly influence the nucleosome structure and then apply this knowledge to provide functional reasoning for their localization to distinct genomic regions. While we focus mainly on transcriptional implications, the principles discussed in this review can also be applied to their roles in other cellular processes. Finally, we highlight some examples of how aberrant modifications of core histone residues can facilitate the pathogenesis of some diseases. PMID- 24789122 TI - Manifestations of pilocytic astrocytoma: a pictorial review. AB - BACKGROUND: Pilocytic astrocytoma can be challenging to diagnose. METHODS: Its clinical presentations can differ, directly related to its size and location, and are relatively unreliable. Similarly, imaging findings also vary with the location of the pilocytic astrocytoma. RESULTS: This review provides an overview of the different imaging findings regarding pilocytic astrocytomas using both conventional and advanced magnetic resonance imaging sequences according to tumour location; the findings are strongly related to the tumour's tendency to infiltrate surrounding structures, being able to carry out gross total resection, and finally the prognosis. CONCLUSIONS: Knowledge of these imaging manifestations of pilocytic astrocytoma may be helpful to arrive at an accurate diagnosis. TEACHING POINTS: * To recognise the various imaging findings of pilocytic astrocytoma on both conventional and advanced magnetic resonance imaging sequences. * To identify the characteristic imaging findings according to tumour location. * To discuss the relevant differential diagnoses of pilocytic astrocytoma in each tumour location. PMID- 24789123 TI - Drug pricing and control of health expenditures: a comparison between a proportional decision rule and a cost-per-QALY rule. AB - BACKGROUND AND AIMS: In Germany, the Institute for Quality and Efficiency in Health Care (IQWiG) makes recommendations for reimbursement prices of drugs on the basis of a proportional relationship between costs and health benefits. This paper analyzed the potential of IQWiG's decision rule to control health expenditures and used a cost-per-quality-adjusted life year (QALY) rule as a comparison. METHODS: A literature search was conducted, and a theoretical model of health expenditure growth was built. RESULTS: The literature search shows that the median incremental cost-effectiveness ratio of German cost-effectiveness analyses was ?7650 per QALY gained, thus yielding a much lower threshold cost effectiveness ratio for IQWiG's rule than an absolute rule at ?30 000 per QALY. The theoretical model shows that IQWiG's rule is able to contain the long-term growth of health expenditures under the conservative assumption that future health increases at a constant absolute rate and that the threshold incremental cost-effectiveness ratio increases at a smaller rate than health expenditures. In contrast, an absolute rule offers the potential for manufacturers to raise drug prices in response to the threshold, thus resulting in an initial spike in expenditures. CONCLUSIONS: Results suggest that IQWiG's proportional rule will lead to lower drug prices and a slower growth of health expenditures than an absolute cost-effectiveness threshold at ?30 000 per QALY. This finding is surprising as IQWiG's rule-in contrast to a cost-per-QALY rule-does not start from a fixed budget. PMID- 24789124 TI - Primary B-lymphoblastic lymphoma of gallbladder involving mandibular bone. AB - We report the case of a 75-year-old man who presented for evaluation of painless hematuria persisting for more than 1 month. At the time of presentation, the patient did not report any systemic symptoms and had no fever, weight loss, or dysuria. Computed tomography showed several enhancing, sessile polyps in the gall bladder (1.5 cm or smaller). There was no associated stone or biliary dilation. Since no other abnormality was evident, we performed laparoscopic cholecystectomy. He was diagnosed as having B-cell lymphoblastic lymphoma (B-LBL) after surgical resection of the gall bladder (GB). As the left mandibular swelling was developed after the diagnosis of the B-LBL involving GB, facial magnetic resonance imaging (MRI) was added to the imaging scan. Facial MRI revealed mass formation in the left mandible, left medial pterygoid, masticator, and buccinator muscles. The biopsy samples from the mandibular bone were also diagnosed as B-LBL. The definitive pathological diagnosis was B-LBL, stage IV. Systemic chemotherapy was done with subsequent response in size of the left mandible mass. PMID- 24789126 TI - Long-term oncologic outcomes of endoscopic stenting as a bridge to surgery for malignant colonic obstruction: comparison with emergency surgery. AB - BACKGROUND: Self-expandable metallic stents (SEMS) are now regarded as an effective and safe intervention for malignant colorectal obstruction (MCO). However, manipulation of the tumor might lead to the spillage of tumor cells and result in distant metastases. We aimed to compare the long-term oncologic outcomes of SEMS as a bridge to surgery with those of emergency surgery for MCO. METHODS: Between June 2005 and December 2011, 60 patients who underwent elective curative resection after endoscopic SEMS insertion were included in the "SEMS group". The SEMS group was matched to 180 patients who underwent emergency curative surgery for MCO during the same period ["Emergency surgery (ES) group"]. The clinicopathologic characteristics, recurrence-free survival (RFS), and overall survival (OS) were compared between the two groups. RESULTS: There were no significant differences in demographics, tumor stage, location, and histology between the SEMS group and the ES group. The median follow-up times were 41.4 months (IQR, 22.2-60.0 months) for the SEMS group and 45.0 months (IQR, 20.9-68.1 months) for the ES group. The proportions of patients who received postoperative adjuvant chemotherapy were comparable (SEMS group vs. ES group, 68.3 % vs. 77.8 %; P = 0.210). The long-term prognosis did not significantly differ between two groups in either the 5-year RFS rate (79.6 % vs. 70.2 %; P = 0.218) or the 5-year OS rate (97.8 % vs. 94.3 %; P = 0.469). CONCLUSIONS: Long-term oncologic outcomes of SEMS insertion as a bridge to surgery were comparable to those of primary curative surgery. PMID- 24789127 TI - A new laparoscopic method of bowel radio-protection before pelvic chemoradiation of locally advanced cervix cancers. AB - BACKGROUND: Chemoradiation therapy (CRT) has become the mainstay of locally advanced cervical carcinomas (LACC). However, the price to pay is a significant rate of both early and late colo-rectal toxicities, which may impact on survivors' quality of life. To reduce the incidence of such complications, we suggest a simple technique of pelvic radioprotection. MATERIALS AND METHODS: An omental flap is created which is placed to fill the Douglas pouch to both increase the space between rectum and uterine cervix and prevent small bowel to fall in and to be exposed to radiation. In addition, a long sigmoid loop is retracted and fixed in the left paracolic gutter to prevent its irradiation as well. RESULTS: From May 2011 to May 2012, 51 successive LACC patients were offered this procedure in addition of a laparoscopic staging. All but 2 with too small an omentum benefitted from omentoplasty, while sigmoidopexy was performed in all but one patient with a long and free sigmoid loop. No immediate adverse effect was observed. The volume of retro-uterine omental flap averaged 7.17 +/- 3.79 cm(3). Sequential measurements of the utero-rectal space throughout CRT duration showed a real and durable increase in the distance between these organs, resulting in a drop in the dose of irradiation to recto-sigmoid. With 10 +/- 4.5 month median follow-up, we did not observe any rectal or small bowel early or late adverse effects of CRT. CONCLUSIONS: Although this series is preliminary, this simple procedure, feasible by laparoscopy (or laparotomy), seems effective to prevent recto-sigmoid as well as small bowel from radio-induced complications due to pelvic CRT. PMID- 24789128 TI - A single port laparoscopic surgery robot with high force transmission and a large workspace. AB - INTRODUCTION: This study presents the design of a novel single port laparoscopic surgery robot that is actuated by plate-spring-driven mechanisms with high force transmission and a larger workspace. Many ongoing studies aim to develop robotic single port laparoscopic surgery platforms due to the potential advantages in terms of a short recovery period and fewer postoperative scars. Most of these investigations of single port access have focused on resolving the inconvenient maneuverability of manual single port laparoscopic surgery. However, drive mechanism structures are another requirement. MATERIALS AND METHODS: Most of the existing robotic platforms cannot transmit sufficient force, as many of them use wire-driven mechanisms, which are prone to mechanical deformation that also negatively affects the accuracy of the end effector. In addition, even the best known laparoscopic surgical robot system has instruments with a limited workspace for single port laparoscopic surgery. Therefore, the purpose of this study was to propose a novel robotic single port laparoscopic surgery platform that uses plate springs to transmit higher forces during tissue handling. RESULTS AND CONCLUSION: Compared to wire- or link-driven mechanisms, the plate-spring mechanism provided surpassing force transmission, with >14 N force transmission achieved, which enables most laparoscopic surgery with single port access. In addition, the high degree of freedom structure of the proposed design permitted an expanded workspace, which might be the most competitive characteristic among the single port systems reported to date. PMID- 24789129 TI - SAGES research agenda in gastrointestinal and endoscopic surgery: updated results of a Delphi study. AB - BACKGROUND: Research in gastrointestinal and endoscopic surgery has witnessed unprecedented growth since the introduction of minimally invasive techniques in surgery. Coordination and focus of research efforts could further advance this rapidly expanding field. The objective of this study was to update the SAGES research agenda for gastrointestinal and endoscopic surgery. METHODS: A modified Delphi methodology was used to create the research agenda. Using an iterative, anonymous web-based survey, the general membership and leadership of SAGES were asked for input over three rounds. Initially submitted research questions were reviewed and consolidated by an expert panel and redistributed to the membership for priority ranking using a 5-point Likert scale of importance. The top 40 research questions of this round were then redistributed to and re-rated by members, and a final ranking was established. Comparisons were made between membership and leadership responses. RESULTS: 283 initially submitted research questions were condensed into 89 distinct questions, which were rated by 388 respondents to determine the top 40 questions. 460 respondents established the final ranking of these 40 most important research questions. Topics represented included training and technique, gastrointestinal, hernia, GERD, bariatric surgery, and endoscopy. The top question was, "How do we best train, assess, and maintain proficiency of surgeons and surgical trainees in flexible endoscopy, laparoscopy, and open surgery?" 28% of responders were leadership and the rest general members with the majority of ratings (73%) being similar between the groups. While SAGES leadership rated the majority of questions (89%) lower, they rated nonclinical questions higher compared with general membership. CONCLUSIONS: An updated research agenda for gastrointestinal and endoscopic surgery was developed using a systematic methodology. This agenda may assist investigators and funding organizations to concentrate their efforts in the highest research priority areas and editors and reviewers in assessing the merit and relevance of scientific work. PMID- 24789131 TI - Laparoscopic right hemicolectomy: a comparison of natural orifice versus transabdominal specimen extraction. AB - BACKGROUND: Conventional laparoscopic right hemicolectomy (LRH) involves making an abdominal incision to remove the specimen and perform the anastomosis. Totally laparoscopic right hemicolectomy with natural orifice specimen extraction (NOSE) may lead to better outcomes compared to LRH. STUDY DESIGN: Forty consecutive female patients total were reviewed: 20 LRH and 20 NOSE. The two groups were matched for sex, age, race, American Society of Anesthesiologist score, benign and malignant disease, tumor stage, lymph node number, tumor size, specimen length, body mass index, previous abdominal surgeries, and comorbidities. RESULTS: The two groups were comparable for all categories. Follow-up was available on all patients (100%). The mean follow-up was 38.93 months (range 15 63 months). There was no difference between postoperative pain score between the two groups on postoperative day (POD) 1, POD 2, and POD day 14 (p = 0.571), (p = 0.861), (p = 0.688), respectively. There was no difference in the postoperative in-hospital morphine equivalents (p = 0.963). The NOSE group had no postoperative hernia formation or wound infections compared to the LRH, however, the difference was not significant (p = 0.439) and (p = 0.267), respectively. There was no difference in postoperative ileus (p = 0.192), septic complications (p = 1.000), readmission rate (p = 0.394), time interval for postoperative chemotherapy (p = 0.645), SDS (p = 0.446) or QLI (p = 0.175). There was no difference in length of hospital stay with 5.3 days for the LRH group and 7.7 days for the NOSE group (p = 0.183). The NOSE group had statistically significant better cosmetic scores (p = 0.018). CONCLUSION: NOSE is comparable LRH with regard to postoperative outcomes and quality of life. NOSE is safe and maintains strict oncologic standards. NOSE is associated with a better cosmetic outcome compared to LRH. PMID- 24789132 TI - Relationship between stent characteristics and treatment outcomes in endoscopic transmural drainage of uncomplicated pancreatic pseudocysts. AB - BACKGROUND: Transmural stents are placed at endoscopy to drain pancreatic fluid collections. This study evaluated the relationship between stent placement and treatment outcomes in patients undergoing endoscopic transmural drainage of uncomplicated pancreatic pseudocysts. METHODS: This is a retrospective study of all patients who underwent endoscopic drainage of uncomplicated pancreatic pseudocysts over a 10-year period. After dilating the transmural tracts in the range of 8-15 mm, single or multiple, 7 or 10Fr double-pigtail plastic stents were deployed. The main outcome measure was to evaluate the relationship between stent characteristics and the number of endoscopic interventions required to achieve resolution of the pancreatic pseudocyst (treatment success). RESULTS: Of 122 patients, 45 (36.9%) had 10Fr stents of which 30 patients (66.7%) had more than one stent; the remaining 77 (63.1%) patients had 7Fr stents of which 56 (72.7%) had more than one stent. The overall treatment success was 94.3%. Treatment was successful in 102 patients (83.6%) with one intervention; 13 patients (10.7%) required re-intervention for successful drainage and 7 patients (5.7%) failed endoscopic treatment. There was no significant difference in the number of interventions required for treatment success between patients with 7 or 10Fr stents (one intervention required in 87.7 vs. 90.5%, respectively; p = 0.766) and between patients with 1 or >1 stent (one intervention required in 88.9 vs. 88.6%, respectively; p = 0.999). On multiple logistic regression analysis, the stent size (OR 1.54; 95% CI 0.23-10.4) and number (OR 1.15; 95% CI 0.25-5.25) were not associated with the number of interventions required for treatment success when adjusted for pseudocyst size, location, drainage modality, the presence or absence of pancreatic duct stent and luminal compression. CONCLUSIONS: There appears to be no relationship between the number of interventions required for treatment success and stent characteristics in patients undergoing endoscopic transmural drainage of uncomplicated pancreatic pseudocysts. PMID- 24789125 TI - EAES recommendations for the management of gastroesophageal reflux disease. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most frequent benign disorders of the upper gastrointestinal tract. Management of GERD has always been controversial since modern medical therapy is very effective, but laparoscopic fundoplication is one of the few procedures that were quickly adapted to the minimal access technique. The purpose of this project was to analyze the current knowledge on GERD in regard to its pathophysiology, diagnostic assessment, medical therapy, and surgical therapy, and special circumstances such as GERD in children, Barrett's esophagus, and enteroesophageal and duodenogastroesophageal reflux. METHODS: The European Association of Endoscopic Surgery (EAES) has tasked a group of experts, based on their clinical and scientific expertise in the field of GERD, to establish current guidelines in a consensus development conference. The expert panel was constituted in May 2012 and met in September 2012 and January 2013, followed by a Delphi process. Critical appraisal of the literature was accomplished. All articles were reviewed and classified according to the hierarchy of level of evidence and summarized in statements and recommendations, which were presented to the scientific community during the EAES yearly conference in a plenary session in Vienna 2013. A second Delphi process followed discussion in the plenary session. RESULTS: Recommendations for pathophysiologic and epidemiologic considerations, symptom evaluation, diagnostic workup, medical therapy, and surgical therapy are presented. Diagnostic evaluation and adequate selection of patients are the most important features for success of the current management of GERD. Laparoscopic fundoplication is the most important therapeutic technique for the success of surgical therapy of GERD. CONCLUSIONS: Since the background of GERD is multifactorial, the management of this disease requires a complex approach in diagnostic workup as well as for medical and surgical treatment. Laparoscopic fundoplication in well-selected patients is a successful therapeutic option. PMID- 24789133 TI - High incidence of trocar site hernia after laparoscopic or robotic Roux-en-Y gastric bypass. AB - BACKGROUND: Trocar Site Hernia (TSH) seems to represent a rare surgical complication, but available data are based only on symptomatic patients and clinically diagnosed cases; moreover, no data are available concerning TSH incidence after robotic-assisted procedures. Aims of the study were to asses TSH incidence in obese patients who underwent Roux-en-Y gastric bypass (RYGB) and to compare it between robotic-assisted and standard laparoscopy. METHODS: Patients who underwent RYGB between November 2007 and June 2012 underwent a clinical examination and an ultrasonography study of the abdominal wall by a single operator. RESULTS: 150 patients entered the study, 102 in the laparoscopic and 48 in the robotic group. Mean pre-operative weight and BMI were 129.3 kg and 47.4 kg/m(2), respectively; both were higher in the laparoscopic group (134.7 vs 117.6 kg, p < 0.001; 49.2 vs 43.8 kg/m(2), p < 0.001), while pre-operative comorbidities were not significantly different between groups. Operative time was lower in the laparoscopic group (182.7 vs 284.0 min, p < 0.001), while post operative complications were not different between groups. The overall incidence of TSH was 39.3% (59/150); incidence was 35.3% (36/102) in the laparoscopic and 47.9% (23/48) in the robotic group (p = 0.195). There were no significant differences between patients with and without TSH, except for higher post operative wound complication in patients without TSH (22 vs 6.8%, p = 0.024; OR 0.26). CONCLUSIONS: TSH revealed a high incidence in a bariatric surgery population, suggesting that it represents a strongly underestimated complication; furthermore, the present study showed a trend towards a higher incidence of TSH in patients who underwent robotic-assisted bariatric surgery. PMID- 24789134 TI - Impact of a hands-on component on learning in the Fundamental Use of Surgical EnergyTM (FUSE) curriculum: a randomized-controlled trial in surgical trainees. AB - BACKGROUND: While energy devices are ubiquitous in the operating room, they remain poorly understood and can result in significant complications. The purpose of this study was to estimate the extent to which adding a novel bench-top component improves learning of SAGES' Fundamental Use of Surgical EnergyTM (FUSE) electrosurgery curriculum among surgical trainees. METHODS: Surgical residents participated in a 1-h didactic electrosurgery (ES) course, based on the FUSE curriculum. They were then randomized to one of two groups: an unstructured hands on session where trainees used ES devices (control group) or a goal-directed hands-on training session (Sim group). Pre- and post-curriculum (immediate and at 3 months) assessments included knowledge of ES (multiple-choice examination), self-perceived competence for each of the 35 course objectives (questionnaire), and self-perceived comfort with performance of seven tasks related to safe use of ES. Data expressed as median[interquartile range], *p < 0.05. RESULTS: 56 (29 control; 27 Sim) surgical trainees completed the curriculum and assessments. Baseline characteristics, including pre-curriculum exam and questionnaire scores, were similar. Total score on the exam improved from 46%[40;54] to 84%[77;91]* for the entire cohort, with higher immediate post-curriculum scores in the Sim group compared to controls (89%[83;94] vs. 83%[71;86]*). At 3 months, performance on the exam declined in both groups, but remained higher in the Sim group (77%[69;90] vs 60%[51;80]*). Participants in both groups reported feeling greater comfort and competence post-curriculum (immediate and at 3 months) compared to baseline. This improvement was greater in the Sim group with a higher proportion feeling "Very Comfortable" or "Fully Competent" (Sim: 3/7 tasks and 28/35 objectives; control: 0/7 tasks and 10/35 objectives). CONCLUSIONS: A FUSE-based curriculum improved surgical trainees' knowledge and comfort in the safe use of electrosurgical devices. The addition of a structured interactive bench-top simulation component further improved learning and retention at 3 months. PMID- 24789135 TI - Is next-day discharge following laparoscopic Roux-en-Y gastric bypass safe in select patients? Analysis of short-term outcomes. AB - BACKGROUND: There is controversy surrounding the safety and feasibility of next day discharge following laparoscopic Roux-en-Y gastric bypass (LRYGB) for morbid obesity. The objective of this study was to determine if next-day discharge following LRYGB is comparable to standard discharge (i.e. postoperative day two) with respect to 30-day patient outcomes. METHODS: A retrospective cohort analysis was performed using data from the American College of Surgeons' National Surgery Quality Improvement Program participant use files. The study population consisted of patients discharged on either postoperative day (POD) 1 or 2 that underwent an elective LRYGB for morbid obesity between 2005 and 2012. Patients were excluded if they had recent surgery, any relative contraindication to bariatric surgery, or any recorded complication/death during their principal admission. The primary outcome was 30-day overall complications and secondary outcomes were 30-day major complications and reoperations. A multiple logistic regression analysis was performed to evaluate each outcome based on discharge day. RESULTS: The study population consisted of 6,166 and 30,966 patients discharged on POD 1 and 2, respectively. No major clinical differences were found between the two groups with respect to relevant patient and operative characteristics. After adjustment, the odds ratios for 30-day overall complications, major complications, and reoperations with next-day discharge were 0.98 (p = 0.870, 95% CI [0.81-1.19]), 0.81 (p = 0.204, 95% CI [0.58-1.12]) and 1.06 (p = 0.717, 95% CI [0.79-1.41]), respectively. Body mass index >=50, operative time >=3 h, diabetes, dyspnea and hypertension were significant predictors for complications in patients discharged the next day. CONCLUSIONS: Using this large national surgical database, LRYGB patients discharged on POD 1 did not have a significantly higher rate of adverse events compared to patients discharged on POD 2. Understanding the important predictors of adverse events following LRYGB will help bariatric surgeons implement next-day discharge protocols based on the appropriate perioperative evaluation. PMID- 24789136 TI - A meta-analysis of robotic versus laparoscopic gastrectomy for gastric cancer. AB - BACKGROUND: Robot-assisted gastrectomy (RAG) for gastric cancer is still a controversial surgical technique for adequate tumor resection, lymphadenectomy, and postoperative outcome. METHODS: A meta-analysis analyzed updated clinical trials that have compared RAG with laparoscopy-assisted gastrectomy (LAG) to evaluate whether RAG is equivalent to LAG. RESULTS: Eight studies were included in the analysis, comprising 1,875 patients. RAG was associated with a longer operative time (p < 0.05), lower estimated blood loss (p < 0.05), and a longer distal margin (p < 0.05). RAG can be performed safely with lower estimated blood loss and a longer distal margin than with LAG. Complications, hospital stay, proximal margin, and harvested lymph nodes for RAG and LAG were similar. CONCLUSIONS: RAG is as acceptable as LAG for obtaining safe complications and for performing radical gastrectomy. PMID- 24789137 TI - Predicting regression of Barrett's esophagus: results from a retrospective cohort of 1342 patients. AB - INTRODUCTION: Barrett's esophagus (BE) is the most predictive risk factor for development of esophageal adenocarcinoma (EAC), a malignancy with the fastest increasing incidence in the US. The aim of this study was to investigate differences in exposures, demographics, and comorbidities between regressing and non-regressing patients. METHODS AND PROCEDURES: We retrospectively collected and analyzed data from a cohort of BE patients participating in a single-center study comprised of all patients diagnosed with BE over a 10-year period. We collected information from the patient's electronic medical records regarding demographic data, endoscopic findings, histological findings, exposures, and history of antireflux surgery. RESULTS: This study included 1,342 BE patients, 505 (37.6%) of which experienced regression. The regressed group was 52.3% male, while the non-regressing group was 68.3% male (p < 0.001). Mean age was 65.2 +/- 12.8 and 62.0 +/- 13.1 years for non-regressing and regressing patients, respectively (p < 0.001). No difference was seen in BMI between regressing and non-regressing groups (27.5 +/- 5.7 vs. 27.7 +/- 5.4, p = 0.52). No difference was seen between groups with respect to PPI use (93.5% non-regressing vs. 94.1% regressed patients, p = 0.70), but regressed patients were more likely to take vitamin D than non-regressing patients (34.1 vs. 42.1%, p = 0.003). Regressed patients had an average segment length of 1.48 cm (+/-1.58 cm), in contrast to those not regressing (3.58 +/- 3.09 cm (p < 0.001)). Interestingly, one patient in the regression group progressed to dysplasia, while 101 of the non-regressing patients progressed to dysplasia/EAC, a result found to be independent of segment length on multivariate analysis (p < 0.001). CONCLUSIONS: Currently, several studies have shown risk factors that can predict progression of non-dysplastic BE, but few investigate predictors for regression. Our study reports several factors that can be used to predict patients who will regress from BE and those who likely will not, tools that will be useful in tailoring therapeutic and surveillance strategies. PMID- 24789138 TI - Cross-cultural variation in men's preference for sexual dimorphism in women's faces. AB - Both attractiveness judgements and mate preferences vary considerably cross culturally. We investigated whether men's preference for femininity in women's faces varies between 28 countries with diverse health conditions by analysing responses of 1972 heterosexual participants. Although men in all countries preferred feminized over masculinized female faces, we found substantial differences between countries in the magnitude of men's preferences. Using an average femininity preference for each country, we found men's facial femininity preferences correlated positively with the health of the nation, which explained 50.4% of the variation among countries. The weakest preferences for femininity were found in Nepal and strongest in Japan. As high femininity in women is associated with lower success in competition for resources and lower dominance, it is possible that in harsher environments, men prefer cues to resource holding potential over high fecundity. PMID- 24789139 TI - Long-term reproductive impairment in a seabird after the Prestige oil spill. AB - Large oil spills are dramatic perturbations on marine ecosystems, and seabirds are one of the worst affected organisms in such events. It has been argued that oil spills may have important long-term consequences on marine organisms, but supporting evidence remains scarce. The European shag (Phalacrocorax aristotelis) was strongly impacted at population level by the Prestige oil spill, the biggest spillage in the eastern North Atlantic. In this paper, we report on the long-term consequences on reproduction of this coastal seabird, using temporal and spatial replicated data (before-after-control-impact design). Our study revealed long term reproductive impairment during at least the first 10 years since the Prestige oil spill. Annual reproductive success did not differ before the impact, but after the impact it was reduced by 45% in oiled colonies compared with unoiled ones. This is a rare documentation of long-term effects after a major oil spill, highlighting the need for long-term monitoring in order to assess the real impact of this type of disturbance on marine organisms. PMID- 24789140 TI - Fenestration: a window of opportunity for carnivorous plants. AB - A long-standing but controversial hypothesis assumes that carnivorous plants employ aggressive mimicry to increase their prey capture success. A possible mechanism is that pitcher plants use aggressive mimicry to deceive prey about the location of the pitcher's exit. Specifically, species from unrelated families sport fenestration, i.e. transparent windows on the upper surfaces of pitchers which might function to mimic the exit of the pitcher. This hypothesis has not been evaluated against alternative hypotheses predicting that fenestration functions to attract insects from afar. By manipulating fenestration, we show that it does not increase the number of Drosophila flies or of two ant species entering pitchers in Sarracenia minor nor their retention time or a pitcher's capture success. However, fenestration increased the number of Drosophila flies alighting on the pitcher compared with pitchers of the same plant without fenestration. We thus suggest that fenestration in S. minor is not an example of aggressive mimicry but rather functions in long-range attraction of prey. We highlight the need to evaluate aggressive mimicry relative to alternative concepts of plant-animal communication. PMID- 24789141 TI - Genotypic variation in a foundation tree (Populus tremula L.) explains community structure of associated epiphytes. AB - Community genetics hypothesizes that within a foundation species, the genotype of an individual significantly influences the assemblage of dependent organisms. To assess whether these intra-specific genetic effects are ecologically important, it is required to compare their impact on dependent organisms with that attributable to environmental variation experienced over relevant spatial scales. We assessed bark epiphytes on 27 aspen (Populus tremula L.) genotypes grown in a randomized experimental array at two contrasting sites spanning the environmental conditions from which the aspen genotypes were collected. We found that variation in aspen genotype significantly influenced bark epiphyte community composition, and to the same degree as environmental variation between the test sites. We conclude that maintaining genotypic diversity of foundation species may be crucial for conservation of associated biodiversity. PMID- 24789142 TI - Coevolution of visual signals and eye morphology in Polistes paper wasps. AB - To be effective, signals must propagate through the environment and be detected by receivers. As a result, signal form evolves in response to both the constraints imposed by the transmission environment and receiver perceptual abilities. Little work has examined the extent to which signals may act as selective forces on receiver sensory systems to improve the efficacy of communication. If receivers benefit from accurate signal assessment, selection could favour sensory organs that improve discrimination of established signals. Here, we provide evidence that visual resolution coevolves with visual signals in Polistes wasps. Multiple Polistes species have variable facial patterns that function as social signals, whereas other species lack visual signals. Analysis of 19 Polistes species shows that maximum eye facet size is positively associated with both eye size and presence of visual signals. Relatively larger facets within the eye's acute zone improve resolution of small images, such as wasp facial signals. Therefore, sensory systems may evolve to optimize signal assessment. Sensory adaptations to facilitate signal detection may represent an overlooked area of the evolution of animal communication. PMID- 24789143 TI - Expression patterns and subcellular localization of carbonic anhydrases are developmentally regulated during tooth formation. AB - Carbonic anhydrases (CAs) play fundamental roles in several physiological events, and emerging evidence points at their involvement in an array of disorders, including cancer. The expression of CAs in the different cells of teeth is unknown, let alone their expression patterns during odontogenesis. As a first step towards understanding the role of CAs during odontogenesis, we used immunohistochemistry, histochemistry and in situ hybridization to reveal hitherto unknown dynamic distribution patterns of eight CAs in mice. The most salient findings include expression of CAII/Car2 not only in maturation-stage ameloblasts (MA) but also in the papillary layer, dental papilla mesenchyme, odontoblasts and the epithelial rests of Malassez. We uncovered that the latter form lace-like networks around incisors; hitherto these have been known to occur only in molars. All CAs studied were produced by MA, however CAIV, CAIX and CARPXI proteins were distinctly enriched in the ruffled membrane of the ruffled MA but exhibited a homogeneous distribution in smooth-ended MA. While CAIV, CAVI/Car6, CAIX, CARPXI and CAXIV were produced by all odontoblasts, CAIII distribution displayed a striking asymmetry, in that it was virtually confined to odontoblasts in the root of molars and root analog of incisors. Remarkably, from initiation until near completion of odontogenesis and in several other tissues, CAXIII localized mainly in intracellular punctae/vesicles that we show to overlap with LAMP-1- and LAMP-2 positive vesicles, suggesting that CAXIII localizes within lysosomes. We showed that expression of CAs in developing teeth is not confined to cells involved in biomineralization, pointing at their participation in other biological events. Finally, we uncovered novel sites of CA expression, including the developing brain and eye, the olfactory epithelium, melanoblasts, tongue, notochord, nucleus pulposus and sebaceous glands. Our study provides important information for future single or multiple gene targeting strategies aiming at deciphering the function of CAs during odontogenesis. PMID- 24789144 TI - Evaluation of anterior cervical reconstruction with titanium mesh cages versus nano-hydroxyapatite/polyamide66 cages after 1- or 2-level corpectomy for multilevel cervical spondylotic myelopathy: a retrospective study of 117 patients. AB - OBJECTIVE: To retrospectively compare the efficacy of the titanium mesh cage (TMC) and the nano-hydroxyapatite/polyamide66 cage (n-HA/PA66 cage) for 1- or 2 level anterior cervical corpectomy and fusion (ACCF) to treat multilevel cervical spondylotic myelopathy (MCSM). METHODS: A total of 117 consecutive patients with MCSM who underwent 1- or 2-level ACCF using a TMC or an n-HA/PA66 cage were studied retrospectively at a mean follow-up of 45.28 +/- 12.83 months. The patients were divided into four groups according to the level of corpectomy (1- or 2-level corpectomy) and cage type used (TMC or n-HA/PA66 cage). Clinical and radiological parameters were used to evaluate outcomes. RESULTS: At the one-year follow-up, the fusion rate in the n-HA/PA66 group was higher, albeit non significantly, than that in the TMC group for both 1- and 2-level ACCF, but the fusion rates of the procedures were almost equal at the final follow-up. The incidence of cage subsidence at the final follow-up was significantly higher in the TMC group than in the n-HA/PA66 group for the 1-level ACCF (24% vs. 4%, p = 0.01), and the difference was greater for the 2-level ACCF between the TMC group and the n-HA/PA66 group (38% vs. 5%, p = 0.01). Meanwhile, a much greater loss of fused height was observed in the TMC group compared with the n-HA/PA66 group for both the 1- and 2-level ACCF. All four groups demonstrated increases in C2-C7 Cobb angle and JOA scores and decreases in VAS at the final follow-up compared with preoperative values. CONCLUSION: The lower incidence of cage subsidence, better maintenance of the height of the fused segment and similar excellent bony fusion indicate that the n-HA/PA66 cage may be a superior alternative to the TMC for cervical reconstruction after cervical corpectomy, in particular for 2-level ACCF. PMID- 24789145 TI - Measures of 'exposure needed for one additional patient to be harmed' in population-based case-control studies. AB - PURPOSE: The magnitude of risk for adverse drug reactions may be communicated by a measure of 'exposure needed for one additional patient to be harmed' (ENH). We present four ENH measures, based on four different counterfactual contrasts, as illustrated by the known effects of NSAID use on peptic ulcer bleeding. METHODS: The four measures were basic ENH (estimating the excess risk when treating the entire source population versus treating no one), age-restricted ENH (the entire source population above, e.g. 50 years old treated versus no one above 50 years old treated), standardised ENH (a population of similar age and gender distribution as those actually treated versus same subjects not treated) and naturalistic ENH (those actually treated versus same subjects not treated). Data were derived from a case-control dataset on NSAIDs and severe peptic ulcer bleeding, collected in Funen County in 1995-2006. We incorporated prescription and census data to account for the source population's drug use. RESULTS: Estimates of basic, age-restricted, standardised and naturalistic ENH were 619 person-years (py) (95% confidence interval (CI): 558-684), 223 py (CI: 201-246), 131 py (CI: 118-144) and 162 py (CI: 151-173). The age-restricted ENH showed strong dependence on the chosen age limit. CONCLUSION: The differing counterfactual contrasts underlying the ENH result in widely different estimates. These differences reflect the clinical and epidemiological aspects of NSAID related peptic ulcer bleeding. The ultimate choice of ENH measure will depend on epidemiological or clinical considerations and on availability of data. PMID- 24789146 TI - Cisplatin handover between copper transporters: the effect of reducing agents. AB - Copper (Cu) transporters emerged as key factors at the basis of the biological response to antitumor platinum (Pt) drugs, which are among the most potent and broadly used chemotherapeutics. ATP7A and ATP7B (the Menkes and Wilson disease proteins, respectively) appear to be implicated in promoting tumor cell resistance to cisplatin. Cu-ATPases could bind the drug and, with the alleged involvement of the chaperone ATOX1, contribute to cell detoxification and survival. Here, we report the spectroscopic characterization of cisplatin binding to ATOX1 and MNK1, the first metal-binding domain of ATP7A, in the presence of the physiological reducing agent glutathione, a sulfur-containing molecule responsible for the majority of Pt detoxification in the cytosol. Under conditions mimicking the cellular environment, we show that cisplatin transfer from ATOX1 to MNK1 does not occur at a detectable rate. These results appear to contradict other literature data which, however, were obtained in the presence of exogenous reducing agents such as tris(2-carboxyethyl)phosphine (TCEP) having good coordinating ability for soft metal ions (such as Pt) and strong trans labilizing effect. A better understanding of Pt drug processing by Cu trafficking proteins under physiological conditions may help to answer key issues, such as drug availability in tumor cells and resistance. PMID- 24789147 TI - Semiconducting clathrates meet gas hydrates: Xe24[Sn136]. AB - Semiconducting Group 14 clathrates are inorganic host-guest materials with a close structural relationship to gas hydrates. Here we utilize this inherent structural relationship to derive a new class of porous semiconductor materials: noble gas filled Group 14 clathrates (Ng(x)[M136], Ng=Ar, Kr, Xe and M=Si, Ge, Sn). We have carried out high-level quantum chemical studies using periodic Local MP2 (LMP2) and dispersion-corrected density functional methods (DFT-B3LYP-D3) to properly describe the dispersive host-guest interactions. The adsorption of noble gas atoms within clathrate-II framework turned out to be energetically clearly favorable for several host-guest systems. For the energetically most favorable noble gas filled clathrate, Xe24[Sn136], the adsorption energy is -52 kJ mol(-1) per guest atom at the LMP2/TZVPP level of theory, corresponding to -9.2 kJ mol( 1) per framework Sn atom. Considering that a hypothetical guest-free Sn clathrate II host framework is only 2.6 kJ mol(-1) per Sn atom less stable than diamond like alpha-Sn, the stabilization resulting from the noble gas adsorption is very significant. PMID- 24789148 TI - Haemolytic anaemia after nitrofurantoin treatment in a pregnant woman with G6PD deficiency. AB - We present a normotensive, pregnant woman with severe haemolytic anaemia in the third trimester of pregnancy. Owing to normal platelet count diagnoses other than HELLP syndrome were considered and investigated. The patient was treated with nitrofurantoin 3 weeks before presentation and she turned out to have a deficiency of glucose-6-phosphate dehydrogenase. After treatment with blood transfusion, vitamin B12 and folic acid the patient recovered completely. Caesarean delivery was performed because of maternal hypertension and fetal distress at 33 weeks' gestation. PMID- 24789149 TI - Oesophageal papillomatosis, not amenable to endoscopic therapies, treated with oesophagectomy. AB - Oesophageal papillomatosis is a very rare entity, with only 10 cases (including ours) reported in the literature. We report a 51-year-old man with a 25-year history of dysphagia with solids and liquids who failed a trial of proton pump inhibitors and fluticasone. His initial endoscopy revealed a viliform mass with dense eosinophilic infiltrate without neoplasia. Endoscopic ultrasound examination revealed a 4*1.6*0.7 cm mucosal hemicircumferential lesion without regional adenopathy. Pathological findings from the oesophagectomy specimen confirmed oesophageal papillomatosis with no malignancy. Surveillance endoscopy 4 months later revealed the lesion had increased in size. Additional ablative therapies failed, and the patient underwent oesophagectomy. Surveillance CT of the chest and abdomen at 3 months and oesophagogastroduodenoscopy at 6 months were negative. This case illustrates that oesophageal squamous papillomatosis not amenable to medical therapy requires surgical treatment. PMID- 24789150 TI - Curious case of calciphylaxis leading to acute mitral regurgitation. AB - Calciphylaxis is uncommon and typically seen in patients with end-stage renal disease. It has been defined as a vasculopathic disorder characterised by cutaneous ischaemia and necrosis due to calcification, intimal fibroplasia and thrombosis of pannicular arterioles. We present the case of a 74-year-old woman with chronic kidney disease stage III who developed calciphylaxis leading to mitral valve calcification, chordae tendineae rupture and acute mitral regurgitation. Although an alternative explanation can typically be found for non uraemic calciphylaxis, her evaluation did not reveal any usual non-uraemic causes including elevated calcium-phosphorus product, hyperparathyroidism, or evidence of connective tissue disease. Her wounds improved with sodium thiosulfate, pamidronate, penicillin and hyperbaric oxygen therapies but she ultimately decompensated with the onset of acute mitral regurgitation attributed to rupture of a previously calcified chordae tendineae. This case highlights an unusual case of calciphylaxis without clear precipitant as well as a novel manifestation of the disease. PMID- 24789151 TI - Carney complex: fourth time excision of recurrent atrial myxoma via left thoracotomy. AB - We report a case of a 51-year-old male patient with a known history of Carney complex, who was operated on for the fourth time due to recurrent left atrial myxomas. Despite surgical challenge, the operation was uneventful. The patient had a difficult postoperative period and needed further treatment for complications. After a prolonged recovery, he is currently well and remains myxoma-free up until now (36 months postsurgery) with regular follow-up using cardiac CT and transthoracic echocardiogram. PMID- 24789152 TI - Ring sequestrum of the tibia. PMID- 24789153 TI - Necrotising fasciitis due to an infected sebaceous cyst. AB - The current case presents a patient who was admitted to our hospital with the diagnosis of cellulitis of the right groin. In the following days, the patient's condition deteriorated and developed a septic shock. Exploration in the operating room showed a necrotising fasciitis of the adductor muscles, with an infected sebaceous cyst in the inguinal crest as port d'entree. After extensive surgical debridement, antibiotic therapy, haemodynamic and respiratory support, the patient recovered. Necrotising fasciitis is a rare but very lethal condition, which necessitates aggressive surgical therapy and antibiotic support. The current case report is the first report to show a necrotising fasciitis due to an infected sebaceous cyst. PMID- 24789154 TI - Acute alveolar sarcoidosis presenting with hypoxaemic respiratory failure. AB - Alveolar sarcoidosis is a less commonly seen pulmonary manifestation of the disease. An acute presentation of this radiological pattern with hypoxaemic respiratory failure has been documented only once, four decades ago. A 30-year old man presented with acute onset of progressive and persistent dyspnoea over 20 days ago with hypoxaemic respiratory failure. Imaging demonstrated mediastinal lymphadenopathy and coalescent parenchymal alveolar opacities having ill-defined margins along with air bronchograms in the mid and lower zones bilaterally, suggestive of alveolar sarcoidosis. A restrictive pattern with a diffusion defect was seen on pulmonary function testing. Bronchoscopic evaluation revealed non caseating granulomas on histopathology confirming pulmonary sarcoidosis. This was further supported by an elevated serum ACE level and negative Mantoux test. Oral prednisolone elicited a rapid clinical and radiological response. Alveolar sarcoidosis can rarely present acutely with hypoxaemic respiratory failure, which can respond remarkably and expeditiously to appropriate therapy. PMID- 24789155 TI - Spondylitic psoriatic arthritis presenting as acute urinary retention. AB - Psoriatic arthritis is a seronegative arthropathy occurring in the presence of psoriasis. In majority of cases, typical psoriatic skin lesions precede joint disease, making diagnosis of psoriatic arthritis without typical skin lesions, a diagnostic challenge. Nail lesions are commonly seen in patients affected by this condition, making it a useful clue in the diagnosis of psoriatic arthritis. This is a case of a 58-year-old Filipino woman presenting with sudden acute urinary retention and weakness of both lower extremities accompanied with active polyarthritis. Onycholytic nail changes initially thought to be a fungal nail infection led to the diagnosis of psoriatic arthritis involving the spine. The patient was eventually treated with methotrexate and non-steroidal anti inflammatory drugs leading to full resolution of symptoms. The patient is currently ambulatory and on regular follow-up. This case report highlights the importance of clinical and physical findings particularly the nails that would lead to a diagnosis of psoriatic arthritis. PMID- 24789156 TI - Postpartum HELLP syndrome and subcapsular liver haematoma. PMID- 24789157 TI - Bilateral eruption cysts associated with primary molars in both the jaws. AB - Disturbances of tooth development may result in anomalies which appear in the form of swelling of the overlying mucosa of the erupting deciduous or permanent teeth, mostly in children. Eruption cyst (EC), a benign cyst is one such lesion associated with erupting teeth. ECs usually present as solitary swellings on the alveolar ridge mucosa, whereas multiple ECs presenting simultaneously or in short intervals are unusual. Here, we present a rare case of four large bilateral ECs presenting with swellings and pain in the posterior region of each quadrant in the mouth. The treatment included surgical excision under general anaesthesia and exposure of the unerupted primary teeth. PMID- 24789158 TI - Prednisone induced two-way myocardial development in a patient with systemic lupus erythematosus. AB - We present a series of echocardiography images to demonstrate the myocardial response to a high dose of prednisone. A young woman with systemic lupus erythematosus (SLE) associated with interventricular septal hypertrophy exhibited a high pressure gradient between the ascending aorta and left ventricular outflow tract as well as significant systolic anterior motion (SAM) and mitral regurgitation (MR) during high-dose prednisone treatment. However, the pressure gradient decreased dramatically and the MR disappeared rapidly when the dose of prednisone was reduced. To the best of our knowledge, this is the only adult case of myocardial hypertrophy that is assumed to be related to prednisone use. PMID- 24789159 TI - Molar pregnancy after tubal ligation in a patient with neuroendocrine tumour: when a rare condition coincides with an unexpected diagnosis. AB - A 40-year-old woman with a history of bilateral tubal ligation and a recent diagnosis of metastatic neuroendocrine tumour in the liver presented with severe nausea, vomiting, diarrhoea and dehydration. She had an inconclusive urine pregnancy test in the emergency department that was followed by an extremely high serum beta-human chorionic gonadotropin. Transvaginal ultrasound, MRI and subsequent pathology from a dilation and curettage (D&C) revealed that the patient had a complete molar pregnancy. This is a case of an unusual patient who reminds us that one person can have a rare diagnosis and an unexpected obstetrical outcome. We could find no evidence in the medical literature of a causal link between these two diagnoses but present this case report of a reproductive age woman with neuroendocrine tumour and complete molar pregnancy. This case also serves as an example of the phenomenon of the 'hook effect.' PMID- 24789160 TI - Anaplastic astrocytoma presenting with simultaneous cranial nerve, brainstem and spinal leptomeningeal metastases. PMID- 24789161 TI - Low back pain in a diabetic on chronic haemodialysis: pyogenic spondylodiscitis. AB - Spondylodiscitis of the lumbar spine is described in a 67-year-old-man receiving chronic haemodialysis via a central venous catheter for diabetic nephropathy. He also had a forearm arteriovenous fistula created 1 month earlier. Clinical, MRI and surgical findings are described. The patient died despite spinal surgery and 1 month of antibiotic therapy from suspected pulmonary embolism. Early recognition by MRI or other imaging technique, prompt antibiotic therapy and often surgery are necessary for a successful outcome in this increasingly recognised complication in patients on chronic haemodialysis. Diabetes mellitus may be an added risk factor. PMID- 24789162 TI - Hepatitis E-associated encephalopathy in a renal transplant recipient. AB - Hepatitis E virus genotype 3 is not rare in developed countries, and may cause chronic hepatitis in immunocompromised patients. This may not only lead to abnormalities in liver test and malaise, but to severe neurological symptoms as well. In this case, chronic hepatitis E infection caused encephalopathy, an atactic gait, Lhermitte's sign, incomplete bladder emptying and peripheral sensory neuropathy in a renal transplant recipient. The diagnosis was not performed until years after the onset of first symptoms and several months after the onset of neurological symptoms. If treated adequately, viral load can be reduced in over two-thirds of patients and neurological symptoms are often resolved. More widespread knowledge about this virus and its extrahepatic manifestations may lead to a quicker diagnosis, and may limit pathology. Serological screening should be added to standard pretransplant virological screening, so that, in the future, patients without antibodies could be vaccinated. PMID- 24789163 TI - Malignant renal angiomyolipoma without tuberous sclerosis. AB - A 68-year-old woman presented with abdominal pain, fatigue, anorexia and night sweats. Imaging studies identified a vascular mass extending from the upper pole of the right kidney with anterior displacement to the abdominal midline, consistent with renal cell carcinoma. A radical nephrectomy and right pelvic lymph node dissection was performed. Pathology determined a grade 4 malignant epithelioid angiomyolipoma that invaded hilar and perinephric adipose tissue. Gross tumour was also present within the renal vein, sinus, pelvis, capsule and perinephric fat. The tumour was HMB-45 positive, supporting the diagnosis of a typical angiomyolipoma in association with the high-grade epithelioid tumour. PMID- 24789164 TI - Spontaneous osteonecrosis of the knee: an unusual cause of knee pain. PMID- 24789165 TI - Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells. AB - Luteolin, a flavonoid extracted from a number of plants with recognized anticancer, anti-inflammatory and anti-oxidative activities, inhibits angiogenic processes and modulates multidrug resistance. However, the efficacy and mechanisms of action of this flavonoid agent are still undergoing study. In order to elucidate whether luteolin exhibits an anticancer effect in cervical cancer cells, HeLa cells were incubated with luteolin and apoptosis was assessed by observing nuclear morphological changes, and performing Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cell cycle analysis, western blotting, RT-PCR and mitochondrial membrane potential measurements were also carried out. Luteolin showed a significant dose-dependent cytotoxic effect only in human papillomavirus (HPV)-positive cervical cancer cells, when compared to its effect on HPV-negative cervical cancer C33A cells. Expression levels of human papilloma virus E6 and E7 oncogenes were suppressed, those of related factors pRb and p53 were recovered and E2F5 was increased by luteolin treatment. Furthermore, luteolin enhanced the expression of death receptors and death receptor downstream factors such as Fas/FasL, DR5/TRAIL and FADD in HeLa cells, and activated caspase cascades. In particular, luteolin enhanced the activity of caspase-3 and -8 in a dose-dependent manner. Activation of caspase-3 induced caspase-8 activity and vice versa. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and inhibited Bcl-2 and Bcl-xL expression. In conclusion, luteolin exerts anticarcinogenic activity through inhibition of E6 and E7 expression and cross-activation of caspase-3 and -8. Taken together, these results suggest that luteolin induces inactivation of HPV 18 oncogene expression and apoptosis by activating the intrinsic and extrinsic pathways. PMID- 24789167 TI - Zygote serine decreased uptake from the fertilization medium is associated with implantation and pregnancy. AB - PURPOSE: To identify an association between amino acids (AAs) metabolism and reproductive outcome. METHODS: Prospective collection, observational study, in patients undergoing fresh, double embryo transfer (ET), in a tertiary hospital referral IVF unit. Spent day 1 and day 3 media were collected. Concentrations of taurine, aspartic acid, proline, and serine in the medium were determined using a liquid-chromatography mass-spectrometer (LCMS/MS). Data was analyzed according to excretion versus uptake, and a cut-off value was calculated based on a receiver operating curve (ROC). Pregnancy rates were also calculated after stratification into subgroups in accordance with AA metabolism. RESULTS: Seven out of 19 patients conceived (36.8 %). The ORs for pregnancy when the zygotes secreted aspartic acid, serine and proline above the cut-off value were 2.9, 5.67 and 5.21 (p < 0.05). When both transferred embryos were above the cut-off value of serine the PR's were 62.5 %, 12.5 % when both were below, and 33.3 % when one was above and the other below (p = 0.04). Similar results were obtained for proline; PR's were 66.7, 18.7 and 28.6 % respectively, but with a borderline statistical significance (p = 0.08). The same trend was observed in the case of aspartic acid but not near statistical significance. No differences in PRs were found in association with taurine turnover during fertilization or any of the studied AAs during the cleavage stage. There was no correlation between zygote or embryo AAs metabolism and embryo morphology. CONCLUSIONS: Serine and possibly proline decreased uptake from the fertilization medium is associated with pregnancy and might be useful for embryo selection. PMID- 24789168 TI - Anethole and eugenol reduce in vitro and in vivo leukocyte migration induced by fMLP, LTB4, and carrageenan. AB - The aim of this study was to investigate the effect of anethole (AN) and eugenol (EUG) on leukocyte migration using in vitro chemotaxis and in situ microcirculation assays. BALB/c mice were used for the in vitro chemotaxis assay, and Wistar rats for the in situ microcirculation assay. We evaluated (a) the in vitro leukocyte migration in response to chemotactic factors (formyl-methionyl leucyl-phenylalanine [fMLP] and leukotriene B4 [LTB4]) and (b) the rolling, adhesion, and migration of leukocytes induced by an injection of carrageenan (100 ug/cavity) into the scrotum of the animal. In the in vitro chemotaxis assay, AN and EUG at doses of 1, 3, 9, and 27 ug/ml significantly inhibited leukocyte migration when stimulated by the chemotactic agents fMLP and LTB4. In the in situ microcirculation assay, AN at doses of 125 and 250 mg/kg and EUG at a dose of 250 mg/kg significantly decreased the number of leukocytes that rolled, adhered, and migrated to perivascular tissue. The results indicate that AN and EUG exert inhibitory effects on leukocyte migration, highlighting their possible use to diminish excessive leukocyte migration in the inflammatory process. PMID- 24789170 TI - Tuberculosis in liver transplant recipients: experience of a South Indian liver transplant center. AB - Tuberculosis (TB) is a serious disease for liver transplant recipients (LTRs). Data on post-liver transplant TB from high-burden countries are scant. The aims of this study were to describe the prevalence of TB in LTRs from a high prevalence area and to analyze the risk factors for the development of post-liver transplant TB. We performed a retrospective review of our database and a case control study of identified cases with TB and age-matched LTRs without TB. The overall prevalence of TB in LTRs was comparable to the prevalence of TB in LTRs from low-prevalence countries (5/214 or 2.3%). A low rate of interferon-gamma release assay (IGRA) testing before liver transplantation was observed (68/214 or 31%). Most patients were screened clinically and with chest radiography alone before transplantation. TB developed variably after transplantation [median = 72 days, interquartile range (IQR) = 534 days]. The presentation was mostly extrapulmonary and/or disseminated (4/5 or 80%). When cases with posttransplant TB were compared with matched healthy LTRs, the presence of unexplained granulomas in explants (2/5 or 40%, P = 0.01) was the only factor associated with the development of TB. When all explants showing granulomas were reviewed, TB (52.9%) remained the most common cause; however, in almost half (47.1%), other attributable causes were found. Patients were treated with a standard daily regimen for a median of 12 months (IQR = 7.5 months). Posttransplant TB was associated with a high mortality rate (2/5 or 40%). In conclusion, we observed a low prevalence of TB in LTRs from a high-prevalence region. The presence of granulomas suggestive of TB in liver explants warrants isoniazid prophylaxis in the absence of disease. Post-liver transplant TB is associated with a high mortality rate. The roles of routine IGRA testing and isoniazid prophylaxis in a high-prevalence setting urgently need to be studied. PMID- 24789169 TI - Evaluation of the neuroprotective effect of chrysin via modulation of endogenous biomarkers in a rat model of spinal cord injury. AB - The objective of the present investigation was to evaluate the neuroprotective efficacy of chrysin in an experimental rat model of spinal cord injury (SCI). SCI was induced in male Sprague-Dawley rats by placing an aneurysm clip extradurally for 60 s at T10. The rats received treatment with either vehicle (SCI control) or chrysin (10, 20 and 40 mg/kg, p.o.) for 28 days. The various behavioral, biochemical and molecular parameters were determined. Chronic treatment with chrysin (20 and 40 mg/kg) significantly and dose-dependently (P < 0.05) attenuated the decrease in body weight, urine output, footprint analysis, sperm count and organ weight (testis, seminal vesicle and urinary bladder). It significantly improved (P < 0.05) the nociceptive threshold, motor and sensory nerve conduction velocity. The decreased activity of superoxide dismutase, reduced glutathione and membrane-bound inorganic phosphate were significantly (P < 0.05) restored by chrysin treatment. SCI resulted in a significant increase (P < 0.05) in lipid peroxidase, nitric oxide, tumor necrosis factor alpha, interleukin-1beta, and bax whereas expression of bcl-2 and caspase-3 were significantly (P < 0.05) reduced. These changes were significantly reduced by treatment with chrysin (20 and 40 mg/kg, P < 0.05). Histological aberration induced after SCI in spinal cord, testis, kidney and urinary bladder were restored by treatment with chrysin (20 and 40 mg/kg). In conclusion, chrysin is a potential flavone-possessing antioxidant and its antiapoptotic property caused the subsequent recovery of both motor and sensory functions via modulation of endogenous biomarkers and neuronal apoptosis to inhibit the incidence of neurological deficits due to SCI. PMID- 24789171 TI - Approval after phase I: ceritinib runs the three-minute mile. PMID- 24789172 TI - NY-ESO-1 expression is tightly linked to TMPRSS2-ERG fusion in prostate cancer. AB - BACKGROUND: NY-ESO-1 has been suggested as therapeutic cancer vaccine in prostate cancer. This study was undertaken to explore the relationship of NY-ESO-1 with tumor phenotype, biochemical recurrence, and molecular subgroups in hormone-naive prostate cancers. METHODS: NY-ESO-1 immunohistochemistry was analyzed on a tissue microarray containing 11,152 prostate cancer samples. Results were compared to clinically follow-up data, ERG status, and deletions on PTEN, 3p13, 5q21, and 6q15. RESULTS: NY-ESO-1 expression was absent in benign prostate glands. In prostate cancer, NY-ESO-1 positivity was found 8.8% of our 8,761 interpretable tumors including 5.8% with weak, 2.5% with moderate, and 0.5% with strong expression. There was a threefold higher rate of NY-ESO-1 expression in ERG fusion positive tumors than in ERG negative cancers (P < 0.0001). There was a significant association with early PSA recurrence, which was largely limited to ERG positive cancers. Within the ERG positive subgroup, high NY-ESO-1 expression was associated with early biochemical recurrence (P = 0.0002) and high Gleason grade (P < 0.0001). In ERG negative cancers, NY-ESO-1 expression was also linked to PTEN (P = 0.0012) and 6q15 deletions (P = 0.0005). CONCLUSIONS: Our observations indicate a tight link of NY-ESO-1 expression to ERG activation and (to a lesser extent) PTEN- and 6q15-deletions in prostate cancer. The impact of these interactions on the likelihood of response to immunotherapy is unclear. The prognostic impact of NY-ESO-1 expression is little and not independent of histologic variables. PMID- 24789173 TI - Enhanced dielectric performance in polymer composite films with carbon nanotube reduced graphene oxide hybrid filler. AB - The electrical conductivity and the specific surface area of conductive fillers in conductor-insulator composite films can drastically improve the dielectric performance of those films through changing their polarization density by interfacial polarization. We have made a polymer composite film with a hybrid conductive filler material made of carbon nanotubes grown onto reduced graphene oxide platelets (rG-O/CNT). We report the effect of the rG-O/CNT hybrid filler on the dielectric performance of the composite film. The composite film had a dielectric constant of 32 with a dielectric loss of 0.051 at 0.062 wt% rG-O/CNT filler and 100 Hz, while the neat polymer film gave a dielectric constant of 15 with a dielectric loss of 0.036. This is attributed to the increased electrical conductivity and specific surface area of the rG-O/CNT hybrid filler, which results in an increase in interfacial polarization density between the hybrid filler and the polymer. PMID- 24789174 TI - Combining bar adsorptive microextraction with capillary electrophoresis- application for the determination of phenolic acids in food matrices. AB - In this contribution, bar adsorptive microextraction coated with a mixed-mode anion exchange/RP followed by liquid desorption was combined for the first time with a capillary electrophoresis-diode array detection system (BAMUE(MAX)-LD/CE DAD), for the determination of phenolic acids in food matrices, using chlorogenic, ferulic, cumaric, and caffeic acids as model compounds. Assays performed in aqueous media spiked at the 0.8 mg/L level yielded average recoveries up to 40% for all four phenolic acids, under optimized experimental conditions. The analytical performance showed also good precision (RSD < 15%), convenient LODs (18.0-85.0 MUg/L) and linear dynamic ranges (0.8-8.0 mg/L) with convenient determination coefficients (r(2) > 0.9900). By using the standard addition method, the application to food matrices such as green tea, red fruit juice, and honey allowed very good performances for the determination of minor amounts of phenolic acids. The proposed methodology proved to be a suitable alternative for the analysis of polar to ionic compounds, showing to be easy to implement, reliable, sensitive, and requiring a low sample volume to determine phenolic acids in food samples. PMID- 24789175 TI - Population genetic structure and demographic history of Atrina pectinata based on mitochondrial DNA and microsatellite markers. AB - The pen shell, Atrina pectinata, is one of the commercial bivalves in East Asia and thought to be recently affected by anthropogenic pressure (habitat destruction and/or fishing pressure). Information on its population genetic structure is crucial for the conservation of A. pectinata. Considering its long pelagic larval duration and iteroparity with high fecundity, the genetic structure for A. pectinata could be expected to be weak at a fine scale. However, the unusual oceanography in the coasts of China and Korea suggests potential for restricted dispersal of pelagic larvae and geographical differentiation. In addition, environmental changes associated with Pleistocene sea level fluctuations on the East China Sea continental shelf may also have strongly influenced historical population demography and genetic diversity of marine organisms. Here, partial sequences of the mitochondrial Cytochrome c oxidase subunit I (COI) gene and seven microsatellite loci were used to estimate population genetic structure and demographic history of seven samples from Northern China coast and one sample from North Korea coast. Despite high levels of genetic diversity within samples, there was no genetic differentiation among samples from Northern China coast and low but significant genetic differentiation between some of the Chinese samples and the North Korean sample. A late Pleistocene population expansion, probably after the Last Glacial Maximum, was also demonstrated for A. pectinata samples. No recent genetic bottleneck was detected in any of the eight samples. We concluded that both historical recolonization (through population range expansion and demographic expansion in the late Pleistocene) and current gene flow (through larval dispersal) were responsible for the weak level of genetic structure detected in A. pectinata. PMID- 24789176 TI - Performance of the OraQuick HCV rapid antibody test for screening exposed patients in a hepatitis C outbreak investigation. AB - During a nosocomial hepatitis C outbreak, emergency public clinics employed the OraQuick HCV rapid antibody test on site, and all results were verified by a standard enzyme immunoassay (EIA). Of 1,157 persons, 1,149 (99.3%) exhibited concordant results between the two tests (16 positive, 1,133 negative). The sensitivity, specificity, positive predictive value, and negative predictive value were 94.1%, 99.5%, 72.7%, and 99.9%, respectively. OraQuick performed well as a screening test during an outbreak investigation and could be integrated into future hepatitis C virus (HCV) outbreak testing algorithms. PMID- 24789177 TI - Whole-genome-based Mycobacterium tuberculosis surveillance: a standardized, portable, and expandable approach. AB - Whole-genome sequencing (WGS) allows for effective tracing of Mycobacterium tuberculosis complex (MTBC) (tuberculosis pathogens) transmission. However, it is difficult to standardize and, therefore, is not yet employed for interlaboratory prospective surveillance. To allow its widespread application, solutions for data standardization and storage in an easily expandable database are urgently needed. To address this question, we developed a core genome multilocus sequence typing (cgMLST) scheme for clinical MTBC isolates using the Ridom SeqSphere(+) software, which transfers the genome-wide single nucleotide polymorphism (SNP) diversity into an allele numbering system that is standardized, portable, and not computationally intensive. To test its performance, we performed WGS analysis of 26 isolates with identical IS6110 DNA fingerprints and spoligotyping patterns from a longitudinal outbreak in the federal state of Hamburg, Germany (notified between 2001 and 2010). The cgMLST approach (3,041 genes) discriminated the 26 strains with a resolution comparable to that of SNP-based WGS typing (one major cluster of 22 identical or closely related and four outlier isolates with at least 97 distinct SNPs or 63 allelic variants). Resulting tree topologies are highly congruent and grouped the isolates in both cases analogously. Our data show that SNP- and cgMLST-based WGS analyses facilitate high-resolution discrimination of longitudinal MTBC outbreaks. cgMLST allows for a meaningful epidemiological interpretation of the WGS genotyping data. It enables standardized WGS genotyping for epidemiological investigations, e.g., on the regional public health office level, and the creation of web-accessible databases for global TB surveillance with an integrated early warning system. PMID- 24789178 TI - Comparative evaluation of the Diagenode multiplex PCR assay on the BD max system versus a routine in-house assay for detection of Bordetella pertussis. AB - This study looked at 128 nasopharyngeal aspirates (NPA) and 162 throat swabs (TS) tested with the Diagenode multiplex assay on the BD Max system versus our in house Bordetella pertussis PCR. Sensitivity and specificity were 97.3% and 100% for NPA and 88.3% and 98% for TS, respectively. Of positive NPA, 42.1% were coinfected with respiratory viruses. PMID- 24789179 TI - Emergence of new CMRSA7/USA400 methicillin-resistant Staphylococcus aureus spa types in Alberta, Canada, from 2005 to 2012. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most significant pathogens affecting global public health and health care systems. In Canada and the United States, the spread of MRSA is primarily attributed to a single dominant epidemic clone: CMRSA10/USA300. Despite this, the CMRSA7/USA400 epidemic clone has been reported to be the predominate epidemic clone in several Canadian provinces and some parts of the United States. This study examined the epidemiology of CMRSA7/USA400 MRSA in Alberta, Canada, from June 2005 to December 2012. Molecular characterization of CMRSA7/USA400 isolates was done using spa, SCCmec, PVL, and PFGE typing and identified two predominant spa types in Alberta: t128 and t1787. Although closely related, these spa types have distinct geographic distributions. From 2010 to 2012, the number of t128 infections has remained stable while there has been a nearly 3-fold increase in the number of provincial t1787 infections, accompanied by 10-fold increases in t1787 infection rates in some communities. Most t128 and t1787 patients were First Nations or Inuit people, and isolates were usually from skin and soft tissue infections in outpatients. t128 patients were significantly older than t1787 patients. Antimicrobial susceptibility testing showed higher mupirocin resistance in t1787 than in t128 MRSA. Improved strategies to reduce or stabilize t1787 infections in Alberta are needed. PMID- 24789180 TI - Use of imipenem to detect KPC, NDM, OXA, IMP, and VIM carbapenemase activity from gram-negative rods in 75 minutes using liquid chromatography-tandem mass spectrometry. AB - Resistance to extended-spectrum beta-lactam antibiotics has led to a greater reliance upon carbapenems, but the expression of carbapenemases threatens to limit the utility of these drugs. Current methods to detect carbapenemase activity are suboptimal, requiring prolonged incubations during which ineffective therapy may be prescribed. We previously described a sensitive and specific assay for the detection of carbapenemase activity using ertapenem and liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we assessed 402 Gram-negative rods, including both Enterobacteriaceae and non Enterobacteriaceae expressing IMP, VIM, KPC, NDM, and/or OXA carbapenemases, by using imipenem, meropenem, and ertapenem with LC-MS/MS assays. LC-MS/MS methods for the detection of intact and hydrolyzed carbapenems from an enrichment broth were developed. No ion suppression was observed, and the limits of detection for all three drugs were below 0.04 MUg/ml. The sensitivity and specificity of meropenem and ertapenem for carbapenemase activity among non-Enterobacteriaceae were low, but imipenem demonstrated a sensitivity and specificity of 96% and 95%, respectively, among all Gram-negative rods (GNR) tested, including both Enterobacteriaceae and non-Enterobacteriaceae. LC-MS/MS allows for the analysis of more complex matrices, and this LC-MS/MS assay could easily be adapted for use with primary specimens requiring growth enrichment. PMID- 24789181 TI - Mixed Mycobacterium tuberculosis complex infections and false-negative results for rifampin resistance by GeneXpert MTB/RIF are associated with poor clinical outcomes. AB - The Xpert MTB/RIF (Xpert) assay is becoming a principal screening tool for diagnosing rifampin-resistant Mycobacterium tuberculosis complex (MTBC) infection. However, little is known about the performance of the Xpert assay in infections with both drug-sensitive and drug-resistant strains (mixed MTBC infections). We assessed the performance of the Xpert assay for detecting rifampin resistance using phenotypic drug sensitivity testing (DST) as the reference standard in 370 patients with microbiologically proven pulmonary tuberculosis. Mixed MTBC infections were identified genetically through 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU VNTR) analysis. Logistic regression was used to identify the factors associated with poor (defined as treatment failure, default, and death from any cause) or good (defined as cure or successful treatment completion) clinical outcomes. The analytic sensitivity of the Xpert assay for detecting rifampin resistance was assessed in vitro by testing cultures containing different ratios of drug sensitive and drug-resistant organisms. Rifampin resistance was detected by the Xpert assay in 52 (14.1%) and by phenotypic DST in 55 (14.9%) patients. Mixed MTBC infections were identified in 37 (10.0%) patients. The Xpert assay was 92.7% (95% confidence interval [CI], 82.4% to 97.9%) sensitive for detecting rifampin resistance and 99.7% (95% CI, 98.3% to 99.9%) specific. When restricted to patients with mixed MTBC infections, Xpert sensitivity was 80.0% (95% CI, 56.3 to 94.3%). False-negative Xpert results (adjusted odds ratio [aOR], 6.6; 95% CI,1.2 to 48.2) and mixed MTBC infections (aOR, 6.5; 95% CI, 2.1 to 20.5) were strongly associated with poor clinical outcome. The Xpert assay failed to detect rifampin resistance in vitro when <90% of the organisms in the sample were rifampin resistant. Our study indicates that the Xpert assay has an increased false negative rate for detecting rifampin resistance with mixed MTBC infections. In hyperendemic settings where mixed infections are common, the Xpert results might need further confirmation. PMID- 24789182 TI - Multicenter feasibility study to assess external quality assessment panels for Xpert MTB/RIF assay in South Africa. AB - External quality assessment (EQA) for the Xpert MTB/RIF assay is part of the quality system required for clinical and laboratory practice. Five newly developed EQA panels that use different matrices, including a lyophilized sample (Vircell, Granada, Spain), a dried tube specimen (CDC), liquid (Maine Molecular Quality Control, Inc. [MMQCI], Scarborough, ME), artificial sputum (Global Laboratory Initiative [GLI]), and a dried culture spot (National Health Laboratory Services [NHLS]), were evaluated at 11 GeneXpert testing sites in South Africa. The panels comprised Mycobacterium tuberculosis complex (MTBC) negative, MTBC-positive (including rifampin [RIF] susceptible and RIF resistant), and nontuberculosis mycobacterial material that was inactivated and safe for transportation. Twelve qualitative and quantitative variables were scored as acceptable (1) or unacceptable (0); the overall panel performance score for the Vircell, CDC, GLI, and NHLS panels was 9 of 12, while the MMQCI panel scored 6 of 12 (owing to the need for cold chain maintenance). All panels showed good compatibility with Xpert MTB/RIF testing, and none showed PCR inhibition. The use of a liquid or dry matrix did not appear to be a distinguishing criterion, as both matrices had reduced scores on insufficient volumes, a need for extra consumables, and the ability to transfer to the Xpert MTB/RIF cartridge. EQA is an important component of the quality system required for diagnostic testing programs, but it must be complemented by routine monitoring of performance indicators and instrument verification. This study aims to introduce EQA concepts for Xpert MTB/RIF testing and evaluates five potential EQA panels. PMID- 24789183 TI - Lowenstein-Jensen selective medium for reducing contamination in Mycobacterium tuberculosis culture. AB - We compared Mycobacterium tuberculosis sputum culture recovery and contamination rates between Lowenstein-Jensen medium (LJ) containing the following decontaminants and LJ alone: (i) PANTA (n = 299), (ii) Selectatab-MB (n = 299), and (iii) penicillin G (n = 234). The contamination rate for LJ alone was approximately 31%, versus 5.0% for PANTA-containing, 2% for Selectatab containing, and 9% for penicillin-containing media (P < 0.001). M. tuberculosis isolation rates were 9.8%, 17%, 18%, and 12% for standard LJ, PANTA, Selectatab, and penicillin cultures, respectively. PMID- 24789184 TI - Next-generation sequencing for typing and detection of resistance genes: performance of a new commercial method during an outbreak of extended-spectrum beta-lactamase-producing Escherichia coli. AB - Next-generation sequencing (NGS) has the potential to provide typing results and detect resistance genes in a single assay, thus guiding timely treatment decisions and allowing rapid tracking of transmission of resistant clones. We evaluated the performance of a new NGS assay (Hospital Acquired Infection BioDetection System; Pathogenica) during an outbreak of sequence type 131 (ST131) Escherichia coli infections in a nursing home in The Netherlands. The assay was performed on 56 extended-spectrum-beta-lactamase (ESBL) E. coli isolates collected during 2 prevalence surveys (March and May 2013). Typing results were compared to those of amplified fragment length polymorphism (AFLP), whereby we visually assessed the agreement of the BioDetection phylogenetic tree with clusters defined by AFLP. A microarray was considered the gold standard for detection of resistance genes. AFLP identified a large cluster of 31 indistinguishable isolates on adjacent departments, indicating clonal spread. The BioDetection phylogenetic tree showed that all isolates of this outbreak cluster were strongly related, while the further arrangement of the tree also largely agreed with other clusters defined by AFLP. The BioDetection assay detected ESBL genes in all but 1 isolate (sensitivity, 98%) but was unable to discriminate between ESBL and non-ESBL TEM and SHV beta-lactamases or to specify CTX-M genes by group. The performance of the hospital-acquired infection (HAI) BioDetection System for typing of E. coli isolates compared well with the results of AFLP. Its performance with larger collections from different locations, and for typing of other species, was not evaluated and needs further study. PMID- 24789185 TI - Incidence of extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates that test susceptible to cephalosporins and aztreonam by the revised CLSI breakpoints. AB - The incidence of aztreonam and cephalosporin susceptibility, determined using the revised CLSI breakpoints, for extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae isolates was evaluated. Our analysis showed that results for aztreonam and/or >=1 cephalosporin were reported as susceptible or intermediate for 89.2% of ESBL-producing E coli isolates (569/638 isolates) and 67.7% of ESBL-producing K. pneumoniae isolates (155/229 isolates). PMID- 24789187 TI - Real-Time Detection of HIV-2 by Reverse Transcription-Loop-Mediated Isothermal Amplification. AB - Currently, there are no FDA-approved nucleic acid amplification tests (NAATs) for the detection or confirmation of HIV-2 infection. Here, we describe the development of a real-time assay for the detection of HIV-2 DNA and RNA using reverse transcription-loop-mediated isothermal amplification (RT-LAMP) and the ESEQuant tube scanner, a portable isothermal amplification/detection device. PMID- 24789186 TI - Clinical, morphological, and molecular characterization of Penicillium canis sp. nov., isolated from a dog with osteomyelitis. AB - Infections caused by Penicillium species are rare in dogs, and the prognosis in these cases is poor. An unknown species of Penicillium was isolated from a bone lesion in a young dog with osteomyelitis of the right ilium. Extensive diagnostic evaluation did not reveal evidence of dissemination. Resolution of lameness and clinical stability of disease were achieved with intravenous phospholipid complexed amphotericin B initially, followed by long-term combination therapy with terbinafine and ketoconazole. A detailed morphological and molecular characterization of the mold was undertaken. Sequence analysis of the internal transcribed spacer revealed the isolate to be closely related to Penicillium menonorum and Penicillium pimiteouiense. Additional sequence analysis of beta tubulin, calmodulin, minichromosome maintenance factor, DNA-dependent RNA polymerase, and pre-rRNA processing protein revealed the isolate to be a novel species; the name Penicillium canis sp. nov. is proposed. Morphologically, smooth, ovoid conidia, a greenish gray colony color, slow growth on all media, and a failure to form ascomata distinguish this species from closely related Penicillium species. PMID- 24789188 TI - First human case of Fastidiosipila sanguinis infection. AB - Fastidiosipila sanguinis is a Gram-positive anaerobic coccus. We report the first case of osteitis implicating this species. The strain was accurately identified by 16S rRNA sequence analysis, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification having failed. The reservoir remained unclear; an endogenous origin is suspected. PMID- 24789189 TI - Evaluation of the Bio-Rad Geenius HIV 1/2 assay as an alternative to the INNO-LIA HIV 1/2 assay for confirmation of HIV infection. AB - The Bio-Rad Geenius HIV 1/2 assay was evaluated as an alternative to the INNO-LIA HIV 1/2 assay for the confirmation of HIV infection in 198 serum samples reactive to 4th-generation HIV enzyme immunoassays (EIAs). The Geenius assay correctly identified 85% of the samples, compared to 75% identified by the INNO-LIA assay, reduced the number of indeterminate results, and shortened the overall turnaround time. PMID- 24789191 TI - Development and clinical evaluation of sdaA loop-mediated isothermal amplification assay for detection of Mycobacterium tuberculosis with an approach to prevent carryover contamination. AB - A rapid and sensitive loop-mediated isothermal amplification assay for the sdaA gene of Mycobacterium tuberculosis was developed using a dUTP-uracil-N glycosylase (dUTP-UNG) strategy to prevent carryover contamination. Evaluation of the assay using clinical specimens (n = 648) showed high specificity (97.2%) and sensitivity (100%), demonstrating its potential as a diagnostic test for tuberculosis, especially in resource-limited settings. PMID- 24789190 TI - Predicted configurations of oligosaccharide extensions in the lipooligosaccharide of nontypeable Haemophilus influenzae isolates. AB - Lipooligosaccharide configurations were predicted in nontypeable Haemophilus influenzae isolates based on the presence of seven oligosaccharide extension initiating genes (or alleles). Predicted configurations with 2 to 3 oligosaccharide extensions were more prevalent among middle ear than throat strains. In addition, strains with these configurations averaged higher levels of serum resistance than strains with other configurations. PMID- 24789192 TI - Breakthrough invasive Candida glabrata in patients on micafungin: a novel FKS gene conversion correlated with sequential elevation of MIC. AB - Candida glabrata strains sequentially isolated from blood developed resistance to micafungin (MICs from <0.015 to 4 MUg/ml). A novel mutation identified in micafungin-resistant strains at bp 262 of FKS2 (containing a deletion of F659 [F659del]) was inserted into the homologous region in FKS1. PMID- 24789193 TI - Mycobacterium arupense flexor tenosynovitis: case report and review of antimicrobial susceptibility profiles for 40 clinical isolates. AB - We describe a case of chronic tenosynovitis in the hand of a 58-year-old cattle farmer. Surgical biopsy specimens grew Mycobacterium arupense. The patient responded to surgery and antimicrobial therapy based on in vitro susceptibility testing. The antimicrobial susceptibility profiles of the isolate from this patient and 39 additional clinical isolates are presented. PMID- 24789194 TI - Comparison of rates of positivity for Bordetella pertussis by real-time PCR between specimens collected with rayon swabs on aluminum wire shaft in Amies gel with charcoal and specimens collected with flocked swabs in universal viral transport medium during an epidemic. AB - A comparison of real-time PCR positivity rates for Bordetella pertussis between specimens collected with rayon swabs on an aluminum wire shaft in Amies gel with charcoal and those collected with flocked swabs in universal viral transport medium during an epidemic revealed that their performances were comparable. PMID- 24789196 TI - Evaluation of Curetis Unyvero, a multiplex PCR-based testing system, for rapid detection of bacteria and antibiotic resistance and impact of the assay on management of severe nosocomial pneumonia. AB - Health care-associated pneumonia due to multidrug-resistant organisms represents a major therapeutic challenge. Unfortunately, treatment is dependent on empirical therapy, which often leads to improper and inadequate antimicrobial therapy. A rapid multiplex PCR-based Unyvero pneumonia application (UPA) assay that assists in timely decision-making has recently become available. In this study, we evaluated the performance of UPA in detecting etiological pathogens and resistance markers in patients with nosocomial pneumonia (NP). The impact of this assay on the management of severe nosocomial pneumonia was also assessed. Appropriate specimens were processed by UPA according to the manufacturer's protocol in parallel with conventional culture methods. Of the 56 patients recruited into the study, 49 (87.5%) were evaluable. Of these, 27 (55.1%) and 4 (8.2%) harbored multiple bacteria by the PCR assay and conventional culture, respectively. A single pathogen was detected in 8 (16.3%) and 4 (8.2%) patients, respectively. Thirteen different genes were detected from 38 patients, including the ermB gene (40.8%), the blaOXA-51-like gene (28.6%), the sul1 (28.6%) and int1 (20.4%) integrase genes, and the mecA and blaCTX-M genes (12.3% each). The time from sample testing to results was 4 h versus 48 to 96 h by UPA and culture, respectively. Initial empirical treatment was changed within 5 to 6 h in 33 (67.3%) patients based on the availability of UPA results. Thirty (62.2%) of the patients improved clinically. A total of 3 (6.1%) patients died, mainly from their comorbidities. These data demonstrate the potential of a multiplex PCR based assay for accurate and timely detection of etiological agents of NP, multidrug-resistant (MDR) organisms, and resistance markers, which can guide clinicians in making early antibiotic adjustments. PMID- 24789195 TI - Rearrangement of a large novel Pseudomonas aeruginosa gene island in strains isolated from a patient developing ventilator-associated pneumonia. AB - Bacterial gene islands add to the genetic repertoire of opportunistic pathogens. Here, we perform comparative analyses of three Pseudomonas aeruginosa strains isolated sequentially over a 3-week period from a patient with ventilator associated pneumonia (VAP) who received clindamycin and piperacillin-tazobactam as part of their treatment regime. While all three strains appeared to be clonal by standard pulsed-field gel electrophoresis, whole-genome sequencing revealed subtle alterations in the chromosomal organization of the last two strains; specifically, an inversion event within a novel 124-kb gene island (PAGI 12) composed of 137 open reading frames [ORFs]. Predicted ORFs in the island included metabolism and virulence genes. Overexpression of a gene island-borne putative beta-lactamase gene was observed following piperacillin-tazobactam exposure and only in those strains that had undergone the inversion event, indicating altered gene regulation following genomic remodeling. Examination of a separate cohort of 76 patients with VAP for integration at this tRNA(lys) recombination site demonstrated that patients exhibiting evidence of integration at this site had significantly higher 28-day mortality. These findings provide evidence that P. aeruginosa can integrate, rapidly remodel, and express exogenous genes, which likely contributes to its fitness in a clinical setting. PMID- 24789197 TI - Viral load detection using dried blood spots in a cohort of HIV-1-infected children in Uganda: correlations with clinical and immunological criteria for treatment failure. AB - Correlations between clinical/immunological treatment failure and viral load (VL) detected by dried blood spot (DBS) sampling were explored in HIV-1-infected children in Uganda. Of 104 children on combined antiretroviral treatment (cART), 12.5% experienced clinical and/or immunological failure, while 28.8%, 44.2%, and 26.9% had VLs of <1,000, 1,000 to 5,000, and >5,000 copies/ml, respectively. Clinical/immunological failure poorly predicted virological failure. PMID- 24789198 TI - Improved molecular typing assay for rhinovirus species A, B, and C. AB - Human rhinoviruses (RVs), comprising three species (A, B, and C) of the genus Enterovirus, are responsible for the majority of upper respiratory tract infections and are associated with severe lower respiratory tract illnesses such as pneumonia and asthma exacerbations. High genetic diversity and continuous identification of new types necessitate regular updating of the diagnostic assays for the accurate and comprehensive detection of circulating RVs. Methods for molecular typing based on phylogenetic comparisons of a variable fragment in the 5' untranslated region were improved to increase assay sensitivity and to eliminate nonspecific amplification of human sequences, which are observed occasionally in clinical samples. A modified set of primers based on new sequence information and improved buffers and enzymes for seminested PCR assays provided higher specificity and sensitivity for virus detection. In addition, new diagnostic primers were designed for unequivocal species and type assignments for RV-C isolates, based on phylogenetic analysis of partial VP4/VP2 coding sequences. The improved assay was evaluated by typing RVs in >3,800 clinical samples. RVs were successfully detected and typed in 99% of the samples that were RV positive in multiplex diagnostic assays. PMID- 24789199 TI - Development and application of a multilocus sequence typing scheme for Streptococcus gallolyticus subsp. gallolyticus. AB - Streptococcus gallolyticus subsp. gallolyticus (formerly known as S. bovis biotype I) is a commensal of the gastrointestinal tract in animals and in up to 15% of healthy humans. Furthermore, it is a facultative pathogen that can cause infectious endocarditis, mastitis, and septicemia. The number of infections is increasing, but the transmission routes and zoonotic potential remain unknown. To assess the zoonotic potential and characterize the epidemiological structure of S. gallolyticus subsp. gallolyticus, we established a multilocus sequence typing (MLST) scheme. We amplified and sequenced internal fragments of seven housekeeping genes. The resulting sequences were analyzed with BioNumerics software 6.6 by using the unweighted-pair group method using average linkages algorithm. A total of 101 S. gallolyticus subsp. gallolyticus strains isolated from animals, humans, and environmental samples were analyzed and divided into 50 sequence types. Our first results highlight the importance of this MLST scheme for investigating the epidemiology, transmission patterns, and infection chains of S. gallolyticus subsp. gallolyticus. PMID- 24789200 TI - DNA damage in buccal mucosa cells of pre-school children exposed to high levels of urban air pollutants. AB - Air pollution has been recognized as a human carcinogen. Children living in urban areas are a high-risk group, because genetic damage occurring early in life is considered able to increase the risk of carcinogenesis in adulthood. This study aimed to investigate micronuclei (MN) frequency, as a biomarker of DNA damage, in exfoliated buccal cells of pre-school children living in a town with high levels of air pollution. A sample of healthy 3-6-year-old children living in Brescia, Northern Italy, was investigated. A sample of the children's buccal mucosa cells was collected during the winter months in 2012 and 2013. DNA damage was investigated using the MN test. Children's exposure to urban air pollution was evaluated by means of a questionnaire filled in by their parents that included items on various possible sources of indoor and outdoor pollution, and the concentration of fine particulate matter (PM10, PM2.5) and NO2 in the 1-3 weeks preceding biological sample collection. 181 children (mean age +/- SD: 4.3 +/- 0.9 years) were investigated. The mean +/- SD MN frequency was 0.29 +/- 0.13%. A weak, though statistically significant, association of MN with concentration of air pollutants (PM10, PM2.5 and NO2) was found, whereas no association was apparent between MN frequency and the indoor and outdoor exposure variables investigated via the questionnaire. This study showed a high MN frequency in children living in a town with heavy air pollution in winter, higher than usually found among children living in areas with low or medium-high levels of air pollution. PMID- 24789201 TI - Coordinated regulation of nuclear receptor CAR by CCRP/DNAJC7, HSP70 and the ubiquitin-proteasome system. AB - The constitutive active/androstane receptor (CAR) plays an important role as a coordinate transcription factor in the regulation of various hepatic metabolic pathways for chemicals such as drugs, glucose, fatty acids, bilirubin, and bile acids. Currently, it is known that in its inactive state, CAR is retained in the cytoplasm in a protein complex with HSP90 and the tetratricopeptide repeat protein cytosoplasmic CAR retention protein (CCRP). Upon activation by phenobarbital (PB) or the PB-like inducer 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), CAR translocates into the nucleus. We have identified two new components to the cytoplasmic regulation of CAR: ubiquitin-dependent degradation of CCRP and protein-protein interaction with HSP70. Treatment with the proteasome inhibitor MG132 (5 uM) causes CAR to accumulate in the cytoplasm of transfected HepG2 cells. In the presence of MG132, TCPOBOP increases CCRP ubiquitination in HepG2 cells co-expressing CAR, while CAR ubiquitination was not detected. MG132 treatment of HepG2 also attenuated of TCPOBOP-induced CAR transcriptional activation on reporter constructs which contain CAR-binding DNA elements derived from the human CYP2B6 gene. The elevation of cytoplasmic CAR protein with MG132 correlated with an increase of HSP70, and to a lesser extent HSP60. Both CCRP and CAR were found to interact with endogenous HSP70 in HepG2 cells by immunoprecipitation analysis. Induction of HSP70 levels by heat shock also increased cytoplasmic CAR levels, similar to the effect of MG132. Lastly, heat shock attenuated TCPOBOP-induced CAR transcriptional activation, also similar to the effect of MG132. Collectively, these data suggest that ubiquitin-proteasomal regulation of CCRP and HSP70 are important contributors to the regulation of cytoplasmic CAR levels, and hence the ability of CAR to respond to PB or PB-like inducers. PMID- 24789202 TI - Cone beam computed tomographic analysis of neurovascular anatomical variations other than the nasopalatine canal in the anterior maxilla in a pediatric population. AB - PURPOSE: This study aimed to analyze and assess the presence of accessory foramina and canals other than the nasopalatine canal (NPC) in the anterior palate region in a pediatric population, through cone beam computed tomography (CBCT) images, describing their location, direction, and diameter. STUDY DESIGN: Reformatted sagittal, coronal and axial slices of 368 individual CBCT images were analyzed. Any bone canal with a minimum diameter of 1.00 mm other than the nasopalatine canal was analyzed regarding size, location, and course, as well as patient gender and age. RESULTS: Eighty-two patients (22.3 %); presented additional foramina in the anterior palate (AFP) and in total 131 additional foramina were registered. A higher frequency of accessory canals was observed in girls (29.5 %) than in boys (15.7 %) (p = 0.012). The average diameter of AFP was 1.2 mm. Their location was variable, with most of the cases occurring in the alveolar process near the incisors or canines. Gender and age did not significantly influence the diameter. CONCLUSIONS: The study confirms the presence of bone channels within the anterior maxilla other than the NPC in a pediatric population. Over 22 % of the population studied had additional foramina other than the NPC in the anterior palate, between 1 and 1.7 mm wide, with variable locations. PMID- 24789203 TI - Mitochondrial calcium handling within the interstitial cells of Cajal. AB - The interstitial cells of Cajal (ICC) drive rhythmic pacemaking contractions in the gastrointestinal system. The ICC generate pacemaking signals by membrane depolarizations associated with the release of intracellular calcium (Ca(2+)) in the endoplasmic reticulum (ER) through inositol-trisphosphate (IP3) receptors (IP3R) and uptake by mitochondria (MT). This Ca(2+) dynamic is hypothesized to generate pacemaking signals by calibrating ER Ca(2+) store depletions and membrane depolarization with ER store-operated Ca(2+) entry mechanisms. Using a biophysically based spatio-temporal model of integrated Ca(2+) transport in the ICC, we determined the feasibility of ER depletion timescale correspondence with experimentally observed pacemaking frequencies while considering the impact of IP3R Ca(2+) release and MT uptake on bulk cytosolic Ca(2+) levels because persistent elevations of free intracellular Ca(2+) are toxic to the cell. MT densities and distributions are varied in the model geometry to observe MT influence on free cytosolic Ca(2+) and the resulting frequencies of ER Ca(2+) store depletions, as well as the sarco-endoplasmic reticulum Ca(2+) ATP-ase (SERCA) and IP3 agonist concentrations. Our simulations show that high MT densities observed in the ICC are more relevant to ER establishing Ca(2+) depletion frequencies than protection of the cytosol from elevated free Ca(2+), whereas the SERCA pump is more relevant to containing cytosolic Ca(2+) elevations. Our results further suggest that the level of IP3 agonist stimulating ER Ca(2+) release, subsequent MT uptake, and eventual activation of ER store operated Ca(2+) entry may determine frequencies of rhythmic pacemaking exhibited by the ICC across species and tissue types. PMID- 24789204 TI - Esophageal reflexes modulate frontoparietal response in neonates: Novel application of concurrent NIRS and provocative esophageal manometry. AB - Central and peripheral neural regulation of swallowing and aerodigestive reflexes is unclear in human neonates. Functional near infrared spectroscopy (NIRS) is a noninvasive method to measure changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbD). Pharyngoesophageal manometry permits evaluation of aerodigestive reflexes. Modalities were combined to investigate feasibility and to test neonatal frontoparietal cortical changes during pharyngoesophageal (visceral) stimulation and/or swallowing. Ten neonates (45.6 +/- 3.0 wk postmenstrual age, 4.1 +/- 0.5 kg) underwent novel pharyngoesophageal manometry concurrent with NIRS. To examine esophagus-brain interactions, we analyzed cortical hemodynamic response (HDR) latency and durations during aerodigestive provocation and esophageal reflexes. Data are presented as means +/- SE or percent. HDR rates were 8.84 times more likely with basal spontaneous deglutition compared with sham stimuli (P = 0.004). Of 182 visceral stimuli, 95% were analyzable for esophageal responses, 38% for HDR, and 36% for both. Of analyzable HDR (n = 70): 1) HbO concentration (MUmol/l) baseline 1.5 +/- 0.7 vs. 3.7 +/- 0.7 poststimulus was significant (P = 0.02), 2) HbD concentration (MUmol/l) between baseline 0.1 +/- 0.4 vs. poststimulus -0.5 +/ 0.4 was not significant (P = 0.73), and 3) hemispheric lateralization was 21% left only, 29% right only, and 50% bilateral. During concurrent esophageal and NIRS responses (n = 66): 1) peristaltic reflexes were present in 74% and HDR in 61% and 2) HDR was 4.75 times more likely with deglutition reflex vs. secondary peristaltic reflex (P = 0.016). Concurrent NIRS with visceral stimulation is feasible in neonates, and frontoparietal cortical activation is recognized. Deglutition contrasting with secondary peristalsis is related to cortical activation, thus implicating higher hierarchical aerodigestive protective functional neural networks. PMID- 24789205 TI - Role of transient receptor potential vanilloid 4 activation in indomethacin induced intestinal damage. AB - Gastrointestinal ulcers and bleeding are serious complications of nonsteroidal anti-inflammatory drug (NSAID) use. Although administration of antibiotics and Toll-like receptor 4 knockdown mitigate NSAID-induced enteropathy, the molecular mechanism of these effects is poorly understood. Intestinal hyperpermeability is speculated to trigger the initial damage due to NSAID use. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel expressed throughout the gastrointestinal tract epithelium that is activated by temperature, extension, and chemicals such as 5,6-epoxyeicosatrienoic acid (5,6 EET). The aim of this study was to investigate the possible role of TRPV4 in NSAID-induced intestinal damage. TRPV4 mRNA and protein expression was confirmed by RT-PCR and immunochemistry, respectively, in mouse and human tissues while TRPV4 channel activity of the intestinal cell line IEC-6 was assessed by Ca(2+) imaging analysis. TRPV4 activators or the NSAID indomethacin significantly decreased transepithelial resistance (TER) in IEC-6 cells, and indomethacin induced TER decreases were inhibited by specific TRPV4 inhibitors or small interfering RNA TRPV4 knockdown, as well as by the epoxygenase inhibitor N (methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, which decreased 5,6-EET levels. In TRPV4 knockout mice, indomethacin-induced intestinal damage was significantly reduced compared with WT mice. Taken together, these results show that TRPV4 activation in the intestinal epithelium caused epithelial hyperpermeability in response to NSAID-induced arachidonic acid metabolites and contributed to NSAID-induced intestinal damage. Thus, TRPV4 could be a promising new therapeutic target for the prevention of NSAID-induced intestinal damage. PMID- 24789207 TI - Mesenchymal stem cells induce epithelial proliferation within the inflamed stomach. AB - Bone marrow-derived mesenchymal stem cells (MSCs) sustain cancer cells by creating a microenvironment favorable for tumor growth. In particular, MSCs have been implicated in gastric cancer development. There is extensive evidence suggesting that Hedgehog signaling regulates tumor growth. However, very little is known regarding the precise roles of Hedgehog signaling and MSCs in tumor development within the stomach. The current study tests that hypothesis that Sonic Hedgehog (Shh), secreted from MSCs, provides a proliferative stimulus for the gastric epithelium in the presence of inflammation. Red fluorescent protein expressing MSCs transformed in vitro (stMSCs) were transduced with lentiviral constructs containing a vector control (stMSC(vect)) or short hairpin RNA (shRNA) targeting the Shh gene (stMSC(ShhKO)). Gastric submucosal transplantation of wild type MSCs (wtMSCs), wild-type MSCs overexpressing Shh (wtMSC(Shh)), stMSC(vect), or stMSC(ShhKO) cells in C57BL/6 control (BL/6) or gastrin-deficient (GKO) mice was performed and mice analyzed 30 and 60 days posttransplantation. Compared with BL/6 mice transplanted with wtMSC(Shh) and stMSC(vect) cells, inflamed GKO mice developed aggressive gastric tumors. Tumor development was not observed in mouse stomachs transplanted with wtMSC or stMSC(ShhKO) cells. Compared with stMSC(ShhKO)-transplanted mice, within the inflamed GKO mouse stomach, Shh expressing stMSC(vect)- and wtMSC(Shh)-induced proliferation of CD44-positive cells. CD44-positive cells clustered in gland-like structures within the tumor stroma and were positive for Patched (Ptch) expression. We conclude that Shh, secreted from MSCs, provides a proliferative stimulus for the gastric epithelium that is associated with tumor development, a response that is sustained by chronic inflammation. PMID- 24789210 TI - Inorganic/organic hybrid solar cells: optimal carrier transport in vertically aligned silicon nanowire arrays. AB - Inorganic/organic hybrid radial heterojunction solar cells that combine vertically-aligned n-type silicon nanowires (SiNWs) with poly(3,4 ethylenedioxythiophene):poly(styrene-sulfonate) (PEDOT:PSS) have great potential for replacing commercial Si solar cells. The chief advantage of such solar cells is that they exhibit higher absorbance for a given thickness than commercial Si solar cells, due to incident light-trapping within the NW arrays, thus enabling lower-cost solar cell production. We report herein on the effects of NW length, annealing and surface electrode on the device performance of SiNW/PEDOT:PSS hybrid radial heterojunction solar cells. The power conversion efficiency (PCE) of the obtained SiNW/PEDOT:PSS hybrid solar cells can be optimized by tuning the thickness of the surface electrode, and the etching conditions during NW formation and post-annealing. The PCE of 9.3% is obtained by forming efficient transport pathways for photogenerated charge carriers to electrodes. Our approach is a significant contribution to design of high-performance and low-cost inorganic/organic hybrid heterojunction solar cells. PMID- 24789206 TI - Chemoprevention in gastrointestinal physiology and disease. Natural products and microbiome. AB - The human intestinal tract harbors a complex ecosystem of commensal bacteria that play a fundamental role in the well-being of their host. There is a general consensus that diet rich in plant-based foods has many advantages in relation to the health and well-being of an individual. In adults, diets that have a high proportion of fruit and vegetables and a low consumption of meat are associated with a highly diverse microbiota and are defined by a greater abundance of Prevotella compared with Bacteroides, whereas the reverse is associated with a diet that contains a low proportion of plant-based foods. In a philosophical term, our consumption of processed foods, widespread use of antibiotics and disinfectants, and our modern lifestyle may have forever altered our ancient gut microbiome. We may never be able to identify or restore our microbiomes to their ancestral state, but dietary modulation to manipulate specific gut microbial species or groups of species may offer new therapeutic approaches to conditions that are prevalent in modern society, such as functional gastrointestinal disorders, obesity, and age-related nutritional deficiency. We believe that this will become an increasingly important area of health research. PMID- 24789209 TI - Deficiency of IKKepsilon inhibits inflammation and induces cardiac protection in high-fat diet-induced obesity in mice. AB - Immune response and metabolic regulation have been recognized as a central homeostatic mechanism, the dysfunction of which can trigger a cluster of chronic metabolic disorders, particularly obesity, type II diabetes and cardio-vascular disease. Serine/threonine kinase IkappaB kinase (IKK) epsilon is a multifunctional regulator that participates in immune regulation, cell proliferation and transformation, and oncogenesis. In the present study, we investigated the role of IKKepsilon in cardiovascular disorders using murine models of apolipo-protein E-deficient [ApoE(-/-)] mice and ApoE/IKKepsilon double knockout [ApoE(-/-)/IKKepsilon(-/-)]mice, which were fed a normal diet (ND) and high-fat diet (HFD) for 12 weeks, respectively. Results of this study showed that mouse obesity correlated in vivo with an increased expression of IKKepsilon. Additionally, chronic low-grade inflammation in cardiac tissue was evident in ApoE(-/-) mice, but was markedly reduced in ApoE(-/-)/IKKepsilon(-/-) mice. However, serum lipid levels in the ApoE(-/-) mice group were not significantly higher than those of the ApoE(-/-)/IKKepsilon(-/-) group. Furthermore, immunofluorescence and western blot analysis demonstrated evident increases in the expression of nuclear factor-kappaB (NF-kappaB) pathway components and downstream factors in the ApoE(-/-) mice group, while these increases were blocked in the ApoE(-/-)/IKKepsilon(-/-) group. Taken together, these data indicate that deficiency of IKKepsilon prevented obesity and inflammatory response in the murine hearts in ApoE(-/-) and ApoE(-/-)/IKKepsilon(-/-) mice fed an ND and HFD, respectively, suggesting that IKKepsilon may play a role in HFD induced inflammation in hearts of obese mice and may serve as a novel target for the treatment of a variety of metabolism-associated cardiovascular diseases. PMID- 24789208 TI - Hyperosmolarity in the small intestine contributes to postprandial ghrelin suppression. AB - Plasma levels of the orexigenic hormone ghrelin are suppressed by meals with an efficacy dependent on their macronutrient composition. We hypothesized that heterogeneity in osmolarity among macronutrient classes contributes to these differences. In three studies, the impact of small intestinal hyperosmolarity was examined in Sprague-Dawley rats. In study 1, isotonic, 2.5*, and 5* hypertonic solutions of several agents with diverse absorption and metabolism properties were infused duodenally at a physiological rate (3 ml/10 min). Jugular vein blood was sampled before and at 30, 60, 90, 120, 180, 240, and 300 min after infusion. Plasma ghrelin was suppressed dose dependently and most strongly by glucose. Hyperosmolar infusions of lactulose, which transits the small intestine unabsorbed, and 3-O-methylglucose (3-O-MG), which is absorbed like glucose but remains unmetabolized, also suppressed ghrelin. Glucose, but not lactulose or 3-O MG, infusions increased plasma insulin. In study 2, intestinal infusions of hyperosmolar NaCl suppressed ghrelin, a response that was not attenuated by coinfusion with the neural blocker lidocaine. In study 3, we reconfirmed that the low-osmolar lipid emulsion Intralipid suppresses ghrelin more weakly than isocaloric (but hypertonic) glucose. Importantly, raising Intralipid's osmolarity to that of the glucose solution by nonabsorbable lactulose supplementation enhanced ghrelin suppression to that seen after glucose. Hyperosmolar ghrelin occurred particularly during the initial 3 postinfusion hours. We conclude that small intestinal hyperosmolarity 1) is sufficient to suppress ghrelin, 2) may combine with other postprandial mechanisms to suppress ghrelin, 3) might contribute to altered ghrelin regulation after gastric bypass surgery, and 4) may inform dietary modifications for metabolic health. PMID- 24789211 TI - Multimodal imaging of intracameral foreign body. PMID- 24789213 TI - Shrimps from the Santana Group (Cretaceous: Albian): new species (Crustacea: Decapoda: Dendrobranchiata) and new record (Crustacea: Decapoda: Caridea). AB - The fossil shrimp Araripenaeus timidus n. gen. n. sp. is the first fossil Penaeoidea from Brazil. Here, we describe, illustrate and compare it with Paleomattea deliciosa, a fossil Sergestoidea (Dendrobranchiata) previously described from the same region. The material of the early Cretaceous (Albian) was collected in the town of Jardim, south of the state of Ceara, in the superior septarian concretion level of the Romualdo Formation. Additionally, a second specimen of Kellnerius jamacaruensis was found in the same site of the Araripe Basin. PMID- 24789212 TI - Hyperoxia arrests pulmonary development in newborn rats via disruption of endothelial tight junctions and downregulation of Cx40. AB - This study investigated changes in vascular endothelial cell tight junction structure and the expression of the gene encoding connexin 40 (Cx40) at the early pneumonedema stage of hyperoxia-induced bronchopulmonary dysplasia (BPD) in a newborn rat model. A total of 96 newborn rats were randomly assigned to one of the following two groups, the hyperoxia group (n=48) and the control group (n=48). A hyperoxia-induced BPD model was established for the first group, while rats in the control group were maintained under normoxic conditions. Extravasation of Evans Blue (EB) was measured; the severity of lung injury was assessed; a transmission electron microscope (TEM) was used to examine the vascular endothelial cell tight junction structures, and immunohistochemical assay, western blotting and reverse transcription-polymerase chain reaction (RT PCR) were used to evaluate the expression of Cx40 at the mRNA and protein level. Our findings showed that injuries due to BPD are progressively intensified during the time-course of exposure to hyperoxic conditions. Pulmonary vascular permeability in the hyperoxia group reached the highest level at day 5, and was significantly higher compared to the control group. TEM observations demonstrated tight junctions between endothelial cells were extremely tight. In the hyperoxia group, no marked changes in the tight junction structure were found at days 1 and 3; paracellular gaps were visible between endothelial cells at days 5 and 7. Immunohistochemical staining revealed that the Cx40 protein is mainly expressed in the vascular endothelial cells of lung tissue. Western blotting and RT-PCR assays showed a gradual decrease in Cx40 expression, depending on the exposure time to hyperoxic conditions. However, the Cx40 mRNA level reached a trough at 5 days. Overall, our study demonstrated that exposure to hyperoxia damages the tight junction structures between vascular endothelial cells and downregulates Cx40. We therefore conclude that hyperoxia may participate in the regulation of pulmonary vascular endothelial permeability. PMID- 24789214 TI - Phytochemical analysis and antioxidant capacity of Tabernaemontana catharinensis A. DC. Fruits and branches. AB - The antioxidant capacity of the crude extract and fractions of Tabernaemontana catharinensis fruits and branches, was evaluated by the 2,2-diphenyl-1 picrylhydrazyl (DPPH) method and the content of polyphenols, flavonoids, alkaloids and condensed tannins were determined by the spectrophotometric method. The ethyl acetate fraction of the fruits and the n-butanol fraction of the branches showed IC50 of 181.82 ug/mL and 78.19 ug/mL, respectively. All fractions were analyzed by high performance liquid chromatography (HPLC), in the branches were quantified chlorogenic acid in the chloroform (8.96 mg/g), ethyl acetate (4.31 mg/g) and n-butanol (3.33 mg/g) fractions; caffeic acid in the ethyl acetate (5.24 mg/g) and n-butanol (1.81 mg/g); gallic acid (0.52 mg/g) in the n butanol. In the fruits, chlorogenic acid in the chloroform (1.67 mg/g); rutin in the ethyl acetate (3.45 mg/g) and n-butanol (8.98 mg/g) fractions. The present study showed that these quantified compounds can contribute to antioxidant capacity which was higher in the branches than in the fruits. PMID- 24789215 TI - Floristics and Reproductive Phenology of Trees and Bushes in Central West Brazil. AB - Environmental conditions such as temperature, soil, photoperiodic factors and precipitation can determine the physical environment favoring the occurrence of given species and interfere with the reproductive period of plants. This work involved monthly excursions to a slope in the Serra de Maracaju between December 2009 and November 2010. Samples were collected in eight 25 x 50 m plots, transverse to the slope, totaling 1 ha sampled. Floristic richness included 79 species distributed into 58 genera and 31 families. Floristic Similarity Analysis and Principal Component Analysis showed the occurrence of two plant formations on the slope: seasonal deciduous forest and cerradao on the eutrophic soil of the slope. Flowering and fruiting occured in the rainy season; correlation with rainfall, mean temperature and photoperiod were negative for flowering and positive for fructification. Trees and bushes presented uniform flowering and a moderately seasonal fructification, which is unexpected in seasonal environments. We discuss the implications of the patterns found and make comparisons with others studies. PMID- 24789217 TI - Selective adsorption of bismuth telluride nanoplatelets through electrostatic attraction. AB - We demonstrate a facile technique to assemble solution phase-synthesized bismuth telluride (Bi2Te3) nanoplatelets into arrays of micropatterns. Aminosilane self assembled monolayers (SAMs) are printed on silicon dioxide (SiO2) substrates using microcontact printing (MUCP). The SAM printed surfaces are terminated with amine-groups allowing Bi2Te3 nanoplatelet selective adsorption by electrostatic attraction. Using Kelvin probe force microscopy, the electrical potential difference between aminosilane SAM and Bi2Te3 nanoplatelet surfaces is found to be ~650 mV, which is larger than that (~400 mV) between the SiO2 substrate and Bi2Te3 nanoplatelet surfaces. The selective adsorption provides an opportunity for integrating solution phase-grown topological insulators toward several device level applications. PMID- 24789216 TI - The CCAAT/enhancer-binding protein beta-2 isoform (CEBPbeta-2) upregulates galectin-7 expression in human breast cancer cells. AB - Galectin-7 is considered a gene under the control of p53. However, elevated expression of galectin-7 has been reported in several forms of cancer harboring an inactive p53 pathway. This is especially true for breast cancer where galectin 7 expression is readily expressed in a high proportion in basal-like breast cancer tissues, conferring cancer cells with increased resistance to cell death and metastatic properties. These observations suggest that other transcription factors are capable of inducing galectin-7 expression. In the present work, we have examined the role of CCAAT/enhancer-binding protein beta (C/EBPbeta) in inducing expression of galectin-7. C/EBP proteins have been shown to contribute to breast cancer by upregulating pro-metastatic genes. We paid particular attention to C/EBPbeta-2 (also known as LAP2), the most transcriptionally active of the C/EBPbeta isoforms. Our results showed that ectopic expression of C/EBPbeta-2 in human breast cancer cells was sufficient to induce expression of galectin-7 at both the mRNA and protein levels. In silico analysis further revealed the presence of an established CEBP element in the galectin-7 promoter. Mutation of this binding site abolished the transcriptional activity of the galectin-7 promoter. Chromatin immunoprecipitation analysis confirmed that C/EBPbeta-2 binds to the endogenous galectin-7 promoter. Analysis of galectin-7 protein expression in normal epithelia and in breast carcinoma by immunohistochemistry further showed the expression pattern of C/EBPbeta closely micmicked that of galectin-7, most notably in mammary myoepithelial cells and basal-like breast cancer where galectin-7 is preferentially expressed. Taken together, our findings suggest that C/EBPbeta is an important mediator of galectin-7 gene activation in breast cancer cells and highlight the different transcriptional mechanisms controlling galectin-7 in cancer cells. PMID- 24789218 TI - Efficacy of myringoplasty in older people. AB - The aim of current investigation was to analyze the efficacy of myringoplasty in an elderly population. The medical records of 12 males and 9 females, aged 65-90 years (mean 70.7 years), who underwent myringoplasty between 2007 and 2013 were retrospectively reviewed for age, gender, co-morbidities, perforation size and location, pre- and postoperative pure tone averages of air/bone thresholds at 500, 1,000, 2,000 and 3,000 Hz, graft material, postoperative complications and surgical outcome. The most frequent co-morbidities included hypertension (n = 8), hyperlipidemia (n = 7), diabetes mellitus (n = 5) and ischemic heart disease (n = 4). Fifteen patients had two or more co-morbidities. All surgeries were performed via a trans-canal approach. Seventeen patients had central perforations and four patients had marginal perforations. Temporalis fascia, perichondrium or chondro perichondrial graft and fat were used as grafting material in 9, 11 and 1 patient, respectively. The post-operative complications were infection (n = 4) and tragal seroma (n = 1). Surgical outcome was successful in 16/21 patients with graft take rates of 89, 72 and 0% for temporalis fascia, perichondrium/cartilage, and fat, respectively. Pre-operative audiometric data were available for all 21 patients; however, the post-operative data were available for only 15 of them. Myringoplasty in older people was a safe procedure with a 76.2% surgical success rate in the current study. The choice of graft material, perforation size, gender and associated co-morbidities had no significant effect on achieving an intact tympanic membrane and a dry ear. The audiometric results did not show significant changes following myringoplasty. PMID- 24789219 TI - Enhancing awareness to mitigate the risk of HIV/AIDS in older adults. AB - HIV is often assumed to only affect younger people, and many older people do not realize that they might risk acquiring the virus. Given that sexual transmission is by far the most common way to contract HIV around the world, health care professionals do not usually pay enough attention to the possibility of HIV/AIDS in older adults, based on the common conviction that they no longer have any sexual desires and that they are sexually inactive. Nevertheless, the sexual behavior of older people is likely to change over time, as aging baby boomers progress into their 60s and 70s, meeting the criteria for "successful aging", and not conforming to the stereotype of "sexless elderly". Hence the urgent need to awareness is that HIV remains as a major health threat even in advanced age. Prompt diagnosis and treatment are especially crucial in older adults because of their general frailty and high comorbidity levels. This article reviews recent literature concerning HIV/AIDS in older adults, as regard the related epidemiological, clinical and public health issues, with a view to suggesting how the rising rate of HIV transmission in this age group might be mitigated, and shows the main points that HCP should tackle to identify older people at risk of HIV infection. In summary, there is a pressing need to develop effective prevention schemes and to adapt clinical and programmatic approaches to improve the survival of older people with HIV. PMID- 24789220 TI - Diagnostic and treatment practices of delirium in a general hospital. AB - BACKGROUND: Despite the increase in research on delirium, it remains underdiagnosed and difficult to manage, and the outcome is poor especially in older people. AIMS: To identify the clinically diagnosed rates of delirium, the possible aetiologies, to describe treatment, number and type of psychotropic medication used and to investigate the reasons for referral to a liaison psychiatric team. METHODS: Retrospective study of medical records of inpatients admitted to Sligo Regional Hospital during an 18-month period. RESULTS: One hundred and fifty-six files had a documentation of delirium (time prevalence 2%). Mean age of the sample was 82 years (SD = 7.2), 66 (42%) were male. Sixty-nine (44.2%) of the total sample had a previous history of dementia, and 57 (36.5%) had a previous history of delirium. In 67 (43.2%) samples, the cause was infection, while in 4, no specific cause was identified. Ninety (58%) were referred to the liaison service, but only in 26 (28.9 %), the reason for referral was "acute confusion" or "delirium". In a majority of referrals, the reason was an affective disorder more often depression. There were no significant differences between delirium subtypes and referrals (chi(2) = 3.868, df 3, p = 0.28). Examination of the amount of antipsychotics prescribed before, during and after delirium shows that there was a significant increase in use during the delirium (chi(2) = 17.512, df 8, p = 0.025) and decrease in z-hypnotics medication (zopiclone/zolpidem), (chi(2) = 20.114, df 4, p < 0.001), while benzodiazepines and antidepressants remained the same. CONCLUSIONS: Delirium is often misdiagnosed and unrecognized in hospital settings; however, when identified the pharmacological management is appropriate. PMID- 24789221 TI - Coronary surgery in an old patient with hemophilia A. AB - Patients with hemophilia because of limited lifespan rarely undergo cardiac surgery. Due to improved healthcare and management in these patients, the life expectancy is increasing. Nevertheless, surgical intervention is a new challenge in patients with hemophilia, particularly very old patients. We describe an old patient with hemophilia A, who underwent coronary artery bypass grafting. PMID- 24789222 TI - HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (Review). AB - Among the heat shock proteins (HSP), HSP27, HSP70 and HSP90 are the most studied stress-inducible HSPs, and are induced in response to a wide variety of physiological and environmental insults, thus allowing cells to survive to lethal conditions based on their powerful cytoprotective functions. Different functions of HSPs have been described to explain their cytoprotective functions, including their most basic role as molecular chaperones, that is to regulate protein folding, transport, translocation and assembly, especially helping in the refolding of misfolded proteins, as well as their anti-apoptotic properties. In cancer cells, the expression and/or activity of the three HSPs is abnormally high, and is associated with increased tumorigenicity, metastatic potential of cancer cells and resistance to chemotherapy. Associating with key apoptotic factors, they are powerful anti-apoptotic proteins, having the capacity to block the cell death process at different levels. Altogether, the properties suggest that HSP27, HSP70 and HSP90 are appropriate targets for modulating cell death pathways. In this review, we summarize the role of HSP90, HSP70 and HSP27 in apoptosis and the emerging strategies that have been developed for cancer therapy based on the inhibition of the three HSPs. PMID- 24789223 TI - Are we there yet? The smallpox research agenda using variola virus. PMID- 24789224 TI - A biocompatible open-surface droplet manipulation platform for detection of multi nucleotide polymorphism. AB - We present a novel and simple method to manipulate droplets applicable to an open surface microfluidic platform. The platform comprised a control module for pneumatic droplets and a superhydrophobic polydimethylsiloxane (PDMS) membrane. With pneumatic suction to cause deflection of the flexible PDMS-based superhydrophobic membrane, the sample and reagent droplets on the membrane become transported and mixed. A facile one-step laser micromachining technique serves to fabricate a superhydrophobic surface; a contact angle of 150 degrees and a hysteresis angle of 4 degrees were achieved without chemical modification. Relative to previous open-surface microfluidic systems, this platform is capable of simultaneous and precise delivery of droplets in two-dimensional (2D) manipulation. Droplets were manipulated with suction, which avoided interference from an external driving energy (e.g. heat, light, electricity) to affect the bio sample inside the droplets. Two common bio-samples, namely protein and DNA, verified the performance of the platform. Based on the experimental results, operations on protein can be implemented without adsorption on the surface of the platform. Another striking result is the visual screening for multi-nucleotide polymorphism with hybridization-mediated growth of gold-nanoparticle (AuNP) probes. The detection results are observable with the naked eye, without the aid of advanced instruments. The entire procedure only takes 5 min from the addition of the sample and reagent to obtaining the results, which is much quicker than the traditional method. The total sample volume consumed in each operation is only 10 MUL, which is significantly less than what is required in a large system. According to this approach, the proposed platform is suitable for biological and chemical applications. PMID- 24789226 TI - Synthesis, cellular uptake, and biodistribution of whey-rich nanoparticles. AB - Whey-poly(acrylic acid) (whey-PAA) nanoparticles are prepared by polymerizing acrylic acid (AA) monomer in the presence of whey protein in a complete aqueous medium. The properties, drug loading, and release as well as in vitro cytotoxicity of whey-PAA nanoparticles are examined. The cellular uptakes and penetration of nanoparticle in the SH-SY5Y monolayer cells and multicellular tumor spheroids are observed. The in vivo distribution of the nanoparticles in tumor-bearing mice is evaluated. Confocal laser scanning microscopy and co localization images show that the nanoparticles are well internalized by the cells through the endocytosis mechanism. Drug-loaded whey-PAA nanoparticles can penetrate multicellular tumor spheroids more deeply. In vivo near-infrared fluorescence imaging examination and in vivo DOX distribution show that the drug loaded whey-PAA nanoparticles can well accumulated in the tumor site. Thus, these whey-rich nanoparticles seem to be very promising drug carriers for drug delivery. PMID- 24789225 TI - Planar microdevices enhance transport of large molecular weight molecules across retinal pigment epithelial cells. AB - Large molecular weight drug delivery to the posterior eye is challenging due to cellular barriers that hinder drug transport. Understanding how to enhance transport across the retinal barrier is important for the design of new drug delivery systems. A novel mechanism to enhance drug transport is the use of geometric properties, which has not been extensively explored in the retina. Planar SU-8/Poly(ethyleneglycol)dimethacrylate microdevices were constructed using photolithography to deliver FITC dextran across an in vitro retinal model. The model consists of retinal pigment epithelial (RPE) cells grown to confluence on transwell inserts, which provides an environment to investigate the influence of geometry on paracellular and transcellular delivery of encapsulated large molecules. Planar microdevices enhanced transport of large molecular weight dextrans across different models of RPE in a size dependent fashion. Increased drug permeation across the RPE was observed with the addition of microdevices as compared to a traditional bolus of FITC dextran. This phenomena was initiated by a non-toxic interaction between the microdevices and the retinal tight junction proteins. Suggesting that increased drug transport occurs via a paracellular pathway. These experiments provide evidence to support the future use of planar unidirectional microdevices for delivery of biologics in ocular applications. PMID- 24789227 TI - Treatment of painful Modic type I changes by vertebral augmentation with bioactive resorbable bone cement. AB - INTRODUCTION: Low back pain is one of the most common causes of seeking medical attention in industrialized western countries. End plate degenerative changes in the acute phase, formally referred to as Modic type I, represent a specific cause. The aim of this study is to evaluate the effectiveness of vertebral augmentation with calcium sulfate and hydroxyapatite resorbable cement in patients with low back pain resistant to conservative treatment whose origin can be recognized in Modic type I changes. METHODS: From February 2009 to October 2013, 1,124 patients with low back pain without radicular symptoms underwent physical and imaging evaluation. Stringent inclusion criteria elected 218 to vertebral augmentation with resorbable cement. Follow-up period was 1 year. RESULTS: One hundred seventy-two (79 %) patients improved quickly during the first 4 weeks after treatment. Forty-two (19 %) patients showed a more gradual improvement over the first 6 months, and at 1 year, their pain level did not differ from that of the previous group. In both groups, pain did not resolved completely, but patients showed significant improvement in their daily life activities. Two (1 %) patients did not show any improvement. Two (1 %) patients died for other reasons. There were no complications related to the procedures. CONCLUSION: Vertebroplasty with bioactive resorbable bone cement seems to be an effective therapeutic option for patients with low back pain resistant to conservative treatment whose origin could be recognized in Modic type I end plate degenerative changes. PMID- 24789228 TI - Intermittent cold exposure enhances fat accumulation in mice. AB - Due to its high energy consuming characteristics, brown adipose tissue (BAT) has been suggested as a key player in energy metabolism. Cold exposure is a physiological activator of BAT. Intermittent cold exposure (ICE), unlike persistent exposure, is clinically feasible. The main objective of this study was to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we found that ICE actually increased adiposity despite enhancing Ucp1 expression in BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did not alter basal systemic insulin sensitivity, but it increased liver triglyceride content and secretion rate as well as blood triglyceride levels. Gene profiling further demonstrated that ICE, despite suppressing lipogenic gene expression in white adipose tissue and liver during cold exposure, enhanced lipogenesis between the exposure periods. Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis. PMID- 24789230 TI - The quality movement in oral health care: who will lead? PMID- 24789229 TI - Interacting symbionts and immunity in the amphibian skin mucosome predict disease risk and probiotic effectiveness. AB - Pathogenesis is strongly dependent on microbial context, but development of probiotic therapies has neglected the impact of ecological interactions. Dynamics among microbial communities, host immune responses, and environmental conditions may alter the effect of probiotics in human and veterinary medicine, agriculture and aquaculture, and the proposed treatment of emerging wildlife and zoonotic diseases such as those occurring on amphibians or vectored by mosquitoes. Here we use a holistic measure of amphibian mucosal defenses to test the effects of probiotic treatments and to assess disease risk under different ecological contexts. We developed a non-invasive assay for antifungal function of the skin mucosal ecosystem (mucosome function) integrating host immune factors and the microbial community as an alternative to pathogen exposure experiments. From approximately 8500 amphibians sampled across Europe, we compared field infection prevalence with mucosome function against the emerging fungal pathogen Batrachochytrium dendrobatidis. Four species were tested with laboratory exposure experiments, and a highly susceptible species, Alytes obstetricans, was treated with a variety of temperature and microbial conditions to test the effects of probiotic therapies and environmental conditions on mucosome function. We found that antifungal function of the amphibian skin mucosome predicts the prevalence of infection with the fungal pathogen in natural populations, and is linked to survival in laboratory exposure experiments. When altered by probiotic therapy, the mucosome increased antifungal capacity, while previous exposure to the pathogen was suppressive. In culture, antifungal properties of probiotics depended strongly on immunological and environmental context including temperature, competition, and pathogen presence. Functional changes in microbiota with shifts in temperature provide an alternative mechanistic explanation for patterns of disease susceptibility related to climate beyond direct impact on host or pathogen. This nonlethal management tool can be used to optimize and quickly assess the relative benefits of probiotic therapies under different climatic, microbial, or host conditions. PMID- 24789231 TI - Case presentation. PMID- 24789232 TI - Author's response. PMID- 24789233 TI - Implant checklist. PMID- 24789234 TI - Authors' response. PMID- 24789235 TI - Educational debt and intended employment choice among dental school seniors. AB - BACKGROUND: The authors examined the association between educational debt and dental school seniors' intended activity after graduation. METHODS: The authors used multinomial logit regression analysis to estimate the relationship between dental educational debt and intended activity after graduation, controlling for potentially confounding variables. They used data from the 2004 through 2011 ADEA (American Dental Education Association) Survey of Dental School Seniors. RESULTS: Fourth-year dental school students with high levels of educational debt were more likely to express an interest in choosing to go into private practice, although the magnitude of this effect was relatively small. For each $10,000 increase in debt, the likelihood of choosing advanced education relative to private practice was 1.5 percent lower (relative risk ratio [RRR], 0.985 [95 percent confidence interval {CI}, 0.978-0.991]). For the same $10,000 increase in debt, the probability of choosing teaching, research and administration was 3.1 percent lower than that for choosing private practice (RRR, 0.969 [95 percent CI, 0.954 0.986]) and was 8.4 percent lower than that for choosing a government service position (RRR, 0.916 [95 percent CI, 0.908-0.924]). CONCLUSIONS: Although educational debt was statistically significant for predicting intended activity after graduation, the magnitude of influence of other variables such as sex, race and whether a parent is a dentist was substantially larger. Practical Implications Concerns regarding rising educational debt and its effect on the dental labor market may be misplaced. The characteristics of the dental school student body may be a more accurate predictor of employment choices that dental school seniors are making than are total educational debt levels. PMID- 24789236 TI - The effect of growing income disparities on U.S. adults' dental care utilization. AB - OBJECTIVE: The authors conducted a study to measure the gap in dental care utilization between poor and nonpoor adults at the state level and to show how the gap has changed over time. METHODS: The authors collected data from the 2002, 2004, 2006, 2008 and 2010 Behavioral Risk Factor Surveillance System prevalence and trends database maintained by the Centers for Disease Control and Prevention to measure differences in dental care utilization between poor and nonpoor adults. Poor adults are defined as those at or below the federal poverty threshold. The authors estimated a series of linear probability models to measure the dental care utilization gap between poor and nonpoor adults, while controlling for potentially confounding covariates. RESULTS: In 12 states (Arkansas, California, Florida, Georgia, Illinois, Indiana, Nebraska, Ohio, Oklahoma, South Carolina, Texas and Washington), the gap in dental care utilization between poor and nonpoor adults grew from 2002 through 2010. The remaining states had a stable utilization gap from 2002 through 2010. The study results show that four states (Alaska, Massachusetts, Minnesota, New York) and the District of Columbia had a smaller gap in dental care utilization in 2010 than that in other states. CONCLUSIONS: At the state level, poor adults face greater access barriers to dental care than do nonpoor adults. As states limit dental coverage through Medicaid, poor adults are at greater risk of experiencing poor oral health outcomes. Practical Implications In states that are experiencing increasing inequality in dental care utilization between poor and nonpoor adults, policymakers may wish to explore alternative approaches that could address this situation. PMID- 24789237 TI - Longitudinal outcomes of using a fluoride performance measure for adults at high risk of experiencing caries. AB - BACKGROUND: Staff of the VA Office of Dentistry, the dental care arm of the U.S. Department of Veterans Affairs' Veterans Health Administration, developed a performance measure (PM) regarding appropriate fluoride use. The authors hypothesized that after the implementation of this PM, veterans at high risk of experiencing caries would require fewer new dental restorations than in the past. METHODS: In a retrospective longitudinal analysis, the authors evaluated the effectiveness of a PM in reducing restoration rates in veterans at high risk of experiencing caries. They evaluated changes in restoration rates for all eligible veterans, as well as the subpopulation at high risk of experiencing caries (defined as receiving two or more restorations in 12 months) both before and after the implementation of the PM. RESULTS: In 2012, 81 percent of clinics provided fluoride for more than 90 percent of their patients at high risk of experiencing caries. After use of the PM for four years, there were 8.6 percent fewer patients needing two or more restorations, a 10.8 percent decrease in the mean number of restorations and a modest 3.4 percent fewer patients at high risk of experiencing caries who required new restorations after the initial 12-month period. CONCLUSIONS: Fluoride use for patients at high risk of experiencing caries rose from 51.8 percent in 2008 to 93.6 percent in 2012. Restoration rates rose before implementation of the PM and fell consistently after its implementation. Practical Implications Fluoride use reduces the need for future restorations in adults at high risk of experiencing caries. PMID- 24789238 TI - Gagging and its associations with dental care-related fear, fear of pain and beliefs about treatment. AB - BACKGROUND: Gagging is a behavioral response that interferes with oral health care and may be related to dental care-related fear. Little is known, however, about the epidemiology of gagging during dental treatment. METHODS: To explore this phenomenon, the authors recruited participants from the waiting area of an oral diagnosis clinic. Participants completed a gagging behavior questionnaire, the Dental Fear Survey, the Fear of Pain Questionnaire-9, the Revised Dental Beliefs Survey and a demographics questionnaire. RESULTS: Almost one-half of the 478 participants reported gagging on at least one occasion during dental visits, and 7.5 percent of participants reported almost always or always gagging. With higher frequency of problems with gagging, patients were more likely to have greater levels of dental care-related fear, fear of pain and more negative beliefs about dental professionals and dental treatment. Furthermore, participants who gagged more readily had greater dental care-related fear than did participants who had less of a propensity to gag. CONCLUSIONS: Gagging in the dental office is a prevalent problem, and dental care-related fear and fear of pain are associated with more frequent gagging. Practical Implications Given the prevalence of patients reporting problems with gagging, it may be helpful for providers to assess patients' propensity for gagging, which can be a barrier to treatment. By targeting dental care-related fear, fear of pain and negative beliefs about dental care in patients who often gag when receiving dental care, clinicians may be able to help reduce gagging in frequency or intensity, potentially making treatment more comfortable for patients and easier for dental care providers. PMID- 24789239 TI - Swallowed and aspirated dental prostheses and instruments in clinical dental practice: a report of five cases and a proposed management algorithm. AB - BACKGROUND: Accidental swallowing or aspiration of dental instruments and prostheses is a complication of dental procedures. Failure to manage these complications appropriately can lead to significant morbidity and possibly death. CASE DESCRIPTION: The authors present three cases of accidental swallowing of dental instruments during procedures and two cases of aspiration, one during a procedure and one long after the procedure. Although three of these five cases of foreign-body aspiration or ingestion were caught early and the patients were referred for endoscopic retrieval, two patients experienced prolonged symptoms that affected their quality of life before intervention occurred. Practical Implications The authors reviewed the literature and propose an evidence-based algorithm for management of such complications. Adherence to the proposed algorithm may decrease morbidity and mortality and improve patient outcomes. PMID- 24789240 TI - An epidemiologic investigation of occupational transmission of Mycobacterium tuberculosis infection to dental health care personnel: infection prevention and control implications. AB - BACKGROUND: The authors describe an investigation of a dental hygienist who developed active pulmonary tuberculosis (TB), worked for several months while infectious and likely transmitted Mycobacterium tuberculosis in a dental setting in Washington state. METHODS: Clark County Public Health (CCPH) conducted an epidemiologic investigation of 20 potentially exposed close contacts and 734 direct-care dental patients in 2010. RESULTS: Of 20 close contacts, one family member and two coworkers, all of whom were from countries in which TB is endemic, had latent TB infection (LTBI). One U.S.-born coworker experienced a tuberculin skin test (TST) conversion from 0 to 8 millimeters. Of the 305 of 731 (41.7 percent) potentially exposed patients who received a single TST, 23 (7.5 percent) had a positive TST result of at least 5 mm. Among the subset of 157 patients tested by CCPH staff, 16 (10.2 percent) had a positive TST result. The dental office did not have infection prevention and control policies related to TB identification, prevention or education. CONCLUSIONS: The coworker's TST conversion indicated a recent infection, likely owed to occupational transmission. The proportion of dental patients with positive TST results was greater than the 1999-2000 National Health and Nutrition Examination Survey prevalence estimate in the general population, and it may reflect transmission from the hygienist with active TB or a prevalence of LTBI in the community. Practical Implications All dental practices should implement administrative procedures for TB identification and control as described in this article, even if none of their patients are known to have TB. PMID- 24789241 TI - Limited jaw opening. PMID- 24789242 TI - Antibiotic prophylaxis reduces infectious complications but increases adverse effects after third-molar extraction in healthy patients. PMID- 24789247 TI - How affordable is health care in the United States and other countries? PMID- 24789248 TI - Coaching dental practice team members. PMID- 24789249 TI - Dealing with ethical challenges when leading student mission trips. PMID- 24789250 TI - Taking care of your child's smile. PMID- 24789251 TI - Two-terminal protonic devices with synaptic-like short-term depression and device memory. AB - Two-terminal protonic devices with PdHx proton conducting contacts and a Nafion channel achieve 25 ms spiking, short term depression, and low-energy memory switching. PMID- 24789252 TI - Intracellular delivery of peptide nucleic acid and organic molecules using zeolite-L nanocrystals. AB - The design and synthesis of smart nanomaterials can provide interesting potential applications for biomedical purposes from bioimaging to drug delivery. Manufacturing multifunctional systems in a way to carry bioactive molecules, like peptide nucleic acids able to recognize specific targets in living cells, represents an achievement towards the development of highly selective tools for both diagnosis and therapeutics. This work describes a very first example of the use of zeolite nanocrystals as multifunctional nanocarriers to deliver simultaneously PNA and organic molecules into living cells. Zeolite-L nanocrystals are functionalized by covalently attaching the PNA probes onto the surface, while the channel system is filled with fluorescent guest molecules. The cellular uptake of the PNA/Zeolite-L hybrid material is then significantly increased by coating the whole system with a thin layer of biodegradable poly-L lysine. The delivery of DAPI as a model drug molecule, inserted into the zeolite pores, is also demonstrated to occur in the cells, proving the multifunctional ability of the system. Using this zeolite nanosystem carrying PNA probes designed to target specific RNA sequences of interest in living cells could open new possibilities for theranostic and gene therapy applications. PMID- 24789253 TI - Brain metastasis from ovarian cancer: a systematic review. AB - To review the existing literature on brain metastasis (BM) from ovarian cancer and to assess the frequency, anatomical, clinical and paraclinical information and factors associated with prognosis. Ovarian cancer is a rare cause of brain metastasis with a recently reported increasing prevalence. Progressive neurologic disability and poor prognosis is common. A comprehensive review on this subject has not been published previously. This systematic literature search used the Pubmed and Yale library. A total of 66 publications were found, 57 of which were used representing 591 patients with BM from ovarian cancer. The median age of the patients was 54.3 years (range 20-81). A majority of patients (57.3 %) had multiple brain lesions. The location of the lesion was cerebellar (30 %), frontal (20 %), parietal (18 %) and occipital (11 %). Extracranial metastasis was present in 49.8 % of cases involving liver (20.7 %), lung (20.4 %), lymph nodes (12.6 %), bones (6.6 %) and pelvic organs (4.3 %). The most common symptoms were weakness (16 %), seizures (11 %), altered mentality (11 %) visual disturbances (9 %) and dizziness (8 %). The interval from diagnosis of breast cancer to BM ranged from 0 to 133 months (median 24 months) and median survival was 8.2 months. Local radiation, surgical resection, stereotactic radiosurgery and medical therapy were used. Factors that significantly increased the survival were younger age at the time of ovarian cancer diagnosis and brain metastasis diagnosis, lower grade of the primary tumor, higher KPS score and multimodality treatment for the brain metastases. Ovarian cancer is a rare cause of brain metastasis. Development of brain metastasis among older patients and lower KPS score correlate with less favorable prognosis. The more prolonged survival after using multimodality treatment for brain metastasis is important due to potential impact on management of brain metastasis in future. PMID- 24789254 TI - Weight of epilepsy in brain tumor patients. AB - About 20-40% of patients with brain tumor have seizures; all of whom must be treated with antiepileptic drugs (AEDs) that can cause side effects which may influence quality of life (QoL). However, little data are available regarding the weight of epilepsy on QoL in brain tumor (BT) patients, despite the fact that epilepsy is considered the most important risk factor for long-term disability in this patient population. Aim of this study is to explore the weight of epilepsy in BT patients, and to identify which factors might contribute to their epilepsy burden, as expressed by them only at their first visit in a specialized epilepsy center, in order to have a snapshot for that moment in their care cycle. We reviewed medical charts and results from a battery of tests (routinely given at our outpatient center), administered to 100 consecutive BTRE patients at their first visit, followed from 2007 to 2010. Our results reveal: (1) neurological performances and global neurocognitive status were not influenced by factors related to neoplastic disease or to epilepsy (2) side effects, cognitive deficits, and QoL concerns, as well as patients' perception of these, were significantly related to polytherapy, especially in patients who had been taking AEDs for a period longer that 6 months (3) the seizure number did not influence patients' QoL. We found that the weight of epilepsy in BTRE patients was related to AED therapy. Our study highlights the fact that epilepsy in our patients adds a significant burden, and suggests the need to give the proper attention to patients' concerns regarding the challenges that this pathology might present. Nevertheless, future studies could be designed with a follow-up period and with a patient stratification in order to better understand the weight of epilepsy for these patients. PMID- 24789255 TI - Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis. AB - Fatty acid synthase (FASN), catalyzing the de novo synthesis of fatty acids, is known to be deregulated in several cancers. Inhibition of this enzyme reduces tumor cell proliferation. Unfortunately, adverse effects and chemical instability prevent the in vivo use of the best-known inhibitors, Cerulenin and C75. Orlistat, a drug used for obesity treatment, is also considered as a potential FASN inhibitor, but its impact on glioma cell biology has not yet been described. In this study, we analyzed FASN expression in human glioma samples and primary glioblastoma cell cultures and the effects of FASN inhibition with Orlistat, Cerulenin and C75. Immunohistochemistry followed by densitometric analysis of 20 glioma samples revealed overexpression of FASN that correlated with the WHO tumor grade. Treatment of glioblastoma cells with these inhibitors resulted in a significant, dose-dependent reduction in tumor cell viability and fatty acid synthesis. Compared to Cerulenin and C75, Orlistat was a more potent inhibitor in cell cultures and cell lines. In LN229, cell-growth was reduced by 63.9 +/- 8.7 % after 48 h and 200 uM Orlistat compared to controls; in LT68, the reduction in cell growth was 76.3 +/- 23.7 %. Nuclear fragmentation assay and Western blotting analysis after targeting FASN with Orlistat demonstrated autophagy and apoptosis. Organotypic slice cultures treated with Orlistat showed reduced proliferation after Ki67 staining and increased caspase-3 cleavage. Our results suggest that FASN may be a therapeutic target in malignant gliomas and identify Orlistat as a possible anti-tumor drug in this setting. PMID- 24789257 TI - The clinical impact of cerebellar grey matter pathology in multiple sclerosis. AB - BACKGROUND: The cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood. OBJECTIVE: To evaluate the clinical and cognitive impact of cerebellar grey-matter pathology in multiple sclerosis patients. METHODS: Forty two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes. RESULTS: After multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015). CONCLUSIONS: Cerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey matter damage. PMID- 24789256 TI - Bevacizumab treatment leads to observable morphological and metabolic changes in brain radiation necrosis. AB - We investigated morphological and metabolic changes of radiation necrosis (RN) of the brain following bevacizumab (BEV) treatment by using neuroimaging. Nine patients with symptomatic RN, who had already been treated with radiation therapy for malignant brain tumors (6 glioblastomas, 1 anaplastic oligodendroglioma, and 2 metastatic brain tumors), were enrolled in this prospective clinical study. RN diagnosis was neuroradiologically determined with Gd-enhanced MRI and 11C methionine positron emission tomography (MET-PET). RN clinical and radiological changes in MRI, magnetic resonance spectroscopy (MRS) and PET were assessed following BEV therapy. Karnofsky performance status scores improved in seven patients (77.8 %). Both volumes of the Gd-enhanced area and FLAIR-high area from MRI decreased in all patients after BEV therapy and the mean size reduction rates of the lesions were 80.0 and 65.0 %, respectively. MRS, which was performed in three patients, showed a significant reduction in Cho/Cr ratio after BEV therapy. Lesion/normal tissue (L/N) ratios in MET- and 11C-choline positron emission tomography (CHO-PET) decreased in 8 (89 %) and 9 patients (100 %), respectively, and the mean L/N ratio reduction rates were 24.4 and 60.7 %, respectively. BEV related adverse effects of grade 1 or 2 (anemia, neutropenia and lymphocytopenia) occurred in three patients. These results demonstrated that BEV therapy improved RN both clinically and radiologically. BEV therapeutic mechanisms on RN have been suggested to be related not only to the effect on vascular permeability reduction by repairing the blood-brain barrier, but also to the effect on suppression of tissue biological activity, such as immunoreactions and inflammation. PMID- 24789258 TI - Suppressive effect of microRNA-126 on oral squamous cell carcinoma in vitro. AB - MicroRNA-126 (miR-126), an endothelial-specific miRNA located within intron 7 of epidermal growth factor-like domain 7 (EGFL7), has been demonstrated to act as a tumor suppressor in various types of human cancer. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, we revealed that the expression of miR-126 was significantly decreased in OSCC tissues, when compared with that in their matched adjacent tissues, and its expression level was also reduced in Tca8113, OSCC-15 and CAL27 cell lines compared with normal tissues. The protein expression of EGFL7 was upregulated in OSCC tissues compared with their matched adjacent tissues as well as normal tissues, and Tca8113, OSCC 15 and CAL27 cells additionally demonstrated a positive expression of EGFL7. The overexpression of miR-126 significantly reduced the protein expression of EGFL7 in OSCC-15 cells, while transfection with the miR-126 inhibitor upregulated the EGFL7 protein level in OSCC-15 cells. Furthermore, transfection with an miR-126 mimic into OSCC-15 cells markedly suppressed cell proliferation, cell cycle progression, cell invasion and colony formation, while inducing cell apoptosis, which contrasted with the effects of transfection with an miR-126 inhibitor. The overexpression of miR-126 suppressed the secretion of two key regulators of angiogenesis, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which was also reversed by miR-126 inhibitor transfection. In conclusion, the present study demonstrated that miR-126 acts as a tumor suppressor in OSCC cells, partially at least via the downregulation of EGFL7. Thus, miR-126 may serve as a promising candidate for the treatment of OSCC. PMID- 24789263 TI - Stature estimation in Japanese cadavers based on pelvic measurements in three dimensional multidetector computed tomographic images. AB - The aim of this study was to examine the feasibility of stature estimation by measuring the pelvic bones of Japanese cadavers using three-dimensional (3D) computed tomography (CT). We assessed 3D reconstructed images of 210 Japanese subjects (108 males, 102 females) who had undergone postmortem CT between May 2011 and November 2013. We defined the linear distance from the anterosuperior margin of the left and right anterior superior iliac spines (ASIS) to the posterior margin of the left and right ischial spines as the LSS and RSS, respectively. We also defined the linear distance from the anterosuperior margin of the left and right ASIS to the anteroinferior margin of the left and right ischial tuberosities as the LST and RST, respectively. The correlation between the cadaver stature (CS) and each parameter (LSS, LST, RSS, and RST) was evaluated using Pearson product-moment correlation coefficients and regression analysis was performed for stature estimation. All four parameters correlated significantly with stature independent of sex, suggesting that they can be used as a tool for stature estimation. The LST had the closest correlation with stature in both sexes. PMID- 24789264 TI - Splenic hypereosinophilia in anaphylaxis-related death: different assessments depending on different types of allergens? AB - The aim of this study was to evaluate splenic eosinophil and mast cell accumulation using pagoda red stain in a series of anaphylaxis-related deaths that underwent medico-legal investigations. Our goal was to assess whether fatal reactions to insect stings, intramuscularly administered antibiotics and intravenously injected contrast media are responsible for specific patterns of eosinophil and mast cell accumulation. Two study groups were prospectively formed, an anaphylaxis-related death group and a control group. Autopsy, histology (haematoxylin-eosin stain, pagoda red stain and immunohistochemistry using anti-tryptase antibodies), toxicology and postmortem biochemistry (beta tryptase, total IgE and specific IgE) were performed in all cases. All tested parameters (spleen weight, beta-tryptase and total IgE levels as well as eosinophil, mast cell and degranulated mast cell numbers in the spleen) were significantly higher in the anaphylaxis-related death group. No statistically significant differences were observed among the various groups (intramuscular antibiotic injection, intravenous contrast medium administration and stinging insects) in any combination, suggesting that mast cell and eosinophil accumulation in the spleen during anaphylaxis does not have any specific pattern related to the triggering allergen. Despite a lower sensitivity than immunohistochemical staining in discriminating eosinophil and mast cells, pagoda red stain allowed these cells to be identified and could therefore be proposed as a low-cost, first-line diagnostic procedure in those situations where immunohistochemistry is not systematically performed or cannot be carried out. PMID- 24789265 TI - Development and characterization of a new 12-plex ChrX miniSTR system. AB - Short tandem repeat (STR) markers are extensively used for human identification as well as paternity and forensic casework. X-chromosome STR (X-STR) markers are a powerful complementary system especially in deficiency paternity testing. This study presents the development and characterization of a new X-chromosomal short tandem repeat (STR) multiplex using short amplicon (<200 bp). A total of 366 samples from Punjabi population and 346 samples from Sindhi population were typed for 11 X-chromosomal STR markers: DXS101, DXS6789, DXS6793, DXS7132, DXS7423, DXS7424, DXS8378, DXS9902, GATA31E08, GATA172D05, and HPRTB along with sex-typing locus, amelogenin. Each marker showed a high degree of polymorphism, and the multiplex was sensitive down to 250 pg of human DNA. A total of 78 alleles were found with 5-11 alleles for each marker. The population data can be used as reference database for Sindhi and Punjabi populations. PMID- 24789266 TI - Cutaneous Rosai-Dorfman disease successfully treated with low-dose methotrexate. PMID- 24789267 TI - Carbamazepine for schizophrenia. AB - BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with just antipsychotic drug treatment and various adjunct medications are used to promote additional response. The antiepileptic carbamazepine is one such drug. OBJECTIVES: To examine whether carbamazepine or oxcarbazepine alone is an effective treatment for schizophrenia and schizoaffective psychoses and whether carbamazepine or oxcarbazepine augmentation of neuroleptic medication is an effective treatment for the same illnesses. SEARCH METHODS: For the original version we searched The Cochrane Schizophrenia Group's Register of Trials (December 2001), The Cochrane Library (Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1980-2001), Biological Abstracts (1980-2001), PsycLIT (1886-2001) and PSYNDEX (1974-2001). For the most recent update we searched the Cochrane Schizophrenia Group's Register of Trials in July 2012. We also inspected references of all identified studies for further trials and contacted relevant pharmaceutical companies and authors for additional data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing carbamazepine or compounds of the carbamazepine family with placebo or no intervention, whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizoaffective psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For homogenous dichotomous data we calculated fixed-effect, risk ratio (RR), with 95% confidence intervals (CIs) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD). We assessed the risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The updated search did not reveal any further studies that met our inclusion criteria. The number of included studies therefore remains at 10 with the number of participants randomised still 283.One study comparing carbamazepine with placebo as the sole treatment for schizophrenia was abandoned early due to high relapse rate with 26 out of 31 participants relapsing by three months. No effect of carbamazepine was evident with no difference in relapse between the two groups (1 RCT n = 31, RR 1.07 CI 0.78 to 1.45). Another study compared carbamazepine with antipsychotics as the sole treatment for schizophrenia. No differences in terms of mental state were found when comparing 50% reduction in Brief Psychiatric Rating Scale (BPRS) scores (1 RCT n = 38, RR 1.23 CI 0.78 to 1.92). A favourable effect for carbamazepine was found when more people who received the antipsychotic (perphenazine) had parkinsonism (1 RCT n = 38, RR 0.03 CI 0.00 to 0.043). Eight studies compared adjunctive carbamazepine versus adjunctive placebo, we were able use GRADE for quality of evidence for these results. Adding carbamazepine to antipsychotic treatment was as acceptable as adding placebo with no difference between the numbers leaving the study early from each group (8 RCTs n = 182, RR 0.47 CI 0.16 to 1.35, very low quality evidence). Carbamazepine augmentation was superior compared with antipsychotics alone in terms of overall global improvement, but participant numbers were low (2 RCTs n = 38, RR 0.57 CI 0.37 to 0.88). There were no differences for the mental state outcome of 50% reduction in BPRS scores (6 RCTs n = 147, RR 0.86 CI 0.67 to 1.12, low quality evidence). Less people in the carbamazepine augmentation group had movement disorders than those taking haloperidol alone (1 RCT n = 20, RR 0.38 CI 0.14 to 1.02). No data were available for the effects of carbamazepine on subgroups of people with schizophrenia and aggressive behaviour, negative symptoms or EEG abnormalities or with schizoaffective disorder. AUTHORS' CONCLUSIONS: Based on currently available randomised trial-derived evidence, carbamazepine cannot be recommended for routine clinical use for treatment or augmentation of antipsychotic treatment of schizophrenia. At present large, simple well-designed and reported trials are justified - especially if focusing on people with violent episodes and people with schizoaffective disorders or those with both schizophrenia and EEG abnormalities. PMID- 24789268 TI - Development of a dendritic cell-targeting lipopeptide as an immunoadjuvant that inhibits tumor growth without inducing local inflammation. AB - Materials used for the past 30 years as immunoadjuvants induce suboptimal antitumor immune responses and often cause undesirable local inflammation. Some bacterial lipopeptides that act as Toll-like receptor (TLR) 2 ligands activate immune cells as immunoadjuvants and induce antitumor effects. Here, we developed a new dendritic cell (DC)-targeting lipopeptide, h11c (P2C-ATPEDNGRSFS), which uses the CD11c-binding sequence of intracellular adhesion molecule-1 to selectively and efficiently activate DCs but not other immune cells. Although the h11c lipopeptide activated DCs similarly to an artificial lipopeptide, P2C-SKKKK (P2CSK4), via TLR2 in vitro, h11c induced more effective tumor inhibition than P2CSK4 at low doses in vivo with tumor antigens. Even without tumor antigens, h11c lipopeptide significantly inhibited tumor growth and induced tumor-specific cytotoxic T cells. P2CSK4 was retained subcutaneously at the vaccination site and induced severe local inflammation in in vivo experiments. In contrast, h11c was not retained at the vaccination site and was transported into the tumor within 24 hr. The recruitment of DCs into the tumor was induced by h11c more effectively, while P2CSK4 induced the accumulation of neutrophils leading to severe inflammation at the vaccination site. Because CD11b+ cells, but not CD11c+ cells, produced neutrophil chemotactic factors such as macrophage inflammatory protein (MIP)-2 in response to stimulation with TLR2 ligands, the DC-targeting lipopeptide h11c induced less MIP-2 production by splenocytes than P2CSK4. In this study, we succeeded in developing a novel immunoadjuvant, h11c, which effectively induces antitumor activity without adverse effects such as local inflammation via the selective activation of DCs. PMID- 24789269 TI - Magnetobiosensors based on viral protein p19 for microRNA determination in cancer cells and tissues. AB - MicroRNAs (miRs) have emerged as important clinical biomarkers with both diagnostic and prognostic value for relevant diseases, such as cancer. MiRs pose unique challenges for detection and are currently detected by northern blotting, real-time PCR, and microarray techniques. These expensive, complicated, and time consuming techniques are not feasible for on-site miR determination. In this study, amperometric magnetobiosensors involving RNA-binding viral protein p19 as a selective biorecognition element were developed for miR quantification. The p19 based magnetosensors were able to detect 0.4 fmol of a synthetic target and endogenous miR-21 (selected as a model for its role in a wide variety of cancers) in only 2 h in total RNA extracted from cancer cells and human breast-tumor specimens without PCR amplification and sample preprocessing. These results open up formidable perspectives for the diagnosis and prognosis of human cancers and for drug-discovery programs. PMID- 24789270 TI - Effects of HIP in protection of HSP70 for stress-induced cardiomyocytes injury and its glucorticoid receptor pathway. AB - Moderate levels of stress can be beneficial to health, while stress overload can cause injury or contribute to diseases. Despite a number of studies of adaptation or stress damage, the mechanisms of adaptation and stress damage remain far from clear. The effect and mechanisms of adaptation on cardiomyocytes damage caused by stress overload are discussed in this study. Data showed that mild repeated stress mitigated stress overload-induced cardiomyocyte injury both in an animal model of restraint stress and in H9C2 cells with GC (glucocorticoid) treatment. HSP70, HIP expression and interaction between HSP70 and HIP increased during adaptation induced by mild stress both in animals and H9C2 cells. Overexpression or inhibition of HSP70 in H9C2 cells with pCDNA-3.1-Hsp70 or KNK437 (HSP70 inhibitor) showed that HSP70 can protect H9C2 cells from GC-induced cell damage. A luciferase assay showed that Hsp70 plays its protective role through inhibition of GR transcription activity dependent on the interaction with HIP. These results indicated that HSP70 may promote adaptation with its interacting protein HIP, and increased levels of HSP70 and its interacting protein HIP during adaptation may play a protective role on stress-overload-induced cardiomyocyte injury. PMID- 24789271 TI - Interaction of heat shock protein 70 with membranes depends on the lipid environment. AB - Heat shock proteins (hsp) are well recognized for their protein folding activity. Additionally, hsp expression is enhanced during stress conditions to preserve cellular homeostasis. Hsp are also detected outside cells, released by an active mechanism independent of cell death. Extracellular hsp appear to act as signaling molecules as part of a systemic response to stress. Extracellular hsp do not contain a consensus signal for their secretion via the classical ER-Golgi compartment. Therefore, they are likely exported by an alternative mechanism requiring translocation across the plasma membrane. Since Hsp70, the major inducible hsp, has been detected on surface of stressed cells, we propose that membrane interaction is the first step in the export process. The question that emerges is how does this charged cytosolic protein interact with lipid membranes? Prior studies have shown that Hsp70 formed ion conductance pathways within artificial lipid bilayers. These early observations have been extended herewith using a liposome insertion assay. We showed that Hsp70 selectively interacted with negatively charged phospholipids, particularly phosphatidyl serine (PS), within liposomes, which was followed by insertion into the lipid bilayer, forming high-molecular weight oligomers. Hsp70 displayed a preference for less fluid lipid environments and the region embedded into the lipid membrane was mapped toward the C-terminus end of the molecule. The results from our studies provide evidence of an unexpected ability of a large, charged protein to become inserted into a lipid membrane. This observation provides a new paradigm for the interaction of proteins with lipid environments. In addition, it may explain the export mechanism of an increasing number of proteins that lack the consensus secretory signals. PMID- 24789272 TI - Polymorphism of cytosolic serine hydroxymethyltransferase and breast cancer risk: evidence from a meta-analysis. AB - One-carbon metabolism has been presumed to influence cancer pathogenesis. Cytosolic serine hydroxymethyltransferase (cSHMT) is a critical enzyme in one carbon metabolism pathway. Until now, many studies have investigated the association between cSHMT (also named SHMT1) C1420T polymorphism and breast cancer risk. However, the results remained conflicting rather than conclusive. Literature search was conducted using PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases until December 2013 to identify studies investigating the association of SHMT1 C1420T polymorphism with breast cancer risk. The strength of the association was assessed by the summary odd ratios (ORs) and their corresponding 95 % confidence interval (CI). Seven studies with a total of 5,534 cases and 6,581 controls were included. Overall, no association was detected between SHMT1 C1420T polymorphism and breast cancer risk (T vs. C, OR = 0.97, 95 % CI = 0.92-1.03). In the subgroup analysis based on ethnicity, SHMT1 C1420T polymorphism has shown a protective effect on breast cancer in Asians (T vs. C, OR = 0.78, 95 % CI = 0.66-0.93) but not in Caucasian (T/T vs. C/C, OR = 0.98, 95 % CI = 0.86-1.12). Significant heterogeneity across studies could be observed in some genetic comparison models in the overall estimation (C/T vs. C/C, P het = 0.004; T/T+C/T vs. C/C, P het = 0.006) but turned to be mild in all comparison models when stratified by ethnicity. Our meta-analysis failed to detect association between SHMT1 C1420T polymorphism and breast cancer risk. However, we found evidence for association of SHMT1 C1420T polymorphism with significantly reduced risk of breast cancer in Asians. Further well-designed studies with larger sample size and better selected controls are warranted. PMID- 24789273 TI - Antimetastatic effects of licochalcone A on oral cancer via regulating metastasis associated proteases. AB - Licochalcone A, a major phenolic constituent of the licorice species Glycyrrhiza inflata, has been proven to possess various biological benefits including anti cancer activity. However, the detailed effects and molecular mechanisms of licochalcone A on the invasiveness and metastasis of oral cancer cells have not been fully understood. Thus, SCC-25 oral cancer cells were subjected to a treatment with licochalcone A at indicated concentrations (25, 50, and 100 MUg/mL) for 36 h and then analyzed for the effect of licochalcone A on the cell migration and invasion. In vitro assays, including wound healing, cell adhesion, and cell invasion/migration assays, revealed that licochalcone A treatment significantly inhibited the cell migration/invasion capacities of SCC-25 cells. Also, results of zymography and Western blotting showed that activity and protein level of matrix metalloproteinase-2 (MMP-2) was suppressed, but TIMP-2 level was increased, indicating the important role of MMP-2 and TIPM-2 in anti-metastatic regulation of SCC-25 cells. Furthermore, licochalcone A was shown to suppress the nuclear factor-kappa B (NF-kappaB) signal, as evidenced by the decreased expression of phosphorylated p65 (p-65) protein in licochalcone A-treated SCC-25 cells. Notably, we also found that licochalcone A treatment increased the expression of the epithelial marker E-cadherin and decreased the expression of mesenchymal markers N-cadherin in SCC-25 cells. This is the first report describing the effects and possible mechanisms of licochalcone A on tumor invasion and metastasis of SCC-25 cells. Taken together, our findings support that licochalcone A can be developed to a potent anti-metastatic candidate for oral cancer therapy. PMID- 24789274 TI - Diagnostic value of serum carbohydrate antigen 19-9 in pancreatic cancer: a meta analysis. AB - Pancreatic cancer is a highly malignant cancer with increasing incidence and mortality worldwide. Carbohydrate antigen 19-9 (CA19-9) has been widely reported to play a role in the diagnosis of pancreatic cancer patients. However, published data on this subject are inconclusive. There was no meta-analysis that has been previously performed to evaluate critically the diagnostic accuracy of CA19-9 for pancreatic cancer. Therefore, we performed a meta-analysis to evaluate the sensitivity and specificity of CA19-9 in the diagnosis of pancreatic cancer. We conducted a comprehensive search to identify studies in which the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating curves (SROC) could be determined. A total of 11 studies that included 2,316 individuals who fulfilled all of the inclusion criteria were considered for analysis. The summary estimates for serum CA19-9 in the diagnosis of pancreatic cancer in these studies were pooled sensitivity 0.80 (95 % confidence interval [CI] 0.77-0.82), specificity 0.80 (95 % CI 0.77-0.82), and DOR 14.79 (95 % CI 8.55-25.59), and the area under the curve was 0.87. Our meta-analysis showed that serum CA19-9 plays important role in the diagnosis of pancreatic cancer. PMID- 24789275 TI - Coordination pays off: a comparison of two models for organizing hip fracture care, outcomes and costs. AB - BACKGROUND AND PURPOSE: With the "graying" of the population, hip fractures place an increasing burden on health systems and call for efficient forms of care. The aim was to compare two models of organizing hip fracture care at one university hospital working at two sites. The differences in organization were coordinated care provided in one of the sites and traditional care, divided between different institutions, in the other. MATERIAL AND METHODS: The study was conducted at a Swedish university hospital and included all 503 hip fracture patients, admitted during the 1-year period of February 2009 through January 2010. Patient gender, age, type of fracture, admission and discharge dates were documented. The patients were surveyed of their health-related quality of life at the time of admission and at 4 and 12 months after discharge. The costs for the inpatient care episode were estimated using three costing methods. RESULTS: The coordinated care model resulted in a shorter hospital stay and consistently lower costs. There was no difference between patient-reported quality of life. INTERPRETATION: The care of hip fracture patients coordinated by a geriatric ward throughout the whole care episode is more cost-efficient than uncoordinated where patients are transferred to other institutions for rehabilitation. PMID- 24789276 TI - A 68 year old woman with deteriorating hearing. PMID- 24789277 TI - Cervical cancer screening trials in India spark controversy. PMID- 24789278 TI - Financial crisis is inevitable in the NHS by 2015-16, King's Fund says. PMID- 24789279 TI - Plan for minimum alcohol price in Scotland is delayed again. PMID- 24789280 TI - The prognostic value of altered eIF3a and its association with p27 in non-small cell lung cancers. AB - BACKGROUND: Over-expressed eukaryotic initiation factor 3a (eIF3a) in non-small cell lung cancer (NSCLC) contributed to cisplatin sensitivity. However, the role of eIF3a in oncogenesis was still controversial. This study was designed to investigate the prognostic impact of eIF3a and p27 in radically resected NSCLC patients. METHODS: The expression levels of subcellular eIF3a and p27 were evaluated immunohistochemically in 537 radically resected NSCLC samples, and another cohort of 210 stage II NSCLC patients. Disease specific survival (DSS) and disease free survival (DFS) were analyzed by Kaplan-Meier method and Cox regression model. RESULTS: The subcellular expression of eIF3a was strongly correlated with status of p27 (Spearman rank coefficient correlation for cytoplasmic eIF3a and p27=0.653, for nuclear staining=0.716). Moreover, survival analysis revealed favorable prognostic impact of nuclear eIF3a, p27, and the combination high nuclear staining on NSCLC (Hazards Ratio=0.360, 95%CI=0.109 0.782, P=0.028). In addition, interaction research between biomarkers and chemotherapy status disclosed cisplatin-based regimen trend to prolong DSS of stage II NSCLC patients with high eIF3a-C (P=0.036)and low p27-N (P=0.031). CONCLUSIONS: Our findings suggested altered eIF3a expression closely correlated with p27 status, and the association was of prognostic value for resected NSCLC. Altered expression of eIF3a and p27 predicted prognosis of NSCLC independently. PMID- 24789281 TI - First-trimester antihistamine exposure and risk of spontaneous abortion or preterm birth. AB - PURPOSE: We tested whether antihistamine exposure during early pregnancy is associated with spontaneous abortion (SAB) or preterm birth (PTB). METHODS: Women were enrolled in Right from the Start (2004-2010), a prospective pregnancy cohort. Data about first-trimester antihistamine use were obtained from screening and first-trimester interviews. Self-reported outcomes included SAB and PTB and were verified by medical records. Cox proportional hazards models were used to test for an association between antihistamine use and each outcome, both performed adjusting for confounders. RESULTS: Among the 2685 pregnancies analyzed, 14% (n = 377) reported use of antihistamines. Among antihistamine users, 12% (n = 44) experienced SABs, and 6% (n = 21) had PTBs. Antihistamine exposure was not associated with SAB (adjusted hazard ratio [aHR] = 0.88, 95% confidence interval [CI] 0.64, 1.21) or PTB, which was modified by maternal race (aHR = 1.03, 95%CI 0.61, 1.72 among White women and aHR = 0.43, 95%CI 0.14, 1.34 among Black women). CONCLUSIONS: Despite the biologic plausibility that antihistamine use may influence pregnancy outcomes, we did not detect evidence of an association with SAB or PTB. These data demonstrate the utility of large prospective cohorts for evaluating drug safety in pregnancy when concerns are raised from animal models. PMID- 24789282 TI - Searching for genomic region of high-fat diet-induced type 2 diabetes in mouse chromosome 2 by analysis of congenic strains. AB - SMXA-5 mice are a high-fat diet-induced type 2 diabetes animal model established from non-diabetic SM/J and A/J mice. By using F2 intercross mice between SMXA-5 and SM/J mice under feeding with a high-fat diet, we previously mapped a major diabetogenic QTL (T2dm2sa) on chromosome 2. We then produced the congenic strain (SM.A-T2dm2sa (R0), 20.8-163.0 Mb) and demonstrated that the A/J allele of T2dm2sa impaired glucose tolerance and increased body weight and body mass index in the congenic strain compared to SM/J mice. We also showed that the combination of T2dm2sa and other diabetogenic loci was needed to develop the high-fat diet induced type 2 diabetes. In this study, to narrow the potential genomic region containing the gene(s) responsible for T2dm2sa, we constructed R1 and R2 congenic strains. Both R1 (69.6-163.0 Mb) and R2 (20.8-128.2 Mb) congenic mice exhibited increases in body weight and abdominal fat weight and impaired glucose tolerance compared to SM/J mice. The R1 and R2 congenic analyses strongly suggested that the responsible genes existed in the overlapping genomic interval (69.6-128.2 Mb) between R1 and R2. In addition, studies using the newly established R1A congenic strain showed that the narrowed genomic region (69.6-75.4 Mb) affected not only obesity but also glucose tolerance. To search for candidate genes within the R1A genomic region, we performed exome sequencing analysis between SM/J and A/J mice and extracted 4 genes (Itga6, Zak, Gpr155, and Mtx2) with non-synonymous coding SNPs. These four genes might be candidate genes for type 2 diabetes caused by gene-gene interactions. This study indicated that one of the genes responsible for high-fat diet-induced diabetes exists in the 5.8 Mb genomic interval on mouse chromosome 2. PMID- 24789284 TI - Characterization of successful root canal treatment. AB - Knowing the outcome of root canal treatment (RCT) is determinant to substantiate the clinical decision making process, especially when RCT is weighed against the extraction of natural teeth or replacement by prosthetic elements. The ideal scenario in all clinical situations should combine healing/prevention of disease (apical periodontitis) and the functional retention of the tooth. Understanding the risk factors associated with endodontic failure is a key factor to increase the chances of success. The logical action is to reverse the existing disease, which requires intervention to neutralize the bacterial invasion and disrupt the bacterial biofilm within the complex anatomy. Success is more predictable when the immune host defenses are favorable. However, success has different meanings to the dentist, to the patient and to the tooth itself. The life of an endodontically treated tooth depends on the accuracy of the diagnosis and planning, excellence of disinfection, instrumentation and filling procedures (antimicrobial strategies, root canal shaping and coronal and apical seal) and finally the rehabilitation management. The interpretation of constant or intermittent pain and/or discomfort associated with apical periodontitis (AP) in endodontically treated tooth may be suggestive of endodontic failure. The success features of RCT, namely absence of pain, regression of AP, tight seal of canal and coronal spaces, and recovery of tooth function, must be reevaluated over time. In case of doubt between success and failure, cone beam computed tomography (CBCT) could be indicated for detection and precise localization of AP. The possibility of map reading on CBCT images characterizes the real multidimensional structure, providing accurate information on the presence, absence or regression of AP. The survival of an endodontically treated tooth implies understanding the biological and mechanical outcomes as multifactorial events over the individual's life span. The objective of this review of literature is to discuss relevant factors associated with patient's health, tooth and dentist that could account for a successful RCT. PMID- 24789285 TI - In vivo accuracy of two electronic foramen locators based on different operation systems. AB - The aim of this study was to compare in vivo the accuracy of two electronic foramen locators (EFLs) based on different operation systems - Root ZX and Propex II. Ten healthy adult patients needing premolar extractions due to orthodontic reasons participated in the study, providing a sample of 17 noncarious, non restored, vital teeth (n= 24 canals). After coronal access preparation and cervical preflaring and prior to tooth extraction, the root canal length was measured alternating the two EFLs. All measurements were performed with K-files well fitted to the canal diameter at the level that each EFL indicated the apical foramen in their display (APEX or 0.0). The last K-file were fixed in place with cyanoacrylate, the tooth was extracted, and the apical 4 mm of each root were resected to measure the distance between the file tip and the apical foramen. The mean errors based on the absolute values of discrepancies were 0.30 +/- 0.29 mm (Root ZX) and 0.32 +/- 0.27 mm (Propex II). Analysis by the Wilcoxon test for paired samples showed no statistically significant differences between the electronic canal measurements performed with the EFLs (p=0.587). The apical foramen was accurately located in 75% (Root ZX) and 66.7% (Propex II) of the cases, considering a +/-0.5 mm error margin, with no statistically significant difference by the chi-square test. Despite having different measurement mechanisms, both EFLs were capable of locating the apical foramen with high accuracy in vivo. Under the tested clinical conditions, Root ZX and Propex II displayed similar results. PMID- 24789286 TI - An in vivo study of working length determination with a new apex locator. AB - The success of an endodontic treatment relies on a correct working length determination. The canal terminus must be detected accurately and a precise control of the working length during the endodontic treatment must be maintained. The aim of this study was to investigate the working length determination in vivo with the Quill Apex Locator(r) for apical limit established at 1 mm short from the apical foramen (AF). Patients scheduled to dental extraction due to orthodontic or periodontal reasons were selected for this study, resulting in a sample of 24 root canals. Written informed consent was obtained from each patient before the treatment. After the administration of local anesthesia each tooth had its pulp cavity accessed. Next, the reading corresponding to the AF showed on the device's display was recorded and the file was removed. With the use of a digital caliper, 1 mm was subtracted from that first measurement. The file with the new measurement was introduced into to the root canal again then fixed with light curing flow composite and the tooth was extracted. Next, one of the apical third walls was worn out to visualize the instrument's point and the AF. The distance from the file tip to the AF was measured by scanning electron microscopy. The average of the measurements was 1.089+/-0.437 mm. The Bicaudal t-test showed no significant difference (p=0.338) between the experimental values and the hypothetical value tested at 1 mm. The present investigation confirmed that the Quill Apex Locator(r) was able to determine the working length with good reliability for the endodontic treatment, established at 1 mm short from the AF. PMID- 24789287 TI - In vitro erosive effect of pediatric medicines on deciduous tooth enamel. AB - This study evaluated, in vitro, the erosive potential of pediatric liquid medicines in primary tooth enamel, depending on the exposure time. Sixty deciduous incisors were randomly assigned to 4 groups (n=15), according to the immersion solutions: guaifenesin; ferrous sulfate; salbutamol sulfate and artificial saliva. The immersion cycles in the medicines were undertaken under a 1-min agitation, which wasperformed three times daily, during 28 days. Surface microhardness was measured at 7,14, 21 and 28 days. The titratable acidity and buffering capacity of the immersion media were determined. Data were analyzed by Analysis of Variance and Tukey's test (alpha=0.05). Salbutamol sulfate caused a gradual loss in enamel microhardness deciduous, observed at all times (p<0.005). Exposure to guaifenesin or ferrous sulfate resulted in significant decrease of enamel microhardness only after 28 days (p<0.005). In the control group (artificial saliva), microhardness did not changed (p>0.005) at any of the studied times. Scanning Electron Microscopy (SEM) images revealed that after 28 days the surfaces clearly exhibited structural loss, which was unlike those immersed in artificial saliva. Erosion of deciduous enamel was dependent on the type of medicine and exposure time. PMID- 24789288 TI - In situ effect of titanium tetrafluoride and sodium fluoride on artificially decayed human enamel. AB - This study compared in situ the application of 4% titanium tetrafluoride (TiF4) solution and 2% sodium fluoride (NaF) gel on artificial white-spot lesions in human enamel. A crossover, double-blind study using in situ caries models was carried out. Eleven volunteers used an intraoral appliance containing five demineralized human enamel blocks. The blocks (n=170) were randomly divided according to treatment into the following groups: TiF4 (n=55), NaF (n=55), positive control (n=55). A negative control group was composed of demineralized specimens (n=5). The microhardness test was performed using a Knoop penetrator. Energy dispersive spectrometer (EDS) was used to analyze the concentration of titanium, calcium, phosphate and oxygen. The enamel microhardness at different depths for TiF4, NaF and positive control samples was not statistically different (p>0.05). The samples from these three groups had statistically higher microhardness values than the negative control samples (p<0.05). EDS analysis did not provide conclusive results about the penetration of titanium in the TiF4 samples. While in some fragments it had substantial penetration, in other fragments it only had superficial penetration. It was possible to conclude that, under in situ conditions, 4% TiF4 solution and 2% NaF gel were able to remineralize artificial white-spot lesions in human enamel. However, the magnitude of the remineralization did not differ between groups. PMID- 24789289 TI - Addition of chlorhexidine gluconate to a glass ionomer cement: a study on mechanical, physical and antibacterial properties. AB - The objective of this work was to determine the effect of different concentrations of chlorhexidine digluconate (CHX) on setting time, surface hardness, maximum tensile bond strength and antibacterial activity of a glass ionomer cement (GIC). The material used as control was Ketac Molar Easymix GIC. CHX was incorporated into the GIC during its manipulation at concentrations of 0.5, 1.0 and 2.0%. Antimicrobial activity against S. mutans and L. acidophilus was evaluated by means of agar diffusion test. Tensile bond strength data were analyzed statistically using Analysis of variance and Tukey's test. Setting time, Vickers hardness and agar diffusion test were analyzed using Kruskal-Wallis and Mann-Whitney tests at a significance level of 5%. It was observed that adding CHX at concentrations of 1% and 2% increased significantly the setting time of the material (p=0.012 and p=0.003, respectively). There was no significant difference between control and 0.5% CHX groups regarding the setting time. Addition of 2% CHX decreased significantly the surface hardness in relation to the control group (p=0.009), followed by the 1% CHX group (p=0.009). The tensile bond strength of the material also decreased significantly after adding CHX at a concentration of 2% (p=0.001). Addition of CHX promoted formation of an inhibition halo in both bacterial strains for all concentrations. The results showed that the best option for clinical use of GIC with CHX is at 0.5% concentration, since antibacterial activity increased and the physical-mechanical properties remained unchanged. PMID- 24789290 TI - Degree of conversion of a resin cement light-cured through ceramic veneers of different thicknesses and types. AB - During the cementation of ceramic veneers the polymerization of resin cements may be jeopardized if the ceramics attenuate the irradiance of the light-curing device. The aim of this study was to evaluate the effect of different types and thicknesses of ceramic veneers on the degree of conversion of a light-cured resin based cement (RelyX Veneer). The cement was light-cured after interposing ceramic veneers [IPS InLine, IPS Empress Esthetic, IPS e.max LT (low translucency) and IPS e.max HT (high translucency) - Ivoclar Vivadent] of four thicknesses (0.5 mm, 1.0 mm, 1.5 mm and 2.0 mm). As control, the cement was light-cured without interposition of ceramics. The degree of conversion was evaluated by FTIR spectroscopy (n=5). Data were analyzed with one-way ANOVA and Tukey's test (alpha=0.05). Significant differences were observed among groups (p<0.001). The degree of conversion was similar to the control for all light-cured groups with interposition of ceramics of 0.5 mm and 1.0 mm (p>0.05). Among 1.5-mm-thick veneers, IPS e.max LT was the only one that showed different results from the control (p<0.05). At the thickness of 2.0 mm, only the IPS e.max LT and HT veneers were able to produce cements with degrees of conversion similar to the control (p>0.05). The degree of conversion of the evaluated light-cured resin cement depends on the thickness and type of ceramics employed when veneers thicker than 1.5 mm are cemented. PMID- 24789291 TI - Trial of an experimental castor oil solution for cleaning dentures. AB - Denture hygiene is essential because denture biofilm is involved in oral infections and systemic diseases. Although there are chemical agents available on the market, none of them have ideal properties and research on such products is still necessary. The aim of this study was to evaluate the efficacy of a castor bean (Ricinus communis)-based solution for removing denture biofilm, compared to two traditional products (sodium hypochlorite and alkaline peroxide). Fifty maxillary complete denture wearers were instructed to brush their dentures after meals and to immerse their dentures once a day in the following solutions: Saline (20 min; control), Polident alkaline peroxide (3 min), NaOCl (20 min) and 2% castor oil solution (20 min). Participants used each solution for a period of 7 consecutive days, according to a random sequence. After each period, the internal surfaces of maxillary complete dentures were stained with a disclosing solution (1% neutral red), photographed and the disclosed biofilm was quantified with the aid of specific software. The influence of treatments on results was verified by the Friedman test (alpha=0.05). Tested solutions presented significant difference (Fr=51.67; p<0.001). Saline and NaOCl were significantly different (median: 2.0% and 0.0%) whereas Polident and castor oil presented intermediate results (median: 1.0% and 1.5%, respectively). It can be concluded that the castor oil solution tested in this study was comparable to alkaline peroxide in terms of efficiency in denture biofilm removal. PMID- 24789292 TI - In vitro microbiological analysis of bacterial seal at the implant-abutment interface using two morse taper implant models. AB - The objective of this study was to evaluate the bacterial seal at the implant abutment interface using two morse taper implant models, by means of an in vitro microbiological analysis. For that were used 15 implants with mini-abutments tightened by friction, no screws (Group 1); and 30 implants with screw-tightened abutments, of which 15 received 20 N.cm of closing torque (Group 2) and the other 15 received 30 N.cm (Group 3). Microbiological analysis was carried out using colonies of Escherichia coli transported directly from a culture dish to the prosthetic component. Friction implants (Group 1) were activated by tapping and a torque wrench was used for screw-tightened implants (Groups 2 and 3). Each abutment/implant set was immersed in test tubes containing 5 mL of brain-heart infusion broth and incubated at 37 degrees C for 14 days, observed daily for the presence of contamination. A statistically significant difference was observed regarding the number of contaminated implants. There was greater contamination in Group 2 implants (p<0.05), with no statistically significant difference between the other groups (Group 1 = 20% and Group 3 = 0%). It was concluded that there was no significant difference in in vitro bacterial sealing between implants with mini-abutments tightened by friction without screws and implants with screw tightened abutments with 30 N.cm of closing torque. The difference in closing torque altered the in vitro sealing ability of the tested abutments, with a greater contamination for components that received a closing torque of 20 N.cm. PMID- 24789293 TI - Severity of TMD related to age, sex and electromyographic analysis. AB - Temporomandibular disorders (TMD) are manifested as a group of signs and symptoms that affect a particular population profile. Some variables such as sex and age influence the clinical expression of this condition. This observational descriptive cross-sectional study aimed to correlate the severity of TMD established by the craniomandibular index (CMI) with the variables: age, sex and electromyographic activity of the masseter and anterior temporal muscles. Fifty four subjects (15 males/39 females) aged between 16 to 65 years (mean age = 41 years) and diagnosed with TMD were evaluated. Severity was determined by the CMI. These subjects also underwent examination by surface electromyography of the masseter and anterior temporal muscles. No correlation was found between age and severity of TMD (p=0.19/r=0.16), however there was a trend of greater severity in young adults (25-50 years). The sex variable in the correlation was positive with the CMI (p=0.03/r=-0.96) and superior to women. A greater EMG activity of the anterior temporal in relation to masseter (p=0.01) was found and the left temporal activity had the highest average (161.5 +/- 44.6 Hz). The electromyographic activity of the anterior temporal and right masseter muscles was positively correlated with the Dysfunction Index CMI (p=0.01). The use of CMI to quantify the severity of TMD and of EMG to assess the functionality of the masticatory muscles can be important allies to direct the treatment. PMID- 24789294 TI - Conceptualization of dental caries by undergraduate dental students from the first to the last year. AB - Dental caries, still one of the most common diseases affecting people around the world, has a multifactorial nature encompassing necessary (biofilm accumulation), determinant (exposure to sugars and fluoride) and modulating factors (biological and social). The concepts about caries learned at dental schools may directly influence the conduct of the future dentists regarding the control and treatment of this disease. The aim of this study was to determine the concept that students at the Piracicaba Dental School, University of Campinas, Brazil, have about dental caries. In this cross-sectional descriptive study, 274 students answered the discursive question "Conceptualize dental caries". Students' answers were analyzed by a content analysis technique that allowed the creation of response categories and classification of the concepts in categories. Frequencies were expressed as absolute numbers and percentages. Differences between the responses according to the students' class years were tested by the chi-square test. Differences with p<0.05 were considered statistically significant. The response categories were: biological concept (53.6%), restrictive multifactorial concept (12.1%), comprehensive multifactorial concept (8.1%), transmissibility concept (15.8%), and other (10.4%). Differences in response category frequencies were seen between the class years (p<0.001). There was no consensus on the disease definition, although students predominantly had a biological concept of dental caries. PMID- 24789295 TI - Scholarships for scientific initiation encourage post-graduation degree. AB - This study aimed to evaluate the factors associated with the decision to attend an academic post-graduation program by dental students. A cross-sectional study was conducted in 2012, last-year undergraduate students from Dental Schools of Southern Brazil. A closed questionnaire was applied including questions grouped in three different blocks: pre-graduate, undergraduate period and future perspectives. The outcome was the decision to pursuit an academic post-graduation degree. Associations were tested using chi-squared test and chi-squared test for linear trends when appropriate. Multivariate Poisson regression was also performed. The sample was composed by 671 students (response rate of 69.9%, n=467). In relation to future perspectives, 68% of the interviewed students intended to attend a post-graduation program, but only 17.5% would choose a program with academic and research post-graduation program (Master and PhD programs). In the final model, students from public universities (PR 2.08, 95%CI 1.41-3.08) and students that received scientific initiation scholarship (PR 1.93 95%CI 1.14-3.27) presented a twice greater prevalence to seek academic post graduate programs. Students with higher family incomes showed a lower prevalence to seek these programs (PR 0.50, 95%IC 0.28-0.90). Scholarships seem to encourage undergraduate students to pursue stricto sensu post-graduation. PMID- 24789296 TI - Cervical necrotizing fasciitis of odontogenic origin in a diabetic patient complicated by substance abuse. AB - Cervical necrotizing fasciitis (CNF) is an uncommon, potentially fatal soft tissue infection with rapid progression characterized by necrosis in the subcutaneous tissue and fascia. A case of CNF of odontogenic origin in a diabetic patient, complicated by alcohol dependence and tobacco abuse, is presented with a literature review. The emergency procedure comprised hydration, colloid administration, glycemic control and broad spectrum antibiotic therapy, followed by aggressive surgical debridement. Necrosis in the platysma muscle was verified by histopathologic analysis. Reconstructive surgery was performed after suppressing the infection, and the wound was closed with an autologous skin graft. The patient had a long hospital stay, in part because the substance abuse led to a difficult recovery. The principles of early diagnosis, aggressive surgical debridement, broad-spectrum antibiotic therapy and intensive supportive care in the treatment of CNF were confirmed in the present case. It was concluded that given the occurrence of CNF in the presence of diabetes mellitus and abuse of substances such as alcohol and tobacco, the health care professional should consider a stronger response to treatment and longer hospitalization. PMID- 24789297 TI - Management of type III dens invaginatus in a mandibular premolar: a case report. AB - Dens invaginatus is a well-known malformation of teeth, which probably results from an invagination of enamel organ into dental papilla during tooth development. The endodontic treatment of invaginated teeth may be challenging due to difficulties in accessing the root canals and also due to complex variations of internal morphology. This article presents the endodontic management and follow-up in a rare case of right mandibular second premolar with Oehlers' type III dens invaginatus. The result of cold pulp testing was positive for this tooth but it was associated to a sinus tract and periapical lesion. Herein, it is described the root canal therapy of this tooth combined with periapical surgery, emphasizing the importance of proper diagnosis and planning by using cone beam computed tomography (CBCT). This case report presents the proper periapical healing 6 months after the combination of nonsurgical and surgical treatments. It also shows that CBCT is an important auxiliary examination to avoid errors in diagnosis and subsequent treatment of dental anomalies. PMID- 24789298 TI - Multiple supernumerary teeth in a nonsyndromic 12-year-old female patient - a case report. AB - Supernumerary teeth (ST) are uncommon alterations of development that may appear in either of the dental arches and that are frequently associated with syndromes such as cleidocranial dysplasia and Gardner syndrome. Multiple ST in individuals with no other disease or syndrome are very rare. In view of this situation, correct diagnosis, treatment and evaluation of ST with the use of appropriate imaging techniques are highly important. This case report presents radiographic images of a nonsyndromic 12-year-old female patient who presented with 14 supernumerary teeth and was treated under general anesthesia, with the extraction of all ST in a single surgical intervention. During the postoperative period, the patient did not complain of pain nor did she present any signs or symptoms of infection. During late follow-up period, due to difficulty in traction of the maxillary right canine and mandibular left first premolar towards the dental arch, it was necessary to extract these teeth under local anesthesia. Radiographic examination 3 years after surgery revealed the absence of ST and of diseases related to the existence of these teeth. PMID- 24789299 TI - Temporal changes in the required shoe-floor friction when walking following an induced slip. AB - Biomechanical aspects of slips and falls have been widely studied to facilitate fall prevention strategies. Prior studies have shown changes in gait after an induced slipping event. As such, most researchers only slip participants one time to avoid such changes that would otherwise reduce the external validity of experimental results. The ability to slip participants more than once, after allowing gait to return to a natural baseline, would improve the experimental efficiency of such studies. Therefore, the goal of this study was to characterize the temporal changes in required shoe-floor friction when walking following an induced slip. Two experiments were completed, and each employed a different potential strategy to promote the return of gait to a natural baseline after slipping. In the first experiment, extended time away from the laboratory was used to promote the return of gait to baseline. We measured required coefficient of-friction among 36 young adult male participants over four sessions. The first three sessions provided measurements during baseline (i.e., natural gait) both prior to slipping and immediately after slipping. The fourth session provided a measurement 1-12 weeks after slipping. In the second experiment, an extensive number of walking trials was used to promote the return of gait to baseline. We measured required coefficient-of-friction among 10 young adult male participants in a single session. Measurements were collected during 10 baseline walking trials, immediately after slipping, and during 50-55 additional trials. In both experiments, required coefficient-of-friction decreased 12-16% immediately after a single slip, increased toward baseline levels over subsequent weeks/walking trials, but remained statistically different from baseline at the end of the experiments. Based on these results, experiments involving slipping participants multiple times may not have a high level of external validity, and researchers are encouraged to continue to limit experimental protocols to a single induced slip per participant. PMID- 24789300 TI - Effectiveness of synovial fluid mesenchymal stem cells embedded in alginate beads for treatment of steroid-induced avascular necrosis of the femoral head. AB - OBJECTIVE: Treatment of early stage avascular necrosis of the femoral head (AVNFH) is still challenging for clinicians today. Core decompression with the implantation of mesenchymal stem cells (MSCs) has become popular and been proven to be an effective therapy for ANNFH. Synovial fluid MSCs, which can be easily harvested by joint aspiration, reportedly have the potential to differentiate into bone and cartilage. The purpose of this investigation is to evaluate the effectiveness of core decompression plus the implantation of alginate beads embedded with synovial fluid MSCs (ABSMSCs) in bone regeneration in the treatment of steroid-induced AVNFH in a rabbit model. METHODS: An in vitro study is carried out to evaluate the bioactivity and osteogenic differentiation of synovial fluid MSCs in the environment formed by alginate beads. In an in vivo study, the application of ABSMSCs was combined with bone decompression to treat steroid induced AVNFH in a rabbit model. Bone mineral density, radiography and histology were used to evaluate the bone growth of the femoral head after the rabbits had been euthanized 6 weeks after surgery. RESULTS: The results obtained in vitro showed that the synovial fluid MSCs in the environment of alginate beads had the potential to differentiate toward bone growth. In vivo, the treatment of steroid induced AVNFH in a rabbit model by core decompression plus the implantation of ABSMSCs preserved the bone density and sphericity of the femoral head and promoted bone regeneration. CONCLUSION: Implantation of ABSMSCs is a novel and effective therapy for AVNFH. Hopefully, this application will improve the outcome of early stage AVNFH and facilitate the harvesting of stem cells. PMID- 24789301 TI - Stress fracture of the bowed femoral shaft is another cause of atypical femoral fracture in elderly Japanese: a case series. AB - BACKGROUND: We have studied stress fractures of the bowed femoral shaft (SBFs) among elderly Japanese for over a decade. On the other hand, severely suppressed bone turnover (SSBT) after long-term bisphosphonates (BPs) use has been considered to be one of the causes of low-energy diaphyseal femoral fractures, often called atypical femoral fractures (AFFs). Some studies have shown that BPs use for more than 5 years is associated with an increased risk of AFFs. Here, we present a report of our SBF case series experienced in the past 15 years in order to examine whether bowing deformity should be considered among the causes of AFFs. METHODS: Subjects were 13 Japanese female patients with low-energy femoral shaft fractures. Mean age at injury was 77.0 years (range 67-88 years). All patients met the criteria of the AFFs' case definition. The first author treated 11 of the 13 patients over 8 years (2005-2012) based on the concept of SBFs. Regarding the regional characteristics of these patients, 10 were treated at 2 rural hospitals, and 3 were treated at 3 urban hospitals. Retrospectively, we assessed fracture type and location, existence of fracture on the contralateral side, bowing deformity, and duration of BPs use. RESULTS: All 13 cases were AO/OTA type 32-A. Incomplete or previous fracture on the contralateral side was noted in 10 cases. Obvious bowing deformity of the femoral shaft was noted in 12 cases. BPs were taken in 7 cases, only 3 of which involved BPs use for more than 5 years. CONCLUSIONS: We experienced 12 cases of low-energy femoral shaft fractures associated with bowing deformity. Six cases were not treated with BPs at all. Stress fractures associated with a femoral shaft bowing deformity do actually exist and should be recognized as another cause of AFFs. PMID- 24789303 TI - Ultrasound deserves to play a prominent role in the diagnosis and management of endometrial cancer. PMID- 24789302 TI - Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38alpha MAPK inhibitors. AB - The protein kinase, p38alpha MAPK, is a key intracellular transducer of stressor induced neuroinflammatory responses and, as such, is of high interest as a potential therapeutic target. We recently reported the synthesis and evaluation of first-in-class CNS-penetrant and highly specific p38 MAPK inhibitors that avoid target crossover issues seen in popular small molecule p38 MAPK inhibitors used in hundreds of previous reports. The novel p38 MAPK inhibitors, represented in this study by MW181, are efficacious in vivo. Pharmacodynamic actions include attenuation of stressor-induced increases in brain proinflammatory cytokine levels. We report here more detailed analyses of MW181 target engagement and specific linkage to the downstream increase in glia proinflammatory cytokine production. In vivo validation included demonstration that oral administration of MW181 suppresses lipopolysaccharide-induced increases in mouse brain IL-1beta, TNFalpha, IL-6, IL-10, and CXCL1 but not in a drug-resistant p38alpha MAPK mutant mouse. PMID- 24789304 TI - Re: Uterine artery Doppler and sFlt-1/PlGF ratio: prognostic value in early-onset pre-eclampsia. P. I. Gomez-Arriaga, I. Herraiz, E. A. Lopez-Jimenez, D. Escribano, B. Denk and A. Galindo. Ultrasound Obstet Gynecol 2014; 43: 525-532. PMID- 24789305 TI - Re: Amnioinfusion in very early preterm prelabor rupture of membranes (AMIPROM): pregnancy, neonatal and maternal outcomes in a randomized controlled pilot study. D. Roberts, S. Vause, W. Martin, P. Green, S. Walkinshaw, L. Bricker, C. Beardsmore, N. Shaw, A. McKay, G. Skotny, P. Williamson and Z. Alfirevic. Ultrasound Obstet Gynecol 2014; 43: 490-499. PMID- 24789306 TI - Re: factors affecting visualization of postmenopausal ovaries: descriptive study from the multicenter United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). PMID- 24789307 TI - Reply: To PMID 23456790. PMID- 24789309 TI - Effects of selected operational parameters on efficacy and selectivity of electromembrane extraction. Chlorophenols as model analytes. AB - Effects of organic solvent type, pH value, and composition of donor/acceptor solution on the efficacy of electromembrane extraction (EME) were examined. For the first time, a comprehensive quantitative study, based also on measurements of electric charge passed through the EME system, was carried out, which demonstrates that apart from the pH value, also the nature of counter-ions in donor and acceptor solution plays a significant role in the electrically induced transfer of charged analytes across supported liquid membranes (SLMs). The EME transfer of model analytes correlated well with electrophoretic mobilities of inorganic cations, which were added to acceptor solutions during their alkalization with alkali metal hydroxides, and were highest for counter-cations with highest mobilities. Up to a 53-fold improvement of extraction efficiency was achieved for EMEs using optimized composition of donor (alkalized with KOH to pH 7) and acceptor (10 mM CsOH, pH 12) solutions. Six chlorophenols (CPs) were selected as model analytes due to the wide range of pH values that are required for their ionization and due to their high environmental relevance; quantitative measurements were carried out by CE with UV detection. Extraction recoveries of the six CPs ranged between 14 and 25% for 5 min EMEs at 150 V and 750 rpm across SLMs impregnated with 1-ethyl-2-nitrobenzene. Calibration curves were strictly linear (r(2) >= 0.999) in 0.01-10 MUg/mL range, repeatability values of peak areas were between 0.7 and 5.6% and LODs for standard solutions and environmental samples were better than 5 ng/mL. PMID- 24789310 TI - Working Long Hours is Associated with Higher Prevalence of Diabetes in Urban Male Chinese Workers: The Rosai Karoshi Study. AB - We investigated the relationship between number of weekly working hours and the prevalence of diabetes in the urban Chinese population. Data regarding anthropometric measurements, fasting blood glucose level and number of hours worked per week were collected from 2228 workers in Shanghai, China (Mage = 44 years; 64% men). Participants were divided into three groups according to the number of hours worked per week (<45, 45-54 and >=55), and multiple logistic regression analysis was conducted with diabetes as the dependent variable. Subjects with a HbA1c of 6.5% or above or those prescribed anti-diabetic medications were defined as having diabetes. The multivariate adjusted odds ratio for having diabetes was found to be significantly higher for those who worked >=55 h per week compared with those who worked <45 h per week, but only for men. This finding indicates that working long hours could be a risk factor for diabetes in Chinese male workers. PMID- 24789311 TI - Tobacco smoking, alcohol drinking, diabetes, low body mass index and the risk of self-reported symptoms of active tuberculosis: individual participant data (IPD) meta-analyses of 72,684 individuals in 14 high tuberculosis burden countries. AB - BACKGROUND: The effects of multiple exposures on active tuberculosis (TB) are largely undetermined. We sought to establish a dose-response relationship for smoking, drinking, and body mass index (BMI) and to investigate the independent and joint effects of these and diabetes on the risk of self-reported symptoms of active TB disease. METHODS AND FINDINGS: We analyzed 14 national studies in 14 high TB-burden countries using self-reports of blood in cough/phlegm and cough lasting > = 3 weeks in the last year as the measures of symptoms of active TB. The random effect estimates of the relative risks (RR) between active TB and smoking, drinking, diabetes, and BMI<18.5 kg/m2 were reported for each gender. Floating absolute risks were used to examine dyads of exposure. Adjusted for age and education, the risks of active TB were significantly associated with diabetes and BMI<18.5 kg/m2 in both sexes, with ever drinking in men and with ever smoking in women. Stronger dose-response relationships were seen in women than in men for smoking amount, smoking duration and drinking amount but BMI<18.5 kg/m2 showed a stronger dose-response relationship in men. In men, the risks from joint exposures were statistically significant for diabetics with BMI<18.5 kg/m2 (RR = 6.4), diabetics who smoked (RR = 3.8), and diabetics who drank alcohol (RR = 3.2). The risks from joint risk factors were generally larger in women than in men, with statistically significant risks for diabetics with BMI<18.5 kg/m2 (RR = 10.0), diabetics who smoked (RR = 5.4) and women with BMI<18.5 kg/m2 who smoked (RR = 5.0). These risk factors account for 61% of male and 34% of female estimated TB incidents in these 14 countries. CONCLUSIONS: Tobacco, alcohol, diabetes, and low BMI are significant individual risk factors but in combination are associated with triple or quadruple the risk of development of recent active TB. These risk factors might help to explain the wide variation in TB across countries. PMID- 24789312 TI - Brain without anatomy: construction and comparison of fully network-driven structural MRI connectomes. AB - MRI connectomics methods treat the brain as a network and provide new information about its organization, efficiency, and mechanisms of disruption. The most commonly used method of defining network nodes is to register the brain to a standardized anatomical atlas based on the Brodmann areas. This approach is limited by inter-subject variability and can be especially problematic in the context of brain maturation or neuroplasticity (cerebral reorganization after brain damage). In this study, we combined different image processing and network theory methods and created a novel approach that enables atlas-free construction and connection-wise comparison of diffusion MRI-based brain networks. We illustrated the proposed approach in three age groups: neonates, 6-month-old infants, and adults. First, we explored a data-driven method of determining the optimal number of equal-area nodes based on the assumption that all cortical areas of the brain are connected and, thus, no part of the brain is structurally isolated. Second, to enable a connection-wise comparison, alignment to a "reference brain" was performed in the network domain within each group using a matrix alignment algorithm with simulated annealing. The correlation coefficients after pair-wise network alignment ranged from 0.6102 to 0.6673. To test the method's reproducibility, one subject from the 6-month-old group and one from the adult group were scanned twice, resulting in correlation coefficients of 0.7443 and 0.7037, respectively. While being less than 1 due to parcellation and noise, statistically, these values were significantly higher than inter-subject values. Rotation of the parcellation largely explained the variability. Through the abstraction from anatomy, the developed framework allows for a fully network driven analysis of structural MRI connectomes and can be applied to subjects at any stage of development and with substantial differences in cortical anatomy. PMID- 24789319 TI - Tumoricidal activity of combining the agonistic DR5 antibody D-6 with cisplatin in C30 cisplatin-resistant ovarian cancer in vitro and in vivo. AB - A previous study by our group reported that the agonistic DR5 antibody D-6 was capable of triggering apoptosis in A2780 cisplatin-sensitive ovarian cancer cells and that this marked effect was enhanced by cisplatin in vitro. The present study examined whether D-6 and cisplatin may exert the same anti-tumor effect on C30 cisplatin-resistant ovarian cancer cells, and the underlying mechanisms were investigated. D-6 exhibited an apoptosis-inducing effect, increased the cell growth inhibition rate of C30 cells in a dose-dependent manner, induced significant morphological changes characteristic for apoptosis, as observed by electron microscopy, and downregulated the expression of caspase 3, 8 and 9 precursors in C30 cells treated with D-6 at the protein level. All of these effects were evidently enhanced when accompanied by cisplatin. Furthermore, D-6 alone or in combination with cisplatin in the established models of C30 tumor xenografts resulted in a significant repression of tumor growth, and evident apoptosis, as determined by a terminal transferase dUTP nick end labeling assay. In addition, the expression of caspase 3, 8 and 9 precursors in the tumor xenografts was as similar to that found in vitro. In conclusion, the present study suggested that D-6 may serve as a novel anti-tumor agent against C30 cisplatin-resistant ovarian cancer, with the ability to trigger apoptosis via caspase-dependent and -independent pathways and the potential to decrease the cisplatin resistance of the C30 cell line. PMID- 24789320 TI - The theoretical account of the ligand field bonding regime and magnetic anisotropy in the DySc2N@C80 Single Ion Magnet endohedral fullerene. AB - Considering the DySc2N@C80 system as a prototype for Single Ion Magnets (SIMs) based on endohedral fullerenes, we present methodological advances and state-of the art computations analysing the electronic structure and its relationship with the magnetic properties due to the Dy(III) ion. The results of the quantum chemical calculations are quantitatively decrypted in the framework of ligand field (LF) theory, extracting the full parametric sets and interpreting in heuristic key the outcome. An important result is the characterization of the magnetic anisotropy in the ground and excited states, drawing the polar maps of the state-specific magnetization functions that offer a clear visual image of the easy axes and account for the pattern of response to perturbations by the magnetic field applied from different space directions. The state-specific magnetization functions are derivatives with respect to the magnetic field, taken for a given eigenvalue of the computed spectrum. The methodology is based on the exploitation of the data from the black box of the ab initio spin-orbit (SO) calculations. The ground state is characterized by the Jz = +/-15/2 quantum numbers with easy axis along the Dy-N bond. The implemented dependence on the magnetic field allowed the first-principles simulation of the magnetic properties. The computational approach to the properties of endohedral fullerenes is an important goal, helping to complement the scarcity of the experimental data on such systems, determined by the limited amount of samples. PMID- 24789321 TI - Diffuse white structural coloration from multilayer reflectors in a squid. PMID- 24789322 TI - Paraneoplastic disseminated intravascular coagulation caused by splenic littoral cell angioma. PMID- 24789324 TI - In memoriam: David L. Epstein, MD, MMM (1943-2014). PMID- 24789308 TI - The contribution of viral genotype to plasma viral set-point in HIV infection. AB - Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms. PMID- 24789323 TI - Larger mid-dorsolateral prefrontal gray matter volume in young binge drinkers revealed by voxel-based morphometry. AB - Binge drinking or heavy episodic drinking is a high prevalent pattern of alcohol consumption among young people in several countries. Despite increasing evidence that binge drinking is associated with impairments in executive aspects of working memory (i.e. self-ordered working memory), processes known to depend on the mid-dorsolateral prefrontal cortex (Brodmann areas 46 and 9), less is known about the impact of binge drinking on prefrontal gray matter integrity. Here, we investigated the effects of binge drinking on gray matter volume of mid- dorsolateral prefrontal cortex in youths. We used voxel-based morphometry on the structural magnetic resonance images of subjects reporting a persistent (at least three years) binge drinking pattern of alcohol use (n = 11; age 22.43 +/- 1.03) and control subjects (n = 21; age 22.18 +/- 1.08) to measure differences in gray matter volume between both groups. In a region of interest analysis of the mid dorsolateral prefrontal cortex, after co-varying for age and gender, we observed significantly larger gray matter volume in the left mid-dorsolateral prefrontal cortex (Brodmann areas 46 and 9) in binge drinkers in comparison with control subjects. Furthermore, there was a significant positive correlation between left mid-dorsolateral prefrontal cortex volume and Self-Ordered Pointing Test (SOPT) total errors score in binge drinkers. The left mid-dorsolateral prefrontal cortex volume also correlated with the quantity and speed of alcohol intake. These findings indicate that a repeated exposure to alcohol -that does not meet criteria for alcohol dependence- throughout post-adolescent years and young adulthood is linked with structural anomalies in mid-dorsolateral prefrontal regions critically involved in executive aspects of working memory. PMID- 24789325 TI - Biocleavable graphene oxide based-nanohybrids synthesized via ATRP for gene/drug delivery. AB - Graphene oxide (GO) has been proven to be promising in many biomedical fields due to its biocompatibility, unique conjugated structure, easily tunable surface functionalization and facile synthesis. In this work, a flexible two-step method was first developed to introduce the atom transfer radical polymerization (ATRP) initiation sites containing disulfide bonds onto GO surfaces. Surface-initiated ATRP of (2-dimethyl amino)ethyl methacrylate (DMAEMA) was then employed to tailor the GO surfaces in a well-controlled manner, producing a series of organic inorganic hybrids (termed as SS-GPDs) for highly efficient gene delivery. Under reducible conditions, the PDMAEMA side chains can be readily cleavable from the GO backbones, benefiting the resultant gene delivery process. Moreover, due to the conjugated structure of the graphene basal plane, SS-GPD can attach and absorb aromatic, water insoluble drugs, such as 10-hydroxycamptothecin (CPT), producing SS-GPD-CPT. The MTT assay and the simultaneous double-staining procedure revealed that SS-GPD-CPT possessed a high potency of killing cancer cells in vitro. With a high aqueous solubility and coulombic interaction with cell membrane, SS-GPDs may have great potential in gene/drug delivery fields. PMID- 24789326 TI - PARV4: an emerging tetraparvovirus. PMID- 24789327 TI - A functional feature analysis on diverse protein-protein interactions: application for the prediction of binding affinity. AB - Protein-protein interactions (PPIs) play crucial roles in diverse cellular processes. There are different types of PPIs based on the composition, affinity and whether the association is permanent or transient. Analyzing the diversity of PPIs at the atomic level is crucial for uncovering the key features governing the interactions involved in PPI. A systematic physico-chemical and conformational studies were implemented on interfaces involved in different PPIs, including crystal packing, weak transient heterodimers, weak transient homodimers, strong transient heterodimers and homodimers. The comparative analysis shows that the interfaces tend to be larger, less planar, and more tightly packed with the increase of the interaction strength. Meanwhile the strong interactions undergo greater conformational changes than the weak ones involving main chains as well as side chains. Finally, using 18 features derived from our analysis, we developed a support vector regression model to predict the binding affinity with a promising result, which further demonstrate the reliability of our studies. We believe this study will provide great help in more thorough understanding the mechanism of diverse PPIs. PMID- 24789328 TI - Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis. AB - Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in malignant lesions, but not in normal pancreatic tissues. To assess the role of Pim-3 in human pancreatic carcinogenesis in vivo and to determine the underlying Pim-3 signaling regulatory mechanisms, we established MiaPaca-2 cells overexpressing wild-type Pim-3 or Pim-3 kinase dead mutants (K69M-Pim-3) as well as PCI55 cells stably expressing Pim-3 shRNA or scrambled shRNA in a tetracycline inducible manner. In addition, we conducted studies utilizing a nude mouse tumor xenograft model. Our results demonstrated that cells stably overexpressing wild type Pim-3 exhibited functionally enhanced phosphorylation of Bad at Ser112 and increased proliferation. In contrast, the stable inactivation of Pim-3 by K69M Pim-3 or silencing of Pim-3 expression by Pim-3 shRNA resulted in functionally decreased phosphorylation of Bad at Ser112 and higher apoptotic cells. Following subcutaneous injection of these stable cell lines, nude mice injected with Pim-3 overexpressing cells developed 100% subcutaneous tumors, together with increased PCNA-positive cells and enhanced intratumoral CD31-positive vascular areas. On the other hand, intratumoral neovascularization and tumor cell proliferation was attenuated in mice injected with Pim-3 kinase inactive cells, eventually reducing tumorigenicity in these mice to 46.6%. Moreover, Pim-3 overexpression upregulated the intratumoral levels of pSTAT3Try705, pSurvivinThr34, HGF, EGF, FGF-2 and VEGF, while the increases were markedly diminished on Pim-3 kinase inactivation. Collectively, the Pim-3 kinase emerges as being involved in accelerating human pancreatic cancer development and in promoting tumor neovascularization and subsequent tumor growth. Targeting Pim-3 may play a dual role in halting tumor progression, by promoting tumor cell death and blocking angiogenesis. PMID- 24789329 TI - Wavelength-tunable light shaping with cholesteric liquid crystal microlenses. AB - The ability to guide light on the mesoscopic scale is important both scientifically and technologically. Especially relevant is the development of wavelength-tunable light-shaping microdevices. Here we demonstrate the use of cholesteric liquid crystal polygonal textures organized as an array of microlenses for this purpose. The beam shaping is controlled by tuning the wavelength of the incident light in the visible spectrum. By taking advantage of the self-organization property of liquid crystals, the structure of the lens and its optical response are tailored by changing the annealing time of the single layer material during a completely integrated one-step process. The intrinsic helical organization of the layer is the cause of the light shaping and not the shape of the surface as for conventional lenses. A new concept of light manipulation using the structure chirality of liquid crystals is demonstrated, which concerns soft matter photonic circuits to mould the light. PMID- 24789330 TI - Pen-on-paper approach toward the design of universal surface enhanced Raman scattering substrates. AB - The translation of a technology from the laboratory into the real world should meet the demand of economic viability and operational simplicity. Inspired by recent advances in conductive ink pens for electronic devices on paper, we present a "pen-on-paper" approach for making surface enhanced Raman scattering (SERS) substrates. Through this approach, no professional training is required to create SERS arrays on paper using an ordinary fountain pen filled with plasmonic inks comprising metal nanoparticles of arbitrary shape and size. We demonstrate the use of plasmonic inks made of gold nanospheres, silver nanospheres and gold nanorods, to write SERS arrays that can be used with various excitation wavelengths. The strong SERS activity of these features allowed us to reach detection limits down to 10 attomoles of dye molecules in a sample volume of 10 MUL, depending on the excitation wavelength, dye molecule and type of nanoparticles. Furthermore, such simple substrates were applied to pesticide detection down to 20 ppb. This universal approach offers portable, cost effective fabrication of efficient SERS substrates at the point of care. This approach should bring SERS closer to the real world through ink cartridges to be fixed to a pen to create plasmonic sensors at will. PMID- 24789331 TI - Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking. AB - PURPOSE: This study examined the association of post-treatment changes in cognitive performance, apolipoprotein E (APOE), and smoking in breast cancer patients treated with adjuvant therapy. PARTICIPANTS AND METHODS: Breast cancer patients treated with chemotherapy (N = 55, age = 51.9 +/- 7.1, education = 15.7 +/- 2.6) were evaluated with a battery of neuropsychological tests prior to chemotherapy and at 1, 6, and 18 months post-chemotherapy. Matched groups of breast cancer patients not exposed to chemotherapy (N = 68, age = 56.8 +/- 8.3, education = 14.8 +/- 2.2) and healthy controls (N = 43, age = 53.0 +/- 10.1, education = 15.2 +/- 2.6) were evaluated at similar intervals. APOE epsilon 4 carrier status (APOE4+) and smoking history were also evaluated. RESULTS: The detrimental effect of APOE4+ genotype on post-treatment cognitive functioning was moderated by smoking history, that is, patients without a smoking history had significantly lower performance on measures of processing speed and working memory compared with those with a smoking history and healthy controls. Exploratory analyses revealed that APOE4+ patients without a smoking history who were exposed to chemotherapy showed a decline in performance in processing speed, compared with patients with a smoking history. A similar but less pronounced pattern was seen in the no chemotherapy group (primarily endocrine treatment). For working memory, the APOE4+ by smoking interaction was observed in the no chemotherapy group only. CONCLUSIONS: The association between APOE status, breast cancer treatment, and cognitive functioning was moderated by smoking history suggesting that both chemotherapy and endocrine therapy interact with APOE status and smoking to influence cognition. A putative mechanism is that smoking corrects a deficit in nicotinic receptor functioning and dopamine levels in APOE4+ individuals. PMID- 24789332 TI - Multiple prenatal ultrasound scans and ocular development: 20-year follow-up of a randomized controlled trial. AB - OBJECTIVES: Through comprehensive ophthalmic examination of adult offspring we sought to determine the impact of multiple prenatal ultrasound scans on ocular development. METHODS: 2743 pregnant women recruited to the Western Australian Pregnancy (Raine) Cohort study during 1989-1991 were randomized to receive at King Edward Memorial Hospital, Western Australia either multiple prenatal ultrasound scans and Doppler flow studies (intensive group) or a single ultrasound scan at 18 weeks' gestation. Neonatal birth weight of the offspring and other physical measurements were collected prospectively. At age 20 years, participants underwent a comprehensive ophthalmic examination including measurement of ocular biometry and visual acuity. RESULTS: Complete data were available for 1134 adult offspring participants. The mothers of 563 of these had been randomized to receive multiple prenatal ultrasound scans. The mean age of participants at follow-up was 20.0 years. There was no statistically significant difference between the two groups with regard to ocular biometric or visual outcomes, except for slightly higher intraocular pressure identified in individuals exposed to multiple ultrasound scans (P = 0.034). Although infants in the intensive-ultrasound arm were more likely to have birth weights in the lower quartiles, this was not reflected in adult eye development. Axial length, lens thickness, corneal curvature and thickness and optic cup to disc ratio (a risk factor for glaucomatous optic neuropathy) were not significantly influenced by the more frequent ultrasound protocol. CONCLUSIONS: Prior to this study, there was a paucity of safety data for ultrasound with regard to eye development. We found that frequent in-utero exposure to ultrasound, including B-mode imaging and the use of spectral Doppler mode from 18 weeks' gestation, had no significant impact on visual outcomes or ocular biometry. PMID- 24789334 TI - Diabetic retinopathy and estimated cerebrospinal fluid pressure. The Beijing Eye Study 2011. AB - PURPOSE: The cerebrospinal fluid pressure (CSFP) is a major determinant of central retinal vein pressure and thus of retinal capillary pressure. We tested the hypothesis whether prevalence and severity of diabetic retinopathy are associated with CSFP. METHODS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6 +/- 9.8 years. A detailed ophthalmic examination was performed including fundus photography for the assessment of diabetic retinopathy according. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44xBody Mass Index[kg/m(2)]+0.16 Diastolic Blood Pressure[mmHg] 0.18xAge[Years]-1.91. RESULTS: In binary regression analysis, presence of diabetic retinopathy was significantly associated with higher levels of HbA1c (P<0.001; regression coefficient B:0.25; odds ratio (OR):1.28; 95% confidence interval (CI):1.15,1.43), higher blood concentration of glucose (P<0.001; B:0.40;OR:1.49;95%CI:1.36,1.63), longer known duration of diabetes mellitus (P<0.001; B:0.14;OR:1.15; 95%CI:1.11,1.19), higher systolic blood pressure (P<0.001; B:0.03;OR:1.03;95%CI:1.02,1.04), lower diastolic blood pressure (P<0.001; B:-0.06;OR:0.94;95%CI:0.91,0.97), and higher CSFP (P = 0.002; B:0.13;OR:1.14;95%CI:1.05,1.24). Severity of diabetic retinopathy was significantly associated with higher HbA1c value (P<0.001; standardized coefficient beta: 0.19; correlation coefficient B: 0.07;95%CI:0.05,0.08), higher blood concentration of glucose (P<0.001; beta:0.18;B:0.04;95%CI:0.04,0.05), longer known duration of diabetes mellitus (P<0.001; beta:0.20;B:0.03;95%CI:0.02,0.03), lower level of education (P = 0.001; beta: 0.05;B:-0.02;95%CI:-0.03,-0.01), lower diastolic blood pressure (P = 0.002; beta: 0.08;B:-0.001;95%CI:-0.004,-0.001), higher systolic blood pressure (P = 0.006; beta:0.06;B:0.001;95%CI:0.000,0.001), and higher CSFP (P = 0.006; beta:0.06;B:0.006;95%CI:0.002,0.010). CONCLUSIONS: Higher prevalence and severity of diabetic retinopathy were associated with higher estimated CSFP after adjusting for systemic parameters. Higher CSFP through a higher retinal vein pressure may lead to more marked retinal venous congestion and vascular leakage in diabetic retinae. PMID- 24789333 TI - Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages. AB - Candida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFkappaB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non matured phagosomes is likely not triggered by initial recognition events via MAPK or NFkappaB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata. PMID- 24789336 TI - Development of a new index of balance in adults with intellectual and developmental disabilities. AB - PURPOSES: The first objective was to propose a new model representing the balance level of adults with intellectual and developmental disabilities (IDD) using Principal Components Analysis (PCA); and the second objective was to use the results from the PCA recorded by regression method to construct and validate summative scales of the standardized values of the index, which may be useful to facilitate a balance assessment in adults with IDD. METHODS: A total of 801 individuals with IDD (509 males) mean 33.1 +/- 8.5 years old, were recruited from Special Olympic Games in Spain 2009 to 2012. The participants performed the following tests: the timed-stand test, the single leg stance test with open and closed eyes, the Functional Reach Test, the Expanded Timed-Get-up-and-Go Test. Data was analyzed using principal components analysis (PCA) with Oblimin rotation and Kaiser normalization. We examined the construct validity of our proposed two factor model underlying balance for adults with IDD. The scores from PCA were recorded by regression method and were standardized. RESULTS: The Component Plot and Rotated Space indicated that a two-factor solution (Dynamic and Static Balance components) was optimal. The PCA with direct Oblimin rotation revealed a satisfactory percentage of total variance explained by the two factors: 51.6 and 21.4%, respectively. The median score standardized for component dynamic and static of the balance index for adults with IDD is shown how references values. CONCLUSIONS: Our study may lead to improvements in the understanding and assessment of balance in adults with IDD. First, it confirms that a two-factor model may underlie the balance construct, and second, it provides an index that may be useful for identifying the balance level for adults with IDD. PMID- 24789335 TI - Squalene synthase as a target for Chagas disease therapeutics. AB - Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. PMID- 24789337 TI - Influence of DMF-induced oxidative stress on membrane and periplasmic proteins in Paracoccus sp. SKG. AB - The present study describes the N,N-dimethylformamide (DMF)-induced oxidative stress in Paracoccus sp. SKG. The oxidative stress was evaluated by analysing membrane and periplasmic proteins and K+ efflux, as well as by monitoring the activities of antioxidant enzymes like catalase, superoxide dismutase (SOD) and glutathione S-transferase (GST). The exposure of bacterial cells to a higher concentration of DMF resulted in the modification of membrane fatty acid composition which is accompanied by K+ efflux. Further, this oxidative stress resulted in increased periplasmic protein which can be attributed to the induction of GST and methionine sulphoxide reductase (Msr) enzymes under solvent stress. Paracoccus sp. SKG is tolerant to high concentrations of DMF up to 6% (v/v) and its toxic effects. DMF concentration-dependent induction of GST and Msr activities advocates the significant role of these enzymes in the bacterial defence system. The present study provides information which helps us to understand the ROS scavenging machinery in bacteria. The high tolerance of Paracoccus sp. SKG to DMF can be efficiently explored for various bioremediation and biotransformation applications. PMID- 24789338 TI - Ontology for the asexual development and anatomy of the colonial chordate Botryllus schlosseri. AB - Ontologies provide an important resource to integrate information. For developmental biology and comparative anatomy studies, ontologies of a species are used to formalize and annotate data that are related to anatomical structures, their lineage and timing of development. Here, we have constructed the first ontology for anatomy and asexual development (blastogenesis) of a bilaterian, the colonial tunicate Botryllus schlosseri. Tunicates, like Botryllus schlosseri, are non-vertebrates and the only chordate taxon species that reproduce both sexually and asexually. Their tadpole larval stage possesses structures characteristic of all chordates, i.e. a notochord, a dorsal neural tube, and gill slits. Larvae settle and metamorphose into individuals that are either solitary or colonial. The latter reproduce both sexually and asexually and these two reproductive modes lead to essentially the same adult body plan. The Botryllus schlosseri Ontology of Development and Anatomy (BODA) will facilitate the comparison between both types of development. BODA uses the rules defined by the Open Biomedical Ontologies Foundry. It is based on studies that investigate the anatomy, blastogenesis and regeneration of this organism. BODA features allow the users to easily search and identify anatomical structures in the colony, to define the developmental stage, and to follow the morphogenetic events of a tissue and/or organ of interest throughout asexual development. We invite the scientific community to use this resource as a reference for the anatomy and developmental ontology of B. schlosseri and encourage recommendations for updates and improvements. PMID- 24789339 TI - Defects of thiamine transport and metabolism. AB - Thiamine, in the form of thiamine pyrophosphate, is a cofactor for a number of enzymes which play important roles in energy metabolism. Although dietary thiamine deficiency states have long been recognised, it is only relatively recently that inherited defects in thiamine uptake, activation and the attachment of the active cofactor to target enzymes have been described, and the underlying genetic defects identified. Thiamine is transported into cells by two carriers, THTR1 and THTR2, and deficiency of these results in thiamine-responsive megaloblastic anaemia and biotin-responsive basal ganglia disease respectively. Defective synthesis of thiamine pyrophosphate has been found in a small number of patients with episodic ataxia, delayed development and dystonia, while impaired transport of thiamine pyrophosphate into the mitochondrion is associated with Amish lethal microcephaly in most cases. In addition to defects in thiamine uptake and metabolism, patients with pyruvate dehydrogenase deficiency and maple syrup urine disease have been described who have a significant clinical and/or biochemical response to thiamine supplementation. In these patients, an intrinsic structural defect in the target enzymes reduces binding of the cofactor and this can be overcome at high concentrations. In most cases, the clinical and biochemical abnormalities in these conditions are relatively non-specific, and the range of recognised presentations is increasing rapidly at present as new patients are identified, often by genome sequencing. These conditions highlight the value of a trial of thiamine supplementation in patients whose clinical presentation falls within the spectrum of documented cases. PMID- 24789341 TI - Use of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases. AB - Sapropterin dihydrochloride (SD) is the first drug treatment for phenylketonuria (PKU), but due to the lack of data, its use in maternal PKU must be undertaken with caution as noted in the FDA and EMEA labels. We collected data from eight pregnancies in PKU women treated with SD and we analysed the phenotypes of these patients, their tetrahydrobiopterin (BH4) responsiveness, the indications for SD treatment, the efficacy (metabolic control, phenylalanine (Phe) tolerance and offspring outcome) and the safety data. Results showed that in the seven patients known to be responsive to BH4, the use of SD during pregnancy was efficient in terms of metabolic control and Phe tolerance. The indications for giving SD included the failure of the low-Phe diet (n = 3), the fact that some of these women had never experienced the low Phe diet (n = 2), one unexpected pregnancy in a woman currently on SD and one pregnancy where the foetus was known to have PKU. The offspring of these seven pregnancies were all normal babies with normal birth measurements and outcomes. No side effect related to SD was observed in these seven cases. In the eighth case, SD was prescribed as a rescue treatment without previous knowledge of the BH4 responsiveness to a woman who was already 8 weeks pregnant without diet. The birth occurred at 33 weeks of gestational age with Potter syndrome (probably related to the absence of metabolic control during the first trimester) and the baby died in the first hours of life. In conclusion, the data presented here provides the first evidence that treatment with pharmacological doses of SD appears to be efficient and safe in women with PKU during pregnancy. Its use should, however, be restricted to those women previously identified to be clear responders to BH4. PMID- 24789343 TI - miR-376b-5p regulates angiogenesis in cerebral ischemia. AB - The profile of microRNAs (miRNAs) altered following middle cerebral artery occlusion (MCAO) and miRNAs are involved in angiogenesis following cerebral ischemia. miR-376b-5p was decreased following MCAO, however, whether miR-376b-5p is important in angiogenesis remains to be elucidated. The present study was designed to identify whether miR-376b-5p is involved in angiogenesis following cerebral ischemia and to elucidate the underlying mechanisms. A rat MCAO model was established and quantitative polymerase chain reaction was performed to analyze the mRNA expression level of miR-376b-5p for 1 to 7 days. In addition, the density of microvessels and the relative mRNA and protein levels of hypoxia inducible factor-1 alpha (HIF-1alpha), vascular endothelial growth factor A (VEGFA) and Notch1 were measured. The miR-376b-5p mimic or the miR-376b-5p inhibitor were transfected into hypoxic human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation were measured. To further examine the underlying mechanisms, shRNA was transfected into cells to knock down HIF-1alpha, and angiogenesis and the expression of associated molecules, including HIF-1alpha, VEGFA and Notch1 were compared between each group. Our results demonstrated that miR-376b-5p repressed angiogenesis in vivo and in vitro, and miR-376b-5p inhibited angiogenesis in HUVECs by targeting the HIF-1alpha-mediated VEGFA/Notch1 signaling pathway. These findings provide new insights into angiogenesis therapy for cerebral ischemia. PMID- 24789345 TI - Long-lasting oscillations in the electro-oxidation of formic acid on PtSn intermetallic surfaces. AB - Even when in contact with virtually infinite reservoirs, natural and manmade oscillators typically drift in phase space on a time-scale considerably slower than that of the intrinsic oscillator. A ubiquitous example is the inexorable aging process experienced by all living systems. Typical electrocatalytic reactions under oscillatory conditions oscillate for only a few dozen stable cycles due to slow surface poisoning that ultimately results in destruction of the limit cycle. We report the observation of unprecedented long-lasting temporal oscillations in the electro-oxidation of formic acid on an ordered intermetallic PtSn phase. The introduction of Sn substantially increases the catalytic activity and retards the irreversible surface oxidation, which results in the stabilization of more than 2200 oscillatory cycles in about 40 h; a 30-40-fold stabilization with respect to the behavior of pure Pt surfaces. The dynamics were modeled and numerical simulations point to the surface processes underlying the high stability. PMID- 24789344 TI - Breast-feeding and maternal risk of type 2 diabetes: a prospective study and meta analysis. AB - AIMS/HYPOTHESIS: We aimed to examine the association between breast-feeding and maternal risk of type 2 diabetes and to investigate whether this association is mediated by anthropometric and biochemical factors. METHODS: A case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study between 1994 and 2005 including 1,262 childbearing women (1,059 in a random sub-cohort and 203 incident cases) mainly aged between 35 and 64 years at baseline was applied. Self-reported lifetime duration of breast feeding was assessed by questionnaire. Blood samples were used for biomarker measurement (HDL-cholesterol, triacylglycerols, C-reactive protein, fetuin-A, gamma-glutamyltransferase, adiponectin). A systematic literature search and meta analysis was conducted of prospective cohort studies investigating breast-feeding and risk of type 2 diabetes. RESULTS: The HR for each additional 6 months of breast-feeding was 0.73 (95% CI 0.56, 0.94) in EPIC-Potsdam. Meta-analysis of three previous prospective studies and the current study revealed an inverse association between breast-feeding duration and risk of diabetes (pooled HR for lifetime breast-feeding duration of 6-11 months compared with no breast-feeding 0.89; 95% CI 0.82, 0.97). Adjustment for BMI and waist circumference attenuated the association (HR per six additional months in EPIC-Potsdam 0.80; 95% CI 0.61, 1.04). Further controlling for potentially mediating biomarkers largely explained this association (HR 0.89; 95% CI 0.68, 1.16). CONCLUSIONS/INTERPRETATION: Longer duration of breast-feeding may be related to a lower risk of diabetes. This potentially protective effect seems to be reflected by a more favourable metabolic profile; however, the role of body weight as a mediator or confounder remains uncertain. PMID- 24789340 TI - X-linked creatine transporter deficiency: clinical aspects and pathophysiology. AB - Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment. PMID- 24789346 TI - Forecasting plant phenology: evaluating the phenological models for Betula pendula and Padus racemosa spring phases, Latvia. AB - A historical phenological record and meteorological data of the period 1960-2009 are used to analyse the ability of seven phenological models to predict leaf unfolding and beginning of flowering for two tree species-silver birch Betula pendula and bird cherry Padus racemosa-in Latvia. Model stability is estimated performing multiple model fitting runs using half of the data for model training and the other half for evaluation. Correlation coefficient, mean absolute error and mean squared error are used to evaluate model performance. UniChill (a model using sigmoidal development rate and temperature relationship and taking into account the necessity for dormancy release) and DDcos (a simple degree-day model considering the diurnal temperature fluctuations) are found to be the best models for describing the considered spring phases. A strong collinearity between base temperature and required heat sum is found for several model fitting runs of the simple degree-day based models. Large variation of the model parameters between different model fitting runs in case of more complex models indicates similar collinearity and over-parameterization of these models. It is suggested that model performance can be improved by incorporating the resolved daily temperature fluctuations of the DDcos model into the framework of the more complex models (e.g. UniChill). The average base temperature, as found by DDcos model, for B. pendula leaf unfolding is 5.6 degrees C and for the start of the flowering 6.7 degrees C; for P. racemosa, the respective base temperatures are 3.2 degrees C and 3.4 degrees C. PMID- 24789348 TI - Development of high power and energy density microsphere silicon carbide-MnO2 nanoneedles and thermally oxidized activated carbon asymmetric electrochemical supercapacitors. AB - In order to achieve high energy and power densities, a high-voltage asymmetric electrochemical supercapacitor has been developed, with activated carbon (AC) as the negative electrode and a silicon carbide-MnO2 nanoneedle (SiC-N-MnO2) composite as the positive electrode. A neutral aqueous Na2SO4 solution was used as the electrolyte. SiC-N-MnO2 was prepared by packing growing MnO2 nanoneedle crystal species in only one direction on the silicon carbide surface. AC was oxidized by thermal treatment in order to introduce oxygen-containing functional groups. Owing to the high capacitance and excellent rate performance of SiC-N MnO2 and AC, as well as the synergistic effects of the two electrodes, a constructed asymmetric supercapacitor exhibited superior electrochemical performance. The optimized asymmetric supercapacitor could be cycled reversibly in the voltage range from 0 to 1.9 V, and it exhibited a specific capacitance of 59.9 F g(-1) at a scan rate of 2 mV s(-1) and excellent energy density and power density (30.06 W h kg(-1) and 113.92 W kg(-1), respectively) with a specific capacitance loss of less than 3.1% after 1000 charge-discharge cycles, indicating excellent electrochemical stability. These encouraging results show great potential in terms of developing energy storage devices with high energy and power densities for practical applications. PMID- 24789347 TI - Efficient gene carriers composed of 2-hydroxypropyl-beta-cyclodextrin, ethanolamine-functionalized poly(glycidyl methacrylate), and poly((2-dimethyl amino)ethyl methacrylate) by combination of ATRP and click chemistry. AB - In this work, a simple one-step method is first employed to produce the bromoisobutyryl-terminated 2-hydroxypropyl-beta-cyclodextrin (HPCD-Br). The pendant epoxy groups of poly(glycidyl methacrylate) block prepared via ATRP from HPCD-Br can be reacted with ethanolamine to produce HPCD-PGEA which exhibits much lower cytotoxicity and better gene transfection yield than polyethylenimine (25 kDa) in COS7 and HepG2 cell lines. Moreover, poly((2-dimethyl amino)ethyl methacrylate) blocks can be incorporated into low-molecular-weight HPCD-PGEA via "click" reaction to further enhance the gene transfection efficiency in HepG2 cell lines. PMID- 24789349 TI - The Fanconi anemia pathway sensitizes to DNA alkylating agents by inducing JNK p53-dependent mitochondrial apoptosis in breast cancer cells. AB - The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to DNA alkylating agents and greatly influences drug response in cancer treatment. However, the molecular mechanisms underlying the FA/BRCA pathway reversed resistance have received limited attention. In the present study, we investigated the effect of Fanconi anemia complementation group F protein (FANCF), a critical factor of the FA/BRCA pathway, on cancer cell apoptosis induced by DNA alkylating agents such as mitomycin c (MMC). We found that FANCF shRNA potentiated MMC-induced cytotoxicity and apoptosis in MCF-7 and MDA-MB-231 breast cancer cells. At a mechanistic level, FANCF shRNA downregulated the anti-apoptotic protein Bcl-2 and upregulated the pro-apoptotic protein Bax, accompanied by release of cyt-c and smac into the cytosol in MMC-treated cells. Furthermore, activation of caspase-3 and -9, other than caspase-8, cleavage of poly(ADP ribose) polymerase (PARP), and a decrease of mitochondrial membrane potential (MMP) indicated that involvement of the mitochondrial apoptotic pathway in FANCF silencing of MMC-treated breast cancer cells. A decrease in IAP family proteins XIAP and survivin were also observed following FANCF silencing in MMC treated breast cancer cells. Notably, FANCF shRNA was able to increase p53 levels through activation of the JNK pathway in MMC-treated breast cancer cells. Furthermore, p53 inhibition using pifithrin-alpha abolished the induction of caspase-3 and PARP by FANCF shRNA and MMC, indicating that MMC-induced apoptosis is substantially enhanced by FANCF shRNA via p53-dependent mechanisms. To our knowledge, we provide new evidence for the potential application of FANCF as a chemosensitizer in breast cancer therapy. PMID- 24789350 TI - Diffuse simple erosions in a neonate. PMID- 24789352 TI - Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. AB - Free iron in lung can cause the generation of reactive oxygen species, an important factor in chronic obstructive pulmonary disease (COPD) pathogenesis. Iron accumulation has been implicated in oxidative stress in other diseases, such as Alzheimer's and Parkinson's diseases, but little is known about iron accumulation in COPD. We sought to determine if iron content and the expression of iron transport and/or storage genes in lung differ between controls and COPD subjects, and whether changes in these correlate with airway obstruction. Explanted lung tissue was obtained from transplant donors, GOLD 2-3 COPD subjects, and GOLD 4 lung transplant recipients, and bronchoalveolar lavage (BAL) cells were obtained from non-smokers, healthy smokers, and GOLD 1-3 COPD subjects. Iron-positive cells were quantified histologically, and the expression of iron uptake (transferrin and transferrin receptor), storage (ferritin) and export (ferroportin) genes was examined by real-time RT-PCR assay. Percentage of iron-positive cells and expression levels of iron metabolism genes were examined for correlations with airflow limitation indices (forced expiratory volume in the first second (FEV1) and the ratio between FEV1 and forced vital capacity (FEV1/FVC)). The alveolar macrophage was identified as the predominant iron positive cell type in lung tissues. Furthermore, the quantity of iron deposit and the percentage of iron positive macrophages were increased with COPD and emphysema severity. The mRNA expression of iron uptake and storage genes transferrin and ferritin were significantly increased in GOLD 4 COPD lungs compared to donors (6.9 and 3.22 fold increase, respectively). In BAL cells, the mRNA expression of transferrin, transferrin receptor and ferritin correlated with airway obstruction. These results support activation of an iron sequestration mechanism by alveolar macrophages in COPD, which we postulate is a protective mechanism against iron induced oxidative stress. PMID- 24789353 TI - The neural basis of event simulation: an FMRI study. AB - Event simulation (ES) is the situational inference process in which perceived event features such as objects, agents, and actions are associated in the brain to represent the whole situation. ES provides a common basis for various cognitive processes, such as perceptual prediction, situational understanding/prediction, and social cognition (such as mentalizing/trait inference). Here, functional magnetic resonance imaging was used to elucidate the neural substrates underlying important subdivisions within ES. First, the study investigated whether ES depends on different neural substrates when it is conducted explicitly and implicitly. Second, the existence of neural substrates specific to the future-prediction component of ES was assessed. Subjects were shown contextually related object pictures implying a situation and performed several picture-word-matching tasks. By varying task goals, subjects were made to infer the implied situation implicitly/explicitly or predict the future consequence of that situation. The results indicate that, whereas implicit ES activated the lateral prefrontal cortex and medial/lateral parietal cortex, explicit ES activated the medial prefrontal cortex, posterior cingulate cortex, and medial/lateral temporal cortex. Additionally, the left temporoparietal junction plays an important role in the future-prediction component of ES. These findings enrich our understanding of the neural substrates of the implicit/explicit/predictive aspects of ES-related cognitive processes. PMID- 24789354 TI - Expression of olfactory signaling genes in the eye. AB - PURPOSE: To advance our understanding how the outer eye interacts with its environment, we asked which cellular receptors are expressed in the cornea, focusing on G protein-coupled receptors. METHODS: Total RNA from the mouse cornea was subjected to next-generation sequencing using the Illumina platform. The data was analyzed with TopHat and CuffLinks software packages. Expression of a representative group of genes detected by RNA-seq was further analyzed by RT-PCR and in situ hybridization using RNAscope technology and fluorescent microscopy. RESULTS: We generated more than 46 million pair-end reads from mouse corneal RNA. Bioinformatics analysis revealed that the mouse corneal transcriptome reconstructed from these reads represents over 10,000 gene transcripts. We identified 194 GPCR transcripts, of which 96 were putative olfactory receptors. RT-PCR analysis confirmed the presence of several olfactory receptors and related genes, including olfactory marker protein and the G protein associated with olfaction, Galphaolf. In situ hybridization showed that mRNA for olfactory marker protein, Galphaolf and possibly some olfactory receptors were found in the corneal epithelial cells. In addition to the corneal epithelium, Galphaolf was present in the ganglionic and inner nuclear layers of the retina. One of the olfactory receptors, Olfr558, was present primarily in vessels of the eye co stained with antibodies against alpha-smooth muscle actin, indicating expression in arterioles. CONCLUSIONS: Several species of mRNA encoding putative olfactory receptors and related genes are expressed in the mouse cornea and other parts of the eye indicating they may play a role in sensing chemicals in the ocular environment. PMID- 24789355 TI - Service providers' views of community participation at six Australian primary healthcare services: scope for empowerment and challenges to implementation. AB - Community participation is a key principle of comprehensive primary health care (PHC). There is little literature on how community participation is implemented at Australian PHC services. As part of a wider study conducted in partnership with five South Australian PHC services, and one Aboriginal community controlled health service in the Northern Territory, 68 staff, manager, regional health executives, and departmental funders were interviewed about community participation, perceived benefits, and factors that influenced implementation. Additional data were collected through analysis of policy documents, service reports on activity, and a web-based survey completed by 130 staff. A variety of community participation strategies was reported, ranging from consultation and participation as a means to improve service quality and acceptability, to substantive and structural participation strategies with an emphasis on empowerment. The Aboriginal community controlled health service in our study reported the most comprehensive community participation. Respondents from all services were positive about the benefits of participation but reported that efforts to involve service users had to compete with a centrally directed model of care emphasising individual treatment services, particularly at state-managed services. More empowering substantive and structural participation strategies were less common than consultation or participation used to achieve prescribed goals. The most commonly reported barriers to community participation were budget and lack of flexibility in service delivery. The current central control of the state-managed services needs to be replaced with more local management decision making if empowering community participation is to be strengthened and embedded more effectively in the culture of services. PMID- 24789356 TI - Age estimation by quantitative features of pubic symphysis using multidetector computed tomography. AB - Macroscopic assessment of the pubic symphysis is commonly used for age estimation because its surface changes over time. However, postmortem computed tomography (PMCT), a method several forensic medical departments and institutes have begun to adopt, has the potential to simplify the information gathering process from the pelvic bone without requiring soft tissue removal. Some studies have previously evaluated the use of three-dimensional images of the pubic symphysis, but because of variance in the graphics processing among image analysis software packages, certain differences have been observed between these studies. Therefore, in this study, the PMCT findings of 199 subjects of known age and sex were retrospectively reviewed to examine the feasibility of age estimation using planar images of the pubic bones and soft tissue. The coronal and axial sectional images were observed at the center of the symphyseal surface, and the pubic bone length and thickness of the connective tissue of the pubic symphysis were measured at each slice. Our results revealed a significant positive correlation between the length of the pubic bone of the coronal section and age, suggesting that the use of a cutoff value for pubic bone length might be feasible for age estimations. In addition, the thickness of the connective tissue tended to narrow over time. Although the prediction interval range of planar images obtained by PMCT was major and is not usable in practice at this moment, it may still be a useful tool if used in conjunction with other findings obtained by PMCT. PMID- 24789357 TI - Morphometric analysis of pelvic sexual dimorphism in a contemporary Western Australian population. AB - Requisite to routine casework involving unidentified skeletal remains is the formulation of an accurate biological profile, including sex estimation. Choice of method(s) is invariably related to preservation and by association, available bones. It is vital that the method applied affords statistical quantification of accuracy rates and predictive confidence so that evidentiary requirements for legal submission are satisfied. Achieving the latter necessitates the application of contemporary population-specific standards. This study examines skeletal pelvic dimorphism in contemporary Western Australian individuals to quantify the accuracy of using pelvic measurements to estimate sex and to formulate a series of morphometric standards. The sample comprises pelvic multi-slice computer tomography (MSCT) scans from 200 male and 200 female adults. Following 3D rendering, the 3D coordinates of 24 landmarks are acquired using OsiriX(r) (v.4.1.1) with 12 inter-landmark linear measurements and two angles acquired using MorphDb. Measurements are analysed using basic descriptive statistics and discriminant functions analyses employing jackknife validation of classification results. All except two linear measurements are dimorphic with sex differences explaining up to 65 % of sample variance. Transverse pelvic outlet and subpubic angle contribute most significantly to sex discrimination with accuracy rates between 100 % (complete pelvis-10 variables) and 81.2 % (ischial length). This study represents the initial forensic research into pelvic sexual dimorphism in a Western Australian population. Given these methods, we conclude that this highly dimorphic bone can be used to classify sex with a high degree of expected accuracy. PMID- 24789359 TI - Effect of neck length on third-generation ceramic head failure; finite element and retrieval analysis. AB - BACKGROUND: Optimized design using finite element analysis (FEA) has considerably increased the longevity of ceramic implants in total hip arthroplasty. Unlike previous FEA studies, a 28-mm head with a short neck was found to be prone to failure, even with third-generation ceramic. We conducted a finite element analysis of the third-generation ceramic head failure according to neck lengths and a retrieval analysis of the four fractured ceramic heads. METHODS: Models of real specimens were created for short-, medium-, and long-neck heads made of alumina, based on data given by the manufacturer and reverse engineering design. Static loading was simulated in a series of five steps to 46 kN, and fatigue loading consisting of 10(7) cycles was simulated in walking (4.3 kN) and high impact (10 kN) conditions to determine the safety factor. RESULTS: Although the maximum principal stress of the long-neck design was the greatest, consistent with a previous FEA study, the safety factor was the lowest at the inner corner between the roof and tapered bore of the ceramic head with the short-neck design in both fatigue-loading conditions. Furthermore, surface analysis of one head revealed that the fracture was propagated from the inner corner between the roof and tapered bore into the base of the ceramic head. CONCLUSION: Our results suggest that the short-neck design with a 28-mm ceramic head has a greater potential risk of ceramic failure than other designs. PMID- 24789360 TI - Comparison of repair between cartilage and osteocartilage defects in rabbits using similarly manipulated scaffold-free cartilage-like constructs. AB - BACKGROUND: Articular cartilage has a limited capacity for spontaneous repair, and its repair remains a clinical challenge. The purpose of this study was to prepare scaffold-free cartilage-like constructs and evaluate the feasibility of their use for the treatment of cartilage and osteocartilage defects in vivo. METHODS: The scaffold-free constructs were prepared by chondrocytes isolated from the articular cartilage of rabbits using a high-density three-dimensional culture system. Two different defects, i.e., a chondral defect without oozing blood and an osteochondral defect with oozing blood, of 4-mm diameter, were created on the patellar groove of rabbits and forwarded to in vivo trials. In each defect, the constructs cut into 4-mm-diameter cylinders were grafted at the bottom of the defects. As a control, defects were only made on the contralateral knee joint in each rabbit. At 2, 4, 8 and 12 weeks after surgery, six rabbits in each group were evaluated macroscopically and histologically. RESULTS: In vitro, histological examination revealed that the constructs have the character of hyaline cartilage with a potential adhesiveness to surrounding tissue. In vivo, in two control groups, incomplete spontaneous cartilage repair was observed in the osteochondral defects, whereas no repair was observed in the chondral defects. In the two treated groups, the surviving constructs in chondral defects showed significantly better repair compared to those in osteochondral defects. CONCLUSIONS: It is possible for a chondral defect to be repaired by scaffold-free constructs in certain conditions. Establishing the optimal environment suitable for cartilage repair is warranted. PMID- 24789358 TI - To be or not to be: the regulation of mRNA fate as a survival strategy during mammalian hibernation. AB - Mammalian hibernators undergo profound behavioral, physiological, and biochemical changes in order to cope with hypothermia, ischemia-reperfusion, and finite fuel reserves over days or weeks of continuous torpor. Against a backdrop of global reductions in energy-expensive processes such as transcription and translation, a subset of genes/proteins are strategically upregulated in order to meet challenges associated with hibernation. Consequently, hibernation involves substantial transcriptional and posttranscriptional regulatory mechanisms and provides a phenomenon with which to understand how a set of common genes/proteins can be differentially regulated in order to enhance stress tolerance beyond that which is possible for nonhibernators. The present review focuses on the involvement of messenger RNA (mRNA) interacting factors that play a role in the regulation of gene/protein expression programs that define the hibernating phenotype. These include proteins involved in mRNA processing (i.e., capping, splicing, and polyadenylation) and the possible role of alternative splicing as a means of enhancing protein diversity. Since the total pool of mRNA remains constant throughout torpor, mechanisms which enhance mRNA stability are discussed in the context of RNA binding proteins and mRNA decay pathways. Furthermore, mechanisms which control the global reduction of cap-dependent translation and the involvement of internal ribosome entry sites in mRNAs encoding stress response proteins are also discussed. Finally, the concept of regulating each of these factors in discrete subcellular compartments for enhanced efficiency is addressed. The analysis draws on recent research from several well-studied mammalian hibernators including ground squirrels, bats, and bears. PMID- 24789361 TI - In vivo kinematics of a robot-assisted uni- and multi-compartmental knee arthroplasty. AB - BACKGROUND: There is great interest in providing reliable and durable treatments for one- and two-compartment arthritic degeneration of the cruciate-ligament intact knee. One approach is to resurface only the diseased compartments with discrete unicompartmental components, retaining the undamaged compartment(s). However, placing multiple small implants into the knee presents a greater surgical challenge than total knee arthroplasty, so it is not certain that the natural knee mechanics can be maintained or restored. The goal of this study was to determine whether near-normal knee kinematics can be obtained with a robot assisted multi-compartmental knee arthroplasty. METHODS: Thirteen patients with 15 multi-compartmental knee arthroplasties using haptic robotic-assisted bone preparation were involved in this study. Nine subjects received a medial unicompartmental knee arthroplasty (UKA), three subjects received a medial UKA and patellofemoral (PF) arthroplasty, and three subjects received medial and lateral bi-unicondylar arthroplasty. Knee motions were recorded using video fluoroscopy an average of 13 months (6-29 months) after surgery during stair and kneeling activities. The three-dimensional position and orientation of the implant components were determined using model-image registration techniques. RESULTS: Knee kinematics during maximum flexion kneeling showed femoral external rotation and posterior lateral condylar translation. All knees showed femoral external rotation and posterior condylar translation with flexion during the step activity. Knees with medial UKA and PF arthroplasty showed the most femoral external rotation and posterior translation, and knees with bicondylar UKA showed the least. CONCLUSIONS: Knees with accurately placed uni- or bi-compartmental arthroplasty exhibited stable knee kinematics consistent with intact and functioning cruciate ligaments. The patterns of tibiofemoral motion were more similar to natural knees than commonly has been observed in knees with total knee arthroplasty. Larger series are required to confirm these as general observations, but the present results demonstrate the potential to restore or maintain closer-to-normal knee kinematics by retaining intact structures and compartments. PMID- 24789362 TI - Personalised cancer medicine. AB - The evolving field of personalised medicine is playing an increasingly important role in cancer prevention, diagnosis, prognosis and therapeutics. Its importance in clinical management is demonstrated by the recent introduction into routine clinical practice of various individualised, molecularly targeted therapies with increased efficacy and/or reduced toxicity. The identification of cancer predisposition genes, such as the BRCA genes in breast cancer, permits screening programmes to identify patients "at-risk" of developing cancer and helps them make decisions on individual risk-modification behaviours. Personalised medicine also plays an increasingly important role in cancer treatment. It is increasingly clear that there are molecularly distinct subtypes of various common cancers, with different therapeutic approaches required for each subtype, for example, the use of the monoclonal antibodies (trastuzumab and cetuximab) in HER2-positive breast cancer and wild-type KRAS colorectal cancer; tyrosine kinase inhibitors (imatinib, gefitinib, erlotinib and crizotinib) in chronic myeloid leukaemia, gastrointestinal stromal tumours and non-small-cell lung cancer and intracellular agents (vemurafenib and olaparib) in metastatic malignant melanoma and ovarian, breast and prostate cancer. The efficacy of various targeted therapies in such disparate tumours suggests that we are entering an era in which treatment decisions will be based on tumour molecular abnormality profile or "signature," rather than tumour tissue type or anatomical site of origin, improving patient prognosis and quality of life. This mini review focuses on the role of personalised medicine in cancer prevention and treatment as well as its future direction in oncology. PMID- 24789363 TI - Developmental toxicity assays using the Drosophila model. AB - The fruit fly (Drosophila melanogaster) has long been a premier model for developmental biologists and geneticists. In toxicology studies, Drosophila has only recently gained broader recognition as a tool to elaborate molecular genetic mechanisms of toxic substances. In this article, two practical applications of Drosophila for developmental toxicity assays are described. The first assay takes advantage of newly developed methods to render the fly embryo accessible to small molecules, toxicants, and drugs. The second assay engages straightforward exposures to developing larvae and easy-to-score outcomes of adult development. With the extensive collections of flies that are publicly available and the ease of creating transgenic flies, these two assays have a unique power for identifying and characterizing molecular mechanisms and cellular pathways specific to the mode of action of a number of toxicants and drugs. PMID- 24789364 TI - High-Content Imaging Assays for Identifying Compounds that Generate Superoxide and Impair Mitochondrial Membrane Potential in Adherent Eukaryotic Cells. AB - Reactive oxygen species (ROS) are constantly produced in cells as a result of aerobic metabolism. When there is an excessive production of ROS and the cell's antioxidant defenses are overwhelmed, oxidative stress occurs. The superoxide anion is a type of ROS that is produced primarily in mitochondria but is also generated in other regions of the cell including peroxisomes, endoplasmic reticulum, plasma membrane, and cytosol. Here, a high-content imaging assay using the dye dihydroethidium is described for identifying compounds that generate superoxide in eukaryotic cells. A high-content imaging assay using the fluorescent dye tetramethylrhodamine methyl ester is also described to identify compounds that impair mitochondrial membrane potential in eukaryotic cells. The purpose of performing both assays is to identify compounds that (1) generate superoxide at lower concentrations than they impair mitochondrial membrane potential, (2) impair mitochondrial membrane potential at lower concentrations than they generate superoxide, (3) generate superoxide and impair mitochondrial function at similar concentrations, and (4) do not generate superoxide or impair mitochondrial membrane potential during the duration of the assays. PMID- 24789365 TI - Prognostic value of serum 25-hydroxyvitamin D in patients with stroke. AB - We aimed to evaluate the association between 25-hydroxyvitamin D [25(OH) D] levels and both clinical severity at admission and outcome at discharge in patients with acute ischemic stroke (AIS). From June 2012 to October 2013, consecutive first-ever AIS patients admitted to the Department of Emergency of The Fourth Affiliated Hospital of Harbin Medical University, China were identified. Clinical information was collected. Serum 25(OH) D levels were measured at baseline. Stroke severity was assessed at admission using the National Institutes of Health Stroke Scale (NIHSS) score. Functional outcome was evaluated at discharge using the modified Rankin scale (m-Rankin). Multivariate analyses were performed using logistic regression models. During the study period, 326 patients were diagnosed as AIS and were included in the analysis. Serum 25(OH) D levels reduced with increasing severity of stroke as defined by the NIHSS score. There was a negative correlation between levels of 25(OH) D and the NIHSS (r = - 0.389, P = 0.000). In multivariate analyses, serum 25(OH) D level was an independent prognostic marker of discharge favorable functional outcome and survival [odds ratio 3.96 (2.85-7.87) and 3.36 (2.12-7.08), respectively, P = 0.000 for both, adjusted for NHISS, other predictors and vascular risk factors] in patients with AIS. Serum 25(OH) D levels are a predictor of both severity at admission and favorable functional outcome in patients with AIS. Additional research is needed on vitamin D supplementation to improve the outcome of post-stroke patients. PMID- 24789366 TI - Energy substrates protect hippocampus against endogenous glutamate-mediated neurodegeneration in awake rats. AB - Excitotoxicity due to excessive glutamatergic neurotransmission is a well-studied phenomenon that has been related to the mechanisms of neuronal death occurring in some disorders of the CNS. We have previously shown that the intrahippocampal perfusion by microdialysis of 4-aminopyridine (4-AP) in rats stimulates endogenous glutamate release from nerve endings and this results in excitotoxic effects such as immediate seizures and delayed neuronal death, due to the overactivation of N-methyl-D-aspartate (NMDA) receptors. To study whether mitochondrial energy dysfunction and oxidative stress could be involved in this 4 AP-induced excitotoxicity, we evaluated in awake rats the protective effect of several energy substrates and antioxidant compounds, using microdialysis, electroencephalographic (EEG) recording and histological analysis. The 4-AP induced behavioral and EEG seizures, which progressed to status epilepticus in about 30 min, were prevented by the NMDA receptor antagonist MK-801, whereas acetoacetate, DL- and L-beta-hydroxybutyrate did not protect against seizures but increased the latency to the onset of status epilepticus; pyruvate, alpha ketoglutarate and glutathione ethyl ester did not show any protective effect. 4 AP also produced nearly complete loss of pyramidal neurons in CA1 and CA3 regions of the ipsilateral hippocampus 24 h after the experiment. MK-801 totally prevented this neuronal death and the energy substrates tested protected by about 50%, whereas the antioxidants showed only a weak protection. We conclude that ketone bodies possess weak anticonvulsant effects and that energy metabolism impairment plays a more important role than oxidative stress in the delayed hippocampal neurodegeneration resulting from the excitotoxic action of 4-AP mediated by endogenous glutamate. PMID- 24789367 TI - Data-driven treatment selection for seamless phase II/III trials incorporating early-outcome data. AB - Seamless phase II/III clinical trials are conducted in two stages with treatment selection at the first stage. In the first stage, patients are randomized to a control or one of k > 1 experimental treatments. At the end of this stage, interim data are analysed, and a decision is made concerning which experimental treatment should continue to the second stage. If the primary endpoint is observable only after some period of follow-up, at the interim analysis data may be available on some early outcome on a larger number of patients than those for whom the primary endpoint is available. These early endpoint data can thus be used for treatment selection. For two previously proposed approaches, the power has been shown to be greater for one or other method depending on the true treatment effects and correlations. We propose a new approach that builds on the previously proposed approaches and uses data available at the interim analysis to estimate these parameters and then, on the basis of these estimates, chooses the treatment selection method with the highest probability of correctly selecting the most effective treatment. This method is shown to perform well compared with the two previously described methods for a wide range of true parameter values. In most cases, the performance of the new method is either similar to or, in some cases, better than either of the two previously proposed methods. PMID- 24789368 TI - A role for LHC1 in higher order structure and complement binding of the Cryptococcus neoformans capsule. AB - Polysaccharide capsules are important virulence factors for many microbial pathogens including the opportunistic fungus Cryptococcus neoformans. In the present study, we demonstrate an unusual role for a secreted lactonohydrolase of C. neoformans, LHC1 in capsular higher order structure. Analysis of extracted capsular polysaccharide from wild-type and lhc1Delta strains by dynamic and static light scattering suggested a role for the LHC1 locus in altering the capsular polysaccharide, both reducing dimensions and altering its branching, density and solvation. These changes in the capsular structure resulted in LHC1 dependent alterations of antibody binding patterns, reductions in human and mouse complement binding and phagocytosis by the macrophage-like cell line J774, as well as increased virulence in mice. These findings identify a unique molecular mechanism for tertiary structural changes in a microbial capsule, facilitating immune evasion and virulence of a fungal pathogen. PMID- 24789369 TI - Cardiomyocyte-specific miRNA-30c over-expression causes dilated cardiomyopathy. AB - MicroRNAs (miRNAs) regulate many aspects of cellular function and their deregulation has been implicated in heart disease. MiRNA-30c is differentially expressed in the heart during the progression towards heart failure and in vitro studies hint to its importance in cellular physiology. As little is known about the in vivo function of miRNA-30c in the heart, we generated transgenic mice that specifically overexpress miRNA-30c in cardiomyocytes. We show that these mice display no abnormalities until about 6 weeks of age, but subsequently develop a severely dilated cardiomyopathy. Gene expression analysis of the miRNA-30c transgenic hearts before onset of the phenotype indicated disturbed mitochondrial function. This was further evident by the downregulation of mitochondrial oxidative phosphorylation (OXPHOS) complexes III and IV at the protein level. Taken together these data indicate impaired mitochondrial function due to OXPHOS protein depletion as a potential cause for the observed dilated cardiomyopathic phenotype in miRNA-30c transgenic mice. We thus establish an in vivo role for miRNA-30c in cardiac physiology, particularly in mitochondrial function. PMID- 24789371 TI - Shikonin blocks migration and invasion of human breast cancer cells through inhibition of matrix metalloproteinase-9 activation. AB - Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicinal herb, has been reported to promote tumor cell death. However, there are few reports concerning its effect on metastasis-related cell invasion and migration behavior. In the present study, we investigated the effect of shikonin on human breast cancer invasion and migration. We found that shikonin inhibited phorbol 12 myristate 13-acetate (PMA)-induced cell migration and invasion in MCF-7 breast cancer cells, which was correlated with modulation of matrix metalloproteinase-9 (MMP-9) through suppression of both expression and proteolytic and promoter activity. We also found that shikonin inhibited both MMP-9 expression and promoter activity in MDA-MB-231 cells with high metastatic potential. These results indicated that shikonin induces the suppression of migration and invasion through modulation of MMP-9 in human breast cancer cells. Therefore, shikonin may be a potential anticancer drug for human breast cancer therapy. PMID- 24789372 TI - Development of a method for analysis of ketamine and norketamine enantiomers in equine brain and cerebrospinal fluid by capillary electrophoresis. AB - Ketamine and norketamine are being transported across the blood brain barrier and are also entering from blood into cerebrospinal fluid (CSF). Enantioselective distributions of these compounds in brain and CSF have never been determined. The enantioselective CE based assay previously developed for equine plasma was adapted to the analysis of these compounds in equine brain via use of an acidic pre-extraction of interferences prior to liquid/liquid extraction at alkaline pH. CSF can be treated as plasma. With 100 mg of brain tissue and 0.5 mL of CSF or plasma, assay conditions for up to 30 nmol/g and 6 MUM, respectively, of each enantiomer with LOQs of 0.5 nmol/g and 0.1 MUM, respectively, were established and the assays were applied to equine samples. CSF and plasma samples analyzed stemmed from anesthetized patient horses and brain, CSF and plasma were obtained from anesthetized horses that were euthanized with an overdose of pentobarbital. Data obtained indicate that ketamine and norketamine enantiomers are penetrating into brain and CSF with those of ketamine being more favorably transported than norketamine, whereas metabolites of norketamine are hindered. More work is required to properly investigate possible stereoselectivities of the ketamine metabolism and transport of metabolites from blood into brain tissue and CSF. PMID- 24789370 TI - LGR5 is required for the maintenance of spheroid-derived colon cancer stem cells. AB - Colon cancer stem cells (CCSCs) are involved in colon cancer and promote tumor progression and recurrence. LGR5, a marker for intestinal stem cells (ISCs), is also considered to serve as a marker for CCSCs. However, the precise function of LGR5 in CCSCs is unclear. In this study, we demonstrated that LGR5 was highly expressed in CCSCs-enriched HT29 spheroid cells. Downregulation of LGR5 with small interfering RNA (siRNA) decreased the expression of stem the cell markers CD133 and CD44 in HT29 spheroid cells. In addition, silencing of LGR5 inhibited cell proliferation, secondary tumor sphere formation and induced cell apoptosis, and G0/G1 phase arrest in vitro by modulating Bcl-2, Bcl-xL and Bax. Knockdown of LGR5 enhanced chemosensitivity and reduced the invasive ability of HT29 spheroid cells. Moreover, LGR5-siRNA suppressed tumorigenicity of HT29 spheroid cells in vivo. The findings suggested that LGR5 plays a vital role in the maintenance of CCSCs and is a potential therapeutic target for colon cancer. PMID- 24789373 TI - Cellular Interactions and Signaling in neuroAIDS: Emerging Issues Colloquium. AB - On May 23, 2013 scientific leaders in the neuroAIDS community met at the University of Nebraska Medical Center to discuss cellular interaction and signaling for the third annual human immunodeficiency virus and neuroAIDS colloquium. The meeting continues a series of contemporary scientific issues related to how virus effects the nervous system. In 2011 the focus was on animal models and in 2012 in biomarkers. Here, our 2013 meeting featured ten presentations from outstanding scientists examining how inter- and intra-cellular processes contribute to neuropathogenesis. Talks highlighted emerging issues, findings, and potential therapies, followed by a panel discussion in which controversies in the field and gaps in our current knowledge were identified. The panel discussion was transcribed into the article and published as a field perspective. A link is available where all of the presentations and the concluding discussion can be seen and heard. The third annual University of Nebraska Medical Center (UNMC) colloquium on current issues in neuroAIDS was held on May 23, 2013. Following the presentations, which can be viewed at http://www.unmc.edu/pharmacology/CISN.htm . A panel discussion ensued. This discussion raised important topical issues. To disseminate this information, a transcript is provided below. PMID- 24789374 TI - Microfluidics for single-cell genetic analysis. AB - The ability to correlate single-cell genetic information to cellular phenotypes will provide the kind of detailed insight into human physiology and disease pathways that is not possible to infer from bulk cell analysis. Microfluidic technologies are attractive for single-cell manipulation due to precise handling and low risk of contamination. Additionally, microfluidic single-cell techniques can allow for high-throughput and detailed genetic analyses that increase accuracy and decrease reagent cost compared to bulk techniques. Incorporating these microfluidic platforms into research and clinical laboratory workflows can fill an unmet need in biology, delivering the highly accurate, highly informative data necessary to develop new therapies and monitor patient outcomes. In this perspective, we describe the current and potential future uses of microfluidics at all stages of single-cell genetic analysis, including cell enrichment and capture, single-cell compartmentalization and manipulation, and detection and analyses. PMID- 24789377 TI - Alkyl transfer from C-C cleavage: replacing the nitro group of nitro-olefins. AB - Alkyl substituted Hantzsch esters are rationally used as alkylation reagents to replace the nitro groups of nitro olefins to give excellent yields of trans olefins. The reaction mechanism is considered to proceed through a free radical mechanism, which is different from the corresponding transfer alkylation of imines. PMID- 24789376 TI - Impact of correlated inputs to neurons: modeling observations from in vivo intracellular recordings. AB - In vivo recordings in rat somatosensory cortex suggest that excitatory and inhibitory inputs are often correlated during spontaneous and sensory-evoked activity. Using a computational approach, we study how the interplay of input correlations and timing observed in experiments controls the spiking probability of single neurons. Several correlation-based mechanisms are identified, which can effectively switch a neuron on and off. In addition, we investigate the transfer of input correlation to output correlation in pairs of neurons, at the spike train and the membrane potential levels, by considering spike-driving and non spike-driving inputs separately. In particular, we propose a plausible explanation for the in vivo finding that membrane potentials in neighboring neurons are correlated, but the spike-triggered averages of membrane potentials preceding a spike are not: Neighboring neurons possibly receive an ongoing bombardment of correlated subthreshold background inputs, and occasionally uncorrelated spike-driving inputs. PMID- 24789378 TI - Potential carbon sequestration of European arable soils estimated by modelling a comprehensive set of management practices. AB - Bottom-up estimates from long-term field experiments and modelling are the most commonly used approaches to estimate the carbon (C) sequestration potential of the agricultural sector. However, when data are required at European level, important margins of uncertainty still exist due to the representativeness of local data at large scale or different assumptions and information utilized for running models. In this context, a pan-European (EU + Serbia, Bosnia and Herzegovina, Montenegro, Albania, Former Yugoslav Republic of Macedonia and Norway) simulation platform with high spatial resolution and harmonized data sets was developed to provide consistent scenarios in support of possible carbon sequestration policies. Using the CENTURY agroecosystem model, six alternative management practices (AMP) scenarios were assessed as alternatives to the business as usual situation (BAU). These consisted of the conversion of arable land to grassland (and vice versa), straw incorporation, reduced tillage, straw incorporation combined with reduced tillage, ley cropping system and cover crops. The conversion into grassland showed the highest soil organic carbon (SOC) sequestration rates, ranging between 0.4 and 0.8 t C ha(-1) yr(-1) , while the opposite extreme scenario (100% of grassland conversion into arable) gave cumulated losses of up to 2 Gt of C by 2100. Among the other practices, ley cropping systems and cover crops gave better performances than straw incorporation and reduced tillage. The allocation of 12 to 28% of the European arable land to different AMP combinations resulted in a potential SOC sequestration of 101-336 Mt CO2 eq. by 2020 and 549-2141 Mt CO2 eq. by 2100. Modelled carbon sequestration rates compared with values from an ad hoc meta analysis confirmed the robustness of these estimates. PMID- 24789379 TI - Inflammation-induced drug release by using a pH-responsive gas-generating hollow microsphere system for the treatment of osteomyelitis. AB - In the conventional treatment of osteomyelitis, the penetration of antibiotics into the infected bone is commonly poor. To ensure that the local antibiotic concentration is adequate, this work develops an injectable calcium phosphate (CP) cement in which is embedded pH-responsive hollow microspheres (HMs) that can control the release of a drug according to the local pH. The HMs are fabricated using a microfluidic device, with a shell of poly(D,L-lactic-co-glycolic acid) (PLGA) and an aqueous core that contains vancomycin (Van) and NaHCO3. At neutral pH, the CP/HM cement elutes a negligible concentration of the drug. In an acidic environment, the NaHCO3 that is encapsulated in the HMs reacts with the acid rapidly to generate CO2 bubbles, disrupting the PLGA shells and thereby releasing Van locally in excess of a therapeutic threshold. The feasibility of using this CP/HM cement to treat osteomyelitis is studied using a rabbit model. Analytical results reveal that the CP/HM cement provides highly effective local antibacterial activity. Histological examination further verifies the efficacy of the treatment by the CP/HM cement. The above findings suggest that the CP/HM cement is a highly efficient system for the local delivery of antibiotics in the treatment of osteomyelitis. PMID- 24789375 TI - Atropine vs patching for treatment of moderate amblyopia: follow-up at 15 years of age of a randomized clinical trial. AB - IMPORTANCE: Initial treatment for amblyopia of the fellow eye with patching and atropine sulfate eyedrops improves visual acuity. Long-term data on the durability of treatment benefit are needed. OBJECTIVE: To report visual acuity at 15 years of age among patients who were younger than 7 years when enrolled in a treatment trial for moderate amblyopia. DESIGN, SETTING, AND PARTICIPANTS: In a multicenter clinical trial, 419 children with amblyopia (visual acuity, 20/40 to 20/100) were randomly assigned to patching (minimum of 6 h/d) or atropine sulfate eyedrops, 1% (1 drop daily), for 6 months. Treatment after 6 months was at the discretion of the investigator. Two years after enrollment, an unselected subgroup of 188 children were enrolled into long-term follow-up. INTERVENTION: Initial treatment with patching or atropine with subsequent treatment at investigator discretion. MAIN OUTCOMES AND MEASURES: Visual acuity at 15 years of age with the electronic Early Treatment Diabetic Retinopathy Study test in amblyopic and fellow eyes. RESULTS: Mean visual acuity in the amblyopic eye measured in 147 participants at 15 years of age was 0.14 logMAR (approximately 20/25); 59.9% of amblyopic eyes had visual acuity of 20/25 or better and 33.3%, 20/20 or better. Mean interocular acuity difference (IOD) at 15 years of age was 0.21 logMAR (2.1 lines); 48.3% had an IOD of 2 or more lines and 71.4%, 1 or more lines. Treatment (other than spectacles) was prescribed for 9 participants (6.1%) aged 10 to 15 years. Mean IOD was similar at examinations at 10 and 15 years of age (2.0 and 2.1 logMAR lines, respectively; P = .39). Better visual acuity at the 15-year examination was achieved in those who were younger than 5 years at the time of entry into the randomized clinical trial (mean logMAR, 0.09) compared with those aged 5 to 6 years (mean logMAR, 0.18; P < .001). When we compared subgroups based on original treatment with atropine or patching, no significant differences were observed in visual acuity of amblyopic and fellow eyes at 15 years of age (P = .44 and P = .43, respectively). CONCLUSIONS AND RELEVANCE: At 15 years of age, most children treated for moderate amblyopia when younger than 7 years have good visual acuity, although mild residual amblyopia is common. The outcome is similar regardless of initial treatment with atropine or patching. The results indicate that improvement occurring with amblyopia treatment is maintained until at least 15 years of age. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000170. PMID- 24789382 TI - Responses of periphytic diatoms to mechanical removal of Pistia stratiotes L. in a hypereutrophic subtropical reservoir: dynamics and tolerance. AB - The Itaqui reservoir in Parana state, southern Brazil, is dominated by the floating macrophyte Pistia stratiotes L. and is used for recreation and irrigation. The reservoir's excessive plant cover suggests an extreme trophic state and interferes with multiple uses. The aims of this study were to determine the trophic state of the reservoir water and to document the limnological conditions and the composition of the periphytic diatom community before and after the mechanical removal of macrophytes. As each diatom species has certain autoecological requirements in a given geographic area, another objective of the study was to identify diatoms that can be considered tolerant of the reservoir's trophic state in a substropical environment. Local water samples collected for physical and chemical analyses, including estimates of chlorophyll a, showed the hypereutrophic status of the reservoir before and after macrophyte removal. Environmental conditions exceeded acceptable values for fishing and irrigation, providing a clear example of how the inadequate management of water resources can directly reduce their usefulness. Trimestral sampling was carried out between May 2008 and February 2009. For quantitative analyses, biofilms were scrubbed off glass slides submerged for 30 days at a depth of approximately 40 cm. Diatom samples were cleaned with potassium permanganate and hydrochloric acid and mounted on permanent slides with Naphrax. All individuals found in random transects under three replicates were identified and counted up to a minimum of 600 valves. Thirteen species tolerant of eutrophication were selected. Four species mostly known from low-nutrient sites may be considered tolerant of eutrophic conditions. The composition of the diatom community was influenced by seasonal changes in temperature and rainfall. Canonical Correspondence Analyses confirmed a correlation between higher diatom densities and the increased photic zone following macrophyte removal. PMID- 24789383 TI - Management of fishing of the broadband anchovy (Anchoviella lepidentostole) (Fowler, 1911), in south Sao Paulo State, Brazil. AB - The broadband anchovy (Anchoviella lepidentostole) is one of the most important fishery resources for economic and social development of Iguape City and for the whole of the south coast of Sao Paulo state. Nowadays this activity involves over 2,500 fishermen. This paper aims to evaluate its fishing, and discuss how the activity is managed. In order to conduct this study, production data and catch per unit effort (CPUE) data from the 1998-2000 period have been collected, and the characterisation of the activity has also been done. A decline in broadband anchovy abundance had been observed in the region up until 2004, when a new regulation was implemented, in an attempt to recover the resource, with the establishment of closed season fishing (defeso) during the catch season, and adjustments in the employed fishing gear. The results have shown a recovery of the abundance of broadband anchovy throughout the 2005-2010 period, showing thus far that the measures taken for the maintenance of the resource have been successful. The activity has been managed through discussions involving people from the fishing sector in order to determine the controversial actions to be taken, that are hard to enforce. In order to achieve a more satisfactory resource management, it is necessary to keep the participatory process, with adaptive co management, based on discussion among all the sectors involved (from government and society), and constant monitoring of the activity. PMID- 24789384 TI - Life history, distribution and abundance of the giant earthworm Rhinodrilus alatus RIGHI 1971: conservation and management implications. AB - Rhinodrilus alatus is an endemic giant earthworm of the Brazilian Cerrado hotspot used as live bait for about 80 years. The goal of this study was to gather ecological data about this species, which will support the establishment of management strategies. The life history, distribution and abundance of R. alatus were investigated in Cerrado, pastures and Eucalyptus plantation areas following the harvesting activities of the local extractors of this species. We found that this earthworm is abundant in all of the sampled areas, showing its resilience to land-use conversion. The Capture Per Unit Effort was 4.4 +/- 5 individuals per 100 metres of transect and 5.6 +/- 3 individuals per hour. The earthworm's annual cycle is markedly seasonal, with an aestivation period throughout the driest and coldest season of the year. Significant differences in the length and diameter of the body and in the diameter and depth of the aestivation chambers were found between the juveniles and adults. The distribution range of the species was expanded from two to 17 counties. The life history, abundance, distribution and resilience of R. alatus to certain perturbations are key elements to be considered in conservation and management strategies for this species. PMID- 24789385 TI - Economic valuation of plant diversity storage service provided by Brazilian rupestrian grassland ecosystems. AB - The rupestrian grassland ecosystems provide various goods and services to society and support a significant amount of biological diversity. Notably the rich plant diversity has high levels of endemism and a variety of uses among the local communities and general society. Despite the socio-ecological importance of these ecosystems, they are subjected to significant anthropogenic pressures. The goal of this study is to perform economic valuation of the plant diversity storage service provided by rupestrian grassland ecosystems to provide grounds for the development of conservation policies and encourage sustainable practices in these ecosystems. Given the intense human disturbances and unique flora, the Serra do Cipo (southern portion of the Espinhaco Range in southeast Brazil) was selected for the study. We estimate the monetary value related to the plant diversity storage service provided by the study area using the maintenance costs of native plants in the living collections of the botanical garden managed by the Zoobotanical Foundation - Belo Horizonte (located 97 km from Serra do Cipo). The plant diversity storage value provided by Serra do Cipo ecosystems is significant, reaching US$25.26 million year-1. This study contributes to the development of perspectives related to the conservation of rupestrian grassland ecosystems as well as others threatened tropical ecosystems with high biodiversity. PMID- 24789386 TI - How does the Taquari River influence in the cladoceran assemblages in three oxbow lakes? AB - This study examined the cladoceran assemblages in three oxbow lakes of the Taquari River floodplain, near the transition between the plateau and the plain. We sought to answer the following questions: does the Taquari River function as a geographical barrier or dispersal corridor for Cladocera? Can different degrees of connection induce different structures in the assemblages in each lake? Cladocerans and limnological variables were sampled every other month for one year. Forty-one species were recorded, four of which were common to all the lakes. Our results indicated that the different degrees of connection between the river and the oxbow lakes favoured environmental heterogeneity and diversification in the cladoceran assemblages. The greatest dissimilarity between the two lakes connected with the river indicates that in this case the river functions better as a barrier than a dispersal corridor. PMID- 24789387 TI - Assessing fish assemblages similarity above and below a dam in a neotropical reservoir with partial blockage. AB - Damming rivers disrupts the water flow and changes the ichthyofauna organisation. We investigated an impoundment with permanent connection and homogeneous environmental conditions between the zones above and below the dam. Temperature was comparatively higher during wet season irrespective of zone, and both zones had higher dissolved oxygen, conductivity and transparency in the dry season. A total of 1687 individuals comprising 27 species were collected in the downriver zone, while the reservoir had 879 individuals and 23 species. Each zone had different fish assemblage composition and structure, but assemblages were not explained by the examined environmental variables (r2 = 0.08; p = 0.307). Migratory species such as Pimelodus maculatus, Pimelodus fur, Leporinus copelandii and Prochilodus lineatus were the most affected, and probably are prevented to perform upriver migrations. On the other hand, lentic adapted species such as G. brasiliensis, Hoplias malabaricus and Hoplosternum littorale successfully colonised the reservoir. Therefore we conclude that the presence of the lateral hydrological connectivity alone does not guarantee the ecological connectivity since fish assemblage similarity differed between the two zones. Fish passage facilities should be monitored and managed to evaluate and improve their functionality. PMID- 24789388 TI - Birds as potential pollinators of the Spathodea nilotica (Bignoniaceae) in the urban environment. AB - Birds play crucial role on the pollination of many plants. However, little is known about the interactions between nectarivorous neotropical birds and exotic Angiosperms. S. nilotica is an exotic African plant widely used in Brazilian urban landscaping. However, it has been poorly studied in relation to its interactions with Neotropical birds. In this way, we studied the feeding nectar strategies and the interspecific antagonistic behaviours among nectarivorous Neotropical birds to verify the bird contributions to the S. nilotica pollination. The study was conducted from May 2008 to April 2011, but only in months of S. nilotica flowering (April to May). From 148 hours of sampling we identified 16 species feeding nectar on S. nilotica: 13 hummingbirds (Trochilidae), Aratinga aurea (Psittacidae), Tangara palmarum (Thraupidae) and Coereba flaveola (Coerebidae). Eupetomena macroura was the most frequent (96.88%), followed by Chlorostilbon lucidus (78.13%) and Coereba flaveola (59.38%). Most birds obtained nectar by punching at the base of the corolla, except for A. aurea that obtained the nectar by the upper opening of the petals in 100% of its visits, Heliomaster furcifer (95.65%), F. fusca (95%) and A. nigricollis (70.27%). Despite E. macroura also obtains nectar only by punching at the base of the corolla, it showed the highest level of legitimate visits. Antagonistic events were more frequent in E. macroura (58.65%), Florisuga fusca (11.04%) and Amazilia fimbriata (10.87%), being E. macroura dominant in all events. These results showed E. macroura plays an important role on this plant being the most important bird as a potential pollinator. Moreover, other birds contribute partially to the S. nilotica pollination. Most probably it is a result of recent Neotropical bird interactions with this African plant. PMID- 24789389 TI - The influence of fish cage culture on delta13C and delta15N of filter-feeding Bivalvia (Mollusca). AB - The objective of this study was to evaluate the effect of Oreochromis niloticus cage culture promoted variations in the delta13C and delta15N in Corbicula fluminea (Mollusca; Bivalvia) and in the sediment of an aquatic food web. Samples were taken before and after net cage installation in the Rosana Reservoir (Paranapanema River, PR-SP). Samples of specimens of the bivalve filterer C. fluminea and samples of sediment were collected using a modified Petersen grab. All samples were dried in an oven (60 degrees C) for 72 hours, macerated to obtain homogenous fine powders and sent for carbon (delta13C) and nitrogen (delta15N) isotopic value analysis in a mass spectrometer. There were significant differences in the delta13C and delta15N values of the invertebrate C. fluminea between the beginning and the end of the experiment. There were no differences between the delta13C and delta15N values of sediment. These results indicate that the installation of fish cage culture promoted impacts in the isotopic composition of the aquatic food web organisms, which could exert influence over the native species and the ecosystem. PMID- 24789390 TI - Variation in body size of Phanocerus clavicornis Sharp, 1882 (Coleoptera: Elmidae: Larainae) in Atlantic Rainforest streams in response to hydraulic disturbance. AB - In this study, patterns of body size of Phanocerus clavicornis Sharp, 1882 (Coleoptera: Elmidae: Larainae) were investigated along a gradient of change in speed of flow conditions in streams of low order in the Atlantic Rainforest in southeastern Brazil. Specifically, the hypothesis that the distribution of P. clavicornis larvae vary in size in response to variations in the speed of flow in streams was tested. A Surber sampler was used to collect larvae from the streambed during two sampling periods, defined by the rain regime: August in the dry season and February in the rainy season. Possible differences in mean measured body size were tested by analysis of variance (ANOVA). The ANOVA result indicated for all measurements on the larvae collected in first-order streams (head width, prothoracic width and total body length), there were significant differences indicating a morphometric variation due to changing hydraulic conditions, the smallest larvae being associated with the period of greater rainfall. However, the larger streams (3rd order), where the rain events had less impact on the larval size, varied widely. The results of this study suggest that the interstitial space is important for the protection of the larvae from water flow, and that populations of P. clavicornis have high plasticity, a key feature for the occupation of unstable environments for this species. These results are important for an understanding of the life history and behavioural characteristics of the species, which allow them to persist in streams along a gradient of flow disturbance. PMID- 24789391 TI - Influence of environmental variables on diffusive greenhouse gas fluxes at hydroelectric reservoirs in Brazil. AB - For almost two decades, studies have been under way in Brazil, showing how hydroelectric reservoirs produce biogenic gases, mainly methane (CH4) and carbon dioxide (CO2), through the organic decomposition of flooded biomass. This somewhat complex phenomenon is due to a set of variables with differing levels of interdependence that directly or indirectly affect greenhouse gas (GHG) emissions. The purpose of this paper is to determine, through a statistical data analysis, the relation between CO2, CH4 diffusive fluxes and environmental variables at the Furnas, Itumbiara and Serra da Mesa hydroelectric reservoirs, located in the Cerrado biome on Brazil's high central plateau. The choice of this region was prompted by its importance in the national context, covering an area of some two million square kilometers, encompassing two major river basins (Parana and Tocantins-Araguaia), with the largest installed power generation capacity in Brazil, together accounting for around 23% of Brazilian territory. This study shows that CH4 presented a moderate negative correlation between CO2 and depth. Additionally, a moderate positive correlation was noted for pH, water temperature and wind. The CO2 presented a moderate negative correlation for pH, wind speed, water temperature and air temperature. Additionally, a moderate positive correlation was noted for CO2 and water temperature. The complexity of the emission phenomenon is unlikely to occur through a simultaneous understanding of all the factors, due to difficulties in accessing and analyzing all the variables that have real, direct effects on GHG production and emission. PMID- 24789392 TI - Feeding activity and influence of intraspecific competition on zooplankton communities by jundia (Rhamdia quelen Quoy and Gaimard, 1824) in laboratory. AB - Experiments were designed to determine if the juvenile forms of jundia (Rhamdia quelen) exhibit selectivity feeding on zooplanktonic organisms and the influence of intraspecific competition on the diet. The fish were maintained in 5000-L containers, and after seven days from birth, they were acclimated in experimental units with different densities and supplied with water containing plankton (natural), where they remained for 24 h in the environment with food. In the first seven days at densities of 5 and 10 fish.L-1, the fish selected the Rotifera more intensely, and at densities of 20 and 40 fish.L-1, the Cladocera were more selected. At 14 days of age, the Cladocera were the most selected for all densities of fish. At 21 days of age, the juvenile forms of jundia maintained a preference for Cladocera, and there was an increase in the capture of Copepoda at a density of 40 fish.L-1. At 28 days of age, the Cladocera were the most captured at densities of 5 to 20 fish.L-1, and the consumption of copepods increased at a density of 40 fish.L-1. The juvenile forms of Rhamdia quelen showed a high feeding preference for Cladocera at all the ages tested (7, 14, 21 and 28 days), but the density of fish per litre influenced the capture of the preferential food. This study showed that the juvenile forms of jundia had a more rapid response to the presence of food at densities of more than 10 fish.L-1, and that at higher densities the fish decreased interactions of territorial defense and formed schools, which allowed the foraging of zooplanktonic organisms, larger in size, more agile and of greater energy gain, such as the Cladocera and copepods. PMID- 24789393 TI - Influence of peak flow changes on the macroinvertebrate drift downstream of a Brazilian hydroelectric dam. AB - Successive daily peak flows from hydropower plants can disrupt aquatic ecosystems and alter the composition and structure of macroinvertebrates downstream. We evaluated the influence of peak flow changes on macroinvertebrate drift downstream of a hydroelectric plant as a basis for determining ecological flows that might reduce the disturbance of aquatic biota. The aim of this study was to assess the influence of flow fluctuations on the seasonal and daily drift patterns of macroinvertebrates. We collected macroinvertebrates during fixed flow rates (323 m3.s-1 in the wet season and 111 m3.s-1 in the dry season) and when peak flows fluctuated (378 to 481 m3.s-1 in the wet season, and 109 to 173 m3.s-1 in the dry season) in 2010. We collected 31,924 organisms belonging to 46 taxa in the four sampling periods. Taxonomic composition and densities of drifting invertebrates differed between fixed and fluctuating flows, in both wet and dry seasons, but family richness varied insignificantly. We conclude that macroinvertebrate assemblages downstream of dams are influenced by daily peak flow fluctuations. When making environmental flow decisions for dams, it would be wise to consider drifting macroinvertebrates because they reflect ecological changes in downstream biological assemblages. PMID- 24789394 TI - Tooth morphology, implantation and replacement system of Hoplias malabaricus (Teleostei, Characiformes, Erythrinidae). AB - The oropharyngeal cavity of Hoplias malabaricus, an ichthyophagous freshwater fish, is anatomically adapted to predation. Macroscopic and microscopic analyses were conducted in order to study the morphology and system of implantation and replacement of teeth. The results showed that this teleost has conical and caniniform teeth, with an orthodentin crown covered by an enameloid cap and a vascularised orthodentin in the root. With regard to the implantation system, there is a junction between the tooth and the bone tissue, as a typical physiological dental ankylosis. The teeth are replaced by a resorption process of multinucleated giant cells that actively eliminate the dentin and bone tissue. PMID- 24789395 TI - Microhabitat use by three species of egret (Pelecaniformes, Ardeidae) in southern Brazil. AB - In the present study, we examined the role of different habitat components and their relationship with microhabitat use by three species of egret: Cocoi heron (Ardea cocoi), Great egret (Ardea alba), and Cattle egret (Bubulcus ibis), in wetlands of southern Brazil. Ardea alba and A. cocoi were not habitat-specific (e.g. vegetation cover and flooding level). Conversely, B. ibis was associated with drier microhabitats. Relative air humidity and air temperature were the main variables which correlated with the occurrence of these species and supported the plasticity of B. ibis and its predominance in drier habitats. PMID- 24789396 TI - First molecular detection of co-infection of honey bee viruses in asymptomatic Bombus atratus in South America. AB - Pollination is critical for food production and has the particularity of linking natural ecosystems with agricultural production systems. Recently, losses of bumblebee species have been reported worldwide. In this study, samples from a commercial exploitation of bumblebees of Argentina with a recent history of deaths were studied using a multiplex PCR for the detection of the honey bee viruses most frequently detected in South America. All samples analysed were positive for co-infections with Deformed wing virus, Black queen cell virus and Sacbrood virus. This is the first report of infection of Bombus atratus with honey bee viruses. A better understanding of viral infections in bumblebees and of the epidemiology of viruses could be of great importance as bumblebees can serve as possible viral reservoirs, resulting in pathogen spillover towards honey bees and native bumblebees. PMID- 24789397 TI - The genus Dasineura Rondani, 1840 (Diptera, Cecidomyiidae) in Brazil. AB - Dasineura (Diptera, Cecidomyiidae) is the gall midge genus with the highest number of known species (466 throughout the world). Only 39 species have been described from the Neotropics, being 10 from Brazil. Many records of not determined species are found in the literature. Furthermore, many unidentified specimens are deposited in the Cecidomyiidae Collection of the Museu Nacional/UFRJ, which comprises material from several Brazilian biomes. This paper provides these data, presents new records of localities and host plants, and discusses the representativeness of Dasineura in Brazil. The results point to the occurrence of 32 species in Brazil and show that the genus is much more diversified than previous knowledge indicates. PMID- 24789398 TI - Compared leaf anatomy of Nymphaea (Nymphaeaceae) species from Brazilian flood plain. AB - Nymphaea has seven species already catalogued in the flood prone areas of the Brazilian Pantanal. However, some species remain difficult to identify and descriptions of the anatomy of vegetative organs are an important tool for infrageneric separation to aid in group taxonomy. The species collected in the Pantanal and prepared according to the usual techniques for anatomical studies showed similar structural characteristics, and data on the arrangement of vascular bundles in the midrib and petiole, as well as the form and distribution of sclereids, were consistent. Nymphaea oxypetala stands out from the other evaluated species for having a greater number of differential characters, including angular collenchyma and the absence of bicollateral bundles in the petiole. Nymphaea lingulata stands out as the only species to feature bicollateral bundles in the leaf blade. The results, summarised in the dichotomous key, facilitate the identification of species that use the flower as the main differentiation, but are in a vegetative stage. PMID- 24789399 TI - Population structure of the bivalve Anomalocardia brasiliana, (Gmelin, 1791) in the semi-arid estuarine region of northeastern Brazil. AB - For several decades, the bivalve mollusk Anomalocardia brasiliana has been extracted in estuarine areas in the semi-arid region of northeastern Brazil. However, information on both dynamics and abundance of their populations are missing. In this context, the present study, therefore, investigated several aspects of the population structure of A. brasiliana on beaches near the estuary of the Apodi River in Northeast Brazil. The aims were to determine the population density of A. brasiliana during different times of the year, to estimate population parameters, and to relate species density and distribution to the abiotic characteristics of the region. Sampling was performed from March/2007 and May/2008, we collected samples of sediments and mollusks along 180 m transects in the intertidal area on the beaches Barra and Pernambuquinho, Grossos - RN. At each sampling site, samples of sediments and mollusks were collected in the intertidal area along 180 m transects. The highest and lowest average densities on Pernambuquinho beach were 1148 (April/2007), and 100 individuals.m-2 (May/ 2008), respectively. On Barra beach, the highest and lowest densities were 1813 (April/2007) and 951 individuals.m-2, (November/2007), respectively. The densities of A. brasiliana on both beaches were significantly different only in the months of January, April and May/ 2008. Length of the individuals ranged from 1 to 28 mm, with most individuals measuring between 22 and 24 mm. Length growth rate parameters for A. brasiliana were Linfinity = 28.68 mm and k = 0.61 year-1 on Barra beach, and Linfinity = 29.87 mm and k = 0.48 year-1 on Pernambuquinho beach. The growth rate curves for A. brasiliana suggest the presence of three well defined cohorts, thus pointing to a continuous reproduction cycle with peak recruitment between October/2007 and March/2008. A. brasiliana density decreased predominantly during the heavy rains of 2008, probably due to an accumulation of sediments and decreasing salinity. This disturbance probably affected population of this species in the region. PMID- 24789400 TI - Individual growth of Drepanotrema cimex (Pulmonata: Planorbidae) from Arenalcito pond, natural reserve multiple uses Martin Garcia Island, Buenos Aires, Argentina. AB - The species of the genus Drepanotrema, most of them endemic to the Neotropical region, belong to the Planorbidae. Of the nine species of this genus, six are found in Argentina. The present investigation analysed the individual growth of Drepanotrema cimex in Arenalcito pond (34 degrees 11' S, 58 degrees 15' W), Martin Garcia Island Natural Reserve of Multiple Uses, Buenos Aires Province, Argentina. A total of 14 samples were collected (n = 1931) from February 2006 to June 2007. Five environmental variables were measured: water temperature, dissolved oxygen (mg L-1), electrical conductivity (uS cm-1), total dissolved solids, and pH. The individual growth of the species was analysed mathematically by means of the von Bertalanffy equation, where: Lt = 5,6(1-e-2,0592 (t-0,293)). The parameter Linfinity was estimated by the Ford-Walford Method. The population of D. cimex was characterised by a complex and dynamic size structure throughout the annual cycle. The analysis of the curves revealed unimodal (2006) and polymodal (April to June 2007) distributions, which pattern served to identify the existence of cohorts within the population studied. PMID- 24789401 TI - Diet of the Fuscous Flycatcher Cnemotriccus fuscatus (Wied, 1831) - Aves, Tyrannidae - in three habitats of the northern Pantanal, Mato Grosso, Brazil. AB - The Fuscous Flycatcher (Cnemotriccus fuscatus) is a medium-sized Tyrannidae widespread in South America. Despite its large distribution, there have been very few studies on its diet, especially in different habitats. This study presents data on diet variation in three habitats in the Pantanal wetlands in the state of Mato Grosso, Brazil. The specimens were captured through a mist-netting programme between February 2000 and May 2010, in the Retiro Novo Farm, in the Pocone municipality. Birds were captured in three vegetation types: Landizal, Cambarazal and Cordilheira. Tartar emetic was used to obtain the regurgitation samples identified at order level. We captured 61 individuals (21, 26 and 14 in the above described habitats, respectively). Diet of C. fuscatus differed between the three habitats. Ants and beetles were the most relevant prey items either in numerical frequency (NF) or in frequency of occurrence (OF), in terms of the overall diet (NF = 27.34% and 37.89%; OF = 36.06% and 75.4%, respectively). However, in Cordilheira, seeds and beetles dominated the NF (21.8% and 38.1%, respectively) and OF (28.5% and 85.7%, respectively). Cnemotriccus fuscatus was found to have an omnivorous diet, although in Cambarazal, individuals preyed exclusively on arthropods. The present study provides an important contribution to the knowledge of the diet of a poorly studied Neotropical bird. PMID- 24789402 TI - Ectoparasitic flies (Diptera, Streblidae) of bats (Chiroptera, Phyllostomidae) in an Atlantic Forest area, southeastern Brazil. AB - We studied infestation rates and parasite-host associations between streblid flies and phyllostomid bats in an Atlantic Forest area of Rio de Janeiro state, southeastern Brazil. We captured 301 individuals from seven Phyllostomidae bat species. Out of that total, 69 bats had been parasitised by nine Streblidae species; the most frequent species were Trichobius joblingi and Trichobius tiptoni. The species Paraeuctenodes longipes, associated with Anoura geoffroyi, was the most frequent species. The highest mean intensity was observed for Paraeuctenodes longipes, associated with A. geoffroyi, and Paratrichobius longicrus associated with Artibeus lituratus, both ectoparasite species with a mean intensity of five individuals per bat. Trichobius joblingi exhibited the highest mean abundance, which was over three on its host species. Streblid richness in the study area was similar to the richness found in other studies carried out in the Atlantic Forest. We observed that streblid richness in this biome depends more on inherent characteristics of each physiognomy and on the host-species than on the sampling effort. PMID- 24789403 TI - Occupancy dynamics of South American sea-lions in Brazilian haul-outs. AB - Along the Brazilian coast only two haul-outs of South American sea lions (Otaria flavescens) are known: Ilha dos Lobos and Molhe Leste, both located in the southernmost state of Brazil, Rio Grande do Sul. Most sea lions observed in these haul-outs are adult and sub-adult males. It is supposed that the species' presence in these areas is due to food supply and absence of parental assistance by males. This study analysed the use of these haul-outs by O. flavescens between 1993 and 2002 based on counting data of observed individuals. Bayesian generalised linear mixed models were used to evaluate differences in abundance between areas, long term trends and seasonal patterns. Results showed that for O. flavescens abundance had a long term trend of increased average occupancy over the study period, with seasonal variation reaching the highest within-year value in August (Ilha dos Lobos) and October (Molhe Leste). The novel application of this powerful statistical modelling approach resulted in a useful tool to quantify occupancy dynamic. PMID- 24789404 TI - Relative growth of Acantholobulus schmitti (Rathbun, 1930) (Crustacea, Brachyura, Panopeidae) at Guaratuba Bay, southern Brazil. AB - A study on the relative growth of the crab Acantholobulus schmitti (Rathbun, 1930) (Decapoda, Brachyura, Panopeidae) was performed with allometric techniques. The species is associated with lanterns used for oyster farming at Guaratuba Bay, southern Brazil. Crabs were obtained from five lanterns from March through December 2009. The following morphological characteristics were measured: the carapace width (CW), the height and length of the major cheliped propodus (LPH and LPL), the width of the female abdomen at the base of the 4th somite (AW) and the length of the male gonopod (GL). A total of 1,004 individuals of A. schmitti were measured, of which 451 were males, 323 non-ovigerous females and 230 ovigerous females. The CW of the males varied from 1.87 to 11.86 mm, that of non ovigerous females from 1.44 to 8.77 mm and that of ovigerous females from 4.09 to 11.12 mm. The plot of LPH against CW showed a mean inflection point at 3.67 mm CW for the males. This result indicated that male crabs are juvenile below this value and adult above it. For the females, the corresponding inflection point occurred at 3.36 mm CW in the plot of AW against CW. These results, CW x LPH and CW x AW, highlight the importance of chelae enlargement at the onset of maturation in males. Similarly, the widening of the abdomen in females is required to accommodate egg clutches during the reproductive period. Heterochely was recorded in both sexes. Right-handed crabs were more frequent than left handed ones, with percentages of 75.8% in males and 82.7% in females. The population of A. schmitti from Guaratuba Bay becomes sexually mature at an earlier age than A. schmitti from the coast of Sao Paulo state. The lanterns used in oyster farming furnish a safe habitat in which these crabs can spend their entire benthic life. PMID- 24789405 TI - Parasite fauna of wild and cultured dusky-grouper Epinephelus marginatus (Lowe, 1834) from Ubatuba, southeastern Brazil. AB - This study aimed at identifying and quantifying the parasites of wild and cultured dusky grouper Epinephelus marginatus. During a year and thereby all four seasons, 20 wild and 20 cultured groupers were examined for the presence of parasites, except in the last season, in which 19 wild and 20 cultured fish were examined, totalling 159 groupers analysed from Ubatuba, southeastern Brazil. Prevalence, mean intensity of infection, mean abundance and mean relative dominance were calculated. Five species of parasites were identified in fish from both origins: Pseudorhabdosynochus beverleyburtonae (Monogenea), Neobenedenia melleni (Monogenea), Pseudempleurosoma sp. (Monogenea), Helicometrina nimia (Digenea) and larvae of Contracaecum sp. (Nematoda). The prevalence of ectoparasites, in most cases, was higher than endoparasites. The most abundant parasite was the monogenea Pseudorhabdosynochus beverleyburtonae in both wild and cultured fish, along all seasons. Neobenedenia melleni was observed in wild and cultured fish in all seasons, with a gradual increase in the number of parasites from the coldest to the hottest seasons, with the highest prevalence and mean intensity in the summer. Helicometrina nimia was found in all seasons in both wild and cultured fish, except for summer, where its presence was detected only in wild fish. Pseudempleurosoma sp. and larvae of Contracaecum sp. showed low prevalence occurring in wild and cultured fish in the autumn and spring, respectively. This study revealed high intensities of potentially pathogenic parasites that could favour disease outbreaks in culture conditions. PMID- 24789406 TI - Species of Anastrepha (Diptera: Tephritidae) captured in a guava orchard (Psidium guajava L., Myrtaceae) in Boa Vista, Roraima, Brazil. AB - The guava fruit (Psidium guajava) is among the most strongly affected by fruit flies in Brazil. In the Brazilian Amazon, 11 species of Anastrepha have been reported in guava orchards to date. This work aimed to identify the species of Anastrepha present in a guava orchard in the municipality of Boa Vista, determine the species infesting the fruits, and identify any parasitoids present. Two McPhail traps with food bait were installed and weekly collections were made between January and December 2008. Fruits were also collected systematically during this period, with a view to determining the association between host plant and tephritid species. Nine species of Anastrepha were identified, in addition to one specimen belonging to a probable new species. Anastrepha striata Schiner, Anastrepha sororcula Zucchi, Anastrepha obliqua (Macquart), and Anastrepha fraterculus (Wiedemann) were the dominant species in the orchard, accounting for 84.8% of all captured individuals. All females collected directly from fruits were A. striata. Doryctobracon areolatus (Szepligeti) was the only parasitoid species obtained. In this work, Anastrepha ethalea (Walker) is reported for the first time in the state of Roraima. PMID- 24789407 TI - Size and shape in Melipona quadrifasciata anthidioides Lepeletier, 1836 (Hymenoptera; Meliponini). AB - This study aimed to identify differences in wing shape among populations of Melipona quadrifasciata anthidioides obtained in 23 locations in the semi-arid region of Bahia state (Brazil). Analysis of the Procrustes distances among mean wing shapes indicated that population structure did not determine shape variation. Instead, populations were structured geographically according to wing size. The Partial Mantel Test between morphometric (shape and size) distance matrices and altitude, taking geographic distances into account, was used for a more detailed understanding of size and shape determinants. A partial Mantel test between morphometris (shape and size) variation and altitude, taking geographic distances into account, revealed that size (but not shape) is largely influenced by altitude (r = 0.54 p < 0.01). These results indicate greater evolutionary constraints for the shape variation, which must be directly associated with aerodynamic issues in this structure. The size, however, indicates that the bees tend to have larger wings in populations located at higher altitudes. PMID- 24789408 TI - Comparative study of the ovarian morphology in the order Polydesmida (Diplopoda) and description of unusual structures in the female reproductive system. AB - Polydesmida is the largest order in the class Diplopoda in terms of the number of species, genera and families, but there are few studies of the ovarian morphology of species in this order. This study aimed to perform a comparative study of the ovarian morphology of three species from this order to increase the understanding of the morphological evolution of this system in Polydesmida. Adults females of two of these species, Poratia salvator and Myrmecodesmus hastatus, belonging to the family Pyrgodesmidae, had a unpaired ovary that formed a tubular organ containing oocytes, with P. salvator present grouping of oocytes into a structure similar to ovisacs. This condition appeared to be apomorphic and was associated with the small size of these species (< 10 mm) and their short life cycle. The third species, Telonychopus klossae (Chelodesmidae), had a large body and an ovary with paired ovisacs, which was symplesiomorphic with other Polydesmida families. PMID- 24789409 TI - A brief observation of morphological and behavioral similarities between the Ichneumonidae wasp Cryptanura sp. and its presumed mimic, Holymenia clavigera (Heteroptera: Coreidae), in Brazil. AB - Some insects use wasps as a model to mimic and previous studies showed cases of Batesian mimicry involving this insect group. However, this relation is poorly known between phytophagous bugs, such as coreids, and Cryptinae ichneumonids. We found in a seasonal secondary forest in Brazil two similar insects representing different orders. The mimic seems to be Holymenia clavigera (Herbst) (Heteroptera: Coreidae) and its model, Cryptanura sp. (Hymenoptera: Ichneumonidae). This study therefore investigated similarities in morphological and behavioural aspects between H. clavigera and the wasp Cryptanura sp. Holymenia clavigera and its ichneumonid model are impressively similar in colour, size, foraging behaviour and sympatric range. The spanning movements of antennae by the coreid bug, which strongly resemble the foraging behaviour of the wasp, were observed frequently. The findings indicate strong evidences that H. clavigera is a mimic of the Ichneumonidae wasp, Cryptanura sp. PMID- 24789410 TI - Characterization of nanoporous gold disks for photothermal light harvesting and light-gated molecular release. AB - Nanoporous gold disks (NPGDs) with 400 nm diameter, 75 nm thickness, and 13 nm pores exhibit large specific surface area and effective photothermal light harvesting capability with a conversion efficiency of 56%. A potential application is demonstrated by light-gated, multi-step molecular release of the pre-adsorbed R6G fluorescent dye on arrayed NPGDs. PMID- 24789415 TI - Characterization and expression patterns of nitrate reductase from Dunaliella bardawil under osmotic stress and dilution shock. AB - A complementary DNA (cDNA) of nitrate reductase (NR) from Dunaliella bardawil was isolated using RT-PCR and RACEs techniques. The full-length D. bardawil NR (DbNR) cDNA is 3,107 bp containing a putative open reading frame of 2,670 bp in length which encodes 889 amino acids with a calculated molecular weight (MW) of 98.37 kDa, a 34-bp 5'-untranslated region, and a 3'-untranslated region of 403 bp with a poly (A) tail. BLAST search showed that the nucleotide and putative protein sequence exhibit sequence identities of 92 and 79% with the corresponding gene from Dunaliella tertiolecta, respectively. Protein structural analysis showed a typical NR structure of DbNR with five structural distinctive domains which form three common subparts of eukaryotic NR (Euk-NR). Phylogenetic analysis based on the holo-DbNR and sulfite oxidase (SO) and cytochrome b reductase (CbR) subparts manifested that (1) DbNR has a closer relationship with those counterparts from algae and higher plants than from other species and (2) DbNR might have evolved from ancient SO and CbR in a "domain shuffling" pattern. The glycerol contents and transcriptional expression patterns of DbNR under salt stress and dilution shock treatments were also traced. The results implied an indirect role of NaCl on the induction of DbNR through an osmoregulation pathway. PMID- 24789416 TI - Amino acid esters substituted phosphorylated emtricitabine and didanosine derivatives as antiviral and anticancer agents. AB - Owing to the promising antiviral activity of amino acid ester-substituted phosphorylated nucleosides in the present study, a series of phosphorylated derivatives of emtricitabine and didanosine substituted with bioactive amino acid esters at P-atom were synthesized. Initially, molecular docking studies were screened to predict their molecular interactions with hemagglutinin-neuraminidase protein of Newcastle disease virus and E2 protein of human papillomavirus. The title compounds were screened for their antiviral ability against Newcastle disease virus (NDV) by their in ovo study in embryonated chicken eggs. Compounds 5g and 9c exposed well mode of interactions with HN protein and also exhibited potential growth of NDV inhibition. The remaining compounds exhibited better growth of NDV inhibition than their parent molecules, i.e., emtricitabine (FTC) and didanosine (ddI). In addition, the in vitro anticancer activity of all the title compounds were screenedagainst HeLa cell lines at 10 and 100 MUg/mL concentrations. The compounds 5g and 9c showed an effective anticancer activity than that of the remaining title compounds with IC50 values of 40 and 60 MUg/mL, respectively. The present in silico and in ovo antiviral and in vitro anticancer results of the title compounds are suggesting that the amino acid ester substituted phosphorylated FTC and ddI derivatives, especially 5g and 9c, can be used as NDV inhibitors and anticancer agents for the control and management of viral diseases with cancerous condition. PMID- 24789417 TI - Antimicrobial agents act differently on Staphyloccocus aureus and Ralstonia eutropha flavohemoglobins. AB - Flavohemoglobins (FlavoHb) play a key role in bacterial resistance to nitrosative stress and NO signaling modulation. In this study, we cloned, expressed, and characterized the flavoHb from the opportunistic pathogen, Staphylococcus aureus. The higher amino-acid sequence homology is shared with that from Saccharomyces cerevisiae which was therefore used to build a model structure by homology modeling. Interestingly, the high sequence homology with S. cerevisiae did not correlate with the enzymatic and kinetic properties which are much similar to those of Escherichia coli. In vitro and aerobically, we showed that S. aureus and Ralstonia eutropha flavoHbs accept cytochrome c and oxygen as substrates. Based on this feature, we investigated the preferences for both substrates depending on miconazole or econazole addition and found that the inhibitor chemical composition is determinant. PMID- 24789419 TI - PCCP's 15th anniversary. PMID- 24789418 TI - Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: a national cohort study. AB - Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >=60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening >=60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers >=60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as "unfavourable." Of 548 BRCA1/2 mutation carriers >=60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected >=60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4.07, 95% confidence interval [1.79-9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening (p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60-year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers >=60 is worthwhile. PMID- 24789420 TI - Identification of the typical miRNAs and target genes in hepatocellular carcinoma. AB - The aim of the present study was to identify miRNAs that were differentially expressed in hepatocellular carcinoma (HCC) by comparing normal and cancer tissue samples and to analyze the correlation of the target genes and HCC. The gene expression profile of GSE31383 was downloaded from the Gene Expression Omnibus database, including 19 samples, 9 normal and 10 from HCC tissue samples. The differentially-expressed miRNAs were identified with packages in R language and further analyzed using bioinformatics methods. Firstly, the verified targets of miRNAs were integrated in two miRNA databases: miRecords and miRTarBase, and the targets of the differentially-expressed miRNAs were obtained. The software STRING was then used to construct the interaction network of target genes. Finally, a functional enrichment analysis of the genes in the interaction network was conducted using the software Gestalt. Typical miR-224 and miR-214 were identified by comparing normal and cancer samples, each of which obtained 14 and 8 target genes, respectively. The functional enrichment analysis of the targets in the two groups highlighted the intracellular signaling cascade. In conclusion, the featured miRNAs (the upregulated miRNA-224 and downregulated miRNA-214) and their target genes are significant in the occurrence and development of HCC, which is likely to be significant for the identification of therapeutic targets and biomarkers to aid in the treatment of HCC. PMID- 24789421 TI - Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. AB - BACKGROUND: The objective of this study was to systematically review all available literature concerning chemotherapy-induced peripheral neuropathy (CIPN) and quality of life (QOL) among cancer patients. METHODS: A computerized search of the literature was performed in December 2013. Articles were included if they investigated CIPN and QOL among cancer patients. Twenty-five articles were selected and were subjected to a 13-item quality checklist independently by two investigators. RESULTS: The methodological quality of the majority of the selected studies was adequate to high. The included studies differed tremendously with respect to study design (19 prospective studies, 5 cross-sectional, 1 both cross-sectional and prospective), patient population (lung, colorectal, ovarian, endometrial, cervical or breast cancer, lymphoma, acute lymphoblastic leukemia, or a mixed population), number of included patients (ranging from 14 to 1643), and ways to assess CIPN (objectively, subjectively, or both). Of the 25 included studies, 11 assessed the association of CIPN on patients' QOL. While three of these studies did not find an association between CIPN and QOL, the others concluded that more CIPN was associated with a lower QOL. IMPLICATIONS FOR CANCER SURVIVORS: Although the included studies in this systematic review were very diverse, which impedes drawing firm conclusions on this topic, CIPN is likely to have a negative association with QOL. The variety of the studied patient populations and chemotherapeutic agents in the existing studies calls for further studies on this topic. These studies are preferably prospective in nature, include a large number of patients, and assess QOL and CIPN with validated questionnaires. PMID- 24789422 TI - Quality of life and satisfaction with care among family caregivers of patients with recurrent or metastasized digestive cancer requiring palliative care. AB - PURPOSE: Satisfaction with care is thought to be important for quality of life (QOL) of family caregivers of patients with recurrent or metastasized digestive cancer requiring palliative care. This study aimed to clarify (1) family caregivers' QOL status and (2) factors related to their QOL, including satisfaction with care. METHODS: Data were collected from 111 family caregivers of patients with recurrent or metastasized digestive cancer. The Short-Form 36 (SF-36) (acute version) was used to measure QOL. RESULTS: Family caregivers' QOL was lower than the national average (Cohen's d = 0.12-0.66). Lower age of patients and family caregivers (standardized regression coefficient (beta) = 0.18, beta = -0.26) and family caregivers' perceived health (beta = 0.22) were related to better physical health of family caregivers, but satisfaction with care was not related to physical health. However, family caregivers' mental health was related to their satisfaction with care (Spearman's rank correlation coefficient (r) = 0.49-0.61, standardized regression coefficient (beta) = 0.24 0.42), as well as higher age of family caregivers (beta = 0.25), their perceived health (beta = 0.30), non-spousal caregiver (beta = -0.20), patient lacking a history of surgery aimed at radical treatment (beta = -0.22), and patient not hospitalized solely for symptom relief (beta = -0.10). CONCLUSIONS: Family caregivers of patients with recurrent or metastasized digestive cancer requiring palliative care had lower QOL, both physically and mentally, than the national average. Improvements in satisfaction with care may contribute to improved QOL. PMID- 24789423 TI - Highly stable carbon nanotube top-gate transistors with tunable threshold voltage. AB - Carbon-nanotube top-gate transistors with fluorinated dielectrics are presented. With PTrFE as the dielectric, the devices have absent or small hysteresis at different sweep rates and excellent bias-stress stability under ambient conditions. Ambipolar single-walled carbon nanotube (SWNT) transistors are observed when P(VDF-TrFE-CTFE) is utilized as a topgate dielectric. Furthermore, continuous tuning of the threshold voltages of both unipolar and ambipolar SWNT thin-film transistors (TFTs) is demonstrated for the first time. PMID- 24789424 TI - Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty: a BOLD analysis--authors' reply. PMID- 24789425 TI - Il buono, il brutto, il cattivo. PMID- 24789426 TI - Intracranial Pressure Monitoring in Children With Severe Traumatic Brain Injury: National Trauma Data Bank-Based Review of Outcomes. AB - IMPORTANCE: The present study is the largest on the use and effect of intracranial pressure (ICP) monitoring in pediatric trauma patients. OBJECTIVE: To determine the effect of ICP monitoring on survival in pediatric patients with severe head injuries using the National Trauma Data Bank. DESIGN, SETTING, AND PARTICIPANTS: The National Trauma Data Bank was queried (version 6.2, 2001-2006) for information on patients younger than 17 years admitted to an intensive care unit with blunt traumatic brain injury (TBI), Injury Severity Score (ISS) greater than 9, and Glasgow Coma Scale (GCS) score less than 9. Patients with incomplete medical records and those with intensive care unit length of stay of less than 24 hours were excluded from the study. MAIN OUTCOMES AND MEASURES: Parametric comparisons (t tests and chi2 as appropriate) were performed to compare patients who received ICP monitoring with those who did not. Stepwise logistic regression methods were used to assess whether ICP monitoring in the presence of other variables (age, sex, ISS, Revised Trauma Score, and GCS score) was associated with survival. RESULTS: Monitoring of ICP was performed in only 7.7% of patients who met the monitoring criteria recommended by the Brain Trauma Foundation. There were no significant differences in age, sex, or GCS score. After adjustment for admission GCS score, age group, sex, Revised Trauma Score, and injury ISS, ICP monitoring was associated with a reduction in mortality only for patients with a GCS score of 3 (odds ratio, 0.64; 95% CI, 0.43-1.00). Comparison between the 2 groups showed that the ICP monitoring group had a longer hospital length of stay (21.0 days vs 10.4 days; P < .001), longer intensive care unit stay (12.6 vs 6.3 days; P < .001), and more ventilator days (9.2 vs 4.7; P < .001). CONCLUSIONS AND RELEVANCE: Despite current Brain Trauma Foundation guidelines, ICP monitoring is used infrequently in the pediatric population. The data suggest that there is a small, yet statistically significant, survival advantage in patients who have ICP monitors and a GCS score of 3. However, all patients with ICP monitors experienced longer hospital length of stay, longer intensive care unit stay, and more ventilator days compared with those without ICP monitors. A prospective observational study would be helpful to accurately define the population for whom ICP monitoring is advantageous. PMID- 24789427 TI - Risk and predictors of attempted and completed suicide in patients with hematological malignancies. AB - BACKGROUND: Hematological malignancies can cause high levels of distress, but few studies have assessed risk of suicidal behavior among these patients. METHODS: We evaluated risk of attempted and completed suicide in a cohort of 46,309 patients diagnosed with malignant lymphoma, myeloma and leukemia in Sweden 1992 to 2009 and 107,736 cancer-free subjects, using Poisson regression. RESULTS: In all, 146 suicide attempts and 63 completed suicides occurred during a median follow up of 3.1 years (maximum 19 years). The risk of completed suicide was 3.5-fold increased among patients with myeloma [incidence rate ratio (IRR) = 3.52, 95% confidence interval (CI) = 2.05-6.03] and 1.9-fold increased among patients with lymphoma (IRR = 1.87, 95% CI = 1.31-2.67) but not significantly increased among patients with leukemia. Risk of attempted suicide was increased among patients with myeloma (IRR = 2.13, CI = 1.39-3.26) and lymphoma (IRR = 1.34, 95% CI = 1.07 1.69). Both male and female patients were at increased risk of attempted as well as completed suicide. A pre-malignant history of mental disorders conferred 15 fold to 30-fold increased risks, but elevated risks were also observed among patients without such history. CONCLUSIONS: Suicidal actions in patients with hematological malignancies have high suicidal intent, and that subgroups of patients should be monitored for suicidal ideation. PMID- 24789428 TI - Combined evaluation of the expression of NUCKS and Ki-67 proteins as independent prognostic factors for patients with gastric adenocarcinoma. AB - Nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) has been recently documented in various malignancies. However, data regarding the expression and prognostic value of NUCKS in gastric adenocarcinoma are limited. Specimens from 159 gastric adenocarcinoma patients who underwent primary gastrectomy were collected. Immunohistochemical method was used to evaluate NUCKS and Ki-67 expression. The correlations between NUCKS and clinical significance were analyzed. Elevated NUCKS expression was significantly associated with TNM stage (P = 0.034), depth of invasion (P = 0.001), and expression of Ki-67 (P = 0.035). Kaplan-Meier analysis indicated that NUCKS overexpression alone (P = 0.045 for overall survival) or in combination with Ki-67 (P = 0.007 for disease free survival, P = 0.002 for overall survival) was correlated with adverse prognosis of the patients. Multivariate analysis revealed that combined NUCKS and Ki-67 overexpression was an independent prognostic factor for both disease-free survival (hazard ratio = 1.623, P = 0.02) and overall survival (hazard ratio = 1.667, P = 0.016) in gastric adenocarcinoma patients. The combination of NUCKS and Ki-67 overexpression in gastric adenocarcinoma further distinguished a subgroup of patients with poor prognosis. PMID- 24789430 TI - Purification of a Pd20-TNFalpha fusion protein that prevents liver metastasis of gastric cancer. AB - The specific binding peptide pd20 of gastric cancer cells with a high potential for liver metastasis was fused with human tumour necrosis factor (TNF) alpha, and a prokaryotic expression vector was established to express the pd20-TNFalpha fusion protein. After purification and identification, the preventive effects of the fusion protein on liver metastasis of gastric cancer were observed in mice. The whole gene synthesis method was used for pd20-TNFalpha fusion gene preparation, and a pd20-TNFalpha prokaryotic expression vector was constructed. The vector was induced and expressed in Escherichia coli BL21. The expression products were analysed and verified by SDS-PAGE electrophoresis and Western blot analysis. The Ni-NTA column method was used to purify the fusion protein, and the L929 cytotoxicity method was used to detect biological activity. Flow cytometry apoptosis experiments and invasion assays were performed to observe the effects of the fusion protein on apoptosis and metastasis of gastric cancer cells with high potential for liver metastasis. Thirty nude mice with liver metastasis of gastric cancer were established and then randomly divided into three groups of ten mice each. The Pd20-TNFalpha recombinant protein (1.2 * 10(6) U/kg day) or standard TNFalpha (1.2 * 10(6) U/kg day) saline was administered via tail vein injection for 7 consecutive days. The pathological changes in various organs of nude mice were observed 4 weeks later. The size of the gastric cancer, the incidence of liver metastasis and the number of liver metastases were measured and calculated. We successfully constructed a Pd20-TNFalpha recombinant plasmid and prepared the fusion protein. Detection of the pd20-TNFalpha protein by immunofluorescence showed a very strong expression in liver tissue, suggesting a targeting of the fusion protein to the liver. The L929 cytotoxicity assays showed that the pd20-TNFalpha fusion purified protein had a significant lethal effect on L929 cells, with a killing activity of up to 7.6 * 10(6) IU/ml. The apoptosis experiments showed that as the concentration of the fusion protein increased, the early gastric cancer cell apoptosis also increased, with the early apoptosis rate increasing from 5.99 % to 9.04 %. Cell invasion experiments showed that the purified pd20-TNFalpha fusion protein significantly inhibited the in vitro invasion of XGC9811-L cells, with the penetrating cells being significantly decreased compared with the control group per unit time (P < 0.01). Vector experiments showed that the pd20-TNFalpha recombinant protein group had significantly reduced cancer lesions and liver metastasis in nude mice compared with the control group. We successfully purified a pd20-TNFalpha fusion protein and confirmed that it had significant biological activity promoting early gastric cancer cell apoptosis, thereby inhibiting gastric cancer cell invasion. PMID- 24789429 TI - Impacts of ICAM-1 gene polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic characteristics in Taiwan. AB - Intercellular adhesion molecule (ICAM)-1, a cell adhesion molecule, is reportedly overexpressed in several cancers and may contribute to tumorgenesis and metastasis. The current study explored the effect of ICAM-1 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. A total of 558 participants, including 279 healthy people and 279 patients with UCC, were recruited for this study. Four single nucleotide polymorphisms of the ICAM-1 gene were assessed by a real-time polymerase chain reaction with the TaqMan assay. After adjusting for other covariants, the individuals carrying at least one G allele at ICAM-1 rs5498 had a 1.603-fold risk of developing UCC than did wild-type (AA) carriers. Furthermore, UCC patients who carried at least one G allele at rs5498 had a higher invasive stage risk (p < 0.05) than did patients carrying the wild-type allele. In conclusion, the rs5498 polymorphic genotypes of ICAM-1 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with ICAM-1 variants in carcinogenesis of UCC in Taiwan. PMID- 24789431 TI - A polysaccharide from pomegranate peels induces the apoptosis of human osteosarcoma cells via the mitochondrial apoptotic pathway. AB - Pomegranate (Punica granatum L.) peels, as one of the most valuable by-products of the food industry, has attracted much attention due to its wide range of bioactivities. In this study, the potential anticancer effect of a polysaccharide from pomegranate peels (PPP) on human osteosarcoma cancer cells was investigated. PPP was found to induce the arrest of G2/M phase, induce apoptosis, and inhibit the growth of U-2 osteosarcoma (OS) cells in a dose-dependent manner. Moreover, Western blotting analysis showed that PPP triggered the mitochondrial apoptotic pathway, as indicated by an increase in Bax/Bcl-2 ratios, a loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-9 and caspase 3, and cleavage of poly(ADP-ribose) polymerase (PARP) in U-2 OS cells. Our results indicate that PPP inhibits the proliferation of human osteosarcoma cancer cells by inducing apoptosis through the intrinsic mitochondrial pathway. PMID- 24789432 TI - Midazolam inhibits the proliferation of human head and neck squamous carcinoma cells by downregulating p300 expression. AB - The objective of this study was to investigate the mechanism of midazolam in inhibiting the proliferation of hypopharyngeal squamous carcinoma cells. Cultured FaDu cancer cells were treated with different concentrations of midazolam. MTT and BrdU incorporation assays were then used to evaluate cancer cell proliferation. The mRNA and protein levels of p300, a key factor involved in the tumorigenesis of numerous cancers, were measured with RT-PCR and Western blotting, respectively. Midazolam inhibited the expression of p300 and the proliferation of FaDu cells. Additionally, knockdown of p300 resulted in increased expression of p21 and p27 and decreased expression of p-Rb while inhibiting the proliferation of FaDu cells. Midazolam inhibits the proliferation of human head and neck squamous carcinoma cells by downregulating p300. Midazolam may be useful for the treatment of hypopharyngeal squamous cancers. PMID- 24789433 TI - Efficacy of Cisplatin-loaded poly butyl cyanoacrylate nanoparticles on the ovarian cancer: an in vitro study. AB - One of the main challenges of treatment of ovarian cancer is initial response to treatment and then acquisition of resistance to Cisplatin. Nanotechnology-based approaches are considered as one way to overcome drug resistance. In this study, the cytotoxicity effects of Cisplatin-loaded poly butyl cyanoacrylate (PBCA) nanoparticles (NPs) on the ovarian cancer cell line A2780cp resistant to Cisplatin were studied. NPs were synthesized by miniemulsion polymerization method. Size, size distribution and zeta potential of NPs were estimated as 489 nm, 0.429, and -20 mV, respectively. Drug loading and encapsulation efficiency were recognized as 5 % and 25 %, respectively. Drug release pattern (3.18 % release after 51 h) demonstrated high level of retention. Toxicological studies showed that cytotoxicity of the nanodrug Cisplatin was about three times as much as that of a free drug. Moreover, NPs presented acceptable stability after 2 months. The results of study suggest the use of this formulation for in vivo experiments. PMID- 24789434 TI - Alterations of circulating follicular helper T cells and interleukin 21 in diffuse large B-cell lymphoma. AB - CD4+ CXCR5+ T cell in peripheral blood is known as circulating follicular helper T cell (Tfh), which can produce interleukin 21 (IL-21). In the current study, we investigated changes of circulating Tfh and its correlation with IL-21 in diffuse large B-cell lymphoma (DLBCL). Circulating Tfh and its subtypes were detected by flow cytometry in the peripheral blood of 32 healthy donors and 62 DLBCL cases. Data demonstrated that percentage of circulating Tfh in CD4+ T cells was significantly increased in DLBCL (11.3 %) than in controls (8.5 %) (p = 0.001). Studying the subtypes of Tfh revealed that the upregulation of circulating Tfh was contributed by Tfh-Th2 subtype and Tfh-Th17 subtype. Also, we identified that prevalence of Tfh was significantly elevated in cases with advanced stages (stages III and IV). Interestingly, the elevation of circulating Tfh was negatively correlated with serum IL-21 in DLBCL patients. In addition, a positive correlation between circulating Tfh and IL-21 receptor on CD + 8 T cells was observed in patients. This study suggests involvement of circulating Tfh and IL 21 in the pathogenesis and progression of DLBCL and provides a potential target for treating this disease. PMID- 24789435 TI - Prognostic factors for desmoid tumor: a surgical series of 233 patients at a single institution. AB - Desmoid tumors are rare soft tissue tumors with limited data on their management and prognosis. We sought to determine the rates of recurrence after surgery for desmoid tumors and analyze factors predictive of recurrence-free survival (RFS). From February 1976 to October 2011, 233 consecutive patients with desmoid tumors who underwent macroscopically complete resection were included in this study. Clinicopathologic and treatment characteristics were evaluated to determine predictors of recurrence. Patterns of presentation included primary (n = 156, 67.0 %) and locally recurrent (n = 77, 33.0 %) disease initially treated elsewhere. Most patients had a R0 resection (n = 169, 72.5 %). In addition to surgery, 43 (18.5 %) patients received radiotherapy and 10 (4.3 %) patients received systemic therapy. Median follow-up was 54 months; recurrence disease was observed in 62 (26.6 %) patients. The estimated 5- and 10-year RFS was 74.2 % (95 % confidence interval (CI), 68.3-80.1) and 70.7 % (95 % CI, 64.2-77.2), respectively. Factors associated with worse RFS were tumor size larger than 5 cm (hazard ratio (HR) = 3.757; 95 % CI, 1.945-7.259; p < 0.001), extra-abdominal tumor location (abdominal wall referent; HR = 3.373; 95 % CI, 1.425-7.984; p = 0.006), and R1 resection status (HR = 1.901; 95 % CI, 1.140-3.171; p = 0.014). Patients were grouped according to the number of unfavorable prognostic factors; the 10-year RFS rates of patients with zero, one, two, and three prognostic factors were 100, 86.9, 48.5, and 34.4 %, respectively (p < 0.001). Regardless of primary or recurrent disease, surgical resection remains central to the management of patients with desmoid tumors. However, there are clearly different prognostic subgroups that could benefit from different therapeutic strategies, and a wait-and-see policy is a possible option for a subset of patients. PMID- 24789436 TI - Proteasome inhibitor MG132 enhances the antigrowth and antimetastasis effects of radiation in human nonsmall cell lung cancer cells. AB - The current treatment for advanced nonsmall cell lung cancer (NSCLC) remains unsatisfactory due to resistance to chemotherapy and ionizing radiation. The ubiquitin-proteasome system (UPS) regulates multiple cellular processes that are crucial for the proliferation and survival of all kinds of cells. Carbobenzoxyl leucinyl-leucinyl-leucinal-H (MG132), a specific and selective reversible inhibitor of the 26S proteasome, represents a novel approach for cancer therapy. However, whether MG132 can potentiate the effect of radiation against the growth and metastasis of NSCLC is not clear. We found that MG132 inhibited the proliferation of human NSCLC cell lines (A549 and H1299) in a dose- and time dependent manner by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Then MG132 at a nontoxic dose (100 nM) was selected for following studies. Pretreatment of A549 and H1299 cells with 100 nM MG132 before ionizing radiation (IR) potentiated the anticancer effect of IR. Moreover, pretreatment with 100 nM MG132 before IR-enhanced radiation induced cell cycle arrest by decreased CyclinD1 but increased Wee1 expression in A549 and H1299 cells. In addition, pretreatment of MG132 combined with IR significantly suppressed cell migration and invasion abilities in NSCLC cell lines, which was accompanied by decreased expression of matrix metalloproteinase (MMP)-2 and MMP-9 in NSCLC cell lines. Taken together, our results demonstrate that MG132 enhances the antigrowth and antimetastatic effects of irradiation in NSCLC cells by modulating expression of cell cycle and invasion- related genes. PMID- 24789439 TI - Dihydromyricetin induces cell cycle arrest and apoptosis in melanoma SK-MEL-28 cells. AB - Dihydromyricetin (DHM) exhibits multiple pharmacological activities; however, the role of DHM in anti-melanoma activities and the underlying molecular mechanisms are unclear. The aim of the present study was to evaluate the effects of DHM on cell proliferation, cell cycle distribution and apoptosis in the human melanoma SK-MEL-28 cell line, and to explore the related mechanisms. The effect of DHM on cell proliferation was investigated by MTT assay, and cell cycle distribution was determined by flow cytometry. TUNEL assay was used to evaluate DHM-mediated apoptosis, and western blotting was applied to examine expression levels of p53, p21, Cdc25A, Cdc2, P-Cdc2, Bax, IKK-alpha, NF-kappaB p65, p38 and P-p38 proteins. The results revealed that DHM suppressed cell proliferation of SK-MEL-28 cells in a concentration- and time-dependent manner, and caused cell cycle arrest at the G1/S phase. DHM increased the production of p53 and p21 proteins and downregulated the production of Cdc25A, Cdc2 and P-Cdc2 proteins, which induced cell cycle arrest. Additionally, DHM significantly induced the apoptosis of SK MEL-28 cells, and enhanced the expression levels of Bax proteins and decreased the protein levels of IKK-alpha, NF-kappaB (p65) and P-p38. The results suggest that DHM may be a novel and effective candidate agent to inhibit the growth of melanoma. PMID- 24789440 TI - Metal nanoparticles with liquid-crystalline ligands: controlling nanoparticle superlattice structure and properties. AB - Nanoparticle ordered aggregates are promising candidates for future application in a variety of sensing, optical and electronic technologies, mainly based on collective interactions between individual nano-building blocks. Physicochemical properties of such assemblies depend on nanoparticle spacing, therefore a lot of effort throughout the last years was put on development of assembly methods allowing control over aggregates structure. In this minireview we describe efficient self-assembly process based on the utilization of liquid-crystalline ligands grafted onto nanoparticle surface. We show strategies used to synthesize liquid-crystalline nanoparticles as well as discuss parameters influencing structural and thermal characteristic of aggregates. It is also demonstrated that the liquid-crystalline approach offers access to dynamic self-assembly and metamaterials with anisotropic plasmonic properties, which makes this strategy unique among others. PMID- 24789442 TI - Rebuttal to: Letter to the Editor by Robert Burton, in response to doi:10.1007/s10549-013-2794-5. PMID- 24789441 TI - Role of CIP2A in the antitumor effect of bortezomib in colon cancer. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A) has been identified as an oncoprotein that is able to promote the proliferation of cancer cells. The role of CIP2A in the anticancer activity of bortezomib in colon cancer remains to be elucidated. In the present study, the antitumor effect of bortezomib was investigated and the role of CIP2A in determining the effect on colon cancer cells was identified. In the present study, bortezomib demonstrated an antitumor effect, as observed by WST-1 assay and flow cytometry. In addition, the mRNA and protein level of CIP2A was inhibited in a dose-dependent manner by bortezomib with quantitative PCR (qPCR) and western blotting. Furthermore, the inhibition of CIP2A with small interfering RNA by treatment with bortezomib inhibited proliferation, increased apoptosis and attenuated the invasion of the cells. Finally, the in vivo data demonstrated that bortezomib was able to decrease the growth of tumors, and that CIP2A was downregulated in the LoVo tumors treated with bortezomib. Therefore, CIP2A was shown to be important in the bortezomib induced inhibitory effect on colon cancer. PMID- 24789443 TI - Racial disparities in initiation of adjuvant endocrine therapy of early breast cancer. AB - Endocrine therapy (ET) is the cornerstone of adjuvant therapy for hormone receptor positive (HR+) breast cancer. The survival gap between African-American (AA) and white women with breast cancer is most pronounced in HR+ subtypes, and could be related to differences in ET use. The relationship between race and initiation of ET is not well defined. We investigated patterns of ET initiation by race in a diverse cohort of women covered by commercial health insurance. We identified 2,640 women with incident HR+ breast cancer in the North Carolina Central Cancer Registry whose records linked to commercial insurance claims using the Integrated Cancer Information and Surveillance System (ICISS) database. The sample included women age <65 years diagnosed with stage I-III HR+ cancers between 2004 and 2009. We used multivariate Poisson regression to examine the effect of race on likelihood of initiating ET. 14 % of women did not initiate ET within 12 months of diagnosis. AA women were 17 % less likely to initiate ET than whites (aRR 0.83, 95 % CI 0.74-0.93). When analyzed by subset, racial disparities persisted among women who received chemotherapy (aHR 0.67, 95 % CI 0.56-0.80) but not among women who did not receive chemotherapy (aHR 0.96, 95 % CI 0.76-1.21). AA women in our sample were less likely to initiate ET than whites, and this disparity was concentrated among chemotherapy-treated women. ET under-utilization may contribute to the racial survival gap in HR+ breast cancer, and represents an opportunity for intervention to reduce breast cancer disparities. PMID- 24789444 TI - Post-diagnosis physical activity and survival after breast cancer diagnosis: the Long Island Breast Cancer Study. AB - Physical activity (PA) is associated with physiological responses thought to beneficially affect survival after breast cancer diagnosis, yet few studies have considered the entire survivorship experience. Effects of post-diagnosis activity on survival were examined in a cohort of 1,423 women diagnosed with in situ or invasive breast cancer in 1996-1997. Subjects were interviewed soon after diagnosis and again after approximately 5 years to assess breast cancer-related factors, including recreational PA before and after diagnosis. Date and cause of death through 2009 were determined from the National Death Index. Adjusted estimates were obtained using proportional hazards regression and a selection model to account for missing data. Survival was improved among women who were highly active after diagnosis (>9.0 MET h/week) compared to inactive women (0 MET h/week) for all-cause [hazard ratio (HR) (95 % credible interval): 0.33 (0.22, 0.48)] and breast cancer-specific mortality [HR: 0.27 (0.15, 0.46)]. The association of PA with overall mortality appeared stronger in the first 2 years after diagnosis [HR: 0.14 (0.03, 0.44)] compared to 2+ years since diagnosis [HR: 0.37 (0.25, 0.55)]. These findings show that post-diagnosis PA is associated with improved survival among women with breast cancer. PMID- 24789445 TI - Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: implications for chemotherapy. AB - The putative tumour suppressor and apoptosis-promoting gene, growth arrest specific 5 (GAS5), encodes long ncRNA (lncRNA) and snoRNAs. Its expression is down-regulated in breast cancer, which adversely impacts patient prognosis. In this preclinical study, the consequences of decreased GAS5 expression for breast cancer cell survival following treatment with chemotherapeutic agents are addressed. In addition, functional responses of triple-negative breast cancer cells to GAS5 lncRNA are examined, and mTOR inhibition as a strategy to enhance cellular GAS5 levels is investigated. Breast cancer cell lines were transfected with either siRNA to GAS5 or with a plasmid encoding GAS5 lncRNA and the effects on breast cancer cell survival were determined. Cellular responses to mTOR inhibitors were evaluated by assaying culture growth and GAS5 transcript levels. GAS5 silencing attenuated cell responses to apoptotic stimuli, including classical chemotherapeutic agents; the extent of cell death was directly proportional to cellular GAS5 levels. Imatinib action in contrast, was independent of GAS5. GAS5 lncRNA promoted the apoptosis of triple-negative and oestrogen receptor-positive cells but only dual PI3K/mTOR inhibition was able to enhance GAS5 levels in all cell types. Reduced GAS5 expression attenuates apoptosis induction by classical chemotherapeutic agents in breast cancer cells, providing an explanation for the relationship between GAS5 expression and breast cancer patient prognosis. Clinically, this relationship may be circumvented by the use of GAS5-independent drugs such as imatinib, or by restoration of GAS5 expression. The latter may be achieved by the use of a dual PI3K/mTOR inhibitor, to improve apoptotic responses to conventional chemotherapies. PMID- 24789449 TI - Intravaginal flux controlled pump for sustained release of macromolecules. AB - PURPOSE: To design a flux controlled pump (FCP) capable of 30-day, controlled release of macromolecules to the vaginal mucosa. METHODS: The FCP is composed of a single chamber fabricated from a rigid thermoplastic with orifices and encloses a pellet of water-swellable polymer containing the drug substance. We performed testing both in vitro and in rabbits. To ensure vaginal retention in the rabbit, we designed and attached an oval shape-memory polyether urethane retainer to the FCP allowing for long-term intravaginal evaluation of a solid dosage form without invasive surgical implantation. RESULTS: The orifices and swelling properties of the polymer pellet control water entry for polymer hydration and expansion, and subsequent extrusion of the drug-containing gel from the orifice. A FCP device containing a pellet composed of hydroxypropyl cellulose compounded with a model macromolecule, achieved controlled in vitro release for 30 days with an average release rate of 24 +/- 2 MUg/day (mean +/- SD) and range of 16 to 42 MUg/day. We observed a slightly lower average release rate in vivo of 20 +/- 0.6 MUg/day (mean +/- SD). CONCLUSIONS: The size of the orifice and nature of the swelling polymer controls the hydration rate and thereby macromolecule release rate and duration from this FCP. PMID- 24789450 TI - Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. AB - PURPOSE: Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults. METHODS: In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day-18 years, bodyweight 415 g-85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs. RESULTS: Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR = Cldrug*(BW/4 kg)(BDE) with BDE = 2.23*BW(-0.065)). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively. DISCUSSION: Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children. PMID- 24789451 TI - LHRH-conjugated micelles for targeted delivery of antiandrogen to treat advanced prostate cancer. AB - PURPOSE: Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer. METHODS: LHRH-PEG-b-p(CB-co-LA) was synthesized by opening polymerization of carbonate (CB), lactide (LA), and HOOC-PEG-OH followed by conjugation with LHRH analogue. Bicalutamide analogue CBIDV17 loaded micelles were formulated by film hydration method, and characterized for critical micelle concentration (CMC), drug loading and in vitro drug release. Formulations were tested on LNCaP and C4-2 cells for cellular uptake, induction of apoptosis, viability and dowregulation of androgen receptor (AR). In vivo studies were performed in ectopic tumor bearing athymic nude mice after tail vein injection at a dose of 10 mg/kg. Tumor volume and body weight were measured for 25 days followed by immunohistochemistry (IHC) of tumor samples for Ki-67, caspase-3, and prostate specific antigen (PSA). RESULTS: HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co LA) were characterized by (1)HNMR and used for preparing micelles, which had a mean particle size of 75.60 +/- 2.25 and 72.64 +/- 1.15 nm, respectively and CBDIV17 loading of 4.6% w/w. LHRH conjugated micelles showed higher cellular uptake, cytotoxicity, and apoptosis in LNCaP and C4-2 cells compared to non targeted micelles. CBDIV17 loaded LHRH micelles more efficiently inhibited the proliferation and induced apoptosis of tumor cells according to Ki-67, caspase-3, and PSA expression. There was significant inhibition of tumor growth with the treatment of CBDIV17 loaded LHRH-conjugated micelles. CONCLUSION: These results demonstrated that LHRH-b-PEG-p(CB-co-LA) micelles have the potential for targeted delivery of CBDIV17 to treat advanced prostate cancer. PMID- 24789452 TI - Adsorption on apatitic calcium phosphates for drug delivery: interaction with bisphosphonate molecules. AB - Bisphosphonates (BPs) are well established as an important class of drugs for the treatment and prevention of several bone disorders including osteoporosis. This work investigated the interaction of two bisphosphonates, risedronate and tiludronate, with several apatitic supports, a well-crystallised hydroxyapatite (HA) and nanocrystalline apatites with varying maturation times, chemical composition and surface characteristics. The purpose was to fully understand the adsorption mechanism and desorption process, by the evaluation of the effect of several physicochemical parameters (temperature, pH and concentration of calcium and phosphate ions). Whatever the nature of the BP and the structure and composition of the apatite, the adsorption of such anti-resorptive agents can be well described as an ion exchange-reaction between phosphates species on the apatitic surface and BP molecules in solution. However, the parameters of adsorption can vary depending on the physicochemical conditions of the adsorption reaction. In addition, the structure and composition of the apatitic surface also influence the adsorption properties. Finally, BPs molecules are slowly released from apatitic supports, because most of the adsorbed molecules are irreversibly bound and not spontaneously released by dilution or simple washing. Moreover, similar to their adsorption, the release of bisphosphonates is strongly affected not only by the chemical properties of the molecule, but also by the chemical and structural characteristics of the apatitic substrates. The understanding of the adsorption and release processes provides fundamental tools for the development of drug delivery systems using apatite materials. PMID- 24789453 TI - Assessment of performance measures and learning curves for use of a virtual reality ultrasound simulator in transvaginal ultrasound examination. AB - OBJECTIVE: To assess the validity and reliability of performance measures, develop credible performance standards and explore learning curves for a virtual reality simulator designed for transvaginal gynecological ultrasound examination. METHODS: A group of 16 ultrasound novices, along with a group of 12 obstetrics/gynecology (Ob/Gyn) consultants, were included in this experimental study. The first two performances of the two groups on seven selected modules on a high-fidelity ultrasound simulator were used to identify valid and reliable metrics. Performance standards were determined and novices were instructed to continue practicing until they attained the performance level of an expert subgroup (n = 4). RESULTS: All 28 participants completed the selected modules twice and all novices reached the expert performance level. Of 153 metrics, 48 were able to be used to discriminate between the two groups' performance. The ultrasound novices scored a median of 43.8% (range, 17.9-68.9%) and the Ob/Gyn consultants scored a median of 82.8% (range, 60.4-91.7%) of the maximum sum score (P < 0.001). The ultrasound novices reached the expert level (88.4%) within a median of five iterations (range, 5-6), corresponding to an average of 219 min (range, 150-251 min) of training. The test/retest reliability was high, with an intraclass correlation coefficient of 0.93. CONCLUSIONS: Competence in the performance of gynecological ultrasound examination can be assessed in a valid and reliable way using virtual-reality simulation. The novices' performance improved with practice and their learning curves plateaued at the level of expert performance, following between 3 and 4 h of simulator training. PMID- 24789454 TI - Comparing algorithms for deriving psychosis diagnoses from longitudinal administrative clinical records. AB - PURPOSE: Registers derived from administrative datasets are valuable tools in psychosis research, but diagnostic accuracy can be problematic. We sought to compare the relative performance of four methods for assigning a single diagnosis from longitudinal administrative clinical records when compared with reference diagnoses. METHODS: Diagnoses recorded in inpatient and community mental health records were compared to research diagnoses of psychotic disorders obtained from semi-structured clinical interviews for 289 persons. Diagnoses were derived from administrative datasets using four algorithms; 'At least one' diagnosis, 'Last' or most recent diagnosis, 'Modal' or most frequently occurring diagnosis, and 'Hierarchy' in which a diagnostic hierarchy was applied. Agreements between algorithm-based and reference diagnoses for overall presence/absence of psychosis and for specific diagnoses of schizophrenia, schizoaffective disorder, and affective psychosis were examined using estimated prevalence rates, overall agreement, ROC analysis, and kappa statistics. RESULTS: For the presence/absence of psychosis, the most sensitive and least specific algorithm ('At least one' diagnosis) performed best. For schizophrenia, 'Modal' and 'Last' diagnoses had greatest agreement with reference diagnosis. For affective psychosis, 'Hierarchy' diagnosis performed best. Agreement between clinical and reference diagnoses was no better than chance for diagnoses of schizoaffective disorder. Overall agreement between administrative and reference diagnoses was modest, but may have been limited by the use of participants who had been screened for likely psychosis prior to assessment. CONCLUSION: The choice of algorithm for extracting a psychosis diagnosis from administrative datasets may have a substantial impact on the accuracy of the diagnoses derived. An 'Any diagnosis' algorithm provides a sensitive measure for the presence of any psychosis, while 'Last diagnosis' is more accurate for specific diagnosis of schizophrenia and a hierarchical diagnosis is more accurate for affective psychosis. PMID- 24789455 TI - Disentangling the influence of neighborhood and individual characteristics on early residential mobility among newly diagnosed patients with schizophrenia: a multilevel analysis. AB - PURPOSE: Early residential mobility of schizophrenic patients may relate to discontinuity of treatment and adverse outcome. However, factors influencing early residential mobility of these patients are still poorly examined. The aim of this study was to disentangle the influence of individual and neighborhood characteristics on early residential mobility of schizophrenic patients. METHODS: The study used administrative data of 13, 400 individuals newly diagnosed with schizophrenia in Quebec between 2001 and 2002. These individuals were nested in 163 different health territories. Multilevel analyses were used to assess the contribution of individual and neighborhood characteristics on early residential mobility. RESULTS: The final model indicates that at the individual level, being men, wonder patients and physical comorbidity increased the likelihood of early residential mobility whereas older patients were less likely to migrate earlier. The health territory level explains about 7 % of the variation of early residential mobility and variables influencing residential mobility at this level are the fourth and the third quartiles of the population density. CONCLUSIONS: Factors influencing early residential mobility of schizophrenic patients are located at both individual and neighborhood levels. This suggests that policies targeting only one-level factors are unlikely to significantly delays early residential mobility. PMID- 24789456 TI - Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors. AB - In the last few decades, mental health research has increasingly provided evidence supporting the role of inflammation in pathogenesis, course and treatment of mental disorders. With such a steep incline of research, resulting in a wealth of emerged findings, it has become difficult to follow developments within the field. The present review sets out to present the recent developments and to give an overview of the inflammatory profiles of depression, psychosis and bipolar disorder, as well as variations within these disorders. Moreover, mediating factors such as social environment and childhood experience are discussed, both in terms of their potential in elucidating the complex interface between the inflammation and other closely related biological systems, as well as the possibly confounding impact of various lifestyle factors. Whilst many issues in this fascinating area of research remain to be fully understood and elaborated, all current evidence suggests that inflammation plays a key role in mental disorders and may open up novel avenues for clinical treatment. PMID- 24789459 TI - Efficacy and safety of antifungal additives in Optisol-GS corneal storage medium. AB - IMPORTANCE: Optisol-GS, the most common corneal storage medium in the United States, contains antibacterial but no antifungal supplementation. Most postkeratoplasty endophthalmitis and keratitis cases are now of a fungal origin. OBJECTIVE: To assess the efficacy and safety of voriconazole and amphotericin B in reducing Candida species contamination of Optisol-GS under normal storage conditions. DESIGN, SETTING, AND PARTICIPANTS: In vitro laboratory study using 15 pairs of research-grade donor corneas and 20-mL vials of Optisol-GS. INTERVENTIONS: Twenty vials of Optisol-GS were supplemented with either voriconazole at 1*, 10*, 25*, or 50* minimum inhibitory concentration (MIC) or amphotericin B at 0.25*, 0.5*, 1*, or 10* MIC. Known concentrations of Candida albicans and Candida glabrata were each added to a set of vials. Safety studies were performed by separating 15 pairs of donor corneas into unsupplemented Optisol-GS or Optisol-GS plus an antifungal. MAIN OUTCOMES AND MEASURES: Efficacy outcomes were viable fungal colony counts determined from samples taken on days 2, 7, and 14 immediately after removal from refrigeration and after warming to room temperature for 2 hours. Safety outcomes included percentage of intact epithelium and endothelial cell density on days 0, 7, and 14, as well as percentage of nonviable endothelial cells by vital dye staining on day 14. RESULTS: Growth of C albicans and C glabrata was observed in all voriconazole supplemented vials. In contrast, there was no growth of either organism in amphotericin B-supplemented vials, except at 0.25* and 0.5* MIC on day 2, when viable counts of C glabrata were reduced by 99% and 96%, respectively. Compared with paired controls, with the exception of Optisol-GS plus amphotericin B at 10* MIC, donor corneas in supplemented Optisol-GS appeared to have no difference in endothelial cell density reduction, percentage of intact epithelium, or percentage of nonviable endothelial cells. CONCLUSIONS AND RELEVANCE: The addition of amphotericin B to Optisol-GS may significantly improve activity against contamination with Candida species, the primary cause of fungal infection after corneal transplantation. This study found significant endothelial toxic effects at the maximal concentration of amphotericin B. PMID- 24789460 TI - Additive effects of EGF and IL-1beta regulate tumor cell migration and invasion in gastric adenocarcinoma via activation of ERK1/2. AB - Growth and inflammatory factors are associated with poor prognosis in gastric adenocarcinoma (GA); however, the additive effects of growth and inflammatory factors in GA remain unclear. In this study, we investigated the ability of epidermal growth factor (EGF) and interleukin (IL-1beta) to activate extracellular signal-regulated kinase (ERK)1/2 in GA cells, and correlated the relationships between their roles with the metastatic potential both in GA cells and GA tissues. The effects of EGF, IL-1beta and EGF plus IL-1beta in AGS and MKN 45 GA cells were examined using western blotting, Transwell migration and invasion assays, immunocytochemical staining and an activator protein (AP)-1 luciferase reporter gene assay, and was further characterized in GA tissues by immunohistochemistry. The results exhibited that EGF and IL-1beta additively activated ERK1/2, increased migration and invasion than either EGF or IL-1beta alone in AGS and MKN-45 cells. The mechanisms were involved in upregulating MMP-9 expression through increasing AP-1 transcriptional activity via ERK1/2 pathway; these effects were dose-dependently inhibited by silencing ERK1/2 or using U0126. In vivo data also confirmed that the overexpression of p-ERK1/2 in GA tissues correlated well with the EGF, IL-1beta, EGF plus IL-1beta, and was associated with metastasis, which was well correlation with the expression of MMP-9 and c fos (AP-1). The results demonstrate that growth and inflammatory factors play an important role in metastasis of GA by additively activating ERK-1/2 and AP-1, and upregulating MMP-9. As both cytokines contribute to the migration and invasion of GA cells, EGF/IL-1beta/ERK1/2 pathways may be key pathways closely associated with GA progression. PMID- 24789461 TI - Characterization of an organic solvent-tolerant lipase from Haloarcula sp. G41 and its application for biodiesel production. AB - A haloarchaeal strain G41 showing lipolytic activity was isolated from the saline soil of Yuncheng Salt Lake, China. Biochemical and physiological characterizations along with 16S rRNA gene sequence analysis placed the isolate in the genus Haloarcula. Lipase production was strongly influenced by the salinity of growth medium with maximum in the presence of 20% NaCl or 15% Na2SO4. The lipase was purified to homogeneity with a molecular mass of 45 kDa. Substrate specificity test revealed that it preferred long-chain p-nitrophenyl esters. The lipase was highly active and stable over broad ranges of temperature (30-80 degrees C), pH (6.0-11.0), and NaCl concentration (10-25%), with an optimum at 70 degrees C, pH 8.0, and 15% NaCl, showing thermostable, alkali-stable, and halostable properties. Enzyme inhibition studies indicated that the lipase was a metalloenzyme, with serine and cysteine residues essential for enzyme function. Moreover, it displayed high stability and activation in the presence of hydrophobic organic solvents with log Pow >= 2.73. The free and immobilized lipases from strain G41 were applied for biodiesel production, and 80.5 and 89.2% of yields were achieved, respectively. This study demonstrated the feasibility of using lipases from halophilic archaea for biodiesel production. PMID- 24789462 TI - Cone implicit time as a predictor of visual outcome in macular hole surgery. AB - PURPOSE: To investigate whether preoperative retinal function measured by full field ERG and multifocal ERG is correlated to postoperative visual acuity after macular hole surgery. METHODS: Standard pars plana vitrectomy with removal of the internal limiting membrane (ILM) was performed on 19 consecutive patients undergoing macular hole surgery. Intraocular gas tamponade with a C2F6 gas-air mixture was employed, followed by a face-down position for at least 5 days. The patients were examined with the ETDRS chart, full-field ERG (Espion), multifocal ERG (Veris 6), and optical coherence tomography (OCT) preoperatively, and 6 weeks, 6 months, and 18 months after surgery. RESULTS: The cone 30-Hz flicker implicit time in the full-field ERG reflecting retinal function was prolonged (p = 0.016) before surgery compared to aged-matched controls. After macula hole surgery, longstanding alteration of cone function reflected by mfERG and full field ERG was verified 18 months after surgery. The prolonged cone 30-Hz flicker implicit time in the full-field ERG before surgery was significantly correlated to the ETDRS visual acuity 6 months postoperatively (p = 0.03). CONCLUSIONS: Preoperative evaluation of retinal function with multifocal ERG and full-field ERG improves the understanding of the retinal recovery process after macular hole surgery. The cone implicit time in full-field 30-Hz flicker ERG could be a valid predictor of long-term visual outcome, which may be useful for selecting patients suitable for surgery. PMID- 24789463 TI - Investigating retinal toxicity of tempol in a model of isolated and perfused bovine retina. AB - PURPOSE: Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl) is a membrane permeable superoxide dismutase and potentially neuroprotective substance. This study evaluates the retinal tolerance of 0.5 mM, 1 mM, 2 mM, and 5 mM tempol measured by the electroretinogram (ERG) of an isolated and perfused retina whole mount. METHODS: For functionality testing, bovine retinas were prepared and perfused with an oxygen-saturated standard solution, and the ERG was recorded until stable b-wave amplitudes were reached. Tempol concentrations of 0.5 mM, 1 mM, 2 mM, and 5 mM were tested for 45 minutes. To investigate the effects on photoreceptor function, 1 mM aspartate was added to suppress the b-wave and obtain isolated a-waves. ERG amplitudes were monitored for 100 minutes. RESULTS: While no toxic effects for concentrations of 0.5 mM and 1 mM tempol could be detected, concentrations of 2 mM tempol and higher caused statistically significant negative effects on the b-wave amplitude (-38 %, p = 0.02 for 2 mM; 54 %, p = 0.02 for 5 mM). The a-wave amplitude remained stable even at higher concentrations. CONCLUSIONS: Although the photoreceptors seem to have a tolerance to high concentrations of tempol, higher intravitreal concentrations than 1 mM should be considered critical. PMID- 24789464 TI - Anti-neovascular effect of chondrocyte-derived extracellular matrix on corneal alkaline burns in rabbits. AB - PURPOSE: We investigated the effect of a chondrocyte-derived extracellular matrix (CDECM) on experimental corneal alkaline burns in rabbits. METHODS: Corneal neovascularization (NV) was induced by applying an 8-mm filter paper soaked in 1 N NaOH to the right central corneas of rabbits for 1 minute. Ten days later, the rabbits were randomly divided into three groups: the alkaline burn group, the CDECM transplantation group, and the human amniotic membrane (HAM) transplantation group. The left eyes were used as controls. CDECM and HAM were transplanted onto the corneal surface to completely cover the resected area and were subsequently sutured. On the 10th day after transplantation, the structural changes of the cornea were analyzed histologically. We examined the effects of CDECM on clinical NV features and on the expression of corneal NV markers. RESULTS: The alkaline burn produced significant NV and increased the corneal thickness. On day 10 after transplantation, the thickness, NV and opacity of the cornea were markedly decreased in the CDECM group (p < 0.001). However, the HAM transplantation group did not exhibit improvements in these clinical parameters, and there were no significant differences relative to the burn group. In addition, the use of CDECM improved the healing of the cornea following the alkaline burn by disrupting the corneal epithelial proliferation and reducing the fibrotic changes of the stroma. The hallmarks of NV were significantly induced in the subepithelium by the alkaline burn, and these levels were also suppressed by CDECM. The CDECM suppressed corneal NV by inhibiting nuclear factor-kappa B (NF kappaB) activation by blocking the PKC and Akt signaling pathways. CONCLUSIONS: CDECM transplantation was markedly effective in healing alkali-burned corneas by modulating the translocation of NF-kappaB to the nucleus, thereby representing a promising material for the noninvasive treatment of ocular surface disease. PMID- 24789465 TI - Aflibercept for inflammatory choroidal neovascularization with persistent fluid on intravitreal ranibizumab therapy. PMID- 24789466 TI - Immunohistopathologic features of surgically excised overhanging filtering bleb: myofibroblasts after filtration surgery--a case report. PMID- 24789467 TI - Megahertz ultra-wide-field swept-source retina optical coherence tomography compared to current existing imaging devices. AB - BACKGROUND: To investigate the image quality of wide-angle cross-sectional and reconstructed fundus images based on ultra-megahertz swept-source Fourier domain mode locking (FDML) OCT compared to current generation diagnostic devices. METHODS: A 1,050 nm swept-source FDML OCT system was constructed running at 1.68 MHz A-scan rate covering approximately 70 degrees field of view. Twelve normal eyes were imaged with the device applying an isotropically dense sampling protocol (1,900 * 1,900 A-scans) with a fill factor of 100 %. Obtained OCT scan image quality was compared with two commercial OCT systems (Heidelberg Spectralis and Stratus OCT) of the same 12 eyes. Reconstructed en-face fundus images from the same FDML-OCT data set were compared to color fundus, infrared and ultra-wide field scanning laser images (SLO). RESULTS: Comparison of cross-sectional scans showed a high overall image quality of the 15* averaged FDML images at 1.68 MHz [overall quality grading score: 8.42 +/- 0.52, range 0 (bad)-10 (excellent)] comparable to current spectral-domain OCTs (overall quality grading score: 8.83 +/- 0.39, p = 0.731). On FDML OCT, a dense 3D data set was obtained covering also the central and mid-peripheral retina. The reconstructed FDML OCT en-face fundus images had high image quality comparable to scanning laser ophthalmoscope (SLO) as judged from retinal structures such as vessels and optic disc. Overall grading score was 8.36 +/- 0.51 for FDML OCT vs 8.27 +/- 0.65 for SLO (p = 0.717). CONCLUSIONS: Ultra-wide-field megahertz 3D FDML OCT at 1.68 MHz is feasible, and provides cross-sectional image quality comparable to current spectral-domain OCT devices. In addition, reconstructed en-face visualization of fundus images result in a wide-field view with high image quality as compared to currently available fundus imaging devices. The improvement of >30* in imaging speed over commercial spectral-domain OCT technology enables high-density scan protocols leading to a data set for high quality cross-sectional and en-face images of the posterior segment. PMID- 24789468 TI - Adsorption of 2,3,7,8-tetrochlorodibenzo-p-dioxins on intrinsic, defected, and Ti (N, Ag) doped graphene: a DFT study. AB - As one of the most hazardous substances in the world, dioxins have received continuous interest in chemistry, materials, and environmental sciences. The rapid detection and capture of carcinogenic 2,3,7,8-tetrochlorodibenzo-p-dioxin (TCDD) are particularly challenging in the fields of materials and environmental sciences. In this study, density functional theory (DFT) method was applied to systematically investigate the interactions between TCDD and different types of graphene samples. The results reveal that the initial configuration of TCDD affects the interactions to a certain extent. As TCDD molecule is parallel to the graphene sheets, the interactions are the largest for all three types of graphene samples (intrinsic, defected and doped). In addition, the "TCDD" capture ability of graphene can be greatly improved by Ti doping. Our study facilitates the rational design of efficient sensors for a variety of applications in environmental science and engineering. PMID- 24789469 TI - Theoretical investigation of a "turn-on" fluorescent sensor induced by complexation of mercury(II) ion. AB - A selective Hg2+/Cu2+-induced OFF-ON-OFF type of signaling pattern was calculated by density functional theory and time-dependent density functional theory method. Geometries, molecular orbitals, and interaction thermal energies were evaluated at the restricted hybrid Becke's three-parameter exchange functional using 6 31+G(d) basis set and relativistic effective core potentials. The optimized geometric structures are used to perform natural bond orbital (NBO) analysis. The main type of driving force is the electrostatic interactions between the metal ions and the electron-donating oxygen and nitrogen atoms. Maximum absorption spectrums of the complexes are mainly contributed by the HOMO -> LOMO transition. The high selectivity of ligand H2NB for Hg2+ results in a "turn-on" fluorescent phenomenon. PMID- 24789470 TI - The complexities of hormonal influences and risk of Parkinson's disease. PMID- 24789473 TI - Respiratory medicine team of the year. PMID- 24789471 TI - The stimulatory effects of Stewartia koreana extract on the proliferation and migration of fibroblasts and the wound healing activity of the extract in mice. AB - Stewartia koreana (S. koreana) has been used in the treatment of inflammatory diseases, such as acute gastroenteritis and aches, in Korean folk medicine and has been reported to have a number of biological activities, such as anti inflammatory activity and the promotion of angiogenesis. In this study, we aimed to determine the effects of S. koreana extract (SKE) and its components on dermal fibroblast growth and migration, and to investigate the wound healing activity of the extract in mice. In vitro experiments revealed that the numbers of SKE treated cells increased by approximately 2.5-- and 3.7-fold with 50 and 100 ug/ml of SKE, respectively. 5-bromo-2'-deoxy-uridine (BrdU) incorporation was also increased in the SKE-treated cells by 2.3-fold. SKE promoted the migration of human skin fibroblasts and, among the isolated compounds, hyperin increased the proliferation and migration of the fibroblasts to almost the same degree as SKE. Western blot analysis demonstrated that SKE stimulated the MEK/ERK1/2 and PI3K/Akt signaling pathways. In in vivo experiments, the SKE-treated wound lesions of mice decreased by approximately 7% in diameter after 2 days of treatment with SKE compared with the wound lesions on the 1st day of the experiment. On the 9th day of treatment, the diameter of the lesions was further reduced by approximately 83% in the SKE-treated wound areas compared with the wound areas on the 1st day of treatment. Our results demonstrate that methanol extracts of S. koreana leaves promote the proliferation and migration of skin fibroblasts and possess effective wound healing activity through the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways. Hyperin was identified as an active compound responsible for the stimulation of fibroblast growth and migration. PMID- 24789472 TI - Addition of CF3 across unsaturated moieties: a powerful functionalization tool. AB - In the last few years, the efficient introduction of trifluoromethyl groups in organic molecules has become a major research focus. This review highlights the recent developments enabling the incorporation of CF3 groups across unsaturated moieties, preferentially alkenes, and the mechanistic scenarios governing these transformations. We have specially focused on methods involving the simultaneous formation of C-CF3 and C-C or C-heteroatom bonds by formal addition reactions across pi-systems, as such difunctionalization processes hold valuable synthetic potential. PMID- 24789474 TI - LL37 peptide@silver nanoparticles: combining the best of the two worlds for skin infection control. AB - Capping silver nanoparticles with LL37 peptide eradicates the antiproliferative effect of silver on primary skin cells, but retains the bactericidal properties of silver nanoparticles with activities comparable to silver nitrate or silver sulfadiazine. In addition, LL37 capped silver nanoparticles have anti-biofilm formation activity. PMID- 24789475 TI - Association between serum magnesium and anemia: china health and nutrition survey. AB - The role of magnesium in anemia remains unclear. We aimed to investigate the prevalence of anemia and its association with serum magnesium in a nationally representative sample. A total of 8,511 participants aged 18 years and over were recruited in this cross-sectional survey in 2009. Anemia was defined as hemoglobin concentration less than 130 g/l for men and less than 120 g/l for women. Multiple logistic regression models were applied to explore the association of magnesium and anemia. The prevalence of anemia in total was 14.0% with 8.8% for men and 18.5% for women (P<0.0001), respectively. The interaction terms between magnesium and gender and ferritin were significant (P<0.001). In men with serum ferritin>=15 ng/ml, compared with the first quartile of magnesium, the odds ratios (ORs) and 95% confidence intervals (CIs) for those in the second, third, and fourth quartile of magnesium were 0.65 (0.46, 0.91), 0.77 (0.55, 1.09), and 0.63 (0.45, 0.89), respectively, after adjusting multiple confounders. Likewise, in women with serum ferritin>=15 ng/ml, the corresponding ORs (95% CIs) were 0.71 (0.56, 0.91), 0.64 (0.49, 0.84), and 0.53 (0.40, 0.71). The associations between magnesium and anemia were not significant in neither men nor women with serum ferritin<15 ng/ml. Serum magnesium was inversely associated with anemia in both men and women, in particular among adults with high serum ferritin levels. PMID- 24789477 TI - Effects of feeding silkworm with nanoparticulate anatase TiO2 (TiO2 NPs) on its feed efficiency. AB - This study aimed to investigate the effects of titanium dioxide nanoparticles (TiO2 NPs) on feed efficiency of silkworm (Bombyx mori) (B. mori). The results showed that the amount of ingested food was increased by 3.31%, the percentage of ingested food was increased by 16.36%, the instar was prolonged by 6.77 h, the body mass of mature silkworm was increased by 11.41%, the cocoon mass was increased by 5.47%, the cocoon shell mass was increased by 9.80%, and the ratio of cocoon shell was increased by 3.54%. Average cocoon filament length, reelability, and neatness were increased by 3.15, 17.57, and 1.72%, respectively, whereas the cocoon filament size was decreased by 0.19%. The gene expression profiles were also examined with digital gene expression (DGE). The results showed that among 4,011 genes detected, 127 genes were differentially expressed including 57 genes whose expression was upregulated and 70 genes whose expression was downregulated. The expression levels of five genes related to metabolism were verified with quantitative real-time PCR, and the results were consistent with the DGE data. The activities of three major digestive enzymes in the midgut were also assayed; the results showed that the activities of trehalase, protease, and lipase in TiO2 NP-fed group were increased by 42.55, 78.13, and 33.33%, respectively. These results indicate that feeding B. mori with TiO2 NPs can stimulate the transcriptional level of genes related to digestion and absorption of nutrients in the midgut and increase the activities of trehalase, protease, and lipase and, thus, increase the feed efficiency of B. mori. PMID- 24789476 TI - The influence of the occupational exposure to heavy metals and tobacco smoke on the selected oxidative stress markers in smelters. AB - The aim of the study was to verify if there is any association between exposure to Cu, Zn, Cd, Pb, As and the formation of malondialdehyde (MDA), 8 hydroxydeoxyguanosine (8-OHdG), advanced oxidation protein products (AOPP), and whether in this process cigarette smoking plays a role. The investigations were performed in the 352 smelters occupationally exposed to heavy metals and 73 persons of control group. Metals concentration was determined by atomic absorption spectrometry. MDA and AOPP concentrations were determined by spectrophotometric methods. The concentration of 8-OHdG was determined by ELISA method. It was demonstrated an increased Cu concentration in smoking smelters compared to non-smoking control group. It was noted no differences in Zn and Mg concentrations between the examined groups. Pb concentration was more than sixfold higher in the group of smoking smelters and about fivefold higher in the group of non-smoking smelters compared to the control groups (smokers and non smokers). It was shown that Cd concentration in the blood was nearly fivefold higher in the smoking control group compared to the non-smoking control group and more than threefold higher in the group of smoking smelters compared to non smoking. It was shown an increased As concentration (more than fourfold) and decreased Ca concentration in both groups of smelters compared to control groups. In groups of smelters (smokers and non-smokers), twofold higher MDA and AOPP concentrations, and AOPP/albumin index compared to control groups (smokers and non-smokers) were shown. Tobacco smoke is the major source of Cd in the blood of smelters. Occupational exposure causes accumulation of Pb in the blood. Occupational exposure to heavy metals causes raise of MDA concentration and causes greater increase in AOPP concentration than tobacco smoke. PMID- 24789478 TI - Peripheral blood lymphocyte typing as a useful tool to objectify the oral mucosa patch test in the diagnosis of allergic contact mucositis to nickel. AB - Nickel (Ni) exposure through the intestinal mucosa may cause a hypersensitivity reaction recently defined as allergic contact mucositis (ACM). This condition is identifiable by the oral mucosa patch test (omPT), a qualitative and subjective examination that requires clinical expertise. Our aim was to evaluate if a peripheral blood lymphocyte typing performed before and after the omPT for Ni may be able to objectify this examination for diagnostic purposes. Thirty patients with symptoms referable to the ingestion of Ni-rich foods were subjected to omPT for Ni. Before and after the omPT, each patient underwent blood sampling for the typing of total lymphocytes and their subsets (T, T helper or Th, T cytotoxic or Tc, B, natural killer or NK). Statistical analysis was performed by Student t test and receiver operating characteristic (ROC) curve analysis. According to the omPT outcomes, 18 patients were defined as Ni-sensitive and the remaining 12 as controls. In Ni-sensitive patients, the number of total, T, Th, Tc, and B lymphocytes/MUL whole blood increased after the omPT (p<0.0001 for the first three, p=0.0004 and p=0.0001 for the last two lymphocyte types). No omPT dependent lymphocyte increase was observed in controls. The post/pre omPT cell ratio, especially if calculated for Th lymphocytes, appears to be an effective index for diagnostic purposes (sensitivity=100%, specificity=83.3%, Youden index=0.833, area under curve (AUC)=0.926, p<0.0001). In conclusion, the peripheral blood lymphocyte typing with calculation of post/pre omPT cell ratio has the potential to support the omPT in diagnosing ACM, with the advantage of providing quantitative and objective data. PMID- 24789479 TI - Thyroid function and serum copper, selenium, and zinc in general U.S. population. AB - Association of the levels of serum selenium (Se), zinc (Zn), and copper (Cu) with thyroid function was assessed by analyzing data from National Health and Nutrition Examination Survey for the cycle 2011-2012. Thyroid function variables analyzed were as follows: thyroid-stimulating hormone (TSH), free and total triiodothyronine (FT3, TT3), free and total thyroxine (FT4, TT4), and thyroglobulin (TGN). Regression models with log-transformed values of thyroid hormones as independent variables and age, race/ethnicity, smoking and iodine sufficiency status, respondents' education, and levels of Se, Zn, and Cu as dependent variables were fitted. For males, levels of Zn were associated with decreased levels of FT4 and TT4, and levels of Cu were associated with increased levels of FT4 and TT4. For females, levels of Cu were associated with increased levels of TT3 and TT4. Smoking was found to be associated with lower levels of TSH and higher levels of TGN in males. Smoking was found to be associated with lower levels of TT4 in females. Males had about 5-10% higher levels of both Se and Zn, but as much as 20% lower levels of Cu than females. Smoking was associated with lower levels of Zn, but higher levels of Cu in males. PMID- 24789480 TI - Medical student education in psychiatry: an international affair. PMID- 24789481 TI - Evaluating the utility, reliability, and validity of a resident performance evaluation instrument. AB - OBJECTIVE: The primary goal of this project was to create and evaluate the utility, validity, and reliability of an instrument assessing resident performance during child and adolescent psychiatry (CAP) training. In three stages, the instrument was developed and evaluated for utility in assessing skills critical to CAP. Items on the Global Assessment Evaluation (GAE) were derived from the six core competencies identified by the American College of Graduate Medical Education (ACGME). Secondary goals included producing an instrument that could be used by other CAP training programs and describing a process that could be followed by training programs to create their own assessment instruments. METHODS: Faculty members developed a CAP resident performance evaluation instrument. In a three-stage process, faculty utilized the tool to evaluate residents during and after rotations. Statistical findings guided revisions to improve the utility and reliability of the instrument. For the final version of the GAE, intra-class correlation coefficients were calculated to assess inter-rater reliability, and Principal Components Analysis provided further insight into the dimensions of resident assessment. RESULTS: The final version of the GAE showed overall and construct validity by capturing significant differences among residents and matched faculty members' overall impressions of resident performance. Intra-class correlation coefficient values for the overall score (0.945) and individual scales showed good reliability. Resident performance was not correlated with rotation site or model of care. CONCLUSIONS: The GAE has proved a valuable instrument in tracking the progress, strengths, and weaknesses in resident performance over the course of training. Data from multiple evaluations over time provide useful information about resident performance in a way that one or few evaluations does not. This finding is consistent with the practice of semiannual reviews and the new Clinical Competency Committees, both of which are required by the ACGME. PMID- 24789482 TI - From networking to next-working: how an academic department "retreated" and advanced at the same time. AB - Department-wide retreats conducted at periods of transition can enrich and benefit academic departments in several ways. Here, the authors describe the organization, conduct, and immediate outcomes of a department-wide retreat in a university department of psychiatry intended to (1) foster networking and communication among faculty who often work in "silos" and (2) invite the faculty to provide "internal consultations" regarding aspirational strategic goals and recommendations for short-term actionable tactics to address these goals. The retreat featured an evening networking and socializing poster session followed by a day-long event consisting of small group and large group interactive sessions. Participants were 120 faculty members including 44 new and younger faculty members who prepared and presented posters about themselves and their work. A variety of aspirational goals and specific recommendations for follow-up emerged from small groups were discussed in plenary sessions and were subsequently summarized and distributed to the faculty to be addressed by ongoing workgroups. Immediate informal feedback suggests that conducting and acting on recommendations ensuing from academic department retreats can foster at least a short-term sense of shared community and purpose, network faculty, identify commonly held values and aspirational goals, and potentially stimulate formation of innovative affinity groups and collaborations. Longer-term workgroup efforts and outcome assessments are required to assess the enduring results and value of such undertakings. PMID- 24789483 TI - [Editor's note]. PMID- 24789484 TI - [Health reform and the creation of the Sistema Unico de Saude: notes on contexts and authors]. AB - Within the context of the return to democracy, the new constitution enacted in 1988 transformed health into an individual right and initiated the process of creating a public, universal and decentralized health system, profoundly altering the organization of public health in Brazil. This article discusses the main institutional, political and social aspects of this health reform, along with the changes, the continuities and the major initiatives, based on the literature published by the most widely read authors in this field of study. Without purporting to offer an exhaustive analysis, we discuss how the historiography written by authors who were also actors in the process assess its main features, along with the genesis of the process and the legacy of health reform in Brazil. PMID- 24789485 TI - [Political challenges facing the consolidation of the Sistema Unico de Saude: a historical approach]. AB - This article investigates the circumstances in which Brazil's sanitation reform was conceived and the Sistema Unico de Saude (SUS) was constructed. A brief analysis is conducted of Brazil's political transition to democracy, focusing on three political challenges facing the consolidation of SUS: its weak support base amongst workers, competition with the private sector, and the fragmentation of its administration caused by its municipalization. Finally, the changes in the scenario caused by the weakening of neoliberalism since the 2008 crisis, the reemergence of a multipolar political scenario internationally, and the financing conditions of the Brazilian State are described. PMID- 24789486 TI - [The history of the public health reform in Brazil and of the Sistema Unico de Saude: changes, continuities, and the current agenda]. AB - The paper offers a historical retrospective of Brazil's Sistema Unico de Saude (SUS), including its background and its legacy on its current design. It begins describing some of the system's structural problems, especially the co-existence of a public system alongside a private one. It identifies problems that have hampered a firmer solidification of SUS, while it also highlights the immense import of establishing a unified, universal system in a country the size of Brazil. The discussion includes the effects of the system, which has represented a major change in the field of social rights, introducing new actors, and internalizing the notion of health as a right. Lastly, recent developments that have put SUS on the public agenda are discussed. PMID- 24789487 TI - [Considerations on the Sistema Unico de Saude in the twenty-first century: an interview with Ligia Bahia]. AB - This interview with Ligia Bahia explores evaluations of the first 25 years of Brazil's Sistema Unico de Saude (SUS) and analyzes the project's progress, impasses, and missteps. Bahia is critical of both tendencies currently found within SUS: the one that sees the system as aimed at equity and the other posing equality as its goal. She criticizes the ambivalence that various spheres of government have displayed in their decisions regarding large corporate groups and private health insurance plans, which conflict with the ideas of SUS. She evaluates the participation of doctors and other healthcare professionals in the system. Lastly, she analyzes the emergence of identity politics, which are missing from the public health reform project, whose emphasis was on equality. PMID- 24789488 TI - [A better Brazil]. AB - Many countries in the Americas describe themselves as "nations of immigrants." In the United States, the myth of the "promised land" suggests that foreigners better themselves upon arrival because the nation is intrinsically great. In Brazil, however, the relationship between immigration and national identity is different. Many intellectuals, politicians, and cultural and economic leaders saw (and see) immigrants as improving an imperfect nation that has been tainted by the history of Portuguese colonialism and African slavery. As a result, immigrants were often hailed as saviors because they modified and improved Brazil, not because they were improved by Brazil. This "improvement" took place through absorption, mixture and with the use of increasingly flexible racial and ethnic categories. PMID- 24789489 TI - [Intellectual exchange between Germany and Latin America: an interview with Stefan Rinke]. AB - Current and former students of the Casa de Oswaldo Cruz/Fiocruz interviewed German historian Stefan Rinke, of the Freie Universitat Berlin, who specializes in examining the historical development of Latin America as it fits into the international context. Rinke's work uses dimensions such as economic and diplomatic relations, migratory flows, and ethnic conflict as tools in his analyses of the networks of interdependence that have tied Latin America to Europe and the USA. His lens goes beyond the Latin American continent to approach globalization as a historical process, with national and regional contexts placed within a general framework. In this interview, Rinke talks about his academic career, global and transnational history, and joint projects between Germany and Latin America. PMID- 24789493 TI - [Institutionalization of integrative, complementary practices in Sistema Unico de Saude!?]. PMID- 24789494 TI - [A critique of Brazil's current research ethics committees]. PMID- 24789497 TI - Interface solution isoelectric focusing with in situ MALDI-TOF mass spectrometry. AB - This paper describes a simple and reusable microfluidic device combining solution IEF (sIEF) with MALDI-TOF MS for rapid proteomic and metabolic analysis of microliter samples. The device contains two glass plates with nanoliter microwell arrays, which can be assembled to form a fluidic path for sIEF separation, and reconfigured for dividing separated bands. One microliter samples can be loaded and separated by sIEF into static bands in 10~30 min. After a slipping operation, the static IEF bands can be divided into nanoliter droplets in microwells without mobilization, and the device can be opened for in situ MALDI-TOF MS detection without loss of separation resolution. The performance of the device is characterized by separating and identifying intact proteins. The applicability in metabolic analysis is demonstrated by preliminary experiments on profiling small molecular metabolites in cerebrospinal fluid microdialysates from rat brain. PMID- 24789498 TI - Integrating microfluidic generation, handling and analysis of biomimetic giant unilamellar vesicles. AB - The key roles played by phospholipids in many cellular processes, has led to the development of model systems, to explore both lipid-lipid and lipid-peptide interactions. Biomimetic giant unilamellar vesicles represent close facsimiles of in vivo cellular membranes, although currently their widespread use in research is hindered by difficulties involving their integration into high-throughput techniques, for exploring membrane biology intensively in situ. This paper presents an integrated microfluidic device for the production, manipulation and high-throughput analysis of giant unilamellar vesicles. Its utility is demonstrated by exploring the lipid interaction dynamics of the pore-forming antimicrobial peptide melittin, assessed through the release of fluorescent dyes from within biomimetic vesicles, with membrane compositions similar to mammalian plasma membranes. PMID- 24789499 TI - Patients with bone metastases from solid tumors initiating treatment with a bone targeted agent in 2011: a descriptive analysis using oncology clinic data in the US. AB - PURPOSE: Three bone-targeted agents (BTAs) are approved in the USA for prevention of bone complications among solid tumor patients with bone metastases: two intravenous bisphosphonates (IV BP) (pamidronate and zoledronic acid), and one subcutaneous receptor activator of nuclear factor-kappaB (RANK) ligand inhibitor (denosumab). Using electronic medical record data from outpatient community and hospital-affiliated oncology clinics, we examined the characteristics of patients who initiated treatment with a BTA in 2011 and followed them for a maximum of 12 months. METHODS: Adult patients with bone metastasis secondary to solid tumors newly treated with a BTA during 2011 were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database. We examined patient characteristics at BTA initiation, treatment patterns, and compliance during a 12 month period. Sensitivity analyses were performed in a subgroup of patients who had confirmed 12 months of follow-up data. RESULTS: Denosumab patients (N = 1,594) were older (65 % >=65 years vs. 60 % >=65 years), further along in their disease progression (time since bone metastasis diagnosis: 16 % >=2 years vs. 10 % >=2 years), less likely to switch BTA (overall: 6 vs. 14 %; subgroup: 8 vs. 19 %), and more compliant with treatment (overall: median doses of 7 vs. 4; subgroup: 11 vs. 8) compared to IV BP patients (N = 1,975). Findings were consistent across gender, age, tumor type, naive, and transition strata. CONCLUSIONS: Patients receiving denosumab and IV BPs may differ. Despite higher age and more advanced disease, patients treated with denosumab are more likely to stay on treatment and have better compliance. PMID- 24789500 TI - Family caregivers' distress levels related to quality of life, burden, and preparedness. AB - OBJECTIVE: Family caregivers (FCGs) caring for loved ones with lung cancer are at risk for psychological distress and impaired quality of life (QOL). This study explores the relationship between FCGs' distress, per the distress thermometer (DT) and FCGs' QOL, burden, and preparedness. The purpose is to identify types of problems unique to FCGs in cancer care. METHODS: Family caregivers of patients diagnosed with non-small cell lung cancer were recruited from an adult outpatient setting at a comprehensive cancer center. Questionnaires included demographic information, City of Hope QOL Scale-Family Version, Caregiver Burden Scale, FCG preparedness, and DT. Baseline data were utilized for this analysis. RESULTS: Of the FCGs (N = 163), 68% were spouses, 64% female, and 34% worked full-time. FCG age ranged from 21 to 88 years with a mean of 57 years. FCGs cared for patients with non-small cell lung cancer stage I-III (44%) and stage IV (56%). Psychological distress (DT mean = 4.40) was moderate. DT scores were highly correlated with seven of the eight explanatory variables. Secondary principal components analysis of the explanatory variables combined correlated variables into three constructs identified as self-care component, FCG role component, and FCG stress component. Simultaneous multiple regression of distress onto the three components showed they accounted for 49% of the variance in distress. CONCLUSION: This exploration of FCGs' concerns associated with elevated distress scores, as measured by the DT, helped identify three component problem areas. These areas warrant further psychosocial assessment and intervention to support FCGs as they care for the patient with cancer. PMID- 24789501 TI - Epstein-Barr virus-positive diffuse large B-cell lymphoma association is not only restricted to elderly patients. AB - Diffuse large B-cell lymphoma (DLBCL), the most common group of malignant lymphomas, account for 30% of adult non-Hodgkin lymphomas. The 2008 World Health Organization (WHO) classification included a new entity, Epstein-Barr virus (EBV)+ DLBCL of the elderly, affecting patients aged 50 years or older. However, some reports of younger EBV+ DLBCL cases, without evidence of underlying immunosuppression, can be found. The role of EBV in tumor microenvironment composition in DLBCL is still not well understood. Our aim was to assess EBV presence and latency pattern as well as tumor T-cell population in an adult DLBCL series of Argentina. The study was conducted on biopsies from 75 DLBCL patients. EBERs expression was performed by in situ hybridization, while EBV gene expression was analyzed using real-time polymerase chain reaction. LMP1, LMP2A, EBNA2, EBNA3A, CD4, CD8 and Foxp3 expression was assessed by immunohistochemistry. Nine percent of cases showed EBV expression, with similar frequency among patients younger than 50 years and 50 years or older (13% and 8%, respectively). T-cell subsets were not altered by EBV presence. Latency type II was the most frequently observed, together with lytic gene expression in EBV+ DLBCL, with >=20% of EBERs+ cells. These findings suggest that EBV+ DLBCL in our series was similar to the previously described in Asia and Latin-America, displaying latency II or III expression profile and no age-specific characteristics. Finally, EBV+ DLBCL may be an entity that is not only restricted to patients who are older than 50 years of age, in consequence the age cutoff revision may be a current goal. PMID- 24789502 TI - microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1. AB - Osteosarcoma (OS), a malignant mesenchymal sarcoma, is the most frequent primary bone tumor, with a peak incidence in young children and adolescents. The downregulation of microRNA-145 (miRNA/miR-145) has previously been identified to be associated with the aggressiveness and metastasis of OS. However, the detailed regulatory mechanism by which miR-145 inhibits OS remains largely unknown. The present study demonstrated that miR-145 was significantly downregulated in OS tissues and KHOS and U2OS cell lines. Rho-associated protein kinase 1 (ROCK1), a key regulator of actin cytoskeleton reorganization, was identified as a novel target of miR-145. Ectopic expression of miR-145 notably suppressed the protein expression of ROCK1 without affecting its mRNA level. Furthermore, the expression of ROCK1 was significantly increased in the OS tissues and in the KHOS and U2OS cells. It was further demonstrated that the overexpression of miR-145 downregulated KHOS and U2OS cell proliferation and invasion, which was reversed by restoration of ROCK1. To the best of our knowledge, the present study demonstrates for the first time that, as a tumor suppressor, miRNA-145 inhibits OS cell proliferation and invasion, at least in part by directly targeting ROCK1. These results indicate that miR-145 may be a potential candidate for the diagnosis and treatment of OS. PMID- 24789503 TI - Introduction to 'Integration of the response to dietary potassium load: a paleolithic perspective'. PMID- 24789504 TI - Integration of the response to a dietary potassium load: a paleolithic perspective. AB - Our purpose is to integrate new insights in potassium (K(+)) physiology to understand K(+) homeostasis and illustrate some of their clinical implications. Since control mechanisms that are essential for survival were likely developed in Paleolithic times, we think the physiology of K(+) homeostasis can be better revealed when viewed from what was required to avoid threats and achieve balance in Paleolithic times. Three issues will be highlighted. First, we shall consider the integrative physiology of the gastrointestinal tract and the role of lactic acid released from enterocytes following absorption of sugars (fruit and berries) to cause a shift of this K(+) load into the liver. Second, we shall discuss the integrative physiology of WNK kinases and modulation of delivery of bicarbonate to the distal nephron to switch the aldosterone response from sodium chloride retention to K(+) secretion when faced with a K(+) load. Third, we shall emphasize the role of intra-renal recycling of urea in achieving K(+) homeostasis when the diet contains protein and K(+). PMID- 24789506 TI - Revelation of intertwining organic and inorganic fractal structures in polymer coatings. AB - X-ray microtomography and serial block face scanning electron microscopy are used to reveal independent clusters of inorganic particles embedded within a polymer. These clusters are interpenetrating, of varying size, and have fractal dimensions that strongly influence transport and structure-property relations. This interpretation forms a baseline for designing hybrid materials for applications in self-healing, drug delivery, and membranes. PMID- 24789507 TI - Trauma Surveillance in Cape Town, South Africa: An Analysis of 9236 Consecutive Trauma Center Admissions. AB - IMPORTANCE: Trauma is a leading cause of death and disability worldwide. In many low- and middle-income countries, formal trauma surveillance strategies have not yet been widely implemented. OBJECTIVE: To formalize injury data collection at Groote Schuur Hospital, the chief academic hospital of the University of Cape Town, a level I trauma center, and one of the largest trauma referral hospitals in the world. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective study of all trauma admissions from October 1, 2010, through September 30, 2011, at Groote Schuur Hospital. A standard admission form was developed with multidisciplinary input and was used for both clinical and data abstraction purposes. Analysis of data was performed in 3 parts: demographics of injury, injury risk by location, and access to and maturity of trauma services. Geographic information science was then used to create satellite imaging of injury "hot spots" and to track referral patterns. Finally, the World Health Organization trauma system maturity index was used to evaluate the current breadth of the trauma system in place. MAIN OUTCOMES AND MEASURES: The demographics of trauma patients, the distribution of injury in a large metropolitan catchment, and the patterns of injury referral and patient movement within the trauma system. RESULTS: The minimum 34-point data set captured relevant demographic, geographic, incident, and clinical data for 9236 patients. Data field completion rates were highly variable. An analysis of demographics of injury (age, sex, and mechanism of injury) was performed. Most violence occurred toward males (71.3%) who were younger than 40 years of age (74.6%). We demonstrated high rates of violent interpersonal injury (71.6% of intentional injury) and motor vehicle injury (18.8% of all injuries). There was a strong association between injury and alcohol use, with alcohol implicated in at least 30.1% of trauma admissions. From a systems standpoint, the data suggest a mature pattern of referral consistent with the presence of an inclusive trauma system. CONCLUSIONS AND RELEVANCE: The implementation of injury surveillance at Groote Schuur Hospital improved insights about injury risk based on demographics and neighborhood as well as access to service based on patterns of referral. This information will guide further development of South Africa's already advanced trauma system. PMID- 24789508 TI - The "how" and "why" of including gender and age in ethnobotanical research and community-based resource management. AB - This paper examines the process and outcome of participatory methods for stakeholder identification. We used focus group style participatory methodology to engage local residents in identifying key sub-groups relevant to conservation in Boumba, Niger. We then conducted a quantitative pictorial recognition study to measure the diversity of local useful plant knowledge across groups. The community identified six gender and age-class groupings relevant to the study. The effect of a participant's gender, socially-defined age class or the interaction of the two factors on the number of plants recognized varied by plant use. Medicinal plant knowledge was highest among elders. Food plant knowledge of food plants increased with age for women only. Where as the interaction of age and gender was strongest on fodder plant knowledge, where mid-aged men scored highest. We reflect on the impact that heterogeneity of local botanical knowledge has on our understanding of local natural resource use and the strengths of using a participatory approach to identifying the stakeholder groups which underlie this heterogeneity. PMID- 24789509 TI - An experiment with forced oxygenation of the deepwater of the anoxic By Fjord, western Sweden. AB - In a 2.5-year-long environmental engineering experiment in the By Fjord, surface water was pumped into the deepwater where the frequency of deepwater renewals increased by a factor of 10. During the experiment, the deepwater became long term oxic, and nitrate became the dominating dissolved inorganic nitrogen component. The amount of phosphate in the water column decreased by a factor of 5 due to the increase in flushing and reduction in the leakage of phosphate from the sediments when the sediment surface became oxidized. Oxygenation of the sediments did not increase the leakage of toxic metals and organic pollutants. The bacterial community was the first to show changes after the oxygenation, with aerobic bacteria also thriving in the deepwater. The earlier azoic deepwater bottom sediments were colonized by animals. No structural difference between the phytoplankton communities in the By Fjord and the adjacent Havsten Fjord, with oxygenated deepwater, could be detected during the experiment. PMID- 24789510 TI - Threats to China's Biodiversity by Contradictions Policy. AB - China has among the highest biodiversities in the world, but faces extreme biodiversity losses due to the country's huge population and its recent explosive socioeconomic development. Despite huge efforts and investments by the government and Chinese society to conserve biodiversity, especially in recent decades, biodiversity losses may not have been reversed, and may even have been exacerbated by unintended consequences resulting from these projects. China's centralized approach to biodiversity conservation, with limited local participation, creates an inflexible and inefficient approach because of conflicts between local communities and national administrators over the benefits. Although community-based conservation may be an imperfect approach, it is an essential component of a successful future national conservation plan. Biodiversity conservation should be considered from the perspective of systems engineering and a governance structure that combines centralization with community-level conservation. In this paper, we describe China's complex challenge: how to manage interactions between humans and nature to find win-win solutions that can ensure long-term biodiversity conservation without sacrificing human concerns. PMID- 24789511 TI - Hsp90 inhibition by WK88-1 potently suppresses the growth of gefitinib-resistant H1975 cells harboring the T790M mutation in EGFR. AB - Heat shock protein 90 (Hsp90) is a molecular chaperone for numerous client proteins, many of which are crucial for the pathogenesis of non-small cell lung cancers (NSCLCs). To date, therapeutic approaches using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib or erlotinib for the treatment of NSCLCs have been limited due to the emergence of acquired drug resistance mainly mediated by a secondary T790M mutation in EGFR. Considering this, Hsp90 inhibition seems promising as it leads to overall degradation of the oncogenic EGFR family proteins. In this regard, the present study provides the preclinical basis for a new Hsp90 inhibitor, WK88-1, for the treatment of NSCLCs harboring the T790M mutation in EGFR. Our data revealed that inhibition of Hsp90 by WK88-1 induced overall degradation of multiple oncogenic signaling molecules including EGFR, ErbB2 and ErbB3, leading to subsequent growth arrest and apoptosis in the gefitinib-resistant H1975 cell line. In addition, treatment with WK88-1 markedly inhibited proliferation, migration and invasion in H1975 cells. Moreover, an in vivo xenograft assay indicated that WK88-1 markedly suppressed tumor growth in the H1975 xenografts, highlighting the potential efficacy of WK88-1 for overcoming gefitinib resistance in NSCLCs harboring the T790M mutation in EGFR. PMID- 24789512 TI - Particle-size effects on the entropy behavior of a LixFePO4 electrode. AB - The particle-size effects on the thermodynamic properties and kinetic behavior of a Li(x)FePO(4) electrode have a direct influence on the electrode properties. Thus, the development of high-performance Li-ion batteries containing a Li(x)FePO(4) cathode requires a complete understanding of the reaction mechanism at the atomic/nano/meso scale. In this work, we report electrochemical calorimetric and potentiometric studies on Li(x)FePO(4) electrodes with different particle sizes and clarify the particle-size effect on the reaction mechanism based on the entropy change of (de)lithiation. Electrochemical calorimetry results show that a reduction in particle size shrinks the miscibility gap of Li(x)FePO(4) while potentiometric measurements demonstrate that the Li(x)FePO(4) particles equilibrate into either a kinetically metastable state or a thermodynamically stable state depending on the particle size. PMID- 24789513 TI - Pingyangmycin stimulates apoptosis in human hemangioma-derived endothelial cells through activation of the p53 pathway. AB - Pingyangmycin (also known as Bleomycin A5) is produced by Streptomyces verticillus var. pingyangensis n.sp., and has anti-tumor activities against a variety of tumor cells. The aim of the present study was to determine the molecular mechanism(s) underlying the therapeutic effects of pingyangmycin against infantile hemangiomas. Human hemangioma-derived endothelial cells (HemECs) were treated with pingyangmycin at varying concentrations (100, 200 or 300 ug/ml), and the morphological changes and apoptosis levels were assessed. The gene expression changes were determined by cDNA microarray technology. Transmission electron microscopy examination revealed that the pingyangmycin treated HemECs exhibited typical apoptotic characteristics, including chromatin condensation and the formation of apoptotic bodies. Annexin-V staining demonstrated that pingyangmycin caused a significant and dose-dependent induction of apoptosis in the HemECs. In the pingyangmycin-treated HemECs, 4,752 genes demonstrated at least 2-fold expression changes at the mRNA level. Quantitative polymerase chain reaction confirmed that pingyangmycin significantly upregulated the expression of p53, p53-induced protein with death domain, Bax, p53 upregulated modulator of apoptosis and p53 inducible gene 3, and downregulated the expression of murine double minute 2. The data demonstrated that the pro apoptotic activity of pingyangmycin against infantile hemangiomas involves p53 pathway activation. PMID- 24789514 TI - Reproductive history and the risk of molecular breast cancer subtypes in a prospective study of Norwegian women. AB - PURPOSE: Breast cancer can be classified into molecular subtypes that differ in clinical characteristics and prognosis. There is some but conflicting evidence that reproductive risk factors may differ between distinct breast cancer subtypes. METHODS: We investigated associations of reproductive factors with the risk for six molecular breast cancer subtypes in a cohort of 21,532 Norwegian women who were born between 1886 and 1928 and followed up for breast cancer incidence between 1961 and 2008. We obtained stored tumor tissue from incident breast cancers and used immunohistochemistry and in situ hybridization to classify 825 invasive tumors into three luminal subtypes [Luminal A, Luminal B (HER2-) and Luminal B (HER2+)] and three non-luminal subtypes [human epidermal growth factor receptor 2 (HER2) subtype, basal-like phenotype (BP) and five negative phenotype (5NP)]. We used Cox regression to assess reproductive factors and risk for each subtype. RESULTS: We found that young age at menarche, old age at first birth and low parity were associated with increased risk for luminal breast cancer subtypes. For the HER2 subtype, we either found no association or associations in the opposite direction compared to the luminal subtypes. The BP subtype appeared to have a similar reproductive risk profile as the luminal subtypes. Breastfeeding was associated with a reduced risk for HER2 and 5NP subtypes, but was not associated with any other subtype. CONCLUSIONS: The results suggest that molecular breast cancer subtypes differ in their reproductive risk factors, but associations with non-luminal subtypes are still poorly understood and warrant further study. PMID- 24789515 TI - Long-term treatment outcome of two patients with pyridoxine-dependent epilepsy caused by ALDH7A1 mutations: normal neurocognitive outcome. AB - Pyridoxine-dependent epilepsy is an autosomal recessively inherited disorder of lysine catabolism caused by mutations in the ALDH7A1 gene. We report 2 patients with normal neurocognitive outcome (full-scale IQ of 108 and 74) and their more than 10 years' treatment outcome on pyridoxine monotherapy. Both patients had specific borderline impairments in visual processing speed. More long-term treatment outcome reports will increase our knowledge about the natural history of the disease. PMID- 24789516 TI - A pilot study for evaluation of hypotonia in children with neurofibromatosis type 1. AB - There are currently no objective criteria to evaluate pediatric hypotonia. The purpose of this pilot study was to identify diagnostic criteria for assessing hypotonia in children with neurofibromatosis type 1. Fifty-five subjects between the ages of 1 and 7 years with a diagnosis of neurofibromatosis type 1 were evaluated. A physical therapist recorded a subjective tone assessment and objective tone metrics, including ankle dorsiflexion, knee extension, hip abduction, triceps fat percentage, grip strength, and head lag during a pull-to sit test. Multivariate logistic regression analysis showed the presence of head lag paired with increased hip range of motion was a significant predictor of hypotonia. The presence of head lag on a pull-to-sit test paired with increased hip range of motion is an accurate predictor of hypotonia in children with neurofibromatosis type 1. These objective measures should be prospectively evaluated in other pediatric populations for their ability to predict hypotonia. PMID- 24789517 TI - Defective auditory processing in a child with temporal epileptic focus. AB - A 9-year-old boy presented with intolerance to noise that was a trigger for violent temper tantrums that occasionally resembled complex partial seizures. The condition was also a cause for withdrawal from all activities and settings that could potentially be associated with noise. Both electroencephalography and magnetoencephalography clearly demonstrated a left temporal (T5) epileptic focus, although the child never had convulsive seizures. Genetic studies failed to reveal a GRIN2A mutation. We suggest that the hyperacusis in the reported child is another variation of the Landau-Kleffner spectrum. PMID- 24789518 TI - Magnetic resonance imaging (MRI) and prognostication in neonatal hypoxic-ischemic injury: a vignette-based study of Canadian specialty physicians. AB - Magnetic resonance imaging (MRI) could improve prognostication in neonatal brain injury; however, factors beyond technical or scientific refinement may impact its use and interpretation. We surveyed Canadian neonatologists and pediatric neurologists using general and vignette-based questions about the use of MRI for prognostication in neonates with hypoxic-ischemic injury. There was inter- and intra-vignette variability in prognosis and in ratings about the usefulness of MRI. Severity of predicted outcome correlated with certainty about the outcome. A majority of physicians endorsed using MRI results in discussing prognosis with families, and most suggested that MRI results contribute to end-of-life decisions. Participating neonatologists, when compared to participating pediatric neurologists, had significantly less confidence in the interpretation of MRI by colleagues in neurology and radiology. Further investigation is needed to understand the complexity of MRI and of its application. Potential gaps relative to our understanding of the ethical importance of these findings should be addressed. PMID- 24789519 TI - Design of large-insert jumping libraries for structural variant detection using Illumina sequencing. AB - Next-generation sequencing is an important and efficient tool for the identification of structural variation, particularly balanced chromosomal rearrangements, because such events are not routinely detected by microarray and localization of altered regions by karyotype is imprecise. Indeed, the degree of resolution that can be obtained through next-generation technologies enables elucidation of precise breakpoints and has facilitated the discovery of numerous pathogenic loci in human disease and congenital anomalies. The protocol described here explains one type of large-insert "jumping library" and the steps required to generate such a library for multiplexed sequencing using Illumina sequencing technology. This approach allows for cost-efficient multiplexing of samples and provides a very high yield of fragments with large inserts, or "jumping" fragments. PMID- 24789520 TI - Recent trends in the use of food additives in the United Kingdom. AB - The E number system for food additives was introduced in the 1960s and the E was intended to reassure consumers that permitted additives were safe. In the 1980s full ingredient declarations had to be provided on food products for the first time and manufacturers were permitted to use either the name or the number of the additive on the ingredient list. This paper outlines some of the trends in the sourcing, use and labelling of additives since the introduction of full ingredient listing. Generally, sourcing has become more global with a large number of suppliers being based in China. From an initial use of E numbers in ingredient lists, manufacturers are increasingly using the names of additives. This trend is being extended to avoid the use of anything the consumer might consider an additive, particularly in connection with colours and preservatives. Specifically, the colours used in the Southampton study on the impact of food colours on hyperactivity in children have largely been replaced by colouring foodstuffs, and the preservative used in the study, sodium benzoate, has been replaced by potassium sorbate in the majority of soft drinks. PMID- 24789521 TI - Isolation and structural determination of C8-vinyl-bacteriochlorophyll d from the bciA and bchU double mutant of the green sulfur bacterium Chlorobaculum tepidum. AB - The mutant lacking enzymes BciA and BchU, that catalyzed reduction of the C8 vinyl group and methylation at the C20 position of bacteriochlorophyll (BChl) c, respectively, in the green sulfur bacterium Chlorobaculum tepidum, were constructed. This mutant accumulated C8-vinyl-BChl d derivatives, and a molecular structure of the major pigment was fully characterized by its NMR, mass, and circular dichroism spectra, as well as by chemical modification: (3(1) R)-8-vinyl 12-ethyl-(R[V,E])BChl d was confirmed as a new BChl d species in the cells. In vitro chlorosome-like self-aggregates of this pigment were prepared in an aqueous micellar solution, and formed more rapidly than those of (3(1) R)-8,12-diethyl (R[E,E])BChl d isolated from the green sulfur bacterium Chlorobaculum parvum NCIB8327d synthesizing BChl d homologs. Their red-shifted Q y absorption bands were almost the same at 761 nm, and the value was larger than those of in vitro self-aggregates of R[E,E]BChl c (737 nm) and R[V,E]BChl c (726 nm), while the monomeric states of the former gave Q y bands at shorter wavelengths than those of the latter. Red shifts by self-aggregation of the two BChl d species were estimated to be 110 nm and much larger than those by BChls c (75 nm for [E,E] and 64 nm for [V,E]). PMID- 24789522 TI - Fetal hemivertebra: associations and perinatal outcome. AB - OBJECTIVES: To assess the accuracy of antenatal diagnosis of hemivertebra, to quantify the association with coexisting anomalies and to determine the perinatal outcome. METHOD: This was a retrospective observational study of all cases of suspected fetal or neonatal hemivertebra identified via the UK Southwest Congenital Anomaly Register (SWCAR) between 2002 and 2012. RESULTS: From a total of 88 cases of hemivertebra identified during the study period, data were obtained for 67 of them: 45 (10 isolated and 35 with coexisting anomalies) cases were suspected antenatally and 22 (10 isolated and 12 with coexisting anomalies) were diagnosed postnatally. Of the cases detected postnatally, five (four with coexisting anomalies) were unsuspected and diagnosed at postmortem examination. The most commonly associated anomalies included additional skeletal abnormalities (n = 16), genitourinary abnormalities (n = 10), VATER/VACTERL association (n = 5), cardiac abnormalities (n = 4) and central nervous system abnormalities (n = 4). In cases with coexisting anomalies there was a 48% fetal/neonatal loss, compared to 19% in cases with isolated hemivertebra. CONCLUSIONS: Although antenatal diagnosis of hemivertebra was accurate, a third of the cases were diagnosed only postnatally. These data suggest a difficulty in antenatal diagnosis of the condition. The majority of cases of hemivertebra had coexisting anomalies, and in these cases the rate of perinatal loss was high. These data should be useful in providing additional information for counseling when a diagnosis of hemivertebra is made. PMID- 24789524 TI - Sparsely-sampled, high-resolution 4-D omit spectra for detection and assignment of intermolecular NOEs of protein complexes. AB - Unambiguous detection and assignment of intermolecular NOEs are essential for structure determination of protein complexes by NMR. Such information has traditionally been obtained with 3-D half-filtered experiments, where scalar coupling-based purging of intramolecular signals allows for selective detection of intermolecular NOEs. However, due to the large variation of (1)JHC scalar couplings and limited chemical shift dispersion in the indirect proton dimension, it is difficult to obtain reliable and complete assignments of interfacial NOEs. Here, we demonstrate a strategy that combines selective labeling and high resolution 4-D NOE spectroscopy with sparse sampling for reliable identification and assignment of intermolecular NOEs. Spectral subtraction of component-labeled complexes from a uniformly-labeled protein complex yields an "omit" spectrum containing positive intermolecular NOEs with little signal degeneracy. Such a strategy can be broadly applied to unbiased detection, assignment and presentation of intermolecular NOEs of protein complexes. PMID- 24789525 TI - Monitoring mercury exposure in reproductive aged women inhabiting the Tapajos river basin, Amazon. AB - Among Amazonian communities, exposure to methylmercury is associated mainly with fish consumption that may affect fetal development in pregnant women. Therefore a temporal assessment was performed to assess the exposure of reproductive aged women to mercury who reside in the riparian communities of Sao Luis do Tapajos and Barreiras located in the Tapajos basin of the Brazilian Amazon from 1999 to 2012. The total mercury concentration in the 519 hair samples was assessed by cold vapor atomic absorption spectrometry. Data analysis showed that the average total mercury concentration decreased from 1.066 to 0.743 MUg/g in those years. In 1999 the proportion of volunteers with mercury levels >= 10 MUg/g was approximately 68 %. In general, exposure to mercury decreased among women of reproductive age, but the potential risks to reproduction and human health is still an issue as 22 % of the woman continued showing high mercury levels (>= 10 MUg/g) in 2012. PMID- 24789526 TI - Accumulation and distribution characteristics of zinc and cadmium in the hyperaccumulator plant Sedum plumbizincicola. AB - Accumulation and distribution of Zn and Cd in the hyperaccumulator plant Sedum plumbizincicola were investigated in a hydroponic experiment. Mean Cd and Zn concentrations in shoots (7,010 and 18,400 mg kg(-1)) were about sevenfold and fivefold higher than those in roots (840 and 3,000 mg kg(-1)) after exposure to 100 MUM CdSO4 and 600 MUM ZnSO4, respectively. Cd and Zn concentrations in young leaves (4,330 and 9,820 mg kg(-1)) were about sixfold and twofold higher than those in mature leaves (636 and 2,620 mg kg(-1)), respectively. MicroPIXE analysis showed that Zn was predominantly localized in epidermal cells in both young and mature leaves, but large amounts of Zn occurred in mesophyll cells in young leaves. Leaf tissue fractionation showed that soluble and cell wall fractions were different at the two stages of leaf growth. Young and mature leaves of S. plumbizincicola also showed different accumulation and distribution characteristics for Zn and Cd. PMID- 24789528 TI - Evaluation of retinal nerve fiber layer thickness in eyes with hypertensive uveitis. AB - IMPORTANCE: Uveitic glaucoma is among the most common causes of irreversible visual loss in uveitis. However, glaucoma detection can be obscured by inflammatory changes. OBJECTIVE: To determine whether retinal nerve fiber layer (RNFL) measurement can be used to detect glaucoma in uveitic eyes with elevated intraocular pressure (IOP). DESIGN, SETTING, AND PARTICIPANTS: Comparative case series of RNFL measurement using optical coherence tomography performed from May 1, 2010, through October 31, 2012, at a tertiary referral center. We assigned 536 eyes with uveitis (309 patients) in the following groups: normal contralateral eyes with unilateral uveitis (n = 72), normotensive uveitis (Uv-N) (n = 143), raised IOP and normal optic disc and/or visual field (Uv-H) (n = 233), and raised IOP and glaucomatous disc and/or visual field (Uv-G) (n = 88). EXPOSURES: Eyes with uveitis and elevated IOP (>21 mm Hg) on at least 2 occasions. MAIN OUTCOMES AND MEASURES: Comparison of RNFL values between groups of eyes and correlation with clinical data; risk factors for raised IOP, glaucoma, and RNFL thinning. RESULTS: Mean (SD) global RNFL was thicker in Uv-N (106.4 [21.4] um) compared with control (96.0 [9.0] um; P < .001) eyes and was thicker in Uv-N eyes with active (119.6 [23.2] um) compared with quiescent (102.3 [20.8] um; P = .001) uveitis, which in turn was not significantly different from control eyes (P = .07). Compared with Uv-N eyes, significant RNFL thinning was seen in all quadrants except the temporal in Uv-G eyes and significant thinning in the inferior quadrant of Uv-H eyes with no evidence of disc or visual field changes (P = .03). Risk factors for elevated IOP were male sex and anterior uveitis. Age, higher peak IOP, longer duration of follow-up, and uveitis-induced elevation of IOP were risk factors for glaucoma and RNFL defect. CONCLUSIONS AND RELEVANCE: Screening for glaucomatous RNFL changes in uveitis must be performed during quiescent periods. Thinning of the inferior quadrant suggests that glaucomatous damage, more than uveitic ocular hypertension, is in fact occurring. Measurement of RNFL may detect signs of damage before disc or visual field changes and therefore identifies a subgroup that should receive more aggressive treatment. PMID- 24789527 TI - Late effects in survivors of childhood CNS tumors treated on Head Start I and II protocols. AB - BACKGROUND: Due to the devastating late effects associated with cranial irradiation in young children with central nervous system (CNS) tumors, treatment for these patients has evolved to include the use of intensive chemotherapy to either avoid or postpone irradiation. While survival outcomes have improved, late effects data in survivors treated on such regimens are needed. OBJECTIVE: This multi-institutional study comprehensively describes late effects in survivors treated on the Head Start I/II protocols. METHODS: Survivors of CNS tumors treated on Head Start I/II protocols were enrolled. Late effects data were collected using a validated parent-report questionnaire. Social, emotional, and behavioral functioning and quality of life were assessed using parent-report on the BASC-2 and CHQ-PF50 questionnaires. RESULTS: Twenty-one survivors (medulloblastoma = 13, sPNET = 4, ATRT = 1, ependymoma = 3) were enrolled. Ten (48%) were irradiation-free. Late effects (frequency; median time of onset since diagnosis) included >= grade III hearing loss (67%; 3.9 years), vision (67%; 4.1 years), hypothyroidism (33%; 4 years), growth hormone (GH) deficiency (48%; 4.7 years), dental (52%; 7.1 years), and no cases of secondary leukemia. Irradiation free (vs. irradiated) survivors reported low rates of hypothyroidism (0/10 vs. 7/11; P = 0.004) and GH deficiency (2/10 vs. 8/11; P = 0.03). The BASC-2 and CHQPF-50 mean composite scores were within average ranges relative to healthy comparison norms. Neither age at diagnosis nor irradiation was associated with these scores. CONCLUSIONS: Irradiation-free Head Start survivors have lower risk of hypothyroidism and GH deficiency. Secondary leukemias are not reported. With extended follow-up, survivors demonstrate quality of life, social, emotional, and behavioral functioning within average ranges. PMID- 24789529 TI - Antitumor DNA vaccination against the Sox2 transcription factor. AB - As cancer stem cells (CSCs) are resistant to chemotherapy, radiotherapy and targeted molecular therapy, immunotherapy of tumors could be aimed at their elimination. Markers specific for CSCs have not been identified to date, but microarray analyses have shown that CSCs and embryonic stem cells use similar transcriptional programs, thus suggesting the production of shared transcription factors. In this study, we developed an experimental DNA vaccine against the transcription factor Sox2 that is important for self-renewal of stem cells and is overexpressed in numerous human cancers. The Sox2 gene was codon optimized for the expression in human cells, its sequences encoding two nuclear localization signals (NLSs) were mutagenized, and the sequence coding for the PADRE helper epitope was fused with its 5' terminus. While codon optimization did not increase Sox2 production and mutagenesis in NLSs only partially reduced nuclear localization of Sox2, the addition of the PADRE epitope was crucial for the enhancement of Sox2 immunogenicity. The antitumor effect was shown after immunization against mouse oncogenic TC-1/B7 cells derived from the lung cancer cell line TC-1 and characterized by high Sox2 production. Sox2-specific reactivity in an ELISPOT assay was further augmented by the depletion of regulatory T (Treg) cells, but this depletion did not enhance the antitumor effect. These data demonstrated the induction of immune responses against the Sox2 self-antigen, but did not confirm the usefulness of Treg depletion when combined with antitumor vaccination. PMID- 24789530 TI - Photoreceptor layer thinning in idiopathic Parkinson's disease. AB - This study was undertaken to quantify retinal and intra-retinal layer thicknesses in Parkinson's disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral-domain optical coherence tomography (OCT), including intra-retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL) scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 um, P = 0.001). Differences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease-related symptoms such as tremor, axial rigidity, or cognitive impairment. PMID- 24789531 TI - In vitro characterization of a novel polymeric system for preparation of amorphous solid drug dispersions. AB - Preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, often a single polymer may not bring about a significant enhancement in solubility or amorphous stability of a poorly water-soluble drug. This study describes application of a unique and novel binary polymeric blend in preparation of solid dispersions. The objective of this study was to investigate amorphous solid dispersions of glipizide, a BCS class II model drug, in a binary polymeric system of polyvinyl acetate phthalate (PVAP) and hypromellose (hydroxypropyl methylcellulose, HPMC). The solid dispersions were prepared using two different solvent methods: rotary evaporation (rotavap) and fluid bed drug layering on sugar spheres. The performance and physical stability of the dispersions were evaluated with non-sink dissolution testing, powder X-ray diffraction (PXRD), and modulated differential scanning calorimetry (mDSC). PXRD analysis demonstrated an amorphous state for glipizide, and mDSC showed no evidence of phase separation. Non-sink dissolution testing in pH 7.5 phosphate buffer indicated more than twofold increase in apparent solubility of the drug with PVAP-HPMC system. The glipizide solid dispersions demonstrated a high glass transition temperature (Tg) and acceptable chemical and physical stability during the stability period irrespective of the manufacturing process. In conclusion, the polymeric blend of PVAP-HPMC offers a unique formulation approach for developing amorphous solid dispersions with the flexibility towards the use of these polymers in different ratios and combined quantities depending on drug properties. PMID- 24789532 TI - Intraretinal brilliant blue G infiltration during internal limiting membrane peeling. PMID- 24789533 TI - Harnessing the chemistry of graphene oxide. AB - Our understanding of the fundamental structure and bonding of graphene oxide (GO) as well as the scope of its utility have grown tremendously over the past decade. As a result, the pace of research efforts directed toward this carbon material continues to increase. Contemporary application now intersects a variety of disciplines and includes heterogeneous catalysis, flow reactor technologies, biomedicine and biotechnology, polymer composites, energy storage, and chemical sensors. Advances in these areas have been buoyed by improvements in the methods used to synthesize and characterize GO, as well as functionalized derivatives thereof. While the diverse uses of GO have been reviewed previously, herein we provide an overview of some of the most recent and significant developments in the field. A brief overview of GO's synthesis and characterization is also provided as well as several recently proposed structural models. The inherent reactivity of GO is described in the context of catalysis, and the utilization of GO's reactive oxygen groups and carbon framework to prepare functionalized derivatives is also discussed. Finally, we provide an outlook of potential areas where GO, its derivatives, and related materials may be expected to find utility or opportunity for further growth and study. PMID- 24789534 TI - Growth arrest-specific gene 6 protein promotes the proliferation and migration of endothelial progenitor cells through the PI3K/AKT signaling pathway. AB - Endothelial progenitor cells (EPCs) play an important role in endothelial repair and vascular regeneration. Growth arrest-specific gene 6 (Gas6) is a novel key regulator of the vascular system, which is linked to a number of cardiovascular diseases. However, the effects of Gas6 on EPCs have not been elucidated to date. The present study was designed to determine the biological function of EPCs treated with Gas6 and to eludicate the underlying mechanisms. EPCs were isolated from umbilical cord blood and treated with various concentrations (25, 50, 100 and 200 ng/ml) of Gas6. The proliferation, migration and angiogenesis of the Gas6 treated EPCs were evaluated by MTT assay, Transwell assay and in vitro tube formation assay, respectively. The phosphorylation status of AKT and ERK was evaluated by western blot analysis. The results demonstrated that treatment with Gas6 enhanced the proliferation and migration of the EPCs in a dose-dependent manner. However, Gas6 did not promote the differentiation of EPCs on Matrigel. Gas6 induced the phosphorylation of AKT, but not that of ERK. The enhanced proliferation and migration induced by Gas6 was markedly suppressed by the inhibitor of PI3K but not by that of ERK. These results suggest that Gas6 activates the AKT signaling pathway, which, in turn, promotes the proliferation and migration of EPCs. PMID- 24789535 TI - Cyclodextrin-based molecular machines. AB - This chapter overviews molecular machines based on cyclodextrins (CDs). The categories of CD-based molecular machines, external stimuli for CD-based molecular machines, and typical examples of CD-based molecular machines are briefly described. PMID- 24789536 TI - Italian consensus for the classification and reporting of thyroid cytology. PMID- 24789538 TI - Irisin in idiopathic foetal growth restriction. AB - PURPOSE: The aim of the present study was to compare maternal serum and cord blood irisin levels in females whose pregnancies were or were not complicated by idiopathic foetal growth restriction. METHODS: A total of 30 subjects participated. The study group consisted of 15 female patients who were referred to our perinatology clinic for delivery because of foetal growth restriction developing in the third trimester. Fifteen females with uncomplicated singleton pregnancies constituted the control group. Irisin levels were assessed in maternal serum, as well as in serum from the umbilical vein and artery. RESULTS: The demographic features of the two groups were similar (p > 0.05). Gestational age at delivery and birth weight were higher in females with uncomplicated pregnancies (p = 0.001). Umbilical artery irisin levels were significantly lower in pregnancies complicated by foetal growth restriction compared to controls (p = 0.003). Umbilical artery irisin levels were positively correlated with foetal weight (p = 0.01) and foetal abdominal circumference (measured by ultrasonography) (p = 0.01). Maternal and umbilical vein irisin levels did not differ between the two groups (p > 0.05). CONCLUSIONS: The data suggest that umbilical artery irisin levels were lower in pregnancies complicated by foetal growth restriction. Such lower irisin levels may contribute to the pathogenesis of this common condition, and metabolic syndrome may be a long-term consequence of idiopathic FGR. PMID- 24789539 TI - Seasonal variations in glycemic control of type 2 diabetes in Korean women. AB - BACKGROUND AND AIMS: Seasonal variations in lifestyle, such as food intake and physical activity, have been reported. Glycemic control in type 2 diabetes mellitus (T2DM) may be affected by such changes. We investigated seasonal variations in glycemic control, food intake, and physical activity in type 2 diabetic patients. METHODS: This prospective observational study included 37 Korean female patients who had <8.0 % hemoglobin A1c (HbA1c) and managed diabetes by oral anti-diabetic drugs or lifestyle modification only. Participants underwent four or five assessments, including total physical activity (household, leisure-time, and occupational activity) (metabolic equivalent of test-h/day), food intake (kcal/day), HbA1c, and anthropometry every 3 months (August, November, February, May, and August in the Northern Hemisphere) over 1 year. When anti-diabetic drugs were changed, we analyzed the data just before the changes. RESULTS: The mean HbA1c levels (%) of August and November in 2008, and February, May, and August in 2009 were 7.0 +/- 0.1, 6.9 +/- 0.1, 7.2 +/- 0.2, 7.4 +/- 0.2, and 7.2 +/- 0.2, respectively (P = 0.018). The change of HbA1c was nearly 0.5 % for the 1-year period. From August to May of the following year, there were also seasonal variations in food intake (1,872 +/- 143, 1,739 +/- 97, 1,673 +/- 86, 1,561 +/- 132, respectively; P = 0.013), and total physical activity [7.7 (3.7 14.6), 6.3 (2.8-10.4), 5.1 (2.7-12.6), and 11.2 (4.7-20.5), respectively; P = 0.048]. However, the seasonal variations of HbA1c and total physical activity became non-significant when farmers were excluded. CONCLUSIONS: These data suggested that glycemic control, total physical activity, and food intake varied seasonally in Korean T2DM patients. These seasonal variations should be considered in education for glycemic control. PMID- 24789540 TI - Lack of association between autonomously functioning thyroid nodules and germline polymorphisms of the thyrotropin receptor and Galphas genes in a mild to moderate iodine-deficient Caucasian population. AB - BACKGROUND: Mutations of the thyrotropin receptor (TSHR) and/or Galphas gene have been found in a number of, but not all, autonomously functioning thyroid nodules (AFTNs). Recently, in a 15-year-old girl with a hyperfunctioning papillary thyroid carcinoma, we found two somatic and germline single nucleotide polymorphisms (SNPs): a SNP of the TSHR gene (exon 7, codon 187) and a SNP of Galphas gene (exon 8, codon 185). The same silent SNP of the TSHR gene had been reported in patients with AFTN or familial non-autoimmune hyperthyroidism. No further data about the prevalence of the two SNPs in AFTNs as well as in the general population are available in the literature. AIM: To clarify the possible role of these SNPs in predisposing to AFTN. METHODS: Germline DNA was extracted from blood leukocytes of 115 patients with AFTNs (43 males and 72 females, aged 31-85 years, mean +/- SD = 64 +/- 13) and 100 sex-matched healthy individuals from the same geographic area, which is marginally iodine deficient. The genotype distribution of the two SNPs was investigated by restriction fragment length polymorphism-polymerase chain reaction. RESULTS: The prevalence of the two SNPs in our study population was low and not different to that found in healthy individuals: 8 % of patients vs. 9 % of controls were heterozygous for the TSHR SNP and 4 % patients vs. 6 % controls were heterozygous for the Galphas SNP. One patient harbored both SNPs. CONCLUSIONS: These results suggest that these two SNPs do not confer susceptibility for the development of AFTN. PMID- 24789541 TI - Comparison between liquid and tablet levothyroxine formulations in patients treated through enteral feeding tube. AB - BACKGROUND: The majority of clinicians suggest that enteral feedings should be held 1-2 h prior to and after L-T4 administration despite lack of data for continuous enteral nutrition. AIM: The aim of this study was to: (1) compare the thyroid hormonal profile in patients submitted to L-T4 treatment in tablets or liquid formulation with an enteral feeding tube; (2) evaluate the nursing compliance with the two different formulations. SUBJECTS AND METHODS: 20 euthyroid patients submitted to total laryngectomy and thyroidectomy consecutively started L-T4 treatment in tablets (Group T) or in liquid formulation (Group L) with enteral feeding tube the day after surgery. Tablets were crushed before administration and enteral feeding was stopped for 30 min before and after L-T4 treatment, whereas liquid formulation was placed into the nasoenteric tube immediately. A questionnaire about the preparation and administration of thyroxine replacement therapy was given to the nurses. RESULTS: No difference of TSH, fT4 and fT3 before and after L-T4 treatment was observed among patients of Group L. A slightly serum TSH increase was observed in Group T, but not reaching statistical significance (2.50 +/- 1.18 vs 2.94 +/- 1.22 mUI/L), whereas no difference in fT4 and fT3 levels was found. Preparation and administration of liquid L-T4 was considered excellent by 12/13 nurses, whereas tablet formulation was considered poor by 10/13. CONCLUSIONS: Our data showed that liquid L-T4 formulation can be administered directly through feeding tube with no need for an empty stomach, with a significant improvement in therapy preparation and administration by nurses. PMID- 24789542 TI - Serum-negative autoimmune thyroiditis: what's in a name? PMID- 24789543 TI - High prevalence of hypovitaminosis D in Sicilian children affected by growth hormone deficiency and its improvement after 12 months of replacement treatment. AB - PURPOSE: Although the correlation between vitamin D and growth hormone (GH) insulin-like growth factor 1 (IGF1) axis is documented, as of date, few and conflicting studies have prospectively analyzed vitamin D before and after GH treatment. Our aim was to evaluate as to how the condition of GH deficiency (GHD) or GH treatment influences vitamin D in children. METHODS: Eighty Sicilian GHD children (M/F 58/22; mean age 10.3 years), grouped according to the season of evaluation in group A (June-September; 41 children) and group B (November February; 39 children), were evaluated at baseline and after 12 months of GH treatment. RESULTS: Twenty-eight children (35 %) were vitamin D insufficient and 32 (40 %) deficient at baseline, and lower vitamin D levels were found in group B than in A (17.3 +/- 5.3 vs. 31.1 +/- 11.1 ng/ml; p < 0.001). A positive correlation between vitamin D and baseline GH levels (p < 0.001) was found. After 12 months, increased vitamin D was found both in all children (34.4 +/- 16.4 vs. 24.5 +/- 11.1 ng/ml; p = 0.002) and in group A (38.5 +/- 14 vs. 31.1 +/- 11.1 ng/ml; p < 0.001) and B (30 +/- 17.7 vs. 17.3 +/- 5.3 ng/ml; p < 0.001). Overall, only 25 (31 %) children remained insufficient and 15 (19 %) deficient, with an increase in prevalence of children with normal levels (p = 0.001). CONCLUSIONS: Our data demonstrated a very high prevalence of hypovitaminosis D in Sicilian GHD children, with an improvement after 12 months of GH treatment. Vitamin D assessment should therefore be considered routinely in GHD children both at diagnosis and during the follow-up. PMID- 24789544 TI - Aryl ethynyl anthraquinones: a useful platform for targeting telomeric G quadruplex structures. AB - Aryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, by the FRET melting assay, circular dichroism, the DNA synthesis arrest assay and molecular docking. Both the binding properties and G-quadruplex vs. duplex selectivity are controlled by the structures of the aryl ethynyl moieties. PMID- 24789545 TI - Matrix metalloproteinase-14 expression and its prognostic value in cervical carcinoma. AB - The objective of the study was to evaluate the expression of matrix metalloproteinase-14 (MMP-14) in cervical carcinoma and correlate its expression with clinicopathological parameters, recurrence, and survival of the patients. The expressions of MMP-14 in normal cervical mucosa and cervical carcinoma tissue were detected with immunohistochemistry. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. The positive expression rate of MMP-14 in cervical carcinoma tissue was 81.6 %(111/136), and there was significant difference on their positive expression rates between in cervical carcinoma tissue and in normal cervical mucosa(22.4 %)(13/58)(P < 0.05);The positive expression rates of MMP-14 in patients with poor histologic differentiation, lymph node metastasis, and recurrence group were heightened. Using Kaplan-Meier analysis, a comparison of survival curves of low versus high expressions of MMP-14 revealed a highly significant difference in human cervical carcinoma tissue (P < 0.05), which suggests that overexpression of MMP-14 is associated with a worse prognosis. The MMP-14 which promotes angiogenes is associated with lymph node metastasis, vascular invasion, and poor prognosis of cervical carcinoma. The current study shows that MMP-14 may be an independent prognostic factor for cervical carcinoma patients. PMID- 24789546 TI - Role of early glycation Amadori products of lysine-rich proteins in the production of autoantibodies in diabetes type 2 patients. AB - In diabetes, protein glycation mostly occurs at intrachain lysine residues resulting in the formation of early stage Amadori products which are finally converted to advance glycation end products (AGEs). Several studies have reported autoantibodies against AGEs in diabetes but not much data are found in respect of Amadori products. In this study, poly-L-lysine (PLL) was glycated with 50 mM glucose and the resultant Amadori products were estimated by fructosamine or nitroblue tetrazolium assay. We report high content of Amadori products in PLL upon glycation. Glycated PLL showed marked hyperchromicity in the UV spectrum, ellipticity changes in CD spectroscopy, and variations in epsilon-methylene protons shift in NMR. It was better recognized by autoantibodies in type 2 diabetics compared to the native PLL. Induced antibodies against glycated PLL were successfully used to probe early glycation in the IgG isolated from diabetes type 2 patients. Role of Amadori products of glycated proteins in the induction of autoantibodies in type 2 diabetes as well as in associated secondary complications has been discussed. PMID- 24789547 TI - Enhanced radiosensitivity and G2/M arrest were observed in radioresistant esophageal cancer cells by knocking down RPA expression. AB - The aim of this study was to evaluate the changes in radiosensitivity of radioresistant esophageal cancer cells (TE-1R) after disruption of replication protein A (RPA) expression and to explore the potential mechanism. A radioresistant human esophageal cancer cell line TE-1R was established by treating TE-1 cells with the radiation. Then, siRPA1 or -2 was transfected to TE 1R cells. The untransfected group (control) and nonsense short interfering RNA (siRNA) transfected group (NC) were used as controls. To investigate the radiosensitivity changes of TE-1R cells, the dose-survival curve was established by colony-forming assay, and the cell cycle distribution was measured by flow cytometry. (1) Comparing with control and NC groups, the protein expression of RPA1 and -2 decreased significantly 48 h after siRPA1 or -2 transfection. (2) The D 0, D q, and SF2 values reduced from 2.09, 1.70, and 0.85 in NC group to 1.67, 0.71, and 0.44 and 1.82, 0.89, and 0.51 in siRNA1 and siRPA2 transfected groups, respectively. The D q sensitization enhancement ratios (SERDq) were 2.39 and 1.91 in siRNA1 and siRPA2 transfected groups, respectively. (3) The G2/M arrest was significantly caused by siRPA1 or -2 transfection as compared with that in the NC group (t value was 2.827, 2.853, p < 0.05). Post transcriptional silencing of RPA1 or -2 via RNAi can enhance the radiosensitivity of human esophageal cancer cells TE-1R, and the potential mechanism may be related to the inhibition of post radiation sublethal damage repair and the halted cell cycle progression at G2/M phase. Therefore, RPA may become a new target for radiosensitization enhancement in esophageal cancer. PMID- 24789548 TI - National standards of care quality would help India enable health coverage for all. PMID- 24789549 TI - The relationship between IL-10 levels and cardiovascular events in patients with CKD. AB - BACKGROUND AND OBJECTIVES: Cardiovascular disease is the leading cause of death in patients with CKD. IL-10 is considered an antiatherosclerotic cytokine. However, previous studies have failed to observe an association between IL-10 and cardiovascular disease in CKD. This study aimed to evaluate whether serum IL-10 levels were associated with the risk of cardiovascular events in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Four hundred three patients with stages 1-5 CKD were followed for a mean of 38 (range=2-42) months for fatal and nonfatal cardiovascular events. IL-10 and IL-6 were measured at baseline together with surrogates of endothelial function (flow-mediated dilatation) and proinflammatory markers (high-sensitivity C-reactive protein and pentraxin-3). The association between IL-10 and flow-mediated dilatation through linear regression analyses was evaluated. The association between IL-10 and the risk of cardiovascular events was assessed with Cox regression analysis. RESULTS: IL-10, IL-6, high-sensitivity C-reactive protein, and pentraxin-3 levels were higher among participants with lower eGFR. Both fatal (25 of 200 versus 6 of 203 patients) and combined fatal and nonfatal (106 of 200 versus 23 of 203 patients) cardiovascular events were more common in patients with IL-10 concentration above the median. Flow-mediated dilatation was significantly lower in patients with higher serum IL-10 levels, but IL-10 was not associated with flow-mediated dilatation in multivariate analysis. Kaplan-Meier survival curves showed that patients with IL-10 below the median value (<21.5 pg/ml) had higher cumulative survival compared with patients who had IL-10 levels above the median value (log rank test, P<0.001). CONCLUSIONS: IL-10 levels increase along with the reduction of kidney function. Higher serum IL-10 levels were associated with the risk of cardiovascular events during follow-up. We speculate that higher IL-10 levels in this context signify an overall proinflammatory milieu. PMID- 24789550 TI - Homeostasis, the milieu interieur, and the wisdom of the nephron. AB - The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the "internal milieu" and allow organisms the "physiologic freedom" to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney's critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology. PMID- 24789551 TI - Derivation of urine output thresholds that identify a very high risk of AKI in patients with septic shock. AB - BACKGROUND AND OBJECTIVES: To promote early detection of AKI, recently proposed pretest probability models combine sub-Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria with baseline AKI risk. The primary objective of this study was to determine sub-KDIGO thresholds that identify patients with septic shock at highest risk for AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective analysis of 390 adult patients admitted to the medical intensive care unit (ICU) of a tertiary, academic medical center with septic shock between January 2008 and December 2010. Hourly urine output was collected from the time of septic shock recognition (hour 0) to hour 96, urine catheter removal, or ICU discharge (whichever occurred first). All available serum creatinine (SCr) measurements were collected until hour 96. The AKI pretest probability model was assessed during the first 12 hours of resuscitation and included the initial episode of oliguria, increase from baseline to peak SCr level, and Acute Physiology and Chronic Health Evaluation (APACHE) III score in a multivariable receiver-operator characteristic (ROC) analysis. The primary outcome was the incidence of stage II or III (stage II+) AKI defined by KDIGO criteria. Secondary outcomes included the need for RRT and 28-day mortality. RESULTS: Ninety-eight (25%) patients developed stage II+ AKI after septic shock recognition. APACHE III score and increase in SCr level in the first 12 hours were not statistically associated with stage II+ AKI in multivariable ROC analysis. Consecutive oliguria for 3 hours had fair predictive ability for achieving stage II+ AKI criteria (area under ROC curve, 0.73; 95% confidence interval [95% CI], 0.68 to 0.78), and oliguria for 5 hours demonstrated optimal accuracy (82%; 95% CI, 79% to 86%). CONCLUSIONS: Three to 5 hours of consecutive oliguria in patients with septic shock may provide a valuable measure of AKI risk. Further validation to support this finding is needed. PMID- 24789552 TI - Assessment of KDIGO definitions in patients with histopathologic evidence of acute renal disease. AB - BACKGROUND AND OBJECTIVES: AKI is a clinical syndrome with various causes involving glomerular, interstitial, tubular, and vascular compartments of the kidney. Acute kidney disease (AKD) is a new concept that includes both AKI and the conditions associated with subacute decreases in GFR (AKD/non-AKI). This study aimed to investigate the correlation between AKI/AKD defined by clinical presentation and diffuse histologic criteria for acute abnormalities based on renal biopsy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All 303 patients who were histologically diagnosed as having acute tubular necrosis (ATN), acute tubulointerstitial nephritis, cellular crescentic GN, acute thrombotic microangiopathy, or complex lesions on renal biopsy from January 2009 to December 2011 were enrolled in the study. The 2012 Kidney Disease Improving Global Outcomes AKD/AKI definitions were applied to classify patients as follows: AKI, AKD/non-AKI, non-AKD, or unclassified. RESULTS: A total of 273 patients (90.1%) met the AKD criteria; 198 patients (65.3%) were classified as having AKI according to serum creatinine (SCr) and urine output criteria. The urine output criteria added 4.3% to the SCr criteria and reclassified 6.7% of the AKI cases into higher stages. Of patients with ATN on pathology, 79.2% met AKI criteria; this was a higher percentage than for those who had other individual pathologic lesions (50%-64%). The major cause of not being defined as having AKI was a slower SCr increase than that required by the definition of AKI (98, 93.3%). Patients with AKI had more severe clinical conditions and worse short-term renal outcome than those in the non-AKI group. CONCLUSIONS: Diffuse, acute abnormality defined by renal biopsy and AKI defined by clinical presentation are two different entities. Most patients who have diffuse acute histologic findings met the criteria for AKD, whereas only two thirds met the definition of AKI. PMID- 24789553 TI - Removal and rebound kinetics of cystatin C in high-flux hemodialysis and hemodiafiltration. AB - BACKGROUND AND OBJECTIVES: Cystatin C is a 13.3 kD middle molecule of similar size to beta2-microglobulin and a marker of GFR in CKD. This study aimed to determine cystatin C kinetics in hemodialysis to understand whether blood concentrations may predict residual renal function and middle-molecule clearance. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cystatin C removal and rebound kinetics were studied in 24 patients on high-flux hemodialysis or hemodiafiltration. To determine whether cystatin C concentrations are predictable, an iterative two-pool mathematical model was applied. RESULTS: Cystatin C was cleared effectively, although less than beta2-microglobulin (reduction ratios +/- SD are 39% +/- 11 and 51% +/- 11). Cystatin C rebounded to 95% +/- 5% of predialysis concentration by 12 hours postdialysis. The two-pool kinetic model showed excellent goodness of fit. Modeled extracellular cystatin C pool volume is smaller than that predicted, comprising 25.5% +/- 9.2 of total body water. Iterated parameters, including nonrenal clearance, showed wide interindividual variation. Modeled nonrenal clearance was substantially higher than renal clearance in this population at 25.1 +/- 6.6 ml/min per 1.73 m(2) body surface area. CONCLUSIONS: Plasma cystatin C levels may be used to measure middle molecule clearance. Levels rebound substantially postdialysis and plateau in the interdialytic period. At low GFR, nonrenal clearance predominates over renal clearance, and its interindividual variation will limit use of cystatin C to predict residual renal function in advanced kidney disease. PMID- 24789554 TI - Sandflies (Diptera: Psychodidae) associated with opossum nests at urban sites in southeastern Brazil: a risk factor for urban and periurban zoonotic Leishmania transmission? AB - Sandflies associated with opossum nests are reported for the first time in the yards of residences located in the urban area of the municipality of Monte Mor, situated in the metropolitan region of Campinas, state of Sao Paulo, Brazil. Eleven specimens of Evandromyia cortelezzii and one of Evandromyia lenti were captured in two Didelphis albiventris nests. Ev. cortelezzii is considered a secondary vector species for the transmission of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum in the Neotropics. This association may contribute to the introduction, establishment and maintenance of urban and periurban zoonotic transmission outbreaks of Leishmania and should therefore be investigated further. PMID- 24789557 TI - Tumour necrosis factor -308 and -238 promoter polymorphisms are predictors of a null virological response in the treatment of Brazilian hepatitis C patients. AB - Certain host single nucleotide polymorphisms (SNPs) affect the likelihood of a sustained virological response (SVR) to treatment in subjects infected with hepatitis C virus (HCV). SNPs in the promoters of interleukin (IL)-10 (-1082 A/G, rs1800896), myxovirus resistance protein 1 (-123 C/A, rs17000900 and -88 G/T, rs2071430) and tumour necrosis factor (TNF) (-308 G/A, rs1800629 and -238 G/A, rs361525) genes and the outcome of PEGylated alpha-interferon plus ribavirin therapy were investigated. This analysis was performed in 114 Brazilian, HCV genotype 1-infected patients who had a SVR and in 85 non-responders and 64 relapsers. A significantly increased risk of having a null virological response was observed in patients carrying at least one A allele at positions -308 [odds ratios (OR) = 2.58, 95% confidence intervals (CI) = 1.44-4.63, p = 0.001] or -238 (OR = 7.33, 95% CI = 3.59-14.93, p < 0.001) in the TNF promoter. The risk of relapsing was also elevated (-308: OR = 2.87, 95% CI = 1.51-5.44, p = 0.001; 238: OR = 4.20, 95% CI = 1.93-9.10, p < 0.001). Multiple logistic regression of TNF diplotypes showed that patients with at least two copies of the A allele had an even higher risk of having a null virological response (OR = 16.43, 95% CI = 5.70-47.34, p < 0.001) or relapsing (OR = 6.71, 95% CI = 2.18-20.66, p = 0.001). No statistically significant association was found between the other SNPs under study and anti-HCV therapy response. PMID- 24789559 TI - On the reliability of seasonal climate forecasts. AB - Seasonal climate forecasts are being used increasingly across a range of application sectors. A recent UK governmental report asked: how good are seasonal forecasts on a scale of 1-5 (where 5 is very good), and how good can we expect them to be in 30 years time? Seasonal forecasts are made from ensembles of integrations of numerical models of climate. We argue that 'goodness' should be assessed first and foremost in terms of the probabilistic reliability of these ensemble-based forecasts; reliable inputs are essential for any forecast-based decision-making. We propose that a '5' should be reserved for systems that are not only reliable overall, but where, in particular, small ensemble spread is a reliable indicator of low ensemble forecast error. We study the reliability of regional temperature and precipitation forecasts of the current operational seasonal forecast system of the European Centre for Medium-Range Weather Forecasts, universally regarded as one of the world-leading operational institutes producing seasonal climate forecasts. A wide range of 'goodness' rankings, depending on region and variable (with summer forecasts of rainfall over Northern Europe performing exceptionally poorly) is found. Finally, we discuss the prospects of reaching '5' across all regions and variables in 30 years time. PMID- 24789555 TI - The multifaceted resources and microevolution of the successful human and animal pathogen methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important bacterial pathogens based on its incidence and the severity of its associated infections. In addition, severe MRSA infections can occur in hospitalised patients or healthy individuals from the community. Studies have shown the infiltration of MRSA isolates of community origin into hospitals and variants of hospital-associated MRSA have caused infections in the community. These rapid epidemiological changes represent a challenge for the molecular characterisation of such bacteria as a hospital or community-acquired pathogen. To efficiently control the spread of MRSA, it is important to promptly detect the mecA gene, which is the determinant of methicillin resistance, using a polymerase chain reaction-based test or other rapidly and accurate methods that detect the mecA product penicillin-binding protein (PBP)2a or PBP2'. The recent emergence of MRSA isolates that harbour a mecA allotype, i.e., the mecC gene, infecting animals and humans has raised an additional and significant issue regarding MRSA laboratory detection. Antimicrobial drugs for MRSA therapy are becoming depleted and vancomycin is still the main choice in many cases. In this review, we present an overview of MRSA infections in community and healthcare settings with focus on recent changes in the global epidemiology, with special reference to the MRSA picture in Brazil. PMID- 24789560 TI - Analysis of self-overlap reveals trade-offs in plankton swimming trajectories. AB - Movement is a fundamental behaviour of organisms that not only brings about beneficial encounters with resources and mates, but also at the same time exposes the organism to dangerous encounters with predators. The movement patterns adopted by organisms should reflect a balance between these contrasting processes. This trade-off can be hypothesized as being evident in the behaviour of plankton, which inhabit a dilute three-dimensional environment with few refuges or orienting landmarks. We present an analysis of the swimming path geometries based on a volumetric Monte Carlo sampling approach, which is particularly adept at revealing such trade-offs by measuring the self-overlap of the trajectories. Application of this method to experimentally measured trajectories reveals that swimming patterns in copepods are shaped to efficiently explore volumes at small scales, while achieving a large overlap at larger scales. Regularities in the observed trajectories make the transition between these two regimes always sharper than in randomized trajectories or as predicted by random walk theory. Thus, real trajectories present a stronger separation between exploration for food and exposure to predators. The specific scale and features of this transition depend on species, gender and local environmental conditions, pointing at adaptation to state and stage-dependent evolutionary trade-offs. PMID- 24789561 TI - Transdifferentiation of autologous bone marrow cells on a collagen-poly(epsilon caprolactone) scaffold for tissue engineering in complete lack of native urothelium. AB - Urological reconstructive surgery is sometimes hampered by a lack of tissue. In some cases, autologous urothelial cells (UCs) are not available for cell expansion and ordinary tissue engineering. In these cases, we wanted to explore whether autologous mesenchymal stem cells (MSCs) from bone marrow could be used to create urological transplants. MSCs from human bone marrow were cultured in vitro with medium conditioned by normal human UCs or by indirect co-culturing in culture well inserts. Changes in gene expression, protein expression and cell morphology were studied after two weeks using western blot, RT-PCR and immune staining. Cells cultured in standard epithelial growth medium served as controls. Bone marrow MSCs changed their phenotype with respect to growth characteristics and cell morphology, as well as gene and protein expression, to a UC lineage in both culture methods, but not in controls. Urothelial differentiation was also accomplished in human bone marrow MSCs seeded on a three-dimensional poly(epsilon caprolactone) (PCL)-collagen construct. Human MSCs could easily be harvested by bone marrow aspiration and expanded and differentiated into urothelium. Differentiation could take place on a three-dimensional hybrid PCL-reinforced collagen-based scaffold for creation of a tissue-engineered autologous transplant for urological reconstructive surgery. PMID- 24789562 TI - Topological properties of robust biological and computational networks. AB - Network robustness is an important principle in biology and engineering. Previous studies of global networks have identified both redundancy and sparseness as topological properties used by robust networks. By focusing on molecular subnetworks, or modules, we show that module topology is tightly linked to the level of environmental variability (noise) the module expects to encounter. Modules internal to the cell that are less exposed to environmental noise are more connected and less robust than external modules. A similar design principle is used by several other biological networks. We propose a simple change to the evolutionary gene duplication model which gives rise to the rich range of module topologies observed within real networks. We apply these observations to evaluate and design communication networks that are specifically optimized for noisy or malicious environments. Combined, joint analysis of biological and computational networks leads to novel algorithms and insights benefiting both fields. PMID- 24789563 TI - Quantification of feather structure, wettability and resistance to liquid penetration. AB - Birds in the cormorant (Phalacrocoracidae) family dive tens of metres into water to prey on fish while entraining a thin layer of air (a plastron film) within the microstructures of their feathers. In addition, many species within the family spread their wings for long periods of time upon emerging from water. To investigate whether wetting and wing-spreading are related to feather structure, microscopy and photographic studies have previously been used to extract structural parameters for barbs and barbules. In this work, we describe a systematic methodology to characterize the quasi-hierarchical topography of bird feathers that is based on contact angle measurements using a set of polar and non polar probing liquids. Contact angle measurements on dip-coated feathers of six aquatic bird species (including three from the Phalacrocoracidae family) are used to extract two distinguishing structural parameters, a dimensionless spacing ratio of the barbule (D*) and a characteristic length scale corresponding to the spacing of defect sites. The dimensionless spacing parameter can be used in conjunction with a model for the surface topography to enable us to predict a priori the apparent contact angles of water droplets on feathers as well as the water breakthrough pressure required for the disruption of the plastron on the feather barbules. The predicted values of breakthrough depths in water (1-4 m) are towards the lower end of typical diving depths for the aquatic bird species examined here, and therefore a representative feather is expected to be fully wetted in a typical deep dive. However, thermodynamic surface energy analysis based on a simple one-dimensional cylindrical model of the feathers using parameters extracted from the goniometric analysis reveals that for water droplets on feathers of all six species under consideration, the non-wetting 'Cassie-Baxter' composite state represents the global energy minimum of the system. By contrast, for other wetting liquids, such as alkanes and common oils, the global energy minimum corresponds to a fully wetted or Wenzel state. For diving birds, individual feathers therefore spontaneously dewet once the bird emerges out of water, and the 'wing-spreading' posture might assist in overcoming kinetic barriers associated with pinning of liquid droplets that retard the rate of drying of the wet plumage of diving birds. PMID- 24789564 TI - On the strength of beta-sheet crystallites of Bombyx mori silk fibroin. AB - Silk fibroin, a natural multi-domain protein, has attracted great attention due to its superior mechanical properties such as ultra-high strength and stretchability, biocompatibility, as well as its versatile biodegradability and processability. It is mainly composed of beta-sheet crystallites and amorphous domains. Although its strength is well known to be controlled by the dissociation of protein chains from beta-sheet crystallites, the way that water as the solvent affects its strength and the reason that its theoretically predicted strength is several times higher than experimental measurement remain unclear. We perform all atom molecular dynamics simulations on a beta-sheet crystallite of Bombyx mori silk. We find that water solvent reduces the number and strength of hydrogen bonds between beta-chains, and thus greatly weakens the strength of silk fibroin. By dissociating protein chains at different locations from the crystallite, we also find that the pulling strength for the interior chains is several times higher than that for the surface/corner chains, with the former being consistent with the theoretically predicted value, while the latter on par with the experimental value. It is shown that the weakest rupture strength controls the failure strength of silk fibre. Hence, this work sheds light on the role of water in the strength of silk fibroin and also provides clues on the origin of the strength difference between theory and experiment. PMID- 24789565 TI - Hydrodynamics of diatom chains and semiflexible fibres. AB - Diatoms are non-motile, unicellular phytoplankton that have the ability to form colonies in the form of chains. Depending upon the species of diatoms and the linking structures that hold the cells together, these chains can be quite stiff or very flexible. Recently, the bending rigidities of some species of diatom chains have been quantified. In an effort to understand the role of flexibility in nutrient uptake and aggregate formation, we begin by developing a three dimensional model of the coupled elastic-hydrodynamic system of a diatom chain moving in an incompressible fluid. We find that simple beam theory does a good job of describing diatom chain deformation in a parabolic flow when its ends are tethered, but does not tell the whole story of chain deformations when they are subjected to compressive stresses in shear. While motivated by the fluid dynamics of diatom chains, our computational model of semiflexible fibres illustrates features that apply widely to other systems. The use of an adaptive immersed boundary framework allows us to capture complicated buckling and recovery dynamics of long, semiflexible fibres in shear. PMID- 24789566 TI - A rapid and effective method for silver staining of PCR products separated in polyacrylamide gels. AB - With the development of molecular quantitative genetics, particularly, genetic linkage map construction, quantitative trait loci mapping or genes fine mapping and association analysis etc., more and more PCR products separated in polyacrylamide gels need to be silver-stained. However, conventional silver staining procedures are complicated and time-consuming as they require a lot of preparation and handling of several solutions prior to use. In this study, a simple and rapid protocol for silver staining of PCR products was developed. The number of steps was reduced compared to conventional protocols, thus achieving detection of PCR products in 7 min, saving time and resources. Fixation and staining solution and developing solution in present staining procedure allowed a reutilization for 12 and 8 times, respectively, reducing the cost greatly. Meanwhile, the sensitivity was significantly improved with the improved method and the minimum of 0.097 ng/MUL of DNA amount can be detected in denaturing polyacrylamide gel. The protocol developed in this study will facilitate the development of molecular quantitative genetics. PMID- 24789567 TI - Bifurcation analysis of models with uncertain function specification: how should we proceed? AB - When we investigate the bifurcation structure of models of natural phenomena, we usually assume that all model functions are mathematically specified and that the only existing uncertainty is with respect to the parameters of these functions. In this case, we can split the parameter space into domains corresponding to qualitatively similar dynamics, separated by bifurcation hypersurfaces. On the other hand, in the biological sciences, the exact shape of the model functions is often unknown, and only some qualitative properties of the functions can be specified: mathematically, we can consider that the unknown functions belong to a specific class of functions. However, the use of two different functions belonging to the same class can result in qualitatively different dynamical behaviour in the model and different types of bifurcation. In the literature, the conventional way to avoid such ambiguity is to narrow the class of unknown functions, which allows us to keep patterns of dynamical behaviour consistent for varying functions. The main shortcoming of this approach is that the restrictions on the model functions are often given by cumbersome expressions and are strictly model-dependent: biologically, they are meaningless. In this paper, we suggest a new framework (based on the ODE paradigm) which allows us to investigate deterministic biological models in which the mathematical formulation of some functions is unspecified except for some generic qualitative properties. We demonstrate that in such models, the conventional idea of revealing a concrete bifurcation structure becomes irrelevant: we can only describe bifurcations with a certain probability. We then propose a method to define the probability of a bifurcation taking place when there is uncertainty in the parameterisation in our model. As an illustrative example, we consider a generic predator-prey model where the use of different parameterisations of the logistic-type prey growth function can result in different dynamics in terms of the type of the Hopf bifurcation through which the coexistence equilibrium loses stability. Using this system, we demonstrate a framework for evaluating the probability of having a supercritical or subcritical Hopf bifurcation. PMID- 24789568 TI - Hypothalamus-pituitary-thyroid feedback control: implications of mathematical modeling and consequences for thyrotropin (TSH) and free thyroxine (FT4) reference ranges. AB - The components of thyrotropic feedback control are well established in mainstream physiology and endocrinology, but their relation to the whole system's integrated behavior remains only partly understood. Most modeling research seeks to derive a generalized model for universal application across all individuals. We show how parameterizable models, based on the principles of control theory, tailored to the individual, can fill these gaps. We develop a system network describing the closed-loop behavior of the hypothalamus-pituitary (HP)-thyroid interaction and the set point targeted by the control system at equilibrium. The stability of this system is defined by using loop gain conditions. Defined points of homeostasis of the hypothalamus-pituitary-thyroid (HPT) feedback loop found at the intersections of the HP and thyroid transfer functions at the boundaries of normal reference ranges were evaluated by loop gain calculations. At equilibrium, the feedback control approaches a point defined in both dimensions by a [TSH] [FT4] coordinate for which the loop gain is greater than unity. This model describes the emergence of homeostasis of the HPT axis from characteristic curves of HP and thyroid, thus supporting the validity of the translation between physiological knowledge and clinical reference ranges. PMID- 24789569 TI - Stabilizing control for a pulsatile cardiovascular mathematical model. AB - In this paper, we develop a pulsatile model for the cardiovascular system which describes the reaction of this system to a submaximal constant workload imposed on a person at a bicycle ergometer test after a period of rest. Furthermore, the model should allow to use measurements for the pulsatile pressure in fingertips which provide information on the diastolic and the systolic pressure for parameter estimation. Based on the assumption that the baroreceptor loop is the essential control loop in this case, we design a stabilizing feedback control for the pulsatile model which is obtained by solving a linear-quadratic regulator problem for the linearization of a non-pulsatile counterpart of the pulsatile model. We also investigate the behavior of the model with respect to changes in the weight of the term in the cost functional for the linear-quadratic regulator problem which penalizes the deviation of the momentary pressure in the aorta from the pressure at the stationary situation which should be obtained. PMID- 24789570 TI - Sustainability and substitutability. AB - Developing a quantitative science of sustainability requires bridging mathematical concepts from fields contributing to sustainability science. The concept of substitutability is central to sustainability but is defined differently by different fields. Specifically, economics tends to define substitutability as a marginal concept while fields such as ecology tend to focus on limiting behaviors. We explain how to reconcile these different views. We develop a model where investments can be made in knowledge to increase the elasticity of substitution. We explore the set of sustainable and optimal trajectories for natural capital extraction and built and knowledge capital accumulation. Investments in substitutability through knowledge stock accumulation affect the value of natural capital. Results suggest that investing in the knowledge stock, which can enhance substitutability, is critical to desirable sustainable outcomes. This result is robust even when natural capital is not managed optimally. This leads us to conclude that investments in the knowledge stock are of first order importance for sustainability. PMID- 24789571 TI - Solvent immersion imprint lithography. AB - We present Solvent Immersion Imprint Lithography (SIIL), a technique for polymer functionalization and microsystem prototyping. SIIL is based on polymer immersion in commonly available solvents. This was experimentally and computationally analyzed, uniquely enabling two practical aspects. The first is imprinting and bonding deep features that span the 1 to 100 MUm range, which are unattainable with existing solvent-based methods. The second is a functionalization scheme characterized by a well-controlled, 3D distribution of chemical moieties. SIIL is validated by developing microfluidics with embedded 3D oxygen sensors and microbioreactors for quantitative metabolic studies of a thermophile anaerobe microbial culture. Polystyrene (PS) was employed in the aforementioned applications; however all soluble polymers - including inorganic ones - can be employed with SIIL under no instrumentation requirements and typical processing times of less than two minutes. PMID- 24789572 TI - Species and endosymbiont diversity of Bemisia tabaci (Homoptera: Aleyrodidae) on vegetable crops in Senegal. AB - Bemisia tabaci-transmitted geminiviruses are one of the major threats on cassava and vegetable crops in Africa. However, to date, few studies are available on the diversity of B. tabaci and their associated endosymbionts in Africa. More than 28 species have been described in the complex of B. tabaci cryptic species; among them, 2 are invasive pests worldwide: MED and MEAM1. In order to assess the species diversity of B. tabaci in vegetable crops in Senegal, several samplings in different localities, hosts and seasons were collected and analyzed with nuclear (microsatellite) and mitochondrial (COI) markers. The bacterial endosymbiont community was also studied for each sample. Two species were detected: MED Q1 and MEAM1 B. Patterns of MED Q1 (dominance on most of the samples and sites, highest nuclear and mitochondrial diversity and broader secondary endosymbiont community: Hamiltonella, Cardinium, Wolbachia and Rickettsia), point toward a predominant resident begomovirus vector group for MED Q1 on market gardening crops. Furthermore, the lower prevalence of the second species MEAM1 B, its lower nuclear and mitochondrial diversity and a narrower secondary endosymbiont community (Hamiltonella/Rickettsia), indicate that this genetic group is exotic and results from a recent invasion in this area. PMID- 24789573 TI - The human gastrointestinal tract-specific transcriptome and proteome as defined by RNA sequencing and antibody-based profiling. AB - BACKGROUND: The gastrointestinal tract (GIT) is subdivided into different anatomical organs with many shared functions and characteristics, but also distinct differences. We have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to describe the gene and protein expression patterns that define the human GIT. METHODS: RNA sequencing data derived from stomach, duodenum, jejunum/ileum and colon specimens were compared to gene expression levels in 23 other normal human tissues analysed with the same method. Protein profiling based on immunohistochemistry and tissue microarrays was used to sub-localize the corresponding proteins with GIT-specific expression into sub-cellular compartments and cell types. RESULTS: Approximately 75% of all human protein-coding genes were expressed in at least one of the GIT tissues. Only 51 genes showed enriched expression in either one of the GIT tissues and an additional 83 genes were enriched in two or more GIT tissues. The list of GIT-enriched genes with validated protein expression patterns included various well-known but also previously uncharacterised or poorly studied genes. For instance, the colon-enriched expression of NXPE family member 1 (NXPE1) was established, while NLR family, pyrin domain-containing 6 (NLRP6) expression was primarily found in the human small intestine. CONCLUSIONS: We have applied a genome-wide analysis based on transcriptomics and antibody-based protein profiling to identify genes that are expressed in a specific manner within the human GIT. These genes and proteins constitute important starting points for an improved understanding of the normal function and the different states of disease associated with the GIT. PMID- 24789574 TI - Agonistic anti-CD137 antibody treatment leads to antitumor response in mice with liver cancer. AB - Immunotherapy is a promising strategy against hepatocellular carcinoma (HCC). We assessed the therapeutic effects of stimulating CD137, a member of the TNF receptor family, with agonistic monoclonal antibodies (mAb). Agonistic anti-CD137 mAb treatment was tested on two in situ models of HCC in immunocompetent mice. We also studied the mediators involved at different time points. In an orthotopic HCC the treatment consistently leads to complete tumor regression in 40-60% of animals. The protection is long lasting in the animals responding to the treatment, which can reject a second tumor challenge more than 3 months after treatment and eradication of the first malignancy. The main mediators of the effect are T lymphocytes and NK cells, demonstrated through depletion experiments. In addition, adoptive transfer of splenocytes prepared from anti CD137 mAb-treated and -cured mice to naive mice allowed them to, in turn, reject the tumor. The efficacy of anti-CD137 mAb treatment is associated with early, sustained recruitment of iNOS-positive macrophages within tumor nodules. Moreover, in the absence of treatment, tumor development is accompanied by infiltration by myeloid derived suppressor cells (MDSC) and regulatory T lymphocytes. In mice responding to the anti-CD137 mAb treatment, this infiltration is very limited, and a combination treatment with a depletion of MDSC leads to the recovery of 80% of the mice. These results demonstrate that agonistic anti-CD137 mAb is a promising therapeutic strategy for anti-tumor immunity stimulation against HCC. PMID- 24789575 TI - Differences in major depressive disorder and generalised anxiety disorder symptomatology between prostate cancer patients receiving hormone therapy and those who are not. AB - OBJECTIVE: The aim of this study is to explore the associations between hormone treatment variables and depression, and the nature of depression in prostate cancer (PCa) patients by comparing the severity and symptom profile of anxiety and depression in men who were currently receiving hormone therapy (HT) versus those who were not. METHOD: Self-reports of anxiety and depression on standardized scales of GAD and major depressive disorder (MDD) were collected from 156 PCa patients across two recruitment sites in Australia. Patients who were currently receiving HT were compared with patients not receiving HT for their severity and symptom profiles on GAD and MDD. RESULTS: Participants receiving HT had significantly higher GAD and MDD total scores than patients who were not receiving HT. In addition, the symptom profiles of these two HT subgroups were differentiated by significantly higher scores on the key criteria for GAD and MDD plus fatigue and sleeping difficulties but not the remaining symptoms of GAD and MDD. However, there were no significant differences between HT subgroups for the degree of functional impairment experienced by these symptoms. CONCLUSION: Although these data confirm the association between HT and anxiety/depression, the range of GAD and MDD symptoms influenced is relatively restricted. Moreover, functional ability does not appear to be impaired by HT. These findings clarify the ways in which HT affects PCa patients and suggests that a simple total scale score for anxiety and depression may not be as helpful in designing treatment as consideration of the symptomatic profiles of PCa patients receiving HT. PMID- 24789576 TI - Regulation of the HMOX1 gene by the transcription factor AP-2delta with unique DNA binding site. AB - AP-2 transcription factors are important sequence-specific DNA-binding regulators that are expressed in the neural crest and other tissues during mammalian development. The human AP-2 family of transcription factors consists of five members, AP-2alpha, -beta, -gamma, -delta and -epsilon, which have an important role in the regulation of gene expression during development and in the differentiation of multiple organs and tissues. The present study aimed to investigate the mechanism by which AP-2delta mediates heme oxygenase-1 (HMOX1) gene expression. It was identified that the human AP-2delta protein exhibited weak binding to a suboptimal AP-2 sequence, 5'-GCCN3GGC-3', to which all other AP 2 proteins bind in vitro, providing the first example of DNA target specificity amongst the AP-2 family. AP-2delta protein bound to an optimized AP-2 consensus DNA sequence, 5'-GCCTGAGGC-3', in vitro and transactivated gene expression in eukaryotic cells. The transactivation domain of Ap-2delta differs notably from those in the other AP-2 proteins as it lacks the PY motif (XPPXY) and several other conserved residues that are important for the transcriptional activity of AP-2 proteins, yet it functions as an equally strong activator. PMID- 24789577 TI - Switchable dielectric, piezoelectric, and second-harmonic generation bistability in a new improper ferroelectric above room temperature. AB - Imidazolium periodate (IPI) is found to be an improper ferroelectric. It shows bistable properties simultaneously in three channels of dielectricity, piezoelectricity, and second-harmonic generation within the temperature window 300-310 K. PMID- 24789578 TI - Spatially selective heteronuclear multiple-quantum coherence spectroscopy for biomolecular NMR studies. AB - Spatially selective heteronuclear multiple-quantum coherence (SS HMQC) NMR spectroscopy is developed for solution studies of proteins. Due to "time staggered" acquisitioning of free induction decays (FIDs) in different slices, SS HMQC allows one to use long delays for longitudinal nuclear spin relaxation at high repetition rates. To also achieve high intrinsic sensitivity, SS HMQC is implemented by combining a single spatially selective (1)H excitation pulse with nonselective (1) H 180 degrees pulses. High-quality spectra were obtained within 66 s for a 7.6 kDa uniformly (13) C,(15) N-labeled protein, and within 45 and 90 s for, respectively, two proteins with molecular weights of 7.5 and 43 kDa, which were uniformly (2)H,(13) C,(15) N-labeled, except for having protonated methyl groups of isoleucine, leucine and valine residues. PMID- 24789579 TI - Efficacy of pharmacologic and psychotherapeutic interventions in psychiatry: to talk or to prescribe: is that the question? PMID- 24789580 TI - Excretion of tectorigenin in rat urine orally administrated at different dosages by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - Tectorigenin (Te) is a main active component in the flowers of Pueraria thomsonii Benth. and the rhizomes of Belamcanda chinensis (L.) DC. Previously, we have reported the pharmacokinetic properties of Te in rat plasma. The purpose of this study was to investigate the urinary excretion of Te after oral administration to rats at different dose levels. Using UHPLC/Q-TOFMS, totally 26 metabolites were detected in rat urine after oral administration of Te at dose of 65 and 130 mg/kg. Among them, nine metabolites, Te, tectorigenin-7-O-glucuronide-4'-sulfate (Te-7G-4'S), tectorigenin-7-O-glucuronide (Te-7G), tectorigenin-7-O-sulfate (Te 7S), tectorigenin-4'-O-glucuronide (Te-4'S), isotectorigenin, genistein, irisolidone-7-O-glucuronide (Ir-7G), and irisolidone, were identified by comparing the retention time, UV and MS spectra with those of authentic standards. A UHPLC/Q-TOFMS method for simultaneous quantification and semi quantification of all the metabolites in urine was developed. The cumulative urinary excretions of Te and the major metabolite Te-7G were 1.99 and 5.80 MUmol at 65 mg/kg, 3.05 and 6.48 MUmol at 130 mg/kg, accounted for 4.17 % and 15.8, 2.81 and 9.49 % of administrated Te, respectively. The excretion rates of Te-7G, Te-7G-4'S, Ir-7G, and Te reached a maximum between 12 and 24 h after oral dosing at 65 and 130 mg/kg. The cumulative urine excretion rates of Te were 23.1 and 20.1 % within 72 h at 65 and 130 mg/kg, respectively. These results suggested that the glucuronidation was the primary metabolic pathway especially at low dose level. PMID- 24789581 TI - Cucurbitacin B inhibits growth and induces apoptosis through the JAK2/STAT3 and MAPK pathways in SH-SY5Y human neuroblastoma cells. AB - Cucurbitacin B (CuB) is a tetracyclic triterpene that is contained in extracts from cucurbitaceous plants and has been demonstrated to have anticancer and anti inflammatory activities. The purpose of the present study was to determine whether CuB exhibits anticancer effects on SH-SY5Y human neuroblastoma cells and to analyze the underlying molecular mechanism. The results demonstrated that CuB not only induced cell cycle arrest at the G2/M phase, but also induced apoptosis as characterized by positive Annexin V staining, downregulation of phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 3 (p STAT3), phospho-extracellular signal-regulated kinases and the activation of c Jun N-terminal kinase and p38 mitogen activated protein kinase (MAPK). CuB also altered the expression of gene products that mediated cell proliferation (Cyclin B1 and cyclin-dependent kinase 1), cell survival (B-cell lymphoma 2, Bcl2 associated X protein) and increased the expression of p53 and p21. These results provide the evidence that JAK2/STAT3 and MAPKs have crucial roles in CuB-induced growth inhibition and apoptosis in SH-SY5Y human neuroblastoma cells. PMID- 24789582 TI - Myocardial signal intensity decay after gadolinium injection: a fast and effective method for the diagnosis of cardiac amyloidosis. AB - Late Gadolinium Enhancement (LGE) pattern of cardiac amyloidosis (CA) at cardiac magnetic resonance (CMR) examination is absent in approximately 30% of patients. We tested whether the evaluation of myocardial gadolinium signal intensity (SI) decay (SID) has a higher diagnostic accuracy for CA. CMR was performed in 59 patients with systemic AL amyloidosis (36 males, 69 +/- 10 years, mean +/- SD), and 20 age/sex-matched healthy controls. LGE images were acquired every minute up to 8 min after gadolinium injection (time of inversion 250 ms). SI regions of interest were plotted in SI/time curves for endocardial (Endo) and epicardial layer of interventricular septum, cavity, and skeletal muscle as reference. SID (a negative exponential function described by the parameter TSID) was expressed as number of heart beats (HB) from each ROI. The typical LGE pattern for CA was detected in 42 patients (Ty-LGE), while 17 showed either absent LGE or an atypical pattern (ATy-LGE). A definite CA diagnosis was confirmed in all Ty-LGE patients and in 10/17 ATy-LGE patients. At ROC analysis Endo-TSID was the most accurate parameter to distinguish Ty-LGE and ATy-LGE patients from controls. A 269 HB threshold (mean + 2 SD Endo-TSID measured in controls) identified 51/52 patients with definite CA diagnosis, with 98% sensitivity, 93% specificity, and 96% diagnostic accuracy. A direct relation was found between the extracellular volume and Endo-TSID in CA patients (r 0.72, 95% CI 0.37-089, p < 0.001). the analysis of myocardial SID after gadolinium injection improves the accuracy of CMR for CA diagnosis. PMID- 24789583 TI - The generalist, the specialist, and the patient with chronic kidney disease. PMID- 24789584 TI - Niacin's effect on cardiovascular risk: have we finally learned our lesson? PMID- 24789585 TI - Syncope during a pharmacologic nuclear stress test. PMID- 24789586 TI - An 18-year-old woman with hepatic cysts. PMID- 24789587 TI - A 20-year-old woman with fatigue and palpitations. PMID- 24789588 TI - Managing advanced chronic kidney disease: a primary care guide. AB - Chronic kidney disease (CKD) is a common disorder that requires close collaboration between the primary care physician and nephrologist. Most aspects of early CKD can be managed in the primary care setting with nephrology input. As the disease progresses, many aspects of care should be transitioned to the nephrologist, especially as the patient nears end-stage renal disease, when dialysis and transplantation must be addressed. PMID- 24789589 TI - Heart failure in African Americans: disparities can be overcome. AB - African Americans are disproportionately affected by heart failure, with a high prevalence at an early age. Hypertension, diabetes, obesity, and chronic kidney disease are all common in African Americans and all predispose to heart failure. Neurohormonal imbalances, endothelial dysfunction, genetic polymorphisms, and socioeconomic factors also contribute. In general, the same evidence-based treatment guidelines that apply to white patients with heart failure also apply to African Americans. However, the combination of hydralazine and isosorbide dinitrate is advised specifically for African Americans. PMID- 24789590 TI - Optimizing transitions of care to reduce rehospitalizations. AB - Transitions of care-when patients move from one health care facility to another or back home-that are poorly executed result in adverse effects for patients. Fortunately, programs can be implemented that enhance collaboration across care settings and improve outcomes including reducing hospital readmission rates. PMID- 24789591 TI - Constrictive pericarditis following surgical repair of a peritoneopericardial diaphragmatic hernia in a cat. AB - A 4-year-old female spayed domestic longhair cat was referred for dyspnea. Further diagnostics revealed severe pleural effusion and a peritoneopericardial diaphragmatic hernia (PPDH). Following surgical correction of the PPDH the pleural effusion persisted. Re-check echocardiogram 4 weeks after initial evaluation revealed leftward deviation of the interventricular septum and interatrial septum occurring with inspiration. There were also exaggerated phasic changes in trans-tricuspid flow velocities suggestive of constrictive pericardial disease. Cardiac catheterization was performed and revealed elevated pressures in the right atrium and right ventricle. Constrictive pericarditis (CP) and epicarditis was confirmed at surgery, where subtotal pericardiectomy was performed with epicardial decortication. The cat continued to develop recurrent pleural effusion after surgery, although the volume and frequency of recurrence slowed over time. This is the first reported case of CP following PPDH repair in a cat. PMID- 24789592 TI - Upregulated expression and activation of membrane-associated proteases in esophageal squamous cell carcinoma. AB - To better understand the role of membrane-associated proteolytic systems in the development of esophageal cancer, we studied the expression of two serine proteases, fibroblast activation protein-alpha (FAP-alpha) and dipeptidyl peptidase IV (DPPIV) and three metalloproteinases, matrix metalloproteinase (MMP) 2, MMP-9 and MT1-MMP in 24 primary esophageal squamous cell carcinoma (ESCC) tissues and paired non-cancer tissues. Using reverse-transcription PCR, western blotting and zymography, we showed that both serine proteases and all three metalloproteinases were highly altered in ESCC. A positive correlation between the expression of FAP-alpha and DPPIV and the activity of both gelatinases was found. This may indicate that these proteolytic systems are tightly linked to each other and collectively are involved in the process of ECM degradation that facilitates cancer cell invasion and metastasis. PMID- 24789593 TI - Radiological and clinical features of vein of Galen malformations. AB - BACKGROUND: Vein of Galen malformations (VOGMs) are rare and complex congenital arteriovenous fistulas. The clinical and radiological features of VOGMs and their relation to clinical outcomes are not fully characterized. OBJECTIVE: To examine the clinical and radiological features of VOGMs and the predictors of outcome in patients. METHODS: We retrospectively reviewed the available imaging and medical records of all patients with VOGMs treated at the University of California, San Francisco between 1986 and 2013. Radiological and clinical features were identified. We applied the modified Rankin Scale to determine functional outcome by chart review. Predictors of outcome were assessed by chi(2) analyses. RESULTS: Forty-one cases were confirmed as VOGM. Most patients (78%) had been diagnosed with VOGM in the first year of life. Age at treatment was bimodally distributed, with predominantly urgent embolization at <10 days of age and elective embolization after 1 year of age. Patients commonly presented with hydrocephalus (65.9%) and congestive heart failure (61.0%). Mixed-type (31.7%) VOGM was more common in our cohort than purely mural (29.3%) or choroidal (26.8%) types. The most common feeding arteries were the choroidal and posterior cerebral arteries. Transarterial embolization with coils was the most common technique used to treat VOGMs at our institution. Functional outcome was normal or only mildly disabled in 50% of the cases at last follow-up (median=3 years, range=0-23 years). Younger age at first diagnosis, congestive heart failure, and seizures were predictive of adverse clinical outcome. The survival rate in our sample was 78.0% and complete thrombosis of the VOGM was achieved in 62.5% of patients. CONCLUSIONS: VOGMs continue to be challenging to treat and manage. Nonetheless, endovascular approaches to treatment are continuing to be refined and improved, with increasing success. The neurodevelopmental outcomes of affected children whose VOGMs are treated may be good in many cases. PMID- 24789594 TI - Primary stentriever versus combined stentriever plus aspiration thrombectomy approaches: in vitro stroke model comparison. AB - BACKGROUND: Artificial stroke models can be used for testing various thrombectomy devices. OBJECTIVE: To determine the value of combined stentriever-aspiration thrombectomy compared with the stentriever-alone approach. METHODS: We designed an in vitro model of the intracranial circulation with a focus on the middle cerebral artery (MCA) that closely resembles the human intracranial circulation. After introducing fresh clot in the MCA, we used conventional biplane angiography and microangiographic fluoroscopy to compare recanalization rates and occurrence of emboli in new, unaffected territory for thrombectomy approaches in which a stentriever (Solitaire flow restoration stentriever, Covidien) was used alone or in combination with continuous manual aspiration through a Navien catheter (Covidien). RESULTS: In a total of 22 experiments (11 for each approach), successful clot delivery to the MCA was achieved in all cases. Successful angiographic recanalization (thrombolysis in cerebral infarction score of 2b-3) was achieved more frequently with the combined stentriever-aspiration approach than with the stentriever-alone approach (in 10 vs 4 experiments, p=0.023). Emboli in new territory occurred in three experiments with the stentriever-alone approach, and none were seen with the combined approach (p=0.21). CONCLUSIONS: The combined stentriever-aspiration approach to thrombectomy leads to better angiographic recanalization rates than use of the stentriever alone. Further experiments are needed to test the value of balloon-guide catheters and aspiration performed using other types of catheters and modes of aspiration. PMID- 24789595 TI - Analyzing the Human Papillomavirus (HPV) Life Cycle in Primary Keratinocytes with a Quantitative Colony-Forming Assay. AB - Papillomavirus genomes replicate as extrachromosomal plasmids within infected keratinocytes, requiring the regulated expression of early viral gene products to initially amplify the viral genomes and subvert cell growth checkpoints as part of a complex path to immortalization. Building on contemporary keratinocyte transfection and culture systems, the methods described in this unit form a detailed approach to analyzing critical events in the human papillomavirus (HPV) life cycle, utilizing physiologic levels of viral gene products expressed from their native promoter(s) in the natural host cells for HPV infection. A quantitative colony-forming assay permits comparison of the capacities of various transfected HPV types and mutant HPV genomes to initially form colonies and immortalize human keratinocytes. In conjunction with additional methods, these protocols enable examination of genomic stability, viral and cellular gene expression, viral integration, and differentiation patterns influenced by HPV persistence in clonal human keratinocytes that effectively mimic early events in HPV infection. PMID- 24789597 TI - Western blot assay for quantitative and qualitative antigen detection in vaccine development. AB - Immunological methods for quantitative measurement, antigenic characterization, and monitoring the stability of active immunogenic component(s) are a critical need in the vaccine development process. This unit describes an enhanced chemiluminescence-based western blot for quantitative detection of Plasmodium falciparum circumsporozoite protein (PfCSP), a major malaria candidate vaccine antigen. The most salient features of this assay are its high sensitivity and reproducibility; it can reliably detect ~5 to 10 pg PfCSP expressed on native parasites or recombinantly expressed in Escherichia coli. Although described for a specific vaccine antigen, this assay should be applicable for any antigen antibody combination for which relevant detection reagents are available. Detailed stepwise experimental procedures and methods for data acquisition and analysis are described. PMID- 24789596 TI - Murine norovirus: propagation, quantification, and genetic manipulation. AB - Murine norovirus (MNV) is a positive-sense, plus-stranded RNA virus in the Caliciviridae family. It is the most common pathogen in biomedical research colonies. MNV is also related to the human noroviruses, which cause the majority of nonbacterial gastroenteritis worldwide. Like the human noroviruses, MNV is an enteric virus that replicates in the intestine and is transmitted by the fecal oral route. MNV replicates in murine macrophages and dendritic cells in cells in culture and in the murine host. This virus is often used to study mechanisms in norovirus biology, because human noroviruses are refractory to growth in cell culture. MNV combines the availability of a cell culture and reverse genetics system with the ability to study infection in the native host. Herein, we describe a panel of techniques that are commonly used to study MNV biology. PMID- 24789598 TI - Biological sand filters: low-cost bioremediation technique for production of clean drinking water. AB - Approximately 1.1 billion people in rural and peri-urban communities of developing countries do not have access to safe drinking water. The mortality from diarrheal-related diseases amounts to ~2.2 million people each year from the consumption of unsafe water. Most of them are children under 5 years of age--250 deaths an hour from microbiologically contaminated water. There is conclusive evidence that one low-cost household bioremediation intervention, use of biological sand filters, is capable of dramatically improving the microbiological quality of drinking water. This unit will describe this relatively new and proven bioremediation technology's ability to empower at-risk populations to use naturally occurring biological principles and readily available materials as a sustainable way to achieve the health benefits of safe drinking water. PMID- 24789599 TI - Bioremediation of Turbid Surface Water Using Seed Extract from the Moringa oleifera Lam. (Drumstick) Tree. AB - An indigenous water treatment method uses Moringa oleifera seeds in the form of a crude water-soluble extract in suspension, resulting in an effective natural clarification agent for highly turbid and untreated pathogenic surface water. Efficient reduction (80.0% to 99.5%) of high turbidity produces an aesthetically clear supernatant, concurrently accompanied by 90.00% to 99.99% (1 to 4 log) bacterial reduction. Application of this low-cost Moringa oleifera protocol is recommended for water treatment where rural and peri-urban people living in extreme poverty are presently drinking highly turbid and microbiologically contaminated water. PMID- 24789600 TI - Isolation of Listeria monocytogenes from Food and Water: Official and Experimental Protocols. AB - Listeria monocytogenes is frequently encountered in foods but often at low concentrations and typically in the presence of other microbiota, including nonpathogenic Listeria spp. The potential of L. monocytogenes to cause severe human disease mandates sensitive, accurate, and rapid detection in foods. Isolation of L. monocytogenes from foods is critical, not only for routine surveillance, but also for epidemiologic investigations. Isolation of the pathogen from water (especially surface water used for irrigation) is similarly important, as produce has been implicated in listeriosis outbreaks and contaminated water can be involved in contamination of produce. This unit provides basic protocols for the isolation of L. monocytogenes from foods and water. PMID- 24789601 TI - Tobacco product developments coinciding with the implementation of plain packaging in Australia. PMID- 24789603 TI - Rapidly increasing promotional expenditures for e-cigarettes. PMID- 24789602 TI - Clinical interventions to reduce secondhand smoke exposure among pregnant women: a systematic review. AB - OBJECTIVE: To conduct a systematic review of clinical interventions to reduce secondhand smoke (SHS) exposure among non-smoking pregnant women. DATA SOURCES: We searched 16 databases for publications from 1990 to January 2013, with no language restrictions. STUDY SELECTION: Papers were included if they met the following criteria: (1) the study population included non-smoking pregnant women exposed to SHS, (2) the clinical interventions were intended to reduce SHS exposure at home, (3) the study included a control group and (4) outcomes included either reduced SHS exposure of non-smoking pregnant women at home or quit rates among smoking partners during the pregnancy of the woman. DATA EXTRACTION: Two coders independently reviewed each abstract or full text to identify eligible papers. Two abstractors independently coded papers based on US Preventive Services Task Force criteria for study quality (good, fair, poor), and studies without biochemically-verified outcome measures were considered poor quality. DATA SYNTHESIS: From 4670 papers, we identified five studies that met our inclusion criteria: four focused on reducing SHS exposure among non-smoking pregnant women, and one focused on providing cessation support for smoking partners of pregnant women. All were randomised controlled trials, and all reported positive findings. Three studies were judged poor quality because outcome measures were not biochemically-verified, and two were considered fair quality. CONCLUSIONS: Clinical interventions delivered in prenatal care settings appear to reduce SHS exposure, but study weaknesses limit our ability to draw firm conclusions. More rigorous studies, using biochemical validation, are needed to identify strategies for reducing SHS exposure in pregnant women. PMID- 24789605 TI - Tobacco control funding for low-income and middle-income countries in a time of economic hardship. AB - OBJECTIVE: To assess how levels of tobacco control funding for low-income and middle-income countries (LMIC) changed following the 2008-2009 global economic downturn. METHODS: In order to estimate the amount of tobacco control funding in LMICs, we created an integrated database of Development Assistance to Control Tobacco (DACT). This database includes data on funding from bilateral and multilateral donors, non-governmental organisations, private foundations and the corporate sector. The database contains information on 1389 disbursements awarded by 30 entities between 2000 and 2012. RESULTS: DACT declined only marginally from US$68.8 million (US$0.016 per adult) in 2009 to US$68.2 million (US$0.016 per adult) in 2011, but deviated significantly from its 2000 to 2009 trend. The sources of funding remain highly concentrated, with nearly a half of the money coming from the Bloomberg Initiative and the Bill & Melinda Gates Foundation in 2011. The relative importance of institutional and research grants has declined. CONCLUSIONS: Our findings are consistent with the patterns in general levels of development assistance for health: after a decade of rapid growth, funding for tobacco control activities in LMICs has levelled off. Just as the tobacco control community is beginning to envision the endgame for tobacco, the funding remains erratic, inadequate, and highly vulnerable due to its level of concentration. Innovative financing mechanisms might help to increase the funding pool. PMID- 24789604 TI - Racial and non-racial discrimination and smoking status among South African adults 10 years after apartheid. AB - BACKGROUND: Despite a long history of discrimination and persisting racial disparities in smoking prevalence, little research exists on the relationship between discrimination and smoking in South Africa. METHODS: This analysis examined chronic (day-to-day) and acute (lifetime) experiences of racial and non racial (eg, age, gender or physical appearance) discrimination and smoking status among respondents to the South Africa Stress and Health study. Logistic regression models were constructed using SAS-Callable SUDAAN. RESULTS: Both chronic racial discrimination (RR=1.45, 95% CI 1.14 to 1.85) and chronic non racial discrimination (RR=1.69, 95% CI 1.37 to 2.08) predicted a higher risk of smoking, but neither type of acute discrimination did. Total (sum of racial and non-racial) chronic discrimination (RR=1.46, 95% CI 1.20 to 1.78) and total acute discrimination (RR=1.28, 95% CI 1.01 to 1.60) predicted a higher risk of current smoking. CONCLUSIONS: Racial and non-racial discrimination may be related to South African adults' smoking behaviour, but this relationship likely varies by the timing and frequency of these experiences. Future research should use longitudinal data to identify the temporal ordering of the relationships studied, include areas outside of South Africa to increase generalisability and consider the implications of these findings for smoking cessation approaches in South Africa. PMID- 24789606 TI - Estimates of the economic contributions of the bidi manufacturing industry in India. AB - BACKGROUND: Bidis, the most common smoking tobacco product in India, remain largely untaxed and are subject to very few regulations to discourage their use. A major argument against tax increases is the large potential loss of economic activity and employment in the bidi industry from reduced consumption. METHODS: We used a nationally representative survey of unorganised bidi manufacturing firms (n=2841) in India to estimate the economic contribution of the industry. RESULTS: We find that of the 35 states and union territories of India, the bidi industry operated across 17 states, with over 95% of its production concentrated in 10 states. Bidi manufacturing firms contributed 0.50% of total sales and 0.6% of the gross value added by the manufacturing economy in 2005-2006. The industry employed approximately 3.4 million full-time workers, which comprise about 0.7% of employment in all sectors. A further 0.7 million were part-time workers. Bidi workers were also among the lowest paid employees in India. The industry offered only 0.09% of all compensation provided in the manufacturing sector (organised and unorganised). CONCLUSIONS: Considering the relatively small economic footprint of the bidi industry in India, higher excise taxes and regulations on bidis are unlikely to disrupt economic growth at an aggregate level, or lead to mass unemployment and economic hardship among small bidi workers. On average, the economic annual output per bidi worker is about US$143, which is an order of magnitude smaller than the large economic losses from the several hundred thousand deaths due to bidi smoking per year. PMID- 24789607 TI - Smoke-free parks and beaches: an interrupted time-series study of behavioural impact in New York City. AB - BACKGROUND: In 2011, New York City (NYC) parks and beaches became smoke-free. There is currently little research evaluating the impact of such laws on smoking behaviour at the population level. METHODS: We used an interrupted time-series study design to analyse data from the New York State Adult Tobacco Survey to assess the law's impact using the rest of New York State as a comparison. Trends in how frequently respondents noticed people smoking in parks and beaches were analysed between the third quarter of 2009 and the fourth quarter of 2012, comparing NYC to the rest of the state. RESULTS: The trend in the frequency of NYC residents noticing people smoking in local parks and beaches decreased significantly over the six quarters after the law took effect. There was no comparable decline among residents in the rest of the state. An increase in the number of respondents who never noticed people smoking in NYC contributed to this decline. CONCLUSIONS: These results are consistent with previous studies and provide population-level evidence that suggest the law has reduced smoking in parks and on beaches. PMID- 24789608 TI - Analysis of simple sequence repeats in the Gaeumannomyces graminis var. tritici genome and the development of microsatellite markers. AB - Understanding the genetic structure of Gaeumannomyces graminis var. tritici is essential for the establishment of efficient disease control strategies. It is becoming clear that microsatellites, or simple sequence repeats (SSRs), play an important role in genome organization and phenotypic diversity, and are a large source of genetic markers for population genetics and meiotic maps. In this study, we examined the G. graminis var. tritici genome (1) to analyze its pattern of SSRs, (2) to compare it with other plant pathogenic filamentous fungi, such as Magnaporthe oryzae and M. poae, and (3) to identify new polymorphic SSR markers for genetic diversity. The G. graminis var. tritici genome was rich in SSRs; a total 13,650 SSRs have been identified with mononucleotides being the most common motifs. In coding regions, the densities of tri- and hexanucleotides were significantly higher than in noncoding regions. The di-, tri-, tetra, penta, and hexanucleotide repeats in the G. graminis var. tritici genome were more abundant than the same repeats in M. oryzae and M. poae. From 115 devised primers, 39 SSRs are polymorphic with G. graminis var. tritici isolates, and 8 primers were randomly selected to analyze 116 isolates from China. The number of alleles varied from 2 to 7 and the expected heterozygosity (He) from 0.499 to 0.837. In conclusion, SSRs developed in this study were highly polymorphic, and our analysis indicated that G. graminis var. tritici is a species with high genetic diversity. The results provide a pioneering report for several applications, such as the assessment of population structure and genetic diversity of G. graminis var. tritici. PMID- 24789609 TI - Recycling slaughterhouse waste into fertilizer: how do pyrolysis temperature and biomass additions affect phosphorus availability and chemistry? AB - BACKGROUND: Pyrolysis of slaughterhouse waste could promote more sustainable phosphorus (P) usage through the development of alternative P fertilizers. This study investigated how pyrolysis temperature (220, 350, 550 and 750 degrees C), rendering before pyrolysis, and wood or corn biomass additions affect P chemistry in bone char, plant availability, and its potential as P fertilizer. RESULTS: Linear combination fitting of synchrotron-based X-ray absorption near edge structure spectra demonstrated that higher pyrolysis temperatures decreased the fit with organic P references, but increased the fit with a hydroxyapatite (HA) reference, used as an indicator of high calcium phosphate (CaP) crystallinity. The fit to the HA reference increased from 0% to 69% in bone with meat residue and from 20% to 95% in rendered bone. Biomass additions to the bone with meat residue reduced the fit to the HA reference by 83% for wood and 95% for corn, and additions to rendered bone by 37% for wood. No detectable aromatic P forms were generated by pyrolysis. High CaP crystallinity was correlated with low water extractable P, but high formic acid-extractable P indicative of high plant availability. Bone char supplied available P which was only 24% lower than Triple Superphosphate fertilizer and two- to five-fold higher than rock phosphate. CONCLUSION: Pyrolysis temperature and biomass additions can be used to design P fertilizer characteristics of bone char through changing CaP crystallinity that optimize P availability to plants. PMID- 24789610 TI - Quality of life in patients with schizophrenia: the impact of socio-economic factors and adverse effects of atypical antipsychotics drugs. AB - This cross-sectional study compared the effects of treatment with atypical antipsychotic drugs on quality of life (QoL) and side effects in 218 patients with schizophrenia attending the ambulatory services of psychiatric in Rio Grande do Norte, Brazil. Socio-economic variables were compared. The five-dimension EuroQoL (EQ-5D) was used to evaluate QoL, and side effects were assessed using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and the Simpson-Angus Scale. Data were analysed using the chi (2) test and Student's t test, with a significance level of 5 %. Average monthly household incomes in the medication groups were 1.1-2.1 minimum wages ($339-$678). UKU Scale scores showed significant differences in side effects, mainly, clozapine, quetiapine and ziprasidone (p < 0.05). EQ-5D scores showed that all drugs except olanzapine significantly impacted mobility (p < 0.05), and proportions of individuals reporting problems in other dimensions were high: 63.6 % of clozapine users reported mobility problems, 63.7 and 56.3 % of clozapine and ziprasidone users, respectively, had difficulties with usual activities, 68.8 and 54.5 % of ziprasidone and clozapine users, respectively, experienced pain and/or discomfort, and 72.8 % of clozapine users reported anxiety and/or depression. Psychiatric, neurological, and autonomous adverse effects, as well as other side effects, were prevalent in users of atypical antipsychotic drugs, especially clozapine and ziprasidone. Olanzapine had the least side effects. QoL was impacted by side effects and economic conditions in all groups. Thus, the effects of these antipsychotic agents appear to have been masked by aggravating social and economic situations. PMID- 24789612 TI - A mathematical model of the unidirectional block caused by the pulmonary veins for anatomically induced atrial reentry. AB - It is widely believed that the pulmonary veins (PVs) of the left atrium play the central role in the generation of anatomically induced atrial reentry but its mechanism has not been analytically explained. To understand this mechanism, a new analytic approach is proposed by adapting the geometric relative acceleration analysis from spacetime physics based on the hypothesis that a large relative acceleration can translate to a dramatic increase in the curvature of a wavefront and subsequently to conduction failure. By verifying the strong dependency of the propagational direction and the magnitude of anisotropy for conduction failure, this analytic method reveals that a unidirectional block can be generated by asymmetric propagation toward the PVs. This model is validated by computational tests in a T-shaped domain, computational simulations for three-dimensional atrial reentry and previous in-silico reports for anatomically induced atrial reentry. PMID- 24789613 TI - Rare form of autosomal dominant thalassemia--hemoglobin Hakkari. AB - Autosomal dominant Beta Thalassemias are rare and are due to point or frame shift mutations resulting in production of abnormal unstable beta chains of hemoglobin which precipitate leading to hemolysis and anemia. We describe a case of Hemoglobin Hakkari, a rare variant of dominant Thalassemia arising due to a de novo mutation in the exon 2 of the beta globin gene. PMID- 24789617 TI - Exogenous lactate supplementation to the injured brain: misleading conclusions with clinical implications. PMID- 24789618 TI - Use of tracheostomy in the PICU among patients requiring prolonged mechanical ventilation. AB - PURPOSE: The purpose of the present study is to describe the use of tracheostomy, specifically frequency, timing (in relation to initiation of mechanical ventilation), and associated factors, in a large cohort of children admitted to North American pediatric intensive care units (PICUs) and requiring prolonged mechanical ventilation. METHODS: This was a retrospective cohort study. De identified data were obtained from the VPS(LLC) database, a multi-site, clinical PICU database. Admissions between 1 July 2009 and 30 June 2011 were enrolled in the study if the patient required mechanical ventilation for at least 72 h and did not have a tracheostomy tube at initiation of mechanical ventilation. RESULTS: A total of 13,232 PICU admissions from 82 PICUs were analyzed in the study; of these, 872 (6.6 %) had a tracheostomy tube inserted after initiation of mechanical ventilation. The rate varied significantly (0-13.4 %, p < 0.001) among the 45 PICUs that had 100 or more admissions included in the study. The median time to insertion of a tracheostomy tube was 14.4 days (IQR 7.4-25.7), and it also varied significantly by unit (4.3-30.4 days, p < 0.001) among those that performed at least ten tracheostomies included in the study. CONCLUSIONS: There is significant variation in both the frequency and time to tracheostomy between the studied PICUs for patients requiring prolonged mechanical ventilation; among those who received a tracheostomy, the majority did so after two or more weeks of mechanical ventilation. Future studies examining tracheostomy benefits, disadvantages, outcomes, and resource utilization of this patient subgroup are indicated. PMID- 24789619 TI - Noninvasive ventilation in blunt chest trauma: beware of missed esophageal injuries! PMID- 24789620 TI - Give me less sugar: how to manage glucose levels in post-anoxic injury? PMID- 24789621 TI - Hypertonic lactate and the injured brain: facts and the potential for positive clinical implications. PMID- 24789622 TI - Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. AB - IMPORTANCE: Demonstrating the usefulness and complications of multiagent intravitreal chemotherapy is necessary for successful treatment in patients with recalcitrant vitreous seeding of retinoblastoma. OBJECTIVE: To determine the efficacy and complications of combined intravitreal chemotherapy (melphalan hydrochloride and topotecan hydrochloride) for viable vitreous seeding from retinoblastoma. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study was conducted in a hospital setting. Trans-pars plana intravitreal injection of melphalan hydrochloride (40 ug in 0.04 mL of diluent) combined with topotecan hydrochloride (8-20 ug in 0.04 mL of balanced salt solution) was performed in 9 eyes, followed by injection site cryotherapy. MAIN OUTCOMES AND MEASURES: Complete regression of vitreous seeds of retinoblastoma. RESULTS: Nine eyes, initially classified as group D (n = 6) or E (n = 3) according to International Classification of Retinoblastoma categorization, received a standard 6 cycles of intravenous chemotherapy and/or intra-arterial chemotherapy and subsequently developed recurrent viable vitreous seeds. Intravitreal administration of melphalan combined with topotecan produced complete control of vitreous seeds in all 9 eyes following a mean of 1.9 injections (median, 2; range, 1-3 injections). In 3 cases (33%), tumor control was achieved with a single injection, whereas in 6 (67%) cases, 2 or 3 injections were necessary. Three patients (33%) subsequently underwent enucleation because of recurrent tumor and persistent anterior chamber lesions. During a mean 15.2 months of follow-up (median, 16; range, 7-25 months), there was no recurrence of new tumor or vitreous seeds in the remaining 6 eyes. Complications included temporary hypotonia of 2 weeks or less (2 [22%]), temporary epithelial defect (1 [11%]), and vitreous hemorrhage (1 [11%]). There was no case of episcleral or orbital retinoblastoma extension or remote retinoblastoma metastasis. There was no change in the a and b waves of bright-flash electroretinograms. CONCLUSIONS AND RELEVANCE: Administration of combined intravitreal melphalan and topotecan in eyes not subsequently enucleated appears to be safe and effective for resistant or recurrent vitreous seeds from retinoblastoma. In 3 of the cases (33%), tumor control was achieved with a single injection. PMID- 24789623 TI - Interphase evolution at two promising electrode materials for Li-ion batteries: LiFePO4 and LiNi1/2 Mn1/2O2. AB - The present review reports the characterization and control of interfacial processes occurring on olivine LiFePO(4) and layered LiNi(1/2) Mn(1/2)O(2), standing here as model compounds, during storage and electrochemical cycling. The formation and evolution of the interphase created by decomposition of the electrolyte is investigated by using spectroscopic tools such as magic-angle spinning nuclear magnetic resonance ((7)Li,(19)F and (31)P) and electron energy loss spectroscopy, in parallel to X-ray photoelectron spectroscopy, to quantitatively describe the interphase and unravel its architecture. The influence of the pristine surface chemistry of the active material is carefully examined. The importance of the chemical history of the surface of the electrode material before any electrochemical cycling and the strong correlation between interface phenomena, the formation/evolution of an interphase, and the electrochemical behavior appear clearly from the use of these combined characterization probes. This approach allows identifying interface aging and failure mechanisms. Different types of surface modifications are then investigated, such as intrinsic modifications upon aging in air or methods based on the use of additives in the electrolyte or carbon coatings on the surface of the active materials. In each case, the species detected on the surface of the materials during storage and cycling are correlated with the electrochemical performance of the modified positive electrodes. PMID- 24789624 TI - Lipopolysaccharide/adenosine triphosphate induces IL-1beta and IL-18 secretion through the NLRP3 inflammasome in RAW264.7 murine macrophage cells. AB - The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome plays pivotal roles in inflammation and autoimmunity. The NLRP3 inflammasome is activated in response to various signals, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). However, its role in inflammation remains unclear. In this study, we used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to simulate an inflammatory environment as the testing model. We found that the exposure of RAW264.7 cells to LPS/ATP triggered the activation of caspase-1 (P<0.01) and the cleavage of interleukin (IL)-1beta (P<0.01), as well as the release of other cytokines, such as IL-18 (P<0.01) and IL-33 (P<0.01). Extracellular potassium chloride at a high concentration (150 mM) abrogated the secretion of IL-1beta and IL-18 (P<0.01), but did not reduce the processing of IL-33 (P>0.05). In addition, the silencing of NLRP3 with small interfering RNA (siRNA) suppressed the generation of proinflammatory cytokines, such as IL-1beta (P<0.01), IL-18 (P<0.01), but not IL 33 (P>0.05), along with the decreased mRNA and protein expression of NLRP3 and caspase-1 (P<0.05). However, extracellular potassium at a high concentration and NLRP3 siRNA did not affect the level of apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC; P>0.05). Our results suggest that the NLRP3/ASC/caspase-1 axis participates in the regulation of pro imflammatory cytokine secretion in RAW264.7 cells, particularly the generation of IL-1beta and IL-18. PMID- 24789625 TI - Effects of Massachusetts health reform on the use of clinical preventive services. AB - BACKGROUND: Expansion of health insurance coverage, and hence clinical preventive services (CPS), provides an opportunity for improvements in the health of adults. The degree to which expansion of health insurance coverage affects the use of CPS is unknown. OBJECTIVE: To assess whether Massachusetts health reform was associated with changes in healthcare access and use of CPS. DESIGN: We used a difference-in-differences framework to examine change in healthcare access and use of CPS among working-aged adults pre-reform (2002-2005) and post-reform (2007 2010) in Massachusetts compared with change in other New England states (ONES). SETTING: Population-based, cross-sectional Behavioral Risk Factor Surveillance System surveys. PARTICIPANTS: A total of 208,831 survey participants aged 18 to 64 years. INTERVENTION: Massachusetts health reform enacted in 2006. MEASUREMENTS: Four healthcare access measures outcomes and five CPS. KEY RESULTS: The proportions of adults who had health insurance coverage, a healthcare provider, no cost barrier to healthcare, an annual routine checkup, and a colorectal cancer screening increased significantly more in Massachusetts than those in the ONES. In Massachusetts, the prevalence of cervical cancer screening in pre-reform and post-reform periods was about the same; however, the ONES had a decrease of -1.6 percentage points (95 % confidence interval [CI] -2.5, -0.7; p <0.001). As a result, the prevalence of cervical cancer screening in Massachusetts was increased relative to the ONES (1.7, 95 % CI 0.2, 3.2; p = 0.02). Cholesterol screening, influenza immunization, and breast cancer screening did not improve more in Massachusetts than in the ONES. LIMITATIONS: Data are self-reported. CONCLUSIONS: Health reform may increase healthcare access and improve use of CPS. However, the effects of health reform on CPS use may vary by type of service and by state. PMID- 24789626 TI - R-E-S-P-E-C-T-implications for physicians and physicians-to-be. PMID- 24789628 TI - Application of a capillary-assembled microfluidic system for separation of cephalosporins. AB - This paper demonstrates a simple and easy setting up of a fused-silica capillary assembled microfluidic system (MUCE). This system incorporates a split-flow pressure injection of the sample into a microfluidic system made from PDMS and a short (~20 cm) length of fused-silica capillary as a separation unit. The on capillary detection was carried out by fiber optic spectrometry. A mixture of six cephalosporin antibiotics was separated in the MUCE system and the obtained results were compared to those achievable by conventional CE. The six components could be separated within 8.5 min with the number of theoretical plates around 10 000. PMID- 24789629 TI - Subnanowatt opto-molecular generation of localized defects in chiral liquid crystals. PMID- 24789627 TI - Poly(A) RNA-binding proteins and polyadenosine RNA: new members and novel functions. AB - Poly(A) RNA-binding proteins (Pabs) bind with high affinity and specificity to polyadenosine RNA. Textbook models show a nuclear Pab, PABPN1, and a cytoplasmic Pab, PABPC, where the nuclear PABPN1 modulates poly(A) tail length and the cytoplasmic PABPC stabilizes poly(A) RNA in the cytoplasm and also enhances translation. While these conventional roles are critically important, the Pab family has expanded recently both in number and in function. A number of novel roles have emerged for both PAPBPN1 and PABPC that contribute to the fine-tuning of gene expression. Furthermore, as the characterization of the nucleic acid binding properties of RNA-binding proteins advances, additional proteins that show high affinity and specificity for polyadenosine RNA are being discovered. With this expansion of the Pab family comes a concomitant increase in the potential for Pabs to modulate gene expression. Further complication comes from an expansion of the potential binding sites for Pab proteins as revealed by an analysis of templated polyadenosine stretches present within the transcriptome. Thus, Pabs could influence mRNA fate and function not only by binding to the nontemplated poly(A) tail but also to internal stretches of adenosine. Understanding the diverse functions of Pab proteins is not only critical to understand how gene expression is regulated but also to understand the molecular basis for tissue-specific diseases that occur when Pab proteins are altered. Here we describe both conventional and recently emerged functions for PABPN1 and PABPC and then introduce and discuss three new Pab family members, ZC3H14, hnRNP-Q1, and LARP4. PMID- 24789630 TI - Insertion of core CpG island element into human CMV promoter for enhancing recombinant protein expression stability in CHO cells. AB - The human cytomegalovirus promoter (hCMV) is susceptible to gene silencing in CHO cells, most likely due to epigenetic events, such as DNA methylation and histone modifications. The core CpG island element (IE) from the hamster adenine phosphoribosyltransferase gene has been shown to prevent DNA methylation. A set of modified hCMV promoters was developed by inserting one or two copies of IE in either forward or reverse orientations either upstream of the hCMV enhancer, between the enhancer and core promoter (CP), or downstream of the CP. The modified hCMV with one copy of IE inserted between the enhancer and core promoter in reverse orientation (MR1) was most effective at enhancing expression stability without compromising expression level when compared with the wild-type (WT) hCMV. A third of 18 EGFP expressing clones generated using MR1 retained 70% of their starting expression level after 8 weeks of culture in the absence of selection pressure, while none of 18 WT hCMV generated clones had expression above 50%. MR1 also improved antibody expression stability of methotrexate (MTX) amplified CHO cell lines. Stably transfected pools generated using MR1 maintained 62% of their original monoclonal antibody titer after 8 weeks of culture in the absence of MTX, compared to only 37% for WT hCMV pools. Low levels of CpG methylation within both WT hCMV and MR1 were observed in all the analyzed cell lines and the methylation levels did not correlate to the expression stability, suggesting IE enhances expression stability by other mechanisms other than preventing methylation. PMID- 24789631 TI - [Professional paths of alumni from doctorate programs in health and biological sciences]. AB - OBJECTIVE: To analyze the career path and professional satisfaction of alumni from the doctorate degree programs in health sector. METHODS: Exploratory study with 827 alumni of doctoral programs in public health, biological and health sciences at the Fundacao Oswaldo Cruz , RJ, Southeastern Brazil, from 1984 to 2007. The subjects were grouped in three cross-temporal cohorts according to year. The profiles of the alumni were analyzed, their career paths mapped and information on the perceptions of the education they received and the reasons that led them to choose the institute for their doctoral courses gathered, as well as their evaluations of the courses. The data were collected by means of an online questionnaire. RESULTS: There are differences between cohorts of alumni related to the periods they followed the courses, their distinct educational backgrounds and labor processes between those from the biological and health sciences areas, and to the specificities of the different areas where the institution offers doctoral courses: public health, biological and health sciences. CONCLUSIONS: The results allow the academic management of the educational processes to expand its knowledge, thus establishing a baseline for tracking the trajectory of alumni, and may contribute to upgrading the follow up process of Brazilian graduate programs. PMID- 24789632 TI - [Timing of clamping and factors associated with iron stores in full-term newborns]. AB - OBJECTIVE: To analyze the impact of timing of clamping and obstetric, biological and socioeconomic factors on the iron stores of full-term newborns. METHODS: Cross-sectional study between October 2011 and July 2012 in which hematological parameters were evaluated for newborns in Vicosa, MG, Southeastern Brazil. It involved collecting 7 mL of umbilical cord blood from 144 full-term not underweight newborns. The parameters investigated were complete blood count, serum iron, ferritin and C-reactive protein. The time of umbilical cord clamping was measured using a digital timer without interfering in the procedures of childbirth. The birth data were collected from Live Birth Certificates and other information was obtained from the mother through a questionnaire applied in the first month postpartum. Analysis of multiple linear regression was then used to estimate the influence of biological, obstetrics and socioeconomic factors on the ferritin levels at birth. RESULTS: The median ferritin was 130.3 ug/L (n = 129, minimum = 16.4; maximum = 420.5 ug/L), the mean serum iron was 137.9 MUg/dL (n = 144, SD = 39.29) and mean hemoglobin was 14.7 g/dL (n = 144, SD = 1.47). The median time of cord clamping was 36 seconds, ranging between 7 and 100. The bivariate analysis detected an association between ferritin levels and color of the child, timing clamping of 60 seconds, type of delivery, the presence of gestational diabetes and per capita family income. In multivariate analysis, the variables per capita income, number of antenatal visits and length at birth accounted for 22.0% of variation in ferritin levels. CONCLUSIONS: Iron stores at birth were influenced by biological, obstetric and social characteristics. Tackling anemia should involve creating policies aimed at reducing social inequalities, improving the quality of antenatal care, as well as implementing a criterion of delayed clamping of the umbilical cord within the guidelines of labor. PMID- 24789633 TI - Prevalence and determinants of child undernutrition and stunting in semiarid region of Brazil. AB - OBJECTIVE: To analyze the evolution in the prevalence and determinants of malnutrition in children in the semiarid region of Brazil. METHODS: Data were collected from two cross-sectional population-based household surveys that used the same methodology. Clustering sampling was used to collect data from 8,000 families in Ceara, Northeastern Brazil, for the years 1987 and 2007. Acute undernutrition was calculated as weight/age < -2 standard deviation (SD); stunting as height/age < -2 SD; wasting as weight/height < -2 SD. Data on biological and sociodemographic determinants were analyzed using hierarchical multivariate analyses based on a theoretical model. RESULTS: A sample of 4,513 and 1,533 children under three years of age, in 1987 and 2007, respectively, were included in the analyses. The prevalence of acute malnutrition was reduced by 60.0%, from 12.6% in 1987 to 4.7% in 2007, while prevalence of stunting was reduced by 50.0%, from 27.0% in 1987 to 13.0% in 2007. Prevalence of wasting changed little in the period. In 1987, socioeconomic and biological characteristics (family income, mother's education, toilet and tap water availability, children's medical consultation and hospitalization, age, sex and birth weight) were significantly associated with undernutrition, stunting and wasting. In 2007, the determinants of malnutrition were restricted to biological characteristics (age, sex and birth weight). Only one socioeconomic characteristic, toilet availability, remained associated with stunting. CONCLUSIONS: Socioeconomic development, along with health interventions, may have contributed to improvements in children's nutritional status. Birth weight, especially extremely low weight (< 1,500 g), appears as the most important risk factor for early childhood malnutrition. PMID- 24789634 TI - Common mental disorders and intimate partner violence in pregnancy. AB - OBJECTIVE: To investigate the association between common mental disorders and intimate partner violence during pregnancy. METHODS: A cross sectional study was carried out with 1,120 pregnant women aged 18-49 years old, who were registered in the Family Health Program in the city of Recife, Northeastern Brazil, between 2005 and 2006. Common mental disorders were assessed using the Self-Reporting Questionnaire (SRQ-20). Intimate partner violence was defined as psychologically, physically and sexually abusive acts committed against women by their partners. Crude and adjusted odds ratios were estimated for the association studied utilizing logistic regression analysis. RESULTS: The most common form of partner violence was psychological. The prevalence of common mental disorders was 71.0% among women who reported all form of violence in pregnancy and 33.8% among those who did not report intimate partner violence. Common mental disorders were associated with psychological violence (OR 2.49, 95%CI 1.8;3.5), even without physical or sexual violence. When psychological violence was combined with physical or sexual violence, the risk of common mental disorders was even higher (OR 3.45; 95%CI 2.3;5.2). CONCLUSIONS: Being assaulted by someone with whom you are emotionally involved can trigger feelings of helplessness, low self-esteem and depression. The pregnancy probably increased women's vulnerability to common mental disorders. PMID- 24789635 TI - [Coping and perception of women with HIV infection]. AB - OBJECTIVE To analyze women's perceptions and coping regarding the discovery of an HIV infection. METHODS A qualitative study in an HIV/AIDS Specialist Helpdesk in Recife, PE, Northeastern Brazil, from January to September 2010, involving eight women living with asymptomatic HIV aged between 27 and 37 years, without criteria for diagnosis of AIDS infected through intercourse and monitored by the service for at least one year. Forms were used to characterize the clinical situation and semi-structured interviews to understand perceptions and feelings related to personal trajectory after diagnosis and different ways of facing the diagnosis in family and social life. Content analysis was performed as suggested by Bardin. RESULTS The thematic category that emerged was stigma and discrimination. The women had life trajectories marked by stigma, which was perceived as discrimination after the diagnosis and in the experiences of everyday life. The revelation of the infection was perceived as limiting to a normal life, leading to the need to conceal the diagnosis. The discriminatory attitudes of some health care professionals, non-specialist in HIV/AIDS, had a negative impact on future experiences in other health services. Besides the effects of institutional stigma, the perception of women was that the service did not include dedicated space for the expression of other needs beyond the disease, which could help in fighting the infection. CONCLUSIONS Living with HIV was strongly linked to stigma. The results show the importance of strengthening educational approaches and emotional support at the time of diagnosis in order to facilitate coping with the condition of seropositivity. PMID- 24789636 TI - [Adolescence, sexual behavior and risk factors to health]. AB - OBJECTIVE: To analyze the relationships between sexual behavior and risk factors to physical and mental health in adolescents. METHODS: Study of 3,195 pupils aged 15 to 19 in secondary education, in public and private schools in 10 state capitals in Brazil between 2007 and 2008. Multi-stage (schools and pupils) cluster sampling was used in each city and public and private educational network. All of the students selected completed a questionnaire on the following items: socioeconomic and demographic data; sexual behavior; having sex with those of the same sex, the opposite sex, or both; alcohol and cannabis use; using condoms; traumatic sexual experiences as a child or adolescent; suicidal thoughts. The analysis included describing frequencies, Chi-square test, analysis of multiple and cluster correspondence. Responses to an open ended question in which the adolescent expressed general comments about themselves and their lives were qualitatively analyzed using content analysis. RESULTS: Around 3.0% of adolescents reported homosexual or bisexual behavior, with no difference according to sex, age, skin color, social status family structure or educational network. Adolescents with homosexual/bisexual sexual behavior, compared to their heterosexual peers, reported: (p < 0.05): getting drunk (18.7% and 10.5%, respectively), frequent cannabis use (6.1% and 2.1%, respectively), suicidal thoughts (42.5% and 18.7%, respectively), and having been the victim of sexual violence (11.7% and 1.5%; respectively). Adolescents with homosexual/bisexual sexual behavior reported that they used condoms less frequently (74.2%) than their heterosexual peers (48.6%, p < 0.001). In the correspondence analysis, three groups were found, one composed of adolescents with homosexual/bisexual behavior and experiencing risk factors; suffering sexual violence, never using a condom, suicidal thoughts, frequent cannabis use; another composed of occasional cannabis and condom users, who got drunk frequently, and adolescents with heterosexual behavior and none of the risk factors investigated. More of the risk factors were found in adolescents with homosexual/bisexual behavior compared with those with heterosexual behavior. Adolescents with homosexual/bisexual sexual behavior were more likely to talk about their positive personal experiences and negative relationship experiences that their heterosexual peers, but spoke less about religion. CONCLUSIONS: Not only should this issue be studied in more detail, but preventative actions aimed at adolescents with homosexual/bisexual behavior should be widened. PMID- 24789637 TI - [Exposure to alcohol among adolescent students and associated factors]. AB - OBJECTIVE: To describe the prevalence of alcohol consumption among adolescent school students and identify its individual and contextual associated factors. METHODS: The present research used data from the 2009 National School Health Survey (PeNSE), which included a sample of 59,699 9th grade students in Brazilian capitals and the Federal District. The association between regular alcohol consumption and independent explanatory variables was measured by means of the Pearson's Chi-square test, with a 0.05 significance level. The explanatory variables were divided into four groups based on affinity (sociodemographic; school and family context; risk factors; and protection factors). A multivariate analysis was carried out for each group, always adjusting for age and sex. Variables with p < 0.10 were used in the final multivariate analysis model. RESULTS: The highest alcohol consumption in the preceding 30 days was independently associated with pupils aged 15 years (OR = 1.46) and over, female (OR = 1.72), white, children of mothers with higher education, studying in private school, students who had tried smoking (OR = 1.72) and drug use (OR = 1.81), with regular tobacco consumption (OR = 2.16) and those who have had sexual intercourse (OR = 2.37). The factors related to family were skipping school without parental knowledge (OR = 1.49), parents not knowing what children do in their free time (OR = 1.34), having fewer meals with their parents (OR = 1.22), reporting that parents do not care (OR = 3.05), or care little (OR = 3.39) if they go home drunk, and having suffered domestic violence (OR = 1.36). CONCLUSIONS: The results reinforce the importance of viewing alcohol consumption among adolescents as a complex, multifactorial and socially determined phenomenon. PMID- 24789638 TI - Convergent validity between SF-36 and WHOQOL-BREF in older adults. AB - OBJECTIVE: To compare the reliability and convergent validity of instruments assessing quality of life in Brazilian older adults. METHODS: Cross-sectional study of 278 literate, community-dwelling older adults attending a municipal university for the elderly in Sao Carlos, SP, Southeastern Brazil between 2006 and 2008. The Brazilian versions of the SF-36 and WHOQOL-BREF instruments to assess quality of life were compared. Cronbach's alpha coefficient was used to estimate reliability and Pearson's correlation for comparison between the two scales. RESULTS: Most of participants were women (87.8%) with a mean age of 63.83+/-7.22 years. Both scales showed an acceptable internal consistency - WHOQOL-BREF Cronbach's alpha was 0.832 and SF-36 was 0.868. There was a weak (r <= 0.6) correlation between the related fields in the two questionnaires. CONCLUSIONS: The SF-36 and WHOQOL-BREF are reliable instruments for clinical and research uses in Brazilian older women. To select one, researchers should consider which aspects of quality of life they aim to capture because of weak convergent validity signs. This study's results indicate that WHOQOL-BREF may be more relevant to evaluate changes in the quality of life of older women because it prioritizes responses to the aging process and avoids focusing on impairment. PMID- 24789639 TI - [Place and type of meals consumed by adults in medium sized cities]. AB - OBJECTIVE: To describe the meals consumed by adults living in a midsize city in the South of Brazil, according to the place and preparation. METHODS: A population-based cross-sectional study was conducted in Pelotas, Southern Brazil, in 2012. The two-stage sampling design used the 2010 census tracts as primary sampling units. Data were collected on the place of meals (at home or out) and on the kind of preparations consumed at home (homemade, snacks, take away food) covering the two days prior to the interview, using a standardized questionnaire. RESULTS: The study included 2,927 adults, of which 59.0% were female, 60.0% were below 50 years of age and 58.0% were in work. Data were collected on 11,581 meals consumed on the two days preceding the interview, 25.0% were consumed outside of the home at lunchtime, and 10.0% at dinnertime. Considering home meals, most participants reported eating food prepared at home at both lunch and dinner. The majority of out-of-home meals (64.0% for lunch and 61.0% for dinner) were consumed in the work place, mostly based on food prepared at home. Individuals eating out of home were mostly male, young and highly educated. The occupational categories that ate at restaurants more often were trade workers, businessmen, teachers and graduate professionals. CONCLUSIONS: Despite the changes in eating patterns described in Brazil in recent years, residents of medium-sized towns still mostly eat at home, consuming homemade food. OBJECTIVE: To describe the meals consumed by adults living in a midsize city in the South of Brazil, according to the place and preparation. METHODS: A population-based cross sectional study was conducted in Pelotas, Southern Brazil, in 2012. The two-stage sampling design used the 2010 census tracts as primary sampling units. Data were collected on the place of meals (at home or out) and on the kind of preparations consumed at home (homemade, snacks, take away food) covering the two days prior to the interview, using a standardized questionnaire. RESULTS: The study included 2,927 adults, of which 59.0% were female, 60.0% were below 50 years of age and 58.0% were in work. Data were collected on 11,581 meals consumed on the two days preceding the interview, 25.0% were consumed outside of the home at lunchtime, and 10.0% at dinnertime. Considering home meals, most participants reported eating food prepared at home at both lunch and dinner. The majority of out-of home meals (64.0% for lunch and 61.0% for dinner) were consumed in the work place, mostly based on food prepared at home. Individuals eating out of home were mostly male, young and highly educated. The occupational categories that ate at restaurants more often were trade workers, businessmen, teachers and graduate professionals. CONCLUSIONS: Despite the changes in eating patterns described in Brazil in recent years, residents of medium-sized towns still mostly eat at home, consuming homemade food. PMID- 24789640 TI - [Health promotion: challenges revealed in successful practices]. AB - OBJECTIVE: To examine successful practices of health promotion in health, education, culture, welfare and sport, leisure, identifying the elements of success and challenges in the field. METHODS: A qualitative study with data obtained from in-depth analysis that included participant observation, interviews with managers, coordinators, professionals and participants from 29 practices reported as successful for promoting health in six municipalities of the metropolitan region of Belo Horizonte, MG, Southeastern Brazil, in 2011. The variables of the study were concept, dimension, dissemination and ease of access, identified in practices guided by content analysis. RESULTS: The results indicate a conceptual and methodological uncertainty about health promotion as evidenced by conflicting objects and contradictory purposes. The practices differ in size, coverage and ease of access, determined by inter-sector coordination and political and financial investment. CONCLUSIONS: We identified challenges to health promotion focusing on vulnerable populations, limits to financing and intersectoral partnerships. PMID- 24789641 TI - [Selection within households in health surveys]. AB - OBJECTIVE: To compare the efficiency and accuracy of sampling designs including and excluding the sampling of individuals within sampled households in health surveys. METHODS: From a population survey conducted in Baixada Santista Metropolitan Area, SP, Southeastern Brazil, lowlands between 2006 and 2007, 1,000 samples were drawn for each design and estimates for people aged 18 to 59 and 18 and over were calculated for each sample. In the first design, 40 census tracts, 12 households per sector, and one person per household were sampled. In the second, no sampling within the household was performed and 40 census sectors and 6 households for the 18 to 59-year old group and 5 or 6 for the 18 and over age group or more were sampled. Precision and bias of proportion estimates for 11 indicators were assessed in the two final sets of the 1000 selected samples with the two types of design. They were compared by means of relative measurements: coefficient of variation, bias/mean ratio, bias/standard error ratio, and relative mean square error. Comparison of costs contrasted basic cost per person, household cost, number of people, and households. RESULTS: Bias was found to be negligible for both designs. A lower precision was found in the design including individuals sampling within households, and the costs were higher. CONCLUSIONS: The design excluding individual sampling achieved higher levels of efficiency and accuracy and, accordingly, should be first choice for investigators. Sampling of household dwellers should be adopted when there are reasons related to the study subject that may lead to bias in individual responses if multiple dwellers answer the proposed questionnaire. PMID- 24789642 TI - [Homicides and territorial struggles in Rio de Janeiro favelas]. AB - OBJECTIVE: To evaluate the risk of homicide in Rio de Janeiro's favelas, taking into account the territorial disputes taking place in the city. METHODS: The study is based on data on mortality from homicide in the city of Rio de Janeiro between 2006 and 2009. Risks in favelas and in surrounding areas were evaluated, as was the domination of armed groups and drug dealing. Geographic and ethnographic concepts and methods were employed, using participant observation, interviews and analysis of secondary data on health. RESULTS: Within the favelas, mortality rates from homicide were equivalent to, or lower than, the rest of the city, although they were considerably higher in areas surrounding the favelas, especially in areas where there was conflict between armed rival gangs. CONCLUSIONS: The presence of trafficking crews and turf war in strategic areas of the city increases homicide rates and promotes the "ecology of danger" in these areas. PMID- 24789644 TI - [The incorporation of activities to control dengue by community health agents]. AB - OBJECTIVE: To evaluate the performance of Community Health Agents when dengue control activities were added to their tasks. METHODS: Performance was measured comparing the evolution of selected indicators from the Brazilian National Dengue Control Program and the Family Health Strategy for 2002 to 2008 in the municipality of Sao Gabriel do Oeste, MS, Central Western Brazil, with those of Rio Verde de Mato Grosso, neighboring municipality with demographic, socioeconomic and health services similarities. Data were collected from municipal databases of the Information System for Yellow Fever and Dengue and the Information System for Primary Healthcare of the Mato Grosso do Sul State Health Office. The variables selected for the family health strategy activities were: monthly home visits, pregnant women whose antenatal care began in the first trimester, children under one with up-to-date vaccinations and hypertensive patients. Those selected for the Brazilian National Dengue Control Program were: properties inspected with Aedes aegypti and properties not inspected. RESULTS: The two municipalities maintained a similar trend in dengue control indicators in the period studied. With regard to the Family Health Strategy, in 2002 Sao Gabriel do Oeste was better off in three of the four indicators studied, however, this situation was reversed at the end of the period when the county was overtaken by Rio Verde de Mato Grosso in three of the four indicators analyzed, including, the monthly average community health worker visits per registered family, the main activity of a Family Health Strategy agent. CONCLUSIONS: Incorporating the National Dengue Control Program into the Family Health Strategy is viable and developed without prejudice to dengue control activities, however, the same did not occur with the activities of family health in Sao Gabriel do Oeste. The additional workload of the community health workers is the most likely hypothesis for the declining performance of these agents in the Family Health Strategy activities. PMID- 24789643 TI - [Risk factors for absenteeism due to sick leave in the petroleum industry]. AB - OBJECTIVE: To identify risk factors for absenteeism among workers with sick leave in an oil company. METHODS: A case-control study (120 cases and 656 controls) nested in a retrospective cohort study following up all employees of an oil company in the North-Northeast of Brazil from 2007 to 2009. The response variable used to represent absenteeism with sick leave was the average incidence of sick leave, defined as the ratio between total sick days and potential working days in the period. Logistic regression techniques were used to investigate the association between average incidence of sick leave > 5.0% over the period and the variables sex, position, age, time at work, shift work, smoking, arterial hypertension, body mass index, physical activity, coronary risk, sleep, glycemia, non-managed diabetes, cardiovascular, digestive, musculoskeletal, neurological and neoplastic diseases, straining body positioning during work, satisfaction at work, relationship with management, and concentrated attention at work. RESULTS: Average incidence of sick leave higher than 5.0% in the cohort period was 15.5%. The logistic model revealed that workers with average incidence of sick leave higher than 5.0% were 2.6 times more likely to be female; 2.0 time more likely to be smokers; 1.8 time more likely to be former smokers; 2.2 times more likely to report abnormal sleep and 10.5 times more likely to report dissatisfaction with their than workers with average incidence of sick leave <= 5.0% in the period. CONCLUSIONS: In this population, female gender, being a smoker or a former smoker, reporting dissatisfaction with the job and reporting abnormal sleep are good predictors of occupational absenteeism with sick leave. OBJECTIVE: To identify risk factors for absenteeism among workers with sick leave in an oil company. METHODS: A case-control study (120 cases and 656 controls) nested in a retrospective cohort study following up all employees of an oil company in the North-Northeast of Brazil from 2007 to 2009. The response variable used to represent absenteeism with sick leave was the average incidence of sick leave, defined as the ratio between total sick days and potential working days in the period. Logistic regression techniques were used to investigate the association between average incidence of sick leave > 5.0% over the period and the variables sex, position, age, time at work, shift work, smoking, arterial hypertension, body mass index, physical activity, coronary risk, sleep, glycemia, non-managed diabetes, cardiovascular, digestive, musculoskeletal, neurological and neoplastic diseases, straining body positioning during work, satisfaction at work, relationship with management, and concentrated attention at work. RESULTS: Average incidence of sick leave higher than 5.0% in the cohort period was 15.5%. The logistic model revealed that workers with average incidence of sick leave higher than 5.0% were 2.6 times more likely to be female; 2.0 time more likely to be smokers; 1.8 time more likely to be former smokers; 2.2 times more likely to report abnormal sleep and 10.5 times more likely to report dissatisfaction with their than workers with average incidence of sick leave <= 5.0% in the period. CONCLUSIONS: In this population, female gender, being a smoker or a former smoker, reporting dissatisfaction with the job and reporting abnormal sleep are good predictors of occupational absenteeism with sick leave. PMID- 24789645 TI - [SUS users' knowledge of and attitude to HPV virus and vaccines available in Brazil]. AB - OBJECTIVE: To investigate knowledge of HPV and HPV vaccines in men and women, users of the Brazilian Unified Health System, and the intention to get themselves and their teenage children vaccinated. METHODS: A descriptive, cross-sectional study with 286 women (18-49 years old) and 252 men (18-60 years old), users of five primary health units and two polyclinics in Campinas, SP, Southeastern Brazil, was carried out. Participants were interviewed in 2011 using a structured questionnaire. Bivariate and Poisson regression analysis were performed to identify variables associated with knowledge of HPV and HPV vaccines, and participants vaccination intentions. RESULTS: Almost 40.0% of the participants reported having heard of HPV and 28.9% mentioned adequate information. The main information source was the media (41.7%). Only 8.6% of the participants had heard of the HPV vaccines. Once the participants were informed of the existence of HPV vaccines about 94% of them said they would get vaccinated and/or vaccinate their teenage children, if the vaccines were available in the public health system. Schooling of over 8 years and being female were the variables independently associated with having heard of HPV, the vaccines and having adequate knowledge of the virus. Advanced age was associated with having heard of HPV vaccines. There were no variables associated with the vaccination intentions. CONCLUSIONS: These results reinforce the need for educational activities that provide the population with adequate information on HPV and preventive measures. PMID- 24789646 TI - [Ombudsmen in health care: case study of a municipal health ombudsman]. AB - OBJECTIVE: To analyze the role of a Municipal Health Ombudsman and its contribution to the public health management from the perspective of the public health system users and the municipal health counselors. METHODS: Qualitative research approach using the case study, descriptive and transversal methods. The unit of analysis was a Municipal Health Ombudsman, in the state of Minas Gerais, Southeastern Brazil, between May and August 2010. The study was observational in nature and data were collected through interviews with two groups of stakeholders: users and municipal health counselors. We interviewed 44 Brazilian Unified Health System users who had made direct use of the Municipal Health Ombudsman and all 20 municipal health counselors. The data obtained were analyzed based on three issues: (1) nature of the data obtained; (2) discussion of subsidies to qualify the ombudsman's functioning as a management tool; (3) proposals for actions to improve democratic management in the area of public health. RESULTS: The complaints to the ombudsman denoted difficulties in access to health care services running the risk of their being perceived as shortcuts to gaining accessibility, disregarding the principle of social justice. The role of the ombudsman has the citizens' approval. Users reported the following main functions of the ombudsman: to support the resolution of health problems, to listen and to clarify issues regarding Brazilian Unified Health System operations and procedures. Information was emphasized by health counselors as an instrument of power and access to the rights of Brazilian Unified Health System users. They highlighted that the ombudsman has the role of ensuring justice to foster an effective health policy, besides playing an important mediating role between the board of the municipal health system, its managers and citizens. Furthermore, the ombudsman was shown to have an execution role that transcends its regular functions. CONCLUSIONS: The study found that the ombudsman is a key management tool in monitoring the health care system. Therefore, the establishment of the ombudsman is an advance in the field of democratic management. Nevertheless, there are challenges to be overcome in order to improve ombudsman contribution to the execution of health policies and representing citizens in ensuring their rights to health care. PMID- 24789647 TI - Effectiveness of motivational interviewing at improving oral health: a systematic review. AB - OBJECTIVE: To analyze the effectiveness of motivational interviewing (MI) at improving oral health behaviors (oral hygiene habits, sugar consumption, dental services utilization or use of fluoride) and dental clinical outcomes (dental plaque, dental caries and periodontal status). METHODS: A systematic search of PubMed, LILACS, SciELO, PsyINFO, Cochrane and Google Scholar bibliographic databases was conducted looking for intervention studies that investigated MI as the main approach to improving the oral health outcomes investigated. RESULTS: Of the 78 articles found, ten met the inclusion criteria, all based on randomized controlled trials. Most studies (n = 8) assessed multiple outcomes. Five interventions assessed the impact of MI on oral health behaviors and nine on clinical outcomes (three on dental caries, six on dental plaque, four on gingivitis and three on periodontal pockets). Better quality of evidence was provided by studies that investigated dental caries, which also had the largest population samples. The evidence of the effect of MI on improving oral health outcomes is conflicting. Four studies reported positive effects of MI on oral health outcomes whereas another four showed null effect. In two interventions, the actual difference between groups was not reported or able to be recalculated. CONCLUSIONS: We found inconclusive effectiveness for most oral health outcomes. We need more and better designed and reported interventions to fully assess the impact of MI on oral health and understand the appropriate dosage for the counseling interventions. PMID- 24789648 TI - [Consumer reaction to information on the labels of genetically modified food]. AB - OBJECTIVE: To analyze consumer opinion on genetically modified foods and the information included on the label. METHODS: A systematic review of the scientific literature on genetically modified food labeling was conducted consulting bibliographic databases (Medline - via PubMed -, EMBASE, ISI-Web of knowledge, Cochrane Library Plus, FSTA, LILACS, CINAHL and AGRICOLA) using the descriptors "organisms, genetically modified" and "food labeling". The search covered the first available date, up to June 2012, selecting relevant articles written in English, Portuguese or Spanish. RESULTS: Forty articles were selected after applying the inclusion and exclusion criteria. All of them should have conducted a population-based intervention focused on consumer awareness of genetically modified foods and their need or not, to include this on the label. The consumers expressed a preference for non-genetically modified products, and added that they were prepared to pay more for this but, ultimately, the product bought was that with the best price, in a market which welcomes new technologies. In 18 of the articles, the population was in favor of obligatory labelling, and in six, in favor of this being voluntary; seven studies showed the consumer knew little about genetically modified food, and in three, the population underestimated the quantity they consumed. Price was an influencing factor in all cases. CONCLUSIONS: Label should be homogeneous and clarify the degree of tolerance of genetically modified products in humans, in comparison with those non-genetically modified. Label should also present the content or not of genetically modified products and how these commodities are produced and should be accompanied by the certifying entity and contact information. Consumers express their preference for non-genetically modified products and they even notice that they are willing to pay more for it, but eventually they buy the item with the best price, in a market that welcomes new technologies. PMID- 24789649 TI - [Permanent education in health: a review]. AB - OBJECTIVE: To undertake a meta-synthesis of the literature on the main concepts and practices related to permanent education in health. METHODS: A bibliographical search was conducted for original articles in the PubMed, Web of Science, LILACS, IBECS and SciELO databases, using the following search terms: "public health professional education", "permanent education", "continuing education", "permanent education health". Of the 590 articles identified, after applying inclusion and exclusion criteria, 48 were selected for further analysis, grouped according to the criteria of key elements, and then underwent meta synthesis. RESULTS: The 48 original publications were classified according to four thematic units of key elements: 1) concepts, 2) strategies and difficulties, 3) public policies and 4) educational institutions. Three main conceptions of permanent education in health were found: problem-focused and team work, directly related to continuing education and education that takes place throughout life. The main strategies for executing permanent education in health are discussion, maintaining an open space for permanent education , and permanent education clusters. The most limiting factor is mainly related to directly or indirect management. Another highlight is the requirement for implementation and maintenance of public policies, and the availability of financial and human resources. The educational institutions need to combine education and service aiming to form critical-reflexive graduates. CONCLUSIONS: The coordination between health and education is based as much on the actions of health services as on management and educational institutions. Thus, it becomes a challenge to implement the teaching-learning processes that are supported by critical reflexive actions. It is necessary to carry out proposals for permanent education in health involving the participation of health professionals, teachers and educational institutions. OBJECTIVE: To undertake a meta-synthesis of the literature on the main concepts and practices related to permanent education in health. METHODS: A bibliographical search was conducted for original articles in the PubMed, Web of Science, LILACS, IBECS and SciELO databases, using the following search terms: "public health professional education", "permanent education", "continuing education", "permanent education health". Of the 590 articles identified, after applying inclusion and exclusion criteria, 48 were selected for further analysis, grouped according to the criteria of key elements, and then underwent meta-synthesis. RESULTS: The 48 original publications were classified according to four thematic units of key elements: 1) concepts, 2) strategies and difficulties, 3) public policies and 4) educational institutions. Three main conceptions of permanent education in health were found: problem focused and team work, directly related to continuing education and education that takes place throughout life. The main strategies for executing permanent education in health are discussion, maintaining an open space for permanent education, and permanent education clusters. The most limiting factor is mainly related to directly or indirect management. Another highlight is the requirement for implementation and maintenance of public policies, and the availability of financial and human resources. The educational institutions need to combine education and service aiming to form critical-reflexive graduates. CONCLUSIONS: The coordination between health and education is based as much on the actions of health services as on management and educational institutions. Thus, it becomes a challenge to implement the teaching-learning processes that are supported by critical-reflexive actions. It is necessary to carry out proposals for permanent education in health involving the participation of health professionals, teachers and educational institutions. PMID- 24789650 TI - [Disability due to mental illness: social security benefits in Brazil 2008-2011]. AB - This communication aimed to analyze the profile variation of disability benefits due to mental disorders. Secondary data published by Brazilian Social Security between 2008 and 2011 were evaluated. Mean annual variation rates over the period were calculated for the economically active population, as were the number insured, paid out overall sickness benefits and for mental and behavioral disorders. Mental disorders are the third most common reason for disability benefits. There was an average annual increase of 0.3% in new benefit claims, with a 2.5% fall in mean annual incidence. Work-related disease was identified in 6.2% of cases, most of it due to mood disorders. The government should use the data from the Social Security Institute to support a debate of public policies regarding mental health. PMID- 24789652 TI - The features of infectious diseases departments and anti-infective practices in France and Turkey: a cross-sectional study. AB - The aim of this study was to assess the infectious diseases (ID) wards of tertiary hospitals in France and Turkey for technical capacity, infection control, characteristics of patients, infections, infecting organisms, and therapeutic approaches. This cross-sectional study was carried out on a single day on one of the weekdays of June 17-21, 2013. Overall, 36 ID departments from Turkey (n = 21) and France (n = 15) were involved. On the study day, 273 patients were hospitalized in Turkish and 324 patients were followed in French ID departments. The numbers of patients and beds in the hospitals, and presence of an intensive care unit (ICU) room in the ID ward was not different in both France and Turkey. Bed occupancy in the ID ward, single rooms, and negative pressure rooms were significantly higher in France. The presence of a laboratory inside the ID ward was more common in Turkish ID wards. The configuration of infection control committees, and their qualifications and surveillance types were quite similar in both countries. Although differences existed based on epidemiology, the distribution of infections were uniform on both sides. In Turkey, anti-Gram positive agents, carbapenems, and tigecycline, and in France, cephalosporins, penicillins, aminoglycosides, and metronidazole were more frequently preferred. Enteric Gram-negatives and hepatitis B and C were more frequent in Turkey, while human immunodeficiency virus (HIV) and streptococci were more common in France (p < 0.05 for all significances). Various differences and similarities existed in France and Turkey in the ID wards. However, the current scene is that ID are managed with high standards in both countries. PMID- 24789653 TI - Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. AB - Coinfections with common bacterial respiratory pathogens and influenza viruses are well-known causes of disease, often via synergistic interactions between the influenza virus, the bacteria, and the human host. However, relatively little is known about interactions between atypical bacteria and influenza viruses. A recent report by Reinton et al. explored this issue by analyzing data from 3,661 patients seeking medical assistance for the presence of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Bordetella pertussis, as well as influenza A or B virus in nasal swab specimens. The report, however, did not accurately assess the epidemiologic interactions of these pathogens. We aimed to describe the interactions between these bacterial species and influenza infections. Strong and highly statistically significant antagonistic interspecies interactions were detected between C. pneumoniae and influenza virus [odds ratio (OR): 0.09; p < 0.0001) and M. pneumoniae and influenza virus infections (OR: 0.29; p = 0.003). No association was detected between B. pertussis and influenza infection (p = 0.34), contrary to the initial report, and coinfection was not detected at a higher-than-by-chance frequency within the population. Further support of these results is supplied by the analysis of two earlier investigations reporting data on influenza virus and these atypical bacteria. Our results supplement the large body of literature regarding interactions between influenza virus and typical respiratory pathogens, providing a fuller picture of the spectrum of interactions between influenza viruses and respiratory bacteria. Further, we demonstrate the importance of choosing the most appropriate reference populations for the analysis being performed and describe the pitfalls that may occur when care is not taken in this regard. PMID- 24789655 TI - Solution-grown single-crystalline microwires of a molecular semiconductor with improved charge transport properties. AB - Preparation and structural analysis of highly ordered single crystalline wires of a diketopyrrolopyrrole (DPP) molecular semiconductor grown through a solution process are reported, and the static/dynamic electrical response of an organic electronic device using the DPP semiconductor has been analyzed. PMID- 24789656 TI - Reconciling the clinical practice guidelines on Bell's palsy from the AAO-HNSF and the AAN. AB - Bell's palsy, named after the Scottish anatomist, Sir Charles Bell, is the most common acute mononeuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. In the past 2 years, both the American Academy of Neurology (AAN) and the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) have published clinical practice guidelines aimed to improve the quality of care and outcomes for patients diagnosed with Bell's palsy. This commentary aims to address the similarities and differences in the scope and final recommendations made by each guideline development group. PMID- 24789657 TI - Response to Jackler et al. "Otolaryngology: 'it's all Greek to me'". PMID- 24789658 TI - Distinct regulatory effect of the p34SEI-1 oncoprotein on cancer metastasis in HER2/neu-positive and -negative cells. AB - The p34(SEI-1) oncoprotein is involved in a transcriptional regulation, cell cycle regulation, apoptosis, development and many other important cellular functions. Our present study suggests that p34(SEI-1) can promote metastasis by enhancing migration and invasion of cancer cells. Consistently, p34(SEI-1) expression was found to be increased as the tumor invasiveness progressed in human breast tissues. p34(SEI-1) may promote cancer metastasis by activating the PI3K/AKT signaling pathway. In this process, p34(SEI-1) activates two different serine/threonine kinases, AKT or ILK, depending on the expression status of HER2/neu oncogene. In HER2/neu suppressed cancer cells, p34(SEI-1) promoted metastasis mainly by activating AKT via phosphorylation of the 473 serine residue. In HER2/neu expressing cancer cells, p34(SEI-1) overexpression downregulates HER2/neu expression, leading to the activation of another crucial serine/threonine kinase ILK due to phosphorylation of the 178 threonine residue instead of AKT. These results suggest that p34(SEI-1) affects cancer metastasis by regulating two different signaling pathways depending on the HER2/neu expression level, in which AKT and ILK modulation can be stimulated by p34(SEI-1) overexpression. PMID- 24789659 TI - A randomized comparison of long-axis and short-axis imaging for in-plane ultrasound-guided popliteal-sciatic perineural catheter insertion. AB - PURPOSE: Ultrasound-guided long-axis in-plane sciatic perineural catheter insertion has been described but not validated. For the popliteal-sciatic nerve, we hypothesized that a long-axis in-plane technique, placing the catheter parallel and posterior to the nerve, results in faster onset of sensory anesthesia compared to a short-axis in-plane technique. METHODS: Preoperatively, patients receiving a popliteal-sciatic perineural catheter were randomly assigned to either the long-axis or short-axis technique. Mepivacaine 2% was administered via the catheter following insertion. The primary outcome was time to achieve complete sensory anesthesia. Secondary outcomes included procedural time, onset time of motor block, and pain on postoperative day 1. RESULTS: Fifty patients were enrolled. In the long-axis group (n = 25), all patients except 1 (4%) had successful catheter placement per protocol. Two patients (8%) in the long-axis group and 1 patient (4%) in the short-axis group (n = 25) did not achieve sensory anesthesia by 30 min and were withdrawn. Seventeen of 24 (71%) and 17 of 22 (77%) patients in the short-axis and long-axis groups, respectively, achieved the primary outcome of complete sensory anesthesia (p = 0.589). The short-axis group (n = 17) required a median (10th-90th 0/00) of 18.0 (8.4-30.0) min compared to 18.0 (11.4-27.6) min for the long-axis group (n = 17, p = 0.208) to achieve complete sensory anesthesia. Procedural time was 6.5 (4.0-12.0) min for the short axis and 9.5 (7.0-12.7) min for the long-axis (p < 0.001) group. There were no statistically significant differences in other secondary outcomes. CONCLUSION: Long-axis in-plane popliteal-sciatic perineural catheter insertion requires more time to perform compared to a short-axis in-plane technique without demonstrating any advantages. PMID- 24789660 TI - Accuracy of the CNAPTM monitor, a noninvasive continuous blood pressure device, in providing beat-to-beat blood pressure measurements during bariatric surgery in severely obese adolescents and young adults. AB - BACKGROUND: During perioperative care, the continuous measurement of blood pressure (BP) provides superior physiological monitoring compared to intermittent techniques, especially for patients with comorbid conditions such as severe obesity. The current study prospectively assesses the accuracy of a continuous, noninvasive BP device in severely obese adolescents and young adults. METHODS: The technology evaluated was the CNAP Monitor 500, developed by CNSystems AG (Graz, Austria). The study cohort was composed of severely obese adolescents (body mass index >= 35 kg/m(2)) undergoing a surgical weight loss procedure (robotically assisted or laparoscopic vertical sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass). Systolic (sBP), diastolic (dBP), and mean arterial (MAP) blood pressure readings were captured from an intraoperatively placed radial arterial cannula (AC) and the CNAP device at regular intervals (once per minute) during anesthetic care. RESULTS: The study cohort consisted of 18 severely obese subjects undergoing weight loss surgery. A total of 2,159 pairs each of sBP, dBP, and MAP values obtained. The correlation coefficient between the AC and the CNAP device was 0.655, 0.667, and 0.783 for the sBP, dBP, and MAP, respectively. The CNAP values (sBP, dBP, MAP) were <=5 mmHg from the AC values in 33, 40, and 41% of the values, respectively. The difference was more than 10 mmHg (sBP, dBP, MAP) in 39, 28, and 25% of the values, respectively. Using a Bland Altman analysis, the precision and bias for the sBP, dBP, and MAP were 0.3 +/- 14.2, -1.3 +/- 9.5, and -0.6 +/- 8.6 mmHg, respectively. CONCLUSION: When compared to previous studies in the adult population, the accuracy of the CNAP device in a cohort of severely obese adolescents undergoing weight loss surgery was slightly less than previously reported. The current data demonstrate a clinically useful trend of the CNAP device with arterial values in this challenging patient population in whom an arterial cannula may at times be difficult. PMID- 24789661 TI - Two overlooked contributors to abandonment of childhood cancer treatment in Kenya: parents' social network and experiences with hospital retention policies. AB - BACKGROUND: The principal reason for childhood cancer treatment failure in low income countries is treatment abandonment, the most severe form of nonadherence. Two often neglected factors that may contribute to treatment abandonment are as follows: (a) lack of information and guidance by doctors, along with the negative beliefs of family and friends advising parents, which contributes to misconceptions regarding cancer and its treatment, and (b) a widespread policy in public hospitals by which children are retained after doctor's discharge until medical bills are settled. OBJECTIVE: This study explored parents' experiences with hospital retention policies in a Kenyan academic hospital and the impact of attitudes of family and friends on parents' decisions about continuing cancer treatment for their child. METHODS: Home visits were conducted to interview parents of childhood cancer patients who had been diagnosed between 2007 and 2009 and who had abandoned cancer treatment. RESULTS: Retrospective chart review revealed 98 children diagnosed between 2007 and 2009 whose parents had made the decisions to abandon treatment. During 2011-2012, 53 families (54%) could be reached, and 46 (87%) of these agreed to be interviewed. Parents reported the attitudes of community members (grandparents, relatives, friends, villagers, and church members); 61% believed that the child had been bewitched by some individual, and 74% advised parents to seek alternative treatment or advised them to stop medical treatment (54%). Parents also reported that they were influenced by discussions with other parents who had a child being treated, including that their child's life was in God's hands (87%), the trauma to the child and family of forced hospital stays (84%), the importance of completing treatment (81%), the financial burden of treatment (77%), and the incurability of cancer (74%). These discussions influenced their perceptions of cancer treatment and its usefulness (65%). Thirty-six families (78%) had no health insurance, and 19 of these parents (53%) could not pay their medical bills and were not allowed to take their child home when treatment ended. Parents reported feelings of desperation (95%), powerlessness (95%), and sadness (84%) and that their child has been imprisoned (80%), during the period of retention. The majority of parents (87%) felt that hospital retention of children must cease. CONCLUSIONS: The attitudes and beliefs of parents of children with cancer are impacted by those close to them and their community and may influence their perceptions of cancer treatment and decisions to stop treatment. Hospital retention policies are highly distressing for parents and may contribute to both treatment delays and treatment abandonment. These factors jeopardize treatment outcomes for young patients and require attention and modification. PMID- 24789662 TI - Galectin-3: a modifiable risk factor in heart failure. AB - Myocardial galectin-3 is upregulated upon cardiac stressors such as angiotensin II and pressure overload leading to cardiac remodeling and heart failure. The expression level of galectin-3 mirrors the progression and severity of heart failure and therefore, galectin-3 is being used as a biomarker for heart failure. However, as galectin-3 is causally involved in pathological myocardial fibrosis it has been suggested that galectin-3 also actively contributes to heart failure development. In this review we discuss how galectin-3 could be a target for therapy in heart failure. Currently, attempts are being made to target or inhibit galectin-3 using natural or pharmaceutical inhibitors with the aim to ameliorate heart failure. Available experimental evidence suggests that galectin-3 inhibition indeed may represent a novel tool to treat heart failure. A strong interaction with aldosterone, another strong pro-fibrotic factor, has been described. Clinical studies are needed to prove if galectin-3 may be used to install specific treatment regimens. PMID- 24789663 TI - Evaluation of poly(2-ethyl-2-oxazoline) containing copolymer networks of varied composition as sustained metoprolol tartrate delivery systems. AB - Segmented copolymer networks (SCN) based on poly(2-ethyl-2-oxazoline) and containing 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and/or methyl methacrylate segments have been evaluated as potential sustained release systems of the water soluble cardioselective beta-blocker metoprolol tartrate. The structure and properties of the drug carriers were investigated by differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy. Swelling kinetics of SCNs in various media was followed, and the conditions for effective MT loading were specified. MT-loaded SCNs with drug content up to 80 wt.% were produced. The release kinetics of metoprolol tartrate from the systems was studied and it was shown that the conetworks of different structure and composition are able to sustain the metoprolol tartrate release without additional excipients. PMID- 24789664 TI - Transdermal permeation of Kaempferia parviflora methoxyflavones from isopropyl myristate-based vehicles. AB - Kaempferia parviflora (K. parviflora) rhizomes have long been used in traditional folk medicines and as general health-promoting agents. Several biological activities of K. parviflora, especially its anti-inflammatory effect, are due to its major constituents, methoxyflavones. However, the oral bioavailability of these methoxyflavones has been shown to be low. The aim of this study was to investigate the permeation behaviors of K. parviflora methoxyflavones from isopropyl myristate (IPM)-based vehicles. We studied the effects of ethanol and propylene glycol (PG) as the hydrophilic, solvent-type vehicles as well as fatty acids as the permeation enhancers. A permeation experiment was performed in vitro, using side-by-side diffusion cells through the full thickness of pig ear skin. The solubility and permeation of methoxyflavones were able to be modified by choice and ratio of vehicles. The ethanol/IPM vehicle was shown to be more effective in enhancing the solubility and permeation of methoxyflavones when compared to the PG/IPM vehicle. Regarding an optimal balance between solubility or affinity to vehicle and skin to vehicle partition coefficient, the ethanol/IPM vehicle in the ratio of 1:9 maximized the flux. Among the investigated fatty acids, oleic acid showed the greatest enhancing effect on the permeation of methoxyflavones, indicating that saturated fatty acids are less effective than unsaturated fatty acids. Long chain fatty acids increased diffusion coefficient parameter and shortened the lag time. The number of carbon atoms and double bonds of fatty acids did not show direct relation to the profile of permeation of methoxyflavones. PMID- 24789665 TI - Complement anaphylatoxin C4a inhibits C5a-induced neointima formation following arterial injury. AB - Interactions between complement anaphylatoxins have been investigated in numerous fields; however, their functions during arterial remodeling following injury have not been studied. The inhibitory effect of complement anaphylatoxin C4a on neointima formation induced by C5a following arterial injury was investigated. Mice were subjected to wire-induced endothelial denudation of the femoral artery and treated with C5a alone or C5a + C4a for two weeks. C4a significantly inhibited C5a-induced neointima formation and the expression of CD68, F4/80, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). In vitro, although C4a did not directly inhibit the migration, proliferation or the expression of vascular cell adhesion molecule 1 (VCAM-1) of C5a-induced vascular smooth muscle cells (VSMCs), C5a-pretreated conditioned medium-induced migration, proliferation and VCAM-1 expression of VSMCs were suppressed when VSMCs were exposed to conditioned medium from C4a pretreated macrophages. In addition, C5a-induced TNF-alpha, IL-6 and MCP-1 expression, Ca2+ influx and extracellular signal-regulated kinase (ERK) activation in macrophages were suppressed by C4a. C4a inhibits C5a-induced neointima formation, not by acting directly on VSMCs, but via a macrophage mediated reaction by inhibiting the Ca2+-dependent ERK pathway in macrophages. PMID- 24789666 TI - Determinants of socioeconomic inequalities in subjective well-being in later life: a cross-country comparison in England and the USA. AB - PURPOSE: To explore country-specific influences on the determinants of two forms of subjective well-being (life satisfaction and quality of life) among older adults in England and the USA. METHODS: Harmonised data from two nationally representative panel studies of individuals aged 50 and over, the English Longitudinal Study of Ageing (ELSA) and the Health and Retirement Study (HRS), are used. Linear regression models are fitted separately for life satisfaction and quality of life scales using cross-sectional samples in 2004. The ELSA sample was 6,733, and the HRS sample was 2,300. Standardised coefficients are reported to determine the country-specific importance of explanatory variables, and predicted values are shown to highlight the relative importance of statistically significant country-level interaction effects. RESULTS: Having a disability, been diagnosed with a chronic conditions or having low household wealth are strongly associated with poorer life satisfaction and quality of life. These statistical effects are consistent in England and the USA. The association of years spent in education, however, varied between the two countries: educational inequalities have a greater adverse effect on subjective well-being in the USA compared with England. CONCLUSION: Interventions are required to counterbalance health and socioeconomic inequalities that restrict sections of the population from enjoying satisfying and meaningful lives in older age. The differential association between education and well-being in England and the USA suggests that the provision of welfare benefits and state-funded public services in England may go some way to protect against the subsequent adverse effect of lower socioeconomic status on subjective well-being. PMID- 24789667 TI - Adaptation and validation of the Spanish version of the Patient-Oriented Prostate Utility Scale (PORPUS). AB - OBJECTIVE: The Patient-Oriented Prostate Utility Scale (PORPUS) is a combined profile and utility-based quality of life measure for prostate cancer patients. Our objectives were to adapt the PORPUS into Spanish and to assess its acceptability, reliability, and validity. METHODS: The PORPUS was adapted into Spanish using forward and back translations and cognitive debriefing. PORPUS was administered jointly with the SF-36 and the Expanded Prostate Index Composite (EPIC) to 480 Spanish prostate cancer patients treated with radical prostatectomy or radiotherapy. The Spanish PORPUS scores' distribution and reliability were examined and compared with the original instrument. To evaluate construct validity, relationships were assessed between PORPUS and other instruments (testing hypotheses of the original PORPUS study), and among known groups defined by side effect severity. RESULTS: Reliability coefficient was 0.76 (similar to the original PORPUS' 0.81). Spanish PORPUS items presented correlations ranging 0.57-0.88 with the corresponding EPIC domains, as in the original PORPUS study (0.60-0.83). Both PORPUS-P and PORPUS-U showed significant differences and large effect sizes (0.94-1.90) when comparing severe versus no problem groups on urinary, bowel, sexual and hormonal side effects defined by EPIC. CONCLUSIONS: A conceptually equivalent Spanish version was obtained, with high reliability and good construct validity, similar to the original Canadian PORPUS version. It can therefore be used to measure health-related quality of life and utilities in Spanish prostate cancer patients. PMID- 24789668 TI - Predictors of health-related quality of life changes after lifestyle intervention in persons at risk of type 2 diabetes mellitus. AB - PURPOSE: To assess health-related quality of life (HRQOL) of subjects at risk of type 2 diabetes undergoing lifestyle intervention, and predictors for improved HRQOL. METHODS: The Finnish Diabetes Risk Score was used by general practitioners to identify individuals at risk. Low-intensity interventions with an 18-month follow-up were employed. HRQOL was assessed using the SF-36 at baseline and compared with results from a general Norwegian population survey and further at 6 and 18 months. Simple and multiple linear regression analyses were applied to identify predictors of changes in HRQOL of clinical importance. RESULTS: Two hundred and thirteen participants (50 % women; mean age: 46 years, mean body mass index: 37) were included: 182 returned for 18-month follow-up, of whom 172 completed the HRQOL questionnaire. HRQOL was reduced with clinical significance compared with general Norwegians. The mean changes in HRQOL from the baseline to the follow-up were not of clinical importance. However, one out of three individuals achieved a moderate or large clinical improvement in HRQOL. The best determinant for improved HRQOL was obtained for a composite, clinically significant lifestyle change, i.e. both a weight reduction of at least 5 % and an improvement in exercise capacity of at least 10 %, which was associated with an improvement in five out of the eight SF-36 domains. CONCLUSION: Subjects at risk of type 2 diabetes report a clinically important reduction in HRQOL compared with general Norwegians. The best predictor of improved HRQOL was a small weight loss combined with a small improvement in aerobic capacity. PMID- 24789669 TI - Effects of phosphodiesterase type 5 inhibitors on Raynaud's phenomenon. AB - Raynaud's phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). However, existing vasodilators have very limited efficacy. In this study, phosphodiesterase type 5 inhibitors (PDE-5Is) were administered to evaluate efficacy on RP. Three patients with mixed connective tissue disease and three patients with systemic sclerosis having RP were enrolled. Oral sildenafil, vardenafil, or tadalafil was administered. The fingertip temperature was measured by thermography before and 120 min after administration. To evaluate longer effects, vardenafil was administered daily for 12 weeks; the fingertip temperature was measured by thermography before and 12 weeks after administration. As compared with the pre-administration of sildenafil, vardenafil, and tadalafil, the mean fingertip temperature increased by 2.17, 3.47, and 3.59 degrees C, respectively, in 120 min. In the 12-week trial with vardenafil in 3 patients, the mean fingertip temperature increased by 3.04, 7.96, and 3.32 degrees C from baseline in each patient. PDE-5Is significantly increased fingertip temperature within 120 min, and the effect of vardenafil lasted for 12 weeks under daily use. PDE-5Is were safe and would be an effective treatment for RP with CTDs. PMID- 24789670 TI - Lower extremity lipedema, upper extremity lipodystrophy and severe calcinosis complicating juvenile dermatomyositis. AB - Juvenile dermatomyositis (JDM) is a rare but complex and potentially life threatening autoimmune disease of childhood. Significant proportions of patients have residual weakness, muscle atrophy, joint contractures, and calcinosis. Recently, new clinical findings, such as lipodystrophy accompanied with increased fat deposition in certain areas, have been reported. So far, it is not known whether the redistribution of body fat may be the type of lipedema of lower extremity. We describe a 39-year-old woman who was diagnosed with JDM at the age of 7. Later she developed symmetrical lipodystrophy of upper extremities and symmetrical lipedema of lower extremities (making 2 and 58.3 % of total body fat mass, respectively), with multiple calcified nodules in the subcutaneous tissues. These nodules gradually increased in size despite therapy. Capillaroscopy findings showed scleroderma-like abnormalities. ANA and anti-U1RNP antibodies were positive. Similar cases with simultaneous occurrence of the lipedema of lower extremities, lipodystrophy of upper extremities, and severe calcinosis complicating JDM have not been published so far. We showed that the calcinosis and lipodystrophy were associated with short duration of active disease. Also, we display case that raises the question whether it is possible overlapping autoimmune diseases revealed during follow-up. PMID- 24789671 TI - Electro-acupuncture promotes the survival and differentiation of transplanted bone marrow mesenchymal stem cells pre-induced with neurotrophin-3 and retinoic acid in gelatin sponge scaffold after rat spinal cord transection. AB - In the past decades, mesenchymal stem cells (MSCs) as a promising cell candidate have received the most attention in the treatment of spinal cord injury (SCI). However, due to the low survival rate and low neural differentiation rate, the grafted MSCs do not perform well as one would have expected. In the present study, we tested a combinational therapy to improve on this situation. MSCs were loaded into three-dimensional gelatin sponge (GS) scaffold. After 7 days of induction with neurotrophin-3 (NT-3) and retinoic acid (RA) in vitro, we observed a significant increase in TrkC mRNA transcription by Real-time PCR and this was confirmed by in situ hybridization. The expression of TrkC was also confirmed by Western blot and immunohistochemistry. Differentiation potential of MSCs in vitro into neuron-like cells or oligodendrocyte-like cells was further demonstrated by using immunofluorescence staining. The pre-induced MSCs seeding in GS scaffolds were then grafted into the transected rat spinal cord. One day after grafting, Governor Vessel electro-acupuncture (GV-EA) treatment was applied to rats in the NR-MSCs + EA group. At 30 days after GV-EA treatment, it found that the grafted MSCs have better survival rate and neuron-like cell differentiation compared with those without GV-EA treatment. The sustained TrkC expression in the grafted MSCs as well as increased NT-3 content in the injury/graft site by GV-EA suggests that NT-3/TrkC signaling pathway may be involved in the promoting effect. This study demonstrates that GV-EA and pre-induction with NT-3 and RA together may promote the survival and differentiation of grafted MSCs in GS scaffold in rat SCI. PMID- 24789673 TI - A controlled spatial distribution of functional units in the two dimensional nanospace of layered silicates and titanates. AB - The immobilization of functional units in the interlayer spaces of layered silicates and titanates is summarized from the viewpoint of how the spatial distribution of functional units in the interlayer affects the performance of the intercalation compounds. The ways of incorporating controlled amounts of functional units with controlled spatial distribution are also discussed. As a result of controlled spatial distribution of functional units in two-dimensional nanospace, one can achieve improved efficiency of photo-induced events (photoluminescence and photoinduced electron/energy transfer), molecular sieving and substrate/product selective catalytic reactions. PMID- 24789672 TI - Human Wharton's jelly stem cells, its conditioned medium and cell-free lysate inhibit the growth of human lymphoma cells. AB - Several groups have reported that primitive mesenchymal stem cells from the gelatinous matrix of the Wharton's jelly of the human umbilical cord (hWJSCs) possess tumoricidal properties and inhibit the growth of solid tumours such as human mammary carcinoma, ovarian carcinoma and osteosarcoma. This unique characteristic led to the hypothesis that hWJSCs serve as a natural defence against migrating cancer cells from mother to fetus thus explaining why tumorigenesis in the fetus is rare. However, it is not known whether non-solid malignant hematopoietic cells are also inhibited by hWJSCs and what the exact tumoricidal mechanisms are. We therefore evaluated the influence of hWJSCs and its extracts on Burkitt's lymphoma cells. Cell proliferation (BrdU and Ki67+), viability (MTT) and cell death (Annexin V-Propidium iodide and live/dead) assays showed significant inhibition of lymphoma cell growth after 48 h exposure to hWJSCs or its extracts compared to controls. Increased cell death was observed at sub-G1 and S and decreased proliferation at G2/M phases of the mitotic cycle. Superoxide dismutase and hydrogen peroxide activity were significantly increased and glutathione peroxidase significantly decreased in treated lymphoma cells. Time lapse imaging and confocal z-stack images showed yellow fluorescent in situ hybridization (FISH) signals of lymphoma cell Y chromosomes within the cytoplasm of female red labelled hWJSCs. We hypothesize that the growth of lymphoma cells is inhibited by the molecules secreted by hWJSCs that use oxidative stress pathways to induce cell death followed by engulfment of the apoptotic remains of the lymphoma cells by the hWJSCs. PMID- 24789674 TI - A concise approach to polysubstituted oxazoles from N-acyl-2-bromo enamides via a copper(I)/amino acid-catalyzed intramolecular C-O bond formation. AB - A straightforward and efficient copper(I)/amino acid-catalyzed intramolecular Ullmann-type C-O coupling reaction has been developed. This protocol affords a facile methodology for the synthesis of a series of novel 2,4,5-substituted oxazoles from readily accessible N-acyl-2-bromo enamides under mild conditions. PMID- 24789675 TI - Efficacy of pharmacotherapy and psychotherapy for adult psychiatric disorders: a systematic overview of meta-analyses. AB - IMPORTANCE: There is debate about the effectiveness of psychiatric treatments and whether pharmacotherapy or psychotherapy should be primarily used. OBJECTIVES: To perform a systematic overview on the efficacy of pharmacotherapies and psychotherapies for major psychiatric disorders and to compare the quality of pharmacotherapy and psychotherapy trials. EVIDENCE REVIEW: We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Library (April 2012, with no time or language limit) for systematic reviews on pharmacotherapy or psychotherapy vs placebo, pharmacotherapy vs psychotherapy, and their combination vs either modality alone. Two reviewers independently selected the meta-analyses and extracted efficacy effect sizes. We assessed the quality of the individual trials included in the pharmacotherapy and psychotherapy meta-analyses with the Cochrane risk of bias tool. FINDINGS: The search yielded 45,233 results. We included 61 meta-analyses on 21 psychiatric disorders, which contained 852 individual trials and 137,126 participants. The mean effect size of the meta-analyses was medium (mean, 0.50; 95% CI, 0.41-0.59). Effect sizes of psychotherapies vs placebo tended to be higher than those of medication, but direct comparisons, albeit usually based on few trials, did not reveal consistent differences. Individual pharmacotherapy trials were more likely to have large sample sizes, blinding, control groups, and intention-to-treat analyses. In contrast, psychotherapy trials had lower dropout rates and provided follow-up data. In psychotherapy studies, wait-list designs showed larger effects than did comparisons with placebo. CONCLUSIONS AND RELEVANCE: Many pharmacotherapies and psychotherapies are effective, but there is a lot of room for improvement. Because of the multiple differences in the methods used in pharmacotherapy and psychotherapy trials, indirect comparisons of their effect sizes compared with placebo or no treatment are problematic. Well-designed direct comparisons, which are scarce, need public funding. Because patients often benefit from both forms of therapy, research should also focus on how both modalities can be best combined to maximize synergy rather than debate the use of one treatment over the other. PMID- 24789676 TI - A preclinical evaluation of a novel multikinase inhibitor, SKLB-329, as a therapeutic agent against hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a serious life-threatening malignant disease of liver. Molecular targeted therapies are considered a promising strategy for the treatment of HCC. Sorafenib is the first, and so far the only targeted drug approved by the US Food and Drug Administration (FDA) for clinical therapy of HCC. Despite being effective in some HCC patients, some demerits of sorafenib in the treatment of HCC, such as modest survival benefits, and drug resistance, have also been reported, which highlights the unmet medical need among patients with HCC. Here, we report a novel multikinase inhibitor discovered by us, SKLB-329, which potently inhibits angiogenesis-related kinases including VEGFR1/2/3, and FGFR2, and the Src kinase. SKLB-329 significantly inhibited endothelial cell growth, migration, invasion and tube formation. It showed potent anti-angiogenic activity in a transgenic zebrafish model. Moreover, SKLB-329 could efficiently restrain the proliferation of HCC cells through down-regulation of Src-mediated FAK and Stat3 activity. In vivo, oral administration of SKLB-329 considerably suppressed the tumor growth in HCC xenograft models (HepG2 and SMMC7721) in a dose-dependent manner. In all of the in vitro and in vivo assays of this investigation, sorafenib was used as a positive control, and in most assays SKLB 329 exhibited a higher potency compared with the positive control. In addition, SKLB-329 also bears favorable pharmacokinetic properties. Collectively, the results of preclinical studies presented here demonstrate that SKLB-329 is a promising drug candidate for HCC treatment. PMID- 24789677 TI - Transcranial direct current stimulation for treatment of freezing of gait: a cross-over study. AB - BACKGROUND AND OBJECTIVE: Progression of Parkinson's disease (PD) is frequently characterized by the occurrence of freezing of gait (FOG) representing a disabling motor complication. We aim to investigate safety and efficacy of transcranial direct current stimulation of the primary motor cortex of PD patients with FOG. METHODS: In this cross-over, double-blind, sham-controlled study, 10 PD patients with FOG persisting in "on" state underwent anodal and sham direct current stimulation for 5 consecutive days. Clinical assessment over a 1 month period was performed. RESULTS: A significant improvement of gait, as assessed by the Stand Walk Sit test, with reduction in number and duration of FOG episodes, along with a significant reduction in the Unified Parkinson's Disease Rating Scale score, were observed after anodal stimulation. Beneficial effects were more evident after the entire 5-day stimulation session, and persisted until the end of the observation period. CONCLUSIONS: Anodal transcranial direct current stimulation of the motor cortex is safe and has therapeutic potential in PD patients with FOG. PMID- 24789678 TI - FOXP1 has a low expression in human gliomas and its overexpression inhibits proliferation, invasion and migration of human glioma U251 cells. AB - The present study aimed to examine the clinical characteristics of forkhead box protein P1 (FoxP1) in gliomas and its role in the proliferation, invasiveness, migration and apoptosis of the human glioma U251 cell line. The expression levels of FOXP1 were first studied in operation resection specimens of glioma and normal peripheral brain tissues. The enhanced green fluorescent protein (EGFP) expression vector of FOXP1 was prepared and transfected into U251 cells. MTT, cell invasion, transwell and scratch assays were utilized to investigate the cell growth activity and the rate of apoptosis of the cells was tested by flow cytometry. Western blot analysis and quantitative polymerase chain reaction assays were employed to measure the transfection efficacy. The results revealed that FOXP1 was highly expressed in glioma, as compared with low levels detected in normal brain tissues. Following transfection with pEGFP-N1-FOXP1, the proliferation, invasiveness and migration capabilities of cells significantly decreased, whilst the rate of apoptosis was markedly enhanced (P<0.01). Furthermore, the expression of FOXP1 in U251 cells was enhanced (P<0.01). In conclusion, the present study indicated that FOXP1 is closely associated with tumorigenesis and development of glioma, as demonstrated by a reduction in the proliferation, migration and invasion of glioma cells upon FOCP1 overexpression. PMID- 24789679 TI - Cx43 reverses the resistance of A549 lung adenocarcinoma cells to cisplatin by inhibiting EMT. AB - Cisplatin (CDDP) is one of the standard first-line chemotherapeutic agents for advanced non-small cell lung cancer (NSCLC). Unfortunately, prolonged exposure to CDDP results in acquired resistance which prevents the successful treatment of lung cancer patients. Thus, it is necessary to explore the mechanism underlying the resistance of NSCLC to CDDP. In the present study, a CDDP-resistant human lung cancer cell line A549/CDDP was established from the parental cell line A549. The results demonstrated that A549/CDDP cells acquired an epithelial-mesenchymal transition (EMT) phenotype, with morphological changes including acquisition of a spindle-like fibroblastic phenotype, downregulation of E-cadherin, upregulation of mesenchymal markers (vimentin, Snail and Slug), and increased capability of invasion and migration. Compared with A549 cells, the A549/CDDP cells showed decreased connexin43 (Cx43) expression. Overexpression of Cx43 reversed EMT and CDDP resistance in the A549/CDDP cells. Conversely, knockdown of Cx43 expression by siRNA-Cx43 initiated EMT and induced CDDP insensitivity in A549 cells. In summary, Cx43 reverses CDDP resistance in A549 CDDP-resistant cells by preventing EMT, making Cx43 a possible therapeutic target for lung cancer. PMID- 24789680 TI - Questions of Khoesan continuity: dental affinities among the indigenous Holocene peoples of South Africa. AB - The present report follows up on the findings of previous research, including recent bioarchaeological study of well-dated Khoesan skeletal remains, that posits long term biological continuity among the indigenous peoples of South Africa after the Pleistocene. The Arizona State University Dental Anthropology System was used to record key crown, root, and intraoral osseous nonmetric traits in six early-through-late Holocene samples from the Cape coasts. Based on these data, phenetic affinities and an identification of traits most important in driving intersample variation were determined using principal components analysis and the mean measure of divergence distance statistic. To expand biological affinity comparisons into more recent times, and thus preliminarily assess the dental impact of disproportionate non-Khoesan gene flow into local peoples, dental data from historic Khoekhoe and San were also included. Results from the prehistoric comparisons are supportive of population continuity, though a sample from Matjes River Rockshelter exhibits slight phenetic distance from other early samples. This and some insignificant regional divergence among these coastal samples may be related to environmental and cultural factors that drove low-level reproductive isolation. Finally, a close affinity of historic San to all samples, and a significant difference of Khoekhoe from most early samples is reflective of documented population history following immigration of Bantu-speakers and, later, Europeans into South Africa. PMID- 24789681 TI - Protein gels and emulsions from mixtures of Cape hake and pea proteins. AB - BACKGROUND: Portioning of frozen fish generates by-products such as fish 'sawdust' and cut-offs which can be further processed into protein concentrates and isolates. The objective of the present work was to produce gels and emulsions using recovered Cape hake protein powder (HPP). In previous works, the structures of the gels produced by HPP were found to be strong, with a high rubbery character. In this work, the addition of commercial pea proteins (PPC) to HPP gels and emulsions was studied. RESULTS: Physical properties of gels and emulsions prepared with different proportions of mixtures of PPC and HPP were evaluated. In general, gels and emulsions showed high values for whiteness and, as expected, the higher content of HPP in the protein mixtures led to higher firmness values of the gels. The gel network was rapidly formed upon heating due to the fish protein macromolecules and further reinforced by the pea protein macromolecules when cooled to 5 degrees C. Both visco-elastic parameters, storage and loss moduli, of the produced gels increased with the HPP proportion in the protein mixtures, corresponding to more structured systems. For the emulsions, two different pH environments were studied: 3.8 and 7.0. At neutral pH a synergy was found between the vegetable and fish protein, which is not so strong when pH is lowered to 3.8, near the isoelectric point of pea proteins (pI = 4.5). This evidence was supported by the results from the texture measurements, viscosity and visco-elastic parameters. CONCLUSIONS: Gels made from Cape hake proteins showed a softer texture and were less rubbery with the addition of pea proteins. Emulsions stabilised by these mixtures showed slightly different behaviour when produced at pH 7.0 or pH 3.8. PMID- 24789682 TI - Genome-wide association studies of agronomic and quality traits in a set of German winter barley (Hordeum vulgare L.) cultivars using Diversity Arrays Technology (DArT). AB - A set of about 100 winter barley (Hordeum vulgare L.) cultivars, comprising diverse and economically important German barley elite germplasm released during the last six decades, was previously genotypically characterized by single nucleotide polymorphism (SNP) markers using the Illumina GoldenGate BeadArray Technology to detect associations with phenotypic data estimated in three-year field trials at 12 locations. In order to identify further associations and to obtain information on whether the marker type influences the outcome of association genetics studies, the set of winter barley cultivars was re-analyzed using Diversity Arrays Technology (DArT) markers. As with the analysis of the SNPs, only polymorphic markers present at an allele frequency >5% were included to detect associations in a mixed linear model (MLM) approach using the TASSEL software (P <= 0.001). The population structure and kinship matrix were estimated on 72 simple sequence repeats (SSRs) covering the whole barley genome. The respective average linkage disequilibrium (LD) analyzed with DArT markers was estimated at 5.73 cM. A total of 52 markers gave significant associations with at least one of the traits estimated which, therefore, may be suitable for marker assisted breeding. In addition, by comparing the results to those generated using the Illumina GoldenGate BeadArray Technology, it turned out that a different number of associations for respective traits is detected, depending on the marker system. However, as only a few of the respective DArT and Illumina markers are present in a common map, no comprehensive comparison of the detected associations was feasible, but some were probably detected in the same chromosomal regions. Because of the identification of additional marker-trait associations, it may be recommended to use both marker techniques in genome-wide association studies. PMID- 24789683 TI - Decreased expression of NPRL2 in renal cancer cells is associated with unfavourable pathological, proliferation and apoptotic features. AB - The tumor suppressor gene nitrogen permease regulator-like 2(NPRL2) NPRL2 expressed obviously in many normal human tissues, but reduced in expression in many human tumors significantly. In this study, we detected the expression of NPRL2 in 78 clear cell renal cell carcinoma (ccRCC) by immunohistochemistry and correlated it with clinicopathological parameters. Meanwhile, the function of NPRL2 in human ccRCC was further explored after transfected recombinant expressing plasmids pEGFP-N1-NPRL2 into human renal cancer 786-0 cells. NPRL2 protein showed high expression in 67 of 78 cases of adjacent normal tissues (85.9 %), which was significantly higher than that in ccRCC tissues (23/78, 29.5 %). Clinic pathological analysis showed that NPRL2 expression was significantly correlated with histological grade (P = 0.044), TNM stage (P = 0.025) and lymph node metastasis (P = 0.028). MTT assay demonstrated that NPRL2 could obviously inhibit renal cancer cell proliferation. Flow cytometric analysis revealed that NPRL2 could induce renal cancer cells apoptosis and arrest the cell cycle in G0/G1 phase. In conclusion, NPRL2 is closely correlated to unfavourable pathological, proliferation and apoptotic features in ccRCC. PMID- 24789684 TI - Unexpected targets and triggers of autoimmunity. AB - Recent findings indicate that the role of Th17 cells in the pathogenesis of tissue inflammation and autoimmunity has become rather complicated. While interleukin-17 (IL-17) producing CD4+ T cells are found frequently within the peripheral target tissue during the course of autoimmune disease, these cells may contribute to or protect from inflammation. Accumulating reports have revealed the existence of both pathogenic and non-pathogenic Th17 cells. These Th17 subsets produce the signature cytokines IL-17A and IL-17F yet have distinct and divergent roles in inducing autoimmune tissue inflammation. Comparative genomic sequence analyses between the pathogenic and non-pathogenic Th17 cells have exposed unexpected and extensive population heterogeneity within the Th17 subset. Here we review some of the unexpected factors that may drive pathogenic divergence. Understanding the functional consequences of Th17 cell diversity may allow for the selection of more precise targets for intervention in autoimmune and inflammatory diseases. PMID- 24789685 TI - Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. AB - OBJECTIVE: Ataxia telangiectasia (AT) is a rare genetic, multi-system disorder characterized by neurodegeneration, chromosome instability, B and T cell immunodeficiency and a predisposition to cancer. We examined immunologic parameters reflecting cell development and proliferation and their relevancy to the clinical phenotype in affected individuals. PATIENTS AND METHODS: AT patients from the AT National Clinic in Israel underwent immunological investigation. Their T and B cell workup included lymphocyte subset counts, immunoglobulin levels, responses to mitogenic stimulations, TCR-Vbeta families and BCR immunoglobulin heavy chain spectratyping, TCR rearrangement excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs). RESULTS: Thirty-seven AT patients (median age 12.7 years, range 4.2-25.1) were evaluated. CD20 B and CD3 T lymphocytes were decreased in 67 % and 64 % of the patients, respectively, while only 33 % of the patients had reduced lymphoproliferative responses. Almost all AT patients displayed extremely low TRECs and KRECs levels, irrespective of their age. Those levels were correlated to one another and to the amounts of CD3+ and CD20+ cells, respectively. Abnormal TCR-Vbeta repertoires were found with different degrees of clonality or reduced expression in these AT patients. There was no clear clustering of expansions to specific TCR-Vbeta genes. PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in peripheral blood was abnormal in 50 % of the patients. CONCLUSION: The immunodeficiency associated with AT is combined, remains low over time and not progressive. It is characterized by low TREC and KREC copies suggestive of abnormal T and B cell neogenesis. PMID- 24789686 TI - Major histocompatibility complex class II deficiency complicated by Mycobacterium avium complex in a boy of mixed ethnicity. AB - Major histocompatibility complex class II (MHCII) deficiency represents a rare form of severe immunodeficiency associated with increased susceptibility to viral, bacterial, and fungal pathogens and commonly leads to failure to thrive and early death. This autosomal recessive disorder is caused by mutations in MHCII transcription regulator genes, resulting in impaired expression of MHCII, and it is usually seen in consanguineous populations. Our patient presented at age 15 months with a history of developmental delay, multiple respiratory infections and skin abscesses, and recently, at 5 years of age, he was found to have disseminated Mycobacterium avium complex. His mother is Mexican-American, and his father is Persian. Laboratory investigations showed hypogammaglobulinemia, modest T-lymphopenia, borderline mitogen responses, absent tetanus toxoid and candida antigen lymphoproliferative assays, and absent tetanus toxoid and Haemophilus influenzae type b antibody levels. Flow cytometry demonstrated absent HLA-DR antigen on monocytes and B-cells, and a diagnosis of MHCII deficiency was made. Genetic analysis yielded a homozygous pathogenic class II transactivator (CIITA) mutation. The same mutation was found in both parents. Coincidently, an Xq28 microduplication was identified and likely was the cause of the patient's developmental delay. This patient demonstrated some of the typical features of MHCII deficiency with the addition of several unique findings: disseminated M. avium complex, homozygosity in a CIITA mutation despite remarkably diverse parental ethnicity, and coincident Xq28 microdeletion with mild intellectual disability. PMID- 24789687 TI - IgG4- related disease as a rare cause of tubulointerstitial nephritis. AB - Isolated IgG4 tubulointerstitial nephritis (TIN) is a rare disorder characterized by raised serum IgG4 levels and histological findings of dense lymphoplasmacytic infiltrates rich in IgG4 positive plasma cells. We report a case of isolated IgG4 TIN that presented with acute kidney injury in an 84 year old man with a polyclonal increase in his total IgG and a raised IgE of 381 kUA/L but without evidence of systemic autoimmunity. We draw a parallel with IgG4-related autoimmune pancreatitis and show raised levels of circulating regulatory T cells. Importantly the plasma levels of the T regulatory cell cytokine, IL10, the TH1 cytokines IL12 and IFNgamma, the proinflammatory TNF alpha and immune regulatory IL27 were all highly raised. Furthermore, the level of IL21 that promotes IgG4 production was also very significantly elevated. These results suggest efforts of the immune system to reduce inflammation and suppress an exaggerated Th2 response. A raised serum IgG in the setting of acute kidney injury and in the absence of autoimmunity and chronic infection should encourage an assessment of the IgG subclasses. Prompt steroid treatment of those with a raised IgG4 may reduce ongoing renal damage. PMID- 24789689 TI - Comments on 'sample size calculation for comparing two negative binomial rates'. PMID- 24789688 TI - Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. AB - Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder caused by mutations in the NF1 gene. One of the hallmarks of NF1 is the high mutation rate in this gene. In this study, we present 127 different NF1 mutations and 54 novel mutations detected at both the genomic DNA and mRNA level using a retrospective case series review. We found that 25.2% of these different mutations induced aberrant splicing. Of note, 40.6% of these splicing errors were caused by exonic variants. In addition, one mutation produced mosaicism in the post-transcriptional profile. However, studies investigating these splicing aberrations are limited. In order to better understand the pathogenicity of NF1 and to provide a more accurate interpretation in molecular diagnostic testing, combined computational analyses were employed to elucidate the underlying mechanisms of the variants modulating NF1 gene splicing. PMID- 24789691 TI - Photothermal effect for localized desorption of primary lymphocytes arrayed on an antibody/DNA-based biochip. AB - This work proposes a miniaturized system able to perform multiple cell capture followed by cell-type selective release from a biochip surface. Unlabelled lymphocytes were first specifically captured onto a DNA array by antibody-DNA conjugates. The immobilized cells were subsequently released under spatiotemporal control within local heating generated by intense Surface Plasmon Resonance (SPR) produced by laser illumination. PMID- 24789693 TI - Functional capacity as a significant independent predictor of postoperative mortality for octogenarian ASA-III patients. AB - BACKGROUND: The American Society of Anesthesiology's (ASA) 6-point physical status classification remains one of the most significant predictors of perioperative morbidity and mortality and is the most widely used risk stratification tool worldwide. Its utility is significantly limited for octogenarians, however, as the majority of these patients are classified as ASA III. Thus, for patients aged 80 or older, we hypothesized that incorporating patients' functional status, defined by the ability to perform activities of daily living independently, would improve perioperative risk stratification. METHODS: All data were extracted from the Veterans Affairs Surgical Quality Improvement Program, a perioperative prospectively maintained computerized database. ASA-III patients were reclassified into subgroups IIIA or IIIB, with IIIA representing functionally independent patients and IIIB representing partially or fully dependent patients. Functional status was self-reported during preoperative assessments. In this database, mortality data (primary outcome) was reliably available for all patients for the duration of the 96-month follow-up period, as were other perioperative patient data. RESULTS: Seven hundred and fifty-nine (72.4%) patients were classified as ASA-IIIA, and 290 (27.6%) patients were ASA-IIIB. Thirty-day and long-term survival was significantly better in the ASA-IIIA group, irrespective of type of surgery (hazard ratio 1.87, confidence interval 1.55-2.25, p < .001). ASA-IIIB hazard ratios for mortality were greatest for orthopedic and vascular surgery patients, but a significant divergence in survival between ASA-IIIA and IIIB patients was observed in all surgical specialties. CONCLUSION: As evidenced by Kaplan-Meier and multivariate analyses, functional capacity was a significant independent predictor of mortality for ASA III patients older than 80 years of age. PMID- 24789692 TI - Varicella zoster immune status in children treated for acute leukemia. AB - Children treated for acute leukemia are at increased risk of severe infection with varicella zoster virus (VZV). We studied the VZV sero-status of children with acute leukemia prior to starting chemotherapy and after completion of chemotherapy. VZV sero-status was assessed using time resolved fluorescence immunoassay (TRFIA) before starting treatment and 6 months after completion of treatment. Prior to starting treatment for acute leukemia, a significant proportion of children (35%) are VZV seronegative. On completion of treatment most patients maintained protective VZV antibody levels; however, 35% had reduced/loss VZV antibody to a level considered non-protective and susceptible to VZV infection. PMID- 24789695 TI - Enhancing circularly polarised luminescence by extending the pi-conjugation of axially chiral compounds. AB - Circularly polarised luminescence (CPL) and photoluminescence (PL) properties of pi-conjugated (R)- and (S)-2,2'-diphenyl-4-biphenanthrol (VAPOL) exhibited an efficient CPL (~1.3 * 10(-3)) with a quantum yield (PhiF) of 0.20 at 376 nm. By comparison, (R)- and (S)-3,3-diphenyl-2,2-bi-1-naphthol (VANOL) exhibited no CPL or PL. PMID- 24789696 TI - A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. AB - OBJECTIVE: This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one or more adequate trials of drug therapy. METHODS: PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment resistant depression. Two researchers independently assessed study quality and extracted data. RESULTS: Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8+/-2.1 prior depressive episodes and illness duration of 4.4+/-3.3 years and had completed 4.7+/-2.7 unsuccessful drug trials involving 2.1+/-.3 drug classes. Response rates for treatment-resistant depression were 36%+/-1%. A total of 17%+/-6% of patients had prior suicide attempts (1.1+/-.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41+/-.8 and .26+/-.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression. CONCLUSIONS: Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression. PMID- 24789697 TI - Identification of genetic variants of lecithin cholesterol acyltransferase in individuals with high HDL-C levels. AB - Among the most common lipid abnormalities, a low level of high-density lipoprotein-cholesterol (HDL-C) is one of the first risk factors identified for coronary heart disease. Lecithin cholesterol acyltransferase (LCAT) has a pivotal role in the formation and maturation of HDL-C and in reverse cholesterol transport. To identify genetic loci associated with low HDL-C in a population based cohort in Tehran, the promoter, coding regions and exon/intron boundaries of LCAT were amplified and sequenced in consecutive individuals (n=150) who had extremely low or high HDL-C levels but no other major lipid abnormalities. A total of 14 single-nucleotide polymorphisms (SNPs) were identified, of which 10 were found to be novel; the L393L, S232T and 16:67977696 C>A polymorphisms have been previously reported in the SNP Database (as rs5923, rs4986970 and rs11860115, respectively) and the non-synonymous R47M mutation has been reported in the Catalogue of Somatic Mutations in Cancer (COSM972635). Three of the SNPs identified in the present study (position 6,531 in exon 5, position 6,696 in exon 5 and position 5,151 in exon 1) led to an amino acid substitution. The most common variants were L393L (4886C/T) in exon 6 and Q177E, a novel mutation, in exon 5, and the prevalence of the heterozygous genotype of these two SNPs was significantly higher in the low HDL-C groups. Univariate conditional logistic regression odds ratios (ORs) were nominally significant for Q177E (OR, 5.64; P=0.02; 95% confidence interval, 1.2-26.2). However, this finding was attenuated following adjustment for confounders. Further studies using a larger sample size may enhance the determination of the role of these SNPs. PMID- 24789698 TI - Magnetic resonance imaging of electrochemical cells containing bulk metal. AB - The development of improved energy-storage devices, as well as corrosion prevention and metal-electrofinishing technologies, requires knowledge of local composition and transport behaviour in electrolytes near bulk metals, in situ and in real time. It remains a challenge to acquire such data and new analytical methods are required. Recent work shows that magnetic resonance imaging (MRI) is able to map concentration gradients and visualise electrochemical processes in electrochemical cells containing bulk metals. This recent work, along with the challenges, and solutions, associated with MRI of these electrochemical cells are reviewed. PMID- 24789699 TI - In vivo high-resolution magic angle spinning proton NMR spectroscopy of Drosophila melanogaster flies as a model system to investigate mitochondrial dysfunction in Drosophila GST2 mutants. AB - In vivo nuclear magnetic resonance spectroscopy (NMR), a non-destructive biochemical tool used for investigating live organisms, has recently been performed in studies of the fruit fly Drosophila melanogaster, a useful model organism for investigating genetics and physiology. We used a novel high resolution magic angle-spinning (HRMAS) NMR method to investigate live Drosophila GST2 mutants using a conventional 14.1-T NMR spectrometer equipped with an HRMAS probe. The results showed that, compared to wild-type (wt) controls, the GST2 mutants had a 48% greater (CH(2))n lipid signal at 1.33 ppm, which is an insulin resistance biomarker in Drosophila skeletal muscle (P=0.0444). The mutants also had a 57% greater CH(2)C= lipid signal at 2.02 ppm (P=0.0276) and a 100% greater CH=CH- signal at 5.33 ppm (P=0.0251). Since the -CH=CH- signal encompasses protons from ceramide, this latter difference is consistent with the hypothesis that the GST2 mutation is associated with insulin resistance and apoptosis. The findings of this study corroborate our previous results, support the hypothesis that the GST2 mutation is associated with insulin signaling and suggest that the IMCL level may be a biomarker of insulin resistance. Furthermore, direct links between GST2 mutation (the Drosophila ortholog of the GSTA4 gene in mammals) and insulin resistance, as suggested in this study, have not been made previously. These findings may thus be directly relevant to a wide range of metabolically disruptive conditions, such as trauma, aging and immune system deficiencies, that lead to increased susceptibility to infection. PMID- 24789700 TI - ABC triblock terpolymer self-assembled core-shell-corona nanotubes with high aspect ratios. AB - Nanotubes have attracted considerable attention due to their unique 1D hollow structure; however, the fabrication of pure nanotubes via block copolymer self assembly remains a challenge. In this work, the successful preparation of core shell-corona (CSC) nanotubular micelles with uniform diameter and high aspect ratio is reported, which is achieved via self-assembly of a poly (styrene-b-4 vinyl pyridine-b-ethylene oxide) triblock terpolymer in binary organic solvents with assistance of solution thermal annealing. Via direct visualization of trapped intermediates, the nanotube is believed to be formed via large sphere large solid cylinderical aggregates-nanotube transformations, wherein the unique solid to hollow transition accompanied with the unidirectional growth is distinct from conventional pathway. In addition, by virtue of the CSC structure, gold nanoparticles are able to be selectively incorporated into different micellar domains of the nanotubes, which may have potential applications in nanoscience and nanotechnology. PMID- 24789702 TI - Effects of nursing intervention models on social adaption capability development in preschool children with malignant tumors: a randomized control trial. AB - OBJECTIVES: The objectives of this study are to compare the effects of two nursing intervention models on the ability of preschool children with malignant tumors to socialize and to determine if these interventions improved their social adaption capability (SAC) and quality of life. METHODS: Inpatient preschool children with malignant tumors admitted to the hospital between December 2009 and March 2012 were recruited and randomized into either the experimental or control groups. The control group received routine nursing care, and the experimental group received family-centered nursing care, including physical, psychological, and social interventions. The Infants-Junior Middle School Student's Social-Life Abilities Scale was used to evaluate SAC development of participants. RESULTS: Participants (n = 240) were recruited and randomized into two groups. After the intervention, the excellent and normal SAC rates were 27.5% and 55% in the experimental group, respectively, compared with 2.5% and 32.5% in the control group (p < 0.001). After the intervention, SAC in experimental group was improved compared with before intervention (54.68 +/- 10.85 vs 79.9 +/- 22.3, p < 0.001). However, no differences in SAC were observed between baseline and after intervention in the control group (54.70 +/- 11.47 vs. 52 +/- 15.8, p = 0.38). CONCLUSION: The family-centered nursing care model that included physical, psychological, and social interventions improved the SAC of children with malignancies compared with children receiving routine nursing care. Establishing a standardized family-school-community-hospital hierarchical multi-management intervention model for children is important to the efficacy of long-term interventions and to the improvement of SAC of children with malignancies. PMID- 24789701 TI - Gut microbiota and GLP-1. AB - A large body of evidence suggests that the regulation of energy balance and glucose homeostasis by fermentable carbohydrates induces specific changes in the gut microbiota. Among the mechanisms, our research group and others have demonstrated that the gut microbiota fermentation (i.e., bacterial digestion of specific compounds) of specific prebiotics or other non-digestible carbohydrates is associated with the secretion of enteroendocrine peptides, such as the glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), produced by L-cells. In this review, we highlight past and recent results describing how dietary manipulation of the gut microbiota, using nutrients or specific microbes, can stimulate GLP-1 secretion in rodents and humans. Furthermore, the purpose of this review is to discuss the putative mechanisms by which specific bacterial metabolites, such as short chain fatty acids, trigger GLP-1 secretion through GPR41/43-dependent mechanisms. Moreover, we conclude by discussing the molecular advance showing that the endocannabinoid system or related bioactive lipids modulated by the gut microbiota may contribute to the regulation of glucose, lipid and energy homeostasis. PMID- 24789703 TI - Orostachys japonicus induces apoptosis and cell cycle arrest through the mitochondria-dependent apoptotic pathway in AGS human gastric cancer cells. AB - We investigated the anticancer mechanisms of the ethylacetate (EtOAc) fraction from Orostachys japonicus in human gastric cancer (AGS) cells. Flow cytometric analysis revealed that the number of total apoptotic cells following treatment with the EtOAc fraction increased in a dose-dependent manner. In the cell cycle analyses, the EtOAc fraction increased the peak in the sub-G1, indicating apoptosis, and in the G2/M phases in a dose-dependent manner. In the RT-PCR analysis, the expression of cyclin-dependent kinase 1 (CDK 1) and cyclin B1 decreased in a dose- and time-dependent manner. The results of western blotting revealed that the protein levels of p53, cytochrome c, and cleaved caspase-3, -8 and -9 proteins increased and those of B cell lymphoma-2 (bcl-2) and pro-caspase 3, -8 and -9 proteins decreased in a dose- and time-dependent manner, whereas the levels of bcl-2-associated x protein (bax) remained unchanged. Furthermore, the changes in the levels of pro-caspase-3, -8 and -9 and cleaved caspase-3, -8 and 9 were abolished by the pan-caspase inhibitor Z-VAD-FMK. In addition, phosphorylation of p38 and JNK increased in a time-dependent manner. These results, for the first time, provide an understanding of the potential anticancer activity of the O. japonicus, which functions through the induction of apoptosis and cell cycle arrest. PMID- 24789704 TI - Protein tyrosine kinase 7 plays a tumor suppressor role by inhibiting ERK and AKT phosphorylation in lung cancer. AB - Protein tyrosine kinase 7 (PTK7) is a catalytically inactive receptor tyrosine kinase that is also known as colon carcinoma kinase-4 (CCK-4). Recent reports have shown that PTK7 plays an important role in carcinogenesis, and it is known to be upregulated in gastric, colon and esophageal cancer, as well as in liposarcoma. However, the role of PTK7 in lung cancer has not been investigated. The aim of the present study was to investigate the expression levels and the role of PTK7 in lung cancer. We found that PTK7 expression was downregulated at the mRNA as well as protein levels in human lung squamous cell carcinoma (LSCC). Upon investigation of the functional role of PTK7 in LSCC, we found that overexpression of PTK7 in LSCC cells resulted in inhibition of cell proliferation, invasion and migration. Furthermore, we confirmed that these phenotypic changes are associated with the inactivation of AKT and ERK. Our findings suggest that PTK7 has different oncogenic roles in organs and target tumors. PMID- 24789705 TI - Results from a horizon scan on risks associated with transplantation of human organs, tissues and cells: from donor to patient. AB - The successful transplantation of human materials such as organs, tissues and cells into patients does not only depend on the benefits, but also on the mitigation of risks. To gain insight into recent publications on risks associated with the process of transferring human materials from donor to recipient we performed a horizon scan by reviewing scientific literature and news websites of 2011 on this subject. We found there is ample information on how extended donor criteria, such as donor age, affect the survival rates of organs or patients. Interestingly, gender mismatch does not appear to be a major risk factor in organ rejection. Data on risks of donor tumor transmission was very scarce; however, risk categories for various tumor types have been suggested. In order to avoid rejection, a lot of research is directed towards engineering tissues from a patient's own tissues and cells. Some but not all of these developments have reached the clinic. Developments in the field of stem cell therapy are rapid. However, many hurdles are yet to be overcome before these cells can be applied on a large scale in the clinic. The processes leading to genetic abnormalities in cells differentiated from stem cells need to be identified in order to avoid transplantation of aberrant cells. New insights have been obtained on storage and preservation of human materials, a critical step for success of their clinical use. Likewise, quality management systems have been shown to improve the quality and safety of human materials used for transplantation. PMID- 24789706 TI - Determination of estrogens in environmental water samples using 1,3 dipentylimidazolium hexafluorophosphate ionic liquid as extraction solvent in dispersive liquid-liquid microextraction. AB - In this work, the potential of a symmetric dialkyl-substituted ionic liquid (IL), 1,3-dipenthylimidazolium hexafluorophosphate ([PPIm][PF6 ]), as extraction solvent in dispersive liquid-liquid microextraction (DLLME) has been studied for the analysis of a group of three natural (estriol, 17beta-estradiol, and 17alpha estradiol) and four synthetic (17alpha-ethynylestradiol, diethylstibestrol, dienestrol, and hexestrol) estrogenic compounds as well as one mycotoxin with estrogenic activity (zearalenone) in different types of water samples (Milli-Q, mineral, and wastewater). Separation, determination, and quantification were developed by HPLC-DAD and a fluorescence detector (FD) connected in series. Factors influencing the IL-DLLME procedure (sample pH, amount of IL, type and volume of disperser solvent, ionic strength, and assistance of vortex agitation) were investigated and optimized by means of a step-by-step approach. Once the optimum extraction conditions were established (10 mL of water at pH 8, 60 mg of [PPIm][PF6 ], 500 MUL of ACN as disperser solvent and vortex agitation for 1 min), the calibration curves of the whole method (IL-DLLME-HPLC-DAD/FD) were obtained and precision and accuracy were evaluated. It was demonstrated that the developed methodology was repeatable, accurate, and selective with limits of detection in the 0.30-0.57 MUg/L and 13.8-37.1 MUg/L range for FD and DAD, respectively. Relative recovery values were higher than 85% for the different types of water samples and the Student's t test demonstrated that there were not significant differences between the added and the found concentration. PMID- 24789707 TI - Carotid I's, L's and T's: collaterals shape the outcome of intracranial carotid occlusion in acute ischemic stroke. AB - BACKGROUND: Collaterals may affect revascularization, ischemic severity, and clinical outcomes in acute stroke owing to internal carotid artery (ICA) occlusion. OBJECTIVE: To examine the hypothesis that morphology of occlusive thrombus and collateral flow patterns may influence the outcome of ICA occlusions after mechanical thrombectomy. METHODS: Pooled analyses of ICA occlusions in the MERCI and Multi-MERCI trials employed central angiography review readings to categorize lesions as I, L, or T clots and functional lesions based on collateral flow patterns. Demographic variables, procedural details, and clinical outcomes were compared across ICA lesion types. RESULTS: A total of 72 subjects (mean age 67 years (SD 16), 51% female, median National Institutes of Health Stroke Scale 20 (range 8-35)) were included, with 90-day modified Rankin score <=2 in 28% and 51% mortality. Clots were categorized as an I lesion in 9/72 (12.5%), L lesion in 12/72 (16.7%), and T lesion in 51/72 (70.8%). Based on collateral flow patterns, cases were categorized as having a functional I lesion in 7/72 (9.7%), functional L in 38/72 (52.8%), and functional T in only 27/72 (37.5%). Multivariate analyses showed that a functional T lesion, with insufficient collateral flow to ipsilateral anterior cerebral arteries via the contralateral ICA, was a strong predictor of both revascularization success and subsequent clinical outcomes. CONCLUSIONS: Collateral flow patterns distinguish the nature and impact of ICA occlusions on expected revascularization and subsequent clinical outcomes in acute ischemic stroke. The nomenclature of terminal ICA occlusions introduced here (carotid I's, L's, and T's) may enhance future endovascular trials targeting such proximal occlusions. TRIAL REGISTRATION NUMBER: NCT00318071 (http://clinicaltrials.gov). MERCI was not registered because enrollment began before July 1, 2005. PMID- 24789709 TI - En bloc resection of primary malignant bone tumors of the cervical spine. AB - BACKGROUND: Due to the poor response of primary malignant bone tumors to adjuvant therapies, surgical resection performed in an en bloc fashion with free margins remains the best option for long-term recurrence-free survival of patients harboring such lesions. METHODS: In this article the authors provide a stepwise review of the technical details involved in the performance of en bloc resections of tumoral lesions in the cervical spine. CONCLUSIONS: Due to the anatomical peculiarities of the cervical spine related to the presence of functional nerve roots as well as the vertebral arteries, en bloc resections in this region remains a challenging surgical procedure. PMID- 24789708 TI - Eic1 links Mis18 with the CCAN/Mis6/Ctf19 complex to promote CENP-A assembly. AB - CENP-A chromatin forms the foundation for kinetochore assembly. Replication independent incorporation of CENP-A at centromeres depends on its chaperone HJURP(Scm3), and Mis18 in vertebrates and fission yeast. The recruitment of Mis18 and HJURP(Scm3) to centromeres is cell cycle regulated. Vertebrate Mis18 associates with Mis18BP1(KNL2), which is critical for the recruitment of Mis18 and HJURP(Scm3). We identify two novel fission yeast Mis18-interacting proteins (Eic1 and Eic2), components of the Mis18 complex. Eic1 is essential to maintain Cnp1(CENP-A) at centromeres and is crucial for kinetochore integrity; Eic2 is dispensable. Eic1 also associates with Fta7(CENP-Q/Okp1), Cnl2(Nkp2) and Mal2(CENP-O/Mcm21), components of the constitutive CCAN/Mis6/Ctf19 complex. No Mis18BP1(KNL2) orthologue has been identified in fission yeast, consequently it remains unknown how the key Cnp1(CENP-A) loading factor Mis18 is recruited. Our findings suggest that Eic1 serves a function analogous to that of Mis18BP1(KNL2), thus representing the functional counterpart of Mis18BP1(KNL2) in fission yeast that connects with a module within the CCAN/Mis6/Ctf19 complex to allow the temporally regulated recruitment of the Mis18/Scm3(HJURP) Cnp1(CENP-A) loading factors. The novel interactions identified between CENP-A loading factors and the CCAN/Mis6/Ctf19 complex are likely to also contribute to CENP-A maintenance in other organisms. PMID- 24789710 TI - Treatment of patients with ruptured aneurysm by neurosurgeons that perform both open surgical and endovascular techniques is safe and effective: results of a single centre in Europe. AB - In Europe only few neurosurgeons are trained in both open surgical clipping as well as in endovascular techniques for treatment of intracranial aneurysms. To investigate the safety and efficacy of performing both techniques we, two dual trained neurosurgeons, analyzed our results in repairing ruptured intracranial aneurysms. Prospectively collected data from 356 patients that underwent open surgical or endovascular repair of a ruptured intracranial aneurysm at the Neurosurgical Centre Nijmegen from 2006 to 2012 by two dual trained neurosurgeons were retrospectively analyzed. Complication rates, occlusion rates, and retreatment rates were obtained. Combined procedural persistent neurological morbidity and mortality after endovascular treatment and open surgical clipping were 2.1 % and 1.4 %, respectively. Overall procedure-related clinical complication rate for endovascular treatment was 5.9 % in 285 procedures for 295 aneurysms. Overall procedure-related clinical complication rate for open treatment was 9.9 % in 71 procedures for 72 aneurysms. Follow-up was available for 255 out of 295 coiled aneurysms, 48 aneurysms recurred and 34 needed retreatment. For clipping 54 out of 72 treated aneurysms had follow-up; four aneurysms were incompletely clipped. One aneurysm was retreated. Treatment of ruptured intracranial aneurysms by neurosurgeons that perform both open surgical clipping as well as endovascular techniques is safe and effective. Developing training programs in Europe for hybrid neurosurgeons that can provide comprehensive patient care should be considered. PMID- 24789718 TI - Structure and function of the archaeal exosome. AB - The RNA-degrading exosome in archaea is structurally very similar to the nine subunit core of the essential eukaryotic exosome and to bacterial polynucleotide phosphorylase (PNPase). In contrast to the eukaryotic exosome, PNPase and the archaeal exosome exhibit metal ion-dependent, phosphorolytic activities and synthesize heteropolymeric RNA tails in addition to the exoribonucleolytic RNA degradation in 3' -> 5' direction. The archaeal nine-subunit exosome consists of four orthologs of eukaryotic exosomal subunits: the RNase PH-domain-containing subunits Rrp41 and Rrp42 form a hexameric ring with three active sites, whereas the S1-domain-containing subunits Rrp4 and Csl4 form an RNA-binding trimeric cap on the top of the ring. In vivo, this cap contains Rrp4 and Csl4 in variable amounts. Rrp4 confers poly(A) specificity to the exosome, whereas Csl4 is involved in the interaction with the archaea-specific subunit of the complex, the homolog of the bacterial primase DnaG. The archaeal DnaG is a highly conserved protein and its gene is present in all sequenced archaeal genomes, although the exosome was lost in halophilic archaea and some methanogens. In exosome containing archaea, DnaG is tightly associated with the exosome. It functions as an additional RNA-binding subunit with poly(A) specificity in the reconstituted exosome of Sulfolobus solfataricus and enhances the degradation of adenine-rich transcripts in vitro. Not only the RNA-binding cap but also the hexameric Rrp41 Rrp42 ring alone shows substrate selectivity and prefers purines over pyrimidines. This implies a coevolution of the exosome and its RNA substrates resulting in 3'-ends with different affinities to the exosome. PMID- 24789717 TI - The application of subset correspondence analysis to address the problem of missing data in a study on asthma severity in childhood. AB - Non-response in cross-sectional data is not uncommon and requires careful handling during the analysis stage so as not to bias results. In this paper, we illustrate how subset correspondence analysis can be applied in order to manage the non-response while at the same time retaining all observed data. This variant of correspondence analysis was applied to a set of epidemiological data in which relationships between numerous environmental, genetic, behavioural and socio economic factors and their association with asthma severity in children were explored. The application of subset correspondence analysis revealed interesting associations between the measured variables that otherwise may not have been exposed. Many of the associations found confirm established theories found in literature regarding factors that exacerbate childhood asthma. Moderate to severe asthma was found to be associated with needing neonatal care, male children, 8- to 9-year olds, exposure to tobacco smoke in vehicles and living in areas that suffer from extreme air pollution. Associations were found between mild persistent asthma and low birthweight, and being exposed to smoke in the home and living in a home with up to four people. The classification of probable asthma was associated with a group of variables that indicate low socio-economic status. PMID- 24789719 TI - Comparison of techniques for the isolation of volatiles from cashew apple juice. AB - BACKGROUND: The aim of this study was to compare the performance of the following techniques on the isolation of volatiles of importance for the aroma/flavor of fresh cashew apple juice: dynamic headspace analysis using PorapakQ((r)) as trap, solvent extraction with and without further concentration of the isolate, and solid-phase microextraction (fiber DVB/CAR/PDMS). RESULTS: A total of 181 compounds were identified, from which 44 were esters, 20 terpenes, 19 alcohols, 17 hydrocarbons, 15 ketones, 14 aldehydes, among others. Sensory evaluation of the gas chromatography effluents revealed esters (n = 24) and terpenes (n = 10) as the most important aroma compounds. CONCLUSION: The four techniques were efficient in isolating esters, a chemical class of high impact in the cashew aroma/flavor. However, the dynamic headspace methodology produced an isolate in which the analytes were in greater concentration, which facilitates their identification (gas chromatography-mass spectrometry) and sensory evaluation in the chromatographic effluents. Solvent extraction (dichloromethane) without further concentration of the isolate was the most efficient methodology for the isolation of terpenes. Because these two techniques also isolated in greater concentration the volatiles from other chemical classes important to the cashew aroma, such as aldehydes and alcohols, they were considered the most advantageous for the study of cashew aroma/flavor. PMID- 24789720 TI - The application of real-time PCR technique to detect rare cell clones with primary T790M Substitution of EGFR gene in metastases of non-small cell lung cancer to central nervous system in chemotherapy naive patients. AB - The time-limited efficacy of reversible EGFR-TKIs in patients with advanced non small cell lung cancer (NSCLC) with EGFR gene activating mutations is associated with development of treatment resistance after some period of therapy. This resistance predominantly results from secondary mutations located in EGFR gene, especially T790M substitution. There is limited information available concerning the prevalence of primary T790M mutations in patients with metastatic NSCLC tumors before treatment with EGFR-TKIs. The aim of work was to assess the prevalence of de novo T790M mutations in EGFR gene in tissue samples from NSCLC metastatases in central nervous system (CNS) in both chemotherapy and EGFR-TKI naive NSCLC patients. We analyzed DNA samples isolated from paraffin-embedded tissue from CNS metastases for T790M mutations using real-time PCR and TaqMan probe against the T790M mutant sequence. The tissue samples were taken during palliative neurosurgery in 143 NSCLC patients. Amplification of the T790M specific sequence was detected in 25 patients (17.5 %). The quantity of mutated DNA was less than 1 % in all samples with amplification, and in vast majority (20 patients, 14 % of all samples) it was even less that 0.1 %. In 5 patients (3.5 %) quantity of mutated DNA ranged from 0.1 to 1 % and true positive results of T790M mutation presence in these patients were most possible. Amplification of this sequence was not concurrent with common EGFR mutations and was not associated with sex, smoking status and pathological type of cancer. There is a possibility to detect the primary T790M mutation in brain metastases of NSCLC in EGFR-TKIs naive patients. PMID- 24789721 TI - Treatment of refractory hairy cell leukemia with a BRAF-inhibitor: lessons to be learnt. AB - Hairy cell leukemia is a rare chronic lymphoproliferative disorder with indolent but progressive clinical course. Patients require treatment when they have significant cytopenia or recurrent infections. The gold standard treatment are purine nucleoside analogues (cladribine and pentostatine), with these agents the rate of complete remission can approach even 95 %. The differential diagnosis between classical hairy cell leukemia and other, rare splenic lymphomas that can mimic this disease might be really challenging. Splenic lymphoma with villous lymphocytes and other new, provisional WHO entities share some, but not all immunophenotypical features with hairy cell leukemia. The correct diagnosis is of an extreme importance as these entities require different treatment. Thus further investigation in the pathogenesis of hairy cell leukemia is required in order to solve this challenge. Discovery of the BRAF V600E mutation as a disease-defining genetic event in hairy cell leukemia can be helpful in both differential diagnosis and treatment of this disease. We report the case of three hairy cell leukemia patients, whose diagnosis or treatment was based on this newly discovered somatic mutation, but the treatment results and side effects were individual. PMID- 24789722 TI - Predictive factors for lymph node metastasis in solitary papillary thyroid carcinomas: a retrospective study. AB - Identifying risk factors for neck lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) is important for patient prognosis establishment. We conducted a retrospective study among 317 patients with solitary PTC. Factors associated with clinically evident LNM were evaluated. LNM were identified in 69 (21.7%) patients. Central compartment (17.3%) and lateral compartment (9.4%) were involved. Thyroid capsule invasion and extrathyroidal extension were found to be independent risk factors for both central and lateral compartment metastasis in multivariate analysis. Larger diameter was associated with central compartment metastasis in logistic regression model, whereas male gender only with lateral compartment metastasis. As closer tumors were positioned in relation to glandular capsule we expected rising rates of nodal spread. It was unlikely to find clinically evident neck LNM among patients with centrally located tumors. PMID- 24789723 TI - Cyclooxygenase-2 polymorphisms and breast cancer associated risk in Pakistani patients. AB - Prostaglandins produced by Cyclooxygenase-2 enzyme have been implicated to have a role in breast carcinogenesis. Several single nucleotide polymorphisms (SNPs) linked to COX-2 enzyme are reported to modulate its expression. The aim of the present study was to examine association of these SNPs to breast cancer risk in Pakistani patients. METHODS: In this case-control study, three sequence variants rs689465, rs689466, rs20417 in the promoter region of COX-2 were screened to evaluate the association with breast cancer risk. A total of 150 breast cancer patients and 101 healthy control genomic DNA were genotyped for rs689456, rs689466, rs20417 and their genotypes distribution in cases and control were compared using Pearson chi square test. Risk association was analyzed through odd ratio calculated by logistic regression. RESULTS: A screening analysis of COX-2 SNPs in 101 healthy controls showed distribution of Minor allelic frequency distribution of SNPs as follows : rs689465 (0.12), rs689466 (0.15), rs20417 (0.23). Further analyses revealed that their observed genotype frequencies were consistent with Hardy Weinberg equilibrium and strong linkage disequilibrium was identified between rs20417, rs689465 and rs689466. The Combined allele variants analysis showed that Haplotype rs68965G- 689466A-20417C (OR 2.909; CI 95 %1.3776.327; P = 0.007) was significantly associated with breast cancer. CONCLUSIONS: Our results indicate no strong association between three most frequent COX-2 SNPs rs689465 rs689466, rs20417 studied with breast cancer risk in the single locus analysis. However, our data suggested that combined COX-2 SNP haplotype have a role in breast cancer associated risk in Pakistani patients. PMID- 24789724 TI - Expression of microRNA-1, microRNA-133a and Hand2 protein in cultured embryonic rat cardiomyocytes. AB - In this study, we investigated the expression of the pathway, SRF-microRNA 1/microRNA-133a-Hand2, in the Wistar rat embryonic ventricular cardiomyocytes under conventional monolayer culture. The morphological observation of the cultured cardiomyocytes and the mRNA expression levels of three vital constituent proteins, MLC-2v, N-cadherin, and connexin43, demonstrated the immaturity of these cultured cells, which was featured by less myofibril density, immature sarcomeric structure, and significantly lower mRNA expression of the three constituent proteins than those in neonatal ventricular samples. More importantly, results in this study suggest that the change of SRF-microRNA 1/microRNA-133a-Hand2 pathway results into the attenuation of the Hand2 repression in cultured cardiomyocytes. These outcomes are valuable to understand the cellular state as embryonic cardiomyocytes to be in vitro model and might be useful for the assessment of engineered cardiac tissue and cardiac differentiation of stem cells. PMID- 24789725 TI - Effects of culture media on the susceptibility of cells to apoptotic cell death. AB - Whether responses of cells to extracellular environments affect the induction of apoptotic cell death is poorly understood. The current study aimed to unravel the different effects of culture media employed in vitro as extracellular environments on the susceptibility of cells to apoptosis. We found that apoptosis is stimulated to the higher levels by culturing human HeLa cells in Opti-MEM with unknown components, a medium that is specifically used for transfections, than by culturing cells in Dulbecco's modified Eagle's medium, a medium that is generally used for maintenance of cells. We showed that apoptosis is suppressed partially by culturing cells in heat-treated Opti-MEM, implicating a heat-sensitive component(s) in stimulating the apoptotic response of cells. Thus, different extracellular environments may contribute to different responses of cells to apoptosis, and this should be considered to evaluate the incidences of apoptotic cell death and could be applied to develop an efficient treatment for curing diseases such as cancer. PMID- 24789726 TI - Depletion of host cell riboflavin reduces Wolbachia levels in cultured mosquito cells. AB - Wolbachia is an obligate intracellular alphaproteobacterium that occurs in arthropod and nematode hosts. Wolbachia presumably provides a fitness benefit to its hosts, but the basis for its retention and spread in host populations remains unclear. Wolbachia genomes retain biosynthetic pathways for some vitamins, and the possibility that these vitamins benefit host cells provides a potential means of selecting for Wolbachia-infected cell lines. To explore whether riboflavin produced by Wolbachia is available to its host cell, we established that growth of uninfected C7-10 mosquito cells decreases in riboflavin-depleted culture medium. A well-studied inhibitor of riboflavin uptake, lumiflavin, further inhibits growth of uninfected C7-10 cells with an LC50 of approximately 12 MUg/ml. Growth of C/wStr1 mosquito cells, infected with Wolbachia from the planthopper, Laodelphax striatellus, was enhanced in medium containing low levels of lumiflavin, but Wolbachia levels decreased. Lumiflavin-enhanced growth thus resembled the improved growth that accompanies treatment with antibiotics that deplete Wolbachia, rather than a metabolic advantage provided by the Wolbachia infection. We used the polymerase chain reaction to validate the decrease in Wolbachia abundance and evaluated our results in the context of a proteomic analysis in which we detected nearly 800 wStr proteins. Our data indicate that Wolbachia converts riboflavin to FMN and FAD for its own metabolic needs, and does not provide a source of riboflavin for its host cell. PMID- 24789727 TI - Single-walled carbon nanotubes induce cytotoxicity and DNA damage via reactive oxygen species in human hepatocarcinoma cells. AB - Carbon nanotubes (CNTs) are gradually used in various areas including drug delivery, nanomedicine, biosensors, and electronics. The current study aimed to explore the DNA damage and cytotoxicity due to single-walled carbon nanotubes (SWCNTs) on human hepatocarcinoma cells (HepG2). Cellular proliferative assay showed the SWCNTs to exhibit a significant cell death in a dose- and time dependent manner. However, SWCNTs induced significant intracellular reactive oxygen species (ROS) production and elevated lipid peroxidation, catalase, and superoxide dismutase in the HepG2 cells. SWCNTs also induced significant decrease in GSH and increase caspase-3 activity in HepG2 cells. DNA fragmentation analysis using the alkaline single-cell gel electrophoresis showed that the SWCNTs cause genotoxicity in a dose- and time-dependent manner. Therefore, the study points towards the capability of the SWCNTs to induce oxidative stress resulting cytotoxicity and genomic instability. This study warrants more careful assessment of SWCNTs before their industrial applications. PMID- 24789729 TI - Starvation is more efficient than the washing technique for purification of rat Sertoli cells. AB - Sertoli cells (SCs), one of the most important components of seminiferous tubules, are vital for normal spermatogenesis and male fertility. In recent years, numerous in vitro studies have shown the potential and actual activities of SCs. However, pure SCs are necessary for various in vitro studies. In this study, we have evaluated the efficiency of the starvation method for SC purification as compared with the washing method. Seminiferous tubule-derived cells (STDCs) of rats' testes underwent two different techniques for SC purification. In the first group (washing group), the medium was changed every 3 4 d, and cells were washed twice with phosphate-buffered saline that lacked CaC12 and MgSO4 (PBS(-)) before the addition of fresh medium. In the second group (starvation), the medium was changed every 7-8 d. Primary culture (P0), passage 1 (P1), and passage 2 (P2) cells were analyzed for the expression of SC-specific genes, vimentin, Wilm's tumor 1 (WT1), germ cell gene (vasa), Leydig cell marker, 17beta-hydroxysteroid dehydrogenase type 3 (Hsd17b3), and a marker of peritubular myoid cells, alpha smooth muscle actin (alphaSma), by reverse transcriptase polymerase chain reaction (RT-PCR) and real-time RT-PCR. Gene expression analysis showed that P0 cells expressed all tested genes except Hsd17b3. The starvation method caused significant downregulation of vasa and alphaSma expression in P0, P1, and P2 cells, whereas vimentin and WT1 were upregulated. In contrast, the washing method was less effective than the starvation method for the removal of germ and pretubular myoid cells (p < 0.001). Totally, the results have revealed that although washing is the only common technique for elimination of contaminant cells in SC cultures, starvation has a stronger effect and is a suitable, affordable technique for SC purification. We propose that starvation is an efficient, inexpensive method that can be used for purification of SCs in animal species. PMID- 24789730 TI - Nicotine inhibits the proliferation by upregulation of nitric oxide and increased HDAC1 in mouse neural stem cells. AB - Cigarette smoking (CS) is considered one of the major risk factors to cause neurodegenerative disorders. Nicotine is the main chemical in CS which is responsible for dysfunction of the brain as a neuroteratogen. Also, nicotine dependency is a real mental illness and disease. Recently, chronic nicotine exposure has been shown to cause oxidative/nitrosative stress leading to a deleterious condition to cellular death in different brain regions. However, little is known about the effects of nicotine on mouse neural stem cells (mNSCs). The aim of this study is to investigate the effects of nicotine on mNSCs and elucidate underlying mechanisms involved in expression of a diversity of genes regulated by nicotine. When mNSCs were isolated from the whole brain of embryonic day 16 mice treated with nicotine at vehicle, 100, 400, and 800 MUM for 5 d, nicotine significantly decreased the number and size of neurospheres. In immunocytochemistry, nicotine-exposed mNSCs expressing nestin showed the shortened filaments and condensed nuclei. In RT-PCR, messenger RNA (mRNA) levels of proliferating cell nuclear antigen (PCNA) and sirtuin1 (SIRT1) were significantly decreased, while the production of nitric oxide and mRNA levels of cyclooxygenase2 (COX-2), tumor necrosis factor-alpha TNF-alpha, and histone deacetylase 1 (HDAC1) were increased in a dose-dependent manner. In addition, sodium butyrate and valproic acid, HDAC inhibitors, partially rescue proliferation of mNSCs via inhibition of HDAC1 expression and NO production. Taken together, these data demonstrate that prolonged exposure of nicotine decreased proliferation of mNSCs by increased NO and inflammatory cytokine through increased HDAC1. Furthermore, this study could help in the development of a therapy for nicotine-induced neurodegenerative disorder and drug abuse. PMID- 24789731 TI - Experimental full-thickness burns induced by CO2 laser. AB - Many studies have been conducted on the treatment of burns because they are important in morbidity and mortality. These studies are mainly focused on improving care and quality of life of patients. The aim of this study is the induction of standardized full-thickness burns of the skin of rats using the CO2 laser. The results show that non-contact technique using the CO2 laser is effective to induce such standardization of burning and is an important step in determining the efficiency of different therapies used in treating burns. PMID- 24789733 TI - Smart, stretchable supercapacitors. AB - Smart supercapacitors are developed by depositing conducting polymers onto aligned carbon-nanotube sheets. These supercapacitors rapidly and reversibly demonstrate color changes in response to a variation in the level of stored energy and the chromatic transitions can be directly observed by the naked eye. PMID- 24789732 TI - Do subjective memory complaints herald the onset of mild cognitive impairment in Parkinson disease? AB - BACKGROUND: Longitudinal studies on healthy participants have shown that subjective memory impairment (defined as subjective cognitive complaints with normal cognitive objective performance) might be a strong predictor of mild cognitive impairment (MCI). Parkinson disease (PD) also manifests cognitive disturbances, but whether subjective memory complaints may predict the development of MCI in PD has not yet been explored. METHODS: We prospectively screened newly diagnosed, untreated patients with PD in order to evaluate whether subjective memory complaints may predict development of MCI over a 2-year follow up evaluation. RESULTS: We enrolled 76 de novo untreated patients with PD. Of the 76 patients, 23 (30.3%) complained memory issues. Among the patients cognitively unimpaired at baseline, those with subjective complaints were more likely to develop MCI at follow-up. The regression model confirmed that presence of subjective memory complaints at baseline was an independent predictor of development of MCI at follow-up. DISCUSSION: This is the first prospective study to explore the relationship between subjective and objective cognitive deficits in newly diagnosed, untreated patients. Our results provide preliminary evidence that subjective memory complaints might predict future development of MCI. PMID- 24789735 TI - Use of outpatient mental health services among children of different ages: are younger children more seriously ill? AB - OBJECTIVE: The study compared use of specialty outpatient mental services among children ages six and seven and children ages eight through 12 and investigated predictors of differences in the patterns of service use by age. METHODS: Eligible children were first-time patients of clinics participating in the Longitudinal Assessment of Manic Symptoms who were between ages six and 12 and who were English speaking. Children who screened positive for symptoms of mania (N=1,124) were invited to participate, and families of 621 (55%) children consented. A matched sample of 86 children without a positive screen for mania also participated. Baseline interviews assessed sociodemographic characteristics of the child and family and the child's functioning, diagnoses, and use of services. RESULTS: Of the 707 children, 30% were younger, and 50% used multiple types of specialty outpatient services. Younger children were more likely to be male, have Medicaid insurance, and have two parents with mental health problems. Use of multiple types of services was related to study site, high depression scores, fewer minor health issues, and fewer stressful life events among younger children and with parental stress, primary diagnosis, poor functioning, and not living with both parents among older children. Younger children were much more likely than older children to have used services before age six. CONCLUSIONS: Younger children showed very early use of multiple types of services for mental health problems and a pattern of persistent impairment despite long-standing use of services. These data argue strongly for focusing on emotional and behavioral issues among young children. PMID- 24789736 TI - Using problem solving therapy to treat veterans with subsyndromal depression: a pilot study. AB - OBJECTIVE: We conducted a pilot study comparing problem solving therapy for primary care (PST-PC) to a dietary education control condition in middle-aged and older veterans with symptoms of emotional distress and subsyndromal depression. METHODS: This was a two-site study at the VA Pittsburgh Healthcare System and Philadelphia VA Medical Center. Participants included veterans >50 years of age referred from primary care clinics who were eligible if they obtained a pre screen score >11 on the Centers for Epidemiologic Studies Depression (CES-D) scale. Exclusions were a DSM-IV Major Depressive Episode within the past year, active substance abuse/dependence within 1 month, current antidepressant therapy, and a Mini mental status exam score <24. Participants were randomized to receive one of two interventions--either PST-PC or an attention control condition consisting of dietary education (DIET)--each consisting of six to eight sessions within a 4-month period. RESULTS: Of 45 individuals randomized, 23 (11 PST-PC and 12 DIET) completed treatment. Using regression models in completers that examined outcomes at end of treatment while controlling for baseline scores, there were significant differences between treatment groups in SF-36 mental health component scores but not in depressive symptoms (as assessed with either the 17-item Hamilton Rating Scale for Depression or the Beck Depression Inventory), social problem solving skills, or physical health status (SF-36 physical health component score). CONCLUSIONS: These pilot study findings suggest that a six-to eight session version of PST-PC may lead to improvements in mental health functioning in primary care veterans with subsyndromal depressive symptoms. PMID- 24789737 TI - Lung tumours reprogram pulmonary dendritic cell immunogenicity at the microRNA level. AB - Lung cancer arises in a context of tumour-induced immune suppression. Dendritic cells (DCs) are central players in the induction of anti-tumoural immunity, providing critical signals that drive the induction of cytotoxic T-cell responses. Meanwhile, microRNAs are associated with tumour development as well as immune regulation. We postulated that lung tumours escape immune control by reprogramming DC immunogenicity at the microRNA level. Using an orthotopic model of lung cancer, we first identified the DC population responsible for transport and cross-presentation of lung tumour-derived antigens to naive T cells in the draining mediastinal lymph nodes (LNs). Profiling the full microRNA repertoire of these DCs revealed a restricted set of microRNAs that was consistently dysregulated in the presence of lung tumours, with miR-301a as one of the top upregulated transcripts. Overexpression of miR-301a in DCs suppressed IL-12 secretion, decreased IFN-gamma release from antigen-specific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-gamma towards IL-13 and IL-17A-secreting T cells. Strikingly, DC-selective Dicer1 gene deletion resulted in delayed lung tumour growth and a survival benefit. Taken together, our data reveal that lung tumours induce an immunosuppressive microRNA signature in pulmonary DCs. Interfering with the DC-intrinsic capacity to remodel microRNA repertoires affects lung tumour outcome. PMID- 24789740 TI - High dose alkylator therapy for extracranial malignant rhabdoid tumors in children. AB - BACKGROUND: Extracranial malignant rhabdoid tumor (MRT) is a rare pediatric cancer with a poor prognosis. The kidney is the most common site. Isolated reports have shown improvements in patient survival, but no specific treatment regimen has shown efficacy over others. PROCEDURE: Retrospective review of patients diagnosed with extracranial MRT at Children's Hospital Los Angeles between 1983 and 2012. RESULTS: The median age at presentation for the 21 patients was 13 months (range, 0-108 months). Ten patients had renal primary tumors. The median time to progression was 4 months (range, 0.4-7 months). The 5 year event free survival (EFS) and overall survival (OS) of the entire cohort was 38 +/- 10.6%. After 2002, patients diagnosed with extracranial MRT were administered a chemotherapy regimen of vincristine, doxorubicin and high dose cyclophosphamide (VDC). The OS for the patients diagnosed before and after 2002 were 20 +/- 12% and 54 +/- 15%, respectively. Of the 13 patients who received VDC containing regimen, eight patients achieved a complete radiological remission; five of these patients are long-term survivors. Four patients who received autologous bone marrow transplantation were alive at last follow-up. All patients with unresectable primary tumors died. Patients who had disease progression or relapse did not survive. CONCLUSIONS: Patients with extracranial MRT have a poor prognosis. Treatment with high dose alkylator therapy followed by consolidation with high dose chemotherapy and autologous bone marrow transplant for those patients in radiographic complete remission appears to have a beneficial effect on survival. PMID- 24789741 TI - Plasma neuronal specific enolase: a potential stage diagnostic marker in human African trypanosomiasis. AB - BACKGROUND: This study was carried out to determine the potential of neuronal specific enolase (NSE) as a stage diagnostic marker in human African trypanosomiasis. METHODS: Plasma and cerebrospinal fluid were obtained from a cohort of Trypanosoma brucei rhodesiense-infected patients and non-infected controls. Neuronal specific enolase concentrations were measured by ELISA and analysed in relation to diagnosis and disease-stage data. RESULTS: Plasma NSE concentration was significantly increased in late-stage patients (median 21 ng/ml), compared to the control (median 11 ng/ml), but not in early-stage patients (median 5.3 ng/ml). Cerebrospinal fluid NSE concentration did not vary between stages. CONCLUSION: Plasma NSE is a potential stage diagnostic in this cohort and merits further investigation. PMID- 24789742 TI - Simple method of using soda for distinguishing Killian-Jamieson diverticulum from a thyroid nodule. PMID- 24789743 TI - Ill-defined germinal centers and severely reduced plasma cells are histological hallmarks of lymphadenopathy in patients with common variable immunodeficiency. AB - Given the severely reduced numbers of circulating class-switched memory B cells and plasmablasts in patients with common variable immunodeficiency (CVID) the germinal center (GC) reaction as the source of both populations is expected to be disturbed in many CVID patients. Therefore immunohistochemical studies were performed on lymph node (LN) biopsies from ten CVID patients with benign lymphoproliferation. According to the Sander classification the majority of patients presented with reactive lymphoid hyperplasia (7/10), 6/10 showed granulomatous inflammation. All cases showed some normal GCs but in 9/10 these concurred to a varying degree with hyperplastic, ill-defined GCs in the same LN. The percentage of ill-defined GCs correlated significantly with the percentage of circulating CD21(low) B cells suggesting a common origin of both immune reactions. In 9/10 CVID LNs significantly higher numbers of infiltrating CD8+ T cells were found in GCs of CVID patients compared to controls, but no HHV-8 and only in 2/10 LNs EBV infection was detected. Class switched plasma cells (PCs) were severely reduced in 8/10 LNs and if present, rarely found in the medulla of the LN. Based on the presence of large GCs in all examined patients, the reduction of circulating memory B cells and PCs points towards a failure of GC output rather than GC formation in CVID patients with lymphadenopathy. PMID- 24789744 TI - The increase in surface EMG could be a misleading measure of neural adaptation during the early gains in strength. AB - PURPOSE: To test the validity of using the increase in surface EMG as a measure of neural adaptation during the early gains in strength. METHODS: Simulation of EMG signals detected by surface bipolar electrode with 20-mm inter-pole distance at different radial distances from the muscle and longitudinal distances from the end-plate area. The increases in the root mean square (RMS) of the EMG signal due to possible alteration in the neural drive or elevation of the intracellular negative after-potentials, detected in fast fatigable muscle fibres during post tetanic potentiation and assumed to accompany post-activation potentiation, were compared. RESULTS: Lengthening of the intracellular action potential (IAP) profile due to elevation of the negative after-potentials could affect amplitude characteristics of surface EMG detected at any axial distance stronger than alteration in the neural drive. This was irrespective of the fact that the elevation of IAP negative after-potential was applied to fast fatigable motor units (MUs) only, while changes in frequency of activation (simulating neural drive changes) were applied to all MUs. In deeper muscles, where the fibre electrode distance was larger, the peripheral effect was more pronounced. The normalization of EMG amplitude characteristics to an M-wave one could result only in partial elimination of peripheral factor influence CONCLUSIONS: The increase in RMS of surface EMG during the early gains in strength should not be directly related to the changes in the neural drive. The relatively small but long-lasting elevated free resting calcium after high-resistance strength training could result in force potentiation and EMG increase. PMID- 24789745 TI - Least-squares fitting of time-domain signals for Fourier transform mass spectrometry. AB - To advance Fourier transform mass spectrometry (FTMS)-based molecular structure analysis, corresponding development of the FTMS signal processing methods and instrumentation is required. Here, we demonstrate utility of a least-squares fitting (LSF) method for analysis of FTMS time-domain (transient) signals. We evaluate the LSF method in the analysis of single- and multiple-component experimental and simulated ion cyclotron resonance (ICR) and Orbitrap FTMS transient signals. Overall, the LSF method allows one to estimate the analytical limits of the conventional instrumentation and signal processing methods in FTMS. Particularly, LSF provides accurate information on initial phases of sinusoidal components in a given transient. For instance, the phase distribution obtained for a statistical set of experimental transients reveals the effect of the first data-point problem in FT-ICR MS. Additionally, LSF might be useful to improve the implementation of the absorption-mode FT spectral representation for FTMS applications. Finally, LSF can find utility in characterization and development of filter-diagonalization method (FDM) MS. PMID- 24789746 TI - Construction of nanoantennas on the bacterial outer membrane. AB - We demonstrate a simple manipulation of gold nanoparticles that creates a structure-dependent nanometer-scale antenna on the surface of bacteria. Our studies illuminate the concept of the "effective use of light" based on the absorption and emission of light by antennas formed on bacteria. PMID- 24789747 TI - Mapping small effect mutations in Saccharomyces cerevisiae: impacts of experimental design and mutational properties. AB - Genetic variants identified by mapping are biased toward large phenotypic effects because of methodologic challenges for detecting genetic variants with small phenotypic effects. Recently, bulk segregant analysis combined with next generation sequencing (BSA-seq) was shown to be a powerful and cost-effective way to map small effect variants in natural populations. Here, we examine the power of BSA-seq for efficiently mapping small effect mutations isolated from a mutagenesis screen. Specifically, we determined the impact of segregant population size, intensity of phenotypic selection to collect segregants, number of mitotic generations between meiosis and sequencing, and average sequencing depth on power for mapping mutations with a range of effects on the phenotypic mean and standard deviation as well as relative fitness. We then used BSA-seq to map the mutations responsible for three ethyl methanesulfonate-induced mutant phenotypes in Saccharomyces cerevisiae. These mutants display small quantitative variation in the mean expression of a fluorescent reporter gene (-3%, +7%, and +10%). Using a genetic background with increased meiosis rate, a reliable mating type marker, and fluorescence-activated cell sorting to efficiently score large segregating populations and isolate cells with extreme phenotypes, we successfully mapped and functionally confirmed a single point mutation responsible for the mutant phenotype in all three cases. Our simulations and experimental data show that the effects of a causative site not only on the mean phenotype, but also on its standard deviation and relative fitness should be considered when mapping genetic variants in microorganisms such as yeast that require population growth steps for BSA-seq. PMID- 24789749 TI - Hybrid gels assembled from Fmoc-amino acid and graphene oxide with controllable properties. AB - A supramolecular gel is obtained from the self-assembly of an ultralow-molecular weight gelator (N-fluorenyl-9-methoxycarbonyl glutamic acid) in good and poor solvents. The gelators can self-assemble into a lamellar structure, which can further form twisted fibers and nanotubes in the gel phase. Rheological studies show that the gels are robust and rigid, and are able to rapidly self-recover to a gel after being destroyed by shear force. Fluorescence experiments reveal the aggregation-induced emission effects of the gel system; the fluorescence intensity is significantly enhanced by gel formation. Graphene oxide (GO) is introduced into the system efficiently to give a hybrid material, and the interaction between gelators-GO sheets is studied. Rheological and fluorescent studies imply that the mechanical properties and the fluorescent emission of the hybrid materials can be fine-tuned by controlling the addition of GO. PMID- 24789750 TI - Two-year follow-up of first human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. AB - OBJECTIVES: To evaluate the safety and effectiveness of endovenous cyanoacrylate based embolization of incompetent great saphenous veins. METHODS: Incompetent great saphenous veins in 38 patients were embolized by cyanoacrylate bolus injections under ultrasound guidance without the use of perivenous tumescent anesthesia or graduated compression stockings. Follow-up was performed over a period of 24 months. RESULT: Of 38 enrolled patients, 36 were available at 12 months and 24 were available at 24 months follow-up. Complete occlusion of the treated great saphenous vein was confirmed by duplex ultrasound in all patients except for one complete and two partial recanalizations observed at, 1, 3 and 6 months of follow-up, respectively. Kaplan-Meier analysis yielded an occlusion rate of 92.0% (95% CI 0.836-1.0) at 24 months follow-up. Venous Clinical Severity Score improved in all patients from a mean of 6.1 +/- 2.7 at baseline to 1.3 +/- 1.1, 1.5 +/- 1.4 and 2.7 +/- 2.5 at 6, 12 and 24 months, respectively (p < .0001). Edema improved in 89% of legs (n = 34) at 48 hours follow-up. At baseline, only 13% were free from pain. At 6, 12 and 24 months, 84%, 78% and 64% were free from leg pain, respectively. CONCLUSIONS: The first human use of endovenous cyanoacrylate for closure of insufficient great saphenous veins proved to be feasible, safe and effective. Clinical efficacy was maintained over a period of 24 months. PMID- 24789751 TI - A microRNA-27a mimic sensitizes human oral squamous cell carcinoma HSC-4 cells to hyperthermia through downregulation of Hsp110 and Hsp90. AB - Hyperthermia (HT) is an important modality in cancer treatment; however, the acquisition of thermal resistance in cancer cells due to the elevation of heat shock proteins (HSPs) makes HT less effective. Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating cellular stress sensitivities, such as drug sensitivity and radio-sensitivity, in cancer cells. However, few studies have investigated the involvement of miRNAs in thermal sensitivity. The aim of this study was thus to investigate the contribution of miRNAs to the thermal sensitivity of human oral squamous cell carcinoma (OSCC) cells. When the HSC-2, HSC-3 and HSC-4 OSCC cell lines were treated with HT at 44C for 60 min, a significant increase in cell death was observed in HSC-2 and HSC-3 cells but not HSC-4 cells, suggesting that HSC-4 cells were thermally resistant under the present experimental conditions. Moreover, the expression levels of HSPs were most elevated in HSC-4 cells. When the basal expression levels of miRNAs were monitored using two different microarray systems in thermal sensitive HSC-2 and HSC-3 cells and thermal-resistant HSC-4 cells, five miRNAs that were differentially expressed were identified. Among these miRNAs, the expression level of miR-27a in HSC-4 cells was markedly reducec compared to the expression levels in HSC-2 and HSC-3 cells. Interestingly, treatment of HSC-4 cells with a miR-27a mimic oligonucleotide significantly enhanced HT-induced cell death. Furthermore, the miR-27a mimic oligonucleotide suppressed the elevation of the expression of Hsp90 and Hsp110 in HSC-4 cells, suggesting that these HSPs may be involved in a mechanism of thermal resistance. From these findings, we concluded that in OSCC cells, miR-27a may contribute to thermal sensitivity by modulating the HSP expression. PMID- 24789752 TI - Revisiting the daily human birth pattern: time of delivery at Casa de Maternidad in Madrid (1887-1892). AB - OBJECTIVES: Among the ancestral characteristics of the primate group to which Homo sapiens belongs we find a pattern of daytime physical activity, but one notable exception is birthing which usually begins with night-time labor. In populations with a moderate or high level of medicalized labor, there is evidence that the medical preferences interfere with the underlying biological mechanism for the circadian pattern of human birth. METHODS: This study analyses the hourly patterns of 4,599 single live births in the House of Maternity in Madrid between 1887 and 1892, a period of very limited obstetric intervention and without the influence of artificial lighting. In order to determine the influence of natural light on labor, two periods of maximum and minimum light have been established around the summer and winter solstices of the years in question. RESULTS: A clear circadian pattern of births emerges, with very early morning and early morning births dominating, and a sharp drop from midday until nightfall. The hourly distribution on both solstices follows this pattern, but with a clear peak shift: in winter, there is a greater concentration of deliveries in the early morning, whereas in the summer, the highest concentration is between 8 and 12 in the morning. CONCLUSIONS: The results confirm that non-intervened human birth has a clear diurnal cycle, with a higher incidence of deliveries in the early morning or morning. The shift in distribution during the winter and summer solstices seems to confirm the effect of light on the labor process. PMID- 24789753 TI - 3D porous chitosan scaffolds suit survival and neural differentiation of dental pulp stem cells. AB - A key aspect of cell replacement therapy in brain injury treatment is construction of a suitable biomaterial scaffold that can effectively carry and transport the therapeutic cells to the target area. In the present study, we created small 3D porous chitosan scaffolds through freeze-drying, and showed that these can support and enhance the differentiation of dental pulp stem cells (DPSCs) to nerve cells in vitro. The DPSCs were collected from the dental pulp of adult human third molars. At a swelling rate of ~84.33 +/- 10.92 %, the scaffold displayed high porosity and interconnectivity of pores, as revealed by SEM. Cell counting kit-8 assay established the biocompatibility of the chitosan scaffold, supporting the growth and survival of DPSCs. The successful neural differentiation of DPSCs was assayed by RT-PCR, western blotting, and immunofluorescence. We found that the scaffold-attached DPSCs showed high expression of Nestin that decreased sharply following induction of differentiation. Exposure to the differentiation media also increased the expression of neural molecular markers Microtubule-associated protein 2, glial fibrillary acidic protein, and 2',3'-cyclic nucleotide phosphodiesterase. This study demonstrates that the granular 3D chitosan scaffolds are non-cytotoxic, biocompatible, and provide a conducive and favorable micro-environment for attachment, survival, and neural differentiation of DPSCs. These scaffolds have enormous potential to facilitate future advances in treatment of brain injury. PMID- 24789754 TI - Year of the Magicicada. PMID- 24789755 TI - Correction: Screening for Cervical Cancer. PMID- 24789756 TI - Cytotoxic activity of the amphibian ribonucleases onconase and r-amphinase on tumor cells from B cell lymphoproliferative disorders. AB - Although major advancements in antitumor treatment have been observed, several B cell-derived malignancies still remain incurable. A promising approach that involves targeting RNA either by the use of specific antisense oligonucleotides or cytostatic/cytotoxic ribonucleases (RNases) is being promoted. Two amphibian RNases, onconase (ONC; ranpirnase) and, more recently, r-amphinase (r-Amph), have already been tested, but thus far, mostly on solid tumors. In this study, for the first time we provide comprehensive data on ex vivo and in vivo cytotoxic activity of ONC or r-Amph against cancer cells from different B cell lymphoid malignancies, together with their detailed mode of antitumor action. Our data revealed strong pro-apoptotic activity of ONC and r-Amph in both chronic lymphocytic leukemia and aggressive B cell lymphomas, with less impact on acute lymphoblastic leukemia or multiple myeloma cells. Moreover, the antitumor action of ONC and r-Amph was markedly selective against neoplastic cells sparing normal, healthy control-derived lymphocytes. PMID- 24789757 TI - Assay of urinary 8-hydroxy-2'-deoxyguanosine by capillary electrophoresis with spectrophotometric detection using a high-sensitivity detection cell and solid phase extraction. AB - A sensitive capillary electrophoretic method featuring spectrophotometric detection using a commercial Z-cell was devised for the assay of 8-hydroxy-2' deoxyguanosine (8OHdG) in human urine. Solid-phase extraction (SPE) based on hydrophilic-lipophilic-balanced RP sorbent was utilized for urine sample pretreatment and analyte preconcentration. The separation was carried out in conventional fused-silica capillaries employing a Z-cell with hydrodynamic sample injection (at 50 mbar for 12 s). The BGE (pH* 9.2, adjusted with 1 M NaOH) contained 0.15 M boric acid and 10% v/v ACN. The detection wavelength was 282 nm. The calibration curve for 8OHdG (measured in spiked urine) was linear in the range 10-1000 ng/mL; R(2) = 0.9993. The LOD was 3 ng/mL (11 nmol/L) of 8OHdG. Determination of the 8OHdG urinary levels was possible even in healthy individuals. PMID- 24789758 TI - Multiplatform metabolome and proteome profiling identifies serum metabolite and protein signatures as prospective biomarkers for schizophrenia. AB - Schizophrenia is a severe mental illness with a biological basis. However, the search for reliable biomarkers suitable for clinical routine has been futile so far. Accordingly, there is a need for innovative approaches such as genomics and proteomics to achieve this goal. In the present study, we compared metabolomic and proteomic data from 26 schizophrenia patients as well as from unaffected controls carefully matched for age and gender in a multi-platform approach. The combined analysis identified many signatures with initially good biomarker characteristics. After statistical analysis and comparison of these identified serum metabolites (analysed by Gas Chromatography Mass Spectrometry) and hydrophobic serum proteins (analysed by matrix-assisted laser desorption ionisation mass spectrometry), several markers (e.g., 2-piperidinec carboxylic acid, 6-deoxy-mannofuranose, galactoseoxime and a serum peptide of m/z 3177) were determined as having the best discriminating value between the groups. Our findings represent a proof of principle indicating that metabolomic and proteomic approaches can be successfully used in psychiatric biomarker research, even though the results should be regarded as preliminary with a need for replication in larger samples. PMID- 24789759 TI - The influence of processing on the microbial risk associated with Rooibos (Aspalathus linearis) tea. AB - This review discusses the influence of processing on the microbial risk associated with Salmonella in Rooibos tea, the identification of Salmonella and preventative and control measures to control microbial contamination. Rooibos tea, like other plant products, naturally contains a high microbial load. Downstream processing steps of these products usually help in reducing any contaminants present. Due to the delicate flavour properties and nature of Rooibos, gentle processing techniques are necessary for the production of good quality tea. However, this has a major influence on the microbiological status of the product. The presence of Salmonella in Rooibos is poorly understood. The ubiquitous distribution of Salmonella in the natural environment and its prevalence in the global food chain, the physiological adaptability, virulence of the bacterial pathogen and its serious economic impact on the food industry, emphasises the need for continued awareness and stringent controls at all levels of food production. With the advances of technology and information at hand, the processing of Rooibos needs to be re-evaluated. Since the delicate nature of Rooibos prohibits the use of harsh methods to control Salmonella, alternative methods for the steam pasteurisation of Rooibos show great potential to control Salmonella in a fast, efficient and cost-effective manner. These alternative methods will significantly improve the microbiological quality of Rooibos and provide a product that is safe to consumers. PMID- 24789760 TI - Multilevel mixed effects parametric survival models using adaptive Gauss-Hermite quadrature with application to recurrent events and individual participant data meta-analysis. AB - Multilevel mixed effects survival models are used in the analysis of clustered survival data, such as repeated events, multicenter clinical trials, and individual participant data (IPD) meta-analyses, to investigate heterogeneity in baseline risk and covariate effects. In this paper, we extend parametric frailty models including the exponential, Weibull and Gompertz proportional hazards (PH) models and the log logistic, log normal, and generalized gamma accelerated failure time models to allow any number of normally distributed random effects. Furthermore, we extend the flexible parametric survival model of Royston and Parmar, modeled on the log-cumulative hazard scale using restricted cubic splines, to include random effects while also allowing for non-PH (time-dependent effects). Maximum likelihood is used to estimate the models utilizing adaptive or nonadaptive Gauss-Hermite quadrature. The methods are evaluated through simulation studies representing clinically plausible scenarios of a multicenter trial and IPD meta-analysis, showing good performance of the estimation method. The flexible parametric mixed effects model is illustrated using a dataset of patients with kidney disease and repeated times to infection and an IPD meta analysis of prognostic factor studies in patients with breast cancer. User friendly Stata software is provided to implement the methods. PMID- 24789761 TI - The role of SON in splicing, development, and disease. AB - SON is a nuclear protein involved in multiple cellular processes including transcription, pre-messenger RNA (mRNA) splicing, and cell cycle regulation. Although SON was discovered 25 years ago, the importance of SON's function was only realized recently when its roles in nuclear organization and pre-mRNA splicing as well as the influence of these activities in maintaining cellular health were unveiled. Furthermore, SON was implicated to have a key role in stem cells as well as during the onset of various diseases such as cancer, influenza, and hepatitis. Here we review the progress that has been made in studying this multifunctional protein and discuss questions that remain to be answered about SON. PMID- 24789762 TI - Comparative study of Western and Japanese criteria for biopsy-based diagnosis of gastric epithelial neoplasia. AB - BACKGROUND: In Western countries, gastric cancer (GC) is diagnosed when there is histological evidence of invasion into the lamina propria or beyond the submucosa. In Japan and some other countries, however, diagnosis of GC is based on the degree of structural and cytological abnormality of tumor glands. The aim of the present study was to compare the accuracy of the Western and Japanese criteria for diagnosis of GC. METHODS: The study included 233 consecutive patients with a postoperative diagnosis of submucosal invasive GC who underwent gastrectomy or endoscopic submucosal dissection. All pretreatment biopsy specimens were independently reviewed by two experts in gastrointestinal pathology employing both the Western and Japanese diagnostic criteria. Diagnostic agreement between pretreatment biopsy specimens and the corresponding resected specimens was evaluated, together with the interobserver agreement for each of the criteria. RESULTS: On the basis of the Western and Japanese criteria, the pretreatment biopsy diagnosis was noncancerous (including dysplasia) in 44 lesions and 1 lesion, respectively. Diagnostic accuracy based on biopsy was 81.1% for the Western criteria and 99.5% for the Japanese criteria (P < 0.001). Interobserver agreement based on the Western and Japanese criteria was 73.8% and 96.5%, respectively (P < 0.001). Invasion into the submucosa was detected by biopsy in only 25 cases. CONCLUSIONS: The Japanese criteria are significantly more accurate for pretreatment biopsy diagnosis of GC. The Western criteria could lead to underdiagnosis of a lesion as high-grade dysplasia, even if submucosal invasive cancer is present. PMID- 24789763 TI - Left atrial appendage devices for stroke prevention in atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia, and stroke prevention remains an integral part of management of AF. Long-term therapy with oral anticoagulants, though effective, has many limitations, and these limitations have encouraged the search for device-based alternatives. In patients with non-valvular AF, approximately 90% of thrombi are thought to arise from the left atrial appendage (LAA). The LAA can be obliterated surgically or percutaneously, and this should reduce the incidence of systemic thromboembolic events in AF, ideally without the need for further anticoagulation. We explore the currently available LAA occlusion devices and the evidence behind these devices. Although additional evidence from randomized trials is required to fully characterize the safety and efficacy of all of these devices, LAA occlusion has the potential to offer an attractive alternative for those at high stroke risk but are under-protected because of contraindications to anticoagulant therapy. PMID- 24789764 TI - Nanoparticles of conjugated polymers prepared from phase-separated films of phospholipids and polymers for biomedical applications. AB - Phase separation in films of phospholipids and conjugated polymers results in nanoassemblies because of a difference in the physicochemical properties between the hydrophobic polymers and the polar lipid heads, together with the comparable polymer side-chain lengths to lipid tail lengths, thus producing nanoparticles of conjugated polymers upon disassembly in aqueous media by the penetration of water into polar regions of the lipid heads. PMID- 24789765 TI - Effects of Tet-induced oxidation products of 5-methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation. AB - We investigated systematically the effects of Tet-induced oxidation products of 5 methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation in synthetic duplex DNA. We found that the replacement of 5-methylcytosine at a CpG site with a 5-hydroxymethylcytosine, 5-formylcytosine, 5-carboxylcytosine or 5 hydroxymethyluracil resulted in altered methylation of cytosine at both the opposite and the neighboring CpG sites. Our results provided important new knowledge about the implications of the 5-methylcytosine oxidation products in maintenance cytosine methylation. PMID- 24789766 TI - Self and carer perspectives of quality of life in dementia using the QoL-AD. AB - OBJECTIVE: Quality of life (QoL) is one of the most important outcomes in improving well-being in people with dementia (PwD). The primary aim of the present study was to compare self and carer ratings of QoL in PwD and to identify the most important factors influencing self and carer ratings. METHODS: We conducted a cross-sectional analytic study of 488 dyads using the Quality of Life in Alzheimer's Disease scale, demographics, data on self-rated health, and clinical characteristics. RESULTS: Higher levels of self-rated health in PwD were associated with higher self-rated QoL after controlling for depression and activities of daily living. When the carer experienced less stress related to caregiving, the PwD reported better QoL. Higher carer-rated QoL was associated with less carer stress, better health for the family carer, and the PwD being of younger age. When carers lived with the PwD, and reported lower levels of depression and better functional ability for their relative, carer-rated QoL was higher. CONCLUSIONS: The self-rated health of PwD and carers influences the ratings they make of the QoL of the PwD indicating that it is an important influence on QoL in this population. PMID- 24789769 TI - The fetal MR appearance of 'nutmeg lung': findings in 8 cases linked to pulmonary lymphangiectasia. AB - BACKGROUND: A pattern of abnormal signal at fetal MRI may be seen in the setting of primary or secondary congenital lymphangiectasia, manifested as a heterogeneous appearance of the lung parenchyma and the presence of subtle T2 hyperintense branching tubular structures that emanate from the hila. We have named this pattern the nutmeg lung. OBJECTIVE: We describe the nutmeg lung appearance seen in fetal MRI scans, with discussion of possible etiologies and outcomes in a series of eight fetuses. MATERIALS AND METHODS: We retrospectively reviewed imaging from a database of patients demonstrating features of nutmeg lung on fetal MRI. Medical records were used to determine the postnatal diagnosis, clinical course and outcome. RESULTS: Among the eight fetal cases of nutmeg lung, two had postnatal confirmation of primary lymphangiectasia and the remaining six had secondary lymphangiectasia, presumably secondary to congenital cardiac anomalies. There were various-size pleural effusions in all cases. Only one of the cases demonstrated hydrops fetalis. CONCLUSION: We present the description of the nutmeg lung sign on fetal MRI as T2-hyperintense heterogeneous lungs with fluid-filled, serpiginous branching structures that extend from the pulmonary hila to the periphery of the lung, often accompanied by pleural effusions. The sign denotes findings of primary or secondary lymphangiectasia. Findings of secondary lymphangiectasia in our series were a result of cardiac insufficiency. Recognizing this sign might be helpful in the diagnostic algorithm of the fetus with abnormal lung parenchyma. PMID- 24789768 TI - Paediatric urinary tract infections: a retrospective application of the National Institute of Clinical Excellence guidelines to a large general practitioner referred historical cohort. AB - BACKGROUND: The National Institute for Clinical Excellence (NICE) is a United Kingdom nondepartmental public body accountable to the Department of Health. Before the introduction of the NICE guidelines in the United Kingdom most children younger than 1 year of age had a urinary tract ultrasound, cyclic micturating cystourethrogram and dimercaptosuccinic acid scintigraphy, the latter delayed 6 months post infection. Children older than 1 year had a urinary tract ultrasound only, and further imaging if necessary. OBJECTIVE: Identify who would have been investigated had the NICE imaging strategy been used and who would not. Compare the diagnostic yield and patient outcome with the previous imaging protocol using our prospectively collected historical data. MATERIALS AND METHODS: We applied the new imaging strategy to a historic cohort of 934 patients with a urinary tract infection (UTI) referred by general practitioners to a specialist children's hospital between 1996 and 2002. RESULTS: Of the 934 patients referred, 218 would have been investigated according to the NICE guidelines. In total, there were 105 patients with abnormal imaging findings, and 44 of these (42%) would have been investigated under the NICE guidelines. CONCLUSION: Applying the NICE guidelines to children presenting with UTI will reduce the number imaged by 77% and will lead to missed identification of 58% of imaging abnormalities in the group. The majority of these abnormalities may be important. While supporting conservative investigation protocols, we are concerned that many abnormalities might go undetected. PMID- 24789767 TI - Tissue-specific and age-dependent effects of global Mdm2 loss. AB - Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. In this study we utilized a conditional Mdm2 allele, Mdm2(FM) , and a CAG-CreER tamoxifen-inducible recombination system to examine the effects of global Mdm2 loss in adult mice. Two different tamoxifen injection regimens caused 100% lethality of Mdm2(FM) (/-) ;CAG-CreER mice; both radio-sensitive and radio insensitive tissues were impaired. Strikingly, a large number of radio insensitive tissues, including the kidney, liver, heart, retina and hippocampus, exhibited various pathological defects. Similar tamoxifen injections in older (16 18 month-old) Mdm2(FM) (/-) ;CAG-CreER mice yielded abnormalities only in the kidney. In addition, transcriptional activation of Cdkn1a (p21), Bbc3 (Puma) and multiple senescence markers in young (2-4 month-old) mice following loss of Mdm2 was dampened in older mice. All phenotypes were p53-dependent, as Mdm2(FM) (/-) ;Trp53(-/-) ;CAG-CreER mice subjected to the same tamoxifen regimens were normal. Our findings implicate numerous possible toxicities in many normal tissues upon use of cancer therapies that aim to inhibit Mdm2 in tumours with wild-type p53. PMID- 24789770 TI - Pulmonary function abnormalities in childhood cancer survivors treated with bleomycin. AB - BACKGROUND: Bleomycin is associated with pulmonary toxic side effects including pneumonitis and pulmonary fibrosis. We evaluated the prevalence of long-term pulmonary function abnormalities in children receiving bleomycin therapy in the context of current chemotherapeutic regimens. METHODS: A retrospective review of patients who received bleomycin between January 1999 and December 2011 was conducted. Abnormalities in the most recent pulmonary function test (PFT) at least 1 year after diagnosis were analyzed. RESULTS: Two-hundred and seven patients had received bleomycin. The results of PFT performed at least 1 year from diagnosis were available for 80 patients. Median time of follow up was 3.9 years (range 1.1-11.76 years). Median cumulative dose of bleomycin was 65 IU/m(2) (range 10-120). The most common diagnoses were Hodgkin lymphoma and germ cell tumor. At least one pulmonary function abnormality was present in 42 (52.5%) patients. When classified in groups, 22.5% patients had obstructive lung disease, 7.5% had restrictive lung disease, 28.8% had hyperinflation and 14% of patients had non-uniform distribution of ventilation. Non-Hispanic patients (OR 2.81) and children younger than 8 years (OR 4.14) had higher odds of having an abnormal PFT parameter. Very few patients had pulmonary symptoms. CONCLUSIONS: More than half the patients who received bleomycin had subclinical pulmonary dysfunction as evidenced by abnormalities in pulmonary function tests, although the incidence of clinical symptoms was low. PMID- 24789771 TI - Spectroscopy and molecular docking study on the interaction behavior between nobiletin and pepsin. AB - In this study, the binding mode of nobiletin (NOB) with pepsin was investigated by spectroscopic and molecular docking methods. NOB can interact with pepsin to form a NOB-pepsin complex. The binding constant, number of binding sites and thermodynamic parameters were measured, which indicated that NOB could spontaneously bind with pepsin through hydrophobic and electrostatic forces with one binding site. Molecular docking results revealed that NOB bound into the pepsin cavity. Synchronous and three-dimensional fluorescence spectra results provide data concerning conformational and some micro-environmental changes of pepsin. Furthermore, the binding of NOB can inhibit pepsin activity in vitro. The present study provides direct evidence at a molecular level to show that NOB could induce changes in the enzyme pepsin structure and function. PMID- 24789772 TI - Effect of non-enzymatic glycation on cystatin: a spectroscopic study. AB - The study shows the effect of nonenzymatic glycation on conformation and inhibitory activity of chick pea cystatin (CPC). CPC was incubated with different reducing sugars, pentose (D-Ribose), hexoses (D-Glucose, D-Fructose) at 37 degrees C for 5 weeks. To evaluate the modification of CPC by these different sugars during the glycation process the extent of the Maillard reaction, conformational, structural and functional changes were investigated. The behaviour of glycated CPC was monitored by the techniques of UV and fluorescence spectroscopies. Specific fluorescence was employed to characterise the glycation and AGEs. The anti-papain activity of glycated CPC was found to be significantly lower as compared to its non-glycated form. Glycation with ribose led to maximum loss in inhibitory activity. It was found that the incubation of CPC with all the mentioned sugars led to a parallel increase in tryptophan fluorescence as well as in Maillard and other AGEs specific fluorescence values and hyperchromicity in the UV-region. Among the sugars studied comparatively ribose was found to be the most active in inducing structural and conformational alterations in the protein suggesting its high reactivity with protein amino groups. PMID- 24789773 TI - Synthesis and spectroscopic properties of novel fluorescent compounds containing bis-pyrazole ring. AB - A series of pyrazoline derivatives containing pyrazole group were synthesized and characterized by means of (1)H NMR, FT-IR, MS and elemental analysis, and their UV-vis absorption behavior and fluorescent properties were also measured. Moreover, the influence of metal ions on spectral properties of synthetic products was examined with compound A5 as an example. It has been found that all synthetic pyrazoline derivatives show two remarkable absorption peaks at about 260 and 360 nm and the maximum emission peak at 445-467 nm. Especially, the joined of Co(2+) can quench the fluorescence of compound A5 obviously. PMID- 24789774 TI - Detection of large ions in time-of-flight mass spectrometry: effects of ion mass and acceleration voltage on microchannel plate detector response. AB - In time-of-flight mass spectrometry (TOF-MS), ion detection is typically accomplished by the generation and amplification of secondary electrons produced by ions colliding with a microchannel plate (MCP) detector. Here, the response of an MCP detector as a function of ion mass and acceleration voltage is characterized, for singly charged peptide/protein ions ranging from 1 to 290 kDa in mass, and for acceleration voltages from 5 to 25 kV. A nondestructive inductive charge detector (ICD) employed in parallel with MCP detection provides a reliable reference signal to allow accurate calibration of the MCP response. MCP detection efficiencies were very close to unity for smaller ions at high acceleration voltages (e.g., angiotensin, 1046.5 Da, at 25 kV acceleration voltage), but decreased to ~11% for the largest ions examined (immunoglobulin G (IgG) dimer, 290 kDa) even at the highest acceleration voltage employed (25 kV). The secondary electron yield gamma (average number of electrons produced per ion collision) is found to be proportional to mv(3.1) (m: ion mass, v: ion velocity) over the entire mass range examined, and inversely proportional to the square root of m in TOF-MS analysis. The results indicate that although MCP detectors indeed offer superlative performance in the detection of smaller peptide/protein species, their performance does fall off substantially for larger proteins, particularly under conditions of low acceleration voltage. PMID- 24789776 TI - Validation of FreeSurfer-estimated brain cortical thickness: comparison with histologic measurements. AB - FreeSurfer software package automatically estimates the cerebral cortical thickness. Its use is widely accepted, albeit this tool was validated against histologic measurements in only two post-mortem isolated brain MR scans. Indeed, a comparison between histologic measurements and FreeSurfer estimation from in vivo data was never performed. At the "Claudio Munari" Center for Epilepsy and Parkinson Surgery we have included FreeSurfer in our presurgical workflow since 2008, mainly because the automatic reconstruction of the brain surface is useful for carefully planning the surgical resection. We therefore compared cortical thickness values obtained by the automatic software pipeline with manual histologic measurements performed on 27 histologic specimens resected from the corresponding brain regions of the same epileptic subjects. This method comparison study, including Passing-Bablok regression and Bland-Altman plot analysis, showed a good agreement between FreeSurfer estimation and histologic measurements of cortical thickness. The mean cortical thickness values (+/ Standard Deviation) obtained with FreeSurfer and histologic measurements were 3.65 mm +/- 0.44 and 3.72 mm +/- 0.36, respectively (P value = 0.32). Our findings strengthen previous reports on cortical thickness changes as biomarkers of different neurological conditions. PMID- 24789777 TI - Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. AB - The recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans, with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to save human lives and address the pandemic concerns. We identified three human monoclonal antibodies (MAbs), m336, m337, and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large naive antibody library (containing ~10(11) antibodies). They bound with high affinity: equilibrium dissociation constants for the three MAbs were equal to 4.2, 9.3, and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337, and m338 was even higher: 99, 820, and 560 pM, respectively. The antibodies bound to overlapping epitopes that overlap the receptor binding site on the RBD as suggested by competition experiments and further supported by site-directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest-affinity MAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency, 50% neutralization at 0.005 and 0.07 MUg/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralization activity of these antibodies and especially m336 suggests that they have great potential for prophylaxis and therapy of MERS CoV infection in humans and as a tool for development of vaccine immunogens. The rapid identification (within several weeks) of potent MAbs suggests a possibility to use the new large antibody library and related methodology for a quick response to the public threat resulting from emerging coronaviruses. Importance: A novel human coronavirus, the Middle East respiratory syndrome coronavirus (MERS CoV), was found to infect humans with a high mortality rate in 2012, just 1 decade after the appearance of the first highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). There are no effective therapeutics available. It is highly desirable to find an approach for rapidly developing potent therapeutics against MERS-CoV, which not only can be implemented for MERS treatment but also can help to develop a platform strategy to combat future emerging coronaviruses. We report here the identification of human monoclonal antibodies (MAbs) from a large nonimmune antibody library that target MERS-CoV. One of the antibodies, m336, neutralized the virus with exceptional potency. It therefore may have great potential as a candidate therapeutic and as a reagent to facilitate the development of vaccines against MERS-CoV. PMID- 24789778 TI - Careers in virology: public health opportunities for early-career basic scientists. AB - Undergraduate, graduate, and postdoctoral scientists trained as virologists can play critical roles in public health, such as in health science policy, epidemiology, and national defense. Despite a need for basic science backgrounds within these fields, finding entry-level careers can be challenging. Volunteer opportunities are a great way for scientists to experience public health careers while still in school, and this article describes volunteering with the Medical Reserve Corps and outlines unique postgraduate opportunities for early-career virologists. PMID- 24789779 TI - A small molecule inhibits virion attachment to heparan sulfate- or sialic acid containing glycans. AB - Primary attachment to cellular glycans is a critical entry step for most human viruses. Some viruses, such as herpes simplex virus type 1 (HSV-1) and hepatitis C virus (HCV), bind to heparan sulfate, whereas others, such as influenza A virus (IAV), bind to sialic acid. Receptor mimetics that interfere with these interactions are active against viruses that bind to either heparan sulfate or to sialic acid. However, no molecule that inhibits the attachment of viruses in both groups has yet been identified. Epigallocatechin gallate (EGCG), a green tea catechin, is active against many unrelated viruses, including several that bind to heparan sulfate or to sialic acid. We sought to identify the basis for the broad-spectrum activity of EGCG. Here, we show that EGCG inhibits the infectivity of a diverse group of enveloped and nonenveloped human viruses. EGCG acts directly on the virions, without affecting the fluidity or integrity of the virion envelopes. Instead, EGCG interacts with virion surface proteins to inhibit the attachment of HSV-1, HCV, IAV, vaccinia virus, adenovirus, reovirus, and vesicular stomatitis virus (VSV) virions. We further show that EGCG competes with heparan sulfate for binding of HSV-1 and HCV virions and with sialic acid for binding of IAV virions. Therefore, EGCG inhibits unrelated viruses by a common mechanism. Most importantly, we have identified EGCG as the first broad-spectrum attachment inhibitor. Our results open the possibility for the development of small molecule broad-spectrum antivirals targeting virion attachment. Importance: This study shows that it is possible to develop a small molecule antiviral or microbicide active against the two largest groups of human viruses: those that bind to glycosaminoglycans and those that bind to sialoglycans. This group includes the vast majority of human viruses, including herpes simplex viruses, cytomegalovirus, influenza virus, poxvirus, hepatitis C virus, HIV, and many others. PMID- 24789780 TI - Mechanistic differences between nucleic acid chaperone activities of the Gag proteins of Rous sarcoma virus and human immunodeficiency virus type 1 are attributed to the MA domain. AB - Host cell tRNAs are recruited for use as primers to initiate reverse transcription in retroviruses. Human immunodeficiency virus type 1 (HIV-1) uses tRNA(Lys3) as the replication primer, whereas Rous sarcoma virus (RSV) uses tRNA(Trp). The nucleic acid (NA) chaperone function of the nucleocapsid (NC) domain of HIV-1 Gag is responsible for annealing tRNA(Lys3) to the genomic RNA (gRNA) primer binding site (PBS). Compared to HIV-1, little is known about the chaperone activity of RSV Gag. In this work, using purified RSV Gag containing an N-terminal His tag and a deletion of the majority of the protease domain (H6.Gag.3h), gel shift assays were used to monitor the annealing of tRNA(Trp) to a PBS-containing RSV RNA. Here, we show that similar to HIV-1 Gag lacking the p6 domain (GagDeltap6), RSV H6.Gag.3h is a more efficient chaperone on a molar basis than NC; however, in contrast to the HIV-1 system, both RSV H6.Gag.3h and NC have comparable annealing rates at protein saturation. The NC domain of RSV H6.Gag.3h is required for annealing, whereas deletion of the matrix (MA) domain, which stimulates the rate of HIV-1 GagDeltap6 annealing, has little effect on RSV H6.Gag.3h chaperone function. Competition assays confirmed that RSV MA binds inositol phosphates (IPs), but in contrast to HIV-1 GagDeltap6, IPs do not stimulate RSV H6.Gag.3h chaperone activity unless the MA domain is replaced with HIV-1 MA. We conclude that differences in the MA domains are primarily responsible for mechanistic differences in RSV and HIV-1 Gag NA chaperone function. Importance: Mounting evidence suggests that the Gag polyprotein is responsible for annealing primer tRNAs to the PBS to initiate reverse transcription in retroviruses, but only HIV-1 Gag chaperone activity has been demonstrated in vitro. Understanding RSV Gag's NA chaperone function will allow us to determine whether there is a common mechanism among retroviruses. This report shows for the first time that full-length RSV Gag lacking the protease domain is a highly efficient NA chaperone in vitro, and NC is required for this activity. In contrast to results obtained for HIV-1 Gag, due to the weak nucleic acid binding affinity of the RSV MA domain, inositol phosphates do not regulate RSV Gag-facilitated tRNA annealing despite the fact that they bind to MA. These studies provide insight into the viral regulation of tRNA primer annealing, which is a potential target for antiretroviral therapy. PMID- 24789781 TI - Cytomegalovirus replication in semen is associated with higher levels of proviral HIV DNA and CD4+ T cell activation during antiretroviral treatment. AB - Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4(+) T cells in blood (P < 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4(+) T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P = 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P = 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4(+) (P < 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations. Importance: Almost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our primary hypothesis, shedding of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies. PMID- 24789782 TI - Specificities of human CD4+ T cell responses to an inactivated flavivirus vaccine and infection: correlation with structure and epitope prediction. AB - Tick-borne encephalitis (TBE) virus is endemic in large parts of Europe and Central and Eastern Asia and causes more than 10,000 annual cases of neurological disease in humans. It is closely related to the mosquito-borne yellow fever, dengue, Japanese encephalitis, and West Nile viruses, and vaccination with an inactivated whole-virus vaccine can effectively prevent clinical disease. Neutralizing antibodies are directed to the viral envelope protein (E) and an accepted correlate of immunity. However, data on the specificities of CD4(+) T cells that recognize epitopes in the viral structural proteins and thus can provide direct help to the B cells producing E-specific antibodies are lacking. We therefore conducted a study on the CD4(+) T cell response against the virion proteins in vaccinated people in comparison to TBE patients. The data obtained with overlapping peptides in interleukin-2 (IL-2) enzyme-linked immunosorbent spot (ELISpot) assays were analyzed in relation to the three-dimensional structures of the capsid (C) and E proteins as well as to epitope predictions based on major histocompatibility complex (MHC) class II peptide affinities. In the C protein, peptides corresponding to two out of four alpha helices dominated the response in both vaccinees and patients, whereas in the E protein concordance of immunodominance was restricted to peptides of a single domain (domain III). Epitope predictions were much better for C than for E and were especially erroneous for the transmembrane regions. Our data provide evidence for a strong impact of protein structural features that influence peptide processing, contributing to the discrepancies observed between experimentally determined and computer-predicted CD4(+) T cell epitopes. Importance: Tick-borne encephalitis virus is endemic in large parts of Europe and Asia and causes more than 10,000 annual cases of neurological disease in humans. It is closely related to yellow fever, dengue, Japanese encephalitis, and West Nile viruses, and vaccination with an inactivated vaccine can effectively prevent disease. Both vaccination and natural infection induce the formation of antibodies to a viral surface protein that neutralize the infectivity of the virus and mediate protection. B lymphocytes synthesizing these antibodies require help from other lymphocytes (helper T cells) which recognize small peptides derived from proteins contained in the viral particle. Which of these peptides dominate immune responses to vaccination and infection, however, was unknown. In our study we demonstrate which parts of the proteins contribute most strongly to the helper T cell response, highlight specific weaknesses of currently available approaches for their prediction, and demonstrate similarities and differences between vaccination and infection. PMID- 24789783 TI - Repertoire of epitopes recognized by serum IgG from humans vaccinated with herpes simplex virus 2 glycoprotein D. AB - The results of a clinical trial of a subunit vaccine against genital herpes were recently reported (R. B. Belshe, P. A. Leone, D. I. Bernstein, A. Wald, M. J. Levin, J. T. Stapleton, I. Gorfinkel, R. L. Morrow, M. G. Ewell, A. Stokes-Riner, G. Dubin, T. C. Heineman, J. M. Schulte, C. D. Deal, N. Engl. J. Med. 366: 34-43, 2012, doi:10.1056/NEJMoa1103151). The vaccine consisted of a soluble form of herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) with adjuvant. The goal of the current study was to examine the composition of the humoral response to gD2 within a selected subset of vaccinated individuals. Serum samples from 30 vaccine recipients were selected based upon relative enzyme-linked immunosorbent assay (ELISA) titers against gD2; 10 samples had high titers, 10 had medium titers, and the remaining 10 had low ELISA titers. We employed a novel, biosensor-based monoclonal antibody (MAb)-blocking assay to determine whether gD2 vaccination elicited IgG responses against epitopes overlapping those of well-characterized MAbs. Importantly, IgGs from the majority of gD2-immunized subjects competed for gD binding with four antigenically distinct virus-neutralizing MAbs (MC2, MC5, MC23, and DL11). Screening of patient IgGs against overlapping peptides spanning the gD2 ectodomain revealed that about half of the samples contained antibodies against linear epitopes within the N and C termini of gD2. We found that the virus-neutralizing abilities of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgGs against the epitopes of MAbs MC2, MC5, MC23, and DL11. This suggests that optimal virus-neutralizing activity is achieved by strong and balanced responses to the four major discontinuous neutralizing epitopes of gD2. Importance: Several herpes simplex virus 2 (HSV-2) subunit vaccine studies have been conducted in human subjects using a recombinant form of HSV-2 glycoprotein D (gD2). Although several distinct, well-characterized virus-neutralizing epitopes on gD2 are targeted by murine monoclonal antibodies, it is not known whether the same epitopes are targeted by the humoral response to gD2 in humans. We have developed a novel, biosensor-based competition assay to directly address this important question. Using this approach, we identified epitopes that elicit strong humoral responses in humans, as well as other epitopes that elicit much weaker responses. These data provide new insight into the human response to known neutralizing gD2 epitopes and reveal characteristics of this response that may guide future vaccine development. PMID- 24789784 TI - Promotion of a subdominant CD8 T cell response during murine gammaherpesvirus 68 infection in the absence of CD4 T cell help. AB - CD8 and CD4 T cells are each critically important for immune control of murine gammaherpesvirus 68 (gammaHV68) infection. In immunocompetent mice, acute gammaHV68 infection results in lifelong latency, but in the absence of CD4 T cell help, mice succumb to viral recrudescence and disease. However, the requirements for CD4 T cell help in the generation and maintenance of antiviral CD8 T cell responses are incompletely understood, and it is unclear whether there are epitope-specific differences in the requirement of CD8 T cells for CD4 help. In this report, we characterized the CD8 T cell response to gammaHV68 in major histocompatibility complex (MHC) class II(-/-) mice, which lack CD4 T cells, or after antibody-mediated depletion of CD4 T cells. All antiviral CD8 T cells exhibited marked upregulation of surface expression of the inhibitory receptor programmed death-1 (PD-1), but surprisingly, while the immunodominant memory response appeared to be functionally impaired, helpless CD8 T cells of a subdominant specificity had increased numbers and enhanced functionality. Thus, we demonstrate differential requirements for CD4 help in the antiviral CD8 T cell response to a latent gammaherpesvirus. Importance: gammaHV68 is a mouse pathogen closely related to the oncogenic human gammaHVs, which infect a majority of the world's population. Reactivation of these viruses from latency can lead to complications, disease, and even death. CD4 T cells are required for complete immune control of long-term infection, in part by providing key signals to dendritic cells that in turn instruct optimal antiviral CD8 T cell responses. We have investigated multiple virus-specific CD8 T cell responses during infection and identified a subdominant CD8 T cell response that is numerically and functionally enhanced in the absence of CD4 T cell help. This occurs in spite of high surface expression of an inhibitory receptor and in contrast to the immunodominant response, which is impaired. Our data suggest that signals from CD4 T cells are important in maintaining the CD8 T cell hierarchy during gammaHV infections. PMID- 24789785 TI - Frequency and abundance of alphaherpesvirus DNA in human thoracic sympathetic ganglia. AB - Alphaherpesvirus reactivation from thoracic sympathetic ganglia (TSG) and transaxonal spread to target organs cause human visceral disease. Yet alphaherpesvirus latency in TSG has not been well characterized. In this study, quantitative PCR detected varicella-zoster virus (VZV), herpes simplex virus 1 (HSV-1), and HSV-2 DNA in 117 fresh TSG obtained postmortem from 15 subjects. VZV DNA was found in 76 (65%) ganglia from all subjects, HSV-1 DNA was found in 5 (4%) ganglia from 3 subjects, and no HSV-2 was found. PMID- 24789786 TI - Reversible nerve damage and corneal pathology in murine herpes simplex stromal keratitis. AB - Herpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4(+) T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted. Importance: HSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4(+) T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease. PMID- 24789787 TI - Extensive recombination-induced disruption of genetic interactions is highly deleterious but can be partially reversed by small numbers of secondary recombination events. AB - Although homologous recombination can potentially provide viruses with vastly more evolutionary options than are available through mutation alone, there are considerable limits on the adaptive potential of this important evolutionary process. Primary among these is the disruption of favorable coevolved genetic interactions that can occur following the transfer of foreign genetic material into a genome. Although the fitness costs of such disruptions can be severe, in some cases they can be rapidly recouped by either compensatory mutations or secondary recombination events. Here, we used a maize streak virus (MSV) experimental model to explore both the extremes of recombination-induced genetic disruption and the capacity of secondary recombination to adaptively reverse almost lethal recombination events. Starting with two naturally occurring parental viruses, we synthesized two of the most extreme conceivable MSV chimeras, each effectively carrying 182 recombination breakpoints and containing thorough reciprocal mixtures of parental polymorphisms. Although both chimeras were severely defective and apparently noninfectious, neither had individual movement-, encapsidation-, or replication-associated genome regions that were on their own "lethally recombinant." Surprisingly, mixed inoculations of the chimeras yielded symptomatic infections with viruses with secondary recombination events. These recombinants had only 2 to 6 breakpoints, had predominantly inherited the least defective of the chimeric parental genome fragments, and were obviously far more fit than their synthetic parents. It is clearly evident, therefore, that even when recombinationally disrupted virus genomes have extremely low fitness and there are no easily accessible routes to full recovery, small numbers of secondary recombination events can still yield tremendous fitness gains. Importance: Recombination between viruses can generate strains with enhanced pathological properties but also runs the risk of producing hybrid genomes with decreased fitness due to the disruption of favorable genetic interactions. Using two synthetic maize streak virus genome chimeras containing alternating genome segments derived from two natural viral strains, we examined both the fitness costs of extreme degrees of recombination (both chimeras had 182 recombination breakpoints) and the capacity of secondary recombination events to recoup these costs. After the severely defective chimeras were introduced together into a suitable host, viruses with between 1 and 3 secondary recombination events arose, which had greatly increased replication and infective capacities. This indicates that even in extreme cases where recombination-induced genetic disruptions are almost lethal, and 91 consecutive secondary recombination events would be required to reconstitute either one of the parental viruses, moderate degrees of fitness recovery can be achieved through relatively small numbers of secondary recombination events. PMID- 24789788 TI - The nucleocapsid domain of Gag is dispensable for actin incorporation into HIV-1 and for association of viral budding sites with cortical F-actin. AB - Actin and actin-binding proteins are incorporated into HIV-1 particles, and F actin has been suggested to bind the NC domain in HIV-1 Gag. Furthermore, F-actin has been frequently observed in the vicinity of HIV-1 budding sites by cryo electron tomography (cET). Filamentous structures emanating from viral buds and suggested to correspond to actin filaments have been observed by atomic force microscopy. To determine whether the NC domain of Gag is required for actin association with viral buds and for actin incorporation into HIV-1, we performed comparative analyses of virus-like particles (VLPs) obtained by expression of wild-type HIV-1 Gag or a Gag variant where the entire NC domain had been replaced by a dimerizing leucine zipper [Gag(LZ)]. The latter protein yielded efficient production of VLPs with near-wild-type assembly kinetics and size and exhibited a regular immature Gag lattice. Typical HIV-1 budding sites were detected by using cET in cells expressing either Gag or Gag(LZ), and no difference was observed regarding the association of buds with the F-actin network. Furthermore, actin was equally incorporated into wild-type HIV-1 and Gag- or Gag(LZ)-derived VLPs, with less actin per particle observed than had been reported previously. Incorporation appeared to correlate with the relative intracellular actin concentration, suggesting an uptake of cytosol rather than a specific recruitment of actin. Thus, the NC domain in HIV-1 Gag does not appear to have a role in actin recruitment or actin incorporation into HIV-1 particles. Importance: HIV-1 particles bud from the plasma membrane, which is lined by a network of actin filaments. Actin was found to interact with the nucleocapsid domain of the viral structural protein Gag and is incorporated in significant amounts into HIV-1 particles, suggesting that it may play an active role in virus release. Using electron microscopy techniques, we previously observed bundles of actin filaments near HIV-1 buds, often seemingly in contact with the Gag layer. Here, we show that this spatial association is observed independently of the proposed actin binding domain of HIV-1. The absence of this domain also did not affect actin incorporation and had a minor effect on the viral assembly rate. Furthermore, actin was not enriched in the virus compared to the average levels in the respective producing cell. Our data argue against a specific recruitment of actin to HIV-1 budding sites by the nucleocapsid domain of Gag. PMID- 24789789 TI - Investigating the role of F-actin in human immunodeficiency virus assembly by live-cell microscopy. AB - Human immunodeficiency virus type 1 (HIV-1) particles assemble at the plasma membrane, which is lined by a dense network of filamentous actin (F-actin). Large amounts of actin have been detected in HIV-1 virions, proposed to be incorporated by interactions with the nucleocapsid domain of the viral polyprotein Gag. Previous studies addressing the role of F-actin in HIV-1 particle formation using F-actin-interfering drugs did not yield consistent results. Filamentous structures pointing toward nascent HIV-1 budding sites, detected by cryo-electron tomography and atomic force microscopy, prompted us to revisit the role of F actin in HIV-1 assembly by live-cell microscopy. HeLa cells coexpressing HIV-1 carrying fluorescently labeled Gag and a labeled F-actin-binding peptide were imaged by live-cell total internal reflection fluorescence microscopy (TIR-FM). Computational analysis of image series did not reveal characteristic patterns of F-actin in the vicinity of viral budding sites. Furthermore, no transient recruitment of F-actin during bud formation was detected by monitoring fluorescence intensity changes at nascent HIV-1 assembly sites. The chosen approach allowed us to measure the effect of F-actin-interfering drugs on the assembly of individual virions in parallel with monitoring changes in the F-actin network of the respective cell. Treatment of cells with latrunculin did not affect the efficiency and dynamics of Gag assembly under conditions resulting in the disruption of F-actin filaments. Normal assembly rates were also observed upon transient stabilization of F-actin by short-term treatment with jasplakinolide. Taken together, these findings indicate that actin filament dynamics are dispensable for HIV-1 Gag assembly at the plasma membrane of HeLa cells. Importance: HIV-1 particles assemble at the plasma membrane of virus producing cells. This membrane is lined by a dense network of actin filaments that might either present a physical obstacle to the formation of virus particles or generate force promoting the assembly process. Drug-mediated interference with the actin cytoskeleton showed different results for the formation of retroviral particles in different studies, likely due to general effects on the cell upon prolonged drug treatment. Here, we characterized the effect of actin-interfering compounds on the HIV-1 assembly process by direct observation of virus formation in live cells, which allowed us to measure assembly rate constants directly upon drug addition. Virus assembly proceeded with normal rates when actin filaments were either disrupted or stabilized. Taken together with the absence of characteristic actin filament patterns at viral budding sites in our analyses, this indicates that the actin network is dispensable for HIV-1 assembly. PMID- 24789790 TI - Ineffectual targeting of HIV-1 Nef by cytotoxic T lymphocytes in acute infection results in no functional impairment or viremia reduction. AB - The human immunodeficiency virus type 1 (HIV-1) accessory protein Nef is heavily targeted by CD8(+) T lymphocytes (CTLs) during acute infection and therefore is included in many candidate vaccines. We investigated whether CTL targeting of Nef during acute infection contributes to immune control by disrupting the function of Nef. The sequence and function of Nef in parallel with CTL responses were assessed longitudinally from peak viremia until the viremia set point in a cohort of six subjects with acute infection. All but one individual had a single founder strain. Nef-specific CTL responses were detected in all subjects and declined in magnitude over time. These responses were associated with mutations, but none of the mutations were detected in important functional motifs. Nef-mediated downregulation of CD4 and major histocompatibility complex (MHC) class I molecules was better preserved in acute infection than in chronic infection. Finally, Nef-specific CTL responses were not associated with a reduction in viremia from its acute-phase peak. Our results indicate that CTLs targeting Nef epitopes outside critical functional domains have little effect on the pathogenic functions of Nef, rendering these responses ineffective in acute infection. Importance: These data indicate that using the whole Nef protein as a vaccine immunogen likely allows immunodominance that leads to targeting of CTL responses that are rapidly escaped with little effect on Nef-mediated pathogenic functions. Pursuing vaccination approaches that can more precisely direct responses to vulnerable areas would maximize efficacy. Until vaccine-induced targeting can be optimized, other approaches, such as the use of Nef function inhibitors or the pursuit of immunotherapies such as T cell receptor gene therapy or adoptive transfer, may be more likely to result in successful control of viremia. PMID- 24789791 TI - Roles of humidity and temperature in shaping influenza seasonality. AB - Experimental studies in guinea pigs demonstrated that influenza virus transmission is strongly modulated by temperature and humidity. A number of epidemiological studies have followed up on these findings and revealed robust associations between influenza incidence in temperate regions and local conditions of humidity and temperature, offering a long-awaited explanation for the wintertime seasonality of influenza in these locales. Despite recent progress, important questions remain as to the mechanism(s) by which humidity and/or temperature affects transmission. PMID- 24789792 TI - Capture of syncytin-Mar1, a fusogenic endogenous retroviral envelope gene involved in placentation in the Rodentia squirrel-related clade. AB - Syncytin genes are fusogenic envelope protein (env) genes of retroviral origin that have been captured for a function in placentation. Within rodents, two such genes have previously been identified in the mouse-related clade, allowing a demonstration of their essential role via knockout mice. Here, we searched for similar genes in a second major clade of the Rodentia order, the squirrel-related clade, taking advantage of the complete sequencing of the ground squirrel Ictidomys tridecemlineatus genome. In silico search for env genes with full coding capacity identified several candidate genes with one displaying placenta specific expression, as revealed by quantitative reverse transcription-PCR analysis of a large panel of tissues. This gene belongs to a degenerate endogenous retroviral element, with recognizable hallmarks of an integrated provirus. Cloning of the gene in an expression vector for ex vivo cell-cell fusion and pseudotype assays demonstrated fusogenicity on a large panel of mammalian cells. In situ hybridization on placenta sections showed specific expression in domains where trophoblast cells fuse into a syncytiotrophoblast at the fetomaternal interface, consistent with a role in syncytium formation. Finally, we show that the gene is conserved among the tribe Marmotini, thus dating its capture back to about at least 25 million years ago, with evidence for purifying selection and conservation of fusogenic activity. This gene that we named syncytin-Mar1 is distinct from all seven Syncytin genes identified to date in eutherian mammals and is likely to be a major effector of placentation in its related clade. Importance: Syncytin genes are fusogenic envelope genes of retroviral origin, ancestrally captured for a function in placentation. Within rodents, two such genes had been previously identified in the mouse-related clade. Here, in the squirrel-related rodent clade, we identified the envelope gene of an endogenous retrovirus with all the features of a Syncytin: it is specifically expressed in the placenta of the woodchuck Marmota monax, at the level of cells fusing into a syncytium; it can trigger cell-cell and virus-cell fusion ex vivo; and it has been conserved for >25 million years of evolution, suggesting an essential role in its host physiology. Remarkably, syncytin-Mar1 is unrelated to all other Syncytin genes identified thus far in mammals (primates, muroids, carnivores, and ruminants). These results extend the range of retroviral envelope gene "domestication" in mammals and show that these events occurred independently, on multiple occasions during evolution to improve placental development in a process of convergent evolution. PMID- 24789794 TI - Analysis of chaotic oscillations induced in two coupled Wilson-Cowan models. AB - Although it is known that two coupled Wilson-Cowan models with reciprocal connections induce aperiodic oscillations, little attention has been paid to the dynamical mechanism for such oscillations so far. In this study, we aim to elucidate the fundamental mechanism to induce the aperiodic oscillations in the coupled model. First, aperiodic oscillations observed are investigated for the case when the connections are unidirectional and when the input signal is a periodic oscillation. By the phase portrait analysis, we determine that the aperiodic oscillations are caused by periodically forced state transitions between a stable equilibrium and a stable limit cycle attractors around the saddle-node and saddle separatrix loop bifurcation points. It is revealed that the dynamical mechanism where the state crosses over the saddle-node and saddle separatrix loop bifurcations significantly contributes to the occurrence of chaotic oscillations forced by a periodic input. In addition, this mechanism can also give rise to chaotic oscillations in reciprocally connected Wilson-Cowan models. These results suggest that the dynamic attractor transition underlies chaotic behaviors in two coupled Wilson-Cowan oscillators. PMID- 24789793 TI - Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. AB - Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). The molecular events leading to HCC following chronic HCV infection remain poorly defined. MicroRNAs (miRNAs) have been implicated in the control of many biological processes, and their deregulation is associated with different viral infections. In this study, we observed that HCV infection of hepatocytes transcriptionally downregulates miR 181c expression by modulating CCAAT/enhancer binding protein beta (C/EBP-beta). Reduced expression of the pri-miR-181c transcript was noted following HCV infection. In silico prediction suggests that homeobox A1 (HOXA1) is a direct target of miR-181c. HOXA1 is a member of the homeodomain-containing transcription factor family and possesses pivotal roles in normal growth, development, and differentiation of mammalian tissues. Our results demonstrated that HOXA1 expression is enhanced in HCV-infected hepatocytes. Exogenous expression of the miR-181c mimic inhibits HOXA1 and its downstream molecules STAT3 and STAT5, which are involved in cell growth regulation. Interestingly, overexpression of miR-181c inhibited HCV replication by direct binding with E1 and NS5A sequences. Furthermore, accumulation of HCV genotype 2a RNA with miR-181c was observed in an RNA-induced silencing complex in Huh7.5 cells. Our results provide new mechanistic insights into the role of miR-181c in HCV-hepatocyte interactions, and miR-181c may act as a target for therapeutic intervention. Importance: Chronic HCV infection is one of the major causes of end-stage liver disease, including hepatocellular carcinoma. An understanding of the molecular mechanisms of HCV-mediated hepatocyte growth promotion is necessary for therapeutic intervention against HCC. In this study, we have provided evidence of HCV mediated transcriptional downregulation of miR-181c. HCV-infected liver biopsy specimens also displayed lower expression levels of miR-181c. We have further demonstrated that inhibition of miR-181c upregulates homeobox A1 (HOXA1), which is important for hepatocyte growth promotion. Exogenous expression of miR-181c inhibited HCV replication by directly binding with HCV E1 and NS5A sequences. Taken together, our results provided new mechanistic insights for an understanding of the role of miR-181c in HCV-hepatocyte interactions and revealed miR-181c as a potential target for therapeutic intervention. PMID- 24789796 TI - Seroepidemiology of astrovirus MLB1. AB - To determine the seroprevalence of astrovirus MLB1 (MLB1), an indirect enzyme linked immunosorbent assay (ELISA) was established. MLB1 seropositivity was high in children <6 months old, decreased to a nadir at 12 to 23 months old, and increased to 100% by adulthood. MLB1 infection is common, and primary exposure occurs in childhood. PMID- 24789795 TI - Evaluation of immune responses in mice after DNA immunization with putative Toxoplasma gondii calcium-dependent protein kinase 5. AB - Toxoplasma gondii can cause serious public health problems and economic losses worldwide. Calcium-dependent protein kinases (CDPKs) are key mediators of T. gondii signaling pathways and are implicated as important virulence factors. In the present study, we cloned a novel T. gondii CDPK gene, named TgCDPK5, and constructed the eukaryotic expression vector pVAX-CDPK5. Then, we evaluated the immune protection induced by pVAX-CDPK5 in Kunming mice. After injection of pVAX CDPK5 intramuscularly, immune responses, determined with lymphoproliferative assays and cytokine and antibody measurements, were monitored, and mouse survival times and brain cyst formation were evaluated following challenges with the T. gondii RH strain (genotype I) and the PRU strain (genotype II). pVAX-CDPK5 effectively induced immune responses with increased specific antibodies, a predominance of IgG2a production, and a strong lymphocyte proliferative response. The levels of gamma interferon (IFN-gamma), interleukin 2 (IL-2), and IL-12(p70) and the percentages of CD3(+) CD4(+) and CD3(+) CD8(+) cells in mice vaccinated with pVAX-CDPK5 were significantly increased. However, IL-4 and IL-10 were not produced in the vaccinated mice. These results demonstrate that pVAX-CDPK5 can elicit strong humoral and cellular Th1 immune responses. The survival time of immunized mice challenged with the T. gondii RH strain (8.67 +/- 4.34 days) was slightly, but not significantly, longer than that in the control groups within 7 days (P > 0.05). The numbers of brain cysts in the mice in the pVAX-CDPK5 group were reduced by ~40% compared with those in the control groups (P < 0.05), which provides a foundation for the further development of effective subunit vaccines against T. gondii. PMID- 24789797 TI - Production and preclinical evaluation of Plasmodium falciparum MSP-119 and MSP 311 chimeric protein, PfMSP-Fu24. AB - A Plasmodium falciparum chimeric protein, PfMSP-Fu24, was constructed by genetically coupling immunodominant, conserved regions of two merozoite surface proteins, the 19-kDa region C-terminal region of merozoite surface protein 1 (PfMSP-119) and an 11-kDa conserved region of merozoite surface protein 3 (PfMSP 311), to augment the immunogenicity potential of these blood-stage malaria vaccine candidates. Here we describe an improved, efficient, and scalable process to produce high-quality PfMSP-Fu24. The chimeric protein was produced in Escherichia coli SHuffle T7 Express lysY cells that express disulfide isomerase DsbC. A two-step purification process comprising metal affinity followed by cation exchange chromatography was developed, and we were able to obtain PfMSP Fu24 with purity above 99% and with a considerable yield of 23 mg/liter. Immunogenicity of PfMSP-Fu24 formulated with several adjuvants, including Adjuplex, Alhydrogel, Adjuphos, Alhydrogel plus glucopyranosyl lipid adjuvant, aqueous (GLA-AF), Adjuphos+GLA-AF, glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE), and Freund's adjuvant, was evaluated. PfMSP-Fu24 formulated with GLA-SE and Freund's adjuvant in mice and with Alhydrogel and Freund's adjuvant in rabbits produced high titers of PfMSP-119 and PfMSP-311-specific functional antibodies. Some of the adjuvant formulations induced inhibitory antibody responses and inhibited in vitro growth of P. falciparum parasites in the presence as well as in the absence of human monocytes. These results suggest that PfMSP-Fu24 can form a constituent of a multistage malaria vaccine. PMID- 24789798 TI - Diagnostic potential of monoclonal antibodies specific to the unique O-antigen of multidrug-resistant epidemic Escherichia coli clone ST131-O25b:H4. AB - The Escherichia coli lineage sequence type 131 (ST131)-O25b:H4 is a globally spread multidrug-resistant clone responsible for a great proportion of extraintestinal infections. Driven by the significant medical needs associated with this successful pathogenic lineage, we generated murine monoclonal antibodies (MAbs) against its lipopolysaccharide (LPS) O25b antigen in order to develop quick diagnostic tests. Murine monoclonal antibodies were generated by immunizing mice with whole killed nonencapsulated ST131-O25b E. coli cells and screening hybridoma supernatants for binding to purified LPS molecules obtained from an E. coli ST131-O25b clinical isolate. The MAbs selected for further study bound to the surface of live E. coli O25b strains irrespective of the capsular type expressed, while they did not bind to bacteria or purified LPS from other serotypes, including the related classical O25 antigen (O25a). Using these specific MAbs, we developed a latex bead-based agglutination assay that has greater specificity and is quicker and simpler than the currently available typing methods. The high specificities of these MAbs can be explained by the novel structure of the O25b repeating unit elucidated in this article. Based on comparative analysis by nuclear magnetic resonance (NMR) and mass spectrometry, the N-acetyl-fucose in the O25a O-antigen had been replaced by O-acetyl-rhamnose in the O25b repeating unit. The genetic determinants responsible for this structural variation were identified by aligning the corresponding genetic loci and were confirmed by trans-complementation of a rough mutant by the subserotype specific fragments of the rfb operons. PMID- 24789800 TI - Laryngopharyngeal reflux: paradigms for evaluation, diagnosis, and treatment. AB - OBJECTIVE: This study aimed to describe current patterns for diagnosis and treatment of laryngopharyngeal reflux (LPR) and analyze differences between laryngologists and non-laryngologists. METHODS: American Academy of Otolaryngology-Head and Neck Surgery and American Broncho-Esophagological Association members were invited to complete an online survey regarding evaluation, diagnosis, and treatment of LPR. Subgroup analysis was performed to identify differences between respondents who completed laryngology fellowships (LF) and those who did not (NL). RESULTS: Of 159 respondents, 40 were LF. Video documentation of laryngopharyngeal exams was almost universal among LF (97% vs 38%, P < .0001). Use of rigid (100%, P = .002) and flexible distal-chip technologies (94%, P = .004) was more common among LF. Diagnostic criteria were similar between the groups, with symptoms of heartburn, globus, and throat clearing thought most suggestive of LPR. Adjunctive tests most commonly used were barium esophagram and dual-probe pH testing with impedance. Laryngology fellowship-trained respondents used dual pH probes with impedance more often (P = .004). They were more likely to prescribe twice daily proton pump inhibitors with concurrent H2-blocker medication initially (P = .004) and to treat for longer than 4 weeks (P = .0003). CONCLUSION: Otolaryngologists are in agreement on symptoms and physical features of LPR; however, significant differences exist between laryngologists and non-laryngologists on the use of adjunctive testing and treatment strategies. PMID- 24789799 TI - Antibodies for treatment of Clostridium difficile infection. AB - Antibodies for the treatment of Clostridium difficile infection (CDI) have been demonstrated to be effective in the research and clinical environments. Early uncertainties about molecular and treatment modalities now appear to have converged upon the systemic dosing of mixtures of human IgG1. Although multiple examples of high-potency monoclonal antibodies (MAbs) exist, significant difficulties were initially encountered in their discovery. This minireview describes historical and contemporary MAbs and highlights differences between the most potent MAbs, which may offer insight into the pathogenesis and treatment of CDI. PMID- 24789801 TI - An analysis of vestibular evoked myogenic potentials in patients with benign paroxysmal positional vertigo. AB - OBJECTIVE: Vestibular evoked myogenic potentials (VEMPs) selectively test the vestibular end-organ. The aim of this study was to analyze how the site of the diseased canal, type of particulate deposition, duration of symptoms, severity of nystagmus, recurrence, and age affect the VEMP in patients with benign paroxysmal positional vertigo (BPPV). METHODS: One hundred two patients were enrolled in the study between 2009 and 2012. There were 36 men and 66 women with ages ranging from 16 to 71 years (mean age, 42.28 +/- 11.29 years). Patients with BPPV were tested with roll-on and head-hanging maneuvers under video-electronystagmography monitoring and with air conduction cervical VEMP testing. Patients were grouped for duration, severity, recurrence, age, site of canal involvement, and so on, and the results were compared in each subgroup. Kruskal-Wallis and Mann-Whitney U tests were used for the comparative analysis. RESULTS: Twenty-four patients (23.5%) had a gross VEMP abnormality (absence of VEMP in 6 and greater than 25% depression of the amplitude in 18). Abnormality of VEMPs was not correlated with factors including age, severity of nystagmus, number of maneuvers applied, and the site of canal involvement (P < .05). However, persistence or recurrence of symptoms has an effect on VEMP results (P = .016). CONCLUSION: Vestibular evoked myogenic potential is a useful tool to study the otolithic function in patients with BPPV and should be included in the test battery. PMID- 24789802 TI - Does rhinoplasty reduce nasal patency? AB - OBJECTIVE: This study aimed to evaluate the effect of rhinoplasty on subjective and objective assessment of nasal patency in patients who underwent rhinoplasty for cosmetic reasons only. SETTING: Tertiary referral center. DESIGN: Prospective, clinical study. SUBJECT AND METHODS: A total of 50 adult patients who underwent rhinoplasty were included in the study. Preoperative and postoperative photographs of the nasal profile (frontal, lateral, and oblique) were obtained. The visual analog scale (VAS) was used for the subjective evaluation of nasal obstruction (0 being the minimum, 10 being the maximum amount of nasal patency). Objective evaluation of nasal obstruction was performed with a peak nasal inspiratory flowmeter (PNIF). RESULTS: Preoperative mean VAS scores and PNIF values of the patients were 7.36 +/- 0.83 and 115.10 +/- 17.45, respectively. Postoperative mean VAS scores and PNIF values of the patients were 7.42 +/- 0.73 and 115.30 +/- 16.7, respectively. There was no statistically significant difference between any of the pre- and postoperative subjective and objective parameters (P > .05). CONCLUSION: Reduction rhinoplasty has been shown not to reduce nasal patency. PMID- 24789803 TI - Notch1 overexpression associates with poor prognosis in human laryngeal squamous cell carcinoma. AB - OBJECTIVE: This study aimed to investigate the expression of Notch1 in human laryngeal squamous cell carcinoma (LSCC) tissues and its relationship to clinicopathologic characteristics as well as their prognostic value in LSCC. METHODS: Samples from 106 patients with LSCC were analyzed for Notch1 expression by immunohistochemical staining. The relationship between Notch1 expression and clinicopathologic parameters was subsequently analyzed. Univariate analysis and multivariate analysis of patient survival were examined using the Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: We found that Notch1 had positive expression in 71 of 106 cases of LSCC (66.98%), which was obviously higher than laryngeal normal tissues (P < .01) and significantly correlated with the clinical stage, lymph node metastasis, and histological grade (all Ps < .05). Univariate analysis revealed that Notch1 expression tended to show an unfavorable influence on overall survival (OS) and disease-free survival (DFS) (both Ps < .01). Multivariate analysis demonstrated that Notch1 was an independent prognostic factor for patients with LSCC (P < .05). CONCLUSION: These results reveal that Notch1 expression is a potential prognostic factor for malignant progression, metastasis, and survival of LSCC patients. Furthermore, it has been demonstrated that high expression of Notch1 was associated with unfavorable OS and DFS in LSCC patients. PMID- 24789804 TI - Immunohistochemical Localization of Bone Morphogenetic Proteins (BMPs) and their Receptors in Solitary and Multiple Human Osteochondromas. AB - The expression of bone morphogenetic proteins (BMPs) and their cognate receptors (BMPRs) in osteochondromas has not been investigated. We determined the immunohistochemical localization and distribution of BMP-2/4, -6 and -7; BMP receptors BMPR-1A, BMPR-1B and BMPR-2; signal transducing proteins phosphorylated Smad1/5/8; and BMP antagonist noggin in the cartilaginous cap of solitary (SO) and multiple (MO) human osteochondromas and compared these with bovine growth plate and articular cartilage. The distribution and localization patterns for BMP 6, BMP-7, BMPR-1A and BMPR-2 were similar between the cartilaginous cap and the growth plate. BMP-2/4 and BMPR-1B were present throughout the growth plate. However, BMP-2/4 and phosphorylated Smad1/5/8 were mainly detected in proliferating chondrocytes of the cartilaginous cap. Also, BMPR-1B was found in hypertrophic chondrocytes of SO and proliferating chondrocytes of MO. Noggin was observed in resting chondrocytes and, to a lesser extent, in clustered proliferating chondrocytes in SO. On the other hand, noggin in MO was observed in proliferating chondrocytes. Since BMPs can stimulate proliferation and hypertrophic differentiation of chondrocytes, these findings suggest that there is an imbalance of BMP-2/4 and noggin interactions that may lead to abnormal regulation of chondrocyte proliferation and differentiation in the cartilaginous cap of human osteochondromas. PMID- 24789805 TI - Quantitative Imaging of Preamyloid Oligomers, a Novel Structural Abnormality, in Human Atrial Samples. AB - Abnormalities in atrial myocardium increase the likelihood of arrhythmias, including atrial fibrillation (AF). The deposition of misfolded protein, or amyloidosis, plays an important role in the pathophysiology of many diseases, including human cardiomyopathies. We have shown that genes implicated in amyloidosis are activated in a cellular model of AF, with the development of preamyloid oligomers (PAOs). PAOs are intermediates in the formation of amyloid fibrils, and they are now recognized to be the cytotoxic species during amyloidosis. To investigate the presence of PAOs in human atrium, we developed a microscopic imaging-based protocol to enable robust and reproducible quantitative analysis of PAO burden in atrial samples harvested at the time of elective cardiac surgery. Using PAO- and myocardial-specific antibodies, we found that PAO distribution was typically heterogeneous within a myocardial sample. Rigorous imaging and analysis protocols were developed to quantify the relative area of myocardium containing PAOs, termed the Green/Red ratio (G/R), for a given sample. Using these methods, reproducible G/R values were obtained when different sections of a sample were independently processed, imaged, and analyzed by different investigators. This robust technique will enable studies to investigate the role of this novel structural abnormality in the pathophysiology of and arrhythmia generation in human atrial tissue. PMID- 24789806 TI - Genetic diversity and haplotype structure of 24 Y-chromosomal STR in Chinese Hui ethnic group and its genetic relationships with other populations. AB - In the present study, 24 Y-chromosomal short tandem repeat (Y-STR) loci were analyzed in 115 unrelated Hui male individuals from Haiyuan county or Tongxin county, Ningxia Hui Autonomous Region, China, to evaluate the forensic application of the 24 STR loci and to analyze interpopulation differentiations by making comparisons between the Hui group data and previously published data of other 13 populations. A total of 115 different haplotypes were observed on these 24 Y-STR loci. The gene diversities ranged from 0.4049 (DYS437) to 0.9729 (DYS385a, b). The overall haplotype diversity was 1 at AGCU 24 Y-STR loci level, while the values were reduced to 0.999237, 0.996949, and 0.996644 at the Y-filer 17 loci, 11 Y-STR loci of extended haplotype and 9 Y-STR loci of minimal haplotype levels, respectively; whereas, haplotype diversity for additional 7 loci (not included in Y-filer 17 loci) was 0.995271. The pairwise FST , multidimensional scaling plot and neighbor-joining tree indicated the Hui group had the closest genetic relationship with Sala in the paternal lineage in the present study. In summary, the results in our study indicated the 24 Y-STRs had a high level of polymorphism in Hui group and hence could be a powerful tool for forensic application and population genetic study. PMID- 24789807 TI - XAV939 inhibits the stemness and migration of neuroblastoma cancer stem cells via repression of tankyrase 1. AB - Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. One fundamental issue regarding NB recurrence and metastasis is the maintenance of cancer stem cells (CSCs) stemness. Tankyrase 1 (TNKS1) is overexpressed in several types of cancers and in NB cell lines. XAV939 is a small molecule inhibitor of TNKS1 and can induce apoptosis of NB cells. In this study, we showed that the surface marker CD133 method was more suitable for isolating NB CSCs than the side-population method, and 60 uM etoposide was optimal for enriching NB CSCs. The NB CSCs were demonstrated in juvenescence or stemness state by electron microscopy, which was in line with the characteristics of CSCs. Furthermore, we demonstrated that the expression of the CSCs marker CD133 and migration ability of CSCs decreased after XAV939 treatment or by RNAi-mediated knockdown of the TNKS1 gene. These findings suggest that XAV939 treatment or RNAi-TNKS1 inhibits the stemness and migration of NB CSCs via the repression of TNKS1, and TNKS1 may be a potential molecular target for eliminating NB CSCs by small molecule drugs. PMID- 24789808 TI - Responsiveness to the Negative Affect System as a Function of Emotion Perception: Relations Between Affect and Sociability in Three Daily Diary Studies. AB - Perceiving emotions clearly and accurately is an important component of emotional intelligence (EI). This skill is thought to predict emotional and social outcomes, but evidence for this point appears somewhat underwhelming in cross sectional designs. The present work adopted a more contextual approach to understanding the correlates of emotion perception. Because emotion perception involves awareness of affect as it occurs, people higher in this skill might reasonably be expected to be more attuned to variations in their affective states and be responsive to them for this reason. This novel hypothesis was pursued in three daily diary studies (total N = 247), which found systematic evidence for the idea that higher levels of daily negative affect predicted lesser sociability particularly, and somewhat exclusively, among people whose emotion perception skills were high rather than low. The results support a contextual understanding of individual differences in emotion perception and how they operate. PMID- 24789809 TI - Get the Message: Punishment Is Satisfying If the Transgressor Responds to Its Communicative Intent. AB - Results from three studies demonstrate that victims' justice-related satisfaction with punishment is influenced by the kind of feedback they receive from offenders after punishment. In contrast to previous studies that found a discrepancy between anticipated and experienced satisfaction from punishment (Carlsmith, Wilson, & Gilbert, 2008), participants were able to accurately predict their satisfaction when made aware of the presence or absence of offender feedback acknowledging the victim's intent to punish. Results also indicate that victims were most satisfied when offender feedback not only acknowledged the victim's intent to punish but also indicated a positive moral change in the offender's attitude toward wrongdoing. These findings indicate that punishment per se is neither satisfying nor dissatisfying but that it is crucial to take its communicative functions and its effects on the offender into account. Implications for psychological and philosophical theories on punishment motives as well as implications for justice procedures are discussed. PMID- 24789810 TI - Splenic artery use for arterial reconstruction in pancreatic surgery. AB - BACKGROUND: Extended resections in the upper GI tract, especially for pancreatic malignancies, can require resection of the hepatic or superior mesenteric artery. Besides venous or allogenous grafting, the splenic artery can be used for reconstruction in both positions. PURPOSE: We hereby describe the different technical possibilities of interposition or transposition to use the splenic artery for restoration of arterial perfusion of the liver or the small bowel following resection of the hepatic or superior mesenteric artery, respectively. CONCLUSION: The use of the splenic artery is a convenient and appropriate possibility to reconstruct the hepatic or superior mesenteric artery in pancreatic resection with regard to interposition and especially transposition of this vessel. It should be considered in patients suitable to undergo these procedures to extend resectability in pancreatic cancer surgery. PMID- 24789811 TI - Surgery for incarcerated hernia: short-term outcome with or without mesh. AB - BACKGROUND: Incarcerated hernias represent about 5-15 % of all operated hernias. Tension-free mesh is the preferred technique for elective surgery due to low recurrence rates. There is however currently no consensus on the use of mesh for the treatment of incarcerated hernias, especially in case of bowel resection. AIM: The aims of this study were (i) to report our current practice for the treatment of incarcerated hernias, (ii) to identify risk factors for postoperative complications, and (iii) to assess the safety of mesh placement in potentially infected surgical fields. METHODS: This retrospective study included 166 consecutive patients who underwent emergency surgery for incarcerated hernia between January 2007 and January 2012 in two university hospitals. Demographics, surgical details, and short-term outcome were collected. Univariate analysis was employed to identify risk factors for overall, infectious, and major complications. RESULTS: Eighty-four patients (50.6 %) presented inguinal hernias, 43 femoral (25.9 %), 37 umbilical hernias (22.3 %), and 2 mixed hernias (1.2 %), respectively. Mesh was placed in 64 patients (38.5 %), including 5 patients with concomitant bowel resection. Overall morbidity occurred in 56 patients (32.7 %), and 8 patients (4.8 %) developed surgical site infections (SSI). Univariate risk factors for overall complications were ASA grade 3/4 (P = 0.03), diabetes (P = 0.05), cardiopathy (P = 0.001), aspirin use (P = 0.023), and bowel resection (P = 0.001) which was also the only identified risk factor for SSI (P = 0.03). In multivariate analysis, only bowel incarceration was associated with a higher rate of major morbidity (OR = 14.04; P = 0.01). CONCLUSION: Morbidity after surgery for incarcerated hernia remains high and depends on comorbidities and surgical presentation. The use of mesh could become current practice even in case of bowel resection. PMID- 24789812 TI - Feeling before knowing why: the role of the orbitofrontal cortex in intuitive judgments--an MEG study. AB - In theory, intuitive decisions are made immediately, without conscious, reasoned thought. They are experienced as decisions based on hunches that cannot be explicitly described but, nevertheless, guide subsequent action. Investigating the underlying neural mechanisms, previous research has found the orbitofrontal cortex (OFC) to be crucial to intuitive processes, but its specific role has remained unclear. On the basis of a two-stage conceptualization of intuition suggested by Bowers, Regehr, Balthazard, and Parker Cognitive Psychology, 22, 72 110 (1990), we attempt to clarify the OFC's role in intuitive processing. We propose that it functions as an early integrator of incomplete stimulus input guiding subsequent processing by means of a coarse representation of the gist of the information. On the subjective level, this representation would be perceived as a (gut) feeling biasing the decision. Our aim in the present study was to test this neural model and rule out alternative explanations of OFC activation in intuitive judgments. We used magnetoencephalography (MEG) to record participants' electromagnetic brain responses during a visual coherence judgment task. As in earlier studies, the OFC was found to be activated when participants perceived coherence. Using MEG, it could be shown that this increase in activation began earlier in the OFC than in temporal object recognition areas. Moreover, the present study demonstrated that OFC activation was independent of physical stimulus characteristics, task requirements, and participants' explicit recognition of the stimuli presented. These results speak to the OFC's fundamental role in the early steps of intuitive judgments and suggest the proposed neural model as a promising starting point for future investigations. PMID- 24789814 TI - Preliminary investigation on hemocompatibility of poly(vinylidene fluoride) membrane grafted with acryloylmorpholine via ATRP. AB - This work provides a promising way to improve the hemocompatibility of PVDF membrane. An amphiphilic copolymer (PVDF-g-PACMO) having PVDF backbones and poly(N-acryloylmorpholine) (PACMO) side chains was synthesized via atom transfer radical polymerization (ATRP). It is found that the grafting degree of the PACMO increases linearly with the increase of ACMO concentration in the reaction solution. The PVDF-g-PACMO membrane was prepared via immersed phase inversion method. The structure and performances were evaluated by X-ray photoelectron spectroscopy, field emission scanning electron microscopy, water contact angle, and filtration experiment. The hemocompatibility of the membranes were preliminarily investigated by protein adsorption, platelet adhesion, anticoagulant evaluation and hemolysis test. The results indicate that the PVDF membrane functionalized by PACMO can suppress the protein adsorption and platelet adhesion, and shows an improved hemocompatibility. PMID- 24789813 TI - A novel C-terminal nonsense mutation, Q315X, of the aryl hydrocarbon receptor interacting protein gene in a Japanese familial isolated pituitary adenoma family. AB - Although the cause of familial isolated pituitary adenoma (FIPA) remains unknown in many cases, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in approximately 20 % of families with FIPA. We investigated the AIP gene mutation by a standard sequencing method in 12 members of a Japanese two-generation FIPA family, which includes 3 patients with early-onset acromegaly. Multiplex ligation-dependent probe amplification analysis in a tumor sample was attempted to examine the loss of heterozygosity (LOH) in the locus. The effect of the detected mutation on cell proliferation was investigated. A germline mutation of c.943C > T (p.Q315X) generating an AIP protein with the C-terminal end deleted was found in the FIPA family. Biallelic inactivation of AIP by a combination of the germline mutation and LOH at 11q13 was confirmed in the tumor. The nonsense mutation disrupted the ability to inhibit cell proliferation. We conclude that p.Q315X mutation in the AIP gene is a pathogenic variant and the C-terminal region of AIP plays an important role in the predisposition to pituitary adenomas. PMID- 24789815 TI - Rapid milk group classification by 1H NMR analysis of Le and H epitopes in human milk oligosaccharide donor samples. AB - Human milk oligosaccharides (HMOs) are a major constituent of human breast milk and play an important role in reducing the risk of infections in infants. The structures of these HMOs show similarities with blood group antigens in protein glycosylation, in particular in relation to fucosylation in Lewis blood group type epitopes, matching the maternal pattern. Previously, based on the Secretor and Lewis blood group system, four milk groups have been defined, i.e. Lewis positive Secretors, Lewis-positive non-Secretors, Lewis-negative Secretors and Lewis-negative non-Secretors. Here, a rapid one-dimensional (1)H nuclear magnetic resonance (NMR) analysis method is presented that identifies the presence/absence of (alpha1-2)-, (alpha1-3)- and (alpha1-4)-linked fucose residues in HMO samples, affording the essential information to attribute different HMO samples to a specific milk group. The developed method is based on the NMR structural-reporter group concept earlier established for glycoprotein glycans. Further evaluation of the data obtained from the analysis of 36 HMO samples shows that within each of the four milk groups the relative levels of the different fucosylation epitopes can greatly vary. The data also allow a separation of the Lewis-positive Secretor milk group into two sub-groups. PMID- 24789816 TI - Risk perception of nuclear power plants among university students in Northeast Asia after the Fukushima nuclear disaster. AB - To examine the perception of nuclear energy risks among Asian university students following the Fukushima nuclear disaster, a standardized questionnaire survey was conducted since July 2011 after the Fukushima disaster. A total of 1814 respondents from 18 universities in China, Japan, Korea, and Taiwan participated in this survey. It showed that students with the following characteristics had a higher preference for "a clear schedule to phase out nuclear power plant (NPP)": females (adjusted odds ratio [aOR] = 1.84, 95% confidence interval [CI] = 1.44 2.34), in Japan (aOR = 2.81, 95% CI = 2.02-3.90), in China (aOR = 1.48, 95% CI = 1.04-2.09), and with perceived relative risks of cancer incidence greaterthan 1 (aOR = 1.42, 95% CI = 1.07-1.88). "If nuclear energy were phased out," the opinions on potential electricity shortage were as follows: Japan, aOR = 0.53, 95% CI = 0.40-0.69; China, aOR = 2.46, 95% CI = 1.75-3.45; and associated with academic majors (science/technology, aOR = 0.43, 95% CI = 0.31-0.59; medicine/health science, aOR = 0.64, 95% CI = 0.49-0.84). The results carried essential messages for nuclear energy policy in East Asia. PMID- 24789817 TI - Social diversity in humans: implications and hidden consequences for biological research. AB - Humans are both similar and diverse in such a vast number of dimensions that for human geneticists and social scientists to decide which of these dimensions is a worthy focus of empirical investigation is a formidable challenge. For geneticists, one vital question, of course, revolves around hypothesizing which kind of social diversity might illuminate genetic variation-and vice versa (i.e., what genetic variation illuminates human social diversity). For example, are there health outcomes that can be best explained by genetic variation-or for social scientists, are health outcomes mainly a function of the social diversity of lifestyles and social circumstances of a given population? Indeed, what is a "population," how is it bounded, and are those boundaries most appropriate or relevant for human genetic research, be they national borders, religious affiliation, ethnic or racial identification, or language group, to name but a few? For social scientists, the matter of what constitutes the relevant borders of a population is equally complex, and the answer is demarcated by the goal of the research project. Although race and caste are categories deployed in both human genetics and social science, the social meaning of race and caste as pathways to employment, health, or education demonstrably overwhelms the analytic and explanatory power of genetic markers of difference between human aggregates. PMID- 24789818 TI - Bioenergetic constraints on the evolution of complex life. AB - All morphologically complex life on Earth, beyond the level of cyanobacteria, is eukaryotic. All eukaryotes share a common ancestor that was already a complex cell. Despite their biochemical virtuosity, prokaryotes show little tendency to evolve eukaryotic traits or large genomes. Here I argue that prokaryotes are constrained by their membrane bioenergetics, for fundamental reasons relating to the origin of life. Eukaryotes arose in a rare endosymbiosis between two prokaryotes, which broke the energetic constraints on prokaryotes and gave rise to mitochondria. Loss of almost all mitochondrial genes produced an extreme genomic asymmetry, in which tiny mitochondrial genomes support, energetically, a massive nuclear genome, giving eukaryotes three to five orders of magnitude more energy per gene than prokaryotes. The requirement for endosymbiosis radically altered selection on eukaryotes, potentially explaining the evolution of unique traits, including the nucleus, sex, two sexes, speciation, and aging. PMID- 24789819 TI - The eukaryotic tree of life from a global phylogenomic perspective. AB - Molecular phylogenetics has revolutionized our knowledge of the eukaryotic tree of life. With the advent of genomics, a new discipline of phylogenetics has emerged: phylogenomics. This method uses large alignments of tens to hundreds of genes to reconstruct evolutionary histories. This approach has led to the resolution of ancient and contentious relationships, notably between the building blocks of the tree (the supergroups), and allowed to place in the tree enigmatic yet important protist lineages for understanding eukaryote evolution. Here, I discuss the pros and cons of phylogenomics and review the eukaryotic supergroups in light of earlier work that laid the foundation for the current view of the tree, including the position of the root. I conclude by presenting a picture of eukaryote evolution, summarizing the most recent progress in assembling the global tree. PMID- 24789821 TI - Role of endosomes and lysosomes in human disease. AB - In addition to their roles in normal cell physiology, endocytic processes play a key role in many diseases. In this review, three diseases are discussed as examples of the role of endocytic processes in disease. The uptake of cholesterol via LDL is central to our understanding of atherosclerosis, and the study of this disease led to many of the key breakthroughs in understanding receptor-mediated endocytosis. Alzheimer's disease is a growing burden as the population ages. Endosomes and lysosomes play important but only partially understood roles in both the formation and the degradation of the amyloid fibrils that are associated with Alzheimer's disease. Inherited lysosomal storage diseases are individually rare, but collectively they affect many individuals. Recent advances are leading to improved enzyme replacement therapy and are also leading to small-molecule drugs to treat some of these diseases. PMID- 24789820 TI - Molecular structure, function, and dynamics of clathrin-mediated membrane traffic. AB - Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice enclosed vesicle, and recycling the components. It integrates as much of the structural information as possible at the time of writing into a sketch of the principal steps in coated-pit and coated-vesicle formation. PMID- 24789822 TI - Endocytosis and autophagy: exploitation or cooperation? AB - Autophagy is a lysosome-mediated degradative system that is a highly conserved pathway present in all eukaryotes. In all cells, double-membrane autophagosomes form and engulf cytoplasmic components, delivering them to the lysosome for degradation. Autophagy is essential for cell health and can be activated to function as a recycling pathway in the absence of nutrients or as a quality control pathway to eliminate damaged organelles or even to eliminate invading pathogens. Autophagy was first identified as a pathway in mammalian cells using morphological techniques, but the Atg (autophagy-related) genes required for autophagy were identified in yeast genetic screens. Despite tremendous advances in elucidating the function of individual Atg proteins, our knowledge of how autophagosomes form and subsequently interact with the endosomal pathway has lagged behind. Recent progress toward understanding where and how both the endocytotic and autophagic pathways overlap is reviewed here. PMID- 24789825 TI - Dental school: balancing education and training. PMID- 24789824 TI - The genesis of tyrosine phosphorylation. AB - Tyrosine phosphorylation of proteins was discovered in 1979, but this posttranslational modification had been "invented" by evolution more than a billion years ago in single-celled eukaryotic organisms that were the antecedents of the first multicellular animals. Because sophisticated cell-cell communication is a sine qua non for the existence of multicellular organisms, the development of cell-surface receptor systems that use tyrosine phosphorylation for transmembrane signal transduction and intracellular signaling seems likely to have been a crucial event in the evolution of metazoans. Like all types of protein phosphorylation, tyrosine phosphorylation serves to regulate proteins in multiple ways, including causing electrostatic repulsion and inducing allosteric transitions, but the most important function of phosphotyrosine (P.Tyr) is to serve as a docking site that promotes a specific interaction between a tyrosine phosphorylated protein and another protein that contains a P.Tyr-binding domain, such as an SH2 or PTB domain. Such docking interactions are essential for signal transduction downstream from receptor tyrosine kinases (RTKs) on the cell surface, which are activated on binding a cognate extracellular ligand, and, as a consequence, elicit specific cellular outcomes. PMID- 24789823 TI - DNA methylation in mammals. AB - DNA methylation is one of the best characterized epigenetic modifications. In mammals it is involved in various biological processes including the silencing of transposable elements, regulation of gene expression, genomic imprinting, and X chromosome inactivation. This article describes how DNA methylation serves as a cellular memory system and how it is dynamically regulated through the action of the DNA methyltransferase (DNMT) and ten eleven translocation (TET) enzymes. Its role in the regulation of gene expression, through its interplay with histone modifications, is also described, and its implication in human diseases discussed. The exciting areas of investigation that will likely become the focus of research in the coming years are outlined in the summary. PMID- 24789827 TI - The effects of student self-assessment on learning in removable prosthodontics laboratory. AB - It has been consistently shown that there is a weak association between student self-assessment and faculty member assessment of student projects in preclinical technique laboratory settings and that students overestimate their performance. Greater overestimation is observed among students judged by faculty to be the weakest, and these students also use a wider range of scores. This study hypothesized that student self-assessment is a function of capacity to perform, accuracy of understanding grading standards, and psychological factors. Further it hypothesized that learning, defined as change in performance, is a function of ability and self-assessment. Dental students at one U.S. dental school self assessed their performance on two projects in a removable prosthodontics laboratory course separated by a six-month period. Faculty evaluations of these projects were used to determine students' understanding of the criteria for the projects, and a standardized psychological test was used to assess the learning orientation of the students. A statistical correction was made for the artifact of regression toward the mean. The study found that self-assessment was a better predictor of future learning under these circumstances than was evaluation by faculty members. PMID- 24789826 TI - Validity and reliability of portfolio assessment of student competence in two dental school populations: a four-year study. AB - The purpose of this study was to empirically investigate the validity and reliability of portfolio assessment in two U.S. dental schools using a unified framework for validity. In the process of validation, it is not the test that is validated but rather the claims (interpretations and uses) about test scores that are validated. Kane's argument-based validation framework provided the structure for reporting results where validity claims are followed by evidence to support the argument. This multivariate generalizability theory study found that the greatest source of variance was attributable to faculty raters, suggesting that portfolio assessment would benefit from two raters' evaluating each portfolio independently. The results are generally supportive of holistic scoring, but analytical scoring deserves further research. Correlational analyses between student portfolios and traditional measures of student competence and readiness for licensure resulted in significant correlations between portfolios and National Board Dental Examination Part I (r=0.323, p<0.01) and Part II scores (r=0.268, p<0.05) and small and non-significant correlations with grade point average and scores on the Western Regional Examining Board (WREB) exam. It is incumbent upon the users of portfolio assessment to determine if the claims and evidence arguments set forth in this study support the proposed claims for and decisions about portfolio assessment in their respective institutions. PMID- 24789828 TI - Why professional judgment is better than objective description in dental faculty evaluations of student performance. AB - Practices intended to increase the appearance of objectivity in grading may work at cross purposes with professional judgment. In this study, an analysis of two removable prosthodontics technique projects in one U.S. dental school found that the use of component criteria (checklist) grading was less consistent than overall judgments of the same work and less predictive of dental students' future learning. A factor analysis revealed latent structures in both projects that would make it inappropriate to use a component criteria approach for grading. Common defenses of objectivity-such as scientific foundation, the relationship between reliability and validity, and legal requirements-are questioned in this article, and it is shown how simple adjustments to judgment scores can be made more effective than checklists, faculty calibration, or deselecting faculty members and with better measurement and teaching features. PMID- 24789829 TI - Dental student perceptions of the educational value of a comprehensive, multidisciplinary OSCE. AB - The aim of this study was to examine student perceptions of the educational value of a comprehensive, multidisciplinary objective structured clinical examination (OSCE). The examination is administered after the second year of the curriculum, prior to the beginning of clinical training at the Columbia University College of Dental Medicine. The quantitative component of the study consisted of a survey administered to students who had taken the OSCE (N=78). Due to the ordinal level of data produced by the Likert-scale survey, statistical analysis was performed through calculation of the median and interquartile range (IQR). Overall, student perceptions of the educational value of the OSCE, as measured using a five-point scale (1=strongly disagree to 5=strongly agree) were positive, demonstrating students' agreement that the exam required the ability to think critically and problem-solve (median=4, IQR=1), assessed clinically relevant skills (median=5, IQR=1), and was a learning experience (median=5, IQR=1). A statistically significant chi-square value (p<0.001) was found for all questions. The qualitative component consisted of phenomenological examination of student focus group interviews (N=15). Four main themes were identified including that the OSCE was an authentic assessment that required integration and application of knowledge. PMID- 24789830 TI - Using experiential learning and OSCEs to teach and assess tobacco dependence education with first-year dental students. AB - Previous research has indicated that dentists do not routinely engage in tobacco cessation interventions with their patients due, in part, to a lack of training in the predoctoral curriculum. From 2010 to 2012, this study at one U.S. dental school evaluated the effectiveness of experiential learning and objective structured clinical examinations (OSCEs) to improve first-year dental students' knowledge and beliefs about tobacco dependence and cessation interventions. Analysis indicated acceptable reliability and student performance for the OSCE. In all three years, there were statistically significant increases in student knowledge (p<0.001). In each year, there were also statistically significant shifts in student perceptions of preparedness (p<0.001 to p=0.034) and willingness (p<0.001 to p=0.005) to provide tobacco dependence treatment to patients. Results suggest that OSCEs utilizing standardized patients may be an effective method for assessing tobacco dependence education. Preparing for and participating in an OSCE with a standardized patient may help increase student knowledge and shape the beliefs of early dental students about engaging in patient tobacco cessation interventions. Findings were mixed on the impact of experiential learning on OSCE performance, suggesting further research is needed. PMID- 24789831 TI - Triple jump examination evaluation of faculty examiners by dental student examinees. AB - The triple jump examination (TJE) is an oral examination that poses challenges for objective assessment. Student satisfaction levels with faculty assessment can provide information on quality of teaching and students' perceptions of the learning environment. The purpose of this study was to determine scale and interrater reliability of an instrument used by approximately 576 first-year dental students at one U.S. dental school for assessment of their faculty evaluators following midterm and final TJEs over a three-year period. One hundred and one faculty members served as administrators of the TJE with a range of one to 187 times (mean=44.10, median=29, mode=11). The grand mean for six items on a six-point Likert scale was 5.39 with a pooled standard deviation of 1.01. Results indicate positive agreement toward performance of examiners with strong interrater reliability (Average Measures ICC=0.936, Single Measures ICC=0.708) (F5,23475 = 51.564, p<0.001) and consistency across all items (Cronbach's alpha=0.936). The a priori assumption that students would rate faculty higher as they gained experience over time was rejected (r=0.018, p=0.429). Indications are that faculty members, who are relatively inexperienced with TJE examining, can perform acceptable assessment from the students' perspective. Overall, these students expressed a high level of satisfaction with TJE faculty performance. PMID- 24789832 TI - Current state of the effectiveness of problem-based learning in prosthodontics: a systematic review. AB - The aim of this study was to systematically review the available literature on the effectiveness of problem-based learning (PBL) in prosthodontics. Both electronic and manual searches were performed by two reviewers. Of the 440 studies identified, ten met the inclusion criteria (Kappa=0.83). Various assessment tools such as standardized examinations (National Board Dental Examination and North East Regional Board of Dental Examiners exam) (22 percent), tutor evaluation (practical and examinations performance) (20 percent), curriculum time (20 percent) and number of units (10 percent), peer evaluation (10 percent), and self-evaluation (100 percent) were used in the included studies. Thirty percent of the studies adopted a control group for all measurements, 30 percent did for only some measurements, and the others lacked any control group. Although 30 percent of the studies implemented a hybrid PBL, the other studies did not mention the type of PBL. Based on the Effective Public Health Practice Project (EPHPP), all of the included studies were rated as being of weak quality. Heterogeneity across these studies in outcome variables, study designs, levels of PBL intervention, and study population limits any attempt to generalize the outcomes. The generally poor quality assessment outcomes warrant further studies on the effectiveness of PBL in prosthodontics education compared to a non-PBL curriculum. PMID- 24789833 TI - Providing care for underserved patients: endodontic residents', faculty members', and endodontists' educational experiences and professional attitudes and behavior. AB - In the United States, access to dental care is often challenging for patients from socioeconomically disadvantaged and/or minority populations and for patients with special health care needs (SHCN). The objectives of this study were to a) explore endodontic residents', endodontic faculty members', and private practice endodontists' perceptions of their education about treating underserved patients, along with their related attitudes and behavior, and b) to determine how their educational experiences were related to their attitudes and behavior concerning these patients. It was hypothesized that the quality of educational experiences related to these issues would correlate with the providers' professional attitudes and behavior. METHODS: Survey data were collected from seventy-eight endodontic residents, forty-eight endodontic faculty members, and seventy-five endodontists in private practice. RESULTS: The residents reported themselves being better prepared to treat these patients than did the endodontists in private practice. The residents and faculty members had more positive attitudes towards patients with SHCN, developmental disabilities, and pro bono cases and were more confident when treating patients with developmental disabilities than private practitioners. However, the three groups did not differ in educational experiences and attitudes concerning patients from different ethnic/racial groups. The better the respondents' graduate education about certain patient groups had been, the more positive were their attitudes and behavior. CONCLUSIONS: Improving endodontic residents' education about treating underserved patients is likely to improve their attitudes and behavior related to providing much-needed care for these patients. These findings are a call-to-action for dental educators to ensure quality education is being provided about these issues in order to decrease access to care problems for underserved patients. PMID- 24789834 TI - Open wide: looking into the safety culture of dental school clinics. AB - Although dentists perform highly technical procedures in complex environments, patient safety has not received the same focus in dentistry as in medicine. Cultivating a robust patient safety culture is foundational to minimizing patient harm, but little is known about how dental teams view patient safety or the patient safety culture within their practice. As a step toward rectifying that omission, the goals of this study were to benchmark the patient safety culture in three U.S. dental schools, identifying areas for improvement. The extensively validated Medical Office Survey on Patient Safety Culture (MOSOPS), developed by the Agency for Healthcare Research and Quality, was administered to dental faculty, dental hygienists, dental students, and staff at the three schools. Forty-seven percent of the 328 invited individuals completed the survey. The "Teamwork" category received the highest marks and "Patient Care Tracking and Follow-Up" and "Leadership Support for Patient Safety" the lowest. Only 48 percent of the respondents rated systems and processes in place to prevent/catch patient problems as good/excellent. All patient safety dimensions received lower marks than in medical practices. These findings and the inherent risk associated with dental procedures lead to the conclusion that dentistry in general, and academic dental clinics in particular, stands to benefit from an increased focus on patient safety. This first published use of the MOSOPS in a dental clinic setting highlights both clinical and educational priorities for improving the safety of care in dental school clinics. PMID- 24789835 TI - Teaching dental students about patient communication following an adverse event: a pilot educational module. AB - Adverse events are an important but understudied area in dentistry. Most dentists will face the issue of an adverse event several times in their clinical careers. The authors implemented a six-hour pilot educational module at one dental school to improve fourth-year dental students' knowledge and confidence in communicating with patients about adverse events. Based on results from the twenty-nine students who completed both the pre- and posttests, the module significantly increased the students' knowledge of the key concepts involved in adverse events. However, the module did not improve the students' confidence that they would be able to implement these communication skills in clinical situations. Based on these results, this article discusses how future educational efforts can be modified to better prepare students for the communication challenges associated with adverse events. PMID- 24789836 TI - Dental students' attitudes toward diabetes counseling, monitoring, and screening. AB - The main objective of this study was to examine attitudes of dental students toward chairside counseling and monitoring of and screening for diabetes. A secondary objective was to examine the psychometric properties of the survey instrument. First- and fourth-year students at one dental school completed a survey examining attitudes toward and perceived barriers to performing glucose monitoring, screening, and counseling in a dental setting. Surveys were completed by seventy-one of ninety first-year dental students (79 percent) and eighty-six fourth-year students (100 percent) for a total of 157 responses. Factor analysis of the survey instrument resulted in a three-factor solution: scope and responsibility, barriers, and glucometer use. In analyses to determine whether there were differences in attitudes by gender, level of education, or family history of diabetes, no statistically significant effects were seen. The dental students were in general agreement that glucose monitoring of patients diagnosed with diabetes is within the scope and responsibility of the dental profession; however, only a minority endorsed screening of patients who have not been diagnosed with diabetes. Psychometric analysis revealed internal reliability of the survey instrument. PMID- 24789837 TI - Advanced predoctoral implant program at UIC: description and qualitative analysis. AB - Dental implant education has increasingly become an integral part of predoctoral dental curricula. However, the majority of implant education emphasizes the restorative aspect as opposed to the surgical. The University of Illinois at Chicago College of Dentistry has developed an Advanced Predoctoral Implant Program (APIP) that provides a select group of students the opportunity to place implants for single-tooth restorations and mandibular overdentures. This article describes the rationale, logistics, experiences, and perspectives of an innovative approach to provide additional learning experiences in the care of patients with partial and complete edentulism using implant-supported therapies. Student and faculty perspectives on the APIP were ascertained via focus group discussions and a student survey. The qualitative analysis of this study suggests that the select predoctoral dental students highly benefited from this experience and intend to increase their knowledge and skills in implant dentistry through formal education following graduation. Furthermore, the survey indicates that the APIP has had a positive influence on the students' interest in surgically placing implants in their future dental practice and their confidence level in restoring and surgically placing implants. PMID- 24789838 TI - Are predoctoral students able to provide single tooth implant restorations in the maxillary esthetic zone? AB - The objective of this study was to assess the ability of the University of Illinois at Chicago College of Dentistry (UIC-COD) predoctoral students to provide single tooth implant (STI) prostheses in the maxillary esthetic zone. The patient's esthetic satisfaction and the correlation between prosthodontists' and patients' perspectives were examined. Twenty-seven patients were recruited for recall examinations at the UIC-COD predoctoral implant program and underwent clinical and radiographic examination with clinical photographs of the implant sites. The patients completed a semantic differential scale questionnaire. The collected information was formulated into a PowerPoint presentation for two Diplomate of the American Board of Prosthodontists to use the Pink/White Esthetic Score (PES/WES) to evaluate the esthetic outcome. Descriptive analyses, Cohen kappa test, and Spearman rank correlation coefficient test were performed. The average PES/WES were above 6.0 (out of 10). The median for the patient satisfaction and esthetic outcome questionnaires were 10 and 9, respectively, on a scale with 10=highest. There was a medium and positive correlation between prosthodontists' and patients' perspectives in esthetic outcome. This study found that, with strict guidance and proper selection criteria, predoctoral students were able to provide esthetically acceptable STI prostheses in the maxillary esthetic zone and patients were satisfied with the treatment provided. PMID- 24789839 TI - Identification of possible factors impacting dental students' ability to locate MB2 canals in maxillary molars. AB - This study examined the effect of the access size and straight-line path of access on third-year dental students' ability to locate a second mesiobuccal (MB2) canal in maxillary first and second molars. One hundred and six third-year dental students at one Faculty of Dentistry performed simulated root canal treatment with the aid of 2x magnification loupes on extracted teeth. A postgraduate endodontic student subsequently made a reasonable search for an untreated MB2 canal with the aid of a dental operating microscope. The mesiobuccal roots were then sectioned horizontally for determination of the canal configuration. The dental students were able to treat an MB2 canal in 15.8 percent of the teeth, but this was not associated with satisfactory access criteria. The postgraduate endodontic student identified an MB2 canal in 54.7 percent of the remaining tooth samples excluding those where the MB2 canal was found by the dental students; this represented 94.3 percent of those teeth confirmed by horizontal sectioning of the root to have an MB2 canal. The postgraduate student troughed, on average, 2.6 mm before negotiating the MB2 canal. As satisfactory access criteria and straight-line path of access did not correlate with the dental students' ability to find a second mesiobuccal canal, this result has important implications for educational goals with respect to endodontic treatment of maxillary molar teeth. PMID- 24789840 TI - Dental rounds: an evolving process of curriculum integration at the LSU School of Dentistry. AB - With the support for curriculum change expressed by the American Dental Education Association's Commission on Change and Innovation in Dental Education (ADEA CCI), the Louisiana State University Health Sciences Center School of Dentistry (LSUSD) initiated a course that vertically integrates the basic sciences and clinical sciences and promotes critical thinking. The resulting Dental Rounds course includes presentations by D3 and D4 students on interesting clinical cases, which the entire student body is required to attend. Following the third year of the program, a formal evaluation was conducted, in which surveys were disseminated to students, recent graduates, and faculty members to collect feedback on the efficacy of the course, its perceived value, and its success as an educational tool. Of the 242 students and graduates who were sent surveys, 181 responded, a 74 percent response rate. Of the eighty full-time faculty members, sixty-one responded, a 76 percent response rate. Most respondents reported that the objectives of the course were being achieved, but they identified case-related discussion as an area for strengthening critical thinking skills. As a result, modifications were planned to include formal participation of D1 and D2 students in the presentations, less frequent sessions to accommodate more complete cases, more emphasis on basic science, more structured mentoring, and a modified question format. Dental Rounds was a necessary integration step in dental education for LSUSD, and it is anticipated that the planned modifications will lead to strengthening of critical thinking skills in both students and faculty. PMID- 24789841 TI - Yes, but don't underestimate estimation: reply to Morey, Rouder, Verhagen, and Wagenmakers (2014). PMID- 24789842 TI - Neural predictors of giving in to temptation in daily life. AB - The ability to control desires, whether for food, sex, or drugs, enables people to function successfully within society. Yet, in tempting situations, strong impulses often result in self-control failure. Although many triggers of self control failure have been identified, the question remains as to why some individuals are more likely than others to give in to temptation. In this study, we combined functional neuroimaging and experience sampling to determine if there are brain markers that predict whether people act on their food desires in daily life. We examined food-cue-related activity in the nucleus accumbens (NAcc), as well as activity associated with response inhibition in the inferior frontal gyrus (IFG). Greater NAcc activity was associated with greater likelihood of self control failures, whereas IFG activity supported successful resistance to temptations. These findings demonstrate an important role for the neural mechanisms underlying desire and self-control in people's real-world experiences of temptations. PMID- 24789843 TI - ER stress induces epithelial differentiation in the mouse oesophagus. AB - OBJECTIVE: Stress in the endoplasmic reticulum (ER) leads to activation of the unfolded protein response (UPR). Xbp1, a key component of the UPR has recently been linked to the risk of developing oesophageal squamous cell carcinoma, suggesting an important role for the UPR in the oesophageal epithelium. Here we examined the role of ER stress and the UPR in oesophageal epithelial homoeostasis. DESIGN: We examined the expression of components of the UPR in the oesophageal epithelium. We used a pharmacological approach and a genetic approach to examine the effects of ER stress in vivo in the mouse oesophagus. The oesophagus of these mice was examined using immunohistochemistry and real-time reverse transcription (RT)-PCR. RESULTS: Components of the UPR were heterogeneously expressed in the basal layer of the epithelium. Induction of ER stress by 24-h treatment with thapsigargin resulted in depletion of proliferating cells in the basal layer of the oesophagus and induced differentiation. We next activated the UPR by inducible deletion of the major ER chaperone Grp78 in Ah1Cre Rosa26-LacZ-Grp78(-/-) mice in which mutant cells could be traced by expression of LacZ. In these mice LacZ-positive mutant cells in the basal layer lost their proliferative capacity, migrated towards the oesophageal lumen and were replaced by LacZ-negative non-mutant cells. We observed no apoptosis in mutant cells. CONCLUSIONS: These results show that ER stress induces epithelial differentiation in precursor cells in the oesophageal epithelium. This UPR induced differentiation may serve as a quality control mechanism that protects against oesophageal cancer development. PMID- 24789844 TI - Public communication of science in Mexico: past, present and future of a profession. AB - In this article, we offer an analysis of the evolution of the professional field of public communication of science in Mexico, particularly at the National Autonomous University of Mexico, the influences it has received from other countries, the impact it has on Mexican society and some of its relationships with other Latin American countries. We present examples of successful programmes in different mass media and an analysis of the evolution and diversification of science communicators over the last four decades. PMID- 24789846 TI - Prospective population-based study of the association between serum 25 hydroxyvitamin-D levels and the incidence of specific types of cancer. AB - BACKGROUND: Observational studies have suggested an inverse association between vitamin D status and cancer. We investigated the prospective associations between vitamin D status and the total and specific type of cancer in three cohorts from the general Danish population. METHODS: A total of 12,204 individuals 18 to 71 years old were included. The level of 25-hydroxyvitamin D was measured at baseline, and information about cancer was obtained from the Danish Cancer Registry. RESULTS: During the 11.3-year median follow-up time, there were 1,248 incident cancers. HRs [95% confidence intervals (CI)] per 10 nmol/L higher baseline vitamin D level were: for all cancers (HR = 1.02; 95% CI, 0.99-1.04), all cancers excluding non-melanoma skin cancer, NMSC (HR = 1.00; 95% CI, 0.97 1.03), head and neck cancer (HR = 0.97; 95% CI, 0.84-1.12), colorectal cancer (HR = 0.95; 95% CI, 0.88-1.02), cancer of bronchus and lung (HR = 0.98; 95% CI, 0.91 1.05), breast cancer (HR = 1.02; 95% CI, 0.96-1.09), cancer of the uterus (HR = 1.10; 95% CI, 0.95-1.27), prostate cancer (HR = 1.00; 95% CI, 0.93-1.08), cancer of the urinary organs (HR = 1.01; 95% CI, 0.90-1.14), NMSC (HR = 1.06; 95% CI, 1.02-1.10), and malignant melanoma (HR = 1.06; 95% CI, 0.95-1.17). CONCLUSIONS: Apart from a significantly higher risk for NMSC with higher vitamin D status, we found no statistically significant associations between vitamin D status and total or specific cancers. IMPACT: Our results do not indicate that there is an impact of vitamin D on total cancer incidence. PMID- 24789845 TI - One-carbon metabolism dietary factors and distal gastric cancer risk in chinese women. AB - BACKGROUND: Previous studies on the association between one-carbon dietary factors and gastric cancer risk have been inconsistent. METHODS: We investigated this association using data from a prospective study, the Shanghai Women's Health Study (1997-2010), including 323 distal gastric cancer cases identified from 73,009 Chinese women. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression after adjusting for confounders. RESULTS: Overall, no statistically significant association of gastric cancer was observed with dietary intake of folate, methionine, or B vitamins. However, when stratified by menopausal status, higher intake of riboflavin was associated with decreased gastric cancer risk in premenopausal women with HR of 0.35 (95% CI, 0.17-0.73), 0.48 (0.24-0.97), 0.28 (0.12-0.65), and 0.23 (0.07-0.91), respectively, for the quintiles 2 to 5 intake groups compared with the lowest quintile intake (P for trend = 0.02). Among premenopausal women, highest intake of folate was associated with increased gastric cancer risk (HR, 2.62; 95% CI, 1.04-6.59). There were no statistically significant associations observed among postmenopausal women. CONCLUSIONS: These results suggest that dietary factors involved in one-carbon metabolism are associated with gastric cancer risk among premenopausal women. IMPACT: Riboflavin may be a protective factor and folate may be a risk factor for premenopausal gastric cancer. PMID- 24789847 TI - The natural history of cervical cancer in chinese women: results from an 11-year follow-up study in china using a multistate model. AB - BACKGROUND: It is important to understand the natural history of cervical cancer, which has implications for cancer prevention and management. However, a dearth of studies on the long-term development of cervical cancer exists in China. METHODS: We investigated the natural history of cervical cancer in Chinese women by creating a multistate model using 11 years of follow-up data from the Shanxi Province Cervical Cancer Screening Study I conducted from 1999 to 2010. In 1999, a total of 1,997 eligible women, ages 35 to 45 years, were enrolled in Xiangyuan County, Shanxi Province. Participants were followed up in 2005 and 2010, respectively. RESULTS: The average time a subject spent in CIN1 before transiting into another state was 1.4693 years [95% confidence interval (CI): 1.1215-1.9251] and the average time a subject spent in CIN2 was 2.9822 years (95% CI: 1.9790 4.4938). A subject's transition probability from CIN1 to normal increased with time. However, the transition probability from CIN1 to CIN2 was relatively lower, with 3-, 5-, and 10-year transition probabilities of 0.1415, 0.1066, and 0.0437. Comparison of 5-year transition probabilities between CIN2 to normal/CIN1 and CIN2 to CIN3(+) yielded a ratio of 2.74. CONCLUSIONS: Women with CIN1 had a substantial tendency for regression. Similarly, women with CIN2 had a higher probability of regression to normal/CIN1 than progression to CIN3(+). Findings in this study may have significant implications for the development and evaluation of formal cervical cancer preventive strategies in China. IMPACT: This study may serve as a valuable reference to future research on other multistate cancer processes. PMID- 24789848 TI - At the heart of an early psychosis centre: the core components of the 2014 Early Psychosis Prevention and Intervention Centre model for Australian communities. AB - OBJECTIVE: To describe the core components of the Early Psychosis Prevention and Intervention Centre service model as the template agreed with the Australian Federal Government for national upscaling. The Early Psychosis Prevention and Intervention Centre model of early intervention has two main goals: to reduce the period of time between the onset of psychosis and the commencement of treatment and to bring about symptomatic recovery and restore the normal developmental trajectory as early as possible. CONCLUSIONS: The Early Psychosis Prevention and Intervention Centre comprises three elements of service provision for young people experiencing a first episode of psychosis: (i) early detection; (ii) acute care during and immediately following a crisis; (iii) recovery-focused continuing care, featuring multimodal interventions to enable the young person to maintain or regain their social, academic and/or career trajectory during the critical first 2-5 years following the onset of a psychotic illness. It does this via a combination of 16 core components, which provide a flexible, comprehensive, integrated service that is able to respond quickly, appropriately and consistently to the individual needs of the young person and their family. Innovative service reforms, such as Early Psychosis Prevention and Intervention Centre, that recognise the value of early intervention are crucial to reducing the impact of serious mental illness on young people and their families and, ultimately, on our society. PMID- 24789849 TI - Use of restrictive interventions in a child and adolescent inpatient unit - predictors of use and effect on patient outcomes. AB - OBJECTIVES: Restrictive interventions (seclusion, physical restraint, and use of acute/p.r.n. sedation) may have negative effects on patients. Identifying factors associated with use of restrictive interventions and examining their effect on admission outcomes is important for optimising inpatient psychiatric care. METHODS: This study documented use of restrictive interventions within a child and adolescent psychiatric inpatient unit for 15 months. Two models examined predictors of use of restrictive interventions: (i) incident characteristics; and (ii) patient characteristics. The relationship between use of restrictive interventions and global clinical outcomes was also examined. RESULTS: Of 134 patients admitted during the study period (61.9% female, mean age=13.8+/-2.9 years), 26.9% received at least one restrictive intervention. Incident factors associated with restrictive interventions were: physical aggression, early admission stage, and occurrence in private space. Patient factors that predicted use of restrictive interventions were developmental disorder and younger age. Use of restrictive interventions was not associated with increased length of stay or diminished improvement in global symptom ratings. CONCLUSIONS: Further research is needed to identify best practice in children at high risk for receiving restrictive interventions. PMID- 24789850 TI - Continuous infusion of remifentanil combined with target-controlled infusion of propofol for tracheal intubation in dogs. AB - Ninety dogs presenting for elective surgery were randomly assigned into three groups of 30. Intubation conditions, haemodynamic responses and other events were evaluated following target controlled infusion (TCI) with propofol at 3.0 MUg/ml, combined with variable infusion rates of remifentanil (R1 0.1 MUg/kg/minute, R2 0.2 MUg/kg/minute, R3 0.3 MUg/kg/minute). Tracheal intubation was recorded as excellent, good or poor according to jaw relaxation, tongue withdrawal, ease of laryngoscopy, swallowing, coughing and limb movement. Excellent overall intubation conditions were present in 5/30 (17 per cent), 12/30 (40 per cent) and 21/30 (70 per cent) of dogs in groups R1-3, respectively. In all three groups, the mean arterial pressure (MAP) and mean heart rate (MHR) decreased following induction of anaesthesia. Following intubation, despite an increase in MAP and MHR values, they remained significantly lower than baseline values. Muscle twitching and involuntary movement was observed after propofol induction in 10 dogs. The results suggest that a plasma concentration of 3 MUg/ml propofol along with an infusion rate of remifentanil at 0.3 MUg/kg/minute may provide satisfactory conditions for intubation, while avoiding major adverse haemodynamic effects. PMID- 24789851 TI - Use of a GnRH agonist implant as alternative for surgical neutering in pet ferrets. AB - In the current study, the duration of effectiveness, owner satisfaction and side effects of a gonadotrophin releasing hormone-agonist (deslorelin) implant were investigated during a two-year follow-up study in which 61 male and 69 female entire pet ferrets were given a 4.7 mg deslorelin implant as alternative to surgical neutering. In 27 participating non-oestrous jills, a double-blind placebo controlled study was performed to investigate whether a single low dose of medroxyprogesterone (2 mg orally) four days preceding placement of the implant could prevent oestrus induction. The duration of effectiveness of the implant ranged from 301 days to over 1339 days (mean 1012+/-38 days), with no sex difference present. Over 90 per cent of owners were pleased with the effects of the implant. Minor local side effects were noted in less than 20 per cent of ferrets, which all resolved within a week without treatment. Oestrus was induced in 77 per cent of jills receiving medroxyprogesterone and 50 per cent of jills receiving the placebo, indicating that administration of a low-dose progestogen cannot prevent postimplant oestrus. Based on the minimum duration of effectiveness, it is advised to place a new implant on a yearly basis to guarantee continuous gonadal suppression, although biannual replacement may be sufficient in the majority of ferrets. PMID- 24789852 TI - Risk factors associated with high bulk milk antibody levels to common pathogens in UK dairies. AB - Infectious diseases pose a severe economic burden on the UK dairy industry. This study used bulk milk antibody levels in 1088 UK dairy herds to estimate the current UK prevalence of bovine viral diarrhoea virus (BVDV), bovine herpes virus 1 (BHV-1) and Leptospira hardjo. Questionnaires collected under the DairyCheck scheme (MSD Animal Health) were used concurrently to gather information on farm demographics and management practices. The prevalence of active BVDV infection was 58.6 per cent, of historic BVDV exposure was 88.6 per cent, of BHV-1 infection was 69.2 per cent and of L hardjo was 71.9 per cent. An increasing herd size and the purchasing of replacement cattle were risk factors for the presence of all three agents. Year-round calving was associated with a 1.9 times increased risk for having BVDV (P<0.005). The presence of a bull was associated with a 1.5 times increased risk for having BHV-1 (P<0.005). When compared with previous results, this study indicates a slight fall in the prevalence of BVDV within the UK dairy herd; however, BHV-1 and L hardjo levels appear to have remained constant. This study shows that herds purchasing cattle are at greater risk of infectious agents being present and therefore, if possible, a closed herd system should be implemented. PMID- 24789853 TI - Evaluation of the specificity of intradermal tuberculin and serological tests for diagnosis of tuberculosis in alpaca (Vicugna pacos) and llama (Lama glama) herds under field conditions in Peru. PMID- 24789854 TI - Coxiella burnetii seroprevalence and risk factors on commercial sheep farms in The Netherlands. AB - Coxiella burnetii seroprevalence was assessed on Dutch dairy and non-dairy sheep farms using ELISA. Risk factors for seropositivity on non-dairy sheep farms were identified at farm and sheep level by univariate and multivariate multilevel analyses. Based on 953 dairy and 5671 non-dairy serum samples, sheep seroprevalences were 18.7 per cent and 2.0 per cent, respectively, and 78.6 per cent and 30.5 per cent at farm level. Significant risk factors for non-dairy sheep farms were farm location in the south of the country, sheep kept on marginal grounds, one or several supply addresses for ewes during 2007-2009 and wearing farm boots and/or outfit by professional visitors. On sheep level, risk factors included among others farm location in the south of the country, lamb breeding as main farm purpose, goat density within 10 km farm radius, use of windbreak curtain or windshields, and presence of >=6 stillborn lambs in 2009. Farm location in the south of the country and goat density suggests that infected goats have played a role in the transmission to non-dairy sheep. Other risk factors suggest introduction of the bacterium through sheep supply and professional visitors. Biosecurity measures should be strengthened, including avoiding infection during handling of stillborn lambs and birth products in the lambing period. PMID- 24789855 TI - Cryptosporidium felis in faeces from cats in the UK. PMID- 24789856 TI - Hindlimb lameness and gait abnormalities in bitches with pyometra. AB - The objective of this study was to assess the frequency of gait abnormalities and lameness (GAL) in bitches with pyometra, and their association with clinical and laboratory findings. The study included 79 bitches diagnosed with pyometra and 35 negative control intact bitches presented with other soft tissue surgical disorders. Dogs with a history of chronic lameness due to orthopaedic or neurological origin were excluded. A history of GAL was more frequent in the pyometra group (47 per cent) compared with the control group (20 per cent) (P=0.007). In the pyometra group, bitches presenting GAL had (P<0.04) higher frequencies of closed-cervix pyometra, anorexia and vomiting, as well as higher serum creatinine concentration and muscle enzymes activity, compared with those in without GAL. GAL signs resolved postovariohysterectomy in all but one bitch. The results suggest that GAL signs occur frequently in bitches with pyometra, especially in closed-cervix disease. Therefore, pyometra should be considered among the differential diagnoses when GAL occurs, especially when the clinical signs are non-specific and the reproductive history is unclear. PMID- 24789857 TI - Reversed thresholds in partial credit models: a reason for collapsing categories? AB - When questionnaire data with an ordered polytomous response format are analyzed in the framework of item response theory using the partial credit model or the generalized partial credit model, reversed thresholds may occur. This led to the discussion of whether reversed thresholds violate model assumptions and indicate disordering of the response categories. Adams, Wu, and Wilson showed that reversed thresholds are merely a consequence of low frequencies in the categories concerned and that they do not affect the order of the rating scale. This article applies an empirical approach to elucidate the topic of reversed thresholds using data from the Revised NEO Personality Inventory as well as a simulation study. It is shown that categories differentiate between participants with different trait levels despite reversed thresholds and that category disordering can be analyzed independently of the ordering of the thresholds. Furthermore, we show that reversed thresholds often only occur in subgroups of participants. Thus, researchers should think more carefully about collapsing categories due to reversed thresholds. PMID- 24789858 TI - Retraction: simultaneous recovery of DNA and RNA from formalin-fixed paraffin embedded tissue and application in epidemiologic studies. PMID- 24789860 TI - Acute refractory intestinal pseudo-obstruction in MELAS: efficacy of prucalopride. PMID- 24789859 TI - Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women. AB - BACKGROUND: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies. METHODS: We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm. RESULTS: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2. CONCLUSIONS: Positive screens were more frequent when HE4 was included in the primary screen. IMPACT: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen. PMID- 24789861 TI - Peripheral hypoxia in restless legs syndrome (Willis-Ekbom disease). AB - OBJECTIVE: A case-control study to measure oxygen and carbon dioxide partial pressures in the legs in order to assess the involvement of peripheral hypoxia or hypercapnia in the pathogenesis of restless legs syndrome (RLS). METHODS: RLS severity was assessed with a standard questionnaire. Suggested immobilization tests were performed twice in 15 patients with RLS and 14 healthy controls. Patients with RLS participated in the tests with and without pramipexole medication. During the tests, peripheral oxygen and carbon dioxide partial pressures were measured noninvasively on the skin of the legs and the chest. RESULTS: During immobilization, the patients with RLS had lower partial pressure of oxygen in their legs (5.54 vs 7.19 kPa, p < 0.01) but not on the chest (8.75 vs 8.20 kPa, p = 0.355). More severe RLS correlated with high chest-to-foot oxygen gradient (rho = 0.692, p < 0.01). Carbon dioxide levels did not differ between the groups. Pramipexole corrected the peripheral hypoxia toward the levels observed in the controls (from 5.54 to 6.65 kPa, p < 0.05). CONCLUSIONS: Peripheral hypoxia is associated with the appearance of RLS symptoms. Strong correlation with RLS severity suggests a close pathophysiologic link between peripheral hypoxia and the symptoms of RLS. This is further supported by the simultaneous reversal of hypoxia and discomfort by dopaminergic treatment. PMID- 24789862 TI - Brain communication in a completely locked-in patient using bedside near-infrared spectroscopy. PMID- 24789863 TI - Effects of cannabis on cognition in patients with MS: a psychometric and MRI study. AB - OBJECTIVE: To determine functional and structural neuroimaging correlates of cognitive dysfunction associated with cannabis use in multiple sclerosis (MS). METHODS: In a cross-sectional study, 20 subjects with MS who smoked cannabis and 19 noncannabis users with MS, matched on demographic and neurologic variables, underwent fMRI while completing a test of working memory, the N-Back. Resting state fMRI and structural MRI data (lesion and normal-appearing brain tissue volumes, diffusion tensor imaging metrics) were also collected. Neuropsychological data pertaining to verbal (Selective Reminding Test Revised) and visual (10/36 Spatial Recall Test) memory, information processing speed (Paced Auditory Serial Addition Test [2- and 3-second versions] and Symbol Digit Modalities Test), and attention (Word List Generation) were obtained. RESULTS: The cannabis group performed more poorly on the more demanding of the Paced Auditory Serial Addition Test tasks (i.e., 2-second version) (p < 0.02) and the 10/36 Spatial Recall Test (p < 0.03). Cannabis users had more diffuse cerebral activation across all N-Back trials and made more errors on the 2-Back task (p < 0.006), during which they displayed increased activation relative to nonusers in parietal (p < 0.007) and anterior cingulate (p < 0.001) regions implicated in working memory. No group differences in resting-state networks or structural MRI variables were found. CONCLUSIONS: Patients with MS who smoke cannabis are more cognitively impaired than nonusers. Cannabis further compromises cerebral compensatory mechanisms, already faulty in MS. These imaging data boost the construct validity of the neuropsychological findings and act as a cautionary note to cannabis users and prescribers. PMID- 24789864 TI - Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. AB - OBJECTIVE: To clarify the phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathies. METHODS: We screened for TRPV4 mutations in 169 French unrelated patients with inherited axonal peripheral neuropathy. Ninety-five patients had dominant Charcot-Marie-Tooth type 2 (CMT2) disease, and 74 patients, including 39 patients with distal hereditary motor neuropathy, 14 with congenital spinal muscular atrophy and arthrogryposis, 13 with CMT2, and 8 with scapuloperoneal spinal muscular atrophy, presented with additional vocal cord paralysis and/or skeletal dysplasia. RESULTS: No deleterious TRPV4 mutation was identified in the 95 patients with "pure" CMT2 (0/95). In contrast, 12 of 74 patients (16%) with neuropathy and vocal cord paralysis and/or skeletal dysplasia presented pathogenic TRPV4 mutations, including 7 patients with distal hereditary motor neuropathy, 2 with scapuloperoneal spinal muscular atrophy, 2 with congenital spinal muscular atrophy and arthrogryposis, and one with CMT2. Investigation of affected relatives allowed us to study 17 patients. All patients had childhood-onset motor neuropathy and showed a variety of associated findings, including foot deformities (100% of cases), kyphoscoliosis (100%), elevated serum creatine kinase levels (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Eight missense mutations were observed in these 12 families, including 2 previously unreported. Six mutations were de novo events, and 2 asymptomatic carriers were identified. CONCLUSION: With 16% of patients affected in our series, this study demonstrates that TRPV4 mutations are a major cause of inherited axonal neuropathy associated with a large spectrum of additional features. PMID- 24789865 TI - Retinal architecture and mfERG: Optic nerve head component response characteristics in MS. AB - OBJECTIVE: To describe a novel neurophysiologic signature of the retinal ganglion cell and to elucidate its relationship to abnormalities in validated structural and functional measures of the visual system. METHODS: We used multifocal electroretinogram-generated optic nerve head component (ONHC) responses from normal subjects (n = 18), patients with multiple sclerosis (MS) (n = 18), and those with glaucoma (n = 3). We then characterized the relationship between ONHC response abnormalities and performance on low-contrast visual acuity, multifocal visual-evoked potential-induced cortical responses, and average and quadrant retinal nerve fiber layer (RNFL) thicknesses, as measured by spectral-domain optical coherence tomography. RESULTS: Compared with the eyes of normal subjects, the eyes of patients with MS exhibited an increased number of abnormal or absent ONHC responses (p < 0.0001). For every 7-letter reduction in low-contrast letter acuity, there were corresponding 4.6 abnormal ONHC responses at 2.5% contrast (p < 0.0001) and 6.6 abnormalities at the 1.25% contrast level (p < 0.0001). Regarding average RNFL thickness, for each 10-MUm thickness reduction, we correspondingly observed 6.8 abnormal ONHC responses (p = 0.0002). The most robust association was between RNFL thinning in the temporal quadrant and ONHC response abnormalities (p < 0.0001). CONCLUSION: Further characterization of ONHC abnormalities (those that are reversible and irreversible) may contribute to the development of novel neurotherapeutic strategies aimed at achieving neuroprotective, and perhaps even neurorestorative, effects in disorders that target the CNS in general, and MS in particular. PMID- 24789866 TI - Factors associated with optic nerve sheath diameter during exposure to hypobaric hypoxia. AB - OBJECTIVE: To monitor the changes in optic nerve sheath diameter (ONSD) induced by acute exposure to hypobaric hypoxia and to investigate factors associated with these changes, including development of acute mountain sickness. METHODS: In this cohort study, neurologic signs and symptoms, cardiovascular parameters, and ultrasonography of ONSD were prospectively assessed in 19 healthy lowlanders at baseline and after ascent to 3,830 m (3 hours, 9 hours, 24 hours, 48 hours, 72 hours, and 8 days) by blinded investigators. Potential confounding factors (e.g., altitude variations, physical effort) were minimized. A multivariate analysis of factors associated with ONSD was performed by means of generalized estimating equations. RESULTS: ONSD increased with exposure to altitude in all participants (p < 0.001). The increase between 9 and 24 hours was larger in patients who developed acute mountain sickness (p = 0.001). There was no influence of sex, oxygen saturation, or acclimatization on ONSD. CONCLUSION: Both physiologic and pathologic responses to hypobaric hypoxia were independently associated with changes in ONSD. Studies on a larger cohort, at a range of altitudes, and with baseline neuroimaging techniques are necessary to further understand the clinical significance of increased ONSD during exposure to hypobaric hypoxia. PMID- 24789867 TI - Influenza vaccination and cardiovascular risk in patients with recent TIA and stroke. AB - OBJECTIVES: To determine whether current influenza vaccination is associated with reduced risk of major vascular events in patients with recent ischemic stroke or TIA of mainly atherothrombotic origin. METHODS: Data were pooled from 2 prospective cohort studies, the OPTIC Registry (n = 3,635) and the AMISTAD Study (n = 618), and from the randomized PERFORM Trial (n = 19,120), all of which included patients with recent ischemic stroke or TIA. Influenza vaccination status was determined in 23,110 patients. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or vascular death up to 2 years. Secondary outcomes were myocardial infarction and stroke separately. RESULTS: Influenza vaccination had no association with the primary outcome in the propensity score-matched cohort (hazard ratio 0.97, 95% confidence interval [CI] 0.85-1.11; p = 0.67) or in the propensity score-adjusted cohort (hazard ratio 1.00, 95% CI 0.89-1.12; p = 0.99). Similarly, the risk of stroke and myocardial infarction did not differ between the vaccinated group and the unvaccinated group; in the matched cohort, the hazard ratio was 1.01 (95% CI 0.88-1.17; p = 0.89) for stroke and 0.84 (95% CI 0.59-1.18; p = 0.30) for myocardial infarction. CONCLUSIONS: Influenza vaccination was not associated with reduced outcome events in patients with recent atherothrombotic ischemic stroke after considering all baseline characteristics (including concomitant medications) associated with influenza vaccination. PMID- 24789868 TI - Locked in, but not out? PMID- 24789869 TI - Putting the legs back into restless legs syndrome: new evidence for the microvascular hypothesis. PMID- 24789870 TI - US state variation in autism insurance mandates: balancing access and fairness. AB - This article examines how nations split decision-making about health services between federal and sub-federal levels, creating variation between states or provinces. When is this variation ethically acceptable? We identify three sources of ethical acceptability-procedural fairness, value pluralism, and substantive fairness-and examine these sources with respect to a case study: the fact that only 30 out of 51 US states or territories passed mandates requiring private insurers to offer extensive coverage of autism behavioral therapies, creating variation for privately insured children living in different US states. Is this variation ethically acceptable? To address this question, we need to analyze whether mandates go to more or less needy states and whether the mandates reflect value pluralism between states regarding government's role in health care. Using time-series logistic regressions and data from National Survey of Children with Special Health Care Needs, Individual with Disabilities Education Act, legislature political composition, and American Board of Pediatrics workforce data, we find that the states in which mandates are passed are less needy than states in which mandates have not been passed, what we call a cumulative advantage outcome that increases between-state disparities rather than a compensatory outcome that decreases between-state disparities. Concluding, we discuss the implications of our analysis for broader discussions of variation in health services provision. PMID- 24789871 TI - What should autism research focus upon? Community views and priorities from the United Kingdom. AB - The rise in the measured prevalence of autism has been accompanied by much new research and research investment internationally. This study sought to establish whether the pattern of current UK autism research funding maps on to the concerns of the autism community. Interviews and focus groups were conducted with autistic adults, family members, practitioners and researchers to identify their priorities for research. We also captured the views of a large number of stakeholders via an online survey. There was a clear disparity between the United Kingdom's pattern of funding for autism research and the priorities articulated by the majority of participants. There was general consensus that future priorities for autism research should lie in those areas that make a difference to people's day-to-day lives. There needs to be greater involvement of the autism community both in priority setting and in research more broadly to ensure that resources reach where they are most needed and can make the most impact. PMID- 24789872 TI - MYC and mitochondrial biogenesis. AB - Mitochondria, the powerhouses of the cell, face two imperatives concerning biogenesis. The first is the requirement for dividing cells to replicate their mitochondrial content by growth of existing mitochondria. The second is the dynamic regulation of mitochondrial content in response to organismal and cellular cues (e.g., exercise, caloric restriction, energy status, temperature). MYC provides the clearest example of a programmed expansion of mitochondrial content linked to the cell cycle. As an oncogene, MYC also presents intriguing questions about the role of its mitochondrial targets in cancer-related phenotypes, such as the Warburg effect and MYC-dependent apoptosis. PMID- 24789873 TI - Long noncoding RNA: significance and potential in skin biology. AB - Over the past few years, advances in genome analyses have identified an emerging class of noncoding RNAs that play critical roles in the regulation of gene expression and epigenetic reprogramming. Given their transcriptional pervasiveness, the potential for these intriguing macromolecules to integrate a myriad of external cellular cues with nuclear responses has become increasingly apparent. Recent studies have implicated noncoding RNAs in epidermal development and keratinocyte differentiation, but the complexity of multilevel regulation of transcriptional programs involved in these processes remains ill defined. In this review, we discuss the relevance of noncoding RNA in normal skin development, their involvement in cutaneous malignancies, and their role in the regulation of adult stem-cell maintenance in stratified epithelial tissues. Furthermore, we provide additional examples highlighting the ubiquity of noncoding RNAs in diverse human diseases. PMID- 24789874 TI - Overview of the indications and contraindications for liver transplantation. AB - Liver transplantation is the only definitive treatment option for patients with irrevocable acute or chronic liver failure. In the last four decades, liver transplantation has developed from an experimental approach with a very high mortality to an almost routine procedure with good short- and long-term survival rates. Here, we present an up-to-date overview of the indications and contraindications for liver transplantation. It is shown how the evaluation of a candidate and finally listing for transplantation has to be performed in a multidisciplinary setting. Meticulous listing, timing, and organ allocation are the crucial factors to achieve an optimal outcome for the individual patient on the one hand, and reasonably using the limited deceased donor pool on the other hand. Living-donor liver transplantation is demanding but necessarily increasing. Because patients after liver transplantation need lifelong aftercare, it is important for primary care clinicians to understand the basic medical problems and risks. PMID- 24789876 TI - Melanocytes and their diseases. AB - Human melanocytes are distributed not only in the epidermis and in hair follicles but also in mucosa, cochlea (ear), iris (eye), and mesencephalon (brain) among other tissues. Melanocytes, which are derived from the neural crest, are unique in that they produce eu-/pheo-melanin pigments in unique membrane-bound organelles termed melanosomes, which can be divided into four stages depending on their degree of maturation. Pigmentation production is determined by three distinct elements: enzymes involved in melanin synthesis, proteins required for melanosome structure, and proteins required for their trafficking and distribution. Many genes are involved in regulating pigmentation at various levels, and mutations in many of them cause pigmentary disorders, which can be classified into three types: hyperpigmentation (including melasma), hypopigmentation (including oculocutaneous albinism [OCA]), and mixed hyper /hypopigmentation (including dyschromatosis symmetrica hereditaria). We briefly review vitiligo as a representative of an acquired hypopigmentation disorder. PMID- 24789877 TI - MYC regulation of cell growth through control of transcription by RNA polymerases I and III. AB - MYC's tumorigenic potential involves increased ribosome biogenesis and translational capacity, which supply the cell with protein required for enhanced cell growth and subsequent cell division. In addition to activation of protein encoding genes transcribed by RNA polymerase II, MYC must stimulate transcription by RNA polymerase I and RNA polymerase III to meet this synthetic demand. In the past decade our knowledge of the mechanisms and importance of MYC regulation of RNA polymerases I and III has flourished. Here we discuss MYC's influence on transcription by these "odd" RNA polymerases and the physiological impact of this regulation is evaluated with relevance to cancer development and treatment. PMID- 24789875 TI - Heart transplantation: challenges facing the field. AB - There has been significant progress in the field of heart transplantation over the last 45 years. The 1-yr survival rates following heart transplantation have improved from 30% in the 1970s to almost 90% in the 2000s. However, there has been little change in long-term outcomes. This is mainly due to chronic rejection, malignancy, and the detrimental side effects of chronic immunosuppression. In addition, over the last decade, new challenges have arisen such as increasingly complicated recipients and antibody-mediated rejection. Most, if not all, of these obstacles to long-term survival could be prevented or ameliorated by the induction of transplant tolerance wherein the recipient's immune system is persuaded not to mount a damaging immune response against donor antigens, thus eliminating the need for chronic immunosuppression. However, the heart, as opposed to other allografts like kidneys, appears to be a tolerance resistant organ. Understanding why organs like kidneys and livers are prone to tolerance induction, whereas others like hearts and lungs are tolerance resistant, could aid in our attempts to achieve long-term, immunosuppression-free survival in human heart transplant recipients. It could also advance the field of pig-to-human xenotransplantation, which, if successful, would eliminate the organ shortage problem. Of course, there are alternative futures to the field of heart transplantation that may include the application of total mechanical support, stem cells, or bioengineered whole organs. Which modality will be the first to reach the ultimate goal of achieving unlimited, long-term, circulatory support with minimal risk to longevity or lifestyle is unknown, but significant progress in being made in each of these areas. PMID- 24789878 TI - Antifungal drug development: challenges, unmet clinical needs, and new approaches. AB - Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges. PMID- 24789881 TI - Diabetes, aging, and their tissue complications. AB - The inactivation of NO by advanced glycation endproducts (AGEs), which accumulate on tissue proteins as a function of age and hyperglycemia, focused attention on the role of these ubiquitous posttranslational modifications in acquired impairments of vascular reactivity and other signaling processes. This observation occurred during a watershed period of basic and translational research in glycation that encompassed new pathologic phenomena and novel intervention strategies. How has the AGE paradigm for the tissue complications of aging and diabetes fared since the identification of the link between these glycation products and NO inactivation, and what lessons may be offered for future investigations? PMID- 24789879 TI - Uterine NK cells: active regulators at the maternal-fetal interface. AB - Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation. PMID- 24789884 TI - Commentaries on viewpoint: justifying small-n research in scientifically amazing settings: challenging the notion that only "big-n" studies are worthwhile. PMID- 24789880 TI - Emerging therapies for food allergy. AB - Food allergy is a common condition for which there are currently no approved treatments except avoidance of the allergenic food and treatment of accidental reactions. There are several potential treatments that are under active investigation in animal and human studies, but it is not yet clear what the best approach may be. Here, we review approaches that are currently in clinical trials, including oral, sublingual, and epicutaneous immunotherapy, immunotherapy combined with anti-IgE, and Chinese herbal medicine as well as approaches that are in preclinical or early clinical investigation, including modified protein immunotherapy, adjuvants, DNA vaccines, and helminth administration. We discuss the importance of fully exploring the risks and benefits of any treatment before it is taken to general clinical practice and the need for clarity about the goals of treatment. PMID- 24789885 TI - Last word on viewpoint: justifying small-n research in scientifically amazing settings: challenging the notion that only "big-n" studies are worthwhile. PMID- 24789886 TI - Discerning normobaric and hypobaric hypoxia: significance of exposure duration. PMID- 24789887 TI - Reply to Debevec and Millet. PMID- 24789888 TI - Link between numbers, pictures, and physiological tests. PMID- 24789889 TI - Reply to Verbanck and Paiva. PMID- 24789890 TI - Effects of resource variation during early life and adult social environment on contest outcomes in burying beetles: a context-dependent silver spoon strategy? AB - Good early nutritional conditions may confer a lasting fitness advantage over individuals suffering poor early conditions (a 'silver spoon' effect). Alternatively, if early conditions predict the likely adult environment, adaptive plastic responses might maximize individual performance when developmental and adult conditions match (environmental-matching effect). Here, we test for silver spoon and environmental-matching effects by manipulating the early nutritional environment of Nicrophorus vespilloides burying beetles. We manipulated nutrition during two specific early developmental windows: the larval environment and the post-eclosion environment. We then tested contest success in relation to variation in adult social environmental quality experienced (defined according to whether contest opponents were smaller (good environment) or larger (poor environment) than the focal individual). Variation in the larval environment influenced adult body size but not contest success per se for a given adult social environment experienced (an 'indirect' silver spoon effect). Variation in post-eclosion environment affected contest success dependent on the quality of the adult environment experienced (a context-dependent 'direct' silver spoon effect). By contrast, there was no evidence for environmental-matching. The results demonstrate the importance of social environmental context in determining how variation in nutrition in early life affects success as an adult. PMID- 24789891 TI - Bumblebees (Bombus terrestris) use social information as an indicator of safety in dangerous environments. AB - Avoiding predation is one of the most important challenges that an animal faces. Several anti-predation behaviours can be employed, yet simply using the presence of conspecifics can be a good signal of safety in an environment with potential predation hazards. Here, we show, for the first time, that past experience of predation causes bumblebees (Bombus terrestris) to aggregate with conspecifics, facilitating the identification of safe foraging patches. Bees were trained to differentiate between flowers that harboured predators and flowers that were predator free. When test subjects were subsequently presented solely with the previously predator-infested flower species, there was a significant preference to only land on flowers occupied by other feeding conspecifics. Yet, when safe flowers were made available to subjects previously entrained to discriminate safe from predator-occupied flowers, subjects ignored other bees and the social information potentially provided by them, demonstrating that attraction towards conspecifics is confined to dangerous situations. Our findings demonstrate a previously unknown social interaction in pollinators which may have important implications for plant-pollinator interactions. PMID- 24789892 TI - Glassfrog embryos hatch early after parental desertion. AB - Both parental care and hatching plasticity can improve embryo survival. Research has found that parents can alter hatching time owing to a direct effect of care on embryogenesis or via forms of care that cue the hatching process. Because parental care alters conditions critical for offspring development, hatching plasticity could allow embryos to exploit variation in parental behaviour. However, this interaction of parental care and hatching plasticity remains largely unexplored. We tested the hypothesis that embryos hatch early to cope with paternal abandonment in the glassfrog Hyalinobatrachium fleischmanni (Centrolenidae). We conducted male-removal experiments in a wild population, and examined embryos' response to conditions with and without fathers. Embryos hatched early when abandoned, but extended development in the egg stage when fathers continued care. Paternal care had no effect on developmental rate. Rather, hatching plasticity was due to embryos actively hatching at different developmental stages, probably in response to deteriorating conditions without fathers. Our experimental results are supported by a significant correlation between the natural timing of abandonment and hatching in an unmanipulated population. This study demonstrates that embryos can respond to conditions resulting from parental abandonment, and provides insights into how variation in care can affect selection on egg-stage adaptations. PMID- 24789894 TI - The relative importance of rapid evolution for plant-microbe interactions depends on ecological context. AB - Evolution can occur on ecological time-scales, affecting community and ecosystem processes. However, the importance of evolutionary change relative to ecological processes remains largely unknown. Here, we analyse data from a long-term experiment in which we allowed plant populations to evolve for three generations in dry or wet soils and used a reciprocal transplant to compare the ecological effect of drought and the effect of plant evolutionary responses to drought on soil microbial communities and nutrient availability. Plants that evolved under drought tended to support higher bacterial and fungal richness, and increased fungal : bacterial ratios in the soil. Overall, the magnitudes of ecological and evolutionary effects on microbial communities were similar; however, the strength and direction of these effects depended on the context in which they were measured. For example, plants that evolved in dry environments increased bacterial abundance in dry contemporary environments, but decreased bacterial abundance in wet contemporary environments. Our results suggest that interactions between recent evolutionary history and ecological context affect both the direction and magnitude of plant effects on soil microbes. Consequently, an eco evolutionary perspective is required to fully understand plant-microbe interactions. PMID- 24789893 TI - Nestling telomere shortening, but not telomere length, reflects developmental stress and predicts survival in wild birds. AB - Developmental stressors often have long-term fitness consequences, but linking offspring traits to fitness prospects has remained a challenge. Telomere length predicts mortality in adult birds, and may provide a link between developmental conditions and fitness prospects. Here, we examine the effects of manipulated brood size on growth, telomere dynamics and post-fledging survival in free-living jackdaws. Nestlings in enlarged broods achieved lower mass and lost 21% more telomere repeats relative to nestlings in reduced broods, showing that developmental stress accelerates telomere shortening. Adult telomere length was positively correlated with their telomere length as nestling (r = 0.83). Thus, an advantage of long telomeres in nestlings is carried through to adulthood. Nestling telomere shortening predicted post-fledging survival and recruitment independent of manipulation and fledgling mass. This effect was strong, with a threefold difference in recruitment probability over the telomere shortening range. By contrast, absolute telomere length was neither affected by brood size manipulation nor related to survival. We conclude that telomere loss, but not absolute telomere length, links developmental conditions to subsequent survival and suggest that telomere shortening may provide a key to unravelling the physiological causes of developmental effects on fitness. PMID- 24789895 TI - Limacina helicina shell dissolution as an indicator of declining habitat suitability owing to ocean acidification in the California Current Ecosystem. AB - Few studies to date have demonstrated widespread biological impacts of ocean acidification (OA) under conditions currently found in the natural environment. From a combined survey of physical and chemical water properties and biological sampling along the Washington-Oregon-California coast in August 2011, we show that large portions of the shelf waters are corrosive to pteropods in the natural environment. We show a strong positive correlation between the proportion of pteropod individuals with severe shell dissolution damage and the percentage of undersaturated water in the top 100 m with respect to aragonite. We found 53% of onshore individuals and 24% of offshore individuals on average to have severe dissolution damage. Relative to pre-industrial CO2 concentrations, the extent of undersaturated waters in the top 100 m of the water column has increased over sixfold along the California Current Ecosystem (CCE). We estimate that the incidence of severe pteropod shell dissolution owing to anthropogenic OA has doubled in near shore habitats since pre-industrial conditions across this region and is on track to triple by 2050. These results demonstrate that habitat suitability for pteropods in the coastal CCE is declining. The observed impacts represent a baseline for future observations towards understanding broader scale OA effects. PMID- 24789896 TI - How choosy should I be? The relative searching time predicts evolution of choosiness under direct sexual selection. AB - Most theoretical research in sexual selection has focused on indirect selection. However, empirical studies have not strongly supported indirect selection. A well established finding is that direct benefits and costs exert a strong influence on the evolution of mate choice. We present an analytical model in which unilateral mate choice evolves solely by direct sexual selection on choosiness. We show this is sufficient to generate the evolution of all possible levels of choosiness, because of the fundamental trade-off between mating rate and mating benefits. We further identify the relative searching time (RST, i.e. the proportion of lifetime devoted to searching for mates) as a predictor of the effect of any variable affecting the mating rate on the evolution of choosiness. We show that the RST: (i) allows one to make predictions about the evolution of choosiness across a wide variety of mating systems; (ii) encompasses all alternative variables proposed thus far to explain the evolution of choosiness by direct sexual selection; and (iii) can be empirically used to infer qualitative differences in choosiness. PMID- 24789897 TI - Social mixing patterns in rural and urban areas of southern China. AB - A dense population, global connectivity and frequent human-animal interaction give southern China an important role in the spread and emergence of infectious disease. However, patterns of person-to-person contact relevant to the spread of directly transmitted infections such as influenza remain poorly quantified in the region. We conducted a household-based survey of travel and contact patterns among urban and rural populations of Guangdong, China. We measured the character and distance from home of social encounters made by 1821 individuals. Most individuals reported 5-10 h of contact with around 10 individuals each day; however, both distributions have long tails. The distribution of distance from home at which contacts were made is similar: most were within a kilometre of the participant's home, while some occurred further than 500 km away. Compared with younger individuals, older individuals made fewer contacts which tended to be closer to home. There was strong assortativity in age-based contact rates. We found no difference between the total number or duration of contacts between urban and rural participants, but urban participants tended to make contacts closer to home. These results can improve mathematical models of infectious disease emergence, spread and control in southern China and throughout the region. PMID- 24789898 TI - Fitness consequences of environmental conditions at different life stages in a long-lived vertebrate. AB - The predictive adaptive response (PAR) hypothesis proposes that animals adjust their physiology and developmental trajectory during early life in anticipation of their future environments. Accordingly, when environmental conditions in early life match environmental conditions during adulthood, individual fitness should be greater. Here, we test this hypothesis in a long-lived mammal, the roe deer, using data from two contrasting populations, intensively monitored for more than 35 years. In the highly productive site, the fitness of female roe deer increased with the quality of environment during adulthood and, contrary to predictions of PAR, individuals born in good conditions always outperformed those born under poor conditions. In the resource-limited site, the fitness of female roe deer born in poor years was better than those born in good conditions in poor years when the animals were adult, but not in good years. Although consistent with predictions of PAR, we showed that this pattern is likely to be a consequence of increased viability selection during the juvenile stage for animals born in poor years. While PARs are often advanced in evolutionary medicine, our findings suggest that detailed biological processes should be investigated before drawing conclusions about the existence of this phenomenon. PMID- 24789900 TI - Low functional redundancy among mammalian browsers in regulating an encroaching shrub (Solanum campylacanthum) in African savannah. AB - Large herbivorous mammals play an important role in structuring African savannahs and are undergoing widespread population declines and local extinctions, with the largest species being the most vulnerable. The impact of these declines on key ecological processes hinges on the degree of functional redundancy within large herbivore assemblages, a subject that has received little study. We experimentally quantified the effects of three browser species (elephant, impala and dik-dik) on individual- and population-level attributes of Solanum campylacanthum (Solanum incanum sensu lato), an encroaching woody shrub, using semi-permeable exclosures that selectively removed different-sized herbivores. After nearly 5 years, shrub abundance was lowest where all browser species were present and increased with each successive species deletion. Different browsers ate the same plant species in different ways, thereby exerting distinct suites of direct and indirect effects on plant performance and density. Not all of these effects were negative: elephants and impala also dispersed viable seeds and indirectly reduced seed predation by rodents and insects. We integrated these diffuse positive effects with the direct negative effects of folivory using a simple population model, which reinforced the conclusion that different browsers have complementary net effects on plant populations, and further suggested that under some conditions, these net effects may even differ in direction. PMID- 24789899 TI - How (and why) the visual control of action differs from visual perception. AB - Vision not only provides us with detailed knowledge of the world beyond our bodies, but it also guides our actions with respect to objects and events in that world. The computations required for vision-for-perception are quite different from those required for vision-for-action. The former uses relational metrics and scene-based frames of reference while the latter uses absolute metrics and effector-based frames of reference. These competing demands on vision have shaped the organization of the visual pathways in the primate brain, particularly within the visual areas of the cerebral cortex. The ventral 'perceptual' stream, projecting from early visual areas to inferior temporal cortex, helps to construct the rich and detailed visual representations of the world that allow us to identify objects and events, attach meaning and significance to them and establish their causal relations. By contrast, the dorsal 'action' stream, projecting from early visual areas to the posterior parietal cortex, plays a critical role in the real-time control of action, transforming information about the location and disposition of goal objects into the coordinate frames of the effectors being used to perform the action. The idea of two visual systems in a single brain might seem initially counterintuitive. Our visual experience of the world is so compelling that it is hard to believe that some other quite independent visual signal-one that we are unaware of-is guiding our movements. But evidence from a broad range of studies from neuropsychology to neuroimaging has shown that the visual signals that give us our experience of objects and events in the world are not the same ones that control our actions. PMID- 24789901 TI - Epigenetic inheritance and genome regulation: is DNA methylation linked to ploidy in haplodiploid insects? AB - Organisms show great variation in ploidy level. For example, chromosome copy number varies among cells, individuals and species. One particularly widespread example of ploidy variation is found in haplodiploid taxa, wherein males are typically haploid and females are typically diploid. Despite the prevalence of haplodiploidy, the regulatory consequences of having separate haploid and diploid genomes are poorly understood. In particular, it remains unknown whether epigenetic mechanisms contribute to regulatory compensation for genome dosage. To gain greater insights into the importance of epigenetic information to ploidy compensation, we examined DNA methylation differences among diploid queen, diploid worker, haploid male and diploid male Solenopsis invicta fire ants. Surprisingly, we found that morphologically dissimilar diploid males, queens and workers were more similar to one another in terms of DNA methylation than were morphologically similar haploid and diploid males. Moreover, methylation level was positively associated with gene expression for genes that were differentially methylated in haploid and diploid castes. These data demonstrate that intragenic DNA methylation levels differ among individuals of distinct ploidy and are positively associated with levels of gene expression. Thus, these results suggest that epigenetic information may be linked to ploidy compensation in haplodiploid insects. Overall, this study suggests that epigenetic mechanisms may be important to maintaining appropriate patterns of gene regulation in biological systems that differ in genome copy number. PMID- 24789902 TI - Short-term variation in sperm competition causes sperm-mediated epigenetic effects on early offspring performance in the zebrafish. AB - The inheritance of non-genetic factors is increasingly seen to play a major role in ecology and evolution. While the causes and consequences of epigenetic effects transmitted from the mother to the offspring have received ample attention, much less is known about how variation in the condition of the father affects the offspring. Here, we manipulated the intensity of sperm competition experienced by male zebrafish Danio rerio to investigate the potential for sperm-mediated epigenetic effects over a relatively short period of time. We found that the rapid responses of males to varying intensity of sperm competition not only affected sperm traits as shown previously, but also the performance of the resulting offspring. We observed that males exposed to high intensity of sperm competition produced faster swimming and more motile sperm, and sired offspring that hatched over a narrower time frame but exhibited a lower survival rate than males exposed to low intensity of sperm competition. Our results provide striking evidence for short-term paternal effects and the possible fitness consequences of such sperm-mediated non-genetic factors not only for the resulting offspring but also for the female. PMID- 24789903 TI - Diet quality in a wild grazer declines under the threat of an ambush predator. AB - Predators influence prey populations not only through predation itself, but also indirectly through prompting changes in prey behaviour. The behavioural adjustments of prey to predation risk may carry nutritional costs, but this has seldom been studied in the wild in large mammals. Here, we studied the effects of an ambush predator, the African lion (Panthera leo), on the diet quality of plains zebras (Equus quagga) in Hwange National Park, Zimbabwe. We combined information on movements of both prey and predators, using GPS data, and measurements of faecal crude protein, an index of diet quality in the prey. Zebras which had been in close proximity to lions had a lower quality diet, showing that adjustments in behaviour when lions are within short distance carry nutritional costs. The ultimate fitness cost will depend on the frequency of predator-prey encounters and on whether bottom-up or top-down forces are more important in the prey population. Our finding is the first attempt to our knowledge to assess nutritionally mediated risk effects in a large mammalian prey species under the threat of an ambush predator, and brings support to the hypothesis that the behavioural effects of predation induce important risk effects on prey populations. PMID- 24789904 TI - Trans-generational immune priming in honeybees. AB - Maternal immune experience acquired during pathogen exposure and passed on to progeny to enhance resistance to infection is called trans-generational immune priming (TgIP). In eusocial insects like honeybees, TgIP would result in a significant improvement of health at individual and colony level. Demonstrated in invertebrates other than honeybees, TgIP has not yet been fully elucidated in terms of intensity and molecular mechanisms underlying this response. Here, we immune-stimulated honeybee queens with Paenibacillus larvae (Pl), a spore-forming bacterium causing American Foulbrood, the most deadly bee brood disease worldwide. Subsequently, offspring of stimulated queens were exposed to spores of Pl and mortality rates were measured to evaluate maternal transfer of immunity. Our data substantiate the existence of TgIP effects in honeybees by direct evaluation of offspring resistance to bacterial infection. A further aspect of this study was to investigate a potential correlation between immune priming responses and prohaemocytes-haemocyte differentiation processes in larvae. The results point out that a priming effect triggers differentiation of prohaemocytes to haemocytes. However, the mechanisms underlying TgIP responses are still elusive and require future investigation. PMID- 24789905 TI - Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy. AB - Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin 1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies. PMID- 24789906 TI - Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. AB - The hypoxia-inducible transcription factors HIF-1 and HIF-2 mediate key cellular adaptions to hypoxia and contribute to renal homeostasis and pathophysiology; however, little is known about the cell type-specific functions of HIF-1 and HIF 2 in response to ischemic kidney injury. Here, we used a genetic approach to specifically dissect the roles of endothelial HIF-1 and HIF-2 in murine models of hypoxic kidney injury induced by ischemia reperfusion or ureteral obstruction. In both models, inactivation of endothelial HIF increased injury-associated renal inflammation and fibrosis. Specifically, inactivation of endothelial HIF-2alpha, but not endothelial HIF-1alpha, resulted in increased expression of renal injury markers and inflammatory cell infiltration in the postischemic kidney, which was reversed by blockade of vascular cell adhesion molecule-1 (VCAM1) and very late antigen-4 (VLA4) using monoclonal antibodies. In contrast, pharmacologic or genetic activation of HIF via HIF prolyl-hydroxylase inhibition protected wild type animals from ischemic kidney injury and inflammation; however, these same protective effects were not observed in HIF prolyl-hydroxylase inhibitor-treated animals lacking endothelial HIF-2. Taken together, our data indicate that endothelial HIF-2 protects from hypoxia-induced renal damage and represents a potential therapeutic target for renoprotection and prevention of fibrosis following acute ischemic injury. PMID- 24789907 TI - MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection. AB - In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8+CD45RClo regulatory T cells (CD8+CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II derived peptide (Du51) that is recognized by TCR-biased CD8+CD40Ig Tregs and activating CD8+CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.Aa/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.Aa/Du51-specific CD8+CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vbeta11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8+CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function. PMID- 24789908 TI - MicroRNA-7a regulates pancreatic beta cell function. AB - Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic beta cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of beta cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in beta cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates beta cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in beta cells developed diabetes due to impaired insulin secretion and beta cell dedifferentiation. Interestingly, perturbation of miR-7a expression in beta cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine beta cell mass. Furthermore, we found that miR-7a levels are decreased in obese/diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated beta cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic beta cells and support a role for miR-7 in the adaptation of pancreatic beta cell function in obesity and type 2 diabetes. PMID- 24789909 TI - Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density. AB - Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network-based approach to determine how Bicc1 influences BMD. Based on this analysis, we inferred that Bicc1 was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency-dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Bicc1 as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels. PMID- 24789912 TI - Medicinal Plants in Light of History: Recognized Therapeutic Modality. AB - Medicinal plants have an unbelievable history in terms of serving humanity in almost all continents of the world. Traditional healers have transferred that incredible knowledge from generation to generation. Even modernity or cultural revolutions have not altered the in-depth wisdom of this natural medical paradigm. Pharmacological rationale in light of traditional uses followed by phytochemical studies could surely bring a new revolution in the treatment of diseases. PMID- 24789911 TI - ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. AB - Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs. PMID- 24789910 TI - MicroRNA-486-dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy-associated symptoms. AB - Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which results in dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmdmdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmdmdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR 486 overexpression in Dmdmdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle. PMID- 24789913 TI - Animal-Assisted Activity: Effects of a Complementary Intervention Program on Psychological and Physiological Variables. AB - Animal-assisted activity is the use of trained animals for the therapeutic, motivational, or educational benefit of patients. Subjects of this study were 218 patients hospitalized on the mental health unit of a community hospital with an existing, complementary animal-assisted activity program. Half of the patients participated in a 1-hour session of animal-assisted activity. The other half, who served as a comparison group, participated in a 1-hour stress management program. It was hypothesized that an animal-assisted activity program would improve ratings of depression, anxiety, and pain and the associated physiological measures of stress and discomfort. Self-report ratings of depression, anxiety, and pain were collected before and after treatment sessions, and blood pressure, pulse, and salivary cortisol were measured. There were significant decreases in depression (P < .0001), anxiety (P < .0001), pain (P < .0001), and pulse (P < .04) after animal-assisted activity program, comparable to those in the more traditional stress management group. PMID- 24789915 TI - Survey of residential power-frequency magnetic fields in Melbourne, Australia. AB - Pooled analyses of epidemiological studies have reported an association between prolonged residential exposure to power-frequency magnetic fields of >0.4 MUT and an increased risk in childhood leukaemia. In order to compare residential magnetic fields in Australia with those in other countries, a survey was conducted in 296 randomly selected homes in Melbourne. Magnetic fields were assessed by performing spot measurements throughout the house and 24-h measurements in rooms where children spend large amounts of time. Children's exposure in Australia was generally comparable with that in other countries with average fields of 0.05-0.06 MUT (95 % CI 0.05-0.06 MUT). Prolonged exposure of >0.4 MUT was shown in ~2 % of the homes (95 % CI 0.2-3.6 %) mainly being due to close proximity of the house to transmission lines. Based on the results of this survey, the public health impact of a causal association between residential magnetic fields and childhood leukaemia is expected to be small. PMID- 24789916 TI - Assessment of bias in a survey of residential magnetic fields in Melbourne, Australia. AB - An important consideration in surveys of residential magnetic fields is whether the sample of homes measured is representative of the population. This study assessed the potential bias in a survey of magnetic fields conducted in 296 homes randomly selected from the telephone directory in Melbourne. The choice of the telephone directory as the sampling frame introduced some bias when compared with census information. There was also evident self-selection bias with residents twice as likely to participate if they lived in the vicinity of visible electrical infrastructure such as transmission lines. However, when corrected for bias the corrected magnetic fields were only slightly lower than the measurements with a percentage difference in the range of 2.8-6.0 %. These results provide confidence that the measurements in the survey were good estimates of the distribution of residential magnetic fields in Melbourne. PMID- 24789914 TI - Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. AB - Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-gamma-producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8- cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-alpha production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8- splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN-inducing pathogens. PMID- 24789917 TI - Circadian secretion of the intestinal hormone GLP-1 by the rodent L cell. AB - Peripheral clocks are known to modulate circadian patterns of insulin secretion. GLP-1 is an incretin hormone produced by the intestinal L cell that acts as a link between the gut and pancreatic beta-cell. Herein, we demonstrate the existence of a diurnal rhythm in GLP-1 secretory responses to an oral glucose load in rats, with increased release immediately preceding the normal feeding period. This profile of GLP-1 release correlated with the pattern in insulin secretion, and both rhythms were completely inverted in animals subjected to a 12 h feeding cycle disruption and abolished in rats maintained under constant light conditions. A daily variation in the insulin response to exogenous GLP-1 was also found. Consistent with these in vivo findings, we demonstrated a circadian pattern in the GLP-1 secretory response to different secretagogues in murine GLUTag L cells, as well as in the mRNA levels of several canonical clock genes. Furthermore, significant changes in the expression of several genes were demonstrated by microarray and knockdown of two of them, thyrotroph embryonic factor and protein tyrosine phosphatase 4a1, resulted in altered GLP-1 secretion. Collectively, these results indicate that an independent peripheral clock in the L cell drives a circadian rhythm in GLP-1 secretory responses. PMID- 24789918 TI - Lysosomal stress in obese adipose tissue macrophages contributes to MITF dependent Gpnmb induction. AB - In obesity, adipose tissue (AT) contains crown-like structures where macrophages surround nonviable adipocytes. To understand how AT macrophages (ATMs) contribute to development of insulin resistance, we examined their character in more detail. In silico analysis of F2 mouse populations revealed significant correlation between adipose glycoprotein nonmetastatic melanoma protein B (Gpnmb) expression and body weight. In obese mice and obese individuals, Gpnmb expression was induced in ATMs. Cultured RAW264.7 cells were used to obtain insight into the mechanism of Gpnmb regulation. Gpnmb was potently induced by lysosomal stress inducers, including palmitate and chloroquine, or Torin1, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1). These stimuli also provoked microphthalmia transcription factor (MITF) translocation to the nucleus, and knockdown of MITF by short hairpin RNA indicated its absolute requirement for Gpnmb induction. In agreement with our in vitro data, reduced mTORC1 activity was observed in isolated ATMs from obese mice, which coincided with increased nuclear MITF localization and Gpnmb transcription. Aberrant nutrient sensing provokes lysosomal stress, resulting in attenuated mTORC1 activity and enhanced MITF dependent Gpnmb induction. Our data identify Gpnmb as a novel marker for obesity induced ATM infiltration and potentiator of interleukin-4 responses and point toward a crucial role for MITF in driving part of the ATM phenotype. PMID- 24789919 TI - Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. AB - The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1alpha and PPARalpha pathways but requires active PPARgamma signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications as a result of lactate transport through monocarboxylate transporters. Further, the ketone body beta hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance. PMID- 24789920 TI - Cdkn2a/p16Ink4a regulates fasting-induced hepatic gluconeogenesis through the PKA CREB-PGC1alpha pathway. AB - Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome-wide association studies have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16(Ink4a), which have not yet been implicated in the control of hepatic glucose homeostasis. Here, we show that p16(Ink4a) deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16(Ink4a) downregulation leads to an activation of PKA-CREB PGC1alpha signaling through increased phosphorylation of PKA regulatory subunits. Taken together, these results provide evidence that p16(Ink4a) controls fasting glucose homeostasis and could as such be involved in T2D development. PMID- 24789921 TI - HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. AB - Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4 hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2-deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipocytes, and less adipose tissue inflammation than their littermates. They also had improved glucose tolerance and insulin sensitivity. Furthermore, the mRNA levels of the HIF-1 targets glucose transporters, glycolytic enzymes, and pyruvate dehydrogenase kinase-1 were increased in their tissues, whereas acetyl-CoA concentration was decreased. The hepatic mRNA level of the HIF-2 target insulin receptor substrate-2 was higher, whereas that of two key enzymes of fatty acid synthesis was lower. Serum cholesterol levels and de novo lipid synthesis were decreased, and the mice were protected against hepatic steatosis. Oral administration of an HIF-P4H inhibitor, FG-4497, to wild-type mice with metabolic dysfunction phenocopied these beneficial effects. HIF-P4H-2 inhibition may be a novel therapy that not only protects against the development of obesity and its consequences but also reverses these conditions. PMID- 24789922 TI - Development of highly stable nifedipine solid-lipid nanoparticles. AB - To improve the solubility of the drug nifedipine (NI), highly stabilized solid lipid nanoparticles (SLNs) of nifedipine (NI-SLNs) were prepared by high pressure homogenization using two phospholipids, followed by lyophilization with individual sugar moieties (four monosaccharides and four disaccharides). The mean particle diameter, polydispersity index (PDI), zeta potential, drug loading, and the encapsulation efficiency of the NI-SLN suspension were determined to be 68.5 nm, 0.3, -62.1 mV, 2.7%, and 97.5%, respectively. In comparison with the NI-SLNs, the NI-SLNs lyophilized with trehalose (NI-SLN-Tre) showed a slight increase in the particle size from 68.5 to 107.7 nm, but the PDI decreased from 0.38 to 0.33, and no significant change in zeta potential was observed. Aqueous re dispersibility study demonstrated that NI-SLNs lyophilized with trehalose had the maximum concentration (14.7 ug/mL) at 5 min, compared with lyophilized SLNs using other sugars; the use of other sugars also resulted in significant changes in the particle size, PDI, and zeta potential. A trehalose concentration of 2.5% w/v and a two-fold dilution of the SLN suspension were found to be the best conditions for lyophilization. Data from lyophilized SLNs using differential scanning calorimetry, powder X-ray diffraction, Fourier-transform infrared spectroscopy, and scanning electron microscopy indicated eventual transformation of NI-SLN-Tre from a crystalline to an amorphous state during the homogenization process. Finally, a stability study was performed with NI-SLN-Tre for up to 6 months at 30 degrees C and 65% relative humidity, with no significant deterioration observed, suggesting that trehalose might be a useful cryoprotectant for NI-SLNs. PMID- 24789923 TI - Formulation design for orally disintegrating tablets containing enteric-coated particles. AB - The purpose of this study was to investigate the applicability of our newly developed technology (RACTAB(r) technology) for preparing orally disintegrating tablets (ODTs) containing enteric-coated particles. Tamsulosin hydrochloride (TAM) was used as a model drug contained in the enteric-coated particles. Enteric coated particles containing TAM (ECP-T) were prepared by spray coating a mixture of TAM with controlled-release materials. ECP-T was then mixed with rapidly disintegrating granules (RDGs), which were prepared using the suspension spray coating method, and was tableted to form ODTs (ODTRAC). ODTRAC was evaluated for its hardness, thickness, internal structure (X-ray-CT scanning), functional properties (controlled-release profile), and in vivo disintegration time. Since RDGs with micronized ethylcellulose (MEC) increased tablet hardness by increasing the contact frequency between granules, ODTRAC containing ECP-T exhibited high hardness (>50 N) and low friability (<0.5%) with a relatively low compression force. After tableting, the structure of ECP-T in ODTRAC remained intact and no damage was observed on the surface. ECP-T recovered from ODTRAC showed the same dissolution profile of TAM in Japanese Pharmacopoeia (JP) 1st and JP 2nd media as that of intact ECP-T, which indicated that the tableting process did not affect the acid-resistibility of the particle. In addition, ODTRAC rapidly disintegrated in vivo (< 30 s), even at a high compression force (at 9 kN). These findings clearly suggest that RACTAB(r) technology is a useful approach to prepare ODTs containing enteric-coated particles. PMID- 24789924 TI - Fabrication of solid collagen nanoparticles using electrospray deposition. AB - Collagen is a promising biomaterial for drug delivery due to advantages including high biocompatibility and biodegradable property. However, transforming collagen into solid nanoparticles is difficult, although the solid dosage form is advantageous for some administration routes including pulmonary and oral drug delivery. In this study, collagen solid nanoparticles are prepared in one-step using electrospray deposition under ambient temperature and pressure conditions. Although collagen molecules formed micron-sized aggregates in acetic acid solutions spontaneously, electrospraying the collagen solutions resulted in formation of nanofibers. Solid nanoparticles were obtained by increasing conductivity of the solution and/or inducing structural perturbation of the collagen molecules using salts. The ability of solid collagen particles as a drug carrier was demonstrated by incorporating theophylline as a model drug using a coaxial spray technique. Release of theophylline was controlled by cross-linking collagen molecules. Electrospray deposition was proved to be a powerful method for producing solid collagen nanoparticles for drug delivery. PMID- 24789925 TI - Synthesis of new 5-substituted hydantoins and symmetrical twin-drug type hydantoin derivatives. AB - In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transformation of 5-methylene hydantoins 4a-c to 5 aminomethyl-substituted hydantoins 5-10 or to 5-amino-5-methyl-disubstituted hydantoins 11-14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives 19-24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosaminoglycans are also described. PMID- 24789926 TI - Synthesis and antimicrobial evaluation of some new 1,2-bis-(2-(N-arylimino)-1,3 thiazolidin-3-yl)ethane derivatives. AB - N,N'-Diarylethylene-bis-thiourea derivatives 1 and 8 were synthesized and their reactions with hydrazonoyl chlorides yielded the corresponding bis-(2-(N arylimino)-1,3-thiazolidine derivatives 5a-d and 11a-c. The reaction of compound 1 with several alpha-haloketones afforded the bis-(5-methyl-2-(N-phenylimino)-1,3 thiazolidine derivatives 15a-c and 19a, b. The newly synthesized compounds were tested for their antimicrobial activity against four fungi, two Gram-positive and two Gram-negative bacteria and showed high antibacterial and antifungal activities against all the test microorganisms except Pseudomonas aeruginosa and Candida albicans. Compounds 5b, 15b and 19a exhibited the highest activities against the test microorganisms. The MIC evaluation showed that compound 15b has higher activity than Amphotericin B and Ampicillin against all tested fungi and Gram-positive bacteria (Staphylococcus pneumonia) and showed similar activity like Ampicillin against Gram-negative bacteria (Escherichia coli). PMID- 24789927 TI - Molecular modelling and synthesis of quinazoline-based compounds as potential antiproliferative agents. AB - In this study, four series of 4-anilinoquinazoline derivatives were designed and synthesized as potential anti-proliferative agents. Mechanism of anticancer activity was explained through molecular docking of the target compounds into epidermal growth factor receptor tyrosine kinase (EGFR-TK) active site which displayed comparable binding mode of certain compounds to that of lapatinib. Moreover, the newly synthesized compounds were tested for their anti proliferative activity on breast carcinoma cell line (MCF-7). 6-(4 Benzylpiperazin-1-ylsulfonyl)-4-(4-bromoanilino)quinazoline (14g) exhibited the most potent inhibitory activity (IC50=5.52 uM). PMID- 24789928 TI - Poligapolide, a PI3K/Akt inhibitor in immunodeficiency virus type 1 TAT transduced CHME5 cells, isolated from the rhizome of Polygala tenuifolia. AB - The rhizome of Polygala tenuifolia WILLD (PT, family Polygalaceae) has been used in traditional Chinese medicine for inflammation, dementia, amnesia, neurasthenia and cancer. The phosphoinositide 3-kinase (PI3K)/Akt inhibitor(s) was isolated from PT by using the cytoprotective phenotype of human immunodeficiency virus type 1 (HIV-1) Tat-transduced CHME5 cells against lipopolysaccharide/cycloheximide. We isolated 9 constituents (1)-(9) from ethyl acetate fraction of PT, which potently showed anti-cytoprotective effect against HIV-1 TAT-transduced cells. Of them, (9R)-(-)-9-peptandecanolide (2), a new compound named poligapolide, most potently abolished the cytoprotective effect of HIV-1 Tat-transduced CHME5 cells. The compound (2) inhibited the phosphorylation of Akt and its downstream molecule, glycogen synthase kinase-3 beta (GSK3beta) in PI3K/Akt cell survival signaling pathway, but did not suppress the phosphorylation of PI3K and pyruvate dehydrogenase lipoamide kinase isozyme 1. Based on these finding, poligapolide may abolish the cytoprotective phenotype of HIV-1 Tat-transduced CHME5 cells by inhibiting Akt phosphorylation in PI3K/Akt pathway. PMID- 24789929 TI - Teucvisins A-E, five new neo-clerodane diterpenes from Teucrium viscidum. AB - Two new neo-clerodane diterpenoids, teucvisins A and B (1, 2), and three new 19 nor-neoclerodane diterpenoids, teucvisins C-E (3-5), together with ten known constituents (6-15) were isolated from the whole plants of Teucrium viscidum. All the isolates were evaluated for their inhibitory activities of lipopolysaccharide (LPS)-induced nitric oxide production in RAW264.7 macrophages. The results indicated that compounds 11 and 15 showed moderate inhibition with an IC50 value of 21.9 and 22.4 uM, respectively. PMID- 24789930 TI - Acyclic sulfides, garlicnins L-1-L-4, E, and F, from Allium sativum. AB - Six novel acyclic sulfides, named garlicnins L-1-L-4 (1-4), E (5), and F (6), were isolated from the acetone extracts, with the ability to suppress M2 macrophage activation, of the bulbs of garlic (Allium sativum L.), and their chemical structures were characterized. PMID- 24789931 TI - Conversion of tomato saponins to pregnane derivatives. AB - Here reports new conversions methods of tomato saponins, esculeoside A (1) and a mixture of esculeosides B-1 (2) and B-2 (3), (the latter two were obtained from tomato cans) into pregnane derivative (5) by an alkal treatment followed by acid treatment. Compound 1 or a mixture of 2 and 3 were each refluxed with 1 N KOH to afford a characteristic pyridine steroidal glycoside (4), which was then treated with 2 N HCl-MeOH to afford a pregnane derivative, 3beta-hydroxy-5alpha-pregn-16 en-20-one (5). The results of the above two reactions indicated that tomato saponins are chemically closely related to pregnane hormones. We assume that the assimilated tomato saponins via the small intestine are metabolized into pregnane derivatives, demonstrating various bioactivities such as anti-cancer, anti osteoporosis, and anti-menopausal disorder activities. PMID- 24789932 TI - Evaluation of degree of blending colored diluents using color difference signal method. AB - We developed a color difference signal method to evaluate the degree of blending powdered medicines in pharmacies. In the method, the degree of blending is expressed as the relative standard deviation of the color difference signal value (Cb or Cr) of the YCbCr color space after digital photos of the blended medicines are analyzed by image processing. While the method is effective to determine the degree of blending colored medicines, it remains unknown whether it can be applied to uncolored or white-colored medicines. To investigate this, we examined colored diluents to identify an indicator of the degree mixtures are blended. In this study, we applied this method to Pontal(r) and Prednisolone(r) powders, which were used as uncolored and white-colored medicines, respectively. Each of these medicines was blended with the colored lactose using a pestle and mortar, and then the uniformity of blending was evaluated. The degree of blending was well-monitored in both mixtures with various blending ratios (1 : 9-9 : 1), showing a sufficient uniformity at 60 rotations of the pestle. Moreover, the Cr values of the mixtures with various blending ratios were correlated with the concentration of active pharmaceutical ingredients in these medicines, which was determined using HPLC. This indicated the usefulness of the color difference signal method for the quantitative determination of medicines. Thus, we demonstrated the applicability and effectiveness of this method to check dispensing powders. PMID- 24789933 TI - Mechanism of peroxisome proliferator-activated receptor gamma (PPARgamma) transactivation by hesperetin glucuronides is distinct from that by a thiazolidine-2,4-dione agent. AB - Hesperidin, a flavanone glycoside present abundantly in citrus fruits, is predominantly metabolized to hesperetin-7-O-beta-D-glucuronide (H7-OG) and hesperetin-3'-O-beta-D-glucuronide (H3'-OG), which exhibit partial agonistic activity towards peroxisome proliferator-activated receptor gamma (PPARgamma). Here, in order to understand the mechanism(s) of action of PPARgamma transactivation elicited by hesperetin glucuronides, we compared the transactivation activities of PPARgamma (ligand-binding domain (LBD)) mutants by hesperetin glucuronides and troglitazone, a thiazolidine-2,4-dione class PPARgamma full agonist. The assay results indicated that the mechanisms of activation of PPARgamma by hesperetin glucuronides and by troglitazone are distinct, probably due to a difference in the binding sites of these compounds on the PPARgamma LBD. Flavanone-class PPARgamma partial agonists, luteolin and hesperetin glucuronides, showed similar activation profiles of the PPARgamma LBD mutants, even though they have different side chain functionalities. PMID- 24789934 TI - Aphanamixins A-F, acyclic diterpenoids from the stem bark of Aphanamixis polystachya. AB - Six new acyclic diterpenoids named Aphanamixins A-F (1-6), together with two known compounds of nemoralisin and nemoralisin C, were isolated from the stem bark of Aphanamixis polystachya (WALL) J. N. BARKER. Their structures were established through a comprehensive analysis of NMR spectroscopic data and high resolution mass spectrometric data. The absolute configurations of carbon stereocenters were determined by means of auxiliary chiral alpha-methoxy-alpha (trifluoromethyl)phenylacetic acid (MTPA) derivatives and circular dichroism (CD), respectively. All the new isolates were tested for their antiproliferative activity against HepG2, AGS, MCF-7, and A-549 cancer cell lines and they exhibited weak cytotoxicities (IC50>10 uM). Moreover, we highlighted that the six new diterpenoids characterized by acyclic skeleton was rarely seen in nature. PMID- 24789935 TI - Bromopyrrole alkaloids from a marine sponge Agelas sp. AB - Five new bromopyrrole alkaloids, 2-bromokeramadine (1), 2-bromo-9,10 dihydrokeramadine (2), tauroacidins C (3) and D (4), and mukanadin G (5), were isolated from an Okinawan marine sponge Agelas sp. The structures of 1-5 were elucidated on the basis of spectroscopic data and conformational analysis. Mukanadin G (5) has a tricyclic skeleton consisting of a fused tetrahydrobenzaminoimidazole and 2,5-dioxopyrrolidine moieties. Antimicrobial activities of 1-3, and 5 as well as three related known bromopyrrole alkaloids, keramadine (6), tauroacidin A (7), and taurodispacamide A (8) were evaluated. PMID- 24789936 TI - Evolution of "the guideline advantage": lessons learned from the front lines of outpatient performance measurement. PMID- 24789937 TI - Exploring post-fall audit report data in an acute care setting. AB - This retrospective, descriptive, chart review study was done to demonstrate one strategy for communicating aggregated and actionable fall data to bedside nurses. It was conducted at a nonprofit acute care hospital in the northwestern United States to analyze the quantitative data captured in post-fall audit reports of patient falls (March 1-December 31, 2012, N = 107 falls). Descriptive and binary statistical analyses were used. The quarterly National Database of Nursing Quality Indicators 2011 and 2012 reports showed that implementation of post-fall audit reports can lead to a lower overall fall rate and a lower fall-injury rate. Increased nursing hours could be a confounding factor of the positive impact of conducting post-fall audits in this study. It is concluded that timely and systematic reporting, analysis, and interpretation of fall data in an electronic format can facilitate prevention of falls and fall injuries. PMID- 24789938 TI - Management of type 2 diabetes in Asian Indians: a review of the literature. AB - Type 2 diabetes mellitus (T2DM) is increasing in Asian Indians globally. In this article, we review published studies of interventions designed to prevent T2DM or improve self-management in South Asian Indians. A PubMed, CINAHL, Medline, EMBASE, Psycinfo, Family & Society Studies Worldwide, Web of Science, and Consumer Health Complete search was conducted using the following search terms: type 2 diabetes mellitus, Asian Indian continental ancestry group, therapy, treatment, management, care, intervention, self-care, exercise, diet, and lifestyle. The review included pilot or full intervention studies examining the prevention and/or management of T2DM and qualitative studies analyzing the influence of various ethnic factors on the prevention and management of T2DM. Seventeen studies met the inclusion criteria. They examined the influence of culture and religion and the effectiveness of individual and community-based education and lifestyle improvement programs, exercise, and complementary therapies. Few programs led to the improved long-term management of T2DM. Further research is needed to develop ethnic-specific interventions. PMID- 24789939 TI - Predictors of serious fall injury in hospitalized patients. AB - The purpose of this study was to identify predictors of falls that result in serious injury in hospitalized patients. The study involved secondary data analysis of 1,438 patient falls in a community hospital system between 2008 and 2010. The analysis included demographics, severity of illness, diagnosis-related group (surgical vs. medical), event type (bathroom, bed, chair, transfer, ambulating), risk factors identified by the Hendrich II fall risk assessment prior to the fall (confusion, depression, altered elimination, dizziness, antiepileptic or benzodiazepine medications), and contributing factors identified through an online event reporting system post-fall (incontinence, confusion, history of falls, alteration in mobility, and medication-related). Logistic regression results indicated that the overall model was a good fit and two predictors, age greater than 64 and male gender, were statistically reliable in predicting which patient falls would result in serious injury. PMID- 24789940 TI - Reducing the modifiable risks of cardiovascular disease in Turkish patients with type 2 diabetes: the effectiveness of training. AB - Our goal was to reduce the number of modifiable risk factors for cardiovascular disease (CVD) through providing lifestyle adjustment training and counseling to patients with type 2 diabetes. In this pre-post intervention study, 139 patients with diabetes were provided with training to reduce the modifiable risks of CVD. One hundred three patients attended the post-training evaluation. Two phone counseling sessions were provided with 1-month intervals. Consumption of red meat and processed food decreased and water consumption, carrying on the recommended diet, and the frequency of exercise increased (p = .000), A1C decreased (p = .05), and the use of aspirin increased (p = .03). Thus, a contribution to the reduction of CVD risk factors in patients with type 2 diabetes was achieved. The training program for reducing CVD risk factors in patients with type 2 diabetes was effective in improving nutrition and lifestyle behaviors and decreasing glycemic control. PMID- 24789941 TI - How to assess the severity of bronchiectasis. PMID- 24789942 TI - Exacerbation frequency and FEV1 decline of COPD: is it geographic? PMID- 24789943 TI - Heterogeneity of pulmonary rehabilitation: like apples and oranges - both healthy fruit. PMID- 24789944 TI - When CPAP is stopped: what are the "on switches" of sleep apnoea? PMID- 24789945 TI - Chronic thromboembolic pulmonary hypertension at the crossroad. PMID- 24789946 TI - Disease stratification in idiopathic pulmonary fibrosis: the dawn of a new era? PMID- 24789947 TI - Risk prediction and end-points in idiopathic pulmonary fibrosis: one step at a time. PMID- 24789948 TI - Can IASLC/ATS/ERS subtype help predict response to chemotherapy in small biopsies of advanced lung adenocarcinoma? PMID- 24789949 TI - The growing chronic disease burden in Europe: a role for respiratory health professionals? PMID- 24789951 TI - Asthma drug ratios and exacerbations: claims data from universal health coverage systems. AB - In claims data, controller-to-total asthma drug ratios may reflect adequacy of disease management. We verified whether asthma patients with high ratios (>= 50%) experienced fewer asthma-related outcomes. Two ratios were studied: that of the inhaled corticosteroids to total asthma drug (ICS/R03) and that of the inhaled corticosteroids plus leukotriene antagonist receptors-to-total asthma drug (ICS+LTRA/R03). Patients aged 13-40 years, with >= 3 respiratory drugs dispensed prescriptions in 2005 were selected from the French national claims data. After excluding null ratios, two groups were defined according to ratio values in 2007: low-ratio group (0% < ratio < 50%) and high-ratio group (ratio >= 50%). For both ratios, asthma-related outcomes and medical-resource utilisation were compared between groups. Of 2162 patients (mean age 27 years and 52% female), patients with non-null ratios were 81% and 85% for ICS/R03 and ICS+LTRA/R03 ratios, respectively. Patients with high ratios were less likely to receive oral corticosteroids than those in the low-ratio group (relative risk 0.79, 95% CI 0.72-0.88, and 0.80, 95% CI 0.72-0.88, for ICS/R03 and ICS+LTRA/R03, respectively). High ratio groups also presented fewer asthma-related hospitalisations. Significant negative correlations were also observed for both ratios, when studied quantitatively, according to patients' dispensed level of oral corticosteroids in 2007. In claims data, both ICS/R03 and ICS+LTRA/R03 >= 50% were related to fewer asthma-related outcomes. Ratios should be explored to identify asthma patients at risk of exacerbations. Low ratios can be considered as risk factors of exacerbation whatever the underlying cause. PMID- 24789952 TI - Complete resolution of idiopathic pulmonary arterial hypertension following chemotherapy. PMID- 24789953 TI - Detecting active pulmonary tuberculosis with a breath test using nanomaterial based sensors. PMID- 24789954 TI - Prevalence and prognosis of unclassifiable interstitial lung disease. PMID- 24789955 TI - Serum CCL18 is predictive for lung disease progression and mortality in systemic sclerosis. PMID- 24789956 TI - Passive stretch of the diaphragm following unilateral phrenic nerve stimulation. PMID- 24789957 TI - Asthma and risk of pulmonary thromboembolism. PMID- 24789958 TI - TLNO/TLCO ratio is not the end of the road. PMID- 24789959 TI - Doxycycline in lymphangioleiomyomatosis: not all questions are answered. PMID- 24789960 TI - Doxycycline in lymphangioleiomyomatosis: not all questions are answered. PMID- 24789961 TI - Is the time constant of the pulmonary circulation truly constant? PMID- 24789962 TI - Is the time constant of the pulmonary circulation truly constant? PMID- 24789963 TI - Sleep quality as a confounding factor of maternal weight and preschool wheezing. PMID- 24789964 TI - Sleep quality as a confounding factor of maternal weight and preschool wheezing. PMID- 24789966 TI - Synthesis of benzofuro[6,7-d]thiazoles, benzofuro[7,6-d]thiazoles and 6 arylaminobenzo[d]thiazole-4,7-diones as antifungal agent. AB - Benzofuro[6,7-d]thiazoles, benzofuro[7,6-d]thiazoles and 6 arylaminobenzo[d]thiazole-4,7-diones were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species and Cryptococcus neoformans. Among them tested, many of synthesized compounds showed potent antifungal activity. The compounds 4d, 6e and 6h completely inhibited the growth of all Candida and Aspergillus species tested at the MIC level of 6.3 ug/mL. The results suggest that benzofuro[6,7-d]thiazoles and 6-arylaminobenzo[d]thiazole 4,7-diones would be promising antifungal agents. PMID- 24789967 TI - The archaeal DNA replication machinery: past, present and future. AB - Living organisms are divided into three domains: Bacteria, Archaea, and Eukarya. Whereas Bacteria and Archaea are both prokaryotes, proteins involved in information processes; replication, transcription, and translation, are more similar in Archaea and Eukarya. Here the history of the research on archaeal DNA replication is summarized and the future of the field is discussed. PMID- 24789968 TI - Dissection of rye chromosomes by the gametocidal system. AB - Chromosome mutations occur in common wheat carrying a monosome of gametocidal (Gc) chromosomes 2C and 3C(SAT). These Gc chromosomes have been known to induce chromosomal breakage in a rye chromosome 1R added to common wheat. We attempted to introduce the two Gc chromosomes into the other six rye chromosome (2R to 7R) addition or substitution lines of common wheat to establish a set of chromosomal rearrangement-inducing lines for rye chromosomes. We obtained critical plants that had a pair of rye chromosomes and one Gc chromosome for 2R, 3R, 4R and 6R, and semi-critical plants that were monotelodisomic and monosomic for 5R. Chromosomal aberrations are expected to occur in the progeny of these plants. Besides we established self-fertile disomic 2C addition lines of common wheat that were disomic substitution for 3R, disomic addition for 6R, monotelodisomic for 5R, and monosomic for 7R. We can produce the critical plants of the respective rye chromosomes by crossing above lines to the respective wheat-rye disomic addition or substitution lines. During the cytological screening in this study, we found Gc-induced chromosomal aberrations for every rye chromosome. The stocks reported here can be used to produce dissection lines for each of the rye chromosomes in common wheat by the Gc system. PMID- 24789972 TI - Sulfur-mediated electron shuttling during bacterial iron reduction. AB - Microbial reduction of ferric iron [Fe(III)] is an important biogeochemical process in anoxic aquifers. Depending on groundwater pH, dissimilatory metal reducing bacteria can also respire alternative electron acceptors to survive, including elemental sulfur (S(0)). To understand the interplay of Fe/S cycling under alkaline conditions, we combined thermodynamic geochemical modeling with bioreactor experiments using Shewanella oneidensis MR-1. Under these conditions, S. oneidensis can enzymatically reduce S(0) but not goethite (alpha-FeOOH). The HS(-) produced subsequently reduces goethite abiotically. Because of the prevalence of alkaline conditions in many aquifers, Fe(III) reduction may thus proceed via S(0)-mediated electron-shuttling pathways. PMID- 24789973 TI - A pause sequence enriched at translation start sites drives transcription dynamics in vivo. AB - Transcription by RNA polymerase (RNAP) is interrupted by pauses that play diverse regulatory roles. Although individual pauses have been studied in vitro, the determinants of pauses in vivo and their distribution throughout the bacterial genome remain unknown. Using nascent transcript sequencing, we identified a 16 nucleotide consensus pause sequence in Escherichia coli that accounts for known regulatory pause sites as well as ~20,000 new in vivo pause sites. In vitro single-molecule and ensemble analyses demonstrate that these pauses result from RNAP-nucleic acid interactions that inhibit next-nucleotide addition. The consensus sequence also leads to pausing by RNAPs from diverse lineages and is enriched at translation start sites in both E. coli and Bacillus subtilis. Our results thus reveal a conserved mechanism unifying known and newly identified pause events. PMID- 24789974 TI - Sulfur oxidation genes in diverse deep-sea viruses. AB - Viruses are the most abundant biological entities in the oceans and a pervasive cause of mortality of microorganisms that drive biogeochemical cycles. Although the ecological and evolutionary effects of viruses on marine phototrophs are well recognized, little is known about their impact on ubiquitous marine lithotrophs. Here, we report 18 genome sequences of double-stranded DNA viruses that putatively infect widespread sulfur-oxidizing bacteria. Fifteen of these viral genomes contain auxiliary metabolic genes for the alpha and gamma subunits of reverse dissimilatory sulfite reductase (rdsr). This enzyme oxidizes elemental sulfur, which is abundant in the hydrothermal plumes studied here. Our findings implicate viruses as a key agent in the sulfur cycle and as a reservoir of genetic diversity for bacterial enzymes that underpin chemosynthesis in the deep oceans. PMID- 24789975 TI - Limitations of the AutoCaptureTM Pacing System in patients with cardiac stimulation devices. AB - AIMS: AutoCapture (St Jude Medical) is a technological development that confirms ventricular capture analysing the evoked response after a pacing impulse and adjusts the energy output to changes in the stimulation threshold. Although this algorithm is aimed to assure capture minimizing energy consumption, some patients might not benefit from it. The objective of this study is to identify them. METHODS AND RESULTS: Long-term AutoCapture efficiency was assessed using the data recorded in the programmer reports of patients undergoing scheduled pacemaker check-ups during 2012 in our institution. We have evaluated 160 consecutive patients (58% men) aged 78 +/- 9 years. Pacemaker stimulation mode was DDD in 116 patients (72.5%) and VVI in 44 patients (27.5%). During the scheduled visits for pacemaker check-up, 73 patients (45.6%) showed abnormalities in the long-term AutoCapture function report (high variability in the AutoCapture stimulation threshold and/or out-of-range values). After multivariate analysis, abnormal AutoCapture pattern was associated to the presence of atrial fibrillation [odds ratio (OR) 3.96 (1.59-9.82; P < 0.05)]; and a ventricular pacing <=25% of the time [OR 4.80 (2.09-11.05; P < 0.05)]. AutoCapture abnormalities were also described in three (1.8%) patients with very low stimulation threshold. CONCLUSION: Although AutoCapture algorithm has shown both efficacy and safety, our findings suggest that some patients with atrial fibrillation or those requiring ventricular pacing <=25% of the time may not benefit from it. Activation of the algorithm should be individualized according to the patient's characteristics and long-term AutoCapture pattern checked in the routine follow up. PMID- 24789976 TI - Challenges of teaching and researching physiology in Sub-Saharan Africa. PMID- 24789977 TI - Adaptive responses using obstructive sleep apnea as the paradigm. PMID- 24789978 TI - Stress adaptation and the resilience of youth: fact or fiction? PMID- 24789979 TI - Physiology in perspective: adaptive responses: changing to survive. PMID- 24789980 TI - Adaptation to heat and water shortage in large, arid-zone mammals. AB - Although laboratory studies of large mammals have revealed valuable information on thermoregulation, such studies cannot predict accurately how animals respond in their natural habitats. Through insights obtained on thermoregulatory behavior, body temperature variability, and selective brain cooling in free living mammals, we show here how we can better understand the physiological capacity of large mammals to cope with hotter and drier arid-zone habitats likely with climate change. PMID- 24789981 TI - Apoptotic cell death under hypoxia. AB - Eukaryotic life depends largely on molecular oxygen. During evolution, ingenious mechanisms have evolved that allow organisms to adapt when oxygen levels decrease. Many of these adaptional responses to low oxygen are orchestrated by the heterodimeric transcription factor hypoxia-inducible factor (HIF). Here, we review the link between HIF and apoptosis. PMID- 24789983 TI - Ion/water channels for embryo implantation barrier. AB - Successful implantation involves three distinct processes, namely the embryo apposition, attachment, and penetration through the luminal epithelium of the endometrium to establish a vascular link to the mother. After penetration, stromal cells underlying the epithelium differentiate and surround the embryo to form the embryo implantation barrier, which blocks the passage of harmful substances to the embryo. Many ion/water channel proteins were found to be involved in the process of embryo implantation. First, ion/water channel proteins play their classical role in establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane. Second, most of ion/water channel proteins are regulated by steroid hormone (estrogen or progesterone), which may have important implications to the embryo implantation. Last but not least, these proteins do not limit themselves as pure channels but also function as an initiator of a series of consequences once activated by their ligand/stimulator. Herein, we discuss these new insights in recent years about the contribution of ion/water channels to the embryo implantation barrier construction during early pregnancy. PMID- 24789982 TI - Beyond the genome: epigenetic mechanisms in lung remodeling. AB - The lung develops from a very simple outpouching of the foregut into a highly complex, finely structured organ with multiple specialized cell types that are required for its normal physiological function. During both the development of the lung and its remodeling in the context of disease or response to injury, gene expression must be activated and silenced in a coordinated manner to achieve the tremendous phenotypic heterogeneity of cell types required for homeostasis and pathogenesis. Epigenetic mechanisms, consisting of DNA base modifications such as methylation, alteration of histones resulting in chromatin modification, and the action of noncoding RNA, control the regulation of information "beyond the genome" required for both lung modeling and remodeling. Epigenetic regulation is subject to modification by environmental stimuli, such as oxidative stress, infection, and aging, and is thus critically important in chronic remodeling disorders such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), and pulmonary hypertension (PH). Technological advances have made it possible to evaluate genome-wide epigenetic changes (epigenomics) in diseases of lung remodeling, clarifying existing pathophysiological paradigms and uncovering novel mechanisms of disease. Many of these represent new therapeutic targets. Advances in epigenomic technology will accelerate our understanding of lung development and remodeling, and lead to novel treatments for chronic lung diseases. PMID- 24789984 TI - The brain melanocortin system, sympathetic control, and obesity hypertension. AB - Excess weight gain is the most significant, preventable cause of increased blood pressure (BP) in patients with primary (essential) hypertension and increases the risk for cardiovascular and renal diseases. In this review, we discuss the role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension. In addition, we highlight potential mechanisms by which the brain melanocortin system modulates metabolic and cardiovascular functions. PMID- 24789985 TI - Alcohol abuse: critical pathophysiological processes and contribution to disease burden. AB - Alcohol abuse; the most common and costly form of drug abuse, is a major contributing factor to many disease categories. The alcohol-attributable disease burden is closely related to the average volume of alcohol consumption, with dose dependent relationships between amount and duration of alcohol consumption and the incidence of diabetes mellitus, hypertension, cardiovascular disease, stroke, and pneumonia. The frequent occurrence of alcohol use disorders in the adult population and the significant and widespread detrimental organ system effects highlight the importance of recognizing and further investigating the pathophysiological mechanisms underlying alcohol-induced tissue and organ injury. PMID- 24789986 TI - Characterization of multi-antibiotic-resistant Escherichia coli Isolated from beef cattle in Japan. AB - The emergence of multiple-antibiotic-resistance bacteria is increasing, which is a particular concern on livestock farms. We previously isolated 1,347 antimicrobial-resistant (AMR) Escherichia coli strains from the feces of beef cattle on 14 Japanese farms. In the present study, the genetic backgrounds and phylogenetic relationships of 45 AMR isolates were characterized by the chromosome phylotype, AMR phenotype, AMR genotype, and plasmid type. These isolates were classified into five chromosome phylotypes, which were closely linked to the farms from which they were isolated, suggesting that each farm had its own E. coli phylotype. AMR phenotype and plasmid type analyses yielded 8 and 14 types, all of which were associated with the chromosomal phylotype and, thus, to the original farms. AMR genotype analysis revealed more variety, with 16 types, indicating both inter- and intra-farm diversity. Different phylotype isolates from the same farm shared highly similar plasmid types, which indicated that plasmids with AMR genes could be transferred between phylotypes, thereby generating multi-antibiotic-resistant microorganisms. This ecological study demonstrated that the chromosome phylotype was strongly correlated with the farm from which they were isolated, while the AMR phenotype, genotype, and plasmid type were generally correlated with the chromosome phylotype and farm source. PMID- 24789991 TI - Role of prostaglandins in determining the increased cardiac sympathetic nerve activity in ovine sepsis. AB - Effective treatment of sepsis remains a significant challenge in intensive care units. During sepsis, there is widespread activation of the sympathetic nervous system, which is thought to have both beneficial and detrimental effects. The sympathoexcitation is thought to be partly due to the developing hypotension, but may also be a response to the inflammatory mediators released. Thus, we investigated whether intracarotid infusion of prostaglandin E2 (PGE2) induced similar cardiovascular changes to those caused by intravenous infusion of Escherichia coli in sheep and whether inhibition of prostaglandin synthesis, with the nonselective cyclooxygenase inhibitor indomethacin, administered at 2 and 8 h after the onset of sepsis, reduced sympathetic nerve activity (SNA), and heart rate (HR). Studies were performed in conscious sheep instrumented to measure mean arterial pressure (MAP), HR, cardiac SNA (CSNA), and renal SNA (RSNA). Intracarotid infusion of PGE2 (50 ng.kg(-1).min(-1)) increased temperature, CSNA, and HR, but not MAP or RSNA. Sepsis, induced by infusion of E. coli, increased CSNA, but caused an initial, transient inhibition of RSNA. At 2 h of sepsis, indomethacin (1.25 mg/kg bolus) increased MAP and caused reflex decreases in HR and CSNA. After 8 h of sepsis, indomethacin did not alter MAP, but reduced CSNA and HR, without altering baroreflex control. These findings indicate an important role for prostaglandins in mediating the increase in CSNA and HR during the development of hyperdynamic sepsis, whereas prostaglandins do not have a major role in determining the early changes in RSNA. PMID- 24789987 TI - An assessment of the diversity of culturable bacteria from main root of sugar beet. AB - The partial sequences of the 16S rRNA genes of 531 bacteria isolated from the main root of the sugar beet (Beta vulgaris L.) were determined and subsequently grouped into 155 operational taxonomic units by clustering analysis (>=99% identity). The most abundant phylum was Proteobacteria (72.5-77.2%), followed by Actinobacteria (9.8-16.6%) and Bacteroidetes (4.3-15.4%). Alphaproteobacteria (46.7-64.8%) was the most dominant class within Proteobacteria. Four strains belonging to Verrucomicrobia were also isolated. Phylogenetic analysis revealed that the Verrucomicrobia bacterial strains were closely related to Haloferula or Verrucomicrobium. PMID- 24789988 TI - Dynamics of different bacterial communities are capable of generating sustainable electricity from microbial fuel cells with organic waste. AB - The relationship between the bacterial communities in anolyte and anode biofilms and the electrochemical properties of microbial fuel cells (MFCs) was investigated when a complex organic waste-decomposing solution was continuously supplied to MFCs as an electron donor. The current density increased gradually and was maintained at approximately 100 to 150 mA m(-2). Polarization curve analyses revealed that the maximum power density was 7.4 W m(-3) with an internal resistance of 110 Omega. Bacterial community structures in the organic waste decomposing solution and MFCs differed from each other. Clonal analyses targeting 16S rRNA genes indicated that bacterial communities in the biofilms on MFCs developed to specific communities dominated by novel Geobacter. Multidimensional scaling analyses based on DGGE profiles revealed that bacterial communities in the organic waste-decomposing solution fluctuated and had no dynamic equilibrium. Bacterial communities on the anolyte in MFCs had a dynamic equilibrium with fluctuations, while those of the biofilm converged to the Geobacter-dominated structure. These bacterial community dynamics of MFCs differed from those of control-MFCs under open circuit conditions. These results suggested that bacterial communities in the anolyte and biofilm have a gentle symbiotic system through electron flow, which resulted in the advance of current density from complex organic waste. PMID- 24789992 TI - Altering the sex determination pathway in Drosophila fat body modifies sex specific stress responses. AB - The stress response in Drosophila melanogaster reveals sex differences in behavior, similar to what has been observed in mammals. However, unlike mammals, the sex determination pathway in Drosophila is well established, making this an ideal system to identify factors involved in the modulation of sex-specific responses to stress. In this study, we show that the Drosophila fat body, which has been shown to be important for energy homeostasis and sex determination, is a dynamic tissue that is altered in response to stress in a sex and time-dependent manner. We manipulated the sex determination pathway in the fat body via targeted expression of transformer and transformer-2 and analyzed these animals for changes in their response to stress. In the majority of cases, manipulation of transformer or transformer-2 was able to change the physiological output in response to starvation and oxidative stress to that of the opposite sex. Our data also uncover the possibility of additional downstream targets for transformer and transformer-2 that are separate from the sex determination pathway and can influence behavioral and physiological responses. PMID- 24789994 TI - Oxidative stress and altered lipid homeostasis in the programming of offspring fatty liver by maternal obesity. AB - Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARgamma and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring. PMID- 24789993 TI - The day/night proteome in the murine heart. AB - Circadian rhythms are essential to cardiovascular health and disease. Temporal coordination of cardiac structure and function has focused primarily at the physiological and gene expression levels, but these analyses are invariably incomplete, not the least because proteins underlie many biological processes. The purpose of this study was to reveal the diurnal cardiac proteome and important contributions to cardiac function. The 24-h day-night murine cardiac proteome was assessed by two-dimensional difference in gel electrophoresis (2D DIGE) and liquid chromatography-mass spectrometry. Daily variation was considerable, as ~7.8% (90/1,147) of spots exhibited statistical changes at paired times across the 24-h light- (L) dark (D) cycle. JTK_CYCLE was used to investigate underlying diurnal rhythms in corresponding mRNA. We next revealed that disruption of the L:D cycle altered protein profiles and diurnal variation in cardiac function in Langendorff-perfused hearts, relative to the L:D cycle. To investigate the role of the circadian clock mechanism, we used cardiomyocyte clock mutant (CCM) mice. CCM myofilaments exhibited a loss of time-of-day dependent maximal calcium-dependent ATP consumption, and altered phosphorylation rhythms. Moreover, the cardiac proteome was significantly altered in CCM hearts, especially enzymes regulating vital metabolic pathways. Lastly, we used a model of pressure overload cardiac hypertrophy to demonstrate the temporal proteome during heart disease. Our studies demonstrate that time of day plays a direct role in cardiac protein abundance and indicate a novel mechanistic contribution of circadian biology to cardiovascular structure and function. PMID- 24789995 TI - The gastroprotective effects of Eugenia dysenterica (Myrtaceae) leaf extract: the possible role of condensed tannins. AB - We applied a taxonomic approach to select the Eugenia dysenterica (Myrtaceae) leaf extract, known in Brazil as "cagaita," and evaluated its gastroprotective effect. The ability of the extract or carbenoxolone to protect the gastric mucosa from ethanol/HCl-induced lesions was evaluated in mice. The contributions of nitric oxide (NO), endogenous sulfhydryl (SH) groups and alterations in HCl production to the extract's gastroprotective effect were investigated. We also determined the antioxidant activity of the extract and the possible contribution of tannins to the cytoprotective effect. The extract and carbenoxolone protected the gastric mucosa from ethanol/HCl-induced ulcers, and the former also decreased HCl production. The blockage of SH groups but not the inhibition of NO synthesis abolished the gastroprotective action of the extract. Tannins are present in the extract, which was analyzed by matrix assisted laser desorption/ionization (MALDI); the tannins identified by fragmentation pattern (MS/MS) were condensed type-B, coupled up to eleven flavan-3-ol units and were predominantly procyanidin and prodelphinidin units. Partial removal of tannins from the extract abolished the cytoprotective actions of the extract. The extract exhibits free-radical scavenging activity in vitro, and the extract/FeCl3 sequence stained gastric surface epithelial cells dark-gray. Therefore, E. dysenterica leaf extract has gastroprotective effects that appear to be linked to the inhibition of HCl production, the antioxidant activity and the endogenous SH-containing compounds. These pleiotropic actions appear to be dependent on the condensed tannins contained in the extract, which bind to mucins in the gastric mucosa forming a protective coating against damaging agents. Our study highlights the biopharmaceutical potential of E. dysenterica. PMID- 24789996 TI - Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts. AB - Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia-reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5*10(-8) M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca(2+)([Ca(2+)]m) uptake induced by changes in the Ca(2+) content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff perfused hearts. Fluvoxamine inhibited the increase in [Ca(2+)]m induced by changes in the Ca(2+) content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca(2+)]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia-reperfusion hearts. PMID- 24789997 TI - Permeability of exendin-4-loaded chitosan nanoparticles across MDCK cell monolayers and rat small intestine. AB - The purpose of this study was to investigate the permeability of exendin-4-loaded chitosan nanoparticles using the Madin Darby canine kidney (MDCK) cell monolayer as an in vitro model and the rat intestine as an ex vivo model of the human intestinal barrier. A series of formulations of sodium tripolyphosphate (TPP) and chitosan with different molecular weights and degrees of deacetylation was evaluated. The formulation consisting of 0.1% TPP and 0.2% chitosan (400 kDa, 95% degree of deacetylation), which gave optimized monodispersed particle size (303.1+/-10.36 nm), zeta potential (18.37+/-1.15 mV) and encapsulation efficiency (38.0+/-2.6%), was used for further analysis. After determining their biocompatibility, the transport potential of drug-loaded chitosan nanoparticles was evaluated and compared with free exendin-4 using both MDCK cell monolayers and different rat intestinal segments. Mechanisms underlying enhanced transport of exendin-4 in the cell model were also explored. Compared with free exendin-4, the absorption of optimized chitosan nanoparticles was enhanced by 4.7-fold in MDCK cell monolayers and by 2.0-2.78-fold in different rat intestinal segments, with no significant difference between the duodenum, jejunum and ileum. As supported by confocal laser scanning microscopic analysis, the lower enhancement of absorption in the intestine compared to the cell monolayer likely resulted from the chitosan nanoparticle-mediated opening of cellular tight junctions and not through intracellular transport. These findings suggest that the potential application of chitosan nanoparticles as delivery carriers of exendin-4 is limited and may need further modifications. PMID- 24789998 TI - 3,3',4',5'-Tetrahydroxyflavone induces formation of large aggregates of amyloid beta protein. AB - Amyloid beta protein (Abeta) self-assembles into insoluble fibrils, and forms the senile plaques associated with Alzheimer's disease. 3,3',4',5' Tetrahydroxyflavone, a synthetic analogue of the natural flavonoid fisetin, has been found to potently inhibit Abeta fibril formation. In the present study, we investigated how inhibition of Abeta fibril formation by this flavonoid affects Abeta conformation and neurotoxicity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of Abeta1-42 (20 uM) incubated with or without 3,3',4',5'-tetrahydroxyflavone demonstrated that 3,3',4',5' tetrahydroxyflavone (100 uM) rapidly caused formation of atypical Abeta conformers, which appeared as a very broad, smear-like band in the high molecular weight region and were distinguishable from soluble Abeta oligomers or mature Abeta fibrils. Transmission electron microscopy (TEM) revealed that large spherical Abeta aggregates were preferentially formed in the presence of 3,3',4',5'-tetrahydroxyflavone. The SDS-resistant, smear-like band on SDS-PAGE and the large spherical aggregates in TEM both disappeared after heat treatment (100 degrees C, 10 min). Furthermore, a neurotoxicity assay with cultured rat hippocampal neurons demonstrated that Abeta incubated with 3,3',4',5' tetrahydroxyflavone was significantly less toxic than Abeta incubated without the flavonoid. These results suggest that the newly synthesized fisetin analogue 3,3',4',5'-tetrahydroxyflavone directly produces atypical, large Abeta aggregates and reduces Abeta toxicity. PMID- 24789999 TI - Ginsenoside F2 reduces hair loss by controlling apoptosis through the sterol regulatory element-binding protein cleavage activating protein and transforming growth factor-beta pathways in a dihydrotestosterone-induced mouse model. AB - This study was conducted to test whether ginsenoside F2 can reduce hair loss by influencing sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and the transforming growth factor beta (TGF-beta) pathway of apoptosis in dihydrotestosterone (DHT)-treated hair cells and in a DHT-induced hair loss model in mice. Results for ginsenoside F2 were compared with finasteride. DHT inhibits proliferation of hair cells and induces androgenetic alopecia and was shown to activate an apoptosis signal pathway both in vitro and in vivo. The cell-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the proliferation rates of DHT-treated human hair dermal papilla cells (HHDPCs) and HaCaTs increased by 48% in the ginsenoside F2 treated group and by 12% in the finasteride-treated group. Western blot analysis showed that ginsenoside F2 decreased expression of TGF-beta2 related factors involved in hair loss. The present study suggested a hair loss related pathway by changing SCAP related apoptosis pathway, which has been known to control cholesterol metabolism. SCAP, sterol regulatory element-binding protein (SREBP) and caspase-12 expression in the ginsenoside F2-treated group were decreased compared to the DHT and finasteride-treated group. C57BL/6 mice were also prepared by injection with DHT and then treated with ginsenoside F2 or finasteride. Hair growth rate, density, thickness measurements and tissue histotological analysis in these groups suggested that ginsenoside F2 suppressed hair cell apoptosis and premature entry to catagen more effectively than finasteride. Our results indicated that ginsenoside F2 decreased the expression of TGF-beta2 and SCAP proteins, which have been suggested to be involved in apoptosis and entry into catagen. This study provides evidence those factors in the SCAP pathway could be targets for hair loss prevention drugs. PMID- 24790000 TI - The aversive, anxiolytic-like, and verapamil-sensitive psychostimulant effects of pulegone. AB - We investigated the psychostimulant, rewarding, and anxiolytic-like effects of pulegone. Possible interactions between pulegone and menthol concerning their psychostimulant effect were also analyzed. General mouse activity after pulegone treatment, and the interacitons between pulegone and menthol, were determined in the open field. The anxiolytic-like activity, motor coordination and strength force were evaluated using the elevated plus maze (EPM), rotarod test and grasping test, respectively. The motivational properties of pulegone were evaluated by pairing the drug effects on the mice with the least preferred compartment (previously determined) of a conditioned place preference (CPP) apparatus. Pulegone increased mouse locomotor activity and immobilization time. Verapamil, but not diltiazem, haloperidol or picrotoxin, decreased the psychostimulation induced by pulegone. Pulegone also decreased grooming and rearing behaviors and caused motor incoordination and weakness at high doses. Pulegone increased the time spent by mice in the open arms of the EPM, and flumazenil pre-treatment did not alter this effect. Pulegone either produced no CPP or induced conditioned place aversion. The changes in mouse ambulatory activity caused by the association of pulegone with menthol were either lower than those predicted by the theoretical curve or not different from the predicted values. Therefore, pulegone induces a verapamil-sensitive psychostimulant effect that appears to independ on the opening of L-type calcium channels. Pulegone has negative reinforcing properties and seems to possess anxiolytic-like actions unrelated to the benzodiazepine site of the gamma-aminobutyric acid type A (GABAA) receptor. Finally, pulegone might act in an addictive or synergic way with menthol. PMID- 24790001 TI - Effect of dietary fiber on the level of free angiotensin II receptor blocker in vitro. AB - The interaction between angiotensin II type 1 (AT1) receptor blockers (ARBs), such as losartan potassium (LO), candesartan (CA), and telmisartan (TE), and dietary fiber was studied as to the level of free ARB in vitro. When ARB was incubated with soluble (sodium alginate, pectin, and glucomannan) or insoluble (cellulose and chitosan) dietary fiber, the levels of free LO, TE, and CA decreased. This resulted only from mixing the dietary fiber with the ARBs and differed among the types of dietary fiber, and the pH and electrolytes in the mixture. The levels of free LO and TE tended to decrease with a higher concentration of sodium chloride in pH 1.2 fluid. These results suggest that it is important to pay attention to the possible interactions between ARBs and dietary fiber. PMID- 24790002 TI - Improvement of the antitumor activity of poorly soluble sapacitabine (CS-682) by using Soluplus(r) as a surfactant. AB - Sapacitabine (CS-682 or CYC682; 1-[2-C-cyano-2-deoxy-beta-D-arabino pentfuranosyl]N4-palmitoyl cytosine), a novel antitumor 2'-deoxycytidine analogue, shows a marked reduction in the water solubility because of the fatty acid side chain on the N4 group of the cytosine moiety. Poor water solubility is one of the important reasons why sapacitabine does not exert maximum antitumor activity. Therefore, we attempted to improve the water solubility of sapacitabine using a novel surfactant, Soluplus(r), which consisted of a polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer. In this study, we examined whether Soluplus(r) increased the water solubility and an antitumor activity of sapacitabine. The cytotoxicity of Soluplus(r) alone was lower than that of Tween 80 and Kolliphor(r) D-alpha-tocopherylpolyethylene glycol 1000 succinate (TPGS). The water solubility and the chemosensitivity of sapacitabine against several tumor cell lines to sapacitabine markedly increased upon using Soluplus(r). In addition, the potential of Soluplus(r) including sapacitabine in increasing the antitumor activity was compared with sapacitabine alone in vivo. Although the total dose in the experimental period was considerably lower than the effective dose of sapacitabine alone, the life span of mice treated with sapacitabine containing 40 mg/mL Soluplus(r) increased by 150%. If Soluplus(r) was used as the solubilizing agent in clinical trials of sapacitabine, a low administration dose was appeared to require, and thus side effects might be prevented. PMID- 24790003 TI - Effects of pH and buffer concentration on the thermal stability of etanercept using DSC and DLS. AB - The protein size, electrical interaction, and conformational stability of etanercept (marketed as Enbrel(r)) were examined by thermodynamic and light scattering methods with changing pH and buffer concentration. As pH of etanercept increased from pH 6.6 to 8.6, electrical repulsion in the solution increased, inducing a decrease in protein size. However, the size changed less in high buffer concentration and irreversible aggregation issues were not observed; in contrast, aggregates of about 1000 nm were observed in low buffer concentration at the pH range. Three significant unfolding transitions (Tm) were observed by differential scanning calorimetry (DSC). Unlikely to Tm1, Tm2 and Tm3 were increased as the pH increased. Higher Tm at high buffer concentration was observed, indicating increased conformational stability. The apparent activation energy of unfolding was further investigated since continuous increase of Tm2 and Tm3 was not sufficient to determine optimal conditions. A higher energy barrier was calculated at Tm2 than at Tm3. In addition, the energy barriers were the highest at pH from 7.4 to 7.8 where higher Tm1 was also observed. Therefore, the conformational stability of protein solution significantly changed with pH dependent steric repulsion of neighboring protein molecules. An optimized pH range was obtained that satisfied the stability of all three domains. Electrostatic circumstances and structural interactions resulted in irreversible aggregation at low buffer concentrations and were suppressed by increasing the concentration. Therefore, increased buffer concentration is recommended during protein formulation development, even in the earlier stages of investigation, to avoid protein instability issues. PMID- 24790004 TI - Amino acid residues involved in the substrate specificity of TauT/SLC6A6 for taurine and gamma-aminobutyric acid. AB - Taurine transporter (TauT/SLC6A6) is an "honorary" gamma-aminobutyric acid (GABA) transporter because of its low affinity for GABA. The sequence analysis of TauT implied the role of Gly57, Phe58, Leu306 and Glu406 in the substrate recognition of TauT, and amino acid-substitutions were performed. Immunocytochemistry supported no marked effect of mutations on the expression of TauT. TauT expressing oocytes showed a reduction in [(3)H]taurine uptake by G57E, F58I, L306Q and E406C, and change in [(3)H]GABA uptake by G57E and E406C, suggesting their significant roles in the function of TauT. G57E lost the activity of [(3)H]taurine and [(3)H]GABA uptake, suggesting that Gly57 is involved in the determination of substrate pocket volume and in the interaction with substrates. E406C exhibited a decrease and an increase in the affinity for taurine and GABA, respectively, suggesting the involvement of Glu406 in the substrate specificity of TauT. The inhibition study supported the role of Glu406 in the substrate specificity since [(3)H]taurine and [(3)H]GABA uptake by E406C was less sensitive to taurine and beta-alanine, and more sensitive to GABA and nipecotic acid than was the case with wild type of TauT. F58I had an increased affinity for GABA, suggesting the involvement of Phe58 in the substrate accessibility. The kinetic parameters showed the decreased and increased affinities of L306Q for taurine and GABA, respectively, supporting that substrate recognition of TauT is conformationally regulated by the branched-side chain of Leu306. In conclusion, the present results suggest that these residues play important roles in the transport function and substrate specificity of TauT. PMID- 24790005 TI - Inhalation anesthesia is preferable for recording rat cardiac function using an electrocardiogram. AB - The effects of inhalation anesthesia (2% isoflurane, sevoflurane, or enflurane) and intraperitoneal anesthesia with pentobarbital (65 mg/kg) were compared in rats using an electrocardiogram (ECG) and determination of blood oxygen saturation (SPO2) levels. Following inhalation anesthesia, heart rate (HR) and SPO2 were acceptable while pentobarbital anesthesia decreased HR and SPO2 significantly. This indicates that inhalation anesthesia is more preferable than pentobarbital anesthesia when evaluating cardiovascular factors. Additionally, pentobarbital significantly increased HR variability (HRV), suggesting a regulatory effect of pentobarbital on the autonomic nervous system, and resulted in a decreased response of the baro-reflex system. Propranolol or atropine had limited effects on ECG recording following pentobarbital anesthesia. Taken together, these data suggest that inhalation anesthesia is suitable for conducting hemodynamic analyses in the rat. PMID- 24790006 TI - Design, synthesis, and biological evaluation of 1,4-diaryl-1,4-dihydropyrazines as novel 11beta-HSD1 inhibitors. AB - The inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has demonstrated potential for the treatment of various components of metabolic syndrome. In this study, a series of 1,4-diaryl-1,4-dihydropyrazines were designed as inhibitors of 11beta-HSD1 based on the structure-activity relationship of known 11beta-HSD1 inhibitors through docking simulations. The docking simulation results supported the initial pharmacophore hypothesis: the docking results of the known inhibitors with 11beta-HSD1 suggested a similar interaction of 1,4-diaryl-1,4-dihydropyrazines with the catalytic site of 11beta HSD1. Twelve of these compounds were synthesized through the cyclization of N,N dialkylanilines with anilines, and their structures were determined by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and single-crystal X-ray diffraction. The inhibitory activities of these compounds against human 11beta-HSD1 were investigated in vitro through a scintillation proximity assay using microsomes containing 11beta-HSD1. PMID- 24790007 TI - Isolation and characterization of isopiperitenol dehydrogenase from piperitenone type Perilla. AB - Studying the biosynthesis of oil compounds in Perilla will help to elucidate regulatory systems for secondary metabolites and reaction mechanisms for natural product synthesis. In this study, two types of alcohol dehydrogenases, isopiperitenol dehydrogenases 1 and 2 (ISPD1 and ISPD2), which are thought to participate the oxidation of isopiperitenol in the biosynthesis of perilla, were isolated from three pure lines of perilla. Both ISPD1 and ISPD2 oxidized isopiperitenol into isopiperitenone with an oxidized form of nicotinamide adenine dinucleotide (NAD(+)) cofactor. ISPD1 used both isopiperitenol diastereomers, whereas ISPD2 used cis-isomer as a substrate. However, only ISPD2 was isolated from piperitenone-type perilla. These results suggests that in perilla, ISPD2 is related to the biosynthesis of piperitenone, which was formed via (-)-cis isopiperitenol. PMID- 24790008 TI - A retrospective study on the influence of nutritional status on pain management in cancer patients using the transdermal fentanyl patch. AB - It is unknown whether nutritional status influences pain intensity in cancer patients receiving a transdermal fentanyl patch (FP). This study aimed to determine whether nutritional status is associated with pain intensity and to evaluate the influence of changes in nutritional status on pain intensity in cancer patients receiving transdermal FP treatment. We included 92 patients receiving transdermal FP treatment for the first time with switching from oxycodone. The patients were classified into low- and normal-nutrition groups based on their nutritional status, which was assessed according to the Nutrition Risk Screening 2002 (NRS 2002) parameters. The pain intensity of each patient was evaluated by a numeric rating scale (11-point scale from 0 to 10). NRS 2002 score and pain intensity were obtained on day 3 after the FP was applied to the skin. Pain intensities were significantly higher among patients in the low-nutrition group than among patients in the normal-nutrition group. NRS 2002 scores showed a significant positive correlation with the pain intensities. In 52 of 92 patients, who were evaluated using the NRS 2002 score and pain intensity on day 30 after FP application, the changes in NRS 2002 scores were significantly related to changes in pain intensities (odds ratio, 30.0; 95% confidence interval, 4.48-200.97; p=0.0005). These results suggest that an increase in the NRS 2002 score is a risk factor for an increase in pain intensity in cancer patients receiving FP treatment. Malnutrition may lead to poor pain management in cancer patients receiving FP treatment. PMID- 24790009 TI - Anti-allodynic and neuroprotective effects of koumine, a Benth alkaloid, in a rat model of diabetic neuropathy. AB - Diabetic neuropathy is characterized by progressive degeneration of nerve fibers associated with diabetes mellitus. Antidepressants and anticonvulsants are the mainstay of pharmacological treatment, but are often limited in effectiveness against the core clinical feature of pain. In the current study, we examined the potential effects of koumine, a Gelsemium elegans Benth alkaloid, using a rat model of diabetic neuropathy. Rats were administered intraperitoneally a single dose of streptozocin (60 mg/kg) to induce type 1 diabetes. Koumine was given at a dose range of 0.056-7 mg/kg subcutaneously for one week starting 3 weeks after streptozocin adminstration. Behavioral responses to mechanical stimuli were evaluated every day after streptozocin injection. At 4 weeks after streptozocin injection, sensory nerve conduction velocity (SNCV) and morphological alternation of sciatic nerves were assessed by electron microscopy. Diabetic rats developed mechanical hyperalgesia within 3 weeks after streptozocin injection and exhibited reduced SNCV and impaired myelin/axonal structure. Koumine treatment of diabetic rats decreased neuropathic pain behavior as early as after the first administration. At a dose of 7 mg/kg, koumine was more effective than gabapentin (100 mg/kg), and decreased mechanical sensitivity threshold to a level comparable to healthy control. Repeated treatment of koumine significantly reduced the damage to axon and myelin sheath of the sciatic nerve and increased SNCV, without affecting body weight and blood glucose. These findings encourage the use of koumine in the treatment of diabetic neuropathy. PMID- 24790010 TI - A redox-silent analogue of tocotrienol inhibits cobalt(II) chloride-induced VEGF expression via Yes signaling in mesothelioma cells. AB - Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and represents an attractive anticancer target. We have previously demonstrated that a redox-silent analogue of alpha-tocotrienol, 6-O-carboxypropyl alpha-tocotrienol (T3E) exhibits potent anti-carcinogenic property in human malignant mesothelioma (MM) cells. However, inhibition of tumor growth by targeting VEGF pathway remains undetermined. In this study, we explored the inhibitory effect of T3E on the paracrine secretion of VEGF in MM cells under mimicked hypoxia by cobalt chloride (CoCl2). In this study we examine whether T3E can suppress the secretion of VEGF in MM cells exposed to mimic hypoxia by cobalt chloride (CoCl2). We found that CoCl2-induced hypoxia treatment leads to increased up-regulated hypoxia-inducible factor-2alpha (HIF-2alpha) and subsequently induced the secretion of VEGF in MM cells. This up-regulation activation mainly depended on the activation of Yes, a member of the Src family of kinases. Treatment of hypoxic MM cells with T3E effectively inhibited the secretion of VEGF, On the other hand, T3E inhibited CoCl2-induced gene expression of VEGF due to the inactivation of Yes/HIF-2alpha signaling. These data suggest that Yes/HIF2-alpha/VEGF could be a promising therapeutic target of T3E in MM cells. PMID- 24790011 TI - Crosslinking of Cys-mutated human galectin-1 to the model glycoprotein ligands asialofetuin and laminin by using a photoactivatable bifunctional reagent. AB - Galectins are a group of animal lectins characterized by their specificity for beta-galactosides. In our previous study, we showed that a human galectin-1 (hGal 1) mutant, in which a cysteine residue was introduced at Lys(28), forms a covalently cross-linked complex with the model glycoprotein ligands asialofetuin and laminin by using the photoactivatable sulfhydryl reagent benzophenone-4 maleimide (BPM). In the present study, we used several hGal-1 mutants in which single cysteine residues were introduced at different positions and examined their ability to form a covalent complex with asialofetuin or laminin by using BPM. We found that the efficiency of formation of the cross-linked products differed depending on the positions of the cysteine introduced and also on the ligand used for crosslinking. Therefore, by using different cysteine hGal-1 mutants, the chances of isolating different ligands for hGal-1 should increase depending on the systems and cells used. PMID- 24790012 TI - The effect of rowing ergometry and resistive exercise on skeletal muscle structure and function during bed rest. AB - Exposure to microgravity causes functional and structural impairment of skeletal muscle. Current exercise regimens are time-consuming and insufficiently effective; an integrated countermeasure is needed that addresses musculoskeletal along with cardiovascular health. High-intensity, short-duration rowing ergometry and supplemental resistive strength exercise may achieve these goals. Twenty seven healthy volunteers completed 5 wk of head-down-tilt bed rest (HDBR): 18 were randomized to exercise, 9 remained sedentary. Exercise consisted of rowing ergometry 6 days/wk, including interval training, and supplemental strength training 2 days/wk. Measurements before and after HDBR and following reambulation included assessment of strength, skeletal muscle volume (MRI), and muscle metabolism (magnetic resonance spectroscopy); quadriceps muscle biopsies were obtained to assess muscle fiber types, capillarization, and oxidative capacity. Sedentary bed rest (BR) led to decreased muscle volume (quadriceps: -9 +/- 4%, P < 0.001; plantar flexors: -19 +/- 6%, P < 0.001). Exercise (ExBR) reduced atrophy in the quadriceps (-5 +/- 4%, interaction P = 0.018) and calf muscle, although to a lesser degree (-14 +/- 6%, interaction P = 0.076). Knee extensor and plantar flexor strength was impaired by BR (-14 +/- 15%, P = 0.014 and -22 +/- 7%, P = 0.001) but preserved by ExBR (-4 +/- 13%, P = 0.238 and +13 +/- 28%, P = 0.011). Metabolic capacity, as assessed by maximal O2 consumption, (31)P-MRS, and oxidative chain enzyme activity, was impaired in BR but stable or improved in ExBR. Reambulation reversed the negative impact of BR. High-intensity, short duration rowing and supplemental strength training effectively preserved skeletal muscle function and structure while partially preventing atrophy in key antigravity muscles. Due to its integrated cardiovascular benefits, rowing ergometry could be a primary component of exercise prescriptions for astronauts or patients suffering from severe deconditioning. PMID- 24790013 TI - Highly sensitive monitoring of chest wall dynamics and acoustics provides diverse valuable information for evaluating ventilation and diagnosing pneumothorax. AB - Current practice of monitoring lung ventilation in neonatal intensive care units, utilizing endotracheal tube pressure and flow, end-tidal CO2, arterial O2 saturation from pulse oximetry, and hemodynamic indexes, fails to account for asymmetric pathologies and to allow for early detection of deteriorating ventilation. This study investigated the utility of bilateral measurements of chest wall dynamics and sounds, in providing early detection of changes in the mechanics and distribution of lung ventilation. Nine healthy New Zealand rabbits were ventilated at a constant pressure, while miniature accelerometers were attached to each side of the chest. Slowly progressing pneumothorax was induced by injecting 1 ml/min air into the pleural space on either side of the chest. The end of the experiment (tPTX) was defined when arterial O2 saturation from pulse oximetry dropped <90% or when vigorous spontaneous breathing began, since it represents the time of clinical detection using common methods. Consistent and significant changes were observed in 15 of the chest dynamics parameters. The most meaningful temporal changes were noted for features extracted from subsonic dynamics (<10 Hz), e.g., tidal amplitude, energy, and autoregressive poles. Features from the high-frequency band (10-200 Hz), e.g., energy and entropy, exhibited smaller but significant changes. At 70% tPTX, identification of asymmetric ventilation was attained for all animals. Side identification of the pneumothorax was achieved at 50% tPTX, within a 95% confidence interval. Diagnosis was, on average, 34.1 +/- 18.8 min before tPTX. In conclusion, bilateral monitoring of the chest dynamics and acoustics provide novel information that is sensitive to asymmetric changes in ventilation, enabling early detection and localization of pneumothorax. PMID- 24790015 TI - Changes in glutamate receptor subunits within the medulla in goats after section of the carotid sinus nerves. AB - The mechanisms which contribute to the time-dependent recovery of resting ventilation and the ventilatory CO2 chemoreflex after carotid body denervation (CBD) are poorly understood. Herein we tested the hypothesis that there are time dependent changes in the expression of specific AMPA, NMDA, and/or neurokinin-1 (NK1R) receptors within respiratory-related brain stem nuclei acutely or chronically after CBD in adult goats. Brain stem tissues were collected acutely (5 days) or chronically (30 days) after sham or bilateral CBD, immunostained with antibodies targeting AMPA (GluA1 or GluA2), NMDA (GluN1), or NK-1 receptors, and optical density (OD) compared. Physiological measurement confirmed categorization of each group and showed ventilatory effects consistent with bilateral CBD (Miller et al. J Appl Physiol 115: 1088-1098, 2013). Acutely after CBD, GluA1 OD was unchanged or slightly increased, but GluA2 and GluN1 OD were reduced 15-30% within the nucleus tractus solitarius (NTS) and in other medullary respiratory nuclei. Chronically after CBD, GluA1 was reduced (P < 0.05) within the caudal NTS and in other nuclei, but there was significant recovery of GluA2 and GluN1 OD. NK1 OD was not significantly different from control after CBD. We conclude that the initial decrease in GluA2 and GluN1 after CBD likely contributes to hypoventilation and the reduced CO2 chemoreflex. The partial recovery of ventilation and the CO2 chemoreflex after CBD parallel a time-dependent return of these receptors to near control levels but likely depend upon additional initiating and maintenance factors for neuroplasticity. PMID- 24790014 TI - Age-related structural alterations in human skeletal muscle fibers and mitochondria are sex specific: relationship to single-fiber function. AB - Age-related loss of skeletal muscle mass and function is implicated in the development of disease and physical disability. However, little is known about how age affects skeletal muscle structure at the cellular and ultrastructural levels or how such alterations impact function. Thus we examined skeletal muscle structure at the tissue, cellular, and myofibrillar levels in young (21-35 yr) and older (65-75 yr) male and female volunteers, matched for habitual physical activity level. Older adults had smaller whole muscle tissue cross-sectional areas (CSAs) and mass. At the cellular level, older adults had reduced CSAs in myosin heavy chain II (MHC II) fibers, with no differences in MHC I fibers. In MHC II fibers, older men tended to have fewer fibers with large CSAs, while older women showed reduced fiber size across the CSA range. Older adults showed a decrease in intermyofibrillar mitochondrial size; however, the age effect was driven primarily by women (i.e., age by sex interaction effect). Mitochondrial size was inversely and directly related to isometric tension and myosin-actin cross-bridge kinetics, respectively. Notably, there were no intermyofibrillar or subsarcolemmal mitochondrial fractional content or myofilament ultrastructural differences in the activity-matched young and older adults. Collectively, our results indicate age-related reductions in whole muscle size do not vary by sex. However, age-related structural alterations at the cellular and subcellular levels are different between the sexes and may contribute to different functional phenotypes in ways that modulate sex-specific reductions in physical capacity with age. PMID- 24790016 TI - A new experimental model to study force depression: the Drosophila jump muscle. AB - Force depression (FD) is a decrease in isometric force following active muscle shortening. Despite being well characterized experimentally, its underlying mechanism remains unknown. To develop a new, genetically manipulatable experimental model that would greatly improve our ability to study the underlying mechanism(s) of FD, we tested the Drosophila jump muscle for classical FD behavior. Steady-state force generation following active shortening decreased by 2, 8, and 11% of maximum isometric force with increasing shortening amplitudes of 5, 10, and 20% of optimal fiber length, and decreased by 11, 8, and 5% with increasing shortening velocities of 4, 20, and 200% of optimal fiber length per second. These steady-state FD (FDSS) characteristics of Drosophila jump muscle mimic those observed in mammalian skeletal muscle. A double exponential fit of transient force recovery following shortening identified two separate phases of force recovery: a rapid initial force redevelopment, and a slower recovery toward steady state. This analysis showed the slower rate of force redevelopment to be inversely proportional to the amount of FDSS, while the faster rate did not correlate with FDSS. This suggests that the mechanism behind the slower, most likely cross-bridge cycling rate, influences the amount of FDSS. Thus the jump muscle, when coupled with the genetic mutability of its sarcomere proteins, offers a unique and powerful experimental model to explore the underlying mechanism behind FD. PMID- 24790017 TI - Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity. AB - Brain parenchymal arterioles (PAs) are high-resistance vessels that branch off pial arteries and perfuse the brain parenchyma. PAs are the target of cerebral small vessel disease and have been shown to have greater pressure-induced tone at lower pressures than pial arteries. We investigated mechanisms by which brain PAs have increased myogenic tone compared with middle cerebral arteries (MCAs), focusing on differences in vascular smooth muscle (VSM) calcium and ion channel function. The amount of myogenic tone and VSM calcium was measured using Fura 2 in isolated and pressurized PAs and MCAs. Increases in intraluminal pressure caused larger increases in tone and cytosolic calcium in PAs compared with MCAs. At 50 mmHg, myogenic tone was 37 +/- 5% for PAs vs. 6.5 +/- 4% for MCAs (P < 0.01), and VSM calcium was 200 +/- 20 nmol/l in PAs vs. 104 +/- 15 nmol/l in MCAs (P < 0.01). In vessels permeabilized with Staphylococcus aureus alpha-toxin, PAs were not more sensitive to calcium, suggesting calcium sensitization was not at the level of the contractile apparatus. PAs were 30-fold more sensitive to the voltage-dependent calcium channel (VDCC) inhibitor nifedipine than MCAs (EC50 for PAs was 3.5 +/- 0.4 vs. 82.1 +/- 2.1 nmol/l for MCAs;P < 0.01); however, electrophysiological properties of the VDCC were not different in VSM. PAs had little to no response to the calcium-activated potassium channel inhibitor iberiotoxin, whereas MCAs constricted ~15%. Thus increased myogenic tone in PAs appears related to differences in ion channel activity that promotes VSM membrane depolarization but not to a direct sensitization of the contractile apparatus to calcium. PMID- 24790018 TI - The aging mouse partially models the aging human spine: lumbar and coccygeal disc height, composition, mechanical properties, and Wnt signaling in young and old mice. AB - Murine lumbar and coccygeal (tail) regions of spines are commonly used to study cellular signaling of age-related disc diseases, but the tissue-level changes of aging intervertebral discs and vertebrae of each spinal region remain unclear. Furthermore, the impact of aging lumbar and coccygeal discs on Wnt/beta-catenin signaling, which is putatively involved in the catabolism of intervertebral discs, is also unclear. We compared disc/vertebrae morphology and mechanics and biochemical composition of intervertebral discs from lumbar and coccygeal regions between young (4-5 mo) and old (20-22 mo) female C57BL/6 mice. Center intervertebral disc height from both regions was greater in old discs than young discs. Compared with young, old lumbar discs had a lower early viscous coefficient (a measure of stiffness) by 40%, while conversely old coccygeal discs were stiffer by 53%. Biochemically, old mice had double the collagen content in lumbar and coccygeal discs of young discs, greater glycosaminoglycan in lumbar discs by 37%, but less glycosaminoglycan in coccygeal discs by 32%. Next, we compared Wnt activity of lumbar and coccygeal discs of 4- to 5-mo and 12- to 14 mo TOPGAL mice. Despite the disc-specific changes, aging decreased Wnt signaling in the nucleus pulposus from both spinal regions by >=64%. Compared with young, trabecular bone volume/tissue volume and ultimate force were less in old lumbar vertebrae, but greater in old coccygeal vertebrae. Thus intervertebral discs and vertebrae age in a spinal region-dependent manner, but these differential age related changes may be uncoupled from Wnt signaling. Overall, lumbar and coccygeal regions are not interchangeable in modeling human aging. PMID- 24790019 TI - Changes in H reflex and neuromechanical properties of the trapezius muscle after 5 weeks of eccentric training: a randomized controlled trial. AB - Trapezius muscle Hoffman (H) reflexes were obtained to investigate the neural adaptations induced by a 5-wk strength training regimen, based solely on eccentric contractions of the shoulder muscles. Twenty-nine healthy subjects were randomized into an eccentric training group (n = 15) and a reference group (n = 14). The eccentric training program consisted of nine training sessions of eccentric exercise performed over a 5-wk period. H-reflex recruitment curves, the maximal M wave (Mmax), maximal voluntary contraction (MVC) force, rate of force development (RFD), and electromyographic (EMG) voluntary activity were recorded before and after training. H reflexes were recorded from the middle part of the trapezius muscle by electrical stimulation of the C3/4 cervical nerves; Mmax was measured by electrical stimulation of the accessory nerve. Eccentric strength training resulted in significant increases in the maximal trapezius muscle H reflex (Hmax) (21.4% [5.5-37.3]; P = 0.01), MVC force (26.4% [15.0-37.7]; P < 0.01), and RFD (24.6% [3.2-46.0]; P = 0.025), while no significant changes were observed in the reference group. Mmax remained unchanged in both groups. A significant positive correlation was found between the change in MVC force and the change in EMG voluntary activity in the training group (r = 0.57; P = 0.03). These results indicate that the net excitability of the trapezius muscle H-reflex pathway increased after 5 wk of eccentric training. This is the first study to investigate and document changes in the trapezius muscle H reflex following eccentric strength training. PMID- 24790020 TI - MRI-based measurements of aerosol deposition in the lung of healthy and elastase treated rats. AB - Aerosolized drugs are increasingly being used to treat chronic lung diseases or to deliver therapeutics systemically through the lung. The influence of disease, such as emphysema, on particle deposition is not fully understood. With the use of magnetic resonance imaging (MRI), the deposition pattern of iron oxide particles with a mass median aerodynamic diameter of 1.2 MUm was assessed in the lungs of healthy and elastase-treated rats. Tracheostomized rats were ventilated with particles, at a tidal volume of 2.2 ml, and a breathing frequency of 80 breaths/min. Maximum airway pressure was significantly lower in the elastase treated (Paw = 7.71 +/- 1.68 cmH2O) than in the healthy rats (Paw = 10.43 +/- 1.02 cmH2O; P < 0.01). This is consistent with an increase in compliance characteristic of an emphysema-like lung structure. Following exposure, lungs were perfusion fixed and imaged in a 3T MR scanner. Particle concentration in the different lobes was determined based on a relationship with the MR signal decay rate, R2 (*). Whole lung particle deposition was significantly higher in the elastase-treated rats (CE,part = 3.03 +/- 0.61 MUm/ml) compared with the healthy rats (CH,part = 1.84 +/- 0.35 MUm/ml; P < 0.01). However, when particle deposition in each lobe was normalized by total deposition in the lung, there was no difference between the experimental groups. However, the relative dispersion [RD = standard deviation/mean] of R2 (*) was significantly higher in the elastase treated rats (RDE = 0.32 +/- 0.02) compared with the healthy rats (RDH = 0.25 +/- 0.02; P < 0.01). These data show that particle deposition is higher and more heterogeneously distributed in emphysematous lungs compared with healthy lungs. PMID- 24790021 TI - Hyperthermia modulates regional differences in cerebral blood flow to changes in CO2. AB - The purpose of this study was to assess blood flow responses to changes in carbon dioxide (CO2) in the internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) during normothermic and hyperthermic conditions. Eleven healthy subjects aged 22 +/- 2 (SD) yr were exposed to passive whole body heating followed by spontaneous hypocapnic and hypercapnic challenges in normothermic and hyperthermic conditions. Right ICA, ECA, and VA blood flows, as well as left middle cerebral artery (MCA) mean blood velocity (Vmean), were measured. Esophageal temperature was elevated by 1.53 +/- 0.09 degrees C before hypocapnic and hypercapnic challenges during heat stress. Whole body heating increased ECA blood flow and cardiac output by 130 +/- 78 and 47 +/- 26%, respectively (P < 0.001), while blood flow (or velocity) in the ICA, MCA, and VA was reduced by 17 +/- 14, 24 +/- 18, and 12 +/- 7%, respectively (P < 0.001). Regardless of the thermal conditions, ICA and VA blood flows and MCA Vmean were decreased by hypocapnic challenges and increased by hypercapnic challenges. Similar responses in ECA blood flow were observed in hyperthermia but not in normothermia. Heat stress did not alter CO2 reactivity in the MCA and VA. However, CO2 reactivity in the ICA was decreased (3.04 +/- 1.17 vs. 2.23 +/- 1.03%/mmHg; P = 0.039) but that in the ECA was enhanced (0.45 +/- 0.47 vs. 0.95 +/- 0.61%/mmHg; P = 0.032). These results indicate that hyperthermia is capable of altering dynamic cerebral blood flow regulation. PMID- 24790022 TI - The effect of saccadic training on early reading fluency. AB - BACKGROUND: Eye movements are necessary for the physical act of reading and have been shown to relate to underlying cognitive and visuoattentional processes during reading. The purpose of this study was to determine the effect of saccadic training using the King-Devick remediation software on reading fluency. METHODS: In this prospective, single-blinded, randomized, crossover trial, a cohort of elementary students received standardized reading fluency testing pre- and posttreatment. Treatment consisted of in-school training 20 minutes per day, 3 days per week for 6 weeks. RESULTS: The treatment group had significantly higher reading fluency scores after treatment (P < .001), and posttreatment scores were significantly higher than the control group (P < .005). CONCLUSION: Saccadic training can significantly improve reading fluency. We hypothesize that this improvement in reading fluency is a result of rigorous practice of eye movements and shifting visuospatial attention, which are vital to the act of reading. PMID- 24790023 TI - Rapid diagnosis and discrimination of bacterial meningitis in children using gram probe real-time polymerase chain reaction. AB - In this study, we developed a method of simultaneous detection and discrimination of bacteria in cerebrospinal fluid (CSF) with gram probe real-time polymerase chain reaction (PCR). Our results showed 25 clinical strains representing 13 gram positive and 12 gram-negative bacterial species. They were identified correctly with the corresponding gram probe. The standard curve showed that the amplification efficiency of templates with different concentrations of bacteria was almost the same with a potential detection limit of 10 colony-forming units/mL. A total of 482 children who were clinically suspected of bacterial meningitis were included in this study. A total of 1.0 mL of CSF was collected from every child and was subjected to gram probe-based PCR (GP-PCR), CSF culture, and CSF routine analysis. The positive rate of the GP-PCR array was (32/482, 6.64%) significantly higher than that of CSF culture (23/482, 4.77%). GP-PCR was proved to be an excellent technique for rapid and accurate diagnosis and discrimination of bacterial meningitis, and hence its use as a diagnostic tool in future seems very promising. PMID- 24790024 TI - Sudden hearing loss in children. AB - Sudden sensorineural hearing loss (SSHL) is defined as a unilateral or bilateral sensorineural hearing loss with at least 30 dB decrease in threshold in 3 contiguous test frequencies occurring over 72 hours or less. It is very rare in children. Sudden hearing loss is a symptom that suggests that there is a problem in the inner ear, surrounding structures, or the whole organism. The etiology and development of this disorder are still not fully understood. The literature contains numerous models of the pathogenesis of SSHL, with childhood SSHL having certain peculiarities. In practical terms, the multifactorial nature of SSHL is important in the choice of diagnostic methods and treatment methods. It is important to determine the cause and effect relationship between the underlying disease and hearing loss. PMID- 24790025 TI - Short-term outcomes of sport- and recreation-related concussion in patients admitted to a pediatric trauma service. AB - The outcomes of patients admitted to the hospital following a sport-related concussion are largely unknown. Medical records of patients admitted to the pediatric trauma service between 2008 and 2011 after sustaining a sport-related concussion were reviewed. In all, 59 participants were in the high-velocity activities group, and 21 in the field or court sport group. Abnormal CT scans were found in 14 patients in the high-velocity group and 2 in the field or court sport group. The majority of participants in the field or court sport group were football players, all of whom had normal CT scans. Headache was predictive of an abnormal CT scan. Among the patients, 56% clinically improved and were discharged the following day. Patients with field or court sport-related concussion admitted to a pediatric trauma service appear to be at low risk for clinically significant intracranial pathology and do well in the acute setting. PMID- 24790026 TI - Preconception dietary patterns in human pregnancies are associated with preterm delivery. AB - Maternal nutrition can have a profound effect on fetal growth, development, and subsequent infant birth weight. Preconception dietary patterns have not been assessed in relation to perinatal outcomes. The objectives of this study were to identify associations between maternal dietary patterns in the 12 mo before conception on fetal growth and preterm delivery. Preconception food frequency data were collected retrospectively in 309 women. Dietary patterns were derived using factor analysis. Perinatal outcomes were collected at delivery with birth weight data calculated into percentiles to assess small and large for gestational age and preterm delivery at <37 wk. Three dietary patterns were identified: 1) high-protein/fruit (characterized by fish, meat, chicken, fruit, and some whole grains); 2) high-fat/sugar/takeaway (takeaway foods, potato chips, refined grains); and 3) vegetarian-type (vegetables, legumes, whole grains). A 1-SD increase in the scores on the high-protein/fruit pattern was associated with decreased likelihood of preterm birth (adjusted OR: 0.31; 95% CI: 0.13, 0.72; P = 0.007), whereas the reverse direction was apparent for the high fat/sugar/takeaway pattern (adjusted OR: 1.54; 95% CI: 1.10, 2.15; P = 0.011). A 1-SD increase in the scores on the high fat/sugar/takeaway pattern was also associated with shorter gestation (adjusted regression coefficient: -2.7; 95% CI: -4.3, -1.1; P = 0.001) and birth length (adjusted regression coefficient: -0.5; 95% CI: -0.8, -0.1; P = 0.004). Nutrition before pregnancy is associated with perinatal outcomes. A dietary pattern containing several protein-rich food sources, fruit, and some whole grains is associated with reduced likelihood for preterm delivery, whereas a dietary pattern mainly consisting of discretionary items is associated with preterm delivery, shorter birth length, and earlier gestation. Poor dietary behaviors in the periconceptional period could be altered to promote behavior change in dietary intake to improve perinatal outcomes and the long-term health of the child. PMID- 24790027 TI - Toll-like receptor 2 activation by beta2->1-fructans protects barrier function of T84 human intestinal epithelial cells in a chain length-dependent manner. AB - Dietary fiber intake is associated with lower incidence and mortality from disease, but the underlying mechanisms of these protective effects are unclear. We hypothesized that beta2->1-fructan dietary fibers confer protection on intestinal epithelial cell barrier function via Toll-like receptor 2 (TLR2), and we studied whether beta2->1-fructan chain-length differences affect this process. T84 human intestinal epithelial cell monolayers were incubated with 4 beta2->1 fructan formulations of different chain-length compositions and were stimulated with the proinflammatory phorbol 12-myristate 13-acetate (PMA). Transepithelial electrical resistance (TEER) was analyzed by electric cell substrate impedance sensing (ECIS) as a measure for tight junction-mediated barrier function. To confirm TLR2 involvement in barrier modulation by beta2->1-fructans, ECIS experiments were repeated using TLR2 blocking antibody. After preincubation of T84 cells with short-chain beta2->1-fructans, the decrease in TEER as induced by PMA (62.3 +/- 5.2%, P < 0.001) was strongly attenuated (15.2 +/- 8.8%, P < 0.01). However, when PMA was applied first, no effect on recovery was observed during addition of the fructans. By blocking TLR2 on the T84 cells, the protective effect of short-chain beta2->1-fructans was substantially inhibited. Stimulation of human embryonic kidney human TLR2 reporter cells with beta2->1-fructans induced activation of nuclear factor kappa-light-chain-enhancer of activated B cells, confirming that beta2->1-fructans are specific ligands for TLR2. To conclude, beta2->1-fructans exert time-dependent and chain length-dependent protective effects on the T84 intestinal epithelial cell barrier mediated via TLR2. These results suggest that TLR2 located on intestinal epithelial cells could be a target of beta2->1-fructan-mediated health effects. PMID- 24790028 TI - Electrically switchable chiral light-emitting transistor. AB - Tungsten diselenide (WSe2) and related transition metal dichalcogenides exhibit interesting optoelectronic properties owing to their peculiar band structures originating from the valley degree of freedom. Although the optical generation and detection of valley polarization has been demonstrated, it has been difficult to realize active valley-dependent functions suitable for device applications. We report an electrically switchable, circularly polarized light source based on the material's valley degree of freedom. Our WSe2-based ambipolar transistors emit circularly polarized electroluminescence from p-i-n junctions electrostatically formed in transistor channels. This phenomenon can be explained qualitatively by the electron-hole overlap controlled by the in-plane electric field. Our device demonstrates a route to exploit the valley degree of freedom and the possibility to develop a valley-optoelectronics technology. PMID- 24790030 TI - Holographic description of a quantum black hole on a computer. AB - Black holes have been predicted to radiate particles and eventually evaporate, which has led to the information loss paradox and implies that the fundamental laws of quantum mechanics may be violated. Superstring theory, a consistent theory of quantum gravity, provides a possible solution to the paradox if evaporating black holes can actually be described in terms of standard quantum mechanical systems, as conjectured from the theory. Here, we test this conjecture by calculating the mass of a black hole in the corresponding quantum mechanical system numerically. Our results agree well with the prediction from gravity theory, including the leading quantum gravity correction. Our ability to simulate black holes offers the potential to further explore the yet mysterious nature of quantum gravity through well-established quantum mechanics. PMID- 24790029 TI - Identification of LRRC8 heteromers as an essential component of the volume regulated anion channel VRAC. AB - Regulation of cell volume is critical for many cellular and organismal functions, yet the molecular identity of a key player, the volume-regulated anion channel VRAC, has remained unknown. A genome-wide small interfering RNA screen in mammalian cells identified LRRC8A as a VRAC component. LRRC8A formed heteromers with other LRRC8 multispan membrane proteins. Genomic disruption of LRRC8A ablated VRAC currents. Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. The isoform combination determined VRAC inactivation kinetics. Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. Our work shows that VRAC defines a class of anion channels, suggests that VRAC is identical to the volume-sensitive organic osmolyte/anion channel VSOAC, and explains the heterogeneity of native VRAC currents. PMID- 24790031 TI - A study of leg edema in immobile patients. AB - BACKGROUND: Our objectives were to elucidate the pathophysiology of leg edema in immobile patients and to discuss reasonable management of this condition. METHODS AND RESULTS: The 30 patients with leg edema had visited our clinic between April 2009 and March 2013; they suffered from severe gait disturbance, had no significant venous abnormalities detected using duplex ultrasound, and did not have any systemic diseases that could cause leg edema. Here, we review their symptoms, examinations, and treatments. Among 59 edematous legs of the 30 patients, 30 legs (51%) had symptoms that indicated advanced chronic venous insufficiency. The ankle range of motion and calf : ankle circumference ratio were abnormal in only 3 (5%) and 10 (17%) of the legs, respectively. The severity of edema and subcutaneous inflammation, which was confirmed using ultrasonography, was significantly influenced by gravity. Air plethysmography and lymphangioscintigraphy were completed in 15 and 10 patients, respectively, neither of which revealed any significant abnormalities. Reasonable success for all patients was achieved by compression therapy and physical therapy without medications. CONCLUSIONS: It was assumed that leg edema in these immobile patients was mainly caused by venous stasis because of the immobility itself, not because of anatomical problems. The patients were successfully managed by compression and physical therapy alone. PMID- 24790032 TI - Abnormal hemodynamics in the pulmonary artery seen on time-resolved 3-dimensional phase-contrast magnetic resonance imaging (4D-flow) in a young patient with idiopathic pulmonary arterial hypertension. PMID- 24790033 TI - Effect of left atrial activity after the maze procedure on clinical and echocardiographic outcomes. AB - BACKGROUND: Although the maze procedure reduces the risk of adverse cardiac events, the clinical importance of post-maze left atrial (LA) activity on long term surgical outcomes is not well defined. METHODS AND RESULTS: Between January 2000 and December 2009, 416 consecutive patients with sinus conversion after a modified Cox III procedure with cryoablation were enrolled and subdivided into patients with restored LA activity (group ReA; n=231) and those without LA activity (group NoA; n=185) assessed using Doppler echocardiographic examination at 3-6 months after the maze procedure. During the long-term follow-up (4.6+/-2.6 years), the NoA group showed more frequent major adverse events (P=0.001) including cardiac death (P=0.145), heart failure events (P=0.032), and thromboembolic stroke (P=0.048) than the ReA group. In multivariate analysis, lack of LA activity was associated with a 2.2-fold increased risk for major adverse events (95% confidence interval [CI], 1.1-6.8; P=0.029) and with a 2.4 fold increased risk for late progression of tricuspid regurgitation (95% CI, 1.0 3.5; P=0.041). CONCLUSIONS: Absence of LA activity after the maze procedure was independently associated with a significantly increased risk of major adverse events and late progression of tricuspid regurgitation. PMID- 24790034 TI - The alpha-importome of mammalian germ cell maturation provides novel insights for importin biology. AB - Importin alpha proteins function as adaptors to connect a cargo protein and importin beta1 in the classical nuclear import pathway. Here we measure for the first time the stoichiometry of importins alpha2, alpha3, alpha4, and beta1 in primary cells corresponding to 2 successive stages of rat spermatogenesis: meiotic spermatocytes and haploid round spermatids. Importin alpha2 levels were more than 2-fold higher in spermatocytes than in spermatids, while importins alpha4 and beta1 levels did not differ significantly. We performed a comprehensive proteomics analysis to identify binding proteins in spermatocytes and spermatids using recombinant importin alpha2 and alpha4 proteins. Among the 100 candidate partners, 42 contained a strong classical nuclear localization signal (cNLS; score of>6 by cNLS Mapper), while 8 nuclear proteins lacked any cNLS. In addition, we developed a new strategy to predict which cargoes bind to importin alpha through the conserved C-terminal acidic domain (ARM repeats 9-10), and provided functional validation of a predicted importin alpha C-terminal binding segment in Senataxin and Smarca4. Evaluation of this set of candidate binding partners from spermatogenic cells using several bioinformatics approaches provides new evidence that individual importin alphas may serve unique and nonredundant roles in mediating cellular differentiation. PMID- 24790036 TI - [Healthcare IT and medication: how does healthcare IT-ization affect medication development and medication safety assurance?]. PMID- 24790035 TI - Connecting the nucleolus to the cell cycle and human disease. AB - Long known as the center of ribosome synthesis, the nucleolus is connected to cell cycle regulation in more subtle ways. One is a surveillance system that reacts promptly when rRNA synthesis or processing is impaired, halting cell cycle progression. Conversely, the nucleolus also acts as a first-responder to growth related stress signals. Here we review emerging concepts on how these "infraribosomal" links between the nucleolus and cell cycle progression operate in both forward and reverse gears. We offer perspectives on how new cancer therapeutic designs that target this infraribosomal mode of cell growth control may shape future clinical progress. PMID- 24790037 TI - [Medical IT-ization and development of pharmacists business]. AB - Two major trends are materializing: the super-aging of society and information technology (IT-ization). Thus, the most important action to benefit patients and society is to establish a medical information network supported by a trustworthy human network. This network should be organized by the people involved in local community healthcare. As such, it is essential for the human network to include not only hospitals and clinics (medical practitioners) but also community pharmacies (pharmacists). This need is apparent, because in the past, drug hazards recurred because fundamental improvement of the means to prevent those hazards was not possible without pharmacists where and when those incidences occurred. The medical information to be IT-ized would include drug notebooks and prescription cards, although electronic medical charts will be the ultimate source of information. The following points will be discussed in this paper: (a) Legal requirements for physical assessments by pharmacists, (b) Physical assessments by hospital pharmacists, (c) Physical assessments by community pharmacists, and (d) Security requirements for the Act for Protection of Personal Information, Articles 20-22. PMID- 24790038 TI - [A community electronic prescription system connecting physicians, pharmacists, and patients, and utilization of clinical information]. AB - We tested a community electronic prescription system (K-CHOPS/PPISS) that we developed in Kagawa, Japan, which connects the prescribing physicians, pharmacists at community pharmacies, and patients through a community data center server. Physicians can send prescriptions, diagnoses, and laboratory data to the datacenter. Pharmacists in community pharmacies can access their patients' information through the datacenter and can return corrected prescriptions and reports containing guidance and adverse events to the hospital or clinic where the prescription was issued. Patients can then see their dispensed medications on their PCs, cellular phones, and smart phones. Additionally, patients can input medication-taking records, allergy and adverse drug reactions (ADR), any over-the counter drug and supplements that they take, and their physical condition through the devices. The system enables pharmacists to appropriately advise and monitor ADR based on patient clinical data and enables physicians to accurately know the medications handed to patients and advisories issued by the pharmacists. Further, physicians and pharmacists can see the patients' condition which they entered on their devices if the patients agree. These would be helpful for avoiding ADR. The information accumulated in the data center can be potentially utilized for evaluation of the effectiveness and ADR of medications and for development of innovative medication. Discussion of the pros and cons for such utilization is needed. PMID- 24790039 TI - [Information technology for ensuring drug safety]. AB - In Japan, information technology (IT) in the medical field has prevailed as a means for handling claims for health insurance reimbursement. In contrast, IT is primarily used for electronic medical records in Western countries. Originally, preparation of health insurance claims was one of the outcomes of computerized medical information in Japan. As its protocols are already well established in Japan, information from the insurance claim system is hard to integrate into the Electronic Medical Chart system. To ensure drug safety, it is necessary to determine the number of users, and to accurately tabulate the incidence of adverse events. For this purpose, three kinds of information are required: prescription information, dispensing information, and drug administration information. Prescription information and dispensing information should be consistent with each other in content. Dispensing information is essential to identify the "substance" when adverse events occur. Drug administration information is the "true drug history". With these three kinds of information, it should be possible to enter drug safety data as evidence. To accurately capture these three kinds of information, it is necessary to utilize Standard Drug Code and Standard Usage Master, suggesting that it may be necessary to reconstruct the current system. PMID- 24790040 TI - [Patient database and orphan drug development]. AB - There is no concept of rare disease (RD) but Nambyo (intractable disease) since 1972. In 1995 the definition of Nambyo included the concept of rareness and the frequency for a Nambyo is less than 50000 in Japanese population. Currently Nambyo are selected for special research support, and special treatment of medical expenses. The budget for research is 10 billion yen. The approximate number of medical recipients is estimated to be 700000. The measures already developed for Nambyo are not comprehensive, therefore currently several additional measures are being envisaged. We are now planning to join the Orphanet. The expectations for Orphanet Japan are to: Enhance international collaboration of RD, providing international up-to-date information of RD in Japanese, inform historical and up-to-date research of Nambyo, and promote information exchange, joint research and network establishment. It is necessary to make a Patient Registry for rare disease, and hopefully have a structure to integrate worldwide registry with same concept. Recently "International Rare Disease Research Consortium (IRDiRC)" was formed. The purpose of this consortium is to make an international coordination of the rare disease research, and to integrate the knowledge of the rare disease research. We will also talk about the Patient Registry by Patient Advocacy group, including Patient Reported Outcome (PRO). PMID- 24790041 TI - [Privacy and public benefit in using large scale health databases]. AB - In Japan, large scale heath databases were constructed in a few years, such as National Claim insurance and health checkup database (NDB) and Japanese Sentinel project. But there are some legal issues for making adequate balance between privacy and public benefit by using such databases. NDB is carried based on the act for elderly person's health care but in this act, nothing is mentioned for using this database for general public benefit. Therefore researchers who use this database are forced to pay much concern about anonymization and information security that may disturb the research work itself. Japanese Sentinel project is a national project to detecting drug adverse reaction using large scale distributed clinical databases of large hospitals. Although patients give the future consent for general such purpose for public good, it is still under discussion using insufficiently anonymized data. Generally speaking, researchers of study for public benefit will not infringe patient's privacy, but vague and complex requirements of legislation about personal data protection may disturb the researches. Medical science does not progress without using clinical information, therefore the adequate legislation that is simple and clear for both researchers and patients is strongly required. In Japan, the specific act for balancing privacy and public benefit is now under discussion. The author recommended the researchers including the field of pharmacology should pay attention to, participate in the discussion of, and make suggestion to such act or regulations. PMID- 24790042 TI - [The cutting edge of epithelium-targeted drug development]. PMID- 24790043 TI - [Molecular organization of tricellular tight junctions]. AB - Within an epithelial cellular sheet, the paracellular pathway can be divided into two routes: one between two adjacent cells and one at tricellular contacts, where the vertices of three cells meet. For epithelial barrier function, tight junctions restrict solute permeability through the paracellular pathway between two cells, while tricellular contacts contain specialized structures of tight junctions, named tricellular tight junctions (tTJs). Two types of membrane proteins, tricellulin and angulin family proteins (angulin-1/LSR, angulin-2/ILDR1 and angulin-3/ILDR2) have been identified as molecular components of tTJs. Angulins recruit triellulin to tTJs and these tTJ-associated proteins are required for normal tTJ formation as well as strong epithelial barrier function. Furthermore, mutations in tricellulin and angulin-2/ILDR1 genes cause autosomal recessive familial deafness, DFNB49 and DFNB42, respectively. Further analyses of the angulin-tricellulin system should lead to better understanding of the molecular mechanism and regulation of tTJs. PMID- 24790044 TI - [Structural and immunological barriers of the skin as potential therapeutic targets]. AB - Skin is the structure that covers our body and protects it from not only the entry of pathogens or allergens but also from the leakage of water, solutes or nutrients. These outside-in and inside-out skin barrier functions are dependent on the epidermis, a stratified epithelial cellular sheet. While mucus covers the epidermis in fish and amphibian tadpoles, terminally differentiated cornified cellular sheets called stratum corneum (SC) constitute the outermost epidermal barrier in amphibian adults, reptiles, birds and mammals. Beneath the mucus or SC, apical paracellular spaces of epidermal cells are sealed with tight junctions (TJs) that limit paracellular leakage of water and electrolytes to maintain fluid homeostasis. We applied time-of-flight secondary-ion-mass-spectrometry (TOF-SIMS) imaging technology to analyze the SC in skin sections, and found that the SC consisting of three layers of distinct functional properties. Under the barriers of the SC and TJ, antigen-presenting dendritic cells called Langerhans cells (LCs) distribute within the epidermis. LCs elongate their dendrites to penetrate through epidermal TJs upon activation and uptake antigens from extra-TJ environment. During antigen uptake, new TJs are formed between keratinocytes and LC dendrites to maintain the integrity of epidermal TJ barriers. To understand the epidermal barrier system and its deficiency observed in human skin diseases, we need to re-evaluate human epidermal barrier as a composite barrier consisting of SC and TJs and to investigate the molecular mechanism and immunological consequences of the extra-TJ antigen uptake activity of LCs. PMID- 24790045 TI - [The development of mucosal vaccine using bacterial function for targeting mucosal tissues]. AB - Most pathogens invade body through the mucosal epithelium, which is a primary target to prevent the infectious diseases. Mucosal vaccine has been considered to be an effective strategy to establish immunosurveillance against pathogens by the induction of antigen-specific immune responses at both mucosal and systemic immune compartments. The development of antigen delivery system and mucosal adjuvants are required for the sufficient induction of protective immunity in the development of mucosal vaccine. In this review, we shed light on the recent advances in the development of antigen delivery system using microbial functions for mucosal vaccines. PMID- 24790046 TI - [Claudin 1 as a target for anti-hepatitis C virus strategy]. AB - Chronic hepatitis C virus (HCV) infection is a global public health issue because ~30% of HCV-carriers develop severe liver diseases including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. Not only viral factors but also host/viral interactions are promising targets for antiviral preventive and therapeutic strategies. Recent studies showed that a tight junction protein claudin 1 is involved in HCV entry into host cells. Consistent with these studies, we isolated the several hepatic Huh7-derived cell clones defective in claudin 1 as HCV-resistant mutants, and cellular permissiveness to HCV was restored by expression of claudin 1 into these cell mutants. These results strongly suggest that claudin 1 is a promising target for antiviral therapy. We thus tried to isolate antibodies against extracellular domain of human claudin 1. Finally we established four mouse anti-claudin 1 monoclonal antibodies by using DNA immunization method and hybridoma screening with the above claudin 1 defective mutant. In the cell culture-infection system using Huh7.5.1 cells and HCV-JFH1 strain, these four antibodies efficiently inhibited infection by HCV in a dose-dependent manner, but do not affect tight junction localization of claudin 1 and cellular barrier function. These monoclonal antibodies targeting claudin 1 might be useful for preventing HCV infection, such as after liver transplantation, and also blocking viral spread in HCV-infected patients. PMID- 24790047 TI - [The new era of epithelium-targeted drug development]. AB - Epithelium plays pivotal roles in biological barrier separating the inside of body and the outside environment. Ninety percent of malignant tumors are derived from epithelium. Most pathological microorganisms invade into the body from mucosal epithelium. Thus, epithelium is potential targets for drug development. Claudins (CLs), a family of tetra-transmembrane protein consisting of over 20 members, are structural and functional components of tight junction-seals in epithelium. Modulation of CL-seals enhanced mucosal absorption of drugs. CLs are often over-expressed in malignant tumors. CL-4 expression is increased in the epithelial cells covering the mucosal immune tissues. Very recently, CLs are also expected to be targets for traumatic brain injury and regenerative therapy. In this review, we overview the past, the present and the future of CLs-targeted drug development. PMID- 24790048 TI - [Unraveling molecular mechanism of cell migration using novel perturbation tools]. AB - Complexity in signaling networks is often derived from co-opting particular sets of molecules for multiple operations. Understanding how cells achieve such sophisticated processing using a finite set of molecules within a confined space what we call the "signaling paradox"- is critical to cell biology and bioengineering as well as the emerging field of synthetic biology. We have recently developed a series of chemical-molecular tools that allow for inducible, quick-onset and specific perturbation of various signaling molecules. The present technique has been employed to unravel several important, previously unresolved questions regarding the regulatory mechanisms of potassium ion channels, the membrane targeting mechanisms of small GTPases and positive feedback machinery in neutrophil migration. Using this novel technique in conjunction with conventional fluorescence imaging and biochemical analysis, we are currently further dissecting intricate signaling networks in living cells. Ultimately, we will generate completely orthogonal machinery in cells to achieve existing, as well as novel, cellular functions. Our synthetic, multidisciplinary approach will elucidate the signaling paradox in cells created by nature. PMID- 24790049 TI - [Multivariate quantification of acupuncture and moxibustion treatment in combination with questionnaire and salivary stress markers]. AB - Pain and stress alleviation after acupuncture treatment was assessed in this study. Patients responded to a questionnaire designed to determine the amount of stress they were experiencing, and data were obtained for patient salivary amylase, cortisol, secretary IgA (s-IgA), and leptin receptor (OBRb). As a part of this study on acute pain, 6 factors were extracted from the questionnaire. The second factor (pain removal) was well correlated with salivary amylase activity in patients with cervico-omo-brachial syndrome. An evaluation of cumulative acupuncture treatments showed that salivary cortisol increased and s-IgA decreased. In addition, a decreased s-IgA level significantly correlated with chronic pain removal. The questionnaire correlated well with measurements of salivary markers suggesting that they can be taken as indices of therapeutic efficacy in acupuncture treatment. PMID- 24790050 TI - [Blending powdered antineoplastic medicine in disposable ointment container]. AB - On dispensing powdered antineoplastic medicines, it is important to prevent cross contamination and environmental exposure. Recently, we developed a method for blending powdered medicine in a disposable ointment container using a planetary centrifugal mixer. The disposable container prevents cross-contamination. In addition, environmental exposure associated with washing the apparatus does not arise because no blending blade is used. In this study, we aimed to confirm the uniformity of the mixture and weight loss of medicine in the blending procedure. We blended colored lactose powder with Leukerin((r)) or Mablin((r)) powders using the new method and the ordinary pestle and mortar method. Then, the blending state was monitored using image analysis. Blending variables, such as the blending ratio (1:9-9:1), container size (35-125 mL), and charging rate (20-50%) in the container were also investigated under the operational conditions of 500 rpm and 50 s. At a 20% charging rate in a 35 mL container, the blending precision of the mixtures was not influenced by the blending ratio, and was less than 6.08%, indicating homogeneity. With an increase in the charging rate, however, the blending precision decreased. The possible amount of both mixtures rose to about 17 g with a 20% charging rate in a 125 mL container. Furthermore, weight loss of medicines with this method was smaller than that with the pestle and mortar method, suggesting that this method is safer for pharmacists. In conclusion, we have established a precise and safe method for blending powdered medicines in pharmacies. PMID- 24790051 TI - [Usefulness of one point measurement method of pediatric dose and UV spectrophotometry for filterability test of in-line filter]. AB - The adsorption of Bevacizumab, Trastuzumab, Rituximab, Nedaplatin, Vincristine sulfate, Nogitecan hydrochloride, Actinomycin D and Ramosetron hydrochloride to 0.2 MUm endotoxin-retentive in-line filters was evaluated with pediatric doses by UV spectrophotometry. The results indicated that some drug adsorption was shown with Nogitecan hydrochloride, Actinomycin D and Ramosetron hydrochloride, and good recovery was shown with the other five drugs. For the three drugs which showed some losses, drug recovery was investigated at multiple test doses. The approximation formula for each drug adsorption was recorded as Y=100-A/X (X: dose (mg), Y: recovery rate (%), A: a constant for individual drug). The results showed there was high correlation between the reciprocal of test drug dose and the recovery rate. Furthermore, in the cases where adsorption to the filter were observed, it was found that it was possible to determine the relationship between dose and the recovery rate from a filterability test with one point pediatric dose. Since the recovery rate obtained from the approximation formula with multiple doses and that calculated from the prediction formula with one point pediatric dose were almost the same, then it was concluded that it is not necessary to conduct the filterability tests with multiple doses. We have shown that using UV spectrophotometry and carrying out a filterability test using one point pediatric dose is relatively easy method and reduces the effort and expense. This method for analysis of drug adsorption is extremely useful when using in-line filters with infusion therapy. PMID- 24790052 TI - [Fundamental study on effect of high-mineral drinking water for osteogenesis in calciprivia ovariectomized rats]. AB - Since osteoporosis is a major public health problem in Japan, it is important to clarify the effect of high-mineral drinking water consumption on osteogenesis. Therefore, in this study, we investigated the relationship between high-mineral drinking water consumption and osteogenesis in ovariectomized rats that received a low-calcium diet and purified water (PW group) or a low-calcium diet and high mineral drinking water (CR group). High-mineral drinking water affected the rats' body weight. After 3 months, the bone density of the CR group was higher than that of the PW group (p<0.05). Furthermore, the CR group showed a decrease in the amount of calcium in the bones after 3 months. These results suggest that high mineral drinking water contributes to the maintenance of bone density and not to the amount of calcium in bone. On the other hand, serum alkaline phosphatase levels in the PW group at 3 months were higher than those in the CR group, which indicates that the blood concentration of calcium in the CR group was maintained. Moreover, the amount of magnesium in the bones and the blood concentration of magnesium in the CR group after 3 months were higher than the corresponding values in the PW group. These results suggest that consumption of high-mineral drinking water could be beneficial for osteogenesis (i.e., for maintaining bone quantity). PMID- 24790053 TI - Incidence and relative risk of hearing disorders in professional musicians. AB - BACKGROUND: Hearing disorders have been associated with occupational exposure to music. Musicians may benefit from non-amplified and low-intensity music, but may also have high risks of music-induced hearing loss. AIMS: To compare the incidence of hearing loss (HL) and its subentities in professional musicians with that in the general population. METHODS: We performed a historical cohort study among insurants between 19 and 66 years who were employed subject to social insurance contributions. The study was conducted with data from three German statutory health insurance providers covering the years 2004-2008 with about 7 million insurants. Incidence rates with 95% CIs of HL and the subentities noise induced hearing loss (NIHL), conductive HL, sensorineural HL, conductive and sensorineural HL, as well as tinnitus were estimated stratified by age, sex and federal state. A Cox regression analysis was conducted to estimate adjusted HRs and two-sided 95% CIs for HL and its subentities. RESULTS: More than 3 million insurants were eligible, of whom 2227 were identified as professional musicians (0.07%). During the 4-year observation period, 283,697 cases of HL were seen, 238 of them among professional musicians (0.08%), leading to an unadjusted incidence rate ratio of 1.27. The adjusted hazard ratio of musicians was 1.45 (95% CI 1.28 to 1.65) for HL and 3.61 (95% CI 1.81 to 7.20) for NIHL. CONCLUSIONS: Professional musicians have a high risk of contracting hearing disorders. Use of already available prevention measures should reduce the incidence of HL in professional musicians. PMID- 24790054 TI - Are there any new pharmacologic therapies on the horizon to better treat hypertension? A state-of-the-art paper. AB - Hypertension is the most important cardiovascular risk factor. We have witnessed a significant improvement in hypertension treatment and control and an impressive growth in the pharmacologic options available to clinicians and hypertension specialists. With up to a third of patients with hypertension not at the recommended goal blood pressures, it is critically important to develop novel therapeutic approaches to better treat hypertension. This review will explore the ever-expanding horizon of antihypertensive treatment and will focus on 2 major areas of drug development. First, we will review novel targets for pharmacologic treatment and novel molecules and classes of drugs in various phases of development and recognize the limitations we face in their transition from research and development to clinical practice. Then, we will discuss an expanding array of combination strategies to better treat hypertension with the goal of minimizing the burden of cardiovascular and renal complications of hypertension. PMID- 24790055 TI - Rescuing the duty to rescue. AB - Clinicians and health researchers frequently encounter opportunities to rescue people. Rescue cases can generate a moral duty to aid those in peril. As such, bioethicists have leveraged a duty to rescue for a variety of purposes. Yet, despite its broad application, the duty to rescue is underanalysed. In this paper, we assess the state of theorising about the duty to rescue. There are large gaps in bioethicists' understanding of the force, scope and justification of the two most cited duties to rescue--the individual duty of easy rescue and the institutional rule of rescue. We argue that the duty of easy rescue faces unresolved challenges regarding its force and scope, and the rule of rescue is indefensible. If the duty to rescue is to help solve ethical problems, these theoretical gaps must be addressed. We identify two further conceptions of the duty to rescue that have received less attention--an institutional duty of easy rescue and the professional duty to rescue. Both provide guidance in addressing force and scope concerns and, thereby, traction in answering the outstanding problems with the duty to rescue. We conclude by proposing research priorities for developing accounts of duties to rescue in bioethics. PMID- 24790056 TI - T-cell immunity in the aging human. PMID- 24790057 TI - Current pre-clinical and clinical advances in the BCR-ABL1-positive and -negative chronic myeloproliferative neoplasms. PMID- 24790058 TI - Nature and importance of follicular lymphoma precursors. AB - It is now widely recognized that cancer development is a protracted process requiring the stepwise acquisition of multiple oncogenic events. In humans, this process can take decades, if not a lifetime, blurring the notion of 'healthy' individuals. Follicular lymphoma exemplifies this multistep pathway of oncogenesis. In recent years, variants of follicular lymphoma have been recognized that appear to represent clonal B-cell expansions at an early stage of follicular lymphoma lymphomagenesis. These include follicular lymphoma in situ, duodenal follicular lymphoma, partial involvement by follicular lymphoma, and in the blood circulating follicular lymphoma-like B cells. Recent genetic studies have identified similarities and differences between the early lesions and overt follicular lymphoma, providing important information for understanding their biological evolution. The data indicate that there is already genomic instability at these early stages, even in instances with a low risk for clinical progression. The overexpression of BCL2 in t(14;18)-positive B cells puts them at risk for subsequent genetic aberrations when they re-enter the germinal center and are exposed to the influences of activation-induced cytidine deaminase and somatic hypermutations. The emerging data provide a rationale for clinical management and, in the future, may identify genetic risk factors that warrant early therapeutic intervention. PMID- 24790060 TI - Quantification of five compounds with heterogeneous physicochemical properties (morphine, 6-monoacetylmorphine, cyamemazine, meprobamate and caffeine) in 11 fluids and tissues, using automated solid-phase extraction and gas chromatography tandem mass spectrometry. AB - An automated solid-phase extraction (SPE) protocol followed by gas chromatography coupled with tandem mass spectrometry was developed for quantification of caffeine, cyamemazine, meprobamate, morphine and 6-monoacetylmorphine (6-MAM) in 11 biological matrices [blood, urine, bile, vitreous humor, liver, kidney, lung and skeletal muscle, brain, adipose tissue and bone marrow (BM)]. The assay was validated for linearity, within- and between-day precision and accuracy, limits of quantification, selectivity, extraction recovery (ER), sample dilution and autosampler stability on BM. For the other matrices, partial validation was performed (limits of quantification, linearity, within-day precision, accuracy, selectivity and ER). The lower limits of quantification were 12.5 ng/mL(ng/g) for 6-MAM, morphine and cyamemazine, 100 ng/mL(ng/g) for meprobamate and 50 ng/mL(ng/g) for caffeine. Analysis of real-case samples demonstrated the performance of the assay in forensic toxicology to investigate challenging cases in which, for example, blood is not available or in which analysis in alternative matrices could be relevant. The SPE protocol was also assessed as an extraction procedure that could target other relevant analytes of interest. The extraction procedure was applied to 12 molecules of forensic interest with various physicochemical properties (alimemazine, alprazolam, amitriptyline, citalopram, cocaine, diazepam, levomepromazine, nordazepam, tramadol, venlafaxine, pentobarbital and phenobarbital). All drugs were able to be detected at therapeutic concentrations in blood and in the alternate matrices. PMID- 24790061 TI - Validation of an automated solid-phase extraction method for the analysis of 23 opioids, cocaine, and metabolites in urine with ultra-performance liquid chromatography-tandem mass spectrometry. AB - The aim of this work was to automate a sample preparation procedure extracting morphine, hydromorphone, oxymorphone, norcodeine, codeine, dihydrocodeine, oxycodone, 6-monoacetyl-morphine, hydrocodone, ethylmorphine, benzoylecgonine, cocaine, cocaethylene, tramadol, meperidine, pentazocine, fentanyl, norfentanyl, buprenorphine, norbuprenorphine, propoxyphene, methadone and 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidine from urine samples. Samples were extracted by solid-phase extraction (SPE) with cation exchange cartridges using a TECAN Freedom Evo 100 base robotic system, including a hydrolysis step previous extraction when required. Block modules were carefully selected in order to use the same consumable material as in manual procedures to reduce cost and/or manual sample transfers. Moreover, the present configuration included pressure monitoring pipetting increasing pipetting accuracy and detecting sampling errors. The compounds were then separated in a chromatographic run of 9 min using a BEH Phenyl analytical column on a ultra-performance liquid chromatography-tandem mass spectrometry system. Optimization of the SPE was performed with different wash conditions and elution solvents. Intra- and inter-day relative standard deviations (RSDs) were within +/-15% and bias was within +/-15% for most of the compounds. Recovery was >69% (RSD < 11%) and matrix effects ranged from 1 to 26% when compensated with the internal standard. The limits of quantification ranged from 3 to 25 ng/mL depending on the compound. No cross-contamination in the automated SPE system was observed. The extracted samples were stable for 72 h in the autosampler (4 degrees C). This method was applied to authentic samples (from forensic and toxicology cases) and to proficiency testing schemes containing cocaine, heroin, buprenorphine and methadone, offering fast and reliable results. Automation resulted in improved precision and accuracy, and a minimum operator intervention, leading to safer sample handling and less time-consuming procedures. PMID- 24790059 TI - Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. AB - Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management. PMID- 24790062 TI - Quantitative analysis of zopiclone, N-desmethylzopiclone, zopiclone N-oxide and 2 amino-5-chloropyridine in urine using LC-MS-MS. AB - A simple liquid chromatography-tandem mass spectrometry method was validated to allow determination of zopiclone (ZOP), N-desmethylzopiclone (NDZOP), zopiclone N oxide (ZOPNO) and 2-amino-5-chloropyridine (ACP) in urine at concentrations up to 3,000 ng/mL within 3.5 min. This method was used for quantitative analysis of the analytes in authentic urine samples obtained 10 h after oral administration of zopiclone (Imovane((r))) and in aliquots of the same urine samples after different storage conditions. In addition, pH of each studied urine sample was measured over time. The results showed that formation of ACP occurred at elevated pH and/or temperature by degradation of ZOP, NDZOP and ZOPNO. This method was also applied to samples obtained from two female victims of drug-facilitated assault. One sample had been exposed to long-term storage conditions at different temperatures and at pH >8.2, which resulted in high concentrations of ACP. The other sample, which was exposed to pH <6.5, showed no formation of ACP. ACP is formed both from ZOP and from its metabolites NDZOP and ZOPNO depending on the pH of the urine, time of storage and/or the temperature conditions. For correct interpretation in forensic cases, ZOP, its major metabolites and ACP should be analyzed. When ACP is identified in urine, the concentrations of ZOP, NDZOP and ZOPNO should be interpreted with great caution. PMID- 24790063 TI - Curing over-use by prescribing fees: an evaluation of the effect of user fees' implementation on healthcare use in the Czech Republic. AB - In 2008, the Czech Republic instituted a new policy that requires most patients to pay a small fee for some inpatient and outpatient healthcare services. Using the Survey of Health Aging and Retirement in Europe, this article examines the changes in healthcare utilization of Czechs 50 years and older following the new fee requirement by constructing difference-in-differences regression models focusing on four outcome measures: any visits to primary care physician, any hospitalization, number of visits to the primary care physician and number of nights hospitalized. For this population, I find that the likelihood of having any primary care visit decreased after the policy was instituted. The likelihood of reporting any hospitalization was not significantly changed. The predicted number of primary care visits per person declined, but the predicted number of nights spent in a hospital did not. I find only mixed evidence of greater effect of the user fees on some subpopulations compared with others. Those 65 or older reduced their use more than those between 50 and 64, and so did those who consider their health to be good, and the less educated. PMID- 24790064 TI - Creation Ethics and the harms of existence. PMID- 24790065 TI - Musculoskeletal disorders and the Global Burden of Disease study. PMID- 24790066 TI - Is there a need for new agents with novel mechanisms of action in psoriatic arthritis? PMID- 24790067 TI - A patient-derived and patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary validation of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, a 13-country EULAR initiative. AB - INTRODUCTION: The objective was to develop a questionnaire that can be used to calculate a score reflecting the impact of psoriatic arthritis (PsA) from the patients' perspective: the PsA Impact of Disease (PsAID) questionnaire. METHODS: Twelve patient research partners identified important domains (areas of health); 139 patients prioritised them according to importance. Numeric rating scale (NRS) questions were developed, one for each domain. To combine the domains into a single score, relative weights were determined based on the relative importance given by 474 patients with PsA. An international cross-sectional and longitudinal validation study was performed in 13 countries to examine correlations of the PsAID score with other PsA or generic disease measures. Test-retest reliability and responsiveness (3 months after a treatment change) were examined in two subsets of patients. RESULTS: Two PsAID questionnaires were developed with both physical and psychological domains: one for clinical practice (12 domains of health) and one for clinical trials (nine domains). Pain, fatigue and skin problems had the highest relative importance. The PsAID scores correlated well with patient global assessment (N=474, Spearman r=0.82-0.84), reliability was high in stable patients (N=88, intraclass correlation coefficient=0.94-0.95), and sensitivity to change was also acceptable (N=71, standardised response mean=0.90 0.91). CONCLUSIONS: A questionnaire to assess the impact of PsA on patients' lives has been developed and validated. Two versions of the questionnaire are available, one for clinical practice (PsAID-12) and one for clinical trials (PsAID-9). The PsAID questionnaires should allow better assessment of the patient's perspective in PsA. Further validation is needed. PMID- 24790068 TI - International differences in acute coronary syndrome patients' baseline characteristics, clinical management and outcomes in Western Europe: the EURHOBOP study. AB - OBJECTIVE: We aimed to describe current characteristics of patients admitted for acute coronary syndrome (ACS) in Western Europe and to analyse whether international in-hospital mortality variations are explained by differences in patients' baseline characteristics and in clinical management. METHODS: We studied a population-based longitudinal cohort conducted in Finland, France, Germany, Greece, Portugal and Spain, and comprising 12 231 consecutive ACS patients admitted in 53 hospitals between 2008 and 2010. Baseline characteristics, clinical management and inhospital outcomes were recorded. Contextual effect of country on death was analysed through multilevel analysis. RESULTS: Of all patients included, 8221 (67.2%) had NSTEMI (non-ST-elevation myocardial infarction), and 4010 (32.8%) had STEMI (ST-elevation myocardial infarction). Inhospital mortality ranged from 15.1% to 4.9% for German and Spanish STEMI patients, and from 6.8% to 1.9% for Finnish and French NSTEMI patients (p<0.001 for both). These international variations were explained by differences in patients' baseline characteristics (older patients more likely to have cardiogenic shock in Germany) and in clinical management, with differences in rates of thrombolysis (less performed in Germany) and primary percutaneous coronary intervention (high in Germany, low in Greece). A remaining contextual effect of country was identified after extensive adjustment. CONCLUSIONS: Inhospital mortality rates of STEMI and NSTEMI patients were two to three times higher in Finland, Germany and Portugal than in Greece and Spain, with intermediate values for France. Differences in baseline characteristics and clinical management partly explain differences in outcome. Our data also suggest an impact of the healthcare system organisation. PMID- 24790069 TI - Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial. AB - OBJECTIVE: Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). METHODS: We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1 year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. RESULTS: Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [-6.6 mm Hg (95% CI -13.0 to -0.3), p=0.042] and augmentation index [-4.4% (95% CI -7.9 to -1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [-0.097 mm (95% CI 0.175 to -0.019), p=0.015]. No difference was observed for measures of endothelial function. CONCLUSIONS: Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. TRIAL REGISTRATION NUMBER: ISRCTN11970568. PMID- 24790070 TI - C-reactive protein in adults with pulmonary arterial hypertension associated with congenital heart disease and its prognostic value. AB - OBJECTIVES: To assess the relationship of C-reactive protein (CRP) to clinical outcome and mortality in adults with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). BACKGROUND: Approximately 5 10% of adults with congenital heart disease (ACHD) develop PAH, which in turn is associated with substantial morbidity and mortality. Although CRP is known to predict outcome in idiopathic PAH, little is known regarding its prognostic value in CHD-PAH. METHODS: We obtained and analysed 1936 CRP values in a total of 225 adults with CHD-PAH (median age at study entry 34.0 years (27.0-41.7); 32.9% male, 35% with Down syndrome), performed over a 12-year period. High CRP values related to infection or blood transfusions were excluded from the analysis. RESULTS: During a median follow-up of 4.8 years (1149 patients-years), 50 patients died. The median CRP concentration on the last assessment was 5.0 mg/L (IQR 2.0-10.0), higher in deceased patients compared with survivors (11.5 mg/L (6.0-23.0) vs 4.0 mg/L (1.5-8.0), p<0.0001). Following univariate Cox regression analysis, CRP emerged as a strong predictor of mortality (HR 1.18; 95% CI 1.11 to 1.26, p<0.0001) and remained significant after adjustment for age, presence of Down syndrome and advanced PAH therapy. Survival-receiver-operator characteristic analysis identified an optimal cut-off value of 10 mg/L. Patients with CRP >10 mg/L had more than a threefold increased risk of death (HR 3.63, 95% CI 2.07 to 6.38, p<0.0001). CONCLUSIONS: Serum CRP is a simple but powerful marker of mortality in CHD-PAH patients and should be incorporated in the risk stratification and routine assessment of these patients. PMID- 24790071 TI - Cleft lip and palate. PMID- 24790072 TI - Infectious diseases in early education and child care programs. PMID- 24790073 TI - Cystic fibrosis. PMID- 24790074 TI - Index of suspicion. PMID- 24790076 TI - Syphilis. PMID- 24790077 TI - Visual diagnosis: nasal congestion and respiratory distress in a 7-day-old girl. PMID- 24790078 TI - Release of interleukin-1alpha or interleukin-1beta depends on mechanism of cell death. AB - The cytokine interleukin-1 (IL-1) has two main pro-inflammatory forms, IL-1alpha and IL-1beta, which are central to host responses to infection and to damaging sterile inflammation. Processing of IL-1 precursor proteins to active cytokines commonly occurs through activation of proteases, notably caspases and calpains. These proteases are instrumental in cell death, and inflammation and cell death are closely associated, hence we sought to determine the impact of cell death pathways on IL-1 processing and release. We discovered that apoptotic regulation of caspase-8 specifically induced the processing and release of IL-1beta. Conversely, necroptosis caused the processing and release of IL-1alpha, and this was independent of IL-1beta processing and release. These data suggest that the mechanism through which an IL-1-expressing cell dies dictates the nature of the inflammatory mechanism that follows. These insights may allow modification of inflammation through the selective targeting of cell death mechanisms during disease. PMID- 24790079 TI - 3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) induced 28-kDa interleukin-1beta interferes with mature IL-1beta signaling. AB - Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1beta (IL-1beta) is synthesized as a non-active precursor. The 31-kDa pro-IL-1beta is processed into the 17-kDa active form by caspase-1 activating inflammasomes. Here, we report a novel signaling pathway induced by statins, which leads to processing of pro-IL-1beta into an intermediate 28-kDa form. This statin-induced IL-1beta processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1beta cannot activate interleukin 1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1beta signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1beta. These results may provide new clues to explain the anti-inflammatory effects of statins. PMID- 24790080 TI - Regulation of TGF-beta1-driven differentiation of human lung fibroblasts: emerging roles of cathepsin B and cystatin C. AB - Lung matrix homeostasis partly depends on the fine regulation of proteolytic activities. We examined the expression of human cysteine cathepsins (Cats) and their relative contribution to TGF-beta1-induced fibroblast differentiation into myofibroblasts. Assays were conducted using both primary fibroblasts obtained from patients with idiopathic pulmonary fibrosis and human lung CCD-19Lu fibroblasts. Pharmacological inhibition and genetic silencing of Cat B diminished alpha-smooth muscle actin expression, delayed fibroblast differentiation, and led to an accumulation of intracellular 50-kDa TGF-beta1. Moreover, the addition of Cat B generated a 25-kDa mature form of TGF-beta1 in Cat B siRNA-pretreated lysates. Inhibition of Cat B decreased Smad 2/3 phosphorylation but had no effect on p38 MAPK and JNK phosphorylation, indicating that Cat B mostly disturbs TGF beta1-driven canonical Smad signaling pathway. Although mRNA expression of cystatin C was stable, its secretion, which was inhibited by brefeldin A, increased during TGF-beta1-induced differentiation of idiopathic pulmonary fibrosis and CCD-19Lu fibroblasts. In addition, cystatin C participated in the control of extracellular Cats, because its gene silencing restored their proteolytic activities. These data support the notion that Cat B participates in lung myofibrogenesis as suggested for stellate cells during liver fibrosis. Moreover, we propose that TGF-beta1 promotes fibrosis by driving the effective cystatin C-dependent inhibition of extracellular matrix-degrading Cats. PMID- 24790082 TI - Synergistic mechanism for tetrandrine on fluconazole against Candida albicans through the mitochondrial aerobic respiratory metabolism pathway. AB - We found that tetrandrine (TET) can reverse the resistance of Candida albicans to fluconazole (FLC) and that this interaction is associated with the inhibition of drug efflux pumps. Mitochondrial aerobic respiration, which plays a major role in C. albicans metabolism, is the primary source of ATP for cellular processes, including the activation of efflux pumps. However, it was unclear if TET exerts its synergistic action against C. albicans via its impact on the mitochondrial aerobic respiratory metabolism. To investigate this mechanism, we examined the impact of FLC in the presence or absence of TET on two C. albicans strains obtained from a single parental source (FLC-sensitive strain CA-1 and FLC resistant strain CA-16). We analysed key measures of energy generation and conversion, including the activity of respiration chain complexes I and III (CI and CIII), ATP synthase (CV) activity, and the generation of reactive oxygen species (ROS), and studied intracellular ATP levels and the mitochondrial membrane potential (DeltaPsim), which has a critical impact on energy transport. Mitochondrial morphology was observed by confocal microscopy. Our functional analyses revealed that, compared with strains treated only with FLC, TET+FLC increased the ATP levels and decreased DeltaPsim in CA-1, but decreased ATP levels and increased DeltaPsim in CA-16 (P<0.05). Additionally, CI, CIII and CV activity decreased by 23-48%. The production of ROS increased by two- to threefold and mitochondrial morphology was altered in both strains. Our data suggested that TET impacted mitochondrial aerobic respiratory metabolism by influencing the generation and transport of ATP, reducing the utilization of ATP, and resulting in the inhibition of drug efflux pump activity. This activity contributed to the synergistic action of TET on FLC against C. albicans. PMID- 24790081 TI - Conserved modular domains team up to latch-open active protein kinase Calpha. AB - Signaling proteins comprised of modular domains have evolved along with multicellularity as a method to facilitate increasing intracellular bandwidth. The effects of intramolecular interactions between modular domains within the context of native proteins have been largely unexplored. Here we examine intra- and intermolecular interactions in the multidomain signaling protein, protein kinase Calpha (PKCalpha). We identify three interactions between two activated PKC molecules that synergistically stabilize a nanomolar affinity homodimer. Disruption of the homodimer results in a loss of PKC-mediated ERK1/2 phosphorylation, whereas disruption of the auto-inhibited state promotes the homodimer and prolongs PKC membrane localization. These observations support a novel regulatory mechanism wherein homodimerization dictates the equilibrium between the auto-inhibited and active states of PKC by sequestering auto inhibitory interactions. Our findings underscore the physiological importance of context-dependent modular domain interactions in cell signaling. PMID- 24790083 TI - Genetic characterization of Shigella spp. isolated from diarrhoeal and asymptomatic children. AB - Phenotypic and genetic characteristics of Shigella spp. isolated from diarrhoeal and asymptomatic children aged up to 5 years were analysed in this study. In total, 91 and 17 isolates were identified from diarrhoeal (case) and asymptomatic (control) children, respectively. All the isolates were tested for antimicrobial resistance, the presence of integrons, plasmid-mediated quinolone resistance (PMQR), virulence-associated genes and Shigella pathogenicity island (SH-PAI). The majority of the Shigella spp. from cases (68.1%) and controls (82.3%) were found to be resistant to fluoroquinolones. Integron carriage was detected more in cases (76.9%) than in controls (35.5%). Atypical class 1 integron was detected exclusively in Shigella flexneri from cases but not from the controls. PMQR genes such as aac(6')-Ib-cr and qnrS1 were detected in 82.4 and 14.3% of the isolates from cases and in 53 and 17.6% in controls, respectively. Shigella isolates from cases as well as from controls were positive for the invasive plasmid antigen H encoding gene ipaH. The other virulence genes such as virF, sat, setA, setB, sen and ial were detected in Shigella isolates in 80.2, 49.4, 27.4, 27.4, 80.2 and 79.1% of cases and in 64.7, 52.9, 17.6, 17.6, 64.7 and 64.7% of controls, respectively. The entire SH-PAI was detected in S. flexneri serotype 2a from cases and controls. In an isolate from a control child, the SH-PAI was truncated. Integrons, PMQR and virulence-encoding genes were detected more frequently in cases than in controls. In diarrhoea endemic areas, asymptomatic carriers may play a crucial role in the transmission of multidrug-resistant Shigella spp. with all the putative virulence genes. PMID- 24790084 TI - Identification of the crucial molecular events during the large-scale myoblast fusion in sheep. AB - It is well known that in sheep most myofibers are formed before birth; however, the crucial myogenic stage and the cellular and molecular mechanisms underpinning phenotypic variation of fetal muscle development remain to be ascertained. We used histological, microarray, and quantitative real-time PCR (qPCR) methods to examine the developmental characteristics of fetal muscle at 70, 85, 100, 120, and 135 days of gestation in sheep. We show that day 100 is an important checkpoint for change in muscle transcriptome and histomorphology in fetal sheep and that the period of 85-100 days is the vital developmental stage for large scale myoblast fusion. Furthermore, we identified the cis-regulatory motifs for E2F1 or MEF2A in a list of decreasingly or increasingly expressed genes between 85 and 100 days, respectively. Further analysis demonstrated that the mRNA and phosphorylated protein levels of E2F1 and MEF2A significantly declined with myogenic progression in vivo and in vitro. qRT-PCR analysis indicated that PI3K and FST, as targets of E2F1, may be involved in myoblast differentiation and fusion and that downregulation of MEF2A contributes to transition of myofiber types by differential regulation of the target genes involved at the stage of 85 100 days. We clarify for the first time the timing of myofiber proliferation and development during gestation in sheep, which would be beneficial to meat sheep production. Our findings present a repertoire of gene expression in muscle during large-scale myoblast fusion at transcriptome-wide level, which contributes to elucidate the regulatory network of myogenic differentiation. PMID- 24790085 TI - NFE2L2 polymorphisms, mortality, and metabolism in the general population. AB - The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) gene regulates transcription of enzymes involved in cellular detoxification and lipids homeostasis. NFE2L2 is associated with pathophysiology of atherosclerosis and chronic obstructive pulmonary disease (COPD). Therefore we studied the relation between NFE2L2 and all-cause, cardiovascular, and COPD mortality and its associations with triglyceride and cholesterol levels. We genotyped five tagging single nucleotide polymorphisms (SNPs) (rs4243387, rs2364723, rs13001694, rs1806649, and rs6726395) in NFE2L2 in 1,390 subjects from the Vlagtwedde Vlaardingen cohort. Participants were examined in 1989/1990 and followed up till the vital status evaluation on December 31st, 2008. Associations between SNPs and mortality were estimated by Cox proportional hazards regression, and associations between SNPs and triglyceride and cholesterol levels were tested with linear regression. After 18 yr, 284 (20.4%) subjects had died, 107 from cardiovascular disease and 20 from COPD. Minor allele carriers of rs13001694 had a significantly reduced risk of all-cause mortality compared with wild types: hazard ratio (HR) 0.8 [95% confidence interval (CI) 0.6 to 1.0]. Minor allele carriers of rs2364723 had significantly reduced risk of cardiovascular mortality: HR = 0.5 (95% CI: 0.3 0.7). This result was consistent in stratified analyses: females 0.4 (0.2-0.7), males 0.6 (0.3-0.9), never smokers 0.5 (0.2-1.1), ever smokers 0.5 (0.3-0.8). Minor allele carriers of rs1806649 had a markedly reduced COPD mortality: HR = 0.3 (95% CI: 0.1-0.9). Rs2364723 was associated with lower triglyceride levels. None of the SNPs was associated with cholesterol levels. This study shows for the first time that NFE2L2 is associated with reduced risk of all-cause, cardiovascular and COPD mortality in humans. PMID- 24790086 TI - Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat. AB - The inbred Brown Norway (BN) rat develops spontaneous ruptures of the internal elastic lamina (RIEL) of the abdominal aorta (AA) and iliac arteries. Prior studies with crosses of the BN/Orl RJ (susceptible) and LOU/M (resistant) showed the presence of a significant QTL on chromosome 5 and the production of congenic rats proved the involvement of this locus. In this study, we further dissected the above-mentioned QTL by creating a new panel of LOU.BN(chr5) congenic and subcongenic lines and reduced the locus to 5.2 Mb. Then we studied 1,002 heterogeneous stock (HS) rats, whose phenotyping revealed a low prevalence and high variability for RIEL. High-resolution mapping in the HS panel detected the major locus on chromosome 5 (log P > 35) and refined it to 1.4 Mb. Subsequently, RNA-seq analysis on AA of BN, congenics, and LOU revealed expression differences for only protease inhibitor 15 (Pi15) gene and a putative long intergenic noncoding RNA (lincRNA) within the linkage region. The high abundance of lincRNA with respect to reduced Pi15 expression, in conjunction with exertion of longitudinal strain, may be related to RIEL, indicating the potential importance of proteases in biological processes related to defective aortic internal elastic lamina structure. Similar mechanisms may be involved in aneurysm initiation in the human AA. PMID- 24790087 TI - Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone. AB - Failure of the ductus arteriosus (DA) to close at birth can lead to serious complications. Conversely, certain profound congenital cardiac malformations require the DA to be patent until corrective surgery can be performed. In each instance, clinicians have a very limited repertoire of therapeutic options at their disposal - indomethacin or ibuprofen to close a patent DA (PDA) and prostaglandin E1 to maintain patency of the DA. Neither treatment is specific to the DA and both may have deleterious off-target effects. Therefore, more therapeutic options specifically targeted to the DA should be considered. We hypothesized the DA possesses a unique genetic signature that would set it apart from other vessels. A microarray was used to compare the genetic profiles of the murine DA and ascending aorta (AO). Over 4,000 genes were differentially expressed between these vessels including a subset of ion channel-related genes. Specifically, the alpha and beta subunits of large-conductance calcium-activated potassium (BKCa) channels are enriched in the DA. Gain- and loss-of-function studies showed inhibition of BKCa channels caused the DA to constrict, while activation caused DA relaxation even in the presence of O2. This study identifies subsets of genes that are enriched in the DA that may be used to develop DA specific drugs. Ion channels that regulate DA tone, including BKCa channels, are promising targets. Specifically, BKCa channel agonists like NS1619 maintain DA patency even in the presence of O2 and may be clinically useful. PMID- 24790088 TI - A disintegrin and metalloprotease 17 dynamic interaction sequence, the sweet tooth for the human interleukin 6 receptor. AB - A disintegrin and metalloprotease 17 (ADAM17) is a major sheddase involved in the regulation of a wide range of biological processes. Key substrates of ADAM17 are the IL-6 receptor (IL-6R) and TNF-alpha. The extracellular region of ADAM17 consists of a prodomain, a catalytic domain, a disintegrin domain, and a membrane proximal domain as well as a small stalk region. This study demonstrates that this juxtamembrane segment is highly conserved, alpha-helical, and involved in IL 6R binding. This process is regulated by the structure of the preceding membrane proximal domain, which acts as molecular switch of ADAM17 activity operated by a protein-disulfide isomerase. Hence, we have termed the conserved stalk region "Conserved ADAM seventeen dynamic interaction sequence" (CANDIS). Finally, we identified the region in IL-6R that binds to CANDIS. In contrast to the type I transmembrane proteins, the IL-6R, and IL-1RII, CANDIS does not bind the type II transmembrane protein TNF-alpha, demonstrating fundamental differences in the respective shedding by ADAM17. PMID- 24790089 TI - The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease. AB - Microbes are detected by the pathogen-associated molecular patterns through specific host pattern recognition receptors. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular pattern recognition receptor that recognizes fragments of the bacterial cell wall. NOD2 is important to human biology; when it is mutated it loses the ability to respond properly to bacterial cell wall fragments. To determine the mechanisms of misactivation in the NOD2 Crohn mutants, we developed a cell-based system to screen for protein protein interactors of NOD2. We identified heat shock protein 70 (HSP70) as a protein interactor of both wild type and Crohn mutant NOD2. HSP70 has previously been linked to inflammation, especially in the regulation of anti-inflammatory molecules. Induced HSP70 expression in cells increased the response of NOD2 to bacterial cell wall fragments. In addition, an HSP70 inhibitor, KNK437, was capable of decreasing NOD2-mediated NF-kappaB activation in response to bacterial cell wall stimulation. We found HSP70 to regulate the half-life of NOD2, as increasing the HSP70 level in cells increased the half-life of NOD2, and down regulating HSP70 decreased the half-life of NOD2. The expression levels of the Crohn-associated NOD2 variants were less compared with wild type. The overexpression of HSP70 significantly increased NOD2 levels as well as the signaling capacity of the mutants. Thus, our study shows that restoring the stability of the NOD2 Crohn mutants is sufficient for rescuing the ability of these mutations to signal the presence of a bacterial cell wall ligand. PMID- 24790090 TI - The function of the transmembrane and cytoplasmic domains of pneumococcal penicillin-binding proteins 2x and 2b extends beyond that of simple anchoring devices. AB - The biosynthesis of cell-wall peptidoglycan is a complex process that involves six different penicillin-binding proteins (PBPs) in Streptococcus pneumoniae. Two of these, PBP2x and PBP2b, are monofunctional transpeptidases that catalyse the formation of peptide cross-links between adjacent glycan strands. Both of them are bitopic membrane proteins with a small cytoplasmic and a large extracellular domain. PBP2x and PBP2b are essential for septal and peripheral peptidoglycan synthesis, respectively. Although several studies have investigated the properties of their extracellular catalytic domains, it is not known whether the role of their N-terminal non-catalytic domains extends beyond that of being simple anchoring devices. We therefore decided to use reciprocal domain swapping and mutational analysis to gain more information about the biological function of the membrane anchors and cytoplasmic tails of PBP2x and PBP2b. In the case of PBP2x both domains are essential, but neither the membrane anchor nor the cytoplasmic domain of PBP2x appear to serve as major localization signals. Instead, our results suggest that they are involved in interactions with other components of the divisome. Mutations of conserved amino acids in the cytoplasmic domain of PBP2x resulted in loss of function, underlining the importance of this region. The cytoplasmic domain of PBP2b could be swapped with the corresponding domain from PBP2x, whereas replacement of the PBP2b transmembrane domain with the corresponding PBP2x domain gave rise to slow-growing cells with grossly abnormal morphology. When both domains were exchanged simultaneously the cells were no longer viable. PMID- 24790091 TI - Inhibition of co-colonizing cystic fibrosis-associated pathogens by Pseudomonas aeruginosa and Burkholderia multivorans. AB - Cystic fibrosis (CF) is a recessive genetic disease characterized by chronic respiratory infections and inflammation causing permanent lung damage. Recurrent infections are caused by Gram-negative antibiotic-resistant bacterial pathogens such as Pseudomonas aeruginosa, Burkholderia cepacia complex (Bcc) and the emerging pathogen genus Pandoraea. In this study, the interactions between co colonizing CF pathogens were investigated. Both Pandoraea and Bcc elicited potent pro-inflammatory responses that were significantly greater than Ps. aeruginosa. The original aim was to examine whether combinations of pro-inflammatory pathogens would further exacerbate inflammation. In contrast, when these pathogens were colonized in the presence of Ps. aeruginosa the pro-inflammatory response was significantly decreased. Real-time PCR quantification of bacterial DNA from mixed cultures indicated that Ps. aeruginosa significantly inhibited the growth of Burkholderia multivorans, Burkholderia cenocepacia, Pandoraea pulmonicola and Pandoraea apista, which may be a factor in its dominance as a colonizer of CF patients. Ps. aeruginosa cell-free supernatant also suppressed growth of these pathogens, indicating that inhibition was innate rather than a response to the presence of a competitor. Screening of a Ps. aeruginosa mutant library highlighted a role for quorum sensing and pyoverdine biosynthesis genes in the inhibition of B. cenocepacia. Pyoverdine was confirmed to contribute to the inhibition of B. cenocepacia strain J2315. B. multivorans was the only species that could significantly inhibit Ps. aeruginosa growth. B. multivorans also inhibited B. cenocepacia and Pa. apista. In conclusion, both Ps. aeruginosa and B. multivorans are capable of suppressing growth and virulence of co colonizing CF pathogens. PMID- 24790092 TI - Structural basis for multiple sugar recognition of Jacalin-related human ZG16p lectin. AB - ZG16p is a soluble mammalian lectin, the first to be described with a Jacalin related beta-prism-fold. ZG16p has been reported to bind both to glycosaminoglycans and mannose. To determine the structural basis of the multiple sugar-binding properties, we conducted glycan microarray analyses of human ZG16p. We observed that ZG16p preferentially binds to alpha-mannose-terminating short glycans such as Ser/Thr-linked O-mannose, but not to high mannose-type N-glycans. Among sulfated glycosaminoglycan oligomers examined, chondroitin sulfate B and heparin oligosaccharides showed significant binding. Crystallographic studies of human ZG16p lectin in the presence of selected ligands revealed the mechanism of multiple sugar recognition. Manalpha1-3Man and Glcbeta1-3Glc bound in different orientations: the nonreducing end of the former and the reducing end of the latter fitted in the canonical shallow mannose binding pocket. Solution NMR analysis using (15)N-labeled ZG16p defined the heparin-binding region, which is on an adjacent flat surface of the protein. On-array competitive binding assays suggest that it is possible for ZG16p to bind simultaneously to both types of ligands. Recognition of a broad spectrum of ligands by ZG16p may account for the multiple functions of this lectin in the formation of zymogen granules via glycosaminoglycan binding, and in the recognition of pathogens in the digestive system through alpha-mannose-related recognition. PMID- 24790093 TI - CDK-dependent phosphorylation of Alp7-Alp14 (TACC-TOG) promotes its nuclear accumulation and spindle microtubule assembly. AB - As cells transition from interphase to mitosis, the microtubule cytoskeleton is reorganized to form the mitotic spindle. In the closed mitosis of fission yeast, a microtubule-associated protein complex, Alp7-Alp14 (transforming acidic coiled coil-tumor overexpressed gene), enters the nucleus upon mitotic entry and promotes spindle formation. However, how the complex is controlled to accumulate in the nucleus only during mitosis remains elusive. Here we demonstrate that Alp7 Alp14 is excluded from the nucleus during interphase using the nuclear export signal in Alp14 but is accumulated in the nucleus during mitosis through phosphorylation of Alp7 by the cyclin-dependent kinase (CDK). Five phosphorylation sites reside around the nuclear localization signal of Alp7, and the phosphodeficient alp7-5A mutant fails to accumulate in the nucleus during mitosis and exhibits partial spindle defects. Thus our results reveal one way that CDK regulates spindle assembly at mitotic entry: CDK phosphorylates the Alp7 Alp14 complex to localize it to the nucleus. PMID- 24790094 TI - A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission. AB - The GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial division, but the mechanisms remain poorly understood. Much of what is attributed to Drp1's mechanism of action in mitochondrial membrane fission parallels that of prototypical dynamin in endocytic vesicle scission. Unlike the case for dynamin, however, no lipid target for Drp1 activation at the mitochondria has been identified. In addition, the oligomerization properties of Drp1 have not been well established. We show that the mitochondria-specific lipid cardiolipin is a potent stimulator of Drp1 GTPase activity, as well as of membrane tubulation. We establish further that under physiological conditions, Drp1 coexists as two morphologically distinct polymeric species, one nucleotide bound in solution and the other membrane associated, which equilibrate via a dimeric assembly intermediate. With two mutations, C300A and C505A, that shift Drp1 polymerization equilibria in opposite directions, we demonstrate that dimers, and not multimers, potentiate the reassembly and reorganization of Drp1 for mitochondrial membrane remodeling both in vitro and in vivo. PMID- 24790095 TI - Characterization of the roles of Blt1p in fission yeast cytokinesis. AB - Spatial and temporal regulation of cytokinesis is essential for cell division, yet the mechanisms that control the formation and constriction of the contractile ring are incompletely understood. In the fission yeast Schizosaccharomyces pombe proteins that contribute to the cytokinetic contractile ring accumulate during interphase in nodes-precursor structures around the equatorial cortex. During mitosis, additional proteins join these nodes, which condense to form the contractile ring. The cytokinesis protein Blt1p is unique in being present continuously in nodes from early interphase through to the contractile ring until cell separation. Blt1p was shown to stabilize interphase nodes, but its functions later in mitosis were unclear. We use analytical ultracentrifugation to show that purified Blt1p is a tetramer. We find that Blt1p interacts physically with Sid2p and Mob1p, a protein kinase complex of the septation initiation network, and confirm known interactions with F-BAR protein Cdc15p. Contractile rings assemble normally in blt1? cells, but the initiation of ring constriction and completion of cell division are delayed. We find three defects that likely contribute to this delay. Without Blt1p, contractile rings recruited and retained less Sid2p/Mob1p and Clp1p phosphatase, and beta-glucan synthase Bgs1p accumulated slowly at the cleavage site. PMID- 24790096 TI - Lipid domain-dependent regulation of single-cell wound repair. AB - After damage, cells reseal their plasma membrane and repair the underlying cortical cytoskeleton. Although many different proteins have been implicated in cell repair, the potential role of specific lipids has not been explored. Here we report that cell damage elicits rapid formation of spatially organized lipid domains around the damage site, with different lipids concentrated in different domains as a result of both de novo synthesis and transport. One of these lipids diacylglycerol (DAG)-rapidly accumulates in a broad domain that overlaps the zones of active Rho and Cdc42, GTPases that regulate repair of the cortical cytoskeleton. Formation of the DAG domain is required for Cdc42 and Rho activation and healing. Two DAG targets, protein kinase C (PKC) beta and eta, are recruited to cell wounds and play mutually antagonistic roles in the healing process: PKCbeta participates in Rho and Cdc42 activation, whereas PKCeta inhibits Rho and Cdc42 activation. The results reveal an unexpected diversity in subcellular lipid domains and the importance of such domains for a basic cellular process. PMID- 24790097 TI - The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein coupled receptor CXCR4. AB - G protein-coupled receptor (GPCR) sorting into the degradative pathway is important for limiting the duration and magnitude of signaling. Agonist activation of the GPCR CXCR4 induces its rapid ubiquitination and sorting to lysosomes via the endosomal sorting complex required for transport (ESCRT) pathway. We recently reported that ESCRT-0 ubiquitination is linked to the efficiency with which CXCR4 is sorted for lysosomal degradation; however mechanistic insight is lacking. Here we define a novel role for the really interesting new gene-domain E3 ubiquitin ligase deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes. We show that DTX3L localizes to early endosomes upon CXCR4 activation and interacts directly with and inhibits the activity of the E3 ubiquitin ligase atrophin-1 interacting protein 4. This serves to limit the extent to which ESCRT-0 is ubiquitinated and is able to sort CXCR4 for lysosomal degradation. Therefore we define a novel role for DTX3L in GPCR endosomal sorting and reveal an unprecedented link between two distinct E3 ubiquitin ligases to control the activity of the ESCRT machinery. PMID- 24790098 TI - The effects of age and lifetime flight behavior on flight capacity in Drosophila melanogaster. AB - The effects of flight behavior on physiology and senescence may be profound in insects because of the extremely high metabolic costs of flight. Flight capacity in insects decreases with age; in contrast, limiting flight behavior extends lifespan and slows the age-related loss of antioxidant capacity and accumulation of oxidative damage in flight muscles. In this study, we tested the effects of age and lifetime flight behavior on flight capacity by measuring wingbeat frequency, the ability to fly in a hypo-dense gas mixture, and metabolic rate in Drosophila melanogaster. Specifically, 5-day-old adult flies were separated into three life-long treatments: (1) those not allowed to fly (no flight), (2) those allowed - but not forced - to fly (voluntary flight) and (3) those mechanically stimulated to fly (induced flight). Flight capacity senesced earliest in flies from the no-flight treatment, followed by the induced-flight group and then the voluntary flight group. Wingbeat frequency senesced with age in all treatment groups, but was most apparent in the voluntary- and induced-flight groups. Metabolic rate during agitated flight senesced earliest and most rapidly in the induced flight group, and was low and uniform throughout age in the no-flight group. Early senescence in the induced-flight group was likely due to the acceleration of deleterious aging phenomena such as the rapid accumulation of damage at the cellular level, while the early loss of flight capacity and low metabolic rates in the no-flight group demonstrate that disuse effects can also significantly alter senescence patterns of whole-insect performance. PMID- 24790099 TI - Free-swimming northern elephant seals have low field metabolic rates that are sensitive to an increased cost of transport. AB - Widely ranging marine predators often adopt stereotyped, energy-saving behaviours to minimize the energetic cost of transport while maximizing energy gain. Environmental and anthropogenic disturbances can disrupt energy balance by prompting avoidance behaviours that increase transport costs, thereby decreasing foraging efficiency. We examined the ability of 12 free-ranging, juvenile northern elephant seals (Mirounga angustirostris) to mitigate the effects of experimentally increased transport costs by modifying their behaviour and/or energy use in a compensatory manner. Under normal locomotion, elephant seals had low energy requirements (106.5+/-28.2 kJ kg(-1) day(-1)), approaching or even falling below predictions of basal requirements. Seals responded to a small increase in locomotion costs by spending more time resting between dives (149+/ 44 s) compared with matched control treatments (102+/-11 s; P<0.01). Despite incurred costs, most other dive and transit behaviours were conserved across treatments, including fixed, rhythmic swimming gaits. Because of this, and because each flipper stroke had a predictable effect on total costs (P<0.001), total energy expenditure was strongly correlated with time spent at sea under both treatments (P<0.0001). These results suggest that transiting elephant seals have a limited capacity to modify their locomotory behaviour without increasing their transport costs. Based on this, we conclude that elephant seals and other ocean predators occupying similar niches may be particularly sensitive to increased transport costs incurred when avoiding unanticipated disturbances. PMID- 24790100 TI - Deep-diving sea lions exhibit extreme bradycardia in long-duration dives. AB - Heart rate and peripheral blood flow distribution are the primary determinants of the rate and pattern of oxygen store utilisation and ultimately breath-hold duration in marine endotherms. Despite this, little is known about how otariids (sea lions and fur seals) regulate heart rate (fH) while diving. We investigated dive fH in five adult female California sea lions (Zalophus californianus) during foraging trips by instrumenting them with digital electrocardiogram (ECG) loggers and time depth recorders. In all dives, dive fH (number of beats/duration; 50+/-9 beats min(-1)) decreased compared with surface rates (113+/-5 beats min(-1)), with all dives exhibiting an instantaneous fH below resting (<54 beats min(-1)) at some point during the dive. Both dive fH and minimum instantaneous fH significantly decreased with increasing dive duration. Typical instantaneous fH profiles of deep dives (>100 m) consisted of: (1) an initial rapid decline in fH resulting in the lowest instantaneous fH of the dive at the end of descent, often below 10 beats min(-1) in dives longer than 6 min in duration; (2) a slight increase in fH to ~10-40 beats min(-1) during the bottom portion of the dive; and (3) a gradual increase in fH during ascent with a rapid increase prior to surfacing. Thus, fH regulation in deep-diving sea lions is not simply a progressive bradycardia. Extreme bradycardia and the presumed associated reductions in pulmonary and peripheral blood flow during late descent of deep dives should (a) contribute to preservation of the lung oxygen store, (b) increase dependence of muscle on the myoglobin-bound oxygen store, (c) conserve the blood oxygen store and (d) help limit the absorption of nitrogen at depth. This fH profile during deep dives of sea lions may be characteristic of deep diving marine endotherms that dive on inspiration as similar fH profiles have been recently documented in the emperor penguin, another deep diver that dives on inspiration. PMID- 24790101 TI - Seasonal accumulation of acetylated triacylglycerols by a freeze-tolerant insect. AB - Most animals store energy as long-chain triacylglycerols (lcTAGs). Trace amounts of acetylated triacylglycerols (acTAGs) have been reported in animals, but are not accumulated, likely because they have lower energy density than lcTAGs. Here we report that acTAGs comprise 36% of the neutral lipid pool of overwintering prepupae of the goldenrod gall fly, Eurosta solidaginis, while only 17% of the neutral lipid pool is made up of typical lcTAGs. These high concentrations of acTAGs, present only during winter, appear to be synthesized by E. solidaginis and are not found in other freeze-tolerant insects, nor in the plant host. The mixture of acTAGs found in E. solidaginis has a significantly lower melting point than equivalent lcTAGs, and thus remains liquid at temperatures at which E. solidaginis is frozen in the field, and depresses the melting point of aqueous solutions in a manner unusual for neutral lipids. We note that accumulation of acTAGs coincides with preparation for overwintering and the seasonal acquisition of freeze tolerance. This is the first observation of accumulation of acTAGs by an animal, and the first evidence of dynamic interconversion between acTAGs and lcTAGs during development and in response to stress. PMID- 24790102 TI - Structure of the small Dictyostelium discoideum myosin light chain MlcB provides insights into MyoB IQ motif recognition. AB - Dictyostelium discoideum MyoB is a class I myosin involved in the formation and retraction of membrane projections, cortical tension generation, membrane recycling, and phagosome maturation. The MyoB-specific, single-lobe EF-hand light chain MlcB binds the sole IQ motif of MyoB with submicromolar affinity in the absence and presence of Ca(2+). However, the structural features of this novel myosin light chain and its interaction with its cognate IQ motif remain uncharacterized. Here, we describe the NMR-derived solution structure of apoMlcB, which displays a globular four-helix bundle. Helix 1 adopts a unique orientation when compared with the apo states of the EF-hand calcium-binding proteins calmodulin, S100B, and calbindin D9k. NMR-based chemical shift perturbation mapping identified a hydrophobic MyoB IQ binding surface that involves amino acid residues in helices I and IV and the functional N-terminal Ca(2+) binding loop, a site that appears to be maintained when MlcB adopts the holo state. Complementary mutagenesis and binding studies indicated that residues Ile-701, Phe-705, and Trp 708 of the MyoB IQ motif are critical for recognition of MlcB, which together allowed the generation of a structural model of the apoMlcB-MyoB IQ complex. We conclude that the mode of IQ motif recognition by the novel single-lobe MlcB differs considerably from that of stereotypical bilobal light chains such as calmodulin. PMID- 24790103 TI - Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick type C1-deficient cells. AB - Niemann-Pick type C1 (NPC1) is a late endosomal transmembrane protein, which, together with NPC2 in the endosome lumen, mediates the transport of endosomal cholesterol to the plasma membrane and endoplasmic reticulum. Loss of function of NPC1 or NPC2 leads to cholesterol accumulation in late endosomes and causes neuronal dysfunction and neurodegeneration. Recent studies indicate that cholesterol also accumulates in mitochondria of NPC1-deficient cells and brain tissue and that NPC1 deficiency leads to alterations in mitochondrial function and energy metabolism. Here, we have investigated the effects of increased mitochondrial cholesterol levels on energy metabolism, using RNA interference to deplete Chinese hamster ovary cells of NPC1 alone or in combination with MLN64, which mediates endosomal cholesterol transport to mitochondria. Mitochondrial cholesterol levels were also altered by depletion of NPC2 in combination with the expression of NPC2 mutants. We found that the depletion of NPC1 increased lactate secretion, decreased glutamine-dependent mitochondrial respiration, and decreased ATP transport across mitochondrial membranes. These metabolic alterations did not occur when transport of endosomal cholesterol to mitochondria was blocked. In addition, the elevated mitochondrial cholesterol levels in NPC1-depleted cells and in NPC2-depleted cells expressing mutant NPC2 that allows endosomal cholesterol trafficking to mitochondria were associated with increased expression of the antioxidant response factor Nrf2. Antioxidant treatment not only prevented the increase in Nrf2 mRNA levels but also prevented the increased lactate secretion in NPC1-depleted cells. These results suggest that mitochondrial cholesterol accumulation can increase oxidative stress and in turn cause increased glycolysis to lactate and other metabolic alterations. PMID- 24790104 TI - The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth. AB - Rap1 is a Ras family GTPase with a well documented role in ERK/MAP kinase signaling and integrin activation. Stimulation of the G-protein-coupled receptor PAR-1 with thrombin in human 1321N1 glioblastoma cells led to a robust increase in Rap1 activation. This response was sustained for up to 6 h and mediated through RhoA and phospholipase D (PLD). Thrombin treatment also induced a 5-fold increase in cell adhesion to fibronectin, which was blocked by down-regulating PLD or Rap1A or by treatment with a beta1 integrin neutralizing antibody. In addition, thrombin treatment led to increases in phospho-focal adhesion kinase (tyrosine 397), ERK1/2 phosphorylation and cell proliferation, which were significantly inhibited in cells treated with beta1 integrin antibody or Rap1A siRNA. To assess the role of Rap1A in tumor formation in vivo, we compared growth of 1321N1 cells stably expressing control, Rap1A or Rap1B shRNA in a mouse xenograft model. Deletion of Rap1A, but not of Rap1B, reduced tumor mass by >70% relative to control. Similar observations were made with U373MG glioblastoma cells in which Rap1A was down-regulated. Collectively, these findings implicate a Rap1A/beta1 integrin pathway, activated downstream of G-protein-coupled receptor stimulation and RhoA, in glioblastoma cell proliferation. Moreover, our data demonstrate a critical role for Rap1A in glioblastoma tumor growth in vivo. PMID- 24790105 TI - Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition. AB - Purified F-ATP synthase dimers of yeast mitochondria display Ca(2+)-dependent channel activity with properties resembling those of the permeability transition pore (PTP) of mammals. After treatment with the Ca(2+) ionophore ETH129, which allows electrophoretic Ca(2+) uptake, isolated yeast mitochondria undergo inner membrane permeabilization due to PTP opening. Yeast mutant strains DeltaTIM11 and DeltaATP20 (lacking the e and g F-ATP synthase subunits, respectively, which are necessary for dimer formation) display a striking resistance to PTP opening. These results show that the yeast PTP originates from F-ATP synthase and indicate that dimerization is required for pore formation in situ. PMID- 24790106 TI - Chemosensory information processing between keratinocytes and trigeminal neurons. AB - Trigeminal fibers terminate within the facial mucosa and skin and transmit tactile, proprioceptive, chemical, and nociceptive sensations. Trigeminal sensations can arise from the direct stimulation of intraepithelial free nerve endings or indirectly through information transmission from adjacent cells at the peripheral innervation area. For mechanical and thermal cues, communication processes between skin cells and somatosensory neurons have already been suggested. High concentrations of most odors typically provoke trigeminal sensations in vivo but surprisingly fail to activate trigeminal neuron monocultures. This fact favors the hypothesis that epithelial cells may participate in chemodetection and subsequently transmit signals to neighboring trigeminal fibers. Keratinocytes, the major cell type of the epidermis, express various receptors that enable reactions to multiple environmental stimuli. Here, using a co-culture approach, we show for the first time that exposure to the odorant chemicals induces a chemical communication between human HaCaT keratinocytes and mouse trigeminal neurons. Moreover, a supernatant analysis of stimulated keratinocytes and subsequent blocking experiments with pyrodoxalphosphate-6-azophenyl-2',4'-disulfonate revealed that ATP serves as the mediating transmitter molecule released from skin cells after odor stimulation. We show that the ATP release resulting from Javanol(r) stimulation of keratinocytes was mediated by pannexins. Consequently, keratinocytes act as chemosensors linking the environment and the trigeminal system via ATP signaling. PMID- 24790107 TI - Blue light-induced dimerization of monomeric aureochrome-1 enhances its affinity for the target sequence. AB - Aureochrome-1 (AUREO1) is a blue light (BL) receptor that mediates the branching response in stramenopile alga, Vaucheria frigida. AUREO1 contains a basic leucine zipper (bZIP) domain in the central region and a light-oxygen-voltage sensing (LOV) domain at the C terminus, and has been suggested to function as a light regulated transcription factor. We have previously reported that preparations of recombinant AUREO1 contained the complete coding sequence (full-length, FL) and N terminal truncated protein (ZL) containing bZIP and LOV domains, and suggested that wild-type ZL (ZLwt2) was in a dimer form with intermolecular disulfide linkages at Cys(162) and Cys(182) (Hisatomi, O., Takeuchi, K., Zikihara, K., Ookubo, Y., Nakatani, Y., Takahashi, F., Tokutomi, S., and Kataoka, H. (2013) Plant Cell Physiol. 54, 93-106). In the present study, we report the photoreactions, oligomeric structures, and DNA binding of monomeric cysteine to serine-mutated ZL (ZLC2S), DTT-treated ZL (DTT-ZL), and FL (DTT-FL). Recombinant AUREO1 showed similar spectral properties and dark regeneration kinetics to those of dimeric ZLwt2. Dynamic light scattering and size exclusion chromatography revealed that ZLC2S and DTT-ZL were monomeric in the dark state. Dissociation of intermolecular disulfide bonds of ZLwt2 was in equilibrium with a midpoint oxidation-redox potential of approximately -245 +/- 15 mV. BL induced the dimerization of monomeric ZL, which subsequently increased its affinity for the target sequence. Also, DTT-FL was monomeric in the dark state and underwent BL induced dimerization, which led to formation of the FL2.DNA complex. Taken together, our results suggest that monomeric AUREO1 is present in vivo, with dimerization playing a key role in its role as a BL-regulated transcription factor. PMID- 24790108 TI - Mis-regulation of mammalian target of rapamycin (mTOR) complexes induced by albuminuria in proximal tubules. AB - High albumin concentrations in the proximal tubule of the kidney causes tubulointerstitial injury, but how this process occurs is not completely known. To address the signal transduction pathways mis-regulated in renal injury, we studied the modulation of mammalian target of rapamycin (mTOR) complexes by physiologic and pathophysiologic albumin concentrations in proximal tubule cells. Physiologic albumin concentrations activated the PI3K/mTORC2/PKB/mTORC1/S6 kinase (S6K) pathway, but pathophysiologically high albumin concentrations overactivated mTORC1 and inhibited mTORC2 activity. This control process involved the activation of ERK1/2, which promoted the inhibition of TSC2 and activation of S6K. Furthermore, S6K was crucial to promoting the over activation of mTORC1 and inhibition of mTORC2. Megalin expression at the luminal membrane is reduced by high concentrations of albumin. In addition, knockdown of megalin mimicked all the effects of pathophysiologic albumin concentrations, which disrupt normal signal transduction pathways and lead to an overactivation of mTORC1 and inhibition of mTORC2. These data provide new perspectives for understanding the molecular mechanisms behind the effects of albumin on the progression of renal disease. PMID- 24790110 TI - Transcriptome sequencing and metabolite analysis reveals the role of delphinidin metabolism in flower colour in grape hyacinth. AB - Grape hyacinth (Muscari) is an important ornamental bulbous plant with an extraordinary blue colour. Muscari armeniacum, whose flowers can be naturally white, provides an opportunity to unravel the complex metabolic networks underlying certain biochemical traits, especially colour. A blue flower cDNA library of M. armeniacum and a white flower library of M. armeniacum f. album were used for transcriptome sequencing. A total of 89 926 uni-transcripts were isolated, 143 of which could be identified as putative homologues of colour related genes in other species. Based on a comprehensive analysis relating colour compounds to gene expression profiles, the mechanism of colour biosynthesis was studied in M. armeniacum. Furthermore, a new hypothesis explaining the lack of colour phenotype of the grape hyacinth flower is proposed. Alteration of the substrate competition between flavonol synthase (FLS) and dihydroflavonol 4 reductase (DFR) may lead to elimination of blue pigmentation while the multishunt from the limited flux in the cyanidin (Cy) synthesis pathway seems to be the most likely reason for the colour change in the white flowers of M. armeniacum. Moreover, mass sequence data obtained by the deep sequencing of M. armeniacum and its white variant provided a platform for future function and molecular biological research on M. armeniacum. PMID- 24790109 TI - Developmental dynamics of Kranz cell transcriptional specificity in maize leaf reveals early onset of C4-related processes. AB - The comparison of the cell-specific transcriptomes of bundle sheath (BS) and mesophyll (M) cells from successive developmental stages of maize (Zea mays) leaves reveals that the number of genes preferentially transcribed in one cell type or the other varies considerably from the sink-source transition to mature photosynthetic stages. The number of differentially expressed (DE) genes is maximal at a stage well before full maturity, including those that encode key functions for C4 photosynthesis. The developmental dynamics of BS/M differential expression can be used to identify candidates for other C4-related functions and to simplify the identification of specific pathways members from otherwise complex gene families. A significant portion of the candidates for C4-related transcription factors identified with this developmental DE strategy overlap with those identified in studies using alternative strategies, thus providing independent support for their potential importance. PMID- 24790112 TI - Genetic variation for the duration of pre-anthesis development in durum wheat and its interaction with vernalization treatment and photoperiod. AB - A recombinant inbred durum wheat population was grown under three contrasting regimes: long days following vernalization (LDV), long days without vernalization (LD), and short days following vernalization (SDV). The length of several pre anthesis stages and the number of leaves and the phyllochron were measured. Different groups of genes were involved in determining the phenology in the three treatments, as demonstrated by a quantitative trait locus (QTL) analysis. The length of the period required to reach the terminal spikelet stage was correlated with the time to anthesis only in the case of LDV- and LD-grown plants where the timing of anthesis depended on the final leaf number. However, for SDV-grown plants, anthesis date was more dependent on the length of the period between the terminal spikelet stage and anthesis and was independent of leaf number. The involvement of the phyllochron in determining the duration of pre-anthesis development was also treatment-dependent. QTL mapping of the various flowering time associated traits uncovered some novel loci (such as those associated with the phyllochron), in addition to confirming the presence of several well established loci. PMID- 24790111 TI - A GAMYB homologue CsGAMYB1 regulates sex expression of cucumber via an ethylene independent pathway. AB - Cucumber (Cucumis sativus L.) is a typical monoecious vegetable with individual male and female flowers, and has been used as a model plant for sex determination. It is well known that sex differentiation of cucumber can be regulated by phytohormones, such as gibberellic acid (GA) and ethylene. The molecular mechanism of female sex expression modulated by ethylene has been widely understood, but how GA controls male sex expression remains elusive. In hermaphroditic Arabidopsis and rice, GA can regulate stamen and anther development via the transcriptional regulation of GAMYB. Here we characterized a GAMYB homologue CsGAMYB1 in cucumber. We found that CsGAMYB1 is predominantly expressed in male flower buds, where its expression is upregulated by GA3 treatment. CsGAMYB1 protein is localized in the nucleus. CsGAMYB1 can partially rescue stamen development and fertility phenotypes of an Arabidopsis myb33 myb65 double mutant. However, constitutive overexpression of CsGAMYB1 in wild-type Arabidopsis resulted in male sterility, which mimics the effect of GA overdose in flower development. Knockdown of CsGAMYB1 in cucumber decreases the ratio of nodes with male and female flowers, and ethylene is not involved in this process. Our data suggest that CsGAMYB1 regulates sex expression of cucumber via an ethylene-independent pathway. PMID- 24790113 TI - RAN1 is involved in plant cold resistance and development in rice (Oryza sativa). AB - Of the diverse abiotic stresses, low temperature is one of the major limiting factors that lead to a series of morphological, physiological, biochemical, and molecular changes in plants. Ran, an evolutionarily conserved small G-protein family, has been shown to be essential for the nuclear translocation of proteins. It also mediates the regulation of cell cycle progression in mammalian cells. However, little is known about Ran function in rice (Oryza sativa). We report here that Ran gene OsRAN1 is essential for the molecular improvement of rice for cold tolerance. Ran also affects plant morphogenesis in transgenic Arabidopsis thaliana. OsRAN1 is ubiquitously expressed in rice tissues with the highest expression in the spike. The levels of mRNA encoding OsRAN1 were greatly increased by cold and indoleacetic acid treatment rather than by addition of salt and polyethylene glycol. Further, OsRAN1 overexpression in Arabidopsis increased tiller number, and altered root development. OsRAN1 overexpression in rice improves cold tolerance. The levels of cellular free Pro and sugar levels were highly increased in transgenic plants under cold stress. Under cold stress, OsRAN1 maintained cell division and cell cycle progression, and also promoted the formation of an intact nuclear envelope. The results suggest that OsRAN1 protein plays an important role in the regulation of cellular mitosis and the auxin signalling pathway. PMID- 24790115 TI - Leaf senescence and nitrogen remobilization efficiency in oilseed rape (Brassica napus L.). AB - Despite its worldwide economic importance for food (oil, meal) and non-food (green energy and chemistry) uses, oilseed rape has a low nitrogen (N) use efficiency (NUE), mainly due to the low N remobilization efficiency (NRE) observed during the vegetative phase when sequential leaf senescence occurs. Assuming that improvement of NRE is the main lever for NUE optimization, unravelling the cellular mechanisms responsible for the recycling of proteins (the main N source in leaf) during sequential senescence is a prerequisite for identifying the physiological and molecular determinants that are associated with high NRE. The development of a relevant molecular indicator (SAG12/Cab) of leaf senescence progression in combination with a (15)N-labelling method were used to decipher the N remobilization associated with sequential senescence and to determine modulation of this process by abiotic factors especially N deficiency. Interestingly, in young leaves, N starvation delayed senescence and induced BnD22, a water-soluble chlorophyll-binding protein that acts against oxidative alterations of chlorophylls and exhibits a protease inhibitor activity. Through its dual function, BnD22 may help to sustain sink growth of stressed plants and contribute to a better utilization of N recycled from senescent leaves, a physiological trait that could improve NUE. Proteomics approaches have revealed that proteolysis involves chloroplastic FtsH protease in the early stages of senescence, aspartic protease during the course of leaf senescence, and the proteasome beta1 subunit, mitochondria processing protease and SAG12 (cysteine protease) during the later senescence phases. Overall, the results constitute interesting pathways for screening genotypes with high NRE and NUE. PMID- 24790114 TI - SPX1 is an important component in the phosphorus signalling network of common bean regulating root growth and phosphorus homeostasis. AB - Proteins containing the SPX domain are believed to play vital roles in the phosphorus (P) signalling network in plants. However, the functions of SPX proteins in legumes remain largely unknown. In this study, three SPX members, PvSPX1-PvSPX3 were cloned from common bean (Phaseolus vulgaris L.). It was found that the transcripts of all three PvSPX members were significantly enhanced in both bean leaves and roots by phosphate (Pi) starvation. Among them, the expression of nuclear localized PvSPX1 showed more sensitive and rapid responses to Pi starvation. Consistently, only overexpression of PvSPX1 resulted in increased root P concentration and modified morphology of transgenic bean hairy roots, such as inhibited root growth and an enlarged root hair zone. It was further demonstrated that PvSPX1 transcripts were up-regulated by overexpressing PvPHR1, and overexpressing PvSPX1 led to increased transcripts of 10 Pi starvation-responsive genes in transgenic bean hairy roots. Taken together, it is suggested that PvSPX1 is a positive regulator in the P signalling network of common bean, and is downstream of PvPHR1. PMID- 24790116 TI - Historical gains in soybean (Glycine max Merr.) seed yield are driven by linear increases in light interception, energy conversion, and partitioning efficiencies. AB - Soybean (Glycine max Merr.) is the world's most widely grown leguminous crop and an important source of protein and oil for food and feed. Soybean yields have increased substantially throughout the past century, with yield gains widely attributed to genetic advances and improved cultivars as well as advances in farming technology and practice. Yet, the physiological mechanisms underlying the historical improvements in soybean yield have not been studied rigorously. In this 2-year experiment, 24 soybean cultivars released between 1923 and 2007 were grown in field trials. Physiological improvements in the efficiencies by which soybean canopies intercepted light (epsiloni), converted light energy into biomass (epsilonc), and partitioned biomass into seed (epsilonp) were examined. Seed yield increased by 26.5kg ha(-1) year(-1), and the increase in seed yield was driven by improvements in all three efficiencies. Although the time to canopy closure did not change in historical soybean cultivars, extended growing seasons and decreased lodging in more modern lines drove improvements in epsiloni. Greater biomass production per unit of absorbed light resulted in improvements in epsilonc. Over 84 years of breeding, soybean seed biomass increased at a rate greater than total aboveground biomass, resulting in an increase in epsilonp. A better understanding of the physiological basis for yield gains will help to identify targets for soybean improvement in the future. PMID- 24790117 TI - Effects of water availability and pest pressures on tea (Camellia sinensis) growth and functional quality. AB - Extreme shifts in water availability linked to global climate change are impacting crops worldwide. The present study examines the direct and interactive effects of water availability and pest pressures on tea (Camellia sinensis; Theaceae) growth and functional quality. Manipulative greenhouse experiments were used to measure the effects of variable water availability and pest pressures simulated by jasmonic acid (JA) on tea leaf growth and secondary metabolites that determine tea quality. Water treatments were simulated to replicate ideal tea growing conditions and extreme precipitation events in tropical southwestern China, a major centre of tea production. Results show that higher water availability and JA significantly increased the growth of new leaves while their interactive effect was not significant. The effect of water availability and JA on tea quality varied with individual secondary metabolites. Higher water availability significantly increased total methylxanthine concentrations of tea leaves but there was no significant effect of JA treatments or the interaction of water and JA. Water availability, JA treatments or their interactive effects had no effect on the concentrations of epigallocatechin 3-gallate. In contrast, increased water availability resulted in significantly lower concentrations of epicatechin 3-gallate but the effect of JA and the interactive effects of water and JA were not significant. Lastly, higher water availability resulted in significantly higher total phenolic concentrations but there was no significant impact of JA and their interaction. These findings point to the fascinating dynamics of climate change effects on tea plants with offsetting interactions between precipitation and pest pressures within agro-ecosystems, and the need for future climate studies to examine interactive biotic and abiotic effects. PMID- 24790118 TI - Genetic variation among mainland and island populations of a native perennial grass used in restoration. AB - Genetic marker studies can assist restoration practice through selection of seed sources that conserve historical levels of gene diversity and population genetic differentiation. We examined genetic variation and structure within and among mainland and island populations of Elymus glaucus, a perennial bunchgrass species native to western North American grasslands that is targeted for grassland restoration. Island populations of E. glaucus represent sensitive sites and potentially distinctive seed sources for reintroduction, and little is known of their genetic composition. Genetic diversity and structure were estimated using amplified fragment length polymorphism markers for 21 populations and 416 individuals distributed across two coastal California mainland locations and three California Channel Islands. Eight primer combinations resulted in 166 markers, of which 165 (99.4 %) were polymorphic. The number of polymorphic bands was significantly greater among mainland populations relative to island sites, and locally common alleles were present for each sampled island and mainland location. Population structure was high (62.9 %), with most variation (55.8 %) distributed among populations, 7.1 % between mainland and island locations, and the remainder (37.1 %) within populations. Isolation by distance was only apparent among islands. Using marker data to recommend appropriate seed sources for restoration, E. glaucus seeds are best derived within islands with collections representing a large number of individuals from matching environments. Given the limited gene flow and prior evidence of adaptive divergence among populations of this species, regional collections are recommended in all cases to maintain diversity and to avoid long-distance introductions of highly differentiated plant material. PMID- 24790119 TI - Chloroplast genes as genetic markers for inferring patterns of change, maternal ancestry and phylogenetic relationships among Eleusine species. AB - Assessment of phylogenetic relationships is an important component of any successful crop improvement programme, as wild relatives of the crop species often carry agronomically beneficial traits. Since its domestication in East Africa, Eleusine coracana (2n = 4x = 36), a species belonging to the genus Eleusine (x = 8, 9, 10), has held a prominent place in the semi-arid regions of India, Nepal and Africa. The patterns of variation between the cultivated and wild species reported so far and the interpretations based upon them have been considered primarily in terms of nuclear events. We analysed, for the first time, the phylogenetic relationship between finger millet (E. coracana) and its wild relatives by species-specific chloroplast deoxyribonucleic acid (cpDNA) polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and chloroplast simple sequence repeat (cpSSR) markers/sequences. Restriction fragment length polymorphism of the seven amplified chloroplast genes/intergenic spacers (trnK, psbD, psaA, trnH-trnK, trnL-trnF, 16S and trnS-psbC), nucleotide sequencing of the chloroplast trnK gene and chloroplast microsatellite polymorphism were analysed in all nine known species of Eleusine. The RFLP of all seven amplified chloroplast genes/intergenic spacers and trnK gene sequences in the diploid (2n = 16, 18, 20) and allotetraploid (2n = 36, 38) species resulted in well-resolved phylogenetic trees with high bootstrap values. Eleusine coracana, E. africana, E. tristachya, E. indica and E. kigeziensis did not show even a single change in restriction site. Eleusine intermedia and E. floccifolia were also shown to have identical cpDNA fragment patterns. The cpDNA diversity in Eleusine multiflora was found to be more extensive than that of the other eight species. The trnK gene sequence data complemented the results obtained by PCR RFLP. The maternal lineage of all three allotetraploid species (AABB, AADD) was the same, with E. indica being the maternal diploid progenitor species. The markers specific to certain species were also identified. PMID- 24790120 TI - Bark and leaf chlorophyll fluorescence are linked to wood structural changes in Eucalyptus saligna. AB - Wood structure and wood anatomy are usually considered to be largely independent of the physiological processes that govern tree growth. This paper reports a statistical relationship between leaf and bark chlorophyll fluorescence and wood density. A relationship between leaf and bark chlorophyll fluorescence and the quantity of wood decay in a tree is also described. There was a statistically significant relationship between the leaf chlorophyll fluorescence parameter Fv/Fm and wood density and the quantity of wood decay in summer, but not in spring or autumn. Leaf chlorophyll fluorescence at 0.05 ms (the O step) could predict the quantity of wood decay in trees in spring. Bark chlorophyll fluorescence could predict wood density in spring using the Fv/Fm parameter, but not in summer or autumn. There was a consistent statistical relationship in spring, summer and autumn between the bark chlorophyll fluorescence parameter Fv/Fm and wood decay. This study indicates a relationship between chlorophyll fluorescence and wood structural changes, particularly with bark chlorenchyma. PMID- 24790121 TI - Rapid flooding-induced adventitious root development from preformed primordia in Solanum dulcamara. AB - Flooding is a common stress factor in both natural and agricultural systems, and affects plant growth by the slow diffusion rate of gases in water. This results in low oxygen concentrations in submerged tissues, and hence in a decreased respiration rate. Understanding the responses of plants to flooding is essential for the management of wetland ecosystems, and may benefit research to improve the flood tolerance of crop species. This study describes the response to partial submergence of bittersweet (Solanum dulcamara). Bittersweet is a Eurasian species that grows both in dry habitats such as coastal dunes, and in wetlands, and therefore is a suitable model plant for studying responses to a variety of environmental stresses. A further advantage is that the species is closely related to flood-intolerant crops such as tomato and eggplant. The species constitutively develops dormant primordia on the stem, which we show to have a predetermined root identity. We investigated adventitious root growth from these primordia during flooding. The synchronized growth of roots from the primordia was detected after 2-3 days of flooding and was due to a combination of cell division and cell elongation. Gene expression analysis demonstrated that the molecular response to flooding began within 2 h and included activation of hypoxia and ethylene signalling genes. Unexpectedly, these early changes in gene expression were very similar in primordia and adjacent stem tissue, suggesting that there is a dominant general response in tissues during early flooding. PMID- 24790122 TI - Phragmites australis management in the United States: 40 years of methods and outcomes. AB - Studies on invasive plant management are often short in duration and limited in the methods tested, and lack an adequate description of plant communities that replace the invader following removal. Here we present a comprehensive review of management studies on a single species, in an effort to elucidate future directions for research in invasive plant management. We reviewed the literature on Phragmites management in North America in an effort to synthesize our understanding of management efforts, identify gaps in knowledge and improve the efficacy of management. Additionally, we assessed recent ecological findings concerning Phragmites mechanisms of invasion and integrated these findings into our recommendations for more effective management. Our overall goal is to examine whether or not current management approaches can be improved and whether they promote reestablishment of native plant communities. We found: (i) little information on community-level recovery of vegetation following removal of Phragmites; and (ii) most management approaches focus on the removal of Phragmites from individual stands or groups of stands over a relatively small area. With a few exceptions, recovery studies did not monitor vegetation for substantial durations, thus limiting adequate evaluation of the recovery trajectory. We also found that none of the recovery studies were conducted in a landscape context, even though it is now well documented that land-use patterns on adjacent habitats influence the structure and function of wetlands, including the expansion of Phragmites. We suggest that Phragmites management needs to shift to watershed-scale efforts in coastal regions, or larger management units inland. In addition, management efforts should focus on restoring native plant communities, rather than simply eradicating Phragmites stands. Wetlands and watersheds should be prioritized to identify ecosystems that would benefit most from Phragmites management and those where the negative impact of management would be minimal. PMID- 24790123 TI - Live cell imaging reveals extensive intracellular cytoplasmic colonization of banana by normally non-cultivable endophytic bacteria. AB - It is generally believed that endophytic microorganisms are intercellular inhabitants present in either cultivable or non-cultivable form primarily as root colonizers. The objective of this study was to determine whether the actively mobile micro-particles observed in the intracellular matrix of fresh tissue sections of banana included endophytic bacteria. Tissue sections (50-100 um) from apical leaf sheaths of surface-disinfected suckers (cv. Grand Naine) displayed 'Brownian motion'-reminiscent abundant motile micro-particles under bright-field and phase-contrast (*1000), which appeared similar in size and motility to the pure cultures of endophytes previously isolated from banana. Observations on callus, embryonic cells and protoplasts with intact cell wall/plasma membrane confirmed their cytoplasmic nature. The motility of these entities reduced or ceased upon tissue fixation or staining with safranin/crystal violet (0.5 % w/v), but continued uninterrupted following treatment with actin-disrupting drugs, ruling out the possibility of micro-organelles like peroxisomes. Staining with 2,3,5-triphenyl tetrazolium chloride (TTC) confirmed them to be live bacteria with similar observations after dilute safranin (0.005 %) treatment. Tissue staining with SYTO-9 coupled with epi-fluorescence or confocal laser scanning microscopy showed bacterial colonization along the peri-space between cell wall and plasma membrane initially. SYTO-9 counterstaining on TTC- or safranin-treated tissue and those subjected to enzymatic permeabilization revealed the cytoplasmic bacteria. These included organisms moving freely in the cytoplasm and those adhering to the nuclear envelope or vacuoles and the intravacuolar colonizers. The observations appeared ubiquitous to different genomes and genotypes of banana. Plating the tissue homogenate on nutrient media seldom yielded colony growth. This study, supported largely by live cell video-imaging, demonstrates enormous intracellular colonization in bananas by normally non-cultivable endophytic bacteria in two niches, namely cytoplasmic and periplasmic, designated as 'Cytobacts' and 'Peribacts', respectively. The integral intracellular association with their clonal perpetuation suggests a mutualistic relationship between endophytes and the host. PMID- 24790124 TI - Floral specialization and angiosperm diversity: phenotypic divergence, fitness trade-offs and realized pollination accuracy. AB - Plant reproduction by means of flowers has long been thought to promote the success and diversification of angiosperms. It remains unclear, however, how this success has come about. Do flowers, and their capacity to have specialized functions, increase speciation rates or decrease extinction rates? Is floral specialization fundamental or incidental to the diversification? Some studies suggest that the conclusions we draw about the role of flowers in the diversification and increased phenotypic disparity (phenotypic diversity) of angiosperms depends on the system. For orchids, for example, specialized pollination may have increased speciation rates, in part because in most orchids pollen is packed in discrete units so that pollination is precise enough to contribute to reproductive isolation. In most plants, however, granular pollen results in low realized pollination precision, and thus key innovations involving flowers more likely reflect reduced extinction rates combined with opportunities for evolution of greater phenotypic disparity (phenotypic diversity) and occupation of new niches. Understanding the causes and consequences of the evolution of specialized flowers requires knowledge of both the selective regimes and the potential fitness trade-offs in using more than one pollinator functional group. The study of floral function and flowering-plant diversification remains a vibrant evolutionary field. Application of new methods, from measuring natural selection to estimating speciation rates, holds much promise for improving our understanding of the relationship between floral specialization and evolutionary success. PMID- 24790126 TI - Corrigendum. PMID- 24790127 TI - Comparison of the morphogenesis of three genotypes of pea (Pisum sativum) grown in pure stands and wheat-based intercrops. AB - Cereal-legume intercrops represent a promising way of combining high productivity and agriculture sustainability. The benefits of cereal-legume mixtures are highly affected by species morphology and functioning, which determine the balance between competition and complementarity for resource acquisition. Studying species morphogenesis, which controls plant architecture, is therefore of major interest. The morphogenesis of cultivated species has been mainly described in mono-specific growing conditions, although morphogenetic plasticity can occur in multi-specific stands. The aim of the present study was therefore to characterize the variability of the morphogenesis of pea plants grown either in pure stands or mixed with wheat. This was achieved through a field experiment that included three pea cultivars with contrasting earliness (hr and HR type) and branching patterns. Results show that most of the assessed parameters of pea morphogenesis (phenology, branching, final number of vegetative organs and their kinetics of appearance) were mainly dependent on the considered genotype, which highlights the importance of the choice of cultivars in intercropping systems. There was however a low variability of pea morphogenesis between sole and mixed stands except for plant height and branching of the long-cycle cultivar. The information provided in the present study at stand and plant scale can be used to build up structural-functional models. These models can contribute to improving the understanding of the functioning of cereal-legume intercrops and also to the definition of plant ideotypes adapted to the growth in intercrops. PMID- 24790125 TI - Identifying the genes underlying quantitative traits: a rationale for the QTN programme. AB - The goal of identifying the genes or even nucleotides underlying quantitative and adaptive traits has been characterized as the 'QTN programme' and has recently come under severe criticism. Part of the reason for this criticism is that much of the QTN programme has asserted that finding the genes and nucleotides for adaptive and quantitative traits is a fundamental goal, without explaining why it is such a hallowed goal. Here we outline motivations for the QTN programme that offer general insight, regardless of whether QTNs are of large or small effect, and that aid our understanding of the mechanistic dynamics of adaptive evolution. We focus on five areas: (i) vertical integration of insight across different levels of biological organization, (ii) genetic parallelism and the role of pleiotropy in shaping evolutionary dynamics, (iii) understanding the forces maintaining genetic variation in populations, (iv) distinguishing between adaptation from standing variation and new mutation, and (v) the role of genomic architecture in facilitating adaptation. We argue that rather than abandoning the QTN programme, we should refocus our efforts on topics where molecular data will be the most effective for testing hypotheses about phenotypic evolution. PMID- 24790129 TI - Spatial and temporal functional changes in alpine summit vegetation are driven by increases in shrubs and graminoids. AB - Classical approaches to investigating temporal and spatial changes in community composition offer only partial insight into the ecology that drives species distribution, community patterns and processes, whereas a functional approach can help to determine many of the underlying mechanisms that drive such patterns. Here, we aim to bring these two approaches together to understand such drivers, using an elevation gradient of sites, a repeat species survey and species functional traits. We used data from a repeat vegetation survey on five alpine summits and measured plant height, leaf area, leaf dry matter content and specific leaf area (SLA) for every species recorded in the surveys. We combined species abundances with trait values to produce a community trait-weighted mean (CTWM) for each trait, and then combined survey results with the CTWMs. Across the gradient of summits, more favourable conditions for plant growth (warmer, longer growing season) occurred at the lower elevations. Vegetation composition changes between 2004 and 2011 (according to non-metric multi-dimensional scaling ordination) were strongly affected by the high and increasing abundance of species with high SLA at high elevations. Species life-form categories strongly affected compositional changes and functional composition, with increasing dominance of tall shrubs and graminoids at the lower-elevation summits, and an overall increase in graminoids across the gradient. The CTWM for plant height and leaf dry matter content significantly decreased with elevation, whereas for leaf area and SLA it significantly increased. The significant relationships between CTWM and elevation may suggest specific ecological processes, namely plant competition and local productivity, influencing vegetation preferentially across the elevation gradient, with the dominance of shrubs and graminoids driving the patterns in the CTWMs. PMID- 24790128 TI - Network epidemiology and plant trade networks. AB - Models of epidemics in complex networks are improving our predictive understanding of infectious disease outbreaks. Nonetheless, applying network theory to plant pathology is still a challenge. This overview summarizes some key developments in network epidemiology that are likely to facilitate its application in the study and management of plant diseases. Recent surveys have provided much-needed datasets on contact patterns and human mobility in social networks, but plant trade networks are still understudied. Human (and plant) mobility levels across the planet are unprecedented-there is thus much potential in the use of network theory by plant health authorities and researchers. Given the directed and hierarchical nature of plant trade networks, there is a need for plant epidemiologists to further develop models based on undirected and homogeneous networks. More realistic plant health scenarios would also be obtained by developing epidemic models in dynamic, rather than static, networks. For plant diseases spread by the horticultural and ornamental trade, there is the challenge of developing spatio-temporal epidemic simulations integrating network data. The use of network theory in plant epidemiology is a promising avenue and could contribute to anticipating and preventing plant health emergencies such as European ash dieback. PMID- 24790130 TI - Inbreeding depression does not increase in foreign environments: a field experimental study. AB - Early successional species often disperse to novel environments, and if they are selfing, this dispersal will frequently be carried out by inbred individuals. If inbred immigrants are less likely to successfully establish populations than outbred immigrants, dispersal will be less effective and mating system evolution will favour outcrossing. I performed a reciprocal transplant of inbred and outbred plants grown in native and foreign planting sites to test the hypothesis that inbred immigrants had lower fitness. Inbreeding within populations was estimated with allozyme loci to confirm that the populations were inbred. While inbred and outbred plants had significantly lower fitness in foreign habitats, inbreeding depression was of similar magnitude at native sites and foreign habitats. There was no significant difference between inbred and outbred plants at foreign sites of the native habitat. Populations appear to be highly selfing, yet there is an advantage to outcrossing in both the native environment and foreign environments. The implications of this advantage with respect to mating system evolution may depend on whether novel environments are occupied or unoccupied. PMID- 24790131 TI - Influence of root-bed size on the response of tobacco to elevated CO2 as mediated by cytokinins. AB - The extent of growth stimulation of C3 plants by elevated CO2 is modulated by environmental factors. Under optimized environmental conditions (high light, continuous water and nutrient supply, and others), we analysed the effect of an elevated CO2 atmosphere (700 ppm, EC) and the importance of root-bed size on the growth of tobacco. Biomass production was consistently higher under EC. However, the stimulation was overridden by root-bed volumes that restricted root growth. Maximum growth and biomass production were obtained at a root bed of 15 L at ambient and elevated CO2 concentrations. Starting with seed germination, the plants were strictly maintained under ambient or elevated CO2 until flowering. Thus, the well-known acclimation effect of growth to enhanced CO2 did not occur. The relative growth rates of EC plants exceeded those of ambient-CO2 plants only during the initial phases of germination and seedling establishment. This was sufficient for a persistently higher absolute biomass production by EC plants in non-limiting root-bed volumes. Both the size of the root bed and the CO2 concentration influenced the quantitative cytokinin patterns, particularly in the meristematic tissues of shoots, but to a smaller extent in stems, leaves and roots. In spite of the generally low cytokinin concentrations in roots, the amounts of cytokinins moving from the root to the shoot were substantially higher in high-CO2 plants. Because the cytokinin patterns of the (xylem) fluid in the stems did not match those of the shoot meristems, it is assumed that cytokinins as long-distance signals from the roots stimulate meristematic activity in the shoot apex and the sink leaves. Subsequently, the meristems are able to synthesize those phytohormones that are required for the cell cycle. Root-borne cytokinins entering the shoot appear to be one of the major control points for the integration of various environmental cues into one signal for optimized growth. PMID- 24790132 TI - Growing up or growing out? How soil pH and light affect seedling growth of a relictual rainforest tree. AB - Seedling growth rates can have important long-term effects on forest dynamics. Environmental variables such as light availability and edaphic factors can exert a strong influence on seedling growth. In the wild, seedlings of Wollemi pine (Wollemia nobilis) grow on very acid soils (pH ~4.3) in deeply shaded sites (~3 % full sunlight). To examine the relative influences of these two factors on the growth of young W. nobilis seedlings, we conducted a glasshouse experiment growing seedlings at two soil pH levels (4.5 and 6.5) under three light levels: low (5 % full sun), medium (15 %) and high (50 %). Stem length and stem diameter were measured, stem number and branch number were counted, and chlorophyll and carotenoid content were analysed. In general, increased plant growth was associated with increased light, and with low pH irrespective of light treatment, and pigment content was higher at low pH. Maximum stem growth occurred in plants grown in the low pH/high light treatment combination. However, stem number was highest in low pH/medium light. We hypothesize that these differences in stem development of W. nobilis among light treatments were due to this species' different recruitment strategies in response to light: greater stem growth at high light and greater investment in multiple stem production at low light. The low light levels in the W. nobilis habitat may be a key limitation on stem growth and hence W. nobilis recruitment from seedling to adult. Light and soil pH are two key factors in the growth of this threatened relictual rainforest species. PMID- 24790133 TI - Giving drought the cold shoulder: a relationship between drought tolerance and fall dormancy in an agriculturally important crop. AB - The growth of fall dormant/freezing tolerant plants often surpasses the growth of non-fall dormant/non-freezing tolerant types of the same species under water limited conditions, while under irrigated conditions non-fall dormant types exhibit superior yield performance. To investigate the mechanism behind this phenomenon, we exposed seven diverse alfalfa (Medicago sativa) cultivars to water limited and fully watered conditions and measured their shoot growth, shoot water potential and gas exchange parameters and the relative abundance of taproot RNA transcripts associated with chilling stress/freezing tolerance. Fall dormant cultivars had greater shoot growth relative to the fully watered controls under a mild water deficit (a cumulative water deficit of 625 mL pot(-1)) and did not close their stomata until lower shoot water potentials compared with the more non fall dormant cultivars. Several gene transcripts previously associated with freezing tolerance increased in abundance when plants were exposed to a mild water deficit. Two transcripts, corF (encodes galactinol synthase) and cas18 (encodes a dehydrin-like protein), increased in abundance in fall dormant cultivars only. Once water deficit stress became severe (a cumulative water deficit of 2530 mL pot(-1)), the difference between fall dormancy groups disappeared with the exception of the expression of a type 1 sucrose synthase gene, which decreased in fall dormant cultivars. The specific adaptation of fall dormant cultivars to mild water deficit conditions and the increase in abundance of specific genes typically associated with freezing tolerance in these cultivars is further evidence of a link between freezing tolerance/fall dormancy and adaption to drought conditions in this species. PMID- 24790134 TI - Adolescent inpatient activity 1999-2010: analysis of English Hospital Episode Statistics data. AB - OBJECTIVE: To investigate patterns and trends of adolescent (10-19 years) inpatient activity in England by sex, disease category, and admitting speciality. DATA: 9 632 844 Finished Consultant Episodes (FCEs) from English patients aged 1 19 between 1999/2000 and 2010/2011 (Hospital Episode Statistics data). ANALYSES: Age trends by sex and major International Classification of Disease 10 (ICD10) chapter; differences in activity rates by age and sex; inpatient activity trends over the past decade, disaggregated by sex, admitting speciality and ICD10 chapter. RESULTS: Adolescent female patients account for more activity than girls aged 1-9 (139.4 vs 107.2 FCEs/1000). Female inpatient activity increases significantly between age 10 (70.9 FCEs/1000) and 19 (281.7 FCES/1000, of which non-obstetric care accounts for 155.9 FCEs/1000). Male activity increases much less during adolescence, with lower overall rates among adolescents than younger children (93.7 vs 142.9 FCEs/1000). Between 1999 and 2010, total adolescent inpatient activity increased faster among adolescents (10-19 years) (+14.2%) than younger children (1-9 years) (+11.0%). Adolescent FCEs/1000 increased by 12.8%, including higher rates admitted under Paediatrics (+47.5%) and Paediatric Surgery (+23.2%). Adolescents were admitted across a range of specialities. CONCLUSIONS: These data challenge the belief that adolescents are a healthy group who rarely use inpatient services. In England, use of inpatient services is higher among female patients aged 10-19 years than those aged 1-9 years, while adolescent activity has increased faster than for younger children over the past 11 years. Improving service quality for adolescents will require engagement of the many different teams that care for them. PMID- 24790135 TI - Toxic shock syndrome surveillance in UK children. AB - BACKGROUND: Toxic shock syndrome (TSS) is an acute toxin-mediated illness caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes. There is no recent data regarding incidence, management and mortality of TSS in UK children. METHODS: Consultants from paediatric and burns units in the UK and Ireland, reported cases of TSS seen between November 2008 and December 2009, via the British Paediatric Surveillance Unit. Respondents were sent questionnaires requesting detailed information about TSS cases. Established criteria were used to divide cases into staphylococcal or streptococcal TSS. RESULTS: Forty-nine cases were identified overall; 29 cases of streptococcal TSS (18 confirmed and 11 probable) and 20 cases of staphylococcal TSS (15 confirmed and 5 probable). The incidence of TSS children in the UK & the Republic of Ireland was calculated to be 0.38 per 100 000 children. Children with staphylococcal TSS were older than those with streptococcal TSS (9.5 vs 3.8 years; p<0.003). Paediatric intensive care facilities were used for 78% of cases (invasive ventilatory support 69%; inotropic support 67%; haemofiltration 12%). Agents with antitoxin effects were underused; clindamycin 67%, intravenous immunoglobulin (IVIG) 20%, fresh frozen plasma 40%. There were eight deaths, all in the streptococcal group (28% of streptococcal cases)-none were given IVIG. CONCLUSIONS: Streptococcal TSS was as frequent as staphylococcal TSS, contrasting with previous literature. Children with streptococcal TSS had a higher mortality than those with staphylococcal TSS (28% vs 0%; p<0.05). Recommended immunomodulatory agents (IVIG and clindamycin) were underused. This study highlights the need for a guideline to improve management of TSS in children. PMID- 24790137 TI - Stem cell factor is a potent endothelial permeability factor. AB - OBJECTIVE: Although stem cell factor (SCF) has been shown to play a critical role in hematopoiesis, gametogenesis, and melanogenesis, the function of SCF in the regulation of vascular integrity has not been studied. APPROACH AND RESULTS: We demonstrated that SCF binds to and activates the cKit receptor in endothelial cells, thereby increasing the internalization of vascular endothelial-cadherin and enhancing extravasation of dyes to a similar extent as vascular endothelial growth factor. SCF-mediated cKit activation in endothelial cells enhanced the phosphorylation of endothelial nitric oxide (NO) synthase via the phosphoinositide 3-kinase/Akt signaling pathway and subsequently increased the production of NO. Inhibition of endothelial NO synthase expression and NO synthesis using small interfering RNA knockdown and chemical inhibitors substantially diminished the ability of SCF to increase the internalization of vascular endothelial-cadherin and in vitro endothelial permeability. SCF-induced increase in extravasation of the dyes was abrogated in endothelial NO synthase knockout mice, which indicates that endothelial NO synthase-mediated NO production was responsible for the SCF-induced vascular leakage. Furthermore, we demonstrated that the expression of SCF and cKit was significantly higher in the retina of streptozotocin-injected diabetic mice than in the nondiabetic control animals. Depletion of SCF by intravitreous injection of anti-SCF-neutralizing immunoglobulin G significantly prevented vascular hyperpermeability in the retinas of streptozotocin-injected diabetic mice. CONCLUSIONS: Our data reveal that SCF disrupts the endothelial adherens junction and enhances vascular leakage, as well as suggest that anti-SCF/cKit therapy may hold promise as a potential therapy for the treatment of hyperpermeable vascular diseases. PMID- 24790138 TI - Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. AB - OBJECTIVE: Among plasma proteins, fibrinogen represents a major target of oxidative modifications. In patients with post-acute myocardial infarction (6 months after the acute event), fibrinogen oxidation-induced carbonyls and fibrinogen function were estimated using in vitro and ex vivo approaches. Fibrinogen structural features and clot architecture were also explored. APPROACH AND RESULTS: In 39 patients with post-acute myocardial infarction and 28 age-, sex-, and risk factor-matched controls, oxidative stress markers (in plasma and in purified fibrinogen fractions), thrombin-catalyzed fibrin polymerization, and plasmin-induced fibrin lysis were estimated. Circular dichroism spectra of purified fibrinogen extracts, electron microscopy, and differential interference contrast microscopy analyses of fibrin clots were also performed. Marked signs of oxidative stress in plasma (P<0.01 versus controls) and, correspondingly, an increased extent of fibrinogen carbonylation (3.5-fold over control values; P<0.01 versus controls) were observed in patients. Furthermore, fibrinogen fractions purified from patients exhibited significantly reduced clotting ability and decreased susceptibility to plasmin-induced lysis (P<0.01 versus controls). Alterations in fibrinogen secondary structure, as suggested by circular dichroism spectroscopy, and in fibrin clot architecture, as analyzed by electron and differential interference contrast microscopy, were also identified. CONCLUSIONS: Here, we report for the first time that patients with post-acute myocardial infarction present with an overall imbalance in redox status and marked fibrinogen carbonylation associated with altered fibrinogen function, thus suggesting a role for carbonylation as a direct mechanism of fibrinogen function. The observed features occur along with modifications in protein structure and in clot architecture. PMID- 24790136 TI - Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure. AB - OBJECTIVE: Small GTPase Ras-related protein 1 (Rap1b) controls several basic cellular phenomena, and its deletion in mice leads to several cardiovascular defects, including impaired adhesion of blood cells and defective angiogenesis. We found that Rap1b(-/-) mice develop cardiac hypertrophy and hypertension. Therefore, we examined the function of Rap1b in regulation of blood pressure. APPROACH AND RESULTS: Rap1b(-/-) mice developed cardiac hypertrophy and elevated blood pressure, but maintained a normal heart rate. Correcting elevated blood pressure with losartan, an angiotensin II type 1 receptor antagonist, alleviated cardiac hypertrophy in Rap1b(-/-) mice, suggesting a possibility that cardiac hypertrophy develops secondary to hypertension. The indices of renal function and plasma renin activity were normal in Rap1b(-/-) mice. Ex vivo, we examined whether the effect of Rap1b deletion on smooth muscle-mediated vessel contraction and endothelium-dependent vessel dilation, 2 major mechanisms controlling basal vascular tone, was the basis for the hypertension. We found increased contractility on stimulation with a thromboxane analog or angiotensin II or phenylephrine along with increased inhibitory phosphorylation of myosin phosphatase under basal conditions consistent with elevated basal tone and the observed hypertension. Cyclic adenosine monophosphate-dependent relaxation in response to Rap1 activator, Epac, was decreased in vessels from Rap1b(-/-) mice. Defective endothelial release of dilatory nitric oxide in response to elevated blood flow leads to hypertension. We found that nitric oxide-dependent vasodilation was significantly inhibited in Rap1b-deficient vessels. CONCLUSIONS: This is the first report to indicate that Rap1b in both smooth muscle and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone. PMID- 24790139 TI - Pharmacological activation of the melanocortin system limits plaque inflammation and ameliorates vascular dysfunction in atherosclerotic mice. AB - OBJECTIVE: Melanocortin peptides have been shown to elicit anti-inflammatory actions and to promote vascular endothelial function by activating type 1 and 3 melanocortin receptors. Here, we addressed whether these favorable properties of melanocortins could reduce atherosclerotic plaque inflammation and improve vasoreactivity in atherosclerotic mice. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 were fed a high-fat diet for 8 or 16 weeks and treated with either vehicle or a stable melanocortin analog, melanotan II (MT-II, 0.3 mg/kg per day, 4 weeks). We determined plaque uptake of fluorine-18-labeled fluorodeoxyglucose as a surrogate marker for atherosclerotic plaque inflammation and vascular function of the aorta by ex vivo analyses. MT-II had no effect on body weight or composition, or plasma cholesterol levels in atherosclerotic mice. Without attenuating atherosclerotic lesion size or lesional macrophage accumulation, MT-II treatment reduced fluorine 18-labeled fluorodeoxyglucose uptake in the atherosclerotic plaques. Resident macrophages in the lesions of MT-II-treated mice were polarized toward the anti inflammatory M2 phenotype. Systemic inflammation was also attenuated by MT-II intervention as evidenced by decreased plasma levels of proinflammatory cytokines. In terms of aortic vasoreactivity, MT-II-treated mice showed enhanced endothelium-dependent relaxations, as well as promotion of vascular sensitivity to nitric oxide-mediated vasodilation, which were markedly impaired in control mice after prolonged duration of diet exposure. CONCLUSIONS: The present study demonstrates that pharmacological activation of the melanocortin system has therapeutic benefits in pre-established atherosclerosis by limiting plaque inflammation and promoting vascular endothelial function, which may provide a novel therapeutic approach for atherosclerosis. PMID- 24790140 TI - Mixed-lineage kinase 3 deficiency promotes neointima formation through increased activation of the RhoA pathway in vascular smooth muscle cells. AB - OBJECTIVE: Mitogen-activated protein kinase pathways play an important role in neointima formation secondary to vascular injury, in part by promoting proliferation of vascular smooth muscle cells (VSMC). Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that activates multiple mitogen-activated protein kinase pathways and has been implicated in regulating proliferation in several cell types. However, the role of MLK3 in VSMC proliferation and neointima formation is unknown. The aim of this study was to determine the function of MLK3 in the development of neointimal hyperplasia and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Neointima formation was analyzed after endothelial denudation of carotid arteries from wild-type and MLK3-deficient mice. MLK3 deficiency promoted injury-induced neointima formation and increased proliferation of primary VSMC derived from aortas isolated from MLK3-deficient mice compared with wild-type mice. Furthermore, MLK3 deficiency increased the activation of p63Rho guanine nucleotide exchange factor, RhoA, and Rho kinase in VSMC, a pathway known to promote neointimal hyperplasia, and reconstitution of MLK3 expression attenuated Rho kinase activation. Furthermore, cJun NH2-terminal kinase activation was decreased in MLK3-deficient VSMC, and proliferation of wild-type but not MLK3 knockout cells treated with a cJun NH2 terminal kinase inhibitor was attenuated. CONCLUSIONS: We demonstrate that MLK3 limits RhoA activation and injury-induced neointima formation by binding to and inhibiting the activation of p63Rho guanine nucleotide exchange factor, a RhoA activator. In MLK3-deficient cells, activation of p63Rho guanine nucleotide exchange factor proceeds in an unchecked manner, leading to a net increase in RhoA pathway activation. Reconstitution of MLK3 expression restores MLK3/p63Rho guanine nucleotide exchange factor interaction, which is attenuated by feedback from activated cJun NH2-terminal kinase. PMID- 24790141 TI - Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling. AB - OBJECTIVE: Interleukin-8 (IL-8) receptors IL8RA and IL8RB (IL8RA/B) on neutrophil membranes bind to IL-8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and inflammation. This study tested the hypothesis that administration of rat pulmonary arterial endothelial cells (ECs) overexpressing IL8RA/B can accelerate the adhesion of ECs to the injured lung and inhibit monocrotaline-induced pulmonary inflammation, arterial thickening and hypertension, and right ventricular hypertrophy. APPROACH AND RESULTS: The treatment groups included 10-week-old ovariectomized Sprague-Dawley rats that received subcutaneous injection of PBS (vehicle), a single injection of monocrotaline (monocrotaline alone, 60 mg/kg, SC), monocrotaline followed by intravenous transfusion of ECs transduced with the empty adenoviral vector (null EC), and monocrotaline followed by intravenous transfusion of ECs overexpressing IL8RA/B (1.5 * 10(6) cells/rat). Two days or 4 weeks after monocrotaline treatment, endothelial nitric oxide synthase, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant-2beta (IL-8 equivalent in rat), and monocyte chemoattractant protein-1 expression, neutrophil and macrophage infiltration into pulmonary arterioles, and arteriolar and alveolar morphology were measured by histological and immunohistochemical techniques. Proinflammatory cytokine/chemokine protein levels were measured by Multiplex rat-specific magnetic bead-based sandwich immunoassay in total lung homogenates. Transfusion of ECs overexpressing IL8RA/B significantly reduced monocrotaline-induced neutrophil infiltration and proinflammatory mediator (IL-8, monocyte chemoattractant protein-1, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant, and macrophage inflammatory protein-2) expression in lungs and pulmonary arterioles and alveoli, pulmonary arterial pressure, and pulmonary arterial and right ventricular hypertrophy and remodeling. CONCLUSIONS: These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature. PMID- 24790143 TI - von Willebrand factor directly interacts with DNA from neutrophil extracellular traps. AB - OBJECTIVE: Inflammatory conditions provoke essential processes in the human vascular system. It leads to the formation of ultralarge von Willebrand factor (VWF) fibers, which are immobilized on the endothelial cell surface and transform to highly adhesive strings under shear conditions. Furthermore, leukocytes release a meshwork of DNA (neutrophil extracellular traps) during the process of the recently discovered cell death program NETosis. In the present study, we characterized the interaction between VWF and DNA and possible binding sites to underline the role of VWF in thrombosis and inflammation besides its function in platelet adhesion. APPROACH AND RESULTS: Both functionalized surfaces and intact cell layers of human umbilical vein endothelial cells were perfused with isolated, protein-free DNA or leukocytes from whole blood at distinct shear rates. DNA-VWF interaction was monitored using fluorescence microscopy, ELISA based assays, molecular dynamics simulations, and electrostatic potential calculations. Isolated DNA, as well as DNA released by stimulated leukocytes, was able to bind to shear-activated, but not inactivated, VWF. However, DNA-VWF binding does not alter VWF degradation by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Moreover, DNA-VWF interaction can be blocked using unfractionated and low-molecular-weight heparin, and DNA-VWF complexes attenuate platelet binding to VWF. These findings were supported using molecular dynamics simulations and electrostatic calculations of the A1- and A2 domains. CONCLUSIONS: Our findings suggest that VWF directly binds and immobilizes extracellular DNA released from leukocytes. Therefore, we hypothesize that VWF might act as a linker for leukocyte adhesion to endothelial cells, supporting leukocyte extravasation and inflammation. PMID- 24790142 TI - Perivascular adipose tissue and coronary vascular disease. AB - Coronary perivascular adipose tissue is a naturally occurring adipose tissue depot that normally surrounds the major coronary arteries on the surface of the heart. Although originally thought to promote vascular health and integrity, there is a growing body of evidence to support that coronary perivascular adipose tissue displays a distinct phenotype relative to other adipose depots and is capable of producing local factors with the potential to augment coronary vascular tone, inflammation, and the initiation and progression of coronary artery disease. The purpose of the present review is to outline previous findings about the cardiovascular effects of coronary perivascular adipose tissue and the potential mechanisms by which adipose-derived factors may influence coronary vascular function and the progression of atherogenesis. PMID- 24790144 TI - Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice. AB - Perforin (pfp)-mediated cytotoxicity is one of the principal immunosurveillance mechanisms involved in the fight against cancer. However, its importance in spontaneous epithelial cancer is still poorly defined. In this study, we use a realistic mouse model that displays many features that are equivalent to human pathology to evaluate the role of pfp-dependent immunosurveillance by comparing tumor progression in rat ERBB-2 (neu) transgenic, pfp-proficient (neu(+)/pfp(+)) or pfp-deficient (neu(+)/pfp(-)) BALB/c male mice. Adult neu(+)/pfp(+) males developed poorly differentiated salivary carcinomas, whereas neu(+)/pfp(-) males displayed their salivary carcinomas noticeably earlier and showed zones of more highly differentiated tumor, indicating that pfp-mediated immunosurveillance is able not only to delay the growth kinetic of an aggressive epithelial tumor, but also to shape its histology. The role of pfp-mediated immunosurveillance appeared to be of even more dramatic importance against the less aggressive male mammary carcinomas. In neu(+)/pfp(+) males, the incidence of mammary carcinomas was a sporadic and late event. In contrast, in neu(+)/pfp(-) males their incidence was four-fold higher. This higher cancer incidence was associated with a 2-fold higher occurrence of persisting mammary remnants, a major risk factor for mammary cancer in male mice, and one that would appear to be due to pfp's previously unidentified involvement in male mammary gland rejection during embryogenesis. This work thus provides further proof of the complex role that the immune system plays in the body and gives new insight into the pathogenesis of epithelial tumors, demonstrating that the penetrance and malignancy of a tumor may be dramatically affected by pfp-dependent mechanisms. PMID- 24790145 TI - Adjustable locks and flexible keys: plasticity of epitope-paratope interactions in germline antibodies. AB - Ag recognition by independent primary Abs against a small flexible Ag with overlapping epitopes was analyzed to address the determinants of Ag specificity during the initial encounter. Crystal structures of two distinct dodecapeptide Ags, GDPRPSYISHLL and PPYPAWHAPGNI, in complex with the germline mAb 36-65 were determined and compared with the structures of the same Ags bound to another independent germline mAb, BBE6.12H3. For each peptide Ag, the two germline mAbs recognized overlapping epitopes, but in different topologies. The peptide structures differed, and the two paratopes attained discrete conformations, leading to different surface topologies, in a mode that can be described as adjustable locks and flexible keys. This is in contrast to mature mAbs, in which conformational convergence of different paratopes while binding to a common epitope in a similar conformation has been reported. These results suggest that the primary immune receptor repertoire is highly versatile as compared with its mature counterpart. Germline and mature mAbs adopt distinct mechanisms for recognizing a flexible epitope. Whereas conservation of conformational repertoire is a key characteristic of mature mAbs achieved through affinity maturation, the germline mAbs, at the initial stages of Ag encounter, maintain substantial plasticity, accommodating a broad specificity repertoire. PMID- 24790146 TI - The ligand-binding domain of Siglec-G is crucial for its selective inhibitory function on B1 cells. AB - Siglec-G is an inhibitory receptor on B1 cells. Siglec-G-deficient mice show a large B1 cell expansion, owing to higher BCR-induced Ca(2+) signaling and enhanced cellular survival. It was unknown why Siglec-G shows a B1 cell restricted inhibitory function. With a new mAb we could show a comparable Siglec G expression on B1 cells and conventional B2 cells. However, Siglec-G has a different ligand sialic acid-binding pattern on peritoneal B1 cells than on splenic B cells, and its sialic acid ligands are expressed differentially on these two B cell populations, suggesting that cis-ligand binding plays a crucial role on B1 cells. This observation was further studied by generation of Siglec-G knockin mice with a mutated ligand-binding domain. These mice show increased B1 cell numbers, increased B1 cell Ca(2+) signaling, better B1 cell survival, and changes in the B1 cell Ig repertoire. These phenotypes are very similar to Siglec G-deficient mice. The mutation of the ligand-binding domain of Siglec-G strongly reduces the Siglec-G-IgM association on the B cell surface. Thus, Siglec-G sialic acid-dependent binding to the BCR is crucial for the B1 cell-restricted inhibitory function of Siglec-G and is regulated in an opposite way to that of the related protein CD22 (Siglec-2) on B cells. PMID- 24790147 TI - Distinct assembly profiles of HLA-B molecules. AB - MHC class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers, and inflammatory diseases. Human MHC class I H chains are encoded by the HLA-A, HLA-B, and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to a distinct set of peptide Ags, which are presented to CD8(+) T cells. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In this study, we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B-folding patterns upon infectious disease outcomes. PMID- 24790149 TI - Cross-dressing by donor dendritic cells after allogeneic bone marrow transplantation contributes to formation of the immunological synapse and maximizes responses to indirectly presented antigen. AB - The stimulation of naive donor T cells by recipient alloantigen is central to the pathogenesis of graft-versus-host disease after bone marrow transplantation (BMT). Using mouse models of transplantation, we have observed that donor cells become "cross-dressed" in very high levels of recipient hematopoietic cell derived MHC class I and II molecules following BMT. Recipient-type MHC is transiently present on donor dendritic cells (DCs) after BMT in the setting of myeloablative conditioning but is persistent after nonmyeloablative conditioning, in which recipient hematopoietic cells remain in high numbers. Despite the high level of recipient-derived alloantigen present on the surface of donor DCs, donor T cell proliferative responses are generated only in response to processed recipient alloantigen presented via the indirect pathway and not in response to cross-dressed MHC. Assays in which exogenous peptide is added to cross-dressed MHC in the presence of naive TCR transgenic T cells specific to the MHC class II peptide combination confirm that cross-dressed APC cannot induce T cell proliferation in isolation. Despite failure to induce T cell proliferation, cross dressing by donor DCs contributes to generation of the immunological synapse between DCs and CD4 T cells, and this is required for maximal responses induced by classical indirectly presented alloantigen. We conclude that the process of cross-dressing by donor DCs serves as an efficient alternative pathway for the acquisition of recipient alloantigen and that once acquired, this cross-dressed MHC can assist in immune synapse formation prior to the induction of full T cell proliferative responses by concurrent indirect Ag presentation. PMID- 24790148 TI - Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. AB - Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis. PMID- 24790150 TI - Soluble, but not transmembrane, TNF-alpha is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology. AB - TNF-alpha is a pleotropic cytokine that has both proinflammatory and anti inflammatory functions during influenza infection. TNF-alpha is first expressed as a transmembrane protein that is proteolytically processed to release a soluble form. Transmembrane TNF-alpha (memTNF-alpha) and soluble TNF-alpha (solTNF-alpha) have been shown to exert distinct tissue-protective or tissue-pathologic effects in several disease models. However, the relative contributions of memTNF-alpha or solTNF-alpha in regulating pulmonary immunopathology following influenza infection are unclear. Therefore, we performed intranasal influenza infection in mice exclusively expressing noncleavable memTNF-alpha or lacking TNF-alpha entirely and examined the outcomes. We found that solTNF-alpha, but not memTNF alpha, was required to limit the size of the immune response and the extent of injury. In the absence of solTNF-alpha, there was a significant increase in the CD8(+) T cell response, including virus-specific CD8(+) T cells, which was due in part to an increased resistance to activation-induced cell death. We found that solTNF-alpha mediates these immunoregulatory effects primarily through TNFR1, because mice deficient in TNFR1, but not TNFR2, exhibited dysregulated immune responses and exacerbated injury similar to that observed in mice lacking solTNF alpha. We also found that solTNF-alpha expression was required early during infection to regulate the magnitude of the CD8(+) T cell response, indicating that early inflammatory events are critical for the regulation of the effector phase. Taken together, these findings suggest that processing of memTNF-alpha to release solTNF-alpha is a critical event regulating the immune response during influenza infection. PMID- 24790151 TI - A polysaccharide virulence factor of a human fungal pathogen induces neutrophil apoptosis via NK cells. AB - Aspergillus fumigatus is an opportunistic human fungal pathogen that sheds galactosaminogalactan (GG) into the environment. Polymorphonuclear neutrophils (PMNs) and NK cells are both part of the first line of defense against pathogens. We recently reported that GG induces PMN apoptosis. In this study, we show that PMN apoptosis occurs via a new NK cell-dependent mechanism. Reactive oxygen species, induced by the presence of GG, play an indispensable role in this apoptotic effect by increasing MHC class I chain-related molecule A expression at the PMN surface. This increased expression enables interaction between MHC class I chain-related molecule A and NKG2D, leading to NK cell activation, which in turn generates a Fas-dependent apoptosis-promoting signal in PMNs. Taken together, our results demonstrate that the crosstalk between PMNs and NK cells is essential to GG-induced PMN apoptosis. NK cells might thus play a role in the induction of PMN apoptosis in situations such as unexplained neutropenia or autoimmune diseases. PMID- 24790152 TI - Through an ITIM-independent mechanism the FcgammaRIIB blocks B cell activation by disrupting the colocalized microclustering of the B cell receptor and CD19. AB - B cell activation is regulated through the interplay of the BCR with the inhibitory coreceptor FcgammaRIIB and the activating coreceptor CD19. Recent studies suggest that Ag-driven BCR microclusters are efficiently converted to a signaling active state on colocalization with CD19 microclusters. Using total internal reflection fluorescence microscopy-based, high-resolution, high-speed live-cell and molecule imaging approaches, we show that when co-ligated to the BCR, the FcgammaRIIB can inhibit B cell activation by blocking the colocalization of BCR and CD19 microclusters within the B cell immunological synapse. Remarkably, this inhibitory function of FcgammaRIIB is dependent not on its well characterized ITIM-containing cytoplasmic domain, but its transmembrane domain. Indeed, human primary B cells from systemic lupus erythematosus patients homozygous for gene encoding the loss-of-function transmembrane domain mutant FcgammaRIIB-I232T fail to block the synaptic colocalization of the BCR with CD19, leading to dysregulated recruitment of downstream signaling molecule p-PI3K to membrane proximal signalosome. This inhibitory function of FcgammaRIIB in impairing the spatial-temporal colocalization of BCR and CD19 microclusters in the B cell immunological synapse may help explain the hyper-reactive features of systemic lupus erythematosus patient B cells in reported studies. These observations may also provide new targets for therapies for systemic autoimmune disease. PMID- 24790154 TI - dbGSH: a database of S-glutathionylation. AB - S-glutathionylation, the reversible protein posttranslational modification (PTM) that generates a mixed disulfide bond between glutathione and cysteine residue, critically regulates protein activity, stability and redox regulation. Due to its importance in regulating oxidative/nitrosative stress and balance in cellular response, a number of methods have been rapidly developed to study S glutathionylation, thus expanding the dataset of experimentally determined glutathionylation sites. However, there is currently no database dedicated to the integration of all experimentally verified S-glutathionylation sites along with their characteristics or structural or functional information. Thus, the dbGSH database has been created to integrate all available datasets and to provide the relevant structural analysis. As of January 31, 2014, dbGSH has manually collected >2200 experimentally verified S-glutathionylated peptides from 169 research articles using a text-mining approach. To solve the problem of heterogeneity of the data collected from different sources, the sequence identity of the reported S-glutathionylated peptides is mapped to UniProtKB protein entries. To delineate the structural correlations and consensus motifs of these S glutathionylation sites, the dbGSH database also provides structural and functional analyses, including the motifs of substrate sites, solvent accessibility, protein secondary and tertiary structures, protein domains and gene ontology. AVAILABILITY AND IMPLEMENTATION: dbGSH is now freely accessible at http://csb.cse.yzu.edu.tw/dbGSH/. The database content is regularly updated with new data collected by the continuous survey of research articles. PMID- 24790153 TI - All-trans retinoic acid induces arginase-1 and inducible nitric oxide synthase producing dendritic cells with T cell inhibitory function. AB - Hepatic stellate cells (HSC) are a major source of the immunoregulatory metabolite all-trans retinoic acid (ATRA), which may contribute to the generation of tolerogenic dendritic cells (DCs) in the liver. The present study seeks to clarify the mechanism(s) through which ATRA promotes the development of tolerogenic DCs. Although bone marrow-derived ATRA-treated DCs (RA-DCs) and conventional DCs had comparable surface phenotype, RA-DCs had diminished stimulatory capacity and could directly inhibit the expansion of DC/OVA stimulated OT-II T cells. Arginase-1 (Arg-1) was found promote suppression because 1) ATRA was a potent inducer of Arg-1 protein and activity, 2) the Arg-1 inhibitor N(w)-hydroxy nor-l-arginine partially reversed suppression, and 3) the suppressive function of RA-DCs was partially compromised using OT-II T cells from GCN2(-/-) mice, which are insensitive to Arg-1. Inducible NO synthase (iNOS), however, was found to be a more significant contributor to RA-DC function because 1) ATRA potentiated the expression of IFN-gamma-induced iNOS, 2) suppressive function in RA-DCs was blocked by the iNOS inhibitor N(G)-monomethyl-l-arginine, monoacetate salt, and 3) RA-DCs derived from iNOS(-/-) mice exhibited near complete loss of tolerogenic function, despite sustained Arg-1 activity. The expression of iNOS and the suppressive function of RA-DCs were dependent on both IFN-gamma and ATRA. Furthermore, the in vivo behavior of RA-DCs proved to be consistent with their in vitro behavior. Thus, we conclude that ATRA enhances both Arg-1 and iNOS expression in IFN-gamma-treated DCs, resulting in a tolerogenic phenotype. These findings elucidate mechanisms through which ATRA may contribute to liver immune tolerance. PMID- 24790155 TI - Detecting clustering and ordering binding patterns among transcription factors via point process models. AB - MOTIVATION: Recent development in ChIP-Seq technology has generated binding data for many transcription factors (TFs) in various cell types and cellular conditions. This opens great opportunities for studying combinatorial binding patterns among a set of TFs active in a particular cellular condition, which is a key component for understanding the interaction between TFs in gene regulation. RESULTS: As a first step to the identification of combinatorial binding patterns, we develop statistical methods to detect clustering and ordering patterns among binding sites (BSs) of a pair of TFs. Testing procedures based on Ripley's K function and its generalizations are developed to identify binding patterns from large collections of BSs in ChIP-Seq data. We have applied our methods to the ChIP-Seq data of 91 pairs of TFs in mouse embryonic stem cells. Our methods have detected clustering binding patterns between most TF pairs, which is consistent with the findings in the literature, and have identified significant ordering preferences, relative to the direction of target gene transcription, among the BSs of seven TFs. More interestingly, our results demonstrate that the identified clustering and ordering binding patterns between TFs are associated with the expression of the target genes. These findings provide new insights into co regulation between TFs. AVAILABILITY AND IMPLEMENTATION: See 'www.stat.ucla.edu/~zhou/TFKFunctions/' for source code. PMID- 24790156 TI - Vacceed: a high-throughput in silico vaccine candidate discovery pipeline for eukaryotic pathogens based on reverse vaccinology. AB - We present Vacceed, a highly configurable and scalable framework designed to automate the process of high-throughput in silico vaccine candidate discovery for eukaryotic pathogens. Given thousands of protein sequences from the target pathogen as input, the main output is a ranked list of protein candidates determined by a set of machine learning algorithms. Vacceed has the potential to save time and money by reducing the number of false candidates allocated for laboratory validation. Vacceed, if required, can also predict protein sequences from the pathogen's genome. AVAILABILITY AND IMPLEMENTATION: Vacceed is tested on Linux and can be freely downloaded from https://github.com/sgoodswe/vacceed/releases (includes a worked example with sample data). Vacceed User Guide can be obtained from https://github.com/sgoodswe/vacceed. PMID- 24790157 TI - ReadXplorer--visualization and analysis of mapped sequences. AB - MOTIVATION: Fast algorithms and well-arranged visualizations are required for the comprehensive analysis of the ever-growing size of genomic and transcriptomic next-generation sequencing data. RESULTS: ReadXplorer is a software offering straightforward visualization and extensive analysis functions for genomic and transcriptomic DNA sequences mapped on a reference. A unique specialty of ReadXplorer is the quality classification of the read mappings. It is incorporated in all analysis functions and displayed in ReadXplorer's various synchronized data viewers for (i) the reference sequence, its base coverage as (ii) normalizable plot and (iii) histogram, (iv) read alignments and (v) read pairs. ReadXplorer's analysis capability covers RNA secondary structure prediction, single nucleotide polymorphism and deletion-insertion polymorphism detection, genomic feature and general coverage analysis. Especially for RNA-Seq data, it offers differential gene expression analysis, transcription start site and operon detection as well as RPKM value and read count calculations. Furthermore, ReadXplorer can combine or superimpose coverage of different datasets. AVAILABILITY AND IMPLEMENTATION: ReadXplorer is available as open source software at http://www.readxplorer.org along with a detailed manual. PMID- 24790158 TI - Human sperm devoid of germinal angiotensin-converting enzyme is responsible for total fertilization failure and lower fertilization rates by conventional in vitro fertilization. AB - In conventional in vitro fertilization (IVF), complete failure of fertilization occurs in 5% to 15% of treatments. Although the causes may be unclear, sperm defects appear to be the major contributor. However, a convincing test is not yet available that can predict the risk of fertilization failure. In this study, we found that germinal angiotensin-converting enzyme (gACE) (also called testicular ACE) was undetectable in sperm from patients who had total fertilization failure (TFF) and lower fertilization rates (LFRs) by IVF based on Western blot and indirect immunofluorescence analyses. Additionally, almost all of the patients without gACE on sperm (23 of 25) manifested a TT genotype of the rs4316 single nucleotide polymorphism of ACE. Overall, our results indicate that the absence of gACE expression is responsible for TFF and LFRs by IVF. The rs4316 polymorphism of ACE might be associated with infertility in those patients. We conclude that sperm lacking gACE may be recognized before commencing IVF and that the patients may be directed instead to consider intracytoplasmic sperm injection. PMID- 24790159 TI - The shrimp heat shock cognate 70 functions as a negative regulator in vitellogenin gene expression. AB - Within the 2.6-kb 5' flanking region of the shrimp (Metapenaeus ensis) vitellogenin gene (MeVg2), several clusters of putative heat shock factor (HSF) response elements were identified. Deletion of these response elements has caused significant increases in MeVg2 promoter activity, suggesting that the HSF and Hsc70 complex may regulate vitellogenin gene expression in a negative manner. To confirm the role of Hsc70 in the regulation of vitellogenin gene expression, the ovary cDNA for Hsc70 was cloned and characterized. The Hsc70 transcript level was high in the ovary and hepatopancreas of females at the early vitellogenic stage but dropped during ovarian maturation. In addition, Western blot analysis revealed the presence of Hsc70 in the nuclear but not in the cytoplasmic fraction during the early stage of ovary maturation. Electrophoretic mobility shift assay (EMSA) results showed that ovary nuclear extract contained a factor that binds to the HSF response element. Since the addition of ATP caused a decrease in the binding of Hsc70, Hsc70 may form a repressor complex with HSF to inhibit MeVg2 expression. An in vitro RNA interference technique was used to study the gene function of Hsc70. Hsc70 gene knockdown resulted in an increased MeVg2 mRNA level in the ovary (54%) and hepatopancreas (62%). In summary, this report describes the first study of vitellogenin gene regulation at the transcription level in crustaceans and provides strong evidence that Hsc70 acts as a molecular chaperone to negatively regulate MeVg2 gene expression in shrimp. PMID- 24790160 TI - Trioecy, a unique breeding strategy in the sea anemone Aiptasia diaphana and its association with sex steroids. AB - Reproductive development of anthozoans reveals wide range of breeding strategies. Here, we report the occurrence of trioecy in the sea anemone Aiptasia diaphana (co-occurrence of males, females, and hermaphrodites), which so far was well documented only in plants. Age-homogeneous populations were obtained from pedal lacerates (asexual propagules) and cultured under control conditions. Careful documentation of growth, gamete morphology, and vertebrate-like steroid (i.e., progesterone, testosterone, and estradiol) levels were carried out over a 9-wk period between 4 and 12 wk postlaceration (wpl). First phenotypic signs of gametes development were observed in 6-wk-old anemones, pointing to the differentiation of males and hermaphrodites. While the males exhibited cellular progression of spermatogenesis, the hermaphrodites underwent a process of sex allocation, giving rise to male, female, and hermaphrodite phenotypes. Testosterone levels were relatively high prior to gamete appearance (4 wpl) and later on during gamete maturation (10 wpl). Conversely, estradiol levels steadily increased from 6 to 10 wpl, reaching their peak concomitant with oocyte maturation. Interestingly, increased oocyte atresia incidences were recorded during 9-12 wpl, coinciding with declining levels of steroid hormones. These results point to a strong similarity between the activity of sex steroids in vertebrates and that of vertebrate-like sex steroids on critical stages of A. diaphana's sexual differentiation and gametogenic cycle. The reproductive characteristics of A. diaphana make this anthozoan an important model species for the study of evolutionary drivers and processes underlying sexual development. PMID- 24790161 TI - Dosage compensation of an aneuploid genome in mouse spermatogenic cells. AB - Autosomal trisomies and monosomies bring serious threats to embryonic development through transcriptional disarray caused primarily by the dosage effect of the aneuploid part of the genome. The present study compared the effect of a mouse viable 30-Mb segmental trisomy on the genome-wide transcriptional profile of somatic (liver) cells and male germ cells. Although the 1.6-fold change in expression of triplicated genes reflected the gene dosage in liver cells, the extra copy genes were compensated in early pachytene spermatocytes, showing 1.18 fold increase. Although more pronounced, the dosage compensation of trisomic genes was concordant with the incidence of HORMAD2 protein and histone gammaH2AX markers of unsynapsed chromatin. A possible explanation for this includes insufficient sensitivity to detect the meiotic silencing of unsynapsed chromatin markers in the 30-Mb region of the chromosome or an earlier silencing effect of another epigenetic factor. Taken together, our results indicate that the meiotic silencing of unsynapsed chromatin is the major, but most likely not the only, factor driving the dosage compensation of triplicated genes in primary spermatocytes. PMID- 24790162 TI - Luteinizing hormone-induced expression of Ptger4b, a prostaglandin E2 receptor indispensable for ovulation of the medaka Oryzias latipes, is regulated by a genomic mechanism involving nuclear progestin receptor. AB - We previously reported that the prostaglandin E2 receptor subtype Ptger4b plays a role in ovulation in a teleost species, medaka and that ptger4b mRNA is drastically induced in preovulatory follicles prior to ovulation. The present study focuses on the hormonal regulation of ptger4b mRNA expression using this nonmammalian vertebrate model. Preovulatory follicles that had not been exposed to luteinizing hormone (Lh) in vivo were incubated in vitro with medaka recombinant Lh (rLh), which induced the ptger4b mRNA expression. The addition of trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase, strongly inhibited rLh-induced ptger4b expression, and trilostane-suppressed ptger4b expression was restored to the level observed in rLh-treated follicles when 17alpha, 20beta-dihydroxy-4-pregnen-3-one was included in the culture. We determined that the expression of the progestin-activated transcription factor nuclear progestin receptor (Pgr) was also induced by medaka rLh in the follicle and that its expression preceded ptger4b expression. Forskolin treatment induced both pgr and ptger4b mRNA expression in the follicle. Follicular ptger4b mRNA expression was drastically suppressed by RU486, which was demonstrated to compete with 17alpha, 20beta-dihydroxy-4-pregnen-3-one for medaka Pgr in vitro, suggesting a role for Pgr in the expression of ptger4b mRNA. A chromatin immunoprecipitation assay with preovulatory follicles isolated from spawning medaka ovaries demonstrated direct binding of Pgr to the ptger4b promoter. These results indicate that ptger4b expression is regulated by a genomic mechanism involving Pgr. PMID- 24790164 TI - Kv7 channels regulate pairwise spiking covariability in health and disease. AB - Low-threshold M currents are mediated by the Kv7 family of potassium channels. Kv7 channels are important regulators of spiking activity, having a direct influence on the firing rate, spike time variability, and filter properties of neurons. How Kv7 channels affect the joint spiking activity of populations of neurons is an important and open area of study. Using a combination of computational simulations and analytic calculations, we show that the activation of Kv7 conductances reduces the covariability between spike trains of pairs of neurons driven by common inputs. This reduction is beyond that explained by the lowering of firing rates and involves an active cancellation of common fluctuations in the membrane potentials of the cell pair. Our theory shows that the excess covariance reduction is due to a Kv7-induced shift from low-pass to band-pass filtering of the single neuron spike train response. Dysfunction of Kv7 conductances is related to a number of neurological diseases characterized by both elevated firing rates and increased network-wide correlations. We show how changes in the activation or strength of Kv7 conductances give rise to excess correlations that cannot be compensated for by synaptic scaling or homeostatic modulation of passive membrane properties. In contrast, modulation of Kv7 activation parameters consistent with pharmacological treatments for certain hyperactivity disorders can restore normal firing rates and spiking correlations. Our results provide key insights into how regulation of a ubiquitous potassium channel class can control the coordination of population spiking activity. PMID- 24790163 TI - Sensory processing and corollary discharge effects in posterior caudal lobe Purkinje cells in a weakly electric mormyrid fish. AB - Although it has been suggested that the cerebellum functions to predict the sensory consequences of motor commands, how such predictions are implemented in cerebellar circuitry remains largely unknown. A detailed and relatively complete account of predictive mechanisms has emerged from studies of cerebellum-like sensory structures in fish, suggesting that comparisons of the cerebellum and cerebellum-like structures may be useful. Here we characterize electrophysiological response properties of Purkinje cells in a region of the cerebellum proper of weakly electric mormyrid fish, the posterior caudal lobe (LCp), which receives the same mossy fiber inputs and projects to the same target structures as the electrosensory lobe (ELL), a well-studied cerebellum-like structure. We describe patterns of simple spike and climbing fiber activation in LCp Purkinje cells in response to motor corollary discharge, electrosensory, and proprioceptive inputs and provide evidence for two functionally distinct Purkinje cell subtypes within LCp. Protocols that induce rapid associative plasticity in ELL fail to induce plasticity in LCp, suggesting differences in the adaptive functions of the two structures. Similarities and differences between LCp and ELL are discussed in light of these results. PMID- 24790165 TI - A magnetoencephalography study of visual processing of pain anticipation. AB - Anticipating pain is important for avoiding injury; however, in chronic pain patients, anticipatory behavior can become maladaptive, leading to sensitization and limiting function. Knowledge of networks involved in pain anticipation and conditioning over time could help devise novel, better-targeted therapies. With the use of magnetoencephalography, we evaluated in 10 healthy subjects the neural processing of pain anticipation. Anticipatory cortical activity elicited by consecutive visual cues that signified imminent painful stimulus was compared with cues signifying nonpainful and no stimulus. We found that the neural processing of visually evoked pain anticipation involves the primary visual cortex along with cingulate and frontal regions. Visual cortex could quickly and independently encode and discriminate between visual cues associated with pain anticipation and no pain during preconscious phases following object presentation. When evaluating the effect of task repetition on participating cortical areas, we found that activity of prefrontal and cingulate regions was mostly prominent early on when subjects were still naive to a cue's contextual meaning. Visual cortical activity was significant throughout later phases. Although visual cortex may precisely and time efficiently decode cues anticipating pain or no pain, prefrontal areas establish the context associated with each cue. These findings have important implications toward processes involved in pain anticipation and maladaptive pain conditioning. PMID- 24790166 TI - The flexible recruitment of muscle synergies depends on the required force generating capability. AB - To simplify redundant motor control, the central nervous system (CNS) may modularly organize and recruit groups of muscles as "muscle synergies." However, smooth and efficient movements are expected to require not only low-dimensional organization, but also flexibility in the recruitment or combination of synergies, depending on force-generating capability of individual muscles. In this study, we examined how the CNS controls activations of muscle synergies as changing joint angles. Subjects performed multidirectional isometric force generations around right ankle and extracted the muscle synergies using nonnegative matrix factorization across various knee and hip joint angles. As a result, muscle synergies were selectively recruited with merging or decomposition as changing the joint angles. Moreover, the activation profiles, including activation levels and the direction indicating the peak, of muscle synergies across force directions depended on the joint angles. Therefore, we suggested that the CNS selects appropriate muscle synergies and controls their activation patterns based on the force-generating capability of muscles with merging or decomposing descending neural inputs. PMID- 24790167 TI - Body stability and muscle and motor cortex activity during walking with wide stance. AB - Biomechanical and neural mechanisms of balance control during walking are still poorly understood. In this study, we examined the body dynamic stability, activity of limb muscles, and activity of motor cortex neurons [primarily pyramidal tract neurons (PTNs)] in the cat during unconstrained walking and walking with a wide base of support (wide-stance walking). By recording three dimensional full-body kinematics we found for the first time that during unconstrained walking the cat is dynamically unstable in the forward direction during stride phases when only two diagonal limbs support the body. In contrast to standing, an increased lateral between-paw distance during walking dramatically decreased the cat's body dynamic stability in double-support phases and prompted the cat to spend more time in three-legged support phases. Muscles contributing to abduction-adduction actions had higher activity during stance, while flexor muscles had higher activity during swing of wide-stance walking. The overwhelming majority of neurons in layer V of the motor cortex, 82% and 83% in the forelimb and hindlimb representation areas, respectively, were active differently during wide-stance walking compared with unconstrained condition, most often by having a different depth of stride-related frequency modulation along with a different mean discharge rate and/or preferred activity phase. Upon transition from unconstrained to wide-stance walking, proximal limb-related neuronal groups subtly but statistically significantly shifted their activity toward the swing phase, the stride phase where most of body instability occurs during this task. The data suggest that the motor cortex participates in maintenance of body dynamic stability during locomotion. PMID- 24790168 TI - A neuromechanical strategy for mediolateral foot placement in walking humans. AB - Stability is an important concern during human walking and can limit mobility in clinical populations. Mediolateral stability can be efficiently controlled through appropriate foot placement, although the underlying neuromechanical strategy is unclear. We hypothesized that humans control mediolateral foot placement through swing leg muscle activity, basing this control on the mechanical state of the contralateral stance leg. Participants walked under Unperturbed and Perturbed conditions, in which foot placement was intermittently perturbed by moving the right leg medially or laterally during the swing phase (by ~50-100 mm). We quantified mediolateral foot placement, electromyographic activity of frontal-plane hip muscles, and stance leg mechanical state. During Unperturbed walking, greater swing-phase gluteus medius (GM) activity was associated with more lateral foot placement. Increases in GM activity were most strongly predicted by increased mediolateral displacement between the center of mass (CoM) and the contralateral stance foot. The Perturbed walking results indicated a causal relationship between stance leg mechanics and swing-phase GM activity. Perturbations that reduced the mediolateral CoM displacement from the stance foot caused reductions in swing-phase GM activity and more medial foot placement. Conversely, increases in mediolateral CoM displacement caused increased swing-phase GM activity and more lateral foot placement. Under both Unperturbed and Perturbed conditions, humans controlled their mediolateral foot placement by modulating swing-phase muscle activity in response to the mechanical state of the contralateral leg. This strategy may be disrupted in clinical populations with a reduced ability to modulate muscle activity or sense their body's mechanical state. PMID- 24790169 TI - Modeling effects of spinal cord stimulation on wide-dynamic range dorsal horn neurons: influence of stimulation frequency and GABAergic inhibition. AB - Spinal cord stimulation (SCS) is a clinical therapy for chronic, neuropathic pain, but an incomplete understanding of the mechanisms underlying SCS contributes to the lack of improvement in SCS efficacy over time. To study the mechanisms underlying SCS, we constructed a biophysically based network model of the dorsal horn circuit consisting of interconnected dorsal horn interneurons and a wide-dynamic range (WDR) projection neuron and representations of both local and surround receptive field inhibition. We validated the network model by reproducing cellular and network responses relevant to pain processing including wind-up, A fiber-mediated inhibition, and surround receptive field inhibition. We then simulated the effects of SCS on the activity of the WDR projection neuron and found that the response of the model WDR neuron to SCS depends on the SCS frequency; SCS frequencies of 30-100 Hz maximally inhibited the model WDR neuron, while frequencies under 30 Hz and over 100 Hz excited the model WDR neuron. We also studied the impacts on the effects of SCS of loss of inhibition due to the loss of either GABA or KCC2 function. Reducing the influence of local and surround GABAergic interneurons by weakening their inputs or their connections to the WDR neuron and shifting the anionic reversal potential of the WDR neurons upward each reduced the range of optimal SCS frequencies and changed the frequency at which SCS had a maximal effect. The results of this study provide insights into the mechanisms of SCS and pave the way for improved SCS parameter selection. PMID- 24790171 TI - Does the antihyperalgesic disruptor of endothelial cells, octoxynol-9, alter nociceptor function? AB - The vasoactive mediator, endothelin-1, elicits a novel form of hyperalgesia, stimulation-dependent hyperalgesia. Acting on its cognate receptor on the vascular endothelial cell, endothelin-1 produces a state in which mechanical stimulation now elicits release of pronociceptive mediators from endothelium that, in turn, acts at receptors on sensory neurons. The only evidence that octoxynol-9, a surface-active agent that attenuates both endothelial cell function and stimulus-dependent hyperalgesia, does not affect nociceptors is indirect (i.e., octoxynol-9 treatment did not affect behavioral nociceptive threshold or hyperalgesia induced by agents that act directly on nociceptors). To help address the question of whether the attenuation of stimulation-dependent hyperalgesia by octoxynol-9 treatment is due to alteration of nociceptor function, we used in vivo single-fiber electrophysiological recordings. Consistent with our previous behavioral observations, we observed no significant effect of octoxynol-9 on mechanical threshold in nociceptors, their response to sustained suprathreshold mechanical stimulation, conduction velocity, and change in mechanical threshold in response to the direct-acting hyperalgesic agent, PGE2. Although octoxynol-9 did not produce a biologically meaningful change in parameters of nociceptor function, we cannot exclude the possibility of a type II error. However, our data provide preliminary evidence of no effect of octoxynol-9 on nociceptors and are consistent with the suggestion that the primary action of octoxynol-9 in our studies is due to its action on the endothelium. PMID- 24790170 TI - Emergence of band-pass filtering through adaptive spiking in the owl's cochlear nucleus. AB - In the visual, auditory, and electrosensory modalities, stimuli are defined by first- and second-order attributes. The fast time-pressure signal of a sound, a first-order attribute, is important, for instance, in sound localization and pitch perception, while its slow amplitude-modulated envelope, a second-order attribute, can be used for sound recognition. Ascending the auditory pathway from ear to midbrain, neurons increasingly show a preference for the envelope and are most sensitive to particular envelope modulation frequencies, a tuning considered important for encoding sound identity. The level at which this tuning property emerges along the pathway varies across species, and the mechanism of how this occurs is a matter of debate. In this paper, we target the transition between auditory nerve fibers and the cochlear nucleus angularis (NA). While the owl's auditory nerve fibers simultaneously encode the fast and slow attributes of a sound, one synapse further, NA neurons encode the envelope more efficiently than the auditory nerve. Using in vivo and in vitro electrophysiology and computational analysis, we show that a single-cell mechanism inducing spike threshold adaptation can explain the difference in neural filtering between the two areas. We show that spike threshold adaptation can explain the increased selectivity to modulation frequency, as input level increases in NA. These results demonstrate that a spike generation nonlinearity can modulate the tuning to second-order stimulus features, without invoking network or synaptic mechanisms. PMID- 24790172 TI - Learning the spatial features of a locomotor task is slowed after stroke. AB - The capacity for humans to learn a new walking pattern has been explored with a split-belt treadmill during single sessions of adaptation, but the split-belt treadmill can also be used to study longer-term motor learning. Although the literature provides some information about motor learning after stroke, existing studies have primarily involved the upper extremity and the results are mixed. The purpose of this study was to characterize learning of a novel locomotor task in stroke survivors. We hypothesized that the presence of neurological dysfunction from stroke would result in slower learning of a locomotor task and decreased retention of what was learned and that these deficits would be related to level of sensorimotor impairment. Sixteen participants with stroke and sixteen neurologically intact participants walked on a split-belt treadmill for 15 min on 5 consecutive days and during a retention test. Step length and limb phase were measured to capture learning of the spatial and temporal aspects of walking. Learning the spatial pattern of split-belt treadmill walking was slowed after stroke compared with neurologically intact subjects, whereas there were no differences between these two groups in learning the temporal pattern. During the retention test, poststroke participants demonstrated equal retention of the split belt treadmill walking pattern compared with those who were neurologically intact. The results suggest that although stroke survivors are slower to learn a new spatial pattern of gait, if given sufficient time they are able to do so to the same extent as those who are neurologically intact. PMID- 24790173 TI - Gravity-dependent estimates of object mass underlie the generation of motor commands for horizontal limb movements. AB - Moving requires handling gravitational and inertial constraints pulling on our body and on the objects that we manipulate. Although previous work emphasized that the brain uses internal models of each type of mechanical load, little is known about their interaction during motor planning and execution. In this report, we examine visually guided reaching movements in the horizontal plane performed by naive participants exposed to changes in gravity during parabolic flight. This approach allowed us to isolate the effect of gravity because the environmental dynamics along the horizontal axis remained unchanged. We show that gravity has a direct effect on movement kinematics, with faster movements observed after transitions from normal gravity to hypergravity (1.8g), followed by significant movement slowing after the transition from hypergravity to zero gravity. We recorded finger forces applied on an object held in precision grip and found that the coupling between grip force and inertial loads displayed a similar effect, with an increase in grip force modulation gain under hypergravity followed by a reduction of modulation gain after entering the zero-gravity environment. We present a computational model to illustrate that these effects are compatible with the hypothesis that participants partially attribute changes in weight to changes in mass and scale incorrectly their motor commands with changes in gravity. These results highlight a rather direct internal mapping between the force generated during stationary holding against gravity and the estimation of inertial loads that limb and hand motor commands must overcome. PMID- 24790174 TI - Effect of amplitude correlations on coherence in the local field potential. AB - Neural activity across the brain shows both spatial and temporal correlations at multiple scales, and understanding these correlations is a key step toward understanding cortical processing. Correlation in the local field potential (LFP) recorded from two brain areas is often characterized by computing the coherence, which is generally taken to reflect the degree of phase consistency across trials between two sites. Coherence, however, depends on two factors-phase consistency as well as amplitude covariation across trials-but the spatial structure of amplitude correlations across sites and its contribution to coherence are not well characterized. We recorded LFP from an array of microelectrodes chronically implanted in the primary visual cortex of monkeys and studied correlations in amplitude across electrodes as a function of interelectrode distance. We found that amplitude correlations showed a similar trend as coherence as a function of frequency and interelectrode distance. Importantly, even when phases were completely randomized between two electrodes, amplitude correlations introduced significant coherence. To quantify the contributions of phase consistency and amplitude correlations to coherence, we simulated pairs of sinusoids with varying phase consistency and amplitude correlations. These simulations confirmed that amplitude correlations can significantly bias coherence measurements, resulting in either over- or underestimation of true phase coherence. Our results highlight the importance of accounting for the correlations in amplitude while using coherence to study phase relationships across sites and frequencies. PMID- 24790176 TI - Eye-centered visual receptive fields in the ventral intraparietal area. AB - The ventral intraparietal area (VIP) processes multisensory visual, vestibular, tactile, and auditory signals in diverse reference frames. We recently reported that visual heading signals in VIP are represented in an approximately eye centered reference frame when measured using large-field optic flow stimuli. No VIP neuron was found to have head-centered visual heading tuning, and only a small proportion of cells had reference frames that were intermediate between eye and head-centered. In contrast, previous studies using moving bar stimuli have reported that visual receptive fields (RFs) in VIP are head-centered for a substantial proportion of neurons. To examine whether these differences in previous findings might be due to the neuronal property examined (heading tuning vs. RF measurements) or the type of visual stimulus used (full-field optic flow vs. a single moving bar), we have quantitatively mapped visual RFs of VIP neurons using a large-field, multipatch, random-dot motion stimulus. By varying eye position relative to the head, we tested whether visual RFs in VIP are represented in head- or eye-centered reference frames. We found that the vast majority of VIP neurons have eye-centered RFs with only a single neuron classified as head-centered and a small minority classified as intermediate between eye- and head-centered. Our findings suggest that the spatial reference frames of visual responses in VIP may depend on the visual stimulation conditions used to measure RFs and might also be influenced by how attention is allocated during stimulus presentation. PMID- 24790175 TI - Directional selective neurons in the awake LGN: response properties and modulation by brain state. AB - Directionally selective (DS) neurons are found in the retina and lateral geniculate nucleus (LGN) of rabbits and rodents, and in rabbits, LGN DS cells project to primary visual cortex. Here, we compare visual response properties of LGN DS neurons with those of layer 4 simple cells, most of which show strong direction/orientation selectivity. These populations differed dramatically, suggesting that DS cells may not contribute significantly to the synthesis of simple receptive fields: 1) whereas the first harmonic component (F1)-to-mean firing rate (F0) ratios of LGN DS cells are strongly nonlinear, those of simple cells are strongly linear; 2) whereas LGN DS cells have overlapped ON/OFF subfields, simple cells have either a single ON or OFF subfield or two spatially separate subfields; and 3) whereas the preferred directions of LGN DS cells are closely tied to the four cardinal directions, the directional preferences of simple cells are more evenly distributed. We further show that directional selectivity in LGN DS neurons is strongly enhanced by alertness via two mechanisms, 1) an increase in responses to stimulation in the preferred direction, and 2) an enhanced suppression of responses to stimuli moving in the null direction. Finally, our simulations show that these two consequences of alertness could each serve, in a vector-based population code, to hasten the computation of stimulus direction when rabbits become alert. PMID- 24790177 TI - Key concepts and limitations of statistical methods for evaluating biomarkers of kidney disease. AB - Interest in developing and using novel markers of kidney injury is increasing. To maintain scientific rigour in these endeavors, a comprehensive understanding of statistical methodology is required to rigorously assess the incremental value of novel biomarkers in existing clinical risk prediction models. Such knowledge is especially relevant, because no single statistical method is sufficient to evaluate a novel biomarker. In this review, we highlight the strengths and limitations of various traditional and novel statistical methods used in the literature for biomarker studies and use biomarkers of AKI as examples to show limitations of some popular statistical methods. PMID- 24790180 TI - Soluble urokinase-type plasminogen activator receptor in FSGS: stirred but not shaken. PMID- 24790179 TI - Administration of recombinant soluble urokinase receptor per se is not sufficient to induce podocyte alterations and proteinuria in mice. AB - Circulating levels of soluble forms of urokinase-type plasminogen activator receptor (suPAR) are generally elevated in sera from children and adults with FSGS compared with levels in healthy persons or those with other types of kidney disease. In mice lacking the gene encoding uPAR, forced increases in suPAR concentration result in FSGS-like glomerular lesions and proteinuria. However, whether overexpression of suPAR, per se, contributes to the pathogenesis of FSGS in humans remains controversial. We conducted an independent set of animal experiments in which two different and well characterized forms of recombinant suPAR produced by eukaryotic cells were administered over the short or long term to wild-type (WT) mice. In accordance with the previous study, the delivered suPARs are deposited in the glomeruli. However, such deposition of either form of suPAR in the kidney did not result in increased glomerular proteinuria or altered podocyte architecture. Our findings suggest that glomerular deposits of suPAR caused by elevated plasma levels are not sufficient to engender albuminuria. PMID- 24790178 TI - Effects of lowering LDL cholesterol on progression of kidney disease. AB - Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. PMID- 24790182 TI - Can cortical stimulation of inferior frontal cortex enhance proactive control? PMID- 24790181 TI - Glomerular autoimmune multicomponents of human lupus nephritis in vivo: alpha enolase and annexin AI. AB - Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against alpha-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of alpha-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-alpha-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-alpha-enolase/low anti-annexin AI IgG2 and patients with low anti-alpha-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti alpha-enolase IgG2 recognized specific epitopes of alpha-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human alpha-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against alpha-enolase and annexin AI predominate in the glomerulus and can be detected in serum. PMID- 24790183 TI - Kainate receptors mediate signaling in both transient and sustained OFF bipolar cell pathways in mouse retina. AB - A fundamental question in sensory neuroscience is how parallel processing is implemented at the level of molecular and circuit mechanisms. In the retina, it has been proposed that distinct OFF cone bipolar cell types generate fast/transient and slow/sustained pathways by the differential expression of AMPA and kainate-type glutamate receptors, respectively. However, the functional significance of these receptors in the intact circuit during light stimulation remains unclear. Here, we measured glutamate release from mouse bipolar cells by two-photon imaging of a glutamate sensor (iGluSnFR) expressed on postsynaptic amacrine and ganglion cell dendrites. In both transient and sustained OFF layers, cone-driven glutamate release from bipolar cells was blocked by antagonists to kainate receptors but not AMPA receptors. Electrophysiological recordings from bipolar and ganglion cells confirmed the essential role of kainate receptors for signaling in both transient and sustained OFF pathways. Kainate receptors mediated responses to contrast modulation up to 20 Hz. Light-evoked responses in all mouse OFF bipolar pathways depend on kainate, not AMPA, receptors. PMID- 24790184 TI - Peripheral administration of a humanized anti-PrP antibody blocks Alzheimer's disease Abeta synaptotoxicity. AB - Alzheimer's disease (AD) is associated with pathological assembly states of amyloid-beta protein (Abeta). Abeta-related synaptotoxicity can be blocked by anti-prion protein (PrP) antibodies, potentially allowing therapeutic targeting of this aspect of AD neuropathogenesis. Here, we show that intravascular administration of a high-affinity humanized anti-PrP antibody to rats can prevent the plasticity-disrupting effects induced by exposure to soluble AD brain extract. These results provide an in vivo proof of principle for such a therapeutic strategy. PMID- 24790185 TI - An adaptive role of TNFalpha in the regulation of striatal synapses. AB - Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNFalpha drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNFalpha drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca(2+)-permeable AMPARs. Striatal TNFalpha signaling appears to be adaptive in nature, as TNFalpha is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNFalpha is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions. PMID- 24790186 TI - Connecting to create: expertise in musical improvisation is associated with increased functional connectivity between premotor and prefrontal areas. AB - Musicians have been used extensively to study neural correlates of long-term practice, but no studies have investigated the specific effects of training musical creativity. Here, we used human functional MRI to measure brain activity during improvisation in a sample of 39 professional pianists with varying backgrounds in classical and jazz piano playing. We found total hours of improvisation experience to be negatively associated with activity in frontoparietal executive cortical areas. In contrast, improvisation training was positively associated with functional connectivity of the bilateral dorsolateral prefrontal cortices, dorsal premotor cortices, and presupplementary areas. The effects were significant when controlling for hours of classical piano practice and age. These results indicate that even neural mechanisms involved in creative behaviors, which require a flexible online generation of novel and meaningful output, can be automated by training. Second, improvisational musical training can influence functional brain properties at a network level. We show that the greater functional connectivity seen in experienced improvisers may reflect a more efficient exchange of information within associative networks of importance for musical creativity. PMID- 24790187 TI - Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space. AB - Hyaluronan (HA), a large anionic polysaccharide (glycosaminoglycan), is a major constituent of the extracellular matrix of the adult brain. To address its function, we examined the neurophysiology of knock-out mice deficient in hyaluronan synthase (Has) genes. Here we report that these Has mutant mice are prone to epileptic seizures, and that in Has3(-/-) mice, this phenotype is likely derived from a reduction in the size of the brain extracellular space (ECS). Among the three Has knock-out models, namely Has3(-/-), Has1(-/-), and Has2(CKO), the seizures were most prevalent in Has3(-/-) mice, which also showed the greatest HA reduction in the hippocampus. Electrophysiology in Has3(-/-) brain slices demonstrated spontaneous epileptiform activity in CA1 pyramidal neurons, while histological analysis revealed an increase in cell packing in the CA1 stratum pyramidale. Imaging of the diffusion of a fluorescent marker revealed that the transit of molecules through the ECS of this layer was reduced. Quantitative analysis of ECS by the real-time iontophoretic method demonstrated that ECS volume was selectively reduced in the stratum pyramidale by ~ 40% in Has3(-/-) mice. Finally, osmotic manipulation experiments in brain slices from Has3(-/-) and wild-type mice provided evidence for a causal link between ECS volume and epileptiform activity. Our results provide the first direct evidence for the physiological role of HA in the regulation of ECS volume, and suggest that HA-based preservation of ECS volume may offer a novel avenue for development of antiepileptogenic treatments. PMID- 24790188 TI - Experience salience gates endocannabinoid signaling at hypothalamic synapses. AB - Alterations in synaptic endocannabinoid signaling are a widespread neurobiological consequence of many in vivo experiences, including stress. Here, we report that stressor salience is critical for bidirectionally modifying presynaptic CB-1 receptor (CB1R) function at hypothalamic GABA synapses controlling the neuroendocrine stress axis in male rats. While repetitive, predictable stressor exposure impairs presynaptic CB1R function, these changes are rapidly reversed upon exposure to a high salience experience such as novel stress or by manipulations that enhance neural activity levels in vivo or in vitro. Together these data demonstrate that experience salience, through alterations in afferent synaptic activity, induces rapid changes in endocannabinoid signaling. PMID- 24790189 TI - Optogenetic stimulation of locus ceruleus neurons augments inhibitory transmission to parasympathetic cardiac vagal neurons via activation of brainstem alpha1 and beta1 receptors. AB - Locus ceruleus (LC) noradrenergic neurons are critical in generating alertness. In addition to inducing cortical arousal, the LC also orchestrates changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Although the association between arousal and increased heart rate is well accepted, the neurobiological link between the LC and parasympathetic neurons that control heart rate has not been identified. In this study, we test directly whether activation of noradrenergic neurons in the LC influences brainstem parasympathetic cardiac vagal neurons (CVNs). CVNs were identified in transgenic mice that express channel-rhodopsin-2 (ChR2) in LC tyrosine hydroxylase neurons. Photoactivation evoked a rapid depolarization, increased firing, and excitatory inward currents in ChR2-expressing neurons in the LC. Photostimulation of LC neurons did not alter excitatory currents, but increased inhibitory neurotransmission to CVNs. Optogenetic activation of LC neurons increased the frequency of isolated glycinergic IPSCs by 27 +/- 8% (p = 0.003, n = 26) and augmented GABAergic IPSCs in CVNs by 21 +/- 5% (p = 0.001, n = 26). Inhibiting alpha1, but not alpha2, receptors blocked the evoked responses. Inhibiting beta1 receptors prevented the increase in glycinergic, but not GABAergic, IPSCs in CVNs. This study demonstrates LC noradrenergic neurons inhibit the brainstem CVNs that generate parasympathetic activity to the heart. This inhibition of CVNs would increase heart rate and risks associated with tachycardia. The receptors activated within this pathway, alpha1 and/or beta1 receptors, are targets for clinically prescribed antagonists that promote slower, cardioprotective heart rates during heightened vigilant states. PMID- 24790190 TI - The anterior cingulate gyrus signals the net value of others' rewards. AB - Evaluating the costs and benefits of our own choices is central to most forms of decision-making and its mechanisms in the brain are becoming increasingly well understood. To interact successfully in social environments, it is also essential to monitor the rewards that others receive. Previous studies in nonhuman primates have found neurons in the anterior cingulate cortex (ACC) that signal the net value (benefit minus cost) of rewards that will be received oneself and also neurons that signal when a reward will be received by someone else. However, little is understood about the way in which the human brain engages in cost benefit analyses during social interactions. Does the ACC signal the net value (the benefits minus the costs) of rewards that others will receive? Here, using fMRI, we examined activity time locked to cues that signaled the anticipated reward magnitude (benefit) to be gained and the level of effort (cost) to be incurred either by a subject themselves or by a social confederate. We investigated whether activity in the ACC covaries with the net value of rewards that someone else will receive when that person is required to exert effort for the reward. We show that, although activation in the sulcus of the ACC signaled the costs on all trials, gyral ACC (ACC(g)) activity varied parametrically only with the net value of rewards gained by others. These results suggest that the ACC(g) plays an important role in signaling cost-benefit information by signaling the value of others' rewards during social interactions. PMID- 24790192 TI - Aberrant white matter microstructure in children with 16p11.2 deletions. AB - Copy number variants (CNVs) of the chromosomal locus 16p11.2, consisting of either deletions or duplications, have been implicated in autism, schizophrenia, epilepsy, and other neuropsychiatric disorders. Since abnormal white matter microstructure can be seen in these more broadly defined clinical disorders, we used diffusion magnetic resonance imaging and tract-based spatial statistics to investigate white matter microstructural integrity in human children with 16p11.2 deletions. We show that deletion carriers, compared with typically developing matched controls, have increased axial diffusivity (AD) in many major central white matter tracts, including the anterior corpus callosum as well as bilateral internal and external capsules. Higher AD correlated with lower nonverbal IQ in the deletion carriers, but not controls. Increases in fractional anisotropy and mean diffusivity were also found in some of the same tracts with elevated AD. Closer examination with neurite orientation dispersion and density imaging revealed that fiber orientation dispersion was decreased in some central white matter tracts. Notably, these alterations of white matter are unlike microstructural differences reported for any other neurodevelopmental disorders, including autism spectrum disorders that have phenotypic overlap with the deletion carriers. These findings suggest that deletion of the 16p11.2 locus is associated with a unique widespread pattern of aberrant white matter microstructure that may underlie the impaired cognition characteristic of this CNV. PMID- 24790191 TI - Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits. AB - Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID- 24790193 TI - Controlling phase noise in oscillatory interference models of grid cell firing. AB - Oscillatory interference models account for the spatial firing properties of grid cells in terms of neuronal oscillators with frequencies modulated by the animal's movement velocity. The phase of such a "velocity-controlled oscillator" (VCO) relative to a baseline (theta-band) oscillation tracks displacement along a preferred direction. Input from multiple VCOs with appropriate preferred directions causes a grid cell's grid-like firing pattern. However, accumulating phase noise causes the firing pattern to drift and become corrupted. Here we show how multiple redundant VCOs can automatically compensate for phase noise. By entraining the baseline frequency to the mean VCO frequency, VCO phases remain consistent, ensuring a coherent grid pattern and reducing its spatial drift. We show how the spatial stability of grid firing depends on the variability in VCO phases, e.g., a phase SD of 3 ms per 125 ms cycle results in stable grids for 1 min. Finally, coupling N VCOs with similar preferred directions as a ring attractor, so that their relative phases remain constant, produces grid cells with consistently offset grids, and reduces VCO phase variability of the order square root of N. The results suggest a viable functional organization of the grid cell network, and highlight the benefit of integrating displacement along multiple redundant directions for the purpose of path integration. PMID- 24790195 TI - Impaired path integration and grid cell spatial periodicity in mice lacking GluA1 containing AMPA receptors. AB - The hippocampus and the parahippocampal region have been proposed to contribute to path integration. Mice lacking GluA1-containing AMPA receptors (GluA1(-/-) mice) were previously shown to exhibit impaired hippocampal place cell selectivity. Here we investigated whether path integration performance and the activity of grid cells of the medial entorhinal cortex (MEC) are affected in these mice. We first tested GluA1(-/-) mice on a standard food-carrying homing task and found that they were impaired in processing idiothetic cues. To corroborate these findings, we developed an L-maze task that is less complex and is performed entirely in darkness, thereby reducing numerous confounding variables when testing path integration. Also in this task, the performance of GluA1(-/-) mice was impaired. Next, we performed in vivo recordings in the MEC of GluA1(-/-) mice. MEC neurons exhibited altered grid cell spatial periodicity and reduced spatial selectivity, whereas head direction tuning and speed modulation were not affected. The firing associations between pairs of neurons in GluA1(-/-) mice were stable, both in time and space, indicating that attractor states were still present despite the lack of grid periodicity. Together, these results support the hypothesis that spatial representations in the hippocampal-entorhinal network contribute to path integration. PMID- 24790196 TI - Local activity determines functional connectivity in the resting human brain: a simultaneous FDG-PET/fMRI study. AB - Over the last decade, synchronized resting-state fluctuations of blood oxygenation level-dependent (BOLD) signals between remote brain areas [so-called BOLD resting-state functional connectivity (rs-FC)] have gained enormous relevance in systems and clinical neuroscience. However, the neural underpinnings of rs-FC are still incompletely understood. Using simultaneous positron emission tomography/magnetic resonance imaging we here directly investigated the relationship between rs-FC and local neuronal activity in humans. Computational models suggest a mechanistic link between the dynamics of local neuronal activity and the functional coupling among distributed brain regions. Therefore, we hypothesized that the local activity (LA) of a region at rest determines its rs FC. To test this hypothesis, we simultaneously measured both LA (glucose metabolism) and rs-FC (via synchronized BOLD fluctuations) during conditions of eyes closed or eyes open. During eyes open, LA increased in the visual system, and the salience network (i.e., cingulate and insular cortices) and the pattern of elevated LA coincided almost exactly with the spatial pattern of increased rs FC. Specifically, the voxelwise regional profile of LA in these areas strongly correlated with the regional pattern of rs-FC among the same regions (e.g., LA in primary visual cortex accounts for ~ 50%, and LA in anterior cingulate accounts for ~ 20% of rs-FC with the visual system). These data provide the first direct evidence in humans that local neuronal activity determines BOLD FC at rest. Beyond its relevance for the neuronal basis of coherent BOLD signal fluctuations, our procedure may translate into clinical research particularly to investigate potentially aberrant links between local dynamics and remote functional coupling in patients with neuropsychiatric disorders. PMID- 24790194 TI - Global Ca2+ signaling drives ribbon-independent synaptic transmission at rod bipolar cell synapses. AB - Ribbon-type presynaptic active zones are a hallmark of excitatory retinal synapses, and the ribbon organelle is thought to serve as the organizing point of the presynaptic active zone. Imaging of exocytosis from isolated retinal neurons, however, has revealed ectopic release (i.e., release away from ribbons) in significant quantities. Here, we demonstrate in an in vitro mouse retinal slice preparation that ribbon-independent release from rod bipolar cells activates postsynaptic AMPARs on AII amacrine cells. This form of release appears to draw on a unique, ribbon-independent, vesicle pool. Experimental, anatomical, and computational analyses indicate that it is elicited by a significant, global elevation of intraterminal [Ca(2+)] arising following local buffer saturation. Our observations support the conclusion that ribbon-independent release provides a read-out of the average behavior of all of the active zones in a rod bipolar cell's terminal. PMID- 24790197 TI - On the same wavelength: predictable language enhances speaker-listener brain-to brain synchrony in posterior superior temporal gyrus. AB - Recent research has shown that the degree to which speakers and listeners exhibit similar brain activity patterns during human linguistic interaction is correlated with communicative success. Here, we used an intersubject correlation approach in fMRI to test the hypothesis that a listener's ability to predict a speaker's utterance increases such neural coupling between speakers and listeners. Nine subjects listened to recordings of a speaker describing visual scenes that varied in the degree to which they permitted specific linguistic predictions. In line with our hypothesis, the temporal profile of listeners' brain activity was significantly more synchronous with the speaker's brain activity for highly predictive contexts in left posterior superior temporal gyrus (pSTG), an area previously associated with predictive auditory language processing. In this region, predictability differentially affected the temporal profiles of brain responses in the speaker and listeners respectively, in turn affecting correlated activity between the two: whereas pSTG activation increased with predictability in the speaker, listeners' pSTG activity instead decreased for more predictable sentences. Listeners additionally showed stronger BOLD responses for predictive images before sentence onset, suggesting that highly predictable contexts lead comprehenders to preactivate predicted words. PMID- 24790198 TI - Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease. AB - Parkinson's disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, >= 10 single units and/or multi units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinson's Disease Rating Scale subscores (OFF medication). The mean spectral power at sub beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype. PMID- 24790199 TI - Free-operant avoidance behavior by rats after reinforcer revaluation using opioid agonists and D-amphetamine. AB - The associative processes that support free-operant instrumental avoidance behavior are still unknown. We used a revaluation procedure to determine whether the performance of an avoidance response is sensitive to the current value of the aversive, negative reinforcer. Rats were trained on an unsignaled, free-operant lever press avoidance paradigm in which each response avoided or escaped shock and produced a 5 s feedback stimulus. The revaluation procedure consisted of noncontingent presentations of the shock in the absence of the lever either paired or unpaired with systemic morphine and in a different cohort with systemic d-amphetamine. Rats were then tested drug free during an extinction test. In both the d-amphetamine and morphine groups, pairing of the drug and shock decreased subsequent avoidance responding during the extinction test, suggesting that avoidance behavior was sensitive to the current incentive value of the aversive negative reinforcer. Experiment 2 used central infusions of D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO), a mu-opioid receptor agonist, in the periacqueductal gray and nucleus accumbens shell to revalue the shock. Infusions of DAMGO in both regions replicated the effects seen with systemic morphine. These results are the first to demonstrate the impact of revaluation of an aversive reinforcer on avoidance behavior using pharmacological agents, thereby providing potential therapeutic targets for the treatment of avoidance behavior symptomatic of anxiety disorders. PMID- 24790200 TI - Sex, age, and cognitive correlates of asymmetries in thickness of the cortical mantle across the life span. AB - We assessed the correlations of age, sex, and cognitive performance with measures of asymmetry in cortical thickness on high-resolution MRIs in 215 healthy human children and adults, 7-59 years of age. A left > right asymmetry in thickness of the cortical mantle was present throughout the entire lateral, dorsal, and mesial surfaces of the frontal lobe, extending into primary sensory, superior parietal, and anterior superior temporal cortices. A right > left asymmetry was present in the lateral, mesial, and dorsal surfaces of the posterior temporal, parietal, and occipital cortices, as well as in the entire inferior surface of the brain. An exaggerated left > right asymmetry was detected in females in anterior brain regions, and an exaggerated right > left asymmetry was detected in males in the orbitofrontal, inferior parietal, and inferior occipital cortices. Weaker moderating effects of sex were scattered along the mesial surface of the brain. Age significantly moderated asymmetry measures in the inferior sensorimotor, inferior parietal, posterior temporal, and inferior occipital cortices. The age * asymmetry interaction derived from a steeper decline in cortical thickness with age in the right hemisphere than in the left on the lateral surface, whereas it derived from a steeper decline with age in the left hemisphere than in the right on the mesial surface. Finally, measures of performance on working memory and vocabulary tasks improved with increasing magnitudes of normal asymmetries in regions thought to support these cognitive capacities. PMID- 24790201 TI - Inhibitory interneuron classes express complementary AMPA-receptor patterns in macaque primary visual cortex. AB - Glutamate receptors mediate excitatory neurotransmission. A very prevalent type of glutamate receptor in the neocortex is the AMPA receptor (AMPAR). AMPARs mediate fast synaptic transmission and their functionality depends on the subunit composition. In primary visual cortex (area V1), the density and subunit composition of AMPARs differ among cortical layers and among cell types. The AMPARs expressed by the different types of inhibitory interneurons, which are crucial for network function, have not yet been characterized systematically. We investigated the distribution of AMPAR subunits in macaque V1 for three distinct subpopulations of inhibitory interneurons: parvalbumin-immunoreactive (PV-IR) interneurons, calbindin-immunoreactive (CB-IR) interneurons, and calretinin immunoreactive (CR-IR) interneurons. We found that PV-IR cells, which have previously been identified as fast spiking, show high expression of the GluA2 and GluA3 subunits. In contrast, CB-IR and CR-IR cells, which tend to be intermediate spiking, show high expression of the GluA1 and GluA4 subunits. Thus, our data demonstrate that the expression of AMPARs divides inhibitory interneurons in macaque V1 into two categories that are compatible with existing classification methods based on calcium-binding proteins and firing behavior. Moreover, our findings suggest new approaches to target the different inhibitory interneuron classes pharmacologically in vivo. PMID- 24790202 TI - Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death. AB - Macrophages in the injured spinal cord arise from resident microglia and infiltrating, peripherally derived monocytes. It is still not clear if macrophages derived from these two populations differ in their roles after CNS injury. The aims of this study are to investigate the phagocytic response and clearance of damaged axons and tissue debris by these distinct subsets of macrophages and assess their viability after spinal cord injury (SCI). The lysozyme M EGFP-knockin mouse tags hematogenous macrophages, but not microglia. Using a combination of immunofluorescence, flow cytometry, and neuronal tracing techniques, we show that microglia contact damaged axons early (24 h) after SCI and are the main type of macrophage to contain phagocytic material at 3 d. Thereafter, infiltrating macrophages become the predominant cell in contact with degenerating axons and contain more phagocytic material, which in contrast to microglia, persists for up to 42 d. Furthermore, after phagocytosis of myelin in vitro, bone marrow-derived macrophages are much more susceptible to apoptotic and necrotic cell death than CNS microglia, which is mirrored in vivo with apoptotic TUNEL-positive cells of infiltrating macrophage origin. This work suggests that microglia play a major role in the early response to SCI, by phagocytosing damaged and degenerating tissue, processing phagocytic material efficiently, and remaining viable. Later, macrophages of peripheral origin contribute predominantly to phagocytosis but are less efficient at processing CNS debris, and their death, in situ, may contribute to the secondary damage after CNS injury. PMID- 24790203 TI - Terminal Schwann cells participate in neuromuscular synapse remodeling during reinnervation following nerve injury. AB - Schwann cells (SCs) at neuromuscular junctions (NMJs) play active roles in synaptic homeostasis and repair. We have studied how SCs contribute to reinnervation of NMJs using vital imaging of mice whose motor axons and SCs are transgenically labeled with different colors of fluorescent proteins. Motor axons most commonly regenerate to the original synaptic site by following SC-filled endoneurial tubes. During the period of denervation, SCs at the NMJ extend elaborate processes from the junction, as shown previously, but they also retract some processes from territory they previously occupied within the endplate. The degree of this retraction depends on the length of the period of denervation. We show that the topology of the remaining SC processes influences the branching pattern of regenerating axon terminals and the redistribution of acetylcholine receptors (AChRs). Upon arriving at the junction, regenerating axons follow existing SC processes within the old synaptic site. Some of the AChR loss that follows denervation is correlated with failure of portions of the old synaptic site that lack SC coverage to be reinnervated. New AChR clustering is also induced by axon terminals that follow SC processes extended during denervation. These observations show that SCs participate actively in the remodeling of neuromuscular synapses following nerve injury by their guidance of axonal reinnervation. PMID- 24790204 TI - GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells. AB - Parallel visual pathways are initiated at the first retinal synapse by signaling between the rod and cone photoreceptors and two general classes of bipolar cells. For normal function, ON or depolarizing bipolar cells (DBCs) require the G protein-coupled receptor, mGluR6, an intact G-protein-coupled cascade and the transient receptor potential melastatin 1 (TRPM1) cation channel. In addition, another seven transmembrane protein, GPR179, is required for DBC function and recruits the regulators of G-protein signaling (RGS) proteins, RGS7 and RGS11, to the dendritic tips of the DBCs. Here we use the Gpr179(nob5) mouse, which lacks GPR179 and has a no b-wave electroretinogram (ERG) phenotype, to demonstrate that despite the absence of both GPR179 and RGS7/RGS11, a small dark-adapted ERG b wave remains and can be enhanced with long duration flashes. Consistent with the ERG, the mGluR6-mediated gating of TRPM1 can be evoked pharmacologically in Gpr179(nob5) and RGS7(-/-)/RGS11(-/-) rod BCs if strong stimulation conditions are used. In contrast, direct gating of TRPM1 by capsaicin in RGS7(-/-)/RGS11(-/ ) and WT rod BCs is similar, but severely compromised in Gpr179(nob5) rod BCs. Noise and standing current analyses indicate that the remaining channels in Gpr179(nob5) and RGS7(-/-)/RGS11(-/-) rod BCs have a very low open probability. We propose that GPR179 along with RGS7 and RGS11 controls the ability of the mGluR6 cascade to gate TRPM1. In addition to its role in localizing RGS7 and RGS11 to the dendritic tips, GPR179 via a direct interaction with the TRPM1 channel alters its ability to be gated directly by capsaicin. PMID- 24790205 TI - Axonal targeting of the serotonin transporter in cultured rat dorsal raphe neurons is specified by SEC24C-dependent export from the endoplasmic reticulum. AB - Export of the serotonin transporter (SERT) from the endoplasmic reticulum (ER) is mediated by the SEC24C isoform of the coatomer protein-II complex. SERT must enter the axonal compartment and reach the presynaptic specialization to perform its function, i.e., the inward transport of serotonin. Refilling of vesicles is contingent on the operation of an efficient relay between SERT and the vesicular monoamine transporter-2 (VMAT2). Here, we visualized the distribution of both endogenously expressed SERT and heterologously expressed variants of human SERT in dissociated rat dorsal raphe neurons to examine the role of SEC24C-dependent ER export in axonal targeting of SERT. We conclude that axonal delivery of SERT is contingent on recruitment of SEC24C in the ER. This conclusion is based on the following observations. (1) Both endogenous and heterologously expressed SERT were delivered to the extensive axonal arborizations and accumulated in bouton like structures. (2) In contrast, SERT-(607)RI(608)-AA, in which the binding site of SEC24C is disrupted, remained confined to the microtubule-associated protein 2 positive somatodendritic compartment. (3) The overexpression of dominant-negative SEC24C-D(796)V/D(797)N (but not of the corresponding SEC24D mutant) redirected both endogenous SERT and heterologously expressed yellow fluorescent protein-SERT from axons to the somatodendritic region. (4) SERT-K(610)Y, which harbors a mutation converting it into an SEC24D client, was rerouted from the axonal to the somatodendritic compartment by dominant-negative SEC24D. In contrast, axonal targeting of the VMAT2 was disrupted by neither dominant-negative SEC24C nor dominant-negative SEC24D. This suggests that SERT and VMAT2 reach the presynaptic specialization by independent routes. PMID- 24790206 TI - Cyclin-dependent kinase 5 in the ventral tegmental area regulates depression related behaviors. AB - Dopamine neurons in the ventral tegmental area (VTA) govern reward and motivation and dysregulated dopaminergic transmission may account for anhedonia and other symptoms of depression. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that regulates a broad range of brain functions through phosphorylation of a myriad of substrates, including tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. We investigated whether and how Cdk5 activity in VTA dopamine neurons regulated depression-related behaviors in mice. Using the Cre/LoxP system to selectively delete Cdk5 in the VTA or in midbrain dopamine neurons in Cdk5(loxP/loxP) mice, we showed that Cdk5 loss of function in the VTA induced anxiety- and depressive-like behaviors that were associated with decreases in TH phosphorylation at Ser31 and Ser40 in the VTA and dopamine release in its target region, the nucleus accumbens. The decreased phosphorylation of TH at Ser31 was a direct effect of Cdk5 deletion, whereas decreased phosphorylation of TH at Ser40 was likely caused by impaired cAMP/protein kinase A (PKA) signaling, because Cdk5 deletion decreased cAMP and phosphorylated cAMP response element-binding protein (p-CREB) levels in the VTA. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, we showed that selectively increasing cAMP levels in VTA dopamine neurons increased phosphorylation of TH at Ser40 and CREB at Ser133 and reversed behavioral deficits induced by Cdk5 deletion. The results suggest that Cdk5 in the VTA regulates cAMP/PKA signaling, dopaminergic neurotransmission, and depression-related behaviors. PMID- 24790207 TI - Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids. AB - The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with omega-3 and omega-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age * genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin related disorders of neurodevelopmental origin. PMID- 24790208 TI - Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. AB - Centrins are ancient calmodulin-related Ca(2+)-binding proteins associated with basal bodies. In lower eukaryotes, Centrin2 (CETN2) is required for basal body replication and positioning, although its function in mammals is undefined. We generated a germline CETN2 knock-out (KO) mouse presenting with syndromic ciliopathy including dysosmia and hydrocephalus. Absence of CETN2 leads to olfactory cilia loss, impaired ciliary trafficking of olfactory signaling proteins, adenylate cyclase III (ACIII), and cyclic nucleotide-gated (CNG) channel, as well as disrupted basal body apical migration in postnatal olfactory sensory neurons (OSNs). In mutant OSNs, cilia base-anchoring of intraflagellar transport components IFT88, the kinesin-II subunit KIF3A, and cytoplasmic dynein 2 appeared compromised. Although the densities of mutant ependymal and respiratory cilia were largely normal, the planar polarity of mutant ependymal cilia was disrupted, resulting in uncoordinated flow of CSF. Transgenic expression of GFP-CETN2 rescued the Cetn2-deficiency phenotype. These results indicate that mammalian basal body replication and ciliogenesis occur independently of CETN2; however, mouse CETN2 regulates protein trafficking of olfactory cilia and participates in specifying planar polarity of ependymal cilia. PMID- 24790209 TI - Acetylcholine controls GABA-, glutamate-, and glycine-dependent giant depolarizing potentials that govern spontaneous motoneuron activity at the onset of synaptogenesis in the mouse embryonic spinal cord. AB - A remarkable feature of early neuronal networks is their endogenous ability to generate spontaneous rhythmic electrical activity independently of any external stimuli. In the mouse embryonic SC, this activity starts at an embryonic age of ~ 12 d and is characterized by bursts of action potentials recurring every 2-3 min. Although these bursts have been extensively studied using extracellular recordings and are known to play an important role in motoneuron (MN) maturation, the mechanisms driving MN activity at the onset of synaptogenesis are still poorly understood. Because only cholinergic antagonists are known to abolish early spontaneous activity, it has long been assumed that spinal cord (SC) activity relies on a core network of MNs synchronized via direct cholinergic collaterals. Using a combination of whole-cell patch-clamp recordings and extracellular recordings in E12.5 isolated mouse SC preparations, we found that spontaneous MN activity is driven by recurrent giant depolarizing potentials. Our analysis reveals that these giant depolarizing potentials are mediated by the activation of GABA, glutamate, and glycine receptors. We did not detect direct nAChR activation evoked by ACh application on MNs, indicating that cholinergic inputs between MNs are not functional at this age. However, we obtained evidence that the cholinergic dependency of early SC activity reflects a presynaptic facilitation of GABA and glutamate synaptic release via nicotinic AChRs. Our study demonstrates that, even in its earliest form, the activity of spinal MNs relies on a refined poly-synaptic network and involves a tight presynaptic cholinergic regulation of both GABAergic and glutamatergic inputs. PMID- 24790210 TI - Stimulated emission depletion (STED) microscopy reveals nanoscale defects in the developmental trajectory of dendritic spine morphogenesis in a mouse model of fragile X syndrome. AB - Dendritic spines are basic units of neuronal information processing and their structure is closely reflected in their function. Defects in synaptic development are common in neurodevelopmental disorders, making detailed knowledge of age dependent changes in spine morphology essential for understanding disease mechanisms. However, little is known about the functionally important fine morphological structures, such as spine necks, due to the limited spatial resolution of conventional light microscopy. Using stimulated emission depletion microscopy (STED), we examined spine morphology at the nanoscale during normal development in mice, and tested the hypothesis that it is impaired in a mouse model of fragile X syndrome (FXS). In contrast to common belief, we find that, in normal development, spine heads become smaller, while their necks become wider and shorter, indicating that synapse compartmentalization decreases substantially with age. In the mouse model of FXS, this developmental trajectory is largely intact, with only subtle differences that are dependent on age and brain region. Together, our findings challenge current dogmas of both normal spine development as well as spine dysgenesis in FXS, highlighting the importance of super resolution imaging approaches for elucidating structure-function relationships of dendritic spines. PMID- 24790211 TI - Social equality in the number of choice options is represented in the ventromedial prefrontal cortex. AB - A distinct aspect of the sense of fairness in humans is that we care not only about equality in material rewards but also about equality in nonmaterial values. One such value is the opportunity to choose freely among many options, often regarded as a fundamental right to economic freedom. In modern developed societies, equal opportunities in work, living, and lifestyle are enforced by antidiscrimination laws. Despite the widespread endorsement of equal opportunity, no studies have explored how people assign value to it. We used functional magnetic resonance imaging to identify the neural substrates for subjective valuation of equality in choice opportunity. Participants performed a two-person choice task in which the number of choices available was varied across trials independently of choice outcomes. By using this procedure, we manipulated the degree of equality in choice opportunity between players and dissociated it from the value of reward outcomes and their equality. We found that activation in the ventromedial prefrontal cortex (vmPFC) tracked the degree to which the number of options between the two players was equal. In contrast, activation in the ventral striatum tracked the number of options available to participants themselves but not the equality between players. Our results demonstrate that the vmPFC, a key brain region previously implicated in the processing of social values, is also involved in valuation of equality in choice opportunity between individuals. These findings may provide valuable insight into the human ability to value equal opportunity, a characteristic long emphasized in politics, economics, and philosophy. PMID- 24790213 TI - Sustained disability improvement is associated with T1 lesion volume shrinkage in natalizumab-treated patients with multiple sclerosis. PMID- 24790212 TI - Long-term outcome of subthalamic nucleus deep brain stimulation for Parkinson's disease using an MRI-guided and MRI-verified approach. AB - BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinson's disease (PD) insufficiently controlled with medical therapies. This study presents the long term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI verified approach without microelectrode recording. METHODS: A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8-11 years. Motor status was evaluated using part III of the Unified Parkinson's Disease Rating Scale (UPDRS III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes. RESULTS: STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively. CONCLUSIONS: Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor 'off' symptoms of PD in the long term with low morbidity. PMID- 24790214 TI - Ataxia meets chorioretinal dystrophy and hypogonadism: Boucher-Neuhauser syndrome due to PNPLA6 mutations. PMID- 24790215 TI - Stimulated PBMC-produced IFN-gamma and TNF-alpha are associated with altered relapse risk in multiple sclerosis: results from a prospective cohort study. AB - BACKGROUND: Altered reactivity of peripheral blood mononuclear cells (PBMC) and their production of cytokines may affect multiple sclerosis (MS) clinical course. We assessed the relationship of stimulated PBMC-produced IFN-gamma, TNF-alpha, IL 4 and IL-10 in modulating relapse risk using a prospective cohort with established relapsing-remitting MS. METHODS: Cytokine production from PBMCs taken in summer and winter was measured by ELISA. Predictors of cytokines assessed by multilevel mixed-effects linear regression. Predictors of relapse assessed by survival analysis. RESULTS: Increasing IFN-gamma was associated with increasing relapse risk, while increasing TNF-alpha reduced relapse risk after adjusting for IFN-gamma. IL-10 and IL4 were not consistently associated with relapse risk. IFN gamma's effects on relapse were greatly attenuated by immunomodulatory therapies, by summer season and by higher serum vitamin D, whereas TNF-alpha's inverse association with relapse was only present in these circumstances. The TNF-alpha inverse association with relapse was only present among persons carrying the wild type of the functional SNP rs1800693 in TNFRSF1A that has been previously associated with MS risk. CONCLUSIONS: We found strong effects of IFN-gamma and TNF-alpha on relapse risk, these differing by immunomodulatory therapy, season, and serum vitamin D, as well as by genotype. These results indicate altered reactivity of immune cells modulate MS disease. PMID- 24790216 TI - Difficulties with control arms in repetitive magnetic stimulation studies. PMID- 24790217 TI - Effect of Chelate Type and Radioisotope on the Imaging Efficacy of 4 Fibrin Specific PET Probes. AB - Thrombus formation plays a major role in cardiovascular diseases, but noninvasive thrombus imaging is still challenging. Fibrin is a major component of both arterial and venous thrombi and represents an ideal candidate for imaging of thrombosis. Recently, we showed that (64)Cu-DOTA-labeled PET probes based on fibrin-specific peptides are suitable for thrombus imaging in vivo; however, the metabolic stability of these probes was limited. Here, we describe 4 new probes using either (64)Cu or aluminum fluoride (Al(18)F) chelated to 2 NOTA derivatives. METHODS: Probes were synthesized using a known fibrin-specific peptide conjugated to either NODAGA (FBP8, FBP10) or NOTA-monoamide (FBP9, FBP11) as chelators, followed by labeling with (64)Cu (FBP8 and FBP9) or Al(18)F (FBP10 and FBP11). PET imaging efficacy, pharmacokinetics, biodistribution, and metabolic stability were assessed in a rat model of arterial thrombosis. RESULTS: All probes had similar nanomolar affinity (435-760 nM) for the soluble fibrin fragment DD(E). PET imaging allowed clear visualization of thrombus by all probes, with a 5-fold or higher thrombus-to-background ratio. Compared with the previous DOTA derivative, the new (64)Cu probes FBP8 and FBP9 showed substantially improved metabolic stability (>85% intact in blood at 4 h after injection), resulting in high uptake at the target site (0.5-0.8 percentage injected dose per gram) that persisted over 5 h, producing increasingly greater target-to-background ratios. The thrombus uptake was 5- to 20-fold higher than the uptake in the contralateral artery, blood, muscle, lungs, bone, spleen, large intestine, and heart at 2 h after injection and 10- to 40-fold higher at 5 h. The Al(18)F derivatives FBP10 and FBP11 were less stable, in particular the NODAGA conjugate (FBP10, <30% intact in blood at 4 h after injection), which showed high bone uptake and low thrombus-to-background ratios that decreased over time. The high thrombus-to-contralateral ratios for all probes were confirmed by ex vivo biodistribution and autoradiography. The uptake in the liver (<0.5 percentage injected dose per gram), kidneys, and blood were similar for all tracers, and they all showed predominant renal clearance. CONCLUSION: FBP8, FBP9, and FBP11 showed excellent metabolic stability and high thrombus-to-background ratios and represent promising candidates for imaging of thrombosis in vivo. PMID- 24790218 TI - Everolimus Reduces (89)Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors. AB - Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. METHODS: Patients with advanced progressive well-differentiated NETs underwent (89)Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. (89)Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUVmax). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). RESULTS: In 4 of the 14 patients entered, no tumor lesions were visualized with (89)Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUVmax decreased during everolimus treatment, with a median of -7% at 2 wk (P = 0.09) and a median of -35% at 12 wk (P < 0.001). The difference in SUVmax at 2 and 12 wk with respect to SUVmax at baseline correlated with percentage change on CT at 6 mo (r(2) = 0.51, P < 0.05, and r(2) = 0.61, P < 0.01, respectively). CONCLUSION: This study demonstrates variable (89)Zr-bevacizumab PET tumor uptake in NET patients. (89)Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial (89)Zr-bevacizumab PET might be useful as an early predictive biomarker of anti-VEGF-directed treatment in NET patients. PMID- 24790220 TI - Workflow Considerations in PET/MR Imaging. AB - Many groups attempt to optimize imaging protocols on PET/MR imaging systems. Although research protocols may take as long as 60-90 min, much more efficient clinical workflows are needed to achieve cost-effective examination times of less than 1 h. Considering these difficulties, simultaneous PET/MR imaging is an intriguing research tool, but its clinical applications are uncertain or just beginning to emerge. However, unlike PET/CT, in which the options for various CT protocols are limited, the MR imaging portion of PET/MR imaging can be extended arbitrarily depending on the MR pulse sequences chosen. For PET/MR imaging to be complementary, feasible, and somewhat competitive with PET/CT, image acquisition times should ideally be limited to 30 min. The purposes of this article are to help the reader to understand the critical workflow issues in simultaneous PET/MR imaging in comparison with sequential PET/MR imaging and to learn how to optimize an imaging examination. Current knowledge toward this goal is summarized. PMID- 24790219 TI - (18)F-MCL-524, an (18)F-Labeled Dopamine D2 and D3 Receptor Agonist Sensitive to Dopamine: A Preliminary PET Study. AB - PET has been used to examine changes in neurotransmitter concentrations in the living brain. Pioneering PET studies on the dopamine system have used D2 and D3 receptor (D2/D3) antagonists such as (11)C-raclopride. However, more recently developed agonist radioligands have shown enhanced sensitivity to endogenous dopamine. A limitation of available agonist radioligands is that they incorporate the short-lived radioisotope (11)C. In the current study, we developed the (18)F labeled D2/D3 receptor agonist (R)-(-)-2-(18)F-fluoroethoxy-N-n propylnorapomorphine ((18)F-MCL-524). METHODS: In total, 10 PET measurements were conducted on 5 cynomolgus monkeys. Initially, the binding of (18)F-MCL-524 was compared with that of (11)C-MNPA in 3 monkeys. Second, the specificity of (18)F MCL-524 binding was examined in pretreatment studies using raclopride (1.0 mg/kg) and d-amphetamine (1.0 mg/kg). Third, a preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function of the baseline studies. Finally, 2 whole-body PET measurements were conducted to evaluate biodistribution and radiation dosimetry after intravenous injection of (18)F-MCL-524. RESULTS: (18)F-MCL-524 entered the brain and provided striatum-to cerebellum ratios suitable for reliable quantification of receptor binding using the multilinear reference tissue model. Mean striatal nondisplaceable binding potential (BPND) values were 2.0 after injection of (18)F-MCL-524 and 1.4 after (11)C-MNPA. The ratio of the BPND values of (18)F-MCL-524 and (11)C-MNPA was 1.5 across striatal subregions. After administration of raclopride and d-amphetamine, the (18)F-MCL-524 BPND values were reduced by 89% and 56%, respectively. Preliminary kinetic analysis demonstrated that BPND values obtained with the 1 tissue- and 2-tissue-compartment models were similar to values obtained with the multilinear reference tissue model. Estimated radiation doses were highest for gallbladder (0.27 mSv/MBq), upper large intestine (0.19 mSv/MBq), and small intestine (0.17 mSv/MBq). The estimated effective dose was 0.035 mSv/MBq. CONCLUSION: The (18)F-labeled agonist (18)F-MCL-524 appears suitable for quantification of D2/D3 receptor binding in vivo, and the results encourage extension to human studies. The longer half-life of (18)F makes (18)F-MCL-524 attractive for studies on modulation of the dopamine concentration-for example, in combination with simultaneous measurement of changes in blood-oxygen-level dependent signal using bimodal PET/functional MRI. PMID- 24790221 TI - SMCHD1 accumulates at DNA damage sites and facilitates the repair of DNA double strand breaks. AB - SMCHD1 is a structural maintenance of chromosomes (SMC) family protein involved in epigenetic gene silencing and chromosome organisation on the female inactive X chromosome and at a limited number of autosomal loci. Here, we demonstrate that SMCHD1 also has a role in DNA repair of double-strand breaks; SMCHD1 is recruited to sites of laser micro-irradiated damage along with other DNA repair factors, including Ku80 (also known as XRCC5 in mammals) and RAD51. Cells deficient in SMCHD1 show evidence of decreased efficiency of repair and cell viability after DNA damage. We suggest that SMCHD1 responds to DNA double-strand breaks in a manner that is likely to involve its ability to alter chromatin states to facilitate DNA repair. PMID- 24790222 TI - Distinct c-Met activation mechanisms induce cell rounding or invasion through pathways involving integrins, RhoA and HIP1. AB - Many carcinomas have acquired oncogenic mechanisms for activating c-Met, including c-Met overexpression and excessive autocrine or paracrine stimulation with hepatocyte growth factor (HGF). However, the biological outcome of c-Met activation through these distinct modes remains ambiguous. Here, we report that HGF-mediated c-Met stimulation triggers a mesenchymal-type collective cell invasion. By contrast, the overexpression of c-Met promotes cell rounding. Moreover, in a high-throughput siRNA screen that was performed using a library of siRNAs against putative regulators of integrin activity, we identified RhoA and the clathrin-adapter protein HIP1 as crucial c-Met effectors in these morphological changes. Transient RhoA activation was necessary for the HGF induced invasion, whereas sustained RhoA activity regulated c-Met-induced cell rounding. In addition, c-Met-induced cell rounding correlated with the phosphorylation of filamin A and the downregulation of active cell-surface integrins. By contrast, a HIP1-mediated increase in beta1-integrin turnover was required for the invasion triggered by HGF. Taken together, our results indicate that c-Met induces distinct cell morphology alterations depending on the stimulus that activates c-Met. PMID- 24790223 TI - CDC-42 and RAC-1 regulate opposite chemotropisms in Neurospora crassa. AB - Cell polarization and fusion are crucial developmental processes that occur in response to intracellular and extracellular signals. Asexual spores (conidia) of the mold Neurospora crassa differentiate two types of polarized cell protrusions, germ tubes and conidial anastomosis tubes (CATs), which exhibit negative and positive chemotropism, respectively. We provide the first evidence that shared and separate functions of the Rho-type GTPases CDC-42 and RAC-1 regulate these opposite chemotropisms. We demonstrate that RAC-1 is essential for CAT formation and cell fusion, whereas CDC-42 is necessary and sufficient for normal germ tube development. Cdc42-Rac-interactive-binding (CRIB) reporters were constructed to exclusively label locally activated GTP-bound GTPases. Time course analyses showed that repositioning of these activated GTPase clusters within germ tube and CAT tip apices controls directional growth in the absence of a tip-localized vesicle supply center (Spitzenkorper). We propose a model in which the local assembly of a plasma-membrane-associated GTPase-PAK-MAPK signaling platform regulates chemoattractant perception and secretion in order to synchronize oscillatory cell-cell communication and directional CAT tip growth. PMID- 24790225 TI - Evolving possibilities: Post-embryonic axial elongation in salamanders with biphasic (Eurcyea cirrigera, E. longicauda, E. quadridigitata) and paedomorphic life cycles (Eurycea nana and Ambystoma mexicanum). Submitted Acta Zoologica. AB - Typically the number of vertebrae an organism will have post-embryonically is determined during embryogenesis via the development of paired somites. Our research investigates the phenomenon of post-embryonic vertebral addition in salamander tails. We describe body and tail growth, and patterns of postsacral vertebral addition and elongation in context with caudal morphology for four plethodontids (Eurycea), and one ambystomatid. Eurycea nana and A. mexicanum have paedomorphic life cycles; E. cirrigera, E. longicauda and E. quadridigitata are biphasic. Specimens were collected, borrowed and/or purchased, and cleared and stained for bone and cartilage. Data collected include snout-vent length (SVL), tail length (TL), vertebral counts and centrum lengths. Eurycea species with biphasic life cycles had TLs that surpassed SVL following metamorphosis. Tails in paedomorphic species elongated but rarely exceeded body length. Larger TLs were associated with more vertebrae and longer vertebrae in all species. We observed that rates of postsacral vertebral addition varied little amongst species. Regional variation along the tail becomes prominent following metamorphosis in biphasic developers. In all species vertebrae in the posterior one-half of the tail taper towards the tip. We suggest a developmental link might exist between the ability to continually add vertebrae and regeneration in salamanders. PMID- 24790226 TI - Veterinary leadership in Canada. PMID- 24790227 TI - An ethicist's commentary on artificial meat. PMID- 24790228 TI - Intra- and inter-observer reliability of combined segmental measurement techniques for predicting immediate post-deployment intraluminal tracheal stent length in dogs. AB - This study evaluated segmental measurement techniques for predicting immediate post-deployment intraluminal tracheal stent length in dogs with naturally occurring tracheal collapse. Radiographs of 12 client-owned dogs that underwent intraluminal tracheal stent placement were retrospectively reviewed. Tracheal lengths were divided into 1, 2, 3, or 4 equal segments. Stent lengths were predicted using the widest dorsoventral height of each segment, with and without the addition of 10%, and an accompanying foreshortening chart. Techniques were compared for intra- and inter-observer reliability, and post-deployment stent length predictability. There was good to high intra- and inter-observer reliability for all segmental measurements; median intra-class correlation coefficients were 0.98 and 0.92, respectively. Measuring 2 segments without the addition of 10% to the widths was significantly more accurate in predicting immediate post-deployment stent length in terms of percent (P = 0.03) and absolute difference (P = 0.02). Segmental measuring techniques are repeatable amongst observers and may help guide stent selection. PMID- 24790229 TI - An investigation of the effects of ketoprofen following rumen fistulation surgery in lactating dairy cows. AB - Post-operative pain management following rumen surgery is not common practice. We examined the effect of providing the pain medication ketoprofen to dairy cattle following the first stage of a rumen cannulation surgery, which involves an incision in the body wall and exteriorizing and clamping the rumen. The results of this study provide clear evidence that the first stage of the surgery was painful and ketoprofen at the time of and 24 h following surgery, alleviated some, but not all, of the post-surgical pain. Pain mitigation should be included when performing flank surgery in cattle. PMID- 24790230 TI - Comparison of the access window created by hemilaminectomy and mini hemilaminectomy in the thoracolumbar vertebral canal using computed tomography. AB - Hemilaminectomy and mini-hemilaminectomy were performed on opposite sides of the spine at T11-T12, T13-L1, and L2-L3 in 11 canine cadavers in order to report differences in the access provided to the thoracolumbar vertebral canal. Measurements of the vertebral canal height, defect height, and dorsal and ventral remnants of the vertebral arch were obtained after computed tomography. A median of 7% to 20% of the vertebral canal height was not removed dorsally after mini hemilaminectomy compared to 1% to 2% in hemilaminectomy. Thirteen to 25% of the vertebral canal height was left ventrally in mini-hemilaminectomy and 11% to 27% in hemilaminectomy. Potential for a restricted exposure of thoracolumbar lesions should be considered if lesions are located in the ventral 11% to 27% vertebral canal height when performing either procedure or in the dorsal 7% to 20% of the canal height when performing a mini-hemilaminectomy. PMID- 24790231 TI - Tetralogy of Fallot in a 6-year-old albino ferret (Mustela putorius furo). AB - Tetralogy of Fallot associated with bidirectional shunting across a large ventricular septal defect, was found in a 6-year-old ferret. The prognosis associated with tetralogy of Fallot is usually poor. This case is interesting given the advanced age of the ferret. The bidirectional shunting, responsible for an acyanotic disease, may explain the unexpected prolonged survival in this ferret. PMID- 24790232 TI - Massive vulvar edema in 2 prepartum dairy cows. AB - Two late gestation Holstein cows about to begin the third lactation developed massive vulvar edema. These were the only affected animals in the herd of 500 milking cows. The vulvar edema spontaneously regressed postpartum for both cows. Massive vulvar swelling is seldom observed in dairy cows in advanced pregnancy and is not described in the literature. PMID- 24790233 TI - Positron emission tomography/computed tomography imaging features of renal cell carcinoma and pulmonary metastases in a dog. AB - A 9-year-old spayed female cocker spaniel dog was referred for hematuria. A large abdominal mass and multiple pulmonary nodules were identified radiographically. A whole-body 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography/computed tomography (PET/CT) scan revealed intensely increased uptake in a renal mass and the pulmonary nodules. Renal cell carcinoma was diagnosed on histological examination. PMID- 24790234 TI - Colonic gastrointestinal stromal tumor resulting in recurrent colic and hematochezia in a warmblood gelding. AB - A 14-year-old Trakehner gelding was evaluated for recurrent colic, with episodes occurring over 1 year. Signs were consistent with intermittent ascending colon obstruction and hematochezia. Necropsy examination revealed an ulcerated mass extending into the lumen of the right dorsal ascending colon. Gross and histologic appearance and immunoreactivity to c-kit (CD117), desmin, vimentin, and smooth muscle actin, were consistent with a diagnosis of gastrointestinal stromal tumor. PMID- 24790235 TI - Metastatic anaplastic adenocarcinoma suspected to be of mammary origin in an intact male rabbit (Oryctolagus cuniculus). AB - A 7-year-old, intact male, pet dwarf rabbit (Oryctolagus cuniculus) was presented for a ventral abdominal subcutaneous mass. Histolopathology of the resected mass was suggestive of a mammary adenocarcinoma. Six months later, the rabbit died from severe dyspnea. Necropsy showed recurrence of the original mass with hepatic and pulmonary metastasis of the anaplastic adenocarcinoma, suspected to be of mammary origin. PMID- 24790236 TI - Staphylococcus pseudintermedius infection associated with nodular skin lesions and systemic inflammatory response syndrome in a dog. AB - A 10-year-old Pekingese dog with atopic dermatitis was referred due to pyrexia, multiple skin nodules, anorexia, and depression. The dog was diagnosed as having systemic inflammatory response syndrome (SIRS) induced by bacterial dermatitis. This case presents diagnosis and treatment of SIRS with staphylococcal skin infection in a dog that was immunosuppressed due to long-term use of corticosteroid. PMID- 24790237 TI - Atherosclerosis associated with vasculopathic lesions in a golden retriever with hypercholesterolemia. AB - A 2-year-old neutered male golden retriever dog presented for lameness secondary to ulcerations of multiple digital paw pads was diagnosed with vasculitis and hypercholesterolemia. Despite treatment, ischemic necrosis progressed to include all distal extremities and the dog eventually expired due to myocardial infarction secondary to severe atherosclerosis. The rapid demise and the dermatologic lesions may have been secondary to cholesterol embolism syndrome which has never before been reported in a dog. PMID- 24790238 TI - Zinc-resistance gene CzrC identified in methicillin-resistant Staphylococcus hyicus isolated from pigs with exudative epidermitis. AB - Methicillin-resistant Staphylococcus hyicus (MRSH) was investigated for czrC, a gene conferring zinc-resistance. The czrC gene was identified in 50% (14/28) of MRSH isolates, representing 14 pigs with exudative epidermitis from 8 farms. Newly weaned pigs, which are particularly susceptible to exudative epidermitis, are commonly fed high levels of zinc oxide. PMID- 24790239 TI - Swine veterinarians are a vital resource for minimizing the incidence of stressed pigs during transport. PMID- 24790241 TI - Results from the 2013 practice owners' economic survey. PMID- 24790243 TI - Prevalence of tinnitus in patients withhypertension and the impact of different anti hypertensive drugs on the incidence of tinnitus: A prospective, single blind, observational study. AB - BACKGROUND: Tinnitus is a common symptom in audiology and neurologypatients. Controversial data have been reported in the literature about the prevalence of tinnitus in hypertensive patients, whereas its relationship with the extent of blood pressure (BP) control has not been substantially explored. OBJECTIVE: The aim of this study was to determine the prevalence of tinnitus in hypertensive patients, and the impact of different antihypertensive drugs on the incidence of tinnitus in these patients. METHODS: This prospective, single-blind, observational study was conducted at the Hypertension Clinic, St. Orsola-Malpighi Hospital, Bologna, Italy. Patients aged 18 to 75 years with uncontrolled hypertension and receiving antihypertensive therapy were enrolled. Patients were asked to complete a standardized questionnaire to assess the presence, frequency, and duration of tinnitus and the apparent effect of their antihypertensive treatment on it. Patients considered by the investigator to have tinnitus, regardless of their audiologic condition, underwent a complete clinical cardiovascular examination, including supine systolic BP (SBP) and diastolic BP measurement and standard 12-lead electrocardiography. Twelve-hour ambulatory BP monitoring was also performed, and patients were asked to record, using patient diaries, times of the onset and resolution of tinnitus that occurred during those 12 hours. From these data, correlations between the onset of tinnitus and BP were calculated. RESULTS: A total of 476 patients participated in the study (283 men, 193 women). Of these, 84 (17.6%) patients reported occasional or prolonged spontaneous tinnitus, whereas 392 (82.4%) reported no tinnitus. The incidence of tinnitus was significantly higher in patients receiving diuretics (72/265 [27.2%]) compared with those receiving angiotensin lI receptor blockers (5/37 [13.5%]), alpha-blockers (12/55 [21.8%]), or 3-hydroxy-3-methylglutaryl coenzyme A reduc tase inhibitors (9/73 [12.3%]) (all, P < 0.05). Mean (SD) SBP was significantly higher in patients without tinnitus compared with those with it (143.2 [11.1 ] vs 140.6 [10.3] mm Hg; P < 0.005). In 10 (11.9%) patients with tinnitus, the onset was correlated with a sudden decrease in SBP (<140 mm Hg). CONCLUSIONS: In this study of tinnitus in patients receiving antihypertensivetherapy, tinnitus was found in 17.6% of patients. Tinnitus was associated with the use of diuretics and with low SBP. Further studies are needed. PMID- 24790242 TI - An evaluation of potential signals for ventricular arrhythmia and cardiac arrest with dolasetron, ondansetron, and granisetron in the fda combined spontaneous reporting system/adverse event reporting system. AB - BACKGROUND: Of the US Food and Drug Administration (FDA)-approved5 hydroxytryptamine type 3 (5-HT3)-receptor antagonists, dolasetron, ondan-setron, granisetron, and palonosetron, only dolasetron and palonosetron have a precaution in their FDA labeling concerning corrected QT interval (QTc) prolongation. At FDA approved doses, QTc prolongation has been observed in clinical trials with some 5 HT3 receptor antagonists (however, palonosetron has been only recently approved, with few published clinical data available). However, due to patient exclusion criteria, such trials with 5-HT3 receptor antagonists may have failed to examine the risk of these agents in "real world" patients with cancer. OBJECTIVE: The aim of this analysis was to assess the potential risk for selected cardiac adverse events associated with dolasetron, ondansetron, and granisetron use. METHODS: The FDA combined Spontaneous Reporting System/Adverse Event Reporting System database was analyzed. The process of analyzing such a database for early warnings of potential hazards is known as signal generation. The statistical technique proportional reporting ratio (PRR) was used to aid detection of a potential signal within the database. PRR is the observed proportion of a given adverse event for the drug of interest (the number of events of interest for the drug divided by the total number of reports for the drug) divided by the expected proportion. Through the third quarter of 2002, the database was searched using the preferred term electrocardiogram qt corrected interval prolonged. RESULTS: One, 3, and 0 cases were reported for dolasetron, ondansetron, andgranisetron, respectively. The number of cases did not satisfy 1 of the 3 criteria we utilized to define a potential signal, the 3 criteria being: 3 or more reported cases of the adverse event, a PRR value of at least 2, and a chi(2) value of >4. As this term may be unlikely to be reported, the database was also searched using the term ventricular arrhythmias and cardiac arrest. The PRR, used as a parameter to detect a potential signal within the database, was 3.23, 1.31, and 1.13 for dolasetron, ondansetron, and granisetron, respectively. The number of observed ventricular arrhythmias and cardiac arrests was ~3-fold higher with dolasetron compared with the expected value (calculated by dividing the individual agent's total number of events reported by the proportion of adverse events for all agents combined). The results for dolasetron fulfilled the criteria we used to define a potential signal. CONCLUSIONS: This analysis detected a potential signal for ventricular arrhythmiasand cardiac arrest with dolasetron, but not with ondansetron or granisetron. However, there are limitations of a PRR analysis, which include only measuring cases that have been reported, providing relative frequencies instead of actual rates, and not providing information on the severity of adverse events or causal relationships. In addition, our analysis does not include consideration of concomitant medications, and only 2 search terms were used. Errors in identifying potential signals may also include confounding factors, such as the underlying disease, potential confusion with reporting under trade and generic names, and potential multiple reporting of the same case. PMID- 24790244 TI - Clinical experience with nonstandard doses ofinterferon alfa-2b and ribavirin in the treatment of chronic hepatitis C infection: A retrospective analysis. AB - BACKGROUND: Hepatitis C virus (HCV) infection is the most common blood-borne virus in the United States. Several mono- and combination therapies have been approved by the US Food and Drug Administration for the treatment of HCV, but their routes of administration, dosing approaches, eras of introduction, and actual use in clinical practice and resulting effectiveness have not yet been reported. OBJECTIVES: The aim of this article was to characterize clinical use and virologic response (VR) of the HCV treatments interferon alfa-2b plus ribavirin (IFN + RBV) and peginterferon alfa-2b plus ribavirin (peg-IFN + RBV). METHODS: This retrospective chart review of office-based practices in theUnited States was conducted at 200 physicians' offices across the United States. We collected data concerning dosing patterns, VR (HCV RNA load, <=1000 IU/mL or "negative" on polymerase chain reaction qualitative analysis), and adverse events (AEs) from the medical records of a geographically diverse sample of patients receiving treatment for chronic HCV infection in the United States from July 2001 to June 2002. For efficacy assessment, factors that were statistically different at baseline were adjusted using logistic regression. Providers also reviewed the medical records for symptoms or signs consistent with HCV treatment-related AEs. RESULTS: Data from the records of 675 patients (423 men, 252 women; mean [SD] age of 45.5 [8.2] years; mean [SD] body weight, 80.8 [19.4] kg) were analyzed. At baseline, the IFN + RBV treatment group (330 patients) had significantly higher percentages of black patients (22.1% vs 15.7%; P = 0.032) and patients with hepatic disease based on clinician-reported cirrhosis and liver dysfunction (18.8% vs 9.9%; P < 0.001), and a significantly lower percentage of white patients (60.3% vs 69.6%; P = 0.012) compared with the peg-IFN + RBV treatment group (345 patients). The difference in log-transformed baseline HCV RNA loads between the 2 treatment groups in this study was <1 log unit. A significantly higher percentage of IFN + RBV-treated patients compared with peg-IFN + RBV treated patients were prescribed HCV therapy on diagnosis (37.3% vs 29.9%; P = 0.041), and the mean (SD) duration of treatment was significantly different between the 2 treatment groups (52.5 [37.0] vs 27.5 [15.0] weeks; P < 0.001). Peg IFN + RBV was associated with a higher rate of VR compared with IFN + RBV on univariate analysis (28.5% vs 17.5%; P = 0.018). Recommended doses of peg-IFN and higher-than-recommended doses of RBV were associated with an increased likelihood of VR. Higher-than-recommended doses of peg-IFN without a concomitant increase in RBV was not associated with an increased likelihood of VR. The incidences of the 3 most commonly reported AEs in the IFN + RSV group were significantly higher compared with those in the peg-IFN + RSV group: fatigue, 217 (65.8%) versus 185 (53.6%) patients (P = 0.001); depression, 147 (44.5%) versus 120 (34.8%) (P = 0.009); and anxiety, 87 (26.4%) versus 64 (18.6%) (P = 0.014). Nausea, however, was reported in a significantly higher number of patients in the peg-IFN group compared with the IFN + RBV group (74 [21.4%] vs 51 [15.5%]; P = 0.045). The frequencies of dose modification and treatment discontinuation due to AEs were similar between the 2 treatments and were similar to or less than those reported in other studies. CONCLUSIONS: In this retrospective data analysis of US office based practicesconcerning HCV treatment, clinicians were observed to prescribe IFN + RBV at doses that differ from recommendations in the product information (PI), as well as prescribe the RBV component of peg-IFN + RBV at doses that differed from PI recommendations. Although patients treated with peg-IFN + RBV appeared to achieve higher VR compared with those treated with IFN + RBV in our analysis of data from clinical practice, peg-IFN + RBV was associated with lower VR rates compared with those reported in clinical studies. PMID- 24790245 TI - Therapy for treatment-refractory chronic hepatitis C virus genotype 1b infection: A retrospective analysis. AB - BACKGROUND: The most effective current therapy for hepatitis C virus (HCV) infection is the combination of pegylated interferon (peg-IFN) plus ribavirin (RBV). OBJECTIVE: The aim of this retrospective analysis was to determine the rateof response to this therapy, and the factors affecting outcome, in patients with treatment-refractory chronic HCV genotype l b. METHODS: The records of patients with chronic HCV infection and HCV geno-type1b who failed (nonresponse or relapse) previous treatment with standard interferon (IFN) + RSV were retrospectively analyzed for demographic data, virologic load, liver histology, biochemistry, treatment-related adverse effects (AEs), and the effects of dose reduction during treatment with peg-IFN + RBV for 48 weeks. Early virologic response (EVR) was defined as >=2-log (copies/mL) decrease from baseline in serum HCV RNA concentration or the absence of detectable serum HCV RNA at treatment week 12. End-of-treatment response (ETR) was defined as the absence of detectable serum HCV RNA at treatment week 48. Sustained virologic response (SVR) was defined as the absence of detectable serum HCV RNA 24 weeks after treatment was discontinued. Factors affecting treatment outcome were determined using correlation analyses. RESULTS: Data from the files of 17 patients (12 men, 5 women; mean [SD] age, 48 [2] years) were analyzed. EVR was achieved in 7 patients; however, viral breakthrough occurred in 2 of these patients during the treatment period, and 5 of these patients discontinued treatment because of severe treatment-related AEs (depression [1 patient] and neutropenia [4]). Seven patients achieved ETR, but HCV infection relapsed during the follow-up period. Three (18%) patients achieved SVR. Data concerning previous patterns of response to IFN + RBV therapy were available in 10 patients. Of these, 3 of 6 patients who had experienced relapse with the previous treatment achieved SVR with peg-IFN + RBV; neither of the 2 patients with nonresponse to the previous treatment achieved SVR. Major determinants of failure to reach SVR in these patients included previous nonresponder pattern, noncompliance with the therapy, and advanced-stage liver fibrosis. Tolerability was similar to that with the previous treatment. CONCLUSIONS: In this study in patients with chronic HCV genotype lb infectionand a history of relapse or nonresponse to standard IFN + RSV treatment, treatment with peg-IFN + RBV achieved an SVR rate of 18%. Further research is needed to determine the role of peg-IFN + RBV in the re-treatment of HCV infection. PMID- 24790246 TI - Choice of atypical antipsychotic therapy for patients with schizophrenia: An analysis of a medicaid population. AB - BACKGROUND: In patients treated at Veterans Affairs facilities, demographicand clinical characteristics have been found to influence the choice of atypical antipsychotic drugs. However, little is known about the influences on the choice between olanzapine and risperidone in patients with schizophrenia enrolled in Medicaid. OBJECTIVE: The aim of this study was to determine whether demographicand/or clinical characteristics and/or medical-service utilization before treatment were related to the choice of olanzapine versus risperidone therapy using data from a Medicaid population with schizophrenia. METHODS: The study sample was identified in the North Carolina (NC)Medicaid claims database. Data were included from patients aged 18 to 64 years who were diagnosed with schizophrenia; had initiated treatment with olanzapine or risperidone between July 1, 1998, and October 31, 2000; had not used atypical antipsychotics during the 6 months before the start of treatment; and were continuously eligible in the NC Medicaid program during the 6 months before the start of treatment. Multivariate logistic regression models were used to estimate the likelihood of the choice of olanzapine or risperidone associated with patients' demographic and clinical characteristics and medical-service utilization during the 6 months before the initiation of treatment. RESULTS: A total of 764 patients (383 women, 381 men; mean age, 42.1 years)were included in the analysis: 420 were initially prescribed olanzapine and 344 were prescribed risperidone. Men were more likely than women to be prescribed olanzapine compared with risperidone. Patients who had a hospitalization related to a psychiatric condition during the pretreatment period were more likely to be prescribed olanzapine compared with risperidone (OR = 1.530; P = 0.043). Significant regional variation in the likelihood of prescribing olanzapine or risperidone was found, with patients being prescribed risperidone at a higher rate compared with olanzapine in 2 counties with the largest schizophrenic populations. CONCLUSIONS: In this study of data from patients with schizophrenia identified in the NC Medicaid claims database, sex, a history of psychiatric-related hospitalization, and geographic residence were found to be correlated with the selection of treatment with olanzapine versus risperidone. These findings need to be confirmed in large, randomized, prospective studies. PMID- 24790247 TI - The coronal fricative problem. AB - This paper examines a range of predicted versus attested error patterns involving coronal fricatives (e.g. [s, z, theta, d]) as targets and repairs in the early sound systems of monolingual English-acquiring children. Typological results are reported from a cross-sectional study of 234 children with phonological delays (ages 3 years; 0 months to 7;9). Our analyses revealed different instantiations of a putative developmental conspiracy within and across children. Supplemental longitudinal evidence is also presented that replicates the cross-sectional results, offering further insight into the life-cycle of the conspiracy. Several of the observed typological anomalies are argued to follow from a modified version of Optimality Theory with Candidate Chains (McCarthy, 2007). PMID- 24790248 TI - Bayesian Inference for Growth Mixture Models with Latent Class Dependent Missing Data. AB - Growth mixture models (GMMs) with nonignorable missing data have drawn increasing attention in research communities but have not been fully studied. The goal of this article is to propose and to evaluate a Bayesian method to estimate the GMMs with latent class dependent missing data. An extended GMM is first presented in which class probabilities depend on some observed explanatory variables and data missingness depends on both the explanatory variables and a latent class variable. A full Bayesian method is then proposed to estimate the model. Through the data augmentation method, conditional posterior distributions for all model parameters and missing data are obtained. A Gibbs sampling procedure is then used to generate Markov chains of model parameters for statistical inference. The application of the model and the method is first demonstrated through the analysis of mathematical ability growth data from the National Longitudinal Survey of Youth 1997 (Bureau of Labor Statistics, U.S. Department of Labor, 1997). A simulation study considering 3 main factors (the sample size, the class probability, and the missing data mechanism) is then conducted and the results show that the proposed Bayesian estimation approach performs very well under the studied conditions. Finally, some implications of this study, including the misspecified missingness mechanism, the sample size, the sensitivity of the model, the number of latent classes, the model comparison, and the future directions of the approach, are discussed. PMID- 24790249 TI - A message from the editor. PMID- 24790250 TI - Surgeon general's perspectives. PMID- 24790251 TI - The need for a comprehensive public health approach to preventing child sexual abuse. PMID- 24790252 TI - Patenting genes: what does Association for Molecular Pathology v. Myriad Genetics mean for genetic testing and research? PMID- 24790255 TI - Digital holographic measurements of shape and 3D sound-induced displacements of Tympanic Membrane. AB - Acoustically-induced vibrations of the Tympanic Membrane (TM) play a primary role in the hearing process, in that these motions are the initial mechanical response of the ear to airborne sound. Characterization of the shape and 3D displacement patterns of the TM is a crucial step to a better understanding of the complicated mechanics of sound reception by the ear. In this paper, shape and sound-induced 3D displacements of the TM in cadaveric chinchillas are measured by a lensless Dual-Wavelength Digital Holography system (DWDHS). The DWDHS consists of Laser Delivery (LD), Optical Head (OH), and Computing Platform (CP) subsystems. Shape measurements are performed in double-exposure mode and with the use of two wavelengths of a tunable laser while nanometer-scale displacements are measured along a single sensitivity direction and with a constant wavelength. In order to extract the three principal components of displacement in full-field-of-view, and taking into consideration the anatomical dimensions of the TM, we combine principles of thin-shell theory together with both, displacement measurements along the single sensitivity vector and TM surface shape. To computationally test this approach, Finite Element Methods (FEM) are applied to the study of artificial geometries. PMID- 24790256 TI - Do Gender Differences Exist in the Academic Identification of African-American Elementary-School Aged Children? AB - The disidentification hypothesis predicts that African-American boys achieve less in school than African-American girls do because boys have less personal investment in doing well academically (i.e., they are disidentified). When do such gender differences emerge? Using self-perception and achievement data from longitudinal studies of children (N = 113) at high-risk for academic problems because they come from low-income families, the authors examined whether elementary school-aged and early adolescent African-American boys are more prone to low achievement and disidentification than African-American girls. Multiple regression analyses indicated no gender differences in reading or mathematics achievement between boys and girls at age 8 or at age 12. At 12, African-American boys' self-esteem was predicted by academic performance in ways similar to that of African-American girls. Thus, no gender differences emerged in elementary school achievement and no gender-specific disengagement patterns were confirmed among at-risk African-American students. PMID- 24790257 TI - Enveloping Spectral Surfaces: Covariate Dependent Spectral Analysis of Categorical Time Series. AB - Motivated by problems in Sleep Medicine and Circadian Biology, we present a method for the analysis of cross-sectional categorical time series collected from multiple subjects where the effect of static continuous-valued covariates is of interest. Toward this goal, we extend the spectral envelope methodology for the frequency domain analysis of a single categorical process to cross-sectional categorical processes that are possibly covariate dependent. The analysis introduces an enveloping spectral surface for describing the association between the frequency domain properties of qualitative time series and covariates. The resulting surface offers an intuitively interpretable measure of association between covariates and a qualitative time series by finding the maximum possible conditional power at a given frequency from scalings of the qualitative time series conditional on the covariates. The optimal scalings that maximize the power provide scientific insight by identifying the aspects of the qualitative series which have the most pronounced periodic features at a given frequency conditional on the value of the covariates. To facilitate the assessment of the dependence of the enveloping spectral surface on the covariates, we include a theory for analyzing the partial derivatives of the surface. Our approach is entirely nonparametric, and we present estimation and asymptotics in the setting of local polynomial smoothing. PMID- 24790258 TI - Reception will recognize the extensive contributions of Professor Thomas Roth to the SRS and AASM. PMID- 24790259 TI - Comparative effectiveness research in complex sleep apnea. PMID- 24790260 TI - It takes your breath away. PMID- 24790261 TI - Actigraphy-measured sleep disruption as a predictor of survival among women with advanced breast cancer. AB - BACKGROUND: Poor sleep, prevalent among cancer survivors, is associated with disrupted hormonal circadian rhythms and poor quality of life. Using a prospective research design, this study aimed to clarify the relationship between objective measures of sleep efficiency and sleep disruption with survival among women with advanced breast cancer. METHOD: We examined sleep quality and duration via wrist-worn actigraphy and sleep diaries for 3 days among 97 women in whom advanced breast cancer was diagnosed (age = 54.6 +/- 9.8 years). Sleep efficiency was operationalized using actigraphy as the ratio of total sleep time to total sleep time plus wake after sleep onset. RESULTS: As hypothesized, better sleep efficiency was found to predict a significant reduction in overall mortality (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.98; P < 0.001) at median 6 y follow-up. This relationship remained significant (HR, 0.94; 95% CI, 0.91-0.97; P < 0.001) even after adjusting for other known prognostic factors (age, estrogen receptor status, cancer treatment, metastatic spread, cortisol levels, and depression). Secondary hypotheses were also supported (after adjusting for baseline prognostic factors) showing that less wake after sleep onset (HR, 0.41; 95% CI, 0.25-0.67; P < 0.001), fewer wake episodes, (HR, 0.93; 95% CI, 0.88-0.98; P = 0.007); and shorter wake episode duration (HR, 0.29; 95% CI, 0.14-0.58; P < 0.001) also contributed to reductions in overall mortality. CONCLUSIONS: These findings show that better sleep efficiency and less sleep disruption are significant independent prognostic factors in women with advanced breast cancer. Further research is needed to determine whether treating sleep disruption with cognitive behavioral and/or pharmacologic therapy could improve survival in women with advanced breast cancer. PMID- 24790262 TI - Obstructive sleep apnea and severe maternal-infant morbidity/mortality in the United States, 1998-2009. AB - STUDY OBJECTIVES: A recent trend in increasing rates of severe maternal morbidity and mortality despite quality improvements has been noted. The goal of this study is to estimate the national prevalence of obstructive sleep apnea (OSA) in pregnant women and examine associations between OSA and pregnancy-related morbidities, including in-hospital maternal mortality. DESIGN: A retrospective, cross-sectional analysis. SETTING: A nationally representative sample of maternal hospital discharges from 1998-2009. PATIENTS OR PARTICIPANTS: The analytic sample included 55,781,965 pregnancy-related inpatient hospital discharges. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The Nationwide Inpatient Sample (NIS) database was used to identify hospital stays for women who were pregnant or gave birth. Among these women, we determined length of hospital stay, in-hospital mortality, and used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify OSA and other outcome measures. Multivariable logistic regression modeling was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between OSA and each outcome. The overall rate of OSA was 3.0 per 10,000; however, the rate climbed substantially from 0.7 in 1998 to 7.3 in 2009, with an average annual increase of 24%. After controlling for obesity and other potential confounders, OSA was associated with increased odds of pregnancy-related morbidities including preeclampsia (OR, 2.5; 95% CI, 2.2-2.9), eclampsia (OR, 5.4; 95% CI, 3.3-8.9), cardiomyopathy (OR, 9.0; 95% CI, 7.5-10.9), and pulmonary embolism (OR, 4.5; 95% CI, 2.3-8.9). Women with OSA experienced a more than fivefold increased odds of in-hospital mortality (95% CI, 2.4-11.5). The adverse effects of OSA on selected outcomes were exacerbated by obesity. CONCLUSIONS: Obstructive sleep apnea is associated with severe maternal morbidity, cardiovascular morbidity, and in-hospital death. Targeted interventions may improve pregnancy outcomes in this group. PMID- 24790263 TI - Sleep impairment and prognosis of acute myocardial infarction: a prospective cohort study. AB - STUDY OBJECTIVES: Impaired sleep is an established risk factor for the development of cardiovascular disease, whereas less is known about how impaired sleep affects cardiovascular prognosis. The aim of this study is to determine how different aspects of impaired sleep affect the risk of case fatality and subsequent cardiovascular events following first-time acute myocardial infarction (AMI). DESIGN: Prospective cohort study. SETTING: The Stockholm Heart Epidemiology Program, Sweden. PARTICIPANTS: There were 2,246 first-time AMI cases. MEASUREMENTS AND RESULTS: Sleep impairment was assessed by the Karolinska Sleep Questionnaire, which covers various indices of impaired sleep: disturbed sleep, impaired awakening, daytime sleepiness, and nightmares. Case fatality, defined as death within 28 days of initial AMI, and new cardiovascular events within up to 10 y of follow-up were identified through national registries. In women, disturbed sleep showed a consistently higher risk of long-term cardiovascular events: AMI (hazard ratio [HR] = 1.69; 95% confidence interval [CI] 0.95-3.00), stroke (HR = 2.61; 95% CI: 1.19-5.76), and heart failure (HR = 2.43; 95% CI: 1.18-4.97), whereas no clear effect of impaired sleep on case fatality was found in women. In men, a strong effect on case fatality (odds ratio = 3.27; 95% CI: 1.76-6.06) was observed in regard to impaired awakening; however, no consistent effect of impaired sleep was seen on long-term cardiovascular prognosis. CONCLUSION: Results suggest sex-specific effects of impaired sleep that differ by short- and long-term prognosis. Sleep complaints are frequent, easily recognizable, and potentially manageable. Evaluation of sleep complaints may, even if they represent prognostic markers rather than risk factors, provide additional information in clinical risk assessment that could benefit secondary cardiovascular prevention. PMID- 24790264 TI - Acute sleep deprivation enhances post-infection sleep and promotes survival during bacterial infection in Drosophila. AB - STUDY OBJECTIVES: Sleep is known to increase as an acute response to infection. However, the function of this behavioral response in host defense is not well understood. To address this problem, we evaluated the effect of acute sleep deprivation on post-infection sleep and immune function in Drosophila. SETTING: Laboratory. PARTICIPANTS: Drosophila melanogaster. METHODS AND RESULTS: Flies were subjected to sleep deprivation before (early DEP) or after (late DEP) bacterial infection. Relative to a non-deprived control, flies subjected to early DEP had enhanced sleep after infection as well as increased bacterial clearance and survival outcome. Flies subjected to late DEP experienced enhanced sleep following the deprivation period, and showed a modest improvement in survival outcome. Continuous DEP (early and late DEP) throughout infection also enhanced sleep later during infection and improved survival. However, improved survival in flies subjected to late or continuous DEP did not occur until after flies had experienced sleep. During infection, both early and late DEP enhanced NFkappaB transcriptional activity as measured by a luciferase reporter (kappaB-luc) in living flies. Early DEP also increased NFkappaB activity prior to infection. Flies that were deficient in expression of either the Relish or Dif NFkappaB transcription factors showed normal responses to early DEP. However, the effect of early DEP on post-infection sleep and survival was abolished in double mutants, which indicates that Relish and Dif have redundant roles in this process. CONCLUSIONS: Acute sleep deprivation elevated NFkappaB-dependent activity, increased post-infection sleep, and improved survival during bacterial infection. PMID- 24790265 TI - Eszopiclone and dexmedetomidine depress ventilation in obese rats with features of metabolic syndrome. AB - STUDY OBJECTIVES: Obesity alters the therapeutic window of sedative/hypnotic drugs and increases the probability of respiratory complications. The current experiments used an established rodent model of obesity to test the hypothesis that the sedative/hypnotic drugs eszopiclone and dexmedetomidine alter ventilation differentially in obese rats compared with lean/fit rats. DESIGN: This study used a within-groups/between-groups experimental design. SETTING: University of Michigan. PARTICIPANTS: Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome. INTERVENTIONS: Breathing was measured with whole-body plethysmography after systemic administration of vehicle (control), the nonbenzodiazepine, benzodiazepine site agonist eszopiclone, or the alpha-2 adrenergic receptor agonist dexmedetomidine. MEASUREMENTS AND RESULTS: Data were analyzed using two way analysis of variance and appropriate post hoc comparisons. At baseline, the obese/metabolic syndrome rats had increased respiratory rates (21.6%), lower tidal volumes/body weight (-24.1%), and no differences in minute ventilation compared to lean/fit rats. In the obese rats, respiratory rate was decreased by dexmedetomidine (-29%), but not eszopiclone. In the lean and the obese rats, eszopiclone decreased tidal volume (-12%). Both sedative/hypnotic drugs caused a greater decrease in minute ventilation in the obese (-26.3%) than lean (-18%) rats. Inspiratory flow rate (VT / TI) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (TI / TTOT) in both rat lines was decreased by dexmedetomidine (-16.5%) but not by eszopiclone. CONCLUSIONS: Dexmedetomidine, in contrast to eszopiclone, decreased minute ventilation in the obese/metabolic syndrome rats by depressing both duty cycle and inspiratory flow rate. The results show for the first time that the obese phenotype differentially modulates the respiratory effects of eszopiclone and dexmedetomidine. These differences in breathing are consistent with previously documented differences in sleep between lean/fit and obese rats. These findings also encourage future studies of obese/metabolic syndrome rats that quantify the effect of sedative/hypnotic drugs on respiratory mechanics as well as hypoxic and hypercapnic ventilatory responses. Continued findings of favorable homology between obese humans and rodents will support the interpretation that these obese rats offer a unique animal model for mechanistic studies. PMID- 24790266 TI - The CaV2.3 R-type voltage-gated Ca2+ channel in mouse sleep architecture. AB - STUDY OBJECTIVES: Voltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L type CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) influx into RTN neurons can trigger small-conductance Ca(2+)-activated K(+)-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca(2+) channels in rodent sleep. METHODS: The role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis. RESULTS: CaV2.3 deficient mice exhibited reduced wake duration and increased slow wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined. CONCLUSIONS: Low-voltage activated CaV2.3 R-type Ca(2+) channels in the thalamocortical loop and extra thalamocortical circuitries substantially regulate rodent sleep architecture thus representing a novel potential target for pharmacological treatment of sleep disorders in the future. PMID- 24790267 TI - Cortical gamma-aminobutyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. AB - STUDY OBJECTIVES: To test if posttraumatic stress disorder (PTSD) is associated with low brain gamma-aminobutyric acid (GABA) levels and if reduced GABA is mediated by poor sleep quality. DESIGN: Laboratory study using in vivo proton magnetic resonance spectroscopy (1H MRS) and behavioral testing. SETTING: VA Medical Center Research Service, Psychiatry and Radiology. PATIENTS OR PARTICIPANTS: Twenty-seven patients with PTSD (PTSD+) and 18 trauma-exposed controls without PTSD (PTSD-), recruited from United States Army reservists, Army National Guard, and mental health clinics. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: 1H MRS at 4 Tesla yielded spectra from three cortical brain regions. In parieto-occipital and temporal cortices, PTSD+ had lower GABA concentrations than PTSD-. As expected, PTSD+ had higher depressive and anxiety symptom scores and a higher Insomnia Severity Index (ISI) score. Higher ISI correlated with lower GABA and higher glutamate levels in parieto-occipital cortex and tended to correlate with lower GABA in the anterior cingulate. The relationship between parieto occipital GABA and PTSD diagnosis was fully mediated through insomnia severity. Lower N-acetylaspartate and glutamate concentrations in the anterior cingulate cortex correlated with higher arousal scores, whereas depressive and anxiety symptoms did generally not influence metabolite concentrations. CONCLUSIONS: Low brain gamma-aminobutyric acid (GABA) concentration in posttraumatic stress disorder (PTSD) is consistent with most findings in panic and social anxiety disorders. Low GABA associated with poor sleep quality is consistent with the hyperarousal theory of both primary insomnia and PTSD. Our data demonstrate that poor sleep quality mediates low parieto-occipital GABA in PTSD. The findings have implications for PTSD treatment approaches. PMID- 24790268 TI - Associations of child insomnia, sleep movement, and their persistence with mental health symptoms in childhood and adolescence. AB - STUDY OBJECTIVES: To examine the patterns of insomnia and sleep-related movement from ages 4.5 to 9 years, their concurrent associations with mental health symptoms in childhood, and the longitudinal associations of sleep-problem persistence with mental health symptoms at ages 9 and 18 years. DESIGN: A 14-year prospective follow-up study. Assessments included maternal report on the Children's Sleep Habits Questionnaire at ages 4.5 and 9, and child mental health symptoms via maternal report at age 4.5, multi-informant (child, teacher, mother) report at age 9, and adolescent report at age 18. SETTING: Community. PARTICIPANTS: A total of 396 children (51% female). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep problems were more common at age 4.5 than 9; symptoms of insomnia and abnormal sleep movement both had persistence rates of 9 10%. At age 4.5, insomnia was associated with hostile-aggressive and hyperactive distractible behavior, but there were no significant associations for sleep movement. At age 9, both insomnia and sleep movement were associated with symptoms of depression, externalizing, and attention deficit hyperactivity disorder (ADHD). Insomnia persistence was associated with symptoms of depression, externalizing, and ADHD at age 9 and anxiety and externalizing at age 18; sleep- movement persistence was associated with externalizing and ADHD at age 9, and ADHD at age 18. The age 18 persistence effects for insomnia and anxiety and for sleep movement and ADHD were significant when controlling for earlier mental health. CONCLUSIONS: Childhood insomnia and sleep movement are common and associated with mental health symptoms. Their persistence from middle to late childhood predicts associations with specific types of mental health symptoms at age 18. PMID- 24790269 TI - Eveningness and insomnia: independent risk factors of nonremission in major depressive disorder. AB - BACKGROUND: It is unclear whether there is an association between chronotype and nonremission of depression, and whether the association is related to the confounding effect of insomnia. METHOD: A cohort of patients with major depressive disorder were assessed for chronotype (by Morningness-Eveningness Questinnaire [MEQ]), depressive symptoms, insomnia severity and clinical outcomes in a naturalistic follow-up study. RESULTS: Of the 253 recruited subjects (age 50.8 +/- 10.2 y; female: 82.6%; response rate 90.0%), 19.4%, 56.1% and 24.5% patients were classified as eveningness, intermediate, and morningness, respectively. Evening-type subjects had higher insomnia severity, more severe depressive symptoms, and higher suicidality. Eveningness was associated with nonremission of depression with an odds ratio (OR) of 3.36 (95% confidence interval [CI] 1.35-8.34, P < 0.01), independent of insomnia severity. In addition, insomnia was an independent significant factor in contributing to nonremission of depression (OR = 1.12; 95% CI 1.05-1.19, P < 0.001). CONCLUSION: The independent association of eveningness with nonremission of depression suggested a significant underpinning of circadian involvement in major depressive disorder. Our findings support the need for a comprehensive assessment of sleep and circadian disturbances as well as integration of sleep and chronotherapeutic intervention in the management of depression. PMID- 24790270 TI - Impact of sleep and breathing in infancy on outcomes at three years of age for children with cleft lip and/or palate. AB - STUDY OBJECTIVES: To evaluate the relationship between sleep disordered breathing (SDB) in early infancy and outcomes at 3 years of age in children with cleft lip and/or palate (CL/P). DESIGN: Observational follow-up study. SETTING: Multidisciplinary CL/P clinic, tertiary centre. PARTICIPANTS: Children with CL/P who participated in a study of sleep and breathing in infancy. MEASUREMENTS AND RESULTS: The families of 52 children were approached for this follow-up study. The children underwent neurocognitive (Bayley Scales of Infant and Toddler Development, Third Edition; BSID-III), quality of life (Infant/Toddler Quality of Life Questionnaire; ITQOL), and growth assessments at 3 years. The families of 33 children (66%) completed follow-up at 36.7 +/- 1.4 months. The apnea-hypopnea index (AHI) in infancy was 23.9 +/- 18.0 events/h. Mean group BSID-III scores fell within the standardized normal range (10 +/- 3) for all domains; however, language scores were lower than control children. Quality of life scores and growth parameter z-scores were similar to published control data. PSG variables in infancy showed significant relationships with outcomes at 3 years of age; lower percentage of AS/REM sleep was associated with lower cognition score; more obstructive events were associated with lower global behavior ITQOL score; and higher number of respiratory events in infancy was associated with lower weight z score. CONCLUSION: Neurocognition, quality of life, and growth measures from children with CL/P fall within a normal range; however, scores in the language domain are lower than controls. Sleep and respiratory elements of SDB in infancy appear to modify these outcomes at 3 years of age. PMID- 24790271 TI - The complex sleep apnea resolution study: a prospective randomized controlled trial of continuous positive airway pressure versus adaptive servoventilation therapy. AB - INTRODUCTION: Prior studies show that adaptive servoventilation (ASV) is initially more effective than continuous positive airway pressure (CPAP) for patients with complex sleep apnea syndrome (CompSAS), but choosing therapies has been controversial because residual central breathing events may resolve over time in many patients receiving chronic CPAP therapy. We conducted a multicenter, randomized, prospective trial comparing clinical and polysomnographic outcomes over prolonged treatment of patients with CompSAS, with CPAP versus ASV. METHODS: Qualifying participants meeting criteria for CompSAS were randomized to optimized CPAP or ASV treatment. Clinical and polysomnographic data were obtained at baseline and after 90 days of therapy. RESULTS: We randomized 66 participants (33 to each treatment). At baseline, the diagnostic apnea-hypopnea index (AHI) was 37.7 +/- 27.8 (central apnea index [CAI] = 3.2 +/- 5.8) and best CPAP AHI was 37.0 +/- 24.9 (CAI 29.7 +/- 25.0). After second-night treatment titration, the AHI was 4.7 +/- 8.1 (CAI = 1.1 +/- 3.7) on ASV and 14.1 +/- 20.7 (CAI = 8.8 +/- 16.3) on CPAP (P <= 0.0003). At 90 days, the ASV versus CPAP AHI was 4.4 +/- 9.6 versus 9.9 +/- 11.1 (P = 0.0024) and CAI was 0.7 +/- 3.4 versus 4.8 +/- 6.4 (P < 0.0001), respectively. In the intention-to-treat analysis, success (AHI < 10) at 90 days of therapy was achieved in 89.7% versus 64.5% of participants treated with ASV and CPAP, respectively (P = 0.0214). Compliance and changes in Epworth Sleepiness Scale and Sleep Apnea Quality of Life Index were not significantly different between treatment groups. CONCLUSION: Adaptive servoventilation (ASV) was more reliably effective than CPAP in relieving complex sleep apnea syndrome. While two thirds of participants experienced success with CPAP, approximately 90% experienced success with ASV. Because both methods produced similar symptomatic changes, it is unclear if this polysomnographic effectiveness may translate into other desired outcomes. CLINICAL TRIALS: Clinicaltrials.Gov NCT00915499. PMID- 24790272 TI - Obstructive sleep apnea and obesity are associated with reduced GPR 120 plasma levels in children. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common health problem, particularly in obese children, in whom a vicious cycle of obesity and OSA interdependencies promotes increased food intake. G protein-coupled receptor 120 (GPR 120) is a long-chain free fatty acid (FFA) receptor that plays an important role in energy homeostasis, and protects against insulin resistance and systemic inflammation. We hypothesized that GPR 120 levels would be reduced in children with OSA, particularly among obese children. STUDY DESIGN: Cross-sectional prospectively recruited cohort. SETTING: Academic pediatric sleep program. METHODS: Two hundred twenty-six children (mean age: 7.0 +/- 2.1 y) underwent overnight polysomnographic evaluation and a fasting blood draw the morning after the sleep study. In addition to lipid profile, homeostasis model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hsCRP) assays, monocyte GPR 120 expression, and plasma GPR 120 levels were assessed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay kits. RESULTS: Obese children and those with OSA had significantly lower GPR 120 monocyte expression and plasma GPR 120 levels. Furthermore, when both obesity and OSA were present, GPR 120 levels were lowest. Linear associations emerged between GPR 120 plasma levels and body mass index (BMI) z score, as well as with apnea-hypopnea index (AHI), saturation of peripheral oxygen (SpO2) nadir, and respiratory arousal index (RAI), with RAI remaining statistically significant when controlling for age, ethnicity, sex, and BMI z score (P < 0.001). Similarly, HOMA-IR was significantly associated with GPR 120 levels, but neither low density lipoprotein nor high density lipoprotein cholesterol or hsCRP levels exhibited significant correlations. CONCLUSIONS: G protein-coupled receptor 120 (GPR 120) levels are reduced in pediatric OSA and obesity (particularly when both are present) and may play a role in modulating the degree of insulin resistance. The short- and long-term significance of reduced GPR 120 relative to food intake and glycemic deregulation remains undefined. PMID- 24790273 TI - Obstructive sleep apnea in obese community-dwelling children: the NANOS study. AB - INTRODUCTION: Obesity in children is assumed to serve as a major risk factor in pediatric obstructive sleep apnea syndrome (OSAS). However, the prevalence of OSAS in otherwise healthy obese children from the community is unknown. AIM: To determine the prevalence of OSAS in obese children identified and recruited from primary care centers. METHODS: A cross-sectional, prospective, multicenter study. Spanish children ages 3-14 y with a body mass index (BMI) greater than or equal to the 95th percentile for age and sex were randomly selected, and underwent medical history, snoring, and Pediatric Sleep Questionnaire (PSQ) assessments, as well as physical examination, nasopharyngoscopy, and nocturnal polysomnography (NPSG) recordings. RESULTS: Two hundred forty-eight children (54.4% males) with mean age of 10.8 +/- 2.6 y were studied with a BMI of 28.0 +/- 4.7 kg/m(2) corresponding to 96.8 +/- 0.6 percentile when adjusted for age and sex. The mean respiratory disturbance index (RDI), obstructive RDI (ORDI), and obstructive apnea-hypopnea index (OAHI) were 5.58 +/- 9.90, 5.06 +/- 9.57, and 3.39 +/- 8.78/h total sleep time (TST), respectively. Using >= 3/h TST as the cutoff for the presence of OSAS, the prevalence of OSAS ranged from 21.5% to 39.5% depending on whether OAHI, ORDI, or RDI were used. CONCLUSIONS: The prevalence of obstructive sleep apnea syndrome (OSAS) in obese children from the general population is high. Obese children should be screened for the presence of OSAS. ClinicalTrials.gov identifier: NCT01322763. PMID- 24790274 TI - Insular cortex metabolite changes in obstructive sleep apnea. AB - STUDY OBJECTIVE: Adults with obstructive sleep apnea (OSA) show significant autonomic and neuropsychologic deficits, which may derive from damage to insular regions that serve those functions. The aim was to assess glial and neuronal status from anterior insular metabolites in OSA versus controls, using proton magnetic resonance spectroscopy (PMRS), and thus to provide insights for neuroprotection against tissue changes, and to reduce injury consequences. DESIGN: Cross-sectional study. SETTING: University-based medical center. PARTICIPANTS: Thirty-six patients with OSA, 53 controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We performed PMRS in bilateral anterior insulae using a 3.0-Tesla magnetic resonance imaging scanner, calculated N acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), myo inositol/creatine (MI/Cr), and MI/NAA metabolite ratios, and examined daytime sleepiness (Epworth Sleepiness Scale, ESS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), and neuropsychologic status (Beck Depression Inventory II [BDI-II] and Beck Anxiety Inventory [BAI]). Body mass index, BAI, BDI-II, PSQI, and ESS significantly differed between groups. NAA/ Cr ratios were significantly reduced bilaterally, and left-sided MI/Cr and MI/NAA ratios were increased in OSA over controls. Significant positive correlations emerged between left insular MI/Cr ratios and apnea-hypopnea index values, right insular Cho/Cr ratios and BDI II and BAI scores, and negative correlations appeared between left insular NAA/Cr ratios and PSQI scores and between right-side MI/Cr ratios and baseline and nadir change in O2 saturation. CONCLUSIONS: Adults with obstructive sleep apnea showed bilaterally reduced N-acetylaspartate and left-side increased myo-inositol anterior insular metabolites, indicating neuronal damage and increased glial activation, respectively, which may contribute to abnormal autonomic and neuropsychologic functions in the condition. The activated glial status likely indicates increased inflammatory action that may induce more neuronal injury, and suggests separate approaches for glial and neuronal protection. PMID- 24790275 TI - Facial phenotyping by quantitative photography reflects craniofacial morphology measured on magnetic resonance imaging in Icelandic sleep apnea patients. AB - STUDY OBJECTIVES: (1) To determine whether facial phenotype, measured by quantitative photography, relates to underlying craniofacial obstructive sleep apnea (OSA) risk factors, measured with magnetic resonance imaging (MRI); (2) To assess whether these associations are independent of body size and obesity. DESIGN: Cross-sectional cohort. SETTING: Landspitali, The National University Hospital, Iceland. PARTICIPANTS: One hundred forty patients (87.1% male) from the Icelandic Sleep Apnea Cohort who had both calibrated frontal and profile craniofacial photographs and upper airway MRI. Mean +/- standard deviation age 56.1 +/- 10.4 y, body mass index 33.5 +/- 5.05 kg/m(2), with on-average severe OSA (apnea-hypopnea index 45.4 +/- 19.7 h(-1)). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Relationships between surface facial dimensions (photos) and facial bony dimensions and upper airway soft-tissue volumes (MRI) was assessed using canonical correlation analysis. Photo and MRI craniofacial datasets related in four significant canonical correlations, primarily driven by measurements of (1) maxillary-mandibular relationship (r = 0.8, P < 0.0001), (2) lower face height (r = 0.76, P < 0.0001), (3) mandibular length (r = 0.67, P < 0.0001), and (4) tongue volume (r = 0.52, P = 0.01). Correlations 1, 2, and 3 were unchanged when controlled for weight and neck and waist circumference. However, tongue volume was no longer significant, suggesting facial dimensions relate to tongue volume as a result of obesity. CONCLUSIONS: Significant associations were found between craniofacial variable sets from facial photography and MRI. This study confirms that facial photographic phenotype reflects underlying aspects of craniofacial skeletal abnormalities associated with OSA. Therefore, facial photographic phenotyping may be a useful tool to assess intermediate phenotypes for OSA, particularly in large-scale studies. PMID- 24790276 TI - Effect of recording duration on the diagnostic accuracy of out-of-center sleep testing for obstructive sleep apnea. AB - STUDY OBJECTIVES: This study investigated the minimum recording time needed during out-of-center sleep testing (OCST) to accurately diagnose the presence and severity of obstructive sleep apnea (OSA). DESIGN AND SETTING: A retrospective analysis was conducted of OCSTs performed from October 2009 to May 2012 at the Mayo Clinic Center of Sleep Medicine using the portable EmblettaTM system. PATIENTS OR PARTICIPANTS: Demographic information was collected for patients who underwent OCSTs during the study period, including presenting symptoms, examination findings, and comorbidities. INTERVENTION: Each study was divided into 60-, 120-, 180-, 240-, 300-, 360-, and 420-min intervals beginning at the recording start time to determine the respiratory event index (REI) for each of these time intervals. These interval values were then compared to the original REI derived from the total recording time (REITRT) by a paired t-test and concordance correlation coefficient (CCC). MEASUREMENTS AND RESULTS: There were significant differences between the REITRT and the REI from the 60-min (P < 0.0001), 120-min (0.0001), 180-min (0.003) and 240-min (0.006) intervals with a lack of concordance, suggesting these intervals are poor diagnostic correlates for the REITRT. REIs determined at 300, 360, and 420 min were not significantly different from the REITRT and had highly significant CCCs, 0.963, 0.987, and 0.995, respectively. CONCLUSIONS: The results suggest that at least 300 min recording time during out-of-center sleep testing is needed for accurate diagnosis of obstructive sleep apnea and determination of obstructive sleep apnea severity. PMID- 24790277 TI - Differential effect of an anticholinergic antidepressant on sleep-dependent memory consolidation. AB - STUDY OBJECTIVES: Rapid eye movement (REM) sleep is considered critical to the consolidation of procedural memory - the memory of skills and habits. Many antidepressants strongly suppress REM sleep, however, and procedural memory consolidation has been shown to be impaired in depressed patients on antidepressant therapy. As a result, it is important to determine whether antidepressive therapy can lead to amnestic impairment. We thus investigated the effects of the anticholinergic antidepressant amitriptyline on sleep-dependent memory consolidation. DESIGN: Double-blind, placebo-controlled, randomized, parallel-group study. SETTING: Sleep laboratory. PARTICIPANTS: Twenty-five healthy men (mean age: 26.8 +/- 5.6 y). INTERVENTIONS: 75 mg amitriptyline versus placebo. MEASUREMENTS/RESULTS: To test memory consolidation, a visual discrimination task, a finger-tapping task, the Rey-Osterrieth Complex Figure Test, and the Rey Auditory-Verbal Learning Test were performed. Sleep was measured using polysomnography. Our findings show that amitriptyline profoundly suppressed REM sleep and impaired perceptual skill learning, but not motor skill or declarative learning. CONCLUSIONS: Our study is the first to demonstrate that an antidepressant can affect procedural memory consolidation in healthy subjects. Moreover, considering the results of a recent study, in which selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors were shown not to impair procedural memory consolidation, our findings suggest that procedural memory consolidation is not facilitated by the characteristics of REM sleep captured by visual sleep scoring, but rather by the high cholinergic tone associated with REM sleep. Our study contributes to the understanding of potentially undesirable behavioral effects of amitriptyline. PMID- 24790278 TI - Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats. AB - STUDY OBJECTIVES: Chronic upper airway obstruction (UAO) elicits a cascade of complex endocrine derangements that affect growth, sleep, and energy metabolism. We hypothesized that elevated hypothalamic orexin has a role in maintaining ventilation during UAO, while at the same time altering sleep-wake activity and energy metabolism. Here, we sought to explore the UAO-induced changes in hypothalamic orexin and their role in sleep-wake balance, respiratory activity, and energy metabolism. INTERVENTIONS: The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed; UAO and sham-operated control animals were monitored for 7 weeks. We measured food intake, body weight, temperature, locomotion, and sleep-wake activity. Magnetic resonance imaging was used to quantify subcutaneous and visceral fat tissue volumes. In week 7, the rats were sacrificed and levels of hypothalamic orexin, serum leptin, and corticosterone were determined. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and respiration was also explored. MEASUREMENTS AND RESULTS: UAO increased hypothalamic orexin mRNA and protein content by 64% and 65%, respectively. UAO led to 30% chronic sleep loss, excessive active phase sleepiness, decreased body temperature, increased food intake, reduction of abdominal and subcutaneous fat tissue volume, and growth retardation. Administration of almorexant normalized sleep but induced severe breathing difficulties in UAO rats, while it had no effect on sleep or on breathing of control animals. CONCLUSIONS: In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth. PMID- 24790279 TI - Sleep fragmentation in mice induces nicotinamide adenine dinucleotide phosphate oxidase 2-dependent mobilization, proliferation, and differentiation of adipocyte progenitors in visceral white adipose tissue. AB - BACKGROUND: Chronic sleep fragmentation (SF) without sleep curtailment induces increased adiposity. However, it remains unclear whether mobilization, proliferation, and differentiation of adipocyte progenitors (APs) occurs in visceral white adipose tissue (VWAT), and whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) activity plays a role. METHODS: Changes in VWAT depot cell size and AP proliferation were assessed in wild-type and Nox2 null male mice exposed to SF and control sleep (SC). To assess mobilization, proliferation, and differentiation of bone marrow mesenchymal stem cells (BM-MSC), Sca-1+ bone marrow progenitors were isolated from GFP+ or RFP+ mice, and injected intravenously to adult male mice (C57BL/6) previously exposed to SF or SC. RESULTS: In comparison with SC, SF was associated with increased weight accrual at 3 w and thereafter, larger subcutaneous and visceral fat depots, and overall adipocyte size at 8 w. Increased global AP numbers in VWAT along with enhanced AP BrDU labeling in vitro and in vivo emerged in SF. Systemic injections of GFP+ BM-MSC resulted in increased AP in VWAT, as well as in enhanced differentiation into adipocytes in SF-exposed mice. No differences occurred between SF and SC in Nox2 null mice for any of these measurements. CONCLUSIONS: Chronic sleep fragmentation (SF) induces obesity in mice and increased proliferation and differentiation of adipocyte progenitors (AP) in visceral white adipose tissue (VWAT) that are mediated by increased Nox2 activity. In addition, enhanced migration of bone marrow mesenchymal stem cells from the systemic circulation into VWAT, along with AP differentiation, proliferation, and adipocyte formation occur in SF-exposed wild-type but not in oxidase 2 (Nox2) null mice. Thus, Nox2 may provide a therapeutic target to prevent obesity in the context of sleep disorders. PMID- 24790280 TI - Lack of hypocretin attenuates behavioral changes produced by glutamatergic activation of the perifornical-lateral hypothalamic area. AB - STUDY OBJECTIVES: The hypocretins (HCRTs) are two hypothalamic peptides predominantly localized to neurons in the perifornical, dorsomedial, and lateral hypothalamic area (PF-LHA). Evidence suggests that HCRT signaling is critical for the promotion and stabilization of active-arousal and its loss or malfunction leads to symptoms of narcolepsy. In the PF-LHA, HCRT neurons are intermingled with glutamate-expressing neurons and also co-express glutamate. Evidence suggests that HCRT-glutamate interactions within the PF-LHA may play a critical role in maintaining behavioral arousal. However, the relative contributions of the glutamate and HCRT in sleep-wake regulation are not known. DESIGN: We determined whether a lack of HCRT signaling in the prepro-orexin-knockout (HCRT KO) mouse attenuates/compromises the wake-promoting ability of glutamatergic activation of the PF-LHA region. We used reverse microdialysis to deliver N methyl-D-aspartate (NMDA) into the HCRT zone of the PF-LHA in HCRT-KO and wild type (WT) mice to evaluate the contributions of glutamatergic vs. HCRT signaling in sleep-wake regulation. MEASUREMENTS AND RESULTS: As compared to respective controls, local perfusion of NMDA into the PF-LHA, dose-dependently increased active-waking with concomitant reductions in nonREM and REM sleep in spontaneously sleeping WT as well as HCRT-KO mice. However, compared to WT, the NMDA-induced behavioral changes in HCRT-KO mice were significantly attenuated, as evidenced by the higher dose of NMDA needed and lower magnitude of changes induced in sleep-wake parameters. Although not observed in WT mice, the number of cataplectic events increased significantly during NMDA-induced behavioral arousal in HCRT-KO mice. CONCLUSIONS: The findings of this study are consistent with a hypothesis that synergistic interactions between hypocretin and glutamatergic mechanisms within the perifornical, dorsomedial, and lateral hypothalamic area are critical for maintaining behavioral arousal, especially arousal involving elevated muscle tone. PMID- 24790281 TI - Lifestyle changes aiming at weight loss should always be included in the treatment of obese patients with obstructive sleep apnea. PMID- 24790282 TI - Power Calculations for General Linear Multivariate Models Including Repeated Measures Applications. AB - Recently developed methods for power analysis expand the options available for study design. We demonstrate how easily the methods can be applied by (1) reviewing their formulation and (2) describing their application in the preparation of a particular grant proposal. The focus is a complex but ubiquitous setting: repeated measures in a longitudinal study. Describing the development of the research proposal allows demonstrating the steps needed to conduct an effective power analysis. Discussion of the example also highlights issues that typically must be considered in designing a study. First, we discuss the motivation for using detailed power calculations, focusing on multivariate methods in particular. Second, we survey available methods for the general linear multivariate model (GLMM) with Gaussian errors and recommend those based on F approximations. The treatment includes coverage of the multivariate and univariate approaches to repeated measures, MANOVA, ANOVA, multivariate regression, and univariate regression. Third, we describe the design of the power analysis for the example, a longitudinal study of a child's intellectual performance as a function of mother's estimated verbal intelligence. Fourth, we present the results of the power calculations. Fifth, we evaluate the tradeoffs in using reduced designs and tests to simplify power calculations. Finally, we discuss the benefits and costs of power analysis in the practice of statistics. We make three recommendations: Align the design and hypothesis of the power analysis with the planned data analysis, as best as practical.Embed any power analysis in a defensible sensitivity analysis.Have the extent of the power analysis reflect the ethical, scientific, and monetary costs. We conclude that power analysis catalyzes the interaction of statisticians and subject matter specialists. Using the recent advances for power analysis in linear models can further invigorate the interaction. PMID- 24790283 TI - A polyphasic taxonomy of Daldinia (Xylariaceae). AB - For a monograph based on a polythetic concept, several thousands of herbarium specimens, and several hundreds of freshly collected and cultured specimens of Daldinia and allied Xylariaceae, originating from around the world, were studied for morphological traits, including by SEM, and chemically by HPLC profiles using UV-visible and mass spectrometric detection. Emphasis was given to tropical material, and importantly, ancient specimens, including as many types as possible, were tracked and studied to review earlier taxonomic concepts. An epitype of D. eschscholtzii was selected as representative of the morphochemotype that is most widely distributed in the tropics. Six new species of Daldinia from the tropics and the southern Hemisphere are described. Daldinia asphalatum is resurrected, and D. cudonia is regarded as its synonym. In addition, the following binomials are epi-, iso-, neo- and/or lectotypified: Daldinia asphalatum, D. caldariorum, D. clavata, D. cuprea, D. durissima, D. eschscholtzii, D. grandis, D. loculata, and D. vernicosa. Annellosporium and Versiomyces are regarded as synonyms of Daldinia. Many new synonymies in Daldinia are proposed, and some previously published names are rejected. In total, 47 taxa in Daldinia are recognised and a key is provided. Their biogeography, chorology, and ecology, as well as the importance of their secondary metabolites, are also discussed. The previous definition of the genus is emended. The species concept is based mainly on morphological and other phenotype-derived characters because, despite diligent search, no molecular data or cultures of several of the accepted species could be obtained. Daldinia is segregated into five major groups, based on phenotypic characteristics. Some unnamed but aberrant specimens were not found in good condition and are therefore not formally described as new species. However, they are illustrated in detail in a hope that this will facilitate the discovery of fresh material in future. A preliminary molecular phylogeny based on 5.8S/ITS nrDNA including numerous representatives of all hitherto described taxa for which cultures are extant, was found basically in agreement with the above mentioned segregation of the genus, based on morphological and chemotaxonomic evidence. In the rDNA based phylogenetic tree, Daldinia appears clearly distinct from members of the genera Annulohypoxylon and Hypoxylon; nevertheless, representatives of small genera of predominantly tropical origin (Entonaema, Phylacia, Ruwenzoria, Rhopalostroma, Thamnomyces) appear to have evolved from daldinioid ancestors and are nested inside the Daldinia clade. Interestingly, these findings correlate with chemotaxonomic characters to a great extent, especially regarding the distribution of marker metabolites in their mycelial cultures. Hence, the current study revealed for the first time that fungal secondary metabolite profiles can have taxonomic value beyond the species rank and even coincide with phylogenetic data. TAXONOMIC NOVELTIES: Daldinia andina sp. nov., D. australis sp. nov., D. hausknechtii sp. nov., D. rehmii sp. nov., D. starbaeckii sp. nov., D. theissenii sp. nov., D. cahuchosa comb. nov., D. nemorosa comb. nov. PMID- 24790284 TI - Sexual Violence, Bodily Pain, and Trauma: A History. AB - Psychological trauma is a favoured trope of modernity. It has become commonplace to assume that all 'bad events' - and particularly those which involve violence - have a pathological effect on the sufferer's psyche, as well as that of the perpetrators. This essay explores the ways victims of rape and sexual assault were understood in psychiatric, psychological, forensic, and legal texts in Britain and America from the 19th to the late 20th century. It argues that, unlike most other 'bad events', which were incorporated within trauma narratives from the 1860s, the ascription of psychological trauma was only applied to rape victims a century later. Why and what were the consequences? PMID- 24790285 TI - Unravelling the architecture of functional variability in wild populations of Polygonum viviparum L. AB - Functional variability (FV) of populations can be decomposed into three main features: the individual variability of multiple traits, the strength of correlations between those traits and the main direction of these correlations, the latter two being known as 'phenotypic integration'. Evolutionary biology has long recognized that FV in natural populations is key to determining potential evolutionary responses, but this topic has been little studied in functional ecology.Here we focus on the arctico-alpine perennial plant species Polygonum viviparum L.. We used a comprehensive sampling of seven functional traits in 29 wild populations covering the whole environmental niche of the species. The niche of the species was captured by a temperature gradient, which separated alpine stressful habitats from species-rich, competitive sub-alpine ones. We seeked to assess the relative roles of abiotic stress and biotic interactions in shaping different aspects of functional variation within and among populations, that is, the multi-trait variability, the strength of correlations between traits, and the main directions of functional trade-offs.Populations with the highest extent of functional variability were found in the warm end of the gradient whereas populations exhibiting the strongest degree of phenotypic integration were located in sites with intermediate temperatures. This could reveal both the importance of environmental filtering and population demography in structuring FV. Interestingly, we found that the main axes of multivariate functional variation were radically different within and across population.Although the proximate causes of FV structure remain uncertain, our study presents a robust methodology for the quantitative study of functional variability in connection with species' niches. It also opens up new perspectives for the conceptual merging of intraspecific functional patterns with community ecology. PMID- 24790286 TI - Estimation and model selection of semiparametric multivariate survival functions under general censorship. AB - We study estimation and model selection of semiparametric models of multivariate survival functions for censored data, which are characterized by possibly misspecified parametric copulas and nonparametric marginal survivals. We obtain the consistency and root-n asymptotic normality of a two-step copula estimator to the pseudo-true copula parameter value according to KLIC, and provide a simple consistent estimator of its asymptotic variance, allowing for a first-step nonparametric estimation of the marginal survivals. We establish the asymptotic distribution of the penalized pseudo-likelihood ratio statistic for comparing multiple semiparametric multivariate survival functions subject to copula misspecification and general censorship. An empirical application is provided. PMID- 24790287 TI - Replicated radiations of the alpine genus Androsace (Primulaceae) driven by range expansion and convergent key innovations. AB - AIM: We still have limited understanding of the contingent and deterministic factors that have fostered the evolutionary success of some species lineages over others. We investigated how the interplay of intercontinental migration and key innovations promoted diversification of the genus Androsace. LOCATION: Mountain ranges and cold steppes of the Northern Hemisphere. METHODS: We reconstructed ancestral biogeographical ranges at regional and continental scales by means of a dispersal-extinction-cladogenesis analysis using dated Bayesian phylogenies and contrasting two migration scenarios. Based on diversification analyses under two frameworks, we tested the influence of life form on speciation rates and whether diversification has been diversity-dependent. RESULTS: We found that three radiations occurred in this genus, at different periods and on different continents, and that life form played a critical role in the history of Androsace. Short-lived ancestors first facilitated the expansion of the genus' range from Asia to Europe, while cushions, which appeared independently in Asia and Europe, enhanced species diversification in alpine regions. One long-distance dispersal event from Europe to North America led to the diversification of the nested genus Douglasia. We found support for a model in which speciation of the North American-European clade is diversity-dependent and close to its carrying capacity, and that the diversification dynamics of the North American subclade are uncoupled from this and follow a pure birth process. MAIN CONCLUSIONS: The contingency of past biogeographical connections combined with the evolutionary determinism of convergent key innovations may have led to replicated radiations of Androsace in three mountain regions of the world. The repeated emergence of the cushion life form was a convergent key innovation that fostered radiation into alpine habitats. Given the large ecological similarity of Androsace species, allopatry may have been the main mode of speciation. PMID- 24790288 TI - Disentangling the drivers of metacommunity structure across spatial scales. AB - AIM: Metacommunity theories attribute different relative degrees of importance to dispersal, environmental filtering, biotic interactions and stochastic processes in community assembly, but the role of spatial scale remains uncertain. Here we used two complementary statistical tools to test: (1) whether or not the patterns of community structure and environmental influences are consistent across resolutions; and (2) whether and how the joint use of two fundamentally different statistical approaches provides a complementary interpretation of results. LOCATION: Grassland plants in the French Alps. METHODS: We used two approaches across five spatial resolutions (ranging from 1 km * 1 km to 30 km * 30 km): variance partitioning, and analysis of metacommunity structure on the site-by species incidence matrices. Both methods allow the testing of expected patterns resulting from environmental filtering, but variance partitioning allows the role of dispersal and environmental gradients to be studied, while analysis of the site-by-species metacommunity structure informs an understanding of how environmental filtering occurs and whether or not patterns differ from chance expectation. We also used spatial regressions on species richness to identify relevant environmental factors at each scale and to link results from the two approaches. RESULTS: Major environmental drivers of richness included growing degree-days, temperature, moisture and spatial or temporal heterogeneity. Variance partitioning pointed to an increase in the role of dispersal at coarser resolutions, while metacommunity structure analysis pointed to environmental filtering having an important role at all resolutions through a Clementsian assembly process (i.e. groups of species having similar range boundaries and co occurring in similar environments). MAIN CONCLUSIONS: The combination of methods used here allows a better understanding of the forces structuring ecological communities than either one of them used separately. A key aspect in this complementarity is that variance partitioning can detect effects of dispersal whereas metacommunity structure analysis cannot. Moreover, the latter can distinguish between different forms of environmental filtering (e.g. individualistic versus group species responses to environmental gradients). PMID- 24790289 TI - A Numerical Method for Estimating the Variance of Age at Maximum Growth Rate in Growth Models. AB - Studies on maturation and body composition mention age at peak height velocity (PHV) as an important measure that could predict adulthood outcome. The age at PHV is often derived from growth models such as the triple logistic fitted to the stature (height) data. Theoretically, for a well behaved growth function, age at PHV could be obtained by setting the second derivative of the growth function to zero and solving for age. Such a solution obviously depends on the parameters of the growth function. Therefore, the uncertainty in the estimation of age at PHV resulting from the uncertainty in the estimation of the growth model, need to be accounted for in the models in which it is used as a predictor. Explicit expressions for the age at PHV and consequently the variance of the estimate of the age at PHV do not exist for some of the commonly used non-linear growth functions, such as the triple logistic function. Once an estimate of this variance is obtained, it could be incorporated in subsequent modeling either through measurement error models or by using the variances as weights. A numerical method for estimating the variance is implemented. The accuracy of this method is demonstrated through comparisons in models where explicit solution for the variance exists. The method of estimating the variance is illustrated by applying to growth data from the Fels study and subsequently used as weights in modeling two adulthood outcomes from the same study. PMID- 24790291 TI - High density lipoprotein particle size in children: relation to atherogenic dyslipidemia. AB - Atherosclerosis begins in childhood. Protection from atherosclerosis is provided by high-density lipoprotein (HDL), a heterogeneous particle, which includes several subclasses differing in size, density and apolipoprotein content. The objective of this study was to document the relevance of assessing HDL particle size as another feature of dyslipidemia related to the develpment of atheosclerosis during childhood. For that purpose, HDL particle size in 268 community-based children (137 boys and 131 girls), 7-13 years old, was measured by gradient gel electrophoresis, and relationships of HDL particle size to plasma lipids parameters and the anthropometric indices were analyzed. There was no gender difference in HDL particle diameter. The results of analysis revealed significant positive correlations between HDL particle diameter and HDL cholesterol level (r=0.363, p<0.01), apolipoprotein AI level (r=0.310, r<0.05) and low-density lipoprotein particle (LDL) size (r=0.290, p<0.05), while there was an inverse correlation with atherogenic index (r=-0.316, p<0.05). There was no significant correlation between HDL particle size and triglyceride levels in the overall analysis (n=268), however, when this relation was analyzed in the limited HDL size range below 11 nm, a significant inverse relation appeared between particle size and TG levels (r =-0.546, P<0.01, n=75). These findings indicate that the general shift toward smaller HDL particle size was associated with dyslipidemia characterized by higher atherogenic index and triglyceride level, lower HDL-C level and smaller LDL particle size. Therefore, HDL size may represent another relevant marker of atherogenic lipid metabolism. PMID- 24790290 TI - Building megaphylogenies for macroecology: taking up the challenge. AB - The last decades have seen an upsurge in ecological studies incorporating phylogenetic information with increasing species samples, motivated by the common conjecture that species with common ancestors should share some ecological characteristics due to niche conservatism. This has been carried out using various methods of increasing complexity and reliability: using only taxonomical classification; constructing supertrees that incorporate only topological information from previously published phylogenies; or building supermatrices of molecular data that are used to estimate phylogenies with evolutionary meaningful branch lengths. Although the latter option is more informative than the others, it remains under-used in ecology because ecologists are generally unaware of or unfamiliar with modern molecular phylogenetic methods. However, a solid phylogenetic hypothesis is necessary to conduct reliable ecological analysis integrating evolutive aspects. Our aim here is to clarify the concepts and methodological issues associated with the reconstruction of dated megaphylogenies, and to show that it is nowadays possible to obtain accurate and well sampled megaphylogenies with informative branch-lengths on large species samples. This is possible thanks to improved phylogenetic methods, vast amounts of molecular data available from databases such as Genbank, and consensus knowledge on deep phylogenetic relationships for an increasing number of groups of organisms. Finally, we include a detailed step-by-step workflow pipeline (Supplementary material), from data acquisition to phylogenetic inference, mainly based on the R environment (widely used by ecologists) and the use of free web servers, that has been applied to the reconstruction of a species-level phylogeny of all breeding birds of Europe. PMID- 24790292 TI - Poor response to substitution therapy with cortisone acetate in patients with congenital adrenal hyperplasia. AB - Although cortisone acetate is approved worldwide as corticosteroid substitution therapy in congenital adrenal hyperplasia (21-hydroxylase deficiency), its effectiveness is uncertain since its biologic activity depends on activation by 11beta-hydroxysteroid dehydrogenase (11beta-HSD). We sought to compare the effect of cortisone acetate with that of hydrocortisone. In 10 patients with congenital adrenal hyperplasia, cortisone acetate was replaced with hydrocortisone in substitution therapy. During this change, blood concentrations of 17-hydroxy progesterone, adrenocorticotropin (ACTH), and requirements for each drug were monitored. Concentrations of 17-hydroxyprogesterone decreased (mean 10.1 vs. 48.6 ng/ml), as did those of ACTH. Cortisone acetate dose requirements averaged 33.9 mg/m(2), while hydrocortisone dose requirements averaged only 20.3 mg/m(2). In one of the patients resistant to cortisone acetate therapy, DNA sequences in the coding regions and promoter of the 11beta-HSD gene were analyzed, detecting no genetic abnormalities. Cortisone acetate is inferior to hydrocortisone as substitution therapy in patients with congenital adrenal hyperplasia. PMID- 24790293 TI - Hormonal and genetical assessment of a Japanese girl with weaver syndrome. AB - We report a case of Japanese girl with a rare disorder of Weaver syndrome, which was characterized by overgrowth with advanced and disharmonic bone age, craniofacial abnormalities, developmental delay, metaphyseal flaring of the long bones and camptodactyly. The patient was delivered at 38 weeks of gestation with a length of 54.2 cm (+ 2.6 SD), a weight of 3805 g (+ 2.5 SD) and an occipitofrontal circumference (OFC) of 35.0 cm (+ 1.1 SD). She manifested hypertonia and flexion contractures in the first few years. She also had submucosal soft cleft palate and difficulty in swallowing and breathing in early infancy. When she was 5 years and 7 months old, her height and weight were 133.3 cm (+ 5.5 SD) and 32.0 kg (+ 5.1 SD), respectively. We could not detect any endocrinological abnormalities for the cause of overgrowth. According to clinical features, Weaver syndrome was suspected and genetical analysis was performed. Fluorescence in situ hybridization (FISH) and direct sequencing analysis showed neither deletion nor point mutation of the nuclear receptor SET-domain-containing protein 1 (NSD1) gene on 5q35, which is responsible for Sotos syndrome. Therefore, we made a diagnosis of Weaver syndrome for this patient and discussed the differential diagnosis in terms of overgrowth syndrome. PMID- 24790294 TI - Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy. AB - We present a 3-yr-old girl with a virilizing adrenocortical carcinoma invading into the right atrium with histological high-grade malignancy and p53 mutation. Development of facial acne and pubic hair were noted at 3 yr and 2 mo. The levels of androgens were high. Diurnal variation in ACTH and cortisol were absent. Abdominal computed tomography revealed a large right suprarenal mass, with extension into the inferior vena cava and right atrium. Based on the diagnosis of a right virilizing adrenocortical tumor with Cushing syndrome, surgery was performed by a combined thoracoabdominal approach with the patient on cardiopulmonary bypass. The tumor was 7 * 5.5 * 3.5 cm in size, and weighed 95 g. The histological diagnosis was adrenocartical carcinoma with high-grade malignancy according to the category of Weiss. A heterozygous mutation of the p53 tumor-suppressor gene (codon 248 CGC->TGG) was found. We did not perform adjuvant chemotherapy because of radical resection on macroscopic observation and no metastasis in radiological findings. Five months after the surgery, her chest X ray and computed tomography revealed multiple lung metastases and a single liver metastasis. In this type of patient with histological high-grade malignancy and p53 mutations, postoperative adjuvant chemotherapy is indicated even if macroscopic total surgical removal had been performed. PMID- 24790295 TI - The long-term effect of replacement therapy in a short girl with autoimmune atrophic thyroiditis of prepubertal onset. AB - A 9 yr 11 mo old girl was admitted to our hospital because of short stature. Her growth rate gradually decreased and her height was 120 cm (-2.5 SD) on admission. The mother's and father's heights were 157 cm (-0.2 SD) and 163 cm (-1.3 SD), respectively. Her bone age was retarded (6 yr 10 mo). An MRI indicated pituitary enlargement, which mimicked adenoma. Evaluation of the pituitary-thyroid axis and thyroid function proved she had primary hypothyroidism (T3 0.5 ng/ml, T4 1.0 MUg/dl, TSH 1,030 MUU/ml). These findings, thyroid autoantibody (anti-microsome antibody 400 xs) and histopathology (moderate fibrosis and mild lymphocytic infiltration) suggested acquired hypothyroidism due to autoimmune atrophic thyroiditis of prepubertal onset. Since the evaluation, she has been treated with levothyroxine. The pituitary enlargement disappeared within 3 mo after levothyroxine replacement. The growth rate increased and her height reached 153.2 cm (-1.0 SD) during 10 yr replacement (at 19 yr 11 mo of age). An improvement in her final height was obtained by long-term thyroid hormone replacement therapy. Enough endocrinological study and repeated MRI evaluation are necessary in cases of pituitary enlargement which mimics adenoma before considering surgery. PMID- 24790296 TI - A Novel Missense Mutation in the Thyroid Peroxidase Gene, R175Q, Resulting in Insufficient Cell Surface Enzyme in Two Siblings. AB - Thyroid peroxidase (TPO) abnormality is one of the causes of congenital hypothyroidism. Two missense mutations were found as a compound heterozygous mutation in two siblings with congenital goitrous hypothyroidism. One of these mutations, G614A (R175Q), was a novel mutation. Characterization of the novel mutation and a cotransfection experiment with two mutated TPO mRNAs were carried out. G614A-mRNA introduced into CHO-K1 cells expressed TPO protein with the same molecular weight as that of wild-type mRNA. The R175Q-TPO was thought to possess enzyme activity. In terms of localization, a very small amount of mutated TPO was expressed on the plasma membrane of CHO-K1 cells. This plasma membrane expression of R175Q-TPO was insufficient to perform thyroid hormone synthesis, but was markedly different from R665W-TPO. When G614A- and C2083T-mRNAs were cotransfected, cell surface TPO-positive cells were only 13.1% in contrast to 54.4% for wild-type mRNA. The low positivity and intensity of cell surface TPO suggested that in the patients' thyroids thyroid hormone synthesis was hardly performed. The congenital hypothyroidism of the patients was thought to be a result of the mutations of the TPO gene (G614A/C2083T). PMID- 24790297 TI - Plasma levels of orexin-a and leptin in obese children. AB - The present study was designed to determine the plasma level of orexin and its relationship with other metabolic and anthropometric markers in obese children. Forty-seven obese Japanese children, consisting of 31 boys and 16 girls, were enrolled in the study. Their ages were 10.4 +/- 0.5 (mean +/- s.e.m.) yr, and their percentage overweight was 42.9 +/- 1.9%. Blood was drawn after an overnight fast. The age-matched control group consisted of 26 nonobese children, 13 boys and 13 girls. Plasma orexin-A concentration was higher in obese children (17.0 +/ 0.4 pg/ml; p<0.001) than in the control children (13.5 +/- 1.1 pg/ml). Similarly, plasma leptin concentration was higher in obese children (12.0 +/- 1.0 ng/ml; p<0.001) than in the control children (5.2 +/- 0.4 ng/ml). There was a highly significant positive correlation between the two parameters in the obese children (r=0.49, p<0.001). Plasma orexin-A level was correlated significantly with waist-to-hip ratio, while leptin level was correlated with percentage overweight, waist circumference and percentage body fat in the obese children. These results suggest that high plasma orexin-A level parallels the leptin level in obese children. PMID- 24790298 TI - The levels of serum low-density lipoprotein cholesterol using direct measurement in healthy Japanese school children. AB - This study aimed to investigate the levels of serum low-density lipoprotein cholesterol (LDLC) using direct measurement in healthy Japanese school children. The subjects were 621 children (325 boys and 296 girls) aged 9 to 10 in the 4th grade, and 688 children (334 boys and 354 girls) aged 12 to 13 in the 7th grade. The levels of serum LDLC and high-density lipoprotein cholesterol were measured by direct determination (Cholestest LDL and Cholestest NHDL; Daiichi Pure Chemicals Co., Ltd., Tokyo, Japan). In boys in the 4th grade, the mean, the 75th, the 90th and the 95th percentiles of LDLC levels (mg/dl) were 91.6, 104, 124 and 134, respectively. In girls in the 4th grade, they were 92.8, 108, 122 and 130. In boys in the 7th grade, they were 83.4, 96, 113 and 123. In girls in the 7th grade, they were 93.0, 106, 126 and 137. Serum LDLC levels in boys in the 7th grade were lower than those of other groups. The direct measurement of serum LDLC level is useful for evaluation of dyslipidemia in healthy school children, because the method is applicable to non-fasting serum. PMID- 24790299 TI - A case of female pseudohermaphroditism caused by aromatase deficiency. AB - Female pseudohermaphroditism is caused by several etiologies. Here we report a case of aromatase deficiency who showed ambiguous genitalia and maternal virilization during pregnancy. The mother had noticed her own virilization from 16 wk of gestation without androgen exposure and had low urinary estriol levels (5~10 MUg/ml at 35 wk of gestation). At birth, the patient presented severe virilization (Prader V), and was assigned as a male with a micropenis and unpalpable testes but the patient had a normal female karyotype and a uterus and cystic ovaries found by magnetic resonance imaging. The patient had a increase in serum 17alpha-hydroxy progesterone levels (basal 4.9 -> 37 ng/ml after a single 0.25 mg/m(2) infusion of ACTH), but the increase in adrenal androgen was not sufficient to virilize the external genitalia. Dehydroepiandrosterone, 17alpha hydroxy pregnenolone and deoxycorticosterone were within the normal ranges. These findings suggested a diagnosis of nonadrenal female pseudohermaphroditism. From the clinical features and biochemical data, we endocrinologically diagnosed her as having an aromatase deficiency. The aromatase gene is now under investigation for definite diagnosis. We finally agreed that aromatase deficiency should be suspected when both the mother and the newborn have been virilized. PMID- 24790300 TI - A Case of a Preterm Infant with 21-Hydroxylase Deficiency: Implications of the Biochemical Diagnosis with Urinary Pregnanetriolone by Gas Chromatography/Mass Spectrometry in Selected Ion Monitoring (GCMS-SIM). AB - The biochemical diagnosis of 21-hydroxylase deficiency (21-OHD) is difficult in preterm infants. To date, no marker for the biochemical diagnosis of 21-OHD has been found. Seventeen alpha-hydroxyprogesterone (17-OHP), is not useful because of interference by delta 5 steroids from the fetal adrenal cortex. A 5-d-old female infant, born at 31 wk of gestation, was suspected of having 21-OHD based on physical findings (mild clitoromegaly, pigmentation of the tongue and gingiva) as well as laboratory data (17-OHP >93.5 ng/ml by ELISA 7 prime extractive method in filter paper-dried blood spot and 718.3 ng/ml by RIA after high performance liquid chromatography extraction in serum; plasma ACTH 690 pg/ml; and serum testosterone 3,169 ng/dl). We examined her urinary steroid profiles by gas chromatography/mass spectrometry in selected ion monitoring (GCMS-SIM) at 8 d of age. The pregnanetriolone (Ptl) level was noticeably high (0.80 mg/g creatinine), which was strongly suggestive of 21-OHD. Gene analysis of CYP21A2 showed compound heterozygosity, one allele having a cluster mutation in exon 6 and the other having a large deletion including CYP21A2, confirming the diagnosis of 21-OHD. This case suggested that, in preterm infants, urinary Ptl by GCMS-SIM can be useful for the biochemical diagnosis of 21-OHD. PMID- 24790301 TI - Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children. AB - Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt. PMID- 24790302 TI - Effect of testosterone on bone mineral gain: observations of male patients with growth hormone deficiency and normal gonadotropin secretion. PMID- 24790303 TI - Treatment for childhood type 2 diabetes. AB - Urine glucose screening at school implemented in Japan is useful for detecting childhood type 2 diabetes at the early stage of the disease. Most patients detected by the screening can improve hyperglycemia and reduce overweight within one to three months by changing lifestyle with diet and exercise. For patients who are unable to alter their lifestyle and for those who have hyperglycemia despite maintaining these changes, a variety of oral hypoglycemic agents, including alpha-glucosidase inhibitors, sulfonylureas, glitinides, metformin, thiazolidenediones, and insulin are available. Metformin is considered to be the most effective oral agent as monotherapy for Japanese young persons with type 2 diabetes, because most of them are obese with insulin resistance. The approach to insulin therapy in patients with type 2 diabetes often differs from that most frequently used in patients with type 1 diabetes. Adjustment of the dose of insulin at each injection using sliding scales or algorithms is not required in most cases. In some cases, combination therapy with metformin and sulfonylureas or use of insulin is more effective for stabilization of blood glucose values. Therapeutic means for childhood type 2 diabetes should be variable depending on each patient's characteristics. PMID- 24790304 TI - Longitudinal Observation of a Patient with Leri-Weill Dyschondrosteosis and SHOX Haploinsufficiency. AB - Haploinsufficiency of the short stature homeobox-containing (SHOX) gene causes Turner skeletal features, a certain proportion of idiopathic short stature and Leri-Weill dyschondrosteosis (LWD). Here we report a Japanese female with LWD. Her physical growth, skeletal deformity, and endocrine status were recorded longitudinally. She exhibited a constant growth rate (average + 6.2 cm/yr) from 6 to 9 yr old, followed by a downward shift at 10 yr old. Her final height was 135 cm (-4.4 SD for an adult female) and weight was 50.5 kg (-0.3 SD) at 12 yr and 10 mo old. Mesomelia and cubitus valgus were noticed from 2 yr old, and metaphyseal lucency and epiphyseal hypoplasia of the medial side of the distal radius were detected at 6 yr old. Madelung deformity was obvious at 10 yr old, when menarche occurred. Fluorescence in situ hybridization (FISH) analysis demonstrated a single copy of the SHOX gene. The short stature of the patient was thought to be exaggerated by the combination of SHOX haploinsufficiency and relatively early puberty. PMID- 24790305 TI - Absence of Heterozygous K83E and R257X Mutations of the AIRE-1 Gene in 46 Children with Type 1 Diabetes and 44 Children with Graves' Disease. AB - Type 1 diabetes mellitus (DM) and Graves' disease are autoimmune diseases, and a number of genetic factors, including HLA and CTLA-4 genes, have been reported to contribute to their etiology. The gene responsible for autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) has been cloned and named the autoimmune regulator-1 (AIRE-1) gene. AIRE-1 protein is thought to be a transcription regulatory protein and to have a role in the maintenance of immunological tolerance. The aim of this study was to determine whether heterozygous AIRE-1 gene mutations are associated with childhood-onset type 1 diabetes and Graves' disease in the Japanese population. We investigated 46 children with type 1 DM (29 females and 17 males; age at the time of diagnosis, 0.5-16 yr) and 44 children with Graves' disease (34 females and 10 males; age at the time of diagnosis, 3-16 yr) for the presence of the K83E mutation in exon 2 and the R257X mutation in exon 6 of the AIRE-1 gene. The alleles were identified by polymerase chain reaction of genomic DNA and restriction fragment-length polymorphism analysis (PCR-RFLP) with endonuclease TaqI. Since no patients with type 1 DM or Graves' disease were found to carry the K83E or the R257X heterozygous mutation, we concluded that neither the K83E nor the R257X heterozygous mutation in the AIRE-1 gene seem to be the cause of the more common isolated endocrinopathies, i.e., type 1 diabetes mellitus and Graves' disease, in Japanese children. PMID- 24790306 TI - Bilateral asynchronous adrenocortical adenoma in a girl with beckwith-wiedemann syndrome. AB - We report a case of asynchronous occurrence of bilateral adrenocortical adenoma in a 13-yr-old girl with Beckwith-Wiedemann syndrome. A right virilizing adrenal adenoma was surgically removed at age 6, following clinical manifestation of virilization such as acne, voice change, clitoris hypertrophy and overgrowth. Histopathological examination of the resected specimen revealed an adrenocortical adenoma predominantly composed of eosinophilic tumor cells expressing all the steroidogenic enzymes. High serum levels of DHEA-S (6,380 ng/ml) and testosterone (547 ng/dl) were noted prior to the operation. Postoperative course was unremarkable. Menstruation started at age 11, with a regular interval. At the age of 13 yr old, a high serum level of DHEA-S (8,250 ng/ml) was detected. In contrast to the episode of virilization at age 6, however, the serum testosterone level was not so high (122 ng/dl), and no clinical symptoms of virilization were apparent. Abdominal ultrasonography demonstrated the presence of a left adrenocortical adenoma. Pathological examination of the resected specimen revealed a circumscribed and well encapsulated tumor with essentially the same histological features as the tumor previously removed, except that the tumor cells showed a more prominent morphological similarity to the fetal adrenal cortex and did not express 3beta HSD. The absence of virilization at the second episode was due to the relatively low serum level of testosterone compared with that of DHEA-S. PMID- 24790307 TI - A novel mutation of the arginine vasopressin receptor 2 gene in a patient with congenital nephrogenic diabetes insipidus. AB - We have identified a novel mutation of the arginine vasopressin receptor 2 (AVPR2) gene in a case of congenital X-linked nephrogenic diabetes insipidus (NDI). The patient was a 2-mo-old Japanese boy with persistent fever and failure to thrive. He was diagnosed as having congenital NDI by clinical and laboratory findings. Molecular analysis demonstrated that he was hemizygous for a G to C transversion in exon 2 of the AVPR2 gene which resulted in a glycine to arginine substitution (G107R) at the 107th codon of the first extracellular loop. His mother was heterozygous for the same mutation. We speculated that the G107R mutation would interfere with the binding capacity of the AVPR2, since G107R is located near F105 and R106, both of which are crucial for ligand binding. In cases of X-linked NDI, mutations in the AVPR2 gene are distributed widely. Thus, DNA analysis throughout the gene is of clinical value for the identification of female carriers, and it also gives precise information for genetic counseling. PMID- 24790308 TI - Cerebral hemorrhage in turner syndrome: a case report. AB - We report the case of a 21-yr-old female with Turner syndrome associated with cerebral hemorrhage (CH). She was transferred to our hospital for loss of consciousness and was diagnosed with right putaminal hemorrhage. Following surgical removal of the hematoma, she regained consciousness, and her left hemiplegia gradually improved after surgery. Angiography revealed absence of vascular abnormality of the cerebral artery, aorta, and renal arteries. Hypertension was noted on arrival at the hospital and persisted after surgery. A slight hypertensive change was observed in her retinas. Plasma renin activity was elevated (20 ng/ml/h) and renovascular hypertension was suspected. In this patient, CH was suspected to have occurred due to hypertension. This case emphasizes the necessity to carefully monitor the blood pressure in Turner syndrome cases, even during childhood. PMID- 24790309 TI - Two cases of pseudohypoparathyroidism type ia in duozygotic twins with different phenotypes. AB - Pseudohypoparathyroidism (PHP) type Ia is characterized by hypocalcemia due to PTH resistance and by features of Albright's hereditary osteodystrophy, including short stature, obesity, subcutaneous calcification and brachydactyly. A wide variety of clinical and biochemical manifestations have been reported. We report two cases of PHP type Ia in duozygotic twins with different phenotypes. The proband was a 10-yr-old girl. She showed subcutaneous ossification, shortening of the metacarpal bone, short stature, obesity and round face. She had normocalcemia (8.9 mg/dl), high-normal phosphate (5.0 mg/dl) and increased levels of serum intact PTH (152 pg/ml) and TSH (9.17 MUIU/ml) levels. Her twin younger brother had atypical Albright's hereditary osteodystrophy with only mild obesity and subcutaneous calcifications, but he showed a low level of serum calcium (7.0 mg/dl) and high levels of serum phosphate (7.6 mg/dl), intact PTH (377 pg/ml) and TSH (6.9 MUIU/ml). We diagnosed them as having PHP type Ia on the basis of clinical and biochemical findings, Ellsworth-Howard test and family history. There is considerable variability in clinical and biochemical features of PHP type Ia even among affected duozygotic twins. The differences of intrauterine environment and growth history cannot account for the variable phenotypes of PHP type Ia. Even if a patient shows no AHO features, examination of all family members should be undertaken. PMID- 24790310 TI - Short stature and turner skeletal features in an 11-year-old boy with a ring y chromosome missing the short stature homeobox containing gene. AB - We report on an 11-yr-old boy with short stature and Turner skeletal features. Chromosome analysis revealed a 46,X,r(Y)(p11.3q11.2) karyotype, and FISH analysis showed loss of the Short stature homeobox containing gene (SHOX) from the ring Y chromosome. The results are consistent with the association of SHOX haploinsufficiency with short stature and Turner skeletal features, and suggest the importance of SHOX analysis in boys with Turner-like skeletal phenotype. PMID- 24790311 TI - Retrospective analysis of infants designated as positive on mass-screening for congenital hypothyroidism at kagoshima university. AB - Mass-screening for congenital hypothyroidism has identified cases of mild hypothyroidism, transient hypothyroidism, and transient hyperthyrotropinemia as well as typical hypothyroidism. In this paper, we examine the clinical data of the cases found positive in the screening test at our hospital. From 1989 to 1999 there were 72 patients with positive screening tests who started levothyroxine sodium (l-T4; Thyradin-S) as supplement therapy. At the age of 3 to 4 yr the patients were re-evaluated to determine whether treatment should be continued. Thyroid scintigraphies were done at the same time. We divided these cases into 4 groups. Those in group 1A started l-T4 in early infancy without a TRH test because of obvious clinical evidence of hypothyroidism, and treatment was continued after re-evaluation (n=37). Those in group 1B also started treatment in early infancy without a TRH test, but treatment was discontinued after re evaluation (n=20). Patients in group 2A started l-T4 after evaluation by a TRH test and treatment was continued after re-evaluation (n=14), while those in group 2B started treatment after a TRH test, but after re-evaluation, treatment was discontinued (n=1). In group 2A, only a low dose of l-T4 was needed, and a slightly elevated TSH and slightly decreased free T4 (FT4) were observed after the drug washout period. However, these patients had an exaggerated response to the TRH test at re-evaluation. These findings indicate that this group, forming not a small part of whole screening-positive subjects, had mild hypothyroidism. Such patients require careful follow-up and repeated evaluation to determine whether treatment should be continued. PMID- 24790312 TI - A case with hyperthyroidism who had been treated with thyroid hormone because of congenital hypothyroidism. AB - We encountered a case with hyperthyroidism at the age of 14 who had been diagnosed with congenital hypothyroidism (CH) and had received thyroid hormone replacement therapy. At the age of 16 d, the patient was referred to our hospital because of positive results at neonatal screening for CH. Serum level of TSH was 91.0 MUU/ml and serum level of T4 was 6.9 MUg/dl. The patient was diagnosed as having hypothyroidism, and hormone replacement therapy was started. Thereafter the dosage of thyroid hormone was adjusted and increased gradually as he grew to a maximum dose of 110 MUg/day at the age of 11. Until the age of 13, the patient's serum levels of TSH were within the normal range; then, at the age of 13 yr and 4 mo, his serum level of TSH dropped to a level below the detectable range. The dosage of administered thyroid hormone was tapered off and eventually eliminated at the age of 14. A thyroid scan and a radioactive iodine uptake test demonstrated a diffuse goiter with homogeneous uptake of radioactive iodine; the uptake rate was 60% at 24 h, and the serum level of TSH receptor antibody (TRAb) was 62.5% at that time. Administration of an antithyroid drug was started after confirmation that our patient had developed hyperthyroidism. There have been no case reports similar to our case. PMID- 24790313 TI - Survey of current medical treatments for childhood-onset type 2 diabetes mellitus in Japan. AB - The prevalence of childhood-onset type 2 diabetes mellitus has increased dramatically over the past two or three decades in Japan, but epidemiological and clinical data remain limited. This survey was conducted to elucidate the current use of antidiabetic medications and the efficacy, safety and problems associated with the use of these agents. Clinical data on 259 children (younger than 18 yr of age; 121 boys and 138 girls) with type 2 diabetes treated at 42 medical centers throughout Japan between June and September 2003 were analyzed. Sixty nine percent of all the type 2 diabetic patients (78% of the boys, 63% of the girls) were obese (percent overweight >= 20%) at the time of diagnosis. Overall, 172 subjects (66%) were treated using anti-hyperglycemic agents, including alpha glucosidase inhibitors (alpha-GI), insulin, metformin and sulfonylureas (SUs). Many patients who were initially treated with a single medication eventually required insulin alone or in combination with an additional agent, suggesting that their diabetic control had deteriorated during the course of treatment. The HbA1c level of the 14 subjects who received only metformin decreased significantly without an improvement in obesity. Three cases with adverse events were reported, but causal relations with anti-hyperglycemic agents were not clear. In conclusion, mainly alpha-GI, insulin and metformin have been prescribed for childhood-onset type 2 diabetes patients in Japan. The results of this survey suggest that metformin is safe and effective for the treatment of type 2 diabetes with obesity in children and adolescents. PMID- 24790315 TI - No Improvement of Adult Height in Non-growth Hormone (GH) Deficient Short Children with GH Treatment. AB - It is still in doubt whether the standard-dose growth hormone (GH) used in Japan (0.5 IU/kg/week, 0.167 mg/kg/week) for growth hormone deficiency is effective for achieving significant adult height improvement in non-growth hormone deficient (non-GHD) short children. We compared the growth of GH-treated non-GHD short children with that of untreated short children to examine the effect of standard dose GH treatment on non-GHD short children. GH treatment with recombinant human growth hormone (rhGH) was started before the age of 11 yr in 64 boys and 76 girls with non-GHD short stature registered at the Foundation for Growth Science who have now reached their adult height. In 119 untreated boys and 127 untreated girls whose height standard deviation score (SDS) was below -2 SD at the age of 6 yr, height growth was followed until 17 yr. Height SDS was significantly lower before GH treatment in the GH-treated group than at the age of 6 yr in the untreated group, in both sexes. Adult height and adult height SDS were significantly greater in the untreated group than in the GH-treated group, in both sexes, although the change in height SDS did not differ significantly. Height SDS was significantly lower before GH treatment in the GH-treated group than at the age of 6 yr in the untreated group, so 57 boys and 57 girls whose height SDS at the age of 6 yr in the untreated group closely matched the height SDS before GH treatment in the GH-treated group were chosen for comparison. Height SDS did not differ significantly between the GH-treated group before GH treatment and the untreated group at the age of 6 yr, nor were there differences between these subgroups in adult height, adult height SDS, or height SDS change, in either sex. The effect of GH treatment is reported to be dose-dependent and doses over 0.23 mg/kg/week are reported to be necessary to improve adult height in non-GHD short children. Currently, the GH dose is fixed at 0.175 mg/kg/week in Japan, and we expected to find, and indeed concluded, that ordinary GH treatment in Japanese, non-GHD short children does not improve adult height. PMID- 24790316 TI - A spectrum of clinical presentations in seven Japanese patients with vitamin d deficiency. AB - Recently, the reemergence of vitamin D deficiency in developed countries has been pointed out. Vitamin D deficiency is diagnosed based on the serum 25 hydroxyvitamin D (25OHD) level. However, its normal range is still controversial, making the diagnosis of vitamin D deficiency difficult. Here, we present seven Japanese patients diagnosed with vitamin D deficiency. Three patients complained of leg bowing, and the other four of tetany. The patients with leg bowing were toddlers. Radiographic surveys demonstrated evidence of rickets. Laboratory findings showed decreased levels of serum inorganic phosphorus and increased levels of alkaline phosphatase (ALP) and intact-parathyroid hormone (iPTH). The serum levels of 25OHD were relatively low, ranging from 13 to 15.2 ng/ml. Of the patients with tetany, three were young infants. Laboratory findings showed decreased levels of serum calcium and increased levels of ALP and iPTH. The serum levels of 25OHD were markedly decreased (below 8 ng/ml). Thus, these results indicate that relatively low levels of 25OHD can cause rickets, a symptom of vitamin D deficiency, and that clinicians should therefore carefully evaluate the levels of 25OHD. PMID- 24790314 TI - Leptin and its emerging role in children and adolescents. AB - Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent "proof of concept" studies involving leptin administration to humans support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/ caloric deprivation. Moreover, interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. The potential clinical usefulness of leptin in several disease states in children and adolescents, including hypothalamic amenorrhea, eating disorders and syndromes of insulin resistance is still under investigation. PMID- 24790317 TI - Nutrient-enriched Diet in the Early Neonatal Period Influences the 3 year-old Height in Very Low Birth Weight Infants. AB - Nutrient-enriched milk has been advocated to enhance premature infants'growth and early nutritional intervention is effective for growth failure in very low birth weight infants (VLBWI). We studied the 3-yr-old physical growth of VLBWI who received nutrient enriched diets in the early neonatal period. VLBWI, who were born in 1996, received nutrient enriched milk around 1 mo of age. By contrast, in VLBWI born in 1998, nutrient enriched milk was started at 1-2 wk after birth. The daily calorie intake of VLBWI in 1998 had a tendency to be high compared to that of VLBWI in 1996. Height and body weight SD of 3-yr-old children who were born in 1998 tended to be greater than those of children who were born in 1996 (mean +/- SD, -0.27 +/- 0.54 vs. -1.01 +/- 0.67; p=0.043, -0.47 +/- 0.61 vs. -0.97 +/- 1.10; p=0.31). Our study suggests that early feeding of nutrient-enriched milk for VLBWI in the neonatal period may affect their growth. PMID- 24790318 TI - Three-Year Follow-up Study on Serum Leptin Levels in GH Deficient Children with GH Replacement Therapy. AB - Interactions between GH and leptin have been extensively studied. However, results of long-term GH therapy on serum leptin levels in GH-deficient children were not consistent. Moreover, no such reports were available in Japanese children with this disease. We studied 35 Japanese patients with GH deficiency (26 boys and 9 girls, mean age: 9.8 +/- 6.2 yr old), of whom 6 patients with complete and 29 with incomplete GH deficiency were identified by GH provocation test. Serum leptin levels, percent of ideal body weight (%IBW) and percent fat (%fat) were determined at 0, 1, 3, 6, 12, 18, 24, and 36 mo after beginning GH therapy. Baseline levels of %fat and leptin were significantly higher in girls than boys (P<0.05), though serum leptin did not change throughout the study period in either group. Further, %IBW did not change significantly, whereas %fat exhibited significant changes after 6 mo in boys and remained virtually constant thereafter for up to 3 yr. In summary, serum leptin levels did not change in GH deficient boys and girls during the 3-yr period after the start of GH replacement therapy, despite a decrease in %fat after 6 mo of therapy in the boys. Thus, it is conceivable that long-term GH replacement therapy can be employed without an effect on normal leptin secretion. PMID- 24790319 TI - A novel v2 vasopressin receptor mutation with x-linked nephrogenic diabetes insipidus. PMID- 24790320 TI - Genetics of human growth. AB - Genes involved in human growth consist of major growth genes and minor growth genes. Major growth genes have fundamental effects on human growth, and their mutations cause growth failure (or overgrowth) which are recognizable as single gene disorders. Minor growth genes exert relative minor additive effects on human growth, and their combination is involved in the development of short (or tall) stature as a multifactorial trait. This review summarizes the current knowledge about the major and the minor growth genes, and refers to the recent molecular approach of identification of the growth genes. PMID- 24790321 TI - A Case Report of Turner Syndrome with Graves' Disease during Recombinant Human GH Therapy and Review of Literature. AB - An increased incidence of Hashimoto thyroiditis has been reported in patients with Turner syndrome, but several cases of Graves' disease were also described ten to 20 years ago. We report the case of a patient with Turner syndrome who developed Graves' disease, 3 years after successful treatment with recombinant human growth hormone (GH). A diagnosis of Graves' disease was made and treatment with thiamazole was started, which resulted in normalization of the thyroid function. It is important to monitor thyroid function as well as growth parameters in patients with Turner syndrome. PMID- 24790322 TI - Prevalence of Mutations in the FGFR3 Gene in Individuals with Idiopathic Short Stature. AB - FGFR3 (fibroblast growth factor receptor 3) is a gene responsible for the most common form of osteodysplasia, achondroplasia, which results in extreme short stature. An allelic disorder, hypochondroplasia, however, presents with a much milder phenotype and is sometimes indistinguishable from idiopathic short stature. In this study, in order to test the possibility of the mildest end of hypochondroplasia being labeled as idiopathic short stature and the possibility of polymorphism of FGFR3 acting as one of the stature genes of normal individuals, we examined the prevalence of sequence alterations of the FGFR3 gene among individuals diagnosed clinically with idiopathic short stature. Sequencing analysis of all exons of the FGFR3 gene on 54 individuals with idiopathic short stature did not reveal any sequence variations related to the stature of the individuals. These results suggest that hidden hypochondroplasia among idiopathic short stature individuals is not a common occurrence and the contribution of polymorphism of the FGFR3 gene as a determinant of stature in normal individuals is small if any. PMID- 24790323 TI - G-protein Stimulatory alpha Subunit Is Involved in Osteogenic Activity in Osteoblastic Cell Line SaOS-2 Cells. AB - In an attempt to study the roles of G-protein stimulatory subunit alpha (Gsalpha) in osteoblasts, we introduced an expression vector encoding Gsalpha into human osteoblastic cell line SaOS-2, and established the clones stably overexpressing Gsalpha (SaOS-2-Gsalpha). In SaOS-2-Gsalpha, the intracellular content of cyclic AMP (cAMP) was increased compared with the parental SaOS-2 cells. In addition, when treated with PTH[1-34], SaOS-2-Gsalpha exhibited more accumulation of intracellular cAMP compared with the parental cells, suggesting an increased responsiveness to PTH. We evaluated the proliferation rates of SaOS-2-Gsalpha and the parental SaOS-2 cells, and found that the proliferation was accelerated in SaOS-2-Gsalpha cells. Reverse transcription-polymerase chain reaction (RT-PCR) analyses exhibited the increased expression of Runx2, a transcription factor involved in osteoblast differentiation, in SaOS-2-Gsalpha cells. Finally, to examine the osteoblastic function in vivo, we inoculated SaOS-2-Gsalpha or parental SaOS-2 cells subcutaneously to immunocompromised nude mice. Although tumors in nude mice were not formed after inoculation of parental SaOS-2 cells, SaOS-2-Gsalpha cells proliferated in host animals leading to the formation of tumors with mineralized bone-like tissues. Taken together, these results suggest that the signals via Gsalpha play critical roles in the proliferation and osteogenic functions of osteoblasts. PMID- 24790324 TI - Relatively small birth size and accelerated early growth of Japanese type 1 diabetic children with younger onset. AB - We investigated the changes of anthropometrical parameters in Japanese children with type 1 diabetes (T1DM) from birth to the onset of diabetes. One-hundred ninety-nine children (79 males and 120 females) diagnosed between 0-16 yr of age during the period between 1990 and 2003 were the subjects of this study. The subjects were categorized into 3 groups according to onset age (0-5 yr; n=74, 5 10 yr; n=61, 10-16 yr; n=64). At birth, the younger onset (<5) group had significant lower height and weight standard deviation score (SDS) compared with the older onset (5<=) group (p=0.01 and p=0.02, respectively). When the changes in height SDS from birth to onset were compared, height SDS at onset were significantly greater than those at birth in the younger onset group (p<0.001). However, no significant difference was observed in the other groups (p=0.95 and p=0.39). These results suggest that relatively small size at birth and accelerated growth after birth until the onset of diabetes may be a characteristic of Japanese T1DM children with younger onset and may further support the hypothesis that emphasizes accelerated growth and subsequent insulin resistance as a cause of earlier onset of T1DM. PMID- 24790325 TI - Standardization of blood growth hormone levels measured by different kits using a linear structural relationship. AB - Accurate and reliable determination of blood growth hormone level is essential in the diagnosis and treatment of short stature children. However, measured levels differed considerably among measurement kits available in Japan until 2003. Therefore, standardization of the measured values was attempted by measuring growth hormone levels in a sample of healthy adult individuals every year using the different kits. A standardization equation was developed for each kit through linear structural relationship with the mean values of the used kits and measured values in each kit as random variables. A Pearson's correlation coefficient between the mean values of all kits and the measured values from each kit was also obtained. Sources for the marked discrepancies amongst the measured values in the different kits were also explored. The obtained values for slopes and intercepts in the equations varied considerably, but the standard values obtained from these equations after the measured values for each kit were transformed into standard values served well as the standard. The standard solutions in the respective measurement kits were found to be the source of variability in the measured values among the kits. PMID- 24790326 TI - Two children with xanthogranuloma of the sellar region. AB - We report the cases of two Japanese children with cystic pituitary enlargement on magnetic resonance imaging (MRI) causing central diabetes insipidus (DI). In the first patient, endocrinological examination demonstrated slightly impaired growth hormone and thyroid stimulating hormone secretions, but normal responses of other anterior pituitary hormones. The second patient had normal basal levels of anterior pituitary hormones. Transsphenoidal resection of the tumors was performed in both patients. Histological analysis of the tumor sections demonstrated granulomatous tissue with cholesterol clefts, foamy macrophages, multinucleated giant cells and no epithelial component. Thus, these tumors were pathologically diagnosed as xanthogranuloma of the sellar region, different from adamantinomatous craniopharyngioma. Post-operatively, the two patients continue to have DI, however other hormone replacement therapy after one year of follow-up has not been required. Currently, it is not clear whether xanthogranuloma is a distinct entity from adamantinomatous craniopharyingioma. Although, to our knowledge, a clinical report of xanthogranuloma of the sellar region has not been reported at pediatric age, it would be included in the differential diagnosis of the sellar region. PMID- 24790327 TI - Dose Adjustments of Hydrocortisone and L-thyroxine in Hypopituitarism Associated with Cholestasis. AB - A patient with congenital hypopituitarism associated with cholestasis is reported here. Large doses of fat-soluble hormones (hydrocortisone (20 mg/m(2)/day) and L thyroxine (14 MUg/kg/day)) were needed to resolve hypoglycemia and hypothyroidism during cholestasis. The doses could be reduced to 10 mg/m(2)/day and 3.5 MUg/kg/day, respectively, after improvement of cholestasis. Sodium valproate, which is a water-soluble drug, did not need any dose adjustments during cholestasis. Adjustment of fat-soluble hormone doses during cholestasis should be considered in patients with cholestasis. PMID- 24790328 TI - Turner syndrome associated with ulcerative colitis. AB - We report the case of a 7-yr-old girl with Turner syndrome, ulcerative colitis (UC) and coarctation of the aorta. The diagnosis of Turner syndrome was made in early infancy (karyotype analysis 45, X). Growth hormone treatment was started at 3 yr and 2 mo of age. From the age of 4 yr and 5 mo, the patient suffered from persistent diarrhea with traces of blood and intermittent abdominal discomfort. As these symptoms gradually deteriorated, she was referred to our clinic at the age of 7 yr for further evaluation. Barium enema showed aphtha and loss of the fine network pattern in the descending colon and rectum. An endoscopic examination showed ulceration, edema, friability, and erythema beginning in the rectum and extending up to the splenic flexure of the descending colon. The histology of the descending colon area showed severe stromal infiltration of inflammatory cells. These endoscopic findings and the histological findings were consistent with UC. Thus, based on these findings, the patient was diagnosed as having UC. Mesalazine therapy was initiated at this time. The patient is currently being treated with mesalazine (1,000 mg/day) and abdominal symptoms and bloody diarrhea have disappeared. GH therapy was not interrupted during the therapy for UC. Retrospectively, growth hormone improved growth velocity (9 cm/year) during the first year of treatment, however from the age of 4 yr, growth velocity decreased (4-5 cm/yr) in spite of the GH treatment. CONCLUSION: Patients with Turner syndrome and gastrointestinal symptoms should be investigated for inflammatory bowel diseases. Growth velocity is useful for evaluating the presence of inflammatory bowel diseases and other systemic diseases. PMID- 24790329 TI - Beneficial Effect of Oral Bisphosphonate Treatment on Bone Loss Induced by Chronic Administration of Furosemide without Alteration of Its Administration and Urinary Calcium Loss. AB - Bisphosphonate is widely used to treat patients with primary and secondary osteoporosis. The chronic administration of furosemide is considered a risk factor for osteoporosis mainly due to the increased urinary excretion of calcium, leading to a long-term negative balance of calcium. We describe two patients with mild heart failure who took furosemide for more than 5 yr and developed hyperparathyroidism and lumbago associated with low bone mineral density. Their serum levels of intact parathyroid hormone and bone mineral density (BMD) of the lumbar spine (L2-L4) were 180.8 and 144.3 pg/ml, and 71% and 80% of the mean of healthy women, respectively. The oral administration of alendronate or risedronate was effective for lumbago and improved BMD, although the urinary excretion of calcium and hyperparathyroidism were not changed. For the medical treatment of lumbago and decreased bone mass secondary to the long-term administration of furosemide, bisphosphonate is proposed when the dose of furosemide cannot be reduced. However, it may be important to give sufficient calcium and vitamin D to patients to improve secondary hyperparathyroidism. PMID- 24790330 TI - Limitations of G-banding Karyotype Analysis with Peripheral Lymphocytes in Diagnosing Mixed Gonadal Dysgenesis. AB - Mixed gonadal dysgenesis (MGD) is an abnormal sexual differentiation syndrome usually presenting with ambiguous genitalia. Karyotype analysis is one of the essential components in the diagnosis of MGD and is conventionally done with peripheral lymphocytes by the G-banding technique. It is speculated that this conventional karyotype analysis has limitations since there are often difference in gonadal tissue analysis. Here we present four cases of MGD, in which karyotype analysis were performed by peripheral lymphocytes fluorescence in situ hybridization (FISH), gonad fibroblasts FISH and gonad fibroblasts G-banding technique, in addition to the conventional peripheral lymphocytes G-banding technique. In Case 1, the percentage of the 45,X cell line in lymphocytes decreased after birth and detection of mosaicism could only be done by karyotype of gonads at 7 mo of age. In Case 2, FISH analysis with peripheral lymphocytes was more useful for detecting low frequency mosaicism. In all cases, phenotype of gonads and external genitalia were more consistent with karyotype of gonads than that of the peripheral lymphocytes G-banding technique. In conclusion, conventional G-banding karyotype analysis with peripheral lymphocytes has limitations in the diagnosis and evaluation of MGD. Karyotype analysis by FISH or by using gonads is useful for diagnosing MGD and understanding of the phenotype of gonadal tissue. PMID- 24790331 TI - Clinical Evaluation of the Needle-free Injection System VISION((r)) for Growth Hormone Therapy in Children. AB - The aim of this study was to compare the therapeutic effects of rhGH administered either by subcutaneous needle-injection (pens) or subcutaneous needle-free jet injection (VISION((r))). Furthermore, a survey was carried out after using VISION((r)) for 12 mo. A needle-free injection group consisting of 18 subjects (11 males and 7 females, mean age 5.87 +/- 2.05 yr at the start of hGH therapy) who have not used pen injectors to date, were allowed to use VISION((r)) in their third to fifth years of GH therapy. In addition, a group of 8 subjects who had been using pen injectors at our clinic (6 males and 2 females, mean age 6.54 +/- 2.78 at the start of GH therapy) was monitored as a control. The results indicate that there are no significant differences between the mean growth rates, growth rate SD scores or height SD scores when comparing injection devices. Furthermore, the survey of VISION((r)) revealed that 70% of the subjects found it slightly or not painful at or after injection, 70% found VISION((r)) very easy or easy to use, and 80% found the weight of the device appropriate. All subjects expressed a desire to continue using VISION((r)) in the future. Our results suggest that there are no problems with the effectiveness of hGH treatment with VISION((r)), a needle-free jet-injection device and that VISION((r)) is an effective device for children who have an aversion to needle injection. PMID- 24790332 TI - Lead and growth. AB - Lead is highly toxic to the human body and children are much more vulnerable to lead toxicity than adults. Many studies have revealed that relatively low levels of blood lead can adversely affect human health, especially childhood growth and development. Blood lead levels (BLL) of children and adults have been decreasing recently almost all over the world, but a safety level for blood lead does not exist, and lead exposure is still a serious health problem especially for fetuses and children. Maternal lead burden causes fetal lead exposure and increases the risk of abortions, prematurity, low birth weight, and some minor anomalies. Infant BLL are inversely associated with weight gain. A negative relationship between somatic growth and BLL in children has been revealed. It has been suggested that lead exposure causes decrease of gonadotropin secretion of adolescents and delay of pubertal development. Several studies have revealed that children who are exposed to cigarette smoke have higher BLL than children who are not. Children should be protected from cigarette smoke for the purpose of avoiding the risk of increased BLL which might adversely affect their intellectual development and physical growth. PMID- 24790333 TI - Molecular bases of diseases characterized by hypophosphatemia and phosphaturia: new understanding. AB - Serum phosphate levels are regulated in both calcium-dependent and -independent fashions. Active vitamin D increases while PTH decreases serum phosphate levels in association with the elevation of serum calcium. On the other hand, a calcium independent phosphaturic factor, historically called phosphatonin is believed to exert a physiological function based on findings in hereditary and tumor-induced diseases characterized by hypophosphatemia with normocalcemia. Among them, autosomal dominant hypophosphatemic rickets (ADHR) has contributed greatly to its elucidation because the gene responsible for ADHR encodes fibroblast growth factor 23 (FGF23) that has been found to have a phosphaturic effect. In addition, FGF23 has been proved to be involved in most cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets that are also characterized by hypophosphatemia and normocalcemia. Moreover, familial tumoral calcinosis, which represents the metabolic mirror image of hypophosphatemic conditions, is caused by a loss-of function mutation in the FGF23 gene in some patients. Very recently, hereditary hypophosphatemic rickets with hypercalciuria has been found to be caused by mutations in the SLC34A1 gene which encodes a type of sodium phosphate cotransporter. These findings may provide new strategies for treating patients with abnormal phosphate metabolism. PMID- 24790334 TI - Two Japanese patients with gitelman syndrome. AB - Gitelman syndrome (GS) is a renal tubular disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria due to defective tubular reabsorption of magnesium and potassium. This disease is caused by mutations of the thiazide-sensitive Na-Cl cotransporter (NCCT) gene, SLC12A3. Manifestations of GS are heterogeneous, from asymptomatic to mild symptoms of cramps and easy fatigue, to tetany and paralysis. Polydipsia, polyuria, and nocturia are also frequent in GS patients. Here we describe two Japanese patients with GS followed as nocturnal enuresis. In the first patient, occasional muscle cramps, easy fatigue and headache led to the diagnosis of GS. The parents of this patient reported that he had been affected by polydipsia and polyuria, especially nocturnal enuresis from early childhood. The second patient was referred to our clinic because of muscular weakness and cramps. He had a past history of transient muscle weakness and muscle cramps. He had also suffered from nocturnal enuresis since 3 yr of age. Laboratory findings of these patients were consistent with those of GS. Sequencing analysis of the SLC12A3 gene from two patients showed four mutations, which were previously reported. In our two patients, their manifestations had been underestimated and the correct diagnosis was delayed. GS is generally likely to be benign, however signs of GS are found in early childhood. Especially, we must recognize that nocturnal enuresis is frequent in symptoms of GS. PMID- 24790335 TI - Gonadal Function in 15 Patients Associated with WT1 Gene Mutations. AB - Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are caused by mutations of the WT1 gene. These disorders are characterized by renal disease, abnormality of male sex differentiation, and Wilms' tumor and gonadoblastoma. There have been few reports on gonadal function in a large series of patients with mutations of the WT1 gene. Here, we evaluated the relation between gonadal function and the phenotype of external genitalia in 15 Japanese patients with WT1 mutations. We confirmed three sets of information. First, if a diagnosis of DDS and FS is arrived at by genetic analysis, there are some overlaps in the phenotypes of external genitalia and renal complications. Second, the responses of serum T for the human CG (HCG) loading test coincided with the phenotype of external genitalia in both DDS and FS, except two patients. One DDS patient had male type external genitalia with a low level of serum T response, and one FS patient had complete female external genitalia despite a definite serum T response to HCG stimulation. Third, four FS patients had incomplete development of pubic hair, together with low DHEA-S levels. PMID- 24790337 TI - Discrepancies between Physician and Parent Perceptions of Psychosocial Problems of GHD Children Undergoing GH Therapy in Japan. AB - This study examined discrepancies between the perceptions of physicians treating short children with GH deficiency (GHD) using GH replacement therapy (GHRT) and the perceptions of the parents of these children and identified the major causes of parental anxiety. Three attending pediatric endocrinologists and the parents of 31 GHD children participated in this study. The physicians and parents completed a specially designed questionnaire to rate the types and degrees of psychosocial problems that GHD children might experience. For 6 of the first 11 questions, the physicians rated psychological problems differently than the parents did, tending to over- or underestimate parental concerns. This discrepancy did not disappear with treatment. However, the difference in the perception of anxiety between the physicians and parents changed for issues regularly discussed between them. Physicians and nurses were ranked as the most reliable providers of information. The parents of children who had previously undergone GHRT were a highly desired source of information. Psychosocial problems remain largely unaddressed by endocrinologists. Endocrinologists treating short stature are encouraged to be more involved in understanding parents' anxieties, evaluation of misperceptions concerning parents' expectations, and addressing these issues in future communication with parents. Support by experienced psychologists may help endocrinologists with this issue. PMID- 24790336 TI - Mutational Analysis of Androgen Receptor (AR) Gene in 46,XY Patients with Ambiguous Genitalia and Normal Testosterone Secretion: Endocrinological Characteristics of Three Patients with AR Gene Mutations. AB - The prevalence of abnormalities in androgen receptor gene (AR) among patients with ambiguous genitalia is unknown. Moreover, endocrinological data from prepubertal patients with AR mutation are very limited. Thus, the aim of this study was to examine the prevalence of abnormalities in AR among patients with both ambiguous genitalia, which was defined as a combination of two or more genital abnormalities (i.e. hypospadias, microphallus (penile length < 25 mm), hypoplastic scrotum, bifid scrotum, undescended testis) in this study, and normal to elevated T levels. We also compared the endocrinological data of prepubertal patients with AR mutation and ambiguous genitalia with that of those without the AR mutation. We screened 26 Japanese prepubertal 46,XY patients (five from three families were included) with both ambiguous genitalia and normal to elevated T levels. Mutations in AR were found in three (two of the three were related). Among the 23 patients without mutation in AR, the steroid 5-alpha-reductase 2 gene (SRD5A2) was also examined in eight patients with elevated T/dehydrotestosterone ratio after the hCG (>10) or with undervirilized family members. No mutation in SRD5A2 was found. Characteristics of the three patients with mutation in AR were compared with the 23 patients without mutation. In two patients, basal T levels (0.3, 0.2 ng/ml) and peak T levels after the hCG tests (8.3, 8.5 ng/ml) tended to be higher, and the peak LH/ peak FSH ratios after the GnRH tests (4.6, 4.0) were higher than in patients without mutation, at the ages of 1 yr and 9 mo and 3 yr and 8 mo, respectively. In conclusion, an abnormality in either AR or SRD5A2 was not common among patients with ambiguous genitalia and normal testosterone secretion. Elevated peak LH/peak FSH ratio (>=4) after the GnRH test in addition to detectable basal T levels and elevated peak T levels after the hCG test may infer AR abnormality in prepubertal patients with ambiguous genitalia at the age of one and over, although further study is needed, because our data were limited. PMID- 24790338 TI - Prevalence of obesity, hyperlipemia and insulin resistance in children with suprasellar brain tumors. AB - Weight gain is a common sequela of suprasellar tumors, referred to as hypothalamic obesity. We undertook an evaluation of obesity and metabolic aberrations among patients treated at our institute. During the 12 mo from Apr. 2005, 23 patients (10 males and 13 females) with remitted suprasellar tumors attended our clinic: 10 patients with craniopharyngioma, 7 with germinoma, 4 with optic nerve glioma and others. Of these, 12 patients (52%) were found to have obesity on the basis of percent overweight and/or percent body fat. Elevated cholesterol and/or triglyceride (TG) was found in 9 patients (39%), and insulin resistance was suspected in 7 patients (30%). Three patients exhibited strikingly elevated postprandial TG levels. All 6 patients with the growth without GH phenomenon had at least one metabolic aberration. In conclusion, the prevalence of hypothalamic obesity was nearly half in our series, and hyperlipemia and insulin resistance were also frequently found. The increased risk for metabolic aberration in growth without GH patients was suggested. PMID- 24790339 TI - A case of primary hyperparathyroidism in childhood found by a chance hematuria. AB - A 10-yr-old boy visited Minoh City Hospital complaining of gross hematuria. Laboratory investigations revealed hypercalcemia, hypophosphatemia, and elevated serum levels of parathyroid hormone. A stone was found in the right ureter with drip infusion pyelography. A parathyroid adenoma was successfully diagnosed with computed tomography, ultrasonography, and methoxy-2-isobutyl isonitrile (MIBI) scintigraphy. Multiple endocrine neoplasia was ruled out by normal results of endocrine laboratory examinations. Extracorporeal shock wave lithotripsy was performed to treat the urolithiasis, and the parathyroid adenoma was surgically removed. Primary hyperparathyroidism is rare in childhood; however, this case suggests that gross hematuria is an important sign of hyperparathyroidism. PMID- 24790340 TI - The circadian variation of cortisol secretion in patients with anorexia nervosa in childhood and adolescence after recovery of body weight by treatment using gas chromatography/mass spectrometry in selected ion monitoring. AB - Anorexia nervosa (AN) is a chronic psychiatric disorder which is characterized by patient-induced weight loss. Complications in many organ systems can be seen in AN such as cardiovascular, gastrointestinal, and endocrine system including hypothalamic-pituitary-adrenal axis, even after recovery of body weight by treatment. Urinary steroid profile analysis using gas chromatography/mass spectrometry (GC/MS) in selected ion monitoring (SIM) has been reported to be useful for the diagnosis of abnormal steroidogenesis in newborn infants, childhood, and adults. The aim of this study was to analyze the circadian variation of cortisol secretion in patients with anorexia nervosa (AN) in childhood and adolescence after recovery of body weight by treatment using GC/MS in SIM. The subjects were 7 healthy young adults (20-23 yr of age, BMI 19.7-24.8 kg/m(2)) and 5 AN patients in childhood and adolescence (13-19 yr of age), who had recovered body weight by treatment (BMI 15.4-19.3 kg/m(2); 3(rd)-25(th) to 50(th) percentile). Urine samples were collected for 26 hours (from 21:00 to 23:00 next day) at each urination. In each sample, the cortisol metabolites were measured by GC/MS in SIM. The sum of all cortisol metabolites was calculated as mg/g creatinine. In all 5 AN patients in childhood and adolescence, the circadian variation of the sum of cortisol metabolites was observed and was similar to that in healthy young adults. Although our data are preliminary, in patients with AN in childhood and adolescence, who have recovered body weight by treatment, the circadian variation of cortisol secretion may be conserved. PMID- 24790341 TI - Longitudinal growth of the short bones of the hand in a girl with pseudohypoparathyroidism type ia. AB - Brachydactyly is a common feature of pseudohypoparathyroidism (PHP) type Ia. We studied the longitudinal growth of the short bones in the hand of a 15-yr-old girl with PHP type Ia who had been followed for congenital hypothyroidism. Radiographs of the hand of the patient, who had been X-rayed every year since 2 yr of age, were studied. She showed cone-shaped epiphyses of the hand at 2 yr of age before showing brachydactyly. At 4 yr of age, she showed brachydactyly and an advanced bone age, and some short bones were prematurely fused at 6 yr of age. The short bones without cone-shaped epiphyses were also short as a result of a disturbance of the longitudinal bone elongation. In conclusion, the brachydactyly of PHP type Ia is thus considered to be caused by both early epiphyseal fusion with cone-shaped epiphyses and a disturbance of the longitudinal bone elongation. PMID- 24790342 TI - Characteristic Height Growth Pattern in Patients with Pseudohypoparathyroidism: Comparison between Type 1a and Type 1b. AB - Pseudohypoparathyroidism (PHP) is a metabolic disorder characterized by organ resistance to the action of parathyroid hormone. PHP type 1 is subclassified into two apparent disorders, type 1a (PHP1a) and type 1b (PHP1b). Patients with PHP1a show Albright hereditary osteodystrophy including short stature. Patients with PHP1b have no such skeletal defects, however, literature regarding the growth of PHP1b is not currently available. We evaluated growth charts of PHP patients, including four PHP1a patients and six PHP1b patients. Growth patterns were different between PHP type 1a and 1b. Adult height was abnormally low in all PHP1a patients. The growth pattern of PHP1a was characterized by mild growth impairment in the prepubertal period, a blunted growth spurt and premature cessation of the growth spurt. The adult height of male PHP1b was slightly lower than average. An early growth spurt was observed only in male patients with PHP1b and it may reduce the adult height of male patients with PHP1b. This warrants further investigation into the growth and pubertal development of PHP1b patients. PMID- 24790343 TI - Pituitary-adrenal axis during human development. AB - Investigation of early human fetal tissue has helped us elucidate the onset of the activation of the pituitary-adrenal axis during human development. Adrenal steroidogenesis and ACTH secretion from the pituitary starts at 7-8 weeks postconception, providing the rationale for prenatal treatment using dexamethasone offered to fetuses at risk of 21-hydroxylase deficiency (21-OHD). Fluctuation of 3beta-hydroxysteroid dehydrogenase (HSD3B2) in human fetal adrenal has several significant meanings. Its activity during early gestation is essential for inhibiting androgen production in the adrenal and safeguarding normal female sexual development. The enzyme may be reduced during mid-gestation in order to maintain pregnancy and to prevent preterm labor. Its reappearance in late gestation is also crucial for fetal maturation and parturition at term. Late onset circulation failure observed in extremely low birth weight newborns may be associated with the paucity of HSD3B2 in their adrenals. In fetuses with 21-OHD, a proportion of increased 17alpha-hydroxyprogesterone may be converted to dihydrotestosterone through the backdoor pathway and contribute to the virilization of female fetuses. PMID- 24790344 TI - Pregnanetriol in the Range of 1.2-2.1 mg/m(2)/day as an Index of Optimal Control in CYP21A2 Deficiency. AB - Auxological data is the gold standard index of the therapeutic condition in CYP21A2 deficiency over a long-range period, whereas urinary pregnanetriol for 24 h (PT) is variable for a shorter-range period. Ideal PT levels in comparison with auxological data have not been reported. The main purpose of this study was to analyze ideal PT values as an index of optimal control for CYP21A2 deficiency. First, inter-daily fluctuation of PT was analyzed in one participant. PT levels were distributed over a wide range of 0.44-14.7 mg/day (n=42) in this participant, suggesting that the therapeutic condition should be judged by multiple PT samples. Second, the therapeutic periods of 15 participants with CYP21A2 deficiency were classified using auxological data and Cushing-like symptoms, and the PT levels were analyzed in each period retrospectively. The 95% confidence intervals for the means of the PT levels in the excessive, good and poor control periods were 0.03-1.25 (n=26), 1.23-2.09 (n=116), and 5.35-8.37 (n=72) mg/m(2)/day, respectively. In conclusion, 1.2-2.1 mg/m(2)/day of PT values can be used as an index of optimal control in CYP21A2 deficiency. PMID- 24790345 TI - Recent change in the annual incidence of childhood type 2 diabetes in the Tokyo metropolitan area. AB - This study evaluated recent changes in the annual incidence of childhood type 2 diabetes in the Tokyo metropolitan area. From 1974 to 2004, a total of 236 students were diagnosed as having type 2 diabetes by the urine glucose screening program at school. The overall incidence of type 2 diabetes was 2.55/100,000. Overall, 83.9% of students with diabetes were obese; junior high school students had a significantly higher incidence than primary school students (0.75 vs. 6.27/100,000). The annual incidences over the 5-yr periods from 1974-2004 were 1.73, 3.23, 3.05, 2.90, 2.70 and 1.41/100,000, respectively. The incidences in 1974-1980 and 2001-2004 were significantly lower than those in 1981-1985, 1986 1990 and 1991-1995, because primary school students in 1974-1980 had a significantly lower incidence (0.27/100,000), and junior high school students in 2001-2004 had a somewhat lower incidence (3.66/100,000) than during 1981-2000. In recent years, Japanese children's lifestyle and eating habits have gradually improved, and this may have contributed to the trend toward decrease in the incidence of type 2 diabetes in 2001-2004 in the Tokyo metropolitan area. PMID- 24790346 TI - A novel mutation of androgen receptor gene in complete androgen insensitivity syndrome. PMID- 24790347 TI - Cholesterol Side-Chain Cleavage Enzyme (SCC) Deficiency. AB - Cholesterol side-chain cleavage enzyme (SCC) catalyzes the conversion of cholesterol to pregnenolone, the first step in the biosynthesis of all steroid hormones. It was once postulated that SCC deficiency would be lethal, but recent studies have established that SCC deficiency is an autosomal recessive disorder caused by inactivating mutations in the CYP11A1 gene. Clinical manifestations include adrenal insufficiency and 46,XY sex reversal due to disrupted steroidogenesis, which are similar to StAR deficiency. Further accumulation of patients with SCC deficiency should clarify the similarities and differences between SCC deficiency and StAR deficiency. PMID- 24790348 TI - Different skeletal phenotypes in a mother and two daughters with short stature homeobox-containing haploinsufficiency. AB - Haploinsufficiency of the short stature homeobox-containing (SHOX) gene causes Turner skeletal features such as short metacarpals, cubitus valgus, and Madelung deformity. We report the clinical findings of a Japanese family consisting of two daughters with SHOX haploinsufficiency (46, X, del(X) (p.22.3)) and their mother with 45,X [9]/ 46, X, del(X) (p22.3) [11] karyotype. Physical and auxological examinations revealed a mesomelic appearance, cubitus valgus, a short neck and short stature in the daughters, but on the other hand, only a short neck and short stature in the mother. Radiological studies indicated markedly curved radii in the daughters, but only mild curvature of the radii in the mother. Regular menstruation had taken place since the age of 12 yr in the elder daughter, but the mother had irregular menstruation and she had received fertility treatment for pregnancy. The different skeletal phenotypes of the mother and her daughters with SHOX haploinsufficiency might be due to the mild gonadal estrogen deficiency found in the mother, which was caused by mosaic Turner syndrome, and the phenotypic variability of SHOX haploinsufficiency. PMID- 24790349 TI - A case of persistent hyperinsulinemic hypoglycemia of infancy successfully managed with subcutaneous octreotide injection and nocturnal intravenous glucose supply. AB - Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is often resistant to medical therapy and is normally treated by subtotal pancreatectomy to avoid neurological complications. However, many problems after surgery, such as recurrence of hypoglycemia and diabetes mellitus, remain to be solved. This report concerns a case of PHHI that was resistant to octreotide or diazoxide alone but was successfully controlled with subcutaneous injection of octreotide in combination with nocturnal glucose infusion through central venous catheter. The patient exhibited natural remission of hyperinsulinism with age, and all treatment was ceased at the age of 4 yr. Growth and neurological development of the patient have been normal. This combined therapy can be a therapeutic option as a substitute for surgical solutions. PMID- 24790350 TI - An infant case of hyperprolactinemia induced by a functional disorder of the hypothalamus. AB - Although functional hyperprolactinemia originating in the hypothalamus has been observed, there have so far been few reports of this condition occurring in children. This report describes a 1-yr-and-4-mo old boy with hyperprolactinemia due to functional disorder of the hypothalamic region. He was referred to our hospital because of left gynecomastia which had been observed for one month. His left breast development was stage II, right breast stage I, and pubic hair stage I by Tanner stages, and his bilateral testicular volume was 1 ml. Both his height and growth velocity were normal and his bone age was not advanced. The basal PRL level was high (40.4 ng/ml), but other sex steroids and adrenal androgen levels were normal. GnRH demonstrated the prepubertal stage. PRL response to TRH was normal and levodopa suppressed the increased basal PRL level. His chromosomal finding was 46, XY and macroprolactinemia was ruled out. Repeated MRI examinations did not demonstrate any organic lesions in the brain. He was diagnosed as having hyperprolactinemia induced by a functional disorder of the hypothalamus. His gynecomastia reduced and the high PRL level decreased without medication after 1 year. PMID- 24790351 TI - Target height and target range for Japanese children: revisited. AB - In 1990, we proposed the equations to calculate target height (TH) and target range (TR) for Japanese, taking account of the positive height secular trend observed over the last ~100 years. However, height difference between generations appears to have become small or negligible in contemporary Japanese populations. Thus, we re-analyzed the Japanese height data, and revised the equations for TH and TR for contemporary Japanese children as follows (cm): Boys, TH = {PH + (MH + 13)} / 2, TR = TH +/- 9; and Girls, TH = {(PH - 13) + MH} / 2; TR = TH +/- 8, where PH indicates paternal height and MH maternal height. PMID- 24790352 TI - Acute vitamin d toxicity in an infant. AB - We report vitamin D toxicity in an infant following consecutive administration use of a large dose of vitamin D, causing symptomatic hypercalcemia, which was successfully managed with injectable calcitonin. However, the child developed bilateral medullary nephrocalcinosis which persisted 42 mon after the initial episode. PMID- 24790353 TI - Growth failure in an infant with congenital nephrogenic diabetes insipidus during sodium restriction. AB - Congenital nephrogenic diabetes insipidus (CNDI) is an inherited disorder characterized by renal tubular insensitivity to antidiuretic hormone, resulting in an inability to concentrate urine. We report on an infant boy with CNDI who showed growth failure during treatment with sodium restriction. At the age of 4 mo, he was diagnosed as having CNDI, judging from fever with hypernatremia (serum Na 153 mEq/L), diluted urine (urine osmolarity 193 mOsm/kg), high antidiuretic hormone (plasma antidiuretic hormone 53 pg/mL), and normal renal function (serum creatinine 0.3 mg/dL). His length and weight were mean +0.4 and -1.1 SD, respectively, at that time. He was treated with sodium restriction (sodium intake; 0.53 mEq/kg/day) using low sodium formula in addition to trichlormethiazide, spironolactone, and mefenamic acid. Growth failure developed: his length and weight were mean -2.4 and -3.3 SD, respectively, at the age of 10 mo. After withdrawal of sodium restriction to 1.5 mEq/kg/day of sodium intake without any change of caloric intake and medication, catch-up growth was observed. At the age of 39 mo, the patient's height and weight were mean -0.8 and -0.6 SD, respectively. We conclude that excessive sodium restriction can cause growth failure in infants with CNDI. PMID- 24790354 TI - KRAS Analysis in 34 Noonan Syndrome Patients without PTPN11 Mutation. PMID- 24790355 TI - Evaluation of the Use of PenNeedle((r)) 32G Taper in Children being Treated with Growth Hormone. AB - Pain resulting from needle injection is a serious problem for patients that self administer medication at home. We studied impressions of needle use by comparing PenNeedle(r) 32G Taper (NovoFine(r) 32G Tip), developed to reduce the sense of fear and pain of injection, with a conventional needle, in children self injecting GH. A total of 34 patients self-injected themselves with needles coupled with Norditropin(r) NordiFlex(r) pre-filled recombinant human GH, and impressions of use were evaluated by a series of questionnaires. Compared to the conventional needle, PenNeedle 32G Taper was slightly less painful at time of insertion according to patient responses, though the difference was not statistically significant (P=0.06). PenNeedle 32G Taper has the same inner diameter as the conventional needle, thus there was no difference in the pain felt at time of injection between these two needles. Large differences in pain perception between the two needles were not seen probably due to their similar shape and appearance and as the subjects of this study were young. Nevertheless, based on the results of post-study questionnaires, significantly more patients (68%, P=0.02) expressed a desire to use PenNeedle 32G Taper for daily injections of GH. PenNeedle 32G Taper thus appears to be a superior needle which reduces insertion-associated pain in children receiving recombinant GH and improves patient QOL. PMID- 24790356 TI - Prediction of pubertal growth at start of estrogen replacement therapy in turner syndrome. AB - In estrogen replacement therapy in Turner syndrome, there is no report which recommends the timing of the start of estrogen therapy in relation to height or adult height prediction. We have established a prediction model for pubertal growth (height difference from the start of estrogen therapy until adult height) at the start of estrogen replacement therapy. Twenty-seven Turner girls without spontaneous puberty were divided into two groups according to birth years; Group I consisted of 16 patients born from 1980-1989 and Group II consisted of 11 patients born before 1980. Using clinical characteristics from Group I, stepwise multiple regression analysis taking pubertal growth as an independent factor, and chronological age, bone age (TW2 RUS method standardized for Japanese children), height and height SDS as dependent factors revealed following formula (p<0.001, R2=0.737): (pubertal growth) = - 1.01x (Chronological age at start of E) - 0.326x (height at start of E) - 1.779x (bone age at start of E) + 90.997. Predicted adult height was obtained by adding predicted pubertal growth to height at the start of estrogen therapy. The mean absolute difference between real adult height (tallest height after height velocity less than 1 cm/yr) and predicted adult height was 1.6 +/- 0.9 cm (0.3-2.8 cm) in Group I. When this prediction model was applied to Group II, The mean absolute difference between real adult height and predicted adult height was 1.0 +/- 0.7 cm (0.1-2.0 cm). A prediction model for pubertal growth at start of estrogen therapy in Turner syndrome was obtained. Using this prediction model, the timing of the start of estrogen therapy can be decided in consideration of the patient's desired adult height. PMID- 24790357 TI - A Neonatal Case of Autosomal Dominant Hypoparathyroidism without Mutation of the CASR Gene. AB - We experienced a case of familial hypoparathyroidism with an autosomal dominant pattern of transmission and performed molecular analysis of the calcium-sensing receptor (CASR) gene. The patient was a female neonate, born by cesarean section at term because of breech presentation. Her mother had been diagnosed with idiopathic hypoparathyroidism at the age of 9 yr and had been receiving vitamin D treatment since then. At birth, the patient's serum calcium concentration was 8.4 mg/dl, but it fell to 4.0 mg/dl on the fifth day after birth. Furthermore, her serum intact PTH level was inappropriately low, while hyperphosphatemia and hypomagnesemia were found. She was diagnosed with familial hypoparathyroidism, and was immediately started on oral administration of 1alpha(OH)D3 (0.1 ug/kg/day) and continuous intravenous infusion of 8.5% calcium gluconate. Additionally, trichlormethiazide was administered because of elevated urinary calcium/creatinine (Ca/Cr) ratio. Her serum calcium concentration gradually improved thereafter. In this case, autosomal dominant hypocalcemia (ADH) due to abnormality in the CASR gene was clinically suspected, but DNA sequencing analysis revealed no mutation of the CASR gene in either the patient or her mother. This result suggests that the patient's hypoparathyroidism may have been caused by abnormality in a gene other than CASR. PMID- 24790358 TI - A Novel Mutation of the Steroidogenic Acute Regulatory Protein (StAR) Gene in a Japanese Patient with Congenital Lipoid Adrenal Hyperplasia. PMID- 24790359 TI - Extreme Tall Stature in a Japanese Boy with a 48,XXYY Karyotype. AB - We report an 18-yr-old Japanese boy with a 48,XXYY karyotype and extreme tall stature (194 cm). A GnRH test at 12.5 yr of age showed hypergonadotropism (LH, 4.2 -> 72.2 mIU/mL; FSH, 28.9 -> 61.7 mIU/mL), and an hCG test at 15.5 yr of age revealed a normal testosterone response (1.67 -> 4.08 ng/mL). The tall stature is remarkable, because the mean adult height of Caucasian 48,XXYY patients is 181 cm. Although the underlying factors for the tall stature are unknown, this report indicates an association of the 48,XXYY karyotype with marked tall stature. PMID- 24790360 TI - cblb Gene Analysis in Japanese Type 1 Diabetes with Younger Age of Onset. AB - To clarify the contribution of Cblb to the development of type1 diabetes (T1D), we investigated Japanese younger-onset T1D patients. We sequenced the cblb gene in 10 T1D patients and screened the identified mutations in 109 Japanese T1D patients and 100 normal subjects. In addition to four previously reported synonymous single nucleotide polymorphisms (SNPs), we identified two novel nonsynonymous variants (786 C>T (A155V) and 1718 A>G (N466D)). The A155V mutation was found in one subject with Basedow's disease whose mother also carried both the mutation and Basedow's disease. The N466D mutation was found in 6 T1D cases including a subject who was classified as fulminant T1D. We found no significant differences in the allele frequency of these SNPs among T1D and control subjects, suggesting that the contribution of cblb to the genetic susceptibility to T1D might not be high for Japanese younger-onset T1D. PMID- 24790361 TI - Changes in glycemic control and quality of life in pediatric type 1 diabetics with continuous subcutaneous insulin infusion of insulin aspart following multiple daily injection therapy. AB - The efficacy of continuous subcutaneous insulin infusion (CSII) of the rapid acting insulin analogue, insulin aspart, was evaluated in 26 patients with childhood-onset type 1 diabetes aged between 6 and 18 yr who had been on basal bolus therapy (multiple daily injection (MDI) of regular human insulin or rapid acting insulin and intermediate/long-acting insulin). The glycemic control in the patients was evaluated based on changes in the clinical parameters and the patient quality of life (QOL) was evaluated by using the insulin therapy-related QOL questionnaire. Twenty two patients continued CSII during the 6-mo study period. The mean HbA1c was 7.8 +/- 1.8% at baseline and it decreased to 7.4 +/- 0.8% at 6 mo after the start of the CSII. Overall, no decrease of the QOL post CSII initiation was noted. The possible superiority of CSII as compared to MDI was suggested for patients who "eat out" or "have to look for an appropriate place for insulin injection." Aside from an inadequate indwelling needle placement detected after the initiation of CSII in several patients, no adverse event associated with NovoRapid((r)) was seen. In conclusion, CSII of rapid acting insulin appears to be a useful therapy for patients with childhood-onset type 1 diabetes. PMID- 24790362 TI - In Vitro Enzyme Assay of CYP21A2 Mutation (R483Q) by A Novel Method Using Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS). AB - Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders in humans, and 21-hydroxylase deficiency (21-OHD) accounts for 90 to 95% of all cases of CAH. Approximately 95% mutations are a consequence of recombination between the CYP21A2 and its highly homologous pseudogene CYP21A1P. Recently, other rare mutations have been identified, increasing the number of reported mutations to more than eighty. The in vitro enzyme assay for the detection of mutated 21-hydroxylase is a well-established method. In this study, we report the characterization of the R483Q mutation using a novel in vitro enzyme assay, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). With this system, we evaluated the activity of the R483Q mutation. The enzyme activities of 21-hydroxylase in the convertion of progesterone to deoxycorticosterone (DOC), and 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol (11-DOF), were measured as 2.00 +/- 0.25% and 1.89 +/- 0.30% of the wild type, respectively. This result was in agreement with that of a previous report, which measured the activities using the (3)H labeled steroid assay. Our results suggest that the R483Q mutation is compatible with the simple virilizing form of 21-OHD and that the LC-ESI-MS/MS assay using picolinoyl derivatives is an alternative to the existing (3)H-labeled steroid assay for the characterization of the CYP21A2 mutation. PMID- 24790363 TI - Palatability of vitamin d3 preparations modulates adherence to the supplementation in infancy. PMID- 24790364 TI - Management challenges in a child with hyperinsulinemic hypoglycemia. AB - Malignant insulinoma is very rare in children. Herein, we present a case of a child with malignant insulinoma along with islet cell hyperplasia. She initially presented with features of hyperinsulinemic hypoglycemia at 18 mo of age. Magnetic resonance imaging (MRI) of the abdomen showed a mass at the junction of the head and body of the pancreas. The tumor was enucleated. Five months later symptoms of hypoglycemia recurred. A subtotal pancreatectomy was performed. She continued to have hypoglycemia, although less frequently. She was put on increasing doses of diazoxide. Seven months later, MRI of the abdomen and a PET scan revealed metastatic deposits in the liver, which were confirmed by histopathology and immunostaining. To the best of our knowledge, this is the youngest child with metastatic insulinoma reported so far. PMID- 24790365 TI - Central Congenital Hypothyroidism Detected by Neonatal Screening in Sapporo, Japan (2000-2004): It's Prevalence and Clinical Characteristics. AB - In Sapporo, Japan, a neonatal screening program for congenital hypothyroidism (CH) has employed measurement of free thyroxine (T4) and TSH in the same filter paper blood spot. This system has enabled us to identify primary CH and central CH during the neonatal period. The aim of this study was to clarify the prevalence and clinical characteristics of central CH. For this purpose, the screening program requested serum from infants with free T4 concentrations below the cut off value regardless of the TSH levels. Between January 2000 and December 2004, 83,232 newborns were screened and six central CH patients were detected as a result of follow-up of low free T4 and non-elevated TSH screening (1:13,872). This frequency is higher than in other studies. Four patients showed multiple pituitary hormone deficiency with pituitary malformations on magnetic resonance imaging. One patient was diagnosed as having Prader-Willie syndrome. The remaining patient was considered to have isolated central CH. Our study demonstrated that the frequency of central CH is 1:13,872. Free T4 measurement would also be advantageous in early recognition of multiple pituitary hormone deficiency. PMID- 24790366 TI - Case Report: Adjuvant Therapy with a High Dose of Mitotane for Adrenocortical Carcinoma in a 4-year-old Boy. AB - This report concerns control of adrenocortical carcinoma in a 4-yr-old boy by adjuvant mitotane therapy. He presented precocious puberty and was diagnosed with adrenocortical carcinoma. He underwent surgical resection, and adjuvant mitotane therapy was initiated, leading to a final dose of 5.0 g/day. Despite monitoring of the plasma mitotane level, encephalopathy developed 5 mo after initiation. Although he recovered from the encephalopathy, careful follow-up of his growth and development is necessary. On the other hand, he has been free of recurrence and metastases for 3 yr since discontinuation of mitotane. A high dose of mitotane is potentially effective as an adjuvant chemotherapy for adrenocortical carcinoma, although optimal and safe usage needs to be established for children. PMID- 24790367 TI - The Range of 2.2-3.3 mg/gCr of Pregnanetriol in the First Morning Urine Sample as an Index of Optimal Control in CYP21 Deficiency. AB - Auxological data are the gold standard indexes of the therapeutic conditions in patients with CYP21 deficiency over long-term periods, whereas urinary pregnanetriol (PT) for 24 h has been used as an index for short-term periods. We previously reported that the range of 1.2-2.1 mg/m(2)/day of PT for 24 h (24-h PT) could be used as an index of optimal control in patients with CYP21 deficiency. The purpose of this study was to analyze the range of PT in the first morning urine samples (morning PT) as an index of optimal control in patients with CYP21 deficiency. First, the therapeutic periods of 15 participants (aged 2 yr and 5 mo to 17 yr and 4 mo) were classified into excessive, good or poor control periods using auxological data and Cushing-like symptoms, and 24-h PT levels were analyzed in each period, retrospectively. The 95% confidence intervals for the means of 24-h PT levels in the excessive, good and poor control periods were 0.24-2.24 (n=25), 2.88-4.92 (n=114) and 13.26-21.28 (n=72) mg/gCr, respectively. Subsequently, 24-h PT and morning PT levels collected on the same day were analyzed for 14 participants (aged 9 mo to 29 yr and 8 mo). There was a significant correlation between the above two PT levels (n=25, p<0.0001). When the 24-h PT range of the good control period, 2.88-4.92 mg/gCr, was adjusted by the correlation, the ideal morning PT range became 2.15-3.34 mg/gCr. In conclusion, a morning PT in the range of 2.2-3.3 mg/gCr can be used as an index of optimal control in patients with CYP21 deficiency. PMID- 24790368 TI - I-Cell Disease (Mucolipidosis II) Presenting as Neonatal Fractures: A Case for Continued Monitoring of Serum Parathyroid Hormone Levels. AB - A severe form of I-cell disease (mucolipidosis II) can present in the newborn period as multiple fractures. The bone disease in these patients is believed to be due to hyperparathyroidism. We report a case where bone disease was present at birth but the parathyroid hormone levels were initially normal and did not increase until 37 d of age. Supplemention with vitamin D was needed to normalize the parathyroid hormone levels despite adequate intake of vitamin D, calcium and phosphorus. We suggest that in patients with I-cell disease, continued evaluation for hyperparathyroidism may be necessary despite initial normal parathyroid hormone levels. PMID- 24790369 TI - MAMLD1 (CXorf6) is a New Gene for Hypospadias. AB - MAMLD1 (mastermind-like domain containing 1), previously known as CXorf6 (chromosome X open reading frame 6), has been shown to be a causative gene for hypospadias. This is primarily based on the identification of nonsense mutations (E124X, Q197X, and R653X), which undergo nonsense mediated mRNA decay, in patients with penoscrotal hypospadias. Subsequent molecular studies have shown that the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period for sex development, and that transient knockdown of Mamld1 results in significantly reduced testosterone production in murine Leydig tumor cells. These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period for sex development. PMID- 24790370 TI - Prenatal diagnosis and treatment of steroid 21-hydroxylase deficiency. AB - Steroid 21-hydroxylase deficiency (21-OHD) accounts for 90-95% of congenital adrenal hyperplasia (CAH) cases. It is classified into three distinct clinical phenotypes: the salt-wasting (SW), simple virilizing (SV) and nonclassical forms (NC). As girls with the SW and SV forms of 21-OHD are exposed to high systemic levels of adrenal androgens during fetal life, they show genital ambiguity. To ameliorate the degree of genital virilization, prenatal dexamethasone treatment has been performed for more than two decades, although mainly in the USA and Europe. This treatment has proven to be effective in preventing or reducing genital virilization. Some data also show that prenatal diagnosis and treatment are safe for the mother and fetus. However, prenatal treatment is still controversial for the following reasons. First, the risk of having an affected female fetus is only one in eight when both parents are known carriers of the autosomal recessive trait. Therefore, seven of eight fetuses will receive dexamethasone unnecessarily, and this raises ethical questions. Furthermore, maternal side effects such as excessive weight gain and hypertension have been observed. Finally, the long-term safety and outcome for dexamethasone-exposed children have not been established. In Japan, prenatal diagnosis and treatment has rarely been reported because of these reasons. Therefore, we must be cautious, and this treatment should be carried out in special centers with the approval of their ethical committees, that are capable of performing chorionic villus sampling (CVS) and subsequently determining the karyotype and genotype of 21-OHD. PMID- 24790371 TI - Molecular mechanisms leading to the phenotypic development in paternal and maternal uniparental disomy for chromosome 14. AB - Human chromosome 14q32.2 carries a cluster of imprinted genes. They include paternally expressed genes (PEGs) such as DLK1 and RTL1, and maternally expressed genes (MEGs) such as GTL2 (alias, MEG3), RTL1as (RTL1 antisense), and MEG8. Consistent with this, paternal and maternal uniparental disomies for chromosome 14 (upd(14)pat and upd(14)mat) cause distinct phenotypes. In this review, we summarize the current knowledge about the underlying factors for the development of upd(14)pat and upd(14)mat phenotypes. The data available suggest that the DLK1 GTL2 intergenic differentially methylated region (IG-DMR) plays an important role in the maternal to paternal epigenotypic switch, and that excessive RTL1 expression and decreased DLK1 and RTL1 expression play a major role in the development of upd(14)pat-like and upd(14)mat-like phenotypes, respectively. PMID- 24790372 TI - Pathogenic characteristics at diagnosis in young children with type 1 diabetes presenting prior to 5 years of age. AB - We examined pathogenic characteristics in Japanese children with type 1 diabetes presenting before 5 years of age. The subjects were 23 Japanese children, 9 males and 14 females, 1.1-4.8 yr of age at diagnosis. The majority had severe metabolic decompensation accompanied by complete absence of beta-cell function at diagnosis. We found a high frequency of preceding viral illness (41.7%) among them. The prevalence of antibodies to GAD and IA-2 at diagnosis in young children were significantly lower than those in older cases diagnosed after 5 yr of age (31.6% vs. 86.3%, 47.1% vs. 82.5%, respectively). These findings suggest that non autoimmune mechanisms or age-related differences in autoimmunity could be involved in the pathogenesis of diabetes in young children. In regard to diabetes related HLA-DRB1 and DQB1 alleles, all subjects had high-risk genotypes in both alleles. On the other hand, none of the patients had any of the protective genotypes in either allele. In regard to haplotypes, the frequencies of DRB1*0405 DQB1*0401 and DRB1*0901/ DQB1*0303 were 60.9% and 52.2%, respectively, and both these haplotypes are associated with strong susceptibility to type 1 diabetes. Patients with early-childhood onset may have diabetes-related autoimmunity and genetic backgrounds different from those of patients diagnosed at a later age. PMID- 24790373 TI - A Novel A461S Mutation of PTPN11 in a Female with LEOPARD Syndrome. PMID- 24790375 TI - Evaluation of Quality of Life in Children with GH Deficiency and Idiopathic Short Stature Using the Child Behavior Checklist. AB - The quality of life (QoL) of short children is an important issue that has been studied in Western countries, but not fully in Japan. We assessed the psychosocial profiles of Japanese children with short stature using the Japanese version of the Child Behavior Checklist (CBCL). A higher score in the CBCL means a lower QoL. A total of 116 children with idiopathic short stature (ISS) and 127 children with GH deficiency (GHD), aged 4 to 15 yr, were enrolled in the study. The total CBCL scores of the children in the GHD/ISS group were found to be higher than those of the normal children group. The QoL subscales for social problems and attention problems of the young (4-11 yr) children in the GHD/ISS group were significantly higher than those of the group of children of normal height. The proportion of children with GHD/ISS classified into the borderline/abnormal range was significantly higher than that of normal children. Children with ISS tended to have higher total scores and more subscale problems, and a greater proportion of these children was classified in the borderline/abnormal range than the children with GHD, although the difference was not significant. These results suggest that QoL is impaired in Japanese children due to short stature. PMID- 24790376 TI - Stress doses of glucocorticoids cannot prevent progression of all adrenal crises. AB - Adrenal crises (ACs) sometimes progress rapidly and can be fatal. The aims of the present study were to reveal whether stress doses of glucocorticoids (SDGs) can prevent progression of severe ACs and to suggest a method of prevention, through analysis of its clinical features. We studied 24 severe ACs (nine patients) that occurred after diagnosis of primary or secondary adrenal insufficiency, retrospectively. The following information was analyzed: 1) whether SDGs were given orally and/or sc; 2) duration from the time when some symptoms started to the time when the patient came to the hospital; and 3) presence of hypoglycemia and electrolyte disturbance (hyponatremia, hyperkalemia). Eleven crises occurred after taking SDGs. Ten crises progressed within 3 h. Six of these ten crises progressed to severe ACs despite the fact that the patients took SDGs. Six crises were observed in association with hypoglycemia, and five of these six crises occurred in patients under 5 yr of age. Three of the six crises in association with hypoglycemia progressed to ACs within 3 h. Two of the three crises progressed to severe status within 3 h despite the fact that the patients took SDGs. Electrolyte disturbance was observed in only one crisis. In conclusion, SDGs cannot prevent progression of all ACs. Progression can be associated with hypoglycemia, particularly in patients under 5 yr of age. Patients should be given guidance on an ongoing basis on how to prevent ACs and hypoglycemia. PMID- 24790374 TI - Growth and Endocrine Function in Long-term Adult Survivors of Childhood Stem Cell Transplant. AB - The number of long-term surviving stem cell transplant (SCT) recipients has increased steadily, and attention has now extended to the late complications of this procedure. The objective of this study was to investigate relationship among growth and endocrine functions in long-term adult survivors of childhood SCT. The inclusion criteria of this study were survival at least 5 yr after SCT and achievement of adult height. Fifty-four patients (39 males) fulfilled these criteria and were included in this study. Growth was mainly evaluated by height standard deviation score (SDS) and individual longitudinal growth curves. Among the 54 patients, those that received SCT before 10 yr of age showed significantly greater reductions in changes in height SDS (mean -1.75, range -4.80 to -0.10) compared with those that received SCT at or after 10 yr of age (mean -0.50, range -1.74 to 1.20; P<0.001). The mean loss of height for all patients who received SCT during childhood was estimated to be approximately 1 SDS/6.5 yr (r=0.517). Individual longitudinal growth curves indicated that a significant growth spurt was absent in severe short stature patients during the pubertal period without severe endocrine dysfunctions including GH deficiency. The incidence of growth disorder in long-term adult survivors depends on the age at SCT and whether they received radiation therapy. Life-long follow-up is necessary for survivors to detect, prevent and treat the late endocrine complications in SCT survivors. PMID- 24790377 TI - Patients with Hypophosphatemic Osteomalacia Need Continuous Treatment during Adulthood. AB - The treatment for hypophosphatemic rickets in children includes phosphate and vitamin D preparations. In children, this regimen significantly improves symptoms, while a treatment for adult patients has not been established. We therefore investigated the clinical courses of 15 adult patients who discontinued therapy when final height was achieved in order to assess the necessity of treatment in adulthood. Thirteen patients developed symptomatic complications, including bone fractures. Among the 13, the 10 patients who restarted therapy all showed clinical improvement, and no side effects of treatment were observed. This study shows that there are some patients with hypophosphatemic osteomalacia who need continuous treatment during adulthood. PMID- 24790378 TI - Pleuropulmonary zygomycosis in a diabetic child. AB - A 12 yr old girl with type 1 diabetes presented in ketoacidosis and consolidation of left lower lobe along with left pleural effusion. A diagnosis of mucormycosis was made on smear examination of an exudative pleural aspirate. Left lower lobe lobectomy was performed along with drainage of pleural collection with tube thoracostomy. Worsening respiratory distress postoperatively due to increase in empyema fluid necessitated a second surgery. Pleuropulmonary involvement as seen in this patient is an extremely rare occurrence possibly related to the propensity of mucor to invade blood vessels rather than extend outwardly into pleural cavity. PMID- 24790379 TI - Wide Range of Biotin (Vitamin H) Content in Foodstuffs and Powdered Milks as Assessed by High-performance Affinity Chromatography. AB - The biotin (vitamin H) contents of various foodstuffs were determined by using a newly developed high-performance affinity chromatography with a trypsin-treated avidin-bound column. Biotin was derivatized with 9-anthryldiazomethane (ADAM) to fluorescent biotin-ADAM ester. A wide range of biotin contents were found in various foodstuffs depending upon the species (strain), season, organ (of plants and animals), geography, freshness, preparation method and storage method. Among the foodstuffs and fermented foods tested, it was found that wide distributions of biotin content were observed in powdered milk, natto, sake (rice wine), beer, edible oil and sea weed. Since powdered milk is important for child health and development, 14 kinds of powdered and special milks for use in children's diseases were intensively measured. We found that several special milk powders for children with allergies contained low levels of free biotin. Use of these powdered milks caused skin diseases and alopecia in some patients possessing thermolabile serum biotinidase, and administration of free biotin improved their symptoms dramatically. Therefore, it is essential to estimate the total and free biotin contents on each foodstuff in order to improve effective biotin intake and support better health and quality of life for people. PMID- 24790380 TI - Isolated neurosarcoidosis revealed by diabetes insipidus, visual loss and diplopia in a child patient: a diagnostic problem. AB - We report a case of 15-yr-old child that was presented with headache, polyuria, polydipsia, recent ocular motor and abducens nerve palsies and rapid visual loss. He had a long history of progressive symmetric muscular weakness predominant in the lower limb girdle. Water deprivation revealed central diabetes insipidus. Hormonal explorations demonstrated preserved pituitary function with mild hyperprolactinemia at 21.5 ng/ml (N: 2.6 to 13.1 ng/ml). Magnetic resonance imaging showed an extensive isosignal T1 and hyposignal T2 enhanced lesion infiltrating the pituitary gland, optic-chiasmal hypothalamic region, cavernous sinus, cerebrum tent and sphenoid and temporal meningeal spaces. The serum level of angiotensin converting enzyme and cerebrospinal fluid analysis were normal. No other systemic localisation was identified. Muscle biopsy objectified dystrophic changes. Genetic study identified a delT 521 mutation characteristic of Limb girdle muscular dystrophy type 2C. Corticotherapy rapidly ameliorated the neurological symptoms. This patient was diagnosed as having neurosarcoidosis. Neurosarcoidosis is rarely reported in childhood. We discuss the problems related to diagnosis in such a situation below. PMID- 24790381 TI - Relationship between Aortic Intima-media Thickening, Serum IGF-I and Low-density Lipoprotein Particle Diameter in Newborns with Intrauterine Growth Restriction. AB - Much epidemiological evidence has linked low birth weight with late cardiovascular risk. In order to investigate the effect of intrauterine growth restriction (IUGR) on early atherosclerosis in the fetus, we measured aortic wall thickness (abdominal aortic intima-media thickness: aIMT) by ultrasonography in 15 neonates with IUGR and in 31 neonates considered to be appropriate for gestational age (AGA). Furthermore, we evaluated the relationship between aIMT, serum insulin-like growth factor-I (IGF-I) and low-density lipoprotein (LDL) particle size to investigate the possible effect of these atherosclerosis-related factors on the early atherosclerosis process. The results showed that the mean aIMT was significantly greater in the IUGR neonates than in the AGA neonates (least squares mean +/- SE, 537 +/- 24.8 vs. 471 +/- 17.0 um, p=0.037). The serum IGF-I levels were lower in the IUGR neonates than in the AGA neonates (27.9 +/- 4.3 vs. 42.7 +/- 2.9 ng/ml, p=0.009). A significant negative correlation was observed between aIMT and IGF-I in the IUGR neonates (r=-0.646, p=0.009); however, a positive correlation was observed between aIMT and IGF-I (r=0.416, p=0.020) in the AGA neonates. There appeared to be no relationship between aIMT and LDL particle diameter. Atherogenic small, dense LDL was not detected in the IUGR infants. In conclusion, neonates with IUGR have significant aortic thickening with decreased IGF-I, suggesting that prenatal events might predispose them to later cardiovascular risk. PMID- 24790382 TI - Cabergoline Effectively Induced Remission of Prolactinoma in a 9-year-old Japanese Boy. AB - Prolactinomas are rarely diagnosed in children under the age of 10. A 9-yr-old Japanese boy complained of severe headache and progressive visual disturbance. His growth had been retarded for approximately 3 yr, and his serum PRL level was 811.6 ng/ml. Brain magnetic resonance imaging (MRI) revealed an enlarged pituitary (2.8 * 2.6 * 2.1 cm) with heterogeneous enhancement. He was diagnosed as having a macroprolactinoma accompanied by pituitary apoplexy and growth hormone deficiency. A surgical approach was initially undertaken due to the progressive visual deficits, but a residual tumor was observed, and the level of serum PRL was still high after the surgery. Cabergoline was then started, and the dose was gradually increased to 1.5 mg/wk. The serum PRL level decreased from 138.8 ng/ml to 32.5 ng/ml and 17.7 ng/ml after 5 wk and 19 wk, respectively. At 33 wk of cabergoline treatment, brain MRI demonstrated no evidence of the residual tumor. Thereafter, the serum level of PRL decreased to less than 10 ng/ml, and remission was consistently confirmed on repeated MRI. No adverse events have been observed. The present case suggests that cabergoline can be an effective treatment for prolactinomas in prepubertal children as well as in adults. PMID- 24790383 TI - A Novel V185DfsX4 Mutation of the AAAS Gene in a 2-year-old Boy with Triple A Syndrome. PMID- 24790384 TI - A Retrospective Analysis of the Growth Pattern in Patients with Salt-wasting 21 Hydroxylase Deficiency. AB - The objective of this study was to investigate the growth pattern of children with the salt-wasting form of congenital adrenal hyperplasia caused by 21 hydroxylase deficiency (21-OHD). We reviewed the medical records of 13 patients in whom salt-wasting 21-OHD was diagnosed during the first 2 mo of life at our hospital from 1980 through 2008. Six reached adult height. Growth patterns, bone age, biochemical data, and the hydrocortisone dose at each growth stage were analyzed retrospectively. The mean adult height was 155.1 +/- 6.5 cm (mean +/- SD) in females and 158.1 +/- 7.1 cm in males. Although length at birth was normal or longer than the national mean in almost all patients, the mean height SD score of both boys and girls decreased to below 0 SD during infancy. Subsequently, both boys and girls transiently showed growth acceleration and reached their peak growth velocity at 3-10 yr of age. In conclusion, in addition to suppression of growth during infancy, there was inappropriate growth acceleration during childhood. Especially from 3 mo to 3 yr of age, decreasing the hydrocortisone dose in patients who exhibit slower growth may lead to satisfactory height outcomes. Also, strict adjustment of the hydrocortisone dose to avoid accelerated growth from childhood to adolescence might improve adult height outcomes of patients with 21-OHD. PMID- 24790385 TI - Results from 28 years of newborn screening for congenital adrenal hyperplasia in sapporo. AB - The primary goal of newborn mass screening (MS) for congenital adrenal hyperplasia (CAH) is the prevention of life-threatening salt-wasting crisis in the most severe forms of CAH, and MS for CAH has been implemented in several countries. We summarize here our experience and results from newborn CAH MS from 1982 to 2010 in Sapporo City. During these 28 yr, the level of 17 hydroxyprogesterone (17-OHP) was determined in MS of samples from 498,147 newborns. During this period, 26 individuals (19 females and 7 males) with 21 hydroxylase deficiency (21-OHD) were detected. Of the 26 CAH, 20 were classified as having the salt-wasting (SW) form, 4 were classified as having the simple virilizing (SV) form, and 2 were classified as having the noncalssic (NC) form. Therefore, the frequency of the classical type of CAH was 1 in 20,756. In order to improve the effectiveness, we employed high-performance liquid chromatography (HPLC) as a second tier test from 2000. During this period, among the recalled babies, 75.4% were born prior to the 37th wk of gestation age, and the recall rate was 5.38% for premature neonates and 0.06% for mature neonates. MS for CAH in Sapporo is effective for the identification of the SW and SV forms of 21-OHD. However, the recall rate of premature babies is still high after the introduction of HPLC as a second tier test. PMID- 24790386 TI - Endocrinological Characteristics of 25 Japanese Patients with CHARGE Syndrome. AB - CHARGE syndrome is a congenital disorder caused by mutation of the chromodomain helicase DNA binding protein 7 (CHD7) gene and is characterized by multiple anomalies including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genital and/or urological abnormalities, ear anomalies, and hearing loss. In the present study, 76% of subjects had some type of endocrine disorder: short stature (72%), hypogonadotropic hypogonadism (60%), hypothyroidism (16%), and combined hypopituitarism (8%). A mutation in CHD7 was found in 80% of subjects. Here, we report the phenotypic spectrum of 25 Japanese patients with CHARGE syndrome, including their endocrinological features. PMID- 24790387 TI - Third-generation Aromatase Inhibitor Improved Adult Height in a Japanese Boy with Testotoxicosis. AB - In this study, we report a Japanese boy with testotoxicosis due to a heterozygous mutation [p. A572V] in the LH/CGR gene, who was the first boy treated with a third-generation aromatase inhibitor (AI) and reached his adult height in Japan. He showed accelerated growth and rapid penile growth from 3 yr of age and was diagnosed as having testotoxicosis. Combined treatment with anastrozole and spironolactone was started when he was 7 yr old and 145.8 cm (+4.45 SD) tall, at which point his bone age (BA) was 13.5 yr. His predicted adult height (PAH) was estimated to be 158.3 cm. The combined treatment was continued until he was 13 yr old and 166.5 cm tall, with his BA being 15.5 yr. He reached his adult height of 166.9 cm at 15 yr of age. Combined treatment with anastrozole and spironolactone successfully decelerated BA advancement, prolonged pubertal period and improved adult height. PMID- 24790389 TI - Heroes and Hysterics: 'Partisan Hysteria' and Communist State-building in Yugoslavia after 1945. AB - This article investigates a novel type of war neurosis defined by Yugoslav psychiatrists in the aftermath of the Second World War. This uniquely Yugoslav war trauma-'partisan hysteria'-was diagnosed exclusively in Communist resistance soldiers-partisans-and did not manifest itself in the form of battle exhaustion or anxiety, as was the case in other armies. Rather, it demonstrated a heightened willingness to fight, and consisted of simulations of wartime battles. Yugoslav psychiatrists argued that 'partisan hysteria' most frequently affected uneducated and immature partisans, who were given important political responsibilities but experienced severe trauma due to their own inadequacy. I argue that 'partisan hysteria' served as an opportunity for upper-middle-class psychiatric professionals to criticise the increasing upward social mobility after the socialist revolution of 1945. Surprisingly, this touched upon an issue that had already provoked deep disquiet within the Communist Party, and resonated with the Party's own concerns regarding social mobility. PMID- 24790388 TI - Thyroid Follicular Carcinoma in a Fourteen-year-old Girl with Graves' Disease. AB - Here we present the case of a 14-yr-old girl who developed thyroid follicular carcinoma accompanied by Graves' disease. She was diagnosed with Graves' disease at 10 yr of age and soon achieved a euthyroid state after starting treatment. When she was 13 yr of age, her hyperthyroidism and goiter worsened despite medical therapy. Multiple nodules were found in her enlarged thyroid gland by ultrasonography. Her serum Tg level seemed within the normal range. She underwent near-total thyroidectomy for control of thyroid function. Histopathological study demonstrated that multiple oxyphilic follicular neoplasms were surrounded by the thyroid tissue compatible with Graves' disease. Capsular invasion was identified in one of the nodules, and thus the histological diagnosis was minimally invasive follicular carcinoma. She did not have signs suggesting metastasis, and has had no relapse for 18 mo after the operation. Although some previous studies showed a high prevalence of thyroid cancer with an aggressive nature in adult patients with Graves' disease, few reports about thyroid cancer accompanied by Graves' disease are available in children. The present case, however, suggests that careful investigation is needed when we detect thyroid nodules or progressive thyroid enlargement, especially in children with Graves' disease. PMID- 24790392 TI - Electronic prescribing vulnerabilities: height and weight mix-up leads to dosing error. AB - Height and weight errors confound electronic prescribing. PMID- 24790391 TI - The Gendered Nose and its Lack: "Medieval" Nose-Cutting and its Modern Manifestations. AB - Time magazine's cover photograph in August 2010 of a noseless Afghan woman beside the emotive strap line, "What happens if we leave Afghanistan," fuelled debate about the "medieval" practices of the Taliban, whose local commander had instructed her husband to take her nose and ears. Press reports attributed the violence to the Pashtun tradition that a dishonored husband "lost his nose." This equation of nose-cutting with tradition begs questions not only about the Orientalist lens of the western press when viewing Afghanistan, but also about the assumption that the word "medieval" can function as a label for such practices. A study of medieval nose-cutting suggests that its identification as an "eastern" practice should be challenged. Rather clearer is its connection with patriarchal values of authority and honor: the victims of such punishment have not always been women, but this is nevertheless a gendered punishment of the powerless by the powerful. PMID- 24790390 TI - The 10th Anniversary of Carbohydrate Microarrays (2002-2012). PMID- 24790394 TI - Pharmaceutical approval update. AB - Dapaglifozin (Farxiga) for improved glycemic control in type-2 diabetes, and trametinib (Mekinist) in combination with dabrafenib (Tafinlar) for the treatment of advanced, unresectable melanoma. PMID- 24790393 TI - Manufacturers and hospitals spar over drug shortage reporting: FDA proposal seeks to improve early warning system. AB - Drug makers and hospitals spar over shortage reporting. PMID- 24790396 TI - Alogliptin (nesina) for adults with type-2 diabetes. AB - Alogliptin (Nesina) for adults with type-2 diabetes. PMID- 24790397 TI - Major Changes for Part D Drug Plans Scheduled for 2015: Health Plans and PBMs Would Be the Chief Beneficiaries. AB - Medicare is proposing significant revisions to its Part D drug program. The biggest change: the elimination of antidepressants and immunosuppressants as "protected classes" on formularies in 2015 and the removal of antipsychotics in 2016. PMID- 24790398 TI - Retrospective analysis of azithromycin versus fluoroquinolones for the treatment of legionella pneumonia. AB - BACKGROUND: Legionella is often associated with life-threatening pneumonia that is responsible for significant morbidity and mortality. Fluoroquinolones (FQ) have demonstrated improved clinical outcomes or decreased complications compared with clarithromycin and erythromycin. However, there is limited data comparing outcomes of FQ to azithromycin (AZM), which exhibits better Legionella activity than erythromycin and clarithromycin. METHODS: This single-center retrospective study compared clinical outcomes of patients with Legionella pneumonia (LP) treated with AZM versus FQ from January 1999 to May 2011. RESULTS: A total of 41 patients were included in the analysis; 21 received FQ and 20 received AZM. Demographics, comorbidities, and disease severity were similar between groups. Mortality (9.5% vs. 5%, P > 0.99), time to clinical stability (15.89 days vs. 10.26 days, P = 0.09), length of hospitalization (19.29 days vs. 11.35 days, P = 0.06), and presentation of any complication (85.7% vs. 90%, P > 0.99) were similar between the FQ and AZM groups, respectively. CONCLUSION: Azithromycin appears to have clinical efficacy similar to FQ for the treatment of Legionella pneumonia. PMID- 24790399 TI - Current and Emerging Treatment Regimens for HER2-Positive Breast Cancer. AB - Overexpression of human epidermal growth factor receptor 2 (HER2) is an important factor in cancer survival, proliferation, and metastasis. Agents that target HER2 positive tumors are used with traditional chemotherapies, with other targeted therapies, or as monotherapy to treat metastatic breast cancers. PMID- 24790400 TI - Breast cancer by the numbers. AB - The American Cancer Society estimates that 40,000 women will die from breast cancer this year. But thanks to steady progress in the war on cancer, millions of U.S. women with a history of the disease are alive today. Key statistics on survival rates, therapies in use, and treatment costs are provided. PMID- 24790401 TI - Use of SSRIs may Impact Bone Density in Adolescent and Young Women with Anorexia Nervosa. AB - OBJECTIVES: Alterations in serotonin impact bone metabolism in animal models, and selective serotonin reuptake inhibitors (SSRI) have been associated with increased fracture risk in older adults. SSRIs are commonly used in anorexia nervosa (AN), a condition that predisposes to low bone mineral density (BMD). Our objective was to determine whether SSRI use is associated with low BMD in AN. METHODS: We examined Z-scores for spine, hip and whole body (WB) BMD, spine bone mineral apparent density and WBBMC/height (Ht) in females with AN 12-21 years old who had never been on SSRIs, on SSRIs for <6 months (<6M) or >6 months (>6M). RESULTS: Subjects on SSRIs for >6M had lower spine, femoral-neck and WBBMD Z scores than those on SSRIs for <6M. Hip BMD and WBBMC/Ht Z-scores were lowest in subjects on SSRIs for >6M. Duration of SSRI use, duration since AN diagnosis and duration of amenorrhea inversely predicted BMD, whereas BMI was a positive predictor. In a regression model, duration of SSRI use remained an independent negative predictor of BMD. DISCUSSION: Duration of SSRI use >6M is associated with low BMD in AN. CONCLUSION: It may be necessary to monitor BMD more rigorously when duration of SSRI use exceeds 6M. PMID- 24790402 TI - Cataract surgery during active methicillin-resistant Staphylococcus aureus infection. AB - We present two patients with active, foul-smelling, methicillin-resistant Staphylococcus aureus (MRSA) wounds of the forehead and sternum following craniotomy or open heart surgery. Both had debilitating cataracts and were told by the infectious diseases team that cataract surgery is very risky. Both underwent sequential bilateral phacoemulsification with no sign of infection. Patients with active MRSA wound infections may safely undergo cataract surgery with additional precautions observed intraoperatively (good wound construction) and postoperatively (topical antibiotics and close observation). Banning such surgeries can unnecessarily jeopardize the lifestyles of such patients. PMID- 24790403 TI - Transformational change: nurses substituting for ophthalmologists for intravitreal injections - a quality-improvement report. AB - BACKGROUND: The dramatic increase in need for anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy in the treatment of retinal disease and the absence of an equivalent increase in ophthalmologists to undertake such intravitreal injections created a patient-safety risk. Timing of intravitreal therapy (IVT) is critical to prevent vision loss and local clinics lacked capacity to treat patients appropriately. We aimed to improve capacity for IVT by nurse injections. MATERIALS AND METHODS: A multidisciplinary prospective service improvement process was undertaken at two adjacent general hospitals in the northwest of England. IVT injections by nurses were a principal component of solution development. After we had obtained appropriate institutional approval, experienced ophthalmic nurses were trained, supervised, and assessed to undertake IVT. Ophthalmologists directly supervised the first 200 injections, and a retina specialist was always on site. RESULTS: Nurses undertook 3,355 intravitreal injections between June 2012 and November 2013, with minor adverse events (0.3% subconjunctival hemorrhage and corneal abrasion). There were no patient complaints at either hospital. CONCLUSION: Experienced ophthalmic nurses quickly learned how to perform such injections safely. IVT by nurses was well accepted by patients and staff. Hospital A trained three nurses sequentially for improved flexibility in scheduling. Novel use of appropriately trained non-medical staff can improve efficiency and access in an overburdened service with time-sensitive disease. Retinal assessment was undertaken by ophthalmologists only. Improved access to IVT is important, as treatment with anti-VEGF therapy reduces blindness at population levels. PMID- 24790404 TI - Intracameral air following pneumatic noncontact tonometry in a recently post perforating keratoplasty patient. AB - PURPOSE: The purpose of this report is to highlight the potential risk of noncontact tonometry after routine uncomplicated penetrating keratoplasty (PK). CASE REPORT: After uncomplicated PK for keratoconus, routine noncontact tonometry was performed on the second postoperative day. In spite of the adequately closed wound and the tight suture, temporary wound dehiscence occurred, and two-thirds of the anterior chamber was occupied by air. The running suture remained intact, and the Seidel test was negative. One week postoperatively, the patient's corrected distance visual acuity was 0.4 (0.4 logMAR), and the air bubble had absorbed. CONCLUSION: This is the first report to conclude that noncontact tonometry may not be sufficiently safe in the early postoperative period in normal PK cases. To prevent possible wound opening, we suggest the use of other tonometry methods during the first several months after PK. PMID- 24790405 TI - Tear fluid signs associated with filtration blebs, as demonstrated by three dimensional anterior segment optical coherence tomography. AB - PURPOSE: To determine the clinical features of tear fluid signs associated with filtration blebs via three-dimensional anterior segment optical coherence tomography (3D AS-OCT). METHODS: In total, 152 eyes (130 patients) with glaucoma that underwent trabeculectomy with mitomycin C were evaluated retrospectively. We investigated tear fluid signs associated with filtration blebs, using 3D AS-OCT with custom software, and compared the findings of lower tear meniscus. We also analyzed postoperative intraocular pressure and the bleb parameters of filtration blebs between eyes with and without tear fluid signs. RESULTS: We found tear fluid signs associated with filtration blebs in 45 (30%) of 152 eyes. The mean postoperative intraocular pressure of the eyes with the tear fluid sign in a filtration bleb was significantly lower than that in eyes without the tear fluid sign (P<0.001). Blebs with tear fluid signs have more frequent identifiable filtration openings, greater total height, increased fluid-filled cavity height, and less wall intensity compared with blebs without these signs. CONCLUSION: We identified tear fluid signs in AS-OCT images on or along filtration blebs that depended on bleb morphology. The occurrence of these signs may be related to the presence of functional blebs, which may thereby control postoperative intraocular pressure. PMID- 24790406 TI - Combined Baerveldt glaucoma drainage implant surgery and surgical bleb revision for preventing a postoperative hypertensive phase. AB - BACKGROUND: In patients with severe optic nerve damage, it is crucial to prevent the hypertensive phase that can develop after Baerveldt glaucoma drainage implant (BGI) surgery. We describe the combination of BGI surgery with surgical bleb revision to prevent the postoperative hypertensive phase. CASE REPORTS: We report two patients who underwent BGI surgery combined with surgical bleb revision. The combined surgery was performed in a 62-year-old man with open-angle glaucoma (patient 1) and a 37-year-old man with neovascular glaucoma (patient 2) at Asahikawa Medical University in 2013. Each patient had undergone a previous failed trabeculectomy and another trabeculectomy was expected to be unsuccessful. In patient 1, the early postoperative intraocular pressure (IOP) was well controlled due to a well-functioning bleb, despite development of a small amount of hyphema. In contrast, in patient 2 the postoperative IOP was higher with poor bleb formation; however, after bleb needling, the IOP was well controlled. Thus, the usual techniques used after trabeculectomy were also applicable in this combined surgery. For comparison, we also report the case of a 54-year-old woman with secondary glaucoma who underwent BGI surgery alone (patient 3). The postoperative IOP remained relatively high compared to patients 1 and 2. CONCLUSION: Combining BGI surgery with surgical bleb revision might be effective to prevent the hypertensive phase that can occur after BGI surgery. PMID- 24790407 TI - Ocular manifestations of idiopathic aplastic anemia: retrospective study and literature review. AB - Aplastic anemia (AA) is a rare disease with few reports on its ophthalmic manifestations. The ocular findings are described in a retrospective consecutive series of 719 AA Korean patients followed at the Hematology Clinic of The Catholic University of Korea. Out of a total of 719 patients, 269 patients had eye examinations, 156 patients had retinal evaluation, and 37 (23.7%) had retinal findings. These 37 patients had unilateral retinal hemorrhage in seven and bilateral retinal hemorrhage in 30 with mean hemoglobin of 6.6 g/dL (range 2.7 12.6 g/dL) and platelet counts of 18.8*10(9)/L (range 4-157*10(9)/L); central retinal vein occlusion-like picture occurred in nine patients and these had similar rheology to the rest of the subjects; optic disc edema, cotton-wool spots, macular edema, and dry eyes occurred in two, three, five, and three patients, respectively. In this Korean series of 141 subjects with AA, systemic bleeding occurred in 24.8% of subjects, retinal hemorrhage in 37% of subjects, and any bleeding site (eye or elsewhere) occurred in 47.5% of subjects with AA. A literature review (1958-2010) of 200 AA cases revealed retinal hemorrhages in 56%, subhyaloid or vitreous hemorrhage in 9%, peripheral retinal vasculopathy in 5.5%, and cotton-wool spots, Sjogren's syndrome, or optic disc edema in 4% each. The prevalence of retinopathy among series of AA patients varied from 20% to 28.3%, which is consistent with the Korean series of 24.8%. Management of AA patients needs to involve multiple specialties, including hematologists, ophthalmologists, and infectious disease specialists. PMID- 24790408 TI - Presumed toxoplasmic central retinal artery occlusion and multifocal retinitis with perivascular sheathing. AB - Central retinal artery occlusion (CRAO) and multifocal retinitis with perivascular sheathing are rare in ocular toxoplasmosis. We report a case of toxoplasmic CRAO and multifocal retinitis with perivascular sheathing. A healthy 83-year-old male developed left panuveitis. Funduscopic examination of the left eye showed a swollen optic disc and sheathing of the retinal artery with a dense vitreous haze and a white retinal lesion. Serum anti-toxoplasma antibodies were positive in a latex agglutination assay. Vitrectomy was performed to improve visualization of the retinal lesions and for examination of causative microorganisms. A postoperative fundus examination revealed CRAO with optic disc involvement and multifocal retinitis with perivascular sheathing. Qualitative multiplex polymerase chain reaction detected the Toxoplasma gondii B1 gene in ocular fluid from both the aqueous and vitreous humor. The presumed diagnosis of ocular toxoplasmosis was made and treatment was started with prednisone and acetylspiramycin with subsequent improvement. Two months later, the patient developed active retinochoroiditis in the left eye. After 6 weeks of anti toxoplasma therapy, the disease involuted. Retinal vascular occlusions and multifocal retinitis with perivascular sheathing are rare in toxoplasmosis. This is the first case report of toxoplasmic CRAO and multifocal retinitis with perivascular sheathing. The diagnosis of ocular toxoplasmosis should be considered in patients with retinal artery occlusions and multifocal retinitis with perivascular sheathing associated with inflammation. PMID- 24790409 TI - Epoetin zeta in the management of anemia associated with chronic kidney disease, differential pharmacology and clinical utility. AB - Epoetin zeta was granted marketing authorization in October 2007 by the European Medicines Agency as a recombinant human erythropoietin erythropoiesis-stimulating agent to treat symptomatic anemia of renal origin in adult and pediatric patients on hemodialysis and adults on peritoneal dialysis, as well as for symptomatic renal anemia in adult patients with renal insufficiency not yet on dialysis. Currently, epoetin zeta can be administered either subcutaneously or intravenously to correct for hemoglobin concentrations <=10 g/dL (6.2 mmol/L) or with dose adjustment to maintain hemoglobin levels at desired levels not in excess of 12 g/dL (7.5 mmol/L). This review article focuses on epoetin zeta indications in chronic kidney disease, its use in managing anemia of renal origin, and discusses its pharmacology and clinical utility. PMID- 24790411 TI - Clinical and comparative utility of afatinib in non-small cell lung cancer. AB - The first targeted agents approved for non-small cell lung cancer (NSCLC) treatment, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, have an impressive activity in the presence of activating mutations of the EGFR gene. However, all patients develop acquired resistance principally through secondary mutations (T790M), HER2 amplification, MET amplification, and other molecular aberrations. An attempt to overcome EGFR TKI resistance has been through the development of irreversible blockers. Afatinib is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family. The pharmacologic properties of afatinib (formation of covalent bonds, inhibition of other family members, and in vitro and in vivo activity on T790M mutation positive tumors) made this drug particularly appealing to study in clinic. Therefore, an intense program of clinical research (LUX-Lung program) was started and clinical results have shown very encouraging activity profiles in patients harboring EGFR activating mutations and in those with acquired resistance to reversible TKIs. PMID- 24790410 TI - Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis. AB - Psoriasis is a chronic, immune-mediated inflammatory disease affecting both the skin and joints. Approximately 20% of patients suffer a moderate to severe form of skin disease and up to 30% have joint involvement. Standard therapies for psoriasis include topical medications, phototherapy, and both oral systemic and biological therapies whereas therapies for psoriatic arthritis include nonsteroidal anti-inflammatory drugs followed by disease modifying antirheumatic drugs and/or tumor necrosis factor (TNF)-alpha inhibitors and interleukin 12/23p40 inhibitors. Treatment of both diseases is typically driven by disease severity. In the past decade, major advances in the understanding of the immunopathogenesis of psoriasis and psoriatic arthritis have led to the development of numerous biological therapies, which have revolutionized the treatment for moderate to severe plaque psoriasis and psoriatic arthritis. Anti TNF-alpha agents are currently considered as first line biological therapies for the treatment of moderate to severe psoriasis and psoriatic arthritis. Currently approved anti-TNF-alpha agents include etanercept, adalimumab, and infliximab for psoriasis and psoriatic arthritis as well as golimumab and certolizumab for psoriatic arthritis. In this article, we aim to evaluate the long term safety and efficacy of etanercept in psoriasis and psoriatic arthritis. PMID- 24790412 TI - Anti-TNF therapy in Jordan: a focus on severe infections and tuberculosis. AB - BACKGROUND: A high rate of infection has been reported in patients receiving treatment with anti-tumor necrosis factor (anti-TNF). This study describes the rate of and risk factors for serious infections in patients receiving anti-TNF agents in Jordan. METHODS: This retrospective observational study was conducted at a large tertiary referral center in the north of Jordan. Between January 2006 and January 2012, 199 patients who received an anti-TNF agent (infliximab, adalimumab, or etanercept) were included. Patients received the anti-TNF treatment for rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, or other conditions. A serious infection was defined as any bacterial, viral, or fungal infection that required hospitalization, administration of appropriate intravenous antimicrobial therapy, and temporary withholding of anti TNF treatment. RESULTS: The mean duration of anti-TNF treatment was 26.2 months. Steroids were used in 29.1% of patients, while 54.8% were given additional immunosuppressant therapy (methotrexate or azathioprine). Only one anti-TNF agent was given in 70.4% of patients, while 29.6% received different anti-TNF agents for the duration of treatment. Serious infections were documented in 39 patients (19.6%), including respiratory tract infections (41%), urinary tract infections (30.8%), and skin infections (20.5%), and extrapulmonary tuberculosis in three patients (7.7%). Exposure to more than one anti-TNF agent was the only factor associated with a significant increase in the rate of infection (relative risk 1.9, 95% confidence interval 1.06-4.0, P=0.03). CONCLUSION: Serious infections, including tuberculosis, were a common problem in patients receiving anti-TNF agents, and exposure to more than one anti-TNF agent increased the risk of serious infection. PMID- 24790414 TI - Clinical outcomes, not clinical utility, should be the major consideration for saxagliptin with or without metformin. PMID- 24790413 TI - Effects of switching from prandial premixed insulin therapy to basal plus two times bolus insulin therapy on glycemic control and quality of life in patients with type 2 diabetes mellitus. AB - BACKGROUND: The effects of switching from prandial premixed insulin therapy (PPT) injected three times a day to basal plus two times bolus insulin therapy (B2B) on glycemic control and quality of life were investigated in patients with type 2 diabetes mellitus. METHODS: The clinical course was prospectively observed during the first 16 weeks after switching to B2B (insulin glargine plus insulin glulisine before breakfast and dinner) in 27 subjects previously treated with PPT using 50/50 premixed insulin. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was administered at the start and end of the study. RESULTS: The glycated hemoglobin (HbA1c) level (8.3% +/- 1.8% to 8.2% +/- 1.1%) and the DTSQ score did not change between the start and end of the study. An improvement in HbA1c level was found in nine (33%) subjects. The change in HbA1c showed a significant negative correlation with baseline HbA1c, and was significantly better in patients with a baseline HbA1c >8.0% than in those with an HbA1c <= 8.0% (-0.9 +/ 2.0 versus 0.3 +/- 0.6, respectively, P = 0.02). The change in DTSQ score representing treatment satisfaction was significantly greater in patients whose HbA1c level was improved than in those in whom it was not (2.7 +/- 3.6 versus 0.8 +/- 3.5, P = 0.04). CONCLUSION: B2B was noninferior to PPT with regard to HbA1c levels in patients with type 2 diabetes mellitus. B2B should be considered particularly for subjects whose glycemic control is poor despite PPT. PMID- 24790415 TI - The association of smoking with medical treatment adherence in the workforce of a large employer. AB - PURPOSE: Prior descriptive epidemiology studies have shown that smokers have lower compliance rates with preventive care services and lower chronic medication adherence rates for preventive care services in separate studies. The goal of this study was to perform a more detailed analysis to validate both of these findings for current smokers versus nonsmokers within the benefit-covered population of a large US employer. PATIENTS AND METHODS: This study involved the analysis of incurred medical and pharmacy claims for employee and spouse health plan enrollees of a single US-based employer during 2010. Multivariate regression models were used to compare data by active or never-smoker status for preventive care services and medication adherence for chronic conditions. Analysis controlled for demographic variables, chronic condition prevalence, and depression. RESULTS: Controlling for demographic variables and comorbid conditions, smokers had significantly lower cancer screening rates, with absolute reductions of 6%-13%. Adherence to chronic medication use for hypertension was also significantly lower among smokers, with nearly 7% fewer smokers having a medication possession ratio of >=80%. Smokers were less adherent to depression medications (relative risk =0.79) than nonsmokers (P=0.10). While not statistically significant, smokers were consistently less adherent to all other medications than nonsmokers. CONCLUSION: Current smokers are less compliant with recommended preventive care and medication use than nonsmokers, likely contributing to smoking-related employer costs. Awareness of these care gaps among smokers and direct management should be considered as part of a comprehensive population health-management strategy. PMID- 24790416 TI - Patient choice as a driver of medication-switching in non-adherent individuals with bipolar disorder. AB - OBJECTIVE: Psychotropic-related weight gain is a common concern among patients with bipolar disorder (BD). This concern affects satisfaction with treatment and may lead to non-adherence and relapse. This was a 12-week, uncontrolled prospective trial of patient-choice-facilitated ziprasidone switching among non adherent BD patients with weight concerns. This study was conducted from January 2011 to July 2012. METHOD: Patients were asked to identify the "offending" BD medication which they believed was causing weight problems, and this agent was replaced with ziprasidone. The primary outcome was change in adherence as measured with the Tablets Routine Questionnaire (TRQ). Secondary outcomes included medication attitudes, BD symptoms, global psychopathology, social functioning, and quality of life. RESULTS: The most common agents causing weight concerns were quetiapine (N=7, 23%), aripiprazole (N=4, 13%), olanzapine, lithium, and divalproex (all N=3, 10%). Adherence improved from a baseline of missing 48.6% of prescribed BD medication in the past week (44.9% in the past month) to missing 25.3% (P=0.002) of prescribed BD medication in the past week (P<0.001, in the past month) at endpoint. Medication attitudes, symptoms, functioning, and quality of life improved but there were no differences in body weight. CONCLUSION: While findings must be tempered by methodological limitations such as small sample and uncontrolled design, patient-facilitated medication switching appeared to improve adherence and BD outcomes in these non-adherent individuals. Additional studies involving patient-facilitated medication switching and shared decision-making in BD are needed. PMID- 24790417 TI - Patient considerations in the management of type 2 diabetes - critical appraisal of dapagliflozin. AB - Type 2 diabetes affects more than 350 million people worldwide, and its prevalence is increasing. Many patients with diabetes do not achieve and/or maintain glycemic targets, despite therapy implementation and escalation. Multiple therapeutic classes of agents are available for the treatment of type 2 diabetes, and the armamentarium has expanded significantly in the past decade. Selective sodium glucose co-transporter 2 inhibitors, including dapagliflozin, represent the latest development in pharmacologic treatment options for type 2 diabetes. This class has a unique mechanism of action, working by increasing glucose excretion in the urine. The insulin-independent mechanism results in decreased serum glucose, without hypoglycemia or weight gain. Dapagliflozin is a once-daily oral therapy. Expanding therapy options for a complex patient population is critical, and dapagliflozin has a distinct niche that can be a viable option for select patients with diabetes. PMID- 24790418 TI - Factors involved in treatment preference in patients with renal cancer: pazopanib versus sunitinib. AB - The last decade has seen a surge in the treatment options for metastatic renal cell carcinoma and life expectancies are now approaching 3 years from diagnosis. There is some suggestion that, for now at least, we may have reached a plateau in efficacy. Patients are often stable and on treatment for years rather than months. Attention has therefore shifted to a focus on patient preference rather than reported frequency of toxicities. The standard first-line treatment for metastatic clear-cell renal cancer is either sunitinib or pazopanib. The COMPARZ trial has shown that sunitinib and pazopanib have similar efficacy. The PISCES trial, with its unique design, has evaluated patient preference between pazopanib and sunitinib. This review explores the factors involved in treatment preference in patients with renal cancer and in particular the choice between pazopanib and sunitinib. PMID- 24790419 TI - Clinical outcomes of transfusion-associated iron overload in patients with refractory chronic anemia. AB - BACKGROUND: The purpose of this study was to evaluate the clinical outcomes of transfusion-associated iron overload in patients with chronic refractory anemia. METHODS: Clinical manifestations, main organ function, results of computed tomography (CT), endocrine evaluation, and serum ferritin levels were analyzed retrospectively in 13 patients who were transfusion-dependent for more than 1 year (receiving >50 units of red blood cells) to determine the degree of iron overload and efficacy of iron-chelating therapy. RESULTS: Serum ferritin levels increased to 1,830-5,740 ng/mL in all patients. Ten patients had abnormal liver function. The CT Hounsfield units in the liver increased significantly in eleven patients, and were proportional to their serum ferritin levels. Skin pigmentation, liver dysfunction, and endocrine dysfunction were observed in nine patients with serum ferritin >3,500 ng/mL, eight of whom have since died. Interestingly, serum ferritin levels did not decrease significantly in nine transfusion-dependent patients who had received 15-60 days of iron-chelating therapy. CONCLUSION: Transfusion-dependent patients may progress to secondary iron overload with organ impairment, which may be fatal in those who are heavily iron-overloaded. The CT Hounsfield unit is a sensitive indicator of iron overload in the liver. Iron chelation therapy should be initiated when serum ferritin is >1,000 ng/mL and continued until it is <1,000 ng/mL in transfusional iron overloaded patients. PMID- 24790420 TI - A very rare case of HPV-53-related cervical cancer, in a 79-year-old woman with a previous history of negative Pap cytology. AB - The introduction of organized cervical cancer (CC) screening programs has drastically reduced the prevalence of CC. However the incidence is still too high, especially among elderly women. All guidelines strongly recommend a regular Papanicolaou (Pap) testing for young and middle-aged patients. On the other hand, many international professional societies no longer advise screening in women who have undergone hysterectomy, and in women aged 65 years and above, who have a previous history of regular Pap smears. Here we report the case of poorly differentiated CC, involving the pelvic lymph nodes and urinary bladder, occurring in a 79-year-old woman who regularly underwent Pap tests, with no reported cytological abnormalities. In this very rare case, the CC cells, as well as cells from metastatic lymph nodes and cells from urinary specimens, molecularly showed human papilloma virus (HPV)-53. With the limitations of a single case, this report brings important information to prevent CC in elderly patients: the utility of molecular tests to increase sensitivity of Pap smears in postmenopausal women; the importance of HPV-53 as one of the four "emergent" genotypes having a possible role in oncogenesis; and the presence of HPV-53 in lymph node metastases from cervical carcinoma, which would support the role of this virus in the maintenance of malignant status. PMID- 24790421 TI - Survival of chronic hemodialysis patients over 80 years of age. AB - BACKGROUND/AIM: The number of elderly patients with chronic kidney disease (CKD) stage 5 management with hemodialysis (HD) is steadily increasing. Therefore we analyzed the number of new CKD patients >=80 years managed with HD and their survival through the study period. We aimed also, to identify which of several key variables might be independently associated with survival in this very elderly population of patients. PATIENTS AND METHODS: This was a single-center, retrospective cohort study that took place during the period from January 1987 to September 2012. The study consisted of 78 (50 male and 28 women) very elderly patients (>=80 years of age); the mean age at which HD was initiated was 83.2+/ 2.5 years. Survival and factors associated with mortality were studied. Survival was defined as the time from start of HD treatment to death (or end of study, if still alive). RESULTS: In the period from 1987 to 2002, patients >=80 years of age were only sporadically treated with HD, but since 2003, the number of new patients has been steadily increasing. The mean survival for our group of patients was 25.1+/-22.4 months (range 1-115 months). Furthermore, 30.8% patients survived <12 months, 29.5% patients survived 12-24 months, 30.8% patients survived 24-60 months, and 9% patients survived >60 months on HD treatment. Older patients were less likely to have diabetes, and primary renal disease did not influence survival. Patients with high C-reactive protein levels and poor nutritional status, as well as those who did not have pre-HD nephrology care and those that had a catheter as vascular access for HD had poor survival. In about half of our patients, the cause of death was cardiovascular disease. CONCLUSION: Among patients who were >=80 years of age at the start of HD treatment, those who received pre-HD nephrology care that followed a planned management pathway, those who had a good nutritional status, and those with an arteriovenous fistula as vascular access for HD at the time of HD initiation had a better survival. PMID- 24790422 TI - The effects of strength and power training on single-step balance recovery in older adults: a preliminary study. AB - Improving muscle strength and power may mitigate the effects of sarcopenia, but it is unknown if this improves an older adult's ability to recover from a large postural perturbation. Forward tripping is prevalent in older adults and lateral falls are important due to risk of hip fracture. We used a forward and a lateral single-step balance recovery task to examine the effects of strength training (ST) or power (PT) training on single-step balance recovery in older adults. Twenty older adults (70.8+/-4.4 years, eleven male) were randomly assigned to either a 6-week (three times/week) lower extremity ST or PT intervention. Maximum forward (FLean(max)) and lateral (LLean(max)) lean angle and strength and power in knee extension and leg press were assessed at baseline and follow-up. Fifteen participants completed the study (ST =7, PT =8). Least squares means (95% CI) for DeltaFLean(max) (ST: +4.1 degrees [0.7, 7.5]; PT: +0.6 degrees [-2.5, 3.8]) and DeltaLLean(max) (ST: +2.2 degrees [0.4, 4.1]; PT: +2.6 degrees [0.9, 4.4]) indicated no differences between groups following training. In exploratory post hoc analyses collapsed by group, DeltaFLean(max) was +2.4 degrees (0.1, 4.7) and DeltaLLean(max) was +2.4 degrees (1.2, 3.6). These improvements on the balance recovery tasks ranged from ~15%-30%. The results of this preliminary study suggest that resistance training may improve balance recovery performance, and that, in this small sample, PT did not lead to larger improvements in single-step balance recovery compared to ST. PMID- 24790423 TI - Comprehension deficits among older patients in a quick diagnostic unit. AB - BACKGROUND: Higher prevalence of multiple illnesses and cognitive impairment among older patients pose a risk of comprehension difficulties, potentially leading to medication errors. Therefore, the objective of this study was to investigate comprehension of discharge instructions among older patients admitted to a Quick Diagnostic Unit (QDU). METHODS: One hundred and two patients discharged from the QDU answered a questionnaire covering understanding of their hospitalization and discharge plan. Patients' ability to recall discharge instructions and awareness of comprehension deficits, ie, ability to identify the misconceived information, were evaluated by comparing the questionnaires with the discharge letters. The population was divided into an older group (age >=65 years) and a younger group. RESULTS: The older group (n=40) was less able to recall correct medication instructions when compared to the younger group (54% versus 78%, respectively; P=0.02). In multiple logistic regression analysis, correct recall of medication instructions was 4.2 times higher for the younger group compared to the older group (odds ratio 4.2, 95% confidence interval 1.5 11.9, P=0.007) when adjusted for sex and education. The older patients were less aware of their own comprehension deficits, and in respect to medication instructions awareness decreased 6.1% for each additional year of age (odds ratio 0.939, 95% confidence interval 0.904-0.98, P=0.001) when adjusted for sex and education. CONCLUSION: Older patients were less able to recall correct medication instructions and less aware of their comprehension deficits after discharge from a QDU. The findings of the present study emphasize the importance of thorough communication and follow-up when treating older patients. PMID- 24790424 TI - Falls and cognitive decline in Mexican Americans 75 years and older. AB - BACKGROUND: Little is known about long-term emotional and cognitive consequences of falls. We examined the association between falls and subsequent cognitive decline, and tested the hypothesis that depression would mediate any falls cognition association among cognitively intact Hispanic Elders. METHODS: We used data from the Hispanic Established Population for the Epidemiological Study of the Elderly to examine change in Mini Mental State Examination (MMSE) scores over the 6-year period according to number of falls. All participants (N=1,119) had MMSE scores >=21 and complete data on Center for Epidemiologic Studies of Depression Scale, social and demographic factors, medical conditions (diabetes, heart attack, stroke, and hypertension), and hand grip muscle strength. RESULTS: At baseline, participants' mean age was 80.8 years (range, 74-109), mean education was 6.3 years (range, 0-17), and mean MMSE was 25.2 (range, 21-30). Of the 1,119 participants, 15.8% experienced one fall and 14.4% had two or more falls. In mixed model analyses, having two or more falls was associated with greater decline in MMSE score (estimate =-0.81, standard error =0.19, P<0.0001) compared to having no fall, after adjusting for age, sex, marital status, and education. The magnitude of the association decreased (estimate =-0.65, standard error =0.19, P=0.0007) when adjustment was made for high depressive symptoms, suggesting a possible mediating effect of depression on the falls-cognition association. Female sex, high level of education, and high performance in hand grip muscle strength were associated with a slower decline in MMSE scores. CONCLUSION: Having two or more falls was independently associated with steeper decline in cognition over 6 years, with a possible mediating effect of depression on the falls-cognition association. PMID- 24790426 TI - Assessment of patients' preferences regarding the characteristics associated with the treatment of chronic obstructive pulmonary disease. AB - OBJECTIVE: Patient preferences regarding characteristics associated with the treatment of chronic obstructive pulmonary disease (COPD) must be determined to increase the compatibility between the patients and the treatments, but as yet no studies have been performed regarding these characteristics. Here, we evaluate the preferred characteristics associated with the treatment of patients with COPD. METHOD: The expectations of patients receiving copd therapy were assessed in six categories: time allocated by the physician to listen to patients' complaints, treatment to be applied, estimated adverse effect frequency concerning the therapy, ability of patients to visit the same physician each time, integral approach of the physician to the treatment of the patient, and therapy cost. These groups were divided into categories of therapy indicating 25 alternative treatment methods, using conjoint analysis. Patients were sorted to the 25 types of treatment with regard to their preferences. RESULTS: The major expectation of conjoint analysis associated with the treatment of COPD patients is for the therapy to allow the patients to completely recover from their complaints. The order preferred by patients of other treatment expectations is from sufficient time to be allowed by the physician to listen to the patient, to no cost for the treatment, to minimum adverse effects resulting from the treatment, to each follow-up to be performed by the same physician, and to the physician performing an assessment of the patient's well-being, rather than examining only the areas of complaint. CONCLUSION: The major expectation of COPD patients regarding treatment was to completely recover with the help of the therapy. Considering the expectations of the patient may help improve the compatibility of the patient with the treatment. PMID- 24790425 TI - A Chinese Chan-based mind-body intervention improves psychological well-being and physical health of community-dwelling elderly: a pilot study. AB - BACKGROUND: The aim of this study was to explore the potential benefits of the Dejian mind-body intervention (DMBI) for psychological and physical health in older Chinese adults. METHODS: After confirmation of eligibility, the subjects were invited to receive DMBI once a week for 12 weeks. The intervention involved components of learning self-awareness and self-control, practicing mind-body exercises, and adopting a special vegetarian diet. Intervention-related changes were measured using the Perceived Stress Scale, Geriatric Depression Scale, Pittsburgh Sleep Quality Index, Chinese Constipation Questionnaire, and self report ratings of health. Indicators of metabolic syndrome and walking speed were also measured. RESULTS: Of the 44 subjects recruited, 42 (54.8% men) completed the study, giving an adherence rate of 95%. There was a significant reduction in perceived stress (P<0.05). A significant improvement was also found in systolic blood pressure among those who had abnormally high blood pressure at baseline (P<0.05). Physical fitness as reflected by walking speed was also significantly increased after the intervention (P<0.05). Sleep disturbances were reduced (P<0.01). Self-rated health was significantly enhanced, with the percentage rating very good health increasing from 14.3% at baseline to 42.8% after the intervention (P<0.001). No intervention effect was found for waist circumference, lipids and fasting blood glucose levels, Pittsburgh Sleep Quality Index global score, and constipation measures. CONCLUSION: The DMBI was feasible and acceptable, and subjects showed some improvements in psychological and physical health. A larger controlled trial is needed to confirm these promising preliminary results. PMID- 24790427 TI - Novel nano-rough polymers for cartilage tissue engineering. AB - This study presents an innovative method for creating a highly porous surface with nanoscale roughness on biologically relevant polymers, specifically polyurethane (PU) and polycaprolactone (PCL). Nanoembossed polyurethane (NPU) and nanoembossed polycaprolactone (NPCL) were produced by the casting of PU and PCL over a plasma-deposited, spiky nanofeatured crystalline titanium (Ti) surface. The variables used in the process of making the spiky Ti surface can be altered to change the physical properties of the spiky particles, and thus, the cast polymer substrate surface can be altered. The spiky Ti surface is reusable to produce additional nanopolymer castings. In this study, control plain PU and PCL polymers were produced by casting the polymers over a plain Ti surface (without spikes). All polymer surface morphologies were characterized using both scanning electron microscopy and atomic force microscopy, and their surface energies were measured using liquid contact angle measurements. The results revealed that both NPU and NPCL possessed a higher degree of nanometer surface roughness and higher surface energy compared with their respective unaltered polymers. Further, an in vitro study was carried out to determine chondrocyte (cartilage-producing cells) functions on NPU and NPCL compared with on control plain polymers. Results of this study provided evidence of increased chondrocyte numbers on NPU and NPCL compared with their respective plain polymers after periods of up to 7 days. Moreover, the results provide evidence of greater intracellular protein production and collagen secretion by chondrocytes cultured on NPU and NPCL compared with control plain polymers. In summary, the present in vitro results of increased chondrocyte functions on NPU and NPCL suggest these materials may be suitable for numerous polymer-based cartilage tissue-engineering applications and, thus, deserve further investigation. PMID- 24790428 TI - Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer. AB - Conventional chemotherapy of ovarian cancer often fails because of initiation of drug resistance and/or side effects and trace of untouched remaining cancerous cells. This highlights an urgent need for advanced targeted therapies for effective remediation of the disease using a cytotoxic agent with immunomodulatory effects, such as shikonin (SHK). Based on preliminary experiments, we found SHK to be profoundly toxic in ovarian epithelial cancer cells (OVCAR-5 and ID8 cells) as well as in normal ovarian IOSE-398 cells, endothelial MS1 cells, and lymphocytes. To limit its cytotoxic impact solely to tumor cells within the tumor microenvironment (TME), we aimed to engineer SHK as polymeric nanoparticles (NPs) with targeting moiety toward tumor microvasculature. To this end, using single/double emulsion solvent evaporation/diffusion technique with sonication, we formulated biodegradable NPs of poly(lactic-co-glycolic acid) (PLGA) loaded with SHK. The surface of NPs was further decorated with solubilizing agent polyethylene glycol (PEG) and tumor endothelial marker 1 (TEM1)/endosialin-targeting antibody (Ab) through carbodiimide/N-hydroxysuccinimide chemistry. Having characterized the physicochemical and morphological properties of NPs, we studied their drug release profiles using various kinetic models. The biological impact of NPs was also evaluated in tumor-associated endothelial MS1 cells, primary lymphocytes, and epithelial ovarian cancer OVCAR-5 cells. Based on particle size analysis and electron microscopy, the engineered NPs showed a smooth spherical shape with size range of 120 to 250 nm and zeta potential value of -30 to -40 mV. Drug entrapment efficiency was ~80%-90%, which was reduced to ~50%-60% upon surface decoration with PEG and Ab. The liberation of SHK from NPs showed a sustained-release profile that was best fitted with Wagner log-probability model. Fluorescence microscopy and flow cytometry analysis showed active interaction of Ab-armed NPs with TEM1-positive MS1 cells, but not with TEM1-negative MS1 cells. While exposure of the PEGylated NPs for 2 hours was not toxic to lymphocytes, long-term exposure of the Ab-armed and PEGylated NPs was significantly toxic to TEM1 positive MS1 cells and OVCAR-5 cells. Based on these findings, we propose SHK loaded Ab-armed PEGylated PLGA NPs as a novel nanomedicine for targeted therapy of solid tumors. PMID- 24790429 TI - Synthesis and in vitro antineoplastic evaluation of silver nanoparticles mediated by Agrimoniae herba extract. AB - A rapid synthesis of silver nanoparticles (AgNPs) using Agrimoniae herba extract as reducing agent and stabilizer (A. herba-conjugated AgNPs [AH-AgNPs]) were designed, characterized, and evaluated for antitumor therapy feasibility. In this study, critical factors in the preparation of silver nanoparticles, including extraction time, reaction temperature, the concentration of AgNO3, and A. herba extract amount, were investigated using ultraviolet-visible spectroscopy. AH AgNPs with well-defined spherical shape, homogeneous distributional small size (30.34 nm), narrow polydispersity index (0.142), and high negative zeta potential (-36.8 mV) were observed by transmission electron microscopy and dynamic light scattering. Furthermore, the results of X-ray diffraction and Fourier-transform infrared spectroscopy further indicated successful preparation of AH-AgNPs. Acceptable long-term storage stability of AH-AgNPs was also confirmed. More importantly, AH-AgNPs displayed significantly higher antiproliferative effect against a human lung carcinoma cell line (A549 cells) compared with A. herba extract and bare AgNPs prepared by sodium citrate. The half-maximal inhibitory concentrations of AH-AgNPs, bare AgNPs, and A. herba extract were 38.13 MUg . mL( 1), 184.87 MUg . mL(-1), and 1.147 * 10(4) MUg . mL(-1), respectively. It is suggested that AH-AgNPs exhibit a strong antineoplastic effect on A549 cells, pointing to feasibility of antitumor treatment in the future. PMID- 24790430 TI - Green synthesis of water-soluble nontoxic polymeric nanocomposites containing silver nanoparticles. AB - New water-soluble nontoxic nanocomposites of nanosized silver particles in a polymer matrix were synthesized by a green chemistry method. Nontoxic poly(1 vinyl-1,2,4-triazole) was used as a stabilizing precursor agent in aqueous medium. Glucose and dimethyl sulfoxide were used as the silver ion-reducing agents to yield silver nanoparticles 2-26 nm and 2-8 nm in size, respectively. The nanocomposites were characterized by transmission electron microscopy, ultraviolet-visible and Fourier transform infrared spectroscopy, X-ray diffraction, atomic absorption, and thermogravimetric data analysis. The nanocomposites showed strong antimicrobial activity against Gram-negative and Gram-positive bacteria. PMID- 24790431 TI - Enhanced primary tumor delineation in pancreatic adenocarcinoma using ultrasmall super paramagnetic iron oxide nanoparticle-ferumoxytol: an initial experience with histopathologic correlation. AB - PURPOSE: To evaluate the role of ferumoxytol-enhanced magnetic resonance imaging (MRI) in delineating primary pancreatic tumors in patients undergoing preoperative neoadjuvant therapy. MATERIALS AND METHODS: Eight patients with pancreatic adenocarcinoma were enrolled in this study, and underwent MRI scans at baseline, immediate post, and at the 48 hour time point after ferumoxytol injection with quantitative T2* sequences. The patients were categorized into two groups; group A received preoperative neoadjuvant therapy and group B did not. The T2* of the primary pancreatic tumor and adjacent parenchyma was recorded at baseline and the 48 hour time point. After surgery, the primary tumors were assessed histopathologically for fibrosis and inflammation. RESULTS: The mean T2* of the primary tumor and adjacent parenchyma at 48 hours in group A were 22.11 ms and 16.34 ms, respectively; in group B, these values were 23.96 ms and 23.26 ms, respectively. The T2* difference between the tumor and adjacent parenchyma in group A was more pronounced compared to in group B. The tumor margins were subjectively more distinct in group A compared to group B. Histopathologic evaluation showed a rim of dense fibrosis with atrophic acini at the periphery of the lesion in group A. Conversely, intact tumor cells/glands were present at the periphery of the tumor in group B. CONCLUSION: Ferumoxytol-enhanced MRI scans in patients receiving preoperative neoadjuvant therapy may offer enhanced primary tumor delineation, contributing towards achieving disease-free margin at the time of surgery, and thus improving the prognosis of pancreatic carcinomas. PMID- 24790432 TI - Sequential release of salidroside and paeonol from a nanosphere-hydrogel system inhibits ultraviolet B-induced melanogenesis in guinea pig skin. AB - Melanin is the one of most important pigments for skin color in mammals. Excessive biosynthesis of melanin induces various pigment disorders. Much effort has been made to develop regulators to minimize skin pigmentation abnormalities. However, only a few of them are used, primarily because of safety concerns and low efficiency. In this study, we aimed to construct a novel nanosphere-gel for sequential delivery of salidroside and paeonol, to investigate the synergistic effects of these drugs in anti-melanogenesis, and to decrease their potential for toxicity in high dosage. Nanospheres were prepared and characterized for their particle size, polydispersity index, zeta potential, and morphological properties. The optimized nanospheres were incorporated in carbomer hydrogel with both paeonol and salidroside entrapped to form a dual drug-releasing nanosphere gel. With this nanosphere-gel, rapid release of salidroside from the hydrogel followed by sustained release of paeonol from the nanosphere was achieved. Using a classical model of the melanogenesis response to ultraviolet exposure, it was shown that the anti-melanogenesis effects of the dual drug-releasing system, in which the doses of the individual drugs were decreased by half, was obviously enhanced when compared with the effects of the single drug preparations. Mechanistically, the burst release of salidroside from the hydrogel may enable prompt suppression of melanocyte proliferation on exposure to ultraviolet B radiation, while the paeonol released in a sustained manner can provide continuous inhibition of tyrosinase activity in melanocytes. Combined delivery of salidroside and paeonol was demonstrated to be a promising strategy for enhancing the therapeutic efficacy of these agents in anti-melanogenesis and reducing their toxicity, so may have great potential in nanomedicine. PMID- 24790433 TI - Preparation and properties of poly(vinyl alcohol)/chitosan blend bionanocomposites reinforced with cellulose nanocrystals/ZnO-Ag multifunctional nanosized filler. AB - A series of novel bionanocomposites were cast using different contents of zinc oxide-silver nanoparticles (ZnO-AgNPs) stabilized by cellulose nanocrystals (CNC) as multifunctional nanosized fillers in poly(vinyl alcohol)/chitosan (PVA/Cs) matrices. The morphological structure, mechanical properties, ultraviolet-visible absorption, and antimicrobial properties of the prepared films were investigated as a function of their CNC/ZnO-AgNP content and compared with PVA/chitosan/CNC bionanocomposite films. X-ray diffraction and field emission scanning electron microscopic analyses showed that the CNC/ZnO-AgNPs were homogeneously dispersed in the PVA/Cs matrix and the crystallinity increased with increasing nanosized filler content. Compared with pure PVA/Cs, the tensile strength and modulus in the films increased from 0.055 to 0.205 GPa and from 0.395 to 1.20 GPa, respectively. Ultraviolet and visible light can be efficiently absorbed by incorporating ZnO-AgNPs into a PVA/Cs matrix, suggesting that these bionanocomposite films show good visibility and ultraviolet-shielding effects. The bionanocomposite films had excellent antimicrobial properties, killing both Gram-negative Salmonella choleraesuis and Gram-positive Staphylococcus aureus. The enhanced physical properties achieved by incorporating CNC/ZnO-AgNPs could be beneficial in various applications. PMID- 24790434 TI - Biodistribution and acute toxicity of a nanofluid containing manganese iron oxide nanoparticles produced by a mechanochemical process. AB - Superparamagnetic iron oxide nanoparticles are candidate contrast agents for magnetic resonance imaging and targeted drug delivery. Biodistribution and toxicity assessment are critical for the development of nanoparticle-based drugs, because of nanoparticle-enhanced biological reactivity. Here, we investigated the uptake, in vivo biodistribution, and in vitro and in vivo potential toxicity of manganese ferrite (MnFe2O4) nanoparticles, synthesized by an original high-yield, low-cost mechanochemical process. Cultures of murine Balb/3T3 fibroblasts were exposed for 24, 48, or 72 hours to increasing ferrofluid concentrations. Nanoparticle cellular uptake was assessed by flow-cytometry scatter-light measurements and microscopy imaging after Prussian blue staining; cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony-forming assays. After a single intravenous injection, in vivo nanoparticle biodistribution and clearance were evaluated in mice by Mn spectrophotometric determination and Prussian blue staining in the liver, kidneys, spleen, and brain at different posttreatment times up to 21 days. The same organs were analyzed for any possible histopathological change. The in vitro study demonstrated dose-dependent nanoparticle uptake and statistically significant cytotoxic effects from a concentration of 50 MUg/mL for the MTT assay and 20 MUg/mL for the colony-forming assay. Significant increases in Mn concentrations were detected in all analyzed organs, peaking at 6 hours after injection and then gradually declining. Clearance appeared complete at 7 days in the kidneys, spleen, and brain, whereas in the liver Mn levels remained statistically higher than in vehicle-treated mice up to 3 weeks postinjection. No evidence of irreversible histopathological damage to any of the tested organs was observed. A comparison of the lowest in vitro toxic concentration with the intravenously injected dose and the administered dose of other ferrofluid drugs currently in clinical practice suggests that there might be sufficient safety margins for further development of our formulation. PMID- 24790435 TI - Photothermolysis mediated by gold nanorods modified with EGFR monoclonal antibody induces Hep-2 cells apoptosis in vitro and in vivo. AB - Gold nanorods (AuNRs) have been used in plasmonic photothermal therapy (PPTT), which is thought to be more efficient and selective than conventional photothermal therapy. The efficiency and safety of PPTT can be improved by functionally modifying the gold nanorods with proteins or biomolecules. In this study, AuNRs were modified with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), and the apoptotic potential of EGFRmAb-AuNR was assessed in Hep-2 cells in vitro and in vivo. The EGFRmAb modification had no obvious influence on the original optical property of the AuNRs, but it significantly increased the entry of AuNRs into Hep-2 cells. EGFRmAb-AuNRs, with appropriate laser irradiation, resulted in higher Hep-2 cells apoptosis than AuNRs did alone, in vitro, and was accompanied by alteration of reactive oxygen species (ROS) production, Ca(2+) release, change in mitochondrial membrane potential (DeltaPsim), cytochrome c (Cyt-c) release, active caspase-3 expression, and level of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma 2 protein-associated X protein (Bax). EGFRmAb-AuNR-mediated apoptosis in Hep-2 cells was also observed in vivo and had an inhibitive effect on growth of Hep-2 tumor xenografts. Our data suggest that the EGFRmAb modification improves AuNR-mediated apoptosis and may have the potential to be used clinically. PMID- 24790436 TI - Comparative toxicological assessment of PAMAM and thiophosphoryl dendrimers using embryonic zebrafish. AB - Dendrimers are well-defined, polymeric nanomaterials currently being investigated for biomedical applications such as medical imaging, gene therapy, and tissue targeted therapy. Initially, higher generation (size) dendrimers were of interest because of their drug carrying capacity. However, increased generation was associated with increased toxicity. The majority of studies exploring dendrimer toxicity have focused on a small range of materials using cell culture methods, with few studies investigating the toxicity across a wide range of materials in vivo. The objective of the present study was to investigate the role of surface charge and generation in dendrimer toxicity using embryonic zebrafish (Danio rerio) as a model vertebrate. Due to the generational and charge effects observed at the cellular level, higher generation cationic dendrimers were hypothesized to be more toxic than lower generation anionic or neutral dendrimers with the same core composition. Polyamidoamine (PAMAM) dendrimers elicited significant morbidity and mortality as generation was decreased. No significant adverse effects were observed from the suite of thiophosphoryl dendrimers studied. Exposure to >=50 ppm cationic PAMAM dendrimers G3-amine, G4-amine, G5-amine, and G6-amine caused 100% mortality by 24 hours post-fertilization. Cationic PAMAM G6 amine at 250 ppm was found to be statistically more toxic than both neutral PAMAM G6-amidoethanol and anionic PAMAM G6-succinamic acid at the same concentration. The toxicity observed within the suite of varying dendrimers provides evidence that surface charge may be the best indicator of dendrimer toxicity. Dendrimer class and generation are other potential contributors to the toxicity of dendrimers. Further studies are required to better understand the relative role each plays in driving the toxicity of dendrimers. To the best of our knowledge, this is the first in vivo study to address such a broad range of dendrimers. PMID- 24790437 TI - Electrosprayed core-shell solid dispersions of acyclovir fabricated using an epoxy-coated concentric spray head. AB - A novel structural solid dispersion (SD) taking the form of core-shell microparticles for poorly water-soluble drugs is reported for the first time. Using polyvinylpyrrolidone (PVP) as a hydrophilic polymer matrix, the SDs were fabricated using coaxial electrospraying (characterized by an epoxy-coated concentric spray head), although the core fluids were unprocessable using one fluid electrospraying. Through manipulating the flow rates of the core drug loaded solutions, two types of core-shell microparticles with tunable drug contents were prepared. They had average diameters of 1.36+/-0.67 and 1.74+/-0.58 MUm, and were essentially a combination of nanocomposites with the active ingredient acyclovir (ACY) distributed in the inner core, and the sweeter sucralose and transmembrane enhancer sodium dodecyl sulfate localized in the outer shell. Differential scanning calorimetry and X-ray diffraction results demonstrated that ACY, sodium dodecyl sulfate, and sucralose were well distributed in the PVP matrix in an amorphous state because of favorable second order interactions. In vitro dissolution and permeation studies showed that the core-shell microparticle SDs rapidly freed ACY within 1 minute and promoted nearly eightfold increases in permeation rate across the sublingual mucosa compared with raw ACY powders. PMID- 24790438 TI - Biological responses according to the shape and size of carbon nanotubes in BEAS 2B and MESO-1 cells. AB - This study aimed to investigate the influence of the shape and size of multi walled carbon nanotubes (MWCNTs) and cup-stacked carbon nanotubes (CSCNTs) on biological responses in vitro. Three types of MWCNTs - VGCF((r))-X, VGCF((r))-S, and VGCF((r)) (vapor grown carbon fibers; with diameters of 15, 80, and 150 nm, respectively) - and three CSCNTs of different lengths (CS-L, 20-80 MUm; CS-S, 0.5 20 MUm; and CS-M, of intermediate length) were tested. Human bronchial epithelial (BEAS-2B) and malignant pleural mesothelioma cells were exposed to the CNTs (1-50 MUg/mL), and cell viability, permeability, uptake, total reactive oxygen species/superoxide production, and intracellular acidity were measured. CSCNTs were less toxic than MWCNTs in both cell types over a 24-hour exposure period. The cytotoxicity of endocytosed MWCNTs varied according to cell type/size, while that of CSCNTs depended on tube length irrespective of cell type. CNT diameter and length influenced cell aggregation and injury extent. Intracellular acidity increased independently of lysosomal activity along with the number of vacuoles in BEAS-2B cells exposed for 24 hours to either CNT (concentration, 10 MUg/mL). However, total reactive oxygen species/superoxide generation did not contribute to cytotoxicity. The results demonstrate that CSCNTs could be suitable for biological applications and that CNT shape and size can have differential effects depending on cell type, which can be exploited in the development of highly specialized, biocompatible CNTs. PMID- 24790440 TI - Folate-targeted paclitaxel-conjugated polymeric micelles inhibits pulmonary metastatic hepatoma in experimental murine H22 metastasis models. AB - Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA) and paclitaxel (PTX) containing composite micelles (FA-M[PTX]) were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX) on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22) on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain), followed by survival analysis. The results indicated that FA-M(PTX) prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA-M(PTX) group gained significantly prolonged survival time when compared with others given equivalent doses of PTX of 30 mg/kg. The enhanced efficacy of FA-M(PTX) is theoretically ascribed to the target effect of FA; moreover, the extensive pulmonary capillary networks may play a role. In conclusion, FA-M(PTX) displayed great potential as a promising antimetastatic agent, and the FA conjugated micelles is a preferential targeted delivery system when compared to micelles without FA. PMID- 24790439 TI - Preparation and characterization of polylactide/poly(epsilon-caprolactone) poly(ethylene glycol)-poly(epsilon-caprolactone) hybrid fibers for potential application in bone tissue engineering. AB - The aim of this study was to develop a kind of osteogenic biodegradable composite graft consisting of human placenta-derived mesenchymal stem cell (hPMSC) material for site-specific repair of bone defects and attenuation of clinical symptoms. The novel nano- to micro-structured biodegradable hybrid fibers were prepared by electrospinning. The characteristics of the hybrid membranes were investigated by a range of methods, including Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. Morphological study with scanning electron microscopy showed that the average fiber diameter and the number of nanoscale pores on each individual fiber surface decreased with increasing concentration of poly(epsilon-caprolactone)-poly(ethylene glycol) poly(epsilon-caprolactone) (PCEC). The prepared polylactide (PLA)/PCEC fibrous membranes favored hPMSC attachment and proliferation by providing an interconnected, porous, three-dimensional mimicked extracellular environment. What is more, hPMSCs cultured on the electrospun hybrid PLA/PCEC fibrous scaffolds could be effectively differentiated into bone-associated cells by positive alizarin red staining. Given the good cellular response and excellent osteogenic potential in vitro, the electrospun PLA/PCEC fibrous scaffolds could be one of the most promising candidates for bone tissue engineering. PMID- 24790441 TI - Tissue-specific direct microtransfer of nanomaterials into Drosophila embryos as a versatile in vivo test bed for nanomaterial toxicity assessment. AB - Nanomaterials are the subject of intense research, focused on their synthesis, modification, and biomedical applications. Increased nanomaterial production and their wide range of applications imply a higher risk of human and environmental exposure. Unfortunately, neither environmental effects nor toxicity of nanomaterials to organisms are fully understood. Cost-effective, rapid toxicity assays requiring minimal amounts of materials are needed to establish both their biomedical potential and environmental safety standards. Drosophila exemplifies an efficient and cost-effective model organism with a vast repertoire of in vivo tools and techniques, all with high-throughput scalability and screening feasibility throughout its life cycle. Here we report tissue specific nanomaterial assessment through direct microtransfer into target tissues. We tested several nanomaterials with potential biomedical applications such as single-wall carbon nanotubes, multiwall carbon nanotubes, silver, gold, titanium dioxide, and iron oxide nanoparticles. Assessment of nanomaterial toxicity was conducted by evaluating progression through developmental morphological milestones in Drosophila. This cost-effective assessment method is amenable to high-throughput screening. PMID- 24790442 TI - Apoptosis selectively induced in BEL-7402 cells by folic acid-modified magnetic nanoparticles combined with 100 Hz magnetic field. AB - OBJECTIVE: To explore the effect of folic acid-modified magnetic nanoparticles (FA-MNPs) combined with a 100 Hz extremely low-frequency electromagnetic field (ELF-EMF) on the apoptosis of liver cancer BEL-7402 cells. MATERIALS AND METHODS: MNPs (20 nm) were prepared by coprecipitation, and then folic acid was coated onto MNPs to prepare FA-MNPs. BEL-7402 cells and HL7702 cells were selected as liver cancer cells and normal liver cells, respectively. The ELF-EMF was generated from a solenoid coil. Cellular uptake of NPs was determined by inductively coupled plasma atomic emission spectroscopy. A 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cell inhibition. Apoptosis was analyzed by flow cytometry. Statistical analyses were performed using two-way analysis of variance. RESULTS: FA-MNPs combined with a 100 Hz magnetic field significantly inhibited cell proliferation and induced higher apoptosis compared to either the ELF-EMF alone or FA-MNPs alone. FA-MNPs showed a better apoptosis effect and higher iron uptake in BEL-7402 cells compared to in HL7702 cells. On the basis of the ELF-EMF, higher doses of FA-MNPs brought higher apoptosis and higher iron uptake in either BEL-7402 cells or HL7702 cells. CONCLUSION: These results suggest that FA-MNPs may induce apoptosis in a cellular iron uptake-dependent manner when combined with an ELF-EMF in BEL-7402 cells. PMID- 24790443 TI - Proposed criteria for schizophrenia remission. PMID- 24790444 TI - Suicidal ideation and the risk of suicide in patients with fibromyalgia: a comparison with non-pain controls and patients suffering from low-back pain. AB - Fibromyalgia is associated with an increased rate of mortality from suicide. In fact, this disease is associated with several characteristics that are linked to an increased risk of suicidal behaviors, such as being female and experiencing chronic pain, psychological distress, and sleep disturbances. However, the literature concerning suicidal behaviors and their risk factors in fibromyalgia is sparse. The objectives of the present study were to evaluate the prevalence of suicidal ideation and the risk of suicide in a sample of patients with fibromyalgia compared with a sample of healthy subjects and a sample of patients with chronic low-back pain. We also aimed to evaluate the relevance of pain intensity, depression, and sleep quality as variables related to suicidal ideation and risks. Logistic regression was applied to estimate the likelihood of suicidal ideation and the risk of suicide adjusted by age and sex. We also used two logistic regression models using age, sex, pain severity score, depression severity, sleep quality, and disease state as independent variables and using the control group as a reference. Forty-four patients with fibromyalgia, 32 patients with low-back pain, and 50 controls were included. Suicidal ideation, measured with item 9 of the Beck Depression Inventory, was almost absent among the controls and was low among patients with low-back pain; however, suicidal ideation was prominent among patients with fibromyalgia (P<0.0001). The risk of suicide, measured with the Plutchik Suicide Risk Scale, was also higher among patients with fibromyalgia than in patients with low-back pain or in controls (P<0.0001). The likelihood for suicidal ideation and the risk of suicide were higher among patients with fibromyalgia (odds ratios of 26.9 and 48.0, respectively) than in patients with low-back pain (odds ratios 4.6 and 4.7, respectively). Depression was the only factor associated with suicidal ideation or the risk of suicide. PMID- 24790445 TI - Agomelatine in the treatment of depressive disorders in clinical practice: multicenter observational CHRONOS study. AB - BACKGROUND: CHRONOS was a large naturalistic study designed to evaluate the effectiveness and safety of agomelatine in the management of patients with major depression in routine clinical practice. METHODS: Patients (n=6,276) with a moderate or severe major depressive episode without psychotic symptoms were treated initially as outpatients (80.2%) or in psychiatric facilities (19.8%) in 54 regions of the Russian Federation. Patients received a flexible-dosing regimen of agomelatine 25 mg or 50 mg once daily for 8 weeks, with frequent study visits (weeks 1, 2, 3, 4, 6, and 8). RESULTS: Patients (mean age 44 years, 72.6% female) showed progressive improvement on the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score from 22+/-6.9 at baseline to 4.7+/-4.7 at week 8 (P<0.0001). The proportion of responders (HAMD-17 decrease of >=50%) was 90.1% and the proportion of remitters (HAMD-17 <7) was 79.1% at week 8. All individual HAMD-17 item scores improved rapidly, and the change relative to baseline was significant (P<0.0001) at week 1 and at each subsequent visit in all cases. There were corresponding rapid improvements in Clinical Global Impression Severity and Improvement scores. In the subgroup of patients with more severe illness (HAMD-17 >=21 at baseline; n=3,478), the proportions of responders and remitters were 92.4% and 72.8%, respectively, at week 8. CONCLUSION: Agomelatine was effective and well tolerated in a large sample of depressed patients in an observational treatment setting, and showed a rapid onset of benefit across all HAMD-17 items. PMID- 24790446 TI - A case report of suicidal behavior related to subclinical hyperthyroidism. AB - Abnormalities in thyroid function are associated with many psychiatric symptoms. We present a report of a 15-year-old girl who was admitted to the psychiatry inpatient unit with symptoms of suicidal behavior, irritability, and impulsivity. One year previously, she had become more short-tempered, and had started to cut her wrists impulsively. Laboratory tests revealed subclinical hyperthyroidism. She was treated with anxiolytic and antithyroid drugs, and her suicidal ideation and irritability resolved. This case demonstrates that subclinical hyperthyroidism can be associated with suicidal behavior as well as overt hyperthyroidism. Early intervention is required to prevent suicidal behavior in patients with subclinical hyperthyroidism. PMID- 24790447 TI - Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population. AB - OBJECTIVE: Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia. MATERIALS AND METHODS: We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls. RESULTS: A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction. CONCLUSION: It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted. PMID- 24790448 TI - Spatial memory impairments in amnestic mild cognitive impairment in a virtual radial arm maze. AB - OBJECTIVE: This study aims to apply the virtual radial arm maze (VRAM) task to find spatial working memory and reference memory impairments in patients of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Spatial memory functions between aMCI converters and nonconverters are also compared using VRAM results. METHODS: We assessed the spatial memory in 20 normal controls, 20 aMCI, and 20 mild AD subjects using VRAM. The Mini-Mental State Examination, Clinical Dementia Rating scale, and other neuropsychological tests were given to the subjects in conjunction with the VRAM test. Scores in working memory errors and reference memory errors were compared among the three groups using repeated measures analysis of variance. In addition, aMCI patients were followed-up after 5 years and surveyed for AD conversion rate. RESULTS: In AD patients, both spatial working and reference memory were impaired. However, in aMCI subjects, only spatial reference memory was impaired. Significant spatial reference memory impairment was found in the aMCI converter group when compared to the nonconverter group. CONCLUSION: Spatial working memory is less impaired in aMCI while reference memory is similarly damaged in AD. In aMCI patients, more severe spatial reference memory deficit is a neuropsychological marker for AD conversion. VRAM may be well utilized in humans to assess spatial memory in normal aging, in aMCI, and in AD. PMID- 24790449 TI - Changes in cerebral blood flow after cognitive behavior therapy in patients with panic disorder: a SPECT study. AB - AIM: Inconsistent results continue to be reported in studies that examine the neural correlates of cognitive behavioral therapy (CBT) in patients with panic disorder. We examined the changes in regional cerebral blood flow (rCBF) associated with the alleviation of anxiety by CBT in panic patients. METHODS: The change in rCBF and clinical symptoms before and after CBT were assessed using single photon emission computed tomography and various clinical measures were analyzed. RESULTS: Fourteen subjects who completed CBT showed significant improvements in symptoms on clinical measures, including the Panic and Agoraphobic Scale and the Anxiety Sensitivity Index-Revised. After CBT, increased rCBF was detected in the left postcentral gyrus (BA 43), left precentral gyrus (BA 4), and left inferior frontal gyrus (BA 9 and BA 47), whereas decreased rCBF was detected in the left pons. Correlation analysis of the association between the changes in rCBF and changes in each clinical measure did not show significant results. CONCLUSION: We found changes in the rCBF associated with the successful completion of CBT. The present findings may help clarify the effects of CBT on changes in brain activity in panic disorder. PMID- 24790450 TI - Letter to the editor regarding "Study design of 'Friends for Life': a process and effect evaluation of an indicated school-based prevention program": response to Lima et al. PMID- 24790451 TI - Building a diagnostic algorithm on localized neuropathic pain (LNP) and targeted topical treatment: focus on 5% lidocaine-medicated plaster. AB - Within the broad definition of neuropathic pain, the refinement of clinical diagnostic procedures has led to the introduction of the concept of localized neuropathic pain (LNP). It is characterized by consistent and circumscribed area(s) of maximum pain, which are associated with negative or positive sensory signs and/or spontaneous symptoms typical of neuropathic pain. This description outlines the clinical features (currently lacking in guidelines and treatment recommendations) in patients for whom topical targeted treatment with 5% lidocaine-medicated plaster is suggested as first-line therapy. Few epidemiologic data are present in the literature but it is generally estimated that about 60% of neuropathic pain conditions are localized, and therefore identifiable as LNP. A mandatory clinical criterion for the diagnosis of LNP is that signs and symptoms must be present in a clearly identified and defined area(s). Cartographic recordings can help to define each area and to assess variations. The diagnosis of LNP relies on careful neurological examination more than on pain questionnaires, but it is recognized that they can be extremely useful for recording the symptom profiles and establishing a more targeted treatment. The most widely studied frequent/relevant clinical presentations of LNP are postherpetic neuralgia, diabetic neuropathy, and neuropathic postoperative pain. They successfully respond to treatment with 5% lidocaine-medicated plaster with equal if not better pain control but with fewer side effects versus conventional systemic treatments. Generally, the more localized the pain (ie, the area of an A4 sheet of paper) the better the results of topical treatment. This paper proposes an easy-to-understand algorithm to identify patients with LNP and to guide targeted topical treatments with 5% lidocaine medicated plaster. PMID- 24790452 TI - Association between MDM2 rs 2279744 polymorphism and breast cancer susceptibility: a meta-analysis based on 9,788 cases and 11,195 controls. AB - PURPOSE: Previous studies have suggested associations between MDM2 (mouse double minute 2 homolog) polymorphisms and cancer risk. The aim of this study was to evaluate the relationship between the MDM2 rs 2279744 polymorphism and the susceptibility of breast cancer. METHODS: We searched PubMed, Web of Knowledge, Embase, and the Chinese National Knowledge Infrastructure (CNKI) database for case-control studies published up to October 2013 that investigated MDM2 rs 2279744 polymorphism and breast cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of these associations. RESULTS: A total of 19 studies were identified for the meta-analysis, including 9,788 cases and 11,195 controls. The variant heterozygote (TG) was associated with breast cancer risk in the overall population (TG vs TT: OR =1.10, 95% CI =1.04 1.17, P=0.001, P=0.23 for heterogeneity test). In the subgroup analyses by ethnicity, a significantly increased risk was observed among Asians (G vs T: OR =1.12, 95% CI =1.02-1.23, P=0.02, P het=0.04; GG vs TT: OR =1.29, 95% CI =1.06 1.56, P=0.01, P het=0.04; TG vs TT: OR =1.36, 95% CI =1.15-1.60, P=0.0004, P het=0.45; dominant model TG+GG vs TT: OR =1.21, 95% CI =1.03-1.41, P=0.02, P het=0.07). However, among Caucasians, rs 2279744 was associated with breast cancer risk in only one genotype (TG vs TT: OR =1.09, 95% CI =1.00-1.18, P=0.04, P het=0.37). No publication bias was found in the present study. CONCLUSION: This meta-analysis provides evidence for the association between the MDM2 rs 2279744 polymorphism and breast cancer susceptibility. The results suggest that the MDM2 rs 2279744 polymorphism plays an important role in breast cancer, especially in Asians. PMID- 24790455 TI - Quality of life in patients with visual impairment in Ibadan: a clinical study in primary care. AB - BACKGROUND: Visual function is important for optimal orientation in functional and social life, and has an effect on physical and emotional well-being. Visual impairment, therefore, leads to restrictions in all aspects of daily living and is related to quality of life. The aim of this study was to provide information on the causes of visual impairment in patients presenting to their family physician, the spectrum of impairment, and its impact on quality of life for these patients. METHODS: This descriptive cross-sectional study of 375 adult patients with ocular symptoms was performed in the general outpatient department of the University College Hospital, Ibadan, from July to September, 2009. After checking their presenting visual acuity, the patients were interviewed using the Vision-Related Quality of Life questionnaire to determine the impact of visual impairment on their quality of life. Ophthalmic examinations were performed to determine the causes of visual impairment. The results were analyzed using proportions and percentages. RESULTS: The main causes of visual impairment were cataracts (58.7%), refractive error (19.4%), and glaucoma (2.9%). Visual impairment was found to be associated with advancing age, low education, and unemployment (P<0.001). Most patients (85.1%) were found to have good quality of life overall. Quality of life was found to be poor in the domains of visual function (64.2%) and social interaction (50.9%). Quality of life was found to be related to the degree of visual impairment, ie, blind patients reported poor quality of life (41.4%) when compared with those having low vision (8.6%) or near normal vision (2.4%, P<0.001). CONCLUSION: This study identified poor quality of life in patients with a higher degree of visual impairment. Family physicians need to identify these visually impaired patients early and make timely referrals. PMID- 24790453 TI - Current and future prospects in the management of granulomatosis with polyangiitis (Wegener's granulomatosis). AB - Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) is a multisystem autoimmune condition associated with anti-neutrophil cytoplasm antibodies. Management of GPA can be complex, owing to the sometimes fulminant and multisystem nature of the presentation, the age demographics of the affected population, and a significant incidence of disease relapse. In this paper, we discuss how some of the challenges in the management of GPA have been and continue to be addressed including: reducing the toxicity of induction therapy; developing biomarkers to determine who can safely stop maintenance immunosuppression; improving the efficacy of maintenance therapy for relapsing patients; managing localized disease; and management of disease and treatment associated comorbidity. Consideration is also given to emerging therapeutics in the treatment of GPA. PMID- 24790454 TI - Acute-on-chronic liver failure: a review. AB - There is no universally accepted definition of acute-on-chronic liver failure; however, it is recognized as an entity characterized by decompensation from an underlying chronic liver disease associated with organ failure that conveys high short-term mortality, with alcoholism and infection being the most frequent precipitating events. The pathophysiology involves inflammatory processes associated with a trigger factor in susceptible individuals (related to altered immunity in the cirrhotic population). This review addresses the different definitions developed by leading research groups, epidemiological and pathophysiological aspects, and the latest treatments for this entity. PMID- 24790456 TI - Optimizing strategies to improve interprofessional practice for veterans, part 1. AB - INTRODUCTION: Interprofessional patient care is a well-recognized path that health care systems are striving toward. The Veteran's Affairs (VA) system initiated interprofessional practice (IPP) models with their Geriatric Evaluation and Management (GEM) programs. GEM programs incorporate a range of specialties, including but not limited to, medicine, nursing, social work, physical therapy and pharmacy, to collaboratively evaluate veterans. Despite being a valuable resource, they are now faced with significant cut-backs, including closures. The primary goal of this project was to assess how the GEM model could be optimized at the Pittsburgh, Pennsylvania VA to allow for the sustainability of this important IPP assessment. Part 1 of the study evaluated the IPP process using program, patient, and family surveys. Part 2 examined how well the geriatrician matched patients to specialists in the GEM model. This paper describes Part 1 of our study. METHODS: THREE STRATEGIES WERE USED: 1) a national GEM program survey; 2) a veteran/family satisfaction survey; and 3) an absentee assessment. RESULTS: Twenty-six of 92 programs responded to the GEM IPP survey. Six strategies were shared to optimize IPP models throughout the country. Of the 34 satisfaction surveys, 80% stated the GEM clinic was beneficial, 79% stated their concerns were addressed, and 100% would recommend GEM to their friends. Of the 24 absentee assessments, the top three reasons for missing the appointments were transportation, medical illnesses, and not knowing/remembering about the appointment. Absentee rate diminished from 41% to 19% after instituting a reminder phone call policy. DISCUSSION: Maintaining the sustainability of IPP programs is crucial for the health of our veterans. This project uncovered tools to improve the GEM IPP model for our veterans that can be incorporated nationally. Despite the lengthy nature of IPP models, patients and families appreciated the thoroughness, requested transportation and food, and responded well to reminder phone calls. A keen eye on these issues and concomitant medical complexity needs to be observed when planning IPP models to ensure sustainability. PMID- 24790457 TI - Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma. AB - In mammalian cells, microtubules are present both in interphase and dividing cells. In the latter, microtubules forming the mitotic spindle are highly dynamic and exquisitely sensitive to therapeutic inhibitors. Developed to alter microtubule function, microtubule-binding agents have been proven to be highly active as an anticancer treatment. Significant development of microtubule-binding agents has taken place in recent years, with newer anti-tubulin agents now showing novel properties of enhanced tumor specificity, reduced neurotoxicity, and insensitivity to chemoresistance mechanisms. Hepatocellular carcinoma remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. There is now evidence to suggest that microtubule-binding agents may be effective in the treatment of hepatocellular carcinoma, especially when used in combination with mammalian target of rapamycin inhibitors. Preclinical models have suggested that the latter may be able to overcome resistance to microtubule binding agents. In this review article, recent developments of novel microtubule binding agents and their relevance to the treatment of hepatocellular carcinoma will be discussed. PMID- 24790458 TI - MiR-519d represses ovarian cancer cell proliferation and enhances cisplatin mediated cytotoxicity in vitro by targeting XIAP. AB - BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that are believed to play fundamental roles in tumorigenesis and tumor development at the posttranscriptional level, as negative regulators of gene expression. This study was designed to evaluate the expression and anticancer effect of miR-519d in ovarian cancer. METHODS: The expression levels of miR-519d in ovarian cancer cells and tissues were detected by TaqMan quantitative reverse transcriptase polymerase chain reaction (TaqMan qRT-PCR; Life Technologies, Carlsbad, CA, USA). The effects of miR-519d on ovarian cancer cell proliferation and cisplatin chemosensitivity were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide, flow cytometry, and Western blotting assay. A luciferase reporter assay was performed to validate the miR-519d binding sites on the 3' untranslated region of X-linked inhibitor of apoptosis protein (XIAP). The expression levels of XIAP mRNA and protein were examined by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting assay, respectively. RESULTS: miR-519d was significantly downregulated in human ovarian cancer cell lines and tissues. Overexpression of miR-519d in ovarian cancer cells decreased cell proliferation and sensitized ovarian cancer cells to cisplatin induced cell death accompanied by increased activation of caspase 3 and cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase 1. Bioinformatics analysis indicated that XIAP was a putative target of miR-519d. Overexpression of miR-519d decreased XIAP expression at both the protein and mRNA levels. In contrast, inhibition of miR-519d increased XIAP expression. Luciferase reporter assay confirmed XIAP as a direct target of miR-519d. XIAP mRNA and protein expression levels were inversely correlated with miR-519d expression in ovarian cancer cell lines and tissues. CONCLUSION: These findings indicate that miR-519d suppresses cell proliferation and sensitizes ovarian cancer cells to cisplatin-induced cell death by targeting the XIAP transcript, suggesting that miR-519d plays a tumor suppressive role in human ovarian cancer and highlighting the therapeutic potential of miR-519d in ovarian cancer treatment. PMID- 24790460 TI - Clinical utility of circulating tumor cell counting through CellSearch((r)): the dilemma of a concept suspended in Limbo. AB - To date, 10 years after the first demonstration of circulating tumor cells (CTCs), prognostic significance in metastatic breast cancer using the US Food and Drug Administration-cleared system CellSearch((r)), the potential utility of CTCs in early clinical development of drugs, their role as a surrogate marker of response to therapy, and their molecular analysis for patient stratification for targeted therapies are still major unsolved questions. Great expectations are pinned on the ongoing interventional trials aimed to demonstrate that CTCs might be of value for guiding treatment of patients and predicting cancer progression. To fill the gap between theory and practice with regard to the clinical utility of CTCs, a bridge is needed, taking into account innovative design for clinical trials, a revised definition of traditional CTCs, next-generation CTC technology, the potential clinical application of CTC analysis in non-validated settings of disease, and finally, expanding the number of patients enrolled in the studies. In this regard, the results of the first European pooled analysis definitely validated the independent prognostic value of CTC counting in metastatic breast cancer patients. PMID- 24790461 TI - Health behaviors and quality of life in Chinese survivors of cervical cancer: a retrospective study. AB - BACKGROUND: The aim of this study was to evaluate health behaviors and quality of life (QoL) in cervical cancer survivors, and to identify factors that may compromise or enhance their health-related QoL. METHODS: Data were collected retrospectively from the records of 102 consecutive patients with cervical cancer treated from May 2007 to January 2009 at the People's Hospital of Xintai City in Shandong Province. The study methodology was guided by the contextual model of health-related QoL. RESULTS: The results showed the significant mediating effects of general health status and psychological well-being between life burden and health-related QoL, between sexual impact of the disease and health-related QoL, and between the patient-doctor relationship and health-related QoL. In addition, there were a significant association between health-related QoL, education level, tumor stage, marital status, and age. Life burden and the patient-doctor relationship was also related to the sexual impact of the disease. However, no significant difference in health-related QoL and sexual impact was observed according to type of treatment received. CONCLUSION: These results advance our understanding of the predictors of health-related QoL and the relationship between them. Health-related QoL in cervical cancer survivors may be improved by mediating life burden, sexual functioning, and the patient-doctor relationship. PMID- 24790462 TI - Drug adherence to olmesartan/amlodipine fixed combination in an Italian clinical practice setting. AB - OBJECTIVE: To investigate the criteria for prescribing a combination pill for hypertensive patients, and whether the combination pill improves medication adherence. MATERIALS AND METHODS: This was a retrospective cohort study, performed in three Italian local health units. We selected all adult subjects who received at least one prescription of antihypertensive drugs between September 1, 2011 and December 31, 2011 (the enrollment period). The date of the first antihypertensive claim was defined as the index date. For each patient, we documented the antihypertensive drug treatments and evaluated patients' adherence to treatment, which was calculated, separately, as the proportion of days covered in the two 6-month periods preceding and following the index date. Only patients treated with olmesartan and/or amlodipine as a single therapy, or as a two-pill combination in the period prior the index date were included. Changes in adherence levels were compared in subjects who moved to the fixed combination of olmesartan/amlodipine after the index date and in subjects who did not. RESULTS: A cohort of 21,008 subjects with a 6-month history of a prescription of olmesartan and amlodipine as two pills in a combination treatment, or as single pill treatment, was obtained. Subjects treated with the two-pill combination treatment moved to the olmesartan/amlodipine fixed combination treatment more frequently than did subjects with a single-pill treatment (P<0.001). Comparing the postindex date period to the preindex date period, adherence to treatment was found to be higher in the 239 subjects who moved to the olmesartan/amlodipine fixed combination therapy (from 59.0% to 78.7%; P<0.001), than in the 20,769 subjects who did not move to the olmesartan/amlodipine fixed combination therapy (from 56.3% to 63.0%, P<0.001). CONCLUSION: The results of the present study show that the fixed combination of olmesartan/amlodipine contributes to increasing treatment adherence in subjects previously treated with a two-pill combination therapy or a single-pill therapy. PMID- 24790459 TI - Neuropathic cancer pain: What we are dealing with? How to manage it? AB - Cancer pain is a serious health problem, and imposes a great burden on the lives of patients and their families. Pain can be associated with delay in treatment, denial of treatment, or failure of treatment. If the pain is not treated properly it may impair the quality of life. Neuropathic cancer pain (NCP) is one of the most complex phenomena among cancer pain syndromes. NCP may result from direct damage to nerves due to acute diagnostic/therapeutic interventions. Chronic NCP is the result of treatment complications or malignancy itself. Although the reason for pain is different in NCP and noncancer neuropathic pain, the pathophysiologic mechanisms are similar. Data regarding neuropathic pain are primarily obtained from neuropathic pain studies. Evidence pertaining to NCP is limited. NCP due to chemotherapeutic toxicity is a major problem for physicians. In the past two decades, there have been efforts to standardize NCP treatment in order to provide better medical service. Opioids are the mainstay of cancer pain treatment; however, a new group of therapeutics called coanalgesic drugs has been introduced to pain treatment. These coanalgesics include gabapentinoids (gabapentin, pregabalin), antidepressants (tricyclic antidepressants, duloxetine, and venlafaxine), corticosteroids, bisphosphonates, N-methyl-D-aspartate antagonists, and cannabinoids. Pain can be encountered throughout every step of cancer treatment, and thus all practicing oncologists must be capable of assessing pain, know the possible underlying pathophysiology, and manage it appropriately. The purpose of this review is to discuss neuropathic pain and NCP in detail, the relevance of this topic, clinical features, possible pathology, and treatments of NCP. PMID- 24790464 TI - Methods for diagnosing perceived age on the basis of an ensemble of phenotypic features. AB - BACKGROUND: Perceived age has been defined as the age that a person is visually estimated to be on the basis of physical appearance. In a society where a youthful appearance are an object of desire for consumers, and a source of commercial profit for cosmetic companies, this concept has a prominent role. In addition, perceived age is also an indicator of overall health status in elderly people, since old-looking people tend to show higher rates of morbidity and mortality. However, there is a lack of objective methods for quantifying perceived age. METHODS: In order to satisfy the need of objective approaches for estimating perceived age, a novel algorithm was created. The novel algorithm uses supervised mathematical learning techniques and error retropropagation for the creation of an artificial neural network able to learn biophysical and clinically assessed parameters of subjects. The algorithm provides a consistent estimation of an individual's perceived age, taking into account a defined set of facial skin phenotypic traits, such as wrinkles and roughness, number of wrinkles, depth of wrinkles, and pigmentation. A nonintervention, epidemiological cross-sectional study of cases and controls was conducted in 120 female volunteers for the diagnosis of perceived age using this novel algorithm. Data collection was performed by clinical assessment of an expert panel and biophysical assessment using the ANTERA 3D((r)) device. RESULTS AND DISCUSSION: Employing phenotype data as variables and expert assignments as objective data, the algorithm was found to correctly classify the samples with an accuracy of 92.04%. Therefore, we have developed a method for determining the perceived age of a subject in a standardized, consistent manner. Further application of this algorithm is thus a promising approach for the testing and validation of cosmetic treatments and aesthetic surgery, and it also could be used as a screening method for general health status in the population. PMID- 24790465 TI - A systematic review of transarterial embolization versus emergency surgery in treatment of major nonvariceal upper gastrointestinal bleeding. AB - BACKGROUND: Emergency surgery or transarterial embolization (TAE) are options for the treatment of recurrent or refractory nonvariceal upper gastrointestinal bleeding. Surgery has the disadvantage of high rates of postoperative morbidity and mortality. Embolization has become more available and has the advantage of avoiding laparotomy in this often unfit and elderly population. OBJECTIVE: To carry out a systematic review and meta-analysis of all studies that have directly compared TAE with emergency surgery in the treatment of major upper gastrointestinal bleeding that has failed therapeutic upper gastrointestinal endoscopy. METHODS: A literature search of Ovid MEDLINE, Embase, and Google Scholar was performed. The primary outcomes were all-cause mortality and rates of rebleeding. The secondary outcomes were length of stay and postoperative complications. RESULTS: A total of nine studies with 711 patients (347 who had embolization and 364 who had surgery) were analyzed. Patients in the TAE group were more likely to have ischemic heart disease (odds ratio [OR] =1.99; 95% confidence interval [CI]: 1.33, 2.98; P=0.0008; I (2)=67% [random effects model]) and be coagulopathic (pooled OR =2.23; 95% CI: 1.29, 3.87; P=0.004; I (2)=33% [fixed effects model]). Compared with TAE, surgery was associated with a lower risk of rebleeding (OR =0.41; 95% CI: 0.22, 0.77; P<0.0001; I (2)=55% [random effects]). There was no difference in mortality (OR =0.70; 95% CI: 0.48, 1.02; P=0.06; I (2)=44% [fixed effects]) between TAE and surgery. CONCLUSION: When compared with surgery, TAE had a significant increased risk of rebleeding rates after TAE; however, there were no differences in mortality rates. These findings are subject to multiple sources of bias due to poor quality studies. These findings support the need for a well-designed clinical trial to ascertain which technique is superior. PMID- 24790466 TI - Granulomatosis with polyangiitis: rapidly progressive necrotizing glomerulonephritis in a pediatric patient. AB - Granulomatosis with polyangiitis (GPA) is associated with a broad range of clinical manifestations including renal disease. It is a systemic vasculitis that is rarely encountered in children. We present a 14-year-old girl who suffered from pharyngitis 1 week before admittance to hospital. She was admitted for macroscopic hematuria and oliguria, under the possibility of nephritic syndrome. Renal failure with rapidly progressive glomerulonephritis occurred within 24 hours. Immunologic tests showed the presence of type-C anti-neutrophil cytoplasmic antibodies (c-ANCA with antiproteinase 3 specificity) and renal biopsy revealed pauci-immune crescentic focal necrotizing glomerulonephritis. Treatment including methylprednisolone and cyclophosphamide intravenous pulses allowed renal recovery after 3 weeks. The clinical, hematological, and biochemical parameters improved substantially, achieving remission. Granulomatosis with polyangiitis, although rare in children, should be considered in the above clinical scenario. This case underlines that knowledge of renal histology diagnosis and early aggressive immunosuppressive therapy are essential for the management of these patients. PMID- 24790463 TI - Psoriasis and comorbidities: links and risks. AB - Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population worldwide. In the past decade, many studies have drawn attention to comorbid conditions in psoriasis. This literature review examines the epidemiological evidence, pathophysiological commonalities, and therapeutic implications for different comorbidities of psoriasis. Cardiovascular disease, obesity, diabetes, hypertension, dyslipidemia, metabolic syndrome, nonalcoholic fatty liver disease, cancer, anxiety and depression, and inflammatory bowel disease have been found at a higher prevalence in psoriasis patients compared to the general population. Because of the wide range of comorbid conditions associated with psoriasis, comprehensive screening and treatment must be implemented to most effectively manage psoriasis patients. PMID- 24790467 TI - Influence of salty food preference on daily salt intake in primary care. AB - PURPOSE: A salt preference questionnaire may be a convenient and cost-effective method for predicting salt intake; however, the influence of salt preference on daily salt intake is unclear. This study aimed at revealing the effectiveness of the salt preference question in determining the daily salt intake in primary care outpatients. PATIENTS AND METHODS: This cross-sectional study included 1,075 outpatients (men, n=436, 40.6%) at six primary care institutions in Japan. Primary outcomes included a salty food preference assessed by using one question and a daily salt intake, assessed using early morning second urine samples. Multivariate analyses determined the relationships between the salt intake and the two salt preference levels. RESULTS: The mean age was 67.6+/-14.6 years, and 594 (55.3%) preferred salty foods. The daily salt intake was 12.3+/-4.0 g per day and 11.4+/-3.7 g per day in the salt preference and nonsalt preference groups, respectively (P<0.001). A salt intake <10 g per day was consumed by 169 (28.5%) and 181 (37.6%) patients (P=0.001), respectively, and <6 g salt per day was consumed by 28 (4.7%) and 26 (5.4%) patients (P=0.606), respectively. The patients who preferred salty foods consumed a significantly larger amount of salt per day than those who did not prefer salty foods (beta coefficient, 0.621; 95% confidence interval [CI], 0.146-1.095). There was no difference in the number of patients who consumed <10 g salt per day (adjusted odds ratio [ad-OR], 1.29; 95% CI, 0.99-1.69) or <6 g salt per day (ad-OR, 1.39; 0.90-1.69) between the groups. CONCLUSION: Preference for salty foods was positively associated with daily salt intake. However, daily salt intake was not always appropriate, even in the patients who did not prefer salty foods. Behavioral interventions for salt restriction after an assessment of daily salt intake are necessary for primary care patients, regardless of their preference for salty foods. PMID- 24790468 TI - Genetic factors and breast cancer laterality. AB - BACKGROUND: Women are more likely to develop cancer in the left breast than the right. Such laterality may influence subsequent management, especially in elderly patients with heart disease who may require radiation therapy. The purpose of this study was to explore possible factors for such cancer laterality. METHODS: In this work, clinical data for consecutive patients with histologically confirmed breast cancer were reviewed, with emphasis on clinical presentation and family history. RESULTS: Between 2005 and 2012, 687 patients with breast cancer were seen. Two women with incomplete data and eleven men were excluded. In total, 343 (50.9%) patients presented with left breast cancer, 311 (46.1%) with right breast cancer, and 20 (3.0%) with simultaneous bilateral malignancy. There were no significant differences between the three groups, especially in regards to clinical presentation and tumor characteristics. A total of 622 (92.3%) patients had unilateral primary, 20 (3.0%) had simultaneous bilateral, and 32 (4.7%) had metachronous primary breast cancer with subsequent contralateral breast cancer after 7.5-236 months. The worst 10-year survival was for bilateral simultaneous (18%) compared with unilateral (28%) and metachronous primaries (90%). There were no differences in survival in relation to breast cancer laterality, handedness, and presence or absence of a family history of cancer. There were significant similarities between patients and first-degree relatives in regards to breast cancer laterality, namely same breast (30/66, 45.5%), opposite breast (9/66, 13.6%), and bilateral cancer (27/66, 40.9, P=0.01163). This was more evident among patients and their sisters (17/32, 53.1%) or mothers (11/27, 40.7%, P=0.0689). There were also close similarities in relation to age at initial diagnosis of cancer for patients and their first-degree relatives for age differences of <=5 years (48/166, 28.9%), 6-10 years (34/166, 20.5%), and >11 years (84/166, 50.6%, P=0.12065). CONCLUSION: High similarities between patients and their first-degree relatives in regards to cancer laterality and possibly age at initial diagnosis of cancer may suggest an underlying inherited genetic predisposition. PMID- 24790469 TI - Relationship between socioeconomic status and HIV infection in a rural tertiary health center. AB - BACKGROUND: There is a scarcity of data in rural health centers in Nigeria regarding the relationship between socioeconomic status (SES) and HIV infection. We investigated this relationship using indicators of SES. METHODS: An analytical case-control study was conducted in the HIV clinic of a rural tertiary health center. Data collection included demographic variables, educational attainment, employment status, monthly income, marital status, and religion. HIV was diagnosed by conventional methods. Data were analyzed with the SPSS version 16 software. RESULTS: A total of 115 (48.5%) HIV-negative subjects with a mean age of 35.49+/-7.63 years (range: 15-54 years), and 122 (51.5%) HIV-positive subjects with a mean age of 36.35+/-8.31 years (range: 15-53 years) were involved in the study. Participants consisted of 47 (40.9%) men and 68 (59.1%) women who were HIV negative. Those who were HIV positive consisted of 35 (28.7%) men and 87 (71.3%) women. Attainment of secondary school levels of education, and all categories of monthly income showed statistically significant relationships with HIV infection (P=0.018 and P<0.05, respectively) after analysis using a logistic regression model. Employment status did not show any significant relationship with HIV infection. CONCLUSION: Our findings suggested that some indicators of SES are differently related to HIV infection. Prevalent HIV infections are now concentrated among those with low incomes. Urgent measures to improve HIV prevention among low income earners are necessary. Further research in this area requires multiple measures in relation to partners' SES (measured by education, employment, and income) to further define this relationship. PMID- 24790470 TI - Navigating a strange and complex environment: experiences of Sudanese refugee women using a new nutrition resource. AB - BACKGROUND: Refugees experience dietary changes as part of the daily challenges they face resettling in a new country. Sudanese women seek to care and feed their families, but face language barriers in the marketplace, limited access to familiar foods, and forced new food choices. This study aimed to understand the acceptability of a purse-sized nutrition resource, "The Market Guide", which was developed to help recently immigrated Sudanese refugee women identify and purchase healthy foods and navigate grocery stores. METHODS: Eight women participated in a focus group, four of whom were also observed during accompanied grocery store visits. Individual interviews were conducted with four health care workers at the resettlement center to gather perceptions about the suitability of The Market Guide. Focus groups and interviews were audiotaped and transcribed. Data from field notes and transcripts were analyzed using grounded theory for preliminary open codes, followed by selective and theoretical coding. RESULTS: The Market Guide was of limited use to Sudanese women. Their response to this resource revealed the struggles of women acculturating during their first year in Calgary, Canada. We discovered the basic social process, "Navigating through a strange and complex environment: learning ways to feed your family." Language, transportation, and an unfamiliar marketplace challenged women and prevented them from exercising their customary role of "knowing" which foods were "safe and good" for their families. The nutrition resource fell short of informing food choices and purchases, and we discovered that "learning to feed your family" is a relational process where trusted persons, family, and friends help navigate dietary acculturation. CONCLUSION: Emergent theory based on the basic social process may help health care professionals consider relational learning when planning health promotion and nutrition activities with Sudanese families. PMID- 24790471 TI - Djenkolism: case report and literature review. AB - Djenkolism is an uncommon but important cause of acute kidney injury. It sporadically occurs after an ingestion of the djenkol bean (Archidendron pauciflorum), which is native to Southeast Asia. The clinical features defining djenkolism include: spasmodic suprapubic and/or flank pain; urinary obstruction; and acute kidney injury. The precise pathogenesis of acute kidney injury following djenkol ingestion remains unknown. However, it is proposed that an interaction between the characteristics of the ingested beans and the host factors causes hypersaturation of djenkolic acid crystals within the urinary system, resulting in subsequent obstructive nephropathy with sludge, stones, or possible spasms. We report a case of djenkolism from our rural clinic in Borneo, Indonesia. Our systematic literature review identified 96 reported cases of djenkolism. The majority of patients recovered with hydration, bicarbonate therapy, and pain medication. Three patients required surgical intervention; one patient required ureteral stenting for the obstructing djenkolic acid stones. Four of the 96 reported patients died from acute kidney failure. We stress the importance of awareness of djenkolism to guide medical practitioners in the treatment of this rare disease in resource-poor areas in Southeast Asia. PMID- 24790472 TI - Evidence-based practice training for health professionals in the Philippines. AB - Evidence-based practice (EBP) is integral in the health care system whether in developed or developing countries. Thus, all health professionals need to be trained in EBP. An EBP training program was conducted to health professionals in a developing country, the Philippines. The health professionals (medical doctors and allied health professionals [physical therapists and occupational therapists]) were working in hospitals in Manila, Philippines. The program aimed to build capacity in EBP in terms of knowledge and skills. The EBP training program was conducted as a 1-day face-to-face training. Pre- and post-test measures of EBP knowledge and skills were taken prior to and immediately after the 1-day training, using the Fresno test of evidence-based medicine for the medical doctors and the Adapted Fresno test for the allied health professionals. The EBP training program resulted in significant improvements in knowledge and skills for both the medical doctors (change in pre- and post-Fresno test measures, 95% confidence interval [CI]: 14.6-23.5; P<=0.05) and the allied health professionals (change in pre- and post-Adapted Fresno test measures, 95% CI: 32.7 38.5; P<=0.05). The EBP training conducted amongst the health professionals is an effective and tested undertaking in introducing EBP in developing countries such as the Philippines. PMID- 24790473 TI - Biomechanical analysis of the swim-start: a review. AB - This review updates the swim-start state of the art from a biomechanical standpoint. We review the contribution of the swim-start to overall swimming performance, the effects of various swim-start strategies, and skill effects across the range of swim-start strategies identified in the literature. The main objective is to determine the techniques to focus on in swimming training in the contemporary context of the sport. The phases leading to key temporal events of the swim-start, like water entry, require adaptations to the swimmer's chosen technique over the course of a performance; we thus define the swim-start as the moment when preparation for take-off begins to the moment when the swimming pattern begins. A secondary objective is to determine the role of adaptive variability as it emerges during the swim-start. Variability is contextualized as having a functional role and operating across multiple levels of analysis: inter subject (expert versus non-expert), inter-trial or intra-subject (through repetitions of the same movement), and inter-preference (preferred versus non preferred technique). Regarding skill effects, we assume that swim-start expertise is distinct from swim stroke expertise. Highly skilled swim-starts are distinguished in terms of several factors: reaction time from the start signal to the impulse on the block, including the control and regulation of foot force and foot orientation during take-off; appropriate amount of glide time before leg kicking commences; effective transition from leg kicking to break-out of full swimming with arm stroking; overall maximal leg and arm propulsion and minimal water resistance; and minimized energy expenditure through streamlined body position. Swimmers who are less expert at the swim-start spend more time in this phase and would benefit from training designed to reduce: (i) the time between reaction to the start signal and impulse on the block, and (ii) the time in transition (i.e., between gliding and leg kicking, and between leg-kicking and full swimming). Key pointsSWIMMERS MEET TWO MAIN CONSTRAINTS DURING THE START MOVEMENT: travelling more distance in the air (to get less resistance) and rotate to enter properly in the water.Swim start is a sum of compromises in all parts of it, and swim-start expertise is distinct from swim stroke expertise corresponding to best ways to manage these compromises.Variability found is contextualized as having a functional role and operating across multiple levels of analysis. PMID- 24790474 TI - The paroxetine effect on exercise performance depends on the aerobic capacity of exercising individuals. AB - This study investigated the influence of aerobic capacity on the activation of the central serotonergic system and exercise fatigue in young men that ingested a selective serotonin reuptake inhibitor and were then subjected to moderate intensity physical exercise. The maximal oxygen consumption of sixteen volunteers was measured during an incremental test. The volunteers were divided into two groups: subjects with higher (HAC) and lower (LAC) aerobic capacities. The volunteers were subjected to four experimental trials in which they ingested either placebo or paroxetine (10, 20 or 40 mg) and, 4.5 h later, cycled at 60% of their maximal power output until reaching fatigue. None of the three paroxetine doses influenced the total exercise time in the LAC group. However, for the HAC group, the time to fatigue in the 20 mg paroxetine condition was 15% less than that in the placebo condition (76.3 +/- 5.1 min vs. 90.0 +/- 7.9 min; p < 0.05). The time to fatigue was higher in the HAC group than in the LAC group for all treatments. Our results provide additional evidence that aerobic capacity modulates the activity of the serotonergic system. However, contrary to what would be expected considering previous reports, the activation of the serotonergic system in exercising subjects in the HAC group was not less than that in the LAC group. Key pointsThe physical performance of the higher aerobic capacity group after administration of 20 mg of paroxetine decreased relative to that after administration of the placebo, whereas the same dose of paroxetine had no effect in the lower aerobic capacity group.Our results provide additional evidence that aerobic capacity modulates the activity of the serotonergic system.Contrary to what would be expected considering previous reports, the present findings suggest that the activity of the serotonergic system during exercise is not attenuated in individuals with a higher aerobic capacity relative to those that have a lower aerobic capacity.A dose-dependent effect of paroxetine on physical performance was not observed in either group; for example, in the subjects with higher aerobic capacity, 40 mg of paroxetine did not enhance or even reproduce the ergolytic effect caused by 20 mg of paroxetine.None of the peripheral variables measured explain the reduced total exercise time after administration of 20 mg of paroxetine in the subjects with higher aerobic capacity. PMID- 24790475 TI - The occurrence of core muscle fatigue during high-intensity running exercise and its limitation to performance: the role of respiratory work. AB - This study investigated the occurrence of core muscle fatigue during high intensity running exercise and its limitation to exercise performance. A secondary aim was to investigate whether respiratory muscle work performed during intense running periods, would contribute to core muscle fatigue. Nine male recreational runners were recruited for two reasons; (1) to perform a continuous treadmill run at 85% VO2max with and without core muscle fatigue in the CR_F and CR trials, respectively; and (2) to mimic the treadmill run-induced respiratory response recorded in the CR trial while subjects were free of whole-body exercise (Mimic trial). The changes in global core muscle function with fatigue in this study were evaluated by performing a sport-specific endurance plank test (SEPT), and the associated influence on running performance was examined by comparing the time to exhaustion during the treadmill run between the CR and CR_F trials. Subsequent to the treadmill run in the CR trial, SEPT (255.7 +/- 85.3 vs 177.3 +/ 80.6 s) was reduced from baseline in all runners. The reduction correlated (r = 0.67) with the concomitant decline in inspiratory muscle function revealed by maximal inspiratory mouth pressure (PImax: 151.3 +/- 18.2 vs 133.3 +/- 17.2 cmH2O, p < 0.05). In the Mimic trial, similar results in SEPT (212.3 +/- 90.2 s), PImax (129.0 +/- 26.7 cmH2O), and correlation (r = 0.77, p < 0.05) were observed following voluntary hyperpneic activity. With the preceded fatigued core muscle workout in the CR_F trial, the running capacity was impaired significantly (10.7 +/- 4.5 vs 6.5 +/- 2.0 min, p < 0.05). The impairment was correlated (r=0.72) to the SEPT reduction resulting from the workout. The results suggest that a high intensity maximum run may induce core muscle fatigue in runners. The core muscle fatigue, which may be partly attributed to the corresponding respiratory work, may limit their running endurance. Inspiratory muscle function appears to be essential for core stabilization during the intense running. Key pointsA high intensity maximum run may induce core muscle fatigue in runners. The core muscle fatigue, which may be partly attributed to the corresponding respiratory work, may limit their running endurance.In support of previous notion, inspiratory muscles may share the work of core stabilization during intense exercise, while simultaneously increasing the demand for breathing.Inspiratory muscle training incorporated into a running specific-core training regime potentially enhances the training effect on the core muscles in a functional manner to deal with the challenges faced during intense exercise. PMID- 24790476 TI - The Influence of Serial Carbohydrate Mouth Rinsing on Power Output during a Cycle Sprint. AB - The objective of the study was to investigate the influence of serial administration of a carbohydrate (CHO) mouth rinse on performance, metabolic and perceptual responses during a cycle sprint. Twelve physically active males (mean (+/- SD) age: 23.1 (3.0) years, height: 1.83 (0.07) m, body mass (BM): 86.3 (13.5) kg) completed the following mouth rinse trials in a randomized, counterbalanced, double-blind fashion; 1. 8 x 5 second rinses with a 25 ml CHO (6% w/v maltodextrin) solution, 2. 8 x 5 second rinses with a 25 ml placebo (PLA) solution. Following mouth rinse administration, participants completed a 30 second sprint on a cycle ergometer against a 0.075 g.kg(-1) BM resistance. Eight participants achieved a greater peak power output (PPO) in the CHO trial, resulting in a significantly greater PPO compared with PLA (13.51 +/- 2.19 vs. 13.20 +/- 2.14 W.kg(-1), p < 0.05). Magnitude inference analysis reported a likely benefit (81% likelihood) of the CHO mouth rinse on PPO. In the CHO trial, mean power output (MPO) showed a trend for being greater in the first 5 seconds of the sprint and lower for the remainder of the sprint compared with the PLA trial (p > 0.05). No significant between-trials difference was reported for fatigue index, perceived exertion, arousal and nausea levels, or blood lactate and glucose concentrations. Serial administration of a CHO mouth rinse may significantly improve PPO during a cycle sprint. This improvement appears confined to the first 5 seconds of the sprint, and may come at a greater relative cost for the remainder of the sprint. Key pointsThe paper demonstrates that repeated administration of a carbohydrate mouth rinse can significantly improve peak power output during a single 30 second cycle sprint.The ergogenic effect of the carbohydrate mouth rinse may relate to the duration of exposure of the oral cavity to the mouth rinse, and associated greater stimulation of oral carbohydrate receptors.The significant increase in peak power output with the carbohydrate mouth rinse may come at a relative cost for the remainder of the sprint, evidenced by non-significantly lower mean power output and a greater fatigue index in the carbohydrate vs. placebo trial.Serial administration of a carbohydrate mouth rinse may be beneficial for sprint athletes as a method of performance enhancement that minimizes the risk of performance decrement through body mass increase and gastrointestinal disturbances associated with ingesting carbohydrate solutions. PMID- 24790477 TI - Effects and sustainability of a 13-day high-intensity shock microcycle in soccer. AB - The preseason in soccer is a short period of 6-8 weeks where conditional abilities, technical and tactical elements need to be trained. Therefore, time is lacking to perform long term preparation periods for different abilities, especially endurance training. There is evidence that the implementation of high intensity shock microcycles in preseason training could be one way to improve physical performance in a short period of time. Therefore, the purpose of the present study was to examine the effects and the sustainability of a high intensity shock microcycle on soccer specific performance. Over 2 weeks, 12 male soccer players (26.1 +/- 4.5 years) performed 12 high-intensity training (HIT) sessions in addition to their usual training. Before (pre), 6 days (6d) and 25 days (25d) after training, subjects performed Counter Movement Jump (CMJ), Repeated-Sprint Ability (RSA) test and Yo-Yo Intermittent Recovery Test Level 2 (YYIR2). Mean sprint time (RSAMean) (cohen's d = -1.15), percentage decrement score (RSAIndex) (cohen's d = -1.99) and YYIR2 (cohen's d = +1.92) improved significantly from pre to 6d. 25d after, values showed a significant reduction for YYIR2 (cohen's d = -0.81) and small to moderate but not significant increase for RSAMean (cohen's d = +0.37) and RSAIndex (cohen's d = +0.7) compared to 6d values. Small but no significant increases were found for CMJ (cohen's d = +0.33) and no significant and substantial changes were found for RSABest (cohen's d = 0.07) from pre to 6d. For competitive soccer players, block periodization of HIT offers a promising way to largely improve RSA and YYIR2 in a short period of time. Despite moderate to large decreases in RSAIndex and YYIR2 performance in the 19 day period without HIT, values still remained significantly higher 25d after the last HIT session compared to pre-values. However, it might be necessary to include isolated high-intensity sessions after a HIT training block in order to maintain the higher level of YYIR2 and RSAIndex performance. Key pointsHIT shock microcycle increases performance in semi-professional soccer players in a short period of time.Despite moderate to large decreases in performance in the 19 day period without HIT, values still remained significantly higher 25d after the last HIT session compared to pre-values.This kind of training block increases YYIR2 performance and the ability to repeated sprints, based on the RSAIndex. PMID- 24790478 TI - An enjoyable distraction during exercise augments the positive effects of exercise on mood. AB - The hypothesis that an enjoyable distraction during exercise will augment the intensity of positive mood post-exercise was tested. A sample of 84 undergraduate students rated their mood and arousal before and after a standardized exercise, which consisted of walking on a treadmill at a pace of 3.6 mph for 10 minutes. During the work out session, participants watched the same television show, which they previously rated as enjoyable, or not enjoyable. As added controls, a third group exercised with no distraction (the TV was turned off); a fourth group did not exercise, but watched the television show. The results showed that exercise alone was sufficient to increase pleasant mood (95% CI 0.61, 1.46) and that including an enjoyable distraction during exercise significantly augmented pleasant mood compared to all other groups (95% CI 1.58, 2.99; R(2) = 0.29). These results show that the enjoyment of a distraction is a key factor that can augment the intensity of positive mood following exercise. Key pointsThe hypothesis that an enjoyable distraction during exercise will augment the intensity of positive mood post-exercise was tested.The results support this hypothesis by showing for the first time that while exercise alone was sufficient to increase the intensity of positive mood; combining exercise with an enjoyable distraction resulted in significantly greater increases in pleasant mood compared to exercise alone.Accounting for the enjoyment of a distraction type in future studies can increase the sensitivity of research designs used to detect changes in positive mood post-exercise. PMID- 24790479 TI - Acute impact of inhaled short acting b2-agonists on 5 km running performance. AB - Whilst there appears to be no ergogenic effect from inhaled salbutamol no study has investigated the impact of the acute inhalation of 1600 ug, the World Anti Doping Agency (WADA) daily upper limit, on endurance running performance. To investigate the ergogenic effect of an acute inhalation of short acting beta2 agonists at doses up to 1600 ug on 5 km time trial performance and resultant urine concentration. Seven male non-asthmatic runners (mean +/- SD; age 22.4 +/- 4.3 years; height 1.80 +/- 0.07 m; body mass 76.6 +/- 8.6 kg) provided written informed consent. Participants completed six 5 km time-trials on separate days (three at 18 degrees C and three at 30 degrees C). Fifteen minutes prior to the initiation of each 5 km time-trial participants inhaled: placebo (PLA), 800 ug salbutamol (SAL800) or 1600 ug salbutamol (SAL1600). During each 5 km time-trial HR, VO2, VCO2, VE, RPE and blood lactate were measured. Urine samples (90 ml) were collected between 30-180 minutes post 5 km time-trial and analysed for salbutamol concentration. There was no significant difference in total 5 km time between treatments (PLA 1714.7 +/- 186.2 s; SAL800 1683.3 +/- 179.7 s; SAL1600 1683.6 +/- 190.7 s). Post 5 km time-trial salbutamol urine concentration between SAL800 (122.96 +/- 69.22 ug.ml(-1)) and SAL1600 (574.06 +/- 448.17 ug.ml(-1)) were not significantly different. There was no improvement in 5 km time-trial performance following the inhalation of up to 1600 ug of salbutamol in non asthmatic athletes. This would suggest that the current WADA guidelines, which allow athletes to inhale up to 1600 ug per day, is sufficient to avoid pharmaceutical induced performance enhancement. Key pointsInhaling up to 1600 ug of Salbutamol does not result in improved 5 km time trial performance.The position of Salbutamol on the World Anti-Doping Agency list of prohibited appears justified.Athletes who use up to 1600 ug Salbutamol in one day need to review their therapy as it would suggest their respiratory condition is not under control. PMID- 24790480 TI - Acute differences in foot strike and spatiotemporal variables for shod, barefoot or minimalist male runners. AB - This study compared stride length, stride frequency, contact time, flight time and foot-strike patterns (FSP) when running barefoot, and in minimalist and conventional running shoes. Habitually shod male athletes (n = 14; age 25 +/- 6 yr; competitive running experience 8 +/- 3 yr) completed a randomised order of 6 by 4-min treadmill runs at velocities (V1 and V2) equivalent to 70 and 85% of best 5-km race time, in the three conditions. Synchronous recording of 3-D joint kinematics and ground reaction force data examined spatiotemporal variables and FSP. Most participants adopted a mid-foot strike pattern, regardless of condition. Heel-toe latency was less at V2 than V1 (-6 +/- 20 vs. -1 +/- 13 ms, p < 0.05), which indicated a velocity related shift towards a more FFS pattern. Stride duration and flight time, when shod and in minimalist footwear, were greater than barefoot (713 +/- 48 and 701 +/- 49 vs. 679 +/- 56 ms, p < 0.001; and 502 +/- 45 and 503 +/- 41 vs. 488 +/-4 9 ms, p < 0.05, respectively). Contact time was significantly longer when running shod than barefoot or in minimalist footwear (211+/-30 vs. 191 +/- 29 ms and 198 +/- 33 ms, p < 0.001). When running barefoot, stride frequency was significantly higher (p < 0.001) than in conventional and minimalist footwear (89 +/- 7 vs. 85 +/- 6 and 86 +/- 6 strides.min(-1)). In conclusion, differences in spatiotemporal variables occurred within a single running session, irrespective of barefoot running experience, and, without a detectable change in FSP. Key pointsDifferences in spatiotemporal variables occurred within a single running session, without a change in foot strike pattern.Stride duration and flight time were greater when shod and in minimalist footwear than when barefoot.Stride frequency when barefoot was higher than when shod or in minimalist footwear.Contact time when shod was longer than when barefoot or in minimalist footwear.Spatiotemporal variables when running in minimalist footwear more closely resemble shod than barefoot running. PMID- 24790481 TI - The effects of interset rest on adaptation to 7 weeks of explosive training in young soccer players. AB - The aim of the study was to compare the effects of plyometric training using 30, 60, or 120 s of rest between sets on explosive adaptations in young soccer players. Four groups of athletes (age 10.4 +/- 2.3 y; soccer experience 3.3 +/- 1.5 y) were randomly formed: control (CG; n = 15), plyometric training with 30 s (G30; n = 13), 60 s (G60; n = 14), and 120 s (G120; n = 12) of rest between training sets. Before and after intervention players were measured in jump ability, 20-m sprint time, change of direction speed (CODS), and kicking performance. The training program was applied during 7 weeks, 2 sessions per week, for a total of 840 jumps. After intervention the G30, G60 and G120 groups showed a significant (p = 0.0001 - 0.04) and small to moderate effect size (ES) improvement in the countermovement jump (ES = 0.49; 0.58; 0.55), 20 cm drop jump reactive strength index (ES = 0.81; 0.89; 0.86), CODS (ES = -1.03; -0.87; -1.04), and kicking performance (ES = 0.39; 0.49; 0.43), with no differences between treatments. The study shows that 30, 60, and 120 s of rest between sets ensure similar significant and small to moderate ES improvement in jump, CODS, and kicking performance during high-intensity short-term explosive training in young male soccer players. Key pointsReplacing some soccer drills by low volume high intensity plyometric training would be beneficial in jumping, change of direction speed, and kicking ability in young soccer players.A rest period of 30, 60 or 120 seconds between low-volume high-intensity plyometric sets would induce significant and similar explosive adaptations during a short-term training period in young soccer players.Data from this research can be helpful for soccer trainers in choosing efficient drills and characteristics of between sets recovery programs to enhance performances in young male soccer players. PMID- 24790482 TI - Effect of Court Dimensions on Players' External and Internal Load during Small Sided Handball Games. AB - The aim of this study was to investigate the effect of three different court dimensions on the internal and external load during small-sided handball games. Six male amateur handball players took part in this study and participated in three different 8-min 3vs3 (plus goalkeepers) small-sided handball games (each repeated twice). The three court dimensions were 12*24m, 30*15m and 32*16m. Through Global Positioning System devices (SPI pro elite 15Hz, GPSports) and video analysis, the following parameters were recorded: cyclic and acyclic movements (distance covered and number of technical actions executed), heart rate, and rating of perceived exertion (RPE). Total distance travelled increased with court dimensions (885.2m +/- 66.6m in 24*12m; 980.0m +/- 73.4m in 30*15m; 1095.0m +/- 112.9m in 32*16m, p < 0.05). The analysis of distance covered in the four speed zones (0-1.4 m.s(-1); 1.4-3.4 m.s(-1); 3.4-5.2 m.s(-1); >5.2 m.s(-1)) highlighted substantial differences: playing with the 30*15m court in comparison to the 24*12m, the players covered less distance in the first speed zone (p = 0.012; ES = 0.70) and more distance in the second (p = 0.049; ES = 0.73) and third (p = 0.012; ES = 0.51) speed zones. Statistical differences were also found between the 24*12m and 32*16m courts: the players covered more distance in the second and third speed zones (p = 0.013, ES = 0.76; p = 0.023 ES = 0.69) with the 32*16m court in comparison to the 24*12m. There was no significant effect of court dimensions on the technical parameters (number of team actions, passes, piston movements toward goal and defensive activities), the number of specific handball jumps and changes of direction, and the time spent in the different heart rate zones. Considering the average data of all the experimental conditions together (24*12m, 30*15m, 32*16m), a pronounced statistical difference was highlighted between the values in first two HR zones and the last two (p < 0.05; large ES). The rating of perceived exertion was significantly higher during the drill with the 32*16m court compared with the 24*12m one (p < 0.05; ES = 2.34). Our findings indicate that changing court dimensions during small-sided handball games can be used to manipulate both external and internal loads on the players. Key pointsTo cover the specific game demands, more specific training methodologies have been developed in many sport games.Specific game exercises may provide a useful conditioning stimulus, together with technical and tactical training components.Changing court dimensions during small-sided handball games can be used to manipulate both external and internal loads on the players.The high ratio of cyclic activity per minute and the high HR values recorded during SSHGs make this type of drills extremely useful for aerobic power training. PMID- 24790483 TI - Ball machine usage in tennis: movement initiation and swing timing while returning balls from a ball machine and from a real server. AB - Practicing with the use of a ball machine could handicap a player compared to playing against an actual opponent. Recent studies have shown some differences in swing timing and movement coordination, when a player faces a ball projection machine as opposed to a human opponent. We focused on the time of movement initiation and on stroke timing during returning tennis serves (simulated by a ball machine or by a real server). Receivers' movements were measured on a tennis court. In spite of using a serving ball speed from 90 kph to 135 kph, results showed significant differences in movement initiation and backswing duration between serves received from a ball machine and serves received from a real server. Players had shorter movement initiation when they faced a ball machine. Backswing duration was longer for the group using a ball machine. That demonstrates different movement timing of tennis returns when players face a ball machine. Use of ball machines in tennis practice should be limited as it may disrupt stroke timing. Key pointsPlayers have shorter initial move time when they are facing the ball machine.Using the ball machine results in different swing timing and movement coordination.The use of the ball machine should be limited. PMID- 24790484 TI - A simplified approach for estimating the ventilatory and respiratory compensation thresholds. AB - This study aimed to investigate whether ventilatory (VT) and respiratory compensation (RCT) thresholds could be derived from percentages of maximal running speed (Vmax). During the model building phase (1), VT & RCT of 31 competitive level athletes were identified with respiratory gas exchange. During the cross-validation phase (2), 20 subjects performed a treadmill test to identify Vmax and then they performed 30-min runs at velocities 2SE below or above the velocity at VT and RCT derived from (1), with measurement of blood lactate [BL], RPE, heart rate (HR), and speech comfort. Phase (1) revealed that VT and RCT were reached at 67 +/- 9% and 84 +/- 6% of Vmax. In (2) sustained running 2SE below VT (64% Vmax) was associated with the ability to finish 30-min, with low and constant [BL] (~2.5 mmol.l(-1)), moderate RPE (~3.0-3.5), a small HR drift, and ability to speak comfortably. Conversely, running at 2SE above RCT (86% Vmax) was associated with the inability to finish 30-min (18.5 +/- 2.5 min to fatigue), increasing [BL] (end-exercise = 11.9 +/- 0.9 mmol.l(-1)), high RPE (end-exercise = 8.9 +/- 1.0), large HR drift (end-exercise = 98 +/- 3% HRmax), and inability to speak comfortably. Simple percentages of Vmax (<=64% and >=86%) obtained from a treadmill test without gas exchange, may be useful for prescribing exercise training intensities. Key pointsSimple performance parameters can be used to provide indications of physiologic thresholds.64% and 86% of the maximal running speed produce conditions consistent with <=VT and >=RCT.The combination of technology free feedback techniques such as the Talk Test and RPE and the simple %Vmax can be used as available and easy methods for the performance evaluation.Training prescription can be better addressed to the improvement of the aerobic or anaerobic capacity. PMID- 24790485 TI - Does acute vibration exercise enhance horizontal jump performance? AB - The aim of this study was to investigate the acute effect of vibration exercise (VbX) on repetitive horizontal jumping performance and to examine the duration of the rest interval between the horizontal jump sets following acute VbX. Fourteen track athlete males (age 20.8 +/- 1.8 yr; height 1.80 +/- 0.05 m; body mass 73.1 +/- 7.5 kg) performed four conditions in a randomised order; (a) VbX with 1 min rest between repetitive horizontal jump (RHJ) sets [VbX-1min]; (b) VbX with 2 min rest between RHJ sets [VbX-2min]; (c) No VbX with 1 min rest between RHJ sets [Con-1min]; (d) No VbX with 2 min rest between RHJ sets [Con-2min]. Intermittent VbX (six 60 s exposures with 30 s rest) at 26 Hz (6 mm peak-to-peak displacement) was performed in an isometric squat position (120 degrees of knee flexion). The mean values of distance, velocity and time taken of RHJ from the four conditions were used in repeated measures [condition (VbX and Control) and rest period (1min; and 2min)] ANOVA. There was a condition effect such that VbX significantly increased RHJ distance (p < 0.05) compared to control (no VbX). Furthermore, VbX significantly increased RHJ velocity (p < 0.05) compared to no VbX and there was an interaction effect (condition x rest) where the velocity was significantly higher in VbX-2min compared to VbX-1 min, Con-2min, and Con-1min respectively. Acute intermittent VbX has the ability to enhance repetitive horizontal jump distance and velocity, which could be used as an additional method for warm-up intervention to increase explosive power performance. Key pointsAcute intermittent VbX can enhance repetitive horizontal jump distance and velocity.Acute intermittent VbX may be used as an additional method for warm-up intervention to increase explosive power performance. PMID- 24790486 TI - Efficacy of the FIFA 11+ Warm-Up Programme in Male Youth Football: A Cluster Randomised Controlled Trial. AB - The FIFA 11+ is a structured warm-up programme specially designed to prevent injuries among football players from age 14 years and above. However, studies to prove its efficacy are generally few and it is yet to be tested in male youth footballers and among African players. The purpose of the study was to examine the efficacy of the FIFA 11+ programme in reducing the risk of injuries among male youth football players of the Lagos Junior League. A cluster randomised controlled trial was conducted. All the 20 teams (414 players aged 14 -19 years) in the Premier League division were block-randomised into either an intervention (INT) or a control (CON) group. The INT group performed the FIFA 11+ exercises as warm-up during training sessions and the CON group performed usual warm-up. Participating teams were prospectively followed through an entire league season of 6 months in which they were visited every week to assess injured players for time-loss injuries in both groups. The primary outcomes were any injury to the players, injuries by type of exposure and injuries specific to the lower extremities. The secondary outcomes were injuries reported by body location, aetiology, mechanism and severity. In total, 130 injuries were recorded affecting 104 (25%) of the 416 players. Team and player compliance with the INT was 60% and 74% respectively. Based on the primary outcome measures of the study, the FIFA 11+ programme significantly reduced the overall rate of injury in the INT group by 41% [RR = 0.59 (95% CI: 0.40 - 0.86; p = 0.006)] and all lower extremity injuries by 48% [RR = 0.52 (95% CI: 0.34 - 0.82; p = 0.004)]. However, the rate of injury reduction based on secondary outcomes mostly did not reach the level of statistical significance. The FIFA 11+ programme is effective in reducing the rates of injuries in male youth football players. Key pointsThe FIFA 11+ has only been tested in randomised controlled trials conducted on female youth football players; this study reports its efficacy in male youth football for the first timeThe FIFA 11+ programme significantly reduced the overall rate of injuries and lower extremity injuries in male youth football playersYouth football administrators in Africa and other parts of the world should pursue the implementation of the FIFA 11+ in order to minimize the incidence of injuries among players. PMID- 24790487 TI - The effects of cervical muscle fatigue on balance - a study with elite amateur rugby league players. AB - Neck muscle fatigue has been shown to alter an individual's balance in a similar way to that reported in subjects suffering from neck pain or subjects that have suffered a neck injury. The main purpose of the present study was to quantify the effects of neck fatigue on neck muscle electromyography (EMG) activity, balance, perceived fatigue and perceived stability. Forty four elite amateur rugby league players resisted with their neck muscles approximately 35% maximum voluntary isometric contraction (MVIC) force for 15 minutes in eight different directions. Sway velocity and surface electromyography were measured. Questionnaires were used to record perceived effort and stability. Repeated measures ANOVA showed that after 15 minutes isometric contraction, significant changes were seen in sway velocity, perceived sway and EMG median frequency. There were no differences in perceived efforts. The changes in sway velocity and median frequency were more pronounced after extension and right and left posterior oblique contractions but there was no significant difference in sway velocity after contraction in the right lateral flexion, right anterior oblique and left anterior oblique direction of contraction. All the subjects showed oriented whole-body leaning in the plane of the contraction. The experiment produced significantly altered and perceived altered balance in this group of physically fit individuals. The results may contribute to our understanding of normal functional capacities of athletes and will provide a basis for further investigation in healthy non-athletes and participants that have suffered neck injuries. This may ultimately help develop accurate and valid rehabilitation outcome measures. Key pointsUsing a percentage of MVIC permits to proportionally fatigue various neck muscle groups evenlyFatigue of different neck muscle groups will alter balance differentlyFatigue of muscles producing extension and posterior oblique will alter balance the most although subjects perceive a greater altered balance after lateral flexion. PMID- 24790488 TI - Evaluation of the physical activity biography: sport and transport. AB - Beside the genetic disposition, physical activity (PA) is one of the major health factors and can play a large role in the prevention and therapy of many diseases (cardiovascular diseases, cancer, obesity-related diseases etc.). In contrast to the genetic disposition, PA can be deliberately influenced by lifestyle. Therefore, it is of high importance to assess PA patterns. In order to assess PA reliably and validly, a new questionnaire (Physical Activity Biography, PAB) was created. The PAB assesses recreational PA (sport and transport) and enables to distinguish between endurance intensity levels and considers strength and high speed activity patterns throughout life. This study aims to evaluate the PAB by means of item analysis, retest-reliability and validity (criteria were physical fitness assessed by the questionnaire FFB-mot and by exercise tests). 141 participants answered the PAB. For deriving retest-reliability, 81 participants completed the PAB after a retest-interval of one month again. 55 participated in exercise tests and answered the FFB-mot to determine construct validity. Retest reliability (ICC) above 0.7 was found for most items. For the items assessing recent PA, the criteria of convergent and discriminant validity were given. Despite the complexity of the question under study, the results fulfilled the expectations concerning reliability and validity. The PAB enables to assess the amount of sport and locomotion a person has accomplished during different life time frames and, because of the protective effects of PA on various diseases, may become an important tool for risk assessment. Key pointsThe risk of chronic diseases depends largely on physical activity biography.A new questionnaire (PAB) assessing recent and lifetime physical activity was created.The PAB assesses physical activity during sports and transport.The results of the evaluation of the PAB fulfilled the expectations.The PAB enables to determine a person's amount of recreational physical activity. PMID- 24790489 TI - The association of flexibility, balance, and lumbar strength with balance ability: risk of falls in older adults. AB - The purpose of the present study was to determine the effects of a proprioceptive training program on older adults, as well as to analyze the association between flexibility, balance and lumbar strength (physical fitness test) with balance ability and fall risk (functional balance tests). This study was a controlled, longitudinal trial with a 12-week follow-up period. Subjects from a population of older adults were allocated to the intervention group (n = 28) or to the usual care (control) group (n = 26). Subjects performed proprioceptive training twice weekly (6 specific exercises with Swiss ball and BOSU). Each session included 50 minutes (10 minutes of warm-up with slow walk, 10 minutes of mobility and stretching exercises, 30 minutes of proprioceptive exercises). The outcome variables were physical fitness (lower-body flexibility, hip-joint mobility, dynamic balance, static balance, and lumbar strength) and functional balance (Berg scale and Tinetti test). The experimental group obtained significantly higher values than the control group in lower-body flexibility, dynamic balance, and lumbar strength (p = 0.019, p < 0.001, and p = 0.034 respectively). Hip-joint mobility, dynamic balance, and lumbar strength were positively associated with balance ability (p < 0.001, p < 0.001, and p = 0.014, respectively) and the prevention of falls (p = 0.001, p < 0.001, and p = 0.017 respectively). These findings suggest that a 12-week proprioception program intervention (twice a week) significantly improves flexibility, balance, and lumbar strength in older adults. Hip-joint mobility, dynamic balance and lumbar strength are positively associated to balance ability and the risk of falls in older adults. This proprioceptive training does not show a significant improvement in hip-joint mobility or static balance. Key pointsA 12-week proprioceptive intervention program (two times per week) significantly improves flexibility, balance, and lumbar strength in older adults.The risk of falls and balance ability are significantly improved after a training program with Bosu and Swiss ball in older adults.An improvement in joint mobility, dynamic balance and lumbar strength is positively associated with balance ability and improved fall risk in older adults.A 12-week proprioceptive intervention program (two times per week) does not show a significant improvement in hip-joint mobility and static balance. PMID- 24790490 TI - Performance indicators related to points scoring and winning in international rugby sevens. AB - Identification of performance indicators related to scoring points and winning is needed to inform tactical approaches to international rugby sevens competition. The aim of this study was to characterize team performance indicators in international rugby sevens and quantify their relationship with a team's points scored and probability of winning. Performance indicators of each team during 196 matches of the 2011/2012 International Rugby Board Sevens World Series were modeled for their linear relationships with points scored and likelihood of winning within (changes in team values from match to match) and between (differences between team values averaged over all matches) teams. Relationships were evaluated as the change and difference in points and probability of winning associated with a two within- and between-team standard deviations increase in performance indicator values. Inferences about relationships were assessed using a smallest meaningful difference of one point and a 10% probability of a team changing the outcome of a close match. All indicators exhibited high within-team match-to-match variability (intraclass correlation coefficients ranged from 0.00 to 0.23). Excluding indicators representing points-scoring actions or events occurring on average less than once per match, 13 of 17 indicators had substantial clear within-team relationships with points scored and/or likelihood of victory. Relationships between teams were generally similar in magnitude but unclear. Tactics that increase points scoring and likelihood of winning should be based on greater ball possession, fewer rucks, mauls, turnovers, penalties and free kicks, and limited passing. Key pointsSuccessful international rugby sevens teams tend to maintain ball possession; more frequently avoid taking the ball into contact; concede fewer turnovers, penalties and free kicks; retain possession in scrums, rucks and mauls; and limit passing the ball.Selected performance indicators may be used to evaluate team performances and plan more effective tactical approaches to competition.There is greater match-to-match variability in performance indicator values within than between international rugby sevens teams.The priorities for a rugby sevens team's technical and tactical preparation should reflect the magnitudes of the relationships between performance indicators, points scoring and the likelihood of winning. PMID- 24790491 TI - Assessment of Isometric Trunk Strength - The Relevance of Body Position and Relationship between Planes of Movement. AB - The aim of the study was to assess the differences in maximal isometric trunk extension and flexion strength during standing, sitting and kneeling. Additionally, we were interested in correlations between the maximal strength in sagittal, frontal and transverse plane, measured in the sitting position. Sixty healthy subjects (24 male, 36 female; age 41.3 +/- 15.1 yrs; body height 1.70 +/- 0.09 m; body mass 72.7 +/- 13.3 kg) performed maximal voluntary isometric contractions of the trunk flexor and extensor muscles in standing, sitting and kneeling position. The subjects also performed lateral flexions and rotations in the sitting position. Each task was repeated three times and average of maximal forces was used for data analysis. RANOVA with post-hoc testing was applied to the flexion and extension data. The level of statistical significance was set to p < 0.05. Overall, in both genders together, the highest average force for trunk extension was recorded in sitting posture (910.5 +/- 271.5 N), followed by kneeling (834.3 +/- 242.9 N) and standing (504.0 +/- 165.4 N), compared with flexion, where we observed the opposite trend (508.5 +/- 213.0 N, 450.9 +/- 165.7 N and 443.4 +/- 153.1 N, respectively). Post-hoc tests showed significant differences in all extension positions (p < 0.0001) and between sitting/standing (p = 0.018) and kneeling/standing (p = 0.033) flexion exertions. The extension/flexion ratio for sitting was 2.1 +/- 0.4, for kneeling 1.9 +/- 0.4, followed by standing, where motion forward approximately equals motion backward (1.1 +/- 0.6). Trunk sagittal-transverse strength showed the strongest correlation, followed by frontal-transverse and sagittal-frontal plane correlation pairs (R(2) = 0.830, 0.712 and 0.657). The baseline trunk isometric strength data provided by this study should help further strength diagnostics, more precisely, the prevention of low back disorders. Key pointsMaximal voluntary isometric force of the trunk extensors increased with the angle at the hips (highest in sitting, medium in kneeling and lowest in upright standing).The opposite trend was true for isometric MVC force of trunk flexors (both genders together and men only).In the sitting position, the strongest correlation between MVC forces was found between sagittal (average flexion/extension) and transverse plane (average left/right rotation).IN ORDER TO INCREASE THE VALIDITY OF TRUNK STRENGTH TESTING THE LETTER SHOULD INCLUDE: specific warm-up, good pelvic fixation and visual feedback. PMID- 24790492 TI - Physical activity and sedentary behavior in an ethnically diverse group of South african school children. AB - Few studies have examined physical activity and inactivity levels in an urban South African setting across 12 years of formal schooling. This information is important for implementing strategies to curb increasing trends of physical inactivity and related negative consequences, especially in low to middle income countries facing multiple challenges on overburdened health care systems. We examined levels of physical activity and sedentary behaviour cross-sectionally over 12 school years from childhood to adolescence in Black, White and Indian boys and girls. The aim of our study was to describe gender and race related patterns of physical and sedentary activity levels in a sample of South African children and to determine whether there were associations between these variables and body mass status. Physical activity questionnaires, previously validated in a South African setting, were used to gather information about activity and sedentary behaviours among 767 Black, White and Indian children (5-18 years of age) across the 12 grades of formal schooling. Body mass and height were also measured. Time spent in moderate-vigorous physical activity declined over the school years for all race groups and was consistently lower for girls than boys (p = 0.03), while time spent in sedentary activity increased with increasing grade (p < 0.001) for boys and girls and across all race groups. Associations between physical activity and body mass were observed for White children (r = 0.22, p < 0.001), but not for Black and Indian children (p > 0.05) whereas time spent in sedentary activities was significantly and positively correlated with body mass across all race groups: Indian (r = 0.25, p < 0.001), White (r = 0.22, p < 0.001) and Black (r = 0.37, p = 0.001). The strength of the associations was similar for boys and girls. Black and Indian children were less physically active than their white peers (p < 0.05), and Black children also spent more time in sedentary activity (p < 0.05). Additionally, Black children had the highest proportion of overweight participants (30%), and Indian children the most number of underweight children (13%). Regardless of ethnicity, children who spent more than 4 hours per day in front of a screen were approximately twice as likely to be overweight (OR, 1.96 [95%CI: 1.06-3.64, p = 0.03]). Regardless of race, inactivity levels are related to body mass. Ethnic and gender disparities exist in physical activity and sedentary activity levels and this may echo a mix of biological and cultural reasons. Key pointsRegardless of race, inactivity levels are related to body mass.In an ethnically diverse urban group of South African school children, there exists an age related decline in physical activity and increase in time spent in front of a screen.Ethnic and gender disparities exist in physical activity and sedentary activity levels and this may echo a mix of biological and cultural reasons. PMID- 24790493 TI - Towards uniform accelerometry analysis: a standardization methodology to minimize measurement bias due to systematic accelerometer wear-time variation. AB - Accelerometers are predominantly used to objectively measure the entire range of activity intensities - sedentary behaviour (SED), light physical activity (LPA) and moderate to vigorous physical activity (MVPA). However, studies consistently report results without accounting for systematic accelerometer wear-time variation (within and between participants), jeopardizing the validity of these results. This study describes the development of a standardization methodology to understand and minimize measurement bias due to wear-time variation. Accelerometry is generally conducted over seven consecutive days, with participants' data being commonly considered 'valid' only if wear-time is at least 10 hours/day. However, even within 'valid' data, there could be systematic wear-time variation. To explore this variation, accelerometer data of Smart Cities, Healthy Kids study (www.smartcitieshealthykids.com) were analyzed descriptively and with repeated measures multivariate analysis of variance (MANOVA). Subsequently, a standardization method was developed, where case specific observed wear-time is controlled to an analyst specified time period. Next, case-specific accelerometer data are interpolated to this controlled wear time to produce standardized variables. To understand discrepancies owing to wear time variation, all analyses were conducted pre- and post-standardization. Descriptive analyses revealed systematic wear-time variation, both between and within participants. Pre- and post-standardized descriptive analyses of SED, LPA and MVPA revealed a persistent and often significant trend of wear-time's influence on activity. SED was consistently higher on weekdays before standardization; however, this trend was reversed post-standardization. Even though MVPA was significantly higher on weekdays both pre- and post standardization, the magnitude of this difference decreased post-standardization. Multivariable analyses with standardized SED, LPA and MVPA as outcome variables yielded more stable results with narrower confidence intervals and smaller standard errors. Standardization of accelerometer data is effective in not only minimizing measurement bias due to systematic wear-time variation, but also to provide a uniform platform to compare results within and between populations and studies. Key pointsSystematic variation in accelerometer wear-time both, within and between participants results in measurement bias.Standardization of data after controlling for wear-time produces stable outcome variables.Descriptive and multivariate analyses conducted with standardized outcome variables minimize measurement bias. PMID- 24790494 TI - Learning effects associated with the least stable level of the biodex(r) stability system during dual and single limb stance. AB - The Biodex(r) Stability System (BSS) has high test-retest reliability when stable (high) resistance levels are used. However, reliability data for lower stability levels, associated with more pronounced learning curves, are rare in the existing literature. Thus, it is likely that BSS scores obtained from lower stability levels require greater familiarization (i.e. practice) to achieve a stable score both within and between test sessions. Therefore, the purpose of this investigation was to determine if a commonly reported 6 trial sequence (3 practice trials, 3 test trials) used with the BSS can achieve a stable within session score on the lowest stability level (i.e. level 1). The secondary purpose was to evaluate the test-retest reliability of the lowest BSS resistance level over a 10-week period. Twenty sedentary university students (11 male, 9 female; age: 21.5 +/- 1.9 years, height: 1.7 +/- 0.1 m, weight: 66.3 +/- 12.1 kg, BMI: 22.4 +/- 2.3) voluntarily participated. Participants completed two test sessions separated by 10-weeks. Twelve, 20-second trials (six dual limb stance, six single limb stance on the dominant limb) on the lowest stability level were completed during both test sessions by all participants. A stable within session dual and single limb stance score was achieved with a maximum of 3 familiarization trials. Reliability ranged between poor and good across all outcomes but all outcomes had large minimal detectable change scores. At least 3 stance specific familiarization trials are needed to achieve a stable BSS score within a single test session on the lowest resistance level. However, the inconsistent reliability and high minimal detectable changes scores suggest that the lowest resistance level should not be used as an objective marker of rehabilitation progress over extended periods of time (e.g. 10-weeks). Key pointsLevel 1 BSS scores should not be used as a test setting to assess rehabilitation.Familiarization trials should not be underestimated by researchers/clinicans.Lower stability levels on the BSS may not be appropriate for use as an objective marker of progression due to poor reliability of the scores over time. PMID- 24790495 TI - Moderate Recovery Unnecessary to Sustain High Stroke Volume during Interval Training. A Brief Report. AB - It has been suggested that the time spent at a high stroke volume (SV) is important for improving maximal cardiac function. The aim of this study was to examine the effect of recovery intensity on cardiovascular parameters during a typical high-intensity interval training (HIIT) session in fourteen well-trained cyclists. Oxygen consumption (VO2), heart rate (HR), SV, cardiac output (Qc), and oxygenation of vastus lateralis (TSI) were measured during a HIIT (3*3-min work period, 2 min of recovery) session on two occasions. VO2, HR and Qc were largely higher during moderate-intensity (60%) compared with low-intensity (30%) (VO2, effect size; ES = +2.6; HR, ES = +2.8; Qc, ES = +2.2) and passive (HR, ES = +2.2; Qc, ES = +1.7) recovery. By contrast, there was no clear difference in SV between the three recovery conditions, with the SV during the two active recovery periods not being substantially different than during exercise (60%, ES = -0.1; 30%, ES = -0.2). To conclude, moderate-intensity recovery may not be required to maintain a high SV during HIIT. Key pointsModerate-intensity recovery periods may not be necessary to maintain high stroke volume during the exercise intervals of HIIT.Stroke volume did not surpass the levels attained during the exercise intervals during the recovery periods of HIIT.The practical implication of these finding is that reducing the intensity of the recovery period during a HIIT protocol may prolong the time to exhaustion, potentially allowing completion of additional high-intensity intervals increasing the time accumulated at maximal cardiac output. PMID- 24790496 TI - Balance training exercises decrease lower-limb strength asymmetry in young tennis players. AB - The issue of functional asymmetries in the lower-limbs has been the subject of numerous recent investigations concerning many different contact, limited-contact and non-contact sports. The presence of strength asymmetries in the lower-limbs of young athletes practicing various sporting disciplines is considered an intrinsic risk factor for injury; in such cases, compensation strategies should thus be implemented aimed at eliminating, or at least limiting, the degree of asymmetry in order to avoid the negative consequences asymmetries can have upon the health of young sportsmen and women on the long-term. The aim of the present study was to examine the presence of functional asymmetries in the lower-limbs of young tennis players in strength and speed drill performance and to test a specific balance-training programme in its capacity to effectively reduce such asymmetries. Twenty-three young tennis players were randomly assigned to the Experimental Group (EG) (n = 11: 4 females, 7 males; 13.2 +/- 0.9 years; 50.8 +/- 8.9 Kg; 1.63 +/- 0.08 m) or Comparison Group (CG) (n = 12: 4 females, 8 males; 13.0 +/- 0.9 years; 51.1 +/- 9.2 Kg; 1.61 +/- 0.09 m). To quantify percent asymmetries in lower-limb strength before (T0) and following (T1) training, performances were assessed in the one-leg hop test (OLH), side-hop test (SH) and side steps and forward 4.115-m test (4m-SSF). Performances in the 10 and 20m sprint tests and the Foran test were also assessed. The EG completed a total of 12 training sessions directed at balance training: two 30-minute sessions/week over a 6-week period. The CG followed an identical training schedule, but training sessions consisted of tennis-specific drills only. The results reveal significant differences between pre- and post-training tests in the EG only: the degree of lower-limb asymmetry was decreased in the EG following completion of the training programme, as assessed using the OLH test (p < 0.001), SH test (p < 0.001) and 4m-SSF test (p < 0.05). A significant interaction and main effect of training was also observed in the EG: balance training led to a significant reduction in the percent of asymmetry in lower-limb strength, as measured using the SH (p < 0.01), 4m-SSF (p < 0.01) and OLH (p < 0.05) tests. These results confirm that balance training exercises are able to counteract/reduce the degree of asymmetry in lower-limb strength in young tennis players. Key pointsThe determination of functional asymmetries in the lower-limbs has been the subject of numerous recent investigations aimed at the prevention of injuries in many different contact, limited-contact and non-contact sports.Sport-specific movements in tennis impose different loads upon the two lower-limbs and can cause the development of lower-limb strength asymmetries in young tennis players.The planning of athletic conditioning in young tennis players requires that strength in the lower-limbs is evaluated such that appropriate injury prevention strategies may be inserted into training programmes.Balance training exercises, and indeed all tasks performed on unstable surfaces, lead to benefits in sport specific performance. PMID- 24790497 TI - Acute effects of static and dynamic stretching on balance, agility, reaction time and movement time. AB - The purpose of this study was to compare the acute effects of three different stretching protocols on balance, agility, reaction time and movement time of the upper limbs. Participants were thirty one female high school athletes (age = 17.3 +/- 0.5 yr.). All participants performed one of the following protocols on different days: (a) 3 min jogging followed by 7 min static stretching (SS), (b) 3 min jogging followed by 7 min dynamic stretching (DS), and (c) 3 min jogging followed by 7 min of rest (NS). After the protocols participants performed the following tests: dynamic balance, 505 agility test, reaction time (time between a sound stimulus and release of a button) and movement time (movement of the upper extremity over a 0.5 m distance). The order of stretching protocols and performance tests were counterbalanced to avoid carryover effects. Repeated measures analysis of variance revealed significant main effects for all variables except reaction time. The DS protocol compared to SS performed significantly better in balance, agility and movement time. Additionally, the DS protocol compared to NS performed significantly better in agility. According to the results of the study, a DS protocol is more appropriate than SS for activities that require balance, rapid change of running direction (agility) and movement time of the upper extremities. Key pointsStatic stretching has a negative effect on balance and agility performance compared to dynamic stretching.There was no effect of the stretching protocols on reaction time.Dynamic stretching was more effective than static stretching for increasing movement time of the upper extremities. PMID- 24790498 TI - Physiological Responses during Cycling With Oval Chainrings (Q-Ring) and Circular Chainrings. AB - The aim of this study was to compare the physiological responses of cyclists using round (C-ring) or oval (Q-ring) chainrings during an incremental test until exhaustion. Following a randomized design, twelve male elite cyclists [age (mean +/- SD): 21.1 +/- 2.1 yr; VO2max: 78.1 +/- 5.3 mLA.kg(-1)min(-1)] performed two incremental maximal tests separated by 48 h (one with C-rings, the other with Q rings). Starting at 100 W, the workload was increased by 25 W every 3 min until volitional exhaustion. Maximal heart rate, power output and oxygen consumption were compared. Blood lactate was monitored throughout the test. After the incremental test, 4 intermittent 20-s maximal sprints with a 60-s recovery period in between were performed. Maximal isometric voluntary contractions were performed at rest and immediately after each 20-s maximal sprint, and the force and EMG RMS amplitude were recorded from the vastus medialis and vastus lateralis muscles. For the incremental exercise test, no significant differences were found in the maximal power output (P=0.12), oxygen consumption (P=0.39), and heart rate (P=0.32) between Q-rings and C-rings. Throughout the incremental test, lactate levels were comparable when using both the C-rings and Q-rings (P=0.47). During the short sprints, power output was 2.5-6.5% greater for Q-rings than for C-rings (P=0.22). The decline in EMG RMS amplitude observed during the incremental tests was comparable for Q-rings and C-rings (0.42). These findings indicate that the oval chainring design, presented here as "Q-rings", did not significantly influence the physiological response to an incremental exercise test as compared to a conventional chainring. Key pointsDuring the incremental exercise test, no significant differences were found in power output, oxygen consumption or heart rate between oval "Q-rings" and conventional chainrings.Over the course of the incremental test, blood lactate levels were comparable for the oval "Q-rings" and conventional chainrings.During the short sprints performed after the incremental test, there were no statistical differences in power production between oval "Q rings" and conventional chainrings. PMID- 24790499 TI - Comparative kinematic analysis of the snatch lifts in elite male adolescent weightlifters. AB - The purpose of the study was to compare the linear kinematics of the barbell and the angular kinematics of the lower limb during the snatch lifts of two different barbell weights in elite male adolescent weightlifters. In the national team level, nine elite male adolescent weightlifters participated in the study. The snatch lifts were recorded by two video cameras under competitive conditions in preparation period before the European Junior Championship (Sony MiniDv PAL- 50 field/s) and the two heaviest successful lifts were selected for kinematic analysis. The little toe, ankle, knee, hip, and shoulder on the body and one point on the barbell were digitized using Ariel Performance Analysis System (APAS, San Diego, CA, USA). Significant decreases were found in the maximum barbell height, the relative power output during the second pull, and the maximum vertical velocity of the barbell during the second pull of the heaviest lift (p < 0.05). Maximum extension velocity of the hip joint significantly increased during the first pull of the heaviest lift (p < 0.05). As the mass of the barbell increased, the maximum vertical velocity and the maximum height of the barbell and relative power output during the second pull decreased in the heaviest lift performed by adolescent weightlifters. Coaches should pay attention to assistant exercises to increase explosive strength during the second pull with maximum strength in male adolescent weightlifters. Key pointsThe results demonstrate that the maximum strength of the extensor muscles of the hip during the first pull and their explosive strength during the second pull must be improved.Coaches should pay attention to assistant exercises to increase explosive strength during the second pull with maximum strength in male adolescent weightlifters. PMID- 24790500 TI - What is the Safest Sprint Starting Position for American Football Players? AB - The main objective of this study was to perform a biomechanical analysis of three different sprint start patterns to determine the safest position in term of neck injury and Sport-Related Concussion (SRC). The second objective was to collect data on the learning process effect between football players and non-players. Three different sprint initial positions adopted by football players were studied (i.e., 4-, 3- and 2-point positions). Twenty five young healthy males, including 12 football players, participated to this study. A stereophotogrammetric system (i.e., Vicon) was used to record motion patterns and body segments positions. Various measurements related to head and trunk orientation, and player field-of view were obtained (e.g., head height, trunk bending, time to reach upright position, head speed (vertical direction) and body speed (horizontal direction)). Learning process was found to have no influence on studied parameters. Head redress is also delayed when adopting a 4-point position leading to a reduce field-of-view during the start and increasing therefore the probability of collision. Concerning the three different positions, the 4-point position seems to be the more dangerous because leading to higher kinetic energy than the 2- and 3-point start positions. This study proposes a first biomechanical approach to understand risk/benefit balance for athletes for those three different start positions. Results suggested that the 4-point position is the most risky for football players. Key pointsMotion analysis and biomechanical analysis of the initial start position of the sprint could be used to increase the safety of the football players.Analysis of kinematic and trajectory of the head and the time to reach the upright position could be used to determine whether or not a player can return to play after concussion.A balance needs to be found between player's safety (2-point start) and speed (4-point start). PMID- 24790501 TI - Cross-cultural adaptation and validation of the spanish version of the performance enhancement attitude scale (petroczi, ). AB - The aim of the present study was to cross-culturally adapt and validate the Spanish version of the Performance Enhancement Attitude Scale (PEAS). A cross sectional multi-sample survey with 17 independent datasets was carried out. Cross cultural adaptation of the PEAS into Spanish was conducted through forward/backward translations, consensus panels and comparative analyses of known groups to establish evidence for its reliability and validity. Weighted Kappa coefficients with quadratic weighting were used to assess the reliability of each item, with Cronbach's internal consistency coefficients for overall scale's reliability and Spearman's correlation coefficient for test-retest reliability over a one-week period. Confirmatory factor analysis (CFA) was performed to assess the scale's structure. Differences between self-admitted doping users and non-users were analysed to verify the PEAS' construct validity in 8 datasets. Spearman's correlation coefficient was also used to assess the relationships between the PEAS and self-esteem, self-efficacy and perceived descriptive norm to establish convergent validity. The scale showed satisfactory levels of internal consistency (alpha = 0.71-0.85), reliability of each item (Kappa values range 0.34-0.64) and temporal stability (r = 0.818; p < 0.001). CFA showed acceptable fit (RMSEA <0.08, mean RMSEA = 0.055; chi(2)/df < 3, mean chi(2)/df = 1.89) for all but one samples. As expected, self-admitted doping users showed more positive attitude toward doping than non-users. Significant and strong negative relationship was found between PEAS and self-efficacy; weak negative correlation with self-esteem and and positive correlation with perceived descriptive norm. The Spanish version of PEAS showed satisfactory psychometric properties. Considerations for application and improvement are outlined. Key pointsFirst study that crosses culturally adapted the PEAS to the Spanish language.The Spanish version of PEAS has satisfactory psychometric properties.Users scored higher than non-users indicating a satisfactory construct validity. Significant positive correlation was found between PEAS and projected use.Significant negative correlation between PEAS and self-esteem and self-efficacy. PMID- 24790502 TI - Correct, fake and absent pre-information does not affect the occurrence and magnitude of the bilateral force deficit. AB - The present study examined whether different pre-information conditions could lead to a volitional modulation of the occurrence and magnitude of the bilateral force deficit (BFD) during isometric leg press. Twenty trained male adults (age: 24.5 +/- 1.7 years; weight: 77.5 +/- 7.1 kg; height: 1.81 +/- 0.05 m) were examined on three days within a week. Isometric leg press was performed on a negatively inclined leg press slide. Each participant completed three maximal isometric strength test sessions with different pre-information conditions given in a graphical chart: no pre-information (NPI; first day), false pre-information (FPI; bilateral force > sum of unilateral forces; second or third day) and correct pre-information (CPI; bilateral force < sum of unilateral forces; second or third day) during bilateral, unilateral-left and unilateral-right leg-press. The sum of left- and right-sided force values were calculated for bilateral (FBL = FBL_left + FBL_right) and unilateral (FUL = FUL_left + FUL_right) analyses. Force data for NPI revealed: Mean (SD): FUL_NPI = 3023 N (435) vs. FBL_NPI = 2812 (453); FPI showed FUL_FPI = 3013 N (459) vs. FBL_FPI = 2843 (446) and the CPI revealed FUL_CPI = 3035 (425) vs. FBL_CPI = 2844 (385). The three (no, false, correct) x 2 (FUL, FBL) rANOVA revealed a high significant main effect of Force (F = 61.82, p < 0.001). No significant main effect of the factor Condition and no significant interaction between Force x Condition was observed. The BFD does not rely on the trueness of the given pre-information (no, false, correct). Cognition based volitional influences on the BFD on supra-spinal level seem negligible. Key pointsBFD is reliable occurring phenomenonAvailable theoretical knowledge does not affect the BFDAlternating sport should include alternating strength exercises. PMID- 24790503 TI - Could Low-Frequency Electromyostimulation Training be an Effective Alternative to Endurance Training? An Overview in One Adult. AB - This preliminary study aimed to investigate the effects of a six-week low frequency electromyostimulation training (10Hz) on the cardiovascular, respiratory and muscular systems. To that purpose, aerobic capacity, knee extensor muscles strength and architecture, muscle sympathetic nervous activity, blood pressure and heart rate have been evaluated in one healthy male subject (33 year-old, 1.73 m, 73 kg). Results showed improvement of aerobic capacity (+4.5% and +11.5% for maximal oxygen uptake and ventilatory threshold) and muscle strength (+11% and +16% for voluntary and evoked force). Moreover, for the first time, this study demonstrated low-frequency training effects on muscle architecture (+3%, +12% and -11% for muscle thickness, pennation angle and fascicle length) and cardiovascular parameters (-22%, -18% and -21% for resting muscle sympathetic nervous activity, heart rate and mean blood pressure). Interestingly, these results suggest that this method may have beneficial effects on all systems of the body. The investigation of training effects on muscle architecture and cardiovascular parameters should therefore be pursued since highly deconditioned subjects are likely to fully benefit from these adaptations. Key pointsThese results confirmed that 5 weeks of low-frequency electrical stimulation have beneficial effects on aerobic capacity and muscle strength.This study demonstrated that low-frequency electrical stimulation applied for as short as 5 weeks have a great impact on muscle architecture and cardiovascular parameters and control.This type of training might therefore be interesting for rehabilitation of patients who are unable to perform endurance exercises. PMID- 24790504 TI - An Unusual Case of Traumatic Internal Carotid Artery Dissection during Snowboarding. AB - The presentation of Horner's syndrome following blunt trauma is uncommon, but is of important clinical significance. Identification of the constellation of signs of Horner's syndrome should, therefore, prompt urgent neuro-radiologic imaging. Early diagnosis and initiation of appropriate treatment can lead to excellent outcomes in the majority of cases and prevent devastating cerebral ischaemic damage. A progressive case of Horner's syndrome following blunt injury to the neck in an amateur snowboarder is presented. Key pointsBlunt injury to the neck can result in Horner's syndrome.Horner's syndrome should alert clinicians to the possibility of a silent ICAD.MRI and MRA of the head and neck constitute the imaging modality of choice to look for ICAD.The treatment of choice for ICAD is anticoagulation for 3-6 months. PMID- 24790505 TI - Lack of enjoyment reduces the motivation to succeed in sport. PMID- 24790506 TI - Stereotypes of athletes' use of performance enhancing products. PMID- 24790507 TI - Reply to letter to editor: stereotypes of athletes' use of performance enhancing products. PMID- 24790508 TI - Role of spiral artery Doppler to screen type 2 endometrial cancer cases. AB - OBJECTIVE: The purpose of this study was to determine the value of endometrial blood flow assessment in predicting type 2 endometrial carcinoma. MATERIAL AND METHODS: Sixty-five consecutive post-menopoausal women who had vaginal bleeding were enrolled in the study. All subjects were directed to transvaginal sonography to determine endometrial blood flow and underwent endometrial biopsy. Doppler findings were analysed to predict endometrial pathology. Subjects with unsatisfactory Doppler analyses were excluded from the study. RESULTS: Mean age of the study population was 50.1+/-6.9 years (42-73). Mean endometrial thickness was 10.1+/-2.9 mm (4-15 mm) and mean cancer antigen 125 (CA125) level was 20.1+/ 17.4 U/mL (3-92). Histopathological evaluation revealed 14 cases of type 2 endometrial cancer and 18 cases of endometrial hyperplasia without atypia, while the other 33 cases had normal endometrial tissue. CA125 (Area under curve (AUC)=0.853, p=0.000), spiral artery resistance index (AUC=0.905, p=0.000), and spiral artery peak systolic velocity (AUC=0.822, p=0.000) were significant predictors for the type 2 endometrial cancer cases. Endometrial thickness did not significantly predict pathologic cases (p>0.05). Hyperplasia cases were not predicted by any of these diagnostic modalities (p>0.05). CONCLUSION: In patients with postmenopausal bleeding, spiral artery Doppler ultrasound, could play a role in refining the diagnosis of type 2 endometrial carcinoma; however, its predictive value should be evaluated with further studies. PMID- 24790509 TI - USG guided FNAC of ovarian mass lesions: A cyto-histopathological correlation, with emphasis on its role in pre-operative management guidelines. AB - OBJECTIVE: Ultrasonography (USG)-guided fine-needle aspiration cytology (FNAC) of ovarian masses is an efficient diagnostic modality for accurately diagnosing ovarian tumours prior to surgery. The main aim of this study was to assess the sensitivity, specificity and accuracy of FNAC in diagnosing ovarian masses. MATERIAL AND METHODS: Eighty-three patients with ovarian masses were recruited and correlation of USG-guided FNAC was made with histopathology in all but 6 cases, where surgery was not indicated. RESULTS: Cytological diagnosis was obtained in all 83 ovarian lesions: 56 cases were benign, 6 possibly benign, 3 suspicious of malignancy and 18 cases as malignant. Out of 77 cases where histology was available, the 12 non-neoplastic cysts were endometriotic cysts and follicular cysts. The majority of neoplastic lesions were surface epithelial tumours. Out of 12 non-neoplastic cysts and 43 benign tumours, all but two were diagnosed as benign or possibly benign on cytology; of the 22 histologically malignant or borderline tumours, 18 were malignant or suspicious of malignancy on cytology, while four were false negative (three of these were borderline tumours). Thus, the sensitivity of cytological diagnosis was 83%, specificity was 97% and accuracy was 93%. CONCLUSION: USG-guided FNAC seems to be a relatively safe, simple, fast and cost-effective procedure where most ovarian malignancies either present late in their course or no screening method is available. In addition, cyto-radiological correlation through this procedure may be useful in deciding management guidelines prior to any surgical intervention. PMID- 24790510 TI - Expression of P-cadherin (cadherin-3) and E-selectin in the villous trophoblast of first trimester human placenta. AB - OBJECTIVE: Although trophoblastic invasion has a critical role in human placental development, very little is known about them. The aim of the present study was to localise the expression of P-cadherin (cadherin-3) and E-selectin in first trimester placenta. MATERIAL AND METHODS: This study was conducted on 140 patients who had applied to Gulhane Military Medical Academy, Haydarpasa Education Hospital, Department of Obstetrics and Gynaecology between 2005 and 2006. The patients were divided into three groups: ectopic pregnancy group (Group 1), spontaneous abortion group (group 2) and curettage group (group 3 and/or control group). Patients with a history of systemic diseases (such as thrombophilia), a disease or anatomical diagnosis that may cause recurrent abortion or an aetiological factor for ectopic pregnancy were excluded from the study. Paraffin blocks were stained with E-selectin and P-cadherin in accordance with the procedure. Demographic characteristics of patients (patient age, gravida, parity, number of previous abortions, and last menstrual period) and staining intensities were compared using Analysis of Variance (ANOVA) among groups. RESULTS: According to the average scale score of P-cadherin staining of cells, the three groups were statistically different from each other (p=0.0001). This difference stems from statistically significantly lower scores in the spontaneous abortion group than in both the ectopic pregnancy group (p<0.001) and the control group (p<0.001). E-selectin immunostaining showed no positive staining in the groups. CONCLUSION: In placental trophoblasts, decreased P cadherin immunoreactivity plays a role in the aetiopathogenesis of spontaneous abortion. PMID- 24790511 TI - Antenatal diagnosis and outcome of agenesis of corpus callosum: A retrospective review of 33 cases. AB - OBJECTIVE: To present antenatal sonographic findings and postnatal outcome of a population of foetuses diagnosed with agenesis of corpus callosum. MATERIAL AND METHODS: The database of our ultrasound laboratory was retrospectively searched for cases of agenesis of the corpus callosum suspected at antenatal sonography between 2002 and 2012. The following variables were assessed: maternal age, gestational age at diagnosis, gender, any additional cerebral and extra-cerebral malformations, results of karyotype analysis and pregnancy and foetal/neonatal outcomes. RESULTS: During the study period, 33 foetuses with agenesis of the corpus callosum were identified antenatally, with a male preponderance. The mean maternal age was 28.48 years. In all cases, pre/postnatal MRI and/or necropsy were performed in order to confirm the diagnosis. Among those, there were additional brain findings in 23 (69.7%) and additional extra-cerebral anomalies in 3 (9.1%) foetuses. Karyotype analysis was performed in 21 of 33 (63.6%) cases. As for pregnancy outcome, the pregnancy was terminated in 14 (42.4%) of the remaining 19 foetuses; eighteen (54.5%) were delivered near term and one (3.1%) who was delivered prematurely died during the neonatal period. CONCLUSION: The diagnosis of congenital brain malformation is a challenging issue, since additional findings have a considerable effect on prognosis; detailed examination with genetic counselling should be performed. PMID- 24790512 TI - Incidence of gestational trophoblastic disease in Tokat province, Turkey. AB - OBJECTIVE: This study investigated the incidence of gestational trophoblastic disease (GTD) in Tokat province, Turkey. MATERIAL AND METHODS: The medical records of patients who had been diagnosed and treated at one university hospital, six government hospitals, and one specialist hospital in Tokat province between January 2005 and December 2012 were evaluated retrospectively. RESULTS: During the study period, there were 59,754 births and GTD was diagnosed in 73 cases. The calculated GTD incidence was 1.22/1000. The mean age of the patients diagnosed with GTD was 28.6+/-7.3 (range 17-51) years. In GTD, complete moles occurred in 26%, partial moles in 74%, and no invasive moles, choriocarcinomas, or placental site trophoblastic tumours were found. Only two patients received chemotherapy (methotrexate). There was no mortality associated with the disease during follow-up. CONCLUSION: The incidence of GTD in Tokat province was 1.2 per 1000 births. Early diagnosis, treatment, and follow-up play a critical role in preventing the morbidity and mortality associated with disease. The incidence of GTD, which has a high recovery rate with adequate treatment and follow-up, can be determined from regional and community-based research. PMID- 24790513 TI - A financial analysis of operating room charges for robot-assisted gynaecologic surgery: Efficiency strategies in the operating room for reducing the costs. AB - OBJECTIVE: To analyse the steps taking place in the operating room (OR) before the console time starts in robot-assisted gynaecologic surgery and to identify potential ways to decrease non-operative time in the OR. MATERIAL AND METHODS: Thirteen consecutive robotic cases for benign gynaecologic disease at the Department of Obstetrics and Gynecology at University of Texas Medical Branch (UTMB) were retrospectively reviewed. The collected data included the specific terms 'Anaesthesia Done' (step 1), 'Drape Done' (step 2), and 'Trocar In' (step 3), all of which refer to the time before the actual surgery began and OR charges were evaluated as level 3, 4, and 5 for open abdominal/vaginal hysterectomy, laparoscopic hysterectomy, and robot-assisted hysterectomy, respectively. RESULTS: The cost of the OR for 0-30 minutes and each additional 30 minutes were $3,693 and $1,488, $4,961 and $2,426, $5,513 and $2,756 in level 3, 4, and 5 surgeries, respectively. The median time for step 1 was 12.1 min (5.25-23.3), for step 2 was 19 (4.59-44) min, and for step 3 was 25.3 (16.45-45) min. The total median time until the actual operation began was 54.58 min (40-100). The total cost was $6948.7 when the charge was calculated according to level 4 and $7771.1 when the charge was calculated according to level 5. CONCLUSION: Robot-assisted surgery is already 'cost-expensive' in the preparation stage of a surgical procedure during anaesthesia induction and draping of the patient because of charging levels. Every effort should be made to shorten the time and reduce the number of instruments used without compromising care. (J Turk Ger Gynecol Assoc 2014; 15: 25-9). PMID- 24790514 TI - The effect of Silymarin on VEGF, VEGFR-1 and IL-1alpha levels in placental cultures of severe preeclamptic women. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of Silymarin on vascular endothelial growth factor (VEGF), soluble VEGF Receptor-1 (sVEGFR-1) and Interleukin-1 alpha (IL-1alpha) levels in placental tissue samples of severely preeclamptic women. MATERIAL AND METHODS: We conducted an in vitro study in Baskent University Faculty of Medicine, Ankara, Turkey between September 2008 and May 2009. A total of 16 placental tissue samples (8 from severe preeclamptic, and 8 from controls) were analysed. Placental samples were incubated, and VEGF, sVEGFR-1, and IL1-alpha were measured in culture media using an ELISA kit. The effect of Silymarin on these levels was investigated. Descriptive statistics were initially performed, followed by Mann Whitney U-test and Kruskal-Wallis test to compare means between groups. P values less than 0.05 were considered statistically significant. RESULTS: Eight patients were included in the severe preeclampsia (SP) group, whereas the remaining 8 patients were included in the control group. There were no significant correlations between gestational age and placental VEGF, sVEGFR-1 and IL-1alpha after 48 or 72 hours of incubation. Basal VEGF levels were lower in the SP group; however, it did not reach statistical significance. sVEGFR-1 and IL-1alpha levels were also similar between the SP and control groups (p>0.05). After 48 and 72 hours of incubation, sVEGFR-1 levels in Silymarin-added SP and control placental cultures were lower than in the samples without Silymarin addition; however, this difference also did not reach significance. CONCLUSION: Although we could not demonstrate a significant effect on placental cytokines, considering the role of vasospasm, inflammation, angiogenesis, endothelial cell activation, and oxidative stress in preeclampsia, the potential benefits of Silymarin should be evaluated in future trials with a larger sample size. PMID- 24790515 TI - Can maternal serum C-reactive protein levels predict successful labour induction with intravenous oxytocin in term pregnancies complicated with premature rupture of the membranes? A cross-sectional study. AB - OBJECTIVE: High sensitive C-reactive protein (hs-CRP) is a serum marker for acute inflammation and/or infection. The diagnostic value of serum levels of this protein has been investigated among patients with preterm delivery, premature rupture of the membranes (PROM) and preeclampsia. In this study, the predictive value of hs-CRP for successful labour induction in patients with PROM has been evaluated. MATERIAL AND METHODS: Eighty-six term pregnant patients who experienced pre-labour amniotic membrane rupture from 37-41 weeks of gestation were selected for the study. Maternal serum hs-CRP levels were determined upon admission to the delivery unit and low dose intravenous oxytocin infusion was started to induce labour. The mode of delivery and time interval from labour induction to delivery were the primary endpoints of the study. RESULTS: Twenty five (29%) out of 86 patients had delivered by caesarean section, while the remaining 61 (71%) had delivered vaginally. The receiver operator characteristic (ROC) curve for testing the significance of higher hs-CRP values and lower probability of vaginal delivery revealed that higher hs-CRP values were found to be insignificant for predicting the need for caesarean section. No statistically significant correlation between high serum hs-CRP levels and the probability of caesarean delivery has been established (Spearman rho:-.126; p=0.24). The mean maternal serum hs-CRP levels during PROM were found to be similar between vaginal and abdominal deliveries. CONCLUSION: Hs-CRP, as an inflammatory marker, was found to be neither specific nor sensitive for the prediction of successful labour induction in term pregnancies with pre-labour rupture of the membranes. PMID- 24790516 TI - Prediction of staging with preoperative parameters and frozen/section in patients with a preoperative diagnosis of grade 1 endometrioid tumor in endometrial cancer. AB - OBJECTIVE: To investigate the likelihood of the detection of the necessity of staging preoperatively with the use of clinical parameters and frozen/section (FS). MATERIAL AND METHODS: 219 patients were included who were operated on between 1996 and 2010 with a diagnosis of grade 1 endometrioid adenocarcinoma in probe curettage. RESULTS: Among the clinical characteristics, only age and body mass index (BMI) predicted staging preoperatively. The probability of staging increased as age increased and BMI decreased. The concordance between preoperative diagnosis and FS was 89.5%. The diagnosis was upgraded at postoperative evaluation for 13 patients (5.9%), and downgraded for 2 patients (0.9%) compared with FS. The wrong diagnosis regarding grade, the depth of myometrial invasion DMI, tumour type and cervical invasion in FS was clinically significant and affected the decision of staging in 10 patients. In conclusion, only 7 patients (3.2%) who acquired staging surgery were missed in FS. CONCLUSION: It was shown that preoperative clinical parameters could not effectively predict the patients who should be staged. FS predicted the lymphatic involvement with high accuracy. The patient with a preoperative diagnosis of grade 1 endometrium cancer should be operated upon in centres where FS is utilised and oncologic staging surgery can be performed. PMID- 24790518 TI - Integration of three-dimensional ultrasonography in the prenatal diagnosis of amniotic band syndrome: A case report. AB - Amniotic band syndrome is a rare disorder which is thought to be caused by early rupture of the amniotic membrane. The extent of the disease may vary from minor digital amputations to severe lethal anomalies. For many years in routine clinical practice, this syndrome has been diagnosed with two-dimensional ultrasonography. Evolving imaging techniques by means of three-dimensional ultrasonography gives the chance of early and accurate diagnosis of this devastating anomaly. By integrating three-dimensional ultrasonography to the suspected findings diagnosed in the two-dimensional ultrasonography allows us to predict possible outcomes and provides convenience in counselling. Herein we present a case of amniotic band syndrome diagnosed at 19 weeks of gestation with three-dimensional ultrasonography and pregnancy was terminated in the 20th week. Using three-dimensional ultrasonography in certain suspected foetal anomalies may provide the early diagnosis and more accurate knowledge about extent of the disease. PMID- 24790517 TI - What do we know about metabolic syndrome in adolescents with PCOS? AB - Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women that manifests itself with a variety of features. For this reason, three different diagnostic criteria have been introduced. For adults, the National Institutes of Health Conference (NIH) criteria, which consists of hyperandrogenism and oligo-anovulation, is the most widely used. Symptoms of PCOS usually start with puberty and may overlap with normal pubertal development. Hormonal fluctuations during this period make the diagnosis of PCOS more difficult. Until now, there is no validated diagnostic criteria for PCOS in adolescents. Although menstrual disorders and cosmetic problems are the most common complaints of adolescents with PCOS, patients should also be evaluated for the potential risk for insulin resistance, obesity, subclinical atherosclerosis, diabetes, metabolic syndrome and cardiovascular disease. Obesity is the most prominent predictor of metabolic syndrome. As the incidence of obesity is increasing both in childhood and adolescence, governments will be faced with a social and economic burden in the future. Adolescents with PCOS are more obese than normal adolescents and have an increased risk of metabolic syndrome. It is suggested that abdominal adiposity increases the risk of metabolic syndrome by inducing various cytokine secretions. Although there is no consensus on metabolic syndrome criteria in the adolescent period, International Diabetes Federation (IDF) criteria may be used for children older than 10 years. Various clinical and metabolic markers are investigated for the prediction of metabolic syndrome in the literature. Waist circumference, serum triglycerides and androgens are the suspected predictors of metabolic syndrome. The prevention of abdominal adiposity and the early diagnosis of PCOS in adolescence should be the main target for the prevention of metabolic syndrome. Clinicians should investigate adolescents with PCOS for metabolic and cardiovascular risks and take preventive action. A Mediterranean diet, low in fat and high in fruits and vegetables, along with moderate-intensity exercise and smoking cessation are the recommended interventions for especially obese adolescents with PCOS. Metformin may be the treatment of choice when lifestyle modifications are ineffective. PMID- 24790519 TI - A diagnostic dilemma of acute abdomen in pregnancy: Leiomyoma of the small intestine. AB - Small intestinal tumours are rare and difficult to diagnose. This neoplasms may be responsible for haemorrhage, occlusion, perforation and subsequent emergent surgeries. A 28 year old G2P1 woman in her 22nd week of pregnancy was referred to our emergency department with a complaint of left lower abdominal pain that had begun the day before. She underwent an emergent laparotomy with the general surgeons. Histopathological examination defined the diagnosis of leiomyoma of the small intestine. Gastrointestinal pathologies should always be taken into consideration in the differential diagnosis of acute abdomen in pregnancy. PMID- 24790520 TI - Two cases of successful pregnancies after hysteroscopic removal of endometrioid adenocarcinoma grade I, stage IA, in young women with Lynch syndrome. AB - We present two cases of endometrioid adenocarcinoma grade I, FIGO IA (staging according to the International Federation of Gynecology and Obstetrics) in young women, diagnosed within endometrial polyps. Both patients underwent repeated hysteroscopies and multiple biopsies after initial treatment to medroxyprogesterone one 400 mg daily or the insertion of IUD-LND (intrauterine device-levonorgestrel) for three months. In both of them, all histological samples were negative. Both of them decided that they would try to conceive. The first patient conceived spontaneously and the second patient after IVF (in vitro fertilisation) treatment. They both gave birth to full-term infants. Hysterectomy was recommended to both of our patients, and was carried out. Both of the patients fulfilled both Amsterdam II and revised Bethesda criteria for hereditary non-polyposis colorectal cancer (HNPCC). PMID- 24790521 TI - What is your diagnosis? PMID- 24790522 TI - Cheiloneurusflaccus (Walker, 1847) (Hymenoptera: Encyrtidae), new to New Zealand. AB - Cheiloneurusflaccus (Walker, 1847) is reported from New Zealand for the first time. PMID- 24790523 TI - DDIT3 Expression in Liposarcoma Development. AB - Liposarcomas are mesenchymal tumors containing variable numbers of lipoblasts or adipocytes. The most common entities, well differentiated/dedifferentiated liposarcoma (WDLS/DDLS) and myxoid/round cell liposarcoma (MLS/RCLS), are both characterized by genetic rearrangements that affect the expression of the transcription factor DDIT3. DDIT3 induces liposarcoma morphology when ectopically expressed in a human fibrosarcoma. The role of DDIT3 in lipomatous tumors is, however, unclear. We have analyzed the expression of DDIT3 in 37 cases of liposarcoma (WDLS/DDLS n = 10, MLS/RCLS n = 16, and pleomorphic liposarcomas (PLS) n = 11) and 11 cases of common benign lipomas. Major cell subpopulations of WDLS/DDLS and MLS/RCLS tumors were found to express DDIT3 or the derived fusion protein, whereas PLS cases showed only a few positive cells. The lipomas contained large subpopulations expressing DDIT3. No correlation between numbers of DDIT3 expressing cells and numbers of lipoblasts/adipocytes was found. In vitro adipogenic treatment of two DDIT3 expressing cell lines induced lipid accumulation in small subpopulations only. Our results suggest a dual, promoting and limiting, role for DDIT3 in the formation of lipoblasts and liposarcoma morphology. PMID- 24790524 TI - Thermal niches are more conserved at cold than warm limits in arctic-alpine plant species. AB - AIM: Understanding the stability of realized niches is crucial for predicting the responses of species to climate change. One approach is to evaluate the niche differences of populations of the same species that occupy regions that are geographically disconnected. Here, we assess niche conservatism along thermal gradients for 26 plant species with a disjunct distribution between the Alps and the Arctic. LOCATION: European Alps and Norwegian Finnmark. METHODS: We collected a comprehensive dataset of 26 arctic-alpine plant occurrences in two regions. We assessed niche conservatism through a multispecies comparison and analysed species rankings at cold and warm thermal limits along two distinct gradients corresponding to (1) air temperatures at 2 m above ground level and (2) elevation distances to the tree line (TLD) for the two regions. We assessed whether observed relationships were close to those predicted under thermal limit conservatism. RESULTS: We found a weak similarity in species ranking at the warm thermal limits. The range of warm thermal limits for the 26 species was much larger in the Alps than in Finnmark. We found a stronger similarity in species ranking and correspondence at the cold thermal limit along the gradients of 2-m temperature and TLD. Yet along the 2-m temperature gradient the cold thermal limits of species in the Alps were lower on average than those in Finnmark. MAIN CONCLUSION: We found low conservatism of the warm thermal limits but a stronger conservatism of the cold thermal limits. We suggest that biotic interactions at the warm thermal limit are likely to modulate species responses more strongly than at the cold limit. The differing biotic context between the two regions is probably responsible for the observed differences in realized niches. PMID- 24790525 TI - Phylogenetic patterns of climatic, habitat and trophic niches in a European avian assemblage. AB - AIM: The origins of ecological diversity in continental species assemblages have long intrigued biogeographers. We apply phylogenetic comparative analyses to disentangle the evolutionary patterns of ecological niches in an assemblage of European birds. We compare phylogenetic patterns in trophic, habitat and climatic niche components. LOCATION: Europe. METHODS: From polygon range maps and handbook data we inferred the realized climatic, habitat and trophic niches of 405 species of breeding birds in Europe. We fitted Pagel's lambda and kappa statistics, and conducted analyses of disparity through time to compare temporal patterns of ecological diversification on all niche axes together. All observed patterns were compared with expectations based on neutral (Brownian) models of niche divergence. RESULTS: In this assemblage, patterns of phylogenetic signal (lambda) suggest that related species resemble each other less in regard to their climatic and habitat niches than they do in their trophic niche. Kappa estimates show that ecological divergence does not gradually increase with divergence time, and that this punctualism is stronger in climatic niches than in habitat and trophic niches. Observed niche disparity markedly exceeds levels expected from a Brownian model of ecological diversification, thus providing no evidence for past phylogenetic niche conservatism in these multivariate niches. Levels of multivariate disparity are greatest for the climatic niche, followed by disparity of the habitat and the trophic niches. MAIN CONCLUSIONS: Phylogenetic patterns in the three niche components differ within this avian assemblage. Variation in evolutionary rates (degree of gradualism, constancy through the tree) and/or non random macroecological sampling probably lead here to differences in the phylogenetic structure of niche components. Testing hypotheses on the origin of these patterns requires more complete phylogenetic trees of the birds, and extended ecological data on different niche components for all bird species. PMID- 24790528 TI - Goals, globalization and the impact factor of the journal. PMID- 24790527 TI - Abnormal expression of A20 and its regulated genes in peripheral blood from patients with lymphomas. AB - BACKGROUND: Cell-mediated immunity is often suppressed in patients with hematological malignancies. Recently, we found that low T cell receptor (TCR)-CD3 signaling was related to abnormal expression of the negative regulator of nuclear factor kappa B (NF-kappaB) A20 in acute myeloid leukemia. To investigate the characteristics of T cell immunodeficiency in lymphomas, we analyzed the expression features of A20 and its upstream regulating factor mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) and genes downstream of NF kappaB in patients with different lymphoma subtypes, including T cell non-Hodgkin lymphoma (T-NHL), B cell non-Hodgkin lymphoma (B-NHL) and NK/T cell lymphoma (NK/T-CL). METHODS: Real-time PCR was used to determine the expression level of the MALT1, MALT-V1 (variant 1), A20 and NF-kappaB genes in peripheral blood mononuclear cells (PBMCs) from 24 cases with T-NHL, 19 cases with B-NHL and 16 cases with NK/T-CL, and 31 healthy individuals (HI) served as control. RESULTS: Significantly lower A20 and NF-kappaB expression was found in patients with all three lymphoma subtypes compared with the healthy controls. Moreover, the MALT1 expression level was downregulated in all three lymphoma subtypes. A significant positive correlation between the expression level of MALT1 and A20, MALT1-V1 and A20, MALT1-V1 and NF-kappaB, and A20 and NF-kappaB was found. CONCLUSIONS: An abnormal MALT1-A20-NF-kappaB expression pattern was found in patients with lymphoma, which may result a lack of A20 and dysfunctional MALT1 and may be related to lower T cell activation, which is a common feature in Chinese patients with lymphoma. This finding may at least partially explain the molecular mechanism of T cell immunodeficiency in lymphomas. PMID- 24790529 TI - Comment on "Outcomes of autologous transplantation for multiple myeloma according to different induction regimens". PMID- 24790526 TI - Diversity of the DNA replication system in the Archaea domain. AB - The precise and timely duplication of the genome is essential for cellular life. It is achieved by DNA replication, a complex process that is conserved among the three domains of life. Even though the cellular structure of archaea closely resembles that of bacteria, the information processing machinery of archaea is evolutionarily more closely related to the eukaryotic system, especially for the proteins involved in the DNA replication process. While the general DNA replication mechanism is conserved among the different domains of life, modifications in functionality and in some of the specialized replication proteins are observed. Indeed, Archaea possess specific features unique to this domain. Moreover, even though the general pattern of the replicative system is the same in all archaea, a great deal of variation exists between specific groups. PMID- 24790530 TI - Comments on: "Frequency of alleles and haplotypes of the human leukocyte antigen in Bauru, Sao Paulo". PMID- 24790531 TI - Comments on the clinical and laboratory characteristics of patients with dengue hemorrhagic fever manifestations and their transfusion profile. PMID- 24790532 TI - Comment on "Influence of betaS-globin haplotypes and hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia". PMID- 24790533 TI - Comments on: iron deficiency anemia among kindergarten children living in the marginalized areas of Gaza Strip, Palestine. PMID- 24790534 TI - Tools to implement and improve blood donor hemovigilance in Brazil. PMID- 24790535 TI - Frequency of alleles and haplotypes of the human leukocyte antigen system in Bauru, Sao Paulo, Brazil. AB - BACKGROUND: HLA allele identification is used in bone marrow transplant programs as HLA compatibility between the donor and recipient may prevent graft rejection. OBJECTIVE: This study aimed to estimate the frequency of alleles and haplotypes of the HLA system in the region of Bauru and compare these with the frequencies found in other regions of the country. METHODS: HLA-A*, HLA-B*, and HLA-DRB1* allele frequencies and haplotypes were analyzed in a sample of 3542 volunteer donors at the National Registry of Voluntary Bone Marrow Donors (REDOME) in Bauru. HLA low resolution typing was performed using reverse line blot with the Dynal Reli(tm) SSO-HLA Typing Kit and automated Dynal AutoReli(tm)48 device (Invitrogen, USA). RESULTS: Twenty, 36, and 13 HLA-A*, HLA-B*, and HLA-DRB1* allele groups, respectively, were identified. The most common alleles for each locus were HLA-A*02, HLA-B*35, and HLA-DRB1*07. The most frequent haplotype was A*01-B*08-DRB1*03. Allele and haplotype frequencies were compared to other regions in Brazil and the similarities and differences among populations are shown. CONCLUSION: The knowledge of the immunogenic profile of a population contributes to the comprehension of the historical and anthropological aspects of different regions. Moreover, this helps to find suitable donors quickly, thereby shortening waiting lists for transplants and thus increasing survival rates among recipients. PMID- 24790536 TI - Clinical and laboratory characteristics of patients with dengue hemorrhagic fever manifestations and their transfusion profile. AB - BACKGROUND: Dengue is an infectious disease with a recurring incidence, especially in developing countries. Despite recent economic growth, success in disease control has not been achieved, and dengue has evolved from cyclic epidemic outbreaks to a lack of seasonality. The lack of scientific basis for the proper management of cases with hemorrhagic manifestations, especially regarding transfusion procedures, might contribute to the high death rate in potentially avoidable cases. OBJECTIVE: The aim of the study was to identify the clinical and laboratory manifestations in hemorrhagic dengue fever treated at the emergency services in Rio Branco, AC, Brazil, as well as to describe transfusion characteristics of patients and identify possible prognostic factors. METHODS: A retrospective descriptive study was performed to analyze the distribution of relative frequencies of clinical and laboratory variables. The study was carried out in Rio Branco with confirmed dengue fever cases. Secondary data were obtained by Acre Epidemiological Surveillance teams of cases with bleeding or platelet counts under 100.0 * 10(9)/L. The patients' clinical, laboratory and transfusion data were obtained from hospital records. RESULTS: A total of 90,553 dengue cases were reported of which 7,447 had serologic confirmation; 267 cases had hemorrhagic manifestations and 193 patients were located. Nearly half of the patients had anemia and the mean of the lowest platelet count of these patients was 26.4 * 10(9)/L. Platelet concentrate was transfused in 22.3% of cases with a mean of 7.5 IU/patient, fresh frozen plasma in 21.2% with a mean of 5.2 IU/patient and just 2.6% of patients received concentrated red blood cells with a mean of 3.2 IU/patient. Bleeding led to transfusions. Signs of plasma leakage and cardiopulmonary dysfunction were correlated to unfavorable outcomes. CONCLUSION: The pattern of clinical and laboratory criteria observed in this investigation does not differ from the literature. Transfusions were used as part of the treatment of dengue hemorrhagic fever manifestations. Some of the clinical manifestations may be related to unfavorable outcomes. PMID- 24790537 TI - Influence of betaS-globin haplotypes and hydroxyurea on tumor necrosis factor alpha levels in sickle cell anemia. AB - BACKGROUND: Sickle cell anemia is a chronic inflammatory disease characterized by an increased production of proinflammatory cytokines including tumor necrosis factor-alpha. Hydroxyurea, by decreasing the polymerization of hemoglobin, reduces inflammatory states. The effect of the genetic polymorphisms of sickle cell patients on tumor necrosis factor-alpha levels remains unknown. OBJECTIVE: The aim of this study was to investigate the association of tumor necrosis factor alpha levels with beta-globin haplotypes and the use of hydroxyurea. METHODS: A cross-sectional study was performed of 67 patients with sickle cell anemia diagnosed at steady-state in a referral hospital in Fortaleza, Ceara, Brazil. A group of 26 healthy individuals was used as control. betaS-haplotype analysis was performed by restriction fragment length polymorphism-polymerase chain reaction. The tumor necrosis factor-alpha levels were measured by the enzyme-linked immunosorbent assay test. Laboratory data (complete blood count and fetal hemoglobin) and information regarding the use of hydroxyurea were obtained from medical records. Statistical analysis was performed using R software with the Kruskal-Wallis and Mann-Whitney tests. Statistical significance was established for p-values < 0.05 for all analyses. RESULTS: The mean age of the participants was 35.48 years. Patients with sickle cell anemia had significantly higher tumor necrosis factor-alpha levels than controls (p-values < 0.0001). Tumor necrosis factor-alpha levels were lower in sickle cell anemia patients who were receiving hydroxyurea treatment than those who were not (p-value = 0.1249). Sickle cell anemia patients with Bantu/n genotype had significantly higher levels than patients with the Bantu/Benin genotype (p-value = 0.0021). CONCLUSION: In summary, betaS-globin haplotypes, but not hydroxyurea therapy, have a role in modulating tumor necrosis factor-alpha levels in sickle cell anemia adults at steady-state. Many previous studies have investigated prognosis and inflammatory states in sickle cell anemia patients, but the discovery that tumor necrosis factor-alpha levels vary according to the genetic polymorphism of the patient is a new finding. PMID- 24790538 TI - Vitamin D deficiency in children and adolescents submitted to hematopoietic stem cell transplantation. AB - BACKGROUND: Sub-optimal levels of vitamin D have been found to be highly prevalent in all age groups, with epidemiologic studies demonstrating a link between vitamin D deficiency and disease susceptibility, such as infection and cancer, and mortality rates. In adult transplant patients, it has been suggested that the immunomodulatory properties of vitamin D may have an important role in the prevention and treatment of graft-versus-host disease. OBJECTIVE: The objective of this study was to assess serum 25-hydroxyvitamin D levels of children and adolescents submitted to allogeneic hematopoietic stem cell transplantation. METHODS: Serum 25-hydroxyvitamin D levels of 66 patients, aged 4 20 years, were assessed at three stages: before hospitalization for hematopoietic stem cell transplantation and at 30 and 180 days after hematopoietic stem cell transplantation. The control group consisted of 25 healthy children. RESULTS: At the pre-hematopoietic stem cell transplantation stage, patients had lower levels of 25-hydroxyvitamin D compared to controls (25.7 +/- 12.3 ng/mL vs. 31.9 +/- 9.9 ng/mL; p-value = 0.01), and a higher prevalence of 25-hydroxyvitamin D deficiency (32% vs. 8%; p-value = 0.01). Prevalence increased significantly after hematopoietic stem cell transplantation (p-value = 0.01) with half of the patients having vitamin D deficiency at 180 days after transplantation. At this stage, mean serum 25-hydroxyvitamin D levels were 20.9 +/- 10.9 ng/mL, a significant decline in relation to baseline (p-value = 0.01). No correlation was found between 25-hydroxyvitamin D levels and vitamin D intake, graft-versus-host disease, corticoid use or survival rates. CONCLUSION: Low levels of 25 hydroxyvitamin D were detected even before hematopoietic stem cell transplantation and were significantly lower at 180 days after hematopoietic stem cell transplantation, thus recommending vitamin D supplementation for children and adolescents submitted to hematopoietic stem cell transplantation. PMID- 24790539 TI - Iron deficiency anemia among kindergarten children living in the marginalized areas of Gaza Strip, Palestine. AB - BACKGROUND: iron deficiency anemia is the most common type of nutritional anemia; it has been recognized as an important health problem in Palestine. This study was conducted to estimate the prevalence and to identify possible risk factors of iron deficiency anemia among kindergarten children living in the marginalized areas of the Gaza Strip and to evaluate the effectiveness of supplementing oral iron formula in the anemic children. METHODS: the study included 735 (384 male and 351 female) kindergarten children. Data was collected by questionnaire interviews, anthropometric measurements, and complete blood count analysis. All iron deficient anemic children were treated using an oral iron formula (50 mg ferrous carbonate + 100 mg vitamin C /5 mL) and the complete blood count was reassessed after three months. A univariate analysis and a multiple logistic regression model were constructed; crude and adjusted odds ratios (OR), and 95% confidence intervals (95% CI) were calculated. RESULTS: the overall prevalence of iron deficiency anemia was 33.5% with no significant differences between boys and girls. Significantly different prevalences of iron deficiency anemia were reported between different governorates of the Gaza Strip. Governorate, low education level of the parents and smoking are significant risk factors for children developing anemia. Significantly lower complete blood count parameters, except for WBC, were reported in anemic children. The oral iron treatment significantly improved hemoglobin concentrations, and normalized the iron deficiency marker. CONCLUSIONS: iron deficiency anemia is a serious health problem among children living in the marginalized areas of the Gaza Strip, which justifies the necessity for national intervention programs to improve the health status for the less fortunate development areas. PMID- 24790540 TI - Translation into Portuguese and validation of the Blood Donation Reactions Inventory. AB - BACKGROUND: the Blood Donation Reactions Inventory (BDRI) scale was proposed as part of a study about the predictors of psychological reactions in volunteer blood donors, as uncomfortable reactions are associated with a lower probability to return for further donations. OBJECTIVE: to translate the Inventory into Brazilian Portuguese and evaluate its psychometric properties (validity and reliability). The inventory has 11 items, but the literature suggests that shorter inventories, of four or six items, should be used. METHODS: this study was carried out at the blood center of Franca, Brazil. Three people with knowledge of English and familiarity with medical terms translated the Blood Donation Reactions Inventory into Brazilian Portuguese. Aiming to evaluate the objectivity and relevance of the items of the translated instrument, its content was independently evaluated by a panel of eight assessors. After this, data on 1,001 blood donors was collected. Internal consistency was assessed by Cronbach's alpha coefficient. An exploratory factor analysis with varimax rotation was used to analyze the measure for construct validity. RESULTS: the sample consisted of 65.8% men, and 27.3% first time donors. Internal consistency determined by Cronbach's alpha coefficient was satisfactory for the 11, 6 and 4-item scales. Considering the factor analysis, the 11-item scale seems to measure more than one construct as three factors were identified with eigenvalues greater than 1. These factors correspond to 'vasovagal adverse reactions', 'fear' and 'anxiety/excitation'. CONCLUSION: the Portuguese version of the Blood Donation Reactions Inventory is a valid and reliable instrument for collecting information regarding systemic reactions experienced by blood donors. The 6-item scale seems to be useful when the objective is to measure only vasovagal adverse reactions. PMID- 24790541 TI - Obesity and inflammation and the effect on the hematopoietic system. AB - Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes. PMID- 24790543 TI - Pericardial effusion and cardiac tamponade: clinical manifestation of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - The authors report a case with pericardial effusion and cardiac tamponade as a rare clinical manifestation of chronic graft-versus-host disease in a young man with acute myelogenous leukemia submitted to an allogeneic hematopoietic stem cell transplantation from a related donor. PMID- 24790542 TI - Contribution of the Retrovirus Epidemiology Donor Study (REDS) to research on blood transfusion safety in Brazil. AB - The Retrovirus Epidemiology Donor Study (REDS) program was established in the United States in 1989 with the purpose of increasing blood transfusion safety in the context of the HIV/AIDS and human T-lymphotropic virus epidemics. REDS and its successor, REDS-II were at first conducted in the US, then expanded in 2006 to include international partnerships with Brazil and China. In 2011, a third wave of REDS renamed the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) was launched. This seven-year research program focuses on both blood banking and transfusion medicine research in the United States of America, Brazil, China, and South Africa. The main goal of the international programs is to reduce and prevent the transmission of HIV/AIDS and other known and emerging infectious agents through transfusion, and to address research questions aimed at understanding global issues related to the availability of safe blood. This article describes the contribution of REDS-II to transfusion safety in Brazil. Articles published from 2010 to 2013 are summarized, including database analyses to characterize blood donors, deferral rates, and prevalence, incidence and residual risk of the main blood-borne infections. Specific studies were developed to understand donor motivation, the impact of the deferral questions, risk factors and molecular surveillance among HIV-positive donors, and the natural history of Chagas disease. The purpose of this review is to disseminate the acquired knowledge and briefly summarize the findings of the REDS-II studies conducted in Brazil as well as to introduce the scope of the REDS-III program that is now in progress and will continue through 2018. PMID- 24790544 TI - Improvement of thrombocytopenia after treatment for Helicobacter pylori in a patient with immunologic thrombocytopenic purpura. AB - Immune thrombocytopenic purpura is the most common autoimmune hematologic disease, affecting individuals of different ages. Recently, the bacterium Helicobacter pylori entered the list of causes of immune thrombocytopenic purpura. Here we present the case of a 55-year-old female patient with low platelet counts initially attributed to chronic vaginal bleeding. As corticosteroid therapy was ineffective she was treated for H. pylori infection. Within four weeks the patient had a platelet count of 87.17 *10(9)/L accompanied by clinical improvement of the symptoms. PMID- 24790545 TI - Affluent Neighborhood Persistence and Change in U.S. Cities. AB - Places are stratified along a hierarchy, with the affluent occupying the most resource-rich neighborhoods. Affluent neighborhood advantages include safety, high quality schools, and proximity to jobs. An additional benefit may be local economic stability over time. In a national context of rising interpersonal income inequality since 1970 and of the Great Recession, trends in neighborhood persistence and change expose this spatial advantage of the affluent. Using census data from 1970 to 2010, I find increasing rates of stability in the affluence and poverty of neighborhoods through 2000, with declines during the last decade. I also find that rates of chronic poverty and persistent affluence are high, ranging between 30 and 35 percent of neighborhoods across the 40-year period. This study highlights the structural persistence of affluence and poverty of neighborhoods as a vehicle for perpetuating social inequality and economic segregation. PMID- 24790546 TI - A survey on investigating the need for intelligent power-aware load balanced routing protocols for handling critical links in MANETs. AB - In mobile ad hoc networks connectivity is always an issue of concern. Due to dynamism in the behavior of mobile nodes, efficiency shall be achieved only with the assumption of good network infrastructure. Presence of critical links results in deterioration which should be detected in advance to retain the prevailing communication setup. This paper discusses a short survey on the specialized algorithms and protocols related to energy efficient load balancing for critical link detection in the recent literature. This paper also suggests a machine learning based hybrid power-aware approach for handling critical nodes via load balancing. PMID- 24790547 TI - Adaptive neuro-fuzzy inference system for classification of background EEG signals from ESES patients and controls. AB - Background electroencephalography (EEG), recorded with scalp electrodes, in children with electrical status epilepticus during slow-wave sleep (ESES) syndrome and control subjects has been analyzed. We considered 10 ESES patients, all right-handed and aged 3-9 years. The 10 control individuals had the same characteristics of the ESES ones but presented a normal EEG. Recordings were undertaken in the awake and relaxed states with their eyes open. The complexity of background EEG was evaluated using the permutation entropy (PE) and sample entropy (SampEn) in combination with the ANOVA test. It can be seen that the entropy measures of EEG are significantly different between the ESES patients and normal control subjects. Then, a classification framework based on entropy measures and adaptive neuro-fuzzy inference system (ANFIS) classifier is proposed to distinguish ESES and normal EEG signals. The results are promising and a classification accuracy of about 89% is achieved. PMID- 24790549 TI - A survey of artificial immune system based intrusion detection. AB - In the area of computer security, Intrusion Detection (ID) is a mechanism that attempts to discover abnormal access to computers by analyzing various interactions. There is a lot of literature about ID, but this study only surveys the approaches based on Artificial Immune System (AIS). The use of AIS in ID is an appealing concept in current techniques. This paper summarizes AIS based ID methods from a new view point; moreover, a framework is proposed for the design of AIS based ID Systems (IDSs). This framework is analyzed and discussed based on three core aspects: antibody/antigen encoding, generation algorithm, and evolution mode. Then we collate the commonly used algorithms, their implementation characteristics, and the development of IDSs into this framework. Finally, some of the future challenges in this area are also highlighted. PMID- 24790548 TI - Y-shaped bilateral self-expandable metallic stent placement for malignant hilar biliary obstruction: data from a referral center for palliative care. AB - BACKGROUND AND AIM: Malignant hilar strictures are a clinical challenge because of the current therapeutic approach and the poor prognosis. In recent years, self expandable metallic stents have proven more effective than plastic stents for palliation of malignant hilar strictures, with the bilateral stent-in-stent technique registering a high success rate. We report our experience with Y-shaped endoscopic self-expandable metallic stents placement for treatment of advanced malignant hilar strictures. METHODS: From April 2009 to August 2012, we prospectively collected data on patients treated with Y-shaped SEMS placement for advanced malignant hilar carcinoma. Data on technical success, clinical success, and complications were collected. RESULTS: Twenty patients (9 males) were treated (mean age 64.2 +/- 15.3 years). The grade of malignant hilar strictures according to the Bismuth classification was II in 5 patients (25%), IIIa in 1 (5%), and IV in 14 (70%). The mean bilirubin level was 14.7 +/- 4.9 mg/dL. Technical success was achieved in all patients, with a significant reduction in bilirubin levels (2.9 +/- 1.7 mg/dL). One patient experienced cholangitis as early complication, while in 2 patients stent ingrowth was observed. No stents migration was recorded. There was no procedure-related mortality. At the end of the follow-up (7.1 +/- 3.1 months), 13 of the 20 patients (65%) had died. CONCLUSIONS: Our experience confirms endoscopic bilateral self-expandable metallic stents placement with stent-in-stent technique (Y-shaped configuration) as a feasible, effective, and safe procedure for palliation of unresectable malignant hilar strictures. PMID- 24790550 TI - Fluorescence enhancement of fluorescent unnatural streptavidin by binding of a biotin analogue with spacer tail and its application to biotin sensing. AB - We designed a novel molecular biosensing system for the detection of biotin, an important vitamin by the combination of fluorescent unnatural streptavidin with a commercialized biotin-(AC5)2-hydrazide. A fluorescent unnatural amino acid, BODIPY-FL-aminophenylalanine (BFLAF), was position-specifically incorporated into Trp120 of streptavidin by four-base codon method. Fluorescence of the Trp120BFLAF mutant streptavidin was enhanced by the addition of biotin-(AC5)2-hydrazide with the concentration dependent, whereas fluorescence enhancement was not observed at all by the addition of natural biotin. It was considered that the spacer tail of biotin-(AC5)2-hydrazide may disturb the fluorescence quenching of the Trp120BFLAF by Trp79 and Trp108 of the neighbor subunit. Therefore, biotin sensing was carried out by the competitive binding reaction of biotin-(AC5)2-hydrazide and natural biotin to the fluorescent mutant streptavidin. The fluorescence intensity decreased by increasing free biotin concentration. The result suggested that molecular biosensor for small ligand could be successfully designed by the pair of fluorescent mutant binding protein and ligand analogue. PMID- 24790551 TI - Effect of monotherapy and combination therapy of pantoprazole and aprepitant in gastric esophageal reflux disease in albino rats. AB - The present study was undertaken to elucidate the effect of pantoprazole and aprepitant on experimental esophagitis in albino rats. Groups of rats, fasted overnight, received normal saline (3 mL/kg, sham control) or toxic control (3 mL/kg) or pantoprazole (30 mg/kg) or aprepitant (10 mg/kg), or their combinations and were subjected to pylorus and forestomach ligation. Animals were sacrificed after 8 h and evaluated for the gastric pH, volume of gastric juices, total acidity, esophagitis index, and free acidity. Esophageal tissues were further subjected to estimations of TBARS, GSH, catalase, and SOD. Treatment with pantoprazole and aprepitant significantly inhibited the gastric secretion, total acidity, and esophagitis index. The treatment also helped to restore the altered levels oxidative stress parameters to normal. PMID- 24790552 TI - Bifurcation analysis in models for vector-borne diseases with logistic growth. AB - We establish and study vector-borne models with logistic and exponential growth of vector and host populations, respectively. We discuss and analyses the existence and stability of equilibria. The model has backward bifurcation and may have no, one, or two positive equilibria when the basic reproduction number R 0 is less than one and one, two, or three endemic equilibria when R 0 is greater than one under different conditions. Furthermore, we prove that the disease-free equilibrium is stable if R 0 is less than 1, it is unstable otherwise. At last, by numerical simulation, we find rich dynamical behaviors in the model. By taking the natural death rate of host population as a bifurcation parameter, we find that the system may undergo a backward bifurcation, saddle-node bifurcation, Hopf bifurcation, Bogdanov-Takens bifurcation, and cusp bifurcation with the saturation parameter varying. The natural death rate of host population is a crucial parameter. If the natural death rate is higher, then the host population and the disease will die out. If it is smaller, then the host and vector population will coexist. If it is middle, the period solution will occur. Thus, with the parameter varying, the disease will spread, occur periodically, and finally become extinct. PMID- 24790553 TI - New similarity of triangular fuzzy number and its application. AB - The similarity of triangular fuzzy numbers is an important metric for application of it. There exist several approaches to measure similarity of triangular fuzzy numbers. However, some of them are opt to be large. To make the similarity well distributed, a new method SIAM (Shape's Indifferent Area and Midpoint) to measure triangular fuzzy number is put forward, which takes the shape's indifferent area and midpoint of two triangular fuzzy numbers into consideration. Comparison with other similarity measurements shows the effectiveness of the proposed method. Then, it is applied to collaborative filtering recommendation to measure users' similarity. A collaborative filtering case is used to illustrate users' similarity based on cloud model and triangular fuzzy number; the result indicates that users' similarity based on triangular fuzzy number can obtain better discrimination. Finally, a simulated collaborative filtering recommendation system is developed which uses cloud model and triangular fuzzy number to express users' comprehensive evaluation on items, and result shows that the accuracy of collaborative filtering recommendation based on triangular fuzzy number is higher. PMID- 24790554 TI - A robust nonlinear observer for a class of neural mass models. AB - A new method of designing a robust nonlinear observer is presented for a class of neural mass models by using the Lur'e system theory and the projection lemma. The observer is robust towards input uncertainty and measurement noise. It is applied to estimate the unmeasured membrane potential of neural populations from the electroencephalogram (EEG) produced by the neural mass models. An illustrative example shows the effectiveness of the proposed method. PMID- 24790555 TI - An improved artificial bee colony algorithm based on balance-evolution strategy for unmanned combat aerial vehicle path planning. AB - Unmanned combat aerial vehicles (UCAVs) have been of great interest to military organizations throughout the world due to their outstanding capabilities to operate in dangerous or hazardous environments. UCAV path planning aims to obtain an optimal flight route with the threats and constraints in the combat field well considered. In this work, a novel artificial bee colony (ABC) algorithm improved by a balance-evolution strategy (BES) is applied in this optimization scheme. In this new algorithm, convergence information during the iteration is fully utilized to manipulate the exploration/exploitation accuracy and to pursue a balance between local exploitation and global exploration capabilities. Simulation results confirm that BE-ABC algorithm is more competent for the UCAV path planning scheme than the conventional ABC algorithm and two other state-of the-art modified ABC algorithms. PMID- 24790556 TI - Cutting force predication based on integration of symmetric fuzzy number and finite element method. AB - In the process of turning, pointing at the uncertain phenomenon of cutting which is caused by the disturbance of random factors, for determining the uncertain scope of cutting force, the integrated symmetric fuzzy number and the finite element method (FEM) are used in the prediction of cutting force. The method used symmetric fuzzy number to establish fuzzy function between cutting force and three factors and obtained the uncertain interval of cutting force by linear programming. At the same time, the change curve of cutting force with time was directly simulated by using thermal-mechanical coupling FEM; also the nonuniform stress field and temperature distribution of workpiece, tool, and chip under the action of thermal-mechanical coupling were simulated. The experimental result shows that the method is effective for the uncertain prediction of cutting force. PMID- 24790557 TI - Network-based analysis of software change propagation. AB - The object-oriented software systems frequently evolve to meet new change requirements. Understanding the characteristics of changes aids testers and system designers to improve the quality of softwares. Identifying important modules becomes a key issue in the process of evolution. In this context, a novel network-based approach is proposed to comprehensively investigate change distributions and the correlation between centrality measures and the scope of change propagation. First, software dependency networks are constructed at class level. And then, the number of times of cochanges among classes is minded from software repositories. According to the dependency relationships and the number of times of cochanges among classes, the scope of change propagation is calculated. Using Spearman rank correlation analyzes the correlation between centrality measures and the scope of change propagation. Three case studies on java open source software projects Findbugs, Hibernate, and Spring are conducted to research the characteristics of change propagation. Experimental results show that (i) change distribution is very uneven; (ii) PageRank, Degree, and CIRank are significantly correlated to the scope of change propagation. Particularly, CIRank shows higher correlation coefficient, which suggests it can be a more useful indicator for measuring the scope of change propagation of classes in object-oriented software system. PMID- 24790558 TI - Response of soil respiration to grazing in an alpine meadow at three elevations in tibet. AB - Alpine meadows are one major type of pastureland on the Tibetan Plateau. However, few studies have evaluated the response of soil respiration (R(s)) to grazing along an elevation gradient in an alpine meadow on the Tibetan Plateau. Here three fenced enclosures were established in an alpine meadow at three elevations (i.e., 4313 m, 4513 m, and 4693 m) in July 2008. We measured R s inside and outside the three fenced enclosures in July-September, 2010-2011. Topsoil (0-20 cm) samples were gathered in July, August, and September, 2011. There were no significant differences for R s , dissolved organic C (DOC), and belowground root biomass (BGB) between the grazed and ungrazed soils. Soil respiration was positively correlated with soil organic C (SOC), microbial biomass (MBC), DOC, and BGB. In addition, both R s and BGB increased with total N(TN), the ratio of SOC to TN, ammonium NH4 +-H4+-N), and the ratio of NH4+-N to nitrate N. Our findings suggested that the negligible response of R s to grazing could be directly attributed to that of respiration substrate and that soil N may indirectly affect R(s) by its effect on BGB. PMID- 24790559 TI - Preparation and evaluation of novel in situ gels containing acyclovir for the treatment of oral herpes simplex virus infections. AB - The objective of this work was to develop an oral mucosal drug delivery system to facilitate the local and systemic delivery of acyclovir for the treatment of oral herpes infection caused by the herpes simplex virus (HSV). An in situ gelling system was used to increase the residence time and thus the bioavailability of acyclovir in oral mucosa. Temperature and pH trigged in situ gel formulations were prepared by cold method using polymers like poloxamer 407, carbopol 934, and HPMC. Glycerin and a mixture of tween 80 and ethanol (1 : 2 ratio) were used as the drug dissolving solvent. The pH of carbopol containing formulation was adjusted to pH 5.8 while the pH of poloxamer solution was adjusted to pH 7. These formulations were evaluated for sol-gel transition temperature, gelling capacity, pH, viscosity, spreadability, gel strength, drug content, ex-vitro permeation, and mucoadhesion. The gelation temperatures of all the formulations were within the range of 28-38 degrees C. All the formulations exhibited fairly uniform drug content (98.15-99.75%). Drug release study of all the formulations showed sustained release properties. The release of drug through these in situ gel formulations followed the Higuchi model and Korsmeyer peppas model mechanism. PMID- 24790561 TI - Evaluation of the nutritive and organoleptic values of food products developed by incorporated Catharanthus roseus (Sadabahar) fresh leaves explore their hypoglycemic potential. AB - Diabetes becomes a real problem of public health in developing countries, where its prevalence is increasing steadily. Diabetes mellitus can be found in almost every population in the world. Since the Ayurvedic practice started in India, plants are being used in the cure of diseases. Although the Catharanthus roseus have been used for their alleged health benefits and avail their hypoglycemic effect, used as medicine by diabetics. Medicinal plants have rarely been incorporated in food preparations. To fill these lacunae, food products were prepared by using Catharanthus roseus (Sadabahar) fresh leaves with hypoglycemic properties. Commonly consumed recipes in India are prepared for diabetic patients and were developed at different levels at 3 g, 4 g, and 6 g per serving. Food product development and their acceptability appraisal through organoleptic evaluation were carried out by semitrained panel comprising 15 trained panelists from the department of Food Science and Nutrition, Banasthali University. Seven products were developed by incorporating Catharanthus roseus fresh leaves. Nine point hedonic scale was used as a medium to know about the product acceptability at various variances. All products are moderately acceptable at different concentrations except product fare "6 g" which was more acceptable than the standard. Among the three variations of incorporating the Catharanthus roseus (Sadabahar) Leaves, 3 g variation is more acceptable than other variations. PMID- 24790560 TI - Atherosclerosis and atheroma plaque rupture: normal anatomy of vasa vasorum and their role associated with atherosclerosis. AB - Atherosclerosis is primarily a degenerative disorder related to aging with a chronic inflammatory component. There are differences in expression among different vascular beds, inflicting a range of vascular diseases. The majority of studies focus on the inner and medial vascular layers, which are affected at the development of atherosclerosis. Recent evidence shows that the outer layer of blood vessels, composed of the adventitial layer and the vasa vasorum, not only plays a significant role in maintaining vessel integrity, but also reacts to atheroma. What is not clear is the extent of contribution of the outer layer to the process of atherosclerosis. Is it involved in the initiation, progression, and clinical expression of atheroma? Is the inflammation associated with atheroma limited to being merely reactive or is there a proactive element? This paper provides an overview of the normal anatomy of vasa vasorum and potential mechanism of plaque formation due to vascular injury (vasa vasorum) and microhemorrhage. PMID- 24790562 TI - Non-probabilistic solution of uncertain vibration equation of large membranes using Adomian decomposition method. AB - This paper proposes a new technique based on double parametric form of fuzzy numbers to handle the uncertain vibration equation for very large membrane for different particular cases. Uncertainties present in the initial condition and the wave velocity of free vibration are modelled through Gaussian convex normalised fuzzy set. Using the single parametric form of fuzzy number, the original fuzzy vibration equation is converted first to an interval fuzzy vibration equation. Next this equation is transformed to crisp form by applying double parametric form of fuzzy numbers. Finally the same governing equation is solved by Adomian decomposition method (ADM) symbolically to obtain the uncertain bounds. The present methods are very simple and effective. Obtained results are depicted in terms of plots to show the efficiency and powerfulness of the present analysis. Results obtained by the methods with new techniques are compared with existing results in special cases. PMID- 24790563 TI - Chaotic multiquenching annealing applied to the protein folding problem. AB - The Chaotic Multiquenching Annealing algorithm (CMQA) is proposed. CMQA is a new algorithm, which is applied to protein folding problem (PFP). This algorithm is divided into three phases: (i) multiquenching phase (MQP), (ii) annealing phase (AP), and (iii) dynamical equilibrium phase (DEP). MQP enforces several stages of quick quenching processes that include chaotic functions. The chaotic functions can increase the exploration potential of solutions space of PFP. AP phase implements a simulated annealing algorithm (SA) with an exponential cooling function. MQP and AP are delimited by different ranges of temperatures; MQP is applied for a range of temperatures which goes from extremely high values to very high values; AP searches for solutions in a range of temperatures from high values to extremely low values. DEP phase finds the equilibrium in a dynamic way by applying least squares method. CMQA is tested with several instances of PFP. PMID- 24790564 TI - Ultrastructural localization of polygalacturonase in ethylene-stimulated abscission of tomato pedicel explants. AB - Polygalacturonase (PG) is crucial in plant organ abscission process. This paper investigated the cellular and subcellular localization of PG in ethylene stimulated abscission of tomato pedicel explants. Confocal laser scanning microscopy of abscission zone sections with the fluorescent probe Cy3 revealed that PG was initially accumulated in parenchyma cells in cortical and vascular tissues after 8 h of ethylene treatment and then extended throughout the abscission zone when the abscission zone separated at 24 h after ethylene treatment. At the subcellular level, transmission electron microscopy with immunogold staining showed that PG showed abundant accumulation in the cortical and vascular tissues at 8 h after ethylene treatment, and the distribution area extended to the central parenchyma cells at 16 h after ethylene treatment. In addition, PGs were observed in the distal and proximal parts of the tomato pedicel explants throughout the abscission process. The results provided a visualized distribution of PG in the pedicel abscission zone and proved that PG was closely related to abscission. PMID- 24790565 TI - Perspectives from nurse managers on informatics competencies. AB - BACKGROUND AND PURPOSE: Nurse managers are in an excellent position for providing leadership and support within the institutions they serve and are often responsible for accessing information that is vital to the improvement of health facility processes and patients' outcomes. Therefore, competency in informatics is essential. The purposes of this study are to examine current informatics competency levels of nurse managers and to identify the variables that influence these competencies. METHODS: A questionnaire designed to assess demographic information and nursing informatics competency was completed by 68 nurse managers. Multiple linear regression analysis was conducted to analyze the factors influencing informatics competency. RESULTS: Descriptive analysis of the data revealed that informatics competency of these nurse managers was in the moderate range (77.65 +/- 8.14). Multiple linear regression analysis indicated that level of education, nursing administration experience, and informatics education/training were significant factors affecting competency levels. CONCLUSION: The factors identified in this study can serve as a reference for nurse managers who were wishing to improve their informatics competency, hospital administrators seeking to provide appropriate training, and nursing educators who were making decisions about nursing informatics curricula. These findings suggest that efforts to enhance the informatics competency of nurse managers have marked potential benefits. PMID- 24790566 TI - The theoretical limits of watermark spread spectrum sequence. AB - At present, the spread spectrum (SS) sequences used in watermark include i.i.d. random sequences and the sequences used in SS communications. They appear earlier than digital watermark. Almost no researchers pay attention to whether they are really fit for watermark. In this paper, we compare the SS watermark channel and the traditional SS communication channel. We find out that their correlation property is different. Considering cropping and translation attacks, we define watermark auto- and cross-correlation and propose Loose Autocorrelation and Tight Cross-Correlation (LAC&TCC) properties for SS watermark. The LAC&TCC properties are that, whether or not synchronized, the autocorrelation is equal or close to 1 and the cross-correlation is equal or close to 0. Accordingly, the peak correlation is divided into the peak autocorrelation Ra (l) and the peak cross correlation Rc (l). We establish the lower bound of R c (l) and the higher bound of Ra (l), respectively. The two bounds indicate that, no matter how small the cover is reserved, the extractor can always find a threshold to distinguish auto- and cross-correlation in theory. PMID- 24790567 TI - Accuracy enhancement for forecasting water levels of reservoirs and river streams using a multiple-input-pattern fuzzification approach. AB - Water level forecasting is an essential topic in water management affecting reservoir operations and decision making. Recently, modern methods utilizing artificial intelligence, fuzzy logic, and combinations of these techniques have been used in hydrological applications because of their considerable ability to map an input-output pattern without requiring prior knowledge of the criteria influencing the forecasting procedure. The artificial neurofuzzy interface system (ANFIS) is one of the most accurate models used in water resource management. Because the membership functions (MFs) possess the characteristics of smoothness and mathematical components, each set of input data is able to yield the best result using a certain type of MF in the ANFIS models. The objective of this study is to define the different ANFIS model by applying different types of MFs for each type of input to forecast the water level in two case studies, the Klang Gates Dam and Rantau Panjang station on the Johor river in Malaysia, to compare the traditional ANFIS model with the new introduced one in two different situations, reservoir and stream, showing the new approach outweigh rather than the traditional one in both case studies. This objective is accomplished by evaluating the model fitness and performance in daily forecasting. PMID- 24790568 TI - Heuristics for multiobjective optimization of two-sided assembly line systems. AB - Products such as cars, trucks, and heavy machinery are assembled by two-sided assembly line. Assembly line balancing has significant impacts on the performance and productivity of flow line manufacturing systems and is an active research area for several decades. This paper addresses the line balancing problem of a two-sided assembly line in which the tasks are to be assigned at L side or R side or any one side (addressed as E). Two objectives, minimum number of workstations and minimum unbalance time among workstations, have been considered for balancing the assembly line. There are two approaches to solve multiobjective optimization problem: first approach combines all the objectives into a single composite function or moves all but one objective to the constraint set; second approach determines the Pareto optimal solution set. This paper proposes two heuristics to evolve optimal Pareto front for the TALBP under consideration: Enumerative Heuristic Algorithm (EHA) to handle problems of small and medium size and Simulated Annealing Algorithm (SAA) for large-sized problems. The proposed approaches are illustrated with example problems and their performances are compared with a set of test problems. PMID- 24790569 TI - The fracture characteristic of three collinear cracks under true triaxial compression. AB - The mechanical behavior of multicracks under compression has become a very important project in the field of fracture mechanics and rock mechanics. In this paper, experimental and numerical studies on the fracture property of three collinear cracks under compression were implemented. The specimens were a square concrete plate, and the cracks were made by a very thin film. The tests were conducted by using true triaxial loading device. In the numerical study, the Abaqus code was employed. The effect of crack orientation and the confining stress on cracked specimen compressive strength were investigated. The results show that the critical stresses of cracked specimens change with crack inclination angles, and, as the angle is 45 degrees , the critical stress is the lowest; the critical stresses increase with the confining stresses. PMID- 24790570 TI - Assessment of trace element levels in muscle tissues of fish species collected from a river, stream, lake, and sea in Sakarya, Turkey. AB - Levels of some trace and essential elements, including Al, B, Ba, Cr, Cu, Fe, Mn, Ni, Sr, and Zn, were determined in 17 different fish species from Sakarya River, Cark Stream, Sapanca Lake, and Western Black Sea using ICP-OES after microwave (MW) digestion procedure. During preparation of samples for analysis, wet and MW digestion methods were also compared. Accuracy of the digestion methods was checked by the analysis of DORM-3 reference material (Fish Protein Certified Reference Material for Trace Metals). Concentrations of trace elements were found as Al: 6.5-48.5, B: 0.06-3.30, Ba: 0.09-2.92, Cr: 0.02-1.64, Cu: 0.13-2.28, Fe: 7.28-39.9, Mn: 0.08-11.4, Ni: 0.01-26.1, Sr: 0.17-13.5, and Zn: 11.5-52.9 ug g( 1). The obtained results were compared with other studies published in the literature. Trace element levels in various fish species collected from waters in Sakarya region were found to be below limit values provided by Turkish Food Codex (TFC), Food and Agriculture Organization (FAO), and World Health Organization (WHO). PMID- 24790571 TI - New fuzzy support vector machine for the class imbalance problem in medical datasets classification. AB - In medical datasets classification, support vector machine (SVM) is considered to be one of the most successful methods. However, most of the real-world medical datasets usually contain some outliers/noise and data often have class imbalance problems. In this paper, a fuzzy support machine (FSVM) for the class imbalance problem (called FSVM-CIP) is presented, which can be seen as a modified class of FSVM by extending manifold regularization and assigning two misclassification costs for two classes. The proposed FSVM-CIP can be used to handle the class imbalance problem in the presence of outliers/noise, and enhance the locality maximum margin. Five real-world medical datasets, breast, heart, hepatitis, BUPA liver, and pima diabetes, from the UCI medical database are employed to illustrate the method presented in this paper. Experimental results on these datasets show the outperformed or comparable effectiveness of FSVM-CIP. PMID- 24790572 TI - Exploration of a capability-focused aerospace system of systems architecture alternative with bilayer design space, based on RST-SOM algorithmic methods. AB - In defense related programs, the use of capability-based analysis, design, and acquisition has been significant. In order to confront one of the most challenging features of a huge design space in capability based analysis (CBA), a literature review of design space exploration was first examined. Then, in the process of an aerospace system of systems design space exploration, a bilayer mapping method was put forward, based on the existing experimental and operating data. Finally, the feasibility of the foregoing approach was demonstrated with an illustrative example. With the data mining RST (rough sets theory) and SOM (self organized mapping) techniques, the alternative to the aerospace system of systems architecture was mapping from P-space (performance space) to C-space (configuration space), and then from C-space to D-space (design space), respectively. Ultimately, the performance space was mapped to the design space, which completed the exploration and preliminary reduction of the entire design space. This method provides a computational analysis and implementation scheme for large-scale simulation. PMID- 24790573 TI - Performance evaluation of heart sound cancellation in FPGA hardware implementation for electronic stethoscope. AB - This paper presents the design and evaluation of the hardware circuit for electronic stethoscopes with heart sound cancellation capabilities using field programmable gate arrays (FPGAs). The adaptive line enhancer (ALE) was adopted as the filtering methodology to reduce heart sound attributes from the breath sounds obtained via the electronic stethoscope pickup. FPGAs were utilized to implement the ALE functions in hardware to achieve near real-time breath sound processing. We believe that such an implementation is unprecedented and crucial toward a truly useful, standalone medical device in outpatient clinic settings. The implementation evaluation with one Altera cyclone II-EP2C70F89 shows that the proposed ALE used 45% resources of the chip. Experiments with the proposed prototype were made using DE2-70 emulation board with recorded body signals obtained from online medical archives. Clear suppressions were observed in our experiments from both the frequency domain and time domain perspectives. PMID- 24790574 TI - Evolutionary approach for relative gene expression algorithms. AB - A Relative Expression Analysis (RXA) uses ordering relationships in a small collection of genes and is successfully applied to classiffication using microarray data. As checking all possible subsets of genes is computationally infeasible, the RXA algorithms require feature selection and multiple restrictive assumptions. Our main contribution is a specialized evolutionary algorithm (EA) for top-scoring pairs called EvoTSP which allows finding more advanced gene relations. We managed to unify the major variants of relative expression algorithms through EA and introduce weights to the top-scoring pairs. Experimental validation of EvoTSP on public available microarray datasets showed that the proposed solution significantly outperforms in terms of accuracy other relative expression algorithms and allows exploring much larger solution space. PMID- 24790576 TI - Meteorological data analysis using MapReduce. AB - In the atmospheric science, the scale of meteorological data is massive and growing rapidly. K-means is a fast and available cluster algorithm which has been used in many fields. However, for the large-scale meteorological data, the traditional K-means algorithm is not capable enough to satisfy the actual application needs efficiently. This paper proposes an improved MK-means algorithm (MK-means) based on MapReduce according to characteristics of large meteorological datasets. The experimental results show that MK-means has more computing ability and scalability. PMID- 24790577 TI - Interaction of Cu(II) and Ni(II) with Ypk9 protein fragment via NMR studies. AB - P1D2E3K4H5E6L7 (PK9-H), a fragment of Ypk9, the yeast homologue of the human Park9 protein, was studied for its coordination abilities towards Ni(II) and Cu(II) ions through mono- and bi-dimensional NMR techniques. Both proteins are involved in the transportation of metal ions, including manganese and nickel, from the cytosol to the lysosomal lumen. Ypk9 showed manganese detoxification role, preventing a Mn-induced Parkinsonism (PD) besides mutations in Park9, linked to a juvenile form of the disease. Here, we tested PK9-H with Cu(II) and Ni(II) ions, the former because it is an essential element ubiquitous in the human body, so its trafficking should be strictly regulated and one cannot exclude that Ypk9 may play a role in it, and the latter because, besides being a toxic element for many organisms and involved in different pathologies and inflammation states, it seems that the protein confers protection against it. NMR experiments showed that both cations can bind PK9-H in an effective way, leading to complexes whose coordination mode depends on the pH of the solution. NMR data have been used to build a model for the structure of the major Cu(II) and Ni(II) complexes. Structural changes in the conformation of the peptide with organized side chain orientation promoted by nickel coordination were detected. PMID- 24790578 TI - Experimental study on tsunami risk reduction on coastal building fronted by sea wall. AB - This experimental study was conducted to idealize the efficacy of sea wall in controlling the tsunami forces on onshore structures. Different types of sea walls were placed in front of the building model. The tsunami forces and the wave heights were measured with and without the sea wall conditions. Types of sea wall, wall height, and wall positions were varied simultaneously to quantify the force reductions. Maximum of 41% forces was reduced by higher sea wall, positioned closer proximity to the model whereas this reduction was about 27% when the wall height was half of the high wall. Experimental investigations revealed that wall with adequate height and placed closer to the structures enables a satisfactory predictor of the force reduction on onshore structures. Another set of tests were performed with perforated wall placing near the building model. Less construction cost makes the provision of perforated sea wall interesting. The overall results showed that the efficacy of perforated wall is almost similar to solid wall. Hence, it can be efficiently used instead of solid wall. Moreover, overtopped water that is stuck behind the wall is readily gone back to the sea through perforations releasing additional forces on the nearby structures. PMID- 24790575 TI - Hypoglycemia induced by insulin as a triggering factor of cognitive deficit in diabetic children. AB - This paper provides an overview of insulin-induced hypoglycemia as a triggering factor of cognitive deficit in children with type 1 diabetes mellitus. For this purpose, databases from 1961 to 2013 were used with the objective of detecting the primary publications that address the impact of hypoglycemia on cognitive performance of diabetic children. The results obtained from experimental animals were excluded. The majority of studies demonstrated that the cognitive deficit in diabetic children involves multiple factors including duration, intensity, severity, and frequency of hypoglycemia episodes. Additionally, age at the onset of type 1 diabetes also influences the cognitive performance, considering that early inception of the disease is a predisposing factor for severe hypoglycemia. Furthermore, the results suggest that there is a strong correlation between brain damage caused by hypoglycemia and cognitive deterioration. Therefore, a more cautious follow-up and education are needed to impede and treat hypoglycemia in children with diabetes mellitus. PMID- 24790579 TI - Privacy-preserving location-based query using location indexes and parallel searching in distributed networks. AB - An efficient location-based query algorithm of protecting the privacy of the user in the distributed networks is given. This algorithm utilizes the location indexes of the users and multiple parallel threads to search and select quickly all the candidate anonymous sets with more users and their location information with more uniform distribution to accelerate the execution of the temporal spatial anonymous operations, and it allows the users to configure their custom made privacy-preserving location query requests. The simulated experiment results show that the proposed algorithm can offer simultaneously the location query services for more users and improve the performance of the anonymous server and satisfy the anonymous location requests of the users. PMID- 24790580 TI - An analysis on local convergence of inexact newton-gauss method for solving singular systems of equations. AB - We study the local convergence properties of inexact Newton-Gauss method for singular systems of equations. Unified estimates of radius of convergence balls for one kind of singular systems of equations with constant rank derivatives are obtained. Application to the Smale point estimate theory is provided and some important known results are extended and/or improved. PMID- 24790581 TI - Evaluation of the effect of concurrent chronic total occlusion and successful staged revascularization on long-term mortality in patients with ST-elevation myocardial infarction. AB - AIMS: To investigate the impact of chronic total occlusion (CTO) in non-infarct related artery (IRA) on the long-term prognosis and evaluate the clinical significance of staged revascularization in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: 1266 STEMI patients with primary percutaneous coronary intervention (PCI) were categorized as single-vessel disease (SVD), multivessel disease (MVD) without and with CTO. We study the clinical outcomes of patients after primary PCI in the following 3 years. Additionally, patients with CTO received staged revascularization, and major adverse cardiac events (MACE) during 3-year follow-up were recorded. RESULTS: Presence of CTO was a predictor of both early mortality [hazard ratio (HR) 3.4, 95% confidence interval (CI) 2.4-4.5, P < 0.01] and late mortality (HR 1.9, 95% CI 1.4-3.6, P < 0.01), whereas MVD without CTO was only a predictor of early mortality (HR 1.7, 95% CI 1.3-2.3, P < 0.05). In CTO group, 100 patients had successful CTO recanalization, and 48 patients failed. During 3-year follow-up, patients with failed procedure had higher cardiac mortality (22.9% versus 9.0%, P = 0.020) and lower MACE-free survival (50.0% versus 72.0%, P = 0.009) compared to patients with successful procedure. CONCLUSION: The presence of CTO and not MVD alone is associated with long-term mortality. Successful revascularization of CTO in the non-IRA is associated with improved clinical outcomes in patients with STEMI undergoing primary PCI. PMID- 24790582 TI - Path-following control of wheeled planetary exploration robots moving on deformable rough terrain. AB - The control of planetary rovers, which are high performance mobile robots that move on deformable rough terrain, is a challenging problem. Taking lateral skid into account, this paper presents a rough terrain model and nonholonomic kinematics model for planetary rovers. An approach is proposed in which the reference path is generated according to the planned path by combining look-ahead distance and path updating distance on the basis of the carrot following method. A path-following strategy for wheeled planetary exploration robots incorporating slip compensation is designed. Simulation results of a four-wheeled robot on deformable rough terrain verify that it can be controlled to follow a planned path with good precision, despite the fact that the wheels will obviously skid and slip. PMID- 24790583 TI - A simulation approach to decision making in IT service strategy. AB - We propose to use simulation modeling to support decision making in IT service strategy scope. Our main contribution is a simulation model that helps service providers analyze the consequences of changes in both the service capacity assigned to their customers and the tendency of service requests received on the fulfillment of a business rule associated with the strategic goal of customer satisfaction. This business rule is set in the SLAs that service provider and its customers agree to, which determine the maximum percentage of service requests that are permitted to be abandoned because they have exceeded the waiting time allowed. To illustrate the use and applications of the model, we include some of the experiments conducted and describe our conclusions. PMID- 24790584 TI - Support vector machine based on adaptive acceleration particle swarm optimization. AB - Existing face recognition methods utilize particle swarm optimizer (PSO) and opposition based particle swarm optimizer (OPSO) to optimize the parameters of SVM. However, the utilization of random values in the velocity calculation decreases the performance of these techniques; that is, during the velocity computation, we normally use random values for the acceleration coefficients and this creates randomness in the solution. To address this problem, an adaptive acceleration particle swarm optimization (AAPSO) technique is proposed. To evaluate our proposed method, we employ both face and iris recognition based on AAPSO with SVM (AAPSO-SVM). In the face and iris recognition systems, performance is evaluated using two human face databases, YALE and CASIA, and the UBiris dataset. In this method, we initially perform feature extraction and then recognition on the extracted features. In the recognition process, the extracted features are used for SVM training and testing. During the training and testing, the SVM parameters are optimized with the AAPSO technique, and in AAPSO, the acceleration coefficients are computed using the particle fitness values. The parameters in SVM, which are optimized by AAPSO, perform efficiently for both face and iris recognition. A comparative analysis between our proposed AAPSO-SVM and the PSO-SVM technique is presented. PMID- 24790585 TI - Upper semicontinuity of pullback attractors for the 3D nonautonomous Benjamin Bona-Mahony equations. AB - We will study the upper semicontinuity of pullback attractors for the 3D nonautonomouss Benjamin-Bona-Mahony equations with external force perturbation terms. Under some regular assumptions, we can prove the pullback attractors A(epsilon)(t) of equation, u(t)-Deltau(t)-nuDeltau+?.(-->)F(u)=epsilong(x,t), x ? Omega, converge to the global attractor A of the above-mentioned equation with epsilon = 0 for any t ? R. PMID- 24790586 TI - Stock price change rate prediction by utilizing social network activities. AB - Predicting stock price change rates for providing valuable information to investors is a challenging task. Individual participants may express their opinions in social network service (SNS) before or after their transactions in the market; we hypothesize that stock price change rate is better predicted by a function of social network service activities and technical indicators than by a function of just stock market activities. The hypothesis is tested by accuracy of predictions as well as performance of simulated trading because success or failure of prediction is better measured by profits or losses the investors gain or suffer. In this paper, we propose a hybrid model that combines multiple kernel learning (MKL) and genetic algorithm (GA). MKL is adopted to optimize the stock price change rate prediction models that are expressed in a multiple kernel linear function of different types of features extracted from different sources. GA is used to optimize the trading rules used in the simulated trading by fusing the return predictions and values of three well-known overbought and oversold technical indicators. Accumulated return and Sharpe ratio were used to test the goodness of performance of the simulated trading. Experimental results show that our proposed model performed better than other models including ones using state of the art techniques. PMID- 24790588 TI - Smooth approximation l(0)-norm constrained affine projection algorithm and its applications in sparse channel estimation. AB - We propose a smooth approximation l(0)-norm constrained affine projection algorithm (SL0-APA) to improve the convergence speed and the steady-state error of affine projection algorithm (APA) for sparse channel estimation. The proposed algorithm ensures improved performance in terms of the convergence speed and the steady-state error via the combination of a smooth approximation l(0)-norm (SL0) penalty on the coefficients into the standard APA cost function, which gives rise to a zero attractor that promotes the sparsity of the channel taps in the channel estimation and hence accelerates the convergence speed and reduces the steady state error when the channel is sparse. The simulation results demonstrate that our proposed SL0-APA is superior to the standard APA and its sparsity-aware algorithms in terms of both the convergence speed and the steady-state behavior in a designated sparse channel. Furthermore, SL0-APA is shown to have smaller steady-state error than the previously proposed sparsity-aware algorithms when the number of nonzero taps in the sparse channel increases. PMID- 24790587 TI - HIF-1 alpha had pivotal effects on downregulation of miR-210 decreasing viability and inducing apoptosis in hypoxic chondrocytes. AB - Hypoxia-inducible factor 1-alpha (HIF-1 alpha ) and some microRNA (miRNAs) play pivotal roles in response to hypoxia-related physiologic and pathophysiologic responses. Up to date, the regulatory mechanisms of these molecules were largely unknown in chondrocytes. In this study, to study the mechanisms of degradation and homeostasis of chondrocytes, the effects of miRNAs and HIF-1 alpha on chondrocytes in physiologic environment were investigated. We found that the overexpression of miR-210 and HIF-1 alpha was present on hypoxia in C28/I2 human chondrocytes significantly by qRT-PCR and western plot. Further study displayed that miR-210 played positive role as a promoter in regulation and its regulated molecules (bcl-xl and PHD-2) in C28/I2 cells on hypoxia by silenced miR-210, silenced HIF-1 alpha , and adding miR-210. Moreover, downregulated miR-210 could significantly repress the viability and increase the apoptosis in C28/I2 cells on hypoxia, compared to those on normoxia. Furthermore, miR-210 could not modulate viability and apoptosis in C28/I2 cells with the HIF-1 alpha knockdown on hypoxia and normoxia. Taken together, this study demonstrated that the MiR-210 was involved in an HIF-1 alpha -dependent way in C28/I2 human chondrocytes for the first time. It also suggested that miR-210 downregulation decreased viability and induced apoptosis in hypoxic chondrocytes depending on HIF-1 alpha . PMID- 24790589 TI - Psychosocial adjustment to sex reassignment surgery: a qualitative examination and personal experiences of six transsexual persons in croatia. AB - In Croatia, transgender individuals face numerous social and medical obstacles throughout the process of transition. The aim of this study was to depict the factors contributing to the psychosocial adjustment of six transsexual individuals living in Croatia following sex reassignment surgery (SRS). A combination of quantitative and qualitative self-report methods was used. Due to the specificity of the sample, the data were collected online. Standardized questionnaires were used to assess mental health and quality of life alongside a series of open-ended questions divided into 4 themes: the decision-making process regarding SRS; social and medical support during the SRS process; experience of discrimination and stigmatizing behaviors; psychosocial adjustment after SRS. Despite the unfavorable circumstances in Croatian society, participants demonstrated stable mental, social, and professional functioning, as well as a relative resilience to minority stress. Results also reveal the role of pretransition factors such as high socioeconomic status, good premorbid functioning, and high motivation for SRS in successful psychosocial adjustment. During and after transition, participants reported experiencing good social support and satisfaction with the surgical treatment and outcomes. Any difficulties reported by participants are related to either sexual relationships or internalized transphobia. The results also demonstrate the potentially protective role that a lengthier process of transition plays in countries such as Croatia. PMID- 24790590 TI - A fusion method of Gabor wavelet transform and unsupervised clustering algorithms for tissue edge detection. AB - This paper proposes two edge detection methods for medical images by integrating the advantages of Gabor wavelet transform (GWT) and unsupervised clustering algorithms. The GWT is used to enhance the edge information in an image while suppressing noise. Following this, the k-means and Fuzzy c-means (FCM) clustering algorithms are used to convert a gray level image into a binary image. The proposed methods are tested using medical images obtained through Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) devices, and a phantom image. The results prove that the proposed methods are successful for edge detection, even in noisy cases. PMID- 24790591 TI - Development of cabozantinib for the treatment of prostate cancer. AB - Cabozantinib (XL184) is a multitargeted receptor tyrosine kinase with predominantly MET and vascular endothelial growth factor inhibition properties. It is currently approved by the US Food and Drug Administration for the treatment of progressive metastatic medullary thyroid cancer. The agent has a convenient once-daily oral dosing schedule and has demonstrated encouraging activity in metastatic castrate-resistant prostate cancer (CRPC). A Phase I/II trial demonstrated responses in soft tissue, visceral disease, and bone metastases in CRPC. An objective response rate of 5%, a stable disease rate of 75%, and a median progression-free survival of 6 months was observed. As compared with the 140 mg daily dose used in thyroid cancer, a lower dose of 60 mg daily is currently being utilized in prostate cancer studies due to the fact that toxicity could be reduced without compromising efficacy. Randomized trials are ongoing in comparison with prednisone or with mitoxantrone and prednisone in pretreated metastatic CRPC. Cabozantinib has demonstrated a unique mechanism of action and preliminary efficacy in the crowded therapeutic field of prostate cancer. Since multiple therapies have recently demonstrated overall survival benefit in metastatic CRPC, cabozantinib will likely face some challenges in clinical application. At present, in this rapidly evolving field, it is unclear what proportion of patients with prostate cancer will be eligible to receive this therapy. The cost of cabozantinib is likely to be another deterrent, especially if it remains more expensive than other oral therapies, such as abiraterone and enzalutamide. Defining the role of MET overexpression and RET mutations as biomarkers in prostate cancer may help to guide patient selection, and enrich and enhance the future applications of this targeted novel agent. PMID- 24790592 TI - Reversible dissociation and ligand-glutathione exchange reaction in binuclear cationic tetranitrosyl iron complex with penicillamine. AB - This paper describes a comparative study of the decomposition of two nitrosyl iron complexes (NICs) with penicillamine thiolic ligands [Fe2(SC5H11NO2)2(NO)4]SO4 .5H2O (I) and glutathione- (GSH-) ligands [Fe2(SC10H17N3O6)2(NO)4]SO4 .2H2O (II), which spontaneously evolve to NO in aqueous medium. NO formation was measured by a sensor electrode and by spectrophotometric methods by measuring the formation of a hemoglobin- (Hb-) NO complex. The NO evolution reaction rate from (I) k 1 = (4.6 +/- 0.1).10(-3) s( 1) and the elimination rate constant of the penicillamine ligand k 2 = (1.8 +/- 0.2).10(-3) s(-1) at 25 degrees C in 0.05 M phosphate buffer, pH 7.0, was calculated using kinetic modeling based on the experimental data. Both reactions are reversible. Spectrophotometry and mass-spectrometry methods have firmly shown that the penicillamine ligand is exchanged for GS(-) during decomposition of 1.5.10(-4) M (I) in the presence of 10(-3) M GSH, with 76% yield in 24 h. As has been established, such behaviour is caused by the resistance of (II) to decomposition due to the higher affinity of iron to GSH in the complex. The discovered reaction may impede S-glutathionylation of the essential enzyme systems in the presence of (I) and is important for metabolism of NIC, connected with its antitumor activity. PMID- 24790594 TI - Working toward integrated models of alpine plant distribution. AB - Species distribution models (SDMs) have been frequently employed to forecast the response of alpine plants to global changes. Efforts to model alpine plant distribution have thus far been primarily based on a correlative approach, in which ecological processes are implicitly addressed through a statistical relationship between observed species occurrences and environmental predictors. Recent evidence, however, highlights the shortcomings of correlative SDMs, especially in alpine landscapes where plant species tend to be decoupled from atmospheric conditions in micro-topographic habitats and are particularly exposed to geomorphic disturbances. While alpine plants respond to the same limiting factors as plants found at lower elevations, alpine environments impose a particular set of scale-dependent and hierarchical drivers that shape the realized niche of species and that require explicit consideration in a modelling context. Several recent studies in the European Alps have successfully integrated both correlative and process-based elements into distribution models of alpine plants, but for the time being a single integrative modelling framework that includes all key drivers remains elusive. As a first step in working toward a comprehensive integrated model applicable to alpine plant communities, we propose a conceptual framework that structures the primary mechanisms affecting alpine plant distributions. We group processes into four categories, including multi scalar abiotic drivers, gradient dependent species interactions, dispersal and spatial-temporal plant responses to disturbance. Finally, we propose a methodological framework aimed at developing an integrated model to better predict alpine plant distribution. PMID- 24790595 TI - PPARG in Human Adipogenesis: Differential Contribution of Canonical Transcripts and Dominant Negative Isoforms. AB - The nuclear receptor PPAR gamma is a key regulator of adipogenesis, and alterations of its function are associated with different pathological processes related to metabolic syndrome. We recently identified two PPARG transcripts encoding dominant negative PPAR gamma isoforms. The existence of different PPARG variants suggests that alternative splicing is crucial to modulate PPAR gamma function, underlying some underestimated aspects of its regulation. Here we investigate PPARG expression in different tissues and cells affected in metabolic syndrome and, in particular, during adipocyte differentiation of human mesenchymal stem cells. We defined the transcript-specific expression pattern of PPARG variants encoding both canonical and dominant negative isoforms and identified a novel PPARG transcript, gamma 1ORF4. Our analysis indicated that, during adipogenesis, the transcription of alternative PPARG variants is regulated in a time-specific manner through differential usage of distinct promoters. In addition, our analysis describes-for the first time-the differential contribution of three ORF4 variants to this process, suggesting a still unexplored role for these dominant negative isoforms during adipogenesis. Therefore, our results highlight crucial aspects of PPARG regulation, suggesting the need of further investigation to rule out the differential impact of all PPARG transcripts in both physiologic and pathologic conditions, such as metabolism-related disorders. PMID- 24790596 TI - Effects of melatonin and epiphyseal proteins on fluoride-induced adverse changes in antioxidant status of heart, liver, and kidney of rats. AB - Several experimental and clinical reports indicated the oxidative stress-mediated adverse changes in vital organs of human and animal in fluoride (F) toxicity. Therefore, the present study was undertaken to evaluate the therapeutic effect of buffalo (Bubalus bubalis) epiphyseal (pineal) proteins (BEP) and melatonin (MEL) against F-induced oxidative stress in heart, liver, and kidney of experimental adult female rats. To accomplish this experimental objective, twenty-four adult female Wistar rats (123-143 g body weights) were divided into four groups, namely, control, F, F + BEP, and F + MEL and were administered sodium fluoride (NaF, 150 ppm elemental F in drinking water), MEL (10 mg/kg BW, i.p.), and BEP (100 ug/kg BW, i.p.) for 28 days. There were significantly (P < 0.05) high levels of lipid peroxidation and catalase and low levels of reduced glutathione, superoxide dismutase, glutathione reductase, and glutathione peroxidase in cardiac, hepatic, and renal tissues of F-treated rats. Administration of BEP and MEL in F-treated rats, however, significantly (P < 0.05) attenuated these adverse changes in all the target components of antioxidant defense system of cardiac, hepatic, and renal tissues. The present data suggest that F can induce oxidative stress in liver, heart, and kidney of female rats which may be a mechanism in F toxicity and these adverse effects can be ameliorated by buffalo (Bubalus bubalis) epiphyseal proteins and melatonin by upregulation of antioxidant defense system of heart, liver, and kidney of rats. PMID- 24790597 TI - Obstetric patients requiring intensive care: a one year retrospective study in a tertiary care institute in India. AB - Background and Objectives. Critically ill obstetric patients are a particularly unique cohort for the intensivist. The objective of this study was to review the indications for admission, demographics, clinical characteristics, and outcomes of obstetric patients admitted to intensive care unit of a medical college hospital in southern India and to identify conditions associated with maternal mortality. Design. Retrospective analysis of pregnant/postpartum (up to 6 weeks) admissions over a 1-year result. We studied 55 patients constituting 11.6% of mixed ICU admissions during the study period. Results. The mean APACHE (acute physiology and chronic health evaluation) II score of patients at admission was 11.8. Most of the patients (76%) were admitted in the antepartum period. The commonest indications for ICU admission were obstetric haemorrhage (51%) and hypertensive disorders of pregnancy (18%). 85% of patients required mechanical ventilation and 78% required inotropic support. Conclusions. Maternal mortality was 13%, and the majority of the deaths were due to disseminated intravascular coagulation and multiorgan failure, following an obstetric haemorrhage. A dedicated obstetric ICU in tertiary hospitals can ensure that there is no delay in patient management and intensive care can be instituted at the earliest. PMID- 24790598 TI - A Multicenter Study of Beta-Lactamase Resistant Escherichia coli and Klebsiella pneumoniae Reveals High Level Chromosome Mediated Extended Spectrum beta Lactamase Resistance in Ogun State, Nigeria. AB - As a result of the ever increasing problem of multiresistant bacteria, we instituted a surveillance program with the aim of identifying the basic molecular properties of ESBL in our environment. About 197 isolates of Escherichia coli and Klebsiella pneumoniae were selected and tested for ESBL production and antimicrobial susceptibility. Plasmid profiles were determined and curing ability was tested. ESBL prevalence was 26.4% for all isolates tested, with E. coli having a greater proportion. There was absolute resistance to ampicilin, tetracycline, and co-trimaxole among tested isolates. There was above average susceptibility to the 2nd and 3rd generation cephalosporins. Plasmid profiles of tested isolates ranged from 9 kbp to 26 kbp with average of 14.99 +/- 2.3 kbp for E. coli and 20.98 +/- 1.8 kbp K. pneumoniae, 9.6% of ESBL positive E. coli plasmids were cured, while 3.9% of K. pneumoniae plasmids were cured after treatment. The present study shows an upsurge in ESBL acquisition by gram negative bacteria and evidence of cocirculation of varying subtypes of ESBL with both plasmid transmissible and chromosome encoded subtypes. This calls for universal surveillance and more effort towards molecular epidemiology of this public health treatment. PMID- 24790593 TI - Early Decision: Effector and Effector Memory T Cell Differentiation in Chronic Infection. AB - As effector memory T cells (Tem) are the predominant population elicited by chronic parasitic infections, increasing our knowledge of their function, survival and derivation, as phenotypically and functionally distinct from central memory and effector T cells will be critical to vaccine development for these diseases. In some infections, memory T cells maintain increased effector functions, however; this may require the presence of continued antigen, which can also lead to T cell exhaustion. Alternatively, in the absence of antigen, only the increase in the number of memory cells remains, without enhanced functionality as central memory. In order to understand the requirement for antigen and the potential for longevity or protection, the derivation of each type of memory must be understood. A thorough review of the data establishes the existence of both memory (Tmem) precursors and effector T cells (Teff) from the first hours of an immune response. This suggests a new paradigm of Tmem differentiation distinct from the proposition that Tmem only appear after the contraction of Teff. Several signals have been shown to be important in the generation of memory T cells, such as the integrated strength of "signals 1-3" of antigen presentation (antigen receptor, co-stimulation, cytokines) as perceived by each T cell clone. Given that these signals integrated at antigen presentation cells have been shown to determine the outcome of Teff and Tmem phenotypes and numbers, this decision must be made at a very early stage. It would appear that the overwhelming expansion of effector T cells and the inability to phenotypically distinguish memory T cells at early time points has masked this important decision point. This does not rule out an effect of repeated stimulation or chronic inflammatory milieu on populations generated in these early stages. Recent studies suggest that Tmem are derived from early Teff, and we suggest that this includes Tem as well as Tcm. Therefore, we propose a testable model for the pathway of differentiation from naive to memory that suggests that Tem are not fully differentiated effector cells, but derived from central memory T cells as originally suggested by Sallusto et al. in 1999, but much debated since. PMID- 24790599 TI - Gene expression profiling of the paracrine effects of uterine natural killer cells on human endometrial epithelial cells. AB - The endometrium contains a population of immune cells that undergo changes during implantation and pregnancy. The majority of these cells are uterine natural killer (uNK) cells; however, it is unclear how these cells interact with endometrial epithelial cells. Therefore, we investigated the paracrine effects of the uNK cell-secretion medium on the gene expression profile of endometrial epithelial cells in vitro through microarray analysis. Our results, which were verified by qRT-PCR and western blot, revealed that soluble factors from uNK cells alter the gene expression profiles of epithelial cells. The upregulated genes included interleukin-15 (IL-15) and interleukin-15 receptor alpha (IL 15RA), which result in a loop that stimulates uNK cell proliferation. In addition, vascular endothelial growth factor C (VEGF-C) and chemokine (C-X-C motif) ligand 10 (CXCL-10) were also determined to be upregulated in epithelial cells, which suggests that uNK cells work synergistically with epithelial cells to support implantation and pregnancy. In addition, oriental herbal medicines have been used to treat infertility since ancient times; however, we failed to find that Zi Dan Yin can regulate these endometrial paracrine effects. PMID- 24790601 TI - Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus. AB - Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n = 133, 115 men and 18 women; age 64.7 +/- 11.5 years; HbA1c 8.1 +/- 1.6%). Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2 +/- 22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r = -0.450, P < 0.01), triglyceride (r = 0.445, P < 0.01), and high sensitive C-reactive protein (r = 0.316, P < 0.01) but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25 hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (beta = -0.411, P < 0.01) and high sensitive C-reactive protein (beta = 0.193, P < 0.05). Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus. PMID- 24790600 TI - Vitamin d status in central europe. AB - Little published information is available regarding epidemiological data on vitamin D status in the large geographical region of Central Europe (CE). We searched the journal literature with regard to 25(OH)D concentrations among community-dwelling or healthy people living in CE. 25(OH)D concentrations varied by age, season, study sample size, and methodological approach [i.e., 25(OH)D assay used]. Concentrations of 25(OH)D in CE appeared lower than 30 ng/mL, and the magnitude of hypovitaminosis D was similar to that reported in Western Europe. While most of the studies reviewed were cross-sectional studies, a longitudinal study was also included to obtain information on seasonal variability. The longitudinal study reported wintertime 25(OH)D values close to 21-23 ng/mL for all studied age groups, with a significant increase of 25(OH)D in August reaching 42 ng/mL for those aged 0-9 years, but only 21 ng/mL for the elderly aged 80-89 years. The decrease in 25(OH)D with respect to age was attributed to decreased time spent in the sun and decreased vitamin D production efficiency. Based on the literature review on vitamin D status in the CE populations, it can be concluded that 25(OH)vitamin D levels are on average below the 30 ng/mL level. PMID- 24790602 TI - Adiponectin Expression in the Porcine Ovary during the Oestrous Cycle and Its Effect on Ovarian Steroidogenesis. AB - Adiponectin is an adipose-secreted hormone that regulates energy homeostasis and is also involved in the control of the reproductive system. The goal of the present study was to investigate changes in adiponectin gene and protein expression in porcine ovarian structures during the oestrous cycle and to examine the effects of in vitro administration of adiponectin on basal and gonadotrophin- and/or insulin-induced secretion of ovarian steroid hormones. Both gene and protein expression of adiponectin were enhanced during the luteal phase of the cycle. Adiponectin affected basal secretion of progesterone by luteal cells, oestradiol by granulosa cells, and testosterone by theca interna cells. The gonadotrophin/insulin-induced release of progesterone from granulosa and theca interna cells and the release of oestradiol and androstenedione from theca cells was also modified by adiponectin. In conclusion, the presence of adiponectin mRNA and protein in the porcine ovary coupled with our previous results indicating adiponectin receptors expression suggest that adiponectin may locally affect ovarian functions. The changes in adiponectin expression throughout the oestrous cycle seem to be dependent on the hormonal status of pigs related to the stage of the oestrous cycle. The effect of adiponectin on ovarian steroidogenesis suggests that this adipokine influences reproductive functions in pigs. PMID- 24790603 TI - Antibiofilm activity, compound characterization, and acute toxicity of extract from a novel bacterial species of paenibacillus. AB - The effectiveness of many antimicrobial agents is currently decreasing; therefore, it is important to search for alternative therapeutics. Our study was carried out to assess the in vitro antibiofilm activity using microtiter plate assay, to characterize the bioactive compounds using Ultra Performance Liquid Chromatography-Diode Array Detection and Liquid Chromatography-Mass Spectrometry and to test the oral acute toxicity on Sprague Dawley rats of extract derived from a novel bacterial species of Paenibacillus strain 139SI. Our results indicate that the crude extract and its three identified compounds exhibit strong antibiofilm activity against a broad range of clinically important pathogens. Three potential compounds were identified including an amino acid antibiotic C8H20N3O4P (MW 253.237), phospholipase A2 inhibitor C21H36O5 (MW 368.512), and an antibacterial agent C14H11N3O2 (MW 253.260). The acute toxicity test indicates that the mortality rate among all rats was low and that the biochemical parameters, hematological profile, and histopathology examination of liver and kidneys showed no significant differences between experimental groups (P > 0.05). Overall, our findings suggest that the extract and its purified compounds derived from novel Paenibacillus sp. are nontoxic exhibiting strong antibiofilm activity against Gram-positive and Gram-negative pathogens that can be useful towards new therapeutic management of biofilm-associated infections. PMID- 24790604 TI - Mucin gene expression in reflux laryngeal mucosa: histological and in situ hybridization observations. AB - Objectives/Hypothesis. To determine if laryngopharyngeal reflux alters mucin gene expression in laryngeal mucosa. Methods. In situ hybridization was employed to study the expression of the 8 well-characterised mucin genes MUC1-4, 5AC, 5B, 6, and 7 in reflux laryngeal mucosa from laryngeal ventricles, posterior commissures, and vocal folds compared to control/normal laryngeal mucosa. Results. MUC1-5 genes are expressed in normal and reflux laryngeal mucosa. MUC1, 3 and 4 are expressed in respiratory and squamous mucosa whereas MUC2 and 5AC are expressed in respiratory mucosa only. MUC3, 4 and 5AC are downregulated in reflux mucosa. MUC5AC expression is significantly reduced in the 3 mucosal sites and when mucosal type was taken into account, this remains significant in combined laryngeal and ventricular mucosa only. Conclusions. MUC3, 4 and 5AC expression is downregulated in laryngopharyngeal reflux. This may be due to laryngeal mucosal metaplasia and/or alteration of mucin gene expression in the preexisting mucosa. Altered mucin gene expression might predispose laryngeal mucosa to the damaging effect of reflux. PMID- 24790605 TI - Social determinants and access to induced abortion in burkina faso: from two case studies. AB - Unsafe abortion constitutes a major public health problem in Burkina Faso and concerns mainly young women. The legal restriction and social stigma make abortions most often clandestine and risky for women who decide to terminate a pregnancy. However, the exposure to the risk of unsafe induced abortion is not the same for all the women who faced unwanted pregnancy and decide to have an abortion. Drawn from a qualitative study on the issue of abortion in Ouagadougou, Burkina Faso's capital, the contrasting cases of two young women who had abortion allow us to show how the women's personal resources (such as the school level, financial resources, the compliance to social norms, the social network, etc.) may determine the degree of vulnerability of women, the delay to have an abortion, the type of care they are likely to benefit from, and the cost they have to face. This study concludes that the poorest always pay more (cost and consequences), take longer to have an abortion, and have more exposure to the risk of unsafe abortion. PMID- 24790606 TI - Bimaxillary keratocystic odontogenic tumour: a case of diagnostic and therapeutic difficulty. AB - Keratocystic odontogenic tumour (KCOT) is a benign cystic intraosseous tumour of odontogenic origin that is usually solitary except when syndromic. It rarely occurs in the maxilla; therefore a rapidly progressive, nonsyndromic bimaxillary KCOT with locoregional extension poses significant diagnostic and management challenges. To the best of the authors' knowledge, documentation of a nonsyndromic bimaxillary KCOT is nonexistent in the English literature. We therefore present the case of an extensive bimaxillary KCOT in a 38-year-old Nigerian male. PMID- 24790607 TI - Identification of an APC Variant in a Patient with Clinical Attenuated Familial Adenomatous Polyposis. AB - Introduction. The objective of this case report is to discuss an unclassified germline variant of the adenomatous polyposis coli (APC) gene identified in an older patient with attenuated familial adenomatous polyposis syndrome (AFAP). Methods. We present a case report of a 66-year-old man diagnosed with AFAP. Colonoscopy found multiple polyps and invasive adenocarcinoma arising in the transverse colon. Samples were tested for mutations in the APC gene. Results. DNA sequencing of germline DNA identified a cytosine (C) to thymine (T) transition at nucleotide 1240, heterozygous. The C to T transition at codon 414 is predicted to convert an arginine residue to a cysteine that is possibly pathogenic. Analysis of the patient's colon tumor DNA indicated that the tumor had lost the mutant variant allele and retained only the normal allele, suggesting that the variant may not be significant. Conclusions. The p.R414C variant has been described previously as a germline mutation of probable pathogenicity. This substitution should be considered an unclassified variant and possibly not pathogenic. These findings support the need for further genetic testing of tissue, as well as for developing a mechanism for testing all variants, as this could significantly impact the lives of patients and their family members. PMID- 24790608 TI - Unique surgical issues in the management of a giant retroperitoneal schwannoma and brief review of literature. AB - Ancient Schwannoma, though benign, can cause diagnostic dilemma because of its clinical presentation and imaging features. We report the management of a giant retroperitoneal schwannoma in a 19-year-old young lady who presented with lower abdominal distension. CT scan reported a large heterogenous lesion in the abdominopelvic retroperitoneum (42 cm * 16 cm * 16 cm) as a malignant tumor. The unique problems we encountered were the enormous size, the location of major part of the tumor in the pelvis, the need for fertility preservation, the external iliac vessels stretching over the tumor making mobilization surgically demanding, and the prospects of neurological deficits. An en bloc resection of schwannoma with common iliac, external iliac and internal iliac veins, internal iliac artery, femoral and obturator nerves, and iliopsoas muscle was done maintaining oncological principles. External iliac artery that was cut to facilitate tumor mobilization was reanastomosed at the end of the procedure. Postoperatively patient had uneventful recovery with patchy sensory loss, foot drop, and quadriceps weakness which was rehabilitated with a foot drop splint and active physiotherapy. PMID- 24790609 TI - Postoperative Delayed Duodenum Perforation following Elective Laparoscopic Cholecystectomy. AB - Background. Duodenum injury is extremely rare complication of laparoscopic cholecystectomy with potentially fatal consequences. Methods. Over the past 13 year period, 3000 laparoscopic cholecystectomies were performed in our institution. Duodenum injury only occurred in one patient recently who had undergone gastrectomy owing to duodenal diverticulum. The diagnosis and management of this rare complication of laparoscopic cholecystectomy are described, and the literature is reviewed. Results. We present this case of duodenum injury on the fourth postoperative day after selective laparoscopic cholecystectomy was treated successfully by percutaneous needle aspiration and catheter drainage. The hospital stay was 26 days. No abscess recurred during the follow-up period. Conclusion. Duodenum injuries are extremely rare complications of laparoscopic cholecystectomy with potentially fatal consequences if not promptly recognized and treated. Sonographically guided percutaneous needle aspiration and catheter drainage can be used to treat the intraperitoneal abscess. Billroth II subtotal gastrectomy and gastrojejunostomy were beneficial for the treatment. PMID- 24790610 TI - Free radicals and antioxidant status in protein energy malnutrition. AB - Background/Objectives. The aim of this study was to evaluate oxidant and antioxidant status in children with different grades of Protein Energy Malnutrition (PEM). Subjects/Methods. A total of two hundred fifty (250) children (age range: 6 months to 5 years) living in eastern UP, India, were recruited. One hundred and ninety-three (193) of these children had different grades of PEM (sixty-five (65) children belong to mild, sixty (60) to moderate, and sixty-eight (68) to severe group). Grading in group was done after standardization in weight and height measurements. Fifty-seven (57) children who are age and and sex matched, healthy, and well-nourished were recruited from the local community and used as controls after checking their protein status (clinical nutritional status) with height and weight standardization. Redox homeostasis was assessed using spectrophotometric/colorimetric methods. Results. In our study, erythrocyte glutathione (GSH), plasma Cu, Zn-superoxide dismutase (Cu,Zn-SOD,EC 1.15.1.1), ceruloplasmin (Cp), and ascorbic acid were significantly (P < 0.001) more decreased in children with malnutrition than controls. Plasma malondialdehyde (MDA), and protein carbonyl (PC) were significantly (P < 0.001) raised in cases as compared to controls. Conclusion. Stress is created as a result of PEM which is responsible for the overproduction of reactive oxygen species (ROSs). These ROSs will lead to membrane oxidation and thus an increase in lipid peroxidation byproducts such as MDA and protein oxidation byproducts such as PC mainly. Decrease in level of antioxidants suggests an increased defense against oxidant damage. Changes in oxidant and antioxidant levels may be responsible for grading in PEM. PMID- 24790611 TI - Characteristics of US Health Care Providers Who Counsel Adolescents on Sports and Energy Drink Consumption. AB - Objective. To examine the proportion of health care providers who counsel adolescent patients on sports and energy drink (SED) consumption and the association with provider characteristics. Methods. This is a cross-sectional analysis of a survey of providers who see patients <=17 years old. The proportion providing regular counseling on sports drinks (SDs), energy drinks (EDs), or both was assessed. Chi-square analyses examined differences in counseling based on provider characteristics. Multivariate logistic regression calculated adjusted odds ratios (aOR) for characteristics independently associated with SED counseling. Results. Overall, 34% of health care providers regularly counseled on both SEDs, with 41% regularly counseling on SDs and 55% regularly counseling on EDs. On adjusted modeling regular SED counseling was associated with the female sex (aOR: 1.44 [95% CI: 1.07-1.93]), high fruit/vegetable intake (aOR: 2.05 [95% CI: 1.54-2.73]), family/general practitioners (aOR: 0.58 [95% CI: 0.41-0.82]) and internists (aOR: 0.37 [95% CI: 0.20-0.70]) versus pediatricians, and group versus individual practices (aOR: 0.59 [95% CI: 0.42-0.84]). Modeling for SD- and ED specific counseling found similar associations with provider characteristics. Conclusion. The prevalence of regular SED counseling is low overall and varies. Provider education on the significance of SED counseling and consumption is important. PMID- 24790612 TI - Risk factors of domestic violence in Iran. AB - OBJECTIVES: In this study, we have evaluated the lifetime and past-year prevalence of exposure to physical violence among married women in the city of Tehran and urban and rural areas of Hashtgerd. METHODS: The target population were noninstitutionalized female citizens, aged 15 years or older, who have at least one history of marriage and who resided in the capital city of Tehran or Hashtgerd County from the summer of 2008 to fall of 2010. We used a multistage sampling method. Tehran's District Six, a central district in Tehran, was selected as a representative cluster of all municipal districts in Tehran. A total of fifty blocks were randomly selected from this district, from which 1,000 married women aged 15 years or older were interviewed using a cross-sectional design. Data was gathered face-to-face using a structured questionnaire. The lifetime prevalence, past-year prevalence, and related factors of domestic violence were measured. SPSS version 11.5 was used for the analyses. RESULTS: Figures for lifetime prevalence and past-year prevalence were measured to be 38.7% and 6.6%, respectively. The independent effects of marital status and location and type of residency for women, along with education and smoking habits of their spouses, were statistically significant in multivariate logistic regression analysis. CONCLUSION: Domestic violence is a public health concern in Iran. Based on our findings, we propose that empowering women through education, and improving their ability to find employment and income, along with increasing public awareness of human rights issues through education could lower the prevalence of domestic violence. PMID- 24790613 TI - Relationship between objectively measured walkability and exercise walking among adults with diabetes. AB - Little is known about the relationship between objectively measured walkability and walking for exercise among adults with diabetes. Information regarding walking behavior of adults with diabetes residing in 3 Upstate New York counties was collected through an interview survey. Walkability measures were collected through an environmental audit of a sample of street segments. Overall walkability and 4 subgroup measures of walkability were aggregated at the ZIP level. Multivariate logistic regression was used for analysis. Study participants (n = 208) were 61.0% female, 56.7% non-Hispanic White, and 35.1% African American, with a mean age of 62.0 years. 108 participants (51.9%) walked for exercise on community streets, and 62 (29.8%) met the expert-recommended level of walking for >=150 minutes/week. After adjustment for age, gender, race/ethnicity, education, BMI, physical impairment, and social support for exercise, walking any minutes/week was associated with traffic safety (OR 1.34, 95% CI 1.15-1.65). Walking >=150 minutes/week was associated with overall walkability of the community (2.65, 1.22, and 5.74), as well as sidewalks (1.73, 1.12-2.67), street amenity (2.04, 1.12-3.71), and traffic safety (1.92, 1.02-3.72). This study suggests that walkability of the community should be an integral part of the socioecologic approach to increase physical activity among adults with diabetes. PMID- 24790614 TI - Hydraulic fracturing: paving the way for a sustainable future? AB - With the introduction of hydraulic fracturing technology, the United States has become the largest natural gas producer in the world with a substantial portion of the production coming from shale plays. In this review, we examined current hydraulic fracturing literature including associated wastewater management on quantity and quality of groundwater. We conclude that proper documentation/reporting systems for wastewater discharge and spills need to be enforced at the federal, state, and industrial level. Furthermore, Underground Injection Control (UIC) requirements under SDWA should be extended to hydraulic fracturing operations regardless if diesel fuel is used as a fracturing fluid or not. One of the biggest barriers that hinder the advancement of our knowledge on the hydraulic fracturing process is the lack of transparency of chemicals used in the practice. Federal laws mandating hydraulic companies to disclose fracturing fluid composition and concentration not only to federal and state regulatory agencies but also to health care professionals would encourage this practice. The full disclosure of fracturing chemicals will allow future research to fill knowledge gaps for a better understanding of the impacts of hydraulic fracturing on human health and the environment. PMID- 24790615 TI - Optimal single 3T MR imaging sequence for HDR brachytherapy of cervical cancer. AB - PURPOSE: The superior image quality of 3 tesla (3T) magnetic resonance (MR) imaging in cervical cancer offers the potential to use a single image set for brachytherapy. This study aimed to determine a suitable single sequence for contouring tumour and organs at risk, applicator reconstruction, and treatment planning. MATERIAL AND METHODS: A 3T (Skyra, Siemens Healthcare AG, Germany) MR imaging system with an 18 channel body matrix coil generated HDR cervical cancer brachytherapy planning images on 20 cases using plastic-based treatment applicators. Seven different T2-weighted Turbo Spin Echo (TSE) sequences including both 3D and contiguous 2D scans based on sagittal, axial (transverse), and oblique planes were analysed. Each image set was assessed for total scanning time and usefulness in tumour localization via inter- and intra-observer analysis of high-risk clinical target volume (HR CTV) contouring. Applicator reconstruction in the treatment planning system was also considered. RESULTS: The intra-observer difference in HR CTV volumes between 2D and 3D axial-based image sets was low with an average difference of 3.1% for each observer. 2D and 3D sagittal image sets had the highest intra- and inter observer differences (over 15%). A 2D axial 'double oblique' sequence was found to produce the best intra- (average difference of 0.6%) and inter-observer (mean SD of 9.2%) consistency and greatest conformity (average 0.80). CONCLUSIONS: There was little difference between 2D and 3D-based scanning sequences; however the increased scanning time of 3D sequences have potential to introduce greater patient motion artifacts. A contiguous 2D sequence based on an axial T2-weighted turbo-spin-echo (TSE) sequence orientated in all planes of the treatment applicator provided consistent tumour delineation whilst allowing applicator reconstruction and treatment planning. PMID- 24790616 TI - High-dose-rate interstitial brachytherapy for mobile tongue cancer: preliminary results of a dose reduction trial. AB - PURPOSE: To compare the outcome of our facility with another about the shortened schedule (60 Gy in 10 fractions to 54 Gy in 9 fractions) of high-dose-rate interstitial brachytherapy (HDR ISBT) for mobile tongue cancer. MATERIAL AND METHODS: Eighteen patients were treated with HDR ISBT as a monotherapy in dose reduction schedule with some unique technique to determine the border of tumor accuracy (lugol's staining and metal marker), and to minimize adverse effect (lead-lined silicon block) at our facility. RESULTS: The 2-year local and regional control rates and cause-specific survival rate were 82%, 80%, and 83% and moderate to severe late complications occurred in five patients (28%), which were almost the same treatment results achieved by another facility. CONCLUSIONS: We recommend 54 Gy in 9 fractions over 7 days as a feasible treatment to reduce patient discomfort in mobile tongue cancer patients. PMID- 24790617 TI - Iodine-125 prostate seed brachytherapy in renal transplant recipients: an analysis of oncological outcomes and toxicity profile. AB - PURPOSE: Prostate cancer is among the most common non-cutaneous neoplasms affecting renal transplant recipients (RTRs). Available treatments including radical prostatectomy and external beam radiotherapy carry a risk of damage to the transplanted kidney, ureters, or bladder. We assessed the safety and efficacy of Iodine-125 ((125)I) prostate seed brachytherapy as an alternative to surgery and radiotherapy in these individuals. MATERIAL AND METHODS: We retrospectively reviewed our brachytherapy database to identify patients with a prior history of renal transplantation, who had undergone seed implantation for localized prostate cancer. Long term PSA control and treatment related toxicity, including graft dysfunction, urinary, rectal, and sexual complications, were assessed and compared with published outcomes for surgery and external beam radiotherapy. RESULTS: Of 1054 patients treated with permanent seed implantation from 2002 2012, we identified four who had a prior history of renal transplantation. Mean time from renal transplantation to prostate cancer diagnosis was 13 years. Mean follow-up after seed implantation was 44 months (range 12-60 months). All four patients remain free of PSA progression. No peri-operative complications were experienced following seed implantation, and all four patients continued to have normal graft function. Long term urinary and rectal function scores were comparable to reported outcomes for seed brachytherapy in the non-transplant population. CONCLUSIONS: (125)I prostate seed brachytherapy is associated with high rates of biochemical control and minimal toxicity to the renal graft in RTRs. This treatment should be considered as an alternative to surgery in managing RTRs with localized prostate cancer. PMID- 24790618 TI - Image guided adaptive brachytherapy for cervical cancer: dose contribution to involved pelvic nodes in two cancer centers. AB - PURPOSE: The goal of this study was to determine the dose contributions from image guided adaptive brachytherapy (IGABT) to individual suspicious pelvic lymph nodes (pLNN) in cervical cancer patients. Data were collected in two cancer centers, University of Pittsburgh Cancer Institute (UPCI) and University Medical Center Utrecht (UMCU). MATERIAL AND METHODS: 27 and 15 patients with node positive cervical cancer treated with HDR (high dose rate) or PDR (pulsed dose rate)-IGABT were analyzed. HDR-IGABT (UPCI) was delivered with CT/MRI compatible tandem-ring applicators with 5.0-6.0 Gy * five fractions. PDR-IGABT (UMCU) dose was delivered with Utrecht tandem-ovoid applicators with 32 * 0.6 Gy * two fractions. Pelvic lymph nodes with short axis diameter of >= 5 mm on pre treatment MRI or PET-CT were contoured for all BT-plans. Dose contributions to individual pLNN expressed as D90 (dose to 90% of the volume) were calculated from dose-volume histograms as absolute and relative physical dose (% of the reference dose) for each fraction. For each node, the total dose from all fractions was calculated, expressed in EQD2 (equivalent total dose in 2 Gy fractions). RESULTS: Fifty-seven (UPCI) and 40 (UMCU) individual pLNN were contoured. The mean D90 pLNN was 10.8% (range 5.7-25.1%) and 20.5% (range 6.8-93.3%), respectively, and therefore different in the two centers. These values translate into 2.7 Gy (1.3 6.6 Gy) EQD2 and 7.1 Gy (2.2-36.7 Gy) EQD2, respectively. Differences are caused by the location of the individual nodes in relation to the spatial dose distribution of IGABT, differences in total dose administered and radiobiology (HDR versus PDR). CONCLUSIONS: The IGABT dose contribution to individual pelvic nodes depends on patient and treatment related factors, and varies considerably. PMID- 24790619 TI - Patterns of care study of brachytherapy in New South Wales: cervical cancer treatment quality depends on caseload. AB - PURPOSE: We previously conducted modelling and a patterns of care study (POCS) that showed gynaecological brachytherapy (BT) was underutilized in New South Wales (NSW), the USA and Western Europe. The aim of the current study was to assess the quality of cervical BT in NSW, and to determine if caseload affects quality of treatment delivery. MATERIAL AND METHODS: All nine NSW radiation oncology departments that treated patients with cervical BT in 2003 were visited. Patient, tumour and treatment related data were collected. Quality of BT was assessed using published quality benchmarks. Higher and lower caseload departments were compared. RESULTS: The four higher cervical BT caseload departments treated 11-15 NSW residents in 2003, compared to 1-8 patients for the lower caseload departments. Cervix cancer patients treated at the higher caseload departments were more likely to be treated to a point A dose >= 80 Gy (58% vs. 14%, p = 0.001), and to have treatment completed within 8 weeks (66% vs. 35%, p = 0.02). Despite higher point A doses, there was no significant difference in proportions achieving lower than recommended rectal or bladder doses, implying better BT insertions in higher caseload departments. CONCLUSIONS: Cervical BT in NSW was dispersed amongst a large number of departments and was frequently of sub optimal quality. Higher quality BT was achieved in departments treating at least 10 patients per year. It is likely that improved outcomes will be achievable if at least 10 patients are treated per department per year. PMID- 24790620 TI - Multisector dosimetry in the immediate post-implant period: significant under dosage of the prostate base. AB - PURPOSE: While there are several reports of prostate multisector dosimetry data obtained from CT or MRI scans performed at intervals ranging from 14-70 days after prostate brachytherapy (PB), there are no reports on multisector dosimetry performed in the immediate post-implant period. This study was undertaken to determine the results of prostate multisector dosimetry performed in the immediate post-implant period on day 1 post-implant dosimetry after (125)I PB. MATERIAL AND METHODS: The day 1 post-implant CT-based V100 and D90 were determined for the prostate base (PGB) and compared to doses to the entire gland (PG), mid-gland (PMG), and apex (PA) in 75 patients who underwent (125)I PB to a dose of 144 Gy. Similar multisector dosimetry was also performed on the pre implant ultrasound volume study scans of these patients. RESULTS: All patients had good quality implants. On day 1 post-implant multisector dosimetry there was significant under dosage of the PGB for both V100 and D90. The average magnitude of under dosage of PGB compared to PMG and PA was 17.2% and 22.7% for V100 and 44.6 Gy and 31.7 Gy for D90, respectively. On pre-implant multisector dosimetry there was no statistically significant under dosage of the PGB for V100, but the PGB D90 was significantly lower compared to PMG and PA, however, the average magnitude of under dosage was small at 12.6 Gy and 4.2 Gy, respectively. CONCLUSIONS: This report demonstrates that similar to other reports on more delayed post-implant multisector dosimetry data, there is significant under dosage of the prostate base in the immediate post-implant period based on day 1 post-implant dosimetry. The clinical significance of this under dosage remains to be defined and further studies are warranted. PMID- 24790621 TI - Dummy source digitization algorithm for reconstruction of flexible brachytherapy catheters with biplane images. AB - PURPOSE: The traditional brachytherapy catheter reconstruction with biplane images is based on digitizing radio-opaque markers with a pointing device on a film or on a screen. An algorithm to automate digitization of radio-opaque marker coordinates on biplane images is presented. MATERIAL AND METHODS: To obtain the marker coordinates in a proper sequence, instead of usual pair of reconstruction images, series of images were taken with insertion of radio-opaque markers consecutively into the catheters. The images were pre-processed to suppress the shield of anatomic structures. The determination of the marker coordinates is based on the detection of characteristic high gradient variation in pre-processed image profiles. The method was tested with six endometrial insertions performed with Simon-Norman catheters using our version of Heyman packing. RESULTS: 28 catheters of six treatment fractions were digitized, typically 10 markers per catheter. To obtain the marker coordinates, adjustment of two threshold levels on the pre-processed images were needed. The coordinates of the radio-opaque markers on the biplane projection images were obtained without positive or negative artefact. CONCLUSIONS: THE DUMMY SOURCE COORDINATES ON THE BIPLANE IMAGES WERE DIGITIZED IN A PROPER SEQUENCE: from the catheters' tip towards the end of the catheters. After the three-dimensional reconstruction of the catheters from the digitized coordinates, the geometry file was imported by the brachytherapy planning system for dose calculation. The method has the advantage to eliminate manual digitization of the dummy sources. PMID- 24790622 TI - Dosimetric characteristics of a new unit for electronic skin brachytherapy. AB - PURPOSE: Brachytherapy with radioactive high dose rate (HDR) (192)Ir source is applied to small skin cancer lesions, using surface applicators, i.e. Leipzig or Valencia type. New developments in the field of radiotherapy for skin cancer include electronic brachytherapy. This technique involves the placement of an HDR X-ray source close to the skin, therefore combining the benefits of brachytherapy with the reduced shielding requirements and targeted energy of low energy X-rays. Recently, the Esteya((r)) Electronic Brachytherapy System (Esteya EBS, Elekta AB Nucletron, Stockholm, Sweden) has been developed specifically for HDR brachytherapy treatment of surface lesions. The system provides radionuclide free HDR brachytherapy by means of a small 69.5 kV X-ray source. The purpose of this study is to obtain the dosimetric characterization required for clinical implementation, providing the detailed methodology to perform the commissioning. MATERIAL AND METHODS: Flatness, symmetry and penumbra, percentage of depth dose (PDD), kV stability, HVL, output, spectrum, linearity, and leakage have been evaluated for a set of applicators (from 10 mm to 30 mm in diameter). RESULTS: Flatness and symmetry resulted better than 5% with around 1 mm of penumbra. The depth dose gradient is about 7%/mm. A kV value of 68.4 +/- 1.0 kV (k = 1) was obtained, in good agreement with manufacturer data (69.5 kV). HVL was 1.85 mm Al. Dose rate for a typical 6 Gy to 7 Gy prescription resulted about 3.3 Gy/min and the leakage value was < 100 uGy/min. CONCLUSIONS: The new Esteya((r)) Electronic Brachytherapy System presents excellent flatness and penumbra as with the Valencia applicator case, combined with an improved PDD, allowing treatment of lesions of up to a depth of 5 mm in combination with reduced treatment duration. The Esteya unit allows HDR brachytherapy superficial treatment within a minimally shielded environment due its low energy. PMID- 24790623 TI - Effect of tissue composition on dose distribution in brachytherapy with various photon emitting sources. AB - PURPOSE: The aim of this study is to compare the dose in various soft tissues in brachytherapy with photon emitting sources. MATERIAL AND METHODS: (103)Pd, (125)I, (169)Yb, (192)Ir brachytherapy sources were simulated with MCNPX Monte Carlo code, and their dose rate constant and radial dose function were compared with the published data. A spherical phantom with 50 cm radius was simulated and the dose at various radial distances in adipose tissue, breast tissue, 4 component soft tissue, brain (grey/white matter), muscle (skeletal), lung tissue, blood (whole), 9-component soft tissue, and water were calculated. The absolute dose and relative dose difference with respect to 9-component soft tissue was obtained for various materials, sources, and distances. RESULTS: There was good agreement between the dosimetric parameters of the sources and the published data. Adipose tissue, breast tissue, 4-component soft tissue, and water showed the greatest difference in dose relative to the dose to the 9-component soft tissue. The other soft tissues showed lower dose differences. The dose difference was also higher for (103)Pd source than for (125)I, (169)Yb, and (192)Ir sources. Furthermore, greater distances from the source had higher relative dose differences and the effect can be justified due to the change in photon spectrum (softening or hardening) as photons traverse the phantom material. CONCLUSIONS: The ignorance of soft tissue characteristics (density, composition, etc.) by treatment planning systems incorporates a significant error in dose delivery to the patient in brachytherapy with photon sources. The error depends on the type of soft tissue, brachytherapy source, as well as the distance from the source. PMID- 24790624 TI - Day to day treatment variations of accelerated partial breast brachytherapy using a multi-lumen balloon. AB - PURPOSE: To evaluate the variations of multi-lumen balloon (MLB)-based brachytherapy from simulation day to treatment day and their dosimetric impacts during accelerated partial breast irradiation (APBI). MATERIAL AND METHODS: A total of 42 CT images scanned from seven patients were evaluated with regards to daily variation due to of: 1) internal uncertainty: size and shape of balloon, seroma volume; 2) geometrical uncertainty-random: length of each catheter was measured for each fraction (total 70); 3) geometrical uncertainty-systematic: virtual systematic errors were tested by offsetting dwell positions. The original plans (as group A) had a mean value of 96.8% on V95 of the PTV_Eval. Plans were rerun (as group B) such that the mean value of the V95 was relaxed to 90.4%. By applying the reference plan to each daily CT image, variations of target coverage under different sources of error were evaluated. RESULTS: Shape and size of the balloon had means of < 1 mm decreased in diameter and < 0.4 cm(3) decreased in volume; the mean seroma volume increased by 0.2 cm(3). This internal variation has a mean of < 1% difference for both V90 and V95. The geometrical uncertainty made a mean deviation of 2.7 mm per root of sum of square. It caused the degradations of V90 and V95 by mean values of 1.0% and 1.2%, respectively. A systematic error of 3 mm and 4 mm would degrade both of V90 and V95 by 4% and 6%, respectively. The degradations on target coverage of the plans in group A were statistically the same as those in group B. CONCLUSIONS: Overall, APBI treatments with MLB based brachytherapy are precise from day to day. However, minor variation due to daily treatment uncertainties can still degrade tumor bed coverage to an unacceptable coverage when V95 of the original plan is close to 90%. PMID- 24790625 TI - Cervical brachytherapy technique for locally advanced carcinoma of the cervix in a patient with septate uterus. AB - PURPOSE: To describe an approach to cervical brachytherapy in a patient with congenital septate uterus and locally advanced cervical carcinoma. MATERIAL AND METHODS: The patient is a 34-year-old female with septate uterus presenting with pelvic pain. Workup demonstrated a stage IIB cervical adenocarcinoma with imaging evidence of an involved right external iliac lymph node. The patient received whole pelvic radiation, with concurrent weekly cisplatin (40 mg/m(2)), to a dose of 45 Gy in 25 fractions followed by a parametrial boost of 5.4 Gy and an additional nodal boost of 9 Gy. RESULTS: The patient was initiated on cervical brachytherapy following fraction 23 of pelvic radiation. To conform to her septated uterus, a Rotte-Y tandem was used. Additionally, 2 CT-compatible ovoids were placed in the vaginal apex to enhance dose distribution and coverage of the target volume. Each fraction of brachytherapy was performed with CT-based planning. A high-risk clinical target volume (HR-CTV) and normal structures were defined and constrained per American Brachytherapy Society (ABS) and Groupe Europeen de Curietherapie/European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) guidelines. The brachytherapy dose was 27.5 Gy in 5 fractions of 5.5 Gy each, prescribed to the HR-CTV. CONCLUSIONS: Herein, we report the first documented case of cervical brachytherapy in a patient with septate uterus and locally advanced cervical carcinoma. Using CT-guided planning, in conjunction with the ABS and GEC-ESTRO guidelines, the patient was effectively treated with adapted cervical brachytherapy, meeting criteria for HR-CTV coverage and normal tissue tolerances. PMID- 24790626 TI - Multi-catheter interstitial accelerated partial breast irradiation - tips and tricks for a good insertion. AB - Adjuvant radiotherapy is recommended post breast conserving surgery. Accelerated Partial Breast Irradiation (APBI) offers a more attractive shorter course of treatment over 5 days compared to standard conventional external beam radiotherapy, which is often protracted. Multi-catheter interstitial APBI offers excellent dosimetric coverage. This article describes two insertion techniques for multi-catheter interstitial APBI, the operator dependent freehand technique, and the easier to learn template technique. The indications, benefits, and drawbacks of these two techniques are discussed. PMID- 24790627 TI - High-dose-rate brachytherapy as monotherapy for prostate cancer: technique, rationale and perspective. AB - High-dose-rate (HDR) brachytherapy as monotherapy is a comparatively new brachytherapy procedure for prostate cancer. Although clinical results are not yet mature enough, it is a highly promising approach in terms of potential benefits for both radiation physics and radiobiology. In this article, we describe our technique for monotherapeutic HDR prostate brachytherapy, as well as the rationale and theoretical background, with educational intent. PMID- 24790628 TI - High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program. AB - High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed. PMID- 24790629 TI - Primary brachytherapy as a radical treatment for endometrial carcinoma. AB - Surgery is the primary treatment for endometrial cancer, with radiation therapy having an established place in the adjuvant treatment setting. However, there is a population of patients with endometrial cancer who may not be suitable for surgery and primary radiation therapy as a treatment option. This article describes the place of radiotherapy in the management of endometrial cancer and describes the author's own experiences with primary brachytherapy in those patients who are unsuitable for surgery. PMID- 24790630 TI - Gender differences in risk factors of congenital hypothyroidism: an interaction hypothesis examination. AB - BACKGROUND: Several studies have demonstrated an increased risk of congenital hypothyroidism (CH) in girls in comparison to boys. OBJECTIVES: The aim of this study was to determine the potential interactions that are able to change the effect of gender on congenital hypothyroidism. PATIENTS AND METHODS: We conducted a matched 1:4 case-control study in Hamadan Province, western of Iran, from 2005 to 2011. Based on screening program data, neonates with TSH >= 10 mU/L and T4 <= 6.4 MUg/dL were considered as congenital hypothyroidism (Cases). Cases and controls were matched regarding the year and place of birth. Data was analyzed using two different approaches including propensity score and multiple conditional logistic regression model. RESULTS: A total of 277 cases and 1036 controls were included in the study. Girls accounted for 57.4% of the cases and 51.2% of controls (P = 0.065). Based on the multiple conditional logistic regressions, only the interaction of gender (girl) and birth season (summer) increased the likelihood of CH significantly (OR = 3.09; 95% CI: 1.09-8.74; P = 0.034). On the other hand, the ORs of the interaction of gender and all other factors (except for birth season) were not statistically significant in CH. CONCLUSIONS: Birth season might act as an interaction that is able to increase the risk of CH in girls. Accordingly, awareness of the birth season could help policymakers who plan preventive programs to reduce the false negative results among neonates, especially girls. PMID- 24790631 TI - An in vitro comparison of root canal system prepared with either hand or rotary instruments. AB - INTRODUCTION: The aim of the present study was to compare hand stainless steel K files and Nickel-Titanium Profile 0.04 taper 29 series rotary instruments for their efficiency, procedural errors and time consumed in preparation of root canal system. MATERIALS AND METHODS: A total of 46 maxillary and mandibular first premolars extracted for orthodontic purposes were collected (two contralateral teeth from each individual). The samples were divided into two groups of 34 canals each. Teeth in the first group were prepared with stainless steel hand K files while the second groups were prepared with profile 0.04 taper series 29 rotary files. Preparation period was recorded for both groups. Impression material was introduced into the prepared canals so that the replica of prepared canals was achieved. These were assessed under stereomicroscope to assess the efficiency in preparing canals in respect to canal smoothness, ability of impression material to flow and quality of taper.Statistical analyses were performed using t-test, Chi-square and Fishers exact tests. RESULTS: RESULTS showed significantly shorter preparation time for Profile than K-file. 8.8% of the canals prepared with K-files showed canal blockage, while all canals prepared with Profile remained patent. Alterations in working length working distance appeared in 23.5% of canals prepared with K-file and 11.7% in canals prepared with Profile. Failed instruments in K-files were significantly higher, mostly deformation (P<0.001). Profiles failed instruments were in the form of fracture and no deformation was detected. Both systems showed unsatisfactory walls smoothness and flow. CONCLUSION: Within the limitation of this study it was concluded that Profile 0.04 taper series 29 rotary systems prepare canals more rapidly, and have lower incidences of fracture and blockages, and only limited loss of working length. Canal preparation with K-file was time consuming and showed higher incidence of deformed instruments; overall, rotary instruments seem to offer greater advantages. PMID- 24790632 TI - Nonsurgical management of a large periapical lesion using aspiration in combination with a triple antibiotic paste and calcium hydroxide. AB - Persistent microorganisms in the root canal are known to cause endodontic treatments failure. Overextended gutta-percha can also act as a periradicular tissue irritant, leading to large periapical lesions. Retrieval of overextended gutta-percha with a nonsurgical approach can prove to be a challenge. This case describes the nonsurgical management of a large periapical lesion associated with overextended gutta-percha. Retrieval of gutta-percha was attempted but the overextended portion could not be removed. Aspiration of the purulent exudate was done through the root canal followed by use of a triple antibiotic paste. After 2 weeks the antibiotic paste was replaced with calcium hydroxide, to enhance the osseous regeneration. The periapical lesion showed a considerable amount of periapical healing after 15 months. The results of this case demonstrate that aspiration in conjunction with the triple antibiotic paste and calcium hydroxide may possibly be used in managing large periapical lesions associated with overextend gutta-percha. PMID- 24790633 TI - Tissue Necrosis due to Chloroform: A Case Report. AB - For many years, gutta-percha has been the root canal filling material of choice. Chloroform is one of the most efficient solvents widely used for gutta-percha removal in retreatment cases, despite being toxic and carcinogenic. The present case report discusses a chloroform extrusion through an existing perforation to the surrounding periodontal ligament space and subsequent necrosis in supporting bone and tissues, during an endodontic retreatment visit for an addicted patient. Subsequently, the management and preventive options are reviewed. PMID- 24790634 TI - Treatment of posttraumatic stress disorder using the traditional Japanese herbal medicine saikokeishikankyoto: a randomized, observer-blinded, controlled trial in survivors of the great East Japan earthquake and tsunami. AB - The Great East Japan earthquake and tsunami caused immense damage over a wide area of eastern Japan. Hence, many survivors are at high risk for posttraumatic stress disorder (PTSD). This randomized, observer-blinded, controlled trial examined the efficacy and safety of the traditional Japanese herbal formula saikokeishikankyoto (SKK) in the treatment of PTSD among survivors of this disaster. Forty-three participants with an Impact of Event Scale-Revised (IES-R) score >= 25 were randomized into SKK (n = 21) and control (n = 22) groups. The primary endpoint was the change in IES-R scores from baseline till after 2 weeks of treatment. Intergroup statistical comparisons were performed. The magnitude of changes in total IES-R scores differed significantly between the two groups (P < 0.001). Post hoc analysis showed that the total IES-R score improved significantly in the SKK group from 49.6 +/- 11.9 to 25.5 +/- 17.0 (P < 0.001). Subscale scores improved significantly in the SKK group (avoidance, P = 0.003; hyperarousal, P < 0.001; intrusion, P < 0.001). Two-week treatment with SKK significantly improved IES-R scores among PTSD patients. This traditional medicine may be a valid choice for the treatment of psychological and physical symptoms in PTSD patients. PMID- 24790635 TI - Updates on the clinical evidenced herb-warfarin interactions. AB - Increasing and inadvertent use of herbs makes herb-drug interactions a focus of research. Concomitant use of warfarin, a highly efficacious oral anticoagulant, and herbs causes major safety concerns due to the narrow therapeutic window of warfarin. This paper presents an update overview of clinical findings regarding herb-warfarin interaction, highlighting clinical outcomes, severity of documented interactions, and quality of clinical evidence. Among thirty-eight herbs, Cannabis, Chamomile, Cranberry, Garlic, Ginkgo, Grapefruit, Lycium, Red clover, and St. John's wort were evaluated to have major severity interaction with warfarin. Herbs were also classified on account of the likelihood of their supporting evidences for interaction. Four herbs were considered as highly probable to interact with warfarin (level I), three were estimated as probable (level II), and ten and twenty-one were possible (level III) and doubtful (level IV), respectively. The general mechanism of herb-warfarin interaction almost remains unknown, yet several pharmacokinetic and pharmacodynamic factors were estimated to influence the effectiveness of warfarin. Based on limited literature and information reported, we identified corresponding mechanisms of interactions for a small amount of "interacting herbs." In summary, herb-warfarin interaction, especially the clinical effects of herbs on warfarin therapy should be further investigated through multicenter studies with larger sample sizes. PMID- 24790637 TI - Sparse-representation-based direct minimum L (p) -norm algorithm for MRI phase unwrapping. AB - A sparse-representation-based direct minimum L (p) -norm algorithm is proposed for a two-dimensional MRI phase unwrapping. First, the algorithm converts the weighted-L (p) -norm-minimization-based phase unwrapping problem into a linear system problem whose system (coefficient) matrix is a large, symmetric one. Then, the coefficient-matrix is represented in the sparse structure. Finally, standard direct solvers are employed to solve this linear system. Several wrapped phase datasets, including simulated and MR data, were used to evaluate this algorithm's performance. The results demonstrated that the proposed algorithm for unwrapping MRI phase data is reliable and robust. PMID- 24790638 TI - A two-stage exon recognition model based on synergetic neural network. AB - Exon recognition is a fundamental task in bioinformatics to identify the exons of DNA sequence. Currently, exon recognition algorithms based on digital signal processing techniques have been widely used. Unfortunately, these methods require many calculations, resulting in low recognition efficiency. In order to overcome this limitation, a two-stage exon recognition model is proposed and implemented in this paper. There are three main works. Firstly, we use synergetic neural network to rapidly determine initial exon intervals. Secondly, adaptive sliding window is used to accurately discriminate the final exon intervals. Finally, parameter optimization based on artificial fish swarm algorithm is used to determine different species thresholds and corresponding adjustment parameters of adaptive windows. Experimental results show that the proposed model has better performance for exon recognition and provides a practical solution and a promising future for other recognition tasks. PMID- 24790639 TI - Introduction: Perspectives on Pain. PMID- 24790636 TI - Evaluation of traditional medicines for neurodegenerative diseases using Drosophila models. AB - Drosophila is one of the oldest and most powerful genetic models and has led to novel insights into a variety of biological processes. Recently, Drosophila has emerged as a model system to study human diseases, including several important neurodegenerative diseases. Because of the genomic similarity between Drosophila and humans, Drosophila neurodegenerative disease models exhibit a variety of human-disease-like phenotypes, facilitating fast and cost-effective in vivo genetic modifier screening and drug evaluation. Using these models, many disease associated genetic factors have been identified, leading to the identification of compelling drug candidates. Recently, the safety and efficacy of traditional medicines for human diseases have been evaluated in various animal disease models. Despite the advantages of the Drosophila model, its usage in the evaluation of traditional medicines is only nascent. Here, we introduce the Drosophila model for neurodegenerative diseases and some examples demonstrating the successful application of Drosophila models in the evaluation of traditional medicines. PMID- 24790640 TI - The Sensible and Insensible Body: A Visual Essay. PMID- 24790641 TI - Small bowel stricture characterization and outcomes of dilatation by double balloon enteroscopy: a single-centre experience. AB - BACKGROUND: There is little data on the role of balloon enteroscopy and small bowel strictures. We aim to characterize the diagnostic role of double balloon enteroscopy (DBE) in small bowel strictures and document the outcomes of dilatation. METHODS: This is a retrospective review from a single tertiary referral centre DBE database from July 2004 to September 2012. All patients with suspected strictures in the small bowel undergoing DBE were included. The position of the small bowel strictures considered for dilatation was determined by diagnostic imaging, i.e. CT enterography, MR enterography or capsule endoscopy in the workup before DBE. Endpoints included stricture description, dilatation parameters and response to treatment. Main outcome measurements were the safety and efficacy of DBE and dilatation. RESULTS: From our DBE database of 594 patients, a total of 32 patients underwent 44 DBE procedures for suspected or known strictures. Stricture aetiology included Crohn's disease (CD), nonsteroidal anti-inflammatory drugs (NSAIDs), surgical, Bechets disease and one unknown. A total of 17 patients did not undergo dilatation as the strictures were ulcerated, nonobstructing or of uncertain aetiology. From the total of 25 dilatations in 15 patients that were attempted, 8/15 (53%) patients had 1 dilatation, 5 patients had 2 dilatations, 1 had 3 dilatations and 1 had 4 dilatations. The mean dilatation diameter was 14 mm. Three patients underwent surgery post-dilatation (2 for perforation). Mean follow up was 16 months. CONCLUSION: DBE is a useful method in determining the need for dilatation by assessing for active ulceration. Dilatation is effective in the 10-18 mm range, however perforation does occur. PMID- 24790642 TI - Bowel preparation regimens for colon capsule endoscopy: a review. AB - Colon capsule endoscopy (CCE) is being actively evaluated as an emerging complementary or alternative procedure for evaluation of the colon. The yield of CCE is significantly dependent on the quality of bowel preparation. In addition to achieving a stool-free colon the bowel preparation protocols need to decrease bubble effect and aid propulsion of the capsule. An extensive English literature search was done using PubMed with search terms of colon capsule endoscopy, PillCam and bowel preparation. Full-length articles which met the criteria were included for review. A total of 12 studies including 1149 patients were reviewed. There was significant variability in the type of bowel preparation regimens. Large-volume (3-4 liters) polyethylene glycol (PEG) was the most widely used laxative. Lower volumes of PEG showed comparable results but larger studies are needed to determine efficacy. Sodium phosphate was used as an effective booster in most studies. Magnesium citrate and ascorbic acid are emerging as promising boosters to replace sodium phosphate when it is contraindicated. The potential benefit of prokinetics needs further evaluation. Over the past decade there has been significant improvement in the bowel preparation regimens for CCE. Further experience and studies are likely to standardize the bowel preparation regimens before CCE is adopted into routine clinical practice. PMID- 24790643 TI - Endoscopic approach to subepithelial lesions. AB - Endoscopy and endoscopic ultrasound (EUS) play a critical role in the detection and management of subepithelial lesions of the gastrointestinal tract. The most common subepithelial lesions detected by endoscopists are gastrointestinal stromal tumors (GISTs), leiomyomas, lipomas, granular cell tumors (GCTs), pancreatic rests and carcinoid tumors. These lesions can be classified based on unique histochemical staining and the gastrointestinal layer of origin. While the majority of the lesions are considered benign, some tumors such as GISTs and carcinoids have a strong propensity for malignant transformation. Therefore, appropriate endoscopic versus surgical management based on size and location is crucial in the prevention of malignant transformation and metastasis. In this review, we provide a systematic approach to the diagnosis, management and treatment of commonly encountered subepithelial lesions. PMID- 24790644 TI - Sofosbuvir, a NS5B polymerase inhibitor in the treatment of hepatitis C: a review of its clinical potential. AB - Treatment of chronic hepatitis C (HCV) is currently undergoing a significant change. Traditional interferon-based therapy has been limited by both efficacy and tolerability, and many direct acting antiviral (DAA) drugs are emerging. Sofosbuvir (GS-7977) is a HCV NS5B nucleotide polymerase inhibitor that has now been evaluated extensively in phase II and III interferon-free clinical trials. The focus of this review is on the clinical potential of sofosbuvir in the treatment of HCV. Sofosbuvir has a pan-genotypic effect on HCV, although viral genotype-specific differences in sustained virological response (SVR) have emerged in phase III clinical trials. Sofosbuvir has been studied both as dual therapy with ribavirin and also as triple therapy with either NS5A inhibitors or a protease inhibitor. High rates of SVR have been reported with these interferon free combinations, particularly with genotypes 1 and 2, and the safety profile has been very favourable in both cirrhotic and noncirrhotic patients, without issues of viral resistance. Interferon-free, once-daily treatment of HCV is now becoming a reality. PMID- 24790645 TI - Dabigatran etexilate for secondary stroke prevention: the first year experience from a multicenter short-term registry. AB - BACKGROUND: There are growing concerns for the side effects of dabigatran etexilate (dabigatran), including higher incidence of dyspepsia and gastrointestinal bleeding. We conducted a multicenter early implementation study to prospectively evaluate the safety, efficacy and adherence to dabigatran for secondary stroke prevention. METHODS: Consecutive atrial fibrillation (AF) patients with ischemic stroke (IS) or transient ischemic attack (TIA) received dabigatran for secondary stroke prevention during their hospital stay according to American Heart Association recommendations at five tertiary care stroke centers. The study population was prospectively followed and outcomes were documented. The primary and secondary safety outcomes were major hemorrhage and all other bleeding events respectively defined according to RE-LY trial methodology. RESULTS: A total of 78 AF patients (mean age 71 +/- 9years; 54% men; 81% IS, 19% TIA; median CHADS2 (Congestive heart failure, Hypertension, diabetes mellitus, age >75 years, prior stroke or TIA); range 2-5) score 4 were treated with dabigatran [(110mg bid (74%); 150mg bid (26%)]. During a mean follow-up period of 7 +/- 5 months (range 1-18) we documented no cases of IS, TIA, intracranial hemorrhage, systemic embolism or myocardial infarction in AF patients treated with dabigatran. There were two (2.6%) major bleeding events (lower gastrointestinal bleeding) and two (2.6%) minor bleedings [hematuria (n = 1) and rectal bleeding (n = 1)]. Dabigatran was discontinued in 26% of the study population with high cost being the most common reason for discontinuation (50%). DISCUSSION: Our pilot data indicate that dabigatran appears to be safe for secondary stroke prevention during the first year of implementation of this therapy. However, high cost may limit the long-term treatment of AF patients with dabigatran, leading to early discontinuation. PMID- 24790647 TI - Experience in the use of clobazam in the treatment of Lennox-Gastaut syndrome. AB - Clobazam is a 1,5-benzodiazepine used successfully worldwide since the 1970s as an anxiolytic and antiepileptic drug. Since its recent Food and Drug Administration (FDA) approval in the United States in 2011 as adjunctive treatment for Lennox-Gastaut syndrome, it has continued to show sustained efficacy and a better safety and tolerability profile compared with other benzodiazepines. The two randomized, controlled studies that led to the US FDA approval, as well as the follow-up multicenter, open-label study of clobazam, showed >=50% seizure reduction for more than 50% of Lennox-Gastaut syndrome patients, while none of the other FDA-approved treatments for LGS have demonstrated efficacy rates better than 50%. Clobazam appears to have a safe profile and sustained effectiveness over the first 3 years of use in LGS and other epilepsy syndromes with intractable seizures, which makes it a viable long term treatment option. PMID- 24790646 TI - Sphenopalatine ganglion stimulation for the treatment of cluster headache. AB - Cluster headache is a severe, debilitating disorder with pain that ranks among the most severe known to humans. Patients with cluster headaches have few therapeutic options and further, 10-20% develop drug-resistant attacks. The often brief duration of cluster attacks makes abortive therapy a challenge, and preventive medications are almost always provided to patients, but the side effects of these preventive medications can be significant. The sphenopalatine ganglion (SPG) is believed to play a role in headache pain and cranial autonomic symptoms associated with cluster headache, which is a result of activation of the trigeminal-autonomic reflex. For over 100 years, the SPG has been a clinical target to treat primary headache disorders using pharmacologic and nonpharmacologic methods. Radiofrequency lesioning and nerve-resection therapies, while initially beneficial, are irreversible procedures, and the use of neurostimulation provides one method of interfacing with the neural pathways without causing permanent damage to neural tissue. SPG neurostimulation is both reversible and adjustable, and has recently been tested in both proof-of-concept work and in a randomized, sham-controlled trial for the treatment of cluster headache. A randomized, sham-controlled study of 32 patients was performed to evaluate further the use of SPG stimulation for the acute treatment of chronic cluster headache. Of the 32 patients, 28 completed the randomized experimental period. Overall, 68% of patients experienced an acute response, a frequency response, or both. In this study the majority of adverse events were related to the implantation procedure, which typically resolved or remained mild in nature at 3 months following the implant procedure. This and other studies highlight the promise of using SPG stimulation to treat the pain-associated cluster headache. SPG stimulation could be a safe and effective option for chronic cluster headache. PMID- 24790648 TI - Para-dichlorobenzene toxicity - a review of potential neurotoxic manifestations. AB - BACKGROUND: Para-dichlorobenzene (PDCB) is an active ingredient of mothballs, deodorizers and fumigants. Due to the easy availability of this chemical, there is a considerable risk for accidental or intentional toxic exposure. Recently, multiple cases of PDCB toxicity due to mothball ingestion were reported. PDCB toxicity can affect multiple organ systems including liver, kidneys, skin, lung and the central nervous system (CNS). CNS toxicity often results in leukoencephalopathy and heterogeneous neurological manifestations. OBJECTIVES: The objective of this study was to illustrate the clinical presentation, imaging findings, diagnosis and management of PDCB toxicity. METHODS: We carried out a literature review of the pharmacological and toxicological properties of PDCB. CONCLUSIONS: PDCB and other aromatic hydrocarbons are capable of CNS tissue damage and in promoting functional neurological decline. While very little is currently known about prevalence of PDCB addiction, it cannot be ruled out that its illicit use among young people is under-recognized. The number of cases of PDCB toxicity might also rise due to the increasing industrial and domestic use of this chemical. PMID- 24790649 TI - Triple-negative breast cancer: bridging the gap from cancer genomics to predictive biomarkers. AB - Triple-negative breast cancer (TNBC) represents a challenge clinically due to a lack of response to hormonal and HER2-targeted agents coupled with an aggressive disease course. As the biology of this breast cancer subtype is better understood, it is clear that TNBC is a heterogeneous disease and one targeted therapy is unlikely to be active in all patients. Biomarkers predictive of response to treatment are thus of great importance in TNBC. This review outlines studies evaluating biomarkers predictive of response to neoadjuvant chemotherapy and to targeted therapies in the advanced setting. The development of validated biomarkers in conjunction with novel targeted therapies represents an opportunity to improve patient outcomes in TNBC. PMID- 24790651 TI - Recent advances in the treatment of gastrointestinal stromal tumors. AB - Constitutively activating mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) RTKs play a crucial role in the biology of gastrointestinal stromal tumors (GISTs), and this disease has served as an effective model for targeting gain-of-function kinase mutations in cancer. Imatinib has entered the clinical arena in the last decade and substantially improved the outcome in these formerly untreatable cancers. However, most advanced GISTs responding to imatinib progress within 2-3 years due to heterogeneous subclones harboring a range of imatinib-resistant secondary KIT mutations. Sunitinib, and more recently, regorafenib, have obtained US Food and Drug Administration approval for the treatment of GISTs after imatinib failure, and thus expanded the treatment options in resistant disease. Within this framework, we present an evaluation of current GIST management, emphasizing the most recent advances in the field together with a discussion on future steps to be taken in refractory disease. PMID- 24790652 TI - Treatment of older patients with colorectal cancer: a perspective review. AB - In a continuously aging population, the burden of colorectal cancer (CRC) is rising among older patients. Despite the fact that almost half of the cases occur in patients over 75 years, this age group is subjected to disparities regarding diagnostic and therapeutic options. So far, exclusion of older patients from randomized clinical trials has resulted in a lack of evidence-based guidelines. Nevertheless, newer data from studies specifically targeting older patients and subgroup analyses indicate that proper treatment planning and specific medical and geriatric assessment can achieve a safe and beneficial treatment result in older patients, often with similar outcomes to their younger counterparts. Resection of the primary tumour, if feasible, should be the primary goal of surgery aiming for cure, although it should be avoided under emergency conditions. Chronological age per se should not be an exclusion criterion for adjuvant or palliative chemotherapy, or targeted therapies. Careful patient selection, dose adjustments, close monitoring and early intervention in the event of side effects are essential. The benefits of treatment must be balanced with potential effects of treatment and patients' wishes. PMID- 24790650 TI - Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies. AB - Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor kappaB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70-80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer. PMID- 24790653 TI - Special issue on current challenges and future directions in monitoring recurrence after treatment of primary cancer. PMID- 24790655 TI - Future directions for the early detection of colorectal cancer recurrence. AB - Surgical resection remains a mainstay of treatment and is highly effective for localized colorectal cancer. However, ~30-40% of patients develop recurrence following surgery and 40-50% of recurrences are apparent within the first few years after initial surgical resection. Several variables factor into the ultimate outcome of these patients, including the extent of disease, tumor biology, and patient co-morbidities. Additionally, the time from initial treatment to the development of recurrence is strongly associated with overall survival, particularly in patients who recur within one year of their surgical resection. Current post-resection surveillance strategies involve physical examination, laboratory, endoscopic and imaging studies utilizing various high and low-intensity protocols. Ultimately, the goal is to detect recurrence as early as possible, and ideally in the asymptomatic localized phase, to allow initiation of treatment that may still result in cure. While current strategies have been effective, several efforts are evolving to improve our ability to identify recurrent disease at its earliest phase. Our aim with this article is to briefly review the options available and, more importantly, examine emerging and future options to assist in the early detection of colon and rectal cancer recurrence. PMID- 24790654 TI - Early detection of colorectal cancer recurrence in patients undergoing surgery with curative intent: current status and challenges. AB - Despite advances in neoadjuvant and adjuvant therapy, attention to proper surgical technique, and improved pathological staging for both the primary and metastatic lesions, almost half of all colorectal cancer patients will develop recurrent disease. More concerning, this includes ~25% of patients with theoretically curable node-negative, non-metastatic Stage I and II disease. Given the annual incidence of colorectal cancer, approximately 150,000 new patients are candidates each year for follow-up surveillance. When combined with the greater population already enrolled in a surveillance protocol, this translates to a tremendous number of patients at risk for recurrence. It is therefore imperative that strategies aim for detection of recurrence as early as possible to allow initiation of treatment that may still result in cure. Yet, controversy exists regarding the optimal surveillance strategy (high-intensity vs. traditional), ideal testing regimen, and overall effectiveness. While benefits may involve earlier detection of recurrence, psychological welfare improvement, and greater overall survival, this must be weighed against the potential disadvantages including more invasive tests, higher rates of reoperation, and increased costs. In this review, we will examine the current options available and challenges surrounding colorectal cancer surveillance and early detection of recurrence. PMID- 24790656 TI - Current approaches and challenges in early detection of breast cancer recurrence. AB - Early detection of breast cancer recurrence is a key element of follow-up care and surveillance after completion of primary treatment. The goal is to improve survival by detecting and treating recurrent disease while potentially still curable assuming a more effective salvage surgery and treatment. In this review, we present the current guidelines for early detection of recurrent breast cancer in the adjuvant setting. Emphasis is placed on the multidisciplinary approach from surgery, medical oncology, and radiology with a discussion of the challenges faced within each setting. PMID- 24790658 TI - Decision arguments to intervene in coronary artery disease: are we serious ? PMID- 24790659 TI - Nature or the natural evolution of plaque: what matters? AB - ABSTRACT: Progression to major acute cardiovascular events often is triggered by an atherosclerotic plaque complicated by rupture or erosion, namely the vulnerable plaque. Early and secure identification of these plaques would allow the development of individualized therapeutic and pharmacological strategies, applied in a timely manner. Imaging methods have a huge potential in detecting and monitoring the evolution of vulnerable plaque. Even though there are multiple invasive and noninvasive techniques, clinical application is for now a matter of choosing the relevant imaging feature for the prognosis, the methodo-logy of study and the target population. PMID- 24790657 TI - Future directions for the early detection of recurrent breast cancer. AB - The main goal of follow-up care after breast cancer treatment is the early detection of disease recurrence. In this review, we emphasize the multidisciplinary approach to this continuity of care from surgery, medical oncology, and radiology. Challenges within each setting are briefly addressed as a means of discussion for the future directions of an effective and efficient surveillance plan of post-treatment breast cancer care. PMID- 24790660 TI - Is small for gestational age status associated with an increased risk of atherogenesis? AB - ABSTRACT: The "catch-up growth" phenomenon in children born small for gestational age (SGA) has been linked to early onset obesity with the subsequent emergence of metabolic syndrome (MetS). The intima media thickness of the common carotid artery (CIMT) is a well-known marker of subclinical atherosclerosis. AIM: to determine the association between being born SGA and CIMT, a measure of atherogenesis and to investigate metabolic risk factors which impact on CIMT in obese children. MATERIAL AND METHODS: A prospective study was carried out over a 1 year period (July 2012-June 2013). We analyzed 122 obese patients, 96 patients appropriate for gestational age (AGA) and 26 patients SGA. Both groups were matched for age, sex and BMI. Blood pressure, lipids and glucose were determined. Oral glucose tolerance tests (oGTT) were performed. Insulin resistance (IR) was assessed by homeostasis model assessment (HOMA). CIMT was measured in all the patients. RESULTS: CIMT in obese children born SGA was significantly increased as compared with obese children born AGA similar age, sex and BMI (p=0.0035). We demonstrated a strong correlation between CIMT and all other metabolic factors (r=0.98). In both groups, mean CIMT of was significantly related to diastolic blood pressure, triglycerides and HOMA. CIMT was not significantly related to systolic blood pressure and baseline glucose. CONCLUSION: High triglycerides levels and low HDL-cholesterol levels, IR and diastolic blood pressure, which are all components of MetS are strong predictors of increased CIMT in obese children. Being born SGA increases the atherogenic risk. PMID- 24790661 TI - Diagnostic approach of angelman syndrome. AB - ABSTRACT: BACKGROUND: Angelman syndrome (AS) is a genetic condition, characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behaviour, movement disorder. It is caused by a variety of genetic mechanisms which all interfere with expression of the UBE3A gene on chromosome 15q11-13. OBJECTIVES: To present our experience regarding diagnosis of children with Angelman syndrome. MATERIAL AND METHODS: 15 children were clinically and genetically diagnosed with AS in the Department of Pediatric Neurology of the "Prof. Dr. Alex. Obregia" Clinical Hospital. In all cases, diagnosis of AS was made by the clinical criteria. The clinical evaluation focused on the patient history, a general examination, dysmorphological evaluation, a neurological examination, psychological evaluation, and paraclinical tests. RESULTS: All patients from this study presented the characteristic facial features and the characteristic behavior phenotype. Psychomotor development was delayed in all children, most of cases (73%) presenting with sever mental retardation. Epileptic seizures were observed in all patients with microdeletion, the partial seizures being the most frequent type. EEG in all children showed the characteristic pattern for AS. CONCLUSIONS: Angelman syndrome is a rare and severe neurodevelopmental disorder, with a complex clinical picture. There are some characteristic facial features, which, in association with hypopigmentation, happy disposition, jerky movements, and ataxia in a child with psychomotor delay should raise the strong suspicion of AS. PMID- 24790662 TI - Iron overload in Beta thalassaemia major and intermedia patients. AB - ABSTRACT: BACKGROUND: In beta thalassaemia major multiple blood transfusions, ineffective erythropoiesis and increased gastrointestinal iron absorption lead to iron overload in the body. Iron overload impairs the immune system, placing patients at greater risk of infection and illness. Iron overload can be determined by serum ferritin measurement. OBJECTIVE: The aim of the present study is to assess the serum ferritin levels in multi-transfused Thalassaemia major and Thalassaemia intermedia patients. The study was also done to estimate the present situation of awareness of iron overload in them. METHODS: Seventy two blood samples from clinically diagnosed thalassaemia major and intermedia patients were collected from different tertiary care hospitals in Bhopal, India for their serum ferritin estimation. Serum ferritin measurement was performed using indirect enzyme linked immune sorbent based serum ferritin assay kit. Data were analyzed to determine association between variables. The association between age, sex, and serum ferritin level were established. RESULTS: 87.4% of the beta thalassaemia major patients showed very high ferritin levels. The mean serum ferritin level was found to be 2767.52 ng/ml. 44.4% patients had serum ferritin between 1000 to 2500 ng/ml, while 43.05% patients had values above 2500 ng/ml. These levels reflect inadequate chelation and vulnerability to develop iron overload related complications. CONCLUSION: There is an urgent need to rationalize the chelation therapy and to create awareness about the consequences of iron overload in the patients. The study showed high levels of serum ferritin beta thalassaemia major patients which give an overall bleak view. PMID- 24790663 TI - Percutaneous transvenous mitral commissurotomy in elderly mitral stenosis patients. A retrospective study at shahid gangalal national heart centre, bansbari, kathmandu, Nepal. AB - ABSTRACT: INTRODUCTION: Percutaneous transvenous Mitral Commissurotomy (PTMC) has been shown to be a valid alternative to surgical therapy in selected patients with mitral stenosis. Though its efficacy in children and young adults is already established, its role in elderly patients is not well reported. We aimed to evaluate the efficacy of PTMC in elderly patients (>=60 years). METHODS: All elderly patients who underwent PTMC from March 2008 to March 2013 were retrospectively reviewed. Mitral valve area and mean left atrial pressure before and after the procedure were compared. RESULTS: During the study period 49 elderly patients underwent PTMC. Thirty eight were female and 11 male. Age ranged from 60 to 77 years with the mean age of 64.5+/-4.0 years. The mean mitral valve area increased from 0.9+/-0.1 cm(2) to 1.6+/-0.3 cm(2) whereas mean left atrial pressure decreased from 25.4+/-6.6 mmHg to 12.9+/-4.5. Successful results were observed in 41 (83.6%) patients. Unsuccessful results were due to suboptimal mitral valve area <1.5 cm(2) in 7 (14.25%) patients and post-procedure MR of more than moderate MR in 1(2%) patients. Unsuccessful PTMC was much more common in severe than in moderate mitral stenosis. CONCLUSIONS: Our study suggests that PTMC in elderly is a safe and effective procedure when performed in experienced centre by experienced operators. PMID- 24790664 TI - Indolent lymphoma: diagnosis and prognosis in medical practice. AB - ABSTRACT: INTRODUCTION: Non-Hodgkin lymphomas represent malignant tumors of lymphoid cells. These chronic lymphoproliferative disorders stand for malignancies with varied histological aspects, clinical features, evolution, prognosis and aggressiveness. Follicular lymphomas are the most frequent form of indolent lymphomas and they represent around 25% of all malignant lymphomas in adults. MATERIAL AND METHOD: Between 2011 and 2012, we have retrospectively observed, analyzed and described a group of 24 patients diagnosed with follicular lymphomas in the Department of Hematology from Coltea Hospital. The admittance criteria were: age, gender, hemoglobin and LDH levels, number lymph nodes affected and the Ann Arbor lymphoma staging system. Also used as patient study parameters were the following immunohistochemical criteria: CD20, UCHL1, CD79a, expression of Bcl 2 and Bcl 6, CD10 and the proliferative index (Ki-67). RESULTS: Multiple studies have shown that prognosis depends far more on clinical and histology parameters, including age, the presence of extra-node diseases and the performance status. In our study, regarding the ratio between the two genders, the male patients were more numerous than the female patients. The impairment of the male patients is associated with an unfavorable prognosis. From the age perspective, most of the diagnosed patients were part of the age group over 60. The age exceeding 60 is considered a negative prognosis factor. The serum lactate dehydrogenase (LDH) level is also considered an unfavorable prognosis factor. In our study, stage III and IV were frequently and this represents a poor prognosis factor. CONCLUSIONS: Although it was a small number of patients, the results obtained correspond to the results existing in literature. PMID- 24790665 TI - Onset risk factors and treatment response features of refractory hodgkin lymphoma. AB - ABSTRACT: BACKGROUND: The International Prognostic Factors Project on Advanced Hodgkin lymphoma (HL) developed a seven factor prognostic score consisting of gender, age, stage, serum albumin, hemoglobin, leukocytosis and lymphocytopenia for the newly diagnosed Hodgkin disease patients in advanced stages, who receive chemotherapy. OBJECTIVES: The purpose of this study was to determine whether this prognostic score would also be useful for refractory Hodgkin lymphoma patients in monitoring response to treatment. MATERIAL AND METHOD: In the period 2000-2012, we performed a study on a group of 91 patients to show that the prognostic factors identified by the International Prognostic Factors (IPF) score affect the event- free survival (EFS) and the overall survival (OS). Our study also intends to show that the results of these factors change with the treatment response in patients with HL included in the category of patients with refractory disease. RESULTS: B symptoms, onset lymph node, more than 3 areas involved, bulky disease, extranodal involvement, low serum albumin, erythrocytes sedimentation rate (ESR), C reactive protein (CRP), lactic dehydrogenase (LDH) and anemia were associated with poorer EFS and OS. Male gender, stage, histological type, age (>45 years) and leukocytosis were not associated with significantly poorer outcomes. CONCLUSIONS: the prognostic score for advanced disease is also useful in predicting relapse in patients with HL and early detection of response in patients with refractory HL. PMID- 24790666 TI - Is there a Role for Spect with (99m)Tc-Tetrofosmin in the Diagnostic Work Up of a Brain Tumor? AB - ABSTRACT: Brain MRI is the gold standard for diagnosis of brain tumors. In some cases preoperative MRI cannot predict the grade of malignancy, diagnostic information that could be very helpful to the surgeon. In such cases functional imaging with nuclear medicine techniques may prove quite useful.We present a case of a 58-year-old man with a brain tumor in the parieto-occipital region. Anatomic brain imaging by magnetic resonance imaging was indicative of a low grade astrocytoma. This was followed by planar imaging and single-photon emission computed tomography (SPECT) with (99m)Tc-tetrofosmin which showed increased radiotracer accumulation in the lesion, suggesting a glioblastoma which was histologically confirmed. We think that in the MRI era sometimes a (99m)Tc tetrofosmin brain scan can contribute to diagnostic workup and improve the final management of the patient. PMID- 24790667 TI - Small cell lung carcinoma associated with progressive systemic sclerosis. AB - ABSTRACT: The association between progressive systemic sclerosis (PSS) and malignancy is uncommon. The possibility of development of small cell carcinoma lung (SCLC), among all the reported lung malignancies in PSS patients is lowest. A fifty-five year old non-smoker female diagnosed as PSS for 1 year presented to our outpatient department with dry cough for 2 months, shortness of breath for the last 1 month and progressive facial and right upper limb oedema for the last 15 days. Chest X-ray showed homogenous opacity in the right upper and mid zones of lung and the obliteration of both costophrenic angles. High resolution computed tomography (CT) of the thorax revealed a right upper lobe lung mass with bilateral minimal pleural effusion and the presence of bilateral reticular opacities, with basal predominance, associated with septal thickening, suggestive of interstitial lung disease of non-specific interstitial pneumonia pattern. CT guided fine needle aspiration cytology (FNAC) from the right upper lobe mass was suggestive of small cell carcinoma. Patient was improved after 6 cycles of chemotherapy with carboplatin and etoposide. PMID- 24790668 TI - Benefit vs. Risk of a Permanent Inferior Vena Cava Filter in Pulmonary Embolism with Anticoagulation Contraindication. AB - ABSTRACT: Cases of pulmonary embolism (PE) with contraindication of anticoagulation have low incidence. Under these circumstances the placement of an inferior vena cava (IVC) filter may be life-saving. Paradoxically, the presence of the filter imposes anticoagulation itself, due to the risk of filter thrombosis, promoting stasis and increasing the risk of filter related deep venous thrombosis (DVT) and PE recurrence by means of a substantial collateral venous return that bypasses the IVC filter (1,2). We present the case of a woman with DVT, complicated with high risk PE. After thrombolysis with alteplase the patient develops retroperitoneal hematoma originating from undiagnosed renal angiomyolipoma. Therefore long term anticoagulation is considered contraindicated and an IVC filter is installed. Shortly after hospital release the patient presents occlusion of the IVC filter with DVT recurrence. The initiation of low molecular weight heparin and afterwards of acenocumarol has a favorable outcome, and after six months of follow up the patient is completely recovered. PMID- 24790669 TI - Ciliary body melanoma - a particularly rare type of ocular tumor. Case report and general considerations. AB - ABSTRACT: Uveal melanoma is the most common primary malignancy of the eye in white adults. Frequently, uveal melanoma arises from choroid or iris. Ciliary body melanoma is a rare if not exceptional subtype of uveal melanoma. Furthermore, ciliary melanoma is often seen in association with the other two subtypes of uveal melanoma. This paper presents a case of primary ciliary melanoma with invasion of the iris. The patient presented with blurred vision, but this symptom could not doubtless be related with the existence of the tumor, because of the small dimension of the malignancy and the lack of medical history of the patient.This tumor was included in the category of "very small ciliary melanoma", a rare diagnosis considering the fast local invasion and the lack of symptoms in such a small tumor. Histopathological and imunohistochemical examinations confirmed the diagnosis of ciliary melanomaThis type of ocular melanoma has a low prognosis due to early metastases. PMID- 24790670 TI - Intentional insulin overdose associated with minimal hypoglycemic symptoms in a non-diabetic patient. AB - ABSTRACT: Non-accidental suicidal insulin overdose is a rare presentation among non-diabetic patients. It seems to be more common among working medical professionals. OBJECTIVES: To present the case of a young patient, who despite injecting a large dose of rapid-acting insulin presented with only mild symptoms, and to familiarize the medical professionals involved in managing this condition with the recognition, pathophysiology and appropriate therapeutic interventions. MATERIALS AND METHODS: We report the case of a previously healthy non-diabetic young medical professional who presented with a rapid-acting insulin overdose. On initial assessment the patient was alert and oriented, and glucose measurement was 1.4 mmol/L. The oral glucose gel and intramuscular glucagon failed to raise the glucose. Hypokalaemia, hypomagnesaemia, hypophosphataemia, lactic acidosis and ECG changes completed the presentation. OUTCOMES: The treatment consisted of dextrose infusion and appropriate electrolytes replacement. An uneventful recovery was made, so 36 hours later the patient was discharged with psychiatric follow-up. CONCLUSIONS: Insulin overdose should be considered as a differential diagnosis in hypoglycaemic patients when blood glucose fails to correct as expected. Improper management carries a significant risk of hypoglycaemic encephalopathy, which can cause lifelong cerebral changes. PMID- 24790671 TI - Secondary Acute Lymphoblastic Leukemia after Hodgkin's Lymphoma or a Coincidental Association of Two Hematological Malignancies? AB - ABSTRACT: Secondary acute lymphoblastic leukaemia (sALL), defined as acute lymphoblastic leukaemia following another malignancy, irrespective of previous treatment, is a rare disease, and its biological characteristics have not been accurately described. We report the case of a 24-year old patient followed for Hodgkin's lymphoma at our clinic, who develops and is diagnosed, less than a year after obtaining complete remission, as having pro-B acute lymphoblastic leukaemia This case has been a real diagnostic and treatment challenge, as sALL following another haematological malignancy is quite rare. CONCLUSION: It is necessary to better identify the prognostic factors of haematological malignancies in order to prevent the appearance of sALL. PMID- 24790672 TI - Traumatic brain injury due to bull assault in a girl: a case report. AB - ABSTRACT: Traumatic brain injury is a common condition in the emergency services, affecting the pediatric and adult population significantly. Patterns of head injury as well as management principles in children are important differences compared to adults. Traumatic brain injury by bull rush is usually seen in adults but has not been described in children-report a pediatric cranial trauma present bull rush, which to our knowledge is the first report in the literature of this nature. PMID- 24790673 TI - Extended exposure in difficult total knee arthroplasty using tibial tubercle osteotomy. AB - ABSTRACT: OBJECTIVES: In some total knee arthroplasty cases, the usual medial parapatellar approach does not allow the appropriate patellar eversion and the desired exposure of the knee joint. Partial disinsertion of the patellar tendon doesn't substantially improve the surgical exposure and can lead to extensor apparatus weakening and complete secondary ruptures, while the V-Y quadricipital plasty leads to post-op immobilization of the knee, which delays the functional rehabilitation, with negative impact on the range of motion. The tibial tubercle osteotomy, however, allows an extension of the approach in total knee arthroplasty, without endangering the quadricipital extensor apparatus. MATERIAL AND METHODS: In this study we analysed the post-operative results of 11 cases of primary total knee arthroplasty in which a frontal plane osteotomy of the tibial tubercle was performed in addition to the standard medial parapatellar approach, as a result of the patients associated conditions, like rheumatoid arthritis with an extension deficit higher than 150, previous knee synovectomy by arthrotomy, progressive genu varum with more than 150 deviation, varus deviation of the lower limb with previous closing wedge proximal tibial osteotomy or patellar fractures with vicious consolidation. OUTCOMES: Overall, the results were more than satisfactory with a significant increase in the patients mean range of motion and Knee Society Score. There were some post-op issues in some of the patients, but they were adressed accordingly, having no long-term impact on the results. CONCLUSIONS: . We could thus conclude that, in special cases, the frontal plane tibial tubercle osteotomy is an effective technique which can provide a wide approach with appropriate protection of the knee extensor apparatus. PMID- 24790674 TI - Methods of investigating metastatic lymph nodes in head and neck cancer. AB - ABSTRACT: When dealing with patients who have head and neck cancer - squamous cell carcinoma and have clinically N0 neck disease it is very difficult to assess the real extension of the malignant proccess. This is why several techniques are curently in use to determine the actual TNM clasiffication for each patient in order to apply best suited therapy management. Up until today the staging of the neck has been done by using a combination of the physical exam and conventional imaging studies. Recent studies and research have tried to determine weather the use of sentinel lymph node biopsy is a more reliable tool in predicting occult metastasis in cancer patients with clinically N0 neck disease. There are no guidelines in this matter and as such the use of the sentinel lymph node detection technique is yet to be used on a routine basis. The authors are trying to assess the benefits of different paraclinical investigation regarding the improvement of overall survival rates in patients with T1/T2 squamous cell carcinoma of the head and neck and N0 neck disease. PMID- 24790675 TI - Cerebral palsy gait, clinical importance. AB - ABSTRACT: Cerebral palsy refers to a lesion on an immature brain, that determines permanent neurological disorders. Knowing the exact cause of the disease does not alter the treatment management. The etiology is 2-2.5/1000 births and the rate is constant in the last 40-50 years because advances in medical technologies have permitted the survival of smaller and premature new born children. Gait analysis has four directions: kinematics (represents body movements analysis without calculating the forces), kinetics (represents body moments and forces), energy consumption (measured by oximetry), and neuromuscular activity (measured by EMG). Gait analysis can observe specific deviations in a patient, allowing us to be more accurate in motor diagnoses and treatment solutions: surgery intervention, botulinum toxin injection, use of orthosis, physical kinetic therapy, oral medications, baclofen pump. PMID- 24790676 TI - Liver involvement in patients with systemic autoimmune diseases. AB - ABSTRACT: A wide variety of systemic autoimmune diseases (SAD) affects the liver, and various forms of hepatic involvement have been reported. Patients who have SAD, the abnormal liver function tests might be caused by SAD. In most of these patients, SAD should be treated primary. Liver involvement in SAD is a matter of great clinical challenge evoking several questions upon diagnostic criteria for liver diseases and the presence of overlap syndromes. This review will describe liver injury caused by various systemic autoimmune diseases. PMID- 24790677 TI - Rationale for management of frontal sinus fractures. AB - ABSTRACT: The optimal treatment of frontal sinus fractures remains controversial. Multiple treatment options and algorithms have been proposed by multiple specialties throughout the years; however, the optimal method of frontal sinus repair has yet to be discovered. Overwhelming complications such as meningitis, encephalitis or brain abscess are quite uncommon nowadays. Nevertheless, late development of invasive mucoceles is not a rarity and therefore long-term follow up is mandatory. PMID- 24790678 TI - Teriflunomide - a new oral agent for multiple sclerosis treatment. PMID- 24790679 TI - Oral human papillomavirus infection: new challenges for a new era? PMID- 24790680 TI - Insights into the Role of PAX-3 in the Development of Melanocytes and Melanoma. AB - Melanoma is the deadliest form of skin cancer in the United States with an increasing prevalence. However, the development of melanoma from a melanocyte precursor is still poorly defined. Understanding the molecules responsible for melanoma progression may lead to improved targeted therapy. One potential molecule is the paired box-3 (PAX-3) protein, which has been implicated in the development of melanocytes and malignant melanoma. In melanoma, the expression of PAX-3 is believed to be differentially regulated, and has been linked with malignancies and staging of the disease. The loss of PAX-3 regulation has also been associated with the loss of transforming growth factor-beta (TGF-beta) activity, but its effect on PAX-3 in differentiated melanocytes as well as metastatic melanoma remains unclear. Understanding PAX-3 regulation could potentially shift melanoma to a less aggressive and less metastatic disease. This review summarizes our current knowledge on PAX-3 during melanocyte development, its regulation, and its implications in the development of novel chemo immunotherapeutics against metastatic melanoma. PMID- 24790681 TI - Ganoderic Acid DM: An Alternative Agent for the Treatment of Advanced Prostate Cancer. AB - Prostate cancer is the most commonly diagnosed cancer in men and accounts for significant morbidity and mortality in the western world. While traditional therapies are effective at clearing early stage cancer, they often fail to treat late stage metastatic disease. Thus, an effective therapy that targets prostate tumor growth and metastasis is desired for alleviating the disease and improving patient outcomes. Natural extracts have been the focus of recent investigation, particularly those with reduced cellular toxicity to healthy tissue. In this review, we discuss one potential candidate, ganoderic acid, an extract from the Ganoderma lucidum mushroom that has been tested in multiple cancer models. Interestingly, ganoderic acid DM (GA-DM) has shown toxicity to both androgen dependent and independent prostate cancer cells with reduced osteoclastogenesis in late stage metastatic disease. This review will discuss the current knowledge on this GA-DM extract and the potential benefit in treating advanced prostate cancer. We will also provide an overview on the targeted delivery of GA-DM through nanoparticles that would reduce bystander toxicity and improve the drug's effectiveness. An improved understanding of this drug and its uses will advance the field of natural chemotherapeutics, particularly in treating advanced prostate cancer. PMID- 24790682 TI - The Norwegian PMS2 founder mutation c.989-1G > T shows high penetrance of microsatellite instable cancers with normal immunohistochemistry. AB - BACKGROUND: Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions. METHODS: All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm. RESULTS: Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers. CONCLUSIONS: The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males. PMID- 24790683 TI - Assessment of Divergent Thinking by means of the Subjective Top-Scoring Method: Effects of the Number of Top-Ideas and Time-on-Task on Reliability and Validity. AB - Divergent thinking tasks are commonly used as indicators of creative potential, but traditional scoring methods of ideational originality face persistent problems such as low reliability and lack of convergent and discriminant validity. Silvia et al. (2008) have proposed a subjective top-2 scoring method, where participants are asked to select their two most creative ideas, which then are evaluated for creativity. This method was found to avoid problems with discriminant validity, and to outperform other scoring methods in terms of convergent validity. These findings motivate a more general, systematic analysis of the subjective top-scoring method. Therefore, this study examined how reliability and validity of the originality and fluency scores depend on the number of top-ideas and on time-on-task. The findings confirm that subjective top scoring avoids the confounding of originality with fluency. The originality score showed good internal consistency, and evidence of reliability was found to increase as a function of the number of top-ideas and of time-on-task. Convergent validity evidence, however, was highest for a time-on-task of about 2 to 3 minutes and when using a medium number of about three top-ideas. Reasons for these findings are discussed together possible limitations of this study and future directions. The article also presents some general recommendations for the assessment of divergent thinking with the subjective top-scoring method. PMID- 24790684 TI - Direct Observation of Active Material Concentration Gradients and Crystallinity Breakdown in LiFePO4 Electrodes During Charge/Discharge Cycling of Lithium Batteries. AB - The phase changes that occur during discharge of an electrode comprised of LiFePO4, carbon, and PTFE binder have been studied in lithium half cells by using X-ray diffraction measurements in reflection geometry. Differences in the state of charge between the front and the back of LiFePO4 electrodes have been visualized. By modifying the X-ray incident angle the depth of penetration of the X-ray beam into the electrode was altered, allowing for the examination of any concentration gradients that were present within the electrode. At high rates of discharge the electrode side facing the current collector underwent limited lithium insertion while the electrode as a whole underwent greater than 50% of discharge. This behavior is consistent with depletion at high rate of the lithium content of the electrolyte contained in the electrode pores. Increases in the diffraction peak widths indicated a breakdown of crystallinity within the active material during cycling even during the relatively short duration of these experiments, which can also be linked to cycling at high rate. PMID- 24790685 TI - Difficult-to-wean: High index of suspicion. AB - PATIENT: Female, 57 FINAL DIAGNOSIS: Syryngomyelia * cervical SYMPTOMS: Acute respiratory insufficiency Medication: - Clinical Procedure: - Specialty: Pulmonology. OBJECTIVE: Rare disease. BACKGROUND: Failed planned extubation occurs in a minority of patients with acute respiratory failure requiring invasive mechanical ventilation. In patients presenting with acute respiratory failure with no identifiable cardiopulmonary causes, uncommon conditions, such as cervical spondylotic myelopathy, should be considered. In very rare instances, when cervical spondylotic myelopathy and syringomyelia present concomitantly, they can be devastating. CASE REPORT: A 57-year-old woman visited the emergency room (ER) after feeling unwell for several days. She was brought to the ER with acute respiratory distress and obtunded state with GCS of 6/15. She was hypotensive and agonally breathing. Her initial neurologic evaluation was unrevealing. Based on these findings, she was intubated. Over the next several days, she was difficult to wean from the ventilator and had persistent respiratory acidosis. After a short-lived extubation, the patient was again re intubated. This time the neurologic evaluation showed decreased movements of all muscle groups against gravity and forces, with generalized weakness. An MRI of the brain and cervical spine demonstrated moderate degenerative disc disease and syringomyelia extending from C2 to C7 level. The patient underwent de-compression laminectomy. After failing several weaning trials, she underwent bronchoscopically-assisted tracheotomy. CONCLUSIONS: Acute cardiopulmonary and intensive care unit-acquired neuromuscular conditions have been attributed as a major cause of difficult weaning and extubation. Failure to identify and correct other rare combinations (such as cervical degenerative disc disease and syringomyelia) may cause acute respiratory failure and subsequent failure to wean and extubation, resulting in high rates of mortality and morbidity. PMID- 24790686 TI - Fatal pulmonary embolism after hemodialysis vascular access declotting. AB - PATIENT: Male, 59 FINAL DIAGNOSIS: Pulmonary embolism Symptoms: Cardiac arrest * chest pain * dyspnea MEDICATION: - Clinical Procedure: Angioplasty Specialty: Nephrology. OBJECTIVE: Rare disease. BACKGROUND: Vascular access is the lifeline of hemodialysis patients and access problems are a major source of morbidity and mortality for these patients. Access stenosis and thrombosis are common problems in dialysis patients and require prompt intervention. Every year thousands of these procedures are performed in the United States by radiologists, surgeons, and interventional nephrologists. CASE REPORT: A 59-year-old man on chronic hemodialysis with multiple medical problems, including diabetes mellitus, hypertension, chronic obstructive lung disease, hepatitis C infection, and end stage renal disease, who had clotted his access several times before ,presented with another episode of access clotting. He underwent declotting successfully but upon angioplasty of the access feeding artery, he developed massive pulmonary embolism and died. Postmortem examination showed multiple pulmonary emboli, including cholesterol crystals in his lungs. CONCLUSIONS: Hemodialysis access declotting and angioplasty are usually benign and do not cause a major problem. However, occasionally they become complicated. In difficult cases and in people with multiple comorbidities, it is preferable to forego the existing dialysis access and either plan for creation of a new vascular access or place a central vein catheter. PMID- 24790687 TI - Getting back on the field. PMID- 24790688 TI - Relationship of the functional movement screen in-line lunge to power, speed, and balance measures. AB - BACKGROUND: The in-line lunge of the Functional Movement Screen (FMS) evaluates lateral stability, balance, and movement asymmetries. Athletes who score poorly on the in-line lunge should avoid activities requiring power or speed until scores are improved, yet relationships between the in-line lunge scores and other measures of balance, power, and speed are unknown. HYPOTHESIS: (1) Lunge scores will correlate with center of pressure (COP), maximum jump height (MJH), and 36.6 meter sprint time and (2) there will be no differences between limbs on lunge scores, MJH, or COP. STUDY DESIGN: Descriptive laboratory study. LEVEL OF EVIDENCE: Level 3. METHODS: Thirty-seven healthy, active participants completed the first 3 tasks of the FMS (eg, deep squat, hurdle step, in-line lunge), unilateral drop jumps, and 36.6-meter sprints. A 3-dimensional motion analysis system captured MJH. Force platforms measured COP excursion. A laser timing system measured 36.6-m sprint time. Statistical analyses were used to determine whether a relationship existed between lunge scores and COP, MJH, and 36.6-m speed (Spearman rho tests) and whether differences existed between limbs in lunge scores (Wilcoxon signed-rank test), MJH, and COP (paired t tests). RESULTS: Lunge scores were not significantly correlated with COP, MJH, or 36.6-m sprint time. Lunge scores, COP excursion, and MJH were not statistically different between limbs. CONCLUSION: Performance on the FMS in-line lunge was not related to balance, power, or speed. Healthy participants were symmetrical in lunging measures and MJH. CLINICAL RELEVANCE: Scores on the FMS in-line lunge should not be attributed to power, speed, or balance performance without further examination. However, assessing limb symmetry appears to be clinically relevant. PMID- 24790689 TI - Changes in landing mechanics in patients following anterior cruciate ligament reconstruction when wearing an extension constraint knee brace. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is associated with a high incidence of second tears (graft tears and contralateral ACL tears). These secondary tears have been attributed to asymmetrical lower extremity mechanics. Knee bracing is one potential intervention that can be used during rehabilitation that has the potential to normalize lower extremity asymmetry; however, little is known about the effect of bracing on movement asymmetry in patients following ACL reconstruction. HYPOTHESIS: Wearing a knee brace would increase knee joint flexion and joint symmetry. It was also expected that the joint mechanics would become more symmetrical in the braced condition. OBJECTIVE: To examine how knee bracing affects knee joint function and symmetry over the course of rehabilitation in patients 6 months following ACL reconstruction. STUDY DESIGN: Controlled laboratory study. LEVEL OF EVIDENCE: Level 3. METHODS: Twenty-three adolescent patients rehabilitating from ACL reconstruction surgery were recruited for the study. The subjects all underwent a motion analysis assessment during a stop-jump activity with and without a functional knee brace on the surgical side that resisted extension for 6 months following the ACL reconstruction surgery. Statistical analysis utilized a 2 * 2 (limb * brace) analysis of variance with a significant alpha level of 0.05. RESULTS: Subjects had increased knee flexion on the surgical side when they were braced. The brace condition increased knee flexion velocity, decreased the initial knee flexion angle, and increased the ground reaction force and knee extension moment on both limbs. Side-to-side asymmetry was present across conditions for the vertical ground reaction force and knee extension moment. CONCLUSION: Wearing a knee brace appears to increase lower extremity compliance and promotes normalized loading on the surgical side. CLINICAL RELEVANCE: Knee extension constraint bracing in postoperative ACL patients may improve symmetry of lower extremity mechanics, which is potentially beneficial in progressing rehabilitation and reducing the incidence of second ACL tears. PMID- 24790690 TI - Influence of stride frequency and length on running mechanics: a systematic review. AB - CONTEXT: A high number of recreational runners sustain a running-related injury each year. To reduce injury risk, alterations in running form have been suggested. One simple strategy for running stride frequency or length has been commonly advocated. OBJECTIVE: To characterize how running mechanics change when stride frequency and length are manipulated. DATA SOURCES: In January 2012, a comprehensive search of PubMed, CINAHL Plus, SPORTDiscus, PEDro, and Cochrane was performed independently by 2 reviewers. A second search of the databases was repeated in June 2012 to ensure that no additional studies met the criteria after the initial search. STUDY SELECTION: Inclusion criteria for studies were an independent variable including manipulation of stride frequency or length at a constant speed with outcome measures of running kinematics or kinetics. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: Two reviewers independently appraised each article using a modified version of the Quality Index, designed for assessing bias of nonrandomized studies. RESULTS: Ten studies met the criteria for this review. There was consistent evidence that increased stride rate resulted in decreased center of mass vertical excursion, ground reaction force, shock attenuation, and energy absorbed at the hip, knee, and ankle joints. All but 1 study had a limited number of participants, with several methodological differences existing among studies (eg, overground and treadmill running, duration of test conditions). Although speed was held constant during testing, it was individually self-selected or fixed. Most studies used only male participants. CONCLUSION: Despite procedural differences among studies, an increased stride rate (reduced stride length) appears to reduce the magnitude of several key biomechanical factors associated with running injuries. PMID- 24790691 TI - Prevalence of freestyle biomechanical errors in elite competitive swimmers. AB - BACKGROUND: Poor freestyle stroke biomechanics is a suggested risk factor for shoulder pain and pathology, but this has not been proven in biomechanical or clinical studies. Furthermore, the prevalence of these theoretical errors has not been identified, which would help coaches, athletic trainers, and researchers determine the most appropriate errors to focus on and develop interventions. HYPOTHESIS: The majority of swimmers will present with at least 1 freestyle stroke error. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: Stroke biomechanics for 31 swimmers from a collegiate swimming team were captured using underwater/above-water cameras. Each video was evaluated for biomechanical errors: a dropped elbow during the pull-through phase, a dropped elbow during the recovery phase, an eyes-forward head-carrying angle, incorrect hand position during hand entry, incorrect hand entry angle, incorrect pull through pattern, and inadequate body roll. Error prevalence was calculated, and relationships among the errors were evaluated using chi-square statistics. RESULTS: A dropped elbow during the pull-through phase (61.3%) and a dropped elbow during the recovery phase (53.2%) had the highest prevalence. A dropped elbow during the recovery phase was significantly associated with a thumb-first hand entry angle (P = 0.027) and incorrect hand entry position (P = 0.009). An eyes-forward head-carrying angle was associated with an incorrect pull-through pattern (P = 0.047). CONCLUSION: Biomechanical errors potentially detrimental to the shoulder are prevalent among swimmers. Many of the errors were interrelated, suggesting that one error may lead to other errors. CLINICAL RELEVANCE: These errors highlight the need for proper stroke instruction and evaluation to decrease the risk of shoulder injury in competitive swimmers. PMID- 24790692 TI - Febrile illness in the athlete. AB - CONTEXT: Acute febrile illnesses are common in athletes over the course of training and competition seasons. Complete recovery and rapid yet safe return to participation are critical for competitive athletes. Alterations in thermoregulation, metabolism, fluid homeostasis, muscle strength, and endurance, as well as potential complications for the athlete and others, must be considered. EVIDENCE ACQUISITION: The PubMed database was searched (1970-2013) for all English-language articles related to febrile illness in sport, using the keywords fever, febrile, body temperature, thermoregulation, infection, illness, disease, exercise, athlete, sport, performance, return to play, metabolism, hydration, and dehydration. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Limited data confirm that febrile illness is correlated with alterations in the body's thermoregulatory system, with increases in metabolic rate, and with effects in fluid homeostasis. Human and animal studies demonstrate a decrease in muscle strength and endurance secondary to muscle catabolism in febrile illness. However, indirect evidence suggests that regular exercise enhances the immune response. No strong clinical research has been published on return to play during or following acute febrile illness, excluding mononucleosis and myocarditis. CONCLUSION: Fever is correlated with an increase in insensible fluid losses, dehydration, metabolic demands, and dysregulation of body temperature. Fever can have detrimental effects on the musculoskeletal system, including decreasing strength and endurance, generalized muscle catabolism, and increase in perceived fatigue. Participating in strenuous exercise during febrile illness can worsen the illness and has demonstrated increased lethality in animal models. No consensus recommendations support return to activity before resolution of fever, and training should be resumed gradually once fever and dehydration have resolved. PMID- 24790693 TI - Return to play after infectious mononucleosis. AB - CONTEXT: Infectious mononucleosis is a disease primarily of adolescence and early adulthood. The risk of splenic injury and chronic fatigue make return-to-play decisions a challenge for the clinician caring for athletes with infectious mononucleosis. EVIDENCE ACQUISITION: Data were obtained from the PubMed and MEDLINE databases through December 2012 by searching for epidemiology, diagnosis, clinical manifestations, management, and the role of the spleen in infectious mononucleosis. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Infectious mononucleosis is commonly encountered in young athletes. Its disease pattern is variable and can affect multiple organ systems. Supportive care is the cornerstone, with little role for medications such as corticosteroids. Physical examination is unreliable for the spleen, and ultrasound imaging has limitations in its ability to guide return-to-play decisions. Exercise does not appear to place the young athlete at risk for chronic fatigue, but determining who is at risk for persistent symptoms is a challenge. CONCLUSION: Return-to-play decisions for the athlete with infectious mononucleosis need to be individualized because of the variable disease course and lack of evidence-based guidelines. PMID- 24790694 TI - Return to play after liver and spleen trauma. AB - CONTEXT: Sport-related spleen and liver injuries pose a challenge for the physician. Although rare, these injuries can have serious and even life threatening outcomes if not accurately diagnosed and managed in a timely fashion. Currently, there are no evidence-based guidelines on duration and intensity of restricted activity and return to play after spleen and liver injury. In addition, there is controversy on follow-up imaging after injury. EVIDENCE ACQUISITION: PubMed was searched using the terms splenic or spleen and trauma and hepatic or liver and trauma from 1980 to 2013. The citations from sentinel papers were also reviewed. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Ultrasound is ideal in the unstable athlete. Nonoperative management of blunt splenic and hepatic injuries is recommended for hemodynamically stable patients regardless of injury grade, patient age, or presence of associated injuries. Follow-up imaging is not routinely recommended unless clinically indicated. Athletes may engage in light activity for the first 3 months after injury and then gradual return to unrestricted activity as tolerated. High-level athletes may choose splenectomy or serial imaging for faster return to play. CONCLUSION: Intravenous contrast-enhanced computed tomography is the diagnostic imaging modality of choice in stable athletes with blunt abdominal trauma. STRENGTH-OF-RECOMMENDATION TAXONOMY: C. PMID- 24790695 TI - In-game Management of Common Joint Dislocations. AB - CONTEXT: Sideline management of sports-related joint dislocations often places the treating medical professional in a challenging position. These injuries frequently require prompt evaluation, diagnosis, reduction, and postreduction management before they can be evaluated at a medical facility. Our objective is to review the mechanism, evaluation, reduction, and postreduction management of sports-related dislocations to the shoulder, elbow, finger, knee, patella, and ankle joints. EVIDENCE ACQUISITION: A literature review was performed using the PubMed database to evaluate previous and current publications focused on joint dislocations. This review focused on articles published between 1980 and 2013. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: The clinician should weigh the benefits and risks of on-field reduction based on their knowledge of the injury and the presence of associated injuries. CONCLUSION: When properly evaluated and diagnosed, most sports-related dislocations can be reduced and initially managed at the game. PMID- 24790696 TI - Allografts in soft tissue reconstructive procedures: important considerations. AB - CONTEXT: Allografts offer several important advantages over autografts in musculoskeletal reconstructive procedures, such as anterior cruciate ligament reconstruction. Despite growing widespread use of allograft tissue, serious concerns regarding safety and functionality remain. We discuss the latest knowledge of the potential benefits and risks of allograft use and offer a critical review of allograft tissue regulation, management, and sterilization to enable the surgeon to better inform athletes considering reconstructive surgery options. EVIDENCE ACQUISITION: A review of sources published in the past 10 years is the primary basis of this research. STUDY DESIGN: Observational analysis (cohort study). LEVEL OF EVIDENCE: Level 3. RESULTS: Comparable outcome data for autografts and allografts do not support universal standards for anterior cruciate ligament reconstruction, and physician recommendation and bias appear to significantly influence patient preference and satisfaction. Sterilization by gamma and electron-beam irradiation diminishes the biomechanical integrity of allograft tissue, but radioprotective agents such as collagen cross-linking and free radical scavengers appear to have potential in mitigating the deleterious effects of irradiation and preserving tissue strength and stability. CONCLUSION: Allografts offer greater graft availability and reduced morbidity in orthopaedic reconstructive procedures, but greater expansion of their use by surgeons is challenged by the need to maintain tissue sterility and biomechanical functionality. Advances in the radioprotection of irradiated tissue may lessen concerns regarding allograft safety and structural stability. PMID- 24790697 TI - Current concepts of articular cartilage restoration techniques in the knee. AB - CONTEXT: Articular cartilage injuries are common in patients presenting to surgeons with primary complaints of knee pain or mechanical symptoms. Treatment options include comprehensive nonoperative management, palliative surgery, joint preservation operations, and arthroplasty. EVIDENCE ACQUISITION: A MEDLINE search on articular cartilage restoration techniques of the knee was conducted to identify outcome studies published from 1993 to 2013. Special emphasis was given to Level 1 and 2 published studies. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: CURRENT SURGICAL OPTIONS WITH DOCUMENTED OUTCOMES IN TREATING CHONDRAL INJURIES IN THE KNEE INCLUDE THE FOLLOWING: microfracture, osteochondral autograft transfer, osteochondral allograft transplant, and autologous chondrocyte transplantation. Generally, results are favorable regarding patient satisfaction and return to sport when proper treatment algorithms and surgical techniques are followed, with 52% to 96% of patients demonstrating good to excellent clinical outcomes and 66% to 91% returning to sport at preinjury levels. CONCLUSION: Clinical, functional, and radiographic outcomes may be improved in the majority of patients with articular cartilage restoration surgery; however, some patients may not fully return to their preinjury activity levels postoperatively. In active and athletic patient populations, biological techniques that restore the articular surface may be options that provide symptom relief and return patients to their prior levels of function. PMID- 24790698 TI - Sideline coverage: when to get radiographs? A review of clinical decision tools. AB - CONTEXT: Sidelines coverage presents unique challenges in the evaluation of injured athletes. Health care providers may be confronted with the question of when to obtain radiographs following an injury. Given that most sidelines coverage occurs outside the elite level, radiographs are not readily available at the time of injury, and the decision of when to send a player for radiographs must be made based on physical examination. Clinical tools have been developed to aid in identifying injuries that are likely to result in radiographically important fractures or dislocations. EVIDENCE ACQUISITION: A search for the keywords x-ray and decision rule along with the anatomic locations shoulder, elbow, wrist, knee, and ankle was performed using the PubMed database. No limits were set regarding year of publication. We selected meta-analyses, randomized controlled trials, and survey results. Our selection focused on the largest, most well-studied published reports. We also attempted to include studies that reported the application of the rules to the field of sports medicine. STUDY DESIGN: Retrospective literature review. LEVEL OF EVIDENCE: Level 4. RESULTS: The Ottawa Foot and Ankle Rules have been validated and implemented and are appropriate for use in both pediatric and adult populations. The Ottawa Knee Rules have been widely studied, validated, and accepted for evaluation of knee injuries. There are promising studies of decision rules for clinically important fractures of the wrist, but these studies have not been validated. The elbow has been evaluated with good outcomes via the elbow extension test, which has been validated in both single and multicenter studies. Currently, there are no reliable clinical decision tools for traumatic sports injuries to the shoulder to aid in the decision of when to obtain radiographs. CONCLUSION: Clinical decision tools have been developed to aid in the diagnosis and management of injuries commonly sustained during sporting events. Tools that have been appropriately validated in populations outside the initial study population can assist sports medicine physicians in the decision of when to get radiographs from the sidelines. PMID- 24790700 TI - Involvement of miRNAs in placental alterations mediated by oxidative stress. AB - Oxidative stress (OS) is known to be strongly involved in a large number of fetal, neonatal, and adult diseases, including placental disorders, leading to pregnancy loss and stillbirths. A growing body of research links OS to preeclampsia, gestational diabetes, obesity, spontaneous abortion, recurrent pregnancy, preterm labor, and intrauterine growth restriction. While a considerable number of miRNAs have been related to physiological functions and pathological conditions of the placenta, a direct link among these miRNAs, placental functions, and OS is still lacking. This review summarizes data describing the role of miRNAs in placental pathophysiological processes and their possible impact on OS damaging responses. As miRNAs can be found in circulation, improving our understanding on their role in the pathogenesis of pregnancy related disorders could have an important impact on the diagnosis and prognosis of these diseases. PMID- 24790701 TI - BMP-2 overexpression augments vascular smooth muscle cell motility by upregulating myosin Va via Erk signaling. AB - BACKGROUND: The disruption of physiologic vascular smooth muscle cell (VSMC) migration initiates atherosclerosis development. The biochemical mechanisms leading to dysfunctional VSMC motility remain unknown. Recently, cytokine BMP-2 has been implicated in various vascular physiologic and pathologic processes. However, whether BMP-2 has any effect upon VSMC motility, or by what manner, has never been investigated. METHODS: VSMCs were adenovirally transfected to genetically overexpress BMP-2. VSMC motility was detected by modified Boyden chamber assay, confocal time-lapse video assay, and a colony wounding assay. Gene chip array and RT-PCR were employed to identify genes potentially regulated by BMP-2. Western blot and real-time PCR detected the expression of myosin Va and the phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Immunofluorescence analysis revealed myosin Va expression locale. Intracellular Ca(2+) oscillations were recorded. RESULTS: VSMC migration was augmented in VSMCs overexpressing BMP-2 in a dose-dependent manner. siRNA-mediated knockdown of myosin Va inhibited VSMC motility. Both myosin Va mRNA and protein expression significantly increased after BMP-2 administration and were inhibited by Erk1/2 inhibitor U0126. BMP-2 induced Ca(2+) oscillations, generated largely by a "cytosolic oscillator". CONCLUSION: BMP-2 significantly increased VSMCs migration and myosin Va expression, via the Erk signaling pathway and intracellular Ca(2+) oscillations. We provide additional insight into the pathophysiology of atherosclerosis, and inhibition of BMP-2-induced myosin Va expression may represent a potential therapeutic strategy. PMID- 24790702 TI - Aging aggravates nitrate-mediated ROS/RNS changes. AB - Nitrates are the most frequently prescribed and utilized drugs worldwide. The elderly are a major population receiving nitrate therapy. Both nitrates and aging can increase in vivo reactive oxygen species (ROS) and reactive nitrogen species (RNS). To date, the effects of aging upon nitrate-induced ROS/RNS alteration are unknown. The present study tested the effects of aging upon nitrate-induced ROS/RNS alteration in vivo. 32 adults and 43 elderly unstable angina (UA) patients were subjected to 48 hours of isosorbide dinitrate intravenous injection (50 MUg/minutes) in this clinical study. Blood samples were obtained at baseline and conclusion. Outcome measures of oxidative stress included plasma malondialdehyde (MDA), myeloperoxidase (MPO), and reduced glutathione (GSH). Plasma concentrations of NOx and nitrotyrosine served as markers of RNS. Because of the significant differences in basic clinical characters between adults and the elderly, we designed an additional experiment determining ROS/RNS stress in rat cardiac tissue. Additionally, rat thoracic aortic NOS activity served as a marker indicating endothelial function. Our study demonstrated that nitrate therapy significantly increased in vivo ROS/RNS stress in the elderly compared to adult patients, confirmed by animal data. Decreased NOS activity was observed in old rats. Taken together, the present study's data suggests a synergism between nitrate treatment and the aging process. PMID- 24790703 TI - Tai Chi exercise increases SOD activity and total antioxidant status in saliva and is linked to an improvement of periodontal disease in the elderly. AB - The aim of this study was to determine the effect of Tai Chi on biological markers of oxidative stress in saliva and its relationship with periodontal disease (PD) in older adults. We carried out a quasi-experimental study with a sample of 71 sedentary volunteers with PD who were divided into a control group of 34 subjects and an experimental group of 37 subjects who performed Tai Chi 5 days a week for a period of 6 months. PD status was characterized using the Periodontal Disease Index (PDI). Superoxide dismutase (SOD), total antioxidant status (TAS), and TBARS levels of both groups were measured by spectrophotometric methods. In addition, inflammation markers (TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10) were measured by flow cytometry. We found a statistically significant increase in SOD activity (P < 0.001) and TAS concentration (P < 0.05), whereas levels of IL-1beta were significantly lower (P < 0.01). Likewise, a statistically significant decrease in the PDI (P < 0.05) was observed in subjects who performed Tai Chi during a period of 6 months. Our findings suggest that the practice of Tai Chi has both antioxidant and anti-inflammatory effects that are linked to the improvement of PD in older adults. PMID- 24790704 TI - Promoter hypermethylation and suppression of glutathione peroxidase 3 are associated with inflammatory breast carcinogenesis. AB - Reactive oxygen species (ROS) play a crucial role in breast cancer initiation, promotion, and progression. Inhibition of antioxidant enzymes that remove ROS was found to accelerate cancer growth. Studies showed that inhibition of glutathione peroxidase-3 (GPX3) was associated with cancer progression. Although the role of GPX3 has been studied in different cancer types, its role in breast cancer and its epigenetic regulation have not yet been investigated. The aim of the present study was to investigate GPX3 expression and epigenetic regulation in carcinoma tissues of breast cancer patients' in comparison to normal breast tissues. Furthermore, we compared GPX3 level of expression and methylation status in aggressive phenotype inflammatory breast cancer (IBC) versus non-IBC invasive ductal carcinoma (IDC). We found that GPX3 mRNA and protein expression levels were downregulated in the carcinoma tissues of IBC compared to non-IBC. However, we did not detect significant correlation between GPX3 and patients' clinical pathological prosperities. Promoter hypermethylation of GPX3 gene was detected in carcinoma tissues not normal breast tissues. In addition, IBC carcinoma tissues showed a significant increase in the promoter hypermethylation of GPX3 gene compared to non-IBC. Our results propose that downregulation of GPX3 in IBC may play a role in the disease progression. PMID- 24790706 TI - Antimalarial Drug Discovery: From Quinine to the Dream of Eradication. AB - The search for antimalarial remedies predates modern medicine and the concept of small molecule chemotherapy, yet has played a central role in the development of both. This history is reviewed in the context of the current renaissance in antimalarial drug discovery, which is seeing modern drug discovery approaches applied to the problem for the first time. Great strides have been made in the past decade, but further innovations from the drug discovery community will be required if the ultimate dream of eradication is to be achieved. PMID- 24790705 TI - The role of antioxidants in skin cancer prevention and treatment. AB - Skin cells are constantly exposed to reactive oxygen species (ROS) and oxidative stress from exogenous and endogenous sources. UV radiation is the most important environmental factor in the development of skin cancer and skin aging. The primary products caused by UV exposure are generally direct DNA oxidation or generation of free radicals which form and decompose extremely quickly but can produce effects that can last for hours, days, or even years. UV-induced generation of ROS in the skin develops oxidative stress when their formation exceeds the antioxidant defense ability. The reduction of oxidative stress can be achieved on two levels: by lowering exposure to UVR and/or by increasing levels of antioxidant defense in order to scavenge ROS. The only endogenous protection of our skin is melanin and enzymatic antioxidants. Melanin, the pigment deposited by melanocytes, is the first line of defense against DNA damage at the surface of the skin, but it cannot totally prevent skin damage. A second category of defense is repair processes, which remove the damaged biomolecules before they can accumulate and before their presence results in altered cell metabolism. Additional UV protection includes avoidance of sun exposure, usage of sunscreens, protective clothes, and antioxidant supplements. PMID- 24790707 TI - Proposal of a "Checklist" for endodontic treatment. AB - OBJECTIVES: On the basis of the "Surgical Checklist" proposed by the WHO, we propose a new Checklist model adapted to the procedures of endodontic treatment. STUDY DESIGN: The proposed document contains 21 items which are broken down into two groups: those which must be verified before beginning the treatment, and those which must be verified after completing it, but before the patient leaves the dentist's office. RESULTS: The Checklist is an easy-to-use tool that requires little time but provides, order, logic and systematization by taking into account certain basic concepts to increase patient safety. DISCUSSION: We believe that the result is a Checklist that is easy to complete and which ensure the fulfillment of the key points on patient safety in the field of endodontics. Key words:Checklist, endodontics, patient safety, adverse event. PMID- 24790708 TI - Microleakage and shear bond strength of orthodontc brackets bonded to hypomineralized enamel following different surface preparations. AB - OBJECTIVES: This study investigated the effects of several conditioning methods on shear bond strength (SBS) and microleakage of orthodontic brackets bonded to demineralized enamel. STUDY DESIGN: One hundred premolars were selected and immersed in a cariogenic solution for 12 weeks. The teeth were randomly assigned into 5 groups. In groups 1 and 2, the teeth underwent acid etching for 30 and 120 seconds, respectively. In group 3, a combination of laser and acid etching was employed. A self-etch primer (SEP) was applied in group 4 and in group 5, the teeth were exposed to acidulated phosphate fluoride (APF) for 4 minutes before etching. After bracket bonding, the teeth were immersed in methylen blue for 12 hours and then were mounted in acrylic resin. SBS was determined with an Instron Universal Testing Machine and the amount of microleakage under the brackets was assessed under a stereomicroscope. RESULTS: The lowest SBS was related to the SEP group and the highest one was observed in the specimens prepared by APF+acid etching. There was a significant difference in SBS (p=0.009), but not in microleakage (p=0.971) of the study groups. The SBS of the specimens treated with SEP was significantly Lower than the other groups, which were not significantly different from each other. The SEP group displayed a higher frequency of bond failure at the enamel-adhesive interface. CONCLUSIONS: Enamel preparation with SEP provided the lowest SBS among the groups. All groups showed some degree of microleakage. There was no significant correlation between SBS and microleakage. Key words:Bond strength, microleakage, bonding, self-etch primer, Er:YAG laser. PMID- 24790709 TI - Prevalence of impacted and supernumerary teeth in the North Indian population. AB - OBJECTIVES: Dental impaction is a very frequent problem. Supernumerary teeth, or hyperdontia, are the presence of additional teeth to the normal series in the either of the dentition. The presence of impacted and/or supernumerary teeth can cause various complications. The objective of the present study was to determine the prevalence of impacted and supernumerary teeth in the North Indian population. STUDY DESIGN: The panoramic radiographic records of 4750 patients attending the Department of Oral Medicine and Radiology, Jodhpur Dental College General Hospital between September 2008 to December 2012 were examined for this retrospective study. The ages of the patients ranged from 8 to 72 years, with a mean of 34.6 years. RESULTS: A total of 798 (16.8%) patients presented with 1126 impacted teeth. Impacted canines were the most prevalent (9.7%), followed by impacted premolars (4.3%). Supernumerary teeth (1.6%) and impacted molars (1.2%) were less prevalent. Among the 842 impacted teeth, the most frequently affected teeth were the canines (56.7%), followed by premolars (27.8%), and supernumerary teeth (9.3%), while the prevalence of impacted molars was quite lower (6.2%). CONCLUSION: The most frequently impacted teeth were maxillary canines and the mesiodens were the most common supernumerary tooth. The early diagnosis of supernumerary and impacted teeth is essential to prevent malocclusion and malalignment of permanent teeth demonstrating the importance of panoramic radiographs in their detection. Key words:Impacted, supernumerary, prevalence, canines, mesiodens. PMID- 24790710 TI - Comparative evaluation of the effect of Er:YAG laser and low level laser irradiation combined with CPP-ACPF cream on treatment of enamel caries. AB - OBJECTIVES: This study investigated the effectiveness of low power red and infrared lasers and that of Er:YAG laser, in association with CPP-ACPF cream, on remineralization of white spot lesions. STUDY DESIGN: Fifty intact premolars were immersed in a demineralization solution for 10 weeks to induce caries like lesions and then were divided into five groups. In group 1, the teeth were covered with a CPP-ACPF cream for 3 minutes and then irradiated with a low power red laser (660 nm, 200 mW) for 1 minute through the cream. In group 2, the treatment was the same as that in group 1, but an infrared laser (810 nm, 200 mW) was employed. The specimens in group 3 were irradiated with an Er:YAG laser (100 mJ, 10 Hz) combined with CPP-ACPF. In group 4, the CPP-ACPF cream was applied for 4 minutes and group 5 was submitted to neither laser nor CPP-ACPF. The micro Vickers hardness was compared at 20, 60 and 100 u from the enamel surface among the groups. RESULTS: The highest microhardness was observed in the low power red and Er:YAG laser groups and the lowest one belonged to the CPP-ACPF alone and control groups. However, no significant difference was found in microhardness of the experimental groups at any of the evaluation depths (p>0.05). CONCLUSIONS: With the laser parameters used in this study, neither the combined application of Er:YAG laser with CPP-ACPF nor the combination of low power lasers with CPP-ACPF provided a significant increase in remineralization of enamel caries. Key words:Low level laser, Er:YAG, laser, enamel caries, CPP-ACP, microhardness, white spot lesion. PMID- 24790711 TI - Orthopantomography contribution to prevent isquemic stroke. AB - OBJECTIVES: The ortopantomography (OPG) can be a valuable way for an early detection of calcified atheroma plaques, thus contributing for a preliminary stroke risk evaluation. The study looks for the existence of calcified atheroma plates through the use of OPG, comparing the results with the stenosis percentage found through eco-doppler. It has been analyzed the correlation of the number of years as a smoker, arterial hypertension and body mass index, against the risk of having calcified atheroma plaques. STUDY DESIGN: Observational, transversal and prospective study with 84 patients from the Dental Center of Hospital Particular de Lisboa. First the patients answered to an inquiry and them they were submitted to an OPG and an eco-doppler. RESULTS AND CONCLUSIONS: It is possible to detect calcified atheroma plaques in the carotid artery through an OPG and patients who have them have got a fifteen fold greater risk of suffering from carotid stenosis. In this study, it has been confirmed the increase in carotid stenosis for long term smokers (OR = 1,033, n=18, 42,9%). The study results show that hypertension patients have a probability 5,426 greater than normal of developing atheroma plaques (with sig=0,049). Amid analyzed patients, the correlation between obesity and the existence of carotid atheroma plaques was significant, although negative (sig=0,047). OPG can help find patients with higher risk of isquemic stroke. Key words:Orthopantomography, Stroke, Carotid disease, Calcified atheroma. PMID- 24790712 TI - Usefulness of salivary alpha amylase as a biomarker of chronic stress and stress related oral mucosal changes - a pilot study. AB - INTRODUCTION: Salivary biomarkers are suggested to provide a reliable, noninvasive and objective measurement of chronic psychosocial stress and helps in assessment of pivotal role of stress in causation or precipitation of multitude of health problems. OBJECTIVES: To evaluate the usefulness of salivary alpha amylase activity as an objective indicator of chronic stress and to find out any correlation between stress- related mucosal complaints and its levels. STUDY DESIGN: Study was conducted among 50 subjects suffering from chronic stress related problems and 50 non-stressed individuals who were screened with a psychometric questionnaire. Brief case history and oral examination was carried out and about one ml of unstimulated saliva was collected. Salivary alpha amylase levels estimated were compared between study and control group and between subjects with and without oral mucosal changes using non parametric Mann Whitney U test. RESULTS: There was statistically significant higher salivary alpha amylase levels in study group (p =.002) and salivary alpha amylase between the oral mucosal complaints group and without oral mucosal complaints group within the total study population were found to be statistically significant (p=0.045). CONCLUSIONS: Salivary amylase activity increases in patients with chronic psychosocial stress and may be used as a biomarker of chronic stress, but it may not be an indicator to suggest the development of stress related oral mucosal changes. Key words:Salivary biomarker, salivary alpha amylase, psychosocial stress, sympathetic nervous system, oral mucosal changes. PMID- 24790713 TI - Testing international dental maturation scoring system and population-specific Demirjian versions on Saudi sub-population. AB - OBJECTIVES: The purpose of this study was to test the applicability of the Demirjian method and revised versions for estimating chronological age (CA) from dental age (DA) in a sample of children. STUDY DESIGN: A sample of 252 individuals of known age (4 to 14 yrs), sex (males: 125, females: 127), and ethnicity (Saudi) was collected. Each individual was aged using the original Demirjian method and revised versions, including Saudi, Kuwaiti, Belgian, and revised international curves. The differences between dental age and chronological age were analyzed using paired sample t-tests with Bonferroni corrections and multinomial regression tests at the 0.05 level of significance. RESULTS: The results indicated an over-aging of the sample as a whole by about 10 months using Demirjian tables, 5.5 months using Kuwaiti tables, 24.7 months using Belgian tables, and 5 months using revised international tables. The sample was under-aged by 0.6 month using Saudi tables. The overall discrepancies between CA and DA were statistically significant (P < 0.0001) for all methods with the exception of Saudi curves. CONCLUSIONS: The findings suggest that the Saudi population method is most accurate on a Saudi population. Key words:Age estimation, juvenile, forensic dentistry, Saudi Arabia. PMID- 24790714 TI - Clinical evaluation of bond failures and survival between mandibular canine-to canine retainers made of flexible spiral wire and fiber-reinforced composite. AB - OBJECTIVES: The purpose of this longitudinal prospective randomized study was to evaluate the clinical reliability of two different types of postorthodontic treatment retainers: a silanised-treated glass fibers-reinforced resin composite (FRC) and a directly bonded multistranded stainless steel wire. The hypothesis of the study was to assess if significant differences are present between failure rates of the two retainers. STUDY DESIGN: This prospective study was based on an assessment of 87 patients (35 men and 52 women),with an average age of 24 years who required a lower arch fixed retainer after orthodontic treatment. Patients were divided in two groups. Assignment was carried out with random tables. A follow-up examination was carried out once a month. The number, cause, and date of single bond adhesive failures were recorded for both retainers over 12 months. Teeth that were rebonded after failure were not included in the success analysis. Statistical analysis was performed by means of a Fisher's exact test, Kaplan Meier survival estimates, and log rank test. RESULTS: Bond failure rate was significantly higher (P=0.0392) for multistranded metallic wire than for FRC. CONCLUSIONS: Glass fiber-reinforced resin composite retainers and multistranded metallic wires showed no significant difference in single bond failure rates over a one-year follow up. Key words:Fiber reinforced composite, fixed retention, multistranded wire, orthodontics, retainer, splint. PMID- 24790715 TI - Etiological factors in second mandibular molar impaction. AB - OBJECTIVES: The impaction of the second mandibular molar (MM2) has recently become more prevalent. Several etiological hypothesis have been proposed to investigate the association between skeletal features and impaction of MM2. The aims of this study were to analyze the skeletal features in patients with MM2 impaction and the association between arrested eruption of MM2 and the presence of the third mandibular molar (MM3). STUDY DESIGN: In this retrospective study 48 subjects from 3,530 Caucasian orthodontic patients with MM2 impaction were included in a study group (SG) and compared to a control group (CG) of 200 subjects without MM2 impaction. Panoramic radiographs evaluated the presence or absence of the MM3 germ. Cephalometric analysis was performed to evaluate linear and angular skeletal values. For the statistical analysis, descriptive statistics, Student's t-test, chi2 test and odds ratio (OR) were used. RESULTS: The paired comparisons between SG and CG showed in cephalometric analysis both a reduced mandibular gonial angle (ArGoMe) and lowered Jarabak's polygon value with a statistically significant difference (P<= 0.05). MM3 was statistically significant associated (P<= 0.05) with MM2 impaction but it is not a risk factor (OR 0.817). CONCLUSIONS: Subjects with MM2 impaction show a vertical condylar growth direction. MM3 is not a risk factor for MM2 impaction. Key words:Impacted mandibular second molar, skeletal features, orthodontic. PMID- 24790716 TI - Dental management of patients receiving anticoagulant and/or antiplatelet treatment. AB - INTRODUCTION: Adequate hemostasis is crucial for the success of invasive dental treatment, since bleeding problems can give rise to complications associated with important morbidity-mortality. The dental treatment of patients who tend to an increased risk of bleeding due to the use of anticoagulant and/or antiplatelet drugs raises a challenge in the daily practice of dental professionals. Adequate knowledge of the mechanisms underlying hemostasis, and the optimized management of such patients, are therefore very important issues. OBJECTIVES: A study is made of the anticoagulant / antiplatelet drugs currently available on the market, with evaluation of the risks and benefits of suspending such drugs prior to invasive dental treatment. In addition, a review is made of the current management protocols used in these patients. MATERIAL AND METHODS: A literature search was made in the PubMed, Cochrane Library and Scopus databases, covering all studies published in the last 5 years in English and Spanish. Studies conducted in humans and with scientific evidence levels 1 and 2 (metaanalyses, systematic reviews, randomized phase 1 and 2 trials, cohort studies and case control studies) were considered. The keywords used for the search were: tooth extraction, oral surgery, hemostasis, platelet aggregation inhibitors, antiplatelet drugs, anticoagulants, warfarin, acenocoumarol. RESULTS AND CONCLUSIONS: Many management protocols have been developed, though in all cases a full clinical history is required, together with complementary hemostatic tests to minimize any risks derived from dental treatment. Many authors consider that patient medication indicated for the treatment of background disease should not be altered or suspended unless so indicated by the prescribing physician. Local hemostatic measures have been shown to suffice for controlling possible bleeding problems resulting from dental treatment. Key words:Tooth extraction, oral surgery, hemostasis, platelet aggregation inhibitors, antiplatelet drugs, anticoagulants, warfarin, acenocoumarol. PMID- 24790717 TI - Forensic dentistry in human identification: A review of the literature. AB - An update is provided of the literature on the role of odontology in human identification, based on a PubMed-Medline search of the last 5 years and using the terms: "forensic dentistry" (n = 464 articles), "forensic odontology" (n = 141 articles) and "forensic dentistry identification" (n = 169 articles). Apart from these initial 774 articles, others considered to be important and which were generated by a manual search and cited as references in review articles were also included. Forensic dentistry requires interdisciplinary knowledge, since the data obtained from the oral cavity can contribute to identify an individual or provide information needed in a legal process. Furthermore, the data obtained from the oral cavity can narrow the search range of an individual and play a key role in the victim identification process following mass disasters or catastrophes. This literature search covering the last 5 years describes the novelties referred to buccodental studies in comparative identification, buccodental evaluation in reconstructive identification, human bites as a method for identifying the aggressor, and the role of DNA in dental identification. The oral cavity is a rich and noninvasive source of DNA, and can be used to solve problems of a social, economic or legal nature. Key words:Forensic identification, DNA, forensic dentistry, rugoscopy, cheiloscopy, saliva. PMID- 24790718 TI - Treatment of recurrent aphthous stomatitis. A literature review. AB - Recurrent aphthous stomatitis (RAS) is the most common chronic disease of the oral cavity, affecting 5-25% of the population. The underlying etiology remains unclear, and no curative treatment is available. The present review examines the existing treatments for RAS with the purpose of answering a number of questions: How should these patients be treated in the dental clinic? What topical drugs are available and when should they be used? What systemic drugs are available and when should they be used? A literature search was made of the PubMed, Cochrane and Scopus databases, limited to articles published between 2008-2012, with scientific levels of evidence 1 and 2 (metaanalyses, systematic reviews, phase I and II randomized clinical trials, cohort studies and case-control studies), and conducted in humans. The results obtained indicate that the management of RAS should be based on identification and control of the possible predisposing factors, with the exclusion of possible underlying systemic causes, and the use of a detailed clinical history along with complementary procedures such as laboratory tests, where required. Only in the case of continuous outbreaks and symptoms should drug treatment be prescribed, with the initial application of local treatments in all cases. A broad range of topical medications are available, including antiseptics (chlorhexidine), antiinflammatory drugs (amlexanox), antibiotics (tetracyclines) and corticosteroids (triamcinolone acetonide). In patients with constant and aggressive outbreaks (major aphthae), pain is intense and topical treatment is unable to afford symptoms relief. Systemic therapy is indicated in such situations, in the form of corticosteroids (prednisone) or thalidomide, among other drugs. Key words:Recurrent aphthous stomatitis, treatment, clinical management. PMID- 24790719 TI - Salivary and crevicular fluid interleukins in gingivitis. AB - INTRODUCTION: Gingivitis is a frequent inflammatory process of the gum tissue that is mainly caused by the accumulation of plaque. The immune response against inflammatory processes is regulated in part by cytokines. AIMS: Given that a continuous inflammation exists in gingivitis, it would be logical to assume that the interleukins will be altered locally in those patients. Therefore, the aim of this review was to check whether there is evidence that the interleukins can be used as diagnostic markers of inflammation levels in patients with gingivitis. MATERIALS AND METHODS: A bibliographical search was undertaken using the key words interleukin and gingivitis in Pubmed, Cochrane, Scopus and Embase. Only those articles published over the last 10 years that were systematic reviews, case-controls or cohort studies in which interleukins in saliva and/or crevicular fluid was investigated in patients with gingivitis were selected. RESULTS: Finally 15 articles were selected, all of them being case-control studies. The interleukins analyzed in the reviewed articles were: IL-1beta, IL-8, IL-18, IL 11, IL-12, TNFalpha, IL-4, IL-17, IL-1alpha and IL-6. The most commonly studied interleukin is IL-1beta and most authors agree that it is higher in the saliva and/or crevicular fluid of patients with gingivitis. Therefore, it could be used as a diagnostic marker of the degree of inflammation in gingivitis. Moreover, as far as the other interleukins studied are concerned, there is no clear consensus among the authors. CONCLUSION: There is sufficient evidence to suggest that IL 1beta in saliva and/or crevicular fluid can be used as a marker of the degree of inflammation in gingivitis. Key words:Interleukins, gingivitis, saliva, crevicular fluid. PMID- 24790720 TI - Peripheral ameloblastoma of the upper gingiva: Report of a case and literature review. AB - According to the 2005 histological classification of odontogenic neoplasms by the World Health Organization, ameloblastoma is a benign, locally invasive epithelial odontogenic tumor of putative enamel organ origin. There are four distinct subgroups in which this neoplasm can be gathered: the solid/multicystic type, the unicystic type, the desmoplastic and the peripheral type. Peripheral ameloblastoma is believed to be the rarest subgroup, making up for 2 to 10% of all ameloblastomas. From its first description by Kuru in 1911 to date, less than 200 cases of PA have been described in literature. PAs commonly affect the mandible, in the maxilla the most common location is the soft palatal tissue of the tuberosity area. The present report discusses a rare case of PA aroused in the gingiva of upper jaw in a 64-year-old woman. The treatment of the lesion and its immunohistochemical phenotype are described. A review of the literature is also performed, focusing on the epidemiological and pathological aspects of the lesions and their implications on the therapy. Key words:Peripheral ameloblastoma, upper gingiva, ameloblastoma. PMID- 24790721 TI - Replantation of a maxillary second molar after removal of a third molar with a dentigerous cyst: Case report and 12-month follow-up. AB - The aim of this study was to describe the replantation of a maxillary second right molar, which had been removed for surgical reasons in order to remove a dentigerous cyst associated with the adjacent third molar, and the case's 12 month follow-up. A 51-year-old man presented swelling in the right maxillary area. Radiographic examination showed a large radiolucency in close proximity to the third molar, suggesting a follicular cyst. The third molar was extracted and the cyst underwent curettage. The second molar had to be extracted to enable complete removal of the cyst and to achieve primary closure of the wound, which would have been impossible without repositioning the molar. With this objective, extraoral endodontic treatment was performed, the root-end was resected and prepared with ultrasonic retrotips, and root-end filling was accomplished with MTA before the molar was replanted. At the 12-month follow-up, the tooth showed no clinical signs or symptoms, probing depth was no greater than 3 mm and radiographic examination showed no evidence of root resorption or periapical lesion. Key words:Replantation, maxillary molar, follicular cyst, dentigerous cyst. PMID- 24790722 TI - Unifocal orofacial granulomatosis in retromolar mucosa: surgical treatment with Er,Cr:YSGG laser. AB - Orofacial granulomatosis is defined by permanent or recurrent swelling of orofacial tissues with different multiform and multifocal clinical patterns. An 11-year old boy presented with a 2-month history of mucosa enlargement. Intraoral examination revealed an erythematous, polylobulated, exophytic lesion with a smooth surface located in retromolar mucosa, non-tender and non-infiltratated to palpation. The diagnosis was inflammatory lesion compatible with pyogenic granuloma and laser excision was decided. Haematological parameters were within normal range, as well as chest Xrays. These findings lead to a diagnosis of non symptomatic orofacial granulomatosis, whose early diagnosis can minimize the impact of systemic-related disorders, like Chron's disease. Key words:Laser, orofacial granulomatosis, childhood, oral lesions, diagnosis. PMID- 24790723 TI - Lingual nerve injury after third molar removal: Unilateral atrophy of fungiform papillae. AB - BACKGROUND: Pain and sensory changes due to lingual nerve injury are one of the most common alterations that follow surgical removal of third molar. They are usually transient but other less common complications, such as the atrophy of fungiform papillae, have an uncertain prognosis. CASE DESCRIPTION: We report a case of a 34-year-old woman who presented a unilateral lingual atrophy of fungiform papillae after third molar extraction accompanied by severe dysesthesia that altered her daily life significantly during the following months and how this complication evolved over time. We conducted a literature review on the different factors that can lead to a lingual nerve injury. CLINICAL IMPLICATIONS: The clinical evolution of temporary and permanent somatosensitve injuries is an important fact to take into consideration during the postoperative management because it will indicate the lesion prognosis. Key words:Lingual nerve, third molar removal, somatosensitive alteration, papillae atrophy, permanent injury, temporary injury. PMID- 24790724 TI - Pregabalin in the treatment of inferior alveolar nerve paraesthesia following overfilling of endodontic sealer. AB - A case of orofacial pain and inferior alveolar nerve (IAN) paraesthesia after extrusion of endodontic sealer within the mandibular canal treated with prednisone and pregabalin is described. A 36-year-old woman underwent root canal treatment of the mandibular second right premolar tooth. Post-operative panoramic radiograph revealed the presence of radiopaque canal sealer in the mandibular canal. Damage to IAN consecutive to extrusion of endodontic sealer was diagnosed. Non-surgical management was decided, including: 1 mg/kg/day prednisone 2 times/day, once-daily regimen, and 150 mg/day pregabalin, two doses per day, monitoring the progress with periodic follow-up visits. Six weeks after the incident the signs and symptoms were gone. The complete resolution of paraesthesia and the control of pain achieved suggest that a non-surgical approach, combining prednisone and the GABA analogue pregabalin, is a good option in the management of the IAN damage subsequent to endodontic sealer extrusion. Key words:Endodontics, inferior alveolar nerve, neuropathic pain, orofacial pain, paraesthesia, pregabalin. PMID- 24790725 TI - Inhibition of macrophage migration inhibitory factor reduces endometriotic implant size in mice with experimentally induced disease. AB - Endometriosis is a debilitating disease common in women of reproductive age characterized by pain and infertility. Macrophage migration inhibitory factor (MIF) is a cytokine whose expression is elevated in endometriotic tissue from women with the disease but the functional role of this factor in the pathogenesis of the disease is uncertain. To examine the role of MIF in the pathogenesis of endometriosis, we induced experimental disease in mice and examined the ability of the MIF antagonist, ISO-1, to reduce endometriotic implant size. Administration of ISO-1 resulted in a significant reduction in implant size and vascularity (as assessed by Flk1 mRNA expression) which was not associated with an alteration in the reproductive cycle. These data suggest that inhibition of MIF activity is associated with a significant reduction in endometriotic implant size and leads us to speculate that a similar approach of targeting MIF may prove useful in treating endometriosis in humans. PMID- 24790726 TI - Autoimmune pancreatitis: pathogenesis, latest developments and clinical guidance. AB - Recently, autoimmune pancreatitis has been classified into two subtypes. Type 1 is related to immunoglobulin G4 and type 2 is related to granulocytic epithelial lesions, but pathogenetic mechanisms in both still remain unclear. Apart from type 2 autoimmune pancreatitis, the pathological features of type 1 autoimmune pancreatitis with increased serum immunoglobulin G4/immunoglobulin E levels, abundant infiltration of immunoglobulin G4+plasmacytes and lymphocytes, fibrosis, and steroid responsiveness are suggestive of abnormal immunity such as allergy or autoimmunity. Although pathophysiological conditions seem to be different in each, both respond well to steroid drugs. After remission, the patients with type 1 autoimmune pancreatitis show high relapse rates (30-50% within 6-12 months), whereas those with type 2 autoimmune pancreatitis seldom relapse. After remission, the steroid maintenance therapy and therapeutic strategy for relapsing patients with type 1 is different among local expertise. In this paper, recent advances in pathogenesis and clinical guidance for therapy are discussed. PMID- 24790728 TI - Pharmacotherapy for obesity: novel agents and paradigms. AB - Public health initiatives focused on obesity prevention and lifestyle intervention programmes for patients with obesity have struggled to contain the obesity epidemic to date. In recent years, antiobesity drug therapies have had a limited role in clinical treatment algorithms for patients with obesity. Indeed, a number of high-profile antiobesity drug suspensions have markedly impacted upon the landscape of obesity pharmacotherapy. In this review, we discuss the advent of an increasing array of pharmacotherapeutic agents, which are effective both in inducing weight loss and in maintaining weight loss achieved by lifestyle measures. The development of these drugs as antiobesity agents has followed varying paths, ranging from lorcaserin, a selective serotonin agent, exploiting the beneficial central actions of fenfluramine but without the associated systemic side effects, to liraglutide, a gut hormone already used as a glucose lowering drug but with appetite-suppressant properties, or the novel drug combination of phentermine/topiramate, two 'old' drugs used in lower doses than with previous therapeutic uses, resulting in an additive effect on weight loss and fewer side effects. We summarize the key findings from recent randomized controlled trials of these three drugs. Although these agents lead to clinically important weight loss when used as monotherapy, the use of antiobesity drugs as adjunctive therapy post intensive lifestyle intervention could prove to be the most successful strategy. Moreover, a progressive approach to obesity pharmacotherapy perhaps offers the best opportunity to finally address the obesity crisis on a mass scale. PMID- 24790727 TI - Update on the therapy of Behcet disease. AB - Behcet disease is a chronic inflammatory systemic disorder, characterized by a relapsing and remitting course. It manifests with oral and genital ulcerations, skin lesions, uveitis, and vascular, central nervous system and gastrointestinal involvement. The main histopathological finding is a widespread vasculitis of the arteries and veins of any size. The cause of this disease is presumed to be multifactorial involving infectious triggers, genetic predisposition, and dysregulation of the immune system. As the clinical expression of Behcet disease is heterogeneous, pharmacological therapy is variable and depends largely on the severity of the disease and organ involvement. Treatment of Behcet disease continues to be based largely on anecdotal case reports, case series, and a few randomized clinical trials. PMID- 24790729 TI - The role of bariatric surgery in the treatment of diabetes. AB - The obesity epidemic contributes to approximately 44% of the world's type 2 diabetes burden. Bariatric surgery is an effective treatment for type 2 diabetes mellitus in patients with morbid obesity as it improves glycaemia, blood pressure, lipids and inflammation. This review describes the evidence supporting the addition of bariatric surgery to the treatment algorithms used by diabetologists. We emphasize the need to view bariatric surgery as an adjuvant therapy which should not be used instead of but rather together with best medical therapy. PMID- 24790730 TI - Apoptosis-Related Single Nucleotide Polymorphisms and the Risk of Non-Small Cell Lung Cancer in Women. AB - BACKGROUND: Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies have looked specifically at apoptosis related SNPs in a racially-stratified analysis of white and African-American women. METHODS: We examined the risk of developing NSCLC associated with 98 germline SNPs in 32 apoptosis-related genes among women in a population-based case-control study from the Detroit metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education. RESULTS: Our logistic regression identified 3 significant apoptosis-related SNPs in whites (APAF-1, rs1007573; CD40 rs3765459, and CD40 rs1535045), and 7 significant SNPs (ATM, rs1801516; BAK1, rs513349; TNF, rs1800629; TP63, rs6790167; TP63, rs7613791, TP63, rs35592567 and TP63, rs3856775) in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites, APAF-1 (rs1007573), CD40 (rs3765459) and CD40 (rs1535045) were all found to be significant by FPRP. In African-Americans, TP63 SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in African-Americans. This procedure identified APAF-1 rs1007573 (OR=1.86, 95% CI: 1.17-2.95) and CD40 rs1535045 (OR=0.58, 95% CI: 0.40-0.84) as significant independent predictors of risk among whites, and ATM rs1801516 (OR=24.15, 95% CI: 3.50-166.55), TNF rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and TP63 rs6790167 (OR: 2.85, 95% CI: 1.33-6.09) as significant, independent predictors in African-Americans. CONCLUSION: In whites, only SNPs APAF-1 rs1007573 and CD40 rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only TP63 rs6790167 was significant by both methodologies. Thus, we have identified three promising variants associated with increased risk of NSCLC that warrant additional investigation in future studies. PMID- 24790731 TI - An outbreak of serogroup C (ST-11) meningococcal disease in Tijuana, Mexico. AB - BACKGROUND: Invasive meningococcal disease (IMD) has been reported to be endemic in children from Tijuana, Mexico and the risk of an outbreak was always a threat. OBJECTIVES: To describe all clinical, epidemiological and microbiological features of a meningococcal outbreak that occurred in Tijuana, Mexico. METHODS: All cases with IMD were admitted at different emergency departments within the city and diagnosed by culture and agglutination tests. Further restriction fragment length polymorphism pulse field gel electrophoresis (RFLP-PFGE) and multi locus sequence typing (MLST) were performed. All clinical and epidemiological characteristics and interventions were evaluated, as well as risk factors associated with mortality. RESULTS: From 30 January 2013 to 30 March 2013 there were 19 cases of IMD all caused by Neisseria meningitidis serogroup C. The median age was 16 years (2-47), with higher frequency among individuals at least 13 years old (73.7%). At admission, meningitis was the main clinical presentation (94.7%), followed by purpura (78.9%), septic shock (42.1%) and disseminated intravascular coagulation (DIC, 36.8%). Overall mortality was seven (36.8%). Variables associated with higher mortality were, at admission, presence of septic shock, DIC and thrombocytopenia less than 70,000. All 19 cases had no identifiable site or cluster as the source of the outbreak. RFLP-PFGE showed a discriminatory power for only one profile on all N. meningitidis strains analyzed and a clone ST-11 was identified in all strains. Public health interventions were continuous case reporting of all suspected cases of IMD, an increase in active surveillance in all hospitals, training of medical and laboratory personnel, massive and rapid chemoprophylaxis to all close contacts as indicated, and promotion of good health habits. CONCLUSIONS: An outbreak with high mortality of IMD occurred in Tijuana, Mexico. This event and evidence of endemicity should encourage health authorities to evaluate meningococcal vaccination in the region. PMID- 24790733 TI - What are our Options in the Fight against Breast Cancer? PMID- 24790732 TI - MHC class I antigen presentation and implications for developing a new generation of therapeutic vaccines. AB - Major histocompatibility complex class I (MHC-I) presented peptide epitopes provide a 'window' into the changes occurring in a cell. Conventionally, these peptides are generated by proteolysis of endogenously synthesized proteins in the cytosol, loaded onto MHC-I molecules, and presented on the cell surface for surveillance by CD8(+) T cells. MHC-I restricted processing and presentation alerts the immune system to any infectious or tumorigenic processes unfolding intracellularly and provides potential targets for a cytotoxic T cell response. Therefore, therapeutic vaccines based on MHC-I presented peptide epitopes could, theoretically, induce CD8(+) T cell responses that have tangible clinical impacts on tumor eradication and patient survival. Three major methods have been used to identify MHC-I restricted epitopes for inclusion in peptide-based vaccines for cancer: genetic, motif prediction and, more recently, immunoproteomic analysis. Although the first two methods are capable of identifying T cell stimulatory epitopes, these have significant disadvantages and may not accurately represent epitopes presented by a tumor cell. In contrast, immunoproteomic methods can overcome these disadvantages and identify naturally processed and presented tumor associated epitopes that induce more clinically relevant tumor specific cytotoxic T cell responses. In this review, we discuss the importance of using the naturally presented MHC-I peptide repertoire in formulating peptide vaccines, the recent application of peptide-based vaccines in a variety of cancers, and highlight the pros and cons of the current state of peptide vaccines. PMID- 24790734 TI - Advances in glomerular filtration rate estimation. PMID- 24790735 TI - Sturge-Weber Syndrome without Facial Nevus. PMID- 24790737 TI - A Brief History of Breast Cancer: Part I: Surgical domination reinvented. PMID- 24790736 TI - The role of vitamin e in human health and some diseases. AB - Vitamin E is the major lipid-soluble component in the cell antioxidant defence system and is exclusively obtained from the diet. It has numerous important roles within the body because of its antioxidant activity. Oxidation has been linked to numerous possible conditions and diseases, including cancer, ageing, arthritis and cataracts; vitamin E has been shown to be effective against these. Platelet hyperaggregation, which can lead to atherosclerosis, may also be prevented by vitamin E; additionally, it also helps to reduce the production of prostaglandins such as thromboxane, which cause platelet clumping. The current literature review discusses the functions and roles of vitamin E in human health and some diseases as well as the consequences of vitamin E deficiency. The main focus of the review is on the tocopherol class of the vitamers. PMID- 24790738 TI - A National Strategy for Promoting Physical Activity in Oman: A call for action. AB - The increasing prevalence of chronic disease in Oman is a public health challenge. Available evidence in Oman on physical inactivity, the fourth leading risk factor for chronic disease, calls for urgent action to reduce physical inactivity as part of a key strategy to address chronic disease in Oman. The public health implications of this evidence for Oman are considered in light of recommendations outlined in the Toronto Charter for Physical Activity. The charter provides a systematic approach of physical activity and outlines an action plan that could be adapted to the Omani context. Urgent intersectoral action focusing on a shared goal and a more deliberate public health response addressing physical inactivity is required. Further research is needed on the determinants of physical inactivity and culturally appropriate interventions in order to guide future public health actions. PMID- 24790739 TI - Epidemiology of Breast Cancer among Bahraini Women: Data from the Bahrain Cancer Registry. AB - OBJECTIVES: The aim of this study was to describe the epidemiology of breast cancer among the Bahraini female population in the years 2000-2010 and examine its health policy implications. METHODS: All breast cancer cases in the Bahrain Cancer Registry from 1(st) January 2000 to 31(st) December 2010 were included. RESULTS: There were 1,005 cases, 12.7% of which were detected by screening. The overall mean age at diagnosis was 50.9 years (95% confidence interval 50.1-51.6). The age-standardised incidence rate declined from 58.2 per 100,000 in 2000 to 44.4 per 100,000 in 2010. The majority of cases were infiltrating ductal carcinoma (76.9%). Of the registered cases, 44.1% and 48.1% had an unknown grade and stage, respectively. The five-year survival rate was 63 +/- 2%. CONCLUSION: The low percentage of cases detected by screening merits further evaluation of Bahrain's screening programme. More effort should be made to reduce the proportion of unknown stage and grade breast cancers. Future research has to be directed towards understanding the reasons for Bahrain having the highest incidence rate of breast cancer in the Gulf Cooperation Council countries. PMID- 24790740 TI - Impaired Fasting Glucose in Omani Adults with no Family History of Type 2 Diabetes. AB - OBJECTIVES: The aim of this study was to estimate the prevalence of impaired fasting glucose (IFG) among Omani adults with no family history (FH) of diabetes and to investigate the factors behind the risk of developing type 2 diabetes (T2D), while excluding a FH of diabetes. METHODS: A total of 1,182 Omani adults, aged >=40 years, visited the Family Medicine & Community Health Clinic at Sultan Qaboos University Hospital, Oman, on days other than the Diabetes Clinic days, from July 2010 to July 2011. The subjects were interviewed and asked if they had T2D or a FH of T2D. RESULTS: Only 191 (16%) reported no personal history of T2D or FH of the disease. Of these, anthropometric and biochemical data was complete in 159 subjects. Of these a total of 42 (26%) had IFG according to the American Diabetes Association criteria. Body mass index, fasting insulin, haemoglobin A1C and blood pressure (BP), were significantly higher among individuals with IFG (P <0.01, P <0.05, P <0.01 and P <0.01, respectively). In addition, fasting insulin, BP and serum lipid profile were correlated with obesity indices (P <0.05). Obesity indices were strongly associated with the risk of IFG among Omanis, with waist circumference being the strongest predictor. CONCLUSION: Despite claiming no FH of diabetes, a large number of Omani adults in this study had a high risk of developing diabetes. This is possibly due to environmental factors and endogamy. The high prevalence of obesity combined with genetically susceptible individuals is a warning that diabetes could be a future epidemic in Oman. PMID- 24790741 TI - Haemostatic Parameters in Patients with Behcet's Disease. AB - OBJECTIVES: This study aimed to evaluate the cause of thrombosis in Behcet's disease (BD) patients, since abnormalities in coagulation and fibrinolytic parameters have shown contradictory results. METHODS: Haemostatic parameters were retrospectively evaluated in BD patients treated between January 2007 and January 2011 at Sultan Qaboos University Hospital, Oman. The blood samples of 35 Omani BD patients and 30 healthy controls were analysed for factor VIII:C levels, activated protein C resistance (APCR), von Willebrand factor (vWF) antigens (Ag), collagen binding and ristocetin co-factor activity (RiCoF), antithrombin (AT), protein C (chromogenic and clotting), protein S, homocysteine, tissue plasminogen activator, plasminogen activator inhibitor, plasminogen, alpha 2-antiplasmin, lupus anticoagulant and anticardiolipin and beta2-glycoprotein-1 antibodies. RESULTS: The mean values of factor VIII:C, vWF Ag, AT and protein S were significantly higher in the patient group (P = 0.01, 0.006, 0.04 and 0.01, respectively). There was no deficiency in protein C. Screening for APCR, anticardiolipin antibodies, anti-beta2-glycoprotein-1 antibodies and lupus anticoagulant was negative and there were no differences in homocysteine levels, nor were there differences between patients with and without thrombosis. Six patients had elevated factor VIII:C levels (>150 IU/dL, P <0.02) which normalised on repeat measurements after three months. CONCLUSION: The elevation of factors VIII:C, vWF Ag and AT most likely represent an acute phase phenomenon. In this study, thrombophilic factors did not seem to explain thrombotic tendency. Therefore, further mechanistic studies in a larger group of patients are needed to elucidate the basis for thrombosis in BD. We hypothesise that active BD causes vasculitic endothelial perturbation with dysfunction, leading to the observed increased propensity for thrombosis. PMID- 24790742 TI - Comparison between Three Different Equations for the Estimation of Glomerular Filtration Rate in Omani Patients with Type 2 Diabetes Mellitus. AB - OBJECTIVES: Estimated glomerular filtration rate (eGFR) is an important component of a patient's renal function profile. The Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease-Epidemiology Collaboration (CKD EPI) equation are both commonly used. The aim of this study was to compare the performance of the original MDRD186, revised MDRD175 and CKD-EPI equations in calculating eGFR in type 2 diabetes mellitus (T2DM) patients in Oman. METHODS: The study included 607 T2DM patients (275 males and 332 females, mean age +/- standard deviation 56 +/- 12 years) who visited primary health centres in Muscat, Oman, during 2011 and whose renal function was assessed based on serum creatinine measurements. The eGFR was calculated using the three equations and the patients were classified based on chronic kidney disease (CKD) stages according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines. A performance comparison was undertaken using the weighted kappa test. RESULTS: The median eGFR (mL/min/1.73 m(2)) was 92.9 for MDRD186, 87.4 for MDRD175 and 93.7 for CKD-EPI. The prevalence of CKD stage 1 was 55.4%, 44.7% and 57% while for stages 2 and 3 it was 43.2%, 54% and 41.8%, based on MDRD186, MDRD175 and CKD EPI, respectively. The agreement between MDRD186 and CKD-EPI (k 0.868) was stronger than MDRD186 and MDRD175 (k 0.753) and MDRD175 and CKD-EPI (k 0.730). CONCLUSION: The performances of MDRD186 and CKD-EPI were comparable. Considering that CKD-EPI-based eGFR is known to be close to isotopically measured GFR, the use of MDRD186 rather than MDRD175 may be recommended. PMID- 24790743 TI - Maternal and fetal outcomes of triplet gestation in a tertiary hospital in oman. AB - OBJECTIVES: The aim of this study was to describe the fetal and maternal outcomes of triplet gestation and to report on the maternal characteristics of those pregnancies in a tertiary care centre in Oman. METHODS: A retrospective study was undertaken of all triplet pregnancies delivered at Sultan Qaboos University Hospital, Muscat, Oman, between January 2009 and December 2011. RESULTS: Over the three-year study period, there were 9,140 deliveries. Of these, there were 18 triplet pregnancies, giving a frequency of 0.2%. The mean gestational age at delivery was 31.0 +/- 3.0 weeks, and the mean birth weight was 1,594 +/- 460 g. The most common maternal complications were preterm labour in 13 pregnancies (72.2%), gestational diabetes in 7 (39%) and gestational hypertension in 5 (28%). Of the total deliveries, there were 54 neonates. Neonatal complications among these included hyaline membrane disease in 25 neonates (46%), hyperbilirubinaemia in 24 (43%), sepsis in 18 (33%) and anaemia in 8 (15%). The perinatal mortality rate was 55 per 1,000 births. CONCLUSION: The maternal and neonatal outcomes of triplet pregnancies were similar to those reported in other studies. PMID- 24790744 TI - A study of post-caesarean section wound infections in a regional referral hospital, oman. AB - OBJECTIVES: The aim of this study was to determine the incidence of surgical site infections (SSI) in patients undergoing a Caesarean section (CS) and to identify risk factors, common bacterial pathogens and antibiotic sensitivity. SSI significantly affect the patient's quality of life by increasing morbidity and extending hospital stays. METHODS: A retrospective cross-sectional study was conducted in Nizwa Hospital, Oman, to determine the incidence of post-Caesarean (PCS) SSI from 2001 to 2012. This was followed by a case-control study of 211 PCS cases with SSI. Controls (220) were randomly selected cases, at the same hospital in the same time period, who had undergone CS without any SSI. Data was collected on CS type, risk factors, demographic profile, type of organism, drug sensitivity and date of infection. RESULTS: The total number of PCS wound infections was 211 (2.66%). There was a four-fold higher incidence of premature rupture of the membranes (37, 17.53%) and a three-fold higher incidence of diabetes (32, 15.16%) in the PCS cases compared with controls. The most common organisms responsible for SSI were Staphylococcus aureus (66, 31.27%) and the Gram-negative Escherichia coli group (40, 18.95%). The most sensitive antibiotics were aminoglycoside and cephalosporin. Polymicrobial infections were noted in 42 (19.90%), while 47 (22.27%) yielded no growth. A high incidence of associated risk factors like obesity, hypertension, anaemia and wound haematoma was noted. CONCLUSION: Measures are recommended to reduce the incidence of SSI, including the implementation of infection prevention practices and the administration of antibiotic prophylaxis with rigorous surgical techniques. PMID- 24790745 TI - Primary School Managers' Knowledge of and Attitude towards Epilepsy among Children in Erbil City, Iraq. AB - OBJECTIVES: This study aimed to determine the knowledge and attitudes of primary school managers regarding epilepsy among school children in Erbil City, Iraq. METHODS: A cross-sectional study was conducted in primary schools between 18 June and 18 August 2013. A total of 80 primary school managers were selected to answer a questionnaire covering three domains: socio-demographical characteristics, knowledge of epilepsy and attitudes towards epilepsy. RESULTS: More than half of the participants (55%) had spent less than 10 years in school administration. More than one-third (37.5%) of the participants believed that epilepsy was an infectious disease, and over half of the respondents (53.75%) stated that epilepsy cannot be treated or prevented. CONCLUSION: Although the respondents' attitudes towards pupils with epilepsy were generally positive, their knowledge of epilepsy was imperfect; thus, an epilepsy education campaign is required. This should focus on the causes of epilepsy and its management. PMID- 24790746 TI - Knowledge and Use of Evidence-based Dentistry among Iranian Dentists. AB - OBJECTIVES: The objective of this study was to assess the knowledge and use of evidence-based dentistry (EBD) among Iranian dentists. METHODS: A cross-sectional survey was conducted by means of a questionnaire among dentists attending the 52(nd) National Annual Congress of the Iranian Dental Association in Tehran in April 2012. The questions covered the participants' level of knowledge and use of EBD. RESULTS: The mean knowledge score of the 310 respondents was 3.66 +/- 1.19 out of a maximum of 5. The majority of the dentists had little (56.1%) or no (20.7%) knowledge of EBD. The main reported barrier to the use of EBD was lack of time (44.1% of respondents) with 42.8% of dentists using the Internet less than one hour per week. CONCLUSION: EBD was not a familiar concept to these Iranian dentists; the majority of them preferred consultation with colleagues over seeking evidence from electronic databases. PMID- 24790747 TI - Adherence to Medications among Type 2 Diabetes Mellitus Patients in Three Districts of Al Dakhliyah Governorate, Oman: A cross-sectional pilot study. AB - OBJECTIVES: This pilot study aimed to assess the medication adherence of type 2 diabetes mellitus (T2DM) patients in three wilayats (districts) of the Al Dakhliyah governorate, Oman, and to identify the probable reasons for medication non-adherence. METHODS: A cross-sectional questionnaire-based pilot survey was conducted among T2DM Omani patients between February and June 2012 to assess their medication adherence and the relationship between their socio-demographic characteristics and adherence levels. RESULTS: A total of 158 patients participated in the survey. The majority of the participants were unemployed or were housewives (66.5%). Forgetfulness was the most frequent reason for medication non-adherence (36.4%). Participants demonstrated an excellent level of adherence to their medicines (median total score = 3). No significant difference in median total adherence scores was observed based on the evaluated parameters. CONCLUSION: The medication adherence of T2DM patients in the area under study was good. A larger study in a wider population is warranted to obtain a more representative picture of this important factor which contributes to public health. PMID- 24790749 TI - Gastrointestinal Basidiobolomycosis: First case report from Oman and literature review. AB - Gastrointestinal basidiobolomycosis (GIB) is a rare fungal infection with few reported cases worldwide. We report here the first case diagnosed in Oman in a previously healthy 5-year-old Omani female child who had been thought initially to have an abdominal malignancy. The case was referred to the Royal Hospital, Muscat, Oman, in July 2012. She was treated successfully with surgical resection and prolonged antifungal therapy (voriconazole). Physicians, including clinicians, radiologists and pathologists, should have a high index of suspicion for GIB when a patient presents with an abdominal mass and fever. PMID- 24790748 TI - Successful Management of Phaeochromocytoma using Preoperative Oral Labetalol and Intraoperative Magnesium Sulphate: Report of four cases. AB - Phaeochromocytoma is a rare neuroendocrine catecholamine-secreting tumour. This type of tumour poses multidimensional anaesthetic challenges as it has an unpredictable clinical course during surgical resection. The alpha-blocking agent phenoxybenzamine remained the mainstay in preoperative preparation before the introduction of beta-blocking agents. We report four cases operated between 2009 2012 at Sultan Qaboos University Hospital, Muscat, Oman. The cases were prepared with oral labetalol, as the alpha-blocking drug phenoxybenzamine was not immediately available. Responses to simulated stress were tested in the theatre before surgery. Anaesthesia was induced under invasive arterial pressure monitoring and magnesium sulphate infusion. Rare intraoperative surges in blood pressure during tumour manipulation were treated with sodium nitroprusside infusions and phentolamine boluses. All of the patients had an uneventful postoperative recovery. Preoperative treatment with labetalol has rarely been reported and can be considered as a potential therapeutic option with optimal patient monitoring if phenoxybenzamine is unavailable. PMID- 24790750 TI - Successful management of a neglected case of nephropathic cystinosis. AB - Cystinosis is a rare metabolic disorder characterised by lysosomal cystine accumulation leading to multi-organ damage; clinically, the kidneys are the first organ affected. Respiratory insufficiency caused by overall respiratory muscle myopathy is a life-threatening complication. Treatment with cysteamine should be initiated rapidly and continued lifelong to prolong renal function and protect the extra-renal organs. We report the case of a four-year-old Omani girl, diagnosed with infantile nephropathic cystinosis at 21 months. Cysteamine was prescribed but with no compliance to medications. She presented to the Child Health Department of Sultan Qaboos University Hospital, Oman, two years later with severe failure to thrive, electrolyte disturbance and respiratory failure. The hypoventilation and early respiratory dysfunction, due to intercostal and diaphragm myopathy, was treated by non-invasive positive-pressure ventilation. The patient was discharged after four months of intensive rehabilitation with no ventilator support. No standard treatment options have yet been established for respiratory dysfunction in cystinosis. PMID- 24790751 TI - Sclerosing Mucoepidermoid Carcinoma: A unique case. AB - Sclerosing mucoepidermoid carcinoma is an unusual type of mucoepidermoid carcinoma with special histological features which differ from those of the classic type of mucoepidermoid carcinoma. We report the case of a 32-year-old male, who reported to the Vydehi Institute of Dental Sciences, Bangalore, India, with an asymptomatic swelling over the right parotid region which had been present for the previous two and a half years. Histopathological sections of the tumour mass showed mucous and epidermoid cell nests in a dense, hyalinised, sclerotic stroma. A diagnosis of sclerosing mucoepidermoid carcinoma was made. A superficial parotidectomy was performed on the patient and he has remained disease free to date. PMID- 24790752 TI - Giant Prostatic Hyperplasia: Fourth largest prostate reported in medical literature. AB - A giant prostatic hyperplasia (GPH) weighing more than 700 g is a rare entity. It is believed that only eight such cases have been previously reported in the medical literature. This case report concerns a patient with a GPH weighing 740 g which was successfully removed by suprapubic prostatectomy. To our knowledge, this is the fourth largest benign prostatic enlargement ever reported in the literature. PMID- 24790753 TI - Three-year-old Girl with Sturge-Weber Syndrome without Facial Nevus. PMID- 24790754 TI - Pseudopyropoikilocytosis leading to spurious results. PMID- 24790755 TI - Bilateral Elastofibroma dorsi: Synchronic or sequential surgery? PMID- 24790756 TI - Re: perinatal mortality rate as a quality indicator of healthcare in Al dakhiliyah region, oman. PMID- 24790757 TI - In Silico Analysis of beta-Galactosidases Primary and Secondary Structure in relation to Temperature Adaptation. AB - beta -D-Galactosidases (EC 3.2.1.23) hydrolyze the terminal nonreducing beta -D galactose residues in beta -D-galactosides and are ubiquitously present in all life forms including extremophiles. Eighteen microbial beta -galactosidase protein sequences, six each from psychrophilic, mesophilic, and thermophilic microbes, were analyzed. Primary structure reveals alanine, glycine, serine, and arginine to be higher in psychrophilic beta -galactosidases whereas valine, glutamine, glutamic acid, phenylalanine, threonine, and tyrosine are found to be statistically preferred by thermophilic beta -galactosidases. Cold active beta galactosidase has a strong preference towards tiny and small amino acids, whereas high temperature inhabitants had higher content of basic and aromatic amino acids. Thermophilic beta -galactosidases have higher percentage of alpha -helix region responsible for temperature tolerance while cold loving beta galactosidases had higher percentage of sheet and coil region. Secondary structure analysis revealed that charged and aromatic amino acids were significant for sheet region of thermophiles. Alanine was found to be significant and high in the helix region of psychrophiles and valine counters in thermophilic beta -galactosidase. Coil region of cold active beta -galactosidase has higher content of tiny amino acids which explains their high catalytic efficiency over their counterparts from thermal habitat. The present study has revealed the preference or prevalence of certain amino acids in primary and secondary structure of psychrophilic, mesophilic, and thermophilic beta -galactosidase. PMID- 24790758 TI - Angiotensinogen Variants among Resistant Hypertensive Patients. PMID- 24790759 TI - National Trends in the Adoption of Laparoscopic Cholecystectomy over 7 Years in the United States and Impact of Laparoscopic Approaches Stratified by Age. AB - Introduction. The aim of this study was to characterize national trends in adoption of laparoscopic cholecystectomy and determine differences in outcome based on type of surgery and patient age. Methods. Retrospective cross-sectional study of patients undergoing cholecystectomy. Trends in open versus laparoscopic cholecystectomy by age group and year were analyzed. Differences in outcomes including in-hospital mortality, complications, discharge disposition, length of stay (LOS), and cost are examined. Results. Between 1999 and 2006, 358,091 patients underwent cholecystectomy. In 1999, patients aged >=80 years had the lowest rates of laparoscopic cholecystectomy, followed by those aged 65-79, 64 50, and 49-18 years (59.7%, 65.3%, 73.2%, and 83.5%, resp., P < 0.05). Laparoscopic cholecystectomy was associated with improved clinical and economic outcomes across all age groups. Over the study period, there was a gradual increase in laparoscopic cholecystectomy performed among all age groups during each year, though elderly patients continued to lag significantly behind their younger counterparts in rates of laparoscopic cholecystectomy. Conclusion. This is the largest study to report trends in adoption of laparoscopic cholecystectomy in the US in patients stratified by age. Elderly patients are more likely to undergo open cholecystectomy. Laparoscopic cholecystectomy is associated with improved clinical outcomes. PMID- 24790761 TI - Production of bioactive compounds by actinomycetes and their antioxidant properties. AB - An actinomycete was isolated from mangrove soil collected from Nellore region of Andhra Pradesh, India, and screened for its ability to produce bioactive compounds. The cultural, morphological, and biochemical characters and 16S rRNA sequencing suggest that the isolated strain is Nocardiopsis alba. The bioactive compounds produced by this strain were purified by column chromatography. The in vitro antioxidant capacity of the isolated compounds (fractions) was estimated and fraction F2 showed very near values to the standard ascorbic acid. The potential fraction obtained by column chromatography was subjected to HPLC for further purification, then this purified fraction F2 was examined by FTIR, NMR, and mass spectroscopy to elucidate its chemical structure. By spectral data, the structure of the isolated compound was predicted as "(Z)-1-((1-hydroxypenta-2,4 dien-1-yl)oxy)anthracene-9,10-dione." PMID- 24790760 TI - The novel diagnostic biomarkers for focal segmental glomerulosclerosis. AB - Background. Focal segmental glomerulosclerosis (FSGS) is a glomerular injury with various pathogenic mechanisms. Urine proteome panel might help in noninvasive diagnosis and better understanding of pathogenesis of FSGS. Method. We have analyzed the urine sample of 11 biopsy-proven FSGS subjects, 8 healthy controls, and 6 patients with biopsy-proven IgA nephropathy (disease controls) by means of liquid chromatography tandem mass spectrometry (nLC-MS/MS). Multivariate analysis of quantified proteins was performed by principal component analysis (PCA) and partial least squares (PLS). Results. Of the total number of 389 proteins, after multivariate analysis and additional filter criterion and comparing FSGS versus IgA nephropathy and healthy subjects, 77 proteins were considered as putative biomarkers of FSGS. CD59, CD44, IBP7, Robo4, and DPEP1 were the most significant differentially expressed proteins. These proteins are involved in pathogenic pathways: complement pathway, sclerosis, cell proliferation, actin cytoskeleton remodeling, and activity of TRPC6.There was complete absence of DPEP1 in urine proteome of FSGS subjects compared with healthy and disease controls. DPEP1 acts via leukotrienes on TRPC6 and results in increased podocyte motility and proteinuria. Conclusion. The results suggest a panel of candidate biomarkers for noninvasive diagnosis of FSGS, while complete absence of DPEP1 might represent a novel marker of FSGS. PMID- 24790762 TI - Recurrent Wernicke's Encephalopathy in a 16-Year-Old Girl with Atypical Clinical and Radiological Features. AB - Background. Wernicke's Encephalopathy (WE) is a clinical diagnosis with serious neurological consequences. Its occurrence is underestimated in nonalcoholics and is uncommon in adolescents. We aim to draw the attention to a rare case, which had additional clinical and radiological features. Case. A 16-year-old girl presented with three-week history of vomiting secondary to intestinal obstruction. She developed diplopia soon after hospitalization. Neurological evaluation revealed restriction of bilateral lateral recti with horizontal nystagmus, and bilateral limb dysmetria. Brain MRI was normal. She had prompt improvement to thiamine. Four months later, she presented with headache, bilateral severe deafness, and tinnitus. Clinically, she had severe sensorineural hearing loss, bilateral lateral recti paresis, and gait ataxia. CT head showed bilateral caudate nucleus hypodensities. MRI brain revealed gadolinium enhancement of mamillary bodies and vermis. She had significant improvement after IV thiamine. Headache completely resolved while the ocular movements, hearing, and tinnitus improved partially in 72 hours. Conclusions. Recurrent WE in adolescence is uncommon. Headache, tinnitus, and deafness are rare clinical features. Although MRI study shows typical features of WE, the presence of bilateral caudate nuclei hypodensities on CT scan is uncommon. Prompt treatment with thiamine is warranted in suspected cases to prevent permanent neurological sequelae. PMID- 24790763 TI - Multiple cranial nerve palsies as the first presentation of sarcoidosis. AB - Sarcoidosis is a disease process which predominantly affects the lungs but can involve virtually any organ in the human body. Neurosarcoidosis is a rare manifestation which can present in a variety of ways. There is no single diagnostic test for sarcoidosis; hence, the diagnosis is based on combined clinical, laboratorial, and radiological grounds. We describe a rare case where a patient presented with dysphagia, hoarseness, hearing loss, and unsteadiness. PMID- 24790764 TI - Isolated retroperitoneal hydatid cyst invading splenic hilum. AB - Introduction. Hydatid disease (HD) is an infestation that is caused by the larval stage of Echinococcus granulosus. The liver is affected in approximately two thirds of patients, the lungs in 25%, and other organs in a small proportion. Primary retroperitoneal hydatid cyst is extremely rare. The most common complaint is abdominal pain; however, the clinical features of HD may be generally dependent on the location of the cyst. Case Presentation. A 43-year-old female was admitted with the complaint of abdominal pain. Her physical examination was normal. Computed tomography (CT) revealed a 17 * 11 cm cystic lesion, with a thick and smooth wall that is located among the left liver lobe, diaphragm, spleen, tail of the pancreas, and transverse colon and invading the splenic hilum. Total cystectomy and splenectomy were performed. Pathological examination was reported as cyst hydatid. Discussion. Cysts in the peritoneal cavity are mainly the result of the spontaneous or traumatic rupture of concomitant hepatic cysts or surgical inoculation of a hepatic cyst. Serological tests contribute to diagnosis. In symptomatic and large hydatid peritoneal cysts, surgical resection is the only curative treatment. Total cystectomy is the gold standard. Albendazole or praziquantel is indicated for inoperable and disseminated cases. Percutaneous aspiration, injection, and reaspiration (PAIR) technique is another nonsurgical option. PMID- 24790765 TI - Utilization of a continuous external tissue expansion system to assist in primary closure of a large anterolateral thigh donor site defect. AB - Primary closure of a large anterolateral thigh (ALT) flap donor site defect with the assistance of an external tissue expansion system is presented. The dimensions of this donor site (12 cm * 40 cm) and its percentage of leg circumference (34%) would make this site likely to require skin grafting or further flap coverage based on the results of previously published literature. PMID- 24790766 TI - Long-term results of combined tunica albuginea plication and penile prosthesis implantation for severe penile curvature and erectile dysfunction. AB - Penile prosthesis implantation is the recommended treatment in patients with penile curvature and severe erectile dysfunction (ED) not responding to pharmacotherapy. Most patients with mild-to-moderate curvature can expect cylinder insertion to correct both ED and penile curvature. In patients with severe curvature and in those with persistent curvature after corporeal dilation and prosthesis placement, intraoperative penile "modelling" over the inflated prosthesis has been introduced as an effective treatment. We report for the first time the long-term results of a patient treated with combined penile plication and placement of an inflatable penile prosthesis. PMID- 24790768 TI - Pathological conditions associated with the male reproductive tract of the sahel bucks. AB - The study of pathological conditions of the male reproductive system is paramount to understanding reproductive inefficiency in the Sahel goat. In this study, 1048 Sahel bucks presented for slaughter at the Maiduguri metropolitan abattoir were evaluated for the presence of various pathological abnormalities of the reproductive system. A total incidence of 15.08% was recorded for various pathological conditions, with testicular, penile, and scrotal conditions having incidences of 7.82%, 4.80 and 2.50%, respectively. Bilateral testicular hypoplasia and atrophy and unilateral cryptorchidism accounted for incidences of 4.10%, 2.38%, and 1.24%, respectively, while paraphimosis and scrotal laceration had incidences of 1.72% and 1.05%, respectively. Age specific incidence of pathological conditions were not significant (P > 0.05) between bucks aged <1-1.5 and 2-2.5 years. However, bucks aged 3-3.5 year a had lower (P < 0.05) incidence of pathological conditions than other age groups. Histopathological evidence of inflammation, degeneration, and atrophy was observed in the testes, while inflammatory changes were observed in the prepuce. PMID- 24790767 TI - The Serum S100B Level as a Biomarker of Enteroglial Activation in Patients with Ulcerative Colitis. AB - Objective. Recent studies have demonstrated that enteric glial cells (EGC) participate in the homeostasis of the gastrointestinal tract. This study investigated whether enteroglial markers, including S100B protein and glial fibrillary acidic protein (GFAP), can serve as noninvasive indicators of EGC activation and disease activity in UC patients. Methods. This clinical prospective study included 35 patients with UC and 40 age- and sex-matched controls. The diagnosis of UC was based on standard clinical, radiological, endoscopic, and histological criteria. Clinical disease activity was evaluated using the Modified Truelove-Witts Severity Index. Serum samples were analyzed for human GFAP and S100B using commercial enzyme-linked immunosorbent assay kits. Results. GFAP was not detected in the serum of either UC patients or controls (P > 0.05). However, we found a significant (P < 0.001) decrease in the serum S100B levels in the UC patients. No correlation between the serum S100B level and the disease activity or duration was observed (P > 0.05). The serum S100B levels did not differ between UC patients with active disease (24 patients, 68.6%) or in remission (11 patients, 31.4%) (P > 0.05). Conclusions. Ulcerative colitis patients had significantly lower serum S100B levels, while GFAP was of no diagnostic value in UC patients. PMID- 24790769 TI - Erratum to "Apparent Prevalence of Beef Carcasses Contaminated with Mycobacterium avium subsp. paratuberculosis Sampled from Danish Slaughter Cattle". PMID- 24790770 TI - Establishment, culture, and characterization of Guinea pig fetal fibroblast cell. AB - Establishment of Guinea pig fetal fibroblast cells and their biological evaluation before and after cryopreservation were the main purposes of this study. After determination of the proper age of pregnancy by ultrasonography, 30 days old fetuses of Guinea pigs were recovered. Their skins were cut into small pieces (1 mm(2)) and were cultured. When reaching 80-90% confluence, the cells were passaged. Cells of the second and eighth passages were cultured in 24-well plates (4 * 10(4) cells/well) for 6 days and three wells per day were counted. The average cell counts at each time point were then plotted against time and the population doubling time (PDT) was determined. Then, vials of cells (2 * 10(6) cells/mL) were cryopreserved for 1 month and after thawing, the cell viability was evaluated. The PDT of the second passage was about 23 h and for the eighth passage was about 30 h. The viability of the cultures was 95% in the second passage and 74.5% in the eighth passage. It was shown that the Guinea pig fetal fibroblast cell culture can be established using the adherent culture method while, after freezing, the viability indices of these cells were favorable. PMID- 24790771 TI - Optimization of fluorometric assay for ozone in solution. AB - Ozone is widely used for sterilization, deodorization, and cleaning. However, the effects of ozone on human are not well understood, because there is currently no reliable assay method for ozone. Therefore the accurate measurement of ozone is important for its safe use. Here, we report optimized conditions for use with fluorescein derivative 1 (probe 1). Under optimum conditions, probe 1 reacted with ozone quantitatively and specifically to generate a fluorescent substance with an excitation maximum at 493 nm and an emission maximum at 523 nm. We conclude that this assay will be useful for quantifying ozone in solution. PMID- 24790772 TI - The Role of Helicobacter pylori Seropositivity in Insulin Sensitivity, Beta Cell Function, and Abnormal Glucose Tolerance. AB - Infection, for example, Helicobacter pylori (H. pylori), has been thought to play a role in the pathogenesis of type 2 diabetes mellitus (T2DM). Our aim was to determine the role of H. pylori infection in glucose metabolism in an American cohort. We examined data from 4,136 non-Hispanic white (NHW), non-Hispanic black (NHB), and Mexican Americans (MA) aged 18 and over from the NHANES 1999-2000 cohort. We calculated the odds ratios for states of glucose tolerance based on the H. pylori status. We calculated and compared homeostatic model assessment insulin resistance (HOMA-IR) and beta cell function (HOMA-B) in subjects without diabetes based on the H. pylori status. The results were adjusted for age, body mass index (BMI), poverty index, education, alcohol consumption, tobacco use, and physical activity. The H. pylori status was not a risk factor for abnormal glucose tolerance. After adjustment for age and BMI and also adjustment for all covariates, no difference was found in either HOMA-IR or HOMA-B in all ethnic and gender groups except for a marginally significant difference in HOMA-IR in NHB females. H. pylori infection was not a risk factor for abnormal glucose tolerance, nor plays a major role in insulin resistance or beta cell dysfunction. PMID- 24790773 TI - Frequencies and specificities of "enzyme-only" detected erythrocyte alloantibodies in patients hospitalized in austria: is an enzyme test required for routine red blood cell antibody screening? AB - The aim of this study was to determine the frequencies and specificities of "enzyme-only" detected red blood cell (RBC) alloantibodies in the routine antibody screening and antibody identification in patients hospitalized in Austria. Routine blood samples of 2420 patients were investigated. The antibody screening was performed with a 3-cell panel in the low-ionic strength saline- (LISS-) indirect antiglobulin test (IAT) and with an enzyme-pretreated (papain) 3 cell panel fully automated on the ORTHO AutoVue Innova System. The antibody identification was carried out manually with an 11-cell panel in the LISS-IAT and with an enzyme-pretreated (papain) 11-cell panel. In total 4.05% (n = 98) of all patients (n = 2420) had a positive RBC antibody screening result. Of them 25.51% (25/98) showed "enzyme-only" detected specific or nonspecific RBC alloantibodies. Rhesus and Lewis system antibodies were found the only specificities of "enzyme only" RBC alloantibodies: all in all 4.8% (4/98) were detected with anti-E, 3.06% (3/98) with anti-Le(a), 3.06% (3/98) with anti-D after anti-D prophylaxis and 1.02% (1/98) with anti-e. In total, 14.29% (14/98) showed a nonspecific RBC alloantibody result with the enzyme test. The results of the present study demonstrate that a high number of unwanted positive reactions with the enzyme technique overshadows the detection of "enzyme-only" RBC alloantibodies. ( TRIAL REGISTRATION: K-37-13). PMID- 24790774 TI - Validation of measures from the smartphone sway balance application: a pilot study. AB - PURPOSE/BACKGROUND: A number of different balance assessment techniques are currently available and widely used. These include both subjective and objective assessments. The ability to provide quantitative measures of balance and posture is the benefit of objective tools, however these instruments are not generally utilized outside of research laboratory settings due to cost, complexity of operation, size, duration of assessment, and general practicality. The purpose of this pilot study was to assess the value and validity of using software developed to access the iPod and iPhone accelerometers output and translate that to the measurement of human balance. METHODS: Thirty healthy college-aged individuals (13 male, 17 female; age = 26.1 +/- 8.5 years) volunteered. Participants performed a static Athlete's Single Leg Test protocol for 10 sec, on a Biodex Balance System SD while concurrently utilizing a mobile device with balance software. Anterior/posterior stability was recorded using both devices, described as the displacement in degrees from level, and was termed the "balance score." RESULTS: There were no significant differences between the two reported balance scores (p = 0.818. Mean balance score on the balance platform was 1.41 +/- 0.90, as compared to 1.38 +/- 0.72 using the mobile device. CONCLUSIONS: There is a need for a valid, convenient, and cost-effective tool to objectively measure balance. Results of this study are promising, as balance score derived from the Smartphone accelerometers were consistent with balance scores obtained from a previously validated balance system. However, further investigation is necessary as this version of the mobile software only assessed balance in the anterior/posterior direction. Additionally, further testing is necessary on a healthy populations and as well as those with impairment of the motor control system. LEVEL OF EVIDENCE: Level 2b (Observational study of validity)(1.) PMID- 24790775 TI - Feasibility and reliability of dynamic postural control measures in children in first through fifth grades. AB - PURPOSE/BACKGROUND: Although dynamic postural control is a prerequisite to the development of fundamental movement skills in children, few studies have examined the feasibility and reliability of assessment techniques that measure dynamic postural control in youth under 13 years of age. Therefore, the purpose of this study was to determine the feasibility and reliability of the Lower Quarter Y Balance Test (YBT-LQ) in children and to examine the reproducibility of these measures across developmental periods of childhood. METHODS: 188 subjects in first through fifth grades (age = 6.9 to 12.1 yr) performed the YBT-LQ on two occasions in a field-based setting. Reach distances and cumulative score (sum of 3 directions) were measured and analyzed using intraclass correlation coefficients (ICC). Sub-cohorts of 14 and 8 subjects were used to assess inter rater reliability within-session and between-session, respectively. RESULTS: The overall ICC was moderate-to-good for the anterior (right=0.82; left=0.82), posteromedial (right=0.77; left=0.75), and posterolateral (right 0.80; left=0.77) reach directions. The combined ICC was also moderate-to-good for children in grades 1 (0.71), 2 (0.74), 3 (0.84), 4 (0.82), and 5 (0.79). Typical error values for right and left limbs were less than 10% of the mean for all reach measures across all grades. Interrater reliability within session (ICC > 0.995) and between sessions (0.907 <= ICC <= 0.974) were both excellent. No unexpected responses or injury occurred during testing. CONCLUSIONS: These findings indicate that the YBT-LQ is a feasible and reproducible measure of dynamic postural control in children in first through fifth grades. LEVEL OF EVIDENCE: 2b. PMID- 24790776 TI - Effect of injury prevention training on knee mechanics in female adolescents during puberty. AB - PURPOSE/BACKGROUND: Female adolescents change their landing mechanics during puberty. It is unknown whether implementation of anterior cruciate ligament (ACL) injury prevention training reduces the loss of knee control in female athletes during puberty. The purpose of this study was to evaluate the effect of injury prevention training on dynamic knee alignment in female basketball players specifically when the knee mechanics were changing during puberty. METHODS: Sixty female junior high school basketball players participated and were divided into two groups: a training group (n = 32) and a control group (n = 28). The training group underwent an injury prevention program for 6 months, whereas the control group maintained a regular training routine. The knee valgus motion and knee flexion range of motion during a drop vertical jump were measured before and after the training period. The probability of a high knee abduction moment (pKAM) was also evaluated using an ACL injury prediction algorithm. RESULTS: The knee valgus motion was significantly increased in the control group (p < 0.001), whereas it did not change in the training group (p = 0.64). Similarly, the knee flexion range of motion was significantly decreased in the control group (p < 0.001), whereas it was not changed in the training group (p = 0.55). The pKAM was significantly increased in the control group (p < 0.001), but not in the training group (p = 0.06). CONCLUSIONS: Implementation of injury prevention training was effective in limiting the loss of knee control in female athletes during puberty. Lowering the risk of ACL injury might be possible in this population. LEVEL OF EVIDENCE: 2b. PMID- 24790777 TI - Effects of hip strengthening on early outcomes following anterior cruciate ligament reconstruction. AB - PURPOSE/BACKGROUND: It is not clear whether the addition of hip strengthening exercises will improve outcomes during the early stages of ACL rehabilitation. The purpose of this study was to determine the effects of the addition of isolated hip strengthening exercises to traditional rehabilitation on early outcomes (within the first 3 months) after ACL reconstruction (ACLR). METHODS: A total of 43 subjects (18.8+/-6.9, 21 females, 22 males) who were in the process of rehabilitation following ACLR participated. Subjects were randomly assigned to one of two different treatment groups (1= traditional rehabilitation [NoHip], 2= traditional plus isolated hip strengthening rehabilitation [Hip]). Assessment included the International Knee Documentation Committee (IKDC) Subjective Knee Form, Visual Analog Scale (VAS) for pain during activities of daily living, and knee extension range of motion (ROM) side to side difference taken at weeks 1, 4, 8, and 12. In addition, dynamic balance was assessed with the Y Balance TestTM at 8 and 12 weeks. A mixed model repeated measures ANOVA was performed for IKDC, VAS, and ROM. A one-way ANOVA was used to assess mean group differences for Y Balance Test - Lower Quarter (YBT-LQ) side to side difference scores at 8 and 12 weeks. RESULTS: There was no significant interaction for group by time across VAS (p = .463), IKDC (p = .819), or ROM (p = .513) side to side differences A significant difference was found between groups for YBT-LQ Anterior Reach (ANT) side to side difference at 12 weeks (p = .008) with the Hip group demonstrating smaller side to side reach differences than the NoHip group. No significant side to side differences were seen between groups for YBT-LQ Posteromedial (PM) or Posterolateral (PL) at 12 weeks (PM: p = .254; PL: p = .617). CONCLUSIONS: Rehabilitation including hip strengthening exercises appears to improve sagittal plane dynamic balance at three months post ACLR as compared to traditional rehabilitation. No differences were seen between groups for pain, ROM, and subjective function during the first 3 months following ACLR. LEVEL OF EVIDENCE: Level 2b. PMID- 24790778 TI - Associations between knee extensor power and functional performance in patients after total knee arthroplasty and normal controls without knee pain. AB - PURPOSE/BACKGROUND: Deficits in functional abilities persist after total knee arthroplasty (TKA), while static measures of knee extensor strength (e.g. isometric contractions) are related to functional performance, little is known about the associations between functional ability and dynamic knee extensor strength (e.g. power). With the growing rate of these procedures, in a progressively younger and more active cohort, a better understanding of the functional importance of dynamic strength (muscle power) is needed. The purpose of this study was to examine the associations between functional performance and peak knee extensor power (isokinetic and isotonic measures) from patients after unilateral TKA. DESIGN: Cross-sectional, controlled laboratory study, with correlation and regression analyses. SETTING: Institutional clinic and research laboratory. PARTICIPANTS: Patients 6 months after TKA (N=24, 12 men and women), most of whom were mildly to very active. A normal control group without knee pain (CON; N=22, 10 men and 12 women) was also assessed for comparison. MAIN OUTCOME MEASURES: Static and dynamic strength measures were assessed during normalized voluntary isometric contractions (NMVIC), isokinetic contractions at three velocities (60, 90, and 120 deg/s), and isotonic contractions against three body weight normalized resistances (20, 30 and 40% BW). Functional performance was assessed using the timed up-and-go (TUG), stair climbing test (SCT), and 6- minute walk (6MW). Analyses of the relationships between functional performance measures and peak knee extensor NMVIC and power were performed. Regression analyses predicting functional performance from power were also performed after controlling for NMVIC. RESULTS: Peak power across isokinetic velocities, isotonic resistances, and NMVICs were correlated with the functional performance measures for the TKA group. Unlike the TKA group, functional performance was not significantly associated with peak power across all isokinetic velocities and isotonic resistances (e.g no significant associations between peak isotonic power and 6MW distance). In the TKA group, inclusion of the isotonic power against 30% BW, after controlling for NMVIC, improved the predictability of all three functional performance tests; TUG (p= 0.022), SCT (p=0.006), and 6MW (p=0.001). CONCLUSIONS: Measurements of knee extensor power may be a useful tool for clinicians when assessing and setting milestones during rehabilitation. LEVEL OF EVIDENCE: Prospective cohort study, level II. PMID- 24790779 TI - A criterion based sling weaning progression (sweap) and outcomes following shoulder arthroscopic surgery in an active duty military population. AB - INTRODUCTION: Little objective evidence is available to guide rehabilitation protocols in regard to the sling weaning process following arthroscopy surgery of the shoulder. The purpose of this study was to establish an objective, criterion based protocol for accelerated sling weaning following shoulder arthroscopy. METHODS: 82 active duty service members (ADSM) underwent elective shoulder arthroscopic surgery by three orthopaedic staff surgeons. One physical therapist progressed patients through the criterion based sling weaning progression (SWEAP) protocol for each surgery and documented pain levels, sleep habits, and decrease in sling use. Preoperative and six month postoperative Quick Disability of the Arm, Shoulder, and Hand (qDASH) and Shoulder Pain and Disability Index (SPADI) scores were obtained. The ability to perform an Army Physical Fitness Test (APFT) was recorded at six months postoperative. RESULTS: Patients completed sling weaning at an overall mean of 16.6 +/- 5.0 days with continued use in unprotected military settings only beyond this timeframe. As patients steadily progressed out of the sling for 1 hour, 2-3 hours, and half-day periods, average pain scores decreased during these time periods at 5.0+/-1.2, 3.7+/-1.2, and 2.1+/-1.3 (0-10 pain scale), respectively. Patients obtained 6-7 hours of sleep or normal sleep habits at an average of 10.9+/-4.4 days postoperative. Overall, preoperative qDASH and SPADI scores improved from 39.8+/-13.0 to 2.4+/-2.0 and 46.4+/-16.1 to 3.3+/-3.2, respectively, at 6 months follow up. All 82 patients were able to return to deployable status. 30 (36.6%) patients required formal restrictions for the push-up portion of the APFT at six months postoperative. 7 of these 30 patients required running restrictions. CONCLUSIONS: Early improvement in quality of life indicators can be obtained in the initial postoperative period with a progressive, criterion based SWEAP protocol. Patients demonstrated favorable outcomes with return to occupational and physical fitness activities. This study will guide orthopedic surgeons and physical therapists to enhance the sling weaning process during rehabilitation protocols and improve preoperative counseling sessions for accurate postoperative expectations. STUDY DESIGN: Retrospective Case Series; Level of evidence 4. PMID- 24790780 TI - Intra-rater and inter-rater reliability of the five image-based criteria of the foot posture index-6. AB - PURPOSE/BACKGROUND: The Foot Posture Index-6 (FPI-6) is considered a simple quantification tool to assess static foot alignment. Palpation of the foot is required for assessment of one of the six criteria that comprise the FPI-6; the remaining five criteria may be evaluated using still-frame photographs. Using only the image-based criteria may allow multiple clinicians to evaluate large groups of patients quickly. Reliability using only these five image-based criteria has not been established. The purposes of the current study were to establish the inter- and intra-rater reliability using five image-based criteria from the Foot Posture Index-6 (FPI-6) as well as to examine the agreement between the raters in identifying foot type using the composite five FPI scores. METHODS: Forty participants (23 females, 17 males; 23.67 +/- 8.49 years; 64.59 +/- 14.43 kg; 166.07 +/- 11.79 cm) volunteered for this study. An investigator took three photos with a digital camera of the medial longitudinal arch, posterior ankle, and of the talonavicular joint approximately 45 degrees from the posterior calcaneus for both right and left feet. Two investigators assessed the five image based criteria of the FPI-6 for both feet of 40 participants on three occasions separated by a day. Inter-and intra-rater reliability were assessed with Intraclass Correlation Coefficients (ICC3,2). The amount of agreement for classification of foot posture type between the two raters was assessed with Cohen's kappa coefficient. Significance was set a priori at P < 0.05. RESULTS: The inter-rater reliability was poor to moderate for all three sessions (ICC3,2 = 0.334-0.634). For the foot posture classification, the amount of agreement between two raters was poor for left (kappa= 0.12) and right (kappa= 0.19) feet. The intra-rater reliability was excellent for left (ICC3,2=0.956) and right feet (ICC3,2=0.959). CONCLUSIONS: Excellent intra-rater and poor to moderate inter rater reliability was found using only the five image-based criteria of the FPI 6. However, the classification of foot posture did not improve the amount of agreement between raters. Therefore, caution is needed when interpreting FPI scores from five image-based criteria. LEVELS OF EVIDENCE: 3b. PMID- 24790781 TI - Intra- and inter-rater reliability of the selective functional movement assessment (sfma). AB - PURPOSE/BACKGROUND: The Selective Functional Movement Assessment (SFMA) is a clinical assessment system designed to identify musculoskeletal dysfunction by evaluation of fundamental movements for limitations or symptom provocation. The purpose of this study was to determine the intra- and inter-rater reliability of the ten fundamental movement patterns of the SFMA in a healthy population using the SFMA categorical and criterion checklist scoring tools. METHODS: 35 healthy subjects (22.9 years +/- 1.9) were recorded with two digital video cameras (1 frontal view/1-sagittal view) while they performed the ten fundamental movements patterns that comprise the SFMA. Evaluators with varying experience with the SFMA (rater A, > 100 hours; rater B, 25 hours; and rater C, 16 hours) and not present at the initial data collection evaluated each video using categorical and criterion checklist scoring tools. Evaluators repeated this process at least one week later. The evaluators' composite results were compared between and within raters using the kappa coefficient and ICC's for categorical scoring and criterion checklist scoring, respectively. RESULTS: Substantial to almost perfect intra-rater reliability of the SFMA (kappa, % agreement) was observed for all raters using the categorical scoring tool (rater A: .83, .91; rater B: .78, .88; and rater C: .72, .85). The criterion checklist scoring tool yielded intra-rater ICCs (3,1; 95% confidence interval) ranging from good to poor with rater A demonstrating the highest reliability (ICC [SEM]) (.52 [2.36]) and rater C the lowest reliability (.26 [3.42]). Inter-rater reliability of the categorical scoring tool was slight to substantial (.41-.61, .69-.79) while the criterion checklist tool (ICC 2,1) demonstrated unacceptable inter-rater reliability when assessed in all raters together (.43 [2.7]). CONCLUSIONS: As hypothesized, intra and inter-rater reliability of categorical scoring and criterion checklist scoring of the ten fundamental movements of the SFMA was higher in raters with greater experience. PMID- 24790782 TI - Rehabilitation of a 23-year-old male after right knee arthroscopy and open reconstruction of the medial patellofemoral ligament with a tibialis anterior allograft: a case report. AB - BACKGROUND: Patellar dislocations are traumatic injuries that occur most often in individuals under the age of twenty and are related to sports and physical activity. Currently, there are no published reports describing the rehabilitation of younger males after arthroscopy and open reconstruction of the medial patellofemoral ligament (MPFL) using a tibialis anterior allograft. CASE DESCRIPTION: The subject of this case report was a 23 year-old recreational male athlete who underwent right knee arthroscopic patellar chondroplasty, lateral retinacular release, partial lateral menisectomy, and an open MPFL reconstruction with a tibialis anterior allograft after sustaining a second patellar dislocation. The purpose of this case report is to present the functional outcomes as well as the rehabilitation strategy used during the treatment of this athlete. OUTCOME: The patient returned to his prior level of activity after finishing 22 weeks of physical therapy. At a one-year follow-up, the patient reported pain-free physical activity including weight training, running, and recreational basketball. DISCUSSION: The results of this four-phase rehabilitation program with this subject were excellent. However, research beyond single subject case reports on post-operative rehabilitation for knee arthroscopy and open MPFL reconstruction with a tibialis anterior allograft is lacking. This is the first report that describes a rehabilitation strategy for this procedure. Although there was a successful rehabilitation outcome, future research is necessary to establish optimal rehabilitation guidelines as well as normative milestones for individuals who undergo this surgery. LEVEL OF EVIDENCE: 4-Case Report. PMID- 24790783 TI - Treatment of distal iliotibial band syndrome in a long distance runner with gait re-training emphasizing step rate manipulation. AB - BACKGROUND & PURPOSE: Iliotibial band syndrome (ITBS) is a common injury associated with long distance running. Researchers have previously described biomechanical factors associated with ITBS. The purpose of this case report is to present the treatment outcomes in a runner with distal ITBS utilizing running gait re-training to increase step rate above the runner's preferred or self chosen step rate. CASE DESCRIPTION: The subject was a 36 year old female runner with a diagnosis of left knee ITBS, whose pain prevented her from running greater than three miles for three months. Treadmill video analysis of running form was utilized to determine that the subject had an excessive stride length, strong heel strike, decreased knee flexion angle at initial foot contact, and excessive vertical displacement. Cadence was 168 steps/minute at a preferred running pace of 6.5 mph. Treatment emphasized gait re-training to increase cadence above preferred. Treatment also included iliotibial band flexibility and multi-plane eccentric lower extremity strengthening. OUTCOMES: The subject reported running pain free within 6 weeks of the intervention with a maximum running distance of 7 miles and 10-15 miles/week progressing to half marathon distance and 20-25 miles/week at 4 month follow up. Step rate increased 5% to 176 steps/minute and was maintained at both the 6 week and 4 month follow up. 5K run pace improved from 8:45 to 8:20 minutes/Km. LEFS score improved from 71/80 to 80/80 at 4 month follow up. DISCUSSION: This case demonstrated that a 5% increased step rate above preferred along with a home exercise program for hip strengthening and iliotibial band stretching, improved running mechanics and reduced knee pain in a distance runner. LEVEL OF EVIDENCE: 4-single case report. PMID- 24790784 TI - Rehabilitation strategies addressing neurocognitive and balance deficits following a concussion in a female snowboard athlete: a case report. AB - Head injuries, including concussions, in athletes can account for an extended period of time lost from sports competition. Neurocognitive and balance deficits which may linger following a concussion affect an athlete's ability to return to sport safely. If these deficits are not specifically addressed in a rehabilitation program then the athlete may be at risk for not only additional concussions but possible musculoskeletal injury. ImPACT testing is a reliable method for identifying neurocognitive deficits and assists in the development of a neurocognitive training program. The information gathered from ImPACT may also indicate risk for musculoskeletal injuries. Research evidence suggesting specific rehabilitation strategies and interventions addressing neurocognitive deficits following a concussion is lacking. Progressions in a neurocognitive training program may include the integration of balance, reaction training, and activities that address memory deficits. The purpose of this case report is to discuss the evaluation and treatment plan for a female snowboard athlete following a concussion. LEVEL OF EVIDENCE: 5. PMID- 24790785 TI - Pediatric sports specific return to play guidelines following concussion. AB - PURPOSE/BACKGROUND: In 2010, the American Academy of Pediatrics officially adopted the recommended return to play guidelines proposed by the International Conference on Concussion in Sport. The guidelines include a six-step process that provides structure to guide an athlete who is recovering from a concussion in a gradual return to play (RTP) by allowing participation in increasingly difficult physical activities. Unfortunately, the guidelines fail to take into account the variability that occurs within different sports and the resulting challenges medical professionals face in making sure each athlete is able to withstand the rigors of their specific sport, without return of symptoms. Therefore, the purpose of this clinical commentary is to expand upon the current general consensus guidelines for treatment of concussed pediatric athletes and provide sport specific RTP guidelines. DESCRIPTION OF TOPIC: The intention of the sport specific guidelines is to maintain the integrity of the current six-step model, add a moderate activity phase highlighted by resistance training, and to provide contact and limited contact drills specific to the athlete's sport and/or position. The drills and activities in the proposed seven-step programs are designed to simulate sport specific movements; the sports include: football, gymnastics, cheerleading, wrestling, soccer, basketball, lacrosse, baseball, softball, and ice hockey. These activities will provide sports specific challenges to each athlete while simultaneously accomplishing the objectives of each stage of the RTP progression. The final RTP determination should occur with documented medical clearance from a licensed healthcare provider who has been trained in the evaluation and management of concussions. DISCUSSION/RELATION TO CLINICAL PRACTICE: There have been significant strides in the management and care of concussed athletes. However, there continues to be a lot of confusion among, athletes, parents, and coaches regarding the proper management of an athlete with a concussion, particularly in the pediatric population. In an effort to eliminate ambiguity and help further promote adherence to the RTP guidelines, the authors developed several sports-specific RTP guidelines. LEVEL OF EVIDENCE: 5. PMID- 24790786 TI - Radiological examination of the hip - clinical indications, methods, and interpretation: a clinical commentary. AB - There is a growing interest in musculoskeletal rehabilitation for young active individuals with non-arthritic hip pathology. History and physical examination can be useful to classify those with non-arthritic intra-articular hip pathology as having impingement or instability. However, the specific type of deformity leading to symptoms may not be apparent from this evaluation, which may compromise the clinical decision-making. Several radiological indexes have been described in the literature for individuals with non-arthritic hip pathology. These indexes identify and quantify acetabular and femoral deformities that may contribute to instability and impingement. The aim of this paper is to discuss clinical indications, methods, and the use of hip radiological images or radiology reports as they relate to physical examination findings for those with non-arthritic hip pathology. LEVEL OF EVIDENCE: 5. PMID- 24790787 TI - Acl reconstruction - it's all about timing. AB - Injury to the anterior cruciate ligament (ACL) is the most common ligamentous injury, ranging from up to 200,000 injuries per year in the United States. Sports such as soccer, football, and skiing have been reported to be high-risk sports that can cause injury to the ACL when compared to other sport activities. Due to the high incidence of ACL injuries, approximately 100,000 ACL reconstructions are performed each year. Although conservative treatment can potentially be successful in the appropriate population, patients with goals of returning to high levels of sport activity may not be successful with conservative treatment. Even though reconstruction is the most common treatment for ACL rupture, there remains debate in the literature regarding the optimal timing of surgery. Therefore, the purpose of this clinical commentary is to review the available evidence to provide insight into the optimal timing of ACL reconstruction. PMID- 24790789 TI - ADAMTS13, TTP and Beyond. PMID- 24790788 TI - Current concepts of rotator cuff tendinopathy. AB - PURPOSE/BACKGROUND: Tendinopathies are a broad topic that can be examined from the lab to their impact upon function. Improved understanding will serve to bring this pathology to the forefront of discussion, whether in the clinic or the classroom. The purpose of this current concepts clinical commentary is to explore intrinsic and extrinsic mechanisms of rotator cuff (RC) tendinopathy in order to improve clinical and research understanding. METHODS: Pubmed, Medline, Cinahl, PEDro, and Cochrane databases were searched, limiting results to those published in the English language, between the years of 2005 and 2012. The key search terms utilized were intrinsic mechanisms, tendinopathy, stem cells, biologics, platelet rich plasma (PRP), healing, rotator cuff tears, full-thickness tears, tests, impingement, imaging, ultrasound, Magnetic Resonance Imaging (MRI), radiograph, shoulder advances, treatment, diagnoses, tendon disorders, pathogenesis, matrix metalloproteinase, injections, and RC repair. Over 150 abstracts were reviewed and 43 articles were analyzed for quality and relevance using the University of Alberta Evidence Based Medicine Toolkit. RESULTS/CONCLUSIONS: Current evidence suggests that tendinopathies arise from a multivariate etiology.It is increasingly evident that intrinsic mechanisms play a greater role than extrinsic mechanisms in this process. Emphasis should be placed on patient information (i.e. background information and personal description of symptoms) and imaging/ injection techniques in order to aid in diagnosis. Future treatment technologies such as cell therapy and biological engineering offer the hope of improving patient outcomes and quality of life. LEVEL OF EVIDENCE: Level 5 - Clinical Commentary Related to a Review of Literature. PMID- 24790790 TI - Sustained CD4+ T cell-driven lymphopenia without a compensatory IL-7/IL-15 response among high-grade glioma patients treated with radiation and temozolomide. AB - Prolonged lymphopenia correlating with decreased survival commonly occurs among glioma patients undergoing radiation therapy (RT) and temozolomide (TMZ) treatment. To better understand the pathophysiology of this phenomenon, we prospectively monitored serum cytokine levels and lymphocyte subsets in 15 high grade glioma patients undergoing combined radiation and TMZ (referred to as RT/TMZ) treatment. Sufficient data for analysis were acquired from 11 of the patients initially enrolled. Lymphocyte phenotyping data were obtained using cytofluorometric analysis and serum cytokine levels were measured using the a multiplex bead-based assays. Total lymphocyte counts (TLCs) were > 1000 cells per MUL peripheral blood in 10/11 patients at baseline, but dropped significantly after treatment. Specifically, after RT/TMZ therapy, the TLCs were found to be < 500 cells/MUL in 2/11 patients, 500-1000 cells/MUL in 7/11 patients, and > 1000 cells/MUL in the remaining 2 patients. Among residual mononuclear blood cells, we observed a proportional drop in B and CD4+ T cells but not in CD8+ T lymphocytes. Natural killer cells remained to near-to-baseline levels and there was a transient and slight (insignificant) increase in regulatory T cells (Tregs). The circulating levels of IL-7 and IL-15 remained low despite marked drops in both the total and CD4+ T lymphocyte counts. Thus, patients with malignant glioma undergoing RT/TMZ treatment exhibit a marked decline in TLCs, affecting both CD4+ T cells and B lymphocytes, in the absence of a compensatory increase in interleukin-7 levels. The failure to mount an appropriate homeostatic cytokine response may be responsible for the prolonged lymphopenia frequently observed in these patients. PMID- 24790792 TI - Understanding the influence of the tumor microenvironment on macrophage responses to CD40 agonists. AB - Both TH1 and TH2 cytokines influence the antitumor functions of macrophages. We have recently shown that interferon gamma (IFNgamma) licenses the antineoplastic functions of CD40 ligand (CD40L)-stimulated macrophages more efficiently than interleukin (IL)-4 and IL-13. The presence of a TH1 and TH2 skewed tumor microenvironment may therefore influence therapeutic responses to CD40 agonists, agents that are showing promise in preliminary clinical trials. PMID- 24790791 TI - A novel minigene scaffold for therapeutic cancer vaccines. AB - Genetic vaccines are emerging as a powerful modality to induce T-cell responses to target tumor associated antigens (TAA). Viral or plasmid DNA or RNA vectors harbor an expression cassette encoding the antigen of choice delivered in vivo by vaccination. In this context, immunizations with minigenes containing selected, highly antigenic, T-cell epitopes of TAAs may have several advantages relative to full-length proteins. The objective of this study was to identify an optimal scaffold for minigene construction. We generated a number of minigenes containing epitopes from the carcinoembryonic antigen (CEA) model TAA and utilized muscle DNA electro-gene-transfer (DNA-EGT) to vaccinate HLA-A*0201 (HHD) and CEA/HHD double transgenic mice. The components utilized to construct the minigenes included CD8+ T cell epitopes and (or) anchor modified analogs that were selected on the basis of their predicted binding to HLA-*A0201, their uniqueness in the human proteome, and the likelihood of cancer cell natural processing and presentation via MHC-I. Other candidate components comparatively tested included: helper CD4+ T-cell epitopes, flanking regions for optimal epitope processing (including both proteasome-dependent and furin-dependent polypeptide processing mechanisms), and immunoenhancing moieties. Through a series of comparative studies and iterations we have identified an optimal minigene scaffold comprising the following elements: human tissue plasminogen activator (TPA) signal peptide, T-cell epitopes connected by furin sensitive linkers, and the E. Coli enterotoxin B subunit. The selected epitope modified minigenes (EMM) delivered by DNA-EGT were able to break immune tolerance in CEA/HHD mice and induce a strong immune response against all epitopes tested, independently of their relative positions within the scaffold. Furthermore, the optimized EMMs delivered via DNA-EGT were more immunogenic and exerted more powerful antitumor effects in a B16-CEA/HHD metastatic melanoma model than a DNA vector encoding the full-length protein or a mixture of the same peptides injected subcutaneously. Our data may shed light on the optimal design of a universal vehicle for epitope-targeted, genetic cancer vaccines. PMID- 24790793 TI - Eomesodermin is required for antitumor immunity mediated by 4-1BB-agonist immunotherapy. AB - CD8+ T cells in progressing tumors frequently fail to mount an effective antitumor response often in association with the expression of inhibitory receptors, including programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (Lag3). Using a lymphoma tumor model, we demonstrate that tumor infiltrating CD8+ T cells from growing tumors co-express inhibitory receptors and co-stimulatory receptors, including 4-1BB (TNFRSF9) as well as high levels of 2 transcription factors, Eomesodermin (Eomes) and T-bet (Tbx21), critical determinants of CD8+ T cell fate. Immunotherapy with an agonistic anti-4-1-BB antibody altered the ratio of Eomes to T-bet expression in tumor-infiltrating CD8+ T cells by increasing Eomes and decreasing T-bet expression. 4-1BB-agonist immunotherapy was also associated with downregulated expression of the inhibitory receptors PD-1 and Lag3 on tumor-infiltrating CD8+ T cells, a molecular phenotype associated with subsequent attenuation of tumor growth. Furthermore, 4-1BB agonist immunotherapy failed to effect tumor progression in mice with Eomes deficient T cells. However, upon resumption of tumor growth, tumor-infiltrating CD8+ T cells from treated animals continued to express high levels of Eomes as well as elevated levels of the inhibitory receptors PD-1 and Lag3. Our data suggest that tumor-infiltrating CD8+ T cells are poised between activation and inhibition as dictated by expression of both co-stimulatory receptors and inhibitory receptors and demonstrate that T cell expression of Eomes is necessary, but not sufficient, for efficacious 4-1BB-agonist-mediated immunotherapy. PMID- 24790794 TI - Toll-like receptor genetic variants and colorectal cancer. AB - Single-nucleotide polymorphisms in Toll-like receptor 5 (TLR5), encoding a sensor for flagellin, have been shown to influence cytokine responses to intestinal bacteria and to be associated with significant alterations in the survival of colorectal carcinoma (CRC) patients. These findings point to a link between TLRs and CRC that may have both therapeutic and prognostic/predictive implications. PMID- 24790796 TI - Stroke prevention in atrial fibrillation: Commentary regarding the AAN's evidence based guideline update. AB - Atrial fibrillation is a common, potentially preventable cause of disabling stroke in the elderly, particularly in elderly women, resulting from embolism of stasis-precipitated thrombi formed in the left atrial appendage. In 1989, the first randomized clinical trial of anticoagulant therapy in atrial fibrillation showed that warfarin produced a large reduction in ischemic stroke.1 In the ensuing 25 years, more than 40 additional randomized trials have permitted stroke prophylaxis to be importantly refined. It has been a period of remarkable progress in stroke prevention. Here, we discuss selected aspects of the American Academy of Neurology (AAN)'s evidence-based guideline update.2. PMID- 24790795 TI - Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy. AB - There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Based on these premises, we attempted to identify metagenes that reflect an intratumoral immune response or local stress responses in the transcriptomes of breast cancer patients. No consistent correlations between immune- and stress-related metagenes could be identified across several cohorts of patients, representing a total of 1045 mammary carcinomas. Moreover, few if any, of the stress-relevant metagenes influenced the probability of pathological complete response to chemotherapy. In contrast, several immune-relevant metagenes had a significant positive impact on response rates. This applies in particular to a CXCL13-centered, highly reproducible metagene signature reflecting the intratumoral presence of interferon-gamma-producing T cells. PMID- 24790797 TI - Prescribing controlled substances during a prescription drug epidemic. AB - We are currently in the midst of an epidemic of deaths caused by the misuse of prescription medications. Opioids, benzodiazepines, and stimulants are among the most frequently misused controlled substances and are integral to the neurologist's armamentarium. Thus, the decision to prescribe a controlled substance and how to mitigate the associated risks of their misuse is often vexing to the clinician. This installment in the "Clinical Challenge" series provides a basic narrative overview of the epidemiology of prescription drug misuse, a summary of each of the major classes of misused drugs, and clinical recommendations regarding screening for misuse and reducing the risks associated with prescribing controlled substances. PMID- 24790798 TI - Neurologic disorders in Medicaid vs privately insured children and working-age adults. AB - This retrospective, observational study reports health utilization and access patterns of Medicaid recipients for neurologic diseases compared to privately insured individuals seen in 2 hospitals at a single institution in the same time period. We reviewed records of patients and compared demographic characteristics, visit types, neurologic diagnoses, and all-cause mortality, by age group, when seen with Medicaid vs private insurance. Adults insured by Medicaid were more likely to present as inpatients and with life-threatening neurologic disease compared to privately insured patients. Moreover, adult patients presenting with neurologic disease on Medicaid had a higher all-cause mortality rate than privately insured patients. Similar disparities in neurologic disease were not observed in children. The relationship of these findings to patient educational status, household income, comorbidities, and the reasons prompting Medicaid eligibility require additional study. PMID- 24790799 TI - Virtual visits for Parkinson disease: A case series. AB - We sought to characterize recommendations and feedback of patients with Parkinson disease, each offered a free telemedicine consultation with a specialist. Visits consisted of history, neurologic examination, and recommendations. Midway through the program, patients were asked to complete an online satisfaction survey. From August 2012 to May 2013, 55 patients in 5 states (mean age 67.8 years) participated, with 80% of visits conducted from their home. Patients with Parkinson disease were recommended to exercise (86%), change current medication (63%), and add new medication (53%). Thirty-three of 35 consecutive patients completed a survey. Patient satisfaction exceeded 90% for virtually all aspects of the visit measured. Providing care to patients in their homes via telemedicine is feasible, results in changes to care, and is well-received. PMID- 24790800 TI - Sports neurology topics in neurologic practice: A survey of AAN members. AB - We sought to assess neurologists' interest in sports neurology and learn about their experience in treating sports-related neurologic conditions. A survey was sent to a random sample of American Academy of Neurology members. A majority of members (77%) see at least some patients with sports-related neurologic issues. Concussion is the most common sports-related condition neurologists treat. More than half of survey participants (63%) did not receive any formal or informal training in sports neurology. At least two-thirds of respondents think it is very important to address the following issues: developing evidence-based return-to play guidelines, identifying risk factors for long-term cognitive-behavioral sequelae, and developing objective diagnostic criteria for concussion. Our findings provide an up-to-date view of the subspecialty of sports neurology and identify areas for future research. PMID- 24790801 TI - The relationship between physicians and Pharma: Playing the devil's advocate. AB - All who practice medicine face, on a daily basis, conflicts of interest (COIs) that have the potential to affect patient care. COIs may exist within our own practice. We may choose to perform (or not perform) a procedure that may (or may not) benefit the patient but clearly brings income to the practice; we may see patients in the office for services that might just as easily be taken care of by phone. PMID- 24790802 TI - Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN). AB - A 31-year-old woman presented with severe dystonia-parkinsonism. She had nonprogressive psychomotor retardation and cognitive dysfunction from childhood without evidence of dystonia or parkinsonism. At age 30, she then developed severe dystonia and gait disturbance. There was neither dystonia nor parkinsonism before age 30. MRI revealed cerebral atrophy and iron accumulation in the globus pallidus and substantia nigra (figure 1, A-D). The characteristic MRI findings were hyperintensity of the substantia nigra with a central band of hypointensity in T1-weighted axial slices (figure 1, B). Beta-propeller protein-associated neurodegeneration (BPAN) was diagnosed based on MRI findings and identification of a novel heterozygous mutation in the WDR45 gene (NM_007075.3: c.519+1_519+3del) (figure 2). This is a neurodegeneration involving brain iron accumulation (NBIA) characterized by psychomotor retardation from childhood and dystonia-parkinsonism in midadulthood.1,2 Although we could not analyze the father's gene since he had died, the mother had no mutation in the WDR45 gene (figure 2). Thus, it might be a de novo mutation in the WDR45 gene, as reported previously.1,2. PMID- 24790803 TI - Rho GEFs in endothelial junctions: Effector selectivity and signaling integration determine junctional response. AB - Rho GTPases are cytoskeleton-regulating proteins that mediate the formation of intercellular junctions. Their localized activation by Rho GEFs (guanine nucleotide exchange factors) and the selective activation of downstream effectors have emerged as areas of active research in the cell adhesion field. We reported recently that the Rho-specific GEFs Syx (Synectin-binding RhoA exchange factor) and TEM4 (Tumor Endothelial Marker 4) are both essential for endothelial junction maturation and barrier function. Syx is recruited to cell contacts via its C terminal PDZ binding motif and it's interaction with Mupp1 and the Crumbs polarity complex, while the junctional localization of TEM4 requires it's N terminal domain and interaction with the cadherin-catenin complex. Our findings support multiple roles for RhoA in junction formation and maintenance. They also suggest that selective coupling of RhoA activation to Dia1 and/or ROCK signaling is critical for determining endothelial junction integrity. PMID- 24790804 TI - NFkB and Nrf2 in esophageal epithelial barrier function. AB - The stratified squamous epithelium of the esophagus forms a tight protective barrier. Defects of the barrier function contribute to gastroesophageal reflux disease (GERD), which is manifested as damage to the esophageal epithelium due to exposure to the gastrointestinal refluxate. In this review, we discuss the involvement of NFkB and Nrf2 in esophageal epithelial barrier function. Understanding these molecular pathways in the esophagus may help us develop therapeutic strategies to improve clinical outcomes in patients with GERD. PMID- 24790805 TI - The application of positive psychology in the practice of education. AB - The purpose of the study is to present the possibility of the application in the field of education this highly interesting and promising trend in the psychology which is the positive psychology. For this reason the origins as well as an outline of the interest scope of this relatively recent, dating back only over 10 years, trend are shown. A crucial question has become in this context the examination of the relationship between the positive psychology and the education, particularly regarding the potential linked to the prospect of the so called strong points". The founding fathers as well as the supporters of the positive psychology try to propagate it in the therapy and in the fields of organization and education. In the following text some selected concepts of the positive psychology and the corresponding examples of their practical use in the form of the so called positive prevention and intervention programs in the domain of education are described. PMID- 24790807 TI - Econo-ESA in semantic text similarity. AB - Explicit semantic analysis (ESA) utilizes an immense Wikipedia index matrix in its interpreter part. This part of the analysis multiplies a large matrix by a term vector to produce a high-dimensional concept vector. A similarity measurement between two texts is performed between two concept vectors with numerous dimensions. The cost is expensive in both interpretation and similarity measurement steps. This paper proposes an economic scheme of ESA, named econo ESA. We investigate two aspects of this proposal: dimensional reduction and experiments with various data. We use eight recycling test collections in semantic text similarity. The experimental results show that both the dimensional reduction and test collection characteristics can influence the results. They also show that an appropriate concept reduction of econo-ESA can decrease the cost with minor differences in the results from the original ESA. PMID- 24790806 TI - Mean-field analysis of orientation selectivity in inhibition-dominated networks of spiking neurons. AB - Mechanisms underlying the emergence of orientation selectivity in the primary visual cortex are highly debated. Here we study the contribution of inhibition dominated random recurrent networks to orientation selectivity, and more generally to sensory processing. By simulating and analyzing large-scale networks of spiking neurons, we investigate tuning amplification and contrast invariance of orientation selectivity in these networks. In particular, we show how selective attenuation of the common mode and amplification of the modulation component take place in these networks. Selective attenuation of the baseline, which is governed by the exceptional eigenvalue of the connectivity matrix, removes the unspecific, redundant signal component and ensures the invariance of selectivity across different contrasts. Selective amplification of modulation, which is governed by the operating regime of the network and depends on the strength of coupling, amplifies the informative signal component and thus increases the signal-to-noise ratio. Here, we perform a mean-field analysis which accounts for this process. PMID- 24790808 TI - Increased cardiovascular risk factors in breast cancer survivors identified by routine measurements of body composition, resting heart rate and arterial blood pressure. AB - PURPOSE: The main objective of this prospective study was to obtain a better understanding of the body composition and vital sign measures of cancers survivors (CS) when compared to regular (R) patients. METHODS: A total of 9,315 female patients were evaluated: 476 CS and 8,839 R patients. Kinesiologists worked side by side with the medical/oncology team to collect a number of base line measurements on body composition, resting heart rate, and blood pressure as part of the standard intake evaluation during the female patients' annual checkup. RESULTS: CS were more likely to have a higher BMI (P = 0.001) and a larger waist circumference (P = 0.001) than R patients. CS were also shown to have higher blood pressure values: diastolic pressure of 76.9 mmHg +/- 10.5 VS 75.5 mmHg +/- 9.9, (P = 0.01) and systolic pressure of 129.8 mmHg +/- 17.2 VS 126.7 mmHg +/-17.4 (P = 0.001) compared to R patients, respectively. Regression analysis looking at the relationship between mean arterial pressure and waist circumference did not show any difference between the two groups (CS vs R). CONCLUSION: CS who had a higher BMI, a larger waist circumference and higher blood pressure levels, are probably at greater risk for developing cardiovascular disease, diabetes, various musculoskeletal problems as well as an increased risk for various forms of cancers including reoccurrence of previously treated cancer when compared to R patients. Changes in body composition should be considered by the medical team when looking at preventative healthcare strategies for their CS patients. PMID- 24790809 TI - Intracranial hypotension after trauma. AB - INTRODUCTION: Intracranial hypotension (IH) occurs typically spontaneous and is a potentially life-threatening condition characterized by symptoms varying from postural headache to coma, with classical magnetic resonance imaging (MRI) findings. CASE DESCRIPTION: We report two cases of clinically relevant trauma related IH and review of the literature. One patient with a cerebral trauma presented unilateral mydriasis and coma resolved by the Trendelenburg position ( 20 degrees ) as urgency intervention. In the second patient, IH was caused by a lesion of the brachial plexus after a motor vehicle accident. DISCUSSION AND CONCLUSION: A history of mild or moderate trauma in association with prolonged postural or permanent headache may indicate IH. Posttraumatic IH is rare, nevertheless life-threatening in case of misdiagnosis. Intracranial hypotension in a trauma context is rarely described and difficult to diagnose. The change from tipical supine 30 degrees to Trendelenburg position (0-20 degrees ) can be a life-saving manoeuver in these patients. PMID- 24790810 TI - Agro-ecosystem and socio-economic role of homegarden agroforestry in Jabithenan District, North-Western Ethiopia: implication for climate change adaptation. AB - Homegarden agroforestry is believed to be more diverse and provide multiple services for household than other monocropping system and this is due to the combination of crops, trees and livestock. The aim of this study was to assess socio-economic and agro-ecological role of homegardens in Jabithenan district, North-western Ethiopia. Two sites purposively and two villages randomly from each site were selected. Totally 96 households; in which 48 from homegarden agroforestry user and 48 from non-tree based garden user were selected for this study. Socio-economic data and potential economic and agro-ecosystem role of homegarden agroforestry over non-tree based garden were collected by using semi structured and structured questionnaires to the households. Homegarden agroforestry significantly (P < 0.05) improved the farmers cash income than non tree based garden. With insignificant garden size; homegarden agroforestry practice provides good socio-economical and agro-ecological service for farmers which have a higher implication for climate change adaptation than non-tree based garden. PMID- 24790811 TI - Numerical modeling of radionuclide migration through a borehole disposal site. AB - The migration of radionuclides from a borehole repository located about 20 km from the Akwapim fault line which lies in an area of high seismicity was analyzed for some selected radionuclides. In the event of a seismic activity, fractures and faults could be rejuvenated or initiated resulting in container failure leading to the release of radionuclides. A numerical model was solved using a two dimensional finite element code (Comsol Multiphysics) by taking into account the effect of heterogeneities. Results showed that, the fractured medium created preferential pathways indicating that, fault zones generated potential paths for released radionuclides from a radioactive waste repository. The results obtained showed that variations in hydraulic conductivity as a result of the heterogeneity considered within the domain significantly affected the direction of flow. PMID- 24790812 TI - The physico-chemical properties and biostimulative activities of humic substances regenerated from lignite. AB - The positive effect of humic acids on the growth of plant roots is well known, however, the mechanisms and role of their physical structure in these processes have not been fully explained yet. In this work, South-Moravian lignite was oxidized by means of nitric acid and hydrogen peroxide to produce a set of regenerated humic acids. The elemental composition, solid state stability and solution characteristics were determined and correlated in vitro with their biological activity. A modified hydroponic method was applied to determine the effects of their potassium salts on Zea mays seedlings roots with respect to the plant weight, root length, root division, and starch and protein content. The relations between the determined parameters were evaluated through Principal Component Analysis and Pearson's correlation coefficients. The results indicated that the most important factor determining the biological activity of South Moravian lignite potassium humates is related to the nature of self-assemblies, while the chemical composition had no direct connection with the root growth of Zea mays seedlings. It was demonstrated a controlled processing that provided humic substances with different chemical and physicochemical properties and variable biological activity. PMID- 24790813 TI - Simulated global change: contrasting short and medium term growth and reproductive responses of a common alpine/Arctic cushion plant to experimental warming and nutrient enhancement. AB - Cushion plants are important components of alpine and Arctic plant communities around the world. They fulfill important roles as facilitators, nurse plants and foundation species across trophic levels for vascular plants, arthropods and soil microorganisms, the importance of these functions increasing with the relative severity of the environment. Here we report results from one of the few experimental studies simulating global change impacts on cushion plants; a factorial experiment with warming and nutrient enhancement that was applied to an alpine population of the common nurse plant, Silene acaulis, in sub-arctic Sweden. Experimental perturbations had significant short-term impacts on both stem elongation and leaf length. S. acaulis responded quickly by increasing stem elongation and (to a lesser extent) leaf length in the warming, nutrient, and the combined warming and nutrient enhancements. Cover and biomass also initially increased in response to the perturbations. However, after the initial positive short-term responses, S. acaulis cover declined in the manipulations, with the nutrient and combined warming and nutrient treatments having largest negative impact. No clear patterns were found for fruit production. Our results show that S. acaulis living in harsh environments has potential to react quickly when experiencing years with favorable conditions, and is more responsive to nutrient enhancement than to warming in terms of vegetative growth. While these conditions have an initial positive impact, populations experiencing longer-term increased nutrient levels will likely be negatively affected. PMID- 24790814 TI - Evaluation of proper prescribing of cardiac medications at hospital discharge for patients with acute coronary syndromes (ACS) in two Lebanese hospitals. AB - BACKGROUND: Coronary artery disease (CAD) is the major leading cause of death worldwide. The national practice guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) promote the use of several medical therapies for secondary prevention for patients with CAD. The purpose of this study was to evaluate whether ACS patients, admitted into two tertiary referral medical centers in Beirut, Lebanon, are discharged on optimal medical therapy based on the current AHA/ACC guidelines. METHODS: We reviewed the medical records of all patients with ACS who were admitted to the coronary care units (CCU) of two hospitals in Beirut, Lebanon between May and August 2012. Discharge prescriptions were reviewed and rating for the appropriateness of discharge cardiac medications was based on the AHA/ACC guidelines. We assessed whether patients were discharged on antiplatelet therapy, beta-blockers, angiotensin converting enzymes inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, and nitrates, unless contraindicated or not tolerated. In addition, we assessed whether patients and/or their caregivers were counseled about their disease(s) and discharge medications. RESULTS: 186 patients with a mean age of 63 +/- 11.78 years, 70.4% of which were males, were admitted with ACS and were included in the study. Fifty three (28.5%) patients had ST elevation MI (STEMI), 64 (34.4%) had non-ST-elevation myocardial infarction (NSTEMI) and 69 (37.1%) had unstable angina (USA). Sixty two patients (33.3%) were treated with medical therapy and 124 patients (66.7%) underwent percutaneous coronary intervention (PCI). Among eligible patients, 98.9% were discharged on aspirin, 89.1% on dual antiplatelet therapy (aspirin + thienopyridine or ticagrelor), 90.5% on a beta blocker, 81.9% on an ACEI or ARB, 89.8% on a statin, and 19.4% on nitroglycerin. Overall, 62.9% of the patients received the optimal cardiovascular drug therapy (the combination of dual antiplatelet therapy, a beta-blocker, an ACEIs or an ARB, and a statin), 55.1% were counseled on their disease state(s) and drug therapy, and 92.2% and 55.9% were counseled on smoking cessation and life style changes, respectively. CONCLUSION: In patients admitted with ACS, discharge cardiac medications are prescribed at suboptimal rates. Education of healthcare providers and implementation of ACS discharge protocols may help improve compliance with ACC/AHA guidelines. In addition, clinicians should be encouraged to provide adequate patient counseling. PMID- 24790815 TI - Modified Taylor series method for solving nonlinear differential equations with mixed boundary conditions defined on finite intervals. AB - ABSTRACT: In this article, we propose the application of a modified Taylor series method (MTSM) for the approximation of nonlinear problems described on finite intervals. The issue of Taylor series method with mixed boundary conditions is circumvented using shooting constants and extra derivatives of the problem. In order to show the benefits of this proposal, three different kinds of problems are solved: three-point boundary valued problem (BVP) of third-order with a hyperbolic sine nonlinearity, two-point BVP for a second-order nonlinear differential equation with an exponential nonlinearity, and a two-point BVP for a third-order nonlinear differential equation with a radical nonlinearity. The result shows that the MTSM method is capable to generate easily computable and highly accurate approximations for nonlinear equations. AMS SUBJECT CLASSIFICATION: 34L30. PMID- 24790816 TI - Development of an open source software module for enhanced visualization during MR-guided interstitial gynecologic brachytherapy. AB - In 2010, gynecologic malignancies were the 4th leading cause of death in U.S. women and for patients with extensive primary or recurrent disease, treatment with interstitial brachytherapy may be an option. However, brachytherapy requires precise insertion of hollow catheters with introducers into the tumor in order to eradicate the cancer. In this study, a software solution to assist interstitial gynecologic brachytherapy has been investigated and the software has been realized as an own module under (3D) Slicer, which is a free open source software platform for (translational) biomedical research. The developed research module allows on-time processing of intra-operative magnetic resonance imaging (iMRI) data over a direct DICOM connection to a MR scanner. Afterwards follows a multi stage registration of CAD models of the medical brachytherapy devices (template, obturator) to the patient's MR images, enabling the virtual placement of interstitial needles to assist the physician during the intervention. PMID- 24790817 TI - Potential statin-drug interactions: prevalence and clinical significance. AB - BACKGROUND: Statins are cholesterol-lowering drugs widely used for cardiovascular prevention. Although safe when used alone, in combination with other drugs the likelihood of adverse drug reactions increases significantly. The exposure of the Bulgarian population to coprescriptions leading to potential statin-drug interactions is currently unknown. OBJECTIVE: The aim of this study was to investigate the incidence of coprescriptions involving statins and to compare the exposure of outpatients and inpatients to potential statin-drug interactions. SETTING: A cardiology clinic of the teaching University hospital in Varna, Bulgaria. METHOD: This observational retrospective study examined the medical records of hospitalized patients prescribed a statin in combination with potentially interacting drugs. Patients who entered the hospital with a statin coprescription (considered outpatients) were compared with those coprescribed a statin at discharge from hospital (considered inpatients). Potentially interacting drugs included inhibitors and inducers of cytochrome P450 (CYP) enzymes and drugs of narrow safety margin (coumarin anticoagulants, digitalis). MAIN OUTCOME MEASURE: The proportion of patients exposed to statin coprescriptions with potentially interacting drugs at hospital admission and discharge. SECONDARY OUTCOME MEASURES: laboratory evidence supporting possible statin-drug interactions. RESULTS: Out of 1641 hospitalized patients examined, 572 were prescribed a statin, either at hospital admission or discharge. Simvastatin was most commonly prescribed and simvastatin-drug coprescription predominated, especially at discharge. The exposure to all potential statin-drug interactions was similar at hospital admission (26.1%) and discharge (24.4%), as was the exposure to statin combinations with CYP inhibitors, 6.4% and 4%, correspondingly. Overall, more coprescriptions were generated, than were eliminated by hospital physicians. Amiodarone was the CYP inhibitor most frequently coprescribed. Of all interacting drugs acenocoumarol was the most commonly found, the proportions of statin-acenocoumarol coprescriptions being roughly the same at hospital entry (11.5%) and discharge (12.4%). In 7 patients out of 69 exposed to the combination, INR was found to be higher than 3, indicating a risk of over-anticoagulation. CONCLUSIONS: Potential statin-drug interactions are common. Although they do not differ between outpatient and inpatient settings, new hazardous coprescriptions are more frequently generated in hospital. Caution is required when acenocoumarol is coprescribed with statins, especially simvastatin. PMID- 24790818 TI - Quantitative analysis of vascular signs on early postmortem multi-detector computed tomography. AB - PURPOSE: To clarify the postmortem multi-detector computed tomography (MDCT) vascular signs that occur shortly after death. MATERIALS AND METHODS: The vascular signs in MDCT images were evaluated quantitatively in 96 early postmortem cardiac arrest patients, 47 cardiac arrest patients who survived due to resuscitation and 47 control patients without cardiac arrest. RESULTS: Elliptical (40 cases) or collapsed deformity (2 cases, in only the abdominal aorta) and high-attenuated sedimentation (19 cases in the aorta and 10 cases in superior or inferior vena cava) were limited to the postmortem patients. The incidence of elliptical deformity was higher for the abdominal aorta, descending thoracic aorta and ascending thoracic aorta in rank. The sedimentation was observed in the ascending thoracic aorta with a higher frequency than in the descending thoracic and abdominal aorta. A high-attenuating wall in any portion of the aorta was observed in 34 of the postmortem patients, 11 of the surviving patients and 10 of the control group, with a predominance of the ascending thoracic aorta. CONCLUSION: Elliptical deformity in the abdominal and descending thoracic aorta and high-attenuated sedimentation in the ascending thoracic aorta were shown to be signs of postmortem MDCT shortly after death. PMID- 24790819 TI - Perceptual video quality assessment in H.264 video coding standard using objective modeling. AB - Since usage of digital video is wide spread nowadays, quality considerations have become essential, and industry demand for video quality measurement is rising. This proposal provides a method of perceptual quality assessment in H.264 standard encoder using objective modeling. For this purpose, quality impairments are calculated and a model is developed to compute the perceptual video quality metric based on no reference method. Because of the shuttle difference between the original video and the encoded video the quality of the encoded picture gets degraded, this quality difference is introduced by the encoding process like Intra and Inter prediction. The proposed model takes into account of the artifacts introduced by these spatial and temporal activities in the hybrid block based coding methods and an objective modeling of these artifacts into subjective quality estimation is proposed. The proposed model calculates the objective quality metric using subjective impairments; blockiness, blur and jerkiness compared to the existing bitrate only calculation defined in the ITU G 1070 model. The accuracy of the proposed perceptual video quality metrics is compared against popular full reference objective methods as defined by VQEG. PMID- 24790821 TI - Patient perceptions and expectations regarding imaging for metastatic disease in early stage breast cancer. AB - PURPOSE: The probability of detecting radiologically evident metastatic disease in asymptomatic women with newly diagnosed operable breast cancer is low. Despite the recommendations of most practice guidelines imaging is still frequently performed. Relatively little is known about what patients believe is important when it comes to radiologic staging. METHODS: Patients with early stage breast cancer who had completed their definitive breast surgery were surveyed about their personal experiences, perceptions, and expectations on the issue of perioperative imaging for distant metastatic disease. RESULTS: Over a 3 month period, 245 women with primary operable breast cancer completed the questionnaire (87.0% response rate) and 80.8% indicated having had at least one imaging test for distant metastatic disease. These were either of the thorax (72.2%), abdomen (55.9%) or skeleton (65.3%) with a total of 701 imaging tests (average of 3.5 tests per patient imaged) performed. Overall, 57.1% indicated that they would want imaging done if the chance of detecting metastases was <=10%. Although 80.0% of patients indicated that, "doing whatever their doctor recommended" was important to them, 70.4% also noted that they would be uncomfortable if their physician did not order imaging, even if this was in keeping with practice guidelines. CONCLUSIONS: Most patients with early stage breast cancer recall having imaging tests for distant metastases. Given the choice, most would prefer having imaging performed, even if this is not in line with current guidelines. If patient expectations are, in part, driving excessive imaging, new strategies addressing this are required. PMID- 24790820 TI - Favorable effects of low-fat and low-carbohydrate dietary patterns on serum leptin, but not adiponectin, among overweight and obese premenopausal women: a randomized trial. AB - PURPOSE: The most effective dietary pattern for breast cancer prevention has been greatly debated in recent years. Studies have examined hypocaloric diets, with particular emphasis on macronutrient composition, yielding inconclusive data. The objective of this study was to examine the effects of calorie-restricted low-fat and low-carbohydrate diets (LFD and LCD, respectively) on circulating adipokines among overweight and obese premenopausal women. METHODS: Seventy-nine overweight and obese premenopausal women were randomized to either LFD or LCD, with increased physical activity, for 52 weeks. Serum adiponectin, leptin and the adiponectin-to-leptin ratio (A/L) were measured at baseline, and at weeks 34 and 52 to assess intervention effects. RESULTS: While there were no significant changes in serum adiponectin concentrations following the LCD and LFD interventions, leptin concentrations significantly decreased by week 34 of the intervention period (LCD: 35.3%, P = 0.004; LFD: 30.0%, P = 0.01), with no difference by intervention arm. At week 52, these reductions were statistically non-significant, indicating a return to baseline levels by the end of the intervention. While there were non-significant increases in the A/L ratio following the LCD and LFD intervention arms, the overall trend, across groups, was marginally significant (P = 0.05) with increases of 16.2% and 35.1% at weeks 34 and 52, respectively. CONCLUSIONS: These findings suggest that caloric restricted LCD and LFD dietary patterns favorably modify leptin and possibly the A/L ratio, and lend support to the hypothesis that these interventions may be effective for obesity-related breast cancer prevention through their effects on biomarkers involved in metabolic pathways. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION NUMBER: NCT01559194. PMID- 24790822 TI - Philadelphia chromosome-positive acute lymphoblastic leukemia with extramedullary and meningeal relapse after allogeneic hematopoietic stem cell transplantation that was successfully treated with dasatinib. AB - Central nervous system (CNS) relapse is a critical issue while treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). A 58-year-old woman with Ph-positive ALL who relapsed after bone marrow transplantation for meningeal leukemia was treated with high-dose methotrexate, which resulted in remission. She underwent allogeneic cord blood transplantation followed by reduced intensity conditioning chemotherapy with imatinib; however, she experienced CNS relapse and developed an extramedullary mass on the right side of the temporal region. We treated 40 mg of dasatinib once daily, which had to be temporarily discontinued because she developed grade 2 pleural effusion and grade 2 hematemesis. After reinitiation of dasatinib, the extramedullary mass disappeared and meningeal leukemia ameliorated almost immediately. With 40 mg dasatinib administered once daily, its trough level and cerebrospinal fluid (CSF) concentration were 32 ng/mL and below the sensitivity threshold of 1 ng/mL, respectively. Treatment was continued, and the patient remained in complete remission until she died of pneumonia 7 years after the initial diagnosis of ALL. Dasatinib can be an effective treatment for Ph-positive ALL with CNS relapse. Although the concentration in the CSF seems low, it may be sufficient to exert anti-leukemic effects in the human CNS. PMID- 24790823 TI - Promoter hypermethylation of tumor suppressor genes correlates with tumor grade and invasiveness in patients with urothelial bladder cancer. AB - PURPOSE: To investigate the promoter methylation status at selected loci which encode for key proteins involved in apoptosis, DNA repair, cell cycle control and progression in urothelial cell carcinoma of bladder and compare the findings from tissue samples with that of plasma. METHODS: Total genomic DNA was isolated from 43 non-muscle invasive (low grade) and 33 muscle invasive (high grade) urothelial bladder cancer samples along with 10 control cases of normal bladder mucosa. Promoter methylation status was investigated for RASSF1A, APC, MGMT, CDKN2A and CDKN2B genes using real-time methylation-specific PCR with SYBR(r) green. Plasma samples from 16 patients with muscle invasive high grade bladder cancer were also subjected to similar analyses. RESULTS: Promoter hypermethylation was frequently observed in RASSF1A, APC and MGMT gene promoters (p-value < 0.001). The methylation was more prominent in the muscle invasive high grade bladder cancer when compared to non-muscle invasive low grade group (p-value < 0.001) and normal bladder mucosa (p-value < 0.05). The RNA expression of RASSF1A, APC and MGMT was also found to be decreased in the muscle-invasive high grade bladder cancer when compared to the non muscle invasive low grade group (p-value < 0.05). RASSF1A, MGMT and CDKN2A showed comparable results when data from 16 plasma samples was compared to the corresponding tissue samples. CONCLUSION: Our results suggest that epigenetic silencing of RASSF1A, APC and MGMT genes is strongly associated with invasive high grade urothelial bladder cancer. Thus, status of promoter methylation has the potential to serve as valuable tool for assessing aggressiveness of urothelial cell carcinoma of bladder. PMID- 24790824 TI - Genetic diversity of rotavirus genome segment 6 (encoding VP6) in Pretoria, South Africa. AB - BACKGROUND: Rotavirus viral protein 6 (VP6), encoded by genome segment (GS) 6, is the primary target for rotavirus diagnosis by serological and some molecular techniques. Selected full length nucleotide sequences of GS 6 of rotavirus strains from South Africa were sequenced and analysed to determine genetic diversity and variations within the circulating rotaviruses. FINDINGS: The VP6 amplicons were sequenced using the Sanger ABI 3130xl. Phylogenetic and pairwise analysis revealed that the VP6 genes of the study strains belonged to two different VP6 [I] genotypes. Five sequences were assigned genotype I1 and seven as genotype I2. Comparison of the group specific antigenic regions of the South African strains to the reference strains, shows that the South African VP6 sequences belonging to the VP6 genotype I2 were highly conserved, with only two amino acids changes at positions 239 (T>N) and 261(I>V). On the other hand, South African VP6 sequences belonging to I1 genotypes revealed several amino acid variations mostly within the antigenic region III. CONCLUSIONS: Rotavirus strains with I1 and I2 genotype are predominantly circulating within the South African communities of which the later seems to be more conserved within the antigenic regions. The observed genetic variations observed within GS 6 of rotaviruses analysed in the current study are unlikely to impact negatively on the performance of the current VP6-based detection methods. Nevertheless, investigators should continually consider this diversity and adapt the primer design for the detection and characterization of the VP6 gene accordingly. PMID- 24790825 TI - Gold leaching by organic base polythionates: new non-toxic and secure technology. AB - The article present a review on own experimental and some published data which are related with the gold leaching. It is well-known that the most common and usual process of the leaching with cyanide can be dangerous, needs a great water consumption, and additional costs for remediation of the poisoned and toxic sites. The experimental data described production of poythionates which are not toxic but perspective for the prosperous gold leaching. The paper dedicated to the safe gold leaching with thiosulfates and organic salts of polythionic acids (organic base polythionates). The method of production of these polythionates based on the Smolyaninov reaction is described in stages and in details for the first time. Possible application of the polythionates application in the gold leaching is discussed and its advantages are compared with the gold leaching by cyanation. PMID- 24790826 TI - Dorsal penile nerve block for robot-assisted radical prostatectomy catheter related pain: a randomized, double-blind, placebo-controlled trial. AB - PURPOSE: Following Robotic-Assisted Radical Prostatectomy (RARP) patients routinely have penile pain and urethral discomfort secondary to an indwelling urethral catheter. Our objective was to assess the effect of dorsal penile nerve block with bupivacaine on urethral catheter-related pain after RARP. METHODS: From 2012-2013, 140 patients with organ-confined prostate cancer were enrolled in an IRB approved double-blinded, randomized control trial comparing a dorsal penile nerve block of bupivacaine versus placebo after RARP performed by a single surgeon. Patients were asked to complete questionnaires using the Wong-Bakers FACES Pain Rating scale while hospitalized and for 9 days post-operatively, until the catheter was removed. The primary end-points were: catheter-related discomfort, abdominal (incisional) pain, and bladder spasm-related discomfort. Secondary end-points included narcotic and other analgesic usage. RESULTS: 120 patients were randomized to placebo vs. bupivacaine dorsal penile nerve bock. The two arms (n = 56 bupivacaine and n = 60 placebo) did not differ in preoperative, perioperative, or pathological results. There was no difference in narcotic utilization between the two cohorts. Abdominal pain was slightly lower in the bupivacaine arm at 6 hours compared to the placebo arm, but there was no difference in abdominal pain at other time points, and there were no differences in reported catheter-related discomfort or bladder spasm-associated discomfort at any of the measured time points. CONCLUSIONS: The data does not support the routine use of a dorsal penile nerve block with bupivacaine following RARP. PMID- 24790827 TI - Comparative analysis reveals similarities between cultured submandibular salivary gland cells and liver progenitor cells. AB - Mouse submandibular salivary gland cells and liver progenitor cells from long term in vitro cultures with a high proliferation potential were side-by-side compared by methods of immunocytochemistry, quantitative real-time PCR, flow cytometry, and transcriptome analysis. The two cell types were found to be similar in expressing cell markers such as EpCAM, CD29, c-Kit, Sca-1, and c-Met. In addition, both cell types expressed cytokeratins 8, 18, and 19, alpha fetoprotein, and (weakly) albumin. Unlike the liver cells, however, the salivary gland cells in culture showed high-level expression of cytokeratin 14 and CD49f, which was indicative of their origin from salivary gland ducts. Quantitative real time PCR and deep-sequencing transcriptome analysis revealed similarities in the expression pattern of transcription factors between the two cell types. In this respect, however, the cultured salivary gland cells proved to be closer to exocrine cells of the pancreas than to the liver progenitor cells. Thus, ductal cells of postnatal submandibular salivary glands in culture show phenotypic convergence with progenitor cells of endodermal origin, suggesting that these glands may serve as a potential cell source for cellular therapy of hepatic and pancreatic disorders. The results of this study provide a deeper insight into the molecular features of salivary gland cells and may help optimize procedures for stimulating their differentiation in a specified direction. PMID- 24790828 TI - The theoretical cognitive process of visualization for science education. AB - The use of visual models such as pictures, diagrams and animations in science education is increasing. This is because of the complex nature associated with the concepts in the field. Students, especially entrant students, often report misconceptions and learning difficulties associated with various concepts especially those that exist at a microscopic level, such as DNA, the gene and meiosis as well as those that exist in relatively large time scales such as evolution. However the role of visual literacy in the construction of knowledge in science education has not been investigated much. This article explores the theoretical process of visualization answering the question "how can visual literacy be understood based on the theoretical cognitive process of visualization in order to inform the understanding, teaching and studying of visual literacy in science education?" Based on various theories on cognitive processes during learning for science and general education the author argues that the theoretical process of visualization consists of three stages, namely, Internalization of Visual Models, Conceptualization of Visual Models and Externalization of Visual Models. The application of this theoretical cognitive process of visualization and the stages of visualization in science education are discussed. PMID- 24790829 TI - In the right order of brush strokes: a sketch of a software philosophy retrospective. AB - This paper follows a discourse on software recognized as a product of art and human creativity progressing probably for as long as software exists. A retrospective view on computer science and software philosophy development is introduced. In so doing we discover parallels between software and various branches of human creative manifestations. Aesthetic properties and mutual dependency of the form and matter of art works are examined in their application to software programs. While exploring some philosophical and even artistic reflection on software we consider extended comprehension of technical sciences of programming and software engineering within the realm of liberal arts. PMID- 24790830 TI - SENTIA: a systematic online monitoring registry for children and adolescents treated with antipsychotics. AB - INTRODUCTION: Despite drastic increases in antipsychotic prescribing in youth, data are still limited regarding their safety in this vulnerable population, necessitating additional tools for capturing long-term, real world data. METHODS: We present SENTIA (SafEty of NeurolepTics in Infancy and Adolescence; https://SENTIA.es), an online registry created in 2010 to track antipsychotic adverse effects in Spanish youth <18 years old currently taking or initiating with any antipsychotic treatment. SENTIA collects information on sociodemographic, diagnostic and treatment characteristics, past personal medical/psychiatric history, healthy lifestyle habits and treatment adherence. Additionally, efficacy and adverse effect data are recorded including the Children's Global Assessment Scale; Clinical Global Impressions scale for Severity and Improvement, the Safety Monitoring Uniform Report Form, Simpson Angus Scale, Abnormal Involuntary Movement Scale, vital signs, blood pressure, and EKG. Finally, fasting blood is drawn for hematology, electrolytes, renal, liver and thyroid function, glucose, insulin, lipid, prolactin and sex hormone levels. Initially, a diagnostic interview and several psychopathology scales were also included. Patients are assessed regularly and followed even beyond stopping antipsychotics. RESULTS: Since 01/17/2011, 85 youth (11.5 +/- 2.9 (range = 4-17) years old, 70.6% male) have been included at one inaugural center. After a mean duration of 17 +/- 11 (range = 1-34) months, 78.8% are still actively followed. For feasibility reasons, the diagnostic interview and detailed psychopathology scales were dropped. The remaining data can be entered in <30 minutes. Several additional centers are currently being added to SENTIA. CONCLUSIONS: Implementation of a systematic online pharmacovigilance system for antipsychotic adverse effects in youth is feasible and promises to generate important information. PMID- 24790831 TI - Participation and significance of self-help groups for social development: exploring the community capacity in Ethiopia. AB - BACKGROUND: There are various Civil Society Organizations (CSOs) in Ethiopia among which the 'Idir' is a social and financial institution widespread both in urban and rural areas of the country. So the objectives of this study is to investigate how women members perceive the contribution of iddirs toward improving their lives and to determine whether and to what extent participation in iddirs has social impacts on their lives. METHODS: A cross-sectional qualitative study using Key Informant In-Depth Interviews (KII) and Focus Group Discussions (FGDs) was conducted in Addis Ababa, Addis Ketema Sub-city. Ethiopia. Data was collected using a semi-structured interview questionnaire and FGD guideline. Analysis of the data was made manually using thematic framework analysis method. RESULT: Though their iddir doesn't provide financial assistance, all the participants revealed the importance of installing credit mechanisms in their iddirs. However, they mentioned the inability of their respective iddirs in assisting members with their financial needs. One major difficulty mentioned was lack of capital. The participants demonstrated that the contribution of iddir in their well-being was more indispensable than the contributions of other voluntary associations they are acquainted with, such as iqub and mahiber. Especially iddir was regarded as crucial and unique in meeting emotional needs. As well, iddirs' meetings are ideal places where women share experience; discuss issues of pressing concern and their worries. Other benefit of iddir include opportunities for social interaction, risk sharing and development of friendships, dispute resolution, Sharing and using timely information more effectively, Lower level of funeral services anxiety, Improvement of self confidence and leadership role, reciprocity and coexistence and trust. CONCLUSION: Women's iddirs are the viable basis in the creation of social network which plays crucial roles in providing solutions to social and economic challenges women are facing. There was a general consensus by the participants that their iddirs were unable to offer financial assistances. Enabling women's iddirs to be independent of borrowing from banks is also indispensable and trainings on effective use of credits and the positive role of social capital formed in women's iddirs is relevant. PMID- 24790832 TI - Factors influencing anti-asthmatic generic drug consumption in Morocco: 1999 2010. AB - BACKGROUND: The increasing availability of generic drugs (GD) resulted in a remarkable reduction in treatment costs that allowed a better access to health care.The aim of this study is to evaluate the share of anti-asthmatic generic drugs during the period 1999-2010 in Morocco and to look at the factors influencing generic development. METHODS: In this study, we used Moroccan sales data from IMS Health (Intercontinental Marketing Services). The consumption of the drugs was expressed in DDD/1000 inhabitants/day according to the WHO ATC/DDD methodology. RESULTS: Between 1999 and 2010, anti-asthmatic consumption increased from 3.91 to 14.43 DDD/1000 inhabitants/day. The market of anti-asthmatic generic drugs progressed from 1.83 (47%) to 2.18 (23%) DDD/1000 inhabitants/day from 1999 to 2010. In 2010, inhaled glucocorticosteroids ranked first (0.83 DDD/1000 inhabitants/day), followed by inhaled short acting beta agonists (0.73 DDD/1000 inhabitants/day). The number of brands went from 27 in 1999 to 34 in 2010, with a generic share increasing from 55.55% to 70.59%. The number of anti-asthmatic pharmaceutical preparations increased from 57 to 64 during the same period, of which 31 and 42 were generic preparations. In 2010, the total cost of anti asthmatic dugs was about 22 million euro, the generics representing 14 million euro. CONCLUSION: Despite the introduction of a compulsory insurance scheme called "AMO", that allows a refund for 69.5% of anti-asthmatic specialties marketed in Morocco, anti-asthmatic generic drug consumption remains limited. The Moroccan market is still largely dominated by the originator drugs with still valid patents. PMID- 24790833 TI - Isolation and characterization of H9N2 influenza virus isolates from poultry respiratory disease outbreak. AB - The present study reports isolation and characterization of H9N2 virus responsible for disease characterized by symptoms including difficulty in respiration, head swelling, nasal discharge, reduced feed intake, cyanotic comb, reduced egg production and mortality. Virus isolation from allantoic fluid inoculated with tracheal aspirates and whole genome sequencing of two isolates were performed on an Ion-Torrent sequencer. Phylogenetic analysis revealed that the two H9N2 isolates are reassortant viruses showing a G1-like lineage for HA, NA and NP, a Hok/49/98-like lineage for PB1 and PA, PK/UDL-01/05-like lineage for PB2, IL/90658/00-like lineage for NS and an unknown lineage for M gene. Analyses of the HA cleavage site showed a sequence of (333PARSSR?GL340) indicating that these isolates are of low pathogenicity. Isolate 2 has leucine at amino acid position 226, a substitution which is associated with mammalian adaptation of avian influenza virus. Isolate 1 has the S31N substitution in the M2 gene that has been associated with drug resistance as well as R57Q and C241Y mutations in the NP gene which are associated with human adaptation. The result reported here gives deep insight in to H9N2 viruses circulating in domestic poultry of India and supports the policy of active efforts to control and manage H9N2 infections in Indian poultry. PMID- 24790835 TI - Video-assisted thoracoscopic surgery. PMID- 24790834 TI - Overcoming challenges and opening new opportunities in glycoproteomics. AB - Glycoproteomics has emerged as a prime area of interest within the field of proteomics because glycoproteins have been shown to function as biomarkers for disease and as promising therapeutic targets. A significant challenge in the study of glycoproteins is the fact that they are expressed in relatively low abundance in cells. In response, various enrichment methods have been developed to improve the detection of glycoproteins. One such method involves their capture via oxidation of their glycan chains and covalent attachment with hydrazide resins which, when catalyzed by PNGase F, release N-linked glycans and convert the glycosite Asn to Asp; this conversion is identifiable with LC/ESI-MS/MS as a corresponding increase of 0.984 Da in molecular weight. The present study builds on this body of work, providing evidence of three additional strategies that improve glycoprotein identification: (1) use of a high resolution mass spectrometer-the Q Exactive MS-which delivers 2-3 times more glycoprotein identifications than a low resolution MS; (2) optimization of instrument settings and database search parameters to reduce misidentification of N-linked glycopeptides to ~1 percent; and (3) labeling glycopeptides with (18)O during PNGase F treatment to locate N-linked glycosites within peptides containing multiple N-linked sequons. PMID- 24790836 TI - Meta-analysis of intentional sublobar resections versus lobectomy for early stage non-small cell lung cancer. AB - BACKGROUND: Surgical resection is the preferred treatment modality for eligible candidates with non-small cell lung cancer (NSCLC). However, the selection of sublobar resection versus lobectomy for early-stage NSCLC remains controversial. Previous meta-analyses comparing these two procedures presented data without considering the significant differences in the patient selection processes in individual studies. The present study aimed to compare the overall survival (OS) and disease-free survival (DFS) outcomes of patients who underwent sublobar resections who were also eligible for lobectomy procedures with those who underwent lobectomy. METHODS: An electronic search was conducted using five online databases from their dates of inception to December 2013. Studies were selected according to predefined inclusion criteria and meta-analyzed using hazard ratio (HR) calculations. RESULTS: Twelve studies met the selection criteria, including 1,078 patients who underwent sublobar resections and 1,667 patients who underwent lobectomies. From the available data, there was no significant differences in OS [HR 0.91; 95% confidence interval (CI) 0.64-1.29] or DFS (HR 0.82; 95% CI 0.60-1.12) between the two treatment arms. In addition, no significant OS difference was detected for patients who underwent segmentectomies compared to lobectomies (HR 1.04; 95% CI 0.66-1.63, P=0.86). CONCLUSIONS: Using the available data in the current literature, patients who underwent sublobar resection for small, peripheral NSCLC after intentional selection rather than ineligibility for greater resections achieved similar long term survival outcomes as those who underwent lobectomies. However, patients included for the present meta-analysis were a highly selected cohort and these results should be interpreted with caution. The importance of the patient selection process in individual studies must be acknowledged to avoid conflicting outcomes in future meta-analyses. PMID- 24790837 TI - Open, thoracoscopic and robotic segmentectomy for lung cancer. AB - While lobectomy is the standard procedure for early stage lung cancer, the role of sublobar resection is currently under investigation for selected patients with small tumors. In this review, studies reporting outcomes on open, thoracoscopic and robotic segmentectomy were analyzed. In patients with stage I lung cancer, with tumors <2 cm in diameter and within segmental anatomic boundaries, segmentectomy appears to have equivalent rates of morbidity, recurrence and survival when compared to lobectomy. Segmentectomy also resulted in greater preservation of lung function and exercise capacity than lobectomy. It appears reasonable to consider segmentectomy for patients with stage I lung cancer (particularly in air-containing tumors with ground glass opacities) where tumors are <2 cm in diameter and acceptable segmental margins are obtainable, especially in patients with advanced age, poor performance status, or poor cardiopulmonary reserve. The results of two ongoing randomized controlled trials (CALGB 140503 and JCOG0802/WJOG4607L) and additional well-designed studies on open, thoracoscopic, and robotic segmentectomy will be important for clarifying the role of segmentectomy for lung cancer. PMID- 24790838 TI - Segmentectomy versus lobectomy for clinical stage IA lung adenocarcinoma. AB - BACKGROUND: Despite the increasing prevalence of the early discovery of small sized non-small cell lung cancers (NSCLCs), particularly adenocarcinoma, sublobar resection has not yet gained acceptance for patients who can tolerate lobectomy. METHODS: We compared the outcomes of segmentectomy (n=155) and lobectomy (n=479) in 634 consecutive patients with clinical stage IA lung adenocarcinoma and in propensity score-matched pairs. Those who had undergone wedge resection were excluded. RESULTS: The 30-day postoperative mortality rate in this population was zero. Patients with large or right-sided tumors, high maximum standardized uptake value (SUVmax), pathologically invasive tumors (with lymphatic, vascular, or pleural invasion), and lymph node metastasis underwent lobectomy significantly more often. Three-year recurrence-free survival (RFS) was significantly higher after segmentectomy compared to lobectomy (92.7% vs. 86.9%, P=0.0394), whereas three-year overall survival (OS) did not significantly differ (95.7% vs. 94.1%, P=0.162). Multivariate analyses of RFS and OS revealed age and SUVmax as significant independent prognostic factors, whereas gender, tumor size and procedure (segmentectomy vs. lobectomy) were not. In 100 propensity score-matched pairs with variables adjusted for age, gender, tumor size, SUVmax, tumor location, the three-year RFS (90.2% vs. 91.5%) and OS (94.8% vs. 93.3%) after segmentectomy and lobectomy respectively were comparable. CONCLUSIONS: Segmentectomy with reference to SUVmax should be considered as an alternative for clinical stage IA adenocarcinoma, even for low-risk patients. PMID- 24790839 TI - Lobectomy vs. segmentectomy for NSCLC (T<2 cm). AB - The extent of surgical resection for peripheral clinical T1N0M0 non-small cell lung cancer (NSCLC) <=2 cm continues to be a matter of debate. Eighteen years ago, a randomized controlled trial (RCT) established lobectomy as the standard of care for peripheral clinical T1N0M0 NSCLC. However, numerous publications since then have reported similar outcomes for patients treated with segmentectomy or lobectomy for peripheral clinical T1N0M0 NSCLC 2 cm or smaller in size. The majority of these publications are retrospective studies. Two ongoing RCTs aim to resolve this debate, one in Japan and the other in the United States. This manuscript is a comprehensive review of the literature that compares lobectomy to segmentectomy for peripheral clinical T1N0M0 NSCLC 2 cm or smaller in size. Until data from the ongoing RCTs become available, this literature review provides the best evidence to guide the thoracic surgeon in the management of these patients. PMID- 24790840 TI - Treatment of stage I lung cancer in high-risk and inoperable patients: SBRT vs. RFA vs. sublobar resection. PMID- 24790841 TI - Techniques to define segmental anatomy during segmentectomy. AB - Pulmonary segmentectomy is generally acknowledged to be more technically complex than lobectomy. Three-dimensional computed tomography (3D CT) angiography is useful for understanding the pulmonary arterial and venous branching, as well as planning the surgery to secure adequate surgical margins. Comprehension of the intersegmental and intrasegmental veins makes the parenchymal dissection easier. To visualize the segmental border, creation of an inflation-deflation line by using a method of inflating the affected segment has become the standard in small sized lung cancer surgery. Various modifications to create the segmental demarcation line have been devised to accurately perform the segmentectomy procedure. PMID- 24790842 TI - Role of segmentectomy for pulmonary metastases. AB - Pulmonary metastasectomy has not been proven by randomized trials to be more effective than non-operative management, but currently has a well-accepted role for certain primary cancers, in particular colorectal cancer and sarcoma. One of the principal tenets for pulmonary metastasectomy is that all lesions are resected. A major technical difference compared to surgical management of primary lung cancer is that management of metastatic disease frequently requires the resection of multiple and possibly bilateral lesions. In addition, surgeons and patients must often consider repeat surgery for management of metachronous lesions that develop some time after a previous resection, given the nature of metastatic cancer. Therefore, surgeons must ensure complete resection of lesions with negative margins but also must be cognizant of minimizing resection of functional lung tissue as much as possible, in order to ensure that both current and future lesions can be resected while leaving patients with adequate pulmonary function. Segmentectomy is generally infrequently utilized for pulmonary metastasectomy, but has a role for lesions for which a wedge resection is technically not possible but a lobectomy is not required. Segmentectomy can be an important tool in achieving the dual goals of complete resection and impacting pulmonary function as little as possible. Using minimally invasive techniques with thoracoscopy to perform segmentectomy is associated with less short-term morbidity than thoracotomy. Although the use of minimally invasive techniques limits manual palpation and therefore potential resection of small lesions not identified by pre-resection imaging, the current literature does not suggest that these procedures should be done via thoracotomy. PMID- 24790843 TI - Surgical atlas of thoracoscopic lobectomy and segmentectomy. AB - Thoracoscopic lobectomy or segmentectomy via the posterior approach is a safe, reliable and reproducible technique. It was first developed by Mr. William Walker from Edinburgh in 1992. The main advantages of the posterior approach include: (I) easy access to posterior hilum and segmental bronchi; (II) safe dissection, as the tips of the instruments are coming towards the operating surgeon; and (III) complete ipsilateral lymph node clearance. PMID- 24790844 TI - VATS segmentectomy for pulmonary metastasis. PMID- 24790845 TI - Minimally invasive VATS left upper lobe apical trisegmentectomy. PMID- 24790846 TI - Totally thoracoscopic left upper lobe tri-segmentectomy. PMID- 24790847 TI - Thoracoscopic superior segmentectomy. PMID- 24790848 TI - Single incision video-assisted thoracoscopic anatomic segmentectomy. PMID- 24790850 TI - VATS segmentectomy utilizing the Copenhagen approach. PMID- 24790849 TI - Nonintubated thoracoscopic segmentectomy-left upper lobe trisegmentectomy. PMID- 24790851 TI - Technical strategy for dealing with bleeding during thoracoscopic lung surgery. PMID- 24790852 TI - Prevention and management of postoperative air leaks. PMID- 24790853 TI - The application of capnography to differentiate peri-chest tube air leak from parenchymal leak following pulmonary surgery. AB - Prolonged air leak is a common complication of pulmonary resection. However, while a bubbling chest drain is commonly related to parenchymal air leakage, it may also be caused by air entering the pleural cavity via an incomplete seal of the tissues at the chest tube insertion site. Examination alone is not sufficient to guide the surgeon as to which of the above complications is responsible for drain bubbling. We describe a simple method, whereby a CO2 monitoring device is attached to the chest drain to determine whether the air loss observed is in fact due to a pulmonary air leak. PMID- 24790854 TI - Smoking and lung cancer. PMID- 24790855 TI - Off-pump bilateral internal thoracic artery grafting. PMID- 24790856 TI - Serum amyloid A and pairing formyl peptide receptor 2 are expressed in corneas and involved in inflammation-mediated neovascularization. AB - AIM: To solidify the involvement of Saa-related pathway in corneal neovascularization (CorNV). The pathogenesis of inflammatory CorNV is not fully understood yet, and our previous study implicated that serum amyloid A (Saa) 1 (Saa1) and Saa3 were among the genes up-regulated upon CorNV induction in mice. METHODS: Microarray data obtained during our profiling project on CorNV were analyzed for the genes encoding the four SAA family members (Saa1-4), six reported SAA receptors (formyl peptide receptor 2, Tlr2, Tlr4, Cd36, Scarb1, P2rx7) and seven matrix metallopeptidases (Mmp) 1a, 1b, 2, 3, 9, 10, 13 reportedly to be expressed upon SAA pathway activation. The baseline expression or changes of interested genes were further confirmed in animals with CorNV using molecular or histological methods. CorNV was induced in Balb/c and C57BL/6 mice by placing either three interrupted 10-0 sutures or a 2 mm filter paper soaked with sodium hydroxide in the central area of the cornea. At desired time points, the corneas were harvested for histology examination or for extraction of mRNA and protein. The mRNA levels of Saa1, Saa3, Fpr2, Mmp2 and Mmp3 in corneas were detected using quantitative reverse transcription-PCR, and SAA3 protein in tissues detected using immunohistochemistry or western blotting. RESULTS: Microarray data analysis revealed that Saa1, Saa3, Fpr2, Mmp2, Mmp3 messengers were readily detected in normal corneas and significantly up-regulated upon CorNV induction. The changes of these five genes were confirmed with real-time PCR assay. On the contrary, other SAA members (Saa2, Saa4), other SAA receptors (Tlr2, Tlr4, Cd36, P2rx7, etc), or other Mmps (Mmp1a, Mmp1b, Mmp9, Mmp10, Mmp13) did not show consistent changes. Immunohistochemistry study and western blotting further confirmed the expression of SAA3 products in normal corneas as well as their up-regulation in corneas with CorNV. CONCLUSION: SAA-FPR2 pathway composing genes were expressed in normal murine corneas and, upon inflammatory stimuli challenge to the corneas, their expressions were up-regulated, suggesting their roles in pathogenesis of CorNV. The potential usefulness of SAA-FPR2 targets in future management of CorNV-related diseases deserves investigation. PMID- 24790857 TI - Interleukin-6 receptor blockade suppresses subretinal fibrosis in a mouse model. AB - AIM: To determine the involvement of the interleukin (IL)-6 with the development of experimental subretinal fibrosis in a mouse model. METHODS: Subretinal fibrosis was induced by subretinal injection of macrophage-rich peritoneal exudate cells and the local expression of IL-6 was assessed by quantitative real time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) at various time points. In addition, we investigated the effect of IL-6 receptor (IL-6R) monoclonal antibody (MR16-1) on subretinal fibrosis development. RESULTS: IL-6 mRNA level was significantly elevated at 1d after subretinal fibrosis induction and increased further to about 12-fold at 2d, reaching the peak. The result of ELISA showed that IL-6 protein was not detected in naive mice. At 2d after subretinal fibrosis induction, IL-6 protein level was upregulated to 67.33+/-14.96 pg/mg in subretinal fibrosis mice. MR16-1 treatment resulted in a reduced subretinal fibrosis area by 48% compared to animals from control group at 7d. CONCLUSION: Our results indicated that IL-6 signaling may contribute to the pathogenesis of subretinal fibrogenesis and IL-6R inhibition may provide an effective, novel treatment of advanced and late-stage neovascular age-related macular degeneration. PMID- 24790858 TI - Inhibition of retinopathy of prematurity in rat by intravitreal injection of sorafenib. AB - AIM: To investigate the effect of intravitreal injection administered sorafenib, a multikinase inhibitor, in a rat model of oxygen-induced retinopathy (OIR). METHODS: Seven-day-old Sprague-Dawley rats (n=144) were randomly assigned to six groups. Group A received normal partial oxygen pressure and groups B, C, D, E and F were exposed to hyperoxia (75+/-2)% from postnatal 7d (P7) to P12 to induce retinopathy of prematurity. The rats in groups C, D, E and F were received intravitreal injections of either vehicle (DMSO) or sorafenib at P12 (5, 20 and 80 ug, respectively). Then they returned to normoxia after P12. The retinas were whole-mounted and imaged with a confocal microscopy. The vascular branching points were counted to quantify neovascularization at P17. Cross-sections of the retina were stained with hematoxylin and eosin (HE). The nuclei of new vessels breaking the internal limiting membrane were counted to quantify the proliferative neovascular response. RESULTS: The retinal vessel in groups B and C turned into tortuosity and a great deal of neovascularization were observed. Sorafenib-treated rats had significantly less neovascularization as compared with vehicle-treated and control rats in a dose dependent manner (P<0.05). The number of vascular branching points in A, B, C, D, E and F were 16.50+/-3.90, 37.44+/ 6.47, 37.08+/-5.10, 30.80+/-6.85, 26.08+/-5.08 and 19.83+/-3.51, respectively. The number of the nuclei of retinal new vessel in A, B, C, D, E and F were 0.22+/ 0.42, 35.66+/-4.70, 35.30+/-4.54, 27.30+/-4.28, 21.41+/-3.53, and 7.41+/-2.87, respectively. There were significant difference between each group (P<0.05) except groups B and C. CONCLUSION: In the rat OIR model, sorafenib could inhibit retinal neovascularization in a dose dependent manner. PMID- 24790860 TI - Keratinocyte growth factor-2 and autologous serum potentiate the regenerative effect of mesenchymal stem cells in cornea damage in rats. AB - AIM: To investigate the healing process after severe corneal epithelial damage in rats treated with mesenchymal stem cells (MSCs) cultured with or without keratinocyte growth factor (KGF-2) and autologous serum (AS) on amniotic membrane (AM). Many patients are blind and devastated by severe ocular surface diseases due to limbal stem cell deficiency. Bone marrow-derived MSCs are potential sources for cell-based tissue engineering to repair or replace the corneal tissue, having the potential to differentiate to epithelial cells. METHODS: The study included 5 groups each including 10 female "Sprague Dawley" rats in addition to 20 male rats used as bone marrow donors. Group I rats received AM+MSCs, Group II rats AM+MSCs cultured with KGF-2, Group III rats AM+MSCs cultured with KGF-2+AS, Group IV rats only AM and Group V rats, none. AS was derived from blood drawn from male rats and bone marrow was obtained from the femur and tibia bones of the same animals. Therapeutic effect was evaluated with clinical, histopathological and immunohistochemical assessment. MSC engraftment was demonstrated via detection of donor genotype (Y+) in the recipient tissue (X) with polymerase chain reaction. RESULTS: Corneal healing was significantly better in Groups I-III rats treated with MSC transplantation compared to Group IV and Group V rats with supportive treatment only. The best results were obtained in Group III rats with 90% transparency, 70% lack of neovascularization, and 100% epithelium damage limited to less than 1/4 of cornea. CONCLUSION: We suggest that culture of MSCs with KGF-2 and AS on AM is effective in corneal repair in case of irreversible damage to limbal stem cells. PMID- 24790859 TI - Evaluation of the in vitro antimicrobial properties of ultraviolet A/riboflavin mediated crosslinking on Candida albicans and Fusarium solani. AB - AIM: To evaluate the antimicrobial properties of ultraviolet A (UVA) (365 nm)/riboflavin against Candida albicans and Fusarium solani. METHODS: Two fungus isolates were cultured in vitro and prepared with 10-fold serial PBS dilutions of cell concentration. For each dilution of fungus suspension, the concentration (colony-forming units/mL, CFU/mL) and the inactivation ratio of fungal cells were evaluated under 4 conditions: no treatment (control), UVA (365 nm)/riboflavin, riboflavin, and UVA (365 nm). RESULTS: The cell concentration decreased in UVA (365 nm)/riboflavin group for Candida albicans at each dilution and Fusarium solani at dilutions of 10(4), 10(3), 10(2) CFU/mL, when compared with that in control, riboflavin, and UVA (365 nm) groups (P<0.01). No difference of cell concentration was detected amongst the culture of control, riboflavin, and UVA (365 nm) groups for the two fungus. There is a negative correlation between suspension concentration (log-transformed) and the inactivation ratio in UVA (365 nm)/riboflavin group for Candida albicans and Fusarium solani (P<0.01). CONCLUSION: According to the standard protocol of corneal collagen cross-linking, UVA (365 nm)/riboflavin combination treatment is found to moderately inactivate the viability of Candida albicans and Fusarium solani in vitro. The inactivation ratio was found to increase with the decrease of cell concentration under UVA (365 nm)/riboflavin condition. PMID- 24790861 TI - Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization. AB - AIM: To evaluate the inhibitory effects of regorafenib (BAY 73-4506), a multikinase inhibitor, on corneal neovascularization (NV). METHODS: Thirty adult male Sprague-Dawley rats weighing 250-300 g, were used. Corneal NV was induced by NaOH in the left eyes of each rat. Following the establishment of alkali burn, the animals were randomized into five groups according to topical treatment. Group 1 (n = 6) received 0.9% NaCl, Group 2 (n = 6) received dimethyl sulfoxide, Group 3 (n = 6) received regorafenib 1 mg/mL, Group 4 (n =6) received bevacizumab 5 mg/mL and Group 5 (n = 6) received 0.1% dexamethasone phosphate. On the 7d, the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea's total area using computer-imaging analysis. The corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by immunostaining. RESULTS: A statistically significant difference in the percent area of corneal NV was found among the groups (P <0.001). Although the Group 5 had the smallest percent area of corneal NV, there was no difference among Groups 3, 4 and 5 (P >0.005). There was a statistically significant difference among the groups in apoptotic cell density (P = 0.002). The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups (P <0.05). The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3, 4 and 5 than in Groups 1 and 2. CONCLUSION: Topical administration of regorafenib 1 mg/mL is partly effective for preventing alkali-induced corneal NV in rats. PMID- 24790862 TI - Effects of Honghua preserved amniotic membrane on scar healing in experimental glaucoma surgery. AB - AIM: To investigate the efficacy and safety of Honghua preserved amniotic membrane (AM) for preventing scar formation of the filtering bleb in a rabbit model of glaucoma trabeculectomy surgery. METHODS: Totally 36 rabbits (36 eyes) were randomly divided into 3 groups: the experimental group (ocular trabeculectomy in combination with Honghua preserved AM transplantation), the control group (ocular trabeculectomy surgery in combination with AM implantation), and the blank group (single trabeculectomy). Clinical observations [including intraocular pressure (IOP), filtering blebs and complications], Masson Trichrome staining, real-time quantitative reverse transcription-polymerase chain reaction (real-time PCR), Western blot were performed on different time points (D1, D7, D14, D21 and D56) after the surgery. RESULTS: After operated for 14d, there were statistically significant differences in the filtering blebs compared to the situation before operation (P<0.05), whereas no statistically difference on that among three groups (P>0.05). After 21d, the IOP of experimental group was lowest (P<0.05). There was significant difference between control group and blank group (P<0.05). On postoperative D14, the mean number of fibroblasts in the experimental group was significantly lower (40.6+/-10.2) compared to those in the control group (54.4+/-10.8) and blank group (68.2+/-11.6) (P<0.05, respectively). The mean numbers of the macrophage in the experimental and control groups were respcitively significantly lower versus the blank group (P<0.05, P<0.05, respectively). Compared to that in blank group, the level of transforming growth factor-beta (TGF-beta1) expression in sclera and conjunctival areas was reduced in the experimental and control groups on protein and mRNA level (P<0.05), but not significant difference between these two groups (P>0.05). CONCLUSION: The trabeculectory surgery with Honghua preserved AM can control IOP, sustain the functional filtration bleb, inhibit the proliferation of fibroblasts and open the filtrating pathway on the rabbit glaucoma models. PMID- 24790863 TI - Establishing an experimental rat model of photodynamically-induced retinal vein occlusion using erythrosin B. AB - AIM: To develop a reliable, reproducible rat model of retinal vein occlusion (RVO) with a novel photosensitizer (erythrosin B) and study the cellular responses in the retina. METHODS: Central and branch RVOs were created in adult male rats via photochemically-induced ischemia. Retinal changes were monitored via color fundus photography and fluorescein angiography at 1 and 3h, and 1, 4, 7, 14, and 21d after irradiation. Tissue slices were evaluated histopathologically. Retinal ganglion cell survival at different times after RVO induction was quantified by nuclear density count. Retinal thickness was also observed. RESULTS: For all rats in both the central and branch RVO groups, blood flow ceased immediately after laser irradiation and retinal edema was evident at one hour. The retinal detachment rate was 100% at 3h and developed into bullous retinal detachment within 24h. Retinal hemorrhages were not observed until 24h. Clearance of the occluded veins at 7d was observed by fluorescein angiography. Disease manifestation in the central RVO eyes was more severe than in the branch RVO group. A remarkable reduction in the ganglion cell count and retinal thickness was observed in the central RVO group by 21d, whereas moderate changes occurred in the branch RVO group. CONCLUSION: Rat RVO created by photochemically induced ischemia using erythrosin B is a reproducible and reliable animal model for mimicking the key features of human RVO. However, considering the 100% rate of retinal detachment, this animal model is more suitable for studying RVO with chronic retinal detachment. PMID- 24790864 TI - Effects of hepatocyte growth factor on MMP-2 expression in scleral fibroblasts from a guinea pig myopia model. AB - AIM: To investigate the effects of hepatocyte growth factor (HGF) on MMP-2 expression in scleral fibroblasts from guinea pig with LIM. METHODS: Sixty 1-week old guinea pigs were chosen for the study. The right eyes were treated with -10.0 D lenses as the LIM group; the left eyes remained untreated as the control group. The refraction and axial length were measured by streak retinoscopy and A-scan ultrasonography respectively prior to and 4 weeks after the experiment. Four weeks later, the guinea pigs were sacrificed and primary scleral fibroblasts were taken for tissue culture. The 3rd-5th generation scleral fibroblasts were chosen for the experiments. The expression levels of HGF and MMP-2 protein in the scleral fibroblasts were analyzed by Western blotting. After HGF with different doses acted on the scleral fibroblasts of the control group, MMP-2 protein expression in the scleral fibroblasts was analyzed by Western blotting. HGF siRNA was transfected into the scleral fibroblasts of the LIM group and the protein expressions of HGF and MMP-2 were analyzed by Western blotting. RESULTS: The LIM group became myopic with a significant increase in axial length (7.97+/-0.29 mm vs 7.01+/-0.26 mm, P<0.05), and a significant decrease in refraction (-5.06+/ 0.31 D vs 0.55+/-0.25 D, P<0.05) compared with the control group. The protein expression of HGF in the scleral fibroblasts of the LIM group was significantly higher compared with the control group ( 1.26+/-0.04 vs 0.32 +/-0.04, P<0.05). The protein expression of MMP-2 in the scleral fibroblasts of the LIM group was significantly higher compared with the control group (0.89+/-0.06 vs 0.42+/-0.05, P<0.05). In the scleral fibroblasts of the control group, HGF(0, 0.1, 1, 10 ng/mL) upregulated MMP-2 protein expression in a dose-dependent manner (0.35+/ 0.03, 0.44+/-0.02, 0.91+/-0.03, 1.33+/-0.04, all P<0.05). In the scleral fibroblasts of the LIM group transfected with HGF siRNA, MMP-2 protein expressions were significantly decreased compared with the negative control group (0.29+/-0.03 vs 0.81+/-0.05, P<0.05). CONCLUSION: HGF is a upstream mediator of MMP-2 in scleral fibroblasts from guinea pig. PMID- 24790865 TI - Comparison of form-deprived myopia and lens-induced myopia in guinea pigs. AB - AIM: To study the efficacy difference between form-deprived myopia (FDM) and lens induced myopia (LIM), the degree of myopia, axial length and pathological changes of the posterior sclera from guinea pigs were evaluated. METHODS: Four-week pigmented guinea pigs were randomly assigned into 3 groups, including normal control (n=6), FDM group with monocular cover (n=11) and LIM group with monocular -7D lens treatment (n=11). FDM group was form-deprived while LIM group was lens induced for 14 d. Refractive error and axial length were measured prior to and post treatment, respectively. Morphological changes of sclera were examined using both light and electronic microscopes. RESULTS: After 14d treatment, refractive errors for FDM group and LIM group were -3.05+/-0.71D and -2.12+/-1.29D, respectively, which were significantly more myopic than that of normal controls and fellow control eyes (P<0.01). As for axial length, it was 7.93+/-0.03 mm for FDM group and 7.89+/-0.06 mm for LIM group, which were significantly longer than both normal and fellow controls (P<0.01). With respect to both refractory error and axial length, the differences between FDM group and LIM group were not significant (P>0.05). Under light microscope, both FDM group and LIM group showed thinned sclera, disarrangement of fibrosis and enlarged disassociation between fibers. Consistently, ultrastructural examination showed degenerated fibroblasts and thinned fibers in posterior sclera. CONCLUSION: Following two weeks of myopia induction in guinea pigs, with regard to the degree of myopia, axial length and pathological alterations, there was no significant difference between FDM and LIM models. Therefore, FDM and LIM are equally effective and useful as a model of experimental myopia and guinea pigs are ideal animals for induction of experimental myopia because their high sensitivity to both form-deprivation and lens-induction. PMID- 24790866 TI - Improvement of visual acuity based on optical coherence tomography patterns following intravitreal bevacizumab treatment in patients with diabetic macular edema. AB - AIM: To report the visual outcome based on various patterns of optical coherence tomography (OCT) morphology in diabetic macular edema (DME), following treatment with anti-VEGF intravitreal bevacizumab (IVB) injection. METHODS: Sixty-seven consecutive subjects with centre involving DME underwent intravitreal injection of Bevacizumab (1.25 mg/0.05 mL) in this retrospective, comparative, non randomized study. The DME was classified into one of four categories: focal, diffuse, focal cystoid and neurosensory detachment based on OCT. Best corrected visual acuity (BCVA), macular appearance, and OCT findings were used to decide whether the subject should have a repeat injection of intravitreal bevacizumab. Outcome measures were a change in mean BCVA (Snellen converted to logMAR) and central macular thickness (CMT) in each group during the six month follow-up period. RESULTS: The mean BCVA improved to logMAR 0.23 at final follow-up from a baseline of 0.32 logMAR (P=0.040) in the focal group, logMAR 0.80 at final follow up from a baseline of 0.82 logMAR (P=0.838) in the diffuse group, worsened to logMAR 0.53 at final follow-up from a baseline of 0.43 logMAR (P=0.276) in the focal cystoid group, and improved to logMAR 0.79 at final follow-up from a baseline of 0.93 logMAR (P=0.490) in the neurosensory detachment group. The mean CMT before treatment were 298.8+/-25.03 um in the focal group, 310.8+/-40.6 um in the diffuse group, 397.15+/-31.05 um in the focal cystoid group and 401.03+/-75.1 um in the neurosensory detachment group. A mean of 2.05 (range: 1-5) injections in the focal group, 1.32 (range: 1-2) in the diffuse group, 2.6 (range: 1-6) in the focal cystoid group and 2.6 (range: 1-6) in the neurosensory detachment group were performed during the six month follow-up period. Following intravitreal bevacizumab treatment, vision improved, remained unchanged or worsened in 11, 7 and 2 subjects in focal group; 11, 9 and 8 in diffuse group; 0, 2 and 4 in focal cystoid group and 5, 5 and 3 subjects respectively in neurosensory detachment group. CONCLUSION: OCT morpholgy patterns in DME may predict the effects of intravitreal bevacizumab treatment, and patients with focal DME are most likely to benefit from the improvent of visual acuity from this treatment. PMID- 24790867 TI - Comparative proteomic analysis of plasma proteins in patients with age-related macular degeneration. AB - AIM: To find the significant altered proteins in age-related macular degeneration (AMD) patients as potential biomarkers of AMD. METHODS: A comparative analysis of the protein pattern of AMD patients versus healthy controls was performed by means of proteomic analysis using two-dimensional gel electrophoresis followed by protein identification with MALDI TOF/TOF mass spectrometry. RESULTS: We identified 28 proteins that were significantly altered with clinical relevance in AMD patients. These proteins were involved in a wide range of biological functions including immune responses, growth cytokines, cell fate determination, wound healing, metabolism, and anti-oxidance. CONCLUSION: These results demonstrate the capacity of proteomic analysis of AMD patient plasma. In addition to the utility of this approach for biomarker discovery, identification of alterations in endogenous proteins in the plasma of AMD patient could improve our understanding of the disease pathogenesis. PMID- 24790869 TI - Comparison of corneal flap thickness using a FS200 femtosecond laser and a moria SBK microkeratome. AB - AIM: To evaluate differences in flap thickness resulting from use of an Alcon Wavelight FS200 femtosecond laser and a MORIA SBK microkeratome when making a 110 um-thick corneal flap and to identify the potential factors that affect corneal flap thickness. METHODS: A prospective case study was performed on 120 eyes of 60 patients who were divided into two groups for LASIK, each group consisting of 60 eyes (30 patients). The corneal flaps were created using an Alcon Wavelight FS200 femtosecond laser or a MORIA SBK microkeratome. The central corneal flap thickness was calculated by subtraction pachymetry. Age, central corneal thickness (CCT), spherical equivalent refraction, mean keratometry, and corneal diameter were recorded preoperatively for analysis. RESULTS: Cutting of all flaps was easily performed without intraoperative complications. In the Alcon Wavelight FS200 femtosecond laser group, the mean right and left corneal flap thicknesses were 114.0+/-6.6 um (range: 98-126) and 111.4+/-7.6 um (range: 98-122), respectively. The difference (2.6+/-9.1 um) in the corneal flap thickness between the right and left eyes was not significant (t=1.59, P=0.12). Stepwise regression analysis indicated that the resulting corneal flap thickness was unrelated to the patient's age, preoperative CCT, spherical equivalent refraction, mean keratometry, or corneal diameter. In the MORIA SBK microkeratome group, the mean right and left corneal flap thicknesses were 110.6+/-7.4 um (range: 97-125 um) and 108.2+/-6.1 um (range: 78-123 um), respectively. The difference in the corneal flap thickness between the right and left eyes (2.4+/-6.5um) was not significant (t=2.039, P=0.0506). The corneal flap thickness was positively correlated with the preoperative CCT through stepwise regression analysis (r=0.297, P=0.021). The corneal flap thickness was not related to age, spherical equivalent refraction, mean keratometry, or corneal diameter. The corneal flap thickness was estimated using the following equation: Tflap=67.77+0.076 CCT (F=5.63, P=0.021). CONCLUSION: Both the Alcon Wavelight FS200 femtosecond laser and the MORIA SBK microkeratome produced 110-um-thick corneal flaps. The central corneal flap thickness was positively correlated with the preoperative CCT in MORIA SBK microkeratome surgery. PMID- 24790868 TI - Multiple methods of surgical treatment combined with primary IOL implantation on traumatic lens subluxation/dislocation in patients with secondary glaucoma. AB - AIM: To describe clinical findings and complications from cases of traumatic lens subluxation/dislocation in patients with secondary glaucoma, and discuss the multiple treating methods of operation combined with primary intraocular lens (IOL) implantation. METHODS: Non-comparative retrospective observational case series. PARTICIPANTS: 30 cases (30 eyes) of lens subluxation/dislocation in patients with secondary glaucoma were investigated which accepted the surgical treatment by author in the Ophthalmology of Xi'an No.4 Hospital from 2007 to 2011. According to the different situations of lens subluxation/dislocation, various surgical procedures were performed such as crystalline lens phacoemulsification, crystalline lens phacoemulsification combined anterior vitrectomy, intracapsular cataract extraction combined anterior vitrectomy, lensectomy combined anterior vitrectomy though peripheral transparent cornea incision, pars plana lensectomy combined pars plana vitrectomy, and intravitreal cavity crystalline lens phacofragmentation combined pars plana vitrectomy. And whether to implement trabeculectomy depended on the different situations of secondary glaucoma. The posterior chamber intraocular lenses (PC-IOLs) were implanted in the capsular-bag or trassclerally sutured in the sulus decided by whether the capsular were present. MAIN OUTCOME MEASURES: visual acuity, intraocular pressure, the situation of intraocular lens and complications after the operations. RESULTS: The follow-up time was 11-36mo (21.4+/-7.13). Postoperative visual acuity of all eyes were improved; 28 cases maintained IOP below 21 mm Hg; 2 cases had slightly IOL subluxation, 4 cases had slightly tilted lens optical area; 1 case had postoperative choroidal detachment; 4 cases had postoperative corneal edema more than 1wk, but eventually recovered transparent; 2 cases had mild postoperative vitreous hemorrhage, and absorbed 4wk later. There was no postoperative retinal detachment, IOL dislocation, and endophthalmitis. CONCLUSION: To take early treatment of traumatic lens subluxation/dislocation in patients with secondary glaucoma by individual surgical plan based on the different eye conditions would be safe and effective, which can effectively control the intraocular pressure and restore some vision. PMID- 24790870 TI - General anesthesia versus local anesthesia for penetrating keratoplasty: a prospective study. AB - AIM: To examine which anesthesia general or local is more effective for penetrating keratoplasty (PKP). METHODS: Patients with indications for PKP (n=141) were enrolled in a prospective study and randomly divided into general anesthesia group (group A, 70 eyes) and local anesthesia group (group B, 71 eyes). Patients received optical PKP (group A1, 30 eyes; group B1, 30 eyes) or therapeutic PKP (group A2, 40 eyes; group B2, 41 eyes). Measurement of anterior chamber treatment time (T) for PKP patients and the ratio (R) of the area of the pupils to that of recipient graft region. T and R values, as well as perioperative and postoperative complications, were compared between groups A and B using t-test or chi (2) test. RESULTS: Patients were followed for 2wk after PKP. T was (13.45+/-8.64)min for group A and (7.36+/-5.24)min for group B, a statistically significant difference (P<0.001). The R value for group A was stable during the operation, while for PKP patients in group B the value initially increased then gradually decreased to normal after suturing. In group B, extrusion of intraocular contents occurred in 5 eyes, and iridal prolapse occured in 11 cases; no perioperative complications occurred in group A. Relapse rate for fungal keratitis was 13.04% in group B and 0% in group A. CONCLUSION: Under general anesthesia, pupils remaine stable during PKP and perioperative complications are averted. General anesthesia gives more time to treat pathological changes in the anterior chamber and treatment success rate is higher. PMID- 24790871 TI - Comparison of Artisan iris-claw intraocular lens implantation and posterior chamber intraocular lens sulcus fixation for aphakic eyes. AB - AIM: To compare the efficacy and complications of Artisan iris-claw intraocular lens (IOL) implantation and posterior chamber IOL sulcus fixation for the treatment of aphakic eyes without capsular support after vitrectomy. METHODS: A prospective study of 45 cases was conducted. Forty-five eyes without sufficient lens capsule support following pars plana vitrectomy (PPV) combined lens extraction were divided into two groups. Group A: 25 eyes received Artisan iris claw IOL implantation. Group B: 20 eyes received posterior chamber IOL sulcus fixation. The corrected distance visual acuity (CDVA) and intraocular pressure (IOP), corneal endothelial cell loss rate, surgical time and complications were compared between the two groups. Pigment changes of trabecular meshwork and anterior chamber depths were measured at each time point in Artisan group. RESULTS: The mean surgical time of Artisan group was significantly shorter (P<0.05). No statistically significant difference in endothelial cell loss rate was noted between two groups at any time point (P>0.05). CDVA of Artian group was better than that of the sulcus fixation group 1d after surgery (P<0.05) and there was no statistically significant difference 1 and 3mo after surgery (P>0.05). Mean IOP showed no significant differences between groups before and after surgery. The postoperative complications of Artisan group were anterior uveitis, iris depigmentation, pupillary distortion and spontaneous lens dislocation. The complications of sulcus fixation group include choroidal detachment, intraocular haemorrhage, tilt of IOL optic part and retinal detachment. CONCLUSION: Secondary Artisan IOL implantation can be performed less invasively and in a shorter surgical time period with earlier visual recovery after surgery compared to transscleral suturing fixation of an IOL. This technique is an effective and safe procedure. It is a promising option for the treatment of aphakic eyes without capsular support after vitrectomy. PMID- 24790872 TI - A self-made disposable iris retractor in small pupil phacoemulsification. AB - AIM: To explore a simple and low-cost self-made disposable flexible iris retractor and study its clinical efficacy and safety in small pupil phacoemulsification. METHODS: Polyproplyene suture and scalp acupuncture were used to make iris retractor. A prospective study were carried on 50 patients (50 eyes) with a maximally dilated pupil size of 2.5-4.0 mm which underwent phacoemulsification using this self-made iris retractor. Another 50 cases of phacoemulsification with normal pupil size sever as control group. The mean operation time, ultrasound time and ultrasonic power, volume of irrigation fluid were documented intraoperatively. The visual acuity, pupil size and complication were observed on 1d, 1wk, 1mo and 1y after operation. Corneal endothelial cell was measured at 1mo postoperatively. RESULT: Pupils could be expanded to approximately 4.5-5.5 mm with our self-made iris retractor in operation. No serious postoperative complication was found. Most (88%) of the pupils returned round or oval shape, light reflex restored to varying degrees at the first day after surgery. Best corrected visual acuity stabilized in 37 eyes (74%) at one day, in 43 eyes (86%) at one week, in 44 eyes (88%) at one month and 46 eyes (92%) at one year. Compared with the control, more time was needed to complete the operation in the small pupil group. There was no significant difference of the mean ultrasound time, ultrasonic power, volume of irrigation fluid required and corneal endothelial cell loss in 1mo follow up between the two groups. CONCLUSION: Our self-made disposable flexible iris retractor could be easy obtained preoperatively or intraoperatively. It performed both safety and efficacy in our clinical trials. This simple self-made device has shown economic and practical values, especially in primary care hospital of the less developed districts. PMID- 24790873 TI - Retinopathy in non diabetics, diabetic retinopathy and oxidative stress: a new phenotype in Central Africa? AB - AIM: To evaluate the rates of retinopathy without diabetes and diabetic retinopathy (DR), associated with some markers of oxidative stress, antioxidants and cardiometabolic risk factors. METHODS: We determined the prevalence of DR in 150 type 2 diabetes mellitus (T2DM) patients, that of retinopathy in 50 non diabetics, the levels of body mass index (BMI), waist circumference (WC), blood pressure, lipids, 8-isoprostane, 8-hydroxydeoxyguanosine (8-OHdG), gamma-glutamyl transferase GT (GGT), oxidized low-density lipoprotein (OxLDL), thiobarbituric acid reacting substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), uric acid, creatinine, albumin, total antioxidant status (TAOS), zinc, selenium, magnesium, vitamin C, vitamin D, vitamin E, glucose, apolipoprotein B (ApoB). RESULTS: The prevalences of DR at 53y and Rtp at 62y were 44% (n=66) and 10% (n=5), respectively. The highest levels of 8-isoprostane, 8-OHdG, TBARS, SOD, and OxLDL were in DR. The lowest levels of vitamin D, vitamin C, TAOS, and vitamin E were in DR. In the case-control study discriminant analysis, the levels of vitamin C, vitamin D, ApoB, 8-OHdG, creatinine, Zn, vitamin E, and WC distinguished significantly non-diabetics without DR (controls), T2DM patients without DR and T2DM patients with DR. CONCLUSION: Anticipation of DR onset is significantly associated with the exageration of oxidative stress biomarkers or decrease of antioxidants in African type 2 diabetics. Prevention of oxidative stress and abdominal obesity is needed. Supplementation in vitamin C, D, and E should be recommended as complement therapies of T2DM. PMID- 24790874 TI - Comparison of central corneal thickness measurements with three new optical devices and a standard ultrasonic pachymeter. AB - AIM: To compare the RTVue spectral optical coherence tomography (SD-OCT), Sirius Scheimpflug-Placido topographer, Lenstar optical low coherence reflectometry (OLCR) and ultrasound pachymetry (USP) devices in terms of their agreement and repeatability of measuring central corneal thickness (CCT). METHODS: In this prospective study, 50 eyes of 50 patients were included. Three repeated measures were obtained using SD-OCT, Scheimpflug-Placido topographer and USP and five measurements were determined with the OLCR. Bland-Altman plots were used to assess agreement among the instruments, and 95% limits of agreement (LoA) for each comparison were calculated. Intra-examiner repeatability was assessed using intraclass correlation coefficients (ICCs). RESULTS: The mean CCT by SD-OCT, Scheimpflug-Placido topographer, OLCR, and USP were 525.90+/-34.08 um, 525.92+/ 34.10 um, 530.30+/-35.62 um, and 543.50+/-37.11 um respectively. All 4 modalities of CCT measurements correlated closely with each other, with Pearson correlation coefficients ranging from 0.977 to 0.995. The mean differences (and upper/lower LoA) for CCT measurements were -0.05+/-6.77 um (13.3/-13.3) between SD-OCT and Scheimpflug-Placido topographer, 4.38+/-3.79 um (11.8/-3.1) between OLCR and SD OCT, 4.38+/-6.03 um (16.2/-7.5) between OLCR and Scheimpflug-Placido topographer, 13.20+/-6.46 um (25.9/0.5) between USP and OLCR, 17.59+/-6.76 um (30.8/4.3) between USP and SD-OCT, and 17.58+/-8.13 um (33.5/1.6) between USP and Scheimpflug-Placido topographer. Intra-examiner repeatability was excellent for all devices with ICCs>0.98. CONCLUSION: For most practical purposes, CCT measurements with the RTVue, Sirius and Lenstar can be used interchangeably. Although highly correlated, CCT measurement differences between USP and these 3 optical instruments can be significant depending on the clinical situation. PMID- 24790875 TI - White-to-white corneal diameter: normal values in healthy Iranian population obtained with the Orbscan II. AB - AIM: To determine the normative values of white-to-white corneal diameter with Orbscan II Topography System and to compare right and left eyes data in the normal young population. METHODS: A total of 1001 healthy participants aged 18 45y participated in this observational cross-sectional study. The study population consisted of 616 female and 385 male subjects. The corneal diameter was measured with the Orbscan II. The differences between genders, between right and left eyes and age-related changes were evaluated. Statistical analyses were performed using Student's t-test. RESULTS: The average white-to-white distance in our study population was recorded as 11.65+/-0.36 mm (median: 11.60 mm, mode: 11.70 mm, minimum: 10.50 mm and maximum: 13.60 mm). The white-to-white distance was 11.60+/-0.35 mm in males and 11.71+/-0.36 mm in females which was statistically different between genders (P<0.01). However, white-to-white distance was not statistically different between right and left eyes. In addition, this parameter decreased with increasing age. Considering 95% confidence interval, corneal diameter less than 10.93 mm and greater than 12.34 mm would be considered as microcornea and megalocornea, respectively based on this study population, using the Orbscan II topography. CONCLUSION: Detailed description and analysis of corneal diameter with Orbscan demonstrate that the obtained average value of horizontal white-to-white is higher in male than female and decreases slightly with increasing age. Our data also suggests the cut off values for definition of microcornea and megalocornea, which can be employed with this population. PMID- 24790876 TI - Scheimpflug imaged corneal changes on anterior and posterior surfaces after collagen cross-linking. AB - AIM: To compare the anterior and posterior corneal parameters before and after collagen cross-linking therapy for keratoconus. METHODS: Collagen cross-linking was performed in 31 eyes of 31 keratoconus patients (mean age 30.6+/-8.9y). Prior to treatment and an average 7mo after therapy, Scheimpflug analysis was performed using Pentacam HR. In addition to corneal thickness assessments, corneal radius, elevation, and aberrometric measurements were performed both on anterior and posterior corneal surfaces. Data obtained before and after surgery were statistically analyzed. RESULTS: In terms of horizontal and vertical corneal radius, and central corneal thickness no deviations were observed an average 7mo after operation. Corneal higher order aberration showed no difference neither on anterior nor on posterior corneal surfaces. During follow-up period, no significant deviation was detected regarding elevation values obtained by measurement in mm units between the 3.0-8.0 mm-zones. CONCLUSION: Corneal stabilization could be observed in terms of anterior and posterior corneal surfaces, elevation and higher order aberration values 7mo after collagen cross linking therapy for keratoconus. PMID- 24790877 TI - Corneal properties in children with congenital isolated growth hormone deficiency. AB - AIM: To compare the corneal parameters of children with congenital isolated growth hormone deficiency and healthy subjects. METHODS: In this cross-sectional, prospective study, 50 cases with growth hormone (GH) deficiency treated with recombinant GH and 71 healthy children underwent a complete ophthalmic examination. The corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) were measured with the Ocular Response Analyzer (ORA). Central corneal thickness (CCT) was measured by a ultrasonic pachymeter. RESULTS: The mean age was 13.0+/-3.0 years in the GH deficiency group consisting of 21 females and 29 males and 13.4+/-2.4 years in the healthy children group consisting of 41 females and 30 males. There was no statistically significant difference between the groups for gender or age (Chi-square test, P=0.09; independent t-test, P=0.28, respectively). The mean duration of recombinant GH therapy was 3.8+/-2.4y in the study group. The mean CH, CRF, IOPg and IOPcc values were 11.0+/-2.0, 10.9+/-1.9, 15.1+/-3.3, and 15.1+/-3.2 mm Hg respectively in the study group. The same values were 10.7+/-1.7, 10.5+/-1.7, 15.2+/-3.3, and 15.3+/-3.4 mm Hg respectively in the control group. The mean CCT values were 555.7+/-40.6, 545.1+/-32.5 um in the study and control groups respectively. There was no statistically significant difference between the two groups for CH, CRF, IOPg, IOPcc measurements or CCT values (independent t-test, P=0.315, 0.286, 0.145, 0.747, 0.13 respectively). CONCLUSION: Our study suggests that GH deficiency does not have an effect on the corneal parameters and CCT values. This observation could be because of the duration between the beginning of disease and the diagnosis and beginning of GH therapy. PMID- 24790878 TI - Conjunctival impression cytology in non-proliferative and proliferative diabetic retinopathy. AB - AIM: To examine the integrity of the ocular surfaces of subjects with and without diabetes with no conjunctival and dry eye signs and symptoms and compare conjunctival impression cytology findings in diabetics with non-proliferative and proliferative diabetic retinopathy. METHODS: Conjunctival impression cytology was performed on 43 eyes of 43 subjects with non-proliferative diabetic retinopathy (NPDR), 42 eyes of 42 subjects with proliferative diabetic retinopathy (PDR), and 30 eyes of 30 control subjects. Impression cytology specimens of each group were graded and scored in the range 0-3 according to Nelson's method. RESULTS: There were 45 (52.9%) women and 40 (47.1%) men. The mean age of the patients was 59.6+/ 9.3y (range, 43-76y) in NPDR group and 58.0+/-8.8y (range, 41-85y) in PDR group. Cases with NPDR and PDR showed statistically significant higher impression cytology scores than control group (P<0.05). There was no difference between the NPDR and PDR patients for impression cytology grading scores. CONCLUSION: It is determined that impression cytology grades are altered in patients with NPDR and PDR. Consequently, we suggest that there might be an association between the impression cytology grading scores and the severity of diabetic retinopathy. PMID- 24790879 TI - Correlation of pattern reversal visual evoked potential parameters with the pattern standard deviation in primary open angle glaucoma. AB - AIM: To evaluate whether glaucomatous visual field defect particularly the pattern standard deviation (PSD) of Humphrey visual field could be associated with visual evoked potential (VEP) parameters of patients having primary open angle glaucoma (POAG). METHODS: Visual field by Humphrey perimetry and simultaneous recordings of pattern reversal visual evoked potential (PRVEP) were assessed in 100 patients with POAG. The stimulus configuration for VEP recordings consisted of the transient pattern reversal method in which a black and white checker board pattern was generated (full field) and displayed on VEP monitor (colour 14") by an electronic pattern regenerator inbuilt in an evoked potential recorder (RMS EMG EP MARK II). RESULTS: The results of our study indicate that there is a highly significant (P<0.001) negative correlation of P100 amplitude and a statistically significant (P<0.05) positive correlation of N70 latency, P100 latency and N155 latency with the PSD of Humphrey visual field in the subjects of POAG in various age groups as evaluated by Student's t-test. CONCLUSION: Prolongation of VEP latencies were mirrored by a corresponding increase of PSD values. Conversely, as PSD increases the magnitude of VEP excursions were found to be diminished. PMID- 24790880 TI - A 4-year retrospective study of add-on therapy to the fixed combination of dorzolamide/timolol for the treatment of POAG. AB - AIM: To evaluate the long-term response to the fixed combination of dorzolamide/timolol in patients with primary open angle glaucoma (POAG) and the addition of other intraocular pressure (IOP) lowering medications such as prostaglandin analogs and brimonidine. METHODS: A retrospective, non-randomized, and descriptive clinical study was performed with 182 eyes diagnosed with POAG. Patients were divided into three groups: a group with fixed combination of dorzolamide/timolol only, a second group with prostaglandin analogs plus fixed combination of dorzolamide/timolol, and a third group with the addition of brimonidine to the same fixed combination. IOP data were gathered retrospectively and the differences between groups were calculated. RESULTS: IOP was reduced satisfactorily in all three groups; however, a progressive IOP reduction was noted in the group with the fixed combination plus prostaglandin analogs. In this group, a progressive, significant and more homogeneous response of the reduction was noted in comparison with the other groups. CONCLUSION: IOP reduction was efficacious in all three groups. The addition of prostaglandin analogs showed progressive IOP reduction, progressive response and absence of long-term drift. Brimonidine did not show a significant additive effect. PMID- 24790881 TI - Combined therapy with bevacizumab and photodynamic therapy for myopic choroidal neovascularization: A one-year follow-up controlled study. AB - AIM: To evaluate the efficacy and safety of a combined treatment for myopic choroidal neovascularization (CNV) using photodynamic therapy (PDT) and intravitreal bevacizumab and to compare it with intravitreal bevacizumab monotherapy. METHODS: Thirty-four eyes with angiographic evidence of myopic CNV were randomly divided into two groups: 17 were treated with one intravitreal bevacizumab injection (1.25 mg) and low-fluence-rate PDT within seven days of the injection (Group A). The other 17 received monotherapy with bevacizumab injections (Group B). Clinical evidence of complications, best corrected visual acuity (BCVA) and fluorescein leakage were evaluated. BCVA and optical coherence tomography (OCT) were evaluated monthly. The timepoints follow-up was established at 6 and 12mo. All patients were retreated following a PRN protocol. RESULTS: A total of 34 eyes of 34 patients (26 women and 8 men) with a mean age of 62.35 years were included. In Group A (17 eyes) the mean BCVA increased from 0.55+/ 0.13 logMAR before the treatment to 0.40+/-0.09 logMAR at the 12mo follow-up (P<0.01). In Group B (17 eyes) the mean BCVA increased from 0.60+/-0.11 logMAR before the treatment to 0.55+/-0.12 logMAR at the 12mo follow-up (P<0.01). There was no statistically significant difference between the two groups in terms of LogMar visual acuity. In Group A the mean number of combined treatments was 1.8+/ 0.11 per patient; in Group B the mean number of intravitreal bevacizumab injections was 3.1+/-0.08 per patient. The number of treatments was significantly fewer in Group A (P<0.01). No local or systemic side effects occurred among any of the patients treated in this study. CONCLUSION: The combination of anti angiogenic injections and PDT appears to be a safe and effective option for myopic CNV treatment and allows for a significant reduction of intravitreal injections. PMID- 24790882 TI - Clinical and impression cytology findings of amniotic membrane and oral mucosal membrane transplantation for the management of socket contracture. AB - AIM: To investigate and compare the cytopathological and clinical effects of amniotic membrane transplantation (AMT) and oral mucosal membrane transplantation (OMMT) in socket contraction. METHODS: Twelve patients who could not be fitted with ocular prosthesis due to socket contracture were included in this study. Seven patients underwent AMT and 5 patients underwent OMMT. Thirteen patients who had healthy sockets were included as control group. Depth of inferior fornix, degree of inflammation, extent of the socket contracture and socket volume were measured in the preoperative period and at sixth and twelfth weeks postoperatively. Impression cytology of conjunctival fornices and tear transforming growth factor beta-1 (TGFbeta1) levels were determined. RESULTS: In the AMT group, socket volume and lower fornix depth values were significantly higher (P=0.030 and P=0.004 respectively) and inflammation levels and impression cytology stages (P=0.037 and P=0.022 respectively) were significantly lower in postoperative period compared to preoperative period. In the OMMT group, no statistical differences were found in terms of clinical parameters, inflammation levels and impression cytology stages of preoperative versus postoperative values. Preoperative tear TGFbeta1 levels were higher in AMT and OMMT groups compared to the control group (25.5 ng/mL, 26.3 ng/mL and 21.7 ng/mL respectively). Decreased tear TGFbeta1 levels were observed in both the AMT and OMMT groups postoperatively (median decrease value=2.1 ng/mL and 2.7 ng/mL respectively). CONCLUSION: AMT is associated with postoperative improvement in inferior fornix depth, socket volume, inflammation and impression cytology levels and may be a more proper alternative method than OMMT in the management of socket contracture. PMID- 24790883 TI - A new technique for Nd:YAG laser posterior capsulotomy. AB - AIM: To investigate the effects of a new opening pattern in neodymium:yttrium aluminum-garnet (Nd:YAG) laser posterior capsulotomy on visual function. METHODS: This technique was conducted along a circular pattern. The energy ranged between 0.8 and 1.2 mJ/pulse was consumed and mean total energy levels were 74+/-21 mJ (mean+/-standard deviation: SD, from 40 to 167) and laser shots aimed at 150 um away behind a datum point and went along an imaginary line which extends 0.5 mm inside from optic margin and into the circular en bloc pattern. Vitreous stands were attached with fragment and then they were cut off by the laser after circular application. The circular fragment was completely separated from vitreous, and then this fragment was quickly sunk in intravitreal space. RESULTS: The follow-up period ranges from at least a week to 40mo, making 15.8mo on average. The procedural outcome showed 96% (74 eyes out of the 77 eyes) enhancement in patients' visual acuity. Cystoid macular edema or retinal detachment was not observed in any of the patients during follow-up periods. CONCLUSION: This new technique is expected to improve the weaknesses that the conventional procedures have by adding the process to cut off vitreous stands attached with the fragment by the laser to the circular application. PMID- 24790884 TI - Comparison of autofluorescence and optical coherence tomography findings in acute and chronic central serous chorioretinopathy. AB - AIM: To discuss and compare the fundus autofluorescence (FAF) and optical coherence tomography (OCT) in acute or chronic central serous chorioretinopathy (CSCR). METHODS: Medical records of 100 cases of CSCR were reviewed. Acute and chronic cases were evaluated according to the duration of decreased visual acuity, serous retinal detachment (RD) and focal leakage on fluorescein angiography (FA). Chi-square test was used for statistical analysis. RESULTS: Forty cases had acute and 60 cases had chronic CSCR. FAF showed focal hypo autofluorescence in 34 (85%) and iso-autofluorescence in 6 (15%) of acute cases and hypo-autofluorescence in 51 (85%), hyper-autofluorescence in 6 (10%) and iso autofluorescence in 3 (5%) of chronic cases. OCT showed serous RD with distinct borders correlated with FAF findings (hypo-autofluorescence) in all acute CSCR cases. In chronic CSCR group, OCT showed serous RD with indistinct borders correlated with FAF findings. The differences between the OCT and FAF findings of the two groups were significant (P=0.000). CONCLUSION: OCT and FAF findings can support the clinical observations in differential diagnosis of acute and chronic CSCR and help clinicians to evaluate retinal pigment epithelium, outer segments of photoreceptors and the components of serous RD. PMID- 24790885 TI - Comparison of bevacizumab and ranibizumab in age-related macular degeneration: a systematic review and meta-analysis. AB - AIM: To compare the effectiveness and safety between bevacizumab and ranibizumab in the treatment of age-related macular degeneration (AMD) through a systematic review and meta-analysis. METHODS: We performed a comprehensive search of randomized controlled trials (RCTs), non-RCTs, case-control and cohort studies that compared bevacizumab and ranibizumab using PubMed and the Cochrane Library. After the related data were extracted by two investigators independently, pooled weighted mean differences (WMDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were estimated using a random-effects or a fixed-effects model. RESULTS: A total of four RCTs involving 1927 patients and eleven retrospective case series involving 2296 patients were included. For the primary outcomes, no significant differences were found between ranibizumab group and bevacizumab group in visual acuity (WMD: -0.04; 95%CI: -0.08 to 0.00; P=0.06), best corrected visual acuity (WMD: -0.05; 95%CI: -0.10 to 0.00; P=0.05), retina thickness (WMD: 4.69; 95%CI: -13.15 to 3.76; P=0.86) and foveal thickness (WMD: 10.91; 95%CI: 14.73 to 36.56; P=0.40). The pooled analyses in the evaluation of safety showed that compared to bevacizumab, ranibizumab was associated with decreased risks of ocular inflammation (RR: 0.45; 95% CI: 0.23 to 0.89; P=0.02) and venous thrombotic events (RR: 0.27; 95%CI: 0.08 to 0.89; P=0.03). However, there were no significant differences observed in deaths (P=0.69) and arterial thromboembolic events (P=0.71) between the two groups. CONCLUSION: With equal clinical efficacy, ranibizumab was found to be associated with less adverse events compared to bevacizumab, indicating that ranibizumab might be a safer management. PMID- 24790887 TI - Long-term vision-threatening complications of phakic intraocular lens implantation for high myopia. AB - AIM: To report the long-term vision-threatening complications in patients who underwent phakic intraocular lens (pIOLs) implantation for high myopia. METHODS: This study was designed from a consecutive series of phakic intraocular lens complication and corrective surgeries. Sixteen eyes of 13 patients had implantation of phakic intraocular lens for correction high myopia and developed serious complications have been included in this study. The mean age of patients was 38.6+/-6.35y (range 32-50y) and the mean time of history of pIOL implantation for high myopia was 6+/-2y (range 2-10y). Before corrective surgery, best spectacle-corrective visual acuity (BSCVA) ranged from perception to 20/200 in the eyes in which severe complications occurred. RESULTS: Corneal decompensation occurred in 12 eyes of 9 high myopic patients after anterior chamber pIOL implantation. Rhegmatogenous retinal detachment (RRD) occurred in 4 eyes of 4 high myopic patients following anterior chamber and posterior chamber pIOL implantation. Patients with corneal decompensation, had combined procedures consisting of pIOL removal and penetrating keratoplasty (PKP). Removals of pIOL, phacoemulsification and pars plana vitrectomy (PPV) with silicone oil tamponade were performed in patients with RRD. After corrective surgeries, all patients but one (P+, patient 2, right eye) achieved moderate BSCVA ranged from 20/200 to 20/50 at the last visit. CONCLUSION: Phakic IOLs may be effective for the correction of high myopia. Although these IOLs may have severe complications and it affects safety and efficacy of this surgery. As seen here, corneal decompensation and rhegmatogenous retinal detachment are possible postoperative vision-threatening complications of phakic IOLs. Patients must be carefully examined before and after surgery for possible endothelial cell loss and vitreoretinal problems. PMID- 24790886 TI - Selenium supplementation in thyroid associated ophthalmopathy: an update. AB - The therapeutic effect of selenium (Se) has already been proven in thyroid disease and thyroid associated ophthalmopathy (TAO). In spite of clear scientific proof of its benefits in TAO, there appears to be no clear agreement among the clinicians regarding its optimum dose, duration of the treatment, efficacy and safety to date. In this review, the author summarises the findings of 135 English language articles published on this subject over the past four decades from 1973 to 2013. The regulation and metabolism of thyroid hormones require a steady supply of Se and recent studies have revealed several possible mechanisms by which Se improves the severity of thyroid disease and TAO. These mechanisms include 1) inhibitory effect of HLA-DR molecule expression on thyrocytes; 2) profound reductions of thyroid stimulating hormone (TSH) receptor antibodies (TSHR-Ab) and TPO antibodies (TPO-Ab); 3) prevention of dysregulation of cell mediated immunity and B cell function; 4) neutralising reactive oxygen species (ROS) and inhibition of redox control processes required for the activation, differentiation and action of lymphocytes, macrophages, neutrophils, natural killer cells involved in both acute and chronic orbital inflammation in TAO; 5) inhibition of expression of pro-inflammatory cytokines and 6) inhibition of prostaglandin and leukotriene synthesis. An increased oxidative stress has been observed in both acute and chronic phases of thyroid disease with raised tissue concentrations of ROS. The benefits of Se supplementation in individuals with TAO appear to be proportionate to the degree of systemic activity of the thyroid disease. The maximal benefit of Se supplementation is therefore seen in the subjects who are hyperthyroid. Restoration of euthyroidism is one of the main goals in the management of TAO and when anti-thyroid drugs are combined with Se, the patients with Graves' disease (GD) and autoimmune thyroiditis (AIT) achieved euthyroidism faster than those treated with anti-thyroid drugs alone. Se status of normal adult humans can vary widely and Se supplementation may confer benefit only if serum Se levels are insufficient. The author recommends that serum Se levels of patients with TAO to be assessed prior to and during Se supplementation at regular intervals to avoid potential iatrogenic chronic Se overdose. PMID- 24790888 TI - Corneal ulcer caused by nocardia brasiliensis in a patient with diabetes. PMID- 24790889 TI - Concurrence of iridocorneal endothelial syndrome in a patient with glaucomatocyclitic crisis. PMID- 24790890 TI - Bilateral acute angle closure glaucoma precipitated by over the counter oral decongestant. PMID- 24790891 TI - Does high intraocular pressure exclude an open globe injury? PMID- 24790892 TI - The challenges of green nanotechnology. AB - Nanomaterials have great impacts on life sciences; however, these advanced materials may induce inadvertant consequences. Thus, this editorial will highlight the futuristic challenges ingreen nanotechnology. PMID- 24790894 TI - The potential effectiveness of nanoparticles as radio sensitizers for radiotherapy. AB - INTRODUCTION: Application of nanoparticles as radio sensitizer is a promising field to improve efficiency of radiotherapy. METHODS: This study was conducted to review nano radio sensitizers. PubMed, Ovid Medline, Science Direct, Scopus, ISI web of knowledge, and Springer databases were searched from 2000 to May 2013 to identify relevant studies. Search was restricted to English language. RESULTS: We included any study that evaluated nanoparticles, volunteer of radio enhancement at radiotherapy on animals or cell lines. Nanoparticles can increase radio sensitivity of tumor cells. This effect was shown in vivo and in vitro, at kilovltage or megavoltage energies, in 24 reviewed studies. Focus of studies was on gold nanoparticles. Radio sensitizing effects of nanoparticles depend on nanoparticles' size, type, concentration, intracellular localization, used irradiation energy and tested cell line. CONCLUSION: Literature suggests potency of nanoparticles for increasing cell radio sensitivity. Reviewed results are promising and warrant future clinical trials. PMID- 24790893 TI - Surface modified multifunctional nanomedicines for simultaneous imaging and therapy of cancer. AB - INTRODUCTION: To date, a growing number of advanced anticancer nanomedicines (e.g., Doxil((r)), Lipoxal((r)), DepoCyte((r))) have entered into different phases of clinical trials. However, most of these medicaments fail to differentiate between diseased and normal cells. They also do not have capability of real time monitoring of disease status trough on-demand imaging/sensing of target molecule(s). Multifunctional nanomedicines and theranostics can resolve such limitations, while formulation of these advanced seamless systems appear to involve various sophisticated process, exploiting several bioconjugations. METHODS: Recent works upon multifunctional nanomedicines for simultaneous imaging and therapy of cancer have been systematically reviewed, focusing on surface modification and application of advanced nanobiomaterials. RESULTS: Ultimate therapy of malignancies, as complex systems, demands implementation of seamless nanosystems (NSs) that can specifically target the cancerous cells and smartly deliver the anticancer agent(s) into the desired target site. Engineering of such NSs requires in-situ coordination of various technologies (e.g., synthesis, surface modification and bioconjugation) in order to achieve improved pharmacokinetics and pharmacodynamics outcomes. CONCLUSION: Seamless multimodal NSs have potential to simultaneously target and monitor the tumor cells through homing and imaging/sensing devices and deliver the therapeutic agents. However, to achieve superior pharmacokinetics with maximal efficacy and minimal side effects, these advanced NSs need to become much more intelligent to sense the disease condition and liberate therapeutics on demand. PMID- 24790895 TI - Marrubium vulgare L. methanolic extract inhibits inflammatory response and prevents cardiomyocyte fibrosis in isoproterenol-induced acute myocardial infarction in rats. AB - INTRODUCTION: Nowadays, finding new therapeutic compounds from natural products for treatment and prevention of a variety of diseases including cardiovascular disorders is getting a great deal of attention. This approach would result in finding new drugs which are more effective and have fewer side effects than the conventional medicines. The present study was designed to investigate the anti inflammatory effect of the methanolic extract of Marrubiumvulgare, a popular traditional medicinal herb, on isoproterenol-induced myocardial infarction (MI) in rat model. METHODS: Male Wistar rats were assigned to 6 groups of control, sham, isoproterenol, and treatment with 10, 20, and 40 mg/kg/12h of the extract given orally concurrent with MI induction. A subcutaneous injection of isoproterenol (100 mg/kg/day) for two consecutive days was used to induce MI. Then, histopathological changes and inflammatory markers were evaluated. RESULTS: Isoproterenol injection increased inflammatory response, as shown by a significant increase in peripheral neutrophil count, myocardial myeloperoxidase (MPO) activity and serum levels of creatinine kinase-MB (CK-MB) and TNF-alpha (p<0.001). In the groups treated with 10, 20 and 40 mg/kg of M.vulgare extract serum CK-MB was subsided by 55.4%, 52.2% and 69%, respectively. Also treatment with the extract (40 mg/kg) significantly reduced (p<0.001) MPO activity in MI group. The levels of TNF-alpha was also considerably declined in the serums of MI group (p<0.001). In addition, peripheral neutrophil count, was significantly lowered by all doses of the extract (p<0.001). Interstitial fibrosis significantly was attenuated in treated groups compared with control MI group. CONCLUSION: The results of study demonstrate that the M. vulgare extract has strong protective effects against isoproterenol-induced myocardial infarction and it seems possible that this protection is due to its anti-inflammatory effects. PMID- 24790896 TI - Comparative study of in vitro release and mucoadhesivity of gastric compacts composed of multiple unit system/bilayered discs using direct compression of metformin hydrochloride. AB - INTRODUCTION: Metformin is an oral anti-diabetic drug in the biguanide class. The goal of this study was to develop gastric-retentive MH discs in order to prolong the retention of drug in gastric mucosa. METHODS: Two groups of metformin hydrochloride (MH) mucoadhesive gastroretentive discs were prepared: (a) bilayered discs prepared by direct compression of powders containing polymers as Carbopol 934P (CP, mucoadhesive polymer) and ethylcellulose (EC, rotardant polymer), (b) multiple unit system (microparticle) discs prepared by the emulsification, solvent evaporation, and compression technique from microparticles using polymers CP and EC. Gastric-mucoadhesive compacts were evaluated by investigating their release pattern, swelling capacity, mucoadhesion property, surface pH, and in vitro gastro-retentive time. Discs formulation was subjected to disintegration and dissolution tests by placing in 0.1 M hydrochloric acid for 8 h. RESULTS: The production yield showed F2 microparticles of 98.80%, mean particle size of 933.25 um and loading efficiency of 98.44%. The results showed that prepared microparticle discs had slower release than bilayered discs (p>0.05). The bilayered discs exhibited very good percentage of mucoadhesion. The results also showed a significant higher retention of mucoadhesive bilayered discs in upper gastrointestinal tract (F'1, 1:2 ratio of CP:EC). Histopathological studies revealed no gastric mucosal damage. CONCLUSION: Mucoadhesive multiple unit system/bilayered discs interact with mucus of gastrointestinal tract and are considered to be localized or trapped at the adhesive site by retaining a dosage form at the site of action as well as improving in the intimacy of contact with underlying absorptive membrane to achieve a better therapeutic performance of anti-diabetic drug. PMID- 24790897 TI - A fast and simple spectrofluorometric method for the determination of alendronate sodium in pharmaceuticals. AB - INTRODUCTION: Alendronate sodium enhances bone formation and increases osteoblast proliferation and maturation and leads to the inhibition of osteoblast apoptosis. Therefore, a rapid and simple spectrofluorometric method has been developed and validated for the quantitative determination of it. METHODS: The procedure is based on the reaction of primary amino group of alendronate with o-phthalaldehyde (OPA) in sodium hydroxide solution. RESULTS: The calibration graph was linear over the concentration range of 0.0-2.4 MUM and limit of detection and limit of quantification of the method was 8.89 and 29 nanomolar, respectively. The enthalpy and entropy of the reaction between alendronate sodium and OPA showed that the reaction is endothermic and entropy favored (DeltaH = 154.08 kJ/mol; DeltaS = 567.36 J/mol K) which indicates that OPA interaction with alendronate is increased at elevated temperature. CONCLUSION: This simple method can be used as a practical technique for the analysis of alendronate in various samples. PMID- 24790898 TI - Analgesic, anti-inflammatory and anti-pyretic activities of Caesalpinia decapetala. AB - INTRODUCTION: In many pathological conditions, pain, inflammation and fever are interdependent to each other. Due to the use of synthetic drugs, many unwanted effects usually appear. Various studies have been conducted on Caesalpinia decapetala (C. decapetala) to evaluate its effects in the treatment of various diseases but no sufficient scientific literature is available online to prove its analgesic, anti-inflammatory and anti-pyretic activities. METHODS: The analgesic, anti-inflammatory and anti-pyretic activities of 70% aqueous methanolic and n hexane extracts of C. decapetala was evaluated using Swiss albino mice (20-30 g). RESULTS: The results showed that aqueous methanolic extract of C. decapetala at the dose of 100 mg/kg exhibited significant (p< 0.05) activities in various pain models including acetic acid-induced writhing (18.4 +/- 0.53), formalin-induced licking (275 +/- 4.18) and hot plate method (2.3 +/- 0.0328); whereas, n-hexane extract showed its effects in acetic acid-induced writhing (20 +/- 0.31), formalin-induced licking (293 +/- 1.20) and hot plate method (2.224 +/- 0.029) compared to the effects observed in control group animals. Similarly, the aqueous methanolic extract of C. decapetala after 2 h of treatment exhibited more significant anti-inflammatory (0.66 +/- 0.06) and anti-pyretic (38.81 +/- 0.05) activities compared to the control group animals. CONCLUSION: From the findings of our present study, we concluded that the aqueous methanolic extract of C. decapetala has stronger analgesic, anti-inflammatory and anti-pyretic effects than its n-hexane extract. Further studies are required to investigate the active constituents of C. decapetala that exhibit analgesic, anti-inflammatory and anti pyretic activities. PMID- 24790899 TI - Lactobacillus with probiotic potential from homemade cheese in Azerbijan. AB - INTRODUCTION: Lactobacillus is believed to be beneficial in human health, thus the search for isolation and identification of friendly human bacteria from traditional fermented foods is important in medicine. One of the dairy products, traditional cheese as a highly-consumed dairy product could be a valuable source of these friendly edible germs. METHODS: In this research, home-made cheese from Lankaran, Jalil Abad and Salian regions in Azerbaijan was characterized for the presence of Lactobacilli with probiotic potential. The bacterial suspension was enriched and screened for acid and bile resistances. Then, the isolates were subjected to antibiotic resistance and antibacterial effects against convenient pathogenic bacteria. The isolates were identified by 16s rDNA sequencing. RESULTS: The results clearly revealed two probiotics with higher homology to Lactobacillus planetarum and Lactobacillus fermentum. CONCLUSION: No antibiotic resistance was detected in any of the potentially probiotic lactobacilli isolates in these regions, where people continue to follow a life-style that is largely traditional, with traditional medications. PMID- 24790900 TI - Comparing Two Different Doses of Intravenous Ondansetron With Placebo on Attenuation of Spinal-induced Hypotension and Shivering. AB - BACKGROUND: Side effects of spinal anesthesia are hypotension, bradycardia and shivering. Five-hydroxytriptamine (5-HT), a serotonergic receptor, may be an important factor associated with inducing the Bezold Jarish reflex (BJR) that may lead to the bradycardia and hypotension in the setting of decreased blood volume. OBJECTIVES: This study aimed to investigate the effect of intravenous administration of ondansetron, a 5-HT3 receptor antagonist, which could attenuate spinal-induced hypotension, bradycardia and shivering. PATIENTS AND METHODS: Two hundred and ten patients aged 20-50 years old were scheduled for spinal anesthesia and were divided randomly into three equal groups. The control group received normal saline and intervention groups received 6 mg or 12 mg of intravenous ondansetron 5 minutes before spinal anesthesia. Mean arterial pressure (MAP), heart rate (HR), and shivering were recorded before and after spinal anesthesia every 5 minutes during first 20 minutes of surgery. RESULTS: Demographic data were not statistically different among groups. HR was statistically different between the experimental groups and the control group. Ten patients (14%) in the control group had HR < 50 bpm, that required intravenous atropine compared to experimental groups (P =0.02). In the control group 12 (17%) patients had MAP < 80 mm Hg and required vasopressors compared to experimental groups (P = 0.04). There were no significant differences in MAP and HR between the experimental groups (P =0.06). Incidence of shivering in the control group was 45% (32.70) that was statistically more than experimental groups (P = 0.02). CONCLUSIONS: Administration of two different doses of intravenous ondansetron, 6 mg and 12 mg, significantly attenuates spinal induced hypotension, bradycardia and shivering compared to the control saline group. However, the hemodynamic profiles and shivering in experimental groups were not statistically different. PMID- 24790901 TI - Comparing the squatting position and traditional sitting position for ease of spinal needle placement: a randomized clinical trial. AB - BACKGROUND: previous evidences suggested that traditional sitting position (flexion of knees approximately 90 degrees , and adduction of hips while feet rest on a stool) and hamstring stretch position (sitting position with maximum extension of knees, adduction of hips, and forward bending) both reversed the lumbar lordosis and the number of spinal needle-bone contacts were identical when placing patients in these positions for neuraxial block. OBJECTIVES: In this study, we suggested that squatting position reverses the lumbar lordosis and reduces the number of spinal needle bone contacts better than a traditional sitting position. PATIENTS AND METHODS: Two hundred and thirty six patients ASA (American Society of Anesthesiologist) class I or II aged 18 to 75 years scheduled for elective surgeries under elective spinal anesthesia were randomized into two groups. We compared the traditional sitting and squatting positions. Our primary endpoint was the number of spinal needle-bone contacts, and secondary endpoint was ease of needle insertion or space identification. RESULTS: The total number of spinal needle bone contact was statistically lower in the squatting position compared to traditional sitting position group (222 versus 230 respectively, P = 0.01). Insertion of needle was easy in 97 (87%) and 94 (84%) of patients and difficult in 20 (18%) and 17 (15%) of patients in traditional sitting and squatting positions, respectively (P = 0.59 and P = 0.12). Needle insertion was not impossible in any patients. CONCLUSIONS: In squatting position the number of spinal needle-bone contacts was lower compared to the traditional sitting position, nonetheless ease of needle insertion or space identification was the same in the both groups. PMID- 24790902 TI - Laparoscopic cortical sparing adrenalectomy for pediatric bilateral pheochromocytoma: anesthetic management. AB - INTRODUCTION: Pheochromocytoma is a catecholamine-secreting tumor, which is seen rarely in children. These tumors predominantly secrete norepinephrine and epinephrine. They might be familial and associated with hereditary tumors such as Von Hippel-Lindau syndrome and multiple endocrine neoplasia type II. CASE PRESENTATION: The child might present with a spectrum of clinical manifestation including hypertension, headache, visual disturbances, and behavioral problems. A meticulous preoperative preparation is essential for a stable intraoperative and postoperative outcome. CONCLUSIONS: We described successful perioperative management of a child who underwent bilateral laparoscopic cortical sparing adrenalectomy and a repeated surgery for the residual tumor removal. PMID- 24790903 TI - Human erythropoietin effect in postoperative visual loss following spine surgery: a case report. AB - INTRODUCTION: Postoperative visual loss (POVL) has become the focus of attention for anesthesiologists as a hallmark of perioperative management in spine surgery. A number of Intraoperative and postoperative factors has been documented but the exact etiology is still unclear. Nowadays, perioperative management and also complete curing of POLV is a big question of ophthalmologists and anesthesiologists. The purpose of this case report is to present a unique experience of complete curing the POLV. CASE PRESENTATION: Our patient was a 61 year-old man, with 75 kg weight and 180 cm height. The patient had no history of visual impairment except mild cataract in his right eye. The patient had a history of diffuse idiopathic skeletal hyperostosis (DISH). The patient had undergone lumbar surgery in prone position. The operation time was about 6 hours. About 30 minutes after transferring to postanesthesia care unit (PACU), patient was awake and complained of losing his eyesight. There was no vision and light perception in his right eye on primary examination. Urgent ophthalmologist consultation was requested. In ophthalmology examinations, the pupil reflex to light was absent in the right eye. After obtaining patients and his family informed consent, four hours after the operation, 40000 I.U. of recombinant human erythropoietin (rhEPO) was administered for patient in PACU (IV infusion, in 30 min). An ophthalmologist visited him every 6 hours after administration of rhEPO. The patient was transferred to intensive care unit (ICU) one hour later with total visual loss in the right eye. Ophthalmologic examination after the second dose of rhEPO, 30 hours after the operation, reported pupil reflex enhancement and light perception in his right eye. Finally the third dose of rhEPO (40000 I.U., IV infusion) was administered on the third day. Ophthalmologic examination after the third dose of rhEPO, 60 hours after the operation, reported normal pupillary light reflex of the right eye and visual acuity improvement to 20/20. The patient was discharged from hospital after six days, with normal visual acuity and without any new complications except surgical site pain. CONCLUSIONS: Our case report showed the therapeutic effect of rhEPO in complete curing of POVL. Regarding the side effects of EPO such as thrombogenic effects or mild hemodynamic changes like transient sinus tachycardia during infusion, it seems that beneficial effects of EPO is more than its disadvantages and expenses, for patients with POVL. PMID- 24790904 TI - Vitamin D activities for health outcomes. AB - Reports describing significant health risks due to inadequate vitamin D status continue to generate considerable interest amongst the medical and lay communities alike. Recent research on the various molecular activities of the vitamin D system, including the nuclear vitamin D receptor and other receptors for 1,25-dihydroxyvitamin D and vitamin D metabolism, provides evidence that the vitamin D system carries out biological activities across a wide range of tissues similar to other nuclear receptor hormones. This knowledge provides physiological plausibility of the various health benefits claimed to be provided by vitamin D and supports the proposals for conducting clinical trials. The vitamin D system plays critical roles in the maintenance of plasma calcium and phosphate and bone mineral homeostasis. Recent evidence confirms that plasma calcium homeostasis is the critical factor modulating vitamin D activity. Vitamin D activities in the skeleton include stimulation or inhibition of bone resorption and inhibition or stimulation of bone formation. The three major bone cell types, which are osteoblasts, osteocytes and osteoclasts, can all respond to vitamin D via the classical nuclear vitamin D receptor and metabolize 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D to activate the vitamin D receptor and modulate gene expression. Dietary calcium intake interacts with vitamin D metabolism at both the renal and bone tissue levels to direct either a catabolic action on the bone through the endocrine system when calcium intake is inadequate or an anabolic action through a bone autocrine or paracrine system when calcium intake is sufficient. PMID- 24790905 TI - Harmonization: the sample, the measurement, and the report. AB - Harmonization of clinical laboratory results means that results are comparable irrespective of the measurement procedure used and where or when a measurement was made. Harmonization of test results includes consideration of pre-analytical, analytical, and post-analytical aspects. Progress has been made in each of these aspects, but there is currently poor coordination of the effort among different professional organizations in different countries. Pre-analytical considerations include terminology for the order, instructions for preparation of the patient, collection of the samples, and handling and transportation of the samples to the laboratory. Key analytical considerations include calibration traceability to a reference system, commutability of reference materials used in a traceability scheme, and specificity of the measurement of the biomolecule of interest. International organizations addressing harmonization include the International Federation for Clinical Chemistry and Laboratory Medicine, the World Health Organization, and the recently formed International Consortium for Harmonization of Clinical Laboratory Results (ICHCLR). The ICHCLR will provide a prioritization process for measurands and a service to coordinate global harmonization activities to avoid duplication of effort. Post-analytical considerations include nomenclature, units, significant figures, and reference intervals or decision values for results. Harmonization in all of these areas is necessary for optimal laboratory service. This review summarizes the status of harmonization in each of these areas and describes activities underway to achieve the goal of fully harmonized clinical laboratory testing. PMID- 24790906 TI - Diagnostic utility of multiprobe fluorescence in situ hybridization assay for detecting cytogenetic aberrations in acute leukemia. AB - BACKGROUND: Specific cytogenetic aberrations detected by conventional karyotyping or FISH play a major role in the diagnosis, prognosis, and treatment of patients with acute leukemia. The FISH technique enhances the capacity of conventional karyotyping to detect subtle chromosomal aberrations. Multiprobe FISH assay (Cytocell, UK) can hybridize multiple probes to a single slide, thereby increasing the detection rate of cytogenetic aberrations. This study aimed to evaluate multiprobe FISH in detecting cytogenetic abnormalities in acute leukemia. METHODS: Thirty newly diagnosed acute leukemia patients who attended the hematology clinic at Dong-A University Hospital from October 2008 to October 2012 were enrolled in the study. The multiprobe FISH results were compared with those of G-banding. RESULTS: Multiprobe FISH detected the chromosomal aberrations identified by G-banding, as well as additional aberrations in 6 of 30 (20.0%) cases, which included ETV6/RUNX1 translocation, p16 deletion, TP53 deletion, and IGH break-apart. CONCLUSIONS: The multiprobe FISH assay was a more sensitive and reliable technique compared with G-banding. It was also more cost-effective and yielded faster results. PMID- 24790907 TI - Evaluation of propidium monoazide real-time PCR for early detection of viable Mycobacterium tuberculosis in clinical respiratory specimens. AB - BACKGROUND: Conventional acid-fast bacilli (AFB) staining cannot differentiate viable from dead cells. Propidium monoazide (PMA) is a photoreactive DNA-binding dye that inhibits PCR amplification by DNA modification. We evaluated whether PMA real-time PCR is suitable for the early detection of viable Mycobacterium tuberculosis (MTB) in clinical respiratory specimens. METHODS: A total of 15 diluted suspensions from 5 clinical MTB isolates were quadruplicated and subjected to PMA treatment and/or heat inactivation. Eighty-three AFB-positive sputum samples were also tested to compare the DeltaCT values (CT value in PMA treated sputum samples-CT value in non-PMA-treated sputum samples) between culture-positive and culture-negative specimens. Real-time PCR was performed using Anyplex MTB/NTM Real-Time Detection (Seegene, Korea), and the CT value changes after PMA treatment were compared between culture-positive and culture negative groups. RESULTS: In MTB suspensions, the increase in the CT value after PMA treatment was significant in dead cells (P=0.0001) but not in live cells (P=0.1070). In 14 culture-negative sputum samples, the median DeltaCT value was 5.3 (95% confidence interval [CI], 4.1-8.2; P<0.0001), whereas that in 69 culture positive sputum samples was 1.1 (95% CI, 0.7-2.0). In the ROC curve analysis, the cutoff DeltaCT value for maximum sensitivity (89.9%) and specificity (85.7%) for differentiating dead from live cells was 3.4. CONCLUSIONS: PMA real-time PCR is a useful approach for differentiating dead from live bacilli in AFB smear-positive sputum samples. PMID- 24790908 TI - Distribution of serotypes and antibiotic susceptibility patterns among invasive pneumococcal diseases in Saudi Arabia. AB - BACKGROUND: Streptococcus pneumoniae causes life-threatening infections such as meningitis, pneumonia, and febrile bacteremia, particularly in young children. The increasing number of drug-resistant isolates has highlighted the necessity for intervening and controlling disease. To achieve this, information is needed on serotype distribution and patterns of antibiotic resistance in children. METHODS: All cases of invasive pneumococcal disease (IPD) in children aged less than 15 yr recorded at King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, were reviewed for serotyping and antibiotic susceptibility. Isolates were collected from 78 consecutive patients with IPD between 2009 and 2012. All collected isolates were subjected to serotyping by co-agglutination, sequential multiplex PCR, and single PCR sequetyping as previously described. RESULTS: The most frequently isolated IPD serotypes were 23F, 6B, 19F, 18C, 4, 14, and 19A, which are listed in decreasing order and cover 77% of total isolates. The serotype coverage for the pneumococcal conjugate vaccine (PCV)7, PCV10, and PCV13 was 77%, 81%, and 90%, respectively. Results from sequential multiplex PCR agreed with co-agglutination results. All serotypes could not be correctly identified using single PCR sequetyping. Minimum inhibitory concentration showed that 50 (64%) isolates were susceptible to penicillin, whereas 70 (90%) isolates were susceptible to cefotaxime. CONCLUSIONS: The most common pneumococcal serotypes occur with frequencies similar to those found in countries where the PCV has been introduced. The most common serotypes in this study are included in the PCVs. Addition of 23A and 15 to the vaccine would improve the PCV performance in IPD prevention. PMID- 24790910 TI - Comparison of total and IgG ABO antibody titers in healthy individuals by using tube and column agglutination techniques. AB - BACKGROUND: Most immune reactions related to transfusion and transplantation are caused by IgM ABO antibodies. However, IgG also plays an important role in these reactions. Therefore, a method to measure antibodies, including IgG, is necessary. We investigated ABO antibody titers of healthy individuals using a column agglutination technique (CAT) with or without dithiothreitol (DTT) and compared them with titers obtained using a conventional tube method. METHODS: Among healthy adults who underwent a medical examination, 180 individuals (60 with blood group A, 60 with group B, and 60 with group O) were selected. Antibody titrations were performed using the immediate spin (IS) tube, anti-human globulin (AHG) tube, and CAT with or without DTT methods. RESULTS: Higher median values of anti-B and anti-A titers in groups A and B individuals, respectively, were obtained using the IS method than using the AHG method. Higher values for group O individuals were obtained using the AHG method. Higher median titers of anti-B and anti-A in group O individuals were obtained using CAT without DTT than using the AHG method. Median titers of anti-B and anti-A in all blood groups were higher in CAT without DTT than in CAT with DTT, especially for group O individuals. CONCLUSIONS: We recommend CAT with and without DTT for titration of anti-A and anti-B, especially in group O individuals, to provide more sensitive results that include IgG data. Adjustment of insurance coverage of fees associated with antibody titration might be necessary, considering the actual cost of reagents and personnel. PMID- 24790909 TI - Evaluation of an immunochromatographic assay for the rapid and simultaneous detection of rotavirus and adenovirus in stool samples. AB - BACKGROUND: We evaluated the analytical and clinical performances of the SD BIOLINE Rota/Adeno Rapid kit (SD Rota/Adeno Rapid; Standard Diagnostics, Inc., Korea), an immunochromatographic assay (ICA), for the simultaneous detection of rotaviruses and adenoviruses in human stool samples. METHODS: We tested 400 clinical stool samples from patients with acute gastroenteritis and compared the ICA results with the results obtained by using ELISA, enzyme-linked fluorescent assays (ELFA), PCR, and multiplex reverse transcription-PCR (mRT-PCR). To assess the analytical performance of the SD BIOLINE Rota/Adeno Rapid kit, we determined its detection limit, reproducibility, cross-reactivity, and analytical reactivity for adenovirus subtypes, and performed interference studies. RESULTS: The overall agreement rates among the tested methods were 91.5% for rotavirus and 85.5% for adenovirus. On the basis of mRT-PCR, the overall agreement, positive agreement, and negative agreement rates of the ICA were 95.6%, 100%, and 94.9% for rotavirus, and 94.0%, 71.4%, and 94.8% for adenovirus, respectively. Using the ICA, we detected all the subtypes of adenovirus tested, but the analytical reactivities for adenovirus subtypes were different between the 4 adenovirus detection methods. The high reproducibility was confirmed, and no cross reactivity or interference was detected. CONCLUSIONS: The SD BIOLINE Rota/Adeno Rapid kit showed acceptable analytical and clinical performances. However, interpretation of adenovirus positive/negative result should be cautious because of different detectability for adenovirus subtypes among adenovirus detection methods. PMID- 24790911 TI - Analysis of reverse transcriptase gene mutations in the hepatitis B virus at a university hospital in Korea. AB - BACKGROUND: Most mutations in the reverse transcriptase (RT) gene of the hepatitis B virus (HBV) are related to resistance to antiviral agents. Cross sectional studies on the mutations of this gene are rare. Thus, we analyzed the mutation patterns of RT genes and their biochemical parameters. METHODS: From 2009 to 2012, 301 blood specimens from patients with chronic hepatitis B at Daegu Catholic University Medical Center were retrospectively analyzed for the RT gene sequence of HBV, ALT, hepatitis B e antigen (HBeAg), and HBV DNA. The mutation patterns of the RT gene were compared with the biochemical parameters. RESULTS: Of the 301 patients, 100 (33.2%) had no RT gene mutations. The remaining showed the following mutation patterns: rtM204I/V (50.2%), rtL180M (39.2%), and rtA181T/V (19.6%). Combined mutations were found in 146 cases (48.5%). Of these, the combination of amino acid changes at rt180+rt204 (49.3%) was most frequently detected, followed by rt181+rt236 (11.0%) and rt173+rt180+rt204 (9.6%). In the mutated group, HBV DNA and HBeAg positive rates were significantly higher (P<0.05 for both). Phenotypic analysis showed that lamivudine resistance was most frequently detected (34.6%), followed by adefovir resistance (15.6%). Multidrug resistance was detected in 48 cases (15.9%). The adefovir-resistant group had a higher proportion of cases with HBV loads greater than 2,000 IU/mL. CONCLUSIONS: We found correlations between the mutation status of the RT domain and biochemical parameters such as HBV DNA and HBeAg positive rate. The presence of RT gene mutations could therefore be utilized to predict clinical status. PMID- 24790912 TI - Evaluation of a rapid membrane enzyme immunoassay for the simultaneous detection of glutamate dehydrogenase and toxin for the diagnosis of Clostridium difficile infection. AB - We evaluated the new C. DIFF QUIK CHEK COMPLETE (CD COMPLETE; TechLab, USA), which is a rapid membrane enzyme immunoassay that uses a combination of glutamate dehydrogenase (GDH) antigen and toxin A and B detection. A total of 608 consecutive loose stool specimens collected from the patients with suspected Clostridium difficile infection (CDI) from August to December 2012 were subjected to the CD COMPLETE and VIDAS Clostridium difficile A & B (VIDAS CDAB; bioMerieux, France). Their performances were compared with a toxigenic culture as a reference. Stool specimens that were culture-negative and CD COMPLETE- or VIDAS CDAB-positive were analyzed by using an enrichment procedure. In comparison to the toxigenic cultures, sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were 63.6%, 98.0%, 76.1%, and 96.4%, respectively, for the CD COMPLETE-toxin and 75.5%, 97.4%, 72.5%, and 97.8%, respectively, for the VIDAS CDAB. In comparison to the enriched C. difficile cultures, the sensitivity, specificity, PPV, and NPV for the CD COMPLETE-GDH were 91.0%, 92.4%, 70.5%, and 98.1%, respectively. The CD COMPLETE is a reliable method for the diagnosis of CDI and provides greater sensitivity than toxin enzyme immunoassay alone. Furthermore, the CD COMPLETE-GDH has advantages over direct culture in detecting C. difficile. PMID- 24790913 TI - Analysis of reporting time for identification of methicillin-resistant Staphylococcus aureus carriers using ChromID MRSA. AB - We assessed the reporting times for identification of nasal methicillin-resistant Staphylococcus aureus (MRSA) carriers in 2011 in a university-affiliated hospital using surveillance cultures incubated for 1 and 2 days with ChromID MRSA (bioMerieux, France). Of 2,732 nasal swabs tested, MRSA was detected in 829 (85.6%) and 140 (14.4%) swabs after 1 and 2 days of incubation, respectively, and the median reporting times for positive specimens were 33.7 hr (range, 18.2-156.9 hr) and 108.1 hr (range, 69.8-181.0 hr), respectively. Detection rate after 1-day incubation was 85%. Additional 1-day incubation improved detection rate; however, it prolonged the reporting times of positive specimens approximately up to 4 days because of the need for confirmatory tests such as species identification and susceptibility tests. Following a 2-day culture with ChromID MRSA, rapid confirmatory tests are warranted to reduce delay in identifying MRSA carriers. PMID- 24790914 TI - Pulmonary infection caused by Mycobacterium neoaurum: the first case in Korea. AB - Mycobacterium neoaurum is rapidly growing mycobacteria that can cause human infections. It commonly causes bloodstream infections in immunocompromised hosts, and unlike other mycobacteria species, it rarely causes pulmonary infections. We confirmed the first pulmonary infection case in Korea caused by M. neoaurum using full-length 16S rRNA gene sequencing. PMID- 24790915 TI - A case of isolated lymphoblastic relapse of the central nervous system in a patient with chronic myelogenous leukemia treated with imatinib. PMID- 24790916 TI - First report of Nocardia farcinica bursitis in a patient with diabetes mellitus. PMID- 24790917 TI - The first Korean case of Moraxella osloensis bacteremia in a patient with acute myeloid leukemia. PMID- 24790918 TI - The first known case of blood group chimerism in monochorionic dizygotic twins in Korea. PMID- 24790919 TI - Biologic response of local hemostatic agents used in endodontic microsurgery. AB - Appropriate use of local hemostatic agent is one of the important factors on the prognosis of endodontic microsurgery. However, most investigations to date focus on the hemostatic efficacy of the agents, whereas their biologic characteristics have not received enough attention. The purpose of this paper was to review the biologic response of local hemostatic agents, and to provide clinical guidelines on their use during endodontic microsurgery. Electronic database (PUBMED) was screened to search related studies from 1980 to 2013, and 8 clinical studies and 18 animal studies were identified. Among the materials used in these studies, most widely-investigated and used materials, epinephrine, ferric sulfate (FS) and calcium sulfate (CS), were thoroughly discussed. Influence of these materials on local tissue and systemic condition, such as inflammatory and foreign body reaction, local ischemia, dyspigmentation, delayed or enhanced bone and soft tissue healing, and potential cardiovascular complications were assessed. Additionally, biological property of their carrier materials, cotton pellet and absorbable collagen, were also discussed. Clinicians should be aware of the biologic properties of local hemostatic agents and their carrier materials, and should pay attention to the potential complications when using them in endodontic microsurgery. PMID- 24790920 TI - Cytotoxicity and physical properties of tricalcium silicate-based endodontic materials. AB - OBJECTIVES: The aim of this study was to evaluate the cytotoxicity, setting time and compressive strength of MTA and two novel tricalcium silicate-based endodontic materials, Bioaggregate (BA) and Biodentine (BD). MATERIALS AND METHODS: Cytotoxicity was evaluated by using a 2,3-bis(2-methoxy-4-nitro-5 sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide (XTT) assay. Measurements of 9 heavy metals (arsenic, cadmium, chromium, copper, iron, lead, manganese, nickel, and zinc) were performed by inductively coupled plasma-mass spectrometry (ICP-MS) of leachates obtained by soaking the materials in distilled water. Setting time and compressive strength tests were performed following ISO requirements. RESULTS: BA had comparable cell viability to MTA, whereas the cell viability of BD was significantly lower than that of MTA. The ICP-MS analysis revealed that BD released significantly higher amount of 5 heavy metals (arsenic, copper, iron, manganese, and zinc) than MTA and BA. The setting time of BD was significantly shorter than that of MTA and BA, and the compressive strength of BA was significantly lower than that of MTA and BD. CONCLUSIONS: BA and BD were biocompatible, and they did not show any cytotoxic effects on human periodontal ligament fibroblasts. BA showed comparable cytotoxicity to MTA but inferior physical properties. BD had somewhat higher cytotoxicity but superior physical properties than MTA. PMID- 24790921 TI - Pull-out bond strength of a self-adhesive resin cement to NaOCl-treated root dentin: effect of antioxidizing agents. AB - OBJECTIVES: This study evaluated the effect of three antioxidizing agents on pull out bond strengths of dentin treated with sodium hypochlorite. MATERIALS AND METHODS: Root canals of 75 single-rooted human teeth were prepared. Fifteen teeth were irrigated with normal saline for a negative control group, and the remaining 60 teeth (groups 2 - 5) with 2.5% NaOCl. The teeth in group 2 served as a positive control. Prior to post cementation, the root canals in groups 3 - 5 were irrigated with three antioxidizing agents including 10% rosmarinic acid (RA, Baridge essence), 10% hesperidin (HPN, Sigma), and 10% sodium ascorbate hydrogel (SA, AppliChem). Seventy-five spreaders (#55, taper .02, Produits Dentaires S.A) were coated with silica and silanized with the Rocatec system and ceramic bond. All the prepared spreaders were cemented with a self-adhesive resin cement (Bifix SE, Voco Gmbh) in the prepared canals. After storage in distilled water (24 h/37C), the spreaders were pulled out in a universal testing machine at a crosshead speed of 1.0 mm/min. Pull-out strength values were analyzed by one-way ANOVA and Tukey's HSD test (alpha = 0.05). RESULTS: There were significant differences between study groups (p = 0.016). The highest pull-out strength was related to the SA group. The lowest strength was obtained in the positive control group. CONCLUSIONS: Irrigation with NaOCl during canal preparation decreased bond strength of resin cement to root dentin. Amongst the antioxidants tested, SA had superior results in reversing the diminishing effect of NaOCl irrigation on the bond strength to root dentin. PMID- 24790922 TI - Effect of passive ultrasonic agitation during final irrigation on cleaning capacity of hybrid instrumentation. AB - OBJECTIVES: To evaluate the effect of passive ultrasonic agitation on the cleaning capacity of a hybrid instrumentation technique. MATERIALS AND METHODS: Twenty mandibular incisors with mesiodistal-flattened root shape had their crowns sectioned at 1 mm from the cementoenamel junction. Instrumentation was initiated by catheterization with K-type files (Denstply Maillefer) #10, #15, and #20 at 3 mm from the working length. Cervical preparation was performed with Largo bur #1 (Dentsply Maillefer) followed by apical instrumentation with K-type files #15, #20 and #25, and finishing with ProTaper F2 file (Denstply Maillefer). All files were used up to the working length under irrigation with 1 mL of 2.5% sodium hypochlorite (Biodynamica) at each instrument change. At the end of instrumentation, the roots were randomly separated into 2 groups (n = 10). All specimens received final irrigation with 1 mL of 2.5% sodium hypochlorite. The solution remained in the root canals in Group 1 for one minute; and ultrasonic agitation was performed in Group 2 for one minute using a straight tip inserted at 1 mm from working length. The specimens were processed histologically and the sections were analyzed under optic microscope (*64) to quantify debris present in the root canal. RESULTS: The samples submitted to ultrasonic agitation (Group 2) presented significant decrease in the amount of debris in comparison with those of Group 1 (p < 0.05). CONCLUSIONS: The hybrid instrumentation technique associated with passive ultrasonic agitation promoted greater debris removal in the apical third of the root canals. PMID- 24790923 TI - Antibacterial properties of composite resins incorporating silver and zinc oxide nanoparticles on Streptococcus mutans and Lactobacillus. AB - OBJECTIVES: Recurrent caries was partly ascribed to lack of antibacterial properties in composite resin. Silver and zinc nanoparticles are considered to be broad-spectrum antibacterial agents. The aim of the present study was to evaluate the antibacterial properties of composite resins containing 1% silver and zinc oxide nanoparticles on Streptococcus mutans and Lactobacillus. MATERIALS AND METHODS: Ninety discoid tablets containing 0%, 1% nano-silver and 1% nano zinc oxide particles were prepared from flowable composite resin (n = 30). The antibacterial properties of composite resin discs were evaluated by direct contact test. Diluted solutions of Streptococcus mutans (PTCC 1683) and Lactobacillus (PTCC 1643) were prepared. 0.01 mL of each bacterial species was separately placed on the discs. The discs were transferred to liquid culture media and were incubated at 37C for 8 hr. 0.01 mL of each solution was cultured on blood agar and the colonies were counted. Data was analyzed with Kruskall Wallis and Mann-Whitney U tests. RESULTS: Composites containing nano zinc-oxide particles or silver nanoparticles exhibited higher antibacterial activity against Streptococcus mutans and Lactobacillus compared to the control group (p < 0.05). The effect of zinc-oxide on Streptococcus mutans was significantly higher than that of silver (p < 0.05). There were no significant differences in the antibacterial activity against Lactobacillus between composites containing silver nanoparticles and those containing zinc-oxide nanoparticles. CONCLUSIONS: Composite resins containing silver or zinc-oxide nanoparticles exhibited antibacterial activity against Streptococcus mutans and Lactobacillus. PMID- 24790924 TI - Management of failed periodontal surgical intervention for a furcal lesion with a nonsurgical endodontic approach. AB - As long as the prognosis of teeth remains a matter of concern, the endodontic periodontal relationship will be considered a challenge for the clinician. Many etiologic factors, including bacteria, fungi, and viruses, plus other contributing factors, such as trauma, root resorptions/perforations, and dental malformations, play a role in the co-occurrence of endodontic and periodontal lesions. Whatever the cause, a correct diagnosis on which to base the treatment plan is the key to successful maintenance of the tooth. This article reports the successful endodontic management of a furcation lesion in a mandibular molar that was nonresponsive to a previous periodontal surgical graft. The case had presented a diagnostic challenge for the clinicians, and this article reviews the key points that can lead to a correct diagnosis and treatment planning. PMID- 24790925 TI - Biodentine-a novel dentinal substitute for single visit apexification. AB - Use of an apical plug in management of cases with open apices has gained popularity in recent years. Biodentine, a new calcium silicate-based material has recently been introduced as a dentine substitute, whenever original dentine is damaged. This case report describes single visit apexification in a maxillary central incisor with necrotic pulp and open apex using Biodentine as an apical barrier, and a synthetic collagen material as an internal matrix. Following canal cleaning and shaping, calcium hydroxide was placed as an intracanal medicament for 1 mon. This was followed by placement of small piece of absorbable collagen membrane beyond the root apex to serve as matrix. An apical plug of Biodentine of 5 mm thickness was placed against the matrix using pre-fitted hand pluggers. The remainder of canal was back-filled with thermoplasticized gutta-percha and access cavity was restored with composite resin followed by all-ceramic crown. One year follow-up revealed restored aesthetics and function, absence of clinical signs and symptoms, resolution of periapical rarefaction, and a thin layer of calcific tissue formed apical to the Biodentine barrier. The positive clinical outcome in this case is encouraging for the use of Biodentine as an apical plug in single visit apexification procedures. PMID- 24790926 TI - Healing after horizontal root fractures: 3 cases with 2-year follow-up. AB - Among dental traumas, horizontal root fractures are relatively uncommon injuries. Proper initial management and periodical evaluation is essential for the successful treatment of a root-fractured tooth. If pulpal necrosis develops, endodontic treatment is indicated, exclusively for the coronal fragment. Fragment diastases exert a great influence on healing at the fracture line and on pulpal necrosis. An adequately treated root-fractured tooth has a good prognosis. This case report describes the treatment and 2-yr follow up of 3 maxillary central incisors, first with horizontal root fracture, second with horizontal root fracture and avulsion, and third with horizontal root fracture and lateral luxation. All three cases were treated with mineral trioxide aggregate (ProRoot, Dentsply). During 2 yr of follow-up evaluation, the root-fractured teeth of the present patients were well retained in the arch, showing periodontal healing, even after endodontic treatment. PMID- 24790929 TI - Statistical notes for clinical researchers: Two-way analysis of variance (ANOVA) exploring possible interaction between factors. PMID- 24790927 TI - Endodontic management of a mandibular second molar with radix entomolaris: a case report. AB - The presence of radix entomolaris (RE) in a mandibular first molar is a common occurrence in certain ethnic groups, but the presence of RE in a mandibular second molar is a rare occurrence. In the present case, RE was identified from preoperative radiographs and confirmed using cone-beam computed tomography (CBCT). The access cavity was modified to locate the RE. Cleaning and shaping were performed with nickel-titanium rotary instruments. Obturation was completed with gutta-percha cones using AH Plus (Dentsply Detrey GmbH) as sealer. From the CBCT axial images, the RE was determined to have a Type III curvature by the De Moor classification, Type B separate RE by the Carlsen and Alexandersen classification, and radiographically, a Type i image by the Wang classification. The presence of RE in the mandibular second molar makes it essential to anticipate and treat the distolingual root canal. This case report highlights the usefulness of CBCT for assessing RE in the mandibular second molar, which can help the clinician in making a confirmatory diagnosis and assessing the morphology of the root canal. PMID- 24790928 TI - Surgical management of a failed internal root resorption treatment: a histological and clinical report. AB - This article presents the successful surgical management of a failed mineral trioxide aggregate (MTA) orthograde obturation of a tooth with a history of impact trauma and perforated internal root resorption. A symptomatic maxillary lateral incisor with a history of perforation due to internal root resorption and nonsurgical repair using MTA was referred. Unintentional overfill of the defect with MTA had occurred 4 yr before the initial visit. The excess MTA had since disappeared, and a radiolucent lesion adjacent to the perforation site was evident radiographically. Surgical endodontic retreatment was performed using calcium enriched mixture (CEM) cement as a repair material. Histological examination of the lesion revealed granulation tissue with chronic inflammation, and small fragments of MTA encapsulated within fibroconnective tissue. At the one and two year follow up exams, all signs and symptoms of disease had resolved and the tooth was functional. Complete radiographic healing of the lesion was observed two years after the initial visit. This case report illustrates how the selection of an appropriate approach to treatment of a perforation can affect the long term prognosis of a tooth. In addition, extrusion of MTA into a periradicular lesion should be avoided. PMID- 24790930 TI - Drying adhesives. PMID- 24790931 TI - Some grand challenges in environmental chemistry. PMID- 24790932 TI - Grand challenges in inorganic chemistry: toward better life quality and a more sustainable world. PMID- 24790933 TI - Advanced oxidation of the commercial nonionic surfactant octylphenol polyethoxylate TritonTM X-45 by the persulfate/UV-C process: effect of operating parameters and kinetic evaluation. AB - This study explored the potential use of a sulfate radical (SO(.-) 4)-based photochemical oxidation process to treat the commercial nonionic surfactant octylphenol polyethoxylate (OPPE) TritonTM X-45. For this purpose, the effect of initial S2O(2-) 8 (0-5.0 mM) and OPPE (10-100 mg/L) concentrations on OPPE and its organic carbon content (TOC) removal were investigated at an initial reaction pH of 6.5. Results indicated that very fast OPPE degradation (100%) accompanied with high TOC abatement rates (90%) could be achieved for 10 and 20 mg/L aqueous OPPE at elevated S2O(2-) 8 concentrations (>=2.5 mM). S2O(2-) 8/UV-C treatment was still capable of complete OPPE removal up to an initial concentration of 40 mg/L in the presence of 2.5 mM S2O(2-) 8. On the other hand, TOC removal efficiencies dropped down to only 40% under the same reaction conditions. S2O(2-) 8/UV-C oxidation of OPPE was also compared with the relatively well-known and established H2O2/UV-C oxidation process. Treatment results showed that the performance of S2O(2-) 8/UV-C was comparable to that of H2O2/UV-C oxidation for the degradation and mineralization of OPPE. In order to elucidate the relative reactivity and selectivity of SO(.-) 4 and HO(.), bimolecular reaction rate coefficients of OPPE with SO(.-) 4 and HO(.) were determined by employing competition kinetics with aqueous phenol (47 MUM) selected as the reference compound. The pseudo-first-order abatement rate coefficient obtained for OPPE during S2O(2-) 8/UV-C oxidation (0.044 min(-1)) was found to be significantly lower than that calculated for phenol (0.397 min(-1)). In the case of H2O2/UV-C oxidation however, similar pseudo-first-order abatement rate coefficients were obtained for both OPPE (0.087 min(-1)) and phenol (0.140 min(-1)). From the kinetic study, second-order reaction rate coefficients for OPPE with SO(.-) 4 and HO(.) were determined as 9.8 * 10(8) M(-1) s(-1) and 4.1 * 10(9) M(-1) s(-1), respectively. The kinetic study also revealed that the selectivity of SO(.-) 4 was found to be significantly higher than that of HO(.). PMID- 24790934 TI - Grand challenges in analytical chemistry: towards more bright eyes for scientific research, social events and human health. PMID- 24790935 TI - From macromolecules to electrons-grand challenges in theoretical and computational chemistry. PMID- 24790936 TI - Toluene oxidation by non-thermal plasma combined with palladium catalysts. AB - The oxidation of toluene in air was investigated using a dielectric barrier discharge (DBD) combined with a Pd/Al2O3 catalyst. When using only plasma, rather low selectivity toward CO2 was obtained: 32-35%. By filling the DBD reactor with Pd/Al2O3 catalyst the CO2 selectivity was significantly enhanced (80-90%), however, a large amount of toluene was desorbed from the catalyst when the discharge was operated. By filling a quarter of the discharge gap with catalyst and placing the rest of the catalyst downstream of the plasma reactor, an important increase of CO2 selectivity (~75%) and a 15% increase in toluene conversion were achieved as compared to the results with plasma alone. The catalyst exhibited a very good stability in this reaction. PMID- 24790937 TI - Catalytic conversion of carbon dioxide into dimethyl carbonate using reduced copper-cerium oxide catalysts as low as 353 K and 1.3 MPa and the reaction mechanism. AB - Synthesis of dimethyl carbonate (DMC) from CO2 and methanol under milder reaction conditions was performed using reduced cerium oxide catalysts and reduced copper promoted Ce oxide catalysts. Although the conversion of methanol was low (0.005 0.11%) for 2 h of reaction, DMC was synthesized as low as 353 K and at total pressure of as low as 1.3 MPa using reduced Cu-CeO2 catalyst (0.5 wt% of Cu). The apparent activation energy was 120 kJ mol(-1) and the DMC synthesis rates were proportional to the partial pressure of CO2. An optimum amount of Cu addition to CeO2 was 0.1 wt% for DMC synthesis under the conditions at 393 K and total pressure of 1.3 MPa for 2 h (conversion of methanol: 0.15%) due to the compromise of two effects of Cu: the activation of H2 during reduction prior to the kinetic tests and the block (cover) of the surface active site. The reduction effects in H2 were monitored through the reduction of Ce(4+) sites to Ce(3+) based on the shoulder peak intensity at 5727 eV in the Ce L3-edge X-ray absorption near-edge structure (XANES). The Ce(3+) content was 10% for reduced CeO2 catalyst whereas it increased to 15% for reduced Cu-CeO2 catalyst (0.5 wt% of Cu). Moreover, the content of reduced Ce(3+) sites (10%) associated with the surface O vacancy (defect sites) decreased to 5% under CO2 at 290 K for reduced Cu-CeO2 catalyst (0.1 wt% of Cu). The adsorption step of CO2 on the defect sites might be the key step in DMC synthesis and thus the DMC synthesis rate dependence on the partial pressure of CO2 was proportional. Subsequent H atom subtraction steps from methanol at the neighboring surface Lewis base sites should combine two methoxy species to the adsorbed CO2 to form DMC, water, and restore the surface O vacancy. PMID- 24790938 TI - Organic-Inorganic Eu(3+)/Tb(3+) codoped hybrid films for temperature mapping in integrated circuits. AB - The continuous decrease on the geometric size of electronic devices and integrated circuits generates higher local power densities and localized heating problems that cannot be characterized by conventional thermographic techniques. Here, a self-referencing intensity-based molecular thermometer involving a di ureasil organic-inorganic hybrid thin film co-doped with Eu(3+) and Tb(3+) tris (beta-diketonate) chelates is used to obtain the temperature map of a FR4 printed wiring board with spatio-temporal resolutions of 0.42 MUm/4.8 ms. PMID- 24790939 TI - Electrogenerated poly(pyrrole-lactosyl) and poly(pyrrole-3'-sialyllactosyl) interfaces: toward the impedimetric detection of lectins. AB - This paper reports on the impedimetric transduction of binding reaction between polymerized saccharides and target lectins. The controlled potential electro oxidation of pyrrole-lactosyl and pyrrole-3'-sialyllactosyl at 0.95 V vs. Ag/AgCl, provides thin and reproducible poly(pyrrole-saccharide) films. The affinity binding of two lectins: Arachis hypogaea, (PNA) and Maackia amurensis (MAA) onto poly(pyrrole-lactosyl) and poly(pyrrole-3'-sialyllactosyl) electrodes, was demonstrated by cyclic voltammetry in presence of ruthenium hexamine and hydroquinone. In addition, rotating disk experiments were carried out to determine the permeability of both polypyrrole films and its evolution after incubating with lectin target. Finally, the possibility of using the poly(pyrrole lactosyl) or poly(pyrrole-3'-siallyllactosyl) films for the impedimetric transduction of the lectin binding reaction, was investigated with hydroquinone (2 * 10(-3) mol L(-1)) as a redox probe in phosphate buffer. The resulting impedance spectra were interpreted and modeled as an equivalent circuit indicating that charge transfer resistance (R ct) and relaxation frequency (f degrees ) parameters are sensitive to the lectin binding. R ct increases from 77 to 97 Omega cm(2) for PNA binding and from 93 to 131 Omega cm(2) for MAA binding. In parallel, f degrees decreases from 276 to 222 Hz for PNA binding and from 223 to 131 Hz for MAA binding. This evolution of both parameters reflects the steric hindrances generated by the immobilized lectins towards the permeation of the redox probe. PMID- 24790940 TI - Catalytic performance of Metal-Organic-Frameworks vs. extra-large pore zeolite UTL in condensation reactions. AB - Catalytic behavior of isomorphously substituted B-, Al-, Ga-, and Fe-containing extra-large pore UTL zeolites was investigated in Knoevenagel condensation involving aldehydes, Pechmann condensation of 1-naphthol with ethylacetoacetate, and Prins reaction of beta-pinene with formaldehyde and compared with large-pore aluminosilicate zeolite beta and representative Metal-Organic-Frameworks Cu3(BTC)2 and Fe(BTC). The yield of the target product over the investigated catalysts in Knoevenagel condensation increases in the following sequence: (Al)beta < (Al)UTL < (Ga)UTL < (Fe)UTL < Fe(BTC) < (B)UTL < Cu3(BTC)2 being mainly related to the improving selectivity with decreasing strength of active sites of the individual catalysts. The catalytic performance of Fe(BTC), containing the highest concentration of Lewis acid sites of the appropriate strength is superior over large-pore zeolite (Al)beta and B-, Al-, Ga-, Fe substituted extra-large pore zeolites UTL in Prins reaction of beta-pinene with formaldehyde and Pechmann condensation of 1-naphthol with ethylacetoacetate. PMID- 24790941 TI - Low-temperature CO oxidation on multicomponent gold based catalysts. AB - In this work the development of gold catalysts, essentially based on gamma alumina with small superficial fraction of Ce-Fe mixed oxides as support for the low temperature CO oxidation is proposed. Characterization results obtained by means of TEM, OSC, XPS, UV-Vis spectroscopy and H2-TPR are employed to correlate the activity data with the catalysts composition. The bare gamma-alumina supported gold catalyst demonstrates the poorest activity within the series. The addition of CeO2 or FeOX improves the catalytic performance, especially observed for the CeO2-FeOx mixed oxide doped samples. This enhanced CO oxidation activity was related to the Ce-Fe interaction producing materials with promoted redox properties and therefore oxidation activity. PMID- 24790942 TI - Electrochemical promotion of propane oxidation on Pt deposited on a dense beta" Al2O3 ceramic Ag(+) conductor. AB - A new kind of electrochemical catalyst based on a Pt porous catalyst film deposited on a beta"-Al2O3 ceramic Ag(+) conductor was developed and evaluated during propane oxidation. It was observed that, upon anodic polarization, the rate of propane combustion was significantly electropromoted up to 400%. Moreover, for the first time, exponential increase of the catalytic rate was evidenced during galvanostatic transient experiment in excellent agreement with EPOC equation. PMID- 24790943 TI - Self-assembly of a helical zinc-europium complex: speciation in aqueous solution and luminescence. AB - Two new tridentate(NNO)-bidentate(NN) compartmental ligands, HL(5) and HL(6), are synthesized from pyridine and benzimidazole synthons. They react in aqueous solution under physiological conditions with Zn(II), Ln(III), or a mixture thereof, to yield complexes of different stoichiometries, 1:3, 2:2, 2:3, 1:1:3, the speciation of which is established by UV-visible titrations and ESI mass spectrometry. Photophysical studies of the Eu(III)-containing solutions in Tris HCl 0.1 M (pH = 7.4) show that lanthanide luminescence arises from a unique N6O3 coordination site with pseudo D 3 symmetry. Relevant parameters such as crystal field splitting, lifetime, radiative lifetime, and intrinsic quantum yield perfectly match those reported for dinuclear 4f-4f helicates in which the Eu(III) ion has the same coordination environment. PMID- 24790944 TI - Carbon supported Ag nanoparticles as high performance cathode catalyst for H2/O2 anion exchange membrane fuel cell. AB - A solution phase-based nanocapsule method was successfully developed to synthesize non-platinum metal catalyst-carbon supported Ag nanoparticles (Ag/C). XRD patterns and TEM image show Ag nanoparticles with a small average size (5.4 nm) and narrow size distribution (2-9 nm) are uniformly dispersed on the carbon black Vulcan XC-72 support. The intrinsic activity and pathway of oxygen reduction reaction (ORR) on the Ag/C and commercial Pt/C were investigated using rotating ring disk electrode (RRDE) tests at room temperature. The results confirmed that the 4-electron pathway of ORR proceeds on small Ag nanoparticles, and showed comparable ORR activities on the self-prepared Ag/C and a commercial Pt/C. A single H2-O2 anion exchange membrane fuel cell (AEMFC) with the Ag/C cathode catalyst exhibited an open circuit potential of 0.98 V and a peak power density of 190 mW/cm(2) at 80 degrees C. PMID- 24790945 TI - Transformation of sodium bicarbonate and CO2 into sodium formate over NiPd nanoparticle catalyst. AB - The present research systematically investigated, for the first time, the transformation of sodium bicarbonate and CO2 into sodium formate over a series of Ni based metal nanoparticles (NPs). Ni NPs and eight NiM (M stands for a second metal) NPs were prepared by a facile wet chemical process and then their catalytic performance were evaluated in sodium bicarbonate hydrogenation. Bimetallic NiPd NPs with a composition of 7:3 were found to be superior for this reaction, which are more active than both pure Ni and Pd NPs. Hot filtration experiment suggested the NPs to be the truly catalytic active species and kinetic analysis indicated the reaction mechanism to be different than most homogeneous catalysts. The enhanced activity of the bimetallic nanoparticles may be attributed to their smaller size and improved stability. PMID- 24790947 TI - Low dielectric and low surface free energy flexible linear aliphatic alkoxy core bridged bisphenol cyanate ester based POSS nanocomposites. AB - The aim of the present work is to develop a new type of flexible linear aliphatic alkoxy core bridged bisphenol cyanate ester (AECE) based POSS nanocomposites for low k applications. The POSS-AECE nanocomposites were developed by incorporating varying weight percentages (0, 5, and 10 wt %) of octakis (dimethylsiloxypropylglycidylether) silsesquioxane (OG-POSS) into cyanate esters. Data from thermal and dielectric studies imply that the POSS reinforced nanocomposite exhibits higher thermal stability and low dielectric value of k = 2.4 (10 wt% POSS-AECE4) compared than those of neat AECE. From the contact angle measurement, it is inferred that, the increase in the percentage incorporation of POSS in to AECE, the values of water contact angle was enhanced. Further, the value of surface free energy was lower when compared to that of neat AECE. The molecular level dispersion of POSS into AECE was ascertained from SEM and TEM analyses. PMID- 24790946 TI - Hierarchically nanostructured materials for sustainable environmental applications. AB - This review presents a comprehensive overview of the hierarchical nanostructured materials with either geometry or composition complexity in environmental applications. The hierarchical nanostructures offer advantages of high surface area, synergistic interactions, and multiple functionalities toward water remediation, biosensing, environmental gas sensing and monitoring as well as catalytic gas treatment. Recent advances in synthetic strategies for various hierarchical morphologies such as hollow spheres and urchin-shaped architectures have been reviewed. In addition to the chemical synthesis, the physical mechanisms associated with the materials design and device fabrication have been discussed for each specific application. The development and application of hierarchical complex perovskite oxide nanostructures have also been introduced in photocatalytic water remediation, gas sensing, and catalytic converter. Hierarchical nanostructures will open up many possibilities for materials design and device fabrication in environmental chemistry and technology. PMID- 24790949 TI - Lanthanoid-free perovskite oxide catalyst for dehydrogenation of ethylbenzene working with redox mechanism. AB - For the development of highly active and robust catalysts for dehydrogenation of ethylbenzene (EBDH) to produce styrene; an important monomer for polystyrene production, perovskite-type oxides were applied to the reaction. Controlling the mobility of lattice oxygen by changing the structure of Ba1 - x SrxFe y Mn1 - y O3 - delta (0 <= x <= 1, 0.2 <= y <= 0.8), perovskite catalyst showed higher activity and stability on EBDH. The optimized Ba/Sr and Fe/Mn molar ratios were 0.4/0.6 and 0.6/0.4, respectively. Comparison of the dehydrogenation activity of Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta catalyst with that of an industrial potassium promoted iron (Fe-K) catalyst revealed that the Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta catalyst showed higher initial activity than the industrial Fe-K oxide catalyst. Additionally, the Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta catalyst showed high activity and stability under severe conditions, even at temperatures as low as 783 K, or at the low steam/EB ratio of 2, while, the Fe-K catalyst showed low activity in such conditions. Comparing reduction profiles of the Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta and the Fe-K catalysts in a H2O/H2 atmosphere, reduction was suppressed by the presence of H2O over the Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta catalyst while the Fe K catalyst was reduced. In other words, Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta catalyst had higher potential for activating the steam than the Fe-K catalyst. The lattice oxygen in perovskite-structure was consumed by H2, subsequently the consumed lattice oxygen was regenerated by H2O. So the catalytic performance of Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta was superior to that of Fe-K catalyst thanks to the high redox property of the Ba0.4Sr0.6Fe0.6Mn0.4O3 - delta perovskite oxide. PMID- 24790948 TI - Detection of mercury ions using silver telluride nanoparticles as a substrate and recognition element through surface-enhanced Raman scattering. AB - In this paper we unveil a new sensing strategy for sensitive and selective detection of Hg(2+) through surface-enhanced Raman scattering (SERS) using Ag2Te nanoparticles (NPs) as a substrate and recognition element and rhodamine 6G (R6G) as a reporter. Ag2Te NPs prepared from tellurium dioxide and silver nitrate and hydrazine in aqueous solution containing sodium dodecyl sulfate at 90 degrees C with an average size of 26.8 +/- 4.1 nm (100 counts) have strong SERS activity. The Ag2Te substrate provides strong SERS signals of R6G with an enhancement factor of 3.6 * 10(5) at 1360 cm(-1), which is comparable to Ag NPs. After interaction of Ag2Te NPs with Hg(2+), some HgTe NPs are formed, leading to decreases in the SERS signal of R6G, mainly because HgTe NPs relative to Ag2Te NPs have weaker SERS activity. Under optimum conditions, this SERS approach using Ag2Te as substrates is selective for the detection of Hg(2+), with a limit of detection of 3 nM and linearity over 10-150 nM. The practicality of this approach has been validated for the determination of the concentrations of spiked Hg(2+) in a pond water sample. PMID- 24790950 TI - Forty years of Clar's aromatic pi-sextet rule. AB - In 1972 Erich Clar formulated his aromatic pi-sextet rule that allows discussing qualitatively the aromatic character of benzenoid species. Now, 40 years later, Clar's aromatic pi-sextet rule is still a source of inspiration for many chemists. This simple rule has been validated both experimentally and theoretically. In this review, we select some particular examples to highlight the achievement of Clar's aromatic pi-sextet rule in many situations and we discuss two recent successful cases of its application. PMID- 24790951 TI - Direct visualization of the reaction transformation and signal amplification in a DNA molecular machine with total internal reflection fluorescence microscopy. AB - In this study, as a proof of concept, the signal amplification in an artificial DNA molecular machine was directly visualized via total internal reflection fluorescence microscopy (TIRFM). The molecular machine brought about obvious morphology change in DNA nanostructures as well as signal amplifications. On one hand, through a triggered and autonomically repeated RCA, a DNA nano-complex featuring a "locked" circular DNA template (serving as raw feed) was converted into a long periodically repeated strand, i.e., the RCA products. On the other hand, this RCA was repeated in three controllable reaction phases, bring about progressive signal amplification. It was testified that the RCA products (presented as long thread-like fluorescent objects) can be easily distinguished from the inputted DNA probes (presented as fluorescent dots), thus the transformation in reaction can be visualized. Also, by quantitive counting of the aforementioned fluorescence objects, the progress of the reaction through the phases, along with time, and over the lysozyme concentration can be demonstrated through TIRFM visualization. Overall, it was demonstrated that TIRFM is an efficient approach to quantitatively visualize the biochemical processes at single-molecule level. PMID- 24790952 TI - On the basis set convergence of electron-electron entanglement measures: helium like systems. AB - A systematic investigation of three different electron-electron entanglement measures, namely the von Neumann, the linear and the occupation number entropy at full configuration interaction level has been performed for the four helium-like systems hydride, helium, Li(+) and Be(2+) using a large number of different basis sets. The convergence behavior of the resulting energies and entropies revealed that the latter do in general not show the expected strictly monotonic increase upon increase of the one-electron basis. Overall, the three different entanglement measures show good agreement among each other, the largest deviations being observed for small basis sets. The data clearly demonstrates that it is important to consider the nature of the chemical system when investigating entanglement phenomena in the framework of Gaussian type basis sets: while in case of hydride the use of augmentation functions is crucial, the application of core functions greatly improves the accuracy in case of cationic systems such as Li(+) and Be(2+). In addition, numerical derivatives of the entanglement measures with respect to the nucleic charge have been determined, which proved to be a very sensitive probe of the convergence leading to qualitatively wrong results (i.e., the wrong sign) if too small basis sets are used. PMID- 24790953 TI - Dissolved and particulate trace metal micronutrients under the McMurdo Sound seasonal sea ice: basal sea ice communities as a capacitor for iron. AB - Dissolved and particulate metal concentrations are reported from three sites beneath and at the base of the McMurdo Sound seasonal sea ice in the Ross Sea of Antarctica. This dataset provided insight into Co and Mn biogeochemistry, supporting a previous hypothesis for water column mixing occurring faster than scavenging. Three observations support this: first, Mn-containing particles with Mn/Al ratios in excess of the sediment were present in the water column, implying the presence of bacterial Mn-oxidation processes. Second, dissolved and labile Co were uniform with depth beneath the sea ice after the winter season. Third, dissolved Co:PO(3-) 4 ratios were consistent with previously observed Ross Sea stoichiometry, implying that over-winter scavenging was slow relative to mixing. Abundant dissolved Fe and Mn were consistent with a winter reserve concept, and particulate Al, Fe, Mn, and Co covaried, implying that these metals behaved similarly. Elevated particulate metals were observed in proximity to the nearby Islands, with particulate Fe/Al ratios similar to that of nearby sediment, consistent with a sediment resuspension source. Dissolved and particulate metals were elevated at the shallowest depths (particularly Fe) with elevated particulate P/Al and Fe/Al ratios in excess of sediments, demonstrating a sea ice biomass source. The sea ice biomass was extremely dense (chl a >9500 MUg/L) and contained high abundances of particulate metals with elevated metal/Al ratios. A hypothesis for seasonal accumulation of bioactive metals at the base of the McMurdo Sound sea ice by the basal algal community is presented, analogous to a capacitor that accumulates iron during the spring and early summer. The release and transport of particulate metals accumulated at the base of the sea ice by sloughing is discussed as a potentially important mechanism in providing iron nutrition during polynya phytoplankton bloom formation and could be examined in future oceanographic expeditions. PMID- 24790954 TI - Force-field functor theory: classical force-fields which reproduce equilibrium quantum distributions. AB - Feynman and Hibbs were the first to variationally determine an effective potential whose associated classical canonical ensemble approximates the exact quantum partition function. We examine the existence of a map between the local potential and an effective classical potential which matches the exact quantum equilibrium density and partition function. The usefulness of such a mapping rests in its ability to readily improve Born-Oppenheimer potentials for use with classical sampling. We show that such a map is unique and must exist. To explore the feasibility of using this result to improve classical molecular mechanics, we numerically produce a map from a library of randomly generated one-dimensional potential/effective potential pairs then evaluate its performance on independent test problems. We also apply the map to simulate liquid para-hydrogen, finding that the resulting radial pair distribution functions agree well with path integral Monte Carlo simulations. The surprising accessibility and transferability of the technique suggest a quantitative route to adapting Born Oppenheimer potentials, with a motivation similar in spirit to the powerful ideas and approximations of density functional theory. PMID- 24790955 TI - Influence of the pi-coordinated arene on the anticancer activity of ruthenium(II) carbohydrate organometallic complexes. AB - The synthesis and in vitro cytotoxicity of a series of Ru(II)(arene) complexes with carbohydrate-derived phosphite ligands and various arene co-ligands is described. The arene ligand has a strong influence on the in vitro anticancer activity of this series of compounds, which correlates fairly well with cellular accumulation. The most lipophilic compound bearing a biphenyl moiety and a cyclohexylidene-protected carbohydrate is the most cytotoxic with unprecedented IC50 values for the compound class in three human cancer cell lines. This compound shows reactivity to the DNA model nucleobase 9-ethylguanine, but does not alter the secondary structure of plasmid DNA, indicating that other biological targets are responsible for its cytotoxic effect. PMID- 24790956 TI - Clay exfoliation and polymer/clay aerogels by supercritical carbon dioxide. AB - Supercritical carbon dioxide (scCO2) treatments of a montmorillonite (MMT) intercalated with ammonium cations bearing two long hydrocarbon tails (organo modified MMT, OMMT) led to OMMT exfoliation, with loss of the long-range order in the packing of the hydrocarbon tails and maintenance of the long-range order in the clay layers. The intercalated and the derived exfoliated OMMT have been deeply characterized, mainly by X-ray diffraction analyses. Monolithic composite aerogels, with large amounts of both intercalated and exfoliated OMMT and including the nanoporous-crystalline delta form of syndiotactic polystyrene (s PS), have been prepared, by scCO2 extractions of s-PS-based gels. Also for high OMMT content, the gel and aerogel preparation procedures occur without re aggregation of the exfoliated clay, which is instead observed for other kinds of polymer processing. Aerogels with the exfoliated OMMT have more even dispersion of the clay layers, higher elastic modulus and larger surface area than aerogels with the intercalated OMMT. Extremely light materials with relevant transport properties could be prepared. Moreover, s-PS-based aerogels with exfoliated OMMT could be helpful for the handling of exfoliated clay minerals. PMID- 24790959 TI - Grand challenges in polymer chemistry: energy, environment, health. PMID- 24790957 TI - Synthesis of functionalized fluorescent silver nanoparticles and their toxicological effect in aquatic environments (Goldfish) and HEPG2 cells. AB - Silver nanoparticles, AgNPs, are widely used in our daily life, mostly due to their antibacterial, antiviral, and antifungal properties. However, their potential toxicity remains unclear. In order to unravel this issue, emissive AgNPs were first synthetized using an inexpensive photochemical method, and then their permeation was assessed in vivo in goldfish and in vitro in human hepatoma cells (HepG2). In addition, the oxidative stress caused by AgNPs was assessed in enzymes such as glutathione-S-transferase (GST), catalase (CAT), and in lipid peroxidation (LPO). This study demonstrates that the smallest sized AgNPs@3 promote the largest changes in gold fish livers, whereas AgNPs@1 were found to be toxic in HEPG2 cells depending on both the size and functionalized/stabilizer ligand. PMID- 24790958 TI - Synthesis of fluorescent analogs of relaxin family peptides and their preliminary in vitro and in vivo characterization. AB - Relaxin, a heterodimeric polypeptide hormone, is a key regulator of collagen metabolism and multiple vascular control pathways in humans and rodents. Its actions are mediated via its cognate G-protein-coupled receptor, RXFP1 although it also "pharmacologically" activates RXFP2, the receptor for the related, insulin-like peptide 3 (INSL3), which has specific actions on reproduction and bone metabolism. Therefore, experimental tools to facilitate insights into the distinct biological actions of relaxin and INSL3 are required, particularly for studies of tissues containing both RXFP1 and RXFP2. Here, we chemically functionalized human (H2) relaxin, the RXFP1-selective relaxin analog H2:A(4 24)(F23A), and INSL3 to accommodate a fluorophore without marked reduction in binding or activation propensity. Chemical synthesis of the two chains for each peptide was followed by sequential regioselective formation of their three disulfide bonds. Click chemistry conjugation of Cy5.5 at the B-chain N-terminus, with conservation of the disulfide bonds, yielded analogs displaying appropriate selective binding affinity and ability to activate RXFP1 and/or RXFP2 in vitro. The in vivo biological activity of Cy5.5-H2 relaxin and Cy5.5-H2:A(4-24)(F23A) was confirmed in mice, as acute intracerebroventricular (icv) infusion of these peptides (but not Cy5.5-INSL3) stimulated water drinking, an established behavioral response elicited by central RXFP1 activation. The central distribution of Cy5.5-conjugated peptides was examined in mice killed 30 min after infusion, revealing higher fluorescence within brain tissue near-adjacent to the cerebral ventricle walls relative to deeper brain areas. Production of fluorophore-conjugated relaxin family peptides will facilitate future pharmacological studies to probe the function of H2 relaxin/RXFP1 and INSL3/RXFP2 signaling in vivo while tracking their distribution following central or peripheral administration. PMID- 24790960 TI - Recent advances in high performance poly(lactide): from "green" plasticization to super-tough materials via (reactive) compounding. AB - Due to its origin from renewable resources, its biodegradability, and recently, its industrial implementation at low costs, poly(lactide) (PLA) is considered as one of the most promising ecological, bio-sourced and biodegradable plastic materials to potentially and increasingly replace traditional petroleum derived polymers in many commodity and engineering applications. Beside its relatively high rigidity [high tensile strength and modulus compared with many common thermoplastics such as poly(ethylene terephthalate) (PET), high impact poly(styrene) (HIPS) and poly(propylene) (PP)], PLA suffers from an inherent brittleness, which can limit its applications especially where mechanical toughness such as plastic deformation at high impact rates or elongation is required. Therefore, the curve plotting stiffness vs. impact resistance and ductility must be shifted to higher values for PLA-based materials, while being preferably fully bio-based and biodegradable upon the application. This review aims to establish a state of the art focused on the recent progresses and preferably economically viable strategies developed in the literature for significantly improve the mechanical performances of PLA. A particular attention is given to plasticization as well as to impact resistance modification of PLA in the case of (reactive) blending PLA-based systems. PMID- 24790961 TI - Response to Commentary on "Force-field functor theory: classical force-fields which reproduce equilibrium quantum distributions". PMID- 24790962 TI - Commentary on "Force-field functor theory: classical force-fields which reproduce equilibrium quantum distributions". PMID- 24790963 TI - Computational engineering of low bandgap copolymers. AB - We present a conceptual approach to low bandgap copolymers, in which we clarify the physical parameters which control the optical bandgap, develop a fundamental understanding of bandgap tuning, unify the terminology, and outline the minimum requirements for accurate prediction of polymer bandgaps from those of finite length oligomers via extrapolation. We then test the predictive power of several popular hybrid and long-range corrected (LC) DFT functionals when applied to this task by careful comparison to experimental studies of homo- and co-oligomer series. These tests identify offset-corrected M06HF, with 100% HF exchange, as a useful alternative to the poor performance of tested hybrid and LC functionals with lower fractions of HF exchange (B3LYP, CAM-B3LYP, optimally-tuned LC-BLYP, BHLYP), which all significantly overestimate changes in bandgap as a function of system size. PMID- 24790964 TI - Reducing the pollutant load of olive mill wastewater by photocatalytic membranes and monitoring the process using both tyrosinase biosensor and COD test. AB - Photocatalytic technique had already been employed in the treatment of olive mill wastewater (OMW) using the photocatalysis in suspension. The coupling of photocatalytic and membrane techniques should result in a very powerful process bringing great innovation to OMW depollution. Despite the potential advantages using these hybrid photoreactors, research on the combined use of photocatalysis and membranes has so far not been sufficiently developed. The present paper describes a study to assess the photocatalytic efficacy of a new ceramic membrane containing titanium dioxide, irradiated by UV light, used to abate the pollutant load of OMW. Good results were obtained (more than 90% of the phenol content was removed and the COD decrease was of the order of 46-51% in 24 h) particularly using the ceramic membrane compared with those offered by analogous catalytic membranes made of metallic or polymeric materials. PMID- 24790965 TI - Selectivity and self-diffusion of CO2 and H2 in a mixture on a graphite surface. AB - We performed classical molecular dynamics (MD) simulations to understand the mechanism of adsorption from a gas mixture of CO2 and H2 (mole fraction of CO2 = 0.30) and diffusion along a graphite surface, with the aim to help enrich industrial off-gases in CO2, separating out H2. The temperature of the system in the simulation covered typical industrial conditions for off-gas treatment (250 550 K). The interaction energy of single molecules CO2 or H2 on graphite surface was calculated with classical force fields (FFs) and with Density Functional Theory (DFT). The results were in good agreement. The binding energy of CO2 on graphite surface is three times larger than that of H2. At lower temperatures, the selectivity of CO2 over H2 is five times larger than at higher temperatures. The position of the dividing surface was used to explain how the adsorption varies with pore size. In the temperature range studied, the self-diffusion coefficient of CO2 is always smaller than of H2. The temperature variation of the selectivities and the self-diffusion coefficient imply that the carbon molecular sieve membrane can be used for gas enrichment of CO2. PMID- 24790966 TI - Cysteine protease inhibition by nitrile-based inhibitors: a computational study. AB - Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density functional theory and quantum mechanics/molecular mechanics study on the reaction of a nitrile-based inhibitor with the enzyme active site amino acids. We show here that small perturbations to the inhibitor structure can have dramatic effects on the catalysis and inhibition processes. Thus, we investigated a range of inhibitor templates and show that specific structural changes reduce the inhibitory efficiency by several orders of magnitude. Moreover, as the reaction takes place on a polar surface, we find strong differences between the DFT and QM/MM calculated energetics. In particular, the DFT model led to dramatic distortions from the starting structure and the convergence to a structure that would not fit the enzyme active site. In the subsequent QM/MM study we investigated the use of mechanical vs. electronic embedding on the kinetics, thermodynamics and geometries along the reaction mechanism. We find minor effects on the kinetics of the reaction but large geometric and thermodynamics differences as a result of inclusion of electronic embedding corrections. The work here highlights the importance of model choice in the investigation of this biochemical reaction mechanism. PMID- 24790967 TI - Chicoric acid: chemistry, distribution, and production. AB - Though chicoric acid was first identified in 1958, it was largely ignored until recent popular media coverage cited potential health beneficial properties from consuming food and dietary supplements containing this compound. To date, plants from at least 63 genera and species have been found to contain chicoric acid, and while the compound is used as a processing quality indicator, it may also have useful health benefits. This review of chicoric acid summarizes research findings and highlights gaps in research knowledge for investigators, industry stakeholders, and consumers alike. Additionally, chicoric acid identification, and quantification methods, biosynthesis, processing improvements to increase chicoric acid retention, and potential areas for future research are discussed. PMID- 24790968 TI - Hyperconjugation in Carbocations, a BLW Study with DFT approximation. AB - The geometry of ethyl cation is discussed, and the hyperconjugation effect in carbocations is evaluated at the B3LYP/6-311G(d) level. The Block Localized Wavefunction (BLW) method is used for all evaluations of the hyperconjugation, considered as the energy gained by the delocalization onto the C(+) atom. This energy is defined as the energy difference between the delocalized (standard) calculation, where the electrons are freely delocalized, and a localized form where the positive charge sits on the carbon center. It is evaluated for 18 carbocations, including conjugated systems. In these cases we were particularly interested in the additional stabilization brought by hyperconjugative effects. Among other effects, the beta-silicon effect is computed. Hyperconjugation amounts in several cases to an energy similar to conjugation effects. PMID- 24790969 TI - TD-DFT insight into photodissociation of the Co-C bond in coenzyme B12. AB - Coenzyme B12 (AdoCbl) is one of the most biologically active forms of vitamin B12, and continues to be a topic of active research interest. The mechanism of Co C bond cleavage in AdoCbl, and the corresponding enzymatic reactions are however, not well understood at the molecular level. In this work, time-dependent density functional theory (TD-DFT) has been applied to investigate the photodissociation of coenzyme B12. To reduce computational cost, while retaining the major spectroscopic features of AdoCbl, a truncated model based on ribosylcobalamin (RibCbl) was used to simulate Co-C photodissociation. Equilibrium geometries of RibCbl were obtained by optimization at the DFT/BP86/TZVP level of theory, and low-lying excited states were calculated by TD-DFT using the same functional and basis set. The calculated singlet states, and absorption spectra were simulated in both the gas phase, and water, using the polarizable continuum model (PCM). Both spectra were in reasonable agreement with experimental data, and potential energy curves based on vertical excitations were plotted to explore the nature of Co-C bond dissociation. It was found that a repulsive (3)(sigmaCo-C -> sigma(*) Co-C) triplet state became dissociative at large Co-C bond distance, similar to a previous observation for methylcobalamin (MeCbl). Furthermore, potential energy surfaces (PESs) obtained as a function of both Co-CRib and Co-NIm distances, identify the S1 state as a key intermediate generated during photoexcitation of RibCbl, attributed to a mixture of a metal-to-ligand charge transfer (MLCT) and a sigma bonding-ligand charge transfer (SBLCT) states. PMID- 24790971 TI - The hygroscopic behavior of plant fibers: a review. AB - Environmental concern has resulted in a renewed interest in bio-based materials. Among them, plant fibers are perceived as an environmentally friendly substitute to glass fibers for the reinforcement of composites, particularly in automotive engineering. Due to their wide availability, low cost, low density, high-specific mechanical properties, and eco-friendly image, they are increasingly being employed as reinforcements in polymer matrix composites. Indeed, their complex microstructure as a composite material makes plant fiber a really interesting and challenging subject to study. Research subjects about such fibers are abundant because there are always some issues to prevent their use at large scale (poor adhesion, variability, low thermal resistance, hydrophilic behavior). The choice of natural fibers rather than glass fibers as filler yields a change of the final properties of the composite. One of the most relevant differences between the two kinds of fiber is their response to humidity. Actually, glass fibers are considered as hydrophobic whereas plant fibers have a pronounced hydrophilic behavior. Composite materials are often submitted to variable climatic conditions during their lifetime, including unsteady hygroscopic conditions. However, in humid conditions, strong hydrophilic behavior of such reinforcing fibers leads to high level of moisture absorption in wet environments. This results in the structural modification of the fibers and an evolution of their mechanical properties together with the composites in which they are fitted in. Thereby, the understanding of these moisture absorption mechanisms as well as the influence of water on the final properties of these fibers and their composites is of great interest to get a better control of such new biomaterials. This is the topic of this review paper. PMID- 24790972 TI - Alkaline ionic liquids applied in supported ionic liquid catalyst for selective hydrogenation of citral to citronellal. AB - The challenge in preparation of ionic liquids containing a strong alkaline anion is to identify a suitable cation which can tolerate the harsh conditions induced by the anion. In this study, a commercial quaternary ammonium compound (quat) benzalkonium [ADBA] (alkyldimethylbenzylammonium) was used as a cation in the synthesis of different alkaline ionic liquids. In fact, the precursor, benzalkonium chloride, is a mixture of alkyldimethylbenzylammonium chlorides of various alkyl chain lengths and is commonly used in the formulation of various antiseptic products. The prepared ionic liquids were utilized as Supported Ionic Liquid Catalysts (SILCAs). Typically, a SILCA contains metal nanoparticles, enzymes, or metal complexes in an ionic liquid layer which is immobilized on a solid carrier material such as an active carbon cloth (ACC). The catalysts were applied in the selective hydrogenation of citral to citronellal which is an important perfumery chemical. Interestingly, 70% molar yield toward citronellal was achieved over a catalyst containing the alkaline ionic liquid benzalkonium methoxide. PMID- 24790970 TI - Stress and polyamine metabolism in fungi. AB - Fungi, as well as the rest of living organisms must deal with environmental challenges such as stressful stimuli. Fungi are excellent models to study the general mechanisms of the response to stress, because of their simple, but conserved, signal-transduction and metabolic pathways that are often equivalent to those present in other eukaryotic systems. A factor that has been demonstrated to be involved in these responses is polyamine metabolism, essentially of the three most common polyamines: putrescine, spermidine and spermine. The gathered evidences on this subject suggest that polyamines are able to control cellular signal transduction, as well as to modulate protein-protein interactions. In the present review, we will address the recent advances on the study of fungal metabolism of polyamines, ranging from mutant characterization to potential mechanism of action during different kinds of stress in selected fungal models. PMID- 24790973 TI - Atmospheric processes on ice nanoparticles in molecular beams. AB - THIS REVIEW SUMMARIZES SOME RECENT EXPERIMENTS WITH ICE NANOPARTICLES (LARGE WATER CLUSTERS) IN MOLECULAR BEAMS AND OUTLINES THEIR ATMOSPHERIC RELEVANCE: (1) Investigation of mixed water-nitric acid particles by means of the electron ionization and sodium doping combined with photoionization revealed the prominent role of HNO3 molecule as the condensation nuclei. (2) The uptake of atmospheric molecules by water ice nanoparticles has been studied, and the pickup cross sections for some molecules exceed significantly the geometrical sizes of the ice nanoparticles. (3) Photodissociation of hydrogen halides on water ice particles has been shown to proceed via excitation of acidically dissociated ion pair and subsequent biradical generation and H3O dissociation. The photodissociation of CF2Cl2 molecules in clusters is also mentioned. Possible atmospheric consequences of all these results are briefly discussed. PMID- 24790974 TI - Computational studies of DNA sequencing with solid-state nanopores: key issues and future prospects. AB - Owing to the potential use for real personalized genome sequencing, DNA sequencing with solid-state nanopores has been investigated intensively in recent time. However, the area still confronts problems and challenges. In this work, we present a brief overview of computational studies of key issues in DNA sequencing with solid-state nanopores by addressing the progress made in the last few years. We also highlight future challenges and prospects for DNA sequencing using this technology. PMID- 24790975 TI - Natural additives and agricultural wastes in biopolymer formulations for food packaging. AB - The main directions in food packaging research are targeted toward improvements in food quality and food safety. For this purpose, food packaging providing longer product shelf-life, as well as the monitoring of safety and quality based upon international standards, is desirable. New active packaging strategies represent a key area of development in new multifunctional materials where the use of natural additives and/or agricultural wastes is getting increasing interest. The development of new materials, and particularly innovative biopolymer formulations, can help to address these requirements and also with other packaging functions such as: food protection and preservation, marketing and smart communication to consumers. The use of biocomposites for active food packaging is one of the most studied approaches in the last years on materials in contact with food. Applications of these innovative biocomposites could help to provide new food packaging materials with improved mechanical, barrier, antioxidant, and antimicrobial properties. From the food industry standpoint, concerns such as the safety and risk associated with these new additives, migration properties and possible human ingestion and regulations need to be considered. The latest innovations in the use of these innovative formulations to obtain biocomposites are reported in this review. Legislative issues related to the use of natural additives and agricultural wastes in food packaging systems are also discussed. PMID- 24790976 TI - Genetic code expansion as a tool to study regulatory processes of transcription. AB - The expansion of the genetic code with non-canonical amino acids (ncAA) enables the chemical and biophysical properties of proteins to be tailored, inside cells, with a previously unattainable level of precision. A wide range of ncAA with functions not found in canonical amino acids have been genetically encoded in recent years and have delivered insights into biological processes that would be difficult to access with traditional approaches of molecular biology. A major field for the development and application of novel ncAA-functions has been transcription and its regulation. This is particularly attractive, since advanced DNA sequencing- and proteomics-techniques continue to deliver vast information on these processes on a global level, but complementing methodologies to study them on a detailed, molecular level and in living cells have been comparably scarce. In a growing number of studies, genetic code expansion has now been applied to precisely control the chemical properties of transcription factors, RNA polymerases and histones, and this has enabled new insights into their interactions, conformational changes, cellular localizations and the functional roles of posttranslational modifications. PMID- 24790977 TI - A personal perspective on medicinal and pharmaceutical chemistry. PMID- 24790979 TI - Hydrogen-bonds structure in poly(2-hydroxyethyl methacrylate) studied by temperature-dependent infrared spectroscopy. AB - Hydrogen-bonds structure in poly(2-hydroxyethyl methacrylate) (PHEMA) were investigated by means of temperature-dependent infrared (IR) spectroscopy. Spectral variations involved with the OH...OH and C=O...HO types of hydrogen bonds were found around the glass transition temperature of 80 degrees C. Hydrogen-bonds among the hydroxyl groups gradually dissociate with increasing temperature. In contrast, discontinuous variation in the carbonyl bands was observed around the glass transition temperature. An association of the C=O...HO type of hydrogen-bond with increasing temperature above the glass transition temperature was revealed. These were concluded from the present study that hydrogen-bonds among the hydroxyl groups in each side chain terminal suppress the main chain mobility in the polymer matrix below the glass transition temperature, while the dissociation of the OH...OH type of hydrogen-bonds induces the association of the C=O...HO type of hydrogen-bond. As a result, the mobility of the main chain is induced by the change in hydrogen-bonds structure at the glass transition temperature. PMID- 24790980 TI - Delivery of chemical cargo to endogenous proteins on live cells. PMID- 24790978 TI - Allosteric modulation of protein oligomerization: an emerging approach to drug design. AB - Many disease-related proteins are in equilibrium between different oligomeric forms. The regulation of this equilibrium plays a central role in maintaining the activity of these proteins in vitro and in vivo. Modulation of the oligomerization equilibrium of proteins by molecules that bind preferentially to a specific oligomeric state is emerging as a potential therapeutic strategy that can be applied to many biological systems such as cancer and viral infections. The target proteins for such compounds are diverse in structure and sequence, and may require different approaches for shifting their oligomerization equilibrium. The discovery of such oligomerization-modulating compounds is thus achieved based on existing structural knowledge about the specific target proteins, as well as on their interactions with partner proteins or with ligands. In silico design and combinatorial tools such as peptide arrays and phage display are also used for discovering compounds that modulate protein oligomerization. The current review highlights some of the recent developments in the design of compounds aimed at modulating the oligomerization equilibrium of proteins, including the "shiftides" approach developed in our lab. PMID- 24790981 TI - Activation of GATA4 gene expression at the early stage of cardiac specification. AB - Currently, there are no effective treatments to directly repair damaged heart tissue after cardiac injury since existing therapies focus on rescuing or preserving reversibly damaged tissue. Cell-based therapies using cardiomyocytes generated from stem cells present a promising therapeutic approach to directly replace damaged myocardium with new healthy tissue. However, the molecular mechanisms underlying the commitment of stem cells into cardiomyocytes are not fully understood and will be critical to guide this new technology into the clinic. Since GATA4 is a critical regulator of cardiac differentiation, we examined the molecular basis underlying the early activation of GATA4 gene expression during cardiac differentiation of pluripotent stem cells. Our studies demonstrate the direct involvement of histone acetylation and transcriptional coactivator p300 in the regulation of GATA4 gene expression. More importantly, we show that histone acetyltransferase (HAT) activity is important for GATA4 gene expression with the use of curcumin, a HAT inhibitor. In addition, the widely used histone deacetylase inhibitor valproic acid enhances both histone acetylation and cardiac specification. PMID- 24790982 TI - Synthetic sugar for sustainable power? PMID- 24790984 TI - Cork: a strategic material. PMID- 24790983 TI - Unnatural amino acid incorporation in E. coli: current and future applications in the design of therapeutic proteins. AB - Unnatural amino acid (UAA) incorporation by amber codon suppression offers scientists a powerful tool to modify the properties of proteins at will. UAA incorporation has been used for a plethora of fundamental research applications and, more recently, also for the selective modification of therapeutic proteins. In this review most recent developments in Escherichia coli codon expansion and, unnatural amino acid incorporation are discussed together with some remarkable recent developments in improved efficient UAA incorporation. We focus on the generation of proteins that hold promise for future therapeutic applications that would be impossible to obtain without unnatural amino acid incorporation, including the generation of bi-specific antibodies and antibody drug conjugates. PMID- 24790985 TI - Grand challenges in chemical engineering. PMID- 24790986 TI - Adverse effects of risperidone in children with autism spectrum disorders in a naturalistic clinical setting at siriraj hospital, Thailand. AB - A cross-sectional study was conducted to evaluate adverse effects associated with risperidone in 45 children with autism spectrum disorders (ASD), aged 2-15 years, who were treated at Siriraj Hospital, Thailand, between the years 2006 and 2007. Adverse effects were assessed by parent interview, using a semistructure questionnaire, and medical records review. The mean +/- SD age of the children at starting risperidone was 8.15 +/- 2.98 years. The mean +/- SD of risperidone dose was 0.94 +/- 0.74 mg/day and the mean +/- SD duration of treatment was 36.8 +/- 27.8 months. Adverse effects were reported in 39 children (86.7%). Common adverse effects included increased appetite, somnolence, and rhinorrhea and most of the adverse effects were tolerable. Tardive dyskinesia or other serious adverse events were not found in this study. The child's mean +/- SD weight gain was 4.18 +/- 2.82 kg/year, which exceeded developmentally expected norms. The results from this study suggest that risperidone treatment in children with ASD is associated with frequent mild and tolerable adverse effects. However, excessive weight gain could be found to be a concerning adverse effect and weight monitoring is warranted when risperidone is being prescribed. PMID- 24790987 TI - Expression data analysis to identify biomarkers associated with asthma in children. AB - Asthma is characterized by recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. It is usually caused by a combination of complex and incompletely understood environmental and genetic interactions. We obtained gene expression data with high-throughput screening and identified biomarkers of children's asthma using bioinformatics tools. Next, we explained the pathogenesis of children's asthma from the perspective of gene regulatory networks: DAVID was applied to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enriching analysis for the top 3000 pairs of relationships in differentially regulatory network. Finally, we found that HAND1, PTK1, NFKB1, ZIC3, STAT6, E2F1, PELP1, USF2, and CBFB may play important roles in children's asthma initiation. On account of regulatory impact factor (RIF) score, HAND1, PTK7, and ZIC3 were the potential asthma-related factors. Our study provided some foundations of a strategy for biomarker discovery despite a poor understanding of the mechanisms underlying children's asthma. PMID- 24790988 TI - Performance of quantification of Modified Hodge Test: an evaluation with Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae isolates. AB - Modified Hodge Test (MHT) has been suggested as screening tests for carbapenemases, but concerns regarding its difficult interpretation and common false-positive results obtained in the presence of other beta -lactamases have been noted. This study aimed to quantify the enhanced growth formed by the indicator strain and thus evaluate the performance of a quantitative interpretation of MHT for KPC screening. MHT was performed in 50 KPC-producing isolates and 334 non-carbapenemase-producing isolates, using ertapenem (ETP) and meropenem (MEM) as substrates. The size of enhanced growth of indicator strain was measured for each isolate tested and for the positive control used, and a ratio was calculated. Our results revealed 17 different ETP and MEM ratios, with distinct sensitivity (SN) and specificity (SP). Higher SN combined to higher SP was achieved when ETP and MEM ratios were 0.45, with a SN value of 96% for both substrates and SP values of 99.4% and 100% for ETP and MEM, respectively. The quantification with both substrates increased SP of the test for KPC detection. Considering that MHT is the unique phenotypic test that is referred to by CLSI, a more accurate approach for its interpretation could be applied to make it a more useful tool. PMID- 24790989 TI - Imbalance between endothelial damage and repair: a gateway to cardiovascular disease in systemic lupus erythematosus. AB - Atherosclerosis is accelerated in patients with systemic lupus erythematosus (SLE) and it leads to excessive cardiovascular complications in these patients. Despite the improved awareness of cardiovascular disease and advent of clinical diagnostics, the process of atherogenesis in most patients remains clinically silent until symptoms and signs of cardiovascular complications develop. As evidence has demonstrated that vascular damage is already occurring before clinically overt cardiovascular disease develops in lupus patients, intervention at the preclinical stage of atherogenesis would be plausible. Indeed, endothelial dysfunction, one of the earliest steps of atherogenesis, has been demonstrated to occur in lupus patients even when they are naive for cardiovascular disease. Currently known "endothelium-toxic" factors including type 1 interferon, proinflammatory cytokines, inflammatory cells, immune complexes, costimulatory molecules, neutrophils extracellular traps, lupus-related autoantibodies, oxidative stress, and dyslipidemia, coupled with the aberrant functions of the endothelial progenitor cells (EPC) which are crucial to vascular repair, likely tip the balance towards endothelial dysfunction and propensity to develop cardiovascular disease in lupus patients. In this review, altered physiology of the endothelium, factors leading to perturbed vascular repair contributed by lupus EPC and the impact of proatherogenic factors on the endothelium which potentially lead to atherosclerosis in lupus patients will be discussed. PMID- 24790990 TI - Pegylated gold nanoparticles induce apoptosis in human chronic myeloid leukemia cells. AB - Gold nanoparticles (AuNPs) have several potential biological applications as well as excellent biocompatibility. AuNPs with surface modification using polyethylene glycol (PEG-AuNPs) can facilitate easy conjugation with various biological molecules of interest. To examine the anticancer bioactivity of PEG-AuNPs, we investigated their effect on human chronic myeloid leukemia K562 cells. The results indicated that PEG-AuNPs markedly inhibited the viability and impaired the cell membrane integrity of K562 cells. The particles caused morphological changes typical of cell death, and a marked increase in the sub-G1 population in DNA histogram, indicating apoptosis. In addition, PEG-AuNPs reduced the mitochondrial transmembrane potential, a hallmark of the involvement of intrinsic apoptotic pathway in K562 cells. Observation of ultrastructure under a transmission electron microscope revealed that the internalized PEG-AuNPs were distributed into cytoplasmic vacuoles and damaged mitochondria, and subsequently accumulated in areas surrounding the nuclear membrane. In conclusion, PEG-AuNPs may have the potential to inhibit growth and induce apoptosis in human chronic myeloid leukemia cells. PMID- 24790991 TI - The effects of acute hydrogen sulfide poisoning on cytochrome P450 isoforms activity in rats. AB - Hydrogen sulfide (H2S) is the second leading cause of toxin related death (after carbon monoxide) in the workplace. H2S is absorbed by the upper respiratory tract mucosa, and it causes histotoxic hypoxemia and respiratory depression. Cocktail method was used to evaluate the influences of acute H2S poisoning on the activities of cytochrome P450 isoforms CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19, and CYP2C9, which were reflected by the changes of pharmacokinetic parameters of six specific probe drugs, bupropion, metoprolol, midazolam, phenacetin, omeprazole, and tolbutamide, respectively. The experimental rats were randomly divided into two groups, control group and acute H2S poisoning group (inhaling 300 ppm for 2 h). The mixture of six probes was given to rats by oral administration and the blood samples were obtained at a series of time points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by LC-MS. The results for acute H2S poisoning and control groups were as follows: there was a statistically significant difference in the AUC and C max for bupropion, metoprolol, phenacetin, and tolbutamide, while there was no statistical pharmacokinetic difference for midazolam and omeprazole. Acute H2S poisoning could inhibit the activity of CYP2B6, CYP2D6, CYP1A2, and CYP2C9 in rats. PMID- 24790992 TI - Association between epsilon2/3/4, promoter polymorphism (-491A/T, -427T/C, and 219T/G) at the apolipoprotein E gene, and mental retardation in children from an iodine deficiency area, China. AB - BACKGROUND: Several common single-nucleotide polymorphisms (SNPs) at apolipoprotein E (ApoE) have been linked with late onset sporadic Alzheimer's disease and declining normative cognitive ability in elder people, but we are unclear about their relationship with cognition in children. RESULTS: We studied 491A/T, -427T/C, and -219G/T promoter polymorphisms and epsilon2/epsilon3/epsilon4 at ApoE among children with mental retardation (MR, n = 130), borderline MR (n = 124), and controls (n = 334) from an iodine deficiency area in China. The allelic and genotypic distribution of individual locus did not significantly differ among three groups with Mantel-Haenszel chi (2) test (P > 0.05). However, frequencies of haplotype of -491A/-427T/-219T/epsilon4 were distributed as MR > borderline MR > controls (P uncorrected = 0.004), indicating that the presence of this haplotype may increase the risk of disease. CONCLUSIONS: In this large population-based study in children, we did not find any significant association between single locus of the four common ApoE polymorphisms (-491A/T, -427T/C, -219T/G, and epsilon2/3/4) and MR or borderline MR. However, we found that the presence of ATTepsilon4 haplotype was associated with an increased risk of MR and borderline MR. Our present work may help enlarge our knowledge of the cognitive role of ApoE across the lifespan and the mechanisms of human cognition. PMID- 24790993 TI - Worldwide dissemination of the NDM-type carbapenemases in Gram-negative bacteria. AB - The emergence of one of the most recently described carbapenemases, namely, the New Delhi metallo-lactamase (NDM-1), constitutes a critical and growingly important medical issue. This resistance trait compromises the efficacy of almost all lactams (except aztreonam), including the last resort carbapenems. Therapeutical options may remain limited mostly to colistin, tigecycline, and fosfomycin. The main known reservoir of NDM producers is the Indian subcontinent whereas a secondary reservoir seems to have established the Balkans regions and the Middle East. Although the spread of bla NDM-like genes (several variants) is derived mostly by conjugative plasmids in Enterobacteriaceae, this carbapenemase has also been identified in P. aeruginosa and Acinetobacter spp. Acinetobacter sp. may play a pivotal role for spreading bla NDM genes for its natural reservoir to Enterobacteriaceae. Rapid diagnostic techniques (Carba NP test) and screening of carriers are the cornerstone to try to contain this outbreak which threatens the efficacy of the modern medicine. PMID- 24790994 TI - Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia. AB - The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL. PMID- 24790995 TI - A new nested allele-specific multiplex polymerase chain reaction method for haplotyping of VKORC1 gene to predict warfarin sensitivity. AB - The vitamin K epoxide reductase complex 1 gene (VKORC1) is commonly assessed to predict warfarin sensitivity. In this study, a new nested allele-specific multiplex polymerase chain reaction (PCR) method that can simultaneously identify single nucleotide polymorphisms (SNPs) at VKORC1 381, 861, 5808, and 9041 for haplotype analysis was developed and validated. Extracted DNA was amplified in the first PCR DNA, which was optimized by investigating the effects of varying the primer concentrations, annealing temperature, magnesium chloride concentration, enzyme concentration, and the amount of DNA template. The amplification products produced from the first round of PCR were used as templates for a second PCR amplification in which both mutant and wild-type primers were added in separate PCR tubes, followed by optimization in a similar manner. The final PCR products were resolved by agarose gel electrophoresis and further analysed by using a VKORC1 genealogic tree to infer patient haplotypes. Fifty patients were identified to have H1H1, one had H1H2, one had H1H7, 31 had either H1H7 or H1H9, one had H1H9, eight had H7H7, and one had H8H9 haplotypes. This is the first method that is able to infer VKORC1 haplotypes using only conventional PCR methods. PMID- 24790996 TI - Comparison of long noncoding RNA and mRNA expression profiles in mesenchymal stem cells derived from human periodontal ligament and bone marrow. AB - Mesenchymal stem cells (MSCs) in different anatomic locations possess diverse biological activities. Maintaining the pluripotent state and differentiation depend on the expression and regulation of thousands of genes, but it remains unclear which molecular mechanisms underlie MSC diversity. Thus, potential MSC applications are restricted. Long noncoding RNAs (lncRNAs) are implicated in the complex molecular circuitry of cellular processes. We investigated differences in lncRNA and mRNA expression profiles between bone marrow stem cells (BMSCs) and periodontal ligament stem cells (PDLSCs) with lncRNA microarray assays and bioinformatics analysis. In PDLSCs, numerous lncRNAs were significantly upregulated (n = 457) or downregulated (n = 513) compared to BMSCs. Furthermore, 1,578 mRNAs were differentially expressed. These genes implicated cellular pathways that may be associated with MSC characteristics, including apoptosis, MAPK, cell cycle, and Wnt signaling pathway. Signal-net analysis indicated that phospholipase C beta 4, filamin B beta, calcium/calmodulin-dependent protein kinase II gamma, and the ionotropic glutamate receptor, AMPA 1, had the highest betweenness centrality among significant genes in the differential gene profile network. A comparison between the coding-noncoding gene coexpression networks of PDLSCs and BMSCs identified chemokine (C-X-C motif) ligand 12 as a core regulatory factor in MSC biology. These results provided insight into the mechanisms underlying MSC biology. PMID- 24790997 TI - Using surgical microscope for sclera buckling and transscleral cryopexy: an alternative procedure of treatment for rhegmatogenous retinal detachment. AB - Purpose. To observe the long-term effectiveness of scleral buckling and transscleral cryopexy conducted under a surgical microscope in the treatment of uncomplicated rhegmatogenous retinal detachment. Methods. This was a retrospective analysis in a total of 227 consecutive patients (244 eyes) with uncomplicated rhegmatogenous retinal detachment (proliferative vitreoretinopathy <= C2). All patients underwent scleral buckling and transscleral cryopexy under a surgical microscope without using a binocular indirect ophthalmoscope or a contact lens. Results. After initial surgery, complete retinal reattachment was achieved in 226 eyes (92.6%), and retinal redetachment developed in 18 eyes (7.4%). The causes of retinal redetachment included presence of new breaks in eight eyes (44%), failure to completely seal the breaks in five eyes (28%), missed retinal breaks in four eyes (22%), and iatrogenic retinal breaks in one eye (6%). Scleral buckling surgery was performed again in 12 eyes (66%). Four eyes (22%) developed proliferative vitreoretinopathy and then were treated by vitrectomy. The sealing of retinal breaks and complete retinal reattachment were achieved in 241 eyes (98.8%). Conclusion. Probably because of clear visualization of retinal breaks and being controllable under a surgical microscope, the microsurgery of scleral buckling and transscleral cryopexy for uncomplicated retinal detachment exhibits advisable effectiveness. PMID- 24790998 TI - The association between the LPA gene polymorphism and coronary artery disease in Chinese Han population. AB - Lp(a) has been well known as an independent risk factor for coronary artery disease (CAD). The LPA gene, as it encodes apo(a) of the Lp(a) lipoprotein particle, was associated with increased risk of CAD. The purpose of this study was to analyze the relationship between the polymorphisms of LPA gene and CAD in Chinese Han population. Five SNPs (rs1367211, rs3127596, rs6415085, rs9347438, and rs9364559) in the LPA gene were genotyped using Sequenom MassARRAY time-of flight mass spectrometer (TOF) in 560 CAD patients as case group and 531 non-CAD subjects as control group. The numbers of these two groups were from Chinese Han ancestry. The results showed that allele (P = 0.046) and genotype (P = 0.026) of rs9364559 in the LPA gene was associated with CAD. The frequency of rs9364559 minor allele (G) in case group was obviously higher than that in control group. Results of haplotype analysis showed that 4 haplotypes which contained rs9364559 G were associated with increased risk of CAD in this population. This study explored rs9364559 in the LPA gene may be associated with the pathogenesis of CAD; and the risk of CAD might be higher in the population carrying 4 haplotypes of different blocks in the LPA gene. PMID- 24790999 TI - Assessment of a human cadaver model for training emergency medicine residents in the ultrasound diagnosis of pneumothorax. AB - OBJECTIVES: To assess a human cadaver model for training emergency medicine residents in the ultrasound diagnosis of pneumothorax. METHODS: Single-blinded observational study using a human cadaveric model at an academic medical center. Three lightly embalmed cadavers were used to create three "normal lungs" and three lungs modeling a "pneumothorax." The residents were blinded to the side and number of pneumothoraces, as well as to each other's findings. Each resident performed an ultrasound examination on all six lung models during ventilation of cadavers. They were evaluated on their ability to identify the presence or absence of the sliding-lung sign and seashore sign. RESULTS: A total of 84 ultrasound examinations (42-"normal lung," 42-"pneumothorax") were performed. A sliding-lung sign was accurately identified in 39 scans, and the seashore sign was accurately identified in 34 scans. The sensitivity and specificity for the sliding-lung sign were 93% (95% CI, 85-100%) and 90% (95% CI, 81-99%), respectively. The sensitivity and specificity for the seashore sign were 80% (95% CI, 68-92%) and 83% (95% CI, 72-94%), respectively. CONCLUSIONS: Lightly embalmed human cadavers may provide an excellent model for mimicking the sonographic appearance of pneumothorax. PMID- 24791000 TI - Global analysis of miRNA gene clusters and gene families reveals dynamic and coordinated expression. AB - To further understand the potential expression relationships of miRNAs in miRNA gene clusters and gene families, a global analysis was performed in 4 paired tumor (breast cancer) and adjacent normal tissue samples using deep sequencing datasets. The compositions of miRNA gene clusters and families are not random, and clustered and homologous miRNAs may have close relationships with overlapped miRNA species. Members in the miRNA group always had various expression levels, and even some showed larger expression divergence. Despite the dynamic expression as well as individual difference, these miRNAs always indicated consistent or similar deregulation patterns. The consistent deregulation expression may contribute to dynamic and coordinated interaction between different miRNAs in regulatory network. Further, we found that those clustered or homologous miRNAs that were also identified as sense and antisense miRNAs showed larger expression divergence. miRNA gene clusters and families indicated important biological roles, and the specific distribution and expression further enrich and ensure the flexible and robust regulatory network. PMID- 24791001 TI - Genotype by energy expenditure interaction and body composition traits: The Portuguese Healthy Family Study. AB - BACKGROUND AND AIMS: Energy expenditure has been negatively correlated with fat accumulation. However, this association is highly variable. In the present study we applied a genotype by environment interaction method to examine the presence of Genotype x by Total Daily Energy Expenditure and Genotype x by Daily Energy Expenditure interactions in the expression of different body composition traits. METHODS AND RESULTS: A total of 958 subjects from 294 families of The Portuguese Healthy Family Study were included in the analysis. TDEE and DEE were assessed using a physical activity recall. Body fat percentages were measured with a bioelectrical impedance scale. GxTDEE and GxDEE examinations were performed using SOLAR 4.0 software. All BC traits were significantly heritable, with heritabilities ranging from 21% to 34%. The GxTDEE and GxDEE interaction models fitted the data better than the polygenic model for all traits. For all traits, a significant GxTDEE and GxDEE interaction was due to variance heterogeneity among distinct levels of TDEE and DEE. For WC, GxTDEE was also significant due to the genetic correlation function. CONCLUSIONS: TDEE and DEE are environmental constraints associated with the expression of individuals' BC genotypes, leading to variability in the phenotypic expression of BC traits. PMID- 24791002 TI - Therapeutic effects of PADRE-BAFF autovaccine on rat adjuvant arthritis. AB - B cell activating factor (BAFF) is a cytokine of tumor necrosis factor family mainly produced by monocytes and dendritic cells. BAFF can regulate the proliferation, differentiation, and survival of B lymphocytes by binding with BAFF-R on B cell membrane. Accumulating evidences showed that BAFF played crucial roles and was overexpressed in various autoimmune diseases such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). This suggests that BAFF may be a therapeutic target for these diseases. In the present study, we developed a BAFF therapeutic vaccine by coupling a T helper cell epitope AKFVAAWTLKAA (PADRE) to the N terminus of BAFF extracellular domains (PADRE-BAFF) and expressed this fusion protein in Escherichia coli. The purified vaccine can induce high titer of neutralizing BAFF antibodies and ameliorate the syndrome of complete Freund's adjuvant (CFA) induced rheumatoid arthritis in rats. Our data indicated that the BAFF autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with high level of BAFF. PMID- 24791003 TI - Synthesis and gene silencing properties of siRNAs containing terminal amide linkages. AB - The active components of the RNAi are 21 nucleotides long dsRNAs containing a 2 nucleotide overhang at the 3' end, carrying 5'-phosphate and 3'-hydroxyl groups (siRNAs). Structural analysis revealed that the siRNA is functionally bound at both ends to RISC. Terminal modifications are considered with interest as the introduction of chemical moieties interferes with the 3' overhang recognition by the PAZ domain and the 5'-phosphate recognition by the MID and PIWI domains of RISC. Herein, we report the synthesis of modified siRNAs containing terminal amide linkages by introducing hydroxyethylglycine PNA (hegPNA) moieties at 5', and at 3' positions and on both terminals. Results of gene silencing studies highlight that some of these modifications are compatible with the RNAi machinery and markedly increase the resistance to serum-derived nucleases even after 24 h of incubation. Molecular docking simulations were attained to give at atomistic level a clearer picture of the effect of the most performing modifications on the interactions with the human Argonaute 2 PAZ, MID, and PIWI domains. This study adds another piece to the puzzle of the heterogeneous chemical modifications that can be attained to enhance the silencing efficiency of siRNAs. PMID- 24791004 TI - Combined cytolytic effects of a vaccinia virus encoding a single chain trimer of MHC-I with a Tax-epitope and Tax-specific CTLs on HTLV-I-infected cells in a rat model. AB - Adult T cell leukemia (ATL) is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I). To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV), LC16m8Delta (m8Delta), and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Delta was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Delta and obtained m8Delta/RT1AlSCTax180L, which can express a single chain trimer (SCT) of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Delta/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Delta presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Delta/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL. PMID- 24791005 TI - Bioenergetics of mammalian sperm capacitation. AB - After ejaculation, the mammalian male gamete must undergo the capacitation process, which is a prerequisite for egg fertilization. The bioenergetics of sperm capacitation is poorly understood despite its fundamental role in sustaining the biochemical and molecular events occurring during gamete activation. Glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) are the two major metabolic pathways producing ATP which is the primary source of energy for spermatozoa. Since recent data suggest that spermatozoa have the ability to use different metabolic substrates, the main aim of this work is to present a broad overview of the current knowledge on the energy-producing metabolic pathways operating inside sperm mitochondria during capacitation in different mammalian species. Metabolism of glucose and of other energetic substrates, such as pyruvate, lactate, and citrate, is critically analyzed. Such knowledge, besides its obvious importance for basic science, could eventually translate into the development of novel strategies for treatment of male infertility, artificial reproduction, and sperm selection methods. PMID- 24791006 TI - Anti-proliferative effect and phytochemical analysis of Cymbopogon citratus extract. AB - The antiproliferative and antioxidant potential of Cymbopogon citratus (Lemon grass) extracts were investigated. The extracts were isolated by solvent maceration method and thereafter subjected to antiproliferative activity test on five different cancer cells: human colon carcinoma (HCT-116), breast carcinoma (MCF-7 and MDA-MB 231), ovarian carcinoma (SKOV-3 and COAV), and a normal liver cell line (WRL 68). The cell viability was determined using MTT assay. The DPPH radical scavenging assay revealed a concentration dependent trend. A maximum percentage inhibition of 45% and an IC50 of 278 MUg/mL were observed when aqueous extract was evaluated. In contrast, 48.3% and IC50 of 258.9 MUg/mL were observed when 50% ethanolic extract was evaluated. Both extracts at concentration of 50 to 800 MUg/mL showed appreciative metal chelating activity with IC50 value of 172.2 +/- 31 MUg/mL to 456.5 +/- 30 MUg/mL. Depending on extraction solvent content, extract obtained from 50% ethanolic solvent proved to be more potent on breast cancer MCF-7 cell line (IC50 = 68 MUg/mL). On the other hand, 90% ethanolic extract showed a moderate potency on the ovarian cancer (COAV) and MCF 7 cells having an IC50 of 104.6 MUg/mL each. These results suggested antiproliferative efficacy of C. citratus ethanolic extract against human cancer cell lines. PMID- 24791007 TI - Developmental stage-specific regulation of the circadian clock by temperature in zebrafish. AB - The circadian clock enables animals to adapt their physiology and behaviour in anticipation of the day-night cycle. Light and temperature represent two key environmental timing cues (zeitgebers) able to reset this mechanism and so maintain its synchronization with the environmental cycle. One key challenge is to unravel how the regulation of the clock by zeitgebers matures during early development. The zebrafish is an ideal model for studying circadian clock ontogeny since the process of development occurs ex utero in an optically transparent chorion and many tools are available for genetic analysis. However, the role played by temperature in regulating the clock during zebrafish development is poorly understood. Here, we have established a clock-regulated luciferase reporter transgenic zebrafish line (Tg (-3.1) per1b::luc) to study the effects of temperature on clock entrainment. We reveal that under complete darkness, from an early developmental stage onwards (48 to 72 hpf), exposure to temperature cycles is a prerequisite for the establishment of self-sustaining rhythms of zfper1b, zfaanat2, and zfirbp expression and also for circadian cell cycle rhythms. Furthermore, we show that following the 5-9 somite stage, the expression of zfper1b is regulated by acute temperature shifts. PMID- 24791008 TI - Impairment in preattentive processing among patients with hypertension revealed by visual mismatch negativity. AB - OBJECTIVE: Patients with hypertension show deficits in cognitive function. However, the neural mechanisms underlying the preattentive information processing in hypertensive patients are poorly understood. We seek to investigate whether hypertensive patients have impairments in preattentive information processing. METHODS: We compared visual mismatch negativity (vMMN) between 15 hypertensive patients and 15 age-matched healthy controls, which was elicited by the change of visual duration randomly presented in both peripheral visual fields. In addition, the global cognitive function for all participants was assessed with Mini-Mental State Examination (MMSE). RESULTS: The vMMN in deviant-standard comparison was observed at occipital-temporal regions. Compared with normal healthy controls, the amplitude of vMMN was significantly decreased in hypertensive patients (P < 0.05). Meanwhile, the vMMN peak latency was delayed in the hypertensive group (P < 0.05). However, the MMSE scores of patients with hypertension were not significantly different from those of controls (P > 0.05), and there was no significant correlation between the mean amplitude of vMMN and SBP, DBP, and MMSE in hypertensive individuals, respectively. CONCLUSIONS: These data indicate dysfunction of automatically change detection processing in patients with hypertension. Moreover, the changes of vMMN provide a more objective and reliable assessment for cognitive impairment in hypertensive patients. PMID- 24791009 TI - Multidrug resistance 1 gene variants, pesticide exposure, and increased risk of DNA damage. AB - The P-glycoprotein, encoded by the multidrug resistance (MDR)1 gene, extrudes fat soluble compounds to the extracellular environment. However, the DNA damage of pesticides in subjects with genetic variation in MDR1 has not been investigated. In this study, the comet assay was applied to examine the extent of DNA damage in the peripheral blood of 195 fruit growers who had been exposed to pesticides and 141 unexposed controls. The MDR1 polymorphisms were identified. Questionnaires were administered to obtain demographic data and occupational history. Results showed subjects experiencing high (2.14 MUm/cell, P < 0.01) or low pesticide exposure (2.18 MUm/cell, P < 0.01) had a significantly greater DNA tail moment than controls (1.28 MUm/cell). Compared to the MDR1 T-129C (rs3213619) TC/CC carriers, the TT carriers had increased DNA tail moment in controls (1.30 versus 1.12 MUm/cell, P < 0.01). Similar results were observed in the high and low pesticide-exposed groups. Combined analysis revealed that pesticide-exposed fruit growers with MDR1 -129 TT genotype had the greatest DNA damage in the subjects with the combinations of pesticide exposure and MDR1 -129 genotypes. In conclusion, pesticide exposed individuals with susceptible MDR1 -129 genotypes may experience increased risk of DNA damage. PMID- 24791010 TI - CD20+ B cell depletion in systemic autoimmune diseases: common mechanism of inhibition or disease-specific effect on humoral immunity? AB - Autoimmunity remains a complex physiologic deviation, enabled and perpetuated by a variety of interplayers and pathways. Simplistic approaches, targeting either isolated end-effectors of more centrally placed interactors of these mechanisms, are continuously tried in an effort to comprehend and halt cascades with potential disabling and deleterious effects in the affected individuals. This review focuses on theoretical and clinically proved effects of rituximab-induced CD20+ B cell depletion on different systemic autoimmune diseases and extrapolates on pathogenetic mechanisms that may account for different interindividual or interdisease responses. PMID- 24791011 TI - Evaluation of biochemical, haematological, and histopathological responses and recovery ability of common carp (Cyprinus carpio L.) after acute exposure to atrazine herbicide. AB - The aim of study was to evaluate the effect of atrazine exposure (5, 15, 20, and 30 mg.L(-1)) on common carp and the ability of regeneration. During 96 h exposure we observed abnormal behavior in fish exposed to 20 and 30 mg.L(-1). Mortality and histological alterations were noticed only in the group exposed to 30 mg.L( 1). Most experimental groups showed significantly (P < 0.05) lower values of haemoglobin, haematocrit, leukocyte, and lymphocyte and significantly higher values of monocytes, segmented and band neutrophile granulocytes, and also metamyelocytes and myelocytes. A significantly lower (P < 0.05) leukocyte count was also recorded in experimental groups (5 and 15 mg.L(-1)) after recovery period. Statistically significant (P < 0.05) alterations in glucose, total protein, lactate, phosphorus, calcium, and biopterin as well as in activities of ALT, AST, ALP, and LDH were found in most experimental groups. These changes were most apparent in the groups exposed to 20 and 30 mg.L(-1). Most of the indices were found to be restored after the 7-day recovery period with the exception of LDH, ALT, and lactate in the group exposed to 15 mg.L(-1). Our results showed that atrazine exposure had a profound negative influence on selected indices and also on histological changes of common carp. PMID- 24791012 TI - Does the diabetic foot have a significant impact on selected psychological or social characteristics of patients with diabetes mellitus? AB - The aim of our case-control study was to compare selected psychological and social characteristics between diabetic patients with and without the DF (controls). METHODS: 104 patients with and 48 without DF were included into our study. Both study groups were compared in terms of selected psychosocial characteristics. RESULTS: Compared to controls, patients with DF had a significantly worse quality of life in the area of health and standard of living as shown by lower physical health domain (12.7 +/- 2.8 versus 14.7 +/- 2.5; P < 0.001) and environment domain (14.1 +/- 2.2 versus 15 +/- 1.8; P < 0.01) that negatively correlated with diabetes duration (r = -0.061; P = 0.003). Patients with DF subjectively felt more depressed in contrast to controls (24.5 versus 7.3%; P < 0.05); however, the depressive tuning was objectively proven in higher percentage in both study groups (83.2 versus 89.6; NS). We observed a significantly lower level of achieved education (P < 0.01), more patients with disability pensions (P < 0.01), and low self-support (P < 0.001) in patients with the DF compared to controls. In the subgroup of patients with a previous major amputation and DF (n = 6), there were significantly worse outcomes as in the environment domain (P < 0.01), employment status, and stress readaptation (P < 0.01) in contrast to the main study groups. CONCLUSIONS: Patients with DF had a predominantly worse standard of living. In contrast to our expectations, patients with DF appeared to have good stress tolerability and mental health (with the exception of patients with previous major amputation) and did not reveal severe forms of depression or any associated consequences. PMID- 24791014 TI - The Phase I Proton CT Scanner and Test Beam Results at LLUMC, invited. PMID- 24791013 TI - Multiple Functional Motifs Are Required for the Tumor Suppressor Activity of a Constitutively-Active ErbB4 Mutant. AB - ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases, which includes the Epidermal Growth Factor Receptor (EGFR/ErbB1), ErbB2 (HER2/Neu), and ErbB3 (HER3). Mounting evidence indicates that ErbB4, unlike EGFR or ErbB2, functions as a tumor suppressor in many human malignancies. Previous analyses of the constitutively-dimerized and -active ErbB4 Q646C mutant indicate that ErbB4 kinase activity and phosphorylation of ErbB4 Tyr1056 are both required for the tumor suppressor activity of this mutant in human breast, prostate, and pancreatic cancer cell lines. However, the cytoplasmic region of ErbB4 possesses additional putative functional motifs, and the contributions of these functional motifs to ErbB4 tumor suppressor activity have been largely underexplored. Here we demonstrate that ErbB4 BH3 and LXXLL motifs, which are thought to mediate interactions with Bcl family proteins and steroid hormone receptors, respectively, are required for the tumor suppressor activity of the ErbB4 Q646C mutant. Furthermore, abrogation of the site of ErbB4 cleavage by gamma-secretase also disrupts the tumor suppressor activity of the ErbB4 Q646C mutant. This last result suggests that ErbB4 cleavage and subcellular trafficking of the ErbB4 cytoplasmic domain may be required for the tumor suppressor activity of the ErbB4 Q646C mutant. Indeed, here we demonstrate that mutants that disrupt ErbB4 kinase activity, ErbB4 phosphorylation at Tyr1056, or ErbB4 cleavage by gamma-secretase also disrupt ErbB4 trafficking away from the plasma membrane and to the cytoplasm. This supports a model for ErbB4 function in which ErbB4 tumor suppressor activity is dependent on ErbB4 trafficking away from the plasma membrane and to the cytoplasm, mitochondria, and/or the nucleus. PMID- 24791015 TI - Rank effects on social stress in lactating chimpanzees. AB - Given the deleterious consequences associated with chronic stress, individual differences in stress susceptibility can have important fitness implications. These differences may be explained in part by dominance status because high rank is typically associated with decreased aggression and improved nutrition. Here, we examined the relationship between dominance and social stress in lactating chimpanzees, Pan troglodytes schweinfurthii, at Gombe National Park, Tanzania. We did so by pairing daily demographic and behavioural data with faecal glucocorticoid metabolite (FGM) concentrations collected over 37 months. While there was no main effect of rank, interesting differences emerged by adult subgroup size and adult sex ratio (males/females). We found that differences in FGM concentrations between high- and low-ranking females were most pronounced as adult subgroup size and sex ratio increased. Low-ranking females had higher FGM concentrations in larger subgroups and in subgroups biased towards adult males; we observed no comparable change in FGM concentrations amongst high-ranking females. Because low-ranking females were the recipient of significantly more male aggression relative to females of high rank, these patterns may be driven by psychosocial stress in low-ranking females. There was no significant change in diet quality across subgroup sizes; this finding suggests that nutritional stressors were not driving differences in female FGM concentrations. Being susceptible to social stress has important fitness implications as it may constrain low-ranking females from 'choosing' optimal subgroups to take advantage of food resources and/or for the socialization of their offspring. PMID- 24791016 TI - A numerical study of blood flow using mixture theory. AB - In this paper, we consider the two dimensional flow of blood in a rectangular microfluidic channel. We use Mixture Theory to treat this problem as a two component system: One component is the red blood cells (RBCs) modeled as a generalized Reiner-Rivlin type fluid, which considers the effects of volume fraction (hematocrit) and influence of shear rate upon viscosity. The other component, plasma, is assumed to behave as a linear viscous fluid. A CFD solver based on OpenFOAM(r) was developed and employed to simulate a specific problem, namely blood flow in a two dimensional micro-channel, is studied. Finally to better understand this two-component flow system and the effects of the different parameters, the equations are made dimensionless and a parametric study is performed. PMID- 24791017 TI - Variability in glutenin subunit composition of Mediterranean durum wheat germplasm and its relationship with gluten strength. AB - The allelic composition at five glutenin loci was assessed by one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis (1D SDS-PAGE) on a set of 155 landraces (from 21 Mediterranean countries) and 18 representative modern varieties. Gluten strength was determined by SDS-sedimentation on samples grown under rainfed conditions during 3 years in north-eastern Spain. One hundred and fourteen alleles/banding patterns were identified (25 at Glu-1 and 89 at Glu 2/Glu-3 loci); 0.85 of them were in landraces at very low frequency and 0.72 were unreported. Genetic diversity index was 0.71 for landraces and 0.38 for modern varieties. All modern varieties exhibited medium to strong gluten type with none of their 13 banding patterns having a significant effect on gluten-strength type. Ten banding patterns significantly affected gluten strength in landraces. Alleles Glu-B1e (band 20), Glu-A3a (band 6), Glu-A3d (bands 6 + 11), Glu-B3a (bands 2 + 4+15 + 19) and Glu-B2a (band 12) significantly increased the SDS-value, and their effects were associated with their frequency. Two alleles, Glu-A3b (band 5) and Glu-B2b (null), significantly reduced gluten strength, but only the effect of the latter locus could be associated with its frequency. Only three rare banding patterns affected gluten strength significantly: Glu-B1a (band 7), found in six landraces, had a negative effect, whereas banding patterns 2 + 4+14 + 15 + 18 and 2 + 4+15 + 18 + 19 at Glu-B3 had a positive effect. Landraces with outstanding gluten strength were more frequent in eastern than in western Mediterranean countries. The geographical pattern displayed from the frequencies of Glu-A1c is discussed. PMID- 24791018 TI - Back to Work: Expectations and Realizations of Work after Retirement. AB - This paper analyzes a puzzling aspect of retirement behavior known as "unretirement." Nearly 50 percent of retirees follow a nontraditional retirement path that involves partial retirement or unretirement, and at least 26 percent of retirees later unretire. I explore two possible explanations: 1) unretirement transitions result from failures in planning or financial shocks; and 2) unretirement transitions are anticipated prior to retirement, reflecting a more complex retirement process. I show that unretirement was anticipated for the vast majority of those returning to work, and is not a result of financial shocks, poor planning or low wealth accumulation. PMID- 24791019 TI - The Decoupling of Marriage and Parenthood? Trends in the Timing of Marital First Births, 1945-2002. AB - Family formation changed dramatically over the twentieth century in the United States. The impact of these changes on childbearing has primarily been studied in terms of nonmarital fertility. However, changes in family formation behavior also have implications for fertility within marriage. We use data from ten fertility surveys to describe changes in the timing of marital childbearing from the 1940s through the 21st century for non-Hispanic white and non-Hispanic black women. Based on harmonized data from the Integrated Fertility Survey Series, our results suggest increasing divergence in fertility timing for white women. A growing proportion of marriages begin with a premarital conception; at the same time, an increasing proportion of white women are postponing fertility within marriage. For black women, marital fertility is increasingly postponed beyond the early years of marriage. Evaluating the sequencing of marriage and parenthood over time is critical to understanding the changing meaning of marriage. PMID- 24791020 TI - Administration time between seasonal live-attenuated influenza vaccine and trivalent influenza vaccine during the "Stop Flu at School" Campaign--Hawaii, 2009. AB - OBJECTIVES: We determined whether the administration time differed between seasonal intranasal live-attenuated influenza vaccine (LAIV) and seasonal injectable trivalent inactivated influenza vaccine (TIV) during Hawaii's 2009 school-located influenza vaccination clinics. This information is useful for public health response and allows further investigation into possible differences between the two vaccines. METHODS: We conducted a prospective cohort study in 15 public schools to determine mean times to administer LAIV and TIV to students. We performed group analyses to control for various clinic characteristics and conducted a stratified, weighted analysis. RESULTS: A total of 4,701 students were enrolled in the study, and administration time was obtained for 3,869 (82%) students (1,492 [39%] LAIV and 2,377 [61%] TIV). The mean administration time for LAIV was 62 seconds and for TIV was 90 seconds, a difference of 28 seconds (p<0.01). This finding remained significant in the stratified analysis. CONCLUSIONS: Although results indicated that both LAIV and TIV can be administered rapidly among school-aged populations, LAIV was faster to administer. This finding, in addition to the greater immunogenicity of LAIV compared with TIV among children, may be an important consideration for public health administrators in planning school-located mass vaccination clinics and encouraging patient acceptance of this vaccine. PMID- 24791021 TI - Accuracy of parental reports of children's HPV vaccine status: implications for estimates of disparities, 2009-2010. AB - OBJECTIVES: Since the introduction of the human papillomavirus (HPV) vaccine in 2006, there have been considerable efforts at the national and state levels to monitor uptake and better understand the individual and system-level factors that predict who gets vaccinated. A common method of measuring the vaccination status of adolescents is through parental recall. We examined how the accuracy of parents' reports of their daughters' HPV vaccination status varied by social characteristics. METHODS: Data were taken from the 2009-2010 National Immunization Survey (NIS)-Teen, which includes a household interview and a provider-completed immunization history. We evaluated concordance between parents' and providers' reports of teens' HPV vaccine initiation (>=1 dose) and completion (>=3 doses). We assessed bivariate associations of sociodemographic characteristics with having a concordant, false-positive (overreporting) or false negative (underreporting) report, and used multinomial logistic regression to estimate the independent impact of each characteristic. RESULTS: In bivariate analyses, concordance of parent-reported HPV vaccine initiation was associated with each of the sociodemographic characteristics investigated. In regression models, self-reported nonwhite race, lower household income, and lower education level of the teen's mother were associated with a higher likelihood of having a false-negative parental report than a concordant report. CONCLUSION: Our results indicate that, while estimates of overall coverage based on parental report may be unbiased, the differences in the accuracy of parental report could result in misleading estimates of disparities in HPV vaccine coverage. PMID- 24791022 TI - Protecting newborns by immunizing family members in a hospital-based vaccine clinic: a successful Tdap cocooning program during the 2010 California pertussis epidemic. AB - OBJECTIVE: Infants are at greatest risk for mortality from pertussis infection. Since 2005, the Advisory Committee on Immunization Practices has recommended a cocooning strategy of vaccinating all close contacts of infants with tetanus, diptheria, and acellular pertussis (Tdap) vaccine to reduce the risk of transmitting pertussis. Difficulties in establishing a complete cocoon have been reported in the literature. We determined whether families of newborns could be fully immunized against pertussis, thereby providing a complete cocoon of protection. METHODS: Tdap vaccine was offered during visiting hours to contacts aged 7 years and older and to postpartum patients who had not received Tdap vaccine during pregnancy. We then conducted retrospective phone interviews with randomly selected mothers (or other family members) to assess vaccination rates. We compared household vaccination rates during intervention and control periods and the demographic factors associated with Tdap vaccination of all members within the households. RESULTS: During the intervention period, 243 postpartum patients and 1,287 other family members of newborns were immunized, with 84.8% of all family members receiving Tdap vaccination. Seventy-six percent of households reported a complete cocoon. In the control group, 52.2% of all family members received Tdap vaccination, and 29.3% of households had a complete cocoon. In the control group, fewer family members completed Tdap vaccination in the larger households than in the smaller households (p=0.008). CONCLUSION: A cocooning strategy can be successfully implemented, such that the majority of newborns leave the hospital with their families fully immunized against pertussis. PMID- 24791023 TI - Disparities in current cigarette smoking prevalence by type of disability, 2009 2011. AB - OBJECTIVES: Smoking, the leading cause of disease and death in the United States, has been linked to a number of health conditions including cancer and cardiovascular disease. While people with a disability have been shown to be more likely to report smoking, little is known about the prevalence of smoking by type of disability, particularly for adults younger than 50 years of age. METHODS: We used data from the 2009-2011 National Health Interview Survey to estimate the prevalence of smoking by type of disability and to examine the association of functional disability type and smoking among adults aged 18-49 years. RESULTS: Adults with a disability were more likely than adults without a disability to be current smokers (38.8% vs. 20.7%, p<0.001). Among adults with disabilities, the prevalence of smoking ranged from 32.4% (self-care difficulty) to 43.8% (cognitive limitation). When controlling for sociodemographic characteristics, having a disability was associated with statistically significantly higher odds of current smoking (adjusted odds ratio = 1.57, 95% confidence interval 1.40, 1.77). CONCLUSIONS: The prevalence of current smoking for adults was higher for every functional disability type than for adults without a disability. By understanding the association between smoking and disability type among adults younger than 50 years of age, resources for cessation services can be better targeted during the ages when increased time for health improvement can occur. PMID- 24791024 TI - Completeness and timeliness of electronic vs. conventional laboratory reporting for communicable disease surveillance--Oklahoma, 2011. AB - OBJECTIVES: The Health Information Technology for Economic and Clinical Health (HITECH) Act encourages the meaningful use of certified electronic health record technology. A HITECH-compliant core component is nationwide electronic laboratory reporting (ELR) implementation for communicable disease surveillance. In Oklahoma, laboratories with >=400 positive tests/year for reportable diseases must use ELR. Of 18 such laboratories, two have adopted ELR. We compared completeness and timeliness of ELR reports from these two laboratories with conventional reports from all other Oklahoma laboratories. METHODS: We retrospectively reviewed confirmed reportable disease cases for January 1 December 31, 2011, excluding tuberculosis, hepatitis, sexually transmitted infections, diseases without laboratory diagnoses, and immediately reportable diseases. Probable reportable tickborne disease cases were included. We compared ELR with conventional reporting (i.e., mail, fax, telephone, and Internet). We assessed data completeness based on eight demographic and two laboratory fields in each disease report and timeliness by percentage of cases reported in <=1 business day. RESULTS: Overall, 1,867 reports met the inclusion criteria; 24% of these reports had been submitted by ELR. Data completeness was 90% for ELR and 95% for conventional reporting. Patient addresses accounted for 97% of the missing data fields for ELR reports. Timeliness was 91% for ELR and 87% for conventional reports. CONCLUSIONS: Although early in the transition to ELR compliance in Oklahoma, ELR has already yielded improved timeliness for communicable disease surveillance. However, ELR did not yield more complete reports than conventional reporting. Requiring specific demographic data fields for ELR reports can improve the completeness of ELR. PMID- 24791025 TI - Persistent racial/ethnic disparities in AIDS diagnosis rates among people who inject drugs in U.S. metropolitan areas, 1993-2007. AB - OBJECTIVES: We estimated race/ethnicity-specific incident AIDS diagnosis rates (IARs) among people who inject drugs (PWID) in U.S. metropolitan statistical areas (MSAs) over time to assess the change in disparities after highly active antiretroviral therapy (HAART) dissemination. METHODS: We compared IARs and 95% confidence intervals (CIs) for black/African American and Hispanic/Latino PWID with those of white PWID in 93 of the most populous MSAs. We selected two three year periods from the years immediately preceding HAART (1993-1995) and the years with the most recent available data (2005-2007). To maximize stability, we aggregated data across three-year periods, and we aggregated data for black/African American and Hispanic/Latino PWID for most comparisons with data for white PWID. We assessed disparities by comparing IAR 95% CIs for overlap. RESULTS: IARs were significantly higher for black/African American and Hispanic/Latino PWID than for white PWID in 81% of MSAs in 1993-1995 and 77% of MSAs in 2005-2007. MSAs where disparities became non-significant over time were concentrated in the West. Significant differences were more frequent in comparisons between black/African American and white PWID (85% of MSAs in 1993 1995, 79% of MSAs in 2005-2007) than in comparisons between Hispanic/Latino and white PWID (53% of MSAs in 1993-1995, 56% of MSAs in 2005-2007). IARs declined modestly across racial/ethnic groups in most MSAs. CONCLUSIONS: AIDS diagnosis rates continue to be substantially higher for black/African American and Hispanic/Latino PWID than for white PWID in most large MSAs. This finding suggests a need for increased targeting of prevention and treatment programs, as well as research on MSA-level conditions that may serve to maintain the disparities. PMID- 24791026 TI - Colorectal cancer screening among American Indians in a Pacific Northwest tribe: Cowlitz Tribal BRFSS Project, 2009-2010. AB - OBJECTIVES: Colorectal cancer (CRC) screening is low among American Indians (AIs). We describe the demographics, health status, prevalence of modifiable CRC risk factors, and use of CRC screening modalities in a Pacific Northwest AI tribe. METHODS: We conducted a survey among Cowlitz tribal members using a Behavioral Risk Factor Surveillance System (BRFSS) questionnaire. We analyzed demographic, health status, behavioral risk factor, and CRC screening variables. Using the Washington State 2010 BRFSS, we compared tribal members with non Hispanic white (NHW) people. We used logistic regression to examine factors associated with CRC screening for tribal members. RESULTS: A greater proportion of tribal members than NHW people reported living below the federal poverty level (12% vs. 7%, p=0.013). A greater proportion of tribal members than NHW people aged>=50 years had poor self-reported health (27% vs. 16%, p=0.006) and were without health insurance (12% vs. 6%, p=0.004). A greater proportion of tribal members than NHW people had a fecal occult blood test within the past year (20% vs. 13%, p=0.006). Being 60-69 years of age (odds ratio [OR]=2.6, 95% confidence interval [CI] 1.4, 4.9), >=70 years of age (OR=2.2, 95% CI 1.1, 4.5), and having a personal health-care provider (OR=3.7, 95% CI 1.4, 9.6) were associated with increased screening adherence in tribal members. CONCLUSION: Data from the Cowlitz Tribal BRFSS demonstrate that members are receiving CRC screening in the same proportions as NHW people despite lower sociodemographic and health status indicators among members. Unique characteristics of the tribe likely contribute to this finding. PMID- 24791027 TI - Assessing the contributions of an academic health department for a school of public health in New York State. PMID- 24791028 TI - Improving processes of care for overweight and obese children: evidence from the 215-GO! program in Philadelphia health centers. PMID- 24791030 TI - Mild oxidation of tosylmethylisocyanide to tosylmethylisocyanate: utility in synthetic and medicinal chemistry. AB - A convenient and efficient (one-step) oxidation is reported of commercially available tosylmethylisocyanide (TOSMIC) to form tosylmethylisocyanate, making this highly reactive bifunctional molecule a readily available synthetic reagent. Besides engaging in nucleophilic addition reactions with alcohols, amines and thiols, tosylmethylisocyanate also reacts with carboxylic acids to form tosylmethylamides, which undergo substitution reactions in the presence of organocopper and organomagnesium reagents. PMID- 24791029 TI - Synthesis and Biological Evaluation of 5'-O-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors. AB - A number of 5'-O-dicarboxylic fatty acyl monoester derivatives of 3'-azido-3' deoxythymidine (zidovudine, AZT), 2',3'-didehydro-2',3'-dideoxythymidine (stavudine, d4T), and 3'-fluoro-3'-deoxythymidine (alovudine, FLT) were synthesized to improve the lipophilicity and potentially the cellular delivery of parent polar 2', 3'-dideoxynucleoside (ddN) analogues. The compounds were evaluated for their anti-HIV activity. Three different fatty acids with varying chain length of suberic acid (octanedioic acid), sebacic acid (decanedioic acid), and dodecanedioic acid were used for the conjugation with the nucleosides. The compounds were evaluated for anti-HIV activity and cytotoxicity. All dicarboxylic ester conjugates of nucleosides exhibited significantly higher anti-HIV activity than that of the corresponding parent nucleoside analogs. Among all the tested conjugates, 5'-O-suberate derivative of AZT (EC50 = 0.10 nM) was found to be the most potent compound and showed 80-fold higher anti-HIV activity than AZT without any significant toxicity (TC50 > 500 nM). PMID- 24791031 TI - Genetic and Environmental Influences of General Cognitive Ability: Is g a valid latent construct? AB - Despite an extensive literature, the "g" construct remains a point of debate. Different models explaining the observed relationships among cognitive tests make distinct assumptions about the role of g in relation to those tests and specific cognitive domains. Surprisingly, these different models and their corresponding assumptions are rarely tested against one another. In addition to the comparison of distinct models, a multivariate application of the twin design offers a unique opportunity to test whether there is support for g as a latent construct with its own genetic and environmental influences, or whether the relationships among cognitive tests are instead driven by independent genetic and environmental factors. Here we tested multiple distinct models of the relationships among cognitive tests utilizing data from the Vietnam Era Twin Study of Aging (VETSA), a study of middle-aged male twins. Results indicated that a hierarchical (higher order) model with a latent g phenotype, as well as specific cognitive domains, was best supported by the data. The latent g factor was highly heritable (86%), and accounted for most, but not all, of the genetic effects in specific cognitive domains and elementary cognitive tests. By directly testing multiple competing models of the relationships among cognitive tests in a genetically-informative design, we are able to provide stronger support than in prior studies for g being a valid latent construct. PMID- 24791032 TI - Tensor Regression with Applications in Neuroimaging Data Analysis. AB - Classical regression methods treat covariates as a vector and estimate a corresponding vector of regression coefficients. Modern applications in medical imaging generate covariates of more complex form such as multidimensional arrays (tensors). Traditional statistical and computational methods are proving insufficient for analysis of these high-throughput data due to their ultrahigh dimensionality as well as complex structure. In this article, we propose a new family of tensor regression models that efficiently exploit the special structure of tensor covariates. Under this framework, ultrahigh dimensionality is reduced to a manageable level, resulting in efficient estimation and prediction. A fast and highly scalable estimation algorithm is proposed for maximum likelihood estimation and its associated asymptotic properties are studied. Effectiveness of the new methods is demonstrated on both synthetic and real MRI imaging data. PMID- 24791033 TI - Acculturative Stress and Depressive Symptomatology Among Mexican and Mexican American Students in the U.S.: Examining Associations with Cultural Incongruity and Intragroup Marginalization. AB - This study examined associations of intragroup marginalization and cultural incongruity with acculturative stress and depressive symptoms among 155 undergraduate U.S. college students of Mexican heritage. Findings indicate that perceived interpersonal distancing by the family (intragroup marginalization) and perceived lack of cultural fit between the respondent and academic institution (cultural incongruity) had statistically significant direct and indirect effects on depressive symptoms via acculturative stress. Results also show that 39.7 % of the variance corresponding with depressive symptoms was accounted for by intragroup marginalization, cultural incongruity, acculturative stress, and other exogenous variables. PMID- 24791034 TI - On penalized likelihood estimation for a non-proportional hazards regression model. AB - In this paper, a semi-parametric generalization of the Cox model that permits crossing hazard curves is described. A theoretical framework for estimation in this model is developed based on penalized likelihood methods. It is shown that the optimal solution to the baseline hazard, baseline cumulative hazard and their ratio are hyperbolic splines with knots at the distinct failure times. PMID- 24791035 TI - Recruiting Fathers to Parenting Programs: Advice from Dads and Fatherhood Program Providers. AB - The benefits of high-quality father-child relationships for fathers and children alike are well documented. While evidence suggests parenting programs can improve the quality of father-child relationships, few fathers participate in such programs. This qualitative study aims to fill the gap in knowledge on best practices for recruiting urban African American fathers, a group of fathers with unique parenting challenges, to parenting programs. Focus groups were conducted with 29 fathers to gain their perspectives on recruitment strategies. Semi structured interviews were also conducted with a nationwide sample of 19 fatherhood program providers to learn about their most successful recruitment strategies. Recruitment strategies based on emergent themes from the focus groups and interviews are presented here. Themes included using word-of-mouth recruitment, increasing advertising, targeting advertising specifically to urban African American fathers, providing transportation and incentives, recruiting through the courts, collaborating with other community agencies, and offering parenting programming along with other programming valued by fathers such as employment assistance. Implications for developing strategies for recruiting urban African American fathers to parenting programs are discussed. PMID- 24791036 TI - The allure of new immigrant destinations and the Great Recession in the United States. AB - In the 1990s, the immigrant population in the United States dispersed to non traditional settlement locations (what have become known as "new immigrant destinations"). This paper examines whether the allure of new destinations persisted in the 2000s with a particular focus on the internal migration of the foreign born during the recent deep recessionary period and its aftermath. Three specific questions motivate the analysis. First, are immigrants, much like the US born population, becoming less migratory within the country over time? Second, is immigrant dispersal from traditional gateways via internal migration continuing despite considerable economic contraction in many new destination metropolitan areas? Third, is immigration from aboard a substitute for what appears to be declining immigrant internal migration to new destinations? The findings reveal a close correlation between the declining internal migration propensity of the US born and immigrants in the last two decades. We also observe parallels between the geographies of migration of native- and foreign-born populations with both groups moving to similar metropolitan areas in the 1990s. This redistributive association, however, weakened in the subsequent decade as new destination metropolitan areas lost their appeal for both groups, especially immigrants. There is no evidence to suggest that immigration from abroad is substituting for the decline in immigrant redistribution through internal migration to new destinations. Across destination types the relationship between immigration from abroad and the internal migration of the foreign born remained the same before, during, and after the Great Recession. PMID- 24791037 TI - "How Would You Feel? What Would You Do?" Development and Underpinnings of Preschoolers' Social Information Processing. AB - Young children's social information processing (SIP) encompasses a series of steps by which they make sense of encounters with other persons; both cognitive and emotional aspects of SIP often predict adjustment in school settings. More attention is needed, however, to the development of preschoolers' SIP and its potential foundations. To this end, a new preschool SIP measure, the Challenging Situations Task (CST), was utilized; preschoolers' (n = 316) self-reported emotional and behavioral responses to hypothetical peer provocation situations on the CST were assessed longitudinally, along with aspects of their self-regulation and emotion knowledge. Age and developmental differences in CST responses were examined. Next, contributions of executive control and emotion knowledge to CST responses were analyzed. Age differences in emotion and behavior choices showed that younger preschoolers were more prone to choose happy responses, whereas older preschoolers chose more adaptive behavior responses. Both self-regulation and emotion knowledge were associated with emotion and behavior responses concurrently and across time. Implications of these findings and suggestions for further research are discussed. PMID- 24791038 TI - Analysis of Ordinal Outcomes with Longitudinal Covariates Subject to Missingness. AB - We propose a mixture model for data with an ordinal outcome and a longitudinal covariate that is subject to missingness. Data from a tailored telephone delivered, smoking cessation intervention for construction laborers are used to illustrate the method, which considers as an outcome a categorical measure of smoking cessation, and evaluates the effectiveness of the motivational telephone interviews on this outcome. We propose two model structures for the longitudinal covariate, for the case when the missing data are missing at random, and when the missing data mechanism is non-ignorable. A generalized EM algorithm is used to obtain maximum likelihood estimates. PMID- 24791039 TI - Kidney injury, fluid, electrolyte and acid-base abnormalities in alcoholics. AB - In the 21(st) century, alcoholism and the consequences of ethyl alcohol abuse are major public health concerns in the United States, affecting approximately 14 million people. Pertinent to the global impact of alcoholism is the World Health Organisation estimate that 140 million people worldwide suffer from alcohol dependence. Alcoholism and alcohol abuse are the third leading causes of preventable death in the United States. Alcohol dependence and alcohol abuse cost the United State an estimated US$220 billion in 2005, eclipsing the expense associated with cancer (US$196 billion) or obesity (US$133 billion). Orally ingested ethyl alcohol is absorbed rapidly without chemical change from the stomach and intestine, reaching maximum blood concentration in about an hour. Alcohol crosses capillary membranes by simple diffusion, affecting almost every organ system in the body by impacting a wide range of cellular functions. Alcohol causes metabolic derangements either directly, via its chemical by-product or secondarily through alcohol-induced disorders. Many of these alcohol-related metabolic disturbances are increased in severity by the malnutrition that is common in those with chronic alcoholism. This review focuses on the acute and chronic injurious consequences of alcohol ingestion on the kidney, as well as the fluid, electrolyte and acid-base abnormalities associated with acute and chronic ingestion of alcohol. PMID- 24791040 TI - Biomedical techniques in translational studies: The journey so far. AB - Biomedical techniques have wide clinical application in many fields of medicine such as oncology, rheumatology, immunology, genomics, cardiology and diagnostics; among others. This has been made possible with the use of genetic engineering and a number of techniques like Immunohistochemistry (IHC), Fluorescent Microscopy, Cell Culture, Genetically Modified (GM) Cells, Monoclonal Antibodies (MAbs), Polymerase Chain Reaction (PCR) and Western blotting. The aim of this literature review is to explore the foundations and bases of the commonly used biomedical techniques, as well as their applications in biomedical research and clinical medicine in general. This review also aims to shed some light on more recent advances in genetic engineering, especially in relation to genetically modified cells and use of monoclonal antibodies which have found more increasing use and relevance in genomics, oncology, rheumatology, immunology, cardiology as well as diagnostics, and have revolutionised patient care, while at the same time resulting in improved standard of health care. Unfortunately, some of these new techniques are associated with unwanted side effects which may pose a risk to the people they are actually intended for. Therefore, there is need for strict regulations and guidelines to control the use and implementation of some of these novel techniques. PMID- 24791041 TI - A survey on doctors' knowledge and attitude of treating chronic pain in three tertiary hospitals in Nigeria. AB - BACKGROUND: Chronic non-cancer pain (CP) is one of the most common complaints that bring patients to the hospital. When pain persists, people move from doctor to-doctor seeking for help, thus the burden of CP is huge. This study, therefore was aimed at assessing attitude and knowledge of doctors in three teaching hospitals in Nigeria to CP. MATERIALS AND METHODS: Structured questionnaire was administered to doctors practicing at the University of Ilorin Teaching Hospital, Usmanu Danfodio University Teaching Hospital and University of Maiduguri Teaching Hospital. Responses were graded on maximum scale of five. RESULTS: Of the 410 doctors who participated in study, 79.7% were men. Their years of practice varied from 1 year to 20 years (mean SD = 4.5 +/- 1.7 years). Close to 58% of participants were resident doctors, 36.4% medical officers and 8.6% consultants. Only 23.3% of participants had basic medical or postgraduate training on pain management. The physicians' mean goal of treating CP in patients was 3.7 +/- 1.1, compared to 4.0 +/- 1.1 in close relative and 4.1 +/- 0.9 for doctors'-self pain. Only 9.5% of doctors use opioids for CP compared to 73% who use Nonsteroidal anti inflammatory drugs (NSAIDs). Few doctors (23%) use >=2 drugs to treat CP. Doctors were indifferent on the appropriateness of patients with CP to request for additional analgesics (mean score = 3.1 + 1.4). Doctors' self-rated knowledge of CP was 1.8 +/- 0.7 compared to 4.1 +/- 0.9 for acute and 0.8 +/- 0.3 for cancer pains (P = 0. 003). CONCLUSION: Incorporation of pain management into continuing medical education could help improve observed deficiency in doctors' knowledge of pain treatment which resulted from lack of basic medical education on pain. PMID- 24791042 TI - Primary hip spica with crossed retrograde intramedullary rush pins for the management of diaphyseal femur fractures in children: A prospective, randomized study. AB - BACKGROUND: Femoral fractures are common in children aged between 2 and 12 yearsand 75% of the lesions affect the femoral shaft. Traction followed by a plaster cast is universally accepted as a conservative treatment. We compared primary hip spica or traction followed by hip spica with closed reduction and fixation with retrogradely passed crossed Rush pins for diaphyseal femur fracture in 25 children of the age group 3-12 years, randomly distributed in each group. MATERIALS AND METHODS: FIFTY CHILDREN (AGE: 3-13 years, mean; 9 years) with femoral fractures were evaluated; 25 of them underwent the conservative treatment using immediate hip spica (group A) and 25 underwent treatment with crossed retrograde Rush pins (group B). RESULTS: Mean duration of fracture union was within 15 weeks in group A and 12 weeks in group B. Mean duration of weight bearing was 14weeks in group A and 7 weeks in group A. Mean hospital stay were 4 days in group A and 8days in group B. The man follow-up period was 16 months in group A and 17 months in group B. Complications like angulation, shortening and infection were compared. Bursitis and penetration of pins at the site of Rush pin insertion is a complication associated with this method of treatment. CONCLUSION: Closed reduction and internal fixation with crossed Rush pins was a superior treatment method in terms of early weight bearing and restoration of normal anatomy. PMID- 24791043 TI - Cluster of differentiation 4+ cell count mean value, reference range and its influencing factors in Human Immunodeficiency Virus-seronegative pregnant women in Lagos. AB - BACKGROUND: Immunity in pregnancy is physiologically compromised and this may affect cluster of differentiation four (CD4) count levels. It is well established that several factors affect CD4 count level in pregnancy. This study aims to determine the effects of maternal age, gestational age, parity and level of education as they influence CD4 count in pregnancy and also to determine the mean and reference range of CD4 count in pregnancy in Lagos, Nigeria. MATERIALS AND METHODS: A descriptive cross-sectional study was carried out at Ante-natal clinics in Lagos State, Nigeria. About 5 mls of blood was collected into Ethylene Diamine Tetracetic Acid (EDTA) bottles from HIV-negative pregnant women in various gestational ages of pregnancy. CD4+ cell count and full blood count of all samples were done within 3 hours of collection. The descriptive data was given as means +/- standard deviation (SD). Pearson's chi-squared test and correlation were used for analytical assessment. RESULTS: A total of 74 pregnant women were recruited. The age range was 19-41 years and a mean age of 30.42 +/- 5.34 years. The CD4+ cell count was not statistically significant when compared with participants ages P = 0.417, neither with gestational ages P = 0.323, nor with parity P = 0.247 nor level of education P = 0.96. An overall mean CD4+ cell count was 771.96 +/- 250 cells/MUl and the range was 193-1370 cells/MUl. CONCLUSION: Maternal age, gestational age, parity and level of education had no significant effects on CD4+ cell count levels in pregnancy. The mean CD4+ cell count of HIV-negative pregnant women in Lagos is 771.96 +/- 250 cells/MUl. PMID- 24791044 TI - Long-term smoking results in haemostatic dysfunction in chronic smokers. AB - BACKGROUND: Smoking has been known to cause endothelial dysfunction and bronchial carcinoma and duration of smoking has been implicated in the effects of smoking on regular smokers. This study evaluated the effects of long-term smoking on some coagulation markers in chronic smokers. MATERIALS AND METHODS: A total of 78 chronic smokers (age, 41 +/- 20 years) where grouped according to duration of time they have smoked (2-6 years, 7-11 years, 12-16 years and 17-21 years), and included in the study. Bleeding time (BT), whole-blood clotting time (WBCT), total platelet count (TPC), prothrombin time (PT) and activated partial thromboplastin time with kaolin (APTTK) were estimated in the subjects using standard operative procedures. STATISTICAL ANALYSIS USED: Graph pad prism software (Statmate) version 2.0 and SPSS version 20.0 were used for the statistical analysis and the test of significance was calculated using paired Student's t-test. RESULTS: There was an inverse correlation between the durations of smoking and BT, WBCT, PT and APTTK coagulation markers and a linear correlation between the different durations and TPC, in the chronic smokers. The strongest effects was in the 12-16 years and 17-21 years duration (P < 0.05). CONCLUSION: The study revealed that long-term chronic cigarette-smoking can lead to haemostatic dysfunction in chronic smokers. Smoking should be generally discouraged as it could have far-reaching medical implications on this group of subjects, especially in bleeding emergency cases. PMID- 24791045 TI - Atrial septal defects: Pattern, clinical profile, surgical techniques and outcome at Innova heart hospital: A 4-year review. AB - BACKGROUND: Atrial septal defect (ASD) is a congenital heart defect that leads to shunting of blood between left and right atria. It may be asymptomatic and sometimes may present with heart failure. Surgical repair is definitive, but currently non-surgical procedure is used to close the defect. MATERIALS AND METHODS: It is a retrospective study of patients who underwent transcatheter closure of ASD at Innova Heart Hospital, Hyderabad, India. Echocardiography was repeated at intervals of 24 hours, then at 1, 3 and 6 months after the procedure to assess complications. The morphological characteristics of the ASD, including its diameter, location, shape and the width of surrounding septal margins, were also evaluated. RESULTS: From April 2007 to June 2011, 69 consecutive children (29 males, 40 females) with a median age of 9.0 years (range = 3.2-19 years) registered with diagnosis of ASD. The median weight was 31.5 kg (range = 7.5-39.0 kg). Five patients (7.2%) were young children aged 3-5 years. Forty-four (63.8%) of these children presented with symptoms of heart failure, whereas 47 (68.1%) of the cases repaired with device were large-sized ASD. The most common interventional procedures done were Searcare Heart((r)) and Amplatzer((r)) technique with a highest success rate obtained in 2010. CONCLUSIONS: ASD is a common congenital heart disease with a high success rate for those who undergo intervention. PMID- 24791046 TI - An audit of paediatric mortality patterns in a Nigerian teaching hospital. AB - BACKGROUND: The 4(th) millennium development goals (2002) reported that sub Saharan Africa countries including Nigeria have a persistently high childhood mortality rates in-spite of all the preventive and interventional measures to reduce this ugly trend. PATIENTS AND METHODS: Childhood mortality data was obtained from the medical records department and post-mortem records of the pathology departments over a 5-year period from January 2007 to December 2011. The selection criteria include all case notes with mortality records involving children admitted into the paediatrics department through the labour ward and the obstetrics theater, children emergency unit (CHER), paediatric out-patient clinic. RESULTS: A total of 12,442 children were admitted during this period. Of this, 711 paediatric deaths were documented accounting for 17.5%. The male to female mortality ratio was 1.4:1. The age range was from birth to 17 years. Neonatal deaths accounted for the most common cause of death constituting 344 (48.4%) of all deaths. Among the neonatal mortality patterns, severe birth asphyxia/perinatal asphyxia was the most common cause of early neonatal deaths accounting for 97 (28.2%). Septicaemia accounted for the most frequent cause of infant mortality accounting for 28 (21.8%). Among the under-5 age group, severe malaria constituted the most common cause of death accounting for 52 (36.6%) cases while malignancy topped the list of 5-17 years mortality rate constituting 15 (15.4%) cases. CONCLUSION: Perinatal and neonatal deaths constitute the vast majority of death in our environment with most of the deaths resulting from severe birth asphyxias, prematurity. Again in the post-neonatal period, infections and other preventable diseases constitute the most common cause of death in children of under age group of five years. Above 5 years childhood malignancies constitutes the highest mortality pattern. PMID- 24791047 TI - The effect of new emergency program on patient length of stay in a teaching hospital emergency department of Tehran. AB - BACKGROUND AND AIM: Ideally, the period of patients admitting in the Emergency Department (ED) should not exceed 6 hours. Prolonged of the patients admitting time affects the ED overcrowding, quality of patient care and patient satisfaction. To evaluate the efficacy of new programs and suggest new strategies to reduce the overcrowding in a typical overcrowded ED of general teaching hospital in Tehran city. MATERIALS AND METHODS: In this descriptive case study, charts of patients held over 24 hours, in Imam Hossein Hospital affiliated to the Shaheed Beheshti Medical University, were reviewed from April 21(rd) on August 23(rd), 2008. RESULTS: Of 15,477 patients, 151 (1%) have been held in the ED over 24 hours. Reasons for this long-stay included:lack of available bed in Intensive Care Unit (ICU) (125 patients), lack of available bed in related wards (18 patients), poor final decision - making by physician (eight patient). CONCLUSION: Long-term stay of patients in ED of teaching hospital is a major problem. The most frequent cause is a limitation of inpatient beds. The long stay time had not been affected by paraclinic procedures, multispecialities involvement or the lack of obvious diagnosis. The following solution is proposed: (1) creation of a holding unit, (2) active inter-facility transfer and (3) governing admittance of patients who need ICU care to related wards. PMID- 24791048 TI - Gestational thrombocytopaenia among pregnant women in Lagos, Nigeria. AB - BACKGROUND: Thrombocytopaenia is a common haematologic abnormality during pregnancy. Pregnant women with thrombocytopenia have a higher risk of bleeding excessively during or after childbirth, particularly if they need to have a caesarean section or other surgical intervention during pregnancy, labour or in the puperium. The aim of this study was to determine the prevalence of gestational thrombocytopaenia among pregnant women reporting for antenatal care at tertiary health care centres in Lagos. MATERIALS AND METHODS: Platelet count was analyzed in 274 consecutive pregnant women who gave informed consent and 70 non-pregnant female staff of the hospitals. Platelet count was performed on each sample using the Sysmex KN-21N automated haematology analyzer. The study design was cross-sectional, proportions were analyzed for statistical significance with the chi-square, and Odds ratio was also calculated. Thrombocytopaenia is classically defined as a platelet count of less than 150 * 10(9)/L.34 Counts from 100 to 150 * 10(9)/L are considered mildly depressed, 50 to 100 * 10(9)/L are moderately depressed and less than 50 * 10(9)/L are severely depressed. RESULTS: Thirty-four (13.5%) pregnant women were thrombocytopaenic compared with three (4.3%) non-pregnant women. This was statistically significant; P = 0.03; Odds ratio: 3.5 (95% CI 1.03-11.82). Out of the 37 pregnant women who were thrombocytopaenic, most of them (78%) had mild thrombocytopenia, only 6% had severe thrombocytopaenia. CONCLUSION: The prevalence of gestational thrombocytopaenia in this study was 13.5%. Although majority of the pregnant women had mild thrombocytopaenia, healthcare providers should screen all pregnant women routinely for thrombocytopaenia to avoid excessive bleeding during or after childbirth. PMID- 24791049 TI - A comparison of Simplified Acute Physiology Score II, Acute Physiology and Chronic Health Evaluation II and Acute Physiology and Chronic Health Evaluation III scoring system in predicting mortality and length of stay at surgical intensive care unit. AB - BACKGROUND: In critically ill patients, several scoring systems have been developed over the last three decades. The Acute Physiology and Chronic Health Evaluation (APACHE) and the Simplified Acute Physiology Score (SAPS) are the most widely used scoring systems in the intensive care unit (ICU). The aim of this study was to assess the prognostic accuracy of SAPS II and APACHE II and APACHE III scoring systems in predicting short-term hospital mortality of surgical ICU patients. MATERIALS AND METHODS: Prospectively collected data from 202 patients admitted to Mashhad University Hospital postoperative ICU were analyzed. Calibration was estimated using the Hosmer-Lemeshow goodness-of-fit test. Discrimination was evaluated by using the receiver operating characteristic (ROC) curves and area under a ROC curve (AUC). RESULT: Two hundred and two patients admitted on post-surgical ICU were evaluated. The mean SAPS II, APACHE II, and APACHE III scores for survivors were found to be significantly lower than of non survivors. The calibration was best for APACHE II score. Discrimination was excellent for APACHE II (AUC: 0.828) score and acceptable for APACHE III (AUC: 0.782) and SAPS II (AUC: 0.778) scores. CONCLUSION: APACHE II provided better discrimination than APACHE III and SAPS II calibration was good at APACHE II and poor at APACHE III and SAPS II. Use of APACHE II was excellent in this post surgical ICU. PMID- 24791050 TI - Perception of quality of maternal healthcare services among women utilising antenatal services in selected primary health facilities in Anambra State, Southeast Nigeria. AB - BACKGROUND: This is a cross-sectional descriptive study aimed at assessing antenatal care service attendees' perception of quality of maternal healthcare (MHC) services in Anambra State, southeast Nigeria. MATERIALS AND METHODS: A total of 310 pregnant women utilising antenatal care (ANC) services in three purposively selected primary health centres (PHCs) in rural communities in Anambra State were studied. Reponses were elicited from the participants selected consecutively over a 4-month period, using a pre-tested, semi-structured interviewer-administered questionnaire on socio-demographic characteristics, utilisation and perception of MHC services. Data collected were analysed using SPSS version 17. RESULTS: Findings showed that utilisation of facility for both antenatal (97.0%; 95% CI, 94.4-98.4%) and natal services (92.7%; 95% CI 89.2 95.2%) were quite high. Generally, most of the women were satisfied with MHC services (89.7%). Most of them were satisfied with the staff attitude (85.1%), waiting time (84.1%) and cost of services (79.5%). Being >=30 years (X (2) = 4.61, P = 0.032), married (X (2) = 9.70, P = 0.008) and multiparous (X (2) = 9.14, P = 0.028), as well as utilisation of formal health facility for antenatal (X (2) = 26.94, P = 0.000) and natal (X (2) = 33.42, P = 0.000) services were associated with satisfaction with maternal health services. CONCLUSIONS: The study showed high level of satisfaction with quality of maternal health services among antenatal attendees and highlights the need to strengthen interventions that increase uptake of formal MHC services. PMID- 24791051 TI - Study of proportion and determinants of depression among college students in Mangalore city. AB - BACKGROUND: Onset of depression is occurring earlier in life today than in past decades. Adolescence being transitional period from childhood to adulthood is a stage of emotional instability resulting from demand for separation and independence. Evidence suggests that early intervention for depression in children can improve long-term outcomes. MATERIALS AND METHODS: This cross sectional study was done in January 2010 to find out the prevalence of depression among pre university students in Mangalore city. Prevalence of depression was assessed using Beck's Depression Inventory II. Data was collected using a self administered questionnaire. RESULTS: Out of 308 participants, depression was seen among 79.2% students. A majority (41.2%) were found to be suffering from moderate followed by mild (26.6%) depression. Prevalence of depression (P = 0.027) and severity of depression (P = 0.0357) was found to significantly increase with age of the participants. Students of commerce were found to be significantly more depressed than students of science stream (P = 0.002). No association of depression with gender of participants or with the type of college they were studying in was observed. CONCLUSION: There is a need for college students to be educated about depression in order to improve recognition and diagnosis. Also student counselling service offering mental health assistance needs to be established at colleges. PMID- 24791052 TI - Prevalence of pulmonary hypertension in sickle cell anaemia patients of a tertiary hospital in Nigeria. AB - BACKGROUND: Sickle cell disease (SCD) is an inherited haemoglobinopathy characterised by recurrent organ hypoxia-reperfusion cycles which may result in repeated organ damage including the lungs and heart. In SCD, pulmonary hypertension is a known complication that may precede or complicate acute chest syndrome which is often fatal. This study seeks to know the prevalence of pulmonary hypertension and its relationship with clinical and laboratory parameters in sickle cell disease patients attending a tertiary hospital in Lagos. MATERIALS AND METHODS: This was a case - control study involving patients with sickle cell disease recruited from adult sickle cell clinic of Lagos State University Teaching Hospital, Ikeja and HbAA controls matched for age and sex from a tertiary educational institution in Lagos. Both the patients and controls were subjected to echocardiography and pulmonary hypertension was deduced from their cardiac tricuspid regurgitant jet velocity. Other parameters measured were age, body mass index, full blood count, red cell indices, foetal haemoglobin, chest X-ray, liver function tests, lactate dehydrogenase and pulmonary function tests. Consenting patients were 56 HbSS in steady state and 28 HbAA controls matched for age and sex. Data was analysed using SPSS version 16.0. RESULTS: The mean age of patients was 22 +/- 6 years. In two 2 of 56 (3.6%) of the participants with sickle cell disease, the pulmonary artery pressure was > 25mmHg and there was significant difference in the mean of the pulmonary artery pressure of the control and that of the patients (P-value 0.013). Also, using the appropriate correlation tests, there was significant relationship between the pulmonary artery pressure and lactate dehydrogenase, aspartate transferase and haematocrit in patients with sickle cell disease. CONCLUSION: Sickle cell disease is an independent cause of pulmonary artery hypertension. Variation in cardiovascular reactions to recurrent hyperhaemolysis and hyperdynamic state in sickle cell disease may explain differences in the development of cardiac complications. Exploration of these reactions may reveal other therapeutic measures to prevent complications in sickle cell disease. Clinical assessment of adult patients with sickle cell disease should include echocardiography. PMID- 24791053 TI - Allergic conjunctivitis in Jos-Nigeria. AB - BACKGROUND: Allergic conjunctivitis (AC) may follow seasonal or perennial pattern. There are climatic and racial risk factors involved in some types of AC. It is more prevalent in warm climatic conditions and among Afro-Caribbeans, Arabs and Asians and less among the White populations. Clinical presentations also seem to follow climatic and genetic predisposition. The purpose of this study is to determine the prevalence of AC and its clinical presentations in a hospital setting in this region in people of all ages. MATERIALS AND METHODS: This is a hospital-based retrospective study of new patients seen at Adoose Specialist Hospital, Jos the capital city of Plateau State in North Central Nigeria with clinical diagnosis of AC from 2000 to 2009. RESULTS: There were 972 subjects, 474 (48.8%) males and 498 (51.2%) females with M:F ratio of 1:1.05. The most common symptom was itching followed by redness, pains, watery/mucoid discharge, sticky eyes, puffy eyes and photophobia. The presence of papillae in the upper tarsal or lower conjunctiva, a discrete or confluent gelatinous hypertrophy of the limbal conjunctiva (Trantas dots), hyperpigmentation, hyperemia/chemosis of the conjunctiva were the common signs. AC was more prevalent in those aged 1-16 years 38.4% decreasing to 4.9% in the age group above 50 years. The presentation followed perennial pattern, with a peak around July. The most prevalent ocular comorbid condition was refractive error (distant RE and presbyopia) in 15.4%, followed by pterygium/pinguecula 3.6%, bacterial conjunctivitis in 2.2%, glaucoma 2.1% and eyelid disorders 1.7%. Cataract was present in 1.3%, and keratopathy 1.1%. Other conditions such as episcleritis, dry eye, vitamin A deficiency and posterior segment disease were also present in decreasing order. Systemic association were few with generalised body atopy in 0.3%. CONCLUSION: The prevalence of AC was 32% and is similar to what pertains in some of the African hospital studies, but differs in presentation from the Caucasians. PMID- 24791054 TI - Disseminated intravascular coagulation in malaria: A case report. AB - Disseminated intravascular coagulation (DIC) is seen in <5% of patients with severe Plasmodium falciparum malaria and is more common in cerebral malaria. Here, we report the diagnosis and management of a case of severe P. falciparum malaria with DIC. PMID- 24791055 TI - Dyskeratosis congenita in a Nigerian boy. AB - Dyskeratosis congenita is a rare hereditary disease. It mainly affects males and manifest between 5 years and 12 years. Its classic manifestation consists of skin pigmentary changes, nail dystrophy, oral leukoplakia, bone marrow failure and predisposition to malignany. We report the case of a 9-year-old boy who presented with hyperpigmentation of the skin, palms and soles, leukoplakia of the tongue, dystrophy of the nails, epiphoria and recurrent epistaxis with gum bleeding. Full blood count showed pancytopenia and bone marrow biopsy showed hypocellular marrow with no abnormal cells. He was transfused with pack red blood cells, platelets concentrate and was commenced on co-trimoxazole prophylaxis and anabolic steroid. He is currently on follow-up in the paediatric clinic. PMID- 24791056 TI - The 8p12 myeloproliferative syndrome. AB - The occurrence of a myeloproliferative disorder in association with an aggressive lymphoproliferative disorder is a distinctly unusual phenomenon. We report a case of concurrent leukaemia-lymphoma syndrome characterized by a BCR/ABL-negative myeloproliferative disease, eosinophilia and a lymphoma. The bone marrow chromosome analysis showed the karyotype 46, XY, t(8;9) (q12; p33), which indicated presence of FGFR1 gene translocations. 8p12 myeloproliferative syndrome (EMS) / stem cell leukaemia-lymphoma syndrome (SCLL) belongs to the tyrosine kinase fusion genes chronic myeloproliferative diseases. The patient was managed conservatively with hydroxyurea, allopurinol and blood component therapy. The patient eventually died of intracerebral haemorrhage due to severe thrombocytopaenia. Based on our experience the overlap in the clinical presentation of this disease with lymphomas, can lead to a delay in diagnosis of EMS/SCLL. Given the aggressive nature of this disease, an accurate clinical and molecular diagnosis of this entity has become increasingly important. PMID- 24791057 TI - A case report of complete mole with co-existent exaggerated placental site reaction and review of the literature. AB - Exaggerated placental site (EPS) is defined as a non-neoplastic trophoblastic lesion, which intermediate trophoblasts infiltrate exaggeratedly into endometrium and myometrium. These lesions may occur following normal pregnancy, ectopic pregnancy, abortus or molar pregnancy. Herein we share a case of EPS detected after evacuation due to molar pregnancy. We also review the related literature, where only a few reports exist describing the clinical course, histopathology and differential diagnosis of EPS. PMID- 24791058 TI - Comparison of the wing polyphenic response of pea aphids (Acyrthosiphon pisum) to crowding and predator cues. AB - 1. Pea aphids (Acyrthosiphon pisum Harris; Hemiptera: Aphididae) exhibit transgenerational wing polyphenism, in which unwinged females produce genetically identical winged offspring in response to environmental cues such as overcrowding and predation risk that indicate poor habitat quality. 2. Laboratory experiments were carried out to explore the intensity of the wing polyphenic response of pea aphids exposed to cues from ladybird predators and crowding, and their response was compared to pea aphids that were not exposed to any cues (control). 3. The study used cues from two different ladybird species: Coccinella septempunctata L. (Coleoptera: Coccinellidae) and Hippodamia convergens Guerin-Meneville (Coleoptera: Coccinellidae) to investigate whether the wing polyphenic response of pea aphids to predator cues can be generalized 4. The intensity of the wing polyphenic response of pea aphids to crowding was found to be much stronger than their response to predator cues. There was no response to H. convergens cues and the response to C. septempunctata cues was mixed. PMID- 24791059 TI - SYNTHESIS OF DE NOVO CHIRAL gamma-AMINO-YNAMIDES USING LITHIATED YNAMIDES. OBSERVATION OF A UNIQUE 5-ENDO-DIG CYCLIZATION WITH AN INVERSION OF S-CENTER. AB - We describe herein details of our efforts in developing a highly stereoselective synthesis of de novo chiral gamma-amino-ynamides through additions of lithiated ynamides to Ellman-Davis chiral N-tert-butanesulfinyl imines. While additions of ynamides could be highly stereoselective even without Lewis acids, the use of BF3 OEt2 completely reversed the stereoselectivity. On the other hand, additions of oxazolidinone-substituted, oxazinanone-substituted and tetrahydropyrimidinone substituted ynamides behaved quite differently and functioned better with BF3 OEt2. The chirality of the oxazolidinone ring exerts no impact on the selectivity. This work also features a unique 5-endo-dig cyclization of oxazolidinone-substituted gamma-amino-ynamides that could be promoted with acid, leading to isothiazoles and 2,3-dihydro-isothiazole S-oxides. PMID- 24791060 TI - [Neighborhood Systematic Social Observation; The Case of Chile and its Perspectives for Social Work.] AB - The study of neighborhood characteristics and their effects on individuals has become an area of increasing attention by scholars from various disciplines in developed countries. Although there are various methods to study neighborhoods and their impact on human populations, one of the most used is the Systematic Social Observation -Observacion Sistematica de Vecindarios (OSV), in Spanish because it allows the collection of information about various features of the physical, social, environmental and economic characteristics of neighborhoods. The purpose of this article is to (i) briefly present some research on neighborhood effects influential in the U.S., ii) describe how they Systematic Social Observation was designed and implemented in the city of Santiago, Chile, iii) discuss some facilitators and obstacles of the implementation process and, finally iv) list possible contributions and limitations this approach would offer the profession of social work in Chile. PMID- 24791062 TI - A comparison of the histological structure of the placenta in experimental animals. AB - The primary function of the placenta is to act as an interface between the dam and fetus. The anatomic structure of the chorioallantoic placenta in eutherian mammals varies between different animal species. The placental types in eutherian mammals are classified from various standpoints based on the gross shape, the histological structure of the materno-fetal interface, the type of materno-fetal interdigitation, etc. Particularly, the histological structure is generally considered one of the most useful and instructive classifications for functionally describing placental type. In this system, three main types are recognized according to the cell layers comprising the interhemal area: (1) epitheliochorial type (horses, pigs and ruminants), (2) endotheliochorial type (carnivores) and (3) hemochorial type (primates, rodents and rabbits). The number of cell layers in the interhemal area is considered to modify the transfer of nutrients between maternal and fetal blood and is one of the important factors with respect to the difference in placental permeability between animal species. Therefore, in reproductive and developmental toxicity studies, careful attention should be paid to the histological structure of the interhemal area when extrapolating information concerning placental transfer characteristics to different animal species. PMID- 24791061 TI - Mechanisms of Mycotoxin-induced Dermal Toxicity and Tumorigenesis Through Oxidative Stress-related Pathways. AB - Among the many mycotoxins, T-2 toxin, citrinin (CTN), patulin (PAT), aflatoxin B1 (AFB1) and ochratoxin A (OTA) are known to have the potential to induce dermal toxicity and/or tumorigenesis in rodent models. T-2 toxin, CTN, PAT and OTA induce apoptosis in mouse or rat skin. PAT, AFB1 and OTA have tumor initiating properties, and OTA is also a tumor promoter in mouse skin. This paper reviews the molecular mechanisms of dermal toxicity and tumorigenesis induced in rodent models by these mycotoxins especially from the viewpoint of oxidative stress mediated pathways. PMID- 24791063 TI - Overdose of D-serine Induces Movement Disorder and Neuromuscular Changes of Zebrafish Larvae. AB - D-serine is a well-known activator of N-methyl-D-aspartate receptors; however, little is known about the teratogenic effects of D-serine overdose during early embryonic development. Here, we used zebrafish as a model to test toxicity and teratogenicity, since they have transparent eggs, making the organogenesis of zebrafish embryos easier to be observed. After D-serine injection (100-1000 ppm), the most evident defective phenotypes were bent trunk phenotypes, including malformed somite boundary, twisted body axis and shorter body length. As the injection dosages increased, the rates of embryos with bent trunk phenotypes decreased (0% for 0 ppm, n=573; 59.9~84.3% for 100-1000 ppm of D-serine, n=383 451). In addition, D-serine-injected embryos exhibited significantly reduced the frequencies of spontaneous in-chorion contraction (21.7 for 0 ppm vs. 18.3-0.9 for 100-1000 ppm D-serine, n=30) in comparison with mock-treated controls (0 ppm). Subtle changes are easily observed by staining with specific monoclonal antibodies F59, Znp1, Zn5 and alpha-bungarotoxin to detect morphological changes in muscle fibers, primary motor axons, secondary motor axon projections and neuromuscular junctions, respectively. Our data show that overdose of D-serine leads to misalignment of muscle fibers and motor neuron defects, especially secondary motor neuron axonal growth defects. PMID- 24791064 TI - Systemic histopathology of infant rats exposed to busulfan. AB - Busulfan is an antineoplastic bifunctional alkylating agent. We previously reported the busulfan-induced systemic histopathological changes in fetal rats and the sequence of brain lesions in fetal and infant rats. In the present study, in order to clarify the nature and sequence of busulfan-induced systemic histopathological changes in infant rats, 6-day-old male infant rats were subcutaneously administered 20 mg/kg of busulfan and histopathologically examined at 1, 2, 4, 7 and 14 days after treatment (DAT). As a result, histopathological changes characterized by pyknosis of component cells were observed in the heart, lungs, stomach, intestines, liver, kidneys, testes, epididymides, hematopoietic and lymphoid tissues, dorsal skin and femur as well as in the brain and eyes (data not shown in this paper). Such pyknosis transiently appeared until 7 DAT with prominence at 2 and/or 4 DAT in each tissue, except for the thymus, in which pyknosis peaked at 1 DAT. Most of the pyknotic nuclei were immunohistochemically positive for cleaved caspase-3, indicating that pyknotic cells were apoptotic. Different from the reports of fetal and adult rats, apoptosis was also found in cardiomyocytes and osteoblasts in infant rats. PMID- 24791065 TI - Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5 HT1B Inhibitor. AB - AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5 hydroxytryptamine (5-HT1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology. PMID- 24791066 TI - Establishment of an invasive prostate cancer model in transgenic rats by intermittent testosterone administration. AB - We have established a transgenic rat for adenocarcinoma of the prostate (TRAP) model that features uniform adenocarcinoma development in prostatic lobes at high incidence within a short experimental period. However, no invasive carcinomas with reactive stroma characteristics similar to those in man were observed. We therefore have focused on a new model for invasive carcinoma of the prostate using TRAP rats. In experiment 1, male TRAP rats in groups 1 and 2 were treated with orchiectomy at day 0 of the experiment. Rats in groups 1-3 underwent testosterone propionate (TP) implantation from weeks 1 to 4 and from weeks 6 to 16. Rats in groups 1 and 3 were given 3,2'-dimethyl-4-aminobiphenyl (DMAB) after TP implantation. The rats of group 4 served as controls. In experiment 2, the rats were divided into three groups, none of which received DMAB or orchiectomy, treated with TP continuously or with the treatment withdrawn once or twice. In experiment 1, invasive adenocarcinomas with abundant collagenous stroma were found in the dorsolateral and anterior prostate, some of which showed perineural space invasion at week 16. The number of invasive carcinoma foci was most frequent in group 3. In experiment 2, invasive adenocarcinoma development in the lateral prostates was correlated with the number of TP administration/withdrawal cycles. In conclusion, our newly established rat model for invasive adenocarcinoma of the prostate could serve as a useful preclinical model for evaluating the in vivo efficacy of preventive and therapeutic agents targeting of the tumor microenvironment. PMID- 24791067 TI - Establishment of a model of spontaneously-running-Tokushima-shikoku rats with left atrial thrombosis. AB - Studies that investigate the underlying mechanisms of disease and treatment options typically require the use of a suitable animal model. Few suitable animal models exist for left atrial thrombosis. Here, we demonstrated that the Spontaneously-Running-Tokushima-Shikoku (SPORTS) rat - a Wistar strain known for its running ability-is predisposed to the development of thrombi in the left atrium. We investigated the incidence of left atrial thrombosis in male (n = 16) and female (n = 17) SPORTS rats and observed organized atrial thrombosis in 57% and 38% of males and female rats, respectively. In the male rats, systolic blood pressures and heart rates were significantly higher in SPORTS rats than in control Wistar rats. We could not find any evidence of arrhythmias, such as atrial fibrillation, during electrocardiographic examination of SPORTS rats. We believe that the SPORTS rat could serve as a new research model for left atrial thrombosis; further, it may be suitable for research investigating the development of new antithrombotic approaches for the control of atrial thrombosis or familial thrombophilia in humans. PMID- 24791068 TI - The Kidneys of Infant Mice are not Sensitive to the Food Mycotoxin Contaminant Nivalenol. AB - Nivalenol (NIV) is a trichothecene mycotoxin produced by Fusarium fungi that frequently contaminates agricultural commodities. Dietary administration of NIV to adult mice affects the renal glomeruli, but data about NIV toxicity in human infants are limited. To evaluate the effects of NIV on infant kidneys, 3-week-old male ICR-derived glomerulonephritis (ICGN) and ICR mice were administered 0, 4, 8 or 16 ppm NIV in diet for 4 weeks, and their renal status was compared with age matched or adult ICR mice. In ICGN mice, the number of glomeruli showing mesangial expansion and alpha-smooth muscle actin (SMA)-positive mesangial cells was higher with 16 ppm NIV compared with controls. No other significant differences were observed in ICGN mice. In infant ICR mice, the IgA serum concentrations were significantly elevated without glomerular morphological changes in the 16 ppm NIV group. There was no difference in NIV sensitivity in the kidneys of infant ICGN and ICR mice. These data suggest that the kidneys in infant mice are not sensitive to nivalenol under the present conditions. PMID- 24791069 TI - The enhancing effects of hyperbaric oxygen on mouse skin carcinogenesis. AB - The effects of hyperbaric oxygen (HBO) on mouse skin two-stage chemical carcinogenesis were examined. Six-week-old inbred CD-1 female mice were divided into the following five groups: group 1, normoxia and application of 25 nmol 7,12 dimethylbenz[a]anthracene (DMBA) and 8.5 nmol 12-O-tetradecanoylphorbol-13 acetate (TPA) (n=19); group 2, HBO and DMBA/TPA (n=21); group 3, HBO and DMBA/acetone (n=3); group 4, normoxia and acetone (n=3); and group 5, non treatment group (n=5). HBO was started at the same time as DMBA. Mice were euthanized at 23 weeks after the start of the experiment. Mice in group 2 showed the occurrence of tumors at 8 weeks after the beginning of the experiment, while the occurrence of tumors in mice in group 1 was observed beginning at 9 weeks. There was a difference in occurrence among low-grade papillomas, high-grade papillomas and SCCs in both groups 1 and 2 by the chi (2)-test at end of the experiment (p<0.05). The Ki-67 labeling indices of tumors revealed that the percentages of positive cells in low-grade papillomas in groups 1 and 2 were 15.27 +/- 2.54% and 29.67 +/- 2.82%, respectively (p<0.01). The results suggested that the tumors in group 2, which was treated with HBO, were more progressive than those in group 1, which was not treated with HBO. In this study, HBO accelerated tumor cell proliferation and advanced tumor progression in skin carcinogenesis by DMBA/TPA. PMID- 24791071 TI - Costal mesenchymal chondrosarcoma with diffuse pleural and pericardial explantation in a pygmy goat. AB - A 3 year old intact male pygmy goat developed progressive weakness and eventual recumbancy over the course of 1 week, while maintaining its ability to eat and drink. The animal died and at necropsy, the parietal pleural surfaces and the pericardial surface were noted to be covered with firm, white, variably sized nodules that often formed linear arrays or coalesced into larger clumped aggregates. The visceral pleural surfaces of the ventral lung lobes were also covered with similar nodules. Histopathological and immunohistochemical evaluation of the submitted tissues revealed a diagnosis of mesenchymal chondrosarcoma with extensive seeding throughout the thoracic cavity. PMID- 24791070 TI - Absorption, distribution and pathological injury in mice due to ricin poisoning via the alimentary pathway. AB - The aim of this work was to investigate the potential interactions between intestinal absorbance and ricin poisoning. The Caco-2 cell monolayer and everted intestinal sac (VEIS) models were used. The distribution of ricin in CD-1 mice intoxicated with 0.1 mg/kg of ricin intragastrically was determined by immunohistochemistry. The results showed that ricin could not transfer across the healthy Caco-2 cell monolayer within three hours after poisoning. However, it could pass through the everted rat intestinal wall after 0.5 h of incubation. The toxin in the liver, spleen, lungs and kidneys of mice could be detected as early as 1 h after intoxication. The pathological results were in accordance with the cytotoxicities of ricin in Caco-2, HepG 2, H1299 and MDCK cells, indicating that though no significant symptom in mice could be observed within 3 h after ricin intoxication, important tissues, especially the kidneys, were being injured by the toxin and that the injuries were progressing. PMID- 24791072 TI - Ectopic tissue consisting of a mixture of glandular gastric, intestinal, and exocrine pancreatic tissue in the forestomach of a rat. AB - The development of ectopic gastric, intestinal, or pancreatic tissue in the gastrointestinal tract is extremely rare in rats, although it is fairly common in humans. In this report, we describe an unusual case in which a mixture of different types of ectopic tissue was found in the forestomach of a rat. A solitary white nodular/polypoid structure, which measured 5 mm in size, was detected on the luminal surface of the greater curvature of the forestomach in an 8-week-old female Crl:CD(SD) rat. A histological examination revealed that the lesion contained ectopic glandular gastric tissue, including gastric surface mucous cells, parietal cells, and pyloric gland cells, which was confirmed by immunohistochemistry. Moreover, the lesion also contained villin-positive columnar intestinal absorptive cells and chymotrypsin-positive pancreatic exocrine tissue. To the best of our knowledge, this is the first study to detect a mixture of ectopic glandular gastric, intestinal, and exocrine pancreatic tissue in a rat. PMID- 24791073 TI - Spontaneous nephroblastoma with lung metastasis in a rat. AB - This report describes a spontaneous nephroblastoma with lung metastasis in a 10 week-old male Crl:CD(SD) rat. Macroscopically, a white mass in the kidney and two white masses in the lung were observed. Histopathologically, the renal mass was located in the cortex of a kidney, and it caused pressure on the surrounding renal parenchyma. Three components could be distinguished in the tumor: blastemal, epithelial (primitive glomerular/tubular structures) and mesenchymal (neoplastic connective tissues) elements. Immunohistochemically, the tumor cells were positive for Wilms tumor 1 protein (WT1) and vimentin. Metastasis was found in the lung. Thus, the case was diagnosed as a nephroblastoma with lung metastasis. PMID- 24791074 TI - Calponin expression in renal tubulointerstitial fibrosis induced in rats by Cisplatin. AB - Renal tubulointerstitial fibrosis is the common feature of chronic renal failure, regardless of its etiology. Myofibroblasts play important roles in progression of the fibrosis and are characterized by expressions of various cytoskeletons such as vimentin, desmin and alpha-smooth muscle actin (alpha-SMA). To pursue the characteristics of the cells, we immunohistochemically investigated the relationship between calponin (a marker of terminal smooth muscles) expression and myofibroblasts in cisplatin-induced rat renal tubulointerstitial fibrosis. Calponin-expressing interstitial cells increased with fibrosis and reacted simultaneously to vimentin or alpha-SMA (a marker of well-differentiated myofibroblasts) but not desmin or Thy-1 (a marker of myofibroblasts at the early stage). The present study shows that calponin may be expressed transiently in relatively well-developed myofibroblasts in rat renal fibrosis. Calponin could become a marker for myofibroblast development in chronic renal toxicity in rats. PMID- 24791075 TI - Do Dyslexics Misread a ROWS for a ROSE? AB - Insufficient knowledge of the subtle relations between words' spellings and their phonology is widely held to be the primary limitation in developmental dyslexia. In the present study the influence of phonology on a semantic-based reading task was compared for groups of readers with and without dyslexia. As many studies have shown, skilled readers make phonology-based false-positive errors to homophones and pseudohomophones in the semantic categorization task. The basic finding was extended to children, teens, and adults with dyslexia from familial and clinically-referred samples. Dyslexics showed the same overall pattern of phonology errors and the results were consistent across dyslexia samples, across age groups, and across experimental conditions using word and nonword homophone foils. The dyslexic groups differed from chronological-age matched controls by having elevated false-positive homophone error rates overall, and weaker effects of baseword frequency. Children with dyslexia also made more false-positive errors to spelling control foils. These findings suggest that individuals with dyslexia make use of phonology when making semantic decisions both to word homophone and non-word pseudohomophone foils and that dyslexics lack adequate knowledge of actual word spellings, compared to chronological-age and reading level matched control participants. PMID- 24791076 TI - Magnetoencephalography: Basic principles. AB - Magnetoencephalography (MEG) is the measurement of the magnetic field generated by the electrical activity of neurons. It is usually combined with a magnetic resonance imaging to get what is called magnetic source imaging. The technology that has helped record these minute magnetic fields is super-conducting quantum interference detector which is like a highly sensitive magnetic field meter. To attenuate the external magnetic noise the MEG is housed inside a magnetically shielded room. The actual sensors recording magnetic fields are magnetometers and/or gradiometers. MEG fields pass through the head without any distortion. This is a significant advantage of MEG over electroencephalography. MEG provides a high spatial and temporal resolution. The recording and identification information should be according to the American Clinical Magnetoencephalography Society guidelines published in 2011. MEG currently has two approved indications in the United States, one is for pre-operative brain mapping and the other is for use in epilepsy surgery. MEG studies have shown functional brain tissue inside brain tumors. PMID- 24791077 TI - Magnetoencephalography recording and analysis. AB - Magnetoencephalography (MEG) non-invasively measures the magnetic field generated due to the excitatory postsynaptic electrical activity of the apical dendritic pyramidal cells. Such a tiny magnetic field is measured with the help of the biomagnetometer sensors coupled with the Super Conducting Quantum Interference Device (SQUID) inside the magnetically shielded room (MSR). The subjects are usually screened for the presence of ferromagnetic materials, and then the head position indicator coils, electroencephalography (EEG) electrodes (if measured simultaneously), and fiducials are digitized using a 3D digitizer, which aids in movement correction and also in transferring the MEG data from the head coordinates to the device and voxel coordinates, thereby enabling more accurate co-registration and localization. MEG data pre-processing involves filtering the data for environmental and subject interferences, artefact identification, and rejection. Magnetic resonance Imaging (MRI) is processed for correction and identifying fiducials. After choosing and computing for the appropriate head models (spherical or realistic; boundary/finite element model), the interictal/ictal epileptiform discharges are selected and modeled by an appropriate source modeling technique (clinically and commonly used - single equivalent current dipole - ECD model). The equivalent current dipole (ECD) source localization of the modeled interictal epileptiform discharge (IED) is considered physiologically valid or acceptable based on waveform morphology, isofield pattern, and dipole parameters (localization, dipole moment, confidence volume, goodness of fit). Thus, MEG source localization can aid clinicians in sublobar localization, lateralization, and grid placement, by evoking the irritative/seizure onset zone. It also accurately localizes the eloquent cortex like visual, language areas. MEG also aids in diagnosing and delineating multiple novel findings in other neuropsychiatric disorders, including Alzheimer's disease, Parkinsonism, Traumatic brain injury, autistic disorders, and so oon. PMID- 24791078 TI - Approaches to refractory epilepsy. AB - Epilepsy is one of the most common serious neurological conditions, and 30 to 40% of people with epilepsy have seizures that are not controlled by medication. Patients are considered to have refractory epilepsy if disabling seizures continue despite appropriate trials of two antiseizure drugs, either alone or in combination. At this point, patients should be referred to multidisciplinary epilepsy centers that perform specialized diagnostic testing to first determine whether they are, in fact, pharmacoresistant, and then, if so, offer alternative treatments. Apparent pharmacoresistance can result from a variety of situations, including noncompliance, seizures that are not epileptic, misdiagnosis of the seizure type or epilepsy syndrome, inappropriate use of medication, and lifestyle issues. For patients who are pharmacoresistant, surgical treatment offers the best opportunity for complete freedom from seizures. Surgically remediable epilepsy syndromes have been identified, but patients with more complicated epilepsy can also benefit from surgical treatment and require more specialized evaluation, including intracranial EEG monitoring. For patients who are not surgical candidates, or who are unwilling to consider surgery, a variety of other alternative treatments can be considered, including peripheral or central neurostimulation, ketogenic diet, and complementary and alternative approaches. When such alternative treatments are not appropriate or effective, quality of life can still be greatly improved by the psychological and social support services offered by multidisciplinary epilepsy centers. A major obstacle remains the fact that only a small proportion of patients with refractory epilepsy are referred for expert evaluation and treatment. PMID- 24791079 TI - Economics of epilepsy surgery. AB - OBJECTIVE: Surgical decision-making is a complex process. First, a medical decision is made to determine if surgery is necessary. Second, another medical decision is made to determine the type of surgery. Third, a corporate decision is made if such a surgery is financially feasible. Finally, a legal decision is made to proceed or refuse the chosen surgery. This paper examines these issues in the case of surgery for medically intractable epilepsy and proposes a method of decision analysis to guide epilepsy surgery. MATERIALS AND METHODS: A stochastic game of imperfect information using techniques of game theory and decision analysis is introduced as an analytical tool for surgical decision-making. RESULTS: Surgery for appropriately chosen patients suffering from medically intractable epilepsy may not only be feasible, but may be the best medical option and the best financial option for the patient, families, society and the healthcare system. Such a situation would then make it legally or ethically difficult to reject or postpone surgery for these patients. CONCLUSIONS: A process to collect data to quantify the parameters used in the decision analysis is hereby proposed. PMID- 24791080 TI - Surgery for drug-resistant focal epilepsy. AB - During the colloquium on drug-resistant epilepsy (DRE) at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore on August 16-18, 2013, a number of presentations were made on the surgically remediable lesional epilepsy syndromes, presurgical evaluation, surgical techniques, neuropathology of drug resistance focal epilepsy and surgical outcome. This pictorial essay with the illustrative case examples provides an overview of the various surgical techniques for the management of drug-resistant focal epilepsy. PMID- 24791081 TI - National epilepsy surgery support activity. AB - While there are over one million people with drug-resistant epilepsy in India, today, there are only a handful of centers equipped to undertake presurgical evaluation and epilepsy surgery. The only solution to overcome this large surgical treatment gap is to establish comprehensive epilepsy care centers across the country that are capable of evaluating and selecting the patients for epilepsy surgery with the locally available technology and in a cost-effective manner. The National Epilepsy Surgery Support Activity (NESSA) aims to provide proper guidance and support in establishing epilepsy surgery programs across India and in neighboring resource-poor countries, and in sustaining them. PMID- 24791082 TI - Epileptogenic networks and drug-resistant epilepsy: Present and future perspectives of epilepsy research-Utility for the epileptologist and the epilepsy surgeon. AB - A multidisciplinary approach is required to understand the complex intricacies of drug-resistant epilepsy (DRE). A challenge that neurosurgeons across the world face is accurate localization of epileptogenic zone. A significant number of patients who have undergone resective brain surgery for epilepsy still continue to have seizures. The reason behind this therapy resistance still eludes us. Thus to develop a cure for the difficult to treat epilepsy, we need to comprehensively study epileptogenesis. Till date, most of the studies on DRE is focused on undermining the abnormal functioning of receptors involved in synaptic transmission and reduced levels of antiepileptic drugs around there targets. But recent advances in imaging and electrophysiological techniques have suggested the role epileptogenic networks in the process of epileptogenesis. According to this hypothesis, the local neurons recruit distant neurons through complex oscillatory circuits, which further recruit more distant neurons, thereby generating a hypersynchronus neuronal activity. The epileptogenic networks may be confined to the lesion or could propagate to distant focus. The success of surgery depends on the precision by which the epileptogenic network is determined while planning a surgical intervention. Here, we summarize various modalities of electrophysiological and imaging techniques to determine the functionally active epileptogenic networks. We also review evidence pertaining to the proposed role of epileptogenic network in abnormal synaptic transmission which is one of the major causes of epileptiform activity. Elucidation of current concepts in regulation of synaptic transmission by networks will help develop therapies for epilepsy cases that cannot be managed pharmacologically. PMID- 24791083 TI - Epilepsy in the elderly: Special considerations and challenges. AB - The elderly are generally defined as those over 60 or 65 years old, but they are a heterogeneous group and may be subdivided into categories based on age and health status. The incidence of epilepsy is highest in the elderly. With a progressive increase in life expectancy, this is the fastest growing segment of patients with epilepsy. Older patients most often have focal seizures, with less prominent auras and automatisms, and longer duration of postictal confusion compared to younger patients. Status epilepticus is common and has a high mortality. The most common specific etiology is cerebrovascular disease, but the cause remains unknown in many patients. Diagnosis can be challenging because of several patient-related, physician-related and investigation-related factors. Over-diagnosis and under-diagnosis are common. Treatment is complicated by the presence of physiological changes related to aging, co-morbidities and cognitive problems as well as concerns regarding drug interactions and medication adherence. Seizures can be controlled in most patients with low doses of a single anti-epileptic drug (AED). Tolerability is an important factor in selection of an AED, as elderly patients tend to be highly sensitive to side effects. Drug resistant epilepsy is uncommon. Epilepsy surgery, especially temporal lobectomy, can be performed in older patients with good results. More studies addressing the pathophysiological mechanisms of epilepsy in this age group, and greater inclusion of the elderly in clinical trials, as well as development of comprehensive care models are needed to provide optimal care to these patients. PMID- 24791084 TI - Practice parameters in management of status epileptics. AB - Status epilepticus (SE) is an emergency neurological problem, more common in the developing countries due to high incidence of infection, stroke and head injury. The protocol for management of SE is intravenous benzodiazepine, followed by phenytoin, valproate (VPA) and phenobarbitone and if uncontrolled general anesthesia (GA). World Federation of Neurology recommends special guidelines for resource poor countries. Use of GA results in hypotension and respiratory depression needing intensive care management. There is a paucity of intensive care facilities hence the recommended antiepileptic drugs (AEDs) which have inherent toxicity of hypotension and respiratory failure cannot be given safely. Under these situations AEDs such as VPA, levetiracetam and lacosamide may be evaluated in SE because of cardiovascular and respiratory safety profile. In this review, the limitations of existing guidelines in the developing countries have been discussed and a way forward has been suggested. PMID- 24791086 TI - Refractory status epilepticus. AB - Refractory status epilepticus is a potentially life-threatening medical emergency. It requires early diagnosis and treatment. There is a lack of consensus upon its semantic definition of whether it is status epilepticus that continues despite treatment with benzodiazepine and one antiepileptic medication (AED), i.e., Lorazepam + phenytoin. Others regard refractory status epilepticus as failure of benzodiazepine and 2 antiepileptic medications, i.e., Lorazepam + phenytoin + phenobarb. Up to 30% patients in SE fail to respond to two antiepileptic drugs (AEDs) and 15% continue to have seizure activity despite use of three drugs. Mechanisms that have made the treatment even more challenging are GABA-R that is internalized during status epilepticus and upregulation of multidrug transporter proteins. All patients of refractory status epilepticus require continuous EEG monitoring. There are three main agents used in the treatment of RSE. These include pentobarbital or thiopental, midazolam and propofol. RSE was shown to result in mortality in 35% cases, 39.13% of patients were left with severe neurological deficits, while another 13% had mild neurological deficits. PMID- 24791085 TI - Epilepsy: Indian perspective. AB - There are 50 million people living with epilepsy worldwide, and most of them reside in developing countries. About 10 million persons with epilepsy are there in India. Many people with active epilepsy do not receive appropriate treatment for their condition, leading to large treatment gap. The lack of knowledge of antiepileptic drugs, poverty, cultural beliefs, stigma, poor health infrastructure, and shortage of trained professionals contribute for the treatment gap. Infectious diseases play an important role in seizures and long term burden causing both new-onset epilepsy and status epilepticus. Proper education and appropriate health care services can make tremendous change in a country like India. There have been many original researches in various aspects of epilepsy across India. Some of the geographically specific epilepsies occur only in certain regions of our country which have been highlighted by authors. Even the pre-surgical evaluation and epilepsy surgery in patients with drug resistant epilepsy is available in many centers in our country. This article attempts to provide a complete preview of epilepsy in India. PMID- 24791087 TI - An overview of pre-surgical evaluation. AB - The success of an epilepsy surgery program depends upon the early identification of potential surgical candidates and selecting from them, ideal candidates for surgery, who are destined to have a post-operative seizure-free outcome without any unacceptable neurological deficits. Since epilepsy surgery centers in resource-poor countries will lack the full range of state-of-the-art technologies usually available in resource-rich countries to perform pre-surgical evaluation, cost-effectively utilization of the locally available investigative facilities to select the surgical candidates becomes challenging. In the present era of rapid electronic communications and telemedicine, it has become possible for epilepsy surgery centers to pool their technological and human resources and to partner with centers nationally and internationally in implementing pre-surgical evaluation strategies. PMID- 24791088 TI - Electrophysiology in epilepsy surgery: Roles and limitations. AB - Successful epilepsy surgery depends on the localization of the seizure onset zone in an area of the brain that can be safely resected. Defining these zones uses multiple diagnostic approaches, which include different types of electroencephalography (EEG) and imaging, and the results are best when all of the tests point to the same region. Although EEG obtained with scalp recordings is often sufficient for the purposes of localization, there are times when intracranial recordings directly from the brain are needed; but the planning, use, value, and interpretation of the these recordings are not standardized, in part because the questions that are to be answered vary considerably across many patients and their heterogenous types of epilepsy that are investigated. Furthermore, there is a desire to use the opportunity of direct brain recordings to understand the pathophysiology of epilepsy, as these recordings are viewed as an opportunity to answer questions that cannot be otherwise answered. In this review, we examine the situations that may require intracranial electrodes and discuss the broad issues that this powerful diagnostic tool can help address, for identifying the seizure focus and for understanding the large scale circuits of the seizures. PMID- 24791089 TI - Video electroencephalogram telemetry in temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is the most commonly encountered medically refractory epilepsy. It is also the substrate of refractory epilepsy that gives the most gratifying results in any epilepsy surgery program, with a minimum use of resources. Correlation of clinical behavior and the ictal patterns during ictal behavior is mandatory for success at epilepsy surgery. Video electroencephalogram (EEG) telemetry achieves this goal and hence plays a pivotal role in pre-surgical assessment. The role of telemetry is continuously evolving with the advent of digital EEG technology, of high-resolution volumetric magnetic resonance imaging and other functional imaging techniques. Most of surgical selection in patients with TLE can be done with a scalp video EEG monitoring. However, the limitations of the scalp EEG technique demand invasive recordings in a selected group of TLE patients. This subset of the patients can be a challenge to the epileptologist. PMID- 24791090 TI - The extratemporal lobe epilepsies in the epilepsy monitoring unit. AB - Extratemporal lobe epilepsies (ETLE) are characterized by the epileptogenic foci outside the temporal lobe. They have a wide spectrum of semiological presentation depending upon the site of origin. They can arise from frontal, parietal, occipital lobes and from hypothalamic hamartoma. We discuss in this review the semiology of different types of ETLE encountered in the epilepsy monitoring unit. PMID- 24791092 TI - Epilepsy surgery in context of neurocysticercosis. AB - The association between neurocysticercosis (NCC) and epilepsy is well known and NCC is an important risk factor for epileptic seizures in many Taenia solium endemic regions of the world. However, while the relationship between NCC and epilepsy is well known, the association between NCC and medically refractory (or surgically remediable epilepsy) has received little attention in the past. Our experience and review of the sparse literature available suggests that NCC is causally related to surgically remediable epilepsy albeit uncommonly so and that association derives its underpinnings from several different scenarios: (1) Medically refractory lesional epilepsy, in which seizures arise from the vicinity of the calcified neurocysticercus lesion (CNL), (2) Medically refractory epilepsy with dual pathology type of relationship between the hippocampal sclerosis (HS) and CNL in which both have been unequivocally demonstrated to give rise to independent seizures and (3) Mesial temporal lobe epilepsy due to HS with a distantly-located CNL, which is in itself not epileptogenic. A major point of controversy revolves around whether or not there exists a causal association between the CNL and HS. We believe that an association exists between NCC and HS and the most important factor influencing this association is the location of the CNL. Furthermore, NCC is a risk factor for medically-refractory epilepsy and that this might account for a considerable proportion of the intractable epilepsy population in endemic regions; the association has been largely ignored owing to the lack of availability of presurgical work-up facilities in these regions. Finally, from a clinical standpoint of presurgical evaluation, patients with CNL and HS should be evaluated on a case by case basis owing to disparate settings underlying the association. PMID- 24791091 TI - Functional neuro-imaging as a pre-surgical tool in epilepsy. AB - Functional neuro-imaging techniques are helpful in the pre-surgical evaluation of epilepsy for localization of the epileptogenic zone as ancillary tools to electroencephalography (EEG) and magnetic resonance imaging (MRI) or when other localization techniques are normal, non-concordant or discordant. Positron emission tomography (PET) and ictal single photon emission computed tomography (ictal SPECT) imaging are traditional tests that have been reported to have good sensitivity and specificity although the results are better with more expertise as is true for any technique. More recently magnetoencephalogram/magnetic source imaging (MEG/MSI), diffusion tensor imaging and functional magnetic resonance imaging (fMRI) have been used in localization and functional mapping during the pre-surgical work-up of epilepsy. Newer techniques such as fMRI-EEG, functional connectivity magnetic resonance imaging and near infra-red spectroscopy, magnetic resonance spectroscopy and magneto nanoparticles hold promise for further development that could then be applied in the work-up of epilepsy surgery. In this manuscript, we review these techniques and their current position in the pre surgical evaluation of epilepsy. PMID- 24791093 TI - Surgery for childhood epilepsy. AB - Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In about 15% of these patients, the seizures are not adequately controlled with antiepileptic drugs; such patients are potential candidates for surgical treatment and the major proportion is in the pediatric group (18 years old or less). Epilepsy surgery in children who have been carefully chosen can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-thirds of children with intractable seizures. Advances in structural and functional neuroimaging, neurosurgery, and neuroanaesthesia have improved the outcomes of surgery for children with intractable epilepsy. Early surgery improves the quality of life and cognitive and developmental outcome and allows the child to lead a normal life. Surgically remediable epilepsies should be identified early and include temporal lobe epilepsy with hippocampal sclerosis, lesional temporal and extratemporal epilepsy, hemispherical epilepsy, and gelastic epilepsy with hypothalamic hamartoma. These syndromes have both acquired and congenital etiologies and can be treated by resective or disconnective surgery. Palliative procedures are performed in children with diffuse and multifocal epilepsies who are not candidates for resective surgery. The palliative procedures include corpus callosotomy and vagal nerve stimulation while deep brain stimulation in epilepsy is still under evaluation. For children with "surgically remediable epilepsy," surgery should be offered as a procedure of choice rather than as a treatment of last resort. PMID- 24791094 TI - Evaluation of magnetic resonance imaging-negative drug-resistant epilepsy. AB - A structural brain lesion in patients with drug-resistant epilepsy (DRE) greatly increases the likelihood of identification of the seizure focus and ultimately seizure-free outcome following resective epilepsy surgery. In contrast, surgical outcomes of true non-lesional DRE are less favorable. Therefore, discovery of an underlying lesion is paramount in the pre-surgical work-up of patients with DRE. Over the years, the surgical treatment of pharmacoresistant epilepsy has evolved from straightforward lesional cases to include cases with hippocampal sclerosis. With the advent of magnetic resonance imaging (MRI), most cases of mesial temporal sclerosis became more easily identifiable on pre-operative neuroimaging. With the widespread use of high-resolution MRI with epilepsy protocols over the last two decades, our ability to visualize subtle structural changes has been greatly enhanced. However, there are some cases of lesional epilepsy, which remain unidentified on these routine MRIs. In such "non-lesional" refractory epilepsies, further investigation with advanced neuroimaging techniques, including metabolic imaging, as well as electrophysiological studies may help to identify the previously non-visualized focal brain abnormalities. In this review, we outline the current status for evaluation of MRI-negative DRE. PMID- 24791095 TI - Invasive electroencephalography monitoring: Indications and presurgical planning. AB - Electroencephalography (EEG) remains a "gold standard" for defining seizures; hence identification of epileptogenic zone for surgical treatment of epilepsy requires precise electrographic localization of the seizures. Routine scalp EEG recording is not sufficient in many instances, such as extratemporal lobe epilepsy or non-lesional temporal lobe epilepsy. In these individuals EEG recording from proximity of the seizure focus is necessary, which can be achieved by placing electrodes on the surface or in the substance of the brain. As this process requires invasive procedures (usually necessitating surgical intervention) EEG obtained via these electrodes is defined as invasive electroencephalography (iEEG). As only limited areas of the brain can be covered by these electrodes in an individual, precise targeting of the presumed seizure onset location is crucial. The presurgical planning includes where to place electrodes, which type of the electrodes to choose and planned duration of the intracranial recording. Though there are general principles that guide such endeavor, each center does it slightly differently depending upon the various technologies available to them and expertise and preferences of the epilepsy surgery team. Here we describe our approach to iEEG recording. We briefly describe the background, types of iEEG recording and rationale for each, various electrode types, and scenarios where iEEG might be useful. We also describe planning of iEEG recording once the need has been established as well as our decision making process of deciding about location of electrode placement, type of electrodes to use, length of recording, choice of arrays, mapping of eloquent cortex and finally surgical planning and decisions. PMID- 24791096 TI - Brain stimulation for intractable epilepsy: Anterior thalamus and responsive stimulation. AB - Despite medications, resective surgery, and vagal nerve stimulation, some patients with epilepsy continue to have seizures. In these patients, other approaches are urgently needed. The biological basis of stimulation of anterior thalamic nucleus and epileptogenic focus is presented. Results from two large randomized controlled trials Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE) and Neuropace pivotal trial are discussed. Neuromodulation provides effective treatment for a select group of refractory epilepsy patients. Future investigations into the mechanism underlying 'response' to brain stimulation are desired. PMID- 24791098 TI - Teaching does not equal learning: the need for more effective education. PMID- 24791097 TI - High frequency oscillations and infraslow activity in epilepsy. AB - In pre-surgical evaluation of epilepsy, there has been an increased interest in the study of electroencephalogram (EEG) activity outside the 1-70 Hz band of conventional frequency activity (CFA). Research over the last couple of decades has shown that EEG activity in the 70-600 Hz range, termed high frequency oscillations (HFOs), can be recorded intracranially from all brain regions both interictally and at seizure onset. In patients with epilepsy, HFOs are now considered as pathologic regardless of their frequency band although it may be difficult to distinguish them from the physiologic HFOs, which occur in a similar frequency range. Interictal HFOs are likely to be confined mostly to the seizure onset zone, thus providing a new measure for localizing it. More importantly, several studies have linked HFOs to underlying epileptogenicity, suggesting that HFOs can serve as potential biomarkers for the illness. Along with HFOs, analysis of ictal baseline shifts (IBS; or direct current shifts) and infraslow activity (ISA) (ISA: <0.1 Hz) has also attracted attention. Studies have shown that: IBSs can be recorded using the routine AC amplifiers with long time constants; IBSs occur at the time of conventional EEG onset, but in a restricted spatial distribution compared with conventional frequencies; and inclusion of IBS contacts in the resection can be associated with favorable seizure outcome. Only a handful of studies have evaluated all the EEG frequencies together in the same patient group. The latter studies suggest that the seizure onset is best localized by the ictal HFOs, the IBSs tend to provide a broader localization and the conventional frequencies could be non-localizing. However, small number of patients included in these studies precludes definitive conclusions regarding post-operative seizure outcome based on selective or combined resection of HFO, IBS and CFA contacts. Large, preferably prospective, studies are needed to further evaluate the implications of different EEG frequencies in epilepsy. PMID- 24791099 TI - Structured curricula and curriculum development in ophthalmology residency. AB - There has been a shift in graduate medical education (GME) from the traditional "apprenticeship" model to a more curriculum-based and competency driven model. Reflecting a global trend towards residency education reform, the International Council of Ophthalmology (ICO) introduced a resident and specialist curriculum and several live educational programs to promote standardization and more effective GME and continuing professional training. Implementation of these educational innovations will require efforts by local educator champions; modification and customization of teaching and assessing tools to the local learning environment; alignment of the implementation blueprint with available resources; and creation of accountability and sustainability mechanisms to insure long-term viability of the educational reforms. An ultimate goal of the ICO curriculum is to allow real world testing and modification so that the ideas generated in one part of the world might be applicable and generalizable in other areas. We aim to describe the Accreditation Council of Graduate Medical Education (ACGME) competencies in the United States (US) and ICO curriculum, as well as to provide a step-by-step plan for implementation of an ophthalmology residency curriculum. PMID- 24791100 TI - Assessment principles and tools. AB - The goal of ophthalmology residency training is to produce competent ophthalmologists. Competence can only be determined by appropriately assessing resident performance. There are accepted guiding principles that should be applied to competence assessment methods. These principles are enumerated herein and ophthalmology-specific assessment tools that are available are described. PMID- 24791101 TI - Adult learning principles and presentation pearls. AB - Although lectures are one of the most common methods of knowledge transfer in medicine, their effectiveness has been questioned. Passive formats, lack of relevance and disconnection from the student's needs are some of the arguments supporting this apparent lack of efficacy. However, many authors have suggested that applying adult learning principles (i.e., relevance, congruence with student's needs, interactivity, connection to student's previous knowledge and experience) to this method increases learning by lectures and the effectiveness of lectures. This paper presents recommendations for applying adult learning principles during planning, creation and development of lectures to make them more effective. PMID- 24791102 TI - Webinar software: a tool for developing more effective lectures (online or in person). AB - PURPOSE: To describe the use of online seminars (webinars) to improve learning experience for medical residents and fostering critical thinking. MATERIALS AND METHODS: Sixty-one online seminars (webinars) for residents were developed from April 2012 to February 2013. Residents attended the lectures in the same room as the presenter or from distant locations. Residents interacted with the presenter using their personal computers, tablets, or smartphones. They were able to ask questions and answer the instructor's multiple choice or open-ended questions. The lecture dynamics consisted of: (1) The presentation of a clinical case by an expert on the clinical topic; (2) the instructor asked open-ended and multiple choice questions about the problem-resolution process; (3) participants responded questions individually; (4) participants received feedback on their answers; (5) a brief conference was given on the learning objectives and the content, also fostering interactive participation; (6) lectures were complemented with work documents. RESULTS: This method allowed for exploration of learning of scientific knowledge and the acquisition of other medical competences (such as patient care, interpersonal and communication skills, and professionalism). The question-and answer activity and immediate feedback gave attendees the chance to participate actively in the conference, reflect on the topic, correct conceptual errors, and exercise critical thinking. All these factors are necessary for learning. CONCLUSIONS: This modality, which facilitates interaction, active participation, and immediate feedback, could allow learners to acquire knowledge more effectively. PMID- 24791103 TI - Training the eye care team: principles and practice. AB - One of the crucial factors to make high quality eye care services available, accessible and affordable to all is the availability of appropriately trained human resources. Providing health through a health care team is a better and cost effective alternative. The concept of the team approach is based on the principles of working together; task shifting; and ensuring continuity of care. Composition of a team varies based on the community needs, population characteristics and disease burden. But for it to be effective, a team must possess four attributes - availability, competency, productivity, and responsiveness. Therefore, training of all team members and training the team to work together as a unit are crucial components in the success of this concept. Some of the critical attributes include: Training across the health spectrum through quality and responsive curricula administered by motivated teachers; accreditation of programs or institutions by national or international bodies; certification and recertification of team members; and training in working together as a team through inter- and intra- disciplinary workshops both during training and as a part of the job activity. PMID- 24791104 TI - Continuing professional development: best practices. AB - Continuing professional development (CPD) involves not only educational activities to enhance medical competence in medical knowledge and skills, but also in management, team building, professionalism, interpersonal communication, technology, teaching, and accountability. This paper aims at reviewing best practices to promote effective CPD. Principles and guidelines, as already defined by some professional societies and world organizations, are emphasized as core actions to best enhance an effective lifelong learning after residency. The personal learning plan (PLP) is discussed as the core of a well-structured CPD and we describe how it should be created. Fundamental CPD principles and how they are integrated in the framework of every physician's professional life will be described. The value of systematic and comprehensive CPD documentation and assessment is emphasized. Accreditation requirements and professional relationships with commercial sponsors are discussed. PMID- 24791105 TI - Resources for eye care at secondary and tertiary level government institutions in Saudi Arabia. AB - PURPOSE: To evaluate the number of healthcare personnel and equipment resources for eye care at government institutions in different administrative zones of the Kingdom of Saudi Arabia (KSA) and to recommend measures for increasing resources to address deficiencies. MATERIALS AND METHODS: Data on resources (personnel and equipment) for eye care were collected from all governmental eye units in 2012. The data was regrouped by zones and administrative areas. The mid-2012 population projections were used to calculate the ophthalmologist to population ratio and optometrist to population ratio. The equipment available for eye care was reviewed. RESULTS: All 60 institutions in 13 administrative areas and five zones of KSA participated in this study. There were 407 ophthalmologists and 147 optometrists. The ophthalmologist to population ratio was 1:43,000 (1:12,900 in the northern zone to 1:80,300 in the western zone). By 2015, 700 ophthalmologists will be required, and by 2020, 1,100 ophthalmologists will be required. The optometrist to population ratio was 1:95,000 (1:34,100 in the northern zone to 1:146,700 in the western zone). Nearly 2,800 and 4,400 allied eye care personnel will be needed by 2015 and 2020. Diagnostic and treatment equipment such as lasers, electrophysiologic and ultrasound equipment, and fundus cameras were not available at all institutions. CONCLUSIONS: Data from the private sector need to be included to draw conclusions on the human resource index for eye care in the Kingdom. An unequal distribution of resources in different zones and administrative areas requires attention. Better utilization of available resources is recommended before fulfilling the demand for additional resources. PMID- 24791106 TI - The Sokoto blind beggars: causes of blindness and barriers to rehabilitation services. AB - PURPOSE: To determine the causes of blindness and the barriers to accessing rehabilitation services (RS) among blind street beggars (bsb) in Sokoto, Nigeria. MATERIALS AND METHODS: A cross-sectional survey of 202 bsb (VA < 3/60) using interviewer administered questionnaire. The causes of blindness were diagnosed by clinical ophthalmic examination. RESULTS: There were 107 (53%) males and 95 (47%) females with a mean age of 49 years (SD 12.2). Most bsb 191 (94.6%) had non formal education. Of 190 (94.1%) irreversibly bsb, 180/190 (94.7%) had no light perception (NPL) bilaterally. The major causes of blindness were non-trachomatous corneal opacity (60.8%) and trachoma corneal opacity (12.8%). There were 166 (82%) blind from avoidable causes and 190 (94.1%) were irreversibly blind with 76.1% due to avoidable causes. The available sub-standard RS were educational, vocational and financial support. The barriers to RS in the past included non availability 151 (87.8%), inability to afford 2 (1.2%), unfelt need 4 (2.3%), family refusal 1 (0.6), ignorance 6 (3.5%) and being not linked 8 (4.7%). The barriers to RS during the study period included inability of 72 subjects (35.6%) to access RS and 59 (81.9%) were due to lack of linkage to the existing services. CONCLUSION: Corneal opacification was the major cause of blindness among bsb. The main challenges to RS include the inadequate services available, societal and users factors. Renewed efforts are warranted toward the prevention of avoidable causes of blindness especially corneal opacities. The quality of life of the blind street beggar should be improved through available, accessible and affordable well-maintained and sustained rehabilitation services. PMID- 24791107 TI - Blindness and cataract surgical services in Atsinanana region, Madagascar. AB - PURPOSE: To assess the prevalence and causes of avoidable blindness in Atsinanana Region, Madagascar, with the Rapid Assessment of Avoidable Blindness (RAAB) survey. We analyzed the hospital records to supplement the findings for public health care planning. MATERIALS AND METHODS: Only villages within a two-hour walk from a road, about half of the population of Atsinanana was included. Seventy-two villages were selected by population-proportional-to-size sampling. In each village, compact segment sampling was used to select 50 people over age 50 for eye examination using standard RAAB methods. Records at the two hospitals providing cataract surgery in the region were analyzed for information on patients who underwent cataract surgery in 2010. Cataract incidence rate and target cataract surgery rate (CSR) was modeled from age-specific prevalence of cataract. RESULTS: The participation rate was 87% and the sample prevalence of blindness was 1.96%. Cataract was responsible for 64% and 85.7% of blindness and severe visual impairment, respectively. Visual impairment was due to cataract (69.4%) and refractive error (14.1%). There was a strong positive correlation between cataract surgical rate by district and the proportion of people living within 2 hours of a road. There were marked differences in the profiles of the cataract patients at the two facilities. The estimated incidence of cataract at the 6/18 level was 2.4 eyes per 100 people over age 50 per year. CONCLUSIONS: Although the survey included only people with reasonable access, the main cause of visual impairment was still cataract. The incidence of cataract is such that it ought to be possible to eliminate it as a cause of visual impairment, but changes in service delivery at hospitals and strategies to improve access will be necessary for this change. PMID- 24791108 TI - Change-readiness of the blind: a hospital based study in a coastal town of South India. AB - PURPOSE: Blindness is a devastating condition with psychosocial and economic effects. The shortcomings result in a burden to the blind person, the family and society. Rehabilitation of the blind can transform their lives. The aim of this study was to assess the "change-readiness" of the blind to undergo a "change management". MATERIALS AND METHODS: The study was a semi-structured pre-tested questionnaire-based study of 50 blind subjects in a medical college hospital. The blind participants were assessed for depression using the Beck Depression Inventory II, for the perceived effect of blindness on family, social life and occupation. The participants were counseled to undergo psychiatric management, vocational training, use blind aids and learn Braille. The willingness of the participants with reasons was assessed using a verbal analogue scale. Pearson Chi square test, ANOVA and the t-test were used for statistical analysis. RESULTS: Over two-thirds of the subjects were depressed. Family life, social life and occupation were perceived to be affected by 44%, 66% and 74%, respectively. Change-readiness scores were low for low vision and blind aids, vocational training, psychiatric management, change of job and learning Braille. The low score was due to the associated taboo, dependence, lack of skills, embarrassment, etc., The most valuable feature was the family cohesiveness. CONCLUSION: The results suggest that there is a need to modify health policy to include blind rehabilitation, to improve visibility of blind rehabilitation centers, to include family members and co-professionals while managing the blind so that we treat the "blind person" and not a "pair of blind eyes". PMID- 24791109 TI - Awareness of and Attitude towards glaucoma among an adult rural population of Osun State, Southwest Nigeria. AB - PURPOSE: To obtain baseline data and assess the level of awareness and attitudes towards glaucoma among rural communities of Osun State, Nigeria. MATERIALS AND METHODS: This was a community-based study that involved interviews and descriptive cross-sectional analysis. Serial-recruitment was performed of consenting participants who presented at a community-based screening service in March 2011. Socio-demographic data and information about glaucoma were obtained through face-to-face semi-structured questionnaires. RESULTS: The study population comprised 259 respondents (mean age 49.73 +/- 16.6 years; range 18 to 90 years). There were 159 females (61.4%). Skilled workers were the most common 130/259 (50.3%) participants. Only 41 (15.8%; 95% CI: 11.4-20.2) participants had ever heard of glaucoma. Sources of information were from visits to an eye clinic for 21/41 (51.2%; 95% CI: 35.9-66.5) participants and 15/41 (36.6%) participants who know someone with glaucoma. Reponses to the causes of glaucoma included 20/41 (48.8%; 33.5-64.1) participant who said 'I don't know' and 24.4% of participants who responded 'curse-from-God'. Responses to questions on treatment included 20/41 (48.8%) participants who responded 'I don't know how it can be treated' and 10/41 (36.6%) said 'medically'. Thirty 30/41 (73.2%) participants would refuse surgery, half of them because 'it cannot cure or reverse the disease' while (26.7%) would refuse out of 'fear'. Only 8/41 (19.5%; 95% CI: 7.4-31.6) would accept surgery for maintenance. Statistically significant predictors of glaucoma awareness were older participants, males and skilled workers (teachers) (P = 0.028, P = 0.018, P = 0.0001, respectively). CONCLUSIONS: The outcomes of study indicate a low level of awareness of glaucoma. Health education at all levels of health and eye care services is required to prevent ocular morbidity and irreversible blindness from glaucoma. PMID- 24791110 TI - A 3-year review of cranial nerve palsies from the University of Port Harcourt Teaching Hospital Eye Clinic, Nigeria. AB - PURPOSE: To provide the types, frequency and clinical information on common cranial nerve palsies seen at the Eye Clinic at the University of Port Harcourt Teaching Hospital. MATERIALS AND METHODS: A chart review was performed of patients who presented with cranial nerve palsy at the Eye Clinic over a 3-year period (January 2009-December 2011). Data were collected on age, sex, type of cranial nerve palsy, a history of systemic disease such as diabetes mellitus (DM), hypertension and cerebrovascular disease. Exclusion criteria included medical charts with incomplete data. Data was analyzed using Epi-info Version 6.04D. Statistical significance was indicated by P < 0.05. RESULTS: Twenty-four patients had cranial nerve palsies. There were 11 males and 13 females with a mean age of 34.50 +/- 18.41 years. Four patients (26.6%) had exotropia while three patients (20%) had esotropia. Complete ophthalmoplegia was noted in two patients (13.3%). The 3(rd) and 6(th) cranial nerves were affected in seven patients each (29.2%) and five patients (20.8%) had 7(th) cranial nerve palsy. Approximately 38% of patients with cranial nerve palsies had systemic disorders (16.7% systemic hypertension; 12.5% DM). The relationship between cranial nerve palsy and systemic disorder was statistically significant (P < 0.01). CONCLUSION: This is the first study in the literature on ocular cranial nerve palsies in Southern Nigeria. Third and sixth cranial nerve palsies were the most common cases to present to the University of Port Harcourt Teaching Hospital Eye Clinic. There was a statistically significant association to systemic disorders such as hypertension and DM and majority of cases with 6(th) cranial nerve palsy. PMID- 24791111 TI - The prevalence of astigmatism and its determinants in a rural population of Iran: the "Nooravaran Salamat" mobile eye clinic experience. AB - PURPOSE: The prevalence of astigmatism, and the astigmatic axis, and their determinants were evaluated in a rural population of Iran. MATERIALS AND METHODS: In a cross-sectional study conducted from May to August 2011, 13 villages in the vicinity of the city of Khaf in northeast Iran were investigated in this study. All the examinations including visual acuity, refraction, slit-lamp biomicroscopy and fundoscopy were performed in a Mobile Eye Clinic. Written informed consent was obtained from all participants. Only phakic eye that could be reliably refracted without a previous history of ocular surgery were included. RESULTS: Out of 2635 participants who were screened, 2124 were analysed for this study of whom 52% were female. The prevalence of astigmatism was 32.2% (95% confidence intervals (CI): 30.2-34.2). Astigmatism significantly increased from 14.3% in the under 15-year-old age group to 67.2% in the age group of over 65-years old (P < 0.001). The prevalence of With-The-Rule (WTR), Against-The-Rule (ATR), and oblique astigmatism was 11.7%, 18.1%, and 2.4 %, respectively. ATR significantly increased with age (P < 0.001). The mean corneal astigmatism was 0.73 D which linearly increased with age (P < 0.001). CONCLUSION: Attention must be paid to astigmatism in rural areas due to the high prevalence. Further studies are suggested to discover the role of the environmental and genetic factors. It seems that environmental and occupational factors in the villages cause a significant increase in the prevalence of astigmatism with age. A high percentage of participants had ATR astigmatism, which was more common at older ages. PMID- 24791112 TI - Development of a web-based glaucoma registry at King Khaled Eye Specialist Hospital, Saudi Arabia: a cost-effective methodology. AB - In this brief communication, we present the steps used to establish a web-based congenital glaucoma registry at our institution. The contents of a case report form (CRF) were developed by a group of glaucoma subspecialists. Information Technology (IT) specialists used Lime Survey softwareTM to create an electronic CRF. A MY Structured Query Language (MySQL) server was used as a database with a virtual machine operating system. Two ophthalmologists and 2 IT specialists worked for 7 hours, and a biostatistician and a data registrar worked for 24 hours each to establish the electronic CRF. Using the CRF which was transferred to the Lime survey tool, and the MYSQL server application, data could be directly stored in spreadsheet programs that included Microsoft Excel, SPSS, and R Language and queried in real-time. In a pilot test, clinical data from 80 patients with congenital glaucoma were entered into the registry and successful descriptive analysis and data entry validation was performed. A web-based disease registry was established in a short period of time in a cost-efficient manner using available resources and a team-based approach. PMID- 24791113 TI - Detailed ophthalmologic evaluation of posterior microphthalmos. AB - We performed various ophthalmic investigations in order to confirm the diagnosis and document the various features of posterior microphthalmos in a 21-year-old male. Ophthalmic examination revealed low vision with high hyperopia, papillomacular folds, midperipheral pigmentary changes and crowded optic discs. The optic discs were small and crowded with increased nerve fiber layer thickness. Fundus fluorescein angiography showed reduced diameter of a capillary free zone. Anterior segment (AS) optical coherence tomography demonstrated near normal anterior chamber depths, but markedly diminished anterior chamber angles. In spite of the increased corneal thickness and steep corneas, lens thickness and endothelial cell counts were normal. Sclerochoroidal thickening and foreshortening of the globes were detected with B-scan ultrasonography. Electroretinographic findings and visual field tests were similar to those in pigmentary retinopathy. Posterior microphthalmos is a complex eye disorder, which affects predominantly the posterior segment but also involves the AS of the eye. PMID- 24791114 TI - Management of paradoxical response in pediatric tubercular meningitis with methylprednisolone. AB - Paradoxical response to anti-tubercular drugs remains a diagnostic dilemma. In India where tuberculosis is quite prevalent, paradoxical response to anti tubercular treatment (ATT) is either misdiagnosed or under-diagnosed. We report two cases of optochiasmatic arachnoiditis due to paradoxical response in children suffering from tuberculous meningitis. Visual acuity was recorded as no light perception in all eyes of both patients while they were taking 4-drug ATT (isoniazid, rifampicin, pyrazinamide and ethambutol). However their systemic conditions did not worsen. They were treated with intravenous methylprednisolone for five days followed by systemic corticosteroids on a tapering dose for four weeks along with ATT. This case report highlights the importance of early recognition of this sight-threatening complication and timely, effective treatment to prevent permanent blindness. PMID- 24791115 TI - Autologous serum for anterior tissue necrosis after porous orbital implant. AB - Orbital implants are now routinely used after enucleation and evisceration. However exposure of the implant can lead to infection and extrusion. Hence, early repair of larger exposure with graft material is required. We describe three cases where early postoperative mucosal dehiscence was successfully managed with autologous serum. PMID- 24791116 TI - Rethinking airbag safety: airbag injury causing bilateral blindness. AB - A healthy 40-year-old man, restrained in the front passenger seat, suffered visually disabling blunt ocular trauma following spontaneous release of the passenger side air-bag module, during vehicular deceleration, without an automobile crash. Though the driver-side airbag was also released, the driver was unharmed. The passenger suffered bilateral hyphema, bilateral vitreous hemorrhage and suspected posterior scleral rupture in the left eye and also had an eyebrow laceration, from impact with the dashboard panel covering the air-bag module, which was detached by the force of airbag deployment. This is the first reported case from West Africa and the first case in which part of the airbag module detached to cause additional trauma. This report adds to the growing burden of evidence world-wide, for a review of the safety aspects of the automobile airbag. This case clearly illustrates that although airbags reduce mortality, they carry a high risk of ocular morbidity, even with seat belt restraint. PMID- 24791117 TI - Ankyloblepharon filiforme adnatum: report of two cases. AB - Ankyloblepharon filiforme adnatum (AFA) is a rare congenital anomaly characterized by partial or complete adhesion of upper and lower eyelids, usually seen as an isolated finding but often associated with other anomalies or a well defined syndrome. We report two cases of AFA who presented at a tertiary eye care center of West Bengal. Family history of consanguinity was absent. One baby had abnormal tuft of hair over the small of the back. No other congenital abnormalities were detected in any of them. The adhesions of the eyelids were divided by a number 15 blade after crushing with mosquito forceps in both cases without any anesthesia. Subsequent ocular examinations following separation and during follow-up revealed normal eyelid function, ocular motility, and fundus. In a case of AFA, timely separation of the eyelids is crucial to avoid the development of occlusion amblyopia. Cases of AFA reported in the literature are reviewed. PMID- 24791118 TI - Collaboration in research and the influential factors in Golestan University of Medical Sciences research projects (2005-2007): an academic sample from Iran. AB - BACKGROUND: Number of Iranian articles published in ISI journals has increased significantly in recent years.Despite the quantitative progress, studies performed in Iran represent low collaboration in research; therefore,we decided to evaluate collaboration in Golestan University of Medical Sciences (GOUMS) research projects. METHODS: In this cross-sectional study, all GOUMS research projects that had got grants from the universitybetween 2005-2007 were studied. Among 107 research projects included in our study, 102 projects were evaluatedand checklists were completed. The researcher's questionnaire was sent to the principle investigators (n=46) of the projects and eventually 40 questionnaires were collected. RESULTS: The review of 102 research proposals shows that 10 projects (9.8%) have been performed in collaborationwith other organizations. Scientific outputs in these projects have been more than projects which wereconfined to the university (98% compare to 68%; p= 0.04). The total cost of the projects under study was a littlemore than 300,000 US$. In just 12 projects (11.8%) a part of the cost had been provided by organizations outsidethe university. About 50% of researchers declared that they had chosen their research topic based on their"personal interest". Only 1 project was performed by the demand of nongovernmental organizations and 12 researchersreported no collaboration in their activities. CONCLUSION: This study shows that collaboration in GOUMS research projects is low. Moreover, collaborationswith governmental and nongovernmental organizations are trivial. The scientific outputs in collaborativeresearch projects are much more than other projects. PMID- 24791119 TI - Comparison of pre-operative bilirubin level in simple appendicitis and perforated appendicitis. AB - BACKGROUND: Delay in diagnosis and treatment of perforated appendicitis may cause life-threatening complications.The aim of this study was to determine and compare pre-operative total and direct bilirubin levels incases of simple and perforated acute appendicitis in order to improve the clinical decision making. METHODS: This prospective observational study included eighty patients who underwent open appendectomy,during a one-year period from March 2010 to March 2011 in the surgical department of Hazrat-e-Rasool AkramHospital, an academic teaching hospital in Tehran- Iran. Pre-operative total and direct levels of bilirubin werecompared in two groups of histologically proved appendicitis (simple and perforated), each including 40 patients. RESULTS: Eighty patients who underwent open appendectomy including 70% men and 30% women with a meanage of 34+/-11 years in Group I (perforated appendicitis) and 47.5% women and 52.5% men with a mean age of33+/-14 in Group II (simple appendicitis) were included in this study. The mean bilirubin levels were higher forpatients with perforated acute appendicitis compared to those with a non-perforated simple appendicitis(1.04+/-05 mg/dl vs 0.7+/-0.1 mg/dl) and this difference is highly significant (p<0.01). CONCLUSION: Assessment of preoperative total bilirubin is useful for the differential diagnosis of perforatedversus acute simple appendicitis and total bilirubin should be used as an independent parameter in the early diagnosisof appendix perforation. PMID- 24791120 TI - Safety and feasibility of intravenous thrombolytic therapy in Iranian patients with acute ischemic stroke. AB - BACKGROUND: Thrombolytic therapy is the only approved treatment for acute cerebral ischemia. The hemorrhagictransformation is the greatest complication of this treatment, which may occur after recanalization of occludedartery. The aim of this study was to determine factors associated with clinical improvement and worseningin patients with acute ischemic stroke treated with intravenous thrombolysis. METHODS: Thirty seven patients who were treated with intravenous thrombolysis between August 2010 andAugust 2012 who had the inclusion criteria were studied. In this prospective study, all of the admitted patients instroke unit, monitored for at least 48 hours. We registered all patients' information in a stroke data registry andfollowed them for at least 6 months. RESULTS: Thirty seven patients with acute ischemic stroke who treated with recombinant tissue plasminogenactivator (r-TPA) were studied. There were hemorrhagic transformations in 9 (24%) patients. Seven of them(18%) revealed intracerebral hemorrhages (ICH) within the control brain CT after 24 hours without any deteriorationof neurologic symptoms (asymptomatic ICH). Although outcomes of patients with symptomatic post r-TPA hemorrhages were worse than non-hemorrhagic post r-TPA patients, there were no significant differencesbetween asymptomatic post r-TPA hemorrhages and non hemorrhagic post r-TPA patients, according to theNational Institutes of Health Stroke Scale (NIHSS) at admission (p = 0.2), after 24 hours (p= 0.07) and after 7days (p= 0.06) post treatment. CONCLUSION: If the r-TPA protocol is followed carefully, the risk of symptomatic hemorrhage is low (about7%). Taking r-TPA was feasible and safe in our study population; thus, it can be applied for other Iranian patients. PMID- 24791121 TI - Development of visual-motor perception in pupils with expressive writing disorder and pupils without expressive writing disorder: a comparative statistical analysis. AB - BACKGROUND: Learning disability is one of the most noticed subjects for behavioral specialists. Most of thelearning difficulties are caused by senso motor development and neurological organization. The main purposeof the present research is to examine the role of delayed perceptual-motor development and brain damage inorigination of expressive writing disorder (EWD). METHODS: The studied sample is 89 pupils divided into two groups, one of which is pupils with expressivewriting disorder (n=43) and the other is pupils without expressive writing disorder (n=46), consisted of secondand third grade elementary school students. First of all, students with EWD are selected through dictation testand intelligence test, and then the two groups, students with and without EWD, would take the Bender Gestalttest. The average score of perceptual visual-motor development and brain damage of two groups is comparedusing T test for independent groups and chi2 test. RESULTS: Results show that there is a significant difference in perceptual visual-motor development betweenstudents with EWD and students without EWD (p<0.01). Based on the results, perceptual motor development ofstudents with EWD is lower than students without EWD. There is no significant difference in brain damagebetween those with EWD and healthy people, (p> 0.05). CONCLUSION: Based on our findings it could be concluded that those who are relatively more developed thantheir peers, in terms of visual-motor perception, are more successful in education, especially in expressive writing. PMID- 24791122 TI - Human Bocavirus in Iranian children with acute gastroenteritis. AB - BACKGROUND: Human Bocavirus (HBoV) infection is of worldwide distribution. There is increasing evidencethat HBoV is pathogenic for the human gastroenteric tract. However, less data are available on the role of HBoVin gastroenteritis. The present study was aimed to determine the prevalence of HBoV in children with gastroenteritis. METHODS: Real-time PCR TaqMan was used to screen 200 stool specimens that had been referred to the virologylaboratory for HBoV evaluation. All of samples were collected on viral transport media. RESULTS: Of the 200 stool samples analyzed, 16 (8%) were positive for HBoV. Human Bocavirus positive samplesfrom patients aged between 1 to 5 years with acute gastroenteritis infection suggest a minor role of HBoVin gastroenteritis (p=0.0001). CONCLUSION: The study showed a high prevalence of human Bocavirus in young children with acute gastroenteritisdiseases in Iran, suggesting that HBoV play a role in the pathogenesis of gastroenteritis. PMID- 24791123 TI - Prevalence of cigarette smoking among Iranian women: a systematic review and meta analysis. AB - BACKGROUND: Smoking has physical, psychological, and social impacts on women's health and subsequentlythe community's health. Therefore, it is important to have an estimation of smoking among Iranian women.Since comprehensive data are not available in this respect, the authors performed a systematic review and metaanalyzedall high-quality studies in this field. METHODS: All available electronic papers were searched by certain keywords and were included in this studyaccording to the inclusion criteria regardless of the publication year. Furthermore, non-electronic resources includingthe final report of research projects, dissertations, unpublished papers (grey literature) and books publishedby the Iranian ministry of health were also evaluated in the study. The materials were assessed for theirquality and meeting the inclusion and exclusion criteria. Considering the high degree of variability in many selectedstudies, we used random effect method for meta-analysis. RESULTS: The highest and lowest rates of cigarette smoking among women were 10.5% and 0.04%, respectively.The prevalence rates of smoking were different in various subgroups; ranging from 0 to 0.4% in students, 1.1to 3.1% in adults, and 1.4 to 8.7% in all subgroups. According to the meta-analyses performed for the subgroups,the mean age of participants, performing the study in urban or rural areas, and the year of paper publicationwere major sources of heterogeneity. CONCLUSION: The studies were highly different with regard to their findings, and it seems that there is an ageand time trend for the findings. Furthermore, the prevalence of smoking was different in various regions of thecountry. PMID- 24791124 TI - Effects of probiotic yogurt on performance, respiratory and digestive systems of young adult female endurance swimmers: a randomized controlled trial. AB - BACKGROUND: To determine the effects of probiotic yogurt on performance and health status of young adultfemale endurance swimmers. METHODS: In a randomized controlled trial, 46 endurance swimmers girls with mean age of 13.8 +/-1.8 years,weight of 48.6+/-7.5kg and height of 159+/-5.6cm, were studied. Subjects were randomly assigned into two groups,receiving either 400 ml probiotic yogurt (intervention group) or ordinary yogurt (control group) daily for 8weeks. At the beginning and at the end of the study, the 400-m free swimming record was done and the HarvardStep test was employed to measure VO2max. Statistical analysis of the data was performed using SPSS software.This trial has been registered with IRCT ID of IRCT2012122311849N1. RESULTS: Average changes in the records of the intervention and control groups were 3.9 and 0.5 seconds, respectively(p= 0.22). The intervention group complained of dyspnea for 2.4 days and the value for the controlwas 4.4 days (p=0.024). Values for ear pain were 0.5 and 1.6 days (p=0.008) respectively. The average numberof episodes of respiratory infection in the intervention group was 0.9 day, which was statistically fewer than thatin the control group (1.4 days), P=0.009. CONCLUSIONS: A reduction in the number of episodes of respiratory infections and duration of some symptomssuch as dyspnea and ear pain was observed. Due to the reduction in upper respiratory tract infections of theathletes following intake of probiotic yogurt, improvement in VO2max is possible. PMID- 24791125 TI - Validity and reliability of Persian translated version of Pediatric Lower Urinary Tract Scoring System Questionnaire for Iranian children. AB - BACKGROUND: Pediatric lower urinary tract scoring system (PLUTSS) is a questionnaire contains items for assessmentof wetting episodes, voiding frequency and pattern. It is used for screening and evaluation of the responseof children with lower urinary tract symptoms to therapy. We studied the validity and reliability of Persiantranslated version of this questionnaire among Iranian children. METHODS: One hundred and ninety-seven children aged 5-15 years with urinary tract infection, voiding dysfunction,enuresis were enrolled in this study. Thirty-three healthy age-matched children without urinary complaintwere considered as controls. PLUTSS questionnaire was filled out for all children. Sonography was performedto rule out urogenital abnormalities. Internal consistency, test-retest reliability, and validity of the questionnairewere assessed using Cronbach's alpha, intra-class correlation coefficient, and ANOVA test respectively.ROC curve was used to define cut-point and its validity in discrimination between groups. P-value < 0.05was considered significant. RESULTS: The means for PLUTSS items were 6.8 (+/-5.4) for voiding dysfunction, 14.4(+/-5) for enuresis,10.5(+/-7.8) for recurrent and 8.9(+/-6) for single urinary tract infection, and 1.9(+/-1.8) for controls (p<0.001).Cronbach's alpha for the 14 items of questionnaire was 0.74. The intraclass coefficient correlation for assessingtest-retest reliability was 0.82 (p<0.001). ROC curve showed cut point of 5 for differing case from controls withsensitivity of 97.0 and specificity of 74.9(p<0.001). CONCLUSIONS: Persian translated PLUTSS has a proper validity and reliability as an instrument for screeningchildren with urinary tract symptoms but some questions need to be changed in some way to be understandableby our culture. PMID- 24791126 TI - An extremely large primary omental hydatid cyst: report of a rare case. AB - Hydatid disease is a parasitic infection caused by Echinococcus granulosus (larval form) in humans with lesionsmost frequently encountered in the liver and lungs. It can rarely involve extra-hepatic organs. It is endemicin some regions of Iran. The omental hydatid cyst is a very rare manifestation of the disease. This report presentsthe interesting case of a very large omental hydatid cyst. PMID- 24791127 TI - Cartilage Hair Hypoplasia: First report from Iran. AB - Cartilage hair hypoplasia (CHH), is a rare cause of metaphyseal chondrodysplasia and short stature. Other featuresincluded hair abnormality, immunodeficiency, anemia, gastrointestinal disorders (Hirschsprung disease,celiac, ...) and increased risk of cancer. The disease is an autosomal recessive disorder and previously has notbeen reported in Iran. We report a 9-year-old boy diagnosed as cartilage hair hypoplasia, with severe short stature,metaphyseal chondrodysplasia, hair hypoplasia, Hirschsprung disease, hypothyroidism, vesicouretral refluxand renal stone. Renal stone and hypothyroidism have been reported in cartilage hair hypoplasia with lower frequencies.This is the first report of cartilage hair hypoplasia in Iran. PMID- 24791128 TI - Is Apnea-Hypopnea Index a proper measure for Obstructive Sleep Apnea severity? PMID- 24791129 TI - High contrast optical imaging methods for image guided laser ablation of dental caries lesions. AB - Laser based methods are well suited for automation and can be used to selectively remove dental caries to minimize the loss of healthy tissues and render the underlying enamel more resistant to acid dissolution. The purpose of this study was to determine which imaging methods are best suited for image-guided ablation of natural non-cavitated carious lesions on occlusal surfaces. Multiple caries imaging methods were compared including near-IR and visible reflectance and quantitative light fluorescence (QLF). In order for image-guided laser ablation to be feasible, chemical and physical modification of tooth surfaces due to laser irradiation cannot greatly reduce the contrast between sound and demineralized dental hard tissues. Sound and demineralized surfaces of 48 extracted human molar teeth with non-cavitated lesions were examined. Images were acquired before and after laser irradiation using visible and near-IR reflectance and QLF at several wavelengths. Polarization sensitive-optical coherence tomography was used to confirm that lesions were present. The highest contrast was attained at 1460-nm and 1500-1700-nm, wavelengths coincident with higher water absorption. The reflectance did not decrease significantly after laser irradiation for those wavelengths. PMID- 24791130 TI - Pulse width modulation-based temperature tracking for feedback control of a shape memory alloy actuator. AB - This work presents a temperature-feedback approach to control the radius of curvature of an arc-shaped shape memory alloy (SMA) wire. The nonlinear properties of the SMA such as phase transformation and its dependence on temperature and stress make SMA actuators difficult to control. Tracking a desired trajectory is more challenging than controlling just the position of the SMA actuator since the desired path is continuously changing. Consequently, tracking the desired strain directly or tracking the parameters such as temperature and electrical resistance that are related to strain with a model is a challenging task. Temperature-feedback is an attractive approach when direct measurement of strain is not practical. Pulse width modulation (PWM) is an effective method for SMA actuation and it can be used along with a compensator to control the temperature of the SMA. Using the constitutive model of the SMA, the desired temperature profile can be obtained for a given strain trajectory. A PWM based nonlinear PID controller with a feed-forward heat transfer model is proposed to use temperature-feedback for tracking a desired temperature trajectory. The proposed controller is used during the heating phase of the SMA actuator. The controller proves to be effective in tracking step-wise and continuous trajectories. PMID- 24791132 TI - Adolescent Precursors of Pathways from School to Work. AB - Longitudinal data from the Youth Development Study is used to examine: (1) how young people establish work with self-identified career potential and how these patterns are linked to educational attainments; and (2) how adolescent achievement orientations, experiences in school and work, and sociodemographic background distinguish youth who establish themselves in careers and those who flounder during this transition. Multilevel latent class models reveal four school-to-work pathways from ages 18 to 31: two groups that attain careers through postsecondary education (via Bachelor's or Associates-Vocational degrees) and two groups that do not (distinguished by attempting college). Multinomial logistic regression models demonstrate that academic orientations, socioeconomic background, and steady paid work during high school help adolescents avoid subsequent floundering during the school-to-work transition. PMID- 24791131 TI - A Systematic Review of Strategies for Implementing Empirically Supported Mental Health Interventions. AB - OBJECTIVE: This systematic review examines experimental studies that test the effectiveness of strategies intended to integrate empirically supported mental health interventions into routine care settings. Our goal was to characterize the state of the literature and to provide direction for future implementation studies. METHODS: A literature search was conducted using electronic databases and a manual search. RESULTS: Eleven studies were identified that tested implementation strategies with a randomized (n = 10) or controlled clinical trial design (n = 1). The wide range of clinical interventions, implementation strategies, and outcomes evaluated precluded meta-analysis. However, the majority of studies (n = 7; 64%) found a statistically significant effect in the hypothesized direction for at least one implementation or clinical outcome. CONCLUSIONS: There is a clear need for more rigorous research on the effectiveness of implementation strategies, and we provide several suggestions that could improve this research area. PMID- 24791133 TI - Generalized Dynamic Factor Models for Mixed-Measurement Time Series. AB - In this article, we propose generalized Bayesian dynamic factor models for jointly modeling mixed-measurement time series. The framework allows mixed-scale measurements associated with each time series, with different measurements having different distributions in the exponential family conditionally on time-varying latent factor(s). Efficient Bayesian computational algorithms are developed for posterior inference on both the latent factors and model parameters, based on a Metropolis Hastings algorithm with adaptive proposals. The algorithm relies on a Greedy Density Kernel Approximation (GDKA) and parameter expansion with latent factor normalization. We tested the framework and algorithms in simulated studies and applied them to the analysis of intertwined credit and recovery risk for Moody's rated firms from 1982-2008, illustrating the importance of jointly modeling mixed-measurement time series. The article has supplemental materials available online. PMID- 24791134 TI - Jezebel at the welfare office: How racialized stereotypes of poor women's reproductive decisions and relationships shape policy implementation. AB - Current welfare scholarship lacks an analysis of how caseworkers discuss sexuality-related issues with clients. Seventy-two of 232 transcribed welfare interviews in three states included discussion of reproductive decisions and relationships. Overall, caseworkers' language reflected negative myths regarding African American women's sexuality and motherhood. By virtue of their status as welfare recipients, regardless of their individual races, clients were placed into racialized myths through workers' talk. This analysis demonstrates that though not present in every welfare interview and often veiled in bureaucratic language, negative ideas about poor women's sexuality persist in welfare policy and are deeply embedded in its day-to-day implementation. PMID- 24791135 TI - Identification of genetic loci associated with primary angle-closure glaucoma in the basset hound. AB - PURPOSE: Primary angle-closure glaucoma (PACG) in dogs is usually caused by the gradual collapse of the iridocorneal angle and cleft, eventually leading to aqueous humor (AH) outflow obstruction. The condition occurs in several breeds of dogs and the prognosis for affected animals is typically poor. We have identified several basset hound (BH) pedigrees, as well as unrelated cases with characteristic PACG that in many aspects recapitulates PACG in human patients. The goal of this study was to utilize the BH PACG model to characterize the genetics of PACG, and potentially discover genetic factors contributing to PACG in humans and animals. METHODS: We conducted a genome-wide logistic regression test for association using 37 PACG cases and 41 unaffected controls. Population stratification and cryptic relatedness were assessed using a multidimensional scaling analysis. The expression of two candidate genes within the target tissues of the BH eye was assessed by immunohistochemistry. RESULTS: We report significant associations at two novel loci, specifically BICF2P31912 in COL1A2 on chromosome 14 with a per-allele odds ratio (OR, 95% confidence interval [CI]) of 3.35 (1.73-6.51), P(genome)=3.6*10-4; and BICF2P893476 residing in proximity to RAB22A on chromosome 24 with a per-allele OR (95% CI) of 3.93 (1.78-8.66), P(genome)=4.9*10-4. COL1A2 and RAB22A demonstrated widespread expression throughout the eye and were prominently noted in the ciliary body (CB), trabecular meshwork (TM), and iris. CONCLUSIONS: Our finding of two genetic associations supports the potential segregation of PACG risk-conferring variants in the BH. The genetic associations identified may contribute to mechanisms underlying the pathogenesis of PACG, which remain to be elucidated. PMID- 24791136 TI - Calcium-independent phospholipase A2, group VIA, is critical for RPE cell survival. AB - PURPOSE: To investigate the significance of calcium-independent phospholipase A2, group VIA (iPLA2-VIA), in RPE cell survival following responses to sodium iodate (SI) in cell cultures. METHODS: The human retinal pigment epithelium (RPE) cell line (ARPE-19) cells and primary mouse-RPE cultures were treated with SI to induce cell death. Cells were transfected with an iPLA2-VIA promoter-luciferase construct to evaluate the regulation of iPLA-VIA after exposure to SI. PCR analysis, western blot analysis, and activity assays were performed to evaluate the mRNA level, protein level, and activity levels of iPLA2-VIA after SI exposure. Inhibitors of iPLA2-VIA were used to explore a potential protective role in cells exposed to SI. Primary RPE cell cultures were grown from iPLA2-VIA knockout mice and wild-type mice. The cultures were exposed to SI to investigate a possible increased protection against SI in iPLA2-VIA knockout mice compared to wild-type mice. RESULTS: The study revealed upregulation of iPLA2-VIA expression (promoter activity, iPLA2-VIA mRNA, iPLA2-VIA protein, and iPLA2-VIA protein activity) in ARPE-19 cells exposed to SI. SI-induced cell death was shown to be inhibited by iPLA2-VIA-specific inhibitors in ARPE-19 cell cultures. RPE cultures from iPLA2-VIA knockout mice were less vulnerable to SI-induced cell death compared to RPE cultures from wild-type mice. CONCLUSIONS: SI -induced RPE cell death involves iPLA2-VIA upregulation and activation, and amelioration of SI induced RPE cell death can be facilitated by inhibitors of iPLA2-VIA. Thus, we suggest iPLA2-VIA as a possible pharmaceutical target to treat RPE-related retinal diseases. PMID- 24791138 TI - Molecular genetic diagnostic techniques in choroideremia. AB - PURPOSE: To optimize and streamline molecular genetics techniques in diagnosing choroideremia (CHM). METHODS: PCR primers were designed for exons 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 15 of the CHM gene. Each PCR protocol was optimized so that all exons could be amplified with the same component ratio and PCR conditions. Sense and antisense primers were tested for their ability to be used as sequencing primers. Fibroblast cells were cultured, and an immunoblot analysis was performed to detect the presence or absence of Rab escort protein 1 (REP-1) in a suspected CHM patient sample when no mutation was detected with sequencing. Multiplex ligation-dependent probe amplification (MLPA) of the CHM gene was performed and used to detect deletions and duplications in affected males and female carriers. RNA analysis using cDNA was used to detect the presence or absence of the CHM transcript and to search for splice defects. RESULTS: The newly designed PCR primers allow for more efficient PCR preparation and sequencing to detect point mutations in affected males and female carriers. Immunoblot successfully detects the absence of REP-1 in a CHM patient. MLPA identifies deletions and duplications spanning multiple exons in the CHM gene. RNA analysis aids in detecting splice variants. CONCLUSIONS: The development of new molecular biology techniques and ongoing optimization of existing methods allows for an improved integrated approach to confirm CHM diagnosis and carrier status in consideration of patient family history and available patient sample materials. CHM can be confirmed with an immunoblot assay. To detect the molecular cause of CHM, an examination of the genomic DNA or the mRNA must be performed. Presymptomatic carriers with no identifiable fundus signs can be identified only through molecular analysis of genomic DNA or through quantitative assays. PMID- 24791137 TI - Notch prevents transforming growth factor-beta-assisted epithelial-mesenchymal transition in cultured limbal progenitor cells through the induction of Smad7. AB - PURPOSE: Continuous culture of limbal epithelial stem cells (LSCs) slows down proliferation, which inevitably results in differentiation. Transforming growth factor-beta (TGFbeta)-assisted epithelial-mesenchymal transition (EMT) is often found in the late stage of LSC culture. Thus, EMT is proposed to be part of the mechanism responsible for the loss of LSCs in culture. To explore the regulation mechanism of EMT, we investigated the early stage culture for factor(s) that may potentially prevent EMT. METHODS: LSCs from the corneal limbus region of rabbits were isolated and expanded to confluence in culture (P0), and then serial passage of these LSCs (P1 to P3) was performed. EMT in LSCs was induced with TGFbeta1, and the corresponding EMT signaling was confirmed with Smad2/3 phosphorylation. The expression of mesenchymal markers, including alpha-smooth muscle actin (alpha SMA) and vimentin, was determined with western blot analysis. Proteins extracted from different passaged cells were also subjected to western blot analysis of TGFbeta signaling components, including TGFbeta1, TGFbeta receptor I/II, and Smad2/3 as well as Smad7, the main negative regulator of TGFbeta signaling. The mitogenic response was measured with the bromodeoxyuridine (BrdU) labeling index and real-time PCR using primers for Ki67. N-(N-[3,5-difluorophenacetyl]-l-alanyl) S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor, and Jagged-1 Notch ligand were used to block and activate Notch signaling, respectively, and their efficacy was evaluated by determining the expression of Hes1, a Notch signaling target. RESULTS: Mesenchymal marker induction and growth arrest were found in the TGFbeta1-treated P1 cells, and the changes were less significant in the TGFbeta1-treated P0 cells. Western blot analysis confirmed that the expressed levels of TGFbeta signaling components, including TGFbeta1, TGFbeta receptor I/II, and Smad2/3, were relatively stable with passages. In contrast, the expression of Hes1 and Smad7 markedly decreased after the first passage, and with each passage, the levels diminished even further. Hes1 and Smad7 were expressed only in the limbal epithelium and not in the corneal epithelium. DAPT effectively blocked the expression of Hes1. DAPT also dose-dependently suppressed Smad7 expression in P0 cells, which was associated with the susceptibility of P0 cells to TGFbeta1-induced Smad2/3 phosphorylation, EMT formation, and growth arrest. Reciprocally, Jagged-1 upregulated Smad7 expression in LSCs against TGFbeta signaling. CONCLUSIONS: These findings indicate that Smad7 plays a crucial role in antagonizing EMT induced by TGFbeta signaling and support our proposition that Smad7 is a Notch signaling target in LSCs, and may mediate the Notch function in preventing the occurrence of EMT. PMID- 24791139 TI - Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype-phenotype correlations. AB - PURPOSE: Retinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype-phenotype correlations. METHODS: The peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old. RESULTS: Thirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations. CONCLUSIONS: Our results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB. PMID- 24791140 TI - Detecting genetic variations in hereditary retinal dystrophies with next generation sequencing technology. AB - PURPOSE: To identify pathogenic mutations responsible for retinal dystrophies (RDs) in three unrelated Chinese families. METHODS: Three probands from unrelated families with RDs were recruited. Genomic DNA prepared from leukocytes was analyzed using gene chip-based next-generation sequencing (NGS) to capture and sequence all of the exons of 100 known RD-associated genes. Candidate variants were validated with PCR and Sanger sequencing in the respective families. Thorough ophthalmic examinations including best-corrected visual acuity, funduscopic examination, and full-field electroretinograms were performed in the affected individuals. RESULTS: We successfully identified causative mutations in patients from the Chinese families with RDS: the known mutation IMPDH1 c.942_944delGAA in a family with retinitis pigmentosa, the novel mutation ABCA4 c.1924T>A in a family with Stargardt disease, and the novel mutation NMNAT1 c.272A>G and known mutation NMNAT1 c.196C>T in a family with Leber congenital amaurosis. All variations segregated with the disease phenotypes in the respective families and were absent from ethnically matched control chromosomes. Prediction analysis demonstrated the two novel missense mutations might be damaging. CONCLUSIONS: The results strongly suggested these mutations were responsible for different RD phenotypes in the Chinese families. NGS technology provides an accurate and economic method for identifying causative genes for RDs. PMID- 24791141 TI - Retinal expression of the serine protease matriptase-2 (Tmprss6) and its role in retinal iron homeostasis. AB - PURPOSE: Matriptase-2 (also known as TMPRSS6) is a critical regulator of the iron regulatory hormone hepcidin in the liver; matriptase-2 cleaves membrane-bound hemojuvelin and consequently alters bone morphogenetic protein (BMP) signaling. Hemojuvelin and hepcidin are expressed in the retina and play a critical role in retinal iron homeostasis. However, no information on the expression and function of matriptase-2 in the retina is available. The purpose of the present study was to examine the retinal expression of matriptase-2 and its role in retinal iron homeostasis. METHODS: RT-PCR, quantitative PCR (qPCR), and immunofluorescence were used to analyze the expression of matriptase-2 and other iron-regulatory proteins in the mouse retina. Polarized localization of matriptase-2 in the RPE was evaluated using markers for the apical and basolateral membranes. Morphometric analysis of retinas from wild-type and matriptase-2 knockout (Tmprss6(msk/msk) ) mice was also performed. Retinal iron status in Tmprss6(msk/msk) mice was evaluated by comparing the expression levels of ferritin and transferrin receptor 1 between wild-type and knockout mice. BMP signaling was monitored by the phosphorylation status of Smads1/5/8 and expression levels of Id1 while interleukin-6 signaling was monitored by the phosphorylation status of STAT3. RESULTS: Matriptase-2 is expressed in the mouse retina with expression detectable in all retinal cell types. Expression of matriptase-2 is restricted to the apical membrane in the RPE where hemojuvelin, the substrate for matriptase-2, is also present. There is no marked difference in retinal morphology between wild-type mice and Tmprss6(msk/msk) mice, except minor differences in specific retinal layers. The knockout mouse retina is iron deficient, demonstrable by downregulation of the iron-storage protein ferritin and upregulation of transferrin receptor 1 involved in iron uptake. Hepcidin is upregulated in Tmprss6(msk/msk) mouse retinas, particularly in the neural retina. BMP signaling is downregulated while interleukin-6 signaling is upregulated in Tmprss6(msk/msk) mouse retinas, suggesting that the upregulaton of hepcidin in knockout mouse retinas occurs through interleukin-6 signaling and not through BMP signaling. CONCLUSIONS: The iron-regulatory serine protease matriptase-2 is expressed in the retina, and absence of this enzyme leads to iron deficiency and increased expression of hemojuvelin and hepcidin in the retina. The upregulation of hepcidin expression in Tmprss6(msk/msk) mouse retinas does not occur via BMP signaling but likely via the proinflammatory cytokine interleukin-6. We conclude that matriptase-2 is a critical participant in retinal iron homeostasis. PMID- 24791142 TI - Multimodal analysis of the progression of Best vitelliform macular dystrophy. AB - PURPOSE: To investigate the multimodal morphological features in the different stages of Best vitelliform macular dystrophy (VMD) in subjects harboring mutations in the BEST1 gene, and their changes during the progression of the disease. METHODS: In this retrospective observational study performed between January 2007 and December 2012, 21 patients (42 eyes) with Best VMD from eight families with the BEST1 mutation were included. Best-corrected visual acuity (BCVA), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SDOCT) were evaluated at study entry and at last visit. RESULTS: The mean age of patients was 26.3+/-17.4 years. Seven new missense mutations in BEST1 were identified. Mean follow-up was 41.1+/-18.5 months. Mean BCVA was 0.34+/-0.34 LogMAR at study entry and 0.32+/-0.33 LogMAR at last follow-up visit (p = 0.2). The overall lesion area on FAF increased from 6.62+/-4.9 mm2 to 7.34+/-6.1 mm2 (p = 0.05). At study entry, on SD-OCT, photoreceptor inner segment ellipsoid portion (ellipsoid zone, EZ) was normal in 15 eyes, disrupted in 14 eyes, and absent in 13 eyes. In two eyes, EZ changed from normal to disrupted during follow-up. Three eyes of three patients showing pseudohypopyon lesions at study entry progressed to vitelliruptive lesions at the last follow-up visit. Three eyes of three patients showing vitelliruptive lesion at study entry reverted to pseudohypopyon lesion with overall enlargement of the lesion size. CONCLUSIONS: Multimodal analysis allowed documenting a continuous material accumulation and reabsorption in Best VMD progression. Blue FAF and SD-OCT could represent noninvasive imaging techniques to monitor Best VMD. PMID- 24791143 TI - A family of null models to distinguish between environmental filtering and biotic interactions in functional diversity patterns. AB - QUESTIONS: Traditional null models used to reveal assembly processes from functional diversity patterns are not tailored for comparing different spatial and evolutionary scales. In this study, we present and explore a family of null models that can help disentangling assembly processes at their appropriate scales and thereby elucidate the ecological drivers of community assembly. LOCATION: French Alps. METHODS: Our approach gradually constrains null models by: (1) filtering out species not able to survive in the regional conditions in order to reduce the spatial scale, and (2) shuffling species only within lineages of different ages to reduce the evolutionary scale of the analysis. We first tested and validated this approach using simulated communities. We then applied it to study the functional diversity patterns of the leaf-height-seed strategy of plant communities in the French Alps. RESULTS: Using simulations, we found that reducing the spatial scale correctly detected a signature of competition (functional divergence) even when environmental filtering produced an overlaying signal of functional convergence. However, constraining the evolutionary scale did not change the identified functional diversity patterns. In the case study of alpine plant communities, investigating scale effects revealed that environmental filtering had a strong influence at larger spatial and evolutionary scales and that neutral processes were more important at smaller scales. In contrast to the simulation study results, decreasing the evolutionary scale tended to increase patterns of functional divergence. CONCLUSION: We argue that the traditional null model approach can only identify a single main process at a time and suggest to rather use a family of null models to disentangle intertwined assembly processes acting across spatial and evolutionary scales. PMID- 24791144 TI - The Value of Consciousness. PMID- 24791145 TI - Ensemble distribution models in conservation prioritization: from consensus predictions to consensus reserve networks. AB - AIM: Conservation planning exercises increasingly rely on species distributions predicted either from one particular statistical model or, more recently, from an ensemble of models (i.e. ensemble forecasting). However, it has not yet been explored how different ways of summarizing ensemble predictions affect conservation planning outcomes. We evaluate these effects and compare commonplace consensus methods, applied before the conservation prioritization phase, to a novel method that applies consensus after reserve selection. LOCATION: Europe. METHODS: We used an ensemble of predicted distributions of 146 Western Palaearctic bird species in alternative ways: four different consensus methods, as well as distributions discounted with variability, were used to produce inputs for spatial conservation prioritization. In addition, we developed and tested a novel method, in which we built 100 datasets by sampling the ensemble of predicted distributions, ran a conservation prioritization analysis on each of them and averaged the resulting priority ranks. We evaluated the conservation outcome against three controls: (i) a null control, based on random ranking of cells; (2) the reference solution, based on an expert-refined dataset; and (3) the independent solution, based on an independent dataset. RESULTS: Networks based on predicted distributions were more representative of rare species than randomly selected networks. Alternative methods to summarize ensemble predictions differed in representativeness of resulting reserve networks. Our novel method resulted in better representation of rare species than pre-selection consensus methods. MAIN CONCLUSIONS: Retaining information about the variation in the predicted distributions throughout the conservation prioritization seems to provide better results than summarizing the predictions before conservation prioritization. Our results highlight the need to understand and consider model based uncertainty when using predicted distribution data in conservation prioritization. PMID- 24791146 TI - Spatial mismatch of phylogenetic diversity across three vertebrate groups and protected areas in Europe. AB - AIM: We investigate patterns of phylogenetic diversity in relation to species diversity for European birds, mammals and amphibians, to evaluate their congruence and highlight areas of particular evolutionary history. We estimate the extent to which the European network of protected areas (PAs) network retains interesting evolutionary history areas for the three groups separately and simultaneously. LOCATION: Europe. METHODS: Phylogenetic (QEPD) and species diversity (SD) were estimated using the Rao's quadratic entropy at 10' resolution. We determined the regional relationship between QEPD and SD for each taxa with a spatial regression model and used the tails of the residuals (QERES) distribution to identify areas of higher and lower QEPD than predicted. Spatial congruence of biodiversity between groups was assessed with Pearson's correlation. A simple classification scheme allowed building a convergence map where a convergent pixel equalled to a QERES value of the same sign for the 3 groups. This convergence map was overlaid to the current PAs network to estimate the level of protection in convergent pixels and compared it to a null expectation built on 1000 randomization of PAs over the landscape. RESULTS: QERES patterns across vertebrates show a strong spatial mismatch highlighting different evolutionary histories. Convergent areas represent only 2.7% of the Western Palearctic, with only 8.4% of these areas being covered by the current PAs network while a random distribution would retain 10.4% of them. QERES are unequally represented within PAs: areas with higher QEPD than predicted are better covered than expected, while low QEPD areas are undersampled. MAIN CONCLUSIONS: Patterns of diversity strongly diverge between groups of vertebrates in Europe. Although Europe has the world's most extensive PAs network, evolutionary history of terrestrial vertebrates is unequally protected. The challenge is now to reconcile effective conservation planning with a contemporary view of biodiversity integrating multiple facets. PMID- 24791147 TI - Titanium-doped cerium oxide nanoparticles protect cells from hydrogen peroxide induced apoptosis. AB - To develop new nanoparticle materials possessing anti-oxidative capacity with improved physical characteristics, we have studied titanium-doped cerium oxide (CeTiO2) nanoparticles. CeTiO2 nanoparticles had a mode diameter of 15-20 nm. These nanoparticles demonstrated catalase activity, and did not promote the activation of hemolytic or cytolytic pathways in living cells. Using surface plasmon resonance enhanced microscopy, we find that these nanoparticles associate with cells. Transmission electron microscopy studies demonstrated that these nanoparticles accumulate within the vacuolar compartment of cells. Importantly, CeTiO2 nanoparticles decrease hydrogen peroxide-mediated apoptosis of cells as judged by the reduced cleavage of a caspase 3-sensitive label. CeTiO2 nanoparticles may contribute to deflecting tissue damage in a broad spectrum of oxidant-mediated diseases, such as macular degeneration and Alzheimer's disease. PMID- 24791148 TI - Rotifers as models for the biology of aging. AB - It has been two decades since 1993 when research on the biology of rotifer aging was last reviewed by Enesco. Much has transpired during this time as rotifer biologists have adapted to the "omics" revolution and incorporated these techniques into the experimental analysis of rotifers. Rotifers are amenable to many of these approaches and getting adequate quantities of DNA, RNA, and protein from rotifers is not difficult. Analysis of rotifer genomes, transcriptomes, and proteomes is rapidly yielding candidate genes that likely regulate a variety of features of rotifer biology. Parallel developments in aging biology have recognized the limitations of standard animal models like worms and flies and that comparative aging research has essentially ignored a large fraction of animal phylogeny in the lophotrochozoans. As experimentally tractable members of this group, rotifers have attracted interest as models of aging. In this paper, I review advances over the past 20 years in the biology of aging in rotifers, with emphasis on the unique contributions of rotifer models for understanding aging. The majority of experimental work has manipulated rotifer diet and followed changes in survival and reproductive dynamics like mean lifespan, maximum lifespan, reproductive lifespan, and mortality rate doubling time. The main dietary manipulation has been some form of caloric restriction, withholding food for some period or feeding continuously at low levels. There have been comparative studies of several rotifer species, with some species responding to caloric restriction with life extension, but others not, at least under the tested food regimens. Other aspects of diet are less explored, like nutritional properties of different algae species and their capacity to extend rotifer lifespan. Several descriptive studies have reported many genes involved in rotifer aging by comparing gene expression in young and old individuals. Classes of genes up or down-regulated during aging have become prime targets for rotifer aging investigations. Alterations of gene expression by exposure to specific inhibitors or RNAi knockdown will probably yield valuable insights into the cellular mechanisms of rotifer life extension. I highlight major experimental contributions in each of these areas and indicate opportunities where I believe additional investigation is likely to be profitable. PMID- 24791149 TI - Scale decisions can reverse conclusions on community assembly processes. AB - AIM: Phylogenetic diversity patterns are increasingly being used to better understand the role of ecological and evolutionary processes in community assembly. Here, we quantify how these patterns are influenced by scale choices in terms of spatial and environmental extent and organismic scales. LOCATION: European Alps. METHODS: We applied 42 sampling strategies differing in their combination of focal scales. For each resulting sub-dataset, we estimated the phylogenetic diversity of the species pools, phylogenetic alpha-diversities of local communities, and statistics commonly used together with null models in order to infer non-random diversity patterns (i.e. phylogenetic clustering versus over-dispersion). Finally, we studied the effects of scale choices on these measures using regression analyses. RESULTS: Scale choices were decisive for revealing signals in diversity patterns. Notably, changes in focal scales sometimes reversed a pattern of over-dispersion into clustering. Organismic scale had a stronger effect than spatial and environmental extent. However, we did not find general rules for the direction of change from over-dispersion to clustering with changing scales. Importantly, these scale issues had only a weak influence when focusing on regional diversity patterns that change along abiotic gradients. MAIN CONCLUSIONS: Our results call for caution when combining phylogenetic data with distributional data to study how and why communities differ from random expectations of phylogenetic relatedness. These analyses seem to be robust when the focus is on relating community diversity patterns to variation in habitat conditions, such as abiotic gradients. However, if the focus is on identifying relevant assembly rules for local communities, the uncertainty arising from a certain scale choice can be immense. In the latter case, it becomes necessary to test whether emerging patterns are robust to alternative scale choices. PMID- 24791150 TI - The physiologic and anesthetic considerations in elderly patients undergoing robotic renal surgery. AB - A number of patients are diagnosed with renal malignancies incidentally worldwide. Once a diagnosis of a renal malignancy is established, after a careful evaluation, patients can be offered a robotic nephrectomy or partial nephrectomy. We present a review of the physiologic and anesthetic considerations in elderly patients who are being considered for robotic renal surgery. PMID- 24791151 TI - Emerging Therapeutic for the Treatment of Skeletal-related Events Associated With Metastatic Castrate-resistant Prostate Cancer. AB - Prostate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who succumb to the disease will ultimately develop bone metastasis. Morbidity from bone metastasis-referred to as skeletal-related events, which include fractures, cord compression, radiation to bone, and surgery to bone-leads to significant costs and impaired quality of life. This article reviews three agents and the roles they play in the ever-changing armamentarium of treatments for metastatic castrate-resistant prostate cancer (mCRPC). The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis. PMID- 24791152 TI - Nephron-sparing Management of Upper Tract Urothelial Carcinoma. AB - Upper tract urothelial carcinoma (UTUC) is a relatively rare tumor, but is characterized by high rates of recurrence, morbidity, and mortality. Choice of treatment modality is generally influenced by lesion size, grade, and focality. Radical nephroureterectomy with bladder cuff excision is the gold-standard management of UTUC, although an organ-sparing approach may be beneficial in selected patients. Conservative endoscopic management of UTUC in appropriate patients has a favorable impact on quality of life and health care costs when compared with patients who progress to dialysis-dependent renal failure. Careful ureteroscopic surveillance following endoscopic management of UTUC is essential. PMID- 24791154 TI - Transitioning to ICD-10: Steps for Urologists and Urology Groups. PMID- 24791153 TI - Calyceal diverticula: a comprehensive review. AB - Calyceal diverticula are rare outpouchings of the upper collecting system that likely have a congenital origin. Stones can be found in up to 50% of calyceal diverticula, although, over the combined reported series, 96% of patients presented with stones. Diagnosis is best made by intravenous urography or computed tomography urogram. Shock wave lithotripsy (SWL) is an option for first line therapy in patients with stone-bearing diverticula that have radiologically patent necks in mid- to upper-pole diverticula and small stone burdens. Stone free rates are the lowest with SWL, although patients report being asymptomatic following therapy in up to 75% of cases with extended follow-up. Ureteroscopy (URS) is best suited for management of anteriorly located mid- to upperpole diverticular stones. Drawbacks to URS include difficulty in identifying the ostium and low rate of obliteration. Percutaneous management is best used in posteriorly located mid- to lower-pole stones, and offers the ability to directly ablate the diverticulum. Percutaneous nephrolithotomy remains effective in the management of upperpole diverticula, but carries the risk of pulmonary complications unless subcostal access strategies such as triangulation or renal displacement are used. Laparoscopic surgery provides definitive management, but should be reserved for cases with large stones in anteriorly located diverticula with thin overlying parenchyma, and cases that are refractory to other treatment. This article reviews the current theories on the pathogenesis of calyceal diverticula. The current classification is examined in addition to the current diagnostic methods. Here we summarize an extensive review of the literature on the outcomes of the different treatment approaches. PMID- 24791155 TI - Metastatic urethral melanoma: case report and review of the literature. AB - Melanoma is a cancer that originates from melanocytes, is predominant in adults with white skin, represents 4% of skin cancers, and has high possibility of forming metastasis. This review reports on the case of a young man, age 36 years, previously diagnosed with melanoma. The patient complained of obstructive urinary symptoms and, while he was undergoing a cystoscopy, it was discovered that he had a lesion corresponding with metastatic melanoma of the prostatic urethra, which occluded almost the entire urethra and resulted in blocked urinary flow. He underwent a transurethral resection of the prostate, followed by resection of the lesion. After the procedure, he had good urinary flow and is currently on follow up. PMID- 24791156 TI - Bladder Leiomyoma Presenting With LUTS and Coexisting Bladder and Uterine Leiomyomata: A Review of Two Cases. AB - Mesenchymal tumors of the urinary bladder are a rare occurrence, the most common among them being leiomyoma of the bladder. These tumors commonly present with irritative urinary symptoms progressing gradually to obstructive symptoms as the size increases. We report on two patients who presented with lower urinary tract symptoms (LUTS). One of the patients also had concomitant bladder and uterine leiomyomata, which is the first such case to be reported in the literature. It is essential to differentiate leiomyoma from other common causes of LUTS. Cold cup biopsy has a significant false-negative rate and, in such cases, a wide local excision provides an optimal cure with excellent results. PMID- 24791157 TI - Recruitment of Rural African Americans for Research Projects: Lessons Learned. AB - Recruiting rural African Americans for research presents special problems because of cultural differences, the view of researchers as cultural "outsiders", and transportation problems. This paper reports successful strategies in recruiting rural African American adults with type 2 diabetes for research studies. The researchers tested recruitment strategies commonly used in research, such as flyers, advertisements in local newspapers and radio stations. The researchers also encouraged referrals from medical professionals. When recruitment goals were not met, the researchers modified strategies. Twenty-two rural African American participants were recruited and randomly assigned to culturally-tailored Group or Individual Diabetes Self Management Education (DSME). The latter included storytelling and an interactive learning approach. The key recruitment strategies involved spending time in the community, visits to churches, and flyers to key leaders in the Black community. Enrolling rural African Americans required cultural competence, careful planning, and time in the community. Recruiting for clinical research is challenging and more difficult when targeting minority members in rural settings. Research in diabetes care is needed with rural African Americans because of high rates of diabetes, and limited health care access for this population. Effective recruitment and retention strategies are needed to test interventions to reduce health disparities. PMID- 24791158 TI - Characterization of the geometry and topology of DNA pictured as a discrete collection of atoms. AB - The structural and physical properties of DNA are closely related to its geometry and topology. The classical mathematical treatment of DNA geometry and topology in terms of ideal smooth space curves was not designed to characterize the spatial arrangements of atoms found in high-resolution and simulated double helical structures. We present here new and rigorous numerical methods for the rapid and accurate assessment of the geometry and topology of double-helical DNA structures in terms of the constituent atoms. These methods are well designed for large DNA datasets obtained in detailed numerical simulations or determined experimentally at high-resolution. We illustrate the usefulness of our methodology by applying it to the analysis of three canonical double-helical DNA chains, a 65-bp minicircle obtained in recent molecular dynamics simulations, and a crystallographic array of protein-bound DNA duplexes. Although we focus on fully base-paired DNA structures, our methods can be extended to treat the geometry and topology of melted DNA structures as well as to characterize the folding of arbitrary molecules such as RNA and cyclic peptides. PMID- 24791159 TI - Early History and Challenges of Implantable Electronics. AB - Implantable systems for biomedical research and clinical care are now a flourishing field of activities in academia as well as industrial institutions. The broad field includes experimental explorations in electronics, mechanical, chemical, and biological components and systems, and the combination of all these. Today virtually all implants involve both electronic circuits and micro electro-mechanical-systems (MEMS). This article offers a very brief glance back at the early history of implant electronics in the period from the 1950s to the 1970s, by employing selected examples from the author's research. This short review also discusses the challenges of implantable electronics at present, and suggests some potentially important trends in the future research and development of implantable microsystems. It is aimed as an introduction of implantable/attached electronic systems to research engineers that are interested in implantable systems as a section of Biomedical Instrumentations. PMID- 24791160 TI - Enhanced resistive switching memory characteristics and mechanism using a Ti nanolayer at the W/TaO x interface. AB - Enhanced resistive memory characteristics with 10,000 consecutive direct current switching cycles, long read pulse endurance of >10(5) cycles, and good data retention of >10(4) s with a good resistance ratio of >10(2) at 85 degrees C are obtained using a Ti nanolayer to form a W/TiO x /TaO x /W structure under a low current operation of 80 MUA, while few switching cycles are observed for W/TaO x /W structure under a higher current compliance >300 MUA. The low resistance state decreases with increasing current compliances from 10 to 100 MUA, and the device could be operated at a low RESET current of 23 MUA. A small device size of 150 * 150 nm(2) is observed by transmission electron microscopy. The presence of oxygen deficient TaO x nanofilament in a W/TiO x /TaO x /W structure after switching is investigated by Auger electron spectroscopy. Oxygen ion (negative charge) migration is found to lead to filament formation/rupture, and it is controlled by Ti nanolayer at the W/TaO x interface. Conducting nanofilament diameter is estimated to be 3 nm by a new method, indicating a high memory density of approximately equal to 100 Tbit/in.(2). PMID- 24791161 TI - Ultrahigh refractive index sensing performance of plasmonic quadrupole resonances in gold nanoparticles. AB - The refractive index sensing properties of plasmonic resonances in gold nanoparticles (nanorods and nanobipyramids) are investigated through numerical simulations. We find that the quadruple resonance in both nanoparticles shows much higher sensing figure of merit (FOM) than its dipolar counterpart, which is attributed mainly to the reduction in resonance linewidth. More importantly, our results predict that at the same sensing wavelength, the sensing FOM of the quadrupole mode can be significantly boosted from 3.9 for gold nanorods to 7.4 for gold nanobipyramids due to the geometry-dependent resonance linewidth, revealing a useful strategy for optimizing the sensing performance of metal nanoparticles. PMID- 24791162 TI - Optical properties of epitaxial BiFeO3 thin film grown on SrRuO3-buffered SrTiO3 substrate. AB - The BiFeO3 (BFO) thin film was deposited by pulsed-laser deposition on SrRuO3 (SRO)-buffered (111) SrTiO3 (STO) substrate. X-ray diffraction pattern reveals a well-grown epitaxial BFO thin film. Atomic force microscopy study indicates that the BFO film is rather dense with a smooth surface. The ellipsometric spectra of the STO substrate, the SRO buffer layer, and the BFO thin film were measured, respectively, in the photon energy range 1.55 to 5.40 eV. Following the dielectric functions of STO and SRO, the ones of BFO described by the Lorentz model are received by fitting the spectra data to a five-medium optical model consisting of a semi-infinite STO substrate/SRO layer/BFO film/surface roughness/air ambient structure. The thickness and the optical constants of the BFO film are obtained. Then a direct bandgap is calculated at 2.68 eV, which is believed to be influenced by near-bandgap transitions. Compared to BFO films on other substrates, the dependence of the bandgap for the BFO thin film on in-plane compressive strain from epitaxial structure is received. Moreover, the bandgap and the transition revealed by the Lorentz model also provide a ground for the assessment of the bandgap for BFO single crystals. PMID- 24791163 TI - Large-scale preparation of nanoporous TiO2 film on titanium substrate with improved photoelectrochemical performance. AB - Fabrication of three-dimensional TiO2 films on Ti substrates is one important strategy to obtain efficient electrodes for energy conversion and environmental applications. In this work, we found that hierarchical porous TiO2 film can be prepared by treating H2O2 pre-oxidized Ti substrate in TiCl3 solution followed by calcinations. The formation process is a combination of the corrosion of Ti substrate and the oxidation hydrolysis of TiCl3. According to the characterizations by scanning electron microscopy (SEM), X-ray diffraction (XRD), and diffuse reflectance spectroscopy (DRS), the anatase phase TiO2 films show porous morphology with the smallest diameter of 20 nm and possess enhanced optical absorption properties. Using the porous film as a working electrode, we found that it displays efficient activity for photoelectrocatalytic decolorization of rhodamine B (RhB) and photocurrent generation, with a photocurrent density as high as 1.2 mA/cm(2). It represents a potential method to fabricate large-area nanoporous TiO2 film on Ti substrate due to the scalability of such chemical oxidation process. PMID- 24791164 TI - Luciferase does not Alter Metabolism in Cancer Cells. AB - Luciferase transfected cell lines are used extensively for cancer models, revealing valuable biological information about disease mechanisms. However, these genetically encoded reporters, while useful for monitoring tumor response in cancer models, can impact cell metabolism. Indeed firefly luciferase and fatty acyl-CoA synthetases differ by a single amino acid, raising the possibility that luciferase activity might alter metabolism and introduce experimental artifacts. Therefore knowledge of the metabolic response to luciferase transfection is of significant importance, especially given the thousands of research studies using luciferase as an in vivo bioluminescence imaging (BLI) reporter. Untargeted metabolomics experiments were performed to examine three different types of lymphoblastic leukemia cell lines (Ramos, Raji and SUP T1) commonly used in cancer research, each were analyzed with and without vector transduction. The Raji model was also tested under perturbed starvation conditions to examine potential luciferase-mediated stress responses. The results showed that no significant metabolic differences were observed between parental and luciferase transduced cells for each cell line, and that luciferase overexpression does not alter cell metabolism under basal or perturbed conditions. PMID- 24791165 TI - Robotic right colectomy for hemorrhagic right colon cancer: a case report and review of the literature of minimally invasive urgent colectomy. AB - Right colon cancer rarely presents as an emergency, in which bowel occlusion and massive bleeding are the most common clinical presentations. Although there are no definite guidelines, the first line treatment for massive right colon cancer bleeding should ideally stop the bleeding using endoscopy or interventional radiology, subsequently allowing proper tumor staging and planning of a definite treatment strategy. Minimally invasive approaches for right and left colectomy have progressively increased and are widely performed in elective settings, with laparoscopy chosen in the majority of cases. Conversely, in emergent and urgent surgeries, minimally invasive techniques are rarely performed. We report a case of an 86-year-old woman who was successfully treated for massive rectal bleeding in an urgent setting by robotic surgery (da Vinci Intuitive Surgical System(r)). At admission, the patient had severe anemia (Hb 6 g/dL) and hemodynamic stability. A computer tomography scanner with contrast enhancement showed a right colon cancer with active bleeding; no distant metastases were found. A colonoscopy did not show any other bowel lesion, while a constant bleeding from the right pre-stenotic colon mass was temporarily arrested by endoscopic argon coagulation. A robotic right colectomy in urgent setting (within 24 hours from admission) was indicated. A three-armed robot was used with docking in the right side of the patient and a fourth trocar for the assistant surgeon. Because of the patient's poor nutritional status, a double-barreled ileocolostomy was performed. The post-operative period was uneventful. As the neoplasia was a pT3N0 adenocarcinoma, surveillance was decided after a multidisciplinary meeting, and restoration of the intestinal continuity was performed 3 months later, once good nutritional status was achieved. In addition, we reviewed the current literature on minimally invasive colectomy performed for colon carcinoma in emergent or urgent setting. No study on robotic approach was found. Seven studies evaluating the role of laparoscopic colectomy concluded that this technique is a safe and feasible option associated with lower blood loss and shorter hospital stay. It may require longer operative time, but morbidity and mortality rates appeared comparable to open colectomy. However, the surgeon's experience and the right selection of candidate patients cannot be understated. PMID- 24791166 TI - Anesthetic challenges of patients with cardiac comorbidities undergoing major urologic surgery. AB - The cardiac patient undergoing major urologic surgery is a complex case requiring a great attention by the anesthesiologist. Number of this group of patients having to go through this procedure is constantly increasing, due to prolonged life, increased agressiveness of surgery and increased anesthesia's safety. The anesthesiologist usually has to deal with several problems of the patient, such as hypertension, chronic heart failure, coronary artery disease, rhythm disturbances, intraoperative hemodymanic changes, intraoperative bleeding, perioperative fluid imbalance, and metabolic disturbances. A cardiac patient undergoing major urologic surgery is a complex case requiring a great attention by the anesthesiologist. The scope of this review article is to present the most frequent issues encountered with this group of patients, and to synthetically discuss the respective strategies and maneuvers during perioperative period, which is the major challenge for the anesthesiologist. PMID- 24791167 TI - The Saudi guidelines for chronic obstructive pulmonary disease: A fresh "Real World" approach to COPD. PMID- 24791169 TI - Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials. AB - The efficacy of magnesium sulphate in chronic obstructive pulmonary disease (COPD) was assessed by conducting a systematic review of published randomized clinical trials through extensive searches in MEDLINE and SCOPUS with no date limits, as well as manual review of journals. Outcome measures varied depending on route(s) of administration of magnesium sulphate and medications co administered. Risk of bias was evaluated and quality of evidence was graded. Four (4) randomized trials were included. All trials had a moderate risk of bias and were of average methodological quality. Magnesium sulphate given intravenously did not seem to have an immediate bronchodilatory effect; however it appears to potentiate the bronchodilatory effect of inhaled beta-2 agonists. Increase in peak expiratory flow rate (PEFR) at 30 and 45 min was greater in those who received magnesium sulphate compared to placebo (P = 0.03), although the mean percentage change in PEFR was just 24%, without significant differences in dyspnoea scores, hospital admission rates, or emergency department readmission rates compared to placebo. Nebulized magnesium sulphate with salbutamol versus nebulized salbutamol with saline placebo showed no significant differences is forced expiratory volume in 1 s (FEV1) measured at 90 min after adjustment for baseline FEV1 (P = 0.34) or differences in the need for hospital admission. Combined inhalational and intravenous magnesium sulphate versus intravenous saline placebo and nebulized ipratropium bromide were comparable in terms of hospital admission, intubation and death, but the ipratropium bromide group showed better bronchodilator effect and improvement in arterial blood gas parameters. Overall, trial evidence for trial evidence for magnesium sulphate in acute exacerbation of COPD is poor, and further well-designed trials are needed. PMID- 24791170 TI - IL-4 receptor alpha single-nucleotide polymorphisms rs1805010 and rs1801275 are associated with increased risk of asthma in a Saudi Arabian population. AB - BACKGROUND: The IL-4 receptor alpha subunit (IL-4Ralpha), when associated with the common gamma chain receptor, or the IL-13Ralpha1 subunit, transduces signals to STAT6 in response to IL-4 and IL-13 stimulations. This results in a number of cell-specific responses including Th2 differentiation, lymphocyte proliferation and IgE production. Given the prominent role of IL-4Ralpha in allergic disorders, several single-nucleotide polymorphisms (SNPs) have been found associated with asthma and other atopic disorders, including rs1805010 (I75V) and rs1801275 (Q576R) SNPs; however, lack of significant association have also been reported for some ethnic groups. The objective of this study was to determine whether IL 4Ralpha rs1805010 and rs1801275 polymorphisms are associated with asthma in patients from Saudi Arabia. MATERIALS AND METHODS: One hundred and ninety severe asthmatic patients (11-70 years old) and 194 healthy subjects of equivalent age range were recruited for blood donation. DNA was purified and genotyping for rs1801275 and rs1805010 polymorphisms in the IL-4Ralpha gene was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis. RESULTS: Pearson's Chi square tests showed that the minor alleles, G, for both rs1805010 and rs1801275 SNPs, were significantly more frequent in asthmatics than in the healthy group (Yates' P < 0.05); conversely, the major alleles, A, were significantly more frequent in healthy than in asthmatics (P < 0.05). Concerning association analysis, odds for A/G-G/G genotypes were significantly higher to be associated with asthma predisposition (rs1801275: OR = 2.12; 95% CI = 1.39-3.22; P < 0.001*; rs1805010: OR = 1.6; 95% CI = 1.01-2.53; P < 0.05*; dominant model). Analysis of gender-genotype interactions, with genders nested within A/G-G/G, indicated higher odds for females than males of significant association with asthma (rs1801275: OR = 5.19, 95% CI = 2.09-12.94*; rs1805010: OR = 3.73, 95% CI = 2.06 6.74*). Rs1805010 and rs1801275 were in linkage disequilibrium (D' = 0.27; P < 0.0004*), with G-G haplotype being more frequent in asthmatics than in healthy subjects (OR = 2.43, 95% CI = 1.59-3.71*). CONCLUSIONS: The risk alleles, G, of IL-4Ralpha rs1805010 and rs1801275 SNPs and corresponding A/G-G/G genotypes were significantly associated with asthma predisposition in asthmatics from Saudi Arabia. PMID- 24791171 TI - Frequency and predictors of obesity hypoventilation in hospitalized patients at a tertiary health care institution. AB - OBJECTIVES: Patients with obesity hypoventilation syndrome (OHS) have significant morbidity and mortality. Early diagnosis and treatment is important and there are limited data on its prevalence and predictive factors. The objective of this observational study was to determine the frequency and predictors of OHS in hospitalized patients at a tertiary health care institution. MATERIALS AND METHODS: All blood gas analyses of hospitalized adult (age over 18 years) patients were prospectively recruited from the biochemistry laboratory at a tertiary health care center between August 2009 and July 2010. Patients who had hypercapnia (PaCO2 >= 45 mmHg) while breathing room air were included and clinical and laboratory data were obtained from hospital records. A standard questionnaire was also filled by face-to-face interview with patients and/or relatives. RESULTS: A total of 9480 patients' arterial blood gases were evaluated and 330 patients (3.4%) who met the selection criteria were included in the analysis during the study period. Hypoventilation was associated with acute diseases in 64.2% and chronic diseases in 35.8% of the patients. Of the chronic hypoventilation patients, 24.4% had OHS. Univariate logistic regression analysis showed that, female gender, body mass index (BMI), smoking, PaO2, SaO2 and a PaCO2/BMI <1.5 were significantly related to OHS. In multivariate logistic regression analysis, BMI >35 kg/m(2), SaO2 <91.4% and PaCO2 /BMI <1.5 were significantly related to OHS. A PaCO2/BMI <1.5 was an independent variable strongly predictive of OHS (odds ratio: 36.9, 95% of the confidence interval: 2.75-492.95, P = 0.007). CONCLUSIONS: OHS is a common cause of chronic alveolar hypoventilation. A careful examination PaCO2 /BMI ratio may prevent misdiagnoses among hypercapnic patients. PMID- 24791168 TI - The Saudi Guidelines for the Diagnosis and Management of COPD. AB - The Saudi Thoracic Society (STS) launched the Saudi Initiative for Chronic Airway Diseases (SICAD) to develop a guideline for the diagnosis and management of chronic obstructive pulmonary disease (COPD). This guideline is primarily aimed for internists and general practitioners. Though there is scanty epidemiological data related to COPD, the SICAD panel believes that COPD prevalence is increasing in Saudi Arabia due to increasing prevalence of tobacco smoking among men and women. To overcome the issue of underutilization of spirometry for diagnosing COPD, handheld spirometry is recommended to screen individuals at risk for COPD. A unique feature about this guideline is the simplified practical approach to classify COPD into three classes based on the symptoms as per COPD Assessment Test (CAT) and the risk of exacerbations and hospitalization. Those patients with low risk of exacerbation (<2 in the past year) can be classified as either Class I when they have less symptoms (CAT < 10) or Class II when they have more symptoms (CAT >= 10). High-risk COPD patients, as manifested with >=2 exacerbation or hospitalization in the past year irrespective of the baseline symptoms, are classified as Class III. Class I and II patients require bronchodilators for symptom relief, while Class III patients are recommended to use medications that reduce the risks of exacerbations. The guideline recommends screening for co-morbidities and suggests a comprehensive management approach including pulmonary rehabilitation for those with a CAT score >=10. The article also discusses the diagnosis and management of acute exacerbations in COPD. PMID- 24791172 TI - Obstructive sleep apnea is associated with higher healthcare utilization in elderly patients. AB - BACKGROUND: Obstructive sleep apnea (OSA) is an important cause of morbidity in the elderly population. Limited data are available regarding the healthcare utilization and predisposing conditions related to OSA in the elderly. Our aim was to evaluate the healthcare utilization and the conditions associated with new and chronic diagnosis of OSA in a large cohort of elderly patients in the Veterans Health Administration (VHA). MATERIALS AND METHODS: This retrospective cohort study used inpatient and outpatient VHA data to identify the individuals diagnosed with OSA using ICD-9 codes during the fiscal years 2003-2005. Primary outcomes were emergency department (ED) visits and hospitalizations. Multivariable logistic regression analysis was performed to identify the demographic and clinical characteristics associated with new and chronic diagnosis of OSA. RESULTS: Of 1,867,876 elderly veterans having 2 years of care, 82,178 (4.4%) were diagnosed with OSA. Individuals with OSA were younger and more likely to have chronic diseases than those without OSA. Individuals with chronic OSA were more likely to have diagnoses of congestive heart failure (CHF), pulmonary circulation disorders, COPD, and obesity and less likely to have diagnoses of hypertension, osteoarthritis, and stroke than individuals with newly diagnosed OSA. The proportion of patients with new OSA diagnosis who required at least one ED visit was higher than the proportion of chronic OSA and no OSA patients (37%, 32%, and 15%, respectively; P-value <0.05). The proportion of new OSA patients who required at least one hospitalization was also higher than the proportion of chronic OSA and no OSA patients (24%, 17%, and 7%, respectively; P value <0.05). CONCLUSION: Patients with OSA had a higher incidence of healthcare utilization compared to patients without OSA. New OSA patients had a higher rate of healthcare utilization in the year of diagnosis compared to chronic patients and patients without OSA. Early OSA recognition may reduce healthcare utilization in these patients. PMID- 24791173 TI - B-lines: Transthoracic chest ultrasound signs useful in assessment of interstitial lung diseases. AB - OBJECTIVE: This prospective study was conducted to evaluate the value of sonographic B-lines (previously called "comet tail artifacts"), which are long, vertical, well-defined, hyperechoic, dynamic lines originating from the pleural line in assessment of interstitial lung diseases (ILD) and compare them with the findings of chest high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). MATERIALS AND METHODS: Sixty-one patients with ILD underwent transthoracic lung ultrasound for assessment of the presence of B-lines and the distance between them. These findings were compared with that of chest HRCT (ground glass, reticular, nodular or honey combing) and PFT as forced vital capacity (FVC), total lung capacity (TLC), diffusion capacity for carbon monoxide (DLCO) and partial arterial oxygen pressure (PaO2). RESULTS: All patients had diffuse bilateral B-lines. The distance between each of the two adjacent B lines correlated with the severity of the disease on chest HRCT where B3 (the distance was 3 mm) correlated with ground glass opacity and B7 (the distance was 7 mm) correlated with extensive fibrosis and honey combing. Also, the distance between B-lines inversely correlated with FVC (r = -0.848, P < 0.001), TLC (r = -0.664, P < 0.001), DLCO (r = -0.817, P < 0.001) and PaO2 (r = -0.902, P < 0.001). CONCLUSION: B-lines that are lung Ultrasound signs seem to be useful in the assessment of ILD. PMID- 24791174 TI - Drug-resistant ventilator associated pneumonia in a tertiary care hospital in Saudi Arabia. AB - BACKGROUND: There is a wide geographic and temporal variability of bacterial resistance among microbial causes of ventilator-associated pneumonia (VAP). The contribution of multi-drug resistant (MDR) pathogens to the VAP etiology in Saudi Arabia was never studied. We sought to examine the extent of multiple-drug resistance among common microbial causes of VAP. MATERIALS AND METHODS: We conducted a retrospective susceptibility study in the adult intensive care unit (ICU) of King Abdulaziz Medical City, Riyadh, Saudi Arabia. Susceptibility results of isolates from patients diagnosed with VAP between October 2004 and June 2009 were examined. The US National Healthcare Safety Network definition of MDR was adopted. RESULTS: A total of 248 isolates including 9 different pathogens were included. Acinetobacter spp. was highly (60-89%) resistant to all tested antimicrobials, including carbapenems (three- and four-class MDR prevalence were 86% and 69%, respectively). Pseudomonas aeruginosa was moderately (13-31%) resistant to all tested antimicrobials, including antipseudomonal penicillins (three- and four-class MDR prevalence were 13% and 10%, respectively). With an exception of ampicillin (fully resistant), Klebsiella spp. had low (0-13%) resistance to other tested antimicrobials with no detected MDR. Staphylococcus aureus was fully susceptible to vancomycin with 42% resistance to oxacillin. There were significant increasing trends of MDR Acinetobacter spp. however not P. aeruginosa during the study. Resistant pathogens were associated with worse profile of ICU patients but not patients' outcomes. CONCLUSION: Acinetobacter in the current study was an increasingly resistant VAP-associated pathogen more than seen in many parts of the world. The current finding may impact local choice of initial empiric antibiotics. PMID- 24791175 TI - Positive end-expiratory pressure attenuates positional effect after thoracotomy. AB - CONTEXT: Thoracotomy is a common procedure. However, thoracotomy leads to lung atelectasis and deteriorates pulmonary gas exchange in operated side. Therefore, different positions with operated side lowermost or uppermost may lead to different gas exchange after thoracotomy. Besides, PEEP (positive end-expiratory pressure) influence lung atelectasis and should influence gas exchange. AIMS: The purpose of this study was to determine the physiological changes in different positions after thoracotomy. In addition, we also studied the influence of PEEP to positional effects after thoracotomy. MATERIALS AND METHODS: There were eight pigs in each group. Group I received left thoracotomy with zero end-expiratory pressure (ZEEP), and group II with PEEP; group III received right thoracotomy with ZEEP and group IV with PEEP. We changed positions to supine, LLD (left lateral decubitus) and RLD (right lateral decubitus) in random order after thoracotomy. RESULTS: PaO2 was decreased after thoracotomy and higher in RLD after left thoracotomy and in LLD after right thoracotomy. PaO2 in groups II and IV was higher than in groups I and III if with the same position. In group I and III, PaCO2 was increased after thoracotomy and was higher in LLD after left thoracotomy and in RLD after right thoracotomy. In groups II and IV, there were no PaCO2 changes in different positions after thoracotomy. Lung compliance (Crs) was decreased after thoracotomy in groups I and III and highest in RLD after left thoracotomy and in LLD after right thoracotomy. In groups II and IV, there were no changes in Crs regardless of the different positions. CONCLUSION: There were significant changes with regards to pulmonary gas exchange, hemodynamics and Crs after thoracotomy. The best position was non-operated lung lowermost Applying PEEP attenuates the positional effects. PMID- 24791176 TI - Endobronchial cryotherapy facilitates end-stage treatment options in patients with bronchial stenosis: A case series. AB - In keeping with international trends, lung cancer incidence and mortality are increasing among the Irish population with many patients presenting with advanced disease that excludes the potential for curative management. Consequently palliative treatment options for this patient group are being increasingly explored with various degrees of success. Endobronchial stenosis represents a particularly challenging area of management among these patients and a number of techniques have been described without the identification of a single gold standard. We report our experience of the first time use of endobronchial cryotherapy in Ireland with reference to a case series, including an example of its use in the management of benign disease, in order to support patients with borderline lung function and enable definitive palliative treatment. PMID- 24791177 TI - Successful management of bilateral refractory chylothorax after double lung transplantation for lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a rare disease that leads to airways and lymphatic channels obstruction due to abnormal smooth muscle proliferation. It presents with dyspnea, pneumothorax or chylothorax. Lung transplantation (LT) has emerged as a valuable therapeutic option with limited reports. We report a case of LAM that underwent double LT and complicated by refractory bilateral chylothorax which was managed successfully by povidone-iodine pleurodesis and the addition of sirolimus to the post-transplantation immunosuppressive therapy. The patient has no recurrence with 24 months follow-up. PMID- 24791178 TI - Endobronchial ultrasound as a confirmatory tool for the diagnosis of pulmonary embolism. PMID- 24791179 TI - Determining an optimal technique for atrial septal defect closure: percutaneous closure as a therapeutic modality of choice. PMID- 24791180 TI - Author reply to the editor. PMID- 24791181 TI - Mitral annulus caseous calcification mimicking cardiac mass in asymptomatic patient - multimodality imaging approach to incidental echocardiographic finding. AB - BACKGROUND: Caseous calcification of mitral annulus is rather rare echocardiographic finding with prevalence of 0.6% in pts. with proven mitral annular calcification and 0.06% to 0.07% in large series of subjects in all ages. Echocardiographic images of caseous calcification are often heterogenous due to calcium and lipid deposits, and the masses show hyperechogenic and hypoechogenic areas. However the appearance of caseous calcification can imitate that of abscess, tumors and cysts, surgical treatment may not be needed when there is no obstruction. CASE REPORT: 76-year old obese (BMI 32 kg/m(2)), female patient with history of hypertension, stable coronary artery disease, diabetes type 2 and hyperlipidemia presented with no symptoms of mitral valve dysfunction and had no abnormalities on physical exam. Transesophageal echocardiography identified well organized, composite, immobile lesion (22*15 mm) localized in the posterior part of the mitral annulus, with markedly calcified margins, and no significant impact on the valve function. In computed tomography (CT) lesion was described as calcified (24*22*17.5 mm), connected with posterior leaflet and posterior part of the mitral annulus, reducing posterior leaflet mobility. CT brought the suggestion of caseous mitral annular calcification. Coming to a conclusion, bearing in mind no mitral valve dysfunction at that time, patient was offered conservative treatment. CONCLUSIONS: Although caseous mitral annular calcification is typically an incidental finding, accurate recognition is needed to avoid mistaking the lesion for a tumor or abscess, which may result in unnecessary cardiac surgery. However this entity is diagnosed on cardiac MRI, multi-modality imaging, especially non-contrast CT, allows for the confident, prospective diagnosis. PMID- 24791182 TI - Hydrogen Surface Reactions and Adsorption Studied on Y2O3, YSZ, and ZrO2. AB - The surface reactivity of Y2O3, YSZ, and ZrO2 polycrystalline powder samples toward H2 has been comparatively studied by a pool of complementary experimental techniques, comprising volumetric methods (temperature-programmed volumetric adsorption/oxidation and thermal desorption spectrometry), spectroscopic techniques (in situ electric impedance and in situ Fourier-transform infrared spectroscopy), and eventually structural characterization methods (X-ray diffraction and scanning electron microscopy). Reduction has been observed on all three oxides to most likely follow a surface or near-surface-limited mechanism involving removal of surface OH-groups and associated formation of water without formation of a significant number of anionic oxygen vacancies. Partly reversible adsorption of H2 was proven on the basis of molecular H2 desorption. Dictated by the specific hydrophilicity of the oxide, readsorption of water eventually takes place. The inference of this surface-restricted mechanism is further corroborated by the fact that no bulk structural and/or morphological changes were observed upon reduction even at the highest reduction temperatures (1173 K). We anticipate relevant implications for the use of especially YSZ in fuel cell research, since in particular the chemical state and structure of the surface under typical reducing high-temperature conditions affects the operation of the entire cell. PMID- 24791184 TI - Childhood hypertension: a problem of epidemic proportion. PMID- 24791183 TI - Precautionary labelling of foods for allergen content: are we ready for a global framework? AB - Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this. PMID- 24791185 TI - Management of hypertension in children with cardiovascular disease and heart failure. AB - Although primary chronic hypertension (HTN) is increasingly common in adolescence, secondary forms of HTN are more common among children. Primary HTN is associated with being overweight and/or a positive family history of HTN. Carotid intima-media thickness, a known risk factor for atherosclerosis is frequent in both adults and children with HTN and other associated cardiovascular (CV) risk factors including obesity, dyslipidemia, diabetes and chronic kidney disease. Left ventricular (LV) hypertrophy is also a common finding in children and adolescents with newly diagnosed HTN. Children with certain medical conditions such as congenital heart disease and Kawasaki disease can develop premature atherosclerosis heart disease that may lead to coronary heart disease and heart failure. Life-style interventions are recommended for all children with HTN, with pharmacologic therapy added for symptomatic children based on the presence of co-morbidities. As an example, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocker and/or calcium channel blockers would be best for children with CV risk factors such as diabetes or renal disease, whereas an ACE inhibitor in combination with a beta-blocker and diuretics including spironolactone are recommended for patients with heart failure and reduced LV ejection fraction. This report will summarize new developments in the management of pediatric HTN complicated with CV disease and heart failure and will address the appropriate antihypertensive therapy that could potentially reduce the future burden of adult CV disease. PMID- 24791186 TI - Strategies to reduce pitfalls in measuring blood pressure. AB - Errors in blood pressure (BP) measurement are common in the clinical practice. Inaccurate measurements of BP may lead to misdiagnosis and inappropriate treatment of hypertension. The preferred method of BP measurement in the clinical setting is auscultation, using the first and the fifth Korotkoff sounds. However, the use of mercury sphygmomanometer is declining. Automated oscillometric devices are an acceptable alternative method of BP measurements if the proper cuff size is used. Aneroid devices are suitable, but they require frequent calibration. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. At 24 h ambulatory monitoring is also useful for diagnosing white-coat hypertension and resistance hypertension. There is increasing evidence that lack of nocturnal BP dipping during the night may be associated with increased cardiovascular event. This report attempts to address the need for accurate BP measurements in children and adolescents by reducing human and equipment errors and providing clinicians with the accurate measurement of BP, which is essential to classify individuals, to ascertain BP-related CV risks and to guide management. PMID- 24791187 TI - Resistant hypertension: current status, future challenges. AB - Resistant hypertension in adolescents is increasing in frequency and is increasingly recognized as having significant short- and long-term health consequences. It may be seen in up to 30% of all hypertensive patients cared for. Adolescents with resistant hypertension are at higher cardiovascular (CV) risk due to a long history of severe hypertension complicated by other CV risk factors such as obesity. Common causes of resistant hypertension include primary aldosteronism, sleep apnea, diabetes and chronic kidney disease. Careful blood pressure (BP) measurement and thorough evaluation of patients with sustained BP elevation should make a possible early diagnosis of resistant hypertension. Successful treatment requires identification and reversal of life-style factors contributing to treatment resistant and diagnosis and appropriate treatment of causes of hypertension. Improved pharmacologic therapies may offer the potential for preventing or at least ameliorating early CV disease. This review highlights these and other important issues in the evaluation and management of adolescents with resistant hypertension and provides practical guidance to the practitioners involved in caring for such patients. PMID- 24791189 TI - Managing hypertension in the newborn infants. AB - Hypertension in newborn infants, particularly those requiring intensive care, is becoming increasingly recognized, with prevalence of 0.2-3%. Recent studies have established normative tables for blood pressure (BP) in both term and pre-term infants based on the gestational age, postnatal age, gender, weight and height, identifying the neonates at increased risk for early-onset cardiovascular disease. Common causes of neonatal hypertension include thromboembolic complications secondary to umbilical artery catheterization, congenital renal structural malformation, renovascular disease, aortic coarctation, as well as acute kidney injury and certain medications. A careful diagnostic evaluation should lead to identification of the underlying cause of hypertension in most infants. Treatment options should be tailored to the severity; and underlying cause of hypertension, including intravenous and/or oral therapy. This review summarizes recent work in these areas, focusing on optimal BP measurement, definition, evaluation and management of hypertension as well as advances in drug therapy of neonatal hypertension. PMID- 24791188 TI - Hypertension and obesity after pediatric kidney transplantation: management based on pathophysiology: a mini review. AB - Hypertension after pediatric renal transplant is a common and important risk factor for graft loss and patient survival. The mechanism of post kidney transplant hypertension is complex and multifactorial. Control of blood pressure in renal transplant patients is important but often times blood pressures remain uncontrolled. The management of hypertension and obesity in pediatric kidney transplant patients is based on the pathophysiology. Compared to the general pediatric hypertensive population, special attention needs to be focused on the additional impact of immunosuppressive medications side effects and interactions, recurrent disease, and donor and recipient comorbidities such as obesity on blood pressure control with thoughtful consideration of the risk of graft failure. In general, there is a need for prospective studies in pediatric kidney transplant patients to understand the pathophysiology of hypertension and obesity and the appropriate approach to achieve a balance between the primary need to avoid rejection and the need to lower blood pressure and prevent obesity. PMID- 24791190 TI - Prehypertension: a warning sign of future cardiovascular risk. AB - Since the report from the national high blood pressure (BP) education program working group on BP in children and adolescents and the introduction of a new description called prehypertension many data have been provided on its rate of progression to hypertension, its prevalence and association with other cardiovascular (CV) risk factors and its therapy. Making a diagnosis of prehypertension in a child or adolescent identifies an individual at increased risk for early-onset CV disease who requires specific treatment. Thus, routine BP measurement is highly recommended at every health-care encounter beginning at 3 years of age. This review will present updated data on prehypertension in children and adolescents to increase awareness of health-care providers to the seriousness of this condition. Optimal BP measurement techniques as well as the evaluation and management of prehypertension will be discussed and preventive strategies to reduce the CV risk will be presented. PMID- 24791191 TI - The Prevalence of Pre-hypertension in Children with Type 1 Diabetes Mellitus. AB - BACKGROUND: Hypertension is more common in adults with type 1 diabetes mellitus (T1DM) than the general population. The aim of this study was to detect the pre hypertensive stage in children with T1D and to evaluate its correlation with diabetic nephropathy compared to non-diabetic children. METHODS: This was a prospective cross-sectional study in an out-patient clinic of a university hospital. A total of 62 which consists of 36 males and 26 females patients with stable T1D with a median age of 13 year and 42 age - sex-matched healthy children were entered in the study between September 2008 and February 2011. Three readings of blood pressure were recorded. Fasting blood sample was drawn for hemoglobin A1C (HbA1C), creatinine and a 24 h urine aliquot was collected to measure microalbumin, creatinine and volume to estimate glomerular filtration rate (eGFR). RESULTS: From 62 children with T1DM, 25.8% were in pre-hypertensive stage, 4.8% Stage 1, and 1.6% Stage 2. In controls, 1 (2.4%) out of 42 children was in pre-hypertensive stage (P < 0.0001). Abnormal blood pressures were correlated with eGFR and the duration of disease (P < 0.05), but there were not associated with microalbominuria or HbA1C level. CONCLUSIONS: There was a higher rate of early stage of high normal blood pressure in children with T1DM compared with the healthy controls and this abnormality was only correlated with puberty stage and glomerular filtration rate. PMID- 24791192 TI - Prehypertension and cardiovascular risk factors in children and adolescents participating in the community-based prevention education program family heart study. AB - BACKGROUND: Because prehypertension identifies children most at risk for the development of future hypertensive disease, the purpose of this study was, to examine the association of prehypertension with risk factors for cardiovascular disease (CVD) in a large sample of youths participating in the community-based prevention education program family heart study. METHODS: We estimated blood pressure and body mass index (BMI) for age and the lipid profile in terms of total cholesterol (TC), low-density-lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), non-HDL-C, triglycerides (TG) and the LDL-C to HDL-C ratio. RESULTS: Among 10,841 (5,628 males) children and adolescents 1,587 (14.6%) had prehypertension (85(th) to <95(th) percentile). This was strongly affected by weight, resulting in 19.7% in overweight (BMI >=85(th) percentile) and 23.7% in obese (>95(th) percentile) youth. The prevalence of dyslipidemia was similar in prehypertensive boys and girls in terms of LDL-C 11.2% versus 11.8%, non HDL-C 11.9% versus 14.3%, TG 2.4% versus 2.7% and for low HDL-C 2.1% versus 2.3%. The prevalence of low HDL-C increased from 2.1% in non-overweight, through 3.9% in overweight to 5.2% in obese youth and of elevated TG from 1.2% via 4.5% to 6.5% respectively. The number of risk factors is affected by BMI. Significant associations between prehypertension and CVD risk factors were observed in boys and girls for overweight/obesity odds ratios (OR 2.0/2.4), for hypertriglyceridemia (OR 1.9/2.0), for high non HDL-C (OR 1.4/1.4) and for elevated LDL-C (OR 1.3/1.1). CONCLUSIONS: Prehypertension was significantly associated with overweight, obesity and dyslipidemia in 10,841 children and adolescents. PMID- 24791193 TI - Prevalence of Prehypertension and Hypertension in a Nationally Representative Sample of Iranian Children and Adolescents: The CASPIAN-IV Study. AB - BACKGROUND: The global health burden has faced toward non-communicable diseases (NCDs). It is suggested that adulthood blood pressure (BP) is tracked from childhood. This study aims to evaluate the mean BP and the prevalence of prehypertension and hypertension in the Iranian pediatric population. METHODS: In a national survey as the 4(th) phase of Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable diseases study and through random multistage cluster sampling, a national sample of Iranian school students, aged 6 18 years, were recruited. Data gathered by means of modified World Health Organization Global school-based student health survey questionnaire, a weight disorders determinants questionnaire and anthropometric and BP measurements. Prehypertension (HTN) was defined as BP equal or greater than 90(th) age and sex specific percentile or >=120/80 mmHg and HTN was defined as BP >=95(th) percentile. RESULTS: A total of 13486 students entered the study (49.2% girls, 75.6% urban). Mean age of participants was 11.47 +/- 3.36 years. A total rate of 4.17% (3.84-4.52 95% CI) for high systolic BP (SBP), 4.33% (3.99-4.68) for high diastolic BP (DBP) and 6.88% (6.45-7.32) for high SBP and/or DBP was depicted. CONCLUSIONS: The prevalence rate of high BP (pre-HTN together with HTN) is substantially high in this population. It is needed to study the causative situations and implement relevant interventions. PMID- 24791194 TI - Hypertension and its correlates among school adolescents in delhi. AB - BACKGROUND: Hypertension is fast emerging as a major health problem amongst all school adolescents, particularly in urban areas. Regular screening of the students for this is required for preventing the emergence of complications later in life. Therefore, the present study was undertaken with the objective to determine the prevalence of hypertension amongst urban school adolescents and its correlation with anthropometric measurements. METHODS: A cross-sectional study was conducted in a school in Central Delhi involving all 315 students of 9(th) and 11(th) standard. A preforma was filled by the students and anthropometric measurements along with blood pressure (BP) measurements were taken for each student. Data was analyzed using Epi-info 2005 and SPSS 16.0. RESULTS: Out of the total 315 students, 208 (66%) were boys and 107 (34%) were girls and the mean age was 14.31 +/- 0.96 years. Overall prevalence of malnutrition was 24% and boys were found to be more obese as compared to girls. There were 5 students (1.6%) who were found to have systolic hypertension while 17 (5.4%) were found to have diastolic hypertension while 4.1% (n = 13) of the participants were systolic pre hypertensive and 26% (n = 82) were in stage of diastolic pre-hypertension. Body mass index and gender were found to be independent predictor for systolic hypertension. CONCLUSIONS: Prevalence of hypertension and pre-hypertension was high amongst the school children. BP check-up for children and adolescents is thus recommended to take remedial action on time. PMID- 24791195 TI - Childhood obesity: a determinant of adolescent and adult hypertension. PMID- 24791196 TI - The Sensory Perception Quotient (SPQ): development and validation of a new sensory questionnaire for adults with and without autism. AB - BACKGROUND: Questionnaire-based studies suggest atypical sensory perception in over 90% of individuals with autism spectrum conditions (ASC). Sensory questionnaire-based studies in ASC mainly record parental reports of their child's sensory experience; less is known about sensory reactivity in adults with ASC. Given the DSM-5 criteria for ASC now include sensory reactivity, there is a need for an adult questionnaire investigating basic sensory functioning. We aimed to develop and validate the Sensory Perception Quotient (SPQ), which assesses basic sensory hyper- and hyposensitivity across all five modalities. METHODS: A total of 359 adults with (n = 196) and without (n = 163) ASC were asked to fill in the SPQ, the Sensory Over-Responsivity Inventory (SensOR) and the Autism Spectrum Quotient (AQ) online. RESULTS: Adults with ASC reported more sensory hypersensitivity on the SPQ compared to controls (P < .001). SPQ scores were correlated with AQ scores both across groups (r = .-38) and within the ASC (r = .18) and control groups (r = -.15). Principal component analyses conducted separately in both groups indicated that one factor comprising 35 items consistently assesses sensory hypersensitivity. The SPQ showed high internal consistency for both the total SPQ (Cronbach's alpha = .92) and the reduced 35 item version (alpha = .93). The SPQ was significantly correlated with the SensOR across groups (r = -.46) and within the ASC (r = -.49) and control group (r = .21). CONCLUSIONS: The SPQ shows good internal consistency and concurrent validity and differentiates between adults with and without ASC. Adults with ASC report more sensitivity to sensory stimuli on the SPQ. Finally, greater sensory sensitivity is associated with more autistic traits. The SPQ provides a new tool to measure individual differences on this dimension. PMID- 24791197 TI - Offering assisted peritoneal dialysis is a cost-effective alternative to the current care pathway in frail elderly Dutch patients. AB - BACKGROUND: With the Dutch population aging, the number of individuals 75 years old or more needing dialysis is growing. This analysis assessed the cost effectiveness of adding nurse-assisted peritoneal dialysis (aPD) to the usual care pathway in frail Dutch end-stage renal disease (ESRD) patients. METHODS: THE CURRENT DUTCH TREATMENT PATHWAY (CONSERVATIVE MANAGEMENT, CM: 40% and PD in nursing home, nhPD: 60%) was compared in a decision-tree model with a new approach where the proportion of patients on dialysis would increase to 80% (i.e. CM: 20%; nhPD: 20%; and aPD: 60%). In-center hemodialysis was added in a secondary analysis. Inputs included survival (from literature), utility (from literature), and costs (2009 official tariffs). A healthcare payer's perspective was used with a 5-year horizon. RESULTS: The new approach was almost cost neutral in the primary analysis (despite more patients on dialysis) and dominant (more effective and less expensive) in the secondary analysis. The incremental cost effectiveness ratio was only ?52/QALY. In the sensitivity analyses (primary and secondary analyses), the new approach was either dominant or cost-effective in approximately 75% of the simulations. CONCLUSIONS: Despite the investment required, offering aPD to frail elderly ESRD patients is a cost-effective alternative to the current pathway for Dutch healthcare payers. PMID- 24791198 TI - Angiogenesis factors involved in the pathogenesis of colorectal cancer. AB - Colorectal cancer stands at the top of oncologic pathology in the world, and in the same measure in Romania because is the third most frequent cancer diagnosed in men and women. Colorectal cancer develops as a result of mutations in genes that control proliferation and cell death. It was established that in the development of a tumor there is originally a prevascular phase followed by a phase of tumor angiogenesis. In the future it is necessary to develop new clinical protocols that angiogenesis inhibitors are associated with chemo or radiotherapy, conventional or other methods such as immunotherapy and gene therapy. PMID- 24791200 TI - Intrapartum ultrasound assessment of fetal head position, tip the scale: natural or instrumental delivery? AB - OBJECTIVES: The main objective of this study was to observe the behavior of the fetal head position during labor, when starting from occiput anterior or posterior position and also to determine their importance in labor management (if the starting fetal head position can be a strong argument in favour of vaginal or cesarean delivery). METHODS: 187 patients in labor were included in this study, with gestational age over 37 weeks and estimated fetal weight over 2500 g, singleton pregnancy, cephalic presentation, empty urinary bladder. For these patients the ultrasound assessed parameters were: fetal head position at the beginning of labour and fetal head rotation during labour. RESULTS: 89,18 percent of the patients starting from OTP (occiput transverse or posterior position) had a vaginal birth after an anterior rotation of the fetal head, and only 10,82 % presented persitent occiput posterior requiring cesarean section for delivery. Furthermore, considering only initial occiput posterior position, we observed an increased rate for cesarean section delivery (22,72%) by persistence of this position during labour. None of the patients starting with an anterior fetal head position rotated posteriorly. CONCLUSIONS: vaginal delivery in occiput anterior position was the most common result in both OTP and OP fetal head initial position. The main reason for cesarean delivery was persistent OP position. Patients with occiput posterior position were subsequent only to an initial posterior/transverse position. PMID- 24791199 TI - Pharmacological mechanisms underlying the association of antipsychotics with metabolic disorders. AB - Obesity and metabolic syndrome in association with an increased risk of cardiovascular disease and type II diabetes are significant problems that contribute to lower life expectancy of patients with schizophrenia. Understanding the pharmacological mechanisms of the current antipsychotic treatment is clearly the key to the improvement of pharmacotherapy, to avoid or to mitigate the metabolic adverse effects. PMID- 24791201 TI - Correlation between High Endothelial Vessels and Histopathological Features of Different Pigmented Lesions. AB - PURPOSE: Tumor infiltrating lymphocytes are playing an important role in cutaneous melanoma being a strong prognostic parameter. Our goal was to study the presence of high endothelial vessels in correlation with the histopathological features in different pigmented skin lesions. MATERIAL AND METHODS: our study group included 60 patients (20 cases with dysplastic nevi, 20 thin melanoma and 20 thick melanoma). For each patient we noted epidemiological and clinico pathological characteristics including: age, gender, anatomic sites, regression, Breslow thickness, mitoses, Clark level and lymphocytic infiltration. Using immunohistochemistry staining we identified the presence of high endothelial vessels in our groups. RESULTS: the most common localization of primary melanoma was trunk 57,5%, followed by extremities 35% and head 7,5%. We found positive MECA-79 vessels in 67% of primary melanoma samples and in 30% of dysplastic nevi. Lymphocytic infiltration was present in 80% samples of dysplastic nevi and 75% of primary melanomas. Using Kruskal Wallis non-parametric test we found a positive association between MECA-79+ vessels and different anatomic sites (p<0,01). We have also found a significant correlation between MECA-79+ vessels and the presence of regression in melanoma samples. In conclusion a better understanding of tumor microenvironment and mechanisms involved in anti-tumor response might play an important role in development of future melanoma therapeutic strategies. PMID- 24791202 TI - Plasma levels of glucose and insulin in patients with brain tumors. AB - In the last years there were many authors that suggest the existence of an association between different components of metabolic syndrome and various cancers. Two important components of metabolic syndrome are hyperglycemia and hyperinsulinemia. Both of them had already been linked with the increased risk of pancreatic, breast, endometrial or prostate cancer. However the correlation of the level of the glucose and insulin with various types and grades of brain tumors remains unclear. In this article we have analysed the values of plasma glucose and insulin in 267 patients, consecutively diagnosed with various types of brain tumors. Our results showed no correlation between the glycemia and brain tumor types or grades. High plasma levels of insulin were found in brain metastasis and astrocytomas while the other types of brain tumors (meningiomas and glioblastomas) had lower levels of the peptide. The levels of insulin were also higher in brain metastasis and grade 3 brain tumors when compared with grade 1, grade 2 and grade 4 brain tumors. PMID- 24791203 TI - The assessment of prognostic histopatholgical parameters depending on histological patterns of papillary thyroid carcinoma. AB - Papillary thyroid carcinoma represents common injuries that can have different histological variants that may influence the patient's prognostic. The study included a total of 44 papillary thyroid carcinomas, for which were followed a series of histological factors of aggressiveness for grading tumors. Most studied papillary carcinomas corresponded to the conventional type, followed by the follicular, micropapillary and tall cell variants. Depending on the presence of nuclear atypia, tumor necrosis, the frequency of mitosis, also the vascular invasion and the extrathyroidian extension there were distributions differences of the cases according to the tumor type, most of the cases belonged to the conventional and tall cell types. The assessment of histopathological parameters of aggressiveness with certain types known to have an unfavorable behavior, justify the use of the histological grading of papillary thyroid carcinomas. PMID- 24791204 TI - Considerations About Risk Factors for Peripheral Neuropathies in Romanian HIV Infected Patients. AB - PURPOSE: The study aims at detecting risk factors for developing peripheral neuropathy in Romanian HIV infected subjects. MATERIAL/METHODS: retrospective study (january 1990-january 2009) who analyzed data from patients hospitalized in the Regional Center Craiova. We have compared 26 patients (group N) diagnosed with peripheral neuropathy with 40 patients (group C) without neuropsychological sufferings, randomly selected. We have analysed: age, height, HIV mode of transmission, AIDS status, the average and nadir of CD4 lymphocytes, the mean viral load, the average duration of antiretroviral treatment (ART), use and duration of use of d-drugs, the presence of certain coinfection, diabetes or ethanol abuse. RESULTS: the following differences were statistically significant: age (31,54+/-14,64 vs 23,9+/-12,03 years, p=0.024), HIV mode of transmission (parenteral/sexual: 13/13 vs 28/8, p = 0.044), the monitoring time duration (5,31+/-3,77 vs 7,75+/-5,4 years, p=0.043), median ART duration (37,2+/-9,66 vs 45,12+/-8,75 months, p=0.001). Close to the threshold of statistical significance are the CD4 nadir (97,33+/-65,6 vs 123,15+/-43,35 cells/mm3, p=0.058) and duration of use of d-drugs (22,5+/-31,94 vs 12,24+/-8,6 months, p=0.057). Odds ratio (OR) and relative risk (RR) increase with age. ROC analysis for the study group establishes a threshold difference of 29 years (sensitivity 50%, specificity 80%). CONCLUSIONS: higher age and advanced immunosupression are the most important risk factors for developing symptomatic peripheral neuropathy in Romanian HIV infected patients; taking into account the small number of cases studied, although not statistically significant, it should be noted the CD4 nadir and the length of d-drug use. PMID- 24791205 TI - Adjuvant Treatment of Intermediate Risk Non-muscle Invasive Bladder Cancer. AB - Despite continuous improvement of diagnosis, surgical and adjuvant treatment procedures for non-muscle invasive bladder cancer (NMIBC), their natural development is still influenced by the high rates of tumor recurrence and progression. The study aims at assessing the value of adjuvant intravesical chemotherapy within the therapeutic protocol for operated intermediate risk non muscle invasive bladder cancers. We analyzed recurrence and progression rates for patients within two samples: group A included 76 patients with intermediate risk NMIBC treated by transurethral resection (TUR) alone between 1995 and 1999 and group B included 89 patients with the same diagnosis with 8 - 12 Farmorubicin 50 mg intravesical instillations associated with the initial TUR between 2000 and 2004. For group A we recorded a 3 months recurrence rate of 27.6% and a general recurrence rate of 38.1% at one year and 51.3% at three years. The recurrence rate was lower for group B at 3 months (14.6%) as well as significantly lower (p<0.05) at one (23.6%) and three years (34.8%). Most NMIBC recurrences were recorded within one year of follow-up (75%), more than 50% of them being present at the first cystoscopy (3 months). Progression rate was unsignificantly 3% lower for group B, probably due to incomplete pathology data. PMID- 24791206 TI - Remission of Walking Parameters in Peripheral Arterial Disease through Association of Galvanic Baths and Kinesytherapy. AB - Chronic peripheral obstructive arteriopathies (CPOA), together with their determinations, play an important role in the elderly pathology and represent one of the most frequent causes of disability, thus having a negative impact on the patient's quality of life. Therefore, in this clinical randomized trial we proposed to study the efficiency of several treatment methods based on physical exercise together with other therapeutical approaches specific to physical medicine such as galvanic baths. We formed a group of 111 patients diagnosed with peripheral arterial disease in inferior limbs randomized into three groups: the control group (drug treatment and hygiene-dietary), the exercise group (12 weeks supervised exercises program, followed by another 12 weeks home unsupervised exercises) and the exercise and procedure group (kinesitherapy and galvanic baths). All the subjects performed the exercise treadmill test, according to the Gardner protocol, at the beginning of the study, after 12 weeks and after 24 weeks, at the end of the study and were measured: the time to pain onset (TDC) and the time to maximum pain onset (maximum walking time=TDD). We observed quite high TDC differences in the two groups that performed physical exercises compared to the control group, while the amelioration of walking periods was recorded after the first 12 weeks, and after 24 weeks they reached walking periods 2.5 times higher than at the beginning of the study. Adding hydrotherapy to the physical exercise led to even higher TDC values. After 12 weeks, we obtained a 54% TDD remission in the exercise group (p<0.005) and a 65% remission in the exercise and hydrotherapy group (p<0.005) and at the end of period, the TDD remission was 90% in the exercise group (p<0.005) and 100% in the exercise and hydrotherapy group (p<0.05). The kinetic-physical modalities show its efficiency in ameliorating the walking parameters in the patients with claudication and may offer low risks compared to the revascularization methods, high addressability, diminished costs. PMID- 24791207 TI - Total thyroidectomy without the use of drainage - case series of 66 patients. AB - AIM: The aim of this series is to study the need of drainage use after total thyreoidectomy. MATERIAL AND METHODS: Retrospective study of a series of patients who underwent total thyroidectomy from 2005 up to 2013. The presence or not of hematomas, seromas and hemorrhage were recorded. RESULTS: Out of the 66 patients included in this series, only one case of post-operative hematoma was recorded. Neither a hemorrhage nor a seroma were identified despite the volume, the underlying pathology and the co-morbidity of the patients involved. CONCLUSION: In our experience a thyroidectomy with adequate hemostasis does not require the use of drains. PMID- 24791208 TI - The pharmacists and homeopathy. AB - Presented at the end of the end of the XVIII(th) century by the German doctor Samuel Hahnemann as a form of complementary therapy, homeopathy has increasingly produced multiple controversies regarding the plausibility, effectiveness and safety of homeopathic remedies. Regardless, there are clients who require pharmacist's advice about their usage indications and effectiveness. As specialists in the field of medication, pharmacists must have basic notions about the principles on which homeopathic remedies have been based, given that it is the opposite of modern pharmacological theories. These describe in great detail the underlying mechanisms of action of the drug. Under these conditions, the ethical role of the pharmacist is to give accurate, impartial information regarding the homeopathic therapy, the current scientific proof on their therapeutic effects, including the placebo effect. This, doubled by a comprehensive, objective presentation of the options of medication-based treatment, guarantee pharmacists a clean reputation as competent authorities in the pharmaceutical field. PMID- 24791209 TI - Bullous pemphigoid associated with psoriasis, breast cancer and Parkinson's disease. AB - Bullous pemphigoid (BP) and psoriasis vulgaris represent two clinically well characterized, inflammatory, chronic skin diseases. A 62 years old female patient, from rural areas, was admitted for the presence of erythematous plaques covered by large tense blisters with clear fluid, located symmetrically on the anterior part of the upper limbs, the trunk, the neck and the lower limbs. Also the lesions were intense itching. Lesions occurred three days before presentation at the clinic. Medical history revealed psoriasis diagnosed 28 years ago, breast cancer treated with surgery, radio and chemotherapy three years ago and Parkinson's disease diagnosed 3 weeks prior to presentation to the dermatology clinic. Histopathology examination revealed: atrophic epidermis with subepidermal presence of a blister containing numerous eosinophils and neutrophils. In the papillary dermis neutrophils and eosinophils predominantly vascular. Bullous pemphigoid has multiple etiology. Bullous pemphigoid is an autoimmune subepidermal bullous dermatosis which may be associated with psoriasis. Medical literature and cases reported in dermatology journals claim that bullous pemphigoid is often associated with psoriasis, though the immunogenetical and immunopathologycal mecanismes are still not known. Our patient has three different diseases but their etiology and pathogenesis can interfere. PMID- 24791210 TI - Secondary haemochromatosis in a patient with thalassemia intermedia. AB - Haemochromatosis is due to excessive accumulation of iron in tissues and organs impairing their function. The most common haematologic disorders that are subject to an intensive transfusion regimen bringing excess iron in the body are: thalassemia and myelodysplastic syndrome. The value of serum ferritin in these patients (indicator of iron stores condition) reaches high values. Red cell substitution bringing additional iron intake must be accompanied by administration of chelation therapy in order to prevent haemochromatosis and related complications. We present the case of a patient with thalassemia intermedia, integumentary secondary haemochromatosis, cirrhosis with haemochromatosis, and secondary diabetes, who died at the age of 33 years because of upper gastrointestinal bleeding due to the rupture of oesophageal varices. PMID- 24791211 TI - A rare case of ocular myositis. AB - We report the case of a 43 year old man who presented recurrent left abducens palsy. His medical history included arterial hypertension, ischemic cardiomiopathy, dyslipidemia, rhinitis, maxillary sinusitis. Physical examination revealed a overweight patient, horizontal gaze diplopia, left nerve VI paresis, mild left retro-orbital pain. The orbital MRI also didn't offer new information: mild external edema on the left eye, with normal tendon aspect, no thickening or enhancement of the muscle belly and also normal aspect of the bony orbit. Recurrent palsy of EOMs can be caused in rare cases by ocular myositis. PMID- 24791212 TI - An unusual tumor of the breast - extraskeletal ewing sarcoma. AB - Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor presenting as a breast mass is uncommon. It may pose a diagnostic challenge. In order to increase awareness and identify potential diagnostic pitfalls, we report a 24 year-old woman extraosseous Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor arising in the breast. PMID- 24791213 TI - Varicella-zoster myocarditis mimicking acute myocardial infarction. AB - A 23-year-old male was admitted with chest pain. The electrocardiogram showed ST elevation in leads DI, aVL, V2-V6. Troponin T was 1.1ng/mL. Left ventricular systolic function was globally reduced (ejection fraction 45%). The patient was treated with thrombolytic. Twenty-four hours after admission pruriginous vesicles with a clear content and surrounded by a pink halo appeared on his face, head and torso, suggesting varicella-zoster infection. This case illustrates the difficulties of diagnosis in acute myocarditis. PMID- 24791215 TI - [Not Available]. PMID- 24791214 TI - Micropatterning of 3D Microenvironments for Living Biosensor Applications. AB - Micro-scale printing and patterning of living cells has multiple applications including tissue engineering, cell signaling assays, and the fabrication of cell based biosensors. In this work, a molecular printing instrument, the Bioforce Nano eNabler, was modified to enable micron-scale -quill-pen based printing of mammalian cells in a 3D hyaluronan/gelatin based hydrogel. Specifically, photo initiated -thiol-ene click chemistry was used to couple the thiol groups of thiolated hyaluronan/thiolated gelatin to the alkene groups of 4-arm polyethylene glycol (PEG)-norbornene molecules. Rapid photopolymerization enabled direct printing and controlled curing of living cells within the hydrogel matrix. The resulting hydrogels were biocompatible with human adipose-derived stem cells, NIH 3T3 cells, and mouse embryonic stem cells. The utility of this printing approach was also explored for cell-based biosensors. Micro-printed cells expressing a redox sensitive variant of the green fluorescent protein (roGFP-R12) showed a measurable fluorescent response to addition of oxidizing and then reducing agents. This work represents a novel approach to micron-scale cell patterning, and its potential for living, cell-based biosensors. PMID- 24791216 TI - [How I do it: neural tube defects in guatemala - myelomeningocele spina bifida unit]. AB - In Guatemala about 786 children are born each year with Neural Tube Defects. At our unit we operate 65 to 70 children with myelomeningocele. We have a multidisciplinary team. We recommend delivery through cesarean section. Preoperative infection is our major problem. Delayed referral is common. Dissection of placode is standard. Suture the edges of placode to resemble shape of normal cord. We perform corpectomy in cases of severe kyphosis. Hydrocephalus: We shunt 80% of the patients. Chiari II: We operate based on symptoms, first we make sure that the shunt is working, then cervical decompression. Tethered cord: We operate if observe that symptoms are progressing. PMID- 24791217 TI - [How I do it: myelomeningocele]. AB - Fortification of food with folic acid is effective. Work needs to be done to raise the awareness of its importance among young couples. Prenatal consult is crucial in countries where abortion is legal. I use microscope to enhance the learning experience of the resident. For that I irrigate frequently the placode to reduce the heat from the lamp. I treat the placode as viable tissue. I don't suture the placode. I use dura patch if required to increase the space in the canal. I don't close muscle. Hydrocephalus: Shunt in case of ventriculomegaly. Tethered cord: At least one untethering, not completely convinced about repeated untethering. Chiari II: Revise the shunt. Follow up: Factor academic performance as an indicator of subtle shunt failure or tethered cord. PMID- 24791218 TI - [How I do it: spinal cord lipomas]. AB - Based on 82 cases reviewed, in 5% we observed pelvic associated anomalies. In children less than 3 years of age the consult was triggered by the lumbar-sacral mass. In older than 3 years (42%) neurological problems triggered the consult. Only 24% at that age were concerned by the mass. The objective of the surgery is to untether the cord, and not to remove the entirety of the lipoma. Filum lipoma is the simplest to treat. Event though the French School is popular in Argentina I favor preventive surgery for lipoma even in asymptomatic patients. We had only 2.5% of added motor impairment and 6% in long term urological deficit. PMID- 24791219 TI - [How I do it: surgical treatment of myelomeningocele]. AB - In Argentina there is national program for fortifying flour with folic acid. Prenatal diagnosis is not always accurate. Closure according to standard technique. We close muscle layer. We don * t favor corpectomy for kyphosis. We suture the placode to restore cylinder shape of the cord. We close muscle layer. Hydrocephalus: V-P shunt. Third ventriculostomy is not effective. Chiari II: Cervical laminectomy. Syringomyelia: We shunt the syrinx to the peritoneum. MMCL is the most common neural tube defect. It consists of a neural placode exposed to environment. The placode is surrounded by arachnoid and by thin epithelial tissue. PMID- 24791220 TI - [How I do it: myelomeningocele in bolivia]. AB - INTRODUCTION: Neural Tube Defects (NTD) are the second congenital malformation, second only to cardiac malformations. Myelomeningocele (MMCL) is the most frequent NTD and the more complex. In Bolivia, like in many countries in South America, the low socio economical level of the population increases its incidences and complicates its management. MATERIALS AND METHODS: Retrospective study of 70 cases of MMC at Hospital Universitario Japones (HUJ), Santa Cruz de la Sierra, between 2008-2011. Sixty had surgery. RESULTS: Prenatal care in 27 women (38.6%), positive diagnosis for spinal disraphism in 2 (7.4%). The child arrived after 24 hours of birth (65.5%). Lumbosacral lesion (64.3%). Of those 67.2% were open, with 32.9% evidencing partial motor lesion in contrast with 47.1% who were paraplegic bellow the level of the lesion. Three children were not operated because they had complex and severe malformations associated to the MMCL. The most common surgical complications were; wound dehiscence or infection (16.6%), CSF fistula (10%) CNS infection (11.7%). Mortality and specifically postoperative mortality were 7.1% y 3.3%, respectively. Hydrocephalus wass evident in 80% of the patients who were operated, they received a VP shunt medium pressure. Nine patients who had long term follow up presented with tethered cord. CONCLUSIONS: A characteristic, delayed referral. No gender predominance. Majority of cases were lumbar or lumbar sacral. Mortality similar to what is reported in the literature. Few patients came for follow up. MMCL is a pathology that requires concentrated attention by the national authorities. A multi center and multi national study will improve our management of these patients. PMID- 24791221 TI - [How I do it: neural tube defects in nicaragua]. AB - Nicaragua does not have a national plan for folic acid fortification. Mothers are often very young. At La Mascota we operated more than 40 cases per year. Delayed arrival is a problem. Pre operative infection has to be ruled out. Vancomycin and Ceftriaxone are indicated. Strict scrub rules are applied. Restore the shape of the cord by suturing the placode. Do not close muscle layer. PMID- 24791222 TI - Improved Adherence to Vision Self-monitoring with the Vision and Memory Stimulating (VMS) Journal for Non-neovascular Age-related Macular Degeneration during a Randomized Controlled Trial. AB - OBJECTIVE: An educational, interactive journal [Vision and Memory Stimulating (VMS) journal] was developed to boost patient confidence and promote long-term adherence with weekly vision self-monitoring in age-related macular degeneration (AMD) patients at risk for vision loss from new-onset neovascularization. METHODS: In a multicenter randomized controlled trial, 198 subjects with intermediate stage, non-neovascular AMD received the VMS journal or followed usual care (e.g. their doctor's instructions for vision monitoring; Amsler grid). At 6 and/or 12 months post-enrollment, 157 subjects completed a questionnaire on vision self-monitoring. RESULTS: At 6 and 12 months, respectively, 85% and 80% of the VMS journal subjects reported vision monitoring at least weekly, which represent statistically significant 7.1 and 4.2 times greater odds than the 50% of controls who monitored weekly at both follow-up times (p<0.001). At 6 and 12 months, respectively, 29% and 25% of controls indicated that they had not checked their vision in the past 6 months, while only 1.5% and 5% of the VMS journal subjects reported no vision self-monitoring. At 6 and 12 months, respectively, only 15% and 13% of the VMS journal subjects vs. 53% and 44% of the controls reported that they did not feel confident that they were taking care of their sight by self-monitoring (p<0.001). Usual care controls had statistically significant 6.7 and 5.0 times greater odds of reporting non-confidence at 6 and 12 months, respectively. There was no statistically significant change in weekly vs. less frequent self-monitoring between the groups (p=0.68), with 81% of all subjects reporting no change in frequency between 6 and 12 months. CONCLUSIONS: These findings support the efficacy of the VMS journal for increasing vision self monitoring adherence and confidence, in addition to promoting persistence in weekly monitoring over the course of a year in AMD subjects at risk for exudative retinal changes. PMID- 24791223 TI - Effects of synaptic plasticity on phase and period locking in a network of two oscillatory neurons. AB - We study the effects of synaptic plasticity on the determination of firing period and relative phases in a network of two oscillatory neurons coupled with reciprocal inhibition. We combine the phase response curves of the neurons with the short-term synaptic plasticity properties of the synapses to define Poincare maps for the activity of an oscillatory network. Fixed points of these maps correspond to the phase-locked modes of the network. These maps allow us to analyze the dependence of the resulting network activity on the properties of network components. Using a combination of analysis and simulations, we show how various parameters of the model affect the existence and stability of phase locked solutions. We find conditions on the synaptic plasticity profiles and the phase response curves of the neurons for the network to be able to maintain a constant firing period, while varying the phase of locking between the neurons or vice versa. A generalization to cobwebbing for two-dimensional maps is also discussed. PMID- 24791224 TI - DNA Aptamer Technology for Personalized Medicine. AB - This review highlights recent progress in developing DNA aptamers for personalized medicine, with more focus on in vivo studies for potential clinical applications. Examples include design of aptamers in combination with DNA nanostructures, nanomaterials, or microfluidic devices as diagnostic probes or therapeutic agents for cancers and other diseases. The use of aptamers as targeting agents in drug delivery is also covered. The advantages and future directions of such DNA aptamer-based technology for the continued development of personalized medicine are discussed. PMID- 24791225 TI - Successful Surgical Management of Airway Perforation in Preterm Infants. AB - Traumatic airway perforation during endotracheal intubation is an uncommon but life-threatening complication in preterm infants. Death usually occurs at the time of the injury, but in rare cases where the infant survives the initial resuscitation, therapeutic options include conservative versus surgical management. We describe three cases of airway perforation treated successfully with surgical intervention and without lung resection, utilizing novel graft material and cardiopulmonary bypass to facilitate repair. In preterm infants who survive the initial injury we advocate for early identification and surgical management with cardiopulmonary bypass when feasible. PMID- 24791226 TI - Why Family Medicine is a Good Career Choice for Indian Medical Graduates? AB - Internationally family medicine has evolved as an independent academic discipline of medical science and speciality vocational training for community based primary care physicians. India has a long tradition of family practice however due to various regulatory barriers family medicine did not optimally develop in mainstream medical education system for many decades. Recently, there is growing interest in this concept in India and family medicine is emerging as a viable career option for medical graduates in India. PMID- 24791227 TI - A Critical Appraisal of Kuppuswamy's Socioeconomic Status Scale in the Present Scenario. AB - The socioeconomic status (SES) is widely recognized as one of the important factors affecting the health condition of an individual or a family. One of the scales widely used and quoted even today is the one developed by Kuppuswamy. The Kuppuswamy scale in its various forms has held steady over three decades now and is still widely used as a measure of socioeconomic status in the urban population. However, it is important to discuss the applicability in the changed modern scenario. PMID- 24791228 TI - Patient Satisfaction and it's Relation to Diabetic Control in a Primary Care Setting. AB - CONTEXT: Patient satisfaction is of increasing importance and recognized as an important indicator for quality of care. It is influenced by the patients, physicians and practice's characteristics. The literature on diabetes has increasingly focused on the quality of care and its measurement. The relationship between the quality of diabetes care and patient satisfaction is poorly understood and it requires further elaboration. AIMS: The aim of this study is to Identify the underlying factors influencing patient's satisfaction with the diabetes care, to assess whether comprehensive diabetes management that provided in diabetic clinic improves satisfaction and glycemic control. SETTINGS AND DESIGN: Cross-sectional study Family Medicine and Diabetic Clinics at King Abdul Aziz Medical City. MATERIALS AND METHODS: A total of 230 type two diabetic patients attending their follow-up were requested to fill the questionnaire. The questionnaire identified patients, doctors and practice related factors. STATISTICAL ANALYSIS USED: SPSS 16 with appropriate statistical test. RESULTS: The response rate was 85%. Mean hemoglobin A1c (HbA1c) level was 0.087 +/- 0.020. Around half of the patients were having high satisfaction rate of (>60%). Doctor's communication ranked the highest satisfaction level among other factors. However, no association between satisfaction with other patient's characteristics and HbA1c. CONCLUSIONS: Physicians play a major role in promoting higher level of satisfaction by good communication with their patients. More efforts are needed to improve certain aspects of diabetic care such as: Patient's education and periodic physical examination. Although the present study did not show any association between satisfaction and important outcome like HbA1c, more studies are needed to explore such complex relationship. To obtain more significant results a bigger sample size might be needed. PMID- 24791229 TI - A Study on Mental Disorders: 5-year Retrospective Study. AB - BACKGROUND: "Mental disorder" is the most common used term in the modern life and the main reason behind this may be the mechanical way of life or stress and strain among youth. AIM: To find the pattern of mental disorders of hospitalized patients in a medical college hospital from 1(st) April 2005 to 31(st) March 2010. SETTINGS AND DESIGN: A retrospective study conducted among the patients admitted with mental disorders in a medical college hospital from 1(st) April 2005 to 31(st) March 2010. MATERIALS AND METHODS: Data collected from the registers maintained in the medical records department. STATISTICAL ANALYSIS: Z test is used for the comparison of proportions. RESULTS: A total of 7908 mental disorder cases reported in the medical college hospital, 5564 (70.36%) were males and 2344 (29.64%) were females. Most cases occurred in the age group of 30-44 years. Mental disorder was more among females than males in 0-29 years and >= 60 years, but in 30-59 years males were more. In each year, mental disorders were reported more in males than females. Of the cases, most of them were mood disorders. Mental and behavioral disorders due to psychoactive substance use were more among males but schizophrenia, delusional disorders, mood disorders, stress related disorders, mental retardation, and so on were more among females. CONCLUSION: Mood disorder was the most occurred mental disorder and the next leading mental disorder was mental and behavioral disorders due to psychoactive substance use. Counseling can be helpful for preventing most of the mental disorders. Improve the mental health care facilities will be the solution for controlling the mental disorders. PMID- 24791230 TI - Self-ear-cleaning among educated young adults in Nigeria. AB - CONTEXT: Self-ear-cleaning has been reported to be common from several hospital based studies and it has been associated with some diseases of the ear. AIMS: To determine community-based prevalence of self-ear-cleaning and its sociodemographic correlates among educated young adults in Nigeria. SETTINGS AND DESIGN: A cross-sectional survey conducted in a National Youth Service Corps camp in Nigeria. SUBJECTS AND METHODS: Semistructured questionnaires were administered on a randomly selected sample of 1280 respondents. The outcome variable was self ear-cleaning. Independent variables were sociodemographic variables, materials used and ear-cleaning habits. STATISTICAL ANALYSIS USED: Statistical Package for the Social Sciences (SPSS) version 15 was utilized for univariate, bivariate, and multiple logistic regression analysis. RESULTS: There were 1012 respondents (M: F = 1.05:1). Mean age was 25.3 (standard deviation, 2.34). Prevalence of self-ear cleaning was 93.4%. Mean age at first cleaning was 7.6 years. Cotton buds were the most frequently used objects (in 85.1%). Prevalence was high irrespective of sociodemographic class, significantly higher among females (chi(2) = 4.549, P = 0.033), those who believed the habit was beneficial (chi(2) = 114.185, P < 0.001) and those whose parents and siblings practiced the habit. Significant predictive factors were self-ear-cleaning in respondent's father [odds ratio (OR) P = 0.011) and owning cotton buds (OR = 0.192, P = 0.007). CONCLUSIONS: Self-ear-cleaning is almost universal. Most of the population is, therefore, at risk of possible harmful effects. Also, medical advice against self-ear-cleaning is not widely known. Rather, the erroneous perception that self-ear-cleaning is beneficial is common. Collaborative health education efforts targeted at families and schools and campaigns and advocacy for legislation regulating the sale of cotton buds are recommended. PMID- 24791231 TI - Knowledge, Attitude and Practices towards Medical Research amongst the Postgraduate Students of Pravara Institute of Medical Sciences University of Central India. AB - BACKGROUND: Health research training is an essential component of medical education and a vital exercise to help develop physician research skills. OBJECTIVES: This study was carried out to assess the knowledge, attitude, and practices towards health research amongst the postgraduate students of Pravara Institute of Medical Sciences University of central India. MATERIALS AND METHODS: A cross-sectional study was carried out from August to October 2012. A total of 116 postgraduate students were interviewed. Knowledge, attitude, and practices related to health research were assessed using a predesigned, pretested and validated questionnaire. Results were analyzed in the form of percentage and proportions whenever appropriate. RESULTS: In present study, the concept of research hypothesis was known to only 18.9% of the postgraduate students, whereas 17.2 and 21.5% students knew the full form of MEDLARS and MEDLINE respectively. Majority (91.4%) students believed that patient outcome improves with continued medical research and 70.7% are willing to participate in workshop for research methodology. Lack of time due to vast curriculum of postgraduate subjects (59.5%), lack of research curriculum (25%), and inadequate facilities (25.8%) were stated as major obstacles for pursuing research. CONCLUSION: Postgraduate students have inadequate knowledge, but have positive attitudes towards health research. Postgraduate training and research facilities at the institution need to undergo major transformation in order to encourage meaningful research by postgraduate trainees. PMID- 24791232 TI - Study of prevalence of type 2 diabetes mellitus and hypertension in overweight and obese people. AB - CONTEXT: In recent years, there has been a marked change in life-style of South Asian countries caused by economic growth, affluence, urbanization and dietary westernization. Few studies on the prevalence of obesity, hypertension and diabetes in the Indian population have been reported. However, there has been scarce literature on the study of prevalence of type 2 diabetes mellitus (DM) and Hypertension in overweight and obese people in India with criteria suggested by World Health Organization (WHO) for Asians. Information on such public health issues would provide evidence based data to develop guidelines and policies on this subject. AIM: The aim of this article is to determine the prevalence of hypertension and type 2 DM in overweight and obese people. SETTING AND DESIGN: A cross-sectional study consisted of people selected from the out-patient department and indoors of a large defense hospital in a semi urban area of Assam. MATERIALS AND METHODS: Patients with overweight and obesity, reporting for consultation and medical examination were taken into the study. The data collected was analyzed using the criteria for overweight, obesity, diabetes and hypertension defined by WHO, Joint National Committee VII and International Diabetes Federation, American Diabetes Association. A descriptive statistical analysis has been carried out in the study. RESULTS: A total of 300 people were the subject population of this study. Among the subject population, there were 97 overweight and 203 obese. The 56 subjects were found to be diabetic. The prevalence of type 2 DM in overweight subjects was 15.5% and in obese was 20.2% and overall was 18.7%. Prevalence of hypertension in the overweight population was 8.2% and in obese was 22.2% and overall found to be 17.7%. CONCLUSIONS: The prevalence of type 2 DM, hypertension in the obese group of the study population were found to be 20.2%, 22.2% and in the overweight population were 15.5% and 8.2%, respectively. This indicates that the prevalence of type 2 DM and hypertension increases with increasing weight of the individuals. The prevalence of type 2 DM and hypertension were relatively higher compared with other studies in India and abroad. PMID- 24791233 TI - Psoriasis and psychiatric morbidity: a profile from a tertiary care centre of eastern India. AB - CONTEXT: Psoriasis has an impact on psychology of the patients. There is a dearth of studies regarding this field in eastern India. AIMS AND OBJECTIVES: The primary objective of this study is to evaluate the psychiatric morbidity in psoriasis and secondary objective is to assess the morbidity in all eight dimensions of psychosocial and physical aspects, i.e. cognitive, social, discomfort, limitations, depression, fear, embarrassment and anger. SETTINGS AND DESIGN: Institutional based case control study. MATERIALS AND METHODS: Forty eight patients of psoriasis and equal number of healthy controls were included in the study. Self-reporting questionnaire-24 (SRQ-24) and skindex (A 61-item survey questionnaire) were used to assess the psychiatric morbidity in both groups. STATISTICAL ANALYSIS USED: "MedCalc version 10.2.0.0" (by Acacialaan 22, B-8400, Ostend, Belgium) was used as statistical software. Chi-square test was used as a test of significance. RESULTS: The SRQ assessed psychiatric morbidity in the study group was 62.5%, compared with 18.5% in the control group. This difference was statistically significant (P < 0.001). Guttate psoriasis had maximum association with psychiatric morbidity (100%), followed by plaque type (63.6%) and palmoplantar type (42.8%). According to the skindex, the most common psychiatric morbidity in psoriasis patients was anger (58.3%), followed by discomfort (52.08%), social problem (52.08%), cognitive impairment (50%), embarrassment (50%), physical limitation (47.91%), fear (47.91%) and depression (43.75%). The skindex observed psychiatric morbidity among the case and control group was statistically significant for all the parameters (P < 0.0001). CONCLUSION: Psoriasis has a high degree of psychiatric morbidity and the extent of this co-morbidity is even greater than hitherto thought of. PMID- 24791234 TI - Role of health education and self-action plan in improving the drug compliance in bronchial asthma. AB - BACKGROUND: Considering the prevalence and associated burden of disease due to bronchial asthma, it is mandatory to obtain an optimal control of the disease and to improve outcomes for these patients. But it has been observed that there is very poor adherence to the inhalational therapy which leads to the suboptimal control of the disease. OBJECTIVES OF THE STUDY: To study the adherence for aerosol therapy in bronchial asthma patients and to assess the impact of health education and self-action plan in improving the compliance to the therapy. METHODOLOGY: A prospective study was done in a total of 500 bronchial asthma patients over a period of 2 years. Once included in the study, the patients were followed-up for a total of 12 weeks for calculation of nonadherence to the aerosol therapy. In nonadherent patients, we employed various health education strategies to improve the compliance in these cases. RESULTS: A total of 500 patients of bronchial asthma who were started on aerosol therapy over duration of 2 years were included in the study. At the end of 12 weeks, it was observed that, only 193 patients (38.6%) had regular compliance and 307 patients (61.4%) were noncompliant to aerosol therapy as prescribed for bronchial asthma. Factors that were associated with poor compliance were: Lower educational level status, poor socioeconomic status, cumbersome regimens, dislike of medication, and distant pharmacies. Nondrug factors that reduced the compliance were: Fears about side effects, anger about condition or its treatment, forgetfulness or complacency, and patient's ill attitudes toward health. After employing the various strategies for improving the compliance in these patients, the compliance increased in 176 patients (57.3%) among the earlier defaulted patients, while the remaining 131 patients (42.7%) were found to be noncompliant even after various educational techniques. CONCLUSION: Noncompliance in asthma management is a fact of life and no single compliance improving strategy probably will be as effective as a good physician-patient relationship. Optimal self-management allowing for optimization of asthma control by adjustment of medications may be conducted by either self adjustment with the aid of a written action plan or by regular medical review. Individualized written action plans based on peak expiratory flow are equivalent to action plans based on symptoms. PMID- 24791235 TI - Knowledge, attitude and practices on malaria among the rural communities in aliero, northern Nigeria. AB - OBJECTIVE: Families' perceptions, beliefs, and attitudes about malaria causation, symptom identification, treatment of malaria, and prevention are often overlooked in malaria control efforts. This study was conducted to understand these issues, which can be an important step towards developing strategies, aimed at controlling malaria. MATERIALS AND METHODS: A community based descriptive cross sectional study in four villages: Danwarai, Gehuru, Jiga, and Kashin Zama of Aliero local government area in Kebbi Sate, in northern Nigeria. Two hundred household were randomly selected and interviewed using standardized questionnaire. RESULTS: Knowledge of the role of mosquitoes in malaria transmission (11.8%) and cause of malaria (9.6%) was observed to be low among the study population. Comprehensive knowledge about malaria prevention measures was high (90%), but not reflecting in their practice (16%). They have good knowledge of mosquito behavior (breeding areas (64.5%), resting places (70%) and biting time (81%)). Seeking hospital care for a febrile child was a good practice (68.5%) observed. Attitudes regarding the best antimalarial therapy was limited (56.7%) to chloroquine. CONCLUSIONS: Misconceptions about malaria transmission and its cause still exist. Knowledge about preventive measures does not necessarily translate into improvement in practices. There is a need for targeted educational programs to increase the communities' efforts to develop desirable attitude and practices regarding malaria and their participation for malaria control. PMID- 24791236 TI - Epidemiological correlates of cataract cases in tertiary health care center in rural area of maharashtra. AB - BACKGROUND: The most recent estimates from World Health Organization (WHO) reveal that 47.8% of global blindness is due to cataract. Cataract has been documented to be the most significant cause of bilateral blindness in India. The most recent estimates from WHO reveal that 47.8% of global blindness is due to cataract and in south Asia region which includes India, 51% of blindness is due to cataract. In India cataract is the principal cause of blindness accounting for 62.6% cases of blindness. The key to the success of the Global Vision 2020: The right to sight initiative is a special effort to tackle cataract blindness which includes estimation of magnitude of the problem and understanding factors associated with it. Therefore, a study was conducted in the hospital to estimate the magnitude of cataract and study various epidemiological factors associated with it. MATERIALS AND METHODS: A cross-sectional study was conducted in a tertiary health center in rural area. Total 746 patients who availed services from ophthalmology department during study period were included in the study and relevant data was collected from them. Data analysis was done by percentages, proportions, and tests of significance (Chi-square test). RESULTS: Out of 746 patients, 400 (53.6%) were suffering from cataract. Senile cataract was the most common cause (54%). Fifty five percent patients were in the age group of 60-80 years and majority of them were from low socioeconomic strata. CONCLUSION: The prevalence of cataract in a medical college hospital in rural area was 53.6%. Age, sex, and educational status were significantly associated with cataract. PMID- 24791237 TI - Anemia among hospitalized children at a multispecialty hospital, bangalore (karnataka), India. AB - BACKGROUND: Due to the limited availability of data related to anemia in hospitalized children, this research was conducted to study the occurrence, morphological patterns, distribution in different age groups, sex, and severity of anemia among children aged 6 months-12 years. SETTING: Inpatients in department of pediatrics at a multispecialty hospital, Bangalore. STUDY DESIGN: Descriptive cross sectional study from Oct, 2011 to Sep, 2012. MATERIALS AND METHODS: Ethical clearance was obtained from the ethical committee of the hospital as per 1964 Declaration of Helsinki. Unrestricted random sampling method was used to select the study group consisting of 882 children between the age of 6 months and 12 years. After obtaining the consent, data were obtained and statistically analyzed using statistical tools like mean, median, standard deviation, and Chi-square test. RESULTS: Out of 882 children selected, 642 (72.79%) were anemic, out of which a majority of 629 (98%) children suffered from nonhemoglobinopathies and a meagre 13 (2%) suffered from hemoglobinopathies. Children in the age group of 6 months-1 year were most affected with nonhemoglobinopathies (33%). Moderate degree of anemia (hemoglobin = 7-9.9 g/dL) was the commonest grade of anemia (80%), while microcytic hypochromic anemia was commonest morphological type of anemia (48%). Among hemoglobinopathies, thalassemia major was the most common (69%, that is 9 out of 13 patients). CONCLUSION: The occurrence of anemia among children aged between 6 months and 12 years is high and nonhemoglobinopathies predominate over the hemoglobinopathies. PMID- 24791238 TI - Clinical profile of cerebral malaria at a secondary care hospital. AB - INTRODUCTION: Cerebral malaria (CM) is one of the most common causes for non traumatic encephalopathy in the world. It affects both the urban and rural population. It is a challenge to treat these patients in a resource limited setting; where majority of these cases present. MATERIALS AND METHODS: This was a prospective study carried out from September 2005 to December 2006 at Jiwan Jyoti Christian Hospital in Eastern Uttar Pradesh in India. This is a secondary level care with limited resources. We studied the clinical profile, treatment and outcome of all the patients above the age of 14 years diagnosed with CM. RESULTS: There were a total of 53 patients with CM of which 38 (71.7%) of them were females. Among them, 35 (66%) patients were less than 30 years of age. The clinical features noted were seizure (39.62%), anemia (84.9%), icterus (16.98%), hypotension (13.2%), bleeding (3.7%), hepatomegaly (5.66%), splenomegaly (5.66%), non-cardiogenic pulmonary edema (16.98%) and renal dysfunction (37.36%). Co infection with Plasmodium vivax was present in 13 (24.53%) of them. Treatment received included artesunin compounds or quinine. Median time of defervescence was 2 (interquartile range1-3). Complete recovery was achieved in 43 (81%) of them. Two (3.7%) of them died. CONCLUSION: CM, once considered to be a fatal disease has shown remarkable improvement in the outcome with the wide availability of artesunin and quinine components. To combat the malaria burden, physicians in resource limited setting should be well trained to manage these patients especially in the endemic areas. The key to management is early diagnosis and initiation of treatment based on a high index of suspicion. Anticipation and early recognition of the various complications are crucial. PMID- 24791239 TI - Preventing coronary heart disease risk of slum dwelling residents in India. AB - Coronary heart disease (CHD) is the top cause of mortality and morbidity in India. People in slums are generally at a higher risk for CHD than Indians living in more affluent areas mostly because of the higher prevalence of major CHD risk factors such as uncontrolled hypertension and tobacco use amongst them. Knowing their CHD risk perceptions and bringing them into line with the actual CHD risk is a prerequisite for effective CHD risk management. Consequently, there is need to develop tailored interventions focusing medication management and tobacco cessation to reduce growing CHD epidemic among slum dwellers and long-term CHD burden in India. PMID- 24791240 TI - Protein energy malnutrition in India: the plight of our under five children. AB - Protein energy malnutrition (PEM) is a major public health problem in India. This affects the child at the most crucial period of time of development, which can lead to permanent impairment in later life. PEM is measured in terms of underweight (low weight for age), stunting (low height for age) and wasting (low weight for height). The prevalence of stunting among under five is 48% and wasting is 19.8% and with an underweight prevalence of 42.5%, it is the highest in the world. Undernutrition predisposes the child to infection and complements its effect in contributing to child mortality. Lalonde model (1974) is used to look into the various determinants of PEM in under five children and its interrelation in causation of PEM. The determinants of PEM are broadly classified under four distinct categories: Environmental factors including the physical and social environment, behavioral factors, health-care service related and biological factors. The socio-cultural factors play an important role wherein, it affects the attitude of the care giver in feeding and care practices. Faulty feeding practice in addition to poor nutritional status of the mother further worsens the situation. The vicious cycle of poor nutritional status of the mother leading to low birth weight child further exposes the child to susceptibility to infections which aggravates the situation. However, it is seen that percapita income of the family did not have much bearing on the poor nutritional status of the child rather lack of proper health-care services adversely contributed to poor nutritional status of the child. PEM is a critical problem with many determinants playing a role in causing this vicious cycle of undernutrition. With almost half of under five children undernourished in India, the Millennium Development Goal (MDG) of halving the prevalence of underweight by 2015 seems a distant dream. PMID- 24791241 TI - Informed consent: corner stone in ethical medical and dental practice. AB - Progress in health care technologies has enabled patients to be better informed about all aspects of health care. Patients' informed consent is a legal regulation and a moral principle which represents patients' rights to take part in the clinical decisions concerning their treatment. With increasing awareness among the patients, the concept of informed consent is also evolving in developing countries like India. It is important for the medical and dental practitioners to have a written and signed informed consent from their patients before performing any invasive or irreversible procedures. Informed consent is also needed when providing medical care to children, foreign patients, and incorporating images of the patients while conducting medical and dental research. The present review addresses some of the vital issues regarding informed consent when providing medical and dental care with current review of the literature. PMID- 24791242 TI - Unfamiliar Manifestations of Anti-tubercular Therapy. AB - Cutaneous drug reactions are frequent in hospitalized patients and vary from simple manifestations like rash and erythema to severe life threatening conditions like angio-oedema, erythroderma, Stevens-Johnson syndrome and toxic epidermal necrolysis. However drug eruptions with antitubercular drugs are largely unknown except few case reports. We highlight here one similar case which presented with pleomorphic cutaneous manifestations after taking anti tubercular therapy and closely mimicked vasculitis. But when the offending drugs were stopped the lesions disappeared and the patient improved. PMID- 24791243 TI - Mononucleosis-like drug rash: an interesting case presentation. AB - Dapsone hypersensitivity syndrome (DHS) is a rare adverse effect of the commonly prescribed drug dapsone. We present a case of a 35-year-old male who was referred to us from the gastroenterologist with complaints of rash, nausea, vomiting, and jaundice since 2 days with a provisional differential diagnosis of infectious mononucleosis or viral exanthema. On enquiry patient gave history of taking dapsone a week prior for refractory urticaria. After thorough investigations we diagnosed him with DHS. This syndrome occurs in a relatively small proportion of patients, but it is associated with considerable morbidity and mortality. The reason for presenting this case is to remind physicians of the unpredictability and potential severity of this reaction which makes it a major concern in clinical practice. PMID- 24791244 TI - Alopecia universalis, renal stones, and hyperuricemia: a familial or an unfamiliar association. AB - Alopecia Universalis is an autoimmune disorder which sometimes may be associated with other autoimmune diseases like vitiligo, atopic dermatitis and endocrine disorders like hypothyroidism. In less than 2% of cases it may be associated with nephrotic syndrome although the underlying etiology has not been reported. We report here one similar case that had alopecia universalis beginning at the age of 17 years and simultaneously developed hyperuricemia. His son also developed alopecia universalis and renal stones at an early age of 10 years. The case represents one of the rare forms of alopecia namely alopecia universalis in two generations of the same family. Apart from this the case highlights the presence of renal stones probably due to hyperuricemia in both the generations which invokes a need to investigate any association of hyperuricemia with alopecia universalis. PMID- 24791245 TI - Scrub typhus complicated by acute respiratory distress syndrome and multiorgan failure; an unrecognized alarming entity in central India: a report of two cases. AB - Scrub typhus is an acute infectious illness, distributed throughout the Asia Pacific rim. In India, it has been reported from northern, eastern, and southern India. However, cases of scrub typhus have not been well-documented from Vidarbha, an eastern region of Maharashtra state in central India. We report two cases of complicated scrub typhus from Vidarbha region. These cases admitted in unconscious state with 8-10 days history of fever, body ache, cough, and progressive breathlessness. The diagnosis in both cases was based on presence of eschar, a positive Weil-Felix test, and a positive rapid diagnostic test (immunochromatographic assay). Both cases were complicated by acute respiratory distress syndrome (ARDS) and multiorgan failure. Both of them presented in their 2(nd) week of illness and died during the hospital course in spite of intensive supportive care. The main cause of mortality was delayed referral leading to delay in diagnosis and treatment. PMID- 24791246 TI - Fulminant guillain-barre syndrome with myocarditis. AB - Guillain-Barre syndrome (GBS) represents a diverse spectrum of diseases, with variable pathophysiological mechanisms, clinical manifestation, presentation pattern, and degree of severity. We report a rare case of fatal fulminant GBS complicated with myocarditis during the course of illness. PMID- 24791247 TI - Recurrent pneumothorax in a young female with pulmonary lymphangiomyomatosis: a case report and overview of literature. AB - Lymphangiomyomatosis (LAM) is a rare cystic interstitial lung disease that exclusively affects women of child bearing age and is associated with vascular proliferation of smooth muscle cells in the lung. We report a case of young female with pulmonary LAM presenting with recurrent pneumothorax. PMID- 24791248 TI - Responding to Domestic Violence in Clinical Practice: Are we Equipped Enough? PMID- 24791249 TI - India and end of life discussions: a comment on end of life discussion in an academic family health team in kingston, ontario, Canada. PMID- 24791250 TI - Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer. AB - Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs). MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with immunotherapies. Optimization of combined approaches that simultaneously downregulate MDSC suppressor pathways, restore APC immune stimulating activity, and expand tumor-reactive T cells will be useful in improving therapy. PMID- 24791251 TI - Extraction of Molecular Features through Exome to Transcriptome Alignment. AB - Integrative Next Generation Sequencing (NGS) DNA and RNA analyses have very recently become feasible, and the published to date studies have discovered critical disease implicated pathways, and diagnostic and therapeutic targets. A growing number of exomes, genomes and transcriptomes from the same individual are quickly accumulating, providing unique venues for mechanistic and regulatory features analysis, and, at the same time, requiring new exploration strategies. In this study, we have integrated variation and expression information of four NGS datasets from the same individual: normal and tumor breast exomes and transcriptomes. Focusing on SNPcentered variant allelic prevalence, we illustrate analytical algorithms that can be applied to extract or validate potential regulatory elements, such as expression or growth advantage, imprinting, loss of heterozygosity (LOH), somatic changes, and RNA editing. In addition, we point to some critical elements that might bias the output and recommend alternative measures to maximize the confidence of findings. The need for such strategies is especially recognized within the growing appreciation of the concept of systems biology: integrative exploration of genome and transcriptome features reveal mechanistic and regulatory insights that reach far beyond linear addition of the individual datasets. PMID- 24791252 TI - Higher effective oronasal versus nasal continuous positive airway pressure in obstructive sleep apnea: effect of mandibular stabilization. AB - BACKGROUND: In some individuals with obstructive sleep apnea (OSA), oronasal continuous positive airway pressure (CPAP) leads to poorer OSA correction than nasal CPAP. The authors hypothesized that this results from posterior mandibular displacement caused by the oronasal mask. OBJECTIVE: To test this hypothesis using a mandibular advancement device (MAD) for mandibular stabilization. METHODS: Subjects whose OSA was not adequately corrected by oronasal CPAP at pressures for which nasal CPAP was effective were identified. These subjects underwent polysomnography (PSG) CPAP titration with each nasal and oronasal mask consecutively, with esophageal pressure and leak monitoring, to obtain the effective pressure (Peff) of CPAP for correcting obstructive events with each mask (maximum 20 cmH2O). PSG titration was repeated using a MAD in the neutral position. Cephalometry was performed. RESULTS: Six subjects with mean (+/- SD) nasal Peff 10.4+/-3.0 cmH2O were studied. Oronasal Peff was greater than nasal Peff in all subjects, with obstructive events persisting at 20 cmH2O by oronasal mask in four cases. This was not due to excessive leak. With the MAD, oronasal Peff was reduced in three subjects, and Peff <20 cmH2O could be obtained in two of the four subjects with Peff >20 cmH2O by oronasal mask alone. Subjects' cephalometric variables were similar to published norms. CONCLUSION: In subjects with OSA with higher oronasal than nasal Peff, this is partially explained by posterior mandibular displacement caused by the oronasal mask. Combination treatment with oronasal mask and MAD may be useful in some individuals if a nasal mask is not tolerated. PMID- 24791253 TI - Management of necrotizing pneumonia and pulmonary gangrene: a case series and review of the literature. AB - BACKGROUND: Necrotizing pneumonia is an uncommon but severe complication of bacterial pneumonia, associated with high morbidity and mortality. The availability of current data regarding the management of necrotizing pneumonia is limited to case reports and small retrospective observational cohort studies. Consequently, appropriate management for these patients remains unclear. OBJECTIVE: To describe five cases and review the available literature to help guide management of necrotizing pneumonia. METHODS: Cases involving five adults with respiratory failure due to necrotizing pneumonia admitted to a tertiary care centre and infected with Streptococcus pneumoniae (n=3), Klebsiella pneumoniae (n=1) and methicillin-resistant Staphylococcus aureus (n=1) were reviewed. All available literature was reviewed and encompassed case reports and retrospective reviews dating from 1975 to the present. RESULTS: All five patients received aggressive medical management and consultation by thoracic surgery. Three patients underwent surgical procedures to debride necrotic lung parenchyma. Two of the five patients died in hospital. CONCLUSIONS: Necrotizing pneumonia often leads to pulmonary gangrene. Computed tomography of the thorax with contrast is recommended to evaluate the pulmonary vascular supply. Further study is necessary to determine whether surgical intervention, in the absence of pulmonary gangrene, results in better outcomes. PMID- 24791254 TI - Patient transitions relevant to individuals requiring ongoing ventilatory assistance: a Delphi study. AB - BACKGROUND: Various terms, including 'prolonged mechanical ventilation' (PMV) and 'long-term mechanical ventilation' (LTMV), are used interchangeably to distinguish patient cohorts requiring ventilation, making comparisons and timing of clinical decision making problematic. OBJECTIVE: To develop expert, consensus based criteria associated with care transitions to distinguish cohorts of ventilated patients. METHODS: A four-round (R), web-based Delphi study with consensus defined as >70% was performed. In R1, participants listed, using free text, criteria perceived to should and should not define seven transitions. Transitions comprised: T1 - acute ventilation to PMV; T2 - PMV to LTMV; T3 - PMV or LTMV to acute ventilation (reverse transition); T4 - institutional to community care; T5 - no ventilation to requiring LTMV; T6 - pediatric to adult LTMV; and T7 - active treatment to end-of-life care. Subsequent Rs sought consensus. RESULTS: Experts from intensive care (n=14), long-term care (n=14) and home ventilation (n=10), representing a variety of professional groups and geographical areas, completed all Rs. Consensus was reached on 14 of 20 statements defining T1 and 21 of 25 for T2. 'Physiological stability' had the highest consensus (97% and 100%, respectively). 'Duration of ventilation' did not achieve consensus. Consensus was achieved on 13 of 18 statements for T3 and 23 of 25 statements for T4. T4 statements reaching 100% consensus included: 'informed choice', 'patient stability', 'informal caregiver support', 'caregiver knowledge', 'environment modification', 'supportive network' and 'access to interprofessional care'. Consensus was achieved for 15 of 17 T5, 16 of 20 T6 and 21 of 24 T7 items. CONCLUSION: Criteria to consider during key care transitions for ventilator-assisted individuals were identified. Such information will assist in furthering the consistency of clinical care plans, research trials and health care resource allocation. PMID- 24791255 TI - Excessive daytime sleepiness among rural residents in Saskatchewan. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common diagnosis in clinical practice. Excessive daytime sleepiness may be a warning for possible OSA. OBJECTIVES: To assess the prevalence of excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) in a rural community population; potential risk factors for OSA were also assessed. METHODS: In 2010, a baseline respiratory health questionnaire within the Saskatchewan Rural Health Study was mailed to 11,982 households in Saskatchewan. A total of 7597 adults within the 4624 (42%) respondent households completed the ESS questionnaire. Participants were categorized according to normal or high (>10) ESS scores. Data obtained included respiratory symptoms, doctor-diagnosed sleep apnea, snoring, hypertension, smoking and demographics. Body mass index was calculated. Multivariable logistic regression analysis examined associations between high ESS scores and possible risk factors. Generalized estimating equations accounted for the two-tiered sampling procedure of the study design. RESULTS: The mean age of respondents was 55.0 years and 49.2% were male. The prevalence of ESS>10 and 'doctor diagnosed' OSA were 15.9% and 6.0%, respectively. Approximately 23% of respondents reported loud snoring and 30% had a body mass index >30 kg/m2. Of those with 'doctor diagnosed' OSA, 37.7% reported ESS>10 (P<0.0001) and 47.7% reported loud snoring (P<0.0001). Risk of having an ESS>10 score increased with age, male sex, obesity, lower socioeconomic status, marriage, loud snoring and doctor-diagnosed sinus trouble. CONCLUSIONS: High levels of excessive daytime sleepiness in this particular rural population are common and men >55 years of age are at highest risk. Examination of reasons for residual sleepiness and snoring in persons with and without sleep apnea is warranted. PMID- 24791256 TI - Allergen-induced asthma. PMID- 24791257 TI - Obesity in chronic obstructive pulmonary disease: is fatter really better? AB - BACKGROUND: Overweight/obesity is associated with longer survival in chronically ill patients, a phenomenon referred to as the 'obesity paradox'. OBJECTIVE: To investigate whether the obesity paradox in patients with chronic obstructive pulmonary disease (COPD) is due to fat accumulation or confounding factors. METHODS: A total of 190 patients with stable COPD who underwent a mean (+/- SD) follow-up period of 72+/-34 months were enrolled. Anthropometry, pulmonary function tests, midthigh muscle cross-sectional area obtained using computed tomography (MTCSACT), arterial blood gas and exercise testing data were measured at baseline. Patients were categorized into two subgroups according to body mass index (BMI) <25 kg/m2 or >=25 kg/m2 (normal and overweight/obese, respectively). RESULTS: Seventy-two patients (38%) died during the follow-up period. Survival tended to be better in the overweight/obese patients but this difference did not reach statistical significance. Overweight/obese patients had better lung function and a larger MTCSACT than those with normal BMI (P<0.001). Overweight/obese patients also had a significantly higher peak work rate than patients with normal BMI (P<0.001). PaO2 and PaCO2 were not significantly different in the two groups. When adjusted for PaCO2, peak work rate and MTCSACT, the tendency for improved survival in overweight/obese patients disappeared. In fact, when these variables were considered in the survival analysis, patients with lower BMI tended to have better survival. CONCLUSION: These results suggest that important confounders, such as hypercapnia, exercise capacity and muscle mass, should be considered when interpreting the association between increased BMI and survival in patients with COPD. PMID- 24791258 TI - Recent advances in thoracic x-ray computed tomography for pulmonary imaging. AB - The present article reviews recent advances in pulmonary computed tomography (CT) imaging, focusing on the application of dual-energy CT and the use of iterative reconstruction. Dual-energy CT has proven to be useful in the characterization of pulmonary blood pool in the setting of pulmonary embolism, characterization of diffuse lung parenchymal diseases, evaluation of thoracic malignancies and in imaging of lung ventilation using inhaled xenon. The benefits of iterative reconstruction have been largely derived from reduction of image noise compared with filtered backprojection reconstructions which, in turn, enables the use of lower radiation dose CT acquisition protocols without sacrificing image quality. Potential clinical applications of iterative reconstruction include imaging for pulmonary nodules and high-resolution pulmonary CT. PMID- 24791259 TI - Small research. PMID- 24791260 TI - The origins of the sneeze: divine gift or mere goldenrod pollen? PMID- 24791261 TI - The Norman Prince Neurosciences Institute: linking research to clinical care. PMID- 24791262 TI - Neurotechnology: a new approach for treating brain disorders. AB - Advances in neuroscience, engineering and computer technologies are creating opportunities to connect the brain directly to devices to treat a variety of disorders, both neurological and psychiatric. They are opening a new field of neuroscience called "neurotechnology." This article reviews efforts in this area that are ongoing at Brown University and the hospitals affiliated with Brown's Alpert Medical School. Two general approaches are being used. One uses advanced electrodes to "sense" the activity of many individual neurons in the cerebral cortex and then use that activity for therapeutic purposes. The other uses various types of devices to stimulate specific networks in the brain in order to restore normal function and alleviate symptoms. PMID- 24791263 TI - The Brown University Traumatic Brain Injury Research Consortium and the Norman Prince Neurosciences Institute. AB - This article provides an overview of the Brown University Traumatic Brain Injury Research Consortium (TBIRC) and summarizes the multidisciplinary basic and clinical neuroscience work being conducted by investigators at Brown University and the affiliate hospitals in association with the Norman Prince Neurosciences Institute (NPNI). PMID- 24791264 TI - Advances in stroke over the past decade. AB - Over the last decade, a number of advances in the care of stroke and TIA patients have been made. These advances include prevention, acute management, and recovery. Some of this work has occurred in Rhode Island. This review will focus on the revised definition of stroke and TIA; short-term risk of TIA; rapid management of TIA; targeted use of medication and lifestyle changes; monitoring for atrial fibrillation; novel anticoagulants for atrial fibrillation; a better understanding of the limitations of intra-arterial therapy for acute ischemic stroke; clinical treatment trials for intracerebral hemorrhage; and the use of robotic, magnetic, and chemical interventions to improve function after stroke. PMID- 24791265 TI - The Rhode Island Consortium for Autism Research and Treatment (RI-CART): a new statewide autism collaborative. AB - Autism is a neurodevelopmental disorder characterized by core deficits in social interaction, language and repetitive behaviors. The need for services is rising sharply as the number of children identified with autism increases. The Rhode Island Consortium for Autism Research and Treatment (RI-CART) was founded in 2009 with the goal of increasing communication among autism researchers throughout the state and improving treatment for children with autism. RI-CART members have several exciting projects in progress, with its larger aim being the creation of a statewide research registry. A statewide registry would benefit research in Rhode Island and allow for larger collaborations nationally. PMID- 24791266 TI - HPV knowledge and vaccine acceptance in an uninsured Hispanic population in Providence, RI. AB - The Food and Drug Administration has approved two human papillomavirus (HPV) vaccines for use by men and women in the United States. The vaccines not only protect against HPV infection, but also reduce the risk of cervical cancer in women. Despite the widespread availability of these vaccines, vulnerable populations such as those with low incomes have been reported to have limited access to and knowlege about HPV vaccines. In order to evaluate and improve HPV vaccination uptake in a population of uninsured, low-income Spanish- speaking individuals attending a free clinic in Rhode Island, we administered a questionnaire regarding knowledge, attitudes, and practices (KAP) and performed an education intervention. We found that knowledge of HPV infection and cervical cancer among the patients sampled was low when comparing Hispanics to non Hispanics (47.2%, 85.7%, respectively) but willingness to vaccinate oneself or one's child was very high after a brief video- based intervention. PMID- 24791267 TI - Solitary pulmonary nodule: pleuropulmonary synovial sarcoma. AB - Pleuropulmonary synovial sarcoma (PPSS) is an extremely rare primary malignancy of the lung. We present a case of a middle-aged female with PPSS that was initially discovered as an incidental indeterminate nodule on chest radiograph. Following evaluation with computed tomography (CT), the patient went on to positron-emission tomography (PET)/CT for work-up of the solitary pulmonary nodule, which demonstrated mild FDG-avidity and no other evidence of FDG-avid disease. The patient then underwent thoracotomy and right upper lobectomy for definitive treatment. Only after evaluation of the gross pathology, histology, immunohistochemistry and cytogenetics was the diagnosis of synovial sarcoma made. Importantly, the preceding PET/CT, in addition to physical exam of the upper and lower extremities, helped exclude the more common extra-thoracic soft-tissue variety of synovial sarcoma, which frequently metastasizes to lung, carrying a worse prognosis. Discussion of synovial sarcoma and PPSS follows. PMID- 24791268 TI - What is MOLST? PMID- 24791269 TI - Increasing trend of HPV-associated oropharyngeal cancers among males in Rhode Island, 1987-2011. PMID- 24791270 TI - Enhanced Raman multigas sensing - a novel tool for control and analysis of (13)CO(2) labeling experiments in environmental research. AB - Cavity-enhanced Raman multigas spectrometry is introduced as a versatile technique for monitoring of (13)CO2 isotope labeling experiments, while simultaneously quantifying the fluxes of O2 and other relevant gases across a wide range of concentrations. The multigas analysis was performed in a closed cycle; no gas was consumed, and the gas composition was not altered by the measurement. Isotope labeling of plant metabolites via photosynthetic uptake of (13)CO2 enables the investigation of resource flows in plants and is now an important tool in ecophysiological studies. In this experiment the (13)C labeling of monoclonal cuttings of Populus trichocarpa was undertaken. The high time resolution of the online multigas analysis allowed precise control of the pulse labeling and was exploited to calculate the kinetics of photosynthetic (13)CO2 uptake and to extrapolate the exact value of the (13)CO2 peak concentration in the labeling chamber. Further, the leaf dark respiration of immature and mature leaves was analyzed. The quantification of the photosynthetic O2 production rate as a byproduct of the (13)CO2 uptake correlated with the amount of available light and the leaf area of the plants in the labeling chamber. The ability to acquire CO2 and O2 respiration rates simultaneously also simplifies the determination of respiratory quotients (rate of O2 uptake compared to CO2 release) and thus indicates the type of combusted substrate. By combining quantification of respiration quotients with the tracing of (13)C in plants, cavity enhanced Raman spectroscopy adds a valuable new tool for studies of metabolism at the organismal to ecosystem scale. PMID- 24791271 TI - A critical review of the reactivity of manganese oxides with organic contaminants. AB - Naturally occurring manganese (Mn(iii/iv)) oxides are ubiquitous in a wide range of environmental settings and play a key role in numerous biogeochemical cycles. In addition, Mn(iii/iv) oxides are powerful oxidants that are capable of oxidizing a wide range of compounds. This review critically assesses the reactivity of Mn oxides with organic contaminants. Initial work with organic reductants employed high concentrations of model compounds (e.g., substituted phenols and anilines) and emphasized the reductive dissolution of the Mn oxides. Studies with lower concentrations of organic contaminants demonstrate that Mn oxides are capable of oxidizing a wide range of compounds (e.g., antibacterial agents, endocrine disruptors, and pesticides). Both model compounds and organic contaminants undergo similar reaction mechanisms on the oxide surface. The oxidation rates of organic compounds by manganese oxides are dependent upon solution conditions, such as pH and the presence of cations, anions, or dissolved organic matter. Similarly, physicochemical properties of the minerals used affect the rates of organic compound oxidation, which increase with the average oxidation state, redox potential, and specific surface area of the Mn oxides. Due to their reactivity with contaminants under environmentally relevant conditions, Mn oxides may oxidize contaminants in soils and/or be applied in water treatment applications. PMID- 24791273 TI - Conductive polymer nanocomposites with hierarchical multi-scale structures via self-assembly of carbon-nanotubes on graphene on polymer-microspheres. AB - A novel and highly conductive 3-dimensional (3D) hierarchical multi-scale structure is formed by a new, simple, facile, and water-based method that enables practical production of conductive carbon nanofiller/polymer composites. More specifically, the pi-pi interaction between CNTs and graphene oxide (GO) is exploited to disperse conductive but non-polar CNTs with amphiphilic GO sheets to form a stable aqueous colloidal solution. Aqueous-dispersible latex-polystyrene microspheres are then added to enable the self-assembly processes of anchoring CNTs on GO and wrapping microspheres with GO-stabilized CNTs for the formation of an intriguing 3D hierarchical multi-scale structure. During this process, GO is reduced to conductive reduced-graphene oxide (RGO). The resultant RGO sheets act as "nano-walls" to prevent CNTs from randomly diffusing into the polymer bulk during thermal pressing of RGO-CNT/microspheres, which results in the formation of a 3D foam-like network of RGO-CNTs with high quality. The resultant composite with such a structure gives an ultra-low percolation threshold (0.03 vol% RGO CNTs) and a reasonably high conductivity (153 S m(-1) at 4 vol% RGO-CNTs), which could satisfy various applications requiring both transparency and electrical conduction characteristics (e.g. transparent antistatic coatings, capacitive touch-screens, and transparent electronic devices). PMID- 24791274 TI - A mild route to mesoporous Mo2C-C hybrid nanospheres for high performance lithium ion batteries. AB - In this work, we have developed a mild route to fabricate typically mesoporous Mo2C-C hybrid nanospheres based on a solvothermal synthesis and reduction carbonization process. This work opens a low-temperature route to synthesize valuable carbides. The resultant Mo2C-C hybrid, for the first time, is used as an anode material in lithium ion batteries (LIBs). Compared with bulk Mo2C, the Mo2C C hybrid exhibits much better electrochemical performance. Remarkably, the hybrid electrode can deliver a specific capacity of over 670 mA h g(-1) after 50 cycles at 100 mA g(-1), which is much higher than that of the bulk material (113 mA h g( 1)). Even cycled at a high current density of 1000 mA g(-1), high capacities of around 400-470 mA h g(-1) can still be retained for the Mo2C-C hybrid. It might benefit from the synergistic effect of the nanohybridization, effectively relieving the volume change during the repeated lithium insertion-extraction reactions and maintaining the integrity of the electrical connections. It is expected that the present synthesis strategy for the Mo2C-C hybrid can be extended to other nanostructured carbides with good energy storage performance. PMID- 24791272 TI - A microfluidic coculture and multiphoton FAD analysis assay provides insight into the influence of the bone microenvironment on prostate cancer cells. AB - In prostate cancer, bone is a frequent site of metastasis; however, the molecular mechanisms of this tumor tropism remain unclear. Here, we integrate a microfluidic coculture platform with multi-photon imaging based techniques to assess both phenotypic cell behavior and FAD fluorescence intensity and fluorescence lifetime in the same cell. This platform combines two independent assays normally performed with two different cell populations into a single device, allowing us to simultaneously assess both phenotypic cell behavior and enzyme activity. We observed that the osteotropic prostate cancer cell line (C4 2B), when in a coculture with bone marrow stromal cells (MC3T3-E1), has increased protrusive phenotype and increased total and protein-bound FAD compared to its parent cell line (LNCaP). We hypothesized that an increase in ROS-generating APAO activity may be responsible for these effects, and found that the effects were decreased in the presence of the antioxidant N-Acetyl Cysteine (NAC). This suggests that an ROS-related signaling mechanism at the bone metastatic site may be correlated with and play a role in increased invasion of metastasizing prostate cancer cells. The studies performed using this combined platform will lead to new insights into the mechanisms that drive prostate cancer metastasis. PMID- 24791275 TI - Facile synthesis of hierarchical dendritic PtPd nanogarlands supported on reduced graphene oxide with enhanced electrocatalytic properties. AB - A simple and facile method is developed for one-pot preparation of hierarchical dendritic PtPd nanogarlands supported on reduced graphene oxide (PtPd/RGO) at room temperature, without using any seed, organic solvent, or complex apparatus. It is found that octylphenoxypolyethoxyethanol (NP-40) as a soft template and its amount are critical to the formation of PtPd garlands. The as-prepared nanocomposites are further applied to methanol and ethanol oxidation with significantly enhanced electrocatalytic activity and better stability in alkaline media. PMID- 24791276 TI - The impact range for smooth wall-liquid interactions in nanoconfined liquids. AB - Bulk and nanoconfined liquids have very different physics; for instance, nanoconfined liquids show stratification and position-dependent relaxation processes. A number of similarities between bulk and nanoconfined liquids have nevertheless been reported in computer simulations during the last decade. Inspired by these observations, we present results from molecular dynamics computer simulations of four nanoconfined liquids (the single-component Lennard Jones liquid, the Kob-Andersen binary Lennard-Jones mixture, an asymmetric dumbbell model, and the Dzugutov liquid) demonstrating also a microscopic similarity between bulk and nanoconfined liquids. The results show that the interaction range for the wall-liquid and liquid-liquid interactions of the nanoconfined liquid is identical to that of the bulk liquid if the liquid is "Roskilde simple" in bulk as well as nanoconfinement, i.e., exhibits strong correlations between virial and potential-energy equilibrium fluctuations in the NVT ensemble. Under this condition, interactions beyond the first coordination shell may be ignored, in particular for the wall-liquid interactions. This is shown not to be the case for non-Roskilde-simple liquids. PMID- 24791277 TI - Precursor film: a key driver to determine wetting behavior in the vicinity of surface heterogeneity. AB - Experimental findings in the recent past have clearly emphasized the role of the three-phase contact line in determining the wetting behavior of liquids. However, at a microscopic level when the precursor film precedes the contact line, the role of thin film in wetting behavior becomes important. The current study presents a series of simple experiments to establish the role of precursor films in controlling the wetting behavior in the context of rising liquids in vertical planes. The experiments have been performed on glass capillaries and cover slips which have been rendered partially hydrophobic by silanisation of some portion. Thus, two regions of significantly different wetting behavior have been created. Experiments have been performed to capture the changes in wetting behavior as manifested by variation in capillary rise height and Wilhelmy force values, where hydrophilic and hydrophobic regions meet each other. The deviations in expected wetting behavior as the liquid approaches the boundary between the two regions from the hydrophilic end have demonstrated the role of precursor films in wetting behavior. PMID- 24791278 TI - Twisting and bending stress in DNA minicircles. AB - The interplay between bending of the molecule axis and appearance of disruptions in circular DNA molecules, with ~100 base pairs, is addressed. Three minicircles with different radii and almost equal contents of AT and GC pairs are investigated. The DNA sequences are modeled by a mesoscopic Hamiltonian which describes the essential interactions in the helix at the level of the base pair and incorporates twisting and bending degrees of freedom. Helix unwinding and bubble formation patterns are consistently computed by a path integral method that sums over a large number of molecule configurations compatible with the model potential. The path ensembles are determined, as a function of temperature, by minimizing the free energy of the system. Fluctuational openings appear along the helix to release the stress due to the bending of the molecule backbone. In agreement with the experimental findings, base pair disruptions are found with larger probability in the smallest minicircle of 66 bps whose bending angle is ~6 degrees . For this minicircle, a sizeable untwisting is obtained with the helical repeat showing a step-like increase at T = 315 K. The method can be generalized to determine the bubble probability profiles of open ends linear sequences. PMID- 24791279 TI - Mesoporous titania thin films as efficient enzyme carriers for paraoxon determination/detoxification: effects of enzyme binding and pore hierarchy on the biocatalyst activity and reusability. AB - In this work we demonstrate the efficient immobilization of histidine 6-tagged organophosphate hydrolase (His6-OPH), an organophosphate-degrading enzyme, on mesoporous titania thin films. This permits the use of the biocatalyst films as efficient tools in the detection/detoxification of paraoxon. His6-OPH was immobilized on mesoporous thin films with uniform (9 nm) and bimodal (13-38 nm) pore size distribution, through covalent attachment and physical adsorption. The biocatalyst films show good activity, and enhanced stability with respect to the free enzyme at extreme conditions of pH and temperature, especially around neutral pH and room temperature. In addition, the bioactive films can be easily separated from the reaction media and reused multiple times without significant loss of activity. PMID- 24791280 TI - Author's reply: To PMID 24357764. PMID- 24791281 TI - Drugs for gout. PMID- 24791282 TI - Medicare program; prospective payment system for federally qualified health centers; changes to contracting policies for rural health clinics; and changes to Clinical Laboratory Improvement Amendments of 1988 enforcement actions for proficiency testing referral. Final rule with comment period. AB - This final rule with comment period implements methodology and payment rates for a prospective payment system (PPS) for federally qualified health center (FQHC) services under Medicare Part B beginning on October 1, 2014, in compliance with the statutory requirement of the Affordable Care Act. In addition, it establishes a policy which allows rural health clinics (RHCs) to contract with nonphysician practitioners when statutory requirements for employment of nurse practitioners and physician assistants are met, and makes other technical and conforming changes to the RHC and FQHC regulations. Finally, this final rule with comment period implements changes to the Clinical Laboratory Improvement Amendments (CLIA) regulations regarding enforcement actions for proficiency testing (PT) referrals. PMID- 24791283 TI - [Current situation in the care of polytrauma]. PMID- 24791284 TI - [Importance of surgical pathology for oncosurgery]. PMID- 24791285 TI - Pericardial constriction and pediatric cardiac CT. PMID- 24791286 TI - Oral cancer: early diagnosis. PMID- 24791287 TI - Who wants to be a millionaire? PMID- 24791288 TI - FOCUS on: minimally invasive endodontics. PMID- 24791289 TI - Endodontics: a key opinion leader colloquy. Interview by Damon Adams. PMID- 24791290 TI - The role of endodontics in interdisciplinary dentistry: are you making the right decisions? PMID- 24791291 TI - Using microscopes in fixed prosthodontics: try-in, adjustment, and insertion of crowns and bridges. PMID- 24791292 TI - A predictable resin composite injection technique, Part I. PMID- 24791293 TI - Tunnel preps: tooth strength preservation. PMID- 24791294 TI - Importance of early detection of squamous cell carcinoma. PMID- 24791295 TI - Impression techniques: clinical properties that matter. PMID- 24791296 TI - Improving the local anesthesia experience for our patients. PMID- 24791298 TI - Biologic restorative systems for predictability. PMID- 24791297 TI - Short implants: a viable alternative to sinus augmentation. PMID- 24791300 TI - Focus on: infection control. PMID- 24791299 TI - How to replace lost production and profit. PMID- 24791301 TI - Get your hygiene patients "off the fence"! PMID- 24791302 TI - A legacy of leading and serving the profession. Interview by Damon Adams. PMID- 24791303 TI - Immediate dental implant placement: technique, part 2. PMID- 24791304 TI - Immediate mini implant placement following extractions. PMID- 24791305 TI - How to optimize an existing removable partial denture. PMID- 24791306 TI - Predictable cementation for monolithic zirconia crowns. PMID- 24791307 TI - Do you know what your endodontic instrument just did? PMID- 24791308 TI - Meaningful mini-makeovers in the new economy. PMID- 24791309 TI - The power of preparation: achieving ideal esthetic results. PMID- 24791310 TI - A technique for optimal core buildups. PMID- 24791312 TI - Hot and cold, at the same time. PMID- 24791311 TI - The stress axis/DNA protocols in denture fabrication, part 2: case examples. PMID- 24791313 TI - Electronic health records: who's running the asylum? PMID- 24791314 TI - Dentistry today. PMID- 24791315 TI - Dr. Adams responds. PMID- 24791316 TI - FOCUS ON: tooth preparation disinfection. PMID- 24791317 TI - Body dysmorphic disorder and cosmetic dentistry: diagnostic, management, and ethical issues. PMID- 24791318 TI - Predictable tooth replacement in the aesthetic zone. PMID- 24791319 TI - Anterior tooth challenges, part 4: canines in the lateral position. PMID- 24791320 TI - Unique clinical presentation of a maxillary incisor. PMID- 24791321 TI - Utilizing an effective protocol for full-mouth reconstructions. PMID- 24791322 TI - Simple flapless surgical overdenture techniques. PMID- 24791323 TI - Nonconventional rehabilitation for anterior single tooth loss: clinical follow-up at 12 years. PMID- 24791324 TI - A simple technique for broken abutment screw repair. PMID- 24791326 TI - Optimize finishing and polishing of posterior composites. PMID- 24791325 TI - Using digital impressions and CAD/CAM in implant dentistry. PMID- 24791327 TI - We will NEVER be silenced. PMID- 24791328 TI - Maintenance of intravascular device patency: a survey of nursing and midwifery flushing practice. PMID- 24791329 TI - Mandatory reporting of child abuse and neglect. PMID- 24791330 TI - A voluntary experience in Bairo Pite Hospital, Timor Leste. PMID- 24791331 TI - Abuse of power. PMID- 24791332 TI - [Neurosteroidogenesis and exploratory responses in rodents]. AB - We have studied the influence of intraperitoneal introduction of a selective blocker of mitochondrial translocation protein 18kD PK11195 (5 mg/kg), indomethacin (5 and 10 mg/kg), finasteride (5 and 15 mg/kg), and neurosteroid pregnenolone (20 mg/kg) on the exploratory behavior of male BALB/c mice, C57BL/6 mice, and Wistar rats in open-field test. It is found that treatment with PK11195 weakens the exploratory behavior in open-field test in mice of both strains. Finasteride and indomethacin decrease the exploratory responses in rodents regardless of the species or type of stress emotional response phenotype. Pregnenolone possesses activating effect in open-field in open-field test, but enhances the inhibitory effect of finasteride in BALB/c mice. PMID- 24791333 TI - [Studying in vitro neuroprotective properties of GK-2(h)--a new original mimetic of human nerve growth factor]. AB - Human nerve growth factor (NGF) mimetic hexamethylenediamide bis-N-monosuccinyl glicyl-lysine) (GK-2(h)) demonstrates protective activity on immortalized mouse hippocampal cell line HT22 in a concentration up to 10(-13)M against hydrogen peroxide toxicity and in concentration up to 10(-8) M against glutamate toxicity. GK-2(h) dipeptide protects rat PC-12 pheochromocytoma cells in a concentration up to 10(-7) M and protects human neuroblastoma SH-SY5Y cells in a concentration up to 10(-8) against 6-hydroxydofamine-induced damage. PMID- 24791334 TI - [Effect of a new derivative of glutamic and apovincaminic acids on brain metabolism in post-ischemic period]. AB - Neuroprotective properties of the new derivative of glutamic and apovincaminic acids, ethyl -(3-alpha,16-alpha)-eburnamenin-14-carbopxylate of 2 aminopentadionic acid (LHT 1-02) were studied on a model of acute brain ischemia in cats. LHT 1-02 has proved to be more effective than the reference drugs vinpocetin and glycine in preventing the reperfusive damage, which was manifested by decreased postischemic hyperglycemia, activated utilization of oxygen in the brain, and suppressed postischemic metabolic lactate acidosis. Thus, the results of this comparative study show expediency of further investigations of LHT 1 - 02 as a potential neuroprotective drug. PMID- 24791335 TI - [Effect of dinitrosyl iron complexes on erythrocyte energy metabolism under thermal trauma conditions]. AB - The effect of dinitrosyl iron complexes (DNIC) on the energy metabolism of erythrocytes under combined thermal trauma conditions has been studied on a group of 30 Wistar rats, which was divided into 3 groups: intact (n = 10), control (n = 10), and main (n = 10). Combined thermal trauma (skin burn + thermoinhalation damage) was modeled in animals of the control and main groups. Rats of control group received infusions of sodium chloride solution (n = 10) every day. Rats of the main group obtained infusions of DNIC solution in sodium chloride. Rat blood samples were characterized by the activity of lactate dehydrogenase in direct and reverse reaction, lactate level, and coefficients of the substrate provision and energy reactions balance. It was stated, that DNIC clearly normalized the energy metabolism of erythrocytes beginning with the third day after thermal trauma onset. PMID- 24791336 TI - [A new technology for evaluating pharmacodynamics of antiaggregants]. AB - The effect of antiaggregants on the system of regulation of the aggregative state of the whole blood in healthy volunteers has been studied using the global test of low-frequency piezothrombelastography. It is established that specific effects of antiaggregants are manifested in all stages of fibrinogenesis (initiation/amplification and propagation). According to the results of the global test at initial stages of hemocoagulation (initiation/amplification), a pronounced specific antiaggregative effect of COX-1 blockers and ADP receptors is accompanied by the intensification of thrombin activity and the formation of chronometric hypercoagulation. The blocker of phosphodiesterase, while losing a specific antiaggregative effect, has a lower influence on the change of thrombin activity, thus ensuring hronometric and structural hypocoagulation at the subsequent stages of fibrinogenesis. The proposed method can be used for real time monitoring of the results of pharmacotherapy and drug effects at various stages of fibrinogenesis in the program of personalized antiaggregant therapy. PMID- 24791337 TI - [Hepatoprotective properties of isoflavonoids from roots of Maackia amurensis on experimental carbon tetrachloride-induced hepatic damage]. AB - Hepatoprotective properties of ethanol extract from the roots of Maackia amurensis Ruper et Maxim have been studied on the model of toxic hepatitis induced by carbon tetrachloride damage. It is established that the extract contains daidzein, 7-O-gentobiosides of isoflavonoids genistein, formononetin, pseudobabtige-nin, and 5-O-methylgenistein, and 3-O-gentobiosides of pterocarpans (6aR, 11aR)-maakiain and (6aR, 11aR)-medicarpin. The administration of extract facilitates the restoration of antioxidant protection enzymes activity and reduced glutathione level, decreases the formation of toxic peroxidation products, produces normalizing impact on liver phospholipid pattern, and improves the erythrocyte tolerance to hemolytic agents. The action of isoflavonoids from Maackia amurensis in restoration of metabolic pathways of the liver and removal of toxic stress was more effective as compared to that of the reference hepatoprotector legalon. PMID- 24791338 TI - [Evaluation of the linearity of pharmacokinetics of the phenolic antioxidant 4 methyl-2,6-diisobornylphenol upon intragastric administration]. AB - The linearity of pharmacokinetics of 4-methyl-2,6-diisobornylphenol after single intragastric administration in doses within 10 - 200 mg/kg has been studied in rats. It has been established that pharmacokinetics of 4-methyl-2,6 diisobornilphenol in the indicated dose range is not linear due to a limited absorption of the drug from the intestine. PMID- 24791339 TI - [Peculiarities and clinical significance of drug pharmacokinetics and pharmacodynamics during pregnancy]. AB - There are relatively few data reported on specific features of drug pharmacokinetics (PK) and pharmacodynamics in pregnancy compared to the non pregnant state. Changes in maternal physiology and metabolic processes during pregnancy effect on PK and show that standard adult dosing is likely to be incorrect during pregnancy. Physiology-based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women and to correctly predict drug exposure and response on the personal level. PMID- 24791340 TI - Parasitoses and mycoses--still current public health hazards. AB - Current environmental aspects of parasitological and mycological diseases, diagnostics problems and some mechanisms of pathogens' action facilitating invasion of human organisms have been presented. Imported humans parasitoses, difficulties in diagnosis and treatment, possibility of expansion of the endemic pathogens' occurrence ranges have been discussed. Mycological topics included evaluation of the role of birds as vectors of potentially pathogenic fungi in biosphere, threats connected with biofilms formation in hospital and home environments, and interrelations among microorganisms in such biofilms. PMID- 24791341 TI - The annual population dynamics of gastrointestinal nematodes in breeding sheep of the Silesian Foothills, southern Poland. AB - The study was carried out on an organic farm. The flock of the sheep (27 individuals) was naturally infected by parasites. The aim of the study was to estimate the prevalence of infection with gastrointestinal nematodes. There were found species of 3 nematode families: Trichostrongylidae (Trichostrongylus spp., Ostertagia sp., Nematodirus spp., Cooperia spp., Haemonchus contortus); Strongylidae (Oesophagostomum spp., Strongyloides papillosus, Chabertia ovina) and Ancylostomatidae (Bunostomum sp.). Three nematode genera were dominant in parasite infection: Trichostrongylus, Ostertagia and Nematodirus. The prevalence of sheep infection with gastrointestinal nematodes were nearly 100%. The main species were Trichostrongylus spp. (59.2%) and Ostertagia sp. (46%). PMID- 24791342 TI - A survey of intestinal helminths in wild carnivores from the Tatra National Park, southern Poland. AB - From January 2011 to July 2012, 144 faecal samples of wild carnivores from the Tatra National Park were examined to evaluate the prevalence of intestinal helminths--72 of wolves (Canis lupus), 45 of red foxes (Vulpes vulpes), 15 of pine martens (Martes martes) and 12 of brown bears (Ursus arctos). In wolves, monospecific infection with Trichuris vulpis (13.9%), Toxocara canis (6.9%), Ancylostoma/Uncinaria (5.6%) and taeniids (1.4%) was revealed. In red foxes, the most prevalent infection was 7 vulpis (64.4%), followed by T. canis (11.1%), Ancylostoma/Uncinaria (8.9%) and taeniids (2.2%). Monospecific infection with T. vulpis was more frequent (44.4%), than infection with two species, i.e. T > vulpis with Ancylostoma/Uncinaria, T. vulpis with T. canis or T. vulpis with taeniids (17.8%). In pine martens, Trichuris spp. was the most prevalent (40.0%), while T. cati and Ancylostoma/Uncinaria were found in 13.3% and 6.7% samples, respectively. In faeces from brown bears, no parasite eggs were found. The present survey of wild carnivores revealed a significant prevalence of parasites such as Toxocara spp. and Trichuris spp. (8.3% and 31.0% in all examined samples, respectively), which are hazardous to human and animal health. PMID- 24791343 TI - A double blind study of the effectiveness of sertaconazole 2% cream vs. metronidazole 1% gel in the treatment of seborrheic dermatitis. AB - Seborrheic dermatitis (SD) is generally treated with topical steroids, antifungals, or both. The aim of this study was to compare the efficacy of sertaconazole 2% cream vs. metronidazole 1% gel in the treatment of seborrheic dermatitis. A group of 156 patients suffering from SD were studied. The patients were randomly divided into two groups. The first group received local sertaconazole 2% cream and they were recommended to use the cream twice a day for 4 weeks. In the control group, thirty patients received metronidazole 1% gel twice a day for four weeks. At the point of referral, and also 2 and 4 weeks after the first visit, the patients were examined by a dermatologist to identify improvement of clinical symptoms. A higher level of satisfaction was observed after 28 days in the sertaconazole group (87.1%) than the metronidazole group (56.4%). Considering its efficacy, safety, and acceptability profiles, sertaconazole 2% cream is a worthwhile alternative to existing antifungal therapies for the treatment of seborrheic dermatitis. PMID- 24791344 TI - Setaria tundra in roe deer (Capreolus capreolus)--new findings in Poland. AB - Setaria tundra is a filarioid nematode transmitted by mosquitoes, which is sporadically observed in Poland. Some ecological factors, such as the synurbisation of some wild ungulates and the climate changes observed in recent years, could affect the possibility of infection, especially with parasites transmitted by arthropod vectors. The study was conducted to evaluate the presence of Setaria sp. in roe deer populations in different environments. Parasitological dissections of 53 roe deer were performed. The animals were taken from the area of the Cracow agglomeration, and from arable and forest lands near the city. During the autopsy, nematode specimens (one to twelve per host) were found only in the abdominal cavity of roe deer from the urban area. All parasites were classified to Setaria tundra species on the basis of morphology and dimensions. The infection observed was probably associated with the specific environmental conditions of the urban area. PMID- 24791345 TI - Quantitative assessment of mycological air pollution in selected rooms of residential and dormitory housing facilities. AB - The qualitative and quantitative mycological composition of indoor areas of three private residencies and an academic dormitory in Wroclaw, Poland was investigated. Seasonal fungal samples were obtained using a MAS-100 air sampler. The samples were cultured on three different media: Sabouraud Agar (SAB), Dichloran Glycerol Selective Medium (DG18) and Malt Extract Agar (MEA). The number of colony forming unit (CFU) values ranged from 10 CFU/m3 to 490 CFU/m3 depending on the culture medium, season, and sampling site. The identification of the cultured fungi was performed using macro- and microscopic observations and diagnostic keys. Eleven fungal genera were identified. The most common fungi were members of genera Cladosporium, Penicillium, Aspergillus, Alternaria, and Fusarium; the least common fungi were members of genera Geotrichum and Paecilomyces. Seasonal variations in the concentration of fungi were observed with the highest concentration of fungi in the spring and the lowest concentration of fungi in the winter. There were no statistically significant correlations between fungal concentrations and the temperature or the relative humidity of the sample sites. PMID- 24791346 TI - The efficacy of permethrin 5% vs. oral ivermectin for the treatment of scabies. AB - Human scabies is caused by an infestation of the skin by the human itch mite (Sarcoptes scabiei var. hominis). The aim of this study is to compare the efficacy and safety of permethrin 5% lotion with oral ivermectin for the treatment of scabies. In total, 60 patients with scabies were enrolled, and randomized into two groups: The first group and their family contacts received 5% permethrin cream twice with a one week interval, and the other received a single dose of oral ivermectin. Treatment was evaluated at intervals of 2 and 4 weeks. A single dose of ivermectin provided a cure rate of 62.4%, which increased to 92.8% with 2 doses at a 2-week interval. Treatment with two applications of permethrin with a one week interval was effective in 96.9% of patients. Permethrin-treated patients recovered earlier. Two applications of permethrin with a one week interval is more effective than a single dose of ivermectin. Two doses of ivermectin is as effective as a single application of permethrin. PMID- 24791347 TI - Morphometrical and ecological analysis of nematodes of the family Capillariidae (Neveu-Lemaire, 1936) in wild ducks (Anatinae) from the north-western Poland. AB - West Pomerania is located on the migratory route of many species of birds. Among them are many representatives of wild duck species (subfamily Anatinae), which are often the primary hosts of many helminths due to the fact of living in two different environments: terrestrial and aquatic. However, until the end of the 90s, research conducted in Poland on the helminth fauna of wild birds, including nematodes of the family Capillariidae, did not include the north-western region of the country. These first studies performed in 1999, aimed at the identification of the nematodes of wild ducks from the West Pomerania region, revealed the presence of three species belonging to family Capillariidae, i.e. Capillaria anatis (Schrank, 1790) Travassos, 1915, Eucoleus contortus (Creplin, 1839) Gagarin, 1951 and Pseudocapillaria mergi (Madsen, 1945). The purpose of the current study was to perform a comprehensive ecological analysis of C. anatis, E. contortus and P. mergi, including such factors as intensity, prevalence, relative density, index of fidelity and dominance index. The experimental material comprised 811 nematodes isolated from the gastrointestinal tracts of 953 ducks. These 9 species of ducks belong to three different tribes of the Anatinae subfamily: Anatini (Anas clypeata, A. crecca, A. platyrhynchos), Aythyini (Aythya fuligula, A. marila) and Mergini (Bucephala clangula, Clangula hyemalis, Mergus merganseri, Somateria mollissima) and diverse in terms of their biology and ecology. The morphometric and morphological analyses fail to identify any significant differences in the body structures of nematodes of the species C. anatis, E. contortus and P. mergi of the West Pomerania region in comparison with those found in other regions of Poland and Europe. The ecological analysis of the Capillariidae family in the West Pomerania region revealed that ducks of the tribe Anatini (mainly A. platyrhynchos) are the most common hosts of E. contortus species, C. anatis is most commonly found in ducks of the tribe Aythyini, and P. mergi is relatively frequent in ducks of the tribe Mergini (mainly in M. merganser). PMID- 24791348 TI - Occurrence of internal parasites in stone martens (Martes foina) from Cracow and suburbs. AB - The pine marten Martes martes and the stone marten Martes foina are the only representatives of the genus Martes in Poland. During the last few decades, an intensive synurbisation of stone martens has been recorded. The aim of the study was to assess the level of infection by internal parasites of Martes foina in the Cracow urban area. Eleven necropsies were performed of stone martens killed during animal-vehicle collisions. Additionally, coprological examination of 129 stone marten scats was included. For further analysis, two standard methods, i.e. flotation and decantation, were used. The intensity of infection by parasites was low. Taenia martis was found to be present in one marten individual by necropsy, while Taeniidae helminths and two genera of nematodes, Capillaria and Toxocara, were identified during coprodiagnosis. The diet analysis of stone marten scats revealed a high proportion of two food categories. Percentage frequency of occurrence for plant material and anthropogenic was calculated as 42.3% and 15.4%, respectively. This type of food composition might suggest lower infection by internal parasites in particular species, especially with an indirect life cycle. PMID- 24791349 TI - The prevalence of Fasciola hepatica L. infection in cattle in the Lublin province in the years 2009-2012. AB - Prevalence of Fasciola hepatica L. infection among cattle slaughtered in the Lublin province in from 2009-2012 was evaluated. The data were taken from annual reports of the Veterinary Inspectorate in Lublin. The results of the study are as follows: the prevalence of Fasciola hepatica infection in the cattle of the Lublin province between 2009 and 2012 is found to be 11.97%. PMID- 24791350 TI - Bitumens and bitumen emmissions, and some N- and S-heterocyclic polycyclic aromatic hydrocarbons. PMID- 24791351 TI - Mentoring: setting a dynamic for success. PMID- 24791352 TI - Data bits: take a swipe at surgical site infections. PMID- 24791353 TI - Blood products and the Jehovah's Witness: an ethical concern. PMID- 24791354 TI - E-cigarettes: what nurses need to know. PMID- 24791355 TI - KNA begins its transition to chapters. PMID- 24791356 TI - American Nurses Foundation announces collaboration with Wolters Kluwer Health to expand "Honor a Nurse" program publicly recognizes RNs who make a difference. PMID- 24791357 TI - Osteoporosis knowledge in patients with a first fragility fracture in Puerto Rico. AB - PURPOSE: To determine the level of knowledge about osteoporosis and factors associated with low level of knowledge in patients with a first osteoporotic fracture. METHODS: A cross-sectional study in adult patients with a first osteoporotic fracture admitted to the University Hospital of the Puerto Rico Medical Center, San Juan, Puerto Rico was performed. Socio-demographic parameters, clinical features, and pharmacologic treatment were examined. A validated questionnaire was used to assess subjects' level of knowledge about osteoporosis. Differences between study groups were evaluated using chi-square and Student's t tests, as appropriate. RESULTS: A total of 54 patients participated in the study. The mean (SD) age was 73.7 (10.7) years; 77.8% were females. Overall, 61.1% of the participants had a low level of knowledge about osteoporosis. Patients with low level of knowledge were more likely to have the Puerto Rico Government health insurance, lower level of education, and higher hip FRAX scores than those with mid/high level of knowledge. Also, they were less likely to receive osteoporosis counseling by their primary care physicians (PCP), have prior BMD measurement, receive bisphosphonates/raloxifene treatment, and to take calcium and vitamin D supplements. CONCLUSIONS: In this population of Hispanic patients with a first osteoporotic fracture, the majority had a low level of knowledge about osteoporosis. Low knowledge was associated with low socio-economic status, lack of counseling about osteoporosis by PCP, prior BMD measurement, and osteoporosis treatment. Better efforts should be undertaken to educate, identify, and manage patients at risk for osteoporotic fractures. PMID- 24791358 TI - Psychosocial factors associated with failure to use contraception among adolescents with repeat pregnancies in Puerto Rico. AB - Social, medical, psychological and economic problems are often associated to teen pregnancy. This is a reality worldwide; Puerto Rico is not an exception, documented in statistics and previous research projects. There are many risks associated with pregnancies among adolescents, including increased maternal morbidity and infant morbidity. In Puerto Rico, the adolescent repeat births reed are 22% for a second child and 6% for a third child. Repeated teen pregnancy has a higher than expected incidence; therefore the investigation of psychosocial factors associated with failure to use contraception is needed,especially to address the intervention at clinics with this population of different needs, mainly when these patients with repeated teen pregnancies have been through the health care system already. METHODOLOGY: The project is a cross sectional survey study, seventy articipants between 12-19 years of age who attended obstetrics or postpartum clinics at an adult University Hospital. A self-administered questionnaire included some psychosocial factors that have been associated withthe failure to use contraceptives as well as demographics tion, education, socioeconomic status and support system. RESULTS: Their partner's age ranged from 15 to 38 years of age. Most participants lived with their partner. Their main activity at the time of the study was housework. Most had left school beforebecoming pregnant and received government help. Of all participants, a small number was legally married. The lack of use of contraceptive was found to be significantly associated to partner (p < 0.05). CONCLUSION: The lack of contraceptive use is a key factor in adolescent pregnancy. It is expected that this data can be helpful for documentation and intervention measurements something canbe done at an educational level, family planning and medical care. PMID- 24791359 TI - [Endovascular management of cavernous sinus dural fistulas]. AB - OBJECTIVE: Describe the outcomes of patients diagnosed with indirect carotid cavernous fistula treated by endovascular methods. DESIGN: A retrospective case series. PARTICIPANTS: Twelve patients with dural cavernous sinus fistula with important ophthalmologic involvement admitted and treated at the National Institute of Neurology and Neurosurgery between February 1990 and January 2005. INTERVENTION: Patients were managed by endovascular embolization for all fistulas. OUTCOME MEASURES: Angiographic controls to 24 hours and at 6 and 12 months were performed. RESULTS: 67 % were female and 33 % male. The mean age was 44 years. 67 % were spontaneous and 33% of traumatic origin. All patients had eye involvement with proptosis (92%) and involvement of the oculomotor nerve (67%). Headache and pulsatile tinnitus were not frequent ophthalmologic data. All were diagnosed by cerebral angiography, 33 % were type C, type D 67 %, and none of the type B classification Barrow. In 17 % of cases the distal arterial robbery showed severe. Predominance of anterior and superior venous drainage in 83 % and 42 % of cases occurred respectively. The surgical approach was arterial in 84% of cases, while in 17 % venous through the superior ophthalmic vein. Cyanoacrylate embolization material was used in 58 % of the cases, as it was associated with the use of removable ball with polyvinyl alcohol particles in 16 % in of venous approach cases. 17% detachable coils were utilized. There were no complications. After angiographic controls at 24 hours 100% occlusion was seen in patients treated with cyanoacrylate (58%) (p = 0.03). The remaining 42% were prescribed maneuver of manual compression. At 12-months angiography all patients had 100% occlusion of the carotid-cavernous fistula. CONCLSUIONS: This is the world's second largest series with indirect carotid-cavernous fistulas treated after trauma. 100 % of cases were cured with the use of a transarterial-controlled approach and N-butyl-cyanoacrylate after long-term observation. PMID- 24791360 TI - Risk factors for hysterectomy in abnormal placentation at the University District Hospital. AB - The aim of this research was to study the relationship of abnormal placentation and cesarean hysterectomy risk factors at the University District Hospital. METHOD: A retrospective study was conducted using 60 medical records of patients in the University District Hospital from 2001 to 2008 with a diagnosis of abnormal placentation. Descriptive statistics and chi square for associations were used for statistical analysis. RESULTS: The mean age in our population was 29 years and mean BMI was 29.6. 45 % of the patients had a previous history of cesarean, 1.7% of placenta previa and 26.7% of uterine curettage. We found that 33.3% had a cesarean hysterectomy and 41.7% had post-partum hemorrhage. Also 51.7% received blood transfusion. The mean hospital stay was 18.1 days. The probability of cesarean hysterectomy in patients with placenta previa was eleven times higher in patients with history of previous cesarean sections (OR 11, CI: 1.29-97.9, p value=0.01). There was no statistically significant difference in cesarean hysterectomy rate between obese (BMI>30) and nonobese patients (OR 3.8 CI: 0.69-20.5, p value=0.11). CONCLUSION: The probability of cesarean hysterectomy in patients with abnormal placentation was significantly increased in patients with previous cesarean sections. By decreasing the rate of cesarean section we can decrease the incidence of cesarean hysterectomy and its comorbidities. PMID- 24791361 TI - Meningeal melanocytoma: case report and literature review. AB - We report a case of a 54-year-old female with progressive chronic pain in lower extremity, paraplegia and loss of function of the anal sphincter. MRI revealed an expansive solid intradural and intramedullar lesion located at the T6 to T9 levels. Histology of the lesion showed melanocytes with the results of immunohistochemistry consistent with a melanocytoma. Melanocytic tumors are rare tumors which present a diagnostic and management challenge for the modern neurosurgeon and neuro-oncologist since MRI and CT features are non-specific and there is scant data to standardise best strategic therapy. PMID- 24791362 TI - [Sensorineural deafness and vertebral artery aneurysm: endovascular management]. AB - Sensorineural deafness and vertigo have different causes among them immunological, vascular and infectious. Vascular causes of sensorineural hearing loss are unusual and among them are the vertebral artery aneurysms. Knowledge by neurosurgeons, neurointerventional and otolaryngologists aneurysms involving the development of sensorineural hearing loss is critical to establishing and determining a targeted therapeutics. We report the case of an adult handled with endovascular techniques and review the current literature of similar cases. PMID- 24791363 TI - Abrupt onset of muscle dysfunction after treatment for Grave's disease: a case report. AB - Myopathy is a known complication of hypothyroidism, commonly characterized by an elevation in Creatine Kinase (CPK) due to increase capillary permeability proportional to the hypothyroid state. Thyroid hormone is important for the expression of fast myofibrillar proteins in the muscle. In hypothyroidism the expression of these proteins are deficient and there is an increase accumulation of slow myofibrillar proteins. A rapid or abrupt descend in thyroid hormones caused by radioiodine therapy after prolonged hyperthyroidism can lead to local hypothyroid state within the muscle tissue, resulting in CPK elevation and hypothyroid myopathy. Hormone replacement leads to resolution of symptoms and normalization of muscle enzymes serum levels. PMID- 24791364 TI - Pasteurella multocida: a nightmare for a replaced joint and the challenge to save it. AB - Pasteurella multocida a small gram-negative coccobacilli is primarily found as normal flora of cats and dogs. These organisms can cause a variety of infections in humans, usually the result of scratches, bites and licks by percutaneous inoculation of the organism. Most cases of septic arthritis involve a cat or dog bite distal to the involved joint without direct penetrating injury to the joint. On scenarios were Pasteurella infection is suspected within a prosthetic joint, aggressive surgical debridement and/or removal of the prosthesis with intravenous antibiotics is recommended. Prosthetic joint infections secondary to animal bites are an extremely rare complication and few cases have been reported in the literature. This is a case report of a patient that suffered a cat's bite of his right prosthetic knee and against all odd was able to save it without surgical intervention. PMID- 24791365 TI - Just a flare---the Pandora's box approach. AB - Systemic lupus erythematosus is a chronic inflammatory autoimmune disease characterized by autoantibodies specific for highly conserved nuclear antigens, such as double-stranded DNA, histones and ribonuclear proteins. The course of the disease is unpredictable and nine times more common in females. Among the neurological manifestations of collagen vascular diseases is the most commonly recognized and better studied disease. Central nervous system lupus is a serious and potentially treatable illness presenting as difficult diagnostic challenge. This is a case report of a patient that suffered central nervous system manifestations of severe active lupus. Early recognition of this entity is essential to expedite appropriate to treatment and avoid future complications. PMID- 24791366 TI - Young female with acromegaloid features and pituitary macroadenoma: what is your diagnosis? AB - Pseudoacromegaly is a extremely rare condition previously described and characterized by acromegaloid changes, tissue overgrowth, without elevations in insulin-like growth factor or growth hormone as seen in Acromegaly. We present the case of a young female seen initially with acromegaloid features and a pituitary microadenoma. After work-up the patient was diagnosed as insulin mediated pseudoacromegaly. Only a few cases of pseudoacromegaly has been reported and should always be considered when evaluating patients for acromegaloid features with negative biochemical and hormonal levels. PMID- 24791367 TI - An unusual case of a borderline Brenner tumor associated with bilateral serous cystadenoma and endometrial carcinoma. AB - Brenner tumor accounts for 1.5 to 2.5% of ovarian tumors. Nearly all are benign and 1% malignant. Less than twenty-five cases of borderline Brenner tumor have been reported worldwide. Our case is the first one related to a bilateral ovarian serous cystadenofibroma and endometrioid adenocarcinoma. This unusual case increases the limited data for borderline Brenner tumors. PMID- 24791368 TI - Wandering spleen torsion causing acute abdominal pain in a child: case report and review of literature. AB - Wandering spleen is a rare occurrence where the spleen normal fixation to the abdominal wall is lost and thus allowed to change in position. We report a case of a child who presented with acute abdominal pain secondary to a wandering spleen complicated by torsion of its vascular pedicle. The diagnosis was promptly made using computed tomography and managed with splenectomy. PMID- 24791369 TI - [Neuro-critical management of glycemia in spontaneous intracerebral hemorrhage: review of the literature]. AB - Spontaneous cerebral hemorrhage or intracranial hemorrhage represents between 10 and 15% of all cerebrovascular events. Intracerebral hemorrhage is far less frequent than ischemic stroke, but leads to increased morbidity and mortality, one of the leading causes of severe disability. Several changes have been identified in the field of intracerebral hemorrhage, including endocrine. These stress-mediated mechanisms exacerbate secondary injury. Deep knowledge of the injuries that are directly involved in the alterations of glucose in the context of an intracerebral hemorrhage, offers a vision of how the cytotoxicity, neuronal death and metabolic disturbances alter the prognosis of patients with spontaneous intracerebral hemorrhage. PMID- 24791370 TI - Uterine curettage post-partum patients with severe preeclampsia: removal of trophoblastic tissue can alter the progression of this condition. AB - Reviewing the literature to evaluate the effect of postpartum uterine curettage in the maternal recovery time of patients with refractory severe preeclampsia determined that uterine curettage can be of benefit in select cases and should be included in hospital protocols to avoid further maternal complications. PMID- 24791371 TI - Gratitude. PMID- 24791372 TI - The long winter. PMID- 24791373 TI - From straight lines to Aspens. PMID- 24791374 TI - Propafenone associated severe central nervous system and cardiovascular toxicity due to mirtazapine: a case of severe drug interaction. AB - We describe a rare case of severe drug-drug interaction between propafenone and mirtazapine leading to propafenone toxicity. A 69-year-old Caucasian male taking propafenone for atrial fibrillation was prescribed mirtazapine for insomnia. Subsequent to the first dose of mirtazapine the patient experienced seizures, bradycardia and prolonged QRS as well as QTc intervals on EKG. The patient was admitted to the ICU and recovered after supportive management. Propafenone is an established class IC antiarrhythmic drug commonly used in the treatment of atrial fibrillation. It is metabolized through the CYP4502D6 pathway. Five to 10 percent of Caucasians are poor metabolizers. Mirtazapine is a commonly prescribed antidepressant drug, which is also metabolized through and may modulate the CYP4502D6 pathway leading to altered metabolism of propafenone and possible adverse effects. In this case, toxicity was reversed once the offending drugs were discontinued. An extensive review of the literature revealed this to be the first described case of drug interaction between propafenone and mirtazapine. PMID- 24791375 TI - Identification of a founder mutation for maple syrup urine disease in Hutterites. AB - Maple syrup urine disease (MSUD) is an organic acidemia detected on newborn screening. The condition has been reported with increased frequency in certain founder populations including Hutterites. We present a case of MSUD in a Hutterite boy. Mutation analysis was completed and identified a candidate founder mutation in the BCKDHB gene, specifically c.595_596delAG. Further testing of other Hutterites with MSUD is needed to determine whether additional mutations may exist. PMID- 24791376 TI - Incidental finding of subclavian steal in a cardiac catheterization for acute coronary syndrome. AB - The subclavian steal syndrome (SSS) refers to neurological symptoms that develop from a proximal subclavian artery occlusion. We present a case of an asymptomatic patient found to have subclavian steal (SS) on angiography. A brief literature review follows. PMID- 24791377 TI - Cystic fibrosis: a review of pathophysiology and current treatment recommendations. PMID- 24791378 TI - Data on the move. PMID- 24791379 TI - Using QTIP trusts to circumvent portability limitations. PMID- 24791380 TI - Quality focus: Medication safety and reconciliation. PMID- 24791381 TI - DAKOTACARE update: Heart disease & stroke in South Dakota. PMID- 24791382 TI - Extenuating circumstances: Effective screening for autism spectrum disorder. PMID- 24791383 TI - Extenuating circumstances: Autism awareness. PMID- 24791384 TI - [Between hammer and anvil]. PMID- 24791385 TI - [Good health and satisfaction at work: how leaders perceive their daily work routine]. PMID- 24791386 TI - ["We must see the organizations through the eyes of a nurse specialist" (interview by Martina Camenzind)]. PMID- 24791387 TI - [Leadership in nursing: leadership style is crucial for work satisfaction]. PMID- 24791388 TI - [Disordered eating behavior in the professional routine: don't look away!]. PMID- 24791389 TI - [A guide in the nursing home: respectful management of heroin addicted patients]. PMID- 24791390 TI - [Intensive care nursing: early mobilization of heart surgery patients]. PMID- 24791391 TI - [Cooperation education nursing HF: sound basic knowledge freely available]. PMID- 24791392 TI - [Gudrun Mariani retires: immense gratitude]. PMID- 24791393 TI - [Current recommendations. Bed sharing and sudden infant death]. PMID- 24791394 TI - [Miriam J. Hirschfeld, nursing science specialist: Jewish and Arab students under one roof]. PMID- 24791395 TI - ["Squeezed dry like a lemon"]. PMID- 24791396 TI - [The complex and the human]. PMID- 24791397 TI - [Dealing with small and significant abuse: solidarity between women]. PMID- 24791398 TI - [A new nursing role: advanced nursing practice: what does it mean?]. PMID- 24791399 TI - [Results of an exploratory survey of advanced practice nursing: the clinicians: essential resource persons]. PMID- 24791400 TI - [Tribute to Dr. Doris Krebs: grande dame of nursing care is gone]. PMID- 24791401 TI - [IUFRS (University Institute of Education and Research in Nursing) symposium: 5 years of integrity and imagination!]. PMID- 24791402 TI - [Night care: in praise of creativity ]. PMID- 24791403 TI - [The loneliness of the setting]. PMID- 24791404 TI - [New law for health professions: "not all requests are taken into consideration"]. PMID- 24791405 TI - Smoking cessation improves anxiety depression. PMID- 24791406 TI - Detecting ovarian disorders in primary care. AB - Ovarian cysts occur more often in premenopausal than postmenopausal women. Most of these cysts will be benign, with the risk of malignancy increasing with age. The risk of a symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1,000 increasing to 3:1,000 at the age of 50. Ovarian cysts may be asymptomatic but presenting symptoms include pelvic pain, pressure symptoms and discomfort and menstrual disturbance. Functional cysts in particular can be linked with irregular vaginal bleeding or menorrhagia. Ovarian torsion is most common in the presence of an ovarian cyst. Dermoid cysts are most likely to tort. Torsion presents with sudden onset of severe colicky unilateral pain radiating from groin to loin. There may be nausea and vomiting. It is often confused with ureteric colic where the pain is similar but radiates loin to groin. Symptoms which may be suggestive of a malignant ovarian cyst, particularly in the over 50 age group, include: weight loss, persistent abdominal distension or bloating, early satiety, pelvic or abdominal pain and increased urinary urgency and frequency. CA125 levels should be checked in women who present with frequent bloating, feeling full quickly, loss of appetite, pelvic or abdominal pain or needing to urinate quickly or urgently. Symptomatic postmenopausal women, those with a cyst > or = 5 cm, or raised CA125 levels, should be referred to secondary care. Functional cysts, particularly when they are < 5 cm diameter, usually resolve spontaneously without the need for intervention. In premenopausal women simple cysts > or = 5 cm are less likely to resolve and need an annual ultrasound assessment as a minimum. PMID- 24791407 TI - Improving the management of urinary incontinence. AB - Urinary incontinence (UI) is the complaint of any involuntary loss of urine and is a common condition that is likely to be under-reported. In the UK, the prevalence is estimated to be 17-40%, and rates are higher in the elderly. UI is more common in women than men. Its frequency increases with age, parity, high BMI, and associated comorbidities. The common types are stress UI, overactive bladder (OAB) or urge UI, and mixed UI a combination of the two. In stress UI there is involuntary loss of urine that occurs in association with an increase in intra-abdominal pressure. OAB is caused by overactivity of the detrusor muscle. This may be idiopathic or secondary to lesions affecting the motor or sensory pathways to the muscle. The history should include the circumstances in which the incontinence occurs, the duration and how it affects the patient's quality of life. The initial assessment should include enquiring for symptoms of urinary tract infection and carrying out a urine dipstick test. Abdominal examination should exclude a large pelvic-abdominal mass and a palpable bladder post micturition. Vulval-vaginal examination should assess for atrophic vaginitis and prolapse, masses and pelvic floor muscle contraction. Involving a skilled continence nurse or dedicated pelvic physiotherapist will improve care and can reduce referrals to secondary care. When conservative measures for OAB are unsuccessful, the next step is pharmacological treatment. Referral to secondary care should be offered when the response to two drugs has not been satisfactory. For stress UI, referral is indicated after failure of pelvic floor muscle training. PMID- 24791408 TI - Managing prolonged disorders of consciousness. AB - After acute severe brain damage, many people are rendered unconscious or comatose for more than 24 hours. Although a significant number can still recover fully, some will not and a substantial minority remain unconscious for days, weeks or longer. These patients have a prolonged disorder of consciousness. A specialist multidisciplinary team should be closely involved in the management of every patient from the outset. Assessment of a patient's level of awareness is not straightforward, and requires a team with suitable experience and expertise. The underlying neurological damage, whether or not there is an intact primary sensory input and motor output, and if there are reversible causes such as a high level of a sedating drug, or a subdural haematoma have to be established. If recovery of awareness has not occurred by six months after hypoxic or hypoglycaemic brain damage and 12 months after most other causes of brain damage, then the patient is very unlikely to recover any awareness and is described as being in a permanent vegetative state. The family must be closely and fully involved from the outset. Families legally cannot, and should not be asked to, make decisions concerning healthcare, unless a family member is a legally appointed deputy or has been given power of attorney in relation to healthcare matters. Family members can, and should be asked to, give information about the patient's wishes, life choices etc as part of the best interests decision-making process, and they should be involved in best interests meetings. PMID- 24791409 TI - Bullous disorders. PMID- 24791411 TI - Prevention is better than cure. PMID- 24791410 TI - A children's casualty department. 1914. PMID- 24791412 TI - Conformational study of N-methylated alanine peptides and design of Abeta inhibitor. AB - N-Methylation increases the proteolytic stability of peptides and leads to improved pharmacological and increased nematicidal property against plant pathogens. In this study, the quantum mechanical and molecular dynamic simulation approaches were used to investigate conformational behavior of peptides containing only N-methylated alanine (NMeAla) residues and N-methylated alanine and alanine residues at alternate positions. The amide bond geometry was found to be trans and the poly NMeAla peptides were shown to populate in the helical structure without hydrogen bond with phi, psi values of - 0, 90 degrees stabilized by carbonyl-carbonyl interactions. Molecular dynamic simulations in water/methanol revealed the formation of beta-strand structure, irrespective of the starting geometry due to the interaction of solvent molecules with the carbonyl groups of peptide backbone. Analysis of simulation results as a function of time suggested that the opening of helical structure without hydrogen bond started from C-terminal. Conformational behavior of peptides containing N-MeAla and Ala was used to design Abeta peptide inhibitor and the model tetrapeptide Ac Ala-NMeAla-Ala-NHMe in the beta-strand structure was shown to interact with the hydrophobic stretch of Abeta15-42 peptide. PMID- 24791413 TI - Study of photodynamic, sonodynamic and antioxidative influence on HeLa cell line. AB - Photodynamic treatment (PDT) in combination with sonodynamic treatment (SDT) can be used as suitable methods to treat malignant and benign diseases or combat resistant bacteria. Both methods affect the production of reactive oxygen species (ROS). On the other hand, antioxidants are useful for cell protection against ROS. This work was aimed to study the effect of PDT and SDT treatments on the HeLa cell line using antioxidant Pronalen Sensitive Skin as a protection from free radicals in the cells. We evaluated the effect of sensitizer ClAlPcS2 using battery of in vitro methods, including MTT assay, kinetic production of ROS, mitochondrial membrane potential change, type of cell death and microscopic analysis. Ultrasound treatment was observed to increase the production of ROS, only in combination with PDT, particularly at higher concentrations of ClAlPcS2. The added antioxidant acts as protection against free radicals and has potential as a dietary supplement against aging or free radicals. The results of study suggested that ClAlPcS2 could be used as a potential photosensitizer for treatment of a specific type of cancers. PMID- 24791414 TI - A quantitative structure-activity relationship (QSAR) study on a few series of potent, highly selective inhibitors of nitric oxide synthase. AB - QSAR study was performed on a series of 1,2-dihydro-4-quinazolinamines, 4,5 dialkylsubstituted-2-imino-1,3-thiazolidine derivatives and 4,5-disubstituted-1,3 oxazolidin-2-imine derivatives studied by Tinker et al. [J Med Chem (2003), 46, 913-916], Ueda et al. [Bioorg Med Chem (2004) 12, 4101-4116] and Ueda et al. [Bioorg Med Chem Lett (2004) 14, 313-316], respectively, as potent, highly selective inhibitors of inducible nitric oxide synthase (iNOS). The iNOS inhibition activity of the whole series of compounds was analyzed in relation to the physicochemical and molecular properties of the compounds. The QSAR analysis revealed that the inhibition potency of the compounds was controlled by a topological parameter 1chi(v) (Kier's first order valence molecular connectivity index), density (D), surface tension (St) and length (steric parameter) of a substituent. This suggested that the drug-receptor interaction predominantly involved the dispersion interaction, but the bulky molecule would face steric problem because of which the molecule may not completely fit in active sites of the receptor and thus may not have the optimum interaction. PMID- 24791415 TI - Azadirachta indica mitigates DMBA-induced hepatotoxicity: a biochemical and radiometric study. AB - The hepatoprotective potential of aqueous Azadirachta indica leaf extract (AAILE) was assessed against DMBA-induced hepatotoxicity. DMBA (7,12-dimethylbenz[a] anthracene) treatment (40 mg/kg body weight, ip) to male Balb/c mice resulted in the derailment of liver function as revealed by extremely slow clearance of 99mTc mebrofenin from liver, elevated levels of alkaline phosphatase (ALP) and alanine transaminase (ALT), compared to control group. In addition, elevated micronuclei score and high apoptotic index indicated hepatogenotoxicity in DMBA-treated mice. DMBA treatment also upregulated cytochrome P450 (CYP), cytochrome b5 (Cyt b5) and decreased glutathione-S-transferase activity in hepatic tissue, compared to control group. Enhanced lipid peroxidation (LPO) levels along with decreased reduced glutathione (GSH) level were also observed in DMBA group, compared to control group. AAILE co-treatment (200 mg/kg body weight, po, thrice a week) for 8 weeks followed by DMBA injection showed significant improvement in hepatic status, as revealed by normalization of 99mTc-mebrofenin clearance rate, decreased ALP and ALT levels, reduced genotoxicity in terms of micronuclei score and apoptotic index. Levels of LPO were significantly decreased along with increased hepatic GST and GSH levels in AAILE + DMBA group, compared to DMBA group. However, no significant change was observed in hepatic CYP and Cyt b5 levels, compared to DMBA group. The results indicated that AAILE effectively ameliorated DMBA-induced hepatotoxicity. PMID- 24791416 TI - In vitro cytotoxic activity of leaves extracts of Holarrhena antidysenterica against some human cancer cell lines. AB - In vitro cytotoxic potential of extracts (95% and 50% ethanolic extract and hot water extract at concentration of 100 microg/ml) from leaves of Holarrhena antidysenterica was evaluated against fourteen human cancer cell lines--A-549, COLO-205, DU-145, HeLa, HEP-2, IMR-32, KB, MCF-7, NCI-H23, OVCAR-5, SiHa, SK-N MC, SW-620 and ZR-75-1 from nine different tissues (breast, colon, cervix, CNS, lung, liver, oral, ovary and prostate) using SRB assay. The 95% ethanolic extract displayed maximum anti-proliferative effect in the range of 73-92% against eight human cancer cell lines, while 50% ethanolic extract showed cytotoxic activity in the range of 70-94% against seven human cancer cell lines. However, the hot water extract did not show any activity. Among the fractions of 95% and 50% ethanolic extract, significant cytotoxic activity was found in the chloroform soluble fraction of 95% ethanolic extract at 100 microg/ml; it inhibited the growth in the range of 71-99% of seven human cancer cell lines from five different tissues viz., OVCAR-5 (ovary), HT-29 (colon), SK-N-MC (neuroblastoma), HEP-2 (liver), COLO-205 (colon), NIH-OVCAR-3 (ovary) and A-549 (lung). The cytotoxic activity of chloroform soluble fraction was found to be higher than 5-flurouracil, adriamycin, mitomycin-c and paclitaxel (anticancer drugs used as positive controls). Further in vivo studies and identification of active components from the chloroform fraction and their exact mechanism of action could be useful in designing new anticancer therapeutic agents. PMID- 24791417 TI - New mathematical derivations for calculation of ATP yield due to the complete oxidation of different types of fatty acids. AB - During the complete oxidation of fatty acids, the electrons removed from fatty acids in different forms (FADH2 and NADH2) pass through the respiratory chain, driving the ATP synthesis. Generally, the ATP yield due to the complete oxidation of fatty acids is calculated by sum total the ATPs obtained due to the oxidation of FADH2 and NADH2 due to lack of any particular method. This calculation is simple for saturated even numbered fatty acids, but in the case of saturated and unsaturated odd numbered fatty acids the calculation of ATP yield is difficult and needs mathematical calculations due to some changes in their beta-oxidation pathway when compared to the pathway of saturated even numbered fatty acids. These calculations are made simple by our derivations and following formulae where we require only number of carbon atoms and double bonds present in a fatty acid. Our method is superior and easier in comparison to long mathematical calculations that are in the practice. PMID- 24791418 TI - Incorporation of Na+/H+ antiporter gene from Aeluropus littoralis confers salt tolerance in soybean (Glycine max L.. AB - To develop a salt-tolerant soybean (Glycine max L.) cultivar, a minimal linear Na+/H+ antiporter gene cassette (35S CaMV promoter, open-reading-frame of AINHX1 from Aeluropus littoralis and NOS terminator) was successfully expressed in soybean cultivar TF-29. Southern and Northern blot analysis showed that AlNHX1 was successfully incorporated into the genome and expressed in the transgenic plants. The AlNHX1 transgenic plant lines exhibited improved growth in severe saline condition (150 mM NaCl). The transgenic lines accumulated a lower level of Na+ and a higher level of K+ in the leaves than wild-type plants under saline condition (150 mM NaCl). Observations on the chlorophyll content, photosynthetic rates, malondialdehyde and relative electrical conductivity indicated that transgenic plants exhibited tolerance to salt stress, growing normally at salt concentrations up to 150 mM. These results demonstrated that AlNHX1 was successfully transferred into soybean and the salt-tolerance was improved by the overexpression of AlNHX1. PMID- 24791419 TI - Purification of a protease inhibitor from Dolichos biflorus using immobilized metal affinity chromatography. AB - Plant protease inhibitors (PIs) are generally small proteins which play key roles in regulation of endogenous proteases and may exhibit antifeedant, antifungal, antitumor and cytokine inducing activities. Dolichos biflorus (horse gram) is an unexploited legume, which is rich in nutrients and also has therapeutic importance. It contains a double-headed PI, which is an anti-nutritional factor. As there is no report available on its simultaneous removal and purification in single step, in this study, a double-headed PI active against both trypsin and chymotrypsin was purified from Dolichos biflorus to -14-fold with -84% recovery using an immobilized metal affinity chromatography (IMAC) medium consisting of Zn alginate beads. The method was single-step, fast, simple, reliable and economical. The purified inhibitor showed a single band on SDS-PAGE corresponding to molecular mass of 16 kDa and was stable over a pH range of 2.0-12.0 and up to a temperature of 100 degrees C for 20 min. The optimum temperature for trypsin and chymotrypsin inhibitor was observed to be 50 degrees C and 37 degrees C, respectively and pH optimum was pH 7.0 and 8.0, respectively. Thus, IMAC using Zn alginate beads was useful in simultaneous purification and removal of an anti nutritional factor from horse gram flour in single step. This procedure may also be employed for purification of other plant PIs in one step. PMID- 24791420 TI - Role of gamma-oryzanol in drought-tolerant and susceptible cultivars of rice (Oryza sativa L.). AB - Drought-tolerant cultivars and their phytochemical composition, which has a role in providing drought tolerance are gaining importance. In this study, rice bran oil and semi-purified oryzanol (SPO) obtained from five rice (Oryza sativa L.) cultivars, namely P1401 and PB1 (drought-susceptible) and N22, PNR381 and APO (drought-tolerant) were analyzed for the gamma-oryzanol content, an antioxidant present in considerable amount in the rice bran. The higher level of gamma oryzanol and its antioxidant activity was observed in drought-tolerant cultivars (N22, PNR381 and APO) as compared to drought-susceptible (PB1 and P1401), suggesting the role of gamma-oryzanol in drought tolerance, as antioxidants are known to play an important role by scavenging free radicals. The total antioxidant activity of gamma-oryzanol might be attributed to 24-methylene cycloartanyl ferulate, a major component of gamma-oryzanol. By enhancing the level of active oryzanol components identified in this study by genetic and molecular means could impart increased drought tolerance. PMID- 24791421 TI - Analysis of water soluble polysaccharides as a potential chemotaxonomic marker for landraces in Bixa orellana. AB - Annatto tree (Bixa orellana L.) is native to Brazil and is now under cultivation in many parts of world for its reddish orange 'annatto' dye. There are three types of landraces in annatto and they are distinguished based on fruit shape i.e., ovate, conical and hemispherical, whose pigment yield differs. Since annatto pigment yield varies with landrace, it is necessary to characterize markers towards the identification of landraces. In this study, we characterized water soluble polysaccharides (WSP) of twigs from three landraces using size exclusion chromatography (SEC), Fourier-transform Infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR) and gas liquid chromatography (GLC) for their potential use as chemotaxonomic markers to distinguish the landraces. GLC analysis on WSP showed hemispherical type contained 38% rhamnose, while conical and ovate types contained 17% and 34% glucose, respectively. Thus, glucose and rhamnose content of WSP could be used to distinguish the three landraces. Further, differences in calculated molecular weight as revealed by SEC (281.8, 151.3 and 79.4 kDa for conical, hemispherical and ovate types, respectively) could also be used to distinguish the three landraces. PMID- 24791422 TI - [The future is not what it was...and this may well be so!]. PMID- 24791423 TI - [Lacunar stroke and cerebral small vessel disease: advocacy for a recognition]. AB - Cerebral small vessel disease (cSVD) represents the sum of lesions which define a rather new clinical entity. Indeed, lacunar infarcts which are acute events of cSVD, represent 25% of all ischemic strokes. However, only few studies have dealt with acute and long term management of such stroke. Despite its rather early description around the XIXth century, the "lacune", the cardinal anatomopathological lesion of cSVD, remains only partially explained and pathogenesis is still debated. The purpose of this paper is to better define the anatomical lesions, to discuss physiopathological hypotheses and to present the most salient clinical features. Once identified cSVD should not be further overlooked. PMID- 24791424 TI - [New anticancer drugs: much ado about nothing?]. AB - Multiple new cancer drugs have been marketed during the last decade, and among those many molecularly targeted agents. Their impact on clinical outcomes population-wide remains hard to measure. Are we merely seeing the development of expensive and toxic drugs that benefit a minority of patients, or are battles actually won in the war on cancer? Both epidemiologic trends and clinical trial data show that a patient's outcome today is significantly better than 10 or 20 years ago, in terms of cure rates and survival time for advanced disease. PMID- 24791425 TI - [Thrombotic microangiopathy: when time is the key factor!]. AB - Thrombotic microangiopathy or "TMA" including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) became a public health problem following the European outbreak of E. coli (O104:H4) gastroenteritis in 2011. A rapid diagnosis and therapy in an intensive care unit provide better patient survival and lower cost for society. Supportive treatment has significantly improved the prognosis over the past decade and includes fresh frozen plasma for TTP, plasmapheresis for HUS, and recently a new therapeutic agent: anti-C5 antibodies. We will provide in this article, through the current literature and four cases encountered in our department, to establish an algorithm to manage patients with TMA. PMID- 24791426 TI - [Geriatric patients with chronic kidney insufficiency: which antalgia?]. AB - Pain is a leading cause of office visits. In the geriatric population, it is known that the prevalence of renal failure increases exponentially with age, modifing the elimination of drugs and of their metabolites. What analgesia should be offered to these patients? The holy grail would be a medication without renal elimination, without toxic metabolites and without nephrotoxicity. Based on the literature we try to propose a specific approach to analgesia in older patients with kidney insufficiency, in order to help practitioners to better prescribe for this group of patients. PMID- 24791428 TI - [Mycobacterium tuberculosis infection: signification, role and performance of mesure of cell-mediated immune response]. AB - Mycobacterium tuberculosis infection: signification, role and performance of mesure of cell-mediated immune response The tuberculin skin test (TST) and IGRAs are to date the unique way to identify individuals latently infected with Mycobacterium tuberculosis. In contrast to IGRAs, test specificity of TST is clearly affected by prior vaccination with attenuated strain M. bovis (BCG). Moreover, there is evidence suggesting that the accuracy of IGRAs is higher than that of TST and therefore IGRAs should perform better to detect latent tuberculosis in immunosuppressed individuals. However, neither TST nor IGRAs permit to discriminate between latent and active infection. Furthermore, there is no available test capable to identify whether individual with latent infection harbor live or dead mycobacteria and thus to detect who is at risk to develop active tuberculosis. PMID- 24791427 TI - [The transition of palliative care from the hospital to the ambulatory care of the general practitioner: the experience in the canton of Fribourg]. AB - Thanks to medical progress, the life expectancy of a majority of severely ill patients has greatly improved. The fact that these patients will live longer with their disease encourages new solutions to respond to the challenges of care continuity, coordination, interprofessional and interinstitutional collaboration. Palliative care represents a chain management based on the involvement of every professional in acute care hospitals, palliative care units, nursing homes and private homes. The collaboration among the different players as well as their education are essential elements linked to the quality of care, to the quality of life for both patients and their relatives. PMID- 24791429 TI - [The dermocorticoids, irreplaceable and feared]. AB - Dermocorticoids represent a significant part of the therapeutic arsenal in dermatology due to their anti-inflammatory and anti-proliferative effects, with an indication in numerous inflammatory dermatoses. Their cutaneous side effects are feared but are also often over-estimated. On the other hand, the systemic adverse effects are less well studied. We present here the properties of this medicament class and especially the rules to respect to avoid adverse reactions. PMID- 24791430 TI - [Persistent tropical diseases among migrants]. AB - Several infectious diseases may remain a- or pauci-symptomatic for many years before causing major clinical manifestations. Migrants are particularly vulnerable to several persistent infectious diseases due to exposure in their country of origin and their specific living conditions. This article emphasizes neglected parasitic diseases among migrants, such as schistosomiasis, strongyloidiasis and Chagas disease. In the case of co-infection with HIV, hepatitis B and C, some of these persistent parasitosis may induce more significant morbidity. These aspects are particularly important to know as these diseases, both viral and parasitic, are particularly common among migrants. PMID- 24791432 TI - [The mountain]. PMID- 24791433 TI - [Are transsexuals the owners of their sexual cells]. PMID- 24791431 TI - [Why does the Ebola virus (which is prevalent in Guinea today) not scare us?]. PMID- 24791435 TI - [Hybridization with the machines]. PMID- 24791434 TI - [Prostate cancer: the French figures of excess screening and its complications]. PMID- 24791436 TI - Things that go bump in the night. A backing mishap illustrates the value of having a spotter. PMID- 24791437 TI - Building accountability in EMS. What does it mean, and how can we achieve it? PMID- 24791438 TI - How to build the crew chain of safety. Safe driving is a priority for Richmond Ambulance Authority crews. PMID- 24791439 TI - How we built a better ambulance. What goes into constructing a safer rig? PMID- 24791440 TI - Withdrawal and the chronic alcohol abuser. Years of drinking can cause big changes and make drying out dangerous. PMID- 24791441 TI - Neurotrauma review series. Part 4: Autonomic dysreflexia. Interrupted brain communications can put spinal cord-injury patients at risk. PMID- 24791442 TI - A small but vital part. Your role in patients' lives may not be large, but it can be important. PMID- 24791443 TI - eQuality. Using hospital data to grade prehospital care. PMID- 24791444 TI - Making a difference: using the safe surgery checklist to initiate continuing education for perioperative nurses in low-income settings. AB - The WHO Safe Surgery Checklist (2008) patient safety focus and communication prompts are widely accepted. In many low-income regions (as defined by the World Bank and accepted by the World Health Organization) perioperative nurses have little or no formal training; continuing and in-service education are virtually unknown; nor does an articulated "culture of safety" exist. In 2009 the Canadian Network for International Surgery (CNIS) piloted a two-day perioperative nursing course, in Addis Ababa, Ethiopia, using lectures, case studies, skills sessions, and role-play exercises based on the SSSL Checklist outline and protocols. Canadian instructors (who are certified after taking the Canadian Network for International Surgery-sponsored Instructor's Course) have since returned and taught at additional sites in Ethiopia and Uganda. Course participants now include perioperative nurses, anaesthetists, and junior surgical residents- mirroring the interdisciplinary teamwork that is crucial to safe perioperative patient care. The course's facilitated discussions focus on workplace and practice issues in order to allow for appropriate evaluation and planning of future educational initiatives. Participants complete pre- and post-course questionnaires, which evaluate baseline and post-course knowledge, and further follow-up is completed four months after course completion. This article explains the need for aiding in the expansion of perioperative nursing knowledge and skill in low-income settings and provides the author's personal perspective and experience in responding to this need. Her experience as facilitator in a pilot project and subsequent course development described. The objective is to discuss ways that other perioperative nurses can work to make a positive difference on professional practice and patient care in low-income regions. PMID- 24791445 TI - Standardization: perioperative point of care best practice. PMID- 24791446 TI - Authentic leadership: develop the leader within. AB - Great leadership usually starts with a willing heart, a positive attitude, and a desire to make a difference. Strong leadership is important, in today's health care climate, to ensure optimal patient outcomes and the fostering of future generations of knowledgeable, motivated and enthusiastic perioperative nurses. This article will explore key elements necessary for the development of authentic leadership. While highlighting the role that personal development plays in leadership skills, this article will also discuss ways to cultivate authenticity in leadership. The following questions will be addressed: What is authentic leadership? How does one become an authentic leader? PMID- 24791447 TI - Fight back on pay: can you afford not to? PMID- 24791448 TI - Student employment concerns over 'optional' nurse prescribing. PMID- 24791449 TI - School nursing boost required to lead new national FGM campaign. PMID- 24791450 TI - School Nurse 121 Campaign. PMID- 24791451 TI - 'McDonaldising the community nursing workforce'. PMID- 24791452 TI - Modern motherhood. PMID- 24791453 TI - Why I'm standing up for generation D-? PMID- 24791454 TI - An assessment of homeless families' diet and nutrition. AB - This article describes an assessment of nutrition of families resident in temporary accommodation. A questionnaire and a 24-hour food diary were completed by the main care provider of each family. The findings demonstrated that adults in temporary accommodation were eating higher proportions of carbohydrates, protein, sugar and fat, and families were eating lower proportions of fruits, vegetables and dairy products than is recommended. Families resident in temporary accommodation were found to have increased difficulties meeting their nutritional needs. PMID- 24791455 TI - Online communities of practice and their role in educational development: a systematic appraisal. AB - Practice teachers and academics have a role in developing knowledge and promoting evidence-based practice with their students in a supportive and creative learning environment. Recent advances in technology are enabling communities of practice' (CoPs) to be developed online and may present a valuable opportunity to form greater connections between educators. To explore this idea, the author conducted a systematic appraisal of published evidence relating to the impact of using an online CoP (OCoP) to develop knowledge among healthcare educators. Three academic databases were targeted for articles and the search retrieved nine articles that were analysed for quality. The findings identified that an OCoP offers a 'polycontextual' environment that can enhance knowledge development, strengthen social ties and build social capital. Communities that support tacit knowledge development, information sharing and problem solving are most valued and existing information and communication technology (ICT) tools can be used to promote usability and accessibility. Recognising the value of tacit knowledge and using ICT for educational development within workload hours will require a shift in cultural thinking at both an individual and organisational level. PMID- 24791456 TI - How do parents look after children's teeth? A qualitative study of attitudes to oral health in the early years. AB - This study aimed to examine how parents and carers of pre-school children care for their children's teeth. Twelve in-depth interviews were conducted with mothers of pre-school children at a children's centre in Bristol. The interviewees were aged between 29 and 37 years, and the number of children in the families ranged from one to four, with their age range spanning four weeks to 11 years. Using a grounded theory approach, transcribed interviews were coded and analysed until several themes emerged from the data. The study identified an overarching theme of parents' belief that oral health care for their children was common sense, which was a key factor influencing advice seeking from professionals. Sub-themes were the difficulties in establishing home oral healthcare routines and a lack of knowledge of when to register their child with a dentist. Advice was often given inconsistently and parents experienced difficulties accessing services, with many not seeking advice and information pro actively. The study concluded that some parents are missing out on important early information, advice and care around oral health for their young children. PMID- 24791457 TI - Be your own boss: manage yourself! PMID- 24791458 TI - Community nursery nursing: the bigger picture. PMID- 24791459 TI - Developing resources to support practice teachers. PMID- 24791460 TI - Wheeze in a pre-school child: is it asthma? AB - Pre-school wheeze is a challenging condition and can cause anxiety in many parents. Hopefully, this article will empower you to support worried families. Education is key and health professionals should support families to get the answers that deal with their worries. Advice should be reinforced or a review sought if the child's symptoms are not improving. PMID- 24791461 TI - Researcher tasks and Editor in Chief tasks. PMID- 24791462 TI - Standard and limit values of mandibular condylar and incisal movement capacity. AB - A clinical functional status was obtained and an instrumental analysis of functional movement patterns of the mandible using the ultrasonic Jaw Motion Analyzer (JMA, Zebris; Isny, Germany) was performed on 259 subjects (100 male, 159 female) who were part of an associated project of the representative population-based Study of Health in Pomerania (SHIP 0). Standardized bilateral "arbitrary" skin points based on anatomical skin references were assumed as posterior reference points in the joint area. The recorded movement patterns were evaluated for condylar movement capacity right and left upon mouth opening (COR and COL, in mm), the incisal right-lateral and left-lateral excursion capacity (IR and IL, in mm), the incisal opening capacity (IO, in mm), and the maximum opening angle (OA, in degrees). For the determination of the standard and limit, the following means were determined with standard deviations and 5th and 95th percentiles: COR 14.52 +/- 4.188 (7.70, 21.40); (33.40; 56.10); OA 32.16 +/- 5.954 (21.40; 41.80). The values for men vs women for IR and for OW and in the age group below 40 years vs 40 years and above for IR were statistically significantly different. Interestingly, the interval between the 5th and 95th percentile in the group with a Helkimo clinical dysfunction index of 1 and approximately the same mean value was significantly greater than in the group with Helkimo 0. Based on this standard and limit values or ranges, individually measured values of functional mandibular movement can be compared and differentiated with respect to hypomobility/limitation (< 5th percentile) or hypermobility (> 95th percentile). This serves to indicate the therapeutic direction for functional treatment to improve the jaw's movement capacity in terms of biomechanical optimization. Objective kinematic measurements can be used for additional documentation of the treatment progress during the treatment course. PMID- 24791463 TI - Variability and reliability of muscle activity measurements during chewing. AB - The objective of this study was to test masseter muscle activity and its variability and reliability in terms of repeatable measurements in fully dentate and healthy volunteers during habitual chewing and deliberate unilateral chewing. Three sessions were performed on three consecutive days, each time recording kinematic data and masseter muscle EMG activities through a series of defined jaw exercises, including maximum voluntary contraction, habitual chewing, and left and right unilateral chewing. Asymmetry index (AI) and deliberate chewing index (DCI) scores were used to evaluate the activities of the left and right masseter muscles, which were separately recorded during each of these chewing exercises. DCI scores were side-specific, including two sets of values for left and right unilateral chewing. Reproducibility testing of the values obtained for all parameters revealed good to excellent reproducibility of masseter muscle activity under standardized recording conditions across the consecutive study sessions, with intra-class correlation coefficients (ICCs) ranging from 0.68 to 0.93. Different individuals were found to utilize different strategies of bilateral masseter activation during both habitual chewing and deliberate unilateral chewing. PMID- 24791464 TI - The reliability of computerized condylar path angle assessment. AB - Recording the track of the mandibular hinge axis and consequently ascertaining the posterior determinants is one of the key requirements for accurately simulating individual oral conditions in the (virtual) articulator. The aim of this study was to determine the reliability of computerized condylar path inclination angle (CPIA) measures and to assess whether the reliability depends on the mandibular dentition. Sagittal and transverse CPIA were measured using computerized axiography (Cadiax Compact 2) at two separate sessions in prosthodontic patients (mean age +/- SD: 64.3 +/- 10.3 years; female: 45%) who were classified into three dentition categories (fully dentate: N = 19, partially dentate: N = 27 and edentulous: N = 19). These measurements were repeated three times at both sessions without removing the computerized axiograph. Reliability was assessed in multilevel analyses using the subject as a grouping variable in linear random-intercept models. Considering all assessment procedures, the patient-specific differences explained 75% of the variance for the sagittal and 38% for the transverse condylar path. This corresponds to the overall reliability of both the sagittal and the transverse CPIA assessment. The dentition had no significant impact on the reliability of the measurements. The sagittal CPIA can be assessed with satisfactory reliability using computerized axiography. It is independent of the status of the dentition, which has no statistically significant impact on the measures. Transverse CPIA measurements have shown poor reliability. Therefore, the electronic determination of the sagittal CPIA is a reliable procedure that can be applied in patients irrespective of the status of the mandibular dentition. PMID- 24791465 TI - New applications for three-dimensional follow-up and quality control using optical impression systems and OraCheck. AB - Intraoral and extraoral scanning systems are continuously improving in terms of operational reliability and image quality. This creates new application options for the standard use of these systems in dental practice. Three-dimensional scans for volumetric and differential analysis of jaw position over time can be generated by superimposing partial or full-arch scans recorded at different time points. These analyses can be performed in a wide range of dental applications to compare and follow treatments or diagnoses over time. In this article, we will describe the indications and applications for OraCheck, a new software application that will be available to Cerec users in Spring 2014. PMID- 24791466 TI - SICAT function: anatomical real-dynamic articulation by merging cone beam computed tomography and jaw motion tracking data. AB - Diagnostic imaging and jaw motion tracking are among the most important technologies used to document and assess the functional status of the stomatognathic system and to plan complex prosthetic restorations. However, the two technologies have not been used together until now. This article introduces SICAT Function (SICAT, Bonn, Germany), a new software application that directly combines and merges three-dimensional cone beam computed tomography (CBCT) and electronic jaw motion tracking (JMT) data. The software can also import digital impressions acquired with intraoral scanners and integrate them in functional movement displays. The result is an anatomically precise yet real-dynamic rendering of jaw movement, ready for comprehensive evaluation and analysis. Moreover, changes in the joint space (gap between the condyle and mandibular fossa) at defined mandibular resting positions or during mandibular movements can be directly measured and displayed. Only one CBCT scan is needed for patient specific assessment of condylar positions (centric and therapeutic), which are displayed together with the joint space. All other positions are derived via correlation with electronic measurements. PMID- 24791467 TI - A new 4-dimensional imaging system for jaw tracking. AB - A non-invasive 4D imaging system that produces high resolution time-based 3D surface data has been developed to capture jaw motion. Fluorescent microspheres are brushed onto both tooth and soft-tissue areas of the upper and lower arches to be imaged. An extraoral hand-held imaging device, operated about 12 cm from the mouth, captures a time-based set of perspective image triplets of the patch areas. Each triplet, containing both upper and lower arch data, is converted to a high-resolution 3D point mesh using photogrammetry, providing the instantaneous relative jaw position. Eight 3D positions per second are captured. Using one of the 3D frames as a reference, a 4D model can be constructed to describe the incremental free body motion of the mandible. The surface data produced by this system can be registered to conventional 3D models of the dentition, allowing them to be animated. Applications include integration into prosthetic CAD and CBCT data. PMID- 24791468 TI - [Structural organization of 5S ribosomal DNA of Rosa rugosa]. AB - In order to clarify molecular organization of the genomic region encoding 5S rRNA in diploid species Rosa rugosa several 5S rDNA repeated units were cloned and sequenced. Analysis of the obtained sequences revealed that only one length variant of 5S rDNA repeated units, which contains intact promoter elements in the intergenic spacer region (IGS) and appears to be transcriptionally active is present in the genome. Additionally, a limited number of 5S rDNA pseudogenes lacking a portion of coding sequence and the complete IGS was detected. A high level of sequence similarity (from 93.7 to 97.5%) between the IGS of major 5S rDNA variants of East Asian R. rugosa and North American R. nitida was found indicating comparatively recent divergence of these species. PMID- 24791469 TI - [Structural mechanisms of interaction of cyanoacrylates with plant tubulin]. AB - Structural mechanisms underlying the specific binding of cyanoacrylate compounds with tubulin of higher plants have been studied by example of interaction of ethyl-(2Z)-3-amino-2-cyano-4-ethylhex-2-enoate (CA1) and isopropyl-(2Z)-3-amino-2 cyano-4-ethylhex-2-enoate (CA2) with Arabidopsis thaliana alpha-tubulin. It was revealed that the cyano group of cyanoacrylates is a functional analog of the nitrile group, which determines the processes of specific interaction with plant tubulin for dinitroaniline compounds. Based on the data of spatial structure fluctuations, dynamics of hydrogen bonds and interaction energy of the CA1 and CA2, the most probable binding mode for these compounds with plant alpha-tubulin was identified and appropriate site of interaction was characterized. Seven out of 10 residues composing this site (Gln-133, Asn-249, Val-250, Asp-251, Val-252, Asn-253 and Glu-254) are obligatory components of the dinitroanilines' binding site on the plant alpha-tubulin surface. Thus, the binding site on the alpha tubulin surface characterized by us is able to recognize and specifically bind the substances which are cardinally different by their chemical nature and have no common pharmacophore groups, under the condition of a certain similarity of their electrostatic topology. PMID- 24791470 TI - [Clinical and genetic features of APC- and MYH-mutation-negative patients with multiple polyposis of large bowel that tested by conventional methods]. AB - The genealogic analysis, molecular and clinical investigations has been carried out in 19 probands with multiple colorectal adenomas (approximately 100 or more). Twelve of these patients (63.1%) were APC and MYH mutation-negative. Three (25%) probands have positive family history. The median of the disease manifestation age in APC-negative patients was intermediate between the median of the disease manifestation age in APC- and MYH-positive patients. Extraintestinal manifestations in the APC-negative probands are more rare than in APC-positive patients. A half of APC- and MYH-negative probands with multiple polyposis had colorectal cancer. APC- and MYH-negative patients formed a genetically heterogenous group. PMID- 24791471 TI - [Endocytic pathway of alpha-fetoprotein in mice bone marrow hematopoietic stem cells: molecular characterization and role in biological activity modification]. AB - Endocytic pathway of alpha-fetoprotein (AFP) in three different, by the degree of maturity, types of the mouse bone marrow hematopoietic stem cells (HSC) is similar in its nature: it was based on the receptor-mediated transport through the membrane p60, p65 and p305 AFP receptors with clathrin-dependent mechanism of receptorosome organization, in the formation and generation of which AP-2 complex, endophilin, and dynamin are involved. In the studied types of HSCs, the non-degraded AFP was detected in Golgi complex through the formed receptorosome merging with it, as well as in the cytoplasm, endoplasmic reticulum, and mitochondria, presumably through sequential binding to the cytoplasmic distributor proteins--p55, p52, p62 and p67 AFP receptors, and also to transorganelle transporter proteins--p147 and p182 AFP receptors. The investigation of the role of AFP endocytosis in changing the biological activity of the studied types of HSCs has shown that it directly regulated the protein synthesis and metabolic activity, while its effect on other examined types of biological activity was mediated by ERK1/2. PMID- 24791472 TI - [Alleles at storage protein loci in Triticum spelta L. accessions and their occurrence in related wheats]. AB - Variation at eight storage protein loci was analyzed in the collection of T. spelta accessions from the National Centre of Plant Genetic Resources of Ukraine, most of which are European spelts. The analysis allowed identification of seven alleles at the Gli-B1 locus, five alleles at the Gli-A1 and Glu-B1 loci, three alleles at the Gli-A3 locus, two at the Gli-D1, Gli-B5, Glu-A1, and Glu-D1 loci. The majority of alleles are encountered among common wheat cultivars, only five alleles were specific for spelts. The high frequency of the alleles Gli-B1hs* and h encoding the 45-type gamma-gliadin in European spelts and durum wheat cultivars, as well as the occurrence of these alleles in T. dicoccum, in particular, in accessions from Switzerland and Germany, supports von Buren's hypothesis that European spelt resulted from hybridization between a tetraploid wheat with the 45-type y-gliadin and a hexaploid wheat. Analysis of genetic distances based on the genotypes at eight storage protein loci permitted differentiation of the Asian spelt accession from European spelts. PMID- 24791473 TI - Cytomorphological investigations in Oxyria digyna Hill. from the Kashmir Himalaya, India. AB - In the present paper, detailed cytomorphological investigations in Oxyria digyna Hill. from Kashmir Himalaya-India have been reported for the first time. All the of 14 investigated populations of O. digyna are diploid based on x = 7. Out of these in two populations 0-2B chromosomes have been recorded for the first time while 6 populations differed significantly in their meiotic characteristics. Meiotic abnormalities during male meiosis observed include inter PMC chromatin transfer (cytomixis). Non-synchronous disjunction of some bivalents, laggards and bridges at anaphases and telophases. Consequent to these meiotic anomalies, microsporogenesis in meiocytes is abnormal resulting in to dyads, triads and polyads with or without micronuclei. The overall effect is seen in reduced pollen fertility. Unreduced pollen grains were observed in some populations, which differed significantly in their size compared to the normal (reduced) pollen grains. It is observed that a smaller frequency of pollen grains differed morphologically in Aharbal and Yosmarg populations. The remaining eight populations showed regular meiotic course, normal microsporogenesis and high percentage of pollen fertility (95.09-99.09%). PMID- 24791474 TI - [Molecular-genetic polymorphism of wheat cell lines resistant to metabolites of G. graminis var. tritici and osmotic stress]. AB - It was analyzed polymorphism of DNA loci, flanked by inverted repeats of LTR retrotransposon Cassandra, in cell lines of bread wheat, resistant to the metabolites of ophiobolus root rot (G. graminis var. tritici), under osmotic stress and induced from them plant-regenerants. The differences in the polynucleotide sequences of DNA at the direct and step cell selection it was identified. Assessment of the level of genetic divergence showed that calluses obtained at the direct selection and calluses in the later stages of step selection were the most genetically distant from the original forms (D(NL) = 0.4855), this means that at the sublethal doses of selective factors occur the most significant changes at the genome of the investigated objects. In contrast to the original form at the spectra of products DNA amplification of calluses and regenerated plants showed the emergence of bands approximately 638 bp length, which may indicate the activation of retrotransposon Cassandra. PMID- 24791475 TI - [Gene networks that regulate secondary metabolism in actinomycetes: pleiotropic regulators]. AB - Current advances in the research and practical applications of pleiotropic regulatory genes for antibiotic production in actinomycetes are reviewed. The basic regulatory mechanisms found in these bacteria are outlined. Examples described in the review show the importance of the manipulation of regulatory systems that affect the synthesis of antibiotics for the metabolic engineering of the actinomycetes. Also, the study of these genes is the basis for the development of genetic engineering approaches towards the induction of "cryptic" part of the actinomycetes secondary metabolome, which capacity for production of biologically active compounds is much bigger than the diversity of antibiotics underpinned by traditional microbiological screening. Besides the practical problems, the study of regulatory genes for antibiotic biosynthesis will provide insights into the process of evolution of complex regulatory systems that coordinate the expression of gene operons, clusters and regulons, involved in the control of secondary metabolism and morphogenesis of actinomycetes. PMID- 24791476 TI - [Research practices of conversion efficiency of resources utilization model of castoff from Chinese material medica industrialization]. AB - The industrialization chains and their products, which were formed from the process of the production of medicinal materials-prepared drug in pieces and deep processed product of Chinese material medica (CMM) resources, have generated large benefits of social and economic. However, The large of herb-medicine castoff of "non-medicinal parts" and "rejected materials" produced inevitably during the process of Chinese medicinal resources produce and process, and the residues, waste water and waste gas were produced during the manufactured and deep processed product of CMM. These lead to the waste of resources and environmental pollution. Our previous researches had proposed the "three utilization strategies" and "three types of resources models" of herb-medicine castoff according to the different physicochemical property of resources constitutes, resources potential and utility value of herb-medicine castoff. This article focus on the conversion efficiency of resources model and analysis the ways, technologies, practices, and application in herb-medicine cast off of the conversion efficiency of resources model based on the recycling economy theory of resources and thoughts of resources chemistry of CMM. These data may be promote and resolve the key problems limited the industrialization of Chinese material medica for long time and promote the realization of herb-medicine castoff resources utilization. PMID- 24791477 TI - [Rapid detection of extrinsic harmful contaminants using quantum dots-coated probes and their application prospects in traditional Chinese medicine]. AB - The contamination of extrinsic harmful contaminants including mycotoxins, heavy metals and pesticides, etc, brings serious risks to traditional Chinese medicines (TCMs), further to human health. Due to their unique photoluminescence, chemiluminescence, electrochemical and electrochemiluminescence properties, semiconductor quantum dots (QDs) nanoparticles are widely used to immobilize bioprobes and biosensors, etc. In this review, the luminescence characteristics and specific ligands of QDs probles which are used to determine contaminants were summed up. Then, the applications of QDs-coated novel probes in the determination of mycotoxins, heavy metals and pesticides were discussed in detail. In addition, the contamination levels and characteristics of extrinsic harmful residues in TCMs were investigated. Further, the maximum levels of those contaminants in TCMs were compared with those set by various countries. Finally, the future development trends and problems of QDs-coated probes in the determination of those extrinsic residues in TCMs were prospected. PMID- 24791478 TI - [Advances in studies on chemical constituents and biological activities of Desmodium species]. AB - The chemical constituents isolated from Desmodium species (Leguminosae) included terpenoids, flavonoids, steroids, alkaloids compounds. Modem pharmacological studies have showed that the Desmodium species have antioxidant, antibacterial, anti-inflammatory, hepatoprotective, diuretic, antipyretic, analgesic and choleretic activity. This article mainly has reviewed the research advances of chemical constituents and biological activities of Desmodium species since 2003. PMID- 24791479 TI - [Application of kidney-nourishing herbal medicine for treating hypertension]. AB - Recent years, the pathogenesis of hypertension in traditional Chinese medicine (TCM) has been changed. Kidney-deficiency has become the key of modern pathogenesis, and the new problem of treating hypertension. It has become the new strategy for treating hypertension with kidney-nourishing herbal medicine. This article reviewed the clinical and experimental researches of kidney-nourishing herbal medicine, including single herb, herbal formulae and traditional Chinese patent medicine, in order to strengthen the evidence of kidney-nourishing herbal medicine for treating hypertension. PMID- 24791480 TI - [Advance in studies on traditional Chinese medicine on Abeta's scavenging effect]. AB - Aggregation and accumulation of beta-amyloid peptide (Abeta) in brain tissues contribute to the pathogenesis of Alzheimer's disease. Therefore, the promotion of Abeta clearance is one of the key targets for preventing and treatment Alzheimer's disease. Studies proved that some traditional Chinese medicine (TCM) compounds and extracts could impact the activity of degrading enzyme in amyloid peptide, the transport of hemato encephalic barrier and the phagocytosis of microglial cells, promote Abeta clearance, and improve learning and memory of animal models with Alzheimer's disease. In this review, we made an summary for the relations between Abeta and Alzheimer's disease, the Abeta clearance mechanism and the clearance effect of traditional Chinese medicines. PMID- 24791481 TI - [Investigation on wild resources of Dendrobium officinale distribution and ecological envirment in Anhui]. AB - The wild resources of Dendrobium officinale in Anhui province were studied by textural research, data collection, interview survey and regional survey, in order to investigate the resources distribution and ecological characters and provide the reference for Anhui Dendrobium industry. In this paper, a part of producing areas of wild D. officinale in Anhui province was selected to analyze the ecological characters. As a result, we find that the wild resources of D. officinale in Anhui distributed only sporadic and the conditions of growth environment were harsh. Our findings may provide some suggestions on wild resources protection and artificial cultivation in suitable environments because the wild resources of D. officinale in Anhui are decreasing rapidly and facing an endangered situation. PMID- 24791482 TI - [Molecular identification of Cynomorii herba using ITS2 DNA barcoding]. AB - OBJECTIVE: To identify the Cynomorii Herba and its analogues species using DNA barcoding technique. METHOD: Total genomic DNA extracted from all materials using the DNA extraction kit. The internal transcribed spacer 2 (ITS2) regions were amplified using polymerase chain reaction (PCR), and purified PCR products were sequenced bi-directionally. Sequence assembly and consensus sequence generation were performed using the CodonCode Aligner 3.7.1. The Kimura 2-Parameter (K2P) distances and GC content were computed using MEGA 5. 0. Species identification analyses were conducted through the species identification system for traditional Chinese medicine and neighbor-joining (NJ) trees. RESULT: The ITS2 sequence lengths of Cynomorii Herba were 229 bp. The average intra-specific genetic distances of Cynomorii Herba were 0.003. The average inter-specific genetic distances between Cynomorii Herba and its adulterants species were 0.760. The results showed that the minimum inter-specific divergence is larger than the maximum intra-specific divergence. The species identification system for traditional Chinese medicine and NJ trees results indicated that Cynomorii Herba and its adulterants species can be easily identification. CONCLUSION: The ITS2 region is an efficient barcode for identification of Cynomorii Herba, which provide a new technique to ensure clinical safety in utilization of traditional Chinese medicine. PMID- 24791483 TI - [Molecular cloning and expression analysis of an Aux/IAA gene (RgIAA1) from Rehmannia glutinosa]. AB - To clone and analyze a member of the Auxin/indole-3-acetic acid (Aux/IAA) gene family, RgIAA1, from Rehmannia glutinosa. The transcriptional EST database of R. glutinosa was used to clone the new Aux/IAA gene by cDNA probe of AtIAA14. Bioinformatics was applied to analyze the sequence characteristics of RgIAA1 protein and construct phylogenetiC trees. Quantitative RT-PCR has been applied to detect the transcription level of RgIAA1 in seven tissues as well as in leaves under three stresses. The results showed that, the cDNA sequence of RgIAA1 contains 903 bp was obtained. The open reading frame (ORF) of RgIAA1 was 681 bp encoding 226 amino acids, which has typical structural domains and characteristic sequence of Aux/IAA family proteins. RgIAA1 showed the highest expression level in unfolded leaf, followed by the stem. And the expression of RglAA1 was quickly decreased with leaf growing up. The transcription level increased under continuous cropping conditions while it reduced both in salinity and waterlogging stresses. RgIAA1, an Aux/IAA gene from R. glutinosa has been obtained for the first time, which can lay the foundation for further studies about its molecular function in development and responses to stress. PMID- 24791484 TI - [Research wilt disease of Salvia miltiorrhiza and its pathogen]. AB - Salvia miltiorrhiza is a highly valued traditional chinese medicine for the treatment of atherosclerosis-related disorders in china, such as cardiovascular and cerebrovascular diseases in China. The wilt disease is serious in the culture of S. miltiorrhiza. Wilt disease cause biomass of plant shoots and roots is lessened, active components are decreased. To solve these problems, we research the pathogen causing wilt disease of S. miltiorrhiza. The suspected pathogen is identified by morphology and etiological test. The identification was further confirmed by alignment the sequences of internal transcribed spacer (ITS) amplified by PCR. Our result show the wilt disease of S. miltiorrhiza mostly occurred in July and August, which is hot and wetter. The wilt disease rate of S. miltiorrhiza continuous cropping for one year in S. miltiorrhiz stubble is 10%, but the wilt disease rate of S. miltiorrhiza continuous cropping for three years in S. miltiorrhiz stubble is 60%-70%. The root rot of S. miltiorrhiz caused by the wilt disease, so the wilt disease was mistaken for the rot root in production. Morphological characteristics show the pathogen is Fusarium oxysporum. The sequence of ITS wes determined and found by BLAST shared 99% identity to that of F. oxysporum f. sp. cucumerinum. So it comes to the conclusion that the causing agent of wilt disease on S. miltiorrhiza belongs to F. oxysporum. PMID- 24791485 TI - [Microscopic observation on mycorrhiza of rare herb Dysosma versipellis]. AB - Endophytic fungi played an important role in the growth of its host plant. To investigate the mycorrhizal characteristics and the distribution of fungi in the root, an endangered wild plant-Dysosma versipellis was collected and observed by electron microscope. The results showed that the host was closely associated with endophytic fungi. The fungi were mainly distributed in the epidermis and cortex. The aseptate and septate fungi with swollen hyphae were observed in some cell of the cortex. The result provides a reference for the study of mycorrhizal structure of Dysosma genus and the interaction between the fungi and its host. PMID- 24791486 TI - [Effects of several factors on cell growth and ginsenoside accumulation of Panax ginseng suspension culture]. AB - To improve cell suspension culture system of Panax ginseng, the dynamic of cell growth and medium consumption were studied, and the effects of filter on the culture vessel, revolution number, and inoculation density on cell growth and ginsenoside accumulation were also investigated. The maximum cell growth and ginsenoside accumulation was found on the 20th days of suspension culture, therefore, 20 days were confirmed as a suitable culture period for mass production of ginsenoside. Cell growth and ginsenoside content were promoted when the culture vessel had a ventilated filter. Revolution speed during suspension culture affected cell growth, but not ginsenoside content, a peak of ginsenoside productivity was found in the treatment of 120 r x min(-1). Inoculation density also influenced cell growth and ginsenoside accumulation, inoculation density of 6 g was better than other inoculation densities, the ginsenoside content and productivity were up to 12.8 mg x g(-1) DW and 146.6 mg x L(-1), respectively. PMID- 24791487 TI - [Construction of prokaryotic expression vector, expression and purification of ginseng Cu/Zn superoxide dismutase]. AB - The total RNA was extracted from ginseng leaves of Panax ginseng. The Cu/Zn-SOD gene was amplified via RT-PCR and the pET-28(a)-Cu/Zn-SOD expression vector was constructed. The pET-28 (a)-Cu/Zn-SOD recombinant plasmid was transformed into Escherichia coli BL21 (DE3) competent cells and was induced by IPTG in order to select optimal induction of expression conditions. The target protein was purified by the nickel ions (Ni ) affinity chromatography and the target protein enzyme activity was determinated by the xanthine oxidase method. The similarity of the Cu/Zn-SOD gene sequences and the Cu/Zn-SOD gene sequences of Korean ginseng in NCBI was 99. 00%. The target protein expression level was about 44.42%, and the molecular weight was 16.30 kDa after the pET-28(a)-Cu/Zn-SOD recombinants were induced by IPTG. The purified Cu/Zn-SOD protease activity reached 10,596.69 U x mg(-1). The P. ginseng pET-28(a)-Cu/Zn-SOD prokaryotic expression vector was built by the method of molecular biology, which provided the foundation for studying the Cu/Zn-SOD biology function. PMID- 24791488 TI - [Significant impact of different induction conditions on metabolic diversity of callus cell lines of Glycyrrhiza sp]. AB - The purpose of this study was to evaluate the impact of callus induction and culture conditions on secondary metabolic diversity of the callus cell lines of traditional Chinese medicinal plant Glycyrrhiza sp. (Glycyrrhiza) by combined chemical analysis and HPLC fingerprint. These callus induction conditions included two Glycyrrhiza species, two types of explants, light and dark conditions, and two combinations of hormones. The evaluation was firstly based on the contents of total flavonoids in the callus by chemical analysis and one way ANOVA. The content of total flavonoids in callus was significantly (P < 0.05) influenced by Glycyrrhiza species, light condition, and the combination of hormones. The callus was further evaluated using diversity factor based on the comparison of HPLC fingerprints of these callus cell lines. Diversity factor varies significantly for calli induced under different conditions, with the highest being at 0.45 under light condition and combination of hormones. These results provide important knowledge for the selection of suitable callus cell lines for the production of pharmacologically important secondary metabolites or bioactive fractions by in vitro culture of Glycyrrhiza sp. PMID- 24791489 TI - [Study on solubilization effect of solid dispersion technology and inclusion technology on pulsatillae total saponins]. AB - OBJECTIVE: To study the effect of solid dispersion technology and inclusion technology on dissolution performance of Pulsatillae total saponins, and preliminarily investigate its mechanism. METHOD: The solid dispersion of Pulsatillae total saponins-PEG 4000 was prepared by the melting method. The inclusion compound of Pulsatillae total saponins-hydroxypropyl-beta-cyclodextrin ( HP-beta-CD) was prepared by the freeze-drying method. The properties of solid dispersion and inclusion compound were identified by using IR, DSC and NMR. And the dissolution of solid dispersion and inclusion compound were also determined by the small glass method. RESULT: IR, DSC and NMR results showed the formation of solid dispersion and inclusion compound. In terms of the dissolution, the inclusion compound ranked first, which was followed by solid dispersion and bulk pharmaceutical chemicals. CONCLUSION: The inclusion technology could significantly increase the dissolution of Pulsatillae total saponins, whereas the solid dispersion showed no notable solubilization effect. PMID- 24791490 TI - [Study on Xinyueshu spray drying assisted with copovidone and its effect on powder property]. AB - To study the application characteristics of copovidone (PVP-S630) in Xinyueshu extracts during the spray drying process, and its effect on such pharmaceutical properties as micromeritics and drug release behavior. PVP-S630 was added into Xinyueshu extracts to study on the spray drying, the effect of different dosages of PVP-S630 against the wall sticking effect of the spray drying, as well as the power property of Xinyueshu spray drying power and the dissolution in vitro behavior of the effective component of hyperoside. The results showed that PVP S630 revealed a significant anti-wall sticking effect, with no notable change in the grain size of the spray drying power, increase in the fluidity, improvement in the moisture absorption and remarkable rise in the dissolution in vitro behavior of hyperoside. It was worth further studying the application of PVP-S630 in spray drying power of traditional Chinese medicine. PMID- 24791491 TI - [Study on preparation process of artesunate polylactic acid microspheres]. AB - This study aims to investigate the preparation process and in vitro release behavior of artesunate polylactic acid microspheres, in order to prepare an artesunate polylactic acid (PLA) administration method suitable for hepatic arterial embolization. With PLA as the material and polyvinyl alcohol (PVA) as the emulsifier, O/W emulsion/solvent evaporation method was adopted to prepare artesunate polylactic acid microspheres, and optimize the preparation process. With drug loading capacity, encapsulation efficiency and particle size as indexes, a single factor analysis was made on PLA concentration, PVA concentration, drug loading ratio and stirring velocity. Through an orthogonal experiment, the optimal processing conditions were determined as follows: PLA concentration was 9. 0% , PVA concentration was 0. 9% , drug loading ratio was 1:2 and stirring velocity was 1 000 r x min(-1). According to the verification of the optimal process, microsphere size, drug loading and entrapment rate of artesunate polylactic acid microspheres were (101.7 +/- 0.37) microm, (30.8 +/- 0.84)%, (53.6 +/- 0.62)%, respectively. The results showed that the optimal process was so reasonable and stable that it could lay foundation for further studies. PMID- 24791492 TI - [Optimization of formulas of Quban gel by uniform design]. AB - OBJECTIVE: To optimize formulas of Quban gel. METHOD: The U6 (6(2) x 3) uniform design was adopted to optimize gel formulas, with rheological parameters, such as viscosity and yield value in room temperature, viscosity and yield value in average temperature of skin, thixlotropy. RESULT: The optimum proportion of matrix was made of 1.0 g carbomer 940, 5 mL glycerin and pH value 5-6. CONCLUSION: The regression model for gel matrix quality and gel rheological parameters was established to directly reflect the impacting effect of various factors, and provide certain preference basis for the screening of gel matrix formulas. Quban gel prepared by the method was evenly distributed, moderately viscous and highly thixotropic PMID- 24791493 TI - [Analysis on biotransformation of Epimedium brevicornu flavonoids]. AB - This study aims to investigate the biotransformation of Epimedium brevicornu flavonoids under the effect of hydrolytic enzymes in vitro. Snailase was mainly used to hydrolyze E. brevicornu flavonoids, and HPLC was used to determine the content of the main flavonoids in E. brevicornu flavonoids. The data results showed that the main known flavonoids included icariin, epimedin A, epi-mendin B and epimendin C, which were completely transformed into baohuoside I, sagittatoside A, sagittatoside B and 2"-O-rhamnosyl-icariside II in 1-2 h, respectively. Their transformed products were continuously hydrolyzed over time. In conclusion, snailase could transform E. brevicornu flavonoids into secondary glycoside or aglycone under 37 degrees C in pH 6.0 HBSS balanced salt solution in 2 h. Moreover, its enzymatic hydrolysates were consistent with intestinal metabolites. PMID- 24791494 TI - [Difference in effect between asthma-based mouse model and Stemona tuberosa extracts]. AB - In this study, OVA-induced asthma mice was taken as the model, and orally administered with different concentration of ethanol extracts of crude and processed Stemona tuberosa, in order to determine the cytokine level released from Th1 and Th2 in splenocytes. RT-PCR was carried out to determine the genetic expression of T-bet/GATA-3 in lung, and compare the differentiation between ethanol extracts of crude and processed S. tuberosa in therapeutic effect on asthma in mice. According to the results, compared with the crude samples, processed samples significantly increased the levels of inflammatory factor INF gamma (P < 0.05) and decreased IL-5 (P < 0.05) in splenocytes. According to the RT-PCR results, the administration of processed samples could increase the ratio of T-bet/GATA-3 (P < 0.05). The experiment showed that ethanol extracts of both crude and processed S. tuberosa could treat asthma by regulating Th1/Th2 ratio, but processed samples showed more notable effect. This indicated that crude and processed S. tuberosa had significant pharmacological difference. Therefore, it was more rational to apply processed S. tuberosa in clinical treatment of asthma and chronic cough, which layed a foundation for further revealing the processing mechanism of S. tuberosa. PMID- 24791495 TI - [Rapid determination of four components in Guizhi Fuling capsule with online two dimensional liquid chromatography]. AB - To establish the online two-dimensional liquid chromatography by using double gradient liquid chromatography system and UV detector, in order to simultaneously determine the content of paeoniflorin, paenol, amygdaloside and cinnamic acid. A pump of the two-dimensional liquid chromatography was adopted as the one dimensional separation pump. C18 (3.0 mm x 150 mm, 3 microm) was used as the analytical column, with acetonitrile as the organic phase and 0.08% phosphoric acid + 0.08% triethylamine as the aqueous phase for gradient elution at the flow rate of 0.5 mL x min(-1). Another pump of the two-dimensional liquid chromatography was adopted as the two-dimensional separation pump. PAII C18 was used as the analytical column, with acetonitrile as the organic phase and 20 mmol, pH 3.0 monopotassium phosphate as the aqueous phase for gradient elution at the flow rate of 0.8 mL x min(-1). The detection wavelengths were set at 218, 230, 275 nm by using wavelength time-switching program. The linearity range of paeoniflorin, amygdaloside, paeonol and cinnamic acid were 5.55-222 (r = 0.999 7), 6.6-264 (r = 0.999 8), 3.3-132 (r = 0.999 5) and 0.315-12.6 mg x L(-1) (r = 0.999 7), respectively. The average recoveries of the four components were between 96.12% and 103.9%. The experiment proved that this method was so rapid and accurate in determination results that it could be used for evaluating drug quality. PMID- 24791496 TI - [Chemical constituents of Euphorbia sikkimensis]. AB - Sixteen compounds were isolated from the aerial parts of Euphorbia sikkimensis by means of various chromatographic techniques such as silica gel, Sephades LH-20 and RP-18, and their structures were elucidated as naringenin (1), kaempferol (2), quercetin (3), kaempferol-3-O-alpha-L-arabinopyranoside (4), quercetin-3-O alpha-L-arabinopyranoside (5), quercetin-3-O-(2"-galloyl)-alpha-L arabinopyranoside (6), 5alpha, 8alpha-epidioxy-(22E, 24R)-ergosta-6,22-dien-3beta ol (7), stigmast-5-ene-7-one-3beta-ol (8), 3beta-hydroxy4a, 14alpha-dimethyl 5alpha-ergosta-8, 24(28)-dien-7-one(9), beta-sitosterol (10) , 10 cucurbitadienol( 1) , scopoletin(12) , ethyl gallate(13), p-hydroxybenzaldehyde (14), 3 betahydroxybenzeneethanol( 15) ,and 2,4-dihydroxy-6-methoxy-acetophenone (16) on the basis of spectroscopic data analysis. All the compounds are isolated from this plant for the first time, and compounds 1, 4-8, 15 are obtained from Euphorbia species for the first time. PMID- 24791497 TI - [Antitussive constituents of Disporum cantoniense]. AB - The antitussive activity assay for the root extraction of Disporum cantoniense was carried out with coughing mice induced by ammonia liquor. The results showed that the ethanol and water extractions of D. cantoniense possess strong antitussive activity, and the high dose of the former was better than positive control, and then the constituents of the ethanol extraction were separated and purified by various modern chromatographic techniques. Their structures were identified by physico-chemical properties and spectroscopic data. As a result, eight compounds were isolated and identified as stigmast-4-en-3-one(1), (22E, 24R)-ergosta-5, 7, 22-trien-3beta-ol(2), obtucarbamate A(3), obtucarbamate B(4), neotigogenin(5), azo-2, 2'-bis[Z-(2,3-dihydroxy-4-methyl-5-methoxy) phenyl ethylene] (6),dimethyl {[carbonylbis (azanediyl)] bis( 2-methyl-5, 1-phenylene) j dicarbamate (7) , and quercetin-3-O-pB-D-glucopyranoside(8). All compounds were isolated from this plant for the first time, and the result of bioactivity directed isolation showed that compounds 3, 4, and 6 had obvious effect on antitussive activity, and compound 6 had the same level as positive control. PMID- 24791498 TI - [Cytotoxic alkaloids from stems of Nelumbo nucifera]. AB - Chemical investigation was carried out to study the alkaloids from stems of Nelumbo nucifera and their cytotoxic activities. The constituents were separated by column chromatography, and their structures were elucidated by spectroscopic data analyses. The isolated compounds were evaluated for their cytotoxic activities by MTr method. Fifteen compounds were isolated from the total alkaloids extract and identified as asimilobine (1), isococlaurine (2), N acetylnorarmepavine (3), crykonisine (4), velucryptine (5), pycnarrhine (6), liriodenine (7), nuciferine (8), nornuciferine (9), armepavine (10), N methylasimilobine (11), coclaurine (12), N-norarmepavine (13), N-methylcoclaurine (14) and lysicamine (15). Compounds 1-7 and 12-15 were isolated from stems of this plant for the first time, and compounds 2-6 were firstly isolated from the family Nelumbonaceae. Compounds 7-10, 13 and 14 showed significant cytotoxic activities against HL-60 carcinoma cell line with inhibitory ratios of 51.36%, 59.09%, 52.51%, 53.93%, 51.43%, and 64.31% at concentration of 1 x 10(-5) mol x L(-1), respectively. PMID- 24791499 TI - [Rapid identification of chemical constituents in Salvia chinensis by HPLC-TOF MS]. AB - It's established a high-performance liquid chromatography-time of flight mass spectrometry(HPLC-TOF-MS) method to analyze chemical constituents in Salvia chinensis. The separation was performed on a SHISEIDO MG C18 reverse phase column (3.0 mm x 100 mm, 3 microm). The mobile phase consisted of acetonitrile (A) and water (containing 0.1% formic acid, B) was used as gradient elute. The gradient of a phase, 10%-90% (0-33 min), 90% (33-40 min). The flow rate was 0.6 mL x min( 1). Post-column split ratio was 2:1. Temperature of column was 25 degrees C. Time of-flight mass spectrometer (TOF-MS) and electrospray ion source (ESI) was applied for qualitative analysis under positive ion mode, and mass scan range was m/z 100-1 000. As a result,28 of the major chemical constituents of S. chinensis were identified by HPLC-TOF-MS. In this study, a rapid and efficient method for studying the chemical constituents in S. chinensis by HPLC-TOF-MS was established, which paves a way for the quality control and further studies of the herb in vivo. PMID- 24791500 TI - [Studies on quality evaluation of Dendrobii devoniani]. AB - To establish the local quality standard for Dendrobii devoniani caulis from Longling, Yunnan, the pharmacognostic characteristics microscopic characteristics and TLC identification were developed. Sulfuric acid-phenol method was used to determine the content of polysaccharide. An HPLC method was adopted to determine the content of mannose, and extractives were determined according to the procedures recorded in the Appendix of Chinese Pharmacopoeia(2010). The results showed a strong characteristics microscopic of Dendrobii devoniani caulis, and its TLC identification had a good resolution with clear spots; the content of polysaccharide is 35.7% -52.1% (average 42.7%), mannose 27.8%-46.1% (average 35.8%), and extract 4.5%-10.6% (average 7.38%). The method is simple, accurate and reliable, with good reproducibility. The established standard is acceptable for quality evaluation of Dendrobii devoniani caulis from Longling, Yunnan. PMID- 24791501 TI - [Effect of ginsenoside Rb1 in ameliorating insulin resistance and ectopic fat deposition in obese mice induced by high fat diet]. AB - Ginsenoside Rb1 is an active component in ginseng. Previous in vitro experiments showed that ginsenoside Rb1, could inhibit lipolysis and promote glucose transporter in adipocytes. This study focused on the effect of ginsenoside Rb1 in insulin resistance and ectopic fat deposit in obese mice induced by high fat diet and its molecular mechanism. Obese male C57/L mice induced by high fat diet were randomly divided into the diet-induced obesity group (DIO group), the ginsenoside Rb1 group (Rb1 group) and the rosiglitazone group (Rog group), and continuously fed with high fat diet. In addition, male C57/L mice fed with normal diet were selected as the normal group (NC group). Mice in Rb1 group and Rog groups were intraperitoneally injected with ginsenoside Rb1 and rosiglitazone with the dosage of 20 mg x kg(-1) and 10 mg x kg(-1), respectively. NC and DIO groups were intraperitoneally injected with the same amount of saline. Two weeks later, the intraperitoneal glucose tolerance test (IPGTT) was performed. Three days later, the mice were killed, and their serum samples were collected to detect insulin and free fatty acid (FFA). Their livers were weighed to examine the triglyceride content, and a pathological detection was performed. Epididymal adipose tissues were weighed, and PDE3B, HSL and perilipin were detected by Western blotting. The results showed that the treatment with ginsenoside Rb1 for two weeks could improve the glucose tolerance of obese mice. Except for 0-120 min, the areas under the glucose tolerance curve (0-30 min, 0-60 min and 0-90 min) in the Rb1 group were less than that in the DIO group (P < 0.05, n = 5), with a much lower HOMA-IR (P < 0.05, n = 5). The fat level of obese mice was significantly reduced by Rbl (P < 0.05, n = 5), and so were liver weight/weight (P < 0.05, n = 8). The increased serum FFA of obese mice declined after the treatment of Rb1 (P < 0.05, n = 8). Rb1 could partially recover the expression of perilipin in adipose tissues, but without obvious change in the expressions of PDE3B and HSL and the phosphorylated activation. The above findings indicated that ginsenoside Rb1 could reduce the release of FFA and alleviate the ectopic deposit of triglyceride by up-regulating the expression of perilipin in adipose tissue, which may be one of its mechanisms for improving the insulin resistance and abnormal glucose metabolism of organisms. PMID- 24791502 TI - [Study on effect of combination of Epimedii Folium and Ligustri Lucidi Fructus on osteoporosis rats induced by retinoic acid]. AB - OBJECTIVE: To explore the effect of combination of Epimedii Folium and Ligustri Lucidi Fructus on osteoporosis rats induced by retinoic acid. METHOD: Sixty three month-old male Wistar rats were randomly divided into the normal control group, the model group, the Epimedii Folium group, the Ligustri Lucidi Fructus group, the combination group of Epimedii Folium and Ligustri Lucidi Fructus and the raloxifene group. The osteoporosis model was established through oral administration with retinoic acid for two weeks. Meanwhile, all of treatment groups were administered with corresponding drugs for three weeks. The contents of serum calcium (Ca), phosphorus (P), alkaline phosphatase (AKP) and tartrate resistant acid phosphatase (StrACP) were detected, and the pathomorphological changes of femurs were observed. RESULT: The model control group showed much lower contents of serum Ca and P than the normal control group, but with significantly higher AKP and StrACP activity than the normal control group. The femoral head area showed reduced, narrow and sparse trabecular bones, with typical osteoporosis-like changes. Compared with the model control group, all of treated groups showed significant increase in Ca and P contents in serum, and down-regulate AKP and StrACP levels, while trabecular bones became more and wider, and densely interweaved as a reticular formation. Among them, the combination group showed the most significant effect. CONCLUSION: Epimedii Folium and Ligustri Lucidi Fructus could effectively correct the abnormal bone metabolism and improve pathological conditions of bone tissues, so as to show the anti-osteoporosis effect. The combined application of the two drugs showed a better efficacy. PMID- 24791503 TI - [Triptolide inhibits cell proliferation by downregulating phosphorylation of estrogen reporters in 4T1 tumor-bearing mice]. AB - In order to investigate the anti-proliferative effects of triptolide (TP) on 4T1 mice breast cancer cell line in vitro and in mouse model, as well as the possible mechanisms, we detected the effect of TP on cell proliferation by MTT assay or Crystal Violet Staining in our research. Flowcytometry combined with FITC-Annexin V/PI staining were used for detecting TP induced 4T1 cell apoptosis. The protein expression of ERalpha, p-ERalpha, ERbeta, p-ERbeta, ERK, p-ERK, p38, p-p38, SAPK/JNK, and p-SAPK/JNK was tested by western blotting. We also compare TP with chemotherapy drug doxorubicin in 4T1 tumor bearing BLAB/c mice model, the Xenogen bioluminescence imaging, H&E, and IHC result indicated that TP exhibits an anticancer proliferation activity. As a result, TP in 100, 10, 1, 0.1 micromol x L(-1), all inhibited the proliferation of 4T1 cells by MTT assay and Crystal Violet Staining. TP which concentrations is 10, 1, 0.1 micromol x L(-1) could induce the apoptosis of 4T1 cells and reduce the cell proliferation. TP in 200 microg x kg(-1) could inhibit the tumor growth in vivo. The anticancer proliferation of TP was involved in its effect on reducing expression of ERalpha, p-ERalpha, ERbeta, and p-ERbeta, but nothing to do with the activation of MAPK signaling pathway. PMID- 24791504 TI - [Study on effect of sophoridine against bone cancer pain and its mechanism]. AB - OBJECTIVE: To study the effect of sophoridine against bone cancer pain in bone cancer pain model rats induced by W256 tumor cells and its mechanism. METHOD: The rat model of bone cancer pain was reproduced by injecting W256 tumor cells into the rat marrow cavity. Ten days after the model establishment, 36 rats were selected and randomly divided into the model control group and the sophoridine treated group. At the same time, other 10 rats with sham-operation were selected to be the normal control group. Since the 15th day after the operation, rats in the treated group had been given sophoridine (25 mg x kg(-1)) for 10 days. The mechanical withdrawal threshold and the thermal withdrawal latency of each group were measured before and after the treatment. After the last treatment, the radiological and histopathological observation shall be conducted for sick legs of all rats. The expressions of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in tumor tissues were detected by mmunohistochemistry. RESULT: Sophoridine could significantly increase the mechanical withdrawal threshold and the thermal withdrawal latency (P < 0.05, P < 0.01), significantly relief the bone injury caused by W256 tumor cells (P < 0.05), and notably down regulate the COX-2 and VEGF expressions in tumor tissues (P < 0.05). CONCLUSIONS: Sophoridine has the effect in relieving pain and inhibiting tumor progression in bone cancer pain rats induced by W256 tumor cells. Its mechanism may be related to the down-regulated expressions of COX-2 and VEGF. PMID- 24791505 TI - [Experimental study on pathogenetic evolvement regularity of phlegm, toxin and blood-stasis syndromes in Chinese miniswine with phlegm-stasis cementation syndrome of coronary heart disease]. AB - OBJECTIVE: To discuss that pathogenesis evolvement regularity of Chinese miniature swine with phlege-stasis cementation syndrome of coronary heart disease. METHOD: Eighteen Chinese miniature swine were randomly divided to the normal control group, the model group and the Danlou tablet group, with six swine in each group. Except for the normal control group, all of the other groups were fed with high fat diet for two weeks. The coronary heart disease model with phlegm-stasis cementation syndrome was established by injuring left anterior descending artery with interventional balloons and continuously feeding with high fat diet for eight weeks. The levels of BMI, hemorheological parameters, lipids in serum and inflammatory cytokines were observed at the 0th (before the experiment), 2nd (before operation or drug administration), 6th (four weeks after drug administration) and 10th week (eight weeks after drug administration) of study. The levels of TG and TC in liver and the pathological changes in coronary artery tissues were also observed at the end of study. RESULT: Compared with the normal control group, the model group had showed significant increase in the levels of TC, TG, LDL-C and VLDL-C in serum (P < 0.01) from the second week to the end of the experiment, with notable rise in the whole blood viscosity under the shear rates of 5 s(-1) and 60 s(-1). At the 6th week, the levels of BMI and TG and TNF-alpha in serum significantly increased. At the 10th week, the levels of BMI and hs-CRP, IL-6 and TNF-alpha in serum significantly increased as well, with remarkable increase in coronary stenosis, intimal thickness and the ratio between intimal thickness and media thickness (P < 0.05 and P < 0.01), and significant rise in TC and TG in livers (P < 0.01). Compared with the model group, the Danlou tablet group showed obvious reduction in severity of coronary artery lesion, intimal thickness and lumen stenosis ratio and ratio between intimal thickness and media thickness (P < 0.01), BMI, TC, TG, LDL-C and VLDL-C in serum, TC and TG in liver, as well as hs-CRP, IL-6 and TNF-alpha levels in serum (P < 0.05 and P < 0.01), with notable decline in the whole blood viscosity under the shear rates of 5 s(-1) and 60 s(-1). CONCLUSION: The interaction of phlegm, blood stasis and toxin syndromes helps promote the progress and development of AS plaques, which is the key pathogenesis of phlegm-stasis cementation syndrome in coronary heart disease. PMID- 24791506 TI - [Effect of cold and cool herbs on liver mitochondria proteome of rats with heat symptom]. AB - In the 1960s, modern science began involving the essence of heat syndrome, but there have still no in-depth systematic studies on pathological mechanisms of heat syndrome and action mechanisms of cold and cool herbs. In this study, the animal model with heat syndrome was set up by feeding herbs with hot property, and then cold and cool herbs was applied in the experimental therapy. The two dimensional electrophoresis and mass spectrometry technologies were adopted to compare the liver mitochondria proteome of the rats of the heat syndrome model and the ones treated with cold and cool herbs, so as to discover specificity related proteins after heat syndrome and treatment with cold and cool herbs. PMID- 24791507 TI - [Effect of nourishing Yin, strengthening Qi and activating blood decoction on Fas/FasL in salivary glands of NOD mice with Sjogren's syndrome and their mRNA expression]. AB - OBJECTIVE: To observe the effect of nourishing Yin, strengthening Qi and activating blood decoction on Fas/FasL in salivary glands of NOD mice with Sjogren's syndrome and their mRNA expression. METHOD: Thirty-two NOD mice were randomly divided into the model group, the traditional Chinese medicine group (TCM group, orally given 0.4 mL nourishing Yin, strengthening Qi and activating blood decoction as per 100 g x kg(-1) everyday), the hydroxychloroquine group (given 0.4 mL hydroxychloroquine as per 60 mg x kg(-1) everyday), the traditional Chinese medicine and western medicine group (TCM WM group, given nourishing Yin, Strengthening Qi and activating blood decoction 50 g x kg(-1) and hydroxychloroquine 60 mg x kg(-1), 0.4 mL everyday), with eight mice in each group. Eight Balb/C mice were selected as the normal control group (normal group). All of mice were killed after eight weeks, and their submaxillary glands were dissected. The expression levels of Fas/FasL were examined by immunohistochemical method, and the FasL mRNA was detected by RT-PCR. RESULT: The expression levels of Fas/FasL in salivary glands of the model group were higher than that of other groups (P < 0.05). The expression level of FasL of the normal group was much lower than that in the hydroxychloroquine group (P < 0.05). The relative expression level of Fas mRNA in salivary glands of the model group was higher than that in other groups, but the control group was notably lower than other groups (P < 0.05). The expression level of FasL mRNA in salivary glands of the model group was higher than that in TCM and TCM WM groups (P < 0.05). But the expression level in TCM WM group was notably lower than the hydroxychloroquine group (P < 0.05). CONCLUSION: The nourishing Yin, strengthening Qi and activating blood decoction could down-regulate the expression level of Fas/FasL in salivary glands of NOD mice with Sjogren's syndrome and their mRNA expression, and had a better efficacy after being combined with hydroxychloroquine. The nourishing Yin, strengthening Qi and activating blood decoction might treat the Sjogren's Syndrome by reducing apoptosis which is regulated by Fas/FasL PMID- 24791508 TI - [Absolute bioavailability of caffeic acid in rats and its intestinal absorption properties]. AB - OBJECTIVE: To investigate the absolute bioavailability of caffeic acid in rats and its intestinal absorption properties. METHOD: The absolute bioavailability (Fabs) of caffeic acid was obtained after iv (2 mg x kg(-1)) or ig (10 mg x kg( 1)) administration to rats. The intestinal absorption of caffeic acid was explored by the recirculating vascularly perfused rat intestinal preparation. Caco-2 cell model was applied to measure the permeability of caffeic acid from apical to basolateral said (A-B) and from basolateral to apical said (B-A). RESULT: A two-compartment pharmacokinetic model was best to describe the pharmacokinetics of caffeic acid following iv or ig administration. The Fabs of caffeic acid was 14. 7% , and its intestinal absorption was 12.4%. The values of Papp A-->B and Papp B-->A of caffeic acid were retained stable while its concentration was changed. The efflux ratio values in this study surveyed were above 2.0, and suggesting caffeic acid was active transport. CONCLUSION: Caffeic acid was shown to have poor permeability across the Caco-2 cells, low intestinal absorption and low oral bioavailability in rats. PMID- 24791510 TI - [Analysis of clinical efficacy of combination therapy of small needle knife and Daqinjiu Tang in treatment of periarthritis of shoulder]. AB - In order to explore the clinical effect of combination therapy of small needle knife and Daqinjiu Tang in treatment of periarthritis of shoulder, 118 patients with periarthritis of shoulder were divided into control group (59) and experimental group (59) evenly and randomly. Control group received treatment of small needle knife while experimental group received combination therapy of small needle knife and Daqinjiu Tang. Clinical efficacy, shoulder pain and shoulder function were assessed and analyzed between groups before and after treatments. It was showed that the total therapeutic efficacy of experimental group was significantly higher than that of control group (P < 0.05, chi2 = 6.781); Shoulder pain and function were improved after treatments for all patients (P < 0.05), but more significantly in experimental group than in treatment group (P < 0.05). It is suggested that there is confirmed therapeutic effects of combination therapy of small needle knife and Daqingjiu Tang in treatment of periarthritis of shoulder, better than utilizing small needle knife therapy alone. PMID- 24791509 TI - [Characteristic of urinary protein spectrum in patients with stage III diabetic nephropathy and its regression analysis with traditional Chinese medicine symptom]. AB - To analyze the characteristic of urinary protein spectrum in patients with stage III diabetic nephropathy (DN) and its compliance with traditional Chinese medicine (TCM)symptom, for the sake of providing a basis for clarifying the rules of TCM syndrome differentiation in DN. Adopting the traditional epidemiological retrospective method, thirty-eight TCM syndromes and urinary protein with medium or low molecular weight, as well as urinary enzyme, including 24 h urinary protein (Upro), urinary albumin( UAlb), urinary retinal binding protein( URBP), urinary cystatin C (UCysC), urinary N-acetyl-beta-D-glucosaminidase (UNAG), were collected from 108 patients with stage III DN, and a multiple factor regression analysis between them was conducted. As the results, the levels of Upro, UAlb, URBP, UCysC, and UNAG were increased in 108 patients with stage III DN. Qi-Yin deficiency type was the major type. The level of UAlb in patients with Qi-Yin deficiency type was significantly higher than those without Qi-Yin deficiency type (P < 0.05). The elevation of Upro with the factors as swift digestion with rapid hungering, lassitude and lack of strength, weakness of waist and knees was complied, the elevation of UA1b with the factors as dry mouth with desire to drink, the elevation of URBP with the factors as numbness of extremities, shortness of breath, the elevation of UCysC with the factors as clear urine in large amounts, and the elevation of UNAG with the factors as frequent micturition, were complied respectively. In conclusion, for 108 stage III DN patients. The increase in urinary protein spectrum including UAlb, URBP, UCysC, and UNAG is the major characteristic. Shen and Pi are the major organs related to the appearance of urinary protein; Pi-Shen deficiency is the basic pathogenesis. The level of UAlb is taken as one of the objective syndrome factors for Qi-Yin deficiency type. The levels of UNAG and UCysC are possibly the objective syndrome factors for Shen-Qi deficiency type. PMID- 24791511 TI - [Management of Chinese materia medica market based on information asymmetry]. AB - Pharmaceutical market is a typical market with information asymmetry, and which can lead to "lemons" problem. In all developed countries, firms must receive regulatory approval to market a pharmaceutical product. Such administrative department including SFDA, EMA, FDA and so on. Chinese materia medica is a special part of pharmaceutical market in China. The management of Chinese materia medica is a special challenge in China. PMID- 24791512 TI - [Study thought of material basis of secondary development of major traditional Chinese medicine varieties on basis of combination of in vivo and in vitro experiments]. AB - The secondary development of major traditional Chinese medicine varieties is one of important links during the modernization, scientification and standardization of traditional Chinese medicines. How to accurately and effectively identify the pharmacodynamic material basis of original formulae becomes the primary problem in the secondary development, as well as the bottleneck in the modernization development of traditional Chinese medicines. On the basis of the existing experimental methods, and according to the study thought that the multi-component and complex effects of traditional Chinese medicine components need to combine multi-disciplinary methods and technologies, we propose the study thought of the material basis of secondary development of major traditional Chinese medicine varieties based on the combination of in vivo and in vitro experiments. It is believed that studies on material basis needs three links, namely identification, screening and verification, and in vivo and in vitro study method corresponding to each link is mutually complemented and verified. Finally, the accurate and reliable material basis is selected. This thought provides reference for the secondary development of major traditional Chinese medicine varieties and studies on compound material basis. PMID- 24791513 TI - [Safety evaluation of Chinese medicine on tumor therapy]. AB - As a characteristic tumor therapy in China, Chinese medicine (CM) plays an important position in comprehensive treatment of tumor. It's a critical issue of objective realization, analysis and evaluation of CM safety for scientific decision-making in tumor safe medication and it also is a pivotal issue which affects the international communication. The safety evaluation of CM includes three phases: pre-clinical safety evaluation, clinical trials (micro-dose studies and traditional clinical trials) and post-marketing CM safety assessment. The key point of evaluation should be distinguished among different stages and various types of CM (such as classic formulas, Chinese herbal extracts, etc). Emphasis should be given to chronic toxicity when evaluating oral Chinese herbal , microdose studies and quality control must be underlined while injection is evaluated and more attention should be pay to the dose-effect relationship and time-effect relationship when turned to toxic Chinese medicine , and so as for the toxicity grading study. Moreover, we should constantly improve CM safety assessment method in various stages of tumor treatment, such as introducing the concept of syndrome classification theory, bringing in metabonomics and real world research method which are similar to the CM therapeutic concept. Most importantly, we must keep its own feature of CM theory when we learn the concept of safety evaluation from abroad. Actively exploring the anti-tumor medicine safety evaluation methods and strategies is of great significance for clinical and experimental research, and it can provide supportability platform to CM's international communication. PMID- 24791514 TI - [Research on Chinese medicine pairs (I)--Their formation and development]. AB - Chinese medicine pair (CMP) was frequently applied in traditional Chinese medicine (TCM) clinic, and its significance was shown in long-term clinical practices and many accumulated experiences. It is the unique combination of two relatively fixed Chinese medicines in TCM clinic with the basic feature and principle of TCM compatibility, is the most fundamental and the simplest form of TCM formulae with certain theory basis and combinatory reason, which is proven effective. And the unique combination is frequently used for achieving mutual reinforcement or detoxication. CMP is an intermediate point between single herb and many TCM formulae, reflecting the regularity of TCM formulae compatibility and connotation of differential treatment. This paper analyzed and summarized the basic characteristics, development process and research significance of CMP, which aims to lead the modern basic and applied research on compatibility theory of CMP. PMID- 24791515 TI - [Research on Chinese medicine pairs (II)--Their data mining]. AB - Data mining technology has become a powerful tool in traditional Chinese medicine (TCM) research. In this paper, based on the principle and basic requirements of data mining, the mining methods and procedures were described. And then the application of data mining technology in Chinese medicine pair research was classified and summarized, such as the compatibility characters, characteristic pairs, dosage-effect relationship and property compatibility, which provide the direction and data base for modern research of Chinese medicine pair. PMID- 24791516 TI - [Research on Chinese medicine pairs (III)--Their bio-active components]. AB - The total effect of Chinese medicine pair (CMP) was not the simply addition of two single herbs, but the interaction of their different components. Therefore, the research on the bio-active components of CMP is the basis of CMP compatibility study, and has important significance for revealing the compatibility effect and action mechanism, and creating traditional Chinese medicine (TCM) new drugs. This paper summed up the latest research progress of CMP on the basis of the bio-active components variation regularity of CMP from chemical solutions and content changes in vitro and the actions of CMP on bodies in vivo, in order to further drive the modern basic and applied research of CMP, and to reveal the scientific essence of CMP compatibility. PMID- 24791517 TI - [Research on Chinese medicine pairs (IV)--Their compatibility effects]. AB - Chinese medicine pairs (CMP) are specific compatibility with traditional Chinese medicine (TCM) theory as principle, which was formed on basis of effect and treatment theory of TCM. The compatibility of CMP can enhance the effect, or reduce the toxicity. So, compatibility effects of CMP were studied from different pharmacology levels including animals, tissues and organs, cell and molecular levels, their synergy and compatibility attenuation were also evaluated with monomer component-component (group) compatibility-single herb-CMP-formulae as the main line, and the action mechanisms were investigated, all of which can provide scientific basis for the clinical applications of CMP and creation of TCM new drugs. PMID- 24791518 TI - [Study on Chinese medicine pairs (V)--Their modern research strategies and approaches]. AB - Along with progress of modern science and technology, human is utilizing natural resources and their inherent law more effectively and more efficiently according to their own purposes. Chinese medicine pair (CMP) is relatively fixed combination of two TCMs which was proven to be effective in clinical application. CMP has its inner specification, and it is an intermediate point between single herb and many TCM formulae. With the aid of modern science and technology, and by means of choosing appropriate strategies and approaches, the compatibility rules of CMP might be revealed, which will be significant to develop the compatibility theory of TCM formulae and create modern TCM new drugs. PMID- 24791519 TI - [Research on Chinese medicine pairs (VI)--Coptidis Rhizoma-Euodiae fructus]. AB - Coptidis Rhizoma-Euodiae Fructus has been widely used for the treatment of digestive diseases since Song Dynasty, and therapeutic efficacy is very obvious. Modern research found that alkaloids are the main bio-active constituents, and some of their contents have striking difference after compatibility of the two herbs. The Chinese medicine pair (CMP) has extensive biological activities, such as the effect of gastrointestinal effect, anti-tumor, lowering the blood pressure and blood fat and so on. And some action mechanism of CMP also got partial demonstration. This paper mainly summarized the bio-active constituents, compatibility effects, action mechanism and clinical applications of the CMP, which can provide a basis for further research and development of the CMP. PMID- 24791520 TI - [Research on Chinese medicine pairs (VII)--Angelicae sinensis radix-chuanxiong rhizoma]. AB - Angelicae Sinensis Radix-Chuanxiong Rhizoma has the effects of nourishing and tonifying blood, activating blood and dissipating blood stasis, regulating menstruation and analgetic, which is commonly used Chinese medicine pair (CMP) in traditional Chinese medicine (TCM) clinic. It might be an independent formula, and is also usually used in many gynecological formulae and modern TCM prescriptions. This paper mainly analyzed and summarized the compatibility theory, bio-active constituents, compatibility effects and action mechanism, and clinical applications of the CMP, which can provide a basis for the depth research and development of the CMP. PMID- 24791521 TI - [Research of Chinese medicine pairs (VIII)--Salviae Miltiorrhizae Radix et Rhizoma-Carthami flos]. AB - Salviae Miltiorrhizae Radix et Rhizoma-Carthami Flos is a famous Chinese medicine pair (CMP). Salviae Miltiorrhizae Radix et Rhizoma can promote blood circulation for removing blood stasis, and Carthami Flos can promote blood circulation for removing meridian obstruction and remove blood stasis for relieving pain. The two herbs are important TCMs for activating blood. Danhong injection is the classic application of the two herbs compatibility, which was made from Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos with scientific formalation by extraction and refining. The CMP is used for treatement of organ flood insufficiency and ischemic infarction diseases. It can obviously relieving symptoms of angina pectoris, improve myocardial ischemia, regress atherosclerosis plaque, and inhibit thrombus. This paper elaberated the bio-active constituents, compatibility effects and action mechanism, and clinical applications of the CMP in order to further upgrade basic research and application levels of the CMP. PMID- 24791522 TI - [Prospect and application of microsatellite population genetics in study of geoherbs]. AB - The author introduces the basic concepts of microsatellite and population genetics and its characteristics, expounds the application of these theories for population genetic structure and genetic diversity, gene flow and evolutionary significant unit ESU division research. This paper discuss its applicationin study of genetic causes, origin of cultivation, different regional origins of geoherbs, aiming at providing a new theory and method for geoherbs. PMID- 24791523 TI - [Status of pesticide registration and residue analysis for traditional Chinese medicine in China]. AB - The present paper outlined pesticide registration status for traditional Chinese medicines (TCMs) and summarized the characteristics of pesticide contamination in different regions of some widely used TCMs by retrieving last 10 years' literatures. At present, the problems of pesticide residues for TCM include less pesticide registrations, widespread high-residue organochlorine pesticides contamination, pesticide abuse, irregular GAP bases and imperfect pesticide limit standards, etc. According to the current situation, we should adopt some control measures to strengthen the quality control of TCMs so as to ensure the safety of TCMs and related products. PMID- 24791524 TI - [Regulatory mechanism of NF-kappaB signaling pathway on renal tissue inflammation in chronic kidney disease and interventional effect of traditional Chinese medicine]. AB - In chronic kidney disease (CKD), inflammatory responses during the progression of renal tissue and tissue injury related causes its progression to end-state renal disease. Among them, nuclear factor (nuclear factor, NF)-kappaB signaling pathway by regulating the corresponding nuclear expression of target gene transcription, as well as affecting the synthesis of inflammatory mediators, induction of inflammation lead to kidney damage and renal fibrosis. Some single herbs and their extracts (such as Astragali Radix, Scutellariae Radix, Ginkgo Folium) and some traditional Chinese medicine (such as Danggui Buxue decoction, Qilian decoction) can reduce the inflammatory damage induced by renal tissue NF-kappaB signaling pathway and delay the progression of CKD. PMID- 24791525 TI - [Influence of continuous cropping years on yield and active compounds in Salvia miltiorrhiza f. alba]. AB - Biological characteristic of Salvia miltiorrhiza f. alba in field was studied. HPLC method was used to determine the lipophilic constituents (dihydrotanshinone, cryptotanshinone, tanshinone, tanshinone II (A) and miltione) and hydrophilic constituents (salvianolic acid, rosemarinic acid). The results showed that the fresh weight of S. miltiorrhiza f. alba which cropped for 2 years was decreased by 80.47%, while dry weight decreased by 79.42%. The normal diameter of the root was 0.3-0.5 cm, however, the diameter was 0.2-0.4 cm after 2 years, it was said that the decrease of the root diameter was the main reason for the decrease of the yield. The average contents of dihydrotanshinone, cryptotanshinone, tanshinone, tanshinone II (A), miltione, salvianolic acid and rosemarinic acid were decreased by 35.26%, 32.26%, 19.35%, 3.39%, 64.40%, 66.93% in plant which continuously cropped for 2 years, respectively. The yield and active constituents were mostly effected in the plant of S. miltiorrhiza f. alba, which continuously cropped for 2 years. PMID- 24791526 TI - [Effect of light quality on growth and quality of Pinellia ternata]. AB - Measuring the content of soluble reducing sugar, total sugar, soluble protein, guanosine, alkaloids, and succinic acid of Pinellia ternata tuber were measured by anthrone-sulfuric acid colorimetric method, Coomassie brilliant blue method, RP-HPLC, reverse potentiometric titration, acid dye colorimetry, respectively. The result showed that yellow light could promote the growth and development of P. ternata and increase the content of soluble reducing sugar, total sugar, alkaloids, and succinic acid. Under blue light could promote the content of soluble protein and guanosine. Red and yellow light increased the content of chlorophyll a and chlorophyll b, contrastively blue light reduced the content of chlorophyll a and chlorophyll b. White film through the most uniform spectrum was most conducive to the synthesis of chlorophyll a. As single film, blue film, yellow film were more conducive to the synthesis of chlorophyll a, green film and red film had been relatively beneficial to the synthesis of chlorophyll b. Bulbil formed the largest number and the biggest propagation coefficient of P. ternata under red light showed that it could increase the production of P. ternata under red light. PMID- 24791527 TI - [Effects on Salvia miltiorrhiza hairy roots of tanshinones content accumulation after treated with fosmidomycin]. AB - Fosmidomycin (100 micromol x L(-1)) which is the effective inhibitor of DXR, key enzyme in terpenoid MEP pathway, was used to treat with hairy roots of Salvia miltiorrhiza. The treated roots were harvested at 2, 4, 6, 8, 10, 16 and 21 d, mRNA level of SmDXR and tanshinone content in treated and negative control groups were detected. Results found that, after treated with fosmidomycin, color of S. miltiorrhiza hairy roots grew pale gradually comparing with controls; mRNA level of SmDXR in hairy roots varied as a shape of parabolic and the highest value achieved at the sixth day after treatment, then it decreased gradually; Content of four kinds of tanshinones were detected. Among of the four kinds of tanshinones, Tanshinone I content changed relatively little, while content of dihydrotanshinone I, cryptotanshinone and tanshinone II (A) decreased gradually in 21 days. The content of total tanshinones in NC groups was 5, 63 times more than FOS-treated roots in the 21th day. The previous results showed that SmDXR played an important role in the accumulation of tanshinone content in MEP pathway. Once the mRNA level of SmDXR was suppressed, the accumulation of secondary metabolites will be significantly affected. PMID- 24791528 TI - [Phenylethanoid glycosides distribution in medicinal plants of Gesneriaceae]. AB - To investigate the role of distribution and phylogeny of phenylethanoid glycoside in medicinal plants of Gesneriaceae, five phenylpropanoid glycosides, acteoside, paraboside B, isonuomioside A, paraboside II, and paraboside III were quantitatively determined in 12 species of Gesneriaceae by HPLC. The existence and content of these compounds were analyzed. The results showed that phenylethanoid glycosides were found in the most of those plants, but the kind of phenylethanoid glycosides varied in different species. Acteoside distribute in most of this plant group, paraboside B, isonuomioside A, paraboside II, and paraboside III were rare in those plants. The results of this study support morphological viewpoint that Trib. Trichosporeae is more developmental than Trib. Didymocarpeae. PMID- 24791529 TI - [Comprehensive yield and quality comparison of Bupleurum chinense' s seeds of different harvesting time from Qingchuan County with Topsis approach]. AB - In order to investigate the comprehensive quality differences of the seeds harvested in different growing time, and offer theoretical guide for the optimization of seeds' production technology, we analyzed the apparent size, 1 000-grain weight, water absorbency, germination indexes, postharvest embryo rate change, relatively contents of coumarins and the yield of single plant of its seeds of different harvesting time, and compared their comprehensive quality by Topsis analysis. The results showed that there existed obvious differences in yield and quality between seeds of 3 harvesting times. While the harvesting time postponed, the yield of single plant raised, and the shrunken seeds rate decreased, the quality of seedlings increased, while the contents of coumarins showed a steady increase, and the germination rate decreased. The comprehensive quality of the seeds harvested in the black ripe time rank the first place, followed by the brown ripe time and the yellow ripe time. As the harvesting time delays, the seeds' comprehensive quality increases, therefore, we could put off the seeds' harvesting time properly for the high efficient seed production. PMID- 24791530 TI - [Effects of acid and alkali stress on ginsenoside content and histochemical localization of ginsenoside in adventitious root of Panax ginseng]. AB - To investigate the effect of acid and alkali stress on ginsenoside content of Panax ginseng, adventitious roots culture in bioreactors were incubated for 30 d and pH value was adjusted. Ginsenoside content increased by reducing or raising the pH in culture medium, the muxium ginsenoside content was determined on the 5th days after acid treatment and on the 7th days after alkali treatment. The result of histochemical localization of ginsenoside revealed that the red color from light to dark were found in the adventitious root tissue, and ginsenoside mainly located in the pericycle cells where appeared the dark red color. PMID- 24791531 TI - [Correlation study on lignin contents of Schisandra chinensis and ecological factors]. AB - The contents of schisandrin, schizandrin A, B and C were determined by HPLC, and the effects of the climate factors and altitude on lignin contents were analyzed in order to select the optimal cultivation area of S. chinensis. The lignin contents were analyzed by HPLC using a ZORBAX SB-C18 column (4.6 mm x 250 mm, 5 microm). The column temperature and detection wave length were set at 35 degrees C and 254 nm, respectively. Methanol-water was used as the mobile phase in gradient elution mode and the flow-rate was 1.0 mL min(-1). The method had a good repeatability, stability and accuracy. The correlation of climate factors and lignins contents was analyzed by SPSS software. The results showed that the schizandrin A content in S. chinensis fruits were higher than 0.4% in Ji'an, Liuhe, Antu and Fusong in Jilin province, which met the quality requirement. It had significant linear negative correlation relationship between schisandrin, schizandrin A, B and altitude, the contents decreased with the increase of altitude. The significant negative linear fitting coefficient was 0.844 1 between schisandrin and altitude; but it had not significant correlation between schizandrin C and altitude. A significant positive correlation of climate factors and the contents of S. chinensis lignins were mainly the temperature factors (the average annual temperature, the highest temperature in July, the average temperature in July, the highest temperature in January, the average temperature in January) and precipitation factor (average annual precipitation), which reveals that higher temperature and precipitation were helpful to the formation and accumulation of lignins of S. chinensis. So the cultivation area of S. chinensis should be in the low elevations region with warm and rainy climate. PMID- 24791532 TI - [Comparative study on two polymerization methods for preparing ginsenoside Rg1 molecularly imprinted polymer separating materials]. AB - To obtain ginsenoside Rg1 molecularly imprinted polymer (MIP) separating materials with high selectivity, enrichment and adsorption performance through directional separation of ginsenoside Rg1 and analogues. In this study, MIPs were respectively prepared by precipitation polymerization and surface imprinted polymerization. Their adsorption performances were compared. The results showed that ginsenoside Rg1 MIPs prepared by the above two methods had a high adsorption performance to template molecules, with the maximum apparent adsorbing capacity of up to 27.74, 46. 80 mg x g(-1), respectively. Moreover, MIPs prepared by surface imprinted polymerization showed higher adsorption capacity than that by precipitation polymerization. The experimental results indicated that as for ginsenoside Rg1 with higher polarity, MIPs prepared by surface imprinted polymerization showed higher selectivity and adsorption performance, which provides provide important reference for preparing imprinted polymers with good adsorption performance with active molecules with strong polarity. PMID- 24791533 TI - [Preparation of colon target pellets of Pulsatilla total saponins-hydroxypropyl beta-cyclodextrin inclusion]. AB - OBJECTIVE: To prepare colon target pellets of Pulsatilla total saponins. METHOD: Pulsatilla total saponins-hydroxypropyl-beta-cyclodextrin inclusion was prepared by the water solution-mixing method. Then plain pills of inclusion were prepared by the granulation-spheronization method, and coated by Glatt fluid bed. RESULT: The dissolution of plain pills of Pulsatilla total saponins at 2 h was 16.0%, while that of plain pills of inclusion at 0.5 h was 91.9%. With Eudragit S100 as the coating material, TEC as the plasticizer and talcum power as the anti adherent, when the coating weight was 12%, the coating efficiency was high, with almost no bonding and drug release of coated pellets in artificial gastric juice for 2 h. The accumulated drug release in artificial intestinal fluid for 4 h was less than 15%, and that in artificial colon fluid for 4 h was more than 90%. CONCLUSION: Coated pellets of Pulsatilla total saponins-hydroxypropyl-beta cyclodextrin inclusion showed a good colon targeted drug release in vitro, thus could be further developed to be oral colon targeted preparations. PMID- 24791534 TI - [Study on preparation and in vitro characteristics of ginsenoside Rg3 binary solid dispersion]. AB - With low molecular weight chitosan and poloxamer 188 as the joint carriers, ginsenoside Rg3 solid dispersions were prepared by using the solvent evaporation method for an in vitro dissolution test. Subsequently, differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray diffraction (X RD) were adopted for a phase analysis. The results showed that the 60 min in vitro cumulative dissolution rate of ginsenoside Rg3 solid dispersions prepared with low molecular weight chitosan and poloxamer 188 at the ratio of 2:1 exceeded 90%, and the drug was dispersed in carriers in an amorphous state. Therefore, ginsenoside Rg3 solid dispersions prepared with low molecular weight chitosan and poloxamer 188 could help significantly improve the drug dissolution, with a practical application value. PMID- 24791535 TI - [Study on thermoanalysis-based calamina processing]. AB - Thermogravimetry (TG), TG-MS, Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM)-energy dispersive spectrometer(EDS) were adopted to investigate the pyrolysis characteristics of calamina. According to the findings of the qualitative and quantitative studies on the changes in the content of relevant elements, the whole shape, the functional groups, and the volatile components of calamina before and after being pyrolyzed, the 200-360, 580-750 degrees C were two sensitive temperature ranges related to the changes in effective component during calamina processing. Thermal weight loss was observed for ZnCO3, Zn(OH)2 and ZnCO3-2Zn(OH)2-H2O under 200-360 degrees C and for CaCO3 under 580-750 degrees C. The results of studies on chemical reaction kinetics showed good linear relations. This experiment integrated relevant methods and theories of physical chemistry and science of traditional Chinese medicine processing, and interpretes calamina processing techniques and mechanism, in order to provide a good example for modem studies on other traditional Chinese medicine processing. PMID- 24791536 TI - [Study on prescription screening and preparation process of compound danshen pulse capsule]. AB - To develop gastric floating erodible plug pulse capsules with compound Danshen as the model drug, in order to realize the pulse release of traditional Chinese medicines. Through the study on impermeable capsules, optimized prescriptions, drug-containing rapid-release tablets and prescription screening, and erodible plug prescription and process, we successfully prepared compounded Danshen pulse capsule, so as to provide a new dosage form for controlling and treating heart disease to better cater to clinical demands. PMID- 24791537 TI - [Optimization of Scutellaria baicalensis extraction process by orthogonal experiment combined with pharmacodynamic index]. AB - To optimize the Scutellaria baicalensis extraction process, the filter paper method and the bacteriostatic ratio method were adopted to determine the in vitro bacteriostatic efficacy of water extracts and 60% alcohol extracts from S. baicalensis. The quantitative analysis of multi-components by single-marker (QAMS) was used to determined the contents of four active components, baicalin, wogonoside, baicalein and wogonin. In addition, with the bacteriostatic ratio and the overall desirability of the contents of four active components as indexes, the orthogonal experiment was adopted to detect the effect of water addition, extraction frequency and extraction time. The optimal extraction process was to add 12 times of water for the first time, 10 times of water for the second time, extract for 2 time, 2 h for each time. This optimization process is stable and feasible, with a higher bacteriostatic ratio in extracts. PMID- 24791538 TI - [Detection on effect of different processed Cibotium barometz on osteoblasts by CCK-8]. AB - The pancreatic enzyme-II type collagenase digestion method was adopted for primary culture of osteoblasts, inoculation and passage. They were identified by alkaline phosphatase dye-liquor. N-butanol extract fractions from different processed products of Cibotium barometz were prepared. The above osteoblasts were jointly cultured with protocatechuic acid, protocatechuic aldehyde, kojic acid and the mixed control liquid of the above three substances, and their proliferation was detected by CCK-8. Various n-butanol extract fractions from different processed products of C. barometz showed a significant proliferative effect on osteoblasts in the order of the wined > the heated > the salted > the sand-heated and wined system > the alcohol-processed > the steamed > the crude. The q test showed no significant difference among sand-heated, alcohol-processed and steamed C. barometz, no significant difference between heated and salted C. barometz. Various control substances also showed a certain proliferative effect on osteoblasts in the order of the mixed control > protocatechuic aldehyde > protocatechuic acid > kojic acid. The q test showed no significant difference between protocatechuic aldehyde and protocatechuic acid. All of n-butanol extract fractions from different processed products of C. barometz showed a significant effect on osteoblast proliferation, of which wined C. barometz showed the best effect. All of phenolic compounds such as protocatechuic aldehyde, protocatechuic acid and kojic acid showed a significant proliferative effect on osteoblasts. PMID- 24791539 TI - [Chemical constituents of Aconitum brachypodum from Dong-Chuan area]. AB - Aconitum brachypodum is traditionally known to be toxic chinese medicie, but its chemical constituents is not enough studied to date. To further elucidate the chemical constituents of A. brachypodum, 80% ethanol extract of A. brachypodum collected from Dong-Chuan area was investigated, which led to isolation of seventeen compounds. By spectroscopic methods, their structures were determined as hypaconitine (1), mesaconitine (2), talatisamine (3), neoline (4), fuziline (5), aconine (6), bullatine A (7), lepeine (8), songrine (9), isocorydine (10), beta-sitosterol (11), daucosterol (12), stearic acid (13), triacontanol (14), palmitic acid (15), benzoic acid (16), and inosine (17), respectively. All compounds except for compounds 1 and 7 were isolated from A. brachypodum for the first time. PMID- 24791540 TI - [Chemical constituents of Osmanthus fragrans fruits]. AB - By Silica gel, Sephadex LH-20 and other materials for isolation and purification and by physicochemical methods and spectral analysis for structural identification, 23 compounds were isolated and identified from ethyl acetate portion of alcohol extract solution of Osmanthus fragrans fruits. Their structures were identified as nicotinamide (1), D-allitol (2), 5-hydroxymethyl-2 furancarboxaldehyde (3), acetyloleanolic acid (4), benzoic acid (5), ergosta-7,22 dien-3-one (6), beta-sitosterol (7), borreriagenin (8), cerevistero (9), c veratroylglycol (10), methyl-2-O-beta-glucopyranosylbenzoate (11), 3', 7 dihydroxy-4'-methoxyisoflavon (12), umbelliferone (13), caffeic acid methyl ester (14), oleanolic acid (15), (-) -chicanine (16), dillapiol (17), 3beta,5alpha, 9alpha-trihydroxyergosta-7-22-dien-6-one (18), 2alpha-hydroxy-oleanolic acid (19), betulinic acid (20), betulin (21), 3, 3'-bisdemethylpinoresinol (22), and lupeol (23). All compounds were isolated from the osmanthus fruit for the first time. Except for compounds 4, 7, 15, 19, 23, the rest ones were isolated from the this plant for the first time. PMID- 24791541 TI - [Chemical constituents from Lyophyllum decastes]. AB - The chemical constituents from the fruiting bodies of Lyophyllum decastes (Fr.) Singer were studied in this paper. Thirteen compounds were isolated and purified by column chromatographies on silica gel and Sephadex LH-20. Their structures were identified by MS and NMR data analysis as adenosine (1), 2R, 3S, 4S, 8E)-2 [(2'R)-2-hydroxyheneicosanoylamino]-8-octadecene-1, 3, 4-triol (2), (2R, 3S, 4S, 8E)-2-[(2'R)-2-hydroxypentacosanoylamino]-8-octadecene-1, 3, 4-triol (3), nicotinic acid (4), (4E, 8E) -2-N-2-hydroxytetracosanoyl-1-O-beta-D glycopyranosyl-9-methyl-4, 8-sphingadienine (5), D-mannitol (6), ergosteryl-3-O beta-D-glucopyranoside (7), tuberoside (8), (2R, 3S, 4S, 8E)-2-[(2'R)-2 hydroxybehenoylamino]-8-octadecene-1, 3, 4-triol (9),(2R, 3S, 4S, 8E)-2-[(2'R) -2 hydroxytricosanoylamino] -8-octadecene-1, 3, 4-triol (10), (22E, 24R)-ergosta-7, 22-dien-3beta, 5alpha, 6beta-triol (11), (22E, 24R)-ergosta-5, 7, 22-trien-3beta ol (12), and 5alpha, 8alpha-epidiory-(22E, 24R)-ergosta-6, 22-dien-3beta-ol (13), respectively. All the above compounds are first obtained from the mushroom and compounds 2-10 are reported to be obtained from the Lyophyllum for the first time. PMID- 24791542 TI - [Splitted fractions and unoverlapping analysis of chemical constituents of Poria cocos]. AB - With the combined applications of steam distillation, water extraction and alcohol precipitation, liquid-liquid extraction and column chromatography over macroporous resin, a splitted-fractions method of the chemical constituents of Poria cocos was established. The unoverlapping property of the fractions of P. cocos was qualitatively analysed by using principal component analysis and cluster analysis. With angle cosine, squared euclidean distance and the overlapping analysis of peak area of crude herbs, the unoverlapping property of the fractions of P. cocos was half-quantitatively analysed. The chemical components of P. cocos was divided into the fractions of polysaccharide, petroleum ether, ethyl acetate, alcohol eluate from macroporous resin and water eluate from macroporous resin. Non similarity degree among each chemical fraction was above 80% and main chemical components were identified. The established method for splitting fractions of P. cocos has good stability and repeatability and all chemical components in P. cocos could be completely divided into six fractions. It is the first time that the author half-quantitatively analyse the unoverlapping property of the chemical fractions of P. cocos. PMID- 24791543 TI - [Determination of dactylorhin A and militarine in three varieties of Cremastrae Pseudobulbus/Pleiones Pseudobulbus by HPLC]. AB - To establish an HPLC method for determination of dactylorhin A and militarine in Cremastrae Pseudobulbus/Pleiones Pseudobulbus. The analysis was achieved on an Alltech Prevail C18 column (4. 6 mm x 250 mm, 5 microm) using a mobile phase of acetonitrile (A), water (B) gradient elution in a total run time of 35 min (0 min, 20:80; 30 min, 55:45; 35 min, 55:45) and a diode array detector was set at 224 nm. The flow rate was 0.8 mL x min(-1). The assay displayed good linearity over the concentration range of 0.257-9.95 microg (r = 0.999 8), and 0.128-10.27 microg (r = 0.999 9), respectively. The average recoveries (n = 9) were 94.70% and 102.8% for dactylorhin A and militarine, respectively. The method is accurate, quick, simple and reproducibility. It can be used for the quality control of Pleione bulbocodioides and Pleione yunnanensis. PMID- 24791544 TI - [Determination of ellagic acid, flavonoids and goshonoside-F5 in Rubi Fructus by HPLC]. AB - High-performance liquid chromatographic coupled with variable wavelength detection (HPLC-VWD) has been developed for simultaneous determination of 5 analytes including ellagic acid, quercetin, kaempferol-3-O-beta-D-rutinoside, tiliroside and kaempferol, and high-performance liquid chromatographic with an evaporative light scattering detector (HPLC-ELSD) has been established to determine goshonoside-F5 in extract of Rubi Fructus. Chromatographic separations were carried out on an Agilent ZORBAX SB-C18 column (4.6 mm x 250 mm, 5.0 microm). All calibration curves of reference standards revealed good linearity (R2 > 0.999 5) within the concentration ranges tested. The method limits of detection ranged 0.297-90.144 ng and the method limits ofquantitation ranged 0.990-300.480 ng, respectively. Recoveries of 6 analytes were from 97.11% to 101.7%, with RSD less than 2.1%. The result shows that amounts of the 6 analytes in the samples from 16 localities were found to be different. The higher latitude of growing environment, the more ellagic acid in herb. The content of total flavonoids in sample from east localities were higher than that in middle and west localities, and the content of goshonoside-F5 in Bozhou, Anhui province was higher than others. This method was found to be simple, accurate, sensitive with good repeatability. Those results might serve as a sound foundation for further study, quality control and application of Rubi Fructus. PMID- 24791545 TI - [Effect of formula of removing both phlegm and blood stasis on Chinese medicine symptom complex score for coronary heart disease Chinese miniature swine model with phlegm-stasis cementation syndrome]. AB - OBJECTIVE: To establish the "clinical-mimetic" Chinese medicine symptom complex score method for the coronary heart disease Chinese miniature swine model with phlegm-stasis cementation syndrome, in order to observe the effect of formula of removing both phlegm and blood stasis (TYTZ) on the Chinese medicine symptom complex score for the coronary heart disease Chinese miniature swine model with phlegm-stasis cementation syndrome. METHOD: Totally 36 Chinese miniature swine were randomly divided to the normal control group, the model group, the Shujiangzhi group, and TYTZ groups with doses of 2.0, 1.0 and 0.5 g x kg(-1), with six in each group. Except for the normal control group, all of the other groups were fed with high fat diet for two weeks. The coronary heart disease model with phlegm-stasis cementation syndrome was established by injuring left anterior descending artery with interventional balloons and continuously feeding with high fat diet for eight weeks. After the operation, the groups were administered with drugs for eight weeks. Their main symptoms, accompanied symptoms, tongue and pulse signs of the coronary heart disease Chinese miniature swine with phlengm-stasis cementation syndrome were observed according to the symptom-graded scoring method. RESULT: Compared with the model group, TYTZ in different doses could reduce the scores of main symptoms at the 6th and 10th week. Specifically, TYTZ in low dose could reduce the scores of tongue at the 6th week and the scores of accompanied symptoms, and tongue and pulse signs at the 10th week; And TYTZ in high dose could decrease all symptom scores at the 6th and 10th week (P < 0.05 or P < 0.01). CONCLUSION: TYTZ can improve the scores of the main symptoms, accompanied symptoms, tongue and pulse signs in coronary heart disease Chinese miniature swine with phlegm-stasis cementation syndrome. It is suggested that the "clinical-mimetic" objective scoring for syndromes of Chinese miniature swine is of great significant to the development of new traditional Chinese medicine drugs. PMID- 24791546 TI - [Research progress of Mongolian medicine digeda]. AB - Traditional Mongolian medicine Digeda processes a significant importance in clinical therapy with notably actions of heat-clear and detoxication effects. This paper intends to provide comprehensive insight into the species textual research, chemical constituents, qualitative identification, pharmacology and clinical application of Mongolian medicine Digeda to provide valuable data for further studies and the development of clinical applications of these medicinal plants. PMID- 24791547 TI - [Thinking of study on secondary development of major traditional Chinese medicine varieties based on system theory]. AB - The secondary development of traditional Chinese medicines (TCMs) is an important content of TCM modernization process, as well as an important path for developing new TCM drugs. Under the guidance of the system theory, in response to the lack of the overall guideline and practical methods for the secondary development of TCMs at present, we introduced the overall thought of the secondary development of major TCM varieties, as well as the roles and contents of clinical research, pharmacology and pharmaceutics in the process of the secondary development of major TCM varieties, so as to provide systematic strategies and methods for the development of major TCM varieties. PMID- 24791548 TI - [Multi-dimensional structure quality control over Salvia miltiorrhiza injection based on component structure theory]. AB - As the preparation process from Salvia miltiorrhiz herbs to S. miltiorrhiz injection involves complicated technology and has relatively more factors impacting quality safety, the overall quality control is required for its effectiveness and safety. On the basis of the component structure theory, and according to the material basis of S. miltiorrhiz injection, we discussed the multi-dimensional structure and process dynamic quality control technology system of the preparation, in order to achieve the quality control over the material basis with safety and effectiveness of S. miltiorrhiz injection, and provide new ideas and methods for production quality standardization of S. miltiorrhis injection. PMID- 24791549 TI - [Differences in clinical characteristics and outcomes of diabetic ketoacidosis (DKA) in Jewish and Bedouin patients]. AB - BACKGROUND: The aim of this study was to compare clinical characteristics and outcomes of diabetic ketoacidosis (DKA) in the Jewish and Bedouin populations. METHODS: A retrospective analysis was conducted of hospital admissions for diabetic ketoacidosis in adult patients between 2003 and 2010. The clinical and biochemical characteristics and outcomes of diabetic ketoacidosis patients of Jewish origin were compared with those of Bedouin origin. The primary outcome was in-hospital all-cause mortality. RESULTS: The study cohort included 220 consecutive patients for whom the admission diagnosis was diabetic ketoacidosis. The cohort was categorized according to Jewish and Bedouin origin as follows: 177 (80.5%) Jewish and 43 (19.5%) Bedouin patients. The Jewish patients were significantly older than the Bedouin patients (45.8 +/- 18.9 vs. 32.9 +/- 15.3, p < 0.001). The majority of the patients with diabetic ketoacidosis in both the Jewish and Bedouin groups had type 1 diabetes mellitus. No differences were found for in-hospital mortality, 30 days mortality or complication rates in groups of Jewish and Bedouin patients. The Length of hospital stay was significantly Longer in the Jewish compared to the Bedouin groups of patients (median 4 days (IQR 2; 6 days) vs. median 3 days (IQR 2; 4 days) respectively, p = 0.05). CONCLUSIONS: We did not find significant differences in the outcomes between Bedouin and Jewish patients with diabetic ketoacidosis. The Bedouin patients in the present study were younger compared to Jewish patients and the Length of the hospital stay was shorter in the Bedouin compared to the Jewish group. Advanced age, mechanical ventilation and bed-ridden state were independent predictors of 30-day mortality in both ethnic groups. PMID- 24791550 TI - [Medical treatment without patient's consent and against her will]. AB - This is a case of a pregnant woman with labor pain, who was admitted to hospital and refused any life-saving medical examination and treatment in spite of the danger to her fetus and herself. There was immediate danger and shortage of time to organize the hospital ethics committee meeting in order to obtain permission to treat the competent patient by force, according to the Israeli Patient Rights Act of 1996. Hence, an urgent application to the District Court was submitted. The District Judge came to the hospital, and the legal procedure was conducted in the medical ward. After hearing all the parties involved, a legal decision was issued, giving the medical staff the permission to perform any examination and give the patient any necessary medical intervention in order to prevent damages to the fetus and the patient, in spite of the lack of informed consent. The case description is followed by a discussion of the legal ways of treating competent patients who refuse life-sustaining treatment by force and against their will. PMID- 24791551 TI - [Survival following the first admission in an integrated dual disorders treatment ward (IDDTW): preliminary results from a cohort study]. AB - BACKGROUND: Dual disorders (co-occurring severe mental illness [SMI] and substance abuse disorders in the same person) are extremely common among patients receiving mental health services. Dual disorders are associated with increased all-cause mortality, as compared with patients with SMI. Scientific evidence is lacking on the survival of dual disorders subjects, who had psychiatric inpatient care. OBJECTIVE: To determine the long term survival rates of patients after the first admission in an IDDTW and to identify their baseline predictors. METHODS: The charts of 258 subjects admitted to IDDTW during the period 2002-2004 were assessed at least 8 years after the first admission. Psychiatric diagnoses were established and grouped according to the International Statistical Classification of Diseases and Related Health Problems 10th edition (ICD-10). The Kaplan-Meier survival analysis was used to estimate the cumulative survival rates, and the predictive values of different variables were assessed by Cox proportional hazards regression model. RESULTS: The cumulative 1-, 2-, 4-, 6- and 8-year survival rates of all subjects were 98.06%, 96.51%, 91.47, 86.43% and 81.78%, respectively, without statistically significant differences between subgroups of psychiatric diagnoses. Multivariate Cox regression analysis revealed that the age at death was the only independent predictor of all-cause mortality (hazard ratio = .96; 95% confidence interval .93 to .99; p < .009). CONCLUSIONS: Those of young age are at a particularly low risk of long term survival. More targeted health care is required to address the specific needs of this vulnerable subgroup. Further research of survival into specific risk groups is required. PMID- 24791552 TI - [Anxiety dyspnea]. AB - BACKGROUND: Patients complaining about chronic dyspnea, in whom the dyspnea remains unexplained following a thorough diagnostic evaluation, will be defined as having unexplained psychogenic or anxiety dyspnea. AIM: To evaluate the clinical picture of patients with anxiety dyspnea, to evaluate their state of anxiety and whether their dyspnea is related to higher than normal perception of dyspnea. PATIENTS AND METHODS: Forty-six patients with continuous complaints of dyspnea, with no obvious cause of dyspnea, were recruited for the study. The perception of dyspnea (POD) and their anxiety state (using the HADS questionnaire) were evaluated. RESULTS: Dyspnea that is not related to effort (100% of the patients), difficulties in filling the lung (93%), the need for occasional sigh breathing (93%), and the need for occasional yawns in order to fill the lung (83%) were the most characteristic symptoms. Thirty-two patients (70%) were positive for anxiety states and surprisingly had lower than normal POD. CONCLUSIONS: Our study suggests that patients with anxiety dyspnea have characteristic clinical presentation: dyspnea that is not related to effort, difficulties in filling the lung, and need for occasional sighs and/or yawns in order to be able to fill the lung. If baseline evaluation is negative for an organic cause of dyspnea, the diagnosis of anxiety dyspnea can be established with no further costly diagnostic procedures. PMID- 24791553 TI - [InoPro trial: collaboration between urologists and primary care physicians in the treatment of osteoporosis in prostate cancer patients]. AB - INTRODUCTION: Osteoporosis is more common in elderly men than previously suspected. Prostate cancer patients may have an increased rate of osteopenia and osteoporosis independent of therapy. Osteopenia and fracture risk are accelerated in men receiving androgen deprivation therapy. Nevertheless, little is done by primary care physicians and urologists to diagnose and treat osteoporosis in men. AIMS: (1) Assess prostate cancer patients' compliance and adherence to bisphosphonate therapy; (2) Increase awareness for osteoporosis in men diagnosed with prostate cancer among urologists and primary care physicians and to evaluate collaboration between the two disciplines. METHODS: We included patients with confirmed diagnosis of prostate cancer who fulfilled one or more of the following criteria: (1) age 70 and above; (2) age 60 and above with androgen deprivation therapy or (3) prior diagnosis of osteopenia and osteoporosis. Qualified patients were referred to DXA bone density test. Patients with osteopenia or osteoporosis, who were naive to bisphosphonates, received recommendations for oral bisphosphonates. Follow-up lasted 6 months and included 2 office visits to ensure patients' compliance and adherence to recommended therapy. RESULTS: A total of 28 community-based urologists recruited 180 patients. Of the 180 prostate cancer patients, 87 (48%) had osteoporosis and 93 (52%) osteopenia, all were naive to bisphosphonates. Of the 180 patients, 153 (85%) patients started treatment with bisphosphonates after inclusion; 147/180 (82%) and 136/180 (76%) patients stayed on bisphosphonates for 3 and 6 months respectively. Primary care physicians adopted recommendations for bisphosphonate in 123/180 (68%). CONCLUSIONS: This study showed high compliance and adherence of prostate cancer patients for bisphosphonate recommendation. PMID- 24791555 TI - [Shaare Zedek Medical Center's model of an integrated division of internal medicine]. AB - BACKGROUND: The specialty and practice of internal medicine have been subject to serious challenges in the last two decades. METHODS: We describe the integrative model of internal medicine as developed in our hospital, providing solutions to some major challenges. RESULTS: Major components include: (1) Senior physicians and residents are employed by the Division rather than individual Departments of Medicine, allowing for balanced distribution of professional capabilities. (2) Two medical departments specialize in geriatric medicine, while the other departments take care of younger, more intellectually challenging patients. Senior and junior staff members rotate through these departments, allowing for exposure to different patient populations and professional expertise. (3) The backbone of senior physicians is rewarded by a set of incentives, including dedicated time for research. (4) Senior staff from the subspecialties contributes annually 1-2 months as senior physicians in the departments and receive academic and other compensation for their efforts. (5) In cases where medical departments elsewhere are flooded with corridor admissions (a source of frustration and burnout), a short admission unit in the emergency department relieves internal medicine pressures and shortens evaluation and therapy for many patients. CONCLUSION: Our integrative model of internal medicine allows for improved patient and staff distribution, greater satisfaction among patients and family members, greater professional satisfaction among physicians, while resident vacancies are filled with competent residents. PMID- 24791554 TI - [Assisted reproductive technology in the presence of chronic viral disease]. AB - INTRODUCTION: The first fertility unit dedicated to the treatment of couples infected with chronic viral diseases in Israel was established at the Rambam Medical Center in 2010. A multidisciplinary approach is needed in order to provide appropriate treatment to the viral disease, and to minimize the risks of infecting the partner, the embryo and others in the fertility unit. OBJECTIVE: To review 2 years-experience providing fertility care to couples seropositive for HIV, HBV and HCV. METHODS: Retrospective study. RESULTS: Between the years 2010 2012, 92 couples underwent 183 oocyte retrievals and fresh embryo transfers and 77 cycles of frozen-thawed embryo transfer. Forty three percent of the couples were seropositive to HBV, 30% seropositive to HIV, 20% seropositive to HCV and 7% infected with more than one virus. In 52.3% of cases the male partner was infected, in 38% the female partner was infected and in 9.7% both partners were infected. Fifty one percent of the couples received antiviral therapy before admission to the unit or did not need antiviral therapy due to inactive disease. Twenty nine percent of the couples received anti-viral drugs while being treated in the fertility unit and 10% needed anti-viral treatment before beginning fertility treatment due to high viral load. Horizontal or vertical viral disease transmissions were not recorded. CONCLUSION: Upon admission to the fertility unit the majority of couples had good control of their viral infections and either was under anti-viral treatment or did not need any further treatment. From our experience and a review of the literature, controlling the viral disease is the key to safe fertility treatment, and eliminating the risk of infecting the embryo, newborn, partner, and others within the fertility unit. PMID- 24791557 TI - [Reciprocal altruism--the resurrection of an old ethical principle in the Israeli organ transplant law]. AB - The new Israeli Organ Transplant Law grants priority in organ allocation to candidates for transplantation who have registered as organ donors at least 3 years prior to being listed or have been Live organ donors or have a first degree relative who has been a deceased donor. This unique law resurrects the old ethical principle of reciprocal altruism in which each partner in society helps the other while he helps himself. The altruist benefits because in time he, in turn, is helped. The law aims to eliminate the "free riding" phenomenon of candidates for organ transplantation who do not accept brain death and therefore object to organ donation after death yet do not abstain from waiting for such donation. The morality of such behavior is discussed along with the ethical appraisal of its solution in the law, suggesting it to be just and fair. PMID- 24791556 TI - [Re-organization of internal medicine wing in hospitals: a last-ditch effort or the beginning of reform?]. AB - Over the last decade numerous publications have dealt with ongoing changes in the traditional practice of internal medicine. In general, in-hospital medicine has evolved into ambulatory or specialized care. In this volume of Harefuah, Yinon et al. discuss trends at Shaare-Zedek Medical Center, focusing on the challenge of attracting residents to general internal medicine. Their model addresses local problems, but they have laid the groundwork for a more radical change. They present an evolutionary process that would transform hospital practice to become both more patient-centered and integrative, with an interdisciplinary team that translates the strengths of in-hospital (in- and out-patient care) vs. ambulatory or over-specialized care. Such reform should also include changes in clinical medical education, coupled with research and academic activities that can only take place in hospitals. The health care system is waiting for the next academic medical center that will take the lead in accepting this challenge and spearhead much needed reform. PMID- 24791558 TI - [Compliance with latent tuberculosis treatment: a public health challenge]. AB - Tuberculosis (TB) is a major infectious cause of morbidity and mortality, mainly in developing countries. Since the incidence of TB has decreased in the developed countries, the role of diagnosis and treatment of latent TB infection (LTBI), has assumed increasing importance as a public health measure to control TB. It is estimated that 5-10% of persons with LTBI go on to develop TB; therefore, the crucial role of LTBI treatment in eliminating TB is well recognized. However, levels of adherence to treatment of LTBI are consistently low, and non-compliance constitutes the major barrier for achieving the full benefits of LTBI treatment, emphasizing the pressing need to implement compliance-enhancing interventions. We present a review of studies in which various interventions aimed at enhancing LTBI treatment adherence were applied. PMID- 24791559 TI - [The relationship between passive smoking, breast cancer risk and n acetyltransferase 2 (NAT2)]. AB - Invasive breast cancer is a leading cause of morbidity and mortality as well as the most common malignancy among Israeli women. Over 3,800 Israeli women are diagnosed with invasive breast cancer every year and around 3400 women are diagnosed with breast carcinoma in-situ. Although smoking, either active or passive, is a controversial risk factor for breast cancer, cigarette smoking involves exposure to substrates of the NAT2 gene. The NAT2 genotype may modify the risk of cancer by activating or detoxifying heterocyclic and aromatic amines. Identification of a potential, modifiable risk factor for common and serious disease is very important for prevention and identification of high risk groups. This literature review aims to describe published studies and increase attention to measures of exposure to tobacco smoke, as well as to aspects of the NAT2 genotype that may modify the association between passive smoking and breast cancer risk. The results suggest that the NAT2 status has a differential effect on the association of active and passive smoking with breast cancer and demonstrates the need to consider possible different mechanisms associated with exposure to main and side-stream tobacco smoke. However, methodological limitations, such as small sample size, and varying definitions of smoking, are likely to have contributed to the inconsistent findings. PMID- 24791560 TI - [Health hazards of energy drinks--the situation in Israel and the world]. AB - Since 1987, with the introduction of the first commercial energy drink in Europe, the level of sale of these drinks increased rapidly throughout the western world. These drinks are based on caffeine that is found in them ndependently, and in other ingredients. Other ingredients in these drinks potentiate the effects of caffeine. Caffeine acts in the organism through inhibition and activation of various receptors, and thus affects almost all the body systems. There is an increasing body of evidence about the medical hazards of uncontrolled use of these drinks, with neurologic, psychiatric, cardiovascular and metabolic complications. There is a direct link between use of energy drinks and abuse of alcohol and drugs. Due to the above, health authorities in Israel and around the world have started addressing the regulatory, medical and informative aspects of the issue. In spite all of the above, there is lack of awareness of the public and medical teams about the hazards of cousuming these drinks. PMID- 24791561 TI - [Infant botulism]. AB - Infant botulism is a paralytic syndrome which manifests as a result of ingesting spores of the toxin secreting bacterium Clostridium botulinum by infants. As opposed to botulism in adults, treating infant botulism with horse antiserum was not approved due to several safety issues. This restriction has led to the development of Human Botulism Immune Globulin Intravenous (BIG-IV; sells under BabyBIG). In this article we review infant botulism and the advantages of treating it with BIG-IV. PMID- 24791562 TI - [Anemia in cardiovascular diseases: a prognostic marker or part of the disease?]. AB - Many patients with cardiovascular diseases are anemic to some extent. Anemia is a well-known prognostic marker for negative outcome in a variety of atherosclerotic and hearts diseases. The detrimental outcome of anemic patients with cardiovascular diseases may be a consequence of the anemia, for instance as a pro ischemic condition. However, anemia may indicate a pro-thrombotic and pro inflammatory condition which contributes to the progression of cardiovascular diseases in general and atherosclerosis in particular. In this review we investigate the association between anemia and cardiovascular diseases, its mechanisms and how to utilize it for better understanding, prediction and treatment. PMID- 24791563 TI - [Syndromic surveillance in public health practice--an updated view]. AB - Syndromic surveillance systems which were developed as part of bioterrorism preparedness initiatives originally focused on early detection. However, the early detection capabilities of such systems proved to be limited, particularly for small-scale outbreaks. On the other hand, syndromic surveillance systems proved to be very effective in situational awareness and in supporting decision making. Today, syndromic surveillance is being implemented in public health practice as a routine tool, working in concert with the traditional surveillance systems. PMID- 24791564 TI - [Women, body and soul--psychosomatics in obstetrics and gynecology]. AB - It has been shown that many of the physical complaints in obstetrics and gynecology patients may be attributed to their exposure to stress, which is associated with our modern lifestyle. Despite the notion that stress may be a causative factor in a variety of such complaints, the obstetrics and gynecology establishment is ambivalent on accepting the psychosomatic aspects of an ailment. This is mainly due to differences in the validity standards between Obstetrics and gynecology practitioners and mental health professionals. PMID- 24791565 TI - [Falls in patients with stroke]. AB - Falls are the most common medical complication during the post-stroke period. Falls are of great concern in this population in particular because of their severe consequences. Stroke survivors have an increased frequency of hip fracture and psychosocial problems such as fear of falling. The most important risk factors for falls in these patients are balance and gait deficits. Balance deficits in post-stroke patients entail reduced postural stability during standing and disturbed responses to self-induced and external balance perturbations. Gait deficits in post-stroke patients involve reduced propulsion at push-off, disturbed hip and knee flexion in the swing phase and disturbed stability in the stance phase. Beneficial effects can be expected from fall prevention programs targeting these deficits. The few studies that have evaluated the efficacy of task-oriented exercises have shown that these programs are the most promising in preventing falls in post-stroke patients. Technological advances in assistive devices also have potential for fall reduction. Larger randomized controlled trials are needed to provide more conclusive evidence. PMID- 24791566 TI - [Long-term complications of sulfur mustard exposure: a therapeutic update]. AB - Sulfur mustard (SM) is an alkylating chemical warfare agent with high military significance due to its high toxicity, resistance and availability. SM was widely used in military conflicts, the last being the Iran-Iraq war with more than 100,000 Iranians exposed, one-third of whom are still suffering from late effects. The intensity of the delayed complications correlates to the extent, the area and the route of exposure. The clinical manifestations most commonly involve respiratory, ocular and dermal effects. Respiratory complications include dyspnea, cough and expectorations and various obstructive and restrictive lung diseases. Dermal complications are itching, burning sensation, blisters, dry skin, dermatitis and pigmentary changes. Ocular complications include photophobia, red eye, tearing, corneal ulcers and blindness. Although the picture remains incomplete the major mechanisms responsible for the clinical and pathological effects of SM are: DNA alkylation and cross-linking, protein modification and membrane damage in addition to induction of inflammatory mediators in the target tissues causing extensive necrosis, apoptosis and loss of tissue structure. The current report reviews long-term complications of SM exposure, focusing on new treatments tested in clinical trials conducted on humans. Such treatments include: N-acetyl cysteine, bronchodilators, corticosteroids, Interferon-gamma, furosemide and morphine for the respiratory complications. Ocular complications may entail: Invasive procedures treating corneal complication, limbal ischemia and stem cell deficiency. Treatment for dermatological complications include: anti-depressants, pimercrolimus, Unna's boot, capsaicin, phenol and menthol, Aloe vera and olive oil, curcumin and Interferon-gamma. PMID- 24791567 TI - [Developing team reflexivity as a learning and working tool for medical teams]. AB - Team reflexivity is a collective activity in which team members review their previous work, and develop ideas on how to modify their work behavior in order to achieve better future results. It is an important learning tool and a key factor in explaining the varying effectiveness of teams. Team reflexivity encompasses both self-awareness and agency, and includes three main activities: reflection, planning, and adaptation. The model of briefing-debriefing cycles promotes team reflexivity. Its key elements include: Pre-action briefing--setting objectives, roles, and strategies the mission, as well as proposing adaptations based on what was previously learnt from similar procedures; Post-action debriefing--reflecting on the procedure performed and reviewing the extent to which objectives were met, and what can be learnt for future tasks. Given the widespread attention to team based work systems and organizational learning, efforts should be made toward ntroducing team reflexivity in health administration systems. Implementation could be difficult because most teams in hospitals are short-lived action teams formed for a particular event, with limited time and opportunity to consciously reflect upon their actions. But it is precisely in these contexts that reflexive processes have the most to offer instead of the natural impulsive collective logics. Team reflexivity suggests a potential solution to the major problems of iatorgenesis--avoidable medical errors, as it forces all team members to participate in a reflexive process together. Briefing-debriefing technology was studied mainly in surgical teams and was shown to enhance team-based learning and to improve quality-related outcomes and safety. PMID- 24791569 TI - [The hospital at Hillersleben Germany, April 1945]. AB - On 6th April 1945, nine days before the liberation of the Bergen Belsen Concentration Camp, about 2,500 Jewish prisoners were ordered to prepare to leave the camp on the next day. On 7th April, the prisoners left through the gates of the camp and began to walk about 10 kilometers to the train station near the city of Celle. There they were ordered to board a train that would take them to the Theresienstadt Concentration Camp. After six days of travel, the train stopped near the village of Farsleben, Germany, where it was liberated by the 743rd Tank Battalion of the 30th Infantry Division, of the U.S. 9th Army, on 13th April 1945. The 105th Medical Battalion of the same Division was the primary care provider for the survivors, who were then taken in vehicles available from the 30th Infantry Division, and organized into a convoy by the Division's Liaison Officer, Lt. Frank W. Towers, to the town of Hillersleben. A former German Air Force Base was located at Hillersleben with a small hospital that could not provide medical attention to all the survivors. On 21st April, Company C of the 95th Medical Battalion, received an order to go to Hillersleben. Colonel Dr. William W. Hurteau, the Commanding Officer of this Battalion, determined that the biggest task given to the Battalion during World War II, was establishing another hospital in the town of Hillersleben and providing additional beds in the existing hospital, which was a structure that had served as a boarding school. Furthermore, they needed to acquire hospital equipment which was obtained from German equipment and supplies that had been captured by the U.S. MiLitary. Also, they took care of obtaining food supplies from German warehouses, and meat and milk from local dairy farms. The lives of the prisoners on this train were saved by the heroism and dedicated work of those brave soldiers of the 30th Infantry Division and the 95th Medical Battalion. PMID- 24791568 TI - [Pharmacogenetics and anxiety disorders: analysis of recent findings]. AB - Anxiety disorders are chronic disorders appearing with a high frequency in the general population and causing much distress to those suffering from them. The current common treatment consists of antidepressants, primarily from the serotonin-selective-reuptake-inhibitor (SSRI) class. However, despite the relative effectiveness of these medications the patients' responses vary widely with one third not responding at all. While we do not currently have the ability to predict who will respond positively to the medication, it is hoped that genetic research will make it possible to prospectively identify responders and thus help avoid failed treatment attempts and side-effects. The field of pharmacogenetics is divided into pharmaco-kinetics (genetic factors that influence the drug metabolism in the body) and pharmco-dynamics (genetic factors that affect the response to the drug at the level of the receptors/transporters/enzymes in the target organs). Contrary to the treatment of depression, there is little research available on the pharmacogenetics of anxiety disorders and the existing research coincides with the studies on depression. The primary pharmacogenetic-dynamic findings are related to serotonergic genes of which those with the long allele of the serotonin transporter gene (5-HTTLPR) are expected to respond positively to treatment, and the same is true regarding genetic variants of several serotonin receptors. The pharmacogenetic-kinetic findings focus on the CYP450 enzyme system. The hope is that with the progression of the pharmacogenetic research new genetic variants will be discovered which, when combined with the clinical characteristics of those suffering from anxiety disorders, will enable the development of novel treatment algorithms to be customized for each patient. PMID- 24791570 TI - [The centenary of the first medical meeting in Eretz Israel--the Trachoma Conference of 1914]. AB - In the spring of 1914 the Jewish physicians in Eretz Israel held their first professional conference in Jerusalem. A total of 24 out of 48 doctors participated. The subject of the conference was trachoma, a common eye disease and a major cause of blindness in the Middle East. The meeting was remarkably successful in every respect and had significant influence on the merging of the Jaffa and Jerusalem physicians' societies into the Hebrew Medical Association. Thus the Trachoma Conference of 1914 became a milestone in the history of medicine in the Holy Land. PMID- 24791571 TI - [From altruism to altruistic punishment: a criticism on granting priority in the waiting list to donor-card holders]. AB - In 2008 Israel enacted a new law on organ transplantation which granted priority on the waiting list to holders of donor-cards who become patients in need of organ transplantation. This paper offers ethical criticism of the priority system arguing that the "reward" is by necessary also a "punishment". Moreover, because donor-cards have no binding power in Israeli law, the reward/punishment is actually directed at declarations, not actions, and, consequently, violates the freedom of conscience and expression. The reward system is also incompatible with fundamental values of medical ethics and with the very logic of talion, because the law punishes non-signers but not patients who are responsible for the loss of their organs. Lastly, I argue, that because priority on a waiting list is a positional good, it communicates a false message as if donation is an excellence of the few, and it legitimizes a rational choice to prefer wholesomeness of the cadaver to the risk of low rank in the priority list. PMID- 24791572 TI - [Summary of the the 6th ICOH Conference on Work Environment and Cardiovascular Disease, Tokyo 2013]. PMID- 24791573 TI - Household food insecurity and nutritional status of children and women in Nepal. AB - BACKGROUND: Information on the association between household food insecurity and nutritional status of children and women based on a nationally representative sample is not available from Nepal. OBJECTIVE: To examine the association between food insecurity and nutritional status of children and married women in Nepal using data from the 2011 Nepal Demographic and Health Survey. METHODS: The Household Food Insecurity Access Scale was used to assess food insecurity in the 2011 Nepal Demographic and Health Survey. We used body mass index (BMI) to assess the nutritional status of married women, and stunting, wasting, and underweight to assess the nutritional status of children under 5 years of age. Binary logistic regression and multinomial logistic regression were performed to examine the associations. RESULTS: In severely food-insecure households, 51% of children were stunted and 40% were underweight; 27% of married women had a BMI below 18.5 kg/m2; children were 1.50 (95% CI, 1.15 to 1.97) and 1.40 (95% CI, 1.05 to 1.85) times as likely as children in food-secure households to be stunted and underweight, respectively; and married women were 1.5 (95% CI, 1.17 to 1.92) times as likely as married women in food-secure households to have a BMI below 18.5 kg/m2. No association was found between household food insecurity and wasting among children. CONCLUSIONS: There is a significant association between food insecurity and malnutrition among children in Nepal. Among women, food insecurity is associated with underweight (BMI < 18.5 kg/m2) but not with overweight (BMI > or = 25.0 kg/m2). PMID- 24791575 TI - Epidemiological study of risk factors for goiter among primary schoolchildren in southern Ethiopia. AB - BACKGROUND: Iodine-deficiency disorders are a major public health problem all over the world. Goiter is the most visible manifestation of iodine-deficiency disorder. Goiter rate is useful to assess the long-term impact of iodine deficiency disorders. OBJECTIVE: To determine the risk factors for goiter in primary schoolchildren in southern Ethiopia. METHODS: A cross-sectional study on a sample population of 270 children 6 to 12 years of age with goiter and 264 without goiter was conducted in a primary school in Sodo Town, southern Ethiopia. All students in each class were examined for the presence of goiter and classified based on World Health Organization criteria. For each child with goiter, the next child without goiter was selected from the same class. Multivariate logistic regression analysis was employed to determine the effect of independent variables on the goiter rate. RESULTS: A total of 534 participants (270 children with goiter and 264 without goiter) were included. Although the difference was not significant, the prevalence of goiter was higher among girls than among boys (54.8% vs. 45.2%), and the prevalence in both sexes increased with age. In the multivariate logistic regression model, consuming common goitrogenic foods (adjusted OR, 1.9; 95% CI, 1.2 to 2.9) and drinking water from the river (adjusted OR, 2.5; 95% CI, 1.2 to 4.9) were independently associated with goiter. CONCLUSIONS: Goiter rate is significantly associated with consumption of goitrogenic food items in the area and contaminated drinking water. Creating awareness in the community about the consumption of food items and provision of tap water by concerned bodies in the area is recommended to prevent iodine-deficiency disorders. PMID- 24791574 TI - Eating habits, inactivity, and sedentary behavior among adolescents in Iraq: sex differences in the hidden risks of noncommunicable diseases. AB - BACKGROUND: Noncommunicable diseases have become the main causes of death in several developing countries. There is a severe shortage of information about the risk factors for these diseases in Iraq. OBJECTIVE: To explore the eating habits, physical activity, and sedentary behaviors of adolescents in Mosul City, Iraq, as risk factors for noncommunicable diseases. METHODS: A multistage stratified sampling method was carried out on adolescents aged 15 to 18 years in Mosul City, Iraq. A pretested and validated questionnaire was used to obtain information on frequency of intake of certain foods, physical activity, and screen time (television, video, and computer). Weight and height were measured to obtain the body composition status. The total sample included 723 adolescents (350 boys and 373 girls). RESULTS: There were significant differences between boys and girls in most eating habits and activity behaviors. The frequency of skipping breakfast and the intakes of fruits and vegetables, french fries, and sweets and chocolates were significantly higher among girls than boys (p < .001). Boys were significantly more likely to consume fast foods, sugar-sweetened drinks, and energy drinks than girls. Boys spent more time in physical activity (p < .001) and looking at screens than girls. CONCLUSIONS: The health authorities of Iraq should focus not only on interventions for undernutrition among adolescents, but also on behavioral risk factors for diet-related noncommunicable diseases. PMID- 24791576 TI - Effectiveness of wetting method for control of konzo and reduction of cyanide poisoning by removal of cyanogens from cassava flour. AB - BACKGROUND: Konzo is an irreversible paralysis of the legs that occurs mainly among children and young women in remote villages in tropical Africa and is associated with a monotonous diet of bitter cassava. Konzo was discovered in 1938 by Dr. G. Trolli in the Democratic Republic of Congo (DRC). It also occurs in Mozambique, Tanzania, Cameroon, Central African Republic, and Angola. It was first controlled in Kay Kalenge village, DRC, in 2011 with the use of a wetting method to remove cyanogens from cassava flour. Fourteen months later, another visit was made to Kay Kalenge. OBJECTIVE: To determine whether Kay Kalenge women were still using the wetting method, whether there were new cases of konzo, and whether the wetting method had spread to other villages. METHODS: Meetings were held with chiefs, leaders, and heads of mothers' groups, women from 30 households were interviewed, and three nearby villages were visited. Total cyanide and thiocyanate were analyzed in cassava flour and urine samples, respectively. RESULTS: The women in Kay Kalenge village still used the wetting method. There were no new cases of konzo. The mean cyanide content of the flour samples was 9 ppm, and no child had a mean urinary thiocyanate content greater than 350 micromol/L. The use of the wetting method had spread naturally to three adjacent villages. CONCLUSIONS: The wetting method has been readily accepted by rural women as a simple and useful method to control konzo by removing cyanide from cassava flour, and its use has spread to nearby villages. The wetting method should be promoted by health authorities to control konzo and reduce cyanide poisoning from high-cyanide cassava flour. PMID- 24791577 TI - Riboflavin intake and 5-year blood pressure change in Chinese adults: interaction with hypertensive medication. AB - BACKGROUND: One previous large cross-sectional study across four countries suggests that riboflavin intake may be inversely associated with blood pressure. OBJECTIVE: The aim of this analysis was to investigate a possible association between riboflavin intake and change in blood pressure over 5 years. METHODS: The study population comprised Chinese men and women who participated in the Jiangsu Nutrition Study. Quantitative data relating to riboflavin intake at baseline in 2002 and measurements of blood pressure at baseline and follow-up in 2007 were available for 1,227 individuals. RESULTS: Overall, 97.2% of the participants had inadequate riboflavin intake (below the Estimated Average Requirement). In multivariable analysis adjusted for sociodemographic and lifestyle factors and dietary patterns, a higher riboflavin intake was inversely associated with change in systolic blood pressure (p = .036). In participants taking antihypertensive medication at baseline, the relationship between riboflavin intake and systolic blood pressure persisted; whereas, in those not taking antihypertensive medication, the diastolic blood pressure was less likely to increase with the increasing intake of riboflavin (p = .031). There was a three-way interaction between antihypertensive medications, body mass index, and riboflavin intake. Among those who were obese and taking antihypertensive medication, a higher riboflavin intake was associated with a smaller increment in systolic blood pressure and pulse pressure. CONCLUSIONS: There are complex interactions between riboflavin intake and blood pressure change that depend on prior antihypertensive use and the presence or absence of obesity. PMID- 24791578 TI - Macronutrient and sociodemographic determinants of gestational weight gain among HIV-negative women in Tanzania. AB - BACKGROUND: The effect of dietary macronutrient composition on the rate of gestational weight gain among women in sub-Saharan Africa is unclear. OBJECTIVE: To examine the effect of macronutrient intake on the rate of gestational weight gain among HIV-negative women in Tanzania. METHODS: The weights of 8,428 women were measured monthly from 12 weeks of gestation to term. Prenatal dietary intake was estimated as the cumulative average of multiple 24-hour dietary recalls. The association between energy intake and percentage of energy from carbohydrate, protein, and total fat and rate of weight gain (grams per month) was estimated from generalized estimating equation models. Macronutrient effects were adjusted for total energy using the nutrient density model and maternal age, maternal height, maternal mid-upper-arm circumference, parity, marital status, maternal occupation, maternal education, household wealth, season, and treatment regimen assignment. Body mass index (BMI) was considered as a confounder and a potential modifier of the effect of macronutrient intake on gestational weight gain. RESULTS: A 6 g/month increase in rate of weight gain was associated with every 100-kcal increment in daily total energy intake (95% CI, 1 to 12; p = .03). Analyses substituting 5% of energy from fat by protein showed that weight gain would decrease by 72 g/month (95% CI, 6 to 140; p = .03); substituting 5% of energy from carbohydrate by protein decreased gain by 70 g/month (95% CI, 15 to 124; p = .01). Baseline BMI did not modify these associations. CONCLUSIONS: Further research on the effects of macronutrient composition on gestational weight gain is needed to inform the design of supplementation programs for women in developing countries. PMID- 24791579 TI - Orange-fleshed sweet potato-based infant food is a better source of dietary vitamin A than a maize-legume blend as complementary food. AB - BACKGROUND: White maize, which is widely used for complementary feeding and is seldom fortified at the household level, may be associated with the high prevalence of vitamin A deficiency among infants in low-income countries. OBJECTIVE: The nutrient composition of complementary foods based on orange fleshed sweet potato (OFSP) and cream-fleshed sweet potato (CFSP), maize-soybean groundnut (Weanimix), and a proprietary wheat-based infant cereal (Nestle Cerelac) were assessed using the Codex Standard (CODEX STAN 074-1981, Rev. 1 2006) specification as a reference. Additionally, the costs of OFSP complementary food, CFSP complementary food, and Weanimix production at the household level were estimated. Phytate and polyphenols, which limit the bioavailability of micronutrients, were assessed. METHODS: Energy, macronutrients, and micronutrients listed as essential composition in the Codex Standard were determined and expressed as energy or nutrient density. RESULTS: All the formulations met the stipulated energy and nutrient densities as specified in the Codex Standard. The beta-carotene content of OFSP complementary food exceeded the vitamin A specification (60 to 180 microg retinol activity equivalents/100 kcal). All the formulations except Weanimix contained measurable amounts of ascorbic acid (> or = 32.0 mg/100 g). The level of phytate in Weanimix was highest, about twice that of OFSP complementary food. The sweet potato-based foods contained about twice as much total polyphenols as the cereal-based products. The estimated production cost of OFSP complementary food was slightly higher (1.5 times) than that of Weanimix. CONCLUSIONS: OFSP complementary food is a good source of beta carotene and would therefore contribute to the vitamin A requirements of infants. Both OFSP complementary food and Weanimix may inhibit iron absorption because of their high levels of polyphenols and phytate, respectively, compared with those of Nestle Cerelac. PMID- 24791580 TI - Nutrient and nontraditional food intakes by Zambian children in a controlled feeding trial. AB - BACKGROUND: Many programs aim to alleviate vitamin A deficiency. Biofortification is an approach to improve provitamin A carotenoid concentrations of staple crops in some developing countries. In rural Zambia, maize accounts for the majority of energy intake. Provitamin A-biofortified (orange) maize has been released in Zambia. OBJECTIVE: This study quantified food intake of Zambian children from records collected in a feeding trial in 2012 in order to compare adoption of orange maize and a new vegetable (green beans) with white maize and traditional foods. METHODS: One hundred thirty-six children with a mean age of 71.5 +/- 6.9 months were fed three meals a day for 6 days a week for 15 weeks at four feeding centers. Breakfast consisted of maize porridge, and lunch and dinner were stiff porridge (nshima) with various side dishes (relishes). There were three treatment groups, which received orange maize and placebo oil, white maize and placebo oil, or white maize and a daily vitamin A supplement. Food was weighed before and after consumption. Nutritionists were trained to interview the children's caregivers about the previous day's intake using dietary recalls. Nine dietary recalls for each child were recorded and analyzed. RESULTS: Total food intake did not differ among the groups (p = .31) and energy intakes on Sundays (< or = 880 kcal) were below recommendations. Nshima intake was lower in the orange-maize group (p = .008), largely due to a genotype effect. Intakes of relish, green bean, and porridge did not differ among the groups (p > .19). Dietary recalls revealed that children living in sites closer to the main road consumed more on Sundays than children living about 8 km from the main road, but less in the evenings when children were off site. CONCLUSIONS: The intakes of energy of these Zambian children were low. Implementation and adoption of new and biofortified foods is possible with promotion. PMID- 24791581 TI - Using formative research to inform the design of a home fortification with micronutrient powders (MNP) Program in Aileu District, Timor-Leste. AB - BACKGROUND: Using formative research to guide the planning and implementation of home fortification programs is critical if they are to achieve the desired level of acceptance and coverage by the target beneficiaries. OBJECTIVE: To explore contextual factors that could influence acceptance, delivery, and use of micronutrient powders (MNP) in Aileu District, Timor-Leste. METHODS: Two focus group discussions were conducted with mothers of children 6 to 23 months of age, and 56 in-depth interviews were conducted with mothers (n = 18), fathers (n = 14), grandmothers (n = 14), health workers (n = 8), and Catholic catechists (n = 2). These were followed by a 14-day usability trial during which 45 mothers fed their children MNP daily and were interviewed about their experience. Participants were selected from three villages. RESULTS: The findings revealed limited exclusive breastfeeding and early introduction of complementary foods due to traditional beliefs and poor knowledge. MNP was generally liked by the respondents. Thirty of the 45 children in the trial consumed all of the 14 MNP sachets provided to them. The majority of mothers (n > or = 30) split and fed the daily dose of MNP at different times of the day. They gave several reasons for this practice, including changes in the color of food when a whole sachet of MNP was added. Only six mothers shared MNP-fortified food among siblings. The participants suggested contextual attributes that could influence their adoption of MNP including preferred name, packaging design, and delivery channel. They preferred orange-colored sachets with a picture of a "healthy" Timorese baby, the logo of the Ministry of Health, and instructions on how to use the product. CONCLUSIONS: The findings offer context-specific knowledge that could guide the success of the MNP program in this district and similar settings. PMID- 24791582 TI - Impact of community-based mitanin programme on undernutrition in rural Chhattisgarh State, India. AB - BACKGROUND: Community health workers known as mitanins undertook family-level counseling and mobilized the community to improve coverage of maternal and child health services in the state of Chhattisgarh, India. The Nutrition Security Innovation (NSI) project was launched in selected blocks with additional inputs for promoting appropriate complementary feeding practices and disseminating information on Public Distribution System (PDS) entitlement. Within 3 years of project implementation, all NSI inputs in the project group (PG) were scaled up in the entire state. OBJECTIVE: To study the impact of interventions on nutritional status in PG and non-NSI comparison group (CG) blocks. METHODS: Quasi experimental mixed methods were used. The sample consisted of 3,626 households with children under 3 years of age and 268 mitanins. RESULTS: A ratio of 1 mitanin per 250 to 500 population was effective. The coverage of exclusive breastfeeding, timely introduction of complementary feeding, DPT immunization, and antenatal care services was more than 70%. The PDS reached almost 90% of beneficiaries. In both the PG and the CG, one-third of children were undernourished, with one-quarter of children undernourished by 6 months of age. The prevalence of low birthweight was over 40%, and half of all women were undernourished. The estimated annual average reduction rate (AARR) for the entire state was estimated to be 4.22% for underweight and 5.64% for stunting. CONCLUSIONS: The strategy of Mitanin Programme in the Indian state of Chhattisgarh was unique with the implementation of direct nutrition actions being spearheaded by the health sector and community health volunteers in coordination with the Integrated Child Development Services (ICDS) and the Public Distribution System (PDS). The highest priority was given to interventions in the first 92 weeks of life. This implied ensuring frequent counseling and delivery of services through the entire pregnancy period and continued follow up till the children were at least one year of age. An accelerated decrease in the annual rate of reduction of underweight and stunting was observed. The emerging findings point to the significant contributions that can be made by the National Rural Health Mission (NRHM) in India by involvement of community health volunteers known as Accredited Social Health Activists (ASHAs) towards reducing the persistent problem of undernutrition in the country. PMID- 24791583 TI - An analysis of the costs of Uganda's Child Days Plus: do low costs reveal an efficient program or an underfinanced one? AB - BACKGROUND: Twice annually, Uganda implements Child Days Plus (CDP), a month-long outreach activity that distributes vitamin A capsules to preschool children and deworms children 6 months to 14 years old. Introduced initially as a temporary, interim strategy, CDP is now a decade old. OBJECTIVE: To assess how well CDP is implemented using an activity-based cost analysis. METHODS: In the absence of a cost-accounting system for CDP, we defined the six major CDP activities as cost centers and identified five important subactivities required to implement a round of CDP. Based on a purposive sample, we conducted a structured interview survey of 59 Ministry of Health facilities, 9 district offices, and national-level CDP staff. RESULTS: Only one-third of the facilities implemented all 11 CDP core activities. The survey revealed that Ministry of Health staff and volunteers are frequently paid substantially less in allowances than they are entitled to for their CDP outreach activities. Viewing these two practices--nonimplementation and less-than-full-reimbursement--as indicators of CDP's underfinancing, we estimate the program is underfinanced by the equivalent of 37% of its 'full implementation" costs. Two-thirds of underfinancing is manifested in nonimplementation and one-third as less-than full-reimbursement. CDP exploits economies of scale and scope and has an average cost per child served of US$0.22. We estimate that it annually saves 367,000 disability-adjusted life-years (DALYs) at an average cost of US$12.5, making it--despite its underfinancing--highly cost effective. CONCLUSIONS AND RECOMMENDATIONS: Increased CDP funding would enable its vitamin A coverage rate of 58% and its deworming coverage rate of 62% to be increased, thereby increasing its effectiveness and efficiency. CDP should be "relaunched," as part of an effort to improve the structure of the program, set expectations about it, and earmark a minimum of resources for CDP. The Ministry of Health should demonstrate its new, greater commitment to CDP by introducing a program-specific budget line item, increasing CDP's budget allocation, and developing and implementing a training program that identifies the minimum uniform activities required to implement CDP. PMID- 24791584 TI - Managing the vitamin A program portfolio: a case study of Zambia, 2013-2042. AB - BACKGROUND: Micronutrient deficiencies continue to constitute a major burden of disease, particularly in Africa and South Asia. Programs to address micronutrient deficiencies have been increasing in number, type, and scale in recent years, creating an ever-growing need to understand their combined coverage levels, costs, and impacts so as to more effectively combat deficiencies, avoid putting individuals at risk for excess intakes, and ensure the efficient use of public health resources. OBJECTIVE: To analyze combinations of the two current programs- sugar fortification and Child Health Week (CHW)--together with four prospective programs--vegetable oil fortification, wheat flour fortification, maize meal fortification, and biofortified vitamin A maize--to identify Zambia's optimal vitamin A portfolio. METHODS: Combining program cost estimates and 30-year Zambian food demand projections, together with the Zambian 2005 Living Conditions Monitoring Survey, the annual costs, coverage, impact, and cost-effectiveness of 62 Zambian portfolios were modeled for the period from 2013 to 2042. RESULTS: Optimal portfolios are identified for each of five alternative criteria: average cost-effectiveness, incremental cost-effectiveness, coverage maximization, health impact maximization, and affordability. The most likely scenario is identified to be one that starts with the current portfolio and takes into account all five criteria. Starting with CHW and sugar fortification, it phases in vitamin A maize, oil, wheat flour, and maize meal (in that order) to eventually include all six individual interventions. CONCLUSIONS: Combining cost and Household Consumption and Expenditure Survey (HCES) data provides a powerful evidence generating tool with which to understand how individual micronutrient programs interact and to quantify the tradeoffs involved in selecting alternative program portfolios. PMID- 24791585 TI - Impacts of agriculture on nutrition: nature of the evidence and research gaps. AB - BACKGROUND: In the past decade, numerous exercises have been undertaken to document knowledge of the effects of agricultural development projects on human nutrition. OBJECTIVE: The present paper reviews 10 papers published since 2000 to synthesize current evidence of agriculture-to-nutrition linkages. RESULTS: Although there are differences in focus, methods used, and standards of evidence across the set of papers considered, three common findings emerge. First, the empirical evidence for plausible and significant impacts of agricultural interventions on defined nutrition outcomes remains disappointingly scarce. Second, absence of evidence should not be equated with evidence of no impact. Weaknesses in study design and survey methods are all too common, leading to weak results and limited generalizability. Third, the broad domains of "agriculture' on the one hand, and "nutritional status' on the other, must be unpackaged in future analyses if statistically significant findings and relevant policy or program conclusions are to be drawn. CONCLUSIONS: Expectations of the potential for nutrition impact of different kinds of investment in agriculture must be set rationally, based on well-defined mechanisms and pathways. Planned and ongoing initiatives aimed at generating such evidence must hold themselves to high standards of both research and communication of findings to appropriate policy audiences globally. PMID- 24791586 TI - How nutrition-friendly are agriculture and health policies in Bangladesh? AB - BACKGROUND: The improvements in nutrition status in Bangladesh, particularly child nutrition outcomes, have been relatively slow, despite remarkable improvements in the country's food situation as well as in the health sector. At present more than 40% of children under 5 years of age are stunted. OBJECTIVE: To examine the specific food, agriculture, and health policies that have existed and currently exist in Bangladesh from the perspective of nutrition and identify gaps in the policy framework for which improvements in nutrition have been slow. METHODS: Policy documents, public financial and budget documents, and related papers were reviewed. Several interviews with former civil servants and bureaucrats were conducted. RESULTS: The approach to achieving food security has been a partial one, with policy provisions focusing excessively on increasing the availability of food, primarily rice. The "accessibility" pillar of food security has received little attention, while the neglect of the "utilization" pillar is conspicuous by the dearth of appropriate policies and laws for ensuring food safety. The efforts in the health sector have largely concentrated on expanding the coverage of primary healthcare, with little consideration of equity and quality. CONCLUSIONS: There exists a wide window of unexplored opportunity to align the remarkable increases in food production and advances in the health sector with nutrition considerations toward an improved nutrition status in Bangladesh. PMID- 24791587 TI - A review of phytotherapy of gout: perspective of new pharmacological treatments. AB - The purpose of this review article is to outline plants currently used and those with high promise for the development of anti-gout products. All relevant literature databases were searched up to 25 March 2013. The search terms were 'gout', 'gouty arthritis', 'hyperuricemia', 'uric acid', 'xanthine oxidase (XO) inhibitor', 'uricosuric', 'urate transporter 1(URAT1)' and 'glucose transporter 9 (GLUT9)'. Herbal keywords included 'herbal medicine', 'medicinal plant', 'natural products', 'phytomedicine' and 'phytotherapy'. 'antiinflammatory effect' combined with the words 'interleukin-6 (IL-6)', 'interleukin-8 (IL-8)', 'interleukin-1beta (IL-1beta)', and 'tumor necrosis factor alpha (TNF-alpha)'. XO inhibitory effect, uricosuric action, and anti-inflammatory effects were the key outcomes. Numerous agents derived from plants have anti-gout potential. In in vitro studies, flavonoids, alkaloids, essential oils, phenolic compounds, tannins, iridoid glucosides, and coumarins show the potential of anti-gout effects by their XO inhibitory action, while lignans, triterpenoids and xanthophyll are acting through their anti-inflammatory effects. In animal studies, essential oils, lignans, and tannins show dual effects including reduction of uric acid generation and uricosuric action. Alkaloids reveal inhibit uric acid generation, show anti-inflammatory effects, or a combination of the two. Phenolic compounds and flavonoids inhibit uric acid production, show uricosuric anti-inflammatory effects. In the rare human studies, colchicine from Colchicum autumnale showed anti-inflammatory effects while for other plant extracts, although revealing anti gout potential, further phytochemical investigations are needed to identify their active constituents. Besides, the plants which give antioxidant activities are much potent in the management of gout and need to be further investigated. The current review is a detailed discussion of the potential of medicinal plants for treatment of gout. PMID- 24791588 TI - 2,4-Dihydroxychalcone derivatives as novel potent cell division cycle 25B phosphatase inhibitors and protein tyrosine phosphatase 1B inhibitors. AB - Eleven 2,4-dihydroxychalcone compounds were synthesized and identified as reversible and competitive cell division cycle 25 (CDC25) B and protein tyrosine phosphatase (PTP) 1B inhibitors with inhibition values in the micromolar range. The results showed that nine compounds significantly inhibited CDC25B phosphatase, whereas seven compounds inhibited the activity against PTP1B in vitro. Compound 8 had the greatest inhibition activity against CDC25B and PTP1B in vitro, with percentage inhibition values of 97.5% and 96.3% at a dose of 20 microg/mL, respectively. Cytotoxic activity assays revealed that compound 8 was the most potent against HCT116, HeLa, and A549 cells. Furthermore, compound 8 exhibited potent antitumor activity in a colo205 xenograft model. PMID- 24791589 TI - Novel renin inhibitors containing a non-peptide aminoalkanoyl moiety at P1-P1' position. AB - Six novel potential renin inhibitors have been designed and synthesized. All these inhibitors contained an unnatural aminoalkanoyl moiety at the central position P1- P1' of the molecule, which is attacked by renin. The moiety consists of pseudodipeptidic units, transition state analogues of a natural dipeptide of the parent substance: 4-amino-3-hydroxybutanoic acid (AHBA), 4-amino-5-(4 ethoxyphenyl)-3-hydroxypentanoic acid (AEPHPA), 4-amino-5-cyclohexyl-3 hydroxypentanoic acid (ACHPA) or 4-amino-3-hydroxynonanoic acid (AHNA). An unnatural moiety, 4-methoxyphenylalanylhistydyl (Phe(4-OMe)-His) has been introduced at the P3-P2 position of the obtained compounds. Five compounds contain isoamylamide of 6-aminohexanoic acid (epsilon-Ahx-laa) at the P2'-P3' position. One of designed inhibitors has been obtained in the form of an ethyl ester. The in vitro renin inhibitory activity of all synthesized compounds is contained within the range 10(-6) - 10(-8) M. The compound in the form of an ethyl ester has proven to be the most active (IC50 = 1.3 x 10(-8) M) but also susceptible to enzymatic degradation. The other five inhibitors were stable to chymotrypsin. PMID- 24791590 TI - A novel brain targeted 5-fU derivative with potential antitumor efficiency and decreased acute toxicity: synthesis, in vitro and in vivo evaluation. AB - The broad-spectrum antitumor agent 5-fluorouracil (5-FU), has been used to treat various solid malignant tumors. However, its short life-time in vivo and poor ability to cross the blood-brain barrier has limited its application to brain tumor therapy. In order to develop a 5-FU derivative that localizes efficiently to the brain while retaining potent antitumor activity, we conjugated 5-FU with N,N-dimethylethylenediamine via an amide bond. The stability of the resulting 5 FU derivative (D-FU) was tested in vitro in phosphate buffer, rat plasma and brain homogenate. The pharmacokinetic and biodistribution studies in brains of the rats showed a higher C(max) (the maximal concentration) and an increased AUC(0-t) (the area under the concentration-time curve) which was 6-fold that of 5 FU. In addition, compared to 5-FU, D-FU exhibited lower toxicity in an acute toxicity assay and similar antitumor activity in the C6 cell line. In conclusion, D-FU has the potential to be developed into an efficient brain delivery drug. PMID- 24791591 TI - Proposal of a new degradation mechanism of enalapril maleate and improvement of enalapril maleate stability in tablet formulation with different stabilizers. AB - Enalapril maleate (EM) is unstable in poorly designed tablet formulations. To improve the stability of EM, the degradation mechanism should be elucidated. In this study, we found that several commonly used excipients promoted the degradants of EM, particularly a diketopiperazine derivative (DKP). We propose two degradation pathways in which both acid and alkali can promote the formation of DKP, although previous reports suggested that DKP is produced mainly in acidic media. Based on the degradation pathways, we believe that subtle control of the microenvironmental pH can inhibit the formation of DKP. This was confirmed by the observation that the degradation rate became slower when certain organic acids were added to the binary mixtures of EM and excipient. The data showed that the stability of EM in the ternary mixtures was much higher than that in binary mixtures. It was further proved that tablets containing these organic acids produced less DKP after the accelerated test. We also found that the formation of DKP in tablets varied with different ratios of tartaric acid, which was used as a model organic acid. This illustrated that an optimum ratio of tartaric acid is required. These results indicated that the stability of EM in tablet formulation is closely associated with microenvironmental pH and the addition of a suitable organic acid based on the reaction mechanism is an effective strategy for improving the stability of EM. PMID- 24791592 TI - Efficacy and toxicity of cisplatin liposomes modified with polyethylenimine. AB - The polycation transfection agent, polyethylenimine (PEI) was introduced into cisplatin (CDDP)-encapsulated liposomes by modification with amphiphilic PEI cholesterol (PEI-Chol) to evaluate its potential application in chemotherapeutic drug delivery. Compared with unmodified neutral liposomes (CDDP-NL), the remarkable features of PEI-modified cationic liposomes (CDDP-CL) increased cytotoxicity attributed to enhanced cellular uptake and extended cellular retention resulting from endosome escape in vitro. In a H22 hepatoma-bearing mouse model, CDDP-CL reduced the nephrotoxicity associated with CDDP and had an antitumor activity similar to free drug, without inducing obvious system toxicity. These results confirm that the cationic modification of liposomes with PEI is efficient and safe for antitumor drug delivery. PMID- 24791593 TI - Let-7 g microRNA sensitizes fluorouracil-resistant human hepatoma cells. AB - Let-7 microRNA is expressed in lower lever in a variety of human tumors and is involved in tumorigenesis. This study investigated the inhibitory effect of the let-7g microRNA on the expression of the HMGA2 gene in the fluorouracil (5-Fu) resistant human hepatoma cell line Bel-7402/5-Fu, and the effect of let-7 g microRNA on drug sensitization in Bel-7402/5-Fu cells. Let-7 g microRNA and negative microRNA plasmids were constructed and transient transfected into Bel 7402/5-Fu cells. Expression levels of HMGA2 mRNA and protein in microRNA transient transfectants were clearly reduced as compared with negative microRNA transfectants and untreated cells. Flow cytometry revealed increased in S phase in let-7 g microRNA cells. dimethylthiazol-diphenyltetrazolium bromide (MTT) results indicated that microRNA transfectants had a higher cell inhibition rate than the negative vector or untreated cells after treatment with 0.13-13 microg/ml 5-Fu. In addition, cyclin A was down-regulated in the let-7 g transfectants cells.The results showed that let-7 g microRNA contributed to an increase of 5-Fu-induced cell cycle inhibit in human hepatoma cell and sensitized cells to 5-Fu, leading to increased the effectiveness of the drug in treating hepatoma cancer. PMID- 24791594 TI - A membrane-tethering pepducin that inhibits formyl peptide receptor 2-induced signaling. AB - Since formyl peptide receptor 2 (FPR2) plays a key role in the regulation of innate immune response and inflammation, it has been a hot topic to develop molecules which inhibit FPR2-induced cellular responses. In this study, we investigated the effect of an FPR2-derived pepducin in human neutrophils and human umbilical vein endothelial cells (HUVECs). The pepducin (F2pal-12) selectively inhibited FPR2 agonists (MMK-1 and serum amyloid A)-stimulated neutrophil chemotaxis. MMK-1-stimulated superoxide anion production was also inhibited by F2pal-12. HUVECs also express FPR2; FPR2 agonists-stimulated HUVECs migration and tube formation were also selectively inhibited by F2pal-12 but not by scrambled control pepducin. Since FPR2 mediates inflammatory response by inducing chemotactic migration of inflammatory cells, F2pal-12 can be used as a useful material to modulate FPR2-mediated inflammatory responses. PMID- 24791595 TI - The effect to IL-3Ralpha, downstream PI3k/Akt signaling of all-trans retinoic acid and arsenic trioxide in NB4 cells. AB - All-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) are the classic drugs used for induction therapy of acute promyelocytic leukemia (APL). IL-3Ralpha (CD123) is a specific marker of acute myeloid leukemia stem cells (AML-LSCs). The over-expression of IL-3Ralpha in patients with AML is related to high white blood cells counts, high percentages of blast cells, and poor prognosis. Moreover, in some studies, IL-3Ralpha has been considered a new detection marker of minimal residual disease in the bone marrow from patients with APL. In contrast to ATRA, As2O3 reduces both mRNA and protein expression of IL-3Ralpha and inhibits the activity of PI3K/Akt after 24 h, 48 h, and 72 h of exposure. Furthermore, NB4 cells adhered to the human stroma cell line HS-5 cells were used as an in vitro model of APL cells in the bone marrow microenvironment. Our results demonstrate that adhesion to HS-5 cells up-regulated IL-3Ralpha protein expression and activated the downstream PI3K/Akt signaling pathway in NB4 cells. Compared with ATRA, As2O3 more potently inhibits proliferation of NB4 cells adhered to stroma cells. PMID- 24791597 TI - Effect of myricetin on cytochrome P450 isoforms CYP1A2, CYP2C9 and CYP3A4 in rats. AB - Myricetin is one of the main ingredients of Chinese bayberry, which is used as a traditional medicine. The purpose of this study was to find out whether myricetin influences the rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9 and CYP3A4) by using cocktail probe drugs in vivo. A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg) and midazolam (10 mg/kg), was orally administered to rats treated for 14 days with myricetin. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. Our study showed that treatment with multiple doses of myricetin had no effects on rat CYP1A2. However, CYP2C9 and CYP3A4 enzyme activities were inhibited after multiple doses of myricetin. Therefore, caution is needed when myricetin is co-administered with CYP2C9 or CYP3A4 substrates, which may result in herb-drug interactions. PMID- 24791596 TI - Effects of icaritin on cytochrome P450 enzymes in rats. AB - The purpose of this study was to find out whether icaritin influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2E1 and CYP3A4) using cocktail probe drugs in vivo. A cocktail solution at a dose of 5 mL/kg, which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), chlorzoxazone (20 mg/kg) and midazolam (10 mg/kg), was orally administered to rats treated with multiple doses of icaritin. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0. Treatment with multiple doses of icaritin had inhibitive effects on rat CYP1A2, CYP2C9 and CYP3A4 enzyme activities. However, icaritin has no inductive or inhibitory effect on the activity of CYP2E1. Therefore, caution is needed when icaritin is co-administered with some CYP1A2, CYP2C9 or CYP3A4 substrates, which may result in treatment failure and herb-drug interactions. PMID- 24791598 TI - Optimization of ultrasonic extraction of total flavonoids from Tussilago farfara L. using response surface methodology. AB - In this work, ultrasound technology was used for the extraction of total flavonoids from Tussilago farfara L. Response surface methodology (RSM), based on a Box-Behnken design (BBD), was used to optimize the effects of processing parameters on total flavonoids yields. The parameters were ultrasonic frequency (X1), extraction time (X2) and ratio of liquid to solid (X3). The statistical analysis indicated that the parameters of ultrasonic power and ratio of liquid to solid, and the square effects among them had significant effects on the yield of flavonoids from Tussilago farfara L. The interaction between ultrasonic power and extraction time, and ultrasonic power and ratio of liquid to solid also caused significant effects on the yields. The optimum extraction conditions were determined as follows: ultrasonic power 420 W, extraction time 30 min, ratio of liquid to solid 25 mL/g. Under these conditions, the experimental yield 6.59 +/- 0.061% agreed closely with the predicted yield (6.64%). PMID- 24791599 TI - Exploring the potential impact of hospital ward-based pharmacy interns on drug safety. AB - Clinical pharmacists play an important role in improving drug safety on hospital wards. However, little is known about the impact of pharmacy interns. The objective of our study was, therefore, to investigate the impact of hospital ward based pharmacy interns on drug safety. This study was conducted as part of the project "P-STAT 2: Pharmacy interns on the ward" on 14 surgical wards in seven hospitals in Germany and a total of 27 pharmacy interns participated. All patients admitted to the participating wards from 1st June 2008 until 31st October 2008 and from 1st December 2008 till 30th April 2009 were included. The pharmacy interns were involved in medication reconciliation, and identifying, resolving, and preventing drug-related problems (DRPs) using the classification system APS-Doc. A total of 6,551 patients were included. Patients received on average (+/- SD) 4.4 +/- 3.9 drugs. The pharmacy interns detected a total of 4,085 DRPs and on average 0.6 +/- 1.2 DRPs per patient. Most frequently detected DRPs were potential drug-drug interactions (n = 591, 14%), missing drug strength, when different strengths were available (n = 373, 9%), and incomplete medication record (n = 296, 7%). The pharmacy interns conducted an intervention for 98% (n = 4,011) of all DRPs. According to their documentation, 74% of the DRPs (n = 3,038) were solved. Drugs which were most often related with DRPs were simvastatin, diclofenac, and ibuprofen. This is the very first study exploring the potential impact of pharmacy interns on drug safety on surgical wards in Europe. Pharmacy interns can play an important role to improve drug safety on hospital wards. PMID- 24791600 TI - Molecular mechanisms involved in the cardiovascular and neuroprotective effects of anthocyanins. AB - Anthocyanins are the main group of natural hydrosoluble pigments in plants. They introduce colouring to foods, with colours ranging from blue to red and orange. Nowadays, their importance for the Food and Pharmaceutical industries is mainly based in the existing scientific work evidencing their beneficial effects on the prevention of cardiovascular diseases and neurological conditions. Different mechanisms have been shown to be involved in those effects. The most consistent ones are related to their antihypertensive and endothelium protective activities, antiatherogenic activity and their interaction with the estrogenic receptor. In some of the existing work, studies on structure-activity relationship have been done, showing that modifications on the structure of anthocyanins, besides having an effect on their colours, have a clear incidence on their interaction with different steps in the principal pathways related to these diseases. Therefore, different colours might show different molecular mechanisms. However, in a normal diet most of these compounds are present simultaneously and, thus; they can act by different mechanisms but can rise to a common final action. Design of new food product or food supplements should take these potential synergies into consideration. PMID- 24791601 TI - What matters for lupus patients? PMID- 24791602 TI - [Cytomegalovirus infection in pregnancy]. AB - Cytomegalovirus is the main cause of neurosensorial deficit due to a congenital infection. Fetal infection may follow a maternal primary infection or a maternal secondary infection. The diagnosis of maternal primary infection remains tricky because the interpretation of IgG avidity test may be difficult. The diagnosis of maternal secondary infections is impossible with usual routine assays. The virological diagnosis of fetal infection is very reliable with a sensitivity over 90% and a specificity next to 100%. In the context of a proven intrauterine infection, the negative predictive value of ultrasound coupled with fetal brain RMI is over 85%. No antenatal treatment is yet validated, two treatments (hyperimmune therapy and antival therapy) are under evaluation. Six months treatment course with valganciclovir improves audiologic and neurodevelopmental outcomes of symptomatic neonates. PMID- 24791603 TI - Serotonin and yawning: A possible adverse drug reaction during antidepressant therapy. PMID- 24791604 TI - Response to 'Re. Carotid endarterectomy with stent removal in management of in stent restenosis: a safe, feasible, and effective technique'. PMID- 24791605 TI - Engaging foster parents in treatment: a randomized trial of supplementing trauma focused cognitive behavioral therapy with evidence-based engagement strategies. AB - The goal of this study was to examine the impact of supplementing Trauma-focused Cognitive Behavioral Therapy (TF-CBT; Cohen et al., 2006) with evidence-based engagement strategies on foster parent and foster youth engagement in treatment, given challenges engaging foster parents in treatment. A randomized controlled trial of TF-CBT standard delivery compared to TF-CBT plus evidence-based engagement strategies was conducted with 47 children and adolescents in foster care and one of their foster parents. Attendance, engagement, and clinical outcomes were assessed 1 month into treatment, end of treatment, and 3 months post-treatment. Youth and foster parents who received TF-CBT plus evidence-based engagement strategies were more likely to be retained in treatment through four sessions and were less likely to drop out of treatment prematurely. The engagement strategies did not appear to have an effect on the number of canceled or no-show sessions or on treatment satisfaction. Clinical outcomes did not differ by study condition, but exploratory analyses suggest that youth had significant improvements with treatment. Strategies that specifically target engagement may hold promise for increasing access to evidence-based treatments and for increasing likelihood of treatment completion. PMID- 24791606 TI - Bridging disulfides for stable and defined antibody drug conjugates. AB - To improve both the homogeneity and the stability of ADCs, we have developed site specific drug-conjugating reagents that covalently rebridge reduced disulfide bonds. The new reagents comprise a drug, a linker, and a bis-reactive conjugating moiety that is capable of undergoing reaction with both sulfur atoms derived from a reduced disulfide bond in antibodies and antibody fragments. A disulfide rebridging reagent comprising monomethyl auristatin E (MMAE) was prepared and conjugated to trastuzumab (TRA). A 78% conversion of antibody to ADC with a drug to antibody ratio (DAR) of 4 was achieved with no unconjugated antibody remaining. The MMAE rebridging reagent was also conjugated to the interchain disulfide of a Fab derived from proteolytic digestion of TRA, to give a homogeneous single drug conjugated product. The resulting conjugates retained antigen-binding, were stable in serum, and demonstrated potent and antigen selective cell killing in in vitro and in vivo cancer models. Disulfide rebridging conjugation is a general approach to prepare stable ADCs, which does not require the antibody to be recombinantly re-engineered for site-specific conjugation. PMID- 24791608 TI - Evaluating success of autotransplantation of embedded/impacted third molars harvested using piezosurgery: a pilot study. AB - OBJECTIVE: To evaluate the success of autogenous transplantation of embedded/impacted third molars harvested using piezosurgery. MATERIALS AND METHODS: This prospective pilot study enrolled 20 healthy patients with non restorable first/second molars and a caries-free retrievable embedded/impacted third molar. Piezosurgery was used for removing inter-radicular bone at the recipient socket as well as for bone removal around the donor teeth. RESULTS: After an average follow-up of 16.4 months (SD = 1.9), 18 cases were successful with formation of periodontal ligament around the teeth. One tooth was lost due to infection at 1 month. One patient was lost to follow-up. There was no root resorption or ankylosis in any of the cases. In six donor teeth with complete root formation, root canal treatment was carried out. All the remaining teeth responded positively with vitality testing. CONCLUSION: Piezosurgery is an effective device if embedded/impacted third molars are to be harvested for successful autogenous transplantation. PMID- 24791607 TI - Antibiotic prophylaxis patterns of Finnish dentists performing dental implant surgery. AB - BACKGROUND: The peri-operative use of prophylactic antibiotics in clinically healthy patients undergoing dental implant surgery is very common in Finland. While antibiotics are prescribed with the hope of preventing both local and systemic complications, their application and utilization is not uniform. OBJECTIVE: The aim of this study was to assess the variation in prescribing patterns among Finnish dentists performing dental implant placement operations. This study also aimed to examine the possible relationship between early implant removal and the use of the prophylactic antibiotics in Finland. MATERIALS AND METHODS: The National Institute for Health and Welfare in Finland granted permission to access the Finnish Dental Implant Register. The peri-operative antibiotic prophylaxis prescribing patterns were assessed in a total of 110 543 dental implant placement procedures and 1038 dental implant removal operations performed in Finland between April 1994 and April 2012. RESULTS: A total of 61 different antibiotics or combinations were prescribed peri-operatively during implant placements in Finland between 1994-2012. Phenoxymethylpenicillin was the most commonly prescribed drug (72.2%). No statistically significant difference in early implant removal rates could be found between patients who had or had not received peri-operative prophylaxis. However, patients who had received peri operative prophylaxis had statistically significant longer implant survival rates. CONCLUSION: There is a variation in antibiotic prescribing patterns among Finnish dentists placing dental implants. The results suggest that the use of prophylactic antibiotics has little effect on the prevention of primary implant surgery-related complications and, hence, success rates. PMID- 24791609 TI - Bacterial leakage in root canals filled with AH Plus and dentine bonding agents. AB - OBJECTIVE: The aim of this study was to compare the efficacy of different dentine adhesives in delaying the coronal bacterial leakage of Enterococcus faecalis in filled root canals. Materials and methods. Ninety-five lower incisors of patients >65 years of age were instrumented using the ProTaper system and were irrigated with 1 mL of 2.5% sodium hypochlorite (NaOCl) alternated with 1 mL 17% EDTA between each file change. Final irrigation was performed with 5 mL of 17% EDTA and then flushed with 5 mL of distilled water. The teeth were randomly divided into five experimental groups (n = 15/group) and one of the following dentine adhesives was applied: (1) AdheSE; (2) Excite DSC; (3) Clearfil Protect Bond; (4) One Coat 7.0; or (5) Control group without adhesive. After filling the root canals, the samples were mounted on a double chamber device to evaluate the bacterial filtration of E. faecalis during a period of 240 days. The results underwent non-parametric Kaplan-Meier survival analysis and comparisons among groups were done using the Log-Rank test. RESULTS: At 240 days, E. faecalis was detected in samples of all groups in the lower chamber. The highest survival value was obtained by One Coat 7.0, giving statistically significant differences from the other groups, whereas Clearfil Protect Bond, AdheSE and Excite DSC showed similar behaviours, likewise similar to the Control group. CONCLUSIONS: One Coat 7.0 adhesive system provides the longest survival value to delay E. faecalis coronal leakage in filled root canals. PMID- 24791610 TI - The adhesive strength and initial viscosity of denture adhesives. AB - OBJECTIVE: To examine the initial viscosity and adhesive strength of modern denture adhesives in vitro. MATERIALS AND METHODS: Three cream-type denture adhesives (Poligrip S, Corect Cream, Liodent Cream; PGS, CRC, LDC) and three powder-type denture adhesives (Poligrip Powder, New Faston, Zanfton; PGP, FSN, ZFN) were used in this study. The initial viscosity was measured using a controlled-stress rheometer. The adhesive strength was measured according to ISO 10873 recommended procedures. All data were analyzed independently by one-way analysis of variance combined with a Student-Newman-Keuls multiple comparison test at a 5% level of significance. RESULTS: The initial viscosity of all the cream-type denture adhesives was lower than the powder-type adhesives. Before immersion in water, all the powder-type adhesives exhibited higher adhesive strength than the cream-type adhesives. However, the adhesive strength of cream type denture adhesives increased significantly and exceeded the powder-type denture adhesives after immersion in water. For powder-type adhesives, the adhesive strength significantly decreased after immersion in water for 60 min, while the adhesive strength of the cream-type adhesives significantly decreased after immersion in water for 180 min. CONCLUSION: Cream-type denture adhesives have lower initial viscosity and higher adhesive strength than powder type adhesives, which may offer better manipulation properties and greater efficacy during application. PMID- 24791611 TI - Displacements, mean-squared displacements, and codisplacements for the calculation of nonequilibrium properties. AB - We study two situations in which nonequilibrium phenomena can be efficiently calculated using displacements, mean-squared displacements, or codisplacements instead of accumulating velocities or currents. The flow velocity profile for a fluid confined within a pore can be expressed as a sum of displacements within slabs from a molecular dynamics trajectory. In this form, an accurate flow profile is obtained from very sparse sampling of the trajectory. We also recast the linear response theory expression for the flow velocity profile in terms of mean codisplacements and demonstrate that this provides an efficient route for estimating the Green-Kubo expression for the velocity profile. Finally, we calculate the ionic contribution to the frequency-dependent electric susceptibility using dipolar displacements, instead of the conventional current current correlation function. We expect these methods to be useful for generating transport properties from stored trajectories in very large systems or systems where relaxation times are long. PMID- 24791613 TI - Thoracic imaging. Editorial. PMID- 24791612 TI - Nervous decision-making: to divide or differentiate. AB - The intricate balance between proliferation and differentiation is of fundamental importance in the development of the central nervous system (CNS). The division versus differentiation decision influences both the number and identity of daughter cells produced, thus critically shaping the overall microstructure and function of the CNS. During the past decade, significant advances have been made to characterise the changes in the cell cycle during differentiation, and to uncover the multiple bidirectional links that coordinate these two processes. Here, we explore the nature and mechanistic basis of these links in the context of the developing CNS, highlighting new insights into transcriptional, post translational, and epigenetic levels of interaction. PMID- 24791614 TI - The imaging spectrum of bronchopulmonary sequestration. AB - Bronchopulmonary sequestration is a rare lesion characterized by abnormal lung tissue that lacks a normal bronchial communication and is supplied by an anomalous systemic artery. It has a variety of imaging appearances, including that of consolidation, a mass, or an air or fluid-filled cystic or multicystic lesion. This article reviews the imaging spectrum of bronchopulmonary sequestration, its important parenchymal mimics, and conditions that share the feature of anomalous systemic arterial supply to the lung. PMID- 24791615 TI - Cystic interstitial lung diseases: recognizing the common and uncommon entities. AB - Cystic lung diseases present a considerable diagnostic challenge because they are less frequently encountered in clinical practice and high-resolution computed tomography findings are often similar in many of these diseases. Here, we review the high-resolution computed tomography findings of cystic lung diseases and their mimics and provide a systematic approach to their diagnosis. Specific diseases that are discussed include pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, Birt-Hogg-Dube syndrome, lymphocytic interstitial pneumonia, and light chain deposition disease. PMID- 24791616 TI - Diffuse pulmonary hemorrhage: clues to the diagnosis. AB - Diffuse pulmonary hemorrhage (DPH) refers to an uncommon but significant condition of bleeding into the alveolar space. Anemia and hemoptysis are important clinical features, but they may be absent. Although the radiographic and computed tomography findings are often varied and nonspecific, the imaging manifestations of pulmonary hemorrhage and the associated findings in the thorax often provide important diagnostic information that may lead to a specific diagnosis. DPH significantly influences patient management and has important prognostic implications. This review article explores the imaging findings in DPH and its differential diagnosis, highlighting important clues to this diagnosis and to its underlying etiology. DPH is an uncommon condition characterized by bleeding into the alveolar space that, when recognized on imaging, provides important diagnostic and prognostic information. PMID- 24791617 TI - Clear vision through the haze: a practical approach to ground-glass opacity. AB - Ground-glass opacity (GGO) is a common, nonspecific imaging finding on chest computed tomography that may occur in a variety of pulmonary diseases. GGO may be the result of partial filling of alveolar spaces, thickening of the alveolar walls or septal interstitium, or a combination of partial filling of alveolar spaces and thickening of the alveolar walls and septal interstitium at the histopathologic level. Diseases that commonly manifest on chest computed tomography as GGO include pulmonary edema, alveolar hemorrhage, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, and pulmonary alveolar proteinosis. Generating an extensive list of possible causes of GGO in radiologic reports would not be helpful to referring physicians. Preferably, a more concise and focused list of differential diagnostic possibilities may be constructed using a systematic approach to further classify GGO based on morphology, distribution, and ancillary imaging findings, such as the presence of cysts, traction bronchiectasis, and air trapping. Correlation with clinical history, such as the chronicity of symptoms, the patient's immune status, and preexisting medical conditions is vital. By thorough analysis of imaging patterns and consideration of relevant clinical information, the radiologist can generate a succinct and useful imaging differential diagnosis when confronted with the nonspecific finding of GGO. PMID- 24791618 TI - Drowsiness and motor responses to consecutive daily doses of promethazine and loratadine. AB - OBJECTIVES: Limited information is available regarding sedation and motor function following repeat dosing of antihistamines. This study examined how promethazine and loratadine affect day-time drowsiness, the commencement of voluntary movement, and involuntary movement when administered on consecutive days. METHODS: Ten healthy young subjects (24+/-5years) were recruited into a double-blind, placebo-controlled, three-way crossover study. Subjects ingested either promethazine, loratadine or a placebo, and ingested the same drug 24h later. Measures of drowsiness, simple reaction time (SRT), choice reaction time (CRT), and postural tremor were obtained pre-ingestion, 1h post-ingestion and 2h post-ingestion on each day. RESULTS: Consecutive daily doses of promethazine and loratadine affected SRT and CRT, respectively, whereby reaction time deficits were less pronounced following the repeat dose. A reduced tremor response was also observed following consecutive daily dosing of promethazine, in contrast to loratadine which caused an increase in tremor amplitude with the consecutive daily dose. CONCLUSIONS: Reaction time and tremor responses differed following the single dose compared to consecutive doses. SIGNIFICANCE: Sufferers of allergic rhinitis often require antihistamine dosing regimens that continue over multiple days. Future studies will benefit from examining drowsiness and movement responses following single doses as well as consecutive dosing. PMID- 24791619 TI - Indiana continent catheterizable urinary reservoir. AB - INTRODUCTION: Radical pelvic surgery requires continent or incontinent urinary diversion. There are many techniques, but the orthotopic neobladder is the most used. A continent catheterizable urinary reservoir is sometimes a good alternative when this derivation is not possible or not indicated. This paper has aimed to present our experience with the Indiana pouch continent urinary reservoir. MATERIAL AND METHODS: The series is made up of 85 patients, 66 women and 19 men, with a mean age of 56 years (31-77 years). Variables analyzed were operating time, estimated blood loss, transfusion rate, hospital stay and peri operatory complications. RESULTS: The main indication in 49 cases was resolution of complications related to the treatment of cervical cancer. Average operation time was 110.5 minutes (range 80-130 minutes). Mean blood loss was 450 cc (100 1000 cc). Immediate postoperative complications, all of which were treated medically, occurred in 16 patients (18.85%). One patient suffered anastomotic leakage. Hospital stay was 19 days (range 5-60 days) and there was no mortality in the series. Late complications occurred in 26 patients (32%), these being ureteral anastomotic stenosis in 11 cases, cutaneous stoma stenosis in 9 cases and reservoir stones in 6 cases. CONCLUSION: The Indiana continent catheterizable urinary reservoir is a valid option for the treatment of both urological and gynecological malignancies as well as for the management of pelvic morbidity related to the treatment of pelvic cancers. PMID- 24791620 TI - Prevalence of renal stones in Andalusian population: results of PreLiRenA study. AB - INTRODUCTION: Urolithiasis is a disease having a high recurrence rate and associated morbidity. A not well quantified increase is being seen in recent years that could be related with various factors. The main purpose of our study has been to estimate urolithiasis prevalence and incidence in the region of Andalusia, determining which factors are associated. MATERIAL AND METHODS: We performed an observational and cross-sectional study. Using a multistage randomized procedure, we selected a sample of 2439 subjects, aging from 40 to 65 years old, who currently lived in Andalusia. Data was collected through phone interviews, questioning the chosen subjects about their kidney stones history, comorbidity and socio-demographic characteristics. We conducted a descriptive, bivariate and multivariate analysis with logistic regression. RESULTS: A total of 2439 subjects were surveyed. Subjects had mean age of 51.1+/-7.61 years - standard deviation; (95% confidence interval - 95% CI: 50.70-51.30), 48.7% of whom were male. Prevalence of urolithiasis obtained was 16.4% (95% CI: 14.87 17.85%) and an incidence of 1.2 (95% CI: .74-1.64). Variables significantly associated with the presence of urolithiasis found in the multivariate study were: presence of a family history of kidney stones (odds ratio -OR: 1.91; 95% CI: 1.51-2.40, P<.001), hypertension (OR:1.58; 95% CI:1.24-2.02; P<.001), gout (OR:1.98; 95% CI: 1.26-3,12; P=.003) and a high BMI (OR: 1.60; 95% CI 1.19-2.17; p=.008). CONCLUSIONS: A significant increase in the prevalence and incidence of urolithiasis is observed in the environment in regards to the previously available figures. The presence of a family history of urolithiasis, hypertension, gout as well as having a high BMI could influence the observed epidemiological changes in renal lithiasis. PMID- 24791622 TI - Evaluation of the clinical usefulness of a health-related quality of life questionnaire in patients with prostate cancer. AB - OBJECTIVES: The PROSQoLI questionnaire evaluates health related quality of life in patients with advanced prostate cancer. Although its utility in different clinical settings has never been assessed, its brevity and good measurement properties make its use recommendable in clinical practice. The objective is to evaluate the clinical usefulness of PROSQoLI in clinical treatment decision making in patients with prostate cancer. MATERIALS AND METHODS: An observational, prospective longitudinal and multi-center study conducted in different Spanish centers. Sociodemographic and clinical data of patients and researchers were collected. Each patient fulfilled PROSQoLI questionnaire in each visit. Besides, physicians answered a survey about clinical usefulness of PROSQoLI questionnaire. RESULTS: The mean age of patients was 74.7 (7.4) years (standard deviation) and of researchers 51.8 (9.7) years. The usefulness in clinical decision-making was considered high by 66.1% of physicians; regarding questionnaire characteristics 71.3% of physicians considered it highly useful and 73.4% of them regarding doctor-patient communication. CONCLUSIONS: The use of health-related quality of life questionnaires improves doctor-patient communication. It is demonstrated that PROSQoLI can be an additional tool in clinical decision-making as well as a means of facilitating doctor-patient communication. PMID- 24791621 TI - Optimizing D'Amico risk groups in radical prostatectomy through the addition of magnetic resonance imaging data. AB - OBJECTIVES: To improve the predictive efficacy of the D'Amico risk classification system with magnetic resonance imaging (MRI) of the pelvis. MATERIAL AND METHODS: We studied 729 patients from a series of 1310 radical prostatectomies for T1-T2 prostate cancer who underwent staging pelvic MRI. Each patient was classified with T2, T3a or T3b MRI, and N (+) patients were excluded. We identified the therapeutic factors that affected the biochemical progression-free survival (BPFS) time (prostate specific antigen [PSA] levels>0.4ng/mL) using a univariate and multivariate study with Cox models. We attempted to improve the predictive power of the D'Amico model (low risk: T1; Gleason 2-6; PSA levels<10ng/mL; intermediate risk: T2 or Gleason 7 or PSA levels 10-20ng/mL; high risk: T3 or Gleason 8-10 or PSA levels>20ng/mL). RESULTS: In the univariate study, the clinical factors that influenced BPFS were the following: Gleason 7 (HR: 1.7); Gleason 8-10 (HR: 2.9); T2 (HR: 1.6); PSA levels 10-20 (HR: 2); PSA levels>20 (HR: 4.3); D'Amico intermediate (HR: 2.1) and high (HR: 4.8) risk; T3a MRI (HR: 2.3) and T3b MRI (HR: 4.5). In the multivariate study, the only variables that affected BPFS were the following: D'Amico intermediate risk (HR: 2; 95% CI 1.2 3.3); D'Amico high risk (HR: 4.1; 95% CI 2.4-6.8); T3a MRI (HR: 1.9; 95% CI 1.2 2.9) and T3b MRI (HR: 3.9; 95% CI 2.5-6.1). Predictive model: Using the multivariate Cox models, we assessed the weight of each variable. A value of 1 was given to D'Amico low risk and T2 MRI; a value of 2 was given to D'Amico intermediate risk and T3a MRI and a value 3 was given to D'Amico high risk and T3b MRI. Each patient had a marker that varied between 2 and 6. The best model included 3 groups, as follows: 494 (67.7%) patients in group 1, with a score of 2 3 points (HR, 1), a BPFS of 86%+/-2% and 79%+/-2% at 5 and 10 years, respectively; 179 (24.6%) patients in group 2, with a score of 4 points (HR, 3), a BPFS of 60%+/-4% and 54%+/-5% at 5 and 10 years, respectively; and 56 (7.7%) patients in group 3, with a score of 5-6 points (HR, 9.3), a BPFS of 29%+/-8% and 19%+/-7% at 5 and 10 years, respectively. The median BPFS time was 1.5 years. CONCLUSION: MRI data significantly improves the predictive capacity of BPFS when using the D'Amico model data. PMID- 24791623 TI - Surgical and ablative therapies for the management of adrenal 'oligometastases' - A systematic review. AB - BACKGROUND: We systematically reviewed the literature on the use of surgery, stereotactic ablative body radiotherapy (SABR) and percutaneous catheter ablation (PCA) techniques for the treatment of adrenal metastases to develop evidence based recommendations. METHODS: A systematic review of the MEDLINE database was performed using structured search terms following PRISMA guidelines. Eligible publications were those published from 1990 to 2012, written in English, had at least five patients treated for adrenal metastasis and reported on patient clinical outcomes (local control, survival and treatment related complications/toxicity). Where possible, pooled 2-year local control and overall survival outcomes were analysed. RESULTS: Our search strategy produced a total of 45 papers addressing the three modalities - 30 adrenalectomy, nine SABR and six PCA (818, 178 and 51 patients, respectively). There was marked heterogeneity in outcome reporting, patient selection and follow-up periods between studies. The weighted 2-year local control and overall survival for adrenalectomy were 84% and 46%, respectively, compared with 63% and 19%, respectively for the SABR cohort. Only one study of PCA with five patients analysed clinical outcomes, reporting an actuarial local control of 80% at 1 year. Treatment related complications/toxicities were inconsistently reported. CONCLUSION: There is insufficient evidence to determine the best local treatment modality for isolated or limited adrenal metastases from any primary tumour. Published data suggests adrenalectomy to be a reasonable treatment approach for isolated adrenal metastasis in suitable patients. SABR is a valid alternative in cases when surgery is not feasible or the operative risk is unacceptable. PCA cannot be recommended until there are more robust studies which include long-term oncological outcomes. PMID- 24791624 TI - Acute coagulopathy in a porcine venous hemorrhage and ischemia reperfusion model. AB - BACKGROUND: Injury-related coagulopathy is a complex process. We analyzed coagulation in a swine model of shock using rotational thromboelastometry (ROTEM). METHODS: Forty-eight swine underwent laparotomy, 35% hemorrhage, supraceliac aortic cross-clamp, then reperfusion and resuscitation. ROTEM measurements and standard labs were taken at baseline and 6 hours into resuscitation. RESULTS: Clot formation time (98 vs 53 seconds, P = .001) and international normalized ratio (1.67 vs 1.01, P < .001) were prolonged after resuscitation. Maximum clot firmness (61 vs 72 mm, P < .001) and fibrinogen levels (94 vs 165, P < .001) declined significantly during resuscitation. Despite decreased fibrinogen levels, there was no significant increase in fibrinolysis as measured by maximum lysis (3.9% vs 3.8%, P = .99). CONCLUSIONS: ROTEM demonstrated the development of an acute coagulopathy. The most significant impacts on coagulopathy were seen with clot initiation and fibrin polymerization. Clot strength decreased over time, although there was little impact on clot breakdown because of fibrinolysis. PMID- 24791625 TI - The way we were: surgical practice at the dawn of the North Pacific Surgical Association. AB - The North Pacific Surgical Association Historian's centennial lecture, with review of the geographic challenges for members of this society at the time of its founding and selected insights into surgical practices and philosophies of a century ago. PMID- 24791626 TI - Normocalcemic hyperparathyroidism: preoperatively a disease, postoperatively cured? AB - BACKGROUND: Up to 44% of primary hyperparathyroidism patients have elevated parathyroid hormone (ePTH) with normal calcium postparathyroidectomy (PTx). The question is whether the surgical approach affects the incidence of this phenomenon. METHODS: Patients with hyperparathyroidism and presumed single-gland disease on preoperative imaging who underwent PTx between 1994 and 2008 were identified and contacted for long-term follow-up. PTx was either a focused approach (minimally invasive approach [MIP]) or a bilateral neck exploration (BNE). RESULTS: In total, 171 patients had PTH measured postoperatively (95 MIP and 76 BNE); 30 of 171 (17%) had ePTH with normal calcium (MIP 21 [22%] and BNE 9 [12%], P = .08). This occurred within 2 years in 48% and 67% and after 2 years in 52% and 33%, MIP vs BNE, respectively. Four patients recurred, 2 MIP and 2 BNE. CONCLUSIONS: There is a trend toward a higher incidence of ePTH in patients having undergone an MIP. The etiology of ePTH is multifactorial but may represent an early recurrence. PMID- 24791627 TI - Experience with partial breast irradiation for treatment of breast cancer at a community-based cancer center. AB - BACKGROUND: Many patients after lumpectomy have barriers to whole breast radiation. Accelerated partial breast irradiation (APBI) was introduced at our institution as an alternative. METHODS: Retrospective review of patients who were treated with ABPI from March 2003 to December 2011 was conducted. Results of demographics, tumor pathology, infection, and recurrence were reviewed. RESULTS: Two hundred ninety-four patients received 298 treatments of APBI. The mean follow up was 58.5 months. Using the American Society for Radiation Oncology criteria, 101 patients were suitable, 142 cautionary, and 52 patients were unsuitable. The average age was 65 with a range of 37 to 93. In our study, true local recurrence occurred in only 1.0% (n = 3). Patients recurring in the same breast elsewhere was 2% (n = 6). CONCLUSIONS: Outcomes after treatment with APBI were excellent, and breast recurrence was similar to whole breast irradiation. It may safely be offered to patients with less than suitable criteria or barriers to whole breast radiation. PMID- 24791628 TI - Influence of nurse navigation on wait times for breast cancer care in a Canadian regional cancer center. AB - BACKGROUND: The wait times for breast cancer care in our region do not meet acceptable benchmarks. We implemented the Interior Breast Rapid Access Investigation and Diagnosis (IB-RAPID) nurse navigation program to address this issue. METHODS: The IB-RAPID prospective database was reviewed for patients entering the program between April 1, 2011 and April 30, 2012 (2011/2012 cohort), and was compared with patients from the same area in 2010. The main end point was the time between the 1st diagnostic imaging test and the surgery. Multiple linear regression was performed to investigate factors influencing the wait times. RESULTS: The wait times decreased with the introduction of IB-RAPID (59 vs 48 days; median). Stage of disease, total number of biopsies, and magnetic resonance imaging (MRI) use influenced wait times. MRI significantly delayed surgical intervention in both groups with those not having an MRI having a shorter wait time to surgery (68.5 vs 57.6 days; mean) in 2011/2012. CONCLUSION: The implementation of nurse navigation for patients with breast cancer appears to be effective at reducing the wait times for surgical treatment. PMID- 24791629 TI - Breast-specific gamma imaging is a cost effective and efficacious imaging modality when compared with MRI. AB - BACKGROUND: Both MRI and breast-specific gamma imaging are tools for surgical planning in newly diagnosed breast cancer. Breast-specific gamma imaging (BSGI) is used less frequently although it is of similar utility and lower cost. We compared the diagnostic and cost efficacy of BSGI with MRI. METHODS: Retrospective review of 1,480 BSGIs was performed in a community breast health center, 539 had a new diagnosis of cancer, 75 patients having both MRI and BSGI performed within 2 months of each other. Institutional charges for BSGI ($850) and MRI ($3,381) were noted. RESULTS: BSGI had a sensitivity of 92%, specificity of 73%, positive predictive value of 78%, and negative predictive value of 90%. This compared favorably with MRI that had sensitivity of 89%, specificity 54%, positive predictive value 67%, and negative predictive value 83%. The accuracy of BSGI was higher at 82% vs MRI at 72%. Total cost of MRI imaging was $253,575 vs BSGI at $63,750. CONCLUSIONS: BSGI is a cost-effective and accurate imaging study for further evaluation of dense breast tissue and new diagnosis of cancer. PMID- 24791630 TI - Clinical impact of sentinel lymph node biopsy in patients with thick (>4 mm) melanomas. AB - BACKGROUND: The role of sentinel lymph node status (SLNS) in thick melanoma is evolving. The purpose of this study was to determine the prognostic value of SLNS in thick melanoma. METHODS: A retrospective analysis of 120 prospectively collected clinically node-negative thick melanomas over 5 years was performed. Patient (age/sex) and tumor (thickness, ulceration, SLNS, mitoses, metastases, and recurrence) features were collected. Multivariate analysis was performed using Cox proportional hazard model. RESULTS: Factors predictive of positive SLN included male sex, ulceration, and high mitoses. Factors associated with positive SLN had higher local-regional recurrence and metastases than negative SLN. SLNS and tumor thickness impacted 5-year disease-free survival (DFS) and overall survival (OS). Positive SLN, ulceration, age, and mitoses were independent predictors of DFS/OS. CONCLUSIONS: Nonulcerated/lower mitoses thick melanomas had lower positive SLN rates. Positive SLN develop recurrence and metastases and have worse OS/DFS. SLNS is an important prognosticator for OS/DFS. Sentinel lymph node biopsy delineates prognostic groups in thick melanomas and can impact management. PMID- 24791631 TI - Failing to reverse a diverting stoma after lower anterior resection of rectal cancer. AB - BACKGROUND: A diverting stoma is an accepted adjunct to low anterior resection (LAR) for rectal cancer. However, some patients do not undergo a subsequent procedure to have the stoma reversed. We aim to determine incidence and risk factors for nonclosure of the diverting stoma. METHODS: This is a retrospective study of stage I to III rectal cancer patients at a single institution having LAR with curative intent and a diverting stoma. RESULTS: We studied 162 patients. Prevalence of nonclosure of the temporary stoma was 14.5% within 13 months of the index surgery. On a multivariate linear regression model, nonclosure was associated with anastomotic leak (odds ratio 9.89, 2.31 to 43.93, P < .001) and age older than 65 (odds ratio 2.76, 1.08 to 7.48, P < .036). CONCLUSIONS: Prevalence of nonclosure of a diverting stoma after LAR for rectal cancer is substantial (14.5%). Patients should be counselled regarding this risk with particular attention to potential risk factors. PMID- 24791632 TI - Predictive utility of cyclo-oxygenase-2 expression by colon and rectal cancer. AB - BACKGROUND: Cyclo-oxygenase-2 (COX-2), an inducible enzyme expressed in areas of inflammation, is a target of interest for colorectal cancer therapy. Currently, the predictive significance of COX-2 in colorectal cancer remains unclear. METHODS: Tissue microarrays were constructed using 118 colon cancer and 85 rectal cancer specimens; 44 synchronous metastatic colon cancer and 22 rectal cancer lymph nodes were also evaluated. COX-2 expression was assessed by immunohistochemistry. Univariate analysis was used to determine the predictive significance of clinicopathologic variables. Overall survival, disease-specific survival, and disease-free survival were the main outcomes examined. RESULTS: COX 2 was found to be expressed in 93% of colon cancers and 87% of rectal cancers. Decreased COX-2 expression was related to decreased disease-specific survival (P = .016) and decreased disease-free survival (P = .019) in the rectal cancer cohort but not in the colon cancer cohort. CONCLUSIONS: COX-2 expression has predictive utility for management of rectal but not colon cancer. PMID- 24791634 TI - The international normalized ratio overestimates coagulopathy in patients after major hepatectomy. AB - BACKGROUND: The International Normalized Ratio (INR) is commonly used to guide therapy after hepatectomy. We hypothesized that the use of thrombelastography (TEG) would demonstrate a decreased incidence of hypocoagulability in this patient population. METHODS: Seventy-eight patients were prospectively enrolled before undergoing hepatectomy. INR, TEG, and coagulation factors were drawn before incision, postoperatively, and on postoperative days 1, 3, and 5. RESULTS: Patients demonstrated an elevated INR at all postoperative time points. However, TEG demonstrated a decreased R value postoperatively, with subsequent normalization. Other TEG measurements were equivalent to preoperative values. All procoagulant factors save factor VIII decreased postoperatively, with a simultaneous decrease in protein C. CONCLUSIONS: TEG demonstrated a brief hypercoagulable state after major hepatectomy, with coagulation subsequently normalizing. The INR significantly overestimates hypocoagulability after hepatectomy and these data call into question current practices using the INR to guide therapy in this patient population. PMID- 24791633 TI - Differential expression of microRNA-320a, -145, and -192 along the continuum of normal mucosa to high-grade dysplastic adenomas of the colorectum. AB - BACKGROUND: MicroRNA (miR)-320a, miR-145, and miR-192 have been shown to play a role in colorectal carcinogenesis and metastasis. We examined if there is a difference in expression during the histologic progression from normal mucosa (NM) to high-grade dysplastic adenomas (HG). METHODS: Genome-wide miRNA expression profiling was performed on 113 colon adenomas. Information included histologic type, tumor grade, location, sex, age, family, and smoking history. A 2-way ANOVA was performed to evaluate the effect of the following factors adjusted for scan dates: location, sex, age, family history, smoking, and histology. RESULTS: The expression of miR-320a increased; miR-145 and miR-192 expression decreased (P < .0001), with higher histologic grade, and were independent of age, sex, family history, and smoking status. CONCLUSIONS: The miRs studied had statistically significant changes in expression with progression of histologic grade. These changes may signify progression of normal mucosa to HG and potentially serve as early markers for disease progression and differentiating high- from low-risk adenomas. PMID- 24791635 TI - Emergency department referral for organ donation: more organ donors and more organs per donor. AB - BACKGROUND: This study sought to determine whether early referral from the emergency department (ED) would increase the number of organ donors and the number of organs transplanted per donor (OTPD). METHODS: This is a retrospective cohort analysis of all patients referred to a single organ procurement organization for a period of 60 months. RESULTS: Patients referred for organ donation evaluation from the ED were more likely to become organ donors than patients referred from the intensive care unit (19.3% vs 5.2%, P < .001). ED referrals had a greater number of OTPD than those referred from the intensive care unit (mean 3.79 vs 3.16, P = .024), even after adjusting for the higher proportion of ED referrals who were trauma patients (P = .001). CONCLUSIONS: Referral for organ donation from the ED is associated with an increased likelihood of organ recovery and with an increased number of OTPD. PMID- 24791636 TI - Outcomes associated with Interstim therapy for medically refractory fecal incontinence. AB - BACKGROUND: Fecal incontinence is a common, socially debilitating disorder. Initial management involves dietary manipulation with bulking agents or antidiarrheal medications and pelvic floor biofeedback. For patients failing these modalities, traditional surgical approaches are morbid and of variable efficacy. Sacral nerve neuromodulation (Interstim, sacral nerve stimulation) was approved in May 2011 for management of medically refractory fecal incontinence. This report summarizes our experience with this treatment modality. METHODS: A prospectively maintained database from a colorectal specialty practice was reviewed from December 2011 to June 2013. Patient demographics, incontinence etiology, and medical treatment regimens were reviewed. Outcomes for Interstim placement and surgical morbidity were reviewed. RESULTS: A total of 330 patients were evaluated in the clinic for fecal incontinence during the study period. A total of 33 patients (10%) were offered Interstim therapy. The mean age was 63 (39 to 91) years, and 91% (30 of 33) were female. The etiology of the incontinence was obstetric (81%), rectal prolapse (11%), neurogenic (5%), and iatrogenic (3%). The entire group failed either supplemental fiber or antidiarrheal medications and 73% (24 of 33) failed pelvic floor biofeedback. The mean number of bowel accidents/2-week bowel diary before implant was 19 (9 to 52). After phase I implant, 88% (29 of 33) experienced a successful test phase and proceeded to phase II permanent implant. The mean number of bowel accidents/2 week diary postimplant was 3 (0 to 12). A trend toward less severe episodes of incontinence postimplant was observed. There were no complications associated with either the phase I or phase II implant. There were no phase II failures although 1 patient underwent device explant 9 months after phase II implant for chronic pain. CONCLUSIONS: Sacral nerve neuromodulation (Interstim, sacral nerve stimulation) is an effective and efficacious tool for management of medically refractory fecal incontinence that offers a less morbid surgical approach to this problem. Interstim should be considered the first-line surgical approach for medically refractory fecal incontinence. PMID- 24791637 TI - Mesenteric irritation as a means to prevent internal hernia formation after laparoscopic gastric bypass surgery. AB - INTRODUCTION: Internal hernias (IHs) occur more frequently in laparoscopic gastric bypass (LGB) surgery than in the classic open procedure. The incidence of small bowel obstruction after LGB ranges from 1.8% and 9.7%. Some have theorized that this occurs because of decreased adhesion formation. METHODS: The mesenteric irritation technique is performed after closure of the jejunojejunal mesenteric defect with a running 2-0 silk suture. A sponge is then rubbed against the closed visceral peritoneal mesentery until petechiae are visualized on the surface of the mesentery. RESULTS: In all, 338 LGBs were performed using the standard closure technique with an IH incidence of 5.3% (range 1.7% to 7.8%). When using the mesenteric irritation technique, 72 LGBs were performed with an IH rate of 1.4% (P = .13). CONCLUSIONS: Mesenteric irritation is a novel technique performed with minimal additional time and no additional equipment. This technique may prove beneficial in reducing the incidence of IHs. PMID- 24791638 TI - The cost of bariatric medical tourism on the Canadian healthcare system. AB - BACKGROUND: Medical tourists are defined as individuals who intentionally travel from their home province/country to receive medical care. Minimal literature exists on the cost of postoperative care and complications for medical tourists. The costs associated with these patients were reviewed. METHODS: Between February 2009 and June 2013, 62 patients were determined to be medical tourists. Patients were included if their initial surgery was performed between January 2003 and June 2013. A chart review was performed to identify intervention costs sustained upon their return. RESULTS: Conservatively, the costs of length of stay (n = 657, $1,433,673.00), operative procedures (n = 110, $148,924.30), investigations (n = 700, $214,499.06), blood work (n = 357, $19,656.90), and health professionals' time (n = 76, $17,414.87) were summated to the total cost of $1.8 million CAD. CONCLUSIONS: The absolute denominator of patients who go abroad for bariatric surgery is unknown. Despite this, a substantial cost is incurred because of medical tourism. Future investigations will analyze the cost effectiveness of bariatric surgery conducted abroad compared with local treatment. PMID- 24791639 TI - The effect of race on outcomes for appendicitis in children: a nationwide analysis. AB - BACKGROUND: We sought to examine the impact of race on the management and outcomes of appendicitis in children aged 20 years or younger. METHODS: We studied 96,865 inpatient admissions for children undergoing an appendectomy for acute appendicitis in 2009 using the Kids' Inpatient Database. RESULTS: Perforation at presentation was more common among African-Americans and Hispanics than Caucasians (27.5% and 32.5%, respectively, vs 23.9%, P < .001). African Americans were less likely to have a laparoscopic procedure (odds ratio [OR]: .839, P < .001) and more likely to experience a complication (OR: 1.753, P < .001). Hispanics were also more likely to have a complication (OR: 1.123, P = .001). African-Americans and Hispanics remained in the hospital for .73 more days than Caucasians (3.07 vs 2.34 days, P < .001). CONCLUSIONS: African-American and Hispanic children present more often with perforation. Adjusting for perforation, they were more likely to have a complication and longer hospital stays. Access to care and delayed presentations may be potential explanations. PMID- 24791640 TI - Pediatric magnet ingestions: the dark side of the force. AB - BACKGROUND: Pediatric magnet ingestions are increasing. Commercial availability of rare-earth magnets poses a serious health risk. This study defines incidence, characteristics, and management of ingestions over time. METHODS: Cases were identified by searching radiology reports from June 2002 to December 2012 at a children's hospital and verified by chart and imaging review. Relative risk (RR) regressions determined changes in incidence and interventions over time. RESULTS: In all, 98% of ingestions occurred since 2006; 57% involved multiple magnets. Median age was 8 years (range 0 to 18); 0% of single and 56% of multiple ingestions required intervention. Compared with 2007 to 2009, ingestions increased from 2010 to 2012 (RR = 1.9, 95% confidence interval 1.2 to 3.0). Intervention proportion was unchanged (RR = .94, 95% confidence interval .4 to 2.2). Small spherical magnets comprised 26.8% of ingestions since 2010; 86% involved multiple magnets and 47% required intervention. CONCLUSIONS: Pediatric magnet ingestions and interventions have increased. Multiple ingestions prompt more imaging and surgical interventions. Magnet safety standards are needed to decrease risk to children. PMID- 24791641 TI - Preoperative computed tomography does not predict resectability in peritoneal carcinomatosis. AB - BACKGROUND: Obtaining a complete cytoreduction in patients with peritoneal carcinomatosis (PC) is one of the most significant prognostic variables for long term survival. This study explored features on preoperative computed tomography (CT) to predict unresectability. METHODS: A retrospective case-control study was conducted of 15 patients with unresectable PC and 15 patients with completely resected PC matched by intraoperative peritoneal cancer index (PCI) and pathology type. Two surgical oncologists blindly analyzed all abdominopelvic CT scans. RESULTS: PCI estimated on imaging was not higher in unresectable patients (P = .851) and significantly underestimated intraoperative PCI measurement (P = .003). No single concerning feature was associated with unresectability. However, patients with 2 or more concerning features were more likely to be unresectable (87.5% vs 36.4%, P = .035). CONCLUSIONS: Two or more concerning CT imaging features appear to be associated with a higher risk of unresectability in patients with PC. However, no specific imaging feature should exclude a patient from an attempted cytoreduction. PMID- 24791642 TI - The hidden war: humanitarian surgery in a combat zone. AB - BACKGROUND: Humanitarian surgical care (HSC) provided during wartime plays a substantial role in military operations, but has not been described or quantified beyond individual experiences. METHODS: Prospective survey was conducted of all military members deployed to Iraq or Afghanistan between 2002 and 2011. RESULTS: There were 266 responses. On average, surgeons had been in practice for 3 years at their 1st deployment and the majority were not fellowship trained. HSC was performed on all body systems and patient populations, including surgery for malignancy. Although 30% of responders performed surgeries they had never done before as a staff surgeon, 84% felt well prepared by their residency. The majority felt that performing HSC improved unit readiness (60%), benefited local population (64%), and contributed to counterinsurgency operations (54%). CONCLUSION: Over our 10-year period, hundreds of military surgeons performed countless HSC cases in Iraq and Afghanistan and the majority felt that HSC had numerous benefits. PMID- 24791643 TI - Attribution, cognition and psychopathology in persistent insomnia disorder: outcome and mediation analysis from a randomized placebo-controlled trial of online cognitive behavioural therapy. AB - OBJECTIVES: Insomnia patients complain that mental events keep them awake. This study investigates how cognitive behavioural therapy (CBT) affects such events and considers how attributional, cognitive and psychopathological symptoms may mediate sleep improvement. METHOD: A pragmatic, parallel-group randomized controlled trial of 164 adults (120 F: (mean 49 years (18-78 years)) meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for insomnia disorder, assigned to CBT (n=55; 40 F), imagery relief therapy (IRT placebo; n=55; 42 F), or treatment as usual (TAU; n=54; 38 F), was conducted. CBT/IRT comprised six online sessions delivered by an animated therapist, with automated web/e-mail support. CBT users had access to a moderated community. TAU comprised 'usual care'. Participants completed the Sleep Disturbance Questionnaire (SDQ), Glasgow Content of Thoughts Inventory (GCTI), Depression Anxiety and Stress Scales (DASS) and Sleep Condition Indicator (SCI) at baseline, post treatment and 8-week follow-up. RESULTS: The sample was characterised by mental arousal, notably 'trying too hard' to sleep (SDQ), and by 'sleep and sleeplessness' and 'rehearsal and planning' thoughts (GCTI). Treatment effects were observed for all SDQ domains (e.g., CBT vs. IRT: d=0.76 for 'trying too hard'). CBT was also superior to IRT on the GCTI (e.g., 'rehearsal and planning', d=0.62; 'sleep and sleeplessness', d=0.74). CBT vs. TAU comparisons yielded larger effects, whereas placebo effects (IRT vs. TAU) were small to moderate. Hierarchical regression demonstrated partial mediation of SCI improvement by attributional and cognitive factors (R2 = 21-27%) following CBT. Improvement in sleep efficiency appears to be independent of such factors. CONCLUSION: Online CBT modifies sleep-related attributions, night-time thought content and psychopathology. This process partly mediates improvement in DSM-5 defined insomnia. PMID- 24791644 TI - Sleep hygeine: exercise and other 'do's and don'ts'. PMID- 24791645 TI - Iliac venous pressure estimates central venous pressure after laparotomy. AB - BACKGROUND: Central venous pressure (CVP) is traditionally obtained through subclavian or internal jugular central catheters; however, many patients who could benefit from CVP monitoring have only femoral lines. The accuracy of illiac venous pressure (IVP) as a measure of CVP is unknown, particularly following laparotomy. METHODS: This was a prospective, observational study. Patients who had both internal jugular or subclavian lines and femoral lines already in place were eligible for the study. Pressure measurements were taken from both lines in addition to measurement of bladder pressure, mean arterial pressure, and peak airway pressure. Data were evaluated using paired t-test, Bland-Altman analysis, and linear regression. RESULTS: Measurements were obtained from 40 patients, 26 of which had laparotomy. The mean difference between measurements was 2.2 mm Hg. There were no significant differences between patients who had laparotomy and nonsurgical patients (P = 0.93). Bland-Altman analysis revealed a bias of 1.63 +/ 2.44 mm Hg. There was no correlation between IVP accuracy and bladder pressure, mean arterial pressure, or peak airway pressure. CONCLUSIONS: IVP is an adequate measure of CVP, even in surgical patients who have had recent laparotomy. Measurement of IVP to guide resuscitation is encouraged in patients who have only femoral venous catheter access. PMID- 24791646 TI - D-dimer levels remain elevated in acute aortic dissection after 24 h. AB - BACKGROUND: D-dimer levels are elevated in patients with acute aortic dissection (AAD). Although D-dimer levels have been used to rule out AAD within 24 h of symptom onset, it is unknown whether they may be used reliably after 24 h but within the acute period. Here, we tested the hypothesis that D-dimer levels remain elevated in AAD patients for at least 10 d after dissection onset. MATERIALS AND METHODS: D-dimer levels were measured in preoperative heparinized plasma samples from 100 patients with confirmed AAD for up to 10 d after onset of dissection. When possible, serial samples were obtained for >=2 d. D-dimer levels were measured in fibrinogen equivalent units using a BCS XP automated coagulation analyzer, which is approved for citrated samples. Therefore, we first validated our samples by comparing D-dimer levels in heparinized and citrated plasma samples from 29 individuals, including patients with and without aortic disease and healthy donors. RESULTS: The correlation between heparinized and citrated plasma samples was 0.991 (P <= 0.001). At a threshold of 1.6 MUg/mL, the overall sensitivity of the D-dimer assay in AAD patients up to 10 d after onset of dissection was 95.3%. CONCLUSIONS: D-dimer levels remained elevated in AAD patients over a 10-d period after dissection onset and may be helpful in ruling out AAD in patients who seek treatment after the first 24 h but within the acute period. Heparinized plasma samples may be substituted for citrated samples when evaluating D-dimer levels using the BCS XP coagulation analyzer. PMID- 24791647 TI - Peroxygenase and oxidase activities of dehaloperoxidase-hemoglobin from Amphitrite ornata. AB - The marine globin dehaloperoxidase-hemoglobin (DHP) from Amphitrite ornata was found to catalyze the H2O2-dependent oxidation of monohaloindoles, a previously unknown class of substrate for DHP. Using 5-Br-indole as a representative substrate, the major monooxygenated products were found to be 5-Br-2-oxindole and 5-Br-3-oxindolenine. Isotope labeling studies confirmed that the oxygen atom incorporated was derived exclusively from H2O2, indicative of a previously unreported peroxygenase activity for DHP. Peroxygenase activity could be initiated from either the ferric or oxyferrous states with equivalent substrate conversion and product distribution. It was found that 5-Br-3-oxindole, a precursor of the product 5-Br-3-oxindolenine, readily reduced the ferric enzyme to the oxyferrous state, demonstrating an unusual product-driven reduction of the enzyme. As such, DHP returns to the globin-active oxyferrous form after peroxygenase activity ceases. Reactivity with 5-Br-3-oxindole in the absence of H2O2 also yielded 5,5'-Br2-indigo above the expected reaction stoichiometry under aerobic conditions, and O2-concentration studies demonstrated dioxygen consumption. Nonenzymatic and anaerobic controls both confirmed the requirements for DHP and molecular oxygen in the catalytic generation of 5,5'-Br2-indigo, and together suggest a newly identified oxidase activity for DHP. PMID- 24791648 TI - Acute renal failure according to the RIFLE and AKIN criteria: a multicenter study. AB - OBJECTIVE: To determine the incidence of acute renal failure (ARF) in critically ill patients using the RIFLE and AKIN criteria. DESIGN: A prospective, multicenter observational study with a duration of one year from February 2010 was carried out. RIFLE and AKIN were employed using the urinary (UC) and creatinine criteria (CC) jointly and separately. SCOPE: Nine polyvalent Critical Care Units (CCUs) in Argentina. PATIENTS: A total of 627 critical patients over 18 years of age were admitted to the CCU for more than 48h. EXCLUSION CRITERIA: inability to quantify diuresis, surgical instrumentation of the urinary tract, and need for renal support therapy (RST). VARIABLES OF INTEREST: Calculated hourly diuresis (CHD) was used to apply the UC. RESULTS: The incidence of ARF was 69.4% and 51.8% according to RIFLE and AKIN, respectively. UC detected ARF in 59.5% of cases, while CC identified ARF in 34.7% (RIFLE) and 25.3% (AKIN). The mortality rate was 40.9% and 44.6% according to RIFLE and AKIN respectively, was significantly higher than in patients without ARF, and increased with disease severity (Data processing: Excel, SQL and SPSS. Levene test, comparison of means with Student t and chi-squared, with 95% confidence interval). CONCLUSIONS: RIFLE identified more cases of ARF. UC proved more effective than CC. The presence of ARF and severity levels were correlated to mortality but not to days of stay in the CCU. Implementation of the unified CHD was useful for implementing UC and achieving comparable results. PMID- 24791649 TI - Multi-parametric MRI of rectal cancer - do quantitative functional MR measurements correlate with radiologic and pathologic tumor stages? AB - PURPOSE: The purpose of this study is two-fold. First, to evaluate, whether functional rectal MRI techniques can be analyzed in a reproducible manner by different readers and second, to assess whether different clinical and pathologic T and N stages can be differentiated by functional MRI measurements. MATERIALS AND METHODS: 54 patients (38 men, 16 female; mean age 63.2 +/- 12.2 years) with pathologically proven rectal cancer were included in this retrospective IRB approved study. All patients were referred for a multi-parametric MRI protocol on a 3 Tesla MR-system, consisting of a high-resolution, axial T2 TSE sequence, DWI and perfusion imaging (plasma flow -s PFTumor) prior to any treatment. Two experienced radiologists evaluated the MRI measurements, blinded to clinical data and outcome. Inter-reader correlation and the association of functional MRI parameters with c- and p-staging were analyzed. RESULTS: The inter-reader correlation for lymph node (rho 0.76-0.94; p<0.0002) and primary tumor (rho 0.78 0.92; p<0.0001) apparent diffusion coefficient and plasma flow (PF) values was good to very good. PFTumor values decreased with cT stage with significant differences identified between cT2 and cT3 tumors (229 versus 107.6 ml/100ml/min; p=0.05). ADCTumor values did not differ significantly. No substantial discrepancies in lymph node ADCLn values or short axis diameter were found among cN1-3 stages, whereas PFLn values were distinct between cN1 versus cN2 stages (p=0.03). In the patients without neoadjuvant RCT no statistically significant differences in the assessed functional parameters on the basis of pathologic stage were found. CONCLUSION: This study illustrates that ADC as well as MR perfusion values can be analyzed with good interobserver agreement in patients with rectal cancer. Moreover, MR perfusion parameters may allow accurate differentiation of tumor stages. Both findings suggest that functional MRI parameters may help to discriminate T and N stages for clinical decision making. PMID- 24791651 TI - Why and how should we measure disease activity and damage in lupus? AB - The assessment of disease activity and flare and differentiating them from permanent damage in patients with SLE is challenging. The SLEDAI, SLEDAI-2K and SELENA-SLEDAI measure global disease activity. The BILAG measures organ-specific activity. The BILAG better captures the change in the different organs at the expense of complexity. The SRI is a composite index incorporating both BILAG and SLEDAI indices and a physician's global assessment. It has been used in the most recent clinical trials. Damage correlates with prognosis; it is assessed by the SLICC/SDI index. This index scores damage whatever the cause, disease or treatment related, or the consequence of concomitant disease. The disease activity and damage indices do not correlate well with the patient's health related quality of life (HRQoL), the degree of disability or the impact of disease. The impact of the patients' joint disease on their HRQoL is assessed via the HAQ questionnaire and the global health status via the SF-36 index, or one of the more recently described lupus specific quality of life indices [Lupus QoL]. The global assessment instruments and the BILAG index can also be used in children and adolescents with SLE. However, a modified paediatric version of the SLICC/SDI damage index is advised. Many advances have been achieved in disease activity and damage measurement in the past 20 years but the problem of how best to capture flare accurately remains. PMID- 24791652 TI - [Pachydermoperiostosis]. PMID- 24791650 TI - Candidate SNP associations of optimism and resilience in older adults: exploratory study of 935 community-dwelling adults. AB - OBJECTIVE: Optimism and resilience promote health and well-being in older adults, and previous reports suggest that these traits are heritable. We examined the association of selected single-nucleotide polymorphisms (SNPs) with optimism and resilience in older adults. DESIGN: Candidate gene association study that was a follow-on at the University of California, San Diego, sites of two NIH-funded multi-site longitudinal investigations: Women's Health Initiative (WHI) and SELenium and vitamin E Cancer prevention Trial (SELECT). PARTICIPANTS: 426 women from WHI older than age 50 years, and 509 men older than age 55 years (age 50 years for African American men) from SELECT. MEASUREMENTS: 65 candidate gene SNPs that were judged by consensus, based on a literature review, as being related to predisposition to optimism and resilience, and 31 ancestry informative marker SNPs, genotyped from blood-based DNA samples and self-report scales for trait optimism, resilience, and depressive symptoms. RESULTS: Using a Bonferroni threshold for significant association (p = 0.00089), there were no significant associations for individual SNPs with optimism or resilience in single-locus analyses. Exploratory multi-locus polygenic analyses with p <0.05 showed an association of optimism with SNPs in MAOA, IL10, and FGG genes, and an association of resilience with a SNP in MAOA gene. CONCLUSIONS: Correcting for Type I errors, there were no significant associations of optimism and resilience with specific gene SNPs in single-locus analyses. Positive psychological traits are likely to be genetically complex, with many loci having small effects contributing to phenotypic variation. Our exploratory multi-locus polygenic analyses suggest that larger sample sizes and complementary approaches involving methods such as sequence-based association studies, copy number variation analyses, and pathway-based analyses could be useful for better understanding the genetic basis of these positive psychological traits. PMID- 24791653 TI - [Facial nerve paralysis secondary to acute otitis media]. AB - OBJECTS: To discuss clinical presentation and therapeutic approaches of facial paralysis in acute otitis media. METHODS: We present five cases of facial palsy in children with acute otitis media managed in our ENT department during a period of 12 years (2001-2012). RESULTS: The mean age was 14.2 years; sex ratio was 0.66. All patients presented with a facial asymmetry, but only 3 of them had otalgia before the onset of facial asymmetry. The facial palsy delay was 3.3 days. The ear examination showed that the tympanic membrane was congestive in 4 patients, associated with a bulging in 2 patients, and a small perforation in one patient. Our patients presented grade III to IV initial facial palsy according to House and Brackmann staging. Computed tomography scan revealed a dehiscence of the bony facial canal in one patient. Antibiotic therapy associated with intravenous corticosteroids was administered in all patients. All patients underwent a facial kinesis therapy. A progressive improvement of facial palsy was observed in 4 patients and complete recovery of facial function in one case. DISCUSSION: Conservative treatment associating intravenous antibiotic and corticosteroids with or without myringotomy is the standard approach. PMID- 24791654 TI - Timing and diversity of complementary food introduction for prevention of allergic diseases. How early and how much? AB - The timing of the introduction of complementary foods appears crucial to the development of allergic diseases later in life. The results from recent observational studies might be misinterpreted to suggest that introducing complementary food prior to the age of four months might have a beneficial effect on the induction of immune tolerance. Since these two recently published papers cannot completely account for reverse causation, as is the case for all observational studies, we recommend that the current ESPGHAN and American Academy of Pediatrics recommendations be maintained as long as new evidence from large randomized controlled intervention trials do not suggest otherwise. That is, complementary foods should be first introduced between the age of 17 to 26 weeks. PMID- 24791656 TI - Personality disorders are important risk factors for disability pensioning. AB - PURPOSE: To determine whether personality disorders (PDs) are associated with increased risk of disability pensioning in young adults, independent of other common mental disorders. METHODS: 2,770 young adults from the general population were assessed for PDs by the Structured Interview for DSM-IV Personality, and for common mental disorders by the Composite of International Diagnostic Interview. These data were linked to the Norwegian National Insurance Administration's recordings of disability benefits for a 10-year period. Logistic regression analyses were applied to investigate the association between PDs and disability pensioning. The analyses were conducted for three types of PD measures: categorical diagnoses (any PD), dimensional scores of individual PDs and higher order components retrieved by principal component analyses. RESULTS: Having any PD was strongly associated with disability pensioning, regardless of disability diagnosis. The estimated odds ratio (OR) was substantially higher for PDs [OR 4.69 (95% confidence interval (CI) 2.6-8.5)] than for mood disorders [OR 1.3 (CI 0.7-2.3)] and anxiety disorders [OR 2.3 (CI 1.3-4.3)]. Measured dimensionally, all PD traits except antisocial traits were significantly associated with disability pensioning. After adjusting for co-occurring traits of other PDs, only schizoid, dependent and borderline PD traits showed a significant positive association with disability pension, while antisocial traits showed a significant negative association. The principal component analyses showed that negative affectivity, psychoticism, and detachment was associated with an increased risk of disability pensioning, while antagonism/disinhibition and obsessivity were not. CONCLUSIONS: PDs are strongly associated with disability pensioning in young adults, and might be more important predictors of work disability than anxiety and depressive disorders. Certain aspects of pathologic personalities are particularly important predictors of disability. PMID- 24791655 TI - The role of commensal bacteria in the regulation of sensitization to food allergens. AB - The prevalence of life-threatening anaphylactic responses to food is rising at an alarming rate. The emerging role of the gut microbiota in regulating food allergen sensitization may help explain this trend. The mechanisms by which commensal bacteria influence sensitization to dietary antigens are only beginning to be explored. We have found that a population of mucosa-associated commensal anaerobes prevents food allergen sensitization by promoting an IL-22-dependent barrier protective immune response that limits the access of food allergens to the systemic circulation. This early response is followed by an adaptive immune response mediated in part by an expansion of Foxp3(+) Tregs that fortifies the tolerogenic milieu needed to maintain non-responsiveness to food. Bacterial metabolites, such as short-chain fatty acids, may contribute to the process through their ability to promote Foxp3(+) Treg differentiation. This work suggests that environmentally induced alterations of the gut microbiota offset the regulatory signals conferred by protective bacterial species to promote aberrant responses to food. Our research presents exciting new possibilities for preventing and treating food allergies based on interventions that modulate the composition of the gut microbiota. PMID- 24791657 TI - Bipolar disorder and parental psychopathology. AB - PURPOSE: Few population-based studies have examined the association between parental psychopathology and bipolar disorder (BPD) in offspring. One limitation is lack of control for potential confounding by indicators of parental socio economic status or maternal smoking during pregnancy. Furthermore, none of them included analyses restricted to parental diagnoses received prior to the birth of the offspring. Associations could not be affected by child-related factors affecting the parent in such analyses. This study explores associations between those parental psychiatric disorders diagnosed at any point of time as well as those diagnosed before offspring birth, and BPD in offspring. METHODS: In this nested case-control study, we identified 1,861 cases, age up to 25 years, 3,643 matched controls, and their parents from Finnish national registers. The associations were examined using conditional logistic regression, calculating odds ratios (OR) and adjusting for region of birth, parental age and education and mother's smoking during pregnancy. RESULTS: Anytime diagnosed parental disorders associating with BPD in offspring (95% confidence interval) were BPD [OR (maternal) 5.2 (2.52-10.62); OR (paternal) 8.1 (3.77-17.26)], schizophrenia and related psychoses [OR (maternal) 3.1 (1.69-5.84); OR (paternal) 4.5 (1.97 10.27)], other affective disorders [OR (maternal) 3.0 (2.08-4.21); OR (paternal) 3.0 (1.97-4.47)] and maternal anxiety disorders OR 2.6 (1.08-6.42). Statistically significant associations were also found for parental schizophrenia and related psychoses, and other affective disorders, diagnosed before offspring birth. CONCLUSIONS: BPD is associated with many parental psychiatric disorders, particularly BPD and schizophrenia and related psychoses. The associations must be partially due to child-independent factors. Covariate adjustments had only a minor impact on the associations. PMID- 24791659 TI - Sepsis? Outcomes? Administration? PMID- 24791658 TI - Self-reported social anxiety symptoms and correlates in a clinical (CAP) and a community (Young-HUNT) adolescent sample. AB - PURPOSE: The frequencies of social anxiety symptoms in a mental health clinical and a community sample of adolescents are compared. Also, we explore if adolescents can be classified in subgroups based on social anxiety symptoms. Associations between social anxiety symptoms and coexisting problems and sociodemographic characteristics are examined. METHODS: Adolescent participants, aged 13-18, in two large Norwegian studies, consisting of a clinical (n = 694, 42.1% participation rate, 55% girls, mean age = 15.6) and a community (n = 7,694, 73.1% participation rate, 51% girls, mean age = 15.8) sample completed identical self-report questionnaires measuring social anxiety and related variables. RESULTS: Median sum scores (interquartile range) of social anxiety symptoms were higher among girls than boys and in the clinical [girls = 16 (12-22); boys = 12 (9-16)] compared to the community sample [girls = 12 (9-15); boys = 10 (7-12)] (p < 0.001). Latent profile analysis revealed two classes of adolescents based on social anxiety profiles. Adolescents scoring high on social anxiety symptoms, which ranged from 16% (boys in community sample) to 40% (girls in clinical sample), had significantly more coexisting problems than those scoring low. Social anxiety symptoms were associated with academic school problems, bullying, eating problems, acne, and general anxiety and depression in both samples. CONCLUSION: Social anxiety symptoms were commonly reported by adolescents, in both clinical and community settings. These symptoms were associated with a broad spectrum of coexisting problems, which can be used to detect adolescents struggling with social anxiety. Adolescent, family, peer, school, and community interventions targeting these associated problems may contribute to prevent and alleviate social anxiety symptoms. PMID- 24791660 TI - The 4Ts test in the critically ill: timing is everything. PMID- 24791661 TI - Cannula for retrograde cardioplegia under direct vision. PMID- 24791662 TI - The use of gastrointestinal cocktail for differentiating gastro-oesophageal reflux disease and acute coronary syndrome in the emergency setting: a systematic review. AB - BACKGROUND: Differentiating acute chest pain caused by myocardial ischaemia from other, potentially more benign causes of chest pain is a frequent diagnostic challenge faced by Emergency Department (ED) clinicians. Only 30% of patients presenting with chest pain will have a cardiac origin for the pain, and gastro oesophageal disorders are one of the common sources of non-cardiac chest pain, yet remain clinically difficult to differentiate from cardiac pain. AIM: A systematic review of the literature was conducted to locate and evaluate clinical trials comparing the use of an oral gastrointestinal (GI) cocktail (oral viscous lidocaine/ antacid +/- anticholinergic) to standard diagnostic protocols (serial electrocardiograms (ECGs), serial biomarkers, imaging and/ or provocative testing) to differentiate emergency patients presenting with acute chest pain caused by gastro-oesophageal disease from those with other aetiologies. METHODS: Studies were identified by searching electronic databases, scanning reference lists of articles, and searching clinical trial databases for relevantly currently registered trials. The search included PubMed (1966 - present), Embase (1980 - present) and Cochrane Central Register of Controlled Trials (CENTRAL). The identified studies were evaluated with a modified QUADAS tool. RESULTS: A total of four studies were identified for inclusion in the review. Studies were of low methodological quality with heterogeneous results. There were no adequately powered and appropriately designed studies identified. DISCUSSION: Current diagnostic protocols for Acute Coronary Syndrome (ACS) revolve around early and serial ECG monitoring and cardiac biomarker testing, imaging and careful clinical examination. In patients with chest pain and suspected ACS, the use of a GI cocktail compared with standard diagnostic protocols (serial ECG and biomarkers and provocative testing or imaging) is not proven to improve accuracy of diagnosis, and cannot reliably exclude myocardial ischaemia. PMID- 24791663 TI - Transcatheter mitral valve repair in osteogenesis imperfecta associated mitral valve regurgitation. AB - OBJECTIVES: Osteogenesis imperfecta is associated with increased prevalence of significant mitral valve regurgitation. Surgical mitral valve repair and replacement are feasible but are associated with increased risk of bleeding and dehiscence of implanted valves may occur more frequently. The present case report describes the outcomes of transcatheter mitral valve repair in a patient with osteogenesis imperfecta. PATIENTS/METHODS: A 60 year-old patient with osteogenesis imperfecta and associated symptomatic moderate to severe mitral regurgitation underwent transthoracic echocardiography which showed a nondilated left ventricle with preserved systolic function and moderate to severe mitral regurgitation. On transoesophageal echocardiography the regurgitant jet originated between the anterolateral scallops of the anterior and posterior leaflets (A1-P1). Considering the comorbidities associated with osteogenesis imperfecta the patient was accepted for transcatheter mitral valve repair using the Mitraclip device (Abbott vascular, Menlo, CA). RESULTS: Under fluoroscopy and 3D transoesophageal echocardiography guidance, a Mitraclip device was implanted between the anterolateral and central scallops with significant reduction of mitral regurgitation. The postoperative evolution was uneventful. At one month follow-up, transthoracic echocardiography showed a stable position of the Mitraclip device with no mitral regurgitation. CONCLUSIONS: Transcatheter mitral valve repair is feasible and safe in patients with osteogenesis imperfecta and associated symptomatic significant mitral regurgitation. PMID- 24791664 TI - Predictability and heritability of individual differences in fear learning. AB - Our objective was to characterize individual differences in fear conditioning and extinction in an outbred rat strain, to test behavioral predictors of these individual differences, and to assess their heritability. We fear-conditioned 100 Long-Evans rats, attempted to extinguish fear the next day, and tested extinction recall on the third day. The distribution of freezing scores after fear conditioning was skewed, with most rats showing substantial freezing; after fear extinction, the distribution was bimodal with most rats showing minimal freezing, but a substantial portion showing maximal freezing. Longer rearing episodes measured prior to conditioning predicted less freezing at the beginning of extinction, but differences in extinction learning were not predicted by any baseline exploratory behaviors. We tested the heritability of extinction differences by breeding rats from the top and bottom 20% of freezing scores during extinction recall. We then ran the offspring through the same conditioning/extinction procedure, with the addition of recording ultrasonic vocalizations throughout training and testing. Only a minority of rats emitted distress vocalizations during fear acquisition, but the incidence was less frequent in the offspring of good extinguishers than in poor extinguishers or randomly bred controls. The occurrence of distress vocalizations during acquisition predicted higher levels of freezing during fear recall regardless of breeding line, but the relationship between vocalization and freezing was no longer evident following extinction training, at which point freezing levels were influenced only by breeding and not by vocalization. The heritability (h(2)) of extinction recall was estimated at 0.36, consistent with human estimates. PMID- 24791665 TI - Health, cultural and socioeconomic factors related to self-rated health of long term Jewish residents, immigrants, and Arab women in midlife in Israel. AB - Self-rated health (SRH) has been found to predict future health, yet its importance is unique in the information it captures, beyond more objective measures. This information can include psychosocial and cultural factors that can be important in understanding women's health. Our goal was to test whether long term Jewish residents (LTJR), immigrant, and Arab women differed in their SRH, whether these differences were maintained after controlling for indicators of health status, and, if so, whether the differences among the three groups reflected psychosocial or socioeconomic factors. A nationally representative sample of 814 women in Israel aged 45-64 years was interviewed (between June 2004 and March 2006) regarding socio-demographics, physical health, health behaviors, and psychosocial aspects. Both immigrant and Arab women reported poorer SRH, physical and mental health, and socioeconomic status. Differences between Arab women and LTJR were mostly explained by differences in health measures (e.g., medications and symptoms) and psychosocial measures (e.g., caregiving load and depressive symptoms) and were eliminated when socioeconomic measures were added to the multiple regression models. Differences in SRH between immigrants and LTJR remained after multiple adjustments, suggesting that they reflected unmeasured cultural factors. Even with universal healthcare coverage in a small country (i.e., with minimal financial and geographical barriers to healthcare) minority groups' health suffers in relation to their socioeconomic and life circumstances. PMID- 24791666 TI - Dieulafoy lesion of the appendix. PMID- 24791667 TI - Superior mesenteric artery syndrome. PMID- 24791668 TI - Late complications after proctectomy in rectal cancer patients who underwent radiotherapy. AB - BACKGROUND: Radiotherapy for advanced rectal cancer is an important treatment to reduce local recurrence. OBJECTIVE: The purpose of this study was to identify the late structural changes of pelvis and adverse effects after radiotherapy for rectal cancer. METHODS: Between January 2000 and December 2009, we performed a single-center case-control study with 687 patients who underwent curative treatments for rectal cancer. A radiotherapy group (RTX) and a non-radiotherapy group (NRTX) were compared. Of the 687 patients, 207 cases in the RTX group were identified, and 207 controls for the NRTX group were selected for analysis. Each case had one control matched for age (+/-5 y), sex, tumor location, and operation type. All instances of radiotherapy were performed as long-course treatment methods (45.0-50.4 Gy) with concurrent 5-fluorouracil (5-FU)-based chemotherapy. Late complications were usually assessed as structural changes of the pelvic organ based on physical examination or radiologic or endoscopic findings 6 months after the rectal resection or pelvic radiation. RESULTS: In terms of overall complications, the RTX group (N = 45, 21.7 %) experienced more frequent complications than the NRTX group (N = 25, 12.1 %, p = 0.009). In particular, anastomosis-related complications were more common in the RTX group (9.2 %) than in the NRTX group (2.4 %, p = 0.003). Successful treatment after late complications in the RTX group (33.3 %) was less likely than in the NRTX group (70.0 %, p = 0.010). Late complications in the RTX group gradually increased with time (11.6 % at 2 y, 17.9 % at 3 y, 19.8 % at 4 y) at a higher rate than in the NRTX group (6.8 % at 2 y, 10.6 % at 3 y, 10.6 % at 4 y, p = 0.009). CONCLUSIONS: Radiotherapy for rectal cancer patients may induce late pelvic complications as time progresses, and irreversible tissue changes due to radiation could disrupt the successful treatment of radiation-related complications. PMID- 24791669 TI - Emergency management in patients with late hemorrhage after pancreatoduodenectomy for a periampullary tumor. AB - BACKGROUND: The mortality rate due to late hemorrhage after surgery for periampullary tumors is high, especially in patients with anastomotic leakage. Patients usually require emergency intervention for late hemorrhage. In this study patients with late hemorrhage and their outcomes were analyzed. Furthermore, independent predictors for late hemorrhage, the need for emergency intervention, and type of intervention are reported. METHODS: From a prospective database that includes 1,035 patients who underwent pancreatoduodenectomy for periampullary tumors between 1992 and 2012, patients with late hemorrhage (>24 h after index operation) were identified. Patient, disease-specific, and operation characteristics, type of intervention, and outcomes were analyzed. Emergency intervention was defined as surgical or radiological intervention in hemodynamically unstable patients. RESULTS: Of the 47 patients (4.5 %) with late hemorrhage, pancreatic fistula was an independent predictor for developing late hemorrhage (OR 10.2). The mortality rate in patients with late hemorrhage was 13 % compared with 1.5 % in all patients without late hemorrhage. Twenty patients required emergency intervention; 80 % underwent primary radiological intervention and 20 % primary surgical intervention. Extraluminal location of the bleeding (OR 5.6) and occurrence of a sentinel bleed (OR 6.6) are indications for emergency intervention. CONCLUSION: The type of emergency intervention needed for late hemorrhage is unpredictable. Radiological intervention is preferred, but if it fails, immediate change to surgical treatment is mandatory. This can be difficult to manage but possible when both radiological and surgical interventions are in close proximity such as in a hybrid operating room and should be considered in the emergency management of patients with late hemorrhage. PMID- 24791670 TI - Papillary thyroid microcarcinoma: an over-treated malignancy? AB - BACKGROUND: The clinical importance of papillary thyroid microcarcinoma (PTMC) remains controversial, with current guidelines suggesting that thyroid lobectomy alone is sufficient. The purpose of this study was to identify population-level treatment patterns in the USA for PTMC. METHODS: Patients with PTMC in SEER (1998 2010) were included; demographic, clinical (extent of surgery, administration of post-operative radioactive iodine [RAI]), and pathologic characteristics were examined. Outcomes of interest were 5- and 10-year overall survival (OS) and disease-specific survival (DSS). RESULTS: The cohort consisted of 29,512 patients. Mean age at diagnosis was 48.5 years; mean tumor size was 0.53 cm. Overall, 73.4 % of patients underwent total thyroidectomy, and RAI was administered to 31.3 %. In multivariate analysis, total thyroidectomy was more frequently performed in patients with multifocal (odds ratio [OR] 2.55), 'regional', or 'distant' PTMC (OR 2.90 and 2.59). Non-operative management was associated with male patients (OR 4.24) and those aged >=65 years (OR 6.31). Post operative RAI was associated with multifocal PTMC (OR 2.57). Overall, 5- and 10 year DSS was 99.6 and 99.3 %, respectively, with no difference in DSS between patients who underwent partial versus total thyroidectomy. OS of patients with PTMC who underwent any thyroid operation was similar to that of the general population of the USA. CONCLUSIONS: An increasing number of patients are undergoing total thyroidectomy and RAI for PTMC. While there may be a subset of patients for whom more aggressive therapy is indicated, many patients with PTMC may be over-treated, with no demonstrable benefit to survival. PMID- 24791671 TI - Invited commentary on Melin et al. (doi: 10.1007/s00268-013-2260-x). PMID- 24791672 TI - Quality of life after surgical treatment of early Barrett's cancer: a prospective comparison of the Ivor-Lewis resection versus the modified Merendino resection. A statistical hint. PMID- 24791673 TI - Prevention of inguinodynia: the need for continuous refinement and quality improvement in inguinal hernia repair. PMID- 24791674 TI - Dynamics of microbial communities in untreated and autoclaved food waste anaerobic digesters. AB - This study describes the microbial community richness and dynamics of two semi continuously stirred biogas reactors during a time-course study of 120 days. The reactors were fed with untreated and autoclaved (160 degrees C, 6.2 bar) food waste. The microbial community was analysed using a bacteria- and archaea targeting 16S rRNA gene-based Terminal-Restriction Fragment Length Polymorphism (T-RFLP) approach. Compared with the archaeal community, the structures and functions of the bacterial community were found to be more complex and diverse. With the principal coordinates analysis it was possible to separate both microbial communities with 75 and 50% difference for bacteria and archaea, respectively, in the two reactors fed with the same waste but with different pretreatment. Despite the use of the same feeding material, anaerobic reactors showed a distinct community profile which could explain the differences in methane yield (2-17%). The community composition was highly dynamic for bacteria and archaea during the entire studied period. This study illustrates that microbial communities are dependent on feeding material and that correlations among specific bacterial and archaeal T-RFs can be established. PMID- 24791675 TI - Scalable approximate policies for Markov decision process models of hospital elective admissions. AB - OBJECTIVE: To demonstrate the feasibility of using stochastic simulation methods for the solution of a large-scale Markov decision process model of on-line patient admissions scheduling. METHODS: The problem of admissions scheduling is modeled as a Markov decision process in which the states represent numbers of patients using each of a number of resources. We investigate current state-of-the art real time planning methods to compute solutions to this Markov decision process. Due to the complexity of the model, traditional model-based planners are limited in scalability since they require an explicit enumeration of the model dynamics. To overcome this challenge, we apply sample-based planners along with efficient simulation techniques that given an initial start state, generate an action on-demand while avoiding portions of the model that are irrelevant to the start state. We also propose a novel variant of a popular sample-based planner that is particularly well suited to the elective admissions problem. RESULTS: Results show that the stochastic simulation methods allow for the problem size to be scaled by a factor of almost 10 in the action space, and exponentially in the state space. We have demonstrated our approach on a problem with 81 actions, four specialities and four treatment patterns, and shown that we can generate solutions that are near-optimal in about 100s. CONCLUSION: Sample-based planners are a viable alternative to state-based planners for large Markov decision process models of elective admissions scheduling. PMID- 24791676 TI - De-identification of health records using Anonym: effectiveness and robustness across datasets. AB - OBJECTIVE: Evaluate the effectiveness and robustness of Anonym, a tool for de identifying free-text health records based on conditional random fields classifiers informed by linguistic and lexical features, as well as features extracted by pattern matching techniques. De-identification of personal health information in electronic health records is essential for the sharing and secondary usage of clinical data. De-identification tools that adapt to different sources of clinical data are attractive as they would require minimal intervention to guarantee high effectiveness. METHODS AND MATERIALS: The effectiveness and robustness of Anonym are evaluated across multiple datasets, including the widely adopted Integrating Biology and the Bedside (i2b2) dataset, used for evaluation in a de-identification challenge. The datasets used here vary in type of health records, source of data, and their quality, with one of the datasets containing optical character recognition errors. RESULTS: Anonym identifies and removes up to 96.6% of personal health identifiers (recall) with a precision of up to 98.2% on the i2b2 dataset, outperforming the best system proposed in the i2b2 challenge. The effectiveness of Anonym across datasets is found to depend on the amount of information available for training. CONCLUSION: Findings show that Anonym compares to the best approach from the 2006 i2b2 shared task. It is easy to retrain Anonym with new datasets; if retrained, the system is robust to variations of training size, data type and quality in presence of sufficient training data. PMID- 24791677 TI - Effect of the F508del genotype on outcomes of endoscopic sinus surgery in children with cystic fibrosis. AB - OBJECTIVE: Numerous authors have sought to describe genotype-phenotype correlations in cystic fibrosis (CF), notably to pancreatic insufficiency and lung disease. However, few studies have focused on the association between the F508del genotype and response to sinus surgery. The objective of this study is to assess the effect of the F508del genotype on sinonasal disease severity and outcomes following functional endoscopic sinus surgery (FESS) in a pediatric population. METHODS: A retrospective chart review of 153 children with CF seen at a tertiary care pediatric hospital from 1995 to 2008 was performed. Patients were classified into one of three groups according to F508del genotype, either as homozygous, heterozygous or not carrying a F508del mutation. The sinonasal disease phenotype of the three groups was compared based on clinical and radiological findings, extent of endoscopic sinus surgery and rate of revision surgery. RESULTS: The relationship between the F508del genotype and pancreatic insufficiency was confirmed (p<0.05). There was no association between the F508del genotype and increased need for FESS (p=0.75). Moreover, no association was established between F508del homozygosity and presence of nasal polyps, Lund Mackay score, extent of surgery or length of postoperative hospitalization. The rates of revision surgery did not differ significantly among the three genotypes analyzed (p=0.59). CONCLUSION: There is no clear association between the F508del genotype and an increased need for FESS, extent of surgery, or revision surgery. Given the phenotypic variability of sinonasal disease in patients with CF, a prospective study is needed to better understand outcomes following FESS and the contribution of gene modifiers to this effect. PMID- 24791678 TI - Clinical assessment of olfactory functions in children who underwent adenotonsillectomy during pre- and post-operative period. AB - OBJECTIVE: The aim of this study was to investigate the changes of both ortho- and retronasal olfactory function in children who underwent adenotonsillectomy (AT) operation due to infectious and/or obstructive adenotonsillar disease. MATERIAL AND METHODS: A total of 25 children with adenotonsillar disease are included in the study; the children were followed for 6 months in the conducted clinics and underwent AT operation. An age- and sex-matched control group was constituted with 25 healthy children free of adenotonsillar disease. Adenoid and tonsillar hypertrophy was graded according to the subjective size scales. Each subject's orthonasal and retronasal olfactory functions were assessed using odor identification test and retronasal olfactory testing. These tests were performed once, at the beginning of the study, for the control group and performed twice, at the beginning of the study and the third month follow-up, for the disease group. Parents of children in the adenotonsillar disease group filled out a visual analog scale to evaluate the children's appetite at the same time with olfactory testing. RESULTS: The current investigation produced four major findings: (1) both ortho- and retronasal olfactory abilities of participants were improving following AT operation, (2) adenoid hypertrophy had a significant negative effect on both ortho- and retronasal olfaction, whereas tonsil hypertrophy had significant negative effect only on the retronasal olfactory score, (3) retronasal olfaction was found to be more affected by the adenoid size than the orthonasal, as shown with correlation analysis, and (4) the increase in appetite of children after AT operation had been specified by parents. CONCLUSIONS: Children with adenotonsillar disease have increased olfaction abilities, namely ortho- and retronasal olfactory function following AT operation. In addition, retronasal olfactory function, an important component of flavor, seems to be more affected than orthonasal function. These results also explain the increased appetite of operated children. PMID- 24791679 TI - The clinical impact of aberrant internal carotid arteries in children. AB - OBJECTIVE: Variations in the course of the internal carotid artery are not rare and likely to be a congenital anomaly. The purpose of this study is to highlight the clinical impact of aberrant internal carotid arteries in children for surgical and interventional procedures in the head and neck. METHODS: Retrospective study of the vessel course in patients under the age of 18 years over a period of 4.5 years. Vessels were classified according to the anatomic classification by Weibel and Fields and related to a previously proposed clinicoradiological risk classification system. Clinical implications are pointed out. RESULTS: Nine patients with a total of 14 aberrations (4 tortuosities, 7 kinkings and 3 coilings) were included. All aberrations were incidental intraoperative or radiological findings; no patient suffered from distinct symptoms. The minimum distance to the pharyngeal wall ranged from 0.8 to 9.0 mm with a mean of 3.8 mm. Anatomic classification and clinical risk of injury did not correlate. CONCLUSIONS: Routine pharyngeal surgery and interventional procedures are usually performed without any preoperative imaging. However, variations in the course of the internal carotid artery may considerably increase the risk of vessel injury and should always be anticipated. PMID- 24791680 TI - Chronic administration of modafinil induces hyperalgesia in mice: reversal by L NG-nitro-arginine methyl ester and 7-nitroindazole. AB - Modafinil [2-((diphenylmethyl) sulfinyl) acetamide] is a central nervous system stimulant. It has received considerable attention as a potential psychotropic agent in several psychiatric disorders. The current study was carried out to investigate the effect of modafinil after acute administration on animal models of pain in mice. Also, this study evaluated the effect of L-NG-nitroarginine methyl ester (L-NAME), 7-nitroindazole (7-NI) and naloxone following chronic administration of modafinil. Modafinil was administered in the doses of 50, 100 or 200 mg/kg once in acute study and it showed significantly increased tail-flick latency (tfl) and paw-licking latency. In formalin test modafinil (100 mg/kg) significantly reduced licking/biting time in both early and late phases in comparison to control. In chronic study, modafinil 100 mg/kg administered for 10 days, produced a progressive decrease in the reaction time (i.e., tfl/paw-licking latency) in comparison to day 1 values which started building up from day 4 and fully established at day 6, indicating hyperalgesic response. Prior administration of 7-NI (on day 7) and L-NAME (on day 10) prevented the hyperalgesic response while naloxone on day 10 did not have a significant effect on modafinil-induced hyperalgesia. These results demonstrate that modafinil has a potential role in pain as it exhibited antinociceptive effect after acute administration in a dose-dependent manner and on chronic administration it caused hyperalgesia. This hyperalgesia is reversed by nitric oxide synthase inhibitors, suggesting the possibility of involvement of nitric oxide pathway. Further studies are required to evaluate the role of modafinil in clinical pain. PMID- 24791681 TI - Assessment of the effect of etomidate on voltage-gated sodium channels and action potentials in rat primary sensory cortex pyramidal neurons. AB - Although it is known that general anesthetics can suppress cortical neurons' activity, the underlying mechanisms are still poorly understood, especially the kinetic changes of voltage-gated Na(+) channels, which are mostly related to neuronal excitability. Some general anesthetics have been reported to affect the voltage-gated Na(+) channels in cell culture derived from humans and animals. However no one has ever investigated the effects of etomidate on voltage-gated Na(+) channels in pyramidal neurons using a brain slice. The present study uses a whole cell patch-clamp technique to investigate the changes of voltage-gated Na(+) channels on primary somatosensory cortex pyramidal neurons under the influence of etomidate. We found that etomidate dose-dependently inhibited Na(+) currents of primary somatosensory cortex pyramidal neurons, while shifted the steady-state inactivation curve towards the left and prolonged the recovery time from inactivation. Conversely, etomidate has no effects on the steady-state activation curve. We demonstrated the detailed suppression process of neural voltage-gated Na(+) channels by etomidate on slice condition. This may offer new insights into the mechanical explanation for the etomidate anesthesia. Finding the effects of anesthetics on primary somatosensory cortex also provides evidence to help elucidate the potential mechanism by which tactile information integrates during general anesthesia. PMID- 24791682 TI - Substance use disorders in hospitalized psychiatric patients: the experience of one psychiatric emergency service in Turin. AB - In the present study we sought: 1) to estimate the frequency of substance use disorders (SUD), and 2) to investigate whether there is a mere association between diagnosis and SUD in a large cohort of patients with severe psychiatric disorders representative of the usual setting and modality of care of a psychiatric emergency service in a geographically well-defined catchment area in Italy, independent of sociodemographic features, anamnestic data and clinical status. The study was conducted between January 2007 and December 2008. The following rating scales were performed: the Clinical Global Impression-Severity (CGI-S), the Global Assessment of Functioning scale (GAF) and the Brief Psychiatric Rating Scale (BPRS). Factors found to be associated (p<0.05) with SUD[+] in the univariate analyses were subjected to multilevel logistic regression model with a backward stepwise procedure. Among 848 inpatients of our sample 29.1% had a SUD codiagnosis. Eleven factors accounted for 30.6% of the variability in SUD[+]: [a] a Personality Disorder diagnosis, [b] a Depressive Disorder diagnosis, [c] male gender, [d] previous outpatient contacts, [e] single marital status, [f] no previous psychiatric treatments, [g] younger age, [h] lower scores for BPRS Anxiety-depression and [i] BPRS Thought Disturbance, [l] higher scores for BPRS Activation and [m] BPRS Hostile-suspiciousness. The findings are important in identifying (1) the complexity of the clinical presentation of SUD in a inpatients sample, (2) the need for collaboration among health care workers, and (3) the need to develop and apply treatment programs that are targeted at particular risk groups. PMID- 24791683 TI - Toronto alexithymia scale for patients with eating disorder: [corrected] performance using the non-parametric item response theory. AB - BACKGROUND: The aim of this study was to investigate the performance of the Toronto Alexithymia Scale (TAS-20) in patients with eating disorders. As a secondary objective, we analyzed a subset of items in order to determine whether the total score is a good tool for classifying these patients and whether the items are ordered according to the difficulty of choosing a particular answer depending on the severity of the patient's condition. SUBJECTS AND METHODS: We administered the TAS-20 to 103 consecutive patients who met DSM-IV-R criteria for anorexia nervosa, bulimia nervosa, or eating disorders not otherwise specified. Mokken scale analysis, nonparametric item response theory (NIRT), and confirmatory factor analysis (CFA) were used to test the psychometric properties of the scale. To improve our understanding of the structure underlying the TAS 20, we used an automated item selection procedure based on the Mokken scale. RESULTS: We identified a subset of 13 independent and clinically interpretable items that are potentially sufficient to rate patients with alexithymia. This subset was considered a unidimensional reduction of the TAS-20. However, the scale composed of this subset needs to be validated. Thirteen of the 20 items were maximally related to alexithymia because they have a one-dimensional structure. The NIRT and CFA enabled us to identify a maximal subset of items that conform to the requirements for good measurement of alexithymia in patients with eating disorders. PMID- 24791684 TI - Towards a unitary perspective between post-traumatic stress disorder and substance use disorder. Heroin use disorder as case study. AB - BACKGROUND: Genetic, neurobiological, environmental and psychosocial mechanisms have received considerable attention in exploring the mechanisms that underlie comorbid PTSD and SUD. PTSD and SUD are not necessarily linked by a causal relationship, as the self-medication hypothesis had supposed. They might, in fact, both be caused by a third factor that predisposes these subjects to develop the two disorders (so allowing a unitary perspective). METHODS: Using a conceptualization of the PTSD spectrum, we studied the PTSD-SUD unitary perspective by testing the correlation between severity of heroin addiction, dose of opioid medication and severity of PTSD spectrum in 82 methadone-treated, heroin-dependent patients. RESULTS: Canonical correlation analysis (Wilks Lambda=0.125F=1.41 p=0.014), univariate and multivariate comparisons between subgroups, identified on the basis of addiction severity, showed a highly positive correlation between the PTSD spectrum and the severity of heroin addiction. In addition, negative correlations were found between PTSD spectrum severity and methadone dose (r=0.225; p=0.042). CONCLUSIONS: This strength and breadth of the correlations encourage us to move towards a unified vision of the two disorders. PMID- 24791685 TI - Anhydrobiosis in yeast: is it possible to reach anhydrobiosis for yeast grown in conditions with severe oxygen limitation? AB - The yeast Saccharomyces cerevisiae was shown to be extremely sensitive to dehydration-rehydration treatments when stationary phase cells were subjected to conditions of severe oxygen limitation, unlike the same cells grown in aerobic conditions. The viability of dehydrated anaerobically grown yeast cells never exceeded 2 %. It was not possible to increase this viability using gradual rehydration of dry cells in water vapour, which usually strongly reduces damage to intracellular membranes. Specific pre-dehydration treatments significantly increased the resistance of anaerobic yeast to drying. Thus, incubation of cells with trehalose (100 mM), increased the viability of dehydrated cells after slow rehydration in water vapour to 30 %. Similarly, pre-incubation of cells in 1 M xylitol or glycerol enabled up to 50-60 % of cells to successfully enter a viable state of anhydrobiosis after subsequent rehydration. We presume that trehalose and sugar alcohols function mainly according to a water replacement hypothesis, as well as initiating various protective intracellular reactions. PMID- 24791686 TI - MicroRNAs and their roles in developmental canalization. AB - Robustness is a fundamental property of biological systems. The type of robustness that ensures uniform phenotypic outcomes in the face of variation during an organism's development is called canalization. Here, we discuss the roles that microRNAs play in providing canalization to animal development, citing recent theoretical and experimental advances. MicroRNAs repress protein expression, and they do this in ways that create thresholds in expression and provide adaptation to regulatory networks. Numerous examples have now been described where the developmental impact of environmental variation is suppressed by individual microRNAs. A recent paper has found that the impact of genomic variation between individuals is similarly suppressed by a microRNA operating in a developmental network. Thus, genetic variability is held in check, which is potentially important for both animal evolution and manifestation of disease. PMID- 24791688 TI - The emerging role of exosomes in Wnt secretion and transport. AB - Exosomes are small extracellular microvesicles that have an endosomal origin and are gaining increasing recognition for their important roles in mediating cell cell communication. The content of exosomes includes a broad range of bioactive molecules, such as miRNA and signaling molecules that can mediate intercellular communication in various functional contexts. Recent studies have pointed to a critical role of exosomes in transmitting morphogen signaling during embryonic development and cancer progression. In this review we focus on recent progress that has revealed a role for exosomes in the secretion and processing of Wnt proteins, a family of morphogens with fundamental roles in homeostasis and cancer. PMID- 24791687 TI - Morphomechanics: transforming tubes into organs. AB - After decades focusing on the molecular and genetic aspects of organogenesis, researchers are showing renewed interest in the physical mechanisms that create organs. This review deals with the mechanical processes involved in constructing the heart and brain, concentrating primarily on cardiac looping, shaping of the primitive brain tube, and folding of the cerebral cortex. Recent studies suggest that differential growth drives large-scale shape changes in all three problems, causing the heart and brain tubes to bend and the cerebral cortex to buckle. Relatively local changes in form involve other mechanisms such as differential contraction. Understanding the mechanics of organogenesis is central to determining the link between genetics and the biophysical creation of form and structure. PMID- 24791689 TI - Compartmentalisation of second messenger signalling pathways. AB - The ability of a cell to transform an extracellular stimulus into a downstream event that directs specific physiological outcomes, requires the orchestrated, spatial and temporal response of many signalling proteins. The notion of compartmentalised signalling pathways was popularised in the 1980s by Brunton and colleagues, with their discovery that spatially segregated cAMP directs a variety of signalling responses in cardiomyocytes. It is now understood that compartmentalisation is a common mechanism used by all cells to ensure the interaction of signalling 'second messenger' molecules with localised 'pools' of appropriate effector proteins. In this way, the cell can elicit differential cellular responses by using a single, freely diffusible, molecular species. Recently, the compartmentalisation schemes employed by signalling systems involving cyclic nucleotides, calcium and nitric oxide have been elucidated and as a result, the varied range of functional consequences underpinned by such strategies can be better appreciated. PMID- 24791690 TI - Feasibility of a first responder programme in rural Bangladesh. AB - OBJECTIVES: To develop and implement a first responder training programme, assess the feasibility of training lay persons with low literacy in rural Bangladesh and determine the acceptability of the programme in the community. METHODS: A first responder training programme including cardiopulmonary resuscitation (CPR) was developed covering 20 villages in a rural sub-district in north-central Bangladesh. 2398 participants received training and 2120 graduated over a 14 month period. Responders were a mix of adolescents, community volunteers and community elders. The programme was evaluated through post-training assessment of knowledge and skills of participants and performance evaluation of trainers. A focus group discussion was used to assess the response of community leaders to usefulness and community acceptance of the programme. RESULTS: Materials developed for training include a low-literacy training manual, posters and a training video. Almost 90 per cent (88.4) of participants qualified in post training assessment. Adolescents and community volunteers had higher pass rates than community elders. In all, CPR skills showed a significant decline over 9 months of assessment, while first aid knowledge appeared stable over the same period. Community leaders considered the programme useful for the community and expressed their support for the programme. CONCLUSION: Developing a first responder training programme that includes CPR in a rural Bangladesh community is feasible if participants have secondary school attainment. Adolescents and young adults are suitable candidates. Evaluation is ongoing to see whether the programme graduates were able to reduce morbidity and mortality through effective first response efforts. PMID- 24791691 TI - Use of target temperature management after cardiac arrest in Germany--a nationwide survey including 951 intensive care units. AB - INTRODUCTION: Target temperature management (TTM) after cardiac arrest is recommended by international guidelines, which have been last updated in 2010. Here we investigate the status of implementation in a nationwide survey in Germany which took place in 2012. METHODS: We conducted a nationwide telephone survey including a total of 951 German intensive care units (ICUs). ICUs were identified by using the online registry for hospitals in Germany. A questionnaire was used for the interview about basic data of the intensive care unit and about details concerning use and implementation of TTM after cardiac arrest. RESULTS: The overall response rate was 91% (865/951). 86% (742/865) of ICUs used TTM after cardiac arrest and implementation peaked in 2010. 95% (702/736) of the ICUs using TTM perform treatment independently of the initial rhythm and 48% (355/738) apply TTM with the use of a feedback device for cooling and controlled re-warming. However, 22% (166/742) still use conventional methods like ice and cold infusion and only 61% (453/742) of the participants provided a written standard operating procedure (SOP). CONCLUSION: With a delay of several years, TTM after cardiac arrest is now implemented in the majority of German ICUs. The moderate proportion of ICUs using SOPs for TTM and feedback-controlled cooling devices indicates the need of further improvement in post cardiac arrest care. PMID- 24791692 TI - Changes over time in delivery room management of extremely low birth weight infants in Italy. AB - AIM: To identify changes in practice between two historical periods (2002 vs. 2011) in early delivery room (DR) management of ELBWI in Italian tertiary centres. METHODS: A questionnaire was sent to the directors of all Italian level III centres between April and August 2012. The same questionnaire was used in a national survey conducted in 2002. Among the participating centres, those that filled the questionnaire in both study periods were selected for inclusion in this study. RESULTS: There was an 88% (n=76/86) and 92% (n=98/107) response rate in the 2 surveys, respectively. The two groups overlapped for 64 centres. During the study period, the use of polyethylene bags/wraps increased from 4.7% to 59.4% of the centres. The units using 100% oxygen concentrations to initiate resuscitation of ELBWI decreased from 56.2% to 6.2%. The approach to respiratory management was changed for the majority of the examined issues: positive pressure ventilation (PPV) administered through a T-piece resuscitator (from 14.0% to 85.9%); use of PEEP during PPV (from 35.9% to 95.3%); use of CPAP (from 43.1% to 86.2%). From 2002 to 2011, the percentages of ELBWI intubated in DR decreased in favor of those managed with N-CPAP; ELBWI receiving chest compressions and medications at birth were clinically comparable. CONCLUSIONS: During the two study periods, the approach to the ELBWI at birth significantly changed. More attention was devoted to temperature control, use of oxygen, and less-invasive respiratory support. Nevertheless, some relevant interventions were not uniformly followed by the surveyed centres. PMID- 24791693 TI - Establishing the importance of human health risk assessment for metals and metalloids in urban environments. AB - Rapid development, industrialisation, and urbanisation have resulted in serious contamination of soil by metals and metalloids from anthropogenic sources in many areas of the world, either directly or indirectly. Exponential urban and economic development has resulted in human populations settling in urban areas and as a result being exposed to these pollutants. Depending on the nature of the contaminant, contaminated urban soils can have a deleterious effect on the health of exposed populations and may require decontamination, recovery, remediation and restoration. Therefore, human health risk assessments in urban environments are very important. In the case of Spain, there are few studies regarding risk assessment of trace elements in urban soils, and those that exist have been derived mainly from areas potentially exposed to industrial contamination or in the vicinity of point pollution. The present study analysed Al, As, Be, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Sn, Ti, Tl, V and Zn soil concentrations in and around the city of Alcala de Henares (35 km NE of Madrid). Soil samples were collected in public parks and recreation areas within the city and in an industrial area on the periphery of the city. From these results, an assessment of the health risk for the population was performed following the methodology described by the US EPA (1989). In general, it was observed that there could be a potential increased risk of developing cancer over a lifetime from exposure to arsenic (As) through ingestion of the soils studied (oral intake), as well as an increased risk of cancer due to inhalation of chromium (Cr) present in re-suspended soils from the industrial area. Our group has previously reported (Granero and Domingo, 2002; Pena-Fernandez et al., 2003) that there was an increased risk of developing cancer following exposure to As in the same soils in a previous study. Therefore, it is necessary to reduce the levels of contaminants in these soils, especially As and Cr as these have been found to exceed safe levels for human health. PMID- 24791694 TI - Gonads and gametogenesis in astigmatic mites (Acariformes: Astigmata). AB - Astigmatans are a large group of mites living in nearly every environment and exhibiting very diverse reproductive strategies. In spite of an uniform anatomical organization of their reproductive systems, gametogenesis in each sex is highly variable, leading to gamete formation showing many peculiar features and emphasizing the distinct position of Astigmata. This review summarizes the contemporary knowledge on the structure of ovaries and testes in astigmatic mites, the peculiarities of oogenesis and spermatogenesis, as well as provides new data on several species not studied previously. New questions are discussed and approaches for future studies are proposed. PMID- 24791695 TI - Gonads in Histiostoma mites (Acariformes: Astigmata): structure and development. AB - The development of male and female gonads in arrhenotokous and thelytokous species of Histiostoma was studied using transmission electron microscopy (TEM). All instars were examined: larvae, protonymphs, facultative heteromorphic deutonymphs (=hypopi), tritonymphs, and adults. In testis primordium, spermatogonia surrounding a testicular central cell (TCC) with a gradually enlarging, branched nucleus are present already at the larval stage. Spermatogonia and the TCC are connected via narrow, tubular intercellular bridges revealing that the TCC is a germline cell. Spermatocytes appear at the protonymphal stage. At the heteromorphic deutonymph stage, the testis primordium is similar to that of the protonymph, but in the tritonymph it is much larger and composed as in the adult: spermatids as well as sperm cells are present. The latter are congregated ventrally in the testis at the entrance of the deferent duct. In the larval ovary, an eccentrically located ovarian nutritive cell (ONC) is surrounded by oogonia which are connected with the ONC via tubular intercellular bridges. In later stages, the ovary grows and oocytes appear in the protonymph. Meiotic synaptonemal complexes in oocytes occur from the tritonymph stage. At about the time of the final molting, tubular intercellular bridges transform into peculiar diaphragm-crossed bridges known only in Histiostoma mites. In the adult female, growing oocytes at the end of previtellogenesis lose intercellular bridges and move ventro-laterally to the ovarian periphery towards the oviduct entrance. Vitellogenesis occurs in oviducts. Germinal cells in both the testis and ovary are embedded in a few somatic stroma cells which may be well discernible already in the larval ovary; in the testis, somatic stroma cells are evident not earlier than the end of the tritonymphal stage. The ovary has a thin wall of flat somatic cells, whereas the testis is covered by a basal lamina only. The obtained results suggest that gonads in Histiostoma and other Astigmata originate from two primordial cells only. PMID- 24791696 TI - Contemporary neurobehavioral genetics. PMID- 24791697 TI - Protein tyrosine phosphatase-PEST (PTP-PEST) regulates mast cell-activating signals in PTP activity-dependent and -independent manners. AB - Aggregation of the high-affinity IgE receptor (FcepsilonRI) in mast cells leads to degranulation and production of numerous cytokines and lipid mediators that promote allergic inflammation. Tyrosine phosphorylation of proteins in response to FcepsilonRI aggregation has been implicated in mast cell activation. Here, we determined the role of PTP-PEST (encoded by PTPN12) in the regulation of mast cell activation using the RBL-2H3 rat basophilic leukemia cell line as a model. PTP-PEST expression was significantly induced upon FcepsilonRI-crosslinking, and aggregation of FcepsilonRI induced the phosphorylation of PTP-PEST at Ser39, thus resulting in the suppression of PTP activity. By overexpressing a phosphatase dead mutant (PTP-PEST CS) and a constitutively active mutant (PTP-PEST SA) in RBL 2H3 cells, we showed that PTP-PEST decreased degranulation and enhanced IL-4 and IL-13 transcription in FcepsilonRI-crosslinked RBL-2H3 cells, but PTP activity of PTP-PEST was not necessary for this regulation. However, FcepsilonRI-induced TNF alpha transcription was increased by the overexpression of PTP-PEST SA and suppressed by the overexpression of PTP-PEST CS. Taken together, these results suggest that PTP-PEST is involved in the regulation of FcepsilonRI-mediated mast cell activation through at least two different processes represented by PTP activity-dependent and -independent pathways. PMID- 24791698 TI - Monocyte subsets in man and other species. AB - Monocytes are white blood cells that belong to the mononuclear phagocyte system. They derive from precursors in bone marrow, from there they go into blood, where they have a half-life of 1-2 days, and then they migrate into the various tissues. Monocyte subsets were discovered by means of flow cytometry in human blood some 20 years ago and their phenotype and function has been characterized in detail in health and disease. The subset classification as classical, intermediate and non-classical monocytes appears to apply to other species as well, as reviewed in here by comparing data on human monocytes with the respective cells in the mouse, the rat, the pig, the cow and the horse. The data show that the subsets are homologous between the species but there are important differences in subset-specific gene expression such that findings in a given species cannot be directly translated to man. PMID- 24791699 TI - Combination of TACI-IgG and anti-IL-15 treats murine lupus by reducing mature and memory B cells. AB - Clinical trials suggest that BAFF inhibitors such as atacicept (TACI-IgG) and belimumab (anti-BAFF antibody) could not reduce memory B-cell numbers, although they reduced the numbers of CD20(+) naive B cells and activated B cells. In the present study, we explored the way to reduce memory B-cell numbers. First, we used TACI-IgG to treat murine lupus. We found that TACI-IgG was effective in reducing mature B cell numbers. Accordingly it controlled the level of the anti dsDNA antibody in lupus-like mice. In addition, TACI-IgG up-regulated memory B cells in murine lupus. Furthermore, we found that TACI-IgG up-regulated IL-15 expression in lupus-like mice. Thus, the combination of TACI-IgG and anti-IL-15 antibodies was explored to understand their effects on the treatment of murine lupus. Compared to treatments with TACI-IgG or anti-IL-15 alone, the combination of TACI-IgG and anti-IL-15 antibodies efficiently ameliorated murine lupus phenotypes. The study provides hints for the clinical application of BAFF- and IL 15-specific therapeutic agents. PMID- 24791700 TI - Evaluation of metabolic and immunological changes in streptozotocin-nicotinamide induced diabetic rats. AB - Type 2 diabetes is a chronic disease with growing public health concern globally. Finding remedies to assist this health issue requires recruiting appropriate animal model for experimental studies. This study was designated to evaluate metabolic and immunologic changes in streptozotocin-nicotinamide induced diabetic rats as a model of type 2 diabetes. Male rats were induced diabetes using nicotinamide (110 mg/kg) and streptozotocin (65 mg/kg). Following 42 days, biochemical and immunological tests showed that diabetic rats had higher levels of blood glucose, WBC, certain abnormalities in lipid profile and insufficient mitogenic responses of lymphocytes (p<0.05). However, the status of the total antioxidant, inflammatory biomarkers and other parameters of full blood count (except HCT) were not significantly altered. Phenotyping assay indicated insignificant lymphocyte subtype imbalances excluding a significant rise in the level of CD4+CD25+ marker (p<0.05). This model of diabetic animals may represent some but not all symptoms of human type 2 diabetes. PMID- 24791701 TI - Vitamin D status in patients attending a Danish migrant health clinic: a clinical retrospective study. AB - Non-western migrants and ethnic minority populations in western countries are particularly at risk of vitamin D deficiency due to darker skin color and low sun exposure. The aim of this study was to examine levels of 25-OH vitamin D in patients attending a Danish health clinic for migrants. Patients attending the clinic represent a distinct group of migrants with longstanding, unresolved symptoms and often multiple illnesses. In this retrospective study, data on patient demographics and vitamin D levels were extracted from the medical records of 156 patients attending a Migrant Health Clinic in 2008-2011 who were considered at-risk for low vitamin D, mainly due to symptoms of diffuse pain in the muscles, bones or joints. Over the follow-up period of 1 year, the number of patients with vitamin D below 50 nmol/L decreased from 80 to 56%. The median vitamin D level increased from 27 nmol/L [(interquartile ranges (IQR 14.5-45.0)] at baseline to 45 nmol/L (IQR 26.5-64.5) at follow-up. Patient consultations with a holistic approach and close follow-up can help patients with complex symptoms and language barriers to overcome barriers to treatment and adherence, thus leading to improved levels of vitamin D. PMID- 24791702 TI - The loss of the inducible Aspergillus carbonarius MFS transporter MfsA leads to ochratoxin A overproduction. AB - Ochratoxin A (OTA), a nephrotoxic compound produced by certain Aspergillus and Penicillium species, is one of the most abundant mycotoxins in food commodities. Aspergillus carbonarius is the main source of OTA in wine, grape juice and dried vine fruits. Although many studies have focused on OTA production by A. carbonarius, little is known about the genes related to OTA production and transport. We have found a transporter that belongs to the major facilitator superfamily (MfsA) which is highly expressed with a 102-fold induction in an ochratoxigenic A. carbonarius strain compared to a low OTA producer strain. The encoding mfsA gene shows similarity to the multidrug efflux transporter flu1 from Candida albicans. A high number of putative transcription factor binding sites involved in the response to stress were identified within the promoter of mfsA. Phenotypical analysis of DeltamfsA deletion mutants revealed that the loss of mfsA leads to a slight growth reduction and increased OTA production. We therefore hypothesize that MfsA could be a stress response transporter whose disruption could cause an increase in oxidative stress together with a stimulation of mycotoxin production. PMID- 24791704 TI - Older age at retirement is associated with decreased risk of dementia. AB - To test the hypothesis that age at retirement is associated with dementia risk among self-employed workers in France, we linked health and pension databases of self-employed workers and we extracted data of those who were still alive and retired as of December 31st 2010. Dementia cases were detected in the database either through the declaration of a long-term chronic disease coded as Alzheimer's disease and other dementia (International Classification of Disease codes G30, F00, F01, F03) or through the claim for reimbursement of one of the anti-dementia drugs. Data were analyzed using Cox proportional hazard model adjusting for potential confounders. Among the 429,803 retired self-employed workers alive on December 31st 2010, prevalence of dementia was 2.65 %. Multivariable analyses showed that the hazard ratio of dementia was 0.968 [95 % confidence interval = (0.962-0.973)] per each extra year of age at retirement. After excluding workers who had dementia diagnosed within the 5 years following retirement, the results remained unchanged and highly significant (p < 0.0001). We show strong evidence of a significant decrease in the risk of developing dementia associated with older age at retirement, in line with the "use it or lose it" hypothesis. Further evidence is necessary to evaluate whether this association is causal, but our results indicate the potential importance of maintaining high levels of cognitive and social stimulation throughout work and retiree life. PMID- 24791706 TI - A new multimedia contaminant fate model for China: how important are environmental parameters in influencing chemical persistence and long-range transport potential? AB - We present a new multimedia chemical fate model (SESAMe) which was developed to assess chemical fate and behaviour across China. We apply the model to quantify the influence of environmental parameters on chemical overall persistence (POV) and long-range transport potential (LRTP) in China, which has extreme diversity in environmental conditions. Sobol sensitivity analysis was used to identify the relative importance of input parameters. Physicochemical properties were identified as more influential than environmental parameters on model output. Interactive effects of environmental parameters on POV and LRTP occur mainly in combination with chemical properties. Hypothetical chemicals and emission data were used to model POV and LRTP for neutral and acidic chemicals with different KOW/DOW, vapour pressure and pKa under different precipitation, wind speed, temperature and soil organic carbon contents (fOC). Generally for POV, precipitation was more influential than the other environmental parameters, whilst temperature and wind speed did not contribute significantly to POV variation; for LRTP, wind speed was more influential than the other environmental parameters, whilst the effects of other environmental parameters relied on specific chemical properties. fOC had a slight effect on POV and LRTP, and higher fOC always increased POV and decreased LRTP. Example case studies were performed on real test chemicals using SESAMe to explore the spatial variability of model output and how environmental properties affect POV and LRTP. Dibenzofuran released to multiple media had higher POV in northwest of Xinjiang, part of Gansu, northeast of Inner Mongolia, Heilongjiang and Jilin. Benzo[a]pyrene released to the air had higher LRTP in south Xinjiang and west Inner Mongolia, whilst acenaphthene had higher LRTP in Tibet and west Inner Mongolia. TCS released into water had higher LRTP in Yellow River and Yangtze River catchments. The initial case studies demonstrated that SESAMe performed well on comparing POV and LRTP of chemicals in different regions across China in order to potentially identify the most sensitive regions. This model should not only be used to estimate POV and LRTP for screening and risk assessments of chemicals, but could potentially be used to help design chemical monitoring programmes across China in the future. PMID- 24791703 TI - Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30 2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively]. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development. PMID- 24791705 TI - Systematic review and metaanalysis of air pollution exposure and risk of diabetes. AB - The present systematic review and metaanalysis of published observational studies was conducted to assess the health effects of exposure to air pollution on diabetes risk. Online databases were searched through January 2013, and the reference lists of pertinent articles reporting observational studies in humans were examined. Pooled relative risks and 95 % confidence intervals were calculated with a random-effects model. Exposure to air pollution was associated with slight increase in risk of diabetes and susceptibility of people with diabetes to air pollution. These results were consistent between time-series, case-crossover and cohort studies and between studies conducted in North America and Europe. The association between exposure to air pollution and diabetes was stronger for gaseous pollutants than for particulate matter. Our metaanalysis suggests that exposure to air pollution may be a risk factor for diabetes and increase susceptibility of people with diabetes to air pollution. PMID- 24791707 TI - Fate of diclofenac in municipal wastewater treatment plant - a review. AB - Diclofenac (DCF) is a common anti-inflammatory pharmaceutical that is often detected in waste wasters, effluents and surface waters. Recently, DCF was included in the watch list of substances in EU that requires its environmental monitoring in the member states. DCF is also known to harmfully affect several environmental species already at concentrations of <= 1 MUg/l. This review focuses on the occurrence and fate of DCF in conventional wastewater treatment processes. Research done in this area was gathered and analyzed in order to find out the possibilities to enhance DCF elimination during biological wastewater treatment. More precisely, human metabolism, concentrations in wastewater influents and effluents, elimination rates in the treatment train, roles of sorption and biotransformation mechanisms during the treatment as well as formation of transformation products are reported. Additionally, the effect of process configuration, i.e. conventional activated sludge (CAS), biological nutrient removal (BNR), membrane bioreactor (MBR) and attached-growth bioreactor, and process parameters, i.e. solids retention time (SRT) and hydraulic retention time (HRT) are presented. Generally, DCF is poorly biodegradable which often translates into low elimination rates during biological wastewater treatment. Only a minor portion is sorbed to sludge. MBR and attached-growth bioreactors may result in higher elimination of DCF over CAS or BNR. Long SRTs (>150 d) favor the DCF elimination due to sludge adaptation. Longer HRTs (>2-3d) could significantly increase the elimination of DCF during biological wastewater treatment. Bioaugmentation could be used to enhance DCF elimination, however, this requires more research on microbial communities that are able to degrade DCF. Also, further research is needed to gain more information about the deconjugation processes and biotic and abiotic transformation and the nature of transformation products. PMID- 24791708 TI - Dissociating strategy-dependent and independent components in task preparation. AB - A central aspect of cognitive control is the capacity to anticipatorily prepare for specific task requirements prior to carrying out a task. To study the changes caused by task preparation, the cued task-switching paradigm has generally been used. While research on anticipatory control has long focused on general processing differences between switch and repeat trials, more recent research suggests that contextual variations strongly modulate such differences. In the current paper, we argue that anticipatory task set preparation strongly depends on contextual variables leading to different strategies to prepare for an upcoming task. We provide behavioral as well as neuroscientific evidence for this claim. Furthermore, we show that some preparatory processes are sensitive to strategic modulations whereas other preparatory processes are not. Based on this, we propose a functional dissociation within the fronto-parietal network involved in task preparation. PMID- 24791709 TI - A neural network model of individual differences in task switching abilities. AB - We use a biologically grounded neural network model to investigate the brain mechanisms underlying individual differences specific to the selection and instantiation of representations that exert cognitive control in task switching. Existing computational models of task switching do not focus on individual differences and so cannot explain why task switching abilities are separable from other executive function (EF) abilities (such as response inhibition). We explore hypotheses regarding neural mechanisms underlying the "Shifting-Specific" and "Common EF" components of EF proposed in the Unity/Diversity model (Miyake & Friedman, 2012) and similar components in related theoretical frameworks. We do so by adapting a well-developed neural network model of working memory (Prefrontal cortex, Basal ganglia Working Memory or PBWM; Hazy, Frank, & O'Reilly, 2007) to task switching and the Stroop task, and comparing its behavior on those tasks under a variety of individual difference manipulations. Results are consistent with the hypotheses that variation specific to task switching (i.e., Shifting-Specific) may be related to uncontrolled, automatic persistence of goal representations, whereas variation general to multiple EFs (i.e., Common EF) may be related to the strength of PFC representations and their effect on processing in the remainder of the cognitive system. Moreover, increasing signal to noise ratio in PFC, theoretically tied to levels of tonic dopamine and a genetic polymorphism in the COMT gene, reduced Stroop interference but increased switch costs. This stability-flexibility tradeoff provides an explanation for why these two EF components sometimes show opposing correlations with other variables such as attention problems and self-restraint. PMID- 24791711 TI - Bioremediation and lipid synthesis through mixotrophic algal consortia in municipal wastewater. AB - Algae grown in outdoor reactors (volume: 10 L and depth: 20 cm) were fed directly with filtered and sterilised municipal wastewater. The nutrient removal efficiencies were 86%, 90%, 89%, 70% and 76% for TOC, TN, NH4-N, TP and OP, respectively, and lipid content varied from 18% to 28.5% of dry algal biomass. Biomass productivity of ~122 mg/l/d (surface productivity 24.4 g/m(2)/d) and lipid productivity of ~32 mg/l/d were recorded. Gas chromatography and mass spectrometry (GC-MS) analyses of the fatty acid methyl esters (FAME) showed a higher content of desirable fatty acids (bearing biofuel properties) with major contributions from saturates such as palmitic acid [C16:0; ~40%] and stearic acid [C18:0; ~34%], followed by unsaturates such as oleic acid [C18:1(9); ~10%] and linoleic acid [C18:2(9,12); ~5%]. The decomposition of algal biomass and reactor residues with an exothermic heat content of 123.4 J/g provides the scope for further energy derivation. PMID- 24791710 TI - A developmental window into trade-offs in executive function: the case of task switching versus response inhibition in 6-year-olds. AB - Good executive function has been linked to many positive outcomes in academic performance, health, and social competence. However, some aspects of executive function may interfere with other cognitive processes. Childhood provides a unique test case for investigating such cognitive trade-offs, given the dramatic failures and developments observed during this period. For example, most children categorically switch or perseverate when asked to switch between rules on a card sorting task. To test potential trade-offs with the development of task switching abilities, we compared 6-year-olds who switched versus perseverated in a card sorting task on two aspects of inhibitory control: response inhibition (via a stop signal task) and interference control (via a Simon task). Across two studies, switchers showed worse response inhibition than perseverators, consistent with the idea of cognitive trade-offs; however, switchers showed better interference control than perseverators, consistent with prior work documenting benefits associated with the development of executive function. This pattern of positive and negative associations may reflect aspects of working memory (active maintenance of current goals, and clearing of prior goals) that help children focus on a single task goal but hurt in situations with conflicting goals. Implications for understanding components of executive function and their relationships across development are discussed. PMID- 24791712 TI - Microbial adaptation to biodegrade toxic organic micro-pollutants in membrane bioreactor using different sludge sources. AB - Biodegradation of toxic organic micro-pollutants in municipal solid waste (MSW) leachate by membrane bioreactor (MBR) was investigated. The MBR systems were seeded with different sludge sources, one was from a pilot-scale MBR system treating MSW leachate and the other was from an activated sludge sewage treatment plant. The biodegradation of BPA, 2,6-DTBP, BHT, DEP, DBP and DEHP, DCP and BBzP, by sludge from both reactors were found improved with time. However, enhanced biodegradation of micro-pollutants was observed in MBR operated under long sludge age condition. Bacterial population analyses determined by PCR-DGGE revealed the development of phenol and phthalate degrading bacteria consortium in MBR sludge during its operation. PMID- 24791713 TI - Microbial catalyzed electrochemical systems: a bio-factory with multi-facet applications. AB - Microbial catalyzed electrochemical systems (MCES) have been intensively pursued in both basic and applied research as a futuristic and sustainable platform specifically in harnessing energy and generating value added bio-products. MCES have documented multiple/diverse applications which include microbial fuel cell (for harnessing bioelectricity), bioelectrochemical treatment system (waste remediation), bioelectrochemical system (bio-electrosynthesis of various value added products) and microbial electrolytic cell (H2 production at lower applied potential). Microorganisms function as biocatalyst in these fuel cell systems and the resulting electron flux from metabolism plays pivotal role in bio electrogenesis. Exo-electron transfer machineries and strategies that regulate metabolic flux towards exo-electron transport were delineated. This review addresses the contemporary progress and advances made in MCES, focusing on its application towards value addition and waste remediation. PMID- 24791714 TI - Maternal high-fat diet alters anxiety behavior and glucocorticoid signaling in adolescent offspring. AB - Maternal obesity and overconsumption of saturated fats during pregnancy have profound effects on offspring health, ranging from metabolic to behavioral disorders in later life. The influence of high-fat diet (HFD) exposure on the development of brain regions implicated in anxiety behavior is not well understood. We previously found that maternal HFD exposure is associated with an increase in anxiety behavior and alterations in the expression of several genes involved in inflammation via the glucocorticoid signaling pathway in adult rat offspring. During adolescence, the maturation of feedback systems mediating corticosteroid sensitivity is incomplete, and therefore distinct from adulthood. In this study, we examined the influence of maternal HFD on several measures of anxiety behavior and gene expression in adolescent offspring. We examined the expression of corticosteroid receptors and related inflammatory processes, as corticosteroid receptors are known to regulate circulating corticosterone levels during basal and stress conditions in addition to influencing inflammatory processes in the hippocampus and amygdala. We found that adolescent animals perinatally exposed to HFD generally showed decreased anxiety behavior accompanied by a selective alteration in the expression of the glucocorticoid receptor and several downstream inflammatory genes in the hippocampus and amygdala. These data suggest that adolescence constitutes an additional period when the effects of developmental programming may modify mental health trajectories. PMID- 24791716 TI - Diagnostic performance of pressure drop coefficient in relation to fractional flow reserve and coronary flow reserve. AB - OBJECTIVES AND BACKGROUND: Functional assessment of coronary lesion severity during cardiac catheterization is conducted using diagnostic parameters like fractional flow reserve (FFR; pressure derived) and coronary flow reserve (CFR; flow derived). However, the complex hemodynamics of stenosis might not be sufficiently explained by either pressure or flow alone, particularly in the case of intermediate stenosis. CDP (ratio of pressure drop across a stenosis to distal dynamic pressure), a non-dimensional index derived from fundamental fluid dynamic principles based on a combination of intracoronary pressure and flow, may improve the functional assessment of coronary lesion severity. METHODS: We performed a meta-analysis of seven studies, retrieved from MEDLINE and PubMed, comparing the results of FFR and CFR of the same lesions. Two studies reported functional measurements (pressure and flow) obtained in individual patients. Five studies reported two-dimensional plots of FFR vs. CFR. The FFR and CFR data were digitized and corresponding functional measurements were extracted using the reported mean values of hemodynamic data from each of the five studies. The receiver operating characteristic (ROC) curve was used to identify the optimal cut-off point of CDP, which corresponds to the clinically used cut-off values (FFR = 0.80, FFR = 0.75, and CFR = 2.0). RESULTS: CDP correlated significantly with FFR (r = 0.78; P<.001) and had significant diagnostic efficiency (area under the ROC curve = 89%), specificity (83% and 85%), and sensitivity (81% and 76%) at FFR <0.8 and FFR <0.75, respectively. The corresponding cut-off value for CDP to detect FFR <0.80 and FFR <0.75 was at CDP >27.1 and CDP >27.9, respectively. CONCLUSIONS: CDP, a functional parameter based on both intracoronary pressure and flow measurements, has close agreement (area under the ROC curve = 89%) with FFR, the most frequently used method for evaluation of coronary stenosis severity. PMID- 24791717 TI - Transradial versus transfemoral coronary intervention for acute myocardial infarction complicated by cardiogenic shock: is transradial coronary intervention suitable for emergency PCI in high-risk acute myocardial infarction? AB - BACKGROUND: Data are limited regarding the clinical results of transradial coronary intervention (TRI) in acute myocardial infarction (AMI) complicated by cardiogenic shock. OBJECTIVE: The aim of this study was to compare the clinical results of TRI and transfemoral coronary intervention (TFI) in AMI patients who had cardiogenic shock and underwent emergency percutaneous coronary intervention (PCI). METHODS: Between January 1, 2006, and August 31, 2012, a total of 507 consecutive patients with AMI underwent emergency PCI within 12 hours of onset. Eighty-five patients presented with cardiogenic shock and were enrolled. Among these patients, 60 underwent TRI and 25 underwent TFI. Outcome measures included the following: major bleeding and vascular complications; major adverse cardiac or cerebrovascular events (MACCE); all-cause death; door-to-balloon time; and PCI procedural success. RESULTS: TRI had a significantly lower rate of major bleeding and vascular complications within 30 days (6.7% vs. 28.0%; P<.05) and 1 year (log rank P<.05) than TFI. No significant differences were observed between the two groups in the MACCE rate within 30 days (28.3% vs. 44.0%; P=.21) and 1 year (log rank P=.06), and the all-cause death rate within 30 days (26.7% vs. 40.0%; P=.30) and 1 year (log-rank P=.09). In addition, TRI was not inferior to TFI in terms of door-to-balloon time (99.8 min vs. 110.4 min; P=.30) and PCI procedural success (95.0% vs. 96.0%; P>.99). CONCLUSION: TRI is associated with fewer major bleeding and vascular complications than TFI, and it appears suitable for both low- and high-risk AMI patients, especially when AMI is complicated by cardiogenic shock. PMID- 24791715 TI - Adult cortical plasticity following injury: Recapitulation of critical period mechanisms? AB - A primary goal of research on developmental critical periods (CPs) is the recapitulation of a juvenile-like state of malleability in the adult brain that might enable recovery from injury. These ambitions are often framed in terms of the simple reinstatement of enhanced plasticity in the growth-restricted milieu of an injured adult brain. Here, we provide an analysis of the similarities and differences between deprivation-induced and injury-induced cortical plasticity, to provide for a nuanced comparison of these remarkably similar processes. As a first step, we review the factors that drive ocular dominance plasticity in the primary visual cortex of the uninjured brain during the CP and in adults, to highlight processes that might confer adaptive advantage. In addition, we directly compare deprivation-induced cortical plasticity during the CP and plasticity following acute injury or ischemia in mature brain. We find that these two processes display a biphasic response profile following deprivation or injury: an initial decrease in GABAergic inhibition and synapse loss transitions into a period of neurite expansion and synaptic gain. This biphasic response profile emphasizes the transition from a period of cortical healing to one of reconnection and recovery of function. Yet while injury-induced plasticity in adult shares several salient characteristics with deprivation-induced plasticity during the CP, the degree to which the adult injured brain is able to functionally rewire, and the time required to do so, present major limitations for recovery. Attempts to recapitulate a measure of CP plasticity in an adult injury context will need to carefully dissect the circuit alterations and plasticity mechanisms involved while measuring functional behavioral output to assess their ultimate success. PMID- 24791718 TI - Same-day discharge or overnight stay after percutaneous coronary intervention: comparison of net adverse cardiovascular events. AB - BACKGROUND: Same-day discharge after percutaneous coronary intervention (PCI), if achieved with acceptable safety, could result in greater patient satisfaction and potential cost savings. Comparative analyses reporting the safety outcomes of same-day discharge vs overnight stay after elective PCI are lacking. METHODS: Data of same-day discharge and overnight-stay patients undergoing elective PCI in a high-volume center were compared. We specifically evaluated the incidence of net adverse cardiovascular events (NACE; i.e., death, myocardial infarction, stroke, target vessel revascularization, vascular complication, and major bleeding) within 48 hours post index procedure among both groups and at 30 days. RESULTS: A total of 188 cases were evaluated, with 93 discharged the same day and 95 after overnight stay following elective PCI. Baseline characteristics were similar, except for older age (73.0 +/- 7 years vs. 64.0 +/- 12 years; P<.001), more prior PCI (49.5% vs. 34.7%; P<.001), and prior coronary artery bypass graft surgery (16.1% vs. 11.6%; P=.01) in the same-day discharge group. Procedural characteristics were similar in both groups. No significant difference in the NACE rate was found between the groups at 48 hours (0 [0%] vs. 2 [2.1%]; P=.25) or at 30 days (3 [3.2%] vs. 6 [6.3%]; P=.26). CONCLUSION: In the population studied, same-day discharge after PCI is safe and feasible. Adequately powered randomized prospective studies are necessary to confirm these results. PMID- 24791719 TI - Early-generation versus new-generation drug-eluting stents in isolated chronic total occlusion: on the road to extinction? AB - BACKGROUND: The performance of second-generation drug-eluting stent (DES) versus first-generation DES implantation in patients with stable angina and single chronic total occlusion (CTO) has not yet been studied. Herein, we sought to investigate whether a successful percutaneous coronary intervention (PCI) for CTO using second-generation versus first-generation polymer-coated DES improved outcomes in a setting of isolated CTO. METHODS: Among 7765 patients undergoing elective PCIs between 2006 and 2011, a total of 742 single CTOs were identified. Of these, 496 had a successful PCI and 193 were implanted with DESs. The major adverse cardiovascular event (MACE) records were extracted from the national administrative database and all patients were linked to the 2-year follow-up. RESULTS: When compared to first-generation DES implantation, second-generation implantation once significantly reduced risk of MACE, both at 1-year (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.06-0.36; P=.01) and 2-year follow-up (HR, 0.27; 95% CI, 0.13-0.56; P=.01). The symptom-driven target lesion revascularization (TLR) also occurred less frequently in patients with second generation DES vs first-generation DES within 2 years of follow-up (HR, 0.15; 95% CI, 0.05-0.44; P=.03). The substantial 2-year benefit of second-generation DES over first-generation DES also persisted after incorporating a propensity score analysis for MACE (HR, 0.24; 95% CI, 0.08-0.72; P=.01) and TLR (HR, 0.15; 95% CI, 0.05-0.49; P=.04). CONCLUSIONS: Successful PCI for CTO using thin-strut polymer coated DES vs early-generation DES implantation improves outcomes after recanalization of isolated CTO in a setting of stable angina. PMID- 24791720 TI - Orbital atherectomy: device evolution and clinical data. AB - A number of atherectomy devices were developed in the last few years. Among them, the DiamondBack 360 degrees Peripheral Orbital Atherectomy System (Cardiovascular Systems, Inc) was specifically designed to work in severely calcified plaque. This article reviews the history, mechanism of action, evolution, clinical data, and future applications of this particular atherectomy device. PMID- 24791721 TI - Use of optical coherence tomography during superficial femoral artery interventions. AB - Superficial femoral artery (SFA) disease accounts for approximately 40% of the symptomatic peripheral arterial disease and remains a common cause of critical limb ischemia and lower-extremity amputation. Optical coherence tomography (OCT) has been extensively studied in the coronary circulation; however, its use in the peripheral arterial circulation is scarce. We present two cases of OCT use as an ancillary imaging tool during SFA endovascular interventions. PMID- 24791722 TI - Hepatic vein anchor-wire technique to prevent stent migration during inferior vena cava stenting for Budd-Chiari syndrome. AB - Inferior vena cava (IVC) stenting in patients suffering from Budd-Chiari syndrome (BCS) is sometimes complicated by stent migration or misplacement. Here, we describe a novel stent anchoring technique to prevent this complication while using balloon-mounted Palmaz stent for angioplasty of short-segment stenosis in the IVC. PMID- 24791723 TI - Here comes the sun: physician relationships with industry and the Sunshine Act. PMID- 24791724 TI - Combined hemodynamic support with the Impella 2.5 device and intra-aortic balloon pump for management of refractory cardiogenic shock. AB - Cardiogenic shock (CS) during elective percutaneous coronary intervention (PCI) is a rare but potentially lethal clinical condition. Pharmacological inotropic support and mechanical circulatory assistance with intra-aortic balloon pump (IABP) counterpulsation remains the gold-standard treatment. We report the case of a patient who developed refractory CS during elective PCI and was successfully managed with concomitant use of IABP and the Impella 2.5 L support device. PMID- 24791725 TI - Modified mother-child technique using a buddy wire. AB - For percutaneous coronary intervention, 6 Fr guiding catheters are the current standard. However, when treating complex coronary lesions, stent delivery is sometimes difficult with a 6 Fr system because of limited back-up support. Several strategies have been proposed in order to overcome this disadvantage, including active/passive guiding- catheter support, wire support, and the anchor balloon technique. The 4-in-6 mother-child technique is one of the most effective techniques to deliver stents into complex lesions. In the present study, we introduced a new technique in which a second guidewire was used as a buddy wire in combination with the 4 Fr mother-child technique in a case in which stent delivery via the standard 4-in-6 technique failed. PMID- 24791726 TI - Use of a thrombectomy catheter for contrast injection: a novel technique for preventing extension of an aortocoronary dissection during the retrograde approach to a chronic total occlusion. AB - Percutaneous coronary intervention of a chronic total occlusion can be complicated by aortocoronary dissection. To prevent extension of the dissection, repeat contrast injections are discouraged; however, they are sometimes required to confirm optimal distal angiographic result. We describe use of a thrombectomy catheter for distal contrast injection in one such patient that allowed distal vessel visualization without propagating the aortocoronary dissection. PMID- 24791727 TI - A new technique for coronary guide catheter exchange over coronary guidewire using GuideLiner catheter. AB - Guide catheter exchange over coronary guidewire can be challenging, yet is necessary in certain clinical scenarios. At the same time, maintaining coronary guidewire position across a predilated lesion is important to prevent vessel lumen closure. We present a technique of guide catheter exchange over a coronary guidewire with GuideLiner support. PMID- 24791728 TI - Dual left anterior descending coronary artery with origin of short left anterior descending coronary artery from left main shaft: a rare coronary anomaly. AB - Dual left anterior descending (LAD) coronary artery with separate origin of the short LAD from the left main (LM) coronary artery is very rare and not reported in the literature. A 49-year-old male was admitted with history of mid-sternal chest pain at rest. He underwent coronary angiography, which showed normal origin of the left and right coronary arteries. A LAD branch (short LAD) with an early take-off from the LM entered the proximal interventricular groove and gave rise to the septal branches. The LM then divided into the circumflex branch and the other LAD branch (long LAD), which ran on the left ventricular side of the interventricular groove and entered the groove distally. The major diagonals originated from the latter LAD. PMID- 24791729 TI - Balloon-assisted tracking in dealing with radial artery loop by transradial approach: a technical report. AB - The transradial approach for various coronary procedures has gained worldwide popularity because it reduces bleeding complications and increases patient comfort level. There may be difficulties encountered at various anatomical levels from radial artery to coronary artery level by this approach. Radial artery loop is one of the most common anatomical reasons for deferring or failure of transradial approach and shifting to the femoral route. Balloon-assisted tracking of catheters may help deal with radial artery loops without injuring the endothelium and increase the success rate of the coronary procedure. PMID- 24791730 TI - Low varicella-related consultation rate in the Netherlands in primary care data. AB - BACKGROUND: In the Netherlands, a relatively low varicella disease burden compared to other European countries is observed within routine surveillance. To validate this, we estimated the varicella-related consultation rate using The Integrated Primary Care Information database. METHODS: In this retrospective cohort study, varicella patients in 2006-2008 were identified by the International Classification of Primary Care (A72) and free text in the electronic medical records, and manually reviewed to be categorised as 'varicella' or 'probable varicella'. The incidence of GP-consultation, specialist referral, emergency department contact and hospitalisation due to varicella was calculated, standardised to the Dutch population. RESULTS: We identified 1881 varicella cases (2348 including probable cases), 14 patients were hospitalised. The overall incidence of GP-consultation due to varicella per 100,000 person years was at least 281 (95%CI 268-294) and when probable cases were also included at maximum 354 (95%CI 340-369). The overall incidence of specialist referral, emergency department contact and hospitalisation per 100,000 person-years was 3.9 (95%CI 2.7-5.6), 2.5 (95%CI 1.5-4.0) and 2.0 (95%CI 1.2-3.4) respectively. CONCLUSIONS: This study confirms the relatively low disease burden due to varicella in the Netherlands. In this study, using primary care data, similar incidences of GP consultation and referral to secondary care due to varicella were found as in routine surveillance. The lower varicella-related consultation rate might be linked to more conservative GP consultation behaviour in the Netherlands, and the relatively young age of infection. This is highly relevant for the decision-making process whether or not to introduce universal childhood varicella vaccination in the Netherlands. PMID- 24791731 TI - The epidemiology of varicella cases among children in Beijing's Fengtai District from 2008 to 2012. AB - In recent years, the number of breakthrough cases of varicella (onset >42 days after vaccination) increased each year, and varicella outbreaks continue to occur in Beijing. Data from the Immunization Information System and the Infectious Disease Reporting System demonstrated that in Beijing's Fengtai District, the varicella breakthrough rate increased from 0.7% in 2008 to 2.5% in 2012 and showed an increased trend (P<0.001). Among the varicella cases in children (age of 3-15 years), the number of breakthrough cases increased from 167 in 2008 to 622 in 2012, which was 45.2% (n=1735) of the total child cases (n=3842). From 2008 to 2012, a total of 62 outbreaks occurred; among the 787 affected child outbreak cases, 61% were vaccinated. Altogether, the results from this study indicated that 1-dose vaccination cannot sufficiently prevent the occurrence of breakthrough cases of varicella or control varicella outbreaks in Beijing's Fengtai District. PMID- 24791732 TI - The utility of ultrasound surveillance of fluid and growth in obese women. AB - OBJECTIVE: The purpose of this study was to evaluate the utility of ultrasound surveillance in obese women. STUDY DESIGN: This is a retrospective cohort of all obese women who underwent sonography at a single center from 2005-2013. Inclusion criteria were body mass index >=30 kg/m(2), singleton, >=1 ultrasound scan performed at <20 weeks of gestation, and >=1 ultrasound scan performed at >=24 weeks of gestation. Pregnancies with medical complications, fetal anomalies, or preterm premature rupture of membranes were excluded. Outcomes that were considered were small for gestational age, large for gestational age (LGA), macrosomia, oligohydramnios, and polyhydramnios. We calculated the number needed to screen (NNS) and 95% confidence interval (CI) for scans that were performed during 3 gestational age ranges (24-31 weeks 6 days, 32-35 weeks 6 days, and >=36 weeks). RESULTS: Two thousand two sonograms were performed in 1164 obese women at >=24 weeks of gestation. Small for gestational age was diagnosed in 59 pregnancies (5.1%); 7 pregnancies (0.6%) were diagnosed at <32 weeks of gestation (NNS, 159; 95% CI, 69-490). LGA was diagnosed in 38 cases (3.3%); only 1 case was identified at <32 weeks of gestation and was not LGA at birth. For every 29 (95% CI, 19-46) scans performed at >36 weeks of gestation, 1 case of macrosomia was identified. Amniotic fluid abnormalities were diagnosed in 44 pregnancies (3.8%; oligohydramnios, 19; polyhydramnios, 25); 34.1% abnormalities were diagnosed at <32 weeks of gestation (NNS: oligohydramnios, 113; 95% CI, 55-282 for oligohydramnios; polyhydramnios, 100; 95% CI, 50-230). At >=36 weeks of gestation, 7 (95% CI, 6-8) scans were needed to diagnose any fluid or growth abnormality. CONCLUSION: In obese women without comorbidities, few sonographic diagnoses of amniotic fluid or fetal growth abnormalities are made at <32 weeks of gestation. Therefore, if a policy of serial sonographic surveillance is used, we suggest ultrasound scans for fluid and growth in obese women to begin at >=32 weeks of gestation. PMID- 24791733 TI - Preeclampsia: 2 placental phenotypes, 1 etiology? PMID- 24791735 TI - Are current cost-effectiveness thresholds for low- and middle-income countries useful? Examples from the world of vaccines. AB - The World Health Organization's CHOosing Interventions that are Cost Effective (WHO-CHOICE) thresholds for averting a disability-adjusted life-year of one to three times per capita income have been widely cited and used as a measure of cost effectiveness in evaluations of vaccination for low- and middle-income countries (LMICs). These thresholds were based upon criteria set out by the WHO Commission on Macroeconomics and Health, which reflected the potential economic returns of interventions. The CHOICE project sought to evaluate a variety of health interventions at a subregional level and classify them into broad categories to help assist decision makers, but the utility of the thresholds for within-country decision making for individual interventions (given budgetary constraints) has not been adequately explored. To examine whether the 'WHO-CHOICE thresholds' reflect funding decisions, we examined the results of two recent reviews of cost-effectiveness analyses of human papillomavirus and rotavirus vaccination in LMICs, and we assessed whether the results of these studies were reflected in funding decisions for these vaccination programmes. We found that in many cases, programmes that were deemed cost effective were not subsequently implemented in the country. We consider the implications of this finding, the advantages and disadvantages of alternative methods to estimate thresholds, and how cost perspectives and the funders of healthcare may impact on these choices. PMID- 24791734 TI - Gastrointestinal hormones and polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is an endocrine disease of women in reproductive age. It is characterized by anovulation and hyperandrogenism. Most often patients with PCOS have metabolic abnormalities such as dyslipidemia, insulin resistance, and glucose intolerance. It is not surprising that obesity is high prevalent in PCOS. Over 60 % of PCOS women are obese or overweight. Modulation of appetite and energy intake is essential to maintain energy balance and body weight. The gastrointestinal tract, where nutrients are digested and absorbed, plays a central role in energy homeostasis. The signals from the gastrointestinal tract arise from the stomach (ghrelin release), proximal small intestine (CCK release), and distal small intestine (GLP-1 and PYY) in response to food. These hormones are recognized as "appetite regulatory hormones." Weight loss is the key in the treatments of obese/overweight patients with PCOS. However, current non pharmacologic management of body weight is hard to achieve. This review highlighted the gastrointestinal hormones, and discussed the potential strategies aimed at modifying hormones for treatment in PCOS. PMID- 24791737 TI - Proanthocyanidins protect against early diabetic peripheral neuropathy by modulating endoplasmic reticulum stress. AB - Diabetic peripheral neuropathy (DPN) is the most common and troublesome complication of type 2 diabetes mellitus (T2DM). Recent findings reveal an important role of endoplasmic reticulum (ER) stress in the development of DPN and identify a potential new therapeutic target. Schwann cells (SC), the myelinating cells in peripheral nervous system, are highly susceptible to ER homeostasis. Grape seed proanthocyanidins (GSPs) have been reported to improve DPN of type 1 diabetic rats and relieve ER stress in skeletal muscles and pancreas of T2DM. We investigated the potential role of ER stress in SC in regulating DPN of T2DM and assessed whether early intervention of GSPs would prevent DPN by modulating ER stress. The present study was performed in Sprague-Dawley rats made T2DM with low dose streptozotocin and a high-carbohydrate/high-fat diet and in rat SC cultured in serum from type 2 diabetic rats. Diabetic rats showed a typical characteristic of T2DM and slowing of nerve conduction velocity (NCV) in sciatic/tibial nerves. The lesions of SC, Ca(2+) overload and ER stress were present in sciatic nerves of diabetic rats, as well as in cell culture models. GSPs administration significantly decreased the low-density lipoprotein level and increased NCV in diabetic rats. GSPs or their metabolites also partially prevented cell injury, Ca(2+) overload and ER stress in animal and cell culture models. Therefore, ER stress is implicated in peripheral neuropathy in animal and cell culture models of T2DM. Prophylactic GSPs treatment might have auxiliary preventive potential for DPN partially by alleviating ER stress. PMID- 24791740 TI - Boy with yellow-orange, rough nodule on right thigh. PMID- 24791741 TI - Cyberbullying. PMID- 24791736 TI - Aquaporin-11 control of testicular fertility markers in Syrian hamsters. AB - The present study sought novel changes to the hamster testicular transcriptome during modulation of fertility by well-characterized photoperiodic stimuli. Transition from long days (LD, 14 h light/day) to short days (SD, 10h light/day) triggered testicular regression (61% reduction of testis weight, relative to LD) in SD-sensitive (SD-S) hamsters within 16 weeks. After 22 weeks of SD exposure, a third cohort of hamsters became SD-refractory (SD-R), and exhibited testicular recrudescence (137% testis weight gain, relative to SD-S). Partial interrogation of the testicular transcriptome by annealing-control-primer-modified differential display PCR provided several candidates for regulation of testicular functions. Multiple linear regression modeling indicated the best correlation for aquaporin 11 (Aqp11) with changes in testis weight. Correlations were also strongest for Aqp11 with expression levels of reference cDNAs that control spermatogenesis (Hspa2 and Tnp2), steroidogenesis (Cox2, 3betaHsd, and Srebp2), sperm motility (Catsper1, Pgk2, and Tnp2), inflammation (Cox2), and apoptosis (Bax and Bcl2). Moreover, siRNA-mediated knockdown of testicular Aqp11 mRNA and protein reduced Hspa2 and Tnp2 mRNA levels, and it increased 3betaHsd mRNA levels. It also reduced mRNA levels for Sept12, which is a testis-specific inducer of spermatogenesis. These results suggest a central role for testicular Aqp11 signaling in the coordinate regulation of crucial components of fertility. PMID- 24791742 TI - Triple jeopardy: adolescent experiences of sex work and migration in Zimbabwe. AB - Adolescence, migration and sex work are independent risk factors for HIV and other poor health outcomes. They are usually targeted separately with little consideration on how their intersection can enhance vulnerability. We interviewed ten women in Zimbabwe who experienced sex work and migration during adolescence, exploring implications for their health and for services to meet their needs. For most, mobility was routine throughout childhood due to family instability and political upheaval. The determinants of mobility, e.g. inability to pay school fees or desire for independence from difficult circumstances, also catalysed entry into sex work, which then led to further migration to maximise income. Respondents described their adolescence as a time of both vulnerability and opportunity, during which they developed survival skills. While these women did not fit neatly into separate risk profiles of "sex worker" "migrant" or "adolescent", the overlap of these experiences shaped their health and access to services. To address the needs of marginalised populations we must understand the intersection of multiple risks, avoiding simplified assumptions about each category. PMID- 24791743 TI - Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. AB - Neuropilins (NRPs) are cell surface receptors for vascular endothelial growth factor (VEGF) and SEMA3 (class 3 semaphorin) family members. The role of NRPs in neurons and endothelial cells has been investigated, but the expression and role of NRPs in epithelial cells is much less clear. Herein, the expression and localization of NRP1 was investigated in human and mouse skin and squamous cell carcinomas (SCCs). Results indicated that NRP1 mRNA and protein was expressed in the suprabasal epithelial layers of the skin sections. NRP1 staining did not overlap with that of keratin 14 (K14) or proliferating cell nuclear antigen, but did co-localize with staining for keratin 1, indicating that differentiated keratinocytes express NRP1. Similar to the expression of NRP1, VEGF-A was expressed in suprabasal epithelial cells, whereas Nrp2 and VEGFR2 were not detectable in the epidermis. The expression of NRP1 correlated with a high degree of differentiation in human SCC specimens, human SCC xenografts, and mouse K14 HPV16 transgenic SCC. UVB irradiation of mouse skin induced Nrp1 upregulation. In vitro, Nrp1 was upregulated in primary keratinocytes in response to differentiating media or epidermal growth factor-family growth factors. In conclusion, the expression of NRP1 is regulated in the skin and is selectively produced in differentiated epithelial cells. NRP1 may function as a reservoir to sequester VEGF ligand within the epithelial compartment, thereby modulating its bioactivity. PMID- 24791744 TI - Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability. AB - The formation of unstable, leaky neovessels underlies the pathogenesis of many chronic inflammatory diseases. Granzyme B (GZMB) is an immune-derived serine protease that accumulates in the extracellular matrix (ECM) during chronic inflammation and is capable of cleaving fibronectin (FN). Vascular endothelial growth factor (VEGF) is a potent vascular permeabilizing agent that is sequestered in the ECM through its interaction with FN. As GZMB levels are elevated in chronic inflammatory diseases that are associated with increased vascular permeability, the role of GZMB in the regulation of VEGF bioavailability and vascular permeability were assessed. GZMB was added to either VEGF bound to FN or VEGF bound to endothelial cell (EC)-derived ECM. Supernatants containing released VEGF were assessed to determine VEGF activity by treating EC and evaluating VEGF receptor-2 (VEGFR2) phosphorylation. GZMB released VEGF from both FN and from EC-derived matrix, whereas GZMB inhibition prevented FN cleavage and VEGF release. GZMB-mediated VEGF release resulted in significant phosphorylation of VEGFR2. The role of GZMB-mediated VEGF release in altering vascular permeability was also assessed in vivo using Miles/Evans blue permeability assay. GZMB induced a significant VEGF-dependent increase in vascular permeability in vivo that was reduced in the presence of an anti-VEGF-neutralizing antibody. Inflammatory-mediated vascular leakage was also assessed in GZMB-KO mice using a delayed-type hypersensitivity model. GZMB-KO mice exhibited reduced microvascular leakage compared with C57?B6 controls. GZMB increases vascular permeability in part through the proteolytic release of ECM-sequestered VEGF, leading to VEGFR2 activation and increased vascular permeability in vivo. These findings present a novel role for GZMB as a modulator of vascular response during chronic inflammation. PMID- 24791745 TI - Decomposing spatiotemporal brain patterns into topographic latent sources. AB - This paper extends earlier work on spatial modeling of fMRI data to the temporal domain, providing a framework for analyzing high temporal resolution brain imaging modalities such as electroencapholography (EEG). The central idea is to decompose brain imaging data into a covariate-dependent superposition of functions defined over continuous time and space (what we refer to as topographic latent sources). The continuous formulation allows us to parametrically model spatiotemporally localized activations. To make group-level inferences, we elaborate the model hierarchically by sharing sources across subjects. We describe a variational algorithm for parameter estimation that scales efficiently to large data sets. Applied to three EEG data sets, we find that the model produces good predictive performance and reproduces a number of classic findings. Our results suggest that topographic latent sources serve as an effective hypothesis space for interpreting spatiotemporal brain imaging data. PMID- 24791746 TI - Correction of inter-scanner and within-subject variance in structural MRI based automated diagnosing. AB - Automated analysis of structural magnetic resonance images is a promising way to improve early detection of neurodegenerative brain diseases. Clinical applications of such methods involve multiple scanners with potentially different hardware and/or acquisition sequences and demographically heterogeneous groups. To improve classification performance, we propose to correct effects of subject specific covariates (such as age, total intracranial volume, and sex) as well as effects of scanner by using a non-linear Gaussian process model. To test the efficacy of the correction, we performed classification of carriers of the genetic mutation leading to Huntington's disease (HD) versus healthy controls. Half of the HD carriers were free of typical HD symptoms and had an estimated 5 to 20years before onset of clinical symptoms, thus providing a model for preclinical diagnosis of a neurodegenerative disease. Structural magnetic resonance brain images were acquired at four sites with pairs of sites which had the identical scanner type, equipment, and acquisition parameters. For automatic classification, we used spatially normalized probabilistic maps of gray matter, then removed confounding effects by Gaussian process regression, and then performed classification with a support vector machine. Voxel-based morphometry of gray matter maps showed disease effects that were spatially wider spread than effects of scanner, but no significant interactions between scanner and disease were found. A model trained with data from a single scanner generalized well to data from a different scanner. When confounding diagnostics groups and scanner during training, e.g. by using controls from one scanner and gene carriers from another, classification accuracy dropped significantly in many cases. By regressing out confounds with Gaussian process regression, the performance levels were comparable to those obtained in scenarios without confound. We conclude that models trained on data acquired with a single scanner generalized well to data acquired with a different same-generation scanner even when the vendor differed. When confounding grouping and scanner during training is unavoidable to gather training data, regressing out inter-scanner and between-subject variability can reduce the loss in accuracy due to the confound. PMID- 24791747 TI - State-of-the-art approach for bone sarcomas. AB - Bone sarcomas are a variety of non-epithelial, malignant neoplasms of bone. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The approach to a patient with a suspected bone sarcoma from initial examination to the histological diagnosis and classification is staging. Staging is of critical importance, in order to classify different treatment options and point out which combination of them is more suitable depending on the severity of the tumor in every individual patient. Staging should include medical history, physical and imaging examination, and biopsy. This article presents the current approach for staging, principles of biopsy, tumor classification, treatment, and follow-up of patients with bone sarcomas. PMID- 24791749 TI - Defining recovery in chronic fatigue syndrome: a critical review. AB - PURPOSE: In chronic fatigue syndrome (CFS), the lack of consensus on how recovery should be defined or interpreted has generated controversy and confusion. The purpose of this paper was to systematically review, compare, and evaluate the definitions of recovery reported in the CFS literature and to make recommendations about the scope of recovery assessments. METHODS: A search was done using the MEDLINE, PubMed, PsycINFO, CINAHL, and Cochrane databases for peer review papers that contained the search terms "chronic fatigue syndrome" and "recovery," "reversal," "remission," and/or "treatment response." RESULTS: From the 22 extracted studies, recovery was operationally defined by reference with one or more of these domains: (1) pre-morbid functioning; (2) both fatigue and function; (3) fatigue (or related symptoms) alone; (4) function alone; and/or (5) brief global assessment. Almost all of the studies measuring recovery in CFS did so differently. The brief global assessment was the most common outcome measure used to define recovery. Estimates of recovery ranged from 0 to 66 % in intervention studies and 2.6 to 62 % in naturalistic studies. CONCLUSIONS: Given that the term "recovery" was often based on limited assessments and less than full restoration of health, other more precise and accurate labels (e.g., clinically significant improvement) may be more appropriate and informative. In keeping with common understandings of the term recovery, we recommend a consistent definition that captures a broad-based return to health with assessments of both fatigue and function as well as the patient's perceptions of his/her recovery status. PMID- 24791750 TI - Expensive helmets do not correct skull flattening in babies. PMID- 24791748 TI - Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys. AB - High-density scalp EEG recordings are widely used to study whole-brain neuronal networks in humans non-invasively. Here, we validate EEG mapping of somatosensory evoked potentials (SSEPs) in macaque monkeys (Macaca fascicularis) for the long term investigation of large-scale neuronal networks and their reorganisation after lesions requiring a craniotomy. SSEPs were acquired from 33 scalp electrodes in five adult anaesthetized animals after electrical median or tibial nerve stimulation. SSEP scalp potential maps were identified by cluster analysis and identified in individual recordings. A distributed, linear inverse solution was used to estimate the intracortical sources of the scalp potentials. SSEPs were characterised by a sequence of components with unique scalp topographies. Source analysis confirmed that median nerve SSEP component maps were in accordance with the somatotopic organisation of the sensorimotor cortex. Most importantly, SSEP recordings were stable both intra- and interindividually. We aim to apply this method to the study of recovery and reorganisation of large scale neuronal networks following a focal cortical lesion requiring a craniotomy. As a prerequisite, the present study demonstrated that a 300-mm(2) unilateral craniotomy over the sensorimotor cortex necessary to induce a cortical lesion, followed by bone flap repositioning, suture and gap plugging with calcium phosphate cement, did not induce major distortions of the SSEPs. In conclusion, SSEPs can be successfully and reproducibly recorded from high-density EEG caps in macaque monkeys before and after a craniotomy, opening new possibilities for the long-term follow-up of the cortical reorganisation of large-scale networks in macaque monkeys after a cortical lesion. PMID- 24791751 TI - Cellular respiration: the nexus of stress, condition, and ornamentation. AB - A fundamental hypothesis for the evolution and maintenance of ornamental traits is that ornaments convey information to choosing females about the quality of prospective mates. A diverse array of ornaments (e.g., colors, morphological features, and behaviors) has been associated with a wide range of measures of individual quality, but decades of study of such indicator traits have failed to produce general mechanisms of honest signaling. Here, I propose that efficiency of cellular respiration, as a product of mitochondrial function, underlies the associations between ornamentation and performance for a broad range of traits across taxa. A large biomedical literature documents the fundamental biochemical links between oxidative phosphorylation (OXPHOS) and the production of reactive oxygen species (ROS), the process of metabolism, the function of the immune system, the synthesis of proteins, and the development and function of the nervous system. The production of virtually all ornaments whose expressions have been demonstrated to be condition-dependent is directly affected by the efficiency of cellular respiration, suggesting that the signaling of respiratory efficiency may be the primary function of such traits. Furthermore, the production of ornaments links to stress-response systems, including particularly the neuroendocrine system, through mitochondrial function, thereby makes ornamental traits effective signals of the capacity to withstand environmental perturbations. The identification of a unifying mechanism of honest signaling holds the potential to connect many heretofore-disparate fields of study related to stress and ornamentation, including neuroendocrinology, respiratory physiology, metabolic physiology, and immunology. PMID- 24791753 TI - Intentions in the brain: the unveiling of Mister Hyde. AB - Is it possible to understand the intentions of others by merely observing their movements? Current debate has been mainly focused on the role that mirror neurons and motor simulation may play in this process, with surprisingly little attention being devoted to how intentions are actually translated into movements. Here, we delineate an alternative approach to the problem of intention-from-movement understanding, which takes "action execution" rather than "action observation" as a starting point. We first consider whether and to what extent, during action execution, intentions shape movement kinematics. We then examine whether observers are sensitive to intention information conveyed by visual kinematics and can use this information to discriminate between different intentions. Finally, we consider the neural mechanisms that may contribute to intention-from movement understanding. We argue that by reframing the relationship between intention and movement, this evidence opens new perspectives into the neurobiology of how we know other minds and predict others' behavior. PMID- 24791752 TI - Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. AB - PURPOSE: Glutathione (GSH), the most abundant endogenous antioxidant, is a critical regulator of oxidative stress and immune function. While oral GSH has been shown to be bioavailable in laboratory animal models, its efficacy in humans has not been established. Our objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults. METHODS: A 6-month randomized, double-blinded, placebo-controlled trial of oral GSH (250 or 1,000 mg/day) on GSH levels in blood, erythrocytes, plasma, lymphocytes and exfoliated buccal mucosal cells was conducted in 54 non-smoking adults. Secondary outcomes on a subset of subjects included a battery of immune markers. RESULTS: GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30-35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). In most cases, the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period. A reduction in oxidative stress in both GSH dose groups was indicated by decreases in the oxidized to reduced glutathione ratio in whole blood after 6 months. Natural killer cytotoxicity increased >twofold in the high-dose group versus placebo (P < 0.05) at 3 months. CONCLUSIONS: These findings show, for the first time, that daily consumption of GSH supplements was effective at increasing body compartment stores of GSH. PMID- 24791754 TI - Iatrogenic nerve injuries: prevalence, diagnosis and treatment. AB - BACKGROUND: Iatrogenic nerve injuries can result from direct surgical trauma, mechanical stress on a nerve due to faulty positioning during anesthesia, the injection of neurotoxic substances into a nerve, and other mechanisms. Treating physicians should know the risk factors and the procedure to be followed when an iatrogenic nerve injury arises. METHOD: This review is based on pertinent articles retrieved by a selective search in PubMed and on the authors' own data from the years 1990-2012. RESULTS: In large-scale studies, 25% of sciatic nerve lesions that required treatment were iatrogenic, as were 60% of femoral nerve lesions and 94% of accessory nerve lesions. Osteosyntheses, osteotomies, arthrodeses, lymph node biopsies in the posterior triangle of the neck, carpal tunnel operations, and procedures on the wrist and knee were common settings for iatrogenic nerve injury. 340 patients underwent surgery for iatrogenic nerve injuries over a 23-year period in the District Hospital of Gunzburg (Neurosurgical Department of the University of Ulm). In a study published by the authors in 2001, 17.4% of the traumatic nerve lesions treated were iatrogenic. 94% of iatrogenic nerve injuries occurred during surgical procedures. CONCLUSION: A thorough knowledge of the anatomy of the vulnerable nerves and of variants in their course can lessen the risk of iatrogenic nerve injury. When such injuries arise, early diagnosis and planning of further management are the main determinants of outcome. If adequate nerve regeneration does not occur, surgical revision should optimally be performed 3 to 4 months after the injury, and 6 months afterward at the latest. On the other hand, if postoperative high resolution ultrasound reveals either complete transection of the nerve or a neuroma in continuity, surgery should be performed without any further delay. If the surgeon becomes aware of a nerve transection during the initial procedure, then either immediate end-to-end suturing or early secondary management after three weeks is indicated. PMID- 24791755 TI - Borderline personality disorder and comorbid addiction: epidemiology and treatment. AB - BACKGROUND: Borderline personality disorder (BPD) affects 2.7% of adults. About 78% of adults with BPD also develop a substance-related disorder or addiction at some time in their lives. These persons are more impulsive and clinically less stable than BPD patients without substance dependency. They display suicidal behavior to a greater extent, drop out of treatment more often, and have shorter abstinence phases. The combination of borderline personality disorder with addiction requires a special therapeutic approach. METHOD: This review is based on a selective literature search about the treatment of patients with BPD and addiction, with particular attention to Cochrane Reviews and randomized controlled trials (RCT). RESULTS: The available evidence is scant. In two RCTs, Dialectical Behavior Therapy for Substance Use Disorders (DBT-SUD) was found to improve patients' overall functional level (standardized mean difference, 1.07 1.78) and to increase the number of abstinence days (effect strength [ES], 1.03) and negative urine samples (ES, 0.75). Dual focus schema therapy (DFST) was evaluated in three RCTs. Because of methodological problems, however, no useful quantitative comparison across trials is possible. In one RCT, dynamic deconstructive psychotherapy (DDP) was found to have only a moderate, statistically insignificant effect. Only a single study provides data about potentially helpful drug therapy over the intermediate term. CONCLUSION: Patients with borderline personality disorder and comorbid addiction should be treated as early as possible for both conditions in a thematically hierarchical manner. There is no evidence for any restriction on drug therapy to prevent recurrent addiction in these patients. The psychotherapeutic techniques that can be used (despite the currently inadequate evidence base) include DBT-SUD, DFST, and DDP. These patients need qualified expert counseling in choosing a suitable type of psychotherapy. Specific treatment is available in only a few places, and the relevant treatment networks in Germany are just beginning to be constructed. PMID- 24791756 TI - Too much diagnostic evaluation and therapy. PMID- 24791757 TI - Benefit of follow-up not confirmed. PMID- 24791758 TI - Inconsistencies. PMID- 24791759 TI - Better diagnostics and treatment. PMID- 24791760 TI - Discrepancy between clinical reality and guidelines. PMID- 24791761 TI - In reply. PMID- 24791762 TI - Cardiomyopathy. AB - Cardiomyopathy is a disease that causes the heart muscle to become weak and ineffective, reducing the heart's ability to pump blood through the body and possibly leading to heart failure. The rate at which cardiomyopathy was recorded by general practitioner (GP) participants in the BEACH program has not changed significantly since 2000. On average, it was managed at 0.9 per 1000 encounters between April 2000 and March 2013, a total of 1175 times over that period. In 9 out of 10 cases, GPs used the general term cardiomyopathy, whereas in the other 10% this was specified as hypertrophic, congestive, secondary or restrictive. PMID- 24791764 TI - Imaging for cardiac disease: a practical guide for general practitioners. AB - BACKGROUND: Cardiac disease is a major cause of morbidity and mortality in Australia. There are many differentials to the diagnosis of coronary artery disease (CAD). A wide range of radiological investigations are available to help diagnose cardiac conditions. OBJECTIVE: This article seeks to provide an up-to date pathway to diagnose CAD using the least invasive and most widely available investigations. DISCUSSION: A significant number of patients presenting with chest pain have diagnostic features of CAD and these require little further study. The equivocal group will require risk stratification, generally through a stress-type examination such as nuclear myocardial perfusion study or stress echocardiography. After stratification, further triaging of those at low and intermediate risk will benefit from non-invasive computed tomography coronary angiography. This is a low-risk, high-specificity study performed as an outpatient procedure. The role of the triple rule out study is not yet established but may change the clinical approach in diagnosing the causes of chest pain in future. At this stage, MRI is not viable in terms of availability and duration of study. PMID- 24791765 TI - Dizziness: if not vertigo could it be cardiac disease? AB - BACKGROUND: Dizziness is a common presentation in general practice. However, the symptom of dizziness represents a spectrum of pathology from benign to serious. OBJECTIVE: This review provides an evaluation of a patient presenting with presyncope/syncope. DISCUSSION: Dizziness can be a symptom of one of four conditions: vertigo, presyncope, disequilibrium or light-headedness. It is often unclear what patients mean by dizziness as they use this term loosely. Hence, clinicians must be vigilant in evaluating patients presenting with dizziness and be mindful of red flags that may indicate serious pathology. This review begins with a case study describing the wide range of causes of dizziness. Careful history taking and physical examination are pivotal in evaluating patients presenting with dizziness. PMID- 24791763 TI - Anticoagulation: a GP primer on the new oral anticoagulants. AB - BACKGROUND: The acceptability of warfarin has been limited by mandatory laboratory monitoring. A number of new orally active anticoagulants (NOACs), which can be used as alternatives to warfarin, are now available. OBJECTIVE: We review the clinical indications and considerations associated with the use of the NOACs. DISCUSSION: The NOACs currently approved in Australia are dabigatran, rivaroxaban and apixaban. Indications include thromboprophylaxis in non-valvular atrial fibrillation and following hip and knee replacement surgery. Rivaroxaban is also approved for treatment and secondary prevention of deep venous thrombosis (DVT) and pulmonary embolus (PE). The NOACs differ from warfarin in that they do not require laboratory monitoring. They need to be used cautiously in patients with renal impairment and are contraindicated in patients with renal failure. Bleeding may require blood product replacement aided by haematological advice and specialist investigations. Antidotes to the NOACS are undergoing clinical trials. PMID- 24791766 TI - We live in testing times - teaching rational test ordering in general practice. AB - BACKGROUND: Pathology, imaging and other tests have an essential role in the diagnosis and screening for disease in medical practice. However, over-testing has recently emerged as a significant issue and has implications for the patient, doctor and health system. Vocational training is arguably the most critical period in the development of future patterns of clinical practice for the GP. This includes the development of test ordering behaviour. The general practitioner (GP) supervisor, therefore, has a key role to play in educating registrars to avoid over-testing. OBJECTIVE: In this article, we discuss general approaches and practical strategies for GP supervisors to teach their registrars rational test ordering. DISCUSSION: Teaching should take a patient-centred focus and an emphasis on fostering a greater tolerance of uncertainty. Role modelling and demonstrated use of relevant clinical guidelines is a strong influence on registrar behaviour. Specific strategies for teaching rational test ordering include random case analysis, investigation audit, topic tutorials and use of targeted resources. PMID- 24791767 TI - Assessment and management of male androgen disorders: an update. AB - BACKGROUND: Male hypogonadism, caused by intrinsic pathology of the hypothalamic pituitary-testicular (HPT) axis, is an under-diagnosed condition not to be missed. By contrast, late onset hypogonadism (LOH), due to functional suppression of the HPT axis from age-related comorbidities, may be less common than previously believed. OBJECTIVE: This article outlines the aetiology, clinical features, investigation and management of male hypogonadism and discusses the more controversial area of LOH. DISCUSSION: Pathologically based hypogonadism is, after a thorough diagnostic work-up, treated with testosterone replacement therapy, unless fertility is desired. LOH with modest reductions in testosterone levels should primarily be managed by attention to lifestyle measures, especially weight loss, and optimisation of comorbidities. Clear treatment goals should be identified, and efficacy and safety should be monitored according to published clinical practice guidelines. PMID- 24791768 TI - Symmetrical cutaneous bilateral appendage - a case study. PMID- 24791769 TI - Approach to low back pain - acupuncture. AB - This article forms part of our allied health series for 2014, which aims to provide information about the management approach of different allied health professionals, using the case example of uncomplicated, mechanical low back pain. PMID- 24791770 TI - Management of dental infections by medical practitioners. AB - BACKGROUND: Patients with dental infections frequently present to primary care practitioners such as emergency physicians or general practitioners. It is important for these healthcare professionals to understand how to assess and treat such conditions, including when to refer and to whom. OBJECTIVE: This article aims to cover basic principles of managing patients with dental infections who present to emergency departments or general practice surgeries. DISCUSSION: Maxillofacial surgeons frequently see serious cases of facial and neck infections that can easily be prevented if appropriately managed early. PMID- 24791771 TI - The role of general practitioners in the continued success of the National Cervical Screening Program. AB - BACKGROUND: As the gateway to healthcare for Australian women, general practitioners (GPs) are critical to the success of the National Cervical Screening Program (NCSP). Despite an enviable record - halving the incidence and mortality of cervical cancer - in 2010-2011 more than 2.7 million women did not comply with the recommended 2-yearly screening interval. OBJECTIVE: General practice strategies are presented to assist GPs in encouraging all women, in particular, high-risk and vulnerable women, to participate in cervical screening. DISCUSSION: GPs play a crucial part in addressing the demographic, psychosocial and healthcare barriers that prevent women's participation in cervical screening. Encouraging uptake of the human papillomavirus vaccine and educating all patients on the importance of continued participation in cervical screening is essential for further decreasing the prevalence of this disease through early detection and treatment of cervical abnormalities. PMID- 24791772 TI - A skin quandary in Fiji. PMID- 24791773 TI - Helicobacter pylori eradication - an update on the latest therapies. AB - BACKGROUND: The eradication of Helicobacter pylori (H. pylori) can be challenging in certain circumstances. There is no current first-line therapy that is curative in all patients. OBJECTIVE: This article summaries the role of emerging novel therapies in the treatment of ?H. pylori. Known as sequential therapy and salvage therapy, these new therapeutic strategies are thought to produce eradication rates superior to currently recommended first-line therapies. This article outlines the growing body of evidence supporting their efficacy. DISCUSSION: Sequential therapy and salvage therapy have emerged recently as alternative regimens for the eradication of H. pylori. Although current guidelines continue to recommend established therapies for first-line management of H. pylori, general practitioners should be aware of these new strategies such that these options could be applied when traditional therapy fails. PMID- 24791774 TI - Recurrent palmar blister. PMID- 24791775 TI - Development of pre-consultation prevention summary and reminder sheets for patients: preliminary study of acceptability and sustainability. AB - BACKGROUND: Patients attending general practices receive about 60% of indicated preventive services. Patients do not know which preventive services are indicated for them and want their GPs to offer those services. METHODS: Patients arriving for consultations in three general practices received individualised prevention summary sheets. Acceptability was assessed by patient survey. Sustainability was assessed by the number of sheets printed over time. RESULTS: Seventy-two percent of patients discussed the advice on their sheet in the consultation, and 89% wanted to receive the sheets in the future. Practices printed 8882 sheets in the 52 weeks from the start of the trial. DISCUSSION: This new intervention seems to be acceptable and sustainable in the Australian setting. It has the potential, therefore, to increase the delivery of preventive care in general practice. A larger trial is needed to demonstrate its effect on performance of preventive activities and on patient outcomes. PMID- 24791776 TI - iPhone ECG screening by practice nurses and receptionists for atrial fibrillation in general practice: the GP-SEARCH qualitative pilot study. AB - BACKGROUND: Atrial fibrillation (AF) is often asymptomatic and substantially increases stroke risk. A single-lead iPhone electrocardiograph (iECG) with a validated AF algorithm could make systematic AF screening feasible in general practice. METHODS: A qualitative screening pilot study was conducted in three practices. Receptionists and practice nurses screened patients aged >=65 years using an iECG (transmitted to a secure website) and general practitioner (GP) review was then provided during the patient's consultation. Fourteen semi structured interviews with GPs, nurses, receptionists and patients were audio recorded, transcribed and analysed thematically. RESULTS: Eighty-eight patients (51% male; mean age 74.8 +/- 8.8 years) were screened: 17 patients (19%) were in AF (all previously diagnosed). The iECG was well accepted by GPs, nurses and patients. Receptionists were reluctant, whereas nurses were confident in using the device, explaining and providing screening. DISCUSSION: AF screening in general practice is feasible. A promising model is likely to be one delivered by a practice nurse, but depends on relevant contextual factors for each practice. PMID- 24791777 TI - 'I can sit and talk to her': Aboriginal people, chronic low back pain and healthcare practitioner communication. AB - BACKGROUND: Chronic low back pain (CLBP) is a complex issue to manage in primary care and under-researched in Aboriginal populations. Good communication between practitioners and patients is essential but difficult to achieve. This study examined communication from the perspective of Aboriginal people with CLBP in regional and remote Western Australia. METHODS: Qualitative, in-depth interviews were conducted with 32 adults with CLBP who identify as Aboriginal. The approach and analysis were informed by clinical ethnography and cultural security. RESULTS: Barriers to communication related to communication content, information that was not evidence-based, miscommunications, communicative absence and the use of medical jargon. Enablers related to communication style described as 'yarning', a two-way dialogue, and healthcare practitioners with good listening and conversational skills. DISCUSSION: Health practitioners need to consider communication content and style to improve interactions with Aboriginal people with CLBP. A 'yarning' style may be a useful framework. Findings may be pertinent to other populations. PMID- 24791778 TI - Increasing GP supervisor research skills - enhancing clinical practice and teaching. AB - BACKGROUND: General practitioner (GP) supervisors have a central role in GP training. Despite critical thinking, research and evidence-based medicine being part of the GP training curriculum, GP supervisors are unlikely to have had much training or practical support to increase their use of research evidence or participate in research themselves, nor to model research activity to their registrars. OBJECTIVE: This article discusses the needs, motivators and barriers to using and participating in research identified by 31 GP supervisors who attended research skills workshops in western Sydney, and potential strategies to increase their research engagement. DISCUSSION: GP supervisors reported interest in increased research engagement, particularly through efficient use of research evidence to guide practice and teaching, and through input into regional research priority setting. They believed training and practical support through regional training providers, universities and Medicare Locals was needed and would allow interested teaching practices to collaborate as practice-based research networks. PMID- 24791779 TI - Mohammed's case. PMID- 24791780 TI - Active commuting throughout adolescence and central fatness before adulthood: prospective birth cohort study. AB - BACKGROUND: Active commuting is a good opportunity to accumulate physical activity (PA) across the lifespan that potentially might influence central body fat. We aimed to examine the prospective associations of active commuting at 11, 15 and 18 years of age with central body fat at 18 years. METHODS: Participants were part of a large birth cohort study in Pelotas, Brazil (n = 3,649 participants). Active commuting, leisure-time PA and income were self-reported at 11, 15 and 18 years. Waist circumference and trunk fat mass were collected at 18 years with the use of a 3-dimensional photonic scanner and dual-energy X-ray absorptiometry, respectively. RESULTS: Active commuting at 11 years was not prospectively associated with central body fat. However, we found that active commuting at 15 and 18 years were prospectively and cross-sectionally associated with central body fat variables, respectively, in boys but not in girls. Also, boys in the highest tertile of accumulated active commuting (i.e., average of active commuting at 11, 13 and 18 years) were associated with -2.09 cm (95%CI: 3.24; -0.94) of waist circumference and -1.11 kg (95%CI: -1.74; -0.48) of trunk fat mass compared to boys in the lowest tertile. Analyses on changes in tertiles of active commuting from 11 and 15 years to 18 years with central body fat variables at 18 years showed that boys who remained consistently in the highest tertile or moved to a higher tertile had lower levels of central body fat compared to those consistently in the lowest tertile. CONCLUSIONS: Active commuting throughout adolescence in boys, especially during middle and late adolescence, is associated with lower levels in central fatness before adulthood. PMID- 24791781 TI - Health-related quality of life in the first year after laparoscopic radical prostatectomy compared with open radical prostatectomy. AB - OBJECTIVE: To assess health-related quality of life in the first year after laparoscopic radical prostatectomy compared with that after open radical prostatectomy. METHODS: The subjects were 105 consecutive patients with localized prostate cancer treated with laparoscopic radical prostatectomy between January 2011 and June 2012. Health-related quality of life was evaluated using the International Prostate Symptom Score, Medical Outcome Study 8-Items Short Form Health Survey (SF-8) and Expanded Prostate Cancer Index Composite at baseline and 1, 3, 6 and 12 months after surgery. Comparisons were made with data for 107 consecutive patients treated with open radical prostatectomy between October 2005 and July 2007. RESULTS: The International Prostate Symptom Score change was similar in each group. The laparoscopic radical prostatectomy group had a better baseline Medical Outcome Study 8-Items Short Form Health Survey mental component summary score and a better Medical Outcome Study 8-Items Short Form Health Survey physical component summary score at 1 month after surgery. In Expanded Prostate Cancer Index Composite, obstructive/irritative symptoms did not differ between the groups, but urinary incontinence was worse until 12 months after surgery and particularly severe after 1 month in the laparoscopic radical prostatectomy group. The rate of severe urinary incontinence was much higher in the laparoscopic radical prostatectomy group in the early period. Urinary bother was worse in the laparoscopic radical prostatectomy group at 1 and 3 months, but did not differ between the groups thereafter. Urinary function and bother were good after nerve sparing procedures and did not differ between the groups. Bowel and sexual function and bother were similar in the two groups. CONCLUSION: Urinary function in the first year after laparoscopic radical prostatectomy is worse than that after open radical prostatectomy. PMID- 24791782 TI - Incidence and risk factors of 30-day early and 90-day late morbidity and mortality of radical cystectomy during a 13-year follow-up: a comparative propensity-score matched analysis of complications between neobladder and ileal conduit. AB - OBJECTIVE: We report on the short and late morbidity and mortality of ileal conduit and neobladder after radical cystectomy with their associated risk factors. METHODS: We retrospectively collected data on 308 non-metastatic bladder cancer patients who underwent radical cystectomy with either ileal conduit or neobladder for a curative intent from January 1999 to December 2011. Post operative morbidity and mortality of 30-day (early) and 90-day (late) complication with their risk factors were examined in association with different types of urinary diversion. A comparative analysis using propensity-score matching was performed with matching variables of age, sex, number of underlying diseases and pathologic T and N stages, lymph node dissection, operative time and time of surgical year for comparison of the early and late morbidities between ileal conduit and neobladder. RESULTS: During the median follow-up of 46.6 months, early and late morbidities were 29.5% (n=91) and 19.8% (n=61), and complication-related mortalities were 2.2 and 6.6%, respectively. The type of urinary diversion significantly affected only the late complications (early: neobladder 57 vs. ileal conduit 47, P=0.096; late: neobladder 67 vs. ileal conduit 37, P<0.001). However, after propensity-score matching, no significant differences in early and late morbidities were observed between neobladder and ileal conduit. For risk factors of morbidity, number of removed lymph node states and hypertension were independently significant for both early and late complications (P<0.05). CONCLUSIONS: The type of urinary diversion affected only late complication, however, results of the matching analysis showed no significant differences in early and late morbidities between neobladder and ileal conduit. PMID- 24791783 TI - The role of dye affinity in optical measurements of Cai(2+) transients in cardiac muscle. AB - Previous experiments in cultures of neonatal rat myocytes demonstrated that the shape of Cai(2+) transients measured using high-affinity Ca(2+)-sensitive dyes may be misrepresented. The purpose of this study was to examine the role of dye affinity in Cai(2+) measurements in intact adult cardiac tissue by comparing optical recordings obtained with high- and low-affinity dyes. Experiments were carried out in porcine left ventricular (LV) wedge preparations stained locally by intramural injection via microcapillaries (diameter = 150 MUm) with a low affinity Ca(2+)-sensitive dye Fluo-4FF or Fluo-2LA (nominal Kd, ~7-10 MUmol/l), high-affinity dye Rhod-2 (Kd = 0.57 MUmol/l), and Fluo-4 or Fluo-2MA (Kd, ~0.4 MUmol/l); in addition, tissue was stained with transmembrane potential (Vm) sensitive dye RH-237. Optical recordings of Vm and Cai(2+) were made using optical fibers (diameter = 325 MUm) glued with the microcapillaries. The durations of Cai(2+) transients measured at 50% level of recovery (CaD50) using high-affinity Fluo-4/Fluo-2MA dyes were up to ~81% longer than those measured with low-affinity Fluo-4FF/Fluo-2LA at long pacing cycle lengths (CL). In Fluo 4/Fluo-2MA measurements at long CLs, Cai(2+) transients often (~50% of cases) exhibited slow upstroke rise and extended plateau. In Rhod-2 measurements, CaD50 was moderately longer (up to ~35%) than in Fluo-4FF recordings, but Cai(2+) transient shapes were similar. In all series of measurements, mean action potential duration values were not significantly different (P > 0.05). The delays between Vm and Cai(2+) upstrokes were comparable for low- and high-affinity dyes (P > 0.05). In conclusion, measurements of Cai(2+) transient in ventricular myocardium are strongly affected by the affinity of Ca(2+) dyes. The high affinity dyes may overestimate the duration and alter the shape of Cai(2+) transients. PMID- 24791784 TI - Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity. AB - Impaired exercise capacity is common after the Fontan procedure and is attributed to cardiovascular limits. The Fontan circulation, however, is also distinctively vulnerable to unfavorable lung mechanics. This study aimed to define the prevalence and physiological relevance of pulmonary dysfunction in patients with Fontan physiology. We analyzed data from the Pediatric Heart Network Fontan Cross Sectional Study to assess the prevalence and pattern of abnormal spirometry in Fontan patients (6-18 yr old) and investigated the relationship between low forced vital capacity (FVC) and maximum exercise variables, including peak O2 consumption (Vo2peak), among those who demonstrated adequate effort (n = 260). Average ages at the time of exercise testing and Fontan completion were 13.2 +/- 3.0 and 3.5 +/- 2.2 yr old, respectively. Aerobic capacity was reduced (Vo2peak: 67.3 +/- 15.6% predicted). FVC averaged 79.0 +/- 14.8% predicted, with 45.8% having a FVC less then the lower limit of normal. Only 7.8% demonstrated obstructive spirometry. Patients with low FVC had lower Vo2peak (64.4 +/- 15.9% vs. 69.7 +/- 14.9% predicted, P < 0.01); low FVC independently predicted lower Vo2peak after adjusting for relevant covariates. Among those with Vo2peak < 80% predicted (n = 204/260), 22.5% demonstrated a pulmonary mechanical contribution to exercise limitation (breathing reserve < 20%). Those with both low FVC and ventilatory inefficiency (minute ventilation/CO2 production > 40) had markedly reduced Vo2peak (61.5 +/- 15.3% vs. 72.0 +/- 14.9% predicted, P < 0.01) and a higher prevalence of pulmonary mechanical limit compared with patients with normal FVC and efficient ventilation (36.1% vs. 4.8%). In conclusion, abnormal FVC is common in young patients after the Fontan procedure and is independently associated with reduced exercise capacity. A large subset has a pathologically low breathing reserve, consistent with a pulmonary mechanical contribution to exercise limitation. PMID- 24791785 TI - Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning. AB - Dystrophin is responsible for the mechanical stabilization of the sarcolemma, and it has been shown that it is one of the most sensitive proteins to ischemic injury. However, the enzyme responsible for this proteolysis is still unknown. Isolated rabbit hearts were subjected to 30 min of global ischemia with and without reperfusion (180 min) to determine whether dystrophin is cleaved by matrix metalloproteinase (MMP)-2 during acute ischemia and whether ischemic preconditioning (PC) prevents dystrophin breakdown through MMP-2 inhibition. The activity of MMP-2 was evaluated by zymography and using doxycycline as an inhibitor. Also, to stimulate MMP-2 activity without ischemia, SIN-1 was administered in the absence and presence of doxycycline. Finally, we considered the PC effect on MMP-2 activity and dystrophin expression. The dystrophin level decreased during ischemia, reaching 21% of control values (P < 0.05), but the spectrin level remained unchanged. MMP-2 activity increased 71% during ischemia compared with control values (P < 0.05). Doxycycline administration before ischemia prevented dystrophin breakdown. In normoxic hearts, SIN-1 increased thiobarbituric acid-reactive substances by 33% (P < 0.05) and MMP-2 activity by 36% (P < 0.05) and significantly reduced the dystrophin level to 23% of control values (P < 0.05). PC significantly prevented dystrophin breakdown by inhibiting MMP-2 activity, and the dystrophin level reached 89% of control values (P < 0.05). In conclusion, MMP-2 could be responsible for the proteolysis of dystrophin. Thus, dystrophin emerges as a possible novel substrate for MMP-2 in the context of ischemic injury. Furthermore, our results demonstrate that ischemic PC prevents dystrophin breakdown most likely by inhibiting MMP-2 activity. PMID- 24791787 TI - Side-specific mechanical properties of valve endothelial cells. AB - Aortic valve endothelial cells (ECs) function in vastly different levels of shear stress. The biomechanical characteristics of cells on each side of valve have not been investigated. We assessed the morphology and mechanical properties of cultured or native valve ECs on intact porcine aortic valve cusps using a scanning ion conductance microscope (SICM). The autocrine influence of several endothelial-derived mediators on cell compliance and the expression of actin were also examined. Cells on the aortic side of the valve are characterized by a more elongated shape and were aligned along a single axis. Measurement of EC membrane compliance using the SICM showed that the cells on the aortic side of intact valves were significantly softer than those on the ventricular side. A similar pattern was seen in cultured cells. Addition of 10(-6) M of the nitric oxide donor sodium nitroprusside caused a significant reduction in the compliance of ventricular ECs but had no effect on cells on the aortic side of the valve. Conversely, endothelin-1 (10(-10)-10(-8) M) caused an increase in the compliance of aortic cells but had no effect on cells on the ventricular side of the valve. Aortic side EC compliance was also increased by 10(-4) M of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester. Immunofluorescent staining of actin filaments revealed a great density of staining in ECs on the ventricular surface. The expression of actin and the relative membrane compliance of ECs on both side of the valve were not affected by ventricular and aortic patterns of flow. This study has shown side-specific differences in the biomechanics of aortic valve ECs. These differences can have important implications for valve function. PMID- 24791786 TI - Validation of pulse rate variability as a surrogate for heart rate variability in chronically instrumented rabbits. AB - Heart rate variability (HRV) is a function of cardiac autonomic tone that is widely used in both clinical and animal studies. In preclinical studies, HRV measures are frequently derived using the arterial pulse waveform from an implanted pressure telemetry device, termed pulse rate variability (PRV), instead of the electrocardiogram signal in accordance with clinical guidelines. The acceptability of PRV as a surrogate for HRV in instrumented animals is unknown. Using rabbits implanted with intracardiac leads and chronically implanted pressure transducers, we investigated the correlation and agreement of time domain, frequency-domain, and nonlinear indexes of HRV and PRV at baseline. We also investigated the effects of ventricular pacing and autonomic blockade on both measures. At baseline, HRV and PRV time- and frequency-domain parameters showed robust correlations and moderate to high agreement, whereas nonlinear parameters showed slightly weaker correlations and varied agreement. Ventricular pacing almost completely eliminated HRV, and spectral analysis of the PRV signal revealed a HRV-independent rhythm. After cardiac autonomic blockade with atropine or metoprolol, the changes in time- and non-normalized frequency-domain measures of PRV continued to show strong correlations and moderate to high agreement with corresponding changes in HRV measures. Blockade-induced changes in nonlinear PRV indexes correlated poorly with HRV changes and showed weak agreement. These results suggest that time- and frequency-domain measures of PRV are acceptable surrogates for HRV even in the context of changing cardiac autonomic tone, but caution should be used when nonlinear measures are a primary end point or when HRV is very low as HRV-independent rhythms may predominate. PMID- 24791788 TI - [Trend analysis of cervical cancer incidence and mortality rates in Chinese women during 1989-2008]. AB - OBJECTIVE: To evaluate the trend of cervical cancer incidence and mortality rates during 1989-2008 in Chinese women, so as to inform the development of relevant policies and strategies in China. METHODS: The incidence and mortality rates of cervical cancer during 1989-2008 in urban and rural areas were calculated based on the data from the National Cancer Registry Database. Age-standardized rates were calculated using the Chinese population of 1982 and World Segi's population of 1985. Joinpoint regression analysis was performed to obtain annual percentage changes (APC) so as to assess the trend of incidence and mortality rates over the period from 1989 to 2008. RESULTS: The crude incidence rate of cervical cancer in Chinese women increased from 3.06/10(5) in 1989-1990 to 11.87/10(5) in 2007-2008 (from 4.96/10(5) to 11.98/10(5) in urban registration areas and from 2.39/10(5) to 11.77/10(5) in rural registration areas).The crude mortality rate slightly increased from 2.19/10(5) in 1989-1990 to 3.20/10(5) in 2007-2008 (from 3.21/10(5) to 2.56/10(5) in urban registration areas and from 1.82/10(5) to 3.75/10(5) in rural registration areas). Generally, the upward trends of crude incidence rates were shown over the year 1989-2008, with an APC of 14.4% after 1997 in urban areas and 22.5% after 1999 in rural areas.After age standardization of world population, the APC of incidence rates in recent decade in urban areas remained stable, and the one in rural areas slightly decreased.Although the overall crude and world age-standardized mortality rates had no significant changes during 1989-2008, the crude mortality rates increased by 8.1% annually after 1999.The upward trends were also shown for crude and world age-standardized mortality rates in urban areas after 2001 with an APC of 7.3%.The crude mortality rates in rural areas increased by 3.9% annually during 1989-2008, but no significant change was found after age standardization. CONCLUSIONS: Over the last decade, the cervical cancer incidence and mortality rates ascended by year in China. It is particularly urgent to establish a comprehensive prevention and control system that combines cervical cancer screening and human papillomavirus vaccination, so as to reduce the burden of cervical cancer in Chinese women. PMID- 24791789 TI - [Right extremities pain caused by a malacia lesion in the left putamen:a resting functional magnetic resonance imaging of the marginal division of the human brain]. AB - OBJECTIVE: To explore the role of marginal division of the human brain in the pain modulation. METHODS: Resting functional magnetic resonance imaging was applied in a patient with right extremities pain caused by a malacia lesion in the left putamen and in 8 healthy volunteers. Marginal division was defined using manual drawing on structure images, and was applied to the computation of fuctional connectivity maps. RESULTS: The functional connectivities in the left marginal division showed an evident decrease in the patient when compared with healthy controls. These connectivities were mainly located in the bilateral head of caudate nucleus, putamen, and left globus pallidus. CONCLUSION: The marginal division may be involved in the pain modulation. PMID- 24791790 TI - [Clinical analysis of two carotid endarterectomy procedures in treating carotid artery stenosis]. AB - OBJECTIVE: To analyze the effectiveness and costs of the eversion carotid endarterectomy (eCEA) and the carotid endarterectomy with patch angioplasty (pCEA) in treating carotid artery stenosis. METHODS: Patients with carotid artery stenosis who underwent the carotid endarterectomy in the vascular surgery department of Peking Union Medical College Hospital from October 2009 to October 2012 were enrolled in this study. According to the two different surgical procedures, the patients were divided into eCEA group and pCEA group. RESULTS: The two groups were not significantly different in terms of gender ,age ,risk factors, stenosis degree of carotid artery, and the ratio of bilateral lesions (all P>0.05).The ratio of shunt and antibiotics application, operative time, hospitalization cost, and length of hospital stay in the eCEA group were significantly lower than those in pCEA group (P<0.05).The therapeutic effectiveness, complications, surgery-related death, restenosis, and ipsilateral stroke were not significantly different between these two groups (P>0.05). CONCLUSION: Both surgical procedures are safe and effective in treating the carotid artery stenosis;however, eCEA has lower cost when compared with pCEA and therefore can be used as the first choice. PMID- 24791792 TI - [Expressions of MicroRNA-96 before and after chemotherapy and its relationship with chemosensitivity in cervical squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression profiles of microRNA-96 (miR-96) in cervical squamous cell carcinoma before and after neoadjuvant chemotherapy and to explore the effects of the treatment on expression of miR-96 and its relationship with clinical efficacy, chemosensitivity, and clinicopathologic features. METHODS: The expression of miR-96 was detected by real-time polymerase chain reaction in 28 patients with cervical squamous cell carcinoma (stage 1b2-2a) before and after neoadjuvant chemotherapy. The correlations between the change of miR-96 and related clinicopathologic features of cervical cancer (age, pathologic pattern, histological grade, depths of interstitial infiltration, lymph node metastasis, and clinical stage) were further analyzed. RESULTS: The relative expression of miR-96 in cervical squamous cell carcinoma before treatment was (5.330 +/- 5.069) times higher than after the treatment with neoadjuvant chemotherapy (P=0.000).The relative change of the expressions of miR-96 in cervical cancer patients between pre-and post-neoadjuvant chemotherapy was closely related with clinicopathological features:it was significantly smaller in poorly-or moderately-differentiated patients (2.345 +/- 1.153) than in well differentiated patients (9.941 +/- 5.359) (P=0.000), significantly larger in patients with the tumor invasion depth < 1/2 interstice (8.236 +/- 5.399) than in >=1/2 interstice (1.978 +/- 1.030) (P=0.000), and significantly smaller in patients with lymph node metastasis (1.848 +/- 0.959) than those without lymph node metastasis (7.942 +/- 5.348) (P=0.000). There was no significant difference in terms of age and clinical stages (1b2-2a) (P>0.05). CONCLUSIONS: Neoadjuvant chemotherapy can effectively reduce miR-96 expression in cervical squamous cell carcinoma tissues.It is therefore speculated that detection of the miR-96 expression before the chemotherapy for cervical cancer may be helpful to predict the therapeutic efficacy and sensitivity of the treatment. PMID- 24791791 TI - [Effects of poly(ADP-ribose)polymerase inhibitor AG014699 combined with chemotherapy on the proliferation of triple-negative breast cancer cell line MDA MB-231]. AB - OBJECTIVE: To observe the effects of poly(ADP-ribose)polymerase (PARP) inhibitor AG014699 alone and combined with docetaxel (DTX) or carboplatin (CBP) on the proliferation of triple-negative breast cancer cell line MDA-MB-231 and to investigate whether PARP inhibitor AG014699 combined with chemotherapy could play a synergistic antitumor effect. METHODS: MDA-MB-231 cells were treated by PARP inhibitor AG014699 alone or combination with DTX or CBP. Cell proliferation was measured by cell counting kit-8 assay. The combined effect was evaluated by q value less than 0.85, in the range of 0.85 and 1.15, more than 1.15, which respectively meant that the combined effect of the drugs was antagonistic, additive, and synergistic. RESULTS: Treatment with PARP inhibitor AG014699, DTX, or CBP alone inhibited the proliferation, induced apoptosis and blocked the cell cycle. The cell viability of AG014699 (10 umol/L) combined with DTX (10(-8), 10( 7), 10(-6), 10(-5) mol/L) or CBP (10(-5), 10(-4) mol/L) were lower than that of the drug used alone, and q value was between 0.85 and 1.15, suggesting the combined effect was additive. The cell viability of AG014699 (10 umol/L) combined with CBP (10(-3) mol/L) was lower than that of the drug used alone, and q value was more than 1.15, suggesting the combined effect was synergetic. A combination of PARP inhibitor AG014699 and DTX or CBP promoted apoptosis and increased the proportion of G2/M stage cells. CONCLUSION: PARP inhibitor AG014699 combined with DTX or CBP can remarkably inhibit MDA-MB-231 cell proliferation, showing additive or synergistic antitumor effects. PMID- 24791793 TI - [Association of interleukin-1beta genetic polymorphisms with obstructive sleep apnea syndrome]. AB - OBJECTIVE: To investigate the association between interleukin (IL)-1beta genetic polymorphisms and obstructive sleep apnea syndrome (OSAS). METHODS: Totally 850 individuals with hypertension were included. All of them were checked by polysomnography in the Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region from January to December in 2010. According to the results of polysomnography, these subjects were divided into non-OSAS group (n=225)and OSAS group (n=625). Genetic variations were sequenced and screened at loci over functional region of IL-1beta gene in 96 patients with severe OSAS.The typical loci were selected for genotyping by TaqMan-polymerase chain reaction in 850 subjects. RESULTS: One novel and 5 known variations in the IL-1beta gene were identified, and then three representative mutation loci were selected for genotyping.The allele frequency distribution of rs1143633 was significantly different between the OSAS and non-OSAS groups in the total and male populations (chi(2)=9.258, P=0.002;chi(2)=5.119, P=0.024, respectively). Although the parameters of sleep apnea monitoring showed no significant difference in individuals with CC, CT, and TT genotypes of rs1143633 in total, male, and female populations (P>0.05), the median of the apnea hypopnea index of CT genotype was significantly higher than that of CC and TT in total and male populations and the mean of the lowest blood oxygen saturation increased in individuals with CC, CT, and TT genotypes of rs1143633 in total and male populations.Haplotype was no significantly associated with OSAS in total,male,and female populations(P>0.05).Logistic regression analysis showed that CT genotype of rs1143633 variation was a risk factor for OSAS in total and male populations (OR=1.574,95% CI=1.061-2.437,P=0.042;OR=1.887,95% CI=1.091- 3.265,P=0.023). CONCLUSION: The rs1143633 polymorphism in IL-1beta gene may be associated with OSAS. PMID- 24791794 TI - [Association of myocardial bridge of the left anterior descending coronary artery with coronary atherosclerotic stenosis in the segment proximal to the site of bridge]. AB - OBJECTIVE: To investigate whether myocardial bridging (MB) is independently associated with coronary atherosclerosis proximal to MB in the left anterior descending coronary artery (LAD) identified by computed tomographic coronary angiography (CCTA). METHODS: From March 2011 to December 2012, patients (n=9 862) with suspected coronary disease underwent CCTA using dual-source CT scanner. The baseline clinical characteristics (age, gender, smoking history, presence of hypertension, dyslipidemia, diabetes mellitus, family history of heart attack, and body mass index) and the results of CCTA were reviewed. Two radiologists evaluated the coronary artery for MB and coronary atherosclerosis stenosis (CAS) in LAD and made a diagnosis by consensus. Significant independent risk factors for CAS were investigated by multivariate logistic regression analysis. RESULTS: A total of 3 182 (32.3%) cases of MB and 3 359 cases of CAS of LAD were identified. No patient with CAS in the tunneled segment was found. The mean length of bridges and the mean thickness of the overlying myocardium was (17.3+/ 5.2) mm and (1.2+/-0.9) mm, respectively. There were 1658 MB cases in 3 359 cases of LAD stenosis and 1 524 MB cases in 6 503 cases of no LAD stenosis (chi(2)=681.12, P<0.05). Logistic regression analysis showed that MB in the LAD were significantly associated with CAS in the proximal LAD (OR=3.07, 95%CI=2.81 3.37, P<0.001), and after final adjustment for age, gender, body mass index, family history of heart attack, smoking, hypertension, dyslipidemia, diabetes mellitus, and resting heart rate (OR=2.86, 95% CI=2.60-3.16, P < 0.001). CONCLUSION: MB in the LAD is independently associated with CAS in the proximal segment to MB. PMID- 24791795 TI - [Clinical features of carotid-cavernous sinus fistulas in 23 patients]. AB - OBJECTIVE: To analyze the clinical features of carotid-cavernous sinus fistulas (CCFs). METHODS: The medical records of 23 patients with CCFs, which was confirmed by conventional cerebral angiography, in Peking Union Medical College Hospital from January 1990 to October 2012 were retrospectively analyzed. Data including patient characteristics, clinical features on ophthalmic examination, neurological assessment, and imaging study were collected.The differences between the direct and the indirect CCFs were compared, and the reasons for misdiagnoses were analyzed. RESULTS: Most patients were presented with ocular symptoms (78.3%). The most common signs were conjunctival injection or chemosis (78.3%), proptosis (69.6%), and ocular motor palsies (56.5%). There were 13 (56.5%) direct CCFs and 1 0(43.5%) indirect CCFs, and a history of encephalic trauma was more frequently reported among the former (61.5%) than the latter (10.0%); also, intracranial vascular murmur was more prevalent in patients with direct CCFs (69.2%vs.20.0%). Nine patients were misdiagnosed as other ocular diseases. Nonspecific clinical symptoms and signs such as chemosis, elevated intraocular pressure, and diplopia were the common causes of the misdiagnoses. CONCLUSIONS: Misdiagnosis of CCFs remains common due to its diverse clinical manifestations.CCFs should be suspected in patients with refractory red eyes, intraocular pressure elevation, proptosis and/or ophthalmoplegia, and a detailed history-taking, careful physical examination, and adequate imaging may minimize the misdiagnosis. PMID- 24791796 TI - [Role of epidermal growth factor receptor expression level in cetuximab cytotoxicity and antibody-dependent cell-mediated cytotoxicity effect against A549 lung cancer cell line]. AB - OBJECTIVE: To investigate the role of epidermal growth factor receptor (EGFR) expression level in cetuximab cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) effect against A549 lung cancer cell line. METHODS: A549 cell line and NKTm cells were used as the target cell and the effector cell, respectively. pEGFR-EGFP plasmids were transfected into A549 cells by nucleofector method. EGFR expression levels were measured by immunohistochemistry. The ADCC activity induced by cetuximab was assessed by cell counting kit-8 assay. RESULTS: A549 cells transfected with pEGFR-EGFP plasmids expressed higher level of EGFR protein on membrane and were more sensitive to ADCC activity mediated by cetuximab (P<0.05). The inhibition rate of A549 cells showed no significant difference between transfection group and wild-type group when treated with cetuximab alone (P> 0.05). CONCLUSION: EGFR expression level influences the sensitivity of A549 lung cancer cell line to ADCC activity mediated by cetuximab but not to cetuximab alone. PMID- 24791797 TI - [Relationship between genetic variation of furin gene and hypercholesterolemia and hyper-low-density lipoprotein cholesterolemia in Kazakh general population]. AB - OBJECTIVE: To investigate the relationship between the genetic variation of Furin gene and the hypercholesterolemia and hyper-low-density lipoprotein cholesterolemia in Kazakh general population. METHODS: Based on a cross-sectional epidemiological study in a Kazakh general population, a case-control study including 878 subjects was conducted. All the sequence variant-located promoters and exon regions of Furin gene were identified by the direct sequencing of PCR products in 48 randomly selected hypercholesterolemic individuals (24 males and 24 females). After having genotyped the representative polymorphisms in 878 subjects by TaqMan PCR, we investigated the relationship between genetic variation of Furin and hypercholesterolemia/hyper-low-density lipoprotein cholesterolemia in these subjects. RESULTS: Twelve genetic variations in Furin gene were identified by sequencing 48 hypercholesterolemic individuals and 4 common single nucleotide polymorphisms (rs6226, rs6227, rs2071410, and rs4932178)were selected as the representatives for genotyping in these subjects. The rs6226, rs6227, rs2071410, and rs4932178 polymorphisms were successfully genotyped. The distribution of the genotypes, alleles, and haplotypes of rs6226, rs6227, rs2071410, and rs4932178 polymorphisms did not differ significantly between the hypercholesterolemia group and the control groups or between the hyper-low-density lipoprotein cholesterolemia group and the control groups (all P>0.05). The cholesterol and low-density lipoprotein cholesterol levels did not differ significantly among individuals with different genotypes (all P>0.05). CONCLUSION: The genetic variation of Furin may not be associated with hypercholesterolemia or hyper-low-density lipoprotein cholesterolemia in Kazakh general population. PMID- 24791798 TI - [Effect of inflammatory factors on cell proliferation and apoptosis in insulin like grown factor 1-slienced human coronary artery smooth muscle cells]. AB - OBJECTIVE: To study the effect of inflammatory factors on cell proliferation and apoptosis in insulin-like grown factor 1 (IGF1)-slienced human coronary artery smooth muscle cells (hCASMCs). METHODS: We silenced the expression of IGF1 in hCASMCs using the lentivirus-mediated RNA interference technology. Blank control group and negative control group were set using the hCASMCs without the infection of a virus vector and the hCASMCs with the infection of a negative control virus vector, respectively. After the treatment of these cells with both tumor necrosis factor-alpha 50 ng/ml and interleukin-1beta 40 ng/ml, the concentration of IGF1 in cell-culture medium was detected by enzyme-linked immunosorbent assay, and the proliferation and apoptosis were evaluated by MTT assay and flow cytometry. RESULTS: After the simulation with inflammatory factors, the concentration of IGF1 in the supernatant fluid of cultured IGF1-slienced hCASMCs was significantly lower than those in the blank control group and negative control group [(426.35+/ 120.96) vs. (1 030.69+/-54.69) and (992.82+/-26.90)pg/ml, P=0.000). The proliferation of IGF1-slienced hCASMCs was substantially much less than the two control groups (0.302+/-0.011 vs. 0.401+/-0.028 and 0.302+/-0.011, F=37.628, P=0.000), and the apoptosis rate of IGF1-slienced hCASMCs was significant increased compared with the other two groups [(10.57+/-0.99)% vs. (0.19+/-0.13)% and (1.31+/-0.30)%, P=0.001]. CONCLUSION: Inflammatory factors can inhibit the cell proliferation and promote apoptosis after the knock-down of IGF1 in hCASMCs. PMID- 24791799 TI - [Reevaluating the role of dilation and curettage in the diagnosis of ectopic pregnancy]. AB - OBJECTIVE: To evaluate the clinical role of dilation and curettage (DC) in the diagnosis of ectopic pregnancy (EP). METHODS: We retrospectively reviewed the clinical data of 108 patients with pregnancy of unknown location who underwent a DC with an abnormal rise in beta-human chorionic gonadotropin (beta-HCG) level and without visible intrauterine pregnancy (IUP) on transvaginal ultrasound and 24 patients who did not receive DC with beta-HCG>5 000 IU/L.The final diagnosis depended on beta-HCG trend review after DC and the pathologic and laparoscopic findings. RESULTS: Overall, 65.3% of the patients were finally diagnosed with EP and 34.7% were found to have a nonviable IUP.Those with EP had significantly higher initial beta-HCG than those with nonviable IUP.IUP patients were more likely to have had a history of delivery.Among the patients with beta-HCG<2 000 IU/L, 40.0% of EP and 11.0% of IUP had endometrial echo complex no more than 5 mm (P=0.035). In beta-HCG<2 000 IU/L and 2 000 IU/L5 000 IU/L, there was no significant difference between those with DC and those without DC (96.7% vs.96%, P=0.915). CONCLUSIONS: Ultrasound findings such as a thin endometrial echo complex and the presence of pelvic mass are associated with but are not diagnostic of an ectopic pregnancy.The patients with the suspected diagnosis of EP are 2 000 IU/L5 000 IU/L and pelvic mass and without intrauterine gestational sac, the value of DC decreases and laparoscopy can be considered directly. PMID- 24791800 TI - [Preliminary analysis on the treatment of ventilator-associated pneumonia caused by pandrug-resistant Acinetobacter baumannii]. AB - OBJECTIVE: To analyze the clinical features of pandrug-resistant Acinetobacter baumannii (PDR-Ab) in the Chinese PLA General Hospital and compare the efficacies of different antibiotic treatments in aged patients with ventilator-associative pneumonia (VAP) caused by PDR-Ab. METHODS: Data were collected from all isolated PDR-Ab strains in our hospital from April 2009 to April 2010. The clinical features, treatment, and outcomes were retrospectively reviewed. RESULTS: PDR-Ab was found to be the dominant pathogen in 42 of 126 aged VAP patients. Cefoperazone/sulbactam plus minocycline showed good efficacy in 20 patients with PDR-Ab VAP, showing a clinical cure rate of 65% (13/20) and a bacterial eradication rate of 40% (8/20). Another 22 patients were treated with other antimicrobial drugs, achieving a clinical cure rate of 22.7% (5/22) and a bacterial eradication rate of 13.6% (3/22). The factors influencing bacterial clearance were prolonged length of hospital stay and mechanical ventilation prior to positive culture (all P<0.01). CONCLUSION: Cefoperazone/sulbactam plus minocycline can be an effective treatment for VAP caused by PDR-Ab. PMID- 24791801 TI - [Treatment of pituitary adenomas invading cavernous sinus with neuroendoscopy assisted by multiple techniques]. AB - OBJECTIVE: To study the effectiveness of treating giant pituitary adenomas invading cavernous sinus with neuroendoscopy assisted by multiple techniques. METHODS: A total of 72 patients who underwent neuroendoscopic surgery and 55 patients who underwent microscopic surgery for giant pituitary adenomas were enrolled in this retrospective analysis. Both groups received expanded endoscopic endonasal transsphenoidal approach, intraoperative application of navigation, and Doppler.The clinical data of two groups were compared. RESULTS: The two groups were significantly different in total tumor removal rate, operation time, postoperative nasal patency, and postoperative recurrence rate (P=0.004, P=0.0003, P=0.000, and P=0.002, respectively), whereas the cerebrospinal fluid leakage, postoperative diabetes insipidus, and cranial nerve injury were not significantly different (P > 0.05). CONCLUSIONS: Expanded neuroendoscopic endonasal transsphenoidal approach assisted by multiple techniques is the preferred surgical method for giant invasive pituitary adenomas invading cavernous sinus.The lateral cavernous sinus approach and the further molecular biology research will bring more options for the treatment of invasive pituitary adenomas. PMID- 24791802 TI - [Effectiveness and safety of endoscopic ultrasound-guided transgastric or transpapillary drainage in treating pancreatic pseudocyst]. AB - OBJECTIVE: To explore the effectiveness and safety of endoscopic transgastric or transpapillary drainage in treating pancreatic pseudocysts. METHODS: The clinical data of 15 patients with pancreatic pseudocyst who underwent endoscopic ultrasound-guided transgastric or transpapillary drainage in the Chinese PLA General Hospital between June 2004 and February 2013 were retrospectively analyzed. Also, we reviewed the relevant Chinese literature in the China Academic Journal Network Publishing Database (from 1994 to 2012) and VIP China Science and Technology Journal Database (from 1989 to 2012) using the key words "pancreatic pseudocyst and drainage". Five literatures including 103 cases were enrolled. RESULTS: The data of 118 cases undergoing endoscopic drainage, included 94 cases with transgastric approach and 24 with transpapillary approach, entered the final analysis. The success rate was 94.9%, and cysts completely disappeared in 83.9% of the patients. The overall incidence of complications (bleeding, infection, and stent clogging or migration) was 19.5%. One patient lost to follow-up and only one case of recurrence was noted. CONCLUSION: Endoscopic transgastric or transpapillary drainage is safe and effective in treating the pancreatic pseudocysts and therefore can be a preferred therapeutic approach. PMID- 24791803 TI - [Retrospective analysis of 50 cases of senile syphilis]. AB - OBJECTIVE: To summarize the epidemiological features of senile syphilis. METHOD: The clinical data of 50 elderly (>60 years) patients with syphilis who were treated in the Clinic of Sexually Transmitted Diseases of Peking Union Medical College Hospital were retrospectively analyzed. RESULTS: There were 31 men and 19 women (male to female ratio:1.6:1). Non-marital sexual intercourse was the main route of transmission. The disease was mainly found before surgeries. Among these 50 syphilis cases, 3 were primary syphilis, 13 were secondary syphilis, 10 were early latent syphilis, 12 were late latent syphilis, and 12 were latent syphilis of unknown duration. Co-morbidities with other sexually transmitted diseases were found in 4 patients. The rate of sero-resistance was 40%. CONCLUSIONS: The incidence of syphilis in the senile population is higher than we expected. Routine serological screening for syphilis is required in clinical settings. The underlying diseases, human hosts-related spirochetes, and laboratory testing techniques are important reasons for the false positive findings in senile patients. PMID- 24791804 TI - [Management options of caesarean scar pregnancy]. AB - Cesarean scar pregnancy is an uncommon ectopic gestation. Without timely and proper management, it may cause major bleeding, uterine rupture, and other life threatening complications. The causes of this condition remain unclear, and no standardized management has been available, although some medical and surgical treatment modalities have been suggested. The main treatment objectives include preventing massive blood loss, preserving the uterus function, and maintain the women's health and quality of life. Current data do not support expectant management. After early diagnosis, single or combined medical and surgical treatment options should be provided to avoid uterine rupture and haemorrhage, so as to preserve the uterus and thus the fertility. PMID- 24791805 TI - [MicroRNA and gastric cancer]. AB - Gastric cancer is caused by the interaction of genetic and environmental factors. MicroRNA (miRNA) is involved in many cellular processes including proliferation, differentiation, and apoptosis and plays an important role in pathogenesis of gastric cancer, as demonstrated in many recent studies from perspectives including miRNA profiling, reciprocal modulation between epigenetic and miRNA, and Helicobacter pylori infection. MiRNA is highly stabe in blood, and therefore non-invasive diagnosis of gastric cancer using circulating miRNA may be promising. PMID- 24791806 TI - [Research advances in epithelial-mesenchymal transition in thyroid carcinoma]. AB - Increasing evidences have demonstrated the roles of epithelial-mesenchymal transition in tumor invasion and metastasis. In the invasive front of papillary thyroid carcinoma, the expressions of adhesion molecules are often lost. In anaplastic thyroid carcinoma, tumor cells showing cancer stem cell characteristics have been identified. Epithelial-mesenchymal transition may thus play a key role in the progression of thyroid cancer. Therefore, it provide new insight for the development of targeted drugs for anaplastic thyroid carcinoma. PMID- 24791807 TI - [Research advances in the expression of co-stimulatory molecules and signaling pathways in gammadeltaT cells]. AB - Human T lymphocytes are divided into alphabetaT cells and gammadeltaT cells on the basis of the different expressions of T cell receptors. In recent years, the studies of the regulation of T cell activation and tolerance by co-stimulatory molecules and their signaling pathways in alphabetaT cell have made remarkable progress; however, relatively fewer investigations have been performed on gammadeltaT cells. A clearer understanding of the roles of co-stimulatory molecules and their signaling pathways in the positive/negative regulation of gammadeltaT cells at different stages will provides new insights for the treatment of viral infections, cancer, autoimmune diseases, transplant rejection, and other conditions. PMID- 24791808 TI - Percutaneous endoscopic gastrostomy tube placement by otorhinolaryngologist-head and neck surgeons. AB - CONCLUSION: Percutaneous endoscopic gastrostomy (PEG) tube placement by an otorhinolaryngologist-head and neck surgeon is a feasible procedure with logistical advantages for the patient. Patient selection, co-morbidities, and the prognosis of the underlying disease are factors determining the outcome. Patient evaluation by a multidisciplinary team, with a gastroenterologist surgeon as a technical adviser, is proposed. OBJECTIVE: PEG tube placement offers an alternative to enteral nutrition. We aimed to analyze complication rates after PEG tube placement in order to evaluate the changed management policy. METHODS: This was a retrospective review of complication rates in two patient cohorts with consecutive PEG tube placement at the Departments of Otorhinolaryngology - Head and Neck Surgery (group I, n = 120) and Surgery (group II, n = 172) at Helsinki University Central Hospital, Helsinki, Finland. Data were collected on the patients' age, sex, preoperative condition, tumor site and stage, preoperative laboratory parameters, coexisting medical diagnoses, indication and date for PEG tube placement, complications, time of PEG use, follow-up time, and clinical status at the last follow-up. RESULTS: The only baseline differences between the cohorts were a higher ASA classification and fewer prophylactic PEG tubes in group II. The rate of major complications was 7.5% in group I and 13.9% in group II; in group I the rate of minor complications was 25%, compared with 15% in group II; and the procedure-related mortality rate was 0.8% in group I and 0.5% in group II. The differences were not significant (p = 0.105-0.795). PMID- 24791809 TI - Depressive symptoms in postmenopausal women: results from the MEDIS Study. AB - Data regarding the factors associated with depressive symptoms are limited, especially in postmenopausal women. The aim of this study was to investigate to what extent depressive symptoms were present in postmenopausal women, to explore characteristics associated with depressive symptoms and to determine if time since menopause was independently associated with depressive symptoms. Data collected within the Mediterranean Islands (MEDIS) Study, a health and nutrition survey of elderly people living on Mediterranean islands was used. A total of 851 postmenopausal women living in various Greek islands, Cyprus, and Malta participated in the study. Depressive symptoms were evaluated using the Geriatric Depression Scale (GDS). Age-adjusted logistic regression analysis showed that a year's increase in the time since menopause increased the likelihood of postmenopausal women having severe depressive symptoms by 3% (odds ratio [OR] per 1 year = 1.03, 95% CI 1.001-1.05). This positive association was also evident when other potential confounding factors (i.e, living conditions, financial status, physical activity, adherence to the Mediterranean diet, smoking habits, and several clinical conditions) were also taken into account in multivariable analyses. Primary health care practitioners and public health care authorities could use the findings of this study to identify depressive symptoms early in postmenopausal women. PMID- 24791810 TI - Next-generation sequencing in precision oncology: challenges and opportunities. AB - High throughput gene sequencing is transforming the utilization of genomics in patient care by providing physicians with a powerful tool to aid the diagnosis and management of disease, particularly in precision oncology. As next-generation sequencing (NGS)-based diagnostic assays are developed, significant hurdles such as assessing tumor heterogeneity, characterizing 'driver' and 'passenger' mutations, typing molecular signatures of individual cancers and determining limits of detection pose significant challenges for clinical laboratories and downstream bioinformatics analyses. Despite these challenges, NGS has the potential to affect all facets of cancer treatment, including early detection and diagnosis through cancer screening in at-risk populations and assessing therapeutic efficacy by detection of circulating tumor DNA via noninvasive blood draws. As the utilization of NGS in precision oncology matures, NGS-based laboratory tests could be used throughout the evolution of cancer in patients and allow for cancers to be monitored and managed as a chronic disease, rather than an acute condition. PMID- 24791811 TI - Comparison of microaspiration around TaperGuard tube cuffs and standard tracheal tubes in obese patients subjected to surgery under general anesthesia. AB - Tracheal secretion leakage might lead to ventilator-associated pneumonia. Standard tracheal tube cuffs are cylindrical in shape. Bronchial tree aspiration is observed in the presence of leakage past tracheal tube cuffs. The new TaperGuard tracheal tube has a cuff in the shape of a cone, preventing from the development of microtubules and microaspiration. The aim of the study was to compare standard tracheal tube cuffs with TaperGuard tubes, in terms of protection from microaspiration under general anesthesia. MATERIAL AND METHODS: The observational study evaluated incidents of leakage during general anesthesia with intubation and mechanical ventilation in patients with significant obesity. The study group comprised 20 patients with the BMI >40 kg/m2 subjected to elective surgery under general anesthesia with intubation and mechanical ventilation, randomly divided into two subgroups: standard tracheal tube and TaperGuard tube. RESULTS: In 4 of 10 patients with standard tracheal tubes we observed leakage around the cuff. In case of TaperGuard tubes no such leakage was observed. CONCLUSION: TaperGuard tubes protect against microaspirations, while standard tracheal tubes have no such properties. PMID- 24791812 TI - Cholelithiasis in home parenteral nutrition (Hpn) patients--complications of the clinical nutrition: diagnosis, treatment, prevention. AB - Long-term home parenteral nutrition (HPN) is an important factor for cholelithiasis. An individualized nutrition program, trophic enteral nutrition and ultrasound bile ducts monitoring is a necessity in those patients. The aim of the study was to evaluate the usefulness of prophylactic cholecystectomy in patients with asymptomatic cholelithiasis requiring HPN. MATERIAL AND METHODS: 292 chronic HPN patients were analyzed in the period from 2005 to 2012. Patients were divided into four groups: A - without cholelithiasis, B - with asymptomatic cholelithiasis, C - urgent cholecystectomy because of cholecystisis caused by gallstones, D - cholecystectomy in patients without cholelithiasis performed during an operation to restore the continuity of the digestive tract. The patients were additionally divided depending on the extent of resection of the small intestine and colon. RESULTS: 36.9% of chronic HPN patients had cholelithiasis confirmed using ultrasonographic examination. Cholecystectomy due to acute cholecystitis symptoms was performed in 14.4% of the patients. The remaining 22.6% patients had asymptomatic cholelithiasis. Prophylactic cholecystectomy was performed in 5.5% patients with no signs of cholelcystisis during the planned operation to restore the continuity of the digestive tract. CONCLUSIONS: Cholelithiasis in chronic HPN patients is a frequent phenomenon. It seems useful to perform prophylactic cholecystectomy during primary subtotal resection of the small intestine, because the risk of cholelithiasis in this group of patients is very high. PMID- 24791813 TI - Immediate and delayed surgical repair of duodenal defects in rats with small intestinal submucosa patch. AB - Duodenal injuries, though rare, carry high rates of morbidity and mortality. The aim of the study was to evaluate the healing of the duodenal wall with the use of a Small Intestinal Submucosa (SIS) patch. MATERIAL AND METHODS: We studied 40 Wistar-Albino rats divided into two groups. In group A, we created a small defect in the duodenal wall, which was immediately covered with a SIS patch. In group B, the SIS patch was sutured over the defect after 6-8 hours, in order to induce peritonitis. The animals of both groups were sacrificed after 2, 6, 12 and 16 weeks respectively. In addition, we studied the immunohistochemical expression of TGF-beta, which is a major constituent of SIS, and plays a central role in the healing process. RESULTS: Histology showed progressive development of the layers of the duodenal wall over the patch as early as the 2nd week in some of the animals of group A. Mucosa developed later on in the animals of group B, presumably due to the more intense inflammation elicited by peritonitis. Expression of TGF-beta was initially more pronounced in the epithelial cells of the regenerating mucosa of animals of group A, but it was maintained in higher levels in the animals of group B, which showed delayed mucosa degeneration. CONCLUSIONS: SIS appears to be both efficient and safe for the management of duodenal trauma. TGF-beta seems to play an important role in the healing process, inducing regeneration of the stroma, and controlling epithelial growth. PMID- 24791814 TI - Rigid bronchoscopy and tracheostomy compared to repeated dilatation of tracheal stenosis prior to tracheal resection and anastomosis; a pilot study. AB - The aim of the study was to compare the results of tracheostomy of the site of stenosis and repeated RB & D in previously published papers. MATERIAL AND METHODS: This prospective study examined the treatment of tracheal stenosis with tracheostomy at the site of stenosis. The recurrence rates, duration of hospitalization before and after tracheal resection, the number of tracheal rings removed, prognosis,and complications were evaluated. RESULTS: It seems that a tracheostomy at the site of stenosis instead of repeated RB & D reduces the recurrence rate and duration of hospital stay, the need for a constant presence of a chest surgeon in the hospital, hospitalization costs. Also, the implementation of this method is possible in more centers. CONCLUSION: Tracheostomy at the site of tracheal stenosis can reduce the recurrence rate of stenosis, and prevent prolonged hospitalization, repeated anesthesia and inappropriate emergency tracheostomy. PMID- 24791815 TI - Vulnerable Elderly Survey 13 as a screening method for frailty in Polish elderly surgical patient--prospective study. AB - The Vulnerable Elders Survey (VES-13) is a simple function based frailty screening tool that can be also administered by the nonclinical personnel within 5 minutes and has been validated in the out- and in patient clinic and acute medical care settings. The aim of the study was to validate the accuracy of the VES-13 screening method for predicting the frailty syndrome based on a CGA in polish surgical patients. MATERIAL AND METHODS: We included prospectively 106 consecutive patients >=65, that qualify for abdominal surgery (both due to oncological and benign reasons), at the tertiary referral hospital.We evaluated the diagnostic performance of VES-13 score comparing to the results from the CGA, accepted as the gold standard for identifying at risk frail elderly patients. RESULTS: The prevalence of frailty as diagnosed by CGA was 59.4%. There was significantly higher number of frail patients in the oncological group (78% vs. 31%; p<0.01). According to the frailty screening methods, the frailty prevalence was 45.3%. The VES-13 score had a 60% sensitivity and 78% specificity in detecting frailty syndrome. The positive and negative predictive value was 81% and 57%, respectively. The overall predictive capacity was intermediate (AUC=0.69) CONCLUSIONS: At present, the VES-13 screening tool for older patients cannot replace the comprehensive geriatric assessment; this is due to the insufficient discriminative power to select patients for further assessment. It might be helpful in a busy clinical practice and in facilities that do not have trained personal for geriatric assessment. PMID- 24791816 TI - The risk of surgical treatment in patients aged 85+, with special consideration of colorectal cancer. AB - The increase in prevalence of chronic diseases in old age is concomitant with increasing risk of neoplasms requiring surgical treatment. The aim of the study was to assess the indications, treatment outcomes, complications and mortality associated with surgical treatment of patients aged 85 or more, with special consideration of colorectal cancer. MATERIAL AND METHODS: The retrospective analysis involved a group of 94 patents (x = 88.9) aged 85 or more and treated surgically in the years 2006-2011. The results were compared with a randomly selected control group of 91 patients aged 45-75 (x = 56,4) and treated surgically in the same period. RESULTS: Neoplastic diseases in the study group (85 >=), compared with the control group (< 75), were a significantly more frequent indication for surgical treatment (p < 0.01). In the group of patients aged 85 or more, the most frequent indications for elective surgery were neoplasms of the skin and subcutaneous tissue (26.4%) and gastrointestinal neoplasms, mainly colorectal cancer (23.5%). Postoperative complications were significantly more frequent (p < 0.01) among patients aged 85 or more (n = 27; 34.8%) than in the younger group (n = 17; 18.7%). Postoperative mortality among patients undergoing emergency surgery was significantly higher (p < 0.05) in the senior group than in the group of younger patients. CONCLUSIONS: Surgical procedures in patients aged 85 or more are most frequently performed in the emergency setting, and their most common cause are neoplastic diseases. Emergency surgical treatment in patients aged 85 or more is associated with a significantly higher risk, compared with younger age groups, of developing multi-organ postoperative complications, usually leading to death. Elective surgical treatment in patients aged 85+ after appropriate preoperative preparation and in the group of younger patients shows similar early outcomes. PMID- 24791817 TI - Analysis of genetic similarities between Clostridium perfringens isolates isolated from patients with gas gangrene and from hospital environment conducted with the use of the PFGE method. AB - The objective of the study was to perform a comparative analysis of genetic similarity, with the use of pulsed field gel electrophoresis (PFGE), of Clostridium perfringens isolates originating from patients with gas gangrene and from the hospital environment. The study encompassed two patients with a clinical and microbiological diagnosis of gas gangrene, who were hospitalized in one of the hospitals of the Malopolska province in the time period between 31st March 2012 and 18th May 2012. Clostridium perfringens isolates genotyping indicated that the isolates originating from the two studied patients did not display genetic similarity and represented two different PFGE types, which corresponded to two different clones (clone A and B). Whereas the strains isolated from the hospital environment were genetically identical with the strain coming from the second patient and represented one PFGE type, which corresponded to one clone (clone A). As a result of the study, it is possible to conclude that both patients developed endogenous infection. Even so, the examination of the hospital environment indicates the possibility of the appearance of exogenous infections. It prompts recommending and following the exact regulations of sanitary regime in the ward and the operating theater if a patient is diagnosed with gas gangrene. PMID- 24791818 TI - Synchronous occurrence of colon and appendiceal adenocarcinoma. AB - The study presented two cases of synchronous occurrence of colon and appendiceal adenocarcinoma. Both patients required surgical intervention, due to acute peritonitis during the course of acute appendicitis. In case of one patient we performed abdominal CT confirming the presence of sigmoid cancer. The patient was subjected to appendectomy and Hartmann's operation. The second patient underwent an appendectomy, and colonoscopy performed two months later revealed the presence of rectal adenocarcinoma. The patient was subjected to low anterior rectal resection. The histopathological results considering both patients revealed the presence of synchronous colon and appendiceal adenocarcinoma. PMID- 24791819 TI - Cell adhesion molecules in terms of carcinogenesis. PMID- 24791820 TI - Identifying high-risk subgroups for alcohol consumption among younger and older pregnant women. AB - AIMS: Recent studies indicate that older women are more likely to consume alcohol during pregnancy, but subgroups at highest risk within the context of maternal age have not been identified. This study identifies subgroups at risk for alcohol use during pregnancy among three age categories using classification and regression trees (CART) analysis. METHODS: Using the 2002-2009 Pregnancy Risk Assessment Monitoring System (PRAMS) dataset (311,428 records of U.S. women), logistic regression and classification trees were constructed separately for age groups, <=24, 25-29, and >=30 years. RESULTS: Overall, 6.5% of women reported drinking alcohol during the last trimester of pregnancy. Alcohol consumption by age group was: 3.7% for <=24, 5.7% for 25-29, and 10.1% for >=30 years of age. Women <=24 years were at greater risk of consuming alcohol if they also smoked (5.8%). Among nonsmokers, higher levels of education and being Hispanic were associated with a 35% increase in alcohol use. Distinct high-risk subgroups emerged for the 25-29-year-old group. Specifically, 12.8% of non-obese women who reported having experienced abuse during pregnancy also reported drinking alcohol in the last trimester. About 16% of women >=30 years with at least 16 years of education, White or Hispanic with normal or underweight BMI, drank alcohol during their last trimester. CONCLUSIONS: Given limited health care resources for prevention and treatment, the early identification of high-risk groups for prenatal alcohol use is critical. This study provides evidence that risk factors contributing to alcohol consumption during pregnancy may differ by maternal age. PMID- 24791821 TI - Incorporating first trimester analytes to predict delivery of a large for gestational infant in women with impaired glucose tolerance. AB - AIM: To investigate first trimester maternal characteristics of women with impaired glucose tolerance that deliver large for gestational age (LGA) infants. METHODS: Nested analysis from a prospective study of singleton pregnancies enrolled at first trimester. We studied women with an abnormal 1 h glucose challenge test that had normal follow-up oral glucose tolerance testing. Maternal characteristics, ultrasound parameters and serum analytes were stratified by subsequent delivery of an LGA infant. Parameters identified as significant on univariate analysis were used for a derivation of prediction by logistic regression. Odds ratio and prediction performance was determined using receiver operator curve (ROC) statistics. RESULTS: A total of 33/114 (28.9%) women meeting the criteria delivered LGA infants. Maternal height (cm), and first trimester pregnancy-associated protein-A and free beta-hCG (MoM) predicted delivery of an LGA infant (ROC area under curve 0.73; 95% CI 0.63-0.83). At a cutoff value of 0.172 the prediction rule achieved 91% sensitivity, 44% specificity, 41% positive predictive and 92% negative predictive value. CONCLUSION: Maternal height and first trimester high free beta-hCG and PAPP-A levels may be used as predictors for delivery of LGA infants in women with impaired glucose tolerance. PMID- 24791822 TI - Ideal cardiovascular health behaviors and factors and high sensitivity C-reactive protein: the Kailuan cross-sectional study in Chinese. AB - BACKGROUND: High sensitivity C-reactive protein (hs-CRP) is an inflammatory marker associated with increased cardiovascular disease risk. Health-related behaviors and factors decrease the risk of cardiovascular disease events, but the association between ideal cardiovascular health behaviors and hs-CRP is not clear. This study evaluated the relationship between the number of ideal cardiovascular health metrics and hs-CRP levels. METHODS: We conducted a cross sectional study from 2006 to 2007 that included 93,967 healthy subjects and 7869 diabetic patients. hs-CRP was measured by high-sensitivity nephelometry. Multivariate logistic regression was performed to analyze the association between the number of ideal cardiovascular health metrics and hs-CRP levels in the general population and in non-diabetic and diabetic subjects. RESULTS: We found that hs-CRP levels decreased as the number of ideal cardiovascular health metrics increased in the general population, different genders, non-diabetic and diabetic subgroups. After adjusting for traditional risk factors, logistic regression analyses revealed that the risk of hs-CRP >3 mg/L in the general population with 6-7 ideal cardiovascular health metrics was 0.39 times lower than in those with 0 1 ideal metrics. Similarly, the risks were 0.39 times lower than in those with 0 1 ideal metrics in non-diabetic population. The risk of hs-CRP >3 mg/L in the diabetic population with 4-6 ideal cardiovascular health metrics was 0.45 times lower than those with 0-1 ideal metrics. CONCLUSIONS: Our findings demonstrate an inverse relationship between the number of ideal health metrics and hs-CRP in the general population, and similar relationships were observed for different gender, non-diabetic and diabetic subgroups. PMID- 24791823 TI - A rare condition: IgE type monoclonal gammopathy of undetermined significance. PMID- 24791824 TI - Serum folate and vitamin B12: does light really matter? PMID- 24791825 TI - 6-year follow-up of 522 HIV-positive individuals screened for Mycobacterium tuberculosis infection in Denmark. PMID- 24791826 TI - In vitro synergy between linezolid and clarithromycin against Mycobacterium tuberculosis. PMID- 24791827 TI - Pulmonary radioaerosol mucociliary clearance in primary ciliary dyskinesia. PMID- 24791828 TI - Medical nanoparticles for next generation drug delivery to the lungs. AB - Respiratory diseases are an increasing burden for the ageing population. Although our understanding of these diseases has improved significantly over the past decades, diagnostic and therapeutic options for treating lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and lung cancer, remain limited. Multidisciplinary approaches that bridge the gap between medicinal and materials sciences will likely contribute to promising new therapeutic and diagnostic solutions. One such multidisciplinary approach is the use of nanoparticles as carriers for the delivery of drugs. The advantages of using nanoparticles to deliver drugs include: increased drug concentration at the disease site; minimised drug degradation and loss; ease of creating inhalable formulations; and the possibility of specific cell targeting. This article gives a brief overview on the emerging field of nanocarriers as drug delivery vehicles for the treatment of lung diseases. PMID- 24791829 TI - Connective tissue disease-associated pulmonary arterial hypertension in Chinese patients. AB - We sought to investigate the characteristics, survival and risk factors for mortality in Chinese patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) in modern therapy era. 129 consecutive adult patients who visited one of three referral centres in China with a diagnosis of CTD-APAH confirmed by right heart catheterisation during the previous 5 years were enrolled. The end-point was all-cause death or data censoring. Systemic lupus erythematosus was the most common underlying CTD (49%) and systemic sclerosis just accounted for 6% in this cohort. The overall survival at 1 and 3 years was 92% and 80%, respectively. Pericardial effusion, a shorter 6 min walk distance, lower mixed venous oxygen saturation, higher pulmonary vascular resistance (PVR) and alkaline phosphatase (ALP), and lower total cholesterol levels were all associated with a higher risk of death among the study population. Higher PVR and ALP were independent predictors of mortality. In conclusion, unlike in western patients, systemic lupus erythematosus is the most common underlying disease in Chinese patients with CTD-APAH. The survival of Chinese patients with CTD-APAH in the modern treatment era is similar to that in western countries. Elevated PVR and ALP are independent risk factors for poor outcomes. PMID- 24791830 TI - Pleuroparenchymal fibroelastosis as a late complication of chemotherapy agents. PMID- 24791831 TI - The effect of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients. PMID- 24791832 TI - Exhaled nitric oxide, nitrite/nitrate levels, allergy, rhinitis and asthma in the EGEA study. AB - Although interest in biomarkers in the nitrate-nitrite-NO pathway has recently increased, associations between nitrite (NO2(-)) and nitrate (NO3(-)), and asthma, allergic sensitisation and rhinitis remain unclear. The study aimed to evaluate the associations between NO2(-)/NO3(-) and exhaled fraction of nitric oxide (FeNO) levels with asthma, allergic sensitisation and rhinitis. Plasma and exhaled breath condensate (EBC) NO2(-)/NO3(-) and FeNO levels were measured in 523 adults of the French Epidemiological study on Genetics and Environment of Asthma. Allergic sensitisation was defined by a positive skin prick test for at least one aeroallergen. Subjects were classified as non-sensitised, sensitised and as having allergic rhinitis. Plasma NO2 (-)/NO3(-) level was unrelated to any disease phenotypes. EBC NO2(-)/NO3(-) level was unrelated to any asthma phenotypes. EBC NO2(-)/NO3(-) and FeNO levels were correlated in sensitised subjects only (r = 0.21 +/- 0.10, p=0.01). EBC NO2(-)/NO3(-) and FeNO levels were higher in sensitised than in non-sensitised subjects (adjusted geometric mean (95% CI): 2.36 (1.96-2.84) versus 1.72 (1.38-2.14) MUmol per mg proteins, p=0.008; and 18.3 (16.7-20.0) versus 14.8 (13.3-16.5) ppb, p=0.0006, respectively), with gradual relationships from sensitised subjects to those with allergic rhinitis (p<0.0001). Results suggest that EBC NO2(-)/NO3(-) and FeNO levels may be considered as biological markers of intensity of allergic sensitisation and rhinitis. PMID- 24791834 TI - Ni-catalyzed direct reductive amidation via C-O bond cleavage. AB - A novel Ni-catalyzed reductive amidation of C(sp(2))-O and C(sp(3))-O electrophiles with isocyanates is described. This umpolung reaction allows for an unconventional preparation of benzamides using simple starting materials and easy to-handle Ni catalysts. PMID- 24791833 TI - SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction. AB - The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology. Right ventricular systolic pressure (RVSP) increased to a mean+/-sd of 106+/-7 mmHg in response to SuHx and decreased but remained elevated at 72+/-8 mmHg upon return to normoxia. Hypoxia-only exposed rats showed a similar initial increase in RVSP, a lower maximum RVSP and near-normalisation of RVSP during subsequent normoxia. Progressive vascular remodelling consisted of a four-fold increase in intima thickness, while only minimal changes in media thickness were found. The circadian range in RVSP provided an accurate longitudinal estimate of vascular remodelling. In conclusion, in SuHx rats, re-exposure to normoxia leads to a partial decrease in pulmonary artery pressure, with persisting hypertension and pulmonary vascular remodelling characterised by progressive intima obstruction. PMID- 24791835 TI - Micro-/nanostructured Co3O4 anode with enhanced rate capability for lithium-ion batteries. AB - Through a facile hydrothermal method with a special surfactant triethanolamine (TEA) followed by thermal treatment, monodispersed micro-/nanostructured Co3O4 powders with unique morphology (cube) have been synthesized successfully as anode material for Li-ion batteries (LIBs). The regular Co3O4 microcubes (~2.37 MUm in the average side length) consist of many irregular nanoparticles (20-200 nm in diameter, 30-40 nm in thickness) bonded to each other, which greatly inherit the morphology and size of the precursor CoCO3. The specific surface area of Co3O4 powders is about 5.10 m(2).g(-1) by the Brunauer-Emmett-Teller (BET) method, and the average pore size is about 3.08 nm by the Barrett-Joyner-Halenda (BJH) method. In addition, the precursor is verified as a single-crystal, while the mesoporous cubic Co3O4 is a polycrystalline characteristic assembled by numerous single-crystal nanoparticles. More remarkable, the high performance of the micro /nanostructured cubic Co3O4 powders has been obtained by the electrochemical measurements including high initial discharge capacities (1298 mAhg(-1) at 0.1 C and 1041 mAhg(-1) at 1 C), impressive rate capability, and excellent capacity retention (99.3%, 97.5%, 99.2%, and 89.9% of the first charge capacities after 60 cycles at 0.1 C, 0.2 C, 0.5 C, and 1 C, respectively). PMID- 24791836 TI - Does the optimum hydrophilic lipophilic balance condition affect the physical properties of mixed reverse micelles? A spectroscopic investigation. AB - Synergism in several physical properties as realized in many mixed surfactant reverse micellar (RM) systems often manifests optimum hydrophilic-lipophilic balance (HLB), interdroplet interaction, or both. Such synergism is often desired for specific applications of RM systems; however, a proper rationale on the effect of such phenomenon imparted on the structure, dynamics, and activity of water molecules in RM waterpool is strongly demanded. In the present contribution we have investigated how the optimum HLB condition of mixed RM composed two nonionic surfactants (Igepal 210 and Igepal 630) affects the physical properties of entrapped water molecules in the RM waterpool. The studied mixed RM exhibits synergistic water solubilization behavior as a function of the mixing ratio with a maximum in solubilization capacity being reached at X(Ig630) = 0.3. Dynamic light scattering (DLS) studies show a bimodal distribution of droplet size in this region, whereas it is monomodal in terminal compositions. Fourier transform infrared spectroscopy (FTIR) study in the 3000-3800 cm(-1) region identifies a linear trend in which the content of "bound" water increases at the expense of the "network" water as the content of the hydrophilic surfactant Igepal 630 is increased in the mixture. Subnanosecond relaxation dynamics of the entrapped water as revealed by the fluoroprobe coumarin 500 corroborates a similar linear trend as observed in the FTIR measurements as the rotational diffusion gets retarded with the increase of ethylene oxide chain length of Igepal. Reaction kinetics of solvolysis of benzoyl chloride reaction, however, does not offer any linear trend as it gets slower in the optimum HLB region, the nonlinearity being a consequence of the distribution of the substrate in the different phases. PMID- 24791837 TI - Has Ultrasound Elastography come to the age of ripening? PMID- 24791838 TI - Quantitative assessment of the masseter muscle's elasticity using Acoustic Radiation Force Impulse. AB - AIMS: The study proposes Acoustic Radiation Force Impulse (ARFI) assessment of the masseter muscle elasticity in the healthy population and in patients who have undergone head and neck radiation therapy. PATIENTS AND METHODS: Twenty-five healthy controls constituted group A, and 13 patients who had underwent radiotherapy (35Gy minimum) formed group B. ARFI was performed bilaterally in the periphery (P) and the muscle center (C), in relaxation and contraction. Means and standard deviations were obtained for the recorded shear waves velocities (SWV). RESULTS: For group A: in the relaxed right muscle C = 1.87+/-0.52 m/s and P = 1.96 +/-0.55 m/s and in the left muscle C = 1.66 +/- 0.47 m/s, P = 1.67 +/-0.53 m/s. For group B, in relaxation, the right side presented C = 1.67 +/-0.6 m/s, P 1.72 +/-0.56 m/s, the left muscle C = 1.6 +/-0.34 m/s, P = 1.73 +/-0.37 m/s. There were no differences (p> 0.05) between P and C of both groups, regardless of the muscle state. The values for relaxation and contraction in A and B (merged values of the right and left) presented no differences (1.79+/-0.52 m/s vs 1.72 +/-0.73 m/s, p = 0.72 and 1.70 +/-0.48 m/s and vs 1.59 +/-0.77 m/s, p = 0.98). All measurements of group A vs B were not different (1.79 +/-0.52 m/s vs 1.65 +/ 0.63 m/s, p = 0.78). CONCLUSIONS: ARFI with SWV measurement enables the quantification of normal and post irradiation elasticity of the masseter. Further studies on a larger population are required to validate the normal and pathologic values. PMID- 24791839 TI - Renal vascular Doppler ultrasonographic indices and carotid artery intima-media thickness in diabetic nephropathy. AB - INTRODUCTION: Diabetes is one of the common causes of renal insufficiency and is responsible for about one third of cases requiring renal transplantation. Conventional sonography provides limited information regarding the severity and prognosis of disease. The present study was carried out to evaluate the renal vascular Doppler indices role in determining renal dysfunction and carotid artery atherosclerosis. METHODS: Fifty five patients with diabetic nephropathy (albuminuria more than 300mg/24 hours) were enrolled into this cross-sectional study. Renal interlobar arterioles were studied using resistive (RI) and pulsatility (PI) indices of Doppler ultrasonography, in addition to conventional kidney length and renal parenchyma thickness. Intima-media thickness of common carotid artery (CCIMT) was also assessed just before the bifurcation. Serum creatinine (sCr), urine albumin and lipid profile were measured using standard methods. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease formula. RESULTS: The renal interlobar arterioles' RI was positively and linearly correlated with the sCr and albuminuria levels (P<0.039 r= +0.320 and P=0.047, r= +0.287). There were negative linear correlations between eGFR and the renal interlobar arterioles' RI (P<0.001, r=-0.539) and PI (P<0.045, r= -0.328). The mean CCIMT was more than 0.7 mm in 90% of the studied patients. No correlation was found between CCIMT and renal ultrasonographic and Doppler findings. CONCLUSION: Although Doppler ultrasonographic indices of renal interlobar arteriols show the severity of renal dysfunction in patients with diabetic nephropathy, these indices do not have any advantage over the simple and cost effective biochemical parameters. PMID- 24791840 TI - Spectrum and prevalence of nodular thyroid diseases detected by ultrasonography in the Western Black Sea region of Turkey. AB - OBJECTIVE: The aim of the study was to investigate thyroid diseases and the prevalence of goiter by ultrasonography (US) in a moderately iodine deficient area. MATERIAL-METHODS: The MELEN Study is a prospective cohort study on the prevalence of thyroid diseases in Turkish adults. A total of 2233 subjects with a mean age of 50 (age range 18 to 92) were submitted to study. Thyroid US was performed and interpreted by the same experienced physician. Goiter prevalence was defined according to Gutekunst's criteria. RESULTS: The most common thyroid disease was multinodular goiter (MNG) (42%), followed by nodular goiter (NG) (14.6%). The crude prevalence of nodular disease in the region was 56.6%. In the study cohort, thyrotoxicosis (TSH <0.35 MUIU/ml) prevalence was 12 % and subclinical and overt hypothyroidism (TSH > 4.5 MUIU/ml) prevalence was 6.5 %. CONCLUSION: We found that thyrotoxicosis and nodular thyroidal diseases are more important public health issues in moderate iodine deficient geographical areas. We recommend the increased rates of US screening especially in the endemic regions in order to detect thyroidal nodules earlier. PMID- 24791841 TI - Conventional ultrasonography and sonoelastography in the assessment of plaque psoriasis under topical corticosteroid treatment - work in progress. AB - AIMS: The objective of the study was to compare the efficiency of 20 MHz skin ultrasonography and 40 MHz conventional ultrasonography in the assessment of plaque psoriasis and to assess the efficiency of 40 MHz real-time sonoelastography in the early detection of steroid-induced skin atrophy in psoriatic plaques. PATIENTS AND METHODS: Ultrasonographic blinded evaluation was performed on 16 plaques in three consecutive patients, at baseline and after hydrocortisone acetate 1% ointment six-week application. The parameters were epidermal and dermal thicknesses for gray-scale ultrasonography and strain ratio for sonoelastography. Strain ratio was computed between the dermis and the adjacent hypodermis. Student's t-test for paired samples was performed. A confidence level of p<.05 was considered significant. RESULTS: At follow-up, epidermal thickness was significantly reduced with 20 MHz (p = .002) and 40 MHz sonography (p = .032), while dermal thickness varied insignifcantly with 20 MHz (p = .35) and 40 MHz sonography (p = .33). Measurements at 40 MHz were significantly higher than their 20 MHz counterparts at baseline (epidermis: p < .001; dermis: p = .003) and at follow-up (epidermis: p < .001; dermis: p = .001). Strain ratio revealed no significant change of dermal elasticity (p = .96). CONCLUSIONS: Although epidermal and dermal measurements varied significantly with 20 MHz and 40 MHz ultrasonography, both techniques efficiently quantified treatment response by measuring the reduction of epidermal thickness. Sonoelastographic findings were consistent with the expected outcome of short term use of low-potency corticosteroid. Further studies are recommended. PMID- 24791842 TI - The role of intraoperative ultrasound for the assessment of the focal liver lesions in patients with colorectal cancer. AB - OBJECTIVE: To evaluate the concordance between intraoperative ultrasound (IOUS) and abdominal ultrasound (US) for the characterization of focal liver lesions in patients with colorectal cancer, and to evaluate the way in which IOUS influences the initially established hepatic surgical protocol based on abdominal US only. METHOD: In this prospective study 73 patients with colorectal cancer and focal liver lesions found during IOUS were included. Abdominal US and IOUS findings were compared. The initially established hepatic surgical protocol based on abdominal US only was recorded. All patients in whom IOUS influenced this protocol and the way in which this was influenced were recorded. RESULTS: Of the 73 patients, 41 (56.2%) had focal liver lesions classified as malignant by IOUS. In 26 of the 73 patients (35.6%), there were discordances between abdominal US and IOUS. IOUS influenced the operative protocol in 9 of the 73 patients included in the study (12.3%), and in 8 of the 41 patients with malignant lesions (19.5%). IOUS influenced the operative protocol by cancelling the preoperative hepatic surgery decision by evidencing the additional multiple malignant focal liver lesions, following the classification of some lesions as benign or by demonstrating the non-resectable character of other lesions. IOUS also determined unplanned hepatic resections by detecting resectable malignant lesions undiagnosed by abdominal US, and extended or limited the scheduled hepatic surgery based on abdominal US only. CONCLUSIONS: There were inconsistencies between IOUS and abdominal US, therefore in patients with colorectal cancer IOUS provided additional information about focal liver lesions. IOUS influenced the operative protocol and consequently, unnecessary liver surgery was avoided. Also, IOUS identified malignant resectable liver lesions which were undetected by abdominal US. PMID- 24791843 TI - Comparison between the M and XL probes for liver fibrosis assessment by transient elastography. AB - OBJECTIVE: Liver stiffness measurement (LSM) using Transient Elastography (TE) for liver fibrosis assessment is difficult to be performed in obese and overweight patients by standard M probe, thus the XL probe was developed. The aim of our paper was to assess the usefulness of the XL probe in daily clinical practice. MATERIAL AND METHOD: Our study included 216 patients (mean BMI 30.1+/ 4.1 kg/m2) with chronic hepatopathies, in which paired measurements were made using the M (3.5MHz) and XL (2.5 MHz) probes in the same session. In each patient 10 valid LSM were acquired with each probe, a median was calculated, expressed in kiloPascals (kPa). Unreliable TE measurements were considered: fewer than 10 valid shots; with a success rate (SR) <60% and/or interquartile range interval (IQR) >=30%. RESULTS: In 127 patients reliable LSM could not be obtained by standard M probe, 10 of them normal weight, 25 of them overweight, and 92 obese. By XL probe reliable measurements were obtained in 80/127(63%) of these patients: 8/10 (80%) of the normal weights, 17/25 (68%) of the overweight and 55/92 (59.8%) of the obese. In 98 patients with reliable M probe measurements, XL probe LSMs were also performed. XL LS values strongly and significantly correlated with those obtained by M probe (Spearman r=0.789, p<0.0001), but were significantly lower [median 6.4 kPa (range 3.1 - 53.8) vs 7.7 kPa (range 3.7-69.1), Wilcoxon paired t test p<0.001)]. CONCLUSION: By using the XL probe, reliable LSM by TE can be obtained in more than 60% of patients with unreliable measurements by M probe. LSM by XL probe are significantly correlated, but lower, than those obtained by M probe. PMID- 24791844 TI - Romanian national guidelines and practical recommendations on liver elastography. AB - The use of liver elastography has substantially developed in the past few years; the introduction of novel elastographic methods (Transient Elastography, point Shear Wave Elastography, Real Time Shear Wave Elastography, Strain Elastography) has changed the perspective in the evaluation of liver disease. The ongoing research in this area is mainly focused on diffuse liver diseases and for predicting liver cirrhosis complication. This guideline created under the auspice of Romanian Society of Ultrasound in Medicine and Biology is intended to accustomize the clinician with the current practical use of liver elastography and has been issued to help in maximizing the clinical benefit for the patients with chronic liver diseases. PMID- 24791845 TI - Ultrasound screening for hepatocellular carcinoma in patients with advanced liver fibrosis. An overview. AB - Liver cirrhosis is the major risk factor for hepatocellular carcinoma (HCC). All etiologic forms of liver cirrhosis may be complicated by HCC but the risk is higher in patients with hepatitis B or C viral infection. Patients at high risk for developing HCC should be included in surveillance programs. Groups at high risk are: all cirrhotic patients; non-cirrhotic patients with chronic hepatitis C and advanced liver fibrosis (F3), non-cirrhotic HBV carriers with active hepatitis. Current guidelines issued by AASLD and EASL recommend surveillance among high-risk patients by ultrasound (with or without alpha-fetoprotein) every 6 months. The aim of ultrasound screening and surveillance is to detect HCC at an early stage, when it is amenable to curative therapy, to reduce mortality. For good results, ultrasound examination must be done by highly experienced personnel, with extensive experience in the field of hepatic ultrasound. PMID- 24791846 TI - Surgical hepatic resection vs. ultrasonographic guided radiofrequency ablation in colorectal liver metastases: what should we choose? AB - Clinical evolution of the colorectal carcinoma occurs in up to 60% with colorectal liver metastases (CRLM). Although hepatic resection is considered to be the golden standard in CRLM, novel less invasive techniques have emerged, of which radiofrequency ablation has received a high credibility. When tumors are not eligible for surgery, guided radiofrequency ablation is considered an alternative. This method is appropriate when there are no more than 5 lesions with a diameter of less than 3 cm. While open surgery guarantees a more precise tumor excision, the effectiveness of ablation must be evaluated either by contrast-enhanced computer tomography, magnetic resonance, or ultrasound. This paper aim to review the current standings in radiofrequency ablation for CRLM and to compare the technique with surgical resection in order to find which one is the best treatment option. PMID- 24791847 TI - Left atrium function assessment by echocardiography - physiological and clinical implications. AB - Left atrium enlargement is a pathophysiological response to volume and pressure overload associated with a wide range of cardiovascular disorders leading to left ventricle systolic and diastolic dysfunction. Physiological factors contribute to significant differences in left atrium size in normal individuals. Moreover, left atrium enlargement was shown to have a significant prognostic value for cardiovascular events such as heart failure, atrial fibrillation or stroke, and increased cardiovascular and all-cause mortality rates. Current imaging techniques such as two- and three dimensional echocardiography, cardiac magnetic resonance imaging and multi-detector computed tomography allow a detailed assessment of the left atrium. The current paper aims to offer an overview of two dimensional echocardiography parameters which provide data concerning left atrium dimensions and phasic functions and may lead to a better understanding of left atrium physiology and pathology. PMID- 24791848 TI - Ovarian and uterine ultrasonography in pediatric patients. Pictorial essay. AB - Ultrasonography represents the method of choice in the investigation of the female pediatric pelvis. While the investigation itself poses no real challenges, an accurate interpretation of the images must take into consideration the specific features of the ovaries and uterus at certain ages. The present essay aims to demonstrate the normal appearance of the female pelvis and the changes that occur during the various stages of development as well as the some of the most common pathological conditions. PMID- 24791849 TI - Prenatal diagnosis of a giant epignathus teratoma in the third trimester of pregnancy using three-dimensional ultrasound and magnetic resonance imaging. Case report. AB - A 20-year-old nulliparous woman was referred due a cervical mass in the fetus in an ultrasound examination performed in the 25th week of pregnancy. The exam revealed an irregular, solid-cystic heterogeneous mass measuring 75x54 mm that came to the exterior through the mouth of the fetus. Three-dimensional ultrasound and magnetic resonance imaging confirmed the diagnosis of epignathus teratoma and the normal finding of the central nervous system. The patient was admitted at 28 weeks, in premature labor. Tocolysis, corticosteroid and amniotic fluid drainage were programmed to be performed before conducting ex utero intrapartum treatment (EXIT). However, there was premature rupture of membranes and the EXIT procedure was brought forward. After premature placental abruption, the newborn's birth was concluded. Tracheostomy was performed, but the newborn's condition progressed to bradycardia and death in a few minutes. PMID- 24791850 TI - Budd-Chiari syndrome as an initial presentation of hepatocellular carcinoma: a case report. AB - We report the case of a 84-year-old admitted with symptoms of congestive heart failure. Ultrasonography revealed a hyperechoic nodule in the left lobe of the liver, with a peripheral hypoechoic rim, multiple irregular hypoechoic nodules in both hepatic lobes, portal vein, inferior vena cava, and right atrium thrombosis. On ultrasonographic and alpha-fetoprotein criteria the case was interpreted as hepatocellular carcinoma with Budd-Chiari syndrome. The particularity of the case is the initial presentation of the hepatocellular carcinoma as Budd-Chiari syndrome. The inferior vena cava and right atrium thrombosis, as a cause of secondary Budd-Chiari syndrome in a patient with hepatocellular carcinoma, has been rarely reported. PMID- 24791852 TI - The thoracic spine sign in bedside ultrasound. Three cases report. AB - The "thoracic spine sign" is visualized when anechoic or hypoechoic fluid is present in the pleural space. Fluid serves as a medium through which the thoracic vertebral bodies are visualized above the diaphragm. We present three cases of emergency department patients with a thoracic spine sign identified on bedside ultrasound. These patients were subsequently diagnosed with pleural fluid accumulations on chest radiograph. Our findings suggest that the identification of the sonographic spine sign may aid the physician in the evaluation and diagnosis of emergency department patients with thoracic complaints. PMID- 24791851 TI - Invasive mole of the uterus- a rare case diagnosed by ultrasound: a case report. AB - Gestational trophoblastic neoplasias (GTN) are rare tumours that constitute less than 1% of all gynecological malignancies. Invasive mole is a distinct subgroup of GTN, which if not diagnosed and treated early, can result in serious complications like uterine perforation and haemoperitoneum. We present a rare case of an invasive mole of the uterus, which developed following the evacuation of a molar pregnancy. It was accurately diagnosed by transvaginal ultrasound and color Doppler, and successfully treated before any major complications could arise. PMID- 24791853 TI - Misleading appearance in cervical lymph node US diagnosis - a report on sarcoidosis, Warthin tumor and squamous cell carcinoma metastases. AB - Ultrasonography, with its various techniques (grey-scale, color Doppler, sonoelastography) offers many signs for the differentiation between benign and malignant neck lymph nodes. In spite of recent progress, the US appearance may be misleading. We present three cases in which the ultrasonographic appearance of the lymph nodes was misleading as compared to the final diagnosis established by histopathology. PMID- 24791854 TI - Calreticulin mutations and long-term survival in essential thrombocythemia. AB - The impact of calreticulin (CALR) mutations on long-term survival in essential thrombocythemia (ET) was examined in 299 patients whose diagnosis predated 2006. Mutational frequencies were 53% for Janus kinase 2 (JAK2), 32% for CALR and 3% for MPL; the remaining 12% were 'triple-negative'. We confirmed the association of mutant CALR (vs JAK2V617F) with younger age (P=0.002), male sex (P=0.01), higher platelet count (0.0004), lower hemoglobin (P<0.0001), lower leukocyte count (0.02) and lower incidence of recurrent thrombosis (0.04). Triple-negative patients were also younger than their JAK2-mutated counterparts (P=0.003) and displayed lower hemoglobin (P=0.003), lower leukocyte count (<0.0001) and lower thrombotic events (P=0.02). Median follow-up time was 12.7 years and 47% of the patients were followed until death. Survival was the longest for triple-negative and shortest for MPL-mutated patients. Median survival was 19 years for JAK2 and 20 years for CALR-mutated cases (P=0.32); the corresponding figures for patients of age ?65 years were 26 and 32 years (P=0.56). The two mutational categories were also similar for leukemic (P=0.28) and fibrotic (P=0.28) progression rates. The current study is uniquely characterized by its very long follow-up period and provides accurate estimates of long-term survival in ET and complements current information on mutation-specific phenotype and prognosis. PMID- 24791855 TI - Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. AB - Direct targeting of rat sarcoma (RAS), which is frequently mutated, has proven to be challenging, and inhibition of individual downstream RAS mediators has resulted in limited clinical efficacy. We designed a chemical screen to identify compounds capable of potentiating mammalian target of rapamycin (mTOR) inhibition in mutant RAS-positive leukemia, and identified a Wee1 inhibitor. Synergy was observed in both mutant neuroblastoma RAS viral oncogene homolog (NRAS)- and mutant kirsten RAS viral oncogene homolog (KRAS)-positive acute myelogenous leukemia (AML) cell lines and primary patient samples. The observed synergy enhanced dephosphorylation of AKT, 4E-binding protein 1 and s6 kinase, and correlated with increased apoptosis. The specificity of Wee1 as the target of MK 1775 was validated by Wee1 knockdown, as well as partial reversal of drug combination-induced apoptosis by a cyclin-dependent kinase 1 (CDK1) inhibitor. Importantly, we also extended our findings to other mutant RAS-expressing malignancies, including mutant NRAS-positive melanoma, and mutant KRAS-positive colorectal cancer, pancreatic cancer and lung cancer. We observed favorable responses with combined Wee1/mTOR inhibition in human cancer cell lines from multiple malignancies, and inhibition of tumor growth in in vivo models of mutant KRAS lung cancer and leukemia. The present study introduces for the first time Wee1 inhibition combined with mTOR inhibition as a novel therapeutic strategy for the selective treatment of mutant RAS-positive leukemia and other mutant RAS expressing malignancies. PMID- 24791856 TI - Dominant-negative Ikaros cooperates with BCR-ABL1 to induce human acute myeloid leukemia in xenografts. AB - Historically, our understanding of mechanisms underlying human leukemogenesis are inferred from genetically engineered mouse models. Relatively, few models that use primary human cells recapitulate the full leukemic transformation as assayed in xenografts and myeloid transformation is infrequent. We report a humanized experimental leukemia model where xenografts develop aggressive acute myeloid leukemia (AML) with disseminated myeloid sarcomas within 4 weeks following transplantation of cord blood transduced with vectors expressing BCR-ABL1 and a dominant-negative isoform of IKAROS, Ik6. Ik6 induced transcriptional programs in BCR-ABL1-transduced progenitors that contained repressed B-cell progenitor programs, along with strong stemness, proliferation and granulocyte-monocytic progenitor (GMP) signatures-a novel combination not induced in control groups. Thus, wild-type IKAROS restrains stemness properties and has tumor suppressor activity in BCR-ABL1-initiated leukemia. Although IKAROS mutations/deletions are common in lymphoid transformation, they are found also at low frequency in AML that progress from a prior myeloproliferative neoplasm (MPN) state. Our experimental system provides an excellent model to gain insight into these rare cases of AML transformation and the properties conferred by IKAROS loss of function as a secondary mutation. More generally, our data points to the importance of deregulated stemness/lineage commitment programs in human myeloid leukemogenesis. PMID- 24791858 TI - Acceleration of Bcr-Abl+ leukemia induced by deletion of JAK2. PMID- 24791859 TI - Seeking help for postpartum depression in the Israeli Jewish orthodox community: factors associated with use of professional and informal help. AB - Postpartum depression (PPD) has potentially devastating personal and familial consequences. However, very few women receive treatment, either professional or informal. Use patterns and factors associated with both professional and informal help for PPD have not yet been investigated. This study examined factors associated with use of professional and informal help for PPD in an Israeli sample that included women from secular, traditional, orthodox, and ultra orthodox Jewish religious groups. One to two days postpartum, 1,059 women were recruited from a large hospital in Jerusalem, Israel, and completed an initial survey; 805 women (76%) participated at the 6-week follow-up; 94 women (12%) screened positive for PPD symptoms at the 6-week follow-up and were referred for help; and 88 women completed the 6-month postpartum follow-up interview. Of the women referred for help, 69% used some sort of help, with 24% using professional help and 45% using informal help. Confidence in mental health professionals and higher levels of PPD symptomatology were associated with use of professional help. Recognition of personal need for professional psychological help was negatively associated with use of informal help. Findings from this study highlight the importance of routine screening for PPD and culturally sensitive referrals using informal sources of help. PMID- 24791857 TI - Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking. AB - The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction. PMID- 24791860 TI - Unnatural killer cells to prevent bloodborne metastasis: inspiration from biology and engineering. AB - Metastasis contributes to over 90% of cancer-related deaths. Many types of cancer metastasize via the bloodstream, where circulating tumor cells (CTCs) originating from the primary tumor can undergo selectin-mediated adhesion with the blood vessel wall and subsequently transmigrate to anatomically distant organs. In an effort to neutralize CTCs with the potential to form metastases, a new therapeutic approach has been developed in which circulating leukocytes are functionalized to target and kill cancer cells in the bloodstream. This approach mimics the cytotoxic activity of natural killer cells and the chemical engineering concept of a fluidized bed reactor, which increases the surface area for surface-catalyzed reactions. The resulting 'unnatural killer cells', proven effective in vitro with human blood and also in the living mouse, holds promise in neutralizing CTCs to interrupt the metastasis process. PMID- 24791861 TI - Clinical and microbiological characterization of Clostridium difficile infection in a tertiary care hospital in Shanghai, China. AB - BACKGROUND: Over the last decade, Clostridium difficile infection (CDI) has emerged as a significant nosocomial infection, yet little has been reported from China. This study aimed to characterize the clinical and microbiological features of CDI from a hospital in Shanghai. METHODS: Patients with CDI seen between December 2010 and March 2013 were included in this study, of which clinical data were retrospectively collected. The microbiological features of corresponding isolates were analyzed including genotype by multi-locus sequence typing (MLST), antimicrobial susceptibility, toxin production, sporulation capacity, biofilm formation, and motility. RESULTS: Ninety-four cases of CDI were included during this study period, 12 of whom were severe cases. By reviewing the clinical data, all patients were treated empirically with proton pump inhibitor or antibiotics or both, and they were distributed widely across various wards, most frequently to the digestive ward (28/94, 29.79%). Comparing the severe with mild cases, no significant differences were found in the basic epidemiological data or the microbiological features. Among the 94 isolates, 31 were toxin A-negative toxin B positive all genotyped as ST37. They generated fewer toxins and spores, as well as similar amounts of biofilm and motility percentages, but exhibited highest drug resistance to cephalosporins, quinolones, macrolide-lincosamide and streptogramin (MLSB), and tetracycline. CONCLUSIONS: No specific clinical genotype or microbiological features were found in severe cases; antimicrobial resistance could be the primary reason for epidemic strains leading to the dissemination and persistence of CDI. PMID- 24791862 TI - High levels of interleukin-6 and 8-iso-prostaglandin in the exhaled breath condensate and serum of patients with chronic obstructive pulmonary disease related pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). Although alveolar hypoxia is considered as a main cause of PH in COPD, structural and functional changes of pulmonary circulation are apparent at the initial stage of COPD. We hypothesized that an inflammatory response and oxidative stress might contribute to the formation of PH in COPD. METHODS: We measured the levels of interleukin-6 (IL-6) and 8-iso prostaglandin (8-iso-PSG) in exhaled breath condensate (EBC) and serum in 40 patients with COPD only or in 45 patients with COPD combined with PH. Pulmonary arterial systolic pressure (PASP) was assessed by Doppler echocardiography and defined as PH when the value of systolic pressure was greater than 40 mmHg. RESULTS: Compared with the COPD only group, the level of IL-6 in EBC was significantly increased in all 45 patients with COPD combined with PH ((8.27+/ 2.14) ng/L vs. (4.95+/-1.19) ng/L, P < 0.01). The level of IL-6 in serum was also elevated in patients with COPD combined with PH compared with the COPD only group ((72.8+/-21.6) ng/L vs. (43.58+/-13.38) ng/L, P < 0.01). Similarly, we also observed a significant increase in the level of 8-iso-PSG in both EBC and serum in the COPD with PH group, compared with the COPD only group (EBC: (9.00+/-2.49) ng/L vs. (5.96+/-2.31) ng/L, P < 0.01 and serum: (41.87+/-9.75) ng/L vs. (27.79+/ 11.09) ng/L, P < 0.01). Additionally, the value of PASP in the PH group was confirmed to be positively correlated with the increase in the levels of IL-6 and 8-iso-PSG in both EBC and serum (r = 0.477-0.589, P < 0.05). CONCLUSION: The increase in the levels of IL-6 and 8-iso-PSG in EBC and serum correlates with the pathogenesis of PH in COPD. PMID- 24791863 TI - Interleukin-32, not reduced by salmeterol/fluticasone propionate in smokers with chronic obstructive pulmonary disease. AB - BACKGROUND: The interleukin (IL)-32/tumor necrosis factor (TNF) a pathway is supposed to play a key role in the amplification of the immune response in chronic obstructive pulmonary disease (COPD) inflammation. Inhaled corticosteroids (ICS) in combination with long-acting beta2-agonists (LABA) have shown airway anti-inflammatory effects in recent studies, but the mechanism is still uncertain. METHODS: Patients were treated in a randomized, open-labeled, parallel group clinical trial with either a combination of salmeterol xinafoate/fluticasone propionate (SF; Seretide, GlaxoSmithKline) Diskus (50/500 ug twice daily) or ipratropium bromide/salbutamol (IS; Combivent, Boehringer Ingelheim) MDI (42 ug/240 ug quartic daily) for 12 weeks. At the start and the end of treatment, induced sputum was collected and the concentration of IL-32 and TNF-alpha, the number of neutrophils and eosinophils were measured. RESULTS: Following 12 weeks of treatment, a statistically significant fall from baseline in the concentration of TNF-alpha in sputum (P = 0.004) was seen after treatment with SF but not with IS. However, neither treatment had significant effects on the concentration of IL-32 in sputum. There was a decrease from baseline in the number of sputum neutrophils with SF that approached statistical significance (P = 0.028) but not with IS, while the number of sputum eosinophils did not change significantly from baseline in either treatment group. There was a statistically significant decline from baseline in the quality of life as assessed by the St George's respiratory questionnaire in both the SF (P = 0.004) and IS (P = 0.030) treatment groups, but no evidence of improvement in lung function was observed in either group. CONCLUSION: The sputum TNF-alpha and neutrophils, but not IL-32 and macrophages, could be reduced by ICS/LABA treatment, suggesting that IL-32 could be involved in the corticosteroid resistance of COPD inflammation. PMID- 24791864 TI - Deaths of obstructive lung disease in the Yangpu district of Shanghai from 2003 through 2011: a multiple cause analysis. AB - BACKGROUND: Obstructive lung disease (OLD, chronic obstructive pulmonary disease or asthma) is an important cause of death in older people. There has been no exhaustive population-based mortality study of this subject in Shanghai. The objective of this study was to use a multiple cause of death methodology in the analysis of OLD mortality trends in the Yangpu district of Shanghai, from 2003 through 2011. METHODS: We analyzed death data from the Shanghai Yangpu District Center for Disease Control and Prevention for Medical Cause of Death database, selecting all death certificates for individuals 40 years or older on which OLD was listed as a cause of death. RESULTS: From 2003 to 2011, there were 8 775 deaths with OLD listed, of which 6 005 (68%) were identified as the underlying cause of death. For the entire period, a significantly decreasing trend of age standardized rates of death from OLD was observed in men (-6.2% per year) and in women (-5.7% per year), similar trends were observed in deaths with OLD. The mean annual rates of deaths from OLD per 100 000 were 161.2 for men and 80.8 for women from 2003 to 2011. While, as the underlying cause of death, the main associated causes of death were as follows: cardiovascular diseases (70.7%), cerebrovascular diseases (13.3%), diabetes (8.6%), and cancer (4.3%). The associated causes and the principal overall underlying causes of death were cardiovascular diseases (37.0%), cancer (30.3%), and cerebrovascular disease (15.3%). A significant seasonal variation, with the highest frequency in winter, occurred in deaths identified with underlying causes of chronic bronchitis, other obstructive pulmonary diseases, and asthma. CONCLUSIONS: Multiple cause mortality analysis provides a more accurate picture than underlying cause of total mortality attributed on death certificates to OLD. The major comorbidities associated with OLD were cardiovascular disease, cancer, and cerebrovascular disease. From 2003 to 2011, the mortality rate from OLD decreased substantially in the Yangpu district of Shanghai. PMID- 24791865 TI - Differences and determinants in access to essential public health services in China: a case study with hypertension people and under-sixes as target population. AB - BACKGROUND: Since 2009, health reform had launched in China and essential public health services were provided for all residents to ensure service equity and accessibility, and to achieve sustained population-wide health improvement. This study aimed to investigate the differences and determinants among populations with different characteristics access to essential public health services in China, especially hypertension people and children aged 0-6 years. METHODS: A cross-sectional study with socio-demographic data analysis was undertaken to estimate distribution characteristics of receiving essential public health services of hypertension patients and children. Regular follow-ups and effective blood pressure control reflected the effective management for hypertension patients, and for children, public services provided were vaccination on schedule and regular physical check-up. Logistic regression was used to determine the predictors for effective management. RESULTS: A total of 1 505 hypertension patients and 749 children were involved; 39.14% of hypertension participants could control their blood pressure in the normal range, and the rate in urban areas (43.61%) was higher than that in rural (31.88%). And 34.68% of them could receive more than 4 times follow-ups by the medical technician. Of 754 children, 79.84% could receive the periodic physical examination and 98.40% had vaccinated regularly. Children living in rural areas were more likely to have regular check ups (83.96%) and regular vaccination (nearly 99%). Overall, geographic location and education level were the determinants of people access to essential public health services. CONCLUSIONS: Implementation of the health reform since 2009 has headed China's public health system in the right direction and promoted the improvement of public health system development. Our study highlights the growing needs for more public health services in China, and China's public health system needs to be greatly improved in terms of its quality and accessibility. PMID- 24791866 TI - Measuring health care efficiency with a tripartite configuration under the "National" Health Insurance system. AB - BACKGROUND: The "National" Health Insurance (NHI) in Taiwan, China is a single payer system that was introduced in 1995 to provide universal health care. It is worth noting that three stakeholders are involved in Taiwan's NHI, which can be seen as a triangular governance regime between the Bureau of "National" Health Insurance (BNHI), the insured and providers. Accordingly, this study intended to assess the efficiency of various different production processes that occur among these stakeholders in Taiwan's NHI system. METHODS: A two-stage relational Data Envelopment Analysis (DEA) model is adopted to investigate the sub-process efficiencies of the health care resources held by 23 cities and counties through stages I or II, where the outputs of the first stage serve the inputs of the second. The dataset was collected from the annual reports published by the Department of Health, Taiwan, China. RESULTS: Under the proposed framework, the efficiency of the whole process can be obtained from the product of productivity and allocative efficiency. Ten DMUs are efficient either in stages I or II, with only two DMUs being efficient with regard to both sub-processes. CONCLUSION: The relational DEA model not only demonstrates the physical relationship between the whole process and the sub-process components, but also produces reliable outcomes in efficiency measurement among different stakeholders in Taiwan's NHI system. PMID- 24791867 TI - Prognostic value of clinical and pathological factors for surgically treated localized clear cell renal cell carcinoma. AB - BACKGROUND: Surgical resection is the most effective treatment for renal cell carcinoma (RCC). Currently several prognostic factors and models are used for outcome prediction. However, whether intratumoral changes are independent prognostic factors for RCC or not remains unclear. The aim of the study was to investigate the prognostic roles of intratumoral changes in surgical treated localized clear cell renal cell carcinoma (ccRCC). METHODS: Patients who received partial or radical nephrectomy between 2004 and 2009 in our center were retrospectively reviewed. Univariate and multivariate analyses were used to assess gender, age, body mass index (BMI), intratumoral hemorrhage, tumor necrosis, cystic degeneration, sarcomatoid change, Ki-67 expression, Fuhrman grade, and T stage on recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: A total of 378 patients were included in our study. In univariate analysis, age, BMI, intratumoral hemorrhage, tumor necrosis, sarcomatoid change, Ki-67 expression level, Fuhrman grade, and T stage were prognostic factors for RFS. Age, BMI, tumor necrosis, sarcomatoid change, Ki-67 expression level, Fuhrman grade, and T stage were prognostic factors effecting CSS. In multivariate analysis, age, BMI, tumor necrosis, sarcomatoid change, Ki-67, Fuhrman grade, and T stage were independent prognostic factors for both RFS and CSS. CONCLUSION: Intratumoral changes such as tumor necrosis and sarcomatoid change are independent prognostic factors for ccRCC. PMID- 24791868 TI - Epigenetic regulation of putative tumor suppressor TGFBI in human leukemias. AB - BACKGROUND: Both in vitro and in vivo data have demonstrated the TGFBI gene functions as a putative tumor suppressor and is frequently downregulated in human tumors of different histological types. The hypermethylation of the TGFBI promoter, as one of the main regulatory mechanisms, is associated with TGFBI silencing. In this study, we used a methylation-specific PCR (MSP) method to evaluate the methylation status of the TGFBI promoter in human leukemias. METHODS: Real-time RT-PCR and methylation-specific PCR approaches were performed to define the TGFBI expression and promoter methylation in human leukemia cell lines and clinical samples. Genomic DNA was isolated from peripheral blood mononuclear cells from leukemia patients, bisulfite-converted, and analyzed by the MSP method. RESULTS: Hypermethylation of the TGFBI promoter occurred in leukemia cell lines and demethylation treatment reexpressed TGFBI at a substantially increased level in most of leukemia cell lines tested. Furthermore, a much higher level of CpG island methylation and a significantly lower TGFBI expression were also identified in clinical leukemia samples. CONCLUSION: The results suggest an important role of promoter methylation in regulating TGFBI expression in leukemia, which provides a useful diagnostic marker for clinical management of human leukemias. PMID- 24791869 TI - Differences in P50 and prepulse inhibition of the startle reflex between male smokers and non-smokers with first episode schizophrenia without medical treatment. AB - BACKGROUND: Nicotine may improve schizophrenia patient's cognitive deficit symptoms. This study was to explore the chronic effects of smoking on prepulse inhibition of the startle reflex (PPI) and P50 in the patients with first-episode schizophrenia (FES). METHODS: The event-related potentials (ERP) recording and analysis instrument made by Brain Products, Germany, was used to detect PPI and P50 in 49 male FES patients (FES group, n = 21 for smokers and n = 28 for non smokers) and 43 normal male controls (control group, n = 19 for smokers and n = 24 for non-smokers). RESULTS: Compared with normal controls, the FES group had prolonged PPI latency when elicited by single stronger stimulus (P < 0.05); the FES group had prolonged PPI latency and increased PPI amplitude (P < 0.05, 0.01) when elicited by weak and strong stimuli. The FES group had lower PPI inhibition rate than normal controls (P < 0.05). Compared with normal controls, the FES group had increased P50-S2 amplitude and increased amplitude ratio S2/S1 (both P <0.05). In the control group, the smokers had a tendency of increase in P50-S2 amplitude (P > 0.05) and shorter P50-S2 latency (P < 0.05) than the non-smokers. The smokers had higher PPI amplitude than the non-smokers (P < 0.05). In the FES group, the smokers had higher P50-S1 amplitude, shorter P50-S2 latency, and higher amplitude ratio S2/S1 than the non-smokers (P < 0.05, 0.01). The smokers had higher PPI amplitude than the non-smokers (P < 0.05). CONCLUSIONS: There is obvious PPI and P50 deficits in schizophrenic patients. However, these deficits are relatively preserved in the smokers compared with the non-smokers, which suggests that long-term smoking might partially improve the sensory gating in schizophrenic patients. Whether this conclusion can be deduced to female patients requires further follow-ups. PMID- 24791870 TI - Effect of human rhinovirus infection in pediatric patients with influenza-like illness on the 2009 pandemic influenza A(H1N1) virus. AB - BACKGROUND: Some research groups have hypothesized that human rhinoviruses (HRVs) delayed the circulation of the 2009 pandemic influenza A(H1N1) virus (A(H1N1)pdm09) at the beginning of Autumn 2009 in France. This study aimed to evaluate the relationship between HRV and A(H1N1)pdm09 in pediatric patients with influenza-like illness in Beijing, China. METHODS: A systematic analysis to detect A(H1N1)pdm09 and seasonal influenza A virus (FLU A) was performed on 4 349 clinical samples from pediatric patients with influenza-like illness during the period June 1, 2009 to February 28, 2010, while a one-step real-time RT-PCR (rRT PCR) assay was used to detect HRV in 1 146 clinical specimens selected from those 4 349 specimens. RESULTS: During the survey period, only one wave of A(H1N1)pdm09 was observed. The percentage of positive cases for A(H1N1)pdm09 increased sharply in September with a peak in November 2009 and then declined in February 2010. Data on the monthly distribution of HRVs indicated that more HRV-positive samples were detected in September (2.2%) and October (3.3%), revealing that the peak of HRV infection in 2009 was similar to that of other years. Among the 1 146 specimens examined for HRVs, 21 (1.8%) were HRV-positive, which was significantly lower than that reported previously in Beijing (15.4% to 19.2%) (P < 0.01). Overall, 6 samples were positive for both A(H1N1)pdm09 and HRV, which represented a positive relative frequency of 1.60% and 2.08% HRV, considering the A(H1N1)pdm09-positive and -negative specimens, respectively. The odds ratio was 0.87 (95% CI 0.32; 2.44, P = 0.80). CONCLUSIONS: HRVs and A (H1N1)pdm09 co circulated in this Chinese population during September and October 2009, and the HRV epidemic in 2009 did not affect A(H1N1)pdm09 infection rates in Beijing, China as suggested by other studies. However, the presence of A(H1N1)pdm09 might explain the unexpected reduction in the percentage of HRV positive cases during the period studied. PMID- 24791871 TI - Retrospective epidemiological study of thyroid nodules by ultrasound in asymptomatic subjects. AB - BACKGROUND: The purpose of this study was to conduct thyroid ultrasound examinations on a large sample of subjects and explore the occurrence, distribution, and characteristics of thyroid nodules and thyroid cancer to provide some information on the epidemic trend of thyroid nodules and cancer. METHODS: The thyroid ultrasonic examination results of 19 895 healthy physical examinees who visited the Department of Health Management, Peking Union Medical College Hospital from January 2009 to December 2011 were analyzed retrospectively to determine the detection rate and characteristics of thyroid nodules. Fine needle aspiration or surgical resection was suggested to subjects suspected of having thyroid cancer. RESULTS: The detection rate of thyroid nodules was 42.6% (8 480/19 895), 40.0% (4 661/11 678) in men and 46.5% (3 819/8 217) in women. The detection rate noticeably increased with increasing age. The detection rate of thyroid nodules by palpation was obviously lower than by ultrasonic examination in various age groups. Among those with thyroid nodules, 61.3% were multiple and 38.7% were solitary; multiple nodule was the major type both in men and women. Twenty-nine cases of malignant nodules were solitary, and 30 cases of malignant nodules were multiple. There was no significant difference. The detection rate of thyroid cancer was 0.30% for the entire group of examinees, and 0.15% in men and 0.50% in women. Among all sex and age groups, 30- to 40-year-old women had the highest detection rate (0.76%). The detection rate of thyroid nodules correlated with age, systolic blood pressure, height, and weight. Increasing age and/or higher systolic blood pressure correlated with a higher detection rate, while smaller height and weight also correlated with a higher detection rate with significant differences. However, there were no significant correlations between the detection rate and diastolic blood pressure or body mass index. CONCLUSIONS: The detection of thyroid cancer increased significantly, especially in women. Thus, precautions needed to be taken. Regular physical examination and timely intervention after detection of malignant nodules are critical to improve the prognosis in thyroid cancer patients. PMID- 24791873 TI - Locking plate fixation combined with iliac crest bone autologous graft for proximal humerus comminuted fracture. AB - BACKGROUND: Although the use of an intramedullary fibular allograft together with locking plate fixation can provide additional medial support and prevent varus malalignment in displaced proximal humeral fractures with promising results, the fibular autograft donor site often sustains significant trauma and cannot restore the articular surface of comminuted fractures. The aim of this study was to evaluate the clinical and radiographic outcomes of a locking plate and crest bone autologous graft for treating proximal humerus comminuted fractures. METHODS: We assessed the functional outcomes and complication rates in 40 patients with proximal humerus comminuted fractures. Eighteen patients were treated with a locking plate and an autologous crest bone graft (experimental group), and 22 were treated with only the locking plate and no bone graft (control group). Postoperative assessments included radiographic imaging, range of motion analysis, pain level based on the visual analogue scale (VAS), and the SF-36 (Short Form (36) Health Survey), as well as whether patients could return to their previous occupation. RESULTS: All fractures healed both clinically and radiologically in the experimental group. There was no more than 2 mm collapse of the humeral head, and no osteonecrosis or screw penetration of the articular surface. In contrast, two patients had a nonunion in the control group, and they eventually accepted total shoulder replacements. The average time from surgery to radiographic union was significantly shorter in the experimental group ((4.66+/ 1.63) months) compared with the control group ((5.98+/-1.57) months) (P < 0.05). For the experimental versus controls groups, the mean shoulder active flexion (148.00+/-18.59 vs. 121.73+/-17.20) degrees, extension (49.00+/-2.22 vs. 42.06+/ 2.06) degrees, internal rotation (45.00+/-5.61 vs. 35.00+/-3.55) degrees, external rotation (64.00+/-9.17 vs. 52.14+/-5.73) degrees, and abduction (138.00+/-28.78 vs. 105.95+/-15.66) degrees were all significantly higher (all P < 0.001). The median SF-36 in the experimental group ((88.00+/-5.71) points) was significantly higher than that of the control group ((69.45+/-9.45) points; P < 0.001). The median VAS pain level (mean rank, 10.50) in the experimental group was lower than that (mean rank, 47.19) of the control group (P < 0.001). All but one patient (17 of 18, 94.4%) in the experimental group returned to their previous activities or occupations, and that one patient changed to a different occupation because of slight restrictions to activities. On the other hand, four patients could not return to their previous activities or occupations in the control group. CONCLUSION: Locking plate fixation combined with an iliac crest bone graft is an effective technique for treating proximal humerus comminuted fractures. PMID- 24791872 TI - Bortezomib improves progression-free survival in multiple myeloma patients overexpressing preferentially expressed antigen of melanoma. AB - BACKGROUND: Significant efforts have been made to identify factors that differentiate patients treated with novel therapies, such as bortezomib in multiple myeloma (MM). The exact expression pattern and prognostic value of the cancer/testis antigen preferentially expressed antigen of melanoma (PRAME) in MM are unknown and were explored in this study. METHODS: The transcript level of PRAME was detected in bone marrow specimens from 100 newly diagnosed MM patients using real-time quantitative polymerase chain reaction, and the prognostic value of PRAME was determined through retrospective survival analysis. PRAME expression higher than the upper limit of normal bone marrow was defined as PRAME overexpression or PRAME (+). RESULTS: Sixty-two patients (62.0%) overexpressed PRAME. PRAME overexpression showed no prognostic significance to either overall survival (n = 100) or progression-free survival (PFS, n = 96, all P > 0.05) of patients. The patients were also categorized according to regimens with or without bortezomib. PRAME overexpression tended to be associated with a lower two year PFS rate in patients treated with non-bortezomib-containing regimens (53.5% vs. 76.9%, P = 0.071). By contrast, it was not associated with the two-year PFS rate in patients with bortezomib-containing regimens (77.5% vs. 63.9%, P > 0.05). When the patients were categorized into PRAME (+) and PRAME (-) groups, treatment with bortezomibcontaining regimens predicted a higher two-year PFS rate in PRAME (+) patients (77.5% vs. 53.5%, P = 0.027) but showed no significant effect on two year PFS rate in PRAME (-) patients (63.9% vs. 76.9%, P > 0.05). CONCLUSION: PRAME overexpression might be an adverse prognostic factor of PFS in MM patients treated with non-bortezomib-containing regimens. Bortezomib improves PFS in patients overexpressing PRAME. PMID- 24791874 TI - Combined treatment with erythropoietin and granulocyte colony-stimulating factor enhances neovascularization and improves cardiac function after myocardial infarction. AB - BACKGROUND: Erythropoietin (EPO) and granulocyte colony-stimulating factor (G CSF) are both potential novel therapeutics for use after myocardial infarction (MI). However, their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial. Therefore, we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms. METHODS: Four groups of rats were used: control (saline injection after MI, i.h.), EPO (a single dose of 5 000 IU/kg after MI, i.h.), G-CSF (a dose of 50 ug* kg(-1)* d(-1) for 5 days after MI, i.h.), and both EPO and G-CSF (EPO+G-CSF, using the same regiment as above). Cardiac function was assessed by echocardiography before and 1 day, 7 days, 14 days and 21 days after MI. CD34(+)/Flk-1(+) cells in the peripheral blood were evaluated by flow cytometry before and 3 days, 5 days and 7 days after MI. The infarct area and angiogenesis in the peri-infarct area were analyzed. The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1a (SDF 1alpha) in the peri-infarct area were detected by real-time quantitative RT-PCR and Western blotting. RESULTS: Compared with the control and monotherapy groups, the EPO+G-CSF group had significantly increased CD34(+)/Flk-1(+) endothelial progenitor cells (EPCs) in the peripheral blood (P < 0.05), up-regulated VEGF and SDF-1alpha levels in the peri-infarct region (P < 0.05), enhanced capillary density (P < 0.05), reduced infarct size (P < 0.05) and improved cardiac structure and function (P < 0.05). G-CSF alone did not dramatically increase EPCs in the peripheral blood, enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group. CONCLUSIONS: Combined treatment with EPO and G-CSF increased EPCs mobilization, up-regulated VEGF and SDF-1alpha levels in the post-infarction microenvironment, subsequently enhanced neovascularization in the peri-infarct region and reduced infarct size. All factors contributed to its beneficial effects on cardiac function in post infarction rats. PMID- 24791875 TI - Surgical treatment of interrupted aortic arch associated with ventricular septal defect and patent ductus arteriosus in patients over one year of age. AB - BACKGROUND: Interrupted aortic arch (IAA) is a rare congenital anomaly affecting 1.5% of infants with congenital heart disease. Neonatal repair of IAA is required to avoid irreversible pulmonary vascular lesion. However, in China, patients with IAA associated with ventricular septal defect (VSD) and patent ductus arteriosus (PDA) over one year of age are common. So we investigated the outcome of surgical treatment of IAA with VSD and PDA in patients over one year of age. METHODS: From January 2009 to December 2012, 19 patients with IAA have undergone complete single-stage repair. The patients' mean age was 4.4 years, ranging 1 to 15 years; and their mean weight was 12.8 kg, ranging 4.2 to 36.0 kg. Fifteen IAA were type A, four were type B. Preoperative cardiac catheterization data were available from all patients. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were measured. The measurements of postoperative pulmonary artery pressure were taken in the operating room at the end of the case. All patients underwent echocardiographic examinations before discharged from the hospital. In addition, cardiac catheterization and echocardiographic examinations were performed during follow-up. Selective brain perfusion through the innominate artery during aortic arch reconstruction was used in all patients. Mean follow-up was (1.6+/-0.8) years. RESULTS: There were two hospital deaths (2/19, 11%). One patient died of pulmonary hypertension crisis, and another died of postoperative low cardiac output. Five cases had other main postoperative complications but no postoperative neurologic complications. Seventeen survivors were followed up, and there were no late deaths or reoperation. Mean cross-clamp duration was (85+/-22) minutes and selective brain perfusion duration was (34+/-11) minutes. Two patients required delayed sternal closure at two days postoperatively. Intensive care unit and hospital stays were (9+/-8) days and (47+/-24) days, respectively. Pressure gradients across the anastomosis at most recent follow up were less than 22 mmHg. mPAP regressed significantly from preoperative (62.1+/-8.1) mmHg to postoperative (37.3+/-11.3) mmHg (P < 0.001) and (24.2+/-6.0) mmHg at six months after discharged from the hospital (P < 0.001). The pulmonary vascular resistance also regressed significantly from preoperative (1 501.4+/-335.7) dyn*s*cm(-5) to (485.0+/-215.1) dyn*s*cm(-5) at six months after discharged from the hospital (P < 0.001). The majority of the seventeen patients (89%) were in New York Heart Association (NYHA) class I, and 11% remained in NYHA class II. CONCLUSIONS: Single-stage repair of patients with IAA, VSD and PDA over one year of age can have good surgical results and functional outcomes. Assessment and treatment of pulmonary artery pressure pre-operatively and postoperatively was crucial. mPAP and pulmonary vascular resistance may have regress significantly compared to preoperative values. PMID- 24791876 TI - Association between CISH polymorphisms and spontaneous clearance of hepatitis B virus in hepatitis B extracellular antigen-positive patients during immune active phase. AB - BACKGROUND: Some hepatitis B extracellular antigen (HBeAg)-positive chronic hepatitis B (CHB) patients in their immune active phase can clear the virus spontaneously and enter into an inactive hepatitis B virus (HBV) carrier state, indicating a benign prognosis. In this study, the association between cytokine inducible SRC homology 2 domain protein (CISH) gene polymorphisms at -292 (rs414171) and the spontaneous clearance of HBV in HBeAg-positive CHB patients in immune the active phase was investigated. METHODS: Seventy HBeAg-positive CHB patients in the immune active phase were followed up for 76 weeks without antiviral therapy. The alanine transaminase, aspartate transaminase, HBV DNA, HBeAg and hepatitis B extracellular antibody levels were tested regularly. At week 76, 27 patients were classified into group A (HBV DNA level below 2 104 IU/ml and the value of HBeAg declined below 10% of the baseline at week 76), and 43 patients were classified into group B (HBV DNA level higher than 2*10(4) IU/ml or the value of HBeAg did not decline substantially at week 76). CISH (rs414171) polymorphisms were also tested using the iPLEX system. RESULTS: The HBV DNA levels at week 12 were significantly greater in group B compared with group A (group A: (6.87+/-1.40) log10IU/ml; group B: (7.61+/-1.38) log10IU/ml, P = 0.034) and the HBeAg values were greater in group B at week 28 compared with group A (P = 0.001). The differences in HBV DNA and HBeAg values increased between the groups over time. Sixteen patients in group A and 11 in group B were genotype AA. Those with genotype AT or TT included 11 in group A and 31 in group B (AA vs. AT and TT, odds ratio 4.10 (95% confidence interval: 1.462-11.491), P = 0.006). CONCLUSION: CISH gene polymorphisms at -292 (rs414171) are associated with HBV clearance in HBeAg-positive CHB patients in the immune active phase, and AA is a favorable genotype for this effect. PMID- 24791877 TI - Value of magnetic resonance imaging including dynamic contrast-enhanced magnetic resonance imaging in differentiation between inverted papilloma and malignant tumors in the nasal cavity. AB - BACKGROUND: Distinguishing inverted papilloma (IP) from malignant tumors in the nasal cavity is difficult in a substantial number of cases, thus hindering the administration of appropriate therapeutic strategies. This study aimed to evaluate whether magnetic resonance imaging (MRI), including dynamic contrast enhanced MRI (DCE-MRI), could improve differentiation between IP and malignant tumors, and to identify which MRI features were the best in discriminating IP from malignant tumors in the nasal cavity. METHODS: Non-enhanced, static, and dynamic contrast enhanced MRI was performed in 88 patients with an IP or a malignant tumor in the nasal cavity that had been confirmed by histological results. MRI features of IP and malignant tumors including side, margin, T1 signal intensity, T1 homogeneity, T2 signal intensity, T2 homogeneity, lobulation signs, convoluted cerebriform pattern, extra-sinonasal involvement, pattern of enhancement, Tpeak, Tmax, CImax, and TIC type were evaluated and correlated with histological findings. RESULTS: There were significant differences between IP and malignant tumors in T2 homogeneity, lobulation signs, convoluted cerebriform pattern, extra-sinonasal involvement, Tpeak, Tmax and TIC types. A convoluted cerebriform pattern had a higher sensitivity and specificity in diagnosis of IP while washout-type TIC had a higher sensitivity and specificity in diagnosis of malignant tumors in the nasal cavity. Non-enhanced combined with static and dynamic enhancement MRI was significantly superior to non-enhanced combined with static enhancement MRI in the differentiation of IP and malignant tumors in the nasal cavity. Multivariate logistic regression analysis identified that the best MRI features were a convoluted cerebriform pattern, extra-sinonasal involvement, and washout-type TIC for both observers (Wang XY and Zhang ZY). CONCLUSION: Non enhanced and static combined with dynamic contrast-enhanced MRI improves differentiation of IP and malignant tumors in the nasal cavity. PMID- 24791878 TI - Characteristics of optic disc parameters and its association in normal Chinese population: the Handan Eye Study. AB - BACKGROUND: Assessment of the optic disc and retinal nerve fiber layer (RNFL) is essential for the diagnosis and monitoring of glaucoma. Knowledge of normal optic disc topography provides a benchmark for evaluating glaucomatous pathologic changes, especially in its early stages. The purpose of this study was to evaluate the characteristics and correlation factors of the optic disc parameters using the Heidelberg Retina Tomograph II (HRT II) in a large sample of normal eyes of adult Chinese subjects. METHODS: Disc data were obtained from 6 830 subjects aged >30 years from the Handan Eye Study. All participants underwent comprehensive eye examinations and physical examinations. The associations of gender, age, body mass index, blood pressure, waist-to-hip ratio; refractive error, intraocular pressure, axial length, and disc area were assessed using simple and multiple regression analysis. The correlation between HRT II parameters was evaluated. RESULTS: Of the 7 557 eligible subjects, 6 830 took part in the study (90.4% response rate) and 2 633 normal eyes with good-quality HRT II images were selected. The mean disc area was 2.28 mm(2) (standard deviation (SD) 0.43) and mean neural rim area was 1.80 mm(2) (SD 0.29). In multiple regression analysis, optic disc area significantly correlated with age, gender, and axial length (P < 0.001). All optic disc parameters showed a significant correlation with disc area (0.054 =2 g/d and estimated glomerular filtration rate 30-89 ml*min( 1)*1.73 m(-2)) were treated with corticosteroids/cyclophosphamide followed by a 12-month follow-up. According to their response, these patients were divided into remission group (proteinuria <0.5 g/d) and non-remission group (proteinuria >=0.5 g/d), and their clinical data collected. RESULTS: In the present study, 72.96% of the individuals underwent a complete remission, and their response was related to baseline proteinuria, urinary osmotic pressure, and renal function (P < 0.05). Patients with baseline proteinuria more than 3 g/d, urinary osmotic pressure greater than 600 mOsm/L, and eGFR 60-89 ml*min(-1)*1.73 m(-2) responded well to the combination of corticosteroids and cyclophosphamide (86.90% vs. 57.33%, P = 0.000; 81.48% vs. 64.10%, P = 0.014; 83.17% vs. 55.17%, P = 0.000). CONCLUSION: The response to the combination of corticosteroids and cyclophosphamide might be well associated with baseline proteinuria, urinary osmotic pressure, and renal function in patients with IgAN. PMID- 24791880 TI - Analysis of pathological data of renal biopsy at one single center in China from 1987 to 2012. AB - BACKGROUND: In China, the prevalence of chronic kidney disease has increased significantly. Many studies shows that the spectrum of kidney disease had changed in recent years. We retrospectively analyzed the pathological types of renal biopsy and its spectrum change at the General Hospital of the Chinese People's Liberation Army from December 1987 to December 2012, in order to offer new supporting evidences for further specifying the distribution of renal pathological types in China. METHODS: According to the "Revised Protocol for the Histological Typing of Glomerulopathy" (WHO, 1995), pathological diagnosis of renal biopsy was classified, detection rate of each pathological type was summarized (i.e., percentage of total renal biopsy cases), study period was divided at an interval of 5 years, and age-stratified distribution change of main pathological types was analyzed. RESULTS: The proportion of pathological types in 11 618 cases of renal biopsy was as follows: primary glomerulonephritis (PGN, 70.7%), secondary glomerulonephritis (SGN, 20.7%), tubular-interstitial nephropathy (4.0%), hereditary/rare nephropathy (0.3%), end-stage renal disease (0.9%), and unclassified renal disease (3.3%). Among PGN, there was IgA nephropathy (IgAN, 37.0%), membranous nephropathy (MN, 11.8%), mesangial proliferative glomerulonephritis (MsPGN, 8.9%), minimal change disease (MCD, 6.6%), and focal segmental glomerulosclerosis (3.9%). Among SGN there was lupus nephritis (LN, 5.5%), Henoch-Schonlein purpura glomerulonephritis (5.3%), hepatitis B virus-associated nephritis (HBVAN, 3.03%), diabetic nephropathy (2.2%), and hypertension/malignant hypertension-associated renal damage (1.9%). Pathological data were analyzed from 1987-1992 to 2008-2012 (after age adjustment). Detection rate of IgAN tended to rise (P < 0.001). Detection rates of MN and MCD rose significantly (P < 0.001), but detection rate of MsPGN dropped significantly (P < 0.001). Among SGN, detection rate of HBVAN tended to drop (P < 0.001). CONCLUSION: In China, PGN was the most common glomerulopathy (mostly IgAN), LN was the most common SGN, and detection rate of MN and MCD rose significantly. PMID- 24791881 TI - Breast milk macronutrient composition and the associated factors in urban Chinese mothers. AB - BACKGROUND: Infancy is a critical period of growth and physiological development, in which breast milk is the best source of nutrients. Compared to western countries, research on breast milk of Chinese population are limited. Thus, it is necessary to measure breast milk energy and macronutrient concentrations of healthy urban Chinese mothers at different lactation stages, to expand the database of milk composition of Chinese population, and to examine whether dietary or other maternal factors can affect the levels of macronutrients in breast milk. METHODS: Breast milk of full expression of one side breast from 436 urban Chinese lactating mothers at 5-11 days, 12-30 days, 31-60 days, 61-120 days, and 121-240 days postpartum was obtained at 9:00 a.m. to 11:00 a.m. Total energy, lactose, protein, and fat contents were measured. 24-hour dietary recall was surveyed, and maternal nutrient intakes were analyzed. RESULTS: Milk composition changed over the course of lactation and large individual variations were documented. The concentrations were 61.3 kcal/dl for total energy, 7.1 g/dl for lactose, 0.9 g/dl for protein, and 3.4 g/dl for fat in mature milk. Stage of lactation was a strong factor affecting milk composition. Minimal evidence was found for associations between maternal current dietary intake and milk macronutrient concentration, consistently with prior research. Maternal body mass index (BMI) was positively associated with milk fat content, to a greater extent than did dietary intake. All other maternal characteristics were not significant for milk composition. CONCLUSION: These findings suggest that milk composition is generally weakly associated with maternal factors except for stage of lactation, and is likely to be more susceptible to long-term maternal nutritional status than short-term dietary fluctuation. PMID- 24791882 TI - Trace glucose fluxes in individuals with prediabetes using stable isotopes. AB - BACKGROUND: The glucose fluxes of individuals with prediabetes in Chinese population are not clear. This study was to determine whether the endogenous glucose production (EGP), oral glucose rate of appearance (Ra) and glucose rate of disappearance (Rd) were different in Chinese individuals with prediabetes under fasting conditions and following an oral glucose challenge. METHODS: Five subjects with type 2 diabetes, 5 subjects with prediabetes and 5 non-diabetic subjects matched for age, weight, fat free mass and body mass index underwent a 180 minute stable glucose isotope tracing ([6, 6-(2)H2] glucose, [1-(13)C] glucose, and [U-(13)C] glucose) study under fasting and after ingestion of a 75 g oral glucose load. Isotope glucose enrichment was measured by gas chromatography mass spectrometry. Insulin sensitivity was estimated using the oral glucose tolerance test (OGTT)-derived insulin sensitivity index, beta cell function was determined by the insulinogenic index (deltaI30/deltaG30). RESULTS: The insulin sensitivity index (P = 0.043) and insulinogenic index (P = 0.021) were decreased in subjects with prediabetes compared with non-diabetes. Fasting EGP was slightly higher (P = 0.29) and postprandial EGP was comparable in subjects with prediabetes and non-diabetes during 120 minutes after glucose ingestion, but nadir EGP occurred later in prediabetic than non-diabetic subjects. Ra did not differ among the three groups. Rd was substantially lower in subjects with prediabetes than non-diabetes after glucose intake (P = 0.013). CONCLUSION: The mild hyperglycemia observed among individuals with prediabetes may result from decreased Rd during the postprandial state. PMID- 24791883 TI - Characterization of hospital waste in Lahore, Pakistan. AB - BACKGROUND: It is a common practice in developing countries that medical/infectious waste openly dumped with municipal solid waste. This paper presented a generation and characterization study of hospital waste. Determination of the waste composition is a basic step for selecting the most efficient treatment method of hospital waste. METHODS: Stratified random sampling was used to collect the samples of general as well as medical wastes for seven days. Medical waste was sorted into 10 categories whereas general waste was classified into 11 categories. Incineration was observed thoroughly for observing flaws in the incineration process. Data was analyzed by using SPSS software version 16.0. RESULTS: The studied hospital produced an average 297 kilograms of medical waste daily and it comprises plastics (71.0%), glass (13.9%), papers etc. (3.8%), cotton/dressings (5.7%), masks/gloves/sheets (0.3%) diapers (0.4%), wasted machines used in operation theaters (2.0%) and blades (0.1%). Laboratories, cancer ward, nursery ward, OPD and emergency ward are the largest infectious waste producing departments in the hospital. The hospital produced an average 3 511 kilograms of general waste daily in which organics constitute (44.3%), diapers etc. (42.8%), demolition materials (3.7%), plastic waste mixing medical plastic waste (2.5%), miscellaneous (2.14%), cloth/clothes (1.6%), cardboard (1.3%), papers (0.8%), cotton dressings (0.28%), glass (0.27%) and iron materials (0.18%). Other alarming facts are: medical waste is recycled in study area, after incineration of hospital waste, ash simply dumped in the premises of the hospital without any liner system. CONCLUSIONS: The studied hospital produces 10% of infectious waste and 90% of general waste. The largest components of the infectious waste are plastic and glass. Organics and diapers are major components of the general waste coming from different sites of the hospital. Lack of training, inadequate knowledge regarding to the composition of the infectious waste and risks associated with the waste are the major issues which must be addressed and resolved. PMID- 24791884 TI - Lysophosphatidic acid increases SLC26A3 expression in inflamed intestine and reduces diarrheal severity in C57BL/6 mice with dextran-sodium-sulfate-induced colitis. AB - BACKGROUND: Diarrhea is a common clinical feature of ulcerative colitis resulting from unbalanced intestinal fluid and salt absorption and secretion. The Cl( )/HCO3(-) exchanger SLC26A3 is strongly expressed in the mid-distal colon and plays an essential role in colonic Cl(-) absorption and HCO3(-) secretion. Slc26a3 expression is up-regulated by lysophosphatidic acid (LPA) in vitro. Our study was designed to investigate the effects of LPA on SLC26A3 expression and the diarrheal phenotype in a mouse colitis model. METHODS: Colitis was induced in C57BL/6 mice by adding 4% of dextran sodium sulfate (DSS) to the drinking water. The mice were assigned to LPA treatment DSS group, phosphate-buffered saline (PBS) treatment DSS group, DSS only group and untreated mice with a completely randomized design. Diarrhea severity was evaluated by measuring mice weight, disease activity index (DAI), stool water content and macroscopic evaluation of colonic damage. The effect of LPA treatment on Slc26a3 mRNA level and protein expression in the different groups of mice was investigated by quantitative PCR and Western blotting. RESULTS: All mice treated with DSS lost weight, but the onset and severity of weight loss was attenuated in the LPA treatment DSS group. The increases in stool water content and the macroscopic inflammation score in LPA treatment DSS group were significantly lower compared to DSS control group or PBS treatment DSS group ((18.89+/-8.67)% vs. (28.97+/-6.95)% or (29.48+/-6.71)%, P = 0.049, P = 0.041, respectively and 2.67+/-0.81 vs. 4.5+/-0.83 or 4.5+/-0.54, P = 0.020, P = 0.006, respectively), as well as the increase in DAI (P = 0.004, P = 0.008, respectively). LPA enema resulted in higher Slc26a3 mRNA and protein expression levels compared to PBS-treated and untreated DSS colitis mice. CONCLUSION: LPA increases Slc26a3 expression in the inflamed intestine and reduces diarrhea severity in DSS-induced colitis, suggesting LPA might be a therapeutic strategy in the treatment of colitis associated diarrhea. PMID- 24791885 TI - Effects of lead exposure on placental cellular apoptosis and endoplasmic reticulum stress in rats. AB - BACKGROUND: Lead exposure during pregnancy contributes to fetal abortion and/or teratogenesis. Endoplasmic reticulum (ER) apoptosis can be induced by various pathological conditions when ER function is disturbed. However, it is unclear whether ER stress and apoptosis play a role in the etiology of lead-exposed disease status. We aimed to investigate whether lead induced placental apoptosis and subsequent toxicity is initiated by ER apoptosis via caspase-12. METHODS: Sixty-three female Wistar rats were exposed to lead in drinking water during various gestational periods. Blood lead level was determined by atomic absorption spectrophotometry. Placental cytoplasmic organelles were examined by electronic microscopy. Placental caspase-12 mRNA expression was evaluated by qRT-PCR. TUNEL assay was used to determine the placental apoptosis. RESULTS: Lead exposure significant induced ER apoptosis compared to that of the controls (P < 0.05), accompanied with increased caspase-12 mRNA expression. Significant differences of caspase-12 mRNA expression levels were observed among the four groups (F = 13.78, P < 0.05). Apoptotic index (AI) was significantly increased in experimental groups compared to that of the controls (F = 96.15, P < 0.05). In lead-exposed groups, trophoblast cells underwent degeneration and fibrin deposition; Mitochondria were swollen and decreased in number; ER swelling, expansion, and vacuolization were observed. CONCLUSION: Lead exposure contributes to placental apoptosis, as well as increased caspase-12 mRNA expression, which in turn promoted ER stress. PMID- 24791886 TI - Minocycline protects retinal ganglion cells after optic nerve crush injury in mice by delaying autophagy and upregulating nuclear factor-kappaB2. AB - BACKGROUND: Currently, no medicine is available that can prevent or treat neural damage associated with optic nerve injury. Minocycline is recently reported to have a neuroprotective function. The aims of this study were to exarmine the neuroprotective effect of minocycline on retinal ganglion cells (RGCs) and determine its underlying mechanisms, using a mouse model of optic nerve crush (ONC). METHODS: ONC was performed in the left eye of adult male mice, and the mice were randomly divided into minocycline-treated group and saline-treated control group. The mice without receiving ONC injury were used as positive controls. RGC densities were assessed in retinal whole mounts with immunofluorescence labeling of betaIII-tubulin. Transmission electron microscopy was used to detect RGC morphologies, and Western blotting and real-time PCR were applied to investigate the expression of autophagy markers LC3-I, LC3-II, and transcriptional factors nuclear factor-kappaB1 (NF-kappaB1), NF-kappaB2. RESULTS: In the early stage after ONC (at Days 4 and 7), the density of RGCs in the minocycline-treated group was higher than that of the saline-treated group. Electron micrographs showed that minocycline prevented nuclei and mitochondria injuries at Day 4. Western blotting analysis demonstrated that the conversion of LC3-I to LC3-II was reduced in the minocycline-treated group at Days 4 and 7, which meant autophagy process was inhibited by minocycline. In addition, the gene expression of NF-kappaB2 was upregulated by minocycline at Day 4. CONCLUSION: The neuroprotective effect of minocycline is generated in the early stage after ONC in mice, partly through delaying autophagy process and regulating NF-kappaB2 pathway. PMID- 24791887 TI - Metformin inhibits nuclear factor-kappaB activation and inflammatory cytokines expression induced by high glucose via adenosine monophosphate-activated protein kinase activation in rat glomerular mesangial cells in vitro. AB - BACKGROUND: The renoprotective mechanisms of adenosine monophosphate (AMP) activated protein kinase (AMPK) agonist - metformin have not been stated clearly. We hypothesized that metformin may ameliorate inflammation via AMPK interaction with critical inflammatory cytokines. The aim of this study was to observe the effects of metformin on expression of nuclear factor-kappaB (NF-kappaB), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta 1 (TGF-beta1) induced by high glucose (HG) in cultured rat glomerular mesangial cells (MCs). METHODS: MCs were cultured in the medium with normal concentration glucose (group NG, 5.6 mmol/L), high concentration glucose (group HG, 25 mmol/L) and different concentrations of metformin (group M1, M2, M3). After 48-hour exposure, the supernatants and MCs were collected. The expression of NF-kappaB, MCP-1, ICAM-1, and TGF-beta1 mRNA was analyzed by real time polymerase chain reaction. Western blotting was used to detect the expression of AMPK, phospho-Thr-172 AMPK (p-AMPK), NF-kappaB p65, MCP 1, ICAM-1, and TGF-beta1 protein. RESULTS: After stimulated by HG, the expression of NF-kappaB, MCP-1, ICAM-1, TGF-beta1 mRNA and protein of MCs in group HG increased significantly compared with group NG (P < 0.05). Both genes and protein expression of NF-kappaB, MCP-1, ICAM-1, TGF-beta1 of MCs induced by high glucose were markedly reduced after metformin treatment in a dose-dependent manner (P < 0.05). The expression of p-AMPK increased with the rising of metformin concentration, presenting the opposite trend, while the level of total-AMPK protein was unchanged with exposure to HG or metformin. Conlusion Metformin can suppress the expression of NF-kappaB, MCP-1, ICAM-1 and TGF-beta1 of glomerular MCs induced by high glucose via AMPK activation, which may partly contribute to its reno-protection. PMID- 24791888 TI - Tumor necrosis factor gene polymorphisms and endometriosis in Asians: a systematic review and meta-analysis. AB - BACKGROUND: Numerous studies have described the association between polymorphisms in the tumor necrosis factor (TNF) gene and risk of endometriosis. However, the results remain controversial. Here we reviewed studies reporting the association between TNF gene polymorphisms and endometriosis risk in Asians. METHODS: PubMed and Embase were searched. Twelve case-control studies assessing the role of multiple TNF gene polymorphisms in endometriosis were included. If no less than two articles evaluated one variant, meta-analysis was conducted; otherwise, narrative analysis was chosen. A fixed- or random-effects model was employed according to the heterogeneity among studies. The strength of the association between TNF gene polymorphisms and endometriosis risk was assessed by odds ratios and 95% confidence intervals. RESULTS: For TNF-alpha -238G>A, -308G>A, -857C>T, and -863C>A, no significant associations were identified from all genetic models. For TNF-a -850T>C, results from one study showed that patients harboring the heterozygote TC were less susceptible to endometriosis than patients harboring the homozygote TT. For TNF-a -1031T>C, a mild increase in endometriosis risk was found in the Asian population. Meta-analysis from two studies found that the TNF beta +252>G polymorphism had a protective effect in Chinese individuals. Due to the limitations of the included studies, it is necessitated to perform more studies to elucidate the possible roles of TNF gene polymorphisms in the pathogenesis of endometriosis. CONCLUSIONS: TNF-alpha -1031T>C and TNF-beta +252A>G were significantly associated with the risk of endometriosis in Asian and Chinese populations, respectively. To further evaluate these associations, more large-scale, rigorously designed studies are needed. PMID- 24791889 TI - Prostate cancer antigen 3 test for prostate biopsy decision: a systematic review and meta analysis. AB - BACKGROUND: The specificity for early interventions of prostate-specific antigen (PSA) in prostate cancer (PCa) is not satisfactory. It is likely that prostate cancer antigen 3 (PCA3) can be used to predict biopsy outcomes more accurately than PSA for the early detection of PCa. We systematically reviewed literatures and subsequently performed a meta-analysis. METHODS: A bibliographic search in the database of Embase, Medline, Web of Science, NCBI, PubMed, CNKI, and those of health technology assessment agencies published before April 2013 was conducted. The key words used were "prostatic neoplasms", "prostate", "'prostate', 'carcinoma' or 'cancer' or 'tumor', or 'PCa,'" and free terms of "upm3", "pca3", "dd3", "aptimapca 3", and "prostate cancer antigen 3". All patients were adults. The intervention was detecting PCA3 in urine samples for PCa diagnosis. We checked the quality based on the QUADAS criteria, collected data, and developed a meta-analysis to synthesize results. Twenty-four studies of diagnostic tests with moderate to high quality were selected. RESULTS: The sensitivity was between 46.9% and 82.3%; specificity was from 55% to 92%; positive predictive value had a range of 39.0%-86.0%; and the negative predictive value was 61.0%-89.7%. The meta analysis has heterogeneity between studies. The global sensitivity value was 0.82 (95% CI 0.72-0.90); specificity was 0.962 (95% CI 0.73-0.99); positive likelihood ratio was 2.39 (95% CI 2.10-2.71); negative likelihood ratio was 0.51 (95% CI 0.46-0.86); diagnostic odds ratio was 4.89 (95% CI 3.94-6.06); and AUC in SROC curve was 0.744 1. CONCLUSION: PCA3 can be used for early diagnosis of PCa and to avoid unnecessary biopsies. PMID- 24791890 TI - Role of BK(Ca) channels in diabetic vascular complications. AB - OBJECTIVE: This review focuses on the role of the large conductance calcium activated potassium (BKCa) channels in diabetic vascular complications. DATA SOURCES: Relevant articles published in English or Chinese from 1981 to present were selected from PubMed. The search terms were "BKCa channels" and "diabetes". Important references from selected articles were also retrieved. STUDY SELECTION: Articles regarding the role of BKCa channels in diabetic vascular complications and relevant mechanisms were selected. RESULTS: The BKCa channels are abundantly expressed in vascular smooth cells and play an important role in regulation of vascular tone. Multiple studies indicated that the expression and function of BKCa channels are altered by different mechanisms in diabetic vascular diseases such as coronary arterial disease, cerebral arterial disease, and diabetic retinopathy. CONCLUSION: BKCa channels may play an important role in diabetic vascular complications and may be an effective therapeutic target for relieving and reducing the burden of diabetic vascular complications. PMID- 24791891 TI - Clinical research of postoperative comprehensive rehabilitation in treating brachial plexus injuries. PMID- 24791892 TI - Arterial embolization of primary sacral aneurysmal bone cyst. PMID- 24791893 TI - Congenital bifurcation of tympanic segment of facial nerve. PMID- 24791894 TI - Clinical outcomes of primary rotating-hinge knee arthroplasty for knees with severe deformity. PMID- 24791895 TI - Delayed diagnosis for tricuspid regurgitation after blunt chest trauma. PMID- 24791896 TI - Spontaneous abdominal wall hematoma caused by abdominal exercise as a complication of warfarin therapy. PMID- 24791897 TI - Pulmonary sequestration with its feeding vessel originating from the proximal right coronary artery. PMID- 24791898 TI - Extracorporeal membrane oxygenation as rescue therapy for H7N9 influenza associated acute respiratory distress syndrome. PMID- 24791899 TI - Erythematous nodules on the pubis: skin metastasis from adenocarcinoma cervix. PMID- 24791900 TI - Intravenous administration of anisodamine is effective on variant angina. PMID- 24791902 TI - Variant association tools for quality control and analysis of large-scale sequence and genotyping array data. AB - Currently there is great interest in detecting associations between complex traits and rare variants. In this report, we describe Variant Association Tools (VAT) and the VAT pipeline, which implements best practices for rare-variant association studies. Highlights of VAT include variant-site and call-level quality control (QC), summary statistics, phenotype- and genotype-based sample selection, variant annotation, selection of variants for association analysis, and a collection of rare-variant association methods for analyzing qualitative and quantitative traits. The association testing framework for VAT is regression based, which readily allows for flexible construction of association models with multiple covariates and weighting themes based on allele frequencies or predicted functionality. Additionally, pathway analyses, conditional analyses, and analyses of gene-gene and gene-environment interactions can be performed. VAT is capable of rapidly scanning through data by using multi-process computation, adaptive permutation, and simultaneously conducting association analysis via multiple methods. Results are available in text or graphic file formats and additionally can be output to relational databases for further annotation and filtering. An interface to R language also facilitates user implementation of novel association methods. The VAT's data QC and association-analysis pipeline can be applied to sequence, imputed, and genotyping array, e.g., "exome chip," data, providing a reliable and reproducible computational environment in which to analyze small- to large-scale studies with data from the latest genotyping and sequencing technologies. Application of the VAT pipeline is demonstrated through analysis of data from the 1000 Genomes project. PMID- 24791901 TI - Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy. AB - In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(*)2];[Glu529Valfs(*)2], and c.[401delT(;)3354G>A], p.[Leu134Argfs(*)45(;)Trp1118(*)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(*)) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families. PMID- 24791903 TI - De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. AB - Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome. PMID- 24791905 TI - ImmPort: disseminating data to the public for the future of immunology. AB - The immunology database and analysis portal (ImmPort) system is the archival repository and dissemination vehicle for clinical and molecular datasets created by research consortia funded by the National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology, and Transplantation. With nearly 100 datasets now publicly available and hundreds of downloads per month, ImmPort is an important source for raw data and protocols from clinical trials, mechanistic studies, and novel methods for cellular and molecular measurements. To facilitate data transfer, templates for data representation and standard operating procedures have also been created and are also publicly available. ImmPort facilitates transparency and reproducibility in immunology research, serves as an important resource for education, and enables newly generated hypotheses and data driven science. PMID- 24791904 TI - AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. AB - Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit sigma1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll like receptor homeostasis. PMID- 24791906 TI - Analysis of prospective trauma registry data in Francophone Africa: a pilot study from Cameroon. AB - INTRODUCTION: Injury rates in sub-Saharan Africa are among the highest in the world, but prospective, registry-based reports from Cameroon are limited. We aimed to create a prospective trauma registry to expand the data elements collected on injury at a busy tertiary center in Yaounde Cameroon. METHODS: Details of the injury context, presentation, care, cost, and disposition from the emergency department (ED) were gathered over a 6-month period, by trained research assistants using a structured questionnaire. Bivariate and multivariate models were built to explore variable relationships and outcomes. RESULTS: There were 2,855 injured patients in 6 months, comprising almost half of all ED visits. Mean age was 30 years; 73 % were male. Injury mechanism was road traffic injury in 59 %, fall in 7 %, penetrating trauma in 6 %, and animal bites in 4 %. Of these, 1,974 (69 %) were discharged home, 517 (18 %) taken to the operating room, and 14 (1 %) to the intensive care unit. The body areas most severely injured were pelvis and extremity in 43 %, head in 30 %, chest in 4 %, and abdomen in 3 %. The estimated injury severity score (eISS) was <9 in 60 %, 9-24 in 35 %, and >25 in 2 %. Mortality was 0.7 %. In the multivariate analysis, independent predictors of mortality were eISS >=9 and Glasgow Coma Score <=12. Road traffic injury was an independent predictor for the need to have surgery. Trauma registry results were presented to the Ministry of Health in Cameroon, prompting the formation of a National Injury Committee. CONCLUSIONS: Injuries comprise a significant proportion of ED visits and utilization of surgical services in Yaounde. A prospective approach allows for more extensive information. Thorough data from a prospective trauma registry can be used successfully to advocate for policy towards prevention and treatment of injuries. PMID- 24791907 TI - Prediction of permanent hypoparathyroidism after total thyroidectomy. AB - BACKGROUND: Hypoparathyroidism is a common complication with thyroid surgery. The ability to predict a high risk of permanent hypoparathyroidism is important for individual prognosis and follow-up. METHODS: Permanent hypoparathyroidism, defined as continuing need for vitamin D medication at 1-year post-operatively, was investigated in patients after total thyroidectomy. Blood levels of calcium and parathyroid hormone (PTH) were measured intra-operatively, the day after surgery and at 1 month post-operatively. Logistic regression analysis was performed to investigate the risk of vitamin D treatment at last follow-up, calculated as odds ratios (ORs) with 95 % confidence intervals (CIs). Patients were followed until cessation of vitamin D and/or calcium medication, until death, loss to follow-up, or end of follow-up, whichever came first. RESULTS: A total of 519 patients were included. The median (range) follow-up in patients unable to cease vitamin D was 2.7 (1.2-10.3) years. The rate of permanent hypoparathyroidism was 10/519, 1.9 %. Parathyroid auto-transplantation was performed in 90/519 (17.3 %) patients. None of these developed permanent hypoparathyroidism, nor did any patient with normal PTH day 1 (>1.6 pmol/l or 15 pg/ml). The adjusted risk (OR, 95 % CI) for permanent hypoparathyroidism for log PTH on day 1 was 0.25 (0.13-0.50). In patients not auto-transplanted and with unmeasurable PTH day 1 (<0.7 pmol/l or 6.6 pg/ml), 8/42 (19.2 %) developed permanent hypoparathyroidism. CONCLUSIONS: Auto-transplantation protects against permanent hypoparathyroidism, whereas low PTH day 1 is associated with high risk. PMID- 24791908 TI - Acute cerebral infarction in watershed distribution in a patient with hypereosinophilic syndrome without cardiac lesion. AB - We here in describe a case of hypereosinophilic syndrome (HES) with acute cerebral infarction in a watershed distribution with lesions of the carotid artery but no damage to the endocardium or myocardium. A 62-year-old Chinese man complained of left-sided hemiparesis. Brain MR showed multiple areas of acute ischemia. The eosinophil count was 4.84 * 10(9)/L, or 41.7 % of all white blood cells. Doppler ultrasound showed multiple medium-high echo plaques in the bilateral carotid bifurcation with reduction in diameter of 10-15 %. Transthoracic echocardiography was normal. A short course of glucocorticoids and aspirin were administered to the patient, and he was discharged with significant improvement of his neurological symptoms and eosinophil count. The patient refused to take prednisone thereafter; however, 6 months later, his eosinophil count was 1.57 * 10(9)/L, or 15.3 % of all white blood cells. Transthoracic echocardiography continued to be normal, but vascular ultrasound demonstrated many bilateral carotid low-medium echo plaques. This case describes a patient HES with acute cerebral infarction in a watershed distribution with lesions of the carotid artery but no cardiac damage. HES should be considered to be a cause of multiple cerebral infarctions. PMID- 24791909 TI - Intramuscular nerve distribution pattern in the human tibialis posterior muscle. AB - The human tibialis posterior muscle (TPM) has developed to maintain the foot arches for adopting bipedal locomotion. The insertion tendon of this muscle is U shaped in a cross section, and the fibular part of the muscle whose muscle fibers originated from the fibula has a unique architecture. To understand the developmental history of the human TPM, distribution pattern of intramuscular nerves was investigated in ten sides of eight cadavers. Muscular branches entering the TPM could be classified into five types according to the distribution pattern in the muscle. The nerves innervating the part deeper to the insertion tendon ran transversely in the medial direction toward the tibia. Muscular branches innervating the fibular part ran medioinferiorly, and in four cases had communicating rami with the nerve innervating the other parts of this muscle. Muscular branches innervating the superficial layer whose muscle bundles originated from the tibia ran laterally toward the fibula. These results suggest that the fibular part might develop from the common primordium of the TPM, and the deeper layer of the muscle might expand laterally during the development to acquire a new attaching space on the interosseous membrane and fibula. The superficial layer might also develop laterally to acquire the additional attaching spaces on the fascia of the flexor digitorum longus muscle and flexor hallucis longus muscle, thus the insertion tendon might become U-shaped. With these measures, the TPM might be able to increase muscle volume to yield stronger power. PMID- 24791910 TI - Carotid artery stenting in patients with brain meningioma. AB - The association between carotid artery stenosis and brain meningioma is rather rare. Indeed, data in literature about this association are scarce and potential risks of carotid artery stenting using different protection devices are not known. We describe the endovascular treatment of severe carotid stenosis in two patients with intracranial meningioma. PMID- 24791911 TI - Effects of pig manure containing copper and zinc on microbial community assessed via phospholipids in soils. AB - Pig manure (PM) is widely used as an organic fertilizer to increase yields of crops. Excessive application of compost containing relatively great concentrations of copper (Cu) and zinc (Zn) can change soil quality. To clarify the effects of different rates of application and to determine the optimal rate of fertilization, PM containing 1,115 mg Cu kg(-1), dry mass (dm) and 1,497 mg Zn kg(-1), dm was applied to alkaline soil at rates of 0, 11, 22, 44, 88, and 222 g PM kg(-1), dm. Phospholipid fatty acids (PLFAs) were used to assess soil microbial community composition. Application of PM resulted in greater concentrations of total nitrogen (TN), NH4 (+)-N, NO3 (-)-N, total carbon (TC), soil organic matter (SOM) but lesser pH values. Soils with application rates of 88-222 g PM kg(-1), dm had concentrations of total and EDTA-extractable Cu and Zn significantly greater than those in soil without PM, and concentrations of T-Cu and T-Zn in these amended soils exceeded maximum limits set by standards in china. Except in the soil with a rate of 11 g PM kg(-1), dm, total bacterial and fungal PLFAs were directly proportional to rate of application of PM. Biomasses of bacteria and fungi were significantly greater in soils with application rates of 44-222 g PM kg(-1), dm than in the soil without PM. SOM, TC and EDTA-Zn had the most direct influence on soil microbial communities. To improve fertility of soils and maintain quality of soil, rate of application should be 22-44 g PM kg( 1) dm, soil containing Cu and Zn. PMID- 24791912 TI - Nutrition and the adaptation to endurance training. AB - Maximizing metabolic stress at a given level of mechanical stress can improve the adaptive response to endurance training, decrease injury, and potentially improve performance. Calcium and metabolic stress, in the form of heat, decreases in the adenosine triphosphate/adenosine diphosphate ratio, glycogen depletion, caloric restriction, and oxidative stress, are the primary determinants of the adaptation to training. These stressors increase the activity and amount of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha), a protein that can directly induce the primary adaptive responses to endurance exercise: mitochondrial biogenesis, angiogenesis, and increases in fat oxidation. The activity of PGC-1alpha is regulated by its charge (phosphorylation and acetylation), whereas its transcription is regulated by proteins that bind to myocyte enhancing factor 2, enhancer box, and cyclic adenosine monophosphate response element sites within the PGC-1alpha promoter. This brief review will describe what is known about the control of PGC-1alpha by these metabolic stressors. As the duration of calcium release and the amount of metabolic stress, and therefore the activation of PGC-1alpha, can be directly modulated by training and nutrition, a simple strategy can be generated to maximize the adaptive response to endurance training. PMID- 24791913 TI - Sleep in elite athletes and nutritional interventions to enhance sleep. AB - Sleep has numerous important physiological and cognitive functions that may be particularly important to elite athletes. Recent evidence, as well as anecdotal information, suggests that athletes may experience a reduced quality and/or quantity of sleep. Sleep deprivation can have significant effects on athletic performance, especially submaximal, prolonged exercise. Compromised sleep may also influence learning, memory, cognition, pain perception, immunity and inflammation. Furthermore, changes in glucose metabolism and neuroendocrine function as a result of chronic, partial sleep deprivation may result in alterations in carbohydrate metabolism, appetite, food intake and protein synthesis. These factors can ultimately have a negative influence on an athlete's nutritional, metabolic and endocrine status and hence potentially reduce athletic performance. Research has identified a number of neurotransmitters associated with the sleep-wake cycle. These include serotonin, gamma-aminobutyric acid, orexin, melanin-concentrating hormone, cholinergic, galanin, noradrenaline, and histamine. Therefore, nutritional interventions that may act on these neurotransmitters in the brain may also influence sleep. Carbohydrate, tryptophan, valerian, melatonin and other nutritional interventions have been investigated as possible sleep inducers and represent promising potential interventions. In this review, the factors influencing sleep quality and quantity in athletic populations are examined and the potential impact of nutritional interventions is considered. While there is some research investigating the effects of nutritional interventions on sleep, future research may highlight the importance of nutritional and dietary interventions to enhance sleep. PMID- 24791914 TI - A step towards personalized sports nutrition: carbohydrate intake during exercise. AB - There have been significant changes in the understanding of the role of carbohydrates during endurance exercise in recent years, which allows for more specific and more personalized advice with regard to carbohydrate ingestion during exercise. The new proposed guidelines take into account the duration (and intensity) of exercise and advice is not restricted to the amount of carbohydrate; it also gives direction with respect to the type of carbohydrate. Studies have shown that during exercise lasting approximately 1 h in duration, a mouth rinse or small amounts of carbohydrate can result in a performance benefit. A single carbohydrate source can be oxidized at rates up to approximately 60 g/h and this is the recommendation for exercise that is more prolonged (2-3 h). For ultra-endurance events, the recommendation is higher at approximately 90 g/h. Carbohydrate ingested at such high ingestion rates must be a multiple transportable carbohydrates to allow high oxidation rates and prevent the accumulation of carbohydrate in the intestine. The source of the carbohydrate may be a liquid, semisolid, or solid, and the recommendations may need to be adjusted downward when the absolute exercise intensity is low and thus carbohydrate oxidation rates are also low. Carbohydrate intake advice is independent of body weight as well as training status. Therefore, although these guidelines apply to most athletes, they are highly dependent on the type and duration of activity. These new guidelines may replace the generic existing guidelines for carbohydrate intake during endurance exercise. PMID- 24791915 TI - Dietary nitrate supplementation and exercise performance. AB - Dietary nitrate is growing in popularity as a sports nutrition supplement. This article reviews the evidence base for the potential of inorganic nitrate to enhance sports and exercise performance. Inorganic nitrate is present in numerous foodstuffs and is abundant in green leafy vegetables and beetroot. Following ingestion, nitrate is converted in the body to nitrite and stored and circulated in the blood. In conditions of low oxygen availability, nitrite can be converted into nitric oxide, which is known to play a number of important roles in vascular and metabolic control. Dietary nitrate supplementation increases plasma nitrite concentration and reduces resting blood pressure. Intriguingly, nitrate supplementation also reduces the oxygen cost of submaximal exercise and can, in some circumstances, enhance exercise tolerance and performance. The mechanisms that may be responsible for these effects are reviewed and practical guidelines for safe and efficacious dietary nitrate supplementation are provided. PMID- 24791916 TI - Exercise, nutrition and the brain. AB - Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and can improve cognitive function. Exercise has been promoted as a possible prevention for neurodegenerative diseases. Exercise will have a positive influence on cognition and it increases the brain-derived neurotrophic factor, an essential neurotrophin. Several dietary components have been identified as having effects on cognitive abilities. In particular, polyphenols have been reported to exert their neuroprotective actions through the potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning, and cognitive function. Dietary factors can affect multiple brain processes by regulating neurotransmitter pathways, synaptic transmission, membrane fluidity, and signal-transduction pathways. Flavonols are part of the flavonoid family that is found in various fruits, cocoa, wine, tea and beans. Although the antioxidant effects of flavonols are well established in vitro, there is general agreement that flavonols have more complex actions in vivo. Several cross-sectional and longitudinal studies have shown that a higher intake of flavonoids from food may be associated with a better cognitive evolution. Whether this reflects a causal association remains to be elucidated. Several studies have tried to 'manipulate' the brain in order to postpone central fatigue. Most studies have clearly shown that in normal environmental circumstances these interventions are not easy to perform. There is accumulating evidence that rinsing the mouth with a carbohydrate solution will improve endurance performance. There is a need for additional well controlled studies to explore the possible impact of diet and nutrition on brain functioning. PMID- 24791917 TI - Polyphenol supplementation: benefits for exercise performance or oxidative stress? AB - Supplement use among athletes is widespread, including non-traditional and biological compounds. Despite increasing research, a comprehensive and critical review on polyphenol supplementation and exercise is still lacking. This review is relevant for researchers directly involved in the topic, as well as those with a broad interest in athletic performance enhancement and sports nutrition. The purpose of this review is to present background information on groups of polyphenols and their derivatives because their differing chemical structures influence mechanisms of action; to discuss the potential of plant, fruit and vegetable-based biological supplements, high in polyphenol content, to affect exercise performance and biomarkers of oxidative stress and exercise-induced muscle damage; and to critically discuss the exercise studies and biomarkers used. Subjects in the studies reviewed were either sedentary, healthy individuals, or active, recreationally trained or well-trained athletes. Polyphenol supplementation in exercise studies included mainly extracts (multicomponent or purified), juices, infusions or an increased intake of polyphenol-rich foods. This review includes details of supplement doses and exercise test protocols. Many studies considered only the performance or one or two selected biomarkers of antioxidant capacity instead of a comprehensive choice of biomarkers to assess damage to lipids or proteins. Evidence is insufficient to make recommendations for or against the use of polyphenol supplementation (neither specific polyphenols nor specific doses) for either recreational, competitive or elite athletes. Polyphenols have multiple biological effects, and future exercise studies must be designed appropriately and specifically to determine physiological interactions between exercise and the selected supplement, rather than considering performance alone. PMID- 24791918 TI - A brief review of critical processes in exercise-induced muscular hypertrophy. AB - With regular practice, resistance exercise can lead to gains in skeletal muscle mass by means of hypertrophy. The process of skeletal muscle fiber hypertrophy comes about as a result of the confluence of positive muscle protein balance and satellite cell addition to muscle fibers. Positive muscle protein balance is achieved when the rate of new muscle protein synthesis (MPS) exceeds that of muscle protein breakdown (MPB). While resistance exercise and postprandial hyperaminoacidemia both stimulate MPS, it is through the synergistic effects of these two stimuli that a net gain in muscle proteins occurs and muscle fiber hypertrophy takes place. Current evidence favors the post-exercise period as a time when rapid hyperaminoacidemia promotes a marked rise in the rate of MPS. Dietary proteins with a full complement of essential amino acids and high leucine contents that are rapidly digested are more likely to be efficacious in this regard. Various other compounds have been added to complete proteins, including carbohydrate, arginine and glutamine, in an attempt to augment the effectiveness of the protein in stimulating MPS (or suppressing MPB), but none has proved particularly effective. Evidence points to a higher protein intake in combination with resistance exercise as being efficacious in allowing preservation, and on occasion increases, in skeletal muscle mass with dietary energy restriction aimed at the promotion of weight loss. The goal of this review is to examine practices of protein ingestion in combination with resistance exercise that have some evidence for efficacy and to highlight future areas for investigation. PMID- 24791919 TI - Gastrointestinal complaints during exercise: prevalence, etiology, and nutritional recommendations. AB - Gastrointestinal problems are common, especially in endurance athletes, and often impair performance or subsequent recovery. Generally, studies suggest that 30-50% of athletes experience such complaints. Most gastrointestinal symptoms during exercise are mild and of no risk to health, but hemorrhagic gastritis, hematochezia, and ischemic bowel can present serious medical challenges. Three main causes of gastrointestinal symptoms have been identified, and these are either physiological, mechanical, or nutritional in nature. During intense exercise, and especially when hypohydrated, mesenteric blood flow is reduced; this is believed to be one of the main contributors to the development of gastrointestinal symptoms. Reduced splanchnic perfusion could result in compromised gut permeability in athletes. However, although evidence exists that this might occur, this has not yet been definitively linked to the prevalence of gastrointestinal symptoms. Nutritional training and appropriate nutrition choices can reduce the risk of gastrointestinal discomfort during exercise by ensuring rapid gastric emptying and the absorption of water and nutrients, and by maintaining adequate perfusion of the splanchnic vasculature. A number of nutritional manipulations have been proposed to minimize gastrointestinal symptoms, including the use of multiple transportable carbohydrates, and potentially the use of nutrients that stimulate the production of nitric oxide in the intestine and thereby improve splanchnic perfusion. However, at this stage, evidence for beneficial effects of such interventions is lacking, and more research needs to be conducted to obtain a better understanding of the etiology of the problems and to improve the recommendations to athletes. PMID- 24791920 TI - New insights into the interaction of carbohydrate and fat metabolism during exercise. AB - Fat and carbohydrate are important fuels for aerobic exercise and there can be reciprocal shifts in the proportions of carbohydrate and fat that are oxidized. The interaction between carbohydrate and fatty acid oxidation is dependent on the intracellular and extracellular metabolic environments. The availability of substrate, both from inside and outside of the muscle, and exercise intensity and duration will affect these environments. The ability of increasing fat provision to downregulate carbohydrate metabolism in the heart, diaphragm and peripheral skeletal muscle has been well studied. However, the regulation of fat metabolism in human skeletal muscle during exercise in the face of increasing carbohydrate availability and exercise intensity has not been well studied until recently. Research in the past 10 years has demonstrated that the regulation of fat metabolism is complex and involves many sites of control, including the transport of fat into the muscle cell, the binding and transport of fat in the cytoplasm, the regulation of intramuscular triacylglycerol synthesis and breakdown, and the transport of fat into the mitochondria. The discovery of proteins that assist in transporting fat across the plasma and mitochondrial membranes, the ability of these proteins to translocate to the membranes during exercise, and the new roles of adipose triglyceride lipase and hormone-sensitive lipase in regulating skeletal muscle lipolysis are examples of recent discoveries. This information has led to the proposal of mechanisms to explain the downregulation of fat metabolism that occurs in the face of increasing carbohydrate availability and when moving from moderate to intense aerobic exercise. PMID- 24791921 TI - The interrelationship of research in the laboratory and the field to assess hydration status and determine mechanisms involved in water regulation during physical activity. AB - Changes in skin blood and sweating are the primary mechanisms for heat loss in humans. A hot, humid environment concomitant with dehydration limits the ability to increase skin blood flow for the purpose of transferring heat from the body core to skin surface and evaporate sweat to maintain core temperature within safe limits during exercise. Adequate hydration improves thermoregulation by maintaining blood volume to support skin blood flow and sweating. Humans rely on fluid intake to maintain total body water and blood volume, and have developed complex mechanisms to sense changes in the amount and composition of fluid in the body. This paper addresses the interrelationship of research in the laboratory and the field to assess hydration status involved in body water and temperature regulation during exercise. In the controlled setting of a research laboratory, investigators are able to investigate the contributions of volume and tonicity of fluid in the plasma to body water and temperature regulation during exercise and recovery. For example, laboratory studies have shown that tonicity in a rehydration beverage maintains the thirst mechanism (and stimulates drinking), and contributes to the ongoing stimulation of renal fluid retention hormones, ultimately leading to a more complete rehydration. Research in the field cannot control the environment precisely, but these studies provide a natural, 'real life' setting to study fluid and temperature regulation during exercise. The conditions encountered in the field are closest to the environment during competition, and data collected in the field can have an immediate impact on performance and safety during exercise. There is an important synergy between these two methods of collecting data that support performance and protect athletes from harm during training and improve performance during competition. PMID- 24791923 TI - Bipolar disorder and criminal offending: a data linkage study. AB - PURPOSE: The current study explored criminal offending among people diagnosed with bipolar disorder with and without comorbid substance use and compared this with a community sample with no history of bipolar disorder. METHODS: A case linkage design was used to compare patterns of officially recorded criminal offending between 1,076 people with bipolar disorder drawn from a state-wide psychiatric case register with a community comparison group. RESULTS: Those with bipolar disorder were significantly more likely than community members to be charged with, convicted of, and be found guilty of, violent, non-violent and intermediate level criminal offences. Those with a comorbid substance use disorder were two times more likely than those without a substance use disorder to offend; both groups had a significantly higher chance of offending than the community sample. Females with bipolar disorder were significantly more likely to have been convicted of violent offences, irrespective of substance use. Significant interactions were found between bipolar disorder and substance use for males and females with respect to violent offending and for males with respect to non-violent offending. CONCLUSIONS: There is a statistically significant association between bipolar disorder and the likelihood of having a criminal history. Co-occurring substance use differentially impacts on the likelihood of criminal offending for males and females. PMID- 24791922 TI - Is there a need for protein ingestion during exercise? AB - Dietary protein ingestion following exercise increases muscle protein synthesis rates, stimulates net muscle protein accretion, and facilitates the skeletal muscle adaptive response to prolonged exercise training. Furthermore, recent studies show that protein ingestion before and during exercise also increases muscle protein synthesis rates during resistance- and endurance-type exercise. Therefore, protein ingestion before and during prolonged exercise may represent an effective dietary strategy to enhance the skeletal muscle adaptive response to each exercise session by extending the window of opportunity during which the muscle protein synthetic response is facilitated. Protein ingestion during exercise has also been suggested to improve performance capacity acutely. However, recent studies investigating the impact of protein ingestion during exercise on time trial performance, as opposed to time to exhaustion, do not report ergogenic benefits of protein ingestion. Therefore, it is concluded that protein ingestion with carbohydrate during exercise does not further improve exercise performance when compared with the ingestion of ample amounts of carbohydrate only. PMID- 24791924 TI - Profiles of acculturation among Hispanics in the United States: links with discrimination and substance use. AB - PURPOSE: Recent research suggests that acculturation is a multifaceted construct with implications for substance use among Hispanics. However, few, if any, studies examining profiles of acculturation have been conducted using national samples. Moreover, no cluster-based studies have examined how acculturation relates to discrimination and substance use disorders among Hispanics in the United States. METHODS: The present study, employing Wave 2 data on Hispanics (n = 6,359) from the National Epidemiologic Survey of Alcohol and Related Conditions, aims to address these gaps. We use latent profile analysis to identify profiles of acculturation among Hispanics in the United States and, in turn, examine the relationships between membership in these profiles and experiences of discrimination and the prevalence of substance use disorders. RESULTS: A five-class solution was the optimal modeling of the data. Classes were identified as Class 1: Spanish-dominant/strongly separated (17 %), Class 2: Spanish-dominant/separated (18 %), Class 3: bilingual/bicultural (33 %), Class 4: English-dominant/bicultural (16 %), and Class 5: English-dominant/assimilated (16 %). Bilingual/bicultural Hispanics (Class 3) reported the highest prevalence of discrimination (31 %). Spanish-language dominant Hispanics (Classes 1 and 2) reported the lowest prevalence of substance use disorders. Significant differences in the prevalence of substance use disorders were observed between the bilingual/bicultural (Class 3) and English-dominant/assimilated classes (Class 5), but no differences were noted between the two English-dominant classes (Classes 4 and 5). CONCLUSIONS: Study findings indicate that acculturation is heterogeneous in its expression among Hispanics and suggest that Hispanics who maintain their Spanish-language capacity are at a substantially lower risk for a variety of substance use disorders. PMID- 24791925 TI - Right axillary arterial perfusion for descending thoracic or thoracoabdominal aortic aneurysm repair with open proximal anastomosis through left thoracotomy. AB - BACKGROUND: We examined the effectiveness of right axillary arterial perfusion through an interposed Dacron graft in the prevention of cerebral embolism or complications related to ascending aortic cannulation in open proximal anastomosis technique of descending thoracic aortic aneurysm (TAA) or thoracoabdominal aortic aneurysm (TAAA) repair under deep hypothermic circulatory arrest through left thoracotomy. METHODS: Between May 2000 and August 2012, 44 patients underwent TAA or TAAA repair using open proximal technique under DHCA. These patients were divided into two groups for evaluation of the effectiveness of right axillary arterial perfusion. Group A included patients who underwent TAA or TAAA repair with ascending aortic cannulation (n=15). Group B was composed of patients who had TAA or TAAA repair with right axillary arterial perfusion through the interposed Dacron graft (n=29). RESULTS: Mortality in this series was 4.5% (2 of 44 patients; 1 in each group); wherein, the causes were sepsis due to graft infection and aortic dissection (Stanford type A). The incidence rates of cerebral embolism were 27 % (4 of 15 patients in group A) and 3.4% (1 of 29 patients in group B) (p=0.0392, Fisher's exact test). The rates of complications in relation to the aortic cannulation site (dissection or bleeding) were 13% (2 of 15 patients in group A) and 0% (0 of 25 patients in group B). CONCLUSIONS: Right axillary perfusion facilitates easy evacuation of air and allows prompt recommencement of upper body circulation. Consequently, it minimizes the risk of cerebral embolism or complications in relation to aortic cannulation through left thoracotomy. PMID- 24791926 TI - Anatomical thoracoscopic segmentectomy for lung cancer. AB - Minimally invasive surgery for lung cancer has seen considerable progress. A segmentectomy is less invasive than a lobectomy as it preserves lung parenchyma. The preservation of pulmonary function can reduce complications. The combination of a thoracoscopic approach with a segmentectomy should be less invasive, and retrospective studies have shown that the thoracoscopic approach is safe and feasible due to the lower postoperative mortality and complication rates as compared to an open thoracotomy. The validity of a segmentectomy for ground-glass opacity-type lung cancer has been demonstrated, and it has also been evaluated for small, predominantly solid, lung cancers. Two prospective studies of segmentectomy versus lobectomy for <=2-cm non-small-cell lung cancer are now underway (CALGB 140503 and JCOG0802/WJTOG4607L) and should clarify the role of segmentectomy. Regarding thoracoscopic segmentectomy, few retrospective studies have reported the oncological outcome for lung cancer and there is inadequate evidence regarding the long-term oncological outcome, although the perioperative complication rate and duration of hospital stay seem to be non-inferior to those of an open approach. For preoperative simulation, three-dimensional multidetector computed tomography (3D-CT) is essential for performing an atypical thoracoscopic segmentectomy safely. Preoperative 3D-CT angiography and bronchography (3D-CTAB) enable accurate identification of the venous branches in the affected segment and the intersegmental vein. This review describes the surgical and oncological outcomes, utility of 3D-CTAB, and surgical techniques and procedure used for a thoracoscopic segmentectomy. PMID- 24791927 TI - Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. AB - This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a test (n = 57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n = 83). All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining "intermediate molecular risk" population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified, with speckled synaptophysin expression indicating worse outcome. Test and independent validation of the score confirmed significant discrimination of patients by risk profile. Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk stratification of medulloblastoma. A simple clinico pathological risk score was identified, which was confirmed in a test set and by independent clinical validation. PMID- 24791928 TI - The VEINES-QOL/Sym questionnaire is a reliable and valid disease-specific quality of life measure for deep vein thrombosis in elderly patients. AB - PURPOSE: To prospectively evaluate the psychometric properties of the Venous Insufficiency Epidemiological and Economic Study (VEINES-QOL/Sym) questionnaire, an instrument to measure disease-specific quality of life and symptoms in elderly patients with deep vein thrombosis (DVT), and to validate a German version of the questionnaire. METHODS: In a prospective multicenter cohort study of patients aged >= 65 years with acute venous thromboembolism, we used standard psychometric tests and criteria to evaluate the reliability, validity, and responsiveness of the VEINES-QOL/Sym in patients with acute symptomatic DVT. We also performed an exploratory factor analysis. RESULTS: Overall, 352 French- and German-speaking patients were enrolled (response rate of 87 %). Both language versions of the VEINES-QOL/Sym showed good acceptability (missing data, floor and ceiling effects), reliability (internal consistency, item-total and inter-item correlations), validity (convergent, discriminant, known-groups differences), and responsiveness to clinical change over time in elderly patients with DVT. The exploratory factor analysis of the VEINES-QOL/Sym suggested three underlying dimensions: limitations in daily activities, DVT-related symptoms, and psychological impact. CONCLUSIONS: The VEINES-QOL/Sym questionnaire is a practical, reliable, valid, and responsive instrument to measure quality of life and symptoms in elderly patients with DVT and can be used with confidence in prospective studies to measure outcomes in such patients. PMID- 24791929 TI - Assessing quality of life in middle-aged and older adults with HIV: psychometric testing of the WHOQOL-HIV-Bref. AB - PURPOSE: The aim of this study was to test the psychometric properties of the World Health Organization quality of life in HIV infection, abbreviated version (WHOQOL-HIV-Bref) in a sample of human immunodeficiency virus (HIV)-infected patients aged 50 years and older. METHODS: The sample consisted of 185 patients, recruited in the main departments of infectious diseases of 10 Portuguese hospitals. In addition to the WHOQOL-HIV-Bref, patients also completed the brief symptom inventory, a self-report questionnaire for measuring psychopathological symptoms. RESULTS: The European Portuguese version of WHOQOL-HIV-Bref showed acceptable reliability (Cronbach's alpha range 0.65-0.86 across domains). Confirmatory factor analysis corroborated the original six-domain structure. Convergent validity with depressive and psychopathological symptoms was satisfactory for all domains. Overall quality of life (QoL), physical and independence domains discriminated well subjects considering the HIV stage. None of the domains were significantly different according to CD4+ T cell count subgroups. CONCLUSIONS: These results offer promising support for the use of the WHOQOL-HIV-Bref as a measure of QoL among HIV-infected patients aged 50 years and older. Its briefness and multidimensionality allow a more practical and comprehensive assessment of QoL, both on clinical and research settings. PMID- 24791930 TI - Comparison of the short- and long-term treatment effect of cervical disk replacement and anterior cervical disk fusion: a meta-analysis. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) has been used as a gold standard for the treatment of cervical spondylosis, but it may cause complications such as pseudarthrosis and junctional degeneration. Cervical disk arthroplasty (CDA) may help overcome such problems, but there are inconsistencies among the published literature on its effectiveness comparing with ACDF. METHODOLOGY: We searched "PubMed" (2000.1-2013.10), "Medline" (2000.1-2013.10), "Elsevier" (2000.1-2013.10), Cochrane library (2008.1-2013.10) databases with the key words of "cervical disk arthroplasy", "CDA", "anterior cervical disk fusion", "ACDF", "cervical", "randomized controlled study", "RCT" and searched for randomized controlled trials comparing the efficacy of ACDF and CDA for the treatment of cervical spondylosis. Neck disability index (NDI), VAS arm pain score, VAS neck pain score, ROM of the adjacent level, SF36-PCS score, SF36-MCS score and patient satisfaction were calculated by Revman5.2 software. RESULTS: From 1,400 papers found, we chose 18 randomized controlled trials and cohorts evaluating the efficacy of CDA and ACDF on symptomatic cerebral spondylosis. The total number of patients is 3,056, in which 1,576 were in the CDA group and 1,480 were in the ACDF group. The CDA group demonstrated better results than the ACDF group concerning VAS arm pain score 1, 2, 4 years after the surgery, VAS neck pain score 1, 2, 4 years after the surgery, ROM of the adjacent level 1 and 2 years after the surgery, patient satisfaction 1, 2, 4 years after the surgery, NDI scores 1, 2, 4 years after the surgery, SF36-PCS score 1 and 2 years after the surgery and SF36-MCS score at 1 and 4 years after the surgery. There are no significant differences between the groups concerning SF36-PCS score 4 years after the surgery and SF36-MCS score at 2 years after the surgery. CONCLUSIONS: CDA can be an effective alternative method to ACDF for the treatment of cervical spondylosis. PMID- 24791931 TI - Substrate deconstruction and the nonadditivity of enzyme recognition. AB - Predicting substrates for enzymes of unknown function is a major postgenomic challenge. Substrate discovery, like inhibitor discovery, is constrained by our ability to explore chemotypes; it would be expanded by orders of magnitude if reactive sites could be probed with fragments rather than fully elaborated substrates, as is done for inhibitor discovery. To explore the feasibility of this approach, substrates of six enzymes from three different superfamilies were deconstructed into 41 overlapping fragments that were tested for activity or binding. Surprisingly, even those fragments containing the key reactive group had little activity, and most fragments did not bind measurably, until they captured most of the substrate features. Removing a single atom from a recognized substrate could often reduce catalytic recognition by 6 log-orders. To explore recognition at atomic resolution, the structures of three fragment complexes of the beta-lactamase substrate cephalothin were determined by X-ray crystallography. Substrate discovery may be difficult to reduce to the fragment level, with implications for function discovery and for the tolerance of enzymes to metabolite promiscuity. Pragmatically, this study supports the development of libraries of fully elaborated metabolites as probes for enzyme function, which currently do not exist. PMID- 24791932 TI - Clinicoradiological correlation of scoliosis in children with Jarcho-Levin and Escobar syndromes: associated "flat bone or wing-like" imaging findings. AB - Congenital or early onset scoliosis may be the lead clinical feature in several rare syndromes. In this paper, we present the imaging findings in two children with early onset scoliosis related to the Jarcho-Levin and Escobar syndromes and an osseous plate or wing-like bar extending along the posterior elements of the spine on computed tomography. The clinical phenotypes in these syndromes are variable. A thorough clinical evaluation with imaging correlation is essential. The recognition of underlying spinal anomalies is essential in planning treatment and estimating prognosis. In young children with progressive scoliosis, cross sectional imaging plays a major role in the diagnostic work-up. CONCLUSION: Congenital scoliosis requires a comprehensive clinical evaluation and imaging work-up. The presence of an osseous plate or wing-like fusion of posterior elements of the spine may suggest the diagnosis of Jarcho-Levin and Escobar syndromes. PMID- 24791933 TI - The effect of inhaled nitric oxide therapy on thromboelastogram in newborns with persistent pulmonary hypertension. AB - Studies about the effects of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in newborns are limited in number and have inconclusive results. Thromboelastogram (TEG) shows the combined effects of coagulation factors and platelet functions. In this preliminary study, we aimed to evaluate the effects of iNO on coagulation using TEG in newborns with persistent pulmonary hypertension (PPH). TEG assays were performed in 10 term infants receiving iNO treatment for PPH and 32 healthy term infants. Samples of the iNO group were collected before and during iNO. Clot reaction time (R), clot kinetics (K), maximum amplitude (MA), and alpha angle were obtained from the TEG tracing. TEG-R values were statistically higher during iNO treatment (7.75 +/- 3.34) when compared to the values before iNO (4.83 +/- 1.38) and the healthy controls (3.75 +/- 0.98). The alpha angle was lower in iNO treated infants at both periods (before iNO, 55.33 +/- 8.58; during iNO, 42.90 +/- 18.34) compared to the control group (64.95 +/- 6.88). MA values before iNO treatment were the lowest (44.43 +/- 14.09) and improved with the iNO treatment (48.40 +/- 9.49) despite still being lower compared to the controls (53.67 +/- 5.56). CONCLUSION: Both PPH and iNO may negatively effect in vitro coagulation tests. Therefore, newborns with PPH requiring iNO treatment should be closely monitored for coagulation problems. PMID- 24791935 TI - Genotype-phenotype correlations in a prospective cohort study of paediatric plaque psoriasis: lack of correlation between HLA-C*06 and family history of psoriasis. AB - This study aims to investigate associations between observed clinical parameters and known genetic risk factors of psoriasis in a well-defined prospective cohort of paediatric patients with plaque psoriasis (n = 151). Significant associations were found for paediatric-onset psoriasis with ERAP1 (p = 0.002), IL23R (p = 0.01), LCE3C_LCE3B-del (p = 0.00049) and HLA-C*06 (p = 3.15 * 10(-30)). Psoriasis severity was associated with the single nucleotide polymorphisms tagging IFIH1 and ERAP1 (p < 0.05). An onset before 10 years of age was associated with IL12B (p = 0.02). Nail psoriasis was more often seen in HLA-C*06-negative patients (p = 0.008). Remarkably, family history is clearly not associated with HLA-C*06 in this specific group. The large proportion of patients with a positive family history in HLA-C*06 negative patients (and the lack of correlation between the two) indicates that other genes, either alone or interaction between two or more genes, may have significant effects on heritability. PMID- 24791934 TI - Optical stimulation of zebrafish hair cells expressing channelrhodopsin-2. AB - Vertebrate hair cells are responsible for the high fidelity encoding of mechanical stimuli into trains of action potentials (spikes) in afferent neurons. Here, we generated a transgenic zebrafish line expressing Channelrhodopsin-2 (ChR2) under the control of the hair-cell specific myo6b promoter, in order to examine the role of the mechanoelectrical transduction (MET) channel in sensory encoding in afferent neurons. We performed in vivo recordings from afferent neurons of the zebrafish lateral line while activating hair cells with either mechanical stimuli from a waterjet or optical stimuli from flashes of ~470-nm light. Comparison of the patterns of encoded spikes during 100-ms stimuli revealed no difference in mean first spike latency between the two modes of activation. However, there was a significant increase in the variability of first spike latency during optical stimulation as well as an increase in the mean number of spikes per stimulus. Next, we compared encoding of spikes during hair cell stimulation at 10, 20, and 40-Hz. Consistent with the increased variability of first spike latency, we saw a significant decrease in the vector strength of phase-locked spiking during optical stimulation. These in vivo results support a physiological role for the MET channel in the high fidelity of first spike latency seen during encoding of mechanical sensory stimuli. Finally, we examined whether remote activation of hair cells via ChR2 activation was sufficient to elicit escape responses in free-swimming larvae. In transgenic larvae, 100-ms flashes of ~470-nm light resulted in escape responses that occurred concomitantly with field recordings indicating Mauthner cell activity. Altogether, the myo6b:ChR2 transgenic line provides a platform to investigate hair-cell function and sensory encoding, hair-cell sensory input to the Mauthner cell, and the ability to remotely evoke behavior in free-swimming zebrafish. PMID- 24791936 TI - A coarse-grained model for peptide aggregation on a membrane surface. AB - The aggregation of peptides on a lipid bilayer is studied using coarse-grained molecular dynamics in implicit solvent. Peptides bind to and self-assemble on the membrane surface into beta-rich fibrillar aggregates, even under conditions where only disordered oligomers form in bulk solution. Relative to a solid surface, the membrane surface facilitates peptide mobility and a more complex network of morphology transitions as aggregation proceeds. Additionally, final aggregate structures realized on the membrane surface are distinct from those observed on a comparable solid surface. The aggregated fibrils alter the local structure and material properties of the lipid bilayer in their immediate vicinity but have only a modest effect on the overall bending rigidity of the bilayer. PMID- 24791937 TI - Synthesis and complexation study of new ExTTF-based hosts for fullerenes. AB - A new series of exTTF hosts has been synthesized for supramolecular binding study of fullerenes C60 and C70. Binding constants for C60 in chlorobenzene, toluene, toluene-CH2Cl2 and CS2 have been calculated for different hosts and a direct structure-affinity relationship has been established. As predicted, receptors with two exTTF moieties (1, 3 and 4) have demonstrated higher binding abilities toward C70 than C60. Depending on the linker used to attach the exTTF unit to the core of the host, different binding modes (1 : 1 and 2 : 1) have been obtained. PMID- 24791938 TI - A solid-state nuclear magnetic resonance study of post-plasma reactions in organosilicone microwave plasma-enhanced chemical vapor deposition (PECVD) coatings. AB - Plasma-polymerized organosilicone coatings can be used to impart abrasion resistance and barrier properties to plastic substrates such as polycarbonate. Coating rates suitable for industrial-scale deposition, up to 100 nm/s, can be achieved through the use of microwave plasma-enhanced chemical vapor deposition (PECVD), with optimal process vapors such as tetramethyldisiloxane (TMDSO) and oxygen. However, it has been found that under certain deposition conditions, such coatings are subject to post-plasma changes; crazing or cracking can occur anytime from days to months after deposition. To understand the cause of the crazing and its dependence on processing plasma parameters, the effects of post plasma reactions on the chemical bonding structure of coatings deposited with varying TMDSO-to-O2 ratios was studied with (29)Si and (13)C solid-state magic angle spinning nuclear magnetic resonance (MAS NMR) using both single-pulse and cross-polarization techniques. The coatings showed complex chemical compositions significantly altered from the parent monomer. (29)Si MAS NMR spectra revealed four main groups of resonance lines, which correspond to four siloxane moieties (i.e., mono (M), di (D), tri (T), and quaternary (Q)) and how they are bound to oxygen. Quantitative measurements showed that the ratio of TMDSO to oxygen could shift the chemical structure of the coating from 39% to 55% in Q-type bonds and from 28% to 16% for D-type bonds. Post-plasma reactions were found to produce changes in relative intensities of (29)Si resonance lines. The NMR data were complemented by Fourier transform infrared (FTIR) spectroscopy. Together, these techniques have shown that the bonding environment of Si is drastically altered by varying the TMDSO-to-O2 ratio during PECVD, and that post-plasma reactions increase the cross-link density of the silicon-oxygen network. It appears that Si H and Si-OH chemical groups are the most susceptible to post-plasma reactions. Coatings produced at a low TMDSO-to-oxygen ratio had little to no singly substituted moieties, displayed a highly cross-linked structure, and showed less post-plasma reactions. However, these chemically more stable coatings are less compatible mechanically with plastic substrates, because of their high stiffness. PMID- 24791939 TI - Ad5/48 hexon oncolytic virus expressing sTGFbetaRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases. AB - We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sTbetaRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTbetaRFc expressing soluble transforming growth factor beta receptor II-Fc fusion protein (sTGbetaRIIFc), were replaced by those of Ad48. mHAd.sTbetaRFc, like Ad.sTbetaRFc, was replication competent in the human PCa cells, and produced high levels of sTGbetaRIIFc expression. Compared to Ad.sTbetaRFc, the systemic delivery of mHAd.sTbetaRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTbetaRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-alpha, and interleukin-6 levels, while mHAd.sTbetaRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTbetaRFc or mHAd.sTbetaRFc (5 * 10(10) viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sTbetaRFc (4 * 10(11) viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTbetaRFc could be developed for the treatment of PCa bone metastases. PMID- 24791941 TI - Breast abscess: evidence based management recommendations. AB - Literature review was carried out and studies reporting on treatment of breast abscesses were critically appraised for quality and their level of evidence using the Strength of Recommendation Taxonomy guidelines, and key recommendations were summarized. Needle aspiration either with or without ultrasound guidance should be employed as first line treatment of breast abscesses. This approach has the potential benefits of: superior cosmesis, shorter healing time, and avoidance of general anaesthesia. Multiple aspiration sessions may be required for cure. Ultrasound-guided percutaneous catheter placement may be considered as an alternative approach for treatment of larger abscesses (>3 cm). Surgical incision and drainage should be considered for first line therapy in large (>5 cm), multiloculated, or long standing abscesses, or if percutaneous drainage is unsuccessful. All patients should be treated concurrently with antibiotics. Patients with recurrent subareolar abscesses and fistulas should be referred for consideration of surgical treatment. PMID- 24791940 TI - Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer. AB - The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial-mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR 200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future. PMID- 24791944 TI - Volume expansion as temporizing measure for cardiac tamponade: when and how? PMID- 24791943 TI - A killer choice for cancer immunotherapy. AB - The promise of cell-based immunotherapies for the treatment of cancer offers the potential of therapeutic synergy with chemo- and radiotherapies that may overcome current limitations leading to durable responses and prevention of recurrence. There is a wide array of cell-based immunotherapies that are either poised to enter cancer clinical trials or are in clinical trials, and many are showing some success. Yet within this field, there are clear obstacles that need to be overcome, including limited access across tissue barriers, development of antigen tolerance, and the immunosuppressive microenvironment of tumors. Through an understanding of immune cell signaling and trafficking, immune cell populations can be selected for adoptive transfer, and delivery strategies can be developed that circumvent these obstacles to effectively direct populations of cells with robust anti-tumor efficacy to the target. Within the realm of immune cell therapies, cytokine-induced killer (CIK) cells have demonstrated promising trafficking patterns, effective delivery of synergistic therapeutics, and stand alone efficacy. Here, we discuss the next generation of CIK therapies and their application for the effective treatment of a wide variety of cancers. PMID- 24791942 TI - An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. AB - Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often "oncogene addicted." The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4(+) T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shutdown of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are involved not only in tumor initiation, tumor progression, and immunosurveillance, but also in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment. PMID- 24791945 TI - Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis. AB - BACKGROUND: The long-term outcome after curative resection of hepatocellular carcinoma (HCC) remains unsatisfactory because of the high incidence of recurrence. The present study was intended to assess the impact of hepatitis B virus (HBV) DNA level and nucleos(t)ide analog therapy on posthepatectomy recurrence of HBV-related HCC. METHODS: Eligible studies were identified through a computerized literature search. The pooled relative risk ratio (RR) with 95 % confidence interval (CI) was calculated using Review Manager 5.1 Software. RESULTS: Twenty studies with a total of 8,204 participants were included for this meta-analysis. Pooled analysis showed that high viral load was significantly associated with risk of recurrence (RR: 1.85, 95 % CI: 1.41-2.42; P < 0.001), poorer disease-free survival (DFS) (RR: 1.96, 95 % CI: 1.62-2.38; P < 0.001), and poorer overall survival (OS) (RR: 1.47, 95 % CI: 1.22-1.77; P < 0.001) of HBV related HCC after surgical resection. Nucleos(t)ide analog therapy significantly decreased the recurrence risk (RR: 0.69, 95 % CI: 0.59-0.80; P < 0.001) and improved both DFS (RR: 0.70, 95 % CI: 0.58-0.83; P < 0.001) and OS (RR: 0.46, 95 % CI: 0.32-0.68; P < 0.001). CONCLUSIONS: High DNA level is associated with posthepatectomy recurrence of HBV-related HCC. Nucleos(t)ide analog therapy improves the prognosis of HBV-related HCC after resection. PMID- 24791946 TI - The extent of soft tissue and musculoskeletal injuries after earthquakes; describing a role for reconstructive surgeons in an emergency response. AB - BACKGROUND: Earthquakes are the leading cause of natural disaster-related mortality and morbidity. Soft tissue and musculoskeletal injuries are the predominant type of injury seen after these events and a major reason for admission to hospital. Open fractures are relatively common; however, they are resource-intense to manage. Appropriate management is important in minimising amputation rates and preserving function. This review describes the pattern of musculoskeletal and soft-tissue injuries seen after earthquakes and explores the manpower and resource implications involved in their management. METHODS: A Medline search was performed, including terms "injury pattern" and "earthquake," "epidemiology injuries" and "earthquakes," "plastic surgery," "reconstructive surgery," "limb salvage" and "earthquake." Papers published between December 1992 and December 2012 were included, with no initial language restriction. RESULTS: Limb injuries are the commonest injuries seen accounting for 60 % of all injuries, with fractures in more than 50 % of those admitted to hospital, with between 8 and 13 % of these fractures open. After the first few days and once the immediate lifesaving phase is over, the management of these musculoskeletal and soft-tissue injuries are the commonest procedures required. CONCLUSIONS: Due to the predominance of soft-tissue and musculoskeletal injuries, plastic surgeons as specialists in soft-tissue reconstruction should be mobilised in the early stages of a disaster response as part of a multidisciplinary team with a focus on limb salvage. PMID- 24791947 TI - Impact of introduction of laparoscopic surgery on management of unresolved intra abdominal malignancies in a West African hospital. AB - BACKGROUND: Intra-abdominal malignancies often pose diagnostic problems to surgeons in resource-challenged centers such as ours due to limitations in modern imaging and other facilities. This prompted the adoption of laparoscopy in our hospital as an adjunctive tool in diagnosing these conditions. METHOD: Pre- and per-operative data of consecutive cases of clinically unresolved advanced intra abdominal tumors subjected to laparoscopy from January 2009 through June 2013 were reviewed. Anatomic diagnosis and tissue biopsies were carried out during the procedures. RESULTS: Of the 152 patients seen with intra-abdominal tumors, 74 (48.7 %) had advanced conditions that could not be resolved clinically. Of these, 33 (44.6 %) were able to afford and had computed tomography (CT), scan while the remaining (N = 41; 55.4 %) less endowed only had an ultrasound scan. This cohort underwent laparoscopic evaluation, and biopsies confirmed the following: 27 (36.5 %) metastatic adenocarcinomas, 12 (16.2 %) primary hepatic malignancies, 11 (14.9 %) cases each of lymphomas and colonic adenocarcinomas, 4 (5.4 %) gastrointestinal stromal tumors, 3 (4.1 %) pancreatic carcinomas, 2 (2.7 %) cases each of carcinoid tumors and abdominal tuberculosis, and one case each of schistosomiasis and HIV-related Kaposi's sarcoma. Additionally, 26 (35.1 %) had ascites, while 29 (39.1 %) had peritoneal surface malignancies. With local adaptations and improvisations, laparoscopy was cheaper than an abdominal CT scan in our setting, with the additional benefit of obtaining tissue diagnosis to institute treatment. CONCLUSION: Although laparoscopy is commonly used for staging intra-abdominal tumors, we found it useful in complementing clinical diagnosis and attaining histopathological confirmation in a setting where access to and funding of modern imaging is limited. PMID- 24791948 TI - Prevalence of surgical conditions in individuals aged more than 50 years: a cluster-based household survey in Sierra Leone. AB - BACKGROUND: With the demographic transition disproportionately affecting developing nations, the healthcare burden associated with the elderly is likely to be compounded by poor baseline surgical capacity in these settings. We sought to assess the prevalence of surgical disease and disability in the elderly population of Sierra Leone to guide future development strategies. METHODS: A cluster randomized, cross-sectional household survey was carried out countrywide in Sierra Leone from January 9th to February 3rd 2012. Using a standardized questionnaire, household member demographics, deaths occurring during the previous 12 months, and presence of any current surgical condition were elucidated. A retrospective analysis of individuals aged 50 and over was performed. RESULTS: The survey included 1,843 households with a total of 3,645 respondents. Of these, 13.6 % (496/3,645) were aged over 50 years. Of the elderly individuals in our sample, 301 (60.7 %) reported a current surgical condition. Of current surgical disease identified among elderly individuals (n = 530), 349 (65.8 %) described it as disabling, and 223 (42.1 %) sought help from traditional medicine practitioners. Women (odds ratio [OR] 0.60; 95 % confidence interval [CI] 0.40-0.90) and individuals living in urban settings (OR 0.44, 95 % CI 0.26 0.75) were less likely to report a current surgical problem. Of the 230 elderly deaths in the previous year, 83 (36.1 %) reported a surgical condition in the week prior. CONCLUSIONS: The unmet burden of surgical disease is prevalent in the elderly in low-resource settings. This patient population is expected to grow significantly in the coming years, and more resources should be allocated to address their surgical needs. PMID- 24791949 TI - An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging, in patients with transient ischaemic attack and minor stroke: a systematic review, meta-analysis and economic evaluation. AB - BACKGROUND: Patients with transient ischaemic attack (TIA) or minor stroke need rapid treatment of risk factors to prevent recurrent stroke. ABCD2 score or magnetic resonance diffusion-weighted brain imaging (MR DWI) may help assessment and treatment. OBJECTIVES: Is MR with DWI cost-effective in stroke prevention compared with computed tomography (CT) brain scanning in all patients, in specific subgroups or as 'one-stop' brain-carotid imaging? What is the current UK availability of services for stroke prevention? DATA SOURCES: Published literature; stroke registries, audit and randomised clinical trials; national databases; survey of UK clinical and imaging services for stroke; expert opinion. REVIEW METHODS: Systematic reviews and meta-analyses of published/unpublished data. Decision-analytic model of stroke prevention including on a 20-year time horizon including nine representative imaging scenarios. RESULTS: The pooled recurrent stroke rate after TIA (53 studies, 30,558 patients) is 5.2% [95% confidence interval (CI) 3.9% to 5.9%] by 7 days, and 6.7% (5.2% to 8.7%) at 90 days. ABCD2 score does not identify patients with key stroke causes or identify mimics: 66% of specialist-diagnosed true TIAs and 35-41% of mimics had an ABCD2 score of >= 4; 20% of true TIAs with ABCD2 score of < 4 had key risk factors. MR DWI (45 studies, 9078 patients) showed an acute ischaemic lesion in 34.3% (95% CI 30.5% to 38.4%) of TIA, 69% of minor stroke patients, i.e. two-thirds of TIA patients are DWI negative. TIA mimics (16 studies, 14,542 patients) make up 40 45% of patients attending clinics. UK survey (45% response) showed most secondary prevention started prior to clinic, 85% of primary brain imaging was same-day CT; 51-54% of patients had MR, mostly additional to CT, on average 1 week later; 55% omitted blood-sensitive MR sequences. Compared with 'CT scan all patients' MR was more expensive and no more cost-effective, except for patients presenting at > 1 week after symptoms to diagnose haemorrhage; strategies that triaged patients with low ABCD2 scores for slow investigation or treated DWI-negative patients as non-TIA/minor stroke prevented fewer strokes and increased costs. 'One-stop' CT/MR angiographic-plus-brain imaging was not cost-effective. LIMITATIONS: Data on sensitivity/specificity of MR in TIA/minor stroke, stroke costs, prognosis of TIA mimics and accuracy of ABCD2 score by non-specialists are sparse or absent; all analysis had substantial heterogeneity. CONCLUSIONS: Magnetic resonance with DWI is not cost-effective for secondary stroke prevention. MR was most helpful in patients presenting at > 1 week after symptoms if blood-sensitive sequences were used. ABCD2 score is unlikely to facilitate patient triage by non-stroke specialists. Rapid specialist assessment, CT brain scanning and identification of serious underlying stroke causes is the most cost-effective stroke prevention strategy. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 24791950 TI - The contribution of the functional IL6R polymorphism rs2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels. AB - The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N ~5,000), and conducted an expression QTL analysis to identify SNPs associated with IL6R gene expression. Based on data from 2,360 twin families, the broad heritability of sIL-6R was estimated at 72 and 51% of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3'-end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression. PMID- 24791952 TI - Prior infections are associated with increased mortality from subsequent blood stream infections among patients with hematological malignancies. AB - Many patients who are evaluated and treated for sepsis have histories of recent infections. The prognostic implications of surviving an infectious process are not well understood. We undertook this study to determine the clinical impact of prior infections among patients with hematological malignancies, a population at high risk for developing and dying from sepsis. The medical records of 203 patients with hematological malignancies and blood-stream infections admitted over a 3-year period to an urban teaching hospital were retrospectively reviewed. The 30-day mortality after blood-stream infection in these high-risk patients was 24 %. There were 46 patients (23 %) who had inpatient infections in the 90 days prior to the index blood-stream infection. History of recent infection portended worse prognosis from blood-stream infection under multivariable analysis [odds ratio (OR) 2.60, p = 0.04, 95 % confidence interval (CI) 1.04-6.47]. There were 86 patients (42 %) who had subsequent infections in the first 90 days after the index blood-stream infection. Patients with subsequent infections had greater mortality during days 91-365 than patients without subsequent infections [hazard ratio (HR) 1.97, p = 0.02, 95 % CI 1.13-3.44]. Recent infections prognosticate worse outcomes from subsequent blood-stream infections for this high-risk population. Further research into the clinical and biochemical reasons for this observation may lead to targets for intervention, and, ultimately, improvements in long-term mortality from sepsis. PMID- 24791951 TI - European Confederation of Medical Mycology (ECMM) epidemiological survey on invasive infections due to Fusarium species in Europe. AB - In order to better understand the epidemiology of fusariosis in Europe, a survey collecting information on the clinical characteristics of the patients infected by Fusarium as well as on the infecting isolates was launched. A total of 76 cases of invasive fusariosis occurring from January 2007 to June 2012 were collected and Fusarium isolates were identified by sequencing the translation elongation factor 1alpha (TEF) gene. Also, antifungal susceptibility was tested by broth microdilution according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Etest. Disseminated disease was considered proven in 46 cases and probable in 17 cases. Localised infection was seen in 13 cases. Gibberella fujikuroi species complex (SC), including Fusarium verticillioides and F. proliferatum, and F. solani SC were the most frequent aetiology of disseminated and localised infections, respectively. The crude mortality rate was 46 %, the highest associated with F. solani SC (67 %) and F. proliferatum (62.5 %). A wide range of antifungal susceptibilities was observed. Amphotericin B was the most potent antifungal in vitro, and itraconazole the least effective. The azoles exhibited lower minimum inhibitory concentrations (MICs) against F. verticillioides strains, with posaconazole having a slightly better performance, while F. solani SC isolates were resistant to all three azoles tested. The essential agreement between the Etest and the EUCAST method was 100 % for itraconazole and voriconazole, and 96 % for amphotericin B and posaconazole. In conclusion, we confirm that fusariosis is a rare but severe event in Europe, that G. fujikuroi SC is the predominant cause of deep infections and that different species have different antifungal in vitro susceptibility patterns. PMID- 24791953 TI - Clinical manifestations of lead-dependent infective endocarditis: analysis of 414 cases. AB - It is important to identify clinical manifestations of lead-dependent infective endocarditis (LDIE), as it begins insidiously with the slow development of nonspecific symptoms. Clinical data from 414 patients with the diagnosis of LDIE according to Modified Duke Lead Criteria (MDLC) were analyzed. Patients with LDIE had been identified in a population of 1,426 subjects submitted to transvenous lead extraction (TLE) in the Reference Clinical Cardiology Center in Lublin between 2006 and 2013. The symptoms of LDIE and pocket infection were detected in 62.1 % of patients. The mean duration of LDIE symptoms prior to referral for TLE was 6.7 months. Fever and shivers were found in 55.3 % of patients, and pulmonary infections in 24.9 %. Vegetations were detected in 67.6 % of patients, and positive cultures of blood, lead, and pocket in 34.5, 46.4, and 30.0 %, respectively. The most common pathogens in all type cultures were coagulase negative staphylococci (CNS), with Staphylococcus epidermidis domination; the second most common organism was Staphylococcus aureus. 76.3 % of patients were treated with empirical antibiotic therapy before hospitalization due to TLE. In the laboratory tests, the mean white blood cell count was 9,671 +/- 5,212/MUl, mean erythrocyte sedimentation rate 43 mm, C-reactive protein (CRP) 46.3 mg/dl +/ 61, and procalcitonin 1.57 +/- 4.4 ng/ml. The multivariate analysis showed that the probability of LDIE increased with increasing CRP. The diagnosis of LDIE based on MDLC may be challenging because of a relatively low sensitivity of major criteria, which is associated with early antibiotic therapy and low usefulness of minor criteria. The important clinical symptoms of LDIE include fever with shivering and recurrent pulmonary infections. The most specific pathogens were Staphylococcus epidermidis and Staphylococcus aureus. Laboratory tests most frequently revealed normal white blood cell count, relatively rarely elevated procalcitonin level, and significantly increased erythrocyte sedimentation rate (ESR) and CRP. This constellation of signs should prompt a more thorough search for LDIE. PMID- 24791954 TI - Association of autophagy-related 16-like 1 (ATG16L1) gene polymorphism with sepsis severity in patients with sepsis and ventilator-associated pneumonia. AB - Autophagy is a highly conserved mechanism of eukaryotic cells implicated in cell homeostasis and elimination of intracellular pathogens. Functional polymorphisms in genes encoding for autophagy have been associated with susceptibility to inflammatory and infectious diseases, but data on severe infections are missing. The aim of the present study was to assess whether polymorphisms in genes encoding proteins involved in autophagy influence susceptibility to ventilator associated pneumonia (VAP). Mechanically ventilated patients with VAP were studied. Genotyping for autophagy-related 16-like 1 (ATG16L1, rs2241880) functional polymorphism was performed using the TaqMan single-nucleotide assay. Monocytes were isolated from patients and stimulated with lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-alpha) was measured in the supernatants of monocytes using an enzyme-linked immunosorbent assay. Procalcitonin (PCT) was also measured in the serum of patients by an immuno-time-resolved amplified cryptate technology assay. A total of 155 patients with VAP were enrolled in the study. Carriage of the minor A allele of ATG16L1 was associated with septic shock with at least one organ failure (odds ratio (OR): 2.40, p: 0.036). TNF-alpha production was significantly greater among the carriers of the polymorphism presenting with at least one organ failure (p: 0.040). PCT was increased upon worsening to septic shock and organ failure only among carriers of the minor frequency A alleles. In a homogeneous cohort of septic patients with VAP, the carriage of autophagy polymorphisms predisposes to VAP severity and septic shock development. This may be related with predisposition to immunoparalysis. PMID- 24791955 TI - Dissipation and residue of metalaxyl and cymoxanil in pepper and soil. AB - A simple and accurate method of determining metalaxyl and cymoxanil in pepper and soil was developed by ultra-performance liquid chromatography-photodiode array detection. The limits of detection were 0.015 mg/kg for metalaxyl and 0.003 mg/kg for cymoxanil. The limits of quantification were 0.05 mg/kg for metalaxyl in pepper and soil as well as 0.01 mg/kg for cymoxanil in pepper and soil. Recoveries of pepper and soil were investigated at three spiking levels and ranged within 77.52 to 102.05 % for metalaxyl and 87.15 to 103.21 % for cymoxanil, with relative standard deviations below 9.30 %. For field experiments, the half-lives of metalaxyl were 3.2 to 3.9 days in pepper and 4.4 to 9.5 days in soil at the three experimental locations in China. At harvest, pepper samples were found to contain metalaxyl and cymoxanil well below the maximum residue limit MRLs of the European Union (EU) following the recommended dosage and the interval of 21 days after last application. PMID- 24791956 TI - Dissipation and residues determination of propamocarb in ginseng and soil by high performance liquid chromatography coupled with tandem mass spectrometry. AB - Two-year field trials were performed at two experimental sites to investigate dissipation and terminal residues of propamocarb in ginseng root, stem, leaf, and soil by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Mean recoveries ranged from 80.5 to 95.6% with relative standard deviations (RSDs) of 5.5-9.1% at fortified levels of 0.01, 0.02, 0.05 and 0.20 mg kg(-1). The half-lives of propamocarb were 5.00-11.36 days in root, 5.07-11.46 days in stem, 6.83-11.31 days in leaf and 6.44-8.43 days in soil. The terminal residues of propamocarb were below the maximum residue limits (MRLs) of EU (0.20 mg kg(-1)) and South Korea (0.50 mg kg(-1) in fresh ginseng and 1.0 mg kg(-1) in dried ginseng) over 28 days after last spraying at recommended dosage. The results provide a quantitative basis for establishing the MRL and give a suggestion of safe and reasonable use of propamocarb in ginseng. PMID- 24791957 TI - Should we consider off-pump coronary artery bypass grafting in patients undergoing coronary endarterectomy? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether off-pump coronary artery bypass grafting with coronary endarterectomy (OPCAB-CE) is a safe and feasible method of myocardial revascularization in patients presenting with diffuse coronary artery disease. Seventy-one papers were identified by a systematic search, of which nine were judged to best answer the clinical question. All were observational studies. Of these, two were comparative and the remaining seven were case series. The authors, journal, date, country of publication, patient group, study type, relevant outcomes and results were tabulated. In total, these 9 studies included 341 patients (225 OPCAB-CE, 116 ONCAB-CE) undergoing coronary endarterectomy in combination with coronary artery bypass grafting. CE was performed either by an open method whereby the atheroma is removed through an arteriotomy made along the length of the stenosis or by a closed method whereby the atheroma is removed by gentle traction through a small arteriotomy made over a proximal area of the plaque. Overall, OPCAB-CE was associated with a low perioperative mortality ranging from zero in smaller case series to 2.8% in the largest study (n = 70). Two comparative studies demonstrate at least equivalent 30-day mortality between OPCAB-CE and ONCAB-CE, although the sample sizes are small. The overall incidence of postoperative myocardial infarction (MI) was 6.1% (11/180) and seems comparable between OPCAB-CE and ONCAB-CE. Notably, both postoperative MI and mortality appeared higher in patients undergoing multiple endarterectomies performed using a closed technique and CE to the right coronary artery was associated with increased postoperative MI. In summary, OPCAB-CE in the setting of diffuse coronary artery disease appears both safe and feasible, yielding comparable results to ONCAB-CE. Where possible, open arteriotomy with on-lay patch angioplasty may improve postoperative outcomes. Large, prospective database studies are now required with explicit sub-group criteria and stratification to number, territory and technique of endarterectomy in order to isolate the patients in whom OPCAB-CE may confer the greatest benefit. PMID- 24791958 TI - UK spending on healthcare lowest of G7 countries. PMID- 24791960 TI - An aged patient with 11-year untreated progressive atlantoaxial subluxation manifesting with dyspnea due to unilateral diaphragmatic paralysis: a case report and literature review. PMID- 24791961 TI - Differences in daily in-hospital physical activity and geriatric nutritional risk index in older cardiac inpatients: preliminary results. AB - BACKGROUND: Little is known about the differences in the geriatric nutritional risk index (GNRI) status in older patients and their relationship to accelerometer-derived measures of physical activity (PA) levels. We determined both differences in daily measured PA based on the GNRI and related cut-off values for PA in elderly cardiac inpatients. METHODS: We divided 235 consecutive elderly cardiac inpatients (mean age 73.6 years, men 70.6%) into four groups by age and GNRI: older-high group, 65-74 years with high GNRI (>=92 points) (n = 111); older-low group, low GNRI (<92 points) (n = 30); very old-high group, >=75 years with high GNRI (n = 55); and very old-low group with low GNRI (n = 39). Average step count and physical activity energy expenditure (PAEE in kcal) per day for 2 days of these inpatients were assessed by accelerometer and compared between the four groups to determine cut-off values of PA. RESULTS: Step counts and PAEE were significantly lower in the low-GNRI versus high-GNRI groups in the older (2,742.1 vs. 4,198.1 steps, 55.4 vs. 101.3 kcal, P < 0.001), and very old (2,469.6 vs. 3,423.7 steps, 54.5 vs. 79.1 kcal, P < 0.001) cardiac inpatients. Respective cut-off values for step counts and PAEE were 3,017.6 steps/day and 69.4 kcal (P < 0.01) in the older and 2,579.4 steps/day and 58.8 kcal in the very old cardiac inpatients (P < 0.01). CONCLUSION: Poor nutritional status, as indicated by a low GNRI, may be a useful predictor of step counts and PAEE. The cut-off values determined in this study might be target values to be attained by older cardiac inpatients. PMID- 24791959 TI - Impact of sepsis on CD4 T cell immunity. AB - Sepsis remains the primary cause of death from infection in hospital patients, despite improvements in antibiotics and intensive-care practices. Patients who survive severe sepsis can display suppressed immune function, often manifested as an increased susceptibility to (and mortality from) nosocomial infections. Not only is there a significant reduction in the number of various immune cell populations during sepsis, but there is also decreased function in the remaining lymphocytes. Within the immune system, CD4 T cells are important players in the proper development of numerous cellular and humoral immune responses. Despite sufficient clinical evidence of CD4 T cell loss in septic patients of all ages, the impact of sepsis on CD4 T cell responses is not well understood. Recent findings suggest that CD4 T cell impairment is a multipronged problem that results from initial sepsis-induced cell loss. However, the subsequent lymphopenia-induced numerical recovery of the CD4 T cell compartment leads to intrinsic alterations in phenotype and effector function, reduced repertoire diversity, changes in the composition of naive antigen-specific CD4 T cell pools, and changes in the representation of different CD4 T cell subpopulations (e.g., increases in Treg frequency). This review focuses on sepsis-induced alterations within the CD4 T cell compartment that influence the ability of the immune system to control secondary heterologous infections. The understanding of how sepsis affects CD4 T cells through their numerical loss and recovery, as well as function, is important in the development of future treatments designed to restore CD4 T cells to their presepsis state. PMID- 24791962 TI - Systemic exposure to a common periodontal pathogen and missing teeth are associated with metabolic syndrome. AB - Periodontitis is a common chronic infection of tooth-supporting tissues leading to tooth loss. Two of the major periodontal pathogens are Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Clinically diagnosed periodontitis has been associated with metabolic syndrome (MetS). The aim of the study was to investigate the association of serum antibody levels against A. actinomycetemcomitans and P. gingivalis and the number of missing teeth with MetS. The population was the PAIS subcohort of the FINRISK '97 study (n = 1,354). The subjects were men aged 45-74 years, and they participated in this cardiovascular risk factor survey in Finland. A total of 534 (39 %) subjects had MetS defined according to the guidelines of the International Diabetes Federation. Serum antibody levels against the pathogens were measured by multiserotype ELISA. A. actinomycetemcomitans antibody levels and the number of missing teeth were significantly higher in subjects with a large waist circumference or with low serum high-density lipoprotein cholesterol. The number of missing teeth was also higher among subjects with a high serum triglyceride concentration or high plasma glucose concentration. Seropositivity for A. actinomycetemcomitans was significantly associated with MetS with an odds ratio (OR) 1.42 (95 % confidence interval 1.09-1.85, p = 0.009). More than four missing teeth and complete edentulousness were also significantly associated with MetS with ORs 1.69 (1.26-2.27, p < 0.001) and 1.93 (1.30-2.86, p = 0.001), respectively. Missing teeth and systemic exposure to A. actinomycetemcomitans were associated with several components of Mets. Infection with this common pathogen or the host response against it is associated with the presence of MetS. PMID- 24791963 TI - Failing beta-cell adaptation in South Asian families with a high risk of type 2 diabetes. AB - We performed an extended oral glucose tolerance test (OGTT) to investigate the relationship between early and late beta-cell response and type 2 diabetes (T2D) in families of South Asian origin and indigenous Dutch, burdened by T2D. Based on the OGTT, 22 individuals were normoglycemic, 12 glucose intolerant and 23 had T2D in the South Asian families; these numbers were 34, 12 and 18 in the Caucasian families, respectively. The OGTT had 11 blood samplings in 3.5 h for glucose, insulin and C-peptide measurements. Through early and late insulin secretion rate (ISR), the above basal glucose area-under-the-curve after glucose load (glucose disposal) and insulin sensitivity index (ISI), we obtained early and late disposition indices (DI). South Asians on average had lower ISI than Caucasians (3.8 +/- 2.9 vs. 6.5 +/- 4.7, respectively, P < 0.001), with rapid decline of their early and late DI between normal glucose tolerance versus impaired fasting glucose/impaired glucose tolerance (late DI; P < 0.0001). Adjusted for ISI, age, gender and waist-to-hip ratio, early ISR was significantly associated with glucose disposal in South Asians (beta = 0.55[0.186; 0.920]), but not in Caucasians (beta = 0.09[-0.257; 0.441]). Similarly, early ISR was strongly associated with late ISR (beta = 0.71[0.291; 1.123]; R (2) = 45.5 %) in South Asians, but not in Caucasians (beta = 0.27[-0.035; 0.576]; R (2) = 17.4 %), with significant interaction between ethnicity and early ISR (beta = 0.341[0.018; 0.664]). Ordinal regression analyses confirmed that all South Asian OGTT subgroups were homogenously resistant to insulin and solely predicted by early ISR (beta = -0.782[-1.922; 0.359], beta = -0.020[-0.037; -0.002], respectively), while in Caucasian families both ISI and early ISR were related to glucose tolerance state (beta = -0.603[-1.105; -0.101], beta = -0.066[-0.105; -0.027], respectively). In South Asian individuals, rapid beta-cell deterioration might occur under insulin resistant conditions. As their early insulin response correlates strongly with both glucose disposal and late insulin response, alterations in beta-cell dynamics may give an explanation to their extreme early onset of T2D, although larger prospective studies are required. PMID- 24791964 TI - Comparison of metal levels in different tissues of seven ray species from Antalya Bay, Mediterranean Sea. AB - The aim of this study was to investigate the metal concentrations in muscle, liver, gill and intestine of seven ray species from Antalya Bay. Because the study is the first for rays in Antalya Bay, this study provides valuable preliminary information about metal contents in different tissues of the examined ray species from the bay and indirectly indicates the environmental contamination of the Antalya Bay. PMID- 24791965 TI - Comparison of 3-dimensional versus 2-dimensional laparoscopic vision system in total laparoscopic hysterectomy: a retrospective study. AB - PURPOSE: We compare the results of total laparoscopic hysterectomy (TLH) operations conducted using standard 2-D and 3-D high definition laparoscopic vision systems and discuss the findings with regard to the recent literature. METHODS: Data from 147 patients who underwent TLH operations with 2-D or 3-D high definition laparoscopic vision systems in Department of Obstetrics and Gynecology, Bagcilar Training and Research Hospital, during 2 year period between December 2010 and December 2012, were reviewed retrospectively. TLH operations were divided into two groups as those performed using 2-D, and those performed using 3-D high definition laparoscopic vision systems. RESULTS: A statistically significant difference was found between the two groups in the operation times (p = 0.037 < 0.05). The mean operation time of the 2-D laparoscopy group (134.2 +/- 61.8 min) was higher than the 3-D laparoscopy group (116.8 +/- 38.5 min). No statistically significant difference was found between the 2-D and 3-D groups with respect to major, minor and total complication rates (p = 0.641 > 0.05). The operation time among obese patients was significantly shorter in those in the 3-D laparoscopy group than those in the 2-D group (p = 0.041 < 0.05). CONCLUSIONS: Recent literature indicates that 3-D laparoscopy vision system needs to be utilized more often and a higher number of ex vivo and in vivo studies have to be conducted. Furthermore, we believe that the prevalent problems encountered during laparoscopy can be overcome by the development of real-time vision devices and the appropriate training of the laparoscopists. 3-D high definition laparoscopic vision system will help to improve surgical performance and outcome of patients undergoing gynecological minimal invasive surgery. PMID- 24791966 TI - Surgical outcome of deep infiltrating colorectal endometriosis in a multidisciplinary setting. AB - BACKGROUND: Endometriosis as a benign disease appears frequently in premenopausal women with highly variable symptoms. In advanced stages bowel involvement is common. In symptomatic disease the adequate treatment requires complete resection of all residues. Indications of colorectal resection for endometriosis remain controversial because of the risk of major complications. The purpose of this study was to show the feasibility of planned complete laparoscopic management of symptomatic deep pelvic endometriosis with bowel involvement performing segmental colorectal resection in a center of excellence. METHODS: Between 2007 and 2012 all patients treated for symptomatic colorectal endometriosis in our institution were included and retrospectively evaluated. Laparoscopic excision of all visible disease was planned. Data analysis included age, previous history of endometriosis, intraoperative findings, operative procedure and intra- and postoperative complications. RESULTS: In this time period 35 patients with bowel infiltrating endometriosis were treated. Affected locations were the rectovaginal space in 31 patients (89 %), the rectum in 32 patients (91 %), the sigmoid colon in 10 patients (29 %), the coecum in 2 patients (5.7 %), the appendix in 3 patients (8.6 %) and the terminal ileum in 1 patient (2.9 %). In the majority of patients (85.7 %) the resection was achieved laparoscopically, in 3 patients a conversion to laparotomy was necessary and in 2 patients a primary laparotomia was performed. Complications occurred in 2 cases with anastomotic leakage in 1 patient (2.8 %) and a rectovaginal fistula in another patient. Radical resection was achieved in almost all patients (97 %). CONCLUSIONS: A well-trained interdisciplinary team can perform treatment of deep infiltrating endometriosis laparoscopically with low incidence of major complications as anastomotic leakage or rectovaginal fistula. Criteria of complete endometriosis restoration of the rectum can be achieved by total or subtotal rectal excision. PMID- 24791967 TI - Does endometrial injury improve implantation of frozen-thawed embryos? AB - PURPOSE: To investigate whether endometrial injury (EI) increases pregnancy rates in subjects undergoing frozen-thawed embryo transfer (FET) cycles. METHODS: We conducted a prospective study of 80 consecutive subjects at a private fertility center. All women were undergoing frozen embryo transfer after one or more unsuccessful in vitro fertilization and embryo transfer cycle(s). Subjects in the experimental group underwent endometrial biopsy in the luteal phase of the cycle preceding the frozen embryo transfer cycle. The primary outcomes were chemical and clinical pregnancy rates. RESULTS: The 40 subjects who underwent EI in the cycle preceding their FET cycle were compared with 40 controls. There were differences in the groups' baseline characteristics; the average age was slightly higher and the duration of infertility was longer in the EI group. Chemical pregnancy rates between the two groups were similar, 27 % (range 17-40 %) in the injury group and 26 % (16-40 %) in the control group (OR for chemical pregnancy = 1.05, 95 % CI 0.42-2.12). The difference in clinical pregnancy rate was not statistically significant: 40 % (25-57 %) in the injury group versus 33 % (19-49 %) in the control group (OR for clinical pregnancy = 1.38, 95 % CI 0.55-3.46). CONCLUSIONS: Based on the results of this pilot study, EI in the luteal phase of the cycle preceding the frozen embryo transfer cycle does not appear to significantly improve implantation or clinical pregnancy rates. PMID- 24791968 TI - Methotrexate for ectopic pregnancy: when and how. AB - PURPOSE: Ectopic pregnancy is the leading cause of maternal death in the first trimester of pregnancy. The dosage of beta fraction of human chorionic gonadotropin (beta-hCG) and improvement of the transvaginal ultrasound allowed an earlier diagnosis and a conservative management. Currently, the use of systemic methotrexate (MTX) proved to be a great alternative with similar success rates and completely non-invasive. METHODS: We searched for the most relevant articles on the use of MTX in ectopic pregnancy published between 2003 and 2013 in high impact journals. We performed a strategic search at the Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), National Institute for Health Research (NHS), International Prospective Register of Systematic Reviews (PROSPERO), The Cochrane Database of Systematic Reviews (CDSR) and Medical Literature Analysis and Retrieval System Online (MEDLINE) according to the descriptors "pregnancy, ectopic" and "methotrexate", alone or combined. RESULTS: Thus, we based this review on 32 studies that were classified following the grades of recommendation and levels of evidence proposed by the Oxford Centre for Evidence-Based Medicine. Additionally, selected papers were used. Scientific evidence points to a growing trend in the choice of conservative treatment for ectopic pregnancies, whereas expectant management still lacks studies for definitive conclusions. Indeed, the well-established protocols which exhibit a greater number of studies are still based on the single-dose treatment. CONCLUSION: Considering MTX, it proved to be more effective in cases of low titers of beta-hCG and masses with a small diameter, although there is still no uniformity of these parameters. The choice largely depends on the experience of the medical team and ultimately, on the woman's reproductive desire. PMID- 24791969 TI - Preemptive dexmedetomidine to prevent propofol injection pain in children. AB - BACKGROUND: The incidence of propofol injection pain is high in children, but no methods have been found to suppress it completely. This study intends to evaluate the efficacy of dexmedetomidine-midazolam in preventing propofol injection pain in children. METHODS: One-hundred ASA I patients, aged 3-12 years, weighing 15-53 kg, undergoing elective surgery were randomized into two groups of 50 each, using computer-generated random numbers. Normal saline 0.15 ml/kg in Group C or dexmedetomidine 0.6 MUg/kg in Group D was infused IV over 10 min. Then midazolam 0.06 mg/kg was administered immediately; 2 min after aforementioned treatments in each group, all patients received propofol 2 mg/kg (propofol was mixed with lidocaine 1 mg/ml in Group C) at an average rate of 0.2 ml per 1 s. Another anesthesiologist, blind to the pretreatment, recorded the occurrence of injection pain using a four-graded pain scale: 1 = no pain (no reaction to injection), 2 = slight pain (minor verbal/facial response or motor reaction to injection), 3 = moderate pain (clear verbal/facial response or motor reaction to injection) and 4 = severe pain (the patient both complained of pain and withdrew the arm). RESULTS: Forty (80 %) patients in Group C (control) had injection pain; however, none of patients in Group D had any injection pain. The total incidence of profol induced pain in Group C was significantly higher (P < 0.01). There were no instances of bradycardia or low blood pressure with either treatment in this study. CONCLUSIONS: Pretreatment with dexmedetomidine 0.6 MUg/kg, then midazolam 0.06 mg/kg could suppress propofol injection pain in children. PMID- 24791971 TI - Anxiety and depression in mothers and fathers of a chronically ill child. AB - We aimed to determine the levels of anxiety and depression in mothers and fathers of a chronically ill child (0-18 years) and to study which parental and child variables are associated with anxiety and depression. In a cross-sectional design, anxiety and depression were assessed with the Hospital Anxiety and Depression Scale. Scores were compared to a Dutch reference group by analysis of variance and logistic regression analysis. Linear regression analyses were performed to examine which variables were associated with anxiety and depression. Mothers of a chronically ill child (n = 566) scored significantly higher than the reference group (p < .001) on anxiety (Mean 5.9 vs 4.8) and depression (Mean 4.5 vs 3.1). Fathers (n = 123) had higher depression scores (Mean 4.5 vs 3.6; p < .05), but fathers' anxiety scores were comparable to the reference group. The percentages of mothers in the clinical range of anxiety (31.8 vs 20.7 %, OR 2.03, 95 % CI 1.46-2.83) and depression (23.0 vs 12.0 %, OR 2.76, 95 % CI 1.84-4.13) were higher (p < .001) than in the reference group. No differences were found for fathers in the clinical range for anxiety and depression. Practical problems in daily life (a: beta = .33, d: beta = .25) and parenting stress (a: beta = .30, d: beta = .32) showed the strongest association with anxiety and depression for parents as a group. Illness-related characteristics of the child were not related. Parents of a chronically ill child, especially mothers, reported high levels of anxiety and depression. Awareness about parental anxiety and depression in pediatrics is important as well as targeted interventions. PMID- 24791972 TI - Exploring maternal patterns of dietary caffeine consumption before conception and during pregnancy. AB - We describe patterns of dietary caffeine consumption before and after pregnancy recognition in a cohort of women who recently gave birth. This study included 8,347 mothers of non-malformed liveborn control infants who participated in the National Birth Defects Prevention Study during 1997-2007. Maternal self-reported consumption of beverages (caffeinated coffee, tea, and soda) and chocolate the year before pregnancy was used to estimate caffeine intake. The proportions of prepregnancy caffeine consumption stratified by maternal characteristics are reported. In addition, patterns of reported change in consumption before and after pregnancy were examined by maternal and pregnancy characteristics. Adjusted prevalence ratios were estimated to assess factors most associated with change in consumption. About 97 % of mothers reported any caffeine consumption (average intake of 129.9 mg/day the year before pregnancy) and soda was the primary source of caffeine. The proportion of mothers reporting dietary caffeine intake of more than 300 mg/day was significantly increased among those who smoked cigarettes or drank alcohol. Most mothers stopped or decreased their caffeinated beverage consumption during pregnancy. Young maternal age and unintended pregnancy were associated with increases in consumption during pregnancy. Dietary caffeine consumption during pregnancy is still common in the US. A high level of caffeine intake was associated with known risk factors for adverse reproductive outcomes. Future studies may improve the maternal caffeine exposure assessment by acquiring additional information regarding the timing and amount of change in caffeine consumption after pregnancy recognition. PMID- 24791970 TI - Methodologies to assess paediatric adiposity. AB - INTRODUCTION: Childhood obesity is associated with increased risk of adult obesity, cardiovascular disease, diabetes and cancer. Appropriate techniques for assessment of childhood adiposity are required to identify children at risk. The aim of this review was to examine core clinical measurements and more technical tools to assess paediatric adiposity. METHODS: The online databases PubMed, CINALH and EMBASE were searched and the abstracts identified were reviewed to determine appropriate studies. Their reference lists were also searched to identify further eligible studies. Publications were included if they described childhood measurement techniques or involved validation. RESULTS AND DISCUSSION: There are many body composition assessment tools available, none of which are direct. Each technique has limitations and a combination of methods may be used. The main clinical techniques are weight, height, body mass index (BMI) and circumferences which provide sufficient information to enable classification of overweight or obesity when growth centile charts and ratios are employed. Further investigation depends on resources available and examiner skill. Skinfold thicknesses are cost-effective but require technical training and only measure subcutaneous fat. Dual energy X-ray absorptiometry (DEXA), air displacement plethysmography (ADP), magnetic resonance imaging (MRI) and computed tomography (CT) are more costly and intensive, requiring the child to remain still for longer periods. DEXA and ADP are capable of accurately measuring adiposity but are unable to distinguish between fat depots. MRI and CT can distinguish intra abdominal from subcutaneous adiposity and are considered gold standards, but CT is unsuitable for adiposity measurement in children due to high levels of radiation exposure. Ultrasound is a promising technique capable of measuring intra-abdominal adiposity in children but requires further validation. CONCLUSION: The core clinical measurements of weight, height, BMI and circumferences are sufficient to enable diagnosis of paediatric overweight and obesity while more technical tools provide further insight. PMID- 24791973 TI - Cesarean birth in the border region: a descriptive analysis based on US Hispanic and Mexican birth certificates. AB - Cesarean birth (CB) is more prevalent in the US-Mexico border region than among all US Hispanics. Comparable data from US and Mexican birth certificates can be used to compare prevalence and identify risk factors on either side of the border. Using 2009 US and Mexican birth certificates, we compared the characteristics of US Hispanic and Mexican CBs in six geographic subgroups: US and Mexican border counties/municipios, US and Mexican non-border counties/municipios and the US and Mexico overall. We also explored cesarean prevalence over time. During 2000-2009, CB rates increased from 22.1 to 31.6 % among US Hispanics and from 25.9 to 37.9 % among Hispanics in the US border region. 2009 rates were 44.5 % in Mexico and 43.1 % in the Mexican border region. In both countries, CB rates were similar for primiparas and multiparas. Higher education, being married and parity >4 were associated with CB in Mexico; being married was associated in the US. Hispanic rates were higher in the US border than non-border region for all age groups. Along the border, cesarean rates for Hispanics were highest in Texas (43.5 %) and neighboring Tamaulipas (49.8 %). Higher cesarean prevalence in Mexico than in US Hispanics, while unexplained, is consistent with high prevalence in some Latin American countries. Higher cesarean prevalence among Hispanics in the US border region than among Hispanics nationwide cannot be explained by maternal age or parity. Medical indications are also unlikely to explain such high rates, which are undesirable for mothers and infants. PMID- 24791974 TI - Skilled birth attendants in Tanzania: a descriptive study of cadres and emergency obstetric care signal functions performed. AB - Although most developing countries monitor the proportion of births attended by skilled birth attendants (SBA), they lack information on the availability and performance of emergency obstetric care (EmOC) signal functions by different cadres of health care providers (HCPs). The World Health Organisation signal functions are set of key interventions that targets direct obstetric causes of maternal deaths. Seven signal functions are required for health facilities providing basic EmOC and nine for facilities providing comprehensive EmOC. Our objectives were to describe cadres of HCPs who are considered SBAs in Tanzania, the EmOC signal functions they perform and challenges associated with performance of EmOC signal functions. We conducted a cross-sectional study of HCPs offering maternity care services at eight health facilities in Moshi Urban District in northern Tanzania. A questionnaire and health facility assessment forms were used to collect information from participants and health facilities. A total of 199 HCPs working at eight health facilities in Moshi Urban District met the inclusion criteria. Out of 199, 158 participated, giving a response rate of 79.4 %. Ten cadres of HCPs were identified as conducting deliveries regardless of the level of health facilities. Most of the participants (81 %) considered themselves SBAs, although some were not considered SBAs by the Ministry of Health and Social Welfare (MOHSW). Only two out of the eight facilities provided all of the required EmOC signal functions. While Assistant Medical Officers are expected to perform all the signal functions, only 38 % and 13 % had performed vacuum extraction or caesarean sections respectively. Very few registered and enrolled nurse-midwives had performed removal of retained products (22 %) or assisted vaginal delivery (24 and 11 %). Inadequate equipment and supplies, and lack of knowledge and skills in performing EmOC were two main challenges identified by health care providers in all the level of care. In the district, gaps existed between performance of EmOC signal functions by SBAs as expected by the MOHSW and the actual performance at health facilities. All basic EmOC facilities were not fully functional. Few health care providers performed all the basic EmOC signal functions. Competency-based in-service training of providers in EmOC and provision of enabling environment could improve performance of EmOC signal functions in the district. PMID- 24791976 TI - Shape-changing and amphiphilicity-reversing Janus particles with pH-responsive surfactant properties. AB - Janus particles are biphasic colloids that have two sides with distinct chemistry and wettability. Because of their amphiphilicity, Janus particles present a unique opportunity for stabilizing multiphasic fluid mixtures such as emulsions. Our work is motivated by one class of molecular amphiphiles that change their surfactant properties in response to environmental stimuli. Depending on the environmental conditions, these stimuli-responsive molecular amphiphiles are able to assemble into different structures, generate emulsions with different morphologies, and also induce phase inversion emulsification. We present a new synthesis method utilizing a combination of polymerization-induced phase separation and seeded emulsion polymerization, which allows for the bulk synthesis of highly uniform pH-responsive Janus particles that are able to completely reverse their surfactant properties in response to solution pH. One side of these Janus particles is rich in a hydrophobic monomer, styrene, whereas the other side is rich in a pH-sensitive hydrophilic repeating unit, acrylic acid. These Janus particles change their aggregation/dispersion behavior and also transform into different shapes in response to pH changes. Furthermore, we demonstrate that these Janus particles can stabilize different types of emulsions (oil-in-water and water-in-oil) and, more importantly, induce phase inversion of emulsions in response to changes in solution pH. The pH-responsive aggregation/dispersion behavior of these Janus particles also allows us to tune the interactions between oil-in-water emulsion droplets without inducing destabilization; that is, emulsion drops with attractive or repulsive interactions can be generated by changing the pH of the aqueous phase. Our study presents a new class of colloidal materials that will further widen the functionality and properties of Janus particles as dynamically tunable solid surfactants. PMID- 24791975 TI - Effects of GLP-1 in the kidney. AB - The incretin hormone, glucagon-like peptide-1 (GLP-1), stimulates insulin secretion and forms the basis of a new drug class for diabetes treatment. GLP-1 has several extra-pancreatic properties which include effects on kidney function. Although renal GLP-1 receptors have been identified, their exact localization and physiological role are incompletely understood. GLP-1 increases natriuresis through inhibition of the sodium-hydrogen ion exchanger isoform 3 in the proximal tubule. This may in part explain why GLP-1 receptor agonists have antihypertensive effects. Glomerular filtration rate is regulated by GLP-1, but the mechanisms are complex and may depend on e.g. glycaemic conditions. Atrial natriuretic peptide or the renin-angiotensin system may be involved in the signalling of GLP-1-mediated renal actions. Several studies in rodents have shown that GLP-1 therapy is renoprotective beyond metabolic improvements in models of diabetic nephropathy and acute kidney injury. Inhibition of renal inflammation and oxidative stress probably mediate this protection. Clinical studies supporting GLP-1-mediated renal protection exist, but they are few and with limitations. However, acute and chronic kidney diseases are major global health concerns and measures improving renal outcome are highly needed. Therefore, the renoprotective potential of GLP-1 therapy need to be thoroughly investigated in humans. PMID- 24791978 TI - Survey of shotgun proteomics. AB - Proteins provide the verbs to biology, and proteomics provides the nouns for their analytical and discovery-driven studies. The term proteomics was coined in the 1990s and deals with the protein complement of the genome-the proteome. Following the classical proteomics era, the development of new mass spectrometric methods for peptide analysis permitted the identification of proteins in peptide mixtures obtained by proteolytic digestion of complex samples, e.g., shotgun proteomics. Since its introduction, shotgun proteomics became the standard technique for the analysis of protein hydrolyzates in a high-throughput way. In this chapter, we provide a survey in shotgun proteomics highlighting instruments and techniques used in modern second and third proteomics generation. PMID- 24791979 TI - LC-MALDI-TOF/TOF for shotgun proteomics. AB - Automated liquid chromatography tandem mass spectrometry (LC-MS/MS) is a well established technique for identification of components from complex mixtures in shotgun proteomics experiments. Approaches involving the use of matrix-assisted laser desorption/ionization mass spectrometry (LC-MALDI-MS/MS) comprise the preparation of protein extracts, their enzymatic digestion, the separation of the resulting peptides by nanoscale liquid chromatography coupled to a collector that deposits the microfractions onto a MALDI plate, and finally the mass spectrometry analysis of the fractions. Using an LC-MALDI strategy, the rate of the collection of MS/MS data is decoupled from the chromatographic separation, thus allowing high-quality data which are often complementary to electrospray ionization (LC ESI-MS/MS) techniques. PMID- 24791980 TI - Fully automatable multidimensional reversed-phase liquid chromatography with online tandem mass spectrometry. AB - Liquid chromatography (LC) is essential for sample fractionation in shotgun proteomics applications. With suitable design, common LC separation chemistries, including reversed-phase (RP) and strong cation exchange (SCX) mode, can be combined in online multidimensional LC to greatly enhance the overall separation power and, thus, proteome coverage. This protocol describes the design and assembly of a flexible online multidimensional RP-SCX-RP LC system that is compatible with deep proteome profiling on common shotgun proteomics platforms. PMID- 24791981 TI - GeLC-MS/MS analysis of complex protein mixtures. AB - Discovery-based proteomics has found its place in nearly every facet of biological research. A key objective of this approach is to maximize sequence coverage for proteins across a wide concentration range. Fractionating samples at the protein level is one of the most common ways to circumvent challenges due to sample complexity and improve proteome coverage. Of the available methods, one dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by liquid chromatography-tandem mass spectrometry (GeLC-MS/MS) is a robust and reproducible method for qualitative and quantitative proteomic analysis. Here we describe a general GeLC-MS/MS protocol and include technical advice and outline caveats to increase the probability of a successful analysis. PMID- 24791982 TI - IPG strip-based peptide fractionation for shotgun proteomics. AB - Efficient fractionation of peptides is an essential prerequisite for comprehensive analysis of complex protein mixtures by shotgun mass spectrometry. The separation of peptides by isoelectric focusing is particularly attractive due to its orthogonality to reverse-phase HPLC. Here, we present a protocol for in gel peptide isoelectric focusing using immobilized pH gradient strips. The method shows high resolving power for up to 1 mg of sample and is highly reproducible. PMID- 24791983 TI - SILAC yeast: from labeling to comprehensive proteome quantification. AB - Mass spectrometry-based quantitative proteomics can identify and quantify thousands of proteins in complex mixtures, enabling characterization and comparison of cellular functional states in a proteome-wide scale. In this context, stable isotope labeling with amino acids in cell culture (SILAC) has emerged as a simple yet powerful approach, which has been applied to address different biological questions across a variety of systems, ranging from single cells to entire multicellular organisms. In this chapter, detailed instructions for SILAC labeling yeast are provided, including a series of quality checks for evaluating labeling efficiency and procedures for determining the optimal labeling parameters for a particular yeast strain. In addition, two different complete workflows for the comprehensive mass spectrometry-based SILAC quantification of close to the entire yeast proteome are described, which can be applied to assess any biological question of interest and, therefore, can be of broad use for the researchers in the field. PMID- 24791984 TI - Analysis of proteome dynamics in mice by isotopic labeling. AB - Recent advances in mass spectrometry and in vivo isotopic labeling have enabled proteome-wide analyses of protein turnover in complex organisms. Here, we describe a protocol for analyzing protein turnover rates in mouse tissues by comprehensive (15)N labeling. The procedure involves the complete isotopic labeling of blue green algae (Spirulina platensis) with (15)N and utilizing it as a source of dietary nitrogen for mice. We outline a detailed protocol for in house production of (15)N-labeled algae, labeling of mice, and analysis of isotope incorporation kinetics by mass spectrometry. The methodology can be adapted to analyze proteome dynamics in most murine tissues and may be particularly useful in the analysis of proteostatic disruptions in mouse models of disease. PMID- 24791985 TI - Stable isotope labeling in mammals (SILAM). AB - Analysis of animal models of disease is essential to the understanding of human disease and the identification of potential targets for clinical drugs. Global analysis of proteins by mass spectrometry is an important tool for these studies. Stable isotope labeling in mammals (SILAM) was developed to quantitate the proteomes of rodents using mass spectrometry. The crux of SILAM analysis is the complete labeling of all proteins in a rodent with heavy nitrogen ((15)N). These (15)N tissues are then employed as an internal standard for quantitative proteomics analysis using a high-resolution and mass-accuracy mass spectrometer. PMID- 24791986 TI - Analysis of individual protein turnover in live animals on a proteome-wide scale. AB - Classical quantitative proteomics studies focus on the relative or absolute concentration of proteins at a given time. In contrast, the investigation of protein turnover reveals the dynamics leading to these states. Analyzing the balance between synthesis and degradation of individual proteins provides insights into the regulation of protein concentration and helps understanding underlying biological processes. Comparing the half-lives of proteins allows detecting functional relationships and common regulation mechanisms. Moreover, comparing turnover of individual brain and plasma proteins between control- and treatment-groups indicates turnover changes induced by the treatment.Here, we describe a procedure for determining turnover information of individual proteins in mice on a proteome-wide scale based on partial (15)N metabolic labeling. We will outline the complete experimental workflow starting from (15)N labeling the animals over sample preparation and mass spectrometric measurement up to the analysis of the data. PMID- 24791987 TI - Determining protein subcellular localization in mammalian cell culture with biochemical fractionation and iTRAQ 8-plex quantification. AB - Protein subcellular localization is a fundamental feature of posttranslational functional regulation. Traditional microscopy based approaches to study protein localization are typically of limited throughput, and dependent on the availability of antibodies with high specificity and sensitivity, or fluorescent fusion proteins. In this chapter we describe how Localization of Organelle Proteins by Isotope Tagging (LOPIT), a mass spectrometry based workflow coupling biochemical fractionation and iTRAQTM 8-plex quantification, can be applied for the high-throughput characterization of protein localization in a mammalian cell culture line. PMID- 24791988 TI - Brain quantitative proteomics combining GeLC-MS and isotope-coded protein labeling (ICPL). AB - Proteomics has been revolutionized by the rapid advance of mass spectrometric instrumentations and techniques. Parallel methodologies for the quantification of proteomes also evolved, including in vitro stable isotope labeling. Here, we present a protocol for employing isotope-coded protein labeling (ICPL) as part of a shotgun proteomics workflow denoting its advantages and disadvantages. This protocol is suitable to studying any proteome of interest, only requiring a specific sample preparation and protein identification. Given our expertise, descriptions here are centered on the study of brain disorders. PMID- 24791989 TI - Employing TMT quantification in a shotgun-MS platform. AB - The blood serum proteome may be an ideal source of disease biomarkers, although its complexity necessitates novel strategies to enrich and quantify lower abundance proteins with biomarker utility. Herein, serum samples from pre diagnosis pancreatic cancer cases and controls were compared using a workflow of immunodepletion, multi-lectin fractionation, and peptide tandem mass tag (TMT) labeling. Samples were then subjected to SCX and high pH reversed-phase fractionation and analyzed by liquid chromatography tandem mass spectrometry (LC MS/MS). The aim was the discovery of candidate serum biomarkers of pancreatic cancer, although the method is applicable to any comparative proteomic analysis of serum samples. PMID- 24791990 TI - Employing TMT quantification in shotgun-MS proteomic analysis: a focus on skeletal muscle. AB - Quantify proteins present in a sample is the ultimate goal of a proteomic experiment. Although it might reveal countless physiological and /or pathological process on a studied model, it is still a daunting task to perform. Of the protein present in a sample, only a small number can be identified and even a lesser number quantified, each with its own weaknesses and strengths. Presented here are the "tandem mass tags" isobaric labels (TMT) and a protocol for its utilization in the quantification of skeletal muscle, which might be adapted also to other animal tissues. PMID- 24791991 TI - Spectral counting label-free proteomics. AB - Label-free proteome quantification methods used in bottom-up mass-spectrometry based proteomics are gaining more popularity as they are easy to apply and can be integrated into different workflows without any extra effort or cost. In the label-free proteome quantification approach, samples of interest are prepared and analyzed separately. Mass-spectrometry is generally not recognized as a quantitative method as the ionization efficiency of peptides is dependent on composition of peptides. Label-free quantification methods have to overcome this limitation by additional computational calculations. There are several algorithms available that take into account the sequence and length of the peptides and compute the predicted abundance of proteins in the sample. Label-free methods can be divided into two categories: peptide peak intensity based quantification and spectral counting quantification that relies on the number of peptides identified from a given protein.This protocol will concentrate on spectral counting quantification-exponentially modified protein abundance index (emPAI). Normalized emPAI, most commonly derived from Mascot search results, can be used for broad comparison of entire proteomes. Absolute quantification of proteins based on emPAI values with or without added standards will be demonstrated. Guidelines will be given on how to easily integrate emPAI into existing data; for example, calculating emPAI based absolute protein abundances from iTRAQ data without added standards. PMID- 24791992 TI - Quantification of proteins by label-free LC-MS(E.). AB - Quantitative proteomics by LC-MS/MS is a widely used approach for quantifying a significant portion of any complex proteome. Among the different techniques used for this purpose, one is by use of Data Independent Acquisition (DIA). We present a descriptive protocol for label-free quantitation of proteins by one DIA method termed LC-MS(E), which facilitates large-scale quantification of proteins without the need for isotopic labelling and with no theoretical limit to the number of samples included in an experiment. PMID- 24791993 TI - Bioinformatics for proteomics: opportunities at the interface between the scientists, their experiments, and the community. AB - Within the last decade, bioinformatics has moved from command line scripts dedicated to single experiments towards production grade software integrated in experimental workflows providing a rich environment for biological investigation. Located at the interface between the scientists, their experiments, and the community, bioinformatics acts as a gateway to a wide source of information. This chapter does not list tools and methods, but rather hints at how bioinformatics can help in improving biological projects, all the way from their initial design to the dissemination of the results. PMID- 24791994 TI - Identification of DNA damage checkpoint-dependent protein interactions in Saccharomyces cerevisiae using quantitative mass spectrometry. AB - The DNA damage checkpoint (DDC) is an evolutionarily conserved signaling pathway that is crucial to maintain genomic integrity. In response to DNA damage, DDC kinases are rapidly activated and phosphorylate an elaborate network of substrates involved in multiple cellular processes. An important role of the DDC response is to assemble protein complexes. However, for most of the DDC substrates, how the DDC-dependent phosphorylation modulates their network of interactions remains to be established. Here, we present a protocol for the identification of DDC-dependent protein-protein interactions based on Stable Isotope Labeling of Amino acids in Cell culture (SILAC) followed by affinity tagged protein purification and quantitative mass spectrometry analysis. Based on a model study using Saccharomyces cerevisiae, we provide a method that can be generally applied to study the role of kinases in mediating protein-protein interactions. PMID- 24791995 TI - Application of shotgun proteomics for discovery-driven protein-protein interaction. AB - Affinity purification of protein complexes and identification of co-purified proteins by mass spectrometry is a powerful method to discover novel protein protein interactions. Application of this method to the study of biological systems often requires the ability to process a large number of samples. Hence, there is great need to generate proteomic workflows compatible with large-scale studies. The major goal of this protocol is to present a fast, reliable, and scalable method to characterize protein complexes by mass spectrometry to overcome the limitations of conventional geLC-MS/MS or MudPIT protocols. This method was successfully employed for the discovery and characterization of novel protein complexes in cultured yeast, mammalian cells, and mice. PMID- 24791996 TI - Mapping protein complexes using covalently linked antibodies and isobaric mass tags. AB - Affinity enrichment techniques in combination with quantitative proteomics enable the unbiased identification of protein-protein interaction, and thus the delineation of protein complexes and interaction networks. Here, we describe an immunoaffinity enrichment approach that employs covalently immobilized antibodies for the identification of protein-protein interactions of endogenously expressed proteins under near-to-physiological conditions. Specifically enriched proteins are identified using shotgun mass spectrometry and isobaric mass tag-based relative quantification. PMID- 24791997 TI - Biomarker verification using selected reaction monitoring and shotgun proteomics. AB - Shotgun proteomics (liquid chromatography-electrospray ionization-mass spectrometry, LC-ESI-MS/MS) has dominated the strategies for global protein expression in subcells, cells, tissues, and whole organisms with several types of approaches, as isobaric tags for relative and absolute quantification (iTRAQ), isotope-coded affinity tags (ICAT), or stable isotope labeling using amino acids in cell culture (SILAC) and non-labeling (label free) methods. Shotgun proteomics practically replaced the classical 2D gel electrophoresis. Selected reaction monitoring (SRM), also denominated multiple reaction monitoring (MRM), is a targeted quantitative technology that uses a complex mixture of tryptic peptides that can be selectively detected by liquid chromatography coupled to electrospray triple-quadrupole mass spectrometer; this system can select precursor ions in combination with their correspondent product ions during collision-induced dissociation to produce specific detection related to a particular protein. Here we describe protocols that are efficient to produce a complete enzymatic trypsin digestion from complex biological matrices and concomitant material to be used for LC-SRM-MS and LC-ESI-MS/MS (labeled or label free). PMID- 24791998 TI - Use of universal stable isotope labeling by amino acids in cell culture (SILAC) based selected reaction monitoring (SRM) approach for verification of breast cancer-related protein markers. AB - Mass spectrometry-based proteomics facilitates high-throughput discovery of protein markers for diagnosis and treatment of breast cancer patients. Hundreds of putative prognostic and predictive markers are being identified every year, but only a very small proportion of them can be validated as clinically relevant markers. A quantitative and cost-efficient verification method is highly desirable to pick up real "nuggets" from the "sand." To fulfill these criteria, we previously introduced a stable isotope labeling by amino acids in cell culture (SILAC)-based selected reaction monitoring (SRM) approach for studying breast cancer-related protein markers. Here we describe a hands-on protocol of using this SILAC-SRM method for verification of breast cancer-related markers, which can also be used for verification of protein markers in other types of solid tumor tissues. PMID- 24791999 TI - The secretome analysis by high-throughput proteomics and multiple reaction monitoring (MRM). AB - The secretome is a sub-proteome of great interest in several fields of biomedical sciences, especially as a source of diagnostics and therapeutic targets. Proteomics has been contributing significantly to elucidate the secretome of a great diversity of cells, tissues, and organisms, turning profiles of thousands of proteins a usual practice. After elucidation of long protein lists, targeted proteomics also plays important roles in accurate quantification and validation of such secreted proteins. Here we present detailed protocols to explore and quantify the secretome of cancer cells, even though this protocol can be employed to any kind of biological material. PMID- 24792000 TI - Preparation of heteroelement-incorporated and stable isotope-labeled protein standards for quantitative proteomics. AB - A major obstacle for further development of quantitative proteomics is the lack of accurately quantified protein standards. The following protocol describes innovative methods for the production of stable isotope-labeled protein standards. Their production is achieved by cell-free protein synthesis, which enables simultaneous incorporation of selenomethionine and stable isotope-labeled amino acids. The selenium tag allows sensitive and accurate quantification by inductively coupled plasma mass spectrometry (ICP-MS). The stable isotope label allows internal standardization in mass spectrometry-based proteomics by electrospray ionization-tandem mass spectrometry (ESI-MS/MS). Both label types can be placed within a single protein RISQ standard (recombinant isotope-labeled and selenium quantified) or can be distributed over two types of related RSQ and RIQ standards for the same target protein (recombinant selenium quantified and recombinant isotope-labeled and quantified). The combination of cell-free synthesis as production method with ICP-MS and ESI-MS/MS as detection methods results in protein standards, which are quantified at an outstanding level of accuracy. PMID- 24792001 TI - One-source peptide/phosphopeptide ratio standards for accurate and site-specific determination of the degree of phosphorylation. AB - Reversible protein phosphorylation is a key mediator for intracellular signal transduction. Here we describe an innovative method for the production of pairs of peptide standards designed for quantitative mass spectrometry. These standard pairs can be used for site-specific analysis of the degree of phosphorylation of proteins in a bottom-up approach. The method starts from an isotopically labeled phosphopeptide analogue of the analyte phosphopeptide and ends up with a labeled peptide/phosphopeptide ratio standard in which the molar ratio between the phosphorylated and the unphosphorylated form is exactly defined. The signals of the ratio standard are used to standardize the corresponding analyte signals. This compensates for differences in LC recovery or ionization efficiency between the phosphorylated and unphosphorylated forms. The method can also be extended to quantitative analysis of multisite phosphorylation in a single peptide, which is exemplified for the presence of two phosphorylation sites. Peptide/phosphopeptide ratio standards exhibit high ratio accuracy, since ratio adjustment is performed by volumetric operations only. PMID- 24792002 TI - Quantitative glycoproteomics for N-glycoproteome profiling. AB - Glycoproteomics, the global analysis of glycoproteins, is a subfield of proteomics with high biological and clinical relevance. Glycoproteomics integrates knowledge and techniques drawing from glycotechnology, separation science, mass spectrometry, and bioinformatics to support systematic identification and quantification of glycoproteins in a complex biological sample. In this chapter, we describe a shotgun proteomics-based glycoproteomics platform that provides precise mapping of protein N-glycosylation sites and quantitative assessment of glycosylation site occupancy on a global scale. PMID- 24792003 TI - A practical recipe to survey phosphoproteomes. AB - The field of cellular signaling is fueled by the discovery of novel protein phosphorylation events. Phosphoproteomics focuses on the large-scale identification and characterization of serine, threonine, and tyrosine phosphorylation of proteins. Phosphopeptide enrichment followed by mass spectrometry has emerged as the most powerful technique for unbiased, discovery driven analysis by offering high sensitivity, resolution, and speed. Methods for mass spectrometry-based phosphoproteomics analysis have improved substantially over the last decade, making the discipline more approachable to the broader scientific community. Herein we describe the status of the field of phosphoproteomics and provide a robust workflow covering the major aspects of large-scale phosphorylation analysis from phosphopeptide enrichment via IMAC to data analysis. PMID- 24792004 TI - Quantitation of the phosphoproteome using the library-assisted extracted ion chromatogram (LAXIC) strategy. AB - Phosphorylation is a key posttranslational modification that regulates many signaling pathways, but quantifying changes in phosphorylation between samples can be challenging due to its low stoichiometry within cells. We have introduced a mass spectrometry-based label-free quantitation strategy termed LAXIC for the analysis of the phosphoproteome. This method uses a spiked-in synthetic peptide library designed to elute across the entire chromatogram for local normalization of phosphopeptides within complex samples. Normalization of phosphopeptides by library peptides that co-elute within a small time frame accounts for fluctuating ion suppression effects, allowing more accurate quantitation even when LC-MS performance varies. Here we explain the premise of LAXIC, the design of a suitable peptide library, and how the LAXIC algorithm can be implemented with software developed in-house. PMID- 24792005 TI - Fast, efficient, and quality-controlled phosphopeptide enrichment from minute sample amounts using titanium dioxide. AB - Bottom-up mass spectrometry (MS) is still the method of choice for analyzing protein phosphorylation. However, the low stoichiometry of phosphorylation, especially in highly complex samples, renders the specific enrichment of phosphopeptides prior to analysis inevitable. In recent years, specific phosphopeptide enrichment strategies combined with high-performance liquid chromatography (HPLC)-MS (LC-MS) provided researchers deeper insights into the phosphorylation networks of biological systems.Here, we describe two protocols for the enrichment of phosphopeptides from biological samples using titanium dioxide (TiO2) resins, enabling the handling of small sample amounts (<20 MUg of protein) as well as larger sample amounts (up to the milligram range), depending on the scientific issue to be solved.Furthermore, we imply quality control steps during sample preparation to ensure the reproducibility and reliability of the phosphoproteomic findings. PMID- 24792006 TI - Quantifying small molecule-induced changes in cellular protein expression and posttranslational modifications using isobaric mass tags. AB - Proteomics enables the comprehensive analysis of cellular perturbations induced by bioactive small molecules and contributes to our understanding of the mechanisms by which drugs elicit their activity in disease situations. Here we describe a quantitative proteomics approach to study dose-dependent changes in protein expression and posttranslational protein modifications in human promyelocytic leukemia cells in response to inhibition of histone deacetylases by Vorinostat. The method employs isobaric mass tags (tandem mass tags, TMT) to enable the multiplexed quantitative analysis of up to six samples and antibodies directed against acetylated lysine residues for immunoenrichment of TMT-encoded acetylated peptides. PMID- 24792007 TI - Analysis of protein structure by cross-linking combined with mass spectrometry. AB - Cross-linking combined with mass spectrometry is a powerful technique to study protein structure. Here, we present an optimized protocol for the preparation, processing, and analysis of a protein sample cross-linked with isotopically coded, affinity-enrichable, and CID-cleavable cross-linker CyanurBiotinDimercaptoPropionylSuccinimide using LC/ESI-MS/MS on a Thermo Scientific Orbitrap mass spectrometer. PMID- 24792008 TI - Top-down proteomics by means of Orbitrap mass spectrometry. AB - Top-down proteomics has become a popular approach for the analysis of intact proteins. The term "top down" has been coined for the analysis of proteins not involving any enzymatic or chemical cleavage but rather the ionization of the protein as a sound molecule and mass analysis of intact species and fragment ions thereof produced upon dissociation inside a mass spectrometer. One or several charge states of the protein are mass-isolated and subjected to dissociation (MS/MS) in the gas phase. The obtained fragment masses, predominantly from cleavages of the protein along its amino acid backbone, are directly related to the intact protein. Using bioinformatics tools the fragment masses are matched against a known protein sequence or can alternatively be used for partial or full de novo sequencing, depending on the size of the protein and the number of fragment ions obtained. Moreover, this approach provides global information about modification states of proteins including the number and types of isoforms and their stoichiometry and allows for the precise localization of modifications within the amino acid sequence. Top-down analysis of a single, purified protein can be performed by matrix-assisted laser desorption ionization or electrospray ionization upon direct infusion without online chromatographic separation, whereas top-down analysis of complex protein mixtures makes pre-fractionation combined with an efficient front-end chromatographic separation coupled online to the mass spectrometer inevitable. PMID- 24792009 TI - Is laparoscopic total gastrectomy a safe operation? A review of various anastomotic techniques and their outcomes. AB - Laparoscopic distal gastrectomy is an accepted option for gastric cancer surgery; however, laparoscopic total gastrectomy (LTG) is not widely performed. There is concern about the safety of the operation due to the difficulty of extracorporeal reconstruction through a mini-laparotomy. Efforts have been made to establish an intracorporeal anastomotic technique for esophagojejunostomy. This article reviews the current techniques available for laparoscopic esophagojejunostomy and their surgical outcomes. Several different techniques using either circular or linear staplers have been reported; however, the apparent superiority of any particular method has not been confirmed. The incidence of anastomosis-related complications varied among studies, but different techniques all successfully achieved excellent outcomes. The overall complication rate of LTG was similar to that of open total gastrectomy, suggesting that LTG is a safe and feasible option. However, the feasibility of LTG with D2 lymph node dissection for advanced upper gastric cancer needs to be confirmed in further studies, because most of the patients included in the LTG studies were diagnosed with early stages of disease. PMID- 24792010 TI - Clinical feasibility of laparoscopic lateral pelvic lymph node dissection following total mesorectal excision for advanced rectal cancer. AB - PURPOSE: To evaluate the technical feasibility, safety and oncological outcomes of laparoscopic lateral pelvic lymph node dissection in patients with advanced low rectal cancer. METHODS: Laparoscopic lateral pelvic lymph node dissection was performed in 18 patients from November 2009 to September 2012. The data regarding the patient demographics, surgical outcomes and short-term oncological outcomes were analyzed. RESULTS: In all 18 patients, the procedures were completed without conversion to open surgery. The mean length of the operation was 603.7 min (473 746 min). The mean number of harvested lateral pelvic lymph nodes was 16.9 (7 27), and five patients (27.8 %) had lymph node metastases. The postoperative mortality and morbidity rates were 0 and 16.7 %, respectively. Three patients developed Grade 2 urinary retention. No local recurrence had developed after a mean follow-up period of 23.6 months. CONCLUSION: Laparoscopic lateral pelvic lymph node dissection is technically feasible, safe and oncologically acceptable within the limitations of the short-term follow-up period. PMID- 24792011 TI - Prospective randomized evaluation of open preperitoneal versus preaponeurotic primary elective mesh repair for paraumbilical hernias. AB - PURPOSE: The aim of this study was to compare the preperitoneal versus the preaponeurotic mesh positioning in open paraumbilical hernia repair. METHODS: During the period from January 2011 until July 2012, 60 adult patients were randomly assigned to two equal groups. The patients in group A were treated by preperitoneal mesh repair and those in group B underwent preaponeurotic mesh repair. Both groups were assessed and compared. RESULTS: There were no significant differences between the two groups in the demographics, hernia characteristics, risk factors, type of anesthesia, American Society of Anesthesiologists score or the mean follow-up period. The length of the operation was significantly shorter in group B than in group A (P value = 0.01). There were no significant differences in the early postoperative complications except for the development of a seroma, which developed only in group B (P value = 0. 044). The postoperative pain was significantly lower in group A than in group B (P value = 0.01). The time of return to normal daily activities was significantly shorter in group A than in group B (P value = 0.001). CONCLUSION: The preperitoneal mesh placement during the repair of paraumbilical hernias is superior to the preaponeurotic placement, because it is associated with fewer complications, less pain and a shorter time of return to normal daily activities. PMID- 24792012 TI - High nasal resistance may be a result rather than a cause of obstructive sleep apnea. AB - Patients with obstructive sleep apnea (OSA) show high nasal resistance (NR). The present study tested the hypothesis that nasal obstruction in OSA patients could be caused by pharyngeal narrow. The aim of this study was to investigate the effect of uvulopalatopharyngoplasty (UPPP) on NR in patients with OSA. Rhinomanometry was performed and the Mallampati score was recorded during wakefulness in a sitting position before and after UPPP for 33 patients with OSA. Thirty-three healthy volunteers were used as a control group. The NR in patients with OSA (0.37 +/- 0.22 Pa/cm(3)/s) was significantly higher than that of the normal controls (0.19 +/- 0.04 Pa/cm(3)/s) (p < 0.01). The NR decreased from 0.37 +/- 0.22 to 0.20 +/- 0.05 Pa/cm(3)/s (p < 0.01) after UPPP with the Mallampati score decreased from 3.00 +/- 0.56 to 1.52 +/- 0.57 (p < 0.01). However, NR values after UPPP were still higher than those of the control group, but there was no significant difference between those two groups (p = 0.34). The present study showed that the high NR may not be completely attributable to nasal anatomic obstruction, but may result from pharyngeal narrow in OSA. High NR may be a result of OSA rather than a cause. PMID- 24792013 TI - The nasal function during sports. PMID- 24792014 TI - Characterisation of seven newly established head and neck squamous cell carcinoma cell lines. AB - Seven squamous cell carcinoma cell lines were disintegrated from biopsies of patients with head and neck cancer. Genotyping tests verified the authenticity and the human origin of all seven lines. The cell lines designated as University of Kiel, Head and Neck (UKHN) -1 to -3 and UKHN-6 to -9 were subjected to flow cytometry and indirect immunofluorescence to assess aberrant DNA content. To confirm the squamous epithelial origin of the cells, the cytokeratin profile was immunocytologically analysed. The cell lines showed individual differences in mitotic frequency. UKHN-1, -6, -7 and -9 grew as monolayers, whereas UKHN-2, -3, and -8 tend to multilayer stratification. Overexpression of LOXL4 and Pim-1 proteins as distinctive features of head and neck carcinomas were shown in all seven cell lines. Inoculating SCID mice with these cell lines resulted in tumour formation, hence corroborating the tumourigenicity of all seven cell lines. The cell lines were also tested for high-risk HPV types using different DNA-based assays and found to be negative. PMID- 24792015 TI - Hyperacute stroke care and NHS England's business plan. PMID- 24792016 TI - Optimal therapy for adult patients with acute myeloid leukemia in first complete remission. AB - Although it is absolutely clear that postremission therapy is currently necessary to obtain disease-free long-term survivorship for patients with acute myeloid leukemia (AML) in first complete remission (CR), it is not entirely clear what form that treatment should take. High-dose cytarabine is clearly effective and there definitely is a dose-response relationship for cytarabine and remission duration. High-dose cytarabine is effective for younger patients but not elderly patients. It is effective for patients with favorable cytogenetics but it is not clear whether it is effective for patients with intermediate or unfavorable cytogenetics. Furthermore, it is not clear what the most effective and least toxic dose and schedule of high-dose cytarabine is. PMID- 24792017 TI - Chinese herbal medicines in the treatment of IBD and colorectal cancer: a review. AB - OPINION STATEMENT: Inflammatory bowel diseases (IBD) are a group of chronic inflammatory gastrointestinal (GI) disorders, mainly represented by Crohn's disease and ulcerative colitis. Although the etiology of IBD is not fully understood, there is substantial evidence that immunologic, genetic, and environmental factors are the main contributors in IBD pathogenesis. Conventional therapies for IBD include anti-inflammatory and immunosuppressive drugs, such as 5-aminosalicylic acid, corticosteroids, antibiotics, and biologicals, such as anti-TNFalpha antibodies. However, because of low efficacy and high risk of side effects, there is a clear need for the development of novel and efficient pharmacologic strategies in IBD treatment. Among various complementary and alternative medicine (CAM) approaches, which are used for the treatment of gastrointestinal (GI) disorders, traditional Chinese medicine (TCM) is one of the most developed and diversified. TCM encompasses methods and therapies that emerged over centuries and is based mostly on ethnic wisdom and observations transmitted from generation to generation. In the recent years, the efficacy of TCM as treatment of IBD has been extensively characterized in preclinical and clinical studies, which resulted in a significant number of research reports. Moreover, the popularity of TCM among patients with IBD has rapidly increased not only in Asia, but also in the Western hemisphere. PMID- 24792018 TI - Giant left paraduodenal hernia. AB - Left paraduodenal hernia (LPDH) is a retrocolic internal hernia of congenital origin that develops through the fossa of Landzert, and extends into the descending mesocolon and left portion of the transverse mesocolon. It carries significant overall risk of mortality, yet delay in diagnosis is not unusual due to subtle and elusive features. Familiarisation with the embryological and anatomical features of this rare hernia is essential for surgical management. This is especially important with respect to vascular anatomy as major mesenteric vessels form intimate relationships with the ventral rim and anterior portion of the hernia. As an illustrative case, we describe our experience with a striking example of LPDH, particularly focusing on the inherent diagnostic challenges and associated critical vascular anatomy. We advocate the role of diagnostic laparoscopy; however caution that decision to safely proceed with laparoscopic repair must occur only with confident identification of the vascular anatomy involved. PMID- 24792020 TI - Delayed subaponeurotic (subgaleal) fluid collection. AB - A 14-week-old boy who is known to have a single right kidney presented to our emergency department with history of fever for 1 day. A sepsis work up was performed (complete blood count, blood culture, urine culture and lumbar puncture) in the emergency room. On the second day of admission he developed swelling in the parieto-occipital area. Head CT showed crescent-shaped extra cranial area of homogeneous low attenuation. He remained asymptomatic with a stable haemoglobin and haematocrit. Swelling subsequently resolved within 5 weeks. PMID- 24792019 TI - A Lilliputian army under the floorboards: persistent delirium with complete though prolonged recovery. AB - We report the case of an 83-year-old man who presented with a history of fluctuating delirium of insidious onset, secondary to an amoebic liver abscess more than 30 years after acute exposure. We describe a 2-year clinical journey that started with a fall and was additionally complicated by severe weight loss and acute kidney injury (AKI). The likely prognosis for such a combination of comorbidities in an older person is for lasting morbidity, institutionalisation and significant mortality. However, the case demonstrates that with timely assessment and care complete recovery is possible though it may take many months. It reminds us of the catalytic implications of falls for older persons and to maintain a differential diagnostic approach to delirium of insidious onset avoiding misdiagnosis as dementia with which it may be associated. Our case report includes extracts from the patient's own account providing added insight into such experiences. PMID- 24792021 TI - "Why do I always see double?" A misdiagnosed case of ocular myasthenia gravis for 10 years. AB - A 58-year-old man presented with diplopia and partial ptosis for 10 years. It was non-progressive in nature, despite inadequate medical attention the patient received from non-specialists/general practitioners. He did not have fatigability or diurnal variation in weakness and was clinically stable without exacerbations of disease for a decade. He did not have features of Graves's disease, oculopharyngeal dystrophy, cranial nerve paralysis, polymyositis and stroke. The possibility of an atypical presentation of myasthenia gravis (MG) was considered and the patient was evaluated. Ice pack test was negative, Cogan's lid twitch (CLT) test was positive and high titres of acetylcholine receptor antibodies (AChR Ab) suggestive of MG were found. He was treated accordingly with a very good response. PMID- 24792022 TI - Giant radicular cyst of the maxilla. AB - Radicular cysts are inflammatory odontogenic cysts of tooth bearing areas of the jaws. Most of these lesions involve the apex of offending tooth and appear as well-defined radiolucencies. Owing to its clinical characteristics similar to other more commonly occurring lesions in the oral cavity, differential diagnosis should include dentigerous cyst, ameloblastoma, odontogenic keratocyst, periapical cementoma and Pindborg tumour. The present case report documents a massive radicular cyst crossing the midline of the palate. Based on clinical, radiographical and histopathological findings, the present case was diagnosed as an infected radicular cyst. The clinical characteristics of this cyst could be considered as an interesting and unusual due to its giant nature. The lesion was surgically enucleated along with the extraction of the associated tooth; preservation of all other teeth and vital structures, without any postoperative complications and satisfactory healing, was achieved. PMID- 24792023 TI - Neutropenic enterocolitis affecting the transverse colon: an unusual complication of chemotherapy. AB - A 66-year-old woman presented with a 1-day history of sudden onset of generalised abdominal pain associated with fever and vomiting. She was previously diagnosed with left breast cancer 2 months ago and completed a course of chemotherapy 1 week prior to presentation. She was clinically unwell with generalised tenderness in her abdomen. Blood investigations showed severe neutropenia. A CT scan was requested which reported a marked oedematous swelling of the transverse colon with features suggestive of a contained perforation. The decision was made to operate. Intraoperatively, the transverse colon was found to be thickened with omentum adherent focally around the distal third. A right hemicolectomy was performed with an end ileostomy and mucus fistula. The patient made a successful recovery and was discharged within 7 days of presenting. Pathology reported typical features of neutropenic enterocolitis affecting the transverse colon with a normal terminal ileum, caecum and ascending colon. PMID- 24792024 TI - A late presentation of isolated lymph node tuberculosis postintravesical BCG therapy for superficial bladder cancer: a novel case. AB - Intravesical BCG immunotherapy is commonly used in the treatment of superficial bladder cancer. We recount the case of an 82-year-old British man who completed a course of BCG immunotherapy in 2011 for superficial bladder cancer, and presented in January 2013 with a loss of appetite, loss of weight and severe back pain. CT scanning, followed by MRI displayed a 5.7 cm * 5 cm conglomerated necrotic, haemorrhagic mass of lymph nodes in the para-aortic region. A CT-guided biopsy revealed granulomatous inflammation, focal fibrosis and acid-fast bacilli consistent with Mycobacterium tuberculosis (TB). The patient was treated with combination antituberculous medication, and is recovering. To our knowledge, this is the only reported case of lymph node TB secondary to intravesical BCG immunotherapy. We suggest that in patients treated with postintravesical BCG with enlarged lymph nodes, a diagnosis of secondary TB should be considered. PMID- 24792025 TI - Unilateral striatal CT and MRI changes secondary to non-ketotic hyperglycaemia. AB - A 62-year-old man presented with a right-sided hemichorea-hemiballismus secondary to underlying non-ketotic hyperglycaemia. This condition is recognised to have a unique finding of unilateral basal ganglia lesion, which is hyperdense on CT and hyperintense on T1-weighted MRI. The clinical course of this condition is benign and has a good prognosis with early correction of the hyperglycaemia. PMID- 24792026 TI - Pulmonary oedema in the emergency room: what is hidden beyond an apparently common presentation. AB - Cardiogenic flash pulmonary oedema is a common and potentially fatal cause of acute respiratory distress. Although it often results from acute decompensated heart failure, abrupt-onset aortic regurgitation can sharply rise cardiac filling pressure and, consequently, pulmonary venous pressure, leading to rapid fluid accumulation in the interstitial and alveolar spaces. We report a case of a 64 year-old woman admitted to the emergency department with a flash pulmonary oedema; a careful clinical investigation subsequently revealed a rare aetiology for this 'common' presentation. After a detailed auscultation that unmasked a diastolic cardiac murmur, an acute severe aortic insufficiency was further confirmed by echocardiography, showing inflammation and thickening of the entire aorta wall. The patient was submitted to valve replacement surgery, and histological examination, to our surprise, showed features of aortitis, remarkable for the presence of giant cells. A diagnosis of idiopathic aortitis versus inaugural giant cell arteritis was proposed and treatment started with corticosteroids. PMID- 24792027 TI - An unusual cause of biliary colic. PMID- 24792028 TI - Missed acute appendicitis presenting as necrotising fasciitis of the thigh. AB - Necrotising fasciitis is a rapidly progressive soft tissue infection that leads to diffuse tissue necrosis. It is associated with systemic toxicity and rapid deterioration resulting in high mortality. Rapid diagnosis and prompt treatment are essential to improve the outcome. We report the case of a 26-year-old woman who presented with severe thigh pain and swelling associated with irritability of a few hours' duration following 2 days history of right abdominal pain. Urgent MRI and CT scan showed features of necrotising fasciitis in the thigh spreading from an inflamed appendix. Emergency surgery was performed which revealed perforated appendix with disseminated infection in the intraperitoneal and retroperitoneal spaces as well as the right thigh. The patient rapidly deteriorated with evidence of sepsis, shock and renal impairment. In spite of surgery and all supportive measures, she succumbed shortly postoperatively. Blood culture revealed Staphylococcus aureus and Streptococci, while tissue culture showed growth of Escherichia coli and proteus. PMID- 24792029 TI - Resolution without treatment of granulomatous pneumonitis due to intravesical BCG for bladder cancer. AB - Granulomatous pneumonitis is a well-recognised complication of intravesical BCG therapy. The mechanism is sometimes thought to be 'hypersensitivity' rather than infection as in most cases mycobacteria are not cultured. Despite this it is usually treated with antituberculous chemotherapy with or without corticosteroid. We describe a case of bladder cancer treated with intravesical BCG followed by a febrile illness and malaise lasting for months and the development of miliary pulmonary shadowing, which markedly improved in around 1 year without any treatment. The clinical syndrome was less severe than some others described but this case provides evidence that, at least in some cases, no specific treatment may be necessary. PMID- 24792030 TI - A single injection of intravitreal ranibizumab in the treatment of choroidal neovascularisation secondary to optic nerve head drusen in a child. AB - Optic nerve head drusen are acellular, calcified deposits which may be found in buried or exposed drusen form. Choroidal neovascularisation secondary to optic nerve head drusen is rarely seen in childhood. This case report summarises the clinical and therapeutic outcomes of a 13-year-old girl with unilateral choroidal neovascularisation secondary to optic nerve head drusen. The patient was successfully treated with a single intravitreal ranibizumab injection. After a month from the injection the visual acuity increased dramatically and maintained at the same level during 9 months of follow-up time. There was no complication related to the injection. PMID- 24792031 TI - Leg pain following Staphylococcus aureus bacteraemia. PMID- 24792032 TI - Stubborn stones: breakages of a mechanical lithotripter by an exceptionally hard gallstone. PMID- 24792033 TI - Young alcoholic patient with acute vision loss: pancreatitis-related or a marker of underlying autoimmune disease. PMID- 24792034 TI - OsLOX2, a rice type I lipoxygenase, confers opposite effects on seed germination and longevity. AB - Rice production and seed storage are confronted with grain deterioration and loss of seed viability. Some members of the lipoxygenase (LOX) family function in degradation of storage lipids during the seed germination, but little is known about their influence on seed longevity during storage. We characterized the role of rice OsLOX2 gene in seed germination and longevity via over-expression and knock-down approaches. Abundant expression of OsLOX2 was detected in panicles, roots, and stems, but not in leaves. Moreover, OsLOX2 was highly induced during germination. OsLOX2 protein, located in the cytoplasm, showed a wide range of temperature adaptation (20-50 degrees C) and a substrate preference to linoleic acid. Lines over-expressing OsLOX2 showed accelerated seed germination under normal condition and lower seed viability after accelerated aging. RNA interference (RNAi) of OsLOX2 caused delayed germination and enhanced seed longevity. RNAi lines with strongly repressed OsLOX2 activity completely lost the capability of germination after accelerated aging. More lipid hydroperoxide were found in OE15 than the control, but less in RNAi lines than in the WT Nipponbare. Therefore, OsLOX2 acts in opposite directions during seed germination and longevity during storage. Appropriate repression of the OsLOX2 gene may delay the aging process during the storage without compromising germination under normal conditions. PMID- 24792037 TI - Human T-cell leukemia virus type 1 and Foxp3 expression: viral strategy in vivo. AB - Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of adult T-cell leukemia (ATL) and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis, uveitis and infective dermatitis. However, it remains to be elucidated how HTLV-1 induces both neoplastic and inflammatory diseases. A critical component in the Treg-cell machinery is the transcription factor Forkhead box P3 (Foxp3), which is expressed in ~5% of CD4(+) T cells of healthy individuals. Foxp3 is expressed in around 80% of ATL cases. Recent studies point to the capacity of Treg cells to convert to other cell types, even to those with an inflammatory phenotype. These characteristics might indicate that Treg cells might be playing a critical role in HTLV-1 infection, either by being targeted by the virus or by regulating and modulating the immune response. In this review, we will discuss the interplay between Foxp3 expression and HTLV-1, focusing on important viral proteins that might help the virus to trigger the development of such diverse pathologies. PMID- 24792036 TI - Down-regulation of Gli-1 inhibits hepatocellular carcinoma cell migration and invasion. AB - Glioma-associated oncogene homolog-1 (Gli-1) is considered a marker of Hedgehog pathway activation and is associated with the progression of several cancers. We have previously reported that Gli-1 was correlated with invasion and metastasis in hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of Gli 1 in HCC invasion are unclear. In this study, we found that small interfering RNA mediated down-regulation of Gli-1 expression significantly suppressed adhesion, motility, migration, and invasion of both SMMC-7721 and SK-Hep1 cells. Furthermore, down-regulation of Gli-1 significantly reduced expressions and activities of both matrix metalloproteinase (MMP)-2 and MMP-9. In addition, we found that down-regulation of Gli-1 resulted in up-regulation of E-cadherin and concomitant down-regulation of Snail and Vimentin, consistent with inhibition of epithelial-mesenchymal transition (EMT). Taken together, our results suggest that down-regulation of Gli-1 suppresses HCC cell migration and invasion likely through inhibiting expressions and activations of MMP-2, 9 and blocking EMT. PMID- 24792035 TI - Platelet-derived growth factor-BB induces matrix metalloproteinase-2 expression and rat vascular smooth muscle cell migration via ROCK and ERK/p38 MAPK pathways. AB - Matrix metalloproteinases (MMP) play a pivotal role in the pathogenesis of cardiovascular diseases. Their expressions are altered in response to a variety of stimuli, including growth factors, inflammatory markers, and cytokines. In this study, we demonstrated that platelet-derived growth factor-BB (PDGF-BB) induces a dose- and time-dependent increase in MMP-2 expression in rat vascular smooth muscle cells (VSMC). Treatment with either the Rho-associated protein kinase (ROCK) inhibitor Y-27632 or suppression of ROCK-1/2 by small interfering RNA technology significantly reduced the MMP-2 expression, thus suggesting that ROCK regulates such expression. Similar results were observed when VSMC were pretreated with either U0126 or SB203580, which are selective inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, respectively, thus suggesting that these kinases are important for the induction of MMP-2 expression by PDGF-BB. In conclusion, these results described a novel mechanism in atherosclerosis through PDGF-BB signaling in VSMC, in which MMP-2 expression is induced via extracellular signal-regulated kinases and p38 mitogen activated protein kinase phosphorylation, as well as ROCK. PMID- 24792039 TI - Unexpected reactivity of amidogen radical in the gas phase degradation of nitric acid. AB - The gas phase reaction between nitric acid and amidogen radical has been investigated employing high level quantun-mechanical electronic structure methods and variational transition state theory kinetic calculations. Our results show that the reaction proceeds through a proton coupled electron transfer mechanism with a rate constant of 1.81 * 10(-13) cm(3).molecule(-1).s(-1) at 298 K. This value is similar to the rate constants for the reactions of hydroxyl radical with either ammonia or nitric acid. An analysis of these data in the context of the chemistry of the atmosphere suggests that the amidogen radical, formed in the oxidation of ammonia by hydroxyl radical, reacts with nitric acid regenerating ammonia. On the basis of these findings, we propose a potential new catalytic like cycle which couples the oxidation of ammonia by hydroxyl radical and the reaction of nitric acid with amidogen radical in the Earth's atmosphere. PMID- 24792038 TI - Regulation of the gut microbiota by the mucosal immune system in mice. AB - The benefits of commensal bacteria to the health of the host have been well documented, such as providing stimulation to potentiate host immune responses, generation of useful metabolites, and direct competition with pathogens. However, the ability of the host immune system to control the microbiota remains less well understood. Recent microbiota analyses in mouse models have revealed detailed structures and diversities of microbiota at different sites of the digestive tract in mouse populations. The contradictory findings of previous studies on the role of host immune responses in overall microbiota composition are likely attributable to the high beta-diversity in mouse populations as well as technical limitations of the methods to analyze microbiota. The host employs multiple systems to strictly regulate their interactions with the microbiota. A spatial segregation between the host and microbiota is achieved with the mucosal epithelium, which is further fortified with a mucus layer on the luminal side and Paneth cells that produce antimicrobial peptides. When commensal bacteria or pathogens breach the epithelial barrier and translocate to peripheral tissues, the host immune system is activated to eliminate them. Defective segregation and tissue elimination of commensals result in exaggerated inflammatory responses and possibly death of the host. In this review, we discuss the current understanding of mouse microbiota, its common features with human microbiota, the technologies utilized to analyze microbiota, and finally the challenges faced to delineate the role of host immune responses in the composition of the luminal microbiota. PMID- 24792040 TI - Developing core collections to optimize the management and the exploitation of diversity of the coffee Coffea canephora. AB - The management of diversity for conservation and breeding is of great importance for all plant species and is particularly true in perennial species, such as the coffee Coffea canephora. This species exhibits a large genetic and phenotypic diversity with six different diversity groups. Large field collections are available in the Ivory Coast, Uganda and other Asian, American and African countries but are very expensive and time consuming to establish and maintain in large areas. We propose to improve coffee germplasm management through the construction of genetic core collections derived from a set of 565 accessions that are characterized with 13 microsatellite markers. Core collections of 12, 24 and 48 accessions were defined using two methods aimed to maximize the allelic diversity (Maximization strategy) or genetic distance (Maximum-Length Sub-Tree method). A composite core collection of 77 accessions is proposed for both objectives of an optimal management of diversity and breeding. This core collection presents a gene diversity value of 0.8 and exhibits the totality of the major alleles (i.e., 184) that are present in the initial set. The seven proposed core collections constitute a valuable tool for diversity management and a foundation for breeding programs. The use of these collections for collection management in research centers and breeding perspectives for coffee improvement are discussed. PMID- 24792042 TI - Online period estimation and determination of rhythmicity in circadian data, using the BioDare data infrastructure. AB - Circadian biology is a major area of research in many species. One of the key objectives of data analysis in this field is to quantify the rhythmic properties of the experimental data. Standalone software such as our earlier Biological Rhythm Analysis Software Suite (BRASS) is widely used. Different parts of the community have settled on different software packages, sometimes for historical reasons. Recent advances in experimental techniques and available computing power have led to an almost exponential growth in the size of the experimental data sets being generated. This, together with the trend towards multinational, multidisciplinary projects and public data dissemination, has led to a requirement to be able to store and share these large data sets. BioDare (Biological Data repository) is an online system which encompasses data storage, data sharing, and processing and analysis. This chapter outlines the description of an experiment for BioDare, how to upload and share the experiment and associated data, and how to process and analyze the data. Functions of BRASS that are not supported in BioDare are also briefly summarized. PMID- 24792041 TI - Measurement of luciferase rhythms. AB - Firefly luciferase (LUC) is a sensitive and versatile reporter for the analysis of gene expression. Transgenic plants carrying CLOCK GENE promoter:LUC fusions can be assayed with high temporal resolution. LUC measurement is sensitive, noninvasive, and nondestructive and can be readily automated, greatly facilitating genetic studies. For these reasons, LUC fusion analysis is a mainstay in the study of plant circadian clocks. PMID- 24792043 TI - Global profiling of the circadian transcriptome using microarrays. AB - Circadian rhythms are biological cycles with a period length of approximately 24 h that are generated by endogenous clocks. The application of microarrays for high-throughput transcriptome analysis has led to the insight that substantial portions of the transcriptomes of both humans and many model organisms are clock regulated. In a typical circadian time course microarray experiment, samples are collected from organisms maintained in constant environmental conditions, gene expression at each time point is determined using microarrays, and finally clock regulated transcripts are identified using statistical algorithms. Here, we describe how to design the experiment, process RNA, determine expression profiles using ATH1 microarrays, and use a nonparametric statistical algorithm named JTK_CYCLE in order to identify circadian-regulated transcripts in Arabidopsis. This basic procedure can be modified to identify clock-regulated transcripts in different organisms or using different expression analysis platforms. PMID- 24792044 TI - ChIP-seq analysis of histone modifications at the core of the Arabidopsis circadian clock. AB - Over the past years, chromatin modification has emerged as a key regulator of gene expression. A very useful method for chromatin analysis is chromatin immunoprecipitation (ChIP), which allows the quantification and localization of specific histone modifications. The basic steps of the ChIP protocol include cross-linking of histones and DNA, chromatin isolation, shearing the DNA into smaller fragments, immunoprecipitation with specific antibodies, and enrichment analysis by several methods including real-time quantitative PCR (ChIP-qPCR), microarray hybridization (ChIP-chip), or sequencing (ChIP-seq). Here, we describe how to use ChIP-qPCR to analyze histone modifications at the core of the Arabidopsis thaliana circadian clock. We also briefly discuss a number of protocol adjustments to be considered in ChIP-seq experiments. PMID- 24792045 TI - Quantitative transcriptome analysis using RNA-seq. AB - RNA-seq has emerged as the technology of choice to quantify gene expression. This technology is a convenient accurate tool to quantify diurnal changes in gene expression, gene discovery, differential use of promoters, and splice variants for all genes expressed in a single tissue. Thus, RNA-seq experiments provide sequence information and absolute expression values about transcripts in addition to relative quantification available with microarrays or qRT-PCR. The depth of information by sequencing requires careful assessment of RNA intactness and DNA contamination. Although the RNA-seq is comparatively recent, a standard analysis framework has emerged with the packages of Bowtie2, TopHat, and Cufflinks. With rising popularity of RNA-seq tools have become manageable for researchers without much bioinformatical knowledge or programming skills. Here, we present a workflow for a RNA-seq experiment from experimental planning to biological data extraction. PMID- 24792046 TI - Rapid and parallel quantification of small and large RNA species. AB - Quantitative real-time PCR (qRT-PCR) is a common technique for mRNA quantification. Several methods have been developed in the past few years in order to adapt qRT-PCR also for small non-coding RNAs (sRNA). We here provide a simple and sensitive protocol that allows quantification of mRNAs, selected sRNAs, and long non-coding RNAs (lncRNA) in one cDNA sample by qRT-PCR. PMID- 24792047 TI - The RIPper case: identification of RNA-binding protein targets by RNA immunoprecipitation. AB - Control at the posttranscriptional level emerges as an important layer of regulation in the circadian timing system. RNA-binding proteins that specifically interact with cis-regulatory motifs within pre-mRNAs are key elements of this regulation. While the ability to interact with RNA in vitro has been demonstrated for numerous Arabidopsis RNA-binding proteins, a full understanding of posttranscriptional networks controlled by an RNA-binding protein requires the identification of its immediate in vivo targets. Here we describe differential RNA immunoprecipitation in transgenic Arabidopsis thaliana plants expressing RNA binding protein variants epitope-tagged with green fluorescent protein. To control for RNAs that nonspecifically co-purify with the RNA-binding protein, transgenic plants are generated with a mutated version of the RNA-binding protein that is not capable of binding to its target RNAs. The RNA-binding protein variants are expressed under the control of their authentic promoter and cis regulatory motifs. Incubation of the plants with formaldehyde in vivo cross-links the proteins to their RNA targets. A whole-cell extract is then prepared and subjected to immunoprecipitation with an antibody against the GFP tag and to mock precipitation with an antibody against the unrelated red fluorescent protein. The RNAs coprecipitating with the proteins are eluted from the immunoprecipitate and identified via reverse transcription-PCR. PMID- 24792048 TI - A protocol for visual analysis of alternative splicing in RNA-Seq data using integrated genome browser. AB - Ultrahigh-throughput sequencing of cDNA (RNA-Seq) is an invaluable resource for investigating alternative splicing in an organism. Alternative splicing is a form of posttranscriptional regulation in which primary RNA transcripts from a single gene can be spliced in multiple ways leading to different RNA and protein products. In plants and other species, it has been shown that many genes involved in circadian regulation are alternatively spliced. As new RNA-Seq data sets become available, these data will lead to new insights into links between regulation RNA splicing and the circadian system. Analyzing RNA-Seq data sets requires software tools that can display RNA-Seq read alignments alongside gene models, enabling assessment of how treatments or developmental stages affect splicing patterns and production of novel variants. The Integrated Genome Browser (IGB) software program is a free and flexible desktop tool that enables discovery and quantification of alternative splicing. In this protocol, we use IGB and a cold-stress RNA-Seq data set to examine alternative splicing of Arabidopsis thaliana LHY, a circadian clock regulator. IGB is freely available from http://www.bioviz.org . PMID- 24792049 TI - AthaMap web tools for the analysis of transcriptional and posttranscriptional regulation of gene expression in Arabidopsis thaliana. AB - The AthaMap database provides a map of verified and predicted transcription factor (TF) and small RNA-binding sites for the A. thaliana genome. The database can be used for bioinformatic predictions of putative regulatory sites. Several online web tools are available that address specific questions. Starting with the identification of transcription factor-binding sites (TFBS) in any gene of interest, colocalizing TFBS can be identified as well as common TFBS in a set of user-provided genes. Furthermore, genes can be identified that are potentially targeted by specific transcription factors or small inhibitory RNAs. This chapter provides detailed information on how each AthaMap web tool can be used online. Examples on how this database is used to address questions in circadian and diurnal regulation are given. Furthermore, complementary databases and databases that go beyond questions addressed with AthaMap are discussed. PMID- 24792050 TI - Analysis of mRNA translation states in Arabidopsis over the diurnal cycle by polysome microarray. AB - Gene regulation at the level of translation occurs in response to environmental perturbation and is increasingly recognized as a factor affecting plant development. Despite extensive knowledge of transcriptional control, very little is known about translational regulation of genes in response to the daily light/dark cycles. Here we describe the experimental layout designed to address how the translation states of genes change at various times during a diurnal cycle in Arabidopsis thaliana seedlings. We have adopted a strategy combining sucrose-gradient profiling of ribosomes and high-throughput microarray analysis of the ribosome-associated mRNA to investigate the translational landscape of the Arabidopsis genome. This is a powerful technique that can be easily extended to study translation regulation in different genetic backgrounds and under various environmental conditions. PMID- 24792051 TI - Immunoprecipitation-based analysis of protein-protein interactions. AB - Several techniques allow the detection of protein-protein interactions. In vivo co-immunoprecipitation (Co-IP) studies are an important complement to other commonly used techniques such as yeast two-hybrid or fluorescence complementation, as they reveal interactions between functional proteins at physiological relevant concentrations. Here, we describe an in vivo Co-IP approach using either GFP affinity matrix or specific antibodies to purify proteins of interests and their interacting partners. PMID- 24792052 TI - Comparative phosphoproteomics to identify targets of the clock-relevant casein kinase 1 in C. reinhardtii Flagella. AB - In the green biflagellate alga Chlamydomonas reinhardtii different clock-relevant components have been identified that are involved in maintaining phase, period, and amplitude of circadian rhythms. It became evident that several of them are interconnected to flagellar function such as CASEIN KINASE1 (CK1). CK1 is involved in keeping the period. But it is also relevant for the formation of flagella, where it is physically located, and it controls the swimming velocity. In this chapter, we describe (1) how the flagellar sub-proteome is purified, (2) how phosphopeptides from this organelle are enriched, (3) how in vivo phosphorylation sites are determined, and (4) how direct and indirect flagellar targets of CK1 can be found using a specific inhibitor. Such a procedure can also be employed with other clock-relevant kinases if specific inhibitors or mutants are available. PMID- 24792053 TI - Pulsed induction of circadian clock genes in Arabidopsis seedlings. AB - The Alc-inducible system is a simple, yet effective, "gene switch" that can be used to transiently induce gene expression in Arabidopsis. Here we provide a protocol for using the Alc-inducible system to give a pulse in expression of a circadian clock gene in transgenic seedlings. The line we use as an example harbors an Alc-inducible copy of the CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) gene (Alc?CCA1). Alc?CCA1 seedlings are grown on solid MS medium and subsequently treated with ethanol vapor. Because the ethanol is quickly absorbed into the medium upon exposure, the seedlings are moved to fresh plates following treatment to avoid continuous induction. After the induction, the seedlings are harvested over a time-course for future total RNA and/or protein extraction that can be used for subsequent gene expression analyses. PMID- 24792054 TI - The use of fluorescent proteins to analyze circadian rhythms. AB - Compared with luciferase which is widely used as a reporter for circadian rhythms in Arabidopsis thaliana, available fluorescent markers are generally too stable to allow circadian oscillations to be measured. However, we have developed a technique to use the nuclear localization of circadian-controlled transcription factors fused to a fluorescent reporter as a means of measuring circadian rhythms. This technique has the advantage of being suitable for analyzing rhythms at the level of individual cells and in living plants. PMID- 24792055 TI - Measuring circadian oscillations of cytosolic-free calcium in Arabidopsis thaliana. AB - Circadian oscillations of cytosolic-free calcium can be measured in plants by observing luminescence of the bioluminescent calcium binding protein aequorin. Here we describe the use of intensified photon-counting CCD cameras to measure circadian oscillations in aequorin bioluminescence from Arabidopsis thaliana. PMID- 24792056 TI - Circadian life without micronutrients: effects of altered micronutrient supply on clock function in Arabidopsis. AB - The plant circadian clock is formed by a number of interlocked feedback loops that control the expression of thousands of genes. Genetic and pharmacological approaches towards the study of the plant clock are routinely carried out on Murashige and Skoog growth medium, which is both Fe-replete and Cu-deficient. However, it has recently become clear that the plant clock responds to available iron (Fe) supply: circadian pace slows down under conditions of Fe deficiency; circadian period progressively shortens with increasing Fe supply. Here, we describe several growth media that may be used to study the effects of varying micronutrient supply on the circadian clock, in which deficiency in a given micronutrient are imposed by the addition of a specific chelator or, alternatively, by using EDTA-washed agar as gelling agent, thus minimizing micronutrient contamination. PMID- 24792057 TI - Assessing redox state and reactive oxygen species in circadian rhythmicity. AB - Redox homeostasis is an important parameter of cell function and cell signaling. Spatial and temporal alterations of redox state control metabolism, developmental processes, as well as acute responses to environmental stresses and stress acclimation. Redox homeostasis is also linked to the circadian clock. This chapter introduces methods to assess important redox parameters such as the low molecular weight redox metabolites glutathione and ascorbate, their amount and redox state, and H2O2 as reactive oxygen species. In vivo redox cell imaging is described by use of the reduction-oxidation sensitive green fluorescent protein (roGFP). Finally, on the level of posttranslational redox modifications of proteins, methods are shown to assess hyperoxidation of 2-cysteine peroxiredoxin and glutathionylation of peroxiredoxin IIE. The redox state of 2-cysteine peroxiredoxin has been identified as a transcription-independent marker of circadian rhythmicity. PMID- 24792058 TI - Circadian regulation of plant immunity to pathogens. AB - The plant circadian clock primes the immune response of Arabidopsis thaliana to infection with the bacterial pathogen Pseudomonas syringae pv tomato DC3000 (Pst DC3000) such that there is a more robust response during the subjective day than subjective night. Thus Pst DC3000 growth in plants infected with the same initial titre of bacteria varies depending on the time of day of infection (Bhardwaj et al., PLoS One 6: e26968, 2011; Zhang et al., PLoS Pathog 9:e1003370, 2013). We describe here a protocol for assaying bacterial leaf titres following pressure infiltration or spray inoculation of Arabidopsis thaliana with Pst DC3000. We also describe a method for assaying plant susceptibility to infection with the necrotrophic fungal pathogen Botrytis cinerea. These methods can be used in studying the circadian clock regulation of signal transduction pathways controlling plant defense responses. PMID- 24792059 TI - Determination of photoperiodic flowering time control in Arabidopsis and barley. AB - The circadian clock serves to prepare plants for predictable changes in the environment both on a daily and a seasonal basis. Floral transition in most plants is dependent on day length and, thus, on the season. Sensing day length allows plants to synchronize their reproduction with favorable outside conditions. This process is known as the photoperiodic pathway of flowering time control, and it is tightly linked with the circadian clock of the plant. Thus, mutants with defects in the circadian system can also be impaired in photoperiodic flower induction. This chapter provides a detailed description of the methods used to determine flowering time in the model species Arabidopsis thaliana and Hordeum vulgare and to assign a mutant or a transgenic plant to the photoperiodic pathway of flowering. PMID- 24792060 TI - The perennial clock is an essential timer for seasonal growth events and cold hardiness. AB - Over the last several decades, changes in global temperatures have led to changes in local environments affecting the growth conditions for many species. This is a trend that makes it even more important to understand how plants respond to local variations and seasonal changes in climate. To detect daily and seasonal changes as well as acute stress factors such as cold and drought, plants rely on a circadian clock. This chapter introduces the current knowledge and literature about the setup and function of the circadian clock in various tree and perennial species, with a focus on the Populus genus. PMID- 24792061 TI - Monitoring seasonal bud set, bud burst, and cold hardiness in Populus. AB - Using a perennial model plant allows the study of reoccurring seasonal events in a way that is not possible using a fast-growing annual such as Arabidopsis thaliana (Arabidopsis). In this study, we present a hybrid aspen (Populus tremula * P. tremuloides) as our perennial model plant. These plants can be grown in growth chambers to shorten growth periods and manipulate day length and temperature in ways that would be impossible under natural conditions. In addition, the use of growth chambers allows easy monitoring of height and diameter expansion, accelerating the collection of data from new strategies that allow evaluation of promoters or inhibitors of growth. Here, we describe how to study and quantify responses to seasonal changes (mainly using P. tremula * P. tremuloides) by measuring growth rate and key events under different photoperiodic cycles. PMID- 24792062 TI - Transformation and measurement of bioluminescence rhythms in the moss Physcomitrella patens. AB - Gene targeting is a highly effective and straightforward technique for the functional analysis of a gene of interest. However, its efficiency is not satisfactorily high in many model plants including Arabidopsis thaliana. In the moss Physcomitrella patens, a model species of basal plants, the efficiency of gene targeting is as high as in yeasts, and this moss is becoming widely recognized as an experimental model of choice in various areas of plant biology. Here we focus on the transformation of protoplast cells and on the measurement of bioluminescence rhythms from protonema tissues of luciferase reporter strains in P. patens, both of which are important for mechanistic studies of the circadian clock. PMID- 24792063 TI - Modeling and simulating the Arabidopsis thaliana circadian clock using XPP-AUTO. AB - Circadian clocks are endogenous timekeepers that produce oscillations with a period of about one day. Their rhythmicity originates from complex gene regulatory networks at the cellular level. In the last decades, computational models have been proven to be a powerful tool in order to understand the dynamics and design principles of the complex regulatory circuitries underlying the circadian clocks of different organisms. We present the process of model development using a small and simplified two-gene regulatory network of the Arabidopsis circadian clock. Subsequently, we discuss important numerical techniques to analyze such a mathematical model using XPP-AUTO. We show how to solve deterministic and stochastic ordinary differential equations and how to compute bifurcation diagrams or simulate phase-shift experiments. We finally discuss the contributions of modeling to the understanding and dissection of the Arabidopsis circadian system. PMID- 24792064 TI - Prospective clinical audit of two neuromodulatory treatments for fecal incontinence: sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS). AB - BACKGROUND AND PURPOSE: Two types of neuromodulation are currently practised for the treatment of fecal incontinence (FI): sacral nerve stimulation (SNS) and percutaneous tibial nerve stimulation (PTNS). This study compares these therapies, as no data exist to prospectively assess their relative efficacy and costs. METHODS: The subjects of this study were two distinct cohorts undergoing SNS (between 2003 and 2008) or PTNS (2008-onwards) for FI. Clinical outcomes assessed at 3 months included incontinence scores and the number of weekly incontinence episodes. The direct medical costs for each procedure were calculated from the audited expenditure of our unit. RESULTS: Thirty-seven patients (94.6 % women) underwent permanent SNS and 146 (87.7 % women) underwent PTNS. The mean pre-treatment incontinence score (+/- SD) was greater in the SNS cohort (14 +/- 4 vs. 12 +/- 4) and the mean post-treatment incontinence scores were similar for the two therapies (9 +/- 5 vs. 10 +/- 4), with a greater effect size evident in the SNS patients. In a 'pseudo case-control' analysis with 37 "matched" patients, the effect of both treatments was similar. The cost of treating a patient for 1 year was L 11,374 ($ 18,223) for permanent SNS vs. L 1740 ($ 2784) for PTNS. CONCLUSION: Given the lesser cost and invasive nature of PTNS, where both techniques are available, a trial of PTNS could be considered for all patients. PMID- 24792065 TI - Impact of nasal obstruction on sleep quality: a community-based study of women. AB - The aim of the study was to analyse the impact of self-reported nasal obstruction on sleep quality in women. A community-based sample of 400 women underwent a full night of polysomnography. Airway diseases, allergies and sleep-related symptoms were assessed by questionnaires. Women with subjective nasal obstruction were subdivided into three groups: persistent nasal obstruction (PNO, n = 46), hay fever (n = 88) and nasal obstruction at night (NON, n = 30). Sleep problems and related daytime symptoms were most prevalent among women with NON. After adjusting for age, BMI, smoking and asthma, NON was an independent predictor of 'Difficulties inducing sleep due to nasal obstruction' [adjusted odds ratio (95 % CI): 89.5 (27.0-296.7)], 'Snoring' [4.2 (1.7-10.2)], 'Sweating at night' [2.6 (1.1-6.1)], 'Difficulties maintaining sleep' [2.7 (1.2-6.2)], and 'Waking up hastily gasping for breath' [32.2 (8.7-119.1)]. 'Dry mouth on awakening' [7.7 (3.2-18.4)], 'Waking up unrefreshed' [2.7 (1.2-6.0)], 'Excessive daytime sleepiness' [2.6 (1.1-6.0)], and 'Daytime nasal obstruction' [12.2 (4.8-31.2)] were also associated with NON. Persistent nasal obstruction and hay fever were both associated with some reported sleep problems due to an overlap with NON. When women with NON were excluded, only 'Daytime nasal obstruction' was still significantly associated with PNO, while hay fever was associated with 'Daytime nasal obstruction' and 'Waking up hastily gasping for breath'. There were no significant differences in objectively measured sleep variables between any of the three subgroups and the study cohort. Self-reported nasal obstruction at night in women has a significant effect on several subjective day- and nighttime symptoms, but it does not appear to affect objectively measured sleep quality. PMID- 24792066 TI - Repair of oronasal fistula with silicone button in patients with head and neck cancer. AB - Until now, there is no optimal technique for repairing oronasal fistula in patients with prior head and neck radiotherapy and trismus. Use of the silicone button is a safe, office-based, and validated method in this situation. The indications of this procedure are also clarified in this study. This is a retrospective study of four patients who underwent a newly designed endoscopic repair of oronasal fistula with silicone button under local anesthesia from July 2012 to August 2012. Data on the size of the defect, length of operation, symptom relief, and post-operative complications were collected. Four patients underwent endoscopic repair of oronasal fistula with silicone button under local anesthesia. The diagnoses were benign palate lesion s/p operation, oral cancer s/p operation and radiotherapy. The defect diameter varied from 1 to 1.5 cm. The operation durations were between 20 and 30 min. In all cases, nasal regurgitation symptoms were relieved. The hypernasality of one case improved, while another had decreased nasal crusting and foul odors. No major complications were noted. There was a minor complication in one case, which exhibited frequent crusting around the silicone button. Silicon button can act as a temporary obturator to improve quality of life of patients. The indications for this procedure include patient undergone head and neck radiotherapy with (1) chronic fistula (>6 months); (2) small defect (1-2 cm); and (3) trismus. LEVEL OF EVIDENCE: 4. PMID- 24792067 TI - Routine tonsillar bed oversew after diathermy tonsillectomy: does it reduce secondary tonsillar haemorrhage? AB - Tonsillectomy is a common otolaryngological procedure and is associated with a small risk of postoperative pharyngeal haemorrhage. This study compares secondary post tonsillectomy haemorrhage rates between two operative techniques: diathermy tonsillectomy and diathermy tonsillectomy with tonsillar bed oversew. A total of 424 patients underwent tonsillectomies with or without other procedures such as adenoidectomy and grommet insertion by two ears, nose and throat surgeons at three hospitals from May 2012 to July 2013. A diathermy tonsillectomy was performed in 266 patients, while a diathermy tonsillectomy with tonsillar bed oversew was performed in 158 patients. All patients were followed up within 2-4 weeks of surgery. Primary haemorrhage did not occur in either surgical technique groups. Secondary haemorrhage occurred in 20 patients (7.52 %) in the diathermy tonsillectomy group and in 9 patients (5.70 %) in the diathermy with tonsillar bed oversew group. This result was not significantly different (OR = 0.74, 95 % CI 0.33-1.67, p = 0.47). Sex, age, indication for surgery and whether or not a tonsillectomy was performed alone or with other procedures were not significant factors for secondary haemorrhage. In summary, routine tonsillar bed oversew after diathermy tonsillectomy does not reduce the risk of secondary tonsillar haemorrhage. PMID- 24792068 TI - Reassessment of insulin dosing guidelines in continuous subcutaneous insulin infusion treated type 1 diabetes. AB - It is a daunting task to initiate or evaluate continuous subcutaneous insulin infusion, pump, dosing in a patient with type 1 diabetes. Choosing a low dose may lead to hyperglycemia or, too high, hypoglycemia. Mathematical dosing guidelines were used with the first human insulin injection in 1922. Since that time, they have been enlarged and modified. The current widely published guidelines were developed from retrospective evaluations of pump-downloads in patients without specified diet conditions or timed glucose testing. When diet is controlled and glucose testing is timed to evaluate post-meal excursions and during sleep, recent prospective studies found that these current dosing recommendations for basal insulin were too high and for bolus insulin too low. Further, simple mathematical interrelationships were published that kept the right proportions between the bolus dosing factors and the basal dose. PMID- 24792070 TI - Cartilage MRI relaxation times after arthroscopic partial medial meniscectomy reveal localized degeneration. AB - PURPOSE: Little is known about the early changes in cartilage composition and tibiofemoral kinematics following partial meniscectomy. The purpose of this study was to determine the effects of partial meniscectomy on cartilage compositional properties using T1rho and T2 relaxation time mapping and to assess changes in tibiofemoral kinematics. It is hypothesize that abnormal tibiofemoral kinematics and relaxation time elevation (a reflection of changes in cartilage biochemical composition) in the weight-bearing regions of the knees following meniscectomy will be observed. METHODS: Nine patients (7 males and 2 females; mean age, 48.6 +/- 10.8 years; BMI = 27.3 +/- 3.8 kg/m(2)) with tears of the posterior horn of the medial meniscus underwent arthroscopic partial meniscectomy. Pre-surgical and 6 months post-surgical MRIs were obtained in all subjects to evaluate cartilage relaxation times and tibiofemoral kinematics. Paired t tests were performed to determine significant changes in cartilage relaxation times from baseline. RESULTS: T1rho relaxation time in the region of the medial femoral condyle directly adjacent to the resection showed an increase of 7.4% at 6 months (p = 0.02). T2 relaxation times in both the medial and lateral tibial plateaus showed significant elevation at 6 months. Consistent kinematic trends were not found in post-meniscectomized knees. CONCLUSIONS: These results suggest that arthroscopic partial meniscectomy affects the biochemical composition of articular cartilage in the knee in as early as 6 months. The largest responses were observed in the weight-bearing regions and the cartilage immediately adjacent to the resection. This suggests that the loading environment has been altered enough to result in cartilage compositional changes in a very brief period of time following meniscectomy. LEVEL OF EVIDENCE: IV. PMID- 24792069 TI - Opioids as an alternative to amide-type local anaesthetics for intra-articular application. AB - PURPOSE: Recently, the safety profile of local anaesthetics in intra-articular use became into focus of investigation. Opioid drugs have a different mode of action and may be a safe and potent alternative for intra-articular application. The purpose of this in vitro study is to provide evidence for significant chondrotoxicity of amide-type local anaesthetics even after short-term application on human chondrocytes and to demonstrate the absence of such negative effects for opioids [morphine, morphine-6-glucuronide (M6G)]. METHOD: Visually intact cartilage explants of human, mainly osteoarthritic joints (n = 9), were harvested and cultivated in monolayer for expansion and transferred into alginate bead. The beads were incubated for increasing incubation times (15 min, 1 and 4 h) in decreasing concentrations (full, 1/2, 1/4 for 15 min) of bupivacaine, ropivacaine, morphine, M6G or saline control. Adenosine triphosphate content of 798 beads was measured 3 days post-incubation to assess cell viability. RESULTS: A clear ranking of cytotoxic potency: bupivacaine > ropivacaine > morphine = M6G = saline was observed. Results reveal a dose- and time-dependent manner of cytotoxic effects on human chondrocytes for bupivacaine and ropivacaine but not for opioids. Cell viability after exposure to morphine and M6G was comparable to exposure to saline. CONCLUSION: The results confirm dose- and time-dependent cytotoxic effects on human chondrocytes for amide-type local anaesthetics. This study confirms the safety of morphine and M6G in terms of an absence of cytotoxic effects after intra-articular application, making them safe potential alternatives in clinical practice. PMID- 24792071 TI - Varization open-wedge osteotomy of the distal femur: comparison between locking plate and angle blade plate constructs. AB - PURPOSE: Biomechanical properties of locking plate and angle blade plate constructs in opening-wedge distal femur osteotomy were compared, with special attention to the impact of opposite cortex breakage and buttressing. METHODS: Forty-eight synthetic femora underwent a lateral opening-wedge distal femur osteotomy, which was fixed either with a locking plate or with an angle blade plate. Two main groups were constituted based on the integrity of the opposite medial cortex-intact medial cortex and fractured medial cortex (FMC). Axial compression and torsion tests were performed comparing stiffness of all bone implant constructs. In the group FMC, a special subgroup has been tested taking into consideration the effect of placing an additional 6.5-mm cancellous screw buttressing the medial cortex. Statistical level of significance was fixed in 0.05 using a confidence interval of 95 %. RESULTS: Intact medial cortex significantly increased the stiffness for both implants tested in this study. In the FMC group, angle blade plate constructs reached higher stiffness mean values for both torsion and axial compression. The insertion of a buttressing screw on the medial cortex increased the stiffness of all tested bone-plate constructs. This additional screw favoured mostly locking plate constructs implementing their stiffness to torsion to mean values comparable to those reached by angle blade plate constructs. CONCLUSIONS: Angle blade plate constructs reached higher stiffness mean values than locking plates for both axial compression and torsion loads. The addition of a buttressing screw on the opposite cortex increased the stability of all bone-implant constructs to levels similar to those showed with an intact medial cortex. The present study findings support the clinical use of angle blade plates, alone or associated with a medial buttressing screw, as an alternative fixation method for supracondylar open-wedge osteotomies of the femur. PMID- 24792072 TI - Assessment of gastrocnemius tensiomyographic neuromuscular characteristics as risk factors for anterior cruciate ligament injury in male soccer players. AB - PURPOSE: There is a large number of publications evaluating neuromuscular risk factors for anterior cruciate ligament (ACL) injury in athletes. However, most of them have involved the female athlete and, in addition, the gastrocnemius muscles have been less investigated by far compared with the quadriceps and hamstring. The purpose of this study was to investigate the role of the gastrocnemius muscles as neuromuscular risk factors for ACL injury in male soccer players, through tensiomyography (TMG). METHODS: All competitive male soccer players with confirmed ACL tear included in this study underwent resting TMG assessment of gastrocnemius medialis (GM) and gastrocnemius lateralis muscles of the uninjured side. The same values were obtained from a sex-, and sports level-matched control group in both sides. The maximal displacement (D m), delay time (T d), contraction time (T c), sustained time (T s), and half-relaxation time (T r) were obtained for both muscles. TMG values of the uninjured side in ACL-injured group were compared with the mean values between both sides in the control subjects. RESULTS: There were no significant between-group differences in demographic characteristics. Most TMG parameters of the gastrocnemius muscles were not significantly different between the two groups. Only the GM-T r (p = 0.02) and GM D m (p = 0.006) were significantly higher in the ACL-injured group compared with control group. CONCLUSIONS: Neuromuscular characteristics in terms of mechanical and contractile properties of the gastrocnemius muscles may not be significant risk factors for ACL injury in male soccer players. PMID- 24792073 TI - Pectoralis major tendon repair: a biomechanical study of suture button versus transosseous suture techniques. AB - PURPOSE: Pectoralis major tendon avulsion injury benefits from surgical repair. The technique used and speed of rehabilitation in this demanding population remains subject to debate. We performed a biomechanical study comparing suture button (Pec ButtonTM, Arthrex, Naples, FL) with a transosseous suture technique (FibreWire, Arthrex, Naples, FL). METHODS: Freshly slaughtered porcine humeri were prepared to model a single transosseous suture or suture button repair. A static, tensile load to failure experiment and a cyclic, tensile load experiment to model standard (10,000 cycles) and accelerated rehabilitation (20,000 cycles) philosophies were tested. The mode of failure, yield and ultimate failure load, extension (clinical failure >10 mm) and the resistance to cyclic loading was measured. RESULTS: The mode of failure was suture fracture in all the static load experiments with 10/11 occurring as the suture passed through the button and 7/11 as the suture passed through the bone tunnels. There was a significant difference in yield load, favouring transosseous suture [p = 0.009, suture button (SB) 673.0 N (647.2-691.7 N), transosseous suture (TOS) 855.0 N (750.0-891.4 N)] and median extension, favouring suture button [p = 0.009, SB 8.8 mm (5.0-12.4 mm), TOS 15.2 mm (13.2-17.1 mm)]. 2/3 transosseous suture and 0/3 suture buttons failed before completing 20,000 cycles. The difference in mean number of cycles completed was non-significant. The difference in mean extension was 5.1 mm (SB 6.7 mm, TOS 11.7 mm). CONCLUSIONS: Both techniques show advantages. The difference in extension is likely to be more clinically relevant than load tolerated at failure, which is well above physiological levels. The findings do not support an accelerated rehabilitation model. PMID- 24792074 TI - Validation of the Dutch language version of the Foot and Ankle Outcome Score. AB - PURPOSE: The aim of this study was to develop a Dutch language version of the Foot and Ankle Outcome Score (FAOS-DLV) and evaluate its measurement properties according to the definitions of the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). METHODS: After a standard forward backward translation procedure, the Dutch version of the FAOS was evaluated for reliability and validity in 110 patients with various hind foot and ankle complaints. Reliability was evaluated by calculation of intraclass correlation coefficients (ICC), Cronbach's alpha for internal consistency, and the smallest detectable change (SDC). Construct validity of the FAOS was assessed by calculation of Spearman's correlation coefficients with similar and dissimilar domains of the SF-36 health survey, American Orthopedic Foot and Ankle Society Ankle and Hindfoot Scale, and visual analogue scales for pain and disability. Dimensionality was tested with confirmatory factor analysis. RESULTS: Reliability of the FAOS-DLV was good. The ICC of the subscales ranged from 0.83 to 0.88. The minimal value of Cronbach's alpha was 0.76. The SDC at individual level ranged from 18 to 21 and at group level between 2.1 and 2.5. Construct validity was supported by confirmation of 85 % of the hypothesized correlations. Unidimensionality of the FAOS-DLV domains was moderate. CONCLUSION: The Dutch version of the FAOS seems to have acceptable measurement properties. The questionnaire can be used for functional assessment of patients with varying hindfoot and ankle symptoms. It is, however, more suitable for clinical evaluation at group level than for monitoring a specific patient. LEVEL OF EVIDENCE: Diagnostic study, Level I. PMID- 24792075 TI - Arthroscopic knotless-anchor rotator cuff repair: a clinical and radiological evaluation. AB - PURPOSE: The goal of this study was to evaluate the clinical and radiological results of the arthroscopic knotless-anchor Speed-Bridge technique, in particular the pattern and the rate of retears. The results were compared with a modified Suture-Bridge knot-tying technique (mDR). The hypothesis is that arthroscopic knotless-anchor Speed-Bridge rotator cuff repair is a sufficient technique to address supraspinatus tears and differs in pattern of retears when compared to mDR. METHODS: This study includes twenty-two consecutive patients (8f/14m o 63.3 +/- 7.2 years) undergoing knotless-anchor Speed-Bridge repair. The subjective shoulder value (SSV), Constant score (CS) and Western Ontario Rotator Cuff (WORC) Score were used for clinical follow-up. MRI scans were conducted within 3 weeks post-operatively, after 1 and after 2 years for analysis of (a) tendon integrity (according to Sugaya), (b) muscle atrophy according to Thomazeau and (c) fatty infiltration. Results were compared with 20 patients operated in mDR (o 61.2 +/- 7.5 years). RESULTS: The mean follow-up was 24.4 +/- 4.7 months. The average SSV was 88.7 +/- 14.9 %, the CS was 78.2 +/- 13.2 points (contralateral side 78.5 +/- 16.6) and the WORC Score averaged 87.1 +/- 18.2 %. On magnetic resonance imaging, the integrity failure rate was 22.7 % (n = 5). The pattern of retear was a medial cuff failure in 2/5 cases (mDR 4/5, n.s.). Muscular atrophy or fatty degeneration did not increase between surgery and follow-up (n.s.). Compared with mDR (25 %) reconstruction, no significant differences were obtained regarding integrity failure rate and muscular atrophy (n.s.). CONCLUSION: The modified knotless anchor Speed-Bridge technique shows good to excellent clinical results as well as acceptable retear rates. This technique eliminates medial and lateral knot impingement. Concerning the potential reduction in the medial strangulation of the tendon, there is a need for further clinical research. PMID- 24792076 TI - Medial capsule reefing in patellar instability. AB - PURPOSE: The efficacy of medial capsule reefing in the treatment of patellar instability is well documented. Aim of the present study was to prospectively evaluate the outcomes of an all-arthroscopic medial capsule reefing technique in young patients with painful patella syndrome and potential patellar instability. METHODS: Thirty patients with painful patellar syndrome and potential patellar instability having undergone a minimum of 6 months of intensive rehabilitation were enrolled in the present study. All subjects were evaluated with physical examination, clinical and functional outcomes and complete imaging study. RESULTS: All patients were reviewed at an intermediate follow-up of 72 months. Average Kujala score improved from 72.9+/-15.0 to 88.4+/-7.6 (p<0.0001), average Larsen score from 15.0+/-2.5 to 17.2+/-2.2 (p<0.002), average Lysholm from 63.8+/ 16.7 to 87.9+/-11.7 (p<0.0001) and average Fulkerson score from 69.5+/-21.5 to 90.8+/-9.8 (p<0.0001). No intraoperative or postoperative complications were recorded. Ninety per cent of patients were very satisfied or satisfied with their functional result. Twenty-eight patients were reviewed at the final follow-up, 120 months after surgery. Average Kujala was 87.7+/-8.8 (p<0.0001), average Larsen was 16.8+/-2.7 (p<0.01), average Lysholm was 87.6+/-14.3 (p<0.0001), and average Fulkerson was 87.2+/-13.9 (p<0.0001). Almost 86% of patients were very satisfied or satisfied with their result. However, slight deterioration of the outcomes over time was observed. CONCLUSION: At the final follow-up, the outcomes of all-arthroscopic technique were significantly improved from preoperative values; however, they were slightly inferior at the 72 months follow-up. This slight deterioration of the outcomes may be the consequence of the reduction in physical activities. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24792077 TI - Tendon response to pharmaco-mechanical stimulation of the chronically retracted rotator cuff in sheep. AB - PURPOSE: Chronic tearing of tendons is associated with molecular and structural alterations causing biomechanical changes, which compromise musculotendinous function and become limiting factors for tendon repair. This study investigated the histological response of chronically retracted sheep rotator cuff tendons to mechanical and pharmacological stimulation in view of tendon repair. METHODS: Sixteen weeks after experimental release of the infraspinatus tendon in 20 sheep, the retracted musculotendinous unit was subjected to continuous traction either with [anabolic steroids (nandrolone) group/insulin-like growth factor (IGF) group] or without (control group) additional pharmacological treatment during 6 weeks. A new degeneration score for tendinous tissues (DSTT), based on established knowledge on histological changes associated with tendon degeneration, was used for histological analysis at the time of tendon release, at the beginning of continuous re-lengthening and at repair in all animals. RESULTS: The DSTT score (inter-observer correlation: r = 0.83), quantifiably representing tendon degeneration, improved from 15.5 (SD 1.3) points before to 9.8 (SD 3.8) points after re-lengthening. It improved in a qualitatively and quantitatively similar fashion if pharmacological stimulation was added. The nandrolone group improved from 13.7 (SD 1.6) to 9.8 (SD 1.9) and the IGF group from 13.3 (SD 3.6) to 8.8 (SD 1.8) points. CONCLUSION: Mechanical stimulation significantly reduced tissue degeneration. However, the addition of a pharmacological stimulation with anabolic steroids or IGF had neither a measurable positive nor negative effect on the degenerative process. Therefore, this investigation does neither support the additional pharmacological use of the anabolic steroid nandrolone or of IGF decanoate for restoration of tendon degeneration, nor otherwise provide evidence for additional tendon damage, if those substances are used to alter the muscular metabolism. PMID- 24792078 TI - Inclusion of Tithonia diversifolia in multinutrient blocks for WestAfrican dwarf goats fed Brachiaria straw. AB - Recent investigations suggest that the development of multinutrient feed blocks with inclusion of tree and shrub leaves could improve the nutritive value and digestibility of straw. In order to test these possibilities, three types of multinutrient blocks (MNB) namely: MNB0 (wheat bran = 100%; Tithonia diversifolia leaf = 0%), MNB50 (wheat bran = 50%; T. diversifolia leaf = 50%) and MNB100 (wheat bran = 0%; T. diversifolia leaf = 100%) were fed for 15 days in a 3 * 3 Latin square arrangement to West African dwarf goats consuming Brachiaria ruziziensis straw. The blocks presented a good cohesion and a good hardness. The inclusion of T. diversifolia improved levels of crude protein, mineral, feed unit for milk production (UFL) and feed unit for meat production (UFV), but decreased palatability. The effects on the digestibility of B. ruziziensis straw were evaluated in nine West African dwarf goats fed individually with MNB0 + straw, MNB50 + straw and MNB100 + straw. The dry matter, organic matter and crude fibre digestibility of B. ruziziensis straw increased slightly with increasing level of inclusion of T. diversifolia. The apparent digestibility of nitrogen was comparable for all diets independent of the level of inclusion of T. diversifolia. This study showed that the inclusion of T. diversifolia leaves in the MNBs can be recommended to improve the feeding of goats during periods of drought. PMID- 24792080 TI - Competing interests concerns must not stop GPs from commissioning primary care, NHS chief says. PMID- 24792079 TI - Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats. AB - Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress. PMID- 24792081 TI - A predictive analytics approach to reducing 30-day avoidable readmissions among patients with heart failure, acute myocardial infarction, pneumonia, or COPD. AB - Hospital readmission has become a critical metric of quality and cost of healthcare. Medicare anticipates that nearly $17 billion is paid out on the 20 % of patients who are readmitted within 30 days of discharge. Although several interventions such as transition care management have been practiced in recent years, the effectiveness and sustainability depends on how well they can identify patients at high risk of rehospitalization. Based on the literature, most current risk prediction models fail to reach an acceptable accuracy level; none of them considers patient's history of readmission and impacts of patient attribute changes over time; and they often do not discriminate between planned and unnecessary readmissions. Tackling such drawbacks, we develop a new readmission metric based on administrative data that can identify potentially avoidable readmissions from all other types of readmission. We further propose a tree-based classification method to estimate the predicted probability of readmission that can directly incorporate patient's history of readmission and risk factors changes over time. The proposed methods are validated with 2011-12 Veterans Health Administration data from inpatients hospitalized for heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease in the State of Michigan. Results shows improved discrimination power compared to the literature (c-statistics >80 %) and good calibration. PMID- 24792082 TI - New directions in the social study of the autism spectrum: a review essay. PMID- 24792083 TI - Contrasting patterns of gene flow between sister plant species in the understorey of African moist forests - the case of sympatric and parapatric Marantaceae species. AB - Gene flow within and between species is a fundamental process shaping the evolutionary history of taxa. However, the extent of hybridization and reinforcement is little documented in the tropics. Here we explore the pattern of gene flow between three sister species from the herbaceous genus Marantochloa (Marantaceae), sympatrically distributed in the understorey of the African rainforest, using data from the chloroplast and nuclear genomes (DNA sequences and AFLP). We found highly contrasting patterns: while there was no evidence of gene flow between M. congensis and M. monophylla, species identity between M. monophylla and M. incertifolia was maintained despite considerable gene flow. We hypothesize that M. incertifolia originated from an ancient hybridization event between M. congensis and M. monophylla, considering the current absence of hybridization between the two assumed parent species, the rare presence of shared haplotypes between all three species and the high percentage of haplotypes shared by M. incertifolia with each of the two parent species. This example is contrasted with two parapatrically distributed species from the same family in the genus Haumania forming a hybrid zone restricted to the area of overlap. This work illustrates the diversity of speciation/introgression patterns that can potentially occur in the flora of tropical Africa. PMID- 24792084 TI - A comprehensive multilocus assessment of sparrow (Aves: Passerellidae) relationships. AB - The New World sparrows (Emberizidae) are among the best known of songbird groups and have long-been recognized as one of the prominent components of the New World nine-primaried oscine assemblage. Despite receiving much attention from taxonomists over the years, and only recently using molecular methods, was a "core" sparrow clade established allowing the reconstruction of a phylogenetic hypothesis that includes the full sampling of sparrow species diversity. In this paper, we use mitochondrial DNA gene sequences from all 129 putative species of sparrow and four additional (nuclear) loci for a subset of these taxa to resolve both generic and species level relationships. Hypotheses derived from our mitochondrial (2184 base pairs) and nuclear (5705 base pairs) DNA data sets were generally in agreement with respect to clade constituency but differed somewhat with respect to among-clade relationships. Sparrow diversity is defined predominantly by eight well-supported clades that indicate a lack of monophyly for at least three currently recognized genera. Ammodramus is polyphyletic and requires the naming of two additional genera. Spizella is also polyphyletic with Tree Sparrow (Spizella arborea) as a taxonomic "outlier". Pselliophorus is embedded within a larger Atlapetes assemblage and should be merged with that group. This new hypothesis of sparrow relationships will form the basis for future comparative analyses of variation within songbirds. PMID- 24792085 TI - Phylogeny and historical biogeography of Isodon (Lamiaceae): rapid radiation in south-west China and Miocene overland dispersal into Africa. AB - Rapid organismal radiations occurring on the Qinghai-Tibetan Plateau (QTP) and the mechanisms underlying Asia-Africa intercontinental disjunctions have both attracted much attention from evolutionary biologists. Here we use the genus Isodon (Lamiaceae), a primarily East Asian lineage with disjunct species in central and southern Africa, as a case study to shed light upon these processes. The molecular phylogeny and biogeographic history of Isodon were reconstructed using sequences of three plastid markers, the nuclear ribosomal internal transcribed spacer (nrITS), and a low-copy nuclear gene (LEAFY intron II). The evolution of chromosome numbers in this genus was also investigated using probabilistic models. Our results support a monophyletic Isodon that includes the two disjunct African species, both of which likely formed through allopolyploidy. An overland migration from Asia to Africa through Arabia during the early Miocene is proposed as the most likely explanation for the present disjunct distribution of Isodon. The opening of the Red Sea in the middle Miocene may appear to have had a major role in disrupting floristic exchange between Asia and Africa. In addition, a rapid radiation of Isodon was suggested to occur in the late Miocene. It corresponds with one of the major uplifts of the QTP and subsequent aridification events. Our results support the hypothesis that geological and climatic events play important roles in driving biological diversification of organisms distributed in the QTP area. PMID- 24792086 TI - Estimating the Phanerozoic history of the Ascomycota lineages: combining fossil and molecular data. AB - The phylum Ascomycota is by far the largest group in the fungal kingdom. Ecologically important mutualistic associations such as mycorrhizae and lichens have evolved in this group, which are regarded as key innovations that supported the evolution of land plants. Only a few attempts have been made to date the origin of Ascomycota lineages by using molecular clock methods, which is primarily due to the lack of satisfactory fossil calibration data. For this reason we have evaluated all of the oldest available ascomycete fossils from amber (Albian to Miocene) and chert (Devonian and Maastrichtian). The fossils represent five major ascomycete classes (Coniocybomycetes, Dothideomycetes, Eurotiomycetes, Laboulbeniomycetes, and Lecanoromycetes). We have assembled a multi-gene data set (18SrDNA, 28SrDNA, RPB1 and RPB2) from a total of 145 taxa representing most groups of the Ascomycota and utilized fossil calibration points solely from within the ascomycetes to estimate divergence times of Ascomycota lineages with a Bayesian approach. Our results suggest an initial diversification of the Pezizomycotina in the Ordovician, followed by repeated splits of lineages throughout the Phanerozoic, and indicate that this continuous diversification was unaffected by mass extinctions. We suggest that the ecological diversity within each lineage ensured that at least some taxa of each group were able to survive global crises and rapidly recovered. PMID- 24792087 TI - A review of molecular-clock calibrations and substitution rates in liverworts, mosses, and hornworts, and a timeframe for a taxonomically cleaned-up genus Nothoceros. AB - Absolute times from calibrated DNA phylogenies can be used to infer lineage diversification, the origin of new ecological niches, or the role of long distance dispersal in shaping current distribution patterns. Molecular-clock dating of non-vascular plants, however, has lagged behind flowering plant and animal dating. Here, we review dating studies that have focused on bryophytes with several goals in mind, (i) to facilitate cross-validation by comparing rates and times obtained so far; (ii) to summarize rates that have yielded plausible results and that could be used in future studies; and (iii) to calibrate a species-level phylogeny for Nothoceros, a model for plastid genome evolution in hornworts. Including the present work, there have been 18 molecular clock studies of liverworts, mosses, or hornworts, the majority with fossil calibrations, a few with geological calibrations or dated with previously published plastid substitution rates. Over half the studies cross-validated inferred divergence times by using alternative calibration approaches. Plastid substitution rates inferred for "bryophytes" are in line with those found in angiosperm studies, implying that bryophyte clock models can be calibrated either with published substitution rates or with fossils, with the two approaches testing and cross validating each other. Our phylogeny of Nothoceros is based on 44 accessions representing all suspected species and a matrix of six markers of nuclear, plastid, and mitochondrial DNA. The results show that Nothoceros comprises 10 species, nine in the Americas and one in New Zealand (N. giganteus), with the divergence between the New Zealand species and its Chilean sister species dated to the Miocene and therefore due to long-distance dispersal. Based on the new tree, we formally transfer two species of Megaceros into Nothoceros, resulting in the new combinations N. minarum (Nees) J.C. Villarreal and N. schizophyllus (Gottsche ex Steph.) J.C. Villarreal, and we also newly synonymize eight names described in Megaceros. PMID- 24792088 TI - The tempo and mode of New World monkey evolution and biogeography in the context of phylogenomic analysis. AB - The development and evolution of organisms is heavily influenced by their environment. Thus, understanding the historical biogeography of taxa can provide insights into their evolutionary history, adaptations and trade-offs realized throughout time. In the present study we have taken a phylogenomic approach to infer New World monkey phylogeny, upon which we have reconstructed the biogeographic history of extant platyrrhines. In order to generate sufficient phylogenetic signal within the New World monkey clade, we carried out a large scale phylogenetic analysis of approximately 40 kb of non-genic genomic DNA sequence in a 36 species subset of extant New World monkeys. Maximum parsimony, maximum likelihood and Bayesian inference analysis all converged on a single optimal tree topology. Divergence dating and biogeographic analysis reconstruct the timing and geographic location of divergence events. The ancestral area reconstruction describes the geographic locations of the last common ancestor of extant platyrrhines and provides insight into key biogeographic events occurring during platyrrhine diversification. Through these analyses we conclude that the diversification of the platyrrhines took place concurrently with the establishment and diversification of the Amazon rainforest. This suggests that an expanding rainforest environment rather than geographic isolation drove platyrrhine diversification. PMID- 24792089 TI - Molecular data indicate the presence of a novel species of Centropomus (Centropomidae - Perciformes) in the Western Atlantic. AB - Centropomus undecimalis is distributed in the coastal waters of the western Atlantic between North Carolina and Sao Paulo, although very little is known of the genetic structure of its populations. Here, 148 C. undecimalis samples were obtained from six sites in the southwestern Atlantic, representing the Brazilian distribution of this species. Segments of three mitochondrial (Cytb, COI and 16S) and one nuclear (IGF1) gene were sequenced. The results of all analyses indicated the presence of a previously undetected lineage of Centropomus in the northern extreme of Brazil (Amapa) in the region of the Oiapoque estuary. This taxon is genetically distinct from all 12 recognized species of Centropomus. The populations from the Brazilian states of Para, Maranhao, Ceara, Rio Grande do Norte, Rio de Janeiro and Sao Paulo were genetically similar to C. undecimalis from coastal areas of the Caribbean and USA. Nucleotide divergence between C. undecimalis and the new Oiapoque taxon are greater than or similar to those found between a number of valid Centropomus species. The estimated time of divergence between C. undecimalis and the new taxon is approximately 2 millionyears. The findings of the present study emphasize the need for a thorough taxonomic revision of this genus. PMID- 24792090 TI - Obesity and hypertension in the Argentinian population compared to the white Hispanic population of the United States. AB - Hypertension and obesity are two closely related pathologies in clinical practice. Currently, about one billion adults worldwide are overweight, and it is estimated that, if no serious action is taken to effect profound change, that figure will continue to rise throughout this century. Hypertension is also a serious public health problem worldwide, one that, along with type 2 diabetes, is growing due to increases in both life expectancy and obesity. However, the rate of increase varies by population group. For example, in the United States, the prevalence of obesity differs quite markedly among the white population of European origin, African American individuals, and the Latin American population. This disparity exists among other populations as well, such as that of Argentina, where obesity is less prevalent than in the United States. This significant difference between the Argentinean population and that of American whites may be explained by the former population's migratory origin and distinct eating habits. PMID- 24792091 TI - Aldosterone excess and resistant hypertension: investigation and treatment. AB - Among patients with resistant hypertension, primary aldosteronism (PA) is worth detecting as it appears to be particularly common in this cohort. It is associated with excessive cardiovascular morbidity in relation to the degree of hypertension and reduced quality of life, both of which can be abrogated with specific surgical or medical treatment. Knowledge concerning factors (including medications) which can influence the results of screening by aldosterone/renin ratio (ARR) testing is expanding, and is important to appreciate, particularly in patients with resistant hypertension, in whom the need for multiple medications can render interpretation challenging. Advances in approaches to confirmatory testing, subtype differentiation and assay methodology are helping to improve feasibility and reliability of the diagnostic workup for PA and new treatment approaches are emerging. Major developments in understanding the genetic bases for PA hold promise towards further improvements and options in diagnosis and therapy. PMID- 24792092 TI - AT2 receptors targeting cardiac protection post-myocardial infarction. AB - The angiotensin AT2-receptor mediates tissue protective actions. Its regenerative potential has been tested in multiple disease models including models of myocardial infarction. These studies used different experimental approaches in order to detect AT2-receptor-related effects such as AT2-receptor deficiency or overexpression, treatment with an AT1-receptor blocker leading to indirect stimulation of the unopposed AT2-receptor, or studies using AT2-receptor agonists. It is a common finding in these studies that the AT2-receptor improves cardiac function in the early phase post-MI, and that this effect is preserved over periods of up to four months. Depending on the experimental protocol, the AT2R also attenuates post-MI left ventricular remodeling or protects the heart from early left ventricular thinning and rupture. In combination with AT1 receptor blockade or deficiency, post-MI cardiac hypertrophy is reduced. This article reviews studies on the role of the AT2-receptor in myocardial infarction with an emphasis on the most recent data obtained in studies using AT2-receptor agonists. PMID- 24792093 TI - Diagnosis and management of pheochromocytoma: a practical guide to clinicians. AB - Pheochromocytomas (PCCs) are rare catecholamine producing neuroendocrine tumors. The majority of these tumors (85 %) arise from the adrenal medulla. Those arising from the extra-adrenal neural ganglia are called paragangliomas (PGLs). Paroxysmal hypertension with sweating, headaches and palpitation are the usual presenting features of PCCs/ PGLs. Gene mutations are reported in 32-79 % of cases, making genetic screening mandatory in all the cases. The malignancy rates are 10-15 % for PCCs and 20-50 % for PGLs. Measurement of plasma or 24-hour urinary fractionated metanephrines is the best biochemical diagnostic test. Computed tomography or magnetic resonance imaging has high sensitivity (90-100 %) and reasonable specificity (70-90 %) for the anatomical localization. The functionality is assessed by different radionuclide imaging modalities such as metaiodobenzylguanidine (MIBG) scintigraphy, positron emission tomography or single photon emission computed tomography. The only modality of curative treatment is tumor excision. Proper peri-operative management improves the surgical outcomes. Annual follow up with clinical and biochemical assessment is recommended in all the cases after treatment. Children, pregnant women and older people have higher morbidity and mortality risk. De-bulking surgery, chemotherapy, radiotherapy, molecular agents like sunitinib and everolimus, radionuclide agents and different ablation procedures may be useful in the palliation of inoperable/metastatic disease. An update on the diagnostic evaluation and management of PCCs and PGLs is presented here. PMID- 24792094 TI - ACE overexpression in myelomonocytic cells: effect on a mouse model of Alzheimer's disease. AB - While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice overexpress ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-beta protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD. PMID- 24792095 TI - Sociodemographic factors and prejudice toward HIV and hepatitis B/C status in a working-age population: results from a national, cross-sectional study in Japan. AB - BACKGROUND: In many countries, HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infected individuals may face discrimination and mistreatment from coworkers. Effective interventions to reduce workplace discrimination are therefore needed to protect these vulnerable populations. The current study investigated potential associations between sociodemographic factors and prejudice toward HIV and HBV/HCV infected colleagues within a Japanese working population. METHODS: An online anonymous, nationwide internet survey was administered to a cross-section of approximately 3,000 individuals in Japan. The survey comprised 14 questions focusing on demographics (five items), basic HIV or HBV/HCV knowledge (eight items), and potential prejudice toward HIV or HBV/HCV infected colleagues (one item). The sociodemographic characteristics evaluated were sex, age, educational level, employment status, and individual income; with multiple logistic regression used for the analysis. RESULTS: In total, 3,055 individuals were recruited for the HIV related survey and 3,129 for the HBV/HCV related survey. Older age was significantly and positively associated with prejudice toward HIV infected colleagues (p<0.01) and negatively associated with prejudice toward HBV/HCV infected colleagues (p<0.01). Statistically significant associations were not observed between other sociodemographic characteristics and potential prejudice toward HIV and HBV/HCV infected coworkers. CONCLUSION: Overall, this study suggests that age may be associated with prejudice toward HIV and HBV/HCV infected colleagues among the working age population of Japan. As such, policy makers should consider the age of participants when formulating efforts to reduce prejudice toward HIV and HBV/HCV infected workers. PMID- 24792096 TI - Two-hit rodent seizure model: a promising new design for research in SUDEP. PMID- 24792097 TI - Object location performance: detection of functional impairment in right temporal lobe epilepsy. AB - A prominent role of the right temporal lobe in nonverbal memory and visuospatial memory is widely accepted. A variety of neuropsychological tests have been shown to be sensitive to functional deficits related to right temporal lobe epilepsies mainly after surgical interventions, whereas preoperative deficits were seldom used to demonstrate test sensitivities. Furthermore, compensation processes or additional cognitive deficits related to left temporal or extratemporal dysfunctions are often not adequately taken into account. We used a modified object location task to demarcate preoperative visuospatial memory deficits of right temporal origin against such processes in patients with clinically verified right temporal, left temporal, or extratemporal lobe epilepsies. Healthy subjects served as controls. By using 8 "unnameable" objects, the positional memory accuracy of patients with right temporal lobe epilepsy was significantly lower than the positional memory performance of patients with left temporal and extratemporal lobe epilepsies, while object location memory performance differentiated patients with right temporal and extratemporal lobe epilepsies from patients with left temporal lobe epilepsy. Our version of a classical object location task might be a useful tool to detect mnestic deficits specifically related to right temporal lobe dysfunction. Future studies should focus on the refinement of testing conditions in order to detect differences induced by more distinct structural or functional deficits. PMID- 24792098 TI - The Symbol Digit Modalities Test is an effective cognitive screen in pediatric onset multiple sclerosis (MS). AB - OBJECTIVE: To evaluate the Symbol Digit Modalities Test (SDMT) as a tool for identifying pediatric-onset MS patients at risk for cognitive impairment. BACKGROUND: The SDMT is a brief measure of cognitive processing speed that is often used in adult MS patients. Approximately one-third of pediatric-onset MS patients have cognitive impairment and there is a need for an effective screening instrument. DESIGN/METHODS: Seventy (70) consecutive outpatients with pediatric onset MS underwent clinical evaluations including the SDMT and were compared to those with other pediatric neurological diagnoses (OND, n=40) and healthy controls (HC, n=32). A subset of the MS group and all healthy controls completed neuropsychological evaluation within one year of SDMT administration. RESULTS: The MS group performed worse on the SDMT compared to the HC group (p=0.02). Thirty-seven percent (37%) of the MS, 20% of the OND, and 9% of HC groups scored in the impaired range. For MS participants who underwent neuropsychological testing (n=31), the SDMT showed 77% sensitivity and 81% specificity for detecting neuropsychological impairment when administered within one year and reached 100% sensitivity when the interval was under two months (n=17). Overall, older age and increased disability predicted poorer SDMT performance (age r=-0.26, p=0.03) and the Expanded Disability Status Scale score or EDSS (r=-0.47, p<0.001), while a history of optic neuritis predicted better performance (p=0.04). Optical coherence tomography measures were not related to SDMT performance. CONCLUSION: In this preliminary study, the SDMT was an effective brief screen for detecting cognitive impairment in pediatric-onset MS. PMID- 24792099 TI - Reliability of transcranial magnetic stimulation induced corticomotor excitability measurements for a hand muscle in healthy and chronic stroke subjects. AB - Transcranial magnetic stimulation (TMS) has been used to evaluate neuroplastic changes in the brain in clinical trials. The purpose of this study was to establish the test-retest reliability of 4 TMS measures of corticomotor excitability - (1) resting motor threshold, (2) slope of input-output curve, (3) peak motor evoked potential amplitude, and (4) cortical silent period duration for the corticospinal projections to the first dorsal interosseous of the contralateral hand. Fourteen healthy subjects (mean age 27.4 years) and 27 subjects with stroke-induced upper limb hemiparesis (mean age 61.3 years) completed 2 repeated sessions of assessment of 1 week apart. Good to excellent test-retest reliability of the TMS measurements was confirmed in the stroke subjects for both hemispheres with the ICC >= 0.88. Measurement reliability was good (ICC >= 0.75) for the 4 outcome measures in healthy subjects. Contrary to the similarity in standard error of measurements in both hemispheres for outcome measures (1) to (3) in the stroke subjects, that of the cortical silent period duration was larger in magnitude in the lesioned hemisphere. The test-retest reliability coefficients determined for the four corticomotor excitability measurements allowed the estimation of 95% minimal detectable changes of these outcome variables for the respective subject group in future clinical trials. PMID- 24792101 TI - The cataract situation in Latin America: barriers to cataract surgery. AB - PURPOSE: To provide an update of cataract data and barriers to cataract surgery in Latin America. DESIGN: Review and longitudinal study. METHODS: Cataract surgery rates and other related indicators that have been reported to the VISION 2020 Latin America program since 2005 were reviewed. PubMed was searched for publications concerning regional epidemiologic studies related to cataract, cataract surgery, barriers, outcomes, and cataract prevalence between January 2012 and October 2013 to obtain the most up-to-date data from 19 countries. RESULTS: The weighted mean regional cataract surgery rate has increased by an impressive 70% since 2005, from 1562 to 2672 cataract surgeries per 1 million inhabitants. The weighted mean number of ophthalmologists per 1 million inhabitants in the region is approximately 62. Cataract surgery coverage varies widely in Latin America, from a meager 15% in El Salvador to a more satisfactory 77% in Uruguay. Five recent surveys indicate that lack of awareness of cataract and the surgery treatment option as well as the cost of the surgery are the main barriers to cataract surgery. CONCLUSIONS: In spite of the increasing rates of cataract surgery and the more-than-adequate number of ophthalmologists in Latin America, it is not known how many ophthalmologists actually perform surgery. Coverage remains less than satisfactory across the region. Barriers to cataract surgery hinder the efforts of eye care programming. More comprehensive eye care programs and training centers are needed so that they can focus on reaching the underserved and unaware communities, increase surgery output and uptake, and improve outcomes. PMID- 24792100 TI - The relationship of major American dietary patterns to age-related macular degeneration. AB - PURPOSE: We hypothesized that major American dietary patterns are associated with risk for age-related macular degeneration (AMD). DESIGN: Cross-sectional study. METHODS: We classified 8103 eyes in 4088 eligible participants in the baseline Age-Related Eye Disease Study (AREDS). They were classified into control (n = 2739), early AMD (n = 4599), and advanced AMD (n = 765) by the AREDS AMD Classification System. Food consumption data were collected by using a 90-item food frequency questionnaire. RESULTS: Two major dietary patterns were identified by factor (principal component) analysis based on 37 food groups and named Oriental and Western patterns. The Oriental pattern was characterized by higher intake of vegetables, legumes, fruit, whole grains, tomatoes, and seafood. The Western pattern was characterized by higher intake of red meat, processed meat, high-fat dairy products, French fries, refined grains, and eggs. We ranked our participants according to how closely their diets line up with the 2 patterns by calculating the 2 factor scores for each participant. For early AMD, multivariate adjusted odds ratio (OR) from generalized estimating equation logistic analysis comparing the highest to lowest quintile of the Oriental pattern score was ORE5O = 0.74 (95% confidence interval (CI): 0.59-0.91; Ptrend =0.01), and the OR comparing the highest to lowest quintile of the Western pattern score was ORE5W = 1.56 (1.18-2.06; Ptrend = 0.01). For advanced AMD, the ORA5O was 0.38 (0.27-0.54; Ptrend < 0.0001), and the ORA5W was 3.70 (2.31-5.92; Ptrend < 0.0001). CONCLUSIONS: Our data indicate that overall diet is significantly associated with the odds of AMD and that dietary management as an AMD prevention strategy warrants further study. PMID- 24792102 TI - Intraocular pressure and wound status in eyes immediately after scleral tunnel incision and clear corneal incision cataract surgery. AB - PURPOSE: To compare intraocular pressure (IOP) and wound architecture immediately after cataract surgery using a scleral tunnel incision or clear corneal incision. DESIGN: Prospective randomized clinical trial. METHODS: Bilateral eyes of 64 patients undergoing phacoemulsification were randomized to 2 groups: 2.4 mm scleral tunnel incision or 2.4 mm clear corneal incision. IOP was adjusted upon completion of surgery to between 15 and 30 mm Hg. The wound was hydrated in 87.5% of eyes in the clear corneal incision group. IOP was measured using a rebound tonometer preoperatively; at the conclusion of surgery; and at 5, 10, 15, 30, and 60 minutes postoperatively. The Seidel test and anterior segment optical coherence tomography (AS OCT) were performed at 30 minutes postoperatively. RESULTS: In the scleral tunnel incision group, mean IOP decreased to the preoperative level within 15 minutes postoperatively and did not change significantly for up to 60 minutes. In the clear corneal incision group, IOP decreased to lower than the preoperative IOP at 30 minutes postoperatively. Mean IOP was significantly higher in the scleral tunnel incision group than in the clear corneal incision group throughout the postoperative period (P<=.0339). Hypotony (<10 mm Hg) was observed in 7 eyes (10.9%) that underwent clear corneal incision and in no eyes that underwent scleral tunnel incision (P=.0131). Wound leakage and loss of wound coaptation were not observed in any eyes. CONCLUSIONS: IOP was significantly higher immediately after scleral tunnel incision without hydration than after clear corneal incision with hydration, and both incisions closed within 30 minutes postoperatively without leakage based on AS OCT. PMID- 24792103 TI - Assessment of rose bengal versus riboflavin photodynamic therapy for inhibition of fungal keratitis isolates. AB - PURPOSE: To compare the in vitro effect of rose bengal and riboflavin as photosensitizing agents for photodynamic therapy (PDT) on fungal isolates that are common causes of fungal keratitis. DESIGN: Experimental study. METHODS: Three isolates (Fusarium solani, Aspergillus fumigatus, Candida albicans) recovered from patients with confirmed fungal keratitis were used in the experiments. Isolates were grown on Sabouraud-Dextrose agar, swabbed, and prepared in suspension, and 1 mL aliquots were inoculated onto test plates in triplicate. Test plates were separated into 5 groups: Group 1, no treatment; Group 2, 0.1% rose bengal alone; Group 3, 518 nm irradiation alone; Group 4, riboflavin PDT (riboflavin + 375 nm irradiation); and Group 5, rose bengal PDT (rose bengal + 518 nm irradiation). Irradiation was performed over a circular area using either a green light-emitting diode (LED) array (peak wavelength: 518 nm) or an ultraviolet-A LED array (peak wavelength: 375 nm). Test plates were irradiated with an energy density of 5.4 J/cm(2). Later, plates were placed in a 30 C incubator and observed for growth. RESULTS: Rose bengal-mediated PDT successfully inhibited the growth of all 3 fungal isolates in the irradiated area. All other groups exhibited unrestricted growth throughout the plate. CONCLUSIONS: Rose bengal-mediated PDT successfully inhibited the growth of 3 types of fungi. No other experimental groups, including riboflavin-mediated PDT, had any inhibitory effect on the isolates. The results might be useful for the treatment of patients suffering from corneal infection. PMID- 24792104 TI - Descemet membrane endothelial keratoplasty tissue preparation from donor corneas using a standardized submerged hydro-separation method. AB - PURPOSE: To standardize a novel submerged hydro-separation technique for Descemet membrane endothelial keratoplasty (DMEK) graft preparation from donor corneal tissues. DESIGN: Experimental study, laboratory investigation. METHODS: SETTING: The Veneto Eye Bank Foundation, Venice, Italy. STUDY POPULATION: Fifty-four random human donor corneal tissues unsuitable for transplantation. INTERVENTION: Donor corneas were laid in a sterile basin partially filled with tissue culture medium. A 25 gauge needle with 1 mL mounted syringe was filled with the tissue culture medium. The needle (with bevel up) was bent to 90 degrees and was inserted in the posterior cornea initiating beneath the trabecular meshwork. It was further advanced toward the midperiphery, ensuring that only the bevel was inserted, considering it as a threshold of insertion. The liquid was injected with a medium to high pressure into the posterior stroma or in the Descemet membrane-stroma interface to create the bubble. The tissues were preserved for 7 days in tissue culture medium at 31 degrees C. Parametrical, physiological and histological analyses were carried out. MAIN OUTCOME MEASURES: Larger-diameter tissue, no tissue wastage, reproducibility, and preshipment evaluation. RESULTS: Complete detachment was achieved in all the cases without any tissue wastage. Average diameter of the excised graft was 10.80 (+/-0.28) mm and endothelial cell loss post preservation was 11.48%. Expression of tight junction protein and regular morphology was observed post preservation. No signs of cell apoptosis were seen. Histological analysis showed elimination of residual stroma in most of the cases. CONCLUSIONS: The submerged hydro-separation method reduces tissue wastage. It allows preshipment evaluation, thus allowing a validated tissue to be transported from the eye banks to the surgeon. Because of the liquid interface, the peeling of the DMEK graft becomes easy for transplantation. PMID- 24792105 TI - Multifocal intraocular lens explantation: a case series of 50 eyes. AB - OBJECTIVE: To assess the visual complaints, reasons, and patient satisfaction for multifocal intraocular lens (IOL) explantation. DESIGN: Retrospective observational case series. METHODS: This study evaluated 50 eyes of 37 patients who underwent multifocal IOL explantation followed by IOL implantation. Before and 3 months after IOL exchange surgery, we investigated the symptoms, reasons, patient demographics, clinical results, and patient satisfaction in eyes undergoing multifocal IOL explantation. Data collected included preoperative subjective and objective findings, reasons, IOL type, postoperative course, and patient satisfaction. RESULTS: The most common complaints for IOL explantation were waxy vision, followed by glare and halos, blurred vision at far, dysphotopsia, blurred vision at near, and blurred vision at intermediate. The most common reasons for IOL explantation were decreased contrast sensitivity, followed by photic phenomenon, unknown origin including neuroadaptation failure, incorrect IOL power, preoperative excessive expectation, IOL dislocation/decentration, and anisometropia. The axial length was 25.13+/-1.83 mm. Of the explanted multifocal IOLs, 84% were diffractive and 16% were refractive. Monofocal IOLs accounted for 90% of the exchanged IOLs. Patient satisfaction was significantly improved from 1.22+/-0.55 preoperatively to 3.78+/ 0.97 postoperatively, which was graded on a scale of 1 (very dissatisfied) to 5 (very satisfied) (Wilcoxon signed-rank test, P<.001). CONCLUSIONS: Multifocal IOL explantation was required in some patients undergoing multifocal IOL implantation. IOL exchange surgery appears to be a feasible surgical option for dissatisfied patients with persistent visual symptoms after multifocal IOL implantation. PMID- 24792106 TI - Comparison of two different ultrasound methods of phacoemulsification. AB - PURPOSE: To compare the safety and efficacy of microcoaxial phacoemulsification surgeries performed with the OZil Intelligent Phaco torsional mode (Alcon Laboratories, Inc., Fort Worth, USA) and combined torsional/longitudinal ultrasound mode using 45 degree aperture angled tips. DESIGN: Prospective randomized clinical trial. METHODS: setting: Maltepe University, Istanbul. patient population: Eighty eyes of 80 cataract patients were randomly assigned to 2.2 mm microcoaxial phacoemulsification using the OZil Intelligent Phaco torsional mode (Group 1) or combined torsional/longitudinal ultrasound mode (Group 2). observation procedure: Intraoperative fluid and energy usage and postoperative examinations were evaluated. main outcome measures: Ultrasound time, cumulative dissipated energy, longitudinal and torsional ultrasound amplitudes, mean operation time, mean volume of fluid used, and surgical complications. RESULTS: Both groups included 40 eyes. Mean ultrasound time, cumulative dissipated energy, and longitudinal and torsional ultrasound amplitudes in Group 1 were 58.21+/-33.81 seconds, 7.74+/-6.23, 0.45+/-0.30, and 26.30+/-12.60%, respectively, and these parameters in Group 2 were 64.75+/-30.23 seconds, 12.61+/-6.21, 26.32+/-5.85, and 40.98+/-8.33%, respectively. Cumulative dissipated energy and longitudinal and torsional amplitudes were found to be significantly lower in Group 1 (P=.001, P<.001, P<.001). Mean volumes of fluid used in Groups 1 and 2 were 73.30+/-19.87 cc and 107.07+/-21.82 cc, respectively (P<.001). CONCLUSION: With the aid of a 45 degree aperture angled tip, the OZil Intelligent Phaco torsional mode provided more effective lens removal than the combined torsional/longitudinal ultrasound mode, with a lower cumulative dissipated energy and volume of fluid used. PMID- 24792107 TI - Spectral-domain optical coherence tomography epithelial and flap thickness mapping in femtosecond laser-assisted in situ keratomileusis. AB - PURPOSE: To evaluate the change of epithelial and flap thickness after femtosecond laser-assisted in situ keratomileusis (LASIK) using spectral-domain optical coherence tomography (SD OCT) in correlation with the spherical equivalent refraction treated and clinical outcomes. DESIGN: Prospective, randomized, contralateral-eye study. METHODS: Forty myopic eyes underwent LASIK using an excimer laser with refraction ranging from -1.00 to -7.25 diopters (mean -3.25+/-1.9). Flap creation was randomized between eyes, using the IntraLASE FS60 laser (IL) in 1 eye and WaveLight FS200 laser (FS) in the contralateral eye. SD OCT was used to evaluate the epithelial and flap thickness profiles and corneal power preoperatively and at 1 week and 1, 3, and 9 months postoperatively. Manifest and wavefront refractions were performed at each postoperative visit. RESULTS: Statistically significant epithelial thickening was observed in both IL and FS groups as early as 1 month postoperatively (P=.033 and P=.042), but this stabilized between 3 (P=.042 and P=.035) and 9 months (P=.043 and P=.041). Femtosecond-LASIK flaps were thicker in the IL group in comparison to the FS group at 3 and 9 months postoperatively (P=.003 and P=.005, respectively). There was a statistically significant correlation between the magnitude of preoperative myopic refraction and the central epithelial thickness at 1, 3, and 9 months (Pearson correlation coefficients 0.485, 0.587 and 0.576) (P=.0021, P=.0010, and P=.0011), respectively. SD OCT corneal power maps showed steepening at 3 and 9 months along with mild myopic shift. CONCLUSION: Progressive epithelial and flap thickening with increased corneal power were observed after femtosecond laser assisted in situ keratomileusis for myopia with consequent stabilization between 3 to 9 months postoperatively. The magnitude of epithelial and flap thickness remodeling correlated to the preoperative myopic refractive error. PMID- 24792108 TI - Export and expression: mRNAs deliver new messages for controlling pluripotency. AB - Fine-tuning of the pluripotency program is executed by a multitude of cellular processes. Two recent studies published in Cell Stem Cell (Wang et al., 2013; Tahmasebi et al., 2014) provide novel insights into the posttranscriptional and translational regulatory mechanisms controlling stem cell pluripotency and somatic cell reprogramming. PMID- 24792109 TI - Aging stem cells: transcriptome meets epigenome meets methylome. AB - Aging is associated with impairments in hematopoietic stem cell (HSC) function and an increased risk of leukemogenesis. In this issue of Cell Stem Cell, Sun et al. (2014) use highly purified HSCs along with an integrated genomic approach to evaluate aging-associated alterations in the epigenome and transcriptome of HSCs. PMID- 24792110 TI - Targeting epigenetics to speed up repair. AB - In this issue of Cell Stem Cell, Palii et al. reveal that TAL1 is a master regulator of adhesion and migration networks in human endothelial progenitors and that ex vivo treatment with the histone deacetylase inhibitor TSA enables their faster vascularization after ischemic injury. PMID- 24792111 TI - Induced hematopoietic stem cells: unlocking restrictions in lineage potential and self-renewal. AB - Obtaining sufficient numbers of immunologically matched hematopoietic stem cells (HSCs) poses a major clinical hurdle in bone marrow transplantation therapies. In a recent study in Cell, Riddell et al. (2014) generate induced HSCs from differentiated blood cells, which may serve as a potential solution to this clinical challenge. PMID- 24792112 TI - Variety in the tumor microenvironment: integrin splicing regulates stemness. AB - Recently in Cell Reports, Goel et al. (2014) identified mechanisms underlying cellular heterogeneity in triple negative breast cancer. They find that expression of alpha6 integrin and its splice variants differs between epithelial and mesenchymal tumor cell subpopulations, the latter of which relies on VEGF signaling to promote cancer stem cell function. PMID- 24792113 TI - Allying with donors to link health and medical information with stem cell lines can advance disease modeling while enhancing data access. PMID- 24792114 TI - Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. AB - The liver is a central organ for homeostasis with unique regenerative capacities. Mature hepatocytes possess a remarkable capacity to proliferate upon injury, challenging efforts to discern the role of adult liver stem cells in this process. In contrast, stem/progenitor cells in the developing liver have been extensively characterized, and these investigations have informed efforts to produce functional hepatocytes in vitro for cell therapy and drug screening. In this Review, we describe recent advances in the characterization of liver stem cells and discuss evidence supporting and refuting whether self-renewable and bipotential liver stem cells exist in development, homeostasis, regeneration, and disease. PMID- 24792115 TI - INO80 facilitates pluripotency gene activation in embryonic stem cell self renewal, reprogramming, and blastocyst development. AB - The master transcription factors play integral roles in the pluripotency transcription circuitry of embryonic stem cells (ESCs). How they selectively activate expression of the pluripotency network while simultaneously repressing genes involved in differentiation is not fully understood. Here, we define a requirement for the INO80 complex, a SWI/SNF family chromatin remodeler, in ESC self-renewal, somatic cell reprogramming, and blastocyst development. We show that Ino80, the chromatin remodeling ATPase, co-occupies pluripotency gene promoters with the master transcription factors, and its occupancy is dependent on OCT4 and WDR5. At the pluripotency genes, Ino80 maintains an open chromatin architecture and licenses recruitment of Mediator and RNA polymerase II for gene activation. Our data reveal an essential role for INO80 in the expression of the pluripotency network and illustrate the coordination among chromatin remodeler, transcription factor, and histone-modifying enzyme in the regulation of the pluripotent state. PMID- 24792116 TI - Trrap-dependent histone acetylation specifically regulates cell-cycle gene transcription to control neural progenitor fate decisions. AB - Fate decisions in neural progenitor cells are orchestrated via multiple pathways, and the role of histone acetylation in these decisions has been ascribed to a general function promoting gene activation. Here, we show that the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (Trrap) specifically regulates activation of cell-cycle genes, thereby integrating discrete cell-intrinsic programs of cell-cycle progression and epigenetic regulation of gene transcription in order to control neurogenesis. Deletion of Trrap impairs recruitment of HATs and transcriptional machinery specifically to E2F cell-cycle target genes, disrupting their transcription with consequent cell-cycle lengthening specifically within cortical apical neural progenitors (APs). Consistently, Trrap conditional mutants exhibit microcephaly because of premature differentiation of APs into intermediate basal progenitors and neurons, and overexpressing cell-cycle regulators in vivo can rescue these premature differentiation defects. These results demonstrate an essential and highly specific role for Trrap-mediated histone regulation in controlling cell cycle progression and neurogenesis. PMID- 24792117 TI - Trichostatin A enhances vascular repair by injected human endothelial progenitors through increasing the expression of TAL1-dependent genes. AB - A major goal of cell therapy for vascular diseases is to promote revascularization through the injection of endothelial stem/progenitor cells. The gene regulatory mechanisms that underlie endothelial progenitor-mediated vascular repair, however, remain elusive. Here, we identify the transcription factor TAL1/SCL as a key mediator of the vascular repair function of primary human endothelial colony-forming cells (ECFCs). Genome-wide analyses in ECFCs demonstrate that TAL1 activates a transcriptional program that promotes cell adhesion and migration. At the mechanistic level, we show that TAL1 upregulates the expression of migratory and adhesion genes through recruitment of the histone acetyltransferase p300. Based on these findings, we establish a strategy that enhances the revascularization efficiency of ECFCs after ischemia through ex vivo priming with the histone deacetylase inhibitor TSA. Thus, small molecule epigenetics drugs are effective tools for modifying the epigenome of stem/progenitor cells prior to transplantation as a means to enhance their therapeutic potential. PMID- 24792118 TI - Mouse spermatogenic stem cells continually interconvert between equipotent singly isolated and syncytial states. AB - The identity and behavior of mouse spermatogenic stem cells have been a long standing focus of interest. In the prevailing "As model," stem cell function is restricted to singly isolated (As) spermatogonia. By examining single-cell dynamics of GFRalpha1+ stem cells in vivo, we evaluate an alternative hypothesis that, through fragmentation, syncytial spermatogonia also contribute to stem cell function in homeostasis. We use live imaging and pulse labeling to quantitatively determine the fates of individual GFRalpha1+ cells and find that, during steady state spermatogenesis, the entire GFRalpha1+ population comprises a single stem cell pool, in which cells continually interconvert between As and syncytial states. A minimal biophysical model, relying only on the rates of incomplete cell division and syncytial fragmentation, precisely predicts the stochastic fates of GFRalpha1+ cells during steady state and postinsult regeneration. Thus, our results define an alternative and dynamic model for spermatogenic stem cell function in the mouse testis. PMID- 24792119 TI - Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. AB - To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-beta signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging. PMID- 24792122 TI - Detection of fast neutrons from shielded nuclear materials using a semiconductor alpha detector. AB - The response of a semiconductor alpha detector to fast (>1 MeV) neutrons was investigated by using measurements and simulations. A polyethylene converter was placed in front of the detector to register recoil protons generated by elastic collisions between neutrons and hydrogen nuclei of the converter. The developed prototype equipment was tested with shielded radiation sources. The low background of the detector and insensitivity to high-energy gamma rays above 1 MeV are advantages when the detection of neutron-emitting nuclear materials is of importance. In the case of a (252)Cf neutron spectrum, the intrinsic efficiency of fast neutron detection was determined to be 2.5*10(-4), whereas three-fold greater efficiency was obtained for a (241)AmBe neutron spectrum. PMID- 24792120 TI - Around-the-clock ambulatory blood pressure monitoring is required to properly diagnose resistant hypertension and assess associated vascular risk. AB - Diagnosis of resistant hypertension (RH) is currently based upon awake-time office blood pressure (BP). An increasing number of studies have documented abnormally elevated sleep-time BP in most RH patients, indicating that diagnosis of true RH cannot be determined solely by comparison of office BP with either patient awake-time BP self-measurements or awake-BP mean from ambulatory monitoring (ABPM), as is customary in the published literature. Moreover, the ABPM-determined sleep-time BP mean is an independent and stronger predictor of cardiovascular and cerebrovascular disease (CVD) risk than either daytime office/ABPM-derived awake or 24-hour means. Results of the recently completed MAPEC (Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares) prospective outcomes study, which included a large cohort of RH patients, established that time of treatment relative to circadian rhythms constituted a critically important yet often neglected variable with respect to BP control. The study found that bedtime versus morning ingestion of the full dose of >=1 BP lowering medications resulted in both better therapeutic normalization of sleep time BP and reduced CVD morbidity and mortality, including in RH patients. Accordingly, ABPM is highly recommended to properly diagnose and manage true RH, with a bedtime hypertension medication regimen as the therapeutic scheme of choice. PMID- 24792121 TI - Hypertension as a risk factor for heart failure. AB - Hypertension remains a significant risk factor for development of congestive heart failure CHF), with various mechanisms contributing to both systolic and diastolic dysfunction. The pathogenesis of myocardial changes includes structural remodeling, left ventricular hypertrophy, and fibrosis. Activation of the sympathetic nervous system and renin-angiotensin system is a key contributing factor of hypertension, and thus interventions that antagonize these systems promote regression of hypertrophy and heart failure. Control of blood pressure is of paramount importance in improving the prognosis of patients with heart failure. PMID- 24792123 TI - The design of a multisource americium-beryllium (Am-Be) neutron irradiation facility using MCNP for the neutronic performance calculation. AB - The americium-beryllium neutron irradiation facility at the National Nuclear Research Institute (NNRI), Ghana, was re-designed with four 20 Ci sources using Monte Carlo N-Particle (MCNP) code to investigate the maximum amount of flux that is produced by the combined sources. The results were compared with a single source Am-Be irradiation facility. The main objective was to enable us to harness the maximum amount of flux for the optimization of neutron activation analysis and to enable smaller sample sized samples to be irradiated. Using MCNP for the design construction and neutronic performance calculation, it was realized that the single-source Am-Be design produced a thermal neutron flux of (1.8+/ 0.0007)*10(6) n/cm(2)s and the four-source Am-Be design produced a thermal neutron flux of (5.4+/-0.0007)*10(6) n/cm(2)s which is a factor of 3.5 fold increase compared to the single-source Am-Be design. The criticality effective, k(eff), of the single-source and the four-source Am-Be designs were found to be 0.00115+/-0.0008 and 0.00143+/-0.0008, respectively. PMID- 24792124 TI - A modified version of the combined in-diffusion/abrasive peeling technique for measuring diffusion of strongly sorbing radionuclides in argillaceous rocks: a test study on the diffusion of caesium in Opalinus Clay. AB - A filter free diffusion set-up was developed for measuring the diffusion of strongly sorbing radionuclides in indurated argillaceous rocks such as Opalinus Clay (OPA) that normally disintegrate when contacted with a solution. Small bore cores drilled parallel to the bedding plane and embedded in epoxy resin were found to be stable and could be used for performing in-diffusion measurements. The method was tested with the diffusion of caesium, spiked with caesium-134, in Opalinus Clay. The profile of Cs in the clay sample was determined with a modified version of the abrasive peeling technique. The diffusion parameters obtained for caesium were in fair agreement with those determined earlier using the classical through-diffusion technique where stainless steel filters were used to confine the samples. PMID- 24792125 TI - Gender-specific metabolic responses in gonad of mussel Mytilus galloprovincialis to 2,2',4,4'-tetrabromodiphenyl ether. AB - Polybrominated diphenyl ethers (PBDEs) are widely used as a class of brominated flame-retardants. As a congener of PBDEs, 2,2',4,4'-tetrabromodiphenylether (BDE 47) is the most toxic congener to animals. In this study, we applied metabolomics to characterize the gender-specific metabolic responses in mussel Mytilus galloprovincialis exposed to BDE 47 for 30 days. Results indicated the apparent gender-specific responses in M. galloprovincialis with BDE 47 exposures (1 and 10 MUg/L) at metabolite level. Basically, BDE 47 induced disruption in osmotic regulation and altered energy metabolism in mussels, via differential metabolic pathways. In addition, the hormesis phenomenon was observed in both male and female mussel samples exposed the two concentrations of BDE 47, indicated by the contrarily altered metabolites from two BDE 47 treatments (1 and 10 MUg/L), respectively. Overall, this study confirmed the gender-specific responses to BDE 47 exposures in mussels and suggested the gender differences should be considered in marine ecotoxicology. PMID- 24792126 TI - Biomarkers for monitoring profluthrin exposure: urinary excretion kinetics of profluthrin metabolites in rats. AB - Recently, a pyrethroid profluthrin [(2,3,5,6-tetrafluoro-4-methylphenyl)methyl 2,2-dimethyl-3-(prop-1-enyl)cyclopropane-1-carboxylate] is widely used as mothproof repellents in indoors. The urinary excretion kinetics of its metabolites was examined in rats to search for urinary metabolites suitable as biomarkers of profluthrin exposure in the general population. A single dose (26 400 mg/kg body weight) of profluthrin was administered intraperitoneally to the rats, and then their urine was collected periodically. Four major profluthrin metabolites, 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol (CH3-FB-Al), 4 hydroxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, 4-methyl-2,3,5,6 tetrafluorobenzoic acid and 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylic acid (MCA) were determined in the urine samples by gas chromatography/mass spectrometry. The kinetic evaluation for each metabolite was achieved by moment analysis of the urinary excretion rate versus time curve. The urinary excretion amounts of the three metabolites, expect for MCA, were estimated to be proportional to the amounts of absorbed profluthrin over a wide exposure range. Urinary CH3-FB-Al was considered to be an optimal biomarker for monitoring of profluthrin. PMID- 24792127 TI - Comparison of three PCR-based assays for the non-invasive diagnosis of malaria: detection of Plasmodium parasites in blood and saliva. AB - The conventional molecular diagnosis of malaria uses 18S rRNA-based PCR assay employing blood samples. This assay presents limitation in terms of long turnaround time and increased chances of false-positive results. Here, we evaluated one-step singleplex or multiplex PCR assay based on high copy species specific consensus repeat sequences (CRS) along with standard 18S rRNA nested PCR (18S n-PCR) assay to detect P. falciparum and P. vivax infection using blood and saliva samples from Indian febrile patients. Out of 327 patients, 187 were found to be positive for malaria parasites by microscopic examination of peripheral blood smears. Among these 130 were P. vivax and 57 were P. falciparum cases. The 18S n-PCR assay and CRS PCR assay identified 186 out of 187 cases (99.4 %). Multiplex CRS PCR assay detected Plasmodium in 176 out of 187 cases (94.1 %). Both singleplex and multiplex CRS PCR assay identified 6 mixed infection cases, while 18S n-PCR assay detected 10 mixed infection cases of P. vivax and P. falciparum, which were not recognized by microscopy. Non-invasive Plasmodium detection rate with DNA derived from saliva samples was highest for 18S n-PCR (87.36 %), followed by singleplex CRS (81 %) and multiplex CRS PCR assay (70.5 %). Specificity for P. vivax and P. falciparum detection for all assays was 98.48 % and 100 % respectively. Detection rate for P. vivax in saliva correlated with parasite density for CRS target-based assays. The species-specific CRS PCR, either as a singleplex or multiplex assay, can have an impact on diagnosis and epidemiological studies in malaria. PMID- 24792128 TI - First description of OXA-48-producing Escherichia coli and the pandemic clone ST131 from patients hospitalised at a military hospital in Algeria. AB - The aim of the study was to assess the frequency and diversity of carbapenemases and extended-spectrum beta-lactamases (ESBL) produced by Escherichia coli isolates from patients hospitalised in the Regional Military Hospital of Constantine (Algeria). E. coli isolates were collected over a 2-year period from patients presenting E. coli infections. Strains with reduced susceptibility to ertapenem and/or positive for ESBL were characterised with regard to antibiotic resistance, bla genes, phylogenetic groups, O25 serotyping, quinolone resistance, repetitive sequence-based polymerase chain reaction (rep-PCR) profiles and multi locus sequence typing (MLST). Of the 448 isolated E. coli, 94 (20.9 %) were multidrug-resistant. One of them (1.1 %) produced a bla OXA-48 and was identified as a B1 ST5 strain. The transposon bearing this gene was Tn1999.2. This strain was isolated from a patient coming from a border province with Tunisia, where this carbapenemase is endemic. In addition, 84 (18.8 %) isolates among them produced an ESBL with predominance (97.6 %) of bla CTX-M-15, which was coupled with qnr genes in 10.9 %. ESBL-producing strains were mainly detected in phylogroups D and A. They displayed 20 rep-PCR profiles and all the clonally related isolates were of the same sequence type (ST). Ten strains (9.4 %) belonged to the pandemic clone ST131. This study describes for the first time the presence of OXA-48-producing E. coli and the emergence of the intercontinental ST131 bla CTX-15-producing E. coli strains in Algeria. PMID- 24792129 TI - Disordered glycometabolism involved in pathogenesis of Kashin-Beck disease, an endemic osteoarthritis in China. AB - Kashin-Beck disease (KBD) is a chronic endemic osteoarthritis in China. Previous studies have suggested a role of metabolic dysfunction in causation of this disease. In this investigation, the metabolomics approach and cell experiments were used to discover the metabolic changes and their effects on KBD chondrocytes. Nuclear magnetic resonance ((1)H NMR) spectroscopy was used to examine serum samples from both the KBD patients and normal controls. The pattern recognition multivariate analysis (OSC-PLS) and quantitative analysis (QMTLS iterator) revealed altered glycometabolism in KBD, with increased glucose and decreased lactate and citrate levels. IPA biological analysis showed the centric location of glucose in the metabolic network. Massive glycogen deposits in chondrocytes and increased uptake of glucose by chondrocytes further confirmed disordered glycometabolism in KBD. An in vitro study showed the effects of disordered glycometabolism in chondrocytes. When chondrocytes were treated with high glucose, expression of type II collagen and aggrecan were decreased, while TNF-alpha expression, the level of cellular reactive oxygen species and cell apoptosis rates all were increased. Therefore, our results demonstrated that disordered glycometabolism in patients with KBD was linked to the damage of chondrocytes. This may provide a new basis for understanding the pathogenesis of KBD. PMID- 24792130 TI - The continued need for interprofessional collaboration and research. PMID- 24792131 TI - Interprofessional health education in Australia: three research projects informing curriculum renewal and development. AB - PURPOSE: This paper reports on three interrelated Australian studies that provide a nationally coherent and evidence-informed approach to interprofessional education (IPE). Based on findings from previous studies that IPE tends to be marginalized in mainstream health curriculum, the three studies aspired to produce a range of resources that would guide the sustainable implementation of IPE across the Australian higher education sector. METHOD: Nine national universities, two peak industry bodies and a non-government organization constituted the study team. Data were gathered via a mixture of stakeholder consultations, surveys and interviews and analyzed using quantitative and qualitative methods. RESULTS & CONCLUSION: An important outcome was a curriculum renewal framework which has been used to explore the implications of the study's findings on Australian nursing. While the findings are pertinent to all health professions, nursing is well placed to take a leading role in establishing IPE as a central element of health professional education. PMID- 24792132 TI - Preparing for a randomized controlled trial: strategies to optimize the design of an individualized cardiovascular surgical patient education intervention. AB - Randomized controlled trial (RCT) designs are standardized to control for bias and allow for replication. Conducting RCTs is generally straightforward when dealing with interventions that contain a single component, such as a drug. However, interventions that do not contain single components, such as a patient education programs, are more difficult to standardize, as they contain multiple elements, which may act independently or interdependently of each other. The purpose of this discursive clinical methods paper is to describe and explain a methodology that can be used to optimize the design of a complex intervention prior to its evaluation in a randomized control trial. PMID- 24792133 TI - Survival of a patient with tetanus in Bhutan using a magnesium infusion managed only by clinical signs. AB - Tetanus is a life-threatening disease that continues to have a high prevalence in developing countries. Severe muscle spasms often require patients to receive tracheostomy, high-dose sedatives, and sometimes prolonged neuromuscular blockade. Magnesium sulfate (MgSO4) infusion has great promise as an adjunct treatment for severe tetanus, as it may allow clinicians to decrease the dose of other sedative medications. Although the mechanism of action of MgSO4 is not well understood, it appears to attenuate both the muscle spasms and autonomic instability associated with severe tetanus infections. However, MgSO4 infusions are often managed based on serial measurements of serum magnesium levels and other laboratory tests such as arterial blood gases, which can be difficult to obtain in resource-poor settings. We describe a case of severe tetanus in Bhutan managed through the use of magnesium infusion titrated solely to physical examination findings. PMID- 24792134 TI - Wilderness search strategy and tactics. AB - Reports of overdue persons are common for search and rescue personnel. Search incidents for missing persons are conducted following established industry standard practices, which are continuously refined through experience and the analysis of previous search operations. Throughout this process, elements of uncertainty exist, and the knowledge and experience of the searchers and search managers may influence the outcome significantly. A sound knowledge of current search tactics will help search and rescue medical providers function more effectively during search operations. Initial actions during a search incident include 3 primary tasks that must be accomplished on any search: investigation, containment, and then hasty search efforts. Concurrent with these initial actions are the establishment of the search area and a formal US National Incident Management System incident command system. That is essential for an efficient operation and will lay the groundwork for expanding the operation past the initial operational period. The goal of applying these standard search management practices is to allow searchers to maximize their efforts, reduce some of the inherent uncertainty, and most importantly, place searchers in a position to detect the missing person. PMID- 24792136 TI - A novel cell-based assay for measuring neutralizing autoantibodies against type I interferons in patients with autoimmune polyendocrine syndrome type 1. AB - An important characteristic of autoimmune polyendocrine syndrome type 1 (APS 1) is the existence of neutralizing autoantibodies (nAbs) against the type I interferons (IFN) -alpha2 and -omega at frequencies close to 100%. Type 1 IFN autoantibodies are detected by antiviral neutralizing assays (AVA), binding assays with radiolabelled antigens (RLBA), enzyme-linked immunosorbent assay (ELISA), or by reporter-based cell assays. We here present a simple and reliable version of the latter utilizing a commercially available cell line (HEK-Blue IFN alpha/beta). All 67 APS 1 patients were positive for IFN-omega nAbs, while 90% were positive for IFN-alpha2 nAbs, a 100% and 96% correlation with RLBA, respectively. All blood donors and non-APS 1 patients were negative. The dilution titer required to reduce the effect of IFN-omega nAbs correlated with the RLBA index. This cell-based autoantibody assay (CBAA) is easy to perform, suitable for high throughput, while providing high specificity and sensitivity. PMID- 24792135 TI - A novel pancreatic beta-cell targeting bispecific-antibody (BsAb) can prevent the development of type 1 diabetes in NOD mice. AB - To prepare a novel Bispecific Antibody (BsAb) as a potential targeted therapy for T1D, we produced a "functionally inert" monoclonal antibody (mAb) against Glucose transporter-2 (GLUT-2) expressed on beta-cells to serve as an anchoring antibody. The therapeutic arm is an agonistic mAb against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), a negative regulator of T-cell activation expressed on activated CD4+ T cells. A BsAb was prepared by chemically coupling an anti-GLUT2 mAb to an agonistic anti-CTLA-4 mAb. This BsAb was able to bind to GLUT2 and CTLA-4 in vitro, and to pancreatic islets, both in vitro and in vivo. We tested the safety and efficacy of this BsAb by treating Non-Obese Diabetes (NOD) mice and found that it could delay the onset of diabetes with no apparent undesirable side effects. Thus, engagement of CTLA-4 on activated T cells from target tissue can be an effective way to treat type-1 diabetes. PMID- 24792137 TI - Applied anatomy of small branches of the portal vein in transverse groove of hepatic hilum. AB - PURPOSE: The objective of this study was to provide the morphological details on small branches of the portal vein in transverse groove of hepatic hilum. METHODS: According to the surgery significance, the small branches of portal vein in transverse groove of hepatic hilum were named as "Short hepatic portal veins (SHPVs)". SHPVs were minutely dissected in 30 adult cadaveric livers. The number, diameter, length, origin points, and entering liver sites of SHPVs were explored and measured. RESULTS: There were 181 SHPVs in 30 liver specimens, including 46% (83/181) from the left portal vein, 31% (56/181) from the bifurcation, and 23% (42/181) from the right portal vein. At the entering liver sites of SHPVs, 22% (40/181) supplied for segment IV, 9% (17/181) for segment V, 4% (7/181) for segment VI, 23% (41/181) for segment VII, and 42% (76/181) for segment I (caudate lobe). There were 6.0 +/- 2.4 branches per liver specimen with range 3-12. The mean diameter of SHPVs was 2.25 +/- 0.89 mm. The average length of SHPVs was 4.86 +/- 2.12 mm. CONCLUSIONS: SHPVs widely existed in each liver specimen. The detailed anatomical study of SHPVs could be useful to avoid damaging the short portal branches during hepatic operations, such as isolated or combined caudate lobectomy. PMID- 24792138 TI - Relationship between ultrasonographic, electromyographic, and clinical parameters in adult stroke patients with spastic equinus: an observational study. AB - OBJECTIVE: To find more accurate indices that could affect decisions in spasticity treatment by investigating the relation between ultrasonographic, electromyographic, and clinical parameters of the gastrocnemius muscle in adults with spastic equinus after stroke. DESIGN: Observational study. SETTING: University hospitals. PARTICIPANTS: Chronic patients with stroke with spastic equinus (N=43). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Ultrasonographic features were spastic gastrocnemius muscle echo intensity, muscle thickness, and posterior pennation angle of the gastrocnemius medialis (GM) and gastrocnemius lateralis (GL) in both legs. Electromyographic evaluation included compound muscle action potentials (CMAPs) recorded from the GM and GL of both legs. Clinical assessment of the spastic gastrocnemius muscle was performed with the Modified Ashworth Scale (MAS) and by measuring ankle dorsiflexion passive range of motion (PROM). RESULTS: Spastic muscle echo intensity was inversely associated with proximal (GM and GL: P=.002) and distal (GM and GL: P=.001) muscle thickness, pennation angle (GM: P< .001; GL: P=.01), CMAP (GM: P=.014; GL: P=.026), and ankle PROM (GM: P=.038; GL: P=.024). The pennation angle was directly associated with the proximal (GM and GL: P< .001) and distal (GM: P=.001; GL: P< .001) muscle thickness of the spastic gastrocnemius muscle. The MAS score was directly associated with muscle echo intensity (GM: P=.039; GL: P=.027) and inversely related to the pennation angle (GM and GL: P=.001) and proximal (GM: P=.016; GL: P=.009) and distal (GL: P=.006) muscle thickness of the spastic gastrocnemius. CONCLUSIONS: Increased spastic muscle echo intensity was associated with reduced muscle thickness, posterior pennation angle, and CMAP amplitude in the gastrocnemius muscle. Building on previous evidence that these instrumental features are related to botulinum toxin response, these new findings may usefully inform spasticity treatment decisions. PMID- 24792139 TI - Effects of cervical spine manual therapy on range of motion, head repositioning, and balance in participants with cervicogenic dizziness: a randomized controlled trial. AB - OBJECTIVE: To evaluate and compare the effects of 2 manual therapy interventions on cervical spine range of motion (ROM), head repositioning accuracy, and balance in patients with chronic cervicogenic dizziness. DESIGN: Randomized controlled trial with 12-week follow-up using blinded outcome assessment. SETTING: University School of Health Sciences. PARTICIPANTS: Participants (N=86; mean age +/- SD, 62.0 +/- 12.7 y; 50% women) with chronic cervicogenic dizziness. INTERVENTIONS: Participants were randomly assigned to 1 of 3 groups: sustained natural apophyseal glides (SNAGs) with self-SNAG exercises, passive joint mobilization (PJM) with ROM exercises, or a placebo. Participants each received 2 to 6 treatments over 6 weeks. MAIN OUTCOME MEASURES: Cervical ROM, head repositioning accuracy, and balance. RESULTS: SNAG therapy resulted in improved (P <=.05) cervical spine ROM in all 6 physiological cervical spine movement directions immediately posttreatment and at 12 weeks. Treatment with PJM resulted in improvement in 1 of the 6 cervical movement directions posttreatment and 1 movement direction at 12 weeks. There was a greater improvement (P<.01) after SNAGs than PJM in extension (mean difference, -7.5 degrees ; 95% confidence interval [CI], -13 degrees to -2.0 degrees ) and right rotation (mean difference, -6.8 degrees ; 95% CI, -11.5 degrees to -2.1 degrees ) posttreatment. Manual therapy had no effect on balance or head repositioning accuracy. CONCLUSIONS: SNAG treatment improved cervical ROM, and the effects were maintained for 12 weeks after treatment. PJM had very limited impact on cervical ROM. There was no conclusive effect of SNAGs or PJMs on joint repositioning accuracy or balance in people with cervicogenic dizziness. PMID- 24792140 TI - How do changes in motor capacity, motor capability, and motor performance relate in children and adolescents with cerebral palsy? AB - OBJECTIVE: To investigate the relations between changes in motor capacity (can do, in standardized environment), motor capability (can do, in daily environment), and motor performance (does do, in daily environment) among children with cerebral palsy (CP). DESIGN: Prospective longitudinal study. After baseline measurements (at the age of 18 mo, 30 mo, 5 y, 7 y, 9 y, 11 y, or 13 y), 2-year follow-up measurements were performed. Change scores were calculated, and Pearson correlations were used for change score relations. SETTING: Outpatient clinic. PARTICIPANTS: Toddlers, school-age children, and adolescents with CP (N=321; 200 boys, 121 girls). Levels of severity according to the Gross Motor Function Classification System included level I (42%), level II (15%), level III (17%), level IV (13%), and level V (13%). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in motor capacity was assessed with the Gross Motor Function Measure-66. Changes in motor capability and motor performance were assessed with the Pediatric Evaluation of Disability Inventory using the Functional Skills Scale and Caregiver Assistance Scale, respectively. RESULTS: Within the total group, change score correlations were moderate (.52-.67) and significant (P<.001). For age groups, correlations were significantly higher in toddlers than school-age children and adolescents. For severity levels, correlations were significantly higher in children at level III than level I, IV, and V. CONCLUSIONS: Results imply that change in motor capacity does not automatically translate to change in motor capability and change in motor capability does not automatically translate to change in motor performance. Results also show different relations for clinically relevant subgroups. These are important insights for clinical practice because they can guide evidence based interventions with a focus on activities. PMID- 24792141 TI - Clinical application of a robotic ankle training program for cerebral palsy compared to the research laboratory application: does it translate to practice? AB - OBJECTIVE: To determine the clinical efficacy of an ankle robotic rehabilitation protocol for patients with cerebral palsy. DESIGN: The clinic cohort was identified from a retrospective chart review in a before-after intervention trial design and compared with a previously published prospective research cohort. SETTING: Rehabilitation hospital. PARTICIPANTS: Children (N=28; mean age, 8.2+/ 3.62 y) with Gross Motor Function Classification System levels I, II, or III who were referred for ankle stretching and strengthening used a robotic ankle device in a clinic setting. Clinic results were compared with a previously published cohort of participants (N=12; mean age, 7.8+/-2.91 y) seen in a research laboratory-based intervention protocol. INTERVENTIONS: Patients in the clinic cohort were seen 2 times per week for 75-minute sessions for a total of 6 weeks. The first 30 minutes of the session were spent using the robotic ankle device for ankle stretching and strengthening, and the remaining 45 minutes were spent on functional movement activities. There was no control group. MAIN OUTCOME MEASURES: We compared pre- and postintervention measures of plantarflexor and dorsiflexor range of motion, strength, spasticity, mobility (Timed Up and Go test, 6-minute walk test, 10-m walk test), balance (Pediatric Balance Scale), Selective Control Assessment of the Lower Extremity (SCALE), and gross motor function measure (GMFM). RESULTS: Significant improvements were found for the clinic cohort in all main outcome measures except for the GMFM. These improvements were equivalent to those reported in the research cohort, except for larger SCALE test changes in the research cohort. CONCLUSIONS: These findings suggest that translation of repetitive, goal-directed biofeedback training into the clinic setting is both feasible and beneficial for patients with cerebral palsy. PMID- 24792142 TI - Psychological resources, appraisals, and coping and their relationship to participation in spinal cord injury: a path analysis. AB - OBJECTIVE: To test the Spinal Cord Injury Adjustment Model and gain a better understanding about whether and how the psychological resources general self efficacy (SE), purpose in life (PIL), appraisals, and coping influence participation in persons with spinal cord injury (SCI). DESIGN: Cross-sectional data collection within the Swiss Spinal Cord Injury Cohort. SETTING: Community setting. PARTICIPANTS: Persons with SCI (N=516) who are >= 16 years old and living in the community in Switzerland. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participation was measured with the restrictions subscale of the Utrecht Scale for Evaluation of Rehabilitation-Participation, General SE with the General Self-Efficacy Scale, PIL with the Purpose in Life Test-Short Form, appraisals with the Appraisal of Life Events Scale, and coping with the Brief COPE. RESULTS: General SE (r=.32) and PIL (r=.23) were associated with less participation restrictions. The initial model yielded a poor model fit. The modified final model had an acceptable fit (chi(2)11=36.2; P<.01; root mean square error of approximation=.067 [90% confidence interval: .045-.09]; comparative fit index=.98). A total of 15% of the variance of participation was explained. In the final model, general SE had a moderate direct effect (beta=.24) and mediated effects via threat appraisal and challenge appraisal and humor on participation, indicating a partial mediation effect. The association between PIL and participation was indirect: challenge appraisal and humor acted as mediators. CONCLUSIONS: The results only partly support the double-mediating effect as suggested in the SCI adjustment model because both direct and indirect effects on participation were observed. Individuals with higher general SE and PIL perceive less participation restrictions. General SE seems an appropriate target to enhance participation. Longitudinal studies are needed to support our findings. PMID- 24792143 TI - Beliefs about abortion risks in women returning to the clinic after their abortions: a pilot study. AB - BACKGROUND: Misinformation regarding the risks of abortion is prevalent and commonly includes medical inaccuracies about health, depression, infertility and breast cancer. This pilot study sought to assess misinformation among abortion clients as well as the origin(s) of their abortion knowledge. STUDY DESIGN: Women who presented to the Mount Sinai School of Medicine Family Planning Division for postabortion follow-up were recruited for participation. Participants completed a researcher-administered survey regarding knowledge and beliefs about abortion. RESULTS: Sixty-seven women completed the survey between 1/11/10 and 8/6/12. Common sources of abortion information included clinicians (79.1%), Web sites (70.1%), friends (50.7%) and family (40.3%). Over two thirds of women (77.6%) overestimated the health risks, and close to half (43.3%) overestimated the risk of depression after a first trimester abortion. CONCLUSIONS: Misperceptions about the health risks of abortion were prevalent among this sample. Education tools should be developed to provide accurate information about the risks of abortion. PMID- 24792144 TI - Post-abortion and induced abortion services in two public hospitals in Colombia. AB - OBJECTIVE: Until 2006, legal induced abortion was completely banned in Colombia. Few facilities are equipped or willing to offer abortion services; often adolescents experience even greater barriers of access in this context. We examined post abortion care (PAC) and legal induced abortion in two large public hospitals. We tested the association of hospital site, procedure type (manual vacuum aspiration vs. sharp curettage), and age (adolescents vs. women 20 years and over) with service type (PAC or legal induced abortion). STUDY DESIGN: Retrospective cohort study using 2010 billing data routinely collected for reimbursement (N=1353 procedures). We utilized descriptive statistics, multivariable logistic regression and predicted probabilities. RESULTS: Adolescents made up 22% of the overall sample (300/1353). Manual vacuum aspiration was used in one-third of cases (vs. sharp curettage). Adolescents had lower odds of documented PAC (vs. induced abortion) compared with women over age 20 (OR=0.42; 95% CI=0.21-0.86). The absolute difference of service type by age, however, is very small, controlling for hospital site and procedure type (.97 probability of PAC for adolescents compared with .99 for women 20 and over). Regardless of age, PAC via sharp curettage is the current standard in these two public hospitals. CONCLUSION: Both adolescents and women over 20 are in need of access to legal abortion services utilizing modern technologies in the public sector in Colombia. Documentation of abortion care is an essential first step to determining barriers to access and opportunities for quality improvement and better health outcomes for women. IMPLICATIONS: Following partial decriminalization of abortion in Colombia, in public hospitals nearly all abortion services are post-abortion care, not induced abortion. Sharp curettage is the dominant treatment for both adolescents and women over 20. Women seek care in the public sector for abortion, and must have access to safe, quality services. PMID- 24792145 TI - Levels and determinants of switching following intrauterine device discontinuation in 14 developing countries. AB - OBJECTIVE: To examine the levels and determinants of switching to any reversible modern contraceptive method following intrauterine device (IUD) discontinuation due to method-related reasons among women in developing countries. STUDY DESIGN: We analysed 5-year contraceptive calendar data from 14 Demographic and Health Surveys, conducted in 1993-2008 (n=218,092 women; 17,151 women contributed a total of 18,485 IUD episodes). Life-table methods were used to determine overall and cause-specific probabilities of IUD discontinuation at 12 months of use. For IUD episodes discontinued due to method-related reasons, the probability of switching to another reversible modern method within 3 months was estimated, overall and by place of residence, education level, motivation for use, age category and wealth tertiles. Country-specific rate ratios (RR) were estimated using generalized linear models, and pooled RRs using meta-analyses. RESULTS: The median duration of uninterrupted IUD use was 37 months. At 12 months, median probability of discontinuation was 13.2% and median probability of discontinuation due to method-related reasons was 8.9%. Within 3 months of discontinuation due to method-related reasons, half of the women had switched to another reversible modern method, 12% switched to traditional methods, 12% became pregnant, and 25% remained at risk for pregnancy. More educated women were more likely to switch to another reversible modern method than women with primary education or less (pooled RR 1.47; 95% CI 1.10-1.96), as were women in the highest wealth tertile (pooled RR 1.38; 95% CI 1.04-1.83) and women who were limiting births (pooled RR 1.35; 95% CI 1.08-1.68). CONCLUSION: Delays to switching and switching to less reliable methods following IUD discontinuation remain a problem, exposing women to the risk of unwanted pregnancy. Family planning programmes should aim to improve quality of services through strengthening of counselling and follow-up services to support women's continuation of effective methods. IMPLICATIONS: The risk of unintended pregnancy following IUD discontinuation remains high in developing countries. The quality of family planning services may be an important factor in switching to alternative modern contraceptive methods. Service providers should focus on counselling services and follow-up of women to support the continued use of effective methods. PMID- 24792146 TI - The free perinatal/postpartum contraceptive services project for migrant women in Shanghai: effects on the incidence of unintended pregnancy. AB - OBJECTIVE: In 2006, the incidence of unintended pregnancy among rural-to-urban migrant women (RUMW) in Shanghai was reported as 12.8 per 100 women-years during the first year postpartum. Among permanent residents of Shanghai, that same rate was 3.8 per 100 women-years. An intervention study was designed to address the unmet need for family planning services among this underserved population of RUMW and reduce their high postpartum unintended pregnancy incidence. STUDY DESIGN: We enrolled 840 migrant women into an intervention study that provided free contraceptive counseling and a choice of methods. Subjects were recruited into the study during hospitalization for childbirth and offered a contraceptive method according to their choice prior to discharge. Counseling and further support were offered at 6 weeks and at 3, 6, 9 and 12 months postpartum via scheduled telephone calls and/or clinic visits. RESULTS: Among all study participants, the median time to contraceptive initiation and sexual resumption was 2 months postpartum, respectively. The overall contraceptive prevalence at 12 months was 97.1%, and more than half of the women were using long-acting contraception. The incidence rate of unintended pregnancy during the first year postpartum was 2.2 per 100 women-years (95% confidence interval: 1.3-3.6). CONCLUSIONS: Integrating free family planning services into existing childbirth delivery services in a maternity setting in Shanghai was effective in addressing the unmet need for family planning and reduced the risk of unintended pregnancy during the first year postpartum. IMPLICATIONS: The maternity setting at the time of early labor and prior to postpartum hospital discharge is a practical venue and an optimal time to provide contraception counseling and for postpartum women to initiate use of contraceptive methods. Supporting services during the first year postpartum are also essential to encourage women to continue contraceptive use and reduce the incidence of postpartum unintended pregnancy. PMID- 24792148 TI - Contraceptive use and the role of contraceptive counseling in reproductive-aged women with cancer. AB - OBJECTIVE: Few data on contraceptive choices in women with cancer exist. Contraception is challenging for women with cancer, particularly those with breast cancer, who are limited to nonhormonal methods. This study characterized contraceptive use during cancer treatment in a group of reproductive-aged women with a recent cancer diagnosis and assessed the impact of contraceptive counseling on the methods they selected. STUDY DESIGN: Cross-sectional, survey study of reproductive-aged women at a large tertiary care health system with a recent cancer diagnosis. RESULTS: A total of 107 women completed the survey. Eighty-two women reported 101 contraceptive choices. Twenty-seven percent (27/101) of all methods selected were Tier I/II, and 35% (35/101) were Tier III/IV. Only 4 used an intrauterine device (IUD). Among women reporting sexual activity after diagnosis, 19 (27%) of 71 reported using Tier I/II methods, 21 (30%) of 71 reported using Tier III/IV methods, 16 (23%) of 71 reported abstinence and 10 (14%) of 71 reported using no method. Factors significantly associated with Tier I/II use in the multivariable model included not having a college degree [odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05-0.92, p=.038], intercourse during treatment (OR 5.92, 95% CI 1.48-23.66, p=.012) and non-breast cancer (OR 3.60, 95% CI 1.03-12.64, p=.046). Report of contraceptive counseling was positively associated with Tier I/II contraceptive use during cancer treatment (OR 6.92, 95% CI 1.14-42.11, p=.036). CONCLUSION: Reproductive aged women diagnosed with cancer underutilized Tier I/II contraceptive agents, especially IUDs. Contraceptive counseling by physicians increases contraceptive use, particularly methods most effective at preventing pregnancy. IMPLICATIONS: The study uniquely described the contraceptive practices of over 100 women with cancer. The study sample commonly reported abstinence and use of contraceptive methods with high failure rates. Our data suggest that contraceptive counseling from a health care provider may increase use of more effective methods among women with cancer. PMID- 24792147 TI - Contraceptive sex acceptability: a commentary, synopsis and agenda for future research. PMID- 24792149 TI - [Prevention and diagnosis of imported malaria in primary care: Asturias 2002 2012]. PMID- 24792150 TI - Impaired behavioural response to alarm substance in rainbow trout exposed to copper nanoparticles. AB - To date, studies of the toxicity of engineered nanoparticles (NPs) in fish have not fully considered effects on olfactory-mediated behaviours, despite their ecological importance. In this study the effects of copper NPs (Cu NPs) on the anti-predator behavioural responses of juvenile rainbow trout (Oncorhynchus mykiss) to trout alarm substance was investigated. Individual fish were exposed for 12h to a control (no added Cu), 50MUgl(-1) of Cu as Cu NPs, or 50MUgl(-1) Cu as CuSO4, after which fish behaviours were analyzed in 10min periods before and after the addition of the alarm substance stimulus. The response of control fish to deionised water (negative control, no alarm substance stimulus) was also analyzed. The alarm substance elicited a behavioural response in the control fish characterized by an immediate freeze response and the slower resumption of swimming activity compared to negative controls exposed to the sham deionised water stimuli. In fish exposed to Cu NPs, the behavioural response to alarm substance was eliminated, with no significant difference in behaviours compared to negative controls. In comparison, exposure to 50MUgl(-1) Cu as CuSO4 decreased, but did not eliminate the response of fish to alarm substance, which indicated a significantly greater effect of Cu NPs on olfactory mediated behaviours than of the equivalent concentration of Cu as CuSO4. Measurement of total Cu concentrations in the tissues of fish demonstrated no significant accumulation of Cu from any treatment in gill, liver or brain, confirming the effects of Cu NPs, and to a lesser extent CuSO4, on behavioural responses were mostly associated with the interaction of the materials with the external surfaces of the fish. Scanning electron microscopy revealed that Cu as CuSO4 caused a pronounced depletion of ciliated sensory and non-sensory cells in the olfactory rosette surrounding the midline raphe, whereas Cu NPs had no impact on the structure of the rosette. However, exposure to Cu NPs caused a significant increase in the ratio of oxidized to reduced glutathione in brains of fish, indicating some systemic oxidative stress that was not observed in either controls or fish exposed to CuSO4. Overall, the study showed that the olfactory mediated behaviours of fish were potentially more sensitive to Cu NPs than CuSO4 and NPs elicited effects via a mechanism that is distinct from that of the metal salt. PMID- 24792151 TI - The predictability of mixture toxicity of demethylase inhibiting fungicides to Daphnia magna depends on life-cycle parameters. AB - A variety of different fungicides are found simultaneously in surface waters, among which demethylase inhibitors (DMIs) are a major group. The joint toxicity of four DMIs from different chemical classes (Fenarimol, Prochloraz, Triadimefon and Pyrifenox) was investigated in the reproduction test with Daphnia magna, following an extended protocol according to ISO 10706. We assessed the toxicity of the DMI mixtures across different endpoints and effect levels and evaluated the predictability of their joint action using Concentration Addition (CA) and Independent Action (IA). The mixture reduced fecundity, delayed molting and caused characteristic malformations in offspring in a concentration-dependent manner which is possibly due to an anti-ecdysteroid action, as previously described for individual DMIs. However, also mixture-specific effects were observed: exposed daphnids reached sexual maturity already after the third juvenile molt, and thus significantly earlier than unexposed daphnids, which needed four juvenile molts to reach maturity. This effect is not caused by any of the DMIs alone. Additionally, the percentage of aborted broods was synergistically higher than expected by either CA or IA. IA underestimates the mixture toxicity for all parameters. The predictive quality of CA differed between life history responses, but was always within a factor of two to the observed toxicity. The parameter "fecundity reduction, counting only normally developed offspring", was the most sensitive endpoint, while the parameter "fecundity reduction, counting all living offspring", was slightly less sensitive. The mixture caused a 90% reduction in fecundity at individual concentrations that only provoke 7% effect or less, which calls for a mixture specific toxicity assessment of DMI fungicides. PMID- 24792152 TI - Warming increases chlorpyrifos effects on predator but not anti-predator behaviours. AB - Recent insights indicate that negative effects of pesticides on aquatic biota occur at concentrations that current legislation considers environmentally protective. We here address two, potentially interacting, mechanisms that may contribute to the underestimation of the impact of sublethal pesticide effects in single species tests at room temperature: the impairment of predator and antipredator behaviours and the stronger impact of organophosphate pesticides at higher temperatures. To address these issues we assessed the effects of chlorpyrifos on the predator and antipredator behaviours of larvae of the damselfly Ischnura elegans, important intermediate predators in aquatic food webs, in a common-garden warming experiment with replicated low- and high latitude populations along the latitudinal gradient of this species in Europe. Chlorpyrifos reduced the levels of predator behavioural endpoints, and this reduction was stronger at the higher temperature for head orientations and feeding strikes. Chlorpyrifos also impaired two key antipredator behavioural endpoints, activity reductions in response to predator cues were smaller in the presence of chlorpyrifos, and chlorpyrifos caused a lower escape swimming speed; these effects were independent of temperature. This suggests chlorpyrifos may impact food web interactions by changing predator-prey interactions both with higher (predators) and lower trophic levels (food). Given that only the interaction with the lower trophic level was more impaired at higher temperatures, the overall pesticide-induced changes in food web dynamics may be strongly temperature-dependent. These findings were consistent in damselflies from low- and high-latitude populations, illustrating that thermal adaptation will not mitigate the increased toxicity of pesticides at higher temperatures. Our study not only underscores the relevance of including temperature and prey predator interactions in ecological risk assessment but also their potential interplay and thereby highlights the complexity of contaminant effects on predator-prey interactions being differentially temperature-dependent pending on the trophic level. PMID- 24792153 TI - Surface histidine mutations for the metal affinity purification of a beta carbonic anhydrase. AB - Metal affinity chromatography using polyhistidine tags is a standard laboratory technique for the general purification of proteins from cellular systems, but there have been no attempts to explore whether the surface character of a protein may be engineered to similar affinity. We present the Arg160His mutation of Haemophilus influenzae carbonic anhydrase (HICA), which mimics the endogenous metal affinity of Escherichia coli carbonic anhydrase (ECCA). The purity and activity of the mutant are reported, and the purification is discussed. This is the first step toward developing a general method to engineer surface metal affinity for use in purification and metal labeling techniques. PMID- 24792154 TI - TALENs facilitate targeted genome editing in human cells with high specificity and low cytotoxicity. AB - Designer nucleases have been successfully employed to modify the genomes of various model organisms and human cell types. While the specificity of zinc finger nucleases (ZFNs) and RNA-guided endonucleases has been assessed to some extent, little data are available for transcription activator-like effector-based nucleases (TALENs). Here, we have engineered TALEN pairs targeting three human loci (CCR5, AAVS1 and IL2RG) and performed a detailed analysis of their activity, toxicity and specificity. The TALENs showed comparable activity to benchmark ZFNs, with allelic gene disruption frequencies of 15-30% in human cells. Notably, TALEN expression was overall marked by a low cytotoxicity and the absence of cell cycle aberrations. Bioinformatics-based analysis of designer nuclease specificity confirmed partly substantial off-target activity of ZFNs targeting CCR5 and AAVS1 at six known and five novel sites, respectively. In contrast, only marginal off target cleavage activity was detected at four out of 49 predicted off-target sites for CCR5- and AAVS1-specific TALENs. The rational design of a CCR5-specific TALEN pair decreased off-target activity at the closely related CCR2 locus considerably, consistent with fewer genomic rearrangements between the two loci. In conclusion, our results link nuclease-associated toxicity to off-target cleavage activity and corroborate TALENs as a highly specific platform for future clinical translation. PMID- 24792155 TI - DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1. AB - Myotonic dystrophy type 1 (DM1) is caused by CUG triplet expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) messenger ribonucleic acid (mRNA). The etiology of this multi-systemic disease involves pre-mRNA splicing defects elicited by the ability of the CUG-expanded mRNA to 'sponge' splicing factors of the muscleblind family. Although nuclear aggregation of CUG-containing mRNPs in distinct foci is a hallmark of DM1, the mechanisms of their homeostasis have not been completely elucidated. Here we show that a DEAD-box helicase, DDX6, interacts with CUG triplet-repeat mRNA in primary fibroblasts from DM1 patients and with CUG-RNA in vitro. DDX6 overexpression relieves DM1 mis-splicing, and causes a significant reduction in nuclear DMPK-mRNA foci. Conversely, knockdown of endogenous DDX6 leads to a significant increase in DMPK-mRNA foci count and to increased sequestration of MBNL1 in the nucleus. While the level of CUG-expanded mRNA is unaffected by increased DDX6 expression, the mRNA re-localizes to the cytoplasm and its interaction partner MBNL1 becomes dispersed and also partially re-localized to the cytoplasm. Finally, we show that DDX6 unwinds CUG-repeat duplexes in vitro in an adenosinetriphosphate-dependent manner, suggesting that DDX6 can remodel and release nuclear DMPK messenger ribonucleoprotein foci, leading to normalization of pathogenic alternative splicing events. PMID- 24792156 TI - XTMS: pathway design in an eXTended metabolic space. AB - As metabolic engineering and synthetic biology progress toward reaching the goal of a more sustainable use of biological resources, the need of increasing the number of value-added chemicals that can be produced in industrial organisms becomes more imperative. Exploring, however, the vast possibility of pathways amenable to engineering through heterologous genes expression in a chassis organism is complex and unattainable manually. Here, we present XTMS, a web-based pathway analysis platform available at http://xtms.issb.genopole.fr, which provides full access to the set of pathways that can be imported into a chassis organism such as Escherichia coli through the application of an Extended Metabolic Space modeling framework. The XTMS approach consists on determining the set of biochemical transformations that can potentially be processed in vivo as modeled by molecular signatures, a specific coding system for derivation of reaction rules for metabolic reactions and enumeration of all the corresponding substrates and products. Most promising routes are described in terms of metabolite exchange, maximum allowable pathway yield, toxicity and enzyme efficiency. By answering such critical design points, XTMS not only paves the road toward the rationalization of metabolic engineering, but also opens new processing possibilities for non-natural metabolites and novel enzymatic transformations. PMID- 24792157 TI - Fifteen years SIB Swiss Institute of Bioinformatics: life science databases, tools and support. AB - The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) was created in 1998 as an institution to foster excellence in bioinformatics. It is renowned worldwide for its databases and software tools, such as UniProtKB/Swiss-Prot, PROSITE, SWISS-MODEL, STRING, etc, that are all accessible on ExPASy.org, SIB's Bioinformatics Resource Portal. This article provides an overview of the scientific and training resources SIB has consistently been offering to the life science community for more than 15 years. PMID- 24792158 TI - The impact of transcriptional tuning on in vitro integrated rRNA transcription and ribosome construction. AB - In vitro ribosome construction could enable studies of ribosome assembly and function, provide a route toward constructing minimal cells for synthetic biology, and permit the construction of ribosome variants with new functions. Toward these long-term goals, we recently reported on an integrated, one-pot ribosomal RNA synthesis (rRNA), ribosome assembly, and translation technology (termed iSAT) for the construction of Escherichia coli ribosomes in crude ribosome-free S150 extracts. Here, we aimed to improve the activity of iSAT through transcriptional tuning. Specifically, we increased transcriptional efficiency through 3' modifications to the rRNA gene sequences, optimized plasmid and polymerase concentrations, and demonstrated the use of a T7-promoted rRNA operon for stoichiometrically balanced rRNA synthesis and native rRNA processing. Our modifications produced a 45-fold improvement in iSAT protein synthesis activity, enabling synthesis of 429 +/- 15 nmol/l green fluorescent protein in 6 h batch reactions. Further, we show that the translational activity of ribosomes purified from iSAT reactions is about 20% the activity of native ribosomes purified directly from E. coli cells. Looking forward, we believe iSAT will enable unique studies to unravel the systems biology of ribosome biogenesis and open the way to new methods for making and studying ribosomal variants. PMID- 24792159 TI - NeuroPID: a classifier of neuropeptide precursors. AB - Neuropeptides (NPs) are short secreted peptides produced in neurons. NPs act by activating signaling cascades governing broad functions such as metabolism, sensation and behavior throughout the animal kingdom. NPs are the products of multistep processing of longer proteins, the NP precursors (NPPs). We present NeuroPID (Neuropeptide Precursor Identifier), an online machine-learning tool that identifies metazoan NPPs. NeuroPID was trained on 1418 NPPs annotated as such by UniProtKB. A large number of sequence-based features were extracted for each sequence with the goal of capturing the biophysical and informational statistical properties that distinguish NPPs from other proteins. Training several machine-learning models, including support vector machines and ensemble decision trees, led to high accuracy (89-94%) and precision (90-93%) in cross validation tests. For inputs of thousands of unseen sequences, the tool provides a ranked list of high quality predictions based on the results of four machine learning classifiers. The output reveals many uncharacterized NPPs and secreted cell modulators that are rich in potential cleavage sites. NeuroPID is a discovery and a prediction tool that can be used to identify NPPs from unannotated transcriptomes and mass spectrometry experiments. NeuroPID predicted sequences are attractive targets for investigating behavior, physiology and cell modulation. The NeuroPID web tool is available at http:// neuropid.cs.huji.ac.il. PMID- 24792160 TI - Repeat 1 of TAL effectors affects target specificity for the base at position zero. AB - AvrBs3, the founding member of the Xanthomonas transcription-activator-like effectors (TALEs), is translocated into the plant cell where it localizes to the nucleus and acts as transcription factor. The DNA-binding domain of AvrBs3 consists of 17.5 nearly-identical 34 amino acid-repeats. Each repeat specifies binding to one base in the target DNA via amino acid residues 12 and 13 termed repeat variable diresidue (RVD). Natural target sequences of TALEs are generally preceded by a thymine (T0), which is coordinated by a tryptophan residue (W232) in a degenerated repeat upstream of the canonical repeats. To investigate the necessity of T0 and the conserved tryptophan for AvrBs3-mediated gene activation we tested TALE mutant derivatives on target sequences preceded by all possible four bases. In addition, we performed domain swaps with TalC from a rice pathogenic Xanthomonas because TalC lacks the tryptophan residue, and the TalC target sequence is preceded by cytosine. We show that T0 works best and that T0 specificity depends on the repeat number and overall RVD-composition. T0 and W232 appear to be particularly important if the RVD of the first repeat is HD ('rep1 effect'). Our findings provide novel insights into the mechanism of T0 recognition by TALE proteins and are important for TALE-based biotechnological applications. PMID- 24792161 TI - SwissTargetPrediction: a web server for target prediction of bioactive small molecules. AB - Bioactive small molecules, such as drugs or metabolites, bind to proteins or other macro-molecular targets to modulate their activity, which in turn results in the observed phenotypic effects. For this reason, mapping the targets of bioactive small molecules is a key step toward unraveling the molecular mechanisms underlying their bioactivity and predicting potential side effects or cross-reactivity. Recently, large datasets of protein-small molecule interactions have become available, providing a unique source of information for the development of knowledge-based approaches to computationally identify new targets for uncharacterized molecules or secondary targets for known molecules. Here, we introduce SwissTargetPrediction, a web server to accurately predict the targets of bioactive molecules based on a combination of 2D and 3D similarity measures with known ligands. Predictions can be carried out in five different organisms, and mapping predictions by homology within and between different species is enabled for close paralogs and orthologs. SwissTargetPrediction is accessible free of charge and without login requirement at http://www.swisstargetprediction.ch. PMID- 24792162 TI - A cytoplasmic quaking I isoform regulates the hnRNP F/H-dependent alternative splicing pathway in myelinating glia. AB - The selective RNA-binding protein quaking I (QKI) plays important roles in controlling alternative splicing (AS). Three QKI isoforms are broadly expressed, which display distinct nuclear-cytoplasmic distribution. However, molecular mechanisms by which QKI isoforms control AS, especially in distinct cell types, still remain elusive. The quakingviable (qk(v)) mutant mice carry deficiencies of all QKI isoforms in oligodendrocytes (OLs) and Schwann cells (SWCs), the myelinating glia of central and peripheral nervous system (CNS and PNS), respectively, resulting in severe dysregulation of AS. We found that the cytoplasmic isoform QKI-6 regulates AS of polyguanine (G-run)-containing transcripts in OLs and rescues aberrant AS in the qk(v) mutant by repressing expression of two canonical splicing factors, heterologous nuclear ribonucleoproteins (hnRNPs) F and H. Moreover, we identified a broad spectrum of in vivo functional hnRNP F/H targets in OLs that contain conserved exons flanked by G-runs, many of which are dysregulated in the qk(v) mutant. Interestingly, AS targets of the QKI-6-hnRNP F/H pathway in OLs are differentially affected in SWCs, suggesting that additional cell-type-specific factors modulate AS during CNS and PNS myelination. Together, our studies provide the first evidence that cytoplasmic QKI-6 acts upstream of hnRNP F/H, which forms a novel pathway to control AS in myelinating glia. PMID- 24792163 TI - Programmable DNA-binding proteins from Burkholderia provide a fresh perspective on the TALE-like repeat domain. AB - The tandem repeats of transcription activator like effectors (TALEs) mediate sequence-specific DNA binding using a simple code. Naturally, TALEs are injected by Xanthomonas bacteria into plant cells to manipulate the host transcriptome. In the laboratory TALE DNA binding domains are reprogrammed and used to target a fused functional domain to a genomic locus of choice. Research into the natural diversity of TALE-like proteins may provide resources for the further improvement of current TALE technology. Here we describe TALE-like proteins from the endosymbiotic bacterium Burkholderia rhizoxinica, termed Bat proteins. Bat repeat domains mediate sequence-specific DNA binding with the same code as TALEs, despite less than 40% sequence identity. We show that Bat proteins can be adapted for use as transcription factors and nucleases and that sequence preferences can be reprogrammed. Unlike TALEs, the core repeats of each Bat protein are highly polymorphic. This feature allowed us to explore alternative strategies for the design of custom Bat repeat arrays, providing novel insights into the functional relevance of non-RVD residues. The Bat proteins offer fertile grounds for research into the creation of improved programmable DNA-binding proteins and comparative insights into TALE-like evolution. PMID- 24792164 TI - Protein kinase C controls activation of the DNA integrity checkpoint. AB - The protein kinase C (PKC) superfamily plays key regulatory roles in numerous cellular processes. Saccharomyces cerevisiae contains a single PKC, Pkc1, whose main function is cell wall integrity maintenance. In this work, we connect the Pkc1 protein to the maintenance of genome integrity in response to genotoxic stresses. Pkc1 and its kinase activity are necessary for the phosphorylation of checkpoint kinase Rad53, histone H2A and Xrs2 protein after deoxyribonucleic acid (DNA) damage, indicating that Pkc1 is required for activation of checkpoint kinases Mec1 and Tel1. Furthermore, Pkc1 electrophoretic mobility is delayed after inducing DNA damage, which reflects that Pkc1 is post-translationally modified. This modification is a phosphorylation event mediated by Tel1. The expression of different mammalian PKC isoforms at the endogenous level in yeast pkc1 mutant cells revealed that PKCdelta is able to activate the DNA integrity checkpoint. Finally, downregulation of PKCdelta activity in HeLa cells caused a defective activation of checkpoint kinase Chk2 when DNA damage was induced. Our results indicate that the control of the DNA integrity checkpoint by PKC is a mechanism conserved from yeast to humans. PMID- 24792165 TI - Engineered zinc-finger transcription factors activate OCT4 (POU5F1), SOX2, KLF4, c-MYC (MYC) and miR302/367. AB - Artificial transcription factors are powerful tools for regulating gene expression. Here we report results with engineered zinc-finger transcription factors (ZF-TFs) targeting four protein-coding genes, OCT4, SOX2, KLF4 and c-MYC, and one noncoding ribonucleic acid (RNA) gene, the microRNA (miRNA) miR302/367 cluster. We designed over 300 ZF-TFs whose targets lie within 1 kb of the transcriptional start sites (TSSs), screened them for increased messenger RNA or miRNA levels in transfected cells, and identified potent ZF-TF activators for each gene. Furthermore, we demonstrate that selected ZF-TFs function with alternative activation domains and in multiple cell lines. For OCT4, we expanded the target range to -2.5 kb and +500 bp relative to the TSS and identified additional active ZF-TFs, including three highly active ZF-TFs targeting distal enhancer, proximal enhancer and downstream from the proximal promoter. Chromatin immunoprecipitation (FLAG-ChIP) results indicate that several inactive ZF-TFs targeting within the same regulatory region bind as well as the most active ZF TFs, suggesting that efficient binding within one of these regulatory regions may be necessary but not sufficient for activation. These results further our understanding of ZF-TF design principles and corroborate the use of ZF-TFs targeting enhancers and downstream from the TSS for transcriptional activation. PMID- 24792166 TI - Unraveling the regulatory connections between two controllers of breast cancer cell fate. AB - Estrogen receptor alpha (ERalpha) expression is critical for breast cancer classification, high ERalpha expression being associated with better prognosis. ERalpha levels strongly correlate with that of GATA binding protein 3 (GATA3), a major regulator of ERalpha expression. However, the mechanistic details of ERalpha-GATA3 regulation remain incompletely understood. Here we combine mathematical modeling with perturbation experiments to unravel the nature of regulatory connections in the ERalpha-GATA3 network. Through cell population average, single-cell and single-nucleus measurements, we show that the cross regulation between ERalpha and GATA3 amounts to overall negative feedback. Further, mathematical modeling reveals that GATA3 positively regulates its own expression and that ERalpha autoregulation is most likely absent. Lastly, we show that the two cross-regulatory connections in the ERalpha-GATA3 negative feedback network decrease the noise in ERalpha or GATA3 expression. This may ensure robust cell fate maintenance in the face of intracellular and environmental fluctuations, contributing to tissue homeostasis in normal conditions, but also to the maintenance of pathogenic states during cancer progression. PMID- 24792167 TI - BioMet Toolbox 2.0: genome-wide analysis of metabolism and omics data. AB - Analysis of large data sets using computational and mathematical tools have become a central part of biological sciences. Large amounts of data are being generated each year from different biological research fields leading to a constant development of software and algorithms aimed to deal with the increasing creation of information. The BioMet Toolbox 2.0 integrates a number of functionalities in a user-friendly environment enabling the user to work with biological data in a web interface. The unique and distinguishing feature of the BioMet Toolbox 2.0 is to provide a web user interface to tools for metabolic pathways and omics analysis developed under different platform-dependent environments enabling easy access to these computational tools. PMID- 24792168 TI - Evolution at protein ends: major contribution of alternative transcription initiation and termination to the transcriptome and proteome diversity in mammals. AB - Alternative splicing (AS), alternative transcription initiation (ATI) and alternative transcription termination (ATT) create the extraordinary complexity of transcriptomes and make key contributions to the structural and functional diversity of mammalian proteomes. Analysis of mammalian genomic and transcriptomic data shows that contrary to the traditional view, the joint contribution of ATI and ATT to the transcriptome and proteome diversity is quantitatively greater than the contribution of AS. Although the mean numbers of protein-coding constitutive and alternative nucleotides in gene loci are nearly identical, their distribution along the transcripts is highly non-uniform. On average, coding exons in the variable 5' and 3' transcript ends that are created by ATI and ATT contain approximately four times more alternative nucleotides than core protein-coding regions that diversify exclusively via AS. Short upstream exons that encompass alternative 5'-untranslated regions and N-termini of proteins evolve under strong nucleotide-level selection whereas in 3'-terminal exons that encode protein C-termini, protein-level selection is significantly stronger. The groups of genes that are subject to ATI and ATT show major differences in biological roles, expression and selection patterns. PMID- 24792169 TI - Validation of a fluorescence-based screening concept to identify ribosome assembly defects in Escherichia coli. AB - While the structure of mature ribosomes is analyzed in atomic detail considerably less is known about their assembly process in living cells. This is mainly due to technical and conceptual hurdles. To analyze ribosome assembly in vivo, we designed and engineered an Escherichiacoli strain--using chromosomal gene knock in techniques--that harbors large and small ribosomal subunits labeled with the fluorescent proteins EGFP and mCherry, respectively. A thorough characterization of this reporter strain revealed that its growth properties and translation apparatus were wild-type like. Alterations in the ratio of EGFP over mCherry fluorescence are supposed to indicate ribosome assembly defects. To provide proof of principle, subunit specific assembly defects were provoked and could be identified by both manual and fully automated fluorometric in vivo assays. This is to our knowledge the first methodology that directly detects ribosome assembly defects in vivo in a high-throughput compatible format. Screening of knock-out collections and small molecule libraries will allow identification of new ribosome assembly factors and possible inhibitors. PMID- 24792171 TI - Direct analysis of Holliday junction resolving enzyme in a DNA origami nanostructure. AB - Holliday junction (HJ) resolution is a fundamental step for completion of homologous recombination. HJ resolving enzymes (resolvases) distort the junction structure upon binding and prior cleavage, raising the possibility that the reactivity of the enzyme can be affected by a particular geometry and topology at the junction. Here, we employed a DNA origami nano-scaffold in which each arm of a HJ was tethered through the base-pair hybridization, allowing us to make the junction core either flexible or inflexible by adjusting the length of the DNA arms. Both flexible and inflexible junctions bound to Bacillus subtilis RecU HJ resolvase, while only the flexible junction was efficiently resolved into two duplexes by this enzyme. This result indicates the importance of the structural malleability of the junction core for the reaction to proceed. Moreover, cleavage preferences of RecU-mediated reaction were addressed by analyzing morphology of the reaction products. PMID- 24792172 TI - Age-related macular degeneration and cognitive impairment show similarities in changes of neutral lipids in peripheral blood mononuclear cells. AB - Starting from previous studies showing that patients with cognitive deficit present neutral lipids (NLs) accumulation in cytoplasm of their peripheral blood mononuclear cells (PBMCs) and considering that there is epidemiological evidence linking age-related macular degeneration (AMD) to cognitive deficit, the first purpose of this study was to test whether neutral lipids also accumulated in PBMCs from AMD subjects. Moreover, the impact of statin use on AMD was explored and whether such use in AMD subjects was associated with NLs accumulation in PBMCs. The study was conducted on 222 subjects: 136 AMD (36 of which - 26.5% - using statins], 48 cognitive deficit (20 of which - 41.7% - using statins) and 38 healthy controls (4 of which -10.1% - using statins), AMD lesions were assessed from color fundus photographs. Mini-mental state examination (MMSE), demographics, lifestyle factors and medical history were collected at interview. MMSE score was categorized as normal (24-30), and impaired (<24), NLs content was evaluated by oil red 0 (ORO) staining method. ORO determination showed that neutral lipids were generally absent or very low (score between 0 and 1) in healthy controls while most of PBMCs from cognitive deficit and AMD had ORO staining levels scoring 2-4. Post hoc analysis (Bonferroni) in a one-way ANOVA revealed that ORO score was significantly higher in cognitive deficit and AMD subjects compared to healthy controls and in cognitive deficit compared to AMD. Bonferroni-test also showed that AMD subjects had significantly lower total cholesterol (TC) levels compared to healthy controls while high density lipoprotein-cholesterol (HDL-C) did not reach statistical significance. The results also revealed a significant higher number of statin-users in AMD compared to healthy controls. Likewise when cognitive deficit vs healthy controls was analyzed, the number of statin users were found to be significant higher in cognitive deficit than in healthy controls. There were no significant differences in statin use between AMD and cognitive deficit. Compared to healthy controls, statin use in cognitive deficit and AMD groups was significantly associated with ORO scores of 2-4. This data supports the hypothesis that AMD and cognitive deficit share similar complex pathophysiology and risk factors including NLs accumulation in their PBMCs, although this does not necessarily imply that one disease causes the other. In addition, they provide further evidence that statin use may increase the risk of AMD. PMID- 24792173 TI - [A prudent deprescription model]. AB - The therapeutic structure of health systems relies heavily on medical prescription, which generates a marked tendency to add drugs to a patient's medical history. There is an absence of incentives for professionals to reassess prescriptions and withdraw those with a negative or neutral risk/benefit. This can create a deviation of medical resources to the maintenance of useless or even harmful treatments. Deprescribing, a process of thoughtful medication withdrawal that complements moderate prescribing, is aimed to stop this unfair deviation of resources towards non-beneficial, if not maleficent, prescription. PMID- 24792174 TI - Discussion forum on mitochondrial calcium. Historical introduction. PMID- 24792170 TI - A fine-scale dissection of the DNA double-strand break repair machinery and its implications for breast cancer therapy. AB - DNA-damage response machinery is crucial to maintain the genomic integrity of cells, by enabling effective repair of even highly lethal lesions such as DNA double-strand breaks (DSBs). Defects in specific genes acquired through mutations, copy-number alterations or epigenetic changes can alter the balance of these pathways, triggering cancerous potential in cells. Selective killing of cancer cells by sensitizing them to further DNA damage, especially by induction of DSBs, therefore requires careful modulation of DSB-repair pathways. Here, we review the latest knowledge on the two DSB-repair pathways, homologous recombination and non-homologous end joining in human, describing in detail the functions of their components and the key mechanisms contributing to the repair. Such an in-depth characterization of these pathways enables a more mechanistic understanding of how cells respond to therapies, and suggests molecules and processes that can be explored as potential therapeutic targets. One such avenue that has shown immense promise is via the exploitation of synthetic lethal relationships, for which the BRCA1-PARP1 relationship is particularly notable. Here, we describe how this relationship functions and the manner in which cancer cells acquire therapy resistance by restoring their DSB repair potential. PMID- 24792175 TI - Outstanding questions regarding the permeation, selectivity, and regulation of the mitochondrial calcium uniporter. AB - The recent discovery of genes encoding the mitochondrial calcium (Ca(2+)) uniporter has revealed new opportunities for studying how abnormal Ca(2+) signals cause disease. Ca(2+) transport across the mitochondrial inner membrane is highly regulated, and the uniporter is the channel that acts as a major portal for Ca(2+) influx. Low amounts of mitochondrial Ca(2+) can boost ATP synthesis, but excess amounts, such as following cytoplasmic Ca(2+) overload in heart failure, triggers mitochondrial failure and cell death. In fact, precisely because mitochondrial Ca(2+) transport is so tightly regulated, a fundamental understanding of how the uniporter functions is necessary. Two key uniporter features allow Ca(2+) influx without mitochondrial damage during normal physiology. First, the channel is significantly more selective than other known Ca(2+) channels. This prevents the permeation of other ions and uncoupling of the electrochemical gradient. Second, the uniporter becomes active at only high Ca(2+) concentrations, preventing a resting leak of cytoplasmic Ca(2+) itself. Now possessing the identities of the various proteins forming the uniporter, we can proceed with efforts to define the molecular determinants of permeation, selectivity and Ca(2+)-regulation. PMID- 24792176 TI - Dephosphorylation of Orc2 by protein phosphatase 1 promotes the binding of the origin recognition complex to chromatin. AB - Phosphorylation of Orc2, one of the six subunits of the origin recognition complex (ORC), by cyclin A/CDK2 during S phase leads to the dissociation of Orc2, Orc3, Orc4, and Orc5 subunits (Orc2-5) from human chromatin and replication origins. Dephosphorylation of the phosphorylated Orc2 by protein phosphatase 1 (PP1) is accompanied by the binding of the dissociated subunits to chromatin. Here we show that PP1 physically interacts with Orc2. The binding of PP1 to Orc2 and the dephosphorylation of Orc2 by PP1 occurred in a cell cycle-dependent manner through an interaction with 119-KSVSF-123, which is the consensus motif for the binding of PP1, of Orc2. The dephosphorylation of Orc2 by PP1 is required for the binding of Orc2 to chromatin. These results support that PP1 dephosphorylates Orc2 to promote the binding of ORC to chromatin and replication origins for the subsequent round of the cell cycle. PMID- 24792177 TI - The Wag31 protein interacts with AccA3 and coordinates cell wall lipid permeability and lipophilic drug resistance in Mycobacterium smegmatis. AB - Mycobacterium tuberculosis, especially drug resistant tuberculosis, is a serious threat to global human health. Compared with other bacterial pathogens, M. tuberculosis gains stronger natural drug resistance from its unusually lipid-rich cell wall. As a DivIVA homolog, Wag31 has been demonstrated to be closely involved in peptidoglycan synthesis, cell growth and cell division. Previous research rarely investigated the role of Wag31 in drug resistance. In this study, we found Wag31 knock-down in Mycobacterium smegmatis resulted in a co-decrease of the resistance to four lipophilic drugs (rifampicin, novobiocin, erythromycin and clofazimine) and an increase in the cell permeability to lipophilic molecules. Six proteins (AccA3, AccD4 and AccD5, Fas, InhA and MmpL3) that are involved in fatty acid and mycolic acid synthesis were identified in the Wag31 interactome through Co-Immunoprecipitation. The Wag31-AccA3 interaction was confirmed by the pull-down assay. AccA3 overexpression resulted in a decrease in lipid permeability and an increase in the resistance of rifampicin and novobiocin. It confirmed the close relationship of lipophilic drug resistance, lipid permeability and the Wag31-AccA3 interaction. These results demonstrated that Wag31 maintained the resistance to lipophilic drugs and that Wag31 could play a role in controlling the lipid permeability of the cell wall through the Wag31 AccA3 interaction. PMID- 24792178 TI - Regulation of the mitochondrial Ca(2+) uniporter by MICU1 and MICU2. PMID- 24792179 TI - Knockdown of WWP1 inhibits growth and induces apoptosis in hepatoma carcinoma cells through the activation of caspase3 and p53. AB - The activation of oncogenes and the loss of tumor suppressor genes are believed to play critical roles in the pathogenesis of human hepatocellular carcinoma (HCC). The human WW domain containing E3 ubiquitin protein ligase 1 (WWP1) gene is frequently amplified in prostate and breast cancers, however, its role in cancer has not yet been extensively studied. Especially, the role of WWP1 in HCC has not yet been studied. Firstly, we analyzed the expression of WWP1 in HCC samples. We found that protein levels of WWP1 are higher in most HCC cancerous tissues as compared with their matched adjacent non-tumor tissues. Additionally, the WWP1 mRNA was also amplified in all 7 HCC tissues. Knockdown of the endogenous WWP1 using small interfering RNA further showed that deficiency of WWP1 suppressed cell growth and caused apoptosis in HCC cells. Knocking down WWP1 promoted cleaved caspase3 protein and p53 expression in HCC cells, and caspase3 inhibition could prevent cell apoptosis induced by the knockdown of WWP1. All together these results indicate that protein levels of WWP1 in most HCC tissues are higher than non-tumor tissues, and knockdown of WWP1 inhibits growth and induces apoptosis in HCC cells through the activation of caspase3 and p53. Therefore, WWP1 gene might be a potential molecular target of HCC. PMID- 24792180 TI - Dystroglycan depletion inhibits the functions of differentiated HL-60 cells. AB - Dystroglycan has recently been characterized in blood tissue cells, as part of the dystrophin glycoprotein complex but to date nothing is known of its role in the differentiation process of neutrophils. We have investigated the role of dystroglycan in the human promyelocytic leukemic cell line HL-60 differentiated to neutrophils. Depletion of dystroglycan by RNAi resulted in altered morphology and reduced properties of differentiated HL-60 cells, including chemotaxis, respiratory burst, phagocytic activities and expression of markers of differentiation. These findings strongly implicate dystroglycan as a key membrane adhesion protein involved in the differentiation process in HL-60 cells. PMID- 24792181 TI - In vitro selection of RNA aptamers that selectively bind danofloxacin. AB - Danofloxacin is a synthetic fluoroquinolone with broad spectrum antibacterial activity that is used for the treatment of respiratory diseases in animal husbandry. However, danofloxacin has many adverse reactions and is toxic to humans. Especially, it detrimentally affects muscle, central nerve system, peripheral nerve system, liver, and skin in those who ingest foods in which danofloxacin has accumulated. Prescreening and determination of the level of danofloxacin in foods or food products is necessary for human health. Aptamers are composing of oligonucleotides that specifically interact with target molecules. They are emerging as detection/diagnostic ligands. Here, we used the SELEX in vitro selection technology to identify specific and high-affinity RNA aptamers with 2'-fluoro-2'-deoxyribonucleotide modified pyrimidine nucleotides against danofloxacin. Selected RNA aptamers bound specifically to danofloxacin, but not to tetracycline. Truncation of RNA aptamer up to 36 mer did not comprise specificity and affinity. The truncated RNA aptamer specifically bound to target chemical, allowing the discrimination of danofloxacin from other fluoroquinolones. The isolated specific aptamer could be a potential agent used for the rapid and cost-effective detection and sensing of danofloxacin, replacing instrumental methods including the more expensive and time-consuming methods of high performance liquid chromatography and liquid chromatography/mass spectrometry. PMID- 24792182 TI - Molecular control of mitochondrial calcium uptake. AB - The recently identified Mitochondrial Calcium Uniporter (MCU) is the protein of the inner mitochondrial membrane responsible for Ca(2+) uptake into the matrix, which plays a role in the control of cellular signaling, aerobic metabolism and apoptosis. At least two properties of mitochondrial calcium signaling are well defined: (i) mitochondrial Ca(2+) uptake varies greatly among different cells and tissues, and (ii) channel opening is strongly affected by extramitochondrial Ca(2+) concentration, with low activity at resting and high capacity after cellular stimulation. It is now becoming clear that these features of the mitochondrial Ca(2+) uptake machinery are not embedded in the MCU protein itself, but are rather due to the contribution of several MCU interactors. The list of the components of the MCU complex is indeed rapidly growing, thus revealing an unexpected complexity that highlights the pleiotropic role of mitochondrial calcium signaling. PMID- 24792183 TI - Adiponectin is partially associated with exosomes in mouse serum. AB - Exosomes are membrane vesicles 30-120 nm in diameter that are released by many cell types and carry a cargo of proteins, lipids, mRNA, and microRNA. Cultured adipocytes reportedly release exosomes that may play a role in cell-to-cell communication during the development of metabolic diseases. However, the characteristics and function of exosomes released from adipocytes in vivo remain to be elucidated. Clearly, adipocyte-derived exosomes could exist in the circulation and may be associated with adipocyte-specific proteins such as adipocytokines. We isolated exosomes from serum of mice by differential centrifugation and analyzed adiponectin, leptin, and resistin in the exosome fraction. Western blotting detected adiponectin but no leptin and only trace amounts of resistin in the exosome fraction. The adiponectin signal in the exosome fraction was decreased by proteinase K treatment and completely quenched by a combination of proteinase K and Triton X-100. Quantitative ELISA showed that the exosome fraction contains considerable amounts of adiponectin, but not leptin or resistin. The concentration of adiponectin in the serum and the ratio of adiponectin to total protein in the exosome fraction were lower in obese mice than in lean mice. These results suggest that a portion of adiponectin exists as a transmembrane protein in the exosomes in mouse serum. We propose adiponectin as a marker of exosomes released from adipocytes in vivo. PMID- 24792184 TI - Role of ICAM-1 polymorphisms (G241R, K469E) in mediating its single-molecule binding ability: atomic force microscopy measurements on living cells. AB - Atherosclerosis (As) is characterized by chronic inflammation and is a major cause of human mortality. ICAM-1-mediated adhesion of leukocytes in vessel walls plays an important role in the pathogenesis of atherosclerosis. Two single nucleotide polymorphisms (SNPs) of human intercellular adhesion molecule-1 (ICAM 1), G241R and K469E, are associated with a number of inflammatory diseases. SNP induced changes in ICAM-1 function rely not only on the expression level but also on the single-molecule binding ability which may be affected by single molecule conformation variations such as protein splicing and folding. Previous studies have shown associations between G241R/K469E polymorphisms and ICAM-1 gene expression. Nevertheless, few studies have been done that focus on the single molecule forces of the above SNPs and their ligands. In the current study, we evaluated both single molecule binding ability and expression level of 4 ICAM-1 mutations - GK (G241/K469), GE (G241/E469), RK (R241/K469) and RE (R241/E469). No difference in adhesion ability was observed via cell adhesion assay or atomic force microscopy (AFM) measurement when comparing the GK, GE, RK, or RE genotypes of ICAM-1 to each other. On the other hand, flow cytometry suggested that there was significantly higher expression of GE genotype of ICAM-1 on transfected CHO cells. Thus, we concluded that genetic susceptibility to diseases related to ICAM 1 polymorphisms, G241R or K469E, might be due to the different expressions of ICAM-1 variants rather than to the single-molecule binding ability of ICAM-1. PMID- 24792185 TI - PDGF-regulated miRNA-138 inhibits the osteogenic differentiation of mesenchymal stem cells. AB - Differentiation-specific microRNAs may play a critical role in MSC differentiation, and they can be altered by PDGF signaling. We propose that PDGF modulates MSC differentiation by regulating microRNA expression. Therefore, we investigated whether PDGF treatment could alter the expression profile of miRNAs in MSCs. Furthermore, we assessed the osteoblast phenotype of MSCs after inducing osteogenic differentiation. We found that PDGF treatment significantly inhibits the osteogenic differentiation of MSCs and that miR-138 gene transcription is controlled by PDGF signaling. Our results confirm that miR-138 inhibits the osteogenic differentiation of MSCs and suppresses the phosphorylation of FAK, ERK1/2, and Runx2. Furthermore, our study clearly demonstrates that downregulation of Runx2 by miR-138 is critical for the PDGF-mediated inhibition of osteogenic differentiation of MSCs. These findings indicate that inhibition of miR-138 function in MSCs, either by treatment with anti-miR-138 or by overexpression of the miR-138 target sequence (miRNA sponge), could represent a potential therapeutic strategy for the treatment of bone homeostasis disorders caused by activation of the PDGF pathway. PMID- 24792186 TI - Unresolved questions from the analysis of mice lacking MCU expression. AB - Entry of mitochondrial calcium is believed to play an essential role in regulating bioenergetics and initiating cell death pathways. We have recently described a mouse model lacking MCU expression. Surprisingly, these mice are viable and the cells and tissues from these animals do not exhibit any marked protection from cell death. Here, we discuss our findings as well as potential explanations for some of the more unexpected results. PMID- 24792187 TI - Live visualization and quantification of pathway signaling with dual fluorescent and bioluminescent reporters. AB - Despite their fundamental importance, the dynamics of signaling pathways in living cells remain challenging to study, due to a lack of non-invasive tools for temporal assessment of signal transduction in desired cell models. Here we report a dual-reporter strategy that enables researchers to monitor signal transduction in mammalian cells in real-time, both temporally and quantitatively. This is achieved by co-expressing green fluorescent protein and firefly luciferase in response to signaling stimuli. To display the versatility of this approach, we constructed and assessed eight unique signaling pathway reporters. We further validated the system by establishing stable NF-kappaB pathway reporter cell lines. Using these stable cell lines, we monitored the activity of NF-kappaB mediated inflammatory pathway in real-time, both visually and quantitatively. Live visualization has the power to reveal individual cell responses and is compatible with single cell analysis, In addition, we provide evidence that this system is readily amenable to a high-throughput format. Together, our findings demonstrate the potential of the dual reporter system, which significantly improves the capacity to study signal transduction pathways in mammalian cells. PMID- 24792188 TI - Sodium and potassium excretion are related to bone mineral density in women with coeliac disease. AB - BACKGROUND & AIMS: Women with coeliac disease may have a lower bone mineral density due to the malabsorption of calcium before diagnosis. A high sodium excretion is associated with increased calcium and bone loss. Our aim was to describe the bone mineral density (BMD) and sodium excretion in women with coeliac disease. METHODS: In a cross-sectional study BMD of the lumbar spine and hip was assessed by dual energy X-ray absorptiometry. Sodium, potassium and calcium excretion were measured from a 24 h urine collection. RESULTS: In 33 women (51 +/- 16 yr) BMD was 1.14 +/- 0.19 g/cm(2) and 0.94 +/- 0.14 g/cm(2) at the lumbar spine and hip respectively. Age matched Z-scores were -0.1 +/- 1.2 and -0.3 +/- 1.1 at lumbar spine and hip respectively. Sodium excretion was 107 +/- 51 mmol/d; 14 (42%) had a sodium excretion >100 mmol Na/d (145 +/- 45 mmol/d). Potassium and calcium excretion were 87 +/- 25 mmol/d and 4.1 +/- 2.0 mmol/d respectively. In women with Na excretion >100 mmol Na/d, Ca excretion was significantly greater than those with <100 mmol/d (4.9 +/- 2.0 vs 3.4 +/- 1.8, p < 0.05). Sodium excretion and BMI were positively correlated (r = 0.61, p < 0.001) as were sodium and calcium excretion (r = 0.43, p < 0.05). Sodium excretion was inversely related to femoral neck BMD (t = -2.4 p = 0.023) after adjustment for weight, age, years since diagnosis and potassium excretion. Weight, but no other variable, was a predictor of BMD at the lumbar spine (t = 2.58 p = 0.018). CONCLUSIONS: Sodium excretion was inversely related and potassium excretion positively related to femoral neck density which was similar to age matched women without coeliac disease. PMID- 24792189 TI - Haematological parameters and serum trace elements in "healthy" and "unhealthy" morbidly obese patients before and after gastric bypass. AB - BACKGROUND & AIMS: We have investigated the differences in plasma parameters and serum trace elements between "healthy" and unhealthy morbidly obese patients before and after Roux-en-Y gastric bypass surgery. METHODS: A group of 32 morbidly obese patients undergoing bariatric surgery were divided into three groups. Group 1 subjects were free of dyslipidemia and type II diabetes mellitus (defined as "healthy" obese, DM-DL-); Group 2 subjects had only the presence of dyslipidemia (DM-DL+), while group 3 patients demonstrated the presence of both (DM + DL+). In all patients, we studied haematological, haemostasis, anaemia, coagulation plasma and trace elements parameters before and 1, 6 and 12 months after gastric bypass surgery. RESULTS: We found significant differences in some haematological parameters, including haemostasis (e.g., T-Quick, p = 0.0048) and coagulation (e.g., ATIII and PAI-1, p = 0.001 and p < 0.0001, respectively) and in anaemia parameters (e.g., folate, cobalamin and transferrin, p = 0.0002, p < 0.0001 and p = 0.0001, respectively) but also in serum trace elements between the groups. However, the response to bariatric surgery was similar in the three groups. CONCLUSION: Any healthy morbid obese subject is really metabolically "unhealthy" because he or she has many other haematologic or serum abnormalities that are often not included in the criteria for the definition of "healthy" in these obese subjects. PMID- 24792190 TI - Resilience and quality of life among Wenchuan earthquake survivors: the mediating role of social support. AB - OBJECTIVES: To examine the extent social support mediates resilience and quality of life in Wenchuan earthquake survivors. STUDY DESIGN: Originals. METHODS: Self report psychological questionnaires, the standard Chinese 12-item Short Form (SF 12v2), the Resilience Scale for Adults (RSA), and the Social Support Rating Scale (SSRS) were used to interview a total of 2080 survivors from 19 counties in the 2008 Wenchuan Earthquake area. A regression analysis was conducted to evaluate the mediating effect of social support on quality of life. RESULTS: Males and individuals with a higher level of education were found to have a better quality of life. The association between resilience and quality of life improved after social support was included, suggesting that at least a part of this association was mediated by the level of social support provided. CONCLUSIONS: This analysis highlighted that the level of resilience and quality of life after an earthquake was associated with the level of social support. This result has clear policy implications, and indicates that more focus needs to be placed on policies that aim for the provision of early mental health intervention and social support to improve the quality of life of earthquake survivors. PMID- 24792191 TI - Cross-border health and productivity effects of alcohol policies. AB - This paper studies the cross-border health and productivity effects of alcohol taxes. We estimate the effect of a large cut in the Finnish alcohol tax on mortality, alcohol-related illnesses and work absenteeism in Sweden. This tax cut led to large differences in the prices of alcoholic beverages between these two countries and to a considerable increase in cross-border shopping. The effect is identified using differences-in-differences strategy where changes in these outcomes in regions near the Finnish border are compared to changes in other parts of northern Sweden. We use register data where micro level data on deaths, hospitalisations and absenteeism is merged to population-wide micro data on demographics and labour market outcomes. Our results show that the Finnish tax cut did not have any clear effect on mortality or alcohol-related hospitalisations in Sweden. However, we find that workplace absenteeism increased by 9% for males and by 15% for females near the Finnish border as a result of the tax cut. PMID- 24792192 TI - Vascular barrier protective effects of orientin and isoorientin in LPS-induced inflammation in vitro and in vivo. AB - Endothelial cell protein C receptor (EPCR) can be shed from the cell surface, and this process is mediated by tumor necrosis factor-alpha converting enzyme (TACE), and high levels of soluble EPCR are involved in vascular inflammation. Orientin, one of the C-glycosyl flavonoids, has been known to have anxiolytic and antioxidative activities. However, the effect of orientin on lipopolysaccharide (LPS)-induced inflammatory response has not been studied. Here we investigated the barrier protective effects of orientin against pro-inflammatory responses induced by LPS and the associated signaling pathways. We found that orientin inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of monocytes to human endothelial cells. Orientin induced potent inhibition of phorbol-12-myristate 13-acetate (PMA) and LPS-induced EPCR shedding. Orientin also suppressed LPS-induced hyperpermeability and leukocyte migration in vivo. Furthermore, orientin suppressed the production of tumor necrosis factor-alpha (TNF-alpha) or Interleukin (IL)-6 and the activation of nuclear factor-kappaB (NF-kappaB) or extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, treatment with orientin resulted in reduced LPS-induced lethal endotoxemia. These results suggest that orientin protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. PMID- 24792193 TI - Synthesis, vibrational, NMR, quantum chemical and structure-activity relation studies of 2-hydroxy-4-methoxyacetophenone. AB - The stable geometry of 2-hydroxy-4-methoxyacetophenone is optimised by DFT/B3LYP method with 6-311++G(**) and cc-pVTZ basis sets. The structural parameters, thermodynamic properties and vibrational frequencies of the optimised geometry have been determined. The effects of substituents (hydroxyl, methoxy and acetyl groups) on the benzene ring vibrational frequencies are analysed. The vibrational frequencies of the fundamental modes of 2-hydroxy-4-methoxyacetophenone have been precisely assigned and analysed and the theoretical results are compared with the experimental vibrations. 1H and 13C NMR isotropic chemical shifts are calculated and assignments made are compared with the experimental values. The energies of important MO's, the total electron density and electrostatic potential of the compound are determined. Various reactivity and selectivity descriptors such as chemical hardness, chemical potential, softness, electrophilicity, nucleophilicity and the appropriate local quantities are calculated. PMID- 24792194 TI - FTIR study of ageing of fast drying oil colour (FDOC) alkyd paint replicas. AB - We propose ATR-FTIR spectroscopy for the characterization of the spectral changes in alkyd resin from the Griffin Alkyd Fast Drying Oil Colour range (Winsor & Newton), occurring over 550 days (~18 months) of natural ageing and over six months of artificial ageing under an acetic acid atmosphere. Acetic acid is one of the atmospheric pollutants found inside museums in concentrations that can have a significant effect on the works exhibited. During natural ageing we observed an increase and broadening of the OH group band around 3300 cm(-1) and an increase in bands in the region 1730-1680 cm(-1) due to carbonyl stretching. We found a broad band around 1635 cm(-1) likely due to CO stretching vibrations of beta dichetons. These spectral changes are the result of autooxidation reactions during natural ageing and crosslinking, which then form f alcohols and carbonyl species. The increase in absorbance at 1635 cm(-1) was selected as a parameter to monitor the ageing process of paintings prepared with FDOC, without the need for any extractive procedure. FTIR spectra of paint replicas kept under an acetic acid atmosphere indicated the chemical groups involved in the reaction with acid, thus suggesting which spectral FTIR regions could be investigated in order to follow any degradation in real paintings. A red paint sample from a hyper-realistic artwork ("Racconta storie", 2003) by the Italian painter Patrizia Zara was investigated by FTIR in order to evaluate the effects of 10 years natural ageing on alkyd colours. The results obtained suggested that after the end of chemical drying (autooxidation), alkyd colours are very stable. PMID- 24792195 TI - Comparative artificial neural network and partial least squares models for analysis of Metronidazole, Diloxanide, Spiramycin and Cliquinol in pharmaceutical preparations. AB - Metronidazole (MNZ) is a widely used antibacterial and amoebicide drug. Therefore, it is important to develop a rapid and specific analytical method for the determination of MNZ in mixture with Spiramycin (SPY), Diloxanide (DIX) and Cliquinol (CLQ) in pharmaceutical preparations. This work describes simple, sensitive and reliable six multivariate calibration methods, namely linear and nonlinear artificial neural networks preceded by genetic algorithm (GA-ANN) and principle component analysis (PCA-ANN) as well as partial least squares (PLS) either alone or preceded by genetic algorithm (GA-PLS) for UV spectrophotometric determination of MNZ, SPY, DIX and CLQ in pharmaceutical preparations with no interference of pharmaceutical additives. The results manifest the problem of nonlinearity and how models like ANN can handle it. Analytical performance of these methods was statistically validated with respect to linearity, accuracy, precision and specificity. The developed methods indicate the ability of the previously mentioned multivariate calibration models to handle and solve UV spectra of the four components' mixtures using easy and widely used UV spectrophotometer. PMID- 24792197 TI - Sensitive and selective spectrophotometric assay of piroxicam in pure form, capsule and human blood serum samples via ion-pair complex formation. AB - A simple, accurate and highly sensitive spectrophotometric method has been developed for the rapid determination of piroxicam (PX) in pure and pharmaceutical formulations. The proposed method involves formation of stable yellow colored ion-pair complexes of the amino derivative (basic nitrogen) of PX with three sulphonphthalein acid dyes namely; bromocresol green (BCG), bromothymol blue (BTB), bromophenol blue (BPB) in acidic medium. The colored species exhibited absorption maxima at 438, 429 and 432 nm with molar absorptivity values of 9.400*10(3), 1.218*10(3) and 1.02*10(4) L mol(-1) cm(-1) for PX-BCG, PX-BTB and PX-BPB complexes, respectively. The effect of optimum conditions via acidity, reagent concentration, time and solvent were studied. The reactions were extremely rapid at room temperature and the absorbance values remained constant for 48h. Beer's law was obeyed with a good correlation coefficient in the concentration ranges 1-100 MUg mL(-1) for BCG, BTB complexes and 1-95 MUg mL(-1) for BPB complex. The composition ratio of the ion-pair complexes were found to be 1:1 in all cases as established by Job's method. No interference was observed from common additives and excipients which may be present in the pharmaceutical preparations. The proposed method was successfully applied for the determination of PX in capsule and human blood serum samples with good accuracy and precision. PMID- 24792196 TI - Synthetic aspects, spectral, thermal studies and antimicrobial screening on bis(N,N-dimethyldithiocarbamato-S,S')antimony(III) complexes with oxo or thio donor ligands. AB - The bis(N,N-dimethyldithiocarbamato-S,S')antimony(III) complexes have been obtained by the reaction of chloro bis(N,N-dimethyldithiocarbamato S,S')antimony(III) with corresponding oxo or thio donor ligands such as sodium benzoate 1, sodium thioglycolate 2, phenol 3, sodium 1-propanethiolate 4, potassium thioacetate 5, sodium salicylate 6, ethane-1,2-dithiolate 7 and disodium oxalate 8. These complexes have been characterized by the physicochemical [melting point, molecular weight determination and elemental analysis (C, H, N, S and Sb)], spectral [UV-Visible, FT-IR, far IR, NMR (1H and 13C)], thermogravimetric (TG & DTA) analysis, ESI-Mass and powder X-ray diffraction studies. Thermogravimetric analysis of the complexes confirmed the final decomposition product as highly pure antimony sulfide (Sb2S3) and powder X ray diffraction studies show that the complexes are in lower symmetry with monoclinic crystal lattice and nano-ranged particle size (11.51-20.82 nm). The complexes have also been screened against some bacterial and fungal strains for their antibacterial and antifungal activities and compared with standard drugs. These show that the complexes have greater activities against some human pathogenic bacteria and fungi than the activities of standard drugs. PMID- 24792198 TI - Discrimination between authentic and adulterated liquors by near-infrared spectroscopy and ensemble classification. AB - Chinese liquor is one of the famous distilled spirits and counterfeit liquor is becoming a serious problem in the market. Especially, age liquor is facing the crisis of confidence because it is difficult for consumer to identify the marked age, which prompts unscrupulous traders to pose off low-grade liquors as high grade liquors. An ideal method for authenticity confirmation of liquors should be non-invasive, non-destructive and timely. The combination of near-infrared spectroscopy with chemometrics proves to be a good way to reach these premises. A new strategy is proposed for classification and verification of the adulteration of liquors by using NIR spectroscopy and chemometric classification, i.e., ensemble support vector machines (SVM). Three measures, i.e., accuracy, sensitivity and specificity were used for performance evaluation. The results confirmed that the strategy can serve as a screening tool applied to verify adulteration of the liquor, that is, a prior step used to condition the sample to a deeper analysis only when a positive result for adulteration is obtained by the proposed methodology. PMID- 24792199 TI - Interactions of tamoxifen with distearoyl phosphatidylcholine multilamellar vesicles: FTIR and DSC studies. AB - Interactions of a non-steroidal antiestrogen drug, tamoxifen (TAM), with distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) multilamellar liposomes (MLVs) were investigated as a function of drug concentration (1-15 mol%) by using two noninvasive techniques, namely Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR spectroscopy results show that increasing TAM concentrations (except 1 mol%) increased the wavenumbers of the CH2 stretching modes, implying an disordering effect for DSPC MLVs both in the gel and liquid crystalline phases. The bandwidth values of the CH2 stretchings except for 1 mol% increased when TAM concentrations increased for DSPC liposomes, indicating an increase in the dynamics of liposomes. The CO stretching and PO2- antisymmetric double bond stretching bands were analyzed to study interactions of TAM with head groups of lipids. As the concentrations of TAM increased, dehydration occurred around these functional groups in the polar part of the lipids. The DSC studies on thermal properties of DSPC lipids indicate that TAM eliminated the pre transition, shifted the main phase transition to lower temperatures and broadened the phase transition curve of the liposomes. PMID- 24792200 TI - Photo-physical behavior of some antitumor anthracycline in solvent media with different polarity. AB - Absorption and emission spectra of three antitumour anthracyclines, with various substituent and stereoisomer groups, were studied in different solvents. The solute's photo-physical behavior strongly depends on solvent-solute interactions and solvent's nature. Solvatochromic method was used to investigate dipole moments of these materials in ground and excited states. Spectral variations were analyzed via means of linear solvation energy relationships concept, proposed by Kamlet and Taft. The results explain the nature of specific and non-specific solvent-solute interactions and functional groups' reorientation of studied anthracyclines in different media. PMID- 24792201 TI - Optical, structural, thermal and dielectric spectroscopy characterizations of seeded melt grown 2-hydroxy biphenyl single crystal. AB - Organic single crystal of 2-hydroxy biphenyl (2-HB) was grown by top seeded melt growth method. Scanning electron microscopy studies has been carried out on the surface of the grown crystals to investigate the nature of growth and defects. The crystalline perfection and lattice parameters of 2-HB has been determined by single crystal XRD analysis and it belongs to orthorhombic crystal system with space group Fdd2. The functional groups and molecular associations were confirmed by FT-IR. The optical characteristics such as cut-off and transmittance were carried out using UV-Vis-NIR spectra. Absence of absorption in the region between 320 and 1100 nm makes the grown crystal desirable to optical applications. Thermal stability of grown crystals was characterized by thermogravimetric (TGA), differential thermal analysis (DTA) and differential scanning calorimetric (DSC) analyses. Broadband dielectric studies reveals that dielectric constant of grown crystal is low. The resistivity of grown crystal was studied by impedance analysis. The second harmonic generation intensity of 3.8 mJ was studied. The grown crystal belongs to soft material studied by hardness test. PMID- 24792202 TI - Synthesis, characterization and experimental, theoretical, electrochemical, antioxidant and antibacterial study of a new Schiff base and its complexes. AB - A new Schiff base ligand was synthesized by reaction of salicylaldehyde with 1,6 bis(4-chloro-2-aminophenoxy)hexane. Then the Schiff base complexes were synthesized by metal salts and the Schiff base. The metal to ligand ratio of metal complexes was found to be 1:1. The Cu(II) complex is proposed to be square planar and the Co(II), Ni(II), Mn(II) and Zn(II) complexes are proposed to be tetrahedral geometry. The Ti(III) and V(III) complexes are proposed to be a capped octahedron in which a seventh ligand has been added to triangular face. The complexes are non-electrolytes as shown by their molar conductivities (LambdaM). The structure of metal complexes is proposed from elemental analysis, FT-IR, UV-vis, magnetic susceptibility measurements, molar conductivity measurements, Mass Spectra and thermal gravimetric analysis. In addition antimicrobial and antioxidant studies, cyclic voltammetry of the complexes, theoretical 1H NMR and HOMO-LUMO energy calculations of the new di-functional ligand were done. PMID- 24792203 TI - A green emitting phosphorescent copper(I) complex with tetrazole derived ligand for electroluminescence application. AB - In this paper, a tetrazole derived diamine ligand of 2-(1H-tetrazol-5-yl)pyridine (TP) owing electron-donors and short conjugation chain was synthesized to increase the band gap of its corresponding phosphorescent Cu(I) complex. This Cu(I) complex was characterized in detail, including its single crystal structure, singlet electronic transitions, photophysical parameters, thermal stability and electrochemical property. Upon on photoexcitation, this Cu(I) complex emitted green emission peaking at 497 nm with biexponential decay pattern of tau1=5.5414 MUs (A1=0.137) and tau2=1.0679 MUs (A2=0.11503). Cyclic voltammerty experiment suggested that this Cu(I) complex owned HOMO and LUMO energy levels of -5.79 eV and -2.39 eV. The thermal decomposition temperature was 170 degrees C as indicated by thermogravimetric analysis. The optimal electroluminescence device constructed by solution processed coating procedure showed green electroluminescence peaking at 525 nm, with maximum luminance of 2860 cd/m2 and maximum current efficiency of 5.9 cd/A. PMID- 24792204 TI - Vibrational assignment and structure of trinuclear oxo-centered of basic formate iron(III) and chromium(III) complexes: a density functional theory study. AB - [Fe3O(OOCH)6(H2O)3]OOCH.HCOOH, and [Cr3O(OOCH)6(H2O)3]OOCH.2.5HNO3 were synthesized and the molecular structure and vibrational assignments of their cations were investigated by means of density functional theory (DFT) calculations. The harmonic vibrational frequencies of [Fe3O(OOCH)6(H2O)3]+ and [Cr3O(OOCH)6(H2O)3]+ were obtained at the UB3LYP level using a series of basis sets. The topological properties of the charge distribution of both cations in their ground states are discussed in detail by means of natural bond orbital (NBO) theory and of [Fe3O(OOCH)6(H2O)3]+ by the quantum theory of atoms in molecules (AIM). The calculated geometrical parameters and vibrational frequencies were compared with the experimental results. The scaled theoretical frequencies and the structural parameters were found to be in good agreement with the experimental data. PMID- 24792206 TI - Isolation of nuc mutant isolates of Staphylococcus aureus from bovine clinical mastitis. AB - Isolates of Staphylococcus aureus with a mutation in the nuclease (nuc) gene were recovered from cases of bovine mastitis in Poland. Three S. aureus isolates from cows in one herd had a 42 base pair duplication in the nuc gene. These isolates belonged to sequence type 97 (ST97) and clonal complex 97 (CC97). They had a different spa type and multiple-locus variable-number tandem-repeat fingerprinting (MLVF) subtype than a S. aureus isolate without the nuc mutation from the same herd. Isolation of nuc mutant S. aureus strains from cases of bovine mastitis may confound diagnostic PCRs based on detection of the nuc gene. PMID- 24792205 TI - Critical evaluation of ex vivo restoration of carious equine maxillary cheek teeth infundibulae following high-pressure gas and micro-particle abrasion. AB - Infundibular caries of the equine maxillary cheek teeth is an important disorder that can lead to dental fracture or apical infection. Treatment by removing food debris and carious dental tissue from affected infundibulae using high-pressure abrasion with aluminium hydroxide micro-particles, followed by filling the cleaned defect with endodontic restorative materials is a recommended treatment. However, although anecdotally considered a successful treatment option, there is currently no objective evidence to support this claim. Forty maxillary cheek teeth (CT) that contained 55 infundibulae with caries (mainly grade 2) were extracted post-mortem from 21 adult horses. Five of the CT were sectioned prior to treatment to facilitate visual examination of the carious infundibulae. The remaining carious infundibulae were cleaned using high-pressure abrasion with aluminium hydroxide particles and five CT were sectioned to assess the efficacy of this cleaning process. The remaining 30 CT containing 39 carious infundibulae were then filled with a composite restorative material. The efficacy of this restoration was assessed by computed tomography imaging followed by direct visual examination after sectioning the teeth. Only 46% (18/39) of restored infundibulae, all with shallow (mean 9.6 mm deep) defects, were fully cleaned of food debris and carious material, and filled with restorative material to their full depth. Of these 18, 11 had peripheral defects around the restoration, leaving just 18% (7/39) of restorations without any gross defects. The remaining 54% (21/39) of infundibulae (mean depth of infundibular caries defect, 18.3 mm) still contained food debris and/or carious material in more apical locations, with infundibulae with the deepest caries defects being the least effectively cleaned. The findings of this study indicate that high-pressure micro-particle abrasion is only effective in cleaning food debris from shallow, carious CT infundibulae and consequently, the majority of subsequent infundibular restorations are imperfect. PMID- 24792207 TI - High ambient temperature alleviates the inflammatory response and growth depression in pigs challenged with Escherichia coli lipopolysaccharide. AB - Pig production has increased in hot climate countries over recent years, but the effect of exposure to high temperatures on the health status of farm animals has not been investigated thoroughly. It is not clear how the ambient temperature (Ta) might influence responses to inflammatory challenge in pigs. The aim of the present study was to evaluate the effects of high Ta on performance and physiological parameters of growing pigs, subjected to repeated administration of Escherichia coli lipopolysaccharide (LPS). Thirty-seven pigs, each fitted with a jugular catheter, were assigned to one of two Ta conditions: thermo-neutral (TN, 24 degrees C) or high (HT, 30 degrees C). After a 14-day adaptation period, and a 7-day measurement period, pigs were administered five repeated injections of LPS at 48 h intervals. Irrespective of Ta, the LPS challenge reduced feed consumption and increased plasma pro-inflammatory cytokines, haptoglobin and cortisol. However, the extent of these responses was greater in pigs at TN than HT. In both groups, plasma thyroxine and triiodothyronine concentrations decreased, following the first LPS injection and thereafter returned to baseline, which occurred faster at HT than at TN. Moreover, the LPS challenge decreased growth and feed efficiency in pigs kept at TN, which was not observed in pigs kept at HT. The results suggest a greater capacity of pigs to limit the physiological and metabolic disturbances caused by inflammatory challenge, when kept at HT, compared to TN. PMID- 24792208 TI - Response of knee cartilage T1rho and T2 relaxation times to in vivo mechanical loading in individuals with and without knee osteoarthritis. AB - OBJECTIVE: The objective of this study was to evaluate the effects of mechanical loading on knee articular cartilage T1rho and T2 relaxation times in patients with and without osteoarthritis (OA). DESIGN: Magnetic resonance (MR) images were acquired from 137 subjects with and without knee OA under two conditions: unloaded and loaded at 50% body weight. Three sequences were acquired: a high resolution 3D-CUBE, a T1rho relaxation time, and a T2 relaxation time sequences. Cartilage regions of interest included: medial and lateral femur (MF, LF); medial and lateral tibia (MT, LT), laminar analysis (superficial and deep layers), and subcompartments. Changes in relaxation times in response to loading were evaluated. RESULTS: In response to loading, we observed significant reductions in T1rho relaxation times in the MT and LT. In both the MF and LF, loading resulted in significant decreases in the superficial layer and significant increases in the deep layer of the cartilage for T1rho and T2. All subcompartments of the MT and LT showed significant reduction in T1rho relaxation times. Reductions were larger for subjects with OA (range: 13-19% change) when compared to healthy controls (range: 3-13% change). CONCLUSIONS: Loading of the cartilage resulted in significant changes in relaxation times in the femur and tibia, with novel findings regarding laminar and subcompartmental variations. In general, changes in relaxation times with loading were larger in the OA group suggesting that the collagen-proteoglycan matrix of subjects with OA is less capable of retaining water, and may reflect a reduced ability to dissipate loads. PMID- 24792209 TI - Pharmacological effects of novel cross-linked hyaluronate, Gel-200, in experimental animal models of osteoarthritis and human cell lines. AB - OBJECTIVE: To study the pharmacological effects of Gel-200, cross-linked hyaluronate. EXPERIMENTAL DESIGN: We examined the chondroprotective, anti inflammatory and analgesic effects of Gel-200 in experimental animal models for osteoarthritis (OA) and in a human synovial sarcoma cell line and normal human articular chondrocytes. RESULTS: In the OA model, a single-dose intra-articular (IA) injection of Gel-200 significantly suppressed cartilage degeneration and reduced synovitis of the knee joint. In the joint pain model, Gel-200 significantly suppressed pain responses for 4 weeks after injection. The residual property of Gel-200 in the knee joint tissue was investigated in rabbits. The mean residual ratio of injected Gel-200 in the synovium was 3.3% (95% confidence interval [CI], 2.4-4.2) at 28 days after the injection. The long-lasting analgesic effect of Gel-200 might be explained by its high residual ratio in the joint. In addition, we investigated the mechanism of action of Gel-200 in a human synovial sarcoma cell line and normal human articular chondrocytes. Gel-200 inhibited IL-1beta-induced production of MMP-1, 3 and 13 in human chondrocytes and production of prostaglandin E2 in human synoviocytes in a concentration dependent manner, respectively. CONCLUSION: A single-dose IA injection of Gel-200 exerts chondroprotective and anti-inflammatory effects in the experimental OA model, and long-lasting analgesia in the joint pain model, suggesting the beneficial multimodal function of Gel-200 against symptomatic OA patients. PMID- 24792210 TI - Evaluation of the therapeutic effect of treatment with intra-articular hyaluronic acid in knees for Kashin-Beck disease: a meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of intra-articular hyaluronic acid (IAHA) injection in knee joints of patients with Kashin-Beck disease (KBD). METHODS: We searched nine electronic databases as well as unpublished data from inception until November 30th 2013 using a combination of search terms for KBD and hyaluronic acid (HA). For dichotomous data, odds ratios (OR) and 95% confidence intervals (CI) were estimated. For continuous data, standard mean difference (SMD) was used for outcomes pooled on the difference scale using a "random-effects" or "fixed-effects" model. We also compared the mean and standard deviation of cytokine levels in post-treatment. RESULTS: The seven eligible trials included 954 IAHA and 495 control patients. The methodological quality of included trials was low. The overall effectiveness of the IAHA group and control group were 93.7% and 62.9%, respectively. IAHA group resulted in very large treatment effects compared to pre-treatment values in 12 months, with SMD values ranging from 1.19-2.64 (all P < 0.05). Compared to controls, SMDs in IAHA group ranged from 0.19-0.64 at 1 week to 1 month (all P > 0.05) and 0.68-1.47 at 2 months to 12 months (all P < 0.05). There was significant improved of HA, cluster of differentiation44 (CD44), keratan sulfate (KS), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) contents in serum compared with that in the post-treatment and healthy control in non-KBD area (all P < 0.05). CONCLUSION: IAHA for the treatment of KBD was safe and efficacious at 12 months with low and transient adverse reactions. However, more high-quality randomized controlled trials (RCTs) are needed to confirm its therapeutic effect. PMID- 24792211 TI - Quantitative X-ray microradiography for high-throughput phenotyping of osteoarthritis in mice. AB - OBJECTIVE: To investigate and validate digital X-ray microradiography as a novel, high-throughput and cost-effective screening approach to identify abnormal joint phenotypes in mice. METHOD: Digital X-ray microradiography was used to quantify the subchondral bone mineral content (BMC) in the medial tibial plateau. Accuracy and reproducibility of the method were determined in 22 samples from C57BL/6(B6Brd;B6Dnk;B6N-Tyr(c-Brd)) wild-type mice. The method was then validated in wild-type mice that had undergone surgical destabilisation of medial meniscus (DMM) and in a genetically modified mouse strain with an established increase in trabecular bone mass. RESULTS: The measurement of subchondral BMC by digital X ray microradiography had a coefficient of variation of 3.6%. Digital X-ray microradiography was able to demonstrate significantly increased subchondral BMC in the medial tibial plateau of male mice 4 and 8 weeks after DMM surgery and in female mice 8 weeks after surgery. Furthermore, digital X-ray microradiography also detected the increase in subchondral BMC in a genetically modified mouse strain with high trabecular bone mass. CONCLUSION: Quantitation of subchondral BMC by digital X-ray microradiography is a rapid, sensitive and cost-effective method to identify abnormal joint phenotypes in mice of both genders at several ages. PMID- 24792213 TI - Identification, expression, and responses to bacterial challenge of the cathepsin C gene from the razor clam Sinonovacula constricta. AB - Cathepsin C (dipeptidyl-peptidaseI, DPPI) is a lysosomal cysteine proteinase that belongs to the papain superfamily, and it is involved in protein degradation and proenzyme activation. However, very little is known about the function of cathepsin C in bivalves. In the present study, we identified the cathepsin C gene in the razor clam Sinonovacula constricta (Sc-CTSC). The full-length Sc-CTSC cDNA contained a complete open reading frame (ORF) of 1371 nt encoding 456 amino acids, a 98 bp 5' UTR, and a 1043 bp 3' UTR. The ORF of Sc-CTSC consisted of a putative signal peptide of 22 aa, a propeptide of 229 aa, and a mature peptide of 205 aa containing the active site triad of Cys, His, and Asn. The Sc-CTSC transcript was expressed in a wide range of tissues but exhibited the greatest level of expression in the digestive gland. During the early developmental stages, the transcript was detected widely. Upon injection with Vibrio anguillarum, the Sc-CTSC transcript was significantly up-regulated in digestive gland, mantle, and gill tissues. The results provided important information for further exploring the roles of cathepsin C in the innate immune responses. PMID- 24792212 TI - Trajectory of cartilage loss within 4 years of knee replacement--a nested case control study from the osteoarthritis initiative. AB - OBJECTIVE: Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior to KR vs non-replaced controls. METHODS: A nested case-control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence (T0), and at 1 4 years prior to T0 (T-1 to T-4). Cartilage loss between cases and controls was compared using paired t-tests and conditional logistic regression. RESULTS: One hundred and eighty-nine knees of 164 OAI participants [55% women; age 64 +/- 8.7; body mass index (BMI) 29 +/- 4.5] had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls [94 +/ 137 vs 55 +/- 104 MUm; P = 0.0017 (paired t); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08-1.70)]. The discrimination was stronger for T-2 -> T0 [OR 1.61 (1.33-1.95), n = 127] than for T-1 -> T0, and was not statistically significant for intervals prior to T-2 [i.e., T-4 -> T-2, OR 0.97 (0.67-1.41), n = 60]. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI. CONCLUSIONS: In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined. PMID- 24792214 TI - Identification of a C-type lectin with antiviral and antibacterial activity from pacific white shrimp Litopenaeus vannamei. AB - C-type lectins (CTLs) play crucial roles in innate immune responses in invertebrates by recognizing and eliminating microinvaders. In this study, a CTL from pacific white shrimp Litopenaeus vannamei (LvCTL3) was identified. LvCTL3 contains a single C-type lectin-like domain (CTLD), which shows similarities to those of other shrimp CTLs and has a mutated 'EPD' motif in Ca(2+)-binding site 2. LvCTL3 mRNA can be detected in all tested tissues and expression of LvCTL3 in gills was up-regulated after Lipopolysaccharides, poly (I:C), Vibrio parahaemolyticus and white spot syndrome virus (WSSV) challenges, suggesting activation responses of LvCTL3 to bacterial, virus and immune stimulant challenges. The 5'flanking regulatory region of LvCTL3 was cloned and we identified a NF-kappaB binding motif in the LvCTL3 promoter region. Dual luciferase reporter assays indicated that over-expression of L. vannamei dorsal can dramatically up regulate the promoter activity of LvCTL3, suggesting that LvCTL3 expression could be regulated through NF-kappaB signaling pathway. As far as we know, this is the first report on signaling pathway involve in shrimp CTLs expression. The recombinant LvCTL3 protein was expressed in Escherichia coli and purified by Ni-affinity chromatography. The purified LvCTL3 can agglutinate Gram negative microbe Vibrio alginolyticus and V. parahaemolyticus and Gram-positive bacteria Bacillus subtilis in the presence of calcium ions, but cannot agglutinate Gram-positive bacteria Streptococcus agalactiae. The agglutination activity of LvCTL3 was abolished when Ca(2+) was chelated with EDTA, suggesting the function of LvCTL3 is Ca(2+)-dependent. In vivo challenge experiments showed that the recombinant LvCTL3 protein can significantly reduce the mortalities of V. parahemolyticus and WSSV infection, indicating LvCTL3 might play significant roles in shrimp innate immunity defense against bacterial and viral infection. PMID- 24792216 TI - For principled model fitting in mathematical biology. AB - I argue for a principled approach to model fitting in mathematical biology that combines statistical and mechanistic insights. PMID- 24792215 TI - CLN3 deficient cells display defects in the ARF1-Cdc42 pathway and actin dependent events. AB - Juvenile Batten disease (juvenile neuronal ceroid lipofuscinosis, JNCL) is a devastating neurodegenerative disease caused by mutations in CLN3, a protein of undefined function. Cell lines derived from patients or mice with CLN3 deficiency have impairments in actin-regulated processes such as endocytosis, autophagy, vesicular trafficking, and cell migration. Here we demonstrate the small GTPase Cdc42 is misregulated in the absence of CLN3, and thus may be a common link to multiple cellular defects. We discover that active Cdc42 (Cdc42-GTP) is elevated in endothelial cells from CLN3 deficient mouse brain, and correlates with enhanced PAK-1 phosphorylation, LIMK membrane recruitment, and altered actin driven events. We also demonstrate dramatically reduced plasma membrane recruitment of the Cdc42 GTPase activating protein, ARHGAP21. In line with this, GTP-loaded ARF1, an effector of ARHGAP21 recruitment, is depressed. Together these data implicate misregulated ARF1-Cdc42 signaling as a central defect in JNCL cells, which in-turn impairs various cell functions. Furthermore our findings support concerted action of ARF1, ARHGAP21, and Cdc42 to regulate fluid phase endocytosis in mammalian cells. The ARF1-Cdc42 pathway presents a promising new avenue for JNCL therapeutic development. PMID- 24792217 TI - Peptide functionalized polyhydroxyalkanoate nanofibrous scaffolds enhance Schwann cells activity. AB - Interactions between Schwann cells (SCs) and scaffolds are important for tissue development during nerve regeneration, because SCs physiologically assist in directing the growth of regenerating axons. In this study, we prepared electrospun scaffolds combining poly (3-hydroxybutyrate) (PHB) and poly (3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) functionalized with either collagen I, H-Gly-Arg-Gly-Asp-Ser-OH (GRGDS), H-Tyr-Ile-Gly-Ser-Arg-NH2 (YIGSR), or H-Arg Asn-Ile-Ala-Glu-Ile-Ile-Lys-Asp-Ile-OH (p20) neuromimetic peptides to mimic naturally occurring ECM motifs for nerve regeneration. Cells cultured on fibrous mats presenting these biomolecules showed a significant increase in metabolic activity and proliferation while exhibiting unidirectional orientation along the orientation of the fibers. Real-time PCR showed cells cultured on peptide modified scaffolds had a significantly higher neurotrophin expression compared to those on untreated nanofibers. Our study suggests that biofunctionalized aligned PHB/PHBV nanofibrous scaffolds may elicit essential cues for SCs activity and could serve as a potential scaffold for nerve regeneration. From the clinical editor: Nanotechnology-based functionalized scaffolds represent one of the most promising approaches in peripheral nerve recovery, as well as spinal cord recovery. In this study, bio-functionalized and aligned PHB/PHBV nanofibrous scaffolds were found to elicit essential cues for Schwann cell activity, therefore could serve as a potential scaffold for nerve regeneration. PMID- 24792219 TI - Serum sex steroids and steroidogenesis-related enzyme expression in skeletal muscle during experimental weight gain in men. AB - OBJECTIVES: Low-circulating testosterone is associated with development of type 2 diabetes in obese men. In this study, we examined the effects of experimental overfeeding and weight gain on serum levels of sex hormones and skeletal muscle expression of steroidogenic enzymes in healthy men with (FH+) and without (FH-) a family history of type 2 diabetes. METHODS: Following a 3-day lead in energy balanced diet, FH+ (n = 9) and FH- men (n = 11) were overfed by 5200 kJ/day (45% fat) for 28 days. Body weight, fasting glucose, insulin, sex steroid, sex hormone binding globulin (SHBG) levels, insulin sensitivity (hyperinsulinaemic euglycaemic clamp) and body fat (DXA) were assessed in all individuals at baseline and day 28, and sex steroidogenesis-related enzyme expression in vastus lateralis biopsies was examined in a subset (n = 11). RESULTS: Body weight, fat mass and fasting insulin levels were increased by overfeeding (P < 0.01) and insulin was increased significantly more in FH+ men (P<0.01). Serum sex hormone binding globulin (SHBG) and 5alpha-dihydrotestosterone (DHT) were reduced with overfeeding (P < 0.05), and serum testosterone and DHT were reduced to a greater extent in FH+ men (P < 0.05). Overfeeding reduced mRNA expression of 3beta hydroxysteroid dehydrogenase (HSD) and 17betaHSD (P <= 0.007), independently of group. 5alpha-Reductase (SRD5A1) mRNA expression was not changed overall, but a time by group interaction was observed (P = 0.04). CONCLUSION: Overfeeding reduced SHBG and muscle expression of enzymes involved in the formation of testosterone in skeletal muscle. Men with a family history of T2DM were more susceptible to deleterious outcomes of overfeeding with greater reductions in serum testosterone and DHT and greater increases in markers of insulin resistance, which may contribute to increased risk of developing type 2 diabetes. PMID- 24792218 TI - Effects of eye dominance (left vs. right) and cannabis use on intermanual coordination and negative symptoms in schizophrenia patients. AB - Based on the previous findings, it has been assumed that in schizophrenia patients, eye dominance and cannabis use will affect negative symptoms and intermanual coordination (IMC), an index of interhemispheric communication. But eye dominance, specifically the clinical findings for it, has been neglected in schizophrenia research. We therefore investigated its effects in 52 right-handed (36 right-eyed and 16 left-eyed) and 51 left-handed (35 left-eyed and 16 right eyed) schizophrenia in-patients without and with drug use. Eye dominance affected IMC in all schizophrenia patients. When comparing right- and left-handers, we found that this result was only significant in the right-handed patients and in the smaller subgroup without drug use. In the right-handers, left eye dominance like left-handedness-was associated with higher values in IMC and less pronounced manifestation of negative symptoms, right eye dominance was not. Thus, left-eyed right-handers may be more closely related to left-handers than to right-handers. In accordance with the results from the literature, we suggest that these findings are due to better interhemispheric connections and less impairment of white matter structures, especially in right-hemispheric regions. Moreover, cannabis use was related to higher scores in IMC and less pronounced negative symptoms, but only in the right-eyed and not in the left-eyed right-handers or in the left-handers. Hence, differences in eye dominance and handedness may be partially responsible for different results in interhemispheric connections among cannabis users. In conclusion, both eye dominance and use of cannabis should be taken into account when assessing clinical symptoms in schizophrenia patients. PMID- 24792220 TI - Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal. AB - Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM. PMID- 24792221 TI - Bigger is not always better: transmission and fitness burden of ~1MB Pseudomonas syringae megaplasmid pMPPla107. AB - BACKGROUND: Horizontal gene transfer (HGT) is a widespread process that enables the acquisition of genes and metabolic pathways in single evolutionary steps. Previous reports have described fitness costs of HGT, but have largely focused on the acquisition of relatively small plasmids. We have previously shown that a Pseudomonas syringae pv. lachrymans strain recently acquired a cryptic megaplasmid, pMPPla107. This extrachromosomal element contributes hundreds of new genes to P. syringae and increases total genomic content by approximately 18%. However, this early work did not directly explore transmissibility, stability, or fitness costs associated with acquisition of pMPPla107. RESULTS: Here, we show that pMPPla107 is self-transmissible across a variety of diverse pseudomonad strains, on both solid agar and within shaking liquid cultures, with conjugation dependent on a type IV secretion system. To the best of our knowledge, this is the largest self-transmissible megaplasmid known outside of Sinorhizobium. This megaplasmid can be lost from all novel hosts although the rate of loss depends on medium type and genomic background. However, in contrast, pMPPla107 is faithfully maintained within the original parent strain (Pla107) even under direct negative selection during laboratory assays. These results suggest that Pla107 specific stabilizing mutations have occurred either on this strain's chromosome or within the megaplasmid. Lastly, we demonstrate that acquisition of pMPPla107 by strains other than Pla107 imparts severe (20%) fitness costs under competitive conditions in vitro. CONCLUSIONS: We show that pMPPla107 is capable of transmitting and maintaining itself across multiple Pseudomonas species, rendering it one of the largest conjugative elements discovered to date. The relative stability of pMPPla107, coupled with extensive fitness costs, makes it a tractable model system for investigating evolutionary and genetic mechanisms of megaplasmid maintenance and a unique testing ground to explore evolutionary dynamics after HGT of large secondary elements. PMID- 24792222 TI - Pharmacokinetics of lincomycin following single intravenous administration in buffalo calves. AB - Lincomycin 10 mg kg(-1), IV in buffalo calves followed two-compartment open model with high distribution rate constant alpha (11.2 +/- 0.42 h(-1)) and K 12/K 21 ratio (4.40 +/- 0.10). Distribution half-life was 0.06 +/- 0.01 h and AUC was 41.6 +/- 1.73 MUg mL(-1) h. Large Vdarea (1.15 +/- 0.03 L kg(-1)) indicated good distribution of lincomycin in various body fluids and tissues. Peak plasma level of lincomycin (71.8 +/- 1.83 MUg mL(-1)) was observed at 1 min as expected by IV route. The elimination half-life and MRT of lincomycin were short (3.30 +/- 0.08 and 4.32 +/- 0.11 h, respectively). Lincomycin 10 mg kg(-1) IV at 12-h interval would be sufficient to maintain T > MIC above 60 % for bacteria with minimum inhibitory concentrations (MIC) values <=1.6 MUg mL(-1). Favourable pharmacokinetic profile in buffalo calves and a convenient dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin. PMID- 24792223 TI - Structure-activity relationships of anthocyanidin glycosylation. AB - This paper summarizes the main achievements about the structure-activity relationships of anthocyanidin glycosylation. Anthocyanidin glycosylation is the essential step of anthocyanin biosynthesis and also the prerequisite of the further modifications of anthocyanins, which is jointly characterized by the glycosylation site, the type and number of the glycosyl as well as the glycosidic bond type. It generally enhances the stability, results in the hypsochromic effect and blueing, decreases the bioavailability and anticancer activity, and decreases, increases, or does not change the antioxidant activity of the anthocyanidins or anthocyanins, which is synergetically determined by the glycosylation site and the type and number of the glycosyl. Thereinto, in nature, the blue hues caused by the glycosylation may also be reinforced by the formation of the anthocyanic vacuolar inclusions. This review could provide a reference for the research of the structure-optimizing and function-exploiting of anthocyanins. PMID- 24792224 TI - System-level multi-target drug discovery from natural products with applications to cardiovascular diseases. AB - The term systems pharmacology describes a field of study that uses computational and experimental approaches to broaden the view of drug actions rooted in molecular interactions and advance the process of drug discovery. The aim of this work is to stick out the role that the systems pharmacology plays across the multi-target drug discovery from natural products for cardiovascular diseases (CVDs). Firstly, based on network pharmacology methods, we reconstructed the drug target and target-target networks to determine the putative protein target set of multi-target drugs for CVDs treatment. Secondly, we reintegrated a compound dataset of natural products and then obtained a multi-target compounds subset by virtual-screening process. Thirdly, a drug-likeness evaluation was applied to find the ADME-favorable compounds in this subset. Finally, we conducted in vitro experiments to evaluate the reliability of the selected chemicals and targets. We found that four of the five randomly selected natural molecules can effectively act on the target set for CVDs, indicating the reasonability of our systems-based method. This strategy may serve as a new model for multi-target drug discovery of complex diseases. PMID- 24792225 TI - An efficient tandem approach for the synthesis of functionalized 2-pyridone-3 carboxylic acids using three-component reaction in aqueous media. AB - Novel analogs of 2-pyridone-3-carboxylic acids 4a-l have been prepared by the three-component reaction of 3-formyl chromone, Meldrum's acid, and primary amines in the presence of a catalytic amount of diammonium hydrogen phosphate in water. Good-to-high yields, easy work-up, and an environmentally friendly profile are the advantages of this method for the synthesis of 2-pyridone-3-carboxylic acid derivatives. PMID- 24792226 TI - Synthesis and crystal structure of new heterocycles containing 1,2,4-oxadiazole, 1,2,4-oxadiazolone (thione), hydantoin, and mercaptobenzimidazole units. AB - A number of 1,2,4-oxadiazolone and mercapto nitro benzimidazole derivatives containing 1,2,4-oxadiazole and hydantoin moieties have been prepared, and their structures were identified by means of spectral/physical characteristics including X-ray diffraction data. PMID- 24792228 TI - Disease invasion on community networks with environmental pathogen movement. AB - The ability of disease to invade a community network that is connected by environmental pathogen movement is examined. Each community is modeled by a susceptible-infectious-recovered (SIR) framework that includes an environmental pathogen reservoir, and the communities are connected by pathogen movement on a strongly connected, weighted, directed graph. Disease invasibility is determined by the basic reproduction number R(0) for the domain. The domain R(0) is computed through a Laurent series expansion, with perturbation parameter corresponding to the ratio of the pathogen decay rate to the rate of water movement. When movement is fast relative to decay, R(0) is determined by the product of two weighted averages of the community characteristics. The weights in these averages correspond to the network structure through the rooted spanning trees of the weighted, directed graph. Clustering of disease "hot spots" influences disease invasibility. In particular, clustering hot spots together according to a generalization of the group inverse of the Laplacian matrix facilitates disease invasion. PMID- 24792227 TI - Integral control for population management. AB - We present a novel management methodology for restocking a declining population. The strategy uses integral control, a concept ubiquitous in control theory which has not been applied to population dynamics. Integral control is based on dynamic feedback-using measurements of the population to inform management strategies and is robust to model uncertainty, an important consideration for ecological models. We demonstrate from first principles why such an approach to population management is suitable via theory and examples. PMID- 24792229 TI - Web-based trial to evaluate the efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder: REMOTE trial. AB - INTRODUCTION: Participatory patient-centered, web-based methods could streamline and improve the convenience of clinical trial participation. We used an entirely web-based approach to conduct a randomized, placebo-controlled, Phase 4 (REMOTE) trial under an Investigational New Drug (IND) application to evaluate tolterodine extended release (ER) 4 mg for overactive bladder. METHODS: The trial was designed to replicate previous clinic-based trials of tolterodine ER but was conducted via the web from one clinical site overseen by physicians. Participants were recruited via the web, screened for eligibility using web-based questionnaires, had laboratory testing in their community, and entered a run-in phase requiring bladder e-diaries. Informed consent was obtained using an interactive web-based method with physician countersignature. Study medication was shipped directly to participants. RESULTS: With a goal of 283 randomized participants, 5157 registered on the trial website. Of 456 who passed initial screening, identification verification, and signed consent, 237 passed additional medical screening and were countersigned by the investigator. After laboratory testing, 118 entered the placebo run-in; only 18 passed e-diary assessments and were randomized to treatment. At week 12, the mean change from the baseline in micturitions/24 hours (primary endpoint) was -2.4 for tolterodine ER versus -0.8 for placebo [treatment difference (95% CI): -1.6 (-3.9, 0.6)]. CONCLUSION: The REMOTE trial is the first entirely web-based trial conducted under an IND application. The efficacy observed was consistent with results from conventional trials. With simplification of multi-step screening and testing, web-based trials or their component parts should provide a participant-friendly approach to many clinical trials. PMID- 24792230 TI - [Evaluation of transit in vivo dosimetry using portal imaging and comparison with measurements using diodes]. AB - PURPOSE: In vivo dosimetry transit using portal imaging is a promising approach for quality assurance in radiotherapy. A comparative evaluation was conducted between a commercial solution, EPIgray((r)) and an in vivo dosimetry control reference using semiconductors diodes. MATERIAL AND METHODS: The performance of the two in vivo dosimetry methods was assessed. The primary endpoint was the dose deviation between the reconstructed dose at the prescription point and the measured dose using the ionization chamber in phantoms or the calculated predictive dose by the treatment planning system with patients. The deviation threshold was set to +/-5%. In total, 107 patients were prospectively included and treated with 3D-conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) techniques for tumours of the brain, chest and head and neck. RESULTS: The dosimetric accuracy of EPIgray((r)) in phantom were comparable to diodes in terms of repeatability (0.11%), reproducibility (0.29-0.51%) with a mean dose deviation of 0.17% (SD: 1.11). The rates of radiotherapy sessions out of the tolerance for the brain (3D-CRT and IMRT), thorax (3D-CRT) and the head and neck (IMRT) were respectively 0%, 9.6% and 5.3% with a mean dose deviation ranging between 0.49% and 1.53%. The mean of dose deviation between three consecutive sessions with EPIgray((r)) validates 99.1% of treatments. CONCLUSION: The performance of EPIgray((r)) in in vivo dosimetry is consistent with the recommendations of the European Society for Radiotherapy and Oncology (ESTRO) and equivalent to semiconductor diodes for 3D-CRT. It also allows adequate control for IMRT, which is technically difficult to perform with the diodes. PMID- 24792231 TI - Sequential voluntary cough and aspiration or aspiration risk in Parkinson's disease. AB - BACKGROUND: Disordered swallowing, or dysphagia, is almost always present to some degree in people with Parkinson's disease (PD), either causing aspiration or greatly increasing the risk for aspiration during swallowing. This likely contributes to aspiration pneumonia, a leading cause of death in this patient population. Effective airway protection is dependent upon multiple behaviors, including cough and swallowing. Single voluntary cough function is disordered in people with PD and dysphagia. However, the appropriate response to aspirate material is more than one cough, or sequential cough. The goal of this study was to examine voluntary sequential coughing in people with PD, with and without dysphagia. METHODS: Forty adults diagnosed with idiopathic PD produced two trials of sequential voluntary cough. The cough airflows were obtained using pneumotachograph and facemask and subsequently digitized and recorded. All participants received a modified barium swallow study as part of their clinical care, and the worst penetration-aspiration score observed was used to determine whether the patient had dysphagia. RESULTS: There were significant differences in the compression phase duration, peak expiratory flow rates, and amount of air expired of the sequential cough produced by participants with and without dysphagia. CONCLUSIONS: The presence of dysphagia in people with PD is associated with disordered cough function. Sequential cough, which is important in removing aspirate material from large- and smaller-diameter airways, is also impaired in people with PD and dysphagia compared with those without dysphagia. There may be common neuroanatomical substrates for cough and swallowing impairment in PD leading to the co-occurrence of these dysfunctions. PMID- 24792232 TI - Expression of matrix metalloproteinase-1 in alveolar macrophages, type II pneumocytes, and airways in smokers: relationship to lung function and emphysema. AB - BACKGROUND: An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. METHODS: We performed quantitative immunohistochemical assessment of matrix metalloproteinase 1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs' surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. RESULTS: There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT. CONCLUSION: These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1. PMID- 24792233 TI - Individual responses to alignment perturbations in socket reaction moments while walking in transtibial prostheses. AB - BACKGROUND: The alignment of transtibial prostheses has a systematic effect on the mean socket reaction moments in amputees. However, understanding their individual differences in response to alignment perturbations is also important for prosthetists to fully utilize the socket reaction moments for dynamic alignment in each unique patient. The aim of this study was to investigate individual responses to alignment perturbations in transtibial prostheses with solid-ankle-cushion-heel feet. METHODS: A custom instrumented prosthesis alignment component was used to measure the socket reaction moments while walking in 11 amputees with transtibial prostheses under 17 alignment conditions, including 3 degrees and 6 degrees of flexion, extension, abduction, and adduction of the socket, 5mm and 10mm of anterior, posterior, lateral, and medial translation of the socket, and an initial baseline alignment. Coronal moments at 30% of stance and maximum sagittal moments were extracted for comparisons from each amputee. FINDINGS: In the coronal plane, varus moment at 30% of stance was generally reduced by adduction or medial translation of the socket in all the amputees. In the sagittal plane, extension moment was generally increased by posterior translation or flexion of the socket; however, this was not necessarily the case for all the amputees. INTERPRETATIONS: Individual responses to alignment perturbations are not always consistent, and prosthetists would need to be aware of this variance when addressing individual socket reaction moments during dynamic alignment in clinical setting. PMID- 24792234 TI - The lateral prefrontal cortex and complex value-based learning and decision making. AB - Tremendous progress has been made in discerning the neurocognitive basis of value based decision making and learning. Although the majority of studies to date have employed simple task paradigms, recent work has started to examine more complex aspects of value processing including: the value of engaging rule-based cognitive control; the integration of multiple pieces of information (e.g., reward magnitude and delay) to discern the best course of action; pursuing future rewards; valuation of abstract concepts (e.g., fairness); and comparing the value of executed versus imagined alternative actions. We provide a comprehensive review of functional neuroimaging, electrophysiological, and lesion evidence suggesting that the lateral prefrontal cortex (LPFC) plays a critical role in these complex aspects of value processing. In particular, we focus on the specific information that the LPFC represents, and argue that it includes both cognitive and value-based information. We also discuss how the role of the LPFC is distinct from other value-related regions. Finally, we articulate a framework for understanding the contribution of subregions along the rostro-caudal axis of the LPFC, and thereby bridge the cognitive control and decision making literatures. PMID- 24792235 TI - Lactoferrin promote primary rat osteoblast proliferation and differentiation via up-regulation of insulin-like growth factor-1 expression. AB - The aim of this study was to explore the effect of lactoferrin (LF) in primary fetal rat osteoblasts proliferation and differentiation and investigate the underlying molecular mechanisms. Primary rat osteoblasts were obtained from the calvarias of neonatal rats. Osteoblasts were treated with LF (0.1-1000 MUg/mL), or OSI-906 [a selective inhibitor of insulin-like growth factor 1 (IGF-1) receptor and insulin receptor]. The IGF-1 was then knocked down by small hairpin RNA (shRNA) technology and then was treated with recombinant human IGF-1 or LF. Cell proliferation and differentiation were measured by MTT assay and alkaline phosphatase (ALP) assay, respectively. The expression of IGF-1 and IGF binding protein 2 (IGFBP2) mRNA were analyzed using real-time PCR. LF promotes the proliferation and differentiation of osteoblasts in a certain range (1-100 MUg/mL) in time- and dose-dependent manner. The mRNA level of IGF-1 was significantly increased, while the expression of IGFBP2 was suppressed by LF treatment. Knockdown of IGF-1 by shRNA in primary rat osteoblast dramatically decreased the abilities of proliferation and differentiation of osteoblasts and blocked the proliferation and differentiation effect of LF in osteoblasts. OSI906 (5 MUM) blocked the mitogenic and differentiation of LF in osteoblasts. Proliferation and differentiation of primary rat osteoblasts in response to LF are mediated in part by stimulating of IGF-1 gene expression and alterations in the gene expression of IGFBP2. PMID- 24792237 TI - Health related lifestyles of children: getting better? PMID- 24792236 TI - Prospective evaluation of plasma kinetic bipolar resection of bladder cancer: comparison to monopolar resection and pathologic findings. AB - OBJECTIVE: To determine whether the Gyrus ACMI plasma kinetic bipolar device (Gyrus ACMI, Southborough, MA) improves pathologic specimen preservation and clinical outcomes compared to standard monopolar electrocautery. PATIENTS AND METHODS: In our prospective study, 83 patients underwent monopolar or bipolar transurethral resection of bladder tumors between April 2006 and February 2007 at Memorial Sloan-Kettering Cancer Center. Dedicated genitourinary oncology pathologists blinded to resection type and assessed pathologic features including stage and grade, presence of muscularis propria, fragment size, presence and thickness of thermal artifacts within the specimen, layer of tissue most affected, severity of tissue distortion, and diagnostic impact of thermal artifacts. Clinical outcomes including, perforation, obturator reflex, need for muscle paralysis, a catheter, or admission, were recorded. Clinical and pathologic outcomes between resection modality were compared. RESULTS: There were no significant thermal artifacts in 9/38 (23.7 %) and 11/45 (24.4 %) monopolar and bipolar specimens, respectively. The layer of bladder tissue most affected by thermal artifacts was readable in 18/38 (47.4 %) monopolar and 27/45 (60.0 %) bipolar specimens. Tissue distortion from thermal artifacts led to areas within 11/38 (28.9 %) monopolar and 7/45 (15.6 %) bipolar specimens being unreadable. Ultimately, thermal artifacts caused moderate diagnostic difficulty in 2/38 (5.3 %) specimens of the monopolar group and severe diagnostic difficulty in 1/45 (2.2 %) bipolar specimens. Clinically, there was no major difference between resection methods. CONCLUSION: Plasma kinetic bipolar equipment appears to cause less tissue distortion and has the potential to facilitate staging and grading of bladder tumors. No differences in clinical outcomes were appreciated between resection methods. If these results can be repeated in larger studies, the bipolar device represents a small advancement in transurethral resection. PMID- 24792238 TI - US health systems made few gains in the years before the Affordable Care Act, report says. PMID- 24792239 TI - Botched execution could lead to legal challenges in death penalty states. PMID- 24792240 TI - Meat consumption in Sao Paulo-Brazil: trend in the last decade. AB - OBJECTIVE: To characterize trends in meat consumption, and verify the percentage of excessive red and processed meat consumption in the last decade in Sao Paulo, Brazil. DESIGN: Cross-sectional weighted data from the Health Survey for Sao Paulo, conducted in Sao Paulo, Brazil among people aged 12 years and older. SETTING: Diet was assessed by two 24-hour recalls in each survey. Usual meat consumption was estimated by Multiple Source Method. Wald tests were used to compare means across survey years. Data were collected from adolescents, adults, and elderly using a representative, complex, multistage probability-based survey in 2003 and in 2008 in Sao Paulo, southeast of Brazil. SUBJECTS: 2631 Brazilians were studied in 2003 and 1662 in 2008. RESULTS: Daily mean of red and processed meat consumption was 100 g/day in 2003, and 113 g/day in 2008. Excessive red and processed meat consumption was observed in almost 75% of the subjects, especially among adolescents in both surveys. Beef represented the largest proportion of meat consumed, followed by poultry, pork and fish in both surveys. CONCLUSIONS: Daily red and processed meat consumption was higher in 2008 than in 2003, and almost the entire population consumed more than what is recommended by World Cancer Research Fund. Public health strategies are needed, in order to reduce red and processed meat consumption to the recommended amounts, for a healthy diet. PMID- 24792242 TI - Reprint of: Elevating the quality of disability and rehabilitation research: Mandatory use of the reporting guidelines. PMID- 24792241 TI - A modular plasmid system for protein co-localization and bimolecular fluorescence complementation in filamentous fungi. AB - To elucidate the function of a protein, it is crucial to know its subcellular location and its interaction partners. Common approaches to resolve those questions rely on the genetic tagging of the gene-of-interest (GOI) with fluorescent reporters. To determine the location of a tagged protein, it may be co-localized with tagged marker proteins. The interaction of two proteins under investigation is often analysed by tagging both with the C- and N-terminal halves of a fluorescent protein. In fungi, the tagged GOI are commonly introduced by serial transformation with plasmids harbouring a single tagged GOI and subsequent selection of suitable strains. In this study, a plasmid system is presented that allows the tagging of several GOI on a single plasmid. This novel double tagging plasmid system (DTPS) allows a much faster and less laborious generation of double-labelled fungal strains when compared with conventional approaches. The DTPS also enables the combination of as many tagged GOI as desired and a simple exchange of existing tags. Furthermore, new tags can be introduced smoothly into the system. In conclusion, the DTPS allows an efficient tagging of GOI with a high degree of flexibility and therefore accelerates functional analysis of proteins in vivo. PMID- 24792243 TI - Physiotherapists have a vital part to play in combatting the burden of noncommunicable diseases. PMID- 24792245 TI - Identification of microRNAs involved in the modulation of pro-angiogenic factors in atherosclerosis by a polyphenol-rich extract from propolis. AB - New vessel formation plays a critical role in the progression and vulnerability of atherosclerotic lesions. It has been shown that polyphenols from propolis attenuate the progression of atherosclerosis and also exert inhibitory effects on angiogenic factors. However, the mechanisms underlying these effects are not completely understood. Thus, this study aimed to identify microRNAs (miRNAs) involved in the modulation of pro-angiogenic factors in the atherosclerotic plaques of LDL receptor gene knockout mice treated with a polyphenol-rich extract of Chilean propolis. The progression of the atherosclerotic lesions was significantly attenuated in treated mice compared with control mice. Using microarray analysis and a bioinformatic approach, we identified 29 differentially expressed miRNAs. Many of these miRNAs were involved in biological processes associated with angiogenesis, such as the cell cycle, cell migration, cell growth and proliferation. Among them, three miRNAs (miR-181a, miR-106a and miR-20b) were over-expressed and inversely related to the expression of Vegfa (vascular endothelial growth factor A) and Hif1a (hypoxia inducible factor 1 alpha). In addition, VEGF-A protein expression was attenuated in histological sections obtained from the aortic sinuses of treated mice. VEGFA is a key pro-angiogenic factor in atherosclerotic plaques, and Hif1a, which is expressed in the necrotic nucleus of the atheroma, is its main inducer. We found a correlation between the over-expression of miR-181a, miR-106a and miR-20b and their target genes, Hif1a and Vegfa, which is consistent with attenuation of the atherosclerotic lesion. In conclusion, our data analysis provides evidence that the anti-angiogenic effects of polyphenols from Chilean propolis can be modulated by miRNAs, in particular miR-181a, miR-106a and miR-20b. PMID- 24792246 TI - When is enough enough? The dilemma of valve replacement in a recidivist intravenous drug user. PMID- 24792244 TI - Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively stressed neuronal cells: implications for Parkinson's disease. AB - The microtubule (MT) system is important for many aspects of neuronal function, including motility, differentiation, and cargo trafficking. Parkinson's disease (PD) is associated with increased oxidative stress and alterations in the integrity of the axodendritic tree. To study dynamic mechanisms underlying the neurite shortening phenotype observed in many PD models, we employed the well characterized oxidative parkinsonian neurotoxin, 6-hydroxydopamine (6OHDA). In both acute and chronic sub-lethal settings, 6OHDA-induced oxidative stress elicited significant alterations in MT dynamics, including reductions in MT growth rate, increased frequency of MT pauses/retractions, and increased levels of tubulin acetylation. Interestingly, 6OHDA decreased the activity of tubulin deacetylases, specifically sirtuin 2 (SIRT2), through more than one mechanism. Restoration of tubulin deacetylase function rescued the changes in MT dynamics and prevented neurite shortening in neuron-differentiated, 6OHDA-treated cells. These data indicate that impaired tubulin deacetylation contributes to altered MT dynamics in oxidatively-stressed cells, conferring key insights for potential therapeutic strategies to correct MT-related deficits contributing to neuronal aging and disease. PMID- 24792247 TI - Invited commentary. PMID- 24792248 TI - Invited commentary. PMID- 24792249 TI - Invited commentary. PMID- 24792250 TI - Invited commentary. PMID- 24792251 TI - Mammalian fetal cardiac regeneration after myocardial infarction is associated with differential gene expression compared with the adult. AB - BACKGROUND: In adults, myocardial infarction (MI) results in a brisk inflammatory response, myocardium loss, and scar formation. We have recently reported the first mammalian large-animal model of cardiac regeneration after MI in fetal sheep. We hypothesize that the ability of the fetus to regenerate functional myocardium after MI is owing to differential gene expression regulating the response to MI in the fetus compared with the adult. METHODS: Myocardial infarction was created in adult (n=4) or early gestation fetal (n=4) sheep. Tissue was harvested after 3 or 30 days, and RNA was extracted for microarray, followed by principal component analysis and global gene expression analysis for the following gene ontology terms: response to wounding, inflammatory response, extracellular matrix, cell cycle, cell migration, cell proliferation, and apoptosis. RESULTS: Principal component analysis demonstrated that the global gene expression pattern in adult infarcts was distinctly different from the uninfarcted region at 3 days and remained different at 30 days after MI. In contrast, gene expression in the fetal infarct was different from the uninfarcted region at 3 days, but by 30 days it returned to a baseline expression pattern similar to the uninfarcted region. Three days after MI there was an increase in the expression of genes related to all gene ontology terms in fetal and adult infarcts, but this increase was much more pronounced in adults. By 30 days, the fetal gene expression returned to baseline, whereas in the adult it remained significantly elevated. CONCLUSIONS: These data demonstrate that the global gene expression pattern is dramatically different in the fetal regenerative response to MI compared with the adult response and may partly be responsible for the regeneration. PMID- 24792252 TI - Invited commentary. PMID- 24792253 TI - Invited commentary. PMID- 24792254 TI - Video-assisted thoracic surgery lobectomy cost variability: implications for a bundled payment era. AB - BACKGROUND: In 2013, the Centers for Medicare and Medicaid Services began its Bundled Payments for Care Improvement Initiative. If payments are to be bundled, surgeons must be able to predict which patients are at risk for more costly care. We aim to identify factors driving variability in hospital costs after video assisted thoracic surgery (VATS) lobectomy for lung cancer. METHODS: Our institutional Society of Thoracic Surgeons data were queried for patients undergoing VATS lobectomy for lung cancer during fiscal years 2010 to 2011. Clinical outcomes data were linked with hospital financial data to determine operative and postoperative costs. Linear regression models were created to identify the impact of preoperative risk factors and perioperative outcomes on cost. RESULTS: One hundred forty-nine VATS lobectomies for lung cancer were reviewed. The majority of patients had clinical stage IA lung cancer (67.8%). Median length of stay was 4 days, with 30-day mortality and morbidity rates of 0.7% and 37.6%, respectively. Mean operative and postoperative costs per case were $8,492.31 (+/-$2,238.76) and $10,145.50 (+/-$7,004.71), respectively, resulting in an average overall hospital cost of $18,637.81 (+/-$8,244.12) per patient. Patients with chronic obstructive pulmonary disease and coronary artery disease, as well as postoperative urinary tract infections and blood transfusions, were associated with statistically significant variability in cost. CONCLUSIONS: Variability in cost associated with VATS lobectomy is driven by assorted patient and clinical variables. Awareness of such factors can help surgeons implement quality improvement initiatives and focus resource utilization. Understanding risk-adjusted clinical-financial data is critical to designing payment arrangements that include financial and performance accountability, and thus ultimately increasing the value of health care. PMID- 24792255 TI - Invited commentary. PMID- 24792256 TI - Invited commentary. PMID- 24792257 TI - Invited commentary. PMID- 24792258 TI - Invited commentary. PMID- 24792259 TI - Invited commentary. PMID- 24792260 TI - Invited commentary. PMID- 24792262 TI - Invited commentary. PMID- 24792261 TI - Orthotopic lung cancer murine model by nonoperative transbronchial approach. AB - PURPOSE: The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. DESCRIPTION: Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunt-tip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5*10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. EVALUATION: When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. CONCLUSIONS: Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies. PMID- 24792263 TI - Takotsubo's syndrome after mitral valve repair and rescue with extracorporeal membrane oxygenation. AB - We report a case of Takotsubo's syndrome in a 37-year-old woman after mitral valve repair for severe mitral regurgitation triggered by a severe protamine reaction that was likely associated with immune-mediated coronary hypersensitivity (Kounis' syndrome) and made worse by resuscitation with high doses of catecholamines. The patient recovered fully after a 4-day course of extracorporeal membrane oxygenation therapy (ECMO). PMID- 24792264 TI - Thoracoabdominal aortic aneurysm repair in a patient with a left ventricular assist device. AB - We report a case of thoracoabdominal aneurysm repair in a 44-year-old man with end-stage heart failure requiring an extracorporeal left ventricular assist device (LVAD). At the age of 31 years, the patient experienced type B acute aortic dissection, which gradually dilated to a maximum dimension of 66 mm at the diaphragm. The aneurysm prevented the patient from meeting heart transplantation criteria. For this reason and because of an increased risk of rupture, we undertook surgical repair of the aneurysm. This report constitutes the first such published case, and we describe the management of the LVAD in the perioperative period. PMID- 24792265 TI - Uncertainty of axillary artery perfusion during surgery for acute aortic dissection. AB - We treated a patient with acute aortic dissection, which affected the innominate and carotid arteries. Although the true lumen was adequately wide and cerebral malperfusion deemed unlikely, extracorporeal circulation through the femoral artery caused right cerebral malperfusion, and addition of right axillary artery perfusion was ineffective. Several minutes after innominate artery snaring, cerebral blood flow was suddenly restored and the clinical outcome was favorable. Axillary artery perfusion is occasionally unreliable and inevitably demands careful cerebral flow monitoring. A dead-end false lumen in the innominate and carotid arteries requires special caution. A dual-artery perfusion strategy permits innominate artery occlusion as an emergency measure against unexpected malperfusion. PMID- 24792266 TI - Unexpected cause of cyanosis and dyspnea in an adult: direct communication of the right pulmonary artery and left atrium. AB - Direct communication of the right pulmonary artery and the left atrium is an extremely rare congenital malformation of the pulmonary vasculature. A 41-year old woman with a history of cyanosis since childhood presented with mild exertional dyspnea. On physical examination, she had central cyanosis, clubbing of the fingers, and an upright position caused by orthodeoxia. Imaging studies showed a very large aneurysm in the distal right pulmonary artery with a direct communication to the left atrium. The patient underwent successful repair, with resolution of hypoxia and exertional symptoms. PMID- 24792267 TI - The use of high-dose hydroxocobalamin for vasoplegic syndrome. AB - We describe a case of hypotension on cardiopulmonary bypass for coronary artery bypass grafting, double valve repairs, and patent foramen ovale closure. The patient experienced vasoplegic syndrome while on cardiopulmonary bypass. He was treated with high-dose hydroxocobalamin (vitamin B12). His blood pressure responded rapidly, obviating any further vasopressor requirements. PMID- 24792268 TI - Thoracoabdominal aortic repair in a patient with Ehlers-Danlos syndrome. AB - Type IV Ehlers-Danlos syndrome is a life-threatening inherited disorder of connective tissue associated with multiple aneurysm formation. Thoracoabdominal aortic repair in these patients has rarely been performed. We report the case of a 13-year-old patient with Ehlers-Danlos syndrome who had multiple aortic operations from the ascending aorta to the thoracoabdominal aorta. PMID- 24792269 TI - Fragmentation injury to the innominate artery in a three-year-old child. AB - The management of vascular trauma in pediatric patients presents numerous challenges, especially in an austere environment. We present the case of a 3-year old girl who sustained multiple fragmentation injuries to the right chest and right upper extremity as a result of combat activity in Iraq. This resulted in an occult pseudoaneurysm of the innominate artery identified during exploration of her right chest for a persistent air leak from the right side of the chest. Computed tomography angiography delineated the injury, which was surgically repaired. This report demonstrates the type of challenging cases encountered in a combat zone and illustrates the need for a national database of such injuries in pediatric patients to better inform surgical decision making. PMID- 24792270 TI - Unusual compression of the right pulmonary artery by the aortic arch. AB - Compression of the right pulmonary artery is unusual. We describe a patient with a double-outlet right ventricle, a ventricular septal defect, and pulmonary stenosis in whom the right pulmonary artery was compressed by a right-sided aortic arch. The condition was successfully managed during surgical correction. PMID- 24792271 TI - Semilunar valve replacement with decellularized homograft after Damus-Kaye Stansel anastomosis and fontan procedure. AB - We describe a patient in whom severe neoaortic (anatomic pulmonary) valve regurgitation developed late after Damus-Kaye-Stansel anastomosis and Fontan operation. The valve was replaced with a fresh decellularized homograft, which we developed and applied in the normal pulmonary and aortic position in more than 100 patients. During follow-up of more than 2 years, the valve function is excellent, and no infectious or thromboembolic complications were seen. The decellularized homograft seems to be an ideal material in this situation. PMID- 24792272 TI - Value of ultrasound in the imaging-guided transthoracic biopsy of lung lesions. AB - Transthoracic needle biopsy with fluoroscopic or computed tomographic guidance is a well-established and safe method for diagnosing malignant and benign thoracic lesions. Nonetheless, ultrasound is as effective as computed tomography for the guidance of transthoracic biopsies of peripheral pulmonary lesions and mediastinal tumors, and it offers some advantages. In this case report, we exemplify the proper use of ultrasound for the percutaneous biopsy of a lung lesion, aiming to show that it can be a safe, inexpensive, rapid, and effective alternative to computed tomography in appropriate cases. PMID- 24792273 TI - Contralateral pulmonary embolism caused by pulmonary artery stump thrombosis after pneumonectomy. AB - A 73-year-old man with atrial fibrillation and previous left pneumonectomy was admitted with pleural effusion. Anticoagulant therapy was discontinued because of chest tube drainage. Six days later, the patient experienced chest discomfort. Echocardiography showed a pedunculated thrombus with swaying motion in the left pulmonary artery (PA) stump. Contrast-enhanced computed tomography of the chest revealed filling defects in not only the left PA stump but also the right PA, implying contralateral pulmonary embolism. Anticoagulants were resumed, and thrombolysis was successful 3 days later. Patients undergoing pneumonectomy in whom anticoagulant therapy is discontinued should be recognized as being at high risk for PA stump thrombosis and subsequent contralateral pulmonary embolism. PMID- 24792274 TI - Castleman's disease presenting as a tracheal mass. AB - Castleman's disease (CD) is a rare lymphoproliferative disorder of uncertain cause. The most common site of involvement is the mediastinum. Endotracheal CD is extremely rare. We report a case of unicentric, hyaline-vascular type CD presenting as an obstructive tracheal mass. The tumor was successfully managed by rigid bronchoscopy with argon plasma coagulation. There was no recurrence at the 2-month follow-up visit. PMID- 24792275 TI - Spontaneous thymic hemorrhage in an adult. AB - Spontaneous thymic hemorrhage in a normal thymus in neonates and infants has been reported in the literature. Only one case of spontaneous thymic hemorrhage in an adult has been reported to our knowledge. We herein report the case of an adult who had a cardiac operation 26 years previously and who was on anticoagulation. He experienced acute hemorrhage in a normal thymus, and this was not thought to be attributable to an accidental cause such as trauma or to hypertension. PMID- 24792276 TI - Recurrent thymoma with stiff-person syndrome and pure red blood cell aplasia. AB - Stiff-person syndrome (formerly known as stiff-man syndrome) is a very rare autoimmune and neurogenic disorder, thought to present as a paraneoplastic variant in association with thymoma. Pure red blood cell aplasia is also a paraneoplastic disorder associated with thymoma. Although separate cases of stiff person syndrome and pure red blood cell aplasia have been reported, we describe here what is to our knowledge the first case of recurrent thymoma with both stiff person syndrome and pure red blood cell aplasia. We describe the successful treatment of the neurogenic symptoms of stiff-person syndrome and the progressive anemia associated with pure red blood cell aplasia by tumor excision. PMID- 24792277 TI - Bilateral lung transplantation in a patient with Vascular Ehlers-Danlos syndrome. AB - We describe the case of a 29-year-old woman with end-stage chronic obstructive pulmonary disease secondary to vascular Ehlers-Danlos syndrome. Because of critical deterioration, respiratory arrest, and complete lung failure, she required urgent implantation of a venovenous extracorporeal membrane oxygenator as a bridge to lung transplantation. After 6 days of extracorporeal life support, a successful bilateral sequential lung transplantation was performed. This is the first case of lung transplantation in a patient with a diagnosis of chronic obstructive pulmonary disease secondary to Ehlers-Danlos syndrome. PMID- 24792278 TI - Prosthetic mitral valve obstructed by occluder device for paravalvular leak. PMID- 24792279 TI - Left atrium the size of a honeydew melon. PMID- 24792280 TI - Migration of worm-shaped vegetation into the left coronary ostium. PMID- 24792281 TI - Valve sizer as retractor. PMID- 24792282 TI - Proposed modification for valve-sparing aortic root replacement. AB - Valve-sparing aortic root replacement (ARR) is the procedure of choice in young patients with aortic root aneurysm and preserved aortic valve leaflets; however, coronary ostial anastomoses remain an issue. Troublesome bleeding sometimes occurs during surgery, and in the long term, there is a risk of aneurysmal formation in the residual aortic wall of the ostial "button." We describe a technique of valve-sparing ARR wherein each coronary button along with its flange of aortic tissue is implanted within the prosthetic graft used for ARR, thereby eliminating the risk of both immediate surgical bleeding and late coronary button aneurysms. PMID- 24792283 TI - Autologous adventitial overlay method reinforces anastomoses in aortic surgery. AB - In this study, we present an inexpensive and effective method for providing a secure and hemostatic anastomosis using autologous adventitia obtained from a dissected or aneurysmal wall. The resected aortic wall is separated between the adventitia and media, and a soft, 2 * 10-cm adventitial strip is overlaid to cover the anastomotic margin. A graft is sutured to the aortic stump. This autologous adventitial overlay method can inexpensively and strongly reinforce the anastomosis during aortic surgery for dissection or aneurysm and will contribute to anastomotic hemostasis and long-term stability. PMID- 24792284 TI - Treatment of mediastinitis by ventrofil plates without sternal rewiring. AB - Mediastinitis is a serious complication of cardiac surgical procedures, with high rates of morbidity and mortality. We describe a new simple surgical technique to treat deep sternal infection based on the removal of all wires and deep sutures, and reapproximation of the sternum with four external plates without rewiring. Fourteen patients were treated with this technique. No complications related to the procedure occurred, the infection was successfully treated in all patients, and only 1 patient underwent vacuum treatment to obtain healing of the wound. PMID- 24792285 TI - Anomalous left coronary artery from nonfacing pulmonary sinus: direct aortic reimplantation. AB - We report a new technique of establishing a direct coronary transfer for anomalous left coronary artery arising from the nonfacing sinus of the pulmonary artery. This easily reproducible technique was successfully used in 2 patients. It achieves a dual coronary repair without the use of complex aortic or pulmonary arterial flaps and without causing any distortion to the great vessels. PMID- 24792286 TI - Internal cuff reimplantation technique for aortic branch reconstruction. AB - Massive blood loss during thoracoabdominal aortic aneurysm repair may impair postoperative outcomes but can be reduced by a secure suture line. Our internal cuff reimplantation is a novel technique for the reconstruction of branch arteries with a cuff of the native aortic wall, which is anastomosed inside the prosthesis through a hole created in it. This technique can ensure hemostasis at the anastomosis by decompression of the suture line, improve patency of the reconstructed branches by leaving the diseased orifices untouched, and prevent future enlargement of the remnant native aortic wall by covering it with the prosthesis. PMID- 24792287 TI - A novel technique of single patch repair of right partial anomalous pulmonary venous return to the superior vena cava by right atrial edge rotation. AB - In patients with partial anomalous pulmonary venous return of the right superior pulmonary veins to the superior vena cava, surgical repair generally consists of either intraatrial baffle with or without caval enlargement, or superior caval transection and cavoatrial anastomosis to the right atrial appendage. We discuss here a novel technique of superior caval enlargement without need for patch material or reimplantation. PMID- 24792288 TI - Reply: To PMID 23647857. PMID- 24792289 TI - Implicating transfusions in infections after cardiac operations. PMID- 24792290 TI - Biologic valved conduits in infants. PMID- 24792291 TI - Pericardial coverage of the bronchial stump. PMID- 24792292 TI - Reply: To PMID 23910124. PMID- 24792293 TI - Reply: To PMID 23972390. PMID- 24792294 TI - Pulmonary arterial stiffness, compliance, and impedance. PMID- 24792295 TI - Pneumonectomy for benign disease: what is the risk? PMID- 24792296 TI - Is a surgical procedure really contraindicated in spontaneous pneumothorax patients who have undergone prior contralateral pneumonectomy? PMID- 24792297 TI - Reply: To PMID 21718823. PMID- 24792298 TI - Surgical experience in a patient with Loeys-Dietz syndrome type I. AB - Loeys-Dietz syndrome is a recently described genetic disorder with aortic and vascular involvement. Here, we present the medical history and surgical management of a patient with Loeys-Dietz syndrome type I caused by a mutation in M253I in the TGFBR1 gene who received complete aortic replacement and various peripheral vascular surgeries over the course of 25 years. PMID- 24792299 TI - Constructive remodeling of CorMatrix extracellular matrix after aortic root repair in a 90-year-old woman. AB - An acellular, noncrosslinked, extracellular-matrix bioscaffold patch was used for aortic root reconstruction after aortic valve replacement in a 90-year-old woman. After her death 3 years later, histologic examination showed constructive remodeling and host-tissue regeneration at the site of the extracellular matrix bioscaffold patch. PMID- 24792300 TI - Guillain-Barre syndrome after lung lobectomy: is there any relationship? AB - Guillain-Barre syndrome (GBS) is an acute inflammatory polyradiculopathy frequently triggered by infection. It has also been reported in some cases after surgical procedures. We describe the first case of GBS occurring 9 days after lung lobectomy for localized lung cancer and efficiently treated with intravenous immunoglobulins. The exact physiopathology of GBS after surgical procedures is unknown. An immune-mediated process and perioperative infection are the most accepted etiologic hypotheses. PMID- 24792301 TI - Endotracheal and endobronchial metastases in a patient with stage I lung adenocarcinoma. AB - Endotracheal or endobronchial metastasis from primary lung cancer is extremely rare. We report a case of endotracheal and endobronchial metastases from peripheral early lung adenocarcinoma 7 months after complete resection. The patient harbored the same gene mutation in both primary and metastatic lesions. This report highlights that enough attention on endotracheal metastases should be paid no matter what the pathologic TNM stage of primary lung cancer is. PMID- 24792302 TI - Use of endobronchial ultrasonography in the diagnosis of a pulmonary artery aneurysm. AB - We present the case of an 84-year-old man with nonmassive hemoptysis and an obstructing endobronchial mass who was referred for rigid bronchoscopy and biopsy of the lesion. We illustrate how the pulsatile movement of his endobronchial lesion could be differentiated by convex probe endobronchial ultrasound bronchoscopy to be a vascular lesion rather than an endobronchial mass or tumor. Although convex probe endobronchial ultrasonography has many mediastinal applications, it has yet to be used to characterize endobronchial masses. We describe the first case of using convex probe endobronchial ultrasonography in the diagnosis of a left upper lobe pulmonary artery aneurysm presenting as an endobronchial mass. PMID- 24792303 TI - Minimally invasive cardiac surgical procedure in a patient with breast implants by use of a fibrous capsule preservation method. AB - We present a case of minimally invasive cardiac surgical procedure in a woman with previous breast implants. The capsule preservation method presented here may simplify cardiac surgical procedures and minimize complications in patients with breast implants. PMID- 24792304 TI - Laparoscopic management of obstructed gastric conduit after minimally invasive esophagectomy. AB - We describe a novel, minimally invasive method of managing an obstructed gastric conduit after minimally invasive esophagectomy. In addition, we briefly review the management of obstructed gastric conduit in patients status-post minimally invasive esophagectomy. On literature review, it was noted that gastrojejunostomy after esophagectomy was exceptionally rare. Only one other reported case of gastrojejunostomy after esophagectomy was found in the literature. This is the first reported case to our knowledge of laparoscopic gastrojejunostomy after minimally invasive esophagectomy (MIE). Laparoscopic gastrojejunostomy after minimally invasive esophagectomy for obstructed gastric conduit is technically feasible, and it effectively managed the obstruction in our patient. PMID- 24792305 TI - Coil embolization of traumatic false aneurysms after penetrating knife wound of a single ventricle. PMID- 24792306 TI - Living-donor lobar lung transplantation for treatment of idiopathic pulmonary arterial hypertension with severe pulmonary arterial dilation. PMID- 24792307 TI - How should synchronous multiple primary adenocarcinomas of the lung be resected? AB - We often encounter patients with multiple primary lung cancers with ground-glass opacity. However, there are no established guidelines regarding the optimal extent of resection for multifocal lung adenocarcinoma, so it is necessary to determine the most suitable strategy for each case. A 62-year-old man visited our hospital with 7 lesions in the lung field. We evaluated the structural information using high-resolution computed tomography (HRCT) and the aggressiveness of the tumors using fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) and then developed a surgical strategy. Using FDG PET/CT in addition to HRCT might improve the selection of appropriate surgical strategies for patients with multifocal lung adenocarcinoma. PMID- 24792308 TI - The role of hemorrhage following spinal-cord injury. AB - Spinal-cord injury is characterized by primary damage as a direct consequence of mechanical insult, and secondary damage that is partly due to the acute inflammatory response. The extent of any hemorrhage within the injured cord is also known to be associated with the formation of intraparenchymal cavities and has been anecdotally linked to secondary damage. This study was designed to examine the contribution of blood components to the outcome of spinal-cord injury. We stereotaxically microinjected collagenase, which causes localized bleeding, into the spinal cord to model the hemorrhage associated with spinal cord injury in the absence of significant mechanical trauma. Tissue damage was observed at the collagenase injection site over time, and was associated with localized disruption of the blood-spinal-cord barrier, neuronal cell death, and the recruitment of leukocytes. The magnitude of the bleed was related to neutrophil mobilization. Interestingly, the collagenase-induced injury also provoked extended axonal damage. With this model, the down-stream effects of hemorrhage are easily discernible, and the impact of treatment strategies for spinal-cord injury on hemorrhage-related injury can be evaluated. PMID- 24792309 TI - Pathophysiological rat model of vascular dementia: magnetic resonance spectroscopy, microimaging and behavioral study. AB - Chronic cerebral hypoperfusion and aging can be related to vascular dementia manifested by the decline in cognitive abilities and memory impairment. The identification of specific biomarkers of vascular disorder in early stages is important for the development of neuroprotective agents. In the present study, a three-vessel occlusion (3-VO) rat model of vascular dementia in the middle-aged rat brain was used to investigate the effect of global cerebral hypoperfusion. A multimodal study was performed using magnetic resonance spectroscopy, MR microimaging, histology and behavioral tests. Our measurements showed a signal alteration in T2-weighted MR images, the elevation of T2 relaxation times and histologically proven neural cell death in the hippocampal area, as well as mild changes in concentration of proton and phosphorus metabolites. These changes were accompanied by mild behavioral alterations in the open field and slightly decreased habituation. The analysis of the effects of vascular pathology on cognitive functions and neurodegeneration can contribute to the development of new treatment strategies for early stages of neurodegeneration. PMID- 24792310 TI - Modulation of glutamatergic transmission by metabotropic glutamate receptor activation in second-order neurons of the guinea pig nucleus tractus solitarius. AB - Activity of second-order relay neurons in the nucleus tractus solitarius (NTS) is regulated by peripheral and intrinsic synaptic inputs, and modulation of those inputs by metabotropic glutamate receptors (mGluRs) has been proposed. This study investigated effects of mGluR activation on glutamatergic transmission in the NTS second-order neurons of guinea pigs. Whole-cell patch-clamp recordings from the brainstem slices revealed that activation of mGluRs exerted its effects on the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) but not on the amplitude. The sEPSC frequency was increased by an agonist of group I mGluRs, and it was decreased by an mGluR1 antagonist but not by an mGluR5 antagonist. The agonists of group II and III mGluRs decreased the sEPSC frequency, while their antagonists alone had no effect. Perfusion of cystine or TBOA, either of which elevates extracellular glutamate concentration, resulted in an increase in the sEPSC frequency, leaving the amplitude unchanged. The increased frequency of sEPSCs was returned to control by an mGluR1 antagonist. The tractus solitarius evoked EPSCs were not altered by an agonist of group I mGluRs, whereas they were decreased along with an increase in paired-pulse ratio by agonists of group II and III mGluRs. These results suggest that mGluRs are present at the presynaptic sites in the NTS second-order neurons in guinea pigs. The mGluR1s function to facilitate the release of glutamate from axon terminals of intrinsic interneurons and the group II and III mGluRs play an inhibitory role in glutamatergic transmission. PMID- 24792311 TI - Infiltration of bupivacaine local anesthetic to trocar insertion sites after laparoscopy: a randomized, double-blind, stratified, and controlled trial. AB - STUDY OBJECTIVE: To determine if injection of local anesthetic into trocar insertion sites after laparoscopy improves postoperative pain. DESIGN: A prospective, 2-arm, randomized, double-blind, stratified, and controlled trial (Canadian Task Force classification I). SETTING: A university-based teaching hospital. PATIENTS: This study was performed on women who had a laparoscopic gynecologic procedure for benign indications from March 2013 to June 2013. One hundred thirty-five subjects were stratified by chronic pelvic pain or no chronic pelvic pain. Chronic pelvic pain was defined as pelvic pain occurring for 6 months or more in duration. Randomization was performed for this trial, with 68 receiving a bupivacaine block and 67 receiving no bupivacaine block. Of the 71 patients with chronic pelvic pain, 35 patients were in group 1 (i.e., bupivacaine block) and 36 patients were in group 2 (i.e., no bupivacaine block). INTERVENTIONS: After the laparoscopic surgery was completed, the trocar incision sites were closed. For subjects randomized to receive a local anesthesia block, bupivacaine (0.25%) was injected. Incisions 8 mm or greater were injected with 10 mL 0.25% bupivacaine. Incisions 5 mm or less were infiltrated with 5 mL. Injecting the local anesthetic through all preperitoneal layers provided a full thickness local injection. Group 2 did not receive a local injection. MEASUREMENTS AND MAIN RESULTS: At the preoperative suite, the nurses gauged the patient's pain using the Numeric Rating Scale. This score was used as the baseline pain level with which the postoperative pain scores were compared. The primary objective was to measure changes in pain scores, from preoperative to postoperative time frames of 2 to 4 hours, 6 to 8 hours, 18 to 24 hours, and 3 to 7 days postoperatively. These score changes were measured as the main objective. Secondary objectives include estimated blood loss, operating time, length of hospital stay, and histopathologic diagnosis. The hospital personnel caring for the patient during the preoperative and postoperative course were given standard pain evaluation protocols. All study pain evaluators and patients were blinded to treatment assignments throughout the pain assessment process. There were no statistically significant differences in patient characteristics between the 2 treatment groups. No significant difference was found in secondary outcomes including estimated blood loss, length of hospital stay, and histopathologic diagnosis. In general, Numeric Rating Scale pain scores were lower (i.e., less pain) in the "bupivacaine block" group compared with the "no bupivacaine" block group at the following postsurgery time assessments: 2 to 4 hours, 6 to 8 hours, 18 to 24 hours, and 3 to 7 days after surgery. However, the effect was not large enough (<1 point) to show a statistical difference between the treatment groups at any of these postsurgery assessments. CONCLUSION: The postoperative injection of bupivacaine in trocar port sites did not significantly improve pain scores after laparoscopic gynecologic surgery. PMID- 24792312 TI - Successful peroral endoscopic myotomy with use of a single instrument multipurpose knife. PMID- 24792313 TI - [Esophagopericardial fistula complicated by a left ventricular pseudoaneurysm]. PMID- 24792314 TI - [The temporomandibular joint in juvenile idiopathic arthritis: what radiologists need to look for on magnetic resonance imaging]. AB - The term "juvenile idiopathic arthritis" (JIA) encompasses a group of arthritis of unknown cause with onset before the age of 16 years that last for at least 6 weeks. The prevalence of temporomandibular joint involvement in published series ranges from 17% to 87%. Temporomandibular joint involvement is difficult to detect clinically, so imaging plays a key role in diagnosis and monitoring treatment. MRI is the technique of choice for the study of arthritis of the temporomandibular joint because it is the most sensitive technique for detecting acute synovitis and bone edema. Power Doppler ultrasonography can also detect active synovitis by showing the hypervascularization of the inflamed synovial membrane, but it cannot identify bone edema. This article describes the MRI technique for evaluating the temporomandibular joint in patients with juvenile idiopathic arthritis, defines the parameters to look for, and illustrates the main findings. PMID- 24792315 TI - [Patterns of pulmonary vascularization on plain-film chest X-rays]. AB - Plain chest films are a fundamental tool in the practice of medicine. The apparent simplicity of plain chest films sometimes leads us to forget that interpreting them correctly can provide very valuable information, especially if the interpretation is grounded in key clinical information. To interpret a plain chest film, it is important to pay attention to the pulmonary vascularization. This article reviews the normal shape and distribution of the pulmonary vessels on plain chest films and the most common pathologic vascular patterns, including those seen in pulmonary hypertension, hyperemia, hypovascularization, and alternative perfusion. PMID- 24792316 TI - [The scientific works of the teachers of human anatomy in the "Universite Libre de Bruxelles" (ULB)]. AB - The "Universite Libre de Bruxelles" was founded in 1834. Between this year and 1904, the teachers of human anatomy were essentially clinicians and surgeons. Their works were mainly practical. Until 1904 (arrival of Albert Brachet) since present, the researches of the anatomical laboratory were devoted to embryology, and included the beginning of causal embryology. More recently, biomechanics appeared in the field of activity of the laboratory. PMID- 24792317 TI - HClO4-silica-catalysed regioselective opening of benzylidene acetals and its application towards regioselective HO-4 glycosylation of benzylidene acetals in one-pot. AB - Here we report a high-yielding method for the regioselective reductive ring opening of 4,6-O-benzylidene acetals of hexapyranosides using inexpensive and robust HClO4-SiO2 as the acidic catalyst and triethylsilane as the hydride donor. Under the optimized condition, gluco- and mannopyranosides give the respective 6 O-benzyl derivative in good to excellent yields while the corresponding galactopyranoside gives the corresponding 6-O-benzyl derivative in lower yield. As the optimized condition involves acidic catalyst, we also successfully developed further application of the present method for the tandem regioselective opening and glycosylation in one-pot. PMID- 24792318 TI - Production of rhamnolipid surfactant and its application in bioscouring of cotton fabric. AB - In the present study, a biosurfactant was synthesized by using a bacterial strain of Pseudomonas aeruginosa in minimal media provided with n-heptadecane as sole carbon source under shake-flask conditions. The biosurfactant was isolated (by acid precipitation, solvent extraction, and rotary evaporation), purified (by column chromatography and TLC), identified (by FAB-MS, FTIR, and 1D-(1)H NMR), and chemo-physical characterized (by tensiometry). Two principal rhamnolipid congeners were identified as dirhamnolipid RRC10C10 and monorhamnolipid RC10C10 with a CMC of 50mg/L. The biosurfactant, hence produced, was applied in sole and in combination with pectinase in scouring of cotton fabric in contrast to conventional scouring agents of NaOH and anionic surfactant SDS. The scoured cotton fabric was investigated for its weight loss, residual oil and grease, wettability, whiteness, and tensile strength. The results were compared both for conventional and biological approaches. The scouring with biosurfactant plus pectinase was equivalent to or better in efficiency than conventional alkaline scouring. The former process is additionally environmentally friendly and bio compatible. Scanning electron microscopy of cotton fabric showed that the alkaline scouring deteriorates the fabric texture whereas bioscouring with biosurfactant plus pectinase gently removes hydrophobic impurities from the cotton fabric. PMID- 24792320 TI - Hemophagocytic syndromes--an update. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome and not an independent disease. HLH represents the extreme end of a severe uncontrolled hyperinflammatory reaction that can occur in many underlying conditions. Genetic forms of HLHs are due to defects in transport, processing and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes, and are not restricted to manifestation in childhood. Acquired forms of HLH are encountered in infections, autoinflammatory and autoimmune diseases, malignancies, acquired immune deficiency. Functional tests allow for differentiation between genetic and acquired HLH. Treatment aims at suppressing hypercytokinemia and eliminating activated and infected cells. It includes immunomodulatory and immunosuppressive agents, cytostatics, T-cell and cytokine antibodies. In genetic HLH cure can only be achieved with hematopoietic stem cell transplantation. Reduced-intensity conditioning regimens have considerably improved survival. PMID- 24792319 TI - Complementary and alternative medicine in reducing radiation-induced skin toxicity. AB - Radiation therapy-induced acute and late effects, particularly skin toxicities, have significant impact on cancer patients' quality of life and long-term survival. To date, no effective topical agents have been routinely used in the clinical setting to prevent skin toxicity. Using SKH-hr1 hairless mice, we investigated two complementary and alternative medicine in their effects on inflammation and ionizing radiation (IR)-induced skin toxicity: Calendula officinalis (CO) and Ching Wan Hung (CWH). They were applied immediately following each IR dosing of 10 Gy/day for 4 days. Skin toxicity and inflammatory factors were evaluated at multiple time points up to 15 days post-radiation. Serum interleukin (IL)-1alpha, monocyte chemotactic protein-1 (MCP1), keratinocyte-derived chemokine (KC), and granulocyte colony-stimulating factor (G CSF) were significantly induced by radiation. Both CO and CWH significantly inhibited IR-induced MCP1 (p < 0.01), KC (p < 0.05), and G-CSF (p < 0.001). IR induced erythema and blood vessel dilation were significantly reduced by CWH (p < 0.001) but not by CO at day 10 post-IR. Both agents inhibited IR-induced IL 1alpha (p < 0.01), MCP1 (p < 0.05), and vascular endothelial growth factor (p < 0.05). There were continuous inhibitory effects of CWH on IR-induced skin toxicities and inflammation. In contrast, CO treatment resulted in skin reactions compared to IR alone. Our results suggest that both CO and CWH reduce IR-induced inflammation and CWH reduced IR-induced erythema. In summary, CWH showed promising effects in reducing IR-related inflammation and skin toxicities, and future proof-of-principal testing in humans will be critical in evaluating its potential application in preventing IR-induced skin toxicities. PMID- 24792321 TI - Canonical and new generation anticancer drugs also target energy metabolism. AB - Significant efforts have been made for the development of new anticancer drugs (protein kinase or proteasome inhibitors, monoclonal humanized antibodies) with presumably low or negligible side effects and high specificity. However, an in depth analysis of the side effects of several currently used canonical (platin based drugs, taxanes, anthracyclines, etoposides, antimetabolites) and new generation anticancer drugs as the first line of clinical treatment reveals significant perturbation of glycolysis and oxidative phosphorylation. Canonical and new generation drug side effects include decreased (1) intracellular ATP levels, (2) glycolytic/mitochondrial enzyme/transporter activities and/or (3) mitochondrial electrical membrane potentials. Furthermore, the anti-proliferative effects of these drugs are markedly attenuated in tumor rho (0) cells, in which functional mitochondria are absent; in addition, several anticancer drugs directly interact with isolated mitochondria affecting their functions. Therefore, several anticancer drugs also target the energy metabolism, and hence, the documented inhibitory effect of anticancer drugs on cancer growth should also be linked to the blocking of ATP supply pathways. These often overlooked effects of canonical and new generation anticancer drugs emphasize the role of energy metabolism in maintaining cancer cells viable and its targeting as a complementary and successful strategy for cancer treatment. PMID- 24792322 TI - Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. AB - This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients. PMID- 24792323 TI - Aristolochic acid-induced apoptosis and G2 cell cycle arrest depends on ROS generation and MAP kinases activation. AB - Ingestion of aristolochic acids (AAs) contained in herbal remedies results in a renal disease and, frequently, urothelial malignancy. The genotoxicity of AA in renal cells, including mutagenic DNA adducts formation, is well documented. However, the mechanisms of AA-induced tubular atrophy and renal fibrosis are largely unknown. To better elucidate some aspects of this process, we studied cell cycle distribution and cell survival of renal epithelial cells treated with AAI at low and high doses. A low dose of AA induces cell cycle arrest in G2/M phase via activation of DNA damage checkpoint pathway ATM-Chk2-p53-p21. DNA damage signaling pathway is activated more likely via increased production of reactive oxygen species (ROS) caused by AA treatment then via DNA damage induced directly by AA. Higher AA concentration induced cell death partly via apoptosis. Since mitogen-activated protein kinases play an important role in cell survival, death and cell cycle progression, we assayed their function in AA-treated renal tubular epithelial cells. ERK1/2 and p38 but not JNK were activated in cells treated with AA. In addition, pharmacological inhibition of ERK1/2 and p38 as well as suppression of ROS generation with N-acetyl-L-cysteine resulted in the partial relief of cells from G2/M checkpoint and a decline of apoptosis level. Cell cycle arrest may be a mechanism for DNA repair, cell survival and reprogramming of epithelial cells to the fibroblast type. An apoptosis of renal epithelial cells at higher AA dose might be necessary to provide space for newly reprogrammed fibrotic cells. PMID- 24792324 TI - Targeting oxidative stress in the hypothalamus: the effect of transcription factor STAT3 knockdown on endogenous antioxidants-mediated appetite control. AB - It has been reported that the redox sensing system in the hypothalamus participates in fuel metabolism and that endogenous antioxidants contribute to the regulation of phenylpropanolamine (PPA), an anorectic drug-induced appetite suppression. We explored whether the signal transducer and activator of transcription-3 (STAT3) is involved in PPA's action. Rats were given PPA once a day for 4 days. Changes in endogenous antioxidants, Janus kinase-2 (JAK2), STAT3, neuropeptide Y (NPY), and proopiomelanocortin (POMC), levels during PPA treatment were assessed and compared. Feeding, body weight, and NPY decreased with the biggest reduction on Day 2 during PPA treatment. Antioxidants, JAK2, pSTAT3, POMC expression, and STAT3/DNA-binding activity increased and were expressed in a pattern opposite to NPY expression. Moreover, cerebral STAT3 knockdown modified PPA-induced anorexia and antioxidants, POMC, and NPY expression. superoxide dismutase immunoreactivity in the hypothalamus increased and the inhibition of hypothalamic reactive oxygen species (ROS) production reversed antioxidants, STAT3, POMC, and NPY expression. It is suggested that hypothalamic JAK2-STAT3 participates in regulating antioxidants-mediated appetite control. This result may further the understanding of ROS-involved appetite control. PMID- 24792325 TI - 8-Oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine concentrations in various human body fluids: implications for their measurement and interpretation. AB - 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is the most investigated product of oxidatively damaged DNA lesion that has been associated with the development of aging, cancer and some degenerative diseases. Here, we present the first liquid chromatography-tandem mass spectrometry method that enables the simultaneous measurement of its repair products in plasma and saliva, namely 8 oxo-7,8-dihydroguanine (8-oxoGua) and 8-oxodGuo. Using this method, we investigated the underlying transport mechanism of the repair products of oxidatively damaged DNA between cellular compartments and biological matrices. Plasma, saliva and urine samples were collected concurrently from 57 healthy subjects. Various deproteinization methods were evaluated, and the precipitants acetonitrile and sodium hydroxide-methanol were, respectively, selected for plasma and saliva samples due to their effect on recovery efficiencies and chromatography. The mean baseline concentrations of 8-oxoGua and 8-oxodGuo in plasma were demonstrated to be 0.21 and 0.016 ng/mL, respectively, while in saliva they were 0.85 and 0.010 ng/mL, respectively. A relatively high concentration of 8-oxoGua was found in saliva with a concentration factor (CF, concentration ratio of saliva to plasma) of 4 as compared to that of 8-oxodGuo (CF: 0.6), implying that 8-oxoGua in plasma may be actively transported to saliva, whereas 8-oxodGuo was most dependent on a passive diffusion. Good correlations between urine and plasma concentrations were observed for 8-oxoGua and 8-oxodGuo, suggesting that blood was a suitable matrix in addition to urine. Significant correlation between 8-oxoGua and 8-oxodGuo in urine was only observed when the concentrations were not corrected for urinary creatinine, raising the issue of applicability of urinary creatinine to adjust 8-oxoGua concentrations. PMID- 24792326 TI - Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype. AB - Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed. Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers. Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process. PMID- 24792327 TI - Downregulation of Pink1 influences mitochondrial fusion-fission machinery and sensitizes to neurotoxins in dopaminergic cells. AB - It is now well established that mitochondria are organelles that, far from being static, are subject to a constant process of change. This process, which has been called mitochondrial dynamics, includes processes of both fusion and fission. Loss of Pink1 (PTEN-induced putative kinase 1) function is associated with early onset recessive Parkinson's disease and it has been proposed that mitochondrial dynamics might be affected by loss of the mitochondrial kinase. Here, we report the effects of silencing Pink1 on mitochondrial fusion and fission events in dopaminergic neuron cell lines. Cells lacking Pink1 were more sensitive to cell death induced by C2-Ceramide, which inhibits proliferation and induces apoptosis. In the same cell lines, mitochondrial morphology was fragmented and this was enhanced by application of forskolin, which stimulates the cAMP pathway that phosphorylates Drp1 and thereby inactivates it. Cells lacking Pink1 had lower Drp1 and Mfn2 expression. Based on these data, we propose that Pink1 may exert a neuroprotective role in part by limiting mitochondrial fission. PMID- 24792328 TI - Investigation of the effects of short-term inhalation of carbon nanoparticles on brains and lungs of c57bl/6j and p47(phox-/-) mice. AB - Recent studies indicate that the brain is a target for toxic carbonaceous nanoparticles present in ambient air. It has been proposed that the neurotoxic effects of such particles are driven by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase mediated generation of reactive oxygen species (ROS) in activated microglia. In the present study, we have evaluated the effects of short term (4h) nose-only inhalation exposure to carbon NP (CNP) in the brains and lungs of C57BL/6J mice and in p47(phox-/-) mice that lack a functional NADPH oxidase. It was shown that the lungs of the p47(phox-/-) mice are less responsive to CNP inhalation than lungs of the corresponding C57BL/6J control animals. Lung tissue mRNA expression of the oxidative stress/DNA damage response genes 8 oxoguanine glycosylase (OGG1) and apurinic/apyrimidinic endonuclease 1 (APE1) were induced by CNP exposure in C57BL/6J but not in the p47(phox-/-) mice. In contrast, the expression of these genes, as well as Tumor Necrosis Factor-alpha (TNFalpha), Cyclooxygenase-2 (COX-2) and Heme Oxygenase-1 (HO-1) was not altered in the olfactory bulb, cerebellum or remaining brain tissue part of either mouse background. This indicates that neuroinflammation was not induced by this exposure. CNP inhalation for 4h or for 4h on three consecutive days also did not affect brain tissue protein expression of interleukin (IL)-1beta, while a clear significant difference in constitutive expression level of this pro-inflammatory cytokine was found between C57BL/6J and p47(phox-/-) mice. In conclusion, short term inhalation exposure to pure carbon nanoparticles can trigger mild p47(phox) dependent oxidative stress responses in the lungs of mice whereas in their brains at the same exposure levels signs of oxidative stress and inflammation remain absent. The possible role of p47(phox) in the neuro-inflammatory effects of nanoparticles in vivo remains to be clarified. PMID- 24792329 TI - Identification and characterization of six cytochrome P450 genes belonging to CYP4 and CYP6 gene families in the silkworm, Bombyx mori. AB - It was predicted that the genome of silkworm, Bombyx mori, has at least 79 P450 genes; however, P450 genes that are related to the catabolism of exogenous compounds were not reported. In this study we cloned two CYP4 (named CPY4M5 and CYP4M9) and four CYP6 (named CYP6AB5, CYP6AE9, CYP6AE22 and CYP6AU1) genes by using both bioinformatics and RT-PCR approaches. Sequence analysis showed that these genes contained conserved P450 gene sequence regions and one conserved intron. CYP4M5 and CYP4M9 genes were clustered together in a mode of "head-to tail" possibly due to gene duplication. Blast analysis showed that these P450 genes shared significant similarity with CYP4 and CYP6 genes that are involved in the catabolism and detoxification of exogenous compounds in other insect species. RT-PCR results showed that these P450 genes were highly expressed in the midgut and fat body of B. mori. As the instar age increased, these P450 genes exhibit different expression patterns. When B. mori was exposed to 1.75 * 10(-5)% of cypermethrin, 3.5 * 10(-6)% of cypermethrin and 0.1% of rutin, expression of CYP6AB5 was increased by 2.3-fold, 2.2-fold and 1.9-fold, respectively. Exposure of B. mori to 0.1% quercetin does not change the expression of CYP6AB5. In contrast, expression of the other five P450 genes was inhibited after exposed to these compounds. PMID- 24792330 TI - Cross-priming of microsatellite loci in subfamily cyprininae (family Cyprinidae): their utility in finding markers for population genetic analysis in three Indian major carps. AB - This study is aimed to identify polymorphic microsatellite markers and establish their potential for population genetics studies in three carp (family cyprinidae; subfamily cyprininae) species, Labeo rohita, Catla catla and Cirrhinus mrigala through use of cyprinid primers. These species have high commercial value and knowledge of genetic variation is important for management of farmed and wild populations. We tested 108 microsatellite primers from 11 species belonging to three different cyprinid subfamilies, Cyprininae, Barbinae and Leuciscinae out of which 63 primers (58.33%) successfully amplified orthologous loci in three focal species. Forty-two loci generated from 29 primers were polymorphic in these three carp species. Sequencing of amplified product confirmed the presence of SSRs in these 42 loci and orthologous nature of the loci. To validate potential of these 42 polymorphic loci in determining the genetic variation, we analyzed 486 samples of three focal species collected from Indus, Ganges and Brahmaputra river systems. Results indicated significant genetic variation, with mean number of alleles per locus ranging from 6.80 to 14.40 and observed heterozygosity ranging from 0.50 to 0.74 in the three focal species. Highly significant (P < 0.00001) allelic homogeneity values revealed that the identified loci can be efficiently used in population genetics analysis of these carp species. Further, thirty-two loci from 19 primers were useful for genotyping in more than one species. The data from the present study was compiled with cross-species amplification data from previous results on eight species of subfamily cyprininae to compare cross transferability of microsatellite loci. It was revealed that out of 226 heterologous loci amplified, 152 loci that originated from 77 loci exhibited polymorphism and 45 primers were of multispecies utility, common for 2-7 species. PMID- 24792331 TI - Molecular cloning and expression analysis of pig CD7. AB - CD7 is an integral membrane protein which mediates an important signal to mediate the differentiation, activation, and regulation of some T cells and NK cells. However, only human and mouse CD7 have been identified and studied among mammalian species. In this study, we cloned pig CD7 cDNA and determined its complete cDNA sequence. Pig CD7 cDNA contained an open reading frame (627 bp) encoding 208 amino acids with well conserved motifs involved in signal transduction within cytoplasmic tail among mammalian species. Pig CD7 mRNA was detected by RT-PCR in mainly lymphoid tissues, indicating the conserved functions of CD7 in pigs. Moreover, we generated soluble pig CD7 fusion immunoglobulin (pig CD7Ig) containing extracellular domain of pig CD7 to test whether pig CD7 binds to pig galectin-3. Flow cytometry and immunohistochemistry analyses indicated that soluble pig CD7Ig can bind to galectin-3 expressed in macrophages and epithelial cells of small intestine. These results help to analyze the structural relationship between CD7 and its ligand transferring signal transduction among mammalian species. PMID- 24792333 TI - Micelles and aggregates of oxyethylated isononylphenols and their extraction properties near cloud point. AB - We used nuclear magnetic resonance (NMR) spectroscopy and dynamic light scattering (DLS) techniques to study the structural and dynamic properties of micellar solutions of nonionic surfactants of a homologous series of oxyethylated isononylphenols--C9H19C6H4O(C2H4O)(n)H, where n = 6, 8, 9, 10, or 12--in a wide range of temperatures, including cloud points. The radii of the micelles and aggregates, as well as their compositions at different concentrations of surfactant, were determined. Using aqueous phenol solutions as a model, we studied the process of cloud point extraction with oxyethylated isononylphenols. PMID- 24792332 TI - The in vitro addition of methotrexate and/or methylprednisolone determines peripheral reduction in Th17 and expansion of conventional Treg and of IL-10 producing Th17 lymphocytes in patients with early rheumatoid arthritis. AB - The aim of our study was to evaluate methotrexate (MTX) and methylprednisolone (MP) effect on peripheral Th17 and Treg subsets in patients with rheumatoid arthritis (RA). We enrolled 15 patients (10 early RA and 5 long-standing disease) with active RA and 10 age-matched healthy donors as controls. Frequencies of Th17 and Treg were quantified using flow cytometry before and after in vitro addition of MTX, MP or both drugs. Our results showed a reduction in the overall Th17 population followed by an increase in Th17 IL-10(+) and Treg, after in vitro treatment of PBMCs with the drugs in patients with early RA. Long-standing disease patients showed a less evident increase in Treg cells and less enhancement of IL-10 Th17 cells. We suggest that the treatment with MTX and MP could ameliorate RA disease activity by normalizing the distribution/imbalance of Th17/Treg and indicate a new regulatory role of IL-17(+) cells in RA patients. PMID- 24792334 TI - The role of (18)F-FDG PET/CT for evaluation of metastatic mediastinal lymph nodes in patients with lung squamous-cell carcinoma or adenocarcinoma. AB - OBJECTIVES: To evaluate the efficacy of (18)F-FDG PET/CT in depicting metastatic mediastinal lymph nodes in patients with lung squamous-cell carcinoma (LSCC) or lung adenocarcinoma (LAC) in a tuberculosis-endemic country. METHODS: This study retrospectively reviewed patients with LSCC or LAC, who underwent preoperative (18)F-FDG PET/CT to assess mediastinal lymph node metastasis. Patients with the short-axis of mediastinal lymph node<=15mm were included. PET/CT interpretation was analyzed in two ways. Firstly, with CT for anatomical localization, lymph nodes showing greater (18)F-FDG uptake than vessel pool on PET were regarded malignant. Secondly, lymph nodes with positive uptake on PET were considered malignant, only when nodes had neither calcification nor higher attenuation than vessel pool on CT. RESULTS: One hundred and sixteen LSCCs and 234 LACs were evaluated. With CT for anatomical localization, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of PET were 78.6%, 45.5%, 53.4%, 31.4% and 87.0% in LSCC group, and 61.8%, 66.3%, 65.0%, 42.9% and 80.9% in LAC group. PET showed higher specificity and accuracy in LAC group compared with LSCC group (p=0.001 and p=0.038, respectively). Considering calcification or high attenuation on CT, the sensitivity, specificity, accuracy, PPV and NPV of PET/CT were 71.4%, 67.0%, 68.1%, 40.8% and 88.1% in LSCC group, and 54.4%, 86.1%, 76.9%, 61.7% and 82.2% in LAC group. Compared with PET, PET/CT possessed higher specificity and accuracy in LSCC group (p=0.000 and p=0.000, respectively), and higher specificity, accuracy and PPV in LAC group (p=0.000, p=0.000 and p=0.022, respectively). CONCLUSIONS: (18)F-FDG PET displays limited efficacy in assessing mediastinal lymph node metastasis with the short-axis diameter <15mm in LSCC and LAC groups and higher false-positivity in LSCC group. The specificity and accuracy in LSCC and LAC groups are enhanced by interpreting attenuation characteristic on CT. PMID- 24792336 TI - TaqMan based real time PCR assay targeting EML4-ALK fusion transcripts in NSCLC. AB - OBJECTIVES: Lung cancer with the ALK rearrangement constitutes only a small fraction of patients with non-small cell lung cancer (NSCLC). However, in the era of molecular-targeted therapy, efficient patient selection is crucial for successful treatment. In this context, an effective method for EML4-ALK detection is necessary. We developed a new highly sensitive variant specific TaqMan based real time PCR assay applicable to RNA from formalin-fixed paraffin-embedded tissue (FFPE). MATERIALS AND METHODS: This assay was used to analyze the EML4-ALK gene in 96 non-selected NSCLC specimens and compared with two other methods (end point PCR and break-apart FISH). RESULTS: EML4-ALK was detected in 33/96 (34%) specimens using variant specific real time PCR, whereas in only 23/96 (24%) using end-point PCR. All real time PCR positive samples were confirmed with direct sequencing. A total of 46 specimens were subsequently analyzed by all three detection methods. Using variant specific real time PCR we identified EML4-ALK transcript in 17/46 (37%) specimens, using end-point PCR in 13/46 (28%) specimens and positive ALK rearrangement by FISH was detected in 8/46 (17.4%) specimens. Moreover, using variant specific real time PCR, 5 specimens showed more than one EML4-ALK variant simultaneously (in 2 cases the variants 1+3a+3b, in 2 specimens the variants 1+3a and in 1 specimen the variant 1+3b). In one case of 96 EML4-ALK fusion gene and EGFR mutation were detected. All simultaneous genetic variants were confirmed using end-point PCR and direct sequencing. CONCLUSION: Our variant specific real time PCR assay is highly sensitive, fast, financially acceptable, applicable to FFPE and seems to be a valuable tool for the rapid prescreening of NSCLC patients in clinical practice, so, that most patients able to benefit from targeted therapy could be identified. PMID- 24792337 TI - Investigate scale and causes of food poverty, say public health specialists. PMID- 24792335 TI - Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer. AB - BACKGROUND: Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens. METHODS: We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls. RESULTS: Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians. CONCLUSIONS: To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs. PMID- 24792338 TI - Longitudinally extensive transverse myelitis. AB - PURPOSE OF REVIEW: Longitudinally extensive transverse myelitis (LETM) is a frequently devastating clinical syndrome which has come into focus for its association with neuromyelitis optica (NMO). Recent advances in the diagnosis of NMO have led to very sensitive and specific tests and advances in therapy for this disorder. LETM is not pathognomonic of NMO, therefore it is important to investigate for other causes of myelopathy in these patients. This review aims to discuss recent advances in NMO diagnosis and treatment, and to discuss the differential diagnosis in patients presenting with LETM. RECENT FINDINGS: Fluorescence-activated cell sorting and cell binding assays for NMO-IgG are the most sensitive for detecting NMO spectrum disorders. Patients who have a clinical presentation of NMO, who have been tested with older ELISA or immunofluorescence assay and been found to be negative, should be retested with a fluorescence activated cell sorting assay when available, particularly in the presence of recurrent LETM. Novel therapeutic strategies for LETM in the context of NMO include eculizumab, which could be considered in patients with active disease who have failed azathioprine and rituximab. Thorough investigation of patients with LETM who are negative for NMO-IgG may lead to an alternate cause for myelopathy. SUMMARY: LETM is a heterogeneous condition. Novel treatment strategies are available for NMO, but other causes need to be excluded in NMO-IgG-seronegative patients. PMID- 24792339 TI - Magnetic resonance outcome measures in multiple sclerosis trials: time to rethink? AB - PURPOSE OF REVIEW: We summarize MRI measures currently available to assess treatment efficacy and safety in multiple sclerosis (MS) clinical trials and discuss novel metrics that could enter the clinical arena in the near future. RECENT FINDINGS: In relapsing remitting MS, MRI measures of disease activity (new T2 and gadolinium-enhancing lesions) provide a good surrogacy of treatment effect on relapse rate and disability progression; however, their value in progressive MS remains elusive. For the progressive disease forms, these measures need to be combined with quantities assessing the extent of irreversible tissue loss, which have already been introduced in some clinical trials (e.g., evolution of active lesions into permanent black holes and brain atrophy). Novel measures (e.g., quantification of gray matter and spinal cord atrophy) have demonstrated a great value in explaining patients' clinical outcome, but still need to be fully validated. Despite showing promise, evaluations of cortical lesions, of microscopic tissue abnormalities, and of functional cortical reorganization are still some way off for monitoring of treatment effects. SUMMARY: Trial outcomes in MS should include measures of inflammation and neurodegeneration, which should be combined according to the disease clinical phenotype, phase of the study, and the supposed mechanism of action of the drug tested. PMID- 24792340 TI - Migraine and estrogen. AB - PURPOSE OF REVIEW: The aim is to systematically and critically review the relationship between migraine and estrogen, the predominant female sex hormone, with a focus on studies published in the last 18 months. RECENT FINDINGS: Recent functional MRI (fMRI) studies of the brain support the existence of anatomical and functional differences between men and women, as well as between participants with migraine and healthy controls. In addition to the naturally occurring changes in endogenous sex hormones over the lifespan (e.g. puberty and menopause), exogenous sex hormones (e.g. hormonal contraception or hormone therapy) also may modulate migraine. Recent data support the historical view of an elevated risk of migraine with significant drops in estrogen levels. In addition, several lines of research support that reducing the magnitude of decline in estrogen concentrations prevents menstrually related migraine (MRM) and migraine aura frequency. SUMMARY: Current literature has consistently demonstrated that headache, in particular migraine, is more prevalent in women as compared with men, specifically during reproductive years. Recent studies have found differences in headache characteristics, central nervous system anatomy, as well as functional activation by fMRI between the sexes in migraine patients. Although the cause underlying these differences is likely multifactorial, considerable evidence supports an important role for sex hormones. Recent studies continue to support that MRM is precipitated by drops in estrogen concentrations, and minimizing this decline may prevent these headaches. Limited data also suggest that specific regimens of combined hormone contraceptive use in MRM and migraine with aura may decrease both headache frequency and aura. PMID- 24792341 TI - SUNCT, SUNA and trigeminal neuralgia: different disorders or variants of the same disorder? AB - PURPOSE OF REVIEW: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) and trigeminal neuralgia are considered different disorders, thus grouped in separate sections of the International Classification of Headache Disorders 3 beta. However, the clinical, radiological and therapeutic overlap between SUNCT, SUNA, and trigeminal neuralgia has challenged this traditional view. This review summarizes the available clinical and pathophysiological evidence on whether SUNCT, SUNA and trigeminal neuralgia should be considered separate entities or variants of the same disorder. RECENT FINDINGS: Data on the clinical phenotype and effective management strategies in SUNCT and SUNA syndromes have shown striking similarities with trigeminal neuralgia. Moreover, studies exploring radiological findings supported the hypothesis of common aetiological and pathophysiological basis between SUNCT/SUNA and trigeminal neuralgia. However, a limitation of most studies is that they have included small samples of patients and therefore any conclusions need to be drawn cautiously. SUMMARY: Despite being considered distinct conditions, emerging clinical and radiological evidence supports a broader nosological concept of SUNCT, SUNA, and trigeminal neuralgia. These conditions may constitute a continuum of the same disorder, rather than separate clinical entities. Further evidence is required to shed light on this nosological issue, given its potential impact on clinical practice and further research studies in this area. PMID- 24792342 TI - Rare primary headaches. AB - PURPOSE OF REVIEW: Little is known about most disorders classified as rare primary headaches. This review summarizes current knowledge about clinical presentation, pathophysiology, epidemiology and treatment options of rare headache disorders. Increasing public awareness on the different types of rare primary headache disorders may lead to more research and better patient identification and treatment. RECENT FINDINGS: The International Headache Society updated the classification criteria for primary headache disorders adding some clinical entities and moving others to different parts of the classification. SUMMARY: Neuroimaging should be performed in all patients suspected to suffer from rare primary headache to rule out secondary causes of headache. Indometacin might have a good therapeutic effect in some of these headache entities, but larger randomized controlled trials are missing. PMID- 24792343 TI - Child and adult forms of human herpesvirus 6 encephalitis: looking back, looking forward. AB - PURPOSE OF REVIEW: This review evaluates publications on human herpesvirus 6 (HHV 6) encephalitis recognizing firstly that HHV-6A and HHV-6B are separate species with differing properties, and secondly the phenomenon of chromosomal integration; this occurs in a minority of persons and the complete viral genome of either HHV-6A or HHV-6B is present in every nucleated cell in the body. Although chromosomal integration has not been associated with disease, the resulting very high level of viral DNA in human tissues and blood has sometimes been wrongly misinterpreted as active infection. RECENT FINDINGS: No disease has been linked to HHV-6A, whereas HHV-6B may cause encephalitis. Encephalitis due to primary HHV-6B infection in young children is commonly reported from Japan, but very rarely elsewhere in the world, suggesting a genetic predisposition. Reports of HHV-6A or HHV-6B encephalitis in immunocompetent older children/adults are most likely due to chromosomal integration and not active infection. HHV-6B reactivation is well established as causing limbic encephalitis after haematopoietic stem cell transplantation, particularly after receipt of cord blood; the outcome is poor and preventive strategies are ineffective. SUMMARY: Understanding the pathophysiology of HHV-6B encephalitis remains incomplete, especially regarding young children. Clinical trials of antiviral therapy are warranted for treatment and prevention of HHV-6B encephalitis after transplantation. PMID- 24792344 TI - Neurological complications of varicella zoster virus reactivation. AB - PURPOSE OF REVIEW: Varicella zoster virus (VZV) reactivation results in zoster, which may be complicated by postherpetic neuralgia, myelitis, meningoencephalitis, and VZV vasculopathy. This review highlights the clinical features, laboratory abnormalities, imaging changes, and optimal treatment of each of those conditions. Because all of these neurological disorders produced by VZV reactivation can occur in the absence of rash, the virological tests proving that VZV caused disease are discussed. RECENT FINDINGS: After primary infection, VZV becomes latent in ganglionic neurons along the entire neuraxis. With a decline in VZV-specific cell-mediated immunity, VZV reactivates from ganglia and travels anterograde to the skin to cause zoster, which is often complicated by postherpetic neuralgia. VZV can also travel retrograde to produce meningoencephalitis, myelitis, and stroke. When these complications occur without rash, VZV-induced disease can be diagnosed by detection of VZV DNA or anti-VZV antibody in cerebrospinal fluid and treated with intravenous acyclovir. SUMMARY: Awareness of the expanding spectrum of neurological complications caused by VZV reactivation with and without rash will improve diagnosis and treatment. PMID- 24792346 TI - Rapid estimation of the oxidative activities of individual phenolics in crude plant extracts. AB - Previous studies of purified phenolic compounds have revealed that some phenolics, especially ellagitannins, can autoxidise under alkaline conditions, which predominate in the midgut of lepidopteran larvae. To facilitate screening for the pro-oxidant activities of all types of phenolic compounds from crude plant extracts, we developed a method that combined our recent spectrophotometric bioactivity method with an additional chromatographic step via UPLC-DAD-MS. This method allowed us to estimate the total pro-oxidant capacities of crude extracts from 12 plant species and to identify the individual phenolic compounds that were responsible for the detected activities. It was found that the pro-oxidant capacities of the plant species (i.e., the concentrations of the easily-oxidised phenolics) varied from 0 to 57 mg/g dry wt, representing from 0% to 46% of the total phenolics from different species. UPLC-DAD-MS analysis revealed that most flavonol and flavone glycosides were only slightly affected by alkaline conditions, thus indicating their low pro-oxidant activity. Interestingly, myricetin-type compounds differed from the other flavonoids, as their concentrations decreased strongly due to alkaline incubation. The same effect was detected for hydrolysable tannins and prodelphinidins, suggesting that a pyrogallol sub-structure could be a key structural component that partially explains their easy oxidation at high pH. Other types of phenolic compounds, such as hydroxycinnamic acids, were relatively active, as well. These findings demonstrate that this method displays the potential to identify most of the active and inactive pro-oxidant phenolic compounds in various plant species. PMID- 24792345 TI - Autoimmune encephalitis as differential diagnosis of infectious encephalitis. AB - PURPOSE OF REVIEW: This review describes the main types of autoimmune encephalitis with special emphasis on those associated with antibodies against neuronal cell surface or synaptic proteins, and the differential diagnosis with infectious encephalitis. RECENT FINDINGS: There is a continuous expansion of the number of cell surface or synaptic proteins that are targets of autoimmunity. The most recently identified include the metabotropic glutamate receptor 5 (mGluR5), dipeptidyl-peptidase-like protein-6 (DPPX), and gamma-aminobutyric acid-A receptor (GABAAR). In these and previously known types of autoimmune encephalitis [N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid-B receptor (GABABR), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 (CASPR2)], the prodromal symptoms or types of presentations often suggest a viral encephalitis. We review here clues that help in the differential diagnosis with infectious encephalitis. Moreover, recent investigations indicate that viral encephalitis (e.g., herpes simplex) can trigger synaptic autoimmunity. In all these disorders, immunotherapy is usually effective. SUMMARY: Autoimmune encephalitis comprises an expanding group of potentially treatable disorders that should be included in the differential diagnosis of any type of encephalitis. VIDEO ABSTRACT: http://links.lww.com/CONR/A25, PMID- 24792347 TI - Homosexual behavior in male goats is more frequent during breeding season and in bucks isolated from females. AB - Male homosexual behavior is observed in many ruminant species; seasonality and isolation from females may affect the display of male-male sexual behavior. Our objectives were to determine whether: 1) homosexual behavior has a seasonal pattern in male goats (Capra hircus); 2) isolation from female goats influences the frequency of the display of homosexual behavior; and 3) the frequency of homosexual behaviors is related to testosterone concentration. Bucks were housed in a pen adjacent to another pen with 3 estrous goats (FC group) or in complete isolation from females (IF group). Homosexual behaviors and testosterone concentrations were recorded in October, December, February and May. Frequencies of penile display and flehmen increased in May and were observed more frequently in the IF than in the FC group. Ano-genital sniffing was more frequent in February and May and was more frequent in IF than in FC bucks. Lateral approaches were more frequent in May, in which period this was more frequently observed in IF bucks. Mount attempts and mounts were only observed in IF bucks. Testosterone concentrations increased from December to February and decreased in May, although they were still greater than in October and December. In May IF bucks had greater testosterone concentrations than FC bucks. Testosterone concentrations were only related to the number of lateral approaches in IF bucks in December. In conclusion, homosexual behavior was more frequent during the late breeding season than during the early and the non-breeding seasons, and in males isolated from females than in males housed near estrous females. Testosterone concentrations appear to be unrelated to homosexual behavior. PMID- 24792348 TI - Coordinated and distinct functions of velvet proteins in Fusarium verticillioides. AB - Velvet-domain-containing proteins are broadly distributed within the fungal kingdom. In the corn pathogen Fusarium verticillioides, previous studies showed that the velvet protein F. verticillioides VE1 (FvVE1) is critical for morphological development, colony hydrophobicity, toxin production, and pathogenicity. In this study, tandem affinity purification of FvVE1 revealed that FvVE1 can form a complex with the velvet proteins F. verticillioides VelB (FvVelB) and FvVelC. Phenotypic characterization of gene knockout mutants showed that, as in the case of FvVE1, FvVelB regulated conidial size, hyphal hydrophobicity, fumonisin production, and oxidant resistance, while FvVelC was dispensable for these biological processes. Comparative transcriptional analysis of eight genes involved in the ROS (reactive oxygen species) removal system revealed that both FvVE1 and FvVelB positively regulated the transcription of a catalase-encoding gene, F. verticillioides CAT2 (FvCAT2). Deletion of FvCAT2 resulted in reduced oxidant resistance, providing further explanation of the regulation of oxidant resistance by velvet proteins in the fungal kingdom. PMID- 24792349 TI - Energy transfer processes in chlorophyll f-containing cyanobacteria using time resolved fluorescence spectroscopy on intact cells. AB - We examined energy transfer dynamics in the unique chlorophyll (Chl) f-containing cyanobacterium Halomicronema hongdechloris. The absorption band of Chl f appeared during cultivation of this organism under far-red light. The absorption maximum of Chl f in organic solvents occurs at a wavelength of approximately 40 nm longer than that of Chl a. In vivo, the cells display a new absorption band at approximately 730 nm at 298 K, which is at a significantly longer wavelength than that of Chl a. We primarily assigned this band to a long wavelength form of Chl a. The function of Chl f is currently unknown. We measured the fluorescence of cells using time-resolved fluorescence spectroscopy in the picosecond-to nanosecond time range and found clear differences in fluorescence properties between the cells that contained Chl f and the cells that did not. After excitation, the fluorescence peaks of photosystem I and photosystem II appeared quickly but diminished immediately. A unique fluorescence peak located at 748 nm subsequently appeared in cells containing Chl f. This finding strongly suggests that the Chl f in this alga exists in photosystem I and II complexes and is located close to each molecule of Chl a. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy. PMID- 24792351 TI - Combined ligand and structure-based approaches on HIV-1 integrase strand transfer inhibitors. AB - HIV-1 integrase (IN) is an essential enzyme in the viral replication cycle and represents a promising target for anti-HIV drug design. In the present study, pharmacophore modeling and atom-based 3D-QSAR studies were carried out on a series of compounds belonging to dihydroxy isoindole derivatives as HIV-1 IN strand transfer inhibitors. The best pharmacophore model generated consists of six features AADHRR: two hydrogen bond acceptors (A), a hydrogen bond donor (D), a hydrophobic group (H) and two aromatic rings (R). Based on the best pharmacophore model, a statistically valid atom-based 3D-QSAR model was developed. The obtained atom-based 3D-QSAR model has an excellent correlation coefficient value (R(2)=0.87) and also exhibited good predictive power (Q(2)=0.72). The best pharmacophore model was further validated through enrichment calculations and it shows strong predictive power with a high performance in identifying active ligands from the total hits (actives+decoys). QM-polarized ligand docking and molecular dynamics simulations of selected active compounds in the active site of prototype foamy virus intasome gave important insights into the chemical and structural basis involved in the molecular recognition process. The O,O,O donor atom triad of compounds show metal chelation with divalent Mg(2+) ions bound to the three catalytic amino acids in the enzyme's active site and pi-stacking interaction with the viral DNA residue DA17. The results might have implications for rational design of specific HIV-1 integrase strand transfer inhibitors with improved affinity and selectivity. PMID- 24792350 TI - Predicting DNA-binding proteins and binding residues by complex structure prediction and application to human proteome. AB - As more and more protein sequences are uncovered from increasingly inexpensive sequencing techniques, an urgent task is to find their functions. This work presents a highly reliable computational technique for predicting DNA-binding function at the level of protein-DNA complex structures, rather than low resolution two-state prediction of DNA-binding as most existing techniques do. The method first predicts protein-DNA complex structure by utilizing the template based structure prediction technique HHblits, followed by binding affinity prediction based on a knowledge-based energy function (Distance-scaled finite ideal-gas reference state for protein-DNA interactions). A leave-one-out cross validation of the method based on 179 DNA-binding and 3797 non-binding protein domains achieves a Matthews correlation coefficient (MCC) of 0.77 with high precision (94%) and high sensitivity (65%). We further found 51% sensitivity for 82 newly determined structures of DNA-binding proteins and 56% sensitivity for the human proteome. In addition, the method provides a reasonably accurate prediction of DNA-binding residues in proteins based on predicted DNA-binding complex structures. Its application to human proteome leads to more than 300 novel DNA-binding proteins; some of these predicted structures were validated by known structures of homologous proteins in APO forms. The method [SPOT-Seq (DNA)] is available as an on-line server at http://sparks-lab.org. PMID- 24792352 TI - Mitochondrial DNA polymorphisms associated with longevity in the Turkish population. AB - The accumulation of mutations in mitochondrial DNA is a widely recognized mechanism for aging and age related diseases. However, studies indicate that some mutations could be beneficial to longevity by slowing down the function of the electron transport chain, reducing free radical production. In this study, we re sequenced the entire mitochondrial DNA from 50 individuals and examined aging related variations in the Turkish population. We evaluated sequence data by comparing whole SNP frequencies, individual SNP frequencies, the effect of SNPs, SNP accumulation in certain mtDNA regions and haplotype profiles between elderly and control groups. The frequency of total mitochondrial SNPs was significantly higher in nonagenarians than controls (p=0.0094). Furthermore, non-coding, synonymous and tRNA mutations were more prevalent in the 90+ group compared to controls (p=0.0001, p<0.001, p=0.0096, respectively). A73G and C152T polymorphisms were significantly associated with longevity in the Turkish population (p=0.0086 and p=0.004, respectively). Additionally, C150T was specific to the 90+ group, but the difference failed to reach statistical significance (p=0.053). We also detected a novel transversion in the ATPase6 gene (C8899A) that was negatively associated with longevity (p=0.0016). Examining the distribution of SNPs among genes and functionally associated gene regions revealed a significant accumulation of mutations in the D-loop region and genes encoding Complex I subunits (ND1-6) (p<0.0001, p=0.0302, respectively). Moreover, there was an increase in the non-synonymous mutation frequency of Complex I genes in aged subjects (p<0.0001). Haplotype H was also significantly increased in the control group (p=0.0405). Overall, our findings support a role for mitochondrial genome variations and the functionality of oxidative phosphorylation in longevity. In this report, we sequenced the whole mtDNA of the Turkish population for the first time. PMID- 24792353 TI - Treatment of severe hyponatremia in patients with kidney failure: role of continuous venovenous hemofiltration with low-sodium replacement fluid. AB - Patients with hypervolemic hyponatremia and kidney failure pose a special therapeutic challenge. Hemodialysis to correct volume overload, azotemia, and abnormal electrolyte levels will result in rapid correction of serum sodium concentration and place the patient at risk for osmotic demyelination syndrome. We present a patient with acute kidney injury and severe hypervolemic hypotonic hyponatremia (serum sodium<100 mEq/L) who was treated successfully with continuous venovenous hemofiltration. This teaching case illustrates the limitations of hemodialysis and demonstrates how to regulate the sodium correction rate by single-pool sodium kinetic modeling during continuous venovenous hemofiltration. Two methods to adjust the replacement fluid to achieve the desired sodium concentration are outlined. PMID- 24792355 TI - Influence of endoscopic submucosal dissection on additional gastric resections. AB - BACKGROUND: Widespread application of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) results in noncurative resection in some patients. The influence of preceding ESD on additional gastric resections has not been completely evaluated. METHODS: Endoscopic, surgical, and pathological records of 255 patients who underwent additional gastrectomy after noncurative ESD at a single prefectural cancer center from September 2002 to December 2010 were reviewed. The estimated gastric resection based on endoscopic images before ESD was compared with the actual gastric resection performed after ESD. RESULTS: Altered gastric resection was performed in 4 (1.6%) of the 255 patients. In 3 patients, total gastrectomy was performed instead of distal gastrectomy; in 1 patient, distal gastrectomy was performed instead of pylorus-preserving gastrectomy because of an insufficient distance from the cardia or pylorus caused by contraction of the ESD scar. Standard gastrectomy including total or distal gastrectomy with D2 lymph node dissection was performed in 33 patients because of deep submucosal invasion with positive/indefinite vertical margins. The final pathology revealed pT2 or deeper in 10 patients. CONCLUSIONS: In conclusion, 98.4% patients underwent the scheduled gastric resection before ESD, and the preceding gastric ESD had almost no influence on changing the gastric resection of the additional surgery. Although rare, the preceding ESD may necessitate alterations in gastric resection to widen the surgical area because of contraction of ESD scar for lesions near the cardia or pylorus. MINI ABSTRACT: A retrospective study of additional gastrectomy after noncurative ESD showed that the preceding ESD had almost no influence on changing the gastric resection of the additional surgery. PMID- 24792356 TI - The evolutionary and ecological consequences of animal social networks: emerging issues. AB - The first generation of research on animal social networks was primarily aimed at introducing the concept of social networks to the fields of animal behaviour and behavioural ecology. More recently, a diverse body of evidence has shown that social fine structure matters on a broader scale than initially expected, affecting many key ecological and evolutionary processes. Here, we review this development. We discuss the effects of social network structure on evolutionary dynamics (genetic drift, fixation probabilities, and frequency-dependent selection) and social evolution (cooperation and between-individual behavioural differences). We discuss how social network structure can affect important coevolutionary processes (host-pathogen interactions and mutualisms) and population stability. We also discuss the potentially important, but poorly studied, role of social network structure on dispersal and invasion. Throughout, we highlight important areas for future research. PMID- 24792354 TI - LMO2 induces T-cell leukemia with epigenetic deregulation of CD4. AB - In this study, we present a remarkable clonal cell line, 32080, derived from a CD2-Lmo2- transgenic T-cell leukemia with differentiation arrest at the transition from the intermediate single positive to double positive stages of T cell development. We observed that 32080 cells had a striking variegated pattern in CD4 expression. There was cell-to-cell variability, with some cells expressing no CD4 and others expressing high CD4. The two populations were isogenic and yet differed in their rates of apoptosis and sensitivity to glucocorticoid. We sorted the 32080 line for CD4-positive or CD4-negative cells and observed them in culture. After 1 week, both sorted populations showed variegated CD4 expression, like the parental line, showing that the two populations could interconvert. We determined that cell replication was necessary to transit from CD4(+) to CD4(-) and CD4(-) to CD4(+). Lmo2 knockdown decreased CD4 expression, while inhibition of intracellular NOTCH1 or histone deacetylase activity induced CD4 expression. Enforced expression of RUNX1 repressed CD4 expression. We analyzed the CD4 locus by Histone 3 chromatin immunoprecipitation and found silencing marks in the CD4( ) cells and activating marks in the CD4(+) population. The 32080 cell line is a striking model of intermediate single positive to double positive T-cell plasticity and invokes a novel mechanism for LMO2's oncogenic functions. PMID- 24792357 TI - Fluoroscopically guided transurethral removal and/or replacement of ureteric stents in women. AB - BACKGROUND: Traditionally double J ureteric stents have been removed and replaced via cystoscopy. Fluoroscopically guided procedures for the removal/replacement of stents using endovascular snare devices have previously been described as a successful alternative. PURPOSE: To evaluate the technical and clinical success of fluoroscopically guided transurethral removal and/or replacement of ureteric stents in women. To assess radiation dose and screening time associated with this approach. MATERIAL AND METHODS: A 31-month retrospective review of all ureteric stent removals and/or replacements under fluoroscopic guidance performed in a university hospital radiology department. RESULTS: One hundred and fourteen procedures were performed in 83 patients. Thirty ureteric stents were removed and 84 ureteric stents were replaced. The majority of patients required stents for urinary tract obstruction secondary to malignancy (78.3%). Overall technical and clinical success rates (defined respectively as satisfactory removal/replacement and drainage of the collecting system) of 98.2% were attained. Mean screening time was 13.9 min (range, 1.0-67.6 min). Effective radiation dose was in the range of 0.69-132 mSv with a mean of 11.18 mSv equating to the dose of a contrast enhanced computed tomography abdomen/pelvis. CONCLUSION: Transurethral ureteric stent removal and replacement under fluoroscopic guidance is highly successful, well tolerated by patients with acceptable radiation exposure, and can obviate the need for cystoscopic retrieval. PMID- 24792358 TI - Changes of gray matter volume and amplitude of low-frequency oscillations in amnestic MCI: An integrative multi-modal MRI study. AB - BACKGROUND: Numerous studies have reported that the amnestic-type mild cognitive impairment (aMCI) patients have impaired brain structural integrity and functional alterations separately. PURPOSE: To investigate the changes of gray matter and amplitude of low-frequency oscillations in patients with aMCI by combining structural and functional magnetic resonance imaging (fMRI). MATERIAL AND METHODS: Thirty-four patients with aMCI and 34 controls were recruited. We adopted optimized voxel-based morphometry to detect regions with gray matter volume (GMV) loss induced by aMCI. Then regional differences in amplitude of slow 4 band (0.027-0.073 Hz) oscillations among these regions between patients and healthy controls were examined. Both slow-4 amplitude of low-frequency fluctuations (ALFF) and slow-4 fractional ALFF (fALFF; the relative amplitude that resides in the low frequencies) were employed. RESULTS: Patients with aMCI demonstrated significant GMV loss in the ventral medial prefrontal cortex (vMPFC), posterior cingulate cortex (PCC), bilateral hippocampus, right superior parietal gyrus, left insula and left middle temporal gyrus (P < 0.01). The patients exhibited significant decreases of slow-4 ALFF in the left hippocampus (P = 0.05) and PCC (P = 0.02), while the decreased slow-4 fALFF was detected in PCC (P = 0.01) and increased slow-4 fALFF in vMPFC (P = 0.03). In PCC, aMCI and controls exhibited significant different GMV-fALFF correlation (P < 0.05), with opposite correlation trend. CONCLUSION: The correlates between anatomical deficits and functional alterations in aMCI suggest that anatomical and functional deficits are linked to each other. The differences of GMV-fALFF correlations demonstrated altered anatomical-functional relationship in aMCI. PMID- 24792359 TI - The first non-African case of Trichophyton rubrum var. raubitschekii or a urease positive Trichophyton rubrum in Central Europe? AB - We report a case of a 34-year-old Polish Caucasian male who was diagnosed with tinea manuum caused by Trichophyton rubrum var. raubitschekii. It would be the first described case of a dermatophytosis caused by this fungus in Poland and one of a few cases in Central Europe described so far. Admittedly, it would be the first case in Central Europe with no evidence pointing to African origin. The clinical condition improved after administering itraconazole (daily dose 100 mg orally) supplemented with a topical treatment, while the patient was totally cured after 2 months. The histopathological examination turned out to be highly useful in the diagnostic process. The genetic analysis of the urease gene pointed to a urease-positive T. rubrum rather than T. rubrum var. raubitschekii. PMID- 24792360 TI - Primary cutaneous mucormycosis presenting as a giant plaque: uncommon presentation of a rare mycosis. AB - Mucormycosis is an uncommon systemic mycosis affecting the immunocompromised individuals. It is usually caused by organisms of the genera Rhizopus and Mucor, although rarely other organisms have also been implicated. Mycoses due to these angioinvasive fungi have an acute onset, rapidly progressive course with high mortality rate. A rare and less well known is the chronic subtype of primary cutaneous mucormycosis (PCM). Herein, we report a case of PCM clinically presenting as a chronic, giant destructive plaque in a young immunocompetent male and coin the term chronic granulomatous mucormycosis. A clinicopathological classification for cutaneous mucormycosis is also proposed. PMID- 24792361 TI - An exploration of load accommodation strategies during walking with extremity carried weights. AB - The strategies used by individuals to respond to loading perturbations have implications for both musculoskeletal health and statistical data analysis. The purpose was to explore load accommodation strategies during walking with extremity weights carried in different positions. Twenty subjects walked on an instrumented treadmill while carrying 0, 44.5 and 89 N at the wrists and ankles. Peak ground reaction force (GRF) during weight acceptance was extracted for analysis. The change in peak GRF due to the addition of weight was calculated and used to quantify strategies. Results indicated that on average GRF increased (p<.05) more than the increase in weight alone in two of three load carriage positions, and ranged from 0.95 to 1.45 N/N. The strategy for weights carried at the wrists with the arms unconstrained (M+/-SD, 1.06+/-.42 N/N) was significantly (p<.017) less than with the wrists constrained (1.35+/-.56 N/N) or with weights carried at the ankles (1.40+/-.72N/N). Individuals exhibited a range of strategies from greatly increasing to slightly decreasing GRF with the addition of weight. Ninety-six percent of strategies resulted in GRF increases. Subject strategies may affect tissue loading and their presence decreases the validity of group statistical analyses. PMID- 24792362 TI - Effectuation of adaptive stability and postural alignment strategies are decreased by alcohol intoxication. AB - Human stability control is a complex process comprising contributions from several partly independent mechanisms such as coordination, feedback and feed forward control, and adaptation. Acute alcohol intoxication impairs these functions and is recognized as a major contributor to fall traumas. The study aimed to investigate how alcohol intoxication at .06% and .10% blood alcohol concentration (BAC) affected the movement spans and control of posture alignment. The angular positions of the head, shoulder, hip and knees relative to the ankles were measured with a 3D motion analysis system in 25 healthy adults during standing with eyes open or closed and with or without vibratory balance perturbations. Alcohol intoxication significantly increased the movement spans of the head, shoulders, hip and knees in anteroposterior and lateral directions during quiet stance (p < or = .047 and p < or = .003) and balance perturbations (p<.001, both directions). Alcohol intoxication also decreased the ability to reduce the movement spans through adaptation in both anteroposterior (p < or = .011) and lateral (p < or = .004) directions. When sober and submitted to balance perturbations, the subjects aligned the head, shoulders, hip and knees more forward relative to the ankle joint (p < .001), hence adopting a more resilient posture increasing the safety margin for backward falls. Alcohol intoxication significantly delayed this forward realignment (p < or = .022). Alcohol intoxication did not cause any significant posture realignment in the lateral direction. Thus, initiation of adaptive posture realignments to alcohol or other disruptions might be context dependent and associated with reaching a certain level of stability threats. PMID- 24792363 TI - Taking a peek at the border of the sarcomere in heart failure and cardiac resynchronization therapy. PMID- 24792364 TI - MicroRNA-34a targets Forkhead box j2 to modulate differentiation of endothelial progenitor cells in response to shear stress. AB - Flow shear stress plays important roles in modulating differentiation of endothelial progenitor cells (EPCs). MicroRNAs are crucial for diverse cellular processes, but the expressions and functions of microRNAs in EPCs responding to mechanical stimuli remain unclear. We sought to determine the effects of microRNA 34a (miR-34a) and a novel target Forkhead box j2 (Foxj2) on shear stress-induced EPC differentiation. Human umbilical cord blood-derived EPCs were exposed to laminar shear stress of 15dyn/cm(2) with parallel plate flow chamber system. Real time RT-PCR showed that shear stress significantly increased miR-34a expression, which was accompanied by the endothelial differentiation of EPCs. Whereas Foxj2, a putative target of miR-34a predicted by multiple algorithms, was suppressed in this process. Dual luciferase reporter assays, as well as miR-34a mimics and inhibitor treatment were used to confirm the interplay between miR-34a and Foxj2. Our results revealed an inverse correlation of miR-34a and Foxj2 expressions implicated in the endothelial differentiation of EPCs. MiR-34a contributed to this process by up-regulating the expressions of endothelial cell markers, and down-regulating smooth muscular cell markers. In addition, Foxj2 overexpression attenuated endothelial differentiation of EPCs, while Foxj2 siRNA had the opposite effect. These data suggested a unique mechanism that shear stress induces the expression of miR-34a, which targets to Foxj2 and promotes endothelial differentiation of EPCs. The results provide new insights into miR 34a/Foxj2 on shear stress-induced EPC differentiation. PMID- 24792365 TI - [Pancreatic calcifications in a young patient: Apropos of a case]. PMID- 24792366 TI - Classifying fibromyalgia patients according to severity: the combined index of severity in fibromyalgia. AB - The aim of this study was to establish the cutoff points in the Combined Index of Fibromyalgia Severity (ICAF) questionnaire which allow classification of patients by severity and to evaluate its application in the clinical practice. The cutoff points were calculated using the area under the ROC curve in two cohorts of patients. Three visits, basal, fourth month and 15th month, were considered. The external criterion for grading severity was the number of drugs consumed by the patient. Sequential changes were calculated and compared. Correlations with drug consumption and comparisons of severity between patients with different types of coping were also calculated. Correlation between the number of drugs and the ICAF total score was significant. Three cutoff points were established: absence of Fibromyalgia (FM), <34; mild, 34-41; moderate, 41-50 and severe, >50, with the following distribution of severity: absence in 0.4 %, mild in 18.7 %, moderate in 32.5 % and severe in 48.4 % of the patients. There were significant differences between groups. The treatment under daily clinical conditions showed a significant improvement of the patients which was maintained at the end of follow up. There was a 17 % reduction in the severe category. The patients with more passive coping factor showed highest punctuations in the remaining scores and were more prevalent in the severe category. The patients with a predominance of the emotional factor showed a better response at the end of follow-up. The established cutoff points allow the classification of FM patients by severity, to know the prognostic and to predict the response to the treatment. PMID- 24792367 TI - Deletion of the aquaporin-4 gene alters expression and phosphorylation of protective kinases in the mouse heart. AB - AIM: Aquaporins are channel-forming proteins highly permeable to water and some small molecular solutes. We have previously shown that aquaporin-4 knockout mice have increased tolerance to ischemia. However, the mechanism of cardioprotection was unclear. The aim of the current study was to investigate the effects of aquaporin-4 deletion on baseline expression and phosphorylation of some cardioprotective protein kinases. METHODS: Proteins were extracted from hearts of aquaporin-4 knockout mice and littermate wild-type controls and analyzed with Western blot. Samples were taken from young (<= 6 months of age), and old (>= 1 year) mice. RESULTS: Western blots showed three different isoforms of aquaporin-4 in wild types, likely representing M1, M23, and Mz. Total AMP-dependent kinase expression was decreased in aquaporin-4 knockout hearts by 18 +/- 13% (p = 0.02), while the expression of Akt kinase, extracellular signal regulated kinase 1/2, protein kinase C-epsilon, mitogen-associated kinase P38 and C-Jun N-terminal kinase was unchanged. The phosphorylation of Akt kinase was reduced in hearts from knockout mice by 41 +/- 16% (p = 0.01). No other alterations in phosphorylation were found. These effects were only detected in young mice. CONCLUSION: Deletion of the aquaporin-4 gene decreased AMP-dependent kinase expression and Akt kinase phosphorylation in the heart. These changes may influence energy metabolism and endogenous cardioprotection. PMID- 24792368 TI - Ionized calcium measurements are influenced by albumin--should ionized calcium be corrected? AB - Measurement of ionized calcium (CaI) has been reported to be dependent on albumin concentration. We examined the correlation between albumin and CaI measured on different ion selective electrode analyzers and in different groups of patients in a large dataset, extracted from the laboratory information system. In 17,281 outpatients and 16,194 inpatients, significantly positive correlations were found between CaI and albumin, with changes in CaI per 10 g/L change in albumin ranging from 0.007-0.043 mmol/L and 0.017-0.028 mmol/L, respectively. Correlations were found to be significantly different when using different analyzers. In order to examine whether the difference in correlations between the analyzers were really due to different patient populations investigated on the different analyzers, data analyzed on the same type of analyzer from inpatients from four different wards (intensive care unit, medical ward, surgical ward and orthopedic ward) were examined. There was no significant difference in correlations between patients from the four wards. Although, these results points towards technical causes behind the observed differences it cannot be entirely ruled out that clinical diseases or treatment might influence albumin interaction with CaI measurements. Combining all data from both out- and inpatients, a correction formula using a change in CaI of 0.03 mmol/L per 10 g/L change in albumin, was constructed. However, the albumin influence on CaI is only a minor part of the total CaI variation and, in most situations, the relatively small effect of changes in albumin on CaI-results is most likely of no clinical importance. PMID- 24792369 TI - Acute exercise in elite rugby players increases the circulating level of the cardiovascular biomarker GDF-15. AB - BACKGROUND: Intense training can lead to a pathophysiological change in serum concentration of a variety of biomarkers. Traditional biomarkers of cardiac injury are very useful in monitoring CVD patients, but in healthy subjects or athletes they cannot be informative enough about the cardiovascular risk, because in these cases their serum levels do not increase over the pathological limit. Therefore novel cardiovascular biomarkers are required in order to allow a better monitoring of sport performance, prediction of overtraining and diagnosis of sport-related cardiac injuries. Growth differentiation factor-15 (GDF-15) is emerging as a powerful cardiovascular injury risk indicator. In this study we investigate the effect of intense physical training of on the circulating levels of GDF-15 in rugby professional players. METHODS: Serum GDF-15, Erythropoietin, IL-6, the cardiovascular parameter ST-2, NT-proBNP and routine hematological parameters were measured in a group of 30 rugby players before and after a session of intense training. RESULTS: While ST-2, IL-6 and hsCRP displayed no significant changes after intense training, NT-proBNP and GDF-15 showed a significant increase, even without reaching the pathological level. DISCUSSION: The measure of GDF-15 in professional rugby players could be a useful tool to monitoring their cardiovascular status during training and competition session in order to prevent the onset of collateral cardiovascular adverse event due to the intense training and, in the case of cardiac injury, it could possibly allow a very early diagnosis at the beginning of the pathogenic process. PMID- 24792370 TI - Identification and fine mapping of a linear B cell epitope of human vimentin. AB - Knowledge about antibody-antigen interactions is important for the understanding of the immune system mechanisms and for supporting development of drugs and biomarkers. A tool for identification of these antigenic epitopes of specific antibodies is epitope mapping. In this study, a modified enzyme-linked immunosorbent assay was applied for epitope mapping of a mouse monoclonal vimentin antibody using overlapping resin-bound peptides covering the entire vimentin protein. The minimal epitope required for binding was identified as the LDSLPLVD sequence using N- and C-terminally truncated peptides. The peptide sequence LDSLPLVDTH was identified as the complete epitope, corresponding to amino acids 428-437 in the C-terminal end of the human vimentin protein. Alanine scanning and functionality scanning applying substituted peptides were used to identify amino acids essential for antibody reactivity. In particular, the two aspartate residues were found to be essential for antibody reactivity since these amino acids could not be substituted without a reduction in antibody reactivity. The majority of the remaining amino acids could be substituted without reducing antibody reactivity notably. These results confirm that charged amino acids are essential for antibody reactivity and that the vimentin antibody is dependent on side-chain interactions in combination with backbone interactions. PMID- 24792371 TI - Postoperative analgesia with transversus abdominis plane catheter infusions of levobupivacaine after major gynecological and obstetrical surgery. A case series. AB - Transversus abdominis plane block has become an important method of postoperative pain management for patients undergoing abdominal surgery but the modest duration is a major limitation. We report the successful use of a novel TAP catheter technique for continuous infusion of levobupivacaine in six gynecologic and obstetric patients. Bilateral TAP catheters were inserted at the end of surgery by ultrasound imaging using a Contiplex(r) C needle (B. Braun, Melsungen, Germany) in the Triangle of Petit or in a postero-subcostal level based on the location of the surgical incision. Following negative aspiration, 0.25% levobupivacaine 5 mL was injected. After withdrawing the needle, while holding the over-the-needle catheter in place, bilateral continuous infusion of 0.125% levobupivacaine at 2 mL/h from elastomeric pumps (INfusor SV2, Baxter, France) was started and continued for up to 50h. Before removal of the catheter, a bolus of 10 mL levobupivacaine 0.25% was administered. Successful analgesia was achieved in all six cases utilizing continuous infusion of levobupivacaine, minimizing the volume required. TAP infusions produce significant opioid sparing and better patient mobility. This technique may be a reliable alternative to neuraxial analgesia in major gynecological and obstetrical surgery. PMID- 24792372 TI - Intestinal adsorption of uraemic toxins: a new strategy for anaemia management? PMID- 24792373 TI - Stigmata of death: for kidneys and patients. PMID- 24792375 TI - Translational diffusion in mixtures of imidazolium ILs with polar aprotic molecular solvents. AB - Self-diffusion coefficients of cations and solvent molecules were determined with (1)H NMR in mixtures of 1-n-butyl-3-methylimidazolium (Bmim(+)) tetrafluoroborate (BF4(-)), hexafluorophosphate (PF6(-)), trifluoromethanesulfonate (TfO(-)), and bis(trifluoromethylsulfonyl)imide (TFSI(-)) with acetonitrile (AN), gamma butyrolactone (gamma-BL), and propylene carbonate (PC) over the entire composition range at 300 K. The relative diffusivities of solvent molecules to cations as a function of concentration were found to depend on the solvent but not on the anion (i.e., IL). In all cases the values exhibit a plateau at low IL content (x(IL) < 0.2) and then increase steeply (AN), moderately (gamma-BL), or negligibly (PC) at higher IL concentrations. This behavior was related to the different solvation patterns in the employed solvents. In BmimPF6-based systems, anionic diffusivities were followed via (31)P nuclei and found to be higher than the corresponding cation values in IL-poor systems and lower in the IL-rich region. The inversion point of relative ionic diffusivities was found around equimolar composition and does not depend on the solvent. At this point, a distinct change in the ion-diffusion mechanism appears to take place. PMID- 24792374 TI - Glomerular hypertrophy in subjects with low nephron number: contributions of sex, body size and race. AB - BACKGROUND: We have shown that low nephron number (Nglom) is a strong determinant of individual glomerular volume (IGV) in male Americans. However, whether the same pattern is present in female Americans remains unclear. The contributions of body surface area (BSA) and race to IGV in the context of Nglom also require further evaluation. METHODS: Kidneys without overt renal disease were collected at autopsy in Mississippi, USA. The extremes of female Nglom were used to define high and low Nglom for both sexes. Nglom and IGV were estimated by design-based stereology. A total of 24 African and Caucasian American females (n = 12 per race; 6 per Nglom extreme) were included. These subjects were subsequently matched to 24 comparable males by age and Nglom and to 18 additional males by age, Nglom and BSA. RESULTS: IGV average and variance were very similar in female African and Caucasian Americans with high and low Nglom. Males with low Nglom from both races showed greater IGV average and variance than comparable females matched by age and Nglom. These differences in IGV between sexes were not observed in Caucasian Americans with low Nglom that were matched by age, Nglom and BSA. In contrast, glomeruli from African Americans were larger than those from Caucasian Americans, especially in subjects with high Nglom. CONCLUSIONS: While female Americans with low Nglom did not show glomerular hypertrophy, comparable males with low Nglom showed marked glomerular hypertrophy that was closely associated with high BSA. Glomerular size in African Americans may be confounded by multiple additional factors. PMID- 24792376 TI - Crystal structure and biochemical properties of the (S)-3-hydroxybutyryl-CoA dehydrogenase PaaH1 from Ralstonia eutropha. AB - 3-Hydroxybutyryl-CoA dehydrogenase is an enzyme involved in the synthesis of the biofuel n-butanol by converting acetoacetyl-CoA to 3-hydroxybutyryl-CoA. To investigate the molecular mechanism of n-butanol biosynthesis, we determined crystal structures of the Ralstonia eutropha-derived 3-hydroxybutyryl-CoA dehydrogenase (RePaaH1) in complex with either its cofactor NAD(+) or its substrate acetoacetyl-CoA. While the biologically active structure is dimeric, the monomer of RePaaH1 comprises two separated domains with an N-terminal Rossmann fold and a C-terminal helical bundle for dimerization. In this study, we show that the cofactor-binding site is located on the Rossmann fold and is surrounded by five loops and one helix. The binding mode of the acetoacetyl-CoA substrate was found to be that the adenosine diphosphate moiety is not highly stabilized compared with the remainder of the molecule. Residues involved in catalysis and substrate binding were further confirmed by site-directed mutagenesis experiments, and kinetic properties of RePaaH1were examined as well. Our findings contribute to the understanding of 3-hydroxybutyryl-CoA dehydrogenase catalysis, and will be useful in enhancing the efficiency of n butanol biosynthesis by structure based protein engineering. PMID- 24792377 TI - Soluble adenylyl cyclase accounts for high basal cCMP and cUMP concentrations in HEK293 and B103 cells. AB - Intact HEK293 cells and B103 neuroblastoma cells possess high basal concentrations of the established second messengers cAMP and cGMP and of the emerging second messengers cCMP and cUMP. We asked the question which nucleotidyl cyclase accounts for the high basal cNMP concentrations. Activators and inhibitors of soluble guanylyl cyclase had no major effects on cNMPs, and the activator of membranous adenylyl cyclase forskolin increased only cAMP. Addition of bicarbonate to medium increased, whereas removal of bicarbonate decreased levels of all four cNMPs. The inhibitor of soluble adenylyl cyclase, 2-(1H benzo[d]imidazol-2-ylthio)-N'-(5-bromo-2-hydroxybenzylidene) propanehydrazide (KH7), reduced bicarbonate-stimulated cNMPs. In conclusion, bicarbonate stimulated soluble adenylyl cyclase plays an important role in the regulation of basal cellular cNMP levels, most notably cCMP and cUMP. PMID- 24792378 TI - First evidence of pathogenicity of V234I mutation of hVAPB found in Amyotrophic Lateral Sclerosis. AB - Amyotrophic Lateral Sclerosis is a motor neurodegenerative disease which is characterized by progressive loss of motor neurons followed by paralysis and eventually death. In human, VAMP-associated protein B (VAPB) is the causative gene of the familial form of ALS8. Previous studies have shown that P56S and T46I point mutations of hVAPB are present in this form of ALS. Recently, another mutation, V234I of hVAPB was found in one familial case of ALS. This is the first study where we have shown that V234I-VAPB does not form aggregate like other two mutants of VAPB and localizes differently than the wild type VAPB. It induces Ubiquitin aggregation followed by cell death. We propose that V234I-VAPB exhibits the characteristics of ALS in spite of not having the typical aggregation property of different mutations in various neurodegenerative diseases. PMID- 24792379 TI - Effect of thymic stromal lymphopoietin on MUC5B expression in human airway epithelial cells. AB - Thymic stromal lymphopoietin (TSLP) is an interleukin 7-like cytokine and a potent factor for B- and T-cell growth and differentiation. Recent studies have demonstrated an association of TSLP with allergic and inflammatory airway diseases. However, no study on the effect of TSLP on expression of mucin genes in airway epithelial cells has been reported. Therefore, the effects and brief signaling pathways of TSLP on expression of mucin genes in human airway epithelial cells were investigated in this study. In mucin-producing human NCI H292 airway epithelial cells and primary cultures of normal nasal epithelial cells, the effect and signaling pathway of TSLP on expression of mucin genes were investigated using reverse transcriptase-polymerase chain reaction (RT-PCR), real time PCR, enzyme immunoassay, and immunoblot analysis with several specific inhibitors and small interfering RNA (siRNA). In human NCI-H292 airway epithelial cells, TSLP increased MUC5B expression. TSLP significantly activated phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase (MAPK). U0126 (ERK1/2 MAPK inhibitor) and SB203580 (p38 MAPK inhibitor) significantly attenuated TSLP-induced MUC5B mRNA expression. Knockdown of ERK1, ERK2, and p38 MAPK by ERK1, ERK2, and p38 MAPK siRNA significantly blocked TSLP-induced MUC5B mRNA expression. In the primary cultures of normal nasal epithelial cells, TSLP significantly increased MUC5B mRNA expression, which was significantly attenuated after pretreatment with U0126 and SB203580. These results suggest that TSLP induces MUC5B expression via the ERK1/2 and p38 MAPK signaling pathway in human airway epithelial cells. PMID- 24792381 TI - US doctors say unnecessary tests and procedures are a serious concern. PMID- 24792380 TI - Practical ways to reduce radiation dose for patients and staff during device implantations and electrophysiological procedures. AB - Despite the advent of non-fluoroscopic technology, fluoroscopy remains the cornerstone of imaging in most interventional electrophysiological procedures, from diagnostic studies over ablation interventions to device implantation. Moreover, many patients receive additional X-ray imaging, such as cardiac computed tomography and others. More and more complex procedures have the risk to increase the radiation exposure, both for the patients and the operators. The professional lifetime attributable excess cancer risk may be around 1 in 100 for the operators, the same as for a patient undergoing repetitive complex procedures. Moreover, recent reports have also hinted at an excess risk of brain tumours among interventional cardiologists. Apart from evaluating the need for and justifying the use of radiation to assist their procedures, physicians have to continuously explore ways to reduce the radiation exposure. After an introduction on how to quantify the radiation exposure and defining its current magnitude in electrophysiology compared with the other sources of radiation, this position paper wants to offer some very practical advice on how to reduce exposure to patients and staff. The text describes how customization of the X-ray system, workflow adaptations, and shielding measures can be implemented in the cath lab. The potential and the pitfalls of different non-fluoroscopic guiding technologies are discussed. Finally, we suggest further improvements that can be implemented by both the physicians and the industry in the future. We are confident that these suggestions are able to reduce patient and operator exposure by more than an order of magnitude, and therefore think that these recommendations are worth reading and implementing by any electrophysiological operator in the field. PMID- 24792382 TI - Genome-wide association study identifies ALLC polymorphisms correlated with FEV1 change by corticosteroid. AB - OBJECTIVES: Asthma can be suppressed by inhaled corticosteroids (ICS). However, response to ICS shows marked inter-individual variability. This study is aimed to identify the genetic variants associated with the change in the percentage of forced expiratory volume in 1second (%DeltaFEV1) following ICS treatment. METHODS: A genome-wide association study was performed in a Korean asthmatic cohort. To further investigate these genetic associations, 11 additional single nucleotide polymorphisms (SNPs) on the allantoicase (ALLC) gene were selected from the HapMap database and genotyped in the same asthmatic patients in the follow-up study. RESULTS: In a genome-wide study, we identified the lowest P value in ALLC, but none of the SNPs met the genome-wide association criteria (P<1.0*10(-8)). However, among 25 SNPs on ALLC in the follow-up study, 6 variants showed significant associations with the mean %DeltaFEV1 in the study subjects (P<3.73*10(-6)). CONCLUSIONS: Although the associated signals could not overcome the genome-wide multiple correction due to small sample size (n=189), our results suggest that associated SNPs of ALLC might be genetic predictors of response to ICS, at least with respect to DeltaFEV1 in Korean asthmatics. PMID- 24792383 TI - Normalization of urinary pteridines by urine specific gravity for early cancer detection. AB - BACKGROUND: Urinary biomarkers, such as pteridines, require normalization with respect to an individual's hydration status and time since last urination. Conventional creatinine-based corrections are affected by a multitude of patient factors whereas urine specific gravity (USG) is a bulk specimen property that may better resist those same factors. We examined the performance of traditional creatinine adjustments relative to USG to six urinary pteridines in aggressive and benign breast cancers. METHODS: 6-Biopterin, neopterin, pterin, 6 hydroxymethylpterin, isoxanthopterin, xanthopterin, and creatinine were analyzed in 50 urine specimens with a previously developed liquid chromatography-tandem mass spectrometry technique. Creatinine and USG performance were evaluated with non-parametric Mann-Whitney hypothesis testing. RESULTS: USG and creatinine were moderately correlated (r=0.857) with deviations occurring in dilute and concentrated specimens. In 48 aggressive and benign breast cancers, normalization by USG significantly outperformed creatinine adjustments which marginally outperformed uncorrected pteridines in predicting pathological status. In addition, isoxanthopterin and xanthopterin were significantly higher in pathological specimens when normalized by USG. CONCLUSION: USG, as a bulk property, can provide better performance over creatinine-based normalizations for urinary pteridines in cancer detection applications. PMID- 24792384 TI - Engineered Fc based antibody domains and fragments as novel scaffolds. AB - Therapeutic monoclonal antibodies (mAbs) have been successful for the therapy of a number of diseases mostly cancer and immune disorders. However, the vast majority of mAbs approved for clinical use are full size, typically in IgG1 format. These mAbs may exhibit relatively poor tissue penetration and restricted epitope access due to their large size. A promising solution to this fundamental limitation is the engineering of smaller scaffolds based on the IgG1 Fc region. These scaffolds can be used for the generation of libraries of mutants from which high-affinity binders can be selected. Comprised of the CH2 and CH3 domains, the Fc region is important not only for the antibody effector function but also for its long half-life. This review focuses on engineered Fc based antibody fragments and domains including native (dimeric) Fc and monomeric Fc as well as CH2 and monomeric CH3, and their use as novel scaffolds and binders. The Fc based binders are promising candidate therapeutics with optimized half-life, enhanced tissue penetration and access to sterically restricted binding sites resulting in an increased therapeutic efficacy. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody. PMID- 24792385 TI - Creating stable stem regions for loop elongation in Fcabs - insights from combining yeast surface display, in silico loop reconstruction and molecular dynamics simulations. AB - Fcabs (Fc antigen binding) are crystallizable fragments of IgG where the C terminal structural loops of the CH3 domain are engineered for antigen binding. For the design of libraries it is beneficial to know positions that will permit loop elongation to increase the potential interaction surface with antigen. However, the insertion of additional loop residues might impair the immunoglobulin fold. In the present work we have probed whether stabilizing mutations flanking the randomized and elongated loop region improve the quality of Fcab libraries. In detail, 13 libraries were constructed having the C-terminal part of the EF loop randomized and carrying additional residues (1, 2, 3, 5 or 10, respectively) in the absence and presence of two flanking mutations. The latter have been demonstrated to increase the thermal stability of the CH3 domain of the respective solubly expressed proteins. Assessment of the stability of the libraries expressed on the surface of yeast cells by flow cytometry demonstrated that loop elongation was considerably better tolerated in the stabilized libraries. By using in silico loop reconstruction and mimicking randomization together with MD simulations the underlying molecular dynamics were investigated. In the presence of stabilizing stem residues the backbone flexibility of the engineered EF loop as well as the fluctuation between its accessible conformations were decreased. In addition the CD loop (but not the AB loop) and most of the framework regions were rigidified. The obtained data are discussed with respect to the design of Fcabs and available data on the relation between flexibility and affinity of CDR loops in Ig-like molecules. PMID- 24792386 TI - Asn112 in Plasmodium falciparum glutathione S-transferase is essential for induced reversible tetramerization by phosphate or pyrophosphate. AB - The glutathione S-transferase from Plasmodium falciparum presents distinct features which are absent from mammalian GST isoenzyme counterparts. Most apparent among these are the ability to tetramerize and the presence of a flexible loop. The loop, situated between the 113-119 residues, has been reported necessary for the tetramerization process. In this article, we report that a residue outside of this loop, Asn112, is a key to the process - to the point where the single Asn112Leu mutation prevents tetramerization altogether. We propose that a structural pattern involving the interaction of the Asn112 and Lys117 residues from two neighboring subunits plays a role in keeping the tetramer structure stable. We also report that, for the tetramerization of the wild-type PfGST to occur, phosphate or pyrophosphate anions must be present. In other words, tetramerization is a phosphate- or pyrophosphate-induced process. Furthermore, the presence of magnesium reinforces this induction. We present experimental evidence for these claims as well as a preliminary calorimetric and kinetic study of the dimeric Asn112Leu PfGST mutant. We also propose a putative binding site for phosphate or pyrophosphate anions through a comparative structural analysis of PfGST and pyrophosphatases from several organisms. Our results highlight the differences between PfGST and the human isoenzymes, which make the parasite enzyme a suitable antimalarial target. PMID- 24792387 TI - Recent progress in generating intracellular functional antibody fragments to target and trace cellular components in living cells. AB - In biomedical research there is an ongoing demand for new technologies, which help to elucidate disease mechanisms and provide the basis to develop novel therapeutics. In this context a comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, posttranslational modifications and dynamic interactions of cellular components is indispensable. Besides their significant impact as therapeutic molecules, antibodies are arguably the most powerful research tools to study endogenous proteins and other cellular components. However, for cellular diagnostics their use is restricted to endpoint assays using fixed and permeabilized cells. Alternatively, live cell imaging using fluorescent protein tagged reporters is widely used to study protein localization and dynamics in living cells. However, only artificially introduced chimeric proteins are visualized, whereas the endogenous proteins, their posttranslational modifications as well as non-protein components of the cell remain invisible and cannot be analyzed. To overcome these limitations, traceable intracellular binding molecules provide new opportunities to perform cellular diagnostics in real time. In this review we summarize recent progress in the generation of intracellular and cell penetrating antibodies and their application to target and trace cellular components in living cells. We highlight recent advances in the structural formulation of recombinant antibody formats, reliable screening protocols and sophisticated cellular targeting technologies and propose that such intrabodies will become versatile research tools for real time cell-based diagnostics including target validation and live cell imaging. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody. PMID- 24792388 TI - NADPH-dependent thioredoxin reductase A (NTRA) confers elevated tolerance to oxidative stress and drought. AB - NADPH-dependent thioredoxin reductases (NTRs) are key-regulatory enzymes determining the redox state of the thioredoxin (Trx) system that provides reducing power to peroxidases or oxidoreductases. Moreover, it also plays an essential function in the direct reduction of ROS and acquiring stress tolerance in plant. Cytoplasmic NTRA, mitochondrial NTRB, and chloroplastic NTRC are the three conserved NTRs which cooperate with specific sub-cellularly localized Trxs in Arabidopsis. However, cytosolic NTRs such as NTRA in Arabidopsis have not previously been identified in plants or mammals as a source of functional redundancy with mitochondrial NTRs. Here, we show the involvement of NTRA in the plant stress response counteracting oxidative and drought stresses. Methyl viologen (MV), an inducer of oxidative stress in plants, enhanced the NTRA transcripts. To identify the physiological role of NTRA influencing ROS homeostasis by stress, NTRA overexpression (NTRAOX) and knock-out mutants (ntra ko) were generated. After exposure to oxidative stress, wild-type and ntra-ko plants were sensitive, but NTRAOX plants tolerant. ROS range was increased by MV in wild-type and ntra-ko plants, but not in NTRAOX. Investigating the involvement of Arabidopsis NTRA in drought, NTRAOX plants exhibited extreme drought tolerance with high survival rates, lower water loss and reduced ROS compared to wild-type and ntra-ko plants. Transcripts of drought-responsive genes, such as RD29A and DREB2A, were highly expressed under drought and antioxidant genes, namely CuZnSOD and APX1 were enhanced in the absence of drought in NTRAOX plants. The results suggest that NTRA overexpression confers oxidative and drought tolerance by regulation of ROS amounts. PMID- 24792389 TI - Arabidopsis thaliana peroxidases involved in lignin biosynthesis: in silico promoter analysis and hormonal regulation. AB - Phytohormones such as auxins, cytokinins, and brassinosteroids, act by means of a signaling cascade of transcription factors of the families NAC, MYB, AP2 (APETALA2), MADS and class III HD (homeodomain) Zip, regulating secondary growth. When the hormonal regulation of Zinnia elegans peroxidase (ZePrx), an enzyme involved in lignin biosynthesis, was studied, it was found that this peroxidase is sensitive to a plethora of hormones which control xylem lignification. In a previous study we sought Arabidopsis thaliana homologues to ZePrx. Peroxidases 4, 52, 49 and 72 are the four peroxidases that fulfill the restrictive conditions that a peroxidase involved in lignification must have. In the present study, we focus our attention on hormonal regulation in order to establish the minimal structural and regulatory elements contained in the promoter region which an AtPrx involved in lignification must have. The results indicate that of the four peroxidases selected in our previous study, the one most likely to be homologous to ZePrx is AtPrx52. The results suggest that hormones such as auxins, cytokinins and BRs directly regulate AtPrx52, and that the AtPrx52 promoter may be the target of the set of transcription factors (NAC, MYB, AP2 and class I and III HD Zip) which are up-regulated by these hormones during secondary growth. In addition, the AtPrx52 promoter contains multiple copies of all the putative cis elements (the ACGT box, the OCS box, the OPAQ box, the L1BX, the MYCL box and the W box) known to confer regulation by NO and H2O2. PMID- 24792390 TI - A reversible functional sensory neuropathy model. AB - Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resiniferatoxin (RTX), a TRPV1 agonist. At day 7, RTX induced significant thermal and mechanical hypoalgesia. At day 28, mechanical and thermal nociception were restored. No nerve degeneration in skin was observed and unmyelinated nerve fiber morphology and density in sciatic nerve were unchanged. At day 7, substance P (SP) was largely depleted in dorsal root ganglia (DRG) neurons, although calcitonin gene-related peptide (CGRP) was only moderately depleted. Three weeks after, SP and CGRP expression was restored in DRG neurons. At the same time, CGRP expression remained low in intraepidermal nerve fibers (IENFs) whereas SP expression had improved. In summary, RTX induced in our model a transient neuropeptide depletion in sensory neurons without nerve degeneration. We think this model is valuable as it brings the opportunity to study functional nerve changes in the very early phase of small fiber neuropathy. Moreover, it may represent a useful tool to study the mechanisms of action of therapeutic strategies to prevent sensory neuropathy of various origins. PMID- 24792391 TI - Fucoidan attenuates the existing allodynia and hyperalgesia in a rat model of neuropathic pain. AB - Fucoidan is an active constituent found in brown seaweeds, which have potential neuroprotection. The current study aimed to investigate the effects of fucoidan on the maintenance of neuropathic pain induced by L5 spinal nerve ligation (SNL) and the underlying mechanism related to the spinal neuroimmune responses. Animals were randomized into 5 groups: sham-operation with vehicle and SNL with vehicle or fucoidan (15, 50, and 100mg/kg). Different doses of fucoidan or vehicle were administered intrathecally once daily from postoperative day (POD) 11-20. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) was measured on 1 day before operation and days 10, 20, 22, 24, 26, 28, 30 after operation. Glial activation markers such as glial fibrillary acidic protein (GFAP) and macrophage antigen complex-1 (mac-1), inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 activation, and extracellular signalregulated protein kinase (ERK) activation in the lumbar spinal cord were determined on day 30 after operation. The results showed that fucoidan caused dose-dependently attenuation of mechanical allodynia and thermal hyperalgesia. Furthermore, fucoidan could markedly inhibit neuroimmune activation characterized by glial activation, production of cytokines as well as ERK activation. The analgesic effect of intrathecal fucoidan in rats receiving SNL might partly attribute to the inhibition of neuroimmune activation associated with the maintenance of neuropathic pain. PMID- 24792392 TI - Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of the total flavonoids extracted from Xiaobuxin-Tang. AB - Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, exerted antidepressant-like effects. Recently, accumulating studies have suggested that l-arginine-NO is implicated in the regulation of depression. Therefore, the aim of current study attempts to explore the involvement of l arginine-NO pathway in the antidepressant-like effect of XBXT-2 in the mouse forced swim test (FST). Our results showed that the antidepressant-like action of XBXT-2 (100mg/kg, i.g.) was reversed by pretreatment with l-arginine (a nitric oxide precursor, 750mg/kg, i.p.). While co-administration of aminoguanidine (a specific inducible NOS inhibitor, 40, 80mg/kg, i.p.) and sub-effective dose of XBXT-2 (50mg/kg, i.g.) did not significantly alter the immobility in FST. In contrast, combined administration of 7-nitroindazole (a specific neuronal NOS inhibitor, 50mg/kg, i.p.) potentiated the antidepressant-like effect of non effective doses of XBXT-2 (50mg/kg, i.g.). Meanwhile, NO modulators were devoid of any locomotor effects on the animals. In conclusion, the antidepressant-like action of XBXT-2 may be involvement of NO signaling pathway. PMID- 24792393 TI - Spicatoside A enhances memory consolidation through the brain-derived neurotrophic factor in mice. AB - Brain-derived neurotrophic factor (BDNF) plays a pivotal role in memory consolidation. Previously, we found that the increased mature BDNF (mBDNF) levels in the hippocampal region at a specific time window after the acquisition trial are required for memory consolidation. In the present study, we investigated whether spicatoside A enhances memory consolidation, and whether its effects on memory consolidation are related to hippocampal mBDNF levels. Spicatoside A (2.5, 5, 10 or 20mg/kg) enhanced memory consolidation in a dose-dependent manner, and enhanced memory consolidation was also observed when spicatoside A was administered 1h after the acquisition trial. Concurrently, when spicatoside A was administered immediately or 1h after the acquisition trial, hippocampal mBDNF levels were similar or significantly increased at 9h after the acquisition trial compared to levels at 6h. These results suggest that increased mBDNF levels in the hippocampal region at 9h after the acquisition trial might play a pivotal role in memory consolidation and that spicatoside A might enhance memory consolidation by increasing hippocampal mBDNF levels. PMID- 24792394 TI - Collagen (NeuraGen(r)) nerve conduits and stem cells for peripheral nerve gap repair. AB - Collagen nerve guides are used clinically for peripheral nerve defects, but their use is generally limited to lesions up to 3 cm. In this study we combined collagen conduits with cells as an alternative strategy to support nerve regeneration over longer gaps. In vitro cell adherence to collagen conduits (NeuraGen((r)) nerve guides) was assessed by scanning electron microscopy. For in vivo experiments, conduits were seeded with either Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC) or left empty (control group), conduits were used to bridge a 1cm gap in the rat sciatic nerve and after 2-weeks immunohistochemical analysis was performed to assess axonal regeneration and SC infiltration. The regenerative cells showed good adherence to the collagen walls. Primary SC showed significant improvement in distal stump sprouting. No significant differences in proximal regeneration distances were noticed among experimental groups. dMSC and dASC-loaded conduits showed a diffuse sprouting pattern, while SC-loaded showed an enhanced cone pattern and a typical sprouting along the conduits walls, suggesting an increased affinity for the collagen type I fibrillar structure. NeuraGen((r)) guides showed high affinity of regenerative cells and could be used as efficient vehicle for cell delivery. However, surface modifications (e.g. with extracellular matrix molecule peptides) of NeuraGen((r)) guides could be used in future tissue-engineering applications to better exploit the cell potential. PMID- 24792395 TI - Oxytocin cells in the paraventricular nucleus receive excitatory synaptic inputs from the contralateral paraventricular and supraoptic nuclei in lactating rats. AB - The present experiments were undertaken to examine whether oxytocin cells in the paraventricular nucleus receive synaptic inputs from the contralateral supraoptic or paraventricular nucleus. Using urethane-anesthetized lactating rats, extracellular action potentials were recorded from single oxytocin or vasopressin cells in the paraventricular nucleus. Electrical stimulation was applied to the contralateral supraoptic nucleus or paraventricular nucleus, and responses of oxytocin or vasopressin cells were analyzed by peri-stimulus time histogram or by change in firing rate of oxytocin or vasopressin cells. Electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus did not cause antidromic excitation in oxytocin or vasopressin cells but caused orthodromic responses. Although analysis by peri-stimulus time histogram showed that electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus caused orthodromic excitation in both oxytocin and vasopressin cells, the proportion of excited oxytocin cells was greater than that of vasopressin cells. Train stimulation applied to the contralateral supraoptic nucleus or paraventricular nucleus at 10 Hz increased firing rates of oxytocin cells and decreased those of vasopressin cells. The results of the present experiments suggest that oxytocin cells in the paraventricular nucleus receive mainly excitatory synaptic inputs from the contralateral supraoptic nucleus and paraventricular nucleus. Receipt these synaptic inputs to oxytocin cells may contribute to the synchronized activation of oxytocin cells during the milk ejection reflex. PMID- 24792396 TI - Effect of nitric oxide synthase inhibitor L-NAME on fear extinction in rats: a task-dependent effect. AB - There is increasing evidence that nitric oxide may be involved in learning and memory. However, there remain comparatively few studies that have explored the relationship between nitric oxide signaling and fear extinction, an inhibitory learning model. In the present study, we tested the effects of nitric oxide synthase inhibitor l-NAME on three tone fear extinction tasks in rats. In task 1, rats received fear conditioning, extinction training and extinction test in the same context (AAA design). In task 2, rats received fear conditioning in context A, extinction training in context B and extinction test in context A (ABA design). In task 3, rats received fear conditioning in context A, extinction training and extinction test in context B (ABB design). l-NAME (10, 20 and 40 mg/kg) was injected intraperitoneally 30 min prior to extinction training in each task. Percent of time spent freezing was used to measure conditioned fear response. We found that l-NAME administrations had no effect on freezing in task 1 and 2 but produced a dose-dependent increase in task 3. Further results indicated that the increased freezing in task 3 was not attributed to state dependency effects or nonspecific changes of locomotor activity that followed l NAME injection. These results showed that l-NAME produced a task-dependent impairment of fear extinction, and implied that nitric oxide signaling was involved in memory process of certain extinction tasks. PMID- 24792397 TI - [Optical coherence tomography and microperimetry after internal limiting membrane peeling for epiretinal membrane]. AB - INTRODUCTION: To evaluate the anatomical and functional consequences of internal limiting membrane (ILM) peeling in epiretinal membrane (ERM) surgery. METHODS: Retrospective single-center study including consecutive patients operated on for idiopathic ERM. The integrity of the ILM was assessed by ILM Blue(r) staining after removal of the ERM: either the peeling was spontaneous (group 1) or a complementary peeling was required (group 2). Pre- and post-operatively (1 and 6 months), all patients were analyzed using visual acuity, SD-OCT (Spectralis HRA OCT, Heidelberg, Germany) and microperimetry (OPKO/OTI, Miami, USA). RESULTS: Twenty-one eyes of 21 patients were included: 12 "active ILM peelings" and 9 "spontaneous peelings". In both groups, visual acuity increased significantly after surgery. Microperimetry revealed more microscotomata at 1 and 6 months for active peeling (P<0.05). Their location corresponded more often to the site where the ERM or ILM was grasped, based on surgical videos (P<0.05), and with the appearance of inner retinal defects using en face OCT. DISCUSSION: ILM peeling is frequently performed to reduce ERM recurrence. Despite lack of effect on visual acuity, active ILM peeling increases the incidence of microscotomas related to the site where the ERM or ILM is grasped. CONCLUSION: Active ILM peeling may be responsible for postoperative visual discomfort related to microscopic trauma during peeling. PMID- 24792398 TI - [Carotid-cavernous fistula: clinical and pathological correlations]. AB - INTRODUCTION: Depending upon the type of communication between the internal carotid artery and the cavernous sinus, two types of carotid-cavernous fistulae can be distinguished: direct carotid-cavernous fistula (DCCF), for which diagnosis is usually easy because of the obvious signs of orbital congestion, and indirect carotid-cavernous fistula (ICCF) or dural fistula, with few symptoms, associated with a delay in diagnosis which can alter prognosis for function and even life. PURPOSE: The purpose of this study is to determine characteristic signs of both types of CCF and to study their correlation with the anatomical type of vessels involved on the angiogram. The prognosis for both types of fistula was also studied. METHOD: Retrospective single-center study, including patients with angiographically confirmed DCCF or ICCF. Demographic, clinical, and prognostic characteristics of these patients were analyzed and compared with the angiogram findings. RESULTS: Six patients (4 DCCF and 2 ICCF) were included in this study. Mean age at diagnosis was 62.7 years in the DCCF group and 62 years in the ICCF group. Mean time until diagnosis was 7 weeks in the DCCF group and 24 weeks in the ICCF group. Signs of orbital congestion were present in 100% of patients with DCCF and absent in all patients in the ICCF group. Mean proptosis was 3.5mm in the DCCF group and 0.5 in the ICCF group. All patients had an audible bruit on auscultation. The location of the bruit was orbital in all patients with DCCF, and pretragal or jugal in 50% of patients with ICCF. CONCLUSIONS: ICCF can impact mortality and are often underdiagnosed. The diagnostic delay observed in our study reflects the difficulties which persist in recognizing the clinical signs of this condition. ICCF must be suspected in the case of a history suggestive of CCF, even if the clinical examination appears normal. The presence of a bruit must be carefully sought, not only in the classical orbital location, but also in other facial locations as shown in our study. Our results demonstrate that there is indeed a good correlation between the site of the CCF, the location of the bruit, and the vessels involved. PMID- 24792399 TI - [Clinical features of retinoblastoma in Tunisia]. AB - PURPOSE: To report the relative frequency of presenting signs in Tunisian children with retinoblastoma and to evaluate their prognostic impact. METHODS: A retrospective study was undertaken of 200 patients with retinoblastoma examined and treated between January 1993 and June 2009. RESULTS: There were 123 boys and 77 girls. For all cases, mean age at diagnosis was 29.8 months (range, 1 month to 9 years). There were 138 (69%) unilateral cases and 62 (31%) bilateral cases. Nineteen children (9.5%) had a family history of retinoblastoma. The most common signs were leukocoria (80%) and strabismus (28%) followed by proptosis. Orbital inflammation, hyphemia and phthisis are rare presenting findings in retinoblastoma. In our series, 26 children (13%) presented with extraocular retinoblastoma. Leukocoria and proptosis are significantly associated with a worse prognosis. CONCLUSION: The ability to recognize the presenting signs and symptoms of retinoblastoma can lead to earlier diagnosis and better prognosis. PMID- 24792401 TI - Estimating the costs of cervical cancer screening in high-burden Sub-Saharan African countries. AB - OBJECTIVE: To estimate the capital investment and recurrent costs of national cervical cancer screening and precancer treatment programs in 23 high-incidence countries in Sub-Saharan Africa in order to provide estimates of the investment required to tackle the burden of cervical cancer in this region. These 23 countries account for 64% of the annual cervical cancer deaths in this region. METHODS: Secondary data were used to estimate the financial costs of equipment purchases and economic costs of screening and treating eligible women over a 10 year period. Screening would be by visual inspection with acetic acid and treatment by cryotherapy or loop electrosurgical excision procedure. RESULTS: Approximately US $59 million would be required to purchase treatment equipment if cryotherapy were placed at every screening facility. Approximately 20 million women would be screened over 10 years. Cost per woman screened in a screen-and treat program was either US $3.33 or US $7.31, and cost per woman treated was either US $38 or US $71 depending on the location of cryotherapy equipment. CONCLUSION: It would take less than US $10 per woman screened to significantly decrease the cervical cancer deaths that will occur in Sub-Saharan Africa over the next 10 years. PMID- 24792400 TI - Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells. AB - The active form of vitamin D3, 1,25(OH)2D3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH)2D3 by itself regulates VDR expression in human CD4+ T cells. We found that activated CD4+ T cells have the capacity to convert the inactive 25(OH)D3 to the active 1,25(OH)2D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2D3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH)2D3-induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2D3, and that 1,25(OH)2D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation. PMID- 24792402 TI - A cross-sectional study on the effect of post-rape training on knowledge and confidence of health professionals in South Africa. AB - OBJECTIVE: To determine whether a national training program on post-rape care in South Africa resulted in improvements in knowledge and confidence in health professionals, and to distinguish baseline factors related to these changes in knowledge and confidence. METHODS: Data for this cross-sectional study were collected over four training sessions in 2008 using questionnaires and multiple choice question papers given to 152 health professionals. Information was collected on demographics, service provision, and previous training. The change in knowledge and confidence was calculated from baseline and post-training scores. Factors related to these changes in knowledge and confidence were tested through the development of two models. RESULTS: Seventy-four percent of the health professionals (n=112) who attended the training had completed all components of the data collection. The average age of the professionals was 41.6 years, 71% were females, and 68% nurses. Health professionals showed significant increases in percentage knowledge (40% at baseline vs 51% post training; P<0.001) and confidence (67% at baseline vs 80% post training; P<0.001) after the training. In the final multivariate models, empathy was significantly associated with a change in knowledge (coefficient -1.2; 95% CI, -1.9 to 0.4; P=0.005), while the facility level and baseline knowledge and confidence were significantly associated with change in confidence. CONCLUSION: The training program was found to improve levels of knowledge and confidence in health professionals. Rollout of this program is critical with expansion into undergraduate curriculums. PMID- 24792403 TI - Improving manual vacuum aspiration service delivery, introducing misoprostol for cases of incomplete abortion, and strengthening postabortion contraception in Bangladesh. AB - The Obstetrical and Gynaecological Society of Bangladesh was an important advocate in mobilizing government authorities to adopt new techniques for postabortion care and provide long-acting contraceptives post abortion. With the support of the International Federation of Gynecology and Obstetrics (FIGO), the Society provided commodities and training to increase the use of these techniques in 7 private and public hospitals and clinics. Data from two of these institutes for the January 2012 to June 2013 period showed a rapid decrease in the use of dilation and curettage, an increase in the use of manual vacuum aspiration (MVA) and misoprostol, and the progressive adoption of long-acting reversible contraceptives, permanent contraception, and injectable contraceptives in one of these two hospitals. The Directorates General of Health and Family Planning incorporated training in the use of MVA and misoprostol in their national operation plans. The success in these hospitals shows that the proposed changes have been well accepted by providers and clients. PMID- 24792404 TI - Estimating the prevalence of urinary and fecal incontinence in a nationally representative survey in Sierra Leone. PMID- 24792405 TI - DNA extraction from filter-paper spots of vaginal samples collected after sexual violence. AB - OBJECTIVE: To detect the presence of male DNA in vaginal samples collected from survivors of sexual violence and stored on filter paper. METHODS: A pilot study was conducted to evaluate 10 vaginal samples spotted on sterile filter paper: 6 collected at random in April 2009 and 4 in October 2010. Time between sexual assault and sample collection was 4-48hours. After drying at room temperature, the samples were placed in a sterile envelope and stored for 2-3years until processing. DNA extraction was confirmed by polymerase chain reaction for human beta-globin, and the presence of prostate-specific antigen (PSA) was quantified. The presence of the Y chromosome was detected using primers for sequences in the TSPY (Y7/Y8 and DYS14) and SRY genes. RESULTS: beta-Globin was detected in all 10 samples, while 2 samples were positive for PSA. Half of the samples amplified the Y7/Y8 and DYS14 sequences of the TSPY gene and 30% amplified the SRY gene sequence of the Y chromosome. Four male samples and 1 female sample served as controls. CONCLUSION: Filter-paper spots stored for periods of up to 3years proved adequate for preserving genetic material from vaginal samples collected following sexual violence. PMID- 24792406 TI - Effect of maternal fasting for religious beliefs on fetal sonographic findings and neonatal outcomes. AB - OBJECTIVE: To investigate the effects of long-lasting maternal fasting on fetal biometry, amniotic fluid volume, fetal Doppler parameters, and neonatal outcomes. METHODS: The present study, conducted at Solhan State Hospital, Bingol, Turkey, between July and August 2013 recruited 82 healthy and otherwise normal pregnant women with a gestational age of 29 weeks or more who were fasting for at least 20 days. The control group comprised 87 healthy non-fasting women matched for maternal age, parity, gestational age. Fetal parameters were measured at the beginning and the end of the fasting month. Perinatal outcomes were compared between the groups. RESULTS: There were no significant differences between the groups in fetal biometry, fetal Doppler parameters, or neonatal outcomes. In the fasting group, however, there was a significantly greater decrease in amniotic fluid index during the fasting period (P<0.001). The number of women who initially had a normal amniotic fluid measurement and subsequently developed oligohydramnios was also significantly higher in the religious fasting group (P<0.05). CONCLUSION: Fetal development, Doppler parameters, and neonatal outcomes were not significantly affected in healthy fasting women; however, there was a significant association between fasting and amniotic fluid index. These findings mandate more frequent follow-up visits for this group of women. PMID- 24792407 TI - Oral and cervical HPV infection in HIV-positive and HIV-negative women attending a sexual health clinic in Sao Paulo, Brazil. AB - OBJECTIVE: To investigate the prevalence of HPV infections in the oral and cervical mucosa of HIV-positive and HIV-negative women attending a sexual health clinic. METHODS: One-hundred HIV-positive women and 100 HIV-negative women were recruited from a sexual health clinic in Sao Paulo, Brazil. All participants were given an oral and cervical examination. Cytologic samples were evaluated via HPV DNA test. RESULTS: In oral samples, HPV DNA was observed in 11 women from the HIV positive group and 2 from the HIV-negative group. High-risk HPV subtypes were prevalent in both groups and no difference between groups was detected. HPV DNA was detected in cervical scrapings from 41 HIV-positive women and 45 HIV-negative women (P=0.67). No participants showed oral lesions, whereas 15 HIV-positive and 17 HIV-negative women presented with macroscopic genital lesions. CONCLUSION: HPV is detected more often in cervical scrapings than in oral samples. However, HPV oral shedding is more frequent in HIV-positive than in HIV-negative individuals. Concurrence of infection (high and low risk) was not observed in oral and cervical mucosa. PMID- 24792408 TI - A cohort study of Plasmodium falciparum malaria in pregnancy and associations with uteroplacental blood flow and fetal anthropometrics in Kenya. AB - OBJECTIVE: To use ultrasound to explore the impact of malaria in pregnancy on fetal growth and newborn outcomes among a cohort of women enrolled in an intermittent presumptive treatment in pregnancy (IPTp) with sulfadoxine/pyrimethamine (SP) program in coastal Kenya. METHODS: Enrolled women were tested for malaria at first prenatal care visit, and physical and ultrasound examinations were performed. In total, 477 women who had term, live births had malaria tested at delivery and their birth outcomes assessed, and were included in the study. RESULTS: Peripheral malaria was detected via polymerase chain reaction among 10.9% (n=87) at first prenatal care visit and 8.8% (n=36) at delivery. Insecticide-treated bed nets (ITNs) were used by 73.6% (n=583) and were associated with decreased malaria risk. There was a trend for impaired fetal growth and placental blood flow in malaria-infected women in the second trimester, but not later in pregnancy. Among women with low body mass index (BMI), malaria was associated with reduced birth weight (P=0.04); anthropometric measures were similar otherwise. CONCLUSION: With IPTp-SP and ITNs, malaria in pregnancy was associated with transient differences in utero, and reduced birth weight was restricted to those with low BMI. PMID- 24792409 TI - Distribution of various types of low-risk human papillomavirus according to cervical cytology and histology in northern Chinese women. AB - OBJECTIVE: To describe the distribution of specific types of low-risk (LR) human papillomavirus (HPV) among a general population of northern Chinese women. METHODS: Between 2007 and 2012, 118 096 women were tested with the HPV Geno-Array Test Kit (HybriBio) at China Medical University's Shengjing Affiliated Hospital, Shenyang, China. Among these women, 80 418 underwent cervical cytology and colposcopic examination, and 30 961 of these had a cervical biopsy. The prevalence of HPV infection among the women was analyzed according to age, and cytologic and histologic findings. RESULTS: CP8304 was the most common type of LR HPV overall, and was most prevalent in the youngest age group. The overall prevalence of LR-HPV (averaged across all types) was 1.7% in women with normal cytology, 8.8% in those with atypical squamous cells of undetermined significance (ASCUS), 8.0% in those with low-grade squamous intraepithelial lesions (LSIL), and 5.8% in those with high-grade squamous intraepithelial lesions (HSIL). LR-HPV alone, without any high-risk (HR)-HPV, was most common among women with ASCUS and cervical intraepithelial neoplasia (CIN) not otherwise specified (CINNOS) together. Co-infections of LR-HPV and HR-HPV were most common among women with LSIL and CIN1. CONCLUSION: These data will facilitate modeling of the cost effectiveness of a prophylactic LR-HPV vaccination in China. PMID- 24792410 TI - Bone marrow derived "fibrocytes" contribute to tumor proliferation and fibrosis in gastric cancer. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) in the stroma are considered to play important roles for gastric cancer proliferation, invasion, and fibrosis, but the source of CAFs and their interaction with cancer cells in the microenvironment have not been fully determined. Here we elucidated the role of bone marrow-derived cells, fibrocytes, in development of gastric cancers, as represented by scirrhous gastric cancer. MATERIALS AND METHODS: In co-culturing MKN45 gastric cancer cells and purified fibrocytes from healthy volunteers, migration and endothelial mesenchymal transition associated gene expression were evaluated using western blot analysis. Also, mouse xenograft models of MKN45 with or without fibrocytes were conducted to investigate their tumorigenicity and immunohistological differences of tumors. RESULTS: Co-culture of fibrocytes with MKN45 resulted in morphological changes from cobblestone-shape to spindle-shape and enhanced expression of alpha-SMA and collagen type I in fibrocytes, suggesting that co-culture with gastric cancer cells may have induced the differentiation of fibrocytes to myofibroblasts. Furthermore, enhanced expression of SDF-1 in MKN45 and CXCR4 in fibrocytes were also determined. Mouse xenograft models inoculated with MKN45 and fibrocytes revealed significantly larger tumors than those inoculated with MKN45 cells alone, and the stroma in co-inoculated tumors consisted of myofibroblasts and fibrosis. Mouse-derived cells expressing both CD45 and type I collagen were also observed in co-inoculated tumors. CONCLUSION: Fibrocytes derived from bone marrow may migrate into the microenvironment of gastric cancer by SDF-1/CXCR4 system, and enhance the tumor proliferation and fibrosis as CAFs. PMID- 24792412 TI - AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility. AB - BACKGROUND: Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations. OBJECTIVE: To examine the impact of genotypic polymorphisms on iAs metabolism. METHODS: We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration. RESULTS: In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism. DISCUSSION: Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs. CONCLUSIONS: Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility. PMID- 24792411 TI - Bone cancer pain: from mechanism to therapy. AB - PURPOSE OF REVIEW: To review how common cancers such as breast, lung, and prostate cancers drive significant and frequently life-altering pain when the cells metastasize to bones. RECENT FINDINGS: Similar to cancer, the factors that drive bone cancer pain evolve and change with disease progression. Bone cancer pain has both a nociceptive and neuropathic component. The nociceptive component is driven by the release of algogenic substances by tumor and their associated stromal cells, acidosis caused by bone-destroying osteoclasts, and mechanical destabilization and fracture of the bone. The neuropathic component is induced by tumor cell growth which injures and destroys the distal ends of nerve fibers that normally innervate the bone, as well as by inducing a highly pathological sprouting of both sensory and sympathetic nerve fibers. SUMMARY: There is both a nociceptive and neuropathic component of bone cancer pain. In bone cancer pain, there is frequently a continual afferent drive of sensory nerve fibers that induces a peripheral and central sensitization. These mechanistic insights have begun to lead to advances in not only how we understand bone cancer pain but to the development of new therapies to treat bone cancer pain. PMID- 24792413 TI - Chronic PM2.5 exposure and inflammation: determining sensitive subgroups in mid life women. AB - BACKGROUND: Several cohort studies report associations between chronic exposure to ambient fine particles (PM2.5) and cardiovascular mortality. Uncertainty exists about biological mechanisms responsible for this observation, but systemic inflammation has been postulated. In addition, the subgroups susceptible to inflammation have not been fully elucidated. METHODS: We investigated whether certain subgroups are susceptible to the effects of long-term exposure to PM2.5 on C-reactive protein (CRP), a marker of inflammation directly linked to subsequent cardiovascular disease. We used data from the SWAN cohort of 1923 mid life women with up to five annual repeated measures of CRP. Linear mixed and GEE models accounting for repeated measurements within an individual were used to estimate the effects of prior-year PM2.5 exposure on CRP. We examined CRP as a continuous and as binary outcome for CRP greater than 3mg/l, a level of clinical significance. RESULTS: We found strong associations between PM2.5 and CRP among several subgroups. For example a 10 ug/m(3) increase in annual PM2.5 more than doubled the risk of CRP greater than 3mg/l in older diabetics, smokers and the unmarried. Larger effects were also observed among those with low income, high blood pressure, or who were using hormone therapy, with indications of a protective effects for those using statins or consuming moderate amounts of alcohol. CONCLUSIONS: In this study, we observed significant associations between long-term exposure to PM2.5 and CRP in several susceptible subgroups. This suggests a plausible pathway by which exposure to particulate matter may be associated with increased risk of cardiovascular disease. PMID- 24792414 TI - Macro-activity patterns of farmworker and non-farmworker children living in an agricultural community. AB - BACKGROUND: Children of farmworkers have significantly higher exposure to pesticides than do other children living in the same agricultural communities, but there is limited information about how and where older farmworker children (>6) spend their time and how their activities might influence the risk of pesticide exposure. OBJECTIVES: Using data from the Community Based Participatory Research Study for Healthy Kids, we compared activity patterns recorded over 7 days during two agricultural seasons (pre thinning and thinning) between farmworker and non-farmworker children aged 6-12 years old living in Eastern Washington State. METHODS: Parents completed a 7-day activity diary recording the activity patterns of their children. Mean differences in individual-level activity patterns across season were analyzed using paired t-tests and the Signed Rank Test. Differences in mean activity patterns comparing farmworker and non farmworker children were analyzed using the Wilcoxon Sum Rank Test to assess differences in distributions across independent samples. RESULTS: We observed substantial differences in child activity patterns between the two seasons. The children in this sample spent more time outdoors (p<0.001) and were more likely to engage in behaviors, such as playing in the fields (p=0.01) and accompanying their parents to work in the fields (p=0.001) during the high-spray thinning season. There were some differences in activities and behaviors between farmworker and non-farmworker children during the thinning season. CONCLUSION: This study demonstrates that multiple factors, including agricultural season and parental occupation, may be associated with differences in activity patterns that could influence risk of pesticide exposure among children living in agricultural communities. As such, these factors may influence variation in exposure risks and should be considered when analyzing pesticide exposure measurements in these groups. PMID- 24792415 TI - Assessment of traffic-related noise in three cities in the United States. AB - BACKGROUND: Traffic-related noise is a growing public health concern in developing and developed countries due to increasing vehicle traffic. Epidemiological studies have reported associations between noise exposure and high blood pressure, increased risk of hypertension and heart disease, and stress induced by sleep disturbance and annoyance. These findings motivate the need for regular noise assessments within urban areas. This paper assesses the relationships between traffic and noise in three US cities. METHODS: Noise measurements were conducted in downtown areas in three cities in the United States: Atlanta, Los Angeles, and New York City. For each city, we measured ambient noise levels, and assessed their correlation with simultaneously measured vehicle counts, and with traffic data provided by local Metropolitan Planning Organizations (MPO). Additionally, measured noise levels were compared to noise levels predicted by the Federal Highway Administration's Traffic Noise Model using (1) simultaneously measured traffic counts or (2) MPO traffic data sources as model input. RESULTS: We found substantial variations in traffic and noise within and between cities. Total number of vehicle counts explained a substantial amount of variation in measured ambient noise in Atlanta (78%), Los Angeles (58%), and New York City (62%). Modeled noise levels were moderately correlated with measured noise levels when observed traffic counts were used as model input. Weaker correlations were found when MPO traffic data was used as model input. CONCLUSIONS: Ambient noise levels measured in all three cities were correlated with traffic data, highlighting the importance of traffic planning in mitigating noise-related health effects. Model performance was sensitive to the traffic data used as input. Future noise studies that use modeled noise estimates should evaluate traffic data quality and should ideally include other factors, such as local roadway, building, and meteorological characteristics. PMID- 24792416 TI - Derivation and validation of BOREAS, a risk score identifying candidates to develop cold-induced hypertension. AB - INTRODUCTION: Blood pressure increases in cold periods, but its implications on prevalence of hypertension and on individual progression to hypertension remain unclear. Our aim was to develop a pre-screening test for identifying candidates to suffer hypertension only in cold months among non-hypertensive subjects. METHODS: We included 95,277 subjects registered on a primary care database from Girona (Catalonia, Spain), with >= 3 blood pressure measures recorded between 2003 and 2009 and distributed in both cold (October-March) and warm (April September) periods. We defined four blood pressure patterns depending on the presence of hypertension through these periods. A Cox model determined the risk to develop vascular events associated with blood pressure patterns. A logistic regression distinguished those nonhypertensive individuals who are more prone to suffer cold-induced hypertension. Validity was assessed on the basis of calibration (using Brier score) and discrimination (using the area under the receiver operating characteristics). RESULTS: In cold months, the mean systolic blood pressure increased by 3.3 +/- 0.1 mmHg and prevalence of hypertension increased by 8.2%. Cold-induced hypertension patients were at higher vascular events risk (Hazard ratio=1.44 [95% Confidence interval 1.15-1.81]), than nonhypertensive individuals. We identified age, diabetes, body mass index and prehypertension as the major contributing factors to cold-induced hypertension onset. DISCUSSION: Hypertension follows a seasonal pattern in some individuals. We recommend screening for hypertension during the cold months, at least in those nonhypertensive individuals identified as cold-induced hypertensive by this assessment tool. PMID- 24792417 TI - Genotype analyses of human commensal scalp fungi, Malassezia globosa, and Malassezia restricta on the scalps of patients with dandruff and healthy subjects. AB - Dandruff and seborrheic dermatitis are common afflictions of the human scalp caused by commensal scalp fungi belonging to the genus Malassezia. Malassezia globosa and Malassezia restricta are the predominant species found on the scalp. The intergenic spacer regions of these species' rRNA genes contain short sequence repeats (SSR): (GT)n and (CT)n in M. globosa and (CT)n and (AT)n in M. restricta. In the present study, we compared the genotypes (SSR) of M. globosa and M. restricta colonizing the scalps of patients with dandruff and healthy individuals. For M. globosa, the genotype (GT)10:(CT)8 (40.3 %, 25/62) was predominant followed by (GT)9:(CT)8 (14.5 %, 9/62) and (GT)11:(CT)8 (14.5 %, 9/62) in patients with dandruff, whereas the genotypes in healthy subjects were diverse. For M. restricta, the genotype (CT)6:(AT)6 (59.7 %, 37/62) was predominant followed by (CT)6:(AT)8 (24.2 %, 15/62) in patients with dandruff, while four genotypes, (CT)6:(AT)6 (10.5 %, 6/57), (CT)6:(AT)7 (22.8 %, 13/57), (CT)6:(AT)8 (17.5 %, 10/57), and (CT)6:(AT)10 (21.1 %, 12/57), accounted for 71.9 % of all combinations in healthy subjects. The results of this study suggest that the M. globosa genotype (GT)10:(CT)8 and the M. restricta genotype (CT)6:(AT)6 may be involved in the development of dandruff. PMID- 24792418 TI - Ultrafast redistribution of E. coli SSB along long single-stranded DNA via intersegment transfer. AB - Single-stranded DNA binding proteins (SSBs) selectively bind single-stranded DNA (ssDNA) and facilitate recruitment of additional proteins and enzymes to their sites of action on DNA. SSB can also locally diffuse on ssDNA, which allows it to quickly reposition itself while remaining bound to ssDNA. In this work, we used a hybrid instrument that combines single-molecule fluorescence and force spectroscopy to directly visualize the movement of Escherichia coli SSB on long polymeric ssDNA. Long ssDNA was synthesized without secondary structure that can hinder quantitative analysis of SSB movement. The apparent diffusion coefficient of E. coli SSB thus determined ranged from 70,000 to 170,000nt(2)/s, which is at least 600 times higher than that determined from SSB diffusion on short ssDNA oligomers, and is within the range of values reported for protein diffusion on double-stranded DNA. Our work suggests that SSB can also migrate via a long-range intersegment transfer on long ssDNA. The force dependence of SSB movement on ssDNA further supports this interpretation. PMID- 24792420 TI - [Successful aging and indicators of frailty in the elderly. Octabaix Study]. AB - Successful aging as a process of adaptation to the optimal state is little known in older people. OBJECTIVE: To describe successful aging and to analyze the factors associated with frailty in people aged 86 years. DESIGN: A cross sectional study of a clinical trial at the second year of follow-up (Octabaix Study). SETTING: Seven Primary Care Centers. PARTICIPANTS: Non-institutionalized subjects born in 1924. MAIN MEASUREMENTS: Data on sociodemographic, comorbidity and geriatric assessment scales were collected. Frailty was defined by the presence of 3 or more of the following criteria: muscle weakness, slow walking, weight loss, exhaustion, low physical activity. Successful aging was defined as: Barthel index >90/100 and Lobo test >= 24/35. Multiple regression analysis was performed. RESULTS: A total of 273 patients were evaluated, 39.2% men. The prevalence of successful aging was 47.2% (129). In the unsuccessful aging, the frailty prevalence was 34.7% (50). The frailty factors associated with unsuccessful aging were low activity (OR: 7.56; 95%CI: 3.8 -14.9), weakness (OR: 6.08; 95%CI: 2.5-14.7), slowness (OR: 5.1; 95%CI: 2.8-9.5), and exhaustion (OR: 3.6; 95%CI: 1.6-8.3). The prevalence of successful aging is high in 86-year-old community-dwelling subjects. The low physical activity multiplied by seven, and muscle weakness by 6, were the factors most associated with unsuccessful aging. Therefore, incorporating screening designed to detect these two factors could improve future interventions towards more optimal aging in the community, if these results are confirmed in future studies. PMID- 24792419 TI - In vivo roles of BamA, BamB and BamD in the biogenesis of BamA, a core protein of the beta-barrel assembly machine of Escherichia coli. AB - Assembly of the beta-barrel outer membrane proteins (OMPs) is an essential cellular process in Gram-negative bacteria and in the mitochondria and chloroplasts of eukaryotes--two organelles of bacterial origin. Central to this process is the conserved beta-barrel OMP that belongs to the Omp85 superfamily. In Escherichia coli, BamA is the core beta-barrel OMP and, together with four outer membrane lipoproteins, BamBCDE, constitutes the beta-barrel assembly machine (BAM). In this paper, we investigated the roles of BamD, an essential lipoprotein, and BamB in BamA biogenesis. Depletion of BamD caused impairment in BamA biogenesis and cessation of cell growth. These defects of BamD depletion were partly reversed by single-amino-acid substitutions mapping within the beta barrel domain of BamA. However, in the absence of BamB, the positive effects of the beta-barrel substitutions on BamA biogenesis under BamD depletion conditions were nullified. By employing a BamA protein bearing one such substitution, F474L, it was demonstrated that the mutant BamA protein could not only assemble without BamD but also facilitate the assembly of wild-type BamA expressed in trans. Based on these data, we propose a model in which the Bam lipoproteins, which are localized to the outer membrane by the BAM-independent Lol pathway, aid in the creation of new BAM complexes by serving as outer membrane receptors and folding factors for nascent BamA molecules. The newly assembled BAM holocomplex then catalyzes the assembly of substrate OMPs and BamA. These in vivo findings are corroborated by recently published in vitro data. PMID- 24792421 TI - Genome-wide identification, characterization and expression analysis of the auxin response factor gene family in Vitis vinifera. AB - KEY MESSAGE: Our study has identified and analyzed the VvARF gene family that may be associated with the development of grape berry and other tissues. Auxin response factors (ARFs) are transcription factors that regulate the expression of auxin responsive genes through specific binding to auxin response elements (AuxREs). The ARF genes are represented by a large multigene family in plants. Until now, many ARF families have been characterized based on genome resources. However, there is no specialized research about ARF genes in grapevine (Vitis vinifera). In this study, a comprehensive bioinformatics analysis of the grapevine ARF gene family is presented, including chromosomal locations, phylogenetic relationships, gene structures, conserved domains and expression profiles. Nineteen VvARF genes were identified and categorized into four groups (Classes 1, 2, 3 and 4). Most of VvARF proteins contain B3, AUX_RESP and AUX_IAA domains. The VvARF genes were widely expressed in a range of grape tissues, and fruit had higher transcript levels for most VvARFs detected in the EST sources. Furthermore, analysis of expression profiles indicated some VvARF genes may play important roles in the regulation of grape berry maturation processes. This study which provided basic genomic information for the grapevine ARF gene family will be useful in selecting candidate genes related to tissue development in grapevine and pave the way for further functional verification of these VvARF genes. PMID- 24792433 TI - Pathophysiogical and therapeutic progress in Friedreich ataxia. AB - Friedreich ataxia (FRDA) is the most common hereditary autosomal recessive ataxia, but is also a multisystemic condition with frequent presence of cardiomyopathy or diabetes. It has been linked to expansion of a GAA-triplet repeat in the first intron of the FXN gene, leading to a reduced level of frataxin, a mitochondrial protein which, by controlling both iron entry and/or sulfide production, is essential to properly assemble and protect the Fe-S cluster during the initial stage of biogenesis. Several data emphasize the role of oxidative damage in FRDA, but better understanding of pathophysiological consequences of FXN mutations has led to develop animal models. Conditional knockout models recapitulate important features of the human disease but lack the genetic context, GAA repeat expansion-based knock-in and transgenic models carry a GAA repeat expansion but they only show a very mild phenotype. Cells derived from FRDA patients constitute the most relevant frataxin-deficient cell model as they carry the complete frataxin locus together with GAA repeat expansions and regulatory sequences. Induced pluripotent stem cell (iPSC)-derived neurons present a maturation delay and lower mitochondrial membrane potential, while cardiomyocytes exhibit progressive mitochondrial degeneration, with frequent dark mitochondria and proliferation/accumulation of normal mitochondria. Efforts in developing therapeutic strategies can be divided into three categories: iron chelators, antioxidants and/or stimulants of mitochondrial biogenesis, and frataxin level modifiers. A promising therapeutic strategy that is currently the subject of intense research is to directly target the heterochromatin state of the GAA repeat expansion with histone deacytelase inhibitors (HDACi) to restore frataxin levels. PMID- 24792422 TI - Heterologous expression of AtMYB12 in kale (Brassica oleracea var. acephala) leads to high flavonol accumulation. AB - KEY MESSAGE: Overexpression of Arabidopsis AtMYB12 transcription factor greatly increases the total phenolic and flavonol content in transgenic kale leaves. Flavonoids are a diverse group of plant secondary metabolites exhibiting a number of health-promoting effects. There has been a growing interest to develop biotechnological methods for the enhanced production of flavonoids in crop plants. AtMYB12 is an Arabidopsis transcription factor which specifically activates flavonol synthesis and its overexpression has led to increased flavonol accumulation in several transgenic plants. In the present study, AtMYB12 was overexpressed in a commercial cultivar of kale and the transgenic plants were tested both in in vitro and in semi-field conditions in cages under natural light. Using this method, a severalfold increase in both total phenolics content and flavonol accumulation was achieved. This study provides a reliable and efficient transformation protocol for kale and suggests the potential of this flavonol-enriched vegetable for the production of kaempferol. PMID- 24792434 TI - An overview of neurological and neuromuscular signs in mitochondrial diseases. AB - Mitochondrial disorders have a broad clinical spectrum and are genetically heterogeneous, involving two genomes. These disorders may be develop at any age, with isolated or multiple system involvement, and any pattern of inheritance. Neurological involvement is the most frequent, and concerns muscular, peripheral and central nervous system. Among these diverse signs, some are suggestive of mitochondrial disease, such as progressive external ophthalmoplegia, exercise intolerance, psychomotor regression, stroke-like episodes, refractory epilepsy and Epilepsia Partialis Continua. Others are less specific and mitochondrial hypothesis may be evocated because of either association of different neuromuscular signs or a multisystemic involvement. This review describes the wealth of this neurological and neuromuscular symptomatology through different syndromes reported in the literature, according to preponderant signs and to modes of inheritance, as key elements to guide genetics testing. PMID- 24792435 TI - Molecular simulation study on Hofmeister cations and the aqueous solubility of benzene. AB - We study the ion-specific salting-out process of benzene in aqueous alkali chloride solutions using Kirkwood-Buff (KB) theory of solutions and molecular dynamics simulations with different empirical force field models for the ions and benzene. Despite inaccuracies in the force fields, the simulations indicate that the decrease of the Setchenow salting-out coefficient for the series NaCl > KCl > RbCl > CsCl is determined by direct benzene-cation correlations, with the larger cations showing weak interactions with benzene. Although ion-specific aqueous solubilities of benzene may be affected by indirect ion-ion, ion-water, and water water correlations, too, these correlations are found to be unimportant, with little to no effect on the Setchenow salting-out coefficients of the various salts. We further considered LiCl, which is experimentally known to be a weaker salting-out agent than NaCl and KCl and, therefore, ranks at an unusual position within the Hofmeister cation series. The simulations indicate that hydrated Li(+) ions can take part of the benzene hydration shell while the other cations are repelled by it. This causes weaker Li(+) exclusion around the solute and a resulting, weaker salting-out propensity of LiCl compared to that of the other salts. Removing benzene-water and benzene-salt electrostatic interactions in the simulations does not affect this mechanism, which may therefore also explain the smaller effect of LiCl, as compared to that of NaCl or KCl, on aqueous solvation and hydrophobic interaction of nonpolar molecules. PMID- 24792436 TI - Tylvalosin exhibits anti-inflammatory property and attenuates acute lung injury in different models possibly through suppression of NF-kappaB activation. AB - Tylvalosin, a new broad-spectrum, third-generation macrolides, may exert a variety of pharmacological activities. Here, we report on its anti-oxidative and anti-inflammatory activity in RAW 264.7 macrophages and mouse treated with lipopolysaccharide (LPS) as well as piglet challenged with porcine reproductive and respiratory syndrome virus (PRRSV). Tylvalosin treatment markedly decreased IL-8, IL-6, IL-1beta, PGE2, TNF-alpha and NO levels in vitro and in vivo. LPS and PRRSV-induced reactive oxygen species (ROS) production, and the lipid peroxidation in mice lung tissues reduced after tylvalosin treatments. In mouse acute lung injury model induced by LPS, tylvalosin administration significantly attenuated tissues injury, and reduced the inflammatory cells recruitment and activation. The evaluated phospholipase A2 (PLA2) activity and the increased expressions of cPLA2-IVA, p-cPLA2-IVA and sPLA2-IVE were lowered by tylvalosin. Consistent with the mouse results, tylvalosin pretreatment attenuated piglet lung scores with improved growth performance and normal rectal temperature in piglet model induced by PRRSV. Furthermore, tylvalosin attenuated the IkappaBalpha phosphorylation and degradation, and blocked the NF-kappaB p65 translocation. These results indicate that in addition to its direct antimicrobial effect, tylvalosin exhibits anti-inflammatory property and attenuates acute lung injury through suppression of NF-kappaB activation. PMID- 24792437 TI - Anti-neoplastic activity of low-dose endothelial-monocyte activating polypeptide II results from defective autophagy and G2/M arrest mediated by PI3K/Akt/FoxO1 axis in human glioblastoma stem cells. AB - Glioblastoma multiforme (GBM) is a life-threatening brain tumor with fatal recurrence, for which glioblastoma stem cells (GSCs) are held responsible. Though endothelial-monocyte activating polypeptide-II (EMAP-II) has been confirmed as a possible antitumor agent that can induce apoptosis of endothelial cells and inhibit tumor angiogenesis, the direct cytotoxicity by EMAP-II on tumor cells and its underlying mechanism are largely unknown. In the present study, it was demonstrated that low-dose (0.05 nM) EMAP-II reduces cell viability and mitochondrial membrane potential in vitro. Likewise, EMAP-II suppressed tumor growth in GSC-xenografted mice. Though no apoptosis was detected, all these antitumor effects were attenuated when GSCs were pretreated with 3-methyladenine (3-MA). Analysis of EMAP-II-treated GSCs exhibited the morphological and biochemical changes typical of autophagy, which was further shown to be defective. Moreover, EMAP-II was found to suppress tumor growth by inducing G2/M arrest in GSCs. Our data further showed that EMAP-II inhibited PI3K/Akt activation with concomitant induction of FoxO1 activation. FoxO1 knockdown significantly attenuated the induction of autophagy and G2/M arrest. Excessive accumulation of lipid droplets was intriguingly detected by transmission electron microscope, which was accompanied by autophagosomes. Further investigation indicated that the transcriptional regulation of Atg2B by FoxO1 was responsible for the induction of autophagy and formation of lipid droplets. These results suggest that EMAP-II is an effective anticancer agent for glioblastoma therapy, which can induce direct growth suppression in GSCs through defective autophagy and G2/M arrest mediated by the PI3K/Akt/FoxO1 axis. PMID- 24792438 TI - Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes. AB - Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines such as interleukin 8 (IL-8) and interleukin-6 by human fibroblast-like synoviocytes from patients with rheumatoid arthritis (RAFLS). In those cells LPA was reported to induce IL-8 secretion through activation of various signaling pathways including p38 mitogen activated protein kinase (p38 MAPK), p42/44 MAPK, and Rho kinase. In addition to those pathways we report that mitogen- and stress-activated protein kinases (MSKs) known to be activated downstream of the ERK1/2 and p38 MAPK cascades and CREB are phosphorylated in response to LPA. The silencing of MSKs with small interfering RNAs and the pharmacological inhibitor of MSKs SB747651A shows a role for both MSK1 and MSK2 in LPA-mediated phosphorylation of CREB at Ser-133 and secretion of IL-8 and MCP-1. Whereas CREB inhibitors have off target effects and increased LPA-mediated IL-8 secretion, the silencing of CREB1 with short hairpin RNA significantly reduced LPA-induced chemokine production in RAFLS. Taken together the data clearly suggest that MSK1 and MSK2 are the major CREB kinases in RAFLS stimulated with LPA and that phosphorylation of CREB1 at Ser-133 downstream of MSKs plays a significant role in chemokine production. PMID- 24792439 TI - The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance. AB - Flavin-containing monooxygenases (FMOs) of mammals are thought to be involved exclusively in the metabolism of foreign chemicals. Here, we report the unexpected finding that mice lacking Fmos 1, 2 and 4 exhibit a lean phenotype and, despite similar food intake, weigh less and store less triglyceride in white adipose tissue (WAT) than wild-type mice. This is a consequence of enhanced whole body energy expenditure, due mostly to increased resting energy expenditure (REE). This is fuelled, in part, by increased fatty acid beta-oxidation in skeletal muscle, which would contribute to depletion of lipid stores in WAT. The enhanced energy expenditure is attributed, in part, to an increased capacity for exercise. There is no evidence that the enhanced REE is due to increased adaptive thermogenesis; instead, our results are consistent with the operation in WAT of a futile energy cycle. In contrast to FMO2 and FMO4, FMO1 is highly expressed in metabolic tissues, including liver, kidney, WAT and BAT. This and other evidence implicates FMO1 as underlying the phenotype. The identification of a novel, previously unsuspected, role for FMO1 as a regulator of energy homeostasis establishes, for the first time, a role for a mammalian FMO in endogenous metabolism. Thus, FMO1 can no longer be considered to function exclusively as a xenobiotic-metabolizing enzyme. Consequently, chronic administration of drugs that are substrates for FMO1 would be expected to affect energy homeostasis, via competition for endogenous substrates, and, thus, have important implications for the general health of patients and their response to drug therapy. PMID- 24792441 TI - Accurate segmentation of leukocyte in blood cell images using Atanassov's intuitionistic fuzzy and interval Type II fuzzy set theory. AB - In this paper automatic leukocyte segmentation in pathological blood cell images is proposed using intuitionistic fuzzy and interval Type II fuzzy set theory. This is done to count different types of leukocytes for disease detection. Also, the segmentation should be accurate so that the shape of the leukocytes is preserved. So, intuitionistic fuzzy set and interval Type II fuzzy set that consider either more number of uncertainties or a different type of uncertainty as compared to fuzzy set theory are used in this work. As the images are considered fuzzy due to imprecise gray levels, advanced fuzzy set theories may be expected to give better result. A modified Cauchy distribution is used to find the membership function. In intuitionistic fuzzy method, non-membership values are obtained using Yager's intuitionistic fuzzy generator. Optimal threshold is obtained by minimizing intuitionistic fuzzy divergence. In interval type II fuzzy set, a new membership function is generated that takes into account the two levels in Type II fuzzy set using probabilistic T co norm. Optimal threshold is selected by minimizing a proposed Type II fuzzy divergence. Though fuzzy techniques were applied earlier but these methods failed to threshold multiple leukocytes in images. Experimental results show that both interval Type II fuzzy and intuitionistic fuzzy methods perform better than the existing non-fuzzy/fuzzy methods but interval Type II fuzzy thresholding method performs little bit better than intuitionistic fuzzy method. Segmented leukocytes in the proposed interval Type II fuzzy method are observed to be distinct and clear. PMID- 24792440 TI - Assessment and treatment relevance in elderly glioblastoma patients. AB - Glioblastoma (GBM) is the most common malignant primary brain tumor. Its incidence continues to increase in the elderly because the older segment of the population is growing faster than any other age group. Most clinical studies exclude elderly patients, and "standards of care" do not exist for GBM patients aged >70 years. We review epidemiology, tumor biology/molecular factors, prognostic factors (clinical, imaging data, therapeutics), and their assessments as well as classic and specific endpoints plus recent and ongoing clinical trials for elderly GBM patients. This work includes perspectives and personal opinions on this topic. Although there are no standards of care for elderly GBM patients, we can hypothesize that (i) Karnofsky performance status (KPS), probably after steroid treatment, is one of the most important clinical factors for determining our oncological strategy; (ii) resection is superior to biopsy, at least in selected patients (depending on location of the tumor and associated comorbidities); (iii) specific schedules of radiotherapy yield a modest but significant improvement; (iv) temozolomide has an acceptable tolerance, even when KPS <70, and could be proposed for methylated elderly GBM patients; and (v) the addition of concomitant temozolomide to radiotherapy has not yet been validated but shows promising results in some studies, yet the optimal schedule of radiotherapy remains to be determined. In the future, specific assessments (geriatric, imaging, biology) and use of new endpoints (quality of life and toxicity measures) will aid clinicians in determining the balance of potential benefits and risks of each oncological strategy. PMID- 24792442 TI - Exploring the third dimension: volume electron microscopy comes of age. AB - Groundbreaking advances in volume electron microscopy and specimen preparation are enabling the 3-dimensional visualisation of specimens with unprecedented detail, and driving a gratifying resurgence of interest in the ultrastructural examination of cellular systems. Serial section techniques, previously the domain of specialists, are becoming increasingly automated with the development of systems such as the automatic tape-collecting ultramicrotome, and serial blockface and focused ion beam scanning electron microscopes. These changes are rapidly broadening the scope of biomedical studies to which volume electron microscopy techniques can be applied beyond the brain. Further innovations in microscope design are also in the pipeline, which have the potential to enhance the speed and quality of data collection. The recent introduction of integrated light and electron microscopy systems will revolutionise correlative light and volume electron microscopy studies, by enabling the sequential collection of data from light and electron imaging modalities without intermediate specimen manipulation. In doing so, the acquisition of comprehensive functional information and direct correlation with ultrastructural details within a 3 dimensional reference space will become routine. The prospects for volume electron microscopy are therefore bright, and the stage is set for a challenging and exciting future. PMID- 24792443 TI - Testes of Astyanax altiparanae: the Sertoli cell functions in a semicystic spermatogenesis. AB - The Astyanax altiparanae (lambari) is a South American freshwater fish belonging to the family Characidae. Although some authors have described reproductive aspects of this species, this is the first study about the morphology of the testes throughout the annual reproductive cycle of A. altiparanae. Fish spermatogenesis differs from that in mammals as it occurs in cysts whose borders are defined by cytoplasmic processes of Sertoli cells, thus creating a favorable environment for spermatogenesis. The functions commonly attributed to fish Sertoli cells were investigated using stereological, light and electron microscopy in A. altiparanae. Results showed that when the Sertoli cells of A. altiparanae are in contact with germ cells, they plan a support function that culminates in the production of spermatozoa. After releasing spermatozoa, modified Sertoli cells form the duct epithelium, transform into secretory cells and release a secretion into the duct lumen where spermatids and sperm are located. Thus, the present study revealed important aspects of the testes of A. altiparanae, and propose a sequence of functions played by the Sertoli cells in this species. PMID- 24792444 TI - Ultrastructure of the female reproductive apparatus of the egg parasitoid Gryon pennsylvanicum (Ashmead) (Hymenoptera, Platygastridae). AB - The growing interest in Leptoglossus occidentalis, the conifer seed bug pest accidentally introduced into Europe in the 1990s, led us to investigate the female reproductive structures of the hymenopteran platygastrid Gryon pennsylvanicum, which is its candidate antagonist for biological control programmes. Our study revealed a genital apparatus with some characteristic features, such as an unusual length of the oviduct (divided into a long proximal and a short distal tract), the absence of accessory glands and the presence of a spermatheca provided with a small spermathecal gland. The ultrastructural investigation revealed that the shorter part of the common oviduct is involved in ion uptake whereas the longer part has two cell types with secretory function: the former with dense bodies and the latter with granular particles. The secretory contents of both are released into the oviduct lumen. The granular particles are formed in a complex of modified endoplasmic reticulum and appear as virus-like particles. PMID- 24792445 TI - Computer aided measurement of melanoma depth of invasion in microscopic images. AB - This paper presents a novel computer aided technique for measurement of melanoma depth of invasion. Melanoma is the deadliest form of skin cancer with worldwide increasing incidences. For a conclusive diagnosis of melanoma, skin biopsies should be examined under a microscope. Visual inspection of microscopic samples is often subjective, time-consuming, cumbersome and prone to human errors. This fact demonstrates the necessity of developing an automated method which assists pathologists in evaluating histopathological samples more accurately in the busy clinical environment. To the best of our knowledge, this is the first time that a computer-assisted diagnosis algorithm has been applied in measurement of melanoma invasion depth. The proposed method uses a clustering algorithm for granular layer extraction and a pre-trained SVM classifier for detection of malignant melanocytes. The experimental results with average error of 3.9MUm demonstrate that the proposed method is reliable and effective. PMID- 24792446 TI - Analysis of the DNA Fourier transform-infrared microspectroscopic signature using an all-reflecting objective. AB - The Fourier transform-infrared (FT-IR) signature of dry samples of DNA and DNA polypeptide complexes, as studied by IR microspectroscopy using a diamond attenuated total reflection (ATR) objective, has revealed important discriminatory characteristics relative to the PO2(-) vibrational stretchings. However, DNA IR marks that provide information on the sample's richness in hydrogen bonds have not been resolved in the spectral profiles obtained with this objective. Here we investigated the performance of an "all reflecting objective" (ARO) for analysis of the FT-IR signal of hydrogen bonds in DNA samples differing in base richness types (salmon testis vs calf thymus). The results obtained using the ARO indicate prominent band peaks at the spectral region representative of the vibration of nitrogenous base hydrogen bonds and of NH and NH2 groups. The band areas at this spectral region differ in agreement with the DNA base richness type when using the ARO. A peak assigned to adenine was more evident in the AT rich salmon DNA using either the ARO or the ATR objective. It is concluded that, for the discrimination of DNA IR hydrogen bond vibrations associated with varying base type proportions, the use of an ARO is recommended. PMID- 24792447 TI - A method of correlative light and electron microscopy for yeast cells. AB - Correlative light and electron microscopy (CLEM) is a method of imaging in which the same specimen is observed by both light microscopy and electron microscopy. Specifically, CLEM compares images obtained by light and electron microscopy and makes a correlation between them. After the advent of fluorescent proteins, CLEM was extended by combining electron microscopy with fluorescence microscopy to enable molecular-specific imaging of subcellular structures with a resolution at the nanometer level. This method is a powerful tool that is used to determine the localization of specific molecules of interest in the context of subcellular structures. Knowledge of the localization of target proteins coupled with the functions of the structures to which they are localized yields valuable information about the molecular functions of these proteins. However, this method has been mostly applied to adherent cells due to technical difficulties in immobilizing non-adherent target cells, such as yeasts, during sample preparation. We have developed a method of CLEM applicable to yeast cells. In this report, we detail this method and present its extension to Live CLEM. The Live CLEM method enabled us to link the dynamic properties of molecules of interest to cellular ultrastructures in the yeast cell. Since yeasts are premier organisms in molecular genetics, combining CLEM with yeast genetics promises to provide important new findings for understanding the molecular basis of the function of cellular structures. PMID- 24792448 TI - Analytical electron microscopy of a crack tip extracted from a stressed Alloy 800 sample exposed to an acid sulfate environment. AB - Alloy 800 (Fe-21Cr-33Ni) has been found susceptible to cracking in acid sulfate environments, but the mechanism is not well understood. Alloy 800 C-ring samples were exposed to an acid sulfate environment at 315 degrees C and cracks were found with depths in excess of 300MUm after 60h. Preparation of a TEM sample containing crack tips is challenging, but the ability to perform high-resolution microscopy at the crack tip would lend insight to the mechanism of acid sulfate stress corrosion cracking (AcSCC). The lift-out technique combined with a focused ion beam sample preparation was used to extract a crack tip along the cross section of an acid sulfate crack in an Alloy 800 C-ring. TEM elemental analysis was done using EDS and EELS which identified a duplex oxide within the crack; an inner oxide consisting of a thin 3-4nm Cr-rich oxide and an outer oxide enriched in Fe and Cr. Preliminary conclusions and hypotheses resulted with respect to the mechanism of AcSCC in Alloy 800. PMID- 24792449 TI - The role of vaccination in the control of tuberculosis in badgers. PMID- 24792450 TI - Oral vaccination of badgers (Meles meles) against tuberculosis: comparison of the protection generated by BCG vaccine strains Pasteur and Danish. AB - Vaccination of badgers by the subcutaneous, mucosal and oral routes with the Pasteur strain of Mycobacterium bovis bacille Calmette-Guerin (BCG) has resulted in significant protection against experimental infection with virulent M. bovis. However, as the BCG Danish strain is the only commercially licensed BCG vaccine for use in humans in the European Union it is the vaccine of choice for delivery to badger populations. As all oral vaccination studies in badgers were previously conducted using the BCG Pasteur strain, this study compared protection in badgers following oral vaccination with the Pasteur and the Danish strains. Groups of badgers were vaccinated orally with 10(8) colony forming units (CFU) BCG Danish 1331 (n = 7 badgers) or 10(8) CFU BCG Pasteur 1173P2 (n = 6). Another group (n = 8) served as non-vaccinated controls. At 12 weeks post-vaccination, the animals were challenged by the endobronchial route with 6 * 10(3) CFU M. bovis, and at 15 weeks post-infection, all of the badgers were euthanased. Vaccination with either BCG strain provided protection against challenge compared with controls. The vaccinated badgers had significantly fewer sites with gross pathology and significantly lower gross pathological severity scores, fewer sites with histological lesions and fewer sites of infection, significantly lower bacterial counts in the thoracic lymph node, and lower bacterial counts in the lungs than the control group. No differences were observed between either of the vaccine groups by any of the pathology and bacteriology measures. The ELISPOT analysis, measuring production of badger interferon - gamma (IFN-gamma), was also similar across the vaccinated groups. PMID- 24792451 TI - Benefits of different urea supplementation methods on the production performances of Merino sheep. AB - The impact of urea supplementation of sheep feed was examined in two experiments. In Experiment 1, 48 8-month-old Merino wethers were randomised into three groups by liveweight and each group was fed one of three diets: (1) untreated oaten chaff hay; (2) hay treated with urea in-paddock (pre-experiment); or (3) hay treated with a 2% urea solution using a feed mixer. In Experiment 2, 48 4-month old Merino ewes were randomised into three groups and each group received one of the following roughages: (1) untreated oaten chaff hay, (2) hay treated with a 2% urea solution in a feed mixer, or (3) a 20 kg urea lick block. Both experiments lasted 40 days, and sheep liveweight (kg), average feed intake (g/day), average daily gain (ADG) and body condition score (BCS) were recorded. Ruminal fluid and blood samples were collected on days 20 and 40 from animals in Experiment 1. Sheep supplemented with additional urea had a greater average dry matter (DM) intake (Experiment 1, P = 0.038; Experiment 2, P = 0.001), ADG (Experiment 1, P = 0.043; Experiment 2, P = 0.041) and average final liveweight (Experiment 1, P = 0.048), compared to sheep receiving no additional supplementary urea. On both days 20 and 40 in Experiment 1, blood analyses revealed that urea supplemented sheep had elevated levels of urea, creatine kinase and total protein (P <0.05). Urea supplementation most likely influenced blood urea and total protein concentrations, as supplemented sheep had an increased crude protein intake (through increased feed intake of urea treated roughage with a higher crude protein percentage). By providing additional urea, the DM intake of sheep in both experiments was increased and offers a practical strategy when providing supplementation to sheep. The practice can benefit sheep production by increasing the nutritional value and digestibility of low energy crop stubbles, when fed over dry summer months to help maintain BCS. PMID- 24792452 TI - Prevalence of paunch calf syndrome carriers in Italian Romagnola cattle. AB - The term 'paunch calf syndrome' encompasses the multi-organic lethal developmental dysplasia reported in the Romagnola breed of cattle and is characterised by facial deformities, an enlarged and floating abdomen containing considerable abdominal effusion, and hepatic fibrosis. Paunch calf syndrome is caused by a missense mutation in the KDM2B gene (c.2503G>A) that is thought to lead to an amino acid exchange (p.D835N). In this study, the prevalence of carriers of the mutant KDM2B allele (and thus the frequency of the allele) was assessed in selected subpopulations of Romagnola cattle. The prevalence of carriers within top-ranked Romagnola sires over the years 2007-2012 was 29.3% (allele frequency 14.6%). In young bull calves, 30.9% were carriers with an allele frequency of 15.4%. PMID- 24792453 TI - Photodynamic therapy has antifungal effect and reduces inflammatory signals in Candida albicans-induced murine vaginitis. AB - BACKGROUND: Vaginal candidiasis (VC) is a disease that affects thousands of women of childbearing age, mainly caused by Candida albicans fungus. Photodynamic therapy (PDT) uses photosensitizing substances that are nontoxic in the dark, but able to produce reactive oxygen species when they are subjected to a light source. In this work our purpose was to investigate PDT effects on fungal burden and inflammatory cells in a murine model of C. albicans-induced vaginal candidiasis. METHODS: Female BALB/c mice 6-10 weeks were estrogenized and maintained in this state during all experiment. After 72h, mices were inoculated intravaginally (IV) with 20MUL of 2*10(5)C. albicans cells suspension. Mice were separated into 5 groups after five days: H (healthy), PBS (control), laser, MB (methylene blue) and PDT. PDT and MB groups received IV 20MUL solution with 1mM of MB, others received PBS. PDT and laser groups were irradiated with a red laser (100mW, 660nm) in one (36J, 6min) or two sessions (18J, 3min). After the end of treatment, mice were submitted to microbiological and histomorphometric analysis with ImageJ software. Data were plotted by mean values and standard deviations of CFU/mL and percentage of inflammatory cells area. ANOVA and Bonferroni post-test were used and data were considered significant when p<0.05. RESULTS: PDT significantly reduced C. albicans after the two tested protocols, however, percentage area of inflammatory cells was significantly reduced just with two sessions of PDT. CONCLUSIONS: PDT with MB and red laser is a promising therapy for VC. It is able to reduce fungal infection in biofilm and inflammatory signals associated with VC in a murine model of vaginitis. PMID- 24792454 TI - Endoluminal tracheal stenting prior to head and neck PDT. PMID- 24792455 TI - Evaluation of a third party enzymatic ammonia method for use on the Roche Cobas 6000 (c501) automated platform. AB - OBJECTIVE: Adaptation of the Randox Enzymatic Manual UV Ammonia method to be used on the Roche Cobas 6000 (c501) automated analyzer platform. DESIGN AND METHODS: The Randox ammonia reagent was evaluated for precision, linearity, accuracy and interference from hemolysis, icterus and lipemia on the Roche c501 analyzer. Comparison studies were conducted for the Randox reagent between Roche c501, Siemens Vista, Ortho Vitros 250, and Beckman DxC methods. RESULTS: The Randox reagent demonstrates acceptable within-run (L1=65 MUmol/L, CV 3.4% L2=168 MUmol/L, CV 1.9%) and between-run precision (L1=29 MUmol/L, CV 7.3% L2=102 MUmol/L, CV 3.0%), Analytical Measurement Range (7-940 MUmol/L), and accuracy. The method interference profile is superior for the Randox method (hemolysis index up to 600, icteric index up to 60, lipemic index up to 100) as compared to the Roche method (hemolysis index up to 200, icteric index up to 10, lipemic index up to 50). Comparison was very good between the Randox reagent and two other wet chemistry platforms. CONCLUSIONS: The Randox Enzymatic Manual UV Ammonia reagent is an available alternative to the Roche Cobas c501 reagent. The method is more robust to endogenous interferences and less prone to instrument error flags, thus allowing the majority of clinical specimens to be reported without additional sample handling at our institution. PMID- 24792456 TI - Marked effects of extreme levels of lipoprotein(a) on estimation of low-density lipoprotein cholesterol. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is usually calculated using the Friedewald equation. However, this calculation method does not account for the cholesterol associated with lipoprotein(a) [Lp(a)]. Using the Dahlen equation, Li et al. have shown a strong positive correlation between serum Lp(a) levels and overestimation of LDL-C levels. OBJECTIVE: To determine how the extreme levels of Lp(a) influence the LDL-C calculation. METHODS: We performed a retrospective chart review of the lipid profile and Lp(a) of 223 patients (men and women). LDL-C was calculated using the Friedewald equation. Lp(a) concentrations were measured by an ELISA. Other serum lipids were measured enzymatically by standard methodology. Corrected LDL-C was calculated using the Dahlen equation. RESULTS: We found that this overestimation is very significant in individuals with extreme levels of Lp(a) (mean overestimation of 40% at Lp(a) >1200mg/L). CONCLUSIONS: Calculated LDL-C is markedly overestimated in patients with extreme levels of Lp(a). PMID- 24792457 TI - Post-shock oversensing by a subcutaneous defibrillator resulting in inappropriate withholding of post-shock bradycardia pacing. PMID- 24792458 TI - [Noma and Burkitt disease; a particular association about three observations seen in the Teaching Hospital Center Yalgado Ouedraogo (Burkina Faso)]. AB - Cancrum oris is a gangrenous stomatitis arising from a periodontal infection and leading to severe soft tissue and bone destruction. The pathology involves numerous factors including local thrombosis, vascularitis, necrotizing gingivitis, immunodeficiency, Gram negative and anaerobic infection. It is usually a disease of infants and malnourished children in tropical areas often occurring after a debilitating disease like measles [3]. Burkitt lymphoma is a highly aggressive non-Hodgkin lymphoma first described by Burkitt in 1958 in African children from areas holoendemic for malaria. It is the first cancer of African child [6]. The association between Burkitt lymphoma and cancrum oris is non common. We report in the present study three cases of this association at the Academic Hospital Yalgado Ouedraogo of Ouagadougou. This association poses a problem of late diagnosis with difficulties in therapeutic management. PMID- 24792459 TI - [Zoon's balanitis in circumcised and HIV infected man, at Cotonou (Benin)]. AB - Balanitis of Zoon (BZ) characterized by an important plasma cell infiltration occurs exclusively in uncircumcised men aged between 40-80 years. We report here a case of BZ in an HIV infected patient who was circumcised since birth. A 43 year old man consulted in 2009 for itchy and not painful glans erosion evolving for one year. He is HIV1 infected and has been under didanosine, lamiduvine and nelfinavir for three years. Under this treatment, his CD4 count increased from 26 cells/mm(3) in 2007 to 206 cells/mm(3) at the time of the consultation. We noted after examination clean burgeoning erosion, red in places, pink in other places, with fuzzy boundary, sitting on the glans and extending into the preputial sulcus. Histopathology showed infiltration by sheets of plasma cells with perivascular topography in the dermis. The bacterial cultures and syphilis serology were negative. We noted a good outcome after four weeks of application of 3% oxytetracycline ointment. This observation suggests that the BZ can occur on a HIV infected patient whether he was circumcised or not. Thus, it appears fair to think of BZ faced with a chronic erosion of the glans in HIV infected patient. PMID- 24792460 TI - [Clinical-epidemiological profile of severe cutaneous drug reactions in children in Abidjan (Cote d'Ivoire)]. AB - Severe cutaneous drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life threatening in adults. They seem to be less common in children. The purpose of this study was to describe the epidemiological, clinical and etiological profile of these drug reactions in African child. It was about a retrospective study carried on for 10 years at the Dermatology center of University Hospital of Treichville, Abidjan (Cote d'Ivoire).Were included all children aged 0-15 years hospitalized for severe cutaneous drug reaction. They represented 14.1% (27 cases) with an estimated hospital rate of 0.01%. The sex ratio (M/F) was 1.2. The mean age was 10.3 years. 19 children were suffering from SJS (63%) and 9 children (33.3%) from TEN. Sulfonamides were the most commonly used drugs with sulfadoxin-pyrimethamin (25.9%), used for malariae, and cotrimoxazole (22.2%). Self-medication was practiced by 70.4% of parents. The average time to onset of lesions from drug intake was 8.2 days. Only one child was HIV infected. Three children affected by TEN (11.1%) died. PMID- 24792461 TI - Bad experiences in early childhood can lead to "health harming life course," study shows. PMID- 24792462 TI - Vascular effects of diphenylmethoxypiperidine-derived dopamine uptake inhibitors. AB - Vascular effects of 4-aryl methoxypiperidinol compounds previously shown to share with cocaine the ability to inhibit the dopamine transporter are described. All the compounds tested inhibit KCl-induced and noradrenaline-dependent contractions in mesenteric arteries ex vivo. Thus, diphenylpyraline and its analogs may have a role as therapeutic options for the treatment of some of the cardiotoxic effects of cocaine intoxications. PMID- 24792463 TI - Synthesis and radical-scavenging activity of a dimethyl catechin analogue. AB - Catechin analogue 1 with methyl substituents ortho to the catechol hydroxyl groups was synthesized to improve the antioxidant ability of (+)-catechin. The synthetic scheme involved a solid acid catalyzed Friedel-Crafts coupling of a cinnamyl alcohol derivative to 3,5-dibenzyloxyphenol followed by hydroxylation and then cyclization through an intermediate orthoester. The antioxidative radical scavenging activity of 1 against galvinoxyl radical, an oxyl radical, was found to be 28-fold more potent than (+)-catechin. PMID- 24792464 TI - Design and synthesis of 3,4-dihydro-2H-benzo[h]chromene derivatives as potential NF-kappaB inhibitors. AB - A novel class of NF-kappaB inhibitors were designed and synthesized based on KL 1156 (6-hydroxy-7-methoxychroman-2-carboxylic acid phenyl amide) which is unambiguously considered to be a promising inhibitor for the translocation step of NF-kappaB. Especially in this study we focused on the modifying the chroman moiety of KL-1156 into four parts for exploring the SAR studies linked with physical properties of substituents resulted the development of novel 1a-k, 2a-f, 3a-d and 4a-d derivatives of 3,4-dihydro-2H-benzo[h]chromene. From the SAR studies we were very delightfully identified that several new N-aryl-3,4-dihydro 2H-benzo[h]chromene-2-carboxamide derivatives (1a-k) exhibited good inhibitory activity and anti-proliferative activity than parent lead compound KL-1156, among them 1i exhibited outstanding inhibitory effect on LPS-induced NF-kappaB transcriptional activity and anti-proliferative activity on NCI-H23 lung cancer cell lines than KL-1156. PMID- 24792465 TI - Synthesis and biological evaluation of (+)-neopeltolide analogues: importance of the oxazole-containing side chain. AB - We describe the synthesis and biological evaluation of (+)-neopeltolide analogues with structural modifications in the oxazole-containing side chain. Evaluation of the antiproliferative activity of newly synthesized analogues against A549 human lung adenocarcinoma cells and PANC-1 human pancreatic carcinoma cells have shown that the C19-C20 and C26-C27 double bonds within the oxazole-containing side chain and the terminal methyl carbamate group are essential for potent activity. PMID- 24792469 TI - Factors affecting UV/H2O2 inactivation of Bacillus atrophaeus spores in drinking water. AB - This study aims at estimating the performance of the Bacillus atrophaeus spores inactivation by the UV treatment with addition of H2O2. The effect of factors affecting the inactivation was investigated, including initial H2O2 dose, UV irradiance, initial cell density, initial solution pH and various inorganic anions. Under the experimental conditions, the B. atrophaeus spores inactivation followed both the modified Hom Model and the Chick's Model. The results revealed that the H2O2 played dual roles in the reactions, while the optimum reduction of 5.88lg was received at 0.5mM H2O2 for 10min. The inactivation effect was affected by the UV irradiance, while better inactivation effect was achieved at higher irradiance. An increase in the initial cell density slowed down the inactivation process. A slight acid condition at pH 5 was considered as the optimal pH value. The inactivation effect within 10min followed the order of pH 5>pH 7>pH 9>pH 3>pH 11. The effects of three added inorganic anions were investigated and compared, including sulfate (SO4(2)(-)), nitrate (NO3(-)) and carbonate (CO3(2)(-)). The sequence of inactivation effect within 10min followed the order of control group>SO4(2)(-)>NO3(-)>CO3(2)(-). PMID- 24792468 TI - Depletion of PKM2 leads to impaired glycolysis and cell death in 2-demethoxy-2,3 ethylenediamino hypocrellin B-photoinduced A549 cells. AB - 2-Demethoxy-2,3-ethylenediamino hypocrellin B (EDAHB) is an efficient photosensitizer that mediates cancer cell apoptosis. In order to better understand the molecular mechanisms involved in its antitumour activity, we used proteomics technology to identify candidate targets in A549 cells using EDAHB mediated photodynamic therapy (EDAHB-PDT). The protein profile changes between untreated and PDT-treated A549 cells were analysed using two-dimensional polyacrylamide gel electrophoresis (2-DE). Differentially expressed protein spots were identified using matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometry; and 15 differentially expressed proteins (over 2-fold, p<0.05) were identified in PDT-treated A549 cells compared with untreated cells. Among them, the expression of pyruvate kinase M2 (PKM2), a key enzyme involved in glycolysis, was found to be significantly decreased in A549 cells following EDAHB PDT. Transient ectopic over-expression of PKM2 attenuated death of EDAHB-PDT treated A549 cells, whereas knockdown of PKM2 expression by RNA interference increased the photocytotoxicity of EDAHB. Moreover, a decrease in lactate production was detected in PDT-treated A549 cells. These observations suggest that PKM2 plays an important role in the antitumour action of EDAHB-PDT; thus, it may be a potential molecular target to increase the efficacy of PDT in cancer therapy. PMID- 24792470 TI - Opening of brain blood barrier induced by red light and central analgesic improvement of cobra neurotoxin. AB - Cobra neurotoxin (NT) has central analgesic effects, but it is difficult to pass through brain blood barrier (BBB). A novel method of red light induction is designed to help NT across BBB, which is based on photosensitizer activation by red light to generate reactive oxygen species (ROS) to open BBB. The effects were evaluated on cell models and animals in vivo with illumination by semiconductor laser at 670nm on photosensitizer pheophorbide isolated from silkworm excrement. Brain microvascular endothelial cells and astrocytes were co-cultured to build up BBB cell model. The radioactivity of (125)I-NT was measured in cells and tissues for NT permeation. Three ways of cranial irradiation, nasal cavity and intravascular irradiation were tested with combined injection of (125)I-NT 20MUg/kg and pheophorbide 100MUg/kg to rats, and organs of rats were separated and determined the radioactivity. Paw pressure test in rats, hot plate and writhing test in mice were applied to appraise the analgesic effects. NT across BBB cell model increased with time of illumination, and reached stable level after 60min. So did ROS in cells. NT mainly distributed in liver and kidney of rats, significantly increased in brain after illumination, and improved analgesic effects. Excitation of pheophorbide at red light produces ROS to open BBB, help NT enter brain, and enhance its central action. This research provides a new method for drug across BBB to improve its central role. PMID- 24792471 TI - Measurement of photodegradation-caused roughness of wood using a new optical method. AB - The aim of this study was to clarify the intensity of the surface roughening of wood caused by light radiation using a fast optical method. The samples were irradiated by mercury lamp and the roughness change was monitored traditionally using a perthometer. The infrared (IR) diffuse reflectance spectrum was measured and the baseline shift was found to be a proper parameter to monitor the roughening effect of photodegradation. Linear correlation was found between the traditionally measured roughness and the baseline shift. This newly developed optical method is able to detect the degradation difference between earlywood and latewood. Some of the samples were immersed in distilled water for a day after an all light irradiation period of two days. This new baseline shift method was able to visualise and determine the small change in roughness caused by the leaching effect of water. PMID- 24792472 TI - Cyclooxygenase 2-mediated apoptotic and inflammatory responses in photodynamic therapy treated breast adenocarcinoma cells and xenografts. AB - Cyclooxygenase 2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation and the development of cancer, and promotes neoplastic transformation, in response to chemical carcinogens and environmental stresses. In this study, we demonstrated that a sublethal dose photodynamic therapy (PDT) led to inflammatory response mediated by the induction of COX-2 and release of Prostaglandin E2 (PGE2). Pretreatment with N-acetylcysteine (NAC) reduced COX-2 expression and PGE2 release induced by PDT. The elevated COX-2 level and PGE2 release following PDT were inhibited by NADPH oxidase inhibitor and NF-kappaB inhibitor. Inhibition of COX-2 attenuated the levels of PGE2 and vascular endothelial growth factor (VEGF) following PDT in treated tumors, and also decreased the expression of proinflammatory mediators interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha). In addition, PDT led to an appreciable accumulation of pSer15-p53/COX-2 complexes, and this association of complexes was partially inhibited by SB203580, an inhibitor of p38. Blockage of COX-2 expression by siRNA enhanced the transcriptional activity of p53, and facilitated PDT-induced loss of mitochondrial membrane potential and cleavage of caspase 3, probably due to the elevated Noxa expression disrupting the interaction of Mcl-1/Bax. Together, this study highlights the important roles of COX-2 in PDT-induced apoptosis and inflammation and the specific COX-2-mediated responses to PDT initiated by reactive oxygen species (ROS) involving the regulation of the multiple signaling pathways. These results indicate the inflammatory mediator COX-2 as a potential therapeutic target for improving PDT efficacy. PMID- 24792473 TI - Gaussian processes retrieval of leaf parameters from a multi-species reflectance, absorbance and fluorescence dataset. AB - Biochemical and structural leaf properties such as chlorophyll content (Chl), nitrogen content (N), leaf water content (LWC), and specific leaf area (SLA) have the benefit to be estimated through nondestructive spectral measurements. Current practices, however, mainly focus on a limited amount of wavelength bands while more information could be extracted from other wavelengths in the full range (400 2500nm) spectrum. In this research, leaf characteristics were estimated from a field-based multi-species dataset, covering a wide range in leaf structures and Chl concentrations. The dataset contains leaves with extremely high Chl concentrations (>100MUgcm(-2)), which are seldom estimated. Parameter retrieval was conducted with the machine learning regression algorithm Gaussian Processes (GP), which is able to perform adaptive, nonlinear data fitting for complex datasets. Moreover, insight in relevant bands is provided during the development of a regression model. Consequently, the physical meaning of the model can be explored. Best estimates of SLA, LWC and Chl yielded a best obtained normalized root mean square error of 6.0%, 7.7%, 9.1%, respectively. Several distinct wavebands were chosen across the whole spectrum. A band in the red edge (710nm) appeared to be most important for the estimation of Chl. Interestingly, spectral features related to biochemicals with a structural or carbon storage function (e.g. 1090, 1550, 1670, 1730nm) were found important not only for estimation of SLA, but also for LWC, Chl or N estimation. Similar, Chl estimation was also helped by some wavebands related to water content (950, 1430nm) due to correlation between the parameters. It is shown that leaf parameter retrieval by GP regression is successful, and able to cope with large structural differences between leaves. PMID- 24792474 TI - Pretreatment with alternation of light/dark periods improves the tolerance of tobacco (Nicotiana tabacum) to clomazone herbicide. AB - This work analyses the effects of alternation of light/dark periods pretreatment (AL) in tobacco plantlets (Nicotiana tabacum L. cv.Virginie vk51) growing in solution with low concentration of the clomazone herbicide. The experimentation has been carried out by exposing the plantlets to successive and regulated periods of light (16min light/8min dark cycles, PAR 50MUmolm(-2)s(-1)) for three days. The photosynthesis efficiency was determined by mean of the chlorophyll fluorescence and JIP-test. The AL pretreatment improved the clomazone tolerance; this has been observed by the increase in the leaf area of the plant, the maximal photochemical quantum efficiency of PSII (Fv/Fm), the actual PSII efficiency (FPSII), the performance index (PIabs), the electron flux beyond Quinone A (1 VJ), and also by the diminution of the energy dissipating into heat (DI0/RC). Furthermore, AL pretreatment led to low accumulation of hydrogen peroxide (H2O2) which proves that the scavenging enzymatic system have been activated before clomazone treatment. In the plantlets pretreated with AL, with regard to the ascorbate content, some of antioxidant enzyme whose function is associated with it have continued to scavenge reactive oxygen species (ROS) induced by clomazone, such as ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR), monodehydroascorbate reductase (MDHAR) and glutathione reductase (GR). So, the observed photooxidative damages induced by clomazone herbicide were noticeably reduced. PMID- 24792476 TI - Interaction of 9-O-N-aryl/arylalkyl amino carbonyl methyl berberine analogs with single stranded ribonucleotides. AB - Studies on the molecular aspects of alkaloid-RNA complexation are of prime importance for the development of rational RNA targeted drug design strategies. Towards this goal, the binding aspects of three novel 9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogs to four single stranded ribonucleotides, poly(G), poly(I), poly(C) and poly(U), were studied for the first time employing multifaceted biophysical tools. Absorbance and fluorescence studies revealed that these analogs bound non-cooperatively to poly(G) and poly(I) with binding affinities remarkably higher than berberine. The binding of these analogs to poly(U) and poly(C) was weaker in comparison to poly(G) and poly(I) but were one order higher in comparison to berberine. Quantum efficiency values revealed that energy transfer occurred from the RNA bases to the analogs upon complexation. The binding was dominated by large positive entropic contributions and small but favorable enthalpic contributions. Salt dependent studies established that the binding was dominated by hydrophobic forces that contributed around 90% of the total standard molar Gibbs energy. The chain length of the substitution at the 9-position was found to be critical in modulating the binding affinities. These results provide new insights into the binding efficacy of these novel berberine analogs to single stranded RNA sequences. PMID- 24792475 TI - Low level laser therapy reduces acute lung inflammation in a model of pulmonary and extrapulmonary LPS-induced ARDS. AB - The present study aimed to investigate the effects low level laser therapy (LLLT) in a LPS-induced pulmonary and extrapulmonary acute respiratory distress syndrome (ARDS) in BALB/c mice. Laser (830nm laser, 9J/cm(2), 35mW, 80s per point, 3 points per application) was applied in direct contact with skin, 1h after LPS administration. Mice were distributed in control (n=6; PBS), ARDS IT (n=7; LPS orotracheally 10MUg/mouse), ARDS IP (n=7; LPS intra-peritoneally 100MUg/mouse), ARDS IT+Laser (n=9; LPS intra-tracheally 10MUg/mouse), ARDS IP+Laser (n=9; LPS intra-peritoneally 100MUg/mouse). Twenty-four hours after last LPS administration, mice were studied for pulmonary inflammation by total and differential cell count in bronchoalveolar lavage (BAL), cytokines (IL-1beta, IL 6, KC and TNF-alpha) levels in BAL fluid and also by quantitative analysis of neutrophils number in the lung parenchyma. LLLT significantly reduced pulmonary and extrapulmonary inflammation in LPS-induced ARDS, as demonstrated by reduced number of total cells (p<0.001) and neutrophils (p<0.001) in BAL, reduced levels of IL-1beta, IL-6, KC and TNF-alpha in BAL fluid and in serum (p<0.001), as well as the number of neutrophils in lung parenchyma (p<0.001). LLLT is effective to reduce pulmonary inflammation in both pulmonary and extrapulmonary model of LPS induced ARDS. PMID- 24792477 TI - The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia. AB - Fibromyalgia typically presents with spontaneous body pain with no apparent cause and is considered pathophysiologically to be a functional disorder of somatosensory processing. We have investigated potential associations between the degree of self-reported clinical pain and resting-state brain functional connectivity at different levels of putative somatosensory integration. Resting state functional magnetic resonance imaging was obtained in 40 women with fibromyalgia and 36 control subjects. A combination of functional connectivity based measurements were used to assess (1) the basic pain signal modulation system at the level of the periaqueductal gray (PAG); (2) the sensory cortex with an emphasis on the parietal operculum/secondary somatosensory cortex (SII); and (3) the connectivity of these regions with the self-referential "default mode" network. Compared with control subjects, a reduction of functional connectivity was identified across the 3 levels of neural processing, each showing a significant and complementary correlation with the degree of clinical pain. Specifically, self-reported pain in fibromyalgia patients correlated with (1) reduced connectivity between PAG and anterior insula; (2) reduced connectivity between SII and primary somatosensory, visual, and auditory cortices; and (3) increased connectivity between SII and the default mode network. The results confirm previous research demonstrating abnormal functional connectivity in fibromyalgia and show that alterations at different levels of sensory processing may contribute to account for clinical pain. Importantly, reduced functional connectivity extended beyond the somatosensory domain and implicated visual and auditory sensory modalities. Overall, this study suggests that a general weakening of sensory integration underlies clinical pain in fibromyalgia. PMID- 24792478 TI - Shoelace Breast Cast. AB - Implant malposition after breast augmentation surgery remains a common complication. Several surgical options exist to correct the resultant deformity; however, all involve additional risks, costs, and the increased potential for patient dissatisfaction. In my practice, I have developed a nonsurgical therapy using shoelaces, which, when tied and placed in a certain fashion, can correct this deformity. When worn continuously, the shoelaces act as an external breast cast that allows the inframammary fold to be set and heal in the correct position. I have achieved great success in using this nonsurgical technique, and it allows me to be aggressive in cases where I need to raise the inframammary fold because I know that I can easily correct if the fold is lowered too much. PMID- 24792479 TI - One-Stage Augmentation Mastopexy: A Review of 1192 Simultaneous Breast Augmentation and Mastopexy Procedures in 615 Consecutive Patients. AB - BACKGROUND: Despite the increasing popularity of the combined augmentation mastopexy procedure among patients, the safety and efficacy of this surgery have been questioned by many surgeons. OBJECTIVE: The authors investigated the safety and efficacy of the combined augmentation mastopexy procedure. METHODS: The authors retrospectively reviewed the medical records of 615 consecutive patients who underwent combined augmentation mastopexy procedures at a single outpatient surgery center from 1992 through 2011. Patient demographics, operative and implant details, and long-term outcomes were analyzed. Rates of complications and revisions were calculated. RESULTS: The most common complications were poor scarring (5.7%), wound-healing problems (2.9%), and deflation of saline implants (2.4%). Of the 615 patients evaluated, 104 (16.9%) elected to undergo revision surgery: 54 revision procedures were secondary to implant-related complications, and 50 were secondary to tissue-related complications. Our data compare favorably with previously reported revision rates for breast augmentation alone and mastopexy alone. CONCLUSIONS: With a skilled surgeon and proper patient selection, the combined augmentation mastopexy procedure can be safe and effective. LEVEL OF EVIDENCE: 4. PMID- 24792480 TI - Transaxillary Nonendoscopic Subpectoral Augmentation Mammaplasty: A 10-Year Experience With Gel vs Saline in 2000 Patients-With Long-Term Patient Satisfaction Measured by the BREAST-Q. AB - BACKGROUND: Transaxillary augmentation mammaplasty (TAM) is an option for patients who wish to avoid a visible breast incision from breast augmentation (BA). OBJECTIVES: The authors compared TAM outcome data for gel and saline implants and evaluated patient satisfaction using the BREAST-Q patient-reported outcome measure (BQ). METHODS: In this 10-year retrospective, comparative, and cross-sectional study, the authors reviewed results of saline implants placed with TAM in a surgeon's practice during the final 5 years of the moratorium of the US Food and Drug Administration (phase 1) and compared them with results for gel and saline implants placed with TAM during the 5 years after the moratorium (phase 2). Outcomes were assessed for the entire BA study population (n = 2430 for primary BA; 4860 implants); 670 patients completed and returned the BQ, from which postoperative satisfaction was evaluated. RESULTS: BQ responses demonstrated a high rate of patient satisfaction, with outcomes comparable to those of other studies. The differences between the median BQ-assessed breast satisfaction and outcome satisfaction scores in the axillary and nonaxillary surgical groups were statistically significant, favoring axillary over nonaxillary. The difference in mean satisfaction scores was marginally significant between the 2 types of implants, favoring silicone gel. The incidence of surgical revision was 7.5% for the entire BA study population and 6.8% for the patients who underwent TAM. CONCLUSIONS: TAM produces long-term patient satisfaction as measured by the BQ. Complication rates are similar to those of other studies. In the present study, patients who underwent TAM and thus had hidden incisions were more satisfied than patients whose incisions were visible. LEVEL OF EVIDENCE: 3. PMID- 24792481 TI - Risk of cutaneous malignant melanoma in patients with celiac disease: a population-based study. AB - BACKGROUND: Celiac disease (CD) carries an increased risk of several malignancies, including cancers of the gastrointestinal tract and hematologic malignancies. The disease course of cutaneous malignant melanoma (CMM) is affected by the immune status of the host, and therefore may be associated with CD. OBJECTIVE: We sought to test for an association between CD and CMM in a population-based setting. METHODS: We queried all (n = 28) pathology departments in Sweden and identified patients with intestinal histology consistent with CD. Each patient was matched to up to 5 control subjects by age, gender, calendar period, and region. Using Cox proportional hazards, we tested for an association between CD and the subsequent diagnosis of CMM. RESULTS: Among patients with CD (n = 29,028), 78 subsequently developed CMM (0.3%). Compared with control subjects there was no significant association between CD and CMM (hazard ratio 0.94, 95% confidence interval 0.73-1.20). This null association was similar for men (hazard ratio 0.99, 95% confidence interval 0.68-1.44) and women (hazard ratio 0.89, 95% confidence interval 0.64-1.24), and in all age strata. LIMITATIONS: Lack of data regarding undiagnosed CD is a limitation. CONCLUSION: In this population-based study we found no association between CD and the subsequent diagnosis of CMM. Prior studies showing a positive association between these 2 entities may have been a result of referral bias. PMID- 24792482 TI - Chemotherapy treatment patterns and neutropenia management in gastric cancer. AB - BACKGROUND: Potentially myelosuppressive doublet and triplet chemotherapy combination regimens are considered the most active treatments in gastric cancer. This multicenter prospective observational study was designed to gain insight into the chemotherapy regimens being used in Europe and to evaluate neutropenia management in patients identified as at high risk for febrile neutropenia (FN). METHODS: Eligible patients had gastric cancer, were scheduled for >= 3 cycles of myelosuppressive chemotherapy, and had an investigator-assessed overall FN risk >= 20%. Data were collected for up to ten cycles. The primary endpoint was the proportion of patients who received granulocyte colony stimulating factor (G-CSF) primary prophylaxis (defined as G-CSF initiated on days 1-7 of cycle 1). Secondary endpoints included FN incidence, chemotherapy administration, and G-CSF use. RESULTS: Of 199 patients who met the eligibility criteria and started at least one cycle of chemotherapy, mean age was 63 years, 76% were men, 83% had an ECOG score of 0 or 1, 54% had metastatic disease, and 24% had received prior chemotherapy. A total of 27 different backbone regimens were given; the most common regimen was modified docetaxel, cisplatin, and 5-fluorouracil (DCF). Despite all patients having been identified as having a >= 20% FN risk, only 70 (35%) received G-CSF primary prophylaxis. FN occurred in 14 patients overall (7%). Most FN events occurred in patients who received DCF/modified DCF (9/14 events, 64%). CONCLUSIONS: The results of this study reveal a high use of myelotoxic treatment regimens in gastric cancer in Europe and low adherence to clinical practice guidelines for the use of primary and secondary G-CSF prophylaxis for FN. PMID- 24792483 TI - Differences between patients with chronic musculoskeletal pain treated in an inpatient or an outpatient multidisciplinary rehabilitation program. AB - Multidisciplinary rehabilitation for patients with chronic musculoskeletal pain can be provided on an inpatient or on an outpatient basis, but the rationale for choosing between the two programs is unknown. The aim of the study was to identify differences between patients provided inpatient or outpatient rehabilitation. It was a cross-sectional study within usual care. The study included 415 adult rehabilitation patients with chronic musculoskeletal pain with complex psychosocial problems. The measurements used were demographics, Short Form 36 Health Survey, Dutch Personality Questionnaire, Coping with Pain Questionnaire, Tampa Scale of Kinesiophobia, Symptom Checklist 90-Revised. In the multiple logistic analysis, five variables remained significantly different between inpatients and outpatients: inpatients were less likely to have a child aged less than 12 years and to have neck pain; their physical and social functioning were poorer; and their current pain period had lasted longer. The total explained variance was 26%. Five variables were identified as influencing the decision on inpatient or outpatient rehabilitation, but the explained variance was low. PMID- 24792484 TI - Maternal inheritance of twist and analysis of MAPK activation in embryos of the polychaete annelid Platynereis dumerilii. AB - In this study, we aimed to identify molecular mechanisms involved in the specification of the 4d (mesentoblast) lineage in Platynereis dumerilii. We employ RT-PCR and in situ hybridization against the Platynereis dumerilii twist homolog (Pdu-twist) to reveal mesodermal specification within this lineage. We show that Pdu-twist mRNA is already maternally distributed. After fertilization, ooplasmatic segregation leads to relocation of Pdu-twist transcripts into the somatoblast (2d) lineage and 4d, indicating that the maternal component of Pdu twist might be an important prerequisite for further mesoderm specification but does not represent a defining characteristic of the mesentoblast. However, after the primordial germ cells have separated from the 4d lineage, zygotic transcription of Pdu-twist is exclusively observed in the myogenic progenitors, suggesting that mesodermal specification occurs after the 4d stage. Previous studies on spiral cleaving embryos revealed a spatio-temporal correlation between the 4d lineage and the activity of an embryonic organizer that is capable to induce the developmental fates of certain micromeres. This has raised the question if specification of the 4d lineage could be connected to the organizer activity. Therefore, we aimed to reveal the existence of such a proposed conserved organizer in Platynereis employing antibody staining against dpERK. In contrast to former observations in other spiralian embryos, activation of MAPK signaling during 2d and 4d formation cannot be detected which questions the existence of a conserved connection between organizer function and specification of the 4d lineage. However, our experiments unveil robust MAPK activation in the prospective nephroblasts as well as in the macromeres and some micromeres at the blastopore in gastrulating embryos. Inhibition of MAPK activation leads to larvae with a shortened body axis, defects in trunk muscle spreading and improper nervous system condensation, indicating a critical function for MAPK signaling for the reorganization of embryonic tissues during the gastrulation process. PMID- 24792485 TI - Perspectives of drug-based neuroprotection targeting mitochondria. AB - Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. PMID- 24792486 TI - Diffuse intrinsic pontine glioma: a reassessment. AB - Diffuse intrinsic pontine glioma (DIPG) is a disease of childhood whose abysmal prognosis has remained unchanged for over 50 years. Biologic investigation has been stymied by lack of pretreatment tissue, as biopsy has been reserved for atypical cases. Recent advances in surgical and molecular-analytic techniques have increased the safety and potential utility of biopsy; brainstem biopsy has now been incorporated into several prospective clinical trials. These and other recent efforts have yielded new insights into DIPG molecular pathogenesis, and opened new avenues for investigation. PMID- 24792487 TI - Pediatric posterior fossa ganglioglioma: unique MRI features and correlation with BRAF V600E mutation status. AB - Ganglioglioma (GG) is a rare pediatric brain tumor (1-4 %) with neoplastic glial and neuronal cells. Posterior fossa GGs (PF GGs) occur less frequently than supratentorial GGs (ST GGs). The BRAF V600E mutation has been reported in GGs and carries therapeutic implications. We compare the presenting symptoms, magnetic resonance imaging, BRAF V600E mutation status, treatment, and prognosis in children with ST and PF GGs. The neuro-oncology database at a tertiary care Children's Hospital was retrospectively reviewed from 1995 to 2010 for patients with ST and PF GG. All available imaging was reviewed. Symptoms, BRAF V600E mutation status, treatment, and survival data were collected from the electronic medical record and analyzed. Our series consisted of 11 PF GG and 20 ST GG. Children with PF GG presented with ataxia, cranial nerve deficits and long tract signs whereas the majority with ST GGs presented with seizures. On imaging, PF GGs were infiltrative and expansile solid masses with dorsal predominant "paintbrush" enhancement whereas ST GGs were well circumscribed mixed solid and cystic masses with heterogeneous enhancement. Five of 11 (45%) PF GGs and 6 of 9 (67%) ST GGs expressed the BRAF V600E mutation. No unique imaging features were identified in BRAF V600E mutation positive tumors. The majority of ST GGs were treated with surgery alone, whereas the majority of PF GGs required multimodality therapy. PF GGs had worse progression-free survival and a higher mortality rate compared with ST GGs. Unlike ST GGs, PF GGs are expansile, infiltrative, show dorsal predominant "paintbrush" enhancement, are not amenable to gross total resection, and have worse progression-free survival and mortality. PMID- 24792488 TI - Stereotactic radiosurgery compared with external radiation therapy as a primary treatment in spine metastasis from renal cell carcinoma: a multicenter, matched pair study. AB - The aim of this multicenter, matched- pair study was to compare the outcome of stereotactic radiosurgery (SRS) with that of external radiation therapy (RT) when used as a primary treatment in spine metastasis from renal cell carcinoma (RCC). From 2005 to 2012, 13 patients underwent SRS as a primary treatment in spine metastasis from RCC. Thirteen patients who underwent RT as the primary treatment of RCC spine metastasis were paired with the SRS patients based on age, number of spine metastasis, time interval from original tumor diagnosis to spine metastasis, Eastern Cooperative Oncology Group status, and year of treatment. The primary outcomes of interest were pain relief and progression free survival. Secondary outcomes were treatment toxicities and need for further treatment. The perioperative VAS score decrease was larger in the SRS group than that in the RT group (P = 0.04). More SRS patients had complete or partial pain relief although the difference was not significant. There was a significant difference in progression free survival between the two groups (P = 0.01). The percentage of patients with toxicities was 38.5 % (5/13) in the SRS group and 53.9 % (7/13) in the RT group, but the difference was not significant. There were 2 SRS patients and 3 RT patients who received further intervention at the index segment. This study showed that, when performed as a primary treatment in spine metastasis from RCC, SRS provides relatively better pain relief and better local control than that obtained from RT. PMID- 24792489 TI - Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations. AB - Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway. PMID- 24792490 TI - EMPACT syndrome: limited evidence despite a high-risk cohort. AB - Serious dermatologic adverse events such as erythema multiforme (EM) and Stevens Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) have been reported in patients receiving antiepileptic drugs (AEDs) and cranial radiotherapy (RT). Given the frequency of AED-associated rashes and the infrequency of serious dermatologic adverse events after cranial RT, we sought to further assess the prevalence of cutaneous eruptions in patients receiving an AED before and after cranial RT. We reviewed medical records of patients taking AEDs while undergoing RT for a high-grade glioma and recorded demographic, disease, and treatment parameters, as well as the development of rashes. Rashes were found in 19 % of patients taking AEDs. Phenytoin was most commonly implicated (93 %) in rash formation compared with other AEDs (P < 0.0001), both before and during RT. Most rashes (76 %) occurred before starting RT (P < 0.0001). However, of those during RT, most were associated with phenytoin compared with other AEDs (P = 0.002). One case of SJS was noted in a patient receiving phenytoin prior to RT. While rashes were slightly less prevalent in patients receiving temozolomide compared with those not receiving temozolomide (3.4 vs 4.8 %), this difference was not statistically significant (P = 0.65). Rashes are relatively common in patients receiving AEDs, with the highest incidence associated with phenytoin. However, the risk of serious dermatologic events is low. There did not appear to be an association between the receipt of cranial radiotherapy and the development of AED-associated rash with phenytoin or other AEDs. PMID- 24792491 TI - FRK suppresses the proliferation of human glioma cells by inhibiting cyclin D1 nuclear accumulation. AB - The Fyn related kinase (FRK) is a noteworthy member of the Src non-receptor tyrosine kinase family for its distinctive tumor suppressive function. Recently, we have shown that FRK plays a protective role against the progression of glioma by suppressing cell migration and invasion. However, it is unclear whether the cell growth of glioma is also regulated by FRK and by which mechanism FRK alters its specific biological functions. In the current study, we found that FRK over expression significantly suppressed the proliferation of glioma cells. In contrast, FRK knockdown by siRNA promoted glioma cell growth. In addition, FRK over-expression caused G1 phase arrest as well as apoptosis of glioma cells. Further investigation disclosed that FRK-induced G1 arrest was accompanied by down-regulation of hyperphosphorylated retinoblastoma protein (pRb), which led to the consequent suppression of E2F1. More importantly, we found that over expression of FRK inhibited proper cyclin D1 accumulation in the nucleus of proliferating cells. Taken together, our results demonstrate a combined mechanism for the anti-proliferative effects of FRK by inhibiting cyclin D1 nucleus accumulation and pRb phosphorylation in glioma cells. PMID- 24792492 TI - Use of agent-based simulations to design and interpret HIV clinical trials. AB - In this study, we illustrate the utility of an agent-based simulation to inform a trial design and how this supports outcome interpretation of randomized controlled trials (RCTs). We developed agent-based Monte Carlo models to simulate existing landmark HIV RCTs, such as the Partners in Prevention HSV/HIV Transmission Study. We simulated a variation of this study using valacyclovir therapy as the intervention, and we used a male circumcision RCT based on the Rakai Male Circumcision Trial. Our results indicate that a small fraction (20%) of the simulated Partners in Prevention HSV/HIV Transmission Study realizations rejected the null hypothesis, which was no effect from the intervention. Our results also suggest that an RCT designed to evaluate the effectiveness of a more potent drug regimen for HSV-2 suppression (valacyclovir therapy) is more likely to identify the efficacy of the intervention. For the male circumcision RCT simulation, the greater biological effect of the male circumcision yielded a major fraction (81%) of RCT realizations' that rejects the null hypothesis, which was no effect from the intervention. Our study highlights how agent-based simulations synthesize individual variation in the epidemiological context of the RCT. This methodology will be particularly useful for designing RCTs aimed at evaluating combination prevention interventions in community-based RCTs, wherein an intervention's effectiveness is challenging to predict. PMID- 24792493 TI - Gait variability and stability measures: minimum number of strides and within session reliability. AB - BACKGROUND: Several methods are proposed in the literature for the quantification of gait variability/stability from trunk accelerations. Since outputs can be influenced by implementation differences, reliability assessment and standardization of implementation parameters are still an issue. The aim of this study is to assess the minimum number of required strides and the within-session reliability of 11 variability/stability measures. METHOD: Ten healthy participants walked in a straight line at self-selected speed wearing two synchronized tri-axial Inertial Measurement Units. Five variability measures were calculated based on stride times namely Standard deviation, Coefficient of variation, Inconsistency of variance, Nonstationary index and Poincare plot. Six stability measures were calculated based on trunk accelerations namely Maximum Floquet multipliers, Short term/long term Lyapunov exponents, Recurrence quantification analysis, Multiscale entropy, Harmonic ratio and Index of harmonicity. The required minimum number of strides and the within-session reliability for each measure were obtained based on the interquartile range/mean ratio. Measures were classified in five categories (namely excellent, good, average, poor, and very poor) based on their reliability. RESULTS: The number of strides required to obtain a reliable measure was generally larger than those conventionally used. Variability measures showed average to poor reliability, while stability measures ranged from excellent to very poor reliability. CONCLUSION: Recurrence quantification analysis and multiscale entropy of trunk accelerations showed excellent reliability and a reasonable number of required strides. Based on these results, these measures should be taken into consideration in the assessment of fall risk. PMID- 24792494 TI - The polyketide synthase gene pks4 is essential for sexual development and regulates fruiting body morphology in Sordaria macrospora. AB - Filamentous ascomycetes have long been known as producers of a variety of secondary metabolites, many of which have toxic effects on other organisms. However, the role of these metabolites in the biology of the fungi that produce them remains in most cases enigmatic. A major group of fungal secondary metabolites are polyketides. They are chemically diverse, but have in common that their chemical scaffolds are synthesized by polyketide synthases (PKSs). In a previous study, we analyzed development-dependent expression of pks genes in the filamentous ascomycete Sordaria macrospora. Here, we show that a deletion mutant of the pks4 gene is sterile, producing only protoperithecia but no mature perithecia, whereas overexpression of pks4 leads to enlarged, malformed fruiting bodies. Thus, correct expression levels of pks4 are essential for wild type-like perithecia formation. The predicted PKS4 protein has a domain structure that is similar to homologs in other fungi, but conserved residues of a methyl transferase domain present in other fungi are mutated in PKS4. Expression of several developmental genes is misregulated in the pks4 mutant. Surprisingly, the development-associated app gene is not downregulated in the mutant, in contrast to all other previously studied mutants with a block at the protoperithecial stage. Our data show that the polyketide synthase gene pks4 is essential for sexual development and plays a role in regulating fruiting body morphology. PMID- 24792496 TI - Effects of dexmedetomidine on P2X4Rs, p38-MAPK and BDNF in spinal microglia in rats with spared nerve injury. AB - Microglia in the spinal cord is evidenced to play a crucial role in neuropathic pain. Spinal P2X4 receptors (P2X4Rs), which are mainly expressed in microglia, have been investigated for their roles in neuropathic pain. Dexmedetomidine (DEX), a highly selective agonist of alpha2-adrenergic receptors, is clinically applied to sedation and analgesia. Despite the proposed mechanisms underlying DEX induced analgesia, the possible interactions between DEX and P2X4Rs at a molecular level have not been elucidated. We designated the spared nerve injury (SNI) to establish the neuropathic pain model. Mechanical paw withdrawal threshold (MWT) was measured to evaluate the sensitivity of neuropathic pain in rats. MWT was significantly decreased in SNI rats versus control rats. Expressions of spinal P2X4Rs, phosphorylated p38-mitogen-activated protein kinase (p-p38-MAPK) and brain-derived neurotrophic factor (BDNF) were upregulated in SNI rats. Immunofluorescence assay indicated higher densities of microglia and P2X4Rs, which appeared yellow in colour, suggesting they were co-labelled. Intraperitoneal injections of DEX 40MUg/kg for 14 consecutive days markedly reversed the SNI-induced decline of MWT; the activation of microglia was markedly inhibited; in addition, the protein expressions of P2X4Rs, p-p38-MAPK and BDNF were significantly downregulated. Thus, DEX could attenuate the neuropathic pain in SNI rats, of which the mechanism might be related to the down-expressed P2X4Rs, p-p38 and BDNF in microglia of spinal dorsal horn. PMID- 24792495 TI - The role of carbon starvation in the induction of enzymes that degrade plant derived carbohydrates in Aspergillus niger. AB - Fungi are an important source of enzymes for saccharification of plant polysaccharides and production of biofuels. Understanding of the regulation and induction of expression of genes encoding these enzymes is still incomplete. To explore the induction mechanism, we analysed the response of the industrially important fungus Aspergillus niger to wheat straw, with a focus on events occurring shortly after exposure to the substrate. RNA sequencing showed that the transcriptional response after 6h of exposure to wheat straw was very different from the response at 24h of exposure to the same substrate. For example, less than half of the genes encoding carbohydrate active enzymes that were induced after 24h of exposure to wheat straw, were also induced after 6h exposure. Importantly, over a third of the genes induced after 6h of exposure to wheat straw were also induced during 6h of carbon starvation, indicating that carbon starvation is probably an important factor in the early response to wheat straw. The up-regulation of the expression of a high number of genes encoding CAZymes that are active on plant-derived carbohydrates during early carbon starvation suggests that these enzymes could be involved in a scouting role during starvation, releasing inducing sugars from complex plant polysaccharides. We show, using proteomics, that carbon-starved cultures indeed release CAZymes with predicted activity on plant polysaccharides. Analysis of the enzymatic activity and the reaction products, indicates that these proteins are enzymes that can degrade various plant polysaccharides to generate both known, as well as potentially new, inducers of CAZymes. PMID- 24792497 TI - Adolescent form of sporadic lymphangioleiomyomatosis (S-LAM). PMID- 24792498 TI - Herpes simplex virus type 1 encephalitis after meningioma resection. PMID- 24792500 TI - Reach and Grasp reconfigurations reveal that proprioception assists reaching and hapsis assists grasping in peripheral vision. AB - The dual visuomotor channel theory proposes that prehension consists of a Reach that transports the hand in relation to an object's extrinsic properties (e.g., location) and a Grasp that shapes the hand to an object's intrinsic properties (e.g., size and shape). In central vision, the Reach and the Grasp are integrated but when an object cannot be seen, the movements can decompose with the Reach first used to locate the object and the Grasp postponed until it is assisted by touch. Reaching for an object in a peripheral visual field is an everyday act, and although it is reported that there are changes in Grasp aperture with target eccentricity, it is not known whether the configuration of the Reach and the Grasp also changes. The present study examined this question by asking participants to reach for food items at 0 degrees or 22.5 degrees and 45 degrees from central gaze. Participants made 15 reaches for a larger round donut ball and a smaller blueberry, and hand movements were analyzed using frame-by frame video inspection and linear kinematics. Perception of targets was degraded as participants could not identify objects in peripheral vision but did recognize their differential size. The Reach to peripheral targets featured a more dorsal trajectory, a more open hand, and less accurate digit placement. The Grasp featured hand adjustments or target manipulations after contact, which were associated with a prolonged Grasp duration. Thus, Grasps to peripheral vision did not consist only of a simple modification of visually guided reaching but included the addition of somatosensory assistance. The kinematic and behavioral changes argue that proprioception assists the Reach and touch assists the Grasp in peripheral vision, supporting the idea that Reach and Grasp movements are used flexibly in relation to sensory guidance depending upon the salience of target properties. PMID- 24792502 TI - Gaze and posture coordinate differently with the complexity of visual stimulus motion. AB - In this study, we explored whether gaze and posture would exhibit coordination with the motion of a presented visual stimulus, specifically with regard to the complexity of the motion structure. Fourteen healthy adults viewed a set of four visual stimulus motion conditions, in both self-selected and semi-tandem stance, during which the stimulus moved horizontally across a screen, with position updated to follow a sine, chaos, surrogate, or random noise trajectory. Posture was measured using a standard force platform in self-selected and semi-tandem stance conditions while gaze was recorded using image-based eye-tracking equipment. Cross-correlation confirmed the continuous coordination of gaze with each type of stimulus motion, with increasing lag as stimulus motion complexity increased. Correlation dimension and approximate entropy were used to assess the complexity of the measured gaze and posture behaviors, with these values compared against those of the actual stimulus via ANOVA and dependent t tests. We found that gaze behavior was particularly sensitive to the complexity of the stimulus motion, according to both metrics. Posture seemed to be unaffected by stimulus motion viewing; however, different stance conditions did exhibit differences in posture metrics. Our results support an evolving understanding of how vision is used for determining perception and action. PMID- 24792501 TI - Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration. AB - Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies. PMID- 24792499 TI - Anticipatory nausea in animal models: a review of potential novel therapeutic treatments. AB - Cancer patients undergoing chemotherapy continue to experience the debilitating side effect of nausea associated with their treatment. Although acute and delayed vomiting have become well managed with the advent of the 5-hydroxytryptamine-3 antagonists, such as ondansetron, and the neurokinin-1 receptor antagonists (such as aprepitant), nausea is still a relatively unmanaged adverse side effect of chemotherapy treatment. When nausea and vomiting are not properly managed, patients are at a greater risk of developing anticipatory nausea (AN)--a conditional association between chemotherapy-related treatment cues, such as the clinic environment, and the subsequent nausea experienced. Once it develops, AN is refractive to pharmacological treatment with classic antiemetics. Currently, non-specific antianxiety drugs (benzodiazepines) are prescribed; however, their sedating side effects are undesirable. Here, we review the animal models of AN that have been developed. These preclinical models have aided researchers in the evaluation of potentially efficacious pharmacological treatments for AN. Accumulating evidence using animal models demonstrates that cannabinoid compounds effectively reduce AN, without producing sedation. These results highlight the need for human clinical trials evaluating the efficacy of these compounds. PMID- 24792503 TI - The role of the parasympathetic nervous system in visually induced motion sickness: systematic review and meta-analysis. AB - The parasympathetic nervous system (PNS) has been implicated in the development of visually induced motion sickness. The objective of this study was to perform a systematic review and meta-analysis of the effect of visually induced motion sickness on validated parameters of PNS tone. Methods followed PRISMA recommendations. Controlled trials reporting validated measures of PNS tone in visually induced motion sickness in healthy adults were included. One reviewer performed the screening of articles and data extraction, and two reviewers independently performed methodological evaluation. Data were synthesised using standardised mean differences (SMDs) for all relevant outcomes using a random effects model. Publication bias was assessed via funnel plots and Egger's test. The search strategy identified seven citations comprising 237 healthy individuals. The mean quality score was 4/10 (range 3-7). There was no difference between baseline PNS tone between individuals who developed visually induced motion sickness and those that did not. Visually induced motion sickness (VIMS) sensitive individuals had a reduction in PNS tone, following exposure to the stimulus (mean weighted SMD = -0.45, 95% confidence interval -0.64 to -0.27, Z = 4.8, p < 0.0001). There was no evidence of heterogeneity or publication bias. These data suggest that baseline PNS parameters do not provide a useful measure of predicting the probability of developing visually induced motion sickness. However, a fall in PNS tone, as indicated by cardiac activity, is characteristic in sensitive individuals. Further work is needed to characterise these responses in clinical populations, in conjunction with improvements and standardisation in study design. PMID- 24792504 TI - An Internet survey of marijuana and hot shower use in adults with cyclic vomiting syndrome (CVS). AB - Cyclic vomiting syndrome (CVS) is a chronic disorder characterized by episodic nausea and vomiting. A large proportion of patients use marijuana to control their symptoms. Several case reports implicate marijuana as a cause of intractable vomiting with compulsive hot water bathing considered pathognomonic of "cannabinoid hyperemesis." We sought to examine the relationship between marijuana use and CVS. Patients >18 years of age diagnosed by a health care provider were invited to participate in an anonymous internet-based survey. A total of 514 patients participated and 437 completed questions about marijuana use. Mean age was 34 +/- 12 years with patients being predominantly female (63%), Caucasian (92%) and from the USA (82%). Nineteen percent never used marijuana and 81% did. Fifty-four percent used marijuana for health issues and 43% for recreational purposes. Users stated that it improved nausea, appetite, general well-being, stress levels and vomiting. Users were more likely to be male and have an associated anxiety disorder. Sixty-seven percent of patients reported taking hot showers/baths for symptom relief, and this was associated with marijuana use. (OR 2.54, CI 1.50-4.31, P = 0.0006). Eighty-one percent of patients with CVS who completed an internet survey reported frequent use of marijuana. With marijuana use, patients noted the greatest improvement with stress levels, appetite and nausea. Marijuana users were more likely to be male and have associated anxiety. Hot showers were not pathognomonic of marijuana use though they were more likely to be associated with its use. PMID- 24792505 TI - Genetic factors associated with pharmacotherapy and background sensitivity to postoperative and chemotherapy-induced nausea and vomiting. AB - Postoperative nausea and vomiting (PONV) continues to be a most common complication of surgery and anesthesia. It has been suggested that the inherited factors may play a significant role in the background sensitivity to both PONV and also chemotherapy-induced nausea and vomiting (CINV), including resistance to antiemetic prophylaxis and/or therapy. This notion could be best exemplified by occurrence of PONV in several generations of families and concordance of PONV in monozygotic twins. The most frequently addressed issue in the research on genomic background of PONV/CINV relates to the inherited resistance to the antiemetic treatment (pharmacogenomics), and in lesser degree to their genomic background. The most common group of antiemetics consists of 5HT3 receptor antagonists, and this group was an initial target of pharmacogenomic research. Most research approaches have been based on the investigation of polymorphic variations in the target for the antiemetic 5HT3 receptor antagonists, i.e., serotonin receptor subunits A and B (HTR3A and HTR3B). The other area of pharmacogenomic investigations includes metabolic pathways of 5HT3 antagonists, in particular polymorphic variants of the CYP450 2D6 isoform (CYP2D6) because most of them are metabolized in various degrees by the CYP2D6 system. The results of targeted genomic association studies indicate that other genes are also associated with PONV and CINV, including OPRM1, and ABCB1. In addition, genes such as DRD2 and CHRM3 genes have recently been associated with PONV. The new genome-wide association studies seem also to indicate that the background genomic sensitivity to PONV and CINV might be multifactorial and include several genomic pathways. PMID- 24792506 TI - Effects of old age and resource demand on double-step adaptation of saccadic eye movements. AB - It is still unknown whether adaptation of saccades--like that of arm movements deteriorates in the presence of a concurrent resource--demanding task, and whether it is affected by old age. We therefore compared double-step adaptation of saccade directions in young and older persons exposed to the adaptation task only (groups CY & CO), to the adaptation task and a spatially adjacent manual tracking task (AY & AO) or to the adaptation task and a spatially distant manual tracking task (DY & DO). Adaptation was similar in all groups except DO: the latter group showed no consistent adaptation and no adequate aftereffects. Tracking improved little by practice in all groups except AY, where the improvement was substantial. Our data therefore provide no evidence for an impact of old age and resource demand on saccadic adaptation, possibly because the neural substrate partly differs from that for arm adaptation. The lack of adaptation in DO probably reflects the well-known shrinkage of the functional field of view in old age. PMID- 24792507 TI - Bimanual and unimanual length perception. AB - From previous studies, it is unclear how bimanual length discrimination differs from unimanual length discrimination. To investigate the difference, we designed an experiment with four conditions. In the first two conditions, unimanual and bimanual discrimination thresholds are determined. In the third and fourth conditions, length is explored with the two index fingers like in the bimanual condition, but the reference is either internal, by clasping the hands together, or external, by grasping handles connected to the table. We find that thresholds for the unimanual condition (7.0%) and the clasping condition (9.2%) are both lower than for the bimanual condition (16%) and the grasping handles condition (15%). We conclude that when discriminating length unimanually and bimanually while clasping the hands together, the internal reference within the hand can be used and that explains the lower discrimination thresholds. PMID- 24792509 TI - Commentary on: why was there no mention of informed consent and ethics committee approval in a prospective trial? PMID- 24792508 TI - Signet ring cell type and other histologic types: differing clinical course and prognosis in T1 gastric cancer. AB - BACKGROUND: The behavior of early stage signet ring cell carcinoma (SRC) is controversial. The purpose of this study was to clarify the behavior of early gastric SRC. METHODS: We retrospectively analyzed data from 2,085 patients who had undergone curative gastrectomy for early gastric cancer between 1989 and 2000. Clinicopathologic outcomes and prognoses were evaluated, and we investigated whether these variables were correlated with histopathologic type. RESULTS: Patients with early gastric SRC were younger and had a greater proportion of females than other histologic types. Lymph node metastasis was the only independent prognostic factor for both mucosal and submucosal forms of SRC. Mucosal SRC had a similar rate of lymph node metastasis to poorly differentiated (PD) tubular adenocarcinoma (TUB), and a higher rate than well-differentiated (WD) or moderately differentiated (MD)-TUB. However, its submucosal form had a similar rate of lymph node metastasis to WD-TUB, and a lower rate than MD- or PD TUB. There was no difference in tumor recurrence or disease-related death according to histopathologic type or depth of invasion. CONCLUSION: In mucosal gastric cancer, SRC has an unfavorable risk factor of lymph node metastasis than that of others and should not be considered for endoscopic resection. In submucosal gastric cancer, SRC is a more favorable risk factor of lymph node metastasis than that of other histologic types. PMID- 24792510 TI - Commentary on: escalation of care and failure to rescue: a multicenter, multiprofessional qualitative study. PMID- 24792511 TI - Reply to "comment on: video-assisted ablation of pilonidal sinus: a new minimally invasive treatment-a pilot study". PMID- 24792512 TI - Novel quasi-subgenotype D2 of hepatitis B virus identified in Taiwanese aborigines. AB - The hepatitis B virus (HBV) genomes in Taiwanese aborigines, whose ancestors have lived in Taiwan for over 10,000 years, have not been characterized. In order to characterize of HBV in this special population, serum samples were obtained from serologically HBsAg-positive 27 Taiwanese aborigines. The pre-S1/S2 region and the full-length 3.2 kb of the HBV genome were amplified by PCR. Obtained amplicons were sequenced and confirmed the HBV genotypes by phylogenetic analysis. By phylogenetic analysis of the sequence of pre-S1/pre-S2 region, HBV/B2 (21/27: 78 %) was the most prevalent followed by genotype D (6/27: 22 %). Two strains of HBV/B2, each having 3,215 bp genomes, had recombination with genotype C in the pre-C/C gene which is characteristic of subgenotype B2 circulating in Southeast Asia. Interestingly, six strains of genotype D formed a distinct cluster between subgenotypes D1 and D2 suggesting a novel group of HBV. A similar finding could also be confirmed based on the entire 3,182 bp genome from four strains of HBV/D. This new cluster was supported by a branch with 99 % bootstrap value and 3.4-5.8 % nucleotide divergence over the entire genome from other known subgenotypes D1 to D9. Four strains of the new D subgenotype showed serotype ayw2, but had unique amino acid sequences consisting of N115 in the preS/S gene; P41 in the X gene; S239, K/E295, V567, and P708 in the P gene, respectively. From the above results, we provisionally proposed to designate it as novel quasi-subgenotype D2 identified in Taiwanese aborigines. PMID- 24792513 TI - Complete genome analysis of human enterovirus B73 isolated from an acute flaccid paralysis patient in Shandong, China. AB - Human enterovirus B73 (EV-B73) is a member of species Enterovirus B. To date, only one complete genome sequence of prototype strain CA55-1988 from California has been available. In this study, the complete genome analysis of an EV-B73 strain 088/SD/CHN/04 isolated from an acute flaccid paralysis case in Shandong Province, China in 2004 is conducted. It had 75.6 and 79.3 % nucleotide similarity with prototype strain CA55-1988 in the VP1 coding region and the complete genome, respectively. It had great VP1 nucleotide divergence (16.7-24.4 %) with EV-B73 strains from other parts of the world. Similarity plot and bootscanning analyses provided evidence of recombination with other EV-B viruses. PMID- 24792514 TI - Complete sequence and phylogenetic analysis of a porcine sapovirus strain isolated from western China. AB - Sapovirus (SaV) is a type of calicivirus that can cause acute viral gastroenteritis in humans and animals. SaVs have been found in several mammalian species, including humans, pigs, minks, dogs, and bats. Porcine sapovirus (PoSaV) was first identified in 1980 in the United States and has been found to be circulating throughout China in recent years. In this study, the complete genomic characterization of PoSaV CH430, first found in west China, was reported and analyzed. The genome was 7,342 bp excluding the 30 nt poly(A) tail at the 3' terminus and comprised two major open reading frames. Comprehensive evolutionary and phylogenetic analyses indicated that the CH430 strain belongs to genotype III SaVs. However, this particular isolate and DG24 strain occupied an independent branch of the phylogenetic tree we generated, indicating that they could form a separate subgenotype in the near future. We predicted the cleavage sites for the ORF1 polyprotein located at Q56/G57, Q310/A311, E649/A650, E934/A935, E1047/G1048, and E1712/A1713, separately. This is the first PoSaV strain isolated from western China to be fully sequenced and characterized. It provided a reliable experimental basis for studying the genetic nature of emerging PoSaVs. PMID- 24792515 TI - Fat saturation in dynamic breast MRI at 3 Tesla: is the Dixon technique superior to spectral fat saturation? A visual grading characteristics study. AB - PURPOSE: To intra-individually compare the diagnostic image quality of Dixon and spectral fat suppression at 3 T. METHODS: Fifty consecutive patients (mean age 55.1 years) undergoing 3 T breast MRI were recruited for this prospective study. The image protocol included pre-contrast and delayed post-contrast spectral and Dixon fat-suppressed T1w series. Two independent blinded readers compared spectral and Dixon fat-suppressed series by evaluating six ordinal (1 worst to 5 best) image quality criteria (image quality, delineation of anatomical structures, fat suppression in the breast and axilla, lesion delineation and internal enhancement). Breast density and size were assessed. Data analysis included Spearman's rank correlation coefficient and visual grading characteristics (VGC) analysis. RESULTS: Four examinations were excluded; 48 examinations in 46 patients were evaluated. In VGC analysis, the Dixon technique was superior regarding image quality criteria analysed (P < 0.01). Smaller breast size and lower breast density were significantly (P < 0.01) correlated with impaired spectral fat suppression quality. No such correlation was identified for the Dixon technique, which showed reconstruction-based water-fat mixups leading to insufficient image quality in 20.8%. CONCLUSIONS: The Dixon technique outperformed spectral fat suppression in all evaluated criteria (P < 0.01). Non diagnostic examinations can be avoided by fat and water image reconstruction. The superior image quality of the Dixon technique can improve breast MRI interpretation. KEY POINTS: Optimal fat suppression quality is necessary for optimal image interpretation. Superior fat suppression quality is achieved using the Dixon technique. Lesion margin and internal enhancement evaluation improves using the Dixon technique. Superior image quality of the Dixon technique improves breast MRI interpretation. PMID- 24792517 TI - Cytotoxic effect of hemin in colonic epithelial cell line: involvement of 18 kDa translocator protein (TSPO). AB - AIMS: The aim of this study is to investigate the effect of hemin in colonic epithelial cells (Caco-2) cell proliferation and if this effect was due to a direct modulation of 18-kDa translocator protein (TSPO) and/or heme oxygenase type 1 (HO-1). MAIN METHODS: The main methods are as follow: cell proliferation and cell cytotoxic assays on Caco-2 cell lines treated with hemin in the presence or not of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3 isoquinolinecarboxamide (PK 11195) and Sn-protoporphyrin IX (Sn-PPIX), and immunoblotting for TSPO and HO-1 protein analysis, siRNA directed against TSPO. KEY FINDINGS: Hemin was shown to be toxic for the Caco-2 cell line in a concentration and time dependent manner. Although hemin was able to induce HO-1 in a dose dependent manner, a specific HO-1 inhibitor, Sn-PPIX, was unable to interfere with the effect of hemin on Caco-2 cells. Instead, PK 11195, a specific TSPO ligand, was able to counteract the effect of hemin, suggesting an important role of TSPO in the hemin activity. Cell viability assay further confirms the high cytotoxic effects exerted by hemin on Caco-2 cells expressing TSPO compared to the siRNA-TSPO targeted cells. In addition, hemin was able to decrease significantly the TSPO protein density in a dose dependent manner after 24h of incubation. SIGNIFICANCE: The interaction and the consecutive down regulation of TSPO by hemin played an important role in the control of Caco-2 cell viability. The presented data suggest that TSPO might contribute to protect cells from potential toxic compounds such as free tetrapyrroles, candidating this receptor as a survival receptor protein. PMID- 24792516 TI - Post-transcriptional regulation by miR-137 underlies the low abundance of CAR and low rate of bilirubin clearance in neonatal mice. AB - AIM: Jaundice, potentially fatal encephalopathy, is common in approximately two thirds of all well term infants. It is largely due to low expression of constitutive androstane receptor (CAR) in newborns; however, the mechanisms for this low expression were poorly understood. MATERIALS AND METHODS: Expression of miR-137 and CAR was compared between neonatal and adult mice and between healthy and a mouse model of obstructive jaundice (OJ) using real-time RT-PCR and Western blot methods. Rate of bilirubin clearance was measured. DNA methylation of miR 137 was analyzed. KEY FINDINGS: Inverse expressions of miR-137 and CAR were consistently observed between newborn and adult mice, with a significantly higher miR-137 level and lower CAR protein and mRNA levels in neonatal liver than in adult liver. Similar reciprocal relationship was found existing between adult OJ mice and healthy control animals with a higher miR-137 level and lower CAR protein and mRNA levels in OJ than in healthy mice. Forced expression of miR-137 in primary hepatocytes repressed CAR protein levels, which was prevented by the inhibitor of miR-137. Knockdown of endogenous miR-137 by its inhibitor increased the rate of bilirubin clearance in OJ mice. Finally, we found that miR-137 was epigenetically over-activated due to hypomethylation in neonatal mice and in adult OJ mice, relative to adult healthy animals. SIGNIFICANCE: Our findings indicate that miR-137 is a repressor of CAR and thus a critical determinant of bilirubin clearance and may be considered a molecular target for the treatment of neonatal hyperbilirubinemia. PMID- 24792518 TI - MicroRNA1 modulates oxLDL-induced hyperlipidemia by down-regulating MLCK and ERK/p38 MAPK pathway. AB - AIMS: This study was aimed to determine whether microRNA1 (miR1) plays a role in the activation of myosin light chain kinase (MLCK) mediated by oxLDL in human umbilical vein endothelial cells (HUVECs). MAIN METHODS: HUVECs were treated with oxLDL along with a control miR or miR1 mimic. MiR1 expression was assayed by miRNA plate assay kit and mirVanaTM miRNA isolation kit. The MLCK protein, transcript, and kinase activity were measured by Western blot, real-time polymerase chain reaction and gamma-(32)P-ATP phosphate incorporation, respectively. In addition, phosphorylation of MLC, ERK and p38 was analyzed by Western blot. KEY FINDINGS: The results showed that upon treatment with oxLDL, miR1 expression was decreased, whereas MLCK expression was increased, in a time- and dose-dependent manner. Consistent with this, miR1 mimic prevented MLCK expression and activation and attenuated the phosphorylation of MLC and ERK/p38 in oxLDL-treated HUVECs. Furthermore, we showed that miR1 was able to bind a site located at the 3'un-translational region of MLCK mRNA and inhibited its expression. SIGNIFICANCE: Taken together, this study demonstrated that the effect of miR1 on hyperlipidemia is mediated through down-regulation of MLCK and the ERK/p38 MAPK pathway. PMID- 24792519 TI - Antiangiogenic and finasteride therapies: responses of the prostate microenvironment in elderly mice. AB - AIMS: The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice. MAIN METHODS: 90 male FVB mice were divided into: Young (18 weeks old) and senile (52 weeks old) groups; finasteride group: finasteride (20mg/kg); SU5416 group: SU5416 (6 mg/kg); TNP-470 group: TNP-470 (15 mg/kg,) and SU5416+TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21 days, prostate ventral lobes were collected for morphological, immunohistochemical and Western blotting analyses. KEY FINDINGS: The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and endostatin reactivities, and an increase for ER alpha, ER-beta and VEGF, were seen in the senile group. Decreased VEGF and ER alpha reactivities and increased ER-beta reactivity were verified in the finasteride, SU5416 groups and especially in SU5416+TNP-470 group. The TNP-470 group showed reduced AR and ER-beta protein levels. SIGNIFICANCE: The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416+TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-beta. PMID- 24792520 TI - Fish oil constituent eicosapentaenoic acid inhibits endothelin-induced cardiomyocyte hypertrophy via PPAR-alpha. AB - AIMS: A growing body of evidence shows the cardiovascular benefits of fish oil ingredients, including eicosapentaenoic acid (EPA), in humans and experimental animals. However, the effects of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy and the involved signaling cascade are largely unknown. A previous study has demonstrated that peroxisomal proliferator-activated receptor (PPAR) alpha ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Although EPA is a ligand of PPAR-alpha, to date, no study has examined a relationship between EPA and PPAR-alpha in cardiomyocyte hypertrophy. Here, we investigated whether EPA can block ET-1-induced cardiomyocyte hypertrophy and the possible underlying mechanisms. MAIN METHODS: At day 4 of culture, neonatal rat cardiomyocytes were divided into four groups: control, control cells treated with EPA (10 MUM), ET-1 (0.1 nM) administered only and EPA-pre-treated ET-1 administered groups. Also, the cardiomyocytes were treated with PPAR-alpha siRNA in order to elucidate the mechanisms that may underlie suppression of hypertrophy via the EPA-PPAR system. KEY FINDINGS: Following ET-1 treatment, 2.12- and 1.92 fold increases in surface area and total protein synthesis rate in cardiomyocytes, respectively, were observed and these changes were greatly blocked by EPA pre-treatment. Further, the expression of PPAR-alpha increased in EPA-treated groups. PPAR-PPRE binding activity was suppressed in ET-1 administered cardiomyocyte and this suppression was improved by EPA treatment. Lastly, pre-treatment of cardiomyocytes with PPAR-alpha siRNA prior to EPA treatment attenuated the suppressing effects of EPA on cardiomyocyte hypertrophy. SIGNIFICANCE: In conclusion, the present study shows that EPA attenuates ET-1 induced cardiomyocyte hypertrophy by up regulating levels of PPAR-alpha pathway. PMID- 24792521 TI - The role of the prefrontal cortex in the development of muscle fatigue in Charcot Marie-Tooth 1A patients. AB - This study aimed at comparing both peripheral and central mechanisms of muscle fatigue between Charcot-Marie-Tooth 1A patients and healthy individuals during a fatiguing voluntary task by simultaneous electromyographic and electroencephalographic recordings. Six Charcot-Marie-Tooth 1A patients (3 females, 40+/-11 years) and 6-matched healthy individuals performed four blocks of sub-maximal isometric knee extensions. At the beginning of the session and after each block, electrically-evoked maximal single-twitch, maximal voluntary contraction and surface-electromyography of the vastus lateralis muscle were measured. The movement-related-cortical potentials were averaged in early (block 1-2) and late (block 3-4) stages of fatigue. The effect of fatigue was demonstrated at peripheral level by the decline of maximal voluntary contraction, maximal twitch and surface electromyography amplitude and at central level by the larger amplitude of movement-related-cortical-potentials during late than early stage of fatiguing sub-maximal contractions. Charcot-Marie-Tooth 1A patients showed lower motor cortex activity during motor planning, with earlier onset and larger prefrontal cortex activity during the late stage of the fatiguing task than healthy controls. These data demonstrate the key role of the prefrontal cortex in the development of fatigue in Charcot-Marie-Tooth 1A patients, which may be activated as a compensatory mechanism for the low motor cortex activation, thus reflecting high awareness of movement complexity. PMID- 24792522 TI - Peripheral myelin protein 22 gene duplication with atypical presentations: a new example of the wide spectrum of Charcot-Marie-Tooth 1A disease. AB - Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases. PMID- 24792523 TI - Distal weakness with respiratory insufficiency caused by the m.8344A > G "MERRF" mutation. AB - The m.8344A>G mutation in the mt-tRNA(Lys) gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A>G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A>G 'MERRF' mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A>G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A>G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb girdle muscular dystrophy in which screening of the common genes prove negative. PMID- 24792524 TI - Knowledge about hereditary cancer of women with family histories of breast, colorectal, or both types of cancer. AB - Usually, the mass media do not address hereditary cancer and their risk factors, nor are these topics discussed at the community level. We used an informative guide on cancer and hereditary cancer, followed by a questionnaire on these topics to investigate the relevant knowledge among women at high risk for hereditary breast and/or colorectal cancer from a population-based cohort. The cohort was composed of 81 Brazilian women with positive family histories of breast and/or colorectal cancer. Strauss and Corbin's Grounded Theory was used for qualitative analysis. The average age of the cohort was 49.9 years old. Three participants (3.9%) were illiterate, 45 (59.2%) had attended elementary school, 14 (18.4%) had secondary school, and 14 (18.4%) held higher education degrees. A total of 47 (54.3%) volunteers were unable to fully understand the information provided in the guide because they did not know the meaning of words such as metastasis, malignant, hereditary, sporadic, or oncogenetics. Notwithstanding, the acceptance of the educational tool utilized was satisfactory, and it enhanced the volunteers' interest in a better understanding of cancer and heredity. Thereby, we concluded that the low knowledge of this important subject and the unawareness about fundamental terms required for the comprehension of this specific type of neoplasm made us believe that the use of the informative guide can provide a great value when used previously to the genetic counseling consultations. Besides, educational tools of easy understanding should be part of everyday clinical practice, from primary to specialized patient care. PMID- 24792525 TI - Willingness to participate in a parental training intervention to reduce neurocognitive late effects among Latino parents of childhood cancer survivors. AB - The purpose of the study was to examine correlates of Spanish-speaking Latino parents' interest for participation in an educational intervention to improve learning and school success in children with cancer-related cognitive and behavioral late effects. Participants included 73 Latino caregivers of school-age children who are survivors of brain tumor or leukemia and at risk for cognitive late effects. The parents completed a battery of surveys relating to interest in and barriers to intervention participation, as well as measures of parental knowledge and beliefs and their children's cognitive functioning, and health related quality of life. Results showed that the majority of parents expressed interest in participating in the proposed 8-week intervention, with over 90% indicating interest in learning more about improving grades, making learning more exciting, being a role model, and the impact of cancer on memory. The factors most strongly related to interest in intervention included lower maternal education as well as perceptions of greater child cognitive difficulties and lower health-related quality of life. The barriers most highly endorsed by the most parents were difficulty paying for gas, child care responsibility, and too much stress in other parts of life. Also highly endorsed as barriers were statements relating to the child's lack of interest and need for services (i.e., my child is doing fine). These findings are consistent with the Health Belief Model wherein decisions to engage in health-related behaviors are made by weighing the potential benefits relative to the costs and barriers. PMID- 24792526 TI - Spontaneous behavior in the social homecage discriminates strains, lesions and mutations in mice. AB - BACKGROUND: Modern molecular genetics create a rapidly growing number of mutant mouse lines, many of which need to be phenotyped behaviorally. Poor reliability and low efficiency of traditional behavioral tests have prompted the development of new approaches to behavioral phenotyping, such as fully automated analysis of behavior in the homecage. NEW METHOD: We asked whether the analysis of spontaneous behavior during the first week in the social homecage system IntelliCage could provide useful prescreening information before specialized and time consuming test batteries are run. To determine how much behavioral variation is captured in this data, we performed principal component analysis on free adaptation data of 1552 mice tested in the IntelliCage during the past years. We then computed individual component scores to characterize and compare groups of mice. RESULT: We found 11 uncorrelated components which accounted for 82% of total variance. They characterize frequency and properties of corner visits and nosepokes, drinking activity, spatial distribution, as well as diurnal time course of activity. Behavioral profiles created using individual component scores were highly characteristic for different inbred strains or different lesion models of the nervous system. They were also remarkably stable across labs and experiments. COMPARISON WITH EXISTING METHODS: Monitoring of mutant mice with known deficits in hippocampus-dependent tests produced profiles very similar to those of hippocampally lesioned mice. CONCLUSIONS: Taken together, our results suggest that already the monitoring of spontaneous behavior during a week of free adaptation in the IntelliCage can contribute significantly to high throughput prescreening of mutant mice. PMID- 24792528 TI - Production of biodegradable polymers (polyhydroxyalkanoate, PHA) by using microbial mixed cultures. Editorial. PMID- 24792527 TI - An open-source analytical platform for analysis of C. elegans swimming-induced paralysis. AB - BACKGROUND: The nematode Caenhorhabditis elegans offers great power for the identification and characterization of genes that regulate behavior. In support of this effort, analytical methods are required that provide dimensional analyses of subcomponents of behavior. Previously, we demonstrated that loss of the presynaptic dopamine (DA) transporter, dat-1, evokes DA-dependent Swimming Induced Paralysis (Swip) (Mcdonald et al., 2007), a behavior compatible with forward genetic screens (Hardaway et al., 2012). NEW METHOD: Here, we detail the development and implementation of SwimR, a set of tools that provide for an automated, kinetic analysis of C. elegans Swip. SwimR relies on open source programs that can be freely implemented and modified. RESULTS: We show that SwimR can display time-dependent alterations of swimming behavior induced by drug treatment, illustrating this capacity with the dat-1 blocker and tricyclic antidepressant imipramine (IMI). We demonstrate the capacity of SwimR to extract multiple kinetic parameters that are impractical to obtain in manual assays. COMPARISON WITH EXISTING METHODS: Standard measurements of C. elegans swimming utilizes manual assessments of the number of animals exhibiting swimming versus paralysis. Our approach deconstructs the time course and rates of movement in an automated fashion, offering a significant increase in the information that can be obtained from swimming behavior. CONCLUSIONS: The SwimR platform is a powerful tool for the deconstruction of worm thrashing behavior in the context of both genetic and pharmacological manipulations that can be used to segregate pathways that underlie nematode swimming mechanics. PMID- 24792529 TI - Enzymatic biodiesel production kinetics using co-solvent and an anhydrous medium: a strategy to improve lipase performance in a semi-continuous reactor. AB - Enzymatic biodiesel production kinetics under previously optimized conditions were investigated. Waste frying oil (WFO) was used as the raw material, Novozym 435 as catalyst, methanol as acyl acceptor and tert-butanol as co-solvent. To investigate pure transesterification kinetics improving product properties, 3A molecular sieves were incorporated into the reaction to provide an anhydrous medium avoiding the side reactions of hydrolysis and esterification. The effects of either WFO or methanol on the reaction rate were analyzed separately. The reaction was described by a Ping Pong mechanism and competitive inhibition by methanol. The results obtained in the kinetics study were applied in the operation of a semi-continuous reactor for biodiesel production. The operational conditions of each reaction cycle were: methanol-to-oil ratio 8/1 (mol/mol), 15% (wt) Novozym 435, 0.75% (v/v) of tert-butanol, 44.5 degrees C, 200 rpm and 4h of reaction time. The enzymes were successively reused by remaining in the reactor during all the cycles. Under these conditions, biodiesel production yields higher than 80% over 7 reaction cycles were observed. Both the kinetics study and the reactor operation showed that Novozym 435 was not inhibited at high methanol concentrations and that the kinetics of the proposed enzymatic process could be comparable to the conventional chemical process. PMID- 24792530 TI - Determination of selected water-soluble vitamins using hydrophilic chromatography: a comparison of photodiode array, fluorescence, and coulometric detection, and validation in a breakfast cereal matrix. AB - Water-soluble vitamins are an important class of compounds that require quantification from food sources to monitor nutritional value. In this study we have analysed six water-soluble B vitamins ([thiamine (B1), riboflavin (B2), nicotinic acid (B3, NAc), nicotinamide (B3, NAm), pyridoxal (B6), folic acid (B9)], and ascorbic acid (vit C) with hydrophilic interaction liquid chromatography (HILIC), and compared UV, fluorescent (FLD) and coulometric detection to optimise a method to quantitate the vitamins from food sources. Employing UV/diode array (DAD) and fluorimetric detection, six B vitamins were detected in a single run using gradient elution from 100% to 60% solvent B [10mM ammonium acetate, pH 5.0, in acetonitrile and water 95:5 (v:v)] over 18 min. UV detection was performed at 268 nm for B1, 260 nm for both B3 species and 284 nm for B9. FLD was employed for B2 at excitation wavelength of 268 nm, emission of 513 nm, and 284 nm/317 nm for B6. Coulometric detection can be used to detect B6 and B9, and vit C, and was performed isocratically at 75% and 85% of solvent B, respectively. B6 was analysed at a potential of 720 mV, while B9 was analysed at 600 mV, and vit C at 30 mV. Retention times (0.96 to 11.81 min), intra-day repeatability (CV 1.6 to 3.6), inter-day variability (CV 1.8 to 11.1), and linearity (R 0.9877 to 0.9995) remained good under these conditions with limits of detection varying from 6.6 to 164.6 ng mL(-1), limits of quantification between 16.8 and 548.7 ng mL(-1). The method was successfully applied for quantification of six B vitamins from a fortified food product and is, to our knowledge, the first to simultaneously determine multiple water-soluble vitamins extracted from a food matrix using HILIC. PMID- 24792531 TI - Bone distribution study of anti leprotic drug clofazimine in rat bone marrow cells by a sensitive reverse phase liquid chromatography method. AB - The aim of the present study was to investigate the distribution of clofazimine (CLF) in rat bone marrow cells by a validated reverse phase high performance liquid chromatography. CLF and chlorzoxazone (I.S) were extracted by liquid liquid extraction from plasma and rat bone marrow cells. The chromatographic separation was performed in isocratic mode by the mobile phase consisting of 10mM ammonium formate (pH 3.0 with formic acid) and acetonitrile in a ratio of 50:50 (v/v). The method was accurate and precise in the linear range of 15.6-2000.0 ng/mL with a correlation coefficient (r(2)) of 0.996 and 0.995 in rat plasma and bone marrow cells, respectively. After single oral dose of 20mg/kg, the maximum concentration of CLF in plasma and bone marrow cells were obtained at 12h with the concentrations of 593.2 and 915.4 ng/mL, respectively. The AUC0-t and mean elimination half life (t1/2) of CLF in bone marrow cells were 54339.02 ng h/mL and 52.46 h, respectively, which signified the low body clearance and high distribution of CLF in bone marrow cells. The single oral dose pharmacokinetic investigation was confirmed the CLF endure for a long period in rat due to high distribution in various tissues. The developed method was successfully applied to the estimation of the pharmacokinetic parameters of CLF in plasma and bone marrow cells after administration of single oral dose of 20mg/kg to rats. PMID- 24792532 TI - Simultaneous determination of 16 synthetic colorants in hotpot condiment by high performance liquid chromatography. AB - A simultaneous determination method for 16 synthetic colorants in hotpot condiment was developed by high performance liquid chromatography. The samples were successively extracted with 2 mol/L carbamide solution containing 5% ammonia (dissolved in methanol) and methanol-acetone solution, and then the target analytes could be divided into two groups named as lipid-soluble and water soluble colorants by ethyl acetate-cyclohexane with liquid-liquid extraction. The lipid-soluble and water-soluble colorants were purified by gel permeation chromatography and solid phase extraction column packed with polyamide resin, respectively. The obtained two eluates were combined, concentrated, and separated by C18 column and determined by diode array detector. Good linear relationships between peak areas and the concentrations of the synthetic colorants were obtained in the range of 0.01-50.0mg/L with correlation coefficients above 0.999 (n=10). The limits of detection and quantitation were 1-3 and 10 MUg/kg for 16 synthetic colorants, respectively. The average recoveries at the spiked levels of 5, 10, 20 and 50 MUg/kg were in the range of 63.2-97.1% with relative standard deviations (n=6) around 1.5-10.6%. This method is sensitive and reliable, and can be used to simultaneously determine 8 lipid-soluble and 8 water-soluble colorants in hotpot condiment. PMID- 24792534 TI - Developing the Australasian Hepatology Association's Consensus-based Guidelines for the Nursing Care of Patients with Liver Disease. AB - Abstract Purpose: Hepatology nursing is an emerging speciality. To define best practice, the Australasian Hepatology Association developed consensus-based guidelines for the nursing care of patients with liver disease. Methods: Using the Delphi technique, six rounds of consultation were conducted with Australian hepatology nurses and non-nursing hepatology professionals. Input was captured through face-to-face and electronic communication and questionnaires. Results: The experts' opinions were collated and consensus on the delivery of hepatology nursing care was achieved. In total, 90 consensus guidelines were developed. The principles underpinning the Guidelines include patient-centred care, non discriminatory practice, cultural competence, collaboration and partnership and working within own scope of practice. Conclusion: Internationally, the Australasian Hepatology Association Guidelines are the first to document a consensus on the scope of hepatology nursing practice. The Guidelines reflect the expansion of hepatology nursing, from viral hepatitis to caring for patients with advanced liver disease and hepatocellular carcinoma, and provides a framework for future nursing practice. PMID- 24792533 TI - Enantioselective and sensitive determination of carvedilol in human plasma using chiral stationary-phase column and reverse-phase liquid chromatography with tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method to quantify carvedilol enantiomers in human plasma was developed and validated as a measure of compliance in clinical research. Carvedilol enantiomers were extracted from human serum (0.5 mL) via liquid-liquid extraction with methyl tert-butyl ether (2.5 mL). Carvedilol-related compound C served as the internal standard. The analyte and internal standard were separated on a Sino-Chiral AD column (150 * 4.6mm, 5 MUm, amylose tris-3,5-dimethylphenylcarbamate coated on silica-gel) using isocratic elution with mobile phases of methanol, water and diethylamine (94:6:0.01, v/v). The total run-time was 10.5 min. Carvedilol enantiomers were quantified using a triple quadrupole mass spectrometer operated in multiple reaction-monitoring mode using positive electrospray ionisation. The mass transitions monitored for quantitation were carvedilol (m/z 407->222) and carvedilol-related compound C (m/z 497->222). The limits of quantification for the S- and R-carvedilol enantiomers in plasma were both 0.08 ng/mL. The method was validated in the linear range of 0.08-50 ng/mL with acceptable inter- and intra-assay precision and accuracy and stability suitable for routine laboratory practice. The method was successfully applied to samples taken from research volunteers treated with carvedilol sustained-release tablet 18 mg. Cmax and AUClast were 9.1 +/- 5.1 ng/mL and 59.4 +/- 39.6 ng h/mL for R-carvedilol, 4.0 +/ 2.3 ng/mL and 24.7 +/-15.0 ng h/mL for S-carvedilol, respectively. tmax and t1/2 were 4.6 +/- 1.9h and 9.6 +/- 4.5h for R-carvedilol, and 4.7 +/- 1.0 h and 10.7 +/- 5.7 h, respectively. PMID- 24792535 TI - The distinct functional roles of the inner and outer chloroplast envelope of Pea (Pisum sativum) as revealed by proteomic approaches. AB - Protein profiles of inner (IE) and outer (OE) chloroplast envelope membrane preparations from pea were studied using shotgun nLC-MS/MS and two-dimensional electrophoresis, and 589 protein species (NCBI entries) were identified. The relative enrichment of each protein in the IE/OE pair of membranes was used to provide an integrated picture of the chloroplast envelope. From the 546 proteins identified with shotgun, 321 showed a significant differential distribution, with 180 being enriched in IE and 141 in OE. To avoid redundancy and facilitate in silico localization, Arabidopsis homologues were used to obtain a nonredundant list of 409 envelope proteins, with many showing significant OE or IE enrichment. Functional classification reveals that IE is a selective barrier for transport of many metabolites and plays a major role in controlling protein homeostasis, whereas proteins in OE are more heterogeneous and participate in a wide range of processes. Data support that metabolic processes previously described to occur in the envelope such as chlorophyll and tocopherol biosynthesis can be ascribed to the IE, whereas others such as carotenoid or lipid biosynthesis occur in both membranes. Furthermore, results allow empirical assignation to the IE and/or OE of many proteins previously assigned to the bulk chloroplast envelope proteome. PMID- 24792536 TI - Primary peripheral retinal nonperfusion in a family with Loeys-Dietz syndrome. AB - Loeys-Dietz syndrome (LDS) is a connective tissue disorder associated with aggressive arterial aneurysms; rarely, it can have clinical features similar to those of Marfan syndrome, with retinal detachment, myopia, and ectopia lentis. A 19-month-old boy with history of LDS was found to have peripheral retinal nonperfusion in both eyes and a combined traction and exudative retinal detachment of the left eye. Ocular findings in the father, who also had LDS, were normal, but the patient's 34-month-old sister with LDS was also found to have less extensive peripheral retinal nonperfusion. To our knowledge, this is the first report of LDS associated with peripheral retinal nonperfusion in siblings with the same LDS mutation. PMID- 24792537 TI - The impact of postpartum haemorrhage management guidelines implemented in clinical practice: a systematic review of the literature. AB - Postpartum haemorrhage (PPH) is an urgent obstetric condition requiring an immediate response and a multidisciplinary approach. The aim of this study was to review PPH management guidelines implemented in clinical practice, to evaluate their impact regarding prevention, diagnosis and treatment, and to analyze how the numbers of PPH cases changed in the post-intervention period. A systematic search in the PubMed database was performed. The references of all included articles were examined. Studies evaluating the management of PPH and the impact on the numbers of cases of this pathology after the implementation of new or updated guidelines were involved in the analysis. Two reviewers independently examined the titles and abstracts of all identified citations, selected potentially eligible studies, and evaluated their full-text versions. Methodological quality was assessed using a checklist based on the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. We analyzed seven articles that evaluated the impact of new or updated guidelines for PPH management implemented in clinical practice. In four trials, the numbers of PPH cases declined after the intervention. Guidelines for PPH management can have a positive impact on the reduction of the number of PPH cases. PMID- 24792538 TI - Prevention and control of Hb Bart's disease in Guangxi Zhuang Autonomous Region, China. AB - OBJECTIVE: To demonstrate the performance of Hb Bart's Disease prevention in Guangxi Zhuang Autonomous Region, China. STUDY DESIGN: A prenatal control program for Hb Bart's disease was conducted from January 2006 to December 2012. A total of 17,555 pregnant women were screened for alpha-thalassemia in our prenatal screening program. Pregnancy at-risk for Hb Bart's disease was offered the choice of direct invasive testing or the non-invasive approach with serial ultrasonography. RESULTS: A total of 1425 at-risk couples attended the prenatal diagnosis. Three hundred ninety couples were screened at our own hospital, and the remaining 1035 couples were referred from other hospitals. Two hundred and three pregnant women chose non-invasive approach, and 1122 chose invasive testing. A total of 365 fetuses were diagnosed with Hb Bart's disease. All cases were finally confirmed by fetal DNA analysis. Eighty-two cases (22.4%) were diagnosed by chorionic villous sampling and 194 (53.2%) by amniocentesis samples. The other 89 (24.4%) cases were performed by cordocentesis. All of the affected pregnancies were terminated. CONCLUSION: Implementation of a prevention and control program accompanying with a referral system for prenatal diagnosis is technically feasible in Guangxi Zhuang Autonomous Region, China. PMID- 24792539 TI - May AMH levels distinguish LOCAH from PCOS among hirsute women? AB - OBJECTIVE: To determine whether women with polycystic ovary syndrome (PCOS) would be distinguishable from women with late onset congenital adrenal hyperplasia (LOCAH) on the basis of antimullerian hormone (AMH) levels. STUDY DESIGN: PCOS was diagnosed in 170 women; 105 were polycystic ovary morphology (PCOM)+/oligo anovulation (OA)+/hyperandrogenism (HA)+, 40 PCOM+/OA-/HA+ and 25 PCOM-/OA+/HA+. These three groups were compared with 25 women in whom LOCAH was diagnosed. RESULTS: The mean serum AMH levels were 8.12+/-1.85ng/ml in PCOM+/OA+/HA+ group, 5.34+/-1.82ng/ml in PCOM+/OA-/HA+ group, 3.02+/-1.76ng/ml in PCOM-/OA+/HA+ group and 4.43+/-1.29ng/ml in LOCAH group. The mean AMH level in PCOM+/OA+/HA+ group was approximately twofold higher than the mean AMH level measured in LOCAH group (p<0.001). Women with PCOM+/OA-/HA+ had higher serum AMH levels than those with LOCAH, women with LOCAH had higher serum AMH levels than those with PCOM-/OA+/HA+ but these differences were not statistically significant (p>0.05). CONCLUSIONS: AMH is not suitable for distinguishing LOCAH from all types of hyperandrogenic patterns of PCOS, but is only applicable for a specific subtype, such as PCOS patients with three main diagnostic criteria. Therefore, ACTH stimulation test remains an essential clinical tool to diagnose LOCAH. PMID- 24792540 TI - Glassy cell carcinoma of the cervix: a literature review. AB - Glassy cell carcinoma (GCC) is a histologically aggressive subtype of cervical cancer with rapid growth and early metastases. The prognosis for patients with GCC is poor. This article reviews the literature pertinent to the epidemiology, cytology, pathology, immunohistochemistry, treatment and prognosis of GCC. MEDLINE (PubMed) was searched for all articles or abstracts on patients diagnosed with GCC published (in English) since the original definition by Glucksmann and Cherry, Cancer 1956;9:971. Accurate diagnosis of GCC enables implementation of the correct treatment strategy. Early-stage GCC should be treated with hysterectomy and pelvic lymph node dissection, with adjuvant radiochemotherapy if at least one intermediate or high risk factor for cervical cancer is present. Advanced GCC should be treated with neoadjuvant radiochemotherapy or chemotherapy with the aim of making the disease operable. There is a need for retrospective evaluation of GCC treatment from several centres to explore knowledge about this rare entity. Future studies should explore the role of targeted therapies and the most efficient chemotherapy regimen for the management of GCC. PMID- 24792541 TI - Effect of 2-aminoethoxydiphenyl borate on ischemia-reperfusion injury in a rat ovary model. AB - OBJECTIVE: The aim of this study is to evaluate the effects of 2 aminoethoxydiphenyl borate (2-APB) as an antioxidant and analyze biochemical and histopathologic changes in experimental ischemia-reperfusion (I/R) injury in rat ovaries. STUDY DESIGN: Thirty female rats were utilized to create four groups. Group 1: I/R and 2-APB (2mg/kg); Group 2: I/R and 2-APB (4mg/kg); Group 3: I/R; Group 4: sham operation. Ovarian tissue and serum malondialdehyde, nitric oxide (NO) levels; ovarian tissue and serum total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) were determined. In ovarian tissue samples histopathologic examination, immunoflourescence staining by TUNEL method was studied. RESULTS: Tissue TOS, serum TOS, and OSI levels were elevated in I/R group. After treatment with 2-APB, tissue and serum TOS levels and OSI levels were markedly decreased. There was a significant difference in terms of tissue and serum NO levels between the sham group and I/R group. Elevation in tissue NO and serum NO levels were decreased after treatment with 2-APB. TUNEL positive cell number gradually decreased with dose of 2-APB in groups 1 and 2. CONCLUSION: Conservative treatment with 2-APB is beneficial for mitigation of I/R injury, and the ovarian protective effect of 2-APB appears to be mediated through its antiapopitotic and antioxidative effects. PMID- 24792542 TI - Studying the performance of bifurcate cryoprobes based on shape factor of cryoablative zones. AB - Conventional cryosurgical process employs extremely low temperatures to kill tumor cells within a closely defined region. However, its efficacy can be markedly compromised if the same treatment method is administrated for highly irregularly shaped tumors. Inadequate controls of freezing may induce tumor recurrence or undesirable over-freezing of surrounding healthy tissue. To address the cryosurgical complexity of irregularly shaped tumors, an analytical treatment on irregularly-shaped tumors has been performed and the degree of tumor irregularities is quantified. A novel cryoprobe coined the bifurcate cryoprobe with the capability to generate irregularly shaped cryo-lesions is proposed. The bifurcate cryoprobe, incorporating shape memory alloy functionality, enables the cryoprobe to regulate its physical configuration. To evaluate the probe's performance, a bioheat transfer model has been developed and validated with in vitro data. We compared the ablative cryo-lesions induced by different bifurcate cryoprobes with those produced by conventional cryoprobes. Key results have indicated that the proposed bifurcate cryoprobes were able to significantly promote targeted tissue destruction while catering to the shape profiles of solid tumors. This study forms an on-going framework to provide clinicians with alternative versatile devices for the treatment of complex tumors. PMID- 24792544 TI - Sampling the processing environment for Listeria. AB - This chapter describes in detail the procedures used when sampling for Listeria in food processing environments. Sampling of food contact surfaces, non-food contact surfaces, and liquids such as drain effluents are addressed. Sponge stick swabs are considered advantageous for surface sampling and tips regarding their application are given. Liquids are collected using sterile dippers and the procedure for their correct use is described. Advice on places to sample, the best time for sampling and the frequency of sampling are also given. Such details help hygienists/microbiologists to be successful in their attempts to isolate strains of Listeria, even if such bacteria are well attached to surfaces or located in niches that are difficult to reach. PMID- 24792543 TI - Analysis of supercooling activities of surfactants. AB - Supercooling-promoting activities (SCAs) of 25 kinds of surfactants including non ionic, anionic, cationic and amphoteric types were examined in solutions (buffered Milli-Q water, BMQW) containing the ice nucleation bacterium (INB) Erwinia ananas, silver iodide (AgI) or BMQW alone, which unintentionally contained unidentified ice nucleators, by a droplet freezing assay. Most of the surfactants exhibited SCA in solutions containing AgI but not in solutions containing the INB E. ananas or BMQW alone. SCAs of many surfactants in solutions containing AgI were very high compared with those of previously reported supercooling-promoting substances. Cationic surfactants, hexadecyltrimethylammonium bromide (C16TAB) and hexadecyltrimethylammonium chloride (C16TAC), at concentrations of 0.01% (w/v) exhibited SCA of 11.8 degrees C, which is the highest SCA so far reported. These surfactants also showed high SCAs at very low concentrations in solutions containing AgI. C16TAB exhibited SCA of 5.7 degrees C at a concentration of 0.0005% (w/v). PMID- 24792545 TI - Traditional methods for isolation of Listeria monocytogenes. AB - Conventional methods for the detection of Listeria monocytogenes in foods and environmental samples relies on selective pre-enrichment, enrichment, and plating. This is followed by confirmation of suspected colonies by testing a limited number of biochemical markers. PMID- 24792546 TI - Confirmation of isolates of Listeria by conventional and real-time PCR. AB - Polymerase chain reaction (PCR) is an invaluable diagnostic technique in microbiology for rapid and specific detection and confirmation of microbial isolates from food and the environment. PCR is a simple, sensitive, specific, and reproducible assay and can be performed in conventional or in real-time formats. Here, we describe the application of real-time and conventional PCR-based methods for confirmation of presumptive Listeria isolates. PMID- 24792547 TI - Serotype assignment by sero-agglutination, ELISA, and PCR. AB - For assessing isolates of Listeria monocytogenes serotype designation is the foremost subtyping method used. Traditionally, serotyping has been done with agglutination reactions. In the last decade, alternative serotyping methods were described using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). Herein are described the three methods, and the advantages and disadvantages of each. PMID- 24792548 TI - Pulsed-field gel electrophoresis (PFGE) analysis of Listeria monocytogenes. AB - PFGE is a valuable tool for assessing Listeria monocytogenes strain interrelatedness. It is based on the study of total bacterial DNA restriction patterns. Cells are embedded in agarose plugs before being lysed. The released DNA is then digested into large fragments by restriction enzymes. As DNA fragments are too large to be separated by traditional electrophoresis in an agarose gel, changes in the direction of the electrical current are periodically applied in order to allow the proper migration of large DNA fragments. Strains are characterized by the obtained DNA fragment patterns or pulsotypes which vary depending on the number and size of bands. PMID- 24792549 TI - Multilocus sequence typing (MLST) of Listeria monocytogenes. AB - Nucleotide sequence-based methods focusing on the single nucleotide polymorphisms (SNPs) of Listeria monocytogenes housekeeping genes facilitate the rapid and interlaboratory comparison on open accessible databases, such as the multilocus sequence typing (MLST) databases that are available. MLST has advantages over other methods as it can reconstruct ancestral and evolutionary linkage between L. monocytogenes isolates. MLST detects all genetic variations within the amplified housekeeping gene that accumulate slowly. This chapter describes how to undertake MLST. PMID- 24792550 TI - Ribotyping and automated ribotyping of Listeria monocytogenes. AB - Ribotyping is a molecular technique that allows identification and typing of bacteria to the strain level. It is based on restriction endonuclease cleavage of total genomic DNA followed by electrophoretic separation, Southern blot transfer, and hybridization of transferred DNA fragments with a radiolabeled ribosomal operon probe. Following autoradiography, only those bands containing a portion of the ribosomal operon are visualized. The number of fragments generated by ribotyping is a reflection of the multiplicity of rRNA operons present in a bacterial species.Automated Ribotyping-AR (RiboPrinter) is a commercially available instrument with a high level of reproducibility and standardization. The RiboPrinter automates all of the steps in the process from cell lysis to data capture and database comparisons. Further, reagent cassettes including the enzymes, enzyme conjugated-hybridization probe, electrophoretic gel, and membrane have been developed to deliver consistent performance. Data capture is accomplished via a CCD camera and the gel patterns obtained stored in a digitized format, making it easier to compare results among laboratories and to exchange data electronically. PMID- 24792551 TI - Fluorescent amplified fragment length polymorphism (fAFLP) analysis of Listeria monocytogenes. AB - Fluorescent amplified fragment length polymorphism (fAFLP) is based on the selective PCR amplification of restriction fragments from a digest of total genomic DNA. Genomic DNA extracted from a purified bacterial isolate is completely digested with two endonucleases generating fragments which are ligated to specific double-stranded adaptors. The ligated fragments are then amplified by PCR using fluorescently labelled primers. Fluorescent amplified fragments are separated by size on an automated sequencer with a size standard. fAFLP is a rapid, highly reproducible technique which can be used to discriminate and subtype Listeria monocytogenes strains. PMID- 24792552 TI - High-throughput characterization of Listeria monocytogenes using the OmniLog Phenotypic Microarray. AB - High-throughput biochemical screening techniques are an important tool in phenotypic analysis of bacteria. New methods, simultaneously measuring many phenotype responses, increase the output of such investigations and allow a more complete overview of the bacterial phenotype, and how this may relate its genotype. This chapter describes the application of OmniLog Phenotype Microarray analysis, a high-throughput assay for the phenotypic characterization of bacterial strains across a variety of different traits, including nutrient utilization and antimicrobial sensitivity, to Listeria species. PMID- 24792553 TI - Analysis of Listeria monocytogenes subproteomes. AB - The proteomic approaches have considerably evolved over the past two decades. This opened the doors for larger scale and deeper explorations of cellular physiology. Like for other living organisms, using the tools of proteomics has undoubtedly improved knowledge about the foodborne pathogen Listeria monocytogenes. Among the different technologies and approaches permanently evolving in the field of proteomics, the 2-DE is an analytical separation method of choice to resolve thousands of proteins simultaneously in a single gel, allowing their quantification, the study of their posttranslational modifications and the understanding of their biological function. In this, 2-DE remains a perfectly complementary technique to the new high-throughput techniques such as shotgun proteomics approaches. Moreover, in order to gain in analysis depth and improve knowledge about the target of action and the function of proteins in relation to their subcellular location, it is necessary to explore more specifically the different subcellular proteomes. Thus, the subproteomic analyses became essential and dramatically increased these last years, particularly on proteins secreted into the extracellular milieu, named exoproteome, or on cell envelope proteins (cell wall and membrane proteins) which are involved in the interactions with the surrounding environment. Here, the extraction and separation of L. monocytogenes subproteomes are described based on cell fractionation and 2-DE techniques. This chapter gives a workflow to obtain the exoproteome, the intracellular proteome, the cell wall, and membrane proteomes of the Gram-positive bacterium L. monocytogenes. The different steps of 2-DE technology, composed of a first dimension based on the separation of proteins according to their charge, an equilibration step, then a second dimension based on the separation of proteins according to their mass, and finally the staining of proteins in the gel are detailed. Emerging technologies to extract the exoproteome or the cell surface proteome after enzymatic shaving and to analyze them by shotgun method are also discussed briefly. PMID- 24792554 TI - The Listeria cell wall and associated carbohydrate polymers. AB - Understanding molecular interactions of bacteria with their environment requires the purification and characterization of cell wall components. Here, we describe detailed experimental methods for the extraction, purification, and analysis of wall teichoic acids (WTA), which assume important roles as major constituents of Gram-positive cell walls, such as mediating interaction with cell wall-associated proteins, eukaryotic host cells, and bacteriophages. Specifically, we present a procedure for compositional WTA characterization to study large diversity of carbohydrate substitution on Listeria monocytogenes WTA. This protocol may also be used and adapted to analyze WTA from other bacteria. PMID- 24792555 TI - Use of bacteriophage cell wall-binding proteins for rapid diagnostics of Listeria. AB - Diagnostic protocols for food-borne bacterial pathogens such as Listeria need to be sensitive, specific, rapid, and inexpensive. Conventional culture methods are hampered by lengthy enrichment and incubation steps. Bacteriophage-derived high affinity binding molecules (cell wall-binding domains, CBDs) specific for Listeria cells have recently been introduced as tools for detection and differentiation of this pathogen in foods. When coupled with magnetic separation, these proteins offer advantages in sensitivity and speed compared to the standard diagnostic methods. Furthermore, fusion of CBDs to differently colored fluorescent reporter proteins enables differentiation of Listeria strains in mixed cultures. This chapter provides protocols for detection of Listeria in food by CBD-based magnetic separation and subsequent multiplexed identification of strains of different serotypes with reporter-CBD fusion proteins. PMID- 24792556 TI - Virulence characterization of Listeria monocytogenes. AB - Listeria monocytogenes, a foodborne intracellular pathogen, is responsible for about 300 deaths every year in the USA. It has the ability to escape host defense mechanisms and causes listeriosis more frequently in immunocompromised individuals. Virulence mechanisms in L. monocytogenes are highly regulated and tightly controlled. A number of virulence factors that play important roles in pathogenesis of listeriosis have been identified and characterized. This review highlights the power of comparative genomics and functional genomics in identifying genes and proteins involved in the infection process. These genes and proteins are potentially useful as biomarkers for detecting virulent L. monocytogenes. This review also focuses on developments in the in vivo and in vitro models used in characterization of listerial virulence. PMID- 24792557 TI - Internalization assays for Listeria monocytogenes. AB - Listeria monocytogenes is a model intracellular pathogen that can invade the cytoplasm of host mammalian cells. Cellular invasion can be measured using standard techniques such as the classical gentamicin protection assay, based on the quantification of colony-forming units from lysates of infected cells. In addition, there are methods based on immunofluorescence microscopy which allow for assaying invasion in a medium- to high-throughput manner. In the following sections we detail two different assays that can be used alone or in combination to quantify the internalization of L. monocytogenes in host cells. PMID- 24792558 TI - Extraction and analysis of plasmid DNA from Listeria monocytogenes. AB - A plasmid preparation is a method used to extract and purify plasmid DNA. Methods developed to purify plasmid DNA from bacteria generally involve harvesting and alkaline lysis of the bacteria and precipitation of chromosomal DNA and protein, followed by purification of the plasmid DNA. Here, we describe the mini preparation of plasmid DNA by a rapid small-scale method, adapted for Listeria monocytogenes. The quality of plasmid DNA isolated using this method is sufficient for analytical purposes but may be upscaled for further downstream analysis. Electrophoretic separation of the resultant lysate allows conclusions to be made on the presence, number, copy number, and size of the plasmids in the analyzed bacterial strains. PMID- 24792559 TI - Generation of nonpolar deletion mutants in Listeria monocytogenes using the "SOEing" method. AB - The ability to manipulate chromosomally encoded genes is a fundamental biological tool for the analysis of gene function. Here, we provide in greater depth protocols for the creation of nonpolar unlabeled gene deletions in Listeria (L.) monocytogenes that are facilitated by the splicing overlap extension PCR technique. For mutagenesis in L. monocytogenes, we describe two different plasmid based approaches, which facilitate the introduction of this spliced amplicon in place of the corresponding segment of chromosomal DNA: the pKSV7 system and the pORI280/pVE6007 system. PMID- 24792560 TI - Mutant construction and integration vector-mediated gene complementation in Listeria monocytogenes. AB - Genes that play role in stress response mechanisms and other phenotypes of bacteria can be identified by construction and screening of mutant libraries. In this chapter, we describe the construction and screening of mutant libraries of Listeria monocytogenes using a plasmid, pMC38, carrying a mariner-based transposon system (TC1/mariner) and constructed by Cao et al. (Appl Environ Microbiol 73:2758-2761, 2007). Following screening of the mutant library, putative mutants are identified and the transposon is localized, leading to identification of the genes that play possible roles in the phenotype of interest. To confirm the role of the gene in the relevant phenotype, transposon mutants are genetically complemented with the wild type gene using the site specific temperature-sensitive integration vector pPL2, constructed by Lauer et al. (J Bacteriol 184:4177-4186, 2002). PMID- 24792561 TI - Absolute and relative gene expression in Listeria monocytogenes using real-time PCR. AB - Reverse transcription combined with the polymerase chain reaction (RT-PCR) is a viable method widely used to quantify gene expression. There are two ways to quantify gene expression by real-time PCR: relative quantification and absolute quantification. Relative quantification relates the PCR signal of the target gene to a control gene, normally a housekeeping gene. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Here we describe both methods from RNA extraction to its quantification by real-time PCR. PMID- 24792562 TI - Genome sequencing of Listeria monocytogenes. AB - Genome sequencing is a key technology in microbiology. A genome sequence is the prerequisite for understanding the molecular basis of a given phenotype; this is of particular importance for pathogens. Particularly for the foodborne pathogen Listeria monocytogenes, which is an important model organism in infection biology, genome sequencing has proven to be invaluable in advancing our understanding of its virulence mechanisms and epidemiology. In this chapter, current technologies and software tools for genome sequencing and genome analysis of L. monocytogenes are described. PMID- 24792563 TI - Using enhanced green fluorescent protein (EGFP) promoter fusions to study gene regulation at single cell and population levels. AB - Reporter gene fusions based on the enhanced green fluorescent protein (EGFP) are powerful experimental tools that allow real-time changes in gene expression to be monitored both in single cells and in populations. Here we describe the development of a chromosomally integrated transcriptional reporter fusion in Listeria monocytogenes that allows real-time measurements of gene expression. To construct a single copy of an EGFP-based fluorescent reporter fused to a promoter of interest (Px) in L. monocytogenes, a suicide shuttle vector carrying the Px::egfp gene fusion is first constructed in Escherichia coli (as an intermediate host). Then, the vector is transformed into L. monocytogenes and integrated into its chromosome by homologous recombination within the selected promoter region. Subsequently, analysis of fluorescence exhibited by cells carrying a single copy reporter can be performed under selected experimental conditions by stringent sample preparation, optimized image acquisition, and processing of the digital data with the image analysis freeware ImageJ. Thus, the methodology described here can be adapted to investigate the activity and regulation of any promoter in L. monocytogenes both at the cell and population levels. PMID- 24792564 TI - Control of Listeria monocytogenes in the processing environment by understanding biofilm formation and resistance to sanitizers. AB - Listeria monocytogenes can colonize in the food processing environment and thus pose a greater risk of cross-contamination to food. One of the proposed mechanisms that facilitates such colonization is biofilm formation. As part of a biofilm, it is hypothesized that L. monocytogenes can survive sanitization procedures. In addition, biofilms are difficult to remove and may require additional physical and chemical mechanisms to reduce their presence and occurrence. The initial stage of biofilm formation is attachment to surfaces, and therefore it is important to be able to determine the ability of L. monocytogenes strains to attach to various inert surfaces. In this chapter, methods to study bacterial attachment to surfaces are described. Attachment is commonly induced by bringing planktonic cells into contact with plastic, glass, or stainless steel surfaces with or without food residues ("soil") in batch or continuous (e.g., with constant flow of nutrients) culture. Measurement of biofilm formed is carried out by detaching cells (with various mechanical methods) and measuring the viable counts or by measuring the total attached biomass. Resistance of biofilms to sanitizers is commonly carried out by exposure of the whole model surface bearing the attached cells to a solution of sanitizer, followed by measuring the survivors as described above. PMID- 24792565 TI - Vaccination studies: detection of a Listeria monocytogenes-specific T cell immune response using the ELISPOT technique. AB - During systemic infection by Listeria monocytogenes the host develops a robust T cell-mediated immune response against the major immunodominant antigens of the pathogen. The enzyme-linked immuno-spot (ELISPOT) test is an accurate and reproducible means of measuring the extent of this T cell response. Here we describe a detailed ELISPOT protocol for measuring an epitope-specific CD8+ T cell-mediated immune response in mice vaccinated with low doses of L. monocytogenes. The basic approach can be easily adapted for the analysis of other vaccination regimes and target epitopes. PMID- 24792566 TI - Sampling the food processing environment: taking up the cudgel for preventive quality management in food processing environments. AB - The Listeria monitoring program for Austrian cheese factories was established in 1988. The basic idea is to control the introduction of L. monocytogenes into the food processing environment, preventing the pathogen from contaminating the food under processing. The Austrian Listeria monitoring program comprises four levels of investigation, dealing with routine monitoring of samples and consequences of finding a positive sample. Preventive quality control concepts attempt to detect a foodborne hazard along the food processing chain, prior to food delivery, retailing, and consumption. The implementation of a preventive food safety concept provokes a deepened insight by the manufacturers into problems concerning food safety. The development of preventive quality assurance strategies contributes to the national food safety status and protects public health. PMID- 24792567 TI - Ultraviolet-B light induced oxidative stress: effects on antioxidant response of Spodoptera litura. AB - Ultraviolet light (UV-B), which emits radiation in the range of 280-315 nm, has been used worldwide in light trapping of insect pests. In this article, we test the hypothesis that one of the duration of UV-B exposure has a differential impact on oxidative stress marker enzymes in Spodoptera litura. Effect of UV-B exposure on total protein and antioxidant activities of superoxide dismutase (SOD), catalase (CAT), peroxidases (POX) and glutathione-S-transferase (GST) were investigated in S. litura. The adults were exposed to UV-B light for various time periods (0, 30, 60, 90 and 120 min). We found that exposure to UV-B light for 30 and 60 min resulted in increased activities of POX. When the exposure time lasted for 60 and 90 min, the activities of SOD remained significantly higher than the control. However, the POX, CAT and GST activity decreased to control levels at 90 and 120 min. whereas relatively long duration exposure activates the xenobiotics detoxifying enzymes like GST and POX and CAT enzymes. Longer UV-B exposure may interfere with pesticide detoxification mechanism in insects, making them more susceptible to insecticides. PMID- 24792568 TI - Combination of chemotherapy and photodynamic therapy using graphene oxide as drug delivery system. AB - Previous research indicated that graphene oxide (GO) can be used to deliver photosensitive anticancer drug, Hypocrellin A (HA), in photodynamic therapy (PDT). However, the anticancer activity of HA was obviously decreased after been loaded on GO. To solve this problem, a chemotherapy drug, 7-ethyl-10 hydroxycamptothecin (SN-38), was co-loaded on the HA loaded GO (HA/SN-38/GO) as a multimodal carrier for the synergistic combination of PDT and chemotherapy for cancer. In vitro results showed that the combination therapy exhibited a synergistic antiproliferative effect compared with PDT and chemotherapy alone. Therefore, HA/SN-38/GO delivery system has the potential to offer dual therapies for the synergistic combination of PDT and chemotherapy for the treatment of cancer. PMID- 24792569 TI - Antibacterial activity of kaolinite/nanoTiO2 composites in relation to irradiation time. AB - The paper addresses laboratory preparation and antibacterial activity testing of kaolinite/nanoTiO2 composite in respect of the daylight irradiation time. Kaolinite/nanoTiO2 composites with 20 and 40 wt% of TiO2 were laboratory prepared, dried at 105 degrees C and calcined at 600 degrees C. The calcination caused transformation of kaolinite to metakaolinite and origination of the metakaolinite/nanoTiO2 composite. X-ray powder diffraction, Raman and FTIR spectroscopic methods revealed titanium dioxide only in the form of anatase in all evaluated samples (non-calcined and calcined) and also transformation of kaolinite to metakaolinite after the calcination treatment. Scanning electron microscopy was used as a method for characterization of morphology and elemental composition of the studied samples. A standard microdilution test was used to determine the antibacterial activity using four human pathogenic bacterial strains (Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa). A lamp with a wide spectrum bulb simulating daylight was used for induction of photocatalysis. The antibacterial assays found all the KATI samples to have antibacterial potency with different onset of the activity when calcined samples exhibited antibacterial activity earlier than the non-calcined. Significant difference in antibacterial activity of KATI samples for different bacterial strains was not observed. PMID- 24792570 TI - Applications of quantum dots with upconverting luminescence in bioimaging. AB - Quantum dots (QDs) have attracted great attention in recent years due to their promising applications in bioimaging. Compared with traditional ultraviolet excitation of QDs, near-infrared laser (NIR) excitation has many advantages, such as being less harmful, little blinking effects, zero autofluorescence and deep penetration in tissue. Composing QDs with upconverting properties is promising to enable NIR excitation. This article provides a review of QDs with upconverting luminescence and their applications in bioimaging. Based on the mechanisms of luminescence, discussion will be divided into four groups: nanoheterostructures/mixtures of QDs and upconverting nanoparticles, graphene quantum dots, lanthanide-doped QDs, and double QDs. The content includes synthetic routes, upconverting luminescence properties, and their applications in bioimaging. PMID- 24792572 TI - An exploration of the relationships between microalgae biomass growth and related environmental variables. AB - Algal community plays critical roles as the primary producer and as a major biotic component in the nutrient/energy cycle in aquatic ecosystems. The potential of fresh water algal biomass to mitigate global problems of food and energy and its significance as a carbon sink have been recognized. In this study, with a view to decreasing the cost of producing algal biomass for various purposes, the natural medium of unsupplemented freshwater was applied to mimic the real world to produce algal biomass. The relevant physicochemical variables in the improvised algal growth environment were analyzed and monitored, to investigate the algal growth mechanism. The simple regression analysis showed the applicability of the unsupplemented natural medium with sufficient natural nutrition for algal biomass production. The multiple linear analyses explained the complexity of the mimicked freshwater mixed-algal community in the laboratory. The laboratory results obtained in the present study also provide better insights that improve our understanding of the natural algal growth characteristics. PMID- 24792571 TI - Study on synthesis, crystal structure, antioxidant and DNA-binding of mono-, di- and poly-nuclear lanthanides complexes with bis(N-salicylidene)-3-oxapentane-1,5 diamine. AB - A Schiff base ligand bis(N-salicylidene)-3-oxapentane-1,5-diamine H2L have been prepared. Reaction of the shape-specific designed ligand with Ln(NO3)3?6H2O afforded three novel complexes, namely, Sm(L)(NO3)(DMF)(H2O) 1, [Eu(H2L)2(NO3)3]n2 and Tb2(L)2(NO3)23. The ligand and complexes were characterized by elemental analysis, UV-Vis, IR, NMR spectroscopy and X-ray crystallography. It is noteworthy that the complexes demonstrate three different types of the structure which changed according to the charge density and acidity of the lanthanide. Complex 1 is a discrete mononuclear species that Sm(III) ion is nine-coordinated in the structure and forming a distorted tricapped trigonal prism geometry. Complex 2 is possessed a 1-D ribbon framework constructed from an extended array of ten-coordinated Eu(3+) centers and the Schiff base ligands. Complex 3 is revealed as a centrosymmetric binuclear neutral entity, in which Tb(III) ion is eight-coordinated with the coordination surround of distorted square antiprism geometry. In order to explore the relationship between the structure and biological properties, the DNA-binding properties have been investigated by electronic absorption, fluorescence, and viscosity measurements. The results suggest that the ligand and complexes bind to DNA via groove modes. The intrinsic binding constants Kb of the complexes 1-3 are (1.19+/-0.112)*10(5), (4.22+/-0.086)*10(4) and (3.89+/-0.104)*10(4) M(-)(1) respectively. Moreover, the antioxidant activity experiments show that these compounds also exhibit good antioxidant activities against OH. and O2(-.) in vitro studies. PMID- 24792574 TI - Impact of protein and ligand impurities on ITC-derived protein-ligand thermodynamics. AB - BACKGROUND: The thermodynamic characterization of protein-ligand interactions by isothermal titration calorimetry (ITC) is a powerful tool in drug design, giving valuable insight into the interaction driving forces. ITC is thought to require protein and ligand solutions of high quality, meaning both the absence of contaminants as well as accurately determined concentrations. METHODS: Ligands synthesized to deviating purity and protein of different pureness were titrated by ITC. Data curation was attempted also considering information from analytical techniques to correct stoichiometry. RESULTS AND CONCLUSIONS: We used trypsin and tRNA-guanine transglycosylase (TGT), together with high affinity ligands to investigate the effect of errors in protein concentration as well as the impact of ligand impurities on the apparent thermodynamics. We found that errors in protein concentration did not change the thermodynamic properties obtained significantly. However, most ligand impurities led to pronounced changes in binding enthalpy. If protein binding of the respective impurity is not expected, the actual ligand concentration was corrected for and the thus revised data compared to thermodynamic properties obtained with the respective pure ligand. Even in these cases, we observed differences in binding enthalpy of about 4kJ?mol(-1), which is considered significant. GENERAL SIGNIFICANCE: Our results indicate that ligand purity is the critical parameter to monitor if accurate thermodynamic data of a protein-ligand complex are to be recorded. Furthermore, artificially changing fitting parameters to obtain a sound interaction stoichiometry in the presence of uncharacterized ligand impurities may lead to thermodynamic parameters significantly deviating from the accurate thermodynamic signature. PMID- 24792575 TI - Metal-mediated oxidative DNA damage induced by methylene blue. AB - BACKGROUND: Methylene blue (MB) is used for various clinical purposes, including chromoendoscopy and methemoglobinemia treatment. However, MB induces tumors of pancreatic islets and small intestine in experimental animals. This finding raises a possibility that MB induces carcinogenicity in these organs via light independent mechanisms, although MB is known to cause light-dependent DNA damage. METHODS: We investigated the mechanism of MB-induced DNA damage using (32)P-5' end-labeled DNA fragments of human tumor-relevant genes. We investigated the redox reaction of MB by UV-visible spectrometry. RESULTS: MB induced DNA damage at the 5'-ACG-3' sequence, a hot spot of the p53 gene, in the presence of NADH and Cu(II). DNA damage was inhibited by catalase and bathocuproine, a Cu(I) specific chelator. MB induced DNA damage at every nucleotide in the presence of NADH and Fe(III)-ethylenediaminetetraacetic acid, which was inhibited by OH scavengers and catalase. MB significantly increased the formation of 8-oxo-7,8 dihydro-2'-deoxyguanosine, an oxidative DNA lesion, in the presence of NADH and metal ions. UV-visible spectrometry revealed that the absorbance of oxidized form of MB at 668nm was decreased by NADH, and the addition of metal ions attenuated the spectral change. CONCLUSIONS: MB undergoes NADH-dependent reduction followed by metal ion-mediated reoxidation. Reduced metal ions [Cu(I) and Fe(II)] interact with H2O2, generated during the redox reaction, to produce Cu(I)OOH and OH that cause DNA damage, respectively. These findings suggest that metal-mediated DNA damage contributes to MB-mediated carcinogenesis. GENERAL SIGNIFICANCE: This study would provide an insight into the mechanism of MB-induced carcinogenesis and its safety assurance for clinical use. PMID- 24792576 TI - EGFR and HER2 exert distinct roles on colon cancer cell functional properties and expression of matrix macromolecules. AB - BACKGROUND: ErbB receptors, EGFR and HER2, have been implicated in the development and progression of colon cancer. Several intracellular pathways are mediated upon activation of EGFR and/or HER2 by EGF. However, there are limited data regarding the EGF-mediated signaling affecting functional cell properties and the expression of extracellular matrix macromolecules implicated in cancer progression. METHODS: Functional assays, such as cell proliferation, transwell invasion assay and migration were performed to evaluate the impact of EGFR/HER2 in constitutive and EGF-treated Caco-2 cells. Signaling pathways were evaluated using specific intracellular inhibitors. Western blot was also utilized to examine the phosphorylation levels of ERK1/2. Real time PCR was performed to evaluate gene expression of matrix macromolecules. RESULTS: EGF increases cell proliferation, invasion and migration and importantly, EGF mediates overexpression of EGFR and downregulation of HER2. The EGF-EGFR axis is the main pathway affecting colon cancer's invasive potential, proliferative and migratory ability. Intracellular pathways (PI3K-Akt, MEK1/2-Erk and JAK-STAT) are all implicated in the migratory profile. Notably, MT1- and MT2-MMP as well as TIMP-2 are downregulated, whereas uPA is upregulated via an EGF-EGFR network. The EGF EGFR axis is also implicated in the expression of syndecan-4 and TIMP-1. However, glypican-1 upregulation by EGF is mainly mediated via HER2. CONCLUSIONS AND GENERAL SIGNIFICANCE: The obtained data highlight the crucial importance of EGF on the expression of both receptors and on the EGF-EGFR/HER2 signaling network, reveal the distinct roles of EGFR and HER2 on expression of matrix macromolecules and open a new area in designing novel agents in targeting colon cancer. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. PMID- 24792577 TI - Admission prevalence and acquisition of nasal carriage of meticillin-resistant Staphylococcus aureus (MRSA) in German rehabilitation centres. AB - This prospective multi-centre study assessed nasal colonization with meticillin resistant Staphylococcus aureus (MRSA) among patients on admission to and discharge from 11 rehabilitation centres in Germany. On admission, 71 of 5896 patients (1.2%) carried MRSA. History of MRSA carriage [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.8-10.6], hospitalization within the previous six months (OR 2.5, 95% CI 1.2-5.2), contact with pigs (OR 22.5, 95% CI 11.1-45.7) and presence of chronic wounds (OR 4.7, 95% CI 1.9-12.0) were independently associated with MRSA. On discharge, 0.3% of the patients had acquired MRSA. PMID- 24792578 TI - Angiographic outcome of intracranial aneurysms with neck remnant following coil embolization. AB - BACKGROUND: The degree of aneurysm occlusion following coil embolization has an impact on aneurysm recanalization. OBJECTIVE: To explain the natural history of intracranial aneurysms with neck remnant, Raymond-Roy Occlusion Classification (RROC) class II. METHODS: A single-center, retrospective study of 198 patients with 209 aneurysms treated with coil embolization that were initially either RROC class I or II. The angiographic outcomes at short- and long-term follow-up were compared as well as the complication/re-treatment rates. Atypical aneurysms and those that had been previously treated were excluded. RESULTS: Ninety-nine class I aneurysms were compared with 110 class II aneurysms. There was no difference in recanalization rate between the groups (class I 3.3% vs class II 8.5%, p=0.478) at short-term follow-up (8.2 months) and at subsequent follow-ups (21.7 and 52.1 months). There was also no difference in re-treatment rates (class I 3.3% vs class II 8.5%, p=0.196) or complication rates (class I 9.1% vs class II 4.6%, p=0.12). There were no aneurysm ruptures after treatment in either group. CONCLUSIONS: The angiographic outcome of aneurysms with neck remnant following coil embolization is similar to that of completely occluded aneurysms in that most remain stable and few recanalize. This understanding could potentially help the interventional neurosurgeon avoid complications such as coil herniation, vessel compromise, and stroke in selected cases. Further investigation with a larger patient population is warranted. PMID- 24792579 TI - Facing multi-drug resistant tuberculosis. AB - Multi-drug resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least two of the most effective anti tuberculosis drugs (i.e., isoniazid and rifampicin). Therapeutic regimens based on second- and third-line anti-tuberculosis medicines showed poor efficacy, safety, and tolerability profiles. It was estimated that in 2012 the multi-drug resistant tuberculosis incidence ranged from 300,000 to 600,000 cases, mainly diagnosed in the Eastern European and Central Asian countries. The highest proportion of cases is among individuals previously exposed to anti-tuberculosis drugs. Three main conditions can favour the emergence and spread of multi-drug resistant tuberculosis: the poor implementation of the DOTS strategy, the shortage or the poor quality of the anti-tuberculosis drugs, and the poor therapeutic adherence of the patients to the prescribed regimens. Consultation with tuberculosis experts (e.g., consilium) is crucial to tailor the best anti tuberculosis therapy. New therapeutic options are necessary: bedaquiline and delamanid seem promising drugs; in particular, during the development phase they demonstrated a protective effect against the emergence of further resistances towards the backbone drugs. In the recent past, other antibiotics have been administered off-label: the most relevant efficacy, safety, and tolerability profile was proved in linezolid-, meropenem/clavulanate-, cotrimoxazole containing regimens. New research and development activities are needed in the diagnostic, therapeutic, preventive fields. PMID- 24792580 TI - Improving the clinical efficiency of T2(*) mapping of ligament integrity. AB - Current MR methods use T2(*) relaxation time as a surrogate measure of ligament strength. Currently, a multi-echo voxel-wise least squares fit is the gold standard to create T2(*) maps; however, the post-processing is time-intensive and serves as a stopgap for clinical use. The study objective was to determine if an alternative method could improve post-processing time without sacrificing fidelity of T2(*) values for eventual translational use in the clinic. Using a 6 echo FLASH sequence, three different methods were used to determine intact posterior cruciate ligament (PCL) median T2(*) Two of these methods utilized a voxel-wise method to establish T2(*) maps: (1) a current "gold standard" method using a voxel-wise 6 echo least-squares fit (6LS) and (2) a voxel-wise 2 echo point T2(*) determination (2MM). The third method used median ligament signal intensity and a single nonlinear least-squares fit (6LSROI) instead of a voxel wise basis. The resulting median T2(*) values of the PCL and computational time were compared. The median T2(*) values were 42% higher using the 2MM compared to the 6LS method (p<0.0001). However, a strong correlation was found for the median T2(*) values between the 2MM and 6LS methods (R(2)=0.80). The median T2(*) values were not significantly different between the 6LS and 6LSROI methods (p=0.519). Using the 2MM (which provides a regional map) and the 6LSROI (which efficiently provides the median T2(*) value) methods in tandem would take only minutes of post-processing computational time compared to the 6LS method (~540 min), and hence would facilitate clinical application of T2(*) maps to predict ligament structural properties as a patient outcome measure. PMID- 24792582 TI - Pilot study to assess effects of collection tube types and processing delay on measurements of persistent organic pollutants and lipids in human serum. AB - Glass red top tubes (RTs), traditionally used to draw blood for biomonitoring studies, have some limitations during field sampling (e.g., tube breakage, timely processing may be difficult). This pilot study examined whether serum separation tubes (SSTs) with delayed processing time (48 h) can be used instead of red top tubes (RTs) to accommodate field conditions. Using state-of-the-art methodologies, PBDEs, PCBs, OCPs, PFCs, cholesterol and triglycerides were measured to evaluate any differences among 2 test conditions (RTs with 2h processing time; SSTs with 48 h processing time). Between the 2 test conditions, we observed high rank correlations among the measured compounds and no statistically significant differences in the levels of measured compounds. We conclude that SSTs with delayed processing time (48 h) produce similar results as RTs with short processing time (2h), suggesting that SSTs could be good substitutes for RTs for new epidemiological and biomonitoring field studies. The use of SSTs offers a tremendous opportunity for the use of samples archived in various SSTs. PMID- 24792581 TI - Human L3L4 intervertebral disc mean 3D shape, modes of variation, and their relationship to degeneration. AB - Intervertebral disc mechanics are affected by both disc shape and disc degeneration, which in turn each affect the other; disc mechanics additionally have a role in the etiology of disc degeneration. Finite element analysis (FEA) is a favored tool to investigate these relationships, but limited data for intervertebral disc 3D shape has forced the use of simplified or single-subject geometries, with the effect of inter-individual shape variation investigated only in specialized studies. Similarly, most data on disc shape variation with degeneration is based on 2D mid-sagittal images, which incompletely define 3D shape changes. Therefore, the objective of this study was to quantify inter individual disc shape variation in 3D, classify this variation into independently occurring modes using a statistical shape model, and identify correlations between disc shape and degeneration. Three-dimensional disc shapes were obtained from MRI of 13 human male cadaver L3L4 discs. An average disc shape and four major modes of shape variation (representing 90% of the variance) were identified. The first mode represented disc axial area and was significantly correlated to degeneration (R(2)=0.44), indicating larger axial area in degenerate discs. Disc height variation occurred in three distinct modes, each also involving non-height variation. The statistical shape model provides an average L3L4 disc shape for FEA that is fully defined in 3D, and makes it convenient to generate a set of shapes with which to represent aggregate inter individual variation. Degeneration grade-specific shapes can also be generated. To facilitate application, the model is included in this paper's supplemental content. PMID- 24792583 TI - Dietary supplementation with vitamin k affects transcriptome and proteome of Senegalese sole, improving larval performance and quality. AB - Nutritional factors strongly influence fish larval development and skeletogenesis, and may induce skeletal deformities. Vitamin K (VK) has been largely disregarded in aquaculture nutrition, despite its important roles in bone metabolism, in gamma-carboxylation of Gla proteins, and in regulating gene expression through the pregnane X receptor (Pxr). Since the mechanisms mediating VK effects over skeletal development are poorly known, we investigated the effects of VK-supplementation on skeletal development in Senegalese sole larvae, aiming to identify molecular pathways involved. Larvae were fed live preys enriched with graded levels of phylloquinone (PK) (0, 50, and 250 mg kg(-1)) and survival rate, growth, VK contents, calcium content and incidence of skeletal deformities were determined, revealing an improvement of larval performance and decreasing the incidence of deformities in VK-supplemented groups. Comparative proteome analysis revealed a number of differentially expressed proteins between Control and Diet 250 associated with key biological processes including skin, muscle, and bone development. Expression analysis showed that genes encoding proteins related to the VK cycle (ggcx, vkor), VK nuclear receptor (pxr), and VK dependent proteins (VKDPs; oc1 and grp), were differentially expressed. This study highlights the potential benefits of increasing dietary VK levels in larval diets, and brings new insights on the mechanisms mediating the positive effects observed on larval performance and skeletal development. PMID- 24792584 TI - RNA biomarker release with ultrasound and phase-change nanodroplets. AB - Microbubbles driven by ultrasound are capable of permeabilizing cell membranes and allowing biomarkers or therapeutics to exit from or enter cancer cells, respectively. Unfortunately, the relatively large size of microbubbles prevents extravasation. Lipid-based perfluorobutane microbubbles can be made seven-fold smaller by pressurization, creating 430-nm nanodroplets. The present study compares microbubbles and nanodroplets with respect to their ability to enhance miR-21 and mammaglobin mRNA release from cultured ZR-75-1 cells. Mammaglobin mRNA and miR-21 release increased with escalating concentrations of nanodroplets up to, respectively, 25- and 42-fold with 2% nanodroplets (v/v), compared with pre ultrasound levels, whereas cell viability decreased to 62.4%. Sonication of ZR-75 1 cells incubated with microbubbles or nanodroplets caused relatively similar levels of cell death and miR-21 release, suggesting that nanodroplets are similar to microbubbles in enhancing cell permeability, but may be more advantageous because of their smaller size, which may allow extravasation through leaky tumor vasculature. PMID- 24792585 TI - Does academic achievement during childhood and adolescence benefit later health? AB - PURPOSE: Educational disparities in health persist after adjustment for income and occupation, suggesting that other purely cognitive and psychosocial mechanisms may be involved. Unlike occupation- or income-mediated effects, effects of cognitive and psychosocial gains-as reflected in academic achievement may be apparent even before schooling is completed. METHODS: We used data spanning 10 years on a national U.S. cohort of 2546 children aged 3-14 years at baseline to estimate the effects of academic achievement, measured by standardized tests of cognitive achievement, on future health. We used marginal structural models to address potential mutual influence of achievement and health on each other over time. RESULTS: One SD higher academic achievement 1997-2002 was associated with a lower prevalence of poorer health status in 2007 in girls (prevalence ratio = 0.87 [(95% confidence interval) 0.78-0.97]) but not in boys (prevalence ratio = 0.96 [0.86-1.08]). Higher achievement was also weakly associated with lower body mass index and less psychological distress among girls only. CONCLUSIONS: Academic achievement may benefit future health but a number of questions remain unanswered, including reasons for the gender differences and how academic achievement-related health disparities may progress over the life course and interact with other social determinants of health. PMID- 24792586 TI - Young adulthood obesity and risk of acute coronary syndromes, stable angina pectoris, and congestive heart failure: a 36-year cohort study. AB - PURPOSE: To examine the association between young adulthood obesity and long-term risk of ischemic heart disease (IHD) and nonischemic congestive heart failure (CHF). METHODS: We conducted a population-based cohort study of 12,850 male conscripts whose fitness for military service was examined by Draft Boards in Northern Denmark. Outcomes were obtained from the Danish National Patient Registry, covering all Danish hospitals since 1977. Follow-up began on the 22nd birthday of each subject and continued until occurrence of an outcome, emigration, death, or on December 31, 2012, whichever came first. We used Cox regression to compute hazard ratios (HRs). RESULTS: The 36-year risk was 7.3% for IHD and 0.8% for CHF without pre-existing IHD among men of normal weight and 11.1% and 4.0% among obese men, respectively. Comparing obese men with men of normal weight, the adjusted HR was 1.63 (95% confidence interval [CI], 0.98-2.73) for IHD overall, 2.86 (95% CI, 1.56-5.25) for myocardial infarction, 5.52 (95% CI, 2.38-12.82) for unstable angina, 1.29 (95% CI, 0.69-2.41) for stable angina, and 6.68 (95% CI, 2.85-15.66) for CHF without pre-existing IHD. CONCLUSIONS: Young adulthood obesity was an important risk factor for IHD but also for CHF without pre-existing IHD. PMID- 24792587 TI - Reproductive windows, genetic loci, and breast cancer risk. AB - PURPOSE: The reproductive windows between age at menarche and age at first birth (standardized age at first birth) and from menarche to menopause (reproductive lifespan) may interact with genetic variants in association with breast cancer risk. METHODS: We assessed this hypothesis in 6131 breast cancer cases and 7274 controls who participated in the population-based Collaborative Breast Cancer Study. Risk factor information was collected through telephone interviews, and DNA samples were collected on a subsample (N= 1484 cases, 1307 controls) to genotype for 13 genome-wide association study-identified loci. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and P values for the interaction between reproductive windows and genotypes were obtained by adding cross-product terms to statistical models. RESULTS: For standardized age at first birth, the OR was 1.52 (CI, 1.36-1.71) comparing the highest quintile with the lowest quintile. Carrier status for rs10941679 (5p12) and rs10483813 (RAD51B) appeared to modify this relationship (P = .04 and P = .02, respectively). For reproductive lifespan, the OR comparing the highest quintile with the lowest quintiles was 1.62 (CI, 1.35-1.95). No interactions were detected between genotype and reproductive lifespan (all P > .05). All results were similar regardless of ductal versus lobular breast cancer subtype. CONCLUSIONS: Our results suggest that the reproductive windows are associated with breast cancer risk and that associations may vary by genetic variants. PMID- 24792588 TI - Retinal neurodegenerative changes in the adult insulin receptor substrate-2 deficient mouse. AB - Insulin receptor substrate-2 (Irs2) mediates peripheral insulin action and is essential for retinal health. Previous investigations have reported severe photoreceptor degeneration and abnormal visual function in Irs2-deficient mice. However, molecular changes in the Irs2(-)(/)(-) mouse retina have not been described. In this study, we examined retinal degenerative changes in neuronal and glial cells of adult (9- and 12-week old) Irs2(-)(/)(-) mice by immunohistochemistry. 9-week old Irs2(-)(/)(-) mice showed significant thinning of outer retinal layers, concomitant to Muller and microglial cell activation. Photoreceptor cells displayed different signs of degeneration, such as outer/inner segment atrophy, redistribution of rod- and cone-opsins and spatial disorganization of cone cells. This was accompanied by synaptic changes at the outer plexiform layer, including the retraction of rod-spherules, reduction of photoreceptor synaptic ribbons and synaptic remodeling in second order neurons (i.e. loss and sprouting of dendritic processes in rod bipolar and horizontal cells). By 12 weeks of age, the thickness of inner retinal layers was severely affected. Although inner plexiform layer stratification remained unchanged at this stage, rod bipolar cell axon terminals were significantly depleted. Significant loss of Brn3a(+) retinal ganglion cells occurred in 12-week old Irs2( )(/)(-) mice, in contrast to younger ages. Adult Irs2(-)(/)(-) mice showed clear hallmarks of neurodegeneration and disruption of the inner retina with increasing age. Pharmacological stimulation of Irs2 signaling pathway may provide additional neuroprotection in certain degenerative retinopathies. PMID- 24792590 TI - Effect of radiation dose level on the detectability of pulmonary nodules in chest tomosynthesis. AB - OBJECTIVE: To investigate the detectability of pulmonary nodules in chest tomosynthesis at reduced radiation dose levels. METHODS: Eighty-six patients were included in the study and were examined with tomosynthesis and computed tomography (CT). Artificial noise was added to simulate that the tomosynthesis images were acquired at dose levels corresponding to 12, 32, and 70% of the default setting effective dose (0.12 mSv). Three observers (with >20, >20 and three years of experience) read the tomosynthesis cases for presence of nodules in a free-response receiver operating characteristics (FROC) study. CT served as reference. Differences between dose levels were calculated using the jack-knife alternative FROC (JAFROC) figure of merit (FOM). RESULTS: The JAFROC FOM was 0.45, 0.54, 0.55, and 0.54 for the 12, 32, 70, and 100% dose levels, respectively. The differences in FOM between the 12% dose level and the 32, 70, and 100% dose levels were 0.087 (p = 0.006), 0.099 (p = 0.003), and 0.093 (p = 0.004), respectively. Between higher dose levels, no significant differences were found. CONCLUSIONS: A substantial reduction from the default setting dose in chest tomosynthesis may be possible. In the present study, no statistically significant difference in detectability of pulmonary nodules was found when reducing the radiation dose to 32%. KEY POINTS: * A substantial radiation dose reduction in chest tomosynthesis may be possible. * Pulmonary nodule detectability remained unchanged at 32% of the effective dose. * Tomosynthesis might be performed at the dose of a lateral chest radiograph. PMID- 24792593 TI - [Anaesthesiological management of patients with dementia]. AB - The aging society challenges anaesthesiologists with a growing number of patients with dementia. These and their relatives worry about an aggravation of an already existing dementia or even the postoperative evocation of one. Common volatile anaesthetics and propofol are suspected to increase dementia - associated protein tau and amyloid-betalevels in the brain. Perioperative complications such as cognitive dysfunction and delirium occur more frequently in dementia patients. For anaesthesiologists, it seems prudent toassess the grade of dementia in the elderly to adjust anaesthesia drug doses and monitoring intra- and postoperatively. Pharmacological interactions with antidementic andneuroleptic current medications affectanaesthetic and analgesic effects.In dementia, perioperative malfunction of cognition, memory, attention, information processing, communication and social interaction abilities is of profound influence on the perioperative management.This review mentions actual knowledge about dementia forms and symptoms in brief. Recommendations for the anaesthesia care are given in more detail. PMID- 24792589 TI - Endoplasmic reticulum stress and the unfolded protein responses in retinal degeneration. AB - The endoplasmic reticulum (ER) is the primary intracellular organelle responsible for protein and lipid biosynthesis, protein folding and trafficking, calcium homeostasis, and several other vital processes in cell physiology. Disturbance in ER function results in ER stress and subsequent activation of the unfolded protein response (UPR). The UPR up-regulates ER chaperones, reduces protein translation, and promotes clearance of cytotoxic misfolded proteins to restore ER homeostasis. If this vital process fails, the cell will be signaled to enter apoptosis, resulting in cell death. Sustained ER stress also can trigger an inflammatory response and exacerbate oxidative stress, both of which contribute synergistically to tissue damage. Studies performed over the past decade have implicated ER stress in a broad range of human diseases, including neurodegenerative diseases, cancer, diabetes, and vascular disorders. Several of these diseases also entail retinal dysfunction and degeneration caused by injury to retinal neurons and/or to the blood vessels that supply retinal cells with nutrients, trophic and homeostatic factors, oxygen, and other essential molecules, as well as serving as a conduit for removal of waste products and potentially toxic substances from the retina. Collectively, such injuries represent the leading cause of blindness world-wide in all age groups. Herein, we summarize recent progress on the study of ER stress and UPR signaling in retinal biology and discuss the molecular mechanisms and the potential clinical applications of targeting ER stress as a new therapeutic approach to prevent and treat neuronal degeneration in the retina. PMID- 24792591 TI - Low tube voltage and low contrast material volume cerebral CT angiography. AB - OBJECTIVES: To evaluate the image quality, radiation dose and diagnostic accuracy of low kVp and low contrast material volume cerebral CT angiography (CTA) in intracranial aneurysm detection. METHODS: One hundred twenty patients were randomly divided into three groups (n = 40 for each): Group A, 70 ml iodinated contrast agent/120 kVp; group B, 30 ml/100 kVp; group C, 30 ml/80 kVp. The CT numbers, noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured in the internal carotid artery (ICA) and middle cerebral artery (MCA). Subjective image quality was evaluated. For patients undergoing DSA, diagnostic accuracy of CTA was calculated with DSA as reference standard and compared. RESULTS: CT numbers of ICA and MCA were higher in groups B and C than in group A (P < 0.01). SNR and CNR in groups A and B were higher than in group C (both P < 0.05). There was no difference in subjective image quality among the three groups (P = 0.939). Diagnostic accuracy for aneurysm detection among these groups had no statistical difference (P = 1.00). Compared with group A, the radiation dose of groups B and C was decreased by 45% and 74%. CONCLUSION: Cerebral CTA at 100 or 80 kVp using 30 ml contrast agent can obtain diagnostic image quality with a low radiation dose while maintaining the same diagnostic accuracy for aneurysm detection. KEY POINTS: * Cerebral CTA is feasible using 100/80 kVp and 30 ml contrast agent. * This approach obtains diagnostic image quality with 45-74% radiation dose reduction. * Diagnostic accuracy for intracranial aneurysm detection seems not to be compromised. PMID- 24792594 TI - [Invasive emergency techniques--cricothyroidotomy]. AB - On-scene invasive emergency procedures, such as cricothyroidotomy, chest drain, intraosseous puncture or even on-field-amputation, are often unavoidable, when indicated, and present a major challenge for the emergency physician. Personal, temporal or local conditions are often unsuitable. Even with regular intervention by the emergency medical service, "last resort" measures occur very infrequently, particularly in relation to paediatric emergencies. As well as theoretical training, practice-oriented course concepts are essential in order to achieve high quality in these procedures. This article presents the use of cricothyroidotomy on adults and children, with reference to indication, implementation, problems and risks. It is part of a series of four articles on the subject of invasive emergency techniques. PMID- 24792595 TI - [Pssst ... AINS Secrets ! - Today, from oral and maxillofacial surgery]. PMID- 24792597 TI - [Patient blood management - must a hospital handle blood management?]. PMID- 24792598 TI - [Patient blood management--The preoperative patient]. AB - Preoperative anaemia is an independent risk factor for an increase in perioperative morbidity and mortality. Patient Blood Management (PBM) aims for an early detection of anaemia in elective surgery patients. Reasons for anaemia should be detected and causally treated if possible. A multidisciplinary team of specialists aims for diagnosis and causative treatment of easily treatable and frequent causes of anaemia like iron deficiency, bleeding or (autoimmune) haemolysis using patients' specific history, examination, laboratory and technical methods. Such an outpatient PBM programme is only feasible, if anaesthesiologists, surgeons, haematologists, gastroenterologists, gynecologists, laboratory and transfusion medicine specialists work together in a PBM team using a common PBM plan. Communication within this team as well as with the patients' physicians in their private offices is key for a long lasting success of such a PBM programme. PMID- 24792599 TI - [Patient blood management--The inpatient care]. AB - The multimodal concept of Patient Blood Management touches many aspects of in hospital treatment. The goals are to preserve and strengthen the patients' own resources in order to avoid transfusion-associated adverse events. This can be achieved by meticulous minimization of perioperative blood loss and the enhancement and full utilization of individual anaemia tolerance. The transfusion of allogeneic blood products shall be guideline-based only. The proposed package of measures has immense potential to increase patient safety! PMID- 24792600 TI - [Patient blood management--How does it work in practice?--the interdisciplinary cooperation]. AB - Patient blood management (PBM), as a multidisciplinary, evidence-based treatment concept for reducing anemia and blood losses, should be realized in individual hospitals after local adaptation according to the available facilities.The implementation of a PBM program in clinical institutions will be a challenging but in every case worthwhile task. The local facilities may be insufficient to fulfill the training requirements of a large group of different personnel. Accordingly, sustained support by the hospital's management with provision of the necessary resources for personnel and materials is essential. The formation of the core PBM team, in our case consisting initially of anaesthesiologists, surgeons, internists and transfusion medicine specialists as well as - the particularly important - motivated nursing personnel, is one of the most pressing and primary tasks in the establishment of a PBM project.It is also extremely important to firmly anchor the PBM project permanently within the hospital. Possible steps and details for this purpose are presented and discussed in terms of value and weighting by the authors on the basis of their actual experience in Frankfurt University Hospital. PMID- 24792606 TI - Qualitative exploration of the perceived barriers and enablers to Aboriginal and Torres Strait Islander people accessing healthcare through one Victorian Emergency Department. AB - Abstract Aboriginal and Torres Strait Islander people experience challenges when accessing health care from the Emergency Department. The aim of this project was to identify the perceived barriers and enablers to accessing health care at one Victorian Emergency Department for the local Aboriginal and Torres Strait Islander community. This qualitative explorative study collected data using focus groups or yarns to investigate the perceptions of the Aboriginal and Torres Strait Islander community presentations to the Emergency Department. Data were analysed following the standards of qualitative data analysis procedure. Three themes emerged organisational process, staff interactions and strategies for improvement. Information from this study will assist hospital and Emergency Department executives and practitioners to collaborate with the Aboriginal and Torres Strait Islander community in developing and implementing policy and practice changes that enable Aboriginal patients to be identified and receive culturally appropriate care. PMID- 24792605 TI - Phospholipids and protein adaptation of Pseudomonas sp. to the xenoestrogen tributyltin chloride (TBT). AB - A tributyltin (TBT)-resistant strain of Pseudomonas sp. isolated from an overworked car filter was tested for its adaptation to TBT. The isolate was checked for organotin degradation ability, as well as membrane lipid and cellular protein composition in the presence of TBT. The phospholipid profiles of bacteria, grown with and without increased amounts of TBT, were characterized using liquid chromatography/electrospray ionization/mass spectrometry. The strain reacted to the biocide by changing the composition of its phospholipids. TBT induced a twofold decline in the amounts of many molecular species of phosphatidylglycerol and an increase in the levels of phosphatidic acid (by 58%) and phosphatidylethanolamine (by 70%). An increase in the degree of saturation of phospholipid fatty acids of TBT exposed Pseudomonas sp. was observed. These changes in the phospholipid composition and concentration reflect the mechanisms which support optimal lipid ordering in the presence of toxic xenobiotic. In the presence of TBT the abundances of 16 proteins, including TonB-dependent receptors, porins and peroxidases were modified, which could indicate a contribution of some enzymes to TBT resistance. PMID- 24792607 TI - Imaging of lumbar spine fusion. AB - This article reviews the imaging of lumbar spinal fusion and its major indications. The most common procedures are described for the purpose of allowing understanding of postoperative imaging. Imaging options are reviewed for preoperative workup, intraoperative guidance, and postoperative purposes. Examples of hardware integrity, fusion, and loosening are provided. PMID- 24792608 TI - Motion preservation surgery in the spine. AB - The primary goal of motion preservation surgery in the spine is to maintain normal or near normal motion in an attempt to prevent adverse outcomes commonly seen with conventional spinal fusion, most notably the development of adjacent level degenerative disc disease. Several different surgical approaches have been developed to preserve motion in the lumbar spine, including total disc replacement, partial disc (nucleus) replacement, interspinous spacers, dynamic stabilization devices, and total facet replacement devices. The design of devices varies greatly. The devices are created using a similar rationale but are unique in design relative to their lumbar counterparts. PMID- 24792609 TI - The postoperative spine: what the spine surgeon needs to know. AB - Radiologists are often required to evaluate postoperative spine imaging to assist the surgeon with further clinical management. This article reviews common spine surgical techniques and their proper evaluation on imaging from a surgical perspective. The article attempts to provide a basic surgical foundation for radiologists and a clearer delineation of important points and complications that should be commented on when evaluating the postoperative spine on imaging. PMID- 24792610 TI - Postoperative spine complications. AB - Imaging of the postoperative spine is common, although it remains a difficult task for radiologists. This article presents an overview of common surgical approaches and spinal hardware, and specific complications that may be associated with each procedure. In addition, expected postoperative changes and complications that are common among procedures, with their differential diagnosis and imaging features, are discussed. PMID- 24792611 TI - Postoperative spine imaging in cancer patients. AB - Primary or metastatic spine tumors can present with pain and/or neurologic compromise depending on their location within the spinal axis. Metastases and multiple myeloma comprise most of these lesions. Management of spinal tumors includes surgical decompression with stabilization (neo), adjuvant chemotherapy and radiation therapy, curettage, bone grafting, bone marrow replacement, and palliative treatment with vertebral augmentation. Pre- and postoperative imaging plays a critical role in the diagnosis and management of patients with spinal tumors. This article reviews postoperative imaging of the spine, including imaging protocols, immediate and long-term routine imaging findings, and emergent findings in symptomatic patients. PMID- 24792612 TI - Post-vertebral augmentation spine imaging. AB - Although imaging plays a critical role and has become an integral part in preprocedure evaluation of osteoporotic patients at risk of compression fracture, many treated patients undergo follow-up imaging, for reasons ranging from potential procedure-related complications to development of new symptoms after initial improvement after successful vertebral augmentation (VA). Although imaging is frequently obtained for evaluation of these patients, there is a general lack of knowledge about imaging characteristics of treated vertebrae. This article reviews various indications for post-VA imaging, the appearance of augmented spine on imaging, and the important complications associated with the VA procedure. PMID- 24792613 TI - Optimized imaging of the postoperative spine. AB - Few tasks in imaging are more challenging than that of optimizing evaluations of the instrumented spine. The authors describe how applying fundamental and more advanced principles to postoperative spine computed tomography and magnetic resonance examinations mitigates the challenges associated with metal implants and significantly improves image quality and consistency. Newer and soon-to-be available enhancements should provide improved visualization of tissues and hardware as multispectral imaging sequences continue to develop. PMID- 24792614 TI - Imaging and management of postoperative spine infection. AB - Imaging evaluation of postoperative spinal infection is challenging. A systematic approach and keen understanding of multimodality imaging techniques, as well as knowledge of the patient's surgical procedure and clinical presentation, are critical for the radiologist to render an accurate diagnosis. Because of the overlap between diagnostic imaging findings in the postoperative spine and the infected spine, in those situations in which the index of clinical suspicion for spine infection is high, then immediate consideration ought to be given to performing a spine biopsy. PMID- 24792616 TI - Neuroimaging Clinics of North America. Imaging of the postoperative spine. Foreword. PMID- 24792615 TI - Radiologic evaluation and management of postoperative spine paraspinal fluid collections. AB - Postoperative paraspinal fluid collections can present a management dilemma to both radiologists and surgeons. Although many of these collections present as incidental findings and are unrelated to the presenting signs and symptoms that led to the imaging study, certain collections in the context of the appropriate clinical scenario may require additional evaluation and even emergent intervention. This article reviews those collections that are most frequently encountered and suggests management strategies that may assist in the evaluation and management of the patient. PMID- 24792617 TI - Postoperative spine imaging and evaluation. PMID- 24792618 TI - Stepwise metabolic engineering of Gluconobacter oxydans WSH-003 for the direct production of 2-keto-L-gulonic acid from D-sorbitol. AB - 2-Keto-L-gulonic acid (2-KLG), the direct precursor of vitamin C, is currently produced by a two-step fermentation route from D-sorbitol. However, this route involves three bacteria, making the mix-culture system complicated and redundant. Thus, replacement of the conventional two-step fermentation process with a one step process could be revolutionary in vitamin C industry. In this study, different combinations of five L-sorbose dehydrogenases (SDH) and two L-sorbosone dehydrogenases (SNDH) from Ketogulonicigenium vulgare WSH-001 were introduced into Gluconobacter oxydans WSH-003, an industrial strain used for the conversion of d-sorbitol to L-sorbose. The optimum combination produced 4.9g/L of 2-KLG. In addition, 10 different linker peptides were used for the fusion expression of SDH and SNDH in G. oxydans. The best recombinant strain (G. oxydans/pGUC-k0203-GS k0095) produced 32.4g/L of 2-KLG after 168h. Furthermore, biosynthesis of pyrroloquinoline quinine (PQQ), a cofactor of those dehydrogenases, was enhanced to improve 2-KLG production. With the stepwise metabolic engineering of G. oxydans, the final 2-KLG production was improved to 39.2g/L, which was 8.0-fold higher than that obtained using independent expression of the dehydrogenases. These results bring us closer to the final one-step industrial-scale production of vitamin C. PMID- 24792619 TI - Spindle assembly checkpoint protein expression correlates with cellular proliferation and shorter time to recurrence in ovarian cancer. AB - Ovarian carcinoma (OC) is the most lethal of the gynecological malignancies, often presenting at an advanced stage. Treatment is hampered by high levels of drug resistance. The taxanes are microtubule stabilizing agents, used as first line agents in the treatment of OC that exert their apoptotic effects through the spindle assembly checkpoint. BUB1-related protein kinase (BUBR1) and mitotic arrest deficient 2 (MAD2), essential spindle assembly checkpoint components, play a key role in response to taxanes. BUBR1, MAD2, and Ki-67 were assessed on an OC tissue microarray platform representing 72 OC tumors of varying histologic subtypes. Sixty-one of these patients received paclitaxel and platinum agents combined; 11 received platinum alone. Overall survival was available for all 72 patients, whereas recurrence-free survival (RFS) was available for 66 patients. Increased BUBR1 expression was seen in serous carcinomas, compared with other histologies (P = .03). Increased BUBR1 was significantly associated with tumors of advanced stage (P = .05). Increased MAD2 and BUBR1 expression also correlated with increased cellular proliferation (P < .0002 and P = .02, respectively). Reduced MAD2 nuclear intensity was associated with a shorter RFS (P = .03), in ovarian tumors of differing histologic subtype (n = 66). In this subgroup, for those women who received paclitaxel and platinum agents combined (n = 57), reduced MAD2 intensity also identified women with a shorter RFS (P < .007). For the entire cohort of patients, irrespective of histologic subtype or treatment, MAD2 nuclear intensity retained independent significance in a multivariate model, with tumors showing reduced nuclear MAD2 intensity identifying patients with a poorer RFS (P = .05). PMID- 24792620 TI - Fibroblast activation protein, a potential diagnostic and therapeutic target for cancer-reply. PMID- 24792621 TI - Leukocyte chemotactic factor 2 amyloidosis cannot be reliably diagnosed by immunohistochemical staining. AB - We investigated the role of leukocyte chemotactic factor (LECT2) immunohistochemical staining in the diagnosis of type of renal amyloidosis. Fifty renal amyloidosis cases with available paraffin blocks in our 2002 to 2012 renal biopsy files were reviewed. Patients were designated as a defined amyloid, including amyloid light chain (AL) and amyloid-associated amyloid (AA), or a non AL/non-AA amyloid group. LECT2-specific antibody immunohistochemistry was performed in all 50 cases. Laser microdissection and mass spectrometry (LMD/MS) were performed in 10 cases. Forty-five patients had amyloid classified as either AL (44) or AA (1), and 5 had undetermined amyloid. Three of the five non-AL/non AA group patient biopsies showed positive LECT2 immunohistochemical staining, and of these, LECT2 was also identified by LMD/MS in 1 patient, fibrinogen-alpha was identified in 1 patient, and apolipoprotein IV was identified in 1 patient. Two of these non-AL/non-AA patients showed negative LECT2 staining, and LMD/MS showed apolipoprotein IV as a major protein component. Five of the 44 AL amyloid patients showed weakly positive LECT2 staining. However, LECT2 was not identified by LMD/MS in any of these 5 cases. The single patient with AA amyloid was negative for LECT2 by immunohistochemical staining. Among 5 non-AL and non-AA amyloidosis patients in our study, 1 had LECT2, 1 had fibrinogen-alpha, and 3 had apolipoprotein IV as a major protein component. The data from this study show that weak LECT2 staining should be regarded as indeterminate or a negative result and does not per se allow diagnosis of specific amyloid type. The diagnosis of LECT2 renal amyloidosis may require LMD/MS confirmation. PMID- 24792622 TI - Squamous cell carcinoma arising in dedifferentiated chondrosarcoma proved by isocitrate dehydrogenase mutation analysis. AB - Dedifferentiated chondrosarcoma is a primary bone tumor characterized by the presence of both low-grade cartilaginous and high-grade malignant noncartilaginous components. The high-grade noncartilaginous component is typically a pleomorphic fibroblastic spindle cell sarcoma. Dedifferentiation into a malignant epithelial component is extremely rare. In this report, we present a 74-year-old woman who developed a metastatic squamous cell carcinoma in the right inguinal area 1 year after wide resection of her right proximal femur for a dedifferentiated chondrosarcoma. The dedifferentiated component was composed of poorly differentiated epithelioid cells with foci of squamous cell carcinoma. Mutational analysis was performed, and the isocitrate dehydrogenase 1 R132C mutation was detected in the low-grade chondrosarcoma, dedifferentiated chondrosarcoma as well as the metastatic squamous cell carcinoma. And this mutation was not detected in patient's normal tissue. Our study supports the theory that both the chondrosarcoma cells and dedifferentiated epithelioid tumor cells arose from the same clonal origin. PMID- 24792624 TI - Diagnostic uncertainty and recall bias in chronic low back pain. AB - Patients' beliefs about the origin of their pain and their cognitive processing of pain-related information have both been shown to be associated with poorer prognosis in low back pain (LBP), but the relationship between specific beliefs and specific cognitive processes is not known. The aim of this study was to examine the relationship between diagnostic uncertainty and recall bias in 2 groups of chronic LBP patients, those who were certain about their diagnosis and those who believed that their pain was due to an undiagnosed problem. Patients (N=68) endorsed and subsequently recalled pain, illness, depression, and neutral stimuli. They also provided measures of pain, diagnostic status, mood, and disability. Both groups exhibited a recall bias for pain stimuli, but only the group with diagnostic uncertainty also displayed a recall bias for illness related stimuli. This bias remained after controlling for depression and disability. Sensitivity analyses using grouping by diagnosis/explanation received supported these findings. Higher levels of depression and disability were found in the group with diagnostic uncertainty, but levels of pain intensity did not differ between the groups. Although the methodology does not provide information on causality, the results provide evidence for a relationship between diagnostic uncertainty and recall bias for negative health-related stimuli in chronic LBP patients. PMID- 24792623 TI - Functional significance of macrophage-derived exosomes in inflammation and pain. AB - Exosomes, secreted microvesicles transporting microRNAs (miRNAs), mRNAs, and proteins through bodily fluids, facilitate intercellular communication and elicit immune responses. Exosomal contents vary, depending on the source and the physiological conditions of cells, and can provide insights into how cells and systems cope with physiological perturbations. Previous analysis of circulating miRNAs in patients with complex regional pain syndrome (CRPS), a debilitating chronic pain disorder, revealed a subset of miRNAs in whole blood that are altered in the disease. To determine functional consequences of alterations in exosomal biomolecules in inflammation and pain, we investigated exosome-mediated information transfer in vitro, in a rodent model of inflammatory pain, and in exosomes from patients with CRPS. Mouse macrophage cells stimulated with lipopolysaccharides secrete exosomes containing elevated levels of cytokines and miRNAs that mediate inflammation. Transcriptome sequencing of exosomal RNA revealed global alterations in both innate and adaptive immune pathways. Exosomes from lipopolysaccharide-stimulated cells were sufficient to cause nuclear factor kappaB activation in naive cells, indicating functionality in recipient cells. A single injection of exosomes attenuated thermal hyperalgesia in a murine model of inflammatory pain, suggesting an immunoprotective role for macrophage-derived exosomes. Macrophage-derived exosomes carry a protective signature that is altered when secreting cells are exposed to an inflammatory stimulus. We also show that circulating miRNAs altered in patients with complex regional pain syndrome are trafficked by exosomes. With their systemic signaling capabilities, exosomes can induce pleiotropic effects potentially mediating the multifactorial pathology underlying chronic pain, and should be explored for their therapeutic utility. PMID- 24792625 TI - Calretinin and pathologic diagnosis of Hirschsprung disease: has the time come to abandon the acetylcholinesterase stain? PMID- 24792627 TI - Fecal transplant for recurrent Clostridium difficile infection in children with and without inflammatory bowel disease. AB - Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or long-term follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician's Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT. PMID- 24792626 TI - Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. AB - OBJECTIVES: Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD. METHODS: WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay. RESULTS: We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-to-glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD. CONCLUSIONS: Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development. PMID- 24792628 TI - Virulence factors and antibiotic resistance in children with Helicobacter pylori gastritis. AB - OBJECTIVES: There are limited data regarding the pattern of Helicobacter pylori (Hp) antibiotic resistance and virulence factors in children. Evaluation of prevalence of drug resistance and virulence-factor genotype in children with Hp gastritis and to investigate whether there is any relation between drug resistance and genotype were our aims in this study. METHODS: Ninety-eight children with polymerase chain reaction-positive Hp gastritis were included. Antimicrobial susceptibility was tested by disc diffusion method and polymerase chain reaction assays were used for the determination of virulence factors. RESULTS: The resistance rates to clarithromycin, metronidazole, and amoxicillin were 23.5%, 11.7%, and 3.9%, respectively. All strains carried vacA genotype, and 51%, 70.4%, 49%, 34.7%, and 25.5% were cagA-, cagE-, babA2-, iceA1-, and iceA2 positive, respectively. Of those 98 specimens, 81.6%, 19.4%, 38.8%, and 63.3% carried vacAs1, vacAs2, vacAm1, and vacAm2, respectively. Dominant vacA type was s1am2 (32.7%), followed by s1am1 (14.3%) and s2m2 (12.2%). Significant rates of clarithromycin resistance were observed in cagE-, iceA1-, babA2-, and vacAs1c positive groups. In those with metronidazole resistance, vacAs1 and vacAs1c were more common (P < 0.05). CONCLUSIONS: The cagE-positive and vacA s1a/m2 genotypes, which are correlated with increased antibiotic resistance, were predominant in our population. In countries where Hp infection is prevalent, studies focusing on virulence factors and antibiotic susceptibility may provide anticipation of the prognosis and may be helpful to reduce morbidity and mortality. PMID- 24792629 TI - Use of upper gastrointestinal series before gastrostomy tube placement. AB - We studied the use of a preoperative upper gastrointestinal series in children with and without major congenital anomalies undergoing gastrostomy tube (G-tube) placement. Of 1163 children evaluated, 743 had major anomalies and a total of 39 episodes of malrotation were found. All of the children with malrotation had either major congenital anomalies or cystic fibrosis. Our study suggests that an upper gastrointestinal series may be unnecessary before G-tube placement in children without other congenital anomalies or cystic fibrosis. PMID- 24792630 TI - Use of a novel laparoscopic gastrostomy technique in children with severe epidermolysis bullosa. AB - OBJECTIVE: Supplementing nutrition in children with severe epidermolysis bullosa (EB) is challenging because of skin and mucosal fragility. Percutaneous endoscopic gastrostomy is contraindicated in EB, whereas more invasive open surgical gastrostomy placement can be complicated by chronic leakage. The aim of the study was to review the efficacy and acceptability, in children with severe EB, of our modified 2-port laparoscopic approach using the Seldinger technique with serial dilatation and tube insertion through a peel-away sheath. METHODS: Retrospective review of children with EB who underwent laparoscopic feeding gastrostomy at our centre since 2009. RESULTS: Seven children (6 severe generalised recessive dystrophic EB, 1 non-Herlitz junctional EB; 2 girls, 5 boys) underwent modified laparoscopic gastrostomy placement at median age 4.85 years (range 1.0-8.8), with fundoplication for gastro-oesophageal reflux in 1 case, with follow-up for 0.3 to 3.9 years. The procedure was well tolerated with oral feeds usually given after 4 hours and whole protein gastrostomy feeds within 24 hours in 6 patients. Improved growth was reflected in mean weight and height z scores: -1.36 (range -2.6 to 0.5) to -0.61 (range -2.34 to 2.0) and -1.09 (range 2.42 to 1.0) to 0.71 (range -1.86 to 1.0), respectively. Postoperatively, 5 patients experienced minor local complications: minimal leakage without skin damage in 3 and transient peristomal granulation rapidly responsive to topical treatment in 2; this followed acute gastrostomy site infection in 1. There was no leakage after the immediate postoperative period. CONCLUSIONS: We conclude that our less-invasive laparoscopic gastrostomy technique is effective and better tolerated in children with severe EB, at least in the medium term, than open gastrostomy placement. Longer follow-up is required. PMID- 24792631 TI - Vitamin D status and adequacy of standard supplementation in preterm neonates from South India. AB - OBJECTIVE: The aim of this study was to assess vitamin D status of preterm babies at birth and adequacy of daily supplementation with vitamin D. METHODS: This prospective cohort study recruited 111 preterm babies, 25 to 32 weeks' gestation from a tertiary care perinatal center in south India. Cord blood was assayed for serum calcium, phosphate, alkaline phosphatase, and 25-hydroxyvitamin D (25(OH)D). All of the babies were fed unfortified breast-milk and supplemented daily with calcium, phosphate, and 400 IU of vitamin D. At 6 weeks serum calcium, phosphate, alkaline phosphatase, parathyroid hormone, and 25(OH)D levels were estimated. RESULTS: Of 111 preterm babies recruited, a total of 90 (81%) of the preterm babies were followed up until 6 weeks. The median (interquartile range) vitamin D level in the preterm group was 34.7 (25.6-50.1) and 19.3 (13.9-27.1) ng/mL at birth and 6 weeks, respectively. Using a cutoff value of <20 ng/mL to determine vitamin D insufficiency (VDI), it was observed that 12.6% of the babies were vitamin D insufficient at birth. This increased to 52.2% at 6 weeks despite the recommended supplementation with vitamin D (P < 0.001). CONCLUSIONS: The prevalence of VDI was not high at birth; however, a large proportion of preterm babies were vitamin D insufficient at 6 weeks despite being supplemented with vitamin D 400 IU/day. The recommended vitamin D supplementation of 400 IU appears to be inadequate to prevent VDI, and hence randomized controlled trials looking at higher doses of vitamin D supplementation are needed. PMID- 24792632 TI - Interleukin 28B rs12979860 single-nucleotide polymorphism predicts spontaneous clearance of hepatitis C virus in children. AB - OBJECTIVE: Recent genome-wide association studies performed in adults correlated single-nucleotide polymorphisms (SNPs rs12979860 and rs8099917) located on chromosome 19, upstream of the interleukin 28B gene, with spontaneous clearance of hepatitis C virus and with response to treatment with paginated interferon and ribavirin. The aim of the present collaborative study was to evaluate the rs12979860 SNP in a large cohort of Italian children with perinatal acquisition of hepatitis C. METHODS: Children were prospectively enrolled in 2 Italian centers. The interleukin 28B rs12979860 SNP was studied according to the diagnosis of chronic infection or spontaneous clearance. RESULTS: One hundred thirty children (86.7%) with chronic infection and 23 (13.3%) with spontaneous clearance of the virus were enrolled. Overall, the interleukin 28B C/C and C/T T/T genotypes were found in 57 (37.3%) and 96 (62.7%) children, respectively. The proportion of C/C genotype was higher among children who cleared infection (14/23; 60.9%) compared with children with chronic infection (43/130; 33.1%; P = 0.01; odds ratio 3.15; 90% confidence intervals 1.34-7.53). CONCLUSIONS: The present study showed that, as already demonstrated in adults, children with the rs12979860 C/C SNP of the interleukin 28B gene have a higher probability of spontaneous clearance of hepatitis C virus. PMID- 24792633 TI - Giant cell hepatitis with autoimmune hemolytic anemia in children: proposal for therapeutic approach. AB - BACKGROUND AND OBJECTIVE: Giant cell hepatitis (GCH) with autoimmune hemolytic anemia (AIHA) is a rare, progressive disorder in infants and young children. The disease is aggressive and may lead to liver or multiorgan failure with fatal prognosis. Therapy with anti-CD20 monoclonal antibody, rituximab (Rtx), proved effective. The primary objective of the study was to evaluate therapy for severe GCH with AIHA. METHODS: We report on 5 cases of severe GCH with AIHA treated in our department between 2006 and 2011. RESULTS: The median age of the children was 7 months (2-12 months), follow-up lasted 44 months (12-78 months), median (min max), and the main observed symptoms were jaundice and hepatosplenomegaly. All of the children had positive direct Coombs test and biopsy-proven giant cell transformation of hepatocytes. Liver failure was observed in 3 children. First line therapy (prednisone, azathioprine) proved ineffective in all but 1 of the patients, who initially responded to the treatment but relapsed after 4 months. The child subsequently developed hemophagocytic lymphohistiocytosis and died 2 months after hemopoietic stem cell transplantation. Four remaining patients finally achieved complete remission after 4 to 6 doses of Rtx. CONCLUSIONS: We propose Rtx as the treatment of choice for severe GCH with AIHA in the early stages of the disease, provided steroids and azathioprine are ineffective. PMID- 24792634 TI - CSF PCR in a child with parainfectious myelopathy associated with HVA infection. PMID- 24792635 TI - Assessment of the role of DNA repair in damaged forensic samples. AB - Previous studies on DNA damage and repair have involved in vitro laboratory procedures that induce a single type of lesion in naked templates. Although repair of singular, sequestered types of DNA damage has shown some success, forensic and ancient specimens likely contain a number of different types of lesions. This study sought to (1) develop protocols to damage DNA in its native state, (2) generate a pool of candidate samples for repair that more likely emulate authentic forensic samples, and (3) assess the ability of the PreCR(TM) Repair Mix to repair the resultant lesions. Complexed, native DNA is more difficult to damage than naked DNA. Modified procedures included the use of higher concentrations and longer exposure times. Three types of samples, those that demonstrated damage based on short tandem repeat (STR) profile signals, were selected for repair experiments: environmentally damaged bloodstains, bleach damaged whole blood, and human skeletal remains. Results showed trends of improved performance of STR profiling of bleach-damaged DNA. However, the repair assay did not improve DNA profiles from environmentally damaged bloodstains or bone, and in some cases resulted in lower RFU values for STR alleles. The extensive spectrum of DNA damage and myriad combinations of lesions that can be present in forensic samples appears to pose a challenge for the in vitro PreCR(TM) assay. The data suggest that the use of PreCR in casework should be considered with caution due to the assay's varied results. PMID- 24792636 TI - Gas analysis of exhumed cadavers buried for 30 years: a case report about long time alteration. AB - Due to important alteration caused by long time decomposition, the gases in human bodies buried for more than a year have not been investigated. For the first time, the results of gas analysis sampled from bodies recently exhumed after 30 years are presented. Adipocere formation has prevented the bodies from too important alteration, and gaseous areas were identified. The sampling was performed with airtight syringes assisted by multi-detector computed tomography (MDCT) in those specific areas. The important amount of methane (CH4), coupled to weak amounts of hydrogen (H2) and carbon dioxide (CO2), usual gaseous alteration indicators, have permitted to confirm methanogenesis mechanism for long period of alteration. H2 and CO2 produced during the first stages of the alteration process were consumed through anaerobic oxidation by methanogenic bacteria, generating CH4. PMID- 24792637 TI - Multi-segment foot mobility in a hinged ankle-foot orthosis: the effect of rotation axis position. AB - Hinged ankle-foot orthoses are prescribed routinely for the treatment of ankle joint deficits, despite the conflicting outcomes and the little evidence on their functional efficacy. In particular, the axis of rotation of the hinge is positioned disregarding the physiological position and orientation. A multi segment model was utilized to assess in vivo the effect of different positions for this axis on the kinematics of foot joints. A special custom-made hinged orthosis was manufactured via standard procedures for a young healthy volunteer. Four locations for the mechanical axis were obtained by a number of holes where two nuts and bolts were inserted to form the hinge: a standard position well above the malleoli, at the level of the medial malleolus, at the level of the lateral malleolus, and the physiological between the two malleoli. The shank and foot were instrumented with 15 reflective markers according to a standard protocol, and level walking was collected barefoot and with the orthosis in the four mechanical conditions. The spatio-temporal parameters observed in the physiological axis condition were the closest to normal barefoot walking. As expected, ankle joint rotation was limited to the sagittal plane. When the physiological axis was in place, rotations of the ankle out-of-sagittal planes, and of all other foot joints in the three anatomical planes, were found to be those most similar to the natural barefoot condition. These preliminary measures of intersegmental kinematics in a foot within an ankle-foot orthosis showed that only a physiological location for the ankle mechanical hinge can result in natural motion at the remaining joints and planes. PMID- 24792638 TI - Higher step length variability indicates lower gray matter integrity of selected regions in older adults. AB - Step length variability (SLV) increases with age in those without overt neurologic disease, is higher in neurologic patients, is associated with falls, and predicts dementia. Whether higher SLV in older adults without neurologic disease indicates presence of neurologic abnormalities is unknown. Our objective was to identify whether SLV in older adults without overt disease is associated with findings from multimodal neuroimaging. A well-characterized cohort of 265 adults (79-90 years) was concurrently assessed by gait mat, magnetic resonance imaging with diffusion tensor, and neurological exam. Linear regression models adjusted for gait speed, demographic, health, and functional covariates assessed associations of MRI measures (gray matter volume, white matter hyperintensity volume, mean diffusivity, fractional anisotropy) with SLV. Regional distribution of associations was assessed by sparse partial least squares analyses. Higher SLV (mean: 8.4, SD: 3.3) was significantly associated with older age, slower gait speed, and poorer executive function and also with lower gray matter integrity measured by mean diffusivity (standardized beta=0.16; p=0.02). Associations between SLV and gray matter integrity were strongest for the hippocampus and anterior cingulate gyrus (both beta=0.18) as compared to other regions. Associations of SLV with other neuroimaging markers were not significant. Lower integrity of normal-appearing gray matter may underlie higher SLV in older adults. Our results highlighted the hippocampus and anterior cingulate gyrus, regions involved in memory and executive function. These findings support previous research indicating a role for cognitive function in motor control. Higher SLV may indicate focal neuropathology in those without diagnosed neurologic disease. PMID- 24792640 TI - Multifaceted roles of BDNF and FGF2 in human striatal primordium development. An in vitro study. AB - Grafting fetal striatal cells into the brain of Huntington's disease (HD) patients has raised certain expectations in the past decade as an effective cell based-therapy for this devastating condition. We argue that the first requirement for successful transplantation is defining the window of plasticity for the striatum during development when the progenitor cells, isolated from their environment, are able to maintain regional-specific-identity and to respond appropriately to cues. The primary cell culture from human fetal striatal primordium described here consists of a mixed population of neural stem cells, neuronal-restricted progenitors and striatal neurons. These cells express trophic factors, such as BDNF and FGF2. We show that these neurotrophins maintain cell plasticity, inducing the expression of neuronal precursor markers and cell adhesion molecules, as well as promoting neurogenesis, migration and survival. We propose that BDNF and FGF2 play an important autocrine-paracrine role during early striatum development in vivo and that their release by fetal striatal grafts may be relevant in the setting of HD cell therapy. PMID- 24792641 TI - Mode of action and clinical studies with alemtuzumab. AB - The lymphocyte depleting anti-CD52 monoclonal antibody alemtuzumab has been used in Cambridge, UK, as an experimental treatment of multiple sclerosis since 1991. One phase-2 trial (CAMMS-223) and two phase-3 studies (CARE-MS1 and CARE-MS2) have confirmed its efficacy in treatment-naive patients, and have established superiority over interferon beta-1a in patients who continue to relapse in spite of first-line therapy (Cohen et al., 2012; Coles et al., 2008; Coles et al., 2012a; Coles et al., 2012b). Despite causing a prolonged T cell lymphopenia, significant infections have not been an issue following treatment; rather alemtuzumab's primary safety concern is secondary autoimmunity, occurring up to five years after treatment and maximally at two years: 30% of patients develops thyroid autoimmunity, and 1% develops idiopathic thrombocytopenic purpura (ITP). In addition, 4 out of 1486 patients (<0.3%) treated on the commercially sponsored studies developed glomerulonephritis. Two of these patients developed anti glomerular basement membrane disease, a condition which may result in renal failure unless treated aggressively. In September 2013, the European Medicine Agency (EMA) ruled that the benefit-to-risk balance for alemtuzumab was favourable, approving it as a first-line therapy for adults with active relapsing remitting multiple sclerosis (under the trade name Lemtrada). Lemtrada is now also approved as a treatment of multiple sclerosis in Canada, Australia, Switzerland, Israel, Mexico and Brazil. However, in December 2013, Lemtrada failed to gain approval from the U.S. Food and Drug Administration (FDA), with concerns over trial design and safety stated as the main reasons. In this review we describe our local experience and explain the rationale behind its initial use as a treatment of multiple sclerosis and behind the design of the commercially sponsored trials, summarising their key findings. We also sum up our understanding of its mechanism of action. PMID- 24792639 TI - N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI. AB - Traumatic brain injury (TBI) has become a growing epidemic but no approved pharmacological treatment has been identified. Our previous work indicates that mitochondrial oxidative stress/damage and loss of bioenergetics play a pivotal role in neuronal cell death and behavioral outcome following experimental TBI. One tactic that has had some experimental success is to target glutathione using its precursor N-acetylcysteine (NAC). However, this approach has been hindered by the low CNS bioavailability of NAC. The current study evaluated a novel, cell permeant amide form of N-acetylcysteine (NACA), which has high permeability through cellular and mitochondrial membranes resulting in increased CNS bioavailability. Cortical tissue sparing, cognitive function and oxidative stress markers were assessed in rats treated with NACA, NAC, or vehicle following a TBI. At 15days post-injury, animals treated with NACA demonstrated significant improvements in cognitive function and cortical tissue sparing compared to NAC or vehicle treated animals. NACA treatment also was shown to reduce oxidative damage (HNE levels) at 7days post-injury. Mechanistically, post-injury NACA administration was demonstrated to maintain levels of mitochondrial glutathione and mitochondrial bioenergetics comparable to sham animals. Collectively these data provide a basic platform to consider NACA as a novel therapeutic agent for treatment of TBI. PMID- 24792642 TI - Comprehensive exploration of autoantibody in Behcet's disease: a novel autoantibody to claudin-1, an essential protein for tight junctions, is identified. PMID- 24792643 TI - All bacillus Calmette-Guerin (BCG) strains are equal, but some BCG strains are more equal than others. PMID- 24792644 TI - Spin-echo echo-planar perfusion prior to chemoradiation is a strong independent predictor of progression-free and overall survival in newly diagnosed glioblastoma. AB - Spin-echo echo planar (EP) perfusion weighted imaging (SE-PWI) has been demonstrated to be more selective than gradient-echo EP PWI for blood volume in microvessels the size of glioma neocapillaries, but it has not been comprehensively studied in human clinical use. We assessed whether SE-PWI before and after initiating chemoradiation can stratify patients with respect to progression free survival (PFS) and overall survival (OS). Sixty-eight patients with newly diagnosed glioblastoma (mean age 58.3, 36 males) were included in analysis. SE EP cerebral blood volumes (SE-CBVs) in enhancing and nonenhancing tumor, normalized to contralateral normal appearing white matter (SE-nCBV), were assessed at baseline and after initial chemoradiation. SE-nCBV parameters predictive of PFS and OS were identified in univariate and multivariate Cox proportional hazards models. Multivariate analysis demonstrated that baseline tumor mean SE-nCBV was predictive of PFS (p = 0.038) and OS (p = 0.004). Within the patient sample, baseline tumor mean SE-nCBV <2.0 predicted longer patient PFS (median 47.0 weeks, p < 0.001) and OS (median 98.6 weeks, p = 0.003) compared with baseline mean SE-nCBV >2.0 (median PFS 25.3, median OS 56.0 weeks). Exploratory multi-group stratification demonstrated that very high (>4.0) tumor SE-nCBV was associated with worse patient OS than intermediate high (>2.0, <4.0) SE-nCBV (p = 0.025). Baseline mean SE-nCBV can stratify patients for PFS and OS prior to initiation of chemoradiation, which may help select patients who require closer surveillance. Our exploratory analysis indicates a magnitude-dependent relationship between baseline SE-nCBV and OS. PMID- 24792645 TI - Overexpression and constitutive nuclear localization of cohesin protease Separase protein correlates with high incidence of relapse and reduced overall survival in glioblastoma multiforme. AB - Separase, an enzyme that cleaves the chromosomal cohesin during mitosis, is overexpressed in a wide range of human epithelial cancers of breast, bone and prostate (Meyer et al., Clin Cancer Res 15(8):2703-2710, 2009). Overexpression of Separase in animal models results in aneuploidy and tumorigenesis. We have examined the expression and localization of Separase protein in adult and pediatric glioblastoma and normal brain specimens. Immunofluorescence microscopy and Western blot analysis showed significant overexpression of Separase in all adult and a subset of pediatric glioblastoma cells. Tumor status and patient survival strongly correlate with the mislocalization of Separase into the nucleus throughout all stages of the cell cycle. Unlike exclusively nuclear localization in mitotic control cells, glioblastoma samples have a significantly higher number of resting (interphase) cells with strong nuclear Separase staining. Additionally, patient survival analysis demonstrated a strong correlation between overexpression of Separase protein in adult glioblastoma and a high incidence of relapse and reduced overall survival. These results further strengthen our hypothesis that Separase is an oncogene whose overexpression induces tumorigenesis, and indicate that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human malignancies. PMID- 24792646 TI - Nano-scale mechanical properties and behavior of pre-sintered zirconia. AB - This paper reports on the mechanical properties and material behavior of pre sintered zirconia using nanoindentation with in situ scanning probe microscopy. Indentation contact hardness, Hc, and Young's modulus, E, were measured at loading rates of 0.1-2mN/s and 10mN peak load to understand the loading rate effect on its properties. Indentation imprints were analyzed using in situ scanning probe imaging to understand the indentation mechanisms. The average measured contact hardness was 0.92-1.28GPa, independent of the loading rate (ANOVA, p>0.05). Young's moduli showed a loading rate dependence, with average 61.25GPa and a great deviation at a low loading rate of 0.1mN/s, which was twice the average moduli at the loading rates of 0.5-2mN/s. Extensive discontinuities and the largest maximum penetration, final and contact depths were also observed on the load-displacement curves at the lowest loading rate. These phenomena corresponded to microstructural compaction (pore closure and opening) and kink band formation, indicating the loading rate dependence for microstructural changes during nanoindentation. The in situ scanning probe images of indentation imprints show plastic deformation without fracture at all loading rates, compaction at the low loading rate and pore filling at the high loading rate. The mechanical behavior studied provides physical insight into the abrasive machining responses of pre-sintered zirconia using sharp diamond abrasives. PMID- 24792647 TI - Cell-free fetal DNA fragments and preeclampsia. PMID- 24792648 TI - Myristicin from nutmeg induces apoptosis via the mitochondrial pathway and down regulates genes of the DNA damage response pathways in human leukaemia K562 cells. AB - Myristicin, an allylbenzene, is a major active component of various spices, such as nutmeg and cinnamon, plants from the Umbelliferae family or in some essential oils, such as oils of clove or marjoram. Human exposure to myristicin is low but widespread due to consumption of these spices and essential oils, added to food (e.g. cola drinks) or in traditional medicine. Occasionally high dose exposure occurs, leading to various clinical symptoms, however the molecular mechanisms underlying them are unknown. Our previous studies revealed that myristicin is not genotoxic and yet presented apoptotic activity. Therefore, in this work we assessed the apoptotic mechanisms induced by myristicin in human leukaemia cells. In order to gain further insight on the potential of myristicin to modulate gene expression we also analysed alterations in expression of 84 genes associated with the DNA damage response pathway. The results obtained show that myristicin can induce apoptosis as characterised by alterations in the mitochondrial membrane potential, cytochrome c release, caspase-3 activation, PARP-cleavage and DNA fragmentation. The gene expression profile revealed an overall down regulation of DNA damage response genes after exposure to myristicin, with significant under expression of genes associated with nucleotide excision repair (ERCC1), double strand break repair (RAD50, RAD51) and DNA damage signalling (ATM) and stress response (GADD45A, GADD45G). On the whole, we demonstrate that myristicin can alter mitochondrial membrane function, induce apoptosis and modulate gene expression in human leukaemia K562 cells. This study provides further detail on the molecular mechanisms underlying the biological activity of myristicin. PMID- 24792649 TI - Screening mammography benefit controversies: sorting the evidence. AB - Numerous clinical studies have confirmed that screening women age 40 years and older reduces breast cancer mortality by 30% to 50%. Several factors including faster breast cancer growth rates and lower breast cancer incidence among younger women, as well as shorter life expectancy and more comorbid conditions among older women, should also be considered in screening guidelines. Annual screening beginning at age 40 years and continuing with no upper age limit, as long as a woman has a life expectancy of at least 5 years and no significant comorbid conditions, is currently recommended. PMID- 24792650 TI - BI-RADS update. AB - The updated American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) has been newly released. This article summarizes the changes and updates that have been made to BI-RADS. The goal of the revised edition continues to be the same: to improve clarification in image interpretation, maintain reporting standardization, and simplify the monitoring of outcomes. The new BI RADS also introduces new terminology to provide a more universal lexicon across all 3 imaging modalities. PMID- 24792651 TI - Digital tomosynthesis: technique. AB - Digital breast tomosynthesis is an extension of digital mammography that produces quasi three-dimensional reconstructed images from a set of low-dose x-ray projections acquired over a limited angular range. The quality of the reconstructed image and the dose to the breast are dependent on the angular range and number of projections, the dose used per projection, and detector resolution and noise characteristics. This article discusses various aspects of tomosynthesis optimization. PMID- 24792652 TI - Clinical implementation of digital breast tomosynthesis. AB - Digital breast tomosynthesis is rapidly being implemented in breast imaging clinics across the world as early clinical data demonstrate that this innovative technology may address some of the long-standing limitations of conventional mammography. This article reviews the recent clinical data supporting digital breast tomosynthesis implementation, the basics of digital breast tomosynthesis image interpretation using case-based illustrations, and potential issues to consider as this new technology is integrated into daily clinical use. PMID- 24792653 TI - High-quality breast ultrasonography. AB - Ultrasonography is an important modality that is frequently used in all aspects of breast imaging, including breast cancer screening, the evaluation of palpable abnormalities, further characterization of lesions seen mammographically, and for determining the method of percutaneous biopsy. Understanding the basic technical aspects of ultrasonography equipment is critical to ensure high breast ultrasonography image quality. PMID- 24792654 TI - Update on screening breast ultrasonography. AB - This article includes current recommendations for screening breast ultrasonography, a review of the literature, a discussion of problems associated with the implementation of screening breast ultrasonography, and a brief discussion of the political and economic factors influencing the use of screening breast ultrasonography. PMID- 24792655 TI - Automated whole breast ultrasound. AB - Bilateral whole breast (screening) ultrasound has been well established in multiple single- and multi-institution published studies as a valuable adjunct to mammography screening for early detection of breast cancer. However, implementation of screening breast ultrasound programs has been limited and has met with resistance because of the number of potential false positives generated by ultrasound screening, and the lack of available personnel to perform the examination. Automated breast ultrasound, which has recently been approved by the US Food and Drug Administration for use in whole-breast ultrasound screening, is a potential option for providing breast ultrasound screening on a widespread basis. PMID- 24792656 TI - High-quality breast MRI. AB - Breast magnetic resonance imaging (MRI) demands the competing factors of high spatial resolution, good temporal resolution, high signal-to-noise ratios, and complete bilateral breast coverage. Achieving these competing factors requires modern MRI equipment with high magnetic field strength and homogeneity, high maximum gradient strength with short rise times, dedicated multichannel bilateral breast coils with prone patient positioning, and 3D (volume) gradient-echo MRI pulse sequences with short TR, short TE, high spatial resolution, and reasonably short acquisition times. This article discusses the equipment and pulse sequences needed to achieve high-quality breast MRI and summarizes requirements of the ACR Breast MRI Accreditation Program. PMID- 24792658 TI - Breast magnetic resonance imaging: management of an enhancing focus. AB - An enhancing focus is a commonly encountered type of lesion on breast magnetic resonance (MR) imaging. No set criteria for appropriate management are available. Often management of these lesions depends on the interpreting radiologist, with varying recommendations for biopsy, short-term follow-up, or routine surveillance. This article reviews published studies in order to develop a strategy for the management of enhancing foci identified on breast MR imaging. PMID- 24792657 TI - Approach to breast magnetic resonance imaging interpretation. AB - With the increasing use of breast magnetic resonance (MR) imaging comes the expectation that the breast radiologist is as fluent in its interpretation as in that of mammography and breast ultrasonography. Knowledge of who should be included for imaging and how to perform the imaging are as essential as interpreting the images. When reading the examination, the radiologist should approach the images from both a global and focused perspective, synthesizing findings into a report that includes a management plan. This article reviews a systematic and organized approach to breast MR imaging interpretation. PMID- 24792659 TI - MR evaluation of breast implants. AB - This article describes the rationale and indications for breast implant-related magnetic resonance (MR) imaging, alone or in combination with breast cancer related MR imaging. Basic silicone chemistry, implant styles, and normal appearances of breast implants are described. The various presentations of breast implant rupture are described, and a 4-point staging scheme for intracapsular rupture is reviewed. Finally, a discussion of what the reviewing physician needs to know is presented, both before breast implant MR examinations are requested and afterward, when results are reported. PMID- 24792660 TI - Contrast-enhanced digital mammography. AB - Mammography is the only technology documented to reduce breast cancer mortality. Its sensitivity, however, is 75% to 80% at best and reduced to 30% to 50% in women with dense breasts. MR imaging is a sensitive modality for the detection of breast cancer but cannot be used in all patients. Its sensitivity is due in large part to its ability to detect enhancement of tumor vascularity so cancers can be detected before a mass is present. Contrast-enhanced dual-energy mammography uses the same capability of vascular enhancement and has been demonstrated to be more sensitive than routine mammography. PMID- 24792661 TI - Radiologic Clinics of North America. Breast imaging. Preface. PMID- 24792662 TI - NMDA receptor hypofunction and the thalamus in schizophrenia. AB - The thalamus can be subdivided into two kinds of nuclei, the higher order (HO) and the first order (FO) relays, which are distinguished based on the origin of their main or driver inputs. The driver inputs to the HO nuclei arrive from the cortex, and the messages they deliver are then relayed to other cortical areas. As the origin of these inputs is the cortical layer V, whose axons branch and innervate lower motor centers in the CNS, the messages are copies of motor instructions issued to those lower motor centers. These copies are thus an integral part of perceptual processes. In schizophrenia, the HO nuclei are shrunken suggesting that a reduced ability to integrate copies of ongoing motor commands in perceptual processes may be one part of the underlying pathophysiology. The driver inputs in the thalamus utilize ionotropic glutamate receptors such as the NMDAR. NMDAR antagonists may exert their pro-psychotic effects by impairing the function of the HO nuclei. Here, we argue that such agents (or the proposed NMDAR hypofunction in schizophrenia) weaken the driver inputs in the HO nuclei, thereby producing a cortico-thalamo-cortical disconnection and impairing sensorimotor integration. PMID- 24792663 TI - Ectoparasitic sea lice (Lepeophtheirus salmonis) affect behavior and brain serotonergic activity in Atlantic salmon (Salmo salar L.): Perspectives on animal welfare. AB - Scientific research and public debate on the welfare of animals in human custody is increasing at present. Fish are in this context mentioned with particular attention to the high numbers of individuals reared in aquaculture. Research on fish has also contributed to the understanding of individual variation in the ability to cope with stress and disease. One mediator of such variation is the brain serotonergic (5-hydroxytryptamine, 5-HT) system, which conveys physiological and behavioral responses to stress and sub-optimal rearing conditions. Here we study links between the 5-HT response, melanin-based skin pigmentation, and behavior in laboratory-reared Atlantic salmon (Salmo salar) experimentally infested with ectoparasitic sea lice (Lepeophtheirus salmonis). Lice numbers were more variable in less pigmented fish, while the neurochemical response to ectoparastic lice-increased levels of the main 5-HT catabolite 5-HIAA in the brain stem-did not differ between pigmentation groups. A strong depression of growth and locomotor activity was seen in all infested fish but less pigmented fish grew better than fish with more skin melanization regardless of infestation status. The observed combination of neurochemical and behavioral effects clearly suggest that animal welfare concerns can be added to the list of negative effects of ectoparasitic sea lice. PMID- 24792664 TI - Isolation and identification of epithelial and stromal stem cells from eutopic endometrium of women with endometriosis. AB - OBJECTIVE: The recent characterization of possible stem/progenitor cells in the endometrium has shed new light on the origins of ectopic endometrial tissue and the mechanism for the pathogenesis of endometriosis, but has raised new questions. Is it possible that abnormal endometrial stem/progenitor cells increase their capacity to implant and establish themselves as ectopic tissue, or that normal stem cells implant in abnormal peritoneum? This study investigated key stem cell properties in cologenic epithelial and stromal cells obtained from eutopic endometrium of women with endometriosis. STUDY DESIGN: Single cell suspensions of endometrial epithelial and stromal cells were cultured at densities of 20, 50, 100 and 200cells/cm(2). Cloning efficiency (CE) was determined, and stem cell phenotypic surface markers were detected using Western blotting and quantitative real-time polymerase chain reaction. RESULTS: CE was significantly higher in cells cultured at a density of 50cells/cm(2) compared with the other groups. After 15 days of culture, small and large colonies were observed. Large-colony-derived epithelial and stromal cells had high proliferative potentials, producing millions of cells in vitro, with strong expression of epithelial and stromal stem cell phenotypic surface markers EMA, CK, CD49f, THY-1(CD90), collagen type I, 5B5 and vimentin. CONCLUSION: Adult stem cells were found in eutopic endometrium of women with endometriosis, and this may play an important role in disease development. PMID- 24792666 TI - When is see-and-treat hysteroscopic polypectomy successful? AB - OBJECTIVE(S): To identify factors associated with a successful see-and-treat hysteroscopic polypectomy. STUDY DESIGN: We have retrospectively studied a population of 229 women with endometrial polyps who were referred to office hysteroscopy at the hysteroscopy unit of a large university hospital. See-and treat polypectomy with 5-French microinstruments was routinely attempted. Cases where the endometrial polyp was successfully removed were compared to those who had to be referred to polyp resection with the resectoscope. Bivariate and multivariate statistical analyses where used to identify factors associated with the success of see-and-treat polypectomy. RESULTS: Outpatient hysteroscopy was feasible on 223 patients, confirming endometrial polyps in all of them. See-and treat polypectomy with 5-French micro-instruments was successful in 65.5% of the cases (146/223). Bivariate analysis suggested an association of successful see and-treat with younger age, lower BMI, premenopausal status, smaller polyps, easy hysteroscopic access and painless examinations. Multiple logistic regression confirmed the independent association of a successful see-and-treat polypectomy with premenopausal status (OR 3.623; 95%CI 1.302-10.084) and smaller polyp size (OR 0.891; 95%CI 0.846-0.938). Pain was confirmed as an independent, limiting factor (OR 0.085; 95%CI 0.034-0.214). CONCLUSION: See-and-treat hysteroscopic polypectomy with 5-French instruments is effective and feasible but its success is lower in case of pain, larger polyps and postmenopausal patients. PMID- 24792665 TI - Effect of cigarette smoking on mRNA and protein levels of oxytocin receptor and on contractile sensitivity of uterine myometrium to oxytocin in pregnant women. AB - OBJECTIVES: Although smoking is the most important modifiable risk factor associated with preterm delivery, the underlying mechanism by which smoking stimulates premature uterine contractions is still poorly understood. In the present study, we investigated whether cigarette smoking affects the contractile sensitivity of uterine myometrium to oxytocin in pregnant women. STUDY DESIGN: Cigarette smoking habits of pregnant women were evaluated by direct interviews and by measuring exhaled carbon monoxide (CO). We isolated myometrial strips from pregnant smokers and non-smokers and evaluated uterine contractile sensitivity to oxytocin. Gene expression levels of oxytocin receptors (OTR) were compared between myometrial strips obtained from smokers and non-smokers by real-time PCR. OTR protein levels in the myometrium were evaluated by Western blotting. RESULTS: The reported number of cigarettes smoked per day by the interviewee significantly correlated with the concentration of exhaled CO. Oxytocin sensitivity increased significantly in smokers (n=6) compared with non-smokers (n=11). Real-time PCR analysis did not reveal any significant difference in OTR mRNA expression between smokers and non-smokers. Western blotting revealed that OTR level was significantly increased in smokers compared with non-smokers. Both number of cigarettes smoked per day and the concentration of exhaled CO correlated with oxytocin sensitivity. CONCLUSION: Our findings suggest that smoking increases oxytocin sensitivity of pregnant myometrium by increasing OTR levels even though OTR mRNA expression remains unaltered, thereby increasing the risk of preterm delivery in women who smoke during pregnancy. The sensitivity is dependent on number of cigarettes smoked per day. PMID- 24792667 TI - Study on the pathogenesis of autoimmune-type recurrent spontaneous abortion by establishing a new mouse model. AB - OBJECTIVE: To establish a new mouse model for autoimmune-type recurrent spontaneous abortion (AI-RSA) and demonstrate the potential role of intrauterine immunization with beta2GP-1-like antigen in AI-RSA, we performed an intrauterine injection of human beta2GP-1 in BALB/c mice and unrelated protein, adjuvants, and normal saline (NS) as controls. The mean number of embryos implanted (MNEI), embryo loss rate (ELR), mean embryo bulk (MEB), and mean placental weight (MPW) were analyzed. Compared with the control mice, BALB/c mice injected with human beta2GP-1 showed increased anti-beta2GP-1 and MPW. Moreover, BALB/c mice immunized with human beta2GP-1 exhibited hypercoagulability and vascular thrombus formation in the placenta. Electron microscopy confirmed the existence of platelet aggregation, mitochondrial swelling, and endothelial cell necrosis in the placentas of BALB/c mice immunized with human beta2GP-1. These finding indicated that intrauterine immunization with beta2GP-1 successfully induced AI RSA in mice. Increased anti-beta2GP-1 antibody could independently induce hypercoagulability, vascular endothelial injury, and vascular thrombus formation in the placenta, which led to AI-RSA. PMID- 24792669 TI - Cystic fibrosis: from a single gene to complex pathophysiology. PMID- 24792668 TI - High-confidence glycosome proteome for procyclic form Trypanosoma brucei by epitope-tag organelle enrichment and SILAC proteomics. AB - The glycosome of the pathogenic African trypanosome Trypanosoma brucei is a specialized peroxisome that contains most of the enzymes of glycolysis and several other metabolic and catabolic pathways. The contents and transporters of this membrane-bounded organelle are of considerable interest as potential drug targets. Here we use epitope tagging, magnetic bead enrichment, and SILAC quantitative proteomics to determine a high-confidence glycosome proteome for the procyclic life cycle stage of the parasite using isotope ratios to discriminate glycosomal from mitochondrial and other contaminating proteins. The data confirm the presence of several previously demonstrated and suggested pathways in the organelle and identify previously unanticipated activities, such as protein phosphatases. The implications of the findings are discussed. PMID- 24792670 TI - Delphinidin inhibits VEGF induced-mitochondrial biogenesis and Akt activation in endothelial cells. AB - Delphinidin, an anthocyanin present in red wine, has been reported to exert vasculoprotective properties on endothelial cells, including vasorelaxing and anti-apoptotic effects. Moreover, delphinidin treatment in a rat model of post ischemic neovascularization has been described to exert anti-angiogenic property. Angiogenesis is an energetic process and VEGF-induced angiogenesis is associated with mitochondrial biogenesis. However, whether delphinidin induces changes in mitochondrial biogenesis has never been addressed. Effects of delphinidin were investigated in human endothelial cells at a concentration described to be anti angiogenic in vitro (10(-2)g/l). mRNA expression of mitochondrial biogenesis factors, mitochondrial respiration, DNA content and enzyme activities were assessed after 48 h of stimulation. Delphinidin increased mRNA expression of several mitochondrial biogenesis factors, including NRF1, ERRalpha, Tfam, Tfb2m and PolG but did not affect neither mitochondrial respiration, DNA content nor enzyme activities. In presence of delphinidin, VEGF failed to increase mitochondrial respiration, DNA content, complex IV activity and Akt activation in endothelial cells. These results suggest a possible association between inhibition of VEGF-induced mitochondrial biogenesis through Akt pathway by delphinidin and its anti-angiogenic effect, providing a novel mechanism sustaining the beneficial effect of delphinidin against pathologies associated with excessive angiogenesis such as cancers. PMID- 24792671 TI - Inhibition of receptor activator of nuclear factor-kappaB ligand- or lipopolysaccharide-induced osteoclast formation by conophylline through downregulation of CREB. AB - The effect of conophylline (CNP) on the receptor activator of nuclear factor kappaB ligand (RANKL) or lipopolysaccharide (LPS)-induced osteoclast formation was studied in vitro using bone marrow-derived macrophages (BMMs) or the mouse macrophage-like cell line RAW 264.7. CNP inhibited RANKL-induced formation of osteoclasts identified as tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells in a culture of BMMs. It also inhibited RANKL- or LPS induced osteoclast formation in RAW 264.7 cells. CNP lowered the osteoclast maturation markers such as calcitonin receptor, MMP9 and cathepsin K in BMMs, suggesting that CNP would inhibit the process of osteoclast differentiation. CNP inhibited the RANKL-induced expressions of c-Fos and nuclear factor of activated T cells (NFATc1), key transcription factors for osteoclastogenesis. On the other hand, CNP did not inhibit the signaling pathway of NF-kappaB and mitogen activated protein kinases (MAPKs) in RANKL-stimulated BMMs. Interestingly, CNP inhibited RANKL-induced CREB activation that can mediate c-Fos and NFATc1. CNP also inhibited RANKL- or LPS-induced CREB, c-Fos and NFATc1 activation in RAW 264.7 cells. We have previously found that CNP directly binds to ADP-ribosylation like factor-6 interacting protein (ARL6ip), although its role in osteoclastogenesis is not clear. Gene knockdown of ARL6ip by siRNA inhibited RANKL-induced c-Fos expression, suggesting that inactivation of ARL6ip may be involved in an inhibitory effect of CNP. Taken together, CNP was shown to inhibit osteoclast formation possibly via CREB inactivation following a decrease in c-Fos and NFATc1 expression. PMID- 24792672 TI - The yin-yang of long pentraxin PTX3 in inflammation and immunity. AB - Pentraxins are a family of multimeric proteins characterized by the presence of a pentraxin signature in their C-terminus region. Based on the primary structure, pentraxins are divided into short and long pentraxin: C-reactive protein (CRP) is the prototype of the short pentraxin subfamily while pentraxin 3 (PTX3) is the prototypic long pentraxin. Despite these two molecules exert similar fundamental actions in the regulation of innate immune and inflammatory responses, several differences exist between CRP and PTX3, including gene organization, protein oligomerization and expression pattern. The pathophysiological roles of PTX3 have been investigated using genetically modified mice since PTX3 gene organization and regulation are well conserved between mouse and human. Such in vivo studies figured out that PTX3 mainly have host-protective effects, even if it could also exert negative effects under certain pathophysiologic conditions. Here we will review the general properties of CRP and PTX3, emphasizing the differences between the two molecules and the regulatory functions exerted by PTX3 in innate immunity and inflammation. PMID- 24792673 TI - MR imaging of the urinary bladder. AB - MR imaging is the modality of choice for accurate local staging of bladder cancer. In addition, bladder MR imaging helps detect lymph node involvement, and in conjunction with computed tomography, provides complete staging. Familiarity with optimal imaging protocols, normal urinary bladder anatomy, and pathologic MR imaging appearances is essential for the radiologist. Evolving techniques, such as use of diffusion-weighted imaging and lymphotropic nanoparticle-enhanced MR imaging, may further enhance the ability of MR imaging in local and nodal staging. PMID- 24792674 TI - MR imaging-guided prostate biopsy techniques. AB - Nearly all prostate biopsies are performed via the transrectal ultrasound (TRUS) guided technique which suffers from its inability to accurately visualize and target suspicious lesions. Advances in prostate MR imaging now allow for the detection of suspicious regions of the prostate gland, opening the door for lesion-directed biopsy techniques. The ability to obtain a definitive histologic grade has become increasingly important due to the rise of active surveillance as a popular method to approach low-grade cancer. Biopsies obtained with MR guidance or MR imaging/transrectal ultrasound fusion can accurately identify and characterize cancers and thus appropriately stratify patients for specific therapies. PMID- 24792675 TI - Diffusion-weighted imaging of the male pelvis. AB - Diffusion-weighted (DW) imaging is playing an increasingly important role in disease detection, prognostication, and monitoring of treatment response. Particularly in the realm of oncology, the potential applications for DW imaging continue to expand. In this article, the authors detail the role of DW imaging for pathologic processes involving the male pelvis. The authors describe the current data, new insights, and ongoing controversies regarding DW imaging of the male pelvis with a particular emphasis on oncologic applications. The authors also discuss imaging techniques and common pitfalls for DW imaging in this anatomic region. PMID- 24792676 TI - Magnetic resonance imaging in rectal cancer. AB - MR imaging plays a key role in staging evaluation of rectal cancer. The cornerstone of staging MR involves high-resolution T2 imaging orthogonal to the rectal lumen. The goals of MR staging are identification of patients who will benefit from neoadjuvant therapy prior to surgery to minimize postoperative recurrence and planning of optimal surgical approach. MR provides excellent anatomic visualization of the rectum and mesorectal fascia, allowing for accurate prediction of circumferential resection margin status and tumor stage. MR has an evolving role for the evaluation of neoadjuvant treatment response, further triaging optimal patient treatment and surgical approach. PMID- 24792677 TI - Magnetic resonance imaging of penile cancer. AB - Penile cancer is a rare neoplasm that, although rare in the developed world, has devastating physical and psychological consequences for the patient. Novel MR imaging techniques such as lymphotropic nanoparticle-enhanced MR imaging may help identify metastatic lymph node disease. This article reviews the normal penile anatomy and MR imaging techniques and features of primary and metastatic penile cancer. Recent advances in penile cancer imaging are discussed. PMID- 24792678 TI - Magnetic resonance imaging of pelvic metastases in male patients. AB - Magnetic resonance (MR) imaging offers a noninvasive tool for diagnosis of primary and metastatic pelvic tumors. The diagnosis of a pelvic metastatic lesion implies an adverse prognosis and dictates the management strategies. Knowledge of normal MR imaging anatomy of the pelvis and the signal characteristics of normal and abnormal structures is essential for accurate interpretation of pelvic MR imaging. This article reviews imaging manifestations of nodal, visceral, and musculoskeletal metastatic lesions of the pelvis along with current and evolving MR imaging techniques. PMID- 24792679 TI - MR imaging of scrotum. AB - Magnetic resonance (MR) imaging of the scrotum has been used as a valuable supplemental diagnostic modality in evaluating scrotal pathology, mostly recommended in cases of inconclusive sonographic findings. Because of the advantages of the technique, MR imaging of the scrotum may provide valuable information in the detection and characterization of various scrotal diseases. The technique may accurately differentiate intratesticular from extratesticular mass lesions and provide important information in the preoperative characterization of the histologic nature of scrotal masses. An accurate estimation of the local extent of testicular carcinomas in patients for whom testis-sparing surgery is planned is possible. PMID- 24792680 TI - Male pelvic MR angiography. AB - MR angiography is a powerful tool in evaluating anatomy and pathology when applied to the male pelvis. MR angiography produces high-quality images of the arterial system approaching the resolution of CT angiography, without ionizing radiation. Additional advantages include the ability to obtain angiographic images in the absence of contrast material with non-contrast-enhanced MR angiographic techniques. Blood pool contrast agents, such as gadofosveset, have significantly improved the quality of venous system imaging. Steady state imaging with blood pool contrast agents allows for acquisition of superior-quality high resolution images and other time-intensive techniques. PMID- 24792681 TI - The male pelvis. PMID- 24792682 TI - A novel optimal sensitivity design scheme for yarn tension sensor using surface acoustic wave device. AB - In this paper, we propose a novel optimal sensitivity design scheme for the yarn tension sensor using surface acoustic wave (SAW) device. In order to obtain the best sensitivity, the regression model between the size of the SAW yarn tension sensor substrate and the sensitivity of the SAW yarn tension sensor was established using the least square method. The model was validated too. Through analyzing the correspondence between the regression function monotonicity and its partial derivative sign, the effect of the SAW yarn tension sensor substrate size on the sensitivity of the SAW yarn tension sensor was investigated. Based on the regression model, a linear programming model was established to gain the optimal sensitivity of the SAW yarn tension sensor. The linear programming result shows that the maximum sensitivity will be achieved when the SAW yarn tension sensor substrate length is equal to 15 mm and its width is equal to 3mm within a fixed interval of the substrate size. An experiment of SAW yarn tension sensor about 15 mm long and 3mm wide was presented. Experimental results show that the maximum sensitivity 1982.39 Hz/g was accomplished, which confirms that the optimal sensitivity design scheme is useful and effective. PMID- 24792683 TI - Active incremental Support Vector Machine for oil and gas pipeline defects prediction system using long range ultrasonic transducers. AB - This work proposes a long range ultrasonic transducers technique in conjunction with an active incremental Support Vector Machine (SVM) classification approach that is used for real-time pipeline defects prediction and condition monitoring. Oil and gas pipeline defects are detected using various techniques. One of the most prevalent techniques is the use of "smart pigs" to travel along the pipeline and detect defects using various types of sensors such as magnetic sensors and eddy-current sensors. A critical short coming of "smart pigs" is the inability to monitor continuously and predict the onset of defects. The emergence of permanently installed long range ultrasonics transducers systems enable continuous monitoring to be achieved. The needs for and the challenges of the proposed technique are presented. The experimental results show that the proposed technique achieves comparable classification accuracy as when batch training is used, while the computational time is decreased, using 56 feature data points acquired from a lab-scale pipeline defect generating experimental rig. PMID- 24792684 TI - Nonlinear guided waves in plates: a numerical perspective. AB - Harmonic generation from non-cumulative fundamental symmetric (S0) and antisymmetric (A0) modes in plate is studied from a numerical standpoint. The contribution to harmonic generation from material nonlinearity is shown to be larger than that from geometric nonlinearity. Also, increasing the magnitude of the higher order elastic constants increases the amplitude of second harmonics. Second harmonic generation from non-phase-matched modes illustrates that group velocity matching is not a necessary condition for harmonic generation. Additionally, harmonic generation from primary mode is continuous and once generated, higher harmonics propagate independently. Lastly, the phenomenon of mode-interaction to generate sum and difference frequencies is demonstrated. PMID- 24792685 TI - Metabolic syndrome, but not insulin resistance, is associated with an increased risk of renal function decline. AB - BACKGROUND & AIMS: The purpose of this study was to evaluate the effect of metabolic syndrome (Mets) and insulin resistance (IR) on the risk of renal function decline (RFD) in a rural Chinese cohort. METHODS: A total of 2696 subjects aged 40-71 years with normal renal function were followed-up for 7 years. RFD was defined using the Kidney Disease: Improving Global Outcome definition, i.e., a drop in estimated glomerular filtration rate (eGFR) category accompanied by a 25% or greater drop in eGFR from baseline or a sustained decline in eGFR of more than 5 mL/min/1.73 m(2)/year. RESULTS: During the 7-year follow up, 9.0% of the subjects developed RFD. Subjects with Mets at baseline had an increased risk of RFD with an adjusted odds ratio (OR) of 1.77 (95%CI: 1.25 2.52), and there was a graded relationship between the numbers of Mets components and the risk for RFD. Exclusion of the subjects with hypertension (1.65; 0.99 2.75) or diabetes (1.86; 1.30-2.67) at baseline or further adjustment for IR (1.72; 1.15-2.57) did not substantially change the association between Mets and the risk of RFD. Moreover, the ORs of Mets status for RFD in the older group (>=55 years) were 2.14 (1.06-4.33) times of that in the younger group (<55 years) and 2.26 (1.07-4.78) times in hypercholesterolemia group (>=5.2 mmol/L) of that in the normal (<5.2 mmol/L) group. The baseline IR was not associated with the risk for RFD. CONCLUSIONS: Mets, but not IR, was associated with an increased risk for RFD. And there was a detrimental interaction of Mets with older age and hypercholesterolemia on the risk of RFD. PMID- 24792686 TI - Finding the right balance: An evaluation of the adequacy of energy and protein intake in childhood cancer patients. AB - BACKGROUND & AIMS: Despite a widespread belief that adequate dietary intake is needed to maintain weight during childhood cancer treatment, conclusive data about adequacy of intake are lacking. Therefore, we aimed to assess the adequacy of energy and protein intake in a heterogeneous childhood cancer population against 3 different norms. METHODS: We conducted a prospective cohort study of 115 children diagnosed with cancer and assessed dietary intake after diagnosis and at 3, 6, and 12 months. Intake was assessed against recommended daily allowances (RDA), intake in healthy controls, and calculated individual requirements; and subsequently related to changes in nutritional status. RESULTS: Energy intake was lower than RDA and lower than in healthy controls at all measurement points; whereas energy intake matched individual requirements at 2 of the 4 measurement points. Protein intake in childhood cancer patients was lower than in healthy children. However, protein intake was almost twice the RDA and one and a half times the individual requirements. During the study period, weight and fat mass (FM) increased significantly while fat free mass (FFM) remained low. Energy intake was negatively associated with weight and FM, and protein intake was not associated with FFM. CONCLUSIONS: The patients' weight increased; whereas their energy intake was lower than RDA and lower than in healthy controls. This indicates that the average intake was more than adequate. Percentage intake of individual requirements matched with increased weight. Therefore, the use of this norm is preferable to RDA or intake in healthy controls when determining the adequacy of dietary intake in both clinical practice and futures studies. PMID- 24792687 TI - Image-guided IMRT for localized prostate cancer with daily repositioning: inferring the difference between planned dose and delivered dose distribution. AB - INTRODUCTION: To investigate the dosimetric impact of daily on-line repositioning during a full course of IMRT for prostate cancer. MATERIALS AND METHODS: Twenty patients were treated with image-guided IMRT. Each pre-treatment plan (Plan A) was compared with a post-treatment plan sum (Plan B) based on couch shifts measured. The delivered dose to the prostate without a daily repositioning was inferred by considering each daily couch shift during the whole course of image guided IMRT (i.e., plan B). Dose metrics were compared for prostate CTV (P-CTV) and PTV (P-PTV) and for organs at risk. Ten patients were treated with a 5 mm margin and 10 patients with a 10 mm margin. RESULTS: For plan A vs. plan B: the average D95, D98, D50, D mean and EUD were: 76.4 Gy vs. 73.9 Gy (p = 0.0007), 75.4 Gy vs. 72.3 Gy (p = 0.001), 78.9 Gy vs. 78.4 Gy (p = 0.014), 78.7 Gy vs. 77.8 Gy (p = 0.003) and 78.1 Gy vs. 75.9 Gy (p = 0.002), respectively for P-CTV, and 73.2 Gy vs. 69.3 Gy (p = 0.0006), 70.7 Gy vs. 66.0 Gy (p = 0.0008), 78.3 Gy vs. 77.5 Gy (p = 0.001), 77.8 Gy vs. 76.4 Gy (p = 0.0002) and 74.4 Gy vs. 69.2 Gy (p = 0.003), respectively for P-PTV. Margin comparison showed no differences in dose metrics between the two plans except for D98 of the rectum in plan B which was significantly higher with a 10 mm margin. CONCLUSIONS: The absence of daily image-guided IMRT resulted in a significantly less uniform and less homogeneous dose distribution to the prostate. A reduction in PTV margin showed neither a lower target coverage nor a better spare of OAR with and without daily image guided IMRT. PMID- 24792688 TI - Is tissue harmonic ultrasound imaging (THI) of the prostatic urethra and rectum superior to brightness (B) mode imaging? An observer study. AB - Quality ultrasound images are an essential part of prostate brachytherapy procedure. The authors have previously reported that tissue harmonic ultrasound images (THI) are superior to brightness (B) mode for the prostate. The objective of the current study was to compare both imaging modes for visualization of the prostatic urethra and rectum. B and THI mode transrectal ultrasound images were acquired for ten patients. The prostatic urethra and rectal wall were contoured by a radiation oncologist (RO) and five observers on randomly presented images. The contours on one patient were repeated four additional times by four observers. All the images were qualitatively scored using a five-level Likert scale. The values of the Pearson product-moment correlation coefficients showed that the observers were in close agreement with the RO. Two sample paired student t-test showed that the rectum volumes with THI were significantly smaller than B mode, but no significant difference for urethra. Two-factor analysis of variances showed significant observer variability in defining the rectum and urethra in both imaging modes. Observer consistency of the rectum volumes, estimated by standard deviations as percentages of means was significantly improved for THI. The Likert scale based qualitative assessment supported quantitative observations. The significant improvement in image quality of the prostate (reported previously) and rectum with THI may offer better-quality treatment plans for prostate brachytherapy and potential improvement in local control. PMID- 24792689 TI - Evaluation of the FRAX model for hip fracture predictions in the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE). AB - Calibration of the Finnish FRAX model was evaluated using a locally derived population-based cohort of postmenopausal women (n = 13,917). Hip fractures were observed from national register-based data and verified from radiological records. For a subpopulation of 11,182 women, there were enough data to calculate the fracture probabilities using the Finnish FRAX tool (without bone mineral density). A 10-year period prevalence of hip fractures to this subpopulation was 0.66 %. The expected numbers of hip fractures were significantly higher than the self reported ones (O/E ratio 0.46; 95 % CI 0.33-0.63), had a tendency to be greater than the observed ones (O/E ratio 0.83; 95 % CI 0.65-1.04), and calibration in terms of goodness-of-fit of absolute probabilities was questionable (P = 0.015). Strikingly, the 10-year period prevalence of hip fractures to the whole cohort was higher (0.84 %) than for the women with FRAX measurements (0.66 %). This was mainly the result of difference between people who had and who had not responded to postal enquiries (0.71 vs. 1.77 %, P < 0.0001). Self-reports missed to capture 38 % of all hip fractures in those who responded and about 45 % of hip fractures in women who had a FRAX estimate. The Finnish FRAX tool seems to provide appropriate discrimination for hip fracture risk, but caution is required in the interpretation of absolute risk, especially if used for population that may not be representing general population per se. Our study also showed that patients with no response had significantly higher hip fracture risk and that the use of purely self-reported hip fractures in calculations results in biased incidence and period prevalence estimates. Such important biases may remain unnoticed if there are no data from other sources available. PMID- 24792690 TI - Distributions of polycyclic musk fragrance in wastewater treatment plant (WWTP) effluents and sludges in the United States. AB - The polycyclic musks, AHTN and HHCB are fragrance ingredients widely used in consumer products. A monitoring campaign was conducted and collected grab effluent and sludge samples at 40 wastewater treatment plants (WWTP) across the United States to understand their occurrence and statistical distribution in these matrices. AHTN concentration in effluent ranged from <0.05 MUg/L (LOQ) to 0.44 MUg/L with a mean and standard deviation of 0.18 +/- 0.11 MUg/L. HHCB concentrations in effluent ranged from 0.45 to 4.79 MUg/L with a mean of 1.86 +/- 1.01 MUg/L. AHTN concentrations in sludge ranged from 0.65 to 15.0mg/kg dw (dry weight) with a mean and standard deviation being 3.69 +/- 2.57 mg/kg dw, while HHCB sludge concentrations were between 4.1 and 91 mg/kg with a mean of 34.0 +/- 23.1mg/kg dw. Measured concentrations of AHTN and HHCB were significantly correlated with each other in both effluent and sludge. The concentrations of HHCB in both effluent and sludge were approximately an order of magnitude higher than those for AHTN, consistent with 2011 usage levels. The highest measured effluent concentrations for both AHTN and HHCB were below their respective freshwater PNECs (predicted no effect concentrations), indicating a negligible risk to biological communities below WWTPs, even in the absence of upstream dilution. Moreover, the large number of effluents and sludges sampled provides a statistical distribution of loadings that can be used to develop more extensive probabilistic exposure assessments for WWTP mixing zones and sludge amended soils. PMID- 24792691 TI - Surpassing the advanced comes from continuous accumulation. PMID- 24792692 TI - Carbon-based sorbents: carbon nanotubes. AB - Carbon nanotubes (CNTs), as an advanced material, have been widely used in various fields since its discovery in 1991. In recent years, as an excellent adsorption material, the pure and modified CNTs are successfully used for the purification and enrichment of food, medicine, environmental samples and so on. In this review, we focus on the detailed description of different CNTs-based extraction modes such as solid-phase extraction (SPE) (including cartridge and disk SPE, dispersive SPE, and MU-SPE) and solid-phase microextraction (SPME) (including fiber SPME, electrosorption-enhanced SPME, stir bar sorptive extraction, needle trap SPME, and hollow fiber SPME). PMID- 24792693 TI - Insights into the impact of shape and electronic properties on the enantioseparation of polyhalogenated 4,4'-bipyridines on polysaccharide-type selectors. Evidence of stereoselective halogen bonding interactions. AB - Starting from the high-performance liquid chromatography (HPLC) enantioseparation data collected by using twelve polyhalogenated 2,2'-dichloro-3-substituted-5,5' dihalo-4,4'-bipyridines as test probes on seven polysaccharide-based chiral stationary phases (CSPs) under multimodal elution, the impact of substitution pattern, shape and electronic properties of the molecules on the separation behaviour was investigated through the evaluation of the chromatographic parameters (k, alpha, Rs) and molecular properties determined by means of quantum chemistry calculations. The computational/chromatographic screening furnished relevant structure-chromatographic behaviour relationships and some molecular interactions involved in the chiral discrimination process could be identified. In particular, a halogen bonding interaction (I(.)O) could reasonably explain the high enantioseparation (alpha=1.80, Rs=8.2) observed for the 2,2'-dichloro-3,5' diiodo-5-bromo-4,4'-bipyridine on Lux Cellulose-1. To the best of our knowledge, this is the first report supporting the involvement of a stereoselective halogen bonding interaction in polysaccharide-based CSPs. Moreover, having at disposal a sufficient set of data, the unknown absolute configurations of the eluted enantiomers of 3-methyl-, 3-thiomethyl- and 3-diphenylphosphinoyl-2,2'-dichloro 5,5'-dibromo-4,4'-bipyridines could be deduced by chromatographic correlation with the enantiomer elution order (EEO) of the related compounds of known absolute configuration. PMID- 24792694 TI - Large volume sample stacking for rapid and sensitive determination of antidiabetic drug metformin in human urine and serum by capillary electrophoresis with contactless conductivity detection. AB - Two CE methods with contactless conductivity detection have been developed for determining the oral antidiabetic drug metformin in human urine and blood. The determination of metformin is performed on a separation capillary with an effective length of 14 cm, using a maximum voltage of 30 kV and with a small injection of 50-fold diluted urine into the capillary. Under these conditions, the migration time of metformin is 35s and the LOD is 0.3 MUM. Large-volume sample stacking was used to determine low metformin levels in serum. The injection of a sample of serum deproteinized with acetonitrile was 10 times greater compared to the injected amount of urine. This enabled reduction of the LOD to 0.03 MUM and the metformin migration time equalled 86 s. The undesirable solvent from sample zone was forced out of the capillary to ensure rapidity and good repeatability of the determination. The RSD values for the migration time are 0.1% for urine and 0.7% for serum; RSD for the peak areas equalled 1.4% for urine and 2.6% for serum. The developed CE technique was tested on performance of routine analyses of metformin in the urine and serum of patients suffering from type II diabetes mellitus. PMID- 24792695 TI - High-performance liquid chromatography coupled with post-column dual-bioactivity assay for simultaneous screening of xanthine oxidase inhibitors and free radical scavengers from complex mixture. AB - Xanthine oxidase (XO) can catalyze hypoxanthine and xanthine to generate uric acid and reactive oxygen species (ROS), including superoxide anion radical (O2(* )) and hydrogen peroxide. XO inhibitors and free radical scavengers are beneficial to the treatment of gout and many related diseases. In the present study, an on-line high-performance liquid chromatography (HPLC) coupled with post column dual-bioactivity assay was established and successfully applied to simultaneously screening of XO inhibitors and free radical scavengers from a complex mixture, Oroxylum indicum extract. The integrated system of HPLC separation, bioactivity screening and mass spectrometry identification was proved to be simple and effective for rapid and sensitive screening of individual bioactive compounds in complex mixtures. PMID- 24792696 TI - The adsorption of naproxen enantiomers on the chiral stationary phase (R,R)-whelk O1 under supercritical fluid conditions. AB - The adsorption isotherms of the Naproxen enantiomers eluted with a mixture of carbon dioxide and methanol on a (R,R)-Whelk-O1 column were measured using frontal analysis and the inverse method. Sharp breakthrough fronts provided using a modified design of the instrument allowed an accurate determination of these isotherms. The adsorption model that best accounts for the data was derived from the analysis of the adsorption isotherm data. The affinity energy distribution of the adsorption of the two enantiomers were calculated to determine the heterogeneity of the adsorbent surface for each compound. The adsorption model chosen based on the adsorbent heterogeneity was fitted to the adsorption isotherm data points and the best fitted isotherm parameters were derived from this fit. The inverse method was used as a second method to derive the parameters of the same adsorption models for the overloaded elution bands of (S)- and (R)-naproxen. The isotherm parameters derived from these independent numerical calculations are discussed and compared in the case of single component adsorption and of competitive adsorption as well. PMID- 24792697 TI - Enantioseparation characteristics of biselector chiral stationary phases based on derivatives of cellulose and amylose. AB - Cellulose tris(4-methylphenylcarbamate) (CMPC) and cellulose tris(4 chlorophenylcarbamate) (CCPC) are well known for their powerful chiral recognition capability, and the chiral columns prepared from these two polymers have been commercialized. However, the chiral stationary phases (CSPs) can be only used in the mobile phases containing no more than 20% ethanol (referring to CMPC) or cannot be used in ethanol-containing mobile phases (referring to CCPC). In order to overcome the defect and to study the enantioseparation characteristics of biselector CSPs, CMPC, cellulose tris(phenylcarbamate) (CPC) and CCPC were, respectively, mixed with amylose tris(3,5-dimethylphenylcarbamte) (ADMPC) at a ratio of 1:1 (mol/mol) of glucose unit, and three new CSPs were prepared by coating the resulting blends on 3-aminopropyl silica gel. For the purpose of enantioseparation comparison, the corresponding single selector CSPs were also prepared with the individual derivatives of cellulose and amylose. The enantioseparation evaluation indicated that the biselector CSPs still bear excellent enantioseparation capability. The interaction between two polymers in each blend was investigated by using circular dichroism (CD) spectroscopy. Owing to the interaction, the durability of the biselector CSP derived from CMPC and ADMPC was significantly improved. The CSP could be analyzed with a mobile phase of 100% ethanol. And the biselector CSP derived from CCPC and ADMPC could safely work in a normal phase containing 30% ethanol. Therefore, the workable ranges of the mobile phases were broadened. The elution order on the biselector CSPs was generally dominated by the one on the corresponding single selector CSPs that provided a higher resolution. In addition, the suprastructure variation caused by the interaction between the individual polymers might also affect the enantioseparation of the biselector CSPs. The trends of the retention factors and the resolutions of partially racemic mixtures were discussed. PMID- 24792698 TI - Preparation of sulfonated graphene/polypyrrole solid-phase microextraction coating by in situ electrochemical polymerization for analysis of trace terpenes. AB - In this study, a novel sulfonated graphene/polypyrrole (SG/PPy) solid-phase microextraction (SPME) coating was prepared and fabricated on a stainless-steel wire by a one-step in situ electrochemical polymerization method. Crucial preparation conditions were optimized as polymerization time of 15min and SG doping amount of 1.5mg/mL. SG/PPy coating showed excellent thermal stability and mechanical durability with a long lifespan of more than 200 stable replicate extractions. SG/PPy coating demonstrated higher extraction selectivity and capacity to volatile terpenes than commonly-used commercial coatings. Finally, SG/PPy coating was practically applied for the analysis of volatile components from star anise and fennel samples. The majority of volatile components identified were terpenes, which suggested the ultra-high extraction selectivity of SG/PPy coating to terpenes during real analytical projects. Four typical volatile terpenes were further quantified to be 0.2-27.4MUg/g from star anise samples with good recoveries of 76.4-97.8% and 0.1-1.6MUg/g from fennel samples with good recoveries of 80.0-93.1%, respectively. PMID- 24792699 TI - Sequential tentacle grafting and charge modification for enhancing charge density of mono-sized beads for facilitated protein refolding and purification from inclusion bodies. AB - We have previously found that addition of like-charged media in a refolding solution can greatly enhance the refolding of pure proteins by suppressing protein aggregation. Herein, negatively charged mono-sized microspheres with sulfonic groups were fabricated to explore the facilitating effect of like charged media on the refolding of enhanced green fluorescent protein (EGFP) expressed as inclusion bodies (IBs). A sequential polymer-tentacle grafting and sulfonate modification strategy was developed to increase the charge density of mono-sized poly(glycidyl methacrylate) (pGMA) beads (2.4MUm). Namely, GMA was first grafted onto the beads by grafting polymerization to form poly(GMA) tentacles on the pGMA beads, and then the epoxy groups on the tentacles were converted into sulfonic groups by modification with sodium sulfite. By this fabrication strategy, the charge density of the beads reached 793MUmol/g, about 2.8 times higher than that modified without prior grafting of the pGMA beads (285MUmol/g). The negatively charged beads of different charge densities were used for facilitating the refolding of like-charged EGFP from IBs. The refolding yield as well as refolding rate increased with increasing charge density. The anti-aggregation effects of urea and like-charged microspheres were synergetic. In addition, partial purification of EGFP was achieved because the ion-exchange adsorption led to 52% removal of positively charged contaminant proteins in the refolded solution. Finally, reusability of the tentacle beads was demonstrated by repetitive EGFP refolding and recovery cycles. PMID- 24792700 TI - Salt effects in electromembrane extraction. AB - Electromembrane extraction (EME) was performed on samples containing substantial amounts of NaCl to investigate how the presence of salts affected the recovery, repeatability, and membrane current in the extraction system. A group of 17 non polar basic drugs with various physical chemical properties were used as model analytes. When EME was performed in a hollow fiber setup with a supported liquid membrane (SLM) comprised of 2-nitrophenyl octyl ether (NPOE), a substantial reduction in recovery was seen for eight of the substances when 2.5% (w/v) NaCl was present. No correlation between this loss and the physical chemical properties of these substances was seen. The recovery loss was hypothesized to be caused by ion pairing in the SLM, and a mathematical model for the extraction recovery in the presence of salts was made according to the experimental observations. Some variations to the EME system reduced this recovery loss, such as changing the SLM solvent from NPOE to 6-undecanone, or by using a different EME setup with more favorable volume ratios. This was in line with the ion pairing hypothesis and the mathematical model. This thorough investigation of how salts affect EME improves the theoretical understanding of the extraction process, and can contribute to the future development and optimization of the technique. PMID- 24792701 TI - Micro-electromembrane extraction across free liquid membranes. Instrumentation and basic principles. AB - A micro-electromembrane extraction (MU-EME) technique using electrically induced transfer of charged analytes across free liquid membranes (FLMs) was presented. A disposable extraction unit was proposed and it was made of a short segment of transparent perfluoroalkoxy tubing, which was successively filled with three liquid plugs serving as acceptor solution, FLM and donor solution. These plugs formed a three-phase extraction system, which was precisely defined, that was stable and required MUL to sub-MUL volumes of all respective solutions. Basic instrumental set-up and extraction principles of MU-EME were examined using an anionic and a cationic dye, 4,5-dihydroxy-3-(p-sulfophenylazo)-2,7-naphthalene disulfonic acid trisodium salt (SPADNS) and crystal violet, respectively. Transfers of the charged dyes from donor into acceptor solutions across FLMs consisting of 1-pentanol were visualized by a microscope camera and quantitative measurements were performed by UV-vis spectrophotometry. The effects of operational parameters of MU-EME system were comprehensively investigated and experimental measurements were accompanied with theoretical calculations. Extraction recoveries above 60% were achieved for 5min MU-EME of 1mM SPADNS at 100V with repeatability values below 5%. Selectivity of FLMs was additionally examined by capillary electrophoretic analyses of acceptor solutions and the potential of FLMs for MU-EME pretreatment of samples with artificial complex matrices was demonstrated. PMID- 24792702 TI - Probing the structure of human protein disulfide isomerase by chemical cross linking combined with mass spectrometry. AB - Protein disulfide-isomerase (PDI) is a four-domain flexible protein that catalyzes the formation of disulfide bonds in the endoplasmic reticulum. Here we have analyzed native PDI purified from human placenta by chemical cross-linking followed by mass spectrometry (CXMS). In addition to PDI the sample contained soluble calnexin and ERp72. Extensive cross-linking was observed within the PDI molecule, both intra- and inter-domain, as well as between the different components in the mixture. The high sensitivity of the analysis in the current experiments, combined with a likely promiscuous interaction pattern of the involved proteins, revealed relatively densely populated cross-link heat maps. The established X-ray structure of the monomeric PDI could be confirmed; however, the dimer as presented in the existing models does not seem to be prevalent in solution as modeling on the observed cross-links revealed new models of dimeric PDI. The observed inter-protein cross-links confirmed the existence of a peptide binding area on calnexin that binds strongly both PDI and ERp72. On the other hand, interaction sites on PDI and ERp72 could not be uniquely identified, indicating a more non-specific interaction pattern. BIOLOGICAL SIGNIFICANCE: The present work demonstrates the use of chemical cross-linking and mass spectrometry (CXMS) for the determination of a solution structure of natural human PDI and its interaction with the chaperones ERp72 and calnexin. The data shows that the dimeric structure of PDI may be more diverse than indicated by present models. We further observe that the temperature influences the cross-linking pattern of PDI, but this does not influence the overall folding pattern of the molecule. PMID- 24792703 TI - A proteomic analysis of the early secondary molecular effects caused by Cn2 scorpion toxin on neuroblastoma cells. AB - Although the primary physiological effects produced by scorpion toxins are already well known, most of the secondary molecular events following scorpion neurotoxins-ion channel interactions are poorly understood and described. For this reason, we used a proteomic approach to determine the changes in relative protein abundance in F11 mouse neuroblastoma cells treated with Cn2, the major beta-toxin from the venom of the scorpion Centruroides noxius Hoffmann. Here we show that the relative abundance of 24 proteins changed after Cn2 treatment. Proteins related to protection from apoptosis and cell survival, as well as those involved in cell morphology and some translation elongation factors were diminished. By contrast, proteins associated with energy metabolism were increased. Additionally, results of western immunoblots confirmed the preference of action towards some special targets. These results suggest that Cn2 could modify the neuronal structure and induce apoptosis and reduction of the proliferation and cell survival. To support this conclusion we directly measured the Cn2 effect on cell proliferation, division and apoptosis. Our results open new avenues for continuing the studies aimed at better understanding the envenomation process caused by scorpion stings. BIOLOGICAL SIGNIFICANCE: The purpose of this work was to identify which proteins, apart from the ion-channels, are involved in the envenomation process in order to develop possible strategies to circumvent the deleterious effects caused by the toxic peptides of the venom. For this reason, we characterized the early changes in the proteome of F11 cells induced by Cn2, the major toxin of the New World scorpion C. noxius Hoffmann, using 2D-PAGE and LC-MS/MS. We identified 24 proteins which relative abundance is modified after the Cn2 treatment. Among these, proteins related with apoptosis protection, cell survival, neuronal morphology and some translation elongation factors were diminished, whereas proteins associated with energy metabolism were increased. PMID- 24792704 TI - [The fourteenth Jn'GOF: one more success!]. PMID- 24792705 TI - [Foley probe and cervical maturation at term]. PMID- 24792706 TI - [P. Tourame et P. Boyer in reply to the article by J. Pfeffer et S. Alvarez]. PMID- 24792707 TI - [Cryoconservation of ovarian tissue: indications and outcome of the patients]. AB - OBJECTIVES: Ovarian Tissue Cryopreservation (OTC) is a very promising approach of fertility preservation for women and young patients who have to follow gonadotoxic treatments (chemotherapy, radiotherapy...). The aim of this study was to analyse the indications and the outcomes of the patients who had OTC in our center during the last 17 years. PATIENTS AND METHODS: The study is retrospective. Forty-six patients, who underwent OTC in the Laboratory of Reproductive Biology of the University Hospital of Clermont-Ferrand, between January 1997 and December 2009, were included. RESULTS: The average age on the day of ovarian tissue harvesting was 19.5 years. Fifty-two percent of the patients were minor. In order of decreasing frequency, the diseases for which OTC has been proposed were hematologic, ovarian tumors, sarcoma ou PNET and breast neoplasia. In 93.5 %, the harvesting of ovarian cortex was performed by laparoscopy. After OTC, 82.6 % of the patients were treated by chemotherapy. A bone marrow transplant was performed for 48 % of the study patients. At the time of data collection, 57 % of the patients who had evaluation of their ovarian function presented premature ovarian failure. Eight patients had one or more pregnancies after treatment. It was a natural pregnancy for five of them. The three others were obtained by medically assisted procreation (in vitro fertilization and oocyte donation). DISCUSSION AND CONCLUSION: We report a long term follow-up of patients treated in our center for OTC. The originality of our study is to evaluate all aspects of OTC from the decision to propose the patients an OTC to their outcomes several years after the ovarian tissue harvesting. It is therefore a multidisciplinary approach both oncology, gynecological and pediatric whereas OTC is often considered restrictively in the literature. Finally, it seems to be essential to establish a specific medical care for these patients. This monitoring will allow an adequate assessment of pubertal development and ovarian function, management of estrogen deficiency and secondary infertility, supporting patients in their desire for motherhood. PMID- 24792708 TI - Multisensory stimulation on mood, behavior, and biomedical parameters in people with dementia: is it more effective than conventional one-to-one stimulation? AB - The purpose of this study was to assess the effects of multisensory stimulation in a multisensory stimulation environment (MSSE) such as a Snoezelen room versus one-to-one activity sessions with regard to mood, behavior, and biomedical parameters (heart rate and blood oxygen saturation). The MSSE group and activity group (one-to-one activities) of patients with dementia participated in 2 weekly individualized intervention sessions over 16 weeks, where mood and behavior before, during, and after the sessions, and biomedical parameters immediately before and after, were recorded. Immediately after the sessions, patients spoke more spontaneously, related better to others, were more attentive to their environments, more active/alert, less bored/inactive, and more relaxed/content. Both groups exhibited decreases in heart rate and increases in oxygen saturation (Spo 2) values from before to after the sessions. The MSSE sessions in a Snoezelen room were found to be as effective as activity sessions, highlighting the importance of the one-to-one interaction with the therapist. PMID- 24792709 TI - Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. AB - Following traumatic brain injury (TBI) SUR1-regulated NCCa-ATP (SUR1/TRPM4) channels are transcriptionally up-regulated in ischemic astrocytes, neurons, and capillaries. ATP depletion results in depolarization and opening of the channel leading to cytotoxic edema. Glibenclamide is an inhibitor of SUR-1 and, thus, might prevent cytotoxic edema and secondary brain damage following TBI. Anesthetized adult Sprague-Dawley rats underwent parietal craniotomy and were subjected to controlled cortical impact injury (CCI). Glibenclamide was administered as a bolus injection 15min after CCI injury and continuously via osmotic pumps throughout 7days. In an acute trial (180min) mean arterial blood pressure, heart rate, intracranial pressure, encephalographic activity, and cerebral metabolism were monitored. Brain water content was assessed gravimetrically 24h after CCI injury and contusion volumes were measured by MRI scanning technique at 8h, 24h, 72h, and 7d post injury. Throughout the entire time of observation neurological function was quantified using the "beam-walking" test. Glibenclamide-treated animals showed a significant reduction in the development of brain tissue water content(80.47%+/-0.37% (glibenclamide) vs. 80.83%+/-0.44% (control); p<0.05; n=14). Contusion sizes increased continuously within 72h following CCI injury, but glibenclamide-treated animals had significantly smaller volumes at any time-points, like 172.53+/-38.74mm(3) (glibenclamide) vs. 299.20+/-64.02mm(3) (control) (p<0.01; n=10; 24h) or 211.10+/ 41.03mm(3) (glibenclamide) vs. 309.76+/-19.45mm(3) (control) (p<0.05; n=10; 72h), respectively. An effect on acute parameters, however, could not be detected, most likely because of the up-regulation of the channel within 3-6h after injury. Furthermore, there was no significant effect on motor function assessed by the beam-walking test throughout 7days. In accordance to these results and the available literature, glibenclamide seems to have promising potency in the treatment of TBI. PMID- 24792710 TI - SGCZ mutations are unlikely to be associated with myoclonus dystonia. AB - BACKGROUND: Myoclonus dystonia syndrome (MDS) is a hyperkinetic movement disorder caused, in a proportion of cases, by mutations of the maternally imprinted epsilon-sarcoglycan gene (SGCE). SGCE mutation rates vary between cohorts, suggesting genetic heterogeneity. E- and zeta-sarcoglycan are both expressed in brain tissue. In this study we tested whether zeta-sarcoglycan gene (SGCZ) mutations also contribute to this disorder. METHODS: Patients with clinically suspected MDS and no SGCE mutation were recruited and classified, according to previously published criteria, as to their likelihood of the movement disorder. All SGCZ exons and intron/exon boundaries were screened by direct sequencing. RESULTS: Fifty-four SGCE mutation-negative patients were recruited from the UK and the Netherlands. Subdivided according to the likelihood of the movement disorder resulted in 17 'definite', 16 'probable' and 21 'possible' cases. No pathogenic SGCZ mutations were identified. CONCLUSIONS: SGCZ mutations are unlikely to contribute to the genetic heterogeneity in MDS. PMID- 24792711 TI - Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons. AB - Chronic pain reflects not only sensitization of the ascending nociceptive pathways, but also changes in descending modulation. The rostral ventromedial medulla (RVM) is a key structure in a well-studied descending pathway, and contains two classes of modulatory neurons, the ON-cells and the OFF-cells. Disinhibition of OFF-cells depresses nociception; increased ON-cell activity facilitates nociception. Multiple lines of evidence show that sensitization of ON cells contributes to chronic pain, and reversing or blocking this sensitization is of interest as a treatment of persistent pain. Neuropeptide Y (NPY) acting via the Y1 receptor has been shown to attenuate hypersensitivity in nerve-injured animals without affecting normal nociception when microinjected into the RVM, but the neural basis for this effect was unknown. We hypothesized that behavioral anti-hyperalgesia was due to selective inhibition of ON-cells by NPY at the Y1 receptor. To explore the possibility of Y1 selectivity on ON-cells, we stained for the NPY-Y1 receptor in the RVM, and found it broadly expressed on both serotonergic and non-serotonergic neurons. In subsequent behavioral experiments, NPY microinjected into the RVM in lightly anesthetized animals reversed signs of mechanical hyperalgesia following either nerve injury or chronic hindpaw inflammation. Unexpectedly, rather than decreasing ON-cell activity, NPY increased spontaneous activity of both ON- and OFF-cells without altering noxious evoked changes in firing. Based on these results, we conclude that the anti hyperalgesic effects of NPY in the RVM are not explained by selective inhibition of ON-cells, but rather by increased spontaneous activity of OFF-cells. Although ON-cells undoubtedly facilitate nociception and contribute to hypersensitivity, the present results highlight the importance of parallel OFF-cell-mediated descending inhibition in limiting the expression of chronic pain. PMID- 24792712 TI - Downregulation of miR-124 in MPTP-treated mouse model of Parkinson's disease and MPP iodide-treated MN9D cells modulates the expression of the calpain/cdk5 pathway proteins. AB - Parkinson's disease (PD) is a debilitating neurodegenerative disorder causing severe motor disabilities resulting from the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) region of the midbrain. MicroRNAs (miRNAs) are small, non-coding RNAs which play a major role in several cellular processes in health and disease by regulating gene expression post-transcriptionally. Aberrant miRNA expression has been detected in post-mortem human PD brain samples, in vitro and in vivo PD models. However, none of the studies have focused on the role of the brain-abundant miR-124 in PD. In this study, we have evaluated the expression changes of miR-124 in the SN of the 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. MiRNA expression analysis by qPCR revealed a decrease in the expression of brain-enriched miR-124 in the SN of MPTP-treated mice as compared to controls. Further, in vitro study revealed a decrease in the expression of miR-124 in MN9D dopaminergic neurons treated with methyl phenyl pyridinium (MPP) iodide. The expression of calpains 1 and 2 which is modulated by miR-124 was increased in the SNc of MPTP-treated mice as observed at different time points after treatment and in the MN9D dopaminergic neurons treated with MPP iodide leading to increased expression of the p35 cleavage product, p25 and cyclin-dependent kinase 5 (cdk5). Calpain-p25-mediated increase in cdk5 expression leading to dopaminergic neuronal death has been demonstrated in human PD and MPTP-PD models. Increased expression of calpain 1/cdk5 pathway proteins was observed in anti-miR-124-transfected MN9D cells in our studies. Knockdown of miR-124 led to increased production of reactive oxygen species (ROS) and hydrogen peroxide (H2O2) both known to increase oxidative stress. Further, experiments with miR-124 target protector sequences specific to calpain 1 revealed an interaction of miR-124 with calpain 1. Overexpression of miR-124 after MPP iodide treatment on MN9D cells was found to attenuate the expression of the calpain 1/p25/cdk5 proteins while improving cell survival. These results suggest that miR-124 acts to modulate the expression of calpain/cdk5 pathway proteins in the dopaminergic neurons. A better understanding of the mechanisms controlling the expression of miR-124 will aid in targeting miR 124 for better treatment strategies for PD. PMID- 24792715 TI - Evaluation of patients' skin, environmental surfaces, and urinary catheters as sources for transmission of urinary pathogens. AB - In hospitalized patients with urinary tract infection or asymptomatic bacteriuria, urinary pathogens frequently contaminate skin, high-touch environmental surfaces, and urinary catheters. Contamination is more common in patients with a urinary catheter in place and with gram-positive pathogens. Patients' skin and environmental surfaces may provide an important source for transmission of urinary pathogens. PMID- 24792713 TI - De novo expression of fetal ED-A(+) fibronectin and B (+) tenascin-C splicing variants in human cardiac allografts: potential impact for targeted therapy of rejection. AB - Management of acute and especially chronic rejection after human cardiac transplantation is still challenging. Chronic rejection, represented by allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) is known to cause severe long-term complications. Rejection associated tissue-remodelling entails the reoccurrence of fetal variants of Fibronectin (Fn) and Tenascin-C (Tn-C), which are virtually absent in adult human organs. In a rat model, an extensive re expression could be demonstrated for ED-A(+) Fn with spatial association to CAV and CIF. Thus, it is of great interest to investigate the cardiac tissue expression and distribution in human samples. From 48 heart transplanted patients, 64 tissue specimens derived from right ventricular biopsies were available. Histopathological analysis was performed according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines for the detection of acute rejection. By immunohistochemistry, protein expression of ED-A(+) Fn, B(+) Tn-C, alpha-smooth muscle actin, CD31 and CD45 was assessed and analysed semiquantitatively. Co-localisation studies were performed by means of immunofluorescence double labelling. Histopathological analysis of the 64 samples revealed different ISHLT grades (0R in 36 cases, 1R in 20 cases and 2R in 8 cases). There was a distinct and quantitatively relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C in most samples. Semi-quantitative evaluation did not show any correlation to the acute rejection grade for all markers. Interestingly, significant correlations to the extent of inflammation could be shown for ED-A(+) Fn (r = 0.442, p = 0.000) and B(+) Tn-C (r = 0.408, p = 0.001) as well as between both proteins (r = 0.663, p = 0.000). A spatial association of ED-A(+) Fn and B(+) Tn-C to CAV and CIF could be demonstrated. A relevant re-occurrence of ED A(+) Fn and B(+) Tn-C following human heart transplantation could be demonstrated with spatial association to signs of rejection and a significant correlation to tissue inflammation. These data might contribute to the identification of novel biomarkers reflecting the rejection process and to the development of promising strategies to image, prevent or treat cardiac rejection. PMID- 24792716 TI - Differential environmental contamination with Acinetobacter baumannii based on the anatomic source of colonization. AB - BACKGROUND: Acinetobacter baumannii is a pathogen of importance worldwide. METHODS: From January 2011 until January 2012, environmental and surveillance cultures were collected from patients admitted to our intensive care units (ICUs). Surveillance cultures were obtained on admission to the ICU and weekly thereafter. Environmental cultures of high-touch surfaces were performed on an alternating basis every week. A room was designated as contaminated if at least 1 object was positive for carbapenem-resistant A baumannii. We only evaluated the rooms belonging to patients who tested positive for Acinetobacter infection. RESULTS: Five hundred eighty-six rooms were cultured across the 5 ICUs surveyed, of which 134 (22.9%) had patients who tested positive for infection with Acinetobacter. Among patients colonized in the rectum, the odds of having bed rails contaminated with A baumannii were 2.55 times the odds of those with only respiratory colonization (P = .03). The odds of having intravenous pumps contaminated with A baumannii among patients with only respiratory colonization were 2.72 times the odds of contamination among patients colonized in the rectum (P = .03). CONCLUSIONS: There was a significant difference in the degree of contamination of bedrails and intravenous pumps based on the occupant's anatomic source of A baumannii infection. PMID- 24792717 TI - Occurrence of extended spectrum beta-lactamase-producing Enterobacteriaceae among pet dogs and cats: an emerging public health threat outside health care facilities. AB - We aimed to investigate the potential role of pet dogs and cats in the epidemiology of extended spectrum beta-lactamase-producing Enterobacteriaceae. Twenty bacterial isolates were recovered from rectal swabs obtained from 110 dogs and cats. The occurrence of extended spectrum beta-lactamase-producing Enterobacteriaceae in pets spotlights the emergence of a significant public health threat. PMID- 24792719 TI - Melatonin: functions and ligands. AB - Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands. PMID- 24792718 TI - Outbreak of carbapenemase-producing Klebsiella pneumoniae neurosurgical site infections associated with a contaminated shaving razor used for preoperative scalp shaving. AB - Between July 5 and 21, 2011, an outbreak of neurosurgical site infections with carbapenemase-producing Klebsiella pneumonia occurred in a tertiary care hospital. The outbreak affected 7 patients. The subsequent investigation revealed that a barber's contaminated shaving razor may have caused the carbapenemase producing Klebsiella pneumonia outbreak. Standardized skin preparation performed by registered nurses using sterilized instruments should be emphasized. PMID- 24792720 TI - Huntington's disease: from disease mechanisms to therapies. PMID- 24792721 TI - Inhibiting RORgammat/Th17 axis for autoimmune disorders. AB - The recent success reported in late-stage clinical trials for the treatment of psoriasis by antibodies directed against interleukin (IL)-17 or its receptor has validated and strongly supports the development of inhibitors of the IL-17 pathway as a new therapeutic modality in chronic inflammation and autoimmunity. These results also encourage the drug discovery of orally available small molecules that can modulate down the production of IL-17 by Th17 cells (the major IL-17 producers) or the downstream signaling of the IL-17 receptor. Here, we review these strategies with an emphasis on inhibiting the retinoic-acid-related orphan nuclear receptor RORgammat, which is the master regulator of Th17 cells and a promising therapeutic target for the treatment of multiple autoimmune disorders. PMID- 24792722 TI - Nox1 activation by betaPix and the role of Ser-340 phosphorylation. AB - Rac is an activating factor for Nox1, an O2(-)-generating NADPH oxidase, expressed in the colon and other tissues. Rac requires a GDP-GTP exchange factor for activation. Nox1 activation by betaPix has been demonstrated in cell lines. We examined the effects of betaPix and its phosphomimetic mutant on endogenous Nox1 in Caco-2 cells transfected with Noxo1 and Noxa1. betaPix expression enhanced O2(-) production in resting cells and cells stimulated with EGF or phorbol ester. betaPix(S340E) further enhanced O2(-) production, while betaPix(S340A) eliminated the betaPix effect. betaPix(S340E), but not betaPix(S340A), had higher affinity and GEF activity for Rac than wild-type betaPix. These results suggest that betaPix phosphorylation at Ser-340 upregulates Nox1 through Rac activation, confirming Rac as a trigger for acute Nox1-dependent ROS production. PMID- 24792723 TI - The underlying dimensions of DSM-5 posttraumatic stress disorder symptoms in an epidemiological sample of Chinese earthquake survivors. AB - The current study investigated the underlying dimensions of DSM-5 PTSD symptoms in an epidemiological sample of Chinese earthquake survivors. The sample consisted of 810 females and 386 males, with a mean age of 47.9 years (SD=10.0, range: 16-73). PTSD symptoms were assessed using the PTSD Checklist for DSM-5, and alternative models were evaluated with confirmatory factor analysis. Results indicated that a six-factor model comprised of intrusion, avoidance, negative affect, anhedonia, dysphoric arousal, and anxious arousal factors emerged as the best fitting model. The current findings add to limited literature on the latent structure of PTSD symptoms described in the recently released DSM-5, and carry implications for further trauma-related research and clinical practice. PMID- 24792724 TI - Outcomes and patterns of care in adult skull base chondrosarcomas from the SEER database. AB - This study aims to demonstrate survival rates and treatment patterns among patients with chondrosarcomas of the skull base using a large population database. Patients with skull base chondrosarcomas between 1973 and 2009 were identified from the USA Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis was used to examine the effect of surgery and radiation on overall survival. We identified 226 patients with skull base chondrosarcomas. Median follow-up was 5.4 years. Median overall survival was 22 years, and 10 year survival was 68.2%. Most patients underwent surgery (92.5%). Few received radiation after diagnosis (38.1%). Ten year survival for all patients treated with surgery was significantly increased compared to those without surgery (69.3% versus 53.9%, p=0.02). There was a significant difference in survival amongst treatment groups (p=0.02), with median overall survival not yet reached for patients who received surgery and radiation (median follow-up 5.3 years), compared to 22 years for non-irradiated surgical patients. Surgery predicted better overall survival by univariate analysis (hazard ratio [HR] 0.420, p=0.03). Female sex (HR 0.470, p=0.011), younger age at diagnosis (HR 1.046, p<0.0001), and later year of diagnosis (HR 0.949, p=0.0006) were prognostic of improved survival in a multivariate model. In subgroup analysis of patients with documented tumor size, smaller tumor size (HR 1.054, p=0.0003) and younger age (HR 1.021, p=0.0067) predicted improved survival. This population based study further reaffirms the role of surgery as an effective treatment for skull base chondrosarcoma as previously reported in small case series. Adjuvant radiation may also confer survival benefit. Optimal treatment strategy has yet to be defined in the literature. PMID- 24792725 TI - Microsurgical clipping of large and giant cerebral aneurysms: a single-center contemporary experience. AB - Several treatment strategies are available to manage large and giant cerebral aneurysms, including surgical, endovascular and combined approaches. We present our experience with microsurgical clipping of large and giant aneurysms. A total of 138 patients with 139 aneurysms of which 128 were large (>=10mm) and 11 were giant (>=25mm) were treated at our institution between 2004 and 2011. Data were collected from a prospectively maintained neurovascular database. Of 138 patients, 53 (38.4%) patients presented with subarachnoid hemorrhage (SAH). Peri operative complications occurred in 16.7% of patients causing permanent morbidity in 4.4% and death in 0.7%. Complete occlusion, as evident on intra-operative angiography, was achieved in all clipped aneurysms (100%). Long-term follow-up angiography showed no recurrence (mean follow-up time, 43.9 months; range: 1-72 months). Favorable outcomes at discharge (Glasgow Outcome Scale score 4 or 5) were noted in 64.1% of SAH patients and 93% of non-SAH patients. Favorable outcomes at follow-up (mean follow up time, 42.5 months) were seen in 96% of patients. In our experience, microsurgical clipping of large and giant aneurysms carries low rates of morbidity and mortality with high rates of favorable outcomes. The excellent durability of surgical treatment stands in stark contrast with the high recurrence rates observed with coiling for this subset of aneurysms. These data suggest that microsurgical clipping continues to be a viable option that can be offered for patients with large and giant aneurysms. PMID- 24792726 TI - Diffusion tensor imaging in blepharospasm and blepharospasm-oromandibular dystonia. AB - Patterns of white matter (WM) abnormalities and correlation with clinical features in patients with blepharospasm (BSP) and patients with blepharospasm oromandibular dystonia (BOM) remain unknown. Using voxel-based analysis, diffusion behaviors of WM including fractional anisotropy (FA), mean diffusivity (MD) and eigenvalues were compared between 20 BSP patients vs. 11 healthy controls (HCs) and 11 patients with BOM vs. 11 HCs. Correlation analyses were performed to assess possible association between diffusion behaviors of significantly different areas and clinical measures. Compared with HCs, BSP patients showed significant FA reductions in the left anterior lobe of cerebellum. Significant increases of MD and radial diffusivity (RD) were detected in right lentiform nucleus and thalamus. Significantly decreased FA in the right precuneus of parietal lobe, increased MD in the right lentiform nucleus and insula, and increased axial diffusivity in the right insula were observed in BOM patients. The FA values in the WM of left cerebellum negatively correlated with disease severity in BSP patients measured by JRS (r = -0.655, p = 0.002). The FA values in the right parietal WM negatively correlated with disease duration in BOM patients (r = -0.745, p = 0.008). Both BSP and BOM are related to microstructural abnormalities of WM in the basal ganglia. WM changes outside the basal ganglia may present trait features that are specific for individual dystonia phenotype. The correlation between FA abnormalities and symptom severity suggests that DTI parameters might be of clinical value in assessing and following disability in BSP patients. PMID- 24792727 TI - Fatigue and health-related quality of life in relapsing-remitting multiple sclerosis after 2 years glatiramer acetate treatment are predicted by changes at 6 months: an observational multi-center study. AB - Observational studies of up to 12 months duration showed that glatiramer acetate (GA) treatment of relapsing-remitting multiple sclerosis may result in decreased fatigue and improves health-related quality of life (HRQoL), with no changes in disability or mood. We investigated whether in the second year of treatment these improvements are sustained, disability or mood yet improved, and 2-year changes may be predicted by changes in the first 6 or 12 months. The multi-center FOCUS Extension study was a prospective extension of the 12-month, international, observational FOCUS study and included 67 patients (38 treatment-naive, 29 pre treated) of the Dutch FOCUS cohort. Fatigue, HRQoL, depression and disability were measured by the Fatigue Impact Scale (FIS), Leeds Multiple Sclerosis Quality of Life (LMSQoL) questionnaire, Beck Depression Inventory-Short Form and the Guy's Neurological Disability Scale. A 2-year period of GA treatment was associated with -0.52 and +0.66 standard deviation changes in mean FIS and LMSQoL scores compared to baseline, whereas disability and mood remained unchanged. For FIS and LMSQoL, the Pearson correlation coefficients between 6-month changes and 2-year scores were 0.47 and 0.50, and between 12-month changes and 2-year scores 0.65 and 0.62. After 2 years GA treatment, the improvements in fatigue and HRQoL observed at 1 year are sustained, whereas disability and mood remain unchanged compared to baseline. Moreover, the levels of fatigue and HRQoL at 2 years GA treatment are predicted by the improvements at 6 months. PMID- 24792728 TI - Urinary angiotensinogen level is increased in preterm neonates. AB - BACKGROUND: All components of the renin-angiotensin system (RAS) are abundantly synthesized in the developing kidney, suggesting that the RAS plays an important role in renal development. To examine this system in human neonates, we measured urinary angiotensinogen levels in preterm and full-term neonates and examined the relationship between urinary angiotensinogen levels and gestational age. METHODS: Urine and plasma samples were collected from 20 preterm and 18 full-term neonates at birth. Angiotensinogen levels were measured using enzyme-linked immunosorbent assay. RESULTS: Plasma angiotensinogen concentrations were not increased in preterm neonates compared with that in full-term neonates (P = 0.7288). However, the urinary angiotensinogen-to-creatinine ratio was significantly higher in preterm neonates compared with that in full-term neonates (P = 0.0011). Importantly, the urinary angiotensinogen-to-creatinine ratio dropped significantly with increasing gestational age (P = 0.0010), whereas the plasma angiotensinogen concentration was not correlated with gestational age (P = 0.7814). CONCLUSIONS: These results suggest that urinary angiotensinogen levels may indicate the involvement of intrarenal RAS activation in prenatal renal development. PMID- 24792730 TI - Disseminated intravascular coagulation: testing and diagnosis. AB - Abnormalities of the hemostatic system in patients with DIC result from the sum of vectors for hypercoagulation and hyperfibrinolysis. DIC is classified into hyperfibrinolysis, hypercoagulation, massive bleeding or nonsymptomatic types according to the balance of the two vectors. Both the antithrombin (AT) and protein C (PC) levels are significantly low in patients with septic DIC, and reduced amounts of AT and PC result in the lack of inhibition of thrombin and activated FVIII, respectively. Thrombin activates FVIII, while activated FVIII accelerates the coagulation pathway to generate thrombin; thus activation of the coagulation system persists. Three sets of diagnostic criteria have been established by the Japanese Ministry of Health, Labour and Welfare, International Society of Thrombosis and Haemostasis and Japanese Association for Acute Medicine, respectively. Although these three diagnostic criteria score hemostatic abnormalities using similar global coagulation tests, the sensitivity and/or specificity for death differ. Treatment with AT or activated PC may not improve the outcomes of patients with sepsis at the early stage, although they may improve the outcomes in those with DIC. Therefore, new diagnostic criteria for determining the appropriate time to initiate anticoagulant treatment are required. PMID- 24792731 TI - (-)-Epigallocatechin gallate protects against cerebral ischemia-induced oxidative stress via Nrf2/ARE signaling. AB - (-)-Epigallocatechin gallate (EGCG) has recently been shown to exert neuroprotection in a variety of neurological diseases; however, its role and the underlying mechanisms in cerebral ischemic injury are not fully understood. This study was conducted to investigate the potential neuroprotective effects of EGCG and the possible role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in the putative neuroprotection against experimental stroke in rats. The results revealed that EGCG exhibit significant neuroprotection, as evidenced by reduced infarction size and the decrease in transferase dUTP nick end labeling-positive neurons. Furthermore, EGCG also enhanced levels of Nrf2 and its downstream ARE pathway genes such as heme oxygenase-1, glutamate-cysteine ligase modulatory subunit and glutamate cysteine ligase regulatory subunit, as compared to control groups. In accordance with its induction of Nrf2 activation, EGCG exerted a robust attenuation of reactive oxygen species generation and an increase in glutathione content in ischemic cortex. Taken together, these results demonstrated that EGCG exerted significant antioxidant and neuroprotective effects following focal cerebral ischemia, possibly through the activation of the Nrf2/ARE signaling pathway. PMID- 24792732 TI - Effects of aluminium on beta-amyloid (1-42) and secretases (APP-cleaving enzymes) in rat brain. AB - Chronic administration of aluminium has been proposed as an environmental factor that may affect some pathological changes related to neurotoxicity and Alzheimer's disease (AD). The abnormal generation and deposition of beta-amyloid (Abeta) in senile plaques are hallmark features in the brains of AD patients. Furthermore, Abeta is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (alpha-secretase, or beta secretase) and gamma-secretase. In the present study, we investigated the modulation of Abeta deposition and neurotoxicity in aluminium-maltolate-treated (0, 15, 30, 45 mmol/kg body weight via intraperitoneal injection) in experimental rats. We measured Abeta1-40 and Abeta1-42 in the cortex and hippocampus in rat brains using ELISA. Subtypes of alpha-secretase, beta-secretase, and gamma secretase, including ADAM9, ADAM10, ADAM17 (TACE), BACE1, presenilin 1 (PS1) and nicastrin (NCT), were determined using western blotting analyses. These results indicated that aluminium-maltolate induced an AD-like behavioural deficit in rats at 30 and 45 mmol/kg body weight. Moreover, the Abeta1-42 content increased significantly, both in the cortex and hippocampus, although no changes were observed in Abeta1-40. Furthermore, ADAM9, ADAM10, and ADAM17 decreased significantly; in contrast, BACE1, PS1, and NCT showed significant increase. Taken together, these results suggest that the changes in secretases may correlate to the abnormal deposition of Abeta by aluminium in rat brains. PMID- 24792733 TI - Brain metabolite alterations in children with primary nocturnal enuresis using proton magnetic resonance spectroscopy. AB - Nocturnal enuresis is a common developmental disorder in children; primary monosymptomatic nocturnal enuresis (PMNE) is the dominant subtype. Previous literature has suggested that the prefrontal cortex and the pons are both involved in micturition control. This study aimed to investigate the metabolic levels of the left prefrontal cortex and the pons in children with PMNE by proton magnetic resonance spectroscopy (1H-MRS). Twenty-five children with PMNE and 25 healthy children took part in our experiments. Magnetic resonance examinations were performed on a Siemens 3T Trio Tim scanner. For each subject, localized 1H MRS was acquired from the left prefrontal cortex (mainly in brodmann area 9) and the pons with a point-resolved spectroscopy sequence with repetition time 2,000 ms, echo time 30 ms and 64 averages. The LCModel software package was used to analyze the MRS raw data, and two-sample t tests were used to determine significant differences between the two groups. The results revealed a significant reduction in metabolite to total creatine ratios of N-acetylaspartate (NAA/tCr) in the left prefrontal cortex and the pons for children with PMNE compared to healthy children. Our study suggests that metabolism is disturbed in the prefrontal cortex and the pons in children with PMNE, which may be associated with the symptoms of enuresis. PMID- 24792734 TI - Ginsenoside Rd attenuates tau protein phosphorylation via the PI3K/AKT/GSK-3beta pathway after transient forebrain ischemia. AB - Phosphorylated tau was found to be regulated after cerebral ischemia and linked to high risk for the development of post-stroke dementia. Our previous study showed that ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, decreased tau phosphorylation in Alzheimer model. As an extending study, here we investigated whether Rd could reduce tau phosphorylation and sequential cognition impairment after ischemic stroke. Sprague-Dawley rats were subjected to focal cerebral ischemia. The tau phosphorylation of rat brains were analyzed following ischemia by Western blot and animal cognitive functions were examined by Morris water maze and Novel object recognition task. Ischemic insults increased the levels of phosphorylated tau protein at Ser199/202 and PHF-1 sites and caused animal memory deficits. Rd treatment attenuated ischemia-induced enhancement of tau phosphorylation and ameliorated behavior impairment. Furthermore, we revealed that Rd inhibited the activity of Glycogen synthase kinase-3beta (GSK-3beta), the most important kinase involving tau phosphorylation, but enhanced the activity of protein kinase B (PKB/AKT), a key kinase suppressing GSK-3beta activity. Moreover, we found that LY294002, an antagonist for phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, abolished the inhibitory effect of Rd on GSK-3beta activity and tau phosphorylation. Taken together, our findings provide the first evidence that Rd may reduce cerebral ischemia-induced tau phosphorylation via the PI3K/AKT/GSK 3beta pathway. PMID- 24792735 TI - One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care] Trial). AB - The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial of very early intravenous glucose-insulin potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefits. Here we report 1-year outcomes. Prespecified 1-year end points of this randomized, placebo-controlled, double blind, effectiveness trial included all-cause mortality and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Of 871 participants randomized to GIK versus placebo, death occurred within 1 year in 11.6% versus 13.5%, respectively (unadjusted hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.57 to 1.23, p = 0.36). The composite of cardiac arrest or 1-year mortality was 12.8% versus 17.0% (HR 0.71, 95% CI 0.50 to 1.02, p = 0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% versus 17.2% (HR 0.98, 95% CI 0.70 to 1.37, p = 0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% versus 20.4% (HR 0.85, 95% CI 0.62 to 1.16, p = 0.30). In patients presenting with suspected ST elevation myocardial infarction, HRs for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33 to 1.27, p = 0.21), 0.52 (95% CI 0.30 to 0.92, p = 0.03), 0.63 (95% CI 0.35 to 1.16, p = 0.14), and 0.51 (95% CI 0.30 to 0.87, p = 0.01). In patients with suspected acute coronary syndromes, serious end points generally were lower with GIK than placebo, but the differences were not statistically significant. However, in those with ST elevation myocardial infarction, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced. PMID- 24792737 TI - Relation of left atrial dysfunction to ischemic stroke in patients with coronary heart disease (from the heart and soul study). AB - This study sought to determine whether left atrial (LA) dysfunction independently predicts ischemic stroke. Atrial fibrillation (AF) impairs LA function and is associated with ischemic stroke. However, ischemic stroke frequently occurs in patients without known AF. The direct relation between LA function and risk of ischemic stroke is unknown. We performed transthoracic echocardiography at rest in 983 subjects with stable coronary heart disease. To quantify LA dysfunction, we used the left atrial function index (LAFI), a validated formula incorporating LA volumes at end-atrial systole and diastole. Cox proportional hazards models were used to evaluate the association between LAFI and ischemic stroke or transient ischemic attack (TIA). Over a mean follow-up of 7.1 years, 58 study participants (5.9%) experienced an ischemic stroke or TIA. In patients without known baseline AF or warfarin therapy (n = 893), participants in the lowest quintile of LAFI had >3 times the risk of ischemic stroke or TIA (hazard ratio 3.3, 95% confidence interval 1.1 to 9.7, p = 0.03) compared with those in the highest quintile. For each standard deviation (18.8 U) decrease in LAFI, the hazard of ischemic stroke or TIA increased by 50% (hazard ratio 1.5, 95% confidence interval 1.0 to 2.1, p = 0.04). Among measured echocardiographic indexes of LA function, including LA volume, LAFI was the strongest predictor of ischemic stroke or TIA. In conclusion, LA dysfunction is an independent risk factor for stroke or TIA, even in patients without baseline AF. PMID- 24792738 TI - Determinants of all-cause mortality in different age groups in patients with severe systolic left ventricular dysfunction receiving an implantable cardioverter defibrillator (from the Italian ClinicalService Multicenter Observational Project). AB - Heart failure (HF) is a common condition in elderly patients. Despite great improvements in medical therapy, HF mortality remains high. Implantable cardioverter defibrillator (ICD) significantly lengthens the survival rate of subjects with severe HF, but little evidence exists on its effect in elderly persons. Aim of this study was to compare the age-related determinants of prognosis in a large population of patients with ICD. We divided all patients who underwent an ICD implantation in 117 Italian centers of the "ClinicalService Project" into 3 age groups (<65, 65 to 74, >= 75 years), and collected clinical and instrumental variables at baseline and during follow-up (median length: 27 months). Between 2004 and 2011, 6,311 patients were enrolled (5,174 men; left ventricular ejection fraction 29% +/- 9%); 1,510 subjects were >= 75 years (23.9%; mean age 78 +/- 3 years). The prevalence of co-morbidities increased with age. HF was most frequently due to coronary artery disease in the elderly, who also showed the worst New York Heart Association class. At multivariate analysis, older age, coronary artery disease, chronic obstructive pulmonary disease, chronic renal failure, diabetes, complex ventricular arrhythmias, and left ventricular ejection fraction were significant predictors of all-cause mortality. After adjustment, the hazard ratio(age group) for mortality was 22.6% less than at univariate analysis. When groups were analyzed separately, age alone predicted mortality in the oldest. In conclusion, a large proportion of our population was aged >= 75 years. Mortality was related to age and several co-morbidities, except for the oldest patients in whom age alone resulted predictive. PMID- 24792739 TI - Frequency and predictors of normalization of left ventricular ejection fraction in recent-onset nonischemic cardiomyopathy. AB - Emerging evidence has shown the potential of marked improvement in left ventricular ejection fraction (LVEF) in patients with recent-onset cardiomyopathy (ROCM) on medical therapy. This study was designed to determine the frequency and to identify predictors of normalization of LVEF in a cohort of Chinese patients with ROCM receiving contemporary medication. A consecutive series of patients admitted from October 2008 to November 2012 with the clinical diagnosis of ROCM and LVEF <= 40% by echocardiography at presentation were followed up at least 12 months to identify those with normalization of LVEF, defined as an increase in LVEF to a final level of >= 50%. An array of clinical and echocardiographic variables regarded as potentially relevant to normalization was evaluated to identify predictors using logistic regression analysis. After a mean follow-up of 31 +/- 13 months, 48% of 128 patients had normalized their LVEF, showing a significant increase in LVEF from 32 +/- 6% to 58 +/- 5%, of which 68% occurred within 1 year after initial diagnosis. Multivariate analysis demonstrated that normalization of LVEF was associated with a history of hypertension, higher systolic blood pressure at presentation, shorter electrocardiographic QRS duration, smaller left ventricular end-diastolic diameter, and higher LVEF by echocardiography at baseline. In conclusion, nearly 1/2 of a relatively large number of Chinese patients with ROCM have shown normalization of LVEF on current medical therapy after a medium-term follow-up, which was associated with some clinical and echocardiographic parameters. PMID- 24792736 TI - Evolution in practice patterns and long-term outcomes of coronary revascularization from bare-metal stent era to drug-eluting stent era in Japan. AB - Treatment of coronary artery disease has significantly changed over the past decade including an introduction of drug-eluting stents and a more stringent adherence to evidence-based medications. However, the impact of these advanced treatment methods on the practice patterns and long-term outcomes in patients undergoing coronary revascularization in the real world has not been yet fully evaluated. The present study population consisted of the 2 groups of patients who underwent their first coronary revascularization in the Coronary REvascularization Demonstrating Outcome Study in Kyoto Registry Cohort-1 (bare metal stent era: January 2000 to December 2002, n = 8,986) and Cohort-2 (drug eluting stent era: January 2005 to December 2007, n = 10,339). Compared with Cohort-1, the proportion of patients treated with percutaneous coronary intervention significantly increased in Cohort-2 (73% vs 81%, p <0.001), particularly for 3-vessel disease (50% vs 61%, p <0.001) and left main disease (18% vs 36%, p <0.001). Evidence-based medications were more frequently used in Cohort-2. The cumulative 2-year incidence of and the adjusted risk for all-cause death were not significantly different between Cohort-1 and Cohort-2 (6.2% vs 6.4%, p = 0.69, and hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.81 to 1.03, p = 0.15). Adjusted risks for both myocardial infarction and repeated coronary revascularization were significantly reduced in Cohort-2 compared with Cohort-1 (HR 0.80, 95% CI 0.67 to 0.96, p = 0.02, and HR 0.73, 95% CI 0.69 to 0.77, p <0.001, respectively). In conclusion, despite changes in treatment methods over time, the long-term mortality of patients undergoing coronary revascularization in the real-world clinical practice has not been changed, although there was a significant reduction of myocardial infarction and repeated coronary revascularization. PMID- 24792740 TI - Usefulness of electrocardiographic parameters for risk prediction in arrhythmogenic right ventricular dysplasia. AB - The value of electrocardiographic findings predicting adverse outcome in patients with arrhythmogenic right ventricular dysplasia (ARVD) is not well known. We hypothesized that ventricular depolarization and repolarization abnormalities on the 12-lead surface electrocardiogram (ECG) predict adverse outcome in patients with ARVD. ECGs of 111 patients screened for the 2010 ARVD Task Force Criteria from 3 Swiss tertiary care centers were digitized and analyzed with a digital caliper by 2 independent observers blinded to the outcome. ECGs were compared in 2 patient groups: (1) patients with major adverse cardiovascular events (MACE: a composite of cardiac death, heart transplantation, survived sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or arrhythmic syncope) and (2) all remaining patients. A total of 51 patients (46%) experienced MACE during a follow-up period with median of 4.6 years (interquartile range 1.8 to 10.0). Kaplan-Meier analysis revealed reduced times to MACE for patients with repolarization abnormalities according to Task Force Criteria (p = 0.009), a precordial QRS amplitude ratio (?QRS mV V1 to V3/?QRS mV V1 to V6) of <= 0.48 (p = 0.019), and QRS fragmentation (p = 0.045). In multivariable Cox regression, a precordial QRS amplitude ratio of <= 0.48 (hazard ratio [HR] 2.92, 95% confidence interval [CI] 1.39 to 6.15, p = 0.005), inferior leads T-wave inversions (HR 2.44, 95% CI 1.15 to 5.18, p = 0.020), and QRS fragmentation (HR 2.65, 95% CI 1.1 to 6.34, p = 0.029) remained as independent predictors of MACE. In conclusion, in this multicenter, observational, long-term study, electrocardiographic findings were useful for risk stratification in patients with ARVD, with repolarization criteria, inferior leads TWI, a precordial QRS amplitude ratio of <= 0.48, and QRS fragmentation constituting valuable variables to predict adverse outcome. PMID- 24792741 TI - Arrhythmogenic right ventricular dysplasia back in force. PMID- 24792742 TI - Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AB - Patients with acute coronary syndromes (ACSs) still experience high rates of recurrent coronary events, particularly, early in their presentation. Statins yield substantial cardiovascular benefits, but the optimal timing of their administration, before or after percutaneous coronary intervention (PCI), remains unclear. We aimed to perform a meta-analysis of randomized controlled trials of statin administration before or after PCI versus no statin or low-dose statin in patients with ACS. Primary end points were 30-day all-cause mortality and 30-day myocardial infarction (MI) stratified by pre- and post-PCI statin administration. Secondary end points were major adverse cardiac events (MACEs) or major adverse cardiac and cerebrovascular events (MACCEs). Long-term analysis beyond 30 days was also performed. Twenty randomized controlled trials enrolling 8,750 patients were included. At 30 days, the rate of MI was significantly lower in the statin group (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.53 to 0.84, p = 0.0007) with a trend toward reduced mortality (p = 0.06) and significant reductions in MACE and MACCE compared with no or low-dose statin. The 30-day incidence of MI was markedly lower when statins were administered before PCI (OR 0.38, 95% CI 0.24 to 0.59, p <0.0001) rather than after PCI (p = 0.28). The direction and magnitude of the estimates for before and after PCI versus no statin or low-dose statin were sustained at long term, not reaching statistical significance for MI (OR 0.81, 95% CI 0.65 to 1.01, p = 0.06) but with significant reductions in MACE (p = 0.0002). By meta-regression, earlier statin administration correlated significantly with lower risk of MI, MACE, and MACCE at 30 days. In conclusion, the present meta-analysis indicates a time-related impact of statin therapy on clinical outcomes of patients with ACS undergoing PCI: the earlier the administration before PCI, the greater the benefits. PMID- 24792743 TI - Statin intolerance. AB - The term statin intolerance refers to an inability to use statins because of muscle symptoms or elevated creatine kinase, and the major diagnostic challenge is to unambiguously link these to statin use. Roughly 5% to 10% of statin users develop statin intolerance, and because statin use is expected to increase- especially after recent updated guidelines have expanded the statin benefit groups--adverse effects from statins will become a growing issue. Unfortunately, the pathophysiology--and even the terminology--of statin-related muscle injury lacks clarity. Several risk factors have been identified, including advanced age, family history of myopathy and statin dose; many cases manifest only after patients are administered an interacting medication (e.g., azole antifungals, cimetidine, clarithromycin, erythromycin and cyclosporine). The diagnosis of myopathy remains challenging, especially because some patients can have normal serum creatine kinase levels despite demonstrable weakness and muscle biopsy proven statin-induced myopathy. A statin withdrawal and rechallenge helps patients distinguish whether their myalgia symptoms are because of statins, but, in at least 1 clinical trial, even 5% of placebo-treated patients developed myalgias during a controlled withdrawal and rechallenge. No consensus exists for management of patients with statin intolerance. Many patients can eventually tolerate a statin but often at suboptimal doses. A subset of patients do well with nondaily regimens such as every other day or once weekly dosing. Some patients cannot tolerate statins at all, requiring nonstatin lipid-lowering medications--the benefit of which remains unclear with regard to preventing atherosclerotic events. Ultimately, statin intolerance undermines the drug adherence that is critical for achieving the benefits of lifelong lipid-lowering therapy. In conclusion, statin myopathy is a common challenge in lipid management, and further work is needed to establish a standard diagnostic criterion as well as treatment algorithms. PMID- 24792744 TI - Hypertrophic cardiomyopathy: one gene ... but many phenotypes. PMID- 24792746 TI - The probable role of cannibalism in spreading Trichinella papuae infection in a crocodile farm in Papua New Guinea. AB - Between 2003 and 2007, 83 (50%) of 167 crocodiles (Crocodylus porosus) purchased as juveniles by a crocodile farm 3 or 4 years earlier from Kikori, Gulf Province, were found to be infected with Trichinella papuae. Between 2005 and 2007 infection was detected in a number of crocodiles at the farm obtained from six localities other than Kikori, as well as in a few animals born on the farm. Up to 2004, all juveniles at the farm, whether wild- or farm-born, were penned together; the practice was then stopped to prevent possible infection through cannibalism. The last infected animal from Kikori was seen in 2007, 4 years after the purchase of crocodiles from there ceased. The last non-Kikori infected crocodile was seen, also, in 2007. None of the 1972 crocodiles (comprising wild- and farm-born animals) tested from 2008 to 2013, using the digestion method, was infected with T. papuae. This indicates that infection of non-Kikori crocodiles was the result of cannibalism within the farm during the years up to 2004 when juvenile crocodiles were kept together, and that the farm is now free of the infection. PMID- 24792745 TI - Restarting anticoagulation after major gastrointestinal bleeding. PMID- 24792747 TI - Neospora caninum serostatus is affected by age and species variables in cohabiting water buffaloes and beef cattle. AB - The aim of this study was to investigate how Neospora caninum serostatus may be affected by variables such as host species (water buffaloes or cattle) and age in animals cohabiting in the same ranch. A convenience cross-sectional study was performed on four ranches in the Northeast of Argentina, where water buffalo are cohabitating with beef cattle. Blood samples were collected from 1350 female water buffaloes (Bubalus bubalis) and 880 female beef cattle (Bos taurus and Bos indicus crossbreeds) from four ranches. Calving and weaning percentages at herd level for each ranch were also recorded. N. caninum antibody levels were measured by an indirect fluorescent antibody test (IFAT) (reciprocal antibody titers >= 100). Serological results were classified into 2 categories (0: negative; 1: positive). A logistic regression model was used to describe the relationship between N. caninum serostatus and specie (water buffalo or cattle), age or ranch and their interactions. Likelihood ratio tests were used to assess the significance of the model and their terms. Odds ratios were estimated and 95% profile likelihood (LR) and Wald confidence intervals (CI) obtained. Overall, specific antibody titers were found in 43.3% (584/1350) of water buffaloes and 28.6% (252/880) of cattle. Seropositive water buffaloes and cattle were observed on all ranches. Age was statistically significant (p=0.01) with an overall estimate of logit (log odds) of age of 0.03 for both species. This indicates that for every one year increase in age, the expected change in log odds of being seropositive increased by 0.03. On three of four ranches a water buffalo was 4.48, 1.54 and 2.25 times more likely to be seropositive than cattle for animals of the same age. The N. caninum serostatus was affected by age in the first place, but also by species on at least three of the four ranches. Calving and weaning percentages were higher in water buffaloes than in beef cattle (p<0.05). Even though the low pathogenicity that N. caninum seems to have in water buffaloes, this study reinforces the importance of this specie as maintenance of the disease. PMID- 24792748 TI - Seasonal infestation of donkeys by lice: phenology, risk factors and management. AB - A longitudinal study was undertaken over a 21 months period to examine the seasonal abundance of lice infesting donkeys, the risk factors which predispose donkeys to infestation and the effectiveness of louse management. All the lice seen were Bovicola (Werneckiella) ocellatus. A strong seasonal pattern, which was correlated with mean monthly temperature, was observed with higher prevalence and intensity in the cooler, winter months (October-March). Overall infestation in these animals was over-dispersed, suggesting that some individuals are strongly predisposed to infestation. Donkey age and mean hair length were characteristics which affected louse prevalence: older and younger donkeys and donkeys with longer hair harboured the highest numbers of lice. However, the practice of coat clipping, to reduce the infestation, resulted in a lower louse prevalence only in the summer, suggesting that clipping is not an effective form of louse control in cooler months. Higher louse burdens were associated with larger areas of visible excoriation and hair damage, suggesting that B. ocellatus does adversely impact animal welfare. However, the ability of animal carers to estimate louse presence or absence accurately on an individual donkey was not sufficiently high to allow targeted selective treatment of heavily infested animals to be employed effectively. As animals are housed in closed herds these findings suggest that clipping in the summer and treating all animals with insecticide in late autumn, prior to turn-in may be an effective louse management strategy. PMID- 24792750 TI - Characteristics of modern triticale quality: glutenin and secalin subunit composition and mixograph properties. AB - Triticale is a hardy, high yielding cereal crop with a reputation for poor gluten strength. The secalogluten formation capacity was investigated in 17 modern triticale cultivars by defining their HMW glutenin and 75K gamma-secalin alleles and then assessing SDS-sedimentation height and mixograph parameters in a subset of cultivars. The allelic diversity was poor with only 13 alleles identified at four loci; nevertheless, sufficient variability existed to allow secalogluten improvement through crossbreeding and selection. SDS-sedimentation height of triticale (35.5 mm) and mixing time (2.7 min) was equivalent to soft wheat but significantly less than hard wheat. However, flour protein content was 16% less in triticale compared to wheat, despite similar grain protein contents, suggesting triticale stores a lower proportion of grain protein in the endosperm. The confounding factor of protein content must be considered as part of an equitable analysis of gluten quality in cultivar breeding, in the interpretation of previous triticale research, and when comparing triticale to wheat. Improved glutenin properties will expand the utility of triticale in human food products and, thus, increase potential profitability. PMID- 24792749 TI - In-depth metabolic phenotyping of genetically engineered mouse models in obesity and diabetes. AB - The world-wide prevalence of obesity and diabetes has increased sharply during the last two decades. Accordingly, the metabolic phenotyping of genetically engineered mouse models is critical for evaluating the functional roles of target genes in obesity and diabetes, and for developing new therapeutic targets. In this review, we discuss the practical meaning of metabolic phenotyping, the strategy of choosing appropriate tests, and considerations when designing and performing metabolic phenotyping in mice. PMID- 24792751 TI - Beyond sofosbuvir: what opportunity exists for a better nucleoside/nucleotide to treat hepatitis C? AB - Sofosbuvir is a liver-targeting uridine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase recently approved by the FDA and EU regulators for treatment of patients infected with genotype 1, 2, 3 and 4 virus. The request for regulatory approval of the fixed-dose combination containing sofosbuvir and the NS5A inhibitor ledipasvir is also under review. Preclinical and clinical studies have shown that sofosbuvir is effective, safe and well tolerated. Review of sofosbuvir's preclinical and clinical profile reveals a drug that has the potential to become the backbone of standard of care. Pursuit of a next generation nucleos(t)ide HCV inhibitor that could compete with sofosbuvir would need to address whatever limitations sofosbuvir exhibits. These include reduced efficacy in genotype 3 patients and use in severe renally impaired patients or those patients currently on drugs that are inducers of P glycoprotein. However, it has been shown that reduced efficacy in genotype 3 is largely eliminated when sofosbuvir is combined with another oral DAA. Next generation inhibitors would also benefit by enabling a reduced duration of therapy and an orthogonal resistance profile. The more recent group of nucleos(t)ides in clinical development maintains similarities to sofosbuvir, in that they are uridine nucleotide prodrugs. The question therefore remains whether these new agents will be sufficiently differentiated from sofosbuvir to provide any additional benefit to patients. This paper forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." PMID- 24792752 TI - Hepatitis C virus NS5A competes with PI4KB for binding to ACBD3 in a genotype dependent manner. AB - Although genotype-dependency of PI4KB involved in HCV replication has been reported, the mechanism underlying that is unknown. In this study, we found that NS5A and PI4KB competed for association of acyl-coenzyme A binding domain containing protein 3 (ACBD3), which inhibited HCV replication. ACBD3 bind to GT1b NS5A with a higher affinity than to GT2a NS5A, which was consistent with higher co-localization between PI4KB and phosphatidylinositol 4-phosphate (PI4P) in GT1b HCV-infected cells than that in GT2a HCV-infected cells. These results suggested that NS5A could rob the preexisting ACBD3/PI4KB complex to form NS5A/ACBD3 complex and PI4KB could relocate to the viral RNA replication sites to facilitate HCV replication. Our findings not only revealed the anti-HCV function of ACBD3, but also shed mechanistic light on how ACBD3 was manipulated by NS5A from different GT of HCV. PMID- 24792754 TI - Intracranial stenting for large vessel recanalization in acute ischemic stroke. PMID- 24792755 TI - Author's response. PMID- 24792753 TI - An interferon-beta promoter reporter assay for high throughput identification of compounds against multiple RNA viruses. AB - Virus infection of host cells is sensed by innate pattern recognition receptors (PRRs) and induces production of type I interferons (IFNs) and other inflammatory cytokines. These cytokines orchestrate the elimination of the viruses but are occasionally detrimental to the hosts. The outcomes and pathogenesis of viral infection are largely determined by the specific interaction between the viruses and their host cells. Therefore, compounds that either inhibit viral infection or modulate virus-induced cytokine response should be considered as candidates for managing virus infection. The aim of the study was to identify compounds in both categories, using a single cell-based assay. Our screening platform is a HEK293 cell-based reporter assay where the expression of a firefly luciferase is under the control of a human IFN-beta promoter. We have demonstrated that infection of the reporter cell line with a panel of RNA viruses activated the reporter gene expression that correlates quantitatively with the levels of virus replication and progeny virus production, and could be inhibited in a dose-dependent manner by known antiviral compound or inhibitors of PRR signal transduction pathways. Using Dengue virus as an example, a pilot screening of a small molecule library consisting of 26,900 compounds proved the concept that the IFN-beta promoter reporter assay can serve as a convenient high throughput screening platform for simultaneous discovery of antiviral and innate immune response modulating compounds. A representative antiviral compound from the pilot screening, 1-(6 ethoxybenzo[d]thiazol-2-yl)-3-(3-methoxyphenyl) urea, was demonstrated to specifically inhibit several viruses belonging to the family of flaviviridae. PMID- 24792756 TI - Journal of Pediatric and Adolescent Gynecology. Introduction. PMID- 24792757 TI - Perceived program qualities and outcomes of a youth program in Hong Kong based on the views of the workers. AB - STUDY OBJECTIVES: Based on the data collected in the extension phase of the Project P.A.T.H.S. in Hong Kong, this study examined the views of 9,765 program implementers on the universal curricula-based program (ie, Tier 1 Program). DESIGN: After the Tier 1 Program was completed, workers responded to a client satisfaction scale (Form B). Utilizing the data supplied by the participating schools, the profiles and correlates of client satisfaction data were examined. RESULTS: Program attributes, implementer attributes, and benefits of the program were viewed positively by the program implementers, with high proportion of the instructors perceiving the program contributing to the development of the students. Small grade differences on client satisfaction levels were found. Regarding predictors of perceived program effectiveness, perceived program and instructor attributes predicted perceived effectiveness of the program. CONCLUSION: Consistent with the data collected from the students, the present findings suggest that the Tier 1 Program was well-received by the major stakeholders, particularly with respect to its ability to promote positive development in Chinese junior high school students. The present finding replicated the previous observation that perceived program and implementer qualities were significant determinants of perceived program effectiveness. PMID- 24792758 TI - Positive youth development programs for adolescents with greater psychosocial needs: subjective outcome evaluation over 3 years. AB - STUDY OBJECTIVES: This study examined the views of 153,761 students participating in a positive youth development program designed for participants with greater psychosocial needs (the Tier 2 Program) in the context of the Project P.A.T.H.S. in Hong Kong. The program was implemented in the extension phase of the project from 2009/10 to 2011/12 school years. DESIGN: A validated subjective outcome evaluation scale was used to assess the views of the program participants toward the program qualities, implementer qualities, and program effectiveness after completion of the program. Nine datasets were used which were derived from the aggregated reports submitted by social service providers designing the Tier 2 Program. RESULTS: Participants generally held favorable views of program qualities, implementer qualities, as well as program effectiveness of the Tier 2 Program. Some small grade and program differences on subjective outcome evaluation were also found. Both program qualities and implementer qualities were significant predictors of program effectiveness in different grades. CONCLUSION: Consistent with the findings of the initial phase of the Project P.A.T.H.S., the present study suggests that the Tier 2 Program of the Project P.A.T.H.S. in Hong Kong is perceived favorably by program participants and its perceived effectiveness was high. Significant but small grade and program approach differences on subjective outcome evaluation were found. Both program and implementer qualities were predictive of perceived program effectiveness in different grades. PMID- 24792759 TI - Evaluation of the Project P.A.T.H.S. based on the client satisfaction approach: view of the students. AB - STUDY OBJECTIVES: Based on several data sets collected from 2009/10 to 2011/12 school years, this study examined the views of 242,705 students participating in the Tier 1 Program in the extension phase of the Project P.A.T.H.S. in Hong Kong. DESIGN: Students responded to a validated client satisfaction measure after completion of the program. Analyses were based on the reports submitted by the schools participating in the project. RESULTS: High proportions of the students viewed the program, implementers, and benefits of the program in a favorable light. Compared with students in lower grades, students in higher grades showed relatively lower satisfaction ratings, although the differences were small. Perceived qualities of program and instructor predicted perceived effectiveness of the program. CONCLUSION: The Tier 1 Program was received favorably by the students. Perceived qualities of the program and the program implementers predicted perceived program effectiveness. The findings are consistent with those reported in the initial phase of the project. PMID- 24792760 TI - Validation of a subjective outcome evaluation tool for participants in a positive youth development program in Hong Kong. AB - STUDY OBJECTIVES: Using confirmatory factor analyses, this study examined the factor structure and reliability of a subjective outcome evaluation tool for students with greater psychosocial needs within the context of the Project P.A.T.H.S. in Hong Kong. DESIGN: To assess the views of program participants on the program content, implementer qualities, and program effectiveness of the Tier 2 Program of the Project P.A.T.H.S., the Subjective Outcome Evaluation Form for Participants (Form C) was used. Data were collected from 8,893 Grade 7 participants after they had completed the Tier 2 Program. RESULTS: The findings based on confirmatory factor analyses are generally consistent with the original hypotheses, providing support for the 3-factor model and the higher-order factor model containing 3 primary factors. Support for different types of factorial invariance based on 2 randomly split subsamples was also found. High coefficient alphas were found for the total scale and the 3 subscales. CONCLUSION: Confirmatory factor analyses support the conceptual model underlying the Form C. Reliability analyses showed that the total scale and subscales possess excellent internal consistency. PMID- 24792761 TI - Factorial validity of a subjective outcome evaluation tool for implementers of a positive youth development program. AB - STUDY OBJECTIVES: This study examined the dimensionality of the subjective outcome evaluation tool assessing the views of program implementers in the context of the Project P.A.T.H.S. in Hong Kong. For illustration purpose, both exploratory and confirmatory factor analyses were performed to examine the factor structure of the instrument. DESIGN: Subjective outcome evaluation findings were collected from 1,170 program implementers who implemented the Grade 7 level program. A validated subjective outcome evaluation scale was used to assess the views of the program implementers. Conceptually, the scale was designed to assess program implementers' perceptions about program content, implementer qualities, and program effectiveness after completion of the program. RESULTS: Exploratory factor analyses showed that 3 factors were abstracted from the scale and they were stable across 2 random subsamples. Confirmatory factor analyses showed that there was support for a higher-order factor model containing 3 primary factors and 1 second-order factor, and that evidence supporting factorial invariance was found. The 3 subscales were also shown to be reliable with acceptable internal consistency. CONCLUSION: Both exploratory and confirmatory factor analyses provided support for the factorial validity of the subjective outcome evaluation tool designed for program implementers in the Project P.A.T.H.S. in Hong Kong. PMID- 24792762 TI - Validation of a subjective outcome evaluation tool for participants in a positive youth development program in Hong Kong. AB - STUDY OBJECTIVE: Utilizing primary-factor and hierarchical confirmatory factor analyses, this study examined the factor structure of a subjective outcome evaluation tool for the program participants for the Project P.A.T.H.S. in Hong Kong. DESIGN AND PARTICIPANTS: A subjective outcome evaluation scale was used to assess the views of program participants on the program, implementer, and program effectiveness of the Project P.A.T.H.S. A total of 28,431 Secondary 2 students responded to this measure after they had completed the program. RESULTS: Consistent with the conceptual model, findings based on confirmatory factor analyses provided support for the primary factor model and the higher-order factor model containing 3 primary factors. By randomly splitting the total sample into 2 subsamples, support for different forms of factorial invariance was found. There was also support for the internal consistency of the total scale and the 3 subscales. CONCLUSION: Confirmatory factor analyses provided support for the factorial validity of the subjective outcome evaluation instrument designed for program participants in the Project P.A.T.H.S. in Hong Kong. PMID- 24792763 TI - Is subjective outcome evaluation related to objective outcome evaluation? Insights from a longitudinal study in Hong Kong. AB - STUDY OBJECTIVES: Empirical studies investigating the inter-relationships among subjective outcomes and objective outcomes are sparse in the scientific literature. This study examined the relationship between these 2 forms of outcome evaluation data in Chinese adolescents, utilizing longitudinal data. DESIGN: In Wave 3 and Wave 4 of a randomized group trial, 2,784 Chinese secondary school students responded to the Chinese Positive Youth Development Scale (CPYDS) assessing objective outcome at pretest (Wave 3) and posttest (Wave 4). Students in the experimental schools also responded to a measure of client satisfaction assessing the subjective outcome of a positive youth development program at posttest (Wave 4). RESULTS: Subjective outcome evaluation measures (eg, process, program, and effectiveness) at Wave 3 were significantly correlated with CPYDS scores at Wave 4 and difference scores. Subjective outcome evaluation measures also predicted changes in the objective outcome evaluation measures scores across time. CONCLUSIONS: The present findings replicated the previous findings that subjective outcome and objective outcome evaluation findings were intimately related, and subjective outcome measures predicted posttest measures and their changes over time. The present study suggests that subjective outcome evaluation findings may yield useful information regarding program effectiveness in youth work settings. PMID- 24792764 TI - Assessment of the spatial and temporal distribution of legacy persistent organic pollutants and recommendations for sample collection from the surficial sediments of estuaries and seas in China. AB - With the rapid economic development in China, environmental pollution has become a major concern, particularly pollution by persistent organic pollutants (POPs). Thus, these pollutants must be monitored over the long term. In this study, we analyze the distribution levels and sources of POPs in the surficial sediments of Chinese estuaries and seas. Results showed that POPs in sediments significantly distribute spatially and temporally. Furthermore, POPs not only concentrate in densely populated cities, bays, and industrial areas, but also follow the natural distribution of and temporal changes in local industrial structures. Hence, we recommend sampling sites and frequencies to monitor POPs in China over the long term and to defer their analysis. PMID- 24792765 TI - Methodological flaws in "the clinical and economic impact of nurse to patient staffing ratios in women receiving intrapartum oxytocin". PMID- 24792766 TI - Prolonged early antibiotic use and bronchopulmonary dysplasia in very low birth weight infants. AB - OBJECTIVE: The objective of the article is to determine if > 48 hours of antibiotic treatment during the 1st week of life is associated with subsequent isolation of bacteria from the endotracheal tube (ETT), and an increased risk of bronchopulmonary dysplasia (BPD). STUDY DESIGN: Retrospective cohort study of very low birth weight infants. Routine weekly surveillance ETT cultures were obtained to monitor bacterial colonization in all intubated infants. Risk factors for BPD were assessed using unadjusted and multivariable analyses. RESULTS: In the study sample (n = 906), infants with BPD (n = 182) were more likely to have received > 48 hours antibiotic treatment (31 vs. 14%, p < 0.01) and have a resistant gram-negative bacilli in ETT (7 vs. 2%, p = 0.0001) compared with infants without BPD. Treatment with > 48 hours of antibiotics remained associated with BPD (adjusted odds ratio, 2.2; 95% confidence interval, 1.4-3.5) after controlling for confounding variables. CONCLUSIONS: Antibiotic duration > 48 hours in the 1st week of life was associated with subsequent BPD and the presence of resistant bacteria in routine ETT cultures. PMID- 24792767 TI - Time trends and payer differences in lengths of initial hospitalization for preterm infants, Arkansas, 2004 to 2010. AB - OBJECTIVE: The objective of this study was to examine the time trend in length of stay (LOS) and explore potential differences in neonatal LOS by insurance type for preterm infants in Arkansas between 2004 and 2010. STUDY DESIGN: There were 18,712 preterm infants included in our analyses. Accelerated failure time models were used to model neonatal LOS as a function of insurance type and discharge year while adjusting for key maternal and infant characteristics, and complication/anomaly indicators. RESULTS: Before adjusting for the complication/anomaly indicators, the LOS for preterm infants delivered to mothers in the Medicaid group was 3.2% shorter than those in the private payer group. Furthermore, each subsequent year was associated with a 1.6% increase in the expected LOS. However, after accounting for complications and anomalies, insurance coverage differences in neonatal LOS were not statistically significant while the trend in LOS persisted at a 0.59% increase for each succeeding year. CONCLUSION: All of the apparent differences in LOS by insurance type and more than half of the apparent increase in LOS over time are accounted for by higher rates of complications among privately insured preterm infants and increasing rates of complications for all surviving preterm infants between 2004 and 2010. PMID- 24792768 TI - Risk factors for the delivery of macrosomic infants at the University Hospital of the West Indies. AB - OBJECTIVE: The aim of this study is to determine the risk factors for the delivery of macrosomic infants at the University Hospital of the West Indies over a 3-year period. DESIGN AND METHODS: A retrospective, descriptive, case controlled study was performed. Data were extracted from the maternal medical records of 316 macrosomic infants (weighing >= 4,000 g) and 316 controls (weighing from 2,500-3,999 g) delivered at the University Hospital of the West Indies. Descriptive analyses were performed comparing maternal characteristics between the two groups. Risk factors were determined using multiple logistic regression models. RESULTS: The incidence of macrosomia for the study period was 4.3%. Women who delivered a macrosomic infant were older, taller, and heavier with a greater body mass index at the start of the pregnancy and gained more weight during pregnancy than their counterparts in the control group (p < 0.05). Maternal obesity, height > 164 cm, abnormalities of glucose control, weight gain > 15 kg, gestational age > 40 weeks, and male gender of the infant were found to increase the risk of delivering a macrosomic infant by over 2-fold (p < 0.05). The greatest risk factor was that of having had a previous macrosomic infant which increased the risk of delivering a macrosomic infant by as much as 6-fold (adjusted odds ratio, 6.0; 95% confidence interval, 1.9-18.7). CONCLUSION: The maternal risk factors for fetal macrosomia identified in this study mirror those of previous studies. PMID- 24792769 TI - Chronic opiate use in pregnancy and newborn head circumference. AB - OBJECTIVE: The aim of the study is to evaluate whether chronic opiate use in pregnancy affects newborn head circumference (HC). STUDY DESIGN: All newborns from January 1, 2010, to June 30, 2012, admitted to the neonatal intensive care unit for treatment of neonatal abstinence syndrome were prospectively collected. The demographic, obstetrical, neonatal, and perinatal ultrasound data were retrospectively obtained. A gestational age-matched control was used for comparison purposes. RESULTS: Of 332 neonates admitted for the treatment of neonatal abstinence syndrome, 98 (29.5%) had a HC <= 10th percentile for gestational age that was significantly increased when compared with controls (p < 0.001). Of these 98, 25 had a HC <= 3rd percentile. Of the case population, 141 had an ultrasound in the perinatal unit within 10 days of birth. A HC < 5th percentile was found in 38.3% of cases of which 74% were <= 10th percentile postdelivery. The ultrasound femur and humerus length measurements were also < 5th percentile in 36.2 and 28.9%, respectively. CONCLUSION: Chronic opiate use in pregnancy appears to increase the risk for a HC <= 10th percentile and <= 3rd percentile when compared with controls. From ultrasound findings, femur and humerus lengths also appear to be shortened suggesting a possible effect on bone growth. PMID- 24792770 TI - Remifentanil analgesia during laser treatment for retinopathy of prematurity: a practical approach in neonatal intensive care unit. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a significant cause of childhood blindness. AIM: The aim of this study is to determine the feasibility of remifentanil analgesia during laser treatment of ROP performed in the neonatal intensive care unit (NICU). PATIENTS AND METHODS: Remifentanil was infused continuously during the procedure starting with a dose of 0.2 ug/kg/min and increased gradually to 0.6 ug/kg/min to provide an adequate level of analgesia. RESULTS: We enrolled 64 infants. Remifentanil was infused continuously at a mean rate of 0.4 +/- 0.1 MUg/kg/min. No major adverse effects were observed except in two patients with reversible bradycardia and hypotension. Premature infant pain profile (PIPP) scores revealed no pain. Patients with bronchopulmonary dysplasia had similar remifentanil dosage, intubation duration, and extubation time. CONCLUSIONS: Remifentanil analgesia for ROP treatment performed in the NICU by pediatricians is a safe and effective modality. This modality offers a practical solution in hospitals without readily available pediatric anesthetists. PMID- 24792771 TI - Advances in fetal imaging. AB - While ultrasound (US) has been a part of prenatal care for almost 40 years, technical progress over the last two decades has resulted in improved image quality and detection rate of congenital anomalies. The past 15 years have also seen the expansion of three-dimensional (3D) US, providing enhancements over with 2D US, and more realistic images of babies to parents and providers. Fetal magnetic resonance imaging (MRI) was first performed over 30 years ago, and has undergone major technical improvement over the past 15 to 20 years. Fetal MRI complements US by providing better visualization in the fetus when US is limited such as in oligohydramnios or severe maternal obesity. It offers a larger field of view and better tissue contrast than US and is not limited by shadowing from osseous structures. However, MRI has a limited resolution compared with US, is less readily available, and more expensive. While indications for fetal MRI have been clearly established for some abnormalities, such as neurological anomalies, other indications especially for fetal body imaging are not as clearly defined. In this article, we discuss recent developments in fetal MRI and 3D US and their common and newest indications. PMID- 24792772 TI - Evaluation of pre-analytical variables in a commercial thrombin generation assay. AB - BACKGROUND: There is minimal data on the influence of pre-analytical variables on the use of calibrated automated thrombography (CAT), to measure thrombin generation. OBJECTIVES: To evaluate the impact of centrifugation methods, time after collection, and contact activation inhibition on the CAT assay performed using two commercial reagents. METHODS AND RESULTS: Six different methods of plasma separation were examined. Thrombin generation triggered by a 5 pM tissue factor reagent was not greatly affected by plasma separation method, with similar results obtained with all methods apart from single centrifugation and membrane filtration. Membrane filtration increased APTT and is not recommended. Extended double centrifugation at higher speed was required to minimise the impact of residual phospholipid with 1 pM tissue factor trigger, particularly with inhibition of contact activation. The effect of a delay of up to 24 hours in preparing plasma was assessed. No significant difference in results was observed among samples processed between 0.5 and 6 hours after blood collection into plastic Vacuette(r) tubes. The presence or absence of corn trypsin inhibitor had a significant impact on all parameters with 1 pM tissue factor trigger, with minor differences seen on Peak and ttPeak results using 5 pM tissue factor. CONCLUSIONS: The impact of pre-analytical variables on thrombin generation results is dependent on the concentration of tissue factor in the trigger reagent used. Results with 1 pM tissue factor are particularly sensitive to centrifugation method and contact activation, and standardisation is required to allow large collaborative studies to be performed. PMID- 24792773 TI - Modulation of miR-203 and its regulators as a function of time during the development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors in presence or absence of the antitumor agents. AB - We investigated the chemopreventive effects of naturally occurring compounds like butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) individually or in combination in 7, 12-dimethylbenz [a] anthracene (DMBA) treated mouse skin at 4 and 16 weeks, the time before and after the tumor development. DMBA application did not show any skin tumors at 4 weeks but well defined tumors appeared at 16 weeks. BA, NA or CAG prevented the tumor development significantly but the protection was highly enhanced when all these compounds were given together. In order to see the molecular changes progressing with tumors, we showed the downregulation of tumor suppressor miR-203 at 16 weeks and upregulation of histone deacetylases (HDAC), DNA methyltransferase, promoter methylation of miR 203 at 4 or 16 weeks. Regulators of micro RNA biogenesis such as DICER1 and Ago2 were also deregulated by DMBA. Proto-oncogene c-myc and BMI1 were upregulated and tumor suppressor gene p16 was downregulated by DMBA as a function of time. Effects of BA, NA or CAG were more pronounced after 16 weeks as compared to 4 weeks in preventing the tumor development and altered gene expression. Concomitant administration of BA, NA and CAG tried to prevent these alterations more effectively than that of individual compound possibly by regulating miR-203 status through epigenetic or biogenetic modulations before and after the tumor development. Study provides a rationale for chemoprevention by combination of different compounds targeting miR-203. PMID- 24792774 TI - Discovery of novel type II c-Met inhibitors based on BMS-777607. AB - Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or alpha-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies. PMID- 24792775 TI - Macrosomic newborns of non-diabetic mothers: anthropometric measurements and neonatal complications. AB - OBJECTIVE: To assess the association of anthropometric measurements with neonatal complications in macrosomic newborns of non-diabetic mothers. DESIGN: Retrospective cohort study. PATIENTS: All liveborn, singleton, full term newborns with birth weight >=4000 g born to non-diabetic mothers at a tertiary medical centre in 1995-2005 (n=2766, study group) were matched to the next born, healthy, full term infant with a birth weight of 3000-4000 g (control group). Exclusion criteria were multiple birth, congenital infection, major malformations and pregnancy complications. INTERVENTION: Data collection by file review. OUTCOME MEASURES: Complication rates were compared between study and control groups and between symmetric and asymmetric macrosomic newborns, defined by weight/length ratio (WLR), Body Mass Index and Ponderal Index. RESULTS: The 2766 non-diabetic macrosomic infants identified were matched to 2766 control infants. The macrosomic group had higher rates of hypoglycaemia (1.2% vs 0.5%, p=0.008), transient tachypnoea of the newborn (1.5% vs 0.5%, p<0.001), hyperthermia (0.6% vs 0.1%, p=0.012), and birth trauma (2% vs 0.7%, p<0.001), with no cases of symptomatic polycythaemia, and only one case of hypoglycaemia. Hypoglycaemia was positively associated with birth weight. It was significantly higher in the asymmetric than the symmetric macrosomic newborns, defined by WLR (1.7% vs 0.3%, p<0.001). CONCLUSIONS: Macrosomic infants of non-diabetic mothers are at increased risk of neonatal complications. However, routine measurements of haematocrit and calcium may not be necessary. Symmetric macrosomic infants (by WLR) have a similar rate of hypoglycaemia as normal-weight infants. Thus, repeat glucose measurements in symmetric macrosomic infants are not justified. PMID- 24792776 TI - Prenatal diagnosis of chromosomal imbalances. AB - Prenatal array comparative genome hybridisation (aCGH) testing has by and large replaced routine karyotyping in many healthcare settings. While this will lead to more diagnoses, uncertain, unexpected or unhelpful findings are also likely to increase. This is the case for aCGH in any setting, but we discuss the particular challenges the prenatal setting generates and suggest areas that need further debate and discussion as well as some pragmatic ways forward. PMID- 24792777 TI - Neonatal drug trials: impact of EU and US paediatric regulations. PMID- 24792778 TI - Diagnostic accuracy of sleep bruxism scoring in absence of audio-video recording: a pilot study. AB - PURPOSE: Based on the most recent polysomnographic (PSG) research diagnostic criteria, sleep bruxism is diagnosed when >2 rhythmic masticatory muscle activity (RMMA)/h of sleep are scored on the masseter and/or temporalis muscles. These criteria have not yet been validated for portable PSG systems. This pilot study aimed to assess the diagnostic accuracy of scoring sleep bruxism in absence of audio-video recordings. METHODS: Ten subjects (mean age 24.7 +/- 2.2) with a clinical diagnosis of sleep bruxism spent one night in the sleep laboratory. PSG were performed with a portable system (type 2) while audio-video was recorded. Sleep studies were scored by the same examiner three times: (1) without, (2) with, and (3) without audio-video in order to test the intra-scoring and intra examiner reliability for RMMA scoring. RESULTS: The RMMA event-by-event concordance rate between scoring without audio-video and with audio-video was 68.3 %. Overall, the RMMA index was overestimated by 23.8 % without audio-video. However, the intra-class correlation coefficient (ICC) between scorings with and without audio-video was good (ICC = 0.91; p < 0.001); the intra-examiner reliability was high (ICC = 0.97; p < 0.001). The clinical diagnosis of sleep bruxism was confirmed in 8/10 subjects based on scoring without audio-video and in 6/10 subjects with audio-video. CONCLUSIONS: Although the absence of audio video recording, the diagnostic accuracy of assessing RMMA with portable PSG systems appeared to remain good, supporting their use for both research and clinical purposes. However, the risk of moderate overestimation in absence of audio-video must be taken into account. PMID- 24792779 TI - Radiologic manifestations of angioedema. AB - OBJECTIVES: The purpose of this pictorial review is to present imaging findings of angioedema involving the various organs. CONCLUSION: The role of imaging for patients with angioedema includes the evaluation of the upper airway for obstruction and the exclusion of other possible aetiologies, such as neoplastic or infectious processes. Glossomegaly is a common finding of head and neck angioedema. Angioedema may involve organ systems beyond the superficial regions and the head and neck including the gastrointestinal and genitourinary tracts. Angioedema of the visceral organs is often accompanied by adjacent fluid, and it is commonly diffuse or concentric but can also be multifocal and asymmetric. TEACHING POINTS: * The evaluation of the upper airway obstruction is important for head and neck angioedema. * Glossomegaly with decreased attenuation is common in head and neck angioedema. * Angioedema of the visceral organs can be multifocal and asymmetric. * Angioedema of the visceral organs is often accompanied by adjacent fluid. * It is important to include clinical and laboratory findings for the diagnosis of angioedema. PMID- 24792780 TI - Evaluation of dexmedetomidine therapy for sedation in patients with toxicological events at an academic medical center. AB - INTRODUCTION: Although clinical use of dexmedetomidine (DEX), an alpha2 adrenergic receptor agonist, has increased, its role in patients admitted to intensive care units secondary to toxicological sequelae has not been well established. OBJECTIVES: The primary objective of this study was to describe clinical and adverse effects observed in poisoned patients receiving DEX for sedation. METHODS: This was an observational case series with retrospective chart review of poisoned patients who received DEX for sedation at an academic medical center. The primary endpoint was incidence of adverse effects of DEX therapy including bradycardia, hypotension, seizures, and arrhythmias. For comparison, vital signs were collected hourly for the 5 h preceding the DEX therapy and every hour during DEX therapy until the therapy ended. Additional endpoints included therapy duration; time within target Richmond Agitation Sedation Score (RASS); and concomitant sedation, analgesia, and vasopressor requirements. RESULTS: Twenty-two patients were included. Median initial and median DEX infusion rates were similar to the commonly used rates for sedation. Median heart rate was lower during the therapy (82 vs. 93 beats/minute, p < 0.05). Median systolic blood pressure before and during therapy was similar (111 vs. 109 mmHg, p = 0.745). Five patients experienced an adverse effect per study definitions during therapy. No additional adverse effects were noted. Median time within target RASS and duration of therapy was 6.5 and 44.5 h, respectively. Seventeen patients (77%) had concomitant use of other sedation and/or analgesia with four (23%) of these patients requiring additional agents after DEX initiation. Seven patients (32%) had concomitant vasopressor support with four (57%) of these patients requiring vasopressor support after DEX initiation. CONCLUSION: Common adverse effects of DEX were noted in this study. The requirement for vasopressor support during therapy warrants further investigation into the safety of DEX in poisoned patients. Larger, comparative studies need to be performed before the use of DEX can be routinely recommended in poisoned patients. PMID- 24792781 TI - Epidemiological trends in electronic cigarette exposures reported to U.S. Poison Centers. AB - CONTEXT: The Centers for Disease Control and Prevention (CDC) has reported an increase in electronic cigarette (e-cigarette) use in both adults and adolescents. Poison Center calls provide data on exposures pertaining to e cigarette devices and components (including nicotine-refill cartridges), potentially identifying epidemiological trends in reported exposures over time. OBJECTIVE: To characterize the trends in e-cigarette exposures reported to United States (U.S.) Poison Centers between 01 June 2010 and 30 September 2013. METHODS: We obtained data from the American Association of Poison Control Centers (AAPCC) for all exposures involving e-cigarettes reported to the National Poison Data System (NPDS) by U.S. Poison Centers and described trends in exposures over time, demographics, geographical characteristics, clinical effects and outcomes, management site, and exposure route. RESULTS: A total of 1,700 exposures were reported to Poison Centers during this time. The most frequent age groups were children 5 years or below with 717 (42.2%) exposures and adults ages 20-39 years with 466 (27.4%) exposures. Temporal trends showed an increase of 1.36 exposures per month [95% CI: 1.16-1.56] from June 2010 through December 2012, after which exposures increased by 9.60 per month [95% CI: 8.64-10.55] from January through September 2013. The majority of patients who were followed reported that they had only minor effects. CONCLUSIONS: The majority of exposures to e-cigarette devices and components occurred in children of 5 years or below due to accidental exposure. Based on the available data, the reported exposures have resulted in minimal toxicity. Calls to Poison Centers regarding these products have rapidly increased since 2010, and continued surveillance may show changes in the epidemiological trends surrounding e-cigarette exposures. PMID- 24792782 TI - Radon inhalation protects against transient global cerebral ischemic injury in gerbils. AB - Although brain disorders are not the main indication for radon therapy, our previous study suggested that radon inhalation therapy might mitigate brain disorders. In this study, we assessed whether radon inhalation protects against transient global cerebral ischemic injury in gerbils. Gerbils were treated with inhaled radon at a concentration of 2,000 Bq/m(3) for 24 h. After radon inhalation, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that transient global cerebral ischemia induced neuronal damage in hippocampal CA1, and the number of damaged neurons was significantly increased compared with control. However, radon treatment inhibited ischemic damage. Superoxide dismutase (SOD) activity in the radon-treated gerbil brain was significantly higher than that in sham-operated gerbils. These findings suggested that radon inhalation activates antioxidative function, especially SOD, thereby inhibiting transient global cerebral ischemic injury in gerbils. PMID- 24792784 TI - Sonocrystallisation of lactose in concentrated whey. AB - Whey concentrated to 32% lactose was sonicated at 30 degrees C in a non-contact approach at flow rates of up to 12L/min. Applied energy density varied from 3 to 16J/mL at a frequency of 20kHz. Sonication of whey initiated the rapid formation of a large number of lactose crystals in response to acoustic cavitation which increased the rate of crystallisation. The rate of sonocrystallisation was greater than stirring for approximately 180min but slowed down between 120 and 180min as the metastable limit was reached. A second treatment with ultrasound at 120min delivering an applied energy density of 4J/mL stimulated further nuclei formation and the rate of crystallisation was maintained for >300min. Yield on the other hand was limited by the solubility of lactose and could not be improved. The crystal size distribution was narrower than that with stirring and the overall crystal size was smaller. PMID- 24792783 TI - Extracellular matrix-regulated neural differentiation of human multipotent marrow progenitor cells enhances functional recovery after spinal cord injury. AB - BACKGROUND CONTEXT: Recent advanced studies have demonstrated that cytokines and extracellular matrix (ECM) could trigger various types of neural differentiation. However, the efficacy of differentiation and in vivo transplantation has not yet thoroughly been investigated. PURPOSE: To highlight the current understanding of the effects of ECM on neural differentiation of human bone marrow-derived multipotent progenitor cells (MPCs), regarding state-of-art cure for the animal with acute spinal cord injury (SCI), and explore future treatments aimed at neural repair. STUDY DESIGN: A selective overview of the literature pertaining to the neural differentiation of the MSCs and experimental animals aimed at improved repair of SCI. METHODS: Extracellular matrix proteins, tenascin-cytotactin (TN C), tenascin-restrictin (TN-R), and chondroitin sulfate (CS), with the cytokines, nerve growth factor (NGF)/brain-derived neurotrophic factor (BDNF)/retinoic acid (RA) (NBR), were incorporated to induce transdifferentiation of human MPCs. Cells were treated with NBR for 7 days, and then TN-C, TN-R, or CS was added for 2 days. The medium was changed every 2 days. Twenty-four animals were randomly assigned to four groups with six animals in each group: one experimental and three controls. Animals received two (bilateral) injections of vehicle, MPCs, NBR induced MPCs, or NBR/TN-C-induced MPCs into the lesion sites after SCI. Functional assessment was measured using the Basso, Beattie, and Bresnahan locomotor rating score. Data were analyzed using analysis of variance followed by Student-Newman-Keuls (SNK) post hoc tests. RESULTS: Results showed that MPCs with the transdifferentiation of human MPCs to neurons were associated with increased messenger-RNA (mRNA) expression of neuronal markers including nestin, microtubule associated protein (MAP) 2, glial fibrillary acidic protein, betaIII tubulin, and NGF. Greater amounts of neuronal morphology appeared in cultures incorporated with TN-C and TN-R than those with CS. The addition of TN-C enhanced mRNA expressions of MAP2, betaIII tubulin, and NGF, whereas TN-R did not significantly change. Conversely, CS exposure decreased MAP2, betaIII tubulin, and NGF expressions. The TN-C-treated MSCs significantly and functionally repaired SCI induced rats at Day 42. Present results indicate that ECM components, such as tenascins and CS in addition to cytokines, may play functional roles in regulating neurogenesis by human MPCs. CONCLUSIONS: These findings suggest that the combined use of TN-C, NBR, and human MPCs offers a new feasible method for nerve repair. PMID- 24792785 TI - Time reducing process for biofuel production from non edible oil assisted by ultrasonication. AB - Limited resources of conventional fuels such as petrodiesel have led to the search for alternative fuels. Various convention batch/continuous processes for the biodiesel production have been developed before the recent year. All processes are time consuming with high labor cost. Thus, we need a new process for biodiesel production which reduces the reaction time and production cost as well as save the energy. In this work, ultrasonic assisted transesterification of Jatrophacurcas oil is carried out in the presence of methanol and potassium hydroxide (KOH) as catalyst, keeping the molar ratio of oil to alcohol 1:5, catalyst concentration 0.75 wt% of oil, ultrasonic amplitude 50% and pulse 0.3 cycle, 7 min reaction time under atmospheric condition. Ultrasonic mixing has increased the rate of transesterification reaction as compare to the mechanical mixing. PMID- 24792786 TI - Expression of transient receptor potential vanilloid 1 and anoctamin 1 in rat trigeminal ganglion neurons innervating the tongue. AB - Transient receptor potential vanilloid 1 (TRPV1) is a polymodal sensor that is activated by heat (>43 degrees C), acid, or capsaicin, the pungent ingredient of hot peppers. Reports that mice lacking TRPV1 display heat avoidance behaviors and TRPV1-negative neurons respond to heat suggest that an additional heat sensor is present. Anoctamin 1 (ANO1; also known as transmembrane protein 16A [TMEM16A]), is a component of Ca(2+)-activated chloride channels (CaCCs), and has been recently identified as a heat sensor, activated by temperatures over 44 degrees C. ANO1 is highly co-localized with TRPV1 in small-diameter dorsal root ganglion (DRG) neurons. The aim of the present study was to investigate co-expression of ANO1 and TRPV1 in rat trigeminal ganglion (TG) neurons innervating the tongue by using retrograde labeling and immunohistochemical techniques. Fluoro-gold (FG) retrograde labeling was used to identify the TG neurons innervating the anterior two thirds of the tongue; as expected, most labeling was detected in the mandibular division of the TGs. The FG-labeled TG neurons showed TRPV1 immunoreactivity (17.9%) and ANO1 immunoreactivity (13.7%), indicating that TRPV1 and ANO1-expressing neurons were present in the mandibular division of the TGs. Seventy-six percent of the ANO1-immunoreactive TG neurons were also immunoreactive for TRPV1; this co-expression was mainly detected in small- to medium-diameter TG neurons. The high degree of co-expression of TRPV1 and ANO1 suggests that cooperation between ANO1 and TRPV1 plays a role in the signaling pathways of nociceptive TG neurons. PMID- 24792787 TI - Shreddability of pizza Mozzarella cheese predicted using physicochemical properties. AB - This study used rheological techniques such as uniaxial compression, wire cutting, and dynamic oscillatory shear to probe the physical properties of pizza Mozzarella cheeses. Predictive models were built using compositional and textural descriptors to predict cheese shreddability. Experimental cheeses were made using milk with (0.25% wt/wt) or without denatured whey protein and renneted at pH 6.5 or 6.4. The cheeses were aged for 8, 22, or 36 d and then tested at 4, 13, or 22 degrees C for textural attributes using 11 descriptors. Adding denatured whey protein and reducing the milk renneting pH strongly affected cheese mechanical properties, but these effects were usually dependent on testing temperature. Cheeses were generally weaker as they aged. None of the compositional or rheological descriptors taken alone could predict the shredding behavior of the cheeses. Using the stepwise method, an objective selection of a few (<4) relevant descriptors made it possible to predict the production of fines (R(2)=0.82), the percentage of long shreds (R(2)=0.67), and to a lesser degree, the adhesion of cheese to the shredding blade (R(2)=0.45). The principal component analysis markedly contrasted the adhesion of cheese to the shredding blade with other shredding properties such as the production of fines or long shreds. The predictive models and principal component analysis can help manufacturers select relevant descriptors for the development of cheese with optimal mechanical behavior under shredding conditions. PMID- 24792788 TI - Herd- and cow-level risk factors associated with subclinical mastitis in dairy farms from the High Plains of the northern Antioquia, Colombia. AB - Mastitis is the main disease entity affecting dairy farms in the Colombian High Plains of northern Antioquia, Colombia. However, no previous epidemiologic studies have determined the characteristics that increase the risk of infection in this region, where manual milking is still the prevailing system of milking. A 24-mo longitudinal study was designed to identify the predominant mastitis pathogens and important herd- and cow-level risk factors. Monthly visits were made to 37 commercial dairy farms to collect herd- and cow-level data and milk samples. Herd size varied from 6 to 136 cows (mean 37.0, median 29). Herd-level factors included type of milking system (manual or mechanical) and a range of management practices recommended by the National Mastitis Council (Madison, WI) to prevent mastitis. Individual cow-level risk factors included parity, stage of lactation, breed, udder hygiene, and lameness. A logistic regression analysis was used to investigate associations between herd- and cow-level risk factors with the presence of subclinical mastitis and infection caused by Streptococcus agalactiae at the quarter level. A quarter was considered to have subclinical mastitis if it had a positive California Mastitis Test and was subsequently confirmed to have a somatic cell count of >=200,000 cells/mL. Any cow with one or more quarters with subclinical mastitis was considered to have subclinical mastitis at the cow level. Using 17,622 cow observations, the mean prevalence of subclinical mastitis at the cow level was 37.2% (95% confidence interval: 31.2, 43.3) for the first month and did not substantially change throughout the study. The predominant microorganisms isolated from quarters meeting the subclinical mastitis definition were contagious pathogens, including Strep. agalactiae (34.4%), Corynebacterium spp. (13.2%), and Staphylococcus aureus (8.0%). Significant variables associated with subclinical mastitis risk at the quarter level included being a purebred Holstein cow, higher parity, and increased months in milk. Variables that were protective for mastitis risk included being a crossbreed cow and adequate premilking udder hygiene. Significant variables associated with Strep. agalactiae infection were higher parity, increased months in milk, and manual milking. Variables that were protective were postmilking teat dipping and adequate cleaning of the udder. The results highlight the importance of hygiene practices in contagious mastitis control in manually milked herds. PMID- 24792789 TI - Potential risk indicators of retained placenta and other diseases in multiparous cows. AB - Retained placenta (RP), defined as fetal membranes not being expelled within 24 h after calving, is a costly disease in multiparous dairy cows that has been linked to immune suppression, infections, elevated lipid mobilization, and depleted status of antioxidants including alpha-tocopherol, and that increases the risk of other diseases (OD) in early lactation. Early detection of cows at increased risk of developing RP, OD, or both in early lactation could improve treatment success and result in improved milk production and reproductive performance. To identify risk indicators of RP, OD, or both, we used a nested case-control design and compared multiparous dairy cows that developed RP (n=32) with cows that remained healthy (H; n=32) or cows that developed OD (n=32) in early lactation. We compared peripartal body condition score (BCS) as well as serum concentrations of alpha-tocopherol, metabolites [beta-hydroxybutyrate (BHBA), cholesterol, glucose, nonesterified fatty acids (NEFA), and urea N], haptoglobin, and macrominerals (i.e., calcium, magnesium, and phosphorus) on d -21, -14, -7, -3, -1, 0, 1, 3, 7, 14, 21, 28, 35, 42, and 49 postpartum. In addition, average serum concentrations were calculated for each cow for the last 3 wk prepartum, for 3 and 2 wk prepartum combined, for the last week prepartum, and for the morning after calving and compared between groups. The RP cows had lower BCS than the H or OD cows until 2 wk postpartum. During the prepartal periods, RP and OD cows had lower alpha-tocopherol concentrations (corrected or not for cholesterol concentration) and higher NEFA and BHBA concentrations than H cows. Thus, lower prepartal BCS could be an early predictor for RP risk, and lower alpha-tocopherol concentrations and higher NEFA and BHBA concentrations could be early predictors for disease. PMID- 24792790 TI - A survey of gross pathologic conditions in cull cows at slaughter in the Great Lakes region of the United States. AB - The prevalence and severity of multiple gross pathologic lesions and abnormalities in cull dairy and beef cows was evaluated at a commercial abattoir in the Great Lakes region of the United States; 1,461 cattle were examined at slaughter over the course of 3 production days and evaluated for the occurrence and severity of lung, liver, rumen, and carcass abnormalities and pathologies. Of the 1,461 cattle examined at slaughter, 87% were classified as Holstein cows and 13% were classified as other cows. Liver abscesses were observed in 32% of the population and over half were classified as severe (18.5% population prevalence). The frequency distribution of cattle observed with a liver abscess was not different among production days. Severe ruminal lesions and rumenitis scars were observed in 10.0% of the population, and 25.1% of cattle were observed to have short or denuded papillae. Severe bovine respiratory disease complex lesions were observed in 10.3% of cattle. The most common reason for USDA postmortem carcass condemnation was malignant lymphoma (9 of 41). Only 45.9% of carcasses were free from bruising. Results indicate that ruminal acidosis and bovine respiratory disease complex occur at a relatively high frequency in this population. Although cows are routinely culled for reproductive failure or low milk production, the underlying reason may be causally related to these relatively prevalent conditions. Further investigation is warranted to assess this relationship and to examine the use of specific health intervention strategies within this demographic of cattle. PMID- 24792791 TI - Genomic predictions based on a joint reference population for the Nordic Red cattle breeds. AB - The main aim of this study was to compare accuracies of imputation and genomic predictions based on single and joint reference populations for Norwegian Red (NRF) and a composite breed (DFS) consisting of Danish Red, Finnish Ayrshire, and Swedish Red. The single nucleotide polymorphism (SNP) data for NRF consisted of 2 data sets: one including 25,000 markers (NRF25K) and the other including 50,000 markers (NRF50K). The NRF25K data set had 2,572 bulls, and the NRF50K data set had 1,128 bulls. Four hundred forty-two bulls were genotyped in both data sets (double-genotyped bulls). The DFS data set (DSF50K) included 50,000 markers of 13,472 individuals, of which around 4,700 were progeny-tested bulls. The NRF25K data set was imputed to 50,000 density using the software Beagle. The average error rate for the imputation of NRF25K decreased slightly from 0.023 to 0.021, and the correlation between observed and imputed genotypes changed from 0.935 to 0.936 when comparing the NRF50K reference and the NRF50K-DFS50K joint reference imputations. A genomic BLUP (GBLUP) model and a Bayesian 4-component mixture model were used to predict genomic breeding values for the NRF and DFS bulls based on the single and joint NRF and DFS reference populations. In the multiple population predictions, accuracies of genomic breeding values increased for the 3 production traits (milk, fat, and protein yields) for both NRF and DFS. Accuracies increased by 6 and 1.3 percentage points, on average, for the NRF and DFS bulls, respectively, using the GBLUP model, and by 9.3 and 1.3 percentage points, on average, using the Bayesian 4-component mixture model. However, accuracies for health or reproduction traits did not increase from the multiple population predictions. Among the 3 DFS populations, Swedish Red gained most in accuracies from the multiple population predictions, presumably because Swedish Red has a closer genetic relationship with NRF than Danish Red and Finnish Ayrshire. The Bayesian 4-component mixture model performed better than the GBLUP model for most production traits for both NRF and DFS, whereas no advantage was found for health or reproduction traits. In general, combining NRF and DFS reference populations was useful in genomic predictions for both the NRF and DFS bulls. PMID- 24792792 TI - Computer simulation of energy use, greenhouse gas emissions, and costs for alternative methods of processing fluid milk. AB - Computer simulation is a useful tool for benchmarking electrical and fuel energy consumption and water use in a fluid milk plant. In this study, a computer simulation model of the fluid milk process based on high temperature, short time (HTST) pasteurization was extended to include models for processes for shelf stable milk and extended shelf-life milk that may help prevent the loss or waste of milk that leads to increases in the greenhouse gas (GHG) emissions for fluid milk. The models were for UHT processing, crossflow microfiltration (MF) without HTST pasteurization, crossflow MF followed by HTST pasteurization (MF/HTST), crossflow MF/HTST with partial homogenization, and pulsed electric field (PEF) processing, and were incorporated into the existing model for the fluid milk process. Simulation trials were conducted assuming a production rate for the plants of 113.6 million liters of milk per year to produce only whole milk (3.25%) and 40% cream. Results showed that GHG emissions in the form of process related CO2 emissions, defined as CO2 equivalents (e)/kg of raw milk processed (RMP), and specific energy consumptions (SEC) for electricity and natural gas use for the HTST process alone were 37.6g of CO2e/kg of RMP, 0.14 MJ/kg of RMP, and 0.13 MJ/kg of RMP, respectively. Emissions of CO2 and SEC for electricity and natural gas use were highest for the PEF process, with values of 99.1g of CO2e/kg of RMP, 0.44 MJ/kg of RMP, and 0.10 MJ/kg of RMP, respectively, and lowest for the UHT process at 31.4 g of CO2e/kg of RMP, 0.10 MJ/kg of RMP, and 0.17 MJ/kg of RMP. Estimated unit production costs associated with the various processes were lowest for the HTST process and MF/HTST with partial homogenization at $0.507/L and highest for the UHT process at $0.60/L. The increase in shelf life associated with the UHT and MF processes may eliminate some of the supply chain product and consumer losses and waste of milk and compensate for the small increases in GHG emissions or total SEC noted for these processes compared with HTST pasteurization alone. The water use calculated for the HTST and PEF processes were both 0.245 kg of water/kg of RMP. The highest water use was associated with the MF/HTST process, which required 0.333 kg of water/kg of RMP, with the additional water required for membrane cleaning. The simulation model is a benchmarking framework for current plant operations and a tool for evaluating the costs of process upgrades and new technologies that improve energy efficiency and water savings. PMID- 24792793 TI - The effect of rearing substrate and space allowance on the behavior and physiology of dairy calves. AB - The objective of this study was to investigate the effect of rearing substrate and space allowance on the behavior and physiology of dairy calves. At 1 wk of age, 72 calves were moved into 1 of 18 experimental pens (n=4 calves/pen) where they remained until 6 wk of age. Half of the pens had floors covered with quarry stones (QS) and the other half were covered with sawdust (SW). For each substrate type, calves were reared at 1 of 3 space allowances: 1.0, 1.5, or 2.0 m(2)/calf. Behavior was video-recorded continuously for 24 h in the home pen at 2, 4, and 6 wk of age; the time calves spent lying, standing, walking, and running were estimated using 1-min instantaneous scan sampling. Body weight, cleanliness, fecal fluidity, and skin surface temperature were recorded at 1, 4, and 6 wk of age. Escherichia coli numbers were assessed on the skin surface of the shoulder and in feces of calves at 4 and 6 wk of age. Blood samples were taken at 1, 4, and 6 wk of age to measure cortisol, creatine kinase, immunoglobulin G, serum amyloid A, and total protein concentrations. Calves reared on QS spent less time lying and walking and more time standing at 4 and 6 wk of age compared with calves reared on SW. Furthermore, calves reared at a space allowance of 2.0 m(2)/calf spent less time lying and more time standing and walking compared with calves reared at a space allowance of 1.0 and 1.5 m(2)/calf. Calves reared on QS had lower skin surface temperatures compared with calves reared on SW. Fecal fluidity scores were lower in calves reared on QS than SW at 2 wk of age. Fewer E. coli were recovered from the shoulder of calves reared on QS than those of calves reared on SW, but fecal E. coli counts were similar between rearing substrates and space allowances. Serum amyloid A concentrations were lower in calves reared on QS than SW. We detected no effect of rearing substrate or space allowance on body weight, cleanliness, or concentrations of cortisol, creatine kinase, immunoglobulin G, and total protein. In conclusion, lower skin temperature in combination with reduced lying behavior may reflect reduced comfort of calves reared on QS. Furthermore, a space allowance of 2.0 m(2)/calf may provide calves with more opportunity to perform active behaviors. PMID- 24792794 TI - Estimation of regional genetic parameters for mortality and 305-d milk yield of US Holsteins in the first 3 parities. AB - Several research reports have indicated increasing dairy cow mortality in recent years. The objectives of this research were to characterize the phenotypic differences in mortality in the first 3 parities across 3 regions of the United States to estimate the heritability of mortality of Holstein cows across regions and parities, and to estimate genetic and environmental correlations between milk yield and mortality across parities and regions. Dairy Herd Information (DHI) milk yield and mortality data were obtained from 3 different US regions: the Southeast (SE), Southwest (SW), and Northeast (NE). A total of 3,522,824 records for the first 3 parities were used: 732,009 (SE), 656,768 (SW), and 2,134,047 (NE) from 1999 to 2008. Cows that received a termination code of 6--"Cow died on the dairy; downer cows that were euthanized should be included here"--were given a mortality score of 2 (dead), whereas all other codes were assigned a mortality score of 1 (alive). Average annual mortalities in the first 3 parities across regions ranged from 2.2 to 7.2%, with mortality frequency increasing with increasing parity across all regions and with the SE having the highest mortality frequency. For genetic analysis, a 2-trait (305-d milk yield and mortality) linear-threshold animal model that fitted fixed effects of herd-year (for 305-d milk yield), cow age, days in milk (in month classes), month-of-termination, and random effects of herd-year (for mortality), animal, and residual was implemented. The model was used to estimate variance components separately for each region and parity. Heritability estimates for mortality were similar for all regions and parities, ranging from 0.04 to 0.07. Genetic correlations between mortality and 305-d milk yield across the first 3 parities were 0.14, 0.20, and 0.29 in SE; -0.01, 0.01, and 0.31 in SW; and 0.28, 0.33, and 0.19 in NE. We detected an adverse genetic relationship between milk production and mortality; however, the moderate magnitudes of the genetic correlations suggest that indices that include both milk yield and mortality could be effective in identifying sires that would provide opportunities for minimizing death loss even when selecting for increased milk yield. PMID- 24792795 TI - Research on degradation of penicillins in milk by beta-lactamase using ultra performance liquid chromatography coupled with time-of-flight mass spectrometry. AB - The degradation of penicillin G, penicillin V, and ampicillin in milk in the presence of beta-lactamase was investigated by ultra-performance liquid chromatography coupled with electrospray ionization-time-of-flight mass spectrometry. Degradation products of the 3 penicillins in milk were identified based on the fact that the metabolites or degradation products contain a substructure of penicillin, and their degradation pathways in acidic milk in presence of beta-lactamase were developed. The influence of factors on the degradation was investigated, including beta-lactamase dosage, temperature, time, and acidity. The ratio of the 2 degradation products (penicilloic acid and penilloic acid) is different at different temperatures and pH. Penicilloic acid was the dominant species obtained at pH 6 under 40 degrees C, but, being unstable, it could not be used as a standard for accurate analysis of penicilloic acid, and also could not be used as target for detection of penicillins in milk. Penilloic acid was the dominant species obtained at pH 2 above 40 degrees C; it was stable and could be used as a standard for quantitative analysis and as target for detecting whether penicillins were used in milk. PMID- 24792796 TI - Development of a Lifetime Merit-based selection index for US dairy grazing systems. AB - Pasture-based dairy producers in the United States face costs, revenue streams, and management challenges that may differ from those associated with confinement dairy production systems. Three Grazing Merit indices (GM$1, GM$2, and GM$3), parallel to the US Lifetime Net Merit (NM$) index, were constructed using economic values appropriate for grazing production in the United States. Milk prices based on averages from the previous 5 yr were used for GM$1, whereas GM$2 and GM$3 used milk prices found in NM$. Cull prices and interest rates from NM$ were used in GM$3 but were updated for GM$1 and GM$2. All other inputs remained constant among GM$1, GM$2, and GM$3. Economic costs and revenues were obtained from surveys, recent literature, and farm financial record summaries. Derived weights for GM$ were then multiplied by the predicted transmitting abilities of 584 active artificial insemination Holstein bulls to compare with NM$. Spearman rank correlations for NM$ were 0.93 with GM$1, 0.98 with GM$2, and 0.98 with GM$3. Traits (and their percentages of weight) comprising GM$1, GM$2, and GM$3, respectively, included milk volume (24, 0, 0%), Fat yield (16, 21, 21%), protein yield (4, 17, 17%), productive life (7, 8, 7%), somatic cell count (-8, -9, -9%), feet and legs composite (4, 4, 4%), body size composite (-3, -4, -4%), udder composite (7, 8, 8%), daughter pregnancy rate (18, 20, 20%), calving ability (3, 3, 3%), and dairy form (6, 6, 6%). These weights compared with NM$ weights of 0, 19, 16, 22, 10, 4, 6, 7, 11, 5, and 0% for the same traits, respectively. Dairy form was added to GM$ to offset the decrease in strength associated with selection to reduce stature through selection against body size. Emphasis on productive life decreased in GM$ because grazing cattle are estimated to remain in the herd considerably longer, diminishing the marginal value of productive life. Although NM$ provides guidance for grazing dairy producers, a GM$ index based upon appropriate costs and revenues allows for selection of cows and bulls for more optimal genetic progress. PMID- 24792797 TI - Time required to determine performance variables and production efficiency of lactating dairy cows. AB - Thirty-five lactating dairy cows throughout weeks of lactation (WOL) 16 to 30 were used to determine optimal time needed for reliable measurement of performance variables, and to classify the cows into high-, medium-, and low efficiency groups. Individual performance variables [body weight (BW), dry matter intake (DMI), and milk production] were measured daily with a computerized monitoring system. Body condition was visually scored weekly and used to calculate retained or depleted body energy as a result of fat content change (REF). Milk composition was analyzed weekly. Body weight, DMI, and total recovered energy (RE), which represents energy in milk production plus REF, were summarized weekly. Efficiency was calculated as RE/DMI and as residual feed intake (RFI; i.e., the difference between actual and expected DMI), which was calculated from multiple linear regression of DMI dependence on BW(0.75) and RE. Unexpectedly, it was found that BW did not affect DMI and RE/DMI. Changes and relative changes in phenotypic coefficient of variation and correlations among data from shortened tests ranging from 1 wk (WOL 16) to a sequence of 15-wk tests were used to determine optimal test period durations for 5 traits: BW, DMI, RE, RE/DMI, and RFI. Traits were fitted into a mixed model with repeated measures. For each week, the traits were summarized as a sequence of cumulative data, starting from WOL 16 and cumulated over periods that increased in 1-wk steps up to WOL 16 to 29. Weekly cumulations were compared with those for entire test period (WOL 16 to 30). Consistency of each cow's efficiency classification as high, medium, or low was tested by the total-agreement procedure; the kappa index P-value was used. Throughout WOL 16 to 30, the effects of increasing test period duration on between-animal coefficient of variation differed with respect to the various performance variables and RE/DMI: it tended to change with respect to BW, did not change with respect to DMI, and decreased with respect to RE and RE/DMI. In conclusion, compared with a 15-wk study, a 2-wk study can classify RFI and RE/DMI to 3 efficiency levels, with an individual correlation coefficient of 0.6. When the study was carried out over 3 wk or more, the lowest significant index of the classification was P<0.004, the lowest individual correlation coefficient was 0.65, and its lowest significance was P<0.01. The current study indicated that the insignificant effect of the BW of dairy lactating cows on their DMI should be validated in more studies. PMID- 24792798 TI - Effect of regrowth interval and a microbial inoculant on the fermentation profile and dry matter recovery of guinea grass silages. AB - The objectives of this study were to characterize and quantify the microbial populations in guinea grass (Panicum maximum Jacq. cultivar Mombasa) harvested at different regrowth intervals (35, 45, 55, and 65 d). The chemical composition and fermentation profile of silages (after 60 d) with or without the addition of a microbial inoculant were also analyzed. Before ensiling, samples of the plants were used for the isolation and identification of lactic acid bacteria (LAB) in the epiphytic microbiota. A 4 * 2 factorial arrangement of treatments (4 regrowth intervals * with/without inoculant) was used in a completely randomized design with 3 replications. Based on the morphological and biochemical characteristics and the carbohydrate fermentation profile, Lactobacillus plantarum was found to be the predominant specie of LAB in guinea grass forage. Linear increases were detected in the dry matter (DM) content and concentrations of neutral detergent fiber, acid detergent fiber, acid detergent insoluble nitrogen, and DM recovery as well as linear reductions in the concentrations of crude protein and NH3-N with regrowth interval. Additionally, linear reductions for gas and effluent losses in silages were detected with increasing regrowth interval. These results demonstrate that guinea grass plants harvested after 55 d of regrowth contain a LAB population sufficiently large to ensure good fermentation and increase the DM recovery. The use of microbial inoculant further enhanced the fermentation of guinea grass at all stages of regrowth by improving the DM recovery. PMID- 24792799 TI - Selection for milk coagulation properties predicted by Fourier transform infrared spectroscopy in the Italian Holstein-Friesian breed. AB - Milk coagulation is based on a series of physicochemical changes at the casein micelle level, resulting in formation of a gel. Milk coagulation properties (MCP) are relevant for cheese quality and yield, important factors for the dairy industry. They are also evaluated in herd bulk milk to reward or penalize producers of Protected Designation of Origin cheeses. The economic importance of improving MCP justifies the need to account for this trait in the selection process. A pilot study was carried out to determine the feasibility of including MCP in the selection schemes of the Italian Holstein. The MCP were predicted in 1,055 individual milk samples collected in 16 herds (66 +/- 24 cows per herd) located in Brescia province (northeastern Italy) by means of Fourier transform infrared (FTIR) spectroscopy. The coefficient of determination of prediction models indicated moderate predictions for milk rennet coagulation time (RCT=0.65) and curd firmness (a30=0.68), and poor predictions for curd-firming time (k20=0.49), whereas the range error ratio (8.9, 6.9, and 9.5 for RCT, k20, and a30, respectively) indicated good practical utility of the predictive models for all parameters. Milk proteins were genotyped and casein haplotypes (alphaS1-, beta-, alphaS2-, and kappa-casein) were reconstructed. Data from 51 half-sib families (19.9 +/- 16.4 daughters per sire) were analyzed by an animal model to estimate (1) the genetic parameters of predicted RCT, k20, and a30; (2) the breeding values for these predicted clotting variables; and (3) the effect of milk protein genotypes and casein haplotypes on predicted MCP (pMCP). This is the first study to estimate both genetic parameters and breeding values of pMCP, together with the effects of milk protein genotypes and casein haplotypes, that also considered k20, probably the most important parameter for the dairy industry (because it indicates the time for the beginning of curd-cutting). Heritability of predicted RCT (0.26) and k20 (0.31) were close to the average heritability described in literature, whereas the heritability of a30 was higher (0.52 vs. 0.27). The effects of milk proteins were statistically significant and similar to those obtained on measured MCP. In particular, haplotypes including uncommon variants showed positive (B-I-A-B) or negative (B-A(1)-A-E) effects. Based on these findings, FTIR spectroscopy-pMCP is proposed as a potential selection criterion for the Italian Holstein. PMID- 24792800 TI - Development of a novel walk-through fly trap for the control of horn flies and other pests on pastured dairy cows. AB - A prototype walk-through fly vacuum system, designed to remove horn flies Haematobia irritans (L.) (Diptera: Muscidae) from cattle, was developed and tested for efficacy. The study was conducted during 4 fly seasons over 17 consecutive weeks each year within the months of May through September at 1 dairy research herd in the coastal plain of North Carolina. Additional data on horn flies, as well as face flies (Musca autumnalis) and stable flies (Stomoxys calcitrans), were collected during 1 yr from 7 commercial pasture-based and organic dairy farms in the piedmont region of North Carolina. The number of flies observed on animals in the pasture was compared with the number of flies collected in the trap. Studies were initiated after horn fly densities had met or exceeded a threshold of 200 flies per animal. The vacuum trap removed between 1.3 and 2.5 million flies annually from the research station cattle. Most fly removal occurred during the first few weeks of operation and maintained densities below threshold thereafter. Cattle using the fly trap at the research farm had only about 28% the number of horn flies as untreated cattle, and reductions ranged from 67.5 to 74.5% across the 4-yr study. In addition to large numbers of horn flies, traps placed on commercial dairies during 1 yr collected stable flies, face flies, and house flies, all species with differing behavior and larger in size than horn flies. The estimated cost of running the trap is $72 per season at commercial rates of $0.12 per hour and an expected 4h of daily operation during the time of milking. Use of a vacuum system as described herein has potential as a cost-effective method in reducing populations of parasitic flies in pasture based dairy production systems without the use of insecticides. PMID- 24792801 TI - Effects of pasture versus confinement and marine oil supplementation on the expression of genes involved in lipid metabolism in mammary, liver, and adipose tissues of lactating dairy cows. AB - Research was conducted to evaluate the effects of management system (MS), marine lipid supplementation (LS), and their interaction on the relative mRNA abundance of 11 genes involved in lipid synthesis in mammary, liver, and subcutaneous adipose tissues in lactating dairy cows. These genes included those involved in FA uptake (LPL), de novo FA synthesis (ACACA, FASN), FA desaturation (SCD1, FADS1, FADS2), and transcriptional regulation of lipogenesis (SREBF1, SCAP, INSIG1, THRSP, and PPARG). Forty-eight peripartal Holstein cows were blocked by parity and predicted calving date and assigned to either a pasture (n=23) or confinement (n=25) system. Within each system, cows were allocated randomly (7-9 cows per treatment) to a control (no oil supplement) or 1 of 2 isolipidic (200 g/d) supplements, fish oil (FO) or microalgae (MA), for 125 +/- 5 d starting 30 d precalving. The experiment was conducted as a split-plot design, with MS being the whole plot treatment and LS as the subplot treatment. At 100 +/- 2 DIM, 4 cows from each treatment combination (24 cows in total) were euthanized and tissue samples were collected for gene expression analysis. No interactions between MS and LS were observed regarding any of the variables measured in this study. Milk production (34.0 vs. 40.1 kg/d), milk fat (1.10 vs. 1.41 kg/d), protein (0.95 vs. 1.22 kg/d), and lactose (1.56 vs. 1.86 kg/d) were lower for pasture compared with confinement. The effect of LS on milk production and milk composition (yields and contents) was significant only for milk fat content that was reduced with MA compared with FO (3.00 vs. 3.40%) and the control (3.56%). The mammary mRNA abundance of PPARG (-32%) and FASN (-29%) was lower in grazing compared with confined cows, which was accompanied by reduced (-43%) secretion of de novo synthesized fatty acids in milk. Grazing was associated with reduced expression of ACACA (-48%), FASN (-48%), and THRSP (-53%) in subcutaneous adipose tissues, which was consistent with the lower body condition score (i.e., lower net adipose tissue deposition) in grazing compared with confined cows. Feeding either FO or MA downregulated hepatic expression of FASN, SCD1, FADS2, and THRSP. The reduced secretion of de novo synthesized fatty acids in milk of grazing cows compared with confined cows might be related in part to the downregulation of genes involved in lipid synthesis, and that LS have tissue-specific effects on expression of genes involved in lipid metabolism, with liver being the most responsive tissue. PMID- 24792802 TI - Technical note: Assessment of milk temperature measured by automatic milking systems as an indicator of body temperature and fever in dairy cows. AB - The objective of this study was to evaluate whether milk temperature (MT) measured by automatic milking system (AMS) is a reliable indicator of body temperature of dairy cows and whether cows with fever could be detected. Data loggers (Minilog 8, Vemco Ltd., Halifax, NS, Canada) measuring body temperature were inserted for 7 +/- 1 d into the vaginal cavity of 31 dairy cows and programmed to take 1 reading/min. Milk temperature was recorded at each milking event by the AMS, and values from the vaginal loggers were paired with the corresponding MT. The correlation (r) between vaginal temperature (VT) and MT was 0.52. Vaginal temperature was higher (39.1 +/- 0.4 degrees C) than MT (38.6 +/- 0.7 degrees C) with a mean difference of 0.5 +/- 0.6 degrees C. The ability of MT to identify cows with fever was assessed using 2 approaches. In the first approach, VT could indicate fever at any time of the day, whereas MT could display fever only during the milking events of a given day. Different definitions of fever based on thresholds of VT and duration exceeding these thresholds were constructed. Different thresholds of MT were tested to distinguish between cows with and without fever. The combination of 39.0 degrees C as a threshold for MT and 39.5 degrees C for at least 2h/d as a threshold for VT resulted in the highest combination of sensitivity (0.65) and specificity (0.65). In the second approach, we evaluated whether MT could identify cows with fever at a given milking event. A threshold of MT >38.7 degrees C delivered the best combination of sensitivity (0.77) and specificity (0.66) when fever was defined as VT >=39.5 degrees C. Therefore, MT measured by AMS can be indicative of fever in dairy cows to a limited extent. PMID- 24792803 TI - Hypothalamic-pituitary-adrenal axis activation and immune regulation in heat stressed sheep after supplementation with polyunsaturated fatty acids. AB - The aim of this study was to assess the effects of supplementation with polyunsaturated fatty acids from different sources on immune regulation and hypothalamic-pituitary-adrenal (HPA) axis activation in heat-stressed sheep. The experiment was carried out during the summer 2012. Thirty-two Comisana ewes were divided into 4 groups (8 sheep/group): (1) supplemented with whole flaxseed (FS); (2) supplemented with Ascophyllum nodosum (AG); (3) supplemented with a combination of flaxseed and A. nodosum (FS+AG); and (4) control (C; no supplementation). On d 22 of the experiment, cortisol concentrations in sheep blood were measured after an injection of ACTH. Cellular immune response was evaluated by intradermic injection of phytohemagglutinin (PHA) at 0, 15, and 30 d of the trial. Humoral response to ovalbumin (OVA) was measured at 0, 15, and 30 d. At 0, 15, and 30 d of the experiment, blood samples were collected from each ewe to determine production of T-helper (Th)1 cytokines (IL-12 and IFN-gamma), and Th2 cytokines (IL-10, IL-4, IL-13), and concentrations of heat shock proteins (HSP) 70 and 90. Ewes supplemented with flaxseed alone had greater cortisol concentrations and a longer-lasting cell-mediated immune response compared with ewes in the control and other groups. Anti-OVA IgG concentrations increased in all groups throughout the trial, even though ewes in the FS+AG group had the lowest anti-OVA IgG concentrations at 15 d. The level of IL-10 increased in all groups throughout the experiment; the FS+AG group had the lowest IL-13 concentration at 15 and 30 d. The concentration of HSP 70 increased in AG ewes at the end of the experiment and decreased in FS ewes, whereas that of HSP 90 increased in FS ewes compared with FS+AG ewes. Flaxseed supplementation was found to influence in vivo HPA activation in heat-stressed sheep, resulting in increased cortisol concentrations, probably to meet increased energy demand for thermoregulation. Flaxseed supplementation also supported Th1 response via a complex cross-talk between IL-10, IL-12, and IFN-gamma production. PMID- 24792804 TI - The effect of acidification of liquid whey protein concentrate on the flavor of spray-dried powder. AB - Off-flavors in whey protein negatively influence consumer acceptance of whey protein ingredient applications. Clear acidic beverages are a common application of whey protein, and recent studies have demonstrated that beverage processing steps, including acidification, enhance off-flavor production from whey protein. The objective of this study was to determine the effect of preacidification of liquid ultrafiltered whey protein concentrate (WPC) before spray drying on flavor of dried WPC. Two experiments were performed to achieve the objective. In both experiments, Cheddar cheese whey was manufactured, fat-separated, pasteurized, bleached (250 mg/kg of hydrogen peroxide), and ultrafiltered (UF) to obtain liquid WPC that was 13% solids (wt/wt) and 80% protein on a solids basis. In experiment 1, the liquid retentate was then acidified using a blend of phosphoric and citric acids to the following pH values: no acidification (control; pH 6.5), pH 5.5, or pH 3.5. The UF permeate was used to normalize the protein concentration of each treatment. The retentates were then spray dried. In experiment 2, 150 MUg/kg of deuterated hexanal (D12-hexanal) was added to each treatment, followed by acidification and spray drying. Both experiments were replicated 3 times. Flavor properties of the spray-dried WPC were evaluated by sensory and instrumental analyses in experiment 1 and by instrumental analysis in experiment 2. Preacidification to pH 3.5 resulted in decreased cardboard flavor and aroma intensities and an increase in soapy flavor, with decreased concentrations of hexanal, heptanal, nonanal, decanal, dimethyl disulfide, and dimethyl trisulfide compared with spray drying at pH 6.5 or 5.5. Adjustment to pH 5.5 before spray drying increased cabbage flavor and increased concentrations of nonanal at evaluation pH values of 3.5 and 5.5 and dimethyl trisulfide at all evaluation pH values. In general, the flavor effects of preacidification were consistent regardless of the pH to which the solutions were adjusted after spray drying. Preacidification to pH 3.5 increased recovery of D12-hexanal in liquid WPC and decreased recovery of D12-hexanal in the resulting powder when evaluated at pH 6.5 or 5.5. These results demonstrate that acidification of liquid WPC80 to pH 3.5 before spray drying decreases off-flavors in spray-dried WPC and suggest that the mechanism for off-flavor reduction is the decreased protein interactions with volatile compounds at low pH in liquid WPC or the increased interactions between protein and volatile compounds in the resulting powder. PMID- 24792805 TI - Risk factors for postpartum problems in dairy cows: explanatory and predictive modeling. AB - The postpartum period is associated with a high incidence of most dairy cattle diseases and a high risk of removal from the herd. Postpartum diseases often share risk factors, and these factors may trigger a cascade of other diseases. The objective of this cohort study was to derive explanatory and predictive models for treatment or removal from the herd within the first 30 d in milk (TXR30). The TXR30 outcome was specifically defined as >=1 treatment for >=1 occurrence of milk fever, retained placenta, metritis, ketosis, displaced abomasum, lameness, or pneumonia; removal from the herd (sold or died); or both treatment and later herd removal. The study population consisted of 765 multiparous and 544 primiparous cows (predominantly Holstein) from 4 large commercial freestall-housed dairy herds. Treatment or removal from the herd was recorded as a binary outcome for each cow. Potential explanatory and predictive variables were limited to routine cow data that could be collected either before or within 24 h of calving. Models for multiparous and primiparous cows were developed separately because previous lactation variables are available only for multiparous cows. Adjusted odds ratios for TXR30 in the explanatory model for the multiparous cohort were 2.1 for lactation 3 compared with lactation 2, and 2.3 for lactation 4 or greater compared with lactation 2; 2.3 for locomotion score 3 or 4 compared with score 1; 3.3 for an abnormality at calving compared with no calving abnormality; 1.8 for each 1-standard deviation increase in previous lactation length; and 0.4 for each 5,000-kg increment in previous lactation milk yield in cows with longer previous lactation length. The final predictive model for TXR30 in multiparous cows included predictors similar but not identical to those included in the explanatory model. The area under the curve for the receiver operating characteristic curve from the final predictive model for the multiparous cohort was 0.70, with 60% sensitivity. For the primiparous cohort, calving abnormality increased the odds of TXR30 and was the only variable included in both the explanatory and predictive models. The area under the curve for the receiver operating characteristic curve from the final predictive model for the primiparous cohort was 0.66, with 35% sensitivity. This study identified key risk factors for TXR30 and developed equations for the prediction of TXR30. This information can help dairy producers better understand causes of postpartum problems. PMID- 24792806 TI - How can farming intensification affect the environmental impact of milk production? AB - The intensification process of the livestock sector has been characterized in recent decades by increasing output of product per hectare, increasing stocking rate, including more concentrated feed in the diet, and improving the genetic merit of the breeds. In dairy farming, the effects of intensification on the environmental impact of milk production are not completely clarified. The aim of the current study was to assess the environmental impacts of dairy production by a life cycle approach and to identify relations between farming intensity and environmental performances expressed on milk and land units. A group of 28 dairy farms located in northern Italy was involved in the study; data collected during personal interviews of farmers were analyzed to estimate emissions (global warming potential, acidification, and eutrophication potentials) and nonrenewable source consumption (energy and land use). The environmental impacts of milk production obtained from the life cycle assessment were similar to those of other recent studies and showed high variability among the farms. From a cluster analysis, 3 groups of farms were identified, characterized by different levels of production intensity. Clusters of farms showed similar environmental performances on product basis, despite important differences in terms of intensification level, management, and structural characteristics. Our study pointed out that, from a product perspective, the most environmentally friendly way to produce milk is not clearly identifiable. However, the principal component analysis showed that some characteristics related to farming intensification, such as milk production per cow, dairy efficiency, and stocking density, were negatively related to the impacts per kilogram of product, suggesting a role of these factors in the mitigation strategy of environmental burden of milk production on a global scale. Considering the environmental burden on a local perspective, the impacts per hectare were positively associated with the intensification level. PMID- 24792807 TI - Short communication: Lameness impairs feeding behavior of dairy cows. AB - The automated, reliable, and early detection of lameness is an important aim for the future development of modern dairy operations. One promising indicator of lameness is a change in the feeding behavior of a cow. In this study, the associations between feeding behavior and lameness were evaluated. A herd of 50 cows was investigated during the winter season in a freestall barn. Feeding behavior, feed intake, milk yield, and body weight were monitored using electronic feeding troughs and an automated milking system. Gait scoring every second week was used as a measure of lameness. To analyze the effect of lameness on feeding behavior and milk yield, linear mixed models were used. Cows with more severe lameness spent less time feeding per day (104 +/- 4, 101 +/- 4, and 91 +/- 4 min/d for lameness scores 2, 3, and 4, respectively). An interaction between parity and lameness score was detected, with severely lame primiparous cows spending the least time feeding. Severely lame cows fed faster; however, their body weights were lower than for less-lame cows. Increase in lactation stage was associated with longer daily feeding time, longer duration of feeding bouts, and lower feeding rate. Worsening of gait was associated with lower silage intake and less time spent feeding even before severe lameness was scored. The results indicate that lameness is associated with changes in feeding behavior and that such changes could be considered in the future development of remote monitoring systems. It should also be noted that impaired feeding behavior along with lameness can put the welfare of especially early lactating primiparous cows at risk. PMID- 24792808 TI - Short communication: Homologous expression of recombinant and native thurincin H in an engineered natural producer. AB - The Bacillus bacteriocin thurincin H exhibits a wide inhibitory spectrum of activity against various foodborne pathogens, such as Listeria monocytogenes, and dairy spoilage bacteria, especially different Bacillus species commonly existing in dairy products. Previously, we constructed 3 plasmids to express native thurincin H homologously in an engineered natural producer, Bacillus thuringiensis SF361thnH(-). This host is deficient in thurincin H production because of an in-frame deletion of structural genes thnA1, thnA2, and thnA3 from the chromosome of the natural producer B. thuringiensis SF361. The previously constructed expression vectors were constructed by cloning the native thurincin H promoter, 3 (or 1) copies of structural genes, and the native (or Cry protein) terminator into an Escherichia coli-B. thuringiensis shuttle vector pHT315. In this study, 3 corresponding expression vectors (pGW134, pGW135, and pGW136) were constructed to express recombinant thurincin H-His6 in the same host, in which a 6-histidine tag was fused to the C terminus of each structural gene. The resulting low level of bacteriocin production indicated that the His tag might negatively interfere with subsequent posttranslational modification or exportation processes after the thurincin H-His6 prepeptide was translated. Additionally, in order to overexpress native thurincin H, 2 additional plasmids (pGW137 and pGW138) were constructed, consisting of the sporulation-dependent Cry protein dual promoter BtI and BtII, the thnA1 structural gene, and the thurincin H native or Cry protein terminator. However, production was low on Luria broth plates and absent on sporulation plates. It is possible that the resulting thurincin H prepeptide was not correctly modified or exported to the extracellular environment, due to the undesired biochemical and physiological changes during the sporulation phase. PMID- 24792809 TI - Effects of dietary amylase and sucrose on productivity of cows fed low-starch diets. AB - Recent studies have observed positive effects of both sucrose and exogenous amylase on the productivity of dairy cattle. Our objective was to evaluate direct effects and interactions of amylase and sucrose on dry matter intake (DMI), milk production, and milk components. Forty-eight multiparous Holstein cows between 70 and 130 d in milk were randomly assigned to each of 4 pens (12 cows/pen). Pens were randomly assigned to treatment sequence in a 4 * 4 Latin square design, balanced for carryover effects. Treatment periods were 28 d, with 24 d for diet adaptation and 4d for sample and data collection. The treatments were a control diet (36% NDF and 21% starch), the control diet with amylase [0.5 g/kg of DM; Ronozyme RumiStar 600 (CT); DSM Nutritional Products Ltd., Basel, Switzerland], a diet with sucrose replacing corn grain at 2% of DM, and the sucrose diet with amylase (0.5 g/kg of DM). All data were analyzed with mixed models, including the fixed effects of sugar, amylase, and their interaction, and the random effects of period and pen. Milk data included the random effects of cow nested within pen and pen * period to provide the error term for the pen-level analysis. Dry matter intake was not affected by treatments. Milk yield and milk composition were not altered by the inclusion of sucrose or amylase; however, a tendency for an amylase * sucrose interaction was observed for milk protein content, reflecting slightly lower milk protein concentrations for amylase and sucrose treatments (3.00 and 2.99 +/- 0.03%) compared with the control and amylase + sucrose treatments (3.02 and 3.03 +/- 0.03%). Solids-corrected and fat-corrected milk yields were not significantly altered by treatment, although the direct effect of amylase approached significance for both variables, suggesting possible small increases with amylase supplementation (~0.5 kg/d). Feed efficiency (energy corrected milk divided by dry matter intake) numerically increased with either amylase (1.57 +/- 0.12) or sucrose (1.60 +/- 0.12) treatment, but the combination of the 2 resulted in feed efficiency similar to the control treatment (both 1.50 +/- 0.12). The inclusion of amylase or sucrose did not affect DMI, productivity, or feed efficiency in mid-lactation cows fed low-starch, high-fiber diets. PMID- 24792810 TI - Are the equations for the creatinine-based estimated glomerular filtration rate applicable to the evaluation of renal function in Japanese children and adult patients receiving chemotherapy? AB - BACKGROUND: Equations for the creatinine-based estimated glomerular filtration rate (eGFR) were recently established for Japanese adults (>18 years old) and children (2-11 years old), respectively, but it is unclear whether eGFR can be as useful as 24-h creatinine clearance (CCr) for assessing renal function in patients receiving chemotherapy. This study examined the degree of concordance between eGFR and CCr and the risk factors leading to the overestimation of renal function by eGFR. METHODS: A total of 53 data points of 19 children and 56 data points of 16 adults who received chemotherapy were analyzed retrospectively. Body mass index, serum creatinine concentration, 24-h urinary creatinine excretion (UCr), and nephrectomy were considered as risk factors for overestimation by eGFR. RESULTS: In the pediatric part of the study, 7 data points from 3 patients who underwent nephrectomy were included. The eGFR in patients with bilateral kidneys overestimated renal function to a greater degree than in patients with a unilateral kidney. In 45.7 % of pediatric patients with bilateral kidneys and in 19.6 % of adult patients, eGFR overestimated renal function. The risk factor for overestimation was lower UCr in pediatric patients with bilateral kidneys and adult patients. CONCLUSIONS: Concordance between eGFR and CCr in pediatric patients with a unilateral kidney should be assessed separately from that in patients with bilateral kidneys. In restricting calculation of eGFR to pediatric patients with bilateral kidneys and adult patients without little muscle mass, eGFR may be useful regardless of whether patients are receiving chemotherapy. PMID- 24792811 TI - Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl 5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity. AB - A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11 MUM and Hela with IC50 value of 2.54 MUM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45 MUM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model. PMID- 24792812 TI - Anti-inflammatory drimane sesquiterpene lactones from an Aspergillus species. AB - IFN-gamma inducible protein 10 (IP-10, CXCL10) is a 10 kDa chemokine, which is secreted from various cell types after exposure to pro-inflammatory stimuli. This chemokine is a ligand for the CXCR3 receptor and regulates immune responses by activating and recruiting leukocytes such as T cells, eosinophils, monocytes, and NK cells to sites of inflammation. Altered expression of CXCL10 has been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents a promising target for the development of new anti-inflammatory drugs. In a search for inhibitors of CXCL10 promoter activity, three structurally related drimane sesquiterpene lactones (compounds 1-3) were isolated from fermentations of an Aspergillus species. Compounds 1 and 2 inhibited the IFN gamma/TNF-alpha/IL-1beta induced CXCL10 promoter activity in transiently transfected human DLD-1 colon carcinoma cells in a dose-dependent manner with IC50 values of 12.4 MUM for 1 and 55 MUM for 2, whereas 3 was devoid of any biological activity. Moreover, compounds 1 and 2 reduced CXCL10 mRNA levels and synthesis in IFN-gamma/TNF-alpha/IL-1beta stimulated DLD-1 cells. PMID- 24792813 TI - Sulfonamide inhibition studies of two beta-carbonic anhydrases from the bacterial pathogen Legionella pneumophila. AB - Two beta-carbonic anhydrases (CAs, EC 4.2.1.1) were identified, cloned and purified in the pathogenic bacterium Legionella pneumophila, denominated LpCA1 and LpCA2. They efficiently catalyze CO2 hydration to bicarbonate and protons, with kcat in the range of (3.4-8.3) * 10(5)s(-1) and kcat/Km of (4.7-8.5) * 10(7)M(-1)s(-1), and are inhibited by sulfonamides and sulfamates. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide(KIs in the range of 40.3 90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide and dichlorophenamide (KIs in the range of 25.2-88.5 nM). As these enzymes may be involved in pH regulation in the phagosome during Legionella infection, their inhibition may lead to antibacterials with a novel mechanism of action. PMID- 24792814 TI - Insomnia: an essential treatment target in psychotherapy for anxiety disorders. PMID- 24792815 TI - You're invited to join the Society for Post-Acute and Long-Term Care Medicine: answer YES! PMID- 24792816 TI - Increasing food intake in nursing home residents: efficacy of the Sorbet Increases Salivation intervention. AB - The purpose of this study was to test the effect of the Sorbet Increases Salivation (SIS) intervention on resident food intake and body weight. Using a pre- post design, thirty-nine nursing home residents received 2 ounces of lemon lime sorbet prior to lunch and dinner meals for 6 weeks. As a comparison and prior to the intervention, participants were offered 2 ounces of a non-citrus drink for 6 weeks prior to the lunch and dinner meals. Twenty-two residents completed both the comparison and intervention periods. Of those, 8 gained weight, 10 maintained and 4 lost weight. The amounts of food ingested during dinner increased significantly (p=0.001) from the comparison period to the intervention period (208-253 g). For liquids, the amounts ingested during dinner decreased significantly (p=0.002) from the comparison period to the intervention period (from 356 ml to 310 ml). Further study is needed to test the efficacy of the intervention with a larger sample of residents from multiple nursing homes. PMID- 24792817 TI - Are conspecific and heterospecific opponents assessed similarly? A test in two species of territorial damselfish (Pomacentridae). AB - Aggression is often a crucial component to interference interspecific competition and yet there are few studies that examine fight behavior when the opponents are different species. To examine conspecific and heterospecific aggression, we used two species of Caribbean damselfish, the dusky (Stegastes adustus) and the longfin (S. diencaeous) with each one serving as the heterospecific opponent to the other species. Our study was confined to whether or not each species measures the body length of the other species as if it were a conspecific intruder. Body length plays an important role in fight outcome in many species of fish and we presumed that both the dusky and the longfin would use it when assessing opponents. Both the dusky and the longfin damselfish were then presented with two individuals that were either greatly different or minimally different in size. When presented with individuals that differed greatly in size, both species spent more time attacking the larger individual, irrespective of species. However, when the size difference was small, the focal dusky and the longfin responded differently; the dusky showed no preference in either conspecific or heterospecific pairs while the longfin continued to show a bias toward the slightly larger individual. Thus, while we were surprised by the species differences, both the dusky and the longfin were internally consistent in how they treated conspecific and heterospecific opponents. PMID- 24792818 TI - The structure of an avian syllable syntax network. AB - A common result in recent linguistic studies on word association networks is that their topology can often be described by Zipf's law, in which most words have few associations, whereas a few words are highly connected. However, little is known about syntactic networks in more rudimentary communication systems, which could represent a window into the early stages of language evolution. In this study, we investigate the syntactic network formed by syllable associations in the song of the oscine bird Troglodytes musculus. We use methods recently developed in the context of the study of complex networks to assess topological characteristics in the syntactic networks of T. musculus. We found statistically significant evidence for nestedness in the syllable association network of T. musculus, indicating network organization around a core of commonly used notes, small-world features, and a non-random degree distribution. Our analyses suggest the possibility of a balance between the maintenance of core notes and the acquisition/loss of rare notes through both cultural drift and improvisation. These results underscore the usefulness of investigating communication networks of other animal species in uncovering the initial steps in the evolution of complex syntax networks. PMID- 24792819 TI - Metabolic and transcriptional responses of gilthead sea bream (Sparus aurata L.) to environmental stress: new insights in fish mitochondrial phenotyping. AB - The aim of the current study was to phenotype fish metabolism and the transcriptionally-mediated response of hepatic mitochondria of gilthead sea bream to intermittent and repetitive environmental stressors: (i) changes in water temperature (T-ST), (ii) changes in water level and chasing (C-ST) and (iii) multiple sensory perception stressors (M-ST). Gene expression profiling was done using a quantitative PCR array of 60 mitochondria-related genes, selected as markers of transcriptional regulation, oxidative metabolism, respiration uncoupling, antioxidant defense, protein import/folding/assembly, and mitochondrial dynamics and apoptosis. The mitochondrial phenotype mirrored changes in fish performance, haematology and lactate production. T-ST especially up-regulated transcriptional factors (PGC1alpha, NRF1, NRF2), rate limiting enzymes of fatty acid beta-oxidation (CPT1A) and tricarboxylic acid cycle (CS), membrane translocases (Tim/TOM complex) and molecular chaperones (mtHsp10, mtHsp60, mtHsp70) to improve the oxidative capacity in a milieu of a reduced feed intake and impaired haematology. The lack of mitochondrial response, increased production of lactate and negligible effects on growth performance in C-ST fish were mostly considered as a switch from aerobic to anaerobic metabolism. A strong down-regulation of PGC1alpha, NRF1, NRF2, CPT1A, CS and markers of mitochondrial dynamics and apoptosis (BAX, BCLX, MFN2, MIRO2) occurred in M-ST fish in association with the greatest circulating cortisol concentration and a reduced lactate production and feed efficiency, which represents a metabolic condition with the highest allostatic load score. These findings evidence a high mitochondrial plasticity against stress stimuli, providing new insights to define the threshold level of stress condition in fish. PMID- 24792820 TI - The number of life-history stages does not influence the androgen responsiveness to male-male interactions: sedentary and migratory black redstarts (Phoenicurus ochruros) do not elevate testosterone in response to simulated territorial intrusions. AB - High plasma levels of testosterone at the beginning of the breeding season adjust male physiology for mating and promote territorial behavior in birds. Conversely intra-sexual competition may elicit a temporary increase in circulating testosterone. Male black redstarts (Phoenicurus ochruros) from migratory populations show the expected increase in baseline testosterone during early breeding, but circulating testosterone levels do not change in response to male male interactions. Because sedentary populations express fewer life-history stages they may be more flexible in timing of life-history stages and more responsive to environmental modulation of hormone concentrations. Therefore, we tested whether the androgen responsiveness to male-male interactions differs between migratory (6 life-history stages) and sedentary black redstarts (3 life history stages) during early breeding, predicting that in contrast to migratory birds, sedentary birds would modulate testosterone in response to simulated territorial intrusions (STI). In contrast to our prediction, sedentary males did not modulate post-capture testosterone levels in response to simulated territorial intrusions. Males of both populations increased testosterone after an injection of gonadotropin releasing hormone (GnRH), demonstrating that they were capable of increasing testosterone. Interestingly, in sedentary males the GnRH injection elicited a higher testosterone response in STI males than in control males. The two populations did not differ in their behavioral response to the STIs, except that sedentary males spent less time close to the decoy. In combination with previous data from black redstarts and other socially monogamous and biparental birds our current study adds to the growing evidence that current theory regarding hormone-behavior relationship needs to be refined. PMID- 24792821 TI - Quantitative computer tomography in children and adolescents: the 2013 ISCD Pediatric Official Positions. AB - In 2007, International Society of Clinical Densitometry Pediatric Positions Task Forces reviewed the evidence for the clinical application of peripheral quantitative computed tomography (pQCT) in children and adolescents. At that time, numerous limitations regarding the clinical application of pQCT were identified, although its use as a research modality for investigation of bone strength was highlighted. The present report provides an updated review of evidence for the clinical application of pQCT, as well as additional reviews of whole body QCT scans of the central and peripheral skeletons, and high-resolution pQCT in children. Although these techniques remain in the domain of research, this report summarizes the recent literature and evidence of the clinical applicability and offers general recommendations regarding the use of these modalities in pediatric bone health assessment. PMID- 24792822 TI - Citral: a monoterpene with prophylactic and therapeutic anti-nociceptive effects in experimental models of acute and chronic pain. AB - Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1 amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-alpha. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain. PMID- 24792823 TI - cRGD grafted siRNA nano-constructs for chemosensitization of gemcitabine hydrochloride in lung cancer treatment. AB - PURPOSE: The aim of present investigation was to effectively deliver ribonucleotide reductase subunit 1 (RRM1) targeted siRNA and assess chemo sensitization of lung cancer cells against Gemcitabine hydrochloride. It was hypothesised that effective and selective delivery of RRM1 siRNA will help in the treatment of lung cancer chemotherapy using Gemcitabine hydrochloride by reducing drug dose and thereby, reduces dose related toxicity of Gemcitabine hydrochloride. METHODS: In this investigation, cRGD grafted siRNA nano-constructs were developed for efficient and targeted intracellular delivery of siRNA. Developed formulations were characterized for gel retardation assay, particle size, zeta potential, cryo transmission electron microscopy, serum stability, in vitro cytotoxicity, qualitative and quantitative cell uptake, gene expression, and chemo-sensitization. RESULTS: Complete complexation of siRNA with cRGD grafted nano-constructs was found at N/P ratio of 2.0. Naked siRNA was found to degrade within 6 h in presence of 50% serum while nano-constructs protected the complexed siRNA even after 24 h. RRM1 level significantly reduced when siRNA was delivered in nano-construct form as compared to naked siRNA. Pre-exposure of RRM1 siRNA decreased the IC50 value of Gemcitabine hydrochloride 5 folds in A-549 cells compared to Gemcitabine hydrochloride alone. CONCLUSION: These results suggest the application of present siRNA delivery strategy to potentiate the chemotherapeutic effect by means of chemosensitization which may be utilized for effective and thorough remission of lung cancer. PMID- 24792824 TI - Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach. AB - OBJECTIVES: Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and pharmacodynamic modeling tools to relate CAT with D2RO in rats and to compare that with the relationship between D2RO and EPS in humans. METHODS: Severity of CAT was assessed in rats at hourly intervals over a period of 8 h after antipsychotic drug treatment. An indirect response model with and without Markov elements was used to explain the relationship of D2RO and CAT. RESULTS: Both models explained the CAT data well for olanzapine, paliperidone and risperidone. However, only the model with the Markov elements predicted the CAT severity well for clozapine and haloperidol. The relationship between CAT scores in rat and EPS scores in humans was implemented in a quantitative manner. Risk of EPS not exceeding 10% over placebo correlates with less than 86% D2RO and less than 30% probability of CAT events in rats. CONCLUSION: A quantitative relationship between rat CAT and human EPS was elucidated and may be used in drug discovery to predict the risk of EPS in humans from D2RO and CAT scores measured in rats. PMID- 24792825 TI - Pharmacokinetics of paracetamol in Gottingen minipigs: in vivo studies and modeling to elucidate physiological determinants of absorption. AB - PURPOSE: Onset and rate of gastric emptying are important determinants of drug absorption after oral dosing. Therefore, robust estimates of these parameters are needed in physiologically based absorption models to predict reliably plasma concentration time profiles. For human and some other laboratory animals, reasonable parameterization of gastric emptying has been established. However gastric emptying is less well characterized in minipigs, a large animal model rapidly gaining importance in pharmaceutical research. METHODS: A pharmacokinetic crossover study using different dosage forms of paracetamol (intravenous and oral solution, capsule and tablet) was conducted in four male and four female Gottingen minipigs after an overnight fast. Deconvolution analysis was performed to determine the absorption kinetics. Estimated lag times and first order gastric emptying parameters were incorporated in a previously published PBPK model of the minipig and simulations verified. Postmortem assessments of minipig stomachs were made after different fasting protocols. RESULTS: Fraction of dose absorbed vs. time profiles showed high interindividual variability, comparable to human fed state absorption. Mean gastric transit times were determined to be 0.63 h, 1.36 h, and 0.73 h for solution, capsules, and tablets, respectively. Postmortem assessment confirmed that minipig stomachs were not empty after an overnight fast. CONCLUSIONS: Gastric transit times in overnight fasted minipigs are longer than those observed in humans. This is most likely caused by delayed and incomplete food emptying and further work is needed to develop feasible and effective fasting protocols for minipigs. PMID- 24792826 TI - Analgesic efficacy and safety of DALDA peptide analog delivery to the brain using oil-in-water nanoemulsion formulation. AB - PURPOSE: The main objective of this study was to develop and evaluate therapeutic efficacy and safety following systemic delivery of a peptide analgesic into the CNS using an oil-in-water nanoemulsion system. METHODS: We have formulated a safe and effective, omega-3 rich polyunsaturated fatty acid containing oil-in-water nanoemulsion formulation, for encapsulating and delivering chemically-modified DALDA, a potent mu-opioid peptide analogue, to the CNS. One of the challenges with CNS delivery is the lack of a non-invasive bioanalytical technique to confirm CNS uptake and therapeutic efficacy. Using blood oxygen-level dependent (BOLD) functional magenetic resonance imaging (fMRI), we provide quantitative evidence of nanoemulsion-based delivery and analgesic activity of DALDA analogue in capsaicin-induced awake rat model of pain. RESULTS: Nanoemulsion formulation effectively encapsulated the modified analgesic peptide and demonstrated efficacy in the capsaicin- pain induced functional magnetic resonance imaging model in rodents. Preliminary safety evaluations show that the nanoemulsion system was well tolerated and did not cause any acute negative effects. CONCLUSIONS: Overall, these results show tremendous opportunity for the development of modified peptide analgesic-encapsulated nanoemulsion formulations for CNS delivery and therapeutic efficacy. PMID- 24792827 TI - Enhancement of nasal HIV vaccination with adenoviral vector-based nanocomplexes using mucoadhesive and DC-targeting adjuvants. AB - PURPOSE: To investigate the vaccine effect of a replication-defective recombinant adenovirus 5 (rAd5)-based nanocomplex with chitooligosaccharides (Oligo) and mannosylated polyethyleneimine-triethyleneglycol (mPEI) as adjuvants for human immunodeficiency virus (HIV) infection. METHODS: Physical characteristics were determined through detecting the size, zeta potential and morphology of Oligo mPEI-rAd5 nanocomplex, and in vitro vaccine uptake and transduction efficiency were estimated. Nanocomplexes were then administered intranasally to Balb/c mice to evaluate in vivo rAd5 residence in nasal cavity and HIVgag-specific immune responses using cytotoxic T lymphocyte (CTL), intracellular cytokine staining (ICS) and ELISA assay. RESULTS: The mucoadhesivity of Oligo prolonged nasal residence time, while the dendritic cell (DC) specificity of mPEI improved vaccine uptake. These two adjuvants jointly enhanced transduction efficiency of rAd5. Oligo-mPEI-rAd5 nanocomplex elicited potent HIVgag-specific CTL response and increased IFN-gamma positive CD8(+)T and IL-4 positive CD4(+)T cells, indicating high cellular immune responses. This vaccine candidate also led to strong humoral immune responses (IgG/IgG1/IgG2a) with balanced Th1/Th2 CD4(+)T cell activity. Moreover, mice nasally immunized with Oligo-mPEI-rAd5 showed higher levels of SIgA in nasal washes than did mice immunized with rAd5. CONCLUSIONS: Intranasal delivery of Oligo-mPEI-rAd5 with a prime-boost regimen is a potential immunization for HIV infection, inducing HIVgag-specific cellular, humoral and mucosal immune responses. PMID- 24792828 TI - Infrared spectroscopic imaging tracks lateral distribution in human stratum corneum. AB - PURPOSE: To demonstrate the efficacy of infrared (IR) spectroscopic imaging for evaluation of lateral diffusion in stratum corneum (SC) and for elucidation of intermolecular interactions between exogenous agents and SC constituents. METHODS: In separate experiments, acyl chain perdeuterated oleic acid (OA-d) and deuterated dimethyl sulfoxide (DMSO-d) were applied to the surface of isolated human SC. The lateral distribution of permeant concentrations was monitored using the time-dependence of IR images. Diffusion coefficients (D) were estimated from Fick's second law. Interactions between the exogenous agents and the SC were tracked from changes in CD2 and Amide I stretching frequencies. RESULTS: Networked glyphs served as the major pathway for lateral distribution of OA-d. In glyph-poor regions, D values from 0.3-1 * 10(-8) cm(2)/s bracketed the OA-d data and apparently decreased with time. Although diffusion of DMSO-d is relatively fast compared to our experimental measurement time, the results suggest values of ~10(-7) cm(2)/s. OA-d spectral changes suggest penetration into the ordered lipids of the SC; DMSO-d penetration results in perturbation of SC keratin structure. CONCLUSIONS: IR imaging provides concentration profiles, diffusion coefficients, and unique molecular level information about structural changes in the endogenous SC constituents and exogenous agents upon their mutual interaction. Transport along glyphs is the dominant mode of distribution for OA d. PMID- 24792829 TI - Molecular motions in sucrose-PVP and sucrose-sorbitol dispersions-II. Implications of annealing on secondary relaxations. AB - PURPOSE: To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions. METHODS: Sucrose was co lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy. RESULTS: In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for beta1- (the slower relaxation) but not for beta2-relaxations. The effect of annealing on beta2-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both beta1- and beta2-relaxations. CONCLUSIONS: An increase in local mobility of sucrose brought about by annealing could be negated with an additive. PMID- 24792830 TI - Handling missing data in a duloxetine population pharmacokinetic/pharmacodynamic model - imputation methods and selection models. AB - PURPOSE: In pharmacokinetic (PK)/pharmacodynamic (PD) modelling and simulations (M&S), omitting dropouts can cause inaccuracies in parameter estimation and clinical trial simulations (CTS). This study examines the impact of different imputation methods for missing data on the interpretation of model results, as well as develops a selection model (where dropout and efficacy are jointly modelled) for use in CTS. METHODS: Missing data were imputed using single and multiple imputation and pattern mixtures methods for a previously reported duloxetine PK/PD model. The probability of dropout was described in the selection model and CTS was conducted with a hypothetical drug to examine the impact of dropout on trial results. RESULTS: The study completion rate was 75% and dropouts were not random. Model parameters obtained with different imputation methods were mostly within 40% (range 0 to 63%) compared to the model without dropouts. CTS showed 0.3 points lower median pain scores and 3% lower coefficient of variation over the 12-week simulations when dropout was included. CONCLUSIONS: Missing data had little impact on the original population PK/PD analyses. Sensitivity analyses for dropouts should be conducted in M&S exercises. The utility of selection models in CTS was explored via a hypothetical case study. PMID- 24792831 TI - Development of liposomal nanoconstructs targeting P-selectin (CD62P)-expressing cells by using a sulfated derivative of sialic acid. AB - PURPOSE: NMSO3, a sulfated derivative of sialic acid, is a specific inhibitor for P-selectin (CD62P)-mediated cell adhesion. We attempted to apply liposomes modified with NMSO3 for selective targeting of activated platelets. METHODS: The binding of fluorescently labeled NMSO3-containing liposomes (NMSO3-liposomes) to CHO cells expressing P-selectin (CHO-P cells) and activated platelets were examined. The distribution of NMSO3-liposomes incorporated into the cells was observed by fluorescence microscopy. RESULTS: The binding assay revealed that NMSO3-liposomes specifically bound to immobilized P-selectin and CHO-P cells in a dose-dependent manner. The binding of NMSO3-liposomes to CHO-P cells was much stronger than that to the parental CHO-K1 cells. Fluorescence microscopic observation showed that NMSO3-liposomes were incorporated into CHO-P cells after the binding and distributed throughout the cytoplasm of the cell. NMSO3-liposomes bound more strongly to thrombin-activated platelets than to resting platelets, as assessed by flow cytometry. CONCLUSIONS: These results suggest that NMSO3 liposomes can be applied for selective drug delivery to activated platelets. PMID- 24792832 TI - Incorporation of ophiobolin a into novel chemoembolization particles for cancer cell treatment. AB - PURPOSE: To design and synthesize chemoembolization particles for the delivery of Ophiobolin A (OphA), a promising fungal-derived chemotherapeutic, directly at the tumour location. To investigate cell death mechanism of OphA on a Rhabdomyosarcoma cancer (RD) cell line. Rhabdomyosarcoma is the most common soft tissue sarcoma in children; with a 5-year survival rate of between 30 and 65%. METHODS: Multimodal chemoembolization particles were prepared by sintering mesoporous silica nanoparticles, prepared by the sol-gel method, onto the surface of polystyrene microspheres, prepared by suspension copolymerisation. The chemoembolization particles were subsequently loaded with OphA. The effects of OphA in vitro were characterised by flow cytometry and nanoparticle tracking analysis (NanoSight). RESULTS: High loading of OphA onto the chemoembolization particles was achieved. The subsequent release of OphA onto RD cells in culture showed a 70% reduction in cell viability. OphA caused RD cells to round up and their membrane to bleb and caused cell death via apoptosis. OphA caused both an increase in the number of microvesicles produced and an increase in DNA content within these microvesicles. CONCLUSIONS: The prepared chemoembolization particles showed good efficacy against RD cells in culture. PMID- 24792833 TI - Health-related quality of life in coronary heart disease in Korea: the Korea National Health and Nutrition Examination Survey 2007 to 2011. AB - Using data from 2007 to 2011 of the Korea National Health and Nutrition Examination Survey, we evaluated the influence of coronary heart disease (CHD) on health-related quality of life (HRQoL) as measured by the EQ-5D in comparison with the general population and the predictors of HRQoL in CHD. Compared with the general population, HRQoL was impaired in the EQ-5D dimensions of mobility, usual activities, pain/discomfort, and anxiety/depression. The impairment of HRQoL was much greater in the older age group and in females. In subjects with CHD, the predictors for a low EQ-5D index were old age, female sex, low education, stroke, and noncardiovascular comorbidities, and the predictors for a low EQ Visual Analogue Scale were low income and noncardiovascular comorbidities. For the improvement in HRQoL, preventing stroke and noncardiovascular comorbidities is important, especially among female and older Asian patients with CHD. PMID- 24792836 TI - Development of a loop-mediated isothermal amplification assay for detection of Trichomonas vaginalis. AB - A loop-mediated isothermal amplification (LAMP) assay targeting the 2-kbp repeated DNA species-specific sequence was developed for detection of Trichomonas vaginalis, the causative agent of trichomoniasis. The analytical sensitivity and specificity of the LAMP assay were evaluated using pooled genital swab and urine specimens, respectively, spiked with T. vaginalis trophozoites. Genital secretion and urine did not inhibit the detection of the parasite. The sensitivity of the LAMP was 10-1000 times higher than the PCR performed. The detection limit of LAMP was 1 trichomonad for both spiked genital swab and urine specimens. Also, LAMP did not exhibit cross-reactivity with closely-related trichomonads, Trichomonas tenax and Pentatrichomonas hominis, and other enteric and urogenital microorganisms, Entamoeba histolytica, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. This is the first report of a LAMP assay for the detection of T. vaginalis and has prospective application for rapid diagnosis and control of trichomoniasis. PMID- 24792835 TI - Pyrrole alkaloids with potential cancer chemopreventive activity isolated from a goji berry-contaminated commercial sample of African mango. AB - Bioassay-guided fractionation of a commercial sample of African mango (Irvingia gabonensis) that was later shown to be contaminated with goji berry (Lycium sp.) led to the isolation of a new pyrrole alkaloid, methyl 2-[2-formyl-5 (hydroxymethyl)-1H-pyrrol-1-yl]propanoate, 1, along with seven known compounds, 2 8. The structures of the isolated compounds were established by analysis of their spectroscopic data. The new compound 1g showed hydroxyl radical-scavenging activity with an ED50 value of 16.7 MUM, whereas 4-[formyl-5-(methoxymethyl)-1H pyrrol-1-yl]butanoic acid (2) was active in both the hydroxyl radical-scavenging (ED50 11.9 MUM) and quinone reductase-induction [CD (concentration required to double QR activity) 2.4 MUM)] assays used. The isolated compounds were shown to be absent in a taxonomically authenticated African mango sample but present in three separate authentic samples of goji berry (Lycium barbarum) using LC-MS and (1)H NMR fingerprinting analysis, including one sample that previously showed inhibitory activity in vivo in a rat esophageal cancer model induced with N nitrosomethylbenzylamine. Additionally, microscopic features characteristic of goji berry were observed in the commercial African mango sample. PMID- 24792837 TI - Molecular epidemiology of Pseudomonas aeruginosa clinical isolates from Korea producing beta-lactamases with extended-spectrum activity. AB - This study was performed to investigate the prevalence and molecular epidemiology of Pseudomonas aeruginosa isolates from Korea that produce enzymes with extended spectrum (ES) activity to beta-lactams. A total of 205 non-duplicate P. aeruginosa clinical isolates were collected from 18 university hospitals in Korea. PCR and sequencing experiments were performed to identify genes encoding beta-lactamases. PCR mapping and sequencing of the regions surrounding the beta lactamase genes were performed. Multilocus sequence typing experiments were performed. The most common sequence type (ST) was ST235 (n = 96), and 2 single locus variants of ST235, ST1015 (n = 1) and ST1162 (n = 1), were also identified. These 3 STs were grouped as a clonal complex (CC), CC235. The remaining 107 isolates were identified as 59 different STs. Isolates belonging to CC235 showed higher rates of non-susceptibility to imipenem (85.4% versus 47.7%) and meropenem (92.7% versus 52.3%) compared to non-CC235 isolates. All the metallo-beta lactamase (MBL)-producing isolates were identified as CC235, except for 1 ST591. Genes encoding OXA-17 and OXA-142 were detected in 1 isolate and 4 isolates of CC235, respectively; while the bla(SHV-12) gene was detected in 4 non-CC235 isolates. Class A and D beta-lactamases with ES activity play a role in acquiring ceftazidime resistance in P. aeruginosa in Korea. Production of IMP-6 and VIM-2 MBLs is the main mechanisms in acquiring resistance to ceftazidime and carbapenems in P. aeruginosa isolates in Korea. Clonal spread of P. aeruginosa CC235 may be an important conduit for the dissemination of MBL genes in Korea. PMID- 24792839 TI - Controlling asthma. PMID- 24792838 TI - Comparison of loop-mediated isothermal amplification (LAMP) and nested-PCR assay targeting the RE and B1 gene for detection of Toxoplasma gondii in blood samples of children with leukaemia. AB - Toxoplasmosis diagnosis constitutes an important measure for disease prevention and control. In this paper, a newly described DNA amplification technique, loop mediated isothermal amplification (LAMP), and nested-PCR targeting the repeated element (RE) and B1 gene, were compared to each other for the detection of Toxoplasma gondii DNA in blood samples of children with leukaemia. One hundred ten blood samples from these patients were analyzed by LAMP and nested-PCR. Out of 50 seropositive samples (IgM+, IgG+), positive results were obtained with 92% and 86% on RE, B1-LAMP and 82% and 68% on RE, B1-nested PCR analyses, respectively. Of the 50 seronegative samples, three, two and one samples were detected positive by RE-LAMP, B1-LAMP and RE-nested PCR assays, respectively, while none were detected positive by B1-nested PCR. None of the 10 IgM-, IgG+ samples was detected positive after testing LAMP and nested-PCR assays in duplicate. This is the first report of a study in which the LAMP method was applied with high sensitivity and efficacy for the diagnosis of T. gonii in blood samples of children with leukaemia. PMID- 24792840 TI - Poor health outcomes in Native Americans and Alaska Natives. PMID- 24792841 TI - Political commitment to MERS-CoV in Saudi Arabia. PMID- 24792842 TI - Trust in the time of markets: protecting patient information. PMID- 24792843 TI - Variola virus archives: a new century, a new approach. PMID- 24792845 TI - Francine Ducharme: the art and the science of childhood asthma. PMID- 24792846 TI - Austerity and health in Greece. PMID- 24792847 TI - Austerity and health in Greece. PMID- 24792848 TI - Austerity and health in Greece. PMID- 24792849 TI - Austerity and health in Greece - authors' reply. PMID- 24792850 TI - Austerity and health in Greece. PMID- 24792851 TI - The Irish health-care system and austerity: sharing the pain. PMID- 24792852 TI - Economic recession and maternal and child health in Italy. PMID- 24792853 TI - A charter for the rights of the dying child. PMID- 24792854 TI - Global elderly care in crisis: a view from Japan. PMID- 24792856 TI - Diagnosis, management, and prognosis of preschool wheeze. AB - Preschool children (ie, those aged 5 years or younger) with wheeze consume a disproportionately high amount of health-care resources compared with older children and adults with wheeze or asthma, representing a diagnostic challenge. Although several phenotype classifications have been described, none have been validated to identify individuals responding to specific therapeutic approaches. Several risk factors related to genetic, prenatal, and postnatal environment are associated with preschool wheezing. Findings from several cohort studies have shown that preschool children with wheeze have deficits in lung function at 6 years of age that persisted until early and middle adulthood, suggesting increased susceptibility in the first years of life that might lead to persistent sequelae. Daily inhaled corticosteroids seem to be the most effective therapy for recurrent wheezing in trials of children with interim symptoms or atopy; intermittent high-dose inhaled corticosteroids are effective in moderate-to severe viral-induced wheezing without interim symptoms. The role of leukotriene receptor antagonist is less clear. Interventions to modify the short-term and long-term outcomes of preschool wheeze should be a research priority. PMID- 24792857 TI - Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis. PMID- 24792855 TI - Outdoor air pollution and asthma. AB - Traffic and power generation are the main sources of urban air pollution. The idea that outdoor air pollution can cause exacerbations of pre-existing asthma is supported by an evidence base that has been accumulating for several decades, with several studies suggesting a contribution to new-onset asthma as well. In this Series paper, we discuss the effects of particulate matter (PM), gaseous pollutants (ozone, nitrogen dioxide, and sulphur dioxide), and mixed traffic related air pollution. We focus on clinical studies, both epidemiological and experimental, published in the previous 5 years. From a mechanistic perspective, air pollutants probably cause oxidative injury to the airways, leading to inflammation, remodelling, and increased risk of sensitisation. Although several pollutants have been linked to new-onset asthma, the strength of the evidence is variable. We also discuss clinical implications, policy issues, and research gaps relevant to air pollution and asthma. PMID- 24792858 TI - Focused review of investigation, management and outcomes of salivary gland disease in specialty-specific journals. AB - We review papers on diseases of the salivary glands published in journals relating to the head and neck, which are commonly read by members of our specialty. Most of the papers focus on the investigation and treatment of diseases of the parotid gland, which reflects the relative prevalence of parotid lesions among salivary gland diseases. Minimally invasive surgery is increasingly of interest. There is a lack of clinical trials that address the many controversies concerning salivary gland surgery, and much of the evidence for treatment is based on small case series and expert opinion, partly because of the relative rarity of salivary disease and the disparate groups that treat it. This problem could be addressed if regional and national oral and maxillofacial surgery (OMFS) units, and possibly other specialties, could collaborate more closely and combine data. PMID- 24792859 TI - Bleeding complications in cutaneous surgery for patients on warfarin who have skin cancer of the head and neck. AB - Many patients who have operations on the head and neck for skin cancer also take warfarin to prevent thromboembolic events, and there is still debate about whether treatment should be continued, adjusted, or temporarily stopped. The main concern is to balance the risk of haemorrhagic and thromboembolic events. In this prospective controlled study we compared bleeding complications in operations for skin cancer of the head and neck between 86 patients who took warfarin (100 tumours) and 87 (100 tumours) who did not. Surgeons of different grades did the operations under the guidance of the same consultant. All those on warfarin had above normal international normalised ratios (INRs) (mean (SD) 2.5 (0.51), mode 2.6, range 1.1-4.0). In the warfarin group 8% of excisions had a bleeding complication compared with 9% in the control group. One patient in each group suffered a severe bleed that required a return to theatre. The difference in tendency to bleed between the groups was not significant (p=0.30), and the site and type of reconstruction did not influence the risk of bleeding significantly. This study shows that patients on warfarin who are within the normal therapeutic range, can be operated on safely for skin cancer by all levels of trained staff. PMID- 24792860 TI - High division of the spinal accessory nerve and communication with a C2 branch of the cervical plexus: a previously unreported anatomical variant. AB - Anatomical variations of the spinal accessory nerve are well known. We describe a previously unreported variant in which the nerve divided high in level II after crossing the internal jugular vein and before entering the sternomastoid muscle. Both branches were joined by a communication from the C2 cervical root. We discuss the clinical implications of this finding. PMID- 24792861 TI - A hundred years of color studies in insects: with thanks to Karl von Frisch and the workers he inspired. PMID- 24792862 TI - Factors associated with mortality after Nissen fundoplication in children. AB - PURPOSE: The purpose of this article was to identify factors associated with mortality after Nissen fundoplication in children. METHODS: After Institutional Review Board approval, children younger than 18 years, from two children's hospitals, with Nissen fundoplication performed between January 1994 and December 2010, were retrospectively reviewed. Inclusion required complete data and follow up to October 2011. Survivors and nonsurvivors were compared, using t-tests for continuous and chi-square tests for categorical variables, to identify factors associated with mortality. Patient factors present before the first fundoplication were analyzed. Surgical factors were surgical complications, gastrostomy placement, operative technique, and redos. Logistic regression evaluated for independence of variables. RESULTS: A total of 823 children were identified, 412 were included and 63 died (15.3%). The median follow-up time for the cohort was 3.7 years (mean, 4.5 +/- 3.2 years). For nonsurvivors, the median time to death after fundoplication was 6.0 months (mean, 13.2 +/- 8.0 months). Significant factors after univariate analysis were surgical complications (p = 0.001), female gender (p = 0.001), neurological impairment (p = 0.010), and fundoplication performed before the age of 18 months (p = 0.035). Independent predictors were surgical complications, odds ratio (OR), 3.30 (95% confidence interval [CI], 1.31-8.29), neurological impairment, OR, 2.58 (95% CI, 1.38-4.83), fundoplication before the age of 18 months, OR, 2.46 (95% CI, 1.23-4.94), and female gender, OR, 2.25 (95% CI, 1.26-4.00). CONCLUSION: After Nissen fundoplication in children, surgical complications, neurological impairment, fundoplication performed before the age of 18 months, and female gender are associated with mortality. The median time to death for nonsurvivors was 6 months. PMID- 24792863 TI - BioVaM in the rat model: a new approach of vascularized 3D tissue for esophageal replacement. AB - INTRODUCTION: A major obstacle in tissue engineering is to create a surgically implantable tissue with long-term viability. Several promising techniques have focused on biological vascularized matrices (BioVaM) with preserved vascular pedicles in the porcine model. However, the handling of this model is time consuming and expensive. Therefore, our aim was to establish a BioVaM in the rat. MATERIALS AND METHODS: Small bowel segments of Sprague-Dawley rats were isolated and perfused via cannulation of the superior mesenteric artery and the portal vein. All cellular matrix components were removed by sequential treatment with sodium dodecyl sulfate, sodium deoxycholate, and DNase. Quality of decellularization was investigated by histology and potential residual DNA by spectrophotometry. Primary endothelial cells (ECs) isolated from the major vessels of Sprague-Dawley rats. Cells were labeled with fluorescent cell tracker and injected into the vascular pedicles of the matrix. Attachment of ECs was assessed using fluorescence microscopy of the whole mount. RESULTS: Decellularized matrix demonstrated the absence of cellular components but conserved matrix architecture as determined by immune fluorescent, pentachrome, and hematoxylin and eosin stains. DNA content was reduced by more than 99%. ECs were characterized by specific staining against endothelial nitric oxide synthase and von Willebrand factor; when injected, ECs attached along the vessel walls including the capillaries of the intestinal wall. CONCLUSIONS: Rat small bowel segments harvested with intact vascular pedicles and associated vascular network can be successfully decellularized and re-endothelialized ex vivo. This model is an inexpensive and easy to handle alternative and appears to be a promising approach for establishing vascularized tissue constructs. PMID- 24792864 TI - Timing of ostomy reversal in neonates with necrotizing enterocolitis. AB - INTRODUCTION: Most neonates with necrotizing enterocolitis (NEC) requiring laparotomy have bowel resection and intestinal diversion. At present, there is no consensus regarding the best time for enterostomy reversal. Our aim is to determine if there is any difference in outcomes of infants whose enterostomy was reversed early versus late. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients with NEC admitted to the neonatal intensive care unit at a large urban children's hospital from 2002 to 2010. The patients underwent operative intervention with creation and subsequent reversal of stomas. Patient characteristics, operative characteristics, and postoperative care were recorded. RESULTS: A total of 206 neonates were diagnosed with NEC and 44 met the inclusion criteria. Seven had ostomies reversed within 8 weeks, 20 underwent reversal 8 to 12 weeks after initial operation, and 17 underwent ostomy reversal greater than 12 weeks from creation. Early reversal did not affect the incidence of total parenteral nutrition-associated cholestasis (p = 0.16), length of parenteral nutrition (p = 0.12), or ability to reach full enteral nutrition (p = 0.30). Ventilator days were not different (p = 0.08). We found no difference in contamination at laparotomy (p = 0.61) or adhesions at reversal (p = 0.73). Mortality rate (p = 0.15) and complications following reversal (p = 0.25) were not different. CONCLUSION: There is no advantage to early or late enterostomy reversal in the endpoints studied. PMID- 24792865 TI - Global help: free medical information. PMID- 24792866 TI - Sorption of isoflavones to river sediment and model sorbents and outcomes for larval fish exposed to contaminated sediment. AB - Isoflavones are compounds whose presence in the aquatic environment is increasingly recognized and may be of concern due to their potential to act as endocrine disruptors. Sorption to particles may be a relevant removal mechanism for isoflavones. This work investigated the influence of pH, ionic strength, and sediment composition on sorption of genistein and daidzein, two key isoflavones, using sorption isotherms and edges. The effect of sorbed isoflavones on the survival, growth, and predator avoidance performance of larval fathead minnows (Pimephales promelas) was assessed. Sorption to goethite and kaolinite was pH dependent, with a maximum near pH 7 for both compounds. Sorption to montmorillonite was ionic-strength dependent but largely pH-independent. Overall, sorption to sediments is likely to sequester less than 5% of isoflavones in a discharge. No statistically significant effects were observed for larvae exposed to sorbed isoflavones, suggesting that sorption to sediments reduces exposure to isoflavones. PMID- 24792868 TI - Telomere length and aneuploidy: clinical and biological insights into human preimplantation embryos. PMID- 24792867 TI - hnRNPA2/B1 and nELAV proteins bind to a specific U-rich element in CDK5R1 3'-UTR and oppositely regulate its expression. AB - Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, a specific activator of cyclin-dependent kinase 5 (CDK5). CDK5 and p35 have a fundamental role in neuronal migration and differentiation during CNS development. Both the CDK5R1 3'-UTR's remarkable size and its conservation during evolution strongly indicate an important role in post-transcriptional regulation. We previously validated different regulatory elements in the 3'-UTR of CDK5R1, which affect transcript stability, p35 levels and cellular migration through the binding with nELAV proteins and miR-103/7 miRNAs. Interestingly, a 138 bp-long region, named C2.1, was identified as the most mRNA destabilizing portion within CDK5R1 3'-UTR. This feature was maintained by a shorter region of 73 bp, characterized by two poly-U stretches. UV-CL experiments showed that this region interacts with protein factors. UV-CLIP assays and pull-down experiments followed by mass spectrometry analysis demonstrated that nELAV and hnRNPA2/B1 proteins bind to the same U-rich element. These RNA-binding proteins (RBPs) were shown to oppositely control CDK5R1 mRNA stability and p35 protein content at post-trascriptional level. While nELAV proteins have a positive regulatory effect, hnRNPA2/B1 has a negative action that is responsible for the mRNA destabilizing activity both of the C2.1 region and of the full-length 3'-UTR. In co-expression experiments of hnRNPA2/B1 and nELAV RBPs we observed an overall decrease of p35 content. We also demonstrated that hnRNPA2/B1 can downregulate nELAV protein content but not vice versa. This study, by providing new insights on the combined action of different regulatory factors, contributes to clarify the complex post-transcriptional control of CDK5R1 gene expression. PMID- 24792869 TI - Introduction to Quality Management in Assisted Reproductive Technology Symposium. PMID- 24792870 TI - Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. AB - Prolonged isolated thrombocytopenia (PT) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, it remains unclear whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PT. This prospective, nested case-control study included 20 patients with PT, 40 matched patients with good graft function (GGF) after allo-HSCT, and 16 healthy donors (HDs). Cellular elements of the BM microenvironment, including BM endothelial cells (BMECs), perivascular cells, and endosteal cells, were analyzed via flow cytometry and via hematoxylin-eosin and immunohistochemical staining in situ. Moreover, stromal-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) were measured in the plasma of BM via an enzyme-linked immunosorbent assay. No significant differences in endosteal cells (15 per high-power field [hpf] versus 16 per hpf versus 20 per hpf, P > .05) were demonstrated among the patients with PT, GGF, and the HDs. The PT patients exhibited remarkable decreases in cellular elements of the vascular microenvironment, including BMECs (.01% versus .18% versus .20%, P < .0001) and perivascular cells (.01% versus .12% versus .13%, P < .0001), compared with the GGF allo-HSCT recipients and the HDs, respectively. Moreover, significantly lower levels of SDF-1 (3163 pg/mL versus 3928 pg/mL, P = .0002) and VEGF (56 pg/mL versus 123 pg/mL, P < .0001) were found in the BM plasma of the PT patients compared with the BM of the GGF patients. A multivariate analysis revealed that BMECs (odds ratio [OR] = 171.57, P = .002) and cytomegalovirus infection after HSCT (OR = 4.35, P = .009) were independent risk factors for PT. Our data suggested that an impaired BM vascular microenvironment and megakaryocyte-active factors may contribute to the occurrence of PT after HSCT. PMID- 24792871 TI - Clostridium difficile colonization and disease in patients undergoing hematopoietic stem cell transplantation. AB - There was an increase in the Clostridium difficile infection (CDI) rate in our bone marrow transplantation unit. To evaluate the role of unit-based transmission, C. difficile screening was performed on adult patients admitted for hematopoietic stem cell transplantation (HSCT) over a 2-year period, and C. difficile isolates were typed. C. difficile testing was performed using a 2-step C. difficile glutamate dehydrogenase antigen plus toxin A/B enzyme immunoassay (EIA) and cytotoxin assay (or molecular toxin assay). Multilocus sequence typing (MLST) was performed on toxin-positive whole stool samples. A retrospective chart review was performed on all patients with a positive toxin assay. Sixteen of 150 patients (10.7%) had toxigenic C. difficile colonization (CDC) on admission. The overall incidence of CDI within 100 days after HSCT was 24.7% (37 of 150). The median time to diagnosis of CDI was 3.5 days after HSCT. In an adjusted logistic regression model, CDC on admission was a significant risk factor for CDI (odds ratio, 68.5; 95% confidence interval, 11.4 to 416.2). MLST on 22 unit patient toxin-positive stool specimens revealed 15 distinct strain types. Further analysis identified at least 1 potential cross-transmission event; some events may have been missed because of incomplete typing from other specimens. Despite aggressive infection control interventions, there was no decline in the number of CDI cases during the study period. These data suggest that prior CDC plays a major role in CDI rates in this high-risk patient population. It remains unclear if CDI was cross-transmitted in the unit. PMID- 24792873 TI - Reply: To PMID 24238646. PMID- 24792872 TI - The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. AB - We conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters. Fifty-seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least 1 prior autologous transplantation were included. Twenty-six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed between related and unrelated. The median follow-up was 52 months. Thirty-two (57.1%) patients achieved a complete response (CR). At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year overall survival (OS) for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared with 38% for those in the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (hazard ratio [HR], 4.05; P = .0196), acute graft-versus-host disease (aGVHD) (HR, 2.99; P = .034), and chronic graft-versus-host disease (cGVHD), which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR .17, P = .008). Our data show that allogeneic transplantation for MM can lead to sustained remissions. aGVHD is significantly deleterious to OS and progression-free survival, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-myeloma effect. PMID- 24792874 TI - Bronchi wall and lumen volumes to assess airway remodeling in asthma by using CT: an innovative method? PMID- 24792875 TI - Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency. AB - BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by B-cell dysfunction and, in a subgroup, by expansion of CD21(low) B cells. The CD21(low) B cells display defects in early B-cell receptor (BCR) signaling resembling those of anergic B cells. OBJECTIVE: We sought to investigate whether B cells from patients with CVID, like anergic B cells, have defects in extracellular signal-regulated kinase (ERK) phosphorylation and in endocytic trafficking of the BCR. METHODS: Using flow cytometry, we evaluated phosphorylated ERK (pERK) expression and internalization of cross-linked BCR in B cell subsets. The localization of internalized BCR to lysosome-associated membrane protein 1-positive late endosomes was evaluated with confocal microscopy. RESULTS: Constitutive pERK levels were increased in naive and IgM(+) memory B cells of patients with CVID compared with those of healthy donors, whereas the pERK increment induced by BCR cross-linking was relatively reduced. Intravenous immunoglobulin administration enhanced these anomalies, but they appeared to be intrinsic to B cells from patients with CVID. Cross-linking induced BCR endocytosis was decreased in the IgM(+) memory B cells, especially in those with a CD21(low) phenotype, but not in the naive B cells of patients with CVID with CD21(low) expansion. Internalized BCR localized normally to late endosomes. Pharmacologic inhibition of ERK phosphorylation suppressed BCR endocytosis in B cells of healthy patients and those with CVID. CONCLUSIONS: The B cells of patients with CVID with CD21(low) B-cell expansion resemble anergic B cells based on high constitutive pERK expression. The IgM(+) memory B cells of these patients, especially those that are CD21(low), have a defect in BCR endocytosis seemingly caused by dysregulated ERK signaling. PMID- 24792876 TI - Association of viral replication capacity with the pathogenicity of enterovirus 71. AB - Enterovirus 71 (EV71) is a major cause of hand-foot-and-mouth disease, which is associated with fatal neurological disease. The mechanism of EV71 pathogenesis remains obscure. We compared the replication capacity of the severe and mild enterovirus 71 isolates. The replication kinetics of EV71 in RD cells and ICR mice was determined by qRT-PCR. The lung, muscular, brain, intestine tissues were used for histopathological and immunohistochemical assays. The growth curves of EV71 strains in RD cells showed that the severe EV71 strains (SDLY107 and SDLY52) replicated faster and generated more viral RNA than the mild EV71 strains (SDLY11 and SDLY1). The mice infected by the severe EV71 strains (SDLY107) showed more severe clinical symptoms, pathological changes and higher viral load than the mice infected by the mild EV71 strains (SDLY11). These results suggest that there was a difference in replication capacity between the severe and mild EV71 strains, which was possibly associated with EV71 pathogenesis. PMID- 24792877 TI - Selective insectivory at Toro-Semliki, Uganda: comparative analyses suggest no 'savanna' chimpanzee pattern. AB - Chimpanzee (Pan troglodytes) insectivory across Africa is ubiquitous. Insects provide a significant nutritional payoff and may be important for chimpanzees in dry, open habitats with narrow diets. We tested this hypothesis at Semliki, Uganda, a long-term dry study site. We evaluated prospects for insectivory by measuring insect abundance along de novo transects and trails, monitoring social insect colonies, and surveying available raw materials for elementary technology. We determined the frequency and nature of insectivory through behavioral observation and fecal analysis. We then compared our results with those from 15 other long-term chimpanzee study sites using a cluster analysis. We found that Semliki chimpanzees are one of the most insectivorous populations studied to date in terms of frequency of consumption, but they are very selective in their insectivory, regularly consuming only weaver ants (Oecophylla longinoda) and honey and bees from hives of Apis mellifera. This selectivity obtains despite having a full range of typical prey species available in harvestable quantities. We suggest that Semliki chimpanzees may face ecological time constraints and therefore bias their predation toward prey taxa that can be quickly consumed. Geographical proximity correlated with the results of the cluster analysis, while rainfall, a relatively gross measure of environment, did not. Because broad taxonomic groups of insects were used in analyses, prey availability was unlikely to have a strong effect on this pattern. Instead, we suggest that transmission of cultural knowledge may play a role in determining chimpanzee prey selection across Africa. Further study is needed to test these hypotheses. PMID- 24792878 TI - Delaying obsolescence. AB - This paper argues that those who emphasise that designers and engineers need to plan for obsolescence are too conservative. Rather, in addition to planning for obsolescence, designers and engineers should also think carefully about what they could do in order delay obsolescence. They should so this by thinking about the design itself, thinking of ways in which products could be useful and appealing for longer before becoming obsolete, as well thinking about the wider context in terms of the marketing of products, and also the social and legal. The paper also considers objections that these suggestions are unrealistically idealistic, failing to recognise the economic realities. I respond to these objections appealing to research in advertising, psychology, cognitive linguistics, philosophy, history, and economics, as well as drawing on the Statement of Ethical Principles developed by the Royal Academy of Engineering and the Engineering Council. PMID- 24792880 TI - Phytoplankton community indicators of changes associated with dredging in the Tagus estuary (Portugal). AB - This work reports changes in suspended particulate matter, turbidity, dissolved Cr, Ni, Cu, Cd, Hg and Pb concentrations, and phytoplankton biomass and composition during a 5-month period dredging operation, in a trace element contaminated area of the Tagus estuary (Portugal). Phytoplankton biomass, diatom:other groups ratio, benthic:pelagic diatom ratio, Margalef's, Simpson's diversity, Shannon-Wiever's, and Warwick and Clarke's taxonomic diversity and distinctness indices, and individual taxa were investigated as indicators of dredging induced changes. Significant rise in sediment resuspension and trace element mobilisation caused by dredging influenced the community structure but not the overall biomass. Benthic diatom displacement into the water column maintained species diversity, and therefore, none of the indices highlighted community changes. Contrastingly, diatom:other groups ratio and benthic:pelagic diatom ratio were reliable indicators for the assessment of dredging induced changes. A shift in composition towards species less susceptible to trace elements was observed, disclosing some individual taxa as potential indicators. PMID- 24792881 TI - Associations of methylmercury and inorganic mercury between human cord blood and maternal blood: a meta-analysis and its application. AB - Considering the different ability of placental transfer, an assessment of the cord:maternal blood ratio for both methylmercury (MeHg) and inorganic mercury (IHg) is needed especially for interpreting the low-level prenatal exposure. In this study, we conducted a Monte Carlo-based meta-analysis to comprehensively estimate that ratio for MeHg (RMeHg) and IHg (RIHg). The obtained values followed log-normal distributions, with a mean (standard deviation) of 1.89 (0.98) and 1.01 (0.55) for RMeHg and RIHg, respectively. We also estimated the percentage of MeHg in the blood by means of THg in cord and maternal blood using the RMeHg and RIHg, and obtained a value very close to the measured one (relative deviation, 0.4%). In conclusion, the fetus is exposed to approximately twice as much MeHg and to the same level of IHg as in maternal blood; the introduced model provides a rough but reasonable estimate of the percentage of MeHg in the blood. PMID- 24792882 TI - Formation of brominated pollutants during the pyrolysis and combustion of tetrabromobisphenol A at different temperatures. AB - Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardant worldwide. A detailed examination of the degradation products emitted during thermal decomposition of TBBPA is presented in the study. Runs were performed in a laboratory furnace at different temperatures (650 and 800 degrees C) and in different atmospheres (nitrogen and air). More than one hundred semivolatile compounds have been identified by GC/MS, with special interest in brominated ones. Presence of HBr and brominated light hydrocarbons increased with temperature and in the presence of oxygen. Maximum formation of PAHs is observed at pyrolytic condition at the higher temperature. High levels of 2,4-, 2,6- and 2,4,6- bromophenols were found. The levels of polybrominated dibenzo-p-dioxins and furans have been detected in the ppm range. The most abundant isomers are 2,4,6,8-TeBDF in pyrolysis and 1,2,3,7,8-PeBDF in combustion. These results should be considered in the assessment of thermal treatment of materials containing brominated flame retardants. PMID- 24792883 TI - Pathways of Pb and Mn observed in a 5-year longitudinal investigation in young children and environmental measures from an urban setting. AB - We monitored 108 children <=5 years on a 6-month basis for up to 5 years in a major urban setting. Samples (n ~ 7000) included blood, urine, handwipes (interior, and after exterior playing), 6-day duplicate diet, drinking water, interior house and day care dust-fall accumulation using petri dishes, exterior dust-fall accumulation, exterior dust sweepings, paint, soil and urban air. The geometric mean blood Pb (PbB) was 2.1 MUg/dL and blood Mn (MnB) was 10.0 MUg/L. Following a path modelling approach, mixed model analyses for a fully adjusted model showed the strongest associations for PbB were with interior house dust and soil; for MnB there were no significant associations with any predictors. Predictor variables only explained 9% of the variance for Pb and 0.7% for Mn. Relationships between environmental measures and PbB in children are not straightforward; soil and dust sweepings contribute only about 1/5th of the amounts to PbB found in other studies. PMID- 24792884 TI - Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation. AB - INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare lifelong disorder characterized by an abnormal ventilatory response with persistent hypercapnia and hypoxia, which worsen during sleep. About 90 % of CCHS individuals are heterozygous for a mutation in the exon 3 of the PHOX2B gene. With higher awareness and better diagnostic tools, cases are identified in late childhood and adulthood, often with distinct mutations. CLINICAL CASE: The authors present a 4-year-old girl admitted to the intensive care unit at 9, 11 and 13 months suffering from severe hypercapnic respiratory failure during viral respiratory infections. Hypercapnia during sleep improved with wakefulness. CCHS was confirmed genetically (heterozygous insertion of an adenine at position 23, leading to a premature stop codon in exon 1 of the PHOX2B gene). The parents' DNA showed no PHOX2B mutations. Hypoventilation was observed by polysomnography, with no autonomic response to declining oxygen or increasing carbon dioxide values. A subsequent sleep study showed less hypoxia and hypercapnia. The patient has been on non-invasive ventilation during sleep, showing good growth and neurocognitive development. DISCUSSION: A greater awareness is required to diagnose late-onset CCHS. A respiratory infection can trigger the disease, with a significant difference in CO2 between sleep and wakefulness as the warning signal. Given the clinical suspicion, a genetic study should be performed. Polysomnography is essential for patient characterization. Follow-up and ventilator support adjustment prevent serious hypoxia and hypercapnia, which impair cardiovascular and neurocognitive functions. This patient's mutation has not been previously described; hence, clinical evolution cannot be predicted. PMID- 24792885 TI - Ethics of bioengineering organs and tissues. AB - Tissue-engineered medical products are now entering the clinical testing phase of development. Therefore, an open discussion is warranted regarding ethical issues that may arise as these novel 'combination' products move forward, such as when to conduct clinical trials, how to regulate such trials, when and how to responsibly introduce these strategies into clinical practice and how to maintain a positive public perception of the tissue-engineering field as a whole. These issues are discussed, and recommendations are provided for conducting first-in human clinical studies. PMID- 24792886 TI - Common variant on MDM2 contributes to endometrial cancer susceptibility: evidence based on 7 studies. AB - Due to its important biological function as a key negative regulator of p53, the mouse double minute 2 homologue (MDM2) gene has been extensively studied. A functional variant in the MDM2 gene promoter, single-nucleotide polymorphism 309 (SNP309) T > G (rs2279744), has been reported to cause an increase in MDM2 protein levels and impairment of p53 tumor suppressor activity, which may be associated with the development of cancer. A number of studies were performed to investigate the relationship between this SNP and endometrial cancer. But, the results remain controversial. Thus, we performed a comprehensive meta-analysis to derive a more precise estimation of this susceptibility. There were seven eligible articles with a total of 1,278 patients and 2,189 controls included in the meta-analysis. In the present study, we found significant associations under the allele contrast and recessive model. The G allele was associated with elevated risk for endometrial cancer [allele contrast OR = 1.33, 95 % confidence interval (CI) = 1.12-1.58, P(Z) = 0.0009, P(Q) = 0.02)], while the homozygous GG genotype may also increase the risk of endometrial cancer [OR = 1.88, 95 % CI = 1.40-2.52, P(Z) < 0.0001, P(Q) = 0.02]. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians [allele contrast OR = 1.41, 95 % CI = 1.04-1.92, P(Z) = 0.03, P(Q) = 0.001; recessive model OR = 1.89, 95 % CI = 1.10-3.23, P(Z) = 0.02, P(Q) = 0.002] and Asians [allele contrast OR = 1.24, 95 % CI = 1.01-1.53, P(Z) = 0.04, P(Q) = 0.86; recessive model OR = 1.75, 95 % CI = 1.24-2.45, P(Z) = 0.001, P(Q) = 0.75]. Overall, the meta-analysis demonstrated that the MDM2 SNP309 polymorphism may be associated with increased risk of endometrial cancer. PMID- 24792887 TI - Aptamer TY04 inhibits the growth of multiple myeloma cells via cell cycle arrest. AB - The aptamer TY04 is a single-stranded DNA. However, its biological function has not been elucidated. Here, we found that TY04 specifically bound to multiple myeloma cells MM.1S, and some membrane proteins on the surface of MM.1S cells constituted the target molecules of TY04. TY04 inhibited the growth of multiple myeloma cell lines, induced cell cycle arrest in mitosis, and resulted in a significant accumulation of binucleated cells. Following TY04 treatment, a concomitant increase in CDK1 and cyclin B1 expression occurred. In addition, TY04 treatment also resulted in a significant downregulation of gamma-tubulin. Considering the unique advantages of aptamers, TY04 shows great potential as a drug candidate to treat multiple myeloma. PMID- 24792888 TI - Prognostic value of PDCD6 polymorphisms and the susceptibility to bladder cancer. AB - Programmed cell death 6 (PDCD6) has recently been found dysregulated in tumors of various origin. The aim of this study is to explore the association between PDCD6 genetic polymorphisms and susceptibility to bladder cancer and survival of patients with bladder cancer. Two tag SNPs of PDCD6, rs3756712 and rs4957014, were genotyped in 332 patients with bladder cancer and 509 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and correlated with patients' survival. The frequencies of G allele and GG genotype of rs3756712 in patients were significantly lower than that of controls (P = 0.001, odds ratio [OR] = 0.68 for G allele; P = 0.024, OR = 0.53 for GG genotype in the recessive genetic model, respectively). The GT genotype of rs4957014 was associated with decreased susceptibility to bladder cancer in the overdominant genetic model (P = 0.023, OR = 0.72). Kaplan-Meier curves revealed a significant higher risk for death in superficial bladder cancer patients harboring GG homozygous of rs3756712 (P < 0.001), and an increased risk for recurrence in invasive bladder cancer patients carrying GT heterozygous of rs4957014 (P = 0.04). Multiple Cox regression analysis identified rs3756712 GG genotype as an independent prognostic factor for death in superficial bladder cancer patients (hazard ratio [HR] = 5.11, P = 0.01), and rs4957014 GT genotype as an independent prognostic factor for recurrence in invasive bladder cancer patients (HR = 1.93, P = 0.03). PDCD6 may represent a biomarker candidate gene that could help to identify a group of patients at high risk for recurrence and death. PMID- 24792889 TI - Shaping of NK cell subsets by aging. AB - NK cells are key players in the innate immune response against virus infection and tumors. Here we describe the current knowledge on age-associated changes in NK cells and the role of persistent CMV infection in configuring NK cell compartment in the elderly. Aging but not CMV causes a redistribution of NK cell subsets as shown by a decrease of CD56bright cells and an increase of CD56-CD16+ NK cells. On the contrary the changes in CD56dimCD16+ NK cells are compatible with the accumulation of CD57+ long-lived NK cells that can also be observed in young CMV-seropositive individuals. NK cell function and dynamics in the elderly will be related not only with age but also with exposure to pathogens, especially CMV. PMID- 24792890 TI - Successful testicular sperm recovery and IVF treatment in a man with Leydig cell hypoplasia. PMID- 24792891 TI - RUNX1 point mutations potentially identify a subset of early immature T-cell acute lymphoblastic leukaemia that may originate from differentiated T-cells. AB - The RUNX1/AML1 gene is among the most frequently mutated genes in human leukaemia. However, its association with T-cell acute lymphoblastic leukaemia (T ALL) remains poorly understood. In order to examine RUNX1 point mutations in T ALL, we conducted an amplicon-based deep sequencing in 65 Southeast Asian childhood patients and 20 T-ALL cell lines, and detected RUNX1 mutations in 6 patients (9.2%) and 5 cell lines (25%). Interestingly, RUNX1-mutated T-ALL cases seem to constitute a subset of early immature T-ALL that may originate from differentiated T-cells. This result provides a deeper insight into the mechanistic basis for leukaemogenesis. PMID- 24792892 TI - Slight variations in the SC35 ESE sequence motif among human chromosomes: a computational approach. AB - Gene expression is initiated by the binding of transcription factors to cis regulatory modules such as enhancer elements binding to the Serine/Arginine proteins. Recently, we noticed an increased ability to identify the location as well as the motifs of enhancers using genome-wide information on spliceosomal factor occupancy, cofactor recruitment and chromatin modifications. In this study, we have undertaken a large-scale genomic analysis in an attempt to uncover if the exonic splicing enhancer motif binding to the SC35 and the SRp40 SR proteins is conserved among several groups of human genes. For the SRp40, the results showed that the ESE consensus is conserved among human genes. Concerning the SC35 SR protein, results showed an ESE motif conserved among human tissues and between different levels of muscular cell differentiation and within the same chromosome. However, this motif displays subtle discrepancies between genes localized in different chromosomes. These results emphasize the presence of different translational isoforms of the SFRS2 gene encoding for the SC35, or different post-translational protein maturations in different chromosomes, confirming that chromatin structure is another layer of gene regulation. These links between chromatin pattern and splicing give further mechanistic support to functional interconnections between splicing, transcription and chromatin structure, and raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications. PMID- 24792893 TI - Identification and characterization of a differentially expressed protein (CAPZB) in skeletal muscle between Meishan and Large White pigs. AB - Actin capping protein beta (CAPZB) protein was identified with considerable differences in the longissimus dorsi muscle between Large White and Meishan pigs using proteomics approach. However, in pigs, the information on CAPZB is very limited. In this study, we cloned and characterized the porcine actin capping protein beta (CAPZB) gene. In addition, we present two novel porcine CAPZB splice variants CAPZB1 and CAPZB2. CAPZB1 was expressed in all twenty tissues. However, CAPZB2 was predominantly expressed in the skeletal muscle and heart. In addition, the two isoforms had different expression profiles during the skeletal muscle development and between breeds. Moreover, the SNP T394G was identified in the coding region of the CAPZB gene, which was significantly associated with the carcass traits including the LFW, CFW, SFT and LEA. Data presented in our study suggests that the CAPZB gene may be a candidate gene of meat production trait and provides useful information for further studies on its roles in porcine skeletal muscle. PMID- 24792894 TI - miR-29, a potential therapeutic target for liver fibrosis. PMID- 24792895 TI - EP-based wavelet coefficient quantization for linear distortion ECG data compression. AB - Reconstruction quality maintenance is of the essence for ECG data compression due to the desire for diagnosis use. Quantization schemes with non-linear distortion characteristics usually result in time-consuming quality control that blocks real time application. In this paper, a new wavelet coefficient quantization scheme based on an evolution program (EP) is proposed for wavelet-based ECG data compression. The EP search can create a stationary relationship among the quantization scales of multi-resolution levels. The stationary property implies that multi-level quantization scales can be controlled with a single variable. This hypothesis can lead to a simple design of linear distortion control with 3-D curve fitting technology. In addition, a competitive strategy is applied for alleviating data dependency effect. By using the ECG signals saved in MIT and PTB databases, many experiments were undertaken for the evaluation of compression performance, quality control efficiency, data dependency influence. The experimental results show that the new EP-based quantization scheme can obtain high compression performance and keep linear distortion behavior efficiency. This characteristic guarantees fast quality control even for the prediction model mismatching practical distortion curve. PMID- 24792896 TI - Interception of the endotoxin-induced arterial hyporeactivity to vasoconstrictors. AB - Septic shock is a severe pathophysiologic condition characterized by vasodilation, hypotension, hypoperfusion, tissue hypoxia, multiple organ failure and death. It is unclear what causes the septic vasodilation that may result from general dysfunction of vascular smooth muscles (VSMs) or selective disruption of vasomotor balances in VSMs. The latter could be due to enhanced vasorelaxation and/or depressed vasoconstriction. Understanding these may lead to pharmacological interventions to septic vasodilation. Therefore, we performed studies in isolated and perfused mesenteric arterial rings. A 20-h exposure of the rings to lipopolysaccharide (LPS, 1 MUg/ml) led to hyporeactivity to phenylephrine (PE). However, the responses of the LPS-treated rings to high concentrations of KCl (60 mM) and ATP remained comparable to control rings, suggesting that contractility of VSMs is retained. The hyporeactivity was marginally affected by atropine, indomethacin and L-NAME, suggesting that endothelium-dependent vasorelaxation does not play a major role. In addition to PE, the LPS-treated rings were hyporeactive to dopamine, histamine and angiotensin II. They showed intermediate hyporeactivity to the thromboxane-A2 receptor agonist U46619. Little hyporeactivity to endothelin-1 (ET-1), serotonin (5-HT) and vasopressin was found. ET-1-induced vasoconstriction occurred without endothelium, whereas the effect of 5-HT was endothelium dependent. Although rings were hyporeactive to some of the vasopressors, their vasoconstriction effects were significantly potentiated by PE co-application. Taken together, these data suggest that the endotoxin-induced vasodilation may not result from general dysfunction of VSMs, neither from the endothelium-dependent vasorelaxation. The promising vascular response to various vasoconstrictors found in this study warrants further investigations of therapeutic potentials of these agents. PMID- 24792897 TI - Study of extracellular matrix in vocal fold biomechanics using a two-phase model. AB - The extracellular matrix (ECM) of the vocal fold tissue consists primarily of fibrous and interstitial proteins. The purpose of this study was to investigate the effects of selective enzymatic digestion of two ECM proteins, namely elastin and versican, on the elasticity of rabbit vocal fold tissue. Quasi-static, sinusoidal, uniaxial tensile tests were performed. The data were analyzed within the framework of a model of the ECM as a two-phase composite material consisting of collagen fibrils as the reinforcing fibers and noncollagenous ECM proteins as the matrix. To validate the two-phase model, the regression parameters for the fibers' volume fraction and shear modulus in a different animal model were compared with corresponding published data. The proposed model was then used to analyze rabbit vocal fold tissues. The mean value and the standard deviation of the fiber volume fraction were found to be 8.49 +/- 3.75 % for the control samples (n = 4), 0.59 +/- 1.13 % after elastin removal (n = 4), and 8.22 +/- 1.06 % after versican removal (n = 4). The results suggest that elastin removal may lead to a reduction in tissue stiffness, through counteracting the reinforcement of collagen fibrils. PMID- 24792898 TI - miR-326 and miR-26a, two potential markers for diagnosis of relapse and remission phases in patient with relapsing-remitting multiple sclerosis. AB - BACKGROUND: Multiple sclerosis is an inflammatory autoimmune disease widely characterized by myelin destruction of CNS. Th-17 cells, have been demonstrated to play a crucial role in pathogenesis of MS. MicroRNAs are a new class of non coding RNAs that participate in post-transcriptional regulation of gene expression. Previous studies have reported a potential role of various miRNAs in induction of Th-17 differentiation and progress of autoimmune diseases. In recent years, it has been shown that miR-326 and miR-26a involved in progress of Th-17 and MS disease. OBJECTIVE: To evaluate expression pattern of miR-326 and miR-26a in peripheral blood lymphocytes of relapsing-remitting MS patients during relapsing and remitting phases compared to healthy control subjects. MATERIALS AND METHODS: Forty RR-MS patients of Isfahan population were diagnosed as relapsing (n=20) or remitting phase (n=20) patients according to clinical manifests and expression level of miR-26a and miR-326 was measured in these groups by quantitative real time PCR method compared to 20 healthy controls. In silico molecular signaling pathway enrichment analysis was also performed on validated and predicted targets (targetome) of miR-26a by DAVID database to explore possible role of miR-26a in Th17 differentiation. RESULTS: We observed up regulation of both miR-326 and miR-26a in relapsing phase of multiple sclerosis patients compared with remitting phase (p value=0.0001) and healthy controls (p value=0.0091). ROC curve analysis confirmed valuable and precise potential of miR 326 to discriminate between relapsing and remitting phases of multiple sclerosis with specificity and sensitivity of 100% at a proposed optimum cutoff point. Furthermore, in-silico molecular signaling pathway enrichment analysis detected TGF-beta signaling pathway as one of the most statistically relevant pathway with miR-26a targetome. CONCLUSION: Our results confirmed potential of miR-326 as a diagnostic biomarker to discriminate between relapsing and remitting phases of multiple sclerosis disease. Similar expression pattern to miR-326 and in-silico molecular enrichment analysis altogether suggest an inducing role of miR-26a in differentiation of pathogenic Th17 cells during pathogenesis of multiple sclerosis by targeting major components of the TGF-beta signaling pathway (i.e. SMAD4 and SMAD1) and disarrangement of this signaling pathway. PMID- 24792899 TI - RNA Polymerase III promoter screen uncovers a novel noncoding RNA family conserved in Caenorhabditis and other clade V nematodes. AB - RNA Polymerase III is a highly specialized enzyme complex responsible for the transcription of a very distinct set of housekeeping noncoding RNAs including tRNAs, 7SK snRNA, Y RNAs, U6 snRNA, and the RNA components of RNaseP and RNaseMRP. In this work we have utilized the conserved promoter structure of known RNA Polymerase III transcripts consisting of characteristic sequence elements termed proximal sequence elements (PSE) A and B and a TATA-box to uncover a novel RNA Polymerase III-transcribed, noncoding RNA family found to be conserved in Caenorhabditis as well as other clade V nematode species. Homology search in combination with detailed sequence and secondary structure analysis revealed that members of this novel ncRNA family evolve rapidly, and only maintain a potentially functional small stem structure that links the 5' end to the very 3' end of the transcript and a small hairpin structure at the 3' end. This is most likely required for efficient transcription termination. In addition, our study revealed evidence that canonical C/D box snoRNAs are also transcribed from a PSE A-PSE B-TATA-box promoter in Caenorhabditis elegans. PMID- 24792901 TI - Implementation of direct LSC method for diesel samples on the fuel market. AB - The European Union develops common EU policy and strategy on biofuels and sustainable bio-economy through several documents. The encouragement of biofuel's consumption is therefore the obligation of each EU member state. The situation in Slovenian fuel market is presented and compared with other EU countries in the frame of prescribed values from EU directives. Diesel is the most common fuel for transportation needs in Slovenia. The study was therefore performed on diesel. The sampling net was determined in accordance with the fuel consumption statistics of the country. 75 Sampling points were located on different types of roads. The quantity of bio-component in diesel samples was determined by direct LSC method through measurement of C-14 content. The measured values were in the range from 0 up to nearly 6 mass percentage of bio-component in fuel. The method has proved to be appropriate, suitable and effective for studies on the real fuel market. PMID- 24792900 TI - Combined effect between CHRNB3-CHRNA6 region gene variant (rs6474412) and smoking in psoriasis vulgaris severity. AB - BACKGROUND: Many factors associated with causing psoriasis have been reported, such as the genetic and environmental factors. Smoking is one of the well established environmental risk factors for psoriasis and also associated with the disease severity. In addition, several studies of psoriasis and psoriatic arthritis have documented gene-environment interactions involving smoking behavior. Although gene polymorphisms on nicotinic acetylcholine receptor subunits CHRNB3-CHRNA6 region gene have been found to correlate with smoking behavior and lung cancer susceptibility in Chinese Han population, the combined effect between the smoking-related genetic variants and smoking behavior on psoriasis vulgaris (PV) has been unreported. OBJECTIVE: To evaluate the combined effect of the smoking-related (rs6474412-C/T) polymorphism on CHRNB3-CHRNA6 region gene and smoking behavior on PV risk and clinic traits in Chinese Han population. METHODS: A hospital-based case-control study including 672 subjects (355 PV cases and 317 controls) was conducted. The variant of rs6474412 was typed by SNaPshot Multiplex Kit (Applied Biosystems Co., USA). RESULTS: The higher body mass index (BMI>=25), smoking behavior and alcohol consumption were risk factors for PV, and the estimated ORs were 1.55 (95% CI, 1.09-2.29), 1.74 (95% CI, 1.22 2.49) and 1.81 (95% CI, 1.25-2.62) respectively. The smoking patients had more severe conditions than non-smokers (OR=1.71, 95% CI, 1.08-2.70, P=0.020). The alleles and genotypes of rs6474412 were not associated with risk of PV, but the combined effect of rs6474412 genotype (TT) and smoking behavior increased severity of PV (OR=5.95; 95% CI, 1.39-25.31; P<0.05; adjusted OR=2.20; 95% CI, 1.55-3.14; P<0.001). CONCLUSIONS: Our results demonstrate that the combined effect of rs6474412-C/T polymorphism in smoking-related CHRNB3-CHRNA6 region gene and smoking behavior may not confer risk to PV, but may have impact on PV severity in Chinese Han population. PMID- 24792903 TI - Difficult ECGs in STEMI: lessons learned from serial sampling of pre- and in hospital ECGs. AB - Prehospital interpretation of electrocardiograms (ECGs) is crucial to ensure early diagnosis and optimal treatment of patients with ST elevation myocardial infarction (STEMI). Recognition of ST-segment elevations (STE) by qualified personnel in the prehospital phase has successfully reduced the delay from the first medical contact to reperfusion. A few other ECG patterns without true STE, referred to as "STEMI equivalents", bear the same prognostic significance, reflect imminent or ongoing transmural ischemia, but are less easily identified. Hyperacute T waves, de Winter ST-T complex, Wellens' syndrome, and posterior STEMI, as well as myocardial infarction in the presence of left bundle branch block, paced rhythm or left ventricular hypertrophy, among others are diagnostic challenges. This article reviews some critical examples of ischemic ECG patterns that may be ephemeral, misinterpreted by medical staff or not identified by automated ECG algorithms, and it emphasizes the importance of serial ECG acquisition. PMID- 24792902 TI - [Proliferation of adult mammalian ventricular cardiomyocytes: a sporadic but feasible phenomenon]. AB - Proliferation of adult mammalian ventricular cardiomyocytes has been ruled out by some researchers, who have argued that these cells are terminally differentiated; however, this dogma has been rejected because other researchers have reported that these cells can present the processes necessary to proliferate, that is, DNA synthesis, mitosis and cytokinesis when the heart is damaged experimentally through pharmacological and surgical strategies or due to pathological conditions concerning the cardiovascular system. This review integrates some of the available works in the literature evaluating the DNA synthesis, mitosis and cytokinesis in these myocytes, when the myocardium is damaged, with the purpose of knowing if their proliferation can be considered as a feasible phenomenon. The review is concluded with a reflection about the perspectives of the knowledge generated in this area. PMID- 24792904 TI - Directionality and proportionality of the ST and ventricular gradient difference vectors during acute ischemia. AB - BACKGROUND: The ECG is important in diagnosis and triage in the initial phase of the acute coronary syndrome (ACS). The primary goal of making an ECG at first medical contact should be the reliable detection of cardiac ischemia, thus facilitating a correct triage by corroborating the diagnosis of ACS. Ischemia detection by ST amplitude analysis is limited to situations in which there is an identifiable J point. The ventricular gradient (VG) is independent of conduction and might be an alternative ECG-based variable for ischemia detection. METHODS: We studied vectorcardiograms (VCGs) synthesized of the ECGs of 67 patients who underwent elective PTCA with prolonged balloon occlusions (mean+/-SD occlusion duration 214+/-77s), and computed, during occlusions, the changes of the ST and VG vectors with respect to baseline, DeltaST and DeltaVG, and the angle between these vectors, ?(DeltaST, DeltaVG). We then analyzed directionality and proportionality of DeltaST and DeltaVG by performing linear regressions of ?(DeltaST, DeltaVG) on time after occlusion, and of DeltaVG on DeltaST, respectively. RESULTS: Linear regression of ?(DeltaST, DeltaVG) on time after occlusion yielded a slope of 1.55*10(-3) degrees /s and an intercept of 11.96 degrees ; r(2)<0.001 (NS). Linear regression of DeltaVG on DeltaST on all data yielded a slope of 253mV and an intercept of 14.4mV*ms; r(2)=0.75 (P<0.001). Broken stick linear regression (breakpoint DeltaST=0.255mV) yielded slopes of 330mV and 160mV, intercepts of 5.6mV*ms and 47.2mV*ms, and r(2) values of 0.66 (P<0.001) and 0.63 (P<0.001) for the smaller and larger DeltaST values, respectively. CONCLUSION: Our study suggests that, because of the directionality and proportionality between DeltaST and DeltaVG, the change in the ventricular gradient, DeltaVG, between a reference ECG and an ischemic ECG is a meaningful measure of ischemia. PMID- 24792905 TI - Clinical use of the combined Sclarovsky Birnbaum Severity and Anderson Wilkins Acuteness scores from the pre-hospital ECG in ST-segment elevation myocardial infarction. AB - This review summarizes the electrocardiographic changes during an evolving ST segment elevation myocardial infarction and discusses associated electrocardiographic scores and the potential use of these indices in clinical practice, in particular the ECG scores developed by Anderson and Wilkins estimating the acuteness of myocardial ischemia and Sclarovsky-Birnbaum's grades of ischemia evaluating the severity of ongoing ischemia. PMID- 24792906 TI - Amyloid-beta alters ongoing neuronal activity and excitability in the frontal cortex. AB - The effects of amyloid-beta on the activity and excitability of individual neurons in the early and advanced stages of the pathological progression of Alzheimer's disease remain unknown. We used in vivo intracellular recordings to measure the ongoing and evoked activity of pyramidal neurons in the frontal cortex of APPswe/PS1dE9 transgenic mice and age-matched nontransgenic littermate controls. Evoked excitability was altered in both transgenic groups: neurons in young transgenic mice displayed hypoexcitability, whereas those in older transgenic mice displayed hyperexcitability, suggesting changes in intrinsic electrical properties of the neurons. However, the ongoing activity of neurons in both young and old transgenic groups showed signs of hyperexcitability in the depolarized state of the membrane potential. The membrane potential of neurons in old transgenic mice had an increased tendency to fail to transition to the depolarized state, and the depolarized states had shorter durations on average than did controls. This suggests a combination of both intrinsic electrical and synaptic dysfunctions as mechanisms for activity changes at later stages of the neuropathological progression. PMID- 24792907 TI - Calcium regulates the interaction of amyloid precursor protein with Homer3 protein. AB - Ca(2+) dysregulation is an important factor implicated in Alzheimer's disease pathogenesis. The mechanisms mediating the reciprocal regulation of Ca(2+) homeostasis and amyloid precursor protein (APP) metabolism, function, and protein interactions are not well known. We have previously shown that APP interacts with Homer proteins, which inhibit APP processing toward amyloid-beta. In this study, we investigated the effect of Ca(2+) homeostasis alterations on APP/Homer3 interaction. Influx of extracellular Ca(2+) upon treatment of HEK293 cells with the ionophore A23187 or addition of extracellular Ca(2+) in cells starved of calcium specifically reduced APP/Homer3 but not APP/X11a interaction. Endoplasmic reticulum Ca(2+) store depletion by thapsigargin followed by store-operated calcium entry also decreased the interaction. Interestingly, application of a phospholipase C stimulator, which causes inositol 1,4,5-trisphosphate-induced endoplasmic reticulum Ca(2+) release, caused dissociation of APP/Homer3 complex. In human neuroblastoma cells, membrane depolarization also disrupted the interaction. This is the first study showing that changes in Ca(2+) homeostasis affect APP protein interactions. Our results suggest that Ca(2+) and Homers play a significant role in the development of Alzheimer's disease pathology. PMID- 24792908 TI - Cerebellar direct current stimulation enhances motor learning in older adults. AB - Developing novel approaches to combat age related declines in motor function is key to maintaining health and function in older adults, a subgroup of the population that is rapidly growing. Motor adaptation, a form of motor learning, has been shown to be impaired in healthy older subjects compared with their younger counterparts. Here, we tested whether excitatory anodal transcranial direct current stimulation (tDCS) over the cerebellum could enhance adaptation in older subjects. Participants performed a "center-out" reaching task, adapting to the sudden introduction of a visual cursor rotation. Older participants receiving sham tDCS (mean age 56.3 +/- 6.8 years) were slower to adapt than younger participants (mean age 20.7 +/- 2.1 years). In contrast, older participants who received anodal tDCS (mean age 59.6 +/- 8.1 years) adapted faster, with a rate that was similar to younger subjects. We conclude that cerebellar anodal tDCS enhances motor adaptation in older individuals. Our results highlight the efficacy of the novel approach of using cerebellar tDCS to combat age related deficits in motor learning. PMID- 24792909 TI - Redefining the dry molten globule state of proteins. AB - Dynamics and function of proteins are governed by the structural and energetic properties of the different states they adopt and the barriers separating them. In earlier work, native-state triplet-triplet energy transfer (TTET) on the villin headpiece subdomain (HP35) revealed an equilibrium between a locked native state and an unlocked native state, which are structurally similar but have different dynamic properties. The locked state is restricted to low amplitude motions, whereas the unlocked state shows increased conformational flexibility and undergoes local unfolding reactions. This classified the unlocked state as a dry molten globule (DMG), which was proposed to represent an expanded native state with loosened side-chain interactions and a solvent-shielded core. To test whether the unlocked state of HP35 is actually expanded compared to the locked state, we performed high-pressure TTET measurements. Increasing pressure shifts the equilibrium from the locked toward the unlocked state, with a small negative reaction volume for unlocking (DeltaV(0)=-1.6+/-0.5cm(3)/mol). Therefore, rather than being expanded, the unlocked state represents an alternatively packed, compact state, demonstrating that native proteins can exist in several compact folded states, an observation with implications for protein function. The transition state for unlocking/locking, in contrast, has a largely increased volume relative to the locked and unlocked state, with respective activation volumes of 7.1+/-0.4cm(3)/mol and 8.7+/-0.9cm(3)/mol, indicating an expansion of the protein during the locking/unlocking transition. The presented results demonstrate the existence of both compact, low-energy and expanded, high-energy DMGs, prompting a broader definition of this state. PMID- 24792910 TI - Oral infection drives a distinct population of intestinal resident memory CD8(+) T cells with enhanced protective function. AB - The intestinal mucosa promotes T cell responses that might be beneficial for effective mucosal vaccines. However, intestinal resident memory T (Trm) cell formation and function are poorly understood. We found that oral infection with Listeria monocytogenes induced a robust intestinal CD8 T cell response and blocking effector T cell migration showed that intestinal Trm cells were critical for secondary protection. Intestinal effector CD8 T cells were predominately composed of memory precursor effector cells (MPECs) that rapidly upregulated CD103, which was needed for T cell accumulation in the intestinal epithelium. CD103 expression, rapid MPEC formation, and maintenance in intestinal tissues were dependent on T cell intrinsic transforming growth factor beta signals. Moreover, intestinal Trm cells generated after intranasal or intravenous infection were less robust and phenotypically distinct from Trm cells generated after oral infection, demonstrating the critical contribution of infection route for directing the generation of protective intestinal Trm cells. PMID- 24792911 TI - Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4(+) T cell responses. AB - Antigen specificity is critical in immune response and requires integration of antigen-specific signals with antigen-nonspecific signals such as those provided by cytokines. The mechanism integrating these pathways is incompletely understood. We report here that antigen-specific proliferative responses of CD4(+) T cells required downmodulation of tumor suppressor p53. In the absence of T cell receptor (TCR) signal, IL-2 induced sustained increase in p53 protein, which prevented proliferative responses despite strong signaling through the IL-2 receptor. In contrast, TCR signaling resulted in early termination of p53 protein expression by decreasing p53 mRNA as well as strong transcriptional induction of the p53-regulating protein Mdm2. Downmodulation of p53 in response to antigen stimulation was in fact critical for antigen-specific T cell proliferation, and preventing p53 degradation by inhibiting Mdm2 resulted in sustained p53 protein and prevented antigen-specific T cell proliferation. It is thus termination of p53 by TCR signaling that allows proliferative responses, enforcing antigen specificity. PMID- 24792912 TI - Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. AB - Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/ )Il10rb(-/-) mice. Similar alterations in the generation and function of anti inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans. PMID- 24792913 TI - Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. AB - Interleukin-10 (IL-10) is a pleiotropic anti-inflammatory cytokine produced and sensed by most hematopoietic cells. Genome-wide association studies and experimental animal models point at a central role of the IL-10 axis in inflammatory bowel diseases. Here we investigated the importance of intestinal macrophage production of IL-10 and their IL-10 exposure, as well as the existence of an IL-10-based autocrine regulatory loop in the gut. Specifically, we generated mice harboring IL-10 or IL-10 receptor (IL-10Ralpha) mutations in intestinal lamina propria-resident chemokine receptor CX3CR1-expressing macrophages. We found macrophage-derived IL-10 dispensable for gut homeostasis and maintenance of colonic T regulatory cells. In contrast, loss of IL-10 receptor expression impaired the critical conditioning of these monocyte-derived macrophages and resulted in spontaneous development of severe colitis. Collectively, our results highlight IL-10 as a critical homeostatic macrophage conditioning agent in the colon and define intestinal CX3CR1(hi) macrophages as a decisive factor that determines gut health or inflammation. PMID- 24792916 TI - Masterclass editorial: a review of Masterclasses. PMID- 24792915 TI - [Liponeurocytoma in the left lateral ventricle. Presentation of the first case reported in Spain and literature review]. AB - Supratentorial liponeurocytoma is a rare tumor, predominantly appearing in young males. It most commonly affects the lateral ventricles, with involvement of the third ventricle being exceptional. It is defined as a low-grade neuroglial tumor, with areas of associated lipomatosis. The most common clinical manifestation is that resulting from the presence of secondary intracranial hypertension and hydrocephalus. We present the first case reported in Spain of this tumor type and one of the few appearing in the literature so far. We report the case of a 33 year-old male patient, suffering from crural sensitive symptoms and recent onset headache. The radiographic study revealed the presence of a large supratentorial tumor; intraventricular, multicystic, heterogeneous and with areas of associated lipomatosis. The patient underwent surgery and complete tumor resection was achieved. The definitive diagnosis was of supratentorial liponeurocytoma. The presence of a supratentorial intraventricular tumor with areas of fatty degeneration should lead us to consider this type of tumor in the differential diagnosis. Complete tumor resection is considered to be the treatment of choice. PMID- 24792914 TI - Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. AB - Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway. PMID- 24792917 TI - An evidence based strategy for normalization of quantitative PCR data from miRNA expression analysis in forensically relevant body fluids. AB - Micro-RNA (miRNA) based analysis of body fluids and composition of complex crime stains has recently been introduced as a potential and powerful tool to forensic genetics. Analysis of miRNA has several advantages over mRNA but reliable miRNA detection and quantification using quantitative PCR requires a solid and forensically relevant normalization strategy. In our study we evaluated a panel of 13 carefully selected reference genes for their suitability as endogenous controls in miRNA qPCR normalization in forensically relevant settings. We analyzed assay performances and variances in venous blood, saliva, semen, menstrual blood, and vaginal secretion and mixtures thereof integrating highly standardized protocols with contemporary methodologies and included several well established computational algorithms. Based on these empirical results, we recommend normalization to the group of SNORD24, SNORD38B, and SNORD43 as this signature exhibits the most stable expression levels and the least expected variation among the evaluated candidate reference genes in the given set of forensically relevant body fluids. To account for the lack of consensus on how best to perform and interpret quantitative PCR experiments, our study's documentation is compliant to MIQE guidelines, defining the "minimum information for publication of quantitative real-time PCR experiments". PMID- 24792918 TI - Integrating genomic, transcriptomic, and interactome data to improve Peptide and protein identification in shotgun proteomics. AB - Mass spectrometry (MS)-based shotgun proteomics is an effective technology for global proteome profiling. The ultimate goal is to assign tandem MS spectra to peptides and subsequently infer proteins and their abundance. In addition to database searching and protein assembly algorithms, computational approaches have been developed to integrate genomic, transcriptomic, and interactome information to improve peptide and protein identification. Earlier efforts focus primarily on making databases more comprehensive using publicly available genomic and transcriptomic data. More recently, with the increasing affordability of the Next Generation Sequencing (NGS) technologies, personalized protein databases derived from sample-specific genomic and transcriptomic data have emerged as an attractive strategy. In addition, incorporating interactome data not only improves protein identification but also puts identified proteins into their functional context and thus facilitates data interpretation. In this paper, we survey the major integrative bioinformatics approaches that have been developed during the past decade and discuss their merits and demerits. PMID- 24792919 TI - Hemin inhibits the large conductance potassium channel in brain mitochondria: a putative novel mechanism of neurodegeneration. AB - Intracerebral hemorrhage (ICH) is a pathological condition that accompanies certain neurological diseases like hemorrhagic stroke or brain trauma. Its effects are severely destructive to the brain and can be fatal. There is an entire spectrum of harmful factors which are associated with the pathogenesis of ICH. One of them is a massive release of hemin from the decomposed erythrocytes. It has been previously shown, that hemin can inhibit the large-conductance Ca(2+) regulated potassium channel in the plasma membrane. However, it remained unclear whether this phenomenon applies also to the mitochondrial large-conductance Ca(2+)-regulated potassium channel. The aim of the present study was to determine the impact of hemin on the activity of the large conductance Ca(2+)-regulated potassium channel in the brain mitochondria (mitoBKCa). In order to do so, we have used a patch-clamp technique and shown that hemin inhibits mitoBKCa in human astrocytoma U-87 MG cell line mitochondria. Since opening of the mitochondrial potassium channels is known to be cytoprotective, we have elucidated whether hemin can attenuate some of the beneficiary effects of potassium channel opening. We have studied the effect of hemin on reactive oxygen species synthesis, and mild mitochondrial uncoupling in isolated rat brain mitochondria. Taken together, our data show that hemin inhibits mitoBKCa and partially abolishes some of the cytoprotective properties of potassium channel opening. Considering the role of the mitoBKCa in cytoprotection, it can be presumed that its inhibition by hemin may be a novel mechanism contributing to the severity of the ICH symptoms. However, the validity of the presented results shall be further verified in an experimental model of ICH. PMID- 24792920 TI - Roles of the periaqueductal gray in descending facilitatory and inhibitory controls of intramuscular hypertonic saline induced muscle nociception. AB - Despite the importance of the periaqueductal gray (PAG) in the modulation of nociception and pain, many aspects of the roles of the different columns of the PAG in descending controls: facilitation and inhibition, are not understood. Employing a tonic muscle pain model established by i.m. injection of 5.8% saline into the gastrocnemius muscle, we now report the results of investigations designed to explore any differences in Fos expression in the different functional columns of the PAG in male Sprague-Dawley rats. In a second series of experiments, effects of the PAG on descending control of spinally-organized nociception were assessed by measuring hind paw withdrawal reflexes to noxious mechanical and heat stimulation before and after electrolytic lesion of specific columns of the PAG. Our results show that Fos expression within different columns of the PAG increases significantly and differentially following i.m. injection of 5.8% saline. The mean number of Fos positive neurons in the dorsolateral (dl), lateral (l), dorsomedial (dm) PAG elicited by i.m. injection of 5.8% saline reached a peak at 4h with a gradual decrease over time, whereas the maximum number of Fos-positive neurons in the ventrolateral (vl) PAG was observed 8h after i.m. injection. Contralateral lesion of the dl PAG significantly depressed ipsilateral secondary mechanical hyperalgesia in intramuscularly induced (5.8% saline) nociception (P<0.05), whereas heat hypoalgesia was not affected (P>0.05). By contrast, contralateral lesion of the vl PAG completely blocked the occurrence of ipsilateral heat hypoalgesia (P<0.05), while bilateral mechanical hyperalgesia was unaffected (P>0.05). In conclusion, functions of specific columns of the PAG in the control of spinal nociceptive activities are not homogeneous. It is suggested that, in this muscle pain model, the dl PAG and vl PAG participate in descending facilitation and inhibition of nociception, respectively. PMID- 24792921 TI - Effect of vitamin C on endothelial function in health and disease: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Observational studies indicate that higher vitamin C intake is associated with reduced risk for cardiovascular diseases. However, randomised controlled trials (RCT) examining the effect of vitamin C on endothelial function (EF) have reported inconsistent results. The aims of this systematic review and meta-analysis were to determine the effect of vitamin C supplementation on EF and to investigate whether the effect was influenced by health status, study duration, dose and route of vitamin C administration. METHODS: We searched the Medline, Embase, Cochrane Library, and Scopus databases from inception to May 2013 for studies that met the following criteria: 1) RCT with adult participants, 2) vitamin C administered alone, 3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography and pulse wave analysis. RESULTS: Pooling the data from 44 clinical trials showed a significant positive effect of vitamin C on EF (SMD: 0.50, 95% CI: 0.34, 0.66, P < 0.001). Stratification of the analysis by health outcome revealed improved EF in atherosclerotic (SMD: 0.84, 95% CI: 0.41, 1.26, P < 0.001), diabetic (SMD: 0.52, 95% CI: 0.21, 0.82, P < 0.001) and heart failure patients (SMD: 0.48, 95% CI: 0.08, 0.88, P < 0.02) after vitamin C supplementation. The effect size appeared to be unaffected by study design, duration, baseline plasma vitamin C concentration or route of administration of vitamin C. The meta-regression showed a significant positive association between vitamin C dose and improvement in EF (beta: 0.00011, 95% CI: 0.00001, 0.00021, P = 0.03). CONCLUSIONS: Vitamin C supplementation improved EF. The effect of vitamin C supplementation appeared to be dependent on health status, with stronger effects in those at higher cardiovascular disease risk. PROSPERO Database registration: CRD42013004567, http://www.crd.york.ac.uk/prospero/ PMID- 24792922 TI - Cardiovascular disease mortality among retired workers chronically exposed to intense occupational noise. AB - OBJECTIVE: The aim of this study, conducted among retired workers (>=65 years), is to estimate the association between long-term risk of cardiovascular disease (CVD) death and (1) duration of occupational noise exposure in career and (2) noise-induced hearing loss (NIHL), the latter being used as an indicator of adverse effects for long-term exposure to occupational noise. METHODS: Data from screening activities of occupational NIHL were paired to data from death records and were used for this study. A nested case-control analysis was performed. Each case was matched with three controls for length of follow-up and economic sector. A total of 161 CVD deaths occured during an average follow-up of 6.8 years. Conditional logistic regression models were used to estimate the risk (OR) of CVD death by tertiles of duration of noise exposure and of NIHL. RESULTS: Conditional logistic regression models indicated that prolonged duration of noise exposure (>=36.5 years) (3rd tertile) was associated with an increased risk of CVD death (OR 1.70; 95 % CI 1.10-2.62), as compared with shorter duration (<27 years) (first tertile). Moderate NIHL (2nd tertile) (OR 1.64; 95 % CI 1.04-2.6) and severe NIHL (3rd tertile) (OR 1.66; 95 % CI 1.06-2.60) were also associated with an increase in risk of CVD death. CONCLUSIONS: Results are consistent with recent findings on the chronic effects of occupational noise exposure persisting after retirement although it is less than during active working life. PMID- 24792923 TI - Monteggia fracture dislocations: a historical review. AB - The eponym Monteggia fracture dislocation originally referred to a fracture of the shaft of the ulna accompanied by anterior dislocation of the radial head that was described by Giovanni Battista Monteggia of Italy in 1814. Subsequently, a further classification system based on the direction of the radial head dislocation and associated fractures of the radius and ulna was proposed by Jose Luis Bado of Uruguay in 1958. This article investigates the evolution of treatment, classification, and outcomes of the Monteggia injury and sheds light on the lives and contributions of Monteggia and Bado. PMID- 24792924 TI - Phenolic content and antioxidant and antimutagenic activities in tomato peel, seeds, and byproducts. AB - The phenolic content and antioxidant and antimutagenic activities from the peel and seeds of different tomato types (grape, cherry, bola and saladette type), and simulated tomato industrial byproducts, were studied. Methanolic extracts were used to quantify total phenolic content, groups of phenolic compounds, antioxidant activities, and the profile of phenolic compounds (by HPLC-DAD). Antimutagenic activity was determined by Salmonella typhimurium assay. The total phenolic content and antioxidant activity of tomato and tomato byproducts were comparable or superior to those previously reported for whole fruit and tomato pomace. Phenolic compounds with important biological activities, such as caffeic acid, ferulic acid, chlorogenic acids, quercetin-3-beta-O-glycoside, and quercetin, were quantified. Differences in all phenolic determinations due to tomato type and part of the fruit analyzed were observed, peel from grape type showing the best results. Positive antimutagenic results were observed in all samples. All evaluated materials could be used as a source of potential nutraceutical compounds. PMID- 24792925 TI - A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression. AB - It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3'UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation. PMID- 24792926 TI - A real-time high-throughput fluorescence assay for sphingosine kinases. AB - Sphingosine kinases (SphKs), of which there are two isoforms, SphK1 and SphK2, have been implicated in regulation of many important cellular processes. We have developed an assay for monitoring SphK1 and SphK2 activity in real time without the need for organic partitioning of products, radioactive materials, or specialized equipment. The assay conveniently follows SphK-dependent changes in 7 nitro-2-1,3-benzoxadiazol-4-yl (NBD)-labeled sphingosine (Sph) fluorescence and can be easily performed in 384-well plate format with small reaction volumes. We present data showing dose-proportional responses to enzyme, substrate, and inhibitor concentrations. The SphK1 and SphK2 binding affinities for NBD-Sph and the IC50 values of inhibitors determined were consistent with those reported with other methods. Because of the versatility and simplicity of the assay, it should facilitate the routine characterization of inhibitors and SphK mutants and can be readily used for compound library screening in high-throughput format. PMID- 24792927 TI - Highly automated nano-LC/MS-based approach for thousand cell-scale quantification of side chain-hydroxylated oxysterols. AB - Iso-octyl chain-hydroxylated oxysterols were determined in attomoles per 10,000 cells concentrations in 10,000-80,000 cultured pancreatic adenocarcinoma cells, using a sensitive, highly automated nano-LC-ESI-MS-based method. Identified oxysterols included 24S hydroxycholesterol (24S-OHC), 25 hydroxycholesterol (25 OHC), and 27 hydroxycholesterol (27-OHC), while 20S hydroxycholesterol and 22S hydroxycholesterol were not detected. Lower mass limit of quantification was 23 fg (65 amol) for 25-OHC and 27-OHC (100 times lower than our previous method) and 54 fg (135 amol) for 24S-OHC, after derivatization into Girard T hydrazones and online sample cleanup using simplified and robust automatic filtration and filter back flushing solid phase extraction LC/MS/MS. The instrument configuration was easily installed using a commercial nano-LC/MS system. Recoveries in spiked sample were 96, 97, and 77% for 24S-OHC, 25-OHC, and 27-OHC, with within- and between-day repeatabilities of 1-21% and 2-20% relative SD, respectively. The study demonstrates the potential of nano-LC in lipidomics/sterolomics. PMID- 24792930 TI - Polymer-encapsulated organic nanoparticles for fluorescence and photoacoustic imaging. AB - Polymer encapsulated organic nanoparticles have recently attracted increasing attention in the biomedical field because of their unique optical properties, easy fabrication and outstanding performance as imaging and therapeutic agents. Of particular importance is the polymer encapsulated nanoparticles containing conjugated polymers (CP) or fluorogens with aggregation induced emission (AIE) characteristics as the core, which have shown significant advantages in terms of tunable brightness, superb photo- and physical stability, good biocompatibility, potential biodegradability and facile surface functionalization. In this review, we summarize the latest advances in the development of polymer encapsulated CP and AIE fluorogen nanoparticles, including preparation methods, material design and matrix selection, nanoparticle fabrication and surface functionalization for fluorescence and photoacoustic imaging. We also discuss their specific applications in cell labeling, targeted in vitro and in vivo imaging, blood vessel imaging, cell tracing, inflammation monitoring and molecular imaging. We specially focus on strategies to fine-tune the nanoparticle property (e.g. size and fluorescence quantum yield) through precise engineering of the organic cores and careful selection of polymer matrices. The review also highlights the merits and limitations of these nanoparticles as well as strategies used to overcome the limitations. The challenges and perspectives for the future development of polymer encapsulated organic nanoparticles are also discussed. PMID- 24792929 TI - Diversification of substrate specificities in teleostei Fads2: characterization of Delta4 and Delta6Delta5 desaturases of Chirostoma estor. AB - Currently existing data show that the capability for long-chain PUFA (LC-PUFA) biosynthesis in teleost fish is more diverse than in other vertebrates. Such diversity has been primarily linked to the subfunctionalization that teleostei fatty acyl desaturase (Fads)2 desaturases have undergone during evolution. We previously showed that Chirostoma estor, one of the few representatives of freshwater atherinopsids, had the ability for LC-PUFA biosynthesis from C18 PUFA precursors, in agreement with this species having unusually high contents of DHA. The particular ancestry and pattern of LC-PUFA biosynthesis activity of C. estor make this species an excellent model for study to gain further insight into LC PUFA biosynthetic abilities among teleosts. The present study aimed to characterize cDNA sequences encoding fatty acyl elongases and desaturases, key genes involved in the LC-PUFA biosynthesis. Results show that C. estor expresses an elongase of very long-chain FA (Elovl)5 elongase and two Fads2 desaturases displaying Delta4 and Delta6/Delta5 specificities, thus allowing us to conclude that these three genes cover all the enzymatic abilities required for LC-PUFA biosynthesis from C18 PUFA. In addition, the specificities of the C. estor Fads2 enabled us to propose potential evolutionary patterns and mechanisms for subfunctionalization of Fads2 among fish lineages. PMID- 24792928 TI - PKCdelta-IRAK1 axis regulates oxidized LDL-induced IL-1beta production in monocytes. AB - This study examined the role of interleukin (IL)-1 receptor-associated kinase (IRAK) and protein kinase C (PKC) in oxidized LDL (Ox-LDL)-induced monocyte IL 1beta production. In THP1 cells, Ox-LDL induced time-dependent secretory IL-1beta and IRAK1 activity; IRAK4, IRAK3, and CD36 protein expression; PKCdelta-JNK1 phosphorylation; and AP-1 activation. IRAK1/4 siRNA and inhibitor (INH) attenuated Ox-LDL induced secreted IL-1beta and pro-IL-1beta mRNA and pro-IL 1beta and mature IL-1beta protein expression, respectively. Diphenyleneiodonium chloride (NADPH oxidase INH) and N-acetylcysteine (free radical scavenger) attenuated Ox-LDL-induced reactive oxygen species generation, caspase-1 activity, and pro-IL-1beta and mature IL-1beta expression. Ox-LDL-induced secretory IL 1beta production was abrogated in the presence of JNK INH II, Tanshinone IIa, Ro 31-8220, Go6976, Rottlerin, and PKCdelta siRNA. PKCdelta siRNA attenuated the Ox LDL-induced increase in IRAK1 kinase activity, JNK1 phosphorylation, and AP-1 activation. In THP1 macrophages, CD36, toll-like receptor (TLR)2, TLR4, TLR6, and PKCdelta siRNA prevented Ox-LDL-induced PKCdelta and IRAK1 activation and IL 1beta production. Enhanced Ox-LDL and IL-1beta in systemic inflammatory response syndrome (SIRS) patient plasma demonstrated positive correlation with each other and with disease severity scores. Ox-LDL-containing plasma induced PKCdelta and IRAK1 phosphorylation and IL-1beta production in a CD36-, TLR2-, TLR4-, and TLR6 dependent manner in primary human monocytes. Results suggest involvement of CD36, TLR2, TLR4, TLR6, and the PKCdelta-IRAK1-JNK1-AP-1 axis in Ox-LDL-induced IL 1beta production. PMID- 24792931 TI - Direct-to-Consumer Advertising: Implications for the Pharmacist and Other Health Professionals. AB - Direct-to-consumer advertising of prescription-only medications is big business for pharmaceutical manufacturers and has altered the relationship between patients and health professionals. Seeing promotional messages from the manufacturer of a pharmaceutical can have both positive and negative impacts. These are discussed along with current efforts to control activities in this area as well as possible future developments. PMID- 24792932 TI - Motivations and barriers to implementing electronic health records and ED information systems in Japan. AB - BACKGROUND: Although electronic health record systems (EHRs) and emergency department information systems (EDISs) enable safe, efficient, and high-quality care, these systems have not yet been studied well. Here, we assessed (1) the prevalence of EHRs and EDISs, (2) changes in efficiency in emergency medical practices after introducing EHR and EDIS, and (3) barriers to and expectations from the EHR-EDIS transition in EDs of medical facilities with EHRs in Japan. MATERIALS AND METHODS: A survey regarding EHR (basic or comprehensive) and EDIS implementation was mailed to 466 hospitals. We examined the efficiency after EHR implementation and perceived barriers and expectations regarding the use of EDIS with existing EHRs. The survey was completed anonymously. RESULTS: Totally, 215 hospitals completed the survey (response rate, 46.1%), of which, 76.3% had basic EHRs, 4.2% had comprehensive EHRs, and 1.9% had EDISs. After introducing EHRs and EDISs, a reduction in the time required to access previous patient information and share patient information was noted, but no change was observed in the time required to produce medical records and the overall time for each medical care. For hospitals with EHRs, the most commonly cited barriers to EDIS implementation were inadequate funding for adoption and maintenance and potential adverse effects on workflow. The most desired function in the EHR-EDIS transition was establishing appropriate clinical guidelines for residents within their system. CONCLUSION: To attract EDs to EDIS from EHR, systems focusing on decreasing the time required to produce medical records and establishing appropriate clinical guidelines for residents are required. PMID- 24792933 TI - The quickest and easiest endotracheal intubation device in difficult airway for emergency residents: video laryngoscope, the easiest laryngoscope for emergency residents. PMID- 24792934 TI - Tuberculous sternal osteomyelitis. AB - A 32-year-old female patient with systemic lupus erythematosus presented with 1 month of nocturnal subjective fevers, night sweats, poor appetite, malaise, 8-kg weight loss, and a 6-cm painful sternal mass. She had normal vital signs with a physical examination notable only for the presence of a fluctuating sternal mass. A computed tomographic scan of the thorax showed a 67 * 32 * 27-mm sternal mass associated with severe sternal osteomyelitis (Fig. 1); then a surgical drainage was performed, and abundant caseous material was removed, leaving a penrose drain (Fig. 2). Histologic examination of the bone tissue revealed extensive necrosis and granulomas with multinucleated giant cells. The bone, secretion, and soft tissue were negative for acid-fast bacillae on Ziehl-Neelsen stain; but culture grew Mycobacterioum tuberculosis, and she was started on 4 first-line antituberculosis medications, showing rapid symptomatic improvement, and was discharged 4 weeks after admission (Fig. 3). PMID- 24792935 TI - Hamate body and capitate fracture in punch injury. AB - Hamate fractures represent only 2% to 4% of all carpal bone fractures because they require a large degree of force to the hand or wrist. This is a case report of a patient with hamate and capitate fractures after a punch injury. It details the minute change seen in routine 3-view radiographic imagery and indications for computed tomography. A 29-year-old African American man with professional boxing training presented to the emergency department with pain and swelling in the hand and wrist after striking a refrigerator with his right hand. Enough force generated along the axial plane of the fourth and fifth metacarpals either from punching or from falling with a clenched fist is capable of fracturing both the hamate and capitate bones. Three-view radiographs may not visualize the fracture, so computed tomography should be ordered to better visualize any pathology. The risks to not detecting a hamate body fracture are nonunion of the bone, posttraumatic arthritis, decreased grip strength, and decreased range of motion of the hand. Because of rarity, there is no criterion standard therapy, but the general approach is open reduction and internal fixation using Kirschner wires and wrist immobilization for a minimum of 8 weeks. A high degree of clinical suspicion on examination is required for the proper approach to confirm a hamate fracture. PMID- 24792936 TI - Ileocolic intussusception secondary to gastrointestinal stromal tumor in a 61 year-old. AB - Intussusception is a common emergency in patients age of 3 months to 5 years. In adults, the diagnosis is infrequent but must be considered in the clinical setting of abdominal pain and vomiting. We present a case of a 61-year-old woman presenting with epigastric abdominal pain and vomiting, diagnosed with intussusception secondary to gastrointestinal stromal tumor. Serial bedside ultrasound examinations uncovered the diagnosis of intussusception, confirmed by computed tomographic scan during a paroxysm of pain. Intussusception has a much higher predilection for neoplasms in adults, with a high morbidity and mortality, so early recognition is critical in improving patient outcomes. PMID- 24792937 TI - Antibiotic prophylaxis for ED patients with simple hand lacerations: a feasibility randomized controlled trial. AB - BACKGROUND: The benefit of antibiotic prophylaxis for simple hand lacerations (lacerations that do not involve special structures) has not been adequately studied. OBJECTIVE: To assess the feasibility of a randomized controlled trial to determine the role of antibiotic prophylaxis in emergency department (ED) patients with simple hand lacerations. METHODS: Randomized, double-blind, placebo controlled pilot trial in 2 urban academic EDs. Adult (>=18 years old) patients with simple hand lacerations were randomized to cephalexin, 500 mg; clindamycin, 300 mg; or placebo (every 6 hours for 7 days, all in identical capsules). OUTCOMES: (1) feasibility determined by the number of patients who agreed to enroll and number of patients who completed follow-up, (2) infection rate (determined by 2 physicians at 10-14 days), (3) satisfaction with wound appearance (measured by a visual analogue scale at 30 days via phone). Medians, quartiles, and percentages with 95% confidence intervals (CI) were used to present data. Groups were compared with Kruskal-Wallis and Fisher exact tests, when appropriate. RESULTS: Over a 5-month period, 123 patients were approached, and 78 consented to enrollment (63%; 95% CI, 55-71%). Five were lost to follow-up (5/78, 6%; 95% CI, 2%-14%). Only one patient had infection on follow-up for an infection rate of 1% (95% CI, 0.01%-8%). Patient's satisfaction with wound appearance did not differ among the groups. CONCLUSION: The findings of this pilot study support the feasibility of a randomized, double-blind, controlled trial. The low rate of infection suggests the need of a large sample size for the trial. PMID- 24792938 TI - Streamlined focused assessment with sonography for mass casualty prehospital triage of blunt torso trauma patients. PMID- 24792939 TI - Lead aVL on electrocardiogram: emerging as important lead in early diagnosis of myocardial infarction? AB - Although a diagnosis of acute myocardial infarction (AMI) that mandates emergency reperfusion therapy requires ST-segment elevation greater than 1 mm in at least 2 contiguous leads, some of the early electrocardiogram (ECG) changes of AMI can be subtle. Any ST-segment depression or T-wave inversion in lead aVL may be implicated in left anterior descending artery lesion or early reciprocal changes of inferior wall myocardial infarction, particularly when the clinical context suggests ischemia. Early recognition of reciprocal changes and serial ECG help initiate early appropriate intervention. Heightened awareness of ST segment and T wave changes in lead aVL is of paramount importance to quickly identifying life threatening condition. PMID- 24792941 TI - Osteoarthritis: moving from evidence to practice. Preface. PMID- 24792942 TI - The epidemiology of osteoarthritis. AB - Osteoarthritis (OA) is a leading cause of disability and its incidence is rising due to increasing obesity and an ageing population. Risk factors can be divided into person-level factors, such as age, sex, obesity, genetics, race/ethnicity and diet, and joint-level factors including injury, malalignment and abnormal loading of the joints. The interaction of these risk factors is complex and provides a challenge to the managing physician. The purpose of this review is to illustrate how each of these factors interact together to instigate incident OA as well as to outline the need for ongoing epidemiologic studies for the future prevention of both incident and progressive OA. It is only by understanding the impact of this disease and the modifiable risk factors that we will be able to truly target public health prevention interventions appropriately. PMID- 24792943 TI - Pathogenesis of post-traumatic OA with a view to intervention. AB - Post-traumatic osteoarthritis (PTOA) subsequent to joint injury accounts for over 12% of the overall disease burden of OA, and higher in the most at-risk ankle and knee joints. Evidence suggests that the pathogenesis of PTOA may be related to inflammatory processes and alterations to the articular cartilage, menisci, muscle and subchondral bone that are initiated in the acute post-injury phase. Imaging of these early changes, as well as a number of biochemical markers, demonstrates the potential for use as predictors of future disease, and may help stratify patients on the likelihood of their developing clinical disease. This will be important in guiding future interventions, which will likely target elements of the inflammatory response within the joint, molecular abnormalities related to cartilage matrix degradation, chondrocyte function and subchondral bone remodelling. Until significant improvements are made, however, in identifying patients most at risk for developing PTOA--and therefore those who are candidates for therapy--primary prevention programmes will remain the most effective current management tools. PMID- 24792944 TI - The role of imaging in osteoarthritis. AB - Osteoarthritis (OA) is the most prevalent joint disorder with no approved disease modifying treatment available. The importance of imaging in assessing all joint structures involved in the disease process, including articular cartilage, meniscus, subarticular bone marrow, and synovium for diagnosis, prognostication, and follow-up, has been well recognized. In daily clinical practice, conventional radiography is still the most commonly used imaging technique for the evaluation of a patient with known or suspected OA and radiographic outcome measures are still the only approved end point by regulatory authorities in clinical trials. The ability of magnetic resonance imaging (MRI) to visualize all joint structures in three-dimensional fashion including tissue ultrastructure has markedly deepened our understanding of the natural history of the disease. This article describes the roles and limitations of different imaging modalities for clinical practice and research in OA, with a focus on radiography and MRI and an emphasis on the knee joint. PMID- 24792945 TI - Biomarkers for osteoarthritis: current position and steps towards further validation. AB - Historically disease knowledge development and treatment innovation in osteoarthritis (OA) has been considered to be slow. One of the many reasons purported as responsible for this slow pace has been the alleged lack of valid and responsive biomarkers to ascertain efficacy, which itself has been dependent upon the slow evolution of the understanding of the complex nature of joint tissue biology. This narrative review outlines the rationale for why we need OA biomarkers with regard to biomarker validation and qualification. The main biomarkers in current development for OA are biochemical and imaging markers. We describe an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation of NIH OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI). With this approach we endeavor to identify, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics for osteoarthritis. PMID- 24792946 TI - Patellofemoral joint osteoarthritis: an individualised pathomechanical approach to management. AB - Patellofemoral joint integrity is maintained by an optimal interaction of passive, dynamic and structural restraints. Disruption of these mechanics can lead to structural joint damage and subsequent patellofemoral osteoarthritis, which is a prevalent and disabling condition with few effective conservative management strategies. Due to the influential role of biomechanics in this disease, targeting the specific pathomechanics exhibited by an individual is logical to improve their likelihood of a positive treatment outcome. This review summarises the effect of different pathomechanical factors on the presence and progression of patellofemoral osteoarthritis. It then presents a synthesis of mechanical effect of treatment strategies specifically addressing these pathomechanics. Identifying the pathomechanics and clinical characteristics of individuals with patellofemoral osteoarthritis that respond to treatment may assist in the development of individualised treatment strategies that alleviate symptoms and slow structural damage. PMID- 24792947 TI - Exercise in osteoarthritis: moving from prescription to adherence. AB - Exercise is recommended for the management of osteoarthritis (OA) in all clinical guidelines irrespective of disease severity, pain levels, and functional status. For knee OA, evidence supports the benefits of various types of exercise for improving pain and function in the short term. However, there is much less research investigating the effects of exercise in patients with OA at other joints such as the hip and hand. It is important to note that while the magnitude of exercise benefits may be considered small to moderate, these effects are comparable to reported estimates for simple analgesics and oral nonsteroidal anti inflammatory drugs for OA pain but exercise has much fewer side effects. Exercise prescription should be individualized based on assessment findings and be patient centered involving shared decision making between the patient and clinician. Given that patient adherence to exercise declines over time, appropriate attention should be pain as reduced adherence attenuates the benefits of exercise. Given this, barriers and facilitators to exercise should be identified and strategies to maximize long-term adherence to exercise implemented. PMID- 24792948 TI - Chronic disease management: improving care for people with osteoarthritis. AB - Chronic disease management (CDM) service models are being developed for many conditions; however, there is limited evidence to support their effectiveness in osteoarthritis (OA). A systematic review was undertaken to examine effectiveness, cost effectiveness and barriers to the use of osteoarthritis-chronic disease management (OA-CDM) service models. Thirteen eligible studies (eight randomised controlled trial (RCTs)) were identified. The majority focussed on delivery system design (n = 9) and/or providing self-management support (SMS) (n = 8). Overall, reported model effectiveness varied, and where positive impacts on process or health outcomes were observed, they were of small to moderate effect. There was no information about cost effectiveness. There is some evidence to support the use of collaborative care/multidisciplinary case management models in primary and community care and evidence-based pathways/standardisation of care in hospital settings. Multiple barriers were identified. Future research should focus on identifying the effective components of multi-faceted interventions and evaluating cost-effectiveness to support clinical and policy decision-making. PMID- 24792949 TI - The role of arthroscopy in the management of knee osteoarthritis. AB - Technological advances throughout the 20th century enabled an increase in arthroscopic knee surgery, particularly arthroscopic debridement for osteoarthritis (OA) and arthroscopic partial meniscectomy for symptomatic meniscal tear in the setting of OA. However, evaluation of the outcomes of these procedures lagged behind their rising popularity. Not until the early 2000s were rigorous outcomes studies conducted; these showed that arthroscopic debridement for OA was no better than a sham procedure in relieving knee pain or improving functional status, and that patients who underwent arthroscopic partial meniscectomy for a degenerative meniscal tear generally did not show more improvement than those who underwent sham meniscal resection or an intensive course of physical therapy. Though the number of arthroscopic knee procedures for OA performed each year has begun to decline, there remains a significant gap between the evidence and actual practice. Further investigation is needed to shore up the evidence base and bring policy and practice in line with rigorous research. PMID- 24792950 TI - Selecting those to refer for joint replacement: who will likely benefit and who will not? AB - Osteoarthritis (OA) is one of the 10 most disabling diseases in developed countries and worldwide estimates are that 10% of men and 18% of women aged over 60 years have symptomatic OA, including moderate and severe forms. Total joint replacement (TJR) is considered the most effective treatment for end-stage OA in those who have exhausted available conservative interventions. The demand for TJR is continually rising due to the ageing population; in the United States, more than 1 million TJRs were performed in 2010 and the number of procedures is projected to exceed 4 million in the US by 2030. It has been estimated that of all hip and knee replacements performed, approximately one quarter of the patients may be considered inappropriate candidates. Predicting who will benefit from TJR and who will not would seem critical in terms of containing the current and projected expenditure as well as improving satisfaction in TJR recipients. Few formal predictive tools are available to aid referring clinicians to determine those likely to be good or poor responders to surgery and current available tools tend to focus on disease severity alone with little consideration of risk factors that may predict a poor outcome or impede an effective response to surgery. This review examines the tools available to assist with assessing appropriateness for TJR; investigates the modifiable risk factors associated with poor outcome; and identifies areas for future research in selecting those appropriate for joint replacement. PMID- 24792954 TI - Chronic kidney disease in patients with cancer and its association with occurrence of venous thromboembolism and mortality. AB - INTRODUCTION: The risk for occurrence of venous thromboembolism (VTE) in cancer patients has been the aim of numerous investigations. Chronic kidney disease (CKD) is a frequent comorbidity in cancer patients and has been found to be a risk factor for VTE in the general population. We investigated the association of CKD with VTE and mortality in cancer patients. METHODS: Patients were recruited into the prospective cohort study, Vienna Cancer and Thrombosis Study (CATS). CKD was estimated with equations for glomerular filtration rate (eGFR) based on serum creatinine by Modification of Diet in Renal Disease (MDRD), CKD Epidemiology collaboration (CKD-EPI) and Cockcroft-Gault equation (C-G). Patients were subsequently classified to stages of CKD according to the Kidney Diseases Outcomes Quality Initiative. Primary endpoint was occurrence of VTE and secondary endpoint was death. RESULTS: The cohort of 1100 patients was prospectively followed over a median of 723 days. CKD with an eGFR of under 90 ml/min was common with a prevalence of 71.1%, 67.0% or 51.5% of patients calculated with MDRD, CKD-EPI and C-G equations, respectively, but severe CKD (eGFR<30 ml/min) was rare. Patients with a moderately decreased eGFR (90-60 ml/min/1.73 m(2)) based on CKD-EPI had a subdistribution hazard ratio of 0.68 (95% confidence interval 0.43-1.06). An association between CKD and occurrence of VTE or mortality could also not be shown with the other equations. CONCLUSIONS: In our investigation of a large cohort of cancer patients with a high prevalence of CKD, a reduced eGFR was not an independent risk factor for occurrence of VTE or death. PMID- 24792952 TI - Designed abscisic acid analogs as antagonists of PYL-PP2C receptor interactions. AB - The plant stress hormone abscisic acid (ABA) is critical for several abiotic stress responses. ABA signaling is normally repressed by group-A protein phosphatases 2C (PP2Cs), but stress-induced ABA binds Arabidopsis PYR/PYL/RCAR (PYL) receptors, which then bind and inhibit PP2Cs. X-ray structures of several receptor-ABA complexes revealed a tunnel above ABA's 3' ring CH that opens at the PP2C binding interface. Here, ABA analogs with sufficiently long 3' alkyl chains were predicted to traverse this tunnel and block PYL-PP2C interactions. To test this, a series of 3'-alkylsulfanyl ABAs were synthesized with different alkyl chain lengths. Physiological, biochemical and structural analyses revealed that a six-carbon alkyl substitution produced a potent ABA antagonist that was sufficiently active to block multiple stress-induced ABA responses in vivo. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class. PMID- 24792955 TI - Further data about catheter related venous thrombosis in oncology. PMID- 24792957 TI - Fat mass is positively associated with bone mass in relatively thin adolescents: data from the Kitakata Kids Health Study. AB - Epidemiologic studies have found that higher body weight is associated with better bone health. Body weight consists of both fat mass (FM) and lean soft tissue mass (LSTM). Previous studies have examined the effects of FM levels during childhood on bone health, with conflicting results. In the present study, we investigated the independent contributions of FM to bone mass in Japanese adolescents. Subjects were 235 adolescents aged 15-18 years old in August 2010 and in August 2013 from the Kitakata Kids Health Study in Japan. We obtained cross-sectional data on body composition as well as bone mineral density (BMD). Body composition and BMD were measured using a dual-energy X-ray absorptiometry scanner. We found moderate and positive relationships between FM index and LSTM index (males, r=0.69; females, r=0.44). To verify a potentially additive effect of FM on the variance of bone variables beyond LSTM, we assessed the association between FM index and bone variables after stratification by tertiles of the LSTM index. In the lowest tertile of the LSTM index, FM index was significantly (P<0.05) associated with both femoral neck BMD (males, beta=0.48; females, beta=0.33) and whole body BMC (males, beta=0.41; females, beta=0.25). On the other hand, we found no significant associations between FM index and bone variables in other tertiles of the LSTM index. These findings indicate that FM can influence how high bone mass is obtained among relatively thin adolescents, but not among those who are of normal weight or overweight. PMID- 24792956 TI - Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage. AB - Connective tissue growth factor (Ctgf) or CCN2 is a protein synthesized by osteoblasts necessary for skeletal homeostasis, although its overexpression inhibits osteogenic signals and bone formation. Ctgf is induced by bone morphogenetic proteins, transforming growth factor beta and Wnt; and in the present studies, we explored whether Notch regulated Ctgf expression in osteoblasts. We employed Rosa(Notch) mice, where the Notch intracellular domain (NICD) is expressed following the excision of a STOP cassette, placed between the Rosa26 promoter and NICD. Notch was activated by transduction of adenoviral vectors expressing Cre recombinase (Ad-CMV-Cre). Notch induced Ctgf mRNA levels in a time dependent manner and increased Ctgf heterogeneous nuclear RNA. Notch also destabilized Ctgf mRNA shortening its half-life from 13h to 3h. The effect of Notch on Ctgf expression was lost following Rbpjkappa downregulation, demonstrating that it was mediated by Notch canonical signaling. However, downregulation of the classic Notch target genes Hes1, Hey1 and Hey2 did not modify the effect of Notch on Ctgf expression. Wild type osteoblasts exposed to immobilized Delta-like 1 displayed enhanced Notch signaling and increased Ctgf expression. In addition to the effects of Notch in vitro, Notch induced Ctgf in vivo, and calvariae and femurs from Rosa(Notch) mice mated with transgenics expressing the Cre recombinase in cells of the osteoblastic lineage exhibited increased expression of Ctgf. In conclusion, Ctgf is a target of Notch canonical signaling in osteoblasts, and may act in concert with Notch to regulate skeletal homeostasis. PMID- 24792958 TI - The role of vitamin D in human fracture healing: a systematic review of the literature. AB - INTRODUCTION: Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality. Mineralization is part of hard callus formation and bone remodelling, processes, which are part of fracture healing. We provide a comprehensive review of the literature to summarize and clarify if possible, the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human. MATERIAL AND METHODS: We conducted a literature search in PubMed, Embase (OVID version), and Web of Science. RESULTS: A total of 75 in vitro and 30 in vivo studies were found with inconsistent results about the cellular effect of vitamin D on fracture involved inflammatory cells, cytokines, growth factors, osteoblasts, osteoclasts and on the process of mineralization. With only five in vitro studies performed on material derived from a fracture site and one in vivo study in fracture patients, the exact cellular role remains unclear. Seven studies investigated the circulating vitamin D metabolites in fracture healing. Although it appears that 25(OH)D and 24,25(OH)2D3 are not affected by the occurrence of a fracture, this might not be the case with serum concentrations of 1,25(OH)2D3. The potential clinical effect of vitamin D deficiency is only described in one case series and three case controlled studies, where the results tend to show no effect of a vitamin D deficiency. No clinical studies were found investigating solely vitamin D supplementation. Two clinical studies found a positive effect of vitamin D supplementation and calcium, of increased bone mineral density or respectively increased fracture callus area at the fracture site. One study found indirect evidence that vitamin D and calcium promoted fracture healing. CONCLUSION: Despite these results, and the presumed beneficial effect of vitamin D supplementation in deficient patients, clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive. We conclude that vitamin D has a role in fracture healing, but the available data are too inconsistent to elucidate how and in what manner. PMID- 24792959 TI - Proton magnetic resonance spectroscopy of skeletal muscle: a comparison of two quantitation techniques. AB - RATIONALE AND OBJECTIVES: The aim of this study was to develop and compare two methods for quantification of metabolite concentrations in human skeletal muscle using phased-array receiver coils at 3T. MATERIALS AND METHODS: Water suppressed and un-suppressed spectra were recorded from the quadriceps muscle (vastus medialis) in 8 healthy adult volunteers, and from a calibration phantom containing 69mM/L N-acetyl aspartate. Using the phantom replacement technique, trimethylamine specifically [TMA] and creatine [Cr] concentrations were estimated, and compared to those values obtained by using the water reference method. RESULTS: Quadriceps [TMA] concentrations were 9.5+/-2.4 and 9.6+/ 4.1mmol/kg wet weight using the phantom replacement and water referencing methods respectively, while [Cr] concentrations were 26.8+/-12.2 and 24.1+/-5.3mmol/kg wet weight respectively. CONCLUSIONS: Reasonable agreement between water referencing and phantom replacement methods was found, although for [Cr] variation was significantly higher for the phantom replacement technique. The relative advantages and disadvantages of each approach are discussed. PMID- 24792961 TI - Detection of a transient intramolecular hydrogen bond using (1)JNH scalar couplings. AB - Hydrogen bonds are essential for the structure, stability and folding of proteins. The identification of intramolecular hydrogen bonds, however, is challenging, in particular in transiently folded states. Here we studied the presence of intramolecular hydrogen bonds in the folding nucleus of the coiled coil structure of the GCN4 leucine zipper. Using one-bond (1)JNH spin-spin coupling constants and hydrogen/deuterium exchange, we demonstrate that a transient intramolecular hydrogen bond is present in the partially helical folding nucleus of GCN(16-31). The data demonstrate that (1)JNH couplings are a sensitive tool for the detection of transient intramolecular hydrogen bonds in challenging systems where the effective/useable protein concentration is low. This includes peptides at natural abundance but also uniformly labeled biomolecules that are limited to low concentrations because of precipitation or aggregation. PMID- 24792962 TI - On a ghost artefact in ultra low field magnetic resonance relaxation imaging. AB - Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are widely used techniques across numerous disciplines. While typically implemented at fields >1T, there has been continuous interest in the methods at much lower fields for reasons of cost, material contrast, or application. There have been numerous demonstrations of MR at much lower fields (from 1MUT to 1mT), the so called ultra-low field (ULF) regime. Approaches to ULF MR have included superconducting quantum interference device (SQUID) sensor technology for ultra sensitive detection and the use of pulsed pre-polarizing fields to enhance the signal strength. There are many advantages to working in the ULF regime. However, due to the low strength of the measurement field, acquisition of MRI at ULF is more susceptible to ambient fields that cause image distortions. Imaging artifacts can be caused by transients associated with non-ideal field switching and from remnant fields in magnetic shielding, among other causes. In this paper, we introduce a general theoretical framework that describes effects of non-ideal measurement field inversion/rotation due to presence of these transient fields. We illustrate imaging artifacts via simulated and experimental examples. PMID- 24792960 TI - Performance of RINEPT is amplified by dipolar couplings under ultrafast MAS conditions. AB - The refocused insensitive nuclei enhanced by polarization transfer (RINEPT) technique is commonly used for heteronuclear polarization transfer in solution and solid-state NMR spectroscopy. Suppression of dipolar couplings, either by fast molecular motions in solution or by a combination of MAS and multiple pulse sequences in solids, enables the polarization transfer via scalar couplings. However, the presence of unsuppressed dipolar couplings could alter the functioning of RINEPT, particularly under fast/ultrafast MAS conditions. In this study, we demonstrate, through experiments on rigid solids complemented by numerical simulations, that the polarization transfer efficiency of RINEPT is dependent on the MAS frequency. In addition, we show that heteronuclear dipolar coupling is the dominant factor in the polarization transfer, which is strengthened by the presence of (1)H-(1)H dipolar couplings. In fact, the simultaneous presence of homonuclear and heteronuclear dipolar couplings is the premise for the polarization transfer by RINEPT, whereas the scalar coupling plays an insignificant role under ultrafast MAS conditions on rigid solids. Our results additionally reveal that the polarization transfer efficiency decreases with the increasing duration of RF pulses used in the RINEPT sequence. PMID- 24792963 TI - Quantum mechanical NMR simulation algorithm for protein-size spin systems. AB - Nuclear magnetic resonance spectroscopy is one of the few remaining areas of physical chemistry for which polynomially scaling quantum mechanical simulation methods have not so far been available. In this communication we adapt the restricted state space approximation to protein NMR spectroscopy and illustrate its performance by simulating common 2D and 3D liquid state NMR experiments (including accurate description of relaxation processes using Bloch-Redfield Wangsness theory) on isotopically enriched human ubiquitin - a protein containing over a thousand nuclear spins forming an irregular polycyclic three-dimensional coupling lattice. The algorithm uses careful tailoring of the density operator space to only include nuclear spin states that are populated to a significant extent. The reduced state space is generated by analysing spin connectivity and decoherence properties: rapidly relaxing states as well as correlations between topologically remote spins are dropped from the basis set. PMID- 24792964 TI - Tissue-specific signals control reversible program of localization and functional polarization of macrophages. AB - Tissue-resident macrophages are highly heterogeneous in terms of their functions and phenotypes as a consequence of adaptation to different tissue environments. Local tissue-derived signals are thought to control functional polarization of resident macrophages; however, the identity of these signals remains largely unknown. It is also unknown whether functional heterogeneity is a result of irreversible lineage-specific differentiation or a consequence of continuous but reversible induction of diverse functional programs. Here, we identified retinoic acid as a signal that induces tissue-specific localization and functional polarization of peritoneal macrophages through the reversible induction of transcription factor GATA6. We further found that GATA6 in macrophages regulates gut IgA production through peritoneal B-1 cells. These results provide insight into the regulation of tissue-resident macrophage functional specialization by tissue-derived signals. PMID- 24792965 TI - Initiation of translation by cricket paralysis virus IRES requires its translocation in the ribosome. AB - The cricket paralysis virus internal ribosome entry site (CrPV-IRES) is a folded structure in a viral mRNA that allows initiation of translation in the absence of any host initiation factors. By using recent advances in single-particle electron cryomicroscopy, we have solved the structure of CrPV-IRES bound to the ribosome of the yeast Kluyveromyces lactis in both the canonical and rotated states at overall resolutions of 3.7 and 3.8 A, respectively. In both states, the pseudoknot PKI of the CrPV-IRES mimics a tRNA/mRNA interaction in the decoding center of the A site of the 40S ribosomal subunit. The structure and accompanying factor-binding data show that CrPV-IRES binding mimics a pretranslocation rather than initiation state of the ribosome. Translocation of the IRES by elongation factor 2 (eEF2) is required to bring the first codon of the mRNA into the A site and to allow the start of translation. PMID- 24792966 TI - Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients. AB - BACKGROUND: In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10-12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies. METHODS: All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm(3)) was subjected to detailed molecular analysis (MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q). RESULTS: 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized. CONCLUSIONS: Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment. PMID- 24792967 TI - The Frankfurt horizontal plane as a reference for the implantation of gravitational units: a series of 376 adult patients. AB - BACKGROUND: The in-line combination of adjustable differential pressure valves with fixed gravitational units is increasingly recommended in the literature. The spatial positioning of the gravitational unit is thereby decisive for the valve opening pressure. We aimed at providing data on factors contributing to primary overdrainage and underdrainage of cerebrospinal fluid (CSF), with special attention paid to the implantation angle of the gravitational unit. METHODS: Weretrospectively analyzed the postoperative course of 376 consecutive patients who received a ventriculoperitoneal shunt with a proGAV valve. The incidence of both primary CSF overdrainage and underdrainage was correlated with the implantation angle of the gravitational unit in regard to the Frankfurt horizontal plane and the patients' general parameters. RESULTS: Primary overdrainage was found in 41 (10.9 %) patients. Primary underdrainage was found in 113 (30.1 %) patients. A mean deviation of 10 degrees (+/-7.8) for the gravitational unit in regard to the vertical line to the Frankfurt horizontal plane was found. In 95 % of the cases the deviation was less than 25 degrees . No significant correlation between the implantation angle and the incidence of overdrainage or underdrainage of CSF was found. The patients' age and having single hydrocephalus entities were identified as factors significantly predisposing patients to overdrainage or underdrainage. CONCLUSION: The implantation of the gravitational unit of the proGAV valve within a range of at least 10 degrees in regard to the vertical line to the Frankfurt horizontal plane does not seem to predispose patients to primary overdrainage or underdrainage in ventriculoperitoneal shunting. The plane may serve as a useful reference for the surgeon's orientation. PMID- 24792968 TI - Cre-loxP-based system for removal and reuse of selection markers in Ashbya gossypii targeted engineering. AB - The filamentous ascomycete Ashbya gossypii is amenable to genetic manipulation and is an excellent model system for studying eukaryotic cell biology. However, the number of selection markers in current use for both targeted gene integration and disruption in this fungus are very limited. Therefore, the Cre-loxP recombination system was adapted for use in A. gossypii and its effectiveness in recycling marker genes was demonstrated by constructing both single and double deleted Agura3 and Agade1 auxotrophic strains free of exogenous markers. In spite of its wide use in other organisms, including other Ascomycete fungi, this is the first report describing Cre-loxP-based methodology for A. gossypii, opening new perspectives for targeted engineering of this fungus with several promising biotechnological applications [corrected]. PMID- 24792969 TI - Beta-blockers in cirrhosis: thank you for your attention. PMID- 24792970 TI - Reply to: "Is the pathway of energy metabolism modified in advanced cirrhosis?". PMID- 24792971 TI - Prevention of periprosthetic joint infection: what are the effective strategies? AB - Periprosthetic joint infection (PJI) following total knee arthroplasty is a major burden for patients and health systems. Prevention of this challenging complication through implementation of effective strategies should be a priority. These strategies should encompass various levels of patient care. Multiple modifiable risk factors such as uncontrolled hyperglycemia, obesity, smoking, substance abuse, and nasal colonization with Staphylococcus aureus have been described for PJI. Preoperative recognition and mitigation of these risk factors along with optimization of nonmodifiable risk factors such as kidney, liver, or immune system insufficiency can considerably decrease the risk of PJI. A comprehensive perioperative protocol should involve optimization of the operative environment to reduce the number of bacteria and particulates in the air. Several surgical and nonsurgical details of intraoperative care such as maintenance of normothermia, skin preparation, surgical field irrigation, wound closure, and duration of surgical and anesthetic procedure can influence the occurrence of PJI. Prophylactic perioperative antibiotic administration is probably one of the most important strategies in preventing PJI. Implementation of surgical safety checklist can diminish the risk of perioperative complications, particularly surgical site infection. Controversy regarding efficacy, efficiency, and optimization of some preventive measures continues to exist due to inconsistency or inadequacy of available evidence. Novel research has focused on designing PJI resistant implants and developing vaccines that target molecule components with major role in the process of bacterial adhesion to the implant or periprosthetic tissues. PMID- 24792972 TI - The contribution of Raman spectroscopy to the analytical quality control of cytotoxic drugs in a hospital environment: eliminating the exposure risks for staff members and their work environment. AB - The purpose of the study was to perform a comparative analysis of the technical performance, respective costs and environmental effect of two invasive analytical methods (HPLC and UV/visible-FTIR) as compared to a new non-invasive analytical technique (Raman spectroscopy). Three pharmacotherapeutic models were used to compare the analytical performances of the three analytical techniques. Statistical inter-method correlation analysis was performed using non-parametric correlation rank tests. The study's economic component combined calculations relative to the depreciation of the equipment and the estimated cost of an AQC unit of work. In any case, analytical validation parameters of the three techniques were satisfactory, and strong correlations between the two spectroscopic techniques vs. HPLC were found. In addition, Raman spectroscopy was found to be superior as compared to the other techniques for numerous key criteria including a complete safety for operators and their occupational environment, a non-invasive procedure, no need for consumables, and a low operating cost. Finally, Raman spectroscopy appears superior for technical, economic and environmental objectives, as compared with the other invasive analytical methods. PMID- 24792973 TI - Mesoporous silica coated gold nanorods loaded doxorubicin for combined chemo photothermal therapy. AB - The efficacy of the combined chemo-photothermal therapy, using a mesoporous silica-coated gold nanorods loaded DOX (pGNRs@mSiO2-DOX), was consistently tested both in vitro and in vivo. The prepared nanoparticles that were characterized using transmission electron microscopy (TEM), UV-vis absorption spectroscopy and zeta potential showed high doxorubicin loading capacity in addition to its pH responsive release. The pGNRs@mSiO2-DOX photo-heat conversion characteristic found to be stable for several repeated NIR irradiated doses was tested in simulated body fluid. In vitro results showed that pGNRs@mSiO2-DOX causes a significant damage in breast cancer cell line MCF-7 compared to free DOX. Contrary to this, it showed low toxicity to human amnion wish cells compared to CTAB coated GNRs and free DOX. In vivo results showed that intravenous administration of pGNRs@mSiO2-DOX (1.7 mg/kg) markedly suppresses the growth of subcutaneous Ehrlich carcinoma in female Balb mice (p<0.0001). Consistently, histopathological examination revealed a complete loss of tumor cellular details for mice that received the combined treatment. Based on the obtained results, this passively targeted pGNRs@mSiO2-DOX could specifically deliver drug and excessive local heat to tumor sites achieving high combined therapeutic efficacy. PMID- 24792974 TI - Stability study of full-length antibody (anti-TNF alpha) loaded PLGA microspheres. AB - Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer((r)) RG505 and Resomer((r)) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5 +/- 3 degrees C, 25 +/- 2 degrees C/60% RH and 40 +/- 2 degrees C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5 +/- 3 degrees C and that the Resomer((r)) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5 degrees C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres. PMID- 24792975 TI - Towards the optimisation and adaptation of dry powder inhalers. AB - Pulmonary drug delivery by dry powder inhalers is becoming more and more popular. Such an inhalation device must insure that during the inhalation process the drug powder is detached from the carrier due to fluid flow stresses. The goal of the project is the development of a drug powder detachment model to be used in numerical computations (CFD, computational fluid dynamics) of fluid flow and carrier particle motion through the inhaler and the resulting efficiency of drug delivery. This programme will be the basis for the optimisation of inhaler geometry and dry powder inhaler formulation. For this purpose a multi-scale approach is adopted. First the flow field through the inhaler is numerically calculated with OpenFOAM((r)) and the flow stresses experienced by the carrier particles are recorded. This information is used for micro-scale simulations using the Lattice-Boltzmann method where only one carrier particle covered with drug powder is placed in cubic flow domain and exposed to the relevant flow situations, e.g. plug and shear flow with different Reynolds numbers. Therefrom the fluid forces on the drug particles are obtained. In order to allow the determination of the drug particle detachment possibility by lift-off, sliding or rolling, also measurements by AFM (atomic force microscope) were conducted for different carrier particle surface structures. The contact properties, such as van der Waals force, friction coefficient and adhesion surface energy were used to determine, from a force or moment balance (fluid forces versus contact forces), the detachment probability by the three mechanisms as a function of carrier particle Reynolds number. These results will be used for deriving the drug powder detachment model. PMID- 24792976 TI - New classification of directly compressible (DC) excipients in function of the SeDeM Diagarm Expert System. AB - As a methodology for characterizing substances with regard to its viability in direct compression, the SeDeM Diagram Expert System may be considered a new tool in terms of the number of parameters applied and its optimization. The paper is based on the experimental SeDeM characterization study of 51 directly compressible (DC) excipients. After selecting the parameters, and comparing the corresponding results, the choices available within the SeDeM Expert System could be expanded. Through applied variants, the maximum and optimal values of the DC diluent excipient were precisely defined and the mathematical limits of the parameters, functions and parametric indices that define the level of direct compressibility were established. These studies have allowed us to propose a new classification of excipients CD based on its rheological and compressibility capability, resulting in a periodic table of CD excipients. It has been determined that the best excipient for direct compression should have an index of good compression (IGC) of 8.832. PMID- 24792977 TI - Lectin-conjugated microspheres for eradication of Helicobacter pylori infection and interaction with mucus. AB - Using second generation mucoadhesives may enhance targeting antibiotics for eradication of Helicobacter pylori from the stomach for the treatment of peptic ulcer. The aim of this research was to prepare and characterise ethylcellulose/chitosan microspheres containing clarithromycin with their surfaces functionalised with concanavalin A to produce a floating-mucoadhesive formulation. The microspheres were prepared using an emulsification-solvent evaporation method. Particle size, surface morphology, in vitro buoyancy profile, zeta potential, drug entrapment efficiency, in vitro drug release and release kinetics of the particles were determined. Lectin was conjugated to the microsphere surface using two-stage carbodiimide activation and confirmed using FTIR, fluorescence studies and zeta potential measurements. Conjugation ranged from 11 to 15 MUg Con A/mg microspheres which represents over 56% efficiency although there was some drug loss during the conjugation process. Conjugation did not have a significant effect on the buoyancy and release of drug from the microspheres using a mucus diffusion model with 53% and 40% of drug released from unconjugated and conjugated microspheres within 12h. Conjugation improved mucoadhesion and interaction with porcine gastric mucin compared to unconjugated microspheres. The buoyancy and improved mucoadhesion of the microspheres provides potential for delivery of clarithromycin and other drugs to the stomach. PMID- 24792978 TI - Active wound dressings based on bacterial nanocellulose as drug delivery system for octenidine. AB - Although bacterial nanocellulose (BNC) may serve as an ideal wound dressing, it exhibits no antibacterial properties by itself. Therefore, in the present study BNC was functionalized with the antiseptic drug octenidine. Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Octenidine release was based on diffusion and swelling according to the Ritger-Peppas equation and characterized by a time dependent biphasic release profile, with a rapid release in the first 8h, followed by a slower release rate up to 96 h. The comparison between lab-scale and up-scale BNC identified thickness, water content, and the surface area to volume ratio as parameters which have an impact on the control of the release characteristics. Compression and tensile strength remained unchanged upon incorporation of octenidine in BNC. In biological assays, drug-loaded BNC demonstrated high biocompatibility in human keratinocytes and antimicrobial activity against Staphylococcus aureus. In a long-term storage test, the octenidine loaded in BNC was found to be stable, releasable, and biologically active over a period of 6 months without changes. In conclusion, octenidine loaded BNC presents a ready-to use wound dressing for the treatment of infected wounds that can be stored over 6 months without losing its antibacterial activity. PMID- 24792979 TI - Influence of different surfactants on the technological properties and in vivo ocular tolerability of lipid nanoparticles. AB - Addition of one or more surfactant agents is often necessary for the production of nanostructured lipid and polymeric systems. The removal of residual surfactants is a required step for technological and toxicological reasons, especially for peculiar applications, such as the ophthalmic field. This study was planned to assess the technological properties of some surfactants, commonly used for the production of lipid nanoparticles, as well as their ocular safety profile. Stable and small-size solid lipid nanoparticles were obtained using Dynasan((r)) 114 as the lipid matrix and all the tested surfactants. However, from a toxicological point of view, the nanocarriers produced using Kolliphor((r)) P188 were the most valuable, showing no irritant effect on the ocular surface up to the highest tested surfactant concentration (0.4%, w/v). The SLN produced using Cremophor((r)) A25 and Lipoid((r)) S100 were tolerated up to a surfactant concentration of 0.2% by weight, while for Tween((r)) 80 and Kolliphor((r)) HS 15 a maximum concentration of 0.05% can be considered totally not-irritant. PMID- 24792980 TI - In-line monitoring of pellet coating thickness growth by means of visual imaging. AB - Coating thickness is the most important attribute of coated pharmaceutical pellets as it directly affects release profiles and stability of the drug. Quality control of the coating process of pharmaceutical pellets is thus of utmost importance for assuring the desired end product characteristics. A visual imaging technique is presented and examined as a process analytic technology (PAT) tool for noninvasive continuous in-line and real time monitoring of coating thickness of pharmaceutical pellets during the coating process. Images of pellets were acquired during the coating process through an observation window of a Wurster coating apparatus. Image analysis methods were developed for fast and accurate determination of pellets' coating thickness during a coating process. The accuracy of the results for pellet coating thickness growth obtained in real time was evaluated through comparison with an off-line reference method and a good agreement was found. Information about the inter-pellet coating uniformity was gained from further statistical analysis of the measured pellet size distributions. Accuracy and performance analysis of the proposed method showed that visual imaging is feasible as a PAT tool for in-line and real time monitoring of the coating process of pharmaceutical pellets. PMID- 24792981 TI - Preparation and study of tramadol imprinted micro-and nanoparticles by precipitation polymerization: microwave irradiation and conventional heating method. AB - In the present work a series of tramadole imprinted micro- and nanoparticles were prepared and study their recognition properties. Methacrylic acid (MAA), as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker and different solvents (chloroform, toluene and acetonitrile (ACN)) were used for the preparation of molecularly imprinted polymers (MIPs) and non-imprinted polymers (NIPs). Several factors such as template/monomer molar ratio, volume of polymerization solvent, total monomers/solvent volume ratio, polymerization condition (heating or microwave irradiation) were also investigated. Particle size of the polymers, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), rebinding, selectivity tests and release study were applied for evaluation of the polymers. The optimized polymers with smaller particle size and superior binding properties were obtained in acetonitrile under heating method. MIPA4 with a size of 42.6 nm and a binding factor (BF) of 6.79 was selected for selectivity and release tests. The polymerization was not successful in acetonitrile and toluene under microwave irradiation. The MIPA4 could selectively adsorb tramadol, compared to imipramine, naltrexone and gabapentin. The data showed that tramadol release from MIPA4 was significantly slower than that of its non-imprinted polymer. Therefore, MIP nanoparticles with high selectivity, binding capacity and ability to control tramadol release could be obtained in precipitation polymerization with optimized condition. PMID- 24792982 TI - Biodegradation of polystyrene-graft-starch copolymers in three different types of soil. AB - Materials based on polystyrene and starch copolymers are used in food packaging, water pollution treatment, and textile industry, and their biodegradability is a desired characteristic. In order to examine the degradation patterns of modified, biodegradable derivates of polystyrene, which may keep its excellent technical features but be more environmentally friendly at the same time, polystyrene-graft starch biomaterials obtained by emulsion polymerization in the presence of new type of initiator/activator pair (potassium persulfate/different amines) were subjected to 6-month biodegradation by burial method in three different types of commercially available soils: soil rich in humus and soil for cactus and orchid growing. Biodegradation was monitored by mass decrease, and the highest degradation rate was achieved in soil for cactus growing (81.30%). Statistical analysis proved that microorganisms in different soil samples have different ability of biodegradation, and there is a significant negative correlation between the share of polystyrene in copolymer and degree of biodegradation. Grafting of polystyrene on starch on one hand prevents complete degradation of starch that is present (with maximal percentage of degraded starch ranging from 55 to 93%), while on the other hand there is an upper limit of share of polystyrene in the copolymer (ranging from 37 to 77%) that is preventing biodegradation of degradable part of copolymers. PMID- 24792983 TI - Salt marsh plants as key mediators on the level of cadmium impact on microbial denitrification. AB - The fate of excess nitrogen in estuaries is determined by the microbial-driven nitrogen cycle, being denitrification a key process since it definitely removes fixed nitrogen as N2. However, estuaries receive and retain metals, which may negatively affect this process efficiency. In this study, we evaluated the role of salt marsh plants in mediating cadmium (Cd) impact on microbial denitrification process. Juncus maritimus and Phragmites australis from an estuary were collected together with the sediment involving their roots, each placed in vessels and maintained in a greenhouse, exposed to natural light, with tides simulation. Similar non-vegetated sediment vessels were prepared. After 3 weeks of accommodation, nine vessels (three per plant species plus three non vegetated) were doped with 20 mg/L Cd(2+) saline solution, nine vessels were doped with 2 mg/L Cd(2+) saline solution and nine vessels were left undoped. After 10 weeks, vessels were dissembled and denitrification potential was measured in sediment slurries. Results revealed that the addition of Cd did not cause an effect on the denitrification process in non-vegetated sediment but had a clear stimulation in colonized ones (39 % for P. australis and 36 % for J. maritimus). In addition, this increase on denitrification rates was followed by a decrease on N2O emissions and on N2O/N2 ratios in both J. maritimus and P. australis sediments, increasing the efficiency of the N2O step of denitrification pathway. Therefore, our results suggested that the presence of salt marsh plants functioned as key mediators on the degree of Cd impact on microbial denitrification. PMID- 24792984 TI - Clinical utility of computed electrocardiographic leads. AB - The standard 12-lead electrocardiogram (ECG) is only one of the possible ways to present the voltage differences between the nine recording electrodes. Other "non conventional" leads may be constructed by physically connecting two or more electrodes in a different manner or by computation from the digital 12-lead ECG. Examples include bipolar or multipolar precordial leads and bipolar chest leads (between one precordial and one limb electrode). Such leads can remove or decrease noise originating from a limb cable/electrode that is present in the unipolar precordial leads. They can be diagnostically useful in Brugada syndrome and can display QRS fractionation that is not visible in the respective unipolar precordial or limb leads. Multipolar precordial leads sometimes display potentially useful information that is not visible in the respective unipolar leads and in bipolar leads computed from them. In conclusion, these computed ECG leads represent a potentially useful supplement to the conventional 12-lead ECG. PMID- 24792985 TI - Assessment of reproducibility--automated and digital caliper ECG measurement in the Framingham Heart Study. AB - BACKGROUND: Digitized electrocardiography permits the rapid, automated quantification of electrocardiograms (ECGs) for analysis. Community- and population-based studies have increasingly integrated such data. Assessing the reproducibility of automated ECG measures with manual measures is a critical step in preparation for using automated measures for research purposes. We recently established an ECG repository of digitally recorded ECGs for the Framingham Heart Study and we sought to assess the reproducibility of automated and manual measures. METHODS: We selected 185 digitally recorded ECGs from routine visits of Framingham Heart Study participants spanning from 1986 to 2012. We selected the following ECG measures for their relevance to clinical and epidemiologic research: P wave duration, P wave amplitude, and PR interval in lead II; QRS duration and R wave amplitude in lead V6; and QT interval in lead V5. We obtained automated values for each waveform, and used a digital caliper for manual measurements. Digital caliper measurements were repeated in a subset (n=81) of the samples for intrarater assessment. RESULTS: We calculated the intraclass correlation coefficient (ICC) values for the interrater and intrarater assessments. P wave duration had the lowest interrater ICC (r=0.46) and lowest intrarater ICC (r=0.57). R wave amplitude had the highest interrater and intrarater ICC (r=0.98) indicating excellent reproducibility. The remaining measures had interrater and intrarater ICCs of r>=0.81. CONCLUSIONS: The interrater reproducibility findings for P wave amplitude, PR interval, QT interval, QRS duration, and R wave amplitude were excellent. In contrast, the reproducibility of P wave duration was more modest. These findings indicate high reproducibility of most automated and manual ECG measurements. PMID- 24792987 TI - Re: Impact of statin use on oncologic outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy: R. D. da Silva, E. Xylinas, L. Kluth, J. J. Crivelli, J. Chrystal, D. Chade, G. B. Guglielmetti, A. Pycha, Y. Lotan, P. I. Karakiewicz, M. Sun, H. Fajkovic, M. Zerbib, D. S. Scherr and S. F. Shariat J Urol 2013;190:487-492. PMID- 24792986 TI - Short-term repeatability of electrocardiographic Tpeak-Tend and QT intervals. AB - BACKGROUND: The electrocardiographic (ECG) Tpeak-Tend interval (TpTe) is associated with arrhythmias and sudden cardiac death. TpTe offers a supplementary measure for the QT interval (QT), yet its repeatability has not been established. PURPOSE: Evaluate short-term repeatability of TpTe and QT. METHODS: Four ECGs were obtained on sixty participants. The sources of variation, intra-class correlation coefficient (ICC) - an index of reproducibility - and minimal detectable change (MDC) were estimated for TpTe and QT. The impact of repeated measurements on repeatability was estimated for a hypothetical clinical trial designed to detect drug-induced prolongation of TpTe and QT. RESULTS: We used heart rate-adjusted QT [(QT)a] but TpTe in the study group was rate-invariant. The ICC [95% confidence interval (CI)] was 0.77 (0.69, 0.85) for TpTe, 0.75 (0.65, 0.85) for QT and 0.60 (0.47, 0.73) for (QT)a. The MDC (ms) was 21, 32 and 26 for TpTe, QT and (QT)a respectively. CONCLUSION: TpTe has excellent repeatability supporting its use as a supplement to QT in observational and clinical studies. PMID- 24792988 TI - Editorial comment. PMID- 24792989 TI - Re: Association of oncofetal protein expression with clinical outcomes in patients with urothelial carcinoma of the bladder: E. Xylinas, E. K. Cha, F. Khani, L. A. Kluth, M. Rieken, B. G. Volkmer, R. Hautmann, R. Kufer, Y.-T. Chen, M. Zerbib, M. A. Rubin, D. S. Scherr, S. F. Shariat and B. D. Robinson J Urol 2014;191:830-841. PMID- 24792990 TI - Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. AB - Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme. PMID- 24792991 TI - Sustained efficacy of apomorphine in Japanese patients with advanced Parkinson's disease. AB - BACKGROUND: This report presents data from one of the first trials of apomorphine rescue treatment for advanced Parkinson's disease (PD) conducted in Japan. This 3 month trial aimed to evaluate the sustainability of efficacy of intermittent apomorphine rescue treatment. METHODS: A phase III, double-blind, placebo controlled trial was conducted in PD patients (n = 31) with motor fluctuations in spite of individually titrated treatment with levodopa and other anti PD. Intermittent treatment was titrated to the maintenance dose with a subsequent unblind 12-week outpatient phase. At the week-12 visit, response to apomorphine or placebo was assessed as primary efficacy endpoint using the Unified Parkinson's Disease Rating Scale (UPDRS) part III (Motor Examination) under double-blind crossover conditions. RESULTS: In the crossover phase (n = 28), least squares mean changes in the UPDRS part III score from pre-dose were -24.5 points with apomorphine and -2.3 points with placebo, showing that apomorphine, compared with placebo, provided a significantly greater improvement in the UPDRS part III score change (difference between treatments: -22.1 [95% confidence interval, -27.8, -16.4]; P < 0.001). The most frequently reported adverse events during the study were increased eosinophil count (8 patients), nausea (7), somnolence (6), dyskinesia (5), yawning (5), and decreased blood pressure (3). CONCLUSIONS: Our results indicate that a 3-month use of intermittent apomorphine is an effective rescue therapy for "off" episodes in advanced PD patients. PMID- 24792992 TI - Adapting the Sniffin' Sticks olfactory test to diagnose Parkinson's disease in Estonia. AB - The aim of the study was to develop a culturally adapted translation of the 12 item smell identification test from Sniffin' Sticks (SS-12) for the Estonian population in order to help diagnose Parkinson's disease (PD). METHODS: A standard translation of the SS-12 was created and 150 healthy Estonians were questioned about the smells used as response options in the test. Unfamiliar smells were replaced by culturally familiar options. The adapted SS-12 was applied to 70 controls in all age groups, and thereafter to 50 PD patients and 50 age- and sex-matched controls. RESULTS: 14 response options from 48 used in the SS-12 were replaced with familiar smells in an adapted version, in which the mean rate of correct response was 87% (range 73-99) compared to 83% with the literal translation (range 50-98). In PD patients, the average adapted SS-12 score (5.4/12) was significantly lower than in controls (average score 8.9/12), p < 0.0001. A multiple linear regression using the score in the SS-12 as the outcome measure showed that diagnosis and age independently influenced the result of the SS-12. A logistic regression using the SS-12 and age as covariates showed that the SS-12 (but not age) correctly classified 79.0% of subjects into the PD and control category, using a cut-off of <7 gave a sensitivity of 76% and specificity of 86% for the diagnosis of PD. CONCLUSIONS: The developed SS-12 cultural adaption is appropriate for testing olfaction in Estonia for the purpose of PD diagnosis. PMID- 24792993 TI - Recent advances in technologies for developing drugs against Chlamydia pneumoniae. AB - INTRODUCTION: The unique morphological characteristics, capacity of manipulating host cell function and association with chronic inflammatory diseases represent the features of Chlamydia pneumoniae that have fascinated scientists and medical professionals for several decades. AREAS COVERED: In this paper, the authors review the current status of attempts to discover and develop drugs against C. pneumoniae, including: the discovery of non-conventional antichlamydial agents, targeting chlamydial type 3 secretion system, approved drug repositioning and combination therapies. In addition, the authors discuss the recent advances in C. pneumoniae-related genomics and proteomics research and genetic manipulation technologies. EXPERT OPINION: Based on current knowledge, it is important for researchers to continue to focus on phenotypic assays on persistent infections. There should also be a careful evaluation of the physicochemical properties of the lead candidates and attempts toward more narrow-spectrum antibacterial agents. All these elements are important for successful lead generation. The recent advances in understanding C. pneumoniae biology and breakthroughs in genetic transformation are likely to improve the potential for identifying and validating therapeutic targets within both the bacterium and its host cells. PMID- 24792994 TI - A new PC(sp(3))P ligand and its coordination chemistry with low-valent iron, cobalt and nickel complexes. AB - A new PC(sp(3))P ligand N,N'-bis(diphenylphosphino)dipyrromethane [PCH2P] (1) was prepared and its iron, cobalt and nickel chemistry was explored. Two pincer-type complexes [PCHP]Fe(H)(PMe3)2 (2) and [PCHP]Co(PMe3)2 (4) were synthesized in the reaction of with Fe(PMe3)4 and Co(Me)(PMe3)4. 1 reacted with Co(PMe3)4 and Ni(PMe3)4 to afford Co(0) and Ni(0) complexes [PCH2P]Co(PMe3)2 (3) and [PCH2P]Ni(PMe3)2 (5). The structures of complexes 2-5 were determined by X-ray diffraction. PMID- 24792995 TI - [Stereotactic radiotherapy for pelvic tumors]. AB - Extracranial stereotactic radiotherapy is booming. The development and spread of dedicated accelerators coupled with efficient methods of repositioning can now allow treatments of mobile lesions with moderate size, with high doses per fraction. Intuitively, except for the prostate, pelvic tumours, often requiring irradiation of regional lymph node drainage, lend little to this type of treatment. However, in some difficult circumstances, such as boost or re radiation, stereotactic irradiation condition is promising and clinical experiences have already been reported. PMID- 24792996 TI - [Stereotactic body radiation therapy and oligometastases]. AB - In stage IV cancers, locoregional management of primitive tumours as surgery and/or radiotherapy improved both progression-free survival and overall survival. Among metastatic cancer patients, some of them are considered as oligometastatic stage as they present few metastatic sites associated with low tumor aggressiveness. For those patients, metastatic local control, and therefore prolonged time to progression should be reached through local treatments as surgery and/or radiofrequency ablation and/or stereotactic radiotherapy. Here we propose a review of oligometastatic stage and results from extracranial stereotactic radiotherapy in terms of efficacy and tolerance. PMID- 24792997 TI - First successful allogeneic hematopoietic stem cell transplantation for a sickle cell disease patient in a low resource country (Nigeria): a case report. AB - BACKGROUND: Sickle cell disease (SCD) has a prevalence of 2-3% in Nigeria (population: over 150 million). We present our first allogeneic hematopoietic stem cell transplantation (HSCT) for a 7-year-old patient with severe sickle cell anemia and debilitating right-sided hemi-paraparesis. CASE REPORT: Conditioning was with (Reduced Intensity Conditioning (FLU/BU).[Fludarabine 160 mg/m2 (days -6 to -2) and Busulphan 16 mg/kg (4*25 mg 6 hly days -5 to -2) and Anti-thymocyte globulin(ATG)(ATGAM) total dose 500 mg (days -6 to -4)]. Graft versus Host Disease (GVHD) prophylaxis was with Cyclosporine A (2*50 mg daily) and Mycophenolate Mofetil (2*500 mg/day). Stem cell source was bone marrow harvested on the 28 September 2011 with 9.8*108 nucleated cells/kg in a total volume of 900 mL from his 14-year-old HLA-matched sibling (6/6). Neutrophil and platelet engraftment was day +18 and +21, respectively. At day +70 full blood count was a total white blood cell count of 3100/ul, absolute Neutrophil count 1200/ul, Hemoglobin (Hb) 11.3 g/dl, Platelet 198,000/ul, Hemoglobin phenotype AA, and no acute or chronic GVHD. He is clinically stable with a Chimerism at 2 years post HSCT of 95% and responding to physiotherapy. CONCLUSIONS: We have successfully performed a stem cell transplanted in a 7-year-old Sickle Cell Anemia case. With the assistance of Government and improved Health Insurance Policy, we could make HSCT available as a cure for many Nigerians with both malignant and non-malignant disorders. PMID- 24792999 TI - Cytoreduction of para-aortic lymph nodes behind the inferior vena cava and the right renal vessels in a patient with fallopian tube cancer. PMID- 24792998 TI - Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells. AB - OBJECTIVES: To characterize the biological activities of LKB1, examine LKB1 protein expression and identify LKB1-regulated genes that may serve as therapeutic targets in cervical cancer. METHODS: Proliferation of cervical cancer HeLa cells expressing LKB1 was examined. LKB1 expression in normal cervical tissues and cervical cancers was assessed by immunohistochemistry. Gene expression profiles of cervical cancer HeLa cells stably expressing LKB1 were analyzed by microarray. Differentially expressed genes were analyzed using Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) PATHWAY database. Quantitative RT-PCR was used to validate the microarray data. The expression of lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) was confirmed by western blotting. RESULTS: Expression of LKB1 inhibited HeLa cell proliferation, activated AMPK and was lost in more than 50% of cervical carcinomas. More than 200 genes were differentially expressed between HeLa cells with and without LKB1. Bioinformatics analysis with GO annotation indicated that LKB1 plays a role in receiving diverse stimuli and converting them into molecular signals. KEGG PATHWAY analysis showed that 8 pathways were significantly regulated. These include arginine and proline metabolism and inositol phosphate metabolism. The differential expression of 7 randomly selected genes was confirmed by quantitative RT-PCR. Furthermore, the steady-state level of INPP4B protein was up-regulated in LKB1-overexpressing cells. CONCLUSIONS: This study establishes LKB1 as an important tumor suppressor in cervical cancer and sheds light on a novel signaling pathway regulated by LKB1. PMID- 24793000 TI - Radiotherapy with concurrent cisplatin-based doublet or weekly cisplatin for cervical cancer: a systematic review and meta-analysis. AB - BACKGROUND: Treatment with weekly cisplatin (CDDP) plus radiotherapy (RT) is the standard regimen for stage IB to stage IVA cervical carcinoma (CC). We performed a systematic review and meta-analysis of published studies to evaluate whether CDDP-based doublet therapy improves survival compared to weekly CDDP plus RT in patients with CC. MATERIALS AND METHODS: We conducted a systematic search for randomized and nonrandomized studies in PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Register of Controlled Trials. We then carried out a meta analysis by using the fixed- or random-effects models. The primary endpoints were overall survival (OS) and progression-free survival (PFS), reported as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Four randomized trials and 4 retrospective studies that included a total of 1500 patients matched our selection criteria. Meta-analysis showed that for locally advanced CC, concurrent RT and with CDDP-based doublet chemotherapy significantly improved the OS (OR, 0.65; 95% CI, 0.51-0.81; p=0.0002), PFS (OR, 0.71; 95% CI, 0.55-0.91; p=0.006), and rate of locoregional relapse (OR, 0.64; 95% CI, 0.47-0.89; p=0.008), compared to RT with concurrent weekly CDDP alone. CONCLUSIONS: In patients with CC, platinum-based doublet chemotherapy plus concurrent RT was associated with improvements in the OS and PFS of 35% and 30% patients, respectively, compared to RT plus weekly CDDP. Therefore, platinum-based combination therapy plus RT should be the preferred treatment over weekly CDDP plus RT for stage IB-IVA CC. PMID- 24793001 TI - Segmental testicular infarction due to minocycline-induced antineutrophil cytoplasmic antibody--positive vasculitis. AB - Segmental testicular infarction is an uncommon clinical entity marked by acute scrotal pain and swelling. Classically, these appear as wedge-shaped, avascular, hypoechoic lesions on a testicular ultrasound. We present a unique case of testicular infarct caused by an antineutrophil cytoplasmic antibody-positive vasculitis secondary to the use of the antibiotic minocycline. The patient's symptoms resolved with cessation of minocycline. We suggest that patients who present with otherwise unexplained testicular infarction undergo a careful review of medications to uncover a potential cause. PMID- 24793002 TI - Spontaneous clitoral hood epidermal inclusion cyst mimicking clitoromegaly in a pediatric patient. AB - Epidermal inclusion cysts are benign lesions that can be found in many parts of the body. They are rarely seen in the clitoral region in pediatric patients but when these are found, they are most commonly seen with a history of trauma. We report an uncommon case of a spontaneous nontraumatic epidermal inclusion cyst in the clitoral hood of a female child. This presentation mimicked clitoromegaly but was ultimately found to be a large epidermal cyst that was successfully excised surgically. We present the important pathologic findings and review the relevant literature. PMID- 24793003 TI - Properdin deficiency-associated bronchiectasis. PMID- 24793004 TI - A feasibility study of a psychoeducational intervention program for gynecological cancer patients. AB - PURPOSE OF THE RESEARCH: This study aimed to test the feasibility of implementing a psychoeducational intervention program for gynecological cancer patients. METHODS AND SAMPLE: A single-blinded randomized controlled trial and mixed-method design were used. Study subjects were newly diagnosed gynecological cancer patients with surgery as the first-line treatment. They were randomly assigned to the intervention group, in which a psychoeducational intervention program based on a thematic counseling model was offered, or to the attention control group. Quantitative data on sexual functioning, quality of life, uncertainty, anxiety, depression and social support were collected at recruitment, post-operative and during the in-hospital period, and eight weeks after the operation. Participants in the intervention group and three nurses working in the clinical setting were invited to have semi-structured interviews. KEY RESULTS: Of the 30 eligible subjects, 26 were successfully recruited into the study. Following the psychoeducational intervention program, there was significant improvement in the level of inconsistent information about the illness within the category of uncertainty among participants in the intervention group. In addition, trends towards improvement were demonstrated in quality of life, uncertainty, depression and perceived social support with the provision of the interventions. Qualitative data indicated the interventions were desired and appreciated by the participants, as well as being feasible and practical to implement in Hong Kong clinical settings. CONCLUSIONS: The findings suggest that it is feasible to deliver the psychoeducational intervention program and it may have beneficial effects in gynecological cancer patients. A full-scale study is warranted to confirm the results. PMID- 24793005 TI - ERK1 phosphorylates Nanog to regulate protein stability and stem cell self renewal. AB - Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability. PMID- 24793007 TI - Unnecessary complexity of home medication regimens among seniors. AB - OBJECTIVE: To determine whether seniors consolidate their home medications or if there is evidence of unnecessary regimen complexity. METHODS: Face-to-face interviews were conducted with 200 community-dwelling seniors >70 years in their homes. Subjects demonstrated how they took their medications in a typical day and the number of times a day patients would take medications was calculated. A pharmacist and physician blinded to patient characteristics examined medication regimens and determined the fewest number of times a day they could be taken by subjects. RESULTS: Home medication regimens could be simplified for 85 (42.5%) subjects. Of those subjects not optimally consolidating their medications, 53 (26.5%) could have had the number of times a day medications were taken reduced by one time per day; 32 (16.0%) reduced by two times or more. The three most common causes of overcomplexity were (1) misunderstanding medication instructions, (2) concern over drug absorption (i.e. before meals), and (3) perceived drug-drug interactions. CONCLUSION: Almost half of seniors had medication regimens that were unnecessarily complicated and could be simplified. This lack of consolidation potentially impedes medication adherence. PRACTICE IMPLICATIONS: Health care providers should ask patients to explicitly detail when medication consumption occurs in the home. PMID- 24793006 TI - Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation. AB - Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) differentiation capacity. BMSCs were isolated from male Sprague Dawley rats and cultured in minimal essential medium alpha (MEM-alpha) supplemented with 15% Fetal Bovine serum (FBS). The results showed that marinobufagenin (MBG), a specific Na/K-ATPase ligand, potentiated rosiglitazone induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPalpha) protein expression through activation of an extracellular regulated kinase (ERK) signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPalpha expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2) expression, which resulted in the inhibition of osteogenesis induced by beta-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation. PMID- 24793008 TI - Residents' and standardized patients' perspectives on empathy: issues of agreement. AB - OBJECTIVE: We investigated correlations between residents' scores on the Jefferson Scale of Empathy (JSE), residents' perceptions of their empathy during standardized-patient encounters, and the perceptions of standardized patients. METHODS: Participants were 214 first-year residents in internal medicine or family medicine from 13 residency programs taking standardized patient-based clinical skills assessment in 2011. We analyzed correlations between residents' JSE scores; standardized patients' perspectives on residents' empathy during OSCE encounters, using the Jefferson Scale of Patient Perceptions of Physician Empathy; and residents' perspectives on their own empathy, using a modified version of this scale. RESULTS: Residents' JSE scores correlated with their perceptions of their own empathy during encounters but correlated poorly with patients' assessments of resident empathy. CONCLUSION: The poor correlation between residents' and standardized patients' assessments of residents' empathy raises questions about residents' abilities to gauge the effectiveness of their empathic communications. The study also points to a lack of congruence between the assessment of empathy by standardized patients and residents as receivers and conveyors of empathy, respectively. PRACTICE IMPLICATIONS: This study adds to the literature on empathy as a teachable skill set and raises questions about use of OSCEs to assess trainee empathy. PMID- 24793009 TI - CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a condition with central feature of hyperandrogensism that affects 5-12 % of women worldwide. P450sec the cholesterol side chain cleavage enzyme encoded by CYP11A1 gene is instrumental in the synthesis of sex hormones. A promoter pentanucleotide repeat (tttta)(n) polymorphism of this gene is reported to be associated with several hormone related diseases including PCOS. Here we aimed to examine the involvement of CYP11A1 polymorphism with PCOS susceptibility in a case-control study conducted among South Indian women. METHODS: A total of 542 subjects comprised of 267 PCOS patients and 275 controls were recruited. DNA was extracted from blood and CYP11A1 (tttta)(n) polymorphism was genotyped by PCR-PAGE. RESULTS: Fifteen different alleles ranging between 2-16 repeats were identified in the studied group and the most frequent allele observed in controls was of 8 repeats. The presence of >8 repeat allele was common in patients (64 % vs. 38 %) and showed a three-fold risk for PCOS susceptibility than controls (OR = 2.93; p < 0.05). PCOS women with higher BMI were markedly elevated in early quartile (p < 0.05). CONCLUSION: CYP11A1 (tttta)(n) repeat polymorphism appeared to be a potential molecular marker for PCOS risk in our population. Gene-gene and gene environmental interactions with respect to obesity may play a role in the early onset of this multifactorial condition. This is the first report from South India; however, replicative studies considering other probable causative factors for PCOS risk are warranted. PMID- 24793010 TI - Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications. AB - PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. METHODS: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. RESULTS: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57% and 39-69% for depression respectively). CONCLUSION: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations. PMID- 24793012 TI - A matter of accuracy. Nanobiochips in diagnostics and in research: ethical issues as value trade-offs. AB - The paper deals with the introduction of nanotechnology in biochips. Based on interviews and theoretical reflections, it explores blind spots left by technology assessment and ethical investigations. These have focused on possible consequences of increased diffusability of a diagnostic device, neglecting both the context of research as well as increased accuracy, despite it being a more essential feature of nanobiochip projects. Also, rather than one of many parallel aspects (technical, legal and social) in innovation processes, ethics is considered here as a ubiquitous system of choices between sometimes antagonistic values. Thus, the paper investigates what is at stake when accuracy is balanced with other practical values in different contexts. Dramatic nanotechnological increase of accuracy in biochips can raise ethical issues, since it is at odds with other values such as diffusability and reliability. But those issues will not be as revolutionary as is often claimed: neither in diagnostics, because accuracy of measurements is not accuracy of diagnostics; nor in research, because a boost in measurement accuracy is not sufficient to overcome significance chasing malpractices. The conclusion extends to methodological recommendations. PMID- 24793011 TI - Synthesis and evaluation of candidate PET radioligands for corticotropin releasing factor type-1 receptors. AB - INTRODUCTION: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. METHODS: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [(125)I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine 18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [(3)H]BMS-728300. RESULTS: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [(3)H]BMS-728300 and the two (18)F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [(18)F]BMS-721313, [(18)F]BMS-732098 and [(11)C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. CONCLUSIONS: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors. PMID- 24793013 TI - Using microRNA profiles to predict and evaluate hepatic carcinogenic potential. AB - Novel chemical entities have to be assessed for potential adverse effects in exposed human populations, including increased cancer incidence. The liver is an organ of particular interest for such evaluations, due to its central metabolic and detoxifying functions that render it a frequent target of exogenous carcinogens. In recent years a number of studies have investigated the use of microRNA (miRNA) biomarkers to facilitate the identification, characterization, and mechanistic understanding of chemical hepatocarcinogens. In this review we discuss the main findings of these studies, the potential biological significance of observed miRNA perturbations, and avenues of future research. PMID- 24793014 TI - Relaxed pericranial flap for distraction osteogenesis to treat craniosynostosis: a technique for wound reinforcement--technical note. AB - PURPOSE: Although distraction osteogenesis has been widely accepted to treat craniosynostosis, it occasionally results in wound complications. Positing that they are attributable to the tense pericranium under the scalp, we developed a simple technique to relax the pericranial flap. METHODS: In 12- to 15-month-old infants (mean 13 months), we placed a coronal skin incision and dissected the scalp at the subgaleal layer. Then, we peeled the intact pericranium away from the skull along the planned osteotomy to obtain flaps with pedicles on the caudal part. After osteotomy and setting of the distraction device, the pericranial flaps freed from the scalp flap were repositioned to fit the osteotomy line, dura, and distraction device. The galea and skin were approximated layer by layer. RESULTS: The shape of the skull was successfully corrected, and the bone defect created by expansion was filled by osteogenesis in all patients. During a mean follow-up period of 42.2 months, we encountered no wound complications. CONCLUSIONS: The replaced relaxed pericranium closely adhered to the osteotomy, and the distraction device facilitated vascular growth and bone restoration. Bone resorption was prevented and skin expansion promoted. In patients with iatrogenic dural injury, the pericranium over the injured dura serves as a barrier to prevent cerebrospinal fluid leakage. PMID- 24793015 TI - Association of DNA repair gene polymorphisms with response to chemotherapy and prognosis of gastric cancer in a Chinese population. AB - We conducted a study to investigate the role of excision repair cross complimentary group 1 gene (ERCC1)-xeroderma pigmentosum complementation group F (XPF) gene polymorphisms in response to chemotherapy and clinical outcome of gastric patients. Three SNPs in ERCC1 (rs11615, rs3212986, and rs2298881) and two SNPs in XPF (rs2276465 and rs6498486) were extracted using Tiangen DNA kit (Tiangen Biotech, Beijing, China) according to the manufacturer's instructions. The median follow-up time was 36.4 months, and ranged from 2-60 months. During the follow-up period, 112 patients died from gastric cancer. Individuals carrying ERCC1 rs11615 AA and XPF rs6498486 CC genotypes were associated with poorer response to chemotherapy when compared with wild-type genotype, with the ORs (95 % CI) of 0.48 (0.25-0.94) and 0.38 (0.14-1.00). In the Cox proportional hazards model, individuals carrying ERCC1 rs11615 GA and AA genotype had 1.91 and 2.66 risk of death when compared with those carrying GG genotype. Patients carrying the XPF rs6498486 AC and CC genotype were associate with 2.17 and 4.91-fold risk of death when compared with wild-type genotype. In conclusion, we found that ERCC1 rs11615 and XPF rs2276465 may substantially contribute to the future design of individualized cancer treatment in gastric cancer patients. PMID- 24793016 TI - ADAM17 is associated with EMMPRIN and predicts poor prognosis in patients with uterine cervical carcinoma. AB - Metalloproteinase activities of a disintegrin and metalloproteinase 17 (ADAM17), amphiregulin (AREG), extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinases (MMPs) are involved in tumor biology. In patients with uterine cervical carcinoma, the expression and prognostic significance of ADAM17 remain to be fully elucidated. The expression of ADAM17, AREG, EMMPRIN, phospho-epidermal growth factor receptor (p-EGFR), phospho-extracellular signal regulated kinase (p-ERK), MMP-2, and MMP-9 was assessed by immunohistochemistry and/or Western blotting from cervical carcinoma cell lines, SiHa and HeLa cells, and cervical carcinoma tissues. AREG activity was measured by ELISA assay. The correlation of ADAM17, AREG, EMMPRIN, and MMP-9 expression with patients' survival rates was assessed by Kaplan-Meier and Cox regression analyses. RNA interference (RNAi) experiment was performed using small interfering mRNA to ADAM17 and EMMPRIN. ADAM17, EMMPRIN, and MMP-9 protein content was overexpressed in cervical carcinoma tissues compared with normal cervical tissues (P < 0.05). Strong expression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly associated with stages, lymph node metastasis, differentiation, and parametrium invasion (P < 0.05). Overexpression of ADAM17, AREG, EMMPRIN, and MMP-9 was significantly correlated with short progression-free survival and overall survival (P < 0.05). Multivariate analysis suggested that lymph node metastasis, parametrium invasion, and ADAM17 expression were independent prognostic indicators for cervical cancer. ADAM17 RNAi decreased EMMPRIN, p-EGFR, p-ERK, MMP 2, and MMP-9 proteins in SiHa and HeLa cells. ELISA assay revealed that AREG activity was stimulated by ADAM17 and was reversed by ADAM17 RNAi in SiHa and HeLa cells. Our data suggest that the increased expression of ADAM17 in cervical cancer is significantly associated with aggressive progression and poor prognosis. ADAM17 may be a molecular marker for predicting the progression and prognosis in cervical cancer. PMID- 24793017 TI - Long non-coding RNA MVIH indicates a poor prognosis for non-small cell lung cancer and promotes cell proliferation and invasion. AB - Long non-coding RNAs (lncRNAs) have emerged as major players in governing fundamental biological processes, and many of which are misregulated in multiple cancers and likely to play a functional role in tumorigenesis. Therefore, identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are important for understanding the development and progression of cancer. lncRNA associated with microvascular invasion in HCC (lncRNA MVIH) was found to be generally upregulated in HCC. Moreover, MVIH overexpression could serve as an independent risk factor to predict poor RFS and promote tumor growth and metastasis via activating angiogenesis. However, its biological role and clinical significance in non-small cell lung cancer (NSCLC) development and progression is unknown. In this study, we found that lncRNA MVIH levels were increased in NSCLC tissues compared with adjacent normal tissues. Its expression level was significantly correlated with TNM stages, tumor size, and lymph node metastasis. Moreover, patients with high levels of MVIH expression had a relatively poor prognosis. Furthermore, knockdown of MVIH expression by siRNA could inhibit cell proliferation and invasion, while ectopic expression of MVIH promoted cell proliferation and invasion in NSCLC cells partly via regulating MMP2 and MMP9 protein expression. Our findings present that increased lncRNA MVIH could be identified as a poor prognostic biomarker in NSCLC and regulate cell proliferation and invasion. PMID- 24793018 TI - Tritrichomonas foetus: characterisation of ecto-phosphatase activities in the endoflagelar form and their possible participation on the parasite's transformation and cytotoxicity. AB - The protist parasite Tritrichomonas foetus displays a pear-shaped (PS) and a pseudocystic or endoflagellar form (EFF). Here, we characterised the ecto phosphatase activity on the surface of EFF and compare its biochemical properties to that of the PS regarding rate of substrate hydrolysis, pH activation profile and sensitivity to well-known phosphatases inhibitors. Two strains exhibiting low and high-cytotoxicity were used. The enzyme activities of PS and EFF exhibited similar characteristics of protein tyrosine phosphatases (PTP). However, the ecto phosphatase activities for both forms presented distinct kinetic parameters and different inhibition patterns by PTP inhibitors, suggesting the presence of distinct ecto-enzyme activities between PS and EFF, as well, between both strains. Ultrastructural cytochemistry confirmed the differential distribution of the ecto-phosphatase activity during the EFF transformation. An increase in the percentage of the EFF resulted in a proportional increase in the ecto-phosphatase activity. During EFF reversion, ecto-phosphatase activity decreased and was restored to the level found in the parasites before EFF induction. PS and EFF from the high-cytotoxic strain exhibited higher ecto-phosphatase activities than PS and EFF from the low-cytotoxic strain, respectively. In both strains, the EFF was more cytotoxic and exhibited higher ecto-phosphatase activity when compared to the PS. A large part of the ecto-phosphatase activities of EFF from both strains and PS from the high-cytotoxic strain was irreversibly inhibited when the parasites were pre-treated with a specific antibody against amoebic PTP (anti EhPRL). Immunoreaction assays revealed that the anti-EhPRL antibody cross-reacted with a 24-kDa protein differentially expressed on the cell surface of PS and EFF T. foetus. A positive correlation was observed between the surface expression of 24-kDa protein and ecto-phosphatase activity. Irreversible inhibition of a part of the ecto-phosphatase activities partially blocked the EFF induction and the cytotoxic effects exerted by both forms. These results suggest that the ecto phosphatase activities could play a role on the EFF transformation and cytotoxicity of T. foetus. PMID- 24793019 TI - A reliable, low-cost picture archiving and communications system for small and medium veterinary practices built using open-source technology. AB - Picture Archiving and Communications Systems (PACS) are the most needed system in a modern hospital. As an integral part of the Digital Imaging and Communications in Medicine (DICOM) standard, they are charged with the responsibility for secure storage and accessibility of the diagnostic imaging data. These machines need to offer high performance, stability, and security while proving reliable and ergonomic in the day-to-day and long-term storage and retrieval of the data they safeguard. This paper reports the experience of the authors in developing and installing a compact and low-cost solution based on open-source technologies in the Veterinary Teaching Hospital for the University of Torino, Italy, during the course of the summer of 2012. The PACS server was built on low-cost x86-based hardware and uses an open source operating system derived from Oracle OpenSolaris (Oracle Corporation, Redwood City, CA, USA) to host the DCM4CHEE PACS DICOM server (DCM4CHEE, http://www.dcm4che.org ). This solution features very high data security and an ergonomic interface to provide easy access to a large amount of imaging data. The system has been in active use for almost 2 years now and has proven to be a scalable, cost-effective solution for practices ranging from small to very large, where the use of different hardware combinations allows scaling to the different deployments, while the use of paravirtualization allows increased security and easy migrations and upgrades. PMID- 24793020 TI - Informatics challenges-lossy compression in medical imaging. PMID- 24793021 TI - Accurate amorphous silica surface models from first-principles thermodynamics of surface dehydroxylation. AB - Accurate atomically detailed models of amorphous materials have been elusive to date due to limitations in both experimental data and computational methods. We present an approach for constructing atomistic models of amorphous silica surfaces encountered in many industrial applications (such as catalytic support materials). We have used a combination of classical molecular modeling and density functional theory calculations to develop models having predictive capabilities. Our approach provides accurate surface models for a range of temperatures as measured by the thermodynamics of surface dehydroxylation. We find that a surprisingly small model of an amorphous silica surface can accurately represent the physics and chemistry of real surfaces as demonstrated by direct experimental validation using macroscopic measurements of the silanol number and type as a function of temperature. Beyond accurately predicting the experimentally observed trends in silanol numbers and types, the model also allows new insights into the dehydroxylation of amorphous silica surfaces. Our formalism is transferrable and provides an approach to generating accurate models of other amorphous materials. PMID- 24793023 TI - Syphilitic gummas mistaken for liver metastases. PMID- 24793022 TI - Integrated analysis of transcriptome and metabolome of Arabidopsis albino or pale green mutants with disrupted nuclear-encoded chloroplast proteins. AB - We used four mutants having albino or pale green phenotypes with disrupted nuclear-encoded chloroplast proteins to analyze the regulatory system of metabolites in chloroplast. We performed an integrated analyses of transcriptomes and metabolomes of the four mutants. Transcriptome analysis was carried out using the Agilent Arabidopsis 2 Oligo Microarray, and metabolome analysis with two mass spectrometers; a direct-infusion Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR/MS) and a gas chromatograph-time of flight mass spectrometer. Among approximately 200 known metabolites detected by the FT ICR/MS, 71 metabolites showed significant changes in the mutants when compared with controls (Ds donor plants). Significant accumulation of several amino acids (glutamine, glutamate and asparagine) was observed in the albino and pale green mutants. Transcriptome analysis revealed altered expressions of genes in several metabolic pathways. For example, genes involved in the tricarboxylic acid cycle, the oxidative pentose phosphate pathway, and the de novo purine nucleotide biosynthetic pathway were up-regulated. These results suggest that nitrogen assimilation is constitutively promoted in the albino and pale green mutants. The accumulation of ammonium ions in the albino and pale green mutants was consistently higher than in Ds donor lines. Furthermore, genes related to pyridoxin accumulation and the de novo purine nucleotide biosynthetic pathway were up-regulated, which may have occurred as a result of the accumulation of glutamine in the albino and pale green mutants. The difference in metabolic profiles seems to be correlated with the disruption of chloroplast internal membrane structures in the mutants. In albino mutants, the alteration of metabolites accumulation and genes expression is stronger than pale green mutants. PMID- 24793024 TI - Reply: To PMID 24703865. PMID- 24793025 TI - Keratitis caused by Pythium insidiosum in an immunosuppressed patient with Crohn's disease. PMID- 24793027 TI - Biliary obstruction from paraesophageal hernia. PMID- 24793026 TI - Nonsteroidal anti-inflammatory drugs and the risk of Barrett's esophagus. AB - BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested to protect against esophageal adenocarcinoma (EAC). This study examined the effect of NSAIDs on the risk of developing Barrett's esophagus (BE), the precursor lesion to EAC. METHODS: We conducted a case-control study among eligible patients scheduled for either elective esophagogastroduodenoscopy (EGD) or recruited from primary care clinics to undergo a study EGD. We compared 323 patients with BE (296 nondysplastic and 27 dysplastic) with 2 separate control groups: 1347 patients from the elective EGD group (endoscopy controls) and 502 patients from the primary care group (primary care controls) with no endoscopic or histopathologic BE. Use of aspirin products and 23 nonaspirin NSAIDs was ascertained from detailed, self-reported questionnaires. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models. RESULTS: There were no significant differences in self reported NSAID use between all BE cases and all controls (58.2% vs 54.6%; P = .33); this was seen for aspirin products (43.0% vs 37.4%; P = .08) and nonaspirin NSAIDs (7.7% vs 8.9%; P = .46). These findings persisted in the multivariable model for any NSAIDs (adjusted OR, 0.89; 95% CI, 0.75-1.28), aspirin (adjusted OR, 1.16; 95% CI, 0.90-1.51), and nonaspirin NSAIDs (adjusted OR, 0.88; 95% CI, 0.55-1.39). Use of a combination of aspirin and nonaspirin NSAIDs was reported in 7.4% of cases and 8.3% of controls, and a nonsignificant inverse association with BE was seen (adjusted OR, 0.70; 95% CI, 0.44-1.11). There was no significant association between BE and daily NSAID use (adjusted OR, 1.03; 95% CI, 0.78 1.37). Similar findings were observed for comparisons involving nondysplastic or dysplastic BE cases, and endoscopy or primary care control groups separately or combined. CONCLUSIONS: The use of NSAIDs was not associated with a reduced risk of BE. It is likely that the protective mechanism of NSAIDs on EAC occurs subsequent to the development of BE. PMID- 24793029 TI - The injectable bulking agent nonanimal stabilized hyaluronic acid/dextranomer is a safe and effective treatment for patients with fecal incontinence. PMID- 24793028 TI - Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis. AB - BACKGROUND & AIMS: Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. METHODS: We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 MUg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 MUg/g. Secondary outcomes were continued remission with FC <100 MUg/g or <200 MUg/g (among patients with pre-randomization values above these levels). RESULTS: The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 MUg/g (P = .04) and 200 MUg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 MUg/g compared with those with FC <200 MUg/g (P = .01). CONCLUSIONS: Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145. PMID- 24793030 TI - Small intestinal CD4+ T-cell lymphoma: a subset with possible indolent clinical behavior. PMID- 24793031 TI - Associations of coagulation factor V Leiden and prothrombin G20210A mutations with Budd-Chiari syndrome and portal vein thrombosis: a systematic review and meta-analysis. AB - BACKGROUND & AIMS: We conducted a systematic review and meta-analysis to evaluate the associations of the coagulation factor V (encoded by F5) Leiden (FVL) or prothrombin (encoded by F2) G20210A mutation with Budd-Chiari syndrome or portal vein thrombosis (PVT). METHODS: Relevant articles were identified in searches of the PubMed, EMBASE, Cochrane Library, and ScienceDirect databases. The prevalence of the FVL and prothrombin G20210A mutations were compared between patients with Budd-Chiari syndrome or PVT without cirrhosis and healthy individuals (controls) and between patients with cirrhosis, with and without PVT. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: We initially identified 869 articles, and included 27 in our final analysis. Compared with controls, patients with Budd-Chiari syndrome had a significantly higher prevalence of the FVL mutation (OR, 6.21; 95% CI, 3.93-9.79) and a similar prevalence of the prothrombin G20210A mutation (OR, 1.90; 95% CI, 0.69-5.23); patients with PVT without cirrhosis had a significantly higher prevalence of the FVL mutation (OR, 1.85; 95% CI, 1.09-3.13) or the prothrombin G20210A mutation (OR, 5.01; 95% CI, 3.03-8.30). Compared with patients with cirrhosis without PVT, patients with cirrhosis and PVT had a significantly higher prevalence of the FVL mutation (OR, 2.55; 95% CI, 1.29-5.07). We observed a trend toward a higher prevalence of the prothrombin G20210A mutation in patients with cirrhosis and PVT, but the difference was not statistically significant (OR, 2.93; 95% CI, 0.94-9.07). CONCLUSIONS: Based on a meta-analysis, the FVL mutation is associated with an increased risk of Budd-Chiari syndrome, PVT without cirrhosis, and PVT in cirrhosis. The prothrombin G20210A mutation is associated with PVT, but not Budd Chiari syndrome. Studies are needed to confirm these findings in different racial and ethnic groups. PMID- 24793032 TI - Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. AB - DNA damage is considered to be a prime factor in several spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. We observed the endogenous accumulation of pathogenic topoisomerase-1 (Top1)-DNA cleavage complexes (Top1ccs) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We found that the defective DNA damage response factors in these two diseases cooperatively modulated Top1cc turnover in a non-epistatic and ATM kinase independent manner. Furthermore, coincident neural inactivation of ATM and DNA single-strand break repair factors, including tyrosyl-DNA phosphodiesterase-1 or XRCC1, resulted in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Notably, direct Top1 poisoning to elevate Top1cc levels phenocopied the neuropathology of the mouse models described above. Our results identify a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating that genome integrity is important for preventing disease in the nervous system. PMID- 24793034 TI - Exploration and comparison of crash modification factors for multiple treatments on rural multilane roadways. AB - As multiple treatments (or countermeasures) are simultaneously applied to roadways, there is a need to assess their combined safety effects. Due to a lack of empirical crash modification factors (CMFs) for multiple treatments, the Highway Safety Manual (HSM) and other related studies developed various methods of combining multiple CMFs for single treatments. However, the literature did not evaluate the accuracy of these methods using CMFs obtained from the same study area. Thus, the main objectives of this research are: (1) develop CMFs for two single treatments (shoulder rumble strips, widening shoulder width) and one combined treatment (shoulder rumble strips+widening shoulder width) using before after and cross-sectional methods and (2) evaluate the accuracy of the combined CMFs for multiple treatments estimated by the existing methods based on actual evaluated combined CMFs. Data was collected for rural multi-lane highways in Florida and four safety performance functions (SPFs) were estimated using 360 reference sites for two crash types (All crashes and Single Vehicle Run-off Roadway (SVROR) crashes) and two severity levels (all severity (KABCO) and injury (KABC)). The results of both before-after and cross-sectional methods show that the two single treatments and the combined treatment produced safety improvement. It was found that safety effects were higher for the roadway segments with shoulder rumble strips and wider shoulder width. It was also found that the treatments were more safety effective (i.e. lower CMF) for the roadway segments with narrower original shoulder width in the before period. However, although CMFs for multiple treatments were generally lower than CMFs for single treatments, they were similar for the roadway segments with shoulder width of 8 12 feet. More specifically, CMFs for single treatments were lower than CMFs for multiple treatments for the roadway segments with shoulder width of 9 feet or higher. Among different methods of combining CMFs, the HSM, Systematic Reduction of Subsequent CMFs, Applying only the most effective CMF, and Weighted average of multiple CMFs (Meta-Analysis) showed good estimates of the combined CMFs for multiple treatments with 2.2% difference between actual and estimated CMFs. The findings suggest that the existing methods of combining multiple CMFs are generally valid but they need to be applied for different crash types and injury levels separately. Lastly, an average of the combined CMFs from the best two methods was closer to the actual CMF than the combined CMF from only one best method. This indicates that it is better not to rely on only one specific existing method of combining CMFs for predicting CMF for multiple treatments. PMID- 24793033 TI - Comparison of self-report-based and physical performance-based frailty definitions among patients receiving maintenance hemodialysis. AB - BACKGROUND: A well-accepted definition of frailty includes measurements of physical performance, which may limit its clinical utility. STUDY DESIGN: In a cross-sectional study, we compared prevalence and patient characteristics based on a frailty definition that uses self-reported function to the classic performance-based definition and developed a modified self-report-based definition. SETTING & PARTICIPANTS: Prevalent adult patients receiving hemodialysis in 14 centers around San Francisco and Atlanta in 2009-2011. INDEX TESTS: Self-report-based frailty definition in which a score lower than 75 on the Physical Function scale of the 36-Item Short Form Health Survey (SF-36) was substituted for gait speed and grip strength in the classic definition; modified self-report definition with optimized Physical Function score cutoff points derived in a development (one-half) cohort and validated in the other half. REFERENCE TEST: Performance-based frailty defined as 3 of the following: weight loss, weakness, exhaustion, low physical activity, and slow gait speed. RESULTS: 387 (53%) patients were frail based on self-reported function, of whom 209 (29% of the cohort) met the performance-based definition. Only 23 (3%) met the performance-based definition of frailty only. The self-report definition had 90% sensitivity, 64% specificity, 54% positive predictive value, 93% negative predictive value, and 72.5% overall accuracy. Intracellular water per kilogram of body weight and serum albumin, prealbumin, and creatinine levels were highest among nonfrail individuals, intermediate among those who were frail by self report, and lowest among those who also were frail by performance. Age, percentage of body fat, and C-reactive protein level followed an opposite pattern. The modified self-report definition had better accuracy (84%; 95% CI, 79%-89%) and superior specificity (88%) and positive predictive value (67%). LIMITATIONS: Our study did not address prediction of outcomes. CONCLUSIONS: Patients who meet the self-report-based but not the performance-based definition of frailty may represent an intermediate phenotype. A modified self-report definition can improve the accuracy of a questionnaire-based method of defining frailty. PMID- 24793036 TI - What if all our patients were friends or family? PMID- 24793037 TI - Protocol design and optimization. PMID- 24793038 TI - PQRS becoming easier for radiology. PMID- 24793039 TI - ACR appropriateness criteria post-treatment follow-up of renal cell carcinoma. AB - Although localized renal cell carcinoma can be effectively treated by surgery or ablative therapies, local or distant metastatic recurrence after treatment is not uncommon. Because recurrent disease can be effectively treated, patient surveillance after treatment of renal cell carcinoma is very important. Surveillance protocols are generally based on the primary tumor's size, stage, and nuclear grade at the time of resection, as well as patterns of tumor recurrence, including where and when metastases occur. Various imaging modalities may be used in the evaluation of these patients. Literature on the indications and usefulness of these radiologic studies is reviewed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 24793040 TI - Performance measures in radiology. AB - Performance measures in radiology play an increasingly significant role in health care quality assessment and now form the basis for a variety of pay-for performance programs, including those administered by CMS. This article introduces the measure development process, beginning with topic selection, followed by measure development and testing, National Quality Forum endorsement, and implementation. Once implemented, measures may undergo further testing and be re-endorsed, modified, or retired. Radiologists should familiarize themselves with the measures relevant to their practice, develop ways to collect and report data efficiently, and implement the necessary practice changes to meet measure criteria and improve the quality of their practice. PMID- 24793041 TI - How competitive is the match for radiology residency? Present view and historical perspective. AB - PURPOSE: Interest in radiology as a career among US medical students has changed. The aim of this study was to investigate the recent and historical trends in residency applications and how they have affected competitiveness in obtaining a position. METHODS: Statistics published by the National Resident Matching Program in "Results and Data: Main Residency Match" for 1991 to 2013 were analyzed. RESULTS: The number of radiology residency positions has trended upward over the past 23 years; however, the number of applicants from US medical schools has been widely variable. The number of applicants peaked in 2009 but has since decreased every year. The number of positions per US senior applicant (PPUSA) is a judge of specialty competitiveness on a supply-and-demand basis. A lower PPUSA indicates a more competitive specialty. Radiology saw its most competitive year in 2001, with only 0.91 PPUSA. PPUSA has been on the rise every year since 2009. From 2009 to 2013, the number of residency positions increased by 56, but there were 241 fewer US senior medical students preferring radiology. In 2013, there were 1,143 residency positions available for only 845 US senior medical students who preferred the specialty. The PPUSA was 1.35, making 2013 the least competitive year in obtaining a radiology residency position since 1998. Over the past 23 years, 5.5% of all US senior medical students have applied to radiology for residency. Interest reached an all-time high in 2009, at almost 7%. In 2013, only 4.8% of all US seniors preferred radiology, the lowest since 1999. The historical (1991-2013), current (2011-2013), and most recent (2013) PPUSAs for radiology were 1.19, 1.29, and 1.35, respectively. For comparison, the current PPUSAs for the following specialties were: 0.74 for plastic surgery, 0.83 for orthopedic surgery, 0.95 for dermatology, 1.10 for general surgery, 1.24 for obstetrics and gynecology, 1.31 for anesthesiology, 1.42 for pediatrics, and 1.80 for internal medicine (1.80). CONCLUSIONS: Although radiology residency positions have continued to increase, interest among US seniors has dropped every year since 2009. The 2013 match was the least competitive since 1998. Over the past 3 years, the competitiveness of matching radiology on a supply-and-demand basis has been close to that of obstetrics and gynecology and anesthesiology. PMID- 24793042 TI - Societal and individual determinants of patients' radiation safety behavior: a preliminary investigation from China. PMID- 24793043 TI - The conundrums surrounding medical imaging radiation dose. PMID- 24793044 TI - Response to letter to the editor: Acinetobacter baumannii using several mechanisms for carbapenem resistance. PMID- 24793045 TI - Skin substitutes: which one do we know, which one do we use? PMID- 24793046 TI - Impact of reduced resuscitation fluid on outcomes of children with 10-20% body surface area scalds. AB - 'Permissive hypovolaemia' fluid regimes in adult burn care are suggested to improve outcomes. Effects in paediatric burn care are less well understood. In a retrospective audit, outcomes of children from the South West Children's Burn Centre (SWCBC) less than 16 years of age with scalds of 10-20% burn surface area (BSA) managed with a reduced volume fluid resuscitation regime (post-2007) were compared to (a) an historical local protocol (pre-2007) and (b) current regimes in burn services across England and Wales (E&W). Outcomes included length of stay per percent burn surface area (LOS/%BSA), skin graft requirement and re-admission rates. 92 SWCBC patients and 475 patients treated in 15 other E&W burn services were included. Median LOS/%BSA for patients managed with the reduced fluid regime was 0.27 days: significantly less than pre-2007 and other E&W burn services (0.54 days, 0.50 days, p<0.001). Skin grafting to achieve healing reduced post-2007 compared to pre-2007 and remains comparable with other E&W services. Re-admission rates were comparable between all groups. A reduced fluid regime has significantly shortened LOS/%BSA without compromising burn depth as measured by skin grafting to achieve healing. A prospective trial comparing permissive hypovolaemia to current regimes for moderate paediatric scald injuries would help clarify. PMID- 24793047 TI - Localization of Kv4.2 and KChIP2 in lipid rafts and modulation of outward K+ currents by membrane cholesterol content in rat left ventricular myocytes. AB - Lipid rafts are cholesterol-enriched microdomains of the cell membrane. Here we investigate the localization of the pore forming K(+)-channel alpha-subunit Kv4.2 and the beta-subunit KChIP2, underlying the transient outward K(+) current (I to), in lipid rafts in left ventricular myocytes. Furthermore, we explored the impact of membrane cholesterol depletion (using 20 mM methyl-beta-cyclodextrin (MBCD)) on K(+) outward currents. Cholesterol-saturated MBCD (20 mM) served as control. Myocytes were isolated from the left ventricular free wall of Wistar rats. The Triton X-100 (4 degrees C) insoluble fraction of whole cell protein was analyzed by sucrose density gradient centrifugation followed by Western blot. Kv4.2 and KChIP2 were partially detected in low-density fractions (lipid rafts). MBCD treatment (5 min) resulted in a shift of Kv4.2 and KChIP2 towards high density fractions. K(+) currents were assessed by whole-cell patch-clamp. MBCD treatment resulted in a 29 +/- 3 % decrease in I to (20.0 +/- 1.6pApF(-1) vs. 28.5 +/- 2.0pApF(-1), n = 15, p < 0.001, V Pip = 40 mV) within 5 min. Control solution resulted in a significantly smaller reduction in I to (17 +/- 3 %, p < 0.001, p < 0.01 compared with MBCD). MBCD induced a 38 +/- 9 % increase in the non-inactivating current component (I sus) (10.1 +/- 0.6pApF(-1) vs. 7.6 +/- 0.4pApF(-1), n = 15, p < 0.001). This effect was absent in control solution. The increase in I sus was not sensitive to 100 MUM 4-aminopyridine or 20 mM tetraethylammonium, making a contribution of Kv1.5 or Kv2.1 unlikely. In conclusion, in rat ventricular cardiomyocytes, a fraction of Kv4.2 and KChIP2 is localized in lipid rafts. Membrane cholesterol depletion results in ~12 % net reduction of I to, a redistribution of the channel proteins Kv4.2 and KChIP2 and an increased delayed rectifier current. PMID- 24793049 TI - Novel drug mechanisms in development for heart failure. AB - Heart failure therapy has seen many advances over the last 40 years and has rapidly expanded beyond diuretics and digoxin to include several new mechanisms of action and devices whose efficacy had been demonstrated in large clinical trials. The evidence for their use is thoroughly summarized and discussed in current heart failure treatment guidelines and is not the subject of this review. Despite these advances, the mortality and morbidity in heart failure patients is still substantial, and there remains a need to develop new heart failure therapies. Recognizing that advances in medical therapy are often driven by the introduction of drugs with novel mechanisms of action, here we provide an overview of investigative heart failure drugs with novel mechanisms of action that are the subject of ongoing clinical trials. PMID- 24793050 TI - Effects of light-emitting diodes on expression of phenylpropanoid biosynthetic genes and accumulation of phenylpropanoids in Fagopyrum tataricum sprouts. AB - Buckwheat sprouts are a popular food item in many countries. The effects of light emitting diodes (LEDs) on sprout growth and development, changes in mRNA transcription, and accumulation of phenylpropanoid compounds were studied in tartary buckwheat 'Hokkai T8' sprouts. The highest transcript levels were observed after 2 days of LED exposure for all genes, especially FtPAL and FtF3'H, which showed higher expression in sprouts grown under blue and white light than in those grown under red light. Catechin content in sprouts grown under red light increased dramatically throughout the 10 day time course. Maximum rutin content (43.37 mg/g dry weight (DW)) was observed in sprouts at 4 days after exposure (DAE) to blue light. Similarly, the highest cyanidin 3-O-rutinoside content (0.85 mg/g DW) was detected at 10 DAE to blue light. On the basis of these results, blue LED light is recommended as a light source for enhancing the content of phenolic compounds in tartary buckwheat sprouts. PMID- 24793048 TI - Hydrogen sulfide impairs shear stress-induced vasodilation in mouse coronary arteries. AB - Hydrogen sulfide has emerged as an important endothelium-dependent vasodilator, but its role in shear stress-mediated dilation of coronary arteries is unclear. We examined the role of H2S on shear stress-mediated dilation of isolated mouse coronary arteries. In these vessels, Na2S produced concentration-dependent dilation, which was significantly inhibited by iberiotoxin and by 4 aminopyridine. In addition, BK and Kv currents in mouse coronary smooth muscle cells were directly activated by Na2S, suggesting that H2S produced vasodilation through BK and Kv channel activation. Using a pressure servo controller system, freshly isolated mouse coronary arteries were subjected to physiological levels of shear stress (1 to 25 dynes/cm(2)) and produced graded dilatory responses, but such effects were diminished in the presence of 100 MUM Na2S. Pre-incubation with the cystathionine gamma-lyase inhibitor, D,L-propargylglycine (PPG), resulted in a paradoxical augmentation of shear stress-mediated vasodilation. However, in the presence of L-NAME or in coronary arteries from eNOS knockout mice, PPG inhibited shear stress-mediated vasodilation, suggesting an interaction between NO and H2S signaling. Na2S inhibited eNOS activity in cultured mouse aortic endothelial cells and reduced the level of phospho-eNOS(serine 1177). These results suggest that both NO and H2S are important shear stress-mediated vasodilators in mouse coronary arteries but there is a complex interaction between these two signaling pathways that results in paradoxical vasoconstrictive effects of H2S through inhibition of NO generation. PMID- 24793051 TI - Study on the disulfide bond and disulfide loop of native and mutated SOD1 protein. AB - The superoxide anions in the human body are reduced into hydrogen peroxide and molecular oxygen by the metallo enzyme Cu-Zn superoxide dismutase 1. The disulfide bond in SOD1 is essential to maintain the structural stability of protein and its proper folding. A computational study on the disulfide bond with the addition of residues was made using three different level of theories viz., B3LYP/6-31G (d,p), M052X/6-31G (d,p) and MP2/6-31G (d,p). The nature of disulfide bond was found to be unaffected with the additional residues being attached to the termini of cysteine residues. This result was found to be in agreement with the experimental values. The results of Molecular Dynamics simulation illustrate the crinkled appearance caused in the disulfide loop of A4V mutation. The conformational change in the disulfide loop was found to have significant effect on the loss of dimerization, metal binding affinity and overall protein stability. It is also noted that the disulfide loop with more number of residues is found to have no effect on the disulfide bond characteristics, but the disulfide loop with less number of residues is found to have remarkable effect for mutation in any position of the wild type protein. PMID- 24793052 TI - Effect of D23N mutation on the dimer conformation of amyloid beta-proteins: ab initio molecular simulations in water. AB - The molecular pathogenesis of Alzheimer's disease (AD) is deeply involved in aggregations of amyloid beta-proteins (Abeta) in a diseased brain. The recent experimental studies indicated that the mutation of Asp23 by Asn (D23N) within the coding sequence of Abeta increases the risk for the pathogeny of cerebral amyloid angiopathy and early-onset familial ADs. Fibrils of the D23N mutated Abetas can form both parallel and antiparallel structures, and the parallel one is considered to be associated with the pathogeny. However, the structure and the aggregation mechanism of the mutated Abeta fibrils are not elucidated at atomic and electronic levels. We here investigated solvated structures of the two types of Abeta dimers, each of which is composed of the wild-type or the D23N mutated Abeta, using classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods, in order to reveal the effect of the D23N mutation on the structure of Abeta dimer as well as the specific interactions between the Abeta monomers. The results elucidate that the effect of the D23N mutation is significant for the parallel structure of Abeta dimer and that the solvating water molecules around the Abeta dimer have significant contribution to the stability of Abeta dimer. PMID- 24793053 TI - Computational study of protein secondary structure elements: Ramachandran plots revisited. AB - Potential energy surface (PES) were built for nineteen amino acids using density functional theory (PW91 and DFT M062X/6-311**). Examining the energy as a function of the phi/psi dihedral angles in the allowed regions of the Ramachandran plot, amino acid groups that share common patterns on their PES plots and global minima were identified. These patterns show partial correlation with their structural and pharmacophoric features. Differences between these computational results and the experimentally noted permitted conformations of each amino acid are rationalized on the basis of attractive intra- and inter molecular non-covalent interactions. The present data are focused on the intrinsic properties of an amino acid - an element which to our knowledge is typically ignored, as larger models are always used for the sake of similarity to real biological polypeptides. PMID- 24793054 TI - Voxel based parallel post processor for void nucleation and growth analysis of atomistic simulations of material fracture. AB - Molecular dynamics (MD) simulations are used in the study of void nucleation and growth in crystals that are subjected to tensile deformation. These simulations are run for typically several hundred thousand time steps depending on the problem. We output the atom positions at a required frequency for post processing to determine the void nucleation, growth and coalescence due to tensile deformation. The simulation volume is broken up into voxels of size equal to the unit cell size of crystal. In this paper, we present the algorithm to identify the empty unit cells (voids), their connections (void size) and dynamic changes (growth and coalescence of voids) for MD simulations of large atomic systems (multi-million atoms). We discuss the parallel algorithms that were implemented and discuss their relative applicability in terms of their speedup and scalability. We also present the results on scalability of our algorithm when it is incorporated into MD software LAMMPS. PMID- 24793055 TI - Molecular dynamics analysis of the interaction between the human BCL6 BTB domain and its SMRT, NcoR and BCOR corepressors: the quest for a consensus dynamic pharmacophore. AB - Targeting the BCL6 protein is a promising therapeutic strategy for the treatment of B cell lymphomas. One approach to treat these diseases consists of finding drug candidates able to disrupt the interactions established between BCL6 and its corepressors. Thus, this work presents a thorough comparative analysis of the interactions between the BCL6 BTB (bric-a-brac tramtrack broad complex) protein domain and its SMRT, NcoR and BCOR corepressor BBDs (BCL6 binding domain) through molecular dynamics. Moreover, a theoretical structure is presented and checked for the BCL6(BTB)-NcoR(BBD) complex. Considering the BBDs to be composed of 17 amino acids, our analyses show the region involving residues 4-15 of these 17 to play a main role in the protein-corepressor interactions. Particularly SER(11) seems to have a high relevance as it establishes specific bonds with BCL6(BTB) and is one of the only two residues sequence equivalent for the three studied corepressors. From this study, 14 pharmacophoric points have been proposed divided in two groups which coincide with residues 4-11 and 11-15, being SER(11) a hinge point. This finding suggests the possibility of searching for 2 small molecule inhibitors, mimicking 8 and 7 pharmacophoric points, respectively, which could incorporate a hydrogen donor pharmacophoric point mimicking SER(11) in any or both molecules. In short, the present work aims to contribute further knowledge in the modeling of drugs mimicking BCL6(BTB)-corepressor complexes. PMID- 24793057 TI - Effects of India's new polio policy on travellers. PMID- 24793056 TI - Monocytes/Macrophages control resolution of transient inflammatory pain. AB - Insights into mechanisms governing resolution of inflammatory pain are of great importance for many chronic pain-associated diseases. Here we investigate the role of macrophages/monocytes and the anti-inflammatory cytokine interleukin-10 (IL-10) in the resolution of transient inflammatory pain. Depletion of mice from peripheral monocytes/macrophages delayed resolution of intraplantar IL-1beta- and carrageenan-induced inflammatory hyperalgesia from 1 to 3 days to >1 week. Intrathecal administration of a neutralizing IL-10 antibody also markedly delayed resolution of IL-1beta- and carrageenan-induced inflammatory hyperalgesia. Recently, we showed that IL-1beta- and carrageenan-induced hyperalgesia is significantly prolonged in LysM-GRK2(+/-) mice, which have reduced levels of G protein-coupled receptor kinase 2 (GRK2) in LysM(+) myeloid cells. Here we show that adoptive transfer of wild-type, but not of GRK2(+/-), bone marrow-derived monocytes normalizes the resolution of IL-1beta-induced hyperalgesia in LysM GRK2(+/-) mice. Adoptive transfer of IL-10(-/-) bone marrow-derived monocytes failed to normalize the duration of IL-1beta-induced hyperalgesia in LysM-GRK2(+/ ) mice. Mechanistically, we show that GRK2(+/-) macrophages produce less IL-10 in vitro. In addition, intrathecal IL-10 administration attenuated IL-1beta-induced hyperalgesia in LysM-GRK2(+/-) mice, whereas it had no effect in wild-type mice. Our data uncover a key role for monocytes/macrophages in promoting resolution of inflammatory hyperalgesia via a mechanism dependent on IL-10 signaling in dorsal root ganglia. PERSPECTIVE: We show that IL-10-producing monocytes/macrophages promote resolution of transient inflammatory hyperalgesia. Additionally, we show that reduced monocyte/macrophage GRK2 impairs resolution of hyperalgesia and reduces IL-10 production. We propose that low GRK2 expression and/or impaired IL 10 production by monocytes/macrophages represent peripheral biomarkers for the risk of developing chronic pain after inflammation. PMID- 24793058 TI - Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations. AB - Mitochondrial diseases are characterised by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is difficult and genotype/phenotype correlations remain elusive. Brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we summarise the various combinations of MRI lesions observed in the most frequent mitochondrial respiratory chain deficiencies so as to direct molecular genetic test in patients at risk of such diseases. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests. PMID- 24793060 TI - Re: R. Shane Tubbs et al. Relationships between the posterior interosseous nerve and the supinator muscle: applications to peripheral nerve compression syndromes and nerve transfer procedures. PMID- 24793059 TI - Hand function is impaired in healthy older adults at risk of Parkinson's disease. AB - Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN+) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN+ subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN+ aged 58 +/- 8 years, 18 SN- aged 57 +/- 6 years) were asked to grip and lift a light weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN+ subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 +/- 0.25 s) than SN- subjects (0.13 +/- 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 +/- 0.42 N vs. -0.21 +/- 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 +/- 7.0 N vs. 14.0 +/- 4.3 N; P = 0.022) than SN- subjects. No between group differences were observed in subsequent trials. SN+ subjects exhibit impaired planning for manipulation of new objects. SN+ individuals over-estimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN+ subjects shares similarities with de novo Parkinson's disease patients. PMID- 24793061 TI - Paddle versus cylindrical leads for percutaneous implantation in spinal cord stimulation for failed back surgery syndrome: a single-center trial. AB - OBJECTIVE: Spinal cord stimulation is an interventional treatment for chronic pain syndromes such as failed back surgery syndrome (FBSS), and it utilizes either cylindrical or paddle electrodes placed percutaneously into the epidural space. This prospective nonrandomized single-center study investigated the specific advantages and disadvantages of percutaneously implanted paddle and cylindrical leads in patients with FBSS. METHODS: Over a 2-year period, 100 patients with FBSS (43 men; 57 women; mean age: 56.3 years) were included. Paddle leads were placed percutaneously under local anesthesia in 50 patients; conventional percutaneous cylindrical lead implantation was performed in the other 50 patients (one lead permitted per patient). Follow-up included the Visual Analog Scale (VAS) assessment of pain and administration of the Oswestry Disability Questionnaire. RESULTS: Similar significant pain reduction (69%) was demonstrated in both groups (VAS pre/post: paddle: 8.8/3.7; cylindrical: 8.5/3.8). Using the same perioperative protocol for each group, we observed higher dislocation and infection rates for the cylindrical group (14% and 10%, respectively) than for the paddle group (6% and 2%, respectively). CONCLUSION: Minimally invasive percutaneous paddle and cylindrical leads are safe and effective, have low complication rates, and perform well in patients with FBSS. Both devices can be implanted using a local anesthetic, so that intraoperative and reproducible testing stimulation can be performed for sufficient paresthesia overlap prior to permanent device fixation. PMID- 24793062 TI - Minimally invasive direct lateral corpectomy for the treatment of a thoracolumbar fracture. AB - Thoracolumbar corpectomies have historically been performed using open exposure procedures. Thoracotomies carry substantial morbidity due to increased complications and postoperative pain. The extreme lateral interbody fusion (XLIF) approach is a safe, minimally invasive alternative approach to the thoracolumbar spine. A recent modification of XLIF allows thoracolumbar corpectomy to be used for tumors, osteomyelitis, and fractures. We reviewed literature relevant to minimally invasive lateral approaches and thoracolumbar pathology. This case report illustrates the usefulness of this approach in the case of a thoracolumbar flexion distraction fracture treated with a corpectomy. The involved surgical technique is described in detail. This approach can be performed without an access surgeon, and the minimally invasive lateral approach reduces the relative morbidity commonly associated with open approaches. PMID- 24793063 TI - Adult and child use of love, like, don't like and hate during family mealtimes. Subjective category assessments as food preference talk. AB - Food preference is now a ubiquitous concept in eating research, and closely associated with actual consumption, particularly in relation to children's food preferences. Research in this area is beginning to reveal the effects of parent child interaction on eating practices though relatively little attention has been paid to the discursive and lexical processes involved. Food preferences are typically associated with the terms 'likes' and 'dislikes' in food preference research. By contrast, adults and children typically use the terms 'love', 'like', 'don't like' and 'hate' to construct and manage food preferences in everyday meal conversations. A corpus of 270 video- and audio-recorded English and Scottish family mealtimes, involving children aged 1-17 years, was searched and analysed for any and all occurrences of subjective category assessments (SCAs; e.g., 'I like X'), featuring the terms 'love', 'like', 'don't like' and 'hate'. Discursive psychology was used to analyse the transcripts and recordings, and illustrated the disparity between adult and child use of SCAs and food preference talk. Within the data set, parents typically made claims about what their children like, and in doing so claimed epistemic primacy over their children's food preferences. Children, by contrast, typically made claims about their own 'don't likes' and likes, and these were frequently countered by their parents or treated as inappropriate claims. Implications for how parents and researchers might reorient to the food preferences lexicon are discussed. PMID- 24793064 TI - Effectiveness of the dorsal thermoplastic locking orthosis to prevent floating toes in postoperative follow-up of Weil osteotomies: pilot study. AB - BACKGROUND: The Weil oblique distal metatarsal osteotomy is regularly used in the treatment of primary metatarsalgia. The most frequent complication is the floating toe, which occurs in up to 36% of postoperative follow-up. The theory of reducing the plantar flexor mechanism tension associated with the retraction of the dorsal structures during the healing process of the surgical procedure may explain this negative evolution. OBJECTIVE: This study aimed at assessing the effectiveness of the Tucade dorsal thermoplastic locking orthosis in the prevention of floating toe after Weil osteotomy. METHODS: In all, 30 patients with metatarsalgia diagnosis submitted to Weil osteotomy were treated in the postoperative period with the Tucade dorsal thermoplastic locking orthosis. RESULTS: The floating toe was not observed in this case series. There was 1 case of superficial wound irritation at the dorsal surgical incision and 1 case that evolved with transfer metatarsalgia. Statistical analyses were performed-American Orthopaedic Foot and Ankle Society Scale for lateral toes and extension of the lateral toes-using the t test, and P < .0001 was obtained for comparison of the preoperative and postoperative periods in the population studied. CONCLUSION: The Tucade dorsal thermoplastic locking orthosis during the postoperative period of Weil osteotomy proved to be effective in the prevention of floating toes. LEVEL OF EVIDENCE: Therapeutic Level IV: Case Series. PMID- 24793065 TI - Behavior of nine selected emerging trace organic contaminants in an artificial recharge system supplemented with a reactive barrier. AB - Artificial recharge improves several water quality parameters, but has only minor effects on recalcitrant pollutants. To improve the removal of these pollutants, we added a reactive barrier at the bottom of an infiltration basin. This barrier contained aquifer sand, vegetable compost, and clay and was covered with iron oxide dust. The goal of the compost was to sorb neutral compounds and release dissolved organic carbon. The release of dissolved organic carbon should generate a broad range of redox conditions to promote the transformation of emerging trace organic contaminants (EOCs). Iron oxides and clay increase the range of sorption site types. In the present study, we examined the effectiveness of this barrier by analyzing the fate of nine EOCs. Water quality was monitored before and after constructing the reactive barrier. Installation of the reactive barrier led to nitrate-, iron-, and manganese-reducing conditions in the unsaturated zone below the basin and within the first few meters of the saturated zone. Thus, the behavior of most EOCs changed after installing the reactive barrier. The reactive barrier enhanced the removal of some EOCs, either markedly (sulfamethoxazole, caffeine, benzoylecgonine) or slightly (trimethoprim) and decreased the removal rates of compounds that are easily degradable under aerobic conditions (ibuprofen, paracetamol). The barrier had no remarkable effect on 1H benzotriazole and tolyltriazole. PMID- 24793066 TI - Semivolatile PAH and n-alkane gas/particle partitioning using the dual model: up to-date coefficients and comparison with experimental data. AB - The gas/particle partitioning coefficient K p, of a semivolatile compound is a key parameter for its atmospheric fate. The most complete method of predicting K p for polycyclic aromatic hydrocarbons (PAHs) is offered by the dual model, as it describes both the adsorption on soot and absorption into organic matter processes. However, experimental and model data exist almost exclusively for PAHs. In order to bridge this gap, experimental data on the phase partitioning of both PAHs and n-alkanes were collected at an urban and a remote site. Moreover, all the necessary parameters (e.g., octanol-air and soot-air partitioning coefficients) for the dual model have been collected and updated or (if missing) estimated for the first time. The results point out that both absorption and adsorption seem to contribute to the partitioning of PAHs and n-alkanes. However, it seems that the dual model always underestimates the particle sorption not only for PAHs but also for n-alkanes. PMID- 24793067 TI - Growth and metal removal potential of a Phormidium bigranulatum-dominated mat following long-term exposure to elevated levels of copper. AB - The present study explores the tolerance and metal removal response of a well developed 2-week-old Phormidium mat after long-term exposure to Cu(2+)-enriched medium. Cu(2+) enrichment inhibited increase in mat biomass in a concentration dependent manner. Mat area and the number of entrapped air bubbles decreased as Cu(2+) concentration increased in the medium. Decrease in number of air bubbles obviously reflects the adverse effect of Cu(2+) on photosynthetic performance of the mat. Metal enrichment did not substantially alter the amount of pigments, such as chlorophyll a, chlorophyll b, carotenoids, and phycocyanin, in the mat. Enhancement of Cu(2+) concentration in the medium led to changes in species composition of the test mat; however, Phormidium bigranulatum always remained the dominant organism. Relative share of green algae and some cyanobacterial taxa, namely, Lyngbya sp. and Oscillatoria tenuis, in the mat were increased by Cu(2+) enrichment. The mat successfully removed 80 to 94 % Cu(2+) from the growth medium containing 10 to 100 MUM Cu(2+). Extracellular polysaccharides, whose share increased in the mat community after metal addition, seem to have contributed substantially to metal binding by the mat biomass. PMID- 24793068 TI - The influence of long-term fertilization on cadmium (Cd) accumulation in soil and its uptake by crops. AB - Continuous application of organic and inorganic fertilizers can affect soil and food quality with respect to heavy metal concentrations. The risk of cadmium (Cd) contamination in a long-term (over 20 years) experimental field in North China with an annual crop rotation of winter wheat and summer maize was investigated. The long-term experiment had a complete randomized block design with seven fertilizer treatments and four replications. The seven fertilizer treatments were (1) organic compost (OM), (2) half organic compost plus half chemical fertilizer (OM + NPK), (3) NPK fertilizer (NPK), (4-6) chemical fertilizers without one of the major nutrients (NP, PK, and NK), and (7) an unamended control (CK). Soil samples from 0 to 20 cm were collected in 1989, 1999, and 2009 to characterize Cd and other soil properties. During the past 20 years, various extents of Cd accumulation were observed in the soil, and the accumulation was mainly affected by atmospheric dry and wet deposition and fertilization. In 2009, the average Cd concentration in the soil was 148 +/- 15 MUg kg(-1) and decreased in the order of NPK ~ OM + NKP ~ PK > NP ~ NK > OM ~ CK. Sequential extraction of Cd showed that the acid-soluble fraction (F1, 32 +/- 7 %) and the residual fraction (F4, 31 +/- 5 %) were the dominant fractions of Cd in the soil, followed by the reducible fraction (F2, 22 +/- 5 %) and oxidizable fraction (F3, 15 +/- 6 %). The acid soluble Cd fraction in the soil and Cd accumulation in the crops increased with soil plant available K. Fraction F3 was increased by soil organic C (SOC) and crop yields, but SOC reduced the uptake of soil Cd by crops. The long-term P fertilization resulted in more Cd buildup in the soil than other treatments, but the uptake of Cd by crops was inhibited by the precipitation of Cd with phosphate in the soil. Although soil Cd was slightly increased over the 20 years of intensive crop production, both soil and grain/kernel Cd concentrations were still below the national standards for environmental and food safety. PMID- 24793069 TI - Fine-scale, spatial and temporal assessment methods for feral swine disturbances to sensitive plant communities in south-central Florida. AB - Feral swine are estimated to annually cost hundreds of millions of dollars in economic loss to property and agriculture in the USA, while their ecological consequences remain largely unmeasured. Using submeter-accurate Global Positioning System technology over a multiyear project, we are quantifying in a novel way the spatial and temporal attributes of swine rooting damage within 587 ha of ecologically sensitive wetland plant communities at Avon Park Air Force Range in south-central Florida. We delineated damage polygons from 0.0023 to 4,335 m(2) and were able to document recurrent damage through time at most sites during each assessment. For each polygon, we also estimated the age of damage and assigned to it a severity index, qualities of the rooting in which we detected changes in proportions over time. Spatially explicit damage assessments at fine scales conducted over several years can assist land managers in determining effects of rooting on rare plant populations, and will allow investigators to hypothesize what factors are driving patterns of this disturbance across ecologically sensitive plant communities. PMID- 24793070 TI - Coupling digestion in a pilot-scale UASB reactor and electrochemical oxidation over BDD anode to treat diluted cheese whey. AB - The efficiency of the anaerobic treatment of cheese whey (CW) at mesophilic conditions was investigated. In addition, the applicability of electrochemical oxidation as an advanced post-treatment for the complete removal of chemical oxygen demand (COD) from the anaerobically treated cheese whey was evaluated. The diluted cheese whey, having a pH of 6.5 and a total COD of 6 g/L, was first treated in a 600-L, pilot-scale up-flow anaerobic sludge blanket (UASB) reactor. The UASB process, which was operated for 87 days at mesophilic conditions (32 +/- 2 degrees C) at a hydraulic retention time (HRT) of 3 days, led to a COD removal efficiency between 66 and 97 %, while the particulate matter of the wastewater was effectively removed by entrapment in the sludge blanket of the reactor. When the anaerobic reactor effluent was post-treated over a boron-doped diamond (BDD) anode at 9 and 18 A and in the presence of NaCl as the supporting electrolyte, complete removal of COD was attained after 3-4 h of reaction. During electrochemical experiments, three groups of organochlorinated compounds, namely trihalomethanes (THMs), haloacetonitriles (HANs), and haloketons (HKs), as well as 1,2-dichloroethane (DCA) and chloropicrin were identified as by-products of the process; these, alongside free chlorine, are thought to increase the matrix ecotoxicity to Artemia salina. PMID- 24793072 TI - Severe particulate pollution from the deposition practices of the primary materials of a cement plant. AB - Global cement production has increased twofold during the last decade. This increase has been accompanied by the installation of many new plants, especially in Southeast Asia. Although various aspects of pollution related to cement production have been reported, the impact of primary material deposition practices on ambient air quality has not yet been studied. In this study, we show that deposition practices can have a very serious impact on levels of ambient aerosols, far larger than other cement production-related impacts. Analyses of ambient particulates sampled near a cement plant show 1.3-30.4 mg/m(3) total suspended particulates in the air and concentrations of particles with a diameter of 10 MUm or less at 0.04-3 mg/m(3). These concentrations are very high and seriously exceed air quality standards. We unequivocally attribute these levels to outdoor deposition of cement primary materials, especially clinker, using scanning electron microscopy/energy-dispersive X-ray spectroscopy. We also used satellite-derived aerosol optical depth maps over the area of study to estimate the extent of the spatial impact. The satellite data indicate a 33% decrease in aerosol optical depth during a 10-year period, possibly due to changing primary material deposition practices. Although the in situ sampling was performed in one location, primary materials used in cement production are common in all parts of the world and have not changed significantly over the last decades. Hence, the results reported here demonstrate the dominant impact of deposition practices on aerosol levels near cement plants. PMID- 24793071 TI - Association between environmental exposure to p, p'-DDE and lindane and semen quality. AB - Scientific concern exists about the toxic effect of dichlorodiphenyldichloroethylene (p, p'-DDE) and lindane on male infertility, and the mechanism underlying male reproductive toxicity of this pesticide remains unanswered. We investigated not only the possible association between the chlorinated pesticide levels and semen quality in nonoccupationally exposed men, but also the probable mode of action using mitochondrial membrane potential (MMP), reactive oxygen species (ROS), lipid peroxidation (LPO), and sperm chromatin structure assay (SCSA). A study in 278 men (21-40 years old) who visited Obstetrics and Gynecology Department, KGMU, Lucknow, for semen analysis was conducted. We performed semen analysis according to the WHO guidelines, while p, p'-DDE and lindane analysis was done by the GLC and LPO by the spectrophotometer, and the sperm mitochondrial status, ROS, and SCSA with the flow cytometer. The questionnaire data showed no significant difference in the demographic characteristics between the two groups, i.e., trying to conceive >1 year and proven fertility. However, a significant difference in the concentration of p, p'-DDE and lindane was observed between the groups. When the subjects were divided among four categories by quartile of exposure, the subjects in the highest quartile showed low sperm motility as compared to the subjects in the lowest quartile. Pearson's correlation showed a significant negative correlation between semen p, p'-DDE, lindane level, and sperm quality and positive association with the number of cells with depolarized mitochondria, elevation in ROS production and LPO, and DNA fragmentation index (DFI). The findings are suggestive that these toxicants might cause a decline in semen quality, and these effects might be ROS, LPO, and mitochondrial dysfunction mediated. PMID- 24793073 TI - Effects of heavy metals (Cd, Cu, Cr, Pb, Zn) on fish glutathione metabolism. AB - The glutathione metabolism contains crucial antioxidant molecules to defend the organisms against oxidants. Thus, the aim of this study was to investigate the response of the glutathione metabolism in the liver of freshwater fish Oreochromis niloticus exposed to metals (Cu, Cd, Cr, Pb, Zn) in different periods. Fish were exposed to metals (as 1 MUg/mL) individually for 1, 7, and 14 days and subsequently antioxidant enzymes (glutathione peroxidase, GPX; glutathione reductase, GR and glutathione S-transferase, GST) and glutathione levels (total glutathione, tGSH; reduced glutathione, rGSH; oxidized glutathione, GSSG and GSH/GSSG ratios) in the liver were measured. There was no fish mortality during the experiments, except Cu exposure. The antioxidant enzymes responded differently to metal exposures depending on metal types and exposure durations. GPX activity increased only after Cd exposure, while GST activity increased following 7 days of all metal exposures. However, GR activity did not alter in most cases. Total GSH and GSH/GSSG levels generally decreased, especially after 7 days. Data showed that metal exposures significantly altered the response of antioxidant system parameters, particularly at day 7 and some recovery occurred after 14 days. This study suggests that the response of antioxidant system could help to predict metal toxicity in the aquatic environments and be useful as an "early warning tool" in natural monitoring studies. PMID- 24793074 TI - Overview on the European green crab Carcinus spp. (Portunidae, Decapoda), one of the most famous marine invaders and ecotoxicological models. AB - Green crabs (Carcinus, Portunidae) include two species native to Europe--Carcinus aestuarii (Mediterranean species) and Carcinus maenas (Atlantic species). These small shore crabs (maximal length carapace, approximately 10 cm) show rapid growth, high fecundity, and long planktonic larval stages that facilitate broad dispersion. Carcinus spp. have a high tolerance to fluctuations of environmental factors including oxygen, salinity, temperature, xenobiotic compounds, and others. Shipping of Carcinus spp. over the past centuries has resulted in its invasions of America, Asia, and Australia. Classified as one of the world's 100 worst invaders by the International Union for Conservation of Nature, Carcinus spp. are the most widely distributed intertidal crabs in the world. Their voracious predatory activity makes them strong interactors in local communities, and they are recognized as a model for invasiveness in marine systems as well as a sentinel species in ecotoxicology. This review shows an exhaustive analysis of the literature on the life cycle, diversity, physiological tolerance, genomic investigations, ecotoxicological use, historical invasion, control programs, and putative economical valorization of shore crabs. PMID- 24793075 TI - [Eye infections caused by Purpureocillium lilacinum: A case report and literature review]. AB - BACKGROUND: Purpureocillium lilacinum eye infections (previously called Paecilomyces lilacinus) make up a significant percentage of the recorded cases of infection by this fungus, and is considered as an emerging pathogen. AIMS: To report a case of ocular mycosis in a patient aged 70, with a double corneal transplantation in the right eye, and exhibiting a poor response to antifungal and surgical treatment. METHODS: Corneal ring and ocular tissues obtained by surgical procedures were cultured in common mycological media. Molecular identification of the isolated fungus was obtained. RESULTS: Colonies of a filamentous fungus were obtained, and according to the macroscopic and microscopic morphology it was identified as P. lilacinum. The identification was confirmed by molecular methods in a reference laboratory. CONCLUSIONS: Eye infections due to P. lilacinum are rare but serious diseases that requires rapid diagnostic and therapeutic measures to enable visual function to recover. PMID- 24793076 TI - Manual therapy directed at the knee or lumbopelvic region does not influence quadriceps spinal reflex excitability. AB - Manual therapies, directed to the knee and lumbopelvic region, have demonstrated the ability to improve neuromuscular quadriceps function in individuals with knee pathology. It remains unknown if manual therapies may alter impaired spinal reflex excitability, thus identifying a potential mechanism in which manual therapy may improve neuromuscular function following knee injury. AIM: To determine the effect of local and distant mobilisation/manipulation interventions on quadriceps spinal reflex excitability. METHODS: Seventy-five individuals with a history of knee joint injury and current quadriceps inhibition volunteered for this study. Participants were randomised to one of five intervention groups: lumbopelvic manipulation (grade V), lumbopelvic manipulation positioning (no thrust), grade IV patellar mobilisation, grade I patellar mobilisation, and control (no treatment). Changes in spinal reflex excitability were quantified by assessing the Hoffmann reflex (H-reflex), presynaptic, and postsynaptic excitability. A hierarchical linear-mixed model for repeated measures was performed to compare changes in outcome variables between groups over time (pre, post 0, 30, 60, 90 min). RESULTS: There were no significant differences in H reflex, presynaptic, or postsynaptic excitability between groups across time. CONCLUSIONS: Manual therapies directed to the knee or lumbopelvic region did not acutely change quadriceps spinal reflex excitability. Although manual therapies may improve impairments and functional outcomes the underlying mechanism does not appear to be related to changes in spinal reflex excitability. PMID- 24793077 TI - Family involvement at the end-of-life and receipt of quality care. AB - CONTEXT: Most patients will lose decision-making capacity at the end of life. Little is known about the quality of care received by patients who have family involved in their care. OBJECTIVES: To evaluate differences in the receipt of quality end-of-life care for patients who died with and without family involvement. METHODS: We retrospectively reviewed the charts of 34,290 decedents from 146 acute and long-term care Veterans Affairs facilities between 2010 and 2011. Outcomes included: (1) palliative care consult, (2) chaplain visit, and 3) death in an inpatient hospice or palliative care unit. We also assessed "do not resuscitate" (DNR) orders. Family involvement was defined as documented discussions with the health care team in the last month of life. We used logistic regression adjusted for demographics, comorbidity, and clustered by facility. For chaplain visit, hospice or palliative care unit death, and DNR, we additionally adjusted for palliative care consults. RESULTS: Mean (SD) age was 74 (+/-12) years, 98% were men, and 19% were nonwhite. Most decedents (94.2%) had involved family. Veterans with involved family were more likely to have had a palliative care consult, adjusted odds ratio (AOR) 4.31 (95% CI 3.90-4.76); a chaplain visit, AOR 1.18 (95% CI 1.07-1.31); and a DNR order, AOR 4.59 (95% CI 4.08-5.16) but not more likely to die in a hospice or palliative care unit. CONCLUSION: Family involvement at the end of life is associated with receipt of palliative care consultation and a chaplain visit and a higher likelihood of a DNR order. Clinicians should support early advance care planning for vulnerable patients who may lack family or friends. PMID- 24793078 TI - A randomized trial of the effectiveness of topical "ABH Gel" (Ativan((r)), Benadryl((r)), Haldol((r))) vs. placebo in cancer patients with nausea. AB - CONTEXT: The topical gel known as "ABH gel," comprising lorazepam (Ativan((r))), diphenhydramine (Benadryl((r))), and haloperidol (Haldol((r))), is frequently used to treat nausea because of its perceived efficacy, relatively low cost, and ease of use in the home setting. There are limited scientific data on this medication, however. Recent pilot studies showed no absorption of the active ingredients of the gel, prompting further prospective studies into the cause of the perceived efficacy in the clinical setting. OBJECTIVES: To determine any difference in the effectiveness of ABH gel compared with placebo in cancer patients with nausea. METHODS: A randomized, double-blind, placebo-controlled, crossover, noninferiority clinical trial was developed to test the hypothesis that there is no difference in the effectiveness of ABH gel compared with placebo in cancer patients with nausea. The primary outcome was the difference in nausea score (on a 0-10 scale) at baseline and at 60 minutes in each treatment group. The difference in the ABH gel-treated group compared with placebo was evaluated for noninferiority. Secondary outcomes included the number of vomiting episodes and side effects over time. RESULTS: The mean change in nausea score from baseline to 60 minutes after treatment in the ABH gel group was 1.7 +/- 2.05 and 0.9 +/- 2.45 for the placebo group (P = 0.42). The placebo group was found to be noninferior to the ABH gel group in reducing the nausea score. ABH gel also did not decrease vomiting events better than placebo (P = 0.34). Only one patient reported any side effects from the treatments in either arm of the study. CONCLUSION: ABH gel in its current formulation should not be used in cancer patients experiencing nausea. PMID- 24793079 TI - Quality of life in patients with advanced cancer at the end of life as measured by the McGill quality of life questionnaire: a survey in China. AB - CONTEXT: Quality of life (QOL) is the main outcome measure for patients with advanced cancer at the end of life. The McGill Quality of Life Questionnaire (MQOL) is designed specifically for palliative care patients and has been translated and validated in Hong Kong and Taiwan. OBJECTIVES: This study aimed to investigate the QOL of patients with advanced cancer using the MQOL-Taiwan version after cultural adaptation to the Chinese mainland. METHODS: A cross sectional survey design was used. QOL data from patients with advanced cancer were gathered from 13 hospitals including five tertiary hospitals, six secondary hospitals, and community health care service centers in Shanghai and analyzed. QOL was assessed using the MQOL-Chinese version. Statistical analyses were performed using descriptive statistics, multiple regression analysis, and Spearman rank correlation analysis. RESULTS: A total of 531 cancer patients (297 male and 234 female) in 13 hospitals were recruited into the study and administered the MQOL-Chinese. The score of the support subscale was highest (6.82), and the score of the existential well-being subscale was the lowest (4.65). The five physical symptoms most frequently listed on the MQOL-Chinese were pain, loss of appetite, fatigue, powerless, and dyspnea. Participants' sex, educational level, number of children, disclosure of the disease, and hospital size were associated with their overall QOL. The Spearman rank correlation analysis found that Karnofsky Performance Status scores correlated with the MQOL Chinese single-item score, physical well-being, psychological well-being, existential well-being, and support domains (P < 0.05). CONCLUSION: Our results revealed the aspects of QOL that need more attention for Chinese palliative care patients with advanced cancer. The association between the characteristics of patients, Karnofsky Performance Status, and their QOL also was identified. PMID- 24793080 TI - Advances in multiparameter optimization methods for de novo drug design. AB - INTRODUCTION: A high-quality drug must achieve a balance of physicochemical and absorption, distribution, metabolism and elimination properties, safety and potency against its therapeutic target(s). Multiparameter optimization (MPO) methods guide the simultaneous optimization of multiple factors to quickly target compounds with the highest chance of downstream success. MPO can be combined with 'de novo design' methods to automatically generate and assess a large number of diverse structures and identify strategies to optimize a compound's overall balance of properties. AREAS COVERED: The article provides a review of MPO methods and recent developments in the methods and opinions in the field. It also provides a description of advances in de novo design that improve the relevance of automatically generated compound structures and integrate MPO. Finally, the article provides discussion of a recent case study of the automatic design of ligands to polypharmacological profiles. EXPERT OPINION: Recent developments have reduced the generation of chemically infeasible structures and improved the quality of compounds generated by de novo design methods. There are concerns about the ability of simple drug-like properties and ligand efficiency indices to effectively guide the detailed optimization of compounds. De novo design methods cannot identify a perfect compound for synthesis, but it can identify high quality ideas for detailed consideration by an expert scientist. PMID- 24793081 TI - Buried centimeter-long micro- and nanochannel arrays in porous silicon and glass. AB - We developed a simple process to fabricate deeply buried micro- and nanoscale channels in glass and porous silicon from bulk silicon using a combination of ion beam irradiation, electrochemical anodization and high temperature oxidation. The depth, width and length of these structures can be controllably varied and we successfully fabricated an array of centimeter-long buried micro- and nanochannels. This process allows densely packed, arbitrary-shaped channel geometries with micro- to nanoscale dimensions to be produced in a three dimensional multilevel architecture, providing a route to fabricate complex devices for use in nanofluidics and lab-on-a-chip systems. We demonstrate the integration of these channels with large reservoirs for DNA linearization in high aspect ratio nanochannels. PMID- 24793082 TI - Simultaneous determination of bendamustine and its active metabolite, gamma hydroxy-bendamustine in human plasma and urine using HPLC-fluorescence detector: application to a pharmacokinetic study in Chinese cancer patients. AB - A simple, sensitive and cost-effective assay based on reversed phase high performance liquid chromatography (RP-HPLC) with isocratic mode for simultaneous determination of bendamustine (BM) and its active metabolite, gamma-hydroxy bendamustine (gamma-OH-BM) in human plasma and urine was developed and validated. Sample preparation involved protein precipitation by 10% perchloric acid-methanol solution. The peaks were recorded by using fluorescence detector (excitation wavelength 328 nm and emission wavelength 420 nm). The calibration curves were linear over concentration ranges of 8.192-10,000 ng mL(-1) and 5-1,000 ng mL(-1) for BM in human plasma and urine as well as 10-1,000 ng mL(-1) and 5-1,000 ng mL( 1) for gamma-OH-BM in human plasma and urine, respectively. Intra- and inter-run precisions of BM and gamma-OH-BM were less than 15% and the bias were within +/- 15% for both plasma and urine. This validated method was successfully applied to a pharmacokinetic study enrolling 10 Chinese patients with indolent B-cell non Hodgkin lymphoma and chronic lymphocytic leukemia administered a single intravenous infusion of 100 mg m(2) bendamustine hydrochloride. PMID- 24793083 TI - Determination of nitroimidazole residues in aquaculture tissue using ultra high performance liquid chromatography coupled to tandem mass spectrometry. AB - An UHPLC-MS/MS method was developed for the quantitative confirmatory analysis of residues of nitroimidazole drugs (dimetridazole, ipronidazole, metronidazole, ornidazole and ronidazole) and their corresponding hydroxy metabolites (HMMNI, ipronidazile-OH and metronidazole-OH) in aquaculture tissue. Samples were extracted by shaking in acetonitrile, water, MgSO4 and NaCl before being defatted with n-hexane pre-saturated with acetonitrile and concentrated under nitrogen. Nitroimidazole residues were determined by UHPLC-MS/MS operating in positive electrospray ionisation mode using a reversed phase BEH C18 column. The method was validated according to the EU Commission Decision 2002/657/EC guidelines. The following performance studies were carried out: specificity, selectivity, linearity, within laboratory repeatability (WLr)/reproducibility (WLR), accuracy, precision, decision limit (CCalpha), detection capability (CCbeta), absolute recovery and stability. The analytical range of the method is 0.1-20 MUg kg(-1). Accuracy and precision of the method, under within-laboratory reproducibility conditions, ranged from 83 to 105% and 2.3 to 14.0%, respectively. CCalpha were 0.07-1.0 MUg kg(-1) depending on analyte and matrix. A total of 50 samples can be analysed in a single day using the assay. The method has been extensively evaluated through application to real test samples. PMID- 24793084 TI - Simultaneous determination of two iridoid glycosides, two anthraquinones and four flavonoid glycosides of Zhi-Zi-Da-Huang decoction in rat plasma by UFLC-MS/MS: application to a comparative pharmacokinetic study in normal and cholestatic liver injury rats. AB - A selective, sensitive and reliable ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method has been developed for the simultaneous determination of two iridoid glycosides (geniposide and genipin gentiobioside), two anthraquinones (rhein and emodin) and four flavonoid glycosides (isonaringin, naringin, hesperidin and neohesperidin), the major active ingredients of Zhi-Zi Da-Huang decoction (ZZDHD), in rat plasma using paeoniflorin as internal standard (IS). After liquid-liquid extraction with ethyl acetate-isopropanol (1:1, v/v), separation was achieved on a Shim-pack XR-ODS C18 column (75 mm*3.0 mm, 2.2 MUm) using gradient elution with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile at a flow rate of 0.4 mL/min. Detection was performed on 4000 QTRAP mass spectrometry equipped with turbo ion spray source in the negative ionization and multiple reaction monitoring (MRM) mode. The intra- and inter-day precisions (as relative standard deviation) were less than 11.4%, and accuracy (as relative error) was within +/- 10.0%. The lower limits of quantification (LLOQ) were 4.0, 0.5, 2.0, 0.1, 1.0, 2.0, 1.0, 2.0 ng/mL for geniposide, genipin gentiobioside, rhein, emodin, isonaringin, naringin, hesperidin and neohesperidin, respectively. The extraction recoveries of the analytes and IS from rat plasma were all more than 86.0%. The method was fully validated and applied to compare the pharmacokinetic profiles of the analytes in normal and cholestatic liver injury (CLI) rats after oral administration of ZZDHD. Results showed that there were remarkable differences in pharmacokinetic properties of the analytes between normal and CLI group. PMID- 24793085 TI - Functionalized magnetic nanoparticles coupled with mass spectrometry for screening and identification of cyclooxygenase-1 inhibitors from natural products. AB - Development of simple and effective methods for high-throughput, high-fidelity screening and identification of cyclooxygenase-1 (COX-1) inhibitors from natural products are important for drug discovery to treat inflammation and carcinogenesis. Here, we developed a new screening assay based on cyclooxygenase 1 (COX-1) functionalized magnetic nanoparticles (i.e. Fe3O4@SiO2-COX-1) for solid phase ligand fishing, and then mass spectrometry (MS) was applied for structural identification. Incubation conditions were optimized. High specificity for isolating COX-1 inhibitors was achieved by testing positive control, indomethacin, with active and inactive COX-1. Moreover, high stability of immobilized COX-1 (remained 95.3% after ten consecutive cycles) allows the analysis reproducible. When applied to turmeric extract, four curcuminoids (i.e. curcumin, demethoxycurcumin, bisdemethoxycurcumin, and 1-(4-hydroxy-3,5 dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-(1E,6E)-1,6-heptadiene-3,5-dione), difficult to be distinguished from original MS spectrum of turmeric extract, were isolated as main COX-1 inhibitors. Their structures were characterized based on their accurate molecular weight and diagnostic fragment ions. The results indicated that the proposed method was a simple, robust and reproducible approach for the discovery of COX-1 inhibitors from complex matrixes. PMID- 24793086 TI - Coronary artery abnormalities in children with systemic-onset juvenile idiopathic arthritis. AB - Still's disease (Systemic-onset Juvenile Idiopathic Arthritis: SoJIA) is characterised by high-spiking daily fevers, arthritis and evanescent rashes. Diagnosis of Still's disease is often challenging. Infectious diseases and other inflammatory conditions, especially in young children, Kawasaki disease may look similar. Clinicians often rely on echocardiographic evidence of coronary artery abnormalities to differentiate between Kawasaki disease and Still's disease. Coronary artery dilation would typically favour the diagnosis of Kawasaki disease. We present four children with Still's disease and coronary artery abnormalities who were initially misdiagnosed as Kawasaki disease. The first patient had pericarditis and an irregular wall of the left coronary artery, without dilation on echocardiography. The second patient had a left coronary artery dilatation and a pericarditis. The third patient had thickened left coronary artery walls, and the fourth patient had a hyperechogenicity of the left and right coronary arteries. They received IVIG without success. The diagnosis of Still's disease was made secondary with evidence of persistent arthritis. All but one patient finally needed biologic treatments. Coronary abnormalities may be observed during various febrile conditions and do not exclude the diagnosis of Still's disease. PMID- 24793087 TI - Spondyloarthritis: a window of opportunity? PMID- 24793088 TI - Mandibuloacral dysplasia. PMID- 24793090 TI - Transcription-independent functions of an RNA polymerase II subunit, Rpb2, during genome rearrangement in the ciliate, Oxytricha trifallax. AB - The RNA polymerase II (Pol-II) holoenzyme, responsible for messenger RNA production, typically consists of 10-12 subunits. Our laboratory previously demonstrated that maternally deposited, long, noncoding, template RNAs are essential for programmed genome rearrangements in the ciliate Oxytricha trifallax. Here we show that such RNAs are bidirectionally transcribed and transported to the zygotic nucleus. The gene encoding the second-largest subunit of Pol-II, Rpb2, has undergone gene duplication, and the two paralogs, Rpb2-a and -b, display different expression patterns. Immunoprecipitation of double-stranded RNAs identified an association with Rpb2-a. Through immunoprecipitation and mass spectrometry, we show that Rpb2-a in early zygotes appears surprisingly unassociated with other Pol II subunits. A partial loss of function of Rpb2-a leads to an increase in expression of transposons and other germline-limited satellite repeats. We propose that evolutionary divergence of the Rpb2 paralogs has led to acquisition of transcription-independent functions during sexual reproduction that may contribute to the negative regulation of germline gene expression. PMID- 24793091 TI - [Multimodal neuromonitoring in traumatic brain injury: contribution of PTiO2]. AB - The main goal of exhaustively monitoring neurocritical patients is to avoid secondary injury. In the last few years we have witnessed an increase in brain monitoring tools, beyond the checking of intracranial and brain perfusion pressures. These widely used systems offer valuable but possibly insufficient information. Awareness and correction of brain hypoxia is a useful and interesting measure, not only for diagnostic purposes but also when deciding treatment, and to predict an outcome. In this context, it would be of great interest to use all the information gathered from brain oxygenation monitoring systems in conjunction with other available multimodal monitoring devices, in order to offer individualized treatment for each patient. PMID- 24793089 TI - A Bayesian approach to inferring the phylogenetic structure of communities from metagenomic data. AB - Metagenomics provides a powerful new tool set for investigating evolutionary interactions with the environment. However, an absence of model-based statistical methods means that researchers are often not able to make full use of this complex information. We present a Bayesian method for inferring the phylogenetic relationship among related organisms found within metagenomic samples. Our approach exploits variation in the frequency of taxa among samples to simultaneously infer each lineage haplotype, the phylogenetic tree connecting them, and their frequency within each sample. Applications of the algorithm to simulated data show that our method can recover a substantial fraction of the phylogenetic structure even in the presence of high rates of migration among sample sites. We provide examples of the method applied to data from green sulfur bacteria recovered from an Antarctic lake, plastids from mixed Plasmodium falciparum infections, and virulent Neisseria meningitidis samples. PMID- 24793092 TI - Effect of high dose vitamin C on Epstein-Barr viral infection. AB - Background Many natural compounds were tested for the ability to suppress viral replication. The present manuscript details an analysis of high dose vitamin C therapy on patients with EBV infection. Material and Methods The data were obtained from the patient history database at the Riordan Clinic. Among people in our database who were treated with intravenous vitamin C (7.5 g to 50 g infusions) between 1997 and 2006, 178 patients showed elevated levels of EBV EA IgG (range 25 to 211 AU) and 40 showed elevated levels of EBV VCA IgM (range 25 to 140 AU). Most of these patients had a diagnosis of chronic fatigue syndrome, with the rest being diagnosed as having mononucleosis, fatigue, or EBV infection. Results Our data provide evidence that high dose intravenous vitamin C therapy has a positive effect on disease duration and reduction of viral antibody levels. Plasma levels of ascorbic acid and vitamin D were correlated with levels of antibodies to EBV. We found an inverse correlation between EBV VCA IgM and vitamin C in plasma in patients with mononucleosis and CFS meaning that patients with high levels of vitamin C tended to have lower levels of antigens in the acute state of disease. In addition, a relation was found between vitamin D levels and EBV EA IgG with lower levels of EBV early antigen IgG for higher levels of vitamin D. Conclusions The clinical study of ascorbic acid and EBV infection showed the reduction in EBV EA IgG and EBV VCA IgM antibody levels over time during IVC therapy that is consistent with observations from the literature that millimolar levels of ascorbate hinder viral infection and replication in vitro. PMID- 24793093 TI - The reinforcing and subjective effects of intravenous and intranasal buprenorphine in heroin users. AB - Abuse of buprenorphine (BUP) by the intravenous (IV) route has been documented in several studies, and reports of intranasal (IN) abuse are increasing. However, no studies have directly compared the effects of BUP when it is administered intranasally and intravenously. The present secondary analysis used data from two separate studies to compare the reinforcing and subjective effects of IV and IN buprenorphine. One study evaluated IV buprenorphine (N=13) and the other evaluated IN buprenorphine (N=12). Participants were maintained on 2 mg sublingual (SL) BUP and tested with each intranasal or intravenous buprenorphine test dose (0 mg, 2 mg, 4 mg, 8 mg, and 16 mg). During morning laboratory sessions, participants received money (US $20) and sample doses of IN or IV BUP, and then completed subjective effects questionnaires. Later that day, they completed a self-administration task to receive 10% portions of the drug and/or money they previously sampled. In general, positive subjective ratings for both IV and IN BUP were significantly greater than placebo, with IV BUP having a greater effect than IN BUP. All active BUP doses (IV and IN) maintained significantly higher progressive ratio breakpoint values than placebo, but breakpoint values for IV BUP were greater than for IN BUP. Buprenorphine is an effective maintenance treatment for opioid dependence, valued for its ability to reduce the positive subjective effects of other opioids. Nevertheless, the present data demonstrate that in participants maintained on a low dose of SL BUP, the medication itself has abuse liability when used intravenously or intranasally. PMID- 24793094 TI - A "turn-off" SERS assay of heparin with high selectivity based on heparin-peptide complex and Raman labelled gold nanoparticles. AB - Stable SERS response originating from gold nanoparticles (Au NPs) is demonstrated for the first time to be suitable for detection of heparin with high selectivity. Herein we report a novel "turn-off" SERS assay for heparin based on Raman labelled Au NPs and competitive bonding between heparin and two specialized peptides, such as RKGSGRRLVKC (11-peptide) and CALNN (5-peptide). By means of coordination interactions and other non-electrostatic forces, these 5-peptide capped Au NPs are induced to undergo controllable aggregation upon the additive of 11-peptide and heparin with a concentration range (0-2.4 U/mL), which correspondingly cause quantitative changes of SERS intensity of 4-MBA conjugated on Au NPs. The decreased Raman intensity obtained by subtracting two cases of additives which contain only 11-peptide and the mixture of 11-peptide and heparin, is proportional to the concentration of heparin over a range of 0.2-2.4 U/mL (R(2)=0.99157), with a limit of detection (LOD) of 0.042 U/mL (S/N=3:1). Moreover, the proposed highly selective method has potential application for rapid, separation-free detection of heparin in human blood serum samples. PMID- 24793095 TI - Orientation of llama antibodies strongly increases sensitivity of biosensors. AB - Sensitivity of biosensors depends on the orientation of bio-receptors on the sensor surface. The objective of this study was to organize bio-receptors on surfaces in a way that their analyte binding site is exposed to the analyte solution. VHH proteins recognizing foot-and-mouth disease virus (FMDV) were used for making biosensors, and azides were introduced in the VHH to function as bioorthogonal reactive groups. The importance of the orientation of bio-receptors was addressed by comparing sensors with randomly oriented VHH (with multiple exposed azide groups) to sensors with uniformly oriented VHH (with only a single azide group). A surface plasmon resonance (SPR) chip exposing cyclooctyne was reacted to azide functionalized VHH domains, using click chemistry. Comparison between randomly and uniformly oriented bio-receptors showed up to 800-fold increase in biosensor sensitivity. This technique may increase the containment of infectious diseases such as FMDV as its strongly enhanced sensitivity may facilitate early diagnostics. PMID- 24793096 TI - Effect of hydrogen-rich water on acute peritonitis of rat models. AB - OBJECTIVE: To study the effect of hydrogen-rich water (HRW) on acute peritonitis with three different rat models. METHODS: Acute peritonitis was induced by three methods including intraperitoneal injection of lipopolysaccharide (LPS), rats' feces or cecal ligation and puncture (CLP) operation. For each model, male Sprague Dawley rats were used and distributed into saline control group, HRW control group, saline plus model group, and HRW plus model group. Saline or HRW (3 ml per rat) was orally administered by gavage for 7 days beforehand and 3 days after modeling. The efficacy was tested by detecting concentrations of white blood cells (WBCs), plasma endotoxin, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. The activities of malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) in visceral peritoneum tissues were also evaluated. Meanwhile, histopathology examination of visceral peritoneum was performed using hematoxylin and eosin staining. The expression and location of nuclear factor kappaB (NF-kappaB) in the visceral peritoneum were detected by immunohistochemistry. RESULTS: Three models showed the same result that hydrogen rich water had an efficient protective effect on acute peritonitis. HRW could significantly lower the levels of WBCs, plasma endotoxin and cytokines, enhance GSH activity and reduce MPO and MDA activities in the peritoneum tissue when compared with that of groups with only saline treated. Simultaneously, we found that HRW could also decrease the NF-kappaB expression in the peritoneum tissues. CONCLUSION: Hydrogen-rich water could alleviate the severity of acute peritonitis, and it might perform this function by its anti-inflammation, anti oxidation and anti-bacterial effects and reducing NF-kappaB expression in the peritoneum tissues. PMID- 24793098 TI - Classical swine fever in China: a minireview. AB - Classical swine fever (CSF), caused by Classical swine fever virus (CSFV), is an OIE-listed, highly contagious, often fatal disease of swine worldwide. Currently, the disease is controlled by prophylactic vaccination in China and many other countries using the modified live vaccines derived from C-strain, which was developed in China in the mid-1950s. This minireview summarizes the epidemiology, diagnostic assays, control and challenges of CSF in China. Though CSF is essentially under control, complete eradication of CSF in China remains a challenging task and needs long-term, joint efforts of stakeholders. PMID- 24793097 TI - Feline fecal virome reveals novel and prevalent enteric viruses. AB - Humans keep more than 80 million cats worldwide, ensuring frequent exposure to their viruses. Despite such interactions the enteric virome of cats remains poorly understood. We analyzed a fecal sample from a single healthy cat from Portugal using viral metagenomics and detected five eukaryotic viral genomes. These viruses included a novel picornavirus (proposed genus "Sakobuvirus") and bocavirus (feline bocavirus 2), a variant of feline astrovirus 2 and sequence fragments of a highly divergent feline rotavirus and picobirnavirus. Feline sakobuvirus A represents the prototype species of a proposed new genus in the Picornaviridae family, distantly related to human salivirus and kobuvirus. Feline astroviruses (mamastrovirus 2) are the closest known relatives of the classic human astroviruses (mamastrovirus 1), suggestive of past cross-species transmission. Presence of these viruses by PCR among Portuguese cats was detected in 13% (rotavirus), 7% (astrovirus), 6% (bocavirus), 4% (sakobuvirus), and 4% (picobirnavirus) of 55 feline fecal samples. Co-infections were frequent with 40% (4/10) of infected cats shedding more than one of these five viruses. Our study provides an initial description of the feline fecal virome indicating a high level of asymptomatic infections. Availability of the genome sequences of these viruses will facilitate future tropism and feline disease association studies. PMID- 24793099 TI - HU-induced polymorphous filamentation in fish pathogen Edwardsiella tarda leading to reduced invasion and virulence in zebrafish. AB - Edwardsiella tarda is a rod-shaped Gram-negative pathogenic bacterium that causes hemorrhagic septicemia in fish. Nucleoid-associated protein HU is a basic DNA binding protein with structural specificity in regulating genes expression. In wild-type E. tarda EIB202, HU is composed of two subunits HUalpha (hupA) and HUbeta (hupB), and exists in homodimer or heterodimer forms. Different from the wild-type and DeltahupB mutant, DeltahupA mutant was found to be defective in cell growth, H2S production, acid adaptation, and exhibited abnormal cell division resulting in a filamentous phenotype in log phase bacteria. The qRT-PCR result showed that deletion of hupA significantly up-regulated the transcription levels of recA and sulA, which in turn stimulated RecA-dependent pathway to prevent cell division, resulting in filamentous morphology in E. tarda. Furthermore, the elongated DeltahupA cells showed a striking defect in EPC cell invasion, and the adhesion and internalization rates were reduced to 25% and 27% of the wild-type in log phase cultures. Confocal laser scanning microscopy revealed that filamentous bacteria failed to adhere to and could not be internalized into EPC. When some of the bacteria regained the rod-shape morphology in stationary cultures, the DeltahupA mutants showed increased adhesion and internalization rates into EPC. Moreover, DeltahupA mutant exhibited delayed mortalities (for two days) in zebrafish but the LD50 increased 17 folds. Immunohistochemical analysis showed that DeltahupA mutant reduced proliferation abilities in the muscle, liver and intestine of zebrafish. This study indicates that HU protein and strains morphology play essential roles in the virulence network of E. tarda. PMID- 24793100 TI - Modeling the dynamics of incentives in community drug distribution programs. AB - Neglected tropical disease (NTD) control programs rely on an army of volunteers, or community drug distributors (CDDs), to distribute preventative drug packages through community and school-based platforms. Both monetary and non-monetary incentives are frequently provided to CDDs, although the impact on program performance is not well documented or understood. This article presents a descriptive framework to help visualize the dynamics of incentives as part of mass drug administration (MDA) campaigns and to guide future research in this area. PMID- 24793101 TI - Role of structural changes induced in biological membranes by hydrolysable tannins from sumac leaves (Rhus typhina L.) in their antihemolytic and antibacterial effects. AB - In this study, we found that the sumac tannins (Rhus typhina L.) exert to a various extent antihemolytic effects and antibacterial activity against Bacillus cereus and Pseudomonas aeruginosa depending on structural specificity of bacteria and different mechanisms of their toxic action. The sumac tannins exert the most expressed activity against B. cereus. The antihemolytic effect of the sumac tannins seems to be connected to a greater extent with their modifying action on the erythrocyte membrane structure. It was found that the sumac tannins are incorporated into the erythrocyte membrane, causing transformation of discocytes into echinocytes and enhancing the rigidity of the hydrophilic region of the lipid bilayer. We suggest that the embedding of sumac tannins into the membrane of erythrocytes alters their physical properties and, as a consequence, can limit their interaction with bacterial toxins. PMID- 24793102 TI - Clinical and electrophysiological characteristics of the patients with relatively slow atrioventricular nodal reentrant tachycardia. AB - OBJECTIVE: The aim of this study is to retrospectively investigate clinical and electrophysiologic characteristics of typical AVNRT with relatively slow tachycardia rates below the average value compared to faster ones, in patients without structural heart disease. METHODS: The present study retrospectively included a total of 1,150 patients receiving successful slow-pathway radio frequency ablation for typical slow-fast AVNRT. Patients were divided into two groups according to their tachycardia cycle length: group I included 1,018 patients with tachycardia cycle length < 400 msn and group II included 132 patients with cycle length > 400 msn. Patients with another form of arrhythmia other than typical AVNRT, the existence of structural heart disease, preexisting prolonged PR interval, history of clinically documented AF, and reasons capable of causing AF were accepted as exclusion criterias. RESULTS: The patients in group II were older than those in group 1 (p=0.039), and male ratio was significantly higher in group II compared to group I (p=0.02). Wenckebach cycle length and AV node antegrade effective refractory period values before the RF ablation were significantly higher in group II compared to group I (p=0.0001 and 0.01, respectively). Right atrium effective refractory period values in both pre- and post-ablation period were significantly higher in group I compared to group II (p=0.0001 and 0.004, respectively). The existence of atrial vulnerability before ablation was significantly higher in group II compared to group I (p=0.007); however, there was no difference between the two groups in terms of atrial vulnerability after the ablation. In addition, while the ratio of anterior location as an ablation site near the His-bundle region was significantly higher in group II, the ratio of posterior location was significantly higher in group I (p=0.0001 for both). CONCLUSION: Our experience demonstrates that clinical and electrophysiologic characteristics of AVNRT patients with relatively slower tachycardia rates were quite different compared to the faster AVNRT cases. PMID- 24793103 TI - A review of the surgical management of sacral chordoma. AB - BACKGROUND: Sacral chordomas are rare low-to-intermediate grade malignant tumours, which arise from remnants of the embryonic notochord. This review explores prognostic factors in the management of sacral chordomas and provides guidance on the optimal treatment regimens based on the current literature. PATIENTS AND METHODS: Electronic searches were performed using MEDLINE, Embase and the Cochrane library to identify studies on prognostic factors in the management of sacral chordomas published between January 1970 and December 2013. The literature search and review process identified 100 articles that were included in the review article. This included both surgical and non-surgical studies on the management of sacral chordomas. RESULTS: Sacrectomy with wide resection margins forms the mainstay of treatment but is associated with high risk of disease recurrence and reduced long-term survival. Adequate resection margins may require sacrifice of adjacent nerve roots, musculature and ligaments leading to functional compromise and mechanical instability. Large tumour size (greater than 5-10 cm in diameter), dedifferentiation and greater cephalad tumour extension are associated with increased risk of disease recurrence and reduced survival. Chordomas are poorly responsive to conventional radiotherapy and chemotherapy. CONCLUSION: Operative resection with wide resection margins offers the best long-term prognosis. Inadequate resection margins, large tumour size, dedifferentiation, and greater cephalad chordoma extension are associated with poor oncological outcomes. Routine long-term follow-up is essential to enable early detection and treatment of recurrent disease. PMID- 24793104 TI - DeltapH-dependent non-photochemical quenching (qE) of excited chlorophylls in the photosystem II core complex of the freshwater cyanobacterium Synechococcus sp PCC 7942. AB - Light-induced and lumen acidity-dependent quenching (qE) of excited chlorophylls (Chl) in vivo has been amply documented in plants and algae, but not in cyanobacteria, using primarily the saturation pulse method of quenching analysis which is applied to continuously illuminated samples. This method is unsuitable for cyanobacteria because the background illumination elicits in them a very large Chl a fluorescence signal, due to a state 2 to state 1 transition, which masks fluorescence changes due to other causes. We investigated the qE problem in the cyanobacterium Synechococcus sp. PCC 7942 using a kinetic method (Chl a fluorescence induction) with which qE can be examined before the onset of the state 2 to state 1 transition and the attendant rise of Chl a fluorescence. Our results confirm the existence of a qE mechanism that operates on excited Chls a in Photosystem II core complexes of cyanobacteria. PMID- 24793105 TI - Should fractures in massive intercalary bone allografts of the lower limb be treated with ORIF or with a new allograft? AB - BACKGROUND: Massive bone allografts have been used for limb salvage of bone tumor resections as an alternative to endoprostheses, although they have different outcomes and risks. There is no general consensus about when to use these alternatives, but when it is possible to save the native joints after the resection of a long bone tumor, intercalary allografts offer some advantages despite complications, such as fracture. The management and outcomes of this complication deserve more study. QUESTIONS/PURPOSES: The purposes of this study were to (1) analyze the fracture frequency in a group of patients treated with massive intercalary bone allografts of the femur and tibia; (2) compare the results of allografts treated with open reduction and internal fixation (ORIF) with those treated with resection and repeat allograft reconstruction; and (3) determine the likelihood that treatment of a fracture resulted in a healed intercalary reconstruction. METHODS: We reviewed patients treated with intercalary bone allografts between 1991 and 2011. During this period, patients were generally treated with intercalary allografts when after tumor resection at least 1 cm of residual epiphysis remained to allow fixation of the osteotomy junction. To obtain a homogeneous group of patients, we excluded allograft prosthesis composites and osteoarticular and hemicylindrical intercalary allografts from this study. We analyzed the fracture rate of 135 patients reconstructed with segmental intercalary bone allografts of the lower extremities (98 femurs and 37 tibias). In patients whose grafts fractured were treated either by internal fixation or a second allograft, ORIF generally was attempted but after early failures in femur fractures, these fractures were treated with a second allograft. Using a chart review, we ascertained the frequency of osseous union, complications, and reoperations after the treatment of fractured intercalary allografts. Followup was at a mean of 101 months (range, 24-260 months); of the original 135 patients, no patient was lost to followup. RESULTS: At latest followup, 19 patients (14%) had an allograft fracture (16 femurs [16%] and three tibias [8%]). Six patients were treated with internal fixation and addition of autologous graft (three femurs and three tibias) and 13 patients were treated with a second intercalary allograft (13 femurs). The three patients with femoral allograft fractures treated with internal fixation and autologous grafts failed and were treated with a second allograft, whereas those patients with tibia allograft fractures treated by the same procedure healed without secondary complications. When we analyzed the 16 patients with a second intercalary allograft (13 as primary treatment of the fracture and three as secondary treatment of the fracture), five failed (31%) and were treated with resection of the allograft and reconstructed with an endoprosthesis (four patients) or an osteoarticular allograft (one patient). CONCLUSIONS: Fractures of intercalary allografts of the tibia could successfully be treated with internal fixation and autologous iliac crest bone graft; however, this treatment failed when used for femur allograft fractures. Femoral fractures could be treated with resection and repeat allograft reconstruction, however, with a higher refracture frequency. The addition of a vascularized fibular graft in the second attempt should be considered. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 24793106 TI - Rectovestibular fistula with vaginal atresia: our experience and a proposed course of management. AB - BACKGROUND: Rectovestibular fistula with coexisting vaginal atresia poses a surgical dilemma with regard to the timing and type of reconstruction. We present our experience and suggest an appropriate course of management. METHODS: Seven patients with rectovestibular fistula and coexisting vestibular atresia were operated in our hospital during January 2004 through December 2013. The details of their bowel, menstrual and sexual functions were recorded. RESULTS: Five of the seven patients who underwent anoplasty in childhood presented to us in their teens with primary amenorrhea and cyclical abdominal pain. All five had sigmoid colon neovaginoplasty. Four of these had the uterus or its remnants anastomosed to the neovagina. All four have regular menstrual cycles. One patient is sexually active and has satisfactory sexual function. The bowel function in all the five patients is good. The remaining two patients presented in their infancy and had the anorectovestibular fistula left as the neovagina. The recto-sigmoid was pulled down to form the neoanus. Both these patients have bowel incontinence. CONCLUSION: We recommend the rectovestibular fistula be used as the neoanus and not as the neovagina. Delayed bowel vaginal replacement has excellent results and allows for optimal assessment of functioning uterine body or remnants. PMID- 24793107 TI - To add or not to add: the use of quenching agents for the analysis of disinfection by-products in water samples. AB - The formation of disinfection by-products (DBPs) is a public health concern due to their potential adverse health effects. Robust and sensitive methods for the analysis of DBPs, as well as appropriate sample handling procedures, are essential to obtain accurate, precise and reliable data on DBP occurrence and formation. In particular, the use of an appropriate quenching agent is critical to prevent further formation of DBPs during the holding time between sample collection and analysis. Despite reports of decomposition of DBPs caused by some quenching agents, particularly sulphite and thiosulphate, a survey of the literature shows that they are still the most commonly used quenching agents in analysis of DBPs. This study investigated the effects of five quenching agents (sodium sulphite, sodium arsenite, sodium borohydride, ascorbic acid, and ammonium chloride) on the stability of seven different classes of DBPs commonly found in drinking waters, in order to determine the most appropriate quenching agent for the different classes of DBPs. All of the quenching agents tested did not adversely affect the concentrations of trihalomethanes (THMs) and haloacetic acids (HAAs), and thus are suitable for quenching of disinfectant residual prior to analysis of these DBPs. Ascorbic acid was found to be suitable for the analysis of haloacetonitriles (HANs) and haloketones (HKs), but should not be used for the analysis of chlorite. Sodium arsenite, sodium borohydride, and ascorbic acid were all acceptable for the analysis of haloacetaldehydes (HALs). All of the quenching agents tested adversely affected the concentration of chloropicrin. A 'universal' quenching agent, suitable for all groups of DBPs studied, was not identified. However, based on the results of this study, we recommend the use of ascorbic acid for quenching of samples to be analysed for organic DBPs (i.e. THMs, HAAs, HANs, HKs, and HALs) and sodium sulphite for analysis of inorganic DBPs. Our study is the first comprehensive study on the effects of quenching agents on the stability of DBPs involving a wide range of DBP classes and quenching agents. PMID- 24793108 TI - Decay of genetic markers for fecal bacterial indicators and pathogens in sand from Lake Superior. AB - Beach sands impact water quality and pathogen loads, however, the comparative decay of the fecal indicator bacteria (FIB) Enterococcus spp. and Escherichia coli, and pathogens in freshwater sand have not been examined. In this study, freshwater sand microcosms were inoculated with sewage and pure cultures of bacterial pathogens to compare relative decay rates. The abundance of culturable Enterococcus spp. and E. coli, genetic markers for Enterococcus spp. (Entero1), total Bacteroides (AllBac), and human-specific Bacteroides (HF183), and genetic markers for the pathogens Campylobacter jejuni, methicillin-resistant Staphylococcus aureus (MRSA), Salmonella enterica subsp. enterica serovar Typhimurium, and Shigella flexneri were monitored over the course of two weeks using conventional culture methods and quantitative PCR (qPCR). The effect of moisture on the persistence of culturable FIB and all genetic markers was also determined. In addition, propidium monoazide (PMA) treatment was used to examine differences in the persistence of total genetic markers and those from live cells. Decay rates were statistically compared using Tukey's test. Moisture had a significant (p <= 0.05) effect on the decay rates of culturable indicator bacteria, total AllBac markers, and genetic markers for FIB, Salmonella, and MRSA from live cells. At 14% sand moisture, the decay rate of total markers was slower than that of live cells for all qPCR assays, but at 28% moisture, there was no difference in the decay rates of total and live markers for any assay. AllBac and MRSA markers increased in sand at 28% moisture, probably indicating cellular growth. Overall, culturable FIB and HF183 had decay rates that were most comparable to the bacterial pathogen markers examined in this study, whereas Entero1 and AllBac rarely exhibited decay rates similar to the bacterial pathogens in this study. The choice of FIB for assessment of fecal contamination in freshwater sand should take into account the pathogen of concern and sand moisture conditions. PMID- 24793109 TI - Aerobic biodegradation of trichloroethene without auxiliary substrates. AB - Trichloroethene (TCE) represents a priority pollutant and is among the most frequently detected contaminants in groundwater. The current bioremediation measures have certain drawbacks like e.g. the need for auxiliary substrates. Here, the aerobic biodegradation of TCE as the sole growth substrate is demonstrated. This new process of metabolic TCE degradation was first detected in groundwater samples. TCE degradation was stable in an enriched mixed bacterial culture in mineral salts medium for over five years and repeated transfers of the culture resulting in a 10(10) times dilution of the original groundwater. Aerobic TCE degradation resulted in stoichiometric chloride formation. Stable carbon isotope fractionation was observed providing a reliable analytical tool to assess this new biodegradation process at field sites. The results suggest that aerobic biodegradation of TCE without auxiliary substrate could be considered as an option for natural attenuation or engineered bioremediation of contaminated sites. PMID- 24793110 TI - Application of human and animal viral microbial source tracking tools in fresh and marine waters from five different geographical areas. AB - Integrated river basin management planning to mitigate the impacts of economic, demographic and climate change is an important issue for the future protection of water resources. Identifying sources of microbial contamination via the emerging science of Microbial Source Tracking (MST) plays a key role in risk assessment and the design of remediation strategies. Following an 18-month surveillance program within the EU-FP7-funded VIROCLIME project, specific MST tools were used to assess human markers such as adenoviruses (HAdV) and JC polyomaviruses (JCPyV) and porcine and bovine markers such as porcine adenoviruses (PAdV) and bovine polyomaviruses (BPyV) via quantification with real-time PCR to analyze surface water collected from five sites within different climatic zones: the Negro River (Brazil), Glafkos River (Greece), Tisza River (Hungary), Llobregat River (Spain) and Umealven River (Sweden). The utility of the viral MST tools and the prevalence and abundance of specific human and animal viruses in the five river catchments and adjacent seawater, which is impacted by riverine contributions from the upstream catchments, were examined. In areas where no sanitation systems have been implemented, sewage can directly enter surface waters, and river water exhibited high viral loads; HAdV and JCPyV could be detected at mean concentrations of 10(5) and 10(4) Genome Copies/Liter (GC/L), respectively. In general, river water samples upstream of urban discharges presented lower human viral loads than downstream sampling sites, and those differences appeared to increase with urban populations but decrease in response to high river flow, as the elevated river water volume dilutes microbial loads. During dry seasons, river water flow decreases dramatically, and secondary effluents can represent the bulk of the riverine discharge. We also observed that ice cover that formed over the river during the winter in the studied areas in North Europe could preserve viral stability due to the low temperatures and/or the lack of solar inactivation. Porcine and bovine markers were detected where intensive livestock and agricultural activities were present; mean concentration values of 10(3) GC/L indicated that farms were sometimes unexpected and important sources of fecal contamination in water. During spring and summer, when livestock is outdoors and river flows are low, animal pollution increases due to diffuse contamination and direct voiding of feces onto the catchment surface. The field studies described here demonstrate the dynamics of fecal contamination in all catchments studied, and the data obtained is currently being used to develop dissemination models of fecal contamination in water with respect to future climate change scenarios. The results concerning human and animal targets presented in this study demonstrate the specificity and applicability of the viral quantitative parameters developed to widely divergent geographical areas and their high interest as new indicators of human and animal fecal contamination in water and as MST tools. PMID- 24793111 TI - The investigation of the LED-activated FeFNS-TiO2 nanocatalyst for photocatalytic degradation and mineralization of organophosphate pesticides in water. AB - This study evaluated the preparation and characterization of an efficient doped TiO2 as a novel catalyst for degradation of diazinon model pesticide using LED activated photocatalysis. TiO2 was doped using N, NS, FeNS, and FeFNS. The FeFNS doped TiO2 showed the highest catalytic activity in LED/photocatalysis. FeFNS doped TiO2 is a mesoporous nanocrystal powder with a mean pore diameter of 10.2 nm, a specific surface area of 104.4 m(2)/g and a crystallite size of 6.7 nm. LED/photocatalysis using FeFNS-doped TiO2 improved diazinon degradation by 52.3% over that of as-made plain TiO2 at an optimum solution pH of 7. The diazinon degradation in LED/photocatalysis using FeFNS-doped TiO2 increased from 44.8% to 96.3% when the catalyst concentration increased from 25% to 300%at a reaction time of 100 min. The degradation and mineralization of diazinon during LED/photocatalysis with FeFNS-doped TiO2 catalyst followed the pseudo-first-order reaction model with the rate constants of 0.973 h(-1) and 0.541 h(-1), respectively. The FeFNS-doped TiO2 was found to be an efficient catalyst that was photoactivated using UV-LED lamps. LED/photocatalysis with FeFNS-doped TiO2 catalyst is a promising alternative to conventional UV/TiO2photocatalysis for producing free OH radicals for use in the degradation and mineralization of water toxic contaminants. PMID- 24793112 TI - Fe@Fe2O3 core-shell nanowires enhanced Fenton oxidation by accelerating the Fe(III)/Fe(II) cycles. AB - In this study we demonstrate Fe@Fe2O3 core-shell nanowires can improve Fenton oxidation efficiency by two times with rhodamine B as a model pollutant at pH > 4. Active species trapping experiments revealed that the rhodamine B oxidation enhancement was attributed to molecular oxygen activation induced by Fe@Fe2O3 core-shell nanowires. The molecular oxygen activation process could generate superoxide radicals to assist iron core for the reduction of ferric ions to accelerate the Fe(III)/Fe(II) cycles, which favored the H2O2 decomposition to produce more hydroxyl radicals for the rhodamine B oxidation. The combination of Fe@Fe2O3 core-shell nanowires and ferrous ions (Fe@Fe2O3/Fe(2+)) offered a superior Fenton catalyst to decompose H2O2 for producing OH. We employed benzoic acid as a probe reagent to check the generation of OH and found the OH generation rate of Fe@Fe2O3/Fe(2+) was 2-4 orders of magnitude larger than those of commonly used iron based Fenton catalysts and 38 times that of Fe(2+). The reusability and the stability of Fe@Fe2O3 core-shell nanowires were studied. Total organic carbon and ion chromatography analyses revealed the mineralization of rhodamine B and the releasing of nitrate ions. Gas chromatograph-mass spectrometry was used to investigate the degradation intermediates to propose the possible rhodamine B Fenton oxidation pathway in the presence of Fe@Fe2O3 nanowires. This study not only provides a new Fenton oxidation system for pollutant control, but also widen the application of molecular oxygen activation induced by nanoscale zero valent iron. PMID- 24793113 TI - Effects of charging on the chromophores of dissolved organic matter from the Rio Negro basin. AB - This study demonstrates that the deprotonation of dissolved organic matter (DOM) originating from a small creek characteristic for DOM-rich waters located in the Rio Negro basin can be quantified based on measurements of pH effects on its absorbance spectra. The method was ascertained by the data of Near-Edge X-Ray Absorbance Spectroscopy (NEXAFS), potentiometric titration to quantify the structural and compositional differences between the colloidal and hydrophobic fractions that contribute 91% of black-water creek DOM. Changes in the absorbance spectra of the DOM fractions caused by deprotonation quantified via numeric deconvolution which indicated the presence of six well-resolved Gaussian bands in the differential spectra. The emergence of these bands was determined to be associated with the engagement of carboxylic and phenolic functionalities and changes of inter-chromophore interactions in DOM molecules. Interpretation of the data based on the NICA-Donnan approach showed that behavior of DOM chromophores was consistent with results of potentiometric titrations. Similar trends were observed for changes of the spectral slope of the DOM absorbance spectra in the range of wavelengths 325-375 nm (DSlope325-375). The behavior of DSlope325-375 values was modeled based on the NICA-Donnan approach and correlated with potentiometrically-estimated charges attributed to the carboxylic and phenolic groups. The correlations between DSlope325-375 and charges of low- and high affinity protonation-active groups in DOM were monotonic but not linear and had important differences between the colloidal and hydrophobic fractions. PMID- 24793114 TI - Flocculation characteristics of polyacrylamide grafted cellulose from Phyllostachys heterocycla: An efficient and eco-friendly flocculant. AB - This work presents a synthesis process and flocculation characteristics of an eco friendly flocculant based on bamboo pulp cellulose (BPC) from Phyllostachys heterocycla. Ployacrylamide (PAM) was grafted onto the BPC by free-radical graft copolymerization in homogeneous aqueous solution. The optimal synthesis conditions of the bamboo pulp cellulose-graft-ployacrylamide flocculant (BPC-g PAM) and its performance on wastewater treatments were investigated. A UV-based method was used to rapidly determine the degree of substitution (DS) of BPC. The results showed that, under the optimal synthesis conditions, the obtained BPC-g PAM held a grafting ratio of 43.8% and DS of 1.31. Turbidity removal of the product reached 98.0% accompanying with the significant flocculation and sedimentation in target suspensions. The flocculation mechanism was explored by means of zeta potential method. For negatively charged contaminants, like kaolin clay particles, the BPC-g-PAM could remove the contaminants efficiently via bridging and charge neutralization in acidic or neutral environment. PMID- 24793115 TI - Bioanalytical and chemical evaluation of disinfection by-products in swimming pool water. AB - Pool water disinfection is vital to prevent microbial pathogens. However, potentially hazardous disinfection by-products (DBP) are formed from the reaction between disinfectants and organic/inorganic precursors. The aim of this study was to evaluate the presence of DBPs in various swimming pool types in Brisbane, Australia, including outdoor, indoor and baby pools, and the dynamics after a complete water renewal. Chemical analysis of 36 regulated and commonly found DBPs and total adsorbable organic halogens as well as in vitro bioassays targeting cytotoxicity, oxidative stress and genotoxicity were used to evaluate swimming pool water quality. Dichloroacetic acid and trichloroacetic acid dominated in the pool water samples with higher levels (up to 2600 MUg/L) than the health guideline values set by the Australian Drinking Water Guidelines (100 MUg/L). Chlorinated DBPs occurred at higher concentrations compared to tap water, while brominated DBPs decreased gradually with increasing pool water age. Biological effects were expressed as chloroacetic acid equivalent concentrations and compared to predicted effects from chemical analysis and biological characterisation of haloacetic acids. The quantified haloacetic acids explained 35-118% of the absorbable organic halogens but less than 4% of the observed non specific toxicity (cytotoxicity), and less than 1% of the observed oxidative stress response and genotoxicity. While the DBP concentrations in Australian pools found in this study are not likely to cause any adverse health effect, they are higher than in other countries and could be reduced by better hygiene of pool users, such as thorough showering prior to entering the pool and avoiding urination during swimming. PMID- 24793117 TI - Effects of the intensity of masking noise on ear canal recorded low-frequency cochlear microphonic waveforms in normal hearing subjects. AB - Compared to auditory brainstem responses (ABRs), cochlear microphonics (CMs) may be more appropriate to serve as a supplement to the test of otoacoustic emissions (OAEs). Researchers have shown that low-frequency CMs from the apical cochlea are measurable at the tympanic membrane using high-pass masking noise. Our objective is to study the effect of such noise at different intensities on low-frequency CMs recorded at the ear canal, which is not completely known. Six components were involved in this CM measurement including an ear canal electrode (1), a relatively long and low-frequency toneburst (2), and high-pass masking noise at different intensities (3). The rest components include statistical analysis based on multiple human subjects (4), curve modeling based on amplitudes of CM waveforms (CMWs) and noise intensity (5), and a technique based on electrocochleography (ECochG or ECoG) (6). Results show that low-frequency CMWs appeared clearly. The CMW amplitude decreased with an increase in noise level. It decreased first slowly, then faster, and finally slowly again. In conclusion, when masked with high-pass noise, the low-frequency CMs are measurable at the human ear canal. Such noise reduces the low-frequency CM amplitude. The reduction is noise-intensity dependent but not completely linear. The reduction may be caused by the excited basal cochlea which the low-frequency has to travel and pass through. Although not completely clear, six mechanisms related to such reduction are discussed. PMID- 24793116 TI - Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways. AB - Pain relievers containing N-acetyl-para-aminophenol, also called APAP, acetaminophen or paracetamol, in combination with opioid narcotics are top selling pharmaceuticals in the U.S. Individuals who abuse these drugs for as little as sixty days can develop tinnitus and progressive bilateral sensorineural hearing loss. Recently published studies indicate that APAP and its metabolic product N-acetyl-p-benzoquinoneimine (NAPQI) are the primary ototoxic agents in this type of pain relievers. However, the mechanisms underlying the deleterious effects of these drugs on auditory cells remain to be fully characterized. In this study, we report cellular, genomic, and proteomic experiments revealing that cytotoxicity by APAP and NAPQI involves two different pathways in Immortomouse derived HEI-OC1 cells, implicating ROS overproduction, alterations in ER morphology, redistribution of intra-cisternal chaperones, activation of the eIF2alpha-CHOP pathway, as well as changes in ER stress and protein folding response markers. Thus, both oxidative and ER stress are part of the cellular and molecular mechanisms that contribute to the cytotoxic effects of APAP and NAPQI in these cells. We suggest that these in vitro findings should be taken into consideration when designing pharmacological strategies aimed at preventing the toxic effects of these drugs on the auditory system. PMID- 24793118 TI - Magnetic resonance imaging-ultrasound fusion biopsy for prediction of final prostate pathology. AB - PURPOSE: We explored the impact of magnetic resonance imaging-ultrasound fusion prostate biopsy on the prediction of final surgical pathology. MATERIALS AND METHODS: A total of 54 consecutive men undergoing radical prostatectomy at UCLA after fusion biopsy were included in this prospective, institutional review board approved pilot study. Using magnetic resonance imaging-ultrasound fusion, tissue was obtained from a 12-point systematic grid (mapping biopsy) and from regions of interest detected by multiparametric magnetic resonance imaging (targeted biopsy). A single radiologist read all magnetic resonance imaging, and a single pathologist independently rereviewed all biopsy and whole mount pathology, blinded to prior interpretation and matched specimen. Gleason score concordance between biopsy and prostatectomy was the primary end point. RESULTS: Mean patient age was 62 years and median prostate specific antigen was 6.2 ng/ml. Final Gleason score at prostatectomy was 6 (13%), 7 (70%) and 8-9 (17%). A tertiary pattern was detected in 17 (31%) men. Of 45 high suspicion (image grade 4-5) magnetic resonance imaging targets 32 (71%) contained prostate cancer. The per core cancer detection rate was 20% by systematic mapping biopsy and 42% by targeted biopsy. The highest Gleason pattern at prostatectomy was detected by systematic mapping biopsy in 54%, targeted biopsy in 54% and a combination in 81% of cases. Overall 17% of cases were upgraded from fusion biopsy to final pathology and 1 (2%) was downgraded. The combination of targeted biopsy and systematic mapping biopsy was needed to obtain the best predictive accuracy. CONCLUSIONS: In this pilot study magnetic resonance imaging-ultrasound fusion biopsy allowed for the prediction of final prostate pathology with greater accuracy than that reported previously using conventional methods (81% vs 40% to 65%). If confirmed, these results will have important clinical implications. PMID- 24793119 TI - Treatment of endothelial cell with flavonoids modulates transendothelial leukocyte migration. AB - OBJECTIVE: This study aimed to investigate the influence of the flavonoid oxerutin (Venoruton(r), Novartis, Basel, Switzerland) on endothelial cell apoptosis and transendothelial migration of peripheral blood mononuclear cells and to elucidate the potential mechanisms affecting these processes. METHODS: Human endothelial cells were treated with Venoruton to assess the potential effect on apoptosis and on the transendothelial migration process. Endothelial nitric oxide synthase and inducible nitric oxide synthase expression in endothelial cell after Venoruton treatment as well as reactive oxygen species levels were analyzed. RESULTS: Low-dose Venoruton shows a protective effect on endothelial cells and inhibits transendothelial migration of peripheral blood mononuclear cells through an endothelial monolayer, but high-dose Venoruton inversely elevated transendothelial migration of peripheral blood mononuclear cells. Meanwhile, a dose-dependent action of Venoruton on endothelial cell apoptosis could be observed. Endothelial nitric oxide synthase and inducible nitric oxide synthase expression were gradually increased in endothelial cells with increasing Venoruton dosage. In addition, reactive oxygen species were significantly reduced by 0.1 mM and 0.5 mM Venoruton and elevated after high dose treatment. CONCLUSION: These data suggest that the increased transendothelial migration of peripheral blood mononuclear cells is related to the excessive activation of the nitric oxide-axis and subsequent relaxation of the endothelial cells. PMID- 24793120 TI - Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. AB - BACKGROUND & AIMS: Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. METHODS: We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. RESULTS: We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. CONCLUSIONS: Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process. PMID- 24793121 TI - Comparative transcriptome analysis of aerial and subterranean pods development provides insights into seed abortion in peanut. AB - The peanut is a special plant for its aerial flowering but subterranean fructification. The failure of peg penetration into the soil leads to form aerial pod and finally seed abortion. However, the mechanism of seed abortion during aerial pod development remains obscure. Here, a comparative transcriptome analysis between aerial and subterranean pods at different developmental stages was produced using a customized NimbleGen microarray representing 36,158 unigenes. By comparing 4 consecutive time-points, totally 6,203 differentially expressed genes, 4,732 stage-specific expressed genes and 2,401 specific expressed genes only in aerial or subterranean pods were identified in this study. Functional annotation showed their mainly involvement in biosynthesis, metabolism, transcription regulation, transporting, stress response, photosynthesis, signal transduction, cell division, apoptosis, embryonic development, hormone response and light signaling, etc. Emphasis was focused on hormone response, cell apoptosis, embryonic development and light signaling relative genes. These genes might function as potential candidates to provide insights into seed abortion during aerial pod development. Ten candidate genes were validated by Real-time RT-PCR. Additionally, consistent with up-regulation of auxin response relative genes in aerial pods, endogenous IAA content was also significantly increased by HPLC analysis. This study will further provide new molecular insight that auxin and auxin response genes potentially contribute to peanut seed and pod development. PMID- 24793122 TI - Effect of azithromycin on enhancement of methane production from waste activated sludge. AB - In the methane production from waste activated sludge (WAS), complex bacterial interactions in WAS have been known as a major contribution to methane production. Therefore, the influence of bacterial community changes toward methane production from WAS was investigated by an application of antibiotics as a simple means for it. In this study, azithromycin (Azm) as an antibiotic was mainly used to observe the effect on microbial changes that influence methane production from WAS. The results showed that at the end of fermentation, Azm enhanced methane production about twofold compared to control. Azm fostered the growth of acid-producing bacterial communities, which synthesized more precursors for methane formation. DGGE result showed that the hydrolysis as well as acetogenesis stage was improved by the dominant of B1, B2 and B3 strains, which are Clostridium species. In the presence of Azm, the total population of archaeal group was increased, resulting in higher methane productivity achievement. PMID- 24793123 TI - SACE_3986, a TetR family transcriptional regulator, negatively controls erythromycin biosynthesis in Saccharopolyspora erythraea. AB - Erythromycin, a medically important antibiotic, is produced by Saccharopolyspora erythraea. Unusually, the erythromycin biosynthetic gene cluster lacks a regulatory gene, and the regulation of its biosynthesis remains largely unknown. In this study, through gene deletion, complementation and overexpression experiments, we identified a novel TetR family transcriptional regulator SACE_3986 negatively regulating erythromycin biosynthesis in S. erythraea A226. When SACE_3986 was further inactivated in an industrial strain WB, erythromycin A yield of the mutant was increased by 54.2 % in average compared with that of its parent strain, displaying the universality of SACE_3986 as a repressor for erythromycin production in S. erythraea. qRT-PCR analysis indicated that SACE_3986 repressed the transcription of its adjacent gene SACE_3985 (which encodes a short-chain dehydrogenase/reductase), erythromycin biosynthetic gene eryAI and the resistance gene ermE. As determined by EMSA analysis, purified SACE_3986 protein specifically bound to the intergenic region between SACE_3985 and SACE_3986, whereas it did not bind to the promoter regions of eryAI and ermE. Furthermore, overexpression of SACE_3985 in A226 led to enhanced erythromycin A yield by at least 32.6 %. These findings indicate that SACE_3986 is a negative regulator of erythromycin biosynthesis, and the adjacent gene SACE_3985 is one of its target genes. The present study provides a basis to increase erythromycin production by engineering of SACE_3986 and SACE_3985 in S. erythraea. PMID- 24793127 TI - Spatial distribution of attentional bias in visuo-spatial working memory following multiple cues. AB - When attention is focused on one location, its spatial distribution depends on many factors, such as the distance between the attended location and the target location, the presence of visual meridians in between them, and the way, endogenous or exogenous, by which attention is oriented. However, it is not well known how attention distributes when more than one location is endogenously or exogenously cued, which was the focus of the current study. Furthermore, the distribution of attention has been manly investigated in perception. In the present study we faced this issue from a different perspective, by examining the spatial distribution of the attentional bias in visuo-spatial working memory (VSWM), when attention is oriented either exogenously or endogenously, i.e., after two peripheral vs. central symbolic cues (also manipulating cue-target predictability). Results indicated a systematic difference between endogenous and exogenous attention regarding the distribution of the attentional bias over VSWM. In fact, attentional bias following endogenous cues was affected by the presence of visual meridians and by the split of the attentional focus, converging in a unipolar attentional distribution, independently of cue-target predictability. On the other hand, when pulled by exogenous cues, attention distributed uni-modally or multi-modally depending on the distance between the cued locations, with larger effects for highly predictive cues. Results are discussed in terms of space-based, object-based and perceptual grouping mechanisms. PMID- 24793124 TI - Microbial enzymatic production and applications of short-chain fructooligosaccharides and inulooligosaccharides: recent advances and current perspectives. AB - The industrial production of short-chain fructooligosaccharides (FOS) and inulooligosaccharides is expanding rapidly due to the pharmaceutical importance of these compounds. These compounds, concisely termed prebiotics, have biofunctional properties and hence health benefits if consumed in recommended dosages. Prebiotics can be produced enzymatically from sucrose elongation or via enzymatic hydrolysis of inulin by exoinulinases and endoinulinases acting alone or synergistically. Exoinulinases cleave the non-reducing beta-(2, 1) end of inulin-releasing fructose while endoinulinases act on the internal linkages randomly to release inulotrioses (F3), inulotetraoses (F4) and inulopentaoses (F5) as major products. Fructosyltransferases act by cleaving a sucrose molecule and then transferring the liberated fructose molecule to an acceptor molecule such as sucrose or another oligosaccharide to elongate the short-chain fructooligosaccharide. The FOS produced by the action of fructosyltransferases are 1-kestose (GF2), nystose (GF3) and fructofuranosyl nystose (GF4). The production of high yields of oligosaccharides of specific chain length from simple raw materials such as inulin and sucrose is a technical challenge. This paper critically explores recent research trends in the production and application of short-chain oligosaccharides. Inulin and enzyme sources for the production of prebiotics are discussed. The mechanism of FOS chain elongation and also the health benefits associated with prebiotics consumption are discussed in detail. PMID- 24793128 TI - Similarities and differences between mind-wandering and external distraction: a latent variable analysis of lapses of attention and their relation to cognitive abilities. AB - The current study examined the extent to which task-unrelated thoughts represent both vulnerability to mind-wandering and susceptibility to external distraction from an individual difference perspective. Participants performed multiple measures of attention control, working memory capacity, and fluid intelligence. Task-unrelated thoughts were assessed using thought probes during the attention control tasks. Using latent variable techniques, the results suggested that mind wandering and external distraction reflect distinct, yet correlated constructs, both of which are related to working memory capacity and fluid intelligence. Furthermore, the results suggest that the common variance shared by mind wandering, external distraction, and attention control is what primarily accounts for their relation with working memory capacity and fluid intelligence. These results support the notion that lapses of attention are strongly related to cognitive abilities. PMID- 24793129 TI - Tactile enumeration of small quantities using one hand. AB - Our study explores various aspects of enumerating small quantities in the tactile modality. Fingertips of one hand were stimulated by a vibro-tactile apparatus (for 100/800 ms). Between 1 and 5 stimuli were presented to the right or the left hand and applied to neighboring (e.g., thumb-index-middle) or non-neighboring (e.g., thumb-middle-pinkie) fingers. The results showed a moderate increase in RT up to 4 stimuli and then a decrease for 5 stimuli. Right hand stimulation evoked more accurate performance than left hand stimulation only under short exposures (100 ms). Importantly, when the stimuli were presented to neighboring fingers, the accuracy rate was higher and the RT was faster than when presented to non neighboring fingers. We discuss the results and suggest that when the stimuli are presented to one hand the subitizing range is 4 rather than 3. Furthermore, the right hand advantage and the efficiency for neighboring fingers are further support for the association between number and spatial arrangement of the fingers. PMID- 24793130 TI - A novel knee prosthesis with asymmetrical joint surfaces and natural behaviour. AB - The natural tibiofemoral joint (TFJ) functions according to the asymmetrical joint surfaces and the rolling-gliding mechanism. In the sagittal section, the human TFG is the tibial plateau on the medial concave side and curved on the lateral convex. With the asymmetrical joint surfaces, the flexion of the knee consists of two parts: the femur rolls backwards over the tibia plateau, and further flexion causes increased gliding. In most knee arthroplasties, these factors are not taken into account; instead, they are equipped with symmetrical medial and lateral joint surfaces. Thereby, the curvatures of the sagittal contours and the medial lateral joint surfaces create a common axis of rotation. The goal of this study was therefore to develop a novel knee endoprosthesis with asymmetrical joint surfaces and natural rolling-sliding behaviour. PMID- 24793131 TI - Could microbe stimulated maggots become a targeted natural antibiotics family? AB - Maggot debridement therapy plays an important role in treatment of diabetic foot ulcers and other chronic infectious wounds, cause of this is its extremely low drug resistance. However, the microbe stimulated maggot, we may call it a derivative of normal sterile maggot, could exhibit stronger bacterial or bactericidal effects. Methods of the pretreatment on maggot was different germ solution were artificially mixed and added with originally sterile maggots, the novel secretions were collected. Some of this have been demonstrated by plate test and telescope analysis. Thus, we hypothesize that maggot especially the larvae of Lucilia sericata was conducted as the germ irritant receptor, and diverse germs interacted with it, at last, novel secretions/excretions we got will offer a great help to the general surgery clinicians as well as researchers who are interested in novel antibiotics discovery. PMID- 24793133 TI - Does expiratory muscle activity influence dynamic hyperinflation and exertional dyspnea in COPD? AB - Increased expiratory muscle activity is common during exercise in patients with COPD but its role in modulating operating lung volumes and dyspnea during incremental cycle ergometry is currently unknown. We compared gastric (Pga) and esophageal (Pes) pressures, operating lung volumes and qualitative descriptors of dyspnea during exercise in 12 COPD patients and 12 age- and sex-matched healthy controls. Pes- and Pga-derived measures of expiratory muscle activity were significantly (p<0.05) greater in COPD than in health during exercise. End expiratory lung volume (EELV) increased by 0.8L, independent of increased expiratory muscle activity in COPD. Dynamic function of the diaphragm was not different in health and COPD throughout exercise. In both groups, dyspnea descriptors alluding to increased work and inspiratory difficulty predominated whereas expiratory difficulty was rarely reported, even at the limits of tolerance. In conclusion, increased expiratory muscle activity did not mitigate the rise in EELV, the relatively early respiratory mechanical constraints or the attendant perceived inspiratory difficulty during exercise in COPD. PMID- 24793132 TI - Dalhousie Dyspnea and perceived exertion scales: psychophysical properties in children and adolescents. AB - Children and adolescents vary widely in their perception of, or capacity to rate, sensations during exercise using the Borg scale. We sought to measure sensory perceptual responses obtained using Dalhousie Dyspnea and Perceived Exertion Scales in 79 pediatric subjects during maximal exercise challenge and to determine the psychophysical function relationship(s). Concurrent validity was assessed by canonical plots of mean ratings on either scale, which showed showing very good correlations for perceived leg exertion vs work, and dyspnea vs ventilation. Both scales yielded similar results with respect to goodness of fit regardless of whether data was fitted to a power or quadratic function provided a delay term was included. The quadratic model fixed the exponent of the power law at 2 but, unlike a power model, allowed characterization of individual responses that increased and then plateaued. Dalhousie Dyspnea and Perceived Exertion Scales offer an alternative to Borg scale during exercise in pediatric populations. PMID- 24793134 TI - Dystrophin is a tumor suppressor in human cancers with myogenic programs. AB - Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS), feature myogenic differentiation. Here we report that intragenic deletion of the dystrophin encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in the non-neoplastic and benign counterparts of GIST, RMS and LMS tumors, and DMD deletions inactivate larger dystrophin isoforms, including 427 kDa dystrophin, while preserving the expression of an essential 71-kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence and invadopodia formation, and dystrophin inactivation was found in 96%, 100% and 62% of metastatic GIST, embryonal RMS and LMS samples, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in the treatment of cancer. PMID- 24793135 TI - A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. AB - Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft tissue sarcoma in children. Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors. Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation, no functionally comparable genetic event has been found in ERMS tumors. Here we report the discovery, through whole-exome sequencing, of a recurrent somatic mutation encoding p.Leu122Arg in the myogenic transcription factor MYOD1 in a distinct subset of ERMS tumors with poor outcomes that also often contain mutations altering PI3K-AKT pathway components. Previous mutagenesis studies had shown that MYOD1 with a p.Leu122Arg substitution can block wild-type MYOD1 function and bind to MYC consensus sequences, suggesting a possible switch from differentiation to proliferation. Our functional data now confirm this prediction. Thus, MYOD1 p.Leu122Arg defines a subset of rhabdomyosarcomas eligible for high-risk protocols and the development of targeted therapeutics. PMID- 24793138 TI - Delayed ear reconstruction: case report of reconstruction of an avulsed ear 2 days after injury. AB - Auricular reattachment and reconstruction following traumatic ear avulsion is a challenging surgical problem. Suggested reconstruction methods include direct reattachment, composite grafting, pocket methods, coverage with periauricular flaps, and microsurgical repair. A published alternative is reattachment and burial of the amputated part under a postauricular flap. If circumstances delay the surgical intervention, what is a safe window to still consider this form of treatment? In the current report, we present a case of a complete partial ear avulsion, which was reattached in the ER as a free graft. Two days later the cartilage was banked under a postauricular flap. A 22 year-old male had his ear was completely bitten off which was re-attached. Two days later the skin of the avulsed segment was dark and bloodless. The avulsed segment was removed from the ear. The overlying skin was dissected off of the attached ear leaving perichondrium on the medial aspect of the ear. The cartilage was then reattached. A postauricular pocket/flap was created and the ear tucked and secured to the postauricular fascia and skin closed overtop. Five weeks later, the patient had division and inset of the flap with a full thickness skin graft to the posterior aspect of the ear. Our results and experiences suggest that immediate reconstruction may not be crucial. PMID- 24793139 TI - An exploration of rural-urban differences in healthcare-seeking trajectories: implications for measures of accessibility. AB - Comparing accessibility between urban and rural areas requires measurement instruments that are equally discriminating in each context. Through focus groups we explored and compared care-seeking trajectories to understand context-specific accessibility barriers and facilitators. Rural care-seekers rely more on telephone access and experience more organizational accommodation but have fewer care options. Urban care-seekers invoke the barrier of distance more frequently. Four consequences of accessibility problems emerged across settings which could be used for valid comparisons of access: having to restart the care-seeking process, abandoning it, using emergency services for primary care, and health deterioration due to delay. PMID- 24793140 TI - Universal method for creating optically active nanostructures on layered materials. AB - The ability to form patterned surface nanostructures has revolutionized the miniaturization of electronics and led to the discovery of emergent behaviors unseen in macroscopic systems. However, the creation of such nanostructures typically requires multiple processing steps, a high level of technical expertise, and highly sophisticated equipment. In this work, we have discovered a simple method to create nanostructures with control size and positioning in a single processing step using a standard scanning electron microscope. The technique can be applied to a wide range of systems and was successful in every layered material tested. Patterned nanostructures were formed on graphite, topological insulators, novel superconductors, and layered transition metal dichalcogenides. The nanostructures were formed via the incorporation of carbon nanoparticles into the samples in a novel form of intercalation. It appears that the electron beam interacts with residual organic molecules available on the sample surface, making it possible for them to intercalate between the layers in their crystal structure and break down into carbon. These carbon nanoparticles have strong broad-wavelength interactions in the visible light range, making these nanostructures easily detectable in an optical microscope and of interest for a range of nanoscale electro-optical devices. PMID- 24793136 TI - Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. AB - Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4-implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins. PMID- 24793142 TI - Deciphering molecular determinants of chemotherapy in gastrointestinal malignancy using systems biology approaches. AB - Gastrointestinal cancers are asymptomatic in early tumor development, leading to high mortality rates. Peri- or postoperative chemotherapy is a common strategy used to prolong the life expectancy of patients with these diseases. Understanding the molecular mechanisms by which anticancer drugs exert their effect is crucial to the development of anticancer therapies, especially when drug resistance occurs and an alternative drug is needed. By integrating high throughput techniques and computational modeling to explore biological systems at different levels, from gene expressions to networks, systems biology approaches have been successfully applied in various fields of cancer research. In this review, we highlight chemotherapy studies that reveal potential signatures using microarray analysis, next-generation sequencing (NGS), proteomic and metabolomic approaches for the treatment of gastrointestinal cancers. PMID- 24793143 TI - Computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (in)activation. AB - Metabotropic glutamate receptors (mGluRs) are high-profile G-protein coupled receptors drug targets because of their involvement in several neurological disease states, and mGluR5 in particular is a subtype whose controlled allosteric modulation, both positive and negative, can potentially be useful for the treatment of schizophrenia and relief of chronic pain, respectively. Here we model mGluR5 with a collection of positive and negative allosteric modulators (PAMs and NAMs) in both active and inactive receptor states, in a manner that is consistent with experimental information, using a specialized protocol that includes homology to increase docking accuracy, and receptor relaxation to generate an individual induced fit with each allosteric modulator. Results implicate two residues in particular for NAM and PAM function: NAM interaction with W785 for receptor inactivation, and NAM/PAM H-bonding with S809 for receptor (in)activation. Models suggest the orientation of the H-bond between allosteric modulator and S809, controlled by PAM/NAM chemistry, influences the position of TM7, which in turn influences the shape of the allosteric site, and potentially the receptor state. NAM-bound and PAM-bound mGluR5 models also reveal that although PAMs and NAMs bind in the same pocket and share similar binding modes, they have distinct effects on the conformation of the receptor. Our models, together with the identification of a possible activation mechanism, may be useful in the rational design of new allosteric modulators for mGluR5. PMID- 24793141 TI - Approaches to in vitro tissue regeneration with application for human disease modeling and drug development. AB - Reliable in vitro human disease models that capture the complexity of in vivo tissue behaviors are crucial to gain mechanistic insights into human disease and enable the development of treatments that are effective across broad patient populations. The integration of stem cell technologies, tissue engineering, emerging biomaterials strategies and microfabrication processes, as well as computational and systems biology approaches, is enabling new tools to generate reliable in vitro systems to study the molecular basis of human disease and facilitate drug development. In this review, we discuss these recently developed tools and emphasize opportunities and challenges involved in combining these technologies toward regenerative science. PMID- 24793144 TI - Serine phosphorylation of CAPA pyrokinin in cockroaches-a taxon-specific posttranslational modification. AB - In insects, posttranslational modifications of neuropeptides are largely restricted to C- and N-terminal amino acids. The most common modifications, N terminal pyroglutamate formation and C-terminal alpha-amidation, may prevent a fast degradation of these messenger molecules. This is particularly important for peptide hormones. Other common posttranslational modifications of proteins such as glycosylation and phosphorylation seem to be very rare in insect neuropeptides. To check this assumption, we used a computer algorithm to search an extensive data set of MALDI-TOF mass spectra from cockroach tissues for ion signal patterns indicating peptide phosphorylation. The results verify that phosphorylation is indeed very rare. However, a candidate was found and experimentally verified as phosphorylated CAPA pyrokinin (GGGGpSGETSGMWFGPRL-NH2) in the cockroach Lamproblatta albipalpus (Blattidae, Lamproblattinae). Tandem mass spectrometry revealed the phosphorylation site as Ser(5). Phosphorylated CAPA pyrokinin was then also detected in most other cockroach lineages (e.g. Blaberidae, Polyphagidae) but not in closely related blattid species such as Periplaneta americana. This is remarkable since the sequence of CAPA pyrokinin is identical in Lamproblatta and Periplaneta. A consensus sequence of CAPA pyrokinins of cockroaches revealed a conserved motif that suggests phosphorylation by a Four-jointed/FAM20C related kinase. PMID- 24793145 TI - [Recognition of interstitial lung diseases]. PMID- 24793146 TI - ["Polish pneumonology and allergology" 2010-2014]. PMID- 24793147 TI - Accuracy of FDG PET/CT in the evaluation of solitary pulmonary lesions - own experience. AB - INTRODUCTION: In recent years, positron emission tomography (PET) has been increasingly applied in the diagnosis of neoplastic lung diseases. In contrast to conventional imaging studies, PET-CT enables the visualisation of not only the morphology of the suspicious lesion, but also its metabolism. The aim of the present study was to investigate the role of PET-CT in the initial assessment of patients with indeterminate solitary pulmonary lesions. MATERIAL AND METHODS: The study was conducted on a group of 82 patients with indeterminate lung nodule diagnosed at the National Institute of Tuberculosis and Lung Diseases in the period from January 2008 to May 2011. CT and PET-CT were performed in all of the patients. Histological or cytological examination of the biopsy specimens obtained from bronchoscopy, mediastinoscopy and intraoperatively were the reference tests. RESULTS: Malignancy was documented in 40 patients (48.8%). Histopathological analysis of all tumours revealed 12 cases of squamous cell carcinoma, 18 cases of adenocarcinoma and 1 case of carcinoid, whereas in 9 patients the diagnosis of "non-small cell cancer not otherwise specified" was made. All lesions except one were of solid character on chest CT. SUV(max) values exceeding 2.5 were found in 38 cancer patients (true positives, TP). The mean value of SUV(max) was 9.1 (1-26.8). Forty-two lesions were documented as benign (51.2%). SUV(max) values equal to or less than 2.5 were found in 37 patients (true negatives, TN). The mean value of SUV(max) in this group was 1.9 (0.5-8.6). The diagnostic value of PET-CT SUV(max) exceeding 2.5 in the prediction of neoplastic origin of solitary pulmonary lesions was: sensitivity - 95% (95% CI 84 99%), specificity - 88% (95% CI 75-95%) and accuracy - 91.5% (95% CI 83-96%). Positive predictive value (PPV) was 88.4% (95% CI 76-95%), and negative predictive value (NPV) was 94.8% (95% CI 83-99%). False negative results concerned two patients, with final diagnosis of carcinoid and adenocarcinoma; false positive results were obtained in 5 patients with various inflammatory lesions. CONCLUSIONS: In the present study, PET-CT appeared to have high sensitivity (95%), but lower specificity (88%) for predicting the malignant character of solitary pulmonary lesions. Overall diagnostic value of PET-CT SUV(max) > 2.5 was high - PPV was 88.4%, NPV was 94.8%. In the authors' opinion, the PET-CT value may increase when clinical data as well as other radiological documentation (with retrospective assessment) are taken into consideration. PMID- 24793148 TI - Pulmonary alveolar proteinosis during a 30-year observation. Diagnosis and treatment. AB - INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by the abnormal accumulation of surfactant-like material in macrophages within the alveolar spaces and distal bronchioles. The course of the disease is variable and the prognosis is often good. However, progressive disease in some patients can cause respiratory dysfunction and can be life threatening. In this situation, the only effective treatment is whole lung lavage. The objective of the study was to present the characteristics and the course of pulmonary alveolar proteinosis in our own material, the diagnostic methods used, the indications for treatment and the treatment efficacy. MATERIAL AND METHODS: Retrospective analysis included 17 patients: 6 women and 11 men, aged from 32 to 56 years, who were observed in the Third Lung Department of Pneumonology at the National Institute of Tuberculosis and Lung Diseases between 1984 and 2013. In all patients chest X-ray, pulmonary function test and blood gases were performed. In 15 patients, high-resolution computed tomography (HRCT) was obtained. Bronchoscopy was performed in all of the patients, and in 7/17, bronchoalveolar lavage (BAL) was carried out. Fourteen patients underwent open lung biopsy. The indications for whole lung lavage (WLL) were progression of dyspnoea with restriction of daily activity and/or hypoxaemia. RESULTS: In most of the patients (13/17) the diagnosis was established outside our institute. Patients were referred to our department to establish further procedures. The criteria of diagnosis of PAP in most patients (16/17) was the histological examination of lung tissue, obtained by open lung biopsy (14 cases) and transbronchial lung biopsy (TBLB) (2 cases). Only in one patient the diagnosis was established on the basis of BAL. HRCT imaging was characteristic of proteinosis in 11/15 patients, and BAL examination in 6/7 patients, in whom BAL was performed. In four patients, who had been exposed to injurious factors for many years, secondary proteinosis was recognised; in other patients, no exposure or no other disease was found, and primary alveolar proteinosis was diagnosed. In one patient granulocyte macrophage colony stimulating factor autoantibody was detected. The majority of patients (10/17) had clinical symptoms at the diagnosis. The most commonly reported was dyspnoea, followed by respiratory tract infections. The most common abnormality (12/17) in pulmonary lung test was a decrease of diffusing capacity of the lung for carbon monoxide (DLCO). Respiratory distress at rest was found in two patients. Patients were observed for the period of 6 months to 19 years. Spontaneous partial remission was observed in 10 out of 13 untreated patients, including one complete remission; in 3 cases stabilisation was found in radiological examinations; and in other 4 patients, whole lung lavagewas used, resulting in clinical improvement with partial resolution of lesions in radiological examinations in 3 patients. In one patient, despite WLL being repeated three times, improvement was not achieved. CONCLUSIONS: Pulmonary alveolar proteinosis is a rare interstitial disease with a mild course in most cases. In 13/17 patients diagnosis was based on histological examination of samples from open lung biopsy. The presented patients were observed in the years 1984-2004, and at that time histologic examination was the main diagnostic method. The most common abnormality in pulmonary function tests was decrease of DLCO. In most cases, spontaneous remission of the disease was observed. In four patients with severe course of PAP, WLL was performed with subjective, functional and radiological improvement in 3 of them. PMID- 24793149 TI - Spectrum of interstitial lung disease at a tertiary care centre in India. AB - INTRODUCTION: The available data on the epidemiology of interstitial lung disease (ILD) from India is sparse. Hence, the present study was undertaken with the aim to analyse the demographic profile and clinical, radiological and pathological characteristics along with physiological parameters of various subgroups of ILD patients. MATERIAL AND METHODS: We retrospectively studied 289 patients diagnosed with ILD during the years 2001-2013 at one of the respiratory units of Vallabhbhai Patel Chest Institute. RESULTS: Mean age at presentation was 44.24 years; females comprised 54.68% of the patients. Prior to presentation at our centre, 14.84% patients had been treated with antituberculous therapy due to misdiagnosis of tuberculosis. In the pool of ILDs analysed, sarcoidosis (37.3%) was found to be the most common subgroup, followed by IPF (27.6%) and NSIP (25.6%). Cough (92.97%) was the most common presenting symptom; exertional dyspnoea was found in 79.2% of patients. Digital clubbing was commonest in IPF, found in 30% of patients. Significant desaturation on six-minute walk test was most frequenty seen (50%) in NSIP patients. The most common pattern on chest roentgenogram was reticular/reticulo-nodular pattern (80.2%) and on HRCT - interstitial fibrosis (49.9%). Mean of predicted total lung capacity (TLC) was 64.3%, the lowest being in the IPF group (58.88%). Mean of predicted DLCO was 50.56%, the lowest being in the IPF group (42.75%). The overall diagnostic yield of bronchoscopic biopsy was 83.04%, the highest yield being among sarcoidosis patients (96.29%). CONCLUSIONS: We found sarcoidosis, IPF and NSIP to be the most common ILDs in northern India. ILDs are still frequently misdiagnosed as TB, and increased awareness, education and diagnostic facilities are required to diagnose ILDs at an early stage. PMID- 24793150 TI - [Polish respiratory society guidelines for chronic obstructive pulmonary disease]. PMID- 24793151 TI - Pulmonary embolism in a young male with tuberculosis and factor V Leiden. AB - There is no doubt that venous thromboembolism (VTE) is a complex and multicausal disease. Tuberculosis (TB) itself is found to have thrombogenic potential. There is an association between tuberculosis and VTE. We present a case of a 31-year old male diagnosed with TB after a 2-month delay. He was treated with an anticoagulant for pulmonary embolism (PE) complicated by pulmonary infarction, and with antibiotics for presumed bacterial pneumonia. The patient did not improve despite in-hospital treatment. Finally, TB was diagnosed with positive sputum smear for acid fast bacilli and subsequent culture of Mycobacterium tuberculosis. Antituberculous therapy was uneventful and the patient was discharged home. Thrombophilia screening revealed a heterozygous factor V Leiden mutation. This case report emphasises that although there is a steady decline in active cases of TB, it should be still placed high on the list as a differential diagnosis in non-resolving lung infection or pulmonary infarction. This is especially relevant in cases with typical radiological findings located in the upper lobes. On the other hand, definitive diagnosis may be challenging in a case of concurrent TB, bacterial pneumonia and pulmonary infarction. Thromboembolic events may develop in TB patients without any clinical VTE risk factors. Therefore, thromboprophylaxis should be cautiously considered in this group of patients. PMID- 24793152 TI - [A 24-year-old male patient with pulmonary veno-occlusive disease - case report]. AB - Pulmonary veno-occlusive disease (PVOD) is a rare cause of severe pulmonary hypertension characterised by poor prognosis. We report the case of a 24-year-old male patient with increasing dyspnea and exercise intolerance treated with calcium channel blockers and glucocorticosteroids, due to suspicion of pulmonary hypertension and interstitial lung disease, until lung biopsy was performed and a diagnosis of PVOD was established on the basis of the histological analysis of the lung biopsy sample. This case highlights that pulmonary veno-occlusive disease is a disorder that is difficult to diagnose and resistant to medical treatment, which is particularly poor prognostic factor. Due to poor response to medical therapy and high mortality in patients with PVOD, understanding the pathogenesis, differentiation with pulmonary arterial hypertension and the search for a new methods of treatment should be the key challenges for modern medicine. PMID- 24793153 TI - Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. AB - Anaerobes used to be the most common cause of community-acquired lung abscess, and Streptococcus species used to be the second most common cause. In recent years, this has been changing. Klebsiella pneumoniae is now an increasing cause of community- acquired lung abscess, but Streptococcus species continue to be major pathogens. Necrotizing pneumonia has generally been regarded as a rare complication of pneumococcal infection in adults. Type 3 Streptococcus pneumoniae was the single most common type implicated in necrosis; however, many other serotypes were implicated. This entity predominately infects children, but is present also in adults. Lung abscess in adults due to Streptococcus pneumoniae is not common. In this regard we present a case series of pulmonary cavitation due to Streptococcus pneumoniae and discuss the possible pathogenic mechanism of the disease. PMID- 24793154 TI - [Immune alterations in lung cancer - the new therapeutic approach]. AB - Lung cancer is the main cause of cancer death worldwide. An advanced stage of the disease at the time of diagnosis, observed in the majority of cases, does not allow for introduction of radical treatment or makes the treatment ineffective. Lung cancer as a solid tumour with a very low antigenicity escapes immune surveillance, and cytotoxic cells attack. Cytotoxic lymphocytes play a key role in anticancer defence, but the population of these cells individually differs. Many suppressor and regulatory mechanisms inhibit the recognition of tumour antigens by dendritic and cytotoxic cell activation. The population of regulatory T cells (T regs) plays a crucial role in this inhibition of immune response. Their function depends on the expression of transcription factor Foxp3 and the presence of CTLA-4 molecules. The increased proportion of T regs and high expression of Foxp3 and CTLA-4 on lung cancer cells and tumour infiltrating lymphocytes were observed. Other components of immune response inhibition and tumour promotion are: Th17 cell population, M2 macrophage polarisation, the presence of myeloid derived suppressor cells (MDSCs) and a significantly elevated concentration of cytokines: TGF-b and IL-10 in the tumour microenvironment. The recognition of these mechanisms may have important therapeutic implications. Several types of agents which are capable of modulating the immune response have recently been used in many clinical trials conducted in lung cancer patients, some of them showing efficacy. Lung cancer immunotherapy has two main directions: the first goal is to improve the cytotoxic effect (for example by inhibition of CTLA-4, stimulation of dendritic cell function, inhibition of lymphocyte apoptosis), and the second way is the production of anti-cancer vaccines using known cancer antigens: MAGE A3, MUC1, EGF and TGF-b. Immunotherapy in lung cancer treatment has a character of personalised therapy - there is a need to specify the patient's immune status prior to treatment. The analysis of immune cells and mediators in the peripheral blood allows this, but the more valuable method seems to be bronchoalveolar lavage (BAL) examination with careful assessment of the tumour microenvironment. PMID- 24793155 TI - [Influence of inhaler and fine particle on efficacy of inhalation therapy in COPD]. AB - Orally inhaled products delivered via inhalation exert their effect directly to the target organ. This allows to administer a very low dose of a drug compared with an oral route with similar clinical effect and significantly reduced toxicity. However inhalation therapy is also limited by several factors. Delivery of the desired dose of the drug to the airways depends on a type of the inhaler - pressurised metered-dose inhaler (pMDI) or dry powder inhaler (DPI), inhaler characteristics (low or high internal resistance, diameter of particles and distribution of the generated aerosol fine particles), thermal conditions of air, and ability of patient to generate sufficient inspiratory flow (for DPI) or to coordinate actuation with inhalation (for pMDI). Unlike pMDIs, DPIs are breath- actuated, hence avoiding the need for the patient to coordinate actuation with inspiration. Furthermore, DPIs are propellant-free and do not produce the cold sensation on inhalation. Currently available DPIs vary widely in design, operating characteristics and performance. And poor inhalation technique may compromise treatment efficacy. Hence, there is a clear need for a careful selection of DPIs for different patient groups, including children, elderly patients and those with severe airway obstruction. PMID- 24793156 TI - [Current methods to detect EGFR gene mutations as predictive factor for targeted therapies in non-small cell lung cancer - is there a "golden standard" in diagnostics?]. AB - According to current Polish and international recommendations, detection of EGFR gene somatic mutations is the essential part of routine diagnostic algorithm in advanced NSCLC patients considered for tyrosine kinase inhibitor therapy. Molecular heterogeneity of tumor tissue and cytology materials used for molecular diagnostics is challenging for classic methods of genetic analysis, such as Sanger sequencing, driving the development and implementation of specialized, highly sensitive techniques for mutations detection. Constant, dynamic progress in molecular biology techniques, particularly development of next-generation sequencing, should enable clinical implementation of simultaneous multiple therapeutic biomarkers analysis as well as non-invasive EGFR mutations diagnostic based on free-circulating DNA isolated from blood of non-small cell lung cancer patients. PMID- 24793157 TI - [Usefulness of IGRA and tuberculin skin test in diagnosis of latent tuberculosis infection in the groups threatened with occupational risk factors - commentary to article of D. Borkowska et al]. PMID- 24793158 TI - Patient-specific finite element modeling of the Cardiokinetix Parachute((r)) device: effects on left ventricular wall stress and function. AB - The Parachute((r)) (Cardiokinetix, Inc., Menlo Park, California) is a catheter based device intended to reverse left ventricular (LV) remodeling after antero apical myocardial infarction. When deployed, the device partitions the LV into upper and lower chambers. To simulate its mechanical effects, we created a finite element LV model based on computed tomography (CT) images from a patient before and 6 months after Parachute((r)) implantation. Acute mechanical effects were determined by in silico device implantation (VIRTUAL-Parachute). Chronic effects of the device were determined by adjusting the diastolic and systolic material parameters to better match the 6-month post-implantation CT data and LV pressure data at end-diastole (ED) (POST-OP). Regional myofiber stress and pump function were calculated in each case. The principal finding is that VIRTUAL-Parachute was associated with a 61.2 % reduction in the lower chamber myofiber stress at ED. The POST-OP model was associated with a decrease in LV diastolic stiffness and a larger reduction in myofiber stress at the upper (27.1%) and lower chamber (78.4%) at ED. Myofiber stress at end-systole and stroke volume was little changed in the POST-OP case. These results suggest that the primary mechanism of Parachute((r)) is a reduction in ED myofiber stress, which may reverse eccentric post-infarct LV hypertrophy. PMID- 24793159 TI - Diversity and evolution of oligopeptide permease systems in staphylococcal species. AB - Several oligopeptide permease (Opp) systems have been found in staphylococcal species, including Opp1-4, Opp3' and the arginine catabolic mobile element (ACME) encoded Opp system (ACME-Opp). They confer upon bacteria the increasing fitness, but their evolutionary histories remain unclear. In this work, we performed a genome-wide identification of Opp systems in staphylococcal species. Novel Opp systems were identified, including the duplicate of Opp4 in Staphylococcus pseudintermedius and the ACME-Opp-like systems in coagulase-negative staphylococci (CoNS). Phylogenetic analysis revealed that all of the identified Opp systems were derived from Opp3 system by operon duplication during species divergence, while lateral gene transfer might also confer to the dissemination of Opp in staphylococci. In addition, we proposed an improved theory on evolution of ACME: the Opp and arginine-deiminase systems were firstly transferred from Staphylococcus haemolyticus to Staphylococcus epidermidis independently; in S. epidermidis they were assembled together and then transferred to Staphylococcus aureus. PMID- 24793160 TI - Genome-wide identification and characterization of WRKY gene family in Hevea brasiliensis. AB - WRKY proteins constitute a large family of transcription factors. In this study, we identified 81 WRKY genes (named HbWRKY1 to HbWRKY81) in the latest rubber tree genome. Tissue-specific expression profiles showed that 74 HbWRKYs were expressed in at least one of the tissues and the other 7 genes showed very low expression in all tissues tested, which suggested that HbWRKYs took part in many cellular processes. The responses of 20 selected HbWRKYs to jasmonic acid (JA) and ethylene (ET) were analyzed in the latex. 17 HbWRKYs responded to at least one treatment, which included 15 HbWRKYs responding to JA treatment, 15 HbWRKYs to ET, which suggested that these HbWRKYs were regulated by JA and ET. We also observed that HbWRKY3, 14, and 55 bind HbSRPP promoter and activate the transcription in yeast. This study suggests that HbWRKY proteins maybe involved in the transcriptional regulation of nature rubber biosynthesis. PMID- 24793161 TI - Asenapine review, part II: clinical efficacy, safety and tolerability. AB - INTRODUCTION: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes. AREAS COVERED: The purpose of this review is to describe the clinical profile of asenapine. EXPERT OPINION: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 - 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin. PMID- 24793162 TI - Zinc ions modulate protein tyrosine phosphatase 1B activity. AB - Protein tyrosine phosphatases (PTPs) are key enzymes in cellular regulation. The 107 human PTPs are regulated by redox signalling, phosphorylation, dimerisation, and proteolysis. Recent findings of very strong inhibition of some PTPs by zinc ions at concentrations relevant in a cellular environment suggest yet another mechanism of regulation. One of the most extensively investigated PTPs is PTP1B (PTPN1). It regulates the insulin and leptin signalling pathway and is implicated in cancer and obesity/diabetes. The development of novel assay conditions to investigate zinc inhibition of PTP1B provides estimates of about 5.6 nM affinity for inhibitory zinc(II) ions. Analysis of three PTP1B 3D structures (PDB id: 2CM2, 3I80 and 1A5Y) identified putative zinc binding sites and supports the kinetic studies in suggesting an inhibitory zinc only in the closed and cysteinyl phosphate intermediate forms of the enzyme. These observations gain significance with regard to recent findings of regulatory roles of zinc ions released from the endoplasmic reticulum. PMID- 24793163 TI - The Mortality Penalty of Incarceration: Evidence from a Population-based Case control Study of Working-age Males. AB - There is a growing body of research on the effects of incarceration on health, though there are few studies in the sociological literature of the association between incarceration and premature mortality. This study examined the risk of male premature mortality associated with incarceration. Data came from the Izhevsk (Russia) Family Study, a large-scale population-based case-control design. Cases (n = 1,750) were male deaths aged 25 to 54 in Izhevsk between October 2003 and October 2005. Controls (n = 1,750) were selected at random from a city population register. The key independent variable was lifetime prevalence of incarceration. I used logistic regression to estimate mortality odds ratios, controlling for age, hazardous drinking, smoking status, marital status, and education. Seventeen percent of cases and 5 percent of controls had been incarcerated. Men who had been incarcerated were more than twice as likely as those who had not to experience premature mortality (odds ratio = 2.2, 95 percent confidence interval: 1.6-3.0). Relative to cases with no prior incarceration, cases who had been incarcerated were more likely to die from infectious diseases, respiratory diseases, non-alcohol-related accidental poisonings, and homicide. Taken together with other recent research, these results from a rigorous case control design reveal not only that incarceration has durable effects on illness, but that its consequences extend to a greater risk of early death. I draw on the sociology of health literature on exposure, stress, and social integration to speculate about the reasons for this mortality penalty of incarceration. PMID- 24793164 TI - Hypoxia-induced mitogenic factor (FIZZ1/RELMalpha) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension. AB - Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMalpha) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH. PMID- 24793165 TI - NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome. AB - Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients in intensive care units that can lead to complications, including multiple organ dysfunction syndrome (MODS). MODS carries a high mortality rate, and it is unclear why some patients resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated in the development of MODS, several recent studies have demonstrated a requirement for NADPH oxidase 2 (NOX2)-derived oxidants in limiting inflammation. We recently demonstrated that NOX2 protects against lung injury and mortality in a murine model of SIRS. In the present study, we investigated the role of NOX2-derived oxidants in the progression from SIRS to MODS. Using a murine model of sterile systemic inflammation, we observed significantly greater illness and subacute mortality in gp91(phox-/y) (NOX2 deficient) mice compared with wild-type mice. Cellular analysis revealed continued neutrophil recruitment to the peritoneum and lungs of the NOX2 deficient mice and altered activation states of both neutrophils and macrophages. Histological examination showed multiple organ pathology indicative of MODS in the NOX2-deficient mice, and several inflammatory cytokines were elevated in lungs of the NOX2-deficient mice. Overall, these data suggest that NOX2 function protects against the development of MODS and is required for normal resolution of systemic inflammation. PMID- 24793166 TI - Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice. AB - Interstitial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg.kg(-1).wk(-1)) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model. PMID- 24793168 TI - Mucociliary clearance and submucosal gland secretion in the ex vivo ferret trachea. AB - In many species submucosal glands are an important source of tracheal mucus, but the extent to which mucociliary clearance (MCC) depends on gland secretion is unknown. To explore this relationship, we measured basal and agonist-stimulated MCC velocities in ex vivo tracheas from adult ferrets and compared the velocities with previously measured rates of ferret glandular mucus secretion (Cho HJ, Joo NS, Wine JJ. Am J Physiol Lung Cell Mol Physiol 299: L124-L136, 2010). Stimulated MCC velocities (mm/min, means +/- SE for 10- to 35-min period poststimulation) were as follows: 1 MUM carbachol: 19.1 +/- 3.3 > 10 MUM phenylephrine: 15.3 +/- 2.4 ~ 10 MUM isoproterenol: 15.0 +/- 1.9 ~ 10 MUM forskolin: 14.6 +/- 3.1 > 1 MUM vasoactive intestinal peptide (VIP): 10.2 +/- 2.2 >> basal (t15): 1.8 +/- 0.3; n = 5-10 for each condition. Synergistic stimulation of MCC was observed between low concentrations of carbachol (100 nM) and isoproterenol (300 nM). Bumetanide inhibited carbachol-stimulated MCC by ~70% and abolished the increase in MCC stimulated by forskolin + VIP, whereas HCO3 (-)-free solutions did not significantly inhibit MCC to either intracellular Ca(2+) concentration or intracellular cAMP concentration ([cAMP]i)-elevating agonists. Stimulation and inhibition of MCC and gland secretion differed in several respects: most importantly, elevating [cAMP]i increased MCC much more effectively than expected from its effects on gland secretion, and bumetanide almost completely inhibited [cAMP]i-stimulated MCC while it had a smaller effect on gland secretion. We conclude that changes in glandular fluid secretion are complexly related to MCC and discuss possible reasons for this. PMID- 24793167 TI - An 11-nt sequence polymorphism at the 3'UTR of human SFTPA1 and SFTPA2 gene variants differentially affect gene expression levels and miRNA regulation in cell culture. AB - Surfactant protein A (SP-A) plays a vital role in maintaining normal lung function and in host defense. Two genes encode SP-A in humans (SFTPA1, SFTPA2), and several gene variants have been identified for these. We have previously shown that sequence elements of SFTPA1 and SFTPA2 3' untranslated regions (UTRs) differentially affect translation efficiency in vitro. Polymorphisms at the 3'UTRs of mRNA variants may account for differential binding of miRNAs, a class of small noncoding RNAs that regulate gene expression. In this work, we generated 3'UTR reporter constructs of the SFTPA1 and SFTPA2 variants most frequently found in the population, as well as mutants of a previously described 11-nt indel element (refSNP rs368700152). Reporter constructs were transfected in NCI-H441 cells in the presence or absence of miRNA mimics, and reporter gene expression was analyzed. We found that human miRNA mir-767 negatively affected expression of constructs containing SFTPA1 and SFTPA2 variants, whereas mir-4507 affected only constructs with 3'UTRs of SFTPA1 variants 6A, 6A(3), and 6A(4) (not containing the 11-nt element). Three miRNAs (mir-183, mir-449b, and mir-612) inhibited expression of recombinants of SFTPA2 variants and the SFTPA1 variant 6A(2), all containing the 11-nt element. Similar results were obtained for SP-A expression when these miRNAs were transfected in Chinese hamster ovary cells expressing SFTPA1 or SFTPA2 variants or in NCI-H441 cells (genotype 1A(5)/1A(5) 6A(4)/6A(4)). Moreover, transfection with a specific antagomir (antagomir-183) reversed the effects of mir-183 on SP-A mRNA levels. Our results indicate that sequence variability at the 3'UTR of SP-A variants differentially affects miRNA regulation of gene expression. PMID- 24793169 TI - Henry Cavendish (1731-1810): hydrogen, carbon dioxide, water, and weighing the world. AB - Henry Cavendish (1731-1810) was an outstanding chemist and physicist. Although he was not a major figure in the history of respiratory physiology he made important discoveries concerning hydrogen, carbon dioxide, atmospheric air, and water. Hydrogen had been prepared earlier by Boyle but its properties had not been recognized; Cavendish described these in detail, including the density of the gas. Carbon dioxide had also previously been studied by Black, but Cavendish clarified its properties and measured its density. He was the first person to accurately analyze atmospheric air and reported an oxygen concentration very close to the currently accepted value. When he removed all the oxygen and nitrogen from an air sample, he found that there was a residual portion of about 0.8% that he could not characterize. Later this was shown to be argon. He produced large amounts of water by burning hydrogen in oxygen and recognized that these were its only constituents. Cavendish also worked on electricity and heat. However, his main contribution outside chemistry was an audacious experiment to measure the density of the earth, which he referred to as "weighing the world." This involved determining the gravitational attraction between lead spheres in a specially constructed building. Although this was a simple experiment in principle, there were numerous complexities that he overcame with meticulous attention to experimental details. His result was very close to the modern accepted value. The Cavendish Experiment, as it is called, assures his place in the history of science. PMID- 24793170 TI - Dynamic expression of chymotrypsin-like elastase 1 over the course of murine lung development. AB - Postnatal lung development requires coordination of three processes (surface area expansion, microvascular growth, and matrix remodeling). Because normal elastin structure is important for lung morphogenesis, because physiological remodeling of lung elastin has never been defined, and because elastin remodeling is angiogenic, we sought to test the hypothesis that, during lung development, elastin is remodeled in a defined temporal-spatial pattern, that a novel protease is associated with this remodeling, and that angiogenesis is associated with elastin remodeling. By elastin in situ zymography, lung elastin remodeling increased 24-fold between embryonic day (E) 15.5 and postnatal day (PND) 14. Remodeling was restricted to major vessels and airways on PND1 with a sevenfold increase in alveolar wall elastin remodeling from PND1 to PND14. By inhibition assays and literature review, we identified chymotrypsin-like elastase 1 (CELA1) as a potential mediator of elastin remodeling. CELA1 mRNA levels increased 12 fold from E15.5 to PND9, and protein levels increased 3.4-fold from E18.5 to PND9. By costaining experiments, the temporal-spatial pattern of CELA1 expression matched that of elastin remodeling, and 58-85% of CELA1(+) cells were <10 MUm from an elastase signal. An association between elastin remodeling and angiogenesis was tested by similar methods. At PND7 and PND14, 60-95% of angiogenin(+) cells were associated with elastin remodeling. Both elastase inhibition and CELA1 silencing impaired angiogenesis in vitro. Our data defines the temporal-spatial pattern of elastin remodeling during lung development, demonstrates an association of this remodeling with CELA1, and supports a role for elastin remodeling in regulating angiogenesis. PMID- 24793173 TI - Determination of passive viscoelastic response of the abdominal muscle and related constitutive modeling: stress-relaxation behavior. AB - In this paper, the authors investigate the passive viscoelastic properties of rabbit abdominal wall. In vitro strain relaxation tests were performed in the oblique muscle (in two perpendicular directions), the rectus abdominis and the linea alba in the longitudinal direction. Based on experimental data, a model for the viscoelastic mechanical properties of this tissue is presented here. In particular, we used a 3D non-linear viscoelastic model to fit data sets obtained from tissue of the rabbit abdominal wall. Uniaxial relaxation tests were carried out for samples obtained from the abdominal wall. The experimental results clearly demonstrate the anisotropy and nonlinearity of the abdominal tissue. The stress relaxation was higher in the transverse direction (closer to muscle fibers) with an average value of the final stress ratio of 48%, than in the longitudinal direction with around 56% of this ratio for the oblique muscle. These tests, at several stretch levels, presented a different behavior depending on the region where the tissue sample was located. There was no dependence between the stress relaxation ratio and the stretch level for the oblique muscles in their longitudinal or transverse directions (p>0.01). In contrast, for rectus abdominis and linea alba a dependence between the stress relaxation ratio and stretch level was found. Our study revealed an increase in the stress relaxation ratio for the rectus abdominis (p<0.01) and a decrease for the linea alba with higher stretch levels (p<0.01). Overall good predictions epsilon<0.115 were obtained with the model proposed for the oblique muscle (no dependence on the stretch level) and to reproduce the non-linear viscoelastic response of rectus abdominis and linea alba. PMID- 24793171 TI - Human airway smooth muscle maintain in situ cell orientation and phenotype when cultured on aligned electrospun scaffolds. AB - Human airway smooth muscle (HASM) contraction plays a central role in regulating airway resistance in both healthy and asthmatic bronchioles. In vitro studies that investigate the intricate mechanisms that regulate this contractile process are predominantly conducted on tissue culture plastic, a rigid, 2D geometry, unlike the 3D microenvironment smooth muscle cells are exposed to in situ. It is increasingly apparent that cellular characteristics and responses are altered between cells cultured on 2D substrates compared with 3D topographies. Electrospinning is an attractive method to produce 3D topographies for cell culturing as the fibers produced have dimensions within the nanometer range, similar to cells' natural environment. We have developed an electrospun scaffold using the nondegradable, nontoxic, polymer polyethylene terephthalate (PET) composed of uniaxially orientated nanofibers and have evaluated this topography's effect on HASM cell adhesion, alignment, and morphology. The fibers orientation provided contact guidance enabling the formation of fully aligned sheets of smooth muscle. Moreover, smooth muscle cells cultured on the scaffold present an elongated cell phenotype with altered contractile protein levels and distribution. HASM cells cultured on this scaffold responded to the bronchoconstrictor bradykinin. The platform presented provides a novel in vitro model that promotes airway smooth muscle cell development toward a more in vivo like phenotype while providing topological cues to ensure full cell alignment. PMID- 24793172 TI - Designed composites for mimicking compressive mechanical properties of articular cartilage matrix. AB - Collagen, chitosan-polycaprolactone (CH-PCL) copolymer with PCL content of around 40wt% and chondroitin sulfate (CS) were mixed together at various ratios to prepare collagen/CH-PCL/CS composites and the resulting composites were used to build stratified porous scaffolds that are potentially applicable for articular cartilage repair. The ternary composites were designed in such a way that collagen content in the scaffolds decreased from the top layer to the bottom layer while the content of CH-PCL and CS altered in a reversed trend in order to reach partial similarity to cartilage matrix in the composition of main components. Porous structures inside collagen/CH-PCL/CS scaffolds were constructed using a low-temperature deposition processing technique and graded average pore-size and porosity for the scaffolds were established. Such produced scaffolds were further crosslinked using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide under optimized conditions, and the obtained scaffolds showed well defined elastic compressive properties. Compressive modulus (E) and stress at 10% strain (sigma10) of full scaffolds in wet state reached about 2.8MPa and 0.3MPa, respectively, and meanwhile, E and sigma10 of layers inside hydrated scaffolds changed in a gradient-increased manner from the top layer to the bottom layer with significant differences between contiguous layers, which partially mimics compressive mechanical properties of cartilage matrix. In addition, in vitro culture of cell-scaffold constructs exhibited that scaffolds were able to well support the ingrowth and migration of seeded cells, and cells also showed relatively uniform distribution throughout the scaffolds. These results suggest that the presently developed collagen/CH-PCL/CS scaffolds have promising potential for applications in articular cartilage repair. PMID- 24793174 TI - Atomic force microscopy in biofilm study. AB - Biofilms have been classically visualized by Scanning Electron Microscopy (SEM). The complex operating procedure of SEM restricts its use in routine practice. There is a need of newer visualizing techniques for examining surfaces of biofilms, in particular under ambient conditions. We have presented the unique advantages of atomic force microscopy (AFM) in studying surfaces of biofilms through analyses of the height images obtained on biofilms of two gram positive and one gram negative bacteria, namely Staphylococcus aureus, Nocardia brasiliensis and Pseudomonas aeruginosa, respectively. Biofilm quality of the three different bacteria, ageing effects on Nocardia spp. biofilm surface and effects of the antibiotic ciprofloxacin at different doses on Staphylococcus and Pseudomonas biofilm surfaces have been investigated under ambient conditions and distinctive features have been observed. PMID- 24793175 TI - Efficacy of re-treatment by peginterferon alpha-2a and ribavirin in a child with hepatitis C. AB - BACKGROUND: There is currently no consensus treatment for children non-responsive to peginterferon (Peg-IFN) and ribavirin. CASE PRESENTATION: Here, we present a Japanese child with chronic hepatitis C with fibrosis, who did not respond to Peg IFN alpha-2b but responded to Peg-IFN alpha-2a with ribavirin, accompanied with fluvastatin. To date, there has been no reported case of re-treatment in children. The early viral response occurred soon after starting treatment using Peg-IFN alpha-2a/ribavirin plus fluvastatin. CONCLUSION: Our result indicates that when treatment by Peg-IFN alpha-2b/ribavirin combination therapy is not efficient, combination therapy using Peg-IFN alpha-2a/ribavirin plus fluvastatin should be considered in children with advanced liver change. PMID- 24793176 TI - [Preliminary results of a community fall prevention programme: Precan study (falls prevention in La Ribera)]. AB - OBJECTIVE: To evaluate the results of a fall prevention programme designed to be applied to the elderly living in the community. MATERIAL AND METHODS: The sample consisted of 249 participants >=70 years of age, who were randomly assigned to one of three groups. The monthly intervention group (GIM): instructions on fall prevention and healthy exercises to improve physical function and balance at beginning of the study, and a monthly theoretical and practical refresher session. The quarterly intervention group (GIT), with the same beginning intervention and a refresher session every three months. The control group (GC), the same beginning intervention but no refresher sessions. RESULTS: The mean age of the sample was 74.47 years (SD 5.33), with 64% women. The incidence of falls was reduced from 0.64 per patient year in the previous year to 0.39 in the post intervention year in GIM, from 0.49 to 0.47 in GIT, and in the GC it remained at 0.47 before and twelve months after, but with no significant differences in the reduction between groups (P=.062). At the end of the study there was a decrease in Rizzo scale of 0.72 points (95% CI: 0.57-0.88, P<.001). CONCLUSION: An interdisciplinary community intervention programme can contribute to reducing the incidence of falls. Further studies are required to continue research into the incidence of falls in the elderly living in the community. PMID- 24793177 TI - Early-life risk factors for panic and separation anxiety disorder: insights and outstanding questions arising from human and animal studies of CO2 sensitivity. AB - Genetically informative studies showed that genetic and environmental risk factors act and interact to influence liability to (a) panic disorder, (b) its childhood precursor separation anxiety disorder, and (c) heightened sensitivity to CO2, an endophenotype common to both disorders. Childhood adversities including parental loss influence both panic disorder and CO2 hypersensitivity. However, childhood parental loss and separation anxiety disorder are weakly correlated in humans, suggesting the presence of alternative pathways of risk. The transferability of tests that assess CO2 sensitivity - an interspecific quantitative trait common to all mammals - to the animal laboratory setting allowed for environmentally controlled studies of early parental separation. Animal findings paralleled those of human studies, in that different forms of early maternal separation in mice and rats evoked heightened CO2 sensitivity; in mice, this could be explained by gene-by-environment interactional mechanisms. While several questions and issues (including obvious divergences between humans and rodents) remain open, parallel investigations by contemporary molecular genetic tools of (1) human longitudinal cohorts and (2) animals in controlled laboratory settings, can help elucidate the mechanisms beyond these phenomena. PMID- 24793178 TI - Hemodynamic effects of various support modes of continuous flow LVADs on the cardiovascular system: a numerical study. AB - BACKGROUND: The aim of this study was to determine the hemodynamic effects of various support modes of continuous flow left ventricular assist devices (CF LVADs) on the cardiovascular system using a numerical cardiovascular system model. MATERIAL AND METHODS: Three support modes were selected for controlling the CF-LVAD: constant flow mode, constant speed mode, and constant pressure head mode of CF-LVAD. The CF-LVAD is established between the left ventricular apex and the ascending aorta, and was incorporated into the numerical model. Various parameters were evaluated, including the blood assist index (BAI), the left ventricular external work (LVEW), the energy of blood flow (EBF), pulsatility index (PI), and surplus hemodynamic energy (SHE). RESULTS: The results show that the constant flow mode, when compared to the constant speed mode and the constant pressure head mode, increases LVEW by 31% and 14%, and EBF by 21% and 15%, respectively, indicating that this mode achieved the best ventricular unloading among the 3 support modes. As BAI is increased, PI and SHE are gradually decreased, whereas PI of the constant pressure head reaches the maximum value. CONCLUSIONS: The study demonstrates that the continuous flow control mode of the CF-LVAD may achieve the highest ventricular unloading. In contrast, the constant rotational speed mode permits the optimal blood perfusion. Finally, the constant pressure head strategy, permitting optimal pulsatility, should optimize the vascular function. PMID- 24793179 TI - Integrin signalling and traffic during axon growth and regeneration. AB - Adult corticospinal tract axons do not regenerate because they have low intrinsic growth ability, and are exposed to inhibitory molecules after injury. PNS axons have a better regenerative capacity, mediated in part by integrins (extracellular matrix receptors). These are subject to complex regulation by signalling and trafficking. Recent studies have found that integrin mediated axon growth relies on signalling via focal adhesion molecules, and that integrins are inactivated by inhibitory molecules in the CNS. Forced activation of integrins can overcome inhibition and increase axon regeneration, however integrins are not transported into some CNS axons. Studies of PNS integrin traffic have identified molecules that can be manipulated to increase axonal integrin expression, suggesting strategies for repairing the injured spinal cord. PMID- 24793181 TI - Paroxysmal features responding to flunarizine in a child with rapid-onset dystonia-parkinsonism. PMID- 24793180 TI - Axon and dendrite pruning in Drosophila. AB - Pruning, a process by which neurons selectively remove exuberant or unnecessary processes without causing cell death, is crucial for the establishment of mature neural circuits during animal development. Yet relatively little is known about molecular and cellular mechanisms that govern neuronal pruning. Holometabolous insects, such as Drosophila, undergo complete metamorphosis and their larval nervous systems are replaced with adult-specific ones, thus providing attractive models for studying neuronal pruning. Drosophila mushroom body and dendritic arborization neurons have been utilized as two appealing systems to elucidate the underlying mechanisms of axon and dendrite pruning, respectively. In this review we highlight recent developments and discuss some similarities and differences in the mechanisms that regulate these two distinct modes of neuronal pruning in Drosophila. PMID- 24793182 TI - Reconciling the clinical practice guidelines on Bell's palsy from the AAO-HNSF and the AAN. AB - Bell palsy, named after the Scottish anatomist Sir Charles Bell, is the most common acute mononeuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. In the past 2 years, both the American Academy of Neurology and the Academy of Otolaryngology-Head and Neck Surgery Foundation have published clinical practice guidelines aimed at improving the quality of care and outcomes for patients diagnosed with Bell palsy. This commentary aims to address the similarities and differences in the scope and final recommendations made by each guideline development group. PMID- 24793183 TI - Association of hypometabolism and amyloid levels in aging, normal subjects. AB - OBJECTIVE: We evaluated the relationship of amyloid, seen on Pittsburgh compound B (PiB)-PET, and metabolism, seen on [(18)F]-fluorodeoxyglucose (FDG)-PET, in normal subjects to better understand pathogenesis and biomarker selection in presymptomatic subjects. METHODS: Normal participants (aged 70-95 years; 600 with PiB-PET, FDG-PET, and MRI) were included. We performed a cross-sectional evaluation and subcategorized participants into amyloid-negative (<1.4), high normal (1.4-1.5), positive (1.5-2.0), and markedly positive (>2.0) PiB standardized uptake value ratio groups representing different levels of amyloid brain load. Associations with metabolism were assessed in each group. Relationships with APOE epsilon4 carriage were evaluated. RESULTS: Hypometabolism in "Alzheimer disease (AD)-signature" regions was strongly associated with PiB load. Hypometabolism was greater with more positive PiB levels. Additional, more diffuse cortical hypometabolism was also found to be associated with PiB, although less so. No hypermetabolism was seen in any subset. No significant incremental hypometabolism was seen in APOE-positive vs -negative subjects. CONCLUSIONS: Hypometabolism in PiB-positive, cognitively normal subjects in a population-based cohort occurs in AD-signature cortical regions and to a lesser extent in other cortical regions. It is more pronounced with higher amyloid load and supports a dose-dependent association. The effect of APOE epsilon4 carriage in this group of subjects does not appear to modify their hypometabolic "AD-like" neurodegeneration. Consideration of hypometabolism associated with amyloid load may aid trials of AD drug therapy. PMID- 24793184 TI - Strategic white matter tracts for processing speed deficits in age-related small vessel disease. AB - OBJECTIVE: Cerebral small vessel disease is the most common cause of vascular cognitive impairment and typically manifests with slowed processing speed. We investigated the impact of lesion location on processing speed in age-related small vessel disease. METHODS: A total of 584 community-dwelling elderly underwent brain MRI followed by segmentation of white matter hyperintensities. Processing speed was determined by the timed measure of the Trail Making Test part B. The impact of the location of white matter hyperintensities was assessed by voxel-based lesion-symptom mapping and graph-based statistical models on regional lesion volumes in major white matter tracts. RESULTS: Voxel-based lesion symptom mapping identified multiple voxel clusters where the presence of white matter hyperintensities was associated with slower performance on the Trail Making Test part B. Clusters were located bilaterally in the forceps minor and anterior thalamic radiation. Region of interest-based Bayesian network analyses on lesion volumes within major white matter tracts depicted the same tracts as direct predictors for an impaired Trail Making Test part B performance. CONCLUSIONS: Our findings highlight damage to frontal interhemispheric and thalamic projection fiber tracts harboring frontal-subcortical neuronal circuits as a predictor for processing speed performance in age-related small vessel disease. PMID- 24793185 TI - Anti-agrin autoantibodies in myasthenia gravis. AB - OBJECTIVE: Because the extracellular matrix protein agrin is essential for neuromuscular junction formation and maintenance, we tested the hypothesis that autoantibodies against agrin are present in sera from patients with myasthenia gravis (MG). METHODS: We determined the presence of anti-agrin antibodies in 54 sera from patients with generalized MG using a solid-phase ELISA with purified mini-agrin protein. Thirty of the 54 sera were seronegative for antibodies against the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK), 15 had elevated levels of anti-MuSK, and 9 had elevated levels of anti AChR autoantibodies. Sixteen sera from healthy volunteers served as control. RESULTS: Five sera with elevated levels of anti-agrin antibodies were identified. The concentration of the antibodies ranged between 0.04 and 0.12 nM. Four of the 5 agrin-positive sera were also positive for anti-MuSK, one was positive for anti AChR, and 2 had elevated levels of anti-low-density lipoprotein receptor-related protein 4 (LRP4) autoantibodies. Some of the sera stained adult mouse neuromuscular junctions and reacted with native mini-agrin expressed in 293HEK cells. CONCLUSIONS: The results provide evidence for agrin as a novel target protein for autoantibodies in patients with MG. Anti-agrin antibodies were always detected in combination with autoantibodies against MuSK, LRP4, or AChRs, indicating a high incidence of autoantibodies against several neuromuscular proteins in the agrin-positive MG cases. PMID- 24793186 TI - Neuromuscular junction as Achilles' heel: yet another autoantibody? PMID- 24793187 TI - Topology of brainstem lesions associated with subjective visual vertical tilt. AB - OBJECTIVE: We aimed to determine the topology of anatomical pathways for verticality perception in the brainstem. METHODS: We measured the subjective visual vertical (SVV) in 82 patients with acute unilateral infarction of the brainstem alone. The topology of the brainstem lesions responsible for pathologic SVV tilt were determined using MRI-based voxel-wise lesion-behavior mapping, from which probabilistic lesion maps were constructed. RESULTS: Fifty percent of patients (41/82) with acute unilateral brainstem infarcts had abnormal SVV tilt, of which 76% (31/41) had ipsiversive tilt and 24% (10/41) had contraversive tilt. Patients with contraversive SVV tilt exhibited overlapping lesions of the rostral medial vestibular nucleus, medial longitudinal fasciculus, rostral interstitial medial longitudinal fasciculus, and interstitial nucleus of Cajal. In contrast, patients with ipsiversive SVV tilt and oculomotor disturbances exhibited lesions of the medial and inferior vestibular nuclei in the caudal medulla, while those with isolated vertical perceptual changes had injury to the medial side of the medial lemniscus. CONCLUSIONS: Our findings provide evidence of a pathway transmitting ipsiversive otolithic signals that bypass the oculomotor system at the medial side of the medial lemniscus, called the ipsilateral vestibulothalamic tract. PMID- 24793189 TI - Understanding brain function through small vessel disease: what zebras can teach us about horses. PMID- 24793188 TI - Antemortem MRI findings associated with microinfarcts at autopsy. AB - OBJECTIVE: To determine antemortem MRI findings associated with microinfarcts at autopsy. METHODS: Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic-based, population-based, and community clinic-based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods. RESULTS: The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts. CONCLUSIONS: Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets. PMID- 24793190 TI - Response: the definition of 'recurrent implantation failure'. PMID- 24793191 TI - Zooming in on the definition of 'recurrent implantation failure'. PMID- 24793192 TI - Toxicity of ZnO nanoparticles, ZnO bulk, and ZnCl2 on earthworms in a spiked natural soil and toxicological effects of leachates on aquatic organisms. AB - The present study assessed the uptake and toxicity of ZnO nanoparticles (NPs), ZnO bulk, and ZnCl2 salt in earthworms in spiked agricultural soils. In addition, the toxicity of aqueous extracts to Daphnia magna and Chlorella vulgaris was analyzed to determine the risk of these soils to the aquatic compartment. We then investigated the distribution of Zn in soil fractions to interpret the nature of toxicity. Neither mortality nor differences in earthworm body weight were observed compared with the control. The most sensitive end point was reproduction. ZnCl2 was notably toxic in eliminating the production of cocoons. The effects induced by ZnO-NPs and bulk ZnO on fecundity were similar and lower than those of the salt. In contrast to ZnO bulk, ZnO-NPs adversely affected fertility. The internal concentrations of Zn in earthworms in the NP group were greater than those in the salt and bulk groups, although bioconcentration factors were consistently <1. No relationship was found between toxicity and internal Zn amounts in earthworms. The results from the sequential extraction of soil showed that ZnCl2 displayed the highest availability compared with both ZnO. Zn distribution was consistent with the greatest toxicity showed by the salt but not with Zn body concentrations. The soil extracts from both ZnO-NPs and bulk ZnO did not show effects on aquatic organisms (Daphnia and algae) after short-term exposure. However, ZnCl2 extracts (total and 0.45-MUm filtered) were toxic to Daphnia. PMID- 24793193 TI - Trace-element interactions in Rook Corvus frugilegus eggshells along an urbanisation gradient. AB - Concentrations of seven trace elements [arsenic (As), chromium (Cr), nickel (Ni), lead (Pb), copper (Cu), zinc (Zn), and cadmium (Cd)] in the eggshells of Rooks Corvus frugilegus, a focal bird species of Eurasian agricultural environments, are increased above background levels and exceed levels of toxicological concern. The concentrations of Cr, Ni, Pb, Cu, and Zn are greater in eggshells from urban rookeries (large cities) compared with rural areas (small towns and villages) suggesting an urbanisation gradient effect among eggs laid by females. In the present study, the investigators assessed whether the pattern of relationships among the seven trace elements in eggshells change along an urbanisation/pollution gradient. Surprisingly, we found that eggshells with the greatest contaminant burden, i.e., from urban rookeries, showed far fewer significant relationships (n = 4) than eggshells from villages (n = 10), small towns (n = 6), or rural areas (n = 8). In most cases, the relationships were positive. As was an exception: Its concentration was negatively correlated with Ni and Cd levels in eggshells from small town rookeries (where As levels were the highest), whereas eggshells from villages (with a lower As level) showed positive relationships between As and Cd. Our findings suggest that at low to intermediate levels, interactions between the trace elements in Rook eggshells are of a synergistic character and appear to operate as parallel coaccumulation. A habitat specific excess of some elements (primarily Cr, Ni, Cu, As) suggests their more competitively selective sequestration. PMID- 24793194 TI - Physical properties and biocompatibility of UHMWPE-derived materials modified by synchrotron radiation. AB - The applications of synchrotron radiation (SR) in medical imaging have become of great use, particularly in angiography, bronchography, mammography, computed tomography, and X-ray microscopy. Thanks to recently developed phase contrast imaging techniques non-destructive preclinical testing of low absorbing materials such as polymers has become possible. The focus of the present work is characterization and examination of UHMWPE-derived materials widely used in medicine, before and after their exposure to SR during such testing. Physical properties, such as wettability, surface energy, IR-spectroscopy, roughness, optical microscopy, microhardness measurements of UHMWPE samples were studied before and after SR. The relationship between a growth of UHMWPE surface hydrophilicity after SR and surface colonization by stromal cells was studied in vitro. Obtained results demonstrate that SR may be used as prospective direction to examine bulk (porous) structure of polymer materials and/or to modify polymer surface and volume for tissue engineering. PMID- 24793195 TI - Continuous enzymatic hydrolysis of lignocellulosic biomass with simultaneous detoxification and enzyme recovery. AB - Recovering hydrolysis enzymes and/or alternative enzyme addition strategies are two potential mechanisms for reducing the cost during the biochemical conversion of lignocellulosic materials into renewable biofuels and biochemicals. Here, we show that enzymatic hydrolysis of acid-pretreated pine wood with continuous and/or fed-batch enzyme addition improved sugar conversion efficiencies by over sixfold. In addition, specific activity of the hydrolysis enzymes (cellulases, hemicellulases, etc.) increased as a result of continuously washing the residual solids with removal of glucose (avoiding the end product inhibition) and other enzymatic inhibitory compounds (e.g., furfural, hydroxymethyl furfural, organic acids, and phenolics). As part of the continuous hydrolysis, anion exchange resin was tested for its dual application of simultaneous enzyme recovery and removal of potential enzymatic and fermentation inhibitors. Amberlite IRA-96 showed favorable adsorption profiles of inhibitors, especially furfural, hydroxymethyl furfural, and acetic acid with low affinity toward sugars. Affinity of hydrolysis enzymes to adsorb onto the resin allowed for up to 92 % of the enzymatic activity to be recovered using a relatively low-molar NaCl wash solution. Integration of an ion exchange column with enzyme recovery into the proposed fed-batch hydrolysis process can improve the overall biorefinery efficiency and can greatly reduce the production costs of lignocellulosic biorenewable products. PMID- 24793196 TI - Kinetics of enzymatic hydrolysis of olive oil in batch and fed-batch systems. AB - This work reports experimental data, kinetic modeling, and simulations of enzyme catalyzed hydrolysis of olive oil. This reaction was performed in batch system and an ordered-sequential Bi Bi model was used to model the kinetic mechanism. A fed-batch system was proposed and experimental data were obtained and compared to the simulated values. The kinetic model used was able to correlate the experimental data, in which a satisfactory agreement between the experimental data and modeling results was obtained under different enzyme concentration and initial free water content. Therefore, the modeling allowed a better understanding of the reaction kinetics and affords a fed-batch simulation for this system. From the results obtained, it was observed that the fed-batch approach showed to be more advantageous when compared to the conventional batch system. PMID- 24793197 TI - Self-repair capability of surgically created incisions in TMJ disc: an experimental study on goats. AB - This study was to investigate whether surgically created incisions in discs at different sizes would heal spontaneously. Thirty mature goats were randomly divided into group A (1 mm), group B (3 mm) and group C (5 mm) according to the length of incision on the discs. Five animals in each group were sacrificed at 3 and 6 months postoperatively. The disc and condyle were evaluated by gross, histological and immunohistochemistry examinations. 1-mm discal incisions healed spontaneously with nearly normal gross and histological appearance at 6 months postoperatively, while 3-mm and 5-mm discal incisions failed to heal. Degenerative changes were observed in the fibrocartilage in both 3-mm and 5-mm incision groups, with a greater extent in the 5-mm group. Our results suggested that the TMJ disc of goat has limited self-repair capability to damage, which will be useful for making pre-surgical decisions related to the size and healing period of TMJ disc perforations. PMID- 24793198 TI - Surgical effects of various orbital decompression methods in thyroid-associated orbitopathy: computed tomography-based comparative analysis. AB - OBJECTIVES: To evaluate the surgical effects of orbital fat decompression and bony decompression in each orbital wall using computed tomography (CT) in thyroid associated orbitopathy (TAO). METHODS: In 27 TAO patients (48 orbits) with exophthalmos who underwent orbital wall decompression combined with fatty decompression, we recorded the resected orbital fat volume intraoperatively and estimated the decompression volume of the orbital wall in the deep lateral, medial and inferior walls using postoperative orbit CT images. Then, the correlation between exophthalmos reduction by Hertel reading and decompression volume in each area was analyzed to validate the surgical predictability, surgical efficiency and contribution level to total exophthalmos reduction. RESULTS: The decompression volume in orbital fat and the deep lateral wall showed relatively high correlation with exophthalmos reduction (surgical predictability) compared to medial and inferior wall. The surgical efficiency was highest at deep lateral wall (2.704 +/- 0.835 mm/cm(3)), followed by medial wall (0.892 +/- 0.527 mm/cm(3)), orbital fat (0.638 +/- 0.178 mm/cm(3)) and inferior wall (0.405 +/- 0.996 mm/cm(3)). The actual contribution level to total exophthalmos reduction was highest in fatty decompression, followed by deep lateral decompression. CONCLUSION: In TAO patients with exophthalmos, orbital fat and deep lateral orbital wall are more predictable and contributory surgical targets for postsurgical exophthalmos reduction. PMID- 24793199 TI - Hydration characteristics of Biodentine and Theracal used as pulp capping materials. AB - OBJECTIVES: Investigation of the hydration and characterization of Theracal and Biodentine used for pulp capping. METHODS: The setting mechanism and characterization of set Biodentine and Theracal after immersion in Hank's balanced salt solution (HBSS) for 28 days was investigated by scanning electron microscopy (SEM) of polished specimens and X-ray diffraction (XRD) analysis. The bioactivity and surface microstructure of cements immersed in HBSS or water was also assessed by similar techniques together with leaching in solution investigated by ion chromatography (IC). RESULTS: Biodentine hydration resulted in the formation of calcium hydroxide which was present in the material matrix and also on the material surface. Theracal was composed of large cement particles which showed some evidence of reaction rims on hydration. The material matrix included a barium zirconate phase as radiopacifier and also a glass phase composed of strontium, silicon and aluminum. This phase could not be detected in XRD analysis. Formation of a calcium phosphate phase was demonstrated on Theracal immersed in HBSS. Both materials leached calcium ions in solution. CONCLUSIONS: The presence of a resin matrix modifies the setting mechanism and calcium ion leaching of Theracal. The clinical implications of these findings need to be investigated. PMID- 24793200 TI - Soft tissue integration versus early biofilm formation on different dental implant materials. AB - OBJECTIVE: Dental implants anchor in bone through a tight fit and osseo integratable properties of the implant surfaces, while a protective soft tissue seal around the implants neck is needed to prevent bacterial destruction of the bone-implant interface. This tissue seal needs to form in the unsterile, oral environment. We aim to identify surface properties of dental implant materials (titanium, titanium-zirconium alloy and zirconium-oxides) that determine the outcome of this "race-for-the-surface" between human-gingival-fibroblasts and different supra-gingival bacterial strains. METHODS: Biofilms of three streptococcal species or a Staphylococcus aureus strain were grown in mono cultures on the different implant materials in a parallel-plate-flow-chamber and their biovolume evaluated using confocal-scanning-laser-microscopy. Similarly, adhesion, spreading and growth of human-gingival-fibroblasts were evaluated. Co culture experiments with bacteria and human-gingival-fibroblasts were carried out to evaluate tissue interaction with bacterially contaminated implant surfaces. Implant surfaces were characterized by their hydrophobicity, roughness and elemental composition. RESULTS: Biofilm formation occurred on all implant materials, and neither roughness nor hydrophobicity had a decisive influence on biofilm formation. Zirconium-oxide attracted most biofilm. All implant materials were covered by human-gingival-fibroblasts for 80-90% of their surface areas. Human-gingival-fibroblasts lost the race-for-the-surface against all bacterial strains on nearly all implant materials, except on the smoothest titanium variants. SIGNIFICANCE: Smooth titanium implant surfaces provide the best opportunities for a soft tissue seal to form on bacterially contaminated implant surfaces. This conclusion could only be reached in co-culture studies and coincides with the results from the few clinical studies carried out to this end. PMID- 24793201 TI - Flavivirus RNAi suppression: decoding non-coding RNA. AB - Flaviviruses are important human pathogens that are transmitted by invertebrate vectors, mostly mosquitoes and ticks. During replication in their vector, flaviviruses are subject to a potent innate immune response known as antiviral RNA interference (RNAi). This defense mechanism is associated with the production of small interfering (si)RNA that lead to degradation of viral RNA. To what extent flaviviruses would benefit from counteracting antiviral RNAi is subject of debate. Here, the experimental evidence to suggest the existence of flavivirus RNAi suppressors is discussed. I will highlight the putative role of non-coding, subgenomic flavivirus RNA in suppression of RNAi in insect and mammalian cells. Novel insights from ongoing research will reveal how arthropod-borne viruses modulate innate immunity including antiviral RNAi. PMID- 24793202 TI - Erysipelas as a superinfection of an oral lymphangioma. PMID- 24793203 TI - Two cases of abdominal pain in children with mesenteric lymphadenitis due to Yersinia pseudotuberculosis infection. PMID- 24793204 TI - Cognitive abilities in preterm and term-born adolescents. AB - OBJECTIVE: To investigate the influence of a range of prenatal and postnatal factors on cognitive development in preterm and term-born adolescents. STUDY DESIGN: Woodcock-Johnson III Tests of Cognitive Abilities were used to assess general intellectual ability and 6 broad cognitive abilities in 145 young adolescents aged approximately 12.5 years and born 25-41 weeks gestational age (GA). To study potential links between neurophysiologic and cognitive outcomes, corticomotor excitability was measured using transcranial magnetic stimulation and surface electromyography. The influence of various prenatal and postnatal factors on cognitive development was investigated using relative importance regression modeling. RESULTS: Adolescents with greater GA tended to have better cognitive abilities (particularly general intellectual ability, working memory, and cognitive efficiency) and higher corticomotor excitability. Corticomotor excitability explained a higher proportion of the variance in cognitive outcome than GA. But the strongest predictors of cognitive outcome were combinations of prenatal and postnatal factors, particularly degree of social disadvantage at the time of birth, birthweight percentile, and height at assessment. CONCLUSIONS: In otherwise neurologically healthy adolescents, GA accounts for little interindividual variability in cognitive abilities. The association between corticomotor excitability and cognitive performance suggests that reduced connectivity, potentially associated with brain microstructural abnormalities, may contribute to cognitive deficits in preterm children. It remains to be determined if the effects of low GA on cognitive outcomes attenuate over childhood in favor of a concomitant increase in the relative importance of heritability, or alternatively, if cognitive development is more heavily influenced by the quality of the postnatal environment. PMID- 24793205 TI - Abnormalities in the growth hormone axis and risk of nonalcoholic steatohepatitis: active player or innocent bystander? PMID- 24793206 TI - Hepatic explant pathology of pediatric intestinal transplant recipients previously treated with omega-3 fatty acid lipid emulsion. AB - OBJECTIVE: To evaluate and compare the biochemical and histologic effect of parenteral fish oil lipid emulsion that is rich in omega-3 polyunsaturated fatty acids (O3FAs), Omegaven (Fresenius Kabi AG, Bad Homburg, Germany) with standard omega-6 polyunsaturated fatty acid (O6FA) parenteral nutrition. STUDY DESIGN: Comparison of hepatic explant pathology and biochemical outcome on pediatric patients with intestinal failure treated with either parental O3FA or O6FA who had received a liver-inclusive intestine transplant. RESULTS: Seven liver inclusive intestinal transplants were performed in 7 patients who received O3FA for a mean of 62% +/- 13% of total patient life-span (16.1 +/- 7.0 months) before transplant. Median total bilirubin fell from 6.9 mg/dL at the start of treatment to 0.7 mg/dL at the time transplant (P < .02), which was a significant decrease compared with the similarly matched O6FA cohort (P = .012). All 7 of the 03FA treated patients received a liver-inclusive intestinal transplant had advanced fibrosis (stage 3 or 4) noted on explant pathologic examination, despite a resolution of cholestasis at the time of transplant. Histologic inflammatory scores were lower (P = .056) in the 03FA group with similar degrees of advanced fibrosis as in the O6FA group. CONCLUSIONS: In a matched comparison of patients undergoing intestinal transplantation with a history of extended O3FA lipid emulsion therapy that successfully reversed hyperbilirubinemia, significant hepatic fibrosis was present in the explanted livers despite a reduction in inflammation. This result confirms concern that the use of O3FA may have a limited role in altering the development of hepatic fibrosis from parenteral nutrition. PMID- 24793207 TI - Femoral tunnel apertures on the lateral cortex in anterior cruciate ligament reconstruction: an analysis of cortical button fixation. AB - PURPOSE: If the aperture of the oval-shaped femoral tunnel on the lateral cortex becomes bigger than half the size of the cortical button, the risk of fixation failure increases. This study investigated the effect of the location of the entry point and diameter of the femoral tunnel on the length of the major axis of the tunnel aperture in anterior cruciate ligament (ACL) reconstruction using an outside-in technique. METHODS: Simulation of femoral tunnel drilling was performed on computed tomography (CT)-based 3-dimensional (3D) bone models obtained from 40 participants. The tunnel connected the center of the ACL footprint and various points on the lateral femoral surface. The diameter of the tunnel was set at 4.2 mm, 5.2 mm, or 6 mm, depending on the commercially available outside-in surgical systems (Arthrex, Naples, FL and Smith & Nephew, Andover, MA). The length of the major axis of the oval-shaped aperture on the lateral femoral surface was measured. RESULTS: When the tunnel was introduced at 2 cm from the lateral epicondyle in a 45 degrees anteroproximal direction, the major axis was lengthened to 130.7% +/- 9.0% (P < .001) of the tunnel diameter, and it was more than 6.5 mm in 65% of participants in whom a 5.2-mm-diameter tunnel was drilled. When the entry point was 3 cm from the lateral epicondyle, 60% of participants had an oval-shaped aperture with a major axis of more than 6.5 mm, even though the diameter of the tunnel was only 4.2 mm. CONCLUSIONS: The risk of fixation failure of a cortical button increases if the entry point for drilling is 2 cm or further from the lateral epicondyle and the tunnel diameter is more than 5 mm. CLINICAL RELEVANCE: This study indicates the potential risk of cortical button fixation failure caused by an oval tunnel aperture on the lateral femoral surface in ACL reconstruction using the outside-in technique. PMID- 24793208 TI - Central compartment release versus lesser trochanter release of the iliopsoas tendon for the treatment of internal snapping hip: a comparative study. AB - PURPOSE: To evaluate the results of 2 different techniques of endoscopic iliopsoas tendon release in the treatment of internal snapping hip syndrome. METHODS: Between January 2008 and January 2012, a consecutive series of patients with the diagnosis of internal snapping hip syndrome were treated with endoscopic release of the iliopsoas tendon. The patients were divided into 2 groups according to the surgical technique used. Group 1 was treated with endoscopic iliopsoas tendon release at the lesser trochanter, and group 2 was treated with iliopsoas release from the central compartment. Hip arthroscopy of both the central and peripheral compartments was performed in both groups by the lateral approach. Associated injuries were identified and treated arthroscopically. The postoperative physical therapy protocol was the same for both groups. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were evaluated preoperatively and at last follow-up at a minimum of 24 months. RESULTS: Twenty patients were included in the study: 6 in group 1 (4 male and 2 female patients; mean age, 35.6 years) and 14 in group 2 (5 male and 9 female patients; mean age, 32.7 years). Associated injuries were found and treated in 4 patients in group 1 and 10 patients in group 2. Every patient in both groups had an improvement in the WOMAC score. One patient in group 2 presented with recurrence of snapping that required surgical intervention. No complications were seen. CONCLUSIONS: Both central compartment release and release at the lesser trochanter produced favorable results, based on WOMAC scores, for the treatment of internal snapping hip syndrome. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24793209 TI - Extra-articular hip impingement: a systematic review examining operative treatment of psoas, subspine, ischiofemoral, and greater trochanteric/pelvic impingement. AB - PURPOSE: Extra-articular hip impingement can be the result of psoas impingement (PI), subspine impingement (SSI), ischiofemoral impingement (IFI), and greater trochanteric/pelvic impingement (GTPI). Symptoms may be due to bony abutment or soft-tissue irritation, and often, it is a challenge to differentiate among symptoms preoperatively. Currently, the clinical picture and diagnostic criteria are still being refined for these conditions. This systematic review was conducted to examine each condition and elucidate the indications for, treatment options for, and clinical outcomes of surgical management. METHODS: We searched online databases (Medline, Embase, and PubMed) for English-language clinical studies published from database inception through December 31, 2013, addressing the surgical treatment of PI, SSI, IFI, and GTPI. For each condition, 2 independent assessors reviewed eligible studies. Descriptive statistics are presented. RESULTS: Overall, 9,521 studies were initially retrieved; ultimately, 14 studies were included examining 333 hips. For PI, arthroscopic surgery resulted in 88% of patients achieving good to excellent results, as well as significant improvements in the Harris Hip Score (P = .008), Hip Outcome Score Activities of Daily Living (P = .02), and Hip Outcome Score-Sport (P = .04). For SSI, arthroscopic decompression, with no major complications, resulted in a mean 18.5 degrees improvement in flexion range of motion, as well as improvements in pain (mean visual analog scale score of 5.9 points preoperatively and 1.2 points postoperatively) and the modified Harris Hip Score (mean of 64.97 points preoperatively and 91.3 points postoperatively). For both IFI and GTPI, open procedures anecdotally improved patient symptoms, with no formal objective outcomes data reported. CONCLUSIONS: This review suggests that there is some evidence to support that surgical treatment, by arthroscopy for PI and SSI and by open surgery for IFI and GTPI, results in improved patient outcomes. LEVEL OF EVIDENCE: Systematic review of Level IV and V (case report) studies. PMID- 24793210 TI - Origin of the direct and reflected head of the rectus femoris: an anatomic study. AB - PURPOSE: This study aimed to define the footprint of the direct and reflected heads of the rectus femoris and the relation of the anterior inferior iliac spine (AIIS) to adjacent neurovascular (lateral circumflex femoral artery and femoral nerve), bony (anterior superior iliac spine [ASIS]), and tendinous structures (iliopsoas). METHODS: Twelve fresh-frozen cadaveric hip joints from 6 cadavers, average age of 44.5 (+/-9.9) years, were carefully dissected of skin and fascia to expose the muscular, capsular, and bony structures of the anterior hip and pelvis. Using digital calipers, measurements were taken of the footprint of the rectus femoris on the AIIS, superior-lateral acetabulum and hip capsule, and adjacent anatomic structures. RESULTS: The average dimensions of the footprint of the direct head of the rectus femoris were 13.4 mm (+/-1.7) * 26.0 mm (+/-4.1), whereas the dimensions of the reflected head footprint were 47.7 mm (+/-4.4) * 16.8 mm (+/-2.2). Important anatomic structures, including the femoral nerve, psoas tendon, and lateral circumflex femoral artery, were noted in proximity to the AIIS. The neurovascular structure closest to the AIIS was the femoral nerve (20.8 +/- 3.4 mm). CONCLUSIONS: The rectus femoris direct and reflected heads originate over a broad area of the anterolateral pelvis and are in close proximity to critical neurovascular structures, and care must be taken to avoid them during hip arthroscopy. CLINICAL RELEVANCE: A thorough knowledge of the anatomy of the proximal rectus femoris is valuable for any surgical exposure of the anterior hip joint, particularly arthroscopic subspine decompression and open femoroacetabular impingement (FAI) surgery. PMID- 24793211 TI - Skin lesions with Lynch syndrome could represent Muir-Torre syndrome. PMID- 24793212 TI - Therapy of complicated Crohn's disease during pregnancy--an interdisciplinary challenge. AB - BACKGROUND: Severe courses of Crohn's disease (CD) during pregnancy are rare. However, if occurring, the risk of miscarriage and low birth weight is increased. At present, only limited data is available on the treatment of CD during pregnancy. In particular, there are no standard guidelines for surgical therapy. Nevertheless, surgery is often unavoidable if complications during the course of the disease arise. PURPOSE: This study provides a critical overview of conventional and interventional treatment options for CD complications during pregnancy and analyses the surgical experience gained thus far. For illustrative purposes, clinical cases of three young women with a severe clinical course during pregnancy are presented. METHODS: After treatment-refractory for conservative and interventional measures, surgery remained as the only treatment option. In all cases, a split stoma was created after resection to avoid anastomotic leaks that would endanger the lives of mother and child. The postoperative course of all three patients was uneventful, and pregnancy remained intact until delivery. No further CD specific medication was required before birth. CONCLUSIONS: The management of CD patients during pregnancy requires close interdisciplinary co-operation between gastroenterologists, obstetricians, anaesthetists and visceral surgeons. For the protection of mother and child treatment should thus be delivered in a specialised centre. This article demonstrates the advantages of surgical therapy by focusing on alleviating CD complaints and preventing postoperative complications. PMID- 24793213 TI - PTGER4 modulating variants in Crohn's disease. AB - PURPOSE: Variants modulating expression of the prostaglandin receptor 4 (PTGER4) have been reported to be associated with Cohn's disease (CD), but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease (IBD) cohort and searched for a potential phenotype association. METHODS: The variants rs4495224 and rs7720838 were studied in adult German IBD patients (CD, n = 475; ulcerative colitis (UC), n = 293) and healthy controls (HC, n = 467). Data were correlated to results from NOD2 genotyping and to clinical characteristics. RESULTS: We found a significant association for the rs7720838 variant with overrepresentation of the T allele to CD (p = 0.0058; OR 0.7703, 95 % CI 0.641-0.926) but not to UC. Furthermore, logistic regression analysis revealed that the presence of the T allele was associated with stricturing disease behavior in CD patients (p = 0.03; OR 1.84, 95 % CI 1.07 3.16). Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs7720838 and NOD2 were present (OR 2.87, 95 % CI 1.42-5.81; p = 0.003). No overall association to CD or UC was found for the rs4495224 variant. CONCLUSIONS: The PTGER4 modulating variant rs7720838 increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior. PMID- 24793214 TI - 1,3,4-Trisubstituted pyrazole analogues as promising anti-inflammatory agents. AB - Twenty-two 1,3,4-trisubstituted pyrazole (3a-d), (4a-d), (5a-d), (6a-l) derivatives were synthesized and structure of newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, and mass spectral analysis. These compounds were screened for the anti-inflammatory activity by carrageenan-induced paw edema method. Compounds 5a, and 5b showed excellent anti-inflammatory activity (?84.2% inhibition) and 3a, 3b, and 3c showed good anti-inflammatory activity (?64.6% inhibition) compared to that of the standard drug diclofenac (86.72%) when measured 3h after the carrageenan injection. Moreover, the cyclooxygenase (COX) enzyme inhibitor activity of selected compounds, which are the excellent anti-inflammatory activities in carrageenan-induced paw edema model, was investigated in vitro COX inhibition assay. Molecular docking study further helped in supporting the observed activity. In addition compound 5a exhibited considerable cytotoxic activity against MCF-7 cell line with IC50 value 6.5 MUM. PMID- 24793215 TI - Absorption and metabolism of three monoester-diterpenoid alkaloids in Aconitum carmichaeli after oral administration to rats by HPLC-MS. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii (AC) is a well-known herbal medicine for its excellent pharmacological effects and toxicity. The monoester diterpenoid alkaloids (MDAs), including benzoylmesaconine (BMC), benzoylaconine (BAC) and benzoylhyaconine (BHC), are the main active components in AC. It was found that the diester alkaloids could be transformed into monoester-diterpenoid alkaloids after being decocted. In Chinese pharmacopoeia, the MDAs are also used as phytochemical markers for the quality control of AC. Benzoylmesaconine, benzoylaconine and benzoylhyaconine are representatives of monoester-diterpenoid alkaloids. It was reported that the absolute bioavailability of MDAs was very low but there was toxicity often occurred in AC. Because most of DDAs are transformed into MDAs after decoction, we speculate that some other components may promote the bioavailability of MDAs but result in toxicity by enhancing their absorption. To demonstrate the dynamic changes of MDAs in vivo and reveal the causes of low bioavailability and toxicity, this study will explore the mechanisms of absorption and metabolism of 3 MDAs. MATERIALS AND METHODS: A sensitive, accurate and specific LC-MS method was developed to determine the three MDAs in rat plasma. The pharmacokinetic parameters were estimated after orally administered 3 MDAs to the Male Sprague-Dawley rats, and the metabolism stability was calculated after incubating with rat liver microsomes, finally, the absorption characteristics of the 3 MDAs were investigated using Caco-2 transwell model. RESULTS: It was found that the pharmacokinetic parameters of 3 MDAs were similar, Cmax and Tmax were very small, and t1/2 was large, which indicated 3 MDAs can be absorbed rapidly and is difficult to be metabolized or excreted. However, the low Cmax indicated that the bioavailability of 3 MDAs will be very low and their absorption may be inhibited by some transport proteins. By incubating three MDAs in rat liver microsomes, it was proved that they almost can't be metabolized in vivo. The Caco-2 transwell experiments reveal that the P-gp inhibits the absorption of MDAs. CONCLUSIONS: LC-MS combined with a direct precipitation method for the simultaneous quantification of 3 MDAs in rat plasma has been developed and validated and successfully used in pharmacokinetic study of 3 MDAs. It was proved that the three components almost can't be metabolized in vivo, and P-gp inhibits the absorption of MDAs. PMID- 24793216 TI - Panax notoginseng saponins (PNS) inhibits breast cancer metastasis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burkill) F.H. Chen (Araliaceae) has been extensively used as a therapeutic agent to treat a variety of diseases. Panax notoginseng saponins (PNS) consist of major therapeutically active components of Panax notoginseng. PNS inhibit the growth of a variety of tumor cells in vitro and in vivo. The aim of the study is to investigate the effects and underlying mechanisms of PNS on breast cancer metastasis. MATERIALS AND METHODS: 4T1 cell, a highly metastatic mouse breast carcinoma cell line, was utilized for in vitro and in vivo assays. In vitro assays were first performed to examine the effects of PNS on 4T1 cell viability, migration and invasion, respectively. Real-time PCR analyses were also performed to examine the effects of PNS on the expression of genes associated with tumor metastasis. The effect of PNS on 4T1 tumor cell metastasis was further assessed in spontaneous and experimental metastasis models in vivo. RESULTS: PNS treatment exhibited a dose dependent effect on impairing 4T1 cell viability in vitro. However, when examined at a lower dose that did not affect cell viability, the migration and invasion of 4T1 cell was remarkably inhibited in vitro. Meanwhile, PNS treatment led to upregulated expression of genes known to inhibit metastasis and downregulated expression of genes promoting metastasis in cultured 4T1 cells. These results suggested a selective effect of PNS on 4T1 migration and invasion. This hypothesis was further addressed in 4T1 metastasis models in vivo. The results showed that the lung metastasis was significantly inhibited by PNS treatment in both spontaneous and experimental metastasis models. CONCLUSION: Taken together, our results demonstrated an inhibitory effect of PNS on 4T1 tumor metastasis, warranting further evaluation of PNS as a therapeutic agent for treating breast cancer metastasis. PMID- 24793217 TI - Traditional uses of medicinal plants in Elazig (Turkey). AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study has identified not only the wild plants collected for medical purposes by local people of Elazig Province in the Eastern Anatolia Region, but also the uses and local names of these plants. These resources are usually regarded as part of a culture's traditional knowledge. Therefore, the aim of this study is to collect information from local population concerning the use of medicinal plants of the Elazig region; identify the most important medicinal plants used; determine the relative importance of the species surveyed and calculate the informant consensus factor (FIC) in relation to medicinal plant use. MATERIALS AND METHODS: A field study had been carried out for a period of approximately 2 years (2012-2013). A questionnaire was administered to the local people, through face-to-face interviews (Appendix A). Demographic characteristics of participants, names of the local plants, their utilized parts and preparation methods were investigated and recorded. The plant species were collected within the scope of the study; herbarium materials were prepared; and the specimens were entitled. The collected data were used to calculate the FIC and the plant use values. RESULTS: 74 Plants were found to be used for medical purposes before in the literature analysis of the plants used in our study, while 6 plants were found to have no literature records. Our results showed that the highest use values were recorded for the species Urtica dioica L. (0.46) and Rosa canina L. (0.42), while the highest FIC was cited for skin diseases (0.60). CONCLUSION: Data obtained showed that in the studied area the folk use of plants is alive and still derives from daily practice. Evaluation of pharmacological activity for the promising medicinal plants is suggested. PMID- 24793219 TI - Testing the therapeutic equivalence of alogliptin, linagliptin, saxagliptin, sitagliptin or vildagliptin as monotherapy or in combination with metformin in patients with type 2 diabetes. AB - BACKGROUND: In studying the therapeutic evidence of innovative drug treatments, increasing attention is being devoted to differentiating between results that indicate no significant differences among the treatments under examination ("no proof of difference") and results that demonstrate the therapeutic equivalence among the treatments ("proof of no difference"). AIM: Our analysis was aimed at evaluating the degree of therapeutic equivalence for dipeptidylpeptidase-4 (DPP 4) inhibitors given in type 2 diabetes as monotherapy or in combination with metformin. METHODS: Equivalence was determined by developing a standard Forest plot that incorporated the information on margins previously reported in randomized trials on these agents. The end point was HbA1c change from baseline; the equivalence margin was set at +/-0.25% change in HbA1c. The clinical material was obtained from a systematic review on this topic. RESULTS: Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another. Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion. CONCLUSIONS: Considering the most recent therapeutic guidelines, our results are of interest particularly as regards the information on DPP-4 inhibitors in combination with metformin. Four of the five DPP-4 inhibitors under examination clearly showed to have the same effectiveness; the fifth agent-alogliptin-failed to meet the equivalence criterion, but only because its superiority could not be excluded. PMID- 24793220 TI - Levator ani deformation during the second stage of labour. AB - A very important medical problem for females is urinary incontinence, sometimes associated with faecal incontinence and pelvic organ prolapse. One of the most common reasons these issues are increasing is clearly the muscle damage during childbirth. This article focusses on understanding the complex behaviour of the levator ani muscles involved in the second stage of labour. A geometrical model obtained from a 23-year-old nulliparous woman was used to simulate childbirth. Several assumptions were introduced in order to simplify the problem without significantly affecting the global response of the system. An anisotropic hyperelastic model was used to characterize the material behaviour; the muscle fibres were assumed to be mostly orientated circumferentially. In addition, particular attention was also put to the boundary conditions of the model. The introduction of the constraints imposed by the coccyx bone in the central area of the levator ani group represents one the most important improvement compared to previous computational models. The maximum deformation and stress were found in the pubococcygeus muscle of the levator ani group. A stretch value close to 2.2 was determined by considering different material parameters. The results seem convincing with respect to medical observation and previous analysis. However, there are still some limitations concerning the material definition and the geometry and trajectory of the head that can be further improved. PMID- 24793218 TI - Factors that influence the reinforcing value of foods and beverages. AB - Behavioral economic principles state that as the cost of a product increases, purchasing or consumption of that product will decrease. To understand the impact of behavioral economics on ingestive behavior, our laboratory utilizes an operant behavior paradigm to measure how much work an individual will engage in to get access to foods and beverages. This task provides an objective measure of the reinforcing value. We have shown that consumption of the same high fat snack food every day for two weeks reduces its reinforcing value in lean individuals, but increases its reinforcing value in a subset of obese individuals. This increase in the reinforcing value of food predicts future weight gain. Similarly, we have shown that repeated intake of caffeinated soda increases its reinforcing value in boys, but not in girls. This increase in reinforcing value is not related to usual caffeine consumption, but may be associated with positive, subjective effects of caffeine that are more likely to be reported by boys than by girls. Because food and beverage reinforcement relates to real-world consumption, it is important to determine factors that increase or decrease the reinforcing value and determine the consequences of these responses. We are especially interested in determining ways to shift the behavioral economic curve in order to develop novel strategies to decrease the reinforcing value of less healthy snack foods and beverages, such as soda, potato chips and candy and to increase the reinforcing value of healthier foods and beverages, such as water, fruits, and vegetables. PMID- 24793221 TI - Taenia solium tapeworms synthesize corticosteroids and sex steroids in vitro. AB - Cysticercosis is a disease caused by the larval stage of Taenia solium cestodes that belongs to the family Taeniidae that affects a number of hosts including humans. Taeniids tapeworms are hermaphroditic organisms that have reproductive units called proglottids that gradually mature to develop testis and ovaries. Cysticerci, the larval stage of these parasites synthesize steroids. To our knowledge there is no information about the capacity of T. solium tapeworms to metabolize progesterone or other precursors to steroid hormones. Therefore, the aim of this paper was to investigate if T. solium tapeworms were able to transform steroid precursors to corticosteroids and sex steroids. T. solium tapeworms were recovered from the intestine of golden hamsters that had been orally infected with cysticerci. The worms were cultured in the presence of tritiated progesterone or androstenedione. At the end of the experiments the culture media were analyzed by thin layer chromatography. The experiments described here showed that small amounts of testosterone were synthesized from (3)H-progesterone by complete or segmented tapeworms whereas the incubation of segmented tapeworms with (3)H-androstenedione, instead of (3)H-progesterone, improved their capacity to synthesize testosterone. In addition, the incubation of the parasites with (3)H-progesterone yielded corticosteroids, mainly deoxicorticosterone (DOC) and 11-deoxicortisol. In summary, the results described here, demonstrate that T. solium tapeworms synthesize corticosteroid and sex steroid like metabolites. The capacity of T. solium tapeworms to synthesize steroid hormones may contribute to the physiological functions of the parasite and also to their interaction with the host. PMID- 24793222 TI - Examining Contextual Influences on Classroom-Based Implementation of Positive Behavior Support Strategies: Findings from a Randomized Controlled Effectiveness Trial. AB - Although it is widely recognized that variation in implementation fidelity influences the impact of preventive interventions, little is known about how specific contextual factors may affect the implementation of social and behavioral interventions in classrooms. Theoretical research highlights the importance of multiple contextual influences on implementation, including factors at the classroom and school level (Domitrovich et al., Advances in School Mental Health Promotion, 1, 6-28, 2008). The current study used multi-level modeling to empirically examine the influence of teacher, classroom, and school characteristics on the implementation of classroom-based positive behavior support strategies over the course of 4 years. Data were collected in the context of a 37-school randomized controlled trial examining the effectiveness of school wide Positive Behavioral Interventions and Supports. Multi-level results identified several school-level contextual factors (e.g., school size, behavioral disruptions) and teacher-level factors (perceptions of school organizational health and grade level taught) associated with variability in the implementation of classroom-based positive behavior supports. Implications for prevention research and practice are discussed. PMID- 24793223 TI - Eye movements disrupt spatial but not visual mental imagery. AB - It has long been known that eye movements are functionally involved in the generation and maintenance of mental images. Indeed, a number of studies demonstrated that voluntary eye movements interfere with mental imagery tasks (e.g., Laeng and Teodorescu in Cogn Sci 26:207-231, 2002). However, mental imagery is conceived as a multifarious cognitive function with at least two components, a spatial component and a visual component. The present study investigated the question of whether eye movements disrupt mental imagery in general or only its spatial component. We present data on healthy young adults, who performed visual and spatial imagery tasks concurrently with a smooth pursuit. In line with previous literature, results revealed that eye movements had a strong disruptive effect on spatial imagery. Moreover, we crucially demonstrated that eye movements had no disruptive effect when participants visualized the depictive aspects of an object. Therefore, we suggest that eye movements serve to a greater extent the spatial than the visual component of mental imagery. PMID- 24793225 TI - Which protects against AMD: allergy itself or antiallergic drugs? PMID- 24793226 TI - Author response: which protects against AMD: allergy itself or antiallergic drugs? PMID- 24793227 TI - Scaphoid nonunions treated with 2 headless compression screws and bone grafting. AB - PURPOSE: To evaluate union and complication rates associated with the use of 2 headless compression screws and bone grafting for the treatment of scaphoid nonunions. METHODS: A total of 19 patients (18 male and 1 female) at an average age of 21 years were treated with open reduction and internal fixation with 2 cannulated, headless, compression screws for scaphoid nonunions. Bone grafting techniques included corticocancellous autograft from the iliac crest in 14 patients, capsular-based vascularized distal radius graft in 3, and medial femoral condyle free vascularized bone graft in 2. Patients were treated an average 19 months after the injury. Fracture nonunions were at the waist (n = 12), proximal third (n = 5), or distal third (n = 2) of the scaphoid. Dorsal (n = 7) and volar (n = 12) surgical approaches were used. RESULTS: All fractures had clinical and radiographic evidence of bone union at an average of 3.6 months. Postoperative computed tomography scans were available in 13 patients and showed union without evidence of screw penetration of the scaphoid cortex. No complications occurred in this series, and no revision procedures have been necessary. CONCLUSIONS: Our results indicate that the use of 2 headless compression screws for the treatment of scaphoid nonunions is safe and effective. A variety of bone grafting techniques can be used with this technique. The use of 2 compression screws may provide superior biomechanical stability and ultimately improve outcomes measured with future long-term comparative studies. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24793228 TI - Metacarpophalangeal joint locking in 3 family members with brachymesophalangy: case report. AB - We report painful locking of the metacarpophalangeal joint in a man, his mother, and his sister, all of whom have brachymesophalangy. Surgical excision of loose osteocartilaginous fragments relieved their symptoms. The fragments appeared to be unfused ossicles of the metacarpal head, unique to patients with brachymesophalangy. PMID- 24793232 TI - Prognostic significance of splenectomy for patients with gastric adenocarcinoma undergoing total gastrectomy: a retrospective cohort study. AB - BACKGROUND: The addition of splenectomy to a D2 gastrectomy in patients with gastric adenocarcinoma (GA) has remained controversial. This study aimed to assess the impact of splenectomy on the overall survival of patients undergoing total gastrectomy for GA. METHODS: This was a retrospective review of 463 GA patients (excluding positive resection margins and pathologic spleen invasion) undergoing curative total gastrectomy with (TS) and without splenectomy (T) between 1994 and 2008. Clinicopathologic factors affecting the prognosis of these patients were collected prospectively and analyzed. RESULTS: Two hundred and ninety one patients had T and 172 patients underwent TS. Patient clinicopathological characteristics were comparable between the 2 groups except for tumor size. There were no significant differences in postoperative morbidity and mortality between T and TS groups. Patients in the T group had similar 3- and 5-year survival rates compared with those in the TS groups (p = 0.181). The addition of splenectomy to a total gastrectomy did not impact on the overall survival rates in patients with GA in terms of depth of tumor invasion and nodal metastasis. CONCLUSIONS: The addition of splenectomy is not associated with survival advantage in GA patients undergoing total gastrectomy. PMID- 24793233 TI - Simulation training: a systematic review of simulation in arthroscopy and proposal of a new competency-based training framework. AB - INTRODUCTION: Traditional orthopaedic training has followed an apprenticeship model whereby trainees enhance their skills by operating under guidance. However the introduction of limitations on training hours and shorter training programmes mean that alternative training strategies are required. AIMS: To perform a literature review on simulation training in arthroscopy and devise a framework that structures different simulation techniques that could be used in arthroscopic training. METHODS: A systematic search of Medline, Embase, Google Scholar and the Cochrane Databases were performed. Search terms included "virtual reality OR simulator OR simulation" and "arthroscopy OR arthroscopic". RESULTS: 14 studies evaluating simulators in knee, shoulder and hip arthroplasty were included. The majority of the studies demonstrated construct and transference validity but only one showed concurrent validity. More studies are required to assess its potential as a training and assessment tool, skills transference between simulators and to determine the extent of skills decay from prolonged delays in training. We also devised a "ladder of arthroscopic simulation" that provides a competency-based framework to implement different simulation strategies. CONCLUSION: The incorporation of simulation into an orthopaedic curriculum will depend on a coordinated approach between many bodies. But the successful integration of simulators in other areas of surgery supports a possible role for simulation in advancing orthopaedic education. PMID- 24793234 TI - Interposition of the omentum and/or the peritoneum in the emergency repair of large ventral hernias with polypropylene mesh. AB - BACKGROUND: Ventral and incisional hernias are common surgical problems and their repairs are among the common surgeries done by a general surgeon. Repair of a large ventral hernia is still associated with high postoperative morbidity and recurrence rates. No single approach to ventral hernia repair will be the best choice for all patients. Large ventral hernias are often better approached with open surgery but may still be problematic when the defect is too wide for primary fascial closure to be achieved, as this leaves mesh exposed, bridging the gap. Techniques for incisional hernia repair have evolved over many years, and the use of mesh has reduced recurrence rates dramatically. The use of polypropylene mesh is reported to be associated with long-term complications such as severe adhesions and enterocutaneous fistula, which occur more commonly if the mesh is applied intraperitoneally with direct contact of the serosal surface of the intestine. Composite meshes containing expanded polytetrafluoroethylene (ePTFE) have been used recently; their major drawbacks lie in their high cost, inferior handling characteristics, and poor incorporation into the tissues. Although several studies have clearly demonstrated the safety and efficacy of prosthetic mesh repair in the emergency management of the incarcerated and/or strangulated inguinal and ventral hernias, however, surgeons remained reluctant to use prosthetics in such settings. PURPOSE: The aim of this work was to evaluate the effectiveness and safety of placing the omentum and/or the peritoneum of the hernia sac as a protective layer over the viscera in the emergency repair of large ventral hernias using on-lay polypropylene mesh whenever complete tension free closure of the abdominal wall was impossible. PATIENTS AND METHODS: This study was carried out on all patients with large ventral hernia presented to the Gastrointestinal Surgery Unit, Main Alexandria University Hospital in an emergency situation during the period from October 2005 till October 2012. All patients were treated by placing the omentum and/or the peritoneum of the hernia sac between the viscera and the mesh whenever complete tension-free closure of the abdominal wall was impossible. Some patients necessitated removal of previous meshes and resection-anastomosis of the non-viable bowel prior to mesh repair. Those who underwent complete closure of the abdominal wall without tension prior to mesh repair were excluded from the study as there was no need for interposition of the omentum and/or peritoneum. All patients' data, surgical procedures, complications and follow-up were collected, reviewed and analyzed. After approval of local ethics committees of both the General Surgery Department and the Alexandria Faculty of Medicine, all patients included in the study were informed well about the operative procedure and use of prosthetic mesh and an informed written consent was obtained from every patient before carrying the procedure. RESULTS: Between October 2005 and October 2012; 105 patients (13 males and 92 females) with incarcerated and/or strangulated large ventral hernias were operated upon in the Gastrointestinal Surgery Unit, Main Alexandria University Hospital using an onlay polypropylene mesh. Their age ranged from 37 to 83 years with a mean of 59.3 + 11.7 years. The hernia was para-umbilical in 5 patients (4.8%), incisional in 22 patients (21%) and recurrent in 78 patients (74.3%). The recurrent hernias were recurrent para-umbilical hernias in 56 patients and recurrent incisional hernias in 22 patients. Resection anastomosis of non-viable, devitalized or injured small intestine during removal of adherent previous meshes was performed in 19 patients (18%). Hospital stay ranged from 2 to 13 days with a mean of 3.57 + 1.6 days. There was one perioperative mortality. Complications were encountered in 28 patients (26.7%) and included wound infection with delayed wound healing in 6 patients, seroma formation in 12 patients, chest infection in 8 patients and deep vein thrombosis in 2 patients. Follow-up duration ranged from 13 to 80 months with a mean of 46.8 + 20.3 months. CONCLUSION: Placing the omentum and/or the peritoneum of the hernia sac as a protective layer over the viscera in repair of incarcerated and/or strangulated large ventral hernia using on-lay polypropylene mesh is cost-effective and safe even with resection anastomosis of small intestine. PMID- 24793235 TI - [Free re-innervated Latissimus Dorsi musculocutaneous flap for treat congenital Volkmann ischemic Contracture: a case report]. AB - OBJECTIVES: Congenital Volkmann ischemic contracture is a rare entity. The neonate presents nerve palsy, cutaneous and muscular necrosis of the forearm. METHODS: We report a case of a newborn who presented with necrotic subcutaneous tissue of the right forearm and absence of active flexion and extension of the wrist and fingers. She was initially treated with debridement of necrotic tissues and orthosis of the wrist. Latissimus dorsi free flap was used for forearm reconstruction at age of 7months. The thoracodorsal nerve was anastomosed with a motor branch of the median nerve. The proximal part of the muscle was fixated to the lateral epicondyle of humerus, and the distal part of muscle was sutured with a flexor digitorum tendons and radial extensor carpi. The cutaneous component of the flap was used to cover a defect of soft tissue of the forearm. RESULTS: At age of 12 months, the patient has a good two-hand function with a pollici digital clamp of the right hand. She also has a recovery of active wrist extension and fingers flexion. DISCUSSION: Free re-innervated latissimus dorsi muscle transfer is an alternative to restore a useful hand function in case of congenital Volkmann ischemic contracture. PMID- 24793237 TI - Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a heritable disorder, in both a dominant and recessive manner, of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms. Here, we show that excessive transforming growth factor-beta (TGF-beta) signaling is a mechanism of OI in both recessive (Crtap(-/ )) and dominant (Col1a2(tm1.1Mcbr)) OI mouse models. In the skeleton, we find higher expression of TGF-beta target genes, higher ratio of phosphorylated Smad2 to total Smad2 protein and higher in vivo Smad2 reporter activity. Moreover, the type I collagen of Crtap(-/-) mice shows reduced binding to the small leucine rich proteoglycan decorin, a known regulator of TGF-beta activity. Anti-TGF-beta treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI and improves the lung abnormalities in Crtap(-/-) mice. Hence, altered TGF-beta matrix-cell signaling is a primary mechanism in the pathogenesis of OI and could be a promising target for the treatment of OI. PMID- 24793240 TI - What have we learned from research into first-episode psychosis? PMID- 24793238 TI - Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. AB - As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function. PMID- 24793239 TI - Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. AB - We describe a new mechanism regulating the tumor endothelial barrier and T cell infiltration into tumors. We detected selective expression of the death mediator Fas ligand (FasL, also called CD95L) in the vasculature of human and mouse solid tumors but not in normal vasculature. In these tumors, FasL expression was associated with scarce CD8(+) infiltration and a predominance of FoxP3(+) T regulatory (Treg) cells. Tumor-derived vascular endothelial growth factor A (VEGF A), interleukin 10 (IL-10) and prostaglandin E2 (PGE2) cooperatively induced FasL expression in endothelial cells, which acquired the ability to kill effector CD8(+) T cells but not Treg cells because of higher levels of c-FLIP expression in Treg cells. In mice, genetic or pharmacologic suppression of FasL produced a substantial increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells. Pharmacologic inhibition of VEGF and PGE2 produced a marked increase in the influx of tumor-rejecting CD8(+) over FoxP3(+) T cells that was dependent on attenuation of FasL expression and led to CD8-dependent tumor growth suppression. Thus, tumor paracrine mechanisms establish a tumor endothelial death barrier, which has a critical role in establishing immune tolerance and determining the fate of tumors. PMID- 24793241 TI - CeO2 nanocrystals from supercritical alcohols: new opportunities for versatile functionalizations? AB - The fast and controlled synthesis of surface-modified cerium oxide nanoparticles was carried out in supercritical {ethanol + alcohol derivative} mixtures. The newly found ability of supercritical alcohols to graft onto cerium oxide nanocrystals (CeO2 NCs) during their synthesis was exploited to control their surface chemistry via the addition of three aminoalcohols: ethanolamine, 3-amino 1-propanol and 6-amino-1-hexanol. Although the ethanol to aminoalcohol ratio was consistent (285:1), the successful grafting of these alcohol derivatives onto CeO2 NCs was identified based on Fourier transform infrared (FTIR) and thermogravimetric analysis-mass spectrometry (TGA-MS) measurements. Smaller crystallite size of CeO2 NCs synthesized in the presence of aminoalcohols, compared to those synthesized in supercritical ethanol alone, were also noticed and attributed to a possible intervention of amine groups helping the grafting of the alcohols, allowing one to stop the growth of the CeO2 NCs faster. The use of supercritical alcohol mixture-ethanol with hexanol, dodecanol, or octadecanol, with a 285:1 ratio-was also investigated. Such mixtures allow accessing a finer control in CeO2 NCs crystallite size compared to pure alcohols, according to calculation made from X-ray diffraction measurements. Finally, fluorescent molecules (fluorescein isothiocyanate) were grafted onto amine-modified CeO2 NCs. The powders displayed a fluorescent behavior under UV light, confirming the suitability and interest of CeO2 NCs surface modification by such technique. PMID- 24793244 TI - The use and impact of cancer medicines in routine clinical care: methods and observations in a cohort of elderly Australians. AB - INTRODUCTION: After medicines have been subsidised in Australia we know little about their use in routine clinical practice, impact on resource utilisation, effectiveness or safety. Routinely collected administrative health data are available to address these issues in large population-based pharmacoepidemiological studies. By bringing together cross-jurisdictional data collections that link drug exposure to real-world outcomes, this research programme aims to evaluate the use and impact of cancer medicines in a subset of elderly Australians in the real-world clinical setting. METHODS AND ANALYSIS: This ongoing research programme involves a series of retrospective cohort studies of Australian Government Department of Veterans' Affairs (DVA) clients. The study population includes 104 635 veterans who reside in New South Wales, Australia, and were aged 65 years and over as of 1 July 2004. We will investigate trends in cancer medicines use according to cancer type and other sociodemographic characteristics as well as predictors of the initiation of cancer medicines and other treatment modalities, survival and adverse outcomes among patients with cancer. The programme is underpinned by the linkage of eight health administrative databases under the custodianship of the DVA and the New South Wales Ministry of Health, including cancer notifications, medicines dispensing data, hospitalisation data and health services data. The cancer notifications database is available from 1994 with all other databases available from 2005 onwards. ETHICS AND DISSEMINATION: Ethics approval has been granted by the DVA and New South Wales Population and Health Service Research Ethics Committees. RESULTS: Results will be reported in peer-reviewed publications, conference presentations and policy forums. The programme has high translational potential, providing invaluable evidence about cancer medicines in an elderly population who are under-represented in clinical trials. PMID- 24793245 TI - A retrospective analysis of factors associated with selection of end-of-life care and actual place of death for patients with cancer. AB - OBJECTIVES: The factors associated with end-of-life (EOL) care that patients with cancer selected and actual place of death (POD) is less elucidated. We analysed how specific EOL care, especially anticancer therapies, selected by patients with pancreatic carcinoma affected their POD in Japan. SETTING: A retrospective cohort study using clinical records of a single institute. PARTICIPANTS: This study included 433 advanced or recurrent patients with pancreatic carcinoma who had completed standard chemotherapies and were receiving hospice care in the National Cancer Center Hospital between April 2008 and April 2011. OUTCOME MEASURES: We analysed statistical association factors, demographic information, geographical differences, medical environment, EOL care selection, along with actual POD using logistic regression analysis. RESULTS: Of the 433 patients, 147 selected palliative care units (PCUs) as the POD; 229, hospital; and 57, home with hospice care. POD selection was associated with several factors. Notably, EOL care selection, especially the use of complementary and alternative medicine (CAM), is associated with POD selection (death in PCU; OR=0.23, p=0.02). CONCLUSIONS: This study is, to the best of our knowledge, the first to unveil that EOL care selection is associated with POD in Japan. Certain factors such as gender, medical environment and EOL care selection might influence the POD. Patients who pursue aggressive anticancer therapies, such as CAM use, were possibly deprived of a chance of early reference to a PCU. PMID- 24793242 TI - ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia. AB - Endothelin-1 (ET-1) acts on endothelial cells to enhance mechanical stimulation induced release of adenosine triphosphate (ATP), which in turn can act on sensory neurons innervating blood vessels to contribute to vascular pain, a phenomenon we have referred to as stimulus-dependent hyperalgesia (SDH). In the present study, we evaluated the role of the major classes of ATP release mechanisms to SDH: vesicular exocytosis, plasma membrane-associated ATP synthase, ATP-binding cassette transporters, and ion channels. Inhibitors of vesicular exocytosis (ie, monensin, brefeldin A, and bafilomycin), plasma membrane-associated ATPase (ie, oligomycin and pigment epithelium-derived factor peptide 34-mer), and connexin ion channels (carbenoxolone and flufenamic acid) but not ATP-binding cassette transporter (ie, dipyridamole, nicardipine, or CFTRinh-172) attenuated SDH. This study reports a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes. PERSPECTIVE: ET-1 acts on endothelial cells to produce mechanical stimulation-induced hyperalgesia. Inhibitors of 3 different ATP release mechanisms attenuated this SDH. This study provides support for a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes. PMID- 24793246 TI - Age, occupational class and sickness absence during pregnancy: a retrospective analysis study of the Norwegian population registry. AB - OBJECTIVE: Western women increasingly delay having children to advance their career, and pregnancy is considered to be riskier among older women. In Norway, this development surprisingly coincides with increased sickness absence among young pregnant women, rather than their older counterparts. This paper tests the hypothesis that young pregnant women have a higher number of sick days because this age group includes a higher proportion of working class women, who are more prone to sickness absence. DESIGN: A zero-inflated Poisson regression was conducted on the Norwegian population registry. PARTICIPANTS: All pregnant employees giving birth in 2004-2008 were included in the study. A total number of 216 541 pregnancies were observed among 180 483 women. OUTCOME MEASURE: Number of sick days. RESULTS: Although the association between age and number of sick days was U-shaped, pregnant women in their early 20s had a higher number of sick days than those in their mid-40s. This was particularly the case for pregnant women with previous births. In this group, 20-year-olds had 12.6 more sick days than 45 year-olds; this age difference was reduced to 6.3 after control for class. Among women undergoing their first pregnancy, 20-year-olds initially had 1.2 more sick days than 45-year-olds, but control for class altered this age difference. After control for class, 45-year-old first-time pregnant women had 2.9 more sick days than 20-year-olds with corresponding characteristics. CONCLUSIONS: The negative association between age and sickness absence was partly due to younger age groups including more working class women, who were more prone to sickness absence. Young pregnant women's needs for job adjustments should not be underestimated. PMID- 24793247 TI - Should vitamin B12 tablets be included in more Canadian drug formularies? An economic model of the cost-saving potential from increased utilisation of oral versus intramuscular vitamin B12 maintenance therapy for Alberta seniors. AB - OBJECTIVE: The aim of this study was to estimate the cost-savings attainable if all patients aged >=65 years in Alberta, Canada, currently on intramuscular therapy were switched to oral therapy, from the perspective of a provincial ministry of health. SETTING: Primary care setting in Alberta, Canada. PARTICIPANTS: Seniors of age 65 years and older currently receiving intramuscular vitamin B12 therapy. INTERVENTION: Oral vitamin B12 therapy at 1000 MUg/day versus intramuscular therapy at 1000 MUg/month. PRIMARY AND SECONDARY OUTCOME MEASURES: Cost saving from oral therapy over intramuscular therapy, from the perspective of the Alberta Ministry of Health, including drug costs, dispensing fees, injection administration fees, additional laboratory monitoring and physician visit fees. RESULTS: Over 5 years, if all Albertans aged 65 years and older who currently receive intramuscular B12 are switched to oral therapy, our model found that $C13 975 883 can be saved. Even if no additional physician visits are billed for among patients receiving intramuscular therapy, $C8 444 346 could be saved from reduced administration costs alone. CONCLUSIONS: Oral B12 therapy has been shown to be an effective therapeutic option for patients with vitamin B12 deficiency, yet only three provinces and the Non-Insured Health Benefits program include oral tablets on their formulary rather than the parenteral preparation. To ensure judicious use of limited health resources, clinicians and formulary committees are encouraged to adopt oral B12 therapy as a clinically and cost-effective first-line therapy for vitamin B12 deficiency. PMID- 24793248 TI - Comparison of three tests for faecal calprotectin in children and young adults: a retrospective monocentric study. AB - OBJECTIVE: Faecal calprotectin is used as a sensitive marker for gastrointestinal mucosal inflammation. We compared the performance of three different assays in a large cohort of symptomatic paediatric patients. DESIGN: Retrospective monocentric study. SETTING: Inpatients and outpatients of a tertiary referral centre for paediatric gastroenterology. PARTICIPANTS: 304 symptomatic patients (163 males, aged 2-20 years) with active inflammatory bowel disease (IBD/A, n=130), IBD in clinical remission (IBD/R, n=62), other intestinal diseases (n=45) and controls without identified intestinal disease (n=67). INTERVENTIONS: Calprotectin was measured in homogenised faecal samples with three tests (A: EliA Calprotectin, Phadia AB, Sweden; B: PhiCal, Calpro AS, Norway; C: EK-Cal, Buhlmann Laboratories, Switzerland). OUTCOMES: Concordance between tests was calculated using Kendall's tau coefficient. RESULTS: IBD/A and controls were correctly classified as 97.7%/82.1% (A), 97.7%/85.1% (B) and 98.4%/62.7% (C; not significant). Test C tended to have higher calprotectin values with a lower specificity compared to tests A and B. The concordance between two tests was 0.835 for tests A and B, 0.782 for tests A and C and 0.765 for tests B and C. CONCLUSIONS: All three tests are very sensitive for detecting mucosal inflammation, but major differences exist between specificity and absolute values. It is highly advisable to use the test of the same manufacturer for follow-up and to monitor for disease activity. PMID- 24793249 TI - Risk factors for exposure of glaucoma drainage devices: a retrospective observational study. AB - OBJECTIVES: The purpose of this study was to identify risk factors for exposure of glaucoma drainage devices (GDD). SETTING: This retrospective, observational study was conducted in the eye clinic of an academic medical centre. PARTICIPANTS: Participants included 1073 consecutive adults who underwent GDD surgery between 1 January 2005 and 1 January 2011. Participants were included if chart review indicated GDD surgery during the study period and excluded if at least 12 months of clinical follow-up was not available in the medical record. PRIMARY OUTCOME MEASURE: The primary outcome measure was exposure of the GDD occurring at least 1 month after implant surgery. The characteristics of participants who experienced exposure of the implant were compared to the characteristics of participants who did not experience exposure. RESULTS: Of the 1073 participants having undergone GDD surgery, 67 experienced exposure of the device. Neither the type of GDD, type of patch graft (eye bank sclera, Tutoplast sclera and Tutoplast pericardium), surgeon, location of GDD, number of GDD previously implanted into the eye, nor history of diabetes or uveitis were associated with likelihood of exposure. Women were more likely than men to experience exposure of the GDD (OR 2.004 (95% CI1.170 to 3.431)) in both univariable (p=0.011) and multivariable (p=0.013) analyses. In survival analysis, exposure of the GDD occurred earlier for women than for men (58 vs 61 months; p=0.024).White race (vs black) was also associated with increased risk of GDD exposure (OR 1.693 (95% CI 1.011 to 2.833)) in univariable (p=0.044) and multivariable (p=0.046) analyses. CONCLUSIONS: Women are two times more likely to experience GDD exposure than men, independent of age. White race is also a risk factor for exposure. PMID- 24793250 TI - Triage tests for identifying atrial fibrillation in primary care: a diagnostic accuracy study comparing single-lead ECG and modified BP monitors. AB - OBJECTIVE: New electronic devices offer an opportunity within routine primary care settings for improving the detection of atrial fibrillation (AF), which is a common cardiac arrhythmia and a modifiable risk factor for stroke. We aimed to assess the performance of a modified blood pressure (BP) monitor and two single lead ECG devices, as diagnostic triage tests for the detection of AF. SETTING: 6 General Practices in the UK. PARTICIPANTS: 1000 ambulatory patients aged 75 years and over. PRIMARY AND SECONDARY OUTCOME MEASURES: Comparative diagnostic accuracy of modified BP monitor and single-lead ECG devices, compared to reference standard of 12-lead ECG, independently interpreted by cardiologists. RESULTS: A total of 79 participants (7.9%) had AF diagnosed by 12-lead ECG. All three devices had a high sensitivity (93.9-98.7%) and are useful for ruling out AF. WatchBP is a better triage test than Omron autoanalysis because it is more specific-89.7% (95% CI 87.5% to 91.6%) compared to 78.3% (95% CI 73.0% to 82.9%), respectively. This would translate into a lower follow-on ECG rate of 17% to rule in/rule out AF compared to 29.7% with the Omron text message in the study population. The overall specificity of single-lead ECGs analysed by a cardiologist was 94.6% for Omron and 90.1% for Merlin. CONCLUSIONS: WatchBP performs better as a triage test for identifying AF in primary care than the single-lead ECG monitors as it does not require expertise for interpretation and its diagnostic performance is comparable to single-lead ECG analysis by cardiologists. It could be used opportunistically to screen elderly patients for undiagnosed AF at regular intervals and/or during BP measurement. PMID- 24793251 TI - Sex-specific trends in 4-year survival in 37 276 men and women with acute myocardial infarction before the age of 55 years in Sweden, 1987-2006: a register based cohort study. AB - OBJECTIVE: To examine sex-specific trends in 4-year mortality among young patients with first acute myocardial infarction (AMI), 1987-2006. DESIGN: Prospective cohort study. SETTING: Sweden. PARTICIPANTS: We identified 37 276 cases (19.4% women; age, 25-54 years) from the Swedish Inpatient Register, 1987 2006, who had survived 28 days after an AMI. OUTCOME MEASURES: 4-year mortality from all causes and standard mortality ratio (SMR). RESULTS: From the first to last 5-year period, the absolute excess risk decreased from 1.38 to 0.50 and 1.53 to 0.59 per 100 person-years among men aged 25-44 and 45-54 years, respectively. Corresponding figures for women were a decrease from 2.26 to 1.17 and from 1.93 to 1.45 per 100 person-years, respectively. Trends for women were non-linear, decreasing to the same extent as those for men until the third period, then increasing. For the last 5-year period, the standardised mortality ratio for young survivors of AMI compared with the general population was 4.34 (95% CI 3.04 to 5.87) and 2.43 (95% CI 2.12 to 2.76) for men aged 25-44 and 45-54 years, respectively, and 13.53 (95% CI 8.36 to 19.93) and 6.42 (95% CI 5.24 to 7.73) for women, respectively. Deaths not associated with cardiovascular causes increased from 21.5% to 44.6% in men and 41.5% to 65.9% in women. CONCLUSIONS: Young male survivors of AMI have low absolute long-term mortality rates, but these rates remain twofold to fourfold that of the general population. After favourable development until 2001, women now have higher absolute mortality than men and a 6 fold to 14-fold risk of death compared with women in the general population. PMID- 24793252 TI - Text messaging reminders for influenza vaccine in primary care: protocol for a cluster randomised controlled trial (TXT4FLUJAB). AB - INTRODUCTION: The UK government recommends that at least 75% of people aged under 64 with certain conditions receive an annual influenza vaccination. Primary care practices often fall short of this target and strategies to increase vaccine uptake are required. Text messaging reminders are already used in 30% of practices to remind patients about vaccination, but there has been no trial addressing their effectiveness in increasing influenza vaccine uptake in the UK. The aims of the study are (1) to develop the methodology for conducting cluster randomised trials of text messaging interventions utilising routine electronic health records and (2) to assess the effectiveness of using a text messaging influenza vaccine reminder in achieving an increase in influenza vaccine uptake in patients aged 18-64 with chronic conditions, compared with standard care. METHODS AND ANALYSIS: This cluster randomised trial will recruit general practices across three settings in English primary care (Clinical Practice Research Datalink, ResearchOne and London iPLATO text messaging software users) and randomise them to either standard care or a text messaging campaign to eligible patients. Flu vaccine uptake will be ascertained using routinely collected, anonymised electronic patient records. This protocol outlines the proposed study design and analysis methods. ETHICS AND DISSEMINATION: This study will determine the effectiveness of text messaging vaccine reminders in primary care in increasing influenza vaccine uptake, and will strengthen the methodology for using electronic health records in cluster randomised trials of text messaging interventions. This trial was approved by the Surrey Borders Ethics Committee (13/LO/0872). The trial results will be disseminated at national conferences and published in a peer-reviewed medical journal. The results will also be distributed to the Primary Care Research Network and to all participating general practices. TRIAL REGISTRATION NUMBER: This study is registered at controlled-trials.com ISRCTN48840025, July 2013. PMID- 24793253 TI - Patient-reported outcomes at hospital discharge from Heart Centres, a national cross-sectional survey with a register-based follow-up: the DenHeart study protocol. AB - INTRODUCTION: Patient reported health status, which includes symptom burden, functional status and quality of life, is an important measure of health. Differences in health status between diagnostic groups within cardiology have only been sparsely investigated. These outcomes may predict morbidity, mortality, labour market affiliation and healthcare utilisation in various diagnostic groups. A national survey aiming to include all cardiac diagnostic groups from a total Heart Centre population has been designed as the DenHeart survey. METHODS AND ANALYSIS: DenHeart is designed as a cross-sectional survey with a register based follow-up. All diagnostic groups at the five national Heart Centres are included during 1 year (15 April 2013 to 15 April 2014) and asked to fill out a questionnaire at hospital discharge. The total eligible population, both responders and non-responders, will be followed in national registers. The following instruments are used: SF-12, Hospital Anxiety and Depression Scale, EQ 5D, Brief Illness Perception Questionnaire (B-IPQ), HeartQoL and Edmonton Symptom Assessment Scale. The following variables are collected from national registers: action diagnosis, procedures, comorbidity, length of hospital stay, type of hospitalisation, visits to general practitioners and other agents in primary healthcare, dispensed prescription medication, vital status and cause of death. Labour market affiliation, sick leave, early retirement pension, educational degree and income will be collected from registers. Frequency distributions and multiple logistic regression analyses will be used to describe and assess differences in patient reported outcomes at hospital discharge between diagnostic groups and in-hospital predicting factors. Cox proportional hazards regression models with age as the time scale will be used to investigate associations between patient reported outcomes at baseline and morbidity/mortality, labour market affiliation and healthcare utilisation after 1 year. ETHICS AND DISSEMINATION: The study complies with the Declaration of Helsinki. The study has been approved by the Danish Data Protection Agency: 2007-58-0015/30-0937 and registered at ClinicalTrials.gov (NCT01926145). Study findings will be disseminated widely through peer reviewed publications and conference presentations. PMID- 24793254 TI - Rural-urban differentials in 30-day and 1-year mortality following first-ever heart failure hospitalisation in Western Australia: a population-based study using data linkage. AB - OBJECTIVES: We examined differentials in short-term (30-day mortality) and 1-year mortality (in 30-day survivors) following index (first-ever) hospitalisation for heart failure (HF), between rural and metropolitan patients resident in Western Australia. DESIGN: A population-based cohort study. SETTING: Hospitalised patients in Western Australia, Australia. PARTICIPANTS: Index patients aged 20-84 years with a first-ever hospitalisation for HF between 2000 and 2009 (with no prior admissions for HF in previous 10 years), identified using the Western Australia linked health data. MAIN OUTCOME MEASURES: 30-day and 1-year all-cause mortality (in 30-day survivors) following index admission for HF. RESULTS: Of 17 379 index patients with HF identified, 25.9% (4499) were from rural areas. Rural patients were significantly younger at first HF hospitalisation than metropolitan patients. Aboriginal patients comprised 1.9% of metropolitan and 17.2% of rural patients. Despite some statistical differences, the prevalence of antecedents including ischaemic heart disease, hypertension, diabetes and chronic kidney disease was high (>20%) in both subpopulations. After adjusting for age only, patients from rural areas had a higher risk of 30-day death (OR 1.16 (95% CI 1.01 to 1.33)) and 1-year death in 30-day survivors (HR 1.11 (95% CI 1.01 to 1.23)). These relative risk estimates increased and remained significant after further progressive adjustments for Aboriginality, socioeconomic status, insurance status, emergency presentation, individual comorbidities and revascularisation with OR 1.25 (1.06 to 1.48) for 30-day mortality and HR 1.13 (1.02 to 1.27) for 1 year mortality. The addition of the weighted Charlson index to the 30-day model improved the 'c' statistic (under the receiver operating characteristic curve) from 0.656 (using a variation of administrative claims model) to 0.714. CONCLUSIONS: Remoteness and variable access to healthcare can cause important disparities in health outcomes. Rural patients with HF in Western Australia have poorer risk-adjusted outcomes compared with metropolitan patients. This finding has important implications for chronic disease management and provision of health services in rural Australia. PMID- 24793255 TI - Scales for predicting risk following self-harm: an observational study in 32 hospitals in England. AB - OBJECTIVE: To investigate the extent to which risk scales were used for the assessment of self-harm by emergency department clinicians and mental health staff, and to examine the association between the use of a risk scale and measures of service quality and repeat self-harm within 6 months. DESIGN: Observational study. SETTING: A stratified random sample of 32 hospitals in England. PARTICIPANTS: 6442 individuals presenting with self-harm to 32 hospital services during a 3-month period between 2010 and 2011. OUTCOMES: 21-item measure of service quality, repeat self-harm within 6 months. RESULTS: A variety of different risk assessment tools were in use. Unvalidated locally developed proformas were the most commonly used instruments (reported in n=22 (68.8%) mental health services). Risk assessment scales were used in one-third of services, with the SAD PERSONS being the single most commonly used scale. There were no differences in service quality score between hospitals which did and did not use scales as a component of risk assessment (median service quality score (IQR): 14.5 (12.8, 16.4) vs 14.5 (11.4, 16.0), U=121.0, p=0.90), but hospitals which used scales had a lower median rate of repeat self-harm within 6 months (median repeat rate (IQR): 18.5% vs 22.7%, p=0.008, IRR (95% CI) 1.18 (1.00 to 1.37). When adjusted for differences in casemix, this association was attenuated (IRR=1.13, 95% CI (0.98 to 1.3)). CONCLUSIONS: There is little consensus over the best instruments for risk assessment following self-harm. Further research to evaluate the impact of scales following an episode of self-harm is warranted using prospective designs. Until then, it is likely that the indiscriminant use of risk scales in clinical services will continue. PMID- 24793256 TI - Rapid Emergency Medicine Score (REMS) in the trauma population: a retrospective study. AB - OBJECTIVE: Rapid Emergency Medicine Score (REMS) is an attenuated version of the Acute Physiology and Chronic Health Evaluation (APACHE) II score and has utility in predicting mortality in non-surgical patients, but has yet to be tested among the trauma population. The objective was to evaluate REMS as a risk stratification tool for predicting in-hospital mortality in traumatically injured patients and to compare REMS accuracy in predicting mortality to existing trauma scores, including the Revised Trauma Score (RTS), Injury Severity Score (ISS) and Shock Index (SI). DESIGN AND SETTING: Retrospective chart review of the trauma registry from an urban academic American College of Surgeons (ACS) level 1 trauma centre. PARTICIPANTS: 3680 patients with trauma aged 14 years and older admitted to the hospital over a 4-year period. Patients transferred from other hospitals were excluded from the study as were those who suffered from burn or drowning related injuries. Patients with vital sign documentation insufficient to calculate an REMS score were also excluded. PRIMARY OUTCOME MEASURES: The predictive ability of REMS was evaluated using ORs for in-hospital mortality. The discriminate power of REMS, RTS, ISS and SI was compared using the area under the receiver operating characteristic curve. RESULTS: Higher REMS was associated with increased mortality (p<0.0001). An increase of 1 point in the 26-point REMS scale was associated with an OR of 1.51 for in-hospital death (95% CI 1.45 to 1.58). REMS (area under the curve (AUC) 0.91+/-0.02) was found to be similar to RTS (AUC 0.89+/-0.04) and superior to ISS (AUC 0.87+/-0.01) and SI (AUC 0.55+/-0.31) in predicting in-hospital mortality. CONCLUSIONS: In the trauma population, REMS appears to be a simple, accurate predictor of in-hospital mortality. While REMS performed similarly to RTS in predicting mortality, it did outperform other traditionally used trauma scoring systems, specifically ISS and SI. PMID- 24793257 TI - Acupuncture, counselling or usual care for depression and comorbid pain: secondary analysis of a randomised controlled trial. AB - BACKGROUND: Depression with comorbid pain is associated with a poor response to various treatments. The objective in this secondary analysis was to determine whether patients reporting pain have different depression and pain outcomes over time in response to acupuncture, counselling or usual care. METHODS: Self reported ratings of depression and pain from 755 patients in a pragmatic randomised controlled trial of acupuncture (302) or counselling (302) compared to usual care alone (151) are described and analysed using a series of regression models and analysis of covariance. Patient-reported outcomes of Patient Health Questionnaire (PHQ)-9 for depression, SF36 bodily pain and EQ-5D, all at baseline, 3, 6, 9 and 12 months. RESULTS: At baseline, 755 patients reported EQ 5D pain categories; 384 (50.9%) reported moderate-to-extreme pain. Controlling for baseline depression, a linear regression model showed that the presence of pain at baseline was associated with poorer depression outcomes at 3 months mean difference=-1.16, (95% CI 0.12 to 2.2). Participants with moderate-to-extreme pain at baseline did better at 3 months if they received acupuncture (mean reduction in Patient Health Questionnaire 9 (PHQ-9) from baseline=6.0, 95% CI 5.0 to 7.1 and a mean reduction in SF-36 bodily pain=11.2, (95% CI 7.1 to 15.2) compared to improvements for those who received counselling (4.3, 95% CI 3.3 to 5.4; 7.6, 95% CI 3.6 to 11.6) or usual care (2.7, 95% CI 1.50 to 4.0: 7.2, 95% CI 2.3 to 12.1). In comparison, no notable differences were seen between treatment arms within the no pain comparator group. CONCLUSIONS: Patients with depression and pain at baseline recovered less well from treatment over 3 months than those with depression and no pain. Reductions in both depression and pain were most marked in the acupuncture group, followed by the counselling group and then the usual care group. PMID- 24793258 TI - Scottish adolescents' sun-related behaviours, tanning attitudes and associations with skin cancer awareness: a cross-sectional study. AB - OBJECTIVES: To describe Scottish adolescents' sun-related behaviours and tanning attitudes and assess associations with skin cancer awareness. DESIGN: Cross sectional study. SETTING: 20 state secondary schools in one Scottish local authority (Glasgow City). PARTICIPANTS: 2173 adolescents (females: 50.7%, n=1102) with a mean age of 12.4 (SD=0.55). OUTCOME MEASURES: Sun-related behaviour (suntan, sunbathing, sunburn, sunscreen use, sunbed use), tanning attitudes, skin cancer-related symptom and risk factor awareness. RESULTS: Adolescents reported poor sun-related practice: 51% of adolescents reported sunburn the previous summer of whom 38% indicated sunburn on more than one occasion. Skin cancer awareness was low: 45% recognised 'change in the appearance of a mole' as a cancer symptom, and 39% agreed that 'getting sunburnt more than once as a child' increased cancer risk. 42% and 26% of adolescents, respectively, reported that friends and family held protanning attitudes. Compared with males, females were statistically significantly more likely to: report sunbathing (p<0.001), use of lotions or oil to aid tanning (p=0.009) and sunburn (p<0.001); know that changes in the appearance of a mole was a skin cancer symptom (p=0.036) and sunburn more than once as a child was a skin cancer risk factor (p=0.005); perceive their friends to hold protanning attitudes (p<0.001) and indicate that a tan made them feel better about themselves (p<0.001), more attractive to others (p=0.011) and healthier (p<0.001). CONCLUSIONS: Scottish adolescents had poor sun protection practice and low skin cancer awareness. Girls adopted riskier sun-related behaviour despite greater awareness of skin cancer-related risk. Urgent action is required to promote positive sun-related behaviour and increase skin cancer awareness among Scottish adolescents. However, further research is needed to inform the development of effective sun-safe interventions. PMID- 24793259 TI - Engaging the public in healthcare decision-making: quantifying preferences for healthcare through citizens' juries. AB - INTRODUCTION: The optimal approach to engage the public in healthcare decision making is unclear. Approaches range from deliberative citizens' juries to large population surveys using discrete choice experiments. This study promotes public engagement and quantifies preferences in two key areas of relevance to the industry partners to identify which approach is most informative for informing healthcare policy. METHODS AND ANALYSIS: The key areas identified are optimising appropriate use of emergency care and prioritising patients for bariatric surgery. Three citizens' juries will be undertaken-two in Queensland to address each key issue and one in Adelaide to repeat the bariatric surgery deliberations with a different sample. Jurors will be given a choice experiment before the jury, immediately following the jury and at approximately 1 month following the jury. Control groups for each jury will be given the choice experiment at the same time points to test for convergence. Samples of healthcare decision-makers will be given the choice experiment as will two large samples of the population. Jury and control group participants will be recruited from the Queensland electoral roll and newspaper advertisements in Adelaide. Population samples will be recruited from a large research panel. Jury processes will be analysed qualitatively and choice experiments will be analysed using multinomial logit models and its more generalised forms. Comparisons between preferences across jurors predeliberation and postdeliberation, control participants, healthcare decision-makers and the general public will be undertaken for each key issue. ETHICS AND DISSEMINATION: The study is approved by Griffith University Human Research Ethics Committee (MED/10/12/HREC). Findings of the juries and the choice experiments will be reported at a workshop of stakeholders to be held in 2015, in reports and in peer reviewed journals. PMID- 24793260 TI - Vanadium pentoxide: risk assessment implications of a treatment- but not dose related tumorigenic response in B6C3F1 mice. AB - The US Environmental Protection Agency (USEPA) is currently conducting a toxicological review of vanadium pentoxide (V2O5). As part of that effort, the Agency will need to address the fact that while a National Toxicology Program (NTP) chronic inhalation bioassay of V2O5 produced clear evidence of treatment related lung tumors in both male and female B6C3F1 mice, neither of these responses were dose-related across the groups exposed to 1, 2, and 4mg/m(3). While lung tumor incidence was significantly elevated in all three exposed groups relative to that in the control groups, it was essentially flat across them. Herein we report results from computing poly-3-adjusted Cochran-Armitage trend test statistics with and without inclusion of the lung tumor incidence data from control group mice. These results confirm the absence of any significant dose related effect on mouse lung tumor incidence in the study groups exposed to V2O5. We also considered two estimates of area under the vanadium lung burden versus time curve as plausible alternative dose metrics to the V2O5 chamber concentration. However, these alternative dose metrics were so highly correlated with the V2O5 chamber concentration (r=0.998) that nothing is to be gained from their use in place of the V2O5 chamber concentration in attempts to perform dose response modeling of the tumor incidence or unit cancer risk computations. At the present time, there is no scientific basis to support linear (or nonlinear) extrapolations of estimated cancer risks to V2O5 exposure levels below 1mg/m(3). Additional tumor data at multiple V2O5 concentrations lower than 1mg/m(3) are required to support such extrapolations. PMID- 24793261 TI - Identification of non-regulated aromatic amines of toxicological concern which can be cleaved from azo dyes used in clothing textiles. AB - Azo dyes in textiles may release aromatic amines after enzymatic cleavage by skin bacteria or after dermal absorption and metabolism in the human body. From the 896 azo dyes with known chemical structure in the available textile dyes database, 426 azo dyes (48%) can generate one or more of the 22 regulated aromatic amines in the European Union in Annex XVII of REACH. Another 470 azo dyes (52%) can be cleaved into exclusively non-regulated aromatic amines. In this study, a search for publicly available toxicity data on non-regulated aromatic amines was performed. For a considerable percentage of non-regulated aromatic amines, the toxicity database was found to be insufficient or non-existent. 62 non-regulated aromatic amines with available toxicity data were prioritized by expert judgment with objective criteria according to their potential for carcinogenicity, genotoxicity, and/or skin sensitization. To investigate the occurrence of azo dye cleavage products, 153 random samples of clothing textiles were taken from Swiss retail outlets and analyzed for 22 high priority non regulated aromatic amines of toxicological concern. Eight of these 22 non regulated aromatic amines of concern could be detected in 17% of the textile samples. In 9% of the samples, one or more of the aromatic amines of concern could be detected in concentrations >30 mg/kg, in 8% of the samples between 5 and 30 mg/kg. The highest measured concentration was 622 mg/kg textile. There is an obvious need to assess consumer health risks for these non-regulated aromatic amines and to fill this gap in the regulation of clothing textiles. PMID- 24793262 TI - The ex-vivo intestinal absorption rate of uranium is a two-phase function of supply. AB - The concentration-dependent absorption behaviour of uranium was investigated with surviving intestinal segments of rat jejunums, using an ex-vivo model. The results showed a monotonic slightly nonlinear increase in absorption as uranium concentrations increased. This trend was observed over the entire concentration range tested. In the lower concentration range a slower linear ascent was observed while a steeper linear ascent was found for the higher concentration range. Statistical fit was only slightly poorer for an exponential function in the range of lower values and a logarithmic function in the range of higher values. The proportion of uranium absorbed expressed as percent of uranium concentrations in the perfusion solutions followed a monotonically increasing trend from 20 to around 200 MUg/l uranium in the perfusion solutions, which thereafter appears to reach a plateau, as further increase towards concentrations around 400 MUg/l is not substantial. The uranium concentration administered had no effect on the vitality and consequently the functionality of the intestinal segments, measured in terms of active glucose transport. The results imply that uranium concentrations of more than 20 MUg/l in drinking water, for example, could lead to elevated absorption rates and thus to higher internal exposures to consider when setting of Guideline values in this concentration range. PMID- 24793263 TI - Health assessment of gasoline and fuel oxygenate vapors: immunotoxicity evaluation. AB - Female Sprague Dawley rats were exposed via inhalation to vapor condensates of either gasoline or gasoline combined with various fuel oxygenates to assess potential immunotoxicity of evaporative emissions. Test articles included vapor condensates prepared from "baseline gasoline" (BGVC), or gasoline combined with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA). Target concentrations were 0, 2000, 10,000 or 20,000mg/mg(3) administered for 6h/day, 5days/week for 4weeks. The antibody-forming cell (AFC) response to the T-dependent antigen, sheep erythrocyte (sRBC), was used to determine the effects of the gasoline vapor condensates on the humoral components of the immune system. Exposure to BGVC, G/MTBE, G/TAME, and G/TBA did not result in significant changes in the IgM AFC response to sRBC, when evaluated as either specific activity (AFC/10(6) spleen cells) or as total spleen activity (AFC/spleen). Exposure to G/EtOH and G/DIPE resulted in a dose-dependent decrease in the AFC response, reaching the level of statistical significance only at the high 20,000mg/m(3) level. Exposure to G/ETBE resulted in a statistically significant decrease in the AFC response at the middle (10,000mg/m(3)) and high (20,000mg/m(3)) exposure concentrations. PMID- 24793264 TI - Aminoadamantanes for chronic hepatitis C. AB - BACKGROUND: Around 3% of the world's population (approximately 160 million people) are chronically infected with hepatitis C virus. The proportion of infected people who develop clinical symptoms varies between 5% and 40%. Combination therapy with pegylated interferon-alpha plus ribavirin eradicates the virus from the blood six months after treatment (sustained virological response) in approximately 40% to 80% of infected patients, depending on the viral genotype. New antiviral agents, such as boceprevir and telaprevir, in combination with standard therapy, can increase sustained virological response in genotype 1 infected patients to at least 70%. There is therefore an unmet need for drugs that can achieve a higher proportion of sustained virological response. Aminoadamantanes are antiviral drugs used for treatment of patients with chronic hepatitis C. OBJECTIVES: To assess the beneficial and harmful effects of aminoadamantanes for patients with chronic hepatitis C infection by conducting a systematic review with meta-analyses of randomised clinical trials, as well as trial sequential analyses. SEARCH METHODS: We conducted electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 11 of 12 (1995 to December 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013 and checked the reference lists of identified publications. SELECTION CRITERIA: Randomised clinical trials assessing aminoadamantanes in patients with chronic hepatitis C infection. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. We assessed for risks of systematic errors ('bias') using the 'Risk of bias' tool. We analysed dichotomous data with risk ratio (RR) and continuous data with mean difference (MD) or standardised mean difference (SMD), both with 95% confidence intervals (CI). We used trial sequential analysis to assess the risk of random errors ('play of chance'). We assessed quality using the GRADE system. MAIN RESULTS: We included 41 randomised clinical trials with 6193 patients with chronic hepatitis C. All trials had high risk of bias. All included trials compared amantadine versus placebo or no intervention. Standard antiviral therapy was administered equally to the intervention and the control groups in 40 trials. The standard antiviral therapy, which was administered to both intervention groups, was interferon alpha, interferon-alpha plus ribavirin, and peg interferon-alpha plus ribavirin, depending on the time when the trial was conducted.When we meta-analysed all trials together, the overall results demonstrated no significant effects of amantadine, when compared with placebo or no intervention, on our all-cause mortality or liver-related morbidity composite outcome (5/2353 (0.2%) versus 6/2264 (0.3%); RR 0.90, 95% CI 0.38 to 2.17; I2 = 0%; 32 trials; very low quality). There was also no significant effect on adverse events (288/2869 (10%) versus 293/2777 (11%); RR 0.98, 95% CI 0.84 to 1.14; I2 = 0%; 35 trials; moderate quality). We used both fixed-effect and random-effects meta-analyses. Amantadine, when compared with placebo or no intervention, did not significantly influence the number of patients who failed to achieve a sustained virological response (1821/2861 (64%) versus 1737/2721 (64%); RR 0.98, 95% CI 0.95 to 1.02; I2 = 35%; 35 trials; moderate quality). However, in the subgroup using interferon plus ribavirin, amantadine decreased the number of patients who failed to achieve a sustained virological response (422/666 (63%) versus 447/628 (71%); RR 0.89, 95% CI 0.83 to 0.96; I2 = 41%; 11 trials; low quality). Similar results were found for failure to achieve an end of treatment virological response. Amantadine, when compared with placebo or no intervention, significantly decreased the number of patients without normalisation of alanine aminotransferase (ALT) serum levels at the end of treatment (671/1141 (59%) versus 732/1100 (67%); RR 0.88, 95% CI 0.83 to 0.94; I2 = 47%; 19 trials; low quality). Amantadine, when compared with placebo or no intervention, did not significantly influence the end of follow-up biochemical response (1133/1896 (60%) versus 1151/1848 (62%); RR 0.95, 95% CI 0.91 to 1.00; I2 = 49%; 21 trials; low quality).The observed beneficial effects could be true effects but could also be due to both systematic errors (bias) and random errors (play of chance). The latter is due to the fact that trial sequential analyses could not confirm or refute our findings. We were not able to perform meta-analyses for failure of histological improvement or quality of life due to a lack of valid data. AUTHORS' CONCLUSIONS: This systematic review does not demonstrate any significant effects of amantadine on all-cause mortality or liver-related morbidity composite outcome and on adverse events in patients with hepatitis C; however, the median trial duration was 12 months, with a median follow-up of six months, which is not long enough to assess the composite outcome sufficiently. Overall, we did not see an effect of amantadine on failure to achieve a sustained virological response. Subgroup analyses demonstrated that the combination of amantadine plus interferon-alpha and ribavirin seems to increase the number of patients achieving a sustained virological response. This finding may be caused by both systematic errors (bias) and risks of random errors (play of chance), but it could also be real. Based on the results of the overall evidence, it appears less likely that future trials assessing amantadine for patients with chronic hepatitis C will show strong benefits. Therefore, it is probably advisable to wait for the results of trials assessing other direct acting antiviral drugs. In the absence of convincing evidence of benefit, the use of amantadine is justified in the context of randomised clinical trials assessing the effects of combination therapy. We found a lack of evidence on other aminoadamantanes than amantadine. PMID- 24793288 TI - Whole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts. AB - A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders. PMID- 24793289 TI - Pleiotropic mutations are subject to strong stabilizing selection. AB - The assumption that pleiotropic mutations are more deleterious than mutations with more restricted phenotypic effects is an important premise in models of evolution. However, empirical evidence supporting this assumption is limited. Here, we estimated the strength of stabilizing selection on mutations affecting gene expression in male Drosophila serrata. We estimated the mutational variance (VM) and the standing genetic variance (VG) from two well-matched panels of inbred lines: a panel of mutation accumulation (MA) lines derived from a single inbred ancestral line and a panel of inbred lines derived from an outbred population. For 855 gene-expression traits, we estimated the strength of stabilizing selection as s = VM/VG. Selection was observed to be relatively strong, with 17% of traits having s > 0.02, a magnitude typically associated with life-history traits. Randomly assigning expression traits to five-trait sets, we used factor analytic mixed modeling in the MA data set to identify covarying traits that shared pleiotropic mutations. By assigning traits to the same trait sets in the outbred line data set, we then estimated s for the combination of traits affected by pleiotropic mutation. For these pleiotropic combinations, the median s was three times greater than s acting on the individual component traits, and 46% of the pleiotropic trait combinations had s > 0.02. Although our analytical approach was biased toward detecting mutations with relatively large effects, likely overestimating the average strength of selection, our results provide widespread support for the prediction that stronger selection can act against mutations with pleiotropic effects. PMID- 24793290 TI - Regulation of sex determination in mice by a non-coding genomic region. AB - To identify novel genomic regions that regulate sex determination, we utilized the powerful C57BL/6J-Y(POS) (B6-Y(POS)) model of XY sex reversal where mice with autosomes from the B6 strain and a Y chromosome from a wild-derived strain, Mus domesticus poschiavinus (Y(POS)), show complete sex reversal. In B6-Y(POS), the presence of a 55-Mb congenic region on chromosome 11 protects from sex reversal in a dose-dependent manner. Using mouse genetic backcross designs and high density SNP arrays, we narrowed the congenic region to a 1.62-Mb genomic region on chromosome 11 that confers 80% protection from B6-Y(POS) sex reversal when one copy is present and complete protection when two copies are present. It was previously believed that the protective congenic region originated from the 129S1/SviMJ (129) strain. However, genomic analysis revealed that this region is not derived from 129 and most likely is derived from the semi-inbred strain POSA. We show that the small 1.62-Mb congenic region that protects against B6-Y(POS) sex reversal is located within the Sox9 promoter and promotes the expression of Sox9, thereby driving testis development within the B6-Y(POS) background. Through 30 years of backcrossing, this congenic region was maintained, as it promoted male sex determination and fertility despite the female-promoting B6-Y(POS) genetic background. Our findings demonstrate that long-range enhancer regions are critical to developmental processes and can be used to identify the complex interplay between genome variants, epigenetics, and developmental gene regulation. PMID- 24793292 TI - Quantitative risk assessment integrated with process simulator for a new technology of methanol production plant using recycled CO2. AB - The use of process simulators can contribute with quantitative risk assessment (QRA) by minimizing expert time and large volume of data, being mandatory in the case of a future plant. This work illustrates the advantages of this association by integrating UNISIM DESIGN simulation and QRA to investigate the acceptability of a new technology of a Methanol Production Plant in a region. The simulated process was based on the hydrogenation of chemically sequestered carbon dioxide, demanding stringent operational conditions (high pressures and temperatures) and involving the production of hazardous materials. The estimation of the consequences was performed using the PHAST software, version 6.51. QRA results were expressed in terms of individual and social risks. Compared to existing tolerance levels, the risks were considered tolerable in nominal conditions of operation of the plant. The use of the simulator in association with the QRA also allowed testing the risk in new operating conditions in order to delimit safe regions for the plant. PMID- 24793293 TI - Bt-transgenic cotton is more sensitive to CeO2 nanoparticles than its parental non-transgenic cotton. AB - Because genetically modified crops are developing widely in the world while nanoparticles (NPs) are being synthesized and applied in various fields, they will have many opportunities for interactions in the future. The effects of NPs on genetically modified crops therefore require investigation. In the present study, CeO2 NPs were revealed to have toxic effects on root biomass of Bt 29317 at 100 and 500 mg L(-1), but had no toxic effects on Jihe 321. Besides, we also studied the effects of CeO2 NPs on nutrient element uptake in transgenic cotton, and found that contents of most nutrient elements (Fe, Ca, Mg, Zn and Na) in roots of Bt 29317 were affected at lower NP concentrations (100 mg L(-1)) compared with Jihe 321. In addition, ICP-MS analysis revealed that CeO2 NPs were more heavily adsorbed by roots of Bt 29317 than Jihe 321, whereas fewer CeO2 NPs were transported from roots to shoots of Bt 29317 than its non-transgenic counterpart. These data confirm that Bt 29317 is more sensitive to CeO2 NPs than its parental non-transgenic cotton, indicating that nanomaterials are potentially more detrimental to transgenic plants than conventional ones. PMID- 24793291 TI - Sex-biased gene expression and evolution of the x chromosome in nematodes. AB - Studies of X chromosome evolution in various organisms have indicated that sex biased genes are nonrandomly distributed between the X and autosomes. Here, to extend these studies to nematodes, we annotated and analyzed X chromosome gene content in four Caenorhabditis species and in Pristionchus pacificus. Our gene expression analyses comparing young adult male and female mRNA-seq data indicate that, in general, nematode X chromosomes are enriched for genes with high female biased expression and depleted of genes with high male-biased expression. Genes with low sex-biased expression do not show the same trend of X chromosome enrichment and depletion. Combined with the observation that highly sex-biased genes are primarily expressed in the gonad, differential distribution of sex biased genes reflects differences in evolutionary pressures linked to tissue specific regulation of X chromosome transcription. Our data also indicate that X dosage imbalance between males (XO) and females (XX) is influential in shaping both expression and gene content of the X chromosome. Predicted upregulation of the single male X to match autosomal transcription (Ohno's hypothesis) is supported by our observation that overall transcript levels from the X and autosomes are similar for highly expressed genes. However, comparison of differentially located one-to-one orthologs between C. elegans and P. pacificus indicates lower expression of X-linked orthologs, arguing against X upregulation. These contradicting observations may be reconciled if X upregulation is not a global mechanism but instead acts locally on a subset of tissues and X-linked genes that are dosage sensitive. PMID- 24793294 TI - The role of the anion in the toxicity of imidazolium ionic liquids. AB - From the environmental protection point of view, the growing interest of ionic liquids in various industrial branches has raised concerns for the toxicity assessment of these compounds. The paper discusses the effect of salts containing the shared 1-ethyl-3-methylimidazolium [EMIM] cation as coupled with five different anions: bromide [Br], nitrate [NO3], p-toluenesulfonate (tosylate) [Ts], dimethylphosphate [dMP] and methanesulfonate [MS] on the growth and development of higher land plants - spring barley and common radish. The experiment was done according to the ISO Standard 11269-2:1995 and the OECD/OCDE Guide 208/2006. As the indications of phytotoxicity, the percentage of sprouts and the level of dry and fresh plant mass were used; in addition, the visual assessment of any signs of damage to the examined plant species, such as growth inhibition and chlorotic changes, was also made. Results of our study has proved the negative impact of ILs on the tested plants and the toxic effect of imidazolium salts was dependent primarily on the applied ionic liquids concentration. The common radish revealed the higher tolerance to the imidazolium as compared to spring barley. The anion type of ionic liquid was crucial for the toxicity against common radish. PMID- 24793295 TI - Reduction of acute toxicity and genotoxicity of dye effluent using Fenton coagulation process. AB - Dye wastewater exhibits significant ecotoxicity even though its physico-chemical parameters meet the discharge standards. In this work, the acute toxicity and genotoxicity of dye effluent were tested, and the Fenton-coagulation process was carried out to detoxify this dye effluent. The acute toxicity was evaluated according to the mortality rate of zebrafish, and genotoxicity was evaluated by micronucleus (MN) and comet assays. Removal of color and chemical oxygen demand (COD) was also investigated. The results indicated that the dye effluent showed strong acute toxicity and genotoxicity to zebrafish. After 4h of treatment by Fenton-coagulation process, the dye effluent exhibited no significant acute toxicity and genotoxicity to zebrafish. In addition, its COD was less than 50mg/L, which met the discharge standard. It demonstrates that Fenton-coagulation process can comprehensively reduce the acute toxicity and genotoxicity as well as the COD of the dye effluent. PMID- 24793296 TI - Sorption performance and mechanism of a sludge-derived char as porous carbon based hybrid adsorbent for benzene derivatives in aqueous solution. AB - A porous sludge-derived char was prepared by a new one-step pyrolytic process with citric acid-ZnCl2 mixed fabricating-pore agents. The sludge-derived char was confirmed to be a hierarchically porous hybrid adsorbent containing-elemental carbon, -highly carbonized organic species and -inorganic ash with a great surface area of 792.4m(2)g(-1). It was used as a carbon-based hybrid adsorbent for four benzene derivatives including 4-chlorophenol, phenol, benzoic acid and 4 hydroxylbenzoic acid in aqueous solution. Results showed that their sorption isotherms were nonlinear at low concentrations and linear at high concentrations. The sorption performance could be described by a multiple sorption model (QT=QA+KPCe). The order of these partition sorption coefficients (KP) of these benzene derivatives was consistent with their octanol-water partition coefficients (logKow), but those saturated amounts (QA) were inconsistent with their logKow. The inconstancy was found to be considerably dependent on the preferential interaction of benzoic acid with SiO2 in the sludge-derived char. Quantum theoretical calculation confirmed that the preferential interaction was attributed to the formation of hydrogen bonds (1.61 and 1.69A) and new Si-O bonds (1.83 and 1.87A) between the carboxyl of benzoic acid and the SiO2 surface in the sorption process. PMID- 24793297 TI - Lipid peroxidation and cytotoxicity induced by respirable volcanic ash. AB - This paper reports that the main component of respirable volcanic ash, allophane, induces lipid peroxidation (LP), the oxidative degradation of lipids in cell membranes, and cytotoxicity in murin monocyle/macrophage cells. Naturally occurring allophane collected from New Zealand, Japan, and Ecuador was studied. The quantification of LP was conducted using the Thiobarbituric Acid Reactive Substances (TBARS) assay. The cytotoxic effect was determined by the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide colorimetric assay. Electron-Paramagnetic Resonance (EPR) determinations of naturally-occurring allophane confirmed the incorporation in the structure and clustering of structural Fe(3+), and nucleation and growth of small-sized Fe (oxyhydr)oxide or gibbsite. LP induced by allophane varied with time, and solid concentration and composition, reaching 6.7 +/- 0.2 nmol TBARS mg prot(-1). LP was surface controlled but not restricted by structural or surface-bound Fe(3+), because redox processes induced by soluble components other than perferryl iron. The reactivity of Fe(3+) soluble species stemming from surface-bound Fe(3+) or small sized Fe(3+) refractory minerals in allophane surpassed that of structural Fe(3+) located in tetrahedral or octahedral sites of phyllosilicates or bulk iron oxides. Desferrioxamine B mesylate salt (DFOB) or ethylenediaminetetraacetic acid (EDTA) inhibited LP. EDTA acted as a more effective inhibitor, explained by multiple electron transfer pathways. Registered cell-viability values were as low as 68.5 +/- 6.7%. PMID- 24793298 TI - Oxidation of sulfamethoxazole (SMX) by chlorine, ozone and permanganate--a comparative study. AB - Sulfamethoxazole (SMX), a typical sulfonamide antibiotic, has been widely detected in secondary wastewater effluents and surface waters. In this work we investigated the oxidative degradation of SMX by commonly used oxidants of chlorine, ozone and permanganate. Chlorine and ozone were shown to be more effective for the removal of SMX (0.05-5.0mg/L), as compared with permanganate. Higher pH enhanced the oxidation of SMX by ozone and permanganate, but decreased the removal by chlorine. Moreover, the ozonation of SMX was significantly influenced by the presence of humic acid (HA), which exhibited negligible influence on the oxidation by chlorine and permanganate. Fairly lower mineralization of SMX occurred during the oxidation reactions, with the highest dissolved organic carbon (DOC) removal of 13% (for ozone). By using LC-MS/MS, 7, 5 and 5 oxidation products were identified for chlorine, ozone and permanganate and possible transformation pathways were proposed. It was shown that different oxidants shared some common pathways, such as the cleavage of SN bond, the hydroxylation of the benzene ring, etc. On the other hand, each of the oxidants also exhibited exclusive degradation mechanisms, leading to the formation of different transformation products (TPs). This work may provide useful information for the selection of oxidants in water treatment processes. PMID- 24793299 TI - Performance assessment and hydrodynamic analysis of a submerged membrane bioreactor for treating dairy industrial effluent. AB - Submerged membrane bioreactor (SMBR) is a relatively advanced technology for waste water treatment that involves integrated aerobic and anaerobic biological processes with membrane filtration. In the present investigation, hydrophobic polyvinylidene fluoride (PVDF) and hydrophilic polyacrylonitrile (PAN) hollow fiber (HF) membranes were tested in an indigenously fabricated SMBR for dairy effluent treatment under aerobic conditions using mixed microbial consortia. Effect of operating parameters such as suction pressure, degree of aeration and trans-membrane pressure (TMP) on membrane performance in terms of flux, rejection of turbidity, BOD and COD besides fouling characteristics was investigated. The observed optimum permeabilities of PVDF and PAN HF membranes were approximately 108 and 115 LMH bar(-1) with high extent of impurity removal. The rejection of COD was found to be 93% for PVDF and 91% for PAN HF membranes whereas corresponding rejection of BOD was observed to be 92% and 86%. A two-dimensional comprehensive model was developed to predict the hydrodynamic profile inside the module. Regression analysis revealed that the simulation results agreed well with experimental data. PMID- 24793300 TI - Endometrial expression of progesterone, estrogen, and oxytocin receptors and of 20alpha-hydroxysteroid dehydrogenase and cyclooxygenase II 2 and 5 days after ovulation in induced short and normal estrous cycles in dairy cows. AB - The aim of this study was to investigate causes of the short estrous cycles that occur frequently in dairy cows after estrus synchronization using PGF2alpha and GnRH. Expression of oxytocin receptor (OR), progesterone receptor (PR), and estrogen receptor (ER); of cyclo-oxygenase II (COX-II) and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD); and of peripheral blood estradiol-17beta and progesterone (P4) concentrations were analyzed in estrous cycles of normal length and in induced short estrous cycles. On Day 8 (ovulation = Day 0), presynchronized dairy cows (n = 14) were given 0.15 mg of dexcloprostenol and 0.1 mg of gonadorelin 24 hours later. Animals were bled once daily for P4 and estradiol-17beta analyses, and endometrial biopsy specimens were taken on Days 2 and 5 for PR, ER, OR, 20alpha-HSD, and COX-II determinations with immunohistochemistry and/or real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Ovulations and ovarian structures were monitored with transrectal ultrasound daily until the next ovulation. After excluding one case of incomplete luteal regression, short estrous cycles occurred in 8 of 13 cases (length from 8 to 12 days). No differences were established in endometrial ER, PR, or COX-II expression between the normal and short cycle groups in the semi-quantitative immunohistochemistry analysis. In qRT-PCR analysis, no differences were found in relative gene expression of endometrial ER, PR, OR, 20alpha-HSD, or COX-II between normal and short cycles. Despite evidence from previous studies that short estrous cycles are induced by premature prostaglandin release, differences in these receptors or in enzyme expression do not explain the release. PMID- 24793302 TI - 5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19. AB - The 5-HT1A receptor is a G protein coupled receptor (GPCR) that activates G proteins of the Galphai/o family. 5-HT1A receptors expressed in the raphe, hippocampus and prefrontal cortex are implicated in the control of mood and are targets for anti-depressant drugs. Regulators of G protein signaling (RGS) proteins are members of a large family that play important roles in signal transduction downstream of G protein coupled receptors (GPCRs). The main role of RGS proteins is to act as GTPase accelerating proteins (GAPs) to dampen or negatively regulate GPCR-mediated signaling. We have shown that a mouse expressing Galphai2 that is insensitive to all RGS protein GAP activity has an anti-depressant-like phenotype due to increased signaling of postsynaptic 5-HT1A receptors, thus implicating the 5-HT1A receptor-Galphai2 complex as an important target. Here we confirm that RGS proteins act as GAPs to regulate signaling to adenylate cyclase and the mitogen-activated protein kinase (MAPK) pathway downstream of the 5-HT1A receptor, using RGS-insensitive Galphai2 protein expressed in C6 cells. We go on to use short hairpin RNA (shRNA) to show that RGS19 is responsible for the GAP activity in C6 cells and also that RGS19 acts as a GAP for 5-HT1A receptor signaling in human neuroblastoma SH-SY5Y cells and primary hippocampal neurons. In addition, in both cell types the synergy between 5-HT1A receptor and the fibroblast growth factor receptor 1 in stimulating the MAPK pathway is enhanced following shRNA reduction of RGS19 expression. Thus RGS19 may be a viable new target for anti-depressant medications. PMID- 24793303 TI - Requirement for lysosomal localization of mTOR for its activation differs between leucine and other amino acids. AB - The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and metabolism. It controls many cell functions by integrating nutrient availability and growth factor signals. Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. The current model for the regulation of mTORC1 by amino acids involves the movement of mTOR to the lysosome mediated by the Rag-GTPases. Here, we have examined the control of mTORC1 signaling and mTOR localization by amino acids and leucine in serum-fed cells, because both serum growth factors (or, e.g., insulin) and amino acids are required for full activation of mTORC1 signaling. We demonstrate that mTORC1 activity does not closely correlate with the lysosomal localization of mTOR. In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Furthermore, data from cells where Rag expression has been knocked down revealed that leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR. Our data complement existing models for the regulation of mTORC1 by amino acids and provide new insights into this important topic. PMID- 24793304 TI - Emerging drugs for neuropathic pain. AB - INTRODUCTION: Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation. AREAS COVERED: A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, alpha-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor. EXPERT OPINION: Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain. PMID- 24793305 TI - On the roles of graphene oxide doping for enhanced supercurrent in MgB2 based superconductors. AB - Due to their graphene-like properties after oxygen reduction, incorporation of graphene oxide (GO) sheets into correlated-electron materials offers a new pathway for tailoring their properties. Fabricating GO nanocomposites with polycrystalline MgB2 superconductors leads to an order of magnitude enhancement of the supercurrent at 5 K/8 T and 20 K/4 T. Herein, we introduce a novel experimental approach to overcome the formidable challenge of performing quantitative microscopy and microanalysis of such composites, so as to unveil how GO doping influences the structure and hence the material properties. Atom probe microscopy and electron microscopy were used to directly image the GO within the MgB2, and we combined these data with computational simulations to derive the property-enhancing mechanisms. Our results reveal synergetic effects of GO, namely, via localized atomic (carbon and oxygen) doping as well as texturing of the crystals, which provide both inter- and intra-granular flux pinning. This study opens up new insights into how low-dimensional nanostructures can be integrated into composites to modify the overall properties, using a methodology amenable to a wide range of applications. PMID- 24793301 TI - Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. AB - The metabotropic glutamate (mGlu) receptors are a group of Class C seven transmembrane spanning/G protein-coupled receptors (7TMRs/GPCRs). These receptors are activated by glutamate, one of the standard amino acids and the major excitatory neurotransmitter. By activating G protein-dependent and non-G protein dependent signaling pathways, mGlus modulate glutamatergic transmission both in the periphery and throughout the central nervous system. Since the discovery of the first mGlu receptor, and especially during the last decade, a great deal of progress has been made in understanding the signaling, structure, pharmacological manipulation and therapeutic indications of the 8 mGlu members. PMID- 24793306 TI - Ligand-independent androgen receptors promote ovarian teratocarcinoma cell growth by stimulating self-renewal of cancer stem/progenitor cells. AB - BACKGROUND: Ovarian teratocarcinoma (OVTC) arises from germ cells and contains a high percentage of cancer stem/progenitor cells (CSPCs), which promote cancer development through their ability to self-renew. Androgen and androgen receptor (androgen/AR) signaling has been reported to participate in cancer stemness in some types of cancer; however, this phenomenon has never been studied in OVTC. METHODS: Ovarian teratocarcinoma cell line PA1 was manipulated to overexpress or knockdown AR by lentiviral deliver system. After analyzing of AR expression in PA1 cells, cell growth assay was assessed at every given time point. In order to determine ligand effect on AR actions, luciferase assay was performed to evaluate endogenous and exogenous AR function in PA1 cells. CD133 stem cell marker antibody was used to identify CSPCs in PA1 cells, and AR expression level in enriched CSPCs was determined. To assess AR effects on CD133+ population progression, stem cell functional assays (side population, sphere formation assay, CD133 expression) were used to analyze role of AR in PA1 CSPCs. In tissue specimen, immunohistochemistry staining was used to carry out AR and CD133 staining in normal and tumor tissue. RESULTS: We examined androgen/AR signaling in OVTC PA1 cells, a CSPCs-rich cell line, and found that AR, but not androgen, promoted cell growth. We also examined the effects of AR on CSPCs characteristics and found that AR expression was more abundant in CD133+ cells, a well-defined ovarian cancer stem/progenitor marker, than in CD133- populations. Moreover, results of the sphere formation assay revealed that AR expression was required to maintain CSPCs populations. Interestingly, this AR-governed self-renewal capacity of CSPCs was only observed in CD133+ cells. In addition, we found that AR mediated CSPCs enrichment was accompanied by down-regulation of p53 and p16. Finally, co-expression of AR and CD133 was more abundant in OVTC lesions than in normal ovarian tissue. CONCLUSION: The results of this study suggest that AR itself might play a ligand-independent role in the development of OVTC. PMID- 24793308 TI - Synthesis of MnO2 nanoparticles from sonochemical reduction of MnO4(-) in water under different pH conditions. AB - MnO2 was synthesized by sonochemical reduction of MnO4(-) in water under Ar atmosphere at 20 degrees C, where the effects of solution pH on the reduction of MnO4(-) were investigated. The obtained XRD results showed that poor crystallinity delta-MnO2 was formed at pH 2.2, 6.0 and 9.3. When solution pH was increased from 2.2 to 9.3, the morphologies of delta-MnO2 changed from aggregated sheet-like or needle-like structures to spherical nanoparticles and finally to cubic or polyhedron nanoparticles. After further irradiation, MnO2 was readily reduced to Mn(2+). It was confirmed that H2O2 and H atoms formed in the sonolysis of water acted as reductants for both reduction for MnO4(-) to MnO2 and MnO2 to Mn(2+). The optimum irradiation time for the effective synthesis of MnO2 was 13 min at pH 2.2, 9 min at pH 6.0, 8 min at pH 9.3, respectively. PMID- 24793307 TI - A switch to Raltegravir improves antiretroviral associated hepatotoxicity in individuals co-infected with HIV and hepatitis C. AB - INTRODUCTION: Raltegravir is a switch option for HIV/HCV co-infected individuals due to its hepatic neutral profile. We evaluated the effect of a switch to Raltegravir from other antiretroviral agents in HIV and HCV-co-infected individuals naive to HCV therapy. METHODS: Observational, single-centre study. Data on alanine aminotransferase levels, HCV-VL, CD4 cell count, HIV viral load levels and hepatic fibrosis score were collated six months pre-switch, at the time of switch and six months post switch to Raltegravir therapy. Results were compared utilizing the Kruskal-Wallis test. RESULTS: Twenty-seven individuals were identified. Median age was 43 years, median duration of HIV infection was 7 years and median documented period of HCV infection at the time of switch was 26 months. A sustained improvement in ALT levels was observed. Median ALT levels were 254 IU/L at the time of switch, decreasing significantly to 176 IU/L, (p = 0.0226) and 90 IU/L (p = 0.0138) 1 month post switch and 6 months post switch respectively. The median Hepatitis C viral load level at the time of the switch was 341,783 copies/mL, which decreased to 224,066 copies/mL 6 months after switch (p = 0.04). DISCUSSION: A switch to Raltegravir in individuals with HIV/HCV co infection was effective in maintaining HIV virological suppression with improvement in drug-associated hepatotoxicity as measured by ALT. PMID- 24793309 TI - Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats. AB - AIM: Sevoflurane postconditioning (SpostC) has been shown to protect the heart from ischemia-reperfusion (I/R) injury. In this study, we examined whether SpostC affected autophagic flux in myocardial tissues that contributed to its cardioprotective effects in rats following acute I/R injury. METHODS: SD rats underwent 30 min of left anterior descending coronary artery ligation followed by 120 min of reperfusion. The rats were subjected to inhalation of 2.4% (v/v) sevoflurane during the first 5 min of reperfusion, and chloroquine (10 mg/kg, ip) was injected 1 h before I/R. Myocardial infarct size was estimated using TTC staining. Autophagosomes in myocardial tissues were detected under TEM. Expression of LC3B-II, beclin-1, p62/SQSTM1, cathepsin B, caspase-3 and cleaved PARP was assessed using Western blot analysis. Plasma cardiac troponin I was measured using ELISA. Cardiomyocyte apoptosis was evaluated with TUNEL staining. RESULTS: I/R procedure produced severe myocardium infarct and apoptosis accompanied by markedly increased number of autophagosomes, as well as increased levels of LC3B-II, beclin-1 and p62 in myocardial tissues. SpostC significantly reduced infarct size, attenuated myocardial apoptosis, restored intact autophagic flux and improved the lysosomal function in myocardial tissues. Administration of chloroquine that blocked autophagic flux abrogated the cardioprotective effects of SpostC. CONCLUSION: SpostC exerts its cardioprotective effects in rats following I/R injury via restoring autophagic flux in myocardial tissues. PMID- 24793311 TI - Atorvastatin prevents amyloid-beta peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway. AB - AIM: To investigate whether atorvastatin treatment could prevent Abeta1-42 oligomer (AbetaO)-induced synaptotoxicity and memory dysfunction in rats, and to elucidate the mechanisms involved in the neuroprotective actions of atorvastatin. METHODS: SD rats were injected with AbetaOs (5 nmol, icv). The rats were administrated with atorvastatin (10 mg.kg(-1).d(-1), po) for 2 consecutive weeks (the first dose was given 5 d before AbetaOs injection). The memory impairments were evaluated with Morris water maze task. The expression of inflammatory cytokines in the hippocampus was determined using ELISA assays. The levels of PSD 95 and p38MAPK proteins in rat hippocampus were evaluated using Western blot analysis. For in vitro experiments, cultured rat hippocampal neurons were treated with AbetaOs (50 nmol/L) for 48 h. The expression of MAP-2 and synaptophysin in the neurons was detected with immunofluorescence. RESULTS: The AbetaO-treated rats displayed severe memory impairments in Morris water maze tests, and markedly reduced levels of synaptic proteins synaptophysin and PSD-95, increased levels of inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and p38MAPK activation in the hippocampus. All these effects were prevented or substantially attenuated by atorvastatin administration. Pretreatment of cultured hippocampal neurons with atorvastatin (1 and 5 MUmol/L) concentration-dependently attenuated the AbetaO induced synaptotoxicity, including the loss of dendritic marker MAP-2, and synaptic proteins synaptophysin and PSD-95. Pretreatment of the cultured hippocampal neurons with the p38MAPK inhibitor SB203580 (5 MUmol/L) blocked the AbetaO-induced loss of synaptophysin and PSD-95. CONCLUSION: Atorvastatin prevents AbetaO-induced synaptotoxicity and memory dysfunction through a p38MAPK dependent pathway. PMID- 24793310 TI - Abrus agglutinin suppresses human hepatocellular carcinoma in vitro and in vivo by inducing caspase-mediated cell death. AB - AIM: Abrus agglutinin (AGG) from the seeds of Indian medicinal plant Abrus precatorius belongs to the class II ribosome inactivating protein family. In this study we investigated the anticancer effects of AGG against human hepatocellular carcinoma in vitro and in vivo. METHODS: Cell proliferation, DNA fragmentation, Annexin V binding, immunocytofluorescence, Western blotting, caspase activity assays and luciferase assays were performed to evaluate AGG in human liver cancer cells HepG2. Immunohistochemical staining and TUNEL expression were studied in tumor samples of HepG2-xenografted nude mice. RESULTS: AGG induced apoptosis in HepG2 cells in a dose- and time-dependent manner. AGG-treated HepG2 cells demonstrated an increase in caspase 3/7, 8 and 9 activities and a sharp decrease in the Bcl-2/Bax ratio, indicating activation of a caspase cascade. Co-treatment of HepG2 cells with AGG and a caspase inhibitor or treatment of AGG in Bax knockout HepG2 cells decreased the caspase 3/7 activity in comparison to HepG2 cells exposed only to AGG. Moreover, AGG decreased the expression of Hsp90 and suppressed Akt phosphorylation and NF-kappaB expression in HepG2 cells. Finally, AGG treatment significantly reduced tumor growth in nude mice bearing HepG2 xenografts, increased TUNEL expression and decreased CD-31 and Ki-67 expression compared to levels observed in the untreated control mice bearing HepG2 cells. CONCLUSION: AGG inhibits the growth and progression of HepG2 cells by inducing caspase-mediated cell death. The agglutinin could be an alternative natural remedy for the treatment of human hepatocellular carcinomas. PMID- 24793312 TI - Telmisartan protects central neurons against nutrient deprivation-induced apoptosis in vitro through activation of PPARgamma and the Akt/GSK-3beta pathway. AB - AIM: To determine whether angiotensin II receptor blockers (ARBs) could protect central neurons against nutrient deprivation-induced apoptosis in vitro and to elucidate the underlying mechanisms. METHODS: Primary rat cerebellar granule cells (CGCs) underwent B27 (a serum substitute) deprivation for 24 h to induce neurotoxicity, and cell viability was analyzed using LDH assay and WST-1 assay. DNA laddering assay and TUNEL assay were used to detect cell apoptosis. The expression of caspase-3 and Bcl-2, and the phosphorylation of Akt and GSK-3beta were detected using Western blot analysis. AT1a mRNA expression was determined using RT-PCR analysis. RESULTS: B27 deprivation significantly increased the apoptosis of CGCs, as demonstrated by LDH release, DNA laddering, caspase-3 activation and positive TUNEL staining. Pretreatment with 10 MUmol/L ARBs (telmisartan, candesartan or losartan) partially blocked B27 deprivation-induced apoptosis of CGCs with telmisartan being the most effective one. B27 deprivation markedly increased the expression of AT1a receptor in CGCs, inhibited Akt and GSK 3beta activation, decreased Bcl-2 level, and activated caspase-3, which were reversed by pretreatment with 1 MUmol/L telmisartan. In addition, pretreatment with 10 MUmol/L PPARgamma agonist pioglitazone was more effective in protecting CGCs against B27 deprivation-induced apoptosis, whereas pretreatment with 20 MUmol/L PPARgamma antagonist GW9662 abolished all the effects of telmisartan in CGCs deprived of B27. CONCLUSION: ARBs, in particular telmisartan, can protect the nutrient deprivation-induced apoptosis of CGCs in vitro through activation of PPARgamma and the Akt/GSK-3beta pathway. PMID- 24793313 TI - gamma-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway. AB - AIM: Trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) is a soluble epoxide hydrolase inhibitor that suppresses glioblastoma cell growth in vitro. The aim of this study was to examine whether the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) could sensitize glioma cells to t-AUCB-induced apoptosis. METHODS: Both U251 and U87 human glioblastoma cell lines were tested. Cell growth was assessed using the cell counting kit-8. Cell apoptosis was detected with caspase-3 activity assay kits and flow cytometry. The protein levels in the p38 MAPK/MAPKAPK2/Hsp27 pathway in the cells were analyzed using Western blots. RESULTS: Pretreatment with DAPT (2 MUmol/L) substantially potentiated the growth inhibition caused by t AUCB (200 MUmol/L) in U251 and U87 cells. Furthermore, pretreatment with DAPT markedly increased t-AUCB-induced apoptosis of U251 and U87 cells. T-AUCB alone did not significant affect caspase-3 activity in the cells, but t-AUCB plus DAPT pretreatment caused significant increase of caspase-3 activity. Furthermore, pretreatment with DAPT completely blocked t-AUCB-induced phosphorylation of p38 MAPK, MAPKAPK2 and Hsp27 in the cells. CONCLUSION: The gamma-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway, suggesting that the combination of t-AUCB and DAPT may be a potentially effective strategy for the treatment of glioblastoma. PMID- 24793314 TI - MEGA ? --Empirical Support for Nomenclature on the Anomalies: Sexually Violent and Predatory Youth. AB - Applied are empirical findings supporting the authors' previously presented nomenclature identifying two subsets of sexually abusive youth overlooked by most contemporary risk assessment tools: sexually violent and predatory sexually violent youth. The cross-validation findings on an ecologically framed risk assessment tool, MEGA (?) (Multiplex Empirically Guided Inventory of Ecological Aggregates for Assessing Sexually Abusive Children and Adolescents [Ages 19 and Under]) (N = 1,056 male and female sexually abusive youth, ages 4-19, including youth with low intellectual functioning), from the United States, Canada, England, and Scotland, were utilized. Findings provided normative data, with cutoff scores according to age and gender. Most contemporary risk assessment tools have three levels (low, moderate, and high), which may in fact be limited in assessing the range of risk level. The MEGA (?) cross-validation established a new range of risk level, with the fourth level (very high) definitively identifying the most dangerous youth, thus empirically supporting the nomenclature of sexually violent and predatory sexually violent youth. PMID- 24793315 TI - Communication about social status. AB - Dominance hierarchies are ubiquitous in social species and serve to organize social systems. Social and sexual status is communicated directly among animals via sensory systems evolved in the particular species. Such signals may be chemical, visual, auditory, postural or a combination of signals. In most species, status is initially established through physical conflict between individuals that leads to ritualized conflict or threats, reducing possibly dangerous results of fighting. Many of the status signals contain other information, as in some bird species that communicate both the size of their group and their individual rank vocally. Recent studies have shown that scent signaling among hyenas of east Africa is unique, being produced by fermentative, odor producing bacteria residing in the scent glands. PMID- 24793316 TI - Dengue fever as a cause of febrile neutropenia in adult acute lymphoblastic leukemia: a single center experience. PMID- 24793317 TI - Taking precautionary concerns seriously: a defense of a misused anti-abortion argument. AB - Abortion critics have argued that one should err on the side of life and prohibit abortion since the status of the fetus is uncertain. David Boonin has criticized this precautionary argument, but his criticism has been ignored. The aim is to elaborate on the precautionary argument by responding to Boonin's criticism. Boonin considers three versions of the precautionary argument-the disaster avoidance argument, the maximin argument, and the expected utility argument; yet all three are judged unsuccessful for the same reasons: they lead to unacceptable implications, they lead to conclusions that are too weak, and they undermine the integrity of moral reasoning. I respond to this criticism by arguing that one can avoid unacceptable implications by considering a criterion of realism, that the weaker conclusions are rather an advantage, and that the application of the precautionary principle makes room for considerations which maintain the integrity of moral reasoning. I also consider some criticism beyond Boonin's objections. PMID- 24793318 TI - Radial variation in wood specific gravity of tropical tree species differing in growth-mortality strategies. AB - * PREMISE OF THE STUDY: Wood specific gravity (WSG) mediates an interspecific trade-off between growth and mortality and is a key measure for estimating carbon stocks. Most studies use species mean values to represent WSG, despite variation at different levels of biological organization. We examined sources of variation in WSG across four nested scales (segments within cores, cores within trees, trees within species, and species), compared the pattern of radial variation in WSG among species differing in growth strategies, and investigated the effect of WSG radial variation on aboveground biomass estimates.* METHODS: We took two perpendicular cores from six individuals each of 20 tropical tree species representing a broad range of mean WSGs and growth-mortality strategies in a lowland tropical moist forest in Panama. Cores were divided into 1-cm segments, and WSG was determined for each segment.* KEY RESULTS: The bulk of the total variance in WSG was dominated by interspecies variation (88%), whereas variation due to measurement error, segments within cores, and cores within trees (8%) was minimal. Radial variation in WSG, defined as change in WSG with increasing distance from the pith, was significant in 17 of the 20 species and included significant monotonic increases in 6 species and nonmonotonic patterns in 11 species. Radial variation in WSG resulted in a small but significant bias in aboveground biomass estimates.* CONCLUSIONS: Radial variation in WSG is related to a species' growth strategy and, though minimal compared with interspecific variation in WSG, can cause a downward bias when not incorporated into aboveground biomass estimates. PMID- 24793319 TI - The role of cigarette smoking and liver enzymes polymorphisms in anti tuberculosis drug-induced hepatotoxicity in Brazilian patients. AB - Tuberculosis (TB) is still a major health concern and side-effects related to the treatment, especially drug-induced hepatotoxicity (DIH), should be better investigated. In the present study, a possible association between anti-TB DIH and cigarette smoking, N-acetyltransferase 2 (NAT2), Cytochrome P450 2E1 (CYP2E1) and Cytochrome P450 3A4 (CYP3A4) genotypes was studied in 131 TB Brazilian patients. The NAT2 and CYP3A4 genetic polymorphisms were determined using a polymerase chain reaction (PCR) direct sequencing approach and genetic polymorphisms of CYP2E1 gene were determined by restriction fragment length polymorphism (RFLP). The risk of anti-TB DIH was lower in rapid/intermediate acetylators when compared to slow acetylators (OR: 0.34, CI 95: 0.16-0.71; p < 0.01). A decreased risk of developing anti-TB DIH was also observed in active smokers when compared to non-smokers (OR: 0.28, 95 CI: 0.11-0.64; p < 0.01). Significant association between CYP3A4 genotypes and hepatotoxicity was not observed, as well as between CYP2E1 genotype and hepatotoxicity, whose frequency of patients with wild homozygous was more prevalent. The anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require to adjust therapeutic regimen dosages or alarm in case of adverse event developments. PMID- 24793320 TI - Suicide by drowning: A forensic challenge. AB - In the case of suicidal drowning forensic examination is difficult, particularly with regard to differentiating between suicide, accident, homicide and natural death. Bondage and weighting with objects, putrescence and attendant lesions aggravate interpretation and investigation of postmortal forensic findings. In this respect, two cases of seemingly homicidal drowning with leg and arm bondage and weighting, to prevent resurfacing, are presented and discussed. PMID- 24793321 TI - Cloning, expression, sequence analysis, and partial characterization of two alkaline beta-1, 4-endoglucanases of Phaeosphaeria sp. LH21 from deep-sea mud. AB - Here we cloned and expressed two alkaline beta-1, 4-endoglucanases of Phaeosphaeria sp. LH21 from deep-sea mud. The two enzymes shared 71 and 63 % of identities with their known beta-1, 4-endoglucanases, respectively. According to the primary and spatial structures, the potential active sites of one of the two enzymes could be Asp122 and Asp11, while the other enzyme could be Asp16. The enzymatic properties of their recombinant enzymes from Pichia pastoris GS115 showed that they were optimally active at pH 8 and 60-65 degrees C, exhibited >90 % residual relative activities at pH 3-10, and obtained relative activities >75 % at pH 5-10. PMID- 24793322 TI - Chronic pain and cardiovascular stress responses in a general population: the Tromso Study. AB - We tested whether cardiovascular stress responsiveness is elevated in individuals experiencing chronic pain in a large general population sample. Blood pressure (BP) and heart rate (HR) were assessed at rest, during the cold pressor test, and during subsequent recovery in 554 individuals reporting daily chronic pain and 3,082 individuals free of chronic pain. After correcting for potential confounds, differences as a function of chronic pain status were noted for only 5 of 23 cardiovascular outcomes despite very high statistical power. Compared to the pain free group, the chronic pain group displayed higher baseline HR/mean arterial pressure (MAP) ratio (p = .03), greater systolic BP (SBP) reactivity during the cold pressor test (p = .04), and higher HR/MAP ratio (p = .047) and significantly less SBP (p = .017) and MAP (p = .041) return to baseline during recovery. Findings suggest that changes in cardiovascular stress responsiveness associated with chronic pain are of limited clinical significance and unlikely to contribute to increased cardiovascular risk in the chronic pain population. PMID- 24793323 TI - Dehydration induced loss of photosynthesis in Arabidopsis leaves during senescence is accompanied by the reversible enhancement in the activity of cell wall beta-glucosidase. AB - The physiology of loss of photosynthetic production of sugar and the consequent cellular sugar reprogramming during senescence of leaves experiencing environmental stress largely remains unclear. We have shown that leaf senescence in Arabidopsis thaliana causes a significant reduction in the rate of oxygen evolution and net photosynthetic rate (Pn). The decline in photosynthesis is further aggravated by dehydration. During dehydration, primary photochemical reaction of thylakoids and net photosynthesis decrease in parallel with the increase in water deficit. Senescence induced loss in photosynthesis is accompanied by a significant increase in the activity of cell wall hydrolyzing enzyme such as beta-glucosidase associated with cell wall catabolism. The activity of this enzyme is further enhanced when the senescing leaves experience dehydration stress. It is possible that both senescence and stress separately or in combination result in the loss in photosynthesis which could be a signal for an enhancement in the activity of beta-glucosidase that breaks down cell wall polysaccharides to sugar to sustain respiration for metabolic activities of plants experiencing stress. Thus dehydration response of cell wall hydrolases of senescing leaves is considered as plants' strategy to have cell wall polysaccharides as an alternative energy source for completion of energy requiring senescence process, stress survival and maintenance of recovery potential of energy deficit cells in the background of loss in photosynthesis. Withdrawal of stress (rehydration) distinctly exhibits recovery of photosynthesis and suppression of enzyme activity. Retention of the signaling for sugar reprogramming through breakdown of cell wall polysaccharides in the senescing leaves exposed to severe drought stress suggests that senescing leaves like mature ones possess potential for stress recovery. The precise mechanism of stress adaptation of senescing leaves is yet to be known. A significant accumulation of anthocyanin and flavonoids may be an indicator of stress adaptation of senescing leaves. In addition, stress induced enhancement of nonphotochemical quenching (NPQ), a stress protection provision in green plants, also suggests the potential of the leaves to develop adaptational mechanism to counter the dehydration stress. PMID- 24793324 TI - Inhibitory effects of polycyclic aromatic hydrocarbons (PAHs) on photosynthetic performance are not related to their aromaticity. AB - Polycyclic aromatic hydrocarbons (PAHs) are very toxic and highly persistent environmental pollutants which accumulate in soil and affect growth of the plants adversely. This study aims to investigate inhibitory effects of 3 major PAH particularly on photosynthetic processes in Arabidopsis thaliana grown in soil treated with PAH. The 3 PAH chosen differ from each other in aromaticity (number of rings) comprising their structure (2 rings: naphthalene, 3 rings: anthracene and 4 rings: pyrene). Several growth parameters and Chlorophyll a fluorescence was monitored in PAH treated plants. BN-PAGe analysis was done in order to get information about change in the protein conformation. PAH treatment led to increased value of Fo which collaborated with increase in the amount of free LHC as seen through BN-Page analysis. Thus PAH were found to inhibit PS II photochemistry and caused distinct change in pigment composition. However the results led us to infer that 3-ring anthracence is more inhibitory as compared to 2-ring naphthalene and 4-ring pyrene. This indicates that aromaticity of PAH is unrelated to their response on photosynthetic processes. PMID- 24793326 TI - Comparison of ambient airborne PM2.5, PM2.5 absorbance and nitrogen dioxide ratios measured in 1999 and 2009 in three areas in Europe. AB - Epidemiological studies often use nitrogen dioxide (NO2) or proximity to roads to characterize exposure to more health-relevant pollutants (e.g., fine particles or black carbon aerosol) in vehicle exhaust. Due to the introduction of diesel-soot filters, particle-to-NO2 ratios may have decreased, but little information is available about these ratios over time. Our study aim was to evaluate the change in particle-to-NO2 ratios between 1999 and 2009. We compared data collected during measurement campaigns in 1999 and 2009 from Munich, the Netherlands, and Stockholm. Traffic-impacted and urban and regional background sites were studied during each campaign. The same pollutants were measured in each campaign (mass concentration of particles <= 2.5 microns in diameter (PM2.5), PM2.5 absorbance (a marker for black carbon), and NO2) using the same methods except for NO2: Palmes tubes were used in 1999 and Ogawa badges in 2009. Both NO2 methods were validated against side-by-side chemiluminescence measurements. The levels of PM2.5 absorbance and PM2.5 were significantly lower (p<0.05) in 2009 at traffic and urban background sites in Stockholm, but only slightly lower in Munich and the Netherlands. In contrast, NO2 levels were not significantly different in the three areas in 2009 compared to 1999. Statistically-significant decreases between 1999 and 2009 pollutant ratios in the Netherlands (PM2.5 absorbance/NO2 and PM2.5/NO2) and in Stockholm (PM2.5 absorbance/NO2 and PM2.5 absorbance/PM2.5) were observed. Smaller decreases in these ratios were observed in Munich. The contrast between traffic and urban background locations was larger in 2009 than 1999 for NO2, whereas it was smaller for PM2.5 absorbance and PM2.5. The lower PM2.5 absorbance/NO2 and PM2.5/NO2 ratios in 2009 is likely explained by the introduction of oxidative particle filters for diesel vehicles that reduce particles but produce NO2. The changed contrasts may affect estimates of health effects related to NO2 as a marker of proximity to roads. PMID- 24793325 TI - Leukocyte telomere length is not associated with mortality in older men. AB - Leukocyte telomere length (LTL) is related to the aging of somatic cells. We hypothesized that LTL is inversely associated with mortality in elderly men. LTL was measured in 2744 elderly men (mean age 75.5, range 69-81years) included in the prospective population-based MrOS-Sweden study. Mortality data were obtained from national health registers with no loss of follow-up. During the follow-up (mean 6.0years), 556 (20%) of the participants died. Using Cox proportional hazards regression, tertile of LTL did not associate with all-cause mortality [tertile 1 (shortest) or 2 (middle) vs. tertile 3 (longest); hazard ratio (HR)=1.05, 95% confidence interval (CI) 0.85-1.28 and HR=0.97, 95% CI 0.79-1.19, respectively]. Furthermore, LTL did not associate with cancer (197 events) or cardiovascular disease (CVD, 206 events) mortality (tertile 1 vs. tertile 3; HR=0.94, 95% CI 0.67-1.34 and HR=0.94, 95% CI 0.68-1.30, respectively). The lack of association between LTL and mortality remained also after adjustment for multiple covariates. Our results demonstrate that LTL is not associated with all cause mortality or mortality due to cancer or CVD in elderly men. Further studies are needed to determine whether LTL can predict the risk of mortality in elderly women. PMID- 24793327 TI - Impact of climate change on mercury concentrations and deposition in the eastern United States. AB - The global-regional climate-air pollution modeling system (GRE-CAPS) was applied over the eastern United States to study the impact of climate change on the concentration and deposition of atmospheric mercury. Summer and winter periods (300 days for each) were simulated, and the present-day model predictions (2000s) were compared to the future ones (2050s) assuming constant emissions. Climate change affects Hg(2+) concentrations in both periods. On average, atmospheric Hg(2+) levels are predicted to increase in the future by 3% in summer and 5% in winter respectively due to enhanced oxidation of Hg(0) under higher temperatures. The predicted concentration change of Hg(2+) was found to vary significantly in space due to regional-scale changes in precipitation, ranging from -30% to 30% during summer and -20% to 40% during winter. Particulate mercury, Hg(p) has a similar spatial response to climate change as Hg(2+), while Hg(0) levels are not predicted to change significantly. In both periods, the response of mercury deposition to climate change varies spatially with an average predicted increase of 6% during summer and 4% during winter. During summer, deposition increases are predicted mostly in the western parts of the domain while mercury deposition is predicted to decrease in the Northeast and also in many areas in the Midwest and Southeast. During winter mercury deposition is predicted to change from -30% to 50% mainly due to the changes in rainfall and the corresponding changes in wet deposition. PMID- 24793328 TI - Metal accumulation strategies in plants spontaneously inhabiting Zn-Pb waste deposits. AB - Metal (Zn, Pb, Cd, Cu, Ni, Cr) accumulation in shoots of 38 plant species spontaneously colonizing three Zn-Pb waste deposits in southern Poland was studied in order to find out if the age of the waste (30-130 years) or its type (slag or flotation residues) influence metal content in plants and to identify species potentially suitable for biomonitoring and phytoremediation. The total metal concentrations in the waste upper layers ranged from 7300 to 171,790 mg kg( 1) for Zn, from 1390 to 22,265 mg kg(-1) for Pb, and from 66 to 1,464 mg kg(-1) for Cd, whereas CaCl2-extracted fractions accounted for 0.034-0.11 %, 0.005-0.03 %, and 0.28-0.62 % of total Zn, Pb and Cd concentrations, respectively. The concentrations of Cu, Ni, and Cr in substrates and in plants were low and ranged within the background values. Metal accumulation in plant shoots was poorly correlated with both total and CaCl2-extracted forms of metals in the substrate and was highly variable among species and also specimens of the same species. The highest mean concentrations of Zn, Pb and Cd were found in Anthyllis vulneraria L. (901.5 mg kg(-1)), Echium vulgare L. (116.92 mg kg(-1)), and Hieracium piloselloides Vill. (26.86 mg kg(-1)), respectively. Besides Reseda lutea L., no species appeared to be a good indicator of polymetallic environment pollution based on chemical analysis of shoots; however, metal accumulation in the whole plant communities of a particular contaminated area might be an accurate tool for assessment of metal transfer to vegetation irrespective of the type or age of the waste. All the species studied developed a metal exclusion strategy, thus exhibiting potential for phytostabilization of metalliferous wastelands. PMID- 24793329 TI - Mass and elemental distributions of atmospheric particles nearby blast furnace and electric arc furnace operated industrial areas in Australia. AB - The improved understanding of mass and elemental distributions of industrial air particles is important due to their heterogeneous atmospheric behaviour and impact on human health and the environment. In this study, particles of different size ranges were collected from three sites in Australia located in the vicinity of iron and steelmaking industries and one urban background site with very little industrial influence. In order to determine the importance of the type of industrial activity on the urban atmospheric quality, the industrial sites selected in this study were in the close proximity to two blast furnace operated and one electric arc furnace based steelmaking sites. The chemical compositions of the collected air particles were analysed using the proton induced X-ray emission (PIXE) technique. This study revealed significantly higher metal concentrations in the atmospheric particles collected in the industrial sites, comparing to the background urban site, demonstrating local influence of the industrial activities to the air quality. The modality types of the particles were found to be variable between the mass and elements, and among elements in the urban and industrial areas indicating that the elemental modal distribution is as important as particle mass for particle pollution modelling. The highest elemental number distribution at all studied sites occurred with particle size of 0.1 MUm. Iron was found as the main dominant metal at the industrial atmosphere in each particle size range. The industrial Fe fraction in the submicron and ultrafine size particles was estimated at up to 95% which may be released from high temperature industrial activities with the iron and steelmaking industries being one of the major contributors. Hence, these industrial elemental loadings can highly influence the atmospheric pollution at local urban and regional levels and are required to consider in the atmospheric modelling settings. PMID- 24793330 TI - Mycological and ecotoxicological characterisation of landfill leachate before and after traditional treatments. AB - Pollution caused by landfill leachates is one of the main problems of urbanised areas, on account of their chemical composition, which turn in an ineffective treatment. A characterisation of leachates, which takes into account chemical, ecotoxicological and mycological aspects, is basilar for the evaluation of environmental impact of leachate and the development of suitable treatment techniques. In this study, the toxicity of a raw leachate and an effluent coming from traditional wastewater treatment plant was assessed by means of 4 ecotoxicological assays. Both the samples exceed the legal threshold value according to all the tested organisms, indicating the ineffectiveness of activated sludge treatment in the reduction of toxicity. The autochthonous mycoflora of the two samples was evaluated by filtration. The fungal load was 73 CFU for leachate and 102 CFU for the effluent. Ascomycetes were the dominant fraction (81% and 61%, for leachate and effluent respectively), followed by basidiomycetes (19% and 39%, respectively). Most of them were potential emerging pathogens. A decolourisation screening with autochthonous fungi was set up towards both samples in the presence or absence of glucose. Eleven fungi (basidiomycetes and ascomycetes) achieved up to 38% decolourisation yields, showing to be promising fungi for the bioremediation of leachates. Further experiment will be aimed to the study of decolourisation mechanism and toxicity reduction. PMID- 24793331 TI - Impact evaluation of green-grey infrastructure interaction on built-space integrity: an emerging perspective to urban ecosystem service. AB - This paper evaluates the role of urban green infrastructure (GI) in maintaining integrity of built-space. The latter is considered as a lateral ecosystem function, worth including in future assessments of integrated ecosystem services. The basic tenet is that integrated green-grey infrastructures (GGIs) would have three influences on built-spaces: (i) reduced wind withering from flow deviation; (ii) reduced material corrosion/degeneration from pollution removal; and (iii) act as a biophysical buffer in altering the micro-climate. A case study is presented, combining the features of computational fluid dynamics (CFD) in micro environmental modelling with the emerging science on interactions of GGIs. The coupled seasonal dynamics of the above three effects are assessed for two building materials (limestone and steel) using the following three scenarios: (i) business as usual (BAU), (ii) summer (REGEN-S), and (iii) winter (REGEN-W). Apparently, integrated ecosystem service from green-grey interaction, as scoped in this paper, has strong seasonal dependence. Compared to BAU our results suggest that REGEN-S leads to slight increment in limestone recession (<10%), mainly from exacerbation in ozone damage, while large reduction in steel recession (up to 37%) is observed. The selection of vegetation species, especially their bVOC emission potential and seasonal foliage profile, appears to play a vital role in determining the impact GI has on the integrity of the neighbouring built-up environment. PMID- 24793332 TI - Hormetic dose-responses in nanotechnology studies. AB - While exposure to nanoparticles is a growing concern, research into their toxicological impact and possible hazard for human health is limited. There remains a lack of information concerning the nature of the dose-response relationship especially at low level exposures. The present paper assesses the occurrence of hormetic-like biphasic dose responses within the nanotoxicology literature. The findings indicate that nanoparticles may induce hormetic-like biphasic dose responses in a wide range of biological cell types, and that these responses can be highly dependent upon the physical and chemical properties of the agent. While the mechanistic foundations of hormetic dose responses induced by chemicals and pharmaceuticals have markedly advanced over the past decade, this remains an important data need for nanotoxicology. PMID- 24793333 TI - Diagnosis of sarcoidosis in the endobronchial ultrasound-guided transbronchial needle aspiration era. AB - BACKGROUND: Sarcoidosis is a multisystemic disorder of unknown etiology. Its diagnosis is based on compatible clinical and radiological features and supported by histological demonstration of epithelioid cell noncaseating granulomas with exclusion of other causes. Endobronchial ultrasound combined with transbronchial needle aspiration (EBUS-TBNA) has been proposed as a valuable tool in obtaining suitable tissue sample. The aim of this study was to evaluate the contribution of EBUS-TBNA to the diagnosis of stages I and II thoracic sarcoidosis in a community based hospital. METHODS: A prospective study was conducted in patients with suspected stages I and II pulmonary sarcoidosis, based on clinical and radiological data, who were being followed in our Interstitial Lung Disorders Outpatient Clinic or sent from other hospitals to our Respiratory Endoscopy Unit for diagnostic procedures. All suitable and fit patients underwent EBUS-TBNA between March 2010 and June 2013. We assessed demographic characteristics, radiological stages, cytological/histological examination and diagnostic techniques performed. RESULTS: In the period considered 39 patients underwent EBUS-TBNA for suspected stages I and II thoracic sarcoidosis and adequate samples were obtained in 38 (97.4%). Within this population, 33 (84.6%) patients had a definite diagnosis of sarcoidosis, of which 31 patients (93.9%) were confirmed to have epithelioid noncaseating granulomas by EBUS-TBNA. Four patients were submitted to surgical procedures (three to mediastinoscopy and one to open surgical lung biopsy). Data analysis allowed to calculate a sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of 93.9%, 100%, 100%, 75.0% and 94.8%, respectively. No complications were observed. CONCLUSIONS: EBUS-TBNA is a valuable tool in the diagnostic workup of patients with suspected stages I and II thoracic sarcoidosis providing a substantial number of pathological confirmations and with few complications. Its high diagnostic accuracy precludes the need for more invasive procedures such as surgical biopsy. PMID- 24793334 TI - Heterocyclic ring extension of androstenedione: synthesis and cytotoxicity of fused pyran, pyrimidine and thiazole derivatives. AB - The reaction of androstenedione with either malononitrile or ethyl cyanoacetate and aromatic aldehydes 2a-c gave the pyran derivatives 4a-f, respectively. On the other hand, the reaction of androstenedione with thiourea and the aromatic aldehydes 2a-c gave the pyrimidine derivatives 6a-c, respectively. Compound 6b reacted with 2-bromo-1-arylethanone derivatives 7a-d to give the indeno[2,1 e]thiazole derivatives 8a-d. Some of the produced compounds were used for further heterocyclization reactions. The cytotoxicity of the newly obtained products was evaluated against some cancer cell lines and a normal cell line. PMID- 24793335 TI - Induction of quinone reductase (QR) by withanolides isolated from Physalis angulata L. var. villosa Bonati (Solanaceae). AB - In the present study, the EtOAc extract of the persistent calyx of Physalis angulata L. var. villosa Bonati (PA) was tested for its potential quinone reductase (QR) inducing activity with glutathione (GSH) as the substrate using an UPLC-ESI-MS method. The result revealed that the PA had electrophiles that could induce quinone reductase (QR) activity, which might be attributed to the modification of the highly reactive cysteine residues in Keap1. Herein, three new withanolides, compounds 3, 6 and 7, together with four known withanolides, compounds 1, 2, 4 and 5 were isolated from PA extract. Their structures were determined by spectroscopic techniques, including (1)H-, (13)C NMR (DEPT), and 2D NMR (HMBC, HMQC, (1)H, (1)H-COSY, NOESY) experiments, as well as by HR-MS. All the seven compounds were tested for their QR induction activities towards mouse hepa 1c1c7 cells. PMID- 24793336 TI - An easy stereoselective synthesis of 5(10)-estrene-3beta,17alpha-diol, a biological marker of pregnancy in the mare. AB - 5(10)-Estrene-3beta,17alpha-diol is an essential reference material for doping analysis in horse-racing laboratories. It is used to detect misuse, for doping purpose, of the pregnancy status in the mare. Its stereoselective synthesis from 17beta-estradiol-3-methyl ether (prepared from estrone or 17beta-estradiol) was performed in four steps: (1) Mitsunobu inversion of the 17beta-alcohol; (2) Birch reduction of the aromatic ring; (3) stereoselective reduction of the 3-ketone via Noyori asymmetric transfer hydrogenation; (4) chemoenzymatic purification. PMID- 24793337 TI - Nonmosaic tetrasomy 15q25.2 -> qter identified with SNP microarray in a patient with characteristic facial appearance and review of the literature. AB - Tetrasomy for the distal chromosome 15q is rare, and only 22 patients (including 6 cases without detailed information) have been described to date in the literature. Here we report on another patient with nonmosaic tetrasomy 15q25.2 qter resulted from an inverted duplication of distal chromosome 15. This patient presents with features of development delay, arachnodactyly, joint contractures and typical facial dysmorphism including frontal bossing, short palpebral fissures, long philtrum, low-set ears, high-arched palate and retrognathia. Unlike most of the related patients, abdominal ultrasound test and brain MRI showed normal. Karyotyping analysis revealed a supernumerary marker chromosome presented in all metaphase cells examined. Parental karyotyping analysis was normal, indicating a de novo chromosome aberration of the patient. SNP microarray analysis found a two copy gain of 17.7 Mb from the distal long arm of chromosome 15 (15q25.2-qter). Further FISH analysis using SureFISH 15q26.3 IGF1R probe proved an inverted duplication of distal long arm of chromosome 15. The segmental duplications which lie in the hotspots of 15q24-26 might increase the susceptibility of chromosome rearrangement. Compared with the George-Abraham' study [2012], ADAMTSL3 might be more related to the cardiac disorders in tetrasomy 15q patients. Considering all patients reported in the literature, different mosaic degrees and segmental sizes don't correlate to the severity of phenotypes. A clear delineation on tetrasomy for distal chromosome 15q could still be investigated. PMID- 24793339 TI - An assessment of progress towards universal health coverage in Brazil, Russia, India, China, and South Africa (BRICS). AB - Brazil, Russia, India, China, and South Africa (BRICS) represent almost half the world's population, and all five national governments recently committed to work nationally, regionally, and globally to ensure that universal health coverage (UHC) is achieved. This analysis reviews national efforts to achieve UHC. With a broad range of health indicators, life expectancy (ranging from 53 years to 73 years), and mortality rate in children younger than 5 years (ranging from 10.3 to 44.6 deaths per 1000 livebirths), a review of progress in each of the BRICS countries shows that each has some way to go before achieving UHC. The BRICS countries show substantial, and often similar, challenges in moving towards UHC. On the basis of a review of each country, the most pressing problems are: raising insufficient public spending; stewarding mixed private and public health systems; ensuring equity; meeting the demands for more human resources; managing changing demographics and disease burdens; and addressing the social determinants of health. Increases in public funding can be used to show how BRICS health ministries could accelerate progress to achieve UHC. Although all the BRICS countries have devoted increased resources to health, the biggest increase has been in China, which was probably facilitated by China's rapid economic growth. However, the BRICS country with the second highest economic growth, India, has had the least improvement in public funding for health. Future research to understand such different levels of prioritisation of the health sector in these countries could be useful. Similarly, the role of strategic purchasing in working with powerful private sectors, the effect of federal structures, and the implications of investment in primary health care as a foundation for UHC could be explored. These issues could serve as the basis on which BRICS countries focus their efforts to share ideas and strategies. PMID- 24793341 TI - Factors associated with higher risk of complications after adrenal surgery. AB - BACKGROUND: Surgeon experience has been demonstrated to result in better outcomes after a variety of advanced operations. Less information is available regarding adrenal surgery. We compared the outcomes after adrenalectomy for a variety of indications and determined the effect of surgeon's case volume. METHODS: Cross sectional analysis was performed using ICD-9 procedure codes included in the Nationwide Inpatient Sample from 2003 to 2009 to identify all adult patients who underwent unilateral or bilateral adrenalectomy for benign or malignant conditions. Logistic regression was used to test for interaction between surgeon case volume (low = 1, intermediate = 2-5, and high = >5 adrenalectomies per year), diagnosis, type of operation performed, and risk of complications. RESULTS: A total of 7,829 adrenalectomies were included. Risk of complications after bilateral adrenalectomy was 23.4 % compared to 15.0 % for unilateral adrenalectomy (odds ratio 2.165, 95 % confidence interval 1.335, 3.512). Malignancy was associated with higher risk of complication (23.1 %) than benign disease (13.2 %) (odds ratio 1.685, 95 % confidence interval 1.371, 2.072). Complication rates for low- and intermediate-volume surgeons were 18.8 and 14.6 %, respectively, and both were significantly higher than complications by high volume surgeons (11.6 %, p < 0.05). Length of stay and charges were both significantly less for high-volume surgeons compared to lower-volume groups (p < 0.05). CONCLUSIONS: Low surgeon case volumes and adrenal surgery for malignant or bilateral disease are associated with increased risk of postoperative complications. Length of stay and charges were significantly less when high volume surgeons perform adrenal surgery. PMID- 24793340 TI - Elevated expression of Girdin in the nucleus indicates worse prognosis for patients with estrogen receptor-positive breast cancer. AB - BACKGROUND: Girdin was identified as a novel Akt substrate that contributes to a positive feedback loop between Girdin and Akt. Although several recent studies have demonstrated that Girdin is involved in tumor metastasis, the clinical implications of Girdin in breast cancer remain unclear. METHODS: To retrospectively evaluate the prognostic value of Girdin in breast cancer, we performed an immunohistochemistry screening for Girdin using tissue microarrays constructed from 250 patients who were histologically confirmed as having invasive ductal breast carcinoma at the Fudan University Shanghai Cancer Center. RESULTS: Our results demonstrated that the levels of Girdin in different subcellular distributions, including Girdin in the nucleus (GN) and the cytoplasm (GC) were each associated with the clinical parameters of breast cancer, including phospho-Akt (S473) [p = 0.014 for GN], phospho-Akt (T308) [p = 0.045 for GC], estrogen receptor (ER) [p = 0.012 for GN and p = 0.004 for GC], progesterone receptor (p = 0.028 for GC) and human epidermal growth factor receptor 2 status (p = 0.004 for GC). Moreover, we showed that elevated expression of GN indicated a worse disease-free survival (p = 0.032) and overall survival (p = 0.011) exclusively in the ER-positive breast cancer population. CONCLUSIONS: Cumulatively, our findings suggest that GN might serve as an important prognostic factor for ER-positive breast carcinoma. PMID- 24793338 TI - Genetic basis of congenital cardiovascular malformations. AB - Cardiovascular malformations are a singularly important class of birth defects and due to dramatic improvements in medical and surgical care, there are now large numbers of adult survivors. The etiologies are complex, but there is strong evidence that genetic factors play a crucial role. Over the last 15 years there has been enormous progress in the discovery of causative genes for syndromic heart malformations and in rare families with Mendelian forms. The rapid characterization of genomic disorders as major contributors to congenital heart defects is also notable. The genes identified encode many transcription factors, chromatin regulators, growth factors and signal transduction proteins- all unified by their required roles in normal cardiac development. Genome-wide sequencing of the coding regions promises to elucidate genetic causation in several disorders affecting cardiac development. Such comprehensive studies evaluating both common and rare variants would be essential in characterizing gene-gene interactions, as well as in understanding the gene-environment interactions that increase susceptibility to congenital heart defects. PMID- 24793342 TI - Triclosan as a surrogate for household biocides: an investigation into biocides in aquatic environments of a highly urbanized region. AB - Biocides are widely formulated in household and personal care products. We investigated the distribution and ecological risks of 16 household biocides in aquatic environments of a highly urbanized region in South China, evaluated triclosan as a chemical indicator for this group of household chemicals, and proposed a novel approach to predict the environmental occurrence and fate of these household biocides by using triclosan usage data and a level-III fugacity model. Eleven biocides were quantitatively detected at concentrations up to 264 +/- 15.3 ng/L for climbazole in surface water, and up to 5649 +/- 748 ng/g for triclocarban in sediment of four rivers in the region. The distribution of biocides in the aquatic environments was significantly correlated with environmental variables such as total nitrogen, total phosphorus and population. Domestic sewage in the region was the dominant pollution source for most biocides such as azole fungicides (fluconazole, climbazole, clotrimazole, ketoconazole, miconazole, and carbendazim) and disinfectants (triclosan and triclocarban). Preliminary risk assessment showed high ecological risks posed by two biocides carbendazim and triclosan in river waters. Mostly important, triclosan was found to be a reliable chemical indicator to surrogate household biocides both in water and sediment based on the correlation analysis. In addition, the fugacity modeling could provide simulated concentrations comparable to the monitoring results. Therefore, with the usage data of the chemical indicator triclosan and correlation formula with other biocides, this model can be applied for predicting the occurrence and fate of various household biocides in a catchment. PMID- 24793343 TI - From the editor: the national meeting of the NLA. PMID- 24793344 TI - JCL roundtable: Clinical management of individuals with obesity. AB - Our topic is the evaluation and treatment of obesity in the practice of medicine. I am joined by Dr. Harold Bays who has carried out many studies of dietary and medical interventions in patients with obesity. I am also honored to have Dr. George Bray who is known for his many years of research into causes of obesity and its therapy. Our goal is bring this clinical and research experience to bear on the office practice of medicine. PMID- 24793345 TI - Can paraoxonase 1 polymorphisms (L55 M and Q192 R) protect children with type 1 diabetes against lipid abnormalities? AB - BACKGROUND: Only a few studies have focused on the possible modulatory role of paraoxonase 1 (PON1) polymorphisms in lipid profiles, especially in children and in adolescents with type 1 diabetes (T1D). OBJECTIVE: We propose to study the association between PON1 polymorphisms (PON1-55 and PON1-192) and a lipid profile in a young Tunisian population with T1D. METHODS: The study compared 122 children and adolescents with T1D with 97 controls. Genomic DNA was collected from 116 patients and 91 controls. Lipid parameters were determined by automated methods. PON1 activity was measured by a spectrophotometric method and genotyping of the PON1 gene was assessed by multiplex polymerase chain reaction followed by restriction fragment-length polymorphism. RESULTS: A significant increase in total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) (Lp(a)) and a significant decrease in apolipoprotein A1 (ApoA1), ApoA1/ApoB ratio, and PON1 activity/HDL-C ratio were observed in children with T1D compared with controls. In the LLQR haplotype, the group with diabetes showed significantly higher values of total cholesterol, LDL-C, apoB, Lp(a), and apoA1/apoB ratio compared with the control group. Those with diabetes with the LLQQ haplotype showed a significant decrease in LDL-C and Lp(a) compared with controls (P < .0001). CONCLUSION: PON1 polymorphisms (PON1-55 and PON1-192) seem to be involved in the altering the lipid profile in T1D. The LLQR haplotype provided an atherogenic lipid profile in children with T1D compared with controls. LLQQ haplotype seemed to have a protective effect against the increase in LDL-C and Lp(a) that are heavily involved in the development of cardiovascular diseases. PMID- 24793346 TI - Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects. AB - BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs. OBJECTIVE: To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects. METHODS: PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction. RESULTS: Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates (P = .059). The 670G allele was associated with high basal levels of LDL cholesterol (P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups (P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes. CONCLUSIONS: PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin. PMID- 24793347 TI - Association of nonalcoholic fatty liver disease with cardiovascular risk factors in obese adolescents: the role of interdisciplinary therapy. AB - BACKGROUND: Obesity is associated with several cardiovascular risk factors, including nonalcoholic fatty liver disease (NAFLD). These risk factors can induce changes in the arteries such as an increase in the carotid intima-media thickness (cIMT), which contributes to the early development of atherosclerosis. OBJECTIVE: To determine whether NAFLD is associated with an atherogenic lipid profile, inflammatory markers, or cIMT in obese adolescents and to compare the effects of therapeutic lifestyle changes in NAFLD and non-NAFLD groups. METHODS: A total of 79 obese adolescents were divided into two groups: 33 NAFLD and 46 non-NAFLD. They were submitted to an interdisciplinary therapy involving diet exercise and psychological support during the course of 1 year. The cIMT and estimates of fat mass (liver, intra-abdominal, and subcutaneous) were determined ultrasonographically. Body composition, glucose, lipid profile, and adipokines were analyzed before and after the therapy. RESULTS: At baseline, only in the NAFLD group was the homeostasis model assessment of insulin resistance positively correlated with cIMT and triglyceride/high-density lipoprotein cholesterol ratio. Therapy was associated with an increase in adiponectin concentrations and reduced visceral fat, cIMT, leptin, and plasminogen activator inhibitor-1 concentrations, as well as the ratios of total cholesterol/high-density lipoprotein cholesterol and triglycerides/high-density lipoprotein cholesterol in both groups. Only in the non-NAFLD group did therapy result in a reduction in the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio and increased high-density lipoprotein cholesterol concentration. CONCLUSIONS: In obese adolescents, NAFLD is associated with cardiovascular risk factors and inflammatory markers of atherosclerosis that were positively correlated with cIMT only in the NAFLD group. Nevertheless, the strength of the present study is that the interdisciplinary therapy effectively improved cIMT and other proinflammatory adipokines in both groups. PMID- 24793348 TI - Association between alcohol intake, overweight, and serum lipid levels and the risk analysis associated with the development of dyslipidemia. AB - BACKGROUND: Alcohol, overweight, and lipid metabolism contribute to fatty liver and atherosclerosis pathogenesis. OBJECTIVE: To study the association of alcoholic intake, overweight, and dyslipidemia. METHODS: We randomly selected 482 age- and sex-matched individuals from East China. Gender, age, education level, smoking, hypertension, daily alcohol intake, drinking duration, and body mass index (BMI) were evaluated in association with triglyceride, total cholesterol, high-density (HDL-C), and low-density lipoprotein-cholesterol. RESULTS: The association between dyslipidemia and 8 predictors of disease was made by regression analysis through the generalized additive model. The results showed that age, daily alcohol intake, and BMI were all closely associated with hypertriglyceridemia. Age, duration of drinking, and BMI were all closely associated with hypercholesterolemia. Age and BMI status were both closely associated with high LDL-C levels. By contrast, none of the 8 predictors was closely associated with low HDL-C levels (all P < .05). CONCLUSIONS: Daily alcohol intake was a risk factor for hypertriglyceridemia. By contrast, drinking duration was a protective factor against hypercholesterolemia. Age and BMI were important risk factors for dyslipidemia (excluding HDL-C). PMID- 24793349 TI - Risk of coronary heart disease associated with metabolic syndrome and its individual components in Iranian subjects: a matched cohort study. AB - BACKGROUND AND OBJECTIVES: To evaluate the risk of coronary heart disease (CHD) associated with metabolic syndrome (MetS) and its individual components in a representative sample of diabetic and nondiabetic Iranians. Moreover, we aimed to define the most hazardous MetS components. METHODS: Two cohorts consisting of 1737 nondiabetic and 2385 diabetic participants were followed for the first CHD event during 8.5 years (until December 2013). RESULTS: MetS is defined as having 3 individual components associated with increased risk of CHD (hazard ratio [HR] for MetS: in the unadjusted were 2.85 [2.27-3.57] and in the fully adjusted model 1.80 [1.42-2.28]). MetS was associated with lower hazard of CHD in subjects older than 65 (HR: 1.50 vs. 3.47; P for interaction < .05) and in men (HR: 1.68 vs. 4.87; P for interaction < .05). Presence of 4 of 5 individual MetS components increased the risk of CHD associated with MetS as a constellation. The value of MetS is augmented in the presence of low high-density lipoprotein-cholesterol (HR: 5.74 [2.52-13.08]) versus its absence (HR 1.91 [1.33-2.75]), high triglycerides (HR: 3.39 [1.38-8.34] vs. 1.99 [1.40-2.82] in its absence) and elevated blood pressure (HR: 2.61 [1.43-4.76] vs. 1.80 [1.26-2.58] in its absence). CONCLUSIONS: We address the value of MetS components in the prediction of CHD and in the absence of traditional risk factors. This study provides evidence for the synergistic effect of MetS components on the incidence of CHD. PMID- 24793350 TI - Genotype-phenotype relationships in patients with type I hyperlipoproteinemia. AB - CONTEXT: Type I hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme hypertriglyceridemia that fails to respond to lipid-lowering agents, predisposing to frequent attacks of acute pancreatitis. Mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), lipase maturation factor 1 (LMF1), glycosyl-phosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and apolipoprotein AV (APOA5) cause T1HLP, but we lack data on phenotypic variations among the different genetic subtypes. OBJECTIVE: To study genotype-phenotype relationships among subtypes of T1HLP patients. DESIGN/INTERVENTION: Genetic screening for mutations in LPL, APOC2, GPIHBP1, LMF1, and APOA5. SETTING: Tertiary referral center. PATIENTS: Ten patients (7 female, 3 male) with chylomicronemia, serum triglyceride levels about 2000 mg/dL, and no secondary causes of hypertriglyceridemia. MAIN OUTCOME MEASURES: Genotyping and phenotypic features. RESULTS: Four patients harbored homozygous or compound heterozygous mutations in LPL, 3 had homozygous mutations in GPIHBP1, and 1 had a heterozygous APOA5 mutation. We failed to fully identify the genetic etiology in 2 cases: 1 had a heterozygous LPL mutation only and another did not have any mutations. We identified 2 interesting phenotypic features: the patient with heterozygous APOA5 mutation normalized triglyceride levels with weight loss and fish oil therapy, and all 7 female patients were anemic. CONCLUSIONS: Our data suggest the possibility of novel loci for T1HLP. We observed that heterozygous APOA5 mutation can cause T1HLP but such patients may unexpectedly respond to therapy, and females with T1HLP suffer from anemia. Further studies of larger cohorts may elucidate more phenotype-genotypes relationships among T1HLP subtypes. PMID- 24793352 TI - Finding Z: a mathematical method for predicting tissue position after implant abutment-restoration placement. AB - A visible abutment-restorative interface is a problematic consequence, especially in the esthetic zone. This article presents formulas to predict the vertical tissue position around the abutment-restoration, which can be used both as a guide to the clinical situation and as an aid to computer-aided design and computer-aided manufacturing design. PMID- 24793351 TI - Using baculovirus/insect cell expressed recombinant actin to study the molecular pathogenesis of HCM caused by actin mutation A331P. AB - Recombinant WT human cardiac actin (WT actin) was expressed using the baculovirus/insect cell expression system, purified, and used to reconstitute the thin-filament of bovine cardiac muscle fibers, together with bovine cardiac tropomyosin (Tm) and troponin (Tn). Effects of [Ca(2+)], [ATP], [phosphate] and [ADP] on tension and tension transients were studied at 25 degrees C by using sinusoidal analysis, and the results were compared with those of native fibers and fibers reconstituted with purified bovine cardiac actin (BVC actin). In actin filament reconstituted fibers (without Tm/Tn), those reconstituted with WT actin showed exactly the same active tension as those reconstituted with purified BVC actin (WT: 0.75+/-0.06 T0, N=11; BVC: 0.73+/-0.07 T0, N=12, where T0 is the tension of original fibers before extraction). After Tm/Tn reconstitution, fibers reconstituted with WT actin generated 0.85+/-0.06 T0 (N=11) compared to 0.98+/ 0.04 T0 (N=12) recovered by those reconstituted with BVC actin. In the presence of Tm/Tn, WT actin reconstituted fibers showed exactly the same Ca(2+) sensitivity as those of the native fibers and BVC actin reconstituted fibers (pCa50: native fibers: 5.69+/-0.01, N=10; WT: 5.69+/-0.02, N=11; BVC: 5.68+/ 0.02, N=12). Sinusoidal analysis showed that the cross-bridge kinetics were the same among native fibers, BVC actin reconstituted fibers and WT actin reconstituted fibers, followed by reconstitution of Tm/Tn. These results demonstrate that baculovirus/insect cell expressed actin has no significant differences from tissue purified actin and can be used for thin-filament reconstitution assays. One hypertrophic cardiomyopathy (HCM) causing actin mutant A331P actin was also expressed and studied similarly, and the results were compared to those of the WT actin. In the reconstituted fibers, A331P significantly decreased the tension both in the absence of Tm/Tn (0.55+/-0.03 T0, N=13) and in their presence (0.65+/-0.02 T0, N=13) compared to those of the WT (0.75+/-0.06 T0 and 0.85+/-0.06 T0, respectively, N=11). A331P also showed decreased pCa50 (5.57+/-0.03, N=13) compared to that of WT (5.69+/-0.02, N=11). The cross-bridge kinetics and its distribution were similar between WT and A331P actin reconstituted fibers, indicating that force/cross-bridge was decreased by A331P. In conclusion, A331P causes a weakened cross-bridge force, which leads to a decreased active tension, reduces left-ventricular ejection fraction, and eventually results in the HCM phenotype. PMID- 24793353 TI - Effects of short-term heating on total polyphenols, anthocyanins, antioxidant activity and lectins of different parts of dwarf elder (Sambucus ebulus L.). AB - Dwarf elder (Sambucus ebulus L.) berries are rich in health-promoting phytochemicals such as polyphenols and anthocyanins, and display a significant antioxidant activity. They are also rich in two lectins (ebulin f and SELfd) that share amino acid sequence homology with the elderberry allergen Sam n1 present in Sambucus nigra pollen and fruits. Ebulin f displays toxicity by oral ingestion. This study was aimed at eliminating the toxicity of these lectins whilst having little or no effect on the antioxidant properties of dwarf elder berries. We thus investigated the potential effects of incubation in a boiling water bath of extracts from several parts of the plant on total polyphenol content, antioxidant activity, total anthocyanins, cyanidin-3-glycoside content, and the sensitivity of purified dwarf elder fruit lectins to a simulated gastric fluid. The study shows that five minutes of said heat treatment fully sensitized both lectins to pepsin digestion, whilst minimally reducing phenol and antioxidant as well as free radical scavenging activities to below 13%. It proved possible to eliminate the potential risks derived from the presence of lectins in dwarf elder juices without any significant reduction in the content of the antioxidant compounds. Dwarf elder berries may thus be a valuable nutritional source. PMID- 24793354 TI - Bioactive compounds, antioxidant and binding activities and spear yield of Asparagus officinalis L. AB - The aim of this investigation was to find a proper harvesting period and establishing fern number, which effects the spear yield, bioactive compounds and antioxidant activities of Asparagus officinalis L. Spears were harvested at 2, 4, and 6 weeks after sprouting. Control for comparison was used without harvest. Spears and total yield increased with prolonged spear harvest period. In harvest of 6 weeks long optimum spear yield was the highest and fern numbers were 5 ~ 8. Bioactive compounds (polyphenols, flavonoids, flavanols, tannins and ascorbic acid) and the levels of antioxidant activities by ferric-reducing/antioxidant power (FRAP) and cupric reducing antioxidant capacity (CUPRAC) assays in asparagus ethanol extracts significantly differed in the investigated samples and were the highest at 6 weeks harvest period (P < 0.05). The first and the second segments from the tip significantly increased with the increase of catalase (CAT). It was interesting to investigate in vitro how human serum albumin (HSA) interacts with polyphenols extracted from investigated vegetables. Therefore the functional properties of asparagus were studied by the interaction of polyphenol ethanol extracts with HSA, using 3D- FL. In conclusion, antioxidant status (bioactive compounds, binding and antioxidant activities) improved with the harvesting period and the first segment from spear tip. Appropriate harvesting is effective for higher asparagus yield and its bioactivity. PMID- 24793355 TI - Homogalacturonan deesterification during pollen-ovule interaction in Larix decidua Mill.: an immunocytochemical study. AB - Studies on angiosperm plants have shown that homogalacturonan present in the extracellular matrix of pistils plays an important role in the interaction with the male gametophyte. However, in gymnosperms, knowledge on the participation of HG in the pollen-ovule interaction is limited, and only a few studies on male gametophytes have been reported. Thus, the aim of this study was to determine the distribution of HG in male gametophytes and ovules during their interaction in Larix decidua Mill. The distribution of HG in pollen grains and unpollinated and pollinated ovules was investigated by immunofluorescence techniques using monoclonal antibodies that recognise high methyl-esterified HG (JIM7), low methyl esterified HG (JIM5) and calcium cross-linked HG (2F4). All studied categories of HG were detected in the ovule. Highly methyl-esterified HG was present in the cell walls of all cells throughout the interaction; however, the distribution of low methyl-esterified and calcium cross-linked HG changed during the course of interaction. Both of these categories of HG appeared only in the apoplast and the extracellular matrix of the ovule tissues, which interact with the male gametophyte. This finding suggests that in L. decidua, low methyl-esterified and calcium cross-linked HG play an important role in pollen-ovule interaction. The last category of HG is most likely involved in adhesion between the pollen and the ovule and might provide an optimal calcium environment for pollen grain germination and pollen tube growth. PMID- 24793356 TI - Organic polaritons: Long-distance relationships. PMID- 24793357 TI - Polariton-mediated energy transfer between organic dyes in a strongly coupled optical microcavity. AB - Strongly coupled optical microcavities containing different exciton states permit the creation of hybrid-polariton modes that can be described in terms of a linear admixture of cavity-photon and the constituent excitons. Such hybrid states have been predicted to have optical properties that are different from their constituent parts, making them a test bed for the exploration of light-matter coupling. Here, we use strong coupling in an optical microcavity to mix the electronic transitions of two J-aggregated molecular dyes and use both non resonant photoluminescence emission and photoluminescence excitation spectroscopy to show that hybrid-polariton states act as an efficient and ultrafast energy transfer pathway between the two exciton states. We argue that this type of structure may act as a model system to study energy-transfer processes in biological light-harvesting complexes. PMID- 24793359 TI - Making Mountains of Morality From Molehills of Virtue: Threat Causes People to Overestimate Their Moral Credentials. AB - Seven studies demonstrate that threats to moral identity can increase how definitively people think they have previously proven their morality. When White participants were made to worry that their future behavior could seem racist, they overestimated how much a prior decision of theirs would convince an observer of their non-prejudiced character (Studies 1a-3). Ironically, such overestimation made participants appear more prejudiced to observers (Study 4). Studies 5 to 6 demonstrated a similar effect of threat in the domain of charitable giving-an effect driven by individuals for whom maintaining a moral identity is particularly important. Threatened participants only enhanced their beliefs that they had proven their morality when there was at least some supporting evidence, but these beliefs were insensitive to whether the evidence was weak or strong (Study 2). Discussion considers the role of motivated reasoning, and implications for ethical decision making and moral licensing. PMID- 24793358 TI - Rigidity sensing and adaptation through regulation of integrin types. AB - Tissue rigidity regulates processes in development, cancer and wound healing. However, how cells detect rigidity, and thereby modulate their behaviour, remains unknown. Here, we show that sensing and adaptation to matrix rigidity in breast myoepithelial cells is determined by the bond dynamics of different integrin types. Cell binding to fibronectin through either alpha5beta1 integrins (constitutively expressed) or alphavbeta6 integrins (selectively expressed in cancer and development) adapts force generation, actin flow and integrin recruitment to rigidities associated with healthy or malignant tissue, respectively. In vitro experiments and theoretical modelling further demonstrate that this behaviour is explained by the different binding and unbinding rates of both integrin types to fibronectin. Moreover, rigidity sensing through differences in integrin bond dynamics applies both when integrins bind separately and when they compete for binding to fibronectin. PMID- 24793360 TI - Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors. AB - We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants. PMID- 24793361 TI - A novel anchoring system for use in a nonfusion scoliosis correction device. AB - BACKGROUND CONTEXT: Insertion of a pedicle screw in the mid- and high thoracic regions has a serious risk of facet joint damage. Because flexible implant systems require intact facet joints, we developed an enhanced fixation that is less destructive to spinal structures. The XSFIX is a posterior fixation system that uses cables that are attached to the transverse processes of a vertebra. PURPOSE: To determine whether a fixation to the transverse process using the XSFIX is strong enough to withstand the loads applied by the XSLATOR (a novel, highly flexible nonfusion implant system) and thus, whether it is a suitable alternative for pedicle screw fixation. STUDY DESIGN: The strength of a novel fixation system using transverse process cables was determined and compared with the strength of a similar fixation using polyaxial pedicle screws on different vertebral levels. METHODS: Each of the 58 vertebrae, isolated from four adult human cadavers, was instrumented with either a pedicle screw anchor (PSA) system or a prototype of the XSFIX. The PSA consisted of two polyaxial pedicle screws and a 5 mm diameter rod. The XSFIX prototype consisted of two bodies that were fixed to the transverse processes, interconnected with a similar rod. Each fixation system was subjected to a lateral or an axial torque. RESULTS: The PSA demonstrated fixation strength in lateral loading and torsion higher than required for use in the XSLATOR. The XSFIX demonstrated high enough fixation strength (in both lateral loading and torsion), only in the high and midthoracic regions (T10-T12). CONCLUSIONS: This experiment showed that the fixation strength of XSFIX is sufficient for use with the XSLATOR only in mid- and high thoracic regions. For the low thoracic and lumbar region, the PSA is a more rigid fixation. Because the performance of the new fixation system appears to be favorable in the high and midthoracic regions, a clinical study is the next challenge. PMID- 24793362 TI - Will we be treating tuberculosis with vaccines in the XXI century? PMID- 24793363 TI - Training of primary care health professionals and quality in spirometry. PMID- 24793364 TI - Prize contingency management for smoking cessation: a randomized trial. AB - BACKGROUND: Adjunctive behavioral smoking cessation treatments have the potential to improve outcomes beyond standard care. The present study had two aims: (1) compare standard care (SC) for smoking (four weeks of brief counseling and monitoring) to SC plus prize-based contingency management (CM), involving the chance to earn prizes on days with demonstrated smoking abstinence (carbon monoxide (CO) <=6 ppm); and (2) compare the relative efficacy of two prize reinforcement schedules-one a traditional CM schedule, and the second an early enhanced CM schedule providing greater reinforcement magnitude in the initial week of treatment but equal overall reinforcement. METHODS: Participants (N=81 nicotine-dependent cigarette smokers) were randomly assigned to one of the three conditions. RESULTS: Prize CM resulted in significant reductions in cigarette smoking relative to SC. These reductions were not apparent at follow-up. We found no meaningful differences between the traditional and enhanced CM conditions. CONCLUSIONS: Our findings reveal that prize CM leads to significant reductions in smoking during treatment relative to a control intervention, but the benefits did not extend long-term. PMID- 24793366 TI - Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. AB - AIMS: We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence. METHODS: This 6-site, 24 week Phase III randomized double-blind placebo controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome. RESULTS: The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of >=42 MUg/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths. CONCLUSIONS: The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence. PMID- 24793365 TI - Pretreatment measures of brain structure and reward-processing brain function in cannabis dependence: an exploratory study of relationships with abstinence during behavioral treatment. AB - BACKGROUND: Cannabis is widely abused, and efficacies of therapeutics for cannabis dependence remain suboptimal. Magnetic resonance imaging (MRI) may aid in the identification of biological markers for successful treatment outcomes (i.e., abstinence). METHODS: Twenty men with cannabis dependence and twenty non substance-using healthy comparison (HC) men underwent MRI scanning. Cannabis dependent individuals then participated in a 12-week randomized clinical trial of behavioral treatments (contingency management (CM), cognitive behavioral therapy (CBT) or both). Pretreatment functional and structural data were compared between the cannabis-dependent and HC participants. In addition, individuals with cannabis dependence were subdivided based on the successful achievement of 21 days of consecutive abstinence during treatment to assess whether abstinent versus non-abstinent cannabis-dependent participants displayed different pretreatment functional and structural characteristics when compared to HC participants. RESULTS: In comparison to HC participants, cannabis-dependent participants demonstrated greater ventral striatal activation during the receipt of losing outcomes and smaller putamenal volumes. Cannabis-dependent participants who did not subsequently achieve 21 days of consecutive abstinence had increased activity within the striatum during the receipt of losing outcomes, relative to HC participants. Cannabis-dependent participants who did not achieve 21 days of abstinence had decreased bilateral putamen volumes prior to treatment, relative to HC participants. CONCLUSIONS: Individual differences in pretreatment striatal function and structure may relate to individual differences in treatment responses for cannabis dependence. While mechanisms underlying these associations require further exploration, the striatum might mediate treatment responses via its role in associative reward-learning (e.g., through skills training in CBT or reinforcement of abstinence in CM). PMID- 24793367 TI - Concordance between DSM-5 and DSM-IV nicotine, alcohol, and cannabis use disorder diagnoses among pediatric patients. AB - BACKGROUND: The recently published Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) includes several major revisions to substance use diagnoses. Studies have evaluated the impact of these changes among adult samples but research with adolescent samples is lacking. METHODS: 525 adolescents (93% African American) awaiting primary care appointments in Baltimore, Maryland were recruited for a study evaluating a substance use screening instrument. Participants were assessed for DSM-5 nicotine, alcohol, and cannabis use disorder, DSM-IV alcohol and cannabis abuse, and DSM-IV dependence for all three substances during the past year using the modified Composite International Diagnostic Interview-2, Substance Abuse Module. Contingency tables examining DSM 5 vs. DSM-IV joint frequency distributions were examined for each substance. RESULTS: Diagnoses were more prevalent using DSM-5 criteria compared with DSM-IV for nicotine (4.0% vs. 2.7%), alcohol (4.6% vs. 3.8%), and cannabis (10.7% vs. 8.2%). Cohen's kappa, Somers' d, and Cramer's V ranged from 0.70 to 0.99 for all three substances. Of the adolescents categorized as "diagnostic orphans" under DSM-IV, 7/16 (43.8%), 9/29 (31.0%), and 13/36 (36.1%) met criteria for DSM-5 disorder for nicotine, alcohol, and cannabis, respectively. Additionally, 5/17 (29.4%) and 1/21 (4.8%) adolescents who met criteria for DSM-IV abuse did not meet criteria for a DSM-5 diagnosis for alcohol and cannabis, respectively. CONCLUSIONS: Categorizing adolescents using DSM-5 criteria may result in diagnostic net widening-particularly for cannabis use disorders-by capturing adolescents who were considered diagnostic orphans using DSM-IV criteria. Future research examining the validity of DSM-5 substance use disorders with larger and more diverse adolescent samples is needed. PMID- 24793368 TI - Alcohol consumption and symptoms as predictors for relapse of DSM-5 alcohol use disorder. AB - BACKGROUND: Alcohol consumption levels and alcohol use disorder (AUD) symptoms may serve as easily quantifiable markers for AUD relapse after remission and might help prevention workers identify at-risk individuals. We investigated the predictive value of alcohol consumption and AUD symptoms on relapse. METHODS: Data are from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS 2). We selected 506 people in >=12-month DSM-5 AUD remission at baseline and assessed their status at 3-year follow-up. AUD symptoms and drinking patterns were assessed using the Composite International Diagnostic Interview 3.0. Time since remission was assessed retrospectively at baseline and ranged from 1 to 48 years. Predictors for relapse were examined using Cox regression analysis. RESULTS: Cumulative AUD relapse rate was 5.6% at 5 years, 9.1% at 10 years and 12.0% at 20 years. Relapse was predicted by both medium (15-28/22-42 drinks weekly for women/men) and high (>=29/43) past alcohol intake, 6+ lifetime AUD symptoms, 'impaired control over use', and at-risk (>=8/15) current intake. The risk of relapse was especially high when medium or high past intake or 6+ lifetime symptoms coincided with current at-risk drinking. CONCLUSIONS: Only a minority of people in DSM-5 AUD remission relapsed, but the risk of relapse increased substantially with the presence of at least one of the risk factors. Moreover, at-risk current drinking coupled with other risk factors substantially increased the likelihood of relapse. Therefore, current drinking may provide an adequate reference point for relapse prevention. PMID- 24793369 TI - Alcohol and marijuana use in early adulthood for at-risk men: time-varying associations with peer and partner substance use. AB - BACKGROUND: Time-varying associations of 185 at-risk men's (from the Oregon Youth Study) substance use with that of their peers and partner over a 10-year period (ages 23 to 32 years) were examined. Moderation of effects by time with peers and partner and their age were tested. METHOD: Growth models were used to predict changes in heavy episodic drinking (HED) alcohol use and marijuana use as a function of substance use by their female partners and male peers. RESULTS: Time with peers and peer substance use significantly predicted HED (ORs=1.6, 2.3), alcohol use (ORs=1.6, 2.1), volume of alcohol use (IRRs=1.5, 1.3), and marijuana use (ORs=12.8, 1.7); peer marijuana use predicted volume of marijuana use (B=2.5). Partner substance use significantly predicated marijuana volume (B=2.7). Partner alcohol use predicted alcohol volume (IRR=1.1), but was moderated by time with partner and age (IRR=1.0). Time with partner and partner marijuana use predicted marijuana use (OR=0.5, 2.7), as did the interaction of the two (OR=3.8). CONCLUSIONS: Outcome-specific substance use of peers and partners was significantly associated with indicators of alcohol and marijuana use in men's early adulthood, with robust effects of peer substance use through age 30 years and with time spent with peers influencing alcohol use. Time with partner was protective against marijuana use unless the partner used marijuana. Peers and partners should be considered in intervention efforts to effectively reduce men's substance use in early adulthood. PMID- 24793370 TI - A novel bromodeoxyuridine-resistant wild boar lung cell line facilitates generation of African swine fever virus recombinants. AB - Manipulation of African swine fever virus (ASFV) genomes, in particular those from field strains, is still a challenge. We have shown recently that generation of a green-fluorescent-protein-expressing, thymidine-kinase-negative (TK-) mutant of the low-pathogenic African swine fever virus field strain NHV was supported by a TK- Vero cell line. Since NHV, like other ASFV field strains, does not replicate well in Vero cells, a bromodeoxyuridine (BrdU)- resistant cell line derived from wild boar lung (WSL) cells, named WSL-Bu, was selected. WSL cells were used because they are suitable for productive replication of NHV and other ASFV field strains. Here, we show that WSL-Bu cells enable positive selection of both TK- and TK+ ASFV recombinants, which allows for novel strategies for construction of ASFV mutants. We further demonstrate for a low-pathogenic ASFV strain that TK expression is required for infectious replication in macrophages infected at low multiplicity and that vaccinia TK fully complements ASFV TK in this respect. PMID- 24793371 TI - Evaluation of peak force of a manually operated chiropractic adjusting instrument with an adapter for use in animals. AB - OBJECTIVE: This study was designed to assess the peak force of a manually operated chiropractic adjusting instrument, the Activator Adjusting Instrument 4 (AAI 4), with an adapter for use in animals, which has a 3- to 4-fold smaller contact surface area than the original rubber tip. METHODS: Peak force was determined by thrusting the AAI 4 with the adapter or the original rubber tip onto a load cell. First, the AAI 4 was applied perpendicularly by a doctor of chiropractic onto the load cell. Then, the AAI 4 was fixed in a rigid framework and applied to the load cell. This procedure was done to prevent any load on the load cell before the thrust impulse. In 2 situations, trials were performed with the AAI 4 at all force settings (settings I, II, III, and IV, minimum to maximum, respectively). A total of 50000 samples per second over a period of 3 seconds were collected. RESULTS: In 2 experimental protocols, the use of the adapter in the AAI 4 increased the peak force only with setting I. The new value was around 80% of the maximum value found for the AAI 4. Nevertheless, the peak force values of the AAI 4 with the adapter and with the original rubber tip in setting IV were similar. CONCLUSION: The adapter effectively determines the maximum peak force value at force setting I of AAI 4. PMID- 24793373 TI - Recent applications of superresolution microscopy in neurobiology. AB - Chemical synapses in brain are structural differentiations where excitatory or inhibitory signals are vectorially transmitted between two neurons. Excitatory synapses occur mostly on dendritic spines, submicron sized protrusions of the neuronal dendritic arborizations. Axons establish contacts with these tiny specializations purported to be the smallest functional processing units in the central nervous system. The minute size of synapses and their macromolecular constituents creates an inherent difficulty for imaging but makes them an ideal object for superresolution microscopy. Here we discuss some representative examples of nanoscopy studies, ranging from quantification of receptors and scaffolding proteins in postsynaptic densities and their dynamic behavior, to imaging of synaptic vesicle proteins and dendritic spines in living neurons or even live animals. PMID- 24793372 TI - A systematic review of the angular values obtained by computerized photogrammetry in sagittal plane: a proposal for reference values. AB - OBJECTIVE: Reference values for postural alignment in the coronal plane, as measured by computerized photogrammetry, have been established but not for the sagittal plane. The objective of this study is to propose reference values for angular measurements used for postural analysis in the sagittal plane for healthy adults. METHODS: Electronic databases (PubMed, BVS, Cochrane, Scielo, and Science Direct) were searched using the following key words: evaluation, posture, photogrammetry, and software. Articles published between 2006 and 2012 that used the PAS/SAPO (postural assessment software) were selected. Another inclusion criterion was the presentation of, at least, one of the following measurements: head horizontal alignment, pelvic horizontal alignment, hip angle, vertical alignment of the body, thoracic kyphosis, and lumbar lordosis. Angle samples of the selected articles were grouped 2 by 2 in relation to an overall average, which made possible total average, variance, and SD calculations. RESULTS: Six articles were included, and the following average angular values were found: 51.42 degrees +/- 4.87 degrees (head horizontal alignment), -12.26 degrees +/- 5.81 degrees (pelvic horizontal alignment), -6.40 degrees +/- 3.86 degrees (hip angle), and 1.73 degrees +/- 0.94 degrees (vertical alignment of the body). None of the articles contained the measurements for thoracic kyphosis and lumbar lordosis. CONCLUSION: The reference values can be adopted as reference for postural assessment in future researches if the same anatomical points are considered. PMID- 24793374 TI - Quantitative super-resolution microscopy: pitfalls and strategies for image analysis. AB - Super-resolution microscopy is an enabling technology that allows biologists to visualize cellular structures at nanometer length scales using far-field optics. To break the diffraction barrier, it is necessary to leverage the distinct molecular states of fluorescent probes. At the same time, the existence of these different molecular states and the photophysical properties of the fluorescent probes can complicate data quantification and interpretation. Here, we review the pitfalls in super-resolution data analysis that must be avoided for proper interpretation of images. PMID- 24793375 TI - Chimaphilin induces apoptosis in human breast cancer MCF-7 cells through a ROS mediated mitochondrial pathway. AB - Chimaphilin, 2,7-dimethyl-1,4-naphthoquinone, is extracted from pyrola [Passiflora incarnata Fisch.]. In this study, the anticancer activity and underlying mechanisms of chimaphilin toward human breast cancer MCF-7 cells are firstly investigated. Chimaphilin could inhibit the viability of MCF-7 cells in a concentration-dependent manner, and the IC50 value was 43.30MUM for 24h. Chimaphilin markedly induced apoptosis through the investigation of characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining. Flow cytometry assay revealed that chimaphilin triggered a significant generation of ROS and disruption of mitochondrial membrane potential. Additionally, western blotting assay showed that chimaphilin suppressed Bcl-2 level and enhanced Bad level, then activated caspase-9 and caspase-3, and further activated the poly ADP-ribose polymerase (PARP), finally induced cell apoptosis involving the mitochondrial pathway. Furthermore, free radical scavengers N-acetyl-L-cysteine (NAC) pretreatment test testified that chimaphilin could increase the generation of ROS, then induce cell apoptosis. In general, the present results demonstrated that chimaphilin induced apoptosis in human breast cancer MCF-7 cells via a ROS mediated mitochondrial pathway. PMID- 24793376 TI - Chronic exposure to aluminum and melatonin through the diet: neurobehavioral effects in a transgenic mouse model of Alzheimer disease. AB - Aluminum (Al) is a known neurotoxic element involved in the etiology of some serious neurodegenerative disorders such as Alzheimer disease (AD). Antioxidants like melatonin might protect neurons against the damage produced in AD. The APPSWE (Tg2576) transgenic mouse is one of the most used animal models developed to mimic AD damage. In the present study, wild type and Tg2576 mice were orally exposed during 14 months to Al, melatonin, and citric acid, as well as to all possible combinations between them. At 17 months of age, mice were evaluated for behavior using the open-field test and the Morris water maze. Transgenic animals exposed to melatonin only and to Al plus citric acid plus melatonin showed a good acquisition. No effects on acquisition in the Morris water maze were observed in wild type mice. With respect to the retention of the task, only melatonin wild type animals, and Al plus citric acid plus melatonin transgenic mice showed retention during the acquisition. Control wild type animals and Al plus citric acid plus melatonin transgenic mice showed good long term retention. Melatonin improved learning and spatial memory in Al-exposed transgenic mice. PMID- 24793377 TI - Comparative study of bisphenol A and its analogue bisphenol S on human hepatic cells: a focus on their potential involvement in nonalcoholic fatty liver disease. AB - For several decades, people have been in contact with bisphenol A (BPA) primarily through their diet. Nowadays it is gradually replaced by an analogue, bisphenol S (BPS). In this study, we compared the effects of these two bisphenols in parallel with the positive control diethylstilbestrol (DES) on different hepatocyte cell lines. Using a cellular impedance system we have shown that BPS is less cytotoxic than BPA in acute and chronic conditions. We have also demonstrated that, contrary to BPA, BPS is not able to induce an increase in intracellular lipid and does not activate the PXR receptor which is known to be involved in part, in this process. In parallel, it failed to modulate the expression of CYP3A4 and CYP2B6, the drug transporter ABCB1 and other lipid metabolism genes (FASN, PLIN). However, it appears to have a weak effect on GSTA4 protein expression and on the Erk1/2 pathway. In conclusion, in contrast to BPA, BPS does not appear to induce the metabolic syndrome that may lead to non-alcoholic fatty liver disease (NAFLD), in vitro. Although we have to pay special attention to BPS, its use could be less dangerous concerning this toxicological endpoint for human health. PMID- 24793378 TI - EGFR activating mutations and their association with response to platinum-doublet chemotherapy in Brazilian non-small cell lung cancer patients. AB - The aim of the study was to analyze the frequency of epidermal growth factor receptor (EGFR) mutations in Brazilian non-small cell lung cancer patients and to correlate these mutations with response to benefit of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). Our cohort consisted of prospective patients with NSCLCs who received chemotherapy (platinum derivates plus paclitaxel) at the [UNICAMP], Brazil. EGFR exons 18-21 were analyzed in tumor derived DNA. Fifty patients were included in the study (25 with adenocarcinoma). EGFR mutations were identified in 6/50 (12 %) NSCLCs and in 6/25 (24 %) adenocarcinomas; representing the frequency of EGFR mutations in a mostly self reported White (82.0 %) southeastern Brazilian population of NSCLCs. Patients with NSCLCs harboring EGFR exon 19 deletions or the exon 21 L858R mutation were found to have a higher chance of response to platinum-paclitaxel (OR 9.67 [95 % CI 1.03-90.41], p = 0.047). We report the frequency of EGFR activating mutations in a typical southeastern Brazilian population with NSCLC, which are similar to that of other countries with Western European ethnicity. EGFR mutations seem to be predictive of a response to platinum-paclitaxel, and additional studies are needed to confirm or refute this relationship. PMID- 24793379 TI - Travel beyond the home neighborhood for delinquent behaviors: moderation of home neighborhood influences. AB - Neighborhood research indicates that adolescents are at higher risk for delinquency when they reside in neighborhoods low in collective efficacy, low in perceived prosocial norms and values, and high in availability of substances and firearms. However, as adolescents develop, they are more likely to independently travel during their day-to-day activities, and the effects of their home neighborhood may be weakened as they spend time in other communities. The current study surveyed 179 adolescents involved in the juvenile justice system in a small Midwestern city on their perceptions of their home neighborhood and self-reported delinquency. While perceptions of several home neighborhood characteristics significantly predicted severity of delinquency for all respondents, neighborhood effects were significantly weaker for those adolescents who tended to engage in illegal behaviors outside their home neighborhood. These findings suggest that future research and prevention efforts should include more attention to how adolescents may be influenced by multiple neighborhoods. PMID- 24793380 TI - The relationship between emotional problems and subsequent school attainment: a meta-analysis. AB - Longitudinal studies have provided mixed findings regarding the relationship between emotional problems and subsequent poor school attainment. A meta-analysis of 26 community-based studies of children and adolescents was performed. Results revealed a prospective association between emotional problems and poor school attainment. More consistent associations were found for depression than anxiety. Moderator analyses indicated that some of the heterogeneity between studies may be due to age and gender, with reduced heterogeneity particularly notable for school grades during early adolescence and for anxiety by gender. Findings suggest that early identification and provision of support for young people with emotional problems may be helpful for improving academic outcomes such as school attainment. PMID- 24793381 TI - The appearance culture between friends and adolescent appearance-based rejection sensitivity. AB - Appearance-based rejection sensitivity (appearance-RS) is the tendency to anxiously expect, readily perceive, and overreact to signs of rejection based on one's appearance, and is associated with a number of psychological and social problems (Park, 2007). This study of 380 adolescents (Mage = 13.84) examined a model linking the appearance culture between friends with appearance-RS in adolescent boys and girls, via internalisation of appearance ideals, social comparison, and body dissatisfaction. Gender differences were also tested. Consistent with expectations, appearance-focused characteristics of the friendship context were associated with heightened appearance-RS via internalization of appearance ideals, social comparison, and body dissatisfaction. The appearance-focused friend characteristics that were associated with appearance-RS included exposure to friends' appearance conversations, appearance teasing that caused distress, and perceived pressure to be attractive. Notably, associations rarely differed for boys and girls, with one exception: the association between BMI and body dissatisfaction was stronger in girls than in boys. PMID- 24793382 TI - The protective role of prosocial behaviors on antisocial behaviors: the mediating effects of deviant peer affiliation. AB - Prosocial behaviors, actions intended to help others, may serve a protective function against association with deviant peers and subsequent delinquent and antisocial behaviors. The present study examined the relations among specific types of prosocial behaviors, deviant peer affiliation, and delinquent and aggressive behaviors. Six hundred and sixty-six adolescents (46% girls; M age = 15.33, SD = .47) from Valencia, Spain completed questionnaires of prosocial behaviors, affiliation with deviant peers, antisocial behaviors, and aggression. Results showed that antisocial behaviors were negatively related only to specific forms of prosocial behaviors. Further analyses showed that deviant peer affiliation mediated the relations between compliant prosocial behavior and delinquency and aggression. Although altruism was not directly related to delinquency and aggression, it was indirectly linked to the behaviors via deviant peer affiliation. Discussion focuses on the relevance of specific forms of prosocial behaviors to antisocial behaviors and the risk of deviant peers for prosocial youth. PMID- 24793383 TI - International note: what factors are associated with reading, mathematics, and science literacy of Indian adolescents? A multilevel examination. AB - A sample of 15-year-olds in India took part in the Program for International Student Assessment (PISA) for the first time in 2010. The PISA reading, mathematics, and science literacy scores of Indian adolescents were considerably lower than their counterparts in most PISA participating countries. In order to explore potential reasons for this, the present study, therefore, drawing on data from the fourth cycle of PISA and employing multilevel modeling, examined the relations of student- and school-level factors to reading, mathematics, and science literacy among 4826 15-year-old students from 213 schools in India. Gender, metacognitive learning strategies, students' positive attitudes toward school, and students' positive perceptions of classroom climate were found to be significantly associated with Indian adolescents' performance on the PISA assessment. PMID- 24793384 TI - Determinants of adolescents' ineffective and improved coping with cyberbullying: a Delphi study. AB - The study's aim was to obtain an overview of all relevant variables involved in ineffective coping behavior and improvement in coping behavior as it pertains to cyberbullying among adolescents, in order to systematically develop a theory- and evidence-based intervention. This was done by means of a three round online Delphi study. First, 20 key experts listed possible relevant determinants. Next, 70 experts scored these determinants on their relevance and finally, experts rerated relevance of each determinant based on group median scores. The experts agreed that 115 items are relevant for ineffective (62) or improvement in (53) coping behavior. New found determinants were the extent to which one can adjust behavior upon feedback, impulsivity, self-confidence, communication style, personality, decision-making skills, conflict resolution skills, previous participation in personal resilience training, social relationships, rumors and self-disclosure. We conclude that the Delphi technique is useful in discovering new and relevant determinants of behavior. PMID- 24793385 TI - International note: parenting, academic achievement and problem behaviour among Chinese adolescents. AB - In light of differing findings regarding the relations between parenting and adolescent academic/behavioural outcomes and the dearth of such research in a Chinese context, we conducted research to examine the relationship between parental supervision/attachment and academic achievement/problem behaviour among mainland Chinese adolescents. In the study, 636 Grade 11 students completed a questionnaire comprising parenting and problem behaviour variables complemented by academic achievement (GPA) data drawn from school records. The study found that the relations between parenting (parental supervision and attachment) and Chinese adolescents' academic and behavioural outcomes are very weak. PMID- 24793386 TI - Measurement of the bystander intervention model for bullying and sexual harassment. AB - Although peer bystanders can exacerbate or prevent bullying and sexual harassment, research has been hindered by the absence of a validated assessment tool to measure the process and sequential steps of the bystander intervention model. A measure was developed based on the five steps of Latane and Darley's (1970) bystander intervention model applied to bullying and sexual harassment. Confirmatory factor analysis with a sample of 562 secondary school students confirmed the five-factor structure of the measure. Structural equation modeling revealed that all the steps were influenced by the previous step in the model, as the theory proposed. In addition, the bystander intervention measure was positively correlated with empathy, attitudes toward bullying and sexual harassment, and awareness of bullying and sexual harassment facts. This measure can be used for future research and to inform intervention efforts related to the process of bystander intervention for bullying and sexual harassment. PMID- 24793387 TI - Brief report: personality correlates of susceptibility to peer influence in adolescence. AB - Adolescents show a heightened susceptibility to peer influence compared to adults. Individual differences in this susceptibility exist, yet there has been little effort to link these with broader personality processes. Reward sensitivity and impulsive behaviour are also heightened in adolescence and could affect the tendency to be influenced by peers. This study examined associations between self-reported resistance to peer influence, facets of reward sensitivity and impulsivity, and subjective social status in a sample of 269 British sixth form students (mean age 16.79). Multiple regression analyses showed that negative and positive urgency were significantly negatively associated with resistance to peer influence. The relationship between negative urgency and resistance was moderated by subjective social status, such that individuals reporting low status showed a stronger negative relationship. Results suggest that a susceptibility to peer influence is linked with a tendency to act impulsively when in heightened emotional states. Adolescents high in negative urgency who feel lower in their social hierarchy may be particularly vulnerable. PMID- 24793389 TI - Brief report: can irritability act as a marker of psychopathology? AB - Irritability is ubiquitous in child and adolescent psychopathology. This study aimed to determine if the Affective Reactivity Index (ARI), a measure of irritability, could be used to screen for psychopathology in adolescents. The clinical sample comprised 31 adolescents with a DSM-IV diagnosis. The control sample was 31 gender and age matched adolescents recruited through schools. Both samples completed a test battery that included the Affective Reactivity Index. The clinical participants reported significantly higher levels of irritability than the control sample by both self- and parent-report. Using ROC analysis a cut off value of 4 on the self-report ARI was found to be optimal for indicating psychopathology; with a specificity of 77.4% and a sensitivity of 77.4%, the area under the curve was 0.86. This paper provides evidence to suggest that irritability may be used as a general predictor of psychopathology in adolescents. PMID- 24793388 TI - Psychosocial working conditions: an analysis of emotional symptoms and conduct problems amongst adolescent students. AB - This study explored how psychosocial features of the schoolwork environment are associated with students' mental health. Data was drawn from 3699 ninth grade (15 year-old) Swedish students participating in the Health Behaviour in School-Aged Children survey. Using Structural Equation Modelling, perceived school demands, decision control and social support from teachers, classmates and parents were examined in relation to students' emotional and conduct problems. Higher demands were associated with greater emotional symptoms and conduct problems. Although weaker social support predicted emotional symptoms and conduct problems, the relative influence of teachers, classmates and parents differed. Teacher support was more closely associated with conduct problems, particularly for girls, while classmate support was more strongly related to emotional symptoms. The findings indicate that while excessive school pressure is associated with poorer mental health, social support can assist in optimising adolescents' emotional health and adaptive behaviour, as well as shaping perceptions of demands. PMID- 24793390 TI - Evening adolescents: the role of family relationships and pubertal development. AB - Accumulating evidence suggests that evening-type adolescents are exposed to a number of determinants that might have a negative impact on their health condition. Despite the fact that biological and psychosocial factors are interrelated, their impacts on the shift toward eveningness during puberty have been considered only separately. In this study, the effects of frequency of conflicts and functional autonomy on the relationship between pubertal development and Morningness-Eveningness (M-E) were tested together. A sample of 2081 adolescents aged 12-16 completed pubertal development, M-E, family frequency of conflicts and functional autonomy scales. Results indicated that greater functional autonomy and more conflicts in the family were unique predictors of greater eveningness, and they both together were better predictors of M-E than an advanced age and pubertal development. Apart from biological development, family relationship seems an important factor explaining progressive tendency toward eveningness during puberty and adolescence. Some implications to adolescent development were indicated. PMID- 24793392 TI - Homeschooled adolescents in the United States: developmental outcomes. AB - The mission of schools has broadened beyond academics to address risk behaviors such as substance use, delinquency, and socialization problems. With an estimated 3.4% of all U.S. youth being homeschooled, this study examines how U.S. homeschoolers fare on these outcomes given their lack of access to these school services. Adolescents (ages 12-17) from the 2002 through 2011 National Surveys of Drug Use and Health (NSDUH) were divided based on school status (home vs. traditional schooling) and religious affiliation (stronger vs. weaker). Controlling for demographic differences, homeschoolers with weaker religious ties were three times more likely to report being behind their expected grade level and two and a half times more likely to report no extracurricular activities in the prior year than their traditionally schooled counterparts. This group was also more likely to report lax parental attitudes toward substance use. Findings suggest homeschoolers with weaker religious ties represent an at-risk group. PMID- 24793391 TI - The development of adolescent self-regulation: reviewing the role of parent, peer, friend, and romantic relationships. AB - Self-regulation plays an important role in adolescent development, predicting success in multiple domains including school and social relationships. While researchers have paid increasing attention to the influence of parents on the development of adolescent self-regulation, we know little about the influence of peers and friends and even less about the influence of romantic partners on adolescent development of self-regulation. Extant studies examined a unidirectional model of self-regulation development rather than a bidirectional model of self-regulation development. Given that relationships and self regulation develop in tandem, a model of bidirectional development between relationship context and adolescent self-regulation may be relevant. This review summarizes extant literature and proposes that in order to understand how adolescent behavioral and emotional self-regulation develops in the context of social relationships one must consider that each relationship builds upon previous relationships and that self-regulation and relationship context develop bidirectionally. PMID- 24793393 TI - Social support, stress, health, and academic success in Ghanaian adolescents: a path analysis. AB - The aim of this study is to gain a better understanding of the role psychosocial factors play in promoting the health and academic success of adolescents. A total of 770 adolescent boys and girls in Senior High Schools were randomly selected to complete a self-report questionnaire. School reported latest terminal examination grades were used as the measure of academic success. Structural equation modelling indicated a relatively good fit to the posteriori model with four of the hypothesised paths fully supported and two partially supported. Perceived social support was negatively related to stress and predictive of health and wellbeing but not academic success. Stress was predictive of health but not academic success. Finally, health and wellbeing was able to predict academic success. These findings have policy implications regarding efforts aimed at promoting the health and wellbeing as well as the academic success of adolescents in Ghana. PMID- 24793394 TI - Emotional intelligence and psychological maladjustment in adolescence: a systematic review. AB - The study of emotional intelligence (EI) and its association with psychological maladjustment in adolescence is a new and active area of research. However, the diverse range of EI measurements and aspects of psychological maladjustment examined make it difficult to synthesize the findings and apply them to practice. Therefore, we conducted a systematic review to summarize the relationship between EI and adolescents' emotional problems, eating disorder symptoms, addictions, and maladaptive coping. Using English and Spanish keywords, we identified 32 studies that found a negative association between EI and internalizing problems, depression, and anxiety. EI was also associated with less substance abuse and with better coping strategies. These associations differed slightly depending on whether EI was evaluated based on self-reporting or by testing maximum performance. We highlight methodological limitations in the literature on EI and adolescence, and we discuss potentially important areas for future research. PMID- 24793395 TI - Widening the participation gap: the effect of educational track on reported voting in England. AB - This article explores the effect of tracked education in upper secondary on voting behaviour. It discusses two causal mechanisms that link tracked education to greater disparities of political participation: the curriculum and peer socialization. Data of Waves 1, 2, 5 and 7 of the Longitudinal Study of Young People in England (LSYPE) is used to assess the hypothesis that educational track has an independent effect on voting. Controlling for several pre- and post-track influences, the paper shows that students who have taken vocational courses in less prestigious schools indeed have lower reported voting levels at age 20 than those who have pursued an academic qualification (A levels) in prestigious schools. It is proposed that the effect of tracked education on political participation is likely to vary across Europe and that this variation may well be explained by differences across Europe in the extent to which the academic and vocational tracks are integrated, both in terms of the curriculum and in their social intake. PMID- 24793396 TI - Negative cognitive style and perceived social support mediate the relationship between aggression and NSSI in hospitalized adolescents. AB - Despite the well-documented association between aggression and NSSI among adolescents, relatively little research has been conducted on the mechanisms underlying this relationship. The purpose of this study was to investigate potential socio-cognitive mechanisms through which aggression and NSSI are related. Participants were 186 adolescents (ages 13-18) recruited from a psychiatric inpatient facility in the northeastern United States. According to teen report, 57.5% of the sample endorsed NSSI in the previous year. Mediation was tested using the modern bootstrapping technique described by Hayes, using 5000 resamples with replacement, including sex and depression diagnosis as covariates. Results demonstrated that greater negative self-talk, a more negative cognitive style, and lower perceived family support were all significant mediators of the relationship between aggression and greater frequency of NSSI, whereas perceived social support from friends was not a significant mediator. Limitations, clinical implications, and future research directions of the current research are discussed. PMID- 24793397 TI - Dopey dopamine: high tonic results in ironic performance. AB - Financial incentives are commonly used as motivational tools to enhance performance. Decades of research have established that the neurotransmitter dopamine (DA) is the fuel that propels reward-motivated behavior, yet a new PET study questions whether dopamine is beneficial to performance, showing that tonic DA synthesis predicts performance decrements when incentives are high. PMID- 24793398 TI - Building, testing and validating a set of home-made von Frey filaments: a precise, accurate and cost effective alternative for nociception assessment. AB - BACKGROUND: A von Frey filament (vFF) is a type of aesthesiometer usually made of nylon perpendicularly held in a base. It can be used in paw withdrawal pain threshold assessment, one of the most popular tests for pain evaluation using animal models. For this test, a set of filaments, each able to exert a different force, is applied to the animal paw, from the weakest to the strongest, until the paw is withdrawn. NEW METHOD: We made 20 low cost vFF using nylon filaments of different lengths and constant diameter glued perpendicularly to the ends of popsicle sticks. They were calibrated using a laboratory balance scale. Building and calibrating took around 4h and confirmed the theoretical prediction that the force exerted is inversely proportional to the length and directly proportional to the width of the filament. RESULTS: The calibration showed that they were precise and accurate. We analyzed the paw withdrawal threshold assessed with the set of home-made vFF and with a high quality commercial set of 5 monofilaments vFF (Stoelting, Wood Dale, USA) in two groups (n=5) of healthy mice. COMPARISON WITH EXISTING METHODS: The home-made vFF precisely and accurately measured the hind paw withdrawal threshold (20.3+/-0.9 g). The commercial vFF have different diameters while our set has the same diameter avoiding the problem of lower sensitivity to larger diameter filaments. CONCLUSION: Building a set of vFF is easy, cost effective, and depending on the kind of tests, can increase precision and accuracy of animal nociception evaluation. PMID- 24793399 TI - Spontaneous versus trained numerical abilities. A comparison between the two main tools to study numerical competence in non-human animals. AB - A large body of experimental evidence shows that animals as diverse as mammals, birds, and fish are capable of processing numerical information. Considerable differences have been reported in some cases among species and a wide debate currently surrounds the issue of whether all vertebrates share the same numerical systems or not. Part of the problem is due to the fact that these studies often use different methods, a circumstance that potentially introduces confounding factors in a comparative analysis. In most studies, two main methodological approaches have been used: spontaneous choice tests and training procedures. The former approach consists of presenting to the subjects two groups of biologically relevant stimuli (e.g., food items or social companions) differing in numerosity with the assumption that if they are able to discriminate between the two quantities, they are expected to spontaneously select the larger/smaller quantity. In the latter approach, subjects undergo extensive training in which some neutral stimuli (e.g., a quantity of dots) are associated with a reward and the capacity to learn a numerical rule is taken as evidence of numerical abilities. We review the literature on this topic, highlighting the relevance, and potential weaknesses in controlling confounding factors obtained with either approach. PMID- 24793400 TI - Social behavior of zebrafish: from synthetic images to biological mechanisms of shoaling. AB - The zebrafish strikes a good balance between system complexity and practical simplicity and as a result it is becoming increasingly frequently utilized in biomedical research as a translational tool. Numerous human brain disorders are associated with abnormal social behavior and the zebrafish has been suggested for modeling such disorders. To start this line of research, however, one may need to first thoroughly examine the laboratory organism, zebrafish, and its features, social behavior in this case. Proper methods need be developed to induce and quantify social behavior. These paradigms may be able to open a window to the brain and facilitate the understanding of the biological mechanisms of social behavior and its abnormalities. This review is based on an oral paper presented at the last Measuring Behavior Conference, and as such it is mainly focused on research conducted in my own laboratory. Tracing the temporal progression of our own work, it discusses questions including what shoaling is, how it can be induced and measured and how it can be utilized in the modeling of certain human brain disorders, for example, alcohol induced abnormalities. PMID- 24793401 TI - Effects of rhamnolipid and initial compost particle size on the two-stage composting of green waste. AB - Composting is a potential alternative to green waste incineration or deposition in landfills. The effects of the biosurfactant rhamnolipid (RL) (at 0.0%, 0.15%, and 0.30%) and initial compost particle size (IPS) (10, 15, and 25 mm) on a new, two-stage method for composting green waste was investigated. A combination of RL addition and IPS adjustment improved the quality of the finished compost in terms of its physical characteristics, pH, C/N ratio, nutrient content, cellulose and hemicellulose contents, water-soluble carbon (WSC) content, xylanase and CMCase activities, numbers of culturable microorganisms (bacteria, actinomycetes, and fungi), and toxicity to germinating seeds. The production of a stable and mature compost required only 24 days with the optimized two-stage composting method described here rather than the 90-270 days required with traditional composting. The best quality compost was obtained with 0.15% RL and an IPS of 15 mm. PMID- 24793402 TI - A general kinetic model for the hydrothermal liquefaction of microalgae. AB - We developed a general kinetic model for hydrothermal liquefaction (HTL) of microalgae. The model, which allows the protein, lipid, and carbohydrate fractions of the cell to react at different rates, successfully correlated experimental data for the hydrothermal liquefaction of Chlorella protothecoides, Scenedesmus sp., and Nannochloropsis sp. The model can faithfully account for the influence of time and temperature on the gravimetric yields of gas, solid, biocrude, and aqueous-phase products from isothermal HTL of a 15 wt% slurry. Examination of the rate constants shows that lipids and proteins are the major contributors to the biocrude, while other algal cell constituents contribute very little to the biocrude. PMID- 24793403 TI - Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. AB - INTRODUCTION: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes. AREAS COVERED: The purpose of this review is to describe the chemistry, pharmacodynamics, and pharmacokinetics of asenapine. EXPERT OPINION: Asenapine has a complex pharmacodynamic profile with affinities at multiple dopamine, serotonin, histamine, and alpha-adrenergic receptors, all at which asenapine functions as an antagonist. Sublingual asenapine tablets are absorbed in the oral mucosa, with a Tmax occurring between 30 and 90 min. Terminal half-life is approximately 24 h. Asenapine has multiple inactive metabolites, produced via direct glucuronidation (primarily via UGT1A4), demethylation, and oxidative metabolism (primarily via CYP1A2). Hepatic and renal routes contribute approximately equally to the elimination of asenapine and its metabolites. Two notable drug-drug interactions are evident: asenapine (an inhibitor of CYP2D6) can increase plasma levels of paroxetine, and fluvoxamine (a CYP1A2 inhibitor) can increase plasma levels of asenapine. Caution is required when coadministering asenapine with drugs that are both substrates and inhibitors of CYP2D6. PMID- 24793404 TI - K63-linked polyubiquitination of IRF1: an essential step in the IL-1 signaling cascade. PMID- 24793405 TI - CD56(bright)CD25+ NK cells are preferentially recruited to the maternal/fetal interface in early human pregnancy. AB - Decidual natural killer (dNK) cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy. However, the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined. Here, we identified a subtype of dNK cells characterized as having a CD3(-)CD56(bright)CD25(+) phenotype. We found that CD56(bright)CD25(+) NK cells preferentially localize to the maternal/fetal interface during early human pregnancy. CD25(+) dNK cells account for approximately 75% of CD25 expressing decidual immune cells (DICs). However, less than 5% of CD25-positive peripheral blood mononuclear cells are CD25(+) NK cells. Furthermore, CD25(+) and CD25(-) dNK cells exhibit distinct phenotypes: CD25(+) dNK cells display a more activated phenotype and greater cytokine-secreting capacity. Interestingly, coculture of peripheral NK (pNK) cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells, resulting in increased expression of activation markers and cytokine production by pNK cells. In addition, we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25(+) dNK cells and contributes to the accumulation of CD3(-)CD56(bright)CD25(+) dNK cells at the maternal/fetal interface. Thus, our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3( )CD56(bright)CD25(+) dNK cells, which exert a regulating effect at the maternal/fetal interface. PMID- 24793407 TI - A universal approach to the synthesis of nanodendrites of noble metals. AB - Nanomaterials usually exhibit structure-dependent catalytic activity, selectivity, and stability. Herein, we report a universal approach for the synthesis of noble metal nanoparticles with a dendritic structure, which is based on the reduction of metal acetylacetonate precursors in oleylamine at a temperature of 160 degrees C. In this strategy, the metal acetylacetonate precursors are reduced into metal atoms by oleylamine and grow into metal nanoparticles, while oleylamine is simultaneously converted into oleylamide to protect the nanoparticles. The competition between particle aggregation and oleylamide passivation is essential to the formation of a large number of particle aggregates, which eventually grow into nanodendrites via Ostwald ripening process. In particular, in comparison with commercial PtRu/C catalysts, the alloy PtRuOs nanodendrites exhibited superior catalytic activity toward methanol oxidation. PMID- 24793406 TI - A naturally occurring CD8(+)CD122(+) T-cell subset as a memory-like Treg family. AB - Despite extensive studies on CD4(+)CD25(+) regulatory T cells (Tregs) during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8(+)CD122(+) T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell (TCM) phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-10 production. We have recently demonstrated that programmed death-1 (PD-1) expression distinguishes between regulatory and memory CD8(+)CD122(+) T cells and that CD8(+)CD122(+) Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4(+)CD25(+) Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8(+)CD122(+) Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic. PMID- 24793408 TI - Comparison of mechanical and ultrasound elastic modulus of ovine tibial cortical bone. AB - Finite element models of bones can be created by deriving geometry from an X-ray CT scan. Material properties such as the elastic modulus can then be applied using either a single or set of homogeneous values, or individual elements can have local values mapped onto them. Values for the elastic modulus can be derived from the CT density values using an elasticity versus density relationship. Many elasticity-density relationships have been reported in the literature for human bone. However, while ovine in vivo models are common in orthopaedic research, no work has been done to date on creating FE models of ovine bones. To create these models and apply relevant material properties, an ovine elasticity-density relationship needs to be determined. Using fresh frozen ovine tibias the apparent density of regions of interest was determined from a clinical CT scan. The bones were the sectioned into cuboid samples of cortical bone from the regions of interest. Ultrasound was used to determine the elastic modulus in each of three directions - longitudinally, radially and tangentially. Samples then underwent traditional compression testing in each direction. The relationships between apparent density and both ultrasound, and compression modulus in each direction were determined. Ultrasound testing was found to be a highly repeatable non destructive method of calculating the elastic modulus, particularly suited to samples of this size. The elasticity-density relationships determined in the longitudinal direction were very similar between the compression and ultrasound data over the density range examined. A clear difference was seen in the elastic modulus between the longitudinal and transverse directions of the bone samples, and a transverse elasticity-density relationship is also reported. PMID- 24793409 TI - Adding "hemodynamic and fluid leads" to the ECG. Part I: the electrical estimation of BNP, chronic heart failure (CHF) and extracellular fluid (ECF) accumulation. AB - OBJECTIVES: In primary care the diagnosis of CHF and ECF accumulation is no triviality. We aimed to predict plasma BNP, CHF and ECF accumulation with segmental impedance spectroscopy while using and extending the electrodes of the conventional electrocardiography. METHODS: Three combined multiple electrodes were added to the 15 lead ECG for segmental impedance spectroscopy and for measuring the maximal rate of segmental fluid volume change with heart action at the thorax and the legs. The obtained signals were analyzed by partial correlation analyses in comparison with plasma BNP, CHF classes, ejection fraction by echocardiography and cardiac index by double gas re-breathing. 119 subjects (34 healthy volunteers, 50 patients with CHF, NYHA classes II to IV and 35 patients without CHF) were investigated. RESULTS: The maximal rate of volume change with heart action at the thorax and at the legs, as well as the ECF/ICF ratio at the legs contribute equally and independently to the prediction of BNP and heart failure in an unknown test sample of 49 patients (multiple r=0.88, p<0.001). The ROC-curve for the predicted plasma BNP>400 pg/ml gave an AUC=0.93. The absence or the presence of heart failure could be predicted correctly by a binomial logistic regression in 92.9 and 87.5% of cases, respectively. CONCLUSION: The methodology, which is based on inverse coupling of BNP release and of maximal blood acceleration and on sensitive detection of ECF overload, could enable the diagnosis of CHF with useful sensitivity and specificity while writing a routine-ECG. PMID- 24793410 TI - Is a black eye a useful sign of facial fractures in patients with minor head injuries? A retrospective analysis in a level I trauma centre over 10 years. AB - Orbital blunt trauma is common, and the diagnosis of a fracture should be made by computed tomographic (CT) scan. However, this will expose patients to ionising radiation. Our objective was to identify clinical predictors of orbital fracture, in particular the presence of a black eye, to minimise unnecessary exposure to radiation. A 10-year retrospective study was made of the medical records of all patients with minor head trauma who presented with one or two black eyes to our emergency department between May 2000 and April 2010. Each of the patients had a CT scan, was over 16 years old, and had a Glasgow Coma Score (GCS) of 13-15. The primary outcome was whether the black eye was a valuable predictor of a fracture. Accompanying clinical signs were considered as a secondary outcome. A total of 1676 patients (mean (SD) age 51 (22) years) and minor head trauma with either one or two black eyes were included. In 1144 the CT scan showed a fracture of the maxillofacial skeleton, which gave an incidence of 68.3% in whom a black eye was the obvious symptom. Specificity for facial fractures was particularly high for other clinical signs, such as diminished skin sensation (specificity 96.4%), diplopia or occulomotility disorders (89.3%), fracture steps (99.8%), epistaxis (95.5%), subconjunctival haemorrhage (90.4%), and emphysema (99.6%). Sensitivity for the same signs ranged from 10.8% to 22.2%. The most striking fact was that 68.3% of all patients with a black eye had an underlying fracture. We therefore conclude that a CT scan should be recommended for every patient with minor head injury who presents with a black eye. PMID- 24793411 TI - Communication of the transverse cervical nerve with the marginal mandibular nerve: a previously unreported anatomical variant. AB - Communications between the transverse cervical nerve (C2 and 3) and the cervical branch of the facial nerve have been reported. We describe a case in which the transverse cervical nerve joined the marginal mandibular branch of the facial nerve. It was found during a selective neck dissection and to our knowledge is the first report of such a communication. We discuss the clinical relevance particularly in relation to confusion with the marginal mandibular branch of the facial nerve when operating in the submandibular region. PMID- 24793412 TI - Fundamental study of application of umbilical cord mesenchymal stem cells to the periodontium to aid healing after autotransplantation of teeth. AB - After autotransplantation of teeth the healing of periodontal tissue regulates the patient's prognosis. Umbilical cord mesenchymal stem cells (UCMSC) have shown excellent pluripotent and proliferation potential. In the present study we investigated the characteristics and developmental capability of osteogenic differentiation to find out whether human UCMSC promote periodontal healing. UCMSC were obtained by primary culture and identified using flow cytometry. Flow cytometry, real-time polymerase chain reaction (PCR), Western blotting, assays of alkaline phosphatase activity, and alizarin red staining were used to assess the potential for hUCMSC to proliferate and differentiate in vitro. Both dentine and predifferentiated or undifferentiated cells were transplanted subcutaneously onto the backs of immunodeficient mice to mimic periodontal tissue healing in vivo. The result showed that hUCMSC were readily obtained, and expressed numerous mesenchymal stem cell markers. Expression of stemness markers decreased notably during osteogenic differentiation. Through investigation of different time points, we found that the osteogenic procedure could be activated and detected at day 7. In the in vivo experiments, the predifferentiated hUCMSC showed increased ability to form cementum-like deposits surrounded by fibroblast-like tissue on the surface of the dentine. In conclusion, the potential for proliferation and differentiation, and the ability to form cementum-like tissue, suggest that hUCMSC are promising candidates as a source of mesenchymal stem cell for sources of periodontal healing after autotransplantation of teeth. PMID- 24793413 TI - Orthognathic surgery in the management of obstructive sleep apnoea: experience from maxillofacial surgery unit in the United Kingdom. AB - In the United Kingdom, maxillofacial techniques are underused in the treatment of obstructive sleep apnoea (OSA). We retrospectively analysed the details and relevant clinical data of consecutive patients who had operations for OSA at the maxillofacial unit in Leicester between 2002 and 2012. They had been referred from the local sleep clinic after investigation and diagnosis, and in all cases treatment with continuous positive airway pressure (CPAP) had failed. We compared preoperative and postoperative apnoea/hypopnoea indices (AHI), scores for the Epworth sleepiness scale (ESS), and lowest oxygen saturation to measure surgical success (AHI of less than 15 and a 50% reduction in the number of apnoeas or hypopnoea/hour) and surgical cure (AHI of less than 5). We identified 51 patients (mean age 44 years, range 21-60) with a mean (SD) body mass index (BMI) of 29 (3.4). Most patients had bimaxillary advancement with genioplasty (n=42). Differences in mean (SD) preoperative and postoperative values were significant for all 3 outcome measures (AHI: 42 (17) to 8 (7) p<0.001; ESS: 14 (4) to 5 (4) p<0.001; lowest oxygen saturation: 76% (11%) to 83% (7%); p=0.006). On the postoperative sleep study 85% of patients met the criteria for surgical success. Our experience has confirmed that bimaxillary advancement results in a high rate of success in patients with OSA. The operation has a role in the management of selected patients in the UK who do not adhere to CPAP. PMID- 24793414 TI - Maxillomandibular synostosis misdiagnosed and treated as ankylosis of the temporomandibular joint. PMID- 24793415 TI - Inhibition of AMPK accentuates prolonged caloric restriction-induced change in cardiac contractile function through disruption of compensatory autophagy. AB - Prolonged caloric restriction often results in alteration in heart geometry and function although the underlying mechanism remains poorly defined. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, preserves energy and nutrient in the face of caloric insufficiency. This study was designed to examine the role of AMPK in prolonged caloric restriction-induced change in cardiac homeostasis and the underlying mechanism(s) involved with a focus on autophagy. Wild-type (WT) and AMPK kinase dead (KD) mice were caloric restricted (by 40%) for 30 weeks. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties, autophagy and autophagy regulatory proteins were evaluated. Caloric restriction compromised echocardiographic indices (decreased ventricular mass, left ventricular diameters, and cardiac output), cardiomyocyte contractile and intracellular Ca2+ properties associated with upregulated autophagy (Beclin-1, Atg5 and LC3BII-to-LC3BI ratio), increased autophagy adaptor protein p62, elevated phosphorylation of AMPK and TSC1/2, depressed phosphorylation of mTOR and ULK1. Although AMPK inhibition did not affect cardiac mechanical function, autophagy and autophagy signaling proteins, it significantly accentuated caloric restriction-induced changes in myocardial contractile function and intracellular Ca2+ handling. Interestingly, AMPK inhibition reversed caloric restriction-induced changes in autophagy and autophagy signaling. AMPK inhibition led to dampened levels of Beclin-1, Atg 5 and LC3B ratio along with suppressed phosphorylation of AMPK and TSC1/2 as well as elevated phosphorylation of mTOR and ULK1. Taken together, these data suggest an indispensible role for AMPK in the maintenance of cardiac homeostasis under prolonged caloric restriction-induced pathological changes possibly through autophagy regulation. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. PMID- 24793416 TI - Sulfite disrupts brain mitochondrial energy homeostasis and induces mitochondrial permeability transition pore opening via thiol group modification. AB - Sulfite oxidase (SO) deficiency is biochemically characterized by the accumulation of sulfite, thiosulfate and S-sulfocysteine in tissues and biological fluids of the affected patients. The main clinical symptoms include severe neurological dysfunction and brain abnormalities, whose pathophysiology is still unknown. The present study investigated the in vitro effects of sulfite and thiosulfate on mitochondrial homeostasis in rat brain mitochondria. It was verified that sulfite per se, but not thiosulfate, decreased state 3, CCCP stimulated state and respiratory control ratio in mitochondria respiring with glutamate plus malate. In line with this, we found that sulfite inhibited the activities of glutamate and malate (MDH) dehydrogenases. In addition, sulfite decreased the activity of a commercial solution of MDH, that was prevented by antioxidants and dithiothreitol. Sulfite also induced mitochondrial swelling and reduced mitochondrial membrane potential, Ca(2+) retention capacity, NAD(P)H pool and cytochrome c immunocontent when Ca(2+) was present in the medium. These alterations were prevented by ruthenium red, cyclosporine A (CsA) and ADP, supporting the involvement of mitochondrial permeability transition (MPT) in these effects. We further observed that N-ethylmaleimide prevented the sulfite elicited swelling and that sulfite decreased free thiol group content in brain mitochondria. These findings indicate that sulfite acts directly on MPT pore containing thiol groups. Finally, we verified that sulfite reduced cell viability in cerebral cortex slices and that this effect was prevented by CsA. Therefore, it may be presumed that disturbance of mitochondrial energy homeostasis and MPT induced by sulfite could be involved in the neuronal damage characteristic of SO deficiency. PMID- 24793417 TI - Gliadin activates arginase pathway in RAW264.7 cells and in human monocytes. AB - Celiac disease (CD) is an autoimmune enteropathy triggered in susceptible individuals by the ingestion of gliadin-containing grains. Recent studies have demonstrated that macrophages play a key role in the pathogenesis of CD through the release of inflammatory mediators such as cytokines and nitric oxide (NO). Since arginine is the obliged substrate of iNOS (inducible nitric oxide synthase), the enzyme that produces large amount of NO, the aim of this work is to investigate arginine metabolic pathways in RAW264.7 murine macrophages after treatment with PT-gliadin (PTG) in the absence and in the presence of IFNgamma. Our results demonstrate that, besides strengthening the IFNgamma-dependent activation of iNOS, gliadin is also an inducer of arginase, the enzyme that transforms arginine into ornithine and urea. Gliadin treatment increases, indeed, the expression and the activity of arginase, leading to the production of polyamines through the subsequent induction of ornithine decarboxylase. This effect is strengthened by IFNgamma. The activation of these pathways takes advantage of the increased availability of arginine due to a decreased system y(+)l-mediated efflux, likely ascribable to a reduced expression of Slc7a6 transporter. A significant induction of arginase expression is also observed in human monocytes from healthy subject upon treatment with gliadin, thus demonstrating that gluten components trigger changes in arginine metabolism in monocyte/macrophage cells. PMID- 24793418 TI - SIRT2 negatively regulates insulin resistance in C2C12 skeletal muscle cells. AB - SIRT2 is primarily a cytoplasmic protein deacetylase and is abundantly expressed in metabolically active tissues like adipocytes and brain. However, its role, if any, in regulating insulin signaling in skeletal muscle cells, is not known. We have examined the role of SIRT2 in insulin-mediated glucose disposal in normal and insulin resistant C2C12 skeletal muscle cells in vitro. SIRT2 was over expressed in insulin resistant skeletal muscle cells. Pharmacological inhibition of SIRT2 increased insulin-stimulated glucose uptake and improved phosphorylation of Akt and GSK3beta in insulin resistant cells. Knockdown of endogenous SIRT2 and over expression of catalytically-inactive SIRT2 mutant under insulin-resistant condition showed similar amelioration of insulin sensitivity. Our results suggest that down-regulation of SIRT2 improved insulin sensitivity in skeletal muscle cells under insulin-resistant condition. Previously it has been reported that down-regulation of SIRT1 and SIRT3 in C2C12 cells results in impairment of insulin signaling and induces insulin resistance. However, we have observed an altogether different role of SIRT2 in skeletal muscle. This implicates a differential regulation of insulin resistance by sirtuins which otherwise share a conserved catalytic domain. The study significantly directs towards future approaches in targeting inhibition of SIRT2 for therapeutic treatment of insulin resistance which is the major risk factor in Type 2 diabetes. PMID- 24793419 TI - Comment on "Modulating DNA configuration by interfacial traction: an elastic rod model to characterize DNA folding and unfolding". AB - In this comment, we point out that the tractions induced by interfacial energy, which are referred to as the tractions on the central axis curve of the DNA elastic rod presented by Huang (J. Biol. Phys. 37(1), 79-90, 2011), are incorrect. The correct tractions are provided in this literature. Further, with the use of the correct tractions, we present new numerical results, which for the values given by Zaixing Huang do not give rise to the physical behavior observed for DNA by the author. PMID- 24793420 TI - Curcumin, a component of golden spice: from bedside to bench and back. AB - Although the history of the golden spice turmeric (Curcuma longa) goes back thousands of years, it is only within the past century that we learned about the chemistry of its active component, curcumin. More than 6000 articles published within the past two decades have discussed the molecular basis for the antioxidant, anti-inflammatory, antibacterial, antiviral, antifungal, and anticancer activities assigned to this nutraceutical. Over sixty five clinical trials conducted on this molecules, have shed light on the role of curcumin in various chronic conditions, including autoimmune, cardiovascular, neurological, and psychological diseases, as well as diabetes and cancer. The current review provides an overview of the history, chemistry, analogs, and mechanism of action of curcumin. PMID- 24793422 TI - Mineral composition of human fascia lata. AB - The mineral composition of pathologically unchanged human fascia lata was examined here using inductively coupled plasma optical emission spectrometry (ICP OES) method for the first time. The total concentrations of Ag, Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, P, Pb, Sr, Ti, V and Zn were simultaneously measured in the tissue secured during autopsy. The age-related changes and between-gender differences in mineral composition of the examined tissue were investigated and discussed. PMID- 24793421 TI - Hydroalcoholic seed extract of Coriandrum sativum (Coriander) alleviates lead induced oxidative stress in different regions of rat brain. AB - Lead exposure is known to cause apoptotic neurodegeneration and neurobehavioral abnormalities in developing and adult brain by impairing cognition and memory. Coriandrum sativum is an herb belonging to Umbelliferae and is reported to have a protective effect against lead toxicity. In the present investigation, an attempt has been made to evaluate the protective activity of the hydroalcoholic extract of C. sativum seed against lead-induced oxidative stress. Male Wistar strain rats (100-120 g) were divided into four groups: control group: 1,000 mg/L of sodium acetate; exposed group: 1,000 mg/L lead acetate for 4 weeks; C. sativum treated 1 (CST1) group: 250 mg/kg body weight/day for seven consecutive days after 4 weeks of lead exposure; C. sativum treated 2 (CST2) group: 500 mg/kg body weight/day for seven consecutive days after 4 weeks of lead exposure. After the exposure and treatment periods, rats were sacrificed by cervical dislocation, and the whole brain was immediately isolated and separated into four regions: cerebellum, hippocampus, frontal cortex, and brain stem along with the control group. After sacrifice, blood was immediately collected into heparinized vials and stored at 4 degrees C. In all the tissues, reactive oxygen species (ROS), lipid peroxidation products (LPP), and total protein carbonyl content (TPCC) were estimated following standard protocols. An indicator enzyme for lead toxicity namely delta amino levulinic acid dehydratase (delta-ALAD) activity was determined in the blood. A significant (p<0.05) increase in ROS, LPP, and TPCC levels was observed in exposed rat brain regions, while delta-ALAD showed a decrease indicating lead induced oxidative stress. Treatment with the hydroalcoholic seed extract of C. sativum resulted in a tissue-specific amelioration of oxidative stress produced by lead. PMID- 24793423 TI - Dietary exposure of the red-crowned crane (Grus japonensis) to total and methyl mercury in Zhalong Wetland, northeastern China. AB - To determine the dietary exposure of the migratory red-crowned crane to mercury (Hg), this study analyzed the concentrations of total mercury (T-Hg) and methyl mercury (MeHg) in its prey, i.e., reeds and three aquatic animal families (Perccottus glenni Dybowski, Cybister japonicus Sharp, and Viviparidae) in northeastern China. Results indicated that the Hg concentration in Zhalong Wetland was elevated through the food chain, and the prey of the red-crowned crane contained measurable levels of T-Hg and MeHg. In prey tissues, MeHg was the main form of the Hg element and accounted for 61% of total Hg concentration in Viviparidae, 58% in C. japonicus Sharp, and 85% in P. glenni Dybowski. The highest T-Hg and MeHg concentrations ranged from 1.66 to 3.89 ppm and from 1.12 to 2.67 ppm, respectively, and they were detected in the feathers of the red crowned cranes. The lowest T-Hg concentration was determined in the excretions of wild red-crowned cranes at 0.21 ppm; furthermore, the content of MeHg was below the detection limit. In Zhalong Wetland, the level of dietary exposure of the population of red-crowned cranes to Hg is below the threshold of Hg toxicity. Moreover, eggshells are suitable indicators of Hg risk levels to the red-crowned crane. PMID- 24793424 TI - Courage, brains and heart: lessons from the Wizard of Oz for difficult healthcare conversations. PMID- 24793425 TI - Platelet donation drives: a novel initiative to recruit platelet donors. AB - The most important strategy to ensure a safe and an adequate supply of blood and blood products is motivation, recruitment, selection and retention of voluntary non remunerated blood donors. With a view of the increased platelet necessity in our oncology setup, the first platelet donation drive in the city and to the best of our knowledge, in India was conducted by our hospital in November 2009. The aim was to identify target groups and expand our donor database. It was also essential that the donor's contribution is acknowledged and appropriately felicitated. A campaign called "Save a Life" was initiated and publicized locally. A core team consisting of Transfusion Medicine specialists, clinicians and an NGO (nongovernment organization) was formed. The best suitable date and venue were finalized for the platelet camp. The audience was addressed and willing donors were registered as volunteer platelet donors with our institute. In a span of 40 months, 15 platelet camps were organized in colleges, social organizations, and corporate offices. A total of 1035 donors were registered out of which, 382 (37%) donated platelets in our hospital. 125/382 (33.2%) donated Single Donor Platelets (SDP) more than once. The largest number of platelet donations by a single camp donor was 24 times. Due to multiple donations from donors, the SDP number was enhanced considerably and lead to addition of 699 SDP units to our inventory. The annual indoor and camp voluntary platelet donor numbers increased from 142 in 2006 to 631 in 2012 due to platelet drives. All platelet donations were altruistic as no incentives were offered to the donors. Ready availability of platelets and planning SDP inventory as per patient blood group requirements had a positive impact on clinical services. PMID- 24793426 TI - ... 25 years of illumination... and the story goes on. PMID- 24793427 TI - Paolo Perseghin, biography. PMID- 24793428 TI - Trends in drug use among drivers killed in U.S. traffic crashes, 1999-2010. AB - OBJECTIVE: Driving under the influence of drugs is a global traffic safety and public health concern. This trend analysis examines the changes in general drug usage other than alcohol, broad categories, and typical prescription and illegal drugs among drivers fatally injured in motor vehicle crashes from 1999 to 2010 in the U.S. METHODS: Data from the Fatality Analysis Reporting System were analyzed from 1999 to 2010. Drug prevalence rates and prevalence ratios (PR) were determined comparing rates in 2009-2010 to 1999-2000 using a random effects model. Changes in general drug usage, broad categories, and representative prescription and illegal drugs including, methadone, oxycodone, hydrocodone, barbiturates, benzodiazepines, and cocaine, were explored. RESULTS: Comparing 2009-2010 to 1999-2000, prevalence of drug usage increased 49% (PR=1.49; 95% confidence interval [CI] 1.42, 1.55). The largest increases in broad drug categories were narcotics (PR=2.73; 95% CI 2.41, 3.08), depressants (PR=2.01; 95% CI 1.80, 2.25), and cannabinoids (PR=1.99; 95% CI 1.84, 2.16). The PR were 6.37 (95% CI 5.07, 8.02) for hydrocodone/oxycodone, 4.29 (95% CI 2.88, 6.37) for methadone, and 2.27 (95% CI 2.00, 2.58) for benzodiazepines. Barbiturates declined in rate over the 12-year period (PR=0.53; 95% CI 0.37, 0.75). Cocaine use increased until 2005 then progressively declined, though the rate remained relatively unchanged (PR=0.94; 95% CI 0.84, 1.06). CONCLUSIONS: While more drivers are being tested and found drug-positive, there is evidence that a shift from illegal to prescription drugs may be occurring among fatally injured drivers in the U.S. Driving under the influence of prescription drugs is a growing traffic concern. PMID- 24793429 TI - Recruitment of women in the National Children's Study Initial Vanguard Study. AB - The initial Vanguard Study of the National Children's Study was conducted during 2009-2010 in 7 locations in the United States. A goal was to evaluate the feasibility and yield of a household-based sampling design to recruit pregnant women. A multistage area probability sampling design was used to identify study locations (generally, counties) that were subsequently divided into smaller geographical units, termed segments. Between 7 and 18 segments were selected in each location, and dwelling units within segments were listed. A household-based recruitment process was implemented, which included enumeration of households to identify age-eligible women, pregnancy screening to identify pregnant women eligible for immediate enrollment and nonpregnant women for telephone follow-up, and administration of informed consent to eligible women. After a recruitment period of 17-20 months, 67,181 (89%) households were enumerated, which identified 34,172 (88%) age-eligible women to whom the pregnancy screener was administered. Among those who completed the screener, 2,285 women became eligible for enrollment, of whom 1,399 (61%) enrolled. Although response rates were fairly high at initial contact and among pregnant women, the overall yield was lower than anticipated. In particular, telephone follow-up of nonpregnant women was not a practicable strategy for prospective recruitment of newly pregnant women. PMID- 24793430 TI - Aptamer Displacement Screen for Flaviviral RNA Methyltransferase Inhibitors. AB - RNA-protein interactions are vital to the replication of the flaviviral genome. Discovery focused on small molecules that disrupt these interactions represent a viable path for identification of new inhibitors. The viral RNA (vRNA) cap methyltransferase (MTase) of the flaviviruses has been validated as a suitable drug target. Here we report the development of a high-throughput screen for the discovery of compounds that target the RNA binding site of flaviviral protein NS5A. The assay described here is based on displacement of an MT-bound polynucleotide aptamer, decathymidylate derivatized at its 5' end with fluorescein (FL-dT10). Based on the measurement of fluorescence polarization, FL dT10 bound to yellow fever virus (YFV) MTase in a saturable manner with a Kd= 231 nM. The binding was reversed by a 250-nucleotide YFV messenger RNA (mRNA) transcript and by the triphenylmethane dye aurintricarboxylic acid (ATA). The EC50for ATA displacement was 1.54 uM. The MTase cofactors guanosine-5' triphosphate and S-adenosyl-methionine failed to displace FL-dT10. Analysis by electrophoretic mobility shift assay (EMSA) suggests that ATA binds YFV MTase so as to displace the vRNA. The assay was determined to have a Z' of 0.83 and was successfully used to screen a library of known bioactives. PMID- 24793431 TI - Inferring the Origin Locations of Tweets with Quantitative Confidence. AB - Social Internet content plays an increasingly critical role in many domains, including public health, disaster management, and politics. However, its utility is limited by missing geographic information; for example, fewer than 1.6% of Twitter messages (tweets) contain a geotag. We propose a scalable, content-based approach to estimate the location of tweets using a novel yet simple variant of gaussian mixture models. Further, because real-world applications depend on quantified uncertainty for such estimates, we propose novel metrics of accuracy, precision, and calibration, and we evaluate our approach accordingly. Experiments on 13 million global, comprehensively multi-lingual tweets show that our approach yields reliable, well-calibrated results competitive with previous computationally intensive methods. We also show that a relatively small number of training data are required for good estimates (roughly 30,000 tweets) and models are quite time-invariant (effective on tweets many weeks newer than the training set). Finally, we show that toponyms and languages with small geographic footprint provide the most useful location signals. PMID- 24793432 TI - Targets of protein carbonylation in spontaneously hypertensive obese Koletsky rats and healthy Wistar counterparts: a potential role on metabolic disorders. AB - The study innovatively pinpoints target proteins of carbonylation, a key PTM induced by oxidative stress, in the SHROB (genetically obese spontaneously hypertensive) rat model of metabolic syndrome (MetS). Protein carbonylation was assessed by a fluorescence-labeling proteomics approach, and complemented with biometric and biochemical markers of MetS. SHROB and healthy Wistar rats were fed two diets, soybean and linseed oil supplementations, in order to distinguish intrinsic carbonylation of SHROB animals from diet-modulated carbonylation unrelated to MetS. First exploratory data showed similar carbonylation patterns and metabolic conditions in SHROB rats fed soybean and linseed, but different from Wistar animals. A total of 18 carbonylated spots in liver, and 12 in skeletal tissue, related to pathways of lipid (29.6%), carbohydrate (25.9%) and amino acid (18.5%) metabolisms, were identified. In particular, SHROB animals present higher carbonylation in four liver proteins belonging to lipid metabolism, redox regulation and chaperone activity (ALDH2, PDI, PDIA3, PECR), and in the skeletal muscle ALDOA that is involved in muscle dysfunction. Conversely, SHROB rats display lower carbonylation in liver albumin, AKR1C9, ADH1 and catalase. This investigation provides a novel perspective of carbonylation in the context of metabolic disorders, and may be a starting point to characterize new redox pathways exacerbating MetS. BIOLOGICAL SIGNIFICANCE: Oxidative stress is a concomitant factor in the pathogenesis of MetS that induces oxidative PTM as carbonylation. Through the use of a redox proteomics approach, we have thoroughly mapped the occurrence of protein targets of carbonylation in the genetically induced MetS model SHROB rat. The present research brings a new insight of MetS pathogenesis and it may provide valuable information to understand the biological impact of oxidative stress in patients with MetS. PMID- 24793433 TI - Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: a comparative study using two strains of mice with different sensitivities to dioxin. AB - We have previously revealed that treating pregnant rats with 2,3,7,8 tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2-20 MUg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20 MUg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects. PMID- 24793434 TI - Interactive effects of cerium oxide and diesel exhaust nanoparticles on inducing pulmonary fibrosis. AB - Cerium compounds have been used as a fuel-borne catalyst to lower the generation of diesel exhaust particles (DEPs), but are emitted as cerium oxide nanoparticles (CeO2) along with DEP in the diesel exhaust. The present study investigates the effects of the combined exposure to DEP and CeO2 on the pulmonary system in a rat model. Specific pathogen-free male Sprague-Dawley rats were exposed to CeO2 and/or DEP via a single intratracheal instillation and were sacrificed at various time points post-exposure. This investigation demonstrated that CeO2 induces a sustained inflammatory response, whereas DEP elicits a switch of the pulmonary immune response from Th1 to Th2. Both CeO2 and DEP activated AM and lymphocyte secretion of the proinflammatory cytokines IL-12 and IFN-gamma, respectively. However, only DEP enhanced the anti-inflammatory cytokine IL-10 production in response to ex vivo LPS or Concanavalin A challenge that was not affected by the presence of CeO2, suggesting that DEP suppresses host defense capability by inducing the Th2 immunity. The micrographs of lymph nodes show that the particle clumps in DEP+CeO2 were significantly larger than CeO2 or DEP, exhibiting dense clumps continuous throughout the lymph nodes. Morphometric analysis demonstrates that the localization of collagen in the lung tissue after DEP+CeO2 reflects the combination of DEP-exposure plus CeO2-exposure. At 4 weeks post-exposure, the histological features demonstrated that CeO2 induced lung phospholipidosis and fibrosis. DEP induced lung granulomas that were not significantly affected by the presence of CeO2 in the combined exposure. Using CeO2 as diesel fuel catalyst may cause health concerns. PMID- 24793435 TI - High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort. AB - PURPOSE: Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length. METHOD: We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay. RESULTS: There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P < 0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015). CONCLUSIONS: High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity. PMID- 24793436 TI - Changes in body composition secondary to neoadjuvant chemotherapy for advanced esophageal cancer are related to the occurrence of postoperative complications after esophagectomy. AB - BACKGROUND: Although a survival benefit of neoadjuvant treatment for patients with esophageal cancer has been highlighted, the influence of neoadjuvant treatment on the nutritional status of patients with esophageal cancer is not well understood. METHODS: Changes in body composition parameters were assessed in 30 patients who underwent neoadjuvant chemotherapy (NAC) comprising docetaxel, cisplatin, and 5-fluorouracil followed by esophagectomy from August 2009 to April 2013. Body composition was evaluated before and after NAC using multifrequency bioelectrical impedance analysis (InBody 720; Biospace, Tokyo, Japan). Postoperative complications were graded according to the Clavien-Dindo classification. RESULTS: Twenty-three postoperative events occurred in 16 patients. A decrease in body protein was observed in 13 patients (43.3 %), while skeletal muscle (SM), body cell mass (BCM), and fat-free mass (FFM) declined in 11 patients (36.7 %) during NAC. Changes in these four parameters during chemotherapy significantly differed between patients with postoperative complications and those without: protein, -1.6 +/- 0.9 versus +4.4 +/- 2.1 kg (P = 0.01); SM, -1.3 +/- 1.1 versus +4.7 +/- 2.4 kg (P = 0.02); BCM, -2.4 +/- 1.6 versus +3.8 +/- 2.2 kg (P = 0.03); and FFM, -1.4 +/- 1.4 versus +4.3 +/- 2.3 kg (P = 0.04). CONCLUSIONS: Changes in body composition parameters are possible predictive markers of postoperative complications after esophagectomy after NAC. Further analysis is needed to clarify whether nutritional intervention improves such parameters and thus contributes to reduced postoperative morbidity. PMID- 24793437 TI - Documentation of quality of care data for colon cancer surgery: comparison of synoptic and dictated operative reports. AB - BACKGROUND: Operative reports are a source of clinical data that can, for quality assurance purposes, be used to document the performance of processes that affect the care of surgical patients. We assessed the degree to which synoptic reports document operative quality indicators for colon cancer surgery. METHODS: Two reviewers independently reviewed 80 prospectively collected synoptic colon cancer operative reports and a case-matched historical cohort of 80 dictated reports. Reviewers rated how well reports documented performance of quality of care indicators using two checklists of previously validated, colon cancer-specific quality measures. Interrater agreement and time to extract data were also recorded. RESULTS: Synoptic reports had significantly higher overall scores on the quality indictors in comparison to dictated reports for both checklist 1 [mean adjusted score +/- standard deviation 18.6 +/- 1.3 vs. 9.2 +/- 3.6, p < 0.01 (maximum score 38)] and checklist 2 [2.0 +/- 0.3 vs. 1.3 +/- 1.1, p < 0.01 (maximum score 3)]. Interrater agreement was significantly higher between synoptic reports for both checklists (data not shown). Data were extracted significantly more quickly from synoptic reports than dictated reports [mean time (minutes:seconds) +/- standard deviation 2:32 +/- 0:44 vs. 4:01 +/- 1:14, p < 0.01]. CONCLUSIONS: Synoptic reports were associated with more complete documentation of quality indicators for colon cancer resection compared to dictated reports. Although synoptic reports may improve the documentation of quality of care data, further refinement may help to better document performance of quality measures and improve reporting standards. PMID- 24793438 TI - NLA Task Force on Statin Safety--2014 update. PMID- 24793439 TI - An assessment by the Statin Diabetes Safety Task Force: 2014 update. AB - Statin therapy reduces the risk of myocardial infarction, stroke, and cardiovascular death by 25% to 30% in primary as well as secondary prevention patients. Thus, statins are the pharmacologic therapy of choice for the management of high blood cholesterol levels. Prompted by examination of clinical trial data suggesting a modest, but statistically significant, increase in the incidence of new-onset type 2 diabetes mellitus with statin use, the US Food and Drug Administration in 2012 added a statement to the labels of statin medications indicating that increases in glycated hemoglobin (HbA1C) and fasting glucose levels have been reported with statin use. This labeling change has raised questions among clinicians regarding the relative benefits and risks of statin use, both among patients with diabetes mellitus and among those with diabetes risk factors. This 2014 report from the Diabetes Subpanel of the National Lipid Association Expert Panel on Statin Safety reviews the published evidence relating statin use to the hazard for diabetes mellitus or worsening glycemia, examines potential mechanisms that may mediate the relationship between statin use and diabetes mellitus risk, and suggests future research efforts. Given the well established benefits of statin therapy in the primary and secondary prevention of cardiovascular events among those with indications for treatment, no changes to clinical practice are recommended other than the measurement of HbA1C or fasting glucose in those deemed to also be at elevated diabetes risk after initiating statin therapy, and potentially before initiation in selected patients considered to be at elevated risk of developing diabetes. The panel advocates following recommendations from the American Diabetes Association, or other relevant guidelines if outside the United States, for screening and diagnosis as well as lifestyle modification for prevention or delay of diabetes mellitus in those with prediabetes or other risk factors. PMID- 24793440 TI - A clinician's guide to statin drug-drug interactions. AB - The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations. PMID- 24793441 TI - An assessment by the Statin Liver Safety Task Force: 2014 update. AB - In the 2006 Report of the National Lipid Association's Statin Safety Task Force, a panel of experts in hepatology published their findings on specific questions related to the liver blood testing during statin therapy. Among their recommendations was that regulatory agencies reconsider the statin-labeling recommendation at that time, which required post-statin liver enzyme testing. Since then, the Food and Drug Administration altered statin labeling such that unless clinically indicated for other reasons, after a pre-statin therapy baseline evaluation, follow-up liver enzyme testing was not uniformly required after statin initiation. This 2014 report provides an update on interim issues relevant to statins and liver safety. Some of the points discussed include the value of baseline liver enzymes before initiating statin therapy, safety of statin use in patients with nonalcoholic fatty liver disease, potential drug interactions between statins and drugs used to treat hepatitis, the use of statins in liver transplant recipients, and the use of statins in patients with autoimmune liver disease. Finally, this panel provides diagnostic and algorithmic approaches when evaluating statin-treated patients who experience elevations in liver enzymes. PMID- 24793442 TI - An assessment by the Statin Cognitive Safety Task Force: 2014 update. AB - The National Lipid Association's Safety Task Force convened a consensus conference of experts to develop a position statement on cognitive function to revise and update that published originally by the Association in the 2006 assessment of statin safety by a panel of neurologists. The current expert panel was charged with addressing the specific issue of potential adverse cognitive effects attributable to statins. Search strategies recently used in systematic reviews were used to identify relevant evidence using keywords and topics via Medline searches from 1966 to December 2013. Manual searches of bibliographies were also conducted. Panel members were asked to use the evidence to formulate answers to a series of questions of relevance to the subject matter. The strength of recommendations and quality of evidence were graded using accepted contemporary definitions and procedures. Recommendations to patients, health professionals, and researchers were put forth by the panel to aid in daily clinical decision making, and in future research endeavors. PMID- 24793443 TI - An assessment by the Statin Muscle Safety Task Force: 2014 update. AB - The National Lipid Association's Muscle Safety Expert Panel was charged with the duty of examining the definitions for statin-associated muscle adverse events, development of a clinical index to assess myalgia, and the use of diagnostic neuromuscular studies to investigate muscle adverse events. We provide guidance as to when a patient should be considered for referral to neuromuscular specialists and indications for the performance of a skeletal muscle biopsy. Based on this review of evidence, we developed an algorithm for the evaluation and treatment of patients who may be intolerant to statins as the result of adverse muscle events. The panel was composed of clinical cardiologists, clinical lipidologists, an exercise physiologist, and a neuromuscular specialist. PMID- 24793444 TI - An assessment by the Statin Intolerance Panel: 2014 update. AB - This article from the National Lipid Association Statin Intolerance Panel provides a framework for understanding statin intolerance and makes general recommendations for health professionals. For specific guidance on adverse events related to muscle, liver, cognition, and glucose metabolism, one should refer to the other reports of the Statin Safety Task Force for those topics. Although statin adverse effects rarely lead to permanent sequelae, symptomatic intolerance frequently hinders cardiovascular risk reduction by statins. We emphasize here the advisory role of the clinician helping each patient to make personal decisions on statin tolerability. We identify a pressing need for further research on statin intolerance and make suggestions for research design. PMID- 24793445 TI - Cultural competence education for health professionals. AB - BACKGROUND: Cultural competence education for health professionals aims to ensure all people receive equitable, effective health care, particularly those from culturally and linguistically diverse (CALD) backgrounds. It has emerged as a strategy in high-income English-speaking countries in response to evidence of health disparities, structural inequalities, and poorer quality health care and outcomes among people from minority CALD backgrounds. However there is a paucity of evidence to link cultural competence education with patient, professional and organisational outcomes. To assess efficacy, for this review we developed a four dimensional conceptual framework comprising educational content, pedagogical approach, structure of the intervention, and participant characteristics to provide consistency in describing and assessing interventions. We use the term 'CALD participants' when referring to minority CALD populations as a whole. When referring to participants in included studies we describe them in terms used by study authors. OBJECTIVES: To assess the effects of cultural competence education interventions for health professionals on patient-related outcomes, health professional outcomes, and healthcare organisation outcomes. SEARCH METHODS: We searched: MEDLINE (OvidSP) (1946 to June 2012); Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (June 2012); EMBASE (OvidSP) (1988 to June 2012); CINAHL (EbscoHOST) (1981 to June 2012); PsycINFO (OvidSP) (1806 to June 2012); Proquest Dissertations and Theses database (1861 to October 2011); ERIC (CSA) (1966 to October 2011); LILACS (1982 to March 2012); and Current Contents (OvidSP) (1993 Week 27 to June 2012).Searches in MEDLINE, CENTRAL, PsycINFO, EMBASE, Proquest Dissertations and Theses, ERIC and Current Contents were updated in February 2014. Searches in CINAHL were updated in March 2014.There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster RCTs, and controlled clinical trials of educational interventions for health professionals working in health settings that aimed to improve: health outcomes of patients/consumers of minority cultural and linguistic backgrounds; knowledge, skills and attitudes of health professionals in delivering culturally competent care; and healthcare organisation performance in culturally competent care. DATA COLLECTION AND ANALYSIS: We used the conceptual framework as the basis for data extraction. Two review authors independently extracted data on interventions, methods, and outcome measures and mapped them against the framework. Additional information was sought from study authors. We present results in narrative and tabular form. MAIN RESULTS: We included five RCTs involving 337 healthcare professionals and 8400 patients; at least 3463 (41%) were from CALD backgrounds. Trials compared the effects of cultural competence training for health professionals, with no training. Three studies were from the USA, one from Canada and one from The Netherlands. They involved health professionals of diverse backgrounds, although most were not from CALD minorities. Cultural background was determined using a validated scale (one study), self-report (two studies) or not reported (two studies). The design effect from clustering meant an effective minimum sample size of 3164 CALD participants. No meta-analyses were performed. The quality of evidence for each outcome was judged to be low.Two trials comparing cultural competence training with no training found no evidence of effect for treatment outcomes, including the proportion of patients with diabetes achieving LDL cholesterol control targets (risk difference (RD) -0.02, 95% CI -0.06 to 0.02; 1 study, USA, 2699 "black" patients, moderate quality), or change in weight loss (standardised mean difference (SMD) 0.07, 95% CI -0.41 to 0.55, 1 study, USA, effective sample size (ESS) 68 patients, low quality).Health behaviour (client concordance with attendance) improved significantly among intervention participants compared with controls (relative risk (RR) 1.53, 95% CI 1.03 to 2.27, 1 study, USA, ESS 28 women, low quality). Involvement in care by "non Western" patients (described as "mainly Turkish, Moroccan, Cape Verdean and Surinamese patients") with largely "Western" doctors improved in terms of mutual understanding (SMD 0.21, 95% CI 0.00 to 0.42, 1 study, The Netherlands, 109 patients, low quality). Evaluations of care were mixed (three studies). Two studies found no evidence of effect in: proportion of patients reporting satisfaction with consultations (RD 0.14, 95% CI -0.03 to 0.31, 1 study, The Netherlands, 109 patients, low quality); patient scores of physician cultural competency (SMD 0.11 95% CI -0.63 to 0.85, 1 study, USA, ESS 68 "Caucasian" and "non-Causcasian" patients (described as Latino, African American, Asian and other, low quality). Client perceptions of health professionals were significantly higher in the intervention group (SMD 1.60 95% CI 1.05 to 2.15, 1 study, USA, ESS 28 "Black" women, low quality).No study assessed adverse outcomes.There was no evidence of effect on clinician awareness of "racial" differences in quality of care among clients at a USA health centre (RR 1.37, 95% CI 0.97 to 1.94. P = 0.07) with no adjustment for clustering. Included studies did not measure other outcomes of interest. Sensitivity analyses using different values for the Intra-cluster coefficient (ICC) did not substantially alter the magnitude or significance of summary effect sizes.All four domains of the conceptual framework were addressed, suggesting agreement on core components of cultural competence education interventions may be possible. AUTHORS' CONCLUSIONS: Cultural competence continues to be developed as a major strategy to address health inequities. Five studies assessed the effects of cultural competence education for health professionals on patient-related outcomes. There was positive, albeit low-quality evidence, showing improvements in the involvement of CALD patients. Findings either showed support for the educational interventions or no evidence of effect. No studies assessed adverse outcomes. The quality of evidence is insufficient to draw generalisable conclusions, largely due to heterogeneity of the interventions in content, scope, design, duration, implementation and outcomes selected.Further research is required to establish greater methodological rigour and uniformity on core components of education interventions, including how they are described and evaluated. Our conceptual framework provides a basis for establishing consensus to improve reporting and allow assessment across studies and populations. Future studies should measure the patient outcomes used: treatment outcomes; health behaviours; involvement in care and evaluations of care. Studies should also measure the impact of these types of interventions on healthcare organisations, as these are likely to affect uptake and sustainability. PMID- 24793446 TI - Microsatellite multiplex assay for the analysis of Atlantic sturgeon populations. AB - We have developed a multiplex assay covering 16 microsatellite loci, amplified in four polymerase chain reaction (PCR) assays, and loaded on the ABI DNA Analyzer in two separate panels. The assay was tested on 603 individuals originating from wild populations and hatchery stocks of Atlantic sturgeon. The assay was also tested on 12 individuals of European sturgeon and appeared to be almost equally useful. The multiplex assay designed in this study can be successfully applied in studies requiring high genetic resolution, such as relatedness analysis, selective breeding programs, and stock identification of Atlantic sturgeon. PMID- 24793447 TI - Beyond trial types. AB - Conventional wisdom on psychological experiments has held that when one or more independent variables are manipulated it is essential that all other conditions are kept constant such that confounding factors can be assumed negligible (Woodworth, 1938). In practice, the latter assumption is often questionable because it is generally difficult to guarantee that all other conditions are constant between any two trials. Therefore, the most common way to check for confounding violations of this assumption is to split the experimental conditions in terms of "trial types" to simulate a reduction of unintended trial-by-trial variation. Here, we pose a method which is more general than the use of trial types: use of mathematical models treating measures of potentially confounding factors and manipulated variables as equals on the single-trial level. We show how the method can be applied with models that subsume under the generalized linear item response theory (GLIRT), which is the case for most of the well-known psychometric models (Mellenbergh, 1994). As an example, we provide a new analysis of a single-letter recognition experiment using a nested likelihood ratio test that treats manipulated and measured variables equally (i.e., in exactly the same way) on the single-trial level. The test detects a confounding interaction with time-on-task as a single-trial measure and yields a substantially better estimate of the effect size of the main manipulation compared with an analysis made in terms of trial types. PMID- 24793448 TI - Large tilts in transmembrane helices can be induced during tertiary structure formation. AB - While early structural models of helix-bundle integral membrane proteins posited that the transmembrane alpha-helices [transmembrane helices (TMHs)] were orientated more or less perpendicular to the membrane plane, there is now ample evidence from high-resolution structures that many TMHs have significant tilt angles relative to the membrane. Here, we address the question whether the tilt is an intrinsic property of the TMH in question or if it is imparted on the TMH during folding of the protein. Using a glycosylation mapping technique, we show that four highly tilted helices found in multi-spanning membrane proteins all have much shorter membrane-embedded segments when inserted by themselves into the membrane than seen in the high-resolution structures. This suggests that tilting can be induced by tertiary packing interactions within the protein, subsequent to the initial membrane-insertion step. PMID- 24793449 TI - Pediatric sinonasal tumors in the United States: incidence and outcomes. AB - BACKGROUND: Sinonasal tumors in the pediatric population are exceedingly rare. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results database was used to identify 250 cases of sinonasal malignancy in patients aged <20 y (1973 2010). Malignant histology codes were based on the International Classification of Disease for Oncology, third edition coding scheme. Incidence rates were adjusted to the 2000 U.S. population. Survival outcomes were plotted using the Kaplan-Meier method and compared with the log-rank test. All other analyses were performed using standard statistical methods. RESULTS: Overall incidence was 0.052 per 100,000. Rhabdomyosarcoma had the highest incidence among histologic groups. Regional stage was the most common at diagnosis (59%). Overall survival at 5-y follow-up was 62.5%. Patients in age groups 1-4 and 15-19 y had the worst survival rates, as median survival was 205 and 104 mo, respectively. Distant metastases at the time of diagnosis signified a poor prognosis. These were associated with a 39-mo median survival. Survival improved during the study period, P=0.003. Gender, race, site of lesion, or histology did not appear to affect mortality. CONCLUSIONS: Sinonasal tumors are rare in children and adolescents. Long-term survival is dependent on age and clinical stage at the time of diagnosis. Cancer-related surgery confers a survival advantage. Gender, race, and histologic type are not associated with mortality. PMID- 24793450 TI - Utility of immature granulocyte percentage in pediatric appendicitis. AB - BACKGROUND: Acute appendicitis is the most common cause of abdominal surgery in children. Adjuncts are used to help clinicians predict acute or perforated appendicitis, which may affect treatment decisions. Automated hematologic analyzers can perform more accurate automated differentials including immature granulocyte percentages (IG%). Elevated IG% has demonstrated improved accuracy for predicting sepsis in the neonatal population than traditional immature-to total neutrophil count ratios. We intended to assess the additional discriminatory ability of IG% to traditionally assessed parameters in the differentiation between acute and perforated appendicitis. MATERIALS AND METHODS: We identified all patients with appendicitis from July 2012-June 2013 by International Classification of Diseases-9 code. Charts were reviewed for relevant demographic, clinical, and outcome data, which were compared between acute and perforated appendicitis groups using Fisher exact and t-tests for categorical and continuous variables, respectively. We used an adjusted logistic regression model using clinical laboratory values to predict the odds of perforated appendicitis. RESULTS: A total of 251 patients were included in the analysis. Those with perforated appendicitis had a higher white blood cell count (P=0.0063), C-reactive protein (CRP) (P<0.0001), and IG% (P=0.0299). In the adjusted model, only elevated CRP (odds ratio 3.46, 95% confidence interval 1.40 8.54) and presence of left shift (odds ratio 2.66, 95% confidence interval 1.09 6.46) were significant predictors of perforated appendicitis. The c-statistic of the final model was 0.70, suggesting fair discriminatory ability in predicting perforated appendicitis. CONCLUSIONS: IG% did not provide any additional benefit to elevated CRP and presence of left shift in the differentiation between acute and perforated appendicitis. PMID- 24793451 TI - Mouse strain influences angiogenic response to dextran sodium sulfate-induced colitis. AB - BACKGROUND: Angiogenesis is a known pathologic factor in chronic inflammatory diseases. Regarding the murine dextran sodium sulfate (DSS) colitis model, different mouse strains produce variable clinical and inflammatory responses. We hypothesize that DSS colitis applied to diverse mouse strains will similarly elevate colonic microvessel density in parallel with inflammation, but will do so with different angiogenic profiles. MATERIALS AND METHODS: We induced DSS colitis in 129S2/SvPas, BALB/c, and C57BL/6 mice, then performed histologic and molecular analysis at day 7 to evaluate colonic inflammation and angiogenesis. RESULTS: Inflammation and microvessel density were similarly increased in DSS groups. The C57BL/6 cohort mounted a more severe colitis with 25% weight loss and greater colonic ulceration. Gene expression of angiogenic factors at baseline and in colitis groups were widely variable among strains. BALB/c mice exhibited higher angiogenic gene expression in control and DSS groups compared with other strains, specifically platelet-derived growth factor, angiopoietin-1, angiopoietin-1 (Ang 2), vascular endothelial growth factor receptor, and PDGF receptor. When evaluating the effect of DSS relative to controls, BALB/c mice were not significantly affected. 129S2/SvPas mice exhibited broad suppression of growth factors, significantly platelet-derived growth factor, Ang-2, and PDGF receptor. In contrast, C57BL/6 mice displayed increased gene expression, especially for angiopoietin-1 and Ang-2. CONCLUSIONS: Genetic heterogeneity influences the angiogenic profile elicited by DSS colitis. We demonstrate that within a model of murine colitis, mouse strain significantly affects inflammation-associated angiogenesis. These results may impact strain selection when using a colitis model focusing on inflammation and angiogenesis. Future studies to further define the angiogenesis pathway and potentially alter the disease course with targeted antiangiogenics are warranted. PMID- 24793452 TI - The effect of docosahexaenoic acid on bone microstructure in young mice and bone fracture in neonates. AB - BACKGROUND: As low bone mineral density is a risk factor for fracture in childhood, optimizing age appropriate bone mass is recommended and might lower the impact of bone loss related to age. Consumption of omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic and docosahexaenoic (DHA) acids have been shown to beneficially modulate bone metabolism. The objective of this study was to determine the incidence of fracture in neonates receiving a fish compared with soybean oil-based intravenous lipid emulsion and evaluate the effect of varying dietary omega-3 PUFA consumption on growing bone in young mice. MATERIALS AND METHODS: Eligibility criteria for the clinical study included gestational age <=37 wk and parenteral nutrition-dependence for >=4 wk. Radiographs were reviewed after lipid initiation to identify radiologic bone fracture. The animal study evaluated female C57/Bl6 mice randomized into one of five groups from age 3-12 wk, at which time femurs were harvested for micro computed tomography and light microscopy analysis. RESULTS: A lower incidence of bone fracture was found in neonates maintained on fish compared with soybean oil. In the animal study, findings suggest the DHA diet provides the best protection against trabecular bone loss as evidenced by increased bone volume fraction, increased trabecular number, and decreased trabecular separation on micro computed tomography. These protective effects appeared to affect the bone microstructure alone. CONCLUSIONS: The lower fracture risk observed in fish oil fed neonates in combination with the protective effects of DHA observed in the femurs of young C57/BL6 mice suggest an important role for omega-3 PUFAs on bone growth. PMID- 24793453 TI - Reversible protein inactivation by optogenetic trapping in cells. AB - We present a versatile platform to inactivate proteins in living cells using light, light-activated reversible inhibition by assembled trap (LARIAT), which sequesters target proteins into complexes formed by multimeric proteins and a blue light-mediated heterodimerization module. Using LARIAT, we inhibited diverse proteins that modulate cytoskeleton, lipid signaling and cell cycle with high spatiotemporal resolution. Use of single-domain antibodies extends the method to target proteins containing specific epitopes, including GFP. PMID- 24793454 TI - Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. AB - Current in vitro hematopoiesis models fail to demonstrate the cellular diversity and complex functions of living bone marrow; hence, most translational studies relevant to the hematologic system are conducted in live animals. Here we describe a method for fabricating 'bone marrow-on-a-chip' that permits culture of living marrow with a functional hematopoietic niche in vitro by first engineering new bone in vivo, removing it whole and perfusing it with culture medium in a microfluidic device. The engineered bone marrow (eBM) retains hematopoietic stem and progenitor cells in normal in vivo-like proportions for at least 1 week in culture. eBM models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not. This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro. PMID- 24793456 TI - A dual activatable photosensitizer toward targeted photodynamic therapy. AB - An unsymmetrical bisferrocenyl silicon(IV) phthalocyanine has been prepared in which the disulfide and hydrazone linkers can be cleaved by dithiothreitol and acid, respectively. The separation of the ferrocenyl quenchers and the phthalocyanine core greatly enhances the fluorescence emission, singlet oxygen production, intracellular fluorescence intensity, and in vitro photocytotoxicity. The results have been compared with those for the two symmetrical analogues which contain either the disulfide or hydrazone linker and therefore can only be activated by one of these stimuli. For the dual activatable agent, the greatest enhancement can be attained under a slightly acidic environment (pH = 4.5-6.8) and in the presence of dithiothreitol (in millimolar range), which can roughly mimic the acidic and reducing environment of tumor tissues. This compound can also be activated in tumor-bearing nude mice. It exhibits an increase in fluorescence intensity in the tumor over the first 10 h after intratumoral injection and can effectively inhibit the growth of tumor upon illumination. PMID- 24793455 TI - Towards error-free profiling of immune repertoires. AB - Deep profiling of antibody and T cell-receptor repertoires by means of high throughput sequencing has become an attractive approach for adaptive immunity studies, but its power is substantially compromised by the accumulation of PCR and sequencing errors. Here we report MIGEC (molecular identifier groups-based error correction), a strategy for high-throughput sequencing data analysis. MIGEC allows for nearly absolute error correction while fully preserving the natural diversity of complex immune repertoires. PMID- 24793457 TI - Epicardial adipose tissue-based defragmentation approach to persistent atrial fibrillation: its impact on complex fractionated electrograms and ablation outcome. AB - BACKGROUND: Increased epicardial adipose tissue (EAT) volume is associated with atrial fibrillation (AF). However, the efficacy of EAT-based left atrial (LA) ablation for persistent AF (PsAF) is unclear. OBJECTIVE: The purpose of this study was to assess whether EAT-based LA ablation is effective for PsAF. METHODS: In 60 PsAF patients (group I), 3-dimensional reconstructed computed tomography images depicting EAT were merged with NavX-based dominant-frequency (DF) and complex fractionated electrogram (CFE) maps obtained during AF. Pulmonary vein antrum isolation (PVAI) was followed by map-guided EAT-based ablation. Results were compared to those in a historical control group (group II, case-matched patients who underwent generalized stepwise ablation including linear plus CFE targeted ablation). RESULTS: In 70% (n = 42) of group I patients, the LA-EAT was located at the pulmonary vein antra; anterior and inferior surfaces, roof, septum, and mitral annulus; and left atrial appendage. EAT was at or near (<3 mm) 71% (390/550) of high-DF (> -8 Hz) sites. In 41 patients with persistent AF despite EAT-targeted ablation, CFE burden decreased significantly (from 96% to 13%, P < .0001), and DF decreased within the coronary sinus (6.9 +/- 0.7 Hz vs 5.9 +/- 0.7 Hz, P < .0001). Radiofrequency energy duration was significantly less in group I than in group II (25 +/- 6 minutes vs 31 +/- 12 minutes, P < .05). During 16-month follow-up, freedom from AF on antiarrhythmic drugs was 78% vs 60% (P < .05). CONCLUSION: PVAI plus EAT-based ablation efficiently eliminates high frequency sources and yields relatively high success. EAT-based LA ablation is a simple, clinically feasible PsAF ablation strategy. PMID- 24793458 TI - His overdrive pacing during supraventricular tachycardia: a novel maneuver for distinguishing atrioventricular nodal reentrant tachycardia from atrioventricular reciprocating tachycardia. AB - BACKGROUND: Because the His bundle is intrinsic to the circuit in orthodromic reciprocating tachycardia and remote from that of atrioventricular nodal reentrant tachycardia (AVNRT), pacing the His bundle during supraventricular tachycardia (SVT) may be useful to distinguish these arrhythmias. OBJECTIVE: The purpose of this study was to test the hypothesis that His overdrive pacing (HOP) would affect SVT immediately for orthodromic reciprocating tachycardia and in a delayed manner for AVNRT. METHODS: Once SVT was induced, HOP was performed by pacing the His bundle 10-30 ms faster than the SVT cycle length. The maneuver was determined to have entered the tachycardia circuit when a nonfused His-capture beat advanced or delayed the subsequent atrial electrogram by >=10 ms or when the tachycardia was terminated. The number of beats required to enter each tachycardia with HOP was recorded. RESULTS: HOP was performed during 66 SVTs (26 atrioventricular reciprocating tachycardia [AVRT] and 40 AVNRT). Entry into the tachycardia within 1 beat had sensitivity of 92%, specificity of 92%, positive predictive value (PPV) of 89% and negative predictive value (NPV) of 95% to confirm the diagnosis of AVRT. A cutoff >=3 beats to enter the circuit had sensitivity of 90%, specificity of 92%, PPV of 95% and NPV of 86% to confirm the diagnosis of AVNRT. HOP had sensitivity, specificity, PPV, and NPV of 100% for distinguishing septal AVRT from atypical AVNRT. CONCLUSION: HOP during SVT is a novel technique for distinguishing orthodromic reciprocating tachycardia from AVNRT. It can reliably distinguish between these arrhythmias with high sensitivity and specificity. PMID- 24793459 TI - Outcomes in African Americans undergoing cardioverter-defibrillator implantation for primary prevention of sudden cardiac death: findings from the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD). AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) reduce the risk of death in patients with left ventricular dysfunction. Little is known regarding the benefit of this therapy in African Americans (AAs). OBJECTIVE: The purpose of this study was to determine the association between AA race and outcomes in a cohort of primary prevention ICD patients. METHODS: We conducted a prospective cohort study of patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end point was appropriate ICD shock defined as a shock for rapid ventricular tachyarrhythmias. The secondary end-point was all-cause mortality. RESULTS: There were 1189 patients (447 AAs and 712 non-AAs) enrolled. Over a median follow-up of 5.1 years, a total of 137 patients experienced an appropriate ICD shock, and 343 died (294 of whom died without receiving an appropriate ICD shock). The multivariate adjusted hazard ratio (95% confidence interval) comparing AAs vs non AAs were 1.24 (0.96-1.59) for all-cause mortality, 1.33 (1.02, 1.74) for all cause mortality without receiving appropriate ICD shock, and 0.78 (0.51, 1.19) for appropriate ICD shock. Ejection fraction, diabetes, and hypertension appeared to explain 24.1% (10.1%-69.5%), 18.7% (5.3%-58.0%), and 13.6% (3.8%-53.6%) of the excess risk of mortality in AAs, with a large proportion of the mortality difference remaining unexplained. CONCLUSION: In patients with primary prevention ICDs, AAs had an increased risk of dying without receiving an appropriate ICD shock compared to non-AAs. PMID- 24793461 TI - A novel RyR2 mutation in a 2-year-old baby presenting with atrial fibrillation, atrial flutter, and atrial ectopic tachycardia. PMID- 24793460 TI - Sudden cardiac arrest recorded during Holter monitoring: prevalence, antecedent electrical events, and outcomes. AB - BACKGROUND: Causative arrhythmias of sudden cardiac arrest (SCA) are changing in this age of improved coronary care. OBJECTIVE: The purpose of this study was to examine the frequency of terminal arrhythmias and the electrical events prior to SCA. METHODS: We analyzed 24-hour Holter recordings of 132 patients enrolled from 41 institutions who either died (n = 88) or had an aborted death (n = 44). The Holter recordings were obtained for diagnosing and evaluating diseases and arrhythmias in those without any episodes suggestive of SCA. RESULTS: In 97 patients (73%), SCA was associated with ventricular tachyarrhythmias and in 35 (27%) with bradyarrhythmias. The bradyarrhythmia-related SCA patients were older than those with a tachyarrhythmia-related SCA (70 +/- 13 years vs. 58 +/- 19 years, P < .001). The most common arrhythmia for a tachyarrhythmia-related SCA was ventricular tachycardia degenerating to ventricular fibrillation (45%). The bradyarrhythmia-related SCA was caused by asystole (74%) or AV block (26%). Spontaneous conversion was observed in 37 patients (38%) with ventricular tachyarrhythmias. Of those, 62% of the patients experienced symptoms including syncope, chest pain, or convulsion. Multivariate logistic analysis revealed that independent predictors of mortality for tachyarrhythmia-related SCAs were advanced age (odds ratio 1.04, 95% confidence interval 1.02-1.08) and ST elevation within the hour before SCA (odds ratio 3.54, 95% confidence interval 1.07-13.5). In contrast, the presence of preceding torsades de pointes was associated with spontaneous conversion (odds ratio 0.20, 95% confidence interval 0.05-0.66). CONCLUSION: The most frequent cause of SCA remains ventricular tachyarrhythmias. Advanced age and ST elevation before SCA are risk factors for mortality in tachyarrhythmia-related SCAs. PMID- 24793463 TI - Human mast cell tryptase in biology and medicine. AB - The most abundant prestored enzyme of human mast cell secretory granules is the serine-protease tryptase. In humans, there are four tryptase isoforms, but only two of them, namely the alpha and beta tryptases, are known as medically important. Low levels of continuous tryptase production as an immature monomer makes up the major part of the baseline serum tryptase levels, while transient release of mature tetrameric tryptase upon mast cell degranulation accounts for the anaphylactic rise of serum tryptase levels. Serum tryptase determination contributes to the diagnosis or monitoring of mast cell disorders including mast cell activation - induced anaphylaxis, mastocytosis and a number of myeloproliferative conditions with mast cell lineage involvement. Baseline serum tryptase levels are predictive of the severity risk in some allergic conditions. PMID- 24793462 TI - Impact of TiO2 nanoparticles on Vicia narbonensis L.: potential toxicity effects. AB - This work was aimed to provide further information about toxicology of TiO2 nanoparticles (NPs) on Vicia narbonensis L., considering different endpoints. After exposure to TiO2 nanoparticle suspension (mixture of rutile and anatase, size <100 nm) at four different concentrations (0.2, 1.0, 2.0 and 4.0 0/00), the seeds of V. narbonensis were let to germinate in controlled environmental conditions. After 72 h, the extent of the success of the whole process (seed germination plus root elongation) was recorded as the vigour index, an indicator of possible phytotoxicity. After the characterisation of the hydric state of different materials, oxidative stress and enzymatic and nonenzymatic antioxidant responses were considered as indicators of possible cytotoxicity and to assess if damage induced by TiO2 NPs was oxidative stress-dependent. Cytohistochemical detection of in situ DNA fragmentation as genotoxicity endpoint was monitored by TUNEL reaction. The treatments with TiO2 NPs in our system induced phytotoxic effects, ROS production and DNA fragmentation. The nonenzymatic and enzymatic antioxidant responses were gradually and differentially activated and were able to maintain the oxidative damage to levels not significantly different from the control. On the other hand, the results of DNA fragmentation suggested that the mechanisms of DNA repair were not effective enough to eliminate early genotoxicity effects. PMID- 24793464 TI - Mast cells in renal inflammation and fibrosis: lessons learnt from animal studies. AB - Mast cells are hematopoietic cells involved in inflammation and immunity and have been recognized also as important effector cells in kidney inflammation. In humans, only a few mast cells reside in kidneys constitutively but in progressive renal diseases their numbers increase substantially representing an essential part of the interstitial infiltrate of inflammatory cells. Recent data obtained in experimental animal models have emphasized a complex role of these cells and the mediators they release as they have been shown both to promote, but also to protect from disease and fibrosis development. Sometimes conflicting results have been reported in similar models suggesting a very narrow window between these activities depending on the pathophysiological context. Interestingly in mice, mast cell or mast cell mediator specific actions became also apparent in the absence of significant mast cell kidney infiltration supporting systemic or regional actions via draining lymph nodes or kidney capsules. Many of their activities rely on the capacity of mast cells to release, in a timely controlled manner, a wide range of inflammatory mediators, which can promote anti inflammatory actions and repair activities that contribute to healing, but in some circumstances or in case of inappropriate regulation may also promote kidney disease. PMID- 24793465 TI - Endoscopic-assisted microsurgical techniques at the craniovertebral junction: 4 illustrative cases and literature review. AB - BACKGROUND: Endoscopic-assisted microsurgery (EAM) techniques are employed to improve visualization of the surgical field while minimizing brain retraction and trauma to neurovascular structures. There have been several reports in the literature on the indications and advantages of endoscopic-assisted techniques when operating at the craniovertebral junction (CVJ). The purpose of this study was to present illustrative cases and to perform a literature review of endoscopic-assisted microsurgical techniques at the CVJ. METHODS: A review of the literature was compiled through MEDLINE/OVID and using cross-references of articles on Pubmed. Illustrative cases from the senior author's clinical series are presented to highlight indications and the utility of EAM at the CVJ. RESULTS: Our literature review supports the utility of the endoscope in the transoral, transcervical, lateral, far lateral and posterolateral approaches. In particular EAM can be used in the transoral approach to increase surgical exposure of the clivus and minimize the need to split the soft palate while in the far lateral and posterolateral approaches, EAM can improve visualization down narrow or deep surgical corridors to help identify critical neurovascular structures and minimize the need for extensive bony removal. In general, the endoscope can be used to look around bony, vascular, or neoplastic lesions to visualize the surgical space behind these structures as well as to assess for tumor remnants after microsurgical resection. CONCLUSION: EAM techniques can improve illumination and visualization of the surgical field at the CVJ. In addition, the EAM techniques can help to minimize the need for brain retraction or extensive exposures. Utilization of both the endoscope and the microscope allows the surgeon to benefit from the advantages of each modality. PMID- 24793466 TI - Cyst formation after linac-based radiosurgery for arteriovenous malformation: examination of predictive factors using magnetic resonance imaging. AB - OBJECTIVE: Cyst formation is a well-known complication following radiosurgery for arteriovenous malformations (AVMs). In this retrospective study, the authors studied predictors for AVMs using magnetic resonance imaging (MRI) to assess the mechanism of cyst formation after linac-based radiosurgery (LBRS). METHODS: From April 1993 to April 2008, LBRS was performed on 109 patients with cerebral AVMs at our institution. Six patients (5.5%) were diagnosed with cyst formation after LBRS, and 5 of them underwent regular MRI follow-up every 3-4 months for 2 years post-LBRS, and every 6-12 months thereafter. RESULTS: Time from initial LBRS until cyst formation ranged from 8 months to 10.5 years. MRI showed contrast changes at the irradiated site and its periphery within a period of 4 months to 7 years after the initial LBRS. Moreover, the emergence of a high-intensity area (HIA) was observed on T2-weighted MRI (T2W-MRI) during the same period when changes were found on contrast-enhanced imaging. The emergence of a low-intensity area on T2W-MRI was observed prior to cyst formation or expansion, which was believed to be due to a subclinical hemorrhage near the irradiated region in all patients. Histological examination of the cyst nodule revealed hemosiderin deposits and microbleeding. CONCLUSIONS: Future cyst formation was suggested by the emergence of subclinical hemorrhage (microbleeding) in an irradiated field after gadolinium-enhanced MRI showed contrast changes and T2W-MRI showed a HIA around the irradiated field. MRI follow-up should be conducted on a regular basis in such patients, even after a complete occlusion has been diagnosed. PMID- 24793467 TI - Severe myelopathy after denture cream use--is copper deficiency or excess zinc the cause? PMID- 24793468 TI - Association of HLA-DR/DQ polymorphisms with Guillain-Barre syndrome in Tunisian patients. AB - Human leukocyte antigen (HLA) alleles have been implicated in many autoimmune diseases. The aim of this study is to assess whether HLA-DR/DQ alleles confer susceptibility to Guillain-Barre syndrome (GBS) in a Tunisian population. METHODS: The HLA-DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) in 38 patients with GBS and 100 healthy Tunisian control subjects. RESULTS: GBS in Tunisian patients was found to be associated with the following alleles with these relative patient versus control frequencies (pc denotes Bonferroni corrected probability values): DRB1*13 (23.68% vs. 9.0%; pc=0.01), followed by DRB1*14 (22.36% vs.5.5%; pc<10(-3)). Two haplotypes, DRB1*14/DQB1*05 and DRB1*13/DQB1*03, were found to be associated with susceptibility to GBS. However DRB1*07/DQB1*02 and DRB1*03/DQB1*02 haplotypes were more frequently observed in controls than in patients (11.5% vs.7.9%; pc=0.007 and 23% vs. 5.26%; pc<10(-3) respectively). These haplotypes seem to confer protection against the disease. CONCLUSION: Our data demonstrated a new GBS predisposition associated with HLA-DRB1*14 and DRB1*13. Theses alleles could be predisposing genetic factors for GBS in the Tunisian population. PMID- 24793470 TI - A giant suprasellar Rathke cleft cyst with psychiatric manifestations: case report. PMID- 24793469 TI - Is there any relation between cervical cord plaques and discopathy in patients with multiple sclerosis? AB - INTRODUCTION: Multiple sclerosis (MS) is the most common chronic autoimmune demyelinating disease of the central nervous system. The purpose of this study is to determine the relationship between the site of the cervical discopathy and cervical spinal cord plaque in MS patients. METHODS: This retrospective study included all patients with a definite diagnosis of MS who were treated at an outpatient clinic between September 2004 and September 2011. All patients underwent cervical magnetic resonance imaging (MRI) for primary investigation of the disease. Cervical MRI scans were evaluated for detection of any evidence of cervical discopathy and cervical MS plaques. Any correlation between the site of the MS lesions and discopathy was recorded. RESULTS: From 536 patients who were involved in the study, 214 patients had both cervical discopathy and cervical cord plaques. In this group 148 (69.1% of patients) had cervical plaque at the same site of cervical discopathy. The number of patients with cervical cord plaque and discopathy at same site was significantly higher than those with plaque and discopathy at different sites (P<0.05). CONCLUSION: The study data suggests a possible correlation between cervical discopathy and cervical MS plaque. PMID- 24793471 TI - Experience with Novalis stereotactic radiosurgery for vestibular schwannomas. AB - BACKGROUND: The Novalis linear accelerator system, a well developed modality, can be used for stereotactic radiosurgery (SRS). The aim of this study was to clarify the efficiency and safety of Novalis SRS in treating vestibular schwannomas. MATERIALS AND METHODS: This 4-year retrospective study enrolled 23 patients with 26 vestibular schwannomas (3 patients suffered from neurofibromatosis Type II). Five patients had undergone tumor resection. All 26 tumors were treated using Novalis SRS, with a prescription dose that varied between 10 and 16Gy (mean, 11.8+/-1.7Gy). The average follow-up period was 56.5+/-22.1 months (range, 17-87 months). RESULTS: There were 9 men and 14 women. Their mean age at the time of treatment was 54.0+/-14.6 years (range, 27-84 years). On average, the original size of the tumor was 19.0+/-7.2mm in maximal diameter (range, 4.6-39.9mm). At the last follow-up, 20 tumors had regressed (76.9%), and there was no observed change in the size of 3 tumors (11.5%). Three of 26 tumors (11.5%) enlarged more than 2mm in one direction. Thus the ultimate radiological tumor control rate was 88.5% (23/26). In addition, 20 (87.0%) patients retained their pre-irradiation hearing function. Facial and trigeminal nerve function were both preserved in all patients. No death occurred during the follow-up, and no patient was treated with a second SRS or converted to tumor resection. CONCLUSION: Novalis SRS is a reliable treatment option for vestibular schwannomas. With an optimal radiation dose, satisfactory tumor control can be achieved while preserving cranial nerve function. PMID- 24793472 TI - Rhinogenic metastatic brain and spinal cord abscesses in Crohn's disease. PMID- 24793473 TI - Clinical/perfusion CT CBV mismatch as prognostic factor in intraarterial thrombectomy in acute anterior circulation stroke. AB - OBJECTIVE: Contradictory results were reported for the outcome after endovascular recanalization (ERT) in acute anterior circulation ischemic stroke. We assessed whether a clinical/perfusion CT cerebral blood volume (CBV) mismatch concept (CPM) can identify patients who will benefit from reperfusion therapy. METHODS: Imaging and clinical data of 58 consecutive ERT cases with acute anterior circulation stroke (ICA, M1, proximal M2) undergoing intraarterial thrombectomy within 4.5h after symptom onset were analyzed retrospectively. CPM was defined as NIHSS>=8 and PCT CBV ASPECTS>=7. Minor CBV lesion was defined as PCT CBV ASPECTS>=7. RESULTS: All baseline characteristics other than blood glucose did not differ between the paired groups. Revascularization was achieved in 87.9% of all patients without significant difference between the paired groups. Favorable clinical outcome after 3 months (mRS<=2) resulted in 29.3% of all patients, in contrast to 47.4% of the CPM positive and 52.2% of the minor CBV lesion groups. CONCLUSION: CPM can identify patients who will benefit from reperfusion therapy in acute anterior circulation ischemic stroke. PMID- 24793474 TI - Antithyroid antibodies as a potential marker of autoimmune-mediated late onset temporal lobe epilepsy. AB - In one third of patients with epilepsy starting in adulthood the aetiology remains undetermined. Some patients with late onset temporal lobe epilepsy (TLE) together with memory decline have elevated antithyroid antibodies. PURPOSE: To compare the prevalence of antithyroid antibodies (aTR-ab) in adult onset temporal lobe epilepsy (TLE) patients with known and unknown TLE aetiology (N=42). Moreover, the sera of these patients was also assayed for antinuclear antibodies (ANA), anticardiolipin antibodies (ACL), anti glutamic acid decarboxylase antibodies (GAD) and antiglidadin antibodies. RESULTS: Positive aTR-ab in the sera of patients with unknown aetiology was 11/23 (47.8%) vs. 1/19 (4.3%) in the group with known aetiology (p=0.005). In 9/11 (81%) a pre-existing autoimmune disease was confirmed. Nine (81%) were women and five (45%) had memory impairment. There were 5/11 (45%) pharmacoresistant patients, and corticosteroid treatment was initiated in 3/5 with cognitive and seizure improvement. The results of other immunological tests were only remarkable for antiGAD antibodies with 3/11 (27%) positive patients, but this subgroup does not have any significant clinical differential feature. CONCLUSIONS: Late-onset TLE with positive aTR-ab tends to be middle-aged women with nonpharmacoresistant cryptogenic epilepsy plus cognitive decline and other associated autoimmune diseases. It could be advisable to test aTR-ab in TLE patients with an unknown aetiology, in order to improve diagnosis and resulting treatment. PMID- 24793475 TI - Pineal calcification is a novel risk factor for symptomatic intracerebral hemorrhage. AB - BACKGROUND: Pineal calcification is associated with symptomatic cerebral infarction in humans. However, there are limited data on the association of pineal calcification and intracerebral hemorrhage. We evaluated this association of symptomatic intracerebral hemorrhage and pineal calcification by computed tomography of the brain. METHODS: We reviewed all computed tomographic (CT) scans of the brains of patients over 15 years of age during the year 2011 at a university teaching hospital. Symptomatic intracerebral hemorrhage was identified by having clinical syndrome of stroke and acute intracerebral hemorrhage from brain CT scans. Pineal calcification was also evidenced by brain CT scans. Other stroke risk factors were recorded. The association of various risk factors including pineal calcification and intracerebral hemorrhage was calculated using logistic regression analysis. RESULTS: There were 2140 CT scans of the brains during the study period. Of those, 1071 scans (50.05%) met the study criteria. Intracerebral hemorrhage and pineal calcification were found in 77 (7.2%) and 689 (64.3%) patients, respectively. Pineal calcification was a significant risk factor for intracerebral hemorrhage with an adjusted odds ratio of 2.36 (95% confidence interval of 1.22-4.54). Other significant factors were age>50 years, hypertension, and diabetes. CONCLUSION: Pineal calcification is associated with symptomatic intracerebral hemorrhage. PMID- 24793476 TI - Comparison of brain 3.0-T with 1.5-T MRI in patients with multiple sclerosis: a 6 month follow-up study. AB - OBJECTIVES: The 2010 revisions to the McDonald criteria for the diagnosis of multiple sclerosis (MS) were recently published. One objective of the revision was to simplify the MRI criteria. The MRI criteria do not specify magnetic field strength. We studied whether there was any difference in diagnosis between brain 3.0-T and 1.5-T MRI according to the 2010 revisions of the McDonald criteria. PATIENTS AND METHODS: We prospectively studied brain 3.0-T and 1.5-T MRI in 22 patients with MS. 1.5-T MRI was performed 24h after 3.0-T MRI, and the scanning protocol included contiguous axial sections of T2-weighted images (T2WI), T1WI, and enhanced T1WI. These two different MRI and neurological assessments were scheduled to be repeated 3 and 6 months after study entry. RESULTS: The regions where MS lesions were better visualized on 3.0-T MRI tended to be in deep white matter on T2WI. Dissemination of lesions in space and time was similar for 3.0-T and 1.5-T MRI. CONCLUSION: Our study found no difference between brain 3.0-T and 1.5-T MRI. There was no apparent impact of brain 3.0-T MRI on the diagnosis of MS according to the 2010 version of the MRI criteria. PMID- 24793477 TI - Comparison of the clinical course of Japanese MM1-type sporadic Creutzfeldt-Jakob disease between subacute spongiform encephalopathy and panencephalopathic-type. AB - BACKGROUND: Approximately half of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases show panencephalopathic-type (PE-type) pathology, which is a rare subtype in North Americans and Europeans. Until now, the differences in the clinical course between subacute spongiform encephalopathy (SSE) cases and PE type cases have been unclear. METHODS: To investigate the clinical course of both subtypes, clinical findings from 42 Japanese MM1-type sCJD cases (20 SSE cases and 22 PE-type cases) were retrospectively evaluated by statistical analysis. RESULTS: No significant differences could be found regarding age at disease onset, the period between disease onset and first observation of myoclonus, the period between disease onset and the first observation of periodic sharp-wave complexes on electroencephalogram, or the period between disease onset and progression to the akinetic mutism state - whereas total disease duration and the period between the akinetic mutism state and death were significantly longer in PE-type cases. The prolonged disease duration was induced by the extended survival period in the akinetic mutism state. There was a statistically significant difference between the two series regarding performance of tube feeding, but no statistically significant difference regarding performance of tracheotomy or gastrostomy. None of the cases received mechanical ventilation. CONCLUSION: We speculate that the most crucial factor of the prolonged survival period of Japanese sCJD cases, particularly in the PE-type, is that the introduction of tube-feeding in the akinetic mutism state leads to the stabilization of the patient's general condition. PMID- 24793478 TI - Natural variation of histone modification and its impact on gene expression in the rat genome. AB - Histone modifications are epigenetic marks that play fundamental roles in many biological processes including the control of chromatin-mediated regulation of gene expression. Little is known about interindividual variability of histone modification levels across the genome and to what extent they are influenced by genetic variation. We annotated the rat genome with histone modification maps, identified differences in histone trimethyl-lysine levels among strains, and described their underlying genetic basis at the genome-wide scale using ChIP-seq in heart and liver tissues in a panel of rat recombinant inbred and their progenitor strains. We identified extensive variation of histone methylation levels among individuals and mapped hundreds of underlying cis- and trans-acting loci throughout the genome that regulate histone methylation levels in an allele specific manner. Interestingly, most histone methylation level variation was trans-linked and the most prominent QTL identified influenced H3K4me3 levels at 899 putative promoters throughout the genome in the heart. Cis- acting variation was enriched in binding sites of distinct transcription factors in heart and liver. The integrated analysis of DNA variation together with histone methylation and gene expression levels showed that histoneQTLs are an important predictor of gene expression and that a joint analysis significantly enhanced the prediction of gene expression traits (eQTLs). Our data suggest that genetic variation has a widespread impact on histone trimethylation marks that may help to uncover novel genotype-phenotype relationships. PMID- 24793479 TI - Green synthesis of iron nanoparticles by various tea extracts: comparative study of the reactivity. AB - Iron nanoparticles (Fe NPs) are often synthesized using sodium borohydride with aggregation, which is a high cost process and environmentally toxic. To address these issues, Fe NPs were synthesized using green methods based on tea extracts, including green, oolong and black teas. The best method for degrading malachite green (MG) was Fe NPs synthesized by green tea extracts because it contains a high concentration of caffeine/polyphenols which act as both reducing and capping agents in the synthesis of Fe NPs. These characteristics were confirmed by a scanning electron microscope (SEM), UV-visible (UV-vis) and specific surface area (BET). To understand the formation of Fe NPs using various tea extracts, the synthesized Fe NPs were characterized by SEM, X-ray energy-dispersive spectrometer (EDS), and X-ray diffraction (XRD). What emerged were different sizes and concentrations of Fe NPs being synthesized by tea extracts, leading to various degradations of MG. Furthermore, kinetics for the degradation of MG using these Fe NPs fitted well to the pseudo first-order reaction kinetics model with more than 20 kJ/mol activation energy, suggesting a chemically diffusion controlled reaction. The degradation mechanism using these Fe NPs included adsorption of MG to Fe NPs, oxidation of iron, and cleaving the bond that was connected to the benzene ring. PMID- 24793480 TI - Impact of in situ preparation of CdS filled PVP nano-composite. AB - Cadmium sulfide nanoparticles filled polyvinyl pyrrolidone (PVP) were prepared by in situ wet chemical precipitation technique. X-ray diffraction (XRD), Fourier transforms infrared spectra (FTIR), transmission electron microscopy (TEM) and ultraviolet-visible (UV/Vis) were used to characterize the prepared nano composites. Density Function Theory (DFT) was used to approve the complexation process. XRD results indicate appearance of two peaks at about 28.1 degrees , 27.4 degrees corresponds to (101) and (002) planes which suggest hexagonal phase of CdS with lattice constants of 4.14, 6.72 A in the polymeric matrix. UV/Vis spectra reveal that nano-composite films show quantum confinement effect. The absorption showed a shift toward the shorter wavelength (blue shift) with decrease in the concentration of Cd+ ions. Optical band gap and particle size were calculated and is in agreement with the results obtained from TEM data. Transmission electron microscopy shows that the prepared CdS nanoparticles were dispersed and nearly uniform in diameter within the polymeric matrix. PMID- 24793481 TI - Nanostructure copper oxocobaltate fabricated by co-precipitation route using copper and cobalt nitrate as precursors: characterization by combined diffuse reflectance and FT infrared spectra. AB - Nanostructure copper oxocobaltate has been fabricated by a co-precipitation route using copper and cobalt nitrate as precursors. The physicochemical properties of copper cobaltate have been characterized via X-ray powder diffractometry (XRD) and field emission scanning electron microscopy (FESEM). The X-ray diffraction patterns indicates the presence of a spinel crystalline phase, (Cu0.30Co0.70)Co2O4, copper oxocobaltate with face-centered cubic lattice and Fd3m space group. FESEM images also illustrated a typical hexagonal morphology with particle size 25 nm, showing a good nanoscale crystalline morphology, which corresponds well with their XRD results. The FTIR spectra confirmed the presence of hydroxyl groups bonded to the metals, stretching vibration of the cobalt oxygen bond in an octahedral coordination and the characteristic band assigned to the vibration of Cu-O bond. UV-VIS diffuse reflectance spectrum shows a broad band over the whole visible range and broad band between 200 nm and 390 nm ascribed to the ligand to metal charge transfer. PMID- 24793482 TI - IR and Raman spectra, ab initio and density functional computations of the vibrational spectra, molecular geometries and atomic charges of uracil and 5 aminouracil. AB - Infrared (IR) and Raman spectra of uracil and 5-aminouracil have been recorded and analyzed between the region 200-4000 cm(-1). The optimized molecular geometries, atomic polar tensor (APT) charges and vibrational characteristics have been studied theoretically using restricted Hartree-Fock (RHF) and density functional theory (DFT) methods. Using the Becke's exchange in conjunction with Lee-Yang-Parr's correlation functional and Becke's three-parameter hybrid method (B3LYP), the ab initio and DFT calculations were carried out to study the optimized molecular fundamental vibrational frequencies for uracil and 5 aminouracil by employing Gaussian-03 program. The fundamental vibrational frequencies along with their corresponding intensities in IR and Raman activities and depolarization ratios of the Raman lines have also been calculated using the RHF and DFT methods employing different basis sets. In quantum chemical calculations, the most of B3LYP/6-311++G** vibrational frequencies are in the excellent agreement with available experimental assignments and helped in the reassignments of some fundamental vibrational modes. On the basis of calculated results, the assignments of some missing frequencies in the experimental study are proposed. Assuming under the Cs point group for both molecules, the distribution of normal mode of vibrations between the two species as planar (a') and non-planar (a") are given by 25a'+11a", of which 30 modes (21a'+9a") correspond to the uracil moiety and 6 modes (4a'+2a") to the NH2 group. Kekule ring stretching mode is found to be comparatively higher frequency magnitude than the mode of uracil due to the involvement of hydrogen bonding of amino group. But, the ring breathing is found to be lower frequency magnitude compared to those for uracil which could be due to mass effect of the NH2 group in place of the hydrogen atom. All other bands have also been assigned different fundamentals/overtones/combinations. PMID- 24793483 TI - Molecular geometry, conformational, vibrational spectroscopic, molecular orbital and Mulliken charge analysis of 2-acetoxybenzoic acid. AB - The Fourier transform infrared (FT-IR) and FT-Raman spectra of 2-acetoxybenzoic acid (2ABA), a painkiller agent were recorded in the region 4000-450 cm(-1) and 5000-50 cm(-1) respectively. Hartree Fock (HF) and Density functional theory (DFT) methods have been used to determine its optimized geometrical parameter, atomic charges, and vibrational wavenumbers and intensity of the vibrational bands of the title molecule. The computed vibrational wave numbers were compared with the FT-IR and FT-Raman experimental data. The computational calculations were done at HF and DFT/B3LYP level with 6-311++G(d,p) basis set. The complete vibrational assignments were performed on the basis of the potential energy distribution (PED) analysis. The Mulliken charges, UV-Visible spectral analysis and HOMO-LUMO energy gap have been calculated and reported. The B3LYP method of calculated parameters is a good complement with the experimental findings. The thermodynamic properties like entropy, heat capacity and zero vibrational energy have been calculated and discussed. The electrostatic potential (ESP) contour surface and molecular electrostatic potential (MESP) of the molecule were constructed. PMID- 24793484 TI - ApoA-I or ABCA1 expression suppresses fatty acid synthesis by reducing 27 hydroxycholesterol levels. AB - Abnormal lipid metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). The ATP-binding cassette transporter A1 (ABCA1) protein mediates the transport of cholesterol and phospholipids from cells to apolipoprotein A-I (apoA-I) to generate nascent HDL particles. Previous studies revealed that overexpression of ABCA1 or apoA-I alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effect of apoA-I and ABCA1 overexpression on genes involved in fatty acid synthesis in QSG-7701 hepatocytes and in mice. Human apoA-I and ABCA1 were overexpressed by transfection in QSG 7701 hepatocytes. Human apoA-I was also overexpressed via an adenoviral vector in C57BL/6J mice fed a methionine choline-deficient diet. Overexpression of either apoA-I or ABCA1 resulted in an increase in cholesterol efflux and a decrease in cellular cholesterol, fatty acids, and triglycerides. Overexpression of these genes also resulted in a reduction in 27-hydroxycholesterol levels and a decrease in the mRNA levels of fatty acid synthase and acetyl-CoA carboxylase 1. Overexpression of apoA-I in mice reduced hepatic lipid levels, 27 hydroxycholesterol levels, and the mRNA levels of fatty acid synthase and acetyl CoA carboxylase 1. These results suggest that expression of apoA-I or ABCA1 can reduce steatosis by decreasing lipid storage and modifying lipid transport in hepatocytes and may also inhibit fatty acid synthesis by decreasing 27 hydroxycholesterol levels. PMID- 24793485 TI - Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: case of aminergic toxins. AB - Composition of mamba's venom is quite atypical and characterized by the presence of a large diversity of three-finger fold toxins (3FTx) interacting with various enzymes, receptors and ion channels. In particular, 3FTx from mambas display the unique property to interact with class A GPCRs, sometimes with a high affinity and selectivity. A screening of five of these toxins (MT1, MT3, MT7, rho-Da1a and rho-Da1b) on 29 different subtypes of bioaminergic receptors, using competition binding experiments, highlights the diversity of their pharmacological profiles. These toxins may display either absolute selectivity for one receptor subtype or a polypharmacological property for various bioaminergic receptors. Nevertheless, adrenoceptor is the main receptor family targeted by these toxins. Furthermore, a new receptor target was identified for 3FTx and toxins in general, the rho-Da1b interacting competitively with the human dopamine D3 receptor in the micromolar range. This result expands the diversity of GPCRs targeted by toxins and more generally highlights the multipotent interacting property of 3FTx. Phylogenic analyzes of these toxins show that muscarinic, adrenergic and dopaminergic toxins may be pooled in one family called aminergic toxins, this family coming probably from a specific radiation of ligands present in mamba venoms. PMID- 24793486 TI - CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition. AB - PI3K/Akt/mTOR pathway plays an important role in tumor progression and anti cancer drug resistance. The aim of the present study is to determine the antitumor effect of CCT128930, a novel small molecule inhibitor of Akt, in the HepG2 hepatoma cancer cells. Our results showed that at low concentrations, CCT128930 increased, but not inhibited, the phosphorylation of Akt in HepG2 and A549 cells. CCT128930 inhibited cell proliferation by inducing cell cycle arrest in G1 phase through downregulation of cyclinD1 and Cdc25A, and upregulation of p21, p27 and p53. A higher dose (20 MUM) of CCT128930 triggered cell apoptosis with activation of caspase-3, caspase-9, and PARP. Treatment with CCT128930 increased phosphorylation of ERK and JNK in HepG2 cells. CCT128930 activated DNA damage response of HepG2 cell characterized by phosphorylation of H2AX, ATM (ataxia-telangiectasia mutated), Chk1 and Chk2. Upon exposure to CCT128930 at a higher concentration, HepG2 cells exhibited autophagy was accompanied by an increase the levels of LC3-II and Beclin-1. Blocking autophagy using chloroquine magnified CCT128930-induced apoptotic cell death and the phosphorylation of H2AX. The results in this study have advanced our current understandings of the anti cancer mechanisms of CCT128930 in cancer cells. PMID- 24793488 TI - Improving maternity care in the Dominican Republic: a pilot study of a community based participatory research action plan by an international healthcare team. AB - This article is a report of the process and results of a feasibility pilot study to improve the quality of maternity care in a sample of 31 women and their newborns delivering in a public, tertiary hospital in the Dominican Republic. The pilot study was the first "action step" taken as a result of a formative, community-based participatory research (CBPR) study conducted between 2008 and 2010 by an interdisciplinary, international partnership of U.S. academic researchers, Dominican medical/nursing personnel, and Dominican community health workers. Health personnel and community health workers separately identified indicators most important to measure quality of antepartum maternity care: laboratory and diagnostic studies and respectful, interpersonal communication. At the midpoint and the completion of data collection, the CBPR team evaluated the change in quality indicators to assess improvement in care. The pilot study supports the idea that joint engagement of community health workers, health personnel, and academic researchers with data creation and patient monitoring is motivating for all to continue to improve services in the cultural context of the Dominican Republic. PMID- 24793489 TI - Plasmonic Cu(x)In(y)S2 quantum dots make better photovoltaics than their nonplasmonic counterparts. AB - A synthetic approach has recently been developed which results in Cu(x)In(y)S2 quantum dots (QDs) possessing localized surface plasmon resonance (LSPR) modes in the near-infrared (NIR) frequencies.1 In this study, we investigate the potential benefits of near-field plasmonic effects centered upon light absorbing nanoparticles in a photovoltaic system by developing and verifying nonplasmonic counterparts as an experimental control. Simple QD-sensitized solar cells (QD SSCs) were assembled which show an 11.5% relative increase in incident photon conversion efficiency (IPCE) achieved in the plasmon-enhanced devices. We attribute this increase in IPCE to augmented charge excitation stemming from near field "antenna" effects in the plasmonic Cu(x)In(y)S2 QD-SSCs. This study represents the first of its kind; direct interrogation of the influence of plasmon-on-semiconductor architectures with respect to excitonic absorption in photovoltaic systems. PMID- 24793490 TI - Aprepitant, a NK-1R antagonist could be employed for cytotoxic therapy induced alimentary tract mucosal inflammation. PMID- 24793491 TI - Predicting posttraumatic stress disorder after childbirth. AB - OBJECTIVE: around 50% of women report symptoms that indicate some aspect of their childbirth experience was 'traumatic', and at least 3.1% meet diagnosis for PTSD six months post partum. Here we aimed to conduct a prospective longitudinal study and examine predictors of birth-related trauma - predictors that included a range of pre-event factors - as a first step in the creation of a screening questionnaire. METHOD: of the 933 women who completed an assessment in their third trimester, 866 were followed-up at four to six week post partum. Two canonical discriminant function analyses were conducted to ascertain factors associated with experiencing birth as traumatic and, of the women who found the birth traumatic, which factors were associated with those who developed PTSD. FINDINGS: a mix of 16 pre-birth predictor variables and event-specific predictor variables distinguished women who reported symptoms consistent with trauma from those who did not. Fourteen predictor variables distinguished women who went on to develop PTSD from those who did not. CONCLUSIONS: anxiety sensitivity to possible birthing problems, breached birthing expectations, and severity of any actual birth problem, predicted those who found the birth traumatic. Prior trauma was the single most important predictive factor of PTSD. Evaluating the utility of brief, cost-effective, and accurate screening for women at risk of developing birth-related PTSD is suggested. PMID- 24793493 TI - Tinnitus specifically alters the top-down executive control sub-component of attention: evidence from the Attention Network Task. AB - Tinnitus can be defined as the perception of noxious disabling internal sounds in the absence of external stimulation. While most individuals with tinnitus show some habituation to these internal sounds, many of them experience significant daily life impairments. There is now convincing evidence that impairment in attentional processes may be involved in tinnitus, particularly by hampering the habituation mechanism related to the prefrontal cortex activity. However, it is thus still unclear whether this deficit is an alteration of alerting and orienting attentional abilities, or the consequence of more general alteration in the executive control of attention. In the present study, 20 tinnitus patients were compared to 20 matched healthy controls using the Attention Network Test, to clarify which attentional networks, among alerting, orienting, and executive networks, show differences between the groups. The results showed that patients with tinnitus do not present a general attentional deficit but rather a specific deficit for top-down executive control of attention. This deficit was highly correlated with patient characteristics of years of tinnitus duration and the frequency of coping strategies employed to alleviate tinnitus distress in daily life. These findings are discussed in terms of recent neurobiological models suggesting that prefrontal cortex activity might especially be related to tinnitus habituation. Therapeutic perspectives focusing both on rehabilitation of the executive control of attention and neuromodulation are also discussed. PMID- 24793492 TI - Pair housing reverses post-stroke depressive behavior in mice. AB - Social isolation (SI) has been linked epidemiologically to high rates of morbidity and mortality following stroke. In contrast, strong social support enhances recovery and lowers stroke recurrence. However, the mechanism by which social support influences stroke recovery has not been adequately explored. The goal of this study was to examine the effect of post-stroke pair housing and SI on behavioral phenotypes and chronic functional recovery in mice. Young male mice were paired for 14 days before a 60 min transient middle cerebral artery occlusion (MCAO) or sham surgery and assigned to various housing environments immediately after stroke. Post-stroke mice paired with either a sham or stroke partner showed significantly higher (P<0.05) sociability after MCAO than isolated littermates. Sociability deficits worsened over time in isolated animals. Pair housed mice showed restored sucrose consumption (P<0.05) and reduced immobility in the tail suspension test compared to isolated cohorts. Pair-housed stroked mice demonstrated significantly reduced cerebral atrophy after 6 weeks (17.5 +/- 1.5% in PH versus 40.8 +/- 1.3% in SI; P<0.001). Surprisingly, total brain arginase-1, a marker of a M2 "alternatively activated" myeloid cells was higher in isolated mice. However, a more detailed assessment of cellular expression showed a significant increase in the number of microglia that co-labeled with arginase-1 in the peri-infarct region in PH stroke mice compared to SI mice. Pair housing enhances sociability and reduces avolitional and anhedonic behavior. Pair housing reduced serum IL-6 and enhanced peri-infarct microglia arginase-1 expression. Social interaction reduces post-stroke depression and improves functional recovery. PMID- 24793494 TI - Pilot-scale culture of somatic embryos of Eleutherococcus senticosus in airlift bioreactors for the production of eleutherosides. AB - PURPOSE OF WORK: To establish pilot scale bioreactor cultures of somatic embryos of Siberian ginseng for the production of biomass and eleutherosides. Somatic embryos of Eleutherococcus senticosus were cultured in airlift bioreactors using Murashige and Skoog medium with 30 g sucrose l(-1) for the production of biomass and eleutherosides. Various parameters including the type of bioreactor, aeration volume, and inoculum density were optimized for 3 l capacity bioreactors. Balloon type airlift bioreactors, utilizing a variable aeration volume of 0.1-0.3 vvm and an inoculum of 5 g l(-1), were suitable for biomass and eleutheroside production. In 500 l balloon-type airlift bioreactors, 11.3 g dry biomass l(-1), 220 ug eleutheroside B l(-1), 413 ug eleutheroside E l(-1), and 262 ug eleutheroside E1 l(-1) were produced. PMID- 24793495 TI - Influence of promoter and signal peptide on the expression of pullulanase in Bacillus subtilis. AB - To achieve efficient expression and secretion of a biologically-active pullulanase, the effect of promoter and signal peptide on the production of pullulanase was studied. Three types of promoters (PP43, P apr and P amy ) and four types of signal peptides (SP sacB , SP amy , SP aprl and SP aprs ) were combined to construct twelve expression cassettes for pullulanase in Bacillus subtilis. The pullulanase activity assay was employed to quantify the level of differential expression, and a real-time PCR assay was applied to comparatively track the transcriptional level. Under the same experimental conditions, the potency ratios among the three promoters were P apr > P amy > PP43. The secretion efficiency ratios mediated by the signal peptides were SP sacB > SP amy > SP aprs > SP aprl . The highest yield of pullulanase could be achieved under the promotion mediated by P apr and secretion by SP sacB . PMID- 24793496 TI - miR-155 regulates the proliferation and cell cycle of colorectal carcinoma cells by targeting E2F2. AB - MicroRNAs play important roles in carcinogenesis by negatively regulating the expression of target genes. Here we explore the biological function of miR-155 and the underlying mechanism in colorectal carcinoma. We validate, for the first time, that E2F2 is a direct target of miR-155 using western blot and a luciferase reporter assay and that miR-155 regulates the proliferation and cell cycle of colorectal carcinoma cells by targeting E2F2 using siRNA technology. We also found, for the first, time that E2F2 acts as a tumor suppressor in colorectal carcinoma. Overall, miR-155 plays an important role in colorectal carcinoma tumorigenesis by negative regulation of its targets including E2F2 and may be a potential therapeutic target for colorectal carcinoma treatment. PMID- 24793497 TI - Directed evolution of an exoglucanase facilitated by a co-expressed beta glucosidase and construction of a whole engineered cellulase system in Escherichia coli. AB - A novel high-throughput screening method is proposed for the directed evolution of exoglucanase facilitated by the co-expression of beta-glucosidase, using the glucose released from filter paper as the screening indicator. Three transformants (B1, D6 and G10) with improved activity were selected from 4,000 colonies. The specific activities of B1, D6 and G10 for releasing glucose were, respectively, 1.4-, 1.3- and 1.6-fold higher than that of the wild type. The engineered exoglucanase gene was inserted into an expression vector carrying the previously engineered endoglucanase and beta-glucosidase genes, and transformed into Escherichia coli to form a completely engineered cellulase system that showed 8.2-fold increase in glucose production (relative activity) compared to the cells equipped with wild-type enzymes. To our knowledge, this is the first report for directed evolution of an exoglucanase using insoluble cellulose as the screening substrate. PMID- 24793498 TI - Bioconversion of deoxysugar moieties to the biosynthetic intermediates of daunorubicin in an engineered strain of Streptomyces coeruleobidus. AB - Daunorubicin (DNR) is a representative anthracycline with anti-tumor bioactivity. Its convergent biosynthetic pathway has promoted the research on pursuing novel anthracyclines by combinatorial biosynthesis. SnoaL is a special polyketide cyclase that catalyzes the closure of nogalonic acid methyl ester with the C9-S stereochemistry. In this study, the gene cluster of DNR was cloned, and snoaL was integrated into the DNR biosynthetic pathway for the substitution of dnrD in Streptomyces coeruleobidus DM, which resulted in the production of epi aklaviketone. The biosynthetic pathway of NDP-4-deacetyl-L-chromose B was then expressed in the engineered strain, which led to the production of corresponding glycosylated anthracycline compounds. Finally, the bioactivities of these engineering strains were evaluated. PMID- 24793499 TI - Domestication changes innate constraints for birdsong learning. AB - Birdsongs are acquired by imitating the sounds produced by conspecifics. Within a species, songs diverge by cultural transmission, but the range of species specific features is restricted by innate constraints. Bengalese finches (Lonchura striata var. domestica) are a domesticated strain of the wild White rumped munia (Lonchura striata). The songs of the domesticated strain have more tonal sounds and more variable sequences than those of the wild strain. We compared the features of songs that were produced by normal birds, isolation reared birds, and cross-fostered birds in both White-rumped munias and Bengalese finches to identify differences in the genetic and environmental factors of their songs. Factor analyses were conducted based on 17 song measurements. We found that isolated songs differed from normal and cross-fostered songs, especially in unstable prosodic features. In addition, there were significant differences in sound property of mean frequency between the two strains regardless of the rearing conditions. Thus, innate constraints that partially determine birdsong phenotypes may be altered through domestication. PMID- 24793500 TI - Structure elucidation of a process-related impurity of dapoxetine. AB - Unknown by-product associated with the synthesis of dapoxetine was isolated. The structure elucidation of this new compound using accurate mass data and NMR spectroscopy is presented herein. The unambiguous resonance assignment concluded to the formation of a tricyclic compound 4-phenyl-2H,3H,4H-naphtho[1,2-b]pyran, a new impurity of dapoxetine which has never been reported previously. A proposed mechanism for the formation of the new carbon-carbon bond is discussed. For the separation of dapoxetine and the process-related impurities, a gradient HPLC method was developed. PMID- 24793501 TI - Rabies-virus-glycoprotein-pseudotyped recombinant baculovirus vaccine confers complete protection against lethal rabies virus challenge in a mouse model. AB - Rabies virus has been an ongoing threat to humans and animals. Here, we developed a new strategy to generate a rabies virus vaccine based on a pseudotyped baculovirus. The recombinant baculovirus (BV-RVG/RVG) was pseudotyped with the rabies virus glycoprotein (RVG) and also simultaneously expressed another RVG under the control of the immediate early CMV promoter. In vitro, this RVG pseudotyped baculovirus vector induced syncytium formation in insect cells and displayed more efficient gene delivery into mammalian cells. Mice immunized with BV-RVG/RVG developed higher levels of virus-neutralizing antibodies, and conferred 100% protection against rabies viral challenge. These data indicate that the RVG-pseudotyped baculovirus BV-RVG/RVG can be used as an alternative strategy to develop a safe and efficacious vaccine against the rabies virus. PMID- 24793502 TI - Innate immunity to recombinant QseC, a bacterial adrenergic receptor, may regulate expression of virulence genes of avian pathogenic Escherichia coli. AB - Certain bacterial pathogens rely on a membrane bound sensor kinase, QseC, to coordinate their virulence gene expression in a process called quorum sensing. The present study evaluated the effect of host immunity to a recombinant QseC protein, on the virulence gene expression of avian pathogenic Escherichia coli (APEC) of O78 serogroup (APECO78). For this purpose, we constructed a plasmid expressing QseC protein which is 50kDa in size and stimulated avian macrophage like cells (AMCs) with the native form of QseC protein at different concentrations. The cell culture medium of QseC-stimulated AMCs was then used to investigate its effect on APECO78 growth rate and virulence gene expression. Growth curve analysis of APECO78 indicated that growth rate of APECO78 in Luria Bertani (LB) broth containing the culture medium of stimulated AMCs was significantly lower and was impeded at entering the exponential phase. The expression of virulence genes of APECO78 such as aufA, fliC, fimH, fyuA, iucC, iutA, msbB and vat were also significantly down-regulated. On the other hand, APECO78 grown in LB containing the cell culture medium of non-stimulated AMCs did not exhibit these changes. Additionally, stimulation with QseC effectively induced interferon gamma (IFN-gamma), Toll-like receptor 4 (TLR-4) and Toll like receptor 15 (TLR-15) expression in AMCs. To summarize, our results demonstrated that recombinant QseC protein could be immunogenic and induces host immunity that regulates selective, yet major, virulence gene expression of APECO78 bacteria. Thus, present data provide evidence that QseC, a bacterial functional analog of adrenergic receptor, holds a promise as one of the vaccine candidates against APEC infections. PMID- 24793503 TI - Retreatment of central nervous system tumours. AB - The purpose of this overview is to describe radiotherapy retreatment of primary central nervous system tumours from a practical clinical management perspective, including patient selection, choice of radiation technique, dose and fractionation. Useful relief of clinical symptoms and occasionally prolonged survival can follow retreatment. Further analysis of a previously published data set shows that the duration of remission after initial radiotherapy does not correlate with the duration of the remission after retreatment. Also there is no clear relationship between delivered tissue and tumour biological effective dose (BED) and duration of second remission. 'Recovery' of radiation tolerance with time is important and the radiobiological experiments that show this phenomenon have important limitations. To improve the decision as to how much recovery safely occurs with increasing time after radiotherapy, a new mathematical formulation is proposed. This is essentially conservative in its intent, compatible with experimental data sets, and provides a method for tentative calculation of retreatment dose and fractionation. Worked examples are provided of such calculations. As an increasing number of relatively young patients are now retreated, it is important to extend the experimental and human evidence base. A nationally co-ordinated analysis of patients already retreated would be valuable, in order to make future retreatment as safe and effective as possible, with validation of the permissible retreatment schedules for the particular radiation technique used. A national register and task force is proposed to facilitate this. PMID- 24793504 TI - An isotoxic planning comparison study for stage II-III non-small cell lung cancer: is intensity-modulated radiotherapy the answer? AB - AIMS: Recent clinical series suggest that treating patients with isotoxic twice daily radiotherapy may be beneficial. This dosimetric planning study compared the use of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DRT) to deliver isotoxic treatment for non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Twenty patients with stage II/III NSCLC were selected. A dose-escalated plan was produced retrospectively for each using three different methods: (i) three to five beams 3DRT; (ii) seven beams inverse planned conformal radiotherapy; (iii) seven beams IMRT. The starting point for dose escalation was 55.8 Gy in 1.8 Gy per fraction twice-daily. The number of fractions was then increased until one or more organ at risk tolerance dose was exceeded or a maximum dose of 79.2 Gy was reached. RESULTS: The median escalated doses were 70.2, 66.6 and 64.8 Gy for IMRT, 3DRT and inverse-planned conformal radiotherapy, respectively. IMRT allowed a significant dose increase in comparison with the other two methods (P < 0.05), whereas no significant difference was found between 3DRT and inverse-planned conformal radiotherapy. IMRT was more successful at escalating dose in patients where the brachial plexus and spinal canal were close to the planning target volume. IMRT did not allow the escalation of dose beyond 70.2 Gy (82.8 Gy BED10, 69 Gy EQD2) due to the proximity of disease to the great vessels and the proximal bronchial tree. CONCLUSIONS: IMRT allows increased dose escalation compared with conformal radiotherapy. However, there is limited opportunity to escalate the prescription dose beyond 70.2 Gy twice-daily in disease close to the central mediastinal structures. PMID- 24793505 TI - YouTube as a tool for pain management with informal caregivers of cancer patients: a systematic review. AB - CONTEXT: Cancer caregivers have information and support needs, especially about cancer pain management. With high Internet use reported among caregivers, YouTube may be an accessible option when looking for information on cancer pain management. OBJECTIVES: The purpose of this study was to explore the availability and characteristics of instructional cancer pain management videos on YouTube and determine to what extent these videos addressed the role of informal caregivers in cancer pain management. METHODS: A systematic review of videos on YouTube resulting from search terms "pain and cancer," "pain and hospice," and "pain and palliative care" was conducted in May 2013. If the video addressed pain management, was in English, and was instructional, it was coded for the scope and design of instructional content that included caregivers. RESULTS: The search terms yielded 1118 unique videos, and 43 videos met the inclusion criteria. Overall, 63% of videos were viewed 500 times or less, and half of the videos received "like" ratings by viewers. Video instruction was primarily talk without any onscreen action (65%), user-generated amateur video (79%), and had poor quality sources of information. Videos were mainly clinician centered (77%). Although most videos addressed the need for caregiver pain assessment (35%) and caregiver education (23%), few actually addressed specific caregiver pain management barriers. CONCLUSION: Most videos were primarily directed toward a clinical audience. Future research is necessary to determine if the platform is feasible and beneficial as a support tool for oncology caregivers. PMID- 24793506 TI - Pain assessment using the critical-care pain observation tool in Chinese critically ill ventilated adults. AB - CONTEXT: The psychometric properties of the Critical-Care Pain Observation Tool (CPOT) need to be tested in general intensive care unit patient populations in China. OBJECTIVES: To further evaluate the psychometric properties of the CPOT and provide a pain assessment method for Chinese critically ill ventilated adults by validating a translation of the CPOT. METHODS: A total of 63 conscious ventilated Chinese adults were repeatedly assessed by two independent raters using the CPOT at rest as well as before and during the two procedures: 1) nociceptive procedure (turning) and 2) non-nociceptive procedure (taking noninvasive blood pressure). A total of 12 assessments were included. RESULTS: The principal component factor analysis revealed that the domain structure of the CPOT was acceptable. Cronbach's alpha coefficient as a measure for the internal consistency ranged from 0.57 to 0.86; intraclass correlation coefficients as a measure for inter-rater reliability ranged from 0.80 to 0.91; Spearman nonparametric coefficients as a measure for test-retest reliability ranged from 0.81 to 0.93. The CPOT total score was significantly higher during the nociceptive procedure, indicating that its discriminant validity was good. Self reported pain was obtained as the gold standard; the receiver operating characteristic curve analysis determined the best cutoff value of the CPOT (>2) with the specificity (73.3-81.8%) and sensitivity (80.8-89.4%) as well as the area under the curve (range 0.849-0.902). CONCLUSION: The CPOT has good psychometric properties and can be used as a reliable and valid instrument for pain assessment in Chinese critically ill ventilated adults. PMID- 24793507 TI - Author reply: To PMID 23972322. PMID- 24793508 TI - Re: Awh et al.: CFH and ARMS2 Genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration (Ophthalmology 2013;120:2317-23). PMID- 24793509 TI - A case of Parry-Romberg syndrome and alien hand. AB - Parry-Romberg syndrome (PRS) is a rare condition characterised by progressive hemi-facial atrophy. Here we present a PRS case with alien-hand syndrome, which has not previously been described in adult onset disease. On the basis of the presumed auto-immune pathology of PRS we justify the treatment strategy we successfully used in this patient. A review of the literature was extensively done for understanding the history of alien hand sign over the years. PMID- 24793510 TI - Opsoclonus-myoclonus syndrome associated with human herpes virus-6 rhomboencephalitis. AB - Opsoclonus-myoclonus syndrome (OMS) is characterized by opsoclonus and arrhythmic action myoclonus that predominantly involves the trunk, limbs, and head. Human herpes virus-6 (HHV-6) can rarely cause encephalitis in immunocompetent children and adults. Here we report on a case of OMS associated with HHV-6 rhomboencephalitis. HHV-6 infection should be considered in OMS adults and detection of cell-free viral DNA, indicative of active infection, is mandatory in such cases. PMID- 24793511 TI - The lateral canthus web and its surgical management. AB - BACKGROUND: The lateral canthus is structurally important for normal eyelid contour and for reconstruction of the periorbital region. An abnormal lateral canthus contour has significant implications regarding lateral visual field and affects periocular cosmesis. PURPOSES: To describe of a series of patients with dehiscence of the lateral canthus and the surgical approach of treatment. METHODS: Four cases with primary lateral canthal web that were seen by the same surgeon between 2005 and 2012. The average age was 69.7 years, (range 52-81 years), one male and three females. Primary complaints were lateral visual field constriction, tired eyes, and abnormal eyelids. In 3 cases, reconstruction of the lateral canthus was performed using periosteal flaps. CONCLUSIONS: Reconstruction of the lateral canthus with periosteal flaps yielded a satisfactory result in cases of lateral canthus web. Additional cases would enhance our understanding of this pathology. PMID- 24793512 TI - Arrhythmogenic right ventricular cardiomyopathy with recessive inheritance related to a new homozygous desmocollin-2 mutation. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential. PMID- 24793513 TI - Atrial fibrillation therapies: lest we forget surgery. AB - Atrial fibrillation (AF) is a disease that causes a significant burden in a patient's life. It is a known risk factor for heart failure, stroke, and premature death. The classic therapeutic strategies include rate control, rhythm control, and prevention of stroke. Pharmacological rhythm control with antiarrhythmic drugs can only be achieved 50% of the time while simultaneously subjecting patients to deleterious adverse reactions. With recent advances in catheter ablation procedures, rhythm control can be safely attained anywhere from 57%-80% of the time, depending on the number of repeat catheter ablation procedures that are performed and concomitant use of antiarrhythmic drugs. The Cox-Maze procedure is a technically challenging cut-and-sew atrial lesion set with associated morbidity, yet is still considered the gold standard for rhythm control. Fortunately, this procedure has been modified in efforts to improve the safety profile (shorter cross clamp and cardiopulmonary bypass time), to simplify lesion set creation with newer energy sources, and to perform this operation in a minimally invasive setting. Minimally invasive surgical AF ablation techniques have excellent safety profiles and can achieve rhythm control in up to 90% of patients. In contrast, patients undergoing open heart surgery can undergo either concomitant endocardial or epicardial AF ablation procedures without jeopardizing the surgery along with success rates from 60% to 88%. Thus, there has been an increase in current surgical options for treating AF because of novel approaches and energy sources which yield effective long-term results in patient care and minimize perioperative complications and thereby optimize the risk/benefit ratio profile. PMID- 24793514 TI - Contained rupture of the aortic annulus after transcatheter aortic valve implantation: uncommon presentation of a rare complication. AB - We report the case of a contained rupture of the aortic annulus after transcatheter aortic valve implantation. The landing zone tear extended cranially to the aortic root and caudally into the perimembranous septum, creating a restrictive ventricular septal defect and severe paravalvular regurgitation into both ventricles, but no pericardial effusion or hemodynamic collapse. We elected conservative management, which proved to be a reasonable option. PMID- 24793515 TI - Percutaneous closure of a small posterior mitral paravalvular leak in a patient with coexistent monoleaflet mechanical aortic valve. AB - Percutaneous closure of a paravalvular leak is a challenging procedure that often presents with multiple simultaneous hurdles. We report a case of percutaneous retrograde paravalvular leak closure in a patient with a coexistent monoleaflet mechanical aortic valve. The leak was crossed and occluded using a combination of techniques deriving from the coronary and peripheral angioplasty fields. PMID- 24793516 TI - Rare earth elements in intertidal sediments of Bohai Bay, China: concentration, fractionation and the influence of sediment texture. AB - Surface sediments from intertidal Bohai Bay were assessed using a four-step sequential extraction procedure to determine their concentrations of rare earth elements (REEs) and the chemical forms in which those elements were present. The normalized ratios La/Gd and La/Yb showed that LREE contents were not significantly higher than the middle REEs or HREE contents. A negative Ce anomaly and positive Eu were observed in sand and silty sand sediments, whereas no significant Ce or Eu anomaly was found in clayey silt sediments. Residual fraction of REEs accounted for the majority of their total concentrations. Middle REEs were more easily leached than other REEs, especially in clayey silt sediment. REEs contents in the surface sediment from the intertidal Bohai Sea were consistent with data from the upper continental crust and China shallow sea sediments, indicating that they were generally unaffected by heavily anthropogenic effects from adjacent areas. PMID- 24793517 TI - Bioabsorption of cadmium, copper and lead by the red macroalga Gelidium floridanum: physiological responses and ultrastructure features. AB - Heavy metals, such as lead, copper, cadmium, zinc, and nickel, are among the most common pollutants found in both industrial and urban effluents. High concentrations of these metals cause severe toxic effects, especially to organisms living in the aquatic ecosystem. Cadmium (Cd), lead (Pb) and copper (Cu) are the heavy metals most frequently implicated as environmental contaminants, and they have been shown to affect development, growth, photosynthesis and respiration, and morphological cell organization in seaweeds. This paper aimed to evaluate the effects of 50MUM and 100MUM of Cd, Pb and Cu on growth rates, photosynthetic pigments, biochemical parameters and ultrastructure in Gelidium floridanum. To accomplish this, apical segments of G. floridanum were individually exposed to the respective heavy metals over a period of 7 days. Plants exposed to Cd, Cu and Pb showed discoloration of thallus pigmentation, chloroplast alteration, especially degeneration of thylakoids, and decrease in photosynthetic pigments, such as chlorophyll a and phycobiliproteins, in samples treated with Cd and Cu. Moreover, cell wall thickness and the volume of plastoglobuli increased. X-ray microanalysis detected Cd, Cu and Pb absorption in the cell wall. The results indicate that Cd, Pb and Cu negatively affect metabolic performance and cell ultrastructure in G. floridanum and that Cu was more toxic than either Pb or Cd. PMID- 24793518 TI - Metal dynamics and tolerance of Typha domingensis exposed to high concentrations of Cr, Ni and Zn. AB - Typha domingensis was exposed to a 100mgL(-1) Cr+100mgL(-1) Ni+100mgL(-1) Zn solution. Metal tolerance and metal accumulation in plant tissues and sediment were studied over time. Although removal rates were different, the three metals were efficiently removed from water. Leaf and root tissues showed high metal concentration. However, the sediment showed the highest accumulation. During the first hours of contact, metals were not only accumulated by sediment and roots but they were also taken up by the leaves in direct contact with the solution. Over time, metals were translocated from roots to leaves and vice versa. Metals caused growth inhibition and a decrease in chlorophyll concentration and affected anatomical parameters. Despite these sub-lethal effects, T. domingensis demonstrated that it could accumulate Cr, Ni and Zn efficiently and survive an accidental dump of high concentrations of contaminants in systems such as natural and constructed wetlands. PMID- 24793519 TI - Expression patterns of metallothionein, cytochrome P450 1A and vitellogenin genes in western mosquitofish (Gambusia affinis) in response to heavy metals. AB - The aim of this study was to evaluate the effects of three metals (Zn, Cd and Pb) on hepatic metallothionein (MT), cytochrome P450 1A (CYP1A) and vitellogenin (Vtg) mRNA expression in the liver of adult female mosquitofish (Gambusia affinis) after 1, 3 or 8d. Both concentration-response and time-course effects of hepatic MT, CYP1A and Vtg at the transcription level were determined by quantitative real-time PCR. The results from this study showed that Zn, Cd and Pb could significantly induced MT, CYP1A and Vtg mRNA expression levels in mosquitofish. In general, this study demonstrated that heavy metals modulate MT, CYP1A and Vtg mRNA expression levels in a metal-, concentration- or time dependent manner. PMID- 24793520 TI - Hydrogen-rich water confers plant tolerance to mercury toxicity in alfalfa seedlings. AB - In this report, the effect of hydrogen-rich water (HRW), which was used to investigate the physiological roles of hydrogen gas (H2) in plants recently, on the regulation of plant adaptation to mercury (Hg) toxicity was studied. Firstly, we observed that the exposure of alfalfa seedlings to HgCl2 triggered production of reactive oxygen species (ROS), growth stunt and increased lipid peroxidation. However, such effects could be obviously blocked by HRW. Meanwhile, significant decreases in the relative ion leakage and Hg accumulation were observed. Hg induced increases in total and isozymatic activities of superoxide dismutase (SOD) were significantly reversed by HRW. Further results suggested that HRW induced the activities of guaiacol peroxidase (POD) and ascorbate peroxidase (APX), two hydrogen peroxide-scavenging enzymes, was at transcriptional levels. Meanwhile, obvious increases of the ratios of reduced/oxidized glutathione (GSH), homoglutathione (hGSH), and ascorbic acid (AsA) and corresponding gene expression were consistent with the decreased oxidative damage in seedling roots. In summary, the results of this investigation indicated that HRW was able to alleviate Hg toxicity in alfalfa seedlings by (i) alleviating growth stunt and reducing Hg accumulation, and (ii) avoidance of oxidative stress and reestablishment of redox homeostasis. PMID- 24793521 TI - Kankariya et al.: management of small pupils in femtosecond-assisted cataract surgery pretreatment (Ophthalmology 2013;120:2359-60). PMID- 24793522 TI - Author reply: To PMID 24182565. PMID- 24793523 TI - Author reply: To PMID 24148654. PMID- 24793524 TI - Author reply: To PMID 24182567. PMID- 24793525 TI - Re: Sundaram et al.: Retinal structure and function in achromatopsia: implications for gene therapy (Ophthalmology 2014;121:234-45). PMID- 24793526 TI - Prevention of retinal detachment in Stickler syndrome: the Cambridge prophylactic cryotherapy protocol. AB - PURPOSE: The Stickler syndromes are the most common causes of inherited and childhood retinal detachment; however, no consensus exists regarding the effectiveness of prophylactic intervention. We evaluate the long-term safety and efficacy of the Cambridge prophylactic cryotherapy protocol, a standardized retinal prophylactic treatment developed to prevent retinal detachment arising from giant retinal tears in type 1 Stickler syndrome. DESIGN: Retrospective comparative case series. PARTICIPANTS: Four hundred eighty seven patients with type 1 Stickler syndrome. METHODS: Time to retinal detachment was compared between patients who received bilateral prophylaxis and untreated controls, with and without individual patient matching. Patients receiving unilateral prophylaxis (after fellow eye retinal detachment) were similarly compared with an appropriate control subgroup. Individual patient matching ensured equal age and follow-up between groups and that an appropriate control (who had not suffered a retinal detachment before the age at which their individually matched treatment patient underwent prophylactic treatment) was selected. Matching was blinded to outcome events. Individual patient matching protocols purposely weighted bias against the effectiveness of treatment. All treatment side effects are reported. MAIN OUTCOME MEASURES: Time to retinal detachment and side effects occurring after prophylactic treatment. RESULTS: The bilateral control group (n = 194) had a 7.4-fold increased risk of retinal detachment compared to the bilateral prophylaxis group (n = 229) (hazard ratio [HR], 7.40; 95% confidence interval [CI], 4.53-12.08; P<0.001); the matched bilateral control group (n = 165) had a 5.0-fold increased risk compared to the matched bilateral prophylaxis group (n = 165) (HR, 4.97; 95% CI, 2.82-8.78; P<0.001). The unilateral control group (n = 104) had a 10.3-fold increased risk of retinal detachment compared to the unilateral prophylaxis group (n = 64) (HR, 10.29; 95% CI, 4.96-21.36; P<0.001); the matched unilateral control group (n = 39) had a 8.4-fold increased risk compared to the matched unilateral prophylaxis group (n = 39) (HR, 8.36; 95% CI, 3.24-21.57; P<0.001). No significant long-term side effects occurred. CONCLUSIONS: In the largest global cohort of type 1 Stickler syndrome patients published, all analyses indicate that the Cambridge prophylactic cryotherapy protocol is safe and markedly reduces the risk of retinal detachment. PMID- 24793527 TI - Subfoveal choroidal thickness in idiopathic choroidal neovascularization. PMID- 24793529 TI - Re: Rudnisky et al.: antibiotic choice for the prophylaxis of post-cataract extraction endophthalmitis (Ophthalmology 2014;121:835-41). PMID- 24793528 TI - Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. AB - PURPOSE: To assess the safety and efficacy of multiple injections of 0.5 and 2.0 mg conbercept using variable dosing regimens in patients with neovascular age related macular degeneration (AMD). DESIGN: Randomized, double-masked, multicenter, controlled-dose, and interval-ranging phase 2 clinical trial divided into a 3-month loading phase followed by a maintenance phase. PARTICIPANTS: Patients with choroidal neovascularization secondary to AMD with lesion sizes of 12 disc areas or less and a best-corrected visual acuity (BCVA) letter score of between 73 and 24 were enrolled. METHODS: Patients were randomized 1:1 to receive either 0.5 or 2.0 mg intravitreal conbercept for 3 consecutive monthly does. After the third dose, each group was reassigned randomly again to monthly (Q1M group) or as-needed (pro re nata [PRN] group) treatment without changing the drug assignment. MAIN OUTCOME MEASURES: The primary end point was the mean change in BCVA from baseline to month 3, with secondary end points being the mean change in BCVA, mean change in central retinal thickness (CRT), and safety at month 12. RESULTS: We enrolled 122 patients. At the primary end point at month 3, mean improvements in BCVA from baseline in the 0.5- and 2.0-mg groups were 8.97 and 10.43 letters, respectively. At month 12, mean improvements in BCVA from baseline were 14.31, 9.31, 12.42, and 15.43 letters for the 0.5-mg PRN, 0.5-mg Q1M, 2.0-mg PRN, and 2.0-mg Q1M regimens, respectively. At month 12, mean reductions in CRT in the 4 regimens were 119.8, 129.7, 152.1, and 170.8 MUm, respectively. There were no significant differences for the pairwise comparisons between all study groups. The difference in the number of injections between the 2 PRN groups was not statistically significant. Treatment with conbercept generally was safe and well tolerated. CONCLUSIONS: The significant gains in BCVA at 3 months were the same or better at 12 months in all conbercept dosing groups of neovascular AMD patients. During the 12 months, repeated intravitreal injections of conbercept were well tolerated in these patients. Future clinical trials are required to confirm its long-term efficacy and safety. PMID- 24793530 TI - Author reply: To PMID 24326107. PMID- 24793531 TI - Re: Morse et al.: effectively implementing evidence-based medicine (Ophthalmology 2013;120:2163-5). PMID- 24793532 TI - Constructing a linear QSAR for some metabolizable drugs by human or pig flavin containing monooxygenases using some molecular features selected by a genetic algorithm trained SVM. AB - A genetic algorithm optimized and feature selectable support vector machine (GFSVM) was designed for classifying some 71 and 151 substrates of human and pig flavin-containing monooxygenases (FMOs; EC 1.14.13.8) collected from the literatures. While a novel fitness function was designed, a feature mask for selecting (represented by bit 1) or masking (represented by bit 0) a feature was also implemented in the chromosomes generated during the evolution process. The feature selection was performed according to the ranked accumulated |w| values computed from several preliminary runs. Some numbers of top ranked features were then selected and gradually increased in a multiple linear regression process employed for building a linear quantitative structure-activity relationships (QSARs) for both human and pig FMOs. Each of these preliminary QSAR models generated was judged by both a conventional and 10 fold cross-validation statistics computed for choosing the best set of top ranked features for building the best linear QSAR model. The best linear QSAR thus constructed for human or pig FMOs was from 89 or 145 top ranked features selected, respectively. Moreover, these two linear QSARs were also found to be specific to their own top ranked features computed and selected. These two linear QSARs constructed may be useful for predicting whether or not a drug is metabolizable by human or pig FMOs if the same feature computation and ranking scheme has been applied on it beforehand. PMID- 24793533 TI - The topology of robustness and evolvability in evolutionary systems with genotype phenotype map. AB - In this paper we formulate a topological definition of the concepts of robustness and evolvability. We start our investigation by formulating a multiscale model of the evolutionary dynamics of a population of cells. Our cells are characterised by a genotype-phenotype map: their chances of survival under selective pressure are determined by their phenotypes, whereas the latter are determined their genotypes. According to our multiscale dynamics, the population dynamics generates the evolution of a genotype-phenotype network. Our representation of the genotype-phenotype network is similar to previously described ones, but has a novel element, namely, our network contains two types of nodes: genotype and phenotype nodes. This network representation allows us to characterise robustness and evolvability in terms of its topological properties: phenotypic robustness by means of the clustering coefficient of the phenotype nodes, and evolvability as the emergence of giant connected component which allows navigation between phenotypes. This topological definition of evolvability allows us to characterise the so-called robustness of evolvability, which is defined in terms of the robustness against attack (i.e. edge removal) of the giant connected component. An investigation of the factors that affect the robustness of evolvability shows that phenotypic robustness and the cryptic genetic variation are key to the integrity of the ability to innovate. These results fit within the framework of a number of models which point out that robustness favours rather than hindering evolvability. We further show that the corresponding phenotype network, defined as the one-component projection of the whole genotype-phenotype network, exhibits the small-world phenomenon, which implies that in this type of evolutionary system the rate of adaptability is enhanced. PMID- 24793534 TI - Biological thresholds of nitrogen and phosphorus in a typical urban river system of the Yangtz delta, China. AB - River health and associated risks are fundamentally dependent on the levels of the primary productivities, i.e., sestonic and benthic chlorophyll-a. We selected a typical urban river system of the Yangtz delta to investigate nutrient and non nutrient responses of chlorophyll-a contents and to determine biological thresholds of N and P. Results showed the mean contents of sestonic and benthic chlorophyll-a across all sampling points reached 10.2 MUg L(-1) and 149.3 mg m( 2). The self-organized mapping analysis suggested both chlorophyll-a contents clearly responded to measurements of N, P, and water temperature. Based on the chlorophyll-a criteria for fresh water and measured variables, we recommend the biological thresholds of N and P for our river system be set at 2.4 mg N L(-1) and 0.2 mg P L(-1), and these be used as initial nutrient reference values for local river managers to implement appropriate strategies to alleviate nutrient loads and trophic status. PMID- 24793535 TI - Safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human parathyroid hormone (1-34) in healthy Chinese subjects. AB - BACKGROUND: The recombinant human parathyroid hormone (1-34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China. OBJECTIVE: The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1-34) after single and multiple subcutaneous doses in healthy Chinese subjects. METHODS: Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1-34) (10, 20, 30, 40, 50, or 60 MUg) or a multiple dose of rhPTH(1 34) (10 and 20 MUg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1 34) (10, 20, or 40 MUg) and a multiple dose of rhPTH(1-34) (20 MUg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters. RESULTS: Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1-34) was well tolerated during the investigated single (10-60 MUg) and multiple (10-20 MUg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1-34), the drug was rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t1/2 of 47.2 to 60.6 minutes. The mean Cmax, AUC0-t, and AUC0-infinity increased in proportion to the doses, whereas the t1/2, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-MUg and 20 MUg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels. CONCLUSIONS: All rhPTH(1-34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874. PMID- 24793536 TI - Tolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthma. AB - BACKGROUND: Asthma is a chronic disease afflicting millions of children worldwide. Short-acting beta2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting beta2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting beta2-agonist. OBJECTIVE: We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting beta2 agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma. METHODS: In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 ug, or FF, 100 ug, in the morning for 14 days, followed by a >=7-day washout period before switching to the other treatment for 14 days; the study duration was <=11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0 4 hours]) parameters on day 14. RESULTS: Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study. CONCLUSIONS: Once-daily repeated dosing of FF/VI, 100/25 ug, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 ug, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma. PMID- 24793537 TI - Left main artery stenosis and anomalous right coronary artery originating from the mid left anterior descending artery: high-risk anatomy. PMID- 24793539 TI - Advanced progress on the relationship between RA and its receptors and malignant tumors. AB - Retinoic acid (RA) is an active derivative of vitamin A, and it has different isomers, including ATRA (all-trans-retinoic acid), 13-cRA (13-cis-retinoic acid) and 9-cRA (9-cis-retinoic acid), etc. Combining with RARs and RXRs, RA plays important roles not only in embryonic development but also in cellular growth and differentiation through transcriptional regulation of its target genes. Following the successful application in the differentiation therapy of acute promyelocytic leukemia (APL) in clinical, recent studies have found that the disturbance of RA signal transduction was also related to differentiation, proliferation or apoptosis of tumor cells. To develop novel mechanisms-based differentiation therapy for other tumors, the relationship between RA or its receptors and tumors will be summarized in this review. PMID- 24793538 TI - Gender-related differences in the associations between sexual impulsivity and psychiatric disorders. AB - OBJECTIVE: Sexual impulsivity (SI) has been associated with conditions that have substantial public health costs, such as sexually transmitted infections and unintended pregnancies. However, SI has not been examined systematically with respect to its relationships to psychopathology. We aimed to investigate associations between SI and psychopathology, including gender-related differences. METHOD: We performed a secondary data analysis of Wave-2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a national sample of 34,653 adults in the United States. DSM-IV-based diagnoses of mood, anxiety, drug and personality disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Scheduled DSM-IV Version. RESULTS: The prevalence of SI was considerable (14.7%), with greater acknowledgment by men than women (18.9% versus 10.9%; p < 0.0001). For both women and men, SI was positively associated with most Axis-I and Axis-II psychiatric disorders (OR range: Women, Axis-I:1.89-6.14, Axis-II:2.10-10.02; Men, Axis-I:1.92-6.21, Axis II:1.63-6.05). Significant gender-related differences were observed. Among women as compared to men, SI was more strongly associated with social phobia, alcohol abuse/dependence, and paranoid, schizotypal, antisocial, borderline, narcissistic, avoidant and obsessive-compulsive personality disorders. CONCLUSION: The robust associations between SI and psychopathology across genders suggest the need for screening and interventions related to SI for individuals with psychiatric concerns. The stronger associations between SI and psychopathology among women as compared to men emphasize the importance of a gender-oriented perspective in targeting SI. Longitudinal studies are needed to determine the extent to SI predates, postdates or co-occurs with specific psychiatric conditions. PMID- 24793540 TI - Blockade of orexin-1 receptors in the ventral tegmental area could attenuate the lateral hypothalamic stimulation-induced potentiation of rewarding properties of morphine. AB - The orexins (hypocretins) are lateral hypothalamic (LH) neuropeptides that have been implicated in a variety of behaviors ranging from feeding to sleep and arousal. Evidence from animal models suggests a role for orexins in reward processing and drug addiction. In the present study, we investigated the direct effect of an orexin antagonist in the ventral tegmental area (VTA) on acquisition and expression of morphine conditioned place preference (CPP) induced by concurrent stimulation of the LH. Eighty-one adult male Wistar rats weighing 220 280 g were unilaterally implanted by two separate cannulae into the LH and VTA. The CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The animals received SB334867 as a selective orexin-1 receptor antagonist (0.1, 1 and 10 nmol/0.3 MUl DMSO) in the VTA, just 5 min prior to intra-LH administration of ineffective dose of carbachol as a cholinergic agonist (62.5 nmol/0.5 MUl saline) that stimulates orexin neurons in the LH and ineffective dose of morphine (1 mg/kg, subcutaneously) concurrently during conditioning phase (acquisition experiments) or post-conditioning phase (expression experiments). Data showed that the blockade of orexin-1 receptors in the VTA could inhibit the acquisition (development) but not expression of LH stimulation-induced morphine CPP in the rats. Our findings suggest that the orexinergic projections from the LH to the VTA are involved in the development of the LH stimulation-induced potentiation of morphine rewarding properties and orexin-1 receptors in the VTA have a substantial role in this phenomenon. PMID- 24793541 TI - The ceramide system as a novel antidepressant target. AB - Major depression is a systems disorder which impairs not only central nervous system aspects of mood and behavior but also peripheral organ systems. Current views on the pathogenesis and treatment of depression are predominantly based on proteins and transmitters and thus are difficult to reconcile central with peripheral pathomechanisms. Recent research showed that there is also a lipid based pathway involved in the pathology of depression, which is activated by psychosocial stress, oxidative stress, or inflammation. Inducible dysfunction of the ceramide pathway, which is abundant in the brain as well as in peripheral organs, may account for mood disorder, behavioral symptoms, and further promote inflammation and oxidative stress in peripheral systems. As such, the lipid ceramide pathway may provide the missing link between brain dysfunction and somatic symptoms of depression. Pharmacological interventions that reduce ceramide abundance also show antidepressant action and may promise a better treatment of major depression. PMID- 24793542 TI - Modeling G protein-coupled receptors in complex with biased agonists. AB - The biological response to the activation of G protein-coupled receptors (GPCRs) typically originates from the simultaneous modulation of various signaling pathways that lead to distinct biological consequences. Hence, 'biased agonists' (i.e., compounds that selectively activate one of the pathways while blocking the others) are highly sought-after molecules to provide fine-tuned pharmacological interventions. This review describes strategies that can be deployed to model the conformation of GPCRs in complex with ligands endowed with specific signaling profiles useful for the generation of hypotheses on the structural requirements for the activation of different signaling pathways or for rational computer-aided ligand discovery campaigns. In particular, it focuses on strategies potentially applicable to model the global or local conformational states of GPCRs stabilized by specific ligands. PMID- 24793543 TI - Synergistic inhibition on acetylcholinesterase by the combination of berberine and palmatine originally isolated from Chinese medicinal herbs. AB - Alzheimer's disease is a multi-factorial neurodegenerative disorder devastatingly affecting the aged population worldwide. Previous studies have shown that medicinal herbs used in traditional Chinese medicine might be benefit to Alzheimer's disease patients. Berberine and palmatine, two isoquinoline alkaloids found in several medicinal herbs, were used for memory enhancement in China. In this study, the inhibitory effects of combined berberine and palmatine on acetylcholinesteras were evaluated using recombinant human acetylcholinesterase. Our results showed that the combination of berberine and palmatine inhibited acetylcholinesterase in a mixed competitive pattern. By the median-effect principle, the calculated combination index of the combination was less than 1, suggesting that berberine and plamatine inhibited acetylcholinesterase synergistically. Furthermore, the drug-reducing index of berberine and palmatine were 2.98 and 2.66, respectively. Taken together, the results showed that the combination of the two alkaloids might potentially be developed as a more effective therapeutic strategy for Alzheimer's disease patients. PMID- 24793545 TI - Fluid therapy for acute bacterial meningitis. AB - BACKGROUND: Acute bacterial meningitis remains a disease with high mortality and morbidity rates. However, with prompt and adequate antimicrobial and supportive treatment, the chances for survival have improved, especially among infants and children. Careful management of fluid and electrolyte balance is an important supportive therapy. Both over- and under-hydration are associated with adverse outcomes. OBJECTIVES: To evaluate treatment of acute bacterial meningitis with differing volumes of initial fluid administration (up to 72 hours after first presentation) and the effects on death and neurological sequelae. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), MEDLINE (1966 to October week 5, 2013), EMBASE (1980 to November 2013), CINAHL (1981 to November 2013), LILACS (1982 to November 2013) and Web of Science (2010 to 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) of differing volumes of fluid given in the initial management of bacterial meningitis were eligible for inclusion. DATA COLLECTION AND ANALYSIS: For this update we identified two abstracts, but after obtaining full texts we excluded them. Previous searches had identified six trials; on careful inspection three trials (415 children) met the inclusion criteria. All four of the original review authors extracted data and assessed trials for quality (one author, ROW, has died since the original review; see Acknowledgements). We combined data for meta analysis using risk ratios (RRs) for dichotomous data or mean difference (MD) for continuous data. We used a fixed-effect statistical model. We assessed overall evidence quality using the GRADE approach. MAIN RESULTS: There were no trials in adult populations. All included trials were on paediatric patient groups. The largest of the three trials was conducted in settings with high mortality rates. The meta-analysis found no significant difference between the maintenance-fluid and restricted-fluid groups in number of deaths (RR 0.82, 95% confidence interval (CI) 0.53 to 1.27; 407 participants) (moderate trial quality); acute severe neurological sequelae (RR 0.67, 95% CI 0.41 to 1.08; 407 participants) (very low trial quality); or in mild to moderate sequelae (RR 1.24, 95% CI 0.58 to 2.65; 357 participants) (moderate trial quality). However, when neurological sequelae were defined further, there was a statistically significant difference in favour of the maintenance-fluid group for spasticity (RR 0.50, 95% CI 0.27 to 0.93; 357 participants); seizures at both 72 hours (RR 0.59, 95% CI 0.42 to 0.83; 357 participants) and 14 days (RR 0.19, 95% CI 0.04 to 0.88; 357 participants); and chronic severe neurological sequelae at three months follow-up (RR 0.42, 95% CI 0.20 to 0.89; 351 participants). AUTHORS' CONCLUSIONS: The quality of evidence regarding fluid therapy in children with acute bacterial meningitis is not high grade and there is a need for further research. Some evidence supports maintaining intravenous fluids rather than restricting them in the first 48 hours in settings with high mortality rates and where children present late. However, where children present early and mortality rates are lower, there is insufficient evidence to guide practice. PMID- 24793544 TI - The long elusive IgM Fc receptor, FcMUR. AB - IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both pre-immune "natural" and antigen-induced "immune" IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcMUR). We have recently identified a bona fide FcMUR in both humans and mice. In this article we briefly review what we have learned so far about FcMUR. PMID- 24793546 TI - Medium conditioned with mesenchymal stromal cell-derived osteoblasts improves the expansion and engraftment properties of cord blood progenitors. AB - Strategies to enhance the expansion of umbilical cord blood hematopoietic stem and progenitor cells (HSPCs) are crucial to enable their widespread application to adults and to overcome important limitations, such as delayed engraftment. Osteoblasts regulate HSPCs under steady-state and also under stress conditions, when HSPCs undergo numerous cycles of expansion. We hypothesized that osteoblasts could provide better stimulation for the expansion of multipotent HSPCs and subsequent hematopoietic recovery than mesenchymal stromal cells. Hence, we assessed the growth and engraftment modulatory activities of mesenchymal stromal cell-derived osteoblasts (M-OSTs) on hematopoietic progenitors. Mesenchymal stromal cells and M-OSTs favored the maintenance of CD34(+) cells. The expansion of cord blood CD34(+) cells and myeloid progenitors was highest in cultures supplemented with unfiltered M-OST-conditioned medium (M-OST CM). In addition, increased expression of cell surface receptors important for the homing of progenitors to the bone marrow, C-X-C chemokine receptor type 4 and lymphocyte function-associated antigen 1, was observed in CM-based cultures. Additionally, M OST CM positively modulated the engraftment properties of expanded progenitors. Most notably, although human platelet levels remained steady in the first 2 weeks in mice transplanted with HSPCs expanded in standard medium, levels in mice transplanted with M-OST CM HSPCs rose continuously. Consistent with this, short term human progenitor reconstitution was consistently greater in M-OST recipients. Finally, cytokine array-based profiling revealed increases in insulin like growth factor binding protein 2, chemokines, and myeloid stimulating cytokines in M-OST CM. In conclusion, this study suggests that M-OSTs represent a new underappreciated source of feeder cells for the expansion of HSPCs with enhanced thrombopoietic activity. PMID- 24793547 TI - Otitis media: an update on current pharmacotherapy and future perspectives. AB - INTRODUCTION: Acute otitis media (AOM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Currently, there is an urgent need for developing novel therapeutic agents for treating AOM. AREAS COVERED: Structured search of current literature. PubMed was searched for published literature in areas of pharmacotherapeutics, preventive therapies and complementary treatments for OM. The intent of this review is to provide a comprehensive evaluation of therapeutics for AOM, including preventive modalities and complementary medicine. EXPERT OPINION: the management of AOM in young children is still evolving and depends on patterns of bacterial colonization and antimicrobial resistance in the community. The introduction of vaccinations against potential respiratory tract pathogens has altered the frequency of recovery of pathogens causing ear infections in children. Even though not all patients require antimicrobial therapy to overcome their infection, these agents improve symptoms faster and lead to fewer treatment failures. Further studies are warranted to evaluate which patients would best benefit from antimicrobial therapy. PMID- 24793548 TI - IL-17F gene polymorphism is associated with susceptibility to acute myeloid leukemia. AB - PURPOSE: Recent studies have suggested that Th17 cells may play a role in the pathogenesis of acute myeloid leukemia (AML). This subset of CD4+ cells is characterized by interleukin (IL)-17A and IL-17F production, which share strong homology, and surface expression of the IL-23 receptor (IL-23R). The present study aimed to determine the association between the polymorphic features located within the IL-17A, IL-17F and IL-23R genes and disease susceptibility, progression and response to therapy. In addition, the relationship between the polymorphic variants and the plasma IL-17 levels in patients was analyzed. METHODS: For this purpose, 187 individuals of Polish origin including 62 AML patients and 125 healthy controls were typed for IL-17A (rs2275913; G-197A), IL 17F (rs763780; A7488G; His161Arg) and IL-23R (rs11209026, G1142A; Arg381Gln) alleles. RESULTS: The rs763780 IL-17F polymorphism appeared to be associated with susceptibility to the disease. The presence of the minor (G) variant (RR = 4.76, p < 0.001) and its homozygosity (RR = 23.02, p < 0.005) was more frequent among patients than healthy individuals. No significant association was observed for either other polymorphisms studied or IL-17 levels. CONCLUSIONS: Thus, the rs763780 IL-17F polymorphism was found to be associated with predisposition to AML in the Polish population. PMID- 24793549 TI - Bleomycin electrochemotherapy in elderly metastatic breast cancer patients: clinical outcome and management considerations. AB - PURPOSE: To evaluate the efficacy and toxicity of electrochemotherapy (ECT) in elderly metastatic breast cancer (BC) patients. METHODS: Retrospective analysis of 55 patients with superficial metastases who underwent ECT according to the European Standard Operative Procedures of electrochemotherapy. Treatment schedule consisted of intravenous or intratumoral bleomycin followed by locally delivered electric pulses. Statistical comparisons were performed between two groups: the patients aged <70 years (n = 27) and those >=70 years (n = 28). Treatment outcomes were as follows: complete response (CR) rate, local progression-free survival (LPFS), new lesions-free survival (NLFS), toxicity and patient compliance. RESULTS: Patient groups were comparable for clinical-pathological features, except for the number of comorbidities (P < .001). The median follow-up was 32 months (range 6-53). Overall, CR rate was 40 % and was significantly higher in elderly patients (57 vs. 26 %, P = .023) and in patients with better performance status (PS = 0-1, 53 vs. PS = 2, 21 %, P = .048), although local tumor control showed a trend for lower values (2-year LPFS, 67 vs. 93 % among elderly and young patients, respectively; P = .061). Older women seemed less likely to progress outside the ECT field (2-year NLFS, 39 vs. 30 %, P = .075), but discontinued treatment more frequently due to impaired performance status (P = .002). Local pain was graded >=3, according to a 10-point visual analog scale, by 16/28 (57.1 %) and 8/28 (28.6 %) elderly patients at 4 and 8 weeks, respectively. Wound debridement was required in 5/28 (18 %) older women, due to G3 skin ulceration. CONCLUSIONS: Elderly BC patients are highly responsive to ECT and achieve durable local tumor control. Physicians should be aware of possible debilitating side effects, such as pain and skin toxicity. Performance status and frailty screening could be a helpful addition to improve patient selection. PMID- 24793550 TI - Urocortin 2 blocks the suppression of gastric antral contractions induced by lipopolysaccharide in freely moving conscious rats. AB - Lipopolysaccharide (LPS) inhibits gastric antral contractions in conscious rats. Since LPS regulates corticotropin-releasing factor type 2 receptor (CRF2) expression in the rat stomach, and activation of peripheral CRF2 alters gastric motility, we tried to determine the role of peripheral CRF2 in the LPS-induced suppression of gastric antral contractions. Intraluminal gastric pressure waves were measured in freely moving conscious non-fasted rats using the perfused manometric method. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1h before and after intraperitoneal injection of drugs. LPS (0.2 mg/kg) significantly decreased MI. Indomethacin (10 mg/kg) itself did not alter MI but blocked this inhibitory action by LPS. Astressin 2-B (200 MUg/kg), a selective CRF2 antagonist, modified neither the basal MI nor the action by LPS. Meanwhile, urocortin 2 (30 MUg/kg), a selective CRF2 agonist, reversed the suppression by LPS without affecting the basal MI. This action by urocortin 2 was blocked by pretreatment with astressin 2 B. In conclusion, LPS inhibited gastric antral contractions possibly through a prostaglandin-dependent pathway. Peripheral CRF2 stimulation reversed this response by LPS. PMID- 24793551 TI - Adiponectin-induced antitumor activity on prostatic cancers through inhibiting proliferation. AB - Adiponectin, an adipose tissue-derived hormone, has been studied intensively for the past decade because of its anti-inflammatory, anti-atherogenic, and anti diabetic properties. Recent advances suggest that adiponectin also plays an important role in the development and progression of various cancers. Accumulating evidence suggests that adiponectin may have an important protective role in carcinogenesis. Adiponectin circulates at high concentrations in human plasma. Plasma levels of adiponectin are approximately 50 % lower in obese than in lean subjects. An association between low plasma levels of adiponectin and higher risk of developing prostate and other cancers was recently reported. Obesity and overweight have also been associated with increased mortality from cancer. To test the hypothesis that adiponectin exerts direct antiproliferative and/or pro-apoptotic effects on cancer cells, we used the PC-3 human prostate adenocarcinoma cell line. The proliferation rate of the PC-3 cells was measured using the MTT method, and apoptosis was examined by quantifying the DNA fragmentation using an ELISA assay. In addition, adiponectin receptor 1 (AdipoR1) and AdipoR2 mRNA expression was detected using RT-PCR. Adiponectin diminished the proliferation rate of PC-3 cells; this effect was significant after 48-96 h of treatment. The presence of receptor expression suggested that the effect of adiponectin on cell proliferation was most likely specific and adiponectin receptor-mediated. Adiponectin induced no apoptosis of PC-3 cells over 48 h. We conclude that adiponectin inhibits proliferation but causes no apoptosis of PC-3 prostate cancer cells. PMID- 24793553 TI - Karolinska Psychodynamic Profile for Sexual Disorders: KAPP-SD. A proposal for a psychodynamic rating scale for sexual disorders. AB - OBJECTIVE: Our first objective in this paper was to review the literature on psychodynamic rating scales of sexual disorders. Our second objective, based on the findings from our review, was to develop a psychodynamic rating scale for people with sexual disorders: the KAPP-SD. METHOD: We developed the KAPP-SD by modifying an existing psychodynamic rating scale, which assesses stable modes of mental functioning and character traits, the Karolinska Psychodynamic Profile (KAPP). We removed items 13 and 14 of the KAPP and replaced them with three other items-sexual fantasies, conceptions and role of gender identity, and conceptions and role of sexual orientation. These items are part of the assessment of an individual's sexuality and are used to evaluate a person with a sexual disorder psychodynamically. RESULTS: The KAPP-SD, a modified version of the KAPP, can be found in the Appendix. CONCLUSION: We developed the KAPP-SD in order to help sex therapists make a rigorous psychodynamic evaluation of persons with sexual disorders, which would give information on the prognosis and on the type of treatment to offer. PMID- 24793554 TI - Comparison of homocysteinemia and MTHFR 677CT polymorphism with Framingham Coronary Heart Risk Score. AB - OBJECTIVE: The Framingham Coronary Heart Disease Risk Score is an important clinical tool. The aim of this cross-sectional study was to compare plasma homocysteine levels and polymorphism 677CT MTHFR with this score to determine the utility of these new biomarkers in clinical practice. METHODS: Plasma homocysteine levels determined by chemiluminescence and polymorphism 677CT MTHFR, detected by PCR-RFLP, were compared with Framingham coronary risk score in a cross-sectional survey on 68 men and 165 women. RESULTS: Coronary heart disease risk augmented with an increase in the quartile of plasma homocysteine. In the 2nd, 3rd and 4th quartile of plasma homocysteine, men showed significantly (P<0.001) higher risk than women. For the highest quartile of plasma homocysteine, OR of high-risk (10-year risk>=20%) compared with the lowest quartile was 17.45 (95% CI: 5.79-52.01). Frequencies of CT and TT genotype and T allele were not over-represented in the individuals with score>=10%. The higher plasma homocysteine concentrations in individuals with score>=10% with respect to those with low risk (P<0.005 and P<0.001) were not due to the presence of T allele. The T allele (CT+TT genotypes) of the MTHFR C677T polymorphism was not significantly associated with an increased risk of coronary disease (OR=1.09, 95% CI=0.50-2.39, P=0.844). CONCLUSIONS: The present study demonstrated an association between plasma homocysteine levels and the severity of coronary heart disease estimated with the Framingham coronary risk score, and this association appeared to be independent on the genotype of MTHFR. We postulate that plasma homocysteine is effective enough, considered even in isolation. PMID- 24793556 TI - United Kingdom and Republic of Ireland renal physicians' experiences of patients undergoing renal transplants abroad: a questionnaire-based cross-sectional survey. AB - BACKGROUND: Due to ongoing poor availability of organs, increasingly patients from developed countries are reported to be travelling abroad for renal transplants. We aimed to assess the extent and characteristics of this trend across the UK and Republic of Ireland. METHODS: A questionnaire-based cross sectional survey; 397 renal consultants from 33 hospitals with renal units across the UK and the Republic of Ireland were contacted through email and 62 replied (16%). RESULTS: Fifty-seven out of 62 (93%) renal consultants managed transplant patients, and of these 36/57 (63%) had managed at least one patient who had undergone a transplant abroad. The most popular reason reported for doing this was being on the UK or Republic of Ireland transplant list but seeking a shorter wait. Respondents reported commencement by overseas doctors of appropriate routine post-transplant prophylaxis with the following medications in all cases they had encountered as follows: co-trimoxazole 12%, isoniazid 3%, anti-fungals 0%, and Cytomegalovirus prophylaxis or treatment 0%. Fourty-four percent of renal consultants reported having some prior warning of a patient undergoing a renal transplant abroad. CONCLUSIONS: Renal transplant tourism has become widely established in the UK and the Republic of Ireland, and care for these patients is often suboptimal. Furthermore, the opportunity exists for pre-transplant counselling. PMID- 24793555 TI - [Registry of non-ST elevation acute coronary syndromes in a tertiary hospital (RESCATA-SEST registry)]. AB - OBJECTIVE: To describe the clinical-epidemiologic profile and the process of care of the non-ST elevation acute coronary syndromes in a tertiary hospital. METHOD: We analyzed the clinical information, the risk stratification and diagnostic methods, the revascularization therapy and the prescription trends at discharge, of patients with non-ST elevation acute coronary syndromes cared for in one year. RESULTS: Two hundred and eighty-three patients with mean age of 58 years were included (63% men). The largest number of non-ST elevation acute coronary syndromes (88.6%) was found between 50 to 59 years of age. The most common risk factor was hypertension; 82.5% of the patients had a low-intermediate TIMI score; residual ischemia was demonstrated in 37% and coronary obstructions were seen in 80 patients (70%). In 90%, a percutaneous coronary intervention was performed, mainly with drug-eluting Stents (87.5%). At discharge, even though antiplatelet agents and statins were prescribed in more than 90%, other drugs were indicated in a few more than 50% of patients. CONCLUSIONS: In this population, non-ST elevation acute coronary syndromes predominates in relatively young men, often with hypertension. To stratify risk, to look for residual ischemia and to revascularize with drug-eluting stents are common practices, but the evidence based guidelines compliance is still suboptimal. PMID- 24793558 TI - Nanoscale temperature measurements using non-equilibrium Brownian dynamics of a levitated nanosphere. AB - Einstein realized that the fluctuations of a Brownian particle can be used to ascertain the properties of its environment. A large number of experiments have since exploited the Brownian motion of colloidal particles for studies of dissipative processes, providing insight into soft matter physics and leading to applications from energy harvesting to medical imaging. Here, we use heated optically levitated nanospheres to investigate the non-equilibrium properties of the gas surrounding them. Analysing the sphere's Brownian motion allows us to determine the temperature of the centre-of-mass motion of the sphere, its surface temperature and the heated gas temperature in two spatial dimensions. We observe asymmetric heating of the sphere and gas, with temperatures reaching the melting point of the material. This method offers opportunities for accurate temperature measurements with spatial resolution on the nanoscale, and provides a means for testing non-equilibrium thermodynamics. PMID- 24793559 TI - Highly stable CO2/N2 and CO2/CH4 selectivity in hyper-cross-linked heterocyclic porous polymers. AB - The largest obstacles for landfill/flue gas separation using microporous materials are small adsorption values and low selectivity ratios. This study demonstrates that these adsorption and selectivity challenges can be overcome by utilizing a series of hyper-cross-linked heterocyclic polymer networks. These microporous organic polymers (MOPs) were synthesized in a single step by inexpensive Friedel-Crafts-catalyzed reactions using dimethoxymethane as an external linker. The amorphous networks show moderate Brunauer-Emmett-Teller surface areas up to 1022 m(2) g(-1), a narrow pore size distribution in the range from 6 to 8 A, and high physicochemical stability. Owing to the presence of the heteroatomic pore surfaces in the networks, they exhibit maximum storage capacities for CO2 of 11.4 wt % at 273 K and 1 atm. Additionally, remarkable selectivity ratios for CO2 adsorption over N2 (100) and CH4 (15) at 273 K were obtained. More importantly, as compared with any other porous materials, much higher selectivity for CO2/N2 (80) and CO2/CH4 (15) was observed at 298 K, showing that these selectivity ratios remain high at elevated temperature. The very high CO2/N2 selectivity values are ascribed to the binding affinity of abundantly available electron-rich basic heteroatoms, high CO2 isoteric heats of adsorption (49-38 kJ mol(-1)), and the predominantly microporous nature of the MOPs. Binding energies calculated using the high level of ab initio theory showed that the selectivity is indeed attributed to the heteroatom-CO2 interactions. By employing an easy and economical synthesis procedure these MOPs with high thermochemical stability are believed to be a promising candidate for selective CO2 capture. PMID- 24793561 TI - Technological advances in neuroimaging: neurosurgical applications for the future. PMID- 24793560 TI - Gender and age differences in suicide mortality in the context of violent death: findings from a multi-state population-based surveillance system. AB - OBJECTIVE: Males are more likely than females to die by all forms of violent death, including suicide. The primary purpose of the present study was to explore whether the gender difference in suicide rates is largely accounted for by males' general greater tendency to experience violent deaths. The current study examined gender and age differences in suicides and other violent deaths, using data from a population-based surveillance system. METHOD: Pearson's chi-square tests and logistic regression analyses were conducted with data for 32,107 decedents in the 2003-2005 National Violent Death Reporting System (NVDRS). Decedents were categorized by gender, age, and death by suicide versus other violent means. RESULTS: When suicides were examined in the greater context of violent death, the total proportion of violent deaths due to suicide did not differ across gender. When deaths were examined by age group, after controlling for ethnicity, marital status, and U.S. location in which the death occurred, males in early to mid childhood were significantly more likely than same-aged females to die by suicide relative to all other violent deaths. The portion of deaths due to suicide was for the most part equal across both genders in late childhood, young adulthood, and mid-adulthood. Older males were more likely than older females to die by suicide relative to other violent deaths. CONCLUSION: Our findings suggest that that the risk of dying by suicide relative to other violent deaths may be more pronounced at certain developmental stages for each gender. This knowledge may be valuable in tailoring prevention strategies. PMID- 24793562 TI - Exposure of wide cerebellomedullary cisterns for vascular lesion surgeries in cerebellomedullary cisterns: opening of unilateral cerebellomedullary fissures combined with lateral foramen magnum approach. AB - OBJECTIVE: To clarify microsurgical anatomic features of the cerebellomedullary fissure (CMF), the natural cleavage plane between the cerebellum and the medulla, and its relationship to the cerebellomedullary cistern (CMC) and to describe a surgical technique that uses the unilateral trans-CMF approach for CMC surgeries. METHODS: In the anatomic study, 2 formalin-fixed cadaver heads were used. In the clinical study, 3 patients with vertebral artery-posterior inferior cerebellar artery aneurysms and 3 patients with glossopharyngeal neuralgia were surgically treated through the unilateral trans-CMF approach combined with the transcondylar fossa approach, which is a lateral foramen magnum approach. RESULTS: The CMC was present at the lateral end of the CMF. The CMF was closed by arachnoidal adhesion, and the cerebellar hemisphere was superiorly attached to the cerebellar peduncle. After the unilateral CMF was completely opened, the cerebellar hemisphere was easily retracted rostrodorsally. Clinically, almost completely opening the unilateral CMF markedly enabled the retraction of the biventral lobule to obtain a wide surgical field safely for vascular CMC lesions. We present 2 representative cases. CONCLUSION: Combined unilateral trans-CMF/lateral foramen magnum approaches provide a wide and close surgical field in the CMC, allowing easy and safe CMC surgery. PMID- 24793564 TI - What is the time-scale of hantavirus evolution? PMID- 24793565 TI - A critical evaluation of salivary testosterone as a method for the assessment of serum testosterone. AB - Although salivary testosterone (T) is often used in clinical studies accuracy is mostly questionable. State of the art data for men is sparse and for women absent. Our objective was to perform a critical evaluation of salivary T (Sal-T) as a method for indirect assessment of serum T using state of the art methods. Saliva was collected via 'Salivette' and 'passive drooling' methods. Sal-T and free T in serum after equilibrium dialysis were measured by LC-MS/MS RESULTS: Evaluation of Sal-T results versus free T by equilibrium dialysis (ED-T) for men gave: 'Salivette' Sal-T=0.05+0.88x ED-T, r=0.43; 'passive drooling' Sal T=0.17+0.91x ED-T r=0.71. In women, correlation was comparable but values are higher than free T: 'passive drooling' Sal-T=0.12+2.32x ED-T, r=0.70. The higher than expected T values in saliva, appear to be explained by T binding to salivary proteins. Iso-electric focusing of saliva proteins, followed by fractionation and LC-MS/MS assay of T showed marked testosterone peaks at pH 5.3 and 8.4, providing evidence for T binding in saliva to proteins such as albumin and proline rich protein (PRP). CONCLUSIONS: Passive drooling is the collection method of choice for testosterone in saliva. Sal-T is not directly comparable to serum free T due to T binding to saliva proteins, which substantially affects the low Sal-T in women but not the higher Sal-T in healthy adult men. PMID- 24793563 TI - CXCR4: a virus's best friend? AB - Viruses are dependent on their hosts for replication and dispersal in the environment; thus, the most successful viruses are those that co-evolve with their hosts. CXCR4 is a cellular chemokine receptor that plays central roles in development, hematopoiesis, and immune surveillance through signaling induced by its ligand, CXCL12. The CXCR4-CXCL12 axis has been besieged by many pathogens that employ a range of strategies to modify or exploit CXCR4 activity. While CXCR4 was identified as a critical co-factor for entry of HIV into CD4+ T cells early on, other viruses may utilize CXCR4 to gain cell entry as well. Moreover, several viruses have been found to modulate CXCR4 expression or alter its functional activity, with direct effects on cell trafficking, immune responses, cell proliferation, and cell survival. Because CXCR4 is targeted by a diverse group of viral pathogens, modification of host CXCR4 signaling activity is emerging as a common theme in virus persistence and is likely to be important for subversion of the host immune system. This review highlights major viral pathogens that use and abuse CXCR4 and explores the possible reasons why this chemokine receptor has become "a virus's best friend". PMID- 24793566 TI - Synthesis and biological evaluation of steroidal derivatives as selective inhibitors of AKR1B10. AB - AKR1B10 is a member of human aldo-keto reductase superfamily, and a promising anti-cancer therapeutic target. In this paper, androst-5-ene-3beta-ol, dehydroepiandrosterone, pregnenolone and cholesterol were used as reactants, sixteen products were obtained through Jones reaction and reduction reaction using NaBH4. Their inhibitory activities against AKR1B10 and AKR1B1 were measured. The most active compound (3a) has the IC50 of 0.50MUM for AKR1B10, and the most AKR1B10 selective compound (2a) has the IC50 of 0.81MUM with AKR1B1/AKR1B10 selectivity of 195. In addition, the binding modes of 2a and 3a in the active site of human AKR1B10 were identified by docking. PMID- 24793567 TI - Ergogenic and metabolic effects of oral glucocorticoid intake during repeated bouts of high-intensity exercise. AB - All systemically administered glucocorticoids (GC) are prohibited in-competition, because of the potential ergogenic effects. Although short-term GC intake has been shown to improve performance during submaximal exercise, literature on its impact during brief intense exercise appears to be very scant. The purpose of this study was to examine the ergogenic and metabolic effects of prednisone during repeated bouts of high-intensity exercise. In a double-blind randomized protocol, ten recreational male athletes followed two 1-week treatments (Cor: prednisone, 60mg/day or Pla: placebo). At the end of each treatment, they hopped on their dominant leg for 30s three times consecutively and then hopped until exhaustion, with intervals of 5min of passive recovery. Blood and saliva samples were collected at rest and 3min after each exercise bout to determine the lactate, interleukin-6, interleukin-10, TNF-alpha, DHEA and testosterone values. The absolute peak force of the dominant leg was significantly increased by Cor but only during the first 30-s hopping bout (p<0.05), whereas time to exhaustion was not significantly changed after Cor treatment vs Pla (Pla: 119.9+/-24.7; Cor: 123.1+/-29.5s). Cor intake lowered basal and end-exercise plasma interleukin-6 and saliva DHEA (p<0.01) and increased interleukin-10 (p<0.01), whereas no significant change was found in blood lactate and TNF-alpha or saliva testosterone between Pla and Cor. According to these data, short-term glucocorticoid intake did not improve endurance performance during repeated bouts of high-intensity exercise, despite the significant initial increase in absolute peak force and anti-inflammatory effect. PMID- 24793568 TI - Fungal transformation and T-cell proliferation inhibitory activity of melengestrol acetate and its metabolite. AB - Biotransformation of melengestrol acetate (MGA, 17alpha-acetoxy-6-methyl-16 methylenepregna-4,6-diene-3,20-dione) (1) was investigated for the first time by using fungal cultures. Incubation of compound 1 with Cunninghamella blakesleeana yielded a new major metabolite, 17alpha-acetoxy-11beta-hydroxy-6-methyl-16 methylenepregna-4,6-diene-3,20-dione (2). The metabolite 2 was purified by using HPLC, followed by characterization through (1)H- and (13)C-NMR and other spectroscopic techniques. Single crystal X-ray diffraction analysis was used to deduce the three dimensional structures of melengestrol acetate (1) and metabolite 2 for the first time. T-cell proliferation assay was employed to evaluate the immunosuppressant effect of compounds 1 and 2 with IC50=0.5+/-0.07 and 0.6+/-0.08MUg/mL, respectively. The results indicated that these compounds possess sixfold potent T-cell proliferation inhibitory activity as compared to the standard prednisolone (IC50<3.1MUg/mL). Both compounds were found to be non toxic in a 3T3 (mouse fibroblast) cell-based cytotoxicity assay. This discovery of potent anti-inflammatory activity of compounds 1 and 2 can lead the way to develop new immunosuppressant compounds for clinical application. PMID- 24793569 TI - An anatomic study of the impressions on the greater trochanter: bony geometry indicates the alignment of the short external rotator muscles. AB - In this study, 44 hip regions from 25 embalmed cadavers were dissected to identify the bony landmarks on the greater trochanter, which indicate the individual short external rotator muscle insertions. Micro-computed tomography (micro-CT) images were obtained to identify the bony impressions on the greater trochanter. Then, the soft tissues were removed and their insertions were identified to assess correlation with micro-CT images. Bony landmarks indicating the insertions and the running course of the piriformis muscle, the obturator internus muscle, and the obturator externus muscle were identified on the greater trochanter in all specimens. These findings could be helpful for preserving muscles during capsular release in the anterior approach because the alignment of the short external rotator muscles can be estimated preoperatively using CT images. PMID- 24793570 TI - Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. AB - The purpose of this study was to compare a novel liposomal bupivacaine to traditional peri-articular injection (PAI) in a multi-modal pain protocol for total knee arthroplasty (TKA). A retrospective cohort study compared 85 consecutive patients undergoing TKA with a traditional PAI of ropivacaine, epinephrine and morphine to 65 patients with a liposomal bupivacaine PAI. After the initial 24h, inpatient self-reported pain scores were higher in the liposomal bupivacaine group compared to the traditional PAI group (P = 0.04) and a smaller percentage (16.9%) of patients in the liposomal bupivacaine group rated their pain as "mild" compared to the traditional group (47.6%). Liposomal bupivacaine PAI provided inferior pain control compared to the less expensive traditional PAI in a multi-modal pain control program in patients undergoing TKA. PMID- 24793571 TI - The effect of severity of disease on cost burden of 30-day readmissions following total joint arthroplasty (TJA). AB - In order to control the unsustainable rise in healthcare costs the Federal Government is experimenting with the bundled payment model for total joint arthroplasty (TJA). In this risk sharing model, providers are given one payment, which covers the costs of the TJA, as well as any additional medical costs related to the procedure for up to 90 days. The amount and severity of comorbid conditions strongly influence readmission rates and costs of readmissions in TJA patients. We identified 2026 TJA patients from our database with APR-DRG SOI data for use in this study. Both the costs of readmission and the readmission rate tended to increase as severity of illness increased. The readmission burden also increased as SOI increased, but increased most markedly in the extreme SOI patients. PMID- 24793572 TI - Rehabilitation regimen after surgical treatment of acute Achilles tendon ruptures: a systematic review with meta-analysis. AB - BACKGROUND: The choice of rehabilitation management after the surgical repair of acute Achilles tendon (AT) ruptures remains controversial because of insufficient clinical evidence. The current study analyzes the postoperative rehabilitation of AT ruptures based on the current clinical evidence. PURPOSE: To identify and analyze the high-level clinical evidence regarding postoperative rehabilitation after the surgical repair of AT ruptures. Subgroup analyses were also performed to obtain more reliable and specific results. STUDY DESIGN: Meta-analysis. METHODS: The studies were retrieved by searching the Medline, Embase, and Cochrane databases through the OVID retrieval engine from 1990 to August 14, 2013. Two independent reviewers critically reviewed the studies using preset inclusion and exclusion criteria. The quality of the eligible studies was assessed by the Cochrane 12-item scale. All included studies were summarized, and their data were extracted. Subgroup analyses were performed according to the different protocols of early functional rehabilitation. RESULTS: Nine studies, consisting of 6 randomized controlled trials and 3 quasi-randomized studies, were ultimately included. A total of 402 patients were identified. Six of the included studies utilized early weightbearing combined with early ankle motion exercises, while the other 3 only employed early ankle motion exercises. The subgroup analyses demonstrated that 11 of the 15 functional outcome measurements were significantly superior for patients who underwent both early weightbearing and ankle motion exercises than for those who underwent conventional cast immobilization. Similar rates of reruptures (odds ratio [OR], 1.36; 95% CI, 0.38 4.91; P = .64) and major complications (OR, 0.67; 95% CI, 0.24-1.87; P = .44) as well as a significantly lower rate of minor complications (OR, 0.51; 95% CI, 0.27 0.95; P = .03) were also observed in this early functional rehabilitation group. For the patients who solely performed early ankle motion exercises, only 2 of the 14 functional measurements were observed to be significantly superior to immobilization. There were also no significant differences in the rates of reruptures (OR, 0.47; 95% CI, 0.08-2.70; P = .40) and other complications (OR, 1.09; 95% CI, 0.41-2.92; P = .86) between the 2 groups. CONCLUSION: Postoperative early weightbearing combined with early ankle motion exercises is associated with a lower minor complication rate and achieves superior and more rapid functional recovery than conventional immobilization after surgical AT repair. In contrast, few advantages were identified when only early ankle motion exercises were applied. PMID- 24793573 TI - [Physical activity in dialysis population: how and why to assess and establish a program?]. AB - The studies that evaluated physical activity in dialysis patients show a significant inactivity. This inactivity is associated with increased mortality. In contrast, the benefits in terms of morbidity and mortality of physical activity in this population are numerous. Recommendations exist for these patients: those set out for the general elderly adult population. However, few centers are implementing training programs in dialysis patients. There are many reasons, among which the lack of knowledge of the medical staff. The purpose of this article is to clarify the assessment of physical activity in dialysis patients and implementation program for the fight against inactivity. The initial assessment by simple means is essential. It ideally requires the intervention of a specialist in physical activity. The main types of exercise are presented as well as the different types of program and their results. It is important to note that no serious adverse events were reported in the different programs and their feasibility has been demonstrated. The fight against the sedentary patients undergoing dialysis should be a goal of health care teams, as well as the fight against the other cardiovascular risk factors. PMID- 24793574 TI - Dermal leiomyosarcoma at the end of the left eyebrow. PMID- 24793575 TI - Umbilical hernia repair with mesh: identifying effectors of ideal outcomes. AB - BACKGROUND: Quality of life has become an important focus for improvement in hernia repair. METHODS: The International Hernia Mesh Registry was queried. The Carolinas Comfort Scale quantitated quality of life at 1-month, 6-month, and annual follow-up. Scores of 0 (completely asymptomatic) in all categories without recurrence defined an ideal outcome. RESULTS: The analysis consisted of 363 umbilical hernia repairs; 18.7% were laparoscopic. Demographics included age of 51.5 +/- 13.8 years, 24.5% were female, and the average body mass index was 30.63 +/- 5.9 kg/m(2). Mean defect size was 4.3 +/- 3.1 cm(2). Mean follow-up was 18.2 months. Absent/minimal preoperative symptoms were predictive of ideal outcome at all time points and increasing age was predictive at 6 months and 1 year. At 6 months, the use of fixation sutures alone versus tacks (odds ratio 14.1) predicted ideal outcome. CONCLUSIONS: Ideal outcomes are dependent on both patient-specific and operative factors. The durable, ideal outcome in umbilical hernia repair is most likely in an older, asymptomatic patient who undergoes mesh fixation with permanent suture. PMID- 24793576 TI - Reactions of hydroxyalkyl radicals with cysteinyl peptides in a nanoESI plume. AB - In biological systems, carbon-centered small molecule radicals are primarily formed via external radiation or internal radical reactions. These radical species can react with a variety of biomolecules, most notably nucleic acids, the consequence of which has possible links to gene mutation and cancer. Sulfur containing peptides and proteins are reactive toward a variety of radical species and many of them behave as radical scavengers. In this study, the reactions between alkyl alcohol carbon-centered radicals (e.g., *CH2OH for methanol) and cysteinyl peptides within a nanoelectrospray ionization (nanoESI) plume were explored. The reaction system involved ultraviolet (UV) irradiation of a nanoESI plume using a low pressure mercury lamp consisting of 185 and 254 nm emission bands. The alkyl alcohol was added as solvent into the nanoESI solution and served as the precursor of hydroxyalkyl radicals upon UV irradiation. The hydroxyalkyl radicals subsequently reacted with cysteinyl peptides either containing a disulfide linkage or free thiol, which led to the formation of peptide-S-hydroxyalkyl product. This radical reaction coupled with subsequent MS/MS was shown to have analytical potential by cleaving intrachain disulfide linked peptides prior to CID to enhance sequence information. Tandem mass spectrometry via collision-induced dissociation (CID), stable isotope labeling, and accurate mass measurement were employed to verify the identities of the reaction products. PMID- 24793577 TI - The spectrum of FBN1, TGFbetaR1, TGFbetaR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). AB - INTRODUCTION: In this study, patients suspected of having a clinical diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) and Thoracic Aortic Aneurysms and Dissections (TAAD) were referred for genetic testing and examined for mutations in the FBN1, TGFbetaR1, TGFbetaR2 and ACTA2 genes. METHODS: We examined 594 samples from unrelated individuals and different combinations of genes were sequenced, including one or more of the following: FBN1, TGFbetaR1, TGFbetaR2, ACTA2, and, in some cases, FBN1 was analyzed by MLPA to detect large deletions. RESULTS: A total of 112 patients had a positive result. Of those, 61 had a clinical diagnosis of MFS, eight had LDS, three had TAAD and 40 patients had clinical features with no specific diagnosis provided. A total of 44 patients had an inconclusive result; of these, 12 patients were referred with a clinical diagnosis of MFS, 4 with LDS and 9 with TAAD and 19 had no clinical diagnosis. A total of 89 mutations were novel. CONCLUSION: This study reveals the rate of detection of variants in several genes associated with MFS, LDS and TAAD. The evaluation of patients by individuals with expertise in the field may decrease the likelihood of ordering unnecessary molecular testing. Nevertheless, genetic testing supports the diagnosis of MFS, LDS and TAAD. PMID- 24793578 TI - Ultrasensitive flow sensing of a single cell using graphene-based optical sensors. AB - On the basis of the polarization-dependent absorption of graphene under total internal reflection, we designed a graphene-based optical refractive index sensor with high resolution of 1.7 * 10(-8) and sensitivity of 4.3 * 10(7) mV/RIU, as well as an extensive dynamic range. This highly sensitive graphene optical sensor enables label-free, live-cell, and highly accurate detection of a small quantity of cancer cells among normal cells at the single-cell level and the simultaneous detection and distinction of two cell lines without separation. It provides an accurate statistical distribution of normal and cancer cells with fewer cells. This facile and highly sensitive sensing refractive index may expand the practical applications of the biosensor. PMID- 24793579 TI - Highlights from the 16th Vitamin D Workshop, San Francisco, CA, June 11-14, 2013. PMID- 24793580 TI - Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. AB - BACKGROUND & AIMS: Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus--Thrombolysis in Myocardial Infarction-53) reported a significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4. METHODS & RESULTS: DATA SOURCES: An extensive Medline, Embase, and Cochrane Database search for "vildagliptin", "sitagliptin", "saxagliptin", "alogliptin", "linagliptin", and "dutogliptin" was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration >=24 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. The principal outcome was the effect of DPP4i on the incidence of acute heart failure. A total of 84 eligible trials was identified. The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo/active comparators (MH-OR: 1.19[1.03; 1.37]; p = 0.015). When trials with non-cardiovascular outcomes were analysed separately no signal of risk was detectable. CONCLUSION: Available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients. PMID- 24793581 TI - Overexpression of erg20 gene encoding farnesyl pyrophosphate synthase has contrasting effects on activity of enzymes of the dolichyl and sterol branches of mevalonate pathway in Trichoderma reesei. AB - The mevalonate pathway is the most diverse metabolic route resulting in the biosynthesis of at least 30,000 isoprenoid compounds, many of which, such as sterols or dolichols, are indispensable for living cells. In the filamentous fungus Trichoderma of major biotechnological interest isoprenoid metabolites are also involved in the biocontrol processes giving the mevalonate pathway an additional significance. On the other hand, little is known about genes coding for enzymes of the mevalonate pathway in Trichoderma. Here, we present cloning and functional analysis of the erg20 gene from Trichoderma reesei coding for farnesyl pyrophosphate (FPP) synthase (EC 2.5.1.10), an enzyme located at the branching point of the mevalonate pathway. Expression of the gene in a thermosensitive erg20-2 mutant of Saccharomyces cerevisiae impaired in the FPP synthase activity suppressed the thermosensitive phenotype. The same gene overexpressed in T. reesei significantly enhanced the FPP synthase activity and also stimulated the activity of cis-prenyltransferase, an enzyme of the dolichyl branch of the mevalonate pathway. Unexpectedly, the activity of squalene synthase from the other, sterol branch, was significantly decreased without, however, affecting ergosterol level. PMID- 24793582 TI - Expression differences of miRNAs and genes on NF-kappaB pathway between the healthy and the mastitis Chinese Holstein cows. AB - In order to discover the variation of microRNAs and genes associated with NF kappaB signaling pathway between the healthy and the mastitis Chinese Holstein cows, Illumina Deep Sequencing and qRT-PCR are applied to detect 25 kinds of miRNAs (miR-16, miR-125b, miR-15, miR-29a, miR-23b, miR-146, miR-301a, miR-181b, let-7, miR-30b, miR-21, miR-223, miR-27b, miR-10a, miR-143, etc.) expression levels in blood samples and 14 genes (RelA, RelB, Rel, p105, p100, IkappaBalpha, IkappaBbeta, IkappaBdelta, IkappaBepsilon, IkappaBzeta, Bcl-3, IKKalpha, IKKbeta, IKKgamma/NEMO) relative expression levels in nine tissues. The total number of miRNAs is declining, and RelA, Rel, p105, p100, IkappaBalpha, IkappaBbeta, IkappaBdelta, IkappaBzeta, Bcl-3, and IKKalpha expressions are rising in mastitis individuals. So, we suppose that NF-kappaB pathway is active in mastitis individuals as a result of the decrease inhibition of miRNAs. While in healthy ones, the NF-kappaB pathway is inactive, because of the miRNAs enhanced inhibition action. However, the specific regulatory mechanism of miRNAs on NF kappaB pathway in mastitis Holstein cows needs further investigation. Moreover, due to obvious expression differences, some miRNAs, especially miR-16 and miR 223, may be used as new markers for the dairy mastitis prognosing. PMID- 24793583 TI - Factors associated with efficacy of pegylated interferon-alpha plus ribavirin for chronic hepatitis C after renal transplantation. AB - Hepatitis C virus (HCV) infection is the major cause of chronic liver disease after renal transplantation (RT), which reduces both graft and patient survival. After RT, the most widely used approach is interferon (IFN)-based therapy of hepatitis C which may be unsatisfactory with both poor efficacy and an increasing risk of allograft rejection. Thus, it is not recommended unless patients develop fibrosing cholestatic hepatitis. Several recent studies, however, suggest that treatment was possible with preservation of both renal and liver functions. From the limited studies on HCV infection after RT, several factors have been identified as important tools for the management of therapy in these patients. Infection with HCV genotypes 2 and 3, low baseline viral load and absence of advanced fibrosis/cirrhosis in the liver are associated with a sustained virologic response (SVR). After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of SVR independent of HCV genotype. Furthermore, some factors must be taken into consideration in order to avoid allograft rejection, such as the time between transplantation and therapy for HCV, the dose and duration of regimen and renal function. Careful evaluation of predictions of stable renal function and SVR for those patients helps to reduce inefficient treatment regimes and to increase the cure rate in addition to reducing the possible risk. In this review, the latest information was collected and we focus on the discussion of the factors influencing the attainment of SVR after RT. PMID- 24793584 TI - Histomorphometric characterization of the intertubular compartment in the testes of the bat Sturnira lilium. AB - Due to the scarcity of information about the reproduction of bats, it is necessary to perform studies on different species to identify the occurrence of annual variations in their reproductive process. Therefore, the aims of this study were to describe and quantify the intertubular components within the testes of the bat Sturnira lilium and to verify whether seasonality takes place in spermatogenesis of this species. The animals were collected in different seasons and time of collection was grouped into dry and rainy seasons. Testicular fragments were routinely processed for light and transmission electron microscopies and blood samples from each animal were collected for quantification of plasma testosterone. Overall, the Leydig cells (LC) were the main intertubular component (83.2%), with abundant lipid droplets in their cytoplasm. Ultrastructural analysis indicated collagen fibers in the connective tissue and lymphatic spaces, with thin walls, surrounding the seminiferous tubules. The proportion and volume of each intertubular component did not vary significantly between seasons. On average, testosterone concentrations did not vary between rainy and dry seasons (21ng/mL). The total number of LC in the testis (50.0*10(5)) and per gram of testis (11*10(7)) did not vary nor did the Leydigosomatic Index (0.03%). Therefore, it is concluded that S. lilium had significant investment in intertubular tissues, especially in LC. Most of the variables that were assessed did not vary with season of the year, which leads to the assumption that S. lilium has a continuous reproductive cycle in southeastern Brazil. PMID- 24793585 TI - Mutation in BMPR-IB gene is associated with litter size in Iranian Kalehkoohi sheep. AB - The single nucleotide polymorphism of BMPR-IB gene (bone morphogenetic protein receptor type IB) was analyzed using PCR-RFLP in Iranian native Kalehkoohi sheep. BMPR-IB which affects the fecundity of Booroola Merino sheep was studied as a candidate gene associated with the prolificacy of Kalehkoohi sheep. Improving the reproductive traits in sheep could be one of the key factors in increasing farm profitability. Major genes for litter size trait provide opportunities for large and rapid increases in the efficiency of sheep production. The same FecB (Booroola) mutation occurred in the BMPR-IB gene in Kalehkoohi sheep as found in Booroola Merino. Allele frequency for B and + was 0.35 and 0.65 respectively. The BB, B+ and ++ genotypes have been identified with the 0.13, 0.446 and 0.424, respectively. The Kalehkoohi sheep with genotypes BB and B+ had 0.52 and 0.35 lambs, more than the homozygous wild-type, respectively (P<0.01). No significant difference was observed between B+ and BB in litter size. Also the effect of parity and flock weren't significant in this study. Results of the present study support the concept that BMPR-IB significantly affected litter size and was associated with litter size in Kalehkoohi sheep and thus it could be used for Marker-assisted selection programmers for the genetic improvement of reproductive characteristics in this breed. PMID- 24793587 TI - Vacancy inter-layer migration in multi-layered graphene. AB - The migration of vacancies between graphene layers and carbon nanotube walls has been observed in experiments, in which it is well known that the migration of vacancies between adjacent layers is prohibited by a very large energy barrier (~7.0 eV). This contradiction has been a major puzzle for a number of years. In the present study, by using density functional tight-binding molecular dynamic simulations and first principle calculations, we have found that interaction between vacancies or vacancy holes in neighbouring graphene layers can greatly reduce the barrier, to ~3 eV or less, and this expedites the migration process. In addition, all the vacancies in a multi-layered graphene gather to form a single hole in one layer. Our study has revealed a new mechanism for healing the defect in graphene materials and successfully explains the experimental puzzle. Our results have important applications in the engineering of graphene materials. PMID- 24793586 TI - An in vivo rat model of artery buckling for studying wall remodeling. AB - Theoretical modeling and in vitro experiments have demonstrated that arterial buckling is a possible mechanism for the development of artery tortuosity. However, there has been no report of whether artery buckling develops into tortuosity, partially due to the lack of in vivo models for long-term studies. The objective of this study was to establish an in vivo buckling model in rat carotid arteries for studying arterial wall remodeling after buckling. Rat left carotid arteries were transplanted to the right carotid arteries to generate buckling under in vivo pressure and were maintained for 1 week to examine wall remodeling and adaptation. Our results showed that a significant buckling was achieved in the carotid arterial grafts with altered wall stress. Cell proliferation and matrix metalloprotinease-2 (MMP-2) expression in the buckled arteries increased significantly compared with the controls. The tortuosity level of the grafts also slightly increased 1 week post-surgery, while there was no change in vessel dimensions, blood pressure, and blood flow velocity. The artery buckling model provides a useful tool for further study of the adaptation of arteries into tortuous shapes. PMID- 24793588 TI - Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages. AB - Iron balance is tightly linked to inflammation and it has been demonstrated that many proteins involved in cellular iron management are up- or down-regulated by inflammatory stimuli, ultimately leading to iron retention in the reticuloendothelial system. Ferroportin is a key player in maintenance of correct iron homeostasis, because it is the only known mammalian cellular iron exporter. In this work we show that incubation of THP-1 monocytes/macrophages with lactoferrin prevents the LPS-induced decrease of ferroportin by reducing secretion of IL-6. PMID- 24793589 TI - Health education via mobile text messaging for glycemic control in adults with type 2 diabetes: a systematic review and meta-analysis. AB - BACKGROUND: Diabetes type 2 is an increasing problem worldwide that may be managed through education. Text-messaging using a cell phone can assist with self care. The aim of this study was to systematically review the impact of education through mobile text-messaging on glycemic control. METHODS: The design was a systematic review with meta-analysis. Five electronic databases were searched to access English studies involving a randomized controlled trial design that used text-messaging educational interventions in patients with type 2 diabetes during an 11-year period (2003-2013). Studies were evaluated using a quality assessment scale adapted from Jadad scale and Cochrane handbook. Extraction of data was carried out by two reviewers. A random-effect model with a standardized mean difference and Hedges's g indices was used for conducting the meta-analysis. Subgroup analyses were conducted and a Funnel plot was used to examine publication bias. RESULTS: Ten studies overall were identified that fulfilled inclusion criteria, involving a total of 960 participants. The mean age of the sample was 52.8 years and majority were females. Data were heterogeneous (I(2)=67.6). Analyses suggested a publication bias based on Egger's regression (P<0.05). HbA1c was reduced significantly in experimental groups compared to control groups (P<0.001). The effect size for glycemic control in studies that used text-messaging only was 44%. For studies that used both text-messaging and Internet, the effect size was 86%. CONCLUSION: Mobile text-messaging for educating Type 2 diabetics appears to be effective on glycemic control. Further investigations on mobile applications to achieve educational goals involving other diseases are recommended. PMID- 24793590 TI - High-signal-intensity abnormalities evaluated by 3D fluid-attenuated inversion recovery imaging within the drainage territory of developmental venous anomalies identified by susceptibility-weighted imaging at 3 T. AB - PURPOSE: To evaluate brain parenchymal high-signal-intensity abnormalities within the drainage territory of developmental venous anomalies (DVAs) identified by susceptibility-weighted imaging (SWI) at 3 T. METHODS: One hundred and thirty patients with 137 DVAs identified by SWI were retrospectively studied. 3D fluid attenuated inversion recovery (FLAIR) images were reviewed for parenchymal high signal-intensity abnormalities and SWI images were reviewed for hypointense foci (microhemorrhages or cavernous malformations) adjacent to DVAs. Patient age, the degree of underlying white matter disease, DVA location (supratentorial or infratentorial), and the presence or absence of hypointense foci were compared across DVAs with and without high-signal-intensity abnormalities. The correlation between patient age and the size of any high-signal-intensity abnormality was analyzed using linear regression. RESULTS: Forty-two of 137 DVAs (30.7 %) had high-signal-intensity abnormalities. An adjusted prevalence of 18/71 (25.4 %) was obtained after excluding patients with considerable underlying white matter disease. Only DVA location (supratentorial) was associated with the presence of high-signal-intensity abnormalities (p < 0.05). There was a significant correlation between patient age and the size of high-signal-intensity abnormalities (p < 0.01). CONCLUSIONS: 3D FLAIR imaging permits detection of small high-signal-intensity abnormalities within the drainage territory of DVAs. The size of high-signal-intensity abnormalities increased with patient age. PMID- 24793592 TI - Antenatal depression: an artefact of sleep disturbance? AB - Research indicates that poor sleep quality is linked to and may precede depressive symptomatology in pregnancy, complicating screening for either condition. Pregnancy onset may also contribute to the development of sleep disordered breathing (SDB). For the first time, the link between SDB and depression was examined in pregnancy. A total of 189 pregnant women completed the Edinburgh Postnatal Depression Scale (EPDS), Pittsburgh Sleep Quality Index (PSQI) for sleep quality and the Berlin Questionnaire for SDB. Women were also asked what they felt was the cause of their symptoms. PSQI-assessed poor sleep quality and self-perceived depression were strongly associated with EPDS scores of probable depression (X (2) 13.39; p < 0.001). Berlin-assessed risk of SDB was also associated with probable depression (X (2) 9.20 p < 0.01), though this was attenuated following multivariate analysis. There was a significant relationship between total PSQI score and the tendency for participants to attribute 'sleep related causes' to their low mood (X (2) 20.78; p < 0.001). This study confirms the link between PSQI-assessed poor sleep quality and depressive symptoms in pregnancy, suggesting the two questionnaires assess the same or overlapping conditions. Although there was a relationship between probable depression and high risk SDB, the effect was attenuated after accounting for other depression risk factors, including body mass index (BMI). PMID- 24793591 TI - Spin equilibrium and O2-binding kinetics of Mycobacterium tuberculosis CYP51 with mutations in the histidine-threonine dyad. AB - The acidic residues of the "acid-alcohol pair" in CYP51 enzymes are uniformly replaced with histidine. Herein, we adopt the Mycobacterium tuberculosis (mt) enzyme as a model system to investigate these residues' roles in finely tuning the heme conformation, iron spin state, and formation and decay of the oxyferrous enzyme. Properties of the mtCYP51 and the T260A, T260V, and H259A mutants were interrogated using UV-Vis and resonance Raman spectroscopies. Evidence supports that these mutations induce comprehensive changes in the heme environment. The heme iron spin states are differentially sensitive to the binding of the substrate, dihydrolanosterol (DHL). DHL and clotrimazole perturb the local environments of the heme vinyl and propionate substituents. Molecular dynamics (MD) simulations of the DHL-enzyme complexes support that the observed perturbations are attributable to changes in the DHL binding mode. Furthermore, the rates of the oxyferrous formation were measured using stopped-flow methods. These studies demonstrate that both HT mutations and DHL modulate the rates of oxyferrous formation. Paradoxically, the binding rate to the H259A mutant-DHL complex was approximately four-fold that of mtCYP51, a phenomenon that is predicted to result from the creation of an additional diffusion channel from loss of the H259-E173 ion pair in the mutant. Oxyferrous enzyme auto-oxidation rates were relatively constant, with the exception of the T260V-DHL complex. MD simulations lead us to speculate that this behavior may be attributed to the distortion of the heme macrocycle by the substrate. PMID- 24793593 TI - Arene-ruthenium(II) acylpyrazolonato complexes: apoptosis-promoting effects on human cancer cells. AB - A series of ruthenium(II) arene complexes with the 4-(biphenyl-4-carbonyl)-3 methyl-1-phenyl-5-pyrazolonate ligand, and related 1,3,5-triaza-7 phosphaadamantane (PTA) derivatives, has been synthesized. The compounds have been characterized by NMR and IR spectroscopy, ESI mass spectrometry, elemental analysis, and X-ray crystallography. Antiproliferative activity in four human cancer cell lines was determined by MTT assay, yielding dose- and cancer cell line-dependent IC50 values of 9-34 MUM for three hexamethylbenzene-ruthenium complexes, whereas the other metal complexes were much less active. Apoptosis was the mechanism involved in the anticancer activity of such compounds. In fact, the hexamethylbenzene-ruthenium complexes activated caspase activity, with consequent DNA fragmentation, accumulation of pro-apoptotic proteins (p27, p53, p89 PARP fragments), and the concomitant down-regulation of antiapoptotic protein Bcl-2. Biosensor-based binding studies indicated that the ancillary ligands were critical in determining the DNA binding affinities, and competition binding experiments further characterized the nature of the interaction. PMID- 24793594 TI - Transcription factor Sp1, also known as specificity protein 1 as a therapeutic target. AB - INTRODUCTION: Specificity protein (Sp) transcription factors (TFs) are members of the Sp/Kruppel-like factor family, and Sp proteins play an important role in embryonic and early postnatal development. Sp1 has been the most extensively investigated member of this family, and expression of this protein decreases with age, whereas Sp1 and other family members (Sp3 and Sp4) are highly expressed in tumors and cancer cell lines. AREA COVERED: The prognostic significance of Sp1 in cancer patients and the functional pro-oncogenic activities of Sp1, Sp3 and Sp4 in cancer cell lines are summarized. Several different approaches have been used to target downregulation of Sp TFs and Sp-regulated genes, and this includes identification of different structural classes of antineoplastic agents including NSAIDs, natural products and their synthetic analogs and several well characterized drugs including arsenic trioxide, aspirin and metformin. The multiple pathways involved in drug-induced Sp downregulation are also discussed. EXPERT OPINION: The recognition by the scientific and clinical community that experimental and clinically used antineoplastic agents downregulate Sp1, Sp3 and Sp4, and pro-oncogenic Sp-regulated genes will facilitate future clinical applications for individual drug and drug combination therapies that take advantage of their unusual effects. PMID- 24793595 TI - Identification and quantitation of the ingredients in a counterfeit Vietnamese herbal medicine against rheumatic diseases. AB - Counterfeit and/or illegally manufactured drugs and herbal medicines are becoming an increasing problem throughout the world. Internet sales simplify distribution and payment of these falsified drugs. Here we report on a Vietnamese herbal medicine, which was advertised for treatment of rheumatic disease from a religious Vietnamese healer. By means of NMR and LC/MS we found 863mg acetaminophen, 262mg sulfamethoxazole, 42mg indomethacin and less than 1% trimethoprim in a sachet of 2.617g powder content, in addition to some cinnamon bark and phosphate. PMID- 24793596 TI - Robot-assisted septal myectomy for hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. PMID- 24793597 TI - Reply to the editor. PMID- 24793598 TI - Computed tomography surveillance of patients with resected lung cancer: Recurrence or second primary lung cancer? PMID- 24793599 TI - Does the Society of Thoracic Surgeons risk score accurately predict operative mortality for patients with pulmonary hypertension? PMID- 24793600 TI - Reply to the editor. PMID- 24793601 TI - The importance of the posterior leaflet angle in chronic ischemic mitral regurgitation. PMID- 24793602 TI - Reply to the editor. PMID- 24793603 TI - Limb ischemia and femoral arterial cannulation for extracorporeal membrane oxygenation: does the perfect technique exist? PMID- 24793604 TI - Reply to the editor. PMID- 24793605 TI - Should the gender and age of an animal be considered for studies on postconditioning? PMID- 24793606 TI - Reply to the editor. PMID- 24793607 TI - Needlescope-assisted 3-point fixation of the pectus bar in the Nuss procedure. PMID- 24793608 TI - Coronary-coronary radial artery conduit to solve the problem of coronary artery aneurysms. PMID- 24793609 TI - Reply to the editor. PMID- 24793610 TI - Reply to the editor. PMID- 24793611 TI - Not convinced that right internal thoracic artery is superior to radial artery. PMID- 24793612 TI - Ray Chu-Jeng Chiu, MD, PhD, FRCSC, FACS, FACC (1934-2014). PMID- 24793613 TI - Should sutureless aortic valve replacement be preferred only for decreasing aortic crossclamp time? PMID- 24793614 TI - Learning curve for video-assisted thoracoscopic lobectomy. PMID- 24793615 TI - Heart failure in a young adult: a rare cause. PMID- 24793616 TI - Invasive assessment of the coronary microcirculation using the index of microcirculatory resistance: description and validation of an animal model. AB - INTRODUCTION: The index of microcirculatory resistance (IMR) enables/provides quantitative, invasive, and real-time assessment of coronary microcirculation status. AIMS: The primary aim of this study was to validate the assessment of IMR in a large animal model, and the secondary aim was to compare two doses of intracoronary papaverine, 5 and 10 mg, for induction of maximal hyperemia and its evolution over time. METHODS: Measurements of IMR were performed in eight pigs. Mean distal pressure (Pd) and mean transit time (Tmn) were measured at rest and at maximal hyperemia induced with intracoronary papaverine, 5 and 10 mg, and after 2, 5, 8 and 10 minutes. Disruption of the microcirculation was achieved by selective injection of 40-MUm microspheres via a microcatheter in the left anterior descending artery. RESULTS: In each animal 14 IMR measurements were made. There were no differences between the two doses of papaverine regarding Pd response and IMR values - 11 +/- 4.5 U with 5 mg and 10.6 +/- 3 U with 10 mg (p=0.612). The evolution of IMR over time was also similar with the two doses, with significant differences from resting values disappearing after five minutes of intracoronary papaverine administration. IMR increased with disrupted microcirculation in all animals (41 +/- 16 U, p=0.001). CONCLUSIONS: IMR provides invasive and real-time assessment of coronary microcirculation. Disruption of the microvascular bed is associated with a significant increase in IMR. A 5-mg dose of intracoronary papaverine is as effective as a 10-mg dose in inducing maximal hyperemia. After five minutes of papaverine administration there is no significant difference from resting hemodynamic status. PMID- 24793617 TI - Combining bevacizumab and panitumumab with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as second-line treatment in patients with metastatic colorectal cancer. AB - Bevacizumab and panitumumab are human monoclonal antibodies with different targeting antigens, vascular endothelial growth factor, and epidermal growth factor receptor. This study examined the efficacy and safety of combining bevacizumab and panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) as the second-line therapy for patients with metastatic colorectal cancer (mCRC). Patients with mCRC, and previously failed with oxaliplatin-based chemotherapy, were given bevacizumab (3 mg/kg) and panitumumab (3 mg/kg) plus FOLFIRI every other week. From September 2008 to July 2012, 173 patients were included in the study. The response rate was 42.3 %, and the disease-controlled rate was 65.7 %. The median progression-free survival was 6.5 months, and the median overall survival was 15.4 months. Various adverse events (AE) including those known toxicities associated with antibody therapy were recorded. The overall AE rate was 64.5 % for grade 3-4. The treatment of combining bevacizumab and panitumumab plus FOLFIRI is effective and safe as a second-line therapy for patients with mCRC. PMID- 24793618 TI - Investigation of the hepatotoxicity of flutamide: pro-survival/apoptotic and necrotic switch in primary rat hepatocytes characterized by metabolic and transcriptomic profiles in microfluidic liver biochips. AB - We investigated the effects of the liver damage induced by flutamide in primary rat hepatocytes using liver microfluidic biochips. Flutamide is a non-steroidal anti-androgenic drug. Two flutamide concentrations, 10 MUM and 100 MUM, were used to expose the hepatocytes for 24h under perfusion. Thanks to the maintenance of hepatocyte differentiation phenotype and to the biotransformation performance in the microfluidic cultures, the metabolic ratio analysis of hydroxyflutamide, flutamide-gluthatione and hydroxyflutamide-gluthatione productions demonstrated saturation of the drug's biotransformation process and the maintenance of a high level of flutamide at 100 MUM when compared to 10 MUM. A microarray analysis comparing flutamide (10 or 100 MUM) with controls revealed a common response for both concentrations illustrated by modulating the expression of the mRNA of genes associated with mitochondrial perturbation, of the proliferator-activated receptors (Ppar) signaling, lipid and fatty acid metabolism, antioxidant defense, and cell death pathways, consistently with in vitro and in vivo reports. Additionally to literature reports, our integration of the transcriptomic profiles demonstrated a specific dose dependent response. We found at 10 MUM a typical pro-survival/apoptosis network activation (through IGF/PDGFD upstream route and via a downstream up regulation in CREB5, BCL2, IKBKG routes in the PI3K/signaling). We also found a down regulation of mRNA levels in sugar and amino acid metabolism pathways. At 100 MUM a typical necrosis switch was observed associated with a down regulation of the tight junctions' pathway, a cellular aggregation and a reduction of the cell viability. Altogether our data demonstrated the potential and the sensitivity of our liver microfluidic cultures to evaluate xenobiotic toxicity by improving in vitro analysis and reproducing both in vitro and in vivo results. Finally, we proposed two integrated synthetic networks to describe the response of rat hepatocytes to both exposure concentrations of flutamide. PMID- 24793620 TI - Identification of CNS neurons with polysynaptic connections to both the sympathetic and parasympathetic innervation of the submandibular gland. AB - Coordinated modulation of sympathetic and parasympathetic nervous activity is required for physiological regulation of tissue function. Anatomically, whilst the peripheral sympathetic and parasympathetic pathways are separate, the distribution of premotor neurons in higher brain regions often overlaps. This co distribution would enable coordinated regulation and might suggest individual premotor neurons could project to both sympathetic and parasympathetic outflows. To investigate this one submandibular gland was sympathectomized. One of two isogenic strains of the pseudorabies virus, expressing different fluorophores, was injected into the cut sympathetic nerve and the other into the submandibular gland. Independent labeling of the peripheral sympathetic and parasympathetic pathways was observed. Dual-labeled neurons were observed in many CNS regions known to be involved in regulating salivary function. We propose these observations highlight a common pattern of organization of the CNS, providing the anatomical framework for the fine control of organ function required for homeostatic regulation and the coordination of organ responses to enable complex behaviors. PMID- 24793619 TI - The microbiome, parturition, and timing of birth: more questions than answers. AB - The causes of preterm birth are multifactorial, but its association with infection has been well-established. The predominant paradigm describes an ascending infection from the lower genital tract through the cervix and into the presumably sterile fetal membranes and placenta. Thus, an evaluation of the role of the vaginal microbiome in preterm birth is implicated. However, emerging fields of data described in this review suggest that the placenta might not be sterile, even in the absence of clinical infection. We thus propose an additional mechanism for placental colonization and infection: hematogenous spread. When considered in the context of decades of evidence demonstrating a strong risk of recurrence for preterm birth, studies on parturition are ideal for applying the rapidly expanding field of metagenomics and analytic pipelines. The translational implications toward identification of innovative treatments for the prevention of preterm birth are further discussed. In sum, exciting advances in understanding the role of both host and microbiota in parturition and preterm birth are on the horizon. PMID- 24793622 TI - What is an active regimen in carcinoma of unknown primary sites? Analysis of correlation between activity endpoints reported in phase II trials. Correlation of activity endpoints in phase II trials. AB - BACKGROUND: The choice of the activity endpoint is crucial when designing phase II screening trials. This choice is usually guided by convention, but the level of evidence for picking-up one of them is limited. METHODS: We have analysed the phase II trials in carcinoma of unknown primary patients (CUP; 48 strata). We calculated the Pearson correlation coefficient using weighted linear regression to measure the degree of association between the different available activity endpoints (Best objective response - BORR, best tumour control rate - BTCR, 3- and 6-month progression-free rates, 3- and 6-month PFR and median progression free survival). We also explored the correlation between these endpoints and OS. RESULTS: All activity endpoints were strongly correlated in CUP studies; all of these endpoints were strongly correlated with OS. The median BORR across the studies was 30%. Positive trials defined by BORR >= 30% were associated with statistically longer PFS (4.8 versus 3.7 months, P = 0.013) and OS (10.0 versus 8.0, P = 0.0007). DISCUSSION: In phase II studies with CUP patients, BORR and the threshold of BORR > 30% for defining promising drug appears adequate. PMID- 24793621 TI - A C-terminal crosslinking telopeptide test-based protocol for patients on oral bisphosphonates requiring extraction: a prospective single-center controlled study. AB - PURPOSE: Patients undergoing extraction are at risk for bisphosphonate-related osteonecrosis of the jaws (BRONJ). A C-terminal crosslinking telopeptide (CTX) level lower than 150 pg/mL has been suggested as a predictor of BRONJ risk. The authors aimed to increase the precision of estimates of the risk of BRONJ in osteoporosis after extraction and to assess value of CTX testing at extraction time in cases of BRONJ in a large prospective cohort. PATIENTS AND METHODS: All patients on oral bisphosphonates for osteoporosis referred for extractions over a period of 6.5 years were included in a standard protocol. Pre-extraction fasted CTX levels were obtained. All patients were followed until healing. If the CTX level was lower than 150 pg/mL, they were offered a drug holiday. If they declined, if the CTX level was above 150 pg/mL at baseline, or after the drug holiday, they had extractions performed under local anesthesia. Age-matched controls not on bisphosphonates were identified. RESULTS: Nine hundred fifty patients had 2,461 extractions. One hundred eighty-one patients had a CTX level lower than 150 pg/mL. Four patients developed BRONJ; all had a CTX level lower than 150 pg/mL. All were on alendronate. The case-control comparison approached significance (<150 pg/mL; P = .073). Alendronate was associated with a low CTX level (P < .05). A CTX level lower than 150 pg/mL had a sensitivity of 100% and specificity of 81%. Bayesian analysis yielded a population expected risk of BRONJ of 0.29% (95% confidence interval, 0.12-0.52); the expected risk was 0.42% for a CTX level lower than 150 pg/mL and 0.13% for a CTX level higher than 150 pg/mL. CONCLUSION: The risk of BRONJ for patients with osteoporosis on bisphosphonates having extractions is approximately 0.2%. A CTX level lower than 150 pg/mL is sensitive and is associated with an approximately 3-fold greater risk of BRONJ. PMID- 24793623 TI - [Nodes Dissections. What's up and what is at stake?]. AB - Radical nodes dissection has a diagnostic value and can play a part in the treatment. Its interest could be questionable according to efficacy of the associated treatments either adjuvant or neo-adjuvant. Above all, sentinel node dissection allows to avoid a radical dissection with deleterious effects. PMID- 24793624 TI - [The place of para-aortic lymphadenectomy in gynaecological malignancies. An old debate]. AB - There is a lack of prospective randomized trial and scientific evidence for the use of para-aortic lymphadenectomy in gynaecological malignancies. This results in variations between countries for its utility. Based on the recommandations of the French Institute of Cancer (INCa), we open the debate of the place of para aortic lymphadenectomy. PMID- 24793625 TI - [Sentinel lymph node in low stage cervical cancers. Current data. Quality assurance. Prospects]. AB - Sentinel node biopsy appears as a promising technique for the assessment of nodal disease in early cervical cancers. Selection of a population with a low risk of nodal metastasis, a minimal training, and simple rules allow a low false negative rate. Sentinel node biopsy provides supplementary information, such as anatomical information (nodes outside of routine lymphadenectomy areas) and histological information (isolated tumors cells and micrometastases). PMID- 24793626 TI - [Detection of residual microscopic disease in melanoma: interest of the sentinel lymph node procedure?]. AB - The prognosis of metastatic melanoma, despite many important and recent progresses, remains poor. The detection of microscopic disease must be a key point in fundamental and clinical research. Current recommendations, with clinical and radiological monitoring, only permit to detect macroscopic relapses. No seric tumor marker is presently sufficiently reproducible and determinant to be used in clinical practice to precociously diagnose a relapse. The sentinel lymph node procedure is currently the only technique largely used to determine microscopic metastasis. This technique allows defining a group of patients with poor prognosis but its therapeutic impact remains discussed. Completion lymph node dissection of the area after positive sentinel lymph node is currently performed but its real benefit to improve overall survival must be proved. Interferon is now the only treatment approved in adjuvant setting, but its interest remains discussed. Therapeutic trials are ongoing to really identify patients who could benefit from adjuvant treatment with interferon. Other trials probably more attractive (anti-CTLA4, BRAF and MEK inhibitors), with molecules recently approved in metastatic phase are also ongoing. PMID- 24793627 TI - [Sentinel node invasion: is it necessary to perform axillary lymph node dissection? Randomized trial SERC]. AB - Contribution of axillary lymph node dissection (ALND) is questioned for positive sentinel node (SN), micro-metastasis and isolated tumor cells but also for macro metastasis. The aim of this work is to precise why a prospective randomized trial is necessary and the design of this trial. Why? For positive SN, the scientific level evidence appears insufficient for validation of ALND omission as a new standard. Rational is presented with non-sentinel node involved rate and number of NSL involved at complementary ALND, axillary recurrence rate, disease free survival rate and adjuvant treatment decision impact. How? The proposed Sentinelle Envahi et Randomisation du Curage (SERC) trial will randomly assign to observation only or complementary ALND with positive SN. The aim is to demonstrate the non-inferiority of ALND omission versus ALND. PMID- 24793628 TI - [The intraoperative study of the sentinel lymph node was made possible through molecular analysis: a new concept and new applications for colon cancer?]. AB - Sentinel lymph node (SLN) is a concept but also a technical possibility that can be studied and applied to almost all organs with cancer. For colorectal cancer surgery, some possibilities of using the SLN are possible, other implausible and some completely new especially aware of possible analysis of SLN by a molecular biology technique. The orientation of dissection or "lymph road mapping" can be designed for this case or the surgeon may want to limit his actions, particularly in patients with a history of colonic surgical resection, to keep the digestive function in maintaining vascular axes considered not involved in the metastatic process. The use of the single analysis of SLN to determine the positive or negative status of the cleaning has failed because of the frequency of false negatives in part to the size of colic advanced cancers at diagnosis. The use of "ultra-stading" by multiple section or exhaustion of the block, can lead to reconsider a stage N0 to N1 as a point, if the analysis technique remains in HES. Unlike the "ultra-stading" by RT- PCR or immunohistochemistry was even more discussed and seems not equivalent in terms of prognosis and therefore no giving formally justification for adjuvant therapy. Currently, a new technique for molecular biology, named "OSNA", allows an analysis of all the SLN in less than 45 minutes. It is therefore possible to obtain during surgery analysis of a node with the same level of information than traditional analysis using HES. If this node is positive and if the strategy in case of positive lymph nodes was determined prior for this patient, it is possible to anticipate this strategy and place after colectomy during the same anesthesia, venous access quickly to start postoperative chemotherapy. This new technique for analyzing lymph applied to the SLN opens a new potential application of this concept in digestive oncology. PMID- 24793629 TI - [Lymph node dissection: what for? From esophagus to rectum: surgical and lymph node related prognostic factors]. AB - Surgery has still a key role in curative treatment of digestive carcinomas, and for almost all localisations, lymph node status is a major prognostic factor. As far as oesophageal and gastric cancer are concerned, there is not yet any internationally standardized approach. Occidental guidelines recommend more limited lymph node dissections than Asiatic ones. Lymph node numbers requested during surgery of such cancers remain high, at least 23 lymph nodes for oesophageal cancer, and 25 for a D2 or D1.5 lymphadenectomy for gastric cancer. Generalisation of neo-adjuvant and adjuvant treatments has not yet modified these standards. On the other hand, rectal cancer surgery is well standardized since the global adoption of Total Mesorectal Excision (TME) for the late eighties. Development of mini-invasive techniques (laparoscopy and robot-assisted surgery) enabled an important decrease of surgery related morbidity as well as an enhanced post-operative recovery. However, rectal cancer surgery still has an important morbidity. Development of neo-adjuvant chemo-radiotherapy as well as in-depth knowledge of risk factor of lymph node invasion opened up the path for transanal full thickness resection without lymphadenectomy. The goal of such an approach is to avoid TME's morbidity without risking local recurrence rate increase. As a consequence, this technique might need to be completed with a TME case histological factors are not favorable. PMID- 24793630 TI - [Colorectal liver metastases: history, sciences and clinical practices]. AB - Colorectal liver metastasis is one of the best-known clinical models of multidisciplinary approach. Chemotherapy, targeted therapies, surgery and interventional radiology permitted to obtain up to 40 months of survival in palliative intent for liver metastases only and between 40 to 50% of overall survival in curative intent. Genetic, epigenetic, cellular and tissular processes are more and more well described but attempts to link biological knowledge to clinical practice are still faint. The cut-off between curative and palliative intents is progressively pushed away but consequently, its signification is less clear. Maybe an additional intermediary new concept should be added, the metastatic disease chronicisation? Evaluating the patient benefice is difficult and should stand on progression free survival as surrogate marker. PMID- 24793631 TI - [Retinoblastoma: recent advances]. AB - Retinoblastoma is the most common intraocular malignancy of infancy with an incidence of 1/15,000 to 1/20,000 births. Sixty percent of retinoblastomas are unilateral, with a median age at diagnosis of two years, and in most cases are not hereditary. Retinoblastoma is bilateral in 40% of cases, with an earlier median age at diagnosis of one year. All bilateral and multifocal unilateral forms are hereditary and are part of a genetic cancer predisposition syndrome. All children with a bilateral or familial form, and 10 to 15% of children with an unilateral form, constitutionally carry an RB1 gene mutation. The two most frequent symptoms revealing retinoblastoma are leukocoria and strabismus. Diagnosis is made by fundoscopy, with ultrasound and magnetic resonance imaging (MRI) contributing both to diagnosis and assessment of the extension of the disease. Treatment of patients with retinoblastoma must take into account the various aspects of the disease (unilateral/bilateral, size, localization...), the risk to vision and the possible hereditary nature of the disease. The main prognostic aspects are still premature detection and adapted coverage by a multi disciplinary specialized team. Enucleation is still often necessary in unilateral disease; the decision for adjuvant treatment is taken according to the histological risk factors. The most important recent therapeutic advances concern the conservative treatment which is proposed for at least one of the two eyes in most bilateral cases: laser alone or in combination with chemotherapy, cryotherapy or brachytherapy. Recently, the development of new conservative techniques of treatment, such as intra-arterial selective chemotherapy perfusion, aims at preserving visual function in these children and decreasing the number of enucleations and the need for external beam radiotherapy. The vital prognosis related to retinoblatoma is now excellent in industrialized countries, but long term survival is still related to the development of secondary tumors, mainly secondary sarcoma. Retinoblastoma requires multi-disciplinary care as well as a long term specialized follow-up. Early counseling of patients and their family concerning the risk of transmission of the disease and the risk of development of secondary tumors is necessary. PMID- 24793632 TI - [Abiraterone acetate (AA): current guidelines of prescription of abiraterone]. AB - Abiraterone acetate (AA) is a selective inhibitor of cytochrom p450 (CYP)17 which is required for androgen biosynthesis, and can block the androgens synthesis by testicles, surrenals and intratumoral secretion. In phase I and II studies in patients with prostate cancer, therapy with AA 250-2000 mg once daily demonstrated reductions in prostate specific antigen (PSA), and/or circulating tumor cells (CTCs). In two large phase III trials in patients with metastatic castration resistant prostate cancer (CRPC) in post-docetaxel and pre-docetaxel setting, AA plus prednisone compared with placebo plus prednisone demonstrated a significant superior overall survival in post-docetaxel setting, and a superior radiological PFS in pre-docetaxel setting. Based of these results, AA is approved in metastatic CRPC patients in post-docetaxel setting or pre-docetaxel setting in 2013. PMID- 24793633 TI - Singing in chronic obstructive pulmonary disease patients: A pilot study in Portugal. PMID- 24793634 TI - The risk of neurodisability and other long-term outcomes for infants born following ART. AB - Children born after assisted reproductive technologies (ART) have an increased morbidity. The risk of developing cerebral palsy is nearly doubled and the risk of developing epilepsy is also higher. Behavioural problems including attention deficit/hyperactivity disorder may be more common in children born following ART than among naturally conceived children but the finding is uncertain. Data on autism are difficult to interpret. There may exist a small increase in the incidence of childhood cancer and there is greater evidence of an elevated risk of asthma. To some extent, these risks are mediated by neonatal complications including prematurity and low birth weight but some effects such as cerebral palsy are likely to be linked to the increased rate of multiple births after ART. Many of the neonatal complications after ART are most likely linked to parental subfertility and are less an effect of the ART technology. The possibility exists that imprinting errors, associated with subfertility and/or ART, may result in long-term morbidity. PMID- 24793635 TI - The relative trending accuracy of noninvasive continuous hemoglobin monitoring during hemodialysis in critically ill patients. AB - The pulse CO-Oximeter (Radical-7; Masimo Corp., Irvine, CA) is a multi-wavelength spectrophotometric method for noninvasive continuous monitoring of hemoglobin (SpHb). Because evaluating the relative change in blood volume (DeltaBV) is crucial to avoid hypovolemia and hypotension during hemodialysis, it would be of great clinical benefit if DeltaBV could be estimated by measurement of SpHb during hemodialysis. The capability of the pulse CO-Oximeter to monitor DeltaBV depends on the relative trending accuracy of SpHb. The purpose of the current study was to evaluate the relative trending accuracy of SpHb by the pulse CO Oximeter using Crit-Line as a reference device. In 12 patients who received hemodialysis (total 22 sessions) in the intensive care unit, DeltaBV was determined from SpHb. Relative changes in blood volume determined from SpHb were calculated according to the equation: DeltaBV(SpHb)=[starting SpHb]/[current SpHb] - 1. The absolute values of SpHb and hematocrit measured by Crit-Line (CL Hct) showed poor correlation. On the contrary, linear regression analysis showed good correlation between DeltaBV(SpHb) and the relative change in blood volume measured by Crit-Line [DeltaBV(CL-Hct)] (r=0.83; P<=0.001). Bland-Altman analysis also revealed good agreement between DeltaBV(SpHb) and DeltaBV(CL-Hct) (bias, 0.77%; precision, 3.41%). Polar plot analysis revealed good relative trending accuracy of SpHb with an angular bias of 4.1 degrees and radial limits of agreement of 24.4 degrees (upper) and -16.2 degrees (lower). The results of the current study indicate that SpHb measurement with the pulse CO-Oximeter has good relative trending accuracy. PMID- 24793636 TI - Neostigmine for reversal of neuromuscular block in paediatric patients. AB - BACKGROUND: Residual neuromuscular block is associated with serious postoperative complications. Some anaesthesiologists use neostigmine to reverse neuromuscular blockade for all paediatric surgical patients. However, the incidence of residual neuromuscular block may be lower in paediatric patients than in adults. The use of neostigmine has also caused complications, such as postoperative nausea, vomiting, excessive salivation and bradycardia. Therefore, whether neostigmine should be used routinely to reverse neuromuscular blockade in each paediatric patient is an important question for paediatric anaesthesiologists. OBJECTIVES: To assess the necessity of routine usage of neostigmine in preventing residual neuromuscular blockade in paediatric patients following the use of muscle relaxants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 8, part of The Cochrane Library; MEDLINE via Ovid (1946 to August 2013); EMBASE via Ovid SP (1974 to August 2013); ClinicalTrials.gov (18 August 2013) and Chinese Clinical Trial Registry (18 August 2013) with no language restrictions. SELECTION CRITERIA: We planned to include randomized controlled trials (RCTs) comparing neostigmine versus placebo in American Society of Anaesthesiologists (ASA) I or II paediatric surgical participants (younger than 12 years of age, including newborns) who had received non-depolarizing muscle relaxants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion. MAIN RESULTS: We found no study that satisfied the inclusion criteria. We found one study awaiting classification. AUTHORS' CONCLUSIONS: No RCTs were found that supported, or argued against, the routine use of neostigmine to reverse neuromuscular block in paediatric patients. PMID- 24793637 TI - "The Promotora Explained Everything": Participant Experiences During a Household Level Diabetes Education Program. AB - PURPOSE: The purpose of this study is to describe participant experiences of a household-level, community health worker-led intervention to improve diabetes related health behaviors and outcomes. METHODS: The Home Health Parties (HHP) aimed to improve diabetes self-management among Hispanics living in a rural, agricultural area in eastern Washington State. Trained promotores (community health workers) delivered a series of education sessions and distributed incentives to support diabetes-related behavior change. Open-ended, semi structured questionnaires were administered to a random sample of 40 HHP participants. Qualitative methods were used to code and analyze the interview transcripts. RESULTS: Four primary themes emerged from interviews: (1) participants' desire for improving knowledge about diabetes; (2) experiences of building skills for diabetes management; (3) developing social support; and (4) embracing household-level change. CONCLUSION: This study shows that involving family members and increasing social support are effective strategies for improving health behaviors and chronic health outcomes among vulnerable Hispanics living with diabetes. Our findings demonstrate several important considerations regarding the design of diabetes management interventions for rural Hispanic populations including the following: (1) promotores are critical as they provide social support and encourage behavior change by building relationships based on trust and cultural understanding; (2) well-designed tools that provide step-by step examples of healthy behaviors, such as cookbooks, and tools that aid participants to monitor behavior change, such as pedometers and glucose monitors, serve to build skills and improve confidence to achieve goals; and (3) targeting households is a promising strategy for individual and family lifestyle changes that benefit the entire family unit. PMID- 24793639 TI - Role of G protein-coupled estrogen receptor 1 in modulating transforming growth factor-beta stimulated mesangial cell extracellular matrix synthesis and migration. AB - Estrogen has been demonstrated to exert beneficial effects on kidney; however, the role of G protein-coupled estrogen receptor 1 (GPER) is still uncertain. In the present study, we investigated the effect of 17beta-estradiol and GPER agonist Fulvestrant on extracellular matrix production under transforming growth factor-beta1 (TGF-beta1) stimulation in human and rat mesangial cells. As a result, 17beta-estradiol and Fulvestrant inhibit TGF-beta1-induced type IV collagen and fibronectin expression in a dose-dependent manner, by suppressing acute Smad2/3 phosphorylation and Smad4 complex formation. Furthermore, estrogen and Fulvestrant also down-regulate Smad signaling by promoting ubiquitin/proteasome-dependent Smad2 degradation. These effects could be abrogated by receptor antagonist G-15 or GPER gene knockdown. GPER is also required for estrogen and Fulvestrant to regulate mesangial cell migration in response to TGF-beta1. To conclude, GPER is crucial in modulating glomerular mesangial cell function including extracellular matrix production and migration. PMID- 24793640 TI - Unexpected and unexplained increase in death due to neurological disorders in 2012 in England and Wales: is cytomegalovirus implicated? AB - In early 2012 deaths (all-cause mortality) in England and Wales showed an unexpected and unexplained increase which continued for 18 months before abating. The highest percentage increase in deaths was noted to be for neurological degenerations (mainly dementia, Alzheimer's, Parkinson's). This study seeks to understand why increased deaths should focus on these conditions and if an unrecognized infectious outbreak could be implicated. Cause of death statistics for England and Wales were compared for 2012 versus 2011 as was the diagnosis for first outpatient appointment and inpatient admissions for these conditions. Deaths for dementia, Alzheimer's and Parkinson's showed a 15% increase with associated age specificity. The increase could not be explained by changes in the coding relating to cause of death. The increase coincided with increased GP referral (as first outpatient attendance) and inpatient admission for a range of neurological conditions. These increases were also observed on previous occasions of a similar event where deaths peaked in 2003 and 2008. A cascade of debility leading to immobility and institutionalization along with specific immune impairments appears to render those suffering from neurological degenerations sensitive to infectious outbreaks and more specifically to the particular agent behind these events. These and other studies point to outbreaks of a previously uncharacterized agent with the outbreak peaking in 2003, 2008 and 2012 (and in other years prior to these dates). Cytomegalovirus is a potential candidate and the necessary research to test this hypothesis is outlined. PMID- 24793638 TI - PPARgamma and the global map of adipogenesis and beyond. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors (TFs) and function as a master regulator of adipocyte differentiation and metabolism. We review recent breakthroughs in the understanding of PPARgamma gene regulation and function in the chromatin context. It is now clear that multiple TFs team up to induce PPARgamma during adipogenesis, and that other TFs cooperate with PPARgamma to ensure adipocyte-specific genomic binding and function. We discuss how this differs in other PPARgamma-expressing cells such as macrophages and how these genome-wide mechanisms are preserved across species despite modest conservation of specific binding sites. These emerging considerations inform our understanding of PPARgamma function as well as of adipocyte development and physiology. PMID- 24793641 TI - How stressful are 105 days of isolation? Sleep EEG patterns and tonic cortisol in healthy volunteers simulating manned flight to Mars. AB - Spaceflights "environment" negatively affects sleep and its functions. Among the different causes promoting sleep alterations, such as circadian rhythms disruption and microgravity, stress is of great interest also for earth-based sleep medicine. This study aims to evaluate the relationships between stress related to social/environmental confinement and sleep in six healthy volunteers involved in the simulation of human flight to Mars (MARS500). Volunteers were sealed in a spaceship simulator for 105 days and studied at 5 specific time points of the simulation period. Sleep EEG, urinary cortisol (24 h preceding sleep EEG recording) and subjectively perceived stress levels were collected. Cognitive abilities and emotional state were evaluated before and after the simulation. Sleep EEG parameters in the time (latency, duration) and frequency (power and hemispheric lateralization) domains were evaluated. Neither cognitive and emotional functions alterations nor abnormal stress levels were found. Higher cortisol levels were associated to: (i) decrease of sleep duration, increase of arousals, and shortening of REM latency; (ii) reduction of delta power and enhancement of sigma and beta in NREM N3; and (iii) left lateralization of delta activity (NREM and REM) and right lateralization of beta activity (NREM). Stressful conditions, even with cortisol fluctuations in the normal range, alter sleep structure and sleep EEG spectral content, mirroring pathological conditions such as primary insomnia or insomnia associated to depression. Correlations between cortisol fluctuations and sleep changes suggest a covert risk for developing allostatic load, and thus the need to develop ad-hoc countermeasures for preventing sleep alterations in long lasting manned space missions. PMID- 24793642 TI - Fasudil hydrochloride protects neurons in rat hippocampal CA1 region through inhibiting GluR6-MLK3-JNKs signal pathway. AB - Fasudil hydrochloride (FH), a Rho kinase (ROCK) inhibitor, has been reported to prevent cerebral ischemia in vivo from increasing cerebral blood flow and inhibiting inflammatory responses. However, it is uncertain by what mechanism a ROCK inhibitor can directly protect neurons against ischemic damage. The present study was designed to evaluate whether FH decreased the increased phosphorylation of glutamate receptor 6 (GluR6) and its downstream in GluR6-MLK3-JNKs signal transduction pathway following global transient cerebral ischemia, as a result of protecting against neuronal apoptosis and death. Transient cerebral ischemia was induced by the Pulsinelli-Brierley four-vessel occlusion method. FH (15 mg/kg) was administered to rats by intraperitoneal injection 30 min before ischemia. The phosphorylation and protein expression of GluR6 at 6 h during reperfusion were detected using immunoprecipitation and immunoblotting analysis. The phosphorylation and protein expression of Mixed lineage kinase 3 (MLK3) at ischemia/reperfusion (I/R) 6 h and c-Jun N-terminal kinase (JNK) at I/R 3 d were detected using immunoblotting analysis, respectively. The same method was used to detect the expression of caspase-3 at I/R 6 h. Furthermore, we also use TUNEL staining and Cresyl violet staining to examine the survival neurons in rat hippocampal CA1 regions after 3 and 5 d reperfusion, respectively. Our study indicated that FH could inhibit the increased phosphorylation of GluR6 and MLK3 and the expression of caspase-3 at peaked 6 h of reperfusion and the phosphorylation of JNK (3 d) (p < 0.5). The results of TUNEL staining and Cresyl violet showed that the number of surviving pyramidal neurons in rats hippocampal CA1 subfield increased markedly in FH-treated rats compared with ischemic groups after 3 or 5 d of reperfusion following ischemia (p < 0.5). These results suggested that FH, as a ROCK inhibitor, may be partly responsible for its protective effects against such damage by taking part in GluR6-MLK3-JNKs signaling pathway which modulates ischemic damage. Taken together, this is the first study investigating Rho and ROCK as the upstream of GluR6 taking part in GluR6-MLK3-JNKs signal transduction pathway following cerebral ischemia. PMID- 24793643 TI - Prediction of survival in terminally ill cancer patients at the time of terminal cancer diagnosis. AB - PURPOSE: We aimed to investigate the prognostic factors that can predict terminal stage survival (TSS) at the time of terminal cancer diagnosis. METHODS: We prospectively evaluated 141 patients immediately after the diagnosis of terminal cancer by their attending oncologists. A total of 32 factors, including performance status, clinical prediction of survival, time to terminal cancer (TTC), clinical symptoms, signs, and laboratory tests including the neutrophil lymphocyte ratio (NLR), were analyzed. TSS was defined as the time from the diagnosis of terminal cancer to death. RESULTS: The mean age of the 141 patients studied was 58.7 years, and 53 were female (38 %). The median TSS was 1.7 months (95 % confidence interval [CI] 1.43-1.97). In the univariate analyses, the TSS was significantly associated with 16 of the 32 factors tested. In the multivariate analysis, a lower Karnofsky performance status (KPS), a shorter TTC (<24 months), a high NLR (>=5), and a high C-reactive protein (CRP) level (>=10 mg/dL) were independently associated with a poorer prognosis. A scoring system (scale, 0-6) developed based on the multivariate analysis could be used to classify terminal cancer patients into better (0-2 points; TSS 3.9 months), intermediate (3-4 points; TSS 1.7 months), or worse (5-6 points; TSS 0.9 month, P < 0.001) prognosis. CONCLUSION: The median TSS after the diagnosis of terminal cancer in advanced cancer patients was 1.7 months. The scoring system using KPS, TTC, NLR, and CRP could predict TSS in these patients. PMID- 24793644 TI - Trichostatin A effectively induces apoptosis in chronic lymphocytic leukemia cells via inhibition of Wnt signaling and histone deacetylation. AB - BACKGROUND: The ontogenetic Wnt pathway shows almost no activity in adult tissues. In contrast, chronic lymphocytic leukemia (CLL) cells show constitutionally active Wnt signaling, which is associated with upregulated levels of pathway members such as Wnt3 and lymphoid enhancer-binding factor-1. Functionally, this results in increased resistance to apoptosis. We therefore assumed that targeting members of the pathway could reveal new therapeutic options for the treatment of CLL. METHODS: Screening a Wnt compound library with 75 Wnt modulators via ATP assay revealed Trichostatin A as an outstanding substance with strong viability decreasing effects on CLL cells and little effect on healthy peripheral blood mononuclear cells (PBMCs). Further survival analysis was performed via fluorescence-activated cell sorting analysis. RESULTS: A maximum effect was achieved after 48 h with a wide therapeutic window in contrast to PBMCs (CLL cells: 0.253 uM, PBMCs: 145.22 uM). Trichostatin A induced caspases and acted via a dual mechanism to reveal histone and non-histone targets. Histone targets were displayed in deacetylation inhibition at DNA level, and non-histone targeting was demonstrated by elevated levels of Dickkopf-related protein 1 mRNA. Primary cells of patients with critical mutations such as TP53 or those who had already undergone extensive previous treatment responded well to the treatment. Moreover, the approved histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA) was not as effective as Trichostatin A (Trichostatin A: 0.253 uM, SAHA: 7.88 uM). Combining Trichostatin A with established CLL drugs fludarabine or bendamustine showed an additive effect in vitro. CONCLUSION: Taken together, Trichostatin A appears to act via a dual anti HDAC/Wnt mechanism with a high selectivity and efficacy in CLL and therefore warrants further investigation. PMID- 24793645 TI - Perspectives on Tiered Older Driver Assessment in Primary Care Settings. AB - PURPOSE OF THE STUDY: Widespread screening of older drivers, with in-depth evaluation only of those who screen positive ("tiered assessment"), might efficiently balance driver safety and mobility. To inform program development, we sought to examine the perspectives of older drivers and clinicians on the concept of tiered assessment in primary care settings. DESIGN AND METHODS: Iterative focus groups and interviews with 33 community-dwelling current drivers aged >=65 years and 8 primary care providers. We used inductive and deductive theme analysis to explore driver and clinician perspectives and to identify barriers and facilitators to establishing a tiered older driver assessment program in primary care settings. RESULTS: Four dominant themes emerged. Two themes addressed the overall concept: (a) support for the concept of tiered older driver assessment and (b) concerns about the consequences of older driver assessment and how these could affect program viability. Two themes addressed screening: (c) tension inherent in using a generalized approach to the highly individualized issue of driving and (d) logistical considerations for screening in primary care settings. IMPLICATIONS: Standardized older driver screening and referral might improve clinician-driver communication, but screening should occur in a context that includes personalized mobility counseling. PMID- 24793646 TI - Antecedents of Attitudes to Aging: A Study of the Roles of Personality and Well being. AB - PURPOSE OF THE STUDY: Little research has examined factors that contribute to the formation of attitudes toward one's own aging. The current study aimed to examine personality as defined by the Five-Factor model of personality as an antecedent of attitudes, while taking into account demographic and health factors known to be relevant to such attitudes. DESIGN AND METHODS: Participants aged 60 years or older (N = 421) were part of a longitudinal study of health and well-being in Australia, and completed a postal survey comprising measures of personality, the Attitudes to Ageing Questionnaire, the SF-12 health survey, and the Satisfaction with Life Scale. RESULTS: Higher levels of neuroticism were associated with less positive attitudes toward old age as a time of psychological growth, and higher extraversion and agreeableness were significant predictors of less negative attitudes toward psychosocial loss. Baseline measures of self-reported mental and physical health, as well as change in those scores, also made significant contributions to attitudes toward aging. IMPLICATIONS: Personality was a significant antecedent of attitudes towards aging, as were mental and physical health. The data highlight the role of potentially modifiable factors, such as mental and physical health. If these factors act as resources that shape an individual's attitudes during the aging process, then one potential foundation for holding positive attitudes to aging is to maintain physical and mental health. This requires interventions and policies that are effective in encouraging health-promoting behaviors. PMID- 24793647 TI - Effects of adenosine monophosphate-activated kinase in the ventral horn of rabbit spinal cord after transient ischemia. AB - OBJECTIVE: To investigate the effect compound C, an adenosine monophosphate activated kinase (AMPK) inhibitor, has on motor neurons of rabbit spinal cord after ischemia/reperfusion. DESIGN: Compound C (30 mg/kg) was administered intraperitoneally to rabbits 30 minutes before ischemia and the animals were sacrificed at 15 minutes after ischemia/reperfusion to measure lactate levels and at 72 hours after ischemia/reperfusion for morphological study. RESULTS: The administration of compound C did not produce any significant changes in physiological parameters such as pH, arterial blood gas (PaCO(2) and PaO(2)), and blood glucose in rabbit either at 10 minutes before ischemia or at 10 minutes after reperfusion. However, the administration of compound C did significantly ameliorate lactate acidosis at 15 minutes after reperfusion. In addition, the administration of compound C significantly improved the neurological scores of the rabbits and reduced the neuronal death seen in the ventral horn of their spinal cords at 72 hours after ischemia/reperfusion. CONCLUSIONS: Inhibition of AMPK can ameliorate the ischemia-induced neuronal death in the spinal cord via the reduction of early lactate acidosis. PMID- 24793648 TI - Risk factors for mortality and failure of conservative treatment after aortic type B dissection. AB - BACKGROUND: Despite medical treatment, one third of patients with uncomplicated type B aortic dissections experience severe late complications. The aim of this study was to identify patients at high risk of mortality during follow-up. METHODS: A total of 183 patients with acute Stanford type B dissection were treated in one of the university hospitals (Aachen [Germany], Maastricht [The Netherlands], and Innsbruck [Austria]) between 1997 and 2010. Records indicated that 120 patients were treated conservatively. Of these patients, 16 were lost to follow-up. The maximum diameter, extent of the dissection, and patency of the side branches were determined from computed tomography angiography data. Survival and treatment failure were analyzed by univariate and multivariate Cox regression analysis. The univariate analysis investigated the influence of aortic diameter (>=41 vs <41 mm) on survival, and the multivariate analysis investigated the influence of aortic diameter, age, sex, and surgery on survival. RESULTS: During the follow-up period, the initial treatment was converted to surgical treatment in 21 patients (20.2%). Sixteen of the 104 patients (15.4%) died after a mean of 845.5+/-805.9 days. The mean maximum aortic transversal diameter at admission was 41.2+/-8.7 mm. The multivariate analysis identified aortic diameter (P=.004; hazard ratio, 1.07) and age (P=.038; hazard ratio, 1.05) as risk factors that significantly reduce survival. CONCLUSIONS: Our study revealed both early aortic dilatation and older age as risk factors for increased mortality after conservative treatment of type B dissection. PMID- 24793649 TI - Cas1-Cas2 complex formation mediates spacer acquisition during CRISPR-Cas adaptive immunity. AB - The initial stage of CRISPR-Cas immunity involves the integration of foreign DNA spacer segments into the host genomic CRISPR locus. The nucleases Cas1 and Cas2 are the only proteins conserved among all CRISPR-Cas systems, yet the molecular functions of these proteins during immunity are unknown. Here we show that Cas1 and Cas2 from Escherichia coli form a stable complex that is essential for spacer acquisition and determine the 2.3-A-resolution crystal structure of the Cas1-Cas2 complex. Mutations that perturb Cas1-Cas2 complex formation disrupt CRISPR DNA recognition and spacer acquisition in vivo. Active site mutants of Cas2, unlike those of Cas1, can still acquire new spacers, thus indicating a nonenzymatic role of Cas2 during immunity. These results reveal the universal roles of Cas1 and Cas2 and suggest a mechanism by which Cas1-Cas2 complexes specify sites of CRISPR spacer integration. PMID- 24793650 TI - Structural basis for protein-RNA recognition in telomerase. AB - Telomerase is a large ribonucleoprotein complex minimally composed of a catalytic telomerase reverse transcriptase (TERT) and an RNA component (TR) that provides the template for telomeric DNA synthesis. However, it remains unclear how TERT and TR assemble into a functional telomerase. Here we report the crystal structure of the conserved regions 4 and 5 (CR4/5) of TR in complex with the TR binding domain (TRBD) of TERT from the teleost fish Oryzias latipes. The structure shows that CR4/5 adopts an L-shaped three-way-junction conformation with its two arms clamping onto TRBD. Both the sequence and conformation of CR4/5 are required for the interaction. Our structural and mutational analyses suggest that the observed CR4/5-TRBD recognition is common to most eukaryotes, and CR4/5 in vertebrate TR might have a similar role in telomerase regulation as that of stem-loop IV in Tetrahymena TR. PMID- 24793652 TI - Stereochemistry in subcomponent self-assembly. AB - CONSPECTUS: As Pasteur noted more than 150 years ago, asymmetry exists in matter at all organization levels. Biopolymers such as proteins or DNA adopt one-handed conformations, as a result of the chirality of their constituent building blocks. Even at the level of elementary particles, asymmetry exists due to parity violation in the weak nuclear force. While the origin of homochirality in living systems remains obscure, as does the possibility of its connection with broken symmetries at larger or smaller length scales, its centrality to biomolecular structure is clear: the single-handed forms of bio(macro)molecules interlock in ways that depend upon their handednesses. Dynamic artificial systems, such as helical polymers and other supramolecular structures, have provided a means to study the mechanisms of transmission and amplification of stereochemical information, which are key processes to understand in the context of the origins and functions of biological homochirality. Control over stereochemical information transfer in self-assembled systems will also be crucial for the development of new applications in chiral recognition and separation, asymmetric catalysis, and molecular devices. In this Account, we explore different aspects of stereochemistry encountered during the use of subcomponent self-assembly, whereby complex structures are prepared through the simultaneous formation of dynamic coordinative (N -> metal) and covalent (N?C) bonds. This technique provides a useful method to study stereochemical information transfer processes within metal-organic assemblies, which may contain different combinations of fixed (carbon) and labile (metal) stereocenters. We start by discussing how simple subcomponents with fixed stereogenic centers can be incorporated in the organic ligands of mononuclear coordination complexes and communicate stereochemical information to the metal center, resulting in diastereomeric enrichment. Enantiopure subcomponents were then incorporated in self-assembly reactions to control the stereochemistry of increasingly complex architectures. This strategy has also allowed exploration of the degree to which stereochemical information is propagated through tetrahedral frameworks cooperatively, leading to the observation of stereochemical coupling across more than 2 nm between metal stereocenters and the enantioselective synthesis of a face-capped tetrahedron containing no carbon stereocenters via a stereochemical memory effect. Several studies on the communication of stereochemistry between the configurationally flexible metal centers in tetrahedral metal-organic cages have shed light on the factors governing this process, allowing the synthesis of an asymmetric cage, obtained in racemic form, in which all symmetry elements have been broken. Finally, we discuss how stereochemical diversity leads to structural complexity in the structures prepared through subcomponent self-assembly. Initial use of octahedral metal templates with facial stereochemistry in subcomponent self assembly, which predictably gave rise to structures of tetrahedral symmetry, was extended to meridional metal centers. These lower-symmetry linkages have allowed the assembly of a series of increasingly intricate 3D architectures of varying functionality. The knowledge gained from investigating different aspects of the stereochemistry of metal-templated assemblies thus not only leads to new means of structural control but also opens pathways toward functions such as stereoselective guest binding and transformation. PMID- 24793651 TI - Structural basis of starvation-induced assembly of the autophagy initiation complex. AB - Assembly of the preautophagosomal structure (PAS) is essential for autophagy initiation in yeast. Starvation-induced dephosphorylation of Atg13 is required for the formation of the Atg1-Atg13-Atg17-Atg29-Atg31 complex (Atg1 complex), a prerequisite for PAS assembly. However, molecular details underlying these events have not been established. Here we studied the interactions of yeast Atg13 with Atg1 and Atg17 by X-ray crystallography. Atg13 binds tandem microtubule interacting and transport domains in Atg1, using an elongated helix-loop-helix region. Atg13 also binds Atg17, using a short region, thereby bridging Atg1 and Atg17 and leading to Atg1-complex formation. Dephosphorylation of specific serines in Atg13 enhanced its interaction with not only Atg1 but also Atg17. These observations update the autophagy-initiation model as follows: upon starvation, dephosphorylated Atg13 binds both Atg1 and Atg17, and this promotes PAS assembly and autophagy progression. PMID- 24793654 TI - Giant iliopsoas bursa presenting as a large pulsatile groin mass. PMID- 24793653 TI - The consequences of dominance and gene flow for local adaptation and differentiation at two linked loci. AB - For a subdivided population the consequences of dominance and gene flow for the maintenance of multilocus polymorphism, local adaptation, and differentiation are investigated. The dispersing population inhabits two demes in which selection acts in opposite direction. Fitness is determined additively by two linked diallelic loci with arbitrary intermediate dominance (no over- or underdominance). For weak as well as strong migration, the equilibrium structure is derived. As a special case, a continuous-time continent-island model (CI model) is analyzed, with one-way migration from the continent to the island. For this CI model, the equilibrium and stability configuration is obtained explicitly for weak migration, for strong migration, for independent loci, and for complete linkage. For independent loci, the possible bifurcation patterns are derived as functions of the migration rate. These patterns depend strongly on the degree of dominance. The effects of dominance, linkage, and migration on the amount of linkage disequilibrium (LD) and the degree of local adaptation are explored. Explicit formulas are obtained for D (=x1x4-x2x3) and r(2) (the squared correlation in allelic state). They demonstrate that dominant island alleles increase D and decrease r(2). Local adaptation is elevated by dominance of the locally adaptive alleles. The effective migration rate at a linked neutral locus is calculated. If advantageous alleles are dominant, it is decreased only slightly below the actual migration rate. For a quantitative trait that is determined by two additive loci, the influence of dominance on measures of differentiation is studied. Explicit expressions for QST and two types of FST at equilibrium are deduced and their relation is discussed. PMID- 24793655 TI - Synergistic hierarchical silicone-modified polysaccharide hybrid as a soft scaffold to control cell adhesion and proliferation. AB - In this study, a new type of polydimethylsiloxane-modified chitosan (PMSC) amphiphilic hydrogel was developed as a soft substrate to explore cellular responses for dermal reconstruction. The hydrogel wettability, mechanical stiffness and topography were controllable through manipulation of the degree of esterification (DE) between hydrophobic polydimethylsiloxane (PDMS) and hydrophilic N,O-(carboxymethyl)-chitosan (NOCC). Based on microphase separation, the incorporation of PDMS into NOCC increased the stiffness of the hybrid through the formation of self-assembled aggregates, which also provided anchor sites for cell adhesion. As the DE exceeded 0.39, the size of the PDMS-rich aggregates changed from nanoscale to microscale. Subsequently, the hierarchical architecture resulted in an increase in the tensile modulus of the hybrid gel up to fourfold, which simultaneously provided mechano-topographic guidance and allowed the cells to completely spread to form spindle shapes instead of forming a spherical morphology, as on NOCC (DE=0). The results revealed that the incorporation of hydrophobic PDMS not only impeded acidic damage resulting from NOCC but also acted as an adhesion modification agent to facilitate long-term cell adhesion and proliferation on the soft substrate. As proved by the promotion on long-term type I collagen production, the PMSC hybrid with self-assembled mechano-topography offers great promise as an advanced scaffold material for use in healing applications. PMID- 24793656 TI - Three-dimensional hypoxic culture of human mesenchymal stem cells encapsulated in a photocurable, biodegradable polymer hydrogel: a potential injectable cellular product for nucleus pulposus regeneration. AB - Nucleus pulposus (NP) tissue damage can induce detrimental mechanical stresses and strains on the intervertebral disc, leading to disc degeneration. This study demonstrates the potential of a novel, photo-curable, injectable, synthetic polymer hydrogel (pHEMA-co-APMA grafted with polyamidoamine (PAA)) to encapsulate and differentiate human mesenchymal stem cells (hMSC) towards a NP phenotype under hypoxic conditions which could be used to restore NP tissue function and mechanical properties. Encapsulated hMSC cultured in media (hMSC and chondrogenic) displayed good cell viability up to day 14. The genotoxicity effects of ultraviolet (UV) on hMSC activity confirmed the acceptability of 2.5min of UV light exposure to cells. Cytotoxicity investigations revealed that hMSC cultured in media containing p(HEMA-co-APMA) grafted with PAA degradation product (10% and 20%v/v concentration) for 14days significantly decreased the initial hMSC adhesion ability and proliferation rate from 24hrs to day 14. Successful differentiation of encapsulated hMSC within hydrogels towards chondrogenesis was observed with elevated expression levels of aggrecan and collagen II when cultured in chondrogenic media under hypoxic conditions, in comparison with culture in hMSC media for 14days. Characterization of the mechanical properties revealed a significant decrease in stiffness and modulus values of cellular hydrogels in comparison with acellular hydrogels at both day 7 and day 14. These results demonstrate the potential use of an in vivo photo curable injectable, synthetic hydrogel with encapsulated hMSC for application in the repair and regeneration of NP tissue. PMID- 24793657 TI - Porous silicon oxide-PLGA composite microspheres for sustained ocular delivery of daunorubicin. AB - A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO2) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA-DNR microspheres without pSiO2, and pSiO2 microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water emulsion method have mean diameters of 52.33+/-16.37MUm for PLGA-pSiO2_21/40-DNR and the mean diameter of 49.31+/-8.87MUm for PLGA-pSiO2_6/20-DNR. The mean size, 26.00+/-8MUm, of PLGA-DNR was significantly smaller, compared with the other two (P<0.0001). Optical microscopy revealed that PLGA-pSiO2-DNR microspheres contained multiple pSiO2 particles. In vitro release experiments determined that control PLGA-DNR microspheres completely released DNR within 38days and control pSiO2-DNR microparticles (with no PLGA coating) released DNR within 14days, while the PLGA-pSiO2-DNR microspheres released DNR for 74days. Temporal release profiles of DNR from PLGA-pSiO2 composite particles indicated that both PLGA and pSiO2 contribute to the sustained release of the payload. The PLGA-pSiO2 composite displayed a more constant rate of DNR release than the pSiO2 control formulation, and displayed a significantly slower release of DNR than either the PLGA or pSiO2 formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with antiproliferation compounds such as DNR. PMID- 24793659 TI - Predictive value of plasma brain natriuretic peptide for postoperative cardiac complications--a systemic review and meta-analysis. AB - BACKGROUND: We aimed to undertake a systematic review and meta-analysis of studies addressing perioperative natriuretic peptide (NP) levels to predict postoperative major adverse cardiac events (MACE) after major surgery. METHODS: We searched MEDLINE and Embase with no language restrictions up to May 2013. The end points were major cardiac complications. We summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random effects models. RESULTS: Of the 662 retrieved articles, 24 studies satisfied the predefined eligibility criteria, including 5438 patients along with 712 (13.1%) events. After major surgery, the diagnostic odds ratio (DOR) of NP in predicting postoperative MACE was 14.3 (95% confidence interval [CI], 9.87-20.7) for overall population, 13.9 (8.43-22.8) for patients undergoing cardiac surgery, and 15.0 (8.84-25.5) for patients undergoing noncardiac surgery. The pooled sensitivity was 0.84 (95% CI, 0.79-0.88) and specificity was 0.76 (95% CI, 0.71-0.81). Postoperative measurement (DOR, 18.9; 7.68-46.3) was associated with higher predictive value than preoperative measurement (DOR, 13.6; 7.68-46.3). Results were similar for a subgroup with the composite outcome including mortality (DOR, 16.4; 10.6-25.5). B type natriuretic peptide was associated with higher predictive accuracy (area under the summary receiver operating characteristic, 0.84; 0.81-0.87) than N terminal pro-b-type natriuretic peptide (area under the summary receiver operating characteristic, 0.90; 0.87-0.92). CONCLUSIONS: The existing literature suggests that perioperative NP testing have reasonable accuracy and can be useful in perioperative risk stratification. Natriuretic peptide testing has high rule out value and low rule-in value for predicting postoperative MACE. Medical decisions should be made in the context of these characteristics. PMID- 24793658 TI - Comparison of invasive and noninvasive positive pressure ventilation delivered by means of a helmet for weaning of patients from mechanical ventilation. AB - PURPOSE: The effectiveness of noninvasive positive pressure ventilation delivered by helmet (H-NPPV) as a weaning approach in patients with acute respiratory failure is unclear. PATIENTS AND METHODS: We randomly and evenly assigned 64 patients intubated for acute respiratory failure to conventional weaning with invasive mechanical ventilation (IMV) or H-NPPV. The primary end point was a reduction in IMV duration by 6 days between the 2 groups. Secondary end points were the occurrence of ventilator-associated pneumonia and major complications, duration of mechanical ventilation and weaning, intensive care unit and hospital length of stay, and survival. RESULTS: The mean duration of IMV was significantly reduced in the H-NPPV group compared with the IMV group (P<.0001), without significant difference in duration of weaning (P=.26) and total ventilatory support (P=.45). In the H-NPPV group, the incidence of major complications was less than the IMV group (P=.032). Compared with the H-NPPV group, the IMV group was associated with a greater incidence of VAP (P=.018) and an increased risk of nosocomial pneumonia (P=.049). The mortality rate was similar between the groups, with no significant difference in overall intensive care unit (P=.47) or hospital length of stay (P=.37). CONCLUSIONS: H-NPPV was well tolerated and effective in patients who were difficult to wean. PMID- 24793660 TI - Successful weaning and decannulation after interventional bronchoscopic recanalization of tracheal stenosis. AB - PURPOSE: Early posttracheostomy tracheal stenosis (PTTS) may cause weaning and decannulation failure. Although bronchoscopic recanalization offers an effective treatment, it is not known how successfully patients can be weaned and decannulated after recanalization. The aims of this study were to determine the incidence of PTTS in a modern weaning center and to elucidate the benefit of interventional recanalization in terms of weaning and decannulation success. MATERIALS AND METHODS: A total of 722 patients admitted within a 24-month period were examined. Patients' baseline characteristics, incidence of weaning and decannulation failure, incidence of PTTS, and rate of postinterventional weaning and decannulation success were determined. RESULTS: Of 722 patients, 450 were deemed suitable for weaning from invasive ventilation. Two hundred eighty-eight patients showed initial weaning and decannulation failure, and 14 of these 288 patients (4.9%) were found to have a PTTS. Recanalization was performed in all cases without procedure-associated complications. Ten (71%) of 14 patients could be successfully weaned and decannulated. Seven of these 10 patients were discharged, 3 patients died during the hospital stay, and 4 (29%) of 14 patients could not be weaned. CONCLUSIONS: Posttracheostomy tracheal stenosis remains a relevant cause of weaning and decannulation failure. Bronchoscopic recanalization is safe and facilitates weaning and successful decannulation in about half of the cases. PMID- 24793661 TI - Duration of prehospital intubation is not a risk factor for development of early ventilator-associated pneumonia. AB - PURPOSE: Ventilator-associated pneumonia (VAP) is a significant cause of morbidity and mortality among critically ill patients with trauma. Few VAP prevention strategies have been studied in the prehospital environment. The objectives of this study are to measure the association between duration of prehospital intubation and intubation location with subsequent incidence of early (within 5 days) VAP. MATERIALS AND METHODS: Single-center retrospective cohort study of all intubated adult (age>=18 years) patients with trauma presenting to a 711-bed Midwestern Level I trauma center between January 2005 and December 2011 (n=860). RESULTS: Thirty-five patients (6.4%) were diagnosed as having early VAP during the study period. Using multivariable logistic regression to adjust for age, injury severity score, and year (corresponding to VAP bundle implementation), the duration of intubation prior to hospital admission was not associated with subsequent diagnosis of VAP (adjusted odds ratio, 0.90 per hour; 95% confidence interval, 0.70-1.15). Location of intubation was similarly not associated with VAP. CONCLUSIONS: Duration of prehospital intubation and intubation location were not different in patients with trauma who developed early VAP. Further prospective analyses should be conducted to better elucidate the effect of prehospital management on the development of traditionally in hospital complications. PMID- 24793662 TI - Sign of the times? Gender, sexuality, and drinking stories. PMID- 24793663 TI - Decay of enteric microorganisms in biosolids-amended soil under wheat (Triticum aestivum) cultivation. AB - There is a growing need for better assessment of health risks associated with land-applied biosolids. This study investigated in-situ decay of seeded human adenovirus (HAdV), Salmonella enterica, Escherichia coli, and bacteriophage (MS2) in biosolids-amended soil under wheat cultivation. The biosolids seeded with microorganisms were placed in decay chambers which were then placed in the topsoil (10 cm depth) at three different sites. Sites were selected in arid wheat growing regions of Australia with loamy-sand soil type (Western Australia) and sandy soil (South Australia). Seeded E. coli and S. enterica had a relatively short decay time (T90 = 4-56 days) in biosolids-amended soil compared to un amended soil (T90 = 8-83 days). The decreasing soil moisture over the wheat growing season significantly (P < 0.05) influenced survival time of both bacteria and MS2 at Western Australia (Moora) and South Australia (Mt Compass) sites, particularly in the un-amended soils. Increasing soil temperature also significantly (P < 0.05) influenced the decay of MS2 at these sites. In this study, no notable decline in HAdV numbers (PCR detectable units) was observed in both biosolids-amended and the un-amended soils at all three sites. The HAdV decay time (T90 >= 180 days) in biosolids-amended and un-amended soils was significantly higher than MS2 (T90 = 22-108 days). The results of this study suggest that adenovirus could survive for a longer period of time (>180 days) during the winter in biosolids-amended soil. The stability of adenovirus suggests that consideration towards biosolids amendment frequency, time, rates and appropriate withholding periods are necessary for risk mitigation. PMID- 24793664 TI - Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test. AB - Zebrafish embryos were exposed to concentration ranges of selected thyroid-active model compounds in order to assess the applicability of zebrafish-based developmental scoring systems withinan alternative testing strategy to detect the developmental toxicity ofthyroid-active compounds. Model compounds tested included triiodothyronine (T3), propylthiouracil (PTU), methimazole (MMI), sodium perchlorate (NaClO4) and amiodarone hydrochloride (AMI), selected to represent different modes of action affecting thyroid activity. Tested time windows included 48-120 hours post fertilization (hpf), 0-72 hpf and 0-120 hpf. All tested compounds resulted in developmental changes, with T3 being the most potent. The developmental parameters affected included reflective iridophores, beat and glide swimming, inflated swim bladders, as well as resorbed yolk sacs. These effects are only evident by 120 hpf and therefore an existing General Morphology Score (GMS) system was extended to create a General Developmental Score(GDS) that extends beyond the 72 hpfscoring limit of GMS and includes additional parameters that are affected by exposure to model thyroid-active compounds. Moreover, the GDS is cumulative as it includes not only the scoring of developmental morphologies but also integrates developmental dysmorphologies. Exposures from 48-120 hpf did not provide additional information to exposures from 0-120 hpf. The results indicate that the zebrafish GDS can detect the developmental toxicity of thyroid toxicants and may be of use in an integrated testing strategy to reduce, refine and in certain cases replace animal testing. PMID- 24793665 TI - 'As long as they are safe--birth mode does not matter' Swedish fathers' experiences of decision-making around caesarean section. AB - BACKGROUND: Decision-making in childbirth involves considerations about both the mother and her unborn baby's wellbeing. For men the safety of both is paramount. AIM: To explore and describe Swedish fathers' beliefs and attitudes around the decision for a caesarean section. METHODS: Qualitative descriptive study. Twenty one Swedish men whose partners had experienced elective or emergency caesarean participated in a telephone interview. Thematic data analysis was used. FINDINGS: The theme, 'Childbirth is Risky', included "Caesarean birth has lots of advantages" and "Birth mode does not matter". In the context of having experienced a caesarean section male partners considered birth mode to be irrelevant. The majority considered caesarean to be a quick and efficient way of giving birth which equated to being safer. Most men could articulate some risks associated with caesarean but these were mainly minimised. The second theme, 'Simply a matter of trust: Birth mode is not my decision', reflected men's belief that they had little to contribute to the decisions made around birth mode. The decision for a caesarean section was considered to lie with the medical practitioner. CONCLUSION: Mode of birth was regarded as unimportant. The recommendation for a caesarean section was readily accepted and appreciated, and shifted responsibility for birth to the medical practitioner. Involving men in the decision-making process by means of giving them information was valued. Men's limited knowledge about the risks of a caesarean may contribute to birth mode decisions. Professionals need to provide balanced and correct information within the context of individual circumstances. PMID- 24793666 TI - Effects of P2Y12 receptor inhibition in patients with ST-segment elevation myocardial infarction. AB - In ST-segment elevation myocardial infarction (STEMI), an effective antiplatelet treatment adjunctive to primary percutaneous coronary intervention is of utmost importance. High dose of clopidogrel, prasugrel, or ticagrelor provides a faster, more potent, and more consistent platelet inhibition than standard clopidogrel. Oral P2Y12 inhibitors have been studied in large clinical trials and are in use in clinical practice. Intravenously administered P2Y12 inhibitors such as cangrelor have also been tested. However, statistically significant anti-ischemic superiority of stronger platelet inhibition regimens versus standard clopidogrel has not been proved exclusively in patients receiving primary percutaneous coronary intervention. Whether orally administered antiplatelet agents suffice in patients with STEMI has been recently disputed, mainly because of their delayed onset of action. Platelet reactivity variability before P2Y12 blockade and its evolution over time, genetic predisposition, antiplatelet agent used, timing, and method of platelet function testing significantly affect the rates of high on treatment platelet reactivity. Although ominous signs of greater bleeding potential of stronger antiplatelet regimens have not appeared in STEMI, this should be carefully tested. PMID- 24793667 TI - Combined score using clinical, electrocardiographic, and echocardiographic parameters to predict left ventricular remodeling in patients having had cardiac resynchronization therapy six months earlier. AB - The aim of this study was to evaluate whether a scoring system integrating clinical, electrocardiographic, and echocardiographic measurements can predict left ventricular reverse remodeling after cardiac resynchronization therapy (CRT). The derivation cohort consisted of 162 patients with heart failure implanted with a CRT device. Baseline clinical, electrocardiographic, and echocardiographic characteristics were entered into univariate and multivariate models to predict reverse remodeling as defined by a >=15% reduction in left ventricular end-systolic volume at 6 months (60%). Combinations of predictors were then tested under different scoring systems. A new 7-point CRT response score termed L2ANDS2: Left bundle branch block (2 points), Age >70 years, Nonischemic origin, left ventricular end-diastolic Diameter <40 mm/m(2), and Septal flash (2 points) was calculated for these patients. This score was then validated against a validation cohort of 45 patients from another academic center. A highly significant incremental predictive value was noted when septal flash was added to an initial 4-factor model including left bundle branch block (difference between area under the curve C statistics = 0.125, p <0.001). The predictive accuracy using the L2ANDS2 score was then 0.79 for the C statistic. Application of the new score to the validation cohort (71% of responders) gave a similar C statistic (0.75). A score >5 had a high positive likelihood ratio (+LR = 5.64), whereas a score <2 had a high negative likelihood ratio (-LR = 0.19). In conclusion, this L2ANDS2 score provides an easy-to-use tool for the clinician to assess the pretest probability of a patient being a CRT responder. PMID- 24793668 TI - Effect of sustaining lifestyle modifications (nonsmoking, weight reduction, physical activity, and mediterranean diet) after healing of myocardial infarction, percutaneous intervention, or coronary bypass (from the REasons for Geographic and Racial Differences in Stroke Study). AB - Guidelines recommend lifestyle modification for patients with coronary heart disease (CHD). Few data demonstrate which lifestyle modifications, if sustained, reduce recurrent CHD and mortality risk in cardiac patients after the postacute rehabilitation phase. We determined the association between ideal lifestyle factors and recurrent CHD and all-cause mortality in REasons for Geographic and Racial Differences in Stroke study participants with CHD (n = 4,174). Ideal lifestyle factors (physical activity >=4 times/week, nonsmoking, highest quartile of Mediterranean diet score, and waist circumference <88 cm for women and <102 cm for men) were assessed through questionnaires and an in-home study visit. There were 447 recurrent CHD events and 745 deaths over a median 4.3 and 4.5 years, respectively. After multivariable adjustment, physical activity >=4 versus no times/week and non-smoking versus current smoking were associated with reduced hazard ratios (HRs; 95% confidence interval [CI]) for recurrent CHD (HR 0.69, 95% CI 0.54 to 0.89 and HR 0.50, 95% CI 0.39 to 0.64, respectively) and death (HR 0.71, 95% CI 0.59 to 0.86 and HR 0.53, 95% CI 0.44 to 0.65, respectively). The multivariable-adjusted HRs (and 95% CIs) for recurrent CHD and death comparing the highest versus lowest quartile of Mediterranean diet adherence were 0.77 (95% CI 0.55 to 1.06) and 0.84 (95% CI 0.67 to 1.07), respectively. Neither outcome was associated with waist circumference. Comparing participants with 1, 2, and 3 versus 0 ideal lifestyle factors (non-smoking, physical activity >=4 times/week, and highest quartile of Mediterranean diet score), the HRs (and 95% CIs) were 0.60 (95% CI 0.44 to 0.81), 0.49 (95% CI 0.36 to 0.67), and 0.38 (95% CI 0.21 to 0.67), respectively, for recurrent CHD and 0.65 (95% CI 0.51 to 0.83), 0.57 (95% CI 0.43 to 0.74), and 0.41 (95% CI 0.26 to 0.64), respectively, for death. In conclusion, maintaining smoking cessation, physical activity, and Mediterranean diet adherence is important for secondary CHD prevention. PMID- 24793669 TI - Effect of one-cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention. AB - Up to 1/3 of percutaneous coronary interventions (PCIs) are complicated by troponin release. Remote ischemic preconditioning (IPC) confers effective cardioprotection; however, a 30-minute remote IPC protocol may be difficult to implement during ad hoc PCI. This study was performed to assess the ability of a brief remote IPC protocol to attenuate cardiac troponin I (cTnI) release after ad hoc PCI. Ninety-four patients undergoing ad hoc PCI for stable coronary artery disease, with undetectable preprocedural cTnI, were recruited and randomized to receive remote IPC (induced by one 5-minute inflation of a blood pressure cuff to 200 mm Hg around the upper arm) or control after the decision for PCI was made. The primary outcome was the difference between cTnI levels 24 hours after PCI and cTnI levels before coronary angiography (DeltacTnI). DeltacTnI in the remote IPC group was significantly lower compared with the control group (0.04 ng/ml [interquartile range 0.01 to 0.14] vs 0.19 ng/ml [interquartile range 0.18 to 0.59], p <0.001). The incidence of PCI-related myocardial infarction (MI) was greater in the control group (42.6% vs 19.1%, p = 0.014). In multivariate analysis, remote IPC was independently associated with DeltacTnI and PCI-related MI. In conclusion, our results suggest that even 1 cycle of remote IPC immediately before ad hoc PCI attenuates periprocedural cTnI release and reduces the incidence of type 4a MI. PMID- 24793670 TI - Impact of female gender on bleeding complications after transradial coronary intervention (from the Korean Transradial Coronary Intervention registry). AB - Besides poor clinical outcomes, female gender has been known as a high-risk factor for bleeding complications. This study aimed to investigate the impact of gender on clinical outcomes and bleeding complications after transradial coronary intervention (TRI). The Korean TRI registry is a retrospective multicenter registry with 4,890 patients who underwent percutaneous coronary intervention in 2009 at 12 centers. To compare clinical outcomes and bleeding complications between the male and female groups, we performed a propensity score matching in patients who received TRI. A total of 1,194 patients (597 in each group) were studied. The primary outcome was 1-year major adverse cardiac events, including all-cause mortality, myocardial infarction, target vessel revascularization, and stroke. The secondary outcome was major bleeding (composite of bleeding requiring transfusion of >=2 units of packed cells or bleeding that was fatal). The proportion of major adverse cardiac events was similar between the 2 groups (6.2% vs 4.7%, p = 0.308). The female group had a greater incidence of major bleeding (0.3% vs 3.2%, p <0.001). On multivariate analysis, female gender (odds ratio [OR] 7.748, 95% confidence interval [CI] 1.767 to 13.399), age >=75 years (OR 5.824, 95% CI 2.085 to 16.274), and chronic kidney disease (OR 7.264, 95% CI 2.369 to 12.276) were independent predictors of major bleeding. In conclusion, the female gender had a tendency for more bleeding complications than male gender after TRI without difference in the clinical outcome. PMID- 24793671 TI - Prevalence of guideline-directed medical therapy among patients receiving cardiac resynchronization therapy defibrillator implantation in the National Cardiovascular Data Registry during the years 2006 to 2008. AB - Cardiac resynchronization therapy (CRT) reduces morbidity and mortality among selected patients with left ventricular systolic dysfunction and severe heart failure symptoms despite guideline-directed medical therapy (GDMT). Contemporaneous guidelines provided clear recommendations regarding selection of patients for CRT, including that all patients should first receive GDMT with beta blockers and renin-angiotensin axis antagonists. Prevalence of GDMT among real world patients receiving CRT defibrillators (CRT-D) has not been well studied. We identified 45,392 patients in the National Cardiovascular Data Registry Implantable Cardioverter-Defibrillator Registry who underwent first CRT-D implantation for primary prevention of sudden death from January 2006 to June 2008. We calculated the proportion of patients with contemporaneous class I guideline indications for CRT-D, the proportion receiving GDMT for heart failure, and the proportion receiving GDMT who had class I guideline indications for CRT D. Among patients without contraindications, 87% were prescribed beta blockers, 78% an angiotensin-converting enzyme inhibitor or an angiotensin II receptor inhibitor, and 70% both a beta blocker and an angiotensin-converting enzyme or angiotensin II receptor inhibitor at discharge. Finally, 50% of patients met class I guideline indications and were prescribed GDMT at discharge; 9% neither met class I indications nor were prescribed GDMT at discharge. The major limitation of this study is the lack of dosage information in the Implantable Cardioverter-Defibrillator Registry and lack of prescribing information at times other than discharge. In conclusion, many patients receiving CRT-D are not receiving GDMT at discharge. Ensuring that all patients receiving CRT-D are also receiving GDMT appears to be a quality improvement target. PMID- 24793672 TI - Prognostic implications of prominent R wave in electrocardiographic leads V1 or V2 in patients with acute coronary syndrome. AB - Although the adverse prognosis of Q-waves on electrocardiogram (ECG) has been demonstrated, the prognostic significance of prominent R wave (PRW) in V1 or V2 across a broad spectrum of acute coronary syndrome (ACS) has not been specifically studied. In the Global Registry of Acute Coronary Events (GRACE) and the Canadian ACS Registry I ECG substudies, admission ECGs were analyzed in an independent core ECG laboratory. PRW was defined as R wave >40 to 50 ms in V1 or V2, R/S >=1 in V1, or R/S >=1.5 in V2. Among 11,895 patients with ACS, 495 (4.2%) had PRW; they were less likely to have a history of hypertension or heart failure and had lower GRACE risk scores, but a higher incidence of ST-segment depression (all p <=0.001). Patients with PRW had similar rates of in-hospital death (2.8% vs 4.1%, respectively, p = 0.15) but lower rates of in-hospital heart failure (8.5% vs 15.2%, respectively, p = 0.02) and 6-month mortality (4.6% vs 8.4%, respectively, p = 0.004). In multivariable analyses, PRW was not a significant independent predictor of in-hospital mortality (adjusted odds ratio = 0.99, 95% confidence interval 0.55 to 1.8) or 6-month mortality (adjusted odds ratio = 0.70, 95% confidence interval 0.43 to 1.15). Among 4,418 patients who underwent coronary angiography, those with PRW had a higher prevalence of left circumflex artery disease (62.5% vs 49.5%, respectively, p = 0.01). In conclusion, across the broad spectrum of patients with ACS, PRW provides no significant additional prognostic utility beyond comprehensive risk assessment using the GRACE risk score. PRW is more frequently associated with left circumflex artery disease. PMID- 24793673 TI - Statin and the risk of renal-related serious adverse events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and other placebo-controlled trials. AB - A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls. PMID- 24793674 TI - Analysis of the invasive strategy decision in patients with acute coronary syndrome without ST-segment elevation in a real-world setting. AB - Observational studies have reported a marked discrepancy between the risk estimated by scores and the use of an invasive strategy in patients with acute coronary syndromes. The objective is to describe the criteria used to decide an early invasive strategy and to determine the differences between those criteria and the thrombolysis in myocardial infarction risk score (TRS). Patients entered to the Epi-Cardio registry with a diagnosis of non-ST-elevation acute coronary syndrome were analyzed. A logistic regression model including variables associated with an early invasive strategy was developed and validated in 2 consecutive cohorts. The association between the TRS and the clinical decision model with an early invasive strategy was evaluated by receiver operating characteristic (ROC) curves. We included a total of 3,187 patients. In the derivation cohort, variables associated with an early invasive strategy were previous angioplasty (odds ratio [OR] 1.63), hypercholesterolemia (OR 1.36), ST changes (OR 1.49), elevated biomarkers (OR 1.42), catheterization laboratory availability (OR 1.7), recurrent angina (OR 3.45), age (OR 0.98), previous coronary bypass (OR 0.65), previous heart failure (OR 0.40), and heart rate at admission (OR 0.98). The areas under the ROC curves to predict invasive strategy were 0.55 for the TRS and 0.69 for the clinical decision model, p <0.0001. In the validation cohort, ROC areas were 0.58 and 0.70, respectively, p <0.0001. In conclusion, invasive strategy was guided by variables not completely included in risk scores. The clinical, evolutionary, and structural variables included in the model can explain, partially, the discordance existing between risk stratification and medical strategies. PMID- 24793675 TI - Performance of bleeding risk-prediction scores in patients with atrial fibrillation undergoing percutaneous coronary intervention. AB - The hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, and drugs/alcohol (HAS-BLED); anticoagulation and risk factors in atrial fibrillation (ATRIA); modified Outpatient Bleeding Risk Index (mOBRI); and reduction of atherothrombosis for continued health (REACH) schemes are validated bleeding risk prediction tools, but their predictive performance in patients with AF receiving multiple antithrombotic drugs after percutaneous coronary intervention (PCI) is unknown. We sought to compare the predictive performance of bleeding risk estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing PCI. Management of patients with AF undergoing coronary artery stenting is a multicenter European prospective registry enrolling patients with AF undergoing PCI. We calculated HAS-BLED, ATRIA, mOBRI, and REACH bleeding risk-prediction scores and assessed the rate of bleeding complications as defined by Bleeding Academic Research Consortium at 12 months follow-up in 929 consecutive patients undergoing PCI. Increasing age, femoral access site, and previous peptic ulcer were independent determinants of bleeding. Low bleeding risk scores as determined by HAS-BLED 0 to 2, ATRIA 0 to 3, mOBRI 0, and REACH 0 to 10 were detected in 23.7%, 73.0%, 7.8%, and 5.7% of patients of the cohort, respectively. No significant differences were detected in the rates of any bleeding or major bleeding events for low versus intermediate/high scores with each risk-prediction tool. In conclusion, the performance of ATRIA, HAS-BLED, mOBRI, and REACH scores in predicting bleeding complications in this high-risk patient subset was useless. PMID- 24793676 TI - Relation of long-term exposure to air pollution to brachial artery flow-mediated dilation and reactive hyperemia. AB - Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may, in part, explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function has not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow-mediated dilation%, and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 [53%] women, mean age 49 +/- 14 years). Spatially resolved average PM2.5 was associated with lower flow-mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 MUg/m(3)) was associated with 0.16% (95% confidence interval [CI] -0.27%, -0.05%) lower flow-mediated dilation% and -0.72 (95% CI -1.38, -0.06) cm/s lower hyperemic flow velocity%. Residential proximity to a major roadway was negatively associated with flow-mediated dilation%. Compared with living >=400 m away, living <50 m from a major roadway was associated with 0.32% lower flow-mediated dilation (95% CI -0.58%, -0.06%), but results for hyperemic flow velocity had wide confidence intervals -0.68 cm/s (95% CI -2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults. PMID- 24793677 TI - Long-term outcomes of percutaneous coronary interventions or coronary artery bypass grafting for left main coronary artery disease in octogenarians (from a Drug-Eluting stent for LefT main Artery registry substudy). AB - Percutaneous coronary intervention (PCI) with drug-eluting stents is an accepted alternative to surgery for the treatment of unprotected left main coronary artery (ULMCA) disease, but the long-term outcome in elderly patients is unclear. Aim of our study was to compare the clinical outcomes of octogenarians with ULMCA disease treated either with PCI with drug-eluting stents or coronary artery bypass grafting (CABG). The primary study end point was the composite of death, cerebrovascular accident, and myocardial infarction at follow-up. A total of 304 consecutive patients with ULMCA stenosis treated with PCI or CABG and aged >=80 years were selected and analyzed in a large multinational registry. Two hundred eighteen were treated with PCI and 86 with CABG. During the hospitalization, a trend toward a higher mortality rate was reported in PCI-treated patients (3.5% vs 7.3%, p = 0.32). At a median follow-up of 1,088 days, the incidence of the primary end point was similar in the 2 groups (32.6% vs 30.2%, p = 0.69). Incidence of target vessel revascularization at follow-up was higher in PCI treated patients (10% vs 4.2%, p = 0.05). At multivariate analysis, left ventricular ejection fraction was the only independent predictor of the primary end point (hazard ratio 0.95, 95% confidence interval 0.91 to 0.98, p = 0.001). After adjustment with propensity score, the revascularization strategy was not significantly correlated to the incidence of the primary end point (hazard ratio 0.98, 95% confidence interval 0.57 to 1.71, p = 0.95). In octogenarians, no difference was observed in the occurrence of the primary end point after PCI or CABG for the treatment of ULMCA disease. However, the rate of target vessel revascularization was higher in the PCI group. PMID- 24793678 TI - Application of the "hybrid approach" to chronic total occlusions in patients with previous coronary artery bypass graft surgery (from a Contemporary Multicenter US registry). AB - Percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) has been traditionally associated with lower success rates in patients with previous coronary artery bypass graft surgery (CABG). We sought to examine the success and complication rates of CTO PCI using the "hybrid" crossing algorithm among patients with a history of previous CABG. The procedural outcomes of 496 consecutive CTO PCIs performed at 5 high-volume PCI centers in the United States from January 2012 to August 2013 were assessed. The outcomes of patients with previous CABG were compared with those of patients without previous CABG. Compared with patients without previous CABG (n = 320), patients with previous CABG (n = 176, 35%) were older, had more coronary artery disease risk factors, and had less favorable baseline angiographic CTO characteristics. Technical and procedural success was slightly lower among patients with previous CABG (88.1% vs 93.4%, p = 0.044 and 87.5 vs 92.5%, p = 0.07, respectively). Patients with previous CABG more commonly underwent CTO PCI using the retrograde approach (39% vs 24%, respectively, p <0.001) and received higher air kerma radiation exposure (4.8 [interquartile range 3.0 to 6.4] vs 3.1 [1.9 to 5.3] Gray, p <0.001) and fluoroscopy time (59 [38 to 77] vs 34 [21 to 55] minutes, p <0.001). Major procedural complications were similar in the 2 groups: 2 of 176 (1.1%) patients with previous CABG versus 7 of 320 (2.1%) patients without previous CABG (p = 0.40). In conclusion, with application of the "hybrid" approach to CTO PCI, success was slightly lower, and complication rates were similar between patients with and without previous CABG. PMID- 24793679 TI - Electrocardiographic markers of repolarization heterogeneity during dofetilide or sotalol initiation for paroxysmal atrial fibrillation. AB - Serial electrocardiographic monitoring of DeltaQTc as an assumed harbinger of proarrhythmia is currently recommended for dofetilide and sotalol initiation. Markers of repolarization heterogeneity such as increased peak to end of T-wave (TpTe) duration and abnormal T-wave morphology may also predict proarrhythmia. We investigated whether such T-wave measurements on baseline electrocardiogram will correlate with DeltaQTc after drug initiation. An analysis of 140 consecutive patients with paroxysmal atrial fibrillation hospitalized in sinus rhythm for sotalol or dofetilide initiation was performed. Baseline and serial electrocardiograms were analyzed using QT Guard Plus software (GE Healthcare), which measured QTc and TpTe and scored T-wave morphology for asymmetry, notching, and flatness using T-wave vector magnitude and principal component analysis algorithms. Sotalol and dofetilide were administered in 71% and 29% of patients, respectively. Mean age was 61 +/- 14 years, and 34% were women. After a single dose of either drug, there was a statistically significant increase in QTc and TpTe (p <0.01), as well as composite and individual T-wave markers of repolarization heterogeneity (p <0.01). QTc increased by a mean of 19 +/- 30 ms after initial antiarrhythmic dose. DeltaQTc was inversely related to baseline QTc and TpTe (p <0.01). After controlling for baseline QTc, there was no independent association between T-wave markers of repolarization heterogeneity and DeltaQTc. In conclusion, for patients with paroxysmal atrial fibrillation admitted for dofetilide or sotalol loading, T-wave markers of increased repolarization heterogeneity are measurable within hours after initiation. A shorter baseline QTc is associated with an increased DeltaQTc; however, there is no independent relation between baseline T-wave markers of repolarization heterogeneity and DeltaQTc. PMID- 24793680 TI - Face-specific capacity limits under perceptual load do not depend on holistic processing. AB - Previous observations that face recognition may proceed automatically, without drawing on attentional resources, have been challenged by recent demonstrations that only a few faces can be processed at one time. However, a question remains about the nature of the stimulus properties that underlie face-specific capacity limits. Two experiments showed that speeded categorization of a famous face (such as a politician or pop star) is facilitated when it is congruent with a peripheral distractor face. This congruency effect is eliminated if the visual search is loaded with more than one face, unlike previous demonstrations of speeded classification using semantic information. Importantly, congruency effects are also eliminated when the search task is loaded with nontarget faces that are shown in an inverted orientation. These results indicate that face specific capacity limits are not determined by the configural ("holistic") properties of face recognition. PMID- 24793681 TI - Evidence for the automatic processing of prelexical codes in an orthographic but not a phonological task. AB - The automatic activation of phonological and orthographic information in auditory and visual word processing was examined using a task-set procedure. Participants engaged in a phonological task (i.e., determining whether the letter "a" in a word sounded like /e/ or /ae/) or an orthographic task (i.e., determining whether the sound /s/ in a word was spelled with an "s" or a "c"). Participants were cued regarding which task to perform simultaneously with, or 750 ms before, a clear or degraded target. The stimulus clarity effect (i.e., clear words responded to faster than degraded words) was absorbed into the time that it took participants to identify the task on the basis of the cue in a simultaneous cue-target as compared to a delayed cue-target condition, but only for the orthographic task. These data are consistent with the claim that prelexical processing occurs in a capacity-free manner upon stimulus presentation when participants are trying to extract orthographic codes from words presented in the visual and auditory modalities. Such affirmative data were not obtained when participants attempted to extract phonological codes from words, since here the effects of stimulus clarity and cue delay were additive. PMID- 24793682 TI - Assessment of different threshold preoperative glomerular filtration rates as markers of outcomes in lung transplantation. AB - BACKGROUND: The evidence behind the widely used pre-lung transplant glomerular filtration rate (GFR) cutoff of 50 mL/min per 1.73 m2 is limited. This study reviews data from a large cohort to assess outcomes associated with this historical cutoff and to estimate other possible cutoffs that might be appropriate in lung transplantation. METHODS: We conducted a retrospective cohort analysis of lung recipients at a single center. Recursive partitioning and receiver operating characteristics analysis were used to estimate other potential GFR cutoffs with 1-year mortality as the outcome. Postoperative outcomes around the various cutoffs, including survival, acute kidney injury, and dialysis, were assessed using chi2, Kaplan-Meier, and Cox regression methods. RESULTS: A total of 794 lung recipients met study inclusion criteria. Compared with 778 patients with GFR 50 mL/min per 1.73 m2 or greater at time of transplant, 16 patients with GFR below this cutoff were older and more likely to have restrictive disease. One year mortality below the cutoff was 31.3% compared with 15.1% above the cutoff (p=0.021). Recursive partitioning estimated potential GFR cutoff values between 46 and 61 mL/min per 1.73 m2. Patients with GFR below these cutoffs were at significantly higher risk for adverse outcomes (p<0.05). Receiver operating characteristics analysis was less successful at identifying meaningful cutoff values with areas under the curve approximately 0.5. CONCLUSIONS: Study results support the practice of requiring candidate GFR 50 mL/min per 1.73 m2 or greater for lung transplantation. Future work should focus on reproducing the analysis in a larger cohort of patients including more individuals with low GFR. PMID- 24793683 TI - Management and outcomes of heterotaxy syndrome associated with pulmonary atresia or pulmonary stenosis. AB - BACKGROUND: Historic outcomes of patients with heterotaxy and pulmonary atresia or pulmonary stenosis (PA/PS) have been poor and in the current era are incompletely described. We reviewed our management of these patients and associated risk factors for death. METHODS: We retrospectively reviewed the records of all patients with heterotaxy and PA/PS treated in our institution from January 1, 2002, to August 31, 2012. Death data were also confirmed with the Social Security Death Index. The log-rank test was done to assess six risk factors for death. RESULTS: We identified 42 patients with heterotaxy and PA/PS. Median age at the first operation was 6.5 days, and median follow-up was 3.5 years. Death data were complete for all patients. Overall mortality was 19% (8 of 42). The 30-day, 1-year, and 5-year mortality estimation was 4.76%, 12.3%, and 19.1% respectively, as determined by the Kaplan-Meier method. The log-rank test showed total anomalous pulmonary venous return (TAPVR) (p<0.05) and obstructed TAPVR requiring an operation at less than 30 days (p=0.001) were significant risk factors for death. CONCLUSIONS: In the current era, surgical treatment of heterotaxy and PA/PS can result in good outcomes. Associated TAPVR and obstructed TAPVR requiring neonatal correction were noted to be risk factors for death. PMID- 24793684 TI - Emergent pneumonectomy for lung gangrene: does the outcome warrant the procedure? AB - BACKGROUND: Sloughing and gangrene of a complete lung are only very infrequently encountered complications of necrotizing pneumonia and fulminant pulmonary abscess formation. Thus far the role of emergent pneumonectomy is not established. METHODS: The outcome of patients who underwent anatomic lung resection for lung gangrene at 3 centers for thoracic surgery during the last 13 years was retrospectively analyzed. Only cases of necrotizing pneumonia were included whereas malignant lesions were excluded. RESULTS: Overall 44 patients were indentified (average age 56.3 years). Pulmonary sepsis (27 of 44), pleural empyema (29 of 44), persistent air leakage (14 of 44), and respiratory failure with mechanical ventilation (14 of 44) were present preoperatively. The mean Charlson comorbidity index was 2.77. Procedures were segmentectomy (7), lobectomy (26), and pneumonectomy (11). In-hospital mortality was 7 of 44; 2 following pneumonectomy and 5 after lobectomy. In comparing the pneumonectomy group with the lobectomy group we found no significant differences in age (p=0.59), Charlson comorbidity index (p=0.18), and postoperative mortality (p=1). Charlson comorbidity index 3 or greater (odds ratio [OR], 8.41; 95% confidence interval [CI], 0.88 to 421.71; p=0.04), preoperative pleural empyema (OR, 3.56; 95% CI, 0.37 to 179.62; p=0.39) and preoperative persistent air leak (OR, 7.34; 95% CI, 1.00 to 89.98; p=0.02) were associated with higher risk for fatal outcome. Furthermore, patients with sepsis (p=0.03) and patients sustaining acute renal failure (p=0.04) had significantly higher mortality. CONCLUSIONS: Pulmonary sepsis and its complications as well as preexisting comorbidity are the major reasons for fatal outcome, whereas the extent of surgical resection shows no significant influence. Emergent pneumonectomy as ultimate ratio is not only justified but also life saving. Further improvement seems achievable by earlier surgical intervention before the onset of pulmonary sepsis. PMID- 24793685 TI - Performing robotic lobectomy and segmentectomy: cost, profitability, and outcomes. AB - BACKGROUND: The primary objective of this study was to evaluate our experience using a completely portal (no access incision) robotic pulmonary lobectomy or segmentectomy. METHODS: This was a retrospective review of a consecutive series of patients. RESULTS: From February 2010 until October 2013, 862 robotic operations were performed by 1 surgeon. Of these, 394 were for a planned anatomic pulmonary resection, comprising robotic lobectomy in 282, robotic segmentectomy in 71, and conversions to open in 41 (10 for bleeding, 1 patient required transfusion; and no conversions for bleeding in the last 100 patients). Indications were malignancy in 88%. A median of 17 lymph nodes were removed. Median hospital stay was 2 days. Approximate financial data yielded: median hospital charges, $32,000 per patient (total, $12.6 million); collections, 23.7%; direct costs, $13,800 per patient; and $4,750 profit per patient (total, $1.6 million). Major morbidity occurred in 9.6%. The 30-day operative mortality was 0.25%, and 90-day mortality was 0.5%. Patients reported a median pain score of 2/10 at their 3-week postoperative clinic visit. CONCLUSIONS: Robotic lobectomy for cancer offers outstanding results, with excellent lymph node removal and minimal morbidity, mortality, and pain. Despite its costs, it is profitable for the hospital system. Disadvantages include capital costs, the learning curve for the team, and the lack of lung palpation. Robotic surgery is an important tool in the armamentarium for the thoracic surgeon, but its precise role is still evolving. PMID- 24793686 TI - Anatomic variability and outcome in prenatally diagnosed absent pulmonary valve syndrome. AB - BACKGROUND: We sought to describe current outcomes and risk factors for mortality for fetuses diagnosed with absent pulmonary valve syndrome (APV). Fetuses with APV were divided into two cohorts, those with underlying tetralogy of Fallot (TOF/APV) and those without underlying TOF and either an intact ventricular septum or small ventricular septal defect (APV/IVS). METHODS: The fetal echocardiographic database was reviewed from January 1, 2001, until June 1, 2010, and all subjects with a diagnosis of APV were included. Multiple clinical and fetal echocardiographic measurements were recorded. Statistical analysis was performed by chi2 analysis and t tests. Survival analysis was performed by Kaplan Meier analysis. Significant relationships between variables were explored by regression analysis. Significance was set at p=0.05. RESULTS: The cohort consisted of 15 fetuses with TOF/APV and 6 fetuses with APV/IVS. There were no fetal demises in either cohort. Survival to birth was 71% in the TOF/APV cohort and 83% in the APV/IVS cohort (p=0.62). Of subjects born alive, survival was 80% for both cohorts (p=0.95). However, in the APV/IVS cohort, transplantation-free survival was only 20%. Underlying single-ventricle physiology strongly predicted those who underwent heart transplantation (p=0.003, R2=0.50). For the entire APV cohort, left ventricular dysfunction (p=0.005, R2=0.41) and a higher pulmonary artery valve-to-aortic valve ratio (p=0.02, R2=0.34) predicted mortality. CONCLUSIONS: Postnatal outcomes continue to improve for fetuses with APV syndrome. Left ventricular dysfunction and higher pulmonary artery valve-to aortic valve ratio accurately predict postnatal mortality for fetuses with APV. PMID- 24793687 TI - In search of the ideal pulmonary blood source for the Norwood procedure: a meta analysis and systematic review. AB - BACKGROUND: A clear consensus regarding the optimal source of pulmonary blood flow in patients with hypoplastic left heart syndrome undergoing the Norwood procedure is lacking. METHODS: A literature search was undertaken to identify relevant articles from 2005 to 2012 using "Norwood, stage 1 palliation," "Modified Blalock Taussig shunt (MBTS)," "right ventricle-to-pulmonary artery shunt (RV-PAS)" alone or in combination. Three end points were selected: early/stage 1 mortality, interstage mortality, and interstage total/shunt intervention. RESULTS: A total of 20 articles, including 19 observational studies and 1 randomized trial (MBTS, n=1,343; RV-PAS, n=1,028), met the inclusion criteria. Mortality after stage 1 was 22% in the MBTS cohort and 16% in RV-PAS cohort. A pooled analysis showed no difference in early mortality between the two groups (risk ratio [RR], 1.20; 95% confidence interval [CI], 0.99 to 1.45; p=0.07). On pooling data from contemporary series (similar era) of 8 studies (MBTS, n=709; RV-PAS, n=631), to minimize variability in surgical and postoperative management practices, early mortality in both cohorts was comparable (RR, 1.14; 95% CI, 0.89 to 1.45; p=0.29). Interstage mortality was 13.8% and 4.6% in the MBTS and RV-PAS cohorts, respectively, and was significantly lower for RV-PAS (RR, 2.85; 95% CI, 1.65 to 4.89; p<0.00002). However, patients with MBTS had fewer shunt interventions (RR, 0.55; 95% CI, 0.44 to 0.68; p<0.001; I2=00%). CONCLUSIONS: Our pooled analysis demonstrated no survival benefit for the MBTS or RV-PAS in patients undergoing the Norwood procedure. There appears to be an advantage with the RV-PAS with regard to interstage mortality at the cost of an increased rate of shunt intervention. PMID- 24793688 TI - Major complications after lung microwave ablation: a single-center experience on 204 sessions. AB - BACKGROUND: The purpose of this study is to retrospectively evaluate the incidence of and risk factors for major complications after microwave ablation (MWA) of lung tumors. METHODS: From January 2011 to May 2013 in 184 consecutive patients (67 women and 117 men; mean age, 61.5 years; range, 19 to 85 years), 204 sessions of MWA were performed on 253 lung tumor lesions. Records were reviewed to evaluate prevalence of major complications and risk factors, which were analyzed using univariate and multivariate analyses. RESULTS: Major complications developed after 42 sessions (20.6%), including 32 cases (15.7%) of pneumothorax requiring chest tube placement which that were associated with emphysema (p=0.001); 6 cases (2.9%) of pleural effusions requiring chest tube placement, which were associated with a distance of less than 1 cm from chest wall to target tumor (p=0.014); 6 cases (2.9%) of pneumonia which that were associated with target tumor maximal diameter (p=0.040); number of pleural punctures (p=0.001) and ablation time (p=0.006); and 1 case (0.5%) of pulmonary abscess. Two cases (1.0%) of the large pneumothorax occurred at the same time with extensive subcutaneous emphysema, including 1 case (0.5%) caused by bronchopleural fistula. Death related to the procedures occurred after 1 session (0.5%). CONCLUSIONS: As a relatively practical and safe modality, lung tumor MWA can induce serious complications. Enough attention should be paid to patients with emphysema, subpleural, or large target tumor, but the indications for lung MWA need not be limited as most major complications were easily managed. PMID- 24793689 TI - Intrapyloric botulinum injection increases postoperative esophagectomy complications. AB - BACKGROUND: Intrapyloric botulinum toxin injection has emerged as a possible alternative to standard pyloric drainage procedures. Possible advantages include decreased operative time and less postoperative dumping and bile reflux symptoms. However, data are lacking to show its effectiveness versus standard drainage procedures. The purpose of this review is to compare the results in a prospective cohort of patients who received pyloric botulinum injection versus patients who received pyloromyotomy or pyloroplasty with esophagectomy. METHODS: We performed a retrospective review of a prospective database of all patients who underwent an open esophageal resection at a single institution from 2005 through 2010. Three hundred twenty-two patients were divided into 3 groups for analysis: botulinum injection (n = 78), pyloromyotomy (n = 45), and pyloroplasty (n = 199). We compared these groups with respect to duration of the procedure, presence of delayed gastric emptying on postoperative swallow studies, requirement of anastomotic dilation, requirement of pyloric dilation, use of postoperative promotility agents, and patient experience of postoperative symptoms of reflux or dumping, or both. RESULTS: Patients receiving botulinum injections experienced similar delayed gastric emptying on postoperative radiologic evaluation as did patients undergoing pyloromyotomy and pyloroplasty (16% versus 5% and 13%, respectively; p = 0.14). Mean operative time was significantly shorter for the patients receiving botulinum as expected (239 minutes versus 312 minutes and 373 minutes, respectively; p < 0.001). However, more patients receiving botulinum and pyloric dilation (22% versus 4% and 2%, respectively; p < 0.001) experienced postoperative reflux symptoms (32% versus 12% and 13%, respectively; p = 0.001) and used postoperative promotility agents (22% versus 5% and 15%, respectively; p = 0.04). There was no statistical difference between the groups regarding postoperative dumping. CONCLUSIONS: Use of intrapyloric botulinum injection significantly decreased operative time. However, the patients receiving botulinum experienced more postoperative reflux symptoms, had increased use of promotility agents as well as a requirement for postoperative endoscopic interventions, and postoperative dumping was not reduced by the reversible procedure. Intrapyloric botulinum injection should not be used as an alternative to standard drainage procedures. Pyloromyotomy appears to be the drainage procedure of choice to accompany an esophagectomy. PMID- 24793690 TI - Clinical significance of intraluminal atheroma in patients with ascending and arch aneurysm. AB - BACKGROUND: Little is known about the clinical significance of intraluminal atheroma (ILA) in ascending and arch aneurysm (Asc-ArcA) regarding aneurysm expansion and associated cardiovascular events. METHODS: We retrospectively investigated 70 consecutive patients with Asc-ArcA who underwent serial multidetector computed tomography between 2004 and 2011. We evaluated the diameter of the aneurysm, as well as the presence and characteristics of ILA. We also evaluated the characteristics of atheroma in terms of the presence of high risk plaque (>4 mm in plaque thickness), vulnerable plaque (<60 HU in density), ulcerated plaque (extension of the contrast medium beyond the vascular lumen into the surrounding plaque with >3 mm orifice), and complex plaque (having all three characteristics). The annual expansion rate of Asc-ArcA and factors associated with cardiovascular events were evaluated. RESULTS: During a median of 47 months of follow-up, cryptogenic stroke occurred in 13 patients (18.6%). Univariate and multivariate logistic regression analyses revealed the presence of ILA as an independent predictor for cryptogenic stroke. Cryptogenic stroke occurred in all 5 patients with complex atheroma. The annual expansion rate of Asc-ArcA was not significantly associated with the occurrence of cryptogenic stroke. CONCLUSIONS: In patients with low to intermediate risk sized Asc-ArcA, ILA, especially complex atheroma, is strongly associated with cryptogenic stroke. Thus, the presence and characteristics of ILA within Asc-ArcA should be carefully evaluated for the prevention of adverse events. PMID- 24793691 TI - Lung resection outcomes and costs in Washington State: a case for regional quality improvement. AB - BACKGROUND: A regional quality improvement effort does not exist for thoracic surgery in the United States. To initiate the development of one, we sought to describe temporal trends and hospital-level variability in associated outcomes and costs of pulmonary resection in Washington (WA) State. METHODS: A cohort study (2000-2011) was conducted of operated-on lung cancer patients. The WA State discharge database was used to describe outcomes and costs for operations performed at all nonfederal hospitals within the state. RESULTS: Over 12 years, 8,457 lung cancer patients underwent pulmonary resection across 49 hospitals. Inpatient deaths decreased over time (adjusted p-trend=0.023) but prolonged length of stay did not (adjusted p-trend=0.880). Inflation-adjusted hospital costs increased over time (adjusted p-trend<0.001). Among 24 hospitals performing at least 1 resection per year, 5 hospitals were statistical outliers in rates of death (4 lower and 1 higher than the state average), and 13 were outliers with respect to prolonged length of stay (7 higher and 6 lower than the state average) and costs (5 higher and 8 lower than the state average). When evaluated for rates of death and costs, there were hospitals with fewer deaths/lower costs, fewer deaths/higher costs, more deaths/lower costs, and more deaths/higher costs. CONCLUSIONS: Variability in outcomes and costs over time and across hospitals suggest opportunities to improve the quality and value of thoracic surgery in WA State. Examples from cardiac surgery suggest that a regional quality improvement collaborative is an effective way to meaningfully and rapidly act upon these opportunities. PMID- 24793692 TI - How slow RNA polymerase II elongation favors alternative exon skipping. AB - Splicing is functionally coupled to transcription, linking the rate of RNA polymerase II (Pol II) elongation and the ability of splicing factors to recognize splice sites (ss) of various strengths. In most cases, slow Pol II elongation allows weak splice sites to be recognized, leading to higher inclusion of alternative exons. Using CFTR alternative exon 9 (E9) as a model, we show here that slowing down elongation can also cause exon skipping by promoting the recruitment of the negative factor ETR-3 onto the UG-repeat at E9 3' splice site, which displaces the constitutive splicing factor U2AF65 from the overlapping polypyrimidine tract. Weakening of E9 5' ss increases ETR-3 binding at the 3' ss and subsequent E9 skipping, whereas strengthening of the 5' ss usage has the opposite effect. This indicates that a delay in the cotranscriptional emergence of the 5' ss promotes ETR-3 recruitment and subsequent inhibition of E9 inclusion. PMID- 24793693 TI - Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. AB - Recent studies have reported that competitive endogenous RNAs (ceRNAs) can act as sponges for a microRNA (miRNA) through their binding sites and that changes in ceRNA abundances from individual genes can modulate the activity of miRNAs. Consideration of this hypothesis would benefit from knowing the quantitative relationship between a miRNA and its endogenous target sites. Here, we altered intracellular target site abundance through expression of an miR-122 target in hepatocytes and livers and analyzed the effects on miR-122 target genes. Target repression was released in a threshold-like manner at high target site abundance (>=1.5 * 10(5) added target sites per cell), and this threshold was insensitive to the effective levels of the miRNA. Furthermore, in response to extreme metabolic liver disease models, global target site abundance of hepatocytes did not change sufficiently to affect miRNA-mediated repression. Thus, modulation of miRNA target abundance is unlikely to cause significant effects on gene expression and metabolism through a ceRNA effect. PMID- 24793695 TI - The 3M complex maintains microtubule and genome integrity. AB - CUL7, OBSL1, and CCDC8 genes are mutated in a mutually exclusive manner in 3M and other growth retardation syndromes. The mechanism underlying the function of the three 3M genes in development is not known. We found that OBSL1 and CCDC8 form a complex with CUL7 and regulate the level and centrosomal localization of CUL7, respectively. CUL7 depletion results in altered microtubule dynamics, prometaphase arrest, tetraploidy, and mitotic cell death. These defects are recaptured in CUL7 mutated 3M cells and can be rescued by wild-type, but not by 3M patient-derived CUL7 mutants. Depletion of either OBSL1 or CCDC8 results in defects and sensitizes cells to microtubule damage similarly to loss of CUL7 function. Microtubule damage reduces the level of CCDC8 that is required for the centrosomal localization of CUL7. We propose that CUL7, OBSL1, and CCDC8 proteins form a 3M complex that functions in maintaining microtubule and genome integrity and normal development. PMID- 24793694 TI - A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer. AB - Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation. PMID- 24793696 TI - CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity. AB - The Cullin 9 (CUL9) gene encodes a putative E3 ligase that localizes in the cytoplasm. Cul9 null mice develop spontaneous tumors in multiple organs; however, both the cellular and the molecular mechanisms of CUL9 in tumor suppression are currently unknown. We show here that deletion of Cul9 leads to abnormal nuclear morphology, increased DNA damage, and aneuploidy. CUL9 knockdown rescues the microtubule and mitosis defects in cells depleted for CUL7 or OBSL1, two genes that are mutated in a mutually exclusive manner in 3M growth retardation syndrome and function in microtubule dynamics. CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7. Depletion of CUL7 decreases survivin level, and overexpression of survivin rescues the defects caused by CUL7 depletion. We propose a 3M-CUL9-survivin pathway in maintaining microtubule and genome integrity, normal development, and tumor suppression. PMID- 24793697 TI - Plant functional types in Earth system models: past experiences and future directions for application of dynamic vegetation models in high-latitude ecosystems. AB - BACKGROUND: Earth system models describe the physical, chemical and biological processes that govern our global climate. While it is difficult to single out one component as being more important than another in these sophisticated models, terrestrial vegetation is a critical player in the biogeochemical and biophysical dynamics of the Earth system. There is much debate, however, as to how plant diversity and function should be represented in these models. SCOPE: Plant functional types (PFTs) have been adopted by modellers to represent broad groupings of plant species that share similar characteristics (e.g. growth form) and roles (e.g. photosynthetic pathway) in ecosystem function. In this review, the PFT concept is traced from its origin in the early 1800s to its current use in regional and global dynamic vegetation models (DVMs). Special attention is given to the representation and parameterization of PFTs and to validation and benchmarking of predicted patterns of vegetation distribution in high-latitude ecosystems. These ecosystems are sensitive to changing climate and thus provide a useful test case for model-based simulations of past, current and future distribution of vegetation. CONCLUSIONS: Models that incorporate the PFT concept predict many of the emerging patterns of vegetation change in tundra and boreal forests, given known processes of tree mortality, treeline migration and shrub expansion. However, representation of above- and especially below-ground traits for specific PFTs continues to be problematic. Potential solutions include developing trait databases and replacing fixed parameters for PFTs with formulations based on trait co-variance and empirical trait-environment relationships. Surprisingly, despite being important to land-atmosphere interactions of carbon, water and energy, PFTs such as moss and lichen are largely absent from DVMs. Close collaboration among those involved in modelling with the disciplines of taxonomy, biogeography, ecology and remote sensing will be required if we are to overcome these and other shortcomings. PMID- 24793699 TI - The evolving role of nuclear transporters in cancer. PMID- 24793700 TI - Chest ultrasonography in emergency Cesarean delivery in multi-valvular heart disease with pulmonary edema during spinal anesthesia. AB - Valvular heart disease in a parturient presenting for Cesarean section is challenging. A 25 year old primigravida parturient with severe mitral stenosis, mild mitral regurgitation, mild aortic regurgitation, and mild pulmonary arterial hypertension required Cesarean delivery after developing pulmonary edema. Low dose spinal with hyperbaric bupivacine 0.5% 1.8 mL plus 25 MUg of fentanyl was used for anesthesia. Chest ultrasonography (US) and transthoracic echocardiography (TTE) were used for monitoring purposes. Spinal-induced preload reduction improved the pulmonary edema, as evidenced by chest US. Chest US and TTE helped in fluid management. PMID- 24793701 TI - Intermittent reinflation is safe to maintain oxygenation without alteration of extravascular lung water during one-lung ventilation. AB - STUDY OBJECTIVE: To investigate whether a maneuver for repeated cycles of collapse and reexpansion of the operative lung, termed "intermittent reinflation" (IR), to counter hypoxemia during one-lung ventilation (OLV), results in a time dependent alteration of extravascular lung water. DESIGN: Prospective, randomized clinical study. SETTING: Operating room and postsurgical intensive care unit of a university hospital. PATIENTS: 36 ASA physical status 1 and 2 patients undergoing elective, video-assisted thoracic surgery for lung tumors. INTERVENTIONS: Patients were randomly assigned to two groups. Group C consisted of 18 patients whose nondependent lung was kept collapsed during OLV, while Group IR included 18 patients with IR that consisted of 4 separate, 10-second manual inflations and 5 second openings within one minute at intervals of 20 minutes during OLV. MEASUREMENTS: Perioperative parameters included transcutaneous oxygen saturation (SpO2), hemodynamic data, extravascular lung water index (EVLWI), pulmonary vascular permeability index (PVPI) as determined by the single-indicator transpulmonary thermodilution technique, and partial pressure of arterial oxygen/inspired oxygen fraction (PaO2/FIO2) ratio. MAIN RESULTS: Group IR had significantly higher SpO2 at 20 minutes after commencement of OLV (98.9% vs 96.3%, P = 0.029) and average SpO2 throughout OLV (98.7% vs 97.0%, P = 0.020). Hemodynamic data, EVLWI, PVPI, and PaO2/FIO2 ratio did not differ between the groups, and there were no differences between groups in postoperative morbidity or hospital stay. CONCLUSIONS: Intermittent reinflation had a beneficial effect on oxygenation during OLV, without any significant effects on EVLW or postoperative outcomes. PMID- 24793702 TI - Postoperative adverse effects after recent or remote lithium therapy. AB - Patients receiving preoperative lithium therapy for bipolar disorder may present unique challenges in the perioperative period and during critical illness. Two cases of critically ill patients who developed lithium-induced adverse reactions in the perioperative period due to the low therapeutic index are reported. PMID- 24793698 TI - Simulating cancer growth with multiscale agent-based modeling. AB - There have been many techniques developed in recent years to in silico model a variety of cancer behaviors. Agent-based modeling is a specific discrete-based hybrid modeling approach that allows simulating the role of diversity in cell populations as well as within each individual cell; it has therefore become a powerful modeling method widely used by computational cancer researchers. Many aspects of tumor morphology including phenotype-changing mutations, the adaptation to microenvironment, the process of angiogenesis, the influence of extracellular matrix, reactions to chemotherapy or surgical intervention, the effects of oxygen and nutrient availability, and metastasis and invasion of healthy tissues have been incorporated and investigated in agent-based models. In this review, we introduce some of the most recent agent-based models that have provided insight into the understanding of cancer growth and invasion, spanning multiple biological scales in time and space, and we further describe several experimentally testable hypotheses generated by those models. We also discuss some of the current challenges of multiscale agent-based cancer models. PMID- 24793703 TI - Maternal and fetal safety of fluid-restrictive general anesthesia for endoscopic fetal surgery in monochorionic twin gestations. AB - STUDY OBJECTIVE: To review our experience with general anesthesia in endoscopic fetal surgery for twin-to-twin transfusion syndrome (TTTS), and to compare fetomaternal outcome before and after protocol implementation. DESIGN: Retrospective impact study. SETTING: University-affiliated medical center. MEASUREMENTS: Data from 85 consecutive patients who underwent endoscopic laser ablation of placenta vessels for severe TTTS were studied. Outcomes were compared in patients before (2000-2007) and after (2008-2012) a change to strict intraoperative intravenous (IV) fluid and liberal vasopressor management. Perioperative parameters (IV fluid administration, vasopressor use, maternal hemoglobin [Hb] concentration); maternal complication rate (respiratory, hemorrhagic); pregnancy outcome; and fetal and neonatal survival were recorded. MAIN RESULTS: Patients in the early group (2000-2007; n = 55) received 1634 +/- 949 mL of crystalloid fluid intraoperatively, compared with 485 +/- 238 mL (P < 0.001; Student's t test) given to the late group (2008-2012; n = 30). Maternal pulmonary edema and any respiratory distress were seen in 5.5% and 12.7% of patients in the early group, respectively, and in none of the late group patients (P < 0.05; Chi-square analysis). CONCLUSIONS: A significant risk of maternal respiratory complications exists after general anesthesia for endoscopic fetal surgery. Judicious fluid management significantly decreases this risk. PMID- 24793704 TI - Unexpected cause of leak in a modern anesthesia workstation. PMID- 24793705 TI - Middle fixation of electromyographic endotracheal tube for intraoperative recurrent laryngeal nerve monitoring. PMID- 24793706 TI - Torticollis following induction of general anesthesia for pediatric scoliosis surgery. PMID- 24793707 TI - Daunting complications of one-lung ventilation: pneumothorax in a patient with lymphangioleiomyomatosis (LAM). PMID- 24793708 TI - Capnography and bronchial blocker may help in the diagnosis of surgical lung injury during thoracoscopy. PMID- 24793709 TI - Complete neurologic recovery in an out-of-hospital cardiac arrest facilitated by initiation of therapeutic hypothermia in a young athlete with an anomalous right coronary artery. AB - Therapeutic hypothermia is an accepted modality for improving neurologic outcome in patients who have sustained cardiac arrest with return of spontaneous circulation. Despite postresuscitative neuroprotection, it is uncommon to have patients who have undergone prolonged cardiopulmonary resuscitation to recover full neurologic function. An unusual case of sudden cardiac arrest in a young athlete with an anomolous right coronary artery is presented. PMID- 24793710 TI - A case of internal jugular vein dissection that occurred during central venous catheter insertion. PMID- 24793712 TI - Unrecognized barriers to perioperative limitations on potentially life-sustaining medical treatment. PMID- 24793711 TI - Effective low dosage of mepivacaine in ultrasound-guided axillary nerve block: a double-blinded, randomized clinical trial of efficacy in patients undergoing distal upper extremity surgery. AB - STUDY OBJECTIVE: To evaluate two low-dose volumes (20 mL or 30 mL) of 1.5% mepivacaine solution used for ultrasound-guided axillary blockade for outpatients undergoing distal upper limb surgery. DESIGN: Prospective, double-blinded randomized study. SETTING: Outpatient surgical setting of a university-affiliated hospital. PATIENTS: 64 adult, ASA physical status 1, 2, and 3 patients, aged 28 46 years, scheduled for upper limb surgery. INTERVENTIONS: Patients were randomized to two groups to receive either 20 mL of 1.5% mepivacaine solution (n=31) or 30 mL of 1.5% mepivacaine solution (n=33) for ultrasound-guided axillary plexus blockade. MEASUREMENTS: Block duration, proportion of surgical and functional successful blocks, onset of sensory and motor blockade measured from 0 to 30 minutes following final needle extraction, total amount of preoperative sedative (midazolam), and intraoperative propofol administered were recorded. MAIN RESULTS: Following axillary plexus blockade, neither patient group showed any statistically significant difference in the percentage of functionally successful blockade (30 mL, 100%: 20 mL, 97%; P = 0.48), surgically successful blockade (30 mL, 100%; 20 mL, 94%; P = 0.23), cumulative sensory or motor blockade surgical time, block performance time, preoperative midazolam use, or intraoperative propofol use. CONCLUSION: Low volumes (30 mL or 20 mL) of 1.5% mepivacaine provides satisfactory anesthesia for ambulatory distal upper limb surgery with no significant difference in clinical outcomes. PMID- 24793713 TI - Anesthesiologists' familiarity with the ASA and ACS guidelines on Advance Directives in the perioperative setting. AB - STUDY OBJECTIVE: To assess anesthesiologists' familiarity with the American Society of Anesthesiologists (ASA) and American College of Surgeons (ACS) guidelines on Advance Directives in the perioperative setting. DESIGN: Single center, 4-question anonymous survey. SETTING: Urban academic medical center. SUBJECTS: Up to 34 subjects responded to each question. MEASUREMENTS AND MAIN RESULTS: Familiarity with the ASA and ACS guidelines on Advance Directives in the perioperative setting ranged from 45% to 100%. CONCLUSIONS: There was inadequate familiarity with components of the ASA and ACS guidelines on advance directives in the perioperative setting. Larger studies are required to assess anesthesiologists' familiarity with national society guidelines that directly affect patient care. Future work should investigate best practices for guideline implementation, and consequences of poor adherence to national guidelines. PMID- 24793714 TI - Efficacy of computer-based video and simulation in ultrasound-guided regional anesthesia training. AB - STUDY OBJECTIVE: To determine the effectiveness of a short educational video and simulation on improvement of ultrasound (US) image acquisition and interpretation skills. DESIGN: Prospective, randomized study. SETTING: University medical center. SUBJECTS: 28 anesthesia residents and community anesthesiologists with varied ultrasound experience were randomized to teaching video with interactive simulation or sham video groups. SUBJECTS: Participants were assessed preintervention and postintervention on their ability to identify the sciatic nerve and other anatomic structures on static US images, as well as their ability to locate the sciatic nerve with US on live models. MAIN RESULTS: Pretest written test scores correlated with reported US block experience (Kendall tau rank r = 0.47) and with live US scanning scores (r = 0.64). The teaching video and simulation significantly improved scores on the written examination (P < 0.001); however, they did not significantly improve live US scanning skills. CONCLUSIONS: A short educational video with interactive simulation significantly improved knowledge of US anatomy, but failed to improve hands-on performance of US scanning to localize the nerve. PMID- 24793715 TI - F0 maternal BPA exposure induced glucose intolerance of F2 generation through DNA methylation change in Gck. AB - BPA, a common environmental endocrine disruptor, has been reported to induce epigenetic changes and disrupt glucose homeostasis in F1 offspring through maternal exposure. However, no studies have examined whether maternal BPA exposure can exert multigenerational effects of glucose metabolic disorder on F2 generation through the altered epigenetic information. The aim of the current study was to investigate whether BPA exposure can disrupt glucose homeostasis in F2 offspring and the underlying epigenetic mechanism. In the present study, F0 pregnant dams were orally administered at a daily dose of 40MUg/kg body weight during gestation and lactation. The F1 and F2 generations were obtained and not exposed to BPA anymore. The glucose and insulin tolerance tests were carried out to evaluate the glucose homeostasis level. The relative hormone level and the relative gene expression were also examined. F2 generation was found to exhibited glucose intolerance and insulin resistance in ipGTT and ipITT, as well as the downregulation of glucokinase (Gck) gene in liver. DNA methylation pattern of Gck promoter in the F2 generation of hepatic tissue and F1 generation of sperm was then performed. The Gck promoter in F2 hepatic tissue became completely methylated in the all CpG sites compared with five unmethylated sites in controls. In the F1 sperm, the global DNA methylation was decreased. However, there is only CpG site -314 was differently methylated between BPA and controls in sperm. In conclusion, F0 maternal BPA exposure during gestation and lactation can induce impaired glucose homeostasis in the F2 offspring through the transmission of sperm. The underlying epigenetic modifications in the sperm of F1 generation remain to be further elucidated. PMID- 24793716 TI - Cell uptake and oral absorption of titanium dioxide nanoparticles. AB - Large efforts are invested on the development of in vitro tests to evaluate nanomaterial (NM) toxicity. In order to assess the relevance of the adverse effects identified in in vitro toxicity tests a thorough understanding of the biokinetics of NMs is critical. We used different in vitro and in vivo test methods to evaluate cell uptake and oral absorption of titanium dioxide nanoparticles (TiO2 NPs). These NPs were readily uptaken by A549 cells (carcinomic human alveolar basal epithelial cells) in vitro. Such rapid uptake contrasted with a very low oral absorption in a differentiated Caco-2 monolayer system (human epithelial colorectal adenocarcinoma cells) and after oral gavage administration to rats. In this oral study, no significant increase in the levels of titanium was recorded by ICP-MS in any of the tissues evaluated (including among other: small intestine, Peyer's patches, mesenteric lymph nodes, liver, and spleen). No NPs were observed by TEM in sections of the small intestine, except for several particles in the cytoplasm of a cell from a Peyer's Patch area. The observation of NPs in Peyer's Patch suggests that the Caco-2 monolayer system is likely to underestimate the potential for oral absorption of NPs and that the model could be improved by including M-cells in co-culture. PMID- 24793717 TI - Preface: SQAB 2013: contextual control. PMID- 24793718 TI - What are the main criteria of science? Unconventional methods in ethnopharmacology. PMID- 24793719 TI - Clinicians' concerns about delivering cognitive-behavioural therapy for eating disorders. AB - Despite research supporting the effectiveness of evidence-based interventions in the treatment of eating disorders, those interventions are under-utilised in routine clinical practice, possibly due to clinicians' concerns about delivering the relevant techniques. This study examined what elements of therapy clinicians worry about when delivering cognitive-behavioural therapy (CBT) for the eating disorders, and what clinician variables are associated with such concerns. The participants were 113 clinicians who used individual CBT with eating disorder patients. They completed a novel measure of concerns about delivering elements of CBT, as well as demographic characteristics and a standardised measure of intolerance of uncertainty. Clinicians worried most about body image work and ending treatment, but least about delivering psychoeducation. Their concerns fell into four distinct factors. Older, more experienced clinicians worried less about delivering the CBT techniques, but those with greater levels of prospective and inhibitory anxiety worried more about specific factors in the CBT techniques. Clinicians' capacity to tolerate uncertainty might impair their delivery of evidence-based CBT, and merits consideration as a target in training and supervision of CBT clinicians. PMID- 24793720 TI - Salpingectomy, why not? PMID- 24793721 TI - Fetal imaging: Executive summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. AB - Given that practice variation exists in the frequency and performance of ultrasound and magnetic resonance imaging in pregnancy, the Eunice Kennedy Shriver National Institute of Child Health and Human Development hosted a workshop to address indications for ultrasound and magnetic resonance imaging in pregnancy, to discuss when and how often these studies should be performed, to consider recommendations for optimizing yield and cost-effectiveness and to identify research opportunities. This article is the executive summary of the workshop. PMID- 24793722 TI - Correlation between initial neonatal and early childhood outcomes following preterm birth. AB - OBJECTIVE: Neonatal diagnoses are often used as surrogate endpoints for longer term outcomes. We sought to characterize the correlation between neonatal diagnoses and early childhood neurodevelopment. STUDY DESIGN: We conducted secondary analysis of a multicenter randomized controlled trial of antenatal magnesium sulfate vs placebo administered to women at imminent risk for delivery <32.0 weeks to prevent death and cerebral palsy in their offspring. Singletons and twins delivering 23.0-33.9 weeks who survived to hospital discharge and had 2 year-old outcome data were included. Those surviving to age 2 years were assessed by trained physicians and the Bayley II Scales of Infant Development Mental Development and Psychomotor Development Indices. Neonatal diagnoses at the time of each baby's initial hospital discharge were examined singly and in combination to determine those most predictive of childhood neurodevelopmental impairment, defined as a childhood diagnosis of moderate/severe cerebral palsy and/or Bayley scores >2 SD below the mean. Data were analyzed by multiple regression models and area under receiver operating characteristic curves. RESULTS: A total of 1771 children met criteria. Children were delivered at a mean of 29.4 weeks' gestation. In all, 459 (25.9%) had neurodevelopmental impairment. In models controlling for gestational age at delivery, maternal education, maternal race, tobacco/alcohol/drug use during pregnancy, randomization to magnesium, fetal sex, and chorioamnionitis, individual neonatal morbidities were moderately predictive of childhood neurodevelopmental impairment (best model area under receiver operating characteristic curve, 0.68; 95% confidence interval, 0.65-0.71). Combinations of 2, 3, and 4 morbidities did not improve the prediction of neurodevelopmental impairment. CONCLUSION: Approximately 1 in 4 previously preterm children had neurodevelopmental impairment at age 2 years. Prediction of childhood outcomes from neonatal diagnoses remains imperfect. PMID- 24793724 TI - A new model for cell division and migration with spontaneous topology changes. AB - Tissue topology, in particular proliferating epithelium topology, is remarkably similar between various species. Understanding the mechanisms that result in the observed topologies is needed for better insight into the processes governing tissue formation. We present a two-dimensional single-cell based model for cell divisions and tissue growth. The model accounts for cell mechanics and allows cell migration. Cells do not have pre-existing shapes or topologies. Shape changes and local rearrangements occur naturally as a response to the evolving cellular environment and cell-cell interactions. We show that the commonly observed tissue topologies arise spontaneously from this model. We consider different cellular rearrangements that accompany tissue growth and study their effects on tissue topology. PMID- 24793723 TI - In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model. AB - OBJECTIVE: Data from animal models show that in utero exposure to a maternal high fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering the risk of adult disease. Because mice heterozygous for the Glut4 gene (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to an HFD in utero, we sought to analyze the genome-wide epigenetic changes that occur in the fetal liver in susceptible offspring. STUDY DESIGN: WT and Glut4(+/-) (G4(+/-)) offspring of WT mothers that were exposed either to a control or an HFD in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5-week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP-on-chip) was used to detect genome-wide changes of histone modifications with HFD exposure. RESULTS: We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4(+/-) fetal and 5-week offspring. Pathway analysis of our ChIP-on-chip data revealed differential H3K14ac and H3K9me3 enrichment along pathways that regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra, and Rora. CONCLUSION: We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4(+/-) offspring, some of which persist up to 5 weeks of age. PMID- 24793726 TI - Neurocognitive assessment in adult onset primary cranial cervical dystonia. PMID- 24793725 TI - Lung ultrasound by emergency nursing as an aid for rapid triage of dyspneic patients: a pilot study. PMID- 24793727 TI - Capsule Commentary on Pyra et al., sexual minority status and violence among HIV infected and at-risk women. PMID- 24793728 TI - At the heart of the old silk road. PMID- 24793729 TI - Intravenous or local injections of flavoxate in the rostral pontine reticular formation inhibit urinary frequency induced by activation of medial frontal lobe neurons in rats. AB - PURPOSE: The rostral pontine reticular formation has a strong inhibitory effect on micturition by facilitating lumbosacral glycinergic neurons. We assessed the influence of the rostral pontine reticular formation on the micturition reflex after noradrenaline injection in the medial frontal lobe. We also examined the relation between the medial frontal lobe and the rostral pontine reticular formation. MATERIALS AND METHODS: Continuous cystometry was performed in 28 female rats. After the interval between bladder contractions was shortened by noradrenaline injection in the medial frontal lobe we injected glutamate or flavoxate hydrochloride in the rostral pontine reticular formation or intravenously injected flavoxate or propiverine. The change in bladder activity was examined. RESULTS: Noradrenaline injection in the medial frontal lobe shortened the interval between bladder contractions. In contrast to the bladder contraction interval before and after noradrenaline injection in the medial frontal lobe, the interval was prolonged after noradrenaline injection when glutamate or flavoxate was injected in the rostral pontine reticular formation, or flavoxate was injected intravenously. Noradrenaline injection in the medial frontal lobe plus intravenous propiverine injection also prolonged the interval compared to that after noradrenaline injection alone. However, the interval after noradrenaline injection in the medial frontal lobe plus intravenous injection of propiverine was shorter than that before noradrenaline injection only. CONCLUSIONS: Medial frontal lobe neurons excited by noradrenaline may facilitate the micturition reflex via activation of inhibitory interneurons, which inhibit descending rostral pontine reticular formation neurons that innervate the lumbosacral glycinergic inhibitory neurons. Therefore, the mechanism of micturition reflex facilitation by the activation of medial frontal lobe neurons involves the rostral pontine reticular formation. PMID- 24793730 TI - Feasibility of integrating research data collection into routine clinical practice using the electronic health record. AB - PURPOSE: The electronic health record is becoming central to routine medical practice and has the potential to facilitate large scale clinical research. We evaluated the completeness and accuracy of data collection using designated research fields integrated into a semistructured clinical note. We hypothesized that prospective research data collection as part of routine clinical charting is feasible, with a high rate of utilization (greater than 80%) and accuracy (kappa greater than 0.80). MATERIALS AND METHODS: Infants with congenital hydronephrosis were followed prospectively at a single institution. Existing functionality in the electronic health record was used for data collection by creation of 28 different data elements captured from a hydronephrosis note or phrase template. Completeness (percent utilization) was calculated and accuracy was assessed by comparing the structured data to manual chart review. Comparisons were conducted using the chi-square test, with 2-tailed p values <0.05 considered statistically significant. RESULTS: A total of 80 patients were eligible for manual chart review. Data were recorded through template use in 64 patients for an overall completeness of 80.0%. Of 28 elements 17 (60%) demonstrated "almost perfect" agreement (kappa greater than 0.80), and all variables reached at least "moderate" agreement (greater than 0.40). CONCLUSIONS: Integrating research fields into routine clinical practice is feasible by using semistructured clinical templates within an electronic health record. High completion and accuracy rates were captured from a variety of fields within a hydronephrosis template. PMID- 24793731 TI - Population-based disparities in survival among patients with core-binding factor acute myeloid leukemia: a SEER database analysis. AB - We performed a retrospective population-based study using the SEER database to assess survival trends in CBF-AML between 2000 and 2010. Median OS increased from 16 months in 2000-2002 to 25 months in 2006-2008 (P=0.002). The 3-year OS rate for patients with inv(16) was 57.3%, but in t(8;21) was only 35.5%. Patients aged 75-84 had worse survival than patients aged 15-44 (HR 5.61, P=0.0002). Black race was associated with higher mortality (HR 1.50, P=0.03). Compared to clinical trial outcomes, CBF-AML survival is poorer in the general population, particularly among African Americans and the elderly, and in t(8;21) compared to inv(16) AML. PMID- 24793733 TI - Synchrony, complexity and directiveness in mothers' interactions with infants pre and post-cochlear implantation. AB - This study investigated effects of profound hearing loss on mother-infant interactions before and after cochlear implantation with a focus on maternal synchrony, complexity, and directiveness. Participants included two groups of mother-infant dyads: 9 dyads of mothers and infants with normal hearing; and 9 dyads of hearing mothers and infants with profound hearing loss. Dyads were observed at two time points: Time 1, scheduled to occur before cochlear implantation for infants with profound hearing loss (mean age=13.6 months); and Time 2 (mean age=23.3 months), scheduled to occur approximately six months after cochlear implantation. Hearing infants were age-matched to infants with hearing loss at both time points. Dependent variables included the proportion of maternal utterances that overlapped infant vocalizations, maternal mean length of utterance, infant word use, and combined maternal directives and prohibitions. Results showed mothers' utterances overlapped the vocalizations of infants with hearing loss more often before cochlear implantation than after, mothers used less complex utterances with infants with cochlear implants compared to hearing peers (Time 2), and mothers of infants with profound hearing loss used frequent directives and prohibitions both before and after cochlear implantation. Together, mothers and infants adapted relatively quickly to infants' access to cochlear implants, showing improved interactional synchrony, increased infant word use, and levels of maternal language complexity compatible with infants' word use, all within seven months of cochlear implant activation. PMID- 24793732 TI - The survival detriment of venous thromboembolism with epithelial ovarian cancer. AB - OBJECTIVE: The aim of this study is to evaluate the effect of venous thromboembolism (VTE) chronology with respect to surgery on survival with epithelial ovarian cancer (EOC). METHODS: An IRB approved, retrospective review was performed of patients treated for Stage I-IV EOC from 1996 to 2011. Cox proportional hazards model was used to assess associations between VTE and the primary outcomes of progression free survival (PFS) and overall survival (OS). SAS 9.3 was used for statistical analyses. RESULTS: 586 patients met study criteria. Median age was 63 years (range, 17-94); median BMI was 27.1 kg/m(2) (range, 13.7-67.0). Most tumors were high grade serous (68.3%) and advanced stage (III/IV, 75.4%). 3.7% had a preoperative VTE; 13.2% had a postoperative VTE. Upon multivariate analysis adjusting for age, stage, histology, performance status, and residual disease, preoperative VTE was predictive of OS (HR 3.1, 95% CI: 1.6 6.1, p=0.001) but not PFS (p=0.55). Postoperative VTE was associated with shorter PFS (HR 1.45, 95% CI: 1.04-2.02, p=0.03) and OS (HR 1.8, 95% CI: 1.3-2.6, p=0.001). When VTE timing was modeled, preoperative VTE (HR 3.5, 95% CI: 1.8-6.9, p<0.001) and postoperative VTE after primary therapy (HR 2.3, 95% CI: 1.4-3.6, p=0.001) were predictive of OS. CONCLUSION: Preoperative and postoperative VTE appear to have a detrimental effect on OS with EOC. When modeled as a binary variable, postoperative VTE attenuated PFS; however, when VTE timing was modeled, postoperative VTE was not associated with PFS. It is unclear whether VTE is an inherent poor prognostic marker or if improved VTE prophylaxis and treatment may enable similar survival to patients without these events. PMID- 24793734 TI - Mutual touch during mother-infant face-to-face still-face interactions: influences of interaction period and infant birth status. AB - Contact behaviours such as touch, have been shown to be influential channels of nonverbal communication between mothers and infants. While existing research has examined the communicative roles of maternal or infant touch in isolation, mutual touch, whereby touching behaviours occur simultaneously between mothers and their infants, has yet to be examined. The present study was designed to investigate mutual touch during face-to-face interactions between mothers and their 51/2 month-old fullterm (n=40), very low birth weight/preterm (VLBW/preterm; n=40) infants, and infants at psychosocial risk (n=41). Objectives were to examine: (1) how the quantitative and qualitative aspects of touch employed by mothers and their infants varied across the normal periods of the still-face (SF) procedure, and (2) how these were associated with risk status. Mutual touch was systematically coded using the mother-infant touch scale. Interactions were found to largely consist of mutual touch and one-sided touch plus movement, highlighting that active touching is pervasive during mother-infant interactions. Consistent with the literature, while the SF period did not negatively affect the amount of mutual touch engaged in for mothers and their fullterm infants and mothers and their infants at psychosocial risk, it did for mothers and their VLBW/preterm infants. Together, results illuminate how both mothers and infants participate in shaping and co-regulating their interactions through the use of touch and underscore the contribution of examining the influence of birth status on mutual touch. PMID- 24793735 TI - Infant's visual preferences for facial traits associated with adult attractiveness judgements: data from eye-tracking. AB - Human preferences for facial attractiveness appear to emerge at an early stage during infant development. A number of studies have demonstrated that infants display a robust preference for facial attractiveness, preferring to look at physically attractive faces versus less attractive faces as judged by adults. However, to-date, relatively little is known about which traits of the face infants use to base these preferences upon. In contrast, a large number of studies conducted with human adults have identified that preference for attractive faces can be attributed to a number of specific facial traits. The purpose of the experiments here was to measure and assess infant's visual preference via eye-tracker technology for faces manipulated for one of three traits known to effect attractiveness judgments in adult preference tests: symmetry, averageness, and sexually dimorphic traits. Sixty-four infants (28 female and 36 male) aged between 12 and 24 months old each completed a visual paired comparison (VPC) task for one of the three facial dimensions investigated. Data indicated that infants displayed a significant visual preference for facial symmetry analogous to those preferences displayed by adults. Infants also displayed a significant visual preference for feminine versions of faces, in line with some studies of adult preferences. Visual preferences for facial non averageness, or distinctiveness were also seen, a pattern opposite to that seen in adults. These findings demonstrate that infant's appreciation for facial attractiveness in adult images between the ages of 12 and 24 months of age is based on some, but not all, traits that adults find attractive. PMID- 24793738 TI - Re: Sundaram et al.: retinal structure and function in achromatopsia: implications for gene therapy (Ophthalmology 2014;121:234-45). PMID- 24793737 TI - Vasodilators, blood pressure-lowering medications, and age-related macular degeneration: the Beaver Dam Eye Study. AB - OBJECTIVE: To examine the association of vasodilator and antihypertensive medication use with the incidence of age-related macular degeneration (AMD). DESIGN: Longitudinal population-based study. PARTICIPANTS: Persons 43 to 86 years of age living in Beaver Dam, Wisconsin, from 1988 through 1990. METHODS: Examinations were performed every 5 years over a 20-year period. There were 9676 total person-visits over the course of the study. Status of AMD was determined from grading retinal photographs. MAIN OUTCOME MEASURES: Incidence of AMD. RESULTS: The 5-year incidence of early AMD over the 20-year period was 8.4%; for late AMD, it was 1.4%; for pure geographic atrophy (GA), it was 0.6%; for exudative AMD, it was 0.9%; and for progression of AMD, it was 24.9%. While adjusting for age, gender, and other factors, using a vasodilator (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.25-2.38), particularly oral nitroglycerin (HR, 1.81; 95% CI, 1.14-2.90), was associated with an increased risk of early AMD. Using an oral beta-blocker was associated with an increased hazard of incident exudative AMD (HR, 1.71; 95% CI, 1.04-2.82), but not pure GA (HR, 0.51; 95% CI, 0.20-1.29) or progression of AMD (HR, 0.92; 95% CI, 0.67-1.28) over the 20-year period. CONCLUSIONS: Use of vasodilators is associated with a 72% increase in the hazard of incidence of early AMD, and use of oral beta blockers is associated with a 71% increase in the hazard of incident exudative AMD. If these findings are replicated, it may have implications for care of older adults because vasodilators and oral beta-blockers are drugs that are used commonly by older persons. PMID- 24793739 TI - In vitro and in vivo anticancer activity of copper(I) complexes with homoscorpionate tridentate tris(pyrazolyl)borate and auxiliary monodentate phosphine ligands. AB - Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses on the representative complexes 1 and 10, respectively. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1, and [HB(pz)3]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model. PMID- 24793740 TI - Robotics in invasive cardiac electrophysiology. AB - Robotic systems allow for mapping and ablation of different arrhythmia substrates replacing hand maneuvering of intracardiac catheters with machine steering. Currently there are four commercially available robotic systems. Niobe magnetic navigation system (Stereotaxis Inc., St Louis, MO) and Sensei robotic navigation system (Hansen Medical Inc., Mountain View, CA) have an established platform with at least 10 years of clinical studies looking at their efficacy and safety. AMIGO Remote Catheter System (Catheter Robotics, Inc., Mount Olive, NJ) and Catheter Guidance Control and Imaging (Magnetecs, Inglewood, CA) are in the earlier phases of implementations with ongoing feasibility and some limited clinical studies. This review discusses the advantages and limitations related to each existing system and highlights the ideal futuristic robotic system that may include the most promising features of the current ones. PMID- 24793741 TI - Food Cravings Questionnaire-Trait (FCQ-T) discriminates between obese and overweight patients with and without binge eating tendencies: the Italian version of the FCQ-T. AB - Food craving (FC) might play an important role in the course of eating disorders and obesity. The question of its measurement has particular importance in relation to the dramatic growth in obesity rates and its relevance for public health. The aim of this study was to investigate the psychometric properties of the Italian version of the Food Cravings Questionnaire-Trait (FCQ-T) in overweight and obese patients who were attending weight loss programs, and its efficiency in discriminating patients with binge eating. Participants were 497 (411 women, 86 men) overweight and obese patients in treatment with low-energy diet therapy. We used structural equation modeling to compare 3 factor models tested in previous studies (a 6-factor model, an 8-factor model, and a 9-factor model), which indicated that the 9-factor model has a better fit over the competing models. The FCQ-T had good internal consistency (Cronbach's alpha of.96 for the total score, and between.76 and.92 for subfactors), and was able to discriminate patients with clinical-level binge eating from those with probable and without binge eating with an efficiency of.74 (sensitivity =.64, specificity =.78). FCQ-T scores were sensitive to changes associated with treatment only for patients who started dietary restriction between the baseline and the follow-up assessment, but not for patients who were already observing dietary restrictions at the time of the baseline assessment. These results suggest that the FCQ-T could be a potentially useful measure for the screening of binge eating problems in overweight and obese patients while in treatment. PMID- 24793742 TI - Genetic and environmental causes of variation in adolescent anxiety symptoms: a multiple-rater twin study. AB - Heritability estimates for adolescent anxiety vary across studies, partly depending on who is rating the symptoms. The goal of our study was to estimate genetic and environmental influences using a multi-informant design with responses from a population-based sample of adolescent twins, their mothers and their fathers (N=1394 families). Results from multivariate biometrical modeling indicated quantitative, but no qualitative sex differences in etiology. The best fitting model was an AE Common Pathway model, defining anxiety as a latent factor common to all informants. This model offers error free estimates of genetic and environmental influences explaining the latent factor variance. Variation in the latent factor was highly genetic, with heritability estimates of 65% for boys and 74% for girls. Non-shared environmental effects explained the remaining variance. In addition, there were significant rater-specific genetic and environmental effects for both sexes. The observed rater differences underline the importance of using several informants when studying adolescent anxiety. PMID- 24793743 TI - Treatment of Troglostrongylus brevior (Metastrongyloidea, Crenosomatidae) in mixed lungworm infections using spot-on emodepside. AB - Feline lungworms have long been known as pathogens of cats. However, an increased incidence of clinical cases in some areas has been the focus of a number of recent epidemiological and clinical studies. While Aelurostrongylus abstrusus causes respiratory signs in cats all over the world, Troglostrongylus brevior has recently been found in domestic cats from Spain and Italy (where it often causes severe clinical signs). Capillaria aerophila, a parasite that infects many wild carnivores, may cause respiratory distress in cats. A variety of treatment options are known for A abstrusus, while almost no information is available on the treatment of troglostrongylosis and capillariosis. This series describes two mixed infections in clinically affected kittens with T brevior, one with concurrent A abstrusus and the other with C aerophila. In both cases, the nematodes were identified and confirmed by copromicroscopic examination and specific DNA-based assays. Kittens showed respiratory signs that resolved after one or two administrations of a spot-on solution containing emodepside. Larval (T brevior and A abstrusus) and egg (C aerophila) shedding was also eliminated 2-4 weeks after treatment. New clinical insights into these parasitoses are discussed. PMID- 24793744 TI - A retrospective molecular study of select intestinal protozoa in healthy pet cats from Italy. AB - The feline gut can harbour a number of protozoan parasites. Recent genetic studies have highlighted new epidemiological findings about species of Cryptosporidium, assemblages of Giardia duodenalis and Toxoplasma gondii. Furthermore, epidemiological studies suggest the occurrence of Tritrichomonas foetus in cats is on the increase worldwide. The prevalence of selected intestinal protozoa was determined by PCR using DNA previously extracted from the faeces of 146 privately owned healthy cats from Italy. Molecular genotyping on T gondii, G duodenalis and Cryptosporidium DNA was achieved. PCR assays were positive in 32 (22.9%) samples. Three animals (2.0%) were positive for T foetus and Cryptosporidium DNA, 15 specimens (10.3%) were positive for T gondii and 11 (7.5%) for G duodenalis. Co-infections were never observed. Results of the typing analysis allowed the identification of Cryptosporidium felis in all cases. The specimens positive for T gondii hinted at clonal genotype I (n = 7), genotype II (n = 1) and genotype III (n = 7). The G duodenalis isolates were referable to assemblages F (n = 9) and C (n = 2). In conclusion, the results obtained in this study add to the literature regarding the epidemiology of these parasites by confirming their presence in the faeces of healthy pet cats. PMID- 24793745 TI - Neutrophil-lymphocyte ratio as a predictor of outcomes for patients with hepatocellular carcinoma undergoing TAE combined with Sorafenib. AB - The aim of this study was to investigate the prognostic significance of blood NLR in patients with intermediate-advanced hepatocellular carcinoma (HCC) who received transcatheter arterial embolization (TAE) combined with Sorafenib. A total of 40 patients with intermediate-advanced HCC from January 1, 2010, through May 31, 2013, treated with concurrent TAE in combination with Sorafenib were admitted to this study in our hospital. Potential prognostic factors, including serum NLR, were analyzed. The pretreatment mean NLR was 3.0; 21 (52.5 %) patients with elevated high NLR (>3.0). The median survival of patients with a high NLR was 14 months (95 % CI 10.1-17.9 months) compared with 26 months (95 % CI 17.4 34.6 months) for patients with a low NLR; a significant difference was found in overall survival (P = 0 0.001). Barcelona Clinical Liver Cancer staging classification and NLR >3.0 were all predictors of poorer over survival. Multivariate analysis showed that high NLR was independent factors associated with worse survival. A high periprocedural NLR independently predicts poor survival in patients with unresectable HCC undergoing TAE combined with Sorafenib. PMID- 24793746 TI - The prognostic significance of polymorphisms in hMLH1/hMSH2 for colorectal cancer. AB - We aimed to investigate the associations between single-nucleotide polymorphisms (SNPs) in two mismatch repair genes (hMLH1 and hMSH2) and colorectal cancer (CRC) prognosis in Northeast China. We genotyped 387 patients for 10 SNPs in hMLH1 and hMSH2, using polymerase chain reaction restriction fragment length polymorphism approach. Associations between genotypes and overall survival (OS) were estimated using hazard ratios (HRs) and 95 % confidence intervals (CIs). Two SNPs of hMLH1 (hMLH1 -93G>A and IVS3-1403A>T) were significantly associated with OS of CRC in dominant model and recessive model, respectively. For hMLH1 -93G>A, the adjusted HR equaled 0.66 (95 % CI 0.45-0.99, p = 0.04). As for hMLH1 IVS3-1403A>T, the adjusted HR equaled 1.90 (95 % CI 1.14-3.17, p = 0.01). When stratified by tumor location, hMLH1 -93G>A and IVS3-1403A>T were associated with colon cancer survival (for hMLH1 -93G>A, AA+AG vs. GG, HRadj = 0.34, 95 % CI 0.17-0.68, p < 0.01; for hMLH1 IVS3-1403A>T, AT vs. AA, HR(adj) = 2.20, 95 % CI 1.11-4.36, p = 0.02), rather than rectal cancer. None of SNPs located at hMSH2 were significantly associated with prognosis of CRC. Our findings suggested that common variants in hMLH1 may serve as a predictor of CRC survival. PMID- 24793747 TI - Assessment of efficacy, safety and quality of life of 110 patients treated with sunitinib as first-line therapy for metastatic renal cell carcinoma: experience in real-world clinical practice in Japan. AB - The objective of this study was to comprehensively evaluate the clinical outcomes of 110 consecutive Japanese patients who received at least two cycles of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) in a routine clinical setting. Initially, 50 mg of sunitinib was administered once daily on a 4 weeks on, followed by 2 weeks off dosing schedule; however, dose modification was required in 102 patients, and the relative dose intensity was 62.6 % throughout this series. As the best responses to sunitinib, 2, 28, 65 and 15 were judged to show a complete response, partial response, stable disease and progressive disease, respectively. The median progression-free survival (PFS) and overall survival (OS) following the treatment with sunitinib were 7.8 and 33.2 months, respectively. Multivariate analyses of several factors identified the following independent predictors of PFS and OS: Memorial Sloan Kettering Cancer Center (MSKCC) classification and C-reactive protein (CRP) level for PFS and liver metastasis, MSKCC classification and CRP level for OS. The common adverse events related to sunitinib corresponding to >=grade 3 were thrombocytopenia in 59, leukopenia in 23, fatigue in 22, hand-foot syndrome in 15 and hypertension in 12. Quality of life (QOL) analysis using 36-Item Short Form revealed no significant differences in any scale scores between surveys performed before and 3 months after the treatment with sunitinib. Collectively, these findings suggest that the introduction of sunitinib as a first-line agent can lead to favorable disease control with acceptable tolerability, resulting in improvement in the prognosis and QOL of Japanese patients with mRCC. PMID- 24793748 TI - Positive correlation between PSI response and oxidative pentose phosphate pathway activity during salt stress in an intertidal macroalga. AB - Studies have demonstrated that photosynthetic limitations and starch degradation are responses to stress; however, the relationship between the two is seldom described in detail. In this article, the effects of salt stress on photosynthesis, the levels of NADPH and total RNA, the starch content and the activities of glucose-6-phosphate dehydrogenase (G6PDH) and ribulose-5-phosphate kinase (RPK) were evaluated. In thalli that underwent salt treatments, the cyclic electron flow through PSI showed greater stress tolerance than the flow through PSII. Even though the linear electron flow was suppressed by DCMU, the cyclic electron flow still operated. The electron transport rate I (ETRI) increased as the salinity increased when the thalli recovered in seawater containing DCMU. These results suggested that PSI receives electrons from a source other than PSII. Furthermore, the starch content and RPK activity decreased, while the content of NADPH and total RNA, and the activity of G6PDH increased under salt stress. Soluble sugar from starch degradation may enter the oxidative pentose phosphate pathway (OPPP) to produce NADPH and ribose 5-phosphate. Data analysis suggests that NADPH provides electrons for PSI in Ulva prolifera during salt stress, the OPPP participates in the stress response and total RNA is synthesized in excess to assist recovery. PMID- 24793749 TI - Membrane crystals of plant light-harvesting complex II disassemble reversibly in light. AB - Using the mass-measuring capability of scanning transmission electron microscopy, we demonstrate that membrane crystals of the main light-harvesting complex of plants possess the ability to undergo light-induced dark-reversible disassociations, independently of the photochemical apparatus. This is the first direct visualization of light-driven reversible reorganizations in an isolated photosynthetic antenna. These reorganizations, identified earlier by circular dichroism (CD), can be accounted for by a biological thermo-optic transition: structural changes are induced by fast heat transients and thermal instabilities near the dissipation, and self-association of the complexes in the lipid matrix. A comparable process in native membranes is indicated by earlier findings of essentially identical kinetics, and intensity and temperature dependences of the DeltaCD in granal thylakoids. PMID- 24793750 TI - miR396a-Mediated basic helix-loop-helix transcription factor bHLH74 repression acts as a regulator for root growth in Arabidopsis seedlings. AB - miR396 targets seven GROWTH-REGULATING FACTOR (GRF) genes and the BASIC HELIX LOOP-HELIX (bHLH) TRANSCRIPTION FACTOR 74 gene (bHLH74) in Arabidopsis. Previous research revealed that the miR396 target module regulates cell proliferation and plays a critical role in leaf development. However, no additional biological functions of miR396 have been investigated in detail. In this study, T-DNA insertion mutants and transgenic plants with altered levels of miR396 or its target genes were used to characterize the regulatory role of miR396 in root development. We found that AtMIR396a was the predominant source for miR396 accumulation in the roots of seedlings, and that the mir396a-1 mutant had longer roots than wild-type seedlings. Overexpression of AtMIR396a decreased the transcript levels of target genes such as GRF genes and bHLH74, and resulted in a shorter root phenotype. Furthermore, the bhlh74-1 mutant had shorter roots, whereas overexpression of an miR396-resistant form of bHLH74 (mbHLH74) had an enhanced root growth phenotype. Moreover, MIR396a regulated root growth by affecting the elongation zone. Taken together, these data indicate that miR396a mediated bHLH74 repression helps regulate root growth in Arabidopsis seedlings. PMID- 24793751 TI - Gel-based comparative phosphoproteomic analysis on rice embryo during germination. AB - Seed germination is a well regulated process, which incorporates many events including signal transduction, mobilization of reserves, reactive oxygen species scavenging and cell division. Although many transcriptomic and proteomic studies have been conducted on this process, regulation of protein modification has not been studied. To better understand the mechanism, a gel-based comparative phosphoproteomic study was performed on rice embryo during the germination process. In total, 168 protein spots exhibited significantly changed Pro-Q staining intensity during germination. Using matrix-assisted laser deionization time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS) analysis, 193 proteins were identified. By combining Pro-Q and Coomassie brilliant blue stain intensity analyses, 109 proteins were verified to be phosphorylation regulation proteins. Functional analyses indicated that phosphorylation of proteins involved in stress response and storage was gradually enhanced. Phosphorylation of signal transduction proteins was mainly activated during the early stage of germination, while stress response and storage protein phosphorylation were enhanced at the late stage. Enzyme assays proved that the phosphorylation of fructokinase, pyruvate kinase, malate dehydrogenase, GDP-mannose 3,5-epimerase1, ascorbate peroxidase and glutathione S-transferase could consistently enhance their activity. This study showed the dynamic changes of protein phosphorylation status in rice embryo during germination and provided new insight into understanding the mechanism underlying this process. PMID- 24793752 TI - Induced and constitutive DNA methylation in a salinity-tolerant wheat introgression line. AB - Cytosine methylation is a well recognized epigenetic mark. Here, the methylation status of a salinity-tolerant wheat cultivar (cv. SR3, derived from a somatic hybridization event) and its progenitor parent (cv. JN177) was explored both globally and within a set of 24 genes responsive to salinity stress. A further comparison was made between DNA extracted from plants grown under control conditions and when challenged by salinity stress. The SR3 and JN177 genomes differed with respect to their global methylation level, and methylation levels were reduced by exposure to salinity stress. We found the genetic stress- (triggered by a combination of different genomes in somatic hybridization) induced methylation pattern of 13 loci in non-stressed SR3; the same 13 loci were found to undergo methylation in salinity-stressed JN177. For the salinity responsive genes, SR3 and JN177 also showed different methylation modifications. C methylation polymorphisms induced by salinity stress were present in both the promoter and coding regions of some of the 24 selected genes, but only the former were associated with changes in transcript abundance. The expression of both TaFLS1 (encoding a flavonol synthase) and TaWRSI5 (encoding a Bowman-Birk-type protease inhibitor), which showed both a different expression and a different DNA methylation level between SR3 and JN177, enhanced the salinity tolerance of Arabidopsis thaliana. C methylation changes appear to be a common component of the plant response to stress, and methylation changes triggered by somatic hybridization may contribute to the superior salinity tolerance of SR3. PMID- 24793753 TI - Repetitive short-pulse light mainly inactivates photosystem I in sunflower leaves. AB - Under field conditions, the leaves of plants are exposed to fluctuating light, as observed in sunfleck. The duration and frequency of sunfleck, which is caused by the canopy being blown by the wind, are in the ranges from 0.2 to 50 s, and from 0.004 to 1 Hz, respectively. Furthermore, >60% of the sunfleck duration ranges from 0.2 to 0.8 s. In the present research, we analyzed the effects of repetitive illumination by short-pulse (SP) light of sunflower leaves on the photosynthetic electron flow. The duration of SP light was set in the range from 10 to 300 ms. We found that repetitive illumination with SP light did not induce the oxidation of P700 in PSI, and mainly inactivated PSI. Increases in the intensity, duration and frequency of SP light enhanced PSI photoinhibition. PSI photoinhibition required the presence of O2. The inactivation of PSI suppressed the net CO2 assimilation. On the other hand, the increase in the oxidized state of P700 suppressed PSI inactivation. That is, PSI with a reduced reaction center would produce reactive oxygen species (ROS) by SP light, leading to PSI photodamage. This mechanism probably explains the PSI photodamage induced by constant light. PMID- 24793755 TI - Effects of preterm birth and gender on temperament and behavior in children. AB - The aim of the present study was to assess the direct and interactive effects of premature birth and gender on temperament and behavioral problems in 80 children aged 18-36 months. The sample was composed of children born preterm (PT; n=44) and children born full-term (FT; n=36). The children's mothers completed temperament (ECBQ) and behavioral problem (CBCL 1.5-5) assessments. Analyses of variance (ANOVA 2*2) were performed. With regard to temperament, PT children exhibited significantly higher scores on high-intensity pleasure and perceptual sensitivity and lower scores on discomfort, cuddliness, and Attentional Focusing compared with FT children. Girls scored higher on fear and discomfort compared with boys. With concern to behavioral problems, PT children scored higher on attention problems compared with FT children. No interactive effect of premature birth and gender on temperament or behavioral problems was found. PMID- 24793754 TI - Significance of the photosystem II core phosphatase PBCP for plant viability and protein repair in thylakoid membranes. AB - PSII undergoes photodamage, which results in photoinhibition-the light-induced loss of photosynthetic activity. The main target of damage in PSII is the reaction center protein D1, which is buried in the massive 1.4 MDa PSII holocomplex. Plants have evolved a PSII repair cycle that degrades the damaged D1 subunit and replaces it with a newly synthesized copy. PSII core proteins, including D1, are phosphorylated in high light. This phosphorylation is important for the mobilization of photoinhibited PSII from stacked grana thylakoids to the repair machinery in distant unstacked stroma lamellae. It has been recognized that the degradation of the damaged D1 is more efficient after its dephosphorylation by a protein phosphatase. Recently a protein phosphatase 2C (PP2C)-type PSII core phosphatase (PBCP) has been discovered, which is involved in the dephosphorylation of PSII core proteins. Its role in PSII repair, however, is unknown. Using a range of spectroscopic and biochemical techniques, we report that the inactivation of the PBCP gene affects the growth characteristic of plants, with a decreased biomass and altered PSII functionality. PBCP mutants show increased phosphorylation of core subunits in dark and photoinhibitory conditions and a diminished degradation of the D1 subunit. Our results on D1 turnover in PBCP mutants suggest that dephosphorylation of PSII subunits is required for efficient D1 degradation. PMID- 24793756 TI - The SHP-1 expression is associated with cytokines and psychopathological status in unmedicated first episode schizophrenia patients. AB - BACKGROUND: Recent lines of research have boosted awareness of the immunological facets of schizophrenia. However, associations with protein tyrosine phosphatase regulators have never been reported. The aim of our study was to investigate the expression and promoter status methylation of phosphatase SHP-1, a key negative regulator of the inflammatory process, in Peripheral blood mononuclear cells (PBMCs) of Schizophrenic patients. METHODS: We enrolled fifty-four (28 men and 26 women) unmedicated first episode subjects (SC) who met DSM-IV and thirty-eight (22 men and 16 women) healthy controls (HC). The SC psychopathological status was assessed using the Positive and Negative Syndrome Scale. We evaluated SHP-1 expression by Quantitative Real-time PCR (qPCR) and Western blotting (WB) methods and promoter status methylation through PCR bisulfate. IKK/NFkB signaling was detected by WB, and medium and plasma levels of pro-inflammatory cytokines (IL 1beta, IL-2, and TNF-alpha) by the ELISA method. SHP-1 was silenced by treating cells with specific siRNA. RESULTS: We found a significantly lower level of SHP-1 gene expression in PBMCs from SC vs. HC, consistently with which the promoter region analyzed presented significant hypermethylation. Silencing of SHP-1 expression induced higher activation of IKK/NF-kB signaling and pro-inflammatory cytokine production in ex vivo PBMCs from both SC and HC. Linear regression among patients generated a model in which SHP-1 expression explained 30% of the clinical negative symptom variance (adjusted R(2)=0.30, ANOVA p<0.001). CONCLUSIONS: Our findings are the first to suggest that impairment of SHP-1 expression is involved in the physiopathology of schizophrenia, opening fruitful new avenues for ameliorating treatment at least of negative symptoms. PMID- 24793757 TI - Elevated serum levels of FGF-2, NGF and IGF-1 in patients with manic episode of bipolar disorder. AB - Multiple neurotrophic and/or growth factors, recently nominated as "angioneurins", play the key roles in mood modulation and neuroplasticity, and their dysfunction might be involved in the pathophysiology and treatment of mood disorders. We examined serum levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2, nerve growth factor (NGF) and insulin-like growth factor (IGF)-1 in 70 drug-naive or drug-free patients with manic episode of bipolar disorder and 50 healthy controls, using the enzyme-linked immunosorbent assay (ELISA) method. The results showed that mean serum levels of VEGF, FGF-2, NGF and IGF-1 were 168.13+/-225.61pg/ml, 279.09+/-378.62pg/ml, 61.38+/-171.67pg/ml and 162.01+/-72.00ng/ml in patients, and 140.80+/ 143.71pg/ml, 275.46+/-235.29pg/ml, 36.34+/-15.14pg/ml and 138.90+/-80.11ng/ml in healthy controls, respectively. Serum levels of FGF-2, NGF and IGF-1 in patients were significantly higher than those in healthy controls, though there was no statistical difference in serum VEGF level between two groups. Moreover, serum NGF level in patients was significantly correlated with duration of disorder and times of previous manic episodes. We conclude that the increase of serum FGF-2, NGF and IGF-1 levels in manic state of bipolar disorder may be associated with their compensatory roles of neuroprotection and angiogenesis, and these angioneurins may be involved in the pathophysiology of bipolar disorder. PMID- 24793758 TI - Transcription: the epicenter of gene expression. PMID- 24793759 TI - Epigenetic regulation by polycomb group complexes: focus on roles of CBX proteins. AB - Polycomb group (PcG) complexes are epigenetic regulatory complexes that conduct transcriptional repression of target genes via modifying the chromatin. The two best characterized forms of PcG complexes, polycomb repressive complexes 1 and 2 (PRC1 and PRC2), are required for maintaining the stemness of embryonic stem cells and many types of adult stem cells. The spectra of target genes for PRCs are dynamically changing with cell differentiation, which is essential for proper decisions on cell fate during developmental processes. Chromobox (CBX) family proteins are canonical components in PRC1, responsible for targeting PRC1 to the chromatin. Recent studies highlight the function specifications among CBX family members in undifferentiated and differentiated stem cells, which reveal the interplay between compositional diversity and functional specificity of PRC1. In this review, we summarize the current knowledge about targeting and functional mechanisms of PRCs, emphasizing the recent breakthroughs related to CBX proteins under a number of physiological and pathological conditions. PMID- 24793760 TI - The polyadenylation code: a unified model for the regulation of mRNA alternative polyadenylation. AB - The majority of eukaryotic genes produce multiple mRNA isoforms with distinct 3' ends through a process called mRNA alternative polyadenylation (APA). Recent studies have demonstrated that APA is dynamically regulated during development and in response to environmental stimuli. A number of mechanisms have been described for APA regulation. In this review, we attempt to integrate all the known mechanisms into a unified model. This model not only explains most of previous results, but also provides testable predictions that will improve our understanding of the mechanistic details of APA regulation. Finally, we briefly discuss the known and putative functions of APA regulation. PMID- 24793761 TI - mRNA quality control at the 5' end. AB - All eukaryotic mRNAs are capped at their 5' end. Capping of mRNAs takes place co transcriptionally and involves three steps. The intermediates of the capping process, as well as the uncapped 5' tri-phosphate RNA, are resistant to decapping and degradation by known factors, leading to the assumption that the capping process always proceeds to completion. This view was recently drastically changed. A novel family of enzymes, including the yeast proteins Rai1, Dxo1/Ydr370C, and the mammalian protein DXO/Dom3Z, has been identified. These enzymes catalyze the conversion of the improperly capped mRNAs to 5' mono phosphate RNA, allowing them to be degraded by 5'-3' exoribonucleases. Several of these enzymes also possess 5'-3' exoribonuclease activities themselves, and can single-handedly clear the improperly capped mRNAs. Studying of these enzymes has led to the realization that mRNA capping does not always proceed to completion, and the identification of an mRNA capping quality control mechanism in eukaryotes. In this paper, we briefly review recent advances in this area. PMID- 24793762 TI - mRNA stability in the nucleus. AB - Eukaryotic gene expression is controlled by different levels of biological events, such as transcription factors regulating the timing and strength of transcripts production, alteration of transcription rate by RNA processing, and mRNA stability during RNA processing and translation. RNAs, especially mRNAs, are relatively vulnerable molecules in living cells for ribonucleases (RNases). The maintenance of quality and quantity of transcripts is a key issue for many biological processes. Extensive studies draw the conclusion that the stability of RNAs is dedicated-regulated, occurring co- and post-transcriptionally, and translation-coupled as well, either in the nucleus or cytoplasm. Recently, RNA stability in the nucleus has aroused much research interest, especially the stability of newly-made transcripts. In this article, we summarize recent progresses on mRNA stability in the nucleus, especially focusing on quality control of newly-made RNA by RNA polymerase II in eukaryotes. PMID- 24793763 TI - Mechanism and factors that control HIV-1 transcription and latency activation. AB - After reverse transcription, the HIV-1 proviral DNA is integrated into the host genome and thus subjected to transcription by the host RNA polymerase II (Pol II). With the identification and characterization of human P-TEFb in the late 1990 s as a specific host cofactor required for HIV-1 transcription, it is now believed that the elongation stage of Pol II transcription plays a particularly important role in regulating HIV-1 gene expression. HIV-1 uses a sophisticated scheme to recruit human P-TEFb and other cofactors to the viral long terminal repeat (LTR) to produce full-length HIV-1 transcripts. In this process, P-TEFb is regulated by the reversible association with various transcription factors/cofactors to form several multi-subunit complexes (e.g., 7SK snRNP, super elongation complexes (SECs), and the Brd4-P-TEFb complex) that collectively constitute a P-TEFb network for controlling cellular and HIV-1 transcription. Recent progresses in HIV-1 transcription were reviewed in the paper, with the emphasis on the mechanism and factors that control HIV-1 transcription and latency activation. PMID- 24793764 TI - Early lethality of shRNA-transgenic pigs due to saturation of microRNA pathways. AB - RNA interference (RNAi) is considered as a potential modality for clinical treatment and anti-virus animal breeding. Here, we investigate the feasibility of inhibiting classical swine fever virus (CSFV) replication by short hairpin RNA (shRNA) in vitro and in vivo. We generate four different shRNA-positive clonal cells and two types of shRNA-transgenic pigs. CSFV could be effectively inhibited in shRNA-positive clonal cells and tail tip fibroblasts of shRNA-transgenic pigs. Unexpectedly, an early lethality due to shRNA is observed in these shRNA transgenic pigs. With further research on shRNA-positive clonal cells and transgenic pigs, we report a great induction of interferon (IFN)-responsive genes in shRNA-positive clonal cells, altered levels of endogenous microRNAs (miRNA), and their processing enzymes in shRNA-positive cells. What is more, abnormal expressions of miRNAs and their processing enzymes are also observed in the livers of shRNA-transgenic pigs, indicating saturation of miRNA/shRNA pathways induced by shRNA. In addition, we investigate the effects of shRNAs on the development of somatic cell nuclear transfer (SCNT) embryos. These results show that shRNA causes adverse effects in vitro and in vivo and shRNA-induced disruption of the endogenous miRNA pathway may lead to the early lethality of shRNA-transgenic pigs. We firstly report abnormalities of the miRNA pathway in shRNA-transgenic animals, which may explain the early lethality of shRNA transgenic pigs and has important implications for shRNA-transgenic animal preparation. PMID- 24793765 TI - Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene. AB - Crigler-Najjar syndrome type I (CN-I) is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene (UGT1A1) on chromosome 2q37. Two patients clinically diagnosed with CN-I were examined in this paper. We sequenced five exons and their flanking sequences, specifically the promoter region of UGT1A1, of the two patients and their parents. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the UGT1A1 gene copy number of one patient. In patient A, two mutations, c.239_245delCTGTGCC (p.Pro80HisfsX6; had not been reported previously) and c.1156G>T (p.Val386Phe), were identified. In patient B, we found that this patient had lost heterozygosity of the UGT1A1 gene by inheriting a deletion of one allele, and had a novel mutation c.1253delT (p.Met418ArgfsX5) in the other allele. In summary, we detected three UGT1A1 mutations in two CN-I patients: c.239_245delCTGTGCC (p.Pro80HisfsX6), c.1253delT (p.Met418ArgfsX5), and c.1156G>T (p.Val386Phe). The former two mutations are pathogenic; however, the pathogenic mechanism of c.1156G>T (p.Val386Phe) is unknown. PMID- 24793767 TI - High-level soluble expression of the hemA gene from Rhodobacter capsulatus and comparative study of its enzymatic properties. AB - The Rhodobacter capsulatus hemA gene, which encodes 5-aminolevulinic acid synthase (ALAS), was expressed in Escherichia coli Rosetta (DE3) and the enzymatic properties of the purified recombinant ALAS (RC-ALAS) were studied. Compared with ALASs encoded by hemA genes from Agrobacterium radiobacter (AR ALAS) and Rhodobacter sphaeroides (RS-ALAS), the specific activity of RC-ALAS reached 198.2 U/mg, which was about 31.2% and 69.5% higher than those of AR-ALAS (151.1 U/mg) and RS-ALAS (116.9 U/mg), respectively. The optimum pH values and temperatures of the three above mentioned enzymes were all pH 7.5 and 37 degrees C, respectively. Moreover, RC-ALAS was more sensitive to pH, while the other two were sensitive to temperature. The effects of metals, ethylene diamine tetraacetic acid (EDTA), and sodium dodecyl sulfate (SDS) on the three ALASs were also investigated. The results indicate that they had the same effects on the activities of the three ALASs. SDS and metal ions such as Co(2+), Zn(2+), and Cu(2+) strongly inhibited the activities of the ALASs, while Mn(2+) exerted slight inhibition, and K(+), Ca(2+), Ba(2+), Mg(2+), or EDTA had no significant effect. The specificity constant of succinyl coenzyme A [(kcat/Km)(S-CoA)] of RC ALAS was 1.4989, which was higher than those of AR-ALAS (0.7456) and RS-ALAS (1.1699), showing its high catalytic efficiency. The fed-batch fermentation was conducted using the recombinant strain containing the R. capsulatus hemA gene, and the yield of 5-aminolevulinic acid (ALA) achieved was 8.8 g/L (67 mmol/L) under the appropriate conditions. PMID- 24793768 TI - Expression of three essential antioxidants of Helicobacter pylori in clinical isolates. AB - OBJECTIVE: Helicobacter pylori maintains long-term persistence in the host and combats oxidative stress via many antioxidant proteins, which are expected to be relevant to bacterial-associated gastric diseases. We aimed to investigate the expression of three essential antioxidants in H. pylori strains isolated from patients with different clinical outcomes. METHODS: Forty H. pylori strains were isolated from endoscopic biopsy specimens of gastric mucosa from 13 patients with gastric cancer, 13 with peptic ulcer, and 14 with gastritis. The expression of thioredoxin 1 (Trx1), arginase (RocF), and alkyl hydroperoxide reductase (AhpC) in H. pylori was measured by real-time PCR. Comparisons among multiple sample sets were analyzed using a one-way ANOVA test. Pearson's correlation test was used to assess relationships among multiple continuous variables. RESULTS: Trx1 expression of H. pylori in gastric cancer and peptic ulcer tissues was higher than that in tissues with gastritis. RocF expression of H. pylori in gastric cancer tissues was higher than that in tissues exhibiting peptic ulcer and gastritis. However, we did not find any differences in AhpC expression in samples from patients with different clinical outcomes. The expression of Trx1 and RocF had a positive, linear correlation. The expression of Trx1 and AhpC had a positive correlation without a linear trend. We found no correlation between the expression of RocF and AhpC. CONCLUSIONS: Our observations indicate that the expression of Trx1 and RocF in H. pylori might be related to gastric carcinogenesis. In H. pylori, the expression of members of the antioxidant system may be correlated and relevant to gastric cancer. PMID- 24793769 TI - Conflict of interest, tailored science, and responsibility of scientific institutions and journals. AB - Recent revelations have raised concerns on how conflicts of interest may involve even leading scientists and prestigious institutions and lead to bias in reporting and assessing scientific evidence. These have highlighted the need for action to safeguard scientific integrity and public health. The Italian Epidemiology Association has declared that the "biased and deliberately tailored use of the scientific evidence" by scientists with a conflict of interest serves to delay needed measures to prevent harm to public health from a polluting Italian steel plant's continuing chemical emissions. In France, unresolved concerns over conflict of interest forced the Centre for Research in Epidemiology and Public Health to cancel its imminent appointment of a prominent scientist as its Director. These negative events demonstrate the necessity for scientific institutions and journals to implement rigorous measures regarding conflict of interest and the safeguarding of scientific integrity and public health. PMID- 24793766 TI - Adipose-derived stem cells transfected with pEGFP-OSX enhance bone formation during distraction osteogenesis. AB - This study was designed to investigate the effects of local delivery of adipose derived stem cells (ADSCs) transfected with transcription factor osterix (OSX) on bone formation during distraction osteogenesis. New Zealand white rabbits (n=54) were randomly divided into three groups (18 rabbits per group). A directed cloning technique was used for the construction of recombinant plasmid pEGFP-OSX, where EGFP is the enhanced green fluorescence protein. After osteodistraction of the right mandible of all experimental rabbits, rabbits in group A were treated with ADSCs transfected with pEGFP-OSX, group B with ADSCs transfected with pEGFP N1, and group C with physiological saline. Radiographic and histological examinations were processed after half of the animals within each group were humanely killed by injection of sodium pentothal at Week 2 or 6 after surgery. The distraction bone density was measured as its projectional bone mineral density (BMD). Three parameters were measured, namely, the thickness of new trabeculae (TNT), and the volumes of the newly generated cortical bone (NBV1) and the cancellous bone (NBV2) of the distracted regions. Good bone generation in the distraction areas was found in group A, which had the highest BMD, TNT, and NBV in the distraction zones among the groups. There was no significant difference in bone generation in the distraction areas between groups B and C. The results indicate that the transplantation of ADSCs transfected with pEGFP-OSX can effectively promote bone generation during distraction in vivo. PMID- 24793770 TI - D-cycloserine enhances both intrinsic excitability of CA1 hippocampal neurons and expression of activity-regulated cytoskeletal (Arc) protein. AB - The interaction of NMDA receptor (NMDAR) activation and other mechanisms regulating neuronal excitability have not been thoroughly described. While excess activation of NMDARs results in excitotoxicity, partial activation of NMDARs by d cycloserine (DCS) is nootropic, enhancing both acquisition and extinction of memories. The mechanism by which DCS treatment enhances memory is unclear. NMDAR activation has been shown to increase expression of the activity-regulated cytoskeletal (Arc) protein associated with neural plasticity and enhanced memory. Enhanced memory is also associated with increases in neuronal intrinsic excitability, i.e. reductions in post-burst afterhyperpolarizations (AHPs) after acquisition of new tasks. Reductions in AHPs can occur when Ca(2+) influx is reduced. This study aimed to determine if either if Arc expression, intrinsic excitability, or both were altered following systemic administration of a memory enhancing dose of DCS, i.e. what form of plasticity would be exhibited. Both Arc protein expression and intrinsic excitability were enhanced in tissue prepared 1h post-administration of a nootropic dose of DCS. Both mechanisms have been strongly associated with memory enhancement, but have not previously been demonstrated to change across the same time frame in the same preparation in response to DCS treatment. PMID- 24793771 TI - Spectrotemporal resolution tradeoff in auditory processing as revealed by human auditory brainstem responses and psychophysical indices. AB - Auditory filter theory dictates a physiological compromise between frequency and temporal resolution of cochlear signal processing. We examined neurophysiological correlates of these spectrotemporal tradeoffs in the human auditory system using auditory evoked brain potentials and psychophysical responses. Temporal resolution was assessed using scalp-recorded auditory brainstem responses (ABRs) elicited by paired clicks. The inter-click interval (ICI) between successive pulses was parameterized from 0.7 to 25 ms to map ABR amplitude recovery as a function of stimulus spacing. Behavioral frequency difference limens (FDLs) and auditory filter selectivity (Q10 of psychophysical tuning curves) were obtained to assess relations between behavioral spectral acuity and electrophysiological estimates of temporal resolvability. Neural responses increased monotonically in amplitude with increasing ICI, ranging from total suppression (0.7 ms) to full recovery (25 ms) with a temporal resolution of ~3-4 ms. ABR temporal thresholds were correlated with behavioral Q10 (frequency selectivity) but not FDLs (frequency discrimination); no correspondence was observed between Q10 and FDLs. Results suggest that finer frequency selectivity, but not discrimination, is associated with poorer temporal resolution. The inverse relation between ABR recovery and perceptual frequency tuning demonstrates a time-frequency tradeoff between the temporal and spectral resolving power of the human auditory system. PMID- 24793772 TI - GABAAergic stimulation modulates intracellular protein arginine methylation. AB - Changes in cytoplasmic pH are known to regulate diverse cellular processes and influence neuronal activities. In neurons, the intracellular alkalization is shown to occur after stimulating several channels and receptors. For example, it has previously demonstrated in P19 neurons that a sustained intracellular alkalinization can be mediated by the Na(+)/H(+) antiporter. In addition, the benzodiazepine binding subtypes of the gamma-amino butyric acid type A (GABAA) receptor mediate a transient intracellular alkalinization when they are stimulated. Because the activities of many enzymes are sensitive to pH shift, here we investigate the effects of intracellular pH modulation resulted from stimulating GABAA receptor on the protein arginine methyltransferases (PRMT) activities. We show that the major benzodiazepine subtype (2alpha1, 2beta2, 1gamma2) is constitutively expressed in both undifferentiated P19 cells and retinoic acid (RA) differentiated P19 neurons. Furthermore stimulation with diazepam and, diazepam plus muscimol produce an intracellular alkalinization that can be detected ex vivo with the fluorescence dye. The alkalinization results in significant perturbation in protein arginine methylation activity as measured in methylation assays with specific protein substrates. Altered protein arginine methylation is also observed when cells are treated with the GABAA agonist muscimol but not an antagonist, bicuculline. These data suggest that pH-dependent and pH-independent methylation pathways can be activated by GABAAergic stimulation, which we verified using hippocampal slice preparations from a mouse model of fragile X syndrome. PMID- 24793773 TI - p16 INK4a and Ki67 expression in normal, dysplastic and neoplastic uterine cervical epithelium and human papillomavirus (HPV) infection. AB - Cellular cycle proteins like the p16(INK4a) and the Ki67 proliferation nuclear antigen have been used as oncogenicity cellular markers. The E6 and E7 oncoproteins interact with tumor suppressor genes p53 and pRb, culminating with the p16(INK4a) overexpression. The objective of this study was to evaluate the presence of HPV-DNA in 174 cervical biopsies and correlate the different histological grades with the p16(INK4a) and Ki67 immunohistochemical expression (IHC). A cross-sectional study that enrolled a total of 174 women who underwent uterine cervical biopsies between February 2003 and December 2006, in southern Brazil, was performed. Cervical smear samples were analyzed for the presence of HPV-DNA through polymerase chain reaction (PCR), and biopsy samples were examined for p16(INK4A) and Ki67 expression through IHC techniques. The presence of HPV DNA was observed in 89% of the tested patients, among which 52% were positive for high-risk (HR) viral types [16, 18 and 31]. Regarding p16(INK4a), an expression of 69% was observed, being expressed in 100% of the high-grade squamous lesions (HSIL) and HR-HPV-DNA positives. Ki67 expression was associated with the lesion grade, being more expressive in the most severe lesions (p<0.001). p16(INK4A) and Ki67 markers coexpression was present in 86% of the samples (p<0.001), being 100% among those positive to HR-HPV-DNA with HSIL (p<0.001). The results suggest an association between the presence of HR-HPV infection and the p16(INK4a) and Ki67 expression and which is even stronger among women with HSIL. PMID- 24793774 TI - In silico approaches to predict the potential of milk protein-derived peptides as dipeptidyl peptidase IV (DPP-IV) inhibitors. AB - Molecular docking of a library of all 8000 possible tripeptides to the active site of DPP-IV was used to determine their binding potential. A number of tripeptides were selected for experimental testing, however, there was no direct correlation between the Vina score and their in vitro DPP-IV inhibitory properties. While Trp-Trp-Trp, the peptide with the best docking score, was a moderate DPP-IV inhibitor (IC50 216MUM), Lineweaver and Burk analysis revealed its action to be non-competitive. This suggested that it may not bind to the active site of DPP-IV as assumed in the docking prediction. Furthermore, there was no significant link between DPP-IV inhibition and the physicochemical properties of the peptides (molecular mass, hydrophobicity, hydrophobic moment (MUH), isoelectric point (pI) and charge). LIGPLOTs indicated that competitive inhibitory peptides were predicted to have both hydrophobic and hydrogen bond interactions with the active site of DPP-IV. DPP-IV inhibitory peptides generally had a hydrophobic or aromatic amino acid at the N-terminus, preferentially a Trp for non-competitive inhibitors and a broader range of residues for competitive inhibitors (Ile, Leu, Val, Phe, Trp or Tyr). Two of the potent DPP-IV inhibitors, Ile-Pro-Ile and Trp-Pro (IC50 values of 3.5 and 44.2MUM, respectively), were predicted to be gastrointestinally/intestinally stable. This work highlights the needs to test the assumptions (i.e. competitive binding) of any integrated strategy of computational and experimental screening, in optimizing screening. Future strategies targeting allosteric mechanisms may need to rely more on structure-activity relationship modeling, rather than on docking, in computationally selecting peptides for screening. PMID- 24793775 TI - Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents. AB - Frog skin constitutes a rich source of peptides with a wide range of biological properties. These include host-defense peptides with cytotoxic activities against bacteria, fungi, protozoa, viruses, and mammalian cells. Several hundred such peptides from diverse species have been described. Although attention has been focused mainly on antimicrobial activity, the therapeutic potential of frog skin peptides as anti-infective agents remains to be realized and no compound based upon their structures has yet been adopted in clinical practice. Consequently, alternative applications are being explored. Certain naturally occurring frog skin peptides, and analogs with improved therapeutic properties, show selective cytotoxicity against tumor cells and viruses and so have potential for development into anti-cancer and anti-viral agents. Some peptides display complex cytokine-mediated immunomodulatory properties. Effects on the production of both pro-inflammatory and anti-inflammatory cytokines by peritoneal macrophages and peripheral blood mononuclear cells have been observed so that clinical applications as anti-inflammatory, immunosuppressive, and immunostimulatory agents are possible. Several frog skin peptides, first identified on the basis of antimicrobial activity, have been shown to stimulate insulin release both in vitro and in vivo and so show potential as incretin-based therapies for treatment of patients with Type 2 diabetes mellitus. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Ascaphidae, Alytidae, Pipidae, Dicroglossidae, Leptodactylidae, Hylidae, and Ranidae families that complement their potential role as anti-infectives for use against multidrug resistant microorganisms. PMID- 24793776 TI - Experimental lens capsular bag model for posterior capsule opacification. AB - An in vitro culture model enabling posterior capsule opacification (PCO) to be investigated was developed and established by using low-melting-point (LMP) agarose gel to support the capsular bag. After removal of the cornea from rodent and porcine eyeballs, the lens zonules were dissected. Whole lens explants were embedded into 2 % (37 degrees C) LMP-agarose gel solution. As performed routinely in cataract surgery, capsulotomy and lens fiber removal were carried out in the solidified LMP-agarose gel as sham cataract surgery. The LMP-agarose gel-supported capsular bag/lens epithelial cell (CB-LEC) complexes were maintained in Dulbecco's modified Eagle medium supplemented with 10 % fetal bovine serum in an anterior face-down position. The proliferation and migration of LECs into the posterior capsule were observed every 12 h by phase-contrast microscopy. Epithelial cells were observed at the central portion of the CB-LEC complexes after 56.57 +/- 16.56 h (n = 7) and 106 +/- 14.03 h (n = 6) of culture, for rodent and porcine lenses, respectively. The solidified gel allowed clear microscopic observations and whole-mount immunostaining evaluations of the whole area of the capsular bag. Histological examinations revealed the proliferation, migration, and transdifferentiation of LECs related to posterior capsule opacification. This new in vitro culture model provides experimental benefits by maintaining the natural contour of the capsule without implants inside or outside of the capsule. In addition, this model system allows pharmacological and histological evaluations of the cultured CB-LEC complexes without additional manipulations. PMID- 24793777 TI - Disturbance of recruitment success of mantis shrimp in Tokyo Bay associated with effects of hypoxia on the early life history. AB - We investigated effects of severe hypoxia (dissolved oxygen <1 ml l(-1)) on recruitment of mantis shrimp Oratosquilla oratoria in Tokyo Bay. Ten-year field surveys were conducted to examine quantitative relationships in annual mean densities of larvae and juveniles, and spatial distribution of juveniles and severe hypoxia. There was no significant correlation between annual mean densities of larvae and juveniles, suggesting that mortality during larval or juvenile stages varies among years, which might have regulated abundance of young of-the-year juveniles. Juvenile density was low in the severely hypoxic area, implying that hypoxia could affect survivals and spatial distribution of juveniles. Meanwhile, there are yearly fluctuations in juvenile density in normoxic areas of both northern and southern part of the bay. This evidence suggests that abundance of post-settled juveniles might have been determined by not only effects of hypoxia, but also other factors influencing mortality during the early life stages. PMID- 24793778 TI - Deep-sea faunal communities associated with a lost intermodal shipping container in the Monterey Bay National Marine Sanctuary, CA. AB - Carrying assorted cargo and covered with paints of varying toxicity, lost intermodal containers may take centuries to degrade on the deep seafloor. In June 2004, scientists from Monterey Bay Aquarium Research Institute (MBARI) discovered a recently lost container during a Remotely Operated Vehicle (ROV) dive on a sediment-covered seabed at 1281 m depth in Monterey Bay National Marine Sanctuary (MBNMS). The site was revisited by ROV in March 2011. Analyses of sediment samples and high-definition video indicate that faunal assemblages on the container's exterior and the seabed within 10 m of the container differed significantly from those up to 500 m. The container surface provides hard substratum for colonization by taxa typically found in rocky habitats. However, some key taxa that dominate rocky areas were absent or rare on the container, perhaps related to its potential toxicity or limited time for colonization and growth. Ecological effects appear to be restricted to the container surface and the benthos within ~10 m. PMID- 24793779 TI - Pyrene induces a reduction in midbrain size and abnormal swimming behavior in early-hatched pufferfish larvae. AB - Spills of heavy oil (HO) have an adverse effect on marine life. We have demonstrated previously that exposure to HO by fertilized eggs of the pufferfish (Takifugu rubripes) induces neural disruption and behavioral abnormality in early hatched larvae. Here, two kinds of polycyclic aromatic hydrocarbons, pyrene and phenanthrene, were selected to examine their toxic effects on larval behavior of another pufferfish species (T. niphobles). Larvae exposed to pyrene or phenanthrene exhibited no abnormalities in morphology. However, those exposed to pyrene but not phenanthrene swam in an uncoordinated manner, although their swimming distance and speed were normal. The optic tectum, a part of the midbrain, of pyrene-exposed larvae did not grow to full size. Thus, these findings are indicated that pyrene might be a contributor to the behavioral and neuro-developmental toxicity, although there is no indication that it is the only compound participating in the toxicity of the heavy oil mixture. PMID- 24793780 TI - 7th International Conference on Marine Pollution and Ecotoxicology. PMID- 24793781 TI - Satellite-observed variability of phytoplankton size classes associated with a cold eddy in the South China Sea. AB - Ocean-color remote sensing has been used as a tool to detect phytoplankton size classes (PSCs). In this study, a three-component model of PSC was reparameterized using seven years of pigment measurements acquired in the South China Sea (SCS). The model was then used to infer PSC in a cyclonic eddy which was observed west of Luzon Island from SeaWiFS chlorophyll-a (chla) and sea-surface height anomaly (SSHA) products. Enhanced productivity and a shift in the PSC were observed, which were likely due to upwelling of nutrient-rich water into the euphotic zone. The supply of nutrients promoted the growth of larger cells (micro- and nanoplankton), and the PSC shifted to greater sizes. However, the picoplankton were still important and contributed ~48% to total chla concentration. In addition, PSC time series revealed a lag period of about three weeks between maximum eddy intensity and maximum chlorophyll, which may have been related to phytoplankton growth rate and duration of eddy intensity. PMID- 24793782 TI - Temperature extremes reduce seagrass growth and induce mortality. AB - Extreme heating (up to 43 degrees C measured from five-year temperature records) occurs in shallow coastal seagrass meadows of the Great Barrier Reef at low tide. We measured effective quantum yield (phiPSII), growth, senescence and mortality in four tropical seagrasses to experimental short-duration (2.5h) spikes in water temperature to 35 degrees C, 40 degrees C and 43 degrees C, for 6 days followed by one day at ambient temperature. Increasing temperature to 35 degrees C had positive effects on phiPSII (the magnitude varied between days and was highly correlated with PPFD), with no effects on growth or mortality. 40 degrees C represented a critical threshold as there were strong species differences and there was a large impact on growth and mortality. At 43 degrees C there was complete mortality after 2-3 days. These findings indicate that increasing duration (more days in a row) of thermal events above 40 degrees C is likely to affect the ecological function of tropical seagrass meadows. PMID- 24793783 TI - Prospective assessment of urinary, gastrointestinal and sexual symptoms before, during and after image-guided volumetric modulated arc therapy for prostate cancer. AB - OBJECTIVE: The aim of this study was to prospectively assess the development of 24 urinary, gastrointestinal and sexual symptoms in patients with prostate cancer (PCa) during and after image-guided volumetric modulated arc therapy (IG-VMAT). MATERIAL AND METHODS: A total of 87 patients with PCa participated in this study. The patients were asked to complete a modified version of the Prostate Cancer Symptom Scale (PCSS) questionnaire before radiotherapy (RT) (baseline), at the start of RT, at the end of RT and 1 year after RT. Changes in symptoms at the start of RT, at the end of RT and 1 year after RT compared to baseline were analysed by a mixed model analysis of repeated measurements with the following covariates: age, comorbidity, smoking and androgen deprivation therapy (ADT). RESULTS: All urinary problems except for haematuria increased significantly at the end of RT compared to baseline. One year after RT, there was no longer any difference compared to baseline for any of the urinary symptoms. All gastrointestinal symptoms except for nausea increased significantly at the end of RT. One year after RT, patients also reported slightly higher degrees of stool frequency, bowel leakage, planning of toilet visits, flatulence, mucus, gastrointestinal bleeding and impact of gastrointestinal bother on daily activities compared to baseline. All sexual symptoms increased significantly at all times compared to baseline. The use of ADT was associated with worse sexual symptoms. CONCLUSIONS: IG-VMAT is a safe treatment for PCa, with few and mild changes in urinary and gastrointestinal symptoms 1 year after RT compared to baseline. Sexual symptoms deteriorated both during and after RT. The use of ADT was associated with worse sexual symptoms. PMID- 24793784 TI - The effectiveness of computerized drug-lab alerts: a systematic review and meta analysis. AB - BACKGROUND: Inadequate lab monitoring of drugs is a potential cause of ADEs (adverse drug events) which is remediable. OBJECTIVES: To determine the effectiveness of computerized drug-lab alerts to improve medication-related outcomes. DATA SOURCES: Citations from the Computerized Clinical Decision Support System Systematic Review (CCDSSR) and MMIT (Medications Management through Health Information Technology) databases, which had searched MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts from 1974 to March 27, 2013. STUDY SELECTION: Randomized controlled trials (RCTs) of clinician-targeted computerized drug lab alerts conducted in any healthcare setting. Two reviewers performed full text review to determine study eligibility. DATA ABSTRACTION: A single reviewer abstracted data and evaluated validity of included studies using Cochrane handbook domains. DATA SYNTHESIS: Thirty-six studies met the inclusion criteria (25 single drug studies with 22,504 participants, 14 targeting anticoagulation; 11 multi-drug studies with 56,769 participants). ADEs were reported as an outcome in only four trials, all targeting anticoagulants. Computerized drug-lab alerts did not reduce ADEs (OR 0.89, 95% CI 0.79-1.00, p=0.05), length of hospital stay (SMD 0.00, 95%CI -0.93 to 0.93, p=0.055, 1 study), likelihood of hypoglycemia (OR 1.29, 95% CI 0.31 5.37) or likelihood of bleeding, but were associated with increased likelihood of prescribing changes (OR 1.73, 95% CI 1.21-2.47) or lab monitoring (OR 1.47, 95% confidence interval 1.12-1.94) in accordance with the alert. CONCLUSIONS: There is no evidence that computerized drug-lab alerts are associated with important clinical benefits, but there is evidence of improvement in selected clinical surrogate outcomes (time in therapeutic range for vitamin K antagonists), and changes in process outcomes (lab monitoring and prescribing decisions). PMID- 24793785 TI - Nonsynonymous substitution rate heterogeneity in the peptide-binding region among different HLA-DRB1 lineages in humans. AB - An extraordinary diversity of amino acid sequences in the peptide-binding region (PBR) of human leukocyte antigen [HLA; human major histocompatibility complex (MHC)] molecules has been maintained by balancing selection. The process of accumulation of amino acid diversity in the PBR for six HLA genes (HLA-A, B, C, DRB1, DQB1, and DPB1) shows that the number of amino acid substitutions in the PBR among alleles does not linearly correlate with the divergence time of alleles at the six HLA loci. At these loci, some pairs of alleles show significantly less nonsynonymous substitutions at the PBR than expected from the divergence time. The same phenomenon was observed not only in the HLA but also in the rat MHC. To identify the cause for this, DRB1 sequences, a representative case of a typical nonlinear pattern of substitutions, were examined. When the amino acid substitutions in the PBR were placed with maximum parsimony on a maximum likelihood tree based on the non-PBR substitutions, heterogeneous rates of nonsynonymous substitutions in the PBR were observed on several branches. A computer simulation supported the hypothesis that allelic pairs with low PBR substitution rates were responsible for the stagnation of accumulation of PBR nonsynonymous substitutions. From these observations, we conclude that the nonsynonymous substitution rate at the PBR sites is not constant among the allelic lineages. The deceleration of the rate may be caused by the coexistence of certain pathogens for a substantially long time during HLA evolution. PMID- 24793786 TI - Self-determined motivation in sport predicts anti-doping motivation and intention: a perspective from the trans-contextual model. AB - OBJECTIVES: Motivation in sport has been frequently identified as a key factor of young athletes' intention of doping in sport, but there has not been any attempt in scrutinizing the motivational mechanism involved. The present study applied the trans-contextual model of motivation to explain the relationship between motivation in a sport context and motivation and the social-cognitive factors (attitude, subjective norm, perceived behavioral control, and intention) from the theory of planned behavior (TPB) in an anti-doping context. DESIGN: A cross sectional survey was conducted. METHODS: Questionnaire data was collected from 410 elite and sub-elite young athletes in Australia (Mean age [17.7+/-3.9 yr], 55.4% male, Years in sport [9.1+/-3.2]). We measured the key model variables of study in relation to sport motivation (Behavioral Regulation in Sport Questionnaire), and the motivation (adapted version of the Treatment Self Regulation Questionnaire) and social cognitive patterns (the theory of planned behavior questionnaire) of doping avoidance. The data was analyzed by variance based structural equation modeling with bootstrapping of 999 replications. RESULTS: The goodness-of-fit of the hypothesized model was acceptable. The bootstrapped parameter estimates revealed that autonomous motivation and amotivation in sport were positively associated with the corresponding types of motivation for the avoidance of doping. Autonomous motivation, subjective norm, and perceived behavioral control in doping avoidance fully mediated the relationship between autonomous motivation in sport and intention for doping avoidance. CONCLUSIONS: The findings support the tenets of the trans-contextual model, and explain how motivation in sport is related to athletes' motivation and intention with respect to anti-doping behaviors. PMID- 24793787 TI - Automatic kinetic bioaccessibility assay of lead in soil environments using flow through microdialysis as a front end to electrothermal atomic absorption spectrometry. AB - In-line microdialysis is in this work hyphenated to electrothermal atomic absorption spectrometry via a dedicated flow-based interface for monitoring the batchwise leaching test endorsed by the Standards, Measurements and Testing Program (SM&T) of the European Commission. The bioaccessible pool of lead in soils is measured using 0.43 mol/L AcOH as extractant. The proposed method allows to gain knowledge of leaching kinetics at real-time, simplify the overall procedure by accurate detection of steady-state conditions and overcome sample filtration or centrifugation. Soil leachates were automatically sampled at specified timeframes (e.g, every 20 or 80 min), processed in an external container (where dilution can be applied at will) and further injected into the atomizer. The method was experimentally validated by comparison of in situ microdialysis sampling results with in-line microfiltration in two soils of varying physicochemical properties. A mathematical framework was used for discrimination of different metal fractions (that is, readily mobilizable against slowly mobilizable lead) and also for estimating the total extractable lead under actual steady-state conditions. We have demonstrated that bioaccessibility tests lasting 16 h as endorsed by SM&T might not suffice for ascertainment of maximum (steady-state) bioaccessibility of lead in terrestrial environments as demanded in risk assessment programs. PMID- 24793788 TI - Understanding bone safety zones during bone marrow aspiration from the iliac crest: the sector rule. AB - PURPOSE: Should the trocar suddenly lose contact with bone during bone marrow aspiration, it may result in visceral injury. The anatomy of the ilium and the structures adjacent to the iliac bone were studied to determine the danger of breach by a trocar introduced into the iliac crest. METHODS: The authors followed two series of patients, one series to do measurements of distance and angles of the structures at risk to the iliac bone and the other to evaluate the risk of a trocar being directed outside the iliac wing during bone marrow aspiration. The authors also examined 24 pelvices by computed tomography (CT) scans of mature adults (48 iliac crests). Lines dividing the iliac wing into six equal sectors were used to form sectors (e.g. sector 1 anterior, sector 6 posterior). Vascular or neurological structures were considered at risk if they were accessible to the tip of a 10-cm trocar introduced into the iliac crest with a possible deviation of 20 degrees from the plane of the iliac wing on the three-dimensional reconstruction. The authors tracked bone marrow aspiration of six different surgeons and calculated among 120 patients (480 entry points) the number of times the needle lost contact with bone in each sector of aspiration. RESULTS: The sector system reliably predicted safe and unsafe areas for trocar placement. Among the 480 entry points in the 120 patients, 94 breaches were observed and higher risks were observed in the thinner sectors. The risk was also higher in obese patients and the risk decreased with more experienced surgeons. The trocar could reach the external iliac artery on pelvic CT scans in the four most anterior sectors with a higher frequency in women. Posterior sectors were at risk for sciatic nerve and gluteal vessel damage when the trocar was pushed deeper than 6 cm into the posterior iliac crest. In cadavers, the dissection demonstrated nine vascular or neurological lesions. CONCLUSIONS: Using the sector system, trocars can be directed away from neural and vascular structures and toward zones that are likely to contain larger bone marrow stock. PMID- 24793789 TI - The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss. AB - Liver kinase B1 (LKB1) loss in lung adenocarcinoma is commonly caused by genetic mutations, but these mutations rarely occur in Asian patients. We recently reported wild-type LKB1 loss via the alteration of NKX2-1/p53-axis-promoted tumor aggressiveness and predicted poor outcomes in cases of lung adenocarcinoma. The mechanistic action of wild-type LKB1 loss within tumor progression remains unknown. The suppression of MYC by LKB1 controls epithelial organization; therefore, we hypothesize that MYC expression can be increased via wild-type LKB1 loss and promotes tumor progression. Here, MYC transcription is upregulated by LKB1-loss-mediated MZF1 expression. The wild-type LKB1-loss-mediated MZF1/MYC axis is responsible for soft-agar growth, migration and invasion in lung adenocarcinoma cells. Moreover, wild-type LKB1 loss-induced cell invasiveness was markedly suppressed by MYC inhibitors (10058-F4 and JQ1). Patients with low LKB1/high-MZF1 or low-LKB1/high-MYC tumors have shorter overall survival and relapse-free-survival periods than patients with high-LKB1/low-MZF1 or high LKB1/low-MYC tumors. In summary, MZF1-mediated MYC expression may promote tumor progression, resulting in poor outcomes in cases of lung adenocarcinoma with low wild-type-LKB1 tumors. PMID- 24793791 TI - Phosphorylated STAT3 physically interacts with NPM and transcriptionally enhances its expression in cancer. AB - The signal transducer and activator of transcription 3 (STAT3) can be activated by the tyrosine kinase domain of the chimeric protein nucleophosmin/anaplastic lymphoma kinase (NPM/ALK), and has a pivotal role in mediating NPM/ALK-related malignant cell transformation. Although the role of STAT3 and wild-type NPM in oncogenesis has been extensively investigated, the relationship between both molecules in cancer remains poorly understood. In the present study, we first demonstrate that STAT3 phosphorylation at tyrosine 705 is accompanied by a concomitant increase in the expression level of NPM. Nuclear co-translocation of phosphorylated STAT3 with NPM can be triggered by interferon-alpha (IFN-alpha) stimulation of Jurkat cells and phosphorylated STAT3 co-localizes with NPM in cancer cells showing constitutive STAT3 activation. We further demonstrate that STAT3 phosphorylation can transcriptionally mediate NPM upregulation in IFN-alpha stimulated Jurkat cells and is responsible for maintaining its expression in cancer cells showing constitutive STAT3 activation. Inhibition of STAT3 phosphorylation or knockdown of NPM expression abrogates their simultaneous transnuclear movements. Finally, we found evidence for a physical interaction between NPM and STAT3 in conditions of STAT3 activation. In conclusion, NPM is a downstream effector of the STAT3 signaling, and can facilitate the nuclear entry of phosphorylated STAT3. These observations might open novel opportunities for targeting the STAT3 pathway in cancer. PMID- 24793792 TI - Progranulin promotes Temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples. PGRN overexpression conferred GBM cells with tumorigenic properties and TMZ resistance by upregulating DNA repair (PARP, ATM, BRCA1, Rad51, XRCC1 and so on) and cancer stemness (CD133, CD44, ABCG2) genes, in part via an AP-1 transcription factor, specifically cFos/JunB. Curcumin, an AP-1 inhibitor, was also found to regulate PGRN promoter activity and expression including its downstream effectors aforementioned. These data suggested a feedforward loop between PGRN signaling and AP-1. PGRN depletion significantly decreased unlimited self-renewal and multilineage differentiation and the malignant properties of GBMs cells S1R1, and enhanced their vulnerability to TMZ. In addition, S1R1 depleted of PGRN also lost the ability to form tumor in an orthotopic xenograft mouse model. In conclusion, PGRN had a critical role in the pathogenesis and chemoresistance of GBM and functioned at the top of the hierarchy of cellular machinery that modulates both DNA repair pathways and cancer stemness. Our data suggest that a new strategy combining current regimens with compounds targeting PGRN/AP-1 loop like curcumin may significantly improve the therapeutic outcome of GBM. PMID- 24793793 TI - Long-lived charge separation and applications in artificial photosynthesis. AB - Researchers have long been interested in replicating the reactivity that occurs in photosynthetic organisms. To mimic the long-lived charge separations characteristic of the reaction center in photosynthesis, researchers have applied the Marcus theory to design synthetic multistep electron-transfer (ET) systems. In this Account, we describe our recent research on the rational design of ET control systems, based on models of the photosynthetic reaction center that rely on the Marcus theory of ET. The key to obtaining a long-lived charge separation is the careful choice of electron donors and acceptors that have small reorganization energies of ET. In these cases, the driving force of back ET is located in the Marcus inverted region, where the lifetime of the charge-separated state lengthens as the driving force of back ET increases. We chose porphyrins as electron donors and fullerenes as electron acceptors, both of which have small ET reorganization energies. By linking electron donor porphyrins and electron acceptor fullerenes at appropriate distances, we achieved charge-separated states with long lifetimes. We could further lengthen the lifetimes of charge-separated states by mixing a variety of components, such as a terminal electron donor, an electron mediator, and an electron acceptor, mimicking both the photosynthetic reaction center and the multistep photoinduced ET that occurs there. However, each step in multistep ET loses a fraction of the initial excitation energy during the long-distance charge separation. To overcome this drawback in multistep ET systems, we used designed new systems where we could finely control the redox potentials and the geometry of simple donor-acceptor dyads. These modifications resulted in a small ET reorganization energy and a high-lying triplet excited state. Our most successful example, 9-mesityl-10-methylacridinium ion (Acr(+)-Mes), can undergo a fast photoinduced ET from the mesityl (Mes) moiety to the singlet excited state of the acridinium ion moiety (Acr(+)) with extremely slow back ET. The high-energy triplet charge-separated state is located deep in the Marcus inverted region, and we have detected the structural changes during the photoinduced ET in this system using X-ray crystallography. To increase the efficiency of both the light-harvesting and photoinduced ET, we assembled the Acr(+)-Mes dyads on gold nanoparticles to bring them in closer proximity to one another. We can also incorporate Acr(+)-Mes molecules within nanosized mesoporous silica-alumina. In contrast to the densely assembled dyads on gold nanoparticles, each Acr(+)-Mes molecule in silica-alumina is isolated in the mesopore, which inhibits the bimolecular back ET and leads to longer lifetimes in solution at room temperature than the natural photosynthetic reaction center. Acr(+)-Mes and related compounds act as excellent organic photocatalysts and facilitate a variety of reactions such as oxygenation, bromination, carbon-carbon bond formation, and hydrogen evolution reactions. PMID- 24793790 TI - Talin1 phosphorylation activates beta1 integrins: a novel mechanism to promote prostate cancer bone metastasis. AB - Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind integrins and are essential for integrin activation. We previously showed that beta1 integrins are activated in metastatic prostate cancer (PCa) cells, increasing PCa metastasis to lymph nodes and bone. However, how beta1 integrins are activated in PCa cells is unknown. In this study, we identified a novel mechanism of beta1 integrin activation. Using knockdown experiments, we first demonstrated that talin1, but not talin2, is important in beta1 integrin activation. We next showed that talin1 S425 phosphorylation, but not total talin1 expression, correlates with metastatic potential of PCa cells. Expressing a non-phosphorylatable mutant, talin1(S425A), in talin1-silenced PC3-MM2 and C4-2B4 PCa cells, decreased activation of beta1 integrins, integrin-mediated adhesion, motility and increased the sensitivity of the cells to anoikis. In contrast, reexpression of the phosphorylation-mimicking mutant talin1(S425D) led to increased beta1 integrin activation and generated biologic effects opposite to talin1(S425A) expression. In the highly metastatic PC3-MM2 cells, expression of a non-phosphorylatable mutant, talin1(S425A), in talin1-silenced PC3-MM2 cells, abolished their ability to colonize in the bone following intracardiac injection, while reexpression of phosphorylation-mimicking mutant talin1(S425D) restored their ability to metastasize to bone. Immunohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in human bone metastases when compared with normal tissues, primary tumors or lymph node metastases. We further showed that p35 expression, an activator of Cdk5, and Cdk5 activity were increased in metastatic tumor cells, and that Cdk5 kinase activity is responsible for talin1 phosphorylation and subsequent beta1 integrin activation. Together, our study reveals Cdk5-mediated phosphorylation of talin1 leading to beta1 integrin activation is a novel mechanism that increases metastatic potential of PCa cells. PMID- 24793794 TI - [Magneto-encephalographic (MEG) brain recordings during traumatic memory recall in women with post-traumatic stress disorder: A pilot study]. AB - AIM OF THE STUDY: The experiment studied the effects of a short duration exposure to traumatic memories using magneto-encephalography (MEG). PATIENTS: Nine right handed DSM-4 PTSD patients were recruited from a unit for anxiety disorders and an organisation supporting victims of violence. In order to have a homogeneous sample, we included only women who suffered from civilian PTSD. Exclusion criteria were co-morbid major medical illness, metallic dental prostheses that would interfere in the magnetic measurement, and current drug treatment. All participants were free from neurological disease and had normal hearing. They signed a written informed consent form. An ethics committee accepted the study. METHOD: A tape-recorded voice administered a script-driven imagery. The patients had to imagine, successively, a neutral image, a traumatic memory and rest, while MEG measured brain activities across delta, theta, alpha and beta bands. Each condition lasted three minutes. Heart rate (HR), anxiety and the vividness of mental images were recorded at the end of each phase. MEG power analysis was carried out with Statistical Parametric Mapping (SPM) 8. The signals were averaged for each of the three conditions of threeminutes duration. The dependent variable was a subtracted value: (trauma - rest) - (neutral - rest). The significance threshold was set at P<0.01. RESULTS: Anxiety and HR significantly increased during the trauma condition and returned to the neutral level during rest. The vividness of the mental imagery remained stable across the three conditions. The left-brain demonstrated a statistically significant power decrease in the secondary visual cortex (BA 18-19) in the delta band, the insula (BA13) in the beta band, the insula (BA13), premotor cortex (BA 6), Broca area (BA 44), and BA 43, in the alpha band. DISCUSSION: The symptom provocation protocol was successful in eliciting subjective anxiety and HR response in relation to traumatic memories. Our MEG results are in keeping with previous neuro-imagery studies showing decreased activities in the insula and Broca area during PTSD symptom provocation. However, we did not replicate the activation in the amygdala and the cingulate and prefrontal cortex found in some studies. Moreover, the within-group design, the small sample, and the inclusion of only female patients with milder dissociative symptoms limit our conclusions. The MEG protocol we used may also explain some partial discrepancies with previous MEG studies. However, our aim was to provoke a specific autobiographic recall of a traumatic event unfolding several sequential mental images along three minutes as in exposure therapy for PTSD. CONCLUSION: Despite its limitations, this pilot study is the first to provide MEG data during trauma recall. It suggests that recalling a specific traumatic event along three minutes results in hypo activations of the brain regions regulating language and emotions. This paves the way to recording whole sessions of specific therapies for PTSD, with MEG using the millisecond resolution. MEG might be of interest to study the suppression of traumatic memories and their activation and habituation through prolonged graduated exposure in imagination across several sessions. MEG could also be used to study the effects of medication on PTSD symptoms. A controlled replication in a larger sample including male and female patients with various traumatic experiences is needed. PMID- 24793795 TI - Newer Indications for ICD and CRT. AB - The first implantable pacemaker was developed about 50 years ago. Since that time, cardiac implantable electronic device therapy (CIED) has undergone dramatic changes. Two of the most significant advances are the development of implantable defibrillators (ICDs) to treat ventricular tachyarrhythmias and prevent sudden death and left ventricular-based pacing to achieve cardiac resynchronization therapy (CRT). In this article, the authors review the current indications for ICD and CRT, with particular emphasis on recent updates in guidelines. Many countries and regions of the world now have guidelines for CIED use. In this article, the authors only focus on US guidelines. PMID- 24793796 TI - Shock avoidance and the newer tachycardia therapy algorithms. AB - Sudden cardiac death is a leading cause of death in the United States and Europe. Implantable cardioverter defibrillators (ICDs) are a cornerstone of therapy for patients at risk of first occurrence of ventricular arrhythmia, or secondary prevention in those who have previously suffered cardiac arrest or life threatening arrhythmias. Despite their efficacy, ICD shocks are associated with significant physical and psychological adverse effects. As technology has progressed, newer device programing methods have allowed for arrhythmia suppression and termination without the need for high-energy defibrillation, thus improving patient satisfaction, health, and outcomes. PMID- 24793797 TI - Lead extractions: indications, procedural aspects, and outcomes. AB - As a result of more cardiac implantable electronic devices being placed, a trend toward increasing device infections, and concerns regarding lead malfunction, there is an increased need for lead extraction skills and comprehensive lead management programs. This review discusses the current indications for lead extractions as well as the training requirements and tools and technology needed to create the foundation for a successful lead management program. PMID- 24793798 TI - Is defibrillation testing necessary? AB - With advancements in implantable cardioverter defibrillator (ICD) technology, the practice of performing defibrillation threshold (DFT) testing at the time of implantation has been questioned. With availability of biphasic waveforms, active cans, and high-output devices, opponents claim that DFT testing is no longer necessary. Clinical trials demonstrating the efficacy of ICDs in prevention of sudden cardiac death have, however, all used some form of defibrillation testing. This debate is fueled by the absence of data from randomized prospective trials evaluating the role of DFT testing in predicting clinical shock efficacy or survival. This review discusses both sides of the argument. PMID- 24793799 TI - The totally subcutaneous implantable defibrillator. AB - The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a new therapeutic option for patients at risk of sudden cardiac arrest. The device uses a pulse generator implanted in the lateral thoracic region and a tunneled subcutaneous electrode. Benefits of this configuration include the preservation of venous access and reduction in the risk of systemic infection, vascular injury, and lead failure. Clinical trials suggest that the device effectively senses, discriminates, and converts both spontaneous and induced ventricular tachycardia and ventricular fibrillation episodes with minimal complications. The S-ICD represents a novel implantable cardioverter-defibrillator configuration that may provide reliably effective therapy for malignant tachyarrhythmias. PMID- 24793800 TI - The modern EP practice: EHR and remote monitoring. AB - Cardiac implantable electronic devices (CIEDs) store clinically valuable, time sensitive information regarding system integrity, arrhythmias, and heart failure parameters. Remote monitoring has impacted clinical practice by reducing scheduled office visits, providing protocols for device recalls and advisories, and facilitating the management of unscheduled encounters. The successful implementation of remote monitoring into clinical practice requires a new work flow and additional staff; the use of the electronic medical record to manage the data emanating from CIEDs poses an additional challenge. Solutions to these issues are discussed, and projections are made regarding the management of CIEDs in a modern electrophysiology practice. PMID- 24793801 TI - The role of the wearable cardioverter defibrillator in clinical practice. AB - The wearable cardioverter defibrillator (WCD) is an option for external monitoring and defibrillation in patients at risk for sudden cardiac arrest caused by ventricular tachycardia or ventricular fibrillation and who are not candidates for or who refuse an implantable cardioverter defibrillator (ICD). WCDs provide monitoring with backup defibrillation protection. WCDs have been used when a patient's condition delays or prohibits ICD implantation, or as a bridge when an indicated ICD must be explanted. WCDs are used for primary prevention of sudden cardiac death during high-risk gap periods early after myocardial infarction, coronary revascularization, or new diagnosis of heart failure. PMID- 24793802 TI - Does atrial fibrillation detected by cardiac implantable electronic devices have clinical relevance? AB - The precise role atrial fibrillation (AF) plays in increasing the risk of stroke is less well understood; this is especially true for the implanted device population. Current cardiac implanted electronic devices have a very high sensitivity and specificity for true AF detection. It does not seem to matter if the AF episode is proximal to the stroke event, and risk seems to be increased by relatively brief AF episodes. The appearance of new atrial high-rate episodes increases thromboembolic event rates. Until larger trials or registries are conducted, it is important to follow established guidelines regarding anticoagulation. PMID- 24793803 TI - Newer algorithms in bradycardia management. AB - Permanent cardiac pacemakers (PPM) are effective in the treatment of bradycardia in a growing number of clinical scenarios. An appreciation of the capacity of PPMs to result in negative hemodynamic and proarrhythmic effects has grown alongside clinical experience with permanent pacing. Such experience has necessitated the development of algorithms aimed at optimizing device functionality across a broad spectrum of physiologic and pathologic conditions. This review highlights recent device-based algorithms used in automated threshold testing, reduction of right ventricular pacing, prevention and treatment of pacemaker-mediated tachycardia, mode switching for atrial tachyarrhythmias, rate modulated pacing, and advances in arrhythmia storage and remote monitoring. PMID- 24793804 TI - Indications for cardiac resynchronization therapy. AB - Initial studies established patient selection criteria for cardiac resynchronization therapy (CRT) as left ventricular ejection fraction less than or equal to 35%, QRS greater than or equal to 120 ms, and New York Heart Association 3-4. Based on newer data, post hoc analyses, and meta-analyses, these criteria have been refined and guidelines updated, highlighting left bundle branch morphology and QRS greater than 150 ms in selecting patients with a likelihood of favorable outcomes. Guidelines will change as more data become available; the decision to apply CRT should be based on patient clinical profile and the balance of risk tolerance and likelihood of benefit. PMID- 24793805 TI - MRI for patients with cardiac implantable electrical devices. AB - MRI has become an invaluable tool in the evaluation of soft tissue and bony abnormalities. The presence of a cardiac implantable electrical device (CIED) may complicate matters, however, because these devices are considered a contraindication to MRI scanning. When MRI is performed in patients with a CIED, risks include reed switch activation in older devices, lead heating, system malfunction, and significant radiofrequency noise resulting in inappropriate inhibition of demand pacing, tachycardia therapies, or programming changes. This report reviews indications and risk-benefit evaluation of MRI in patients with CIED and provides a clinical algorithm for performing MRI in patients with implanted devices. PMID- 24793806 TI - Implantable defibrillators in long QT syndrome, Brugada syndrome, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. AB - Sudden death is often the first manifestation in inherited cardiac arrhythmia syndromes. Patients with long QT syndrome who have an episode of syncope while on beta-blockade should be offered an implantable cardioverter-defibrillator (ICD). In Brugada syndrome and hypertrophic cardiomyopathy, ICDs are often the most effective treatment of primary and secondary prevention of cardiac arrest. Risk stratification is crucial in identifying those at greatest risk to provide lifesaving therapy with an ICD while avoiding complications in those unlikely to receive benefit. PMID- 24793807 TI - Pacemakers and ICDs. PMID- 24793809 TI - alpha5 Nicotinic acetylcholine receptor mediates nicotine-induced HIF-1alpha and VEGF expression in non-small cell lung cancer. AB - By binding to nicotinic acetylcholine receptors (nAChRs), nicotine induces the proliferation and apoptosis of non-small cell lung cancer (NSCLC). Previous studies have indicated that alpha5-nAChR is highly associated with lung cancer risk and nicotine dependence. However, the mechanisms through which alpha5-nAChRs may influence lung carcinogenesis are far from clear. In the present study, we investigated the roles of alpha5-nAChR in the nicotine-induced expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). Immunohistochemistry was used to detect the expression of alpha5 nAChR and HIF-1alpha in 60 specimens of lung cancer and para-carcinoma tissue. The correlations between the expression levels of alpha5-nAChR and HIF-1alpha and other clinicopathological data were analyzed. In a cell line that highly expressed alpha5-nAChR, the loss of alpha5-nAChR function by siRNA was used to study whether alpha5-nAChR is involved in the nicotine-induced expression of HIF 1alpha and VEGF through the activation of the ERK1/2 and PI3K/Akt signaling pathways. Cell growth was detected using the cell counting kit-8 (CCK-8). alpha5 nAChR (78.3%) and HIF-1alpha (88.3%) were both overexpressed in NSCLC, and their expression levels were found to be correlated with each other (P<0.05). In the A549 cell line, alpha5-nAChR and HIF-1alpha were found to be expressed under normal conditions, and their expression levels were significantly increased in response to nicotine treatment. The silencing of alpha5-nAChR significantly inhibited the nicotine-induced cell proliferation compared with the control group and attenuated the nicotine-induced upregulation of HIF-1alpha and VEGF, and these effects required the cooperation of the ERK1/2 and PI3K/Akt signaling pathways. These results show that the alpha5-nAChR/HIF-1alpha/VEGF axis is involved in nicotine-induced tumor cell proliferation, which suggests that alpha5 nAChR may serve as a potential anticancer target in nicotine-associated lung cancer. PMID- 24793808 TI - Effects of oral exposure to naturally-occurring and synthetic deoxynivalenol congeners on proinflammatory cytokine and chemokine mRNA expression in the mouse. AB - The foodborne mycotoxin deoxynivalenol (DON) induces a ribotoxic stress response in mononuclear phagocytes that mediate aberrant multi-organ upregulation of TNF alpha, interleukins and chemokines in experimental animals. While other DON congeners also exist as food contaminants or pharmacologically-active derivatives, it is not known how these compounds affect expression of these cytokine genes in vivo. To address this gap, we compared in mice the acute effects of oral DON exposure to that of seven relevant congeners on splenic expression of representative cytokine mRNAs after 2 and 6h. Congeners included the 8-ketotrichothecenes 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), nivalenol (NIV), the plant metabolite DON-3 glucoside (D3G) and two synthetic DON derivatives with novel satiety-inducing properties (EN139528 and EN139544). DON markedly induced transient upregulation of TNF-alpha IL-1beta, IL-6, CXCL-2, CCL-2 and CCL-7 mRNA expressions. The two ADONs also evoked mRNA expression of these genes but to a relatively lesser extent. FX induced more persistent responses than the other DON congeners and, compared to DON, was: 1) more potent in inducing IL-1beta mRNA, 2) approximately equipotent in the induction of TNF-alpha and CCL-2 mRNAs, and 3) less potent at upregulating IL-6, CXCL-2, and CCL-2 mRNAs. EN139528's effects were similar to NIV, the least potent 8-ketotrichothecene, while D3G and EN139544 were largely incapable of eliciting cytokine or chemokine mRNA responses. Taken together, the results presented herein provide important new insights into the potential of naturally-occurring and synthetic DON congeners to elicit aberrant mRNA upregulation of cytokines associated with acute and chronic trichothecene toxicity. PMID- 24793810 TI - Rosiglitazone inhibits chlorpyrifos-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells. AB - Oxidative stress can lead to expression of inflammatory transcription factors, which are important regulatory elements in the induction of inflammatory responses. One of the transcription factors, nuclear transcription factor kappa-B (NF-kappaB) plays a significant role in the inflammation regulatory process. Inflammatory cell death has been implicated in neuronal cell death in some neurodegenerative disorders such as Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying apoptosis initiated by chlorpyrifos (CPF)-mediated oxidative stress. Based on the cytotoxic mechanism of CPF, we examined the neuroprotective effects of rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, against CPF-induced neuronal cell death. The treatment of SH-SY5Y cells with CPF induced oxidative stress. In addition, CPF activated the p38, JNK and ERK mitogen-activated protein kinases (MAPKs), and induced increases in the inflammatory genes such as COX-2 and TNF-alpha. CPF also induced nuclear translocation of NF-kappaB and inhibitors of NF-kappaB abolished the CPF-induced COX-2 expression. Pretreatment with RGZ significantly reduced ROS generation and enhanced HO-1 expression in CPF-exposed cells. RGZ blocked the activation of both p38 and JNK signaling, while ERK activation was strengthened. RGZ also attenuated CPF-induced cell death through the reduction of NF-kappaB-mediated proinflammatory factors. Results from this study suggest that RGZ may exert an anti-apoptotic effect against CPF-induced cytotoxicity by attenuation of oxidative stress as well as inhibition of the inflammatory cascade via inactivation of signaling by p38 and JNK, and NF-kappaB. PMID- 24793811 TI - Soy isoflavones interfere with thyroid hormone homeostasis in orchidectomized middle-aged rats. AB - We previously reported that genistein (G) and daidzein (D) administered subcutaneously (10mg/kg) induce changes in the angio-follicular units of the thyroid gland, reduce concentration of total thyroid hormones (TH) and increase thyrotropin (TSH) in serum of orchidectomized middle-aged (16-month-old) rats. To further investigate these effects, we now examined expression levels of the thyroglobulin (Tg), thyroperoxidase (Tpo), vascular endothelial growth factor A (Vegfa) and deiodinase type 1 (Dio 1) genes in the thyroid; in the pituitary, genes involved in TH feedback control (Tsh beta, Dio 1, Dio 2, Trh receptor); and in the liver and kidney, expression of T3-activated genes Dio 1 and Spot 14, as well as transthyretin (Ttr), by quantitative real-time PCR. We also analyzed TPO immunopositivity and immunofluorescence of T4 bound to Tg, determined thyroid T4 levels and measured deiodinase enzyme activities in examined organs. Decreased expression of Tg and Tpo genes (p<0.05) correlated with immunohistochemical staining results, and together with decreased serum total T4 levels, indicates decreased Tg and TH synthesis following treatments with both isoflavones. However, expression of Spot 14 (p<0.05) gene in liver and kidney was up regulated, and liver Dio 1 expression and activity (p<0.05) increased. At the level of pituitary, no significant change in gene expression levels, or Dio 1 and 2 enzyme activities was observed. In conclusion, both G and D impaired Tg and TH synthesis, but at the same time increased tissue availability of TH in peripheral tissues of Orx middle-aged rats. PMID- 24793812 TI - The genetics of common disorders - congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. Although numerous chromosomal aberrations and gene mutations have been associated with CDH, the etiology of the diaphragmatic defect is identified in less than 50% of patients. This review discusses the some of the more frequent, recurrent karyotypic abnormalities in which CDH is a feature, including 15q26, 8p23.1 and 4p16.3 deletions and tetrasomy 12p (Pallister-Killian syndrome), together with some of the syndromes in which CDH is a relatively common feature, including Fryns syndrome, Matthew-Wood syndrome, overgrowth syndromes and Donnai-Barrow syndrome. In the era of genomic technologies, our knowledge of the genes and chromosome regions involved in pathogenesis of CDH is likely to advance significantly. PMID- 24793813 TI - Co-occurrence in body site of malformations and cancer. AB - In many malformation syndromes benign and malignant tumours develop more frequently than in the general population. Malformations result from an abnormal intrinsic developmental process. It can be hypothesised that disturbed regulation of cell growth as can become evident by the presence of benign and malignant tumours, which will occur at the same site of a malformation or at other sites at which the gene involved in the malformation is functioning. The present study aimed to compare the localisation of malignant and benign tumours to the localisation of major and minor characteristics of syndromes that have either of two malformations, i.e. microtia and hypospadias. To eliminate co-occurrence of a malformation syndrome and tumours by chance we confined evaluations to syndromes which have been described in >100 individuals. We identified 11 syndromes associated with microtia and 26 syndromes associated with hypospadias, for which co-localisation of (benign and malignant) tumours with (major and minor) syndrome characteristics was determined. In both groups of syndromes tumours were found to be localised at the same body site as the major and minor characteristics of the syndromes in two-third of the tumours. There was no significant difference in co occurrence in site between benign and malignant tumours. We conclude that in two groups of malformation syndromes which go along with a different core malformation, benign and malignant tumours co-localise with the core malformation or with other sites at which the gene involved is functioning. This adds further proof that tumours in malformation syndromes can usually be explained by abnormal functioning of the same gene that has caused the malformation syndrome. PMID- 24793816 TI - Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2 positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. AB - BACKGROUND: Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients. METHODS: This randomised, open label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (>=18 years, left ventricular ejection fraction >=50%, Eastern Cooperative Oncology Group performance status 0-2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3.6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197. FINDINGS: From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7.2 months (IQR 5.0-10.1 months) in the trastuzumab emtansine group and 6.5 months (IQR 4.1 9.7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6.2 months [95% CI 5.59-6.87] vs 3.3 months [2.89 4.14]; stratified hazard ratio [HR] 0.528 [0.422-0.661]; p<0.0001). Interim overall survival analysis showed a trend favouring trastuzumab emtansine (stratified HR 0.552 [95% CI 0.369-0.826]; p=0.0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events [32%] in 403 patients vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [<1%] vs eight [4%]), and febrile neutropenia (one [<1%] vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. INTERPRETATION: Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib. FUNDING: Genentech. PMID- 24793817 TI - HER2-positive breast cancer: a new piece of the puzzle. PMID- 24793819 TI - The sensitivity of three methods to nonnormality and unequal variances in interval estimation of effect sizes. AB - Confidence interval (CI) estimation for an effect size (ES) provides a range of possible population ESs supported by data. In this article, we investigated the noncentral t method, Bonett's method, and the bias-corrected and accelerated (BCa) bootstrap method for constructing CIs when a standardized linear contrast of means is defined as an ES. The noncentral t method assumes normality and equal variances, Bonett's method assumes only normality, and the BCa bootstrap method makes no assumptions. We simulated data for three and four groups from a variety of populations (one normal and five nonnormals) with varied variance ratios (1, 2.25, 4, 8), population ESs (0, 0.2, 0.5, 0.8), and sample size patterns (one equal and two unequal). Results showed that the noncentral method performed the best among the three methods under the joint condition of ES = 0 and equal variances. Performance of the noncentral method was comparable to that of the other two methods under (1) equal sample size, unequal weight for each group, and the last group sampled from a leptokurtic distribution, or (2) equal sample size and equal weight for all groups, when all are sampled from a normal population, or only the last group sampled from a nonnormal distribution. In the remaining conditions, Bonett's and the BCa bootstrap methods performed better than the noncentral method. The BCa bootstrap method is the method of choice when the sample size per group is 30 or more. Findings from this study have implications for simultaneous comparisons of means and of ranked means in between- and within subjects designs. PMID- 24793820 TI - A novel approach for fit analysis of thermal protective clothing using three dimensional body scanning. AB - The garment fit played an important role in protective performance, comfort and mobility. The purpose of this study is to quantify the air gap to quantitatively characterize a three-dimensional (3-D) garment fit using a 3-D body scanning technique. A method for processing of scanned data was developed to investigate the air gap size and distribution between the clothing and human body. The mesh model formed from nude and clothed body was aligned, superimposed and sectioned using Rapidform software. The air gap size and distribution over the body surface were analyzed. The total air volume was also calculated. The effects of fabric properties and garment size on air gap distribution were explored. The results indicated that average air gap of the fit clothing was around 25-30 mm and the overall air gap distribution was similar. The air gap was unevenly distributed over the body and it was strongly associated with the body parts, fabric properties and garment size. The research will help understand the overall clothing fit and its association with protection, thermal and movement comfort, and provide guidelines for clothing engineers to improve thermal performance and reduce physiological burden. PMID- 24793818 TI - Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. AB - BACKGROUND AND AIMS: Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC. METHODS: Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro inflammatory cytokines were determined by quantitative-real-time-polymerase-chain reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3(+) T cells after pharmacological blockade of KV1.3 and KCa3.1. RESULTS: Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4(+) and 23% of CD8(+) T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-alpha (R(2)=0.61) and IL-17A (R(2)=0.51), the mayo endoscopic subscore (R(2)=0.13), and histological inflammation (R(2)=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-gamma, TNF-alpha, and IL-17A. CONCLUSIONS: High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro inflammatory IL-17A and TNF-alpha in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy. PMID- 24793821 TI - The application of SEAT values for predicting how compliant seats with backrests influence vibration discomfort. AB - The extent to which a seat can provide useful attenuation of vehicle vibration depends on three factors: the characteristics of the vehicle motion, the vibration transmissibility of the seat, and the sensitivity of the body to vibration. The 'seat effective amplitude transmissibility' (i.e., SEAT value) reflects how these three factors vary with the frequency and the direction of vibration so as to predict the vibration isolation efficiency of a seat. The SEAT value is mostly used to select seat cushions or seat suspensions based on the transmission of vertical vibration to the principal supporting surface of a seat. This study investigated the accuracy of SEAT values in predicting how seats with backrests influence the discomfort caused by multiple-input vibration. Twelve male subjects participated in a four-part experiment to determine equivalent comfort contours, the relative discomfort, the location of discomfort, and seat transmissibility with three foam seats and a rigid reference seat at 14 frequencies of vibration in the range 1-20 Hz at magnitudes of vibration from 0.2 to 1.6 ms(-2) r.m.s. The 'measured seat dynamic discomfort' (MSDD) was calculated for each foam seat from the ratio of the vibration acceleration required to cause similar discomfort with the foam seat and with the rigid reference seat. Using the frequency weightings in current standards, the SEAT values of each seat were calculated from the ratio of overall ride values with the foam seat to the overall ride values with the rigid reference seat, and compared to the corresponding MSDD at each frequency. The SEAT values provided good predictions of how the foam seats increased vibration discomfort at frequencies around the 4 Hz resonance but reduced vibration discomfort at frequencies greater than about 6.3 Hz, with discrepancies explained by a known limitation of the frequency weightings. PMID- 24793822 TI - Metabolic rate of carrying added mass: a function of walking speed, carried mass and mass location. AB - The effort of carrying additional mass at different body locations is important in ergonomics and in designing wearable robotics. We investigate the metabolic rate of carrying a load as a function of its mass, its location on the body and the subject's walking speed. Novel metabolic rate prediction equations for walking while carrying loads at the ankle, knees and back were developed based on experiments where subjects walked on a treadmill at 4, 5 or 6km/h bearing different amounts of added mass (up to 2kg per leg and 22kg for back). Compared to previously reported equations, ours are 7-69% more accurate. Results also show that relative cost for carrying a mass at a distal versus a proximal location changes with speed and mass. Contrary to mass carried on the back, mass attached to the leg cannot be modeled as an increase in body mass. PMID- 24793823 TI - Estimating oxygen consumption from heart rate using adaptive neuro-fuzzy inference system and analytical approaches. AB - In new approaches based on adaptive neuro-fuzzy systems (ANFIS) and analytical method, heart rate (HR) measurements were used to estimate oxygen consumption (VO2). Thirty-five participants performed Meyer and Flenghi's step-test (eight of which performed regeneration release work), during which heart rate and oxygen consumption were measured. Two individualized models and a General ANFIS model that does not require individual calibration were developed. Results indicated the superior precision achieved with individualized ANFIS modelling (RMSE = 1.0 and 2.8 ml/kg min in laboratory and field, respectively). The analytical model outperformed the traditional linear calibration and Flex-HR methods with field data. The General ANFIS model's estimates of VO2 were not significantly different from actual field VO2 measurements (RMSE = 3.5 ml/kg min). With its ease of use and low implementation cost, the General ANFIS model shows potential to replace any of the traditional individualized methods for VO2 estimation from HR data collected in the field. PMID- 24793824 TI - A review of technical aspects of T1-weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in human brain tumors. AB - In the last few years, several imaging methods, such as magnetic resonance imaging (MRI) and computed tomography, have been used to investigate the degree of blood-brain barrier (BBB) permeability in patients with neurological diseases including multiple sclerosis, ischemic stroke, and brain tumors. One promising MRI method for assessing the BBB permeability of patients with neurological diseases in vivo is T1-weighted dynamic contrast-enhanced (DCE)-MRI. Here we review the technical issues involved in DCE-MRI in the study of human brain tumors. In the first part of this paper, theoretical models for the DCE-MRI analysis will be described, including the Toft-Kety models, the adiabatic approximation to the tissue homogeneity model and the two-compartment exchange model. These models can be used to estimate important kinetic parameters related to BBB permeability. In the second part of this paper, details of the data acquisition, issues related to the arterial input function, and procedures for DCE-MRI image analysis are illustrated. PMID- 24793825 TI - Demonstration of the cell clonality in canine hematopoietic tumors by X chromosome inactivation pattern analysis. AB - X-chromosome inactivation pattern (XCIP) analysis has been widely used to assess cell clonality in various types of human neoplasms. In this study, a polymerase chain reaction-based canine XCIP analysis of the androgen receptor (AR) gene was applied for the assessment of cell clonality in canine hematopoietic tumors. This XCIP analysis is based on the polymorphic CAG repeats in the AR gene and the difference of methylation status between active and inactive X chromosomes. We first examined the polymorphisms of 2 CAG tandem repeats in the AR gene in 52 male and 150 female dogs of various breeds. The 2 polymorphic CAG repeats contained 9 to 12 and 10 to 14 CAGs in the first and second CAG repeats, respectively. Of the 150 female dogs, 74 (49.3%) were heterozygous for the first and/or second polymorphic CAG tandem repeats, indicating the utility of XCIP analysis in these dogs. Canine XCIP analysis was then applied to clinical samples from female dogs with canine high-grade lymphoma, chronic myelogenous leukemia, acute myelogenous leukemia, and benign lymph node hyperplasia. Of 10 lymphoma cell samples, 9 (90%) showed skewed XCIPs, indicating their clonal origins, whereas all the nonneoplastic lymph node samples showed balanced XCIPs. Moreover, bone marrow specimen from a dog with acute myelogenous leukemia and peripheral leukocyte specimens from 2 dogs with chronic myelogenous leukemia showed skewed XCIPs. XCIP analysis was successfully employed to demonstrate the cell clonality of canine hematopoietic tumors in this study and will be applicable to evaluate the clonality in various proliferative disorders in dogs. PMID- 24793826 TI - Fatal Parastrongylus dujardini infection in captive callitrichids. AB - Intravascular nematodes were considered the cause of death of 14 captive callitrichids. All animals were captive born at zoos in France and died with little or no premonitory signs of disease. No consistent gross lesions were observed at necropsy, although in certain cases intracardiac adult parasites were noted. The most significant histologic findings were verminous pneumonia and pulmonary endarteritis. In all cases except one, intravascular adult nematodes were observed with eggs and larvae in the lungs. Adult nematodes were obtained from 8 animals and in all cases were identified as Parastrongylus dujardini. To the authors' knowledge, this is the first report of intravascular angiostrongylosis with primary cardiopulmonary location in callitrichids in France. PMID- 24793827 TI - Aberrant forms of Yersinia pseudotuberculosis as spheroplasts and filaments in yersiniosis in squirrel monkeys. AB - This report describes atypical cases of yersiniosis in squirrel monkeys in which aberrant forms of Yersinia pseudotuberculosis were seen. There were 2 outbreaks due to yersiniosis in squirrel monkeys in Japan. The monkeys had systemic necrotizing and hemorrhagic lesions with Gram-negative rod-shaped bacilli and microthromboembolism in the kidneys. Some lesions contained filaments, globular bodies, and other pleomorphic forms of bacteria. All forms were usually seen in the same lesions, and those with pleomorphic morphology appeared to be an intermediate form between the rod-shaped bacteria and the filaments or globular bodies. In addition, they had strong immunolabeling for Y. pseudotuberculosis, as did the rod-shaped bacteria. Therefore, the globular bodies, filaments, and others are strongly suspected to be shape-changed bacilli of Y. pseudotuberculosis. These morphologically altered bacteria could cause errors in diagnosis since they resemble fungi or protozoa, and special staining techniques, including immunohistochemistry, can be helpful in establishing the correct diagnosis. PMID- 24793828 TI - Molecular characterization of cat factor XII gene and identification of a mutation causing factor XII deficiency in a domestic shorthair cat colony. AB - Coagulation factor XII (FXII) may be important in cardiovascular and inflammatory diseases. We have identified and characterized a naturally occurring mutation in the feline FXII gene that results in a mutant protein and enzymatic loss of activity. Feline intron/exon gene structure and sequence were acquired by comparing DNA sequences obtained from a fragmented Felis catus genomic sequence and the National Center for Biotechnology Information's Cross Species Megablast of multiple species' FXII gene sequences. Fourteen exons ranging in size from 57 to 222 base pairs were confirmed spanning 8 Kb on chromosome A1. The 1828-base pair feline FXII messenger RNA (mRNA) sequence contains an open reading frame that encodes a protein of 609 amino acids with high homology to human FXII protein. Total RNA and mRNA purified from liver tissue of 4 wild-type/normal and 8 FXII-deficient cats confirmed the predicted mRNA sequence and identified one important single-nucleotide polymorphism (SNP). A single base deletion in exon 11 of the FXII coding gene in our colony of cats results in deficient FXII activity. Translation of the mRNA transcript shows a frame shift at L441 (C441fsX119) resulting in a nonsense mutation and a premature stop codon with a predicted 560 amino acid protein. The mutant FXII protein is truncated in the 3' proteolytic light chain region of the C-terminus, explaining its loss of enzymatic activity. This study is the first molecular characterization of the feline FXII gene and the first identification of an FXII mutation in the domestic cat, providing insights into the origin and nature of feline FXII deficiency. PMID- 24793829 TI - A hierarchical model for simultaneous detection and estimation in multi-subject fMRI studies. AB - In this paper we introduce a new hierarchical model for the simultaneous detection of brain activation and estimation of the shape of the hemodynamic response in multi-subject fMRI studies. The proposed approach circumvents a major stumbling block in standard multi-subject fMRI data analysis, in that it both allows the shape of the hemodynamic response function to vary across region and subjects, while still providing a straightforward way to estimate population level activation. An efficient estimation algorithm is presented, as is an inferential framework that allows for not only tests of activation, but also tests for deviations from some canonical shape. The model is validated through simulations and application to a multi-subject fMRI study of thermal pain. PMID- 24793830 TI - Lesion segmentation from multimodal MRI using random forest following ischemic stroke. AB - Understanding structure-function relationships in the brain after stroke is reliant not only on the accurate anatomical delineation of the focal ischemic lesion, but also on previous infarcts, remote changes and the presence of white matter hyperintensities. The robust definition of primary stroke boundaries and secondary brain lesions will have significant impact on investigation of brain behavior relationships and lesion volume correlations with clinical measures after stroke. Here we present an automated approach to identify chronic ischemic infarcts in addition to other white matter pathologies, that may be used to aid the development of post-stroke management strategies. Our approach uses Bayesian Markov Random Field (MRF) classification to segment probable lesion volumes present on fluid attenuated inversion recovery (FLAIR) MRI. Thereafter, a random forest classification of the information from multimodal (T1-weighted, T2 weighted, FLAIR, and apparent diffusion coefficient (ADC)) MRI images and other context-aware features (within the probable lesion areas) was used to extract areas with high likelihood of being classified as lesions. The final segmentation of the lesion was obtained by thresholding the random forest probabilistic maps. The accuracy of the automated lesion delineation method was assessed in a total of 36 patients (24 male, 12 female, mean age: 64.57+/-14.23yrs) at 3months after stroke onset and compared with manually segmented lesion volumes by an expert. Accuracy assessment of the automated lesion identification method was performed using the commonly used evaluation metrics. The mean sensitivity of segmentation was measured to be 0.53+/-0.13 with a mean positive predictive value of 0.75+/ 0.18. The mean lesion volume difference was observed to be 32.32%+/-21.643% with a high Pearson's correlation of r=0.76 (p<0.0001). The lesion overlap accuracy was measured in terms of Dice similarity coefficient with a mean of 0.60+/-0.12, while the contour accuracy was observed with a mean surface distance of 3.06mm+/ 3.17mm. The results signify that our method was successful in identifying most of the lesion areas in FLAIR with a low false positive rate. PMID- 24793831 TI - Low-frequency rTMS inhibitory effects in the primary motor cortex: Insights from TMS-evoked potentials. AB - The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) have been mostly investigated by peripheral motor-evoked potentials (MEPs). New TMS-compatible EEG systems allow a direct investigation of the stimulation effects through the analysis of TMS-evoked potentials (TEPs). We investigated the effects of 1-Hz rTMS over the primary motor cortex (M1) of 15 healthy volunteers on TEP evoked by single pulse TMS over the same area. A second experiment in which rTMS was delivered over the primary visual cortex (V1) of 15 healthy volunteers was conducted to examine the spatial specificity of the effects. Single-pulse TMS evoked four main components: P30, N45, P60 and N100. M1 rTMS resulted in a significant decrease of MEP amplitude and in a significant increase of P60 and N100 amplitude. There was no effect after V1-rTMS. 1-Hz rTMS appears to increase the amount of inhibition following a TMS pulse, as demonstrated by the higher N100 and P60, which are thought to originate from GABAb-mediated inhibitory post-synaptic potentials. Our results confirm the reliability of the TMS-evoked N100 as a marker of cortical inhibition and provide insight into the neuromodulatory effects of 1-Hz rTMS. The present finding could be of relevance for therapeutic and diagnostic purposes. PMID- 24793832 TI - Coping with confounds in multivoxel pattern analysis: what should we do about reaction time differences? A comment on Todd, Nystrom & Cohen 2013. AB - Multivoxel pattern analysis (MVPA) is a sensitive and increasingly popular method for examining differences between neural activation patterns that cannot be detected using classical mass-univariate analysis. Recently, Todd et al. ("Confounds in multivariate pattern analysis: Theory and rule representation case study", 2013, NeuroImage 77: 157-165) highlighted a potential problem for these methods: high sensitivity to confounds at the level of individual participants due to the use of directionless summary statistics. Unlike traditional mass univariate analyses where confounding activation differences in opposite directions tend to approximately average out at group level, group level MVPA results may be driven by any activation differences that can be discriminated in individual participants. In Todd et al.'s empirical data, factoring out differences in reaction time (RT) reduced a classifier's ability to distinguish patterns of activation pertaining to two task rules. This raises two significant questions for the field: to what extent have previous multivoxel discriminations in the literature been driven by RT differences, and by what methods should future studies take RT and other confounds into account? We build on the work of Todd et al. and compare two different approaches to remove the effect of RT in MVPA. We show that in our empirical data, in contrast to that of Todd et al., the effect of RT on rule decoding is negligible, and results were not affected by the specific details of RT modelling. We discuss the meaning of and sensitivity for confounds in traditional and multivoxel approaches to fMRI analysis. We observe that the increased sensitivity of MVPA comes at a price of reduced specificity, meaning that these methods in particular call for careful consideration of what differs between our conditions of interest. We conclude that the additional complexity of the experimental design, analysis and interpretation needed for MVPA is still not a reason to favour a less sensitive approach. PMID- 24793833 TI - Bipolar and borderline patients display differential patterns of functional connectivity among resting state networks. AB - Bipolar disorder (BD) and borderline personality (BPD) disorder share clinical features such as emotional lability and poor interpersonal functioning but the course of illness and treatment differs in these groups, which suggests that the underlying neurobiology of BD and BPD is likely to be different. Understanding the neural mechanisms behind the pathophysiology of BD and BPD will facilitate accurate diagnosis and inform the administration of targeted treatment. Since deficits in social cognition or emotion regulation or in the self-referential processing system can give rise to these clinical features, and impairment in these domains have been observed in both patient groups, functional connectivity within and between networks subserving these processes during resting was investigated using functional magnetic resonance imaging. Data were acquired from 16 patients with BD, 14 patients with BPD, and 13 healthy controls (HC) and functional connectivity strength was correlated with scores using the Difficulties in Emotion Regulation Scale. Functional network connectivity (FNC) patterns differentiated BD and BPD patients from HC. In BD, FNC was increased while in BPD it was decreased. In BD impaired FNC was evident primarily among networks involved in self-referential processing while in BPD it also involved the emotion regulatory network. Impaired FNC displayed an association with impulsivity in BPD and emotional clarity and emotional awareness in BD. This study shows that BD and BPD can perhaps be differentiated using resting state FNC approach and that the neural mechanisms underpinning overlapping symptoms discernibly differ between the groups. These findings provide a potential platform for elucidating the targeted effects of psychological interventions in both disorders. PMID- 24793834 TI - Electrical neuroimaging reveals content-specific effects of threat in primary visual cortex and fronto-parietal attentional networks. AB - Whereas effects of anticipatory anxiety on attention are usually assumed to remain largely undifferentiated, discrepant findings in the literature suggest that, depending on its content and causes, different modulatory effects on attention control and early sensory processing may arise. Using electrical neuroimaging and psychophysiology in a cross-over design, we tested the hypothesis that different types of anticipatory anxiety (bodily vs. psychological), transiently induced in healthy participants, had dissociable effects on brain systems regulating attention control. Attention control corresponded to the ability to maintain efficient goal-directed processing (indexed by the P300 ERP component and by activations in the attentional networks), as well as the ability to filter out irrelevant stimuli in early sensory cortex (C1 component, indexing attentional gating in V1). Results showed that while psychosocial threat, very much like perceptual load, primarily led to a stronger gating in V1, bodily threat resulted in impaired goal-directed processing within the fronto-parietal attentional network, as well as decreased filtering in V1. These results suggest that anticipatory anxiety is multifaceted, exerting different effects on attention control and early visual processing depending on its sub-type. PMID- 24793836 TI - Attenuated predictive power of a normal myocardial perfusion scan in young smokers. AB - BACKGROUND: The negative predictive value of a normal myocardial perfusion image (MPI) for myocardial infarction or cardiac death is very high. However, it is unclear whether a normal MPI, reflecting non-compromised blood flow in the stable state, would have the same prognostic implications in smokers as in patients who do not smoke. METHODS: The incidence of total mortality, cardiovascular mortality, and myocardial infarction was evaluated in 11,812 subjects (14.6% of whom were current smokers at the time of the study) with a normal MPI study and no past history of coronary artery disease during the period 1997 to 2008. RESULTS: During an average follow-up of 72.4 +/- 32.4 months the risk for an acute myocardial infarction in current smokers was approximately 50% higher than the corresponding risk in non-smokers, despite a younger average age. Cox proportional regression models show that current smoking was associated with an increased hazard rate for the composite endpoint below age 60 (HR=2.09, 95%CI 1.43-3.07, p<0.001), but not at older ages (HR=1.16, 95% CI 0.81-1.66, p=0.4). CONCLUSIONS: In individuals below age 60, but not at older ages, current smoking is associated with increased short- and long-term risk of cardiac death and acute myocardial infarction even in subjects with a normal MPI. PMID- 24793835 TI - Uric acid as a potential mediator of cardiovascular morbidity in obstructive sleep apnea syndrome. AB - BACKGROUND AND AIMS: Obstructive sleep apnea (OSA) is now considered as an independent risk factor for cardiovascular (CV) disease. Although uric acid is increasingly being implicated in CV morbidity and mortality, no study attempted to determine independent role of uric acid in CV morbidity of OSA patients. We aimed to assess the role of serum uric acid as a potential mechanism of CV morbidity in a nonselected cohort of OSA patients. METHODS: This was a cohort study in which patients who had undergone a formal sleep study for diagnosis of OSA were recruited. Included patients were grouped according to apnea-hypopnea index (AHI) as mild, moderate and severe OSA. Patients with AHI<5 served as control group. Patients were interrogated as to cardiovascular morbid conditions which included prior history and an established diagnosis of coronary artery disease, cerebrovascular accident, congestive heart failure due to coronary artery disease and arrhythmias. RESULTS: 436 OSA patients included (72 controls, 97 with mild, 75 with moderate, and 192 with severe OSA). The severe group also had higher serum uric acid level compared with the control and other OSA groups. Linear regression showed that the Ln uric acid was positively associated with Ln AHI score. In unadjusted logistic regression, severe OSA was associated with higher odds of a cardiovascular event, OR=2.81 (1.307-6.041), p=0.0081 while the other categories of sleep apnea were not. However, severe OSA was no longer significant after adjusting for age, gender, diabetes mellitus status, hypertension status, BMI, and smoking, OR=1.882 (0.826-4.287), p=0.1322. Uric acid was significantly higher in those who had a cardiovascular event even in the mild, moderate and severe OSA groups. CONCLUSION: Hyperuricemia is strongly associated with cardiovascular disease in OSA patients. This strong relationship persists even after controlling for well-known traditional risk factors for cardiovascular disease. PMID- 24793837 TI - 'Heart attack' symptoms and decision-making: the case of older rural women. AB - INTRODUCTION: Women are just as vulnerable to 'heart attacks' (used throughout this study to mean 'myocardial infarction') as men and are often unaware of many associated symptoms. Researchers have illustrated that women have difficulty identifying the symptoms of cardiovascular disease, with patients often delaying treatment after the onset of symptoms. Some individuals wait hours or even days before seeking medical care. This is particularly concerning for older rural women because the rates of death from cardiovascular disease and cancer are higher in some rural areas. Despite idealistic views of country life as being active, less stressful, and possessing strong social and community support, rural Americans are more likely than their urban counterparts to face challenges to maintaining health.
AIM: The purpose of this paper is to utilize information gathered from a qualitative study exploring older rural women's identification of symptoms and health decision-making specific to heart attack vignettes. METHODS: Snowball sampling was the main approach utilized to access participants; after an initial contact was successful, participants contacted additional older rural women to see if they might be willing to participate in an interview. This resulted in a final sample of 33 women who resided in rural Midwestern areas of the USA, were 65 years or older, lived in a county defined as rural by the US Census, and were willing to participate in a face-to-face interview. Each interview included a demographic questionnaire, a health questionnaire, and three health vignettes with follow-up questions. Vignettes provided a way of initiating discussions about health decisions without invading the privacy known to be important to rural residents. The term 'heart attack' was used in the interviews because it was thought to be better recognised than the medical term 'myocardial infarction'. All data were audio taped, transcribed, and coded using line-by-line coding. Data were analyzed using content analysis. RESULTS: The study showed that women had difficulty identifying heart attack symptoms when they did not have previous exposure to the symptoms either through personal experience or educational programs. Individuals incorrectly identified symptoms of a heart attack by associating symptoms with sleep problems, stroke, arthritis, stiffness in the neck, influenza, nerve damage, osteoporosis, bone cancer, tooth infection, and a pulled muscle. Misdiagnosis of symptoms most often led to a delay in seeking treatment in these women. Additionally, the women in this study discussed a reluctance to access care because of concerns related to maintaining their privacy, belief that the ambulance would take too long to reach them, and they did not want to bother their relatives for help. CONCLUSIONS: The findings of this study suggest implications for educational programs and interventions in rural environments and provide information that can facilitate better-informed communication between healthcare professionals and rural women. PMID- 24793838 TI - Monitoring process induced attrition of drug substance particles within formulated blends. AB - The aim of the study was to investigate the impact of unit processing steps such as blending, cone milling and powder feeding systems on the particle size of a formulated API. The particle properties of a single component (API) within formulated samples were tracked using an image based particle characterisation system with an integrated Raman probe. In addition to the primary aim, the impact of excipient selection was also assessed. The study demonstrated the ability to track the size and shape of particles of a single component within a blended system. Process induced attrition can affect significant changes in the size and shape characteristics of the API particles. Whilst blending and cone milling were found to have minimal impact on the API properties, significant particle attrition was induced through transmission of the formulations through a powder feeding system. The impact of excipients within the formulated blends on API attrition propensity was observed to be low. The findings suggest that the propensity for particles to undergo process induced attrition should be taken into consideration when designing a manufacturing process and/or relating initial particle properties to the performance of intermediate or final dosage forms. PMID- 24793839 TI - Low-frequency shift dispersive Raman spectroscopy for the analysis of respirable dosage forms. AB - A high performance Raman system equipped with a CCD (charged coupled device) sensor and recently developed optical filter technology is described. It provides high sensitivity, high resolution, and access to low-frequency vibrations enabling resolution of spectral features due to lattice vibrational modes and internal vibrational modes, greatly improving the ability to detect small changes due to variations in the three dimensional molecular arrangement, e.g., during loss of crystallinity. Applications to solid state analysis, such as solid phase identification and differentiation of glycopyrronium bromide and formoterol fumarate in pharmaceutical powders, and identification of active pharmaceutical ingredients, e.g., salmeterol xinafoate, fluticasone propionate, mometasone furoate, and salbutamol sulphate, as well as excipients, e.g., amino acids, in different formulations, are presented. For the first time, low-frequency shift Raman spectra of mannitol polymorphs were measured and used for solid phase identification. Unambiguous identification of two similar bronchodilator metered dose inhalers, Ventolin((r)) HFA and Airomir((r)), was accomplished. The low frequency shift Raman signals can be used for the analysis of crystallinity of small samples (<5mg) of respiratory dosage forms in a multi-component formulation matrix containing less than 3% by weight of the component of interest. PMID- 24793840 TI - Polybrominated diphenyl ethers (PBDEs) and dechlorane plus (DP) in a conventional wastewater treatment plant (WWTP) in Shanghai: seasonal variations and potential sources. AB - Wastewater treatment plants (WWTPs) are considered an important medium for the transport and transformation of organic pollutants, such as polybrominated diphenyl ethers (PBDEs) and dechlorane plus (DP). However, limited data on PBDEs and no data on DP were available regarding wastewater and sludge from China, especially in Shanghai, one of the most developed cities in China. This study examined the occurrence of PBDEs and DP in a conventional WWTP in Shanghai for one year. The levels of the total PBDEs in the influent and dewatered sludge ranged from 5.31 to 27.9 ng/L and 31.0 to 99.5 ng/g, respectively, which were at the low end of the global range. DP was reported in wastewater with a mean concentration of 0.46 ng/L (range: 0.05 to 1.40 ng/L) and sludge contained DP in the range of 1.1 to 2.0 ng/g. For both PBDEs and DP, there were no significant seasonal variations observed in the four seasons. Indoor dust and outdoor air could be two main sources of PBDEs and DP in the WWTP. In both the influent and sewage sludge, BDE-209 was the most abundant congener, with contributions to the total PBDE levels ranging from 52.9 to 82.6% and 82.7 to 84.0%, respectively. The fraction of anti-DP was consistently higher than that of syn-DP, and the average of fsyn ranged from 0.16 to 0.33, which fell in the range of two commercial DP mixtures. The annual releases of PBDEs and DP via sewage sludge from WWTPs in Shanghai were estimated to be 6,370 g and 164.8 g, respectively. The fate and risk of these compounds after being released into the environment require further research. To the best of our knowledge, this study is the first to report on the occurrence of DP in wastewater. PMID- 24793841 TI - The effect of humic acid on the aggregation of titanium dioxide nanoparticles under different pH and ionic strengths. AB - With the increasingly widespread use of titanium dioxide nanoparticles (TiO2 NPs), the particles' environmental impacts have attracted concern, making it necessary to understand the fate and transport of TiO2 NPs in aqueous media. In this study, we investigated TiO2 NP aggregation caused by the effects of humic acid (HA), ionic strength (IS) and different pH using dynamic light scattering (DLS) to monitor the size distribution of the TiO2 NPs continuously. It was determined that HA can influence the stability of TiO2 NPs through charge neutralization, steric hindrance and bridging effects. In the absence of IS, aggregation was promoted by adding HA only when the pH (pH=4) is less than the point of zero charge for the TiO2 NPs (pHPZC~6) because HA reduces the zeta potential of the TiO2 NPs via charge neutralization. At pH=4 and when the concentration of HA is 94.5 MUg/L, the zeta potential of TiO2 NPs is close to zero, and they reach an aggregation maximum. A higher concentration of HA results in more negatively charged TiO2 NP surfaces, which hinder their aggregation. When the pH is 5.8, HA enhances the negative zeta potential of the TiO2 NPs and increases their stability via electrostatic repulsion and steric hindrance. When the pH (pH=8) is greater than pHpzc, the zeta potential of the TiO2 NPs is high (~40 mV), and it barely changes with increasing HA concentration. Thus, the TiO2 NPs are notably stable, and their size does not grow at pH8. The increase in the critical coagulation concentration (CCC) of TiO2 NPs indicated that there is steric hindrance after the addition of HA. HA can enhance the coagulation of TiO2 NPs, primarily due to bridging effect. These findings are useful in understanding the size change of TiO2 NPs, as well as the removal of TiO2 NPs and HA from aqueous media. PMID- 24793842 TI - Quantification of non-stormwater flow entries into storm drains using a water balance approach. AB - To make decisions about correcting illicit or inappropriate connections to storm drains, quantification of non-stormwater entries into storm drains was performed using a water flow balance approach, based on data analysis from 2008 to 2011 in a separate storm drainage system in a Shanghai downtown area of 374 ha. The study revealed severe sewage connections to storm drains; meanwhile, misconnections between surface water and storm drains were found to drive frequent non stormwater pumping discharges at the outfall, producing a much larger volume of outfall flows in a short period. This paper presented a methodology to estimate quantities of inappropriate sewage flow, groundwater infiltration and river water backflow into the storm drains. It was concluded that inappropriate sewage discharge and groundwater seepage into storm drains were approximately 17,860 m(3)/d (i.e., up to 51% of the total sewage flow in the catchment) and 3,624 m(3)/d, respectively, and surface water backflow was up to an average 28,593 m(3)/d. On the basis of this work, end-of-storm pipe interceptor sewers of 0.25 m(3)/s (i.e., 21,600 m(3)/d) would be effective to tackle the problem of sewage connections and groundwater seepage to storm drains. Under this circumstance, the follow-up non-stormwater outfall pumping events indicate misconnections between surface water and storm drains, featuring pumping discharge equivalent to surface water backflow; hence the misconnections should be repaired. The information provided here is helpful in estimating the magnitude of non-stormwater flow entries into storm drains and designing the necessary pollution control activities, as well as combating city floods in storm events. PMID- 24793843 TI - Sensitivity of whole-body CT and MRI versus projection radiography in the detection of osteolyses in patients with monoclonal plasma cell disease. AB - PURPOSE: To compare sensitivity of whole-body Computed Tomography (wb-CT) and whole-body Magnetic Resonance Imaging (wb-MRI) with Projection Radiography (PR) regarding each method's ability to detect osteolyses in patients with monoclonal plasma cell disease. PATIENTS AND METHODS: The bone status of 171 patients was evaluated. All patients presented with multiple myeloma (MM) of all stages, monoclonal gammopathy of unknown significance (MGUS) or solitary plasmacytoma. Two groups were formed. Group A consisted of 52 patients (26 females, 26 males) with an average age of 62 years (range, 45-89 years) who received, both, PR and wb-CT as part of their diagnostic work-up. Group B comprised 119 patients (58 females, 61 males) averaging 57 years of age (range, 20-80 years) who received, both, PR and wb-MRI. Two experienced radiologists were blinded regarding the disease status and assessed the number and location of osteolyses in consensus. A distinction was made between axial and extra-axial lesions. RESULTS: In group A, wb-CT revealed osteolyses in 12 patients (23%) that were not detected in PR. CT was superior in detecting lesions in patients with osteopenia and osteoporosis. Compared with PR, wb-CT was significantly more sensitive in detecting osteolyses than PR (p<0.001). This was particularly true for axial lesions. Additionally, CT revealed clinically relevant incidental findings in 33 patients (63%). In group B, wb-MRI revealed lesions in 19 patients (16%) that were not detected in PR. All lesions detected by PR were also detected by wb-MRI and wb-CT. Wb-MRI and wb-CT are each superior to PR in detecting axial lesions. CONCLUSION: Wb-CT can detect 23% more focal lesions than PR, especially in the axial skeleton. Therefore, this imaging method should be preferred over PR in the diagnostic work-up and staging of patients with monoclonal plasma cell disease. PMID- 24793844 TI - Animal models of Alzheimer disease: historical pitfalls and a path forward. AB - Alzheimer disease (AD) is a medically and financially overwhelming condition, and incidence rates are expected to triple by 2050.Despite decades of research in animal models of AD, the disease remains incompletely understood, with few treatment options. This review summarizes historical and current AD research efforts, with emphasis on the disparity between preclinical animal studies and the reality of human disease and how this has impacted clinical trials. Ultimately, we provide a mechanism for shifting the focus of AD research away from animal models to focus primarily on human biology as a means to improve the applicability of research findings to human disease. Implementation of these alternatives may hasten development of improved strategies to prevent, detect, ameliorate, and possibly cure this devastating disease. PMID- 24793845 TI - Cluster analysis of European Y-chromosomal STR haplotypes using the discrete Laplace method. AB - The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous studies. We also compared pairwise distances (between geographically separated samples) with those obtained using the AMOVA method and found good agreement. Further analyses that are impossible with AMOVA were made using the discrete Laplace method: analysis of the homogeneity in two different ways and calculating marginal STR distributions. We found that the Y STR haplotypes from e.g. Finland were relatively homogeneous as opposed to the relatively heterogeneous Y-STR haplotypes from e.g. Lublin, Eastern Poland and Berlin, Germany. We demonstrated that the observed distributions of alleles at each locus were similar to the expected ones. We also compared pairwise distances between geographically separated samples from Africa with those obtained using the AMOVA method and found good agreement. PMID- 24793847 TI - Selective capillary coating materials for in-tube solid-phase microextraction coupled to liquid chromatography to determine drugs and biomarkers in biological samples: a review. AB - In-tube solid-phase microextraction (in-tube SPME) coupled with high performance liquid chromatography (HPLC) or liquid chromatography coupled to mass spectrometry (LC-MS) successfully determines drugs or biomarkers in biological samples by direct sample injection or by simple sample treatment. This technique uses a capillary column as extraction device. Several capillaries (wall-coated open tubular, sorbent-packed, porous monolithic rods, or fiber-packed) with unique phases have been developed and evaluated, aiming to improve the efficiency and selectivity of the in-tube SPME-LC technique. This review describes new developments and applications occurred in recent years, and discusses future trends with emphasis on new extraction devices and current technology used for the synthesis of selective sorbents for bioanalysis, such as (i) polypyrrole, (ii) restricted-access materials, (iii) immunosorbents, (iv) molecular imprinting polymers, (v) monolithic polymers, and (vi) bi-functional materials. PMID- 24793848 TI - Facilitated ion transfer of protonated primary organic amines studied by square wave voltammetry and chronoamperometry. AB - The transfer of the protonated forms of heptylamine, octylamine, decylamine, procaine and procainamide facilitated by dibenzo-18-crown-6 from water to a solvent polymeric membrane has been investigated by using cyclic square wave voltammetry. The experimental voltammograms obtained are in good agreement with theoretical predictions. The values of the standard ion transfer potential, complexation constant and diffusion coefficient in water have been obtained from these experiments, and have been used to draw some conclusions about the lipophilicity of these species and the relative stability of the organic ammonium complexes with dibenzo-18-crown-6. The results have been compared with those provided by linear sweep voltammetry. Calibration graphs were obtained with both techniques. An interesting chronoamperometric method for the determination of the diffusion coefficient of the target ion in the membrane has been developed and applied to all these protonated amines. PMID- 24793846 TI - The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status. AB - Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays. PMID- 24793849 TI - Highly sensitive and selective sensing platform based on pi-pi interaction between tricyclic aromatic hydrocarbons with thionine-graphene composite. AB - We are just beginning to exploit the fascinating potential of thionine, called electrochemical probe that can selectively recognize specific polycyclic aromatic hydrocarbons (PAHs), as tools for the detection of tricyclic aromatic hydrocarbons phenanthrene (PHE) and anthracene (ANT). A novel electrochemical sensing platform by modification of electroactive thionine functionalized graphene onto glass carbon electrode (Th/GRs/GCE) surface was constructed. The immobilized thionine showed a remarkable stability, which may benefit from the pi pi stacking force with graphene. Under optimum conditions, the proposed electrochemical sensor exhibited high sensitivity and low detection limit for detecting PHE and ANT. The total amount of PHE and ANT could be quantified in a wide range of 10pM-0.1MUM with a good linearity (R(2)=0.9979) and a low detection limit of 0.1pM (S/N=3). Compounds which possess one or two benzene rings or PAHs with more than three rings, such as benzene, naphthalene (NAP), benzo[a]pyrene (BaP) and pyrene (PYR) show little interference on the detection. Consequently, a simple and sensitive electrochemical method was proposed for the determination of PHE and ANT, which was used to determine PHE and ANT in waste water samples. The electrochemical method provides a general tool that complements the commonly used spectroscopic methods and immune method for the detection of PAHs. PMID- 24793850 TI - Determination of atranol and chloroatranol in perfumes using simultaneous derivatization and dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometry. AB - A new analytical method based on simultaneous derivatization and dispersive liquid-liquid microextraction (DLLME) followed by gas chromatography-mass spectrometry (GC-MS), for the determination of the allergenic compounds atranol and chloroatranol in perfumes, is presented. Derivatization of the target analytes by means of acetylation with anhydride acetic in carbonate buffer was carried out. Thereby volatility and detectability were increased for improved GC MS sensitivity. In addition, extractability by DLLME was also enhanced due to a less polar character of the solutes. A liquid-liquid extraction was performed before DLLME to clean up the sample and to obtain an aqueous sample solution, free of the low polar matrix from the essential oils, as donor phase. Different parameters, such as the nature and volume of both the extraction and disperser solvents, the ionic strength of the aqueous donor phase or the effect of the derivatization reagent volume, were optimized. Under the selected conditions (injection of a mixture of 750MUL of acetone as disperser solvent, 100MUL of chloroform as extraction solvent and 100MUL of anhydride acetic as derivatization reagent) the figures of merit of the proposed method were evaluated. Limits of detection in the low ngmL(-1) range were obtained. Matrix effect was observed in real perfume samples and thus, standard addition calibration is recommended. PMID- 24793851 TI - Cold column trapping-cloud point extraction coupled to high performance liquid chromatography for preconcentration and determination of curcumin in human urine. AB - A cold column trapping-cloud point extraction (CCT-CPE) method coupled to high performance liquid chromatography (HPLC) was developed for preconcentration and determination of curcumin in human urine. A nonionic surfactant, Triton X-100, was used as the extraction medium. In the proposed method, a low surfactant concentration of 0.4% v/v and a short heating time of only 2min at 70 degrees C were sufficient for quantitative extraction of the analyte. For the separation of the extraction phase, the resulted cloudy solution was passed through a packed trapping column that was cooled to 0 degrees C. The temperature of the CCT column was then increased to 25 degrees C and the surfactant rich phase was desorbed with 400MUL ethanol to be directly injected into HPLC for the analysis. The effects of different variables such as pH, surfactant concentration, cloud point temperature and time were investigated and optimum conditions were established by a central composite design (response surface) method. A limit of detection of 0.066mgL(-1) curcumin and a linear range of 0.22-100mgL(-1) with a determination coefficient of 0.9998 were obtained for the method. The average recovery and relative standard deviation for six replicated analysis were 101.0% and 2.77%, respectively. The CCT-CPE technique was faster than a conventional CPE method requiring a lower concentration of the surfactant and lower temperatures with no need for the centrifugation. The proposed method was successfully applied to the analysis of curcumin in human urine samples. PMID- 24793852 TI - Decrease of dynamic range of proteins in human plasma by ampholine immobilized polymer microspheres. AB - A novel protein sample pretreatment method based on ampholine immobilized polymer microsphere (ampholine@PM) was developed for the fractionation of intact proteins prior to protein digestion and peptide analysis to reduce the dynamic range of human plasma proteome. After incubation with our prepared ampholine@PM, the captured plasma proteins were successively desorbed by 2M NaCl, 100mM glycine hydrochloric acid, and 30% (v/v) acetonitrile with 0.1% (v/v) trifluoroacetic acid. The SDS-PAGE results showed the protein dynamic range in such three fractions was obviously reduced as compared with the native plasma. On-particle digestion was ultimately performed to release all proteins retained on ampholine@PM. Followed by MuPIT analysis, the number of identified proteins in plasma was improved by 75% after ampholine@PM treatment. Furthermore, the spectral count of 9 high abundance proteins was decreased by 37.6-97.2%, and the identified low abundance protein (<100ngmL(-1)) number was increased from 4 to 17. These results demonstrated that the fractionation by ampholine@PM could efficiently decrease the protein dynamic range in abundance, beneficial to achieve the deep coverage identification of human plasma proteome. PMID- 24793853 TI - Segmented continuous-flow multiplex polymerase chain reaction microfluidics for high-throughput and rapid foodborne pathogen detection. AB - High-throughput and rapid identification of multiple foodborne bacterial pathogens is vital in global public health and food industry. To fulfill this need, we propose a segmented continuous-flow multiplex polymerase chain reaction (SCF-MPCR) on a spiral-channel microfluidic device. The device consists of a disposable polytetrafluoroethylene (PTFE) capillary microchannel coiled on three isothermal blocks. Within the channel, n segmented flow regimes are sequentially generated, and m-plex PCR is individually performed in each regime when each mixture is driven to pass three temperature zones, thus providing a rapid analysis throughput of m*n. To characterize the performance of the microfluidic device, continuous-flow multiplex PCR in a single segmented flow has been evaluated by investigating the effect of key reaction parameters, including annealing temperatures, flow rates, polymerase concentration and amount of input DNA. With the optimized parameters, the genomic DNAs from Salmonella enterica, Listeria monocytogenes, Escherichia coli O157:H7 and Staphylococcus aureus could be amplified simultaneously in 19min, and the limit of detection was low, down to 10(2) copiesMUL(-1). As proof of principle, the spiral-channel SCF-MPCR was applied to sequentially amplify four different bacterial pathogens from banana, milk, and sausage, displaying a throughput of 4*3 with no detectable cross contamination. PMID- 24793854 TI - Reproducible quantification of ethanol in gasoline via a customized mobile near infrared spectrometer. AB - This work describes the modification of an InGaAs diode array detector equipped miniaturized near-infrared (NIR) spectrometer enabling the reliable quantification of ethanol blended gasoline. A transflectance measurement cell is presented, utilizing a thermoelectric cooling (TEC) appliance ensuring thermostatic measurement conditions and a gold-coated spherical mirror as a reflector superior to conventional Spectralon((r)). In total, four measurement modes (Spectralon((r)) reflector, gold reflector and either reflectors with employed TEC) are discussed, enabling a straightforward comparison of the results. The test-set validated multivariate partial least squares regression (PLSR) model of the measurement mode involving both gold mirror and TEC yielded an Rval(2) value of 0.997, a limit of detection (LOD) of 0.68% w/w, a limit of quantification (LOQ) of 2.04% w/w, a standard error of prediction (SEP) of 0.21% w/w and a ratio performance deviation (RPD) of 15.2 while utilizing a single latent variable (LV). The NIR band assignment in this work has been established by employing the vibrational self-consistent field second order perturbative treatment (PT2-VSCF) and the computationally derived absorption maxima are compared to the experimentally observed data. PMID- 24793855 TI - Development of a real-time capacitive biosensor for cyclic cyanotoxic peptides based on Adda-specific antibodies. AB - The harmful effects of cyanotoxins in surface waters have led to increasing demands for accurate early warning methods. This study proposes a capacitive immunosensor for broad-spectrum detection of the group of toxic cyclic peptides called microcystins (~80 congeners) at very low concentration levels. The novel analytical platform offers significant advances compared to the existing methods. Monoclonal antibodies (mAbs, clone AD4G2) that recognize a common element of microcystins were used to construct the biosensing layer. Initially, a stable insulating anchor layer for the mAbs was made by electropolymerization of tyramine onto a gold electrode surface, with subsequent incorporation of gold nanoparticles (AuNPs) on the glutaraldehyde (5%) activated polytyramine surface. The biosensor responded linearly to microcystin concentrations from 1*10(-13)M to 1*10(-10)M MC-LR standard with a limit of detection of 2.1*10(-14)M. The stability of the biosensor was evaluated by repeated measurements of the antigen and by determining the capacitance change relative to the original response, which decreased below 90% after the 30th cycle. PMID- 24793856 TI - A new turn-on fluorescence probe for Zn(2+) in aqueous solution and imaging application in living cells. AB - We designed and synthesized a new pyrazoline-based turn-on fluorescence probe for Zn(2+) by the reaction of chalcone and thiosemicarbazide. The structure of the probe was characterized by IR, NMR and HRMS spectroscopy. The probe (L) exhibits high selectivity and sensitivity for detecting Zn(2+) in buffered EtOH/HEPES solution (EtOH/HEPES=1/1, pH 7.2) with 80-fold fluorescence enhancement, which is superior to previous reports. Job's plot analysis revealed 1:1 stoichiometry between probe L and Zn(2+) ions. The association constant estimated by the Benesi Hildebrand method and the detection limit were 3.92*10(3)M(-1) and 5.2*10(-7)M, respectively. A proposed binding mode was confirmed by (1)H NMR titration experiments and density functional theory (DFT) calculations. The probe is cell permeable and stable at the physiological pH range in biological systems. Because of its fast response to Zn(2+), the probe can monitor Zn(2+) in living cells. Moreover, the selective binding of L and Zn(2+) was reversible with the addition of EDTA in buffered EtOH/HEPES solution and Zn(2+) could be imaged in SH-SY5Y neuron cells. PMID- 24793857 TI - On-line column coupled isotachophoresis-capillary zone electrophoresis hyphenated with tandem mass spectrometry in drug analysis: varenicline and its metabolite in human urine. AB - A new highly advanced analytical approach, based on two-dimensional column coupled CE (ITP-CZE) hyphenated with tandem mass spectrometry (MS/MS, here triple quadrupole, QqQ) was developed, evaluated and applied in biomedical field in the present work. Capillary isotachophoresis (ITP) coupled on-line with capillary zone electrophoresis (CZE) used in hydrodynamically closed separation system was favorable for increasing the sample load capacity, increasing the analyte concentration, and removing the deteriorative highly conductive major matrix constituents. These factors considerably reduced the concentration limits of detection (cLOD) and external sample preparation (comparing to single column CZE), and, by that, provided favorable conditions for the mass spectrometry (enhanced signal to noise ratio, reproducibility of measurements, working life of MS). Here, the CZE-ESI combination provided more effective interfacing than ITP ESI resulting in both a higher obtainable intensity of MS detection signal of the analyte as well as reproducibility of measurements of the analyte's peak area. The optimized ITP-CZE-ESI-QqQ method was successfully evaluated as for its performance parameters (LOD, LOQ, linearity, precision, recovery/accuracy) and applied for the direct identification and ultratrace (pgmL(-1)) determination of varenicline and, in addition, identification of its targeted metabolite, 2 hydroxy-varenicline, in unpretreated/diluted human urine. This application example demonstrated the real analytical potential of this new analytical approach and, at the same time, served as currently the most effective routine clinical method for varenicline. PMID- 24793858 TI - [Improving treatment adherence in kidney transplantation: a major challenge]. AB - The kidney transplant recipient is faced not only with the perspective of taking immunosuppressive drugs lifelong, but also the possibility of other long-term treatments prescribed for preexisting conditions, complications, or side effects. Proper management, and most importantly patient adherence, can become a complex challenge. Here we recall current definitions and describe methods for measuring treatment adherence, followed by a discussion on the prevalence of non-adherence in kidney transplant recipients, its effect on graft survival, and factors predictive of non-adherence. Ways of improving adherence are examined, leading to the conviction that helping patients take their medications regularly would probably have a greater impact on graft survival than marketing a new immunosuppressive agent. PMID- 24793859 TI - [Use of hierarchical models in nephrology]. AB - The use of hierarchical models in public health research is recently increasing in order to study all the factors explaining health outcomes. Thus, a better understanding of those models is needed first to identify questions that may be answered by using them and also to be aware of there limitations. On the one hand, hierarchical models managed to take into account the hierarchical structure of the data allowing a better estimation of the effects of the explanatory variables and the study of the impact of the "environment" (i.e.: neighborhood, treatment center, same clinical trial...) on health outcomes. They also allow the study of factors that may explain this impact of the "environment". On the other hand, they are more complex and a reflection on which determinant to include and how the environment is supposed to impact patients' health is much needed. This article reviews the rationale for using hierarchical models in public health research and especially in nephrologic research. We attempt to give a simple presentation of these models and to illustrate their results and potential use in the field of nephrology, as well as their limits. PMID- 24793860 TI - An improved synthesis of 3,6-anhydro-D-glucal and a study of its unusual chemical reactivity. AB - 6-O-Tosyl-d-glucal 1 upon treatment with excess LiAlH4 unexpectedly gave 3,6 anhydro-d-glucal 2 as a major product in good yield. A crystal structure was obtained. Reaction of the anhydride 2 with N-iodosuccinimide (NIS) in excess methanol resulted in the formation of diastereomeric 2-deoxy-2-iodoglycosides. Addition of ceric (IV) ammonium nitrate and thiophenol to a solution of 2 in acetonitrile gave a mixture of 2-deoxy and 2,3-unsaturated thioglycosides. Reaction of 1,2:3,4-di-O-isopropylidine-alpha-d-galactopyranose with the anhydro sugar 2 in the presence of N-iodosuccinimide did not give the expected iodoglycoside mixture, but instead gave an unusual 1,4:3,6-dianhydride 7 as the major product. PMID- 24793861 TI - Co-maturation of theta and low-beta rhythms during child development. AB - The present report examines a possible co-maturation pattern between different frequency ranges on the spontaneous electroencephalogram (EEG) during development in childhood, adolescence and young adulthood. One hundred and sixty-seven subjects, between 6 and 26 years old were recorded during 3 min of spontaneous EEG. The power spectral density (PSD) logarithm was computed. There was a decrease in all frequency band ranges between 1 and 46 Hz. Correlation matrices for these frequencies were computed. A general trend of PSD correlation with neighboring frequencies was obtained. Furthermore, there was a high correlation during development between theta and beta ranges, and between high-beta and gamma frequency ranges. The correlation of theta versus beta was particularly high between the anterior and posterior electrode sites. Principal component analysis allowed the extraction of six components explaining the variance associated with the delta, theta, alpha, low-beta, high-beta and gamma ranges. Interestingly, the component explaining the theta rhythm also explained a fraction of the low-beta rhythm during development. The results suggest a pattern of co-maturation in the PSD of spontaneous EEG between theta and low-beta, and between high-beta and gamma, which would be due to the maturation of neural tissue underlying the sources of different frequencies. The possible functional role of theta-beta co maturation in fronto-parietal electrode sites is suggested. PMID- 24793862 TI - Child malnutrition and prenatal care: evidence from three Latin American countries. AB - OBJECTIVE: To examine the effect of prenatal care (PNC) on the level and distribution of child stunting in three Andean countries-Bolivia, Colombia, and Peru-where expanding access to such care has been an explicit policy intervention to tackle child malnutrition in utero and during early childhood. METHODS: An econometric analysis of cross-sectional Demographic and Health Survey (DHS) data was conducted. The analysis included ordinary least-squares (OLS) regressions, estimates of concentration curves, and decompositions of a concentration index. RESULTS: The analysis shows that the use of PNC in Bolivia, Colombia, and Peru is only weakly associated with a reduction in the level of child malnutrition. CONCLUSIONS: Further expansion of PNC programs is unlikely to play a large role in reducing inequalities in malnutrition. PMID- 24793863 TI - [Natural history of breast cancer diagnostic procedures]. AB - OBJECTIVE: To build a model that explains the natural history of breast cancer diagnostic procedures. METHODS: Descriptive cross-sectional study of 245 women between 40 and 69 years of age, selected by simple random sampling, who underwent a mammography and met the requirements of the breast cancer diagnostic procedure. Diagnosis was made by biopsy. For the diagnostic procedure, an estimate was made of the percentage of patients seen by each service, the total number of patients per service, and the total number of consultations in each service, with 95% confidence intervals. RESULTS: Of the patients who initiated the breast cancer diagnostic procedure in preventive medicine services, 20% underwent a mammography; 23.7% were seen in family medicine services and of these patients, 70.9% were referred to a breast clinic, where 7.3% underwent a harpoon biopsy. The prevalence of breast cancer confirmed by biopsy was 0.48% (95%CI: 0.0-1.3). Per 1 000 patients who initiated the procedure, 47.4 were seen in family medicine services and 33.6 in a breast clinic, and open biopsies were performed on 2.4. Per 1 000 patients who initiated the procedure, there were 211.4 consultations in radiology services, 51.6 in family medicine services, and 54.6 in a breast clinic. CONCLUSIONS: The model described here may be useful in planning and evaluation activities. PMID- 24793864 TI - Mental health and poor recovery in female nursing workers: a contribution to the study of gender inequities. AB - OBJECTIVE: To address the association between work and mental health from a gender perspective by investigating the combination of domestic work and adverse aspects of professional work (night shifts and psychosocial stress) with regard to minor psychiatric disorders (MPD) and poor recovery from work. METHODS: A cross-sectional study was carried out at three public hospitals in Rio de Janeiro, Brazil, in 2006 (n = 1 122). Data collection was based on a census of all female nurses, technicians, and auxiliary nurses. A multidimensional instrument containing information about health, professional work, and the domestic work was used. The domestic work hours (longer or shorter than 10 hours per week) were combined with the work schedule (day or night shifts) and with psychosocial stress (absence or presence of effort-reward imbalance [ERI]). These combinations were tested with regard to the association with MPD and poor recovery from work. The adjusted odds ratios (OR) and their confidence intervals were calculated using multiple regression models. RESULTS: The combination of long domestic work hours with night work was significantly associated with MPD (OR = 1.94) and poor recovery (OR = 2.67). Long domestic work hours combined with the presence of ERI resulted in significantly higher odds ratios (OR = 4.37 and OR = 5.53, respectively). In all analyses, greater odds ratios were observed in groups with long domestic work hours, compared to short work hours. CONCLUSIONS: These findings suggest that carrying out domestic activities over a certain number of hours can increase the detrimental consequences of professional work in regard to MPD and poor recovery. The interaction between professional and domestic work and its potential implications to mental suffering must be considered in discussions on health equity. PMID- 24793865 TI - [An algorithm to monitor the incidence of malaria in the Brazilian Amazon, 2003 to 2010]. AB - OBJECTIVE: To evaluate an algorithm developed for detecting variations in the incidence of malaria in the Brazilian Amazon. METHODS: An evaluation was conducted of an automated monitoring system based on an algorithm that had been previously developed by the authors. The algorithm employs quartile diagrams to classify municipalities according to variations in the incidence of malaria: group 1 (reduced incidence)-municipalities with below the expected incidence rates; group 2 (expected incidence)- within the expected incidence rates; group 3 (epidemics)-higher than the expected incidence rates; and group 4 (sporadic case) a single case during a year. The period from 2003 to 2010 was analyzed. All the municipalities in the nine states that make up the Brazilian Amazon were studied (805 municipalities in 2003 and 807 starting in 2004). RESULTS: Based on this method, Amazonian municipalities were classified as follows: group 1, 152 (18.8%) municipalities in 2003 and 109 (13.5%) in 2010; group 2, 206 (25.6%) municipalities in 2003 and 331 (41.0%) in 2010; group 3, 391 (48.6%) municipalities in 2003 and 308 (38.2%) in 2010; and group 4, 56 (7.0%) municipalities in 2003 and 59 (7.3%) in 2010. CONCLUSIONS: The use of the algorithm revealed that in 2010, the number of Amazonian municipalities in group 3 (epidemics) decreased when compared to 2003, while the number of municipalities in group 2 (expected incidence) increased. In the same period, there was no significant variation in the number of municipalities in group 1 (reduced incidence) and in group 4 (sporadic case). PMID- 24793866 TI - Outsourcing versus in-house maintenance of medical devices: a longitudinal, empirical study. AB - OBJECTIVE: To determine what factors have a significant influence on the performance of medical device maintenance outsourcing, and to determine how the performance of external governance structures differs depending on whether a hospital is private or public. METHODS: This was a longitudinal study of 590 maintenance transactions at 20 hospitals in Bogota, Colombia, involving 764 medical devices and 72 maintenance service providers. Maintenance performance data (i.e., turn-around time in hours; TAT) for the service providers (either in house or outsourced) were primarily collected over a 20-month period, from December 2009-August 2011, by means of a monitoring procedure; then, a hazards model was run. RESULTS: The availability of specific repair parts, in-stock, in the city in which the medical devices were located, had a positive impact on the performance of both internal and external governance structures. Online service also had a positive impact on both, with a stronger positive impact on the performance of internal governance than on that of external governance. For transactions governed by external structures, better performance was seen in private hospitals than in public ones. In public health institutions, internal governance showed better performance than external governance. Both internal and external governance structures showed better performance in private healthcare institutions than in public ones. CONCLUSIONS: In public health institutions, internal governance shows better performance than external governance; this suggests that healthcare managers should reconsider the trend to eliminate in house maintenance service staff in public healthcare institutions. PMID- 24793867 TI - Health-related quality of life in patients with hepatitis C virus infection in Brazil. AB - OBJECTIVE: To quantify the health-related quality of life (HRQoL) burden of hepatitis C virus (HCV) infection among a broad sample of adults in Brazil, particularly among those 40 years of age and older. METHODS: This was a retrospective observational study of data from the 2011 Brazil National Health and Wellness Survey, a large (n = 12 000) cross-sectional survey that includes information on medical conditions and health outcomes, including the Medical Outcomes Study Short-form 12 health questionnaire, version 2 (SF-12v2). Respondents who reported a physician diagnosis of HCV infection were compared with those who reported never experiencing HCV on the Mental (MCS) and Physical (PCS) Component Summary scores and SF-6D health utility scores. Unadjusted comparisons were conducted with chi-square tests for categorical variables and t tests for continuous variables. Regression was used to adjust outcomes for potential confounds. Subgroup analyses were conducted on those 40 years of age and older. RESULTS: Unadjusted comparisons between respondents infected with HCV (n = 100) and controls (n = 11 694) revealed similar MCS and PCS scores, but HCV patients had lower SF-6D utility scores (0.70 vs. 0.73, P < 0.05). Regressions adjusting for demographic and health characteristics provided similar results to unadjusted comparisons. Subgroup analyses of respondents 40 years of age and older revealed decrements in both MCS (45.95 vs. 49.72, P < 0.05) and SF-6D (0.71 vs. 0.76, P < 0.05). PCS scores were comparable in HCV patients and controls. CONCLUSIONS: HCV infection in Brazil causes significant HRQoL burden, especially among the older population. Prevention measures to curtail the spread of the virus in Brazil should provide societal benefits in terms of quality of life, in addition to preventing morbidity and mortality from chronic infection. PMID- 24793868 TI - "Peri-border" health care programs: the Ecuador-Peru experience. AB - OBJECTIVE: To identify the main strengths, weaknesses, and challenges of the Ecuador-Peru "peri-border" health care program and to analyze the legislative, managerial, and organizational arrangements adopted to integrate the two country's national health systems in the border area. METHODS: A descriptive, qualitative case study was carried out using three complementary methods: literature review and analysis of official Peruvian and Ecuadoran national and binational documents, 18 semi-structured interviews of key informants, and a survey of the entire health worker population of the Suyo-Macara binational micro network. RESULTS: The key program challenge was the absence of reciprocity; Peruvian citizens were entitled to free health care services in Ecuador but Ecuadoran citizens did not receive the same benefit in Peru. The need for improvements in the binational system's human resources was also identified. The program's main strength was its organizational structure, which is designed mainly for the implementation of 1) the binational network and 2) a patient referral / counter-referral system that includes the transfer of patient clinical information. CONCLUSIONS: Notwithstanding considerable challenges, peri-border programs are feasible and replicable. Program success seems to be highly dependent on the completion of a number of steps, including 1) consolidation of the original binational memorandum into a binding binational agreement between the two countries; 2) achievement of similar standards in both countries for the provision and quality of health care services, focusing on complementarities; and 3) development of an integrated binational information system. PMID- 24793869 TI - [Dengue-related knowledge, attitudes, and practices in primary schools in Tapachula, Chiapas, Mexico]. AB - OBJECTIVE: To identify dengue-related knowledge, attitudes, and practices among primary school students in Tapachula, Chiapas, Mexico, before and after an educational intervention. METHODS: The study was carried out at 19 randomly selected public primary schools. Surveys of knowledge, attitudes, and practices were conducted before and after educational sessions with fifthand sixth-grade elementary school students. The educational strategy "Escuelas sin mosquitos" ("Schools without Mosquitoes") emphasized the importance of students' participation in taking care of their schools and homes in order to prevent dengue through vector control. RESULTS: Before and after the educational sessions, a total of 3 124 surveys were conducted on the knowledge, attitudes, and practices of 1 562 fifth and sixth-grade students (772 and 790 students, respectively) between 10 and 12 years of age. The students' level of knowledge was significantly higher after the implementation of the educational strategy. In comparison with the fifth-graders, the sixth-grade students both already had and also acquired significantly more knowledge of several aspects of the disease and the vector. In all the schools, there were containers with water identified as potential breeding sites, and in 68% of the schools, these containers tested positive for Aedes aegypti larvae. CONCLUSIONS: It was demonstrated that by implementing an educational strategy, children's knowledge, attitudes, and practices were improved in terms of taking care of their schools and promoting a change of attitude to this disease at home. PMID- 24793870 TI - [Economic evaluation of health technologies: checklist for critical analysis of published articles]. AB - OBJECTIVE: To propose a tool for critical analysis of economic evaluation studies based on a synthesis of checklists and guidelines available in the literature. METHODS: The following databases were searched: MEDLINE, Embase, Centre for Reviews and Dissemination, and International Society for Pharmacoeconomics and Outcomes Research. Two investigators independently selected the studies and extracted the data of interest. The number of questions that the checklists contained were counted on the following domains: study design, measurement of costs and health outcomes, analysis and interpretation of results, and general information. A matrix containing the items in each domain was constructed, and a tool for critical analysis was built based on that matrix. RESULTS: The literature search retrieved 406 non-duplicated articles, 19 of which were included in the study. Five hundred sixty-six questions were identified in the checklists employed in these studies: 109 (19%) dealt with health outcomes, 93 (16%) with quantification of costs, 73 (13%) with modeling, 54 (10%) with generalization of findings, and 52 (9%) with uncertainty. The resulting critical analysis checklist contains 32 questions organized into four domains: study design, measurement of costs and health outcomes, analysis and interpretation of results, and general information. CONCLUSIONS: The proposed critical analysis checklist is useful to standardize the assessment of the quality of evidence in all types of economic evaluations. PMID- 24793871 TI - [Indicators for drug selection in health systems: an integrative review]. AB - OBJECTIVE: To produce a panel of the main drug selection indicators by performing an integrative literature review. METHODS: After the elaboration of a review protocol, searches were conducted in LILACS, MEDLINE, Embase, and SciELO databases. The following search terms were used: "indicators"; "criteria"; "drug selection"; "pharmacy and therapeutics committee"; and "medication form"; with the applicable variations in English and Spanish. Sixteen original articles published between January 1996 and March 2012 were retrieved and reviewed to compose a panel of indicators. RESULTS: Forty-five quantitative and qualitative indicators were identified. These indicators were grouped according to conceptual similarities in three categories: 1) assessment of pharmacy and therapeutics committee structure; 2) evaluation of the general processes of drug selection; and 3) evaluation of the results of drug selection. CONCLUSIONS: The indicators identified reveal relative uniformity in the established patterns for drug selection. The group of indicators established in this study should serve as reference for the development and consolidation of drug selection in public health services. PMID- 24793872 TI - Human abuse liability evaluation of CNS stimulant drugs. AB - Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID- 24793874 TI - Gender differences in autoimmune disease. AB - Autoimmune diseases are a range of diseases in which the immune response to self antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease. PMID- 24793873 TI - Neuronal substrates and functional consequences of prenatal cannabis exposure. AB - Cannabis remains one of the world's most widely used substance of abuse amongst pregnant women. Trends of the last 50 years show an increase in popularity in child-bearing women together with a constant increase in cannabis potency. In addition, potent herbal "legal" highs containing synthetic cannabinoids that mimic the effects of cannabis with unknown pharmacological and toxicological effects have gained rapid popularity amongst young adults. Despite the surge in cannabis use during pregnancy, little is known about the neurobiological and psychological consequences in the exposed offspring. In this review, we emphasize the importance of maternal programming, defined as the intrauterine presentation of maternal stimuli to the foetus, in neurodevelopment. In particular, we focus on cannabis-mediated maternal adverse effects, resulting in direct central nervous system alteration or sensitization to late-onset chronic and neuropsychiatric disorders. We compare clinical and preclinical experimental studies on the effects of foetal cannabis exposure until early adulthood, to stress the importance of animal models that permit the fine control of environmental variables and allow the dissection of cannabis-mediated molecular cascades in the developing central nervous system. In sum, we conclude that preclinical experimental models confirm clinical studies and that cannabis exposure evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioural abnormalities. PMID- 24793875 TI - Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A. AB - A series of 2-adamantanamines with alkyl adducts of various lengths were examined for efficacy against strains of influenza A including those having an S31N mutation in M2 proton channel that confer resistance to amantadine and rimantadine. The addition of as little as one CH2 group to the methyl adduct of the amantadine/rimantadine analogue, 2-methyl-2-aminoadamantane, led to activity in vitro against two M2 S31N viruses A/Calif/07/2009 (H1N1) and A/PR/8/34 (H1N1) but not to a third A/WS/33 (H1N1). Solid state NMR of the transmembrane domain (TMD) with a site mutation corresponding to S31N shows evidence of drug binding. But electrophysiology using the full length S31N M2 protein in HEK cells showed no blockade. A wild type strain, A/Hong Kong/1/68 (H3N2) developed resistance to representative drugs within one passage with mutations in M2 TMD, but A/Calif/07/2009 S31N was slow (>8 passages) to develop resistance in vitro, and the resistant virus had no mutations in M2 TMD. The results indicate that 2-alkyl 2-aminoadamantane derivatives with sufficient adducts can persistently block p2009 influenza A in vitro through an alternative mechanism. The observations of an HA1 mutation, N160D, near the sialic acid binding site in both 6-resistant A/Calif/07/2009(H1N1) and the broadly resistant A/WS/33(H1N1) and of an HA1 mutation, I325S, in the 6-resistant virus at a cell-culture stable site suggest that the drugs tested here may block infection by direct binding near these critical sites for virus entry to the host cell. PMID- 24793876 TI - Associations between patient expectations of joint arthroplasty surgery and pre- and post-operative clinical status. AB - Improvements in implant materials and designs have broadened surgical indications and improved the technical successes of joint arthroplasty surgery. Nevertheless, a small but notable proportion of patients remain dissatisfied despite technically successful surgery. Given reported associations between unfulfilled patient expectations and dissatisfaction, we performed a systematic review to investigate the current state of knowledge concerning potential associations between clinical status and patient expectations of joint arthroplasty procedures. A wide range of expectation assessment instruments was identified, some of which assessed probabilistic expectations and other value-based expectations. Consistent associations were identified between probabilistic expectations of surgery and better pre-operative disease-specific and general health status, as well as more desirable post-operative disease specific scores. In contrast, no consistent associations were identified between clinical status and value-based expectations. Fulfillment of expectations was consistently associated with superior disease-specific and general health absolute and change scores, irrespective of the expectations paradigm used. PMID- 24793878 TI - New 2H-chromene-3-carboxamide derivatives: design, synthesis and use as inhibitors of hMAO. AB - A series new 2H-chromene-3-carboxamide derivatives 4a-4t were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. Among them, compound 4d (IC50 = 0.93 MUM, IC(50 iproniazid) = 7.80 MUM) showed the most activity and higher MAO-B selectivity (64.5-fold vs. 1-fold) with respect to the MAO-A isoform. The active compound 4d was also docked into the hMAO-B complex structure active site to determine the probable binding model. The results indicated that conserved residue CYSA 172 was important for ligand binding via hydrogen bond interaction, Pi-Pi interaction was found between the benzene-ring of compound 4d and residue ILEA 199. PMID- 24793877 TI - Design and synthesis of the novel DNA topoisomerase II inhibitors: esterification and amination substituted 4'-demethylepipodophyllotoxin derivates exhibiting anti tumor activity by activating ATM/ATR signaling pathways. AB - According to the structure-activity relationship, drug combination principle and bioisosterism, a series of the novel esterification and amination 4' demethylepipodophyllotoxin derivates were rationally designed in order to discover the potential antitumor prodrug. And then these compounds were tested by the drug-topoisomerase II docking models for virtual screening. Thus, twelve target compounds were screened out and synthesized. Most of compounds exhibited promising in vitro anti-tumor activity, particularly 4-N tris(hydroxymethyl)metylaminomethane-4-deoxy-4'-demethylepipodophyllotoxin (Compound 1). The anti-tumor activity of Compound 1 against the tumor cell lines BGC-823 (i.e., the IC50 value of 5.35 +/- 0.77 MUM), HeLa (i.e., the IC50 value of 160.48 +/- 14.50 MUM), and A549 (i.e., the IC50 value of 13.95 +/- 5.41 MUM) was significantly improved by 706%, 31% and 900% than that of etoposide (i.e., the IC50 values of 43.74 +/- 5.13, 209.90 +/- 13.42, and 139.54 +/- 7.05 MUM), respectively. Moreover, the IC50 value of Compound 1 against the normal human cell line HK-2 (i.e., 16.3 +/- 3.77 MUM) was 78% lower than that of etoposide (i.e., 9.17 +/- 1.58 MUM). Compound 1 could diminish the relaxation reaction topoisomerase II DNA decatenation at a concentration of 10 MUM and induce BGC-823 apoptosis by breaking DNA double-strand and activating ATM/ATR signaling pathways. PMID- 24793879 TI - Localization and interaction of hydroxyflavones with lipid bilayer model membranes: a study using DSC and multinuclear NMR. AB - The localization and interaction of six naturally occurring flavones (FLV, 5HF, 6HF, 7HF, CHY and BLN) in DPPC bilayers were studied using DSC and multi-nuclear NMR. DSC results indicate that FLV and 6HF interact with alkyl chains. The (1)H NMR shows interaction of flavones with the sn-glycero region. Ring current induced chemical shifts indicate that 6HF and BLN acquire parallel orientation in bilayers. 2D NOESY spectra indicate partitioning of the B-ring into the alkyl chain region. The DSC, NMR and binding studies indicate that 5HF and 7HF are located near head group region, while 6HF, CHY and BLN are located in the vicinity of sn-glycero region, and FLV is inserted deepest in the membrane. PMID- 24793880 TI - Oxazolidinone derivatives: cytoxazone-linezolid hybrids induces apoptosis and senescence in DU145 prostate cancer cells. AB - In this study, we report the synthesis of novel oxazolidinone derivatives derived from linezolid 3 having p-methoxyphenyl group at C-4 position. In vitro evaluation for their anticancer activity toward cultured A549, DU145, HELA, and MCF7 were carried out. The series of compounds prepared displayed wide range of cytotoxicity in MTT assays (10-70 MUM) across the cell lines tested. Of the all tested compounds 16 and 17 displayed good anticancer potential against A549 (lung) and DU145 (prostate) cancer cells. Further, to determine their anticancer potential, in the present study we have assessed effect of 17 on DU145 cells growth in in vitro assays. The results clearly demonstrated that the exposure of DU145 cells to 17 inhibits cell proliferation and induces apoptosis by activation of caspase-3 and -9. Long term exposure of DU145 cells to 17 induced cellular senescence confirmed by senescence marker beta-galactosidase staining of cells on post exposure to 17. The results from this current report support that the oxazolidinone derivatives with ethyl and acryl substitutions showed promising anticancer activity which will be helpful to develop further novel anticancer agents with better therapeutic potential. PMID- 24793881 TI - Enantiopure bifunctional chelators for copper radiopharmaceuticals--does chirality matter in radiotracer design? AB - It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S . Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the alphavbeta3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the alphavbeta3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 +/- 0.45, 2.60 +/- 0.52, 2.45 +/- 0.48 and 2.88 +/- 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 +/- 0.21, 2.13 +/- 0.58, 1.70 +/- 0.20 and 1.90 +/- 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 +/- 0.46, 2.30 +/- 1.49, 1.73 +/- 0.31 and 2.23 +/- 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in alphavbeta3 targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents. PMID- 24793882 TI - Ruthenium(II) complexes as apoptosis inducers by stabilizing c-myc G-quadruplex DNA. AB - Two ruthenium(II) complexes, [Ru(L)2(p-tFMPIP)](ClO4)2 (L = bpy, 1; phen, 2; p tFMPIP = 2-(4-(trifluoromethyphenyl)-1H-imidazo[4,5f][1,10] phenanthroline)), were prepared by microwave-assisted synthesis technology. The inhibitory activity evaluated by MTT assay shown that 2 can inhibit the growth of MDA-MB-231 cells with inhibitory activity (IC50) of 16.3 MUM, which was related to the induction of apoptosis. Besides, 2 exhibit low toxicity against normal HAcat cells. The inhibitory growth activity of both complexes related to the induction of apoptosis was also confirmed. Furthermore, the studies on the interaction of both complexes with c-myc G4 DNA shown that 1 and 2 can stabilize the conformation of c-myc G4 DNA in groove binding mode, which has been rational explained by using DFT theoretical calculation methods. In a word, this type of ruthenium(II) complexes can act as potential apoptosis inducers with low toxicity in clinic by stabilizing c-myc G4 DNA. PMID- 24793883 TI - Synthesis and optimization of an original V-shaped collection of 4-7 disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors. AB - We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7 dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 MUM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM. PMID- 24793884 TI - Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors. AB - The Cell division cycle 7 (Cdc7) protein kinase is essential for DNA replication and maintenance of genome stability. We systematically explored thiazole-based compounds as inhibitors of Cdc7 kinase activity in cancer cells. Our studies resulted in the identification of a potent, selective Cdc7 inhibitor that decreased phosphorylation of the direct substrate MCM2 in vitro and in vivo, and inhibited DNA synthesis and cell viability in vitro. PMID- 24793885 TI - Structure-activity relationships studies of quinoxalinone derivatives as aldose reductase inhibitors. AB - Novel quinoxalinone derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Among them, N1-acetate derivatives had significant activity in a range of IC50 values from low micromolar to submicromolar, and compound 15a bearing a C3-phenethyl side chain was identified as the most potent inhibitor with an IC50 value of 0.143 MUM. The structure activity studies suggested that both C3-phenethyl and C6-NO2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based inhibitors. PMID- 24793886 TI - Earphones in extended high-frequency audiometry and ISO 389-5. AB - OBJECTIVE: To determine common reference equivalent threshold sound pressure levels (RETSPL) for the earphones used in the extended high-frequency (EHF) range, as different earphones are commercially available, but there are not RETSPLs for each model. DESIGN: Hearing threshold sound pressure levels were measured up to 20 kHz for the Sennheiser HDA 200 audiometric earphone, and were compared to the ISO 389-5 (2006) norm and other investigations using that earphone and different ones. STUDY SAMPLE: A total of 223 otologically-normal subjects (aged 5-25 years old) participated in the hearing determination. RESULTS: The results are in good agreement with previous studies of hearing thresholds using the same and other earphones. CONCLUSIONS: The results of the present investigation are relevant for the international standard for the calibration of audiometric equipment in the 8 to 16 kHz frequency range, ISO 389 5. The data may be used for a future update of the RETSPL for circumaural and insert audiometric earphones. PMID- 24793888 TI - Distribution and phenotype of GJB2 mutations in 102 Sicilian patients with congenital non syndromic sensorineural hearing loss. AB - OBJECTIVE: To evaluate the frequency of GJB2 mutations and their correlation with phenotype in Sicilian non-syndromic sensorineural hearing loss (NSHL) patients. DESIGN: Sequencing of the coding region, basal promoter, exon 1, and donor splice site of the GJB2 gene; screening for the presence of the two common GJB6 deletions. STUDY SAMPLE: A cohort of 102 Sicilian NSHL patients. RESULTS: Fifteen different mutations in GJB2 and seventeen different genotypes were detected. No GJB6 mutations were found. The hearing impairment was profound in the 64.72% of probands (mean PTA0.25-4 kHz of 88.82 +/- 26.52 dB HL). A total of 81.37% of patients harboured at least one c.35delG allele; c.167delT and c.-23 + 1G> A were identified in 10.78% and the 9.8% of patients respectively; c.35delG homozygotes presented more severe hearing impairment (75.59% of profound hearing loss) and a higher mean PTA0.25-4 kHz (96.79 +/- 21.11 dB HL) with respect to c.35delG/non c.35delG and c.35delG/Wt patients (P < 0.05). CONCLUSIONS: This work underlines the role of c.35delG, c.167delT and c.-23 + 1G> A as the most frequent causes of NSHL in Sicily. The c.35delG frequency found is similar to those reported in other populations of the Mediterranean area. The analysis of genetic and audiologic data confirmed a variability in the phenotype associated to a single genotype. PMID- 24793889 TI - The mechanical stability of allografts after a cleaning process: comparison of two preparation modes. AB - In revision hip arthroplasty, bone loss can be compensated by impacting allograft material. Cleaning processes reduce the risk of bacterial and viral contamination. Cleaned allograft material was compared to native untreated allografts by using a uniaxial compression test. 30 measurements were performed for each group before and after compaction. Grain size distribution and weight loss were determined. A reduction in the amount of large bone fragments and a higher compaction rate were observed in the cleaned bone grafts. The cleaned bone chips presented with a better mechanical resistance to a compression force and a reduced flowability. The benefit of a cleaner and a mechanical stable graft material comes with the drawback that higher initial amounts of graft material are needed. PMID- 24793890 TI - MRI findings following metal on metal hip arthroplasty and their relationship with metal ion levels and acetabular inclination angles. AB - Following the global recall of all ASR metal on metal hip products, our aim was to correlate MRI findings with acetabular inclination angles and metal ion levels in patients with these implants. Both cobalt and chromium levels were significantly higher in the presence of a periprosthetic fluid collection. There was no association between the presence of a periprosthetic mass, bone marrow oedema, trochanteric bursitis or greater levels of abductor muscle destruction for cobalt or chromium. There was no association between the level of periprosthetic tissue reaction and the acetabular inclination angle with any of the pathologies identified on MRI. The relationship between MRI pathology, metal ion levels and acetabular inclination angles in patients with ASR implants remains unclear adding to the complexity of managing patients. PMID- 24793891 TI - A nomogram to predict major complications after hip and knee arthroplasty. AB - We aimed to develop a nomogram for risk stratification of major postoperative complications in hip and knee arthroplasty based on preoperative and intraoperative variables, and assessed whether this tool would have better predictive performance compared to the Surgical Apgar Score (SAS). Logistic regression analysis was performed to develop a nomogram. Discrimination and calibration were assessed. Net reclassification improvement (NRI) was used to compare to the SAS. All variables were found to be statistically significant predictors of post-operative complications except race and lowest heart rate. The concordance index was 0.76 with good calibration. Compared to the SAS, the NRI was 71.5% overall. We developed a clinical prediction tool, the Morbidity and Mortality Acute Predictor for arthroplasty (arthro-MAP) that might be useful for postoperative risk stratification. PMID- 24793892 TI - A comparison of stability and clinical outcomes in single-radius versus multi radius femoral design for total knee arthroplasty. AB - We compared the intraoperative varus-valgus stability from 0 degrees to 90 degrees of flexion and postoperative clinical outcomes in patients receiving TKA via either a single-radius femoral design (50 TKA, SR group) or multi-radius femoral design (50 TKA, MR group). We measured stabilities at 0 degrees , 30 degrees , 60 degrees and 90 degrees of flexion using a navigation system. The clinical outcomes including HSS scores, WOMAC scores and VAS score during stair climbing were compared after a minimum of 2-year follow-up. The single-radius femoral designs in TKA showed better intra-operative stability at 30 degrees of flexion (7.6 vs. 8.3) compared with the multi-radius femoral design, but not at other angles. However, the clinical outcomes revealed no other significant differences in terms of HSS scores, WOMAC scores and VAS score between two groups. PMID- 24793893 TI - Topical application of tranexamic acid in primary total hip arthroplasty: a randomized double-blind controlled trial. AB - So far, studies of topical tranexamic acid (TXA) in total hip arthroplasty (THA) were still lacking and controversial. We conducted this randomized double-blind controlled trial which included 101 patients to assess the effect of a high-dose 3g topical TXA in THA. The results showed that 3g topical TXA could significantly reduce transfusions from 22.4% to 5.7% (P<0.05) without increasing the risk of deep vein thrombosis (DVT), pulmonary embolism (PE) and other complications. In addition, topical TXA significantly reduced total blood loss, reduced drain blood loss, and the drops of HB and HCT in topical TXA group were lower than control group. We concluded that 3g topical TXA was effective and safe in reducing bleeding and transfusions in THA. PMID- 24793894 TI - Recombinant cellulase accumulation in the leaves of mature, vegetatively propagated transgenic sugarcane. AB - The cost of enzymes that hydrolyse lignocellulosic substrates to fermentable sugars needs to be reduced to make cellulosic ethanol a cost-competitive liquid transport fuel. Sugarcane is a perennial crop and the successful integration of cellulase transgenes into the sugarcane production system requires that transgene expression is stable in the ratoon. Herein, we compared the accumulation of recombinant fungal cellobiohydrolase I (CBH I), fungal cellobiohydrolase II (CBH II), and bacterial endoglucanase (EG) in the leaves of mature, initial transgenic sugarcane plants and their mature ratoon. Mature ratoon events containing equivalent or elevated levels of active CBH I, CBH II, and EG in the leaves were identified. Further, we have demonstrated that recombinant fungal CBH I and CBH II can resist proteolysis during sugarcane leaf senescence, while bacterial EG cannot. These results demonstrate the stability of cellulase enzyme transgene expression in transgenic sugarcane and the utility of sugarcane as a biofactory crop for production of cellulases. PMID- 24793896 TI - Provesicular granisetron hydrochloride buccal formulations: in vitro evaluation and preliminary investigation of in vivo performance. AB - Granisetron hydrochloride (granisetron) is a potent antiemetic that has been proven to be effective in acute and delayed emesis in cancer chemotherapy. Granisetron suffers from reduced oral bioavailability (~60%) due to hepatic metabolism. In this study the combined advantage of provesicular carriers and buccal drug delivery has been explored aiming to sustain effect and improve bioavailability of granisetron via development of granisetron provesicular buccoadhesive tablets with suitable quality characteristics (hardness, drug content, in vitro release pattern, exvivo bioadhesion and in vivo bioadhesion behavior). Composition of the reconstituted niosomes from different prepared provesicular carriers regarding type of surfactant used and cholesterol concentration significantly affected both entrapment efficiency (%EE) and vesicle size. Span 80 proniosome-derived niosomes exhibited higher encapsulation efficiency and smaller particle size than those derived from span 20. Also, the effect of %EE and bioadhesive polymer type on in vitro drug release and in vivo performance of buccoadhesive tablets was investigated. Based on achievement of required in vitro release pattern (20-30% at 2h, 40-65% at 6h and 80-95% at 12h), in vivo swelling behavior, and in vivo adhesion time (>14 h) granisetron formulation (F19, 1.4 mg) comprising HPMC:carbopol 974P (7:3) and maltodextrin coated with the vesicular precursors span 80 and cholesterol (9:1) was chosen for in vivo study. In vivo pharmacokinetic study revealed higher bioavailability of buccal formulation relative to conventional oral formulation of granisetron (AUC0 infinity is 89.97 and 38.18 ng h/ml for buccal and oral formulation, respectively). A significantly lower and delayed Cmax (12.09+/-4.47 ng/ml, at 8h) was observed after buccal application compared to conventional oral tablet (31.66+/-10.15 ng/ml, at 0.5 h). The prepared provesicular buccoadhesive tablet of granisetron (F19) might help bypass hepatic first-pass metabolism and improve bioavailability of granisetron with the possibility of reducing reported daily dose (2mg) and reducing dosing frequency. PMID- 24793895 TI - Quality of depression treatment in Black Americans with major depression and comorbid medical illness. AB - OBJECTIVE: The objective was to evaluate how comorbid type 2 diabetes (T2DM) and hypertension (HT) influence depression treatment and to assess whether these effects operate differently in a nationally representative community-based sample of Black Americans. METHODS: Data came from the National Survey of American Life (N=3673), and analysis is limited to respondents who met lifetime criteria for major depression (MD) (N=402). Depression care was defined according to American Psychiatric Association (APA) guidelines and included psychotherapy, pharmacotherapy and satisfaction with services. Logistic regression was used to examine the effects of T2DM and HT on quality of depression care. RESULTS: Only 19.2% of Black Americans with MD alone, 7.8% with comorbid T2DM and 22.3% with comorbid HT reported APA-guideline-concordant psychotherapy or antidepressant treatment. Compared to respondents with MD alone, respondents with MD+T2DM/HT were no more or less likely to receive depression care. Respondents with MD+HT+T2DM were more likely to report any guideline-concordant care (odds ratio=3.32; 95% confidence interval, 1.07-10.31). CONCLUSIONS: Although individuals with MD and comorbid T2DM+HT were more likely to receive depression care, guideline-concordant depression care is low among Black Americans, including those with comorbid medical conditions. PMID- 24793897 TI - Serial brain 18FDG-PET in anti-AMPA receptor limbic encephalitis. AB - Immunotherapy-responsive autoimmune CNS syndromes linked to antibodies targeting surface neuronal antigens lack reliable biomarkers of disease activity. We report serial cerebral (18)FDG PET studies in a woman with AMPA receptor (AMPA-R) autoimmune limbic encephalitis. During her follow-up, despite an aggressive immunotherapy, she displayed a persistent, predominantly left hippocampal FDG hypermetabolism, in the absence of CNS inflammatory signs. Brain metabolism abnormalities regressed after increasing antiepileptic treatment, correlating with a moderate clinical improvement. Brain (18)F-FDG PET could thus represent a useful complementary tool to orient the clinical follow-up. PMID- 24793898 TI - Activation-induced cell death in T lymphocytes from multiple sclerosis patients. AB - Apoptosis is a major mechanism regulating immune tolerance by the elimination of autoreactive T lymphocytes. A failure of activation induced cell-death (AICD) has been described in T lymphocytes from patients with multiple sclerosis (MS). The aims of this study were to evaluate AICD in T lymphocytes from patients with MS and healthy controls, and to explore the molecular mechanisms underlying the deregulation observed in apoptosis induction. PHA-induced AICD was reduced in T lymphocytes from patients with relapsing-remitting MS compared with controls. This finding was associated with a diminished expression of Fas and a failure in caspase 3 activation. PMID- 24793901 TI - Emergence of genetically unrelated NDM-1-producing Acinetobacter pittii strains in Paraguay. PMID- 24793902 TI - Pleuromutilins: use in food-producing animals in the European Union, development of resistance and impact on human and animal health. AB - Pleuromutilins (tiamulin and valnemulin) are antimicrobial agents that are used mainly in veterinary medicine, especially for swine and to a lesser extent for poultry and rabbits. In pigs, tiamulin and valnemulin are used to treat swine dysentery, spirochaete-associated diarrhoea, porcine proliferative enteropathy, enzootic pneumonia and other infections where Mycoplasma is involved. There are concerns about the reported increases in the MICs of tiamulin and valnemulin for porcine Brachyspira hyodysenteriae isolates from different European countries, as only a limited number of antimicrobials are available for the treatment of swine dysentery where resistance to these antimicrobials is already common and widespread. The loss of pleuromutilins as effective tools to treat swine dysentery because of further increases in resistance or as a consequence of restrictions would present a considerable threat to pig health, welfare and productivity. In humans, only one product containing pleuromutilins (retapamulin) is authorized currently for topical use; however, products for oral and intravenous administration to humans with serious multidrug-resistant skin infections and respiratory infections, including those caused by methicillin resistant Staphylococcus aureus (MRSA), are being developed. The objective of this review is to summarize the current knowledge on the usage of pleuromutilins, resistance development and the potential impact of this resistance on animal and human health. PMID- 24793903 TI - Enterococcal multiresistance gene cluster in methicillin-resistant Staphylococcus aureus from various origins and geographical locations. PMID- 24793905 TI - Patient-specific instruments for surgical resection of painful tarsal coalition in adolescents. AB - INTRODUCTION: Congenital tarsal coalition resection in adolescents may be hindered by the complex three-dimensional anatomy of the talocalcaneal joint. Peroperative fluoroscopy is not greatly contributive, especially for talocalcaneal coalition. HYPOTHESIS: 3D planning and patient-specific instruments facilitate the procedure. MATERIALS AND METHODS: A made-to-measure surgical guide (patient-specific instrument) was used in 9 consecutive patients for tarsal coalition resection (7 talocalcaneal and 2 calcaneonavicular coalitions). The guide was created by 3D modeling from the CT scan of the foot. Placed on the bone surface, it oriented the saw blade to resect the bone bridge at the appropriate depth. A fascia lata allograft was interposed. Complete resection and absence of recurrence were checked on postoperative CT in talocalcaneal and on radiography in calcaneonavicular coalitions. RESULTS: Resection was complete in all cases, with no recurrence at last follow-up. DISCUSSION: This technique makes tarsal coalition resection easier and more reliable and may be recommended to improve precision. LEVEL OF EVIDENCE: Level IV, prospective study of a new surgical technique. PMID- 24793904 TI - Gene expression and beta-adrenergic signaling are altered in hypoplastic left heart syndrome. AB - BACKGROUND: The purpose of the current study was to define the myocellular changes and adaptation of the beta-adrenergic receptor (beta-AR) system that occur in the systemic right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS). METHODS: Explanted hearts from children with HLHS and non failing controls were used for this study. HLHS patients were divided into 2 groups: "compensated" (C-HLHS), infants listed for primary transplant with normal RV function and absence of heart failure symptoms, and "decompensated" (D-HLHS), patients listed for transplant after failed surgical palliation with RV failure and/or refractory protein-losing enteropathy or plastic bronchitis. RESULTS: Compared with non-failing control RVs, the HLHS RV demonstrated decreased sarcoplasmic reticulum calcium-adenosine triphosphatase 2a and alpha-myosin heavy chain (MHC) gene expression, decreased total beta-AR due to down-regulation of beta1-AR, preserved cyclic adenosine monophosphate levels, and increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity. There was increased atrial natriuretic peptide expression only in the C-HLHS group. Unique to those in the D-HLHS group was increased beta-MHC and decreased alpha-MHC protein expression (MHC isoform switching), increased adenylyl cyclase 5 expression, and increased phosphorylation of the CaMK target site on phospholamban, threonine 17. CONCLUSIONS: The HLHS RV has an abnormal myocardial gene expression pattern, downregulation of beta1-AR, preserved cyclic adenosine monophosphate levels, and increased CaMKII activity compared with the non-failing control RV. There is MHC isoform switching, increased adenylyl cyclase 5, and increased phosphorylation of phospholamban threonine 17 only in the D-HLHS group. Although abnormal gene expression and changes in the beta-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation. PMID- 24793906 TI - A rhodamine-based "off-on" colorimetric and fluorescent chemosensor for Cu(II) in aqueous and non-aqueous media. AB - A new rhodamine derivative (RhB-NSal) bearing an electron-withdrawing group -NO2 at the 5-position of 2-hydroxyphenyl moiety was synthesized and its sensing behaviors for Cu(2+) in acetonitrile and aqueous acetate-buffer/acetonitrile (2/3, v/v, pH 4.8) media were investigated. In each medium, significant absorption and fluorescence enhancements accompanied by an instant color change from colorless to pink were observed for RhB-NSal upon addition of Cu(2+). RhB NSal binds with Cu(2+) forming a 1:1 stoichiometric complex with an association constant of 6.72 (+/-0.03) * 10(4) M(-1) and 4.23 (+/-0.03) * 10(4) M(-1), respectively. RhB-NSal displayed high selectivity for Cu(2+) over possibly competitive metal ions except that Fe(3+) and Bi(3+) ion can respectively bring about a little interference in absorption and fluorescence with its sensing for Cu(2+). In dry acetonitrile, pronounced enhancements in the absorbance and emission of RhB-NSal were induced by Cu(2+), with a detection limit of 0.49 MUM, exhibiting higher sensitivity than that of a known analogue bearing no substituent on its phenol ring, RhB-Sal. In aqueous solution, RhB-NSal displayed likewise a high selectivity but a lower sensitivity for Cu(2+) than that in acetonitrile, with a detection limit of 14.98 MUM, still more sensitive than RhB Sal in absorption. By virtue of these properties, RhB-NSal could be used as an "Off-On" fluorescent and colorimetric chemosensor for Cu(2+) in acetonitrile medium, and be developed to be a promising candidate of "Off-On" eye-naked chemosensor for Cu(2+) in a weakly acidic aqueous medium. PMID- 24793907 TI - [Psychosocial vulnerability and substance use screening during pregnancy: Evaluation of a composite auto-questionnaire versus usual medical questioning]. AB - AIM: To evaluate auto-questionnaire use for psychosocial vulnerability and substance use (smoking, alcohol consumption, depression, intimate violence) screening during pregnancy versus usual medical report. MATERIAL AND METHODS: An auto-questionnaire based on validated tests (Fagerstrom/HSI, T-ACE, EPDS, SSQ6) was proposed to 1977 pregnant patients at their first obstetrical consultation. We compared results of auto-questionnaire and usual medical questioning. RESULTS: The auto-questionnaire was filled by 1676 pregnant patients (89.4 %). The two Fagerstrom/HIS questions showed that 20.7 % smoked during pregnancy. T-ACE score was better than usual medical questioning to detect excessive alcohol consumption (4.0 % vs 0.1 %, P<0.05). Drug use before pregnancy was reported by 9.8 % patients in auto-questionnaire, but was only found in 4.9 % of medical files (P<0.001). Seven percent patients reported at least 3 depressive symptoms on 4 purposed in auto-questionnaire. Intimate violence, physical or psychological, was reported in 9.4 %. All of these vulnerability factors were linked together, in auto-questionnaire or in usual medical reports. CONCLUSION: Using auto questionnaire based on standardized screening tests could help medical practioneers to detect psychosocial vulnerability and/or substance use during pregnancy. PMID- 24793908 TI - Persistent nociception induces anxiety-like behavior in rodents: role of endogenous neuropeptide S. AB - Anxiety disorder is a comorbid condition of chronic pain. Analgesics and anxiolytics, subject to addiction and abuse, are currently used to manage pain and anxiety symptoms. However, the cellular mechanism underlying chronic pain and anxiety interaction remains to be elucidated. We report that persistent nociception following peripheral nerve injury induced anxiety-like behavior in rodents. Brain expression and release of neuropeptide S (NPS), a proposed endogenous anxiolytic peptide, was diminished in rodents with coexisting nociceptive and anxiety-like behaviors. Intracerebroventricular administration of exogenous NPS concurrently improved both nociceptive and anxiety-like behaviors. At the cellular level, NPS enhanced intra-amygdaloidal inhibitory transmission by increasing presynaptic gamma-aminobutyric acid (GABA) release from interneurons. These findings indicate that the interaction between nociceptive and anxiety-like behaviors in rodents may be regulated by the altered NPS-mediated intra amygdaloidal GABAergic inhibition. The data suggest that enhancing the brain NPS function may be a new strategy to manage comorbid pain and anxiety. PMID- 24793909 TI - Short-term improvement in insomnia symptoms predicts long-term improvements in sleep, pain, and fatigue in older adults with comorbid osteoarthritis and insomnia. AB - In a primary care population of 367 older adults (aged ?60 years) with osteoarthritis (OA) pain and insomnia, we examined the relationship between short term improvement in sleep and long-term sleep, pain, and fatigue outcomes through secondary analyses of randomized controlled trial data. Study participants, regardless of experimental treatment received, were classified either as improvers (?30% baseline to 2-month reduction on the Insomnia Severity Index [ISI]) or as nonimprovers. After controlling for treatment arm and potential confounders, improvers showed significant, sustained improvements across 18 months compared with nonimprovers in pain severity (P<0.001, adjusted mean difference=-0.51 [95% CI: -0.80, -0.21), arthritis symptoms (P<0.001, 0.63 [0.26, 1.00]), and fear avoidance (P=0.009, -2.27 [-3.95, -0.58]) but not in catastrophizing or depression. Improvers also showed significant, sustained improvements in ISI (P<0.001, -3.03 [-3.74, -2.32]), Pittsburgh Sleep Quality Index Total (P<0.001, -1.45 [-1.97, -0.93]) and general sleep quality (P<0.001, 0.28 [-0.39, -0.16]) scores, Flinders Fatigue Scale (P<0.001, -1.99 [-3.01, 0.98]), and Dysfunctional Beliefs About Sleep Scale (P=0.037, -2.44 [-4.74, 0.15]), but no improvements on the Functional Outcomes of Sleep Questionnaire or the Epworth Sleepiness Scale. We conclude that short-term (2-month) improvements in sleep predicted long-term (9- and 18-month) improvements for multiple measures of sleep, chronic pain, and fatigue. These improvements were not attributable to nonspecific benefits for psychological well-being, such as reduced depression. These findings are consistent with benefits of improved sleep for chronic pain and fatigue among older persons with osteoarthritis pain and comorbid insomnia if robust improvements in sleep are achieved and sustained. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01142349. PMID- 24793910 TI - Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons. AB - Unlike most classical analgesics, botulinum toxin type A (BoNT/A) does not alter acute nociceptive thresholds, and shows selectivity primarily for allodynic and hyperalgesic responses in certain pain conditions. We hypothesized that this phenomenon might be explained by characterizing the sensory neurons targeted by BoNT/A in the central nervous system after its axonal transport. BoNT/A's central antinociceptive activity following its application into the rat whisker pad was examined in trigeminal nucleus caudalis (TNC) and higher-level nociceptive brain areas using BoNT/A-cleaved synaptosomal-associated protein 25 (SNAP-25) and c-Fos immunohistochemistry. Occurrence of cleaved SNAP-25 in TNC was examined after nonselective ganglion ablation with formalin or selective denervation of capsaicin-sensitive (vanilloid receptor-1 or TRPV1-expressing) neurons, and in relation to different cellular and neuronal markers. Regional c-Fos activation and effect of TRPV1-expressing afferent denervation on toxin's antinociceptive action were studied in formalin-induced orofacial pain. BoNT/A-cleaved SNAP-25 was observed in TNC, but not in higher-level nociceptive nuclei. Cleaved SNAP-25 in TNC disappeared after formalin-induced trigeminal ganglion ablation or capsaicin-induced sensory denervation. Occurrence of cleaved SNAP-25 in TNC and BoNT/A antinociceptive activity in formalin-induced orofacial pain were prevented by denervation with capsaicin. Cleaved SNAP-25 localization demonstrated toxin's presynaptic activity in TRPV1-expressing neurons. BoNT/A reduced the c-Fos activation in TNC, locus coeruleus, and periaqueductal gray. Present experiments suggest that BoNT/A alters the nociceptive transmission at the central synapse of primary afferents. Targeting of TRPV1-expressing neurons might be associated with observed selectivity of BoNT/A action only in certain types of pain. PMID- 24793911 TI - Mood factors should be balanced in the trigeminal neuralgia study of white matter. PMID- 24793912 TI - Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. AB - The epithelial-mesenchymal transition (EMT) is a pivotal cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which, in turn, promotes the metastatic potential of cancer. Ginseng is a perennial plant belonging to the genus Panax that exhibits a wide range of pharmacological and physiological activities. Ginsenosides 20-Rg3, which is the active component of ginseng, has various medical effects, such as anti tumorigenic, anti-angiogenesis, and anti-fatiguing activities. In addition, ginsenosides 20(S)-Rg3 and 20(R)-Rg3 are epimers, and this epimerization is produced by steaming. However, the possible role of 20(S)-Rg3 and 20(R)-Rg3 in the EMT is unclear. We investigated the effect of 20(S)-Rg3 and 20(R)-Rg3 on the EMT. Transforming growth factor-beta 1 (TGF-beta1) induces the EMT to promote lung adenocarcinoma migration, invasion, and anoikis resistance. To understand the repressive role of 20(S)-Rg3 and 20(R)-Rg3 in lung cancer migration, invasion, and anoikis resistance, we investigated the potential use of 20(S)-Rg3 and 20(R)-Rg3 as inhibitors of TGF-beta1-induced EMT development in A549 lung cancer cells in vitro. Here, we show that 20(R)-Rg3, but not 20(S)-Rg3, markedly increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker vimentin during initiation of the TGF-beta1-induced EMT. 20(R)-Rg3 also inhibited the TGF-beta1-induced increase in cell migration, invasion, and anoikis resistance of A549 lung cancer cells. Additionally, 20(R)-Rg3 markedly inhibited TGF-beta1-regulated matrix metalloproteinase-2 and activation of Smad2 and p38 mitogen activated protein kinase. Taken together, our findings provide new evidence that 20(R)-Rg3 suppresses lung cancer migration, invasion, and anoikis resistance in vitro by inhibiting the TGF-beta1-induced EMT. PMID- 24793915 TI - Decreased mortality with tight glycemic control in critically ill patients: a retrospective analysis in a large community hospital system. AB - OBJECTIVE: To measure the efficacy and possible adverse consequences of tight blood glucose (BG) control when compared to relaxed control. METHODS: A retrospective, observational study was conducted at a community-based teaching hospital system among adult, nonmaternity hospitalized patients admitted to the intensive care unit (ICU). Tight glycemic control of BG was compared with less strict BG control, and the following outcome measurements were compared: BG, average length of stay (ALOS), severe hypoglycemia, and mortality. RESULTS: Between 2008 and 2012, 18,919 patients were admitted to the ICU. The mortality rate was significantly lower (P = .0001) in patients with an average BG between 80 and 110 mg/dL (8%) and 111 and 140 mg/dL (9.4%) than in patients with average BG between 141 and 180 mg/dL (12.9%). Using tight glycemic control (80 to 110 mg/dL), the ALOS in the ICU decreased from 4 to 2.9 days (P<.0001) among all patients, and from 4.2 to 2.1 days (P<.0001) among patients who had undergone coronary artery bypass graft. Comparatively, the ALOS for the hospital decreased from 9.4 to 8 days. The incidence of severe hypoglycemia (BG <40 mg/dL) was higher (P = .01) in the tight BG control group (4.78%) compared with the relaxed control group (3.5%). This rate was lower than in previously published studies that analyzed the use of tight control. CONCLUSION: Tight glycemic control using protocolbased insulin administration resulted in a decrease in mortality and ALOS among all patients in the ICU. The incidence of severe hypoglycemic episodes was slightly higher in the tightly controlled group but remained lower than in previously published studies. PMID- 24793913 TI - Involvement of P2Y11 receptor in silica nanoparticles 30-induced IL-6 production by human keratinocytes. AB - We have previously reported that P2Y11 receptor mediates IFN-gamma-induced IL-6 production in human keratinocytes, suggesting the importance of purinergic signaling in skin inflammatory diseases. In this study, the involvement of various P2 receptors in IL-6 production induced by silica nanoparticle 30 (SNP30) was examined in a human keratinocyte cell line, HaCaT. Exposure to SNP30 increased IL-6 production in the cells. Ecto-nucleotidase (apyrase), a non selective antagonist of P2Y receptors (suramin), and a selective P2Y11 receptor antagonist (NF157) all inhibited IL-6 production. Nucleotides such as ATP and UTP themselves also significantly increased IL-6 production in the cells. It was further confirmed that ATP was released from HaCaT cells exposed to SNP30. These results support the possible role of ATP in SNP30-induced IL-6 production by HaCaT cells. In conclusion, these data demonstrate that P2Y11 receptor also mediates SNP30-induced IL-6 production in human keratinocytes, confirming that the ATP-P2Y11 purinergic signaling is a common pathway of IL-6 production leading to induction of skin inflammatory diseases. PMID- 24793916 TI - Levothyroxine liquid solution versus tablet for replacement treatment in hypothyroid patients. AB - BACKGROUND: Although replacement treatment with L-thyroxine (LT4) seems easy to manage, about one-third of hypothyroid patients show thyroid-stimulating hormone (TSH) values outside the normal range. OBJECTIVES: To explore whether LT4 liquid formulation (monodose vials or drops) affects TSH stability values and to assess its ability to maintain TSH within the normal range compared to tablets. METHODS: A total of 100 hypothyroid patients on replacement treatment with LT4 liquid solution were enrolled (Liquid Group) at a follow-up visit (revisit). The inclusion criteria were 1) treatment for surgical hypothyroidism for at least 2 years or autoimmune hypothyroidism for at least 5 years, 2) normal TSH at the previous visit 12 months before enrollment (baseline visit), and 3) maintenance of the same LT4 dosage during the time interval between the baseline and the follow-up visit. Using the same selection process, we also enrolled 100 hypothyroid patients on replacement treatment with LT4 tablets (Tablet Group). RESULTS: At the follow-up visit, 19 patients of the Tablet Group and 8 patients of the Liquid Group had abnormal TSH values (P = .023). Weekly and daily LT4 dosage per kilogram were higher in Tablet Group (P = .016 and .006, respectively). The magnitude of TSH change from baseline to follow-up visit was greater in the Tablet Group (P<.001). CONCLUSION: The use of LT4 liquid formulation compared to tablet resulted in a significantly higher number of hypothyroid patients who maintained the euthyroid state in a 12-month follow-up period and a reduced variability in TSH values. PMID- 24793917 TI - The differential diagnosis of central compartment radioactive iodine uptake after thyroidectomy: anatomic and surgical considerations. AB - OBJECTIVE: Foci of increased radioactive iodine (RAI) uptake in the thyroid bed following total thyroidectomy (TT) indicate residual thyroid tissue that may be benign or malignant. The use of postoperative RAI therapy in the form of remnant ablation, adjuvant therapy, or therapeutic intervention is often followed by a posttherapy scan. Our objective is to improve the clinician's understanding of the anatomic complexity of this region and to enhance the interpretation of postoperative scans. METHODS: We conducted a comprehensive review of the literature evaluating RAI uptake in the central compartment following thyroid cancer treatment and literature related to anatomic nuances associated with this region. Thirty-eight articles were selected. RESULTS: Through extensive surgical experience and a literature review, we identified the 5 most important anatomic considerations for clinicians to understand in the interpretation of foci of increased RAI uptake in the thyroid bed on a diagnostic scan: 1) residual benign thyroid tissue at the level of the posterior thyroid ligament, 2) residual benign thyroid tissue at the superior portion of the pyramidal lobe and/or superior poles of the lateral thyroid lobes, 3) residual benign thyroid tissue that was left attached to a parathyroid gland in order to preserve its vascularity, 4) ectopic benign thyroid tissue, and 5) malignant thyroid tissue that has metastasized to central compartment nodes or invaded visceral structures. CONCLUSION: By correlating anatomic description, medical illustrations, surgical photos, and scans, we have attempted to clarify the reasons for foci of increased uptake following TT to improve the clinician's understanding of the anatomic complexity of this region. PMID- 24793918 TI - Comparative Accuracy of 3 Blood Glucose Monitoring Systems that Communicate with an Insulin Pump. AB - OBJECTIVE: This study compared the accuracy of the Contour(r) Next Link blood glucose monitoring system (BGMS) with 2 other BGMSs (OneTouch(r) UltraLink(r) and Nova Max LinkTM), all 3 of which can communicate wirelessly with an insulin pump. METHODS: Study staff tested fingerstick samples from 112 subjects aged >=18 years with each BGMS. All BGMS results were compared to YSI 2300 STAT PlusTM Glucose Analyzer results from the same sample source. To safely obtain a wide range of glucose values, 3 blood samples were obtained from each subject (1 sample was tested fresh from the fingertip [unmodified], and the other 2 samples were modified to raise or lower the glucose concentration). The primary endpoint evaluated was difference in accuracy among the BGMSs across the entire tested glucose range (34 to 561 mg/dL). Additional comparisons were made of accuracy in the low (<=80 mg/dL) and high (>180 mg/dL) glucose ranges. BGMS accuracy was assessed by mean absolute relative difference (MARD). RESULTS: The Contour(r) Next Link BGMS had a statistically significantly lower MARD from the reference value than the other BGMSs across the entire tested glucose range, calculated using all samples as well as only unmodified (i.e., natural) samples. In the low and high glucose ranges, the Contour(r) Next Link also had a statistically significantly lower MARD from the reference value than the other BGMSs. CONCLUSION: As assessed by MARD, the Contour(r) Next Link BGMS was significantly more accurate than the other BGMSs evaluated, all of which can communicate wirelessly with an insulin pump. PMID- 24793919 TI - Clinical consequences of a change in anti-thyroglobulin antibody assays during the follow-up of patients with differentiated thyroid cancer. AB - OBJECTIVE: Thyroglobulin (Tg) quantitation by immunometric assays is compromised by anti-thyroglobulin antibodies (TgAbs), potentially resulting in falsely low Tg concentrations. TgAb screening is recommended when measuring Tg, but current TgAb immunoassays do not detect all possible TgAbs in circulation. We assessed the impact of a change in TgAb assay on apparent disease status of patients with differentiated thyroid carcinoma (DTC). METHODS: Patients seen at the Mayo Clinic, Rochester, Minnesota, for follow-up of DTC, who had been tested using 2 different TgAb assays (Beckman Access and Roche Elecsys) were identified. Electronic medical records were reviewed to evaluate any impact the change in TgAb assay had on clinical disease status assessment and follow-up. RESULTS: A total of 1,457 patients were tested using both assays. A change in TgAb status was found in 124 (8.5%) patients; a total of 117 patients who were TgAb-negative on the Beckman assay became TgAb-positive with the Roche assay. Additional testing was performed in 5 of these patients. Seven patients previously considered TgAb-positive were now TgAb-negative. In all 7 cases, physicians documented that they considered these patients now to be truly TgAb-negative and free of disease. CONCLUSION: Discrepancies in TgAb status are seen when using different TgAb assays. Relying on Tg and TgAb measurements to determine disease status may lead to underestimation of residual cancer. A multimodal (clinical, biochemical, and radiologic) approach to follow up on patients with DTC should be continued, pending the development of Tg quantitation methods that are highly sensitive and not affected by TgAb interference. PMID- 24793920 TI - Lithium as an adjunct to radioactive iodine for the treatment of hyperthyroidism: a systematic review and meta-analysis. AB - BACKGROUND: Radioactive iodine (RAI) is commonly used in the treatment of hyperthyroidism but is not uniformly successful. Lithium increases thyroidal iodine retention without reducing iodide uptake, increasing the radiation dose to the thyroid when administered with RAI. Although these actions suggest that adjuvant lithium may increase the efficacy of RAI, its role as an adjunct to RAI remains contentious. OBJECTIVE: To evaluate the safety and efficacy of adding lithium to RAI to treat hyperthyroidism. METHODS: Relevant studies were identified by a search of Medline and the Cochrane Central Register of Controlled Trials. To be included, a study had to be a controlled trial comparing the effect of RAI alone to RAI with lithium in the treatment of hyperthyroidism. Relevant data were extracted and meta-analyses were performed. RESULTS: Of the 75 identified studies, 6 met the inclusion criteria; 4 of these studies were interventional and 2 were observational trials. Meta-analysis of the observational trials (N = 851), both of which were retrospective cohort studies, showed significant improvement in the primary outcome (i.e., cure rate) with adjunctive lithium (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.24 to 2.96). The combined interventional trials (N = 485) also showed an improvement in cure rate, but the difference did not reach statistical significance (OR, 1.28; 95% CI, 0.85 to 1.91). Adjunctive lithium reduced time to cure and blunted thyroid hormone excursions after RAI. Lithium-related side effects were infrequent and usually mild. CONCLUSION: The observational trials demonstrated significant improvement in the cure rate of hyperthyroidism when lithium is added to RAI. The improvements shown in the interventional trials did not reach statistical significance due to the effect of a single, large negative trial. PMID- 24793921 TI - Calcitonin-secreting pancreatic neuroendocrine tumors: a case report and review of the literature. AB - OBJECTIVE: We report the presentation and novel therapy of a calcitonin-secreting pancreatic neuroendocrine tumor (PNET) and review the literature on this unusual neoplasm. METHODS: We cite the history of a 38-year-old male who presented with fatigue, weight loss, and diarrhea and was found to have a pancreatic head mass on cross-sectional imaging, as well as liver metastases. RESULTS: The patient's laboratory evaluation was notable for a >100-fold elevation of the peptide hormone calcitonin in serum. As calcitonin is typically secreted by thyroid C cells, hypercalcitoninemia is considered a marker for medullary thyroid cancer (MTC) or C-cell hyperplasia, but it may be present in several physiologic or pathologic conditions or may be ectopically secreted in rare PNETs. An octreotide scan confirmed the presence of somatostatin (SST) receptors on the pancreatic mass and liver metastases, leading to the diagnosis of a calcitonin-secreting PNET. We initiated treatment with long-acting SST analogs and peptide receptor radionuclide therapy (90Yttrium-DOTATOC) and achieved disease regression while maintaining a high quality of life. CONCLUSION: Functional PNETs that secrete calcitonin are exceedingly rare, but they are important to consider in the differential diagnosis of nonthyroid-mediated hypercalcitonemia or pancreatic tumors that present with diarrhea, as the management differs markedly from both MTC and other pancreatic malignancies. PMID- 24793922 TI - Ultrasound assessment of degrees of extrathyroidal extension in papillary thyroid microcarcinoma. AB - OBJECTIVE: This study aimed to assess the diagnostic accuracy of ultrasound (US) based T staging of papillary thyroid microcarcinoma (PTMC). METHODS: From January to June 2013, a total of 185 patients underwent preoperative thyroid US for the treatment of thyroid malignancy. A single radiologist immediately determined sonographic T staging for PTMC during real-time US examination. Based on histopathologic results, the diagnostic accuracy of sonographic T staging for PTMC and the difference in the frequency of level VI node metastasis according to the T stage of PTMC were evaluated. RESULTS: Of 105 PTMC cases, the preoperative sonographic diagnoses included intraglandular location (n = 35), subcapsular location (n = 30), mild capsule abutment (n = 7), moderate capsule abutment (n = 19), and perithyroidal invasion without adjacent strap muscle invasion (n = 14). When the sonographic T stages were compared with histopathologic results, all the sonographic categories showed high specificity and low sensitivity. The intraglandular and subcapsular location cases in preoperative US diagnosis showed a low rate of extrathyroidal tumor invasion (6.2%, 4/65). The extrathyroidal tumor invasion cases in preoperative US diagnosis only included 26 extrathyroidal fat invasion cases, and 12 (46.2%, 12/26) true positives. There was a significant correlation between multifocality and histopathologic T stage, but no significant relationship between level VI node metastasis and histopathologic T stage was found. CONCLUSION: The sonographic T staging categorization described here may be helpful for the preoperative evaluation of PTMC patients. PMID- 24793923 TI - Metformin safety in the management of gestational diabetes. AB - OBJECTIVE: The use of metformin in pregnant women is still controversial, despite the increasing reports on metformin's safety and effectiveness. We aimed to evaluate the maternal and neonatal safety of metformin in subjects with gestational diabetes mellitus (GDM). METHODS: We retrospectively reviewed the clinical records of 186 pregnancies complicated with GDM surveilled at Hospital de Santa Maria, Lisboa, between 2011 and 2012. The maternal and neonatal outcomes of 32 females who took metformin during pregnancy were compared with 121 females controlled with diet and 33 insulin-treated females. RESULTS: Of the 186 GDM subjects, 32 (17.2%) received metformin during pregnancy. No statistical differences between the diet and metformin groups were found with regard to the rates of abortion, prematurity, preeclampsia, macrosomy, small-for-gestational age (SGA) or large-for-gestational-age (LGA) newborns, cesarean deliveries, neonatal intensive care unit (NICU) admissions, and birth malformations or neonatal injuries. Similarly, there were no differences between the metformin and insulin groups with regard to the referred outcomes. No abortions or perinatal deaths were recorded in the metformin group. Ten out of 32 metformin patients required additional insulin. CONCLUSION: This retrospective study suggests that metformin is a safe alternative or additional treatment to insulin in females with GDM. Metformin was not associated with a higher risk of maternal or neonatal complications when compared to the insulin or diet groups. PMID- 24793925 TI - Visual vignette. PMID- 24793924 TI - Frequency of Continuous Glucose Monitoring Use and Change in Hemoglobin A1C for Adults with Type 1 Diabetes in a Clinical Practice Setting. AB - OBJECTIVE: To estimate the frequency of continuous glucose monitoring (CGM) use and change in hemoglobin A1c (HbA1c) compared to self-monitoring of blood glucose (SMBG) alone in adults with type 1 diabetes in a clinical practice setting. METHODS: We retrospectively identified 66 adult type 1 diabetes patients at the Barbara Davis Center for Diabetes (BDC) who first initiated CGM between 2006 and 2011 and 67 controls using SMBG. The frequency of CGM use was estimated from survey recall and defined as the mean number of days/month of CGM use during a maximum follow-up of 10 months. Change in HbA1c was calculated as the difference between the baseline value and the lowest follow-up value. RESULTS: The mean change in HbA1c for CGM users was -0.48% (95% confidence interval [CI]: -0.67, 0.28) and for SMBG users was -0.37% (95% CI: -0.56, -0.18). The between-group mean difference in change in HbA1c, adjusted for patient characteristics, was 0.11% (95% CI: -0.38, 0.16), whereas the subgroup with a baseline HbA1c >=7.0% and users of CGM >=21 days/month was -0.36% (95% CI: -0.78, 0.05). Nearly half (n = 32, 48%) used CGM <21 days/month. The reasons for low frequency of CGM use or discontinuation included sensor costs, frequency of alarms, inaccuracy, and discomfort. CONCLUSIONS: These CGM data from clinical practice suggest a trend toward decreasing HbA1c for adults with type 1 diabetes, especially in patients with higher baseline HbA1c and higher frequency of CGM use. Future studies are needed to assess the use of CGM in larger populations of clinical practice adult type 1 diabetes patients. PMID- 24793926 TI - Rotary suspension culture enhances mesendoderm differentiation of embryonic stem cells through modulation of Wnt/beta-catenin pathway. AB - Recently, physical factors in the local cellular microenvironment have been confirmed with strong influences on regulating stem cell fate. Despite the recent identification of the rotary cell culture system (RCCS) as a bioreactor for culturing stem cells, the underlying biological role provided by RCCS in the lineage differentiation of embryonic stem cells (ESCs) remains largely undefined. Here, we explored the embryoid body (EB) formation and subsequent differentiation of mouse ESCs in RCCS. We demonstrated that EBs formed in RCCS were more homogeneous and bigger in size compared with those in the static condition. Further, we determined that mesendoderm differentiation was prominently enhanced, while neuroectodermal differentiation was significantly suppressed in RCCS. Surprisingly, we found that Wnt/beta-catenin signaling was greatly enhanced mainly due to the increased expression of Wnt3 during ESC differentiation in RCCS. Inhibition of Wnt/beta-catenin signaling by DKK1 decreased the expression of Brachyury and attenuated mesendoderm differentiation in RCCS. Intriguingly, Wnt3a markedly increased Brachyury expression under static condition rather than in RCCS. Taken together, our findings uncover a new role of rotary suspension culture in initializing the early differentiation of ESCs. PMID- 24793927 TI - An evidence in vitro for the influence of bisphenol A on uterine leiomyoma. AB - OBJECTIVE: To study the effect and mechanism of environmental estrogens bisphenol A (BPA) on uterine leiomyoma (UL) cells. METHODS: Primary cultures and subcultures of human UL cells, which were identified by immunocytochemical staining with a monoclonal anti-alpha-smooth muscle actin antibody, were performed. The viability of cells in different concentration of bisphenol A of 24h, 48h and 72h were analyzed by CCK-8. The expressions of mRNA of ERalpha, IGF 1 and VEGF in all groups were detected by real-time quantitative PCR assay, and then the expressions of proteins detected by Western blot assay. RESULTS: BPA promoted the growth of UL cells and the expressions of ERalpha, IGF-1 and VEGF, which had positive correlation with the concentration and action time of BPA treatment. CONCLUSION: BPA promotes the growth of leiomyoma cells. The expressions of IGF-1, VEGF can be up-regulated by ERalpha, which may be possible mechanism of BPA promote the growth of leiomyoma cells. PMID- 24793928 TI - Can intracytoplasmic sperm injection prevent total fertilization failure and enhance embryo quality in patients with non-male factor infertility? AB - OBJECTIVE: To determine whether intracytoplasmic sperm injection (ICSI) could prevent total fertilization failure (TFF) and enhance the embryo quality in patients with non-male factor infertility. STUDY DESIGN: A total of 296 in vitro fertilization (IVF) cycles performed in patients with non-male factor infertility between April 2009 and March 2013 were included in this retrospective study. During the period, ICSI and conventional IVF were performed in 142 and 154 cycles, respectively. The usual indications for ICSI were in the cycles of patients with (1) known low fertilization rate, (2) repetitive implantation failure, (3) advanced maternal age, (4) presence of endometrioma, (5) low oocyte yield (number of oocytes <=3), or (6) poor quality oocytes. The rate of TFF, normal fertilization, abnormal pronuclei (PN) formation, embryo quality, and pregnancy outcomes between the patients treated with ICSI and conventional IVF cycles were compared. RESULTS: The patients treated with ICSI (ICSI group, n=142) presented fewer number of oocytes than patients treated with conventional IVF cycles (n=154). The TFF rate was not different (4.2% vs. 0.6%, P=0.059), but the ICSI group presented a significantly higher rate of normal fertilization (83.4% vs. 79.1%, P=0.04) and lower rate of abnormal PN formation (3.9% vs. 13.3%, P<0.01). The cleavage stage embryo quality was better in the ICSI group (grade A: 31.1% vs. 21.3%, P=0.001; grade A+B: 65.1% vs. 47.6%, P<0.001). CONCLUSION: The result of this study does not support the use of ICSI to prevent TFF in patients with non-male factor infertility. However, ICSI improved the fertilization rate and the embryo quality. PMID- 24793929 TI - The protective effect of quercetin on IMA levels and apoptosis in experimental ovarian ischemia-reperfusion injury. AB - OBJECTIVE: To investigate the protective effect of quercetin (QE), an anti inflammatory and anti-oxidant agent, on torsion-detorsion induced histopathological changes and blood IMA levels in experimental ovarian ischemia reperfusion (IR) injury. STUDY DESIGN: Twenty-four female Wistar rats were randomly divided into four groups in this study (n=6). Group I, (sham operation); Group II, torsion-detorsion plus saline (IR); Group III, torsion-detorsion plus solvent (dimethylsulfoxide: DMSO, IR+DMSO); Group IV, torsion-detorsion plus 15 mg/kg/bw quercetin (IR+QE) injected intraperitoneally 30 min prior to detorsion. After 3h of reperfusion, the right ovaries were removed surgically. The ovary tissue samples were fixed in 10% formalin solution for histopathological and immunohistochemical examination. Blood samples were obtained at the end of the procedures for each group of animals. RESULTS: Ovarian sections in Groups II and III showed higher follicular cell degeneration, hemorrhage, vascular congestion and edema when compared with Group I. Administration of quercetin in rats significantly prevented degenerative changes in the ovary. Significantly less histopathological changes were found in Group IV compared with Groups II and III. Caspase-3 and TUNEL positive cells were detected in the ovarian surface, follicle epithelium, and stromal cells in all experimental groups, and there was a significant increase in Groups II and III compared with Group I (P<0.05). Treatment with quercetin decreased the number of caspase-3 and TUNEL positive cells. IR increased the ischemia modified albumin (IMA) levels in comparison to the sham group (1.06 +/- 0.10 ABSU and 0.92 +/- 0.08 ABSU, P<0.05). Quercetin administration before IR reduced the levels of IMA (0.93 +/- 0.08 ABSU, P<0.05). CONCLUSION: Administration of quercetin is effective in preventing tissue damage induced by IR injury in ovaries. PMID- 24793930 TI - Risk factors for mesh erosion after vaginal sling procedures for urinary incontinence. AB - OBJECTIVES: To identify risk factors for mesh erosion in women undergoing vaginal sling procedures for urinary incontinence with synthetic meshes, and to estimate the incidence of mesh erosion after these procedures. STUDY DESIGN: Retrospective study of women who underwent vaginal sling procedures between January 2007 and January 2013. In total, 1439 consecutive women with stress urinary incontinence were investigated. Five hundred and sixty-six (39.3%) women underwent a tension free vaginal tape (TVT) procedure and 873 (60.7%) women underwent a transobturator tape (TOT) procedure. All procedures were performed using meshes of the same type and size. Women who experienced mesh erosion were defined as cases, and women who were not re-admitted or identified with mesh erosion during the study period were defined as controls. Demographics, operative techniques and outcomes were taken from medical records. Multivariate regression identified the odds of mesh erosion. RESULTS: Sixty-one of 1439 (4.2%) women were found to have mesh erosion in the postoperative period: 41 (67.2%) after TOT procedures and 20 (32.8%) after TVT procedures. The rate of mesh erosion was 4.7% in the TOT group and 3.5% in the TVT group, and this difference was significant (p<0.05). Mean age, body mass index, current smoking, menopausal status and diabetes mellitus were significantly higher among cases than controls. Univariate analysis showed that length of vaginal incision >2 cm, recurrent vaginal incision for postoperative complications, and previous pelvic organ prolapse or incontinence surgery were significant risk factors for erosion. Multivariate analysis demonstrated that older age, diabetes mellitus, current smoking, length of vaginal incision >2 cm, recurrent vaginal incision for postoperative complications, and previous pelvic organ prolapse or incontinence surgery were independent risk factors for mesh erosion. CONCLUSIONS: Mesh erosion following vaginal sling procedures is a frustrating complication with relatively low incidence. It was found to occur more often after TOT procedures than TVT procedures. Older age, diabetes mellitus, smoking, length of vaginal incision >2 cm, recurrent vaginal incision for postoperative complications, and previous vaginal surgery for pelvic organ prolapse or incontinence increased the risk of mesh erosion. Identification of risk factors may enable surgeons to prevent or minimize this complication. PMID- 24793931 TI - The effects of giving patients verbal or written pre-operative information in gynecologic oncology surgery: a randomized study and the medical-legal point of view. AB - OBJECTIVES: To evaluate the verbal and written preoperative information in patients undergoing surgery for malignant gynaecologic disease, in terms of satisfaction about preoperative received informations, hospitalization days, postoperative pain experienced using visual analogue scale (VAS) and number of pain drugs used daily. STUDY DESIGN: From January 2008 to December 2012, consecutive patients with diagnosis of endometrial cancer, referred to the Division of Gynecology of University Campus Bio-Medico of Rome, were enrolled. Eligible subjects were randomized into two groups: Group V (Verbal information ward) consisted of patients who had verbal preoperative information about surgical procedure and postoperative management and Group W (Written Information ward) consisted of patients who had written preoperative information. All preoperative and postoperative data were recorded. Concerning satisfaction about preoperative received informations, patients were asked to complete the QLQ-C30 and the EORTC INFO25. RESULTS: 190 patients were considered in this study. Group W (n=92) has a better info satisfaction (p=0.0008, statistically significant), a mean VAS value lower (p=0.02, statistically significant) and also a lower number of hospitalization days (p=0.0265, statistically significant) and pain medications used daily, (p=0.0120, statistically significant), comparing with group V (n=98). CONCLUSIONS: We support the use of preoperative information leaflet to better prepare patients for a surgical procedure, showing a faster recovery, low medications use and a better quality of life outcome. PMID- 24793932 TI - 2009 A/H1N1 influenza vaccination in pregnancy: uptake and pregnancy outcomes - a historical cohort study. AB - OBJECTIVES: To describe the uptake of 2009 A/H1N1 influenza vaccination among pregnant women and determine if vaccination was associated with adverse pregnancy outcomes. STUDY DESIGN: A historical cohort study was performed using booking, delivery suite and neonatal unit discharge records from the Coombe Women and Infants University Hospital, Dublin, Ireland. Singleton deliveries to women pregnant before (December 2008-September 2009) and during the pandemic (December 2009-September 2010) were included. Information on vaccination status and type of vaccine was collected on admission to the delivery suite. Logistic regression analyses were used to determine maternal characteristics associated with vaccination. Pregnancy outcomes were compared for vaccinated and unvaccinated women, with adjustment for differing maternal characteristics. Outcomes included vaccination status, preterm birth, size for gestational age, neonatal intensive care admission, congenital anomalies and perinatal death. RESULTS: Of 6894 women pregnant during the pandemic, 2996 [43.5%] reported vaccination at delivery. In the early weeks of the vaccination programme rates of over 70% were achieved. Of those vaccinated, 246 [8.2%], 1709 [57.0%] and 1034 [34.5%] were vaccinated in the first, second and third trimesters respectively. Vaccination was less likely in younger age groups, those who were not in the professional/manager/employer socioeconomic group, women from Eastern Europe, Africa and Asia/Middle East, those who reported an unplanned pregnancy, women who booked late for antenatal care and recipients of publicly-funded obstetric care. Irish nationality was associated with reporting vaccination. There was no association between vaccination during pregnancy and adverse pregnancy outcomes. Women who were vaccinated were less likely to have a preterm delivery than unvaccinated women. CONCLUSION: 2009 A/H1N1 influenza vaccination uptake was influenced by maternal sociodemographic factors. High vaccination uptake can be achieved in a pandemic situation. Future public health campaigns should provide clear information on vaccination safety in pregnancy, ensure consistent vaccination recommendations from healthcare professionals and provide easy access to vaccination in order to optimise uptake rates in subgroups of the population who less likely to be vaccinated. There was no association between vaccination and adverse pregnancy outcomes. PMID- 24793933 TI - Effect of intraabdominal administration of Allium sativum (garlic) oil on postoperative peritoneal adhesion. AB - OBJECTIVE(S): Peritoneal adhesion is a serious problem that develops after most abdominopelvic surgeries. Allium sativum (garlic) has been used for centuries as both a nutrient and a traditional medicine. The anti-inflammatory, antibacterial, fibrinolytic, and wound-healing properties of garlic are well-recognized. We evaluated the effect of garlic on formation of postoperative adhesions in rats. STUDY DESIGN: Thirty Wistar-Albino female rats weighing 200-250 g were randomly divided into three groups (10 rats/group). Group 1 rats received 5 ml/kg garlic oil intraperitoneally and no surgery was performed. The ceca of Group 2 rats (controls) were scraped, to trigger adhesion formation, and no treatment was given. In Group 3 rats, 5 ml/kg garlic oil was added to the peritoneal cavity immediately after the cecum was scraped. All animals were sacrificed 10 d after surgery and adhesions graded in terms of severity and histopathologic characteristics. RESULTS: All animals tolerated the operations well. No adhesions were evident upon laparotomy of Group 1 animals. In Group 2 three rats had an adhesion grade 2 and seven rats had an adhesion of grade 3, whereas in Group 3 no adhesions were found in four rats, five rats had an adhesion grade of 1. Only one rat had a grade 2 adhesion. Macroscopic adhesions and mean adhesion scores of Group 3 were significantly lower than Group 2 (p<0.001). Histopathologic evaluation of the specimens also revealed a statistically significant differences in inflammation, fibrosis, and neovascularization scores between Group 2 and 3 (p=0.001, p=0.001, and p=0.011, respectively). Inflammation, fibrosis and vascularization scores in Group 3 were found significantly lower than Group 2. CONCLUSION: The anti-inflammatory, antibacterial, fibrinolytic, antithrombotic, and wound-healing effects of garlic likely prevent formation of peritoneal adhesions in a rat model, and garlic may be effective and cheap when used to prevent such adhesions in humans. PMID- 24793934 TI - An unusual site of thrombosis in a patient with a rare ovarian cyst. PMID- 24793935 TI - Dienogest improves human leucocyte antigen-DR underexpression and reduces tumour necrosis factor-alpha production in peritoneal fluid cells from women with endometriosis. AB - OBJECTIVE: To determine the immunological effect of dienogest (DNG), an oral anti endometriosis drug, on peritoneal fluid (PF) macrophages collected from women with endometriosis. Although it has been suggested that DNG has direct effects on endometriotic cells, including decreased cell proliferation and decreased anti inflammatory cytokine production, the effects of DNG on PF cells are unclear. STUDY DESIGN: The effects of DNG on PF cells from 34 women with endometriosis and 22 women without endometriosis (controls) were investigated. Expression of human leucocyte antigen (HLA)-DR in PF macrophages, obtained from the peritoneal cavity during laparoscopic surgery, was determined by flow cytometry. HLA-DR expression was measured again after PF cells had been cultured for 72 h in a humidified atmosphere at 37 degrees C in 5% CO2-95% air with or without DNG. After 72 h of incubation, the concentration of pro-inflammatory tumour necrosis factor (TNF) alpha in the media was measured by enzyme-linked immunosorbent assay. RESULTS: HLA-DR expression was lower in PF macrophages from women with endometriosis compared with controls. However, after DNG treatment, HLA-DR expression in PF macrophages from women with endometriosis was increased to the same level as in controls. The TNF-alpha concentration in the media was decreased by DNG. CONCLUSIONS: DNG can restore the antigen-presenting ability of PF macrophages by increased HLA-DR expression, and may have an anti-inflammatory effect on PF macrophages in women with endometriosis. PMID- 24793936 TI - Deconvolution of isotope signals from bundles of multiple hairs. AB - Segmental analysis of hair has been used in diverse fields ranging from forensics to ecology to measure the concentration of substances such as drugs and isotopes. Multiple hairs are typically combined into a bundle for segmental analysis to obtain a high-resolution series of measurements. Individual hair strands cycle through multiple phases of growth and grow at different rates when in the growth phase. Variation in growth of hair strands in a bundle can cause misalignment of substance concentration between hairs, attenuating the primary body signal. We developed a mathematical model based on the known physiology of hair growth to describe the signal averaging caused by bundling multiple hairs for segmental analysis. The model was used to form an inverse method to estimate the primary body signal from measurements of a hair bundle. The inverse method was applied to a previously described stable oxygen isotope chronology from the hair of a murder victim and provides a refined interpretation of the data. Aspects of the reconstruction were confirmed when the victim was later identified. PMID- 24793937 TI - Trout reverse the effect of water temperature on the foraging of a mayfly. AB - Climate change is likely to increase the metabolisms of ectothermic animals living below their thermal optimum. While ectothermic top predators may compensate by increasing foraging, ectothermic prey may be unable to increase foraging because of increased predation risk from ectothermic predators. We examined how the diurnal drift behavior (i.e., the downstream movement associated with foraging) of the mayfly Baetis, an ectothermic herbivore, responds to changing temperature in the implied presence and absence of trout, an ectothermic predator. In an experiment replicated at the catchment scale, water temperature and trout presence strongly interacted to affect the diurnal drift of Baetis from artificial channels lacking periphyton over a water temperature range of 4.2-14.8 degrees C. In fishless streams, daytime drift increased with increasing water temperature, likely because of increased metabolic demand for food. However, in trout-bearing streams, daytime drift decreased with increasing water temperature. Our interpretation is that the perceived threat of trout rose with increasing water temperature, causing mayflies to reduce foraging despite heightened metabolic demand. These results suggest that anticipated increases in stream temperature due to climate change may further escalate divergence in structure and process between fishless and trout-bearing streams. Similar dynamics may occur in other ecosystems with ectothermic predators and prey living below their thermal optima. PMID- 24793938 TI - B-cell responses after intranasal vaccination with the novel attenuated Bordetella pertussis vaccine strain BPZE1 in a randomized phase I clinical trial. AB - Despite high vaccination coverage, pertussis is still a global concern in infant morbidity and mortality, and improved pertussis vaccines are needed. A live attenuated Bordetella pertussis strain, named BPZE1, was designed as an intranasal vaccine candidate and has recently been tested in man in a phase I clinical trial. Here, we report the evaluation of the B-cell responses after vaccination with BPZE1. Forty-eight healthy males with no previous pertussis vaccination were randomized into one of three dose-escalating groups or into a placebo group. Plasma blast- and memory B-cell responses were evaluated by ELISpot against three different pertussis antigens: pertussis toxin, filamentous haemagglutinin and pertactin. Seven out of the 36 subjects who had received the vaccine were colonized by BPZE1, and significant increases in the memory B-cell response were detected against all three tested antigens in the culture-positive subjects between days 0 and 28 post-vaccination. The culture-positive subjects also mounted a significant increase in the filamentous haemagglutinin-specific plasma blast response between days 7 and 14 post-vaccination. No response could be detected in the culture-negatives or in the placebo group post-vaccination. These data show that BPZE1 is immunogenic in humans and is therefore a promising candidate for a novel pertussis vaccine. This trial is registered at ClinicalTrials.gov (NCT01188512). PMID- 24793939 TI - Risk factors associated with immunoprophylaxis failure against mother to child transmission of hepatitis B virus and hepatitis B vaccination status in Yunnan province, China. AB - OBJECTIVE: To explore the risk factors associated with immunoprophylaxis failure against mother to child transmission of hepatitis B virus (HBV) and hepatitis B vaccination status in Yunnan province, China. METHODS: Multicenter cluster sampling was used to select pregnant women who were positive for hepatitis B surface antigen (HBsAg). HBV immunoprophylaxis was carried out for the newborns. Blood samples were collected and tested for HBV markers from 7 to 10 month old infants. The factors were analyzed by univariate and logistic regression. RESULTS: A total of 2765 mothers and their infants were enrolled. The failure rate of prevention of mother to child transmission (PMTCT) was 4.12%. The rate of timely HepB1 vaccination within 24h was 98.04%, the rate of three-dose vaccination was 92.30% and the rate of hepatitis B immune globulin (HBIG) administration was 68.97%. Place of residence, maternal education, gestational age and birth weight were related to administration of HBV immunoprophylaxis. It was remarkable that the rate of HBIG administration of infants was only 63.89% with whose mothers were both HBsAg and hepatitis B e antigen (HBeAg)-positive. Further analysis showed that there were three risk factors associated with HBV immunoprophylaxis failure: mothers who were positive for HBsAg and HBeAg, maternal HBVDNA level, and HBIG administration or not. CONCLUSIONS: PMTCT of HBV was well implemented in Yunnan. However, in order to achieve optimal prevention of vertical HBV transmission, it is mandatory to make additional efforts to improve the implementation of regulatory HBV immunoprophylaxis, especially for HBsAg-positive pregnant women. PMID- 24793940 TI - Development and immunological evaluation of HLA-specific chronic myeloid leukemia polyepitope vaccine in Chinese population. AB - BACKGROUND: BCR/ABL and Wilms' tumor 1 (WT1) are an ideal tumor associated antigens which can be used to develop a potential chronic myeloid leukemia (CML) dentritic cell (DC) vaccine. Here, we constructed a novel polyepitope vaccine which used recombinant lentiviral vector carrying BCR/ABL and WT1 genes, and determined the immunological effects of this vaccine in vitro. METHODS: The DC vaccine was constructed using lentiviral vector transduced DCs. T lymphocytes were stimulated with DC vaccine and then co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) from CML or ALL patients, respectively. The cytotoxicity of proliferous cytotoxic T lymphocytes (CTLs) was determined by the LDH assay. The IFN-gamma production of CTLs was detected using ELISPOT assay. RESULTS: We constructed an lentiviral vector encoding 50 different epitopes from BCR/ABL and WT1 antigens, and transferred it into DCs to prepare the DC vaccine successfully. The in vivo stimulation of CTLs with this DC vaccine were proved to show strong cytotoxicity and produce high level of IFN-gamma. CONCLUSIONS: The novel recombinant lentiviral polyepitope DC vaccine is a promising candidate for clinical trials and may be an effective approach for CML immunotherapy. PMID- 24793942 TI - Rotaviruses: is their surveillance needed? AB - Rotaviruses, a major cause of gastroenteritis in children worldwide accounts for around 0.5 million deaths annually. Owing to their segmented genome and frequently evolving capability, these display a wide variation in their genotypes. In addition to commonly circulating genotypes (G1, G2, G3, G4, G9, P[4] and P[8]), a number of infrequent genotypes are being continuously reported to infect humans. These viral strains exhibit variation from one geographical setting to another in their distribution. Though the introduction of vaccines (RotaTeq and Rotarix) proved to be very effective in declining rotavirus associated morbidity and mortality, the number of infections remained same. Unusual genotypes significantly contribute to the rotavirus associated diarrhoeal burden, may reduce the efficacy of the vaccines in use and hence vaccinated individuals may not be benefited. Vaccine introduction may bring about a notable impact on the distribution and prevalence of these viruses due to selection pressure. Moreover, there is a sudden emergence of G2 and G3 in Brazil and United States, respectively, during the years 2006-2008 post-vaccination introduction; G9 and G12 became predominant during the years 1986 through 1998 before the vaccine introduction and now are commonly prevalent strains; and disparity in the predominance of strains after introduction of vaccines and their natural fluctuations poses a vital question on the impact of vaccines on rotavirus strain circulation. This interplay between vaccines and rotavirus strains is yet to be explored, but it certainly enforces the need to continuously monitor these changes in strains prevalence in a particular region. Furthermore, these fluctuations should be considered while administration or development of a vaccine, if rotavirus associated mortality is ever to be controlled. PMID- 24793941 TI - Cluster randomized trial of a toolkit and early vaccine delivery to improve childhood influenza vaccination rates in primary care. AB - PURPOSE: To increase childhood influenza vaccination rates using a toolkit and early vaccine delivery in a randomized cluster trial. METHODS: Twenty primary care practices treating children (range for n=536-8183) were randomly assigned to Intervention and Control arms to test the effectiveness of an evidence-based practice improvement toolkit (4 Pillars Toolkit) and early vaccine supplies for use among disadvantaged children on influenza vaccination rates among children 6 months-18 years. Follow-up staff meetings and surveys were used to assess use and acceptability of the intervention strategies in the Intervention arm. Rates for the 2010-2011 and 2011-2012 influenza seasons were compared. Two-level generalized linear mixed modeling was used to evaluate outcomes. RESULTS: Overall increases in influenza vaccination rates were significantly greater in the Intervention arm (7.9 percentage points) compared with the Control arm (4.4 percentage points; P<0.034). These rate changes represent 4522 additional doses in the Intervention arm vs. 1390 additional doses in the Control arm. This effect of the intervention was observed despite the fact that rates increased significantly in both arms - 8/10 Intervention (all P<0.001) and 7/10 Control sites (P-values=0.04 to <0.001). Rates in two Intervention sites with pre intervention vaccination rates >58% did not significantly increase. In regression analyses, a child's likelihood of being vaccinated was significantly higher with: younger age, white race (Odds ratio [OR]=1.29; 95% confidence interval [CI]=1.23 1.34), having commercial insurance (OR=1.30; 95%CI=1.25-1.35), higher pre intervention practice vaccination rate (OR=1.25; 95%CI=1.16-1.34), and being in the Intervention arm (OR=1.23; 95%CI=1.01-1.50). Early delivery of influenza vaccine was rated by Intervention practices as an effective strategy for raising rates. CONCLUSIONS: Implementation of a multi-strategy toolkit and early vaccine supplies can significantly improve influenza vaccination rates among children in primary care practices but the effect may be less pronounced in practices with moderate to high existing vaccination rates. Clinical trial registry name/number: From Innovation to Solutions: Childhood Influenza/NCT01664793. PMID- 24793943 TI - A recombinant Newcastle disease virus (NDV) expressing infectious laryngotracheitis virus (ILTV) surface glycoprotein D protects against highly virulent ILTV and NDV challenges in chickens. AB - Infectious laryngotracheitis (ILT) is a highly contagious acute respiratory disease of chickens caused by infectious laryngotracheitis virus (ILTV). Currently, modified live ILTV vaccines are used to control ILT infections. However, the live ILTV vaccines can revert to virulence after bird-to-bird passage and are capable of establishing latent infections, suggesting the need to develop safer vaccines against ILT. We have evaluated the role of three major ILTV surface glycoproteins, namely, gB, gC, and gD in protection and immunity against ILTV infection in chickens. Using reverse genetics approach, three recombinant Newcastle disease viruses (rNDVs) designated rNDV gB, rNDV gC, and rNDV gD were generated, each expressing gB, gC, and gD, respectively, of ILTV. Chickens received two immunizations with rNDVs alone (gB, gC, and gD) or in combination (gB+gC, gB+gD, gC+gD, and gB+gC+gD). Immunization with rNDV gD induced detectable levels of neutralizing antibodies with the magnitude of response greater than the rest of the experimental groups including those vaccinated with commercially available vaccines. The birds immunized with rNDV gD showed complete protection against virulent ILTV challenge. The birds immunized with rNDV gC alone or multivalent vaccines consisting of combination of rNDVs displayed partial protection with minimal disease and reduced replication of challenge virus in trachea. Immunization with rNDV gB neither reduced the severity of the disease nor the replication of challenge virus in trachea. The superior protective efficacy of rNDV gD vaccine compared to rNDV gB or rNDV gC vaccine was attributed to the higher levels of envelope incorporation and infected cell surface expression of gD than gB or gC. Our results suggest that rNDV expressing gD is a safe and effective bivalent vaccine against NDV and ILTV. PMID- 24793944 TI - A synthetic peptide from Trypanosoma cruzi mucin-like associated surface protein as candidate for a vaccine against Chagas disease. AB - Chagas disease, caused by Trypanosoma cruzi, is responsible for producing significant morbidity and mortality throughout Latin America. The disease has recently become a public health concern to nonendemic regions like the U.S. and Europe. Currently there are no fully effective drugs or vaccine available to treat the disease. The mucin-associated surface proteins (MASPs) are glycosylphosphatidylinositol (GPI)-anchored glycoproteins encoded by a multigene family with hundreds of members. MASPs are among the most abundant antigens found on the surface of the infective trypomastigote stage of T. cruzi, thus representing an attractive target for vaccine development. Here we used immunoinformatics to select a 20-mer peptide with several predicted overlapping B cell, MHC-I, and MHC-II epitopes, from a MASP family member expressed on mammal dwelling stages of T. cruzi. The synthetic MASP peptide conjugated to keyhole limpet hemocyanin (MASPpep-KLH) was tested in presence or not of an adjuvant (alum, Al) as a vaccine candidate in the C3H/HeNsd murine model of T. cruzi infection. In considerable contrast to the control groups receiving placebo, Al, or KLH alone or the group immunized with MASPpep-KLH/Al, the group immunized with MASPpep-KLH showed 86% survival rate after challenge with a highly lethal dose of trypomastigotes. As evaluated by quantitative real-time polymerase chain reaction, MASPpep-KLH-immunized animals had much lower parasite load in the heart, liver, and spleen than control animals. Moreover, protected animals produced trypanolytic, protective antibodies, and a cytokine profile conducive to resistance against parasite infection. Finally, in vivo depletion of either CD4(+) or CD8(+) T cells indicated that the latter are critical for protection in mice immunized with MASPpep-KLH. In summary, this new peptide-based vaccine with overlapping B- and T-cell epitopes is able to control T. cruzi infection in mice by priming both humoral and cellular immunity. PMID- 24793945 TI - Delayed-type hypersensitivity and hepatitis B vaccine responses, in vivo markers of cellular and humoral immune function, and the risk of AIDS or death. AB - BACKGROUND: Delayed-type hypersensitivity (DTH) test responsiveness is associated with HIV disease progression; however it is unknown whether other immune markers, such as hepatitis B virus (HBV) vaccine seroresponse, also predict HIV outcomes. METHODS: Eligible participants received HBV vaccine after HIV diagnosis, had non anergic DTH testing at the time of last HBV vaccination, and available post vaccine HBV antibody responses. The risk of progression to AIDS or death from the time of last HBV vaccination was evaluated. RESULTS: Of 369 eligible participants with non-anergic DTH responses, 148 (40%) were HBV vaccine responders. In a multivariate model adjusted for age, CD4 count, viral load, and number of vaccinations, HBV vaccine non-responders had an increased risk of progression to AIDS or death (HR 1.81; 95% CI, 1.03-3.19). CONCLUSIONS: HBV vaccine seroresponses were independent of DTH responses which suggest that non-response to HBV vaccine is not solely due to cell-mediated immune dysfunction in HIV infected persons. PMID- 24793946 TI - A novel gE-deleted pseudorabies virus (PRV) provides rapid and complete protection from lethal challenge with the PRV variant emerging in Bartha-K61 vaccinated swine population in China. AB - The currently used Bartha-K61 strain is a very safe and effective vaccine against pseudorabies (PR) and has played a critical role in the control and eradication of PR worldwide. Since late 2011, however, PR reemerged among Bartha-K61 vaccinated pig population in many regions in China. Our previous studies demonstrated that the Bartha-K61 vaccine was unable to provide complete protection from the challenge with the PRV TJ strain (PRVTJ), a representative emerging PRV variant that was isolated from a Bartha-K61-immunized pig farm in Tianjin, China. Here, we generated a gE-deleted PRV, named as rPRVTJ-delgE, based on PRVTJ and evaluated its safety and immunogenicity in pigs. Our results showed that groups of piglets (n=5) immunized with 10(3), 10(4) or 10(5)TCID50 rPRVTJ delgE did not exhibit clinical signs following immunization and challenge and were protected clinically and virologically from the lethal challenge with PRVTJ as early as 1 week post-immunization, in contrast with the incomplete protection provided by the Bartha-K61 vaccine. These indicate that rPRVTJ-delgE is a promising candidate vaccine for updating Bartha-K61 for the control of the currently epidemic PR in China. PMID- 24793947 TI - Co-administration of non-carrier nanoparticles boosts antigen immune response without requiring protein conjugation. AB - Nanotechnology promises a revolution in medicine including through new vaccine approaches. The use of nanoparticles in vaccination has, to date, focused on attaching antigen directly to or within nanoparticle structures to enhance antigen uptake by immune cells. Here we question whether antigen incorporation with the nanoparticle is actually necessary to boost vaccine effectiveness. We show that the immunogenicity of a sub-unit protein antigen was significantly boosted by formulation with silica nanoparticles even without specific conjugation of antigen to the nanoparticle. We further show that this effect was observed only for virus-sized nanoparticles (50 nm) but not for larger (1,000 nm) particles, demonstrating a pronounced effect of nanoparticle size. This non attachment approach has potential to radically simplify the development and application of nanoparticle-based formulations, leading to safer and simpler nanoparticle applications in vaccine development. PMID- 24793948 TI - Long-term viremia and fecal shedding in pups after modified-live canine parvovirus vaccination. AB - Canine parvovirus (CPV) modified live virus vaccines are able to infect vaccinated dogs replicating in the bloodstream and enteric mucosa. However, the exact duration and extent of CPV vaccine-induced viremia and fecal shedding are not known. With the aim to fill this gap, 26 dogs were administered two commercial vaccines containing a CPV-2 or CPV-2b strain and monitored for 28 days after vaccination. By using real-time PCR, vaccine-induced viremia and shedding were found to be long lasting for both vaccinal strains. Vaccinal CPV-2b shedding was detected for a shorter period than CPV-2 (12 against 19 mean days) but with greater viral loads, whereas viremia occurred for a longer period (22 against 19 mean days) and with higher titers for CPV-2b. Seroconversion appeared as early as 7 and 14 days post-vaccination for CPV-2b and CPV-2 vaccines, respectively. With no vaccine there was any diagnostic interference using in-clinic or hemagglutination test, since positive results were obtained only by fecal real time PCR testing. The present study adds new insights into the CPV vaccine persistence in the organism and possible interference with diagnostic tests. PMID- 24793949 TI - Potency of an inactivated influenza vaccine prepared from A/duck/Mongolia/119/2008 (H7N9) against the challenge with A/Anhui/1/2013 (H7N9). AB - H7N9 influenza virus infection in humans was reported in China on March 31, 2013. Humans are immunologically naive to the H7N9 subtype, for which the seasonal influenza vaccine is not effective. Thus, the development of an H7N9 influenza virus vaccine is an urgent issue. To prepare for the emergence of an influenza pandemic, we have established a library comprising more than 1300 influenza virus strains with 144 different combinations of 16 HA and 9 NA subtypes. An H7N9 virus strain isolated from a 35-year-old woman, A/Anhui/1/2013 (H7N9), was found to be antigenically similar to H7N9 influenza viruses isolated from migratory ducks. In the present study, the potency of an inactivated whole virus particle vaccine prepared from an H7N9 low pathogenic avian influenza virus, A/duck/Mongolia/119/2008 (H7N9), selected from the library, was assessed by a challenge with A/Anhui/1/2013 (H7N9). The results indicate that the test vaccine was potent enough to induce sufficient immunity to reduce the impact of disease caused by the challenge with A/Anhui/1/2013 (H7N9) in mice. The present results indicate that an inactivated whole virus particle vaccine prepared from an influenza virus strain stored in the library could be useful as a vaccine strain in case of an influenza pandemic. PMID- 24793950 TI - National surveillance of invasive pneumococcal diseases in Taiwan, 2008-2012: differential temporal emergence of serotype 19A. AB - INTRODUCTION: Serotype replacement after the introduction of seven-valent pneumococcal conjugate vaccine (PCV7) and the future availability of multivalent PCVs prompted the listing of invasive pneumococcal disease (IPD) as a notifiable disease in Taiwan in October 2007. Here, we report the national surveillance results. METHODS: The study population comprised the whole nation of Taiwan from 2008 to 2012. Restricting to cases with viable isolates, we calculated the incidence, case fatality ratio, prevalence of serotype 19A, and percentage of vaccine preventable IPD. RESULTS: 3659 cases of IPD were identified yielding an incidence of 3.2 per 100,000 population; the highest incidence was among children aged 2-4 years (21.1 per 100,000 population). The case fatality ratio was 9.2% and the highest ratio was among adults aged >=75 years (19.0%). The percentage of PCV7 preventable IPD decreased for all age groups, especially sharply among children aged 2-4 years, from 65.8% in 2008 to 12.9% in 2012. The prevalence of serotype 19A increased from 5.5% in 2008 to 25.3% in 2012 among all Streptococcus pneumoniae, displaying a differential temporal emergence among different age groups. Serotype 19A became the most prevalent serotype among children aged <2 years in 2009, children aged 2-4 and 5-17 years in 2010, and adults aged 18-49 years in 2012. CONCLUSIONS: The incidence of IPD fluctuated during the study period, with ongoing decrease due to PCV7 vaccine serotypes and increase due to non-vaccine serotypes. Serotype 19A became the most prevalent serotype in 2010 among all S. pneumoniae. PMID- 24793951 TI - Risk factors associated with anaphylaxis and other allergic-like events following receipt of 2009 monovalent AS03-adjuvanted pandemic influenza vaccine in Quebec, Canada. AB - INTRODUCTION: In Quebec, Canada, receipt of the 2009 AS03-adjuvanted pandemic H1N1 vaccine was associated with increased risk of anaphylaxis and other allergic like events (ALE), especially among women of childbearing age. In response to this safety signal, a case-control study was conducted to identify potential risk factors. METHODS: A total of 435 ALE (50 anaphylaxis) occurring <24h following pandemic vaccination were compared to 849 age-gender matched controls randomly selected from the provincial Pandemic Influenza Vaccination Registry. More than 60 potential risk factors were evaluated through phone interviews and included demographic information, medical history, medication use or acute respiratory illnesses (ARI) concurrent with vaccination and other risk factors associated with general allergy. Odds ratios (ORs) with 95% confidence intervals were estimated with unconditional logistic regression. RESULTS: Factors associated with increased risk of anaphylaxis included concurrent ARI (18% cases vs. 4% controls, ORadj 7.67, 95%CI: 3.04-13.37), food allergy (26% cases vs. 4% controls, ORadj 3.84, 95%CI: 1.51-9.74) and vaccination during the first four weeks of the campaign (66% cases vs. 50% controls, ORadj 2.16, 95%CI: 1.10-4.25) whereas alcohol exposure (>=1 drink/week) was associated with reduced risk (29% cases vs. 42% controls, ORadj 0.26, 95%CI: 0.13-0.57). These factors were also significantly associated with any ALE but the strength of association was weaker. Allergy to components found in the vaccine (e.g., egg, thimerosal) was infrequent and did not significantly differ between cases and controls. CONCLUSION: Increased anaphylaxis and other allergic-like events observed in association with AS03-adjuvanted pandemic H1N1 vaccine remain mostly unexplained despite extensive risk factor review. However, prior to mass vaccination with similar formulations this safety signal warrants further consideration and better understanding. In particular, the predominance among women of childbearing age may be a clue to underlying biological or hormonal influences on adverse immunological responses to vaccine. PMID- 24793952 TI - Differential loss of humoral immunity against measles, mumps, rubella and varicella-zoster virus in children treated for cancer. AB - BACKGROUND: Intensive chemotherapy in children with cancer results in long-term impairment of humoral immunity. Whereas most studies to date focused on children with acute lymphoblastic leukemia (ALL), little data have been published on patients suffering from Hodgkin disease or from solid tumors. We therefore analyzed the loss of protective immunity (defined as immunity at the time of diagnosis and lack of immunity after completion of therapy) against vaccine preventable diseases in children treated for various malignancies. METHODS: Children and adolescents <21 years of age at diagnosis and treated between 2001 and 2010 for various malignancies in the Department of Pediatric Hematology and Oncology, University of Frankfurt, were included in the retrospective chart review. Antibody levels against measles, mumps, rubella and varicella-zoster virus (VZV) were routinely assessed at the time of diagnosis and within 12 months after completion of therapy. RESULTS: The study population consisted of 195 children (122 male); 80 patients had ALL, 15 acute myelogenous leukemia (AML), 18 non-Hodgkin lymphoma (NHL), 22 Hodgkin disease, and 60 various solid tumors. Overall, 27%, 47%, 19%, and 17% of the patients lost their humoral immunity against measles, mumps, rubella, and VZV, respectively. The risk of losing protective antibody titers depended on age with a higher risk in younger children. The loss of protective humoral immunity occurred significantly more often in patients with ALL compared to patients with any other underlying malignant disease (hematological malignancies such AML and NHL, Hodgkin disease or solid tumors). CONCLUSIONS: Our data demonstrate that a significant number of children lose pre-existing humoral immunity against measles, mumps, rubella, and VZV after completion of chemotherapy. This loss occurs more often in children with ALL than in children with AML, solid tumors and Hodgkin disease. Our results underline the need for post-chemotherapy revaccination of childhood cancer survivors. PMID- 24793953 TI - A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and cancer risk in humans. AB - Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are ubiquitous synthetic chemicals with no known effect on human cancer development. This article systematically and critically reviews the epidemiologic evidence regarding the association between PFOA and PFOS exposure and cancer risk in humans. Eighteen epidemiologic studies - eight of PFOA, four of PFOS, and six of both PFOA and PFOS - have estimated associations of exposure to these chemicals with cancer incidence or mortality, with studies equally divided between occupational and nonoccupational settings. Although some statistically significant positive associations have been reported, for example, with cancers of the prostate, kidney, testis, and thyroid, the majority of relative risk estimates for both PFOA and PFOS have been between 0.5 and 2.0 (with 95% confidence intervals including 1.0), inconsistently detected across studies, counterbalanced by negative associations, not indicative of a monotonic exposure response relationship, and not coherent with toxicological evidence in animals, in which the primary target organs are the liver, testis (Leydig cells), and pancreas (acinar cells). Many positive associations with PFOA exposure were detected in community settings without occupational exposure and were not supported by results in exposed workers. Given that occupational exposure to PFOA and PFOS is one to two orders of magnitude higher than environmental exposure, the discrepant positive findings are likely due to chance, confounding, and/or bias. Taken together, the epidemiologic evidence does not support the hypothesis of a causal association between PFOA or PFOS exposure and cancer in humans. PMID- 24793954 TI - The potential for markers of epithelial-mesenchymal transition to improve colorectal cancer outcomes: a systematic review. AB - Epithelial-mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. PMID- 24793955 TI - The global burden of disease for skin, lung, and bladder cancer caused by arsenic in food. AB - BACKGROUND: Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant human cancer risk. While water consumption provides the majority of human exposure, millions of individuals worldwide are significantly exposed to arsenic through naturally occurring levels of arsenic in grains, vegetables, meats and fish, as well as through food processed with water containing arsenic. Thus, we estimated the global burdens of disease for bladder, lung, and skin cancers attributable to inorganic arsenic in food. METHODS: To determine foodborne inorganic arsenic exposures worldwide, we used World Health Organization estimates of food consumption in thirteen country clusters, in conjunction with reported measurements of total and inorganic arsenic in different foods. We estimated slope factors for arsenic-related bladder and lung cancers, and used the U.S. Environmental Protection Agency skin cancer slope factor, to calculate the annual risk of the cancer incidence in males and females within each country cluster. RESULTS: We estimated that each year 9,129 to 119,176 additional cases of bladder cancer, 11,844 to 121,442 of lung cancer, and 10,729 to 110,015 of skin cancer worldwide are attributable to inorganic arsenic in food. CONCLUSIONS: These estimates indicate that foodborne arsenic exposure causes a significant global burden of human disease. IMPACT: Estimating the global cancer burden caused by arsenic exposure in food will support policies that reduce exposure to disease-promoting environmental hazards. PMID- 24793956 TI - Patterns of colorectal cancer screening uptake in newly eligible men and women. AB - BACKGROUND: We describe patterns of colorectal cancer screening uptake in a U.S. insured population as individuals become newly eligible for screening at age 50 and assess temporal trends and patient characteristics with screening uptake. METHODS: We identified a cohort of 81,223 men and women who were members of Group Health and turned 50 years old from 1996 to 2010. We ascertained receipt of colorectal cancer screening within five years. Time to screening was estimated by year of cohort entry using cumulative incidence curves and Cox proportional hazards models-estimated patient characteristics associated with screening uptake. RESULTS: Stool-based screening tests were the most common, 72% of first screening tests. The proportion of individuals initiating colorectal cancer screening via colonoscopy increased from 8% in 1996 to 1998 to 33% in 2008 to 2010. Patient factors associated with increased colorectal cancer screening were: turning 50 more recently (2008-2010; Ptrend < 0.0001) or Asian race [HR, 1.14; 95% confidence interval (CI), 1.10-1.19]. Patient factors associated with decreased screening were: being a woman (HR, 0.70; 95% CI, 0.68-0.72), Native American (HR, 0.68; 95% CI, 0.60-0.78), or Pacific Islander race (HR, 0.82; 95% CI, 0.72-0.95), and having prevalent diabetes (HR, 0.78; 95% CI, 0.75-0.82) and higher body mass index (Ptrend < 0.0001). CONCLUSIONS: Patient characteristics associated with initiation of colorectal cancer screening in a newly eligible population are similar to characteristics associated with overall screening participation in all age-eligible adults. Our results identify patient populations to target in outreach programs. IMPACT: Disparities in receipt of colorectal cancer screening are evident from onset of an age-eligible cohort, identifying key groups for future interventions for screening. PMID- 24793958 TI - Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis. AB - BACKGROUND: Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, we quantify the prognostic impact of this biomarker. METHODS: A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling. RESULTS: Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups (<150/150-300/>300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 [HR = 1.87; 95% confidence interval (CI, 1.49-2.34); P < 0.001] and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97-1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HR[group 1] = 2.0; 95% CI, 1.6-2.7; HR[group 2] = 1.6; 95% CI, 1.1-2.4) than for early-stage disease (HR[group 1] = 1.5; 95% CI, 1.0-2.2; HR[group 2] = 1.0; 95% CI, 0.8-1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2. CONCLUSION: A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted. IMPACT: PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors. PMID- 24793957 TI - Exposure to infections and risk of leukemia in young children. AB - BACKGROUND: Epidemiologic studies indicate that infections in early childhood may protect against pediatric acute lymphoblastic leukemia (ALL). METHODS: We identified 3,402 ALL cases among children 0 to 5 years of age using the California Cancer Registry. From California birth records we randomly selected controls in a 20:1 ratio and frequency matched them to cases by birth year. We investigated markers of exposure to infections, including month of birth, timing of birth in relation to influenza and respiratory syncytial virus (RSV) seasons, and birth order based on data from California birth certificates and national infection surveillance systems. RESULTS: We observed an increased risk of ALL for spring and summer births, and for those first exposed to an influenza or RSV season at nine to twelve months of age compared with those exposed during the first three months of life, and this association was stronger among first born children [odds ratios (OR), 1.44 and 95% confidence intervals (CI), 1.13-1.82, for influenza exposure at nine to twelve months of age]. Decreased risk was observed with increasing birth order among non-Hispanic whites but not Hispanics (OR, 0.76 and 95% CI, 0.59-096, for fourth or higher birth order among whites). CONCLUSION: Our results support the hypothesis that infections in early childhood decrease risk of ALL. IMPACT: Our findings implicate early life exposure to infections as protective factors for ALL in young children. PMID- 24793959 TI - ACR Appropriateness Criteria colorectal cancer screening. AB - Colorectal cancer is the third leading cause of cancer deaths in the United States. Most colorectal cancers can be prevented by detecting and removing the precursor adenomatous polyp. Individual risk factors for the development of colorectal cancer will influence the particular choice of screening tool. CT colonography (CTC) is the primary imaging test for colorectal cancer screening in average-risk individuals, whereas the double-contrast barium enema (DCBE) is now considered to be a test that may be appropriate, particularly in settings where CTC is unavailable. Single-contrast barium enema has a lower performance profile and is indicated for screening only when CTC and DCBE are not available. CTC is also the preferred test for colon evaluation following an incomplete colonoscopy. Imaging tests including CTC and DCBE are not indicated for colorectal cancer screening in high-risk patients with polyposis syndromes or inflammatory bowel disease. This paper presents the updated colorectal cancer imaging test ratings and is the result of evidence-based consensus by the ACR Appropriateness Criteria Expert Panel on Gastrointestinal Imaging. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 24793960 TI - Being first. PMID- 24793961 TI - Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. AB - OBJECTIVES: To determine the prevalence and spectrum of mutations and genotype phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result. PATIENTS AND METHODS: Between April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean +/- SD age at diagnosis, 44.4 +/- 19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records. RESULTS: Overall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present. CONCLUSION: In this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session. PMID- 24793962 TI - Comparing cardiopulmonary exercise testing in severe COPD patients with and without pulmonary hypertension. AB - PURPOSE: To determine; (i) the effect of PH on exercise capacity, gas exchange and oxygen pulse; (ii) the variables that correlate with mean pulmonary artery pressure (mPAP) in severe COPD patients. METHODS: We reviewed 98 severe COPD patients who had pulmonary function, right heart catheterisation, and cardiopulmonary exercise testing (CPET) performed within six months of each other. PH was defined by a resting mPAP > 25 mmHg. COPD patients with and without PH were compared using the independent samples t-test and Mann-Whitney U test. Pearson correlation coefficients were used to assess the relationship between continuous variables. RESULTS: PH was present in 32% of patients and the majority of PH was mild (mPAP, 25-35 mmHg). Peak workload, oxygen uptake and oxygen pulse on CPET were significantly lower in the PH group. Mean PAP was found to inversely correlate with peak oxygen uptake, with a tendency towards lower six-minute walk distance. No difference between two groups was seen in any of the gas exchange variables. CONCLUSION: In severe COPD, there is a relatively high percentage of PH which causes a decrease in exercise capacity and oxygen pulse without significantly altered ventilation as measured by CPET. Lower than expected exercise performance without a change in pulmonary function may indicate a need for evaluation for possible PH. PMID- 24793964 TI - A strong interferon response correlates with a milder dengue clinical condition. AB - BACKGROUND: Type 1 interferon (IFNalpha/beta) has a significant role in establishing protection against virus infections. It has been well documented by in vitro studies that dengue virus (DENV) activates a robust IFNalpha/beta response. However, DENV also induces a down-regulation of the JAK/STAT pathway, inhibiting the induction of interferon regulated genes. As a consequence, the role played by the IFN type 1 response in the protection of dengue patients is not fully understood. OBJECTIVE: To compare IFN-alpha levels in dengue patients with dengue fever (DF) or dengue hemorrhagic fever (DHF) undergoing primary or secondary infections. STUDY DESIGN: Two hundred and four serum samples were analyzed for IFN-alpha level by cytometric bead array. Patients' clinical condition was assigned following the WHO 1997 criteria and specific IgG and IgM antibodies were measured using commercial assays to determine primary and secondary infections. The infecting serotype was determined by qRT-PCR. RESULTS AND CONCLUSION: The IFN-alpha levels were found significantly higher in DF than DHF patients irrespective of the infecting serotype (DENV1 or 2), and were found to decline rapidly at day 3 after fever onset. For DENV2 infections, higher IFN alpha level was found during primary than secondary infections. These results suggest that an early strong interferon response correlates with a better clinical condition. PMID- 24793963 TI - Specific probiotics and virological findings in symptomatic conscripts attending military service in Finland. AB - BACKGROUND: Viral upper respiratory tract infections occur frequently among conscripts. Probiotics have reduced viral infections in children attending day care. Limited data are available on the effects of probiotics on the nasopharyngeal presence of respiratory viruses. OBJECTIVES: To assess, whether probiotics could decrease nasopharyngeal occurrence of respiratory viruses in Finnish conscripts. STUDY DESIGN: In a randomized, double-blind, placebo controlled 90- and 150-day intervention study, 239 nasopharyngeal swab samples were collected from 192 symptomatic conscripts receiving daily chewable probiotic tablet containing Lactobacillus rhamnosus GG and Bifidobacterium animalis ssp. lactis BB-12 (46.9%) or control tablet (53.1%) on visits to a garrison's health care center due to symptoms of infection. The presence of respiratory viruses was tested by PCR-methods, and viral findings were compared between the intervention groups. RESULTS: 184 (76.9%) nasopharyngeal samples were positive for at least one respiratory virus. Picornaviruses were the most common viruses and were detected in 155 (84.2%) of samples. Of these, 143 (92.3%) were rhinovirus positive and 20 (12.9%) were enterovirus-positive. The control group had 83 (64%) and the probiotic group 72 (66%) picornavirus infections (p=0.79). Monthly distribution of picornaviruses showed that there were less picornavirus findings after 3 months in the probiotic group than in the control group (p=0.0069). However, probiotics did not reduce picornavirus occurrence in other months. CONCLUSIONS: Overall, probiotics did not reduce viral occurrence in symptomatic conscripts. However, probiotics decreased the presence of picornaviruses after 3 months, which may imply that probiotics play a role against viruses causing common cold. Further investigations are necessary to clarify the mechanisms involved in order to target specific probiotics on specific respiratory viruses. PMID- 24793965 TI - Non dermatomal rash and pancytopenia in a 5 year old child. PMID- 24793966 TI - Prevalence of R5 and X4 HIV variants in antiretroviral treatment experienced patients with virologic failure. AB - BACKGROUND: Antiretroviral therapy (ART) inhibits virus replication. Nevertheless, ART has the disadvantage of generate selective resistance and adverse events. Coreceptor antagonists are a family of antiretroviral drugs that are used with the prior knowledge of patients HIV tropism. OBJECTIVES: The purpose of this work was to estimate the prevalence of R5 and X4 variants among Chilean patients under antiretroviral therapy and virological failure and investigate variables such as plasma viral load (pVL) and CD4 cell count in the population studied. STUDY DESIGN: HIV RNA or proviral DNA was extracted from 454 consecutives patients and tropism testing was performed using a genotypic method performed with Geno2pheno setting a cutoff value for FPR 5.75%. RESULTS: Among 454 individuals analyzed, 299 (66%) harbouring exclusively R5 variants. They not displayed a better clinical profile than individuals harbouring X4 strains (22%). For R5 patients the median of pVL and CD4 cell count were 268,000copies/mL, and 223cells/MUL respectively. For X4 samples the values were 368,000copies/mL and 214cells/MUL [P>0.05]). Only, 53 patients (12%) could not be analyzed and were categorized as non-reportable. CONCLUSIONS: The genotypic method confirmed that R5 strains were more prevalent despite the fact that patients were treatment experienced for several years. The genotypic strategy proved to be a faster and cost-effective option as compared to phenotypic assays. According to our results, two of every three patients under antiretroviral therapy and with virologic failure harbour R5 strains, and may be candidates for use of a CCR5 antagonist. PMID- 24793967 TI - Seroprevalence of antibodies against SFTS virus infection in farmers and animals, Jiangsu, China. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a newly identified viral zoonosis caused by a phlebovirus. Most reported SFTS cases are farmers living in rural areas. The seroprevalence of SFTS virus in farmers has not been investigated. The current knowledge of SFTS virus seroprevalence in animals, especially in wild animals, is still poor. OBJECTIVES: To investigate SFTS virus seroprevalence among farmers and a variety of animal species. STUDY DESIGN: SFTS virus antibodies in sera were determined using a double-antigen sandwich ELISA. Serum samples were collected from 2547 farmers and 2741 animals in 6 SFTS-endemic counties from March 2012 to February 2013 in Jiangsu province. The farmer participants aged from 15 to 90 years. All of them were interviewed using a structured questionnaire. The animals sampled included 6 domesticated animal species and 2 wild animal species. RESULTS: SFTSV antibodies were found in a total of 33 farmers (1.30%) and was more prevalent in males than in females (respectively 1.87% and 0.71%, P<0.01). The mean age of seropositive farmers was 56.5 years and seroprevalence increased gradually with age. Seroprevalence in animal species were: goats (66.8%), cattle (28.2%), dogs (7.4%), pigs (4.7%), chickens (1.2%), geese (1.7%), rodents (4.4%) and hedgehogs (2.7%). Multiple variable logistic regression analysis showed that grazing, grass mowing, raising cattle, age, farm work time and tick bites were risk factors for SFTS virus infection among farmers. CONCLUSIONS: SFTSV readily infects humans with farming related exposures as well as numerous domestic and wild animals. Serological results further suggest that the virus circulates widely in Jiangsu province. PMID- 24793968 TI - Biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co infected patients in the SMART study. AB - BACKGROUND: Previous results from the SMART study showed that HIV/viral hepatitis co-infected persons with impaired liver function are at increased risk of death following interruption of antiretroviral therapy (ART). OBJECTIVES: To investigate the influence of fibrosis and ART interruption on levels of biomarkers of inflammation, coagulation and microbial translocation in HIV/HCV co infected persons in the SMART study. STUDY DESIGN: All HIV/HCV co-infected persons with stored plasma at study entry and at six months of follow-up were included (N=362). D-dimer, IL-6, sCD14 and hepatic synthesized coagulation markers were measured and compared according to the liver fibrosis marker hyaluronic acid (HA) at study entry. Percent difference in changes in biomarker levels from study entry to month 6 was compared between randomization groups and according to study entry HA levels. RESULTS: At study entry, persons with elevated HA (>75ng/mL vs. <=75ng/mL) had higher median (IQR) levels of IL-6 [4.14pg/mL (2.60-6.32) vs. 2.74pg/mL (1.88-3.97)] and soluble CD14 [2163ng/mL (1952-2916) vs. 1979ng/mL (1742-2310)] (p<0.001). Elevated HA was also associated with alterations of both pro- and anti-coagulation markers but the overall coagulation profile was not affected. Interruption of ART lead to a particularly pronounced increase in IL-6 levels in persons with elevated HA levels (p=0.01 for interaction between randomization group and continuous HA level). CONCLUSIONS: HIV/HCV co-infected persons with impaired liver function are in an enhanced pro inflammatory state which is further exacerbated upon interruption of ART. PMID- 24793969 TI - Serologic assay for avian-origin influenza A (H7N9) virus in adults of Shanghai, Guangzhou and Yunnan, China. AB - BACKGROUND AND OBJECTIVE: To investigate serologic status for novel avian influenza A (H7N9) virus in different areas in China, we examined serum samples collected in winter of 2011 from adult population of Shanghai (eastern China), Guangzhou (southern China) and Yunnan (southwest China) for the antibody responses to this virus. STUDY DESIGN: A total of 900 stored serum samples of adult outpatients (300 samples for each area) were subjected to anti hemagglutinin (HA) antibodies assay using enzyme-linked immunosorbent assay (ELISA) and neutralizing antibodies assay using H7N9 pseudotyped particles (H7N9pp) and authentic H7N9 virus based neutralization test. RESULTS: Anti-H7 antibodies were detected in 164, 186 and 123 samples from three areas above, respectively. Among anti-H7 positive sera, 20, 42 and 13 samples had neutralizing titers of >=10 when 8*10(2) focus-forming units (FFU) of H7N9 pseudotyped particles (pp) were adopted in neutralizing assay, respectively. When neutralizing antibodies were assayed using classic microneutralization (MN) test, MN titers of >=10 were found in 7 samples from Guangzhou, but none from Shanghai and Yunnan. CONCLUSION: Low levels of protective immunity pre-existed in some general adult population of the three areas, and pre-existing immunity against H7N9 in Guangzhou appears stronger than that in Shanghai and Yunnan. PMID- 24793970 TI - Evaluation of mercury stress in plants from the Almaden mining district by analysis of phytochelatins and their Hg complexes. AB - To evaluate plant response to Hg stress, glutathione, phytochelatins, and their Hg complexes were analyzed using HPLC with amperometric detection in samples of Asparagus acutifolius grown in the Almaden mining district (Ciudad Real, Spain), one of the most Hg-contaminated sites in the world. Soils of the Almaden mining district, and specifically from the Almadenejos zone, are highly contaminated, with some zones having values above 4,000 MUg Hg g(-1) soil. Although soils have an extremely high concentration of mercury, generally less than 2% is available for plants, as is shown by various soil extractions simulating bioavailability. In plants, Hg concentration increases depending on the content of Hg in soils. In addition, Hg levels in roots are higher than in aerial parts, which is a strategy of plants for protecting their more sensitive aerial parts from the deleterious effects of metal stress. The total content of phytochelatins (PCs) and their complexes are directly related with the amount of mercury in soils. These findings highlight the important role of thiol compounds and their metal complexes in capturing and fixing Hg from soils, giving plants the capacity to deal with the heavy metal toxicity of polluted soils. PMID- 24793971 TI - Surgical reconstruction of the genitalia in a 3-year-old infant with a 46XX karyotype: case report. AB - A 3-year-old patient was hospitalized with ambiguous genitalia (clitoromegaly, labioscrotal fusion, absence of vaginal introitus), classified as stage III/IV according to Prader's virilization scale. Our patient, with a 46XX karyotype, was previously diagnosed with congenital adrenal hyperplasia caused by a deficiency of the adrenal enzyme 21-hydroxylase; corticosteroids and salt replacement therapy have been used. At the present admission, the surgical treatment consisted on clitoroplasty (with the removal of erectile tissue), reconstruction of the labia minor, creation of a neovulva and vaginoplasty. It was a single-step operation to restore the anatomical female structures. She had an uneventful postoperative period and the wound healed well with good cosmetic results. We present the details about the surgical procedure and a short review of data from literature. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24793972 TI - Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor. AB - GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2 PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Galphai. 2 PCCA did not induce calcium mobilization in GPR88 cells, indicating no Galphaq mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity. PMID- 24793973 TI - MiR-31 is an independent prognostic factor and functions as an oncomir in cervical cancer via targeting ARID1A. AB - OBJECTIVES: MicroRNAs(miRNAs) play important roles in tumor development and progression. The purposes of this study were to investigate the role of miR-31 in cervical cancer and clarified the regulation of ARID1A by miR-31. METHODS: Quantitative RT-PCR was used to examine miR-31 expression in cervical cancer cell lines and patient specimens. The clinicopathological significance of miR-31 upregulation was further analyzed. The MTT, colony formation, apoptosis, cell cycle, wound healing and Transwell invasion assays, and a xenograft model were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-31, and the results were validated in cell lines and patient specimens. RESULTS: MiR-31 was significantly up-regulated in cervical cancer cell lines and clinical tissues. The high miR-31 level was significantly correlated with higher FIGO stage, node metastasis, vascular involvement and deep stromal invasion. Patients with high expression of miR-31 had poorer overall survival than patients with low expression. MiR-31 was an independent prognostic factor in cervical cancer in multivariate Cox regression analysis. Down-regulation of miR-31 impaired cell proliferation, colony formation, and cell migration and invasion in vitro, and inhibited xenograft tumor growth in vivo. ARID1A was verified as a direct target of miR-31, which was further confirmed by the inverse expression of miR-31 and ARID1A in patient specimens. CONCLUSIONS: The newly identified miR 31/ARID1A pathway provides insight into cervical cancer progression, and may represent a novel therapeutic target. PMID- 24793975 TI - Reply: To PMID 23999424. PMID- 24793974 TI - Hyperglycemia impairs cytotrophoblast function via stress signaling. AB - OBJECTIVE: Diabetes mellitus is a risk factor for preeclampsia. Cytotrophoblast (CTB) invasion is facilitated from the conversion of plasminogen to plasmin by urokinase plasminogen activator (uPA), regulated by plasminogen activator inhibitor 1 (PAI-1), and may be inhibited in preeclampsia. This study assessed signaling mechanisms of hyperglycemia-induced CTB dysfunction. STUDY DESIGN: Human CTBs were treated with 45, 135, 225, 495, or 945 mg/dL glucose for 48 hours. Some cells were pretreated with a p38 inhibitor (SB203580) or a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand (rosiglitazone). Expression of uPA, PAI-1, and PPAR-gamma levels and p38 mitogen-activated protein kinase phosphorylation were measured by Western blot in cell lysates. Messenger ribonucleic acid of uPA and PAI-1 was measured by quantitative polymerase chain reaction. Levels of interleukin-6, angiogenic (vascular endothelial growth factor [VEGF], placenta growth factor [PlGF]) and antiangiogenic factors (soluble fms like tyrosine kinase-1 [sFlt-1], soluble endoglin [sEng]) were measured in the media by enzyme-linked immunosorbent assay kits. Statistical comparisons were performed using analysis of variance with a Duncan's post-hoc test. RESULTS: Both uPA and PAI-1 protein and messenger ribonucleic acid were down-regulated (P < .05) in CTBs treated with 135 mg/dL glucose or greater compared with basal (45 mg/dL). The sEng, sFlt-1, and interleukin-6 were up-regulated, whereas the VEGF and PlGF were down-regulated by 135 mg/dL glucose or greater. p38 phosphorylation and PPAR-gamma were up-regulated (P < .05) in hyperglycemia-treated CTBs. The SB203580 or rosiglitazone pretreatment showed an attenuation of glucose-induced down-regulation of uPA and PAI-1. CONCLUSION: Hyperglycemia disrupts the invasive profile of CTB by decreasing uPA and PAI-1 expression; down-regulating VEGF and PlGF; and up-regulating sEng, sFlt-1, and interleukin-6. Attenuation of CTB dysfunction by SB203580 or rosiglitazone pretreatment suggests the involvement of stress signaling. PMID- 24793976 TI - Reply: To PMID 24036400. PMID- 24793977 TI - The PORTO study and the gestational age perspective of Doppler interrogation of IUGR fetuses. PMID- 24793979 TI - Posterior hypothalamic deep brain stimulation. The impact on cluster headache control and other indications. PMID- 24793978 TI - Adjustment of suboptimally placed lumbar pedicle screws decreases pullout strength and alters biomechanics of the construct: a pilot cadaveric study. AB - BACKGROUND: Lumbar pedicle screws are placed for internal fixation and help to enhance bony fusion. Optimal screws are medially directed, should be parallel or pointing to the superior endplate, and penetrate 50%-80% of the vertebral body. "Nonparallel" pedicle screws can be inadvertently placed within the confines of the pedicle and vertebral body but are sometimes replaced to obtain a more acceptable postoperative image. A nonparallel (suboptimal) screw is one that is located within the pedicle and body and does not violate bone; however, it is not parallel to the superior endplate. These "cored-out" grooves left in the bone from the initial tap and screw placement may compromise the integrity of the bone and the construct. METHODS: Dual-energy x-ray absorptiometry scans and L4-5 laminectomies were performed on 6 fresh-frozen cadaveric lumbar spines. We placed 2 optimal pedicle screws in L4, 1 optimal screw in L5, and 1 suboptimal screw in L5 (construct A). Axial rotation, flexion/extension, and lateral bending were tested. The suboptimal screw was repositioned in an optimal trajectory and retested (construct B). Pullout strength was performed on optimal and revised L5 pedicle screws. RESULTS: The mean axial rotation stiffness was 1.31 N-m/degrees +/- 0.22 in construct A and 1.19 N-m/degrees +/- 0.17 in construct B (P = 0.023; 95% CI [CI], 0.20-0.02). The mean lateral bending stiffness was 0.015 N/mm +/- 0.002 in construct A and 0.016 N/mm +/- 0.002 in construct B (P = 0.3; 95% CI, 0.0008-0.001). The mean flexion/extension stiffness was 0.0139 N/mm +/- 0.002 in construct A and 0.0126 N/mm +/- 0.002 in construct B (P = 0.01; 95% CI, 0.002 0.0004). Axial rotation and flexion/extension stiffness were significantly different between the 2 groups. The mean pullout strength was significantly higher in the nonrevised parallel screw group compared with the reimplanted parallel screw group (906.93 N +/- 271.17 vs. 608.32 N +/- 207.23, P = 0.031). Dual-energy x-ray absorptiometry imaging demonstrated 4 osteopenic and 2 osteoporotic specimens, although differences in bone mineral density did not play a significant role in assessing either the biomechanical parameters or the pullout strength. CONCLUSIONS: Great care is warranted in the initial placement of lumbar pedicle screws. Revising a nonparallel screw placement decreases pullout strength and alters biomechanical movements (axial rotation and flexion/extension) in patients with decreased bone mineral density. If a screw is inadvertently placed nonparallel to the endplate but is within the confines of the pedicle and vertebral body with adequate bone purchase, it should not be revised and rather be left in its place. PMID- 24793980 TI - The Preferred Learning Styles of Neurosurgeons, Neurosurgery Residents, and Neurology Residents: Implications in the Neurosurgical Field. AB - OBJECTIVE: To delineate the learning style that best defines a successful practitioner in the field of neurosurgery by using a validated learning style inventory. METHODS: The Kolb Learning Style Inventory, a validated assessment tool, was administered to all practicing neurosurgeons, neurosurgical residents, and neurology residents employed at Chang Gung Memorial Hospital, an institution that provides primary and tertiary clinical care in 3 locations, Linkou, Kaohsiung, and Chiayi. There were 81 participants who entered the study, and all completed the study. RESULTS: Neurosurgeons preferred the assimilating learning style (52%), followed by the diverging learning style (39%). Neurosurgery residents were slightly more evenly distributed across the learning styles; however, they still favored assimilating (32%) and diverging (41%). Neurology residents had the most clearly defined preferred learning style with assimilating (76%) obtaining the large majority and diverging (12%) being a distant second. CONCLUSIONS: The assimilating and diverging learning styles are the preferred learning styles among neurosurgeons, neurosurgery residents, and neurology residents. The assimilating learning style typically is the primary learning style for neurosurgeons and neurology residents. Neurosurgical residents start off with a diverging learning style and progress toward an assimilating learning style as they work toward becoming practicing neurosurgeons. The field of neurosurgery has limited opportunities for active experimentation, which may explain why individuals who prefer reflective observation are more likely to succeed in this field. PMID- 24793981 TI - Obesity attenuates D2 autoreceptor-mediated inhibition of putative ventral tegmental area dopaminergic neurons. AB - Abstract The ventral tegmental area (VTA) in the midbrain is important for food reward. High-fat containing palatable foods have reinforcing effects and accelerate obesity. We have previously reported that diet-induced obesity selectively decreased the spontaneous activity of VTA GABA neurons, but not dopamine neurons. The spontaneous activity of VTA dopamine neurons is regulated by D2 autoreceptors. In this study, we hypothesized that obesity would affect the excitability of VTA dopamine neurons via D2 autoreceptors. To examine this hypothesis, we compared D2 receptor-mediated responses of VTA dopamine neurons between lean and obese mice. Mice fed on a high-fat (45%) diet and mice fed on a standard diet were used as obese and lean models, respectively. Brain slice preparations were made from these two groups. Spontaneous activity of VTA neurons was recorded by extracellular recording. Putative VTA dopamine neurons were identified by firing inhibition with a D2 receptor agonist quinpirole, and electrophysiological criteria (firing frequency <5 Hz and action potential current duration >1.2 msec). Single-dose application of quinpirole (3-100 nmol/L) exhibited similar firing inhibition of putative VTA dopamine neurons between lean and obese mice. In stepwise application by increasing quinpirole concentrations of 3, 10, 30, and 100 nmol/L subsequently, quinpirole-induced inhibition of firing decreased in putative VTA dopamine neurons of obese mice compared with those of lean mice. In conclusion, high-fat diet-induced obesity attenuated D2 receptor-mediated inhibition of putative VTA dopamine neurons due to the acceleration of D2 receptor desensitization. PMID- 24793982 TI - Validity and reliability of a field technique for sweat Na+ and K+ analysis during exercise in a hot-humid environment. AB - Abstract This study compared a field versus reference laboratory technique for extracting (syringe vs. centrifuge) and analyzing sweat [Na(+)] and [K(+)] (compact Horiba B-722 and B-731, HORIBA vs. ion chromatography, HPLC) collected with regional absorbent patches during exercise in a hot-humid environment. Sweat samples were collected from seven anatomical sites on 30 athletes during 1-h cycling in a heat chamber (33 degrees C, 67% rh). Ten minutes into exercise, skin was cleaned/dried and two sweat patches were applied per anatomical site. After removal, one patch per site was centrifuged and sweat was analyzed with HORIBA in the heat chamber (CENTRIFUGE HORIBA) versus HPLC (CENTRIFUGE HPLC). Sweat from the second patch per site was extracted using a 5-mL syringe and analyzed with HORIBA in the heat chamber (SYRINGE HORIBA) versus HPLC (SYRINGE HPLC). CENTRIFUGE HORIBA, SYRINGE HPLC, and SYRINGE HORIBA were highly related to CENTRIFUGE HPLC ([Na(+)]: ICC = 0.96, 0.94, and 0.93, respectively; [K(+)]: ICC = 0.87, 0.92, and 0.84, respectively), while mean differences from CENTRIFUGE HPLC were small but usually significant ([Na(+)]: 4.7 +/- 7.9 mEql/L, -2.5 +/- 9.3 mEq/L, 4.0 +/- 10.9 mEq/L (all P < 0.001), respectively; [K(+)]: 0.44 +/- 0.52 mEq/L (P < 0.001), 0.01 +/- 0.49 mEq/L (P = 0.77), 0.50 +/- 0.48 mEq/L (P < 0.001), respectively). On the basis of typical error of the measurement results, sweat [Na(+)] and [K(+)] obtained with SYRINGE HORIBA falls within +/-15.4 mEq/L and +/-0.68 mEq/L, respectively, of CENTRIFUGE HPLC 95% of the time. The field (SYRINGE HORIBA) method of extracting and analyzing sweat from regional absorbent patches may be useful in obtaining sweat [Na(+)] when rapid estimates in a hot humid field setting are needed. PMID- 24793983 TI - Protective effect and localization by optical imaging of human renal CD133+ progenitor cells in an acute kidney injury model. AB - Abstract Recent approaches of regenerative medicine can offer a therapeutic option for patients undergoing acute kidney injury. In particular, mesenchymal stem cells were shown to ameliorate renal function and recovery after acute damage. We here evaluated the protective effect and localization of CD133(+) renal progenitors from the human inner medulla in a model of glycerol-induced acute tubular damage and we compared the results with those obtained with bone marrow-derived mesenchymal stem cells. We found that CD133(+) progenitor cells promoted the recovery of renal function, preventing tubular cell necrosis and stimulating resident cell proliferation and survival, similar to mesenchymal stem cells. In addition, by optical imaging analysis, CD133(+) progenitor cells accumulated within the renal tissue, and a reduced entrapment in lung, spleen, and liver was observed. Mesenchymal stem cells were detectable at similar levels in the renal tissue, but a higher signal was present in extrarenal organs. Both cell types produced several cytokines/growth factors, suggesting that a combination of different mediators is involved in their biological action. These results indicate that human CD133(+) progenitor cells are renotropic and able to improve renal regeneration in acute kidney injury. PMID- 24793984 TI - Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease. AB - Abstract The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter- and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) MUg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) MUg/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) MUg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) MUg/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics. PMID- 24793985 TI - Time perspective and the theory of planned behavior: moderate predictors of physical activity among central Appalachian adolescents. AB - INTRODUCTION: The purpose of this study was to determine how well time perspective and the Theory of Planned Behavior (TPB) predicted physical activity among adolescents residing in the central Appalachian region of the United States. METHOD: A descriptive, correlational design was used. The setting was a rural high school in central Appalachia. The sample included 185 students in grades 9 through 12. Data were collected in school. Variables included components of the TPB, time perspective, and various levels of exercise. Data were analyzed using Pearson's correlation coefficients and multiple regression analysis. RESULTS: The TPB was a moderate predictor of exercise frequency among central Appalachian adolescents, accounting for 42% of the variance. Time perspective did not add to the predictive ability of the TPB to predict exercise frequency in this sample. DISCUSSION: This study provides support for the TPB for predicting frequency of exercise among central Appalachian adolescents. By understanding the role of the TPB in predicting physical activity among adolescents, nurse practitioners will be able to adapt intervention strategies to improve the physical activity behaviors of this population. PMID- 24793986 TI - Findings and implications of developmental screening for high-risk children referred to a tertiary developmental disability center. AB - INTRODUCTION: The primary goal of this article is to describe an intake process and results of screening for developmental and autism spectrum disorders in children referred to a tertiary center. A secondary analysis of abnormal screening results, demographic variables, and parental concerns of autism was conducted, along with a correlation analysis between developmental and autism specific screening tools. METHODS: A total of 379 children younger than 6 years were "prescreened" with the Ages and Stages Questionnaire-3 and the Modified Checklist for Autism in Toddlers or the Social Communication Questionnaire. Medical records were reviewed to identify demographic variables and parental primary concerns. RESULTS: In approximately 11% of participants who screened positive for autism, no parental concerns of autism were present. Medium effect size correlations were found between the failed autism screening tools and delays in two domains on the Ages and Stages Questionnaire-3. DISCUSSION: Clinical implications are addressed concerning diligent use of developmental and autism specific rating scales to identify children at risk. PMID- 24793987 TI - Genetic of gonadal determination. AB - Fetal sexual differentiation results from complex subsequent intracellular signaling and hormonal events that interact together in a definite timing. This process contributes to the setting of gonad determination, internal and external genitalia resulting in a female or male phenotype. Here, we review our current knowledge of gonadal determination drawing on insights from knock-out and transgenic mouse models and analysis of patients with disorders of sex development (DSD). PMID- 24793988 TI - Steroidogenesis of the testis -- new genes and pathways. AB - Defects of androgen biosynthesis cause 46,XY disorder of sexual development (DSD). All steroids are produced from cholesterol and the early steps of steroidogenesis are common to mineralocorticoid, glucocorticoid and sex steroid production. Genetic mutations in enzymes and proteins supporting the early biosynthesis pathways cause adrenal insufficiency (AI), DSD and gonadal insufficiency. The classic androgen biosynthesis defects with AI are lipoid CAH, CYP11A1 and HSD3B2 deficiencies. Deficiency of CYP17A1 rarely causes AI, and HSD17B3 or SRD5A2 deficiencies only cause 46,XY DSD and gonadal insufficiency. All androgen biosynthesis depends on 17,20 lyase activity of CYP17A1 which is supported by P450 oxidoreductase (POR) and cytochrome b5 (CYB5). Therefore 46,XY DSD with apparent 17,20 lyase deficiency may be due to mutations in CYP17A1, POR or CYB5. Illustrated by patients harboring mutations in SRD5A2, normal development of the male external genitalia depends largely on dihydrotestosterone (DHT) which is converted from circulating testicular testosterone (T) through SRD5A2 in the genital skin. In the classic androgen biosynthetic pathway, T is produced from DHEA and androstenedione/-diol in the testis. However, recently found mutations in AKR1C2/4 genes in undervirilized 46,XY individuals have established a role for a novel, alternative, backdoor pathway for fetal testicular DHT synthesis. In this pathway, which has been first elucidated for the tammar wallaby pouch young, 17-hydroxyprogesterone is converted directly to DHT by 5alpha-3alpha reductive steps without going through the androgens of the classic pathway. Enzymes AKR1C2/4 catalyse the critical 3alphaHSD reductive reaction which feeds 17OH-DHP into the backdoor pathway. In conclusion, androgen production in the fetal testis seems to utilize two pathways but their exact interplay remains to be elucidated. PMID- 24793989 TI - Andropause--lessons from the European Male Ageing Study. AB - Andropause or late-onset hypogondism (LOH) is a situation where a middle-aged or older man has low serum testosterone (T) in conjunction with diffuse symptoms reminiscent of those of genuine male hypogonadism (e.g. reduced sexual function, loss of vigor, muscle weakness, depression). Opinions about the diagnostic criteria, prevalence and treatment options of andropause vary considerably amongst experts. We review here some salient findings on the prevalence, diagnostic criteria and impact on health of andropause, obtained from the European Male Ageing Study (EMAS), a multicenter study of ageing among community dwelling middle-aged and older men. PMID- 24793990 TI - New approaches to the Klinefelter syndrome. AB - The Klinefelter syndrome (KS), with an incidence of 1 to 2 per 1000 male neonates, is one of the most frequent congenital chromosome disorders. The 47,XXY karyotype causes infertility, testosterone deficiency and a spectrum of further symptoms and comorbidities. In recent years, significant progress has been made in the elucidation of the pathophysiology and the treatment of the KS. It became clear that, to a large extent, the clinical picture is determined by gene dosage effects of the supernumerary X-chromosome. The origin of the extra X-chromosome from either the father or the mother influences behavioural features of patients with KS. The CAGn polymorphism of the androgen receptor, located on the X chromosome, has a distinct impact on the KS phenotype. KS predisposes to the metabolic syndrome and its cardiovascular sequelae, contributing to the increased mortality of patients with KS. Neuroimaging studies have correlated anomalies in brain structures with psychosocial problems. The unexpected possibility to produce pregnancies and live birth with either ejaculated sperm--about 8% of KS men have a few sperm in semen--or with sperm extracted from individual tubules obtained by testicular biopsy can be considered a breakthrough. Testosterone substitution requires further optimisation in terms of when to initiate therapy and which preparations and dosages to use. Recently developed animal models help to further elucidation the genetic and pathophysiological basis and may lead to new therapeutic approaches to KS. PMID- 24793991 TI - Mini-puberty and true puberty: differences in testicular function. AB - The ontogeny of the hypothalamic-pituitary-gonadal axis is particularly characterised by incomplete functional maturation in utero and during early postnatal life, followed by functional regression and partial quiescence during childhood, and subsequently by final complete maturation during puberty. This review addresses the distinctive features of testis developmental physiology- especially in the seminiferous tubule compartment--which explain the differences observed in testicular function and its disorders between the early postnatal activation period--which many authors call "mini-puberty"--and canonical puberty. PMID- 24793992 TI - Male fertility preservation, where are we in 2014? AB - Male fertility preservation receives growing attention in the field of reproductive medicine. The first clinical programs were established to preserve reproductive potential in men needing gonadotoxic treatment. Sperm cryopreservation is now a standard procedure. Since a few years, several centres offer testicular tissue cryopreservation to prepubertal boys. This method is still experimental and further research is needed to implement the transplantation techniques in the clinic. With the aim to preserve or restore fertility in patients affected by other diseases (Klinefelter syndrome, Sertoli cell only syndrome), techniques for in vitro spermatogenesis are being developed. PMID- 24793993 TI - Effects of endocrine disruptors on the human fetal testis. AB - The modern societies are exposing us to a huge variety of potentially harmful pollutants. Among these endocrine disruptors (EDs) have been especially scrutinized as several were proven to display reprotoxic effects in rodent models. In the context of high and growing concerns about the reprotoxicity of EDs, it is crucial to carry out studies in order to assess their impact on the human reproductive function. However, such evidence remains scarce. The fetal period is critical for the proper development of the testis and is known as a period of high sensitivity to many EDs. Our team has shown in 2009 that a phthalate, mono-(2-ethylhexyl) phthalate (MEHP), has a potential deleterious effect on the development of human male germ cells. This result was the first direct experimental proof of the toxic effect of an ED in human testis. More recently, we also reported that bisphenol A (BPA) impaired testosterone production in the human fetal testis. Here, we will summarize the known effects of EDs on the various cell types composing the human developing testis and discuss their relevancy to propose future directions. PMID- 24793994 TI - Hormonal control of spermatogenesis in men: therapeutic aspects in hypogonadotropic hypogonadism. AB - During the first two trimesters of intrauterine life, fetal sex steroid production is driven by maternal human chorionic gonadotropin (hCG). The HPG axis is activated around the third trimester and remains active for the first 6-months of neonatal life. This so-called mini-puberty is a developmental window that has profound effects on future potential for fertility. In early puberty, GnRH secretion is reactivated first at night and then night and day. Pulsatile GnRH stimulates both LH and FSH, which induce maturation of the seminiferous tubules and Leydig cells. Congenital hypogonadotropic hypogonadism (CHH) results from GnRH deficiency. Men with CHH lack the mini-pubertal and pubertal periods of Sertoli Cell proliferation and thus present with prepubertal testes (<4mL) and low inhibin serum levels --reflecting diminished SC numbers. To induce full maturation of the testes, GnRH-deficient patients can be treated with either pulsatile GnRH, hCG or combined gonadotropin therapy (FSH+hCG). Fertility outcomes with each of these regimens are highly variable. Recently, a randomized, open label treatment study (n=13) addressed the question of whether a sequential treatment with FSH alone prior to LH and FSH (via GnRH pump) could enhance fertility outcomes. All men receiving the sequential treatment developed sperm in the ejaculate, whereas 2/6 men in the other group remained azoospermic. A large, multicenter clinical trial is needed to definitively prove the optimal treatment approach for severe CHH. PMID- 24793995 TI - Disrupting the male germ line to find infertility and contraception targets. AB - Genetically-manipulated mouse models have become indispensible for broadening our understanding of genes and pathways related to male germ cell development. Until suitable in vitro systems for studying spermatogenesis are perfected, in vivo models will remain the gold standard for inquiry into testicular function. Here, we discuss exciting advances that are allowing researchers faster, easier, and more customizable access to their mouse models of interest. Specifically, the trans-NIH Knockout Mouse Project (KOMP) is working to generate knockout mouse models of every gene in the mouse genome. The related Knockout Mouse Phenotyping Program (KOMP2) is performing systematic phenotypic analysis of this genome-wide collection of knockout mice, including fertility screening. Together, these programs will not only uncover new genes involved in male germ cell development but also provide the research community with the mouse models necessary for further investigations. In addition to KOMP/KOMP2, another promising development in the field of mouse models is the advent of CRISPR (clustered regularly interspaced short palindromic repeat)-Cas technology. Utilizing 20 nucleotide guide sequences, CRISPR/Cas has the potential to introduce sequence-specific insertions, deletions, and point mutations to produce null, conditional, activated, or reporter-tagged alleles. CRISPR/Cas can also successfully target multiple genes in a single experimental step, forgoing the multiple generations of breeding traditionally required to produce mouse models with deletions, insertions, or mutations in multiple genes. In addition, CRISPR/Cas can be used to create mouse models carrying variants identical to those identified in infertile human patients, providing the opportunity to explore the effects of such mutations in an in vivo system. Both the KOMP/KOMP2 projects and the CRISPR/Cas system provide powerful, accessible genetic approaches to the study of male germ cell development in the mouse. A more complete understanding of male germ cell biology is critical for the identification of novel targets for potential non-hormonal contraceptive intervention. PMID- 24793996 TI - Hyperacute flash pulmonary oedema after transcatheter pulmonary valve implantation: The melody of an overwhelmed left ventricle. AB - Percutaneous transcatheter Melody Valve implantation has achieved standard of care for the management of certain patients with right ventricular outflow tract dysfunction. With its widespread use, some rare and potentially fatal complications, such as right ventricular outflow tract rupture and coronary artery compression, have been reported. We report hyperacute flash pulmonary oedema after Melody Valve implantation for the first time in two patients and describe some possible predictors. PMID- 24793997 TI - [Donation of remains of biological samples and informed consent for secondary use]. PMID- 24793998 TI - First evidence of simultaneous occurrence of West Nile virus and Usutu virus neuroinvasive disease in humans in Croatia during the 2013 outbreak. AB - PURPOSE: We report on first evidence of simultaneous occurrence of West Nile virus (WNV) and Usutu virus (USUV) neuroinvasive infection in humans in Croatia during the transmission season 2013. METHODS: From June to December 2013, a total of 95 patients with clinically suspected WNV infection (WNV fever and neuroinvasive disease) were tested for WNV IgM/IgG antibodies using enzyme-linked immunosorbent assay. Twenty-six reactive samples were further tested by virus neutralization test for confirmation. RESULTS: WNV neuroinvasive infection was confirmed in 20 patients, while in three patients USUV neutralizing antibodies were detected. Cases occurred during the 11-week interval (from 24 July to 07 October 2013). Both WNV and USUV cases were distributed in three north-western Croatian counties. In addition to human cases, recent asymptomatic WNV infection (detection of IgM antibodies) was recorded in 9/3,460 (0.3 %) tested sentinel horses. Infected animals were recorded in two eastern and one north-western county. CONCLUSIONS: Our results indicate co-circulation of WNV and USUV in Croatia. WNV infection could be misdiagnosed with other emerging infectious diseases presenting with neurological symptoms such as USUV infection. PMID- 24793999 TI - The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma. AB - PURPOSE: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. In ccRCC, microRNAs (miRs) differentially expressed in tumour tissue have been identified and have been proposed to predict prognosis. The purpose of this study was to evaluate candidate miR markers identified from analysis of The Cancer Genome Atlas (TCGA) datasets in a large RCC cohort and to elucidate whether a ratio of miRs provided additional prognostic information. EXPERIMENTAL DESIGN: Deep sequencing data from TCGA datasets were analysed using biostatistical methods to identify candidate miRs that correlate with factors such as survival and stage of disease. Candidate miRs were analysed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in a cohort of 198 RCC tumours (ccRCC, n=152) and 50 normal kidney samples. RESULTS: Four candidate miRs (miR-10b, miR-21, miR-101 and miR-223) were selected from the TCGA analysis and analysed in our cohort. Of these, miR-21 and miR-10b were differentially expressed in RCC subtypes and in ccRCC nuclear grades. Individually, the two miRs demonstrated a non-significant trend to correlate with survival. Importantly, the ratio of miR-21/miR10b (miR(21/10b)) correlated significantly with disease severity and survival, a high miR(21/10b) being associated with poor prognosis (P=0.0095). In particular, the miR(21/10b) was found to be an independent prognostic factor in metastasis-free patients (P=0.016; confidence interval (CI) 1.201-5.736). CONCLUSIONS: We have shown that the miR(21/10b) ratio is an independent prognostic factor for M0 ccRCC patients, which could be useful to identify high-risk M0 patients who could benefit from increased surveillance. PMID- 24794000 TI - Loss of anterior gradient-2 expression is an independent prognostic factor in colorectal carcinomas. AB - AIMS: The human Anterior Gradient-2 (AGR2) protein is strongly expressed in various human cancers, and it has been described to promote aggressive tumour features in some entities. So far, a comprehensive analysis of AGR2 expression in colorectal carcinomas has not been described. METHODS: Normal intestinal cells and colorectal carcinoma cell lines were analysed for AGR2 expression. AGR2 protein expression was immunohistochemically analysed in 28 normal tissue samples and 1068 tissue samples of clinically well characterised colorectal carcinomas. For statistical analysis, chi square test, spearman rank correlations, Kaplan Meier estimates (Log rank test) and Cox regression were applied to test for diagnostic or prognostic associations. RESULTS: In the normal intestinal cell line and in normal colon mucosa AGR2 was found in all cases (n=28). In contrast, loss of AGR2 was found in all six analysed colorectal cancer cell lines and in 833/1068 (78%) of the colorectal carcinoma tissue samples analysed, and it was significantly associated with a higher tumour grade and tumour localisation in the left-sided colon. In addition to the conventional prognostic tumour parameters pT category, nodal status, metastasis and histological tumour grade the loss of AGR2 expression was significantly associated with reduced overall survival times in univariate and multivariate analyses, thus suggesting AGR2 as an independent prognostic factor in primary colorectal carcinoma. CONCLUSIONS: AGR2 is frequently lost in colorectal carcinomas and might be a novel independent prognostic factor for overall patient survival. PMID- 24794001 TI - Ever developing TGF-beta. PMID- 24794002 TI - Editorial. DNA replication. PMID- 24794003 TI - Role of DNA replication in establishment and propagation of epigenetic states of chromatin. AB - DNA replication is the fundamental process of duplication of the genetic information that is vital for survival of all living cells. The basic mechanistic steps of replication initiation, elongation and termination are conserved among bacteria, lower eukaryotes, like yeast and metazoans. However, the details of the mechanisms are different. Furthermore, there is a close coordination between chromatin assembly pathways and various components of replication machinery whereby DNA replication is coupled to "chromatin replication" during cell cycle. Thereby, various epigenetic modifications associated with different states of gene expression in differentiated cells and the related chromatin structures are faithfully propagated during the cell division through tight coupling with the DNA replication machinery. Several examples are found in lower eukaryotes like budding yeast and fission yeast with close parallels in metazoans. PMID- 24794004 TI - Endpoint matrix: a conceptual tool to promote consideration of the multiple dimensions of humane endpoints. AB - This paper proposes a framework to support appropriate application of endpoints in animal experiments. It is recommended that unpredicted endpoints should be explicitly considered alongside scientific endpoints and justifiable endpoints as the three types of endpoint which comprise the "humane." We suggest there is a need for clear identification of each type of endpoint and an understanding of the interactions between these types. The use of an "endpoint matrix" during study planning is proposed to promote methodically sound and consistent definition, determination, and detection of unpredicted, scientific, and justifiable endpoints in animal experiments. It is claimed that the further development and use of this tool will support a more effective and harmonized practical application of humane endpoints for all animal use in line with best practice recommendations. PMID- 24794005 TI - German animal welfare act in breach with Directive 2010/63/EU. AB - The German Federal Administrative Court recently announced an order (finalized on January 20, 2014) on the neurobiological experiments on primate brains of Prof. Kreiter at the University of Bremen. With this order, a preceding court decision by the Higher Administrative Court of Bremen was established as final and absolute and the last glimmer of hope to end the suffering of the primates in Bremen was extinguished. The court decision had claimed the experiments to be ethically justified. The Federal Administrative Court upheld the court decision and issued the order on the grounds that due to the phrasing of both the former and the current German Animal Welfare Act, authorities had no entitlement to assess the ethical justification of an experiment, but were obliged to approve an application if all formalities were complied with. The impact the order will have on the authorization of animal experiments and testing in Germany caused an outrage in the animal welfare community. PMID- 24794006 TI - International STakeholder NETwork (ISTNET) for creating a developmental neurotoxicity testing (DNT) roadmap for regulatory purposes. PMID- 24794007 TI - Alternatives initiative in Sri Lanka: pre- and post-conference workshops at the Inaugural Scientific Conference of the Sri Lanka Association for Laboratory Animal Science. PMID- 24794008 TI - O-Linked glycosylation in Acanthamoeba polyphaga mimivirus. AB - Acanthamoeba polyphaga mimivirus is a member of the giant nucleocytoplasmic large DNA viruses, infecting various Acanthamoeba spp. The genomes of giant viruses encode components previously thought to be exclusive to cellular life, such as proteins involved in nucleic acid and protein synthesis. Recent work on enzymes involved in carbohydrate biosynthesis and metabolism show that instead of utilizing host cell resources, Mimivirus produces its own glycosylation machinery. To obtain a more detailed view of glycosylation in Mimivirus, we developed a periodate oxidation-based method to selectively enrich Mimivirus surface glycoproteins. O-Glycosylation in Mimivirus glycoproteins was identified by permethylation and matrix-assisted laser desorption/ionization-mass spectrometry analyses of beta-eliminated glycans. We sequenced 26 previously undescribed O-glycans, most of which contain glucose as their reducing end saccharide. These data will facilitate future studies on the functional significance of glycosylation in Mimivirus. PMID- 24794010 TI - Clinical applications of pathogen phylogenies. AB - Innovative sequencing techniques now allow the routine access of whole genomes of pathogens, generating vast amounts of data. Phylogenetic trees are a common method for synthesizing this information. Unfortunately, these trees are often seen only as a visual support to guide researchers, thus neglecting the value of employing phylogenetic techniques to perform hypothesis testing on clinical questions. These include investigating how a pathogen spreads within a patient, or whether the infection severity (often measured by virus load) is controlled by viral genetics. Advances in methodology mean the time is ripe for combining phylogenies with clinical data to better understand and fight infectious diseases. PMID- 24794011 TI - Predicting infant neurodevelopmental outcomes using the placenta? AB - Identifying those infants most at risk for poor neurodevelopmental outcomes is crucial to allow for targeted surveillance or preventative interventions to be instigated from birth. One intriguing possibility is to use the molecular characteristics of the placenta at birth as a 'molecular barometer' of the in utero experience to predict future infant neurodevelopmental outcomes. Here we highlight the recent advances in the field and discuss the possibilities for an integrated approach across the '-omics' categories. PMID- 24794009 TI - Endothelial and leukocyte heparan sulfates regulate the development of allergen induced airway remodeling in a mouse model. AB - Heparan sulfate (HS) proteoglycans (HSPGs) participate in several aspects of inflammation because of their ability to bind to growth factors, chemokines, interleukins and extracellular matrix proteins as well as promote inflammatory cell trafficking and migration. We investigated whether HSPGs play a role in the development of airway remodeling during chronic allergic asthma using mice deficient in endothelial- and leukocyte-expressed N-deacetylase/N sulfotransferase-1 (Ndst1), an enzyme involved in modification reactions during HS biosynthesis. Ndst1-deficient and wild-type (WT) mice exposed to repetitive allergen (ovalbumin [OVA]) challenge were evaluated for the development of airway remodeling. Chronic OVA-challenged WT mice exhibited increased HS expression in the lungs along with airway eosinophilia, mucus hypersecretion, peribronchial fibrosis, increased airway epithelial thickness and smooth muscle mass. In OVA challenged Ndst1-deficient mice, lung eosinophil and macrophage infiltration as well as airway mucus accumulation, peribronchial fibrosis and airway epithelial thickness were significantly lower than in allergen-challenged WT mice along with a trend toward decreased airway smooth muscle mass. Leukocyte and endothelial Ndst 1 deficiency also resulted in significantly decreased expression of IL-13 as well as remodeling-associated mediators such as VEGF, FGF-2 and TGF-beta1 in the lung tissue. At a cellular level, exposure to eotaxin-1 failed to induce TGF beta1 expression by Ndst1-deficient eosinophils relative to WT eosinophils. These studies suggest that leukocyte and endothelial Ndst1-modified HS contribute to the development of allergen-induced airway remodeling by promoting recruitment of inflammatory cells as well as regulating expression of pro-remodeling factors such as IL-13, VEGF, TGF-beta1 and FGF-2 in the lung. PMID- 24794012 TI - Extracting a medicine or extracting knowledge. PMID- 24794013 TI - Arnebin-1 promotes the angiogenesis of human umbilical vein endothelial cells and accelerates the wound healing process in diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zicao is a traditional wound healing herbal medicine that has been used for several hundred years in China. A survey of the published literatures revealed that arnebin-1, one of the naphthoquinone derivatives, played the most important role in wound healing property of this plant. However, whether arnebin-1 affects angiogenesis in vitro and has an effect on wound healing process in diabetic rats remains enigmatic. To investigate the effect of arnebin-1 with or without VEGF on proliferation, migration and tube formation of HUVECs in vitro and the effect of its topical application in the form of ointment on wound healing in a cutaneous punch wound model of alloxan induced diabetic rats in vivo. MATERIALS AND METHODS: The pro-angiogenic functions of arnebin-1 on HUVECs including proliferation, migration and angiogenesis were evaluated through MTT assay, wound healing assay, transwell assay and tube formation assay in vitro. Male Sprague-Dawley rats were injected intraperitoneally with alloxan to induce type I diabetic rats. Three wounds were created in each rat on the dorsal surface, and then divided to be basement treated, arnebin-1 ointment treated and untreated group correspondingly. The indicators including wound closure rate and histological evaluation were investigated on day 4 and 7 post-wounding. RESULTS: Without VEGF, arnebin-1 did not affect the proliferation of HUVECs significantly, but had a positive effect on cell migration and tube formation. However, in the presence of minimal VEGF, Arnebin-1 could increase the proliferation, enhance the migration and promote the tube formation of HUVECs significantly. The wound closure rate was increased significantly in arnebin-1 treated group compared to that of untreated and basement treated groups in diabetic rats, and the histological evaluation also showed well organized dermal layer, reduced number of macrophages, increased number of fibroblasts, remarkable degree of neovascularization and epithelization in arnebin-1 treated group. CONCLUSION: These findings suggest that arnebin-1 has a pro-angiogenic effect, and a synergetic effect with VEGF promotes the wound healing process in diabetic rats. PMID- 24794014 TI - Ferulic acid enhances the vasorelaxant effect of epigallocatechin gallate in tumor necrosis factor-alpha-induced inflammatory rat aorta. AB - Previously, we demonstrated synergistic enhancement of vasorelaxation by combination treatment with Trp-His and epigallocatechin gallate (EGCg) in intact rat aorta. The aim of the present study was to determine whether this vasorelaxant synergy could be recapitulated in tumor necrosis factor-alpha (TNF alpha)-induced inflammatory rat aorta, and to determine the extent of its modulation by anti-inflammatory phenolic acids. Synergistic enhancement of vasorelaxation in rat aorta by Trp-His and EGCg was significantly attenuated in the presence of TNF-alpha, an effect that was reversed by the addition of ferulic acid (FA, 250 MUM). Moreover, FA markedly enhanced EGCg-induced vasorelaxation, but not Trp-His-induced vasorelaxation, in TNF-alpha-treated aorta. Structure activity analysis showed that the unsaturated 2-propenoic moiety and the methoxy group of FA were important for the enhancement of vasorelaxation by EGCg. The stimulation of EGCg-induced vasorelaxation by FA was antagonized by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine acetate, while FA enhanced vasorelaxant properties of the endothelial nitric oxide (NO) synthase activator acetylcholine in TNF-alpha-treated inflammatory aorta. Moreover, the EGCg stimulated NO production was also enhanced by FA in TNF-alpha-treated aorta. These data indicate that stimulation of NO production by FA enhances the vasorelaxant properties of EGCg in TNF-alpha-induced inflammatory aorta. PMID- 24794015 TI - Temporal proteomic analysis reveals defects in small-intestinal development of porcine fetuses with intrauterine growth restriction. AB - The fetus/neonate with intrauterine growth restriction (IUGR) has a high perinatal mortality and morbidity rate, as well as reduced efficiency for nutrients utilization. Our previous studies showed alterations of intestinal proteome in IUGR piglets both at birth and during the nursing period. Considering the potential long-term impacts of fetal programming and substantial increases in amounts of amniotic fluid nutrients from mid-gestation in pigs, the present study involved IUGR porcine fetuses from days 60 to 110 of gestation (mid to late gestation). We identified 59 differentially expressed proteins in the fetal small intestine that are related to intestinal growth, development and reprogramming. Our results further indicated increased abundances of proteins and enzymes associated with oxidative stress, apoptosis and protein degradation, as well as decreased abundances of proteins that are required for maintenance of cell structure and motility, absorption and transport of nutrients, energy metabolism, and protein synthesis in the fetal gut. Moreover, IUGR from middle to late gestation was associated with reduced expression of intestinal proteins that participate in regulation of gene expression and signal transduction. Collectively, these findings provide the first evidence for altered proteomes in the small intestine of IUGR fetuses, thereby predisposing the gut to metabolic defects during gestation and neonatal periods. PMID- 24794016 TI - Conjugated linoleic acid suppresses dendritic cell activation and subsequent Th17 responses. AB - PUFAs (polyunsaturated fatty acids) can modify immune responses, so they may have potential therapeutic effects in inflammatory disorders. We previously demonstrated that the cis-9, trans-11 isomer of the PUFA conjugated linoleic acid (CLA) can modulate dendritic cell (DC) cytokine production. Since DCs play a central role in initiating inflammation by directing T helper (Th) cell differentiation, here we examined the effects of CLA on DC maturation and migration and the subsequent generation of Th cell responses. We examined the effect of CLA in vitro on the function of lipopolysaccharide (LPS)-activated bone marrow-derived DCs and ex vivo using cells from mice with high levels of CLA in their diet. We report that CLA inhibits DC migration and modulates TLR-induced production of key cytokines involved in Th cell differentiation both in vitro and in vivo. These changes were accompanied by a significant decrease in expression of MHCII, CD80 and CD86 on the DC surface. Exposure of DCs to CLA suppressed their ability to promote differentiation of naive T cells into Th1 and/or Th17 cells in vitro and following their adoptive transfer in vivo. Furthermore, in a murine model of endotoxic shock, treatment with CLA suppressed LPS-induced induction of circulating IFN-gamma, IL-12p40 and IL-1beta. This is the first study to demonstrate that exposure of antigen-presenting cells to CLA can modulate the subsequent Th cell response, and the findings may explain some of the beneficial effects of c9, t11-CLA in inflammatory diseases mediated by Th1 and Th17 cells. PMID- 24794017 TI - Effects of ammonium on the activity and community of methanotrophs in landfill biocover soils. AB - The influence of NH4(+) on microbial CH4 oxidation is still poorly understood in landfill cover soils. In this study, effects of NH4(+) addition on the activity and community structure of methanotrophs were investigated in waste biocover soil (WBS) treated by a series of NH4(+)-N contents (0, 100, 300, 600 and 1200mgkg( 1)). The results showed that the addition of NH4(+)-N ranging from 100 to 300mgkg(-1) could stimulate CH4 oxidation in the WBS samples at the first stage of activity, while the addition of an NH4(+)-N content of 600mgkg(-1) had an inhibitory effect on CH4 oxidation in the first 4 days. The decrease of CH4 oxidation rate observed in the last stage of activity could be caused by nitrogen limitation and/or exopolymeric substance accumulation. Type I methanotrophs Methylocaldum and Methylobacter, and type II methanotrophs (Methylocystis and Methylosinus) were abundant in the WBS samples. Of these, Methylocaldum was the main methanotroph in the original WBS. With incubation, a higher abundance of Methylobacter was observed in the treatments with NH4(+)-N contents greater than 300mgkg(-1), which suggested that NH4(+)-N addition might lead to the dominance of Methylobacter in the WBS samples. Compared to type I methanotrophs, the abundance of type II methanotrophs Methylocystis and/or Methylosinus was lower in the original WBS sample. An increase in the abundance of Methylocystis and/or Methylosinus occurred in the last stage of activity, and was likely due to a nitrogen limitation condition. Redundancy analysis showed that NH4(+)-N and the C/N ratio had a significant influence on the methanotrophic community in the WBS sample. PMID- 24794018 TI - Rural emergency medical technician pre-hospital electrocardiogram transmission. AB - INTRODUCTION: Emergent care of the acute heart attack patient continues to be at the forefront of quality and cost reduction strategies throughout the healthcare industry. Although the average cardiac door-to-balloon (D2B) times have decreased substantially over the past few years, there are still vast disparities found in D2B times in populations that reside in rural areas. Such disparities are mostly related to prolonged travel time and subsequent delays in cardiac catherization lab team activation. Urban ambulance companies that are routinely staffed with paramedic level providers have been successful in the implementation of pre hospital 12-lead electrocardiogram (ECG) protocols as a strategy to reduce D2B times. METHOD: The authors sought to evaluate the evidence related to the risk and benefits associated with the replication of an ECG transmission protocol in a small rural emergency medical service. The latter is staffed with emergency medical technician-basics (EMT-B), emergency medical technician-advanced (EMT-A), and emergency medical technician-intermediate (EMT-I) level. RESULTS: The evidence reviewed was limited to studies with relevant data regarding the challenges and complexities of the ECG transmission process, the difficulties associated with ECG transmission in rural settings, and ECG transmission outcomes by provider level. CONCLUSIONS: The evidence supports additional research to further evaluate the feasibility of ECG transmission at the non-paramedic level. Multiple variables must be investigated including equipment cost, utilization, and rural transmission capabilities. Clearly, pre-hospital ECG transmission and early activation of the cardiac catheterization laboratory are critical components to successfully decreasing D2B times. PMID- 24794019 TI - Fast targeted analysis of 132 acidic and neutral drugs and poisons in whole blood using LC-MS/MS. AB - The aim of this study was to develop an LC-MS/MS based screening technique that covers a broad range of acidic and neutral drugs and poisons by combining a small sample volume and efficient extraction technique with simple automated data processing. After protein precipitation of 100MUL of whole blood, 132 common acidic and neutral drugs and poisons including non-steroidal anti-inflammatory drugs, barbiturates, anticonvulsants, antidiabetics, muscle relaxants, diuretics and superwarfarin rodenticides (47 quantitated, 85 reported as detected) were separated using a Shimadzu Prominence HPLC system with a C18 separation column (Kinetex XB-C18, 4.6mm*150mm, 5MUm), using gradient elution with a mobile phase of 25mM ammonium acetate buffer (pH 7.5)/acetonitrile. The drugs were detected using an ABSciex((r)) API 2000 LC-MS/MS system (ESI+ and -, MRM mode, two transitions per analyte). The method was fully validated in accordance with international guidelines. Quantification data obtained using one-point calibration compared favorably to that using multiple calibrants. The presented LC-MS/MS assay has proven to be applicable for determination of the analytes in blood. The fast and reliable extraction method combined with automated processing gives the opportunity for high throughput and fast turnaround times for forensic and clinical toxicology. PMID- 24794020 TI - Testing for ethanol markers in hair: discrepancies after simultaneous quantification of ethyl glucuronide and fatty acid ethyl esters. AB - The hair of 97 cases were analysed for ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEE, including ethyl myristate, ethyl palmitate, ethyl oleate and ethyl stearate) according to the Society of Hair Testing guidelines to examine the role of both tests in documenting chronic excessive alcohol drinking, particularly when the results are in contradiction. 27 (27.8%) results were EtG negative and FAEE positive, when applying the SoHT cut-offs, probably due to the use of alcohol-containing hair products. Four cases (4.1%) were EtG positive and FAEE negative that were attributed to the use of herbal lotions containing EtG. PMID- 24794021 TI - Evolving understanding of the epidemiology of HIV and prevention needs among men who have sex with men in Ulaanbaatar, Mongolia. AB - This study describes HIV and syphilis bio-behavioral survey conducted among 200 men who have sex with men (MSM) recruited via respondent-driven sampling (RDS) between January 4 and February 1, 2012 in Ulaanbaatar, Mongolia. Participants were administered a structured questionnaire and data were analyzed with RDS network program in STATA. Of 196 participants who agreed to be tested for HIV and syphilis, 21 (10.7 %; weighted 7.5; 95 % CI: 4.9, 11.4) and 8 (4.1 %; weighted 3.4; 95 % CI: 1.7, 6.7) were positive for HIV and syphilis, respectively. Exposure to HIV prevention programs in the last 12 months was reported by 51.8 % (weighted 33.6; 95 % CI: 27.6, 40.1) of participants. This study found high HIV prevalence and limited uptake of HIV prevention services among MSM in Mongolia. Given the concentrated HIV epidemic among MSM in Mongolia, HIV prevention, treatment and care services should focus on MSM as the population group most affected by HIV. PMID- 24794022 TI - Isolated non-hepatic metastasis from upper gastrointestinal adenocarcinoma: A case for surgical resection. AB - INTRODUCTION: Upper Gastrointestinal Tract (UGIT) malignancy is an increasing problem in western society and its prognosis is generally poor. The prognosis dims even further with the presence of loco regional recurrences or distant metastasis. This article looks at the feasibility and potential benefit from resection of non-hepatic, non-nodal metastases and recurrences. PRESENTATION OF CASE: Case 1. A 72-year-old male who underwent total gastrectomy for a gastric adenocarcinoma presented with a splenic mass 40 months later and underwent a splenectomy. He is disease free at 30 months post-metastectomy. Case 2. A 54-year old male with oesophagogastric junctional adenocarcinoma, underwent an Ivor-Lewis oesophagectomy. He developed a distal pancreatic mass at 24 months follow-up and underwent distal pancreatectomy and splenectomy. He is disease free at 12 months post-metastectomy. Case 3. A 75-year-old male underwent subtotal gastrectomy for lesser curvature adenocarcinoma. At 42 months follow-up, he developed solitary abdominal wall recurrence. This was locally resected with clear margins. After 12 months, he developed another full thickness abdominal wall recurrence with involvement of the hepatic flexure. Enbloc resection including right hemicolectomy was performed and he is disease free at 3 months. DISCUSSION: There is very scarce literature on resection of non-hepatic, non-nodal recurrences/distant metastasis in oesophagogastric cancers. Based on these cases, a surgical resection in selected cases may provide prolonged survival with good quality of life. CONCLUSION: Resection for isolated recurrences and metachronous metastasis from UGIT cancers may be worthwhile, especially if patients have minimal co-morbidities. PMID- 24794024 TI - Splenic cyst during pregnancy. AB - INTRODUCTION: Splenic cyst during pregnancy is rare and may result in spontaneous rupture during the third trimester, which increases perinatal morality. PRESENTATION OF CASE: We present a 27-year-old healthy Caucasian female who presented at 18 weeks gestation with left flank pain, early satiety and weight loss. Imaging studies demonstrated a large complex multiloculated splenic cyst. The patient underwent a successful laparoscopic splenectomy and delivered a healthy child at term without complication. DISCUSSION: Spontaneous rupture of a splenic cyst during the third trimester incurs a perinatal mortality rate as high as 70%. Surgical management includes open or laparoscopic splenectomy or fenestration and preservation of the spleen. CONCLUSION: Laparoscopic splenectomy during the second trimester appears to be safe and offers definitive management of a large symptomatic splenic cyst during pregnancy. PMID- 24794023 TI - Copper-deficiency anemia after esophagectomy: A pitfall of postoperative enteral nutrition through jejunostomy. AB - INTRODUCTION: Copper deficiency leads to functional disorders of hematopoiesis and neurological system. There have been some reports of copper deficiency occurring to the patients on enteral nutrition through a jejunostomy in long-term care hospitals. However, it is extremely rare to find patients with copper deficiency several months after esophagectomy, regardless of enteral nutrition through the jejunostomy. To the best of our knowledge, this is the first case report of a patient who experienced copper-deficiency anemia after esophagectomy and subsequent enteral nutrition through the jejunostomy. PRESENTATION OF CASE: A 73-year-old man presented with pulmonary failure after esophagectomy for esophageal cancer with video-assisted thoracoscopic surgery, and needed long-term artificial ventilator support. Nutritional management included enteral nutrition through a jejunostomy from the early postoperative period. Copper-deficiency anemia was detected 3 months postoperatively; therefore, copper supplementation with cocoa powder was performed, and both serum copper and hemoglobin levels subsequently recovered. DISCUSSION: Copper-deficiency anemia has already been reported to occur in patients receiving enteral nutrition in long-term care hospitals. However, this is the first case report of copper deficiency after esophagectomy despite administration of standard enteral nutrition through the jejunostomy for several months. CONCLUSION: It is extremely rare to find copper deficiency anemia several months after esophagectomy followed by enteral nutrition through the jejunostomy. However, if anemia of unknown origin occurs in such patients, copper-deficiency anemia must be considered among the differential diagnoses. PMID- 24794025 TI - Management of giant inferior triangle lumbar hernia (Petit's triangle hernia): A rare complication following delayed breast reconstruction with extended latissimus dorsi myocutaneous flap. AB - INTRODUCTION: Lumbar triangle hernia after breast reconstruction with latissimus dorsi flap (LDMF) is a very rare complication and few cases were previously described. Muscle mobilization and iatrogenic fascia defect are related etiologic factors. PRESENTATION OF CASE: The authors describe a rare case of lumbar hernia in a 58-year-old woman who underwent delayed left breast reconstruction with LDMF. Two months after surgery, a progressive symptomatic lower left lumbar bulge was observed. The CT scan confirmed the diagnosis and delineated an 18cm lumbar defect filled with lower and large bowel. At operation, the defect was exposed and the hernia sac reduced. In order to obtain stability, the remained local muscle and fascia flaps were mobilized into the defect. Additional strength was achieved with a two-layer closure of prosthetic mesh (intra/extra peritoneal). The patient is currently in the 10th postoperative year of hernia repair and satisfactory lumbar wall contour was achieved. Neither the recurrence of lumbar hernia nor symptoms compliance was noted. DISCUSSION: Lumbar hernia is an uncommon complication of LDMF harvest. Although it is a rare disease, general and plastic surgeons must be on alert to avoid complications and misdiagnosis. Seroma differential diagnosis is important in order to avoid bowel perforation due to aspiration. Defect reconstruction is necessary with a muscular and fascia flaps mobilization and synthetic mesh in order to obtain a stable repair. CONCLUSION: The knowledge of this rare post-operative complication following delayed breast reconstruction is crucial to its surgical management. Early surgical intervention is warranted in order to avoid severe complications. PMID- 24794026 TI - Imaging and histopathological evaluation of a cystlike formation in subchondral insufficiency fracture of the femoral head: A case report and literature review. AB - INTRODUCTION: In the majority of subchondral insufficiency fractures (SIFs) of the femoral head, T1-weighted magnetic resonance imaging shows an irregular, serpiginous, low-intensity band that is convex to the articular surface. We report a case of a cystlike formation in SIF of the femoral head in an elderly woman. PRESENTATION OF CASE: A 71-year-old woman reported right hip pain without any history of antecedent trauma. The initial radiograph showed a slight narrowing of the joint space in the right hip. The patient was treated with conservative therapy for 2 months. Radiographs obtained 3 months after the onset of pain showed non-progressive joint-space narrowing. T1-weighted magnetic resonance images obtained 2 months after pain onset revealed a round, cystlike, low-intensity area just beneath the articular cartilage. The patient underwent total hip arthroplasty. Histopathological examination showed fracture callus and granulation tissue in the subchondral area, surrounded by vascular-rich granulation tissue and fibrous tissue, which corresponded to the round, low intensity band observed on the T1-weighted image. DISCUSSION: This case was a rare SIF of the femoral head which had a cystlike formation with a low signal intensity on T1-weighted images and a very high signal intensity on STIR sequences in the superolateral portion of the femoral head, surrounded by a pattern of edema in the bone marrow. To our knowledge, no similar cases were cited in the literature. CONCLUSION: It is important for surgeons to keep in mind that sometimes SIFs of the femoral head can appear as a round cystlike formation. PMID- 24794028 TI - Association of race/ethnicity, socioeconomic status, and breast cancer subtypes in the National Cancer Data Base (2010-2011). AB - To estimate the odds of breast cancer subtypes in minority populations versus non Hispanic (NH) whites stratified by socioeconomic status (SES) [a composite of individual-level SES (insurance status) and area-level SES (median household income quartile from 2000 U.S. Census data)] using a large nationwide cancer database. We used the National Cancer Data Base to identify breast cancer cases diagnosed in 2010 and 2011, the only 2 years since U.S. cancer registries uniformly began collecting HER2 results. Breast cancer cases were classified into five subtypes based on hormone receptor (HR) and HER2 status: HR+/HER2-, HR+/HER2+, HR-/HER2+ (HER2-overexpressing), HR-/HER2- (TN), and unknown. A polytomous logistic regression was used to estimate odds ratios (ORs) comparing the odds of non-HR+/HER2-subtypes to HR+/HER2- for racial/ethnic groups controlling for and stratifying by SES, using a composite of insurance status and area-level income. Compared with NH whites, NH blacks and Hispanics were 84 % (OR = 1.84; 95 % CI 1.77-1.92) and 17 % (OR = 1.17; 95 % CI 1.11-1.24) more likely to have TN subtype versus HR+/HER2-, respectively. Asian/Pacific Islanders (API) had 1.45 times greater odds of being diagnosed with HER2-overexpressing subtype versus HR+/HER2- compared with NH whites (OR = 1.45; 95 % CI 1.31-1.61). We found similar ORs for race in high and low strata of SES. In a large nationwide hospital-based dataset, we found higher odds of having TN breast cancer in black women and of HER2-overexpressing in API compared with white women in every level of SES. PMID- 24794027 TI - Central papillary cystadenocarcinoma of the mandible: A case report and review of the literature. AB - INTRODUCTION: Central papillary cystadenocarcinoma of the jaw is an extremely rare tumor with only three previously reported cases in the English literature. This tumor is a histologically low-grade cancer, affecting more commonly in the mandible than in the maxilla. PRESENTATION OF CASE: A 65-year-old woman presented with a two months history of a rapidly growing, painless mass of the right ascending ramus of the mandible. The pathologic report from incisional biopsy was a papillary cystic tumor with a differential diagnosis of cystadenoma versus cystadenocarcinoma. Segmental mandibulectomy, parotidectomy and submandibular gland resection were performed. The final pathology was intraosseous papillary cystadenocarcinoma. DISCUSSION: Clinical features of central papillary cystadenocarcinoma of the mandible mimic an odontogenic lesion and metastatic bone disease, careful review of radiograph and pathology should be done. Surgical excision with wide margins is the appropriate treatment. Postoperative radiation therapy should be considered in histologically aggressive or high-stage tumor. CONCLUSION: This is the fourth case of central papillary cystadenocarcinoma of the mandible in the English literature. Although it is usually a low-grade cancer, en bloc resection with adjuvant postoperative radiotherapy in a high stage disease, and long-term follow-up allow the patient to have a favorable prognosis. PMID- 24794029 TI - A 2-year follow-up study of discharged psychiatric patients with bipolar disorder. AB - This study investigated medication compliance, disease recurrence and the recovery of social function in discharged psychiatric patients with bipolar disorder. A 2-year follow-up was conducted on all patients with bipolar disorder, who were hospitalized in our psychiatric department between June 2010 and May 2011. Risk factors for recurrence were analyzed based on a self-designed questionnaire. Of the 252 patients in the study, 210 had complete information (83.3%) for the 2-year follow-up: 170 cases of bipolar I disorder and 40 cases of bipolar II disorder. The 1-year and 2-year full-compliance rates were 41.0% and 35.7%, respectively. The 1-year and 2-year recurrence rates were 42.4% and 61.0%, respectively. Statistically significant differences in rates were found between the bipolar subtypes for 1-year full compliance, 1-year non-compliance, 2-year recurrence, and 2-year readmission. Logistic regression identified different sets of independent variables that were risk factors for recurrence, and protective factors for recurrence at 1 year and 2 years after hospital discharge. The results of the follow-up indicated that the situation of patients with bipolar disorder after discharge is not optimistic, because of high recurrence rates, high non-compliance rates and low recovery rates. Clinical and social experts should pay more attention to the situation. PMID- 24794031 TI - An updated meta-analysis of oxidative stress markers in bipolar disorder. AB - Despite its debilitating symptoms, the pathophysiology of bipolar disorder (BD) remains unclear. One consistently compelling finding, however, has been the presence of oxidative stress. In the present investigation, we conducted a meta analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls. Search terms and selection criteria were determined a priori to identify and include all studies that measured a marker of oxidative stress in BD compared to healthy controls. Eight markers were included: superoxide dismutase, catalase, protein carbonyl, glutathione peroxidase, 3 nitrotyrosine, lipid peroxidation, nitric oxide, and DNA/RNA damage. A meta analysis of standardized means was conducted using a random-effects model with generic inverse weighting. Between-study heterogeneity, publication bias, and sensitivity analyses were also examined for each marker. Twenty-seven papers were included in the meta-analysis, which comprised a total of 971 unique patients with BD and 886 healthy controls. Lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in BD patients compared to healthy controls. Additionally, the effect size for lipid peroxidation was very high. Publication bias was not detected for any of the markers. The main limitations in this meta analysis are the high degree of heterogeneity between studies and the small number of studies used in the analysis of some markers. Additionally, the sensitivity analysis indicated that some results are not very robust. The results from this meta-analysis support the role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids. PMID- 24794032 TI - Thermal treatment of solid waste in view of recycling: Chromate and molybdate formation and leaching behaviour. AB - Elevated Cr and Mo concentrations are often found in leachates of thermally treated solid waste, but there is no general explanation for this so far. Therefore, we studied the leaching behaviour after thermal treatment as a function of heating temperature and residence time for two types of solid waste: contaminated sludge and bottom ash from municipal solid waste incineration. The leaching behaviour of both waste streams was compared with experiments on synthetic samples, allowing deduction of a general mechanism for Cr and Mo leaching. Cr and Mo showed a similar leaching behaviour: after an initial increase, the leaching decreased again at higher temperatures. Oxidation of these elements from their lower oxidation states to chromate and molybdate at temperatures up to 600 degrees C was responsible for the increased leaching. At higher temperatures, both Mo and Cr leaching decreased again owing to the formation of an amorphous phase, incorporating the newly formed chromate and molybdate salts, which prevents them from leaching. PMID- 24794030 TI - The concomitant use of second-generation antipsychotics and long-term antiretroviral therapy may be associated with increased cardiovascular risk. AB - To study the effect of concurrent use of second-generation antipsychotics (SGAs) on metabolic syndrome (MetS) components conferring increased cardiovascular risk in a sample of human immunodeficiency virus (HIV)-infected adults taking antiretroviral therapy (ART). A retrospective study of participants consecutively recruited at the UCSD HIV Neurobehavioral Research Program examined effects of combined ART and SGAs on body mass index (BMI), nonfasting serum lipids, diabetes mellitus (DM) incidence, and mean arterial pressure (MAP). Metabolic outcome variables and covariates were compared using t-tests, Chi-squared or Fisher's exact tests. Linear and logistic multivariable models explored metabolic outcomes for participants taking (SGA+) or not taking (SGA-) concomitant SGAs, after controlling for demographic and HIV disease- and ART-related covariates. Of 2229 HIV-infected participants, 12% (N=258) were treated with SGAs. In multivariable models adjusted for relevant covariates, the SGA+ group had significantly higher mean triglycerides, significantly higher odds of DM, significantly higher MAPs and marginally higher BMI. The use of SGAs in HIV-infected adults taking ART was independently associated with worse indicators of MetS and cardiovascular risk. Aggressive monitoring for the metabolic complications from concurrent SGA and ART is indicated in all patients receiving these medication combinations. PMID- 24794033 TI - Structural and functional characterization of 4-hydroxyphenylpyruvate dioxygenase from the thermoacidophilic archaeon Picrophilus torridus. AB - 4-Hydroxyphenylpyruvate dioxygenase (Hpd, EC 1.13.11.27) catalyzes the conversion of 4-hydroxyphenylpyruvate into homogentisate in the second step of oxidative tyrosine catabolism. This pathway is known from bacteria and eukaryotes, but so far no archaeal Hpd has been described. Here, we report the biochemical characterization of an Hpd from the extremophilic archaeon Picrophilus torridus (Pt_Hpd), together with its three-dimensional structure at a resolution of 2.6 A. Two pH optima were observed at 50 degrees C: pH 4.0 (close to native conditions) and pH 7.0. The enzyme showed only moderate thermostability and was inactivated with a half-life of ~1.5 h even under optimal reaction conditions. At the ideal physiological growth conditions of P. torridus, Pt_Hpd was inactive after 1 h, showing that the enzyme is protected in vivo from denaturation and/or is only partially adapted to the harsh environmental conditions in the cytosol of P. torridus. The influence of different additives on the activity was investigated. Pt_Hpd exhibited a turnover number k(cat) of 9.9 +/- 0.6 s(-1) and a substrate binding affinity K(m) of 142 +/- 23 uM. In addition, substrate inhibition with a binding affinity K(i) of 1.9 +/- 0.3 mM was observed. Pt_Hpd is compared with isoenzymes from other species and the putative bacterial origin of the gene is discussed. PMID- 24794035 TI - From FUS to Pandora syndrome: where are we, how did we get here, and where to now? AB - NEW CONCEPTS: Ideas about the causes of lower urinary tract signs (LUTS) in cats have changed significantly in the past 40 years. Recent research is challenging the conventional view that the bladder is always the perpetrator of LUTS, and suggests that the bladder can also be one victim of a systemic process associated with a sensitized central stress response system. AIM: In this article the authors provide their perspective on the implications of these findings for the diagnosis and treatment of cats with LUTS, provide some historical context, and suggest ways that the veterinary profession might work together to better understand the disorders underlying these signs, and possibly reduce their prevalence. PMID- 24794034 TI - Characterization of family D DNA polymerase from Thermococcus sp. 9 degrees N. AB - Accurate DNA replication is essential for maintenance of every genome. All archaeal genomes except Crenarchaea, encode for a member of Family B (polB) and Family D (polD) DNA polymerases. Gene deletion studies in Thermococcus kodakaraensis and Methanococcus maripaludis show that polD is the only essential DNA polymerase in these organisms. Thus, polD may be the primary replicative DNA polymerase for both leading and lagging strand synthesis. To understand this unique archaeal enzyme, we report the biochemical characterization of a heterodimeric polD from Thermococcus. PolD contains both DNA polymerase and proofreading 3'-5' exonuclease activities to ensure efficient and accurate genome duplication. The polD incorporation fidelity was determined for the first time. Despite containing 3'-5' exonuclease proofreading activity, polD has a relatively high error rate (95 * 10(-5)) compared to polB (19 * 10(-5)) and at least 10-fold higher than the polB DNA polymerases from yeast (polepsilon and poldelta) or Escherichia coli DNA polIII holoenzyme. The implications of polD fidelity and biochemical properties in leading and lagging strand synthesis are discussed. PMID- 24794036 TI - Pancreatitis in cats: is it acute, is it chronic, is it significant? AB - PRACTICAL RELEVANCE: Pancreatitis is a frequent finding in cats, the chronic form being more common than the acute form. Despite the large number of diseases or conditions that may be associated with feline pancreatitis, in most cases no cause is diagnosed and the pancreatitis is said to be idiopathic. The chronic form can be mild and asymptomatic, and has a high prevalence in apparently healthy cats. This has generated debate concerning the clinical significance of chronic feline pancreatitis. However, several reports have demonstrated the severity of clinical signs in certain forms of acute feline pancreatitis, while other studies have reported a strong association between chronic pancreatitis and the development of comorbidities such as hepatic lipidosis, diabetes mellitus, inflammatory bowel disease or exocrine pancreatic insufficiency. This suggests that feline pancreatitis should not be overlooked. CLINICAL CHALLENGES: Diagnosis of feline pancreatitis is complicated by the non-specific clinical signs and poor diagnostic value of basic biochemistry and haematology or imaging techniques. Development of a feline-specific pancreatic lipase immunoassay has improved our diagnostic ability in the past decade, but may have more limited application for mild and chronic forms of pancreatitis. Moreover, histopathology (the 'gold standard' diagnostic test) can be associated with false-negative results due to multifocal distribution of lesions or mild forms of the disease. With respect to treatment, it is important to take into account the idiosyncrasies of the feline species when considering medical therapies. EVIDENCE BASE: This article reviews the literature on feline pancreatitis, focusing on the different forms and their relative clinical significance, while explaining difficulties inherent in the diagnosis of this disease. An overview of current recommendations for the management of cats with pancreatitis is also provided. PMID- 24794037 TI - Feline dermatophytosis: steps for investigation of a suspected shelter outbreak. AB - PRACTICAL RELEVANCE: Dermatophytosis (ringworm) is the most important infectious and contagious skin disease of cats in shelters. Its importance relates to the fact that it can affect all cats, but tends to affect those which would otherwise have good chances for adoption. Although many diseases in shelters fit this description, dermatophytosis is of particular significance because of associated public health concerns. CLINICAL CHALLENGES: Disease management in animal shelters is challenging because new animals are frequently entering the population, numerous animals are often housed together, and resources are almost always limited. GLOBAL RELEVANCE: Outbreaks of dermatophytosis occur worldwide and no animal shelter is completely shielded from possible introduction of the disease into the population. AUDIENCE: This article offers a flexible stepwise approach to dealing with a known or suspected outbreak of dermatophytosis in an animal shelter. It is based on the authors' experiences spanning more than a decade of responses and/or consultations. While primarily aimed at veterinarians involved in shelter medicine, the principles largely apply to other group-housing situations, such as catteries and breeding establishments. AIMS: The goals in dealing with a potential dermatophytosis outbreak are to ascertain if the 'outbreak' is actually an outbreak, to develop a shelter-specific outbreak management plan and to implement a long-term plan to prevent recurrences. PMID- 24794038 TI - Feline dermatophytosis: aspects pertinent to disease management in single and multiple cat situations. AB - PRACTICAL RELEVANCE: Dermatophytosis (ringworm) is a superficial fungal skin disease of cats that, depending on the geographic region and practice caseload, may be encountered uncommonly through to commonly. This is a self-curing disease in an immunocompetent cat. GLOBAL IMPORTANCE: Dermatophytosis is prevalent worldwide and is one of a number of zoonotic skin diseases that cat owners are at risk of contracting. CLINICAL CHALLENGES: Dermatophytosis causes non-specific signs of hair loss, erythema and scaling, making it a differential diagnosis for many skin diseases of cats. The fact that this disease is infectious and contagious, and does not have any one classic clinical presentation, makes knowledge of diagnostic tools important in detection. The veterinarian's role is in early disease recognition and institution of appropriate therapy to hasten resolution of the disease. AIM: The focus of this article is to provide an update and review of the most pertinent aspects that may be helpful in the management of dermatophytosis in any single or multiple cat situation. EVIDENCE BASE: Where appropriate, evidence from the literature is used to supplement a summary of the author's clinical experience and research in feline dermatophytosis. PMID- 24794039 TI - Polyostotic hyperostosis in a domestic shorthair cat. AB - CLINICAL PRESENTATION: An 11-year-old male neutered domestic shorthair cat was presented for investigation of weight loss and inappetence. On physical examination there was palpable enlargement and thickening of many bones, and this finding was confirmed radiographically. PROPOSED DIAGNOSIS: Based on clinical, radiological and histopathological findings, a polyostotic bone disease, best described as generalised idiopathic hyperostosis, was diagnosed. This condition has not been reported in cats previously. Canine and human diseases with similarities to this presentation are discussed. PMID- 24794040 TI - In conversation: Tony Buffington. PMID- 24794041 TI - Population data of 16 autosomal STR loci of the Powerplex ESX 17 System in a Brazilian Population from the State of Sao Paulo. AB - The State of Sao Paulo is the most populous state in Brazil, including approximately one fifth of the population of the country. In addition to a strong economy, the state has relatively good social indicators when compared with the rest of the country. The capital city, also called Sao Paulo, is the sixth largest city in the world. Its population is considered the most multicultural and racially mixed in Brazil. Currently, the largest populations in Sao Paulo are of Italian, Lebanese, Spanish and Japanese origin, and the state has the largest number of Northeasterners outside of the Northeast region. This population structure may lead to a particular genotype frequency. In this context, the formation of a new database containing the allele frequencies of five new genetic markers (D2S441, D10S1248, D22S1045, D1S1656 and D12S391) in a sample population is relevant. The allele frequencies of 16 STR loci, including the five new European Standard Set (ESS) loci, were calculated in a sample of 1088-1098 unrelated individuals, who geographically represent the Capital city. PMID- 24794042 TI - Tubercular vertebral osteomyelitis. PMID- 24794043 TI - Adsorption of uranium composites onto saltrock oxides - experimental and theoretical study. AB - The study encompassed experimental mass spectrometric and theoretical quantum chemical studies on adsorption of uranium species in different oxidation states of the metal ion, and oxides of UxOy(n+) type, where x = 1 or 3, y = 2 or 8, and n = 0, 1 or 2 onto nanosize-particles of saltrock oxides MO (M = Mg(II), Ca(II), Ni(II), Co(II), Sr(II) or Ba(II)), M2Oy (M = Au(III) or Ag(I), y = 3 or 1) silicates 3Al2O3.2SiO2, natural kaolinite (Al2O2.2SiO2.2H2O), illite (K0.78Ca0.02Na0.02(Mg0.34Al1.69Fe(III)0.02)[Si3.35Al0.65]O10(OH)2.nH2O), CaSiO3, 3MgO.4SiO2,H2O, and M(1)M(2)(SiO4)X2 (M(1) = M(2) = Al or M(1) = K, M(2) = Al, X = F or Cl), respectively. The UV-MALDI-Orbitrap mass spectrometry was utilized in solid-state and semi-liquid colloidal state, involving the laser ablation at lambdaex = 337.2 nm. The theoretical modeling and experimental design was based on chemical-, physico-chemical, physical and biological processes involving uranium species under environmental conditions. Therefore, the results reported are crucial for quality control and monitoring programs for assessment of radionuclide migration. They impact significantly the methodology for evaluation of human health risk from radioactive contamination. The study has importance for understanding the coordination and red-ox chemistry of uranium compounds as well. Due to the double nature of uranium between rare element and superconductivity like materials as well as variety of oxidation states ? (+1)-(+6), the there remain challenging areas for theoretical and experimental research, which are of significant importance for management of nuclear fuel cycles and waste storage. PMID- 24794044 TI - Myocardial depression in sepsis: from pathogenesis to clinical manifestations and treatment. AB - The cardiovascular system plays a key role in sepsis, and septic myocardial depression is a common finding associated with increased morbidity and mortality. Myocardial depression during sepsis is not clearly defined, but it can perhaps be best described as a global (systolic and diastolic) dysfunction of both the left and right sides of the heart. The pathogenesis of septic myocardial depression involves a complex mix of systemic (hemodynamic) factors and genetic, molecular, metabolic, and structural alterations. Pulmonary artery catheterization and modern echo-Doppler techniques are important diagnostic tools in this setting. There are no specific therapies for septic myocardial depression, and the cornerstone of management is control of the underlying infectious process (adequate antibiotic therapy, removal of the source) and hemodynamic stabilization (fluids, vasopressor and inotropic agents). In this review, we will summarize the pathogenesis, diagnosis, and treatment of myocardial depression in sepsis. Additional studies are needed in order to improve diagnosis and identify therapeutic targets in septic myocardial dysfunction. PMID- 24794045 TI - Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy. AB - It has recently been demonstrated that the apelin receptor (APJ) plays a significant role in mediating the stretch response within the heart in a G protein-independent and beta-arrestin-dependent fashion. This discovery adds to the consolidated literature describing the potential benefits of APJ agonists. In this review, the authors will examine the functional selectivity of APJ and stretch with respect to their ability to signal via both G-protein-dependent and G-protein-independent mechanisms, with a focus on the multifunctional protein, beta-arrestin. The possibility of selecting or designing novel ligands that differentially activate only a subset of functions via a single receptor holds great promise for the treatment of diseases such as heart failure and hypertension. Finally, hypothetical approaches to target APJ, taking into account its downstream pathways, will be described. PMID- 24794047 TI - Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides). AB - Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20MUg/kg of cadmium chloride (mean exposure level - 2.6MUg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly increased in the liver including genes encoding for the rate limiting steroidogenic acute regulatory protein and the catalytic enzyme 7-dehydrocholesterol reductase. Integration of the transcriptomic data using functional enrichment analyses revealed a number of enriched gene networks associated with previously reported adverse outcomes of cadmium exposure such as liver toxicity and impaired reproduction. PMID- 24794046 TI - Optimization of single-cell electroporation protocol for forced gene expression in primary neuronal cultures. AB - The development and function of the central nervous system (CNS) are realized through interactions between many neurons. To investigate cellular and molecular mechanisms of the development and function of the CNS, it is thus crucial to be able to manipulate the gene expression of single neurons in a complex cell population. We recently developed a technique for gene silencing by introducing small interfering RNA into single neurons in primary CNS cultures using single cell electroporation. However, we had not succeeded in forced gene expression by introducing expression plasmids using single-cell electroporation. In the present study, we optimized the experimental conditions to enable the forced expression of green fluorescent protein (GFP) in cultured cerebellar Purkinje neurons using single-cell electroporation. We succeeded in strong GFP expression in Purkinje neurons by increasing the inside diameter of micropipettes or by making the size of the original plasmid smaller by digestion and cyclizing it by ligation. Strong GFP expression in Purkinje neurons electroporated under the optimal conditions continued to be observed for more than 25 days after electroporation. Thus, this technique could be used for forced gene expression in single neurons to investigate cellular and molecular mechanisms of the development, function, and disease of the CNS. PMID- 24794049 TI - Prenatal maternal factors in the development of cognitive impairments in the offspring. AB - Different environmental factors acting during sensitive prenatal periods can have a negative impact on neurodevelopment and predispose the individual to the development of various psychiatric conditions that often share cognitive impairments as a common component. As cognitive symptoms remain one of the most challenging and resistant aspects of mental illness to be treated pharmacologically, it is important to investigate the mechanisms underlying such cognitive deficits, with particular focus on the impact of early life adverse events that predispose the individual to mental disorders. Multiple clinical studies have, in fact, repeatedly confirmed that prenatal maternal factors, such as infection, stress or malnutrition, are pivotal in shaping behavioral and cognitive functions of the offspring, and in the past decade many preclinical studies have investigated this hypothesis. The purpose of this review is to describe recent preclinical studies aimed at dissecting the relative impact of various prenatal maternal factors on the development of cognitive impairments in offspring, focusing on animal models of prenatal stress and prenatal infection. These recent studies point to the pivotal role of prenatal stressful experiences in shaping memory and learning functions associated with specific brain structures, such as the hippocampus and the prefrontal cortex. More importantly, such experimental evidence suggests that different insults converge on similar downstream functional targets, such as cognition, which may therefore represent an endophenotype for several pathological conditions. Future studies should thus focus on investigating the mechanisms contributing to the convergent action of different prenatal insults in order to identify targets for novel therapeutic intervention. PMID- 24794048 TI - Chronic exposure of killifish to a highly polluted environment desensitizes estrogen-responsive reproductive and biomarker genes. AB - Reproductive and endocrine disruption is commonly reported in aquatic species exposed to complex contaminant mixtures. We previously reported that Atlantic killifish (Fundulus heteroclitus) from the chronically contaminated Newark Bay, NJ, exhibit multiple endocrine disrupting effects, including inhibition of vitellogenesis (yolk protein synthesis) in females and false negative vitellogenin biomarker responses in males. Here, we characterized the effects on estrogen signaling and the transcriptional regulation of estrogen-responsive genes in this model population. First, a dose-response study tested the hypothesis that reproductive biomarkers (vtg1, vtg2, chg H, chg Hm, chg L) in Newark Bay killifish are relatively less sensitive to 17beta-estradiol at the transcriptional level, relative to a reference (Tuckerton, NJ) population. The second study assessed expression for various metabolism (cyp1a, cyp3a30, mdr) and estrogen receptor (ER alpha, ER betaa, ER betab) genes under basal and estrogen treatment conditions in both populations. Hepatic metabolism of 17beta-estradiol was also evaluated in vitro as an integrated endpoint for adverse effects on metabolism. In the third study, gene methylation was evaluated for promoters of vtg1 (8 CpGs) and vtg2 (10 CpGs) in both populations, and vtg1 promoter sequences were examined for single nucleotide polymorphism (SNPs). Overall, these studies show that multi-chemical exposures at Newark Bay have desensitized all reproductive biomarkers tested to estrogen. For example, at 10ng/g 17beta estradiol, inhibition of gene induction ranged from 62% to 97% for all genes tested in the Newark Bay population, relative to induction levels in the reference population. The basis for this recalcitrant phenotype could not be explained by a change in 17beta-estradiol metabolism, nuclear estrogen receptor expression, promoter methylation (gene silencing) or SNPs, all of which were unaltered and normal in the Newark Bay population. The decreased transcriptional sensitivity of estrogen-responsive genes is suggestive of a broad effect on estrogen receptor pathway signaling, and provides insight into the mechanisms of the endocrine disrupting effects in the Newark Bay population. PMID- 24794050 TI - Rapid tolerance induction by hematopoietic progenitor cells in the absence of donor-matched lymphoid cells. AB - BACKGROUND: Donor specific hematopoietic cell transplantation has long been recognized for its potential in tolerance induction for subsequently transplanted organs. We have recently published that co-administration of Myeloid Progenitor (MP) and third party Hematopoietic Stem Cells (HSC) can induce MP-specific tolerance for subsequently transplanted organs [1]. METHODS: Mice received an allogeneic HSC and third party MP transplantation simultaneous with placement of a MP-matched skin graft. Variants tested include time of graft placement, MP genotype and source of cells. RESULTS: Using B10;B6-Rag2(-/-)Il2rg(-/-) mice, we demonstrate that specific tolerance can be induced by MP given simultaneous with the skin graft in the complete absence of MP-donor-matched lymphoid cells. Ex vivo expanded MP function as well as sorted cells in inducing tolerance. In addition we demonstrate that tolerance can be induced by MP in the context of autologous HSC transplantation. CONCLUSIONS: Our results demonstrate that the previously observed expansion of organ donor matched Treg is not essential for tolerance, and that MP tolerance protocols can be envisioned in most clinical settings, including those involving deceased donor organs. PMID- 24794051 TI - I can't get no satisfaction: potential causes of boredom. AB - A variety of causes of boredom have been proposed including environmental, motivational, emotional, and cognitive factors. Here, we explore four potential cognitive causes of boredom: inattention, hyperactivity, impulsivity, and executive dysfunction. Specifically, we examine the unique and common associations between these factors and boredom propensity. Recent research has established that the two most commonly used measures of boredom propensity (BPS and BSS) are not measuring the same underlying construct. Thus, a second goal of the present project is to determine the unique and common roles of inattention, hyperactivity, impulsivity and poor executive system functioning in predicting the BPS and BSS specifically. The findings reveal that inattention, hyperactivity and executive dysfunction predict boredom propensity, with shared variance accounting for the greater part of this effect. Further, executive dysfunction and hyperactivity uniquely predict boredom propensity as measured by the BPS and BSS, respectively. PMID- 24794052 TI - Life course adiposity and adolescent depressive symptoms among Hong Kong adolescents. AB - PURPOSE: Depression is a public health issue, which often emerges in adolescence. Adiposity may be a factor in this emergence; however, in Western settings, both adiposity and depression tend to be socially patterned, making it unclear whether any association is biologically based or contextually specific. METHODS: Multivariable analysis was used to assess the adjusted association of birth weight and life course body mass index (BMI) z score (at 3 and 9 months and 3, 7, 9, 11, and 12 years of age) and changes in BMI z score with adolescent depressive symptoms score at ~14 years of age, assessed from Patient Health Questionnaire-9 (PHQ-9) in a population-representative Chinese study, Hong Kong's "Children of 1997" birth cohort, which has little social patterning of birth weight or BMI. We also assessed whether associations varied with sex. RESULTS: PHQ-9 was available for 5,797 term births (73% follow-up). Birth weight z score, BMI z scores at 3 and 9 months and at 3, 7, 9, 11, and 12 years of age, and successive BMI z score changes had little association with PHQ-9 at ~14 years of age, adjusted for socioeconomic position, parental depressive symptoms, and survey mode. CONCLUSIONS: In a developed non-Western setting, life course adiposity does not appear to be a factor in the development of depressive symptoms in adolescence, suggesting that observed associations to date may be contextually specific rather than biologically based. PMID- 24794053 TI - Tobacco use and smoking intentions among U.S. fifth-grade students. AB - PURPOSE: To identify the risk and protective factors for cigarette smoking and future intentions among racially/ethnically diverse preadolescent children. METHODS: We analyzed data from 5,119 fifth-grade children and their parents living in three U.S. metropolitan areas. Using the multivariate logistic regression models, we examined how cigarette smoking and intentions to smoke within 1 year are associated with (1) number of friends who smoke, (2) parental disapproval of smoking, (3) parental communication about not smoking, (4) performance in school, and (5) educational aspirations. RESULTS: Twenty-nine percent of the children were black, 44% were Hispanic, 22% were white, and 5% were of another race/ethnicity. Mean age was 11.1 years. The prevalence of ever smoking a cigarette among black, Hispanic, and white children was 9.8%, 5.6%, and 4.9%, respectively. In adjusted analyses, children were more likely to have smoked a cigarette if their friends smoked (adjusted odds ratio [aOR] 5.1, 95% confidence interval [CI] 3.8-6.9), they frequently had trouble with schoolwork (aOR 2.1, 95% CI 1.5-3.1), or their parents were not college graduates (aOR 2.0, 95% CI 1.2-3.5 for high school graduate). They were less likely to have smoked cigarettes if their parents disapproved of smoking (aOR .3, 95% CI .1-.6). Parental communication (aOR .1, 95% CI .0-.6) and disapproval (aOR .2, 95% CI .1 .7) had protective associations for future intentions among children who had ever and had never smoked, respectively. CONCLUSIONS: Fifth-graders share many of the same risk factors for smoking identified in older adolescents, some of which are modifiable. Antismoking policies and programs should be designed for preadolescents as well as adolescents, and campaigns targeting parents should place greater emphasis on communication and expressed disapproval of smoking. PMID- 24794055 TI - Giant left atrial appendage mimicking a mediastinal mass in a new diagnosis of atrial septal defect and pulmonic stenosis. PMID- 24794054 TI - Factors informing HIV providers' decisions to start antiretroviral therapy for young people living with behaviorally acquired HIV. AB - PURPOSE: Young people with behaviorally acquired HIV (BHIV) are less likely than adults to initiate antiretroviral therapy (ART) despite meeting treatment criteria. We explored critical factors involved in healthcare providers' decision making regarding ART initiation for young people with BHIV (aged 12-24 years). METHODS: Semistructured interviews were conducted with 23 HIV providers from diverse training backgrounds caring for youth with BHIV at four adult clinics and one pediatric clinic in a high prevalence urban city. Interview domains probed clinical and nonclinical patient characteristics, the role of adherence, and provider attitudes working with youth to establish decision-making priorities for ART initiation. The constant comparative approach was used to develop grounded theory on providers' decision making on ART initiation. RESULTS: Clinical criteria, particularly the CD4 count, and the public health implications of HIV transmission determined the urgency for ART initiation. However, patient-related concerns regarding treatment readiness and adherence hampered the decision to initiate, especially at higher CD4 counts. Providers who acknowledged developmental characteristics of youth (e.g., evolving adult identity and self efficacy around health management) appeared more cautious in assessing future ART adherence and responded with intensive clinical support. Extensive involvement of multidisciplinary teams was identified as an important strategy to retain youth in care, whereas strengthening youth-targeted approaches may be an unmet need in adult clinics. CONCLUSION: Evaluation of providers' awareness of the developmental features of youth and characteristics of youth-targeted approaches in clinics caring for youth with BHIV may inform interventions to increase youth engagement in care and subsequent decisions to successfully initiate ART. PMID- 24794056 TI - Contemporary prevalence of pulmonary arterial hypertension in adult congenital heart disease following the updated clinical classification. AB - BACKGROUND: The aging congenital heart disease (CHD) population is prone to develop a variety of sequelae, including pulmonary arterial hypertension (PAH). Previous prevalence estimates are limited in applicability due to the use of tertiary centers, or database encoding only. We aimed to investigate the contemporary prevalence of PAH in adult CHD patients, using a nationwide population. METHODS: A cross-sectional study was performed, using the population based Dutch CONgenital CORvitia (CONCOR) registry. All patients born with a systemic-to-pulmonary shunt, thereby at risk of developing PAH, were identified. From this cohort, a random sample was obtained and carefully reviewed. RESULTS: Of 12,624 registered adults with CHD alive in 2011, 5,487 (44%) were at risk of PAH. The random sample consisted of 1,814 patients (mean age 40 +/- 15 years) and 135 PAH cases were observed. PAH prevalence in patients born with a systemic-to pulmonary shunt was 7.4%. The prevalence of PAH after corrective cardiac surgery was remarkably high (5.7%). Furthermore, PAH prevalence increased with age, from 2.5% under 30 years until 35% in the eldest. PAH prevalence in the entire CHD population was 3.2%. Based on 3000 per million adult CHD patients in the general population, we can assume that PAH-CHD is present in 100 per million. CONCLUSIONS: This new approach using a nationwide CHD population reports a PAH prevalence of 3.2% in CHD patients, and 100 per million in the general adult population. Especially in patients after shunt closure and the elderly, physicians should be aware of PAH-CHD, to provide optimal therapeutic and clinical care. PMID- 24794057 TI - Long-term prognosis of patients with arrhythmogenic right ventricular cardiomyopathy and implantable defibrillator. PMID- 24794058 TI - Percutaneous tricuspid valve-in-valve implantation in Ebstein's anomaly: one-year follow-up of valve function. PMID- 24794059 TI - From abstract to peer-reviewed publication: country matters. PMID- 24794060 TI - Enterococcus faecalis bacteremia and mitral valve endocarditis under dabigatran for stroke prevention. PMID- 24794061 TI - A case series of patients with poorly-tolerated arrhythmias related to a preexcitation syndrome and presenting with atypical ECG. AB - The aim of study was to report different and unusual patterns of preexcitation syndrome (PS) noted in patients referred for studied for poorly-tolerated arrhythmias and their frequency. Electrophysiologic study (EPS) is an easy means to identify a patient with PS at risk of serious events. However the main basis for this diagnosis is the ECG which associates short PR interval and widening of QRS complex with a delta wave. METHODS: ECGs of 861 patients in whom PS related to an atrioventricular accessory pathway (AP) was identified at electrophysiological study (EPS), were studied. RESULTS: The most frequent unusual presentation (9.6%) was the PS presenting with a normal or near normal ECG, noted preferentially for left lateral AP and rarely for posteroseptal or right lateral location. More exceptional (0.1%) was the presence of a long PR interval, which did not exclude a rapid conduction over AP. The association of a complete AV block with symptomatic tachycardias was exceptional (0.3%) and was shown related to a rapid conduction over AP after isoproterenol. Most of the presented patients were at high-risk at EPS. CONCLUSION: The diagnosis of PS is not always evident and symptoms should draw attention to minor abnormalities and lead to enlarge indications of EPS, only means to confirm or not PS. PMID- 24794062 TI - Tightrope walking: achieving the best possible balance between better model fit and accurate prediction: response to letter (IJC-D-14-00417). PMID- 24794063 TI - Perceptions, training experiences, and preferences of surgical residents toward laparoscopic simulation training: a resident survey. AB - INTRODUCTION: Simulation training for surgical residents can shorten learning curves, improve technical skills, and expedite competency. Several studies have shown that skills learned in the simulated environment are transferable to the operating room. Residency programs are trying to incorporate simulation into the resident training curriculum to supplement the hands-on experience gained in the operating room. Despite the availability and proven utility of surgical simulators and simulation laboratories, they are still widely underutilized by surgical trainees. Studies have shown that voluntary use leads to minimal participation in a training curriculum. Although there are several simulation tools, there is no clear evidence of the superiority of one tool over the other in skill acquisition. The purpose of this study was to explore resident perceptions, training experiences, and preferences regarding laparoscopic simulation training. Our goal was to profile resident participation in surgical skills simulation, recognize potential barriers to voluntary simulator use, and identify simulation tools and tasks preferred by residents. Furthermore, this study may help to inform whether mandatory/protected training time, as part of the residents' curriculum is essential to enhance participation in the simulation laboratory. METHODS: A cross-sectional study on general surgery residents (postgraduate years 1-5) at Yale University School of Medicine and the University of Toronto via an online questionnaire was conducted. Overall, 67 residents completed the survey. The institutional review board approved the methods of the study. RESULTS: Overall, 95.5% of the participants believed that simulation training improved their laparoscopic skills. Most respondents (92.5%) perceived that skills learned during simulation training were transferrable to the operating room. Overall, 56.7% of participants agreed that proficiency in a simulation curriculum should be mandatory before operating room experience. The simulation laboratory was most commonly used during work hours; lack of free time during work hours was most commonly cited as a reason for underutilization. Factors influencing use of the simulation laboratory in order of importance were the need for skill development, an interest in minimally invasive surgery, mandatory/protected time in a simulation environment as part of the residency program curriculum, a recommendation by an attending surgeon, and proximity of the simulation center. The most preferred simulation tool was the live animal model followed by cadaveric tissue. Virtual reality simulators were among the least-preferred (25%) simulation tools. Most residents (91.0%) felt that mandatory/protected time in a simulation environment should be introduced into resident training protocols. CONCLUSIONS: Mandatory and protected time in a simulation environment as part of the resident training curriculum may improve participation in simulation training. A comprehensive curriculum, which includes the use of live animals, cadaveric tissue, and virtual reality simulators, may enhance the laparoscopic training experience and interest level of surgical trainees. PMID- 24794064 TI - Does intentional support of degree programs in general surgery residency affect research productivity or pursuit of academic surgery? AB - OBJECTIVE: Many residents supplement general surgery training with years of dedicated research, and an increasing number at our institution pursue additional degrees. We sought to determine whether it was worth the financial cost for residency programs to support degrees. DESIGN: We reviewed graduating chief residents (n = 69) in general surgery at Vanderbilt University from 2001 to 2010 and collected the data including research time and additional degrees obtained. We then compared this information with the following parameters: (1) total papers, (2) first-author papers, (3) Journal Citation Reports impact factors of journals in which papers were published, and (4) first job after residency or fellowship training. SETTING: The general surgery resident training program at Vanderbilt University is an academic program, approved to finish training 7 chief residents yearly during the time period studied. PARTICIPANTS: Chief residents in general surgery at Vanderbilt who finished their training 2001 through 2010. RESULTS: We found that completion of a degree during residency was significantly associated with more total and first-author publications as compared with those by residents with only dedicated research time (p = 0.001 and p = 0.017). Residents completing a degree also produced publications of a higher caliber and level of authorship as determined by an adjusted resident impact factor score as compared with those by residents with laboratory research time only (p = 0.005). Degree completion also was significantly correlated with a first job in academia if compared to those with dedicated research time only (p = 0.046). CONCLUSIONS: Our data support the utility of degree completion when economically feasible and use of dedicated research time as an effective way to significantly increase research productivity and retain graduates in academic surgery. Aggregating data from other academic surgery programs would allow us to further determine association of funding of additional degrees as a means to encourage academic productivity and retention. PMID- 24794066 TI - Barium determination in gastric contents, blood and urine by inductively coupled plasma mass spectrometry in the case of oral barium chloride poisoning. AB - A serious case of barium intoxication from suicidal ingestion is reported. Oral barium chloride poisoning with hypokalemia, neuromuscular and cardiac toxicity, treated with intravenous potassium supplementation and hemodialysis, was confirmed by the determination of barium concentrations in gastric contents, blood, serum and urine using the inductively coupled plasma mass spectrometry method. Barium concentrations in the analyzed specimens were 20.45 ug/L in serum, 150 ug/L in blood, 10,500 ug/L in urine and 63,500 ug/L in gastric contents. Results were compared with barium levels obtained from a non-intoxicated person. PMID- 24794065 TI - Cost sharing and hereditary cancer risk: predictors of willingness-to-pay for genetic testing. AB - Increasing use of predictive genetic testing to gauge hereditary cancer risk has been paralleled by rising cost-sharing practices. Little is known about how demographic and psychosocial factors may influence individuals' willingness-to pay for genetic testing. The Gastrointestinal Tumor Risk Assessment Program Registry includes individuals presenting for genetic risk assessment based on personal/family cancer history. Participants complete a baseline survey assessing cancer history and psychosocial items. Willingness-to-pay items include intention for: genetic testing only if paid by insurance; testing with self-pay; and amount willing-to-pay ($25-$2,000). Multivariable models examined predictors of willingness-to-pay out-of-pocket (versus only if paid by insurance) and willingness-to-pay a smaller versus larger sum (<=$200 vs. >=$500). All statistical tests are two-sided (alpha = 0.05). Of 385 evaluable participants, a minority (42%) had a personal cancer history, while 56% had >=1 first-degree relative with colorectal cancer. Overall, 21.3% were willing to have testing only if paid by insurance, and 78.7% were willing-to-pay. Predictors of willingness-to pay were: 1) concern for positive result; 2) confidence to control cancer risk; 3) fewer perceived barriers to colorectal cancer screening; 4) benefit of testing to guide screening (all p < 0.05). Subjects willing-to-pay a higher amount were male, more educated, had greater cancer worry, fewer relatives with colorectal cancer, and more positive attitudes toward genetic testing (all p < 0.05). Individuals seeking risk assessment are willing-to-pay out-of-pocket for genetic testing, and anticipate benefits to reducing cancer risk. Identifying factors associated with willingness-to-pay for genetic services is increasingly important as testing is integrated into routine cancer care. PMID- 24794067 TI - Roles of carbonic anhydrase 8 in neuronal cells and zebrafish. AB - BACKGROUND: Carbonic anhydrase 8 (CA8) is an isozyme of alpha-carbonic anhydrases (CAs). Previous studies showed that CA8 can be detected in human adult brain, with more intense expression in the cerebellum. Single mutations in CA8 were reported to cause novel syndromes like ataxia, mild mental retardation or the predisposition to quadrupedal gait. METHODS: In the present study, we examine the functions of CA8 in neuronal cell lines, mouse cerebellar granule neurons and zebrafish. RESULTS AND CONCLUSIONS: We demonstrated that overexpression of CA8 in neuronal cells significantly decreased cell death under staurosporine treatment. Moreover, CA8 overexpression significantly increased cell migration and invasion ability in neuronal cells and in mouse cerebellar granule neurons, implicating that CA8 may be involved in neuron motility and oncogenesis. By using zebrafish as an animal model, motor reflection of 3dpf zebrafish embryos was significantly affected after the down-regulation of CA8 through ca8 morpholino. CONCLUSIONS: We concluded that CA8 overexpression desensitizes neuronal cells to STS induced apoptotic stress and increases cell migration and invasion ability in neuronal cells. In addition, down-regulated CA8 decreases neuron mobility in neuronal cells and leads to abnormal calcium release in cerebellar granule neurons. Knockdown of the ca8 gene results in an abnormal movement pattern in zebrafish. GENERAL SIGNIFICANCE: Our findings provide evidence to support that the impaired protective function of CA8 contributes to human neuropathology, and to suggest that zebrafish can be used as an animal model to study the biological functions of human CA8 in vivo. PMID- 24794068 TI - Normal thyroid-stimulating hormone levels, autoimmune activation, and coronary heart disease risk. AB - Whether euthyroid status affects cardiovascular disease risk is unclear. We aimed to investigate whether serum thyroid-stimulating hormone (TSH) levels within the normal range are related to the risk of coronary heart disease (CHD). In participants of the Turkish Adult Risk Factor Study (mean age 52.7+/-11.5), in whom TSH was measured in the 2004/05 survey, cross-sectional and longitudinal analyses were performed. Subjects with TSH concentrations<0.3 and >4.2 mIU/L were excluded to ensure euthyroid status leaving 956 individuals as the study sample. Mean follow-up was 4.81+/-1.3 years. Men had 18% lower (p<0.001) geometric mean TSH levels (1.10 mIU/L) than women (1.35 mIU/L). Correlations of TSH with risk variables were notably virtually absent except weakly positive ones in men with age and systolic blood pressure (SBP). The age-adjusted TSH mid-tertile in men was associated with lowest lipoprotein [Lp](a), apoB, and total cholesterol values. Incident CHD was predicted in Cox regression analyses in men [HR of 2.45 (95 %CI 1.05; 5.74] and in combined sexes by the lowest compared with the highest TSH tertile, after adjustment for age, smoking status, SBP, and LDL-cholesterol. Analysis for combined prevalent and incident CHD stratified by metabolic syndrome (MetS) confirmed the independent association with the lowest TSH tertile in men, specifically in men without MetS. TSH levels within normal range, low due to partial assay failure, may manifest as independent predictors of incident CHD, particularly in middle-aged men. Autoimmune responses involving serum Lp(a) under oxidative stress might be implicated mechanistically. PMID- 24794069 TI - Structure, evolution and virtual screening of NDM-1 strain from Kolkata. AB - beta-lactam antibiotics are utilised to treat bacterial infection. beta-lactamase enzymes (EC 3.5.2.6) are produced by several bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillin, cephamycins and carbapenems. New Delhi Metallo-beta-lactamase (NDM-1) is a gene that makes bacteria resistant to beta-lactam antibiotics. Preparing a compound against NDM-1 will require additional investment and development by drug manufacturers as the current antibiotics will not treat patients with NDM-1 resistance. NDM-1 of Kolkata showed convergent-type evolution with other NDM-1 producing strains. The modelled structure exhibited alpha-beta-alpha barrel-type domain along with Zn metallo-beta-lactamase N-terminal domain. Compounds belonging to cephalosporins (relatively resistant to beta-lactamase) and other antibiotics ceftaroline, ceftobiprole, piperacillin, penamecillin, azidocillin, cefonicid, tigecycline and colistin have exhibited better binding affinity with the modelled NDM-1. PMID- 24794070 TI - Tools, resources and databases for SNPs and indels in sequences: a review. AB - Single Nucleotide Polymorphism (SNP) is a mutation where, a single base in the DNA differs from the usual base at that position. SNPs are the marker of choice in genetic analysis and also useful in locating genes associated with diseases. SNPs are important and frequently occurring point mutations in genomes and have many practical implications. In silico methods are easy to study the SNPs that are occurring in known genomes or sequences of a species of interest during the post genomic era. There are many on-line and stand alone tools to analyse the SNPs. We intend to guide the reader with the software details such as algorithmic background, file requirements, operating system specificity and species specificity, if any, for the tools of SNPs detection in plants and animals. We also list many databases and resources available today to describe SNPs in wide range of organisms. PMID- 24794071 TI - In silico analysis of plant and animal transposable elements. AB - Transposable Elements (TEs) play important roles in the evolution of eukaryotic organisms. TEs widely distribute depending on their properties present in the genome. This study elucidated the molecular characteristics of TEs in land plants and animals using bioinformatics and in silico mutational approach. We discovered that the GC-rich class I TEs is the predominant class of TEs in animal, but the AT-rich class II TEs is prevalent in plants. The GC-rich class I TEs appears to be evolved within the animals. On contrary, the preserved in AT-rich in class II TEs is believed to be contributed in host defence systems. PMID- 24794072 TI - A classifier system for predicting RNA secondary structure. AB - Finding the secondary structures of ribonucleic acid sequences is a very important task. The secondary structure helps determine their functionalities which in turn plays a role in the proteins production. Manual laboratory methods use X-ray diffraction to predict secondary structures but it is complex, slow and expensive. Therefore, different computational approaches are used to predict RNA secondary structure in order to reduce the time and cost associated with the manual process. We propose a system called IsRNA to predict a single element, internal loop, of the RNA secondary structure. IsRNA experiments with different classifiers such as SVM, KNN, Naive Bayes and Simple K means to find the most accurate classifier. We present a through experimental evaluation of 24 features, classified into five groups, to determine the most relevant feature groups. The system is evaluated using Rfam sequences and achieves an overall sensitivity, selectivity, and accuracy of 96.1%, 98%, and 96.1%, respectively. PMID- 24794073 TI - Fast decision tree-based method to index large DNA-protein sequence databases using hybrid distributed-shared memory programming model. AB - In recent times, the size of biological databases has increased significantly, with the continuous growth in the number of users and rate of queries; such that some databases have reached the terabyte size. There is therefore, the increasing need to access databases at the fastest rates possible. In this paper, the decision tree indexing model (PDTIM) was parallelised, using a hybrid of distributed and shared memory on resident database; with horizontal and vertical growth through Message Passing Interface (MPI) and POSIX Thread (PThread), to accelerate the index building time. The PDTIM was implemented using 1, 2, 4 and 5 processors on 1, 2, 3 and 4 threads respectively. The results show that the hybrid technique improved the speedup, compared to a sequential version. It could be concluded from results that the proposed PDTIM is appropriate for large data sets, in terms of index building time. PMID- 24794075 TI - A "PSA pyramid" for men with initial prostate-specific antigen <=3 ng/ml: a plea for individualized prostate cancer screening. AB - BACKGROUND: In daily routine business, various prostate-specific antigen (PSA) retest strategies are being promoted. OBJECTIVE: To investigate rescreening intervals according to baseline PSA <3 ng/ml stratified by any and aggressive prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: From 1998 to 2012, data from 4350 men aged 55-70 yr were analyzed from a population-based prospective screening study (median follow-up: 11.6 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was detection of aggressive PCa (Gleason score 7 10). Cox regression analysis was used to examine the relationship between covariates. RESULTS AND LIMITATIONS: Baseline PSA of <1.0 ng/ml, 1-1.9 ng/ml, and 2-2.9 ng/ml was present in 2416 men (55.5%: group 1), 1371 men (31.6%: group 2), and 563 men (12.9%: group 3), respectively. Stratified according to these PSA groups, aggressive PCa was detected in 25 patients (1.0%), 80 patients (5.8%), and 34 patients (6.0%), respectively. During 4 yr, these numbers were 0.0%, 0.29%, and 1.8%, whereas during 8 yr, the numbers were 0.2%, 1.4%, and 2.5%, respectively. In multivariable Cox regression analysis, the only independent risk factor for aggressive PCa was baseline PSA (hazard ratio [HR]: 6.06; 95% confidence interval [CI], 3.82-9.61; p<0.0001, group 2 vs group 1; and HR: 7.33; 95% CI, 4.29-12.52; p<0.0001, group 3 vs group 1). CONCLUSIONS: Baseline PSA was the only predictor regarding aggressive PCa. According to the low rate of potentially missed PCa in these groups, rescreening intervals can be safely adapted to baseline PSA values corresponding to a "PSA pyramid": 6-8 yr if baseline PSA is <1.0 ng/ml, 3-4 yr if baseline PSA is 1-1.99 ng/ml, and yearly if baseline PSA is 2-2.99 ng/ml. PATIENT SUMMARY: We observed men with a prostate specific antigen (PSA) value <=3 ng/ml during 12 yr and found that men can be retested according to their initial PSA value ("PSA pyramid"): PSA <1 (base), retest interval every 8 yr; PSA 1-2 (center), retest interval every 4 yr; and PSA 2-3 (top), retest yearly after risk stratification. PMID- 24794077 TI - Family history unawareness of blood clot risk: links to misdiagnoses and illness uncertainties in personal and expert realms. AB - The difficulty of diagnosing blood clots makes salient the question, "What role does family history awareness have for guiding lay and expert actions?" The authors examine the in-depth life reflection interviews of 20 women who experienced a first venous blood clot between the ages of 18 and 50 years, identifying causal attributions the women made for thrombosis after the event. Twelve participants described an understanding of the cascade of events linked to thrombosis, revealing that there is seldom a single cause. The other eight identified belief in a single determining cause for their thrombosis. The authors reflect on the symptoms the women experienced during the course of the clotting event, patterns of care that they executed to self-manage their blood clot, and their misdiagnoses associated with symptoms and care. The women recalled the patterns of care received through formal health care systems and the reported misdiagnoses linked to these interactions. The recollections reveal that the subtle nature of venous blood clot symptoms contributes to lay and expert misdiagnoses. Use of antibiotics and pain killers in the wake of misdiagnosis masks symptoms, contributing to costly delays in accurate diagnoses. Four women were aware of a family history of clotting when the event occurred, 13 had such a history but lacked awareness until the clotting event, and three had no known history. Among women with awareness of their family history, blood clot diagnosis occurred sooner, promoting survival and efficiencies in health care. Implications for communicating about family history of thrombosis are considered. PMID- 24794076 TI - Loss of migration and urbanization in birds: a case study of the blackbird (Turdus merula). AB - Many organisms have invaded urban habitats, although the underlying factors initially promoting urbanization remain poorly understood. Partial migration may facilitate urbanization because such populations benefit from surplus food in urban environments during winter, and hence enjoy reduced fitness costs of migratory deaths. We tested this hypothesis in the European blackbird Turdus merula, which has been urbanized since the 19th century, by compiling information on timing of urbanization, migratory status, and population density for 99 cities across the continent. Timing of urbanization was spatially auto-correlated at scales up to 600 km. Analyses of timing of urbanization revealed that urbanization occurred earlier in partially migratory and resident populations than in migratory populations of blackbirds. Independently, this effect was most pronounced in the range of the distribution that currently has the highest population density, suggesting that urbanization facilitated population growth. These findings are consistent with the hypothesis that timing of urbanization is facilitated by partial migration, resulting in subsequent residency and population growth. PMID- 24794078 TI - Women's experiences after a radical vaginal trachelectomy for early stage cervical cancer. A descriptive phenomenological study. AB - PURPOSE: This paper reports on a phenomenological study of women's experiences 1 10 years following a radical vaginal trachelectomy and describes the impact on health, sexuality, fertility and perceived supportive care needs. METHOD AND SAMPLE: Qualitative telephone interviews employing a descriptive phenomenological approach were conducted using a purposive sample of 12 women. KEY RESULTS: Several felt their cancer experience was positive; bringing them closer to family and changed their outlook on life. A few experienced delayed psychological reactions and/or fears of recurrence. Many experienced isolation and the desire to contact others with similar experiences. Women recovered well but a few experienced fears/concerns about lymphoedema and intermenstrual bleeding. Sexual function was not a long-term issue for most. Some that could feel the cerclage (stitch) during intercourse, developed techniques to reduce this. Single women felt vulnerable in new relationships. Pregnancy was an anxious time, especially for those that experienced a miscarriage or pre-term birth. Sources of support included the clinical nurse specialist, family/friends, surgical consultant, online patient forums and a support group. Women needed more information on trachelectomy statistics, pregnancy care recommendations as well as access to counselling, peer support, being seen by the same person and increased public awareness. CONCLUSIONS: This study has provided an interesting and detailed insight into women's experiences in the years following a trachelectomy, with results that have important considerations for practice such as provision of statistical information; counselling; peer support; consistent pregnancy recommendations; increased public awareness and increased identification and management or prevention of long-term physical effects. PMID- 24794079 TI - Accumulation and hazard assessment of mercury to waterbirds at Lake Chapala, Mexico. AB - Lake Chapala is the largest tropical lake in Mexico. The objectives of this study were to determine bioaccumulation of Hg in fish and to evaluate the potential impacts of Hg in the diet of aquatic birds, particularly the American white pelican (AWPE), in Lake Chapala. Hg concentrations in three fish species ranged from 0.021 to 0.568 MUg/g wet weight. Mercury in fish was positively and significantly correlated with total fish length (R2=0.44, P<0.05). The delta15N values in fish were significantly correlated with Hg concentrations in Chapala and the San Antonio Reservoir (R2=0.69, P<0.001 and R2=0.40, P<0.001, respectively). However, Hg concentrations in bird feathers were not significantly different between years, among locations, or among species. Hg concentrations in fish from Lake Chapala were within values reported in many parts of the world. The Hg (mean range of 2.75 to 4.54 MUg/g dw) and deltaD (mean range of -620/00 to -110/00) values in bird feathers suggested a wide pattern of exposure for highly migratory AWPE and egrets, although birds with lower deltaD values in feathers appeared to have greater concentrations of Hg than those with higher deltaD values. Contaminant exposure in aquatic birds in Chapala during the breeding season should be monitored next to better determine the potential effects of Hg on resident aquatic birds. PMID- 24794081 TI - Introduction. Personalizing patient care with precision medicine. PMID- 24794082 TI - Precision medicine for nurses: 101. AB - OBJECTIVES: To introduce the key concepts and terms associated with precision medicine and support understanding of future developments in the field by providing an overview and history of precision medicine, related ethical considerations, and nursing implications. DATA SOURCES: Current nursing, medical and basic science literature. CONCLUSION: Rapid progress in understanding the oncogenic drivers associated with cancer is leading to a shift toward precision medicine, where treatment is based on targeting specific genetic and epigenetic alterations associated with a particular cancer. IMPLICATIONS FOR NURSING PRACTICE: Nurses will need to embrace the paradigm shift to precision medicine, expend the effort necessary to learn the essential terminology, concepts and principles, and work collaboratively with physician colleagues to best position our patients to maximize the potential that precision medicine can offer. PMID- 24794083 TI - Precision medicine in oncology standard of care. AB - OBJECTIVES: To review the histologic subtypes and staging of non-small cell lung cancer and metastatic melanoma, as well as the molecular markers used to direct standard therapy. DATA SOURCES: Book chapters and journal articles from medical and nursing literature, as well as published clinical guidelines. CONCLUSION: Patients with metastatic non-small cell lung cancer and metastatic melanoma have had a paucity of treatment options, most fraught with toxicity with limited benefit. Increased understanding of tumor genetics and molecular markers has expanded the treatment options for these patients, often providing them with durable responses and improved quality of life. IMPLICATIONS FOR NURSING PRACTICE: To provide education and support to their patients, nurses caring for these patients need to understand the role that genetics and molecular markers play in directing these therapies. PMID- 24794084 TI - Precision medicine clinical trials: defining new treatment strategies. AB - OBJECTIVES: To discuss the role of clinical trials in the changing landscape of cancer care resulting in individualized cancer treatment plans including a discussion of several innovative randomized studies designed to evaluate multiple targeted therapies in molecularly defined subsets of individuals. DATA SOURCES: Medical and nursing literature, research articles, and clinicaltrials.gov. CONCLUSION: Recent advancements in cancer biomarkers and biomedical technology have begun to transform fundamentals of cancer therapeutics and clinical trials through innovative adaptive trial designs. The goal of these studies is to learn not only if a drug is safe and effective but also how it is best delivered and who will derive the most benefit. IMPLICATIONS FOR NURSING PRACTICE: Implementation of clinical trials in the cancer biomarker era requires knowledge, skills, and expertise related to the use of biomarkers and molecularly defined processes underlying a malignancy, as well as an understanding of associated ethical, legal, and social issues to provide competent, safe, and effective health care and patient communication. PMID- 24794085 TI - Biospecimen collection, processing, and analysis: new challenges for oncology nurses. AB - OBJECTIVES: To provide an overview of emerging applications for and challenges associated with biospecimen collection for evaluating personalized disease risk and/or treatment response in cancer clinical trials. DATA SOURCES: Published nursing and medical literature. CONCLUSION: Blood- and tissue-based biomarkers are increasingly utilized to identify the molecular signatures of disease that can inform the determination of a course of treatment in a very precise manner. There are challenges for the oncology nurse related to specimen collection, processing, analysis, and translation to precision treatment. IMPLICATIONS FOR NURSING PRACTICE: It is important for nurses to have appropriate training and a working understanding of the procedures for biospecimen collection and how biospecimen analyses can inform precision assessment of risk and prognosis. PMID- 24794086 TI - Information technology and precision medicine. AB - OBJECTIVES: To provide oncology nurses with an overview of clinical decision support (CDS) and explore opportunities for genomic CDS interventions. The nation's first personalized cancer decision support tool, My Cancer Genome, is presented as an exemplar of a novel CDS tool. DATA SOURCES: Published nursing and medical literature and the internet for an exemplar. CONCLUSION: CDS is a sophisticated health information technology that can translate and integrate genomic knowledge with patient information, providing recommendations at the point of care. IMPLICATIONS FOR NURSING PRACTICE: Nurses, as key stakeholders, must have an understanding of CDS interventions and their application to fully participate in all stages of CDS development and implementation. PMID- 24794087 TI - Nursing implications of personalized and precision medicine. AB - OBJECTIVES: Identify and discuss the nursing implications of personalized and precision oncology care. DATA SOURCES: PubMed, CINAHL. CONCLUSION: The implications in personalized and precision cancer nursing care include interpretation and clinical use of novel and personalized information including genetic testing; patient advocacy and support throughout testing, anticipation of results and treatment; ongoing chronic monitoring; and support for patient decision-making. Attention must also be given to the family and ethical implications of a personalized approach to care. IMPLICATIONS FOR NURSING PRACTICE: Nurses face increasing challenges and opportunities in communication, support, and advocacy for patients given the availability of advanced testing, care and treatment in personalized and precision medicine. Nursing education and continuing education, clinical decision support, and health systems changes will be necessary to provide personalized multidisciplinary care to patients, in which nurses play a key role. PMID- 24794088 TI - The association between cigarette rod length, slim design, and blood cadmium levels among U.S. smokers: NHANES 1999-2010. AB - BACKGROUND: Previous research has shown that long or slim cigarette design can mitigate perception of harmfulness. Cadmium (Cd) is a toxicant in cigarettes and is associated with adverse outcomes. We assessed the relationship between cigarette rod length/circumference and blood Cd levels among U.S. smokers using data from the 1999-2010 National Health and Nutrition Examination Survey. METHODS: The analyses were performed on 4486 current cigarette smokers aged >=20years old. Cigarette rod length included regular (68-72mm), king (79-88mm), long (94-101mm), and ultra-long (110-121mm) cigarettes currently smoked. Overall and gender stratified multivariate linear regression analyses were performed, adjusting for other influential covariates. RESULTS: Gender stratified analysis indicated that female smokers of long and ultra-long cigarette had 20% and 27% higher mean Cd levels compared to smokers of regular sized cigarettes respectively, despite the fact that all the ultra-long cigarettes were slim cigarettes. Furthermore, among females, slim cigarette users did not reduce blood cadmium levels compared to non-slim users. CONCLUSIONS: Female smokers of long or ultra-long cigarettes had higher mean blood Cd levels compared to smokers of regular cigarettes independent of slim design. Further research into this association is warranted. PMID- 24794089 TI - Paracentral acute middle maculopathy in nonischemic central retinal vein occlusion. AB - PURPOSE: To better characterize a novel spectral-domain optical coherence tomography (OCT) presentation, termed paracentral acute middle maculopathy, to describe this finding in patients with nonischemic central retinal vein occlusion (CRVO), and to support a proposed pathogenesis of intermediate and deep retinal capillary ischemia. DESIGN: Retrospective observational case series. METHODS: Clinical histories, high-resolution digital color imaging, red-free photography, fluorescein angiography, near-infrared reflectance, and spectral-domain OCT images of 484 patients with acute CRVO from 2 centers were evaluated for the presence of coexisting paracentral acute middle maculopathy. RESULTS: Of 484 patients diagnosed with CRVO, 25 (5.2%) demonstrated evidence of concurrent paracentral acute middle maculopathy. Patients averaged 51 years of age and presented with complaints of paracentral scotomas. All patients demonstrated hyper-reflective plaquelike lesions at the level of the inner nuclear layer by spectral-domain OCT and showed corresponding dark-gray lesions on near-infrared reflectance and perivenular deep retinal whitening on color fundus photography. There was no fluorescein angiographic correlate to these lesions. On follow-up spectral-domain OCT imaging, the lesions had resolved into areas of inner nuclear layer atrophy with persistence of scotomas. CONCLUSIONS: Paracentral acute middle maculopathy refers to characteristic hyper-reflective spectral-domain OCT lesions involving the middle layers of the retina at the level of the inner nuclear layer that may develop in response to ischemia of the intermediate and deep capillary plexuses. This series is the largest to describe this spectral-domain OCT finding to date, and it is the first to associate it with nonischemic CRVO. PMID- 24794090 TI - Changes in postoperative refractive outcomes following combined phacoemulsification and pars plana vitrectomy for rhegmatogenous retinal detachment. AB - PURPOSE: To evaluate changes in postoperative refractive outcomes following combined phacoemulsification and pars plana vitrectomy for rhegmatogenous retinal detachment (RRD) compared with other retinal diseases. DESIGN: Retrospective observational case-control study. METHODS: A total of 55 patients who had combined surgery between January 2007 and December 2012 were enrolled. The 25 patients who underwent combined surgery for RRD were included in the RRD group, and 30 patients who underwent combined surgery for other vitreoretinal pathology were included in the control group. Refractive axial length and intraocular pressure (IOP) measurements were performed, and the factors influencing the postoperative refractive outcomes were analyzed. RESULTS: The mean differences between the postoperative and predicted refractive outcomes in the RRD group and the control group were -0.43D+/-0.67 (P=.046) and -0.08D+/-0.53 (P=.767), respectively. The mean preoperative IOPs of the affected eye and the fellow eye in the RRD group were 11.44 mm Hg+/-3.15 and 13.16 mm Hg+/-2.73 (P=.045), but no differences were found in the affected eyes and fellow eyes of the control group. The differences were 14.20 mm Hg+/-2.95 and 14.17 mm Hg+/-3.50, respectively (P=.974). The mean postoperative IOPs in the affected eyes and the fellow eyes of the 2 groups were not significantly different. For all eyes, the refractive differences correlated with IOP changes in the RRD group. (r=.659, r2=.435, P<.001). CONCLUSIONS: The postoperative refractive outcomes in the RRD group shifted toward myopia by a mean of 0.35 diopters compared with the control group. Normalizing preoperative lowered IOP after combined surgery in RRD may be the key factor in understanding this myopic shift. PMID- 24794091 TI - Ultra-widefield imaging with autofluorescence and indocyanine green angiography in central serous chorioretinopathy. AB - PURPOSE: To describe the spectrum of ultra-widefield autofluorescence (AF) and indocyanine green (ICG) angiographic findings in central serous chorioretinopathy (CSC). DESIGN: Retrospective observational case series. METHODS: In 37 patients, 65 eyes with CSC from 2 vitreoretinal clinical practices were imaged using ultra widefield AF and 24 of these eyes with ultra-widefield ICG angiography. Images were correlated with clinical findings and spectral-domain optical coherence tomography (OCT). RESULTS: In 37 (57%) eyes, a variety of altered AF patterns, including gravitational tracts, extended beyond the posterior 50 degrees of retina. Hyper-AF corresponded to areas of subretinal fluid (SRF) on spectral domain OCT and was found to persist in 44 (70%) eyes for up to 8 years despite resolution of SRF. These areas corresponded to outer retinal atrophy with viable retinal pigment epithelium (RPE) on spectral-domain OCT and may be explained by the unmasking of normal background RPE AF. Ultra-widefield ICG angiography revealed dilated choroidal vessels and choroidal hyperpermeability in areas corresponding to altered AF on ultra-widefield AF in all 24 eyes. In 20 (83.3%) eyes, dilated vessels were observed in association with 1 or more congested vortex veins ampullas, suggesting that outflow congestion may be a contributing factor to the pathogenesis of CSC. CONCLUSIONS: Ultra-widefield AF and ICG angiography in CSC revealed more widespread disease in a single image than with standard field imaging and may be useful for identifying peripheral areas of previous or ongoing SRF and choroidal hyperpermeability that can assist in the diagnosis of CSC, surveillance of recurrent disease and treatment of active disease. PMID- 24794092 TI - Predicting the need for surgical intervention in pediatric orbital cellulitis. AB - PURPOSE: To investigate the predictive value of the complete ophthalmic examination at first presentation in foreseeing the need for surgery in patients with pediatric orbital cellulitis. DESIGN: Retrospective observational case series. METHODS: We reviewed 136 cases of radiographically confirmed orbital cellulitis between 2004 and 2012 at Children's Hospital Colorado. The presenting ophthalmic examinations, imaging results, medical and surgical interventions, and clinical complications were recorded. The main outcome measures were ophthalmic examinations on presentation, medical or surgical interventions, and complications. RESULTS: The median age was 6.5 years. Of the patients, 56 (41%) underwent surgical intervention, and 80 patients (59%) were managed medically. Patients requiring surgery had higher rates of extraocular motility (EOM) restriction (78.6% vs 38.8% P<0.01), proptosis (64.3% vs 21.2%, P<0.01), elevated intraocular pressure (IOP) (35.7% vs 12.5%, P<0.01), and age over 9 years (58.9% vs 20.0%, P<0.01). Using any combination of the above risk factors at presentation, the probability of surgical intervention increases from 7% (95% confidence interval [CI] 1%-13%) with zero risk factors to 95% (95% CI 89%-100%) with 4 risk factors. CONCLUSIONS: In pediatric orbital cellulitis, the likelihood of surgical intervention can be estimated accurately based on the ophthalmic examination on initial presentation to the hospital. Risk factors for surgery include age older than 9 years, proptosis, EOM restriction, and elevated IOP. These factors may be used to identify patients at high risk for failure of medical management early in the clinical course. PMID- 24794093 TI - Bone mineral density changes following discontinuation of ronacaleret treatment: off-treatment extension of a randomized, dose-finding phase II trial. AB - CONTEXT: Parathyroidectomy in patients with hyperparathyroidism can produce subsequent increases in bone mineral density (BMD). Ronacaleret, a selective calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release, induced mild hyperparathyroidism. OBJECTIVE: The aim of this study is to evaluate whether BMD changes after cessation of ronacaleret treatment. DESIGN: Observational, off-treatment, extension of a randomized, placebo-controlled, dose-ranging phase II trial. SETTING: Fifteen academic centers in seven countries. PATIENTS: Postmenopausal women with low BMD; 171 out of 569 women in the parent study were enrolled in the extension study. INTERVENTIONS: Subjects were treated with ronacaleret 100mg (n=16), 200mg (n=38), 300mg (n=35), or 400mg (n=32) once daily, alendronate 70mg (n=17) once weekly, or matching placebo (n=33) for 10-12months; BMD was measured after discontinuation of ronacaleret or alendronate treatment. MAIN OUTCOME MEASURE: Mean percent change in lumbar spine areal BMD by dual-energy X-ray absorptiometry at 6 12months after discontinuing ronacaleret or alendronate compared with the 10- to 12-month BMD measurement of the parent study. RESULTS: At the lumbar spine, all doses of ronacaleret resulted in gains in BMD while on treatment. These increases in BMD were maintained or increased after discontinuation of ronacaleret. All doses of ronacaleret caused bone loss at the total hip while on active treatment. However, there was an attenuation of this loss in the off-treatment extension study. CONCLUSION: The gain in BMD at the lumbar spine was maintained post treatment and the loss of BMD at the total hip was attenuated. We hypothesize that there may have been some bone remineralization after cessation of ronacaleret. PMID- 24794096 TI - Chylothorax following anterior thoraco-lumbar spine exposure. A case report and review of literature. AB - Pleural effusion is a possible complication of the thoraco-abdominal approach to the spine. It is more commonly a reactive effusion, but it also may be caused by hemothorax, empyema or, less commonly, a chylothorax. The case of a chylothorax is reported as a late onset complication of a double anterior and posterior instrumented fusion of the lumbar spine. Its management and clinical outcome, and a review of the literature is presented. PMID- 24794094 TI - Calcium-dependent PKC isoforms have specialized roles in short-term synaptic plasticity. AB - Posttetanic potentiation (PTP) is a widely observed form of short-term plasticity lasting for tens of seconds after high-frequency stimulation. Here we show that although protein kinase C (PKC) mediates PTP at the calyx of Held synapse in the auditory brainstem before and after hearing onset, PTP is produced primarily by an increased probability of release (p) before hearing onset, and by an increased readily releasable pool of vesicles (RRP) thereafter. We find that these mechanistic differences, which have distinct functional consequences, reflect unexpected differential actions of closely related calcium-dependent PKC isoforms. Prior to hearing onset, when PKCgamma and PKCbeta are both present, PKCgamma mediates PTP by increasing p and partially suppressing PKCbeta actions. After hearing onset, PKCgamma is absent and PKCbeta produces PTP by increasing RRP. In hearing animals, virally expressed PKCgamma overrides PKCbeta to produce PTP by increasing p. Thus, two similar PKC isoforms mediate PTP in distinctly different ways. PMID- 24794097 TI - Treatment effects for dysphagia in Parkinson's disease: a systematic review. AB - BACKGROUND: Dysphagia remains a common problem in Parkinson's disease (PD). Previous systematic reviews on therapy effects for oropharyngeal dysphagia in PD have shown a lack of evidence. In the past 5 years several placebo or sham controlled trials with varying results have been published. OBJECTIVE: The aim of this systematic literature review is to summarize and qualitatively analyze the published studies on this matter. METHOD(S): Studies published up to December 2013 were found via a systematic comprehensive electronic database search using PubMed, Embase, and The Cochrane Library. Two reviewers independently assessed the studies using strict inclusion criteria. RESULT(S): Twelve studies were included and qualitatively analyzed using critical appraisal items. The review includes rehabilitative (exercises, electrical stimulation, bolus modification etc.) and pharmacologic treatment. Some well-designed controlled trials were included. However, none of the included studies fulfilled all criteria for external and internal validity. A meta-analysis was not carried out as most of the studies were not of sufficient quality to warrant doing so. CONCLUSION: Expiratory Muscle Strength Training (EMST) and Video-Assisted Swallowing Therapy (VAST) may be effective dysphagia treatments solely or in addition to dopaminergic therapy for PD. However, these preliminary results warrant further investigation concerning their clinical applicability, and further research should be based on randomized sham-controlled trials to determine the effectiveness and long-term effects of different therapies for dysphagia in PD. PMID- 24794095 TI - Sleep and movement differentiates actions of two types of somatostatin-expressing GABAergic interneuron in rat hippocampus. AB - Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM cells in freely moving rats. Bistratified cells fire at higher rates during sleep than O-LM cells and, unlike O-LM cells, strongly increase spiking during sharp wave-associated ripples (SWRs). In contrast, O-LM interneurons decrease firing during sleep relative to awake states and are mostly inhibited during SWRs. During movement, both cell types fire cooperatively at the troughs of theta oscillations but with different frequencies. Somatostatin and GABA are differentially released to distinct dendritic zones of CA1 pyramidal cells during sleep and wakefulness to coordinate segregated glutamatergic inputs from entorhinal cortex and CA3. PMID- 24794098 TI - Cardiac sympathetic denervation without Lewy bodies in a case of multiple system atrophy. PMID- 24794099 TI - Crude oil treatment leads to shift of bacterial communities in soils from the deep active layer and upper permafrost along the China-Russia Crude Oil Pipeline route. AB - The buried China-Russia Crude Oil Pipeline (CRCOP) across the permafrost associated cold ecosystem in northeastern China carries a risk of contamination to the deep active layers and upper permafrost in case of accidental rupture of the embedded pipeline or migration of oil spills. As many soil microbes are capable of degrading petroleum, knowledge about the intrinsic degraders and the microbial dynamics in the deep subsurface could extend our understanding of the application of in-situ bioremediation. In this study, an experiment was conducted to investigate the bacterial communities in response to simulated contamination to deep soil samples by using 454 pyrosequencing amplicons. The result showed that bacterial diversity was reduced after 8-weeks contamination. A shift in bacterial community composition was apparent in crude oil-amended soils with Proteobacteria (esp. alpha-subdivision) being the dominant phylum, together with Actinobacteria and Firmicutes. The contamination led to enrichment of indigenous bacterial taxa like Novosphingobium, Sphingobium, Caulobacter, Phenylobacterium, Alicylobacillus and Arthrobacter, which are generally capable of degrading polycyclic aromatic hydrocarbons (PAHs). The community shift highlighted the resilience of PAH degraders and their potential for in-situ degradation of crude oil under favorable conditions in the deep soils. PMID- 24794100 TI - Role of atypical antipsychotics in the treatment of generalized anxiety disorder. AB - Evidence-based treatment approaches for generalized anxiety disorder (GAD) comprise psychotherapy, pharmacotherapy, or a combination of the two. First-line pharmacotherapy agents include selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, and, in certain European guidelines, pregabalin, which gained European Commission approval. Although short and long-term efficacy have been established for these agents in controlled trials, response rates of 60-70 % are insufficient, remission rates are relatively modest, and relapse rates considerable. Moreover, questions increasingly arise regarding tolerability and side-effect profiles. As an alternative, antipsychotics have long been of interest for the treatment of anxiety disorders, but investigation had been tempered by their potential for irreversible side effects. With the improved side-effect profiles of atypical antipsychotics, these agents are increasingly being investigated across Axis I disorders. Atypical antipsychotics such as quetiapine, aripiprazole, olanzapine, and risperidone have been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and have since been used in the treatment of a range of mood and anxiety disorders. In this article, we review the efficacy and tolerability of atypical antipsychotics as adjunctive therapy and/or monotherapy for individuals with GAD, a currently off-label indication. The most evidence has accumulated for quetiapine. Findings suggest that approximately 50 % of participants tolerate the side effects, most commonly sedation and fatigue. Among this subset, those who continue treatment demonstrate significant reductions in anxiety when used as adjunctive therapy or monotherapy. The appropriateness of the use of antipsychotics in the treatment of GAD is discussed. PMID- 24794102 TI - Chemotypes sensitivity and predictivity of in vivo outcomes for cytotoxic assays in THLE and HepG2 cell lines. AB - In the present study, we demonstrate the utility of in vitro ATP depletion assays in both THLE and HepG2 cells for predicting the toxicological outcome in Exploratory Toxicology Studies across 446 Pfizer proprietary compounds. Our results suggest a higher likelihood of selecting suitable compounds for in vivo safety studies by using cytotoxicity assays in multiple cell-lines over a single cell line. In addition, we demonstrate that different cell-lines have different sensitivities to compounds depending on their ionization state, that is, acid, base or neutral. HepG2 cells are more sensitive for basic compounds, whereas THLE cells have a relatively higher sensitivity for the acidic and neutral compounds. These in vitro cytotoxicity assays when combined with physicochemical properties (cLogP >3 and topological polar surface area (TPSA) <75A(2)), are the most effective means to prioritize compounds having a lower probability of causing adverse events in vivo. PMID- 24794103 TI - Identification of 2,3-disubstituted pyridines as potent, non-emetic PDE4 inhibitors. AB - A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non emetic PDE4 inhibitor. Compound 1 showed significant efficacy in an animal model of asthma without inducing emesis. PMID- 24794101 TI - Comparative efficacy and risk of harms of immediate- versus extended-release second-generation antidepressants: a systematic review with network meta analysis. AB - BACKGROUND: Major depressive disorder (MDD) has detrimental effects on an individual's personal life, leads to increased risk of comorbidities, and places an enormous economic burden on society. Several 'second-generation' antidepressants are available as both immediate-release (IR) and extended-release formulations. The advantage of extended-release formulations may be the potentially improved adherence and a lower risk of adverse events. OBJECTIVE: We conducted a systematic review to assess the comparative efficacy, risk of harms, and patients' adherence of IR and extended-release antidepressants for the treatment of MDD. DATA SOURCE: English-language abstracts were retrieved from PubMed, EMBASE, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to October 2012, as well as from reference lists of pertinent review articles and grey literature searches. ELIGIBILITY CRITERIA: We included head-to-head randomized controlled trials (RCTs) of at least 6 weeks' duration that compared an IR formulation with an extended-release formulation of the same antidepressant in adult patients with MDD. We also included placebo-controlled trials to conduct a network meta-analysis. To assess harms and adherence, in addition to RCTs, we searched for observational studies with >=1,000 participants and a follow-up of >=12 weeks. STUDY APPRAISAL AND SYNTHESIS METHODS: We dually reviewed abstracts and full texts and assessed quality ratings. Lacking head-to head evidence for many comparisons of interest, we conducted network meta analyses using Bayesian methods. Our outcome measure of choice was response on the Hamilton Depression Rating Scale. RESULTS: We located seven head-to-head trials and 94 placebo- and active-controlled trials for network meta-analysis. Overall, our analyses indicate that IR and extended-release formulations do not differ substantially with respect to efficacy and risk of harms. The evidence is mixed with respect to differences in adherence, indicating lower adherence for IR formulations. LIMITATIONS: The lack of head-to-head comparisons for many drugs compromises our conclusions. Network meta-analyses have methodological limitations that need to be taken into consideration when interpreting findings. CONCLUSION: Available evidence currently shows no clear differences between the two formulations and therefore we cannot recommend a first choice. However, if adherence or compliance with one medication is an issue, then clinicians and patients should consider the alternative medication. If adherence or costs are a problem with one formulation, consideration of the other formulation to provide an adequate treatment trial is reasonable. PMID- 24794104 TI - Serendipitous oxidation product of BIBN4096BS: a potent CGRP receptor antagonist. AB - An oxidation product (5) formed during the synthesis of BIBN-4096BS (1) was found to be a potent CGRP antagonist (IC50=0.11nM). While 5 was found to be ten-fold less potent than 1, another analog 8 with lower molecular weight containing the oxidized fragment demonstrated twenty-fold higher activity than its parent 7. Alternative conditions which preclude the formation of the oxidation product are described. The activities of 1, 5, 7 and 8 in functional cAMP assay are also discussed. PMID- 24794105 TI - alpha-Tetralone derivatives as inhibitors of monoamine oxidase. AB - In the present study, a series of fifteen alpha-tetralone (3,4-dihydro-2H naphthalen-1-one) derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The alpha-tetralone derivatives examined are structurally related to a series of chromone (1 benzopyran-4-one) derivatives which has previously been shown to act as MAO-B inhibitors. The results document that the alpha-tetralones are highly potent MAO B inhibitors with all compounds exhibiting IC50 values in the nanomolar range (<78nM). Although most compounds are selective inhibitors of MAO-B, the alpha tetralones are also potent MAO-A inhibitors with ten compounds exhibiting IC50 values in the nanomolar range (<792nM). The most potent MAO-B inhibitor, 6-(3 iodobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 4.5nM with a 287-fold selectivity for MAO-B over the MAO-A isoform, while the most potent MAO-A inhibitor, 6-(3-cyanobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 24nM with a 3.25-fold selectivity for MAO-A. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C6 position of the alpha-tetralone moiety is a requirement for MAO-A and MAO-B inhibition, and that a benzyloxy substituent on this position is more favourable for MAO-A inhibition than phenylethoxy and phenylpropoxy substitution. For MAO-B inhibition, alkyl and halogen substituents on the meta and para positions of the benzyloxy ring enhance inhibitory potency. It may be concluded that alpha-tetralone derivatives are promising leads for design of therapies for Parkinson's disease and depression. PMID- 24794106 TI - Asymmetric syntheses and bio-evaluation of novel chiral esters derived from substituted tetrafluorobenzyl alcohol. AB - A series of novel chiral esters derived from tetrafluorobenzyl alcohol were designed and prepared via asymmetric synthesis. The target molecules have been identified on the basis of analytical spectra data. All newly synthesized compounds have been screened their potential insecticidal activity against Plutella xylostella compared with those of fenvalerate and d-trans-phenothrin by standard method, and the respective pairs of enantiomers (3-B1-R/S, 3-C1-R/S, 3 D1-R/S) indicated significantly different activities. PMID- 24794108 TI - Synthesis of 5-methyl phenanthridium derivatives: a new class of human DOPA decarboxylase inhibitors. AB - DOPA decarboxylase (DDC) is responsible for the decarboxylation of l-DOPA and related aromatic amino acids and correlates closely with a number of clinical disorders. Sanguinarine, a natural quaternary benzophenanthridine alkaloid (QBA), was reported to be inhibitor of rat DDC and possessed a different inhibitory mechanism. In this study, several natural QBAs were assayed as human DDC inhibitors for the first time. A series of 5-methyl phenanthridium derivatives that contain the basic core structure of QBAs were also synthesized and evaluated as human DDC inhibitors. The title compounds still possessed DDC inhibitory potential. Among the synthesized compounds, 2-hydroxyl-8-methoxy-5 methylphenanthridinium chloride (11k) showed good inhibitory activity with an IC50 value of 0.12mM. Preliminary structure-activity relationship indicated that DDC inhibitory potential of 5-methyl phenanthridium derivatives correlated with the pi-electro densities on CN double bond of iminium cation. The hydroxyl group on compound 11k possibly contributed to the formation of hydrogen bond between DDC and the inhibitor. PMID- 24794107 TI - Benzo[d]isothiazole 1,1-dioxide derivatives as dual functional inhibitors of 5 lipoxygenase and microsomal prostaglandin E(2) synthase-1. AB - A series of 6-nitro-3-(m-tolylamino) benzo[d]isothiazole 1,1-dioxide analogues were synthesized and evaluated for their inhibition activity against 5 lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES-1). These compounds can inhibit both enzymes with IC50 values ranging from 0.15 to 23.6MUM. One of the most potential compounds, 3g, inhibits 5-LOX and mPGES-1 with IC50 values of 0.6MUM, 2.1MUM, respectively. PMID- 24794109 TI - Stability studies on the newly discovered cyclic form of tRNA N(6) threonylcarbamoyladenosine (ct(6)A). AB - A cyclic form of N(6)-threonylcarbamoyladenosine bearing an oxazolone moiety (ct(6)A) was discovered very recently at the position 37 in several tRNA sequences. Our study on the synthesized 5',3',2'-O-acetylated derivative of ct(6)A confirmed high stability of the modified nucleoside under physiological conditions (PBS buffer, pH 7.4) and revealed remarkable stability of the oxazolone ring in acidic (100mM HCl, pH 1) and basic (0.1mM NaOH, pH 10) conditions. This feature may allow for the post-synthetic conversion of t(6)A into ct(6)A in assembled oligoribonucleotides. PMID- 24794110 TI - alpha-Methylated simplified resiniferatoxin (sRTX) thiourea analogues as potent and stereospecific TRPV1 antagonists. AB - A series of alpha-methylated analogues of the potent sRTX thiourea antagonists were investigated as rTRPV1 ligands in order to examine the effect of alpha methylation on receptor activity. The SAR analysis indicated that activity was stereospecific with the (R)-configuration of the newly formed chiral center providing high binding affinity and potent antagonism while the configuration of the C-region was not significant. PMID- 24794111 TI - Cell membrane mediated (-)-epicatechin effects on upstream endothelial cell signaling: evidence for a surface receptor. AB - The consumption of cacao-derived products, particularly in the form of dark chocolate is known to provide beneficial cardiovascular effects in normal individuals and in those with vascular dysfunction (reduced nitric oxide [NO] bioavailability and/or synthesis). Upstream mechanisms by which flavonoids exert these effects are poorly understood and may involve the participation of cell membrane receptors. We previously demonstrated that the flavanol (-)-epicatechin (EPI) stimulates NO production via Ca(+2)-independent eNOS activation/phosphorylation. We wished to investigate the plausible participation of a cell surface receptor using a novel cell-membrane impermeable EPI-Dextran conjugate (EPI-Dx). Under Ca(2+)-free conditions, human coronary artery endothelial cells (HCAEC) were treated for 10min with EPI or EPI-Dx at equimolar concentrations (100nM). Results demonstrate that both EPI and EPI-Dx induced the phosphorylation/activation of PI3K, PDK-1, AKT and eNOS. Interestingly, EPI-Dx effects were significantly higher in magnitude than those of EPI alone. The capacity of EPI-Dx to stimulate cell responses supports the existence of an EPI cell membrane receptor mediating eNOS activation. PMID- 24794112 TI - Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu(2)/mGlu(3) NAMs. AB - Herein we report the design and synthesis of a series of substituted pyrazolo[1,5 a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu2 and mGlu3, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu2/mGlu3 NAMs, with excellent selectivity versus the other mGluRs. PMID- 24794113 TI - Genetic shifting: a novel approach for controlling vector-borne diseases. AB - Rendering populations of vectors of diseases incapable of transmitting pathogens through genetic methods has long been a goal of vector geneticists. We outline a method to achieve this goal that does not involve the introduction of any new genetic variants to the target population. Rather we propose that shifting the frequencies of naturally occurring alleles that confer refractoriness to transmission can reduce transmission below a sustainable level. The program employs methods successfully used in plant and animal breeding. Because no artificially constructed genetically modified organisms (GMOs) are introduced into the environment, the method is minimally controversial. We use Aedes aegypti and dengue virus (DENV) for illustrative purposes but point out that the proposed program is generally applicable to vector-borne disease control. PMID- 24794114 TI - A dawning demand for a new cannabis policy: A study of Swedish online drug discussions. AB - BACKGROUND: This study examines how online discussions on drug policy are formulating an oppositional cannabis discourse in an otherwise prohibitionist country like Sweden. The focus of the paper is to identify demands for an alternative cannabis policy as well as analysing how these demands are linked to governance. METHODS: The empirical material is 56 discussion-threads from the online message-board Flashback Forum that were active during the first eight months of 2012. Discourse theory was used to locate the discourse, and governmentality theory was used to locate the political belonging of the discourse. RESULTS: On Flashback Forum demands for a new cannabis policy are articulated in opposition to Swedish prohibitionist discourse. The oppositional discourse is constructed around the nodal points cannabis, harm, state and freedom that fill legalisation/decriminalisation/liberalisation with meaning. The nodal points are surrounded by policy demands that get their meaning through the particular nodal. These demands originate from neo-liberal and welfarist political rationalities. Neo-liberal and welfarist demands are mixed, and participants are simultaneously asking for state and individual approaches to handle the cannabis issue. CONCLUSION: Swedish online discourse on cannabis widens the scope beyond the confines of drug policy to broader demands such as social justice, individual choice and increased welfare. These demands are not essentially linked together and many are politically contradictory. This is also significant for the discourse; it is not hegemonised by a political ideology. The discourse is negotiated between the neo-liberal version of an alternative policy demanding individual freedom, and the welfarist version demanding social responsibility. This implies the influence of the heritage from the social democratic discourse, centred on state responsibility, which have been dominating Swedish politics in modern times. Consequently, this study refutes that the demand for a new cannabis policy is strictly neo-liberal. PMID- 24794116 TI - Is it finally time to dispel the concept of metabolically-healthy obesity? PMID- 24794117 TI - One weapon, two blows in the war against the thrombus. PMID- 24794115 TI - Rotor stability separates sustained ventricular fibrillation from self terminating episodes in humans. AB - OBJECTIVES: This study mapped human ventricular fibrillation (VF) to define mechanistic differences between episodes requiring defibrillation versus those that spontaneously terminate. BACKGROUND: VF is a leading cause of mortality; yet, episodes may also self-terminate. We hypothesized that the initial maintenance of human VF is dependent upon the formation and stability of VF rotors. METHODS: We enrolled 26 consecutive patients (age 64 +/- 10 years, n = 13 with left ventricular dysfunction) during ablation procedures for ventricular arrhythmias, using 64-electrode basket catheters in both ventricles to map VF prior to prompt defibrillation per the institutional review board-approved protocol. A total of 52 inductions were attempted, and 36 VF episodes were observed. Phase analysis was applied to identify biventricular rotors in the first 10 s or until VF terminated, whichever came first (11.4 +/- 2.9 s to defibrillator charging). RESULTS: Rotors were present in 16 of 19 patients with VF and in all patients with sustained VF. Sustained, but not self-limiting VF, was characterized by greater rotor stability: 1) rotors were present in 68 +/- 17% of cycles in sustained VF versus 11 +/- 18% of cycles in self-limiting VF (p < 0.001); and 2) maximum continuous rotations were greater in sustained (17 +/- 11, range 7 to 48) versus self-limiting VF (1.1 +/- 1.4, range 0 to 4, p < 0.001). Additionally, biventricular rotor locations in sustained VF were conserved across multiple inductions (7 of 7 patients, p = 0.025). CONCLUSIONS: In patients with and without structural heart disease, the formation of stable rotors identifies individuals whose VF requires defibrillation from those in whom VF spontaneously self-terminates. Future work should define the mechanisms that stabilize rotors and evaluate whether rotor modulation may reduce subsequent VF risk. PMID- 24794118 TI - Antithrombotic treatment in patients with heart failure and associated atrial fibrillation and vascular disease: a nationwide cohort study. AB - OBJECTIVES: The aim of this study was to investigate the impact of atrial fibrillation (AF) and antithrombotic treatment on the prognosis in patients with heart failure (HF) as well as vascular disease. BACKGROUND: HF, vascular disease, and AF are pathophysiologically related, and understanding antithrombotic treatment for these conditions is crucial. METHODS: In hospitalized patients with HF and coexisting vascular disease (coronary artery disease or peripheral arterial disease) followed from 1997 to 2009, AF status was categorized as prevalent AF, incident AF, or no AF. Risk of thromboembolism (TE), myocardial infarction (MI), and serious bleeding was assessed by Cox regression models (hazard ratio [HR] with 95% confidence interval [CI]) with antithrombotic therapy and AF as time-dependent variables. RESULTS: A total of 37,464 patients were included (age, 74.5 +/- 10.7 years; 36.3% females) with a mean follow-up of 3 years during which 20.7% were categorized as prevalent AF and 17.2% as incident AF. Compared with vitamin K antagonist (VKA) in prevalent AF, VKA plus antiplatelet was not associated with a decreased risk of TE (HR: 0.91; 95% CI: 0.73 to 1.12) or MI (HR: 1.11; 95% CI: 0.96 to 1.28), whereas bleeding risk was significantly increased (HR: 1.31; 95% CI: 1.09 to 1.57). Corresponding estimates for incident AF were HRs of 0.77 (95% CI: 0.56 to 1.06), 1.07 (95% CI: 0.89 to 1.28), and 2.71 (95% CI: 1.33 to 2.21) for TE, MI, and bleeding, respectively. In no AF patients, no statistical differences were seen between antithrombotic therapies in TE or MI risk, whereas bleeding risk was significantly increased for VKA with and without single-antiplatelet therapy. CONCLUSIONS: In AF patients with coexisting HF and vascular disease, adding single-antiplatelet therapy to VKA therapy is not associated with additional benefit in thromboembolic or coronary risk, but notably increased bleeding risk. PMID- 24794119 TI - Metabolically-healthy obesity and coronary artery calcification. AB - OBJECTIVES: The purpose of this study was to compare the coronary artery calcium (CAC) scores of metabolically-healthy obese (MHO) and metabolically healthy normal-weight individuals in a large sample of apparently healthy men and women. BACKGROUND: The risk of cardiovascular disease among obese individuals without obesity-related metabolic abnormalities, referred to as MHO, is controversial. METHODS: We conducted a cross-sectional study of 14,828 metabolically-healthy adults with no known cardiovascular disease who underwent a health checkup examination that included estimation of CAC scores by cardiac tomography. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homeostasis model assessment of insulin resistance <2.5. RESULTS: MHO individuals had a higher prevalence of coronary calcification than normal weight subjects. In multivariable-adjusted models, the CAC score ratio comparing MHO with normal-weight participants was 2.26 (95% confidence interval: 1.48 to 3.43). In mediation analyses, further adjustment for metabolic risk factors markedly attenuated this association, which was no longer statistically significant (CAC score ratio 1.24; 95% confidence interval: 0.79 to 1.96). These associations did not differ by clinically-relevant subgroups. CONCLUSIONS: MHO participants had a higher prevalence of subclinical coronary atherosclerosis than metabolically-healthy normal-weight participants, which supports the idea that MHO is not a harmless condition. This association, however, was mediated by metabolic risk factors at levels below those considered abnormal, which suggests that the label of metabolically healthy for obese subjects may be an artifact of the cutoff levels used in the definition of metabolic health. PMID- 24794120 TI - Pulmonary hypertension of sickle cell disease beyond classification constraints. PMID- 24794121 TI - Reply: the latest generation of troponin immunoassays: the "cholesterol" of the third millennium? PMID- 24794122 TI - Is it not timely to consider how to balance cardiorenometabolic benefits and risks of statins? PMID- 24794123 TI - Reply: is it not timely to consider how to balance cardiorenometabolic benefits and risks of statins? PMID- 24794124 TI - Reply: pulmonary hypertension of sickle cell disease beyond classification constraints. PMID- 24794125 TI - Placebo in autologous cell-based interventions: hard pill to swallow? PMID- 24794126 TI - The latest generation of troponin immunoassays: the "cholesterol" of the third millennium? PMID- 24794127 TI - Analysis of feasibility of in vitro nuclear magnetic resonance tracking human umbilical cord mesenchymal stem cells by Gd-DTPA labeled. AB - OBJECTIVE: Three different kinds of transfection reagents were used to mediate the transfection of gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) into human umbilical-cord-derived mesenchymal stem cells (hUCMSCs). The efficacy of different transfection reagents and the feasibility of NMR tracer in vitro of magnetized stem cells were estimated. METHODS: After purification by tissue explants adherent method, the biological characteristics of hUCMSCs in vitro were identified by subculture and amplification. Calcium phosphate, Effectene and liposome2000 were used to transfect Gd-DTPA-labeled hUCMSCs respectively, and cell counting was used to mediate the transfection of Gd-DTPA into hUCMSCs, which were then induced to lipoblast and osteoblast in vitro. The determination of the transfection activities of the transfection reagents was conducted by measuring the magnetic resonance imaging (MRI) signal intensity of the Gd-DTPA-labeled cells and the concentration of gadolinium ion in the cells. Furthermore, the relationship between the signal intensity of Gd-DTPA-labeled hUCMSCsMRI, cell subculture and generations was studied. RESULTS: Primary cells were obtained by tissue explants adherent for two weeks. The cells displayed a long spindle form and grew in swirl. After two passage generations, the cellular morphology became more homogeneous. The result detected by the flow cytometer showed that CD29C, D44, CD90, and CD105 were highly expressed, while no CD45, CD40, and HLA-DR expression was detected in the third generation cells. Directional induction in vitro caused the differentiation into lipoblast and osteoblast. After transfected by calcium phosphate, Effectene and liposome 2000, the signal intensity of stem cells was 2281.2+/-118.8, 2031.9+/-59.7 and 1887.4+/-40.8 measured by MRI. Differences between these three groups were statistically significant (P<0.05). The concentrations of gadolinium ion in three groups of stem cells were 0.178+/ 0.009mg/L, 0.158+/-0.003mg/L and 0.120+/-0.002mg/L respectively, examined by inductively coupled plasma atomic emission spectrometry. No significant differences were found among these three groups (P<0.05). The proliferation and differentiation abilities of the Gd-DTPA-labeled stem cells were not affected. A minimum 5*10(4) Gd-DTPA-labeled stem cells could be traced with MRI in vitro and presented in high signal. The trace duration time in vitro was about 12days. CONCLUSIONS: Tissue explants adherent method can be availably applied to purify hUCMSCs. The Effectene method was proved to have the best transfection effect. The proliferation ability and differentiation potency of Gd-DTPA-labeled hUCMSCs were not affected, and the NMR of labeled stem cells in vitro was proved to be feasible. PMID- 24794128 TI - Interview with Jeffrey L. Dangl. PMID- 24794129 TI - Junior scientists are sceptical of sceptics of open access: a reply to Agrawal. PMID- 24794131 TI - Interview with Rebecca A. Mosher. PMID- 24794130 TI - Retention mechanisms for ER and Golgi membrane proteins. AB - Unless there are mechanisms to selectively retain membrane proteins in the endoplasmic reticulum (ER) or in the Golgi apparatus, they automatically proceed downstream to the plasma or vacuole membranes. Two types of coat protein complex I (COPI)-interacting motifs in the cytosolic tails of membrane proteins seem to facilitate membrane retention in the early secretory pathway of plants: a dilysine (KKXX) motif (which is typical of p24 proteins) for the ER and a KXE/D motif (which occurs in the Arabidopsis endomembrane protein EMP12) for the Golgi apparatus. The KXE/D motif is highly conserved in all eukaryotic EMPs and is additionally present in hundreds of other proteins of unknown subcellular localization and function. This novel signal may represent a new general mechanism for Golgi targeting and the retention of polytopic integral membrane proteins. PMID- 24794132 TI - Open access is worth considering: a reply to Agrawal. PMID- 24794134 TI - Walk into the Light Response: Direct Targets of Phytochrome A Include Genes That Respond to Light, Stress, and Hormones. PMID- 24794133 TI - Arabidopsis Phytochrome A Directly Targets Numerous Promoters for Individualized Modulation of Genes in a Wide Range of Pathways. AB - The far-red light (FR) photoreceptor phytochrome A (phyA) contains no DNA binding domain but associates with the CHALCONE SYNTHASE promoter through its chaperone FAR-RED ELONGATED HYPOCOTYL1 and transcription factors. Here, we performed a genome-wide identification of phyA targets using a combination of phyA chromatin immunoprecipitation and RNA sequencing methods in Arabidopsis thaliana. Our results indicate that phyA signaling widely affects gene promoters involved in multiple FR-modulated aspects of plant growth. Furthermore, we observed an enrichment of hormone- and stress-responsive elements in the phyA direct target promoters, indicating that a much broader than expected range of transcription factors is involved in the phyA signaling pathway. To verify our hypothesis that phyA regulates genes other than light-responsive ones through the interaction with corresponding transcription factors, we examined the action of phyA on one of its direct target genes, NAC019, which encodes an abscisic acid-dependent transcription factor. The phyA signaling cascade not only targets two G-boxes on the NAC019 promoter for subsequent transcriptional regulation but also positively coordinates with the abscisic acid signaling response for root elongation inhibition under FR. Our study provides new insight into how plants rapidly fine tune their growth strategy upon changes in the light environment by escorting photoreceptors to the promoters of hormone- or stress-responsive genes for individualized modulation. PMID- 24794135 TI - Arabidopsis Transporter MGT6 Mediates Magnesium Uptake and Is Required for Growth under Magnesium Limitation. AB - Although magnesium (Mg2+) is the most abundant divalent cation in plant cells, little is known about the mechanism of Mg2+ uptake by plant roots. Here, we report a key function of Magnesium Transport6 (MGT6)/Mitochondrial RNA Splicing2 4 in Mg2+ uptake and low-Mg2+ tolerance in Arabidopsis thaliana. MGT6 is expressed mainly in plant aerial tissues when Mg2+ levels are high in the soil or growth medium. Its expression is highly induced in the roots during Mg2+ deficiency, suggesting a role for MGT6 in response to the low-Mg2+ status in roots. Silencing of MGT6 in transgenic plants by RNA interference (RNAi) resulted in growth retardation under the low-Mg2+ condition, and the phenotype was restored to normal growth after RNAi plants were transferred to Mg2+-sufficient medium. RNAi plants contained lower levels of Mg2+ compared with wild-type plants under low Mg2+ but not under Mg2+-sufficient conditions. Further analysis indicated that MGT6 was localized in the plasma membrane and played a key role in Mg2+ uptake by roots under Mg2+ limitation. We conclude that MGT6 mediates Mg2+ uptake in roots and is required for plant adaptation to a low-Mg2+ environment. PMID- 24794136 TI - Agreement between assays of cell-mediated immunity utilizing Mycobacterium bovis specific antigens for the diagnosis of tuberculosis in African buffaloes (Syncerus caffer). AB - We assessed the use of Mycobacterium bovis-specific peptides for the diagnosis of tuberculosis in African buffaloes (Syncerus caffer) by evaluating the agreement between the single intradermal comparative tuberculin test (SICTT), the Bovigam((r)) EC (BEC) assay, the Bovigam((r)) HP (BHP) assay and two assays utilizing the QuantiFERON((r)) TB-Gold (in tube) system employing 20 h (mQFT20 assay) and 30 h (mQFT30 assay) whole blood incubation periods. Of 84 buffaloes, 45% were SICTT-positive, 48% were BEC-positive, 50% were BHP-positive, 37% were mQFT20-positive and 43% were mQFT30-positive. Agreement between the BEC and BHP Bovigam((r)) assays was high (kappa=0.86, 95% CI 0.75-0.97) and these detected the most test-positive animals suggesting that they were the most sensitive assays. Interferon-gamma release was significantly greater in buffaloes that were test-positive for all tests than in animals with discordant but positive Bovigam((r)) results. Agreement between the mQFT assays was equally high (kappa=0.88, 95% CI 0.77-0.98); however, all buffaloes with discordant mQFT results (n=6) were mQFT30-positive/mQFT20-negative, including three confirmed M. bovis-infected animals, suggesting that the mQFT30 assay is the more sensitive of the two. Agreements between the two Bovigam((r)) and two mQFT assays were moderate, suggesting that in its current format the mQFT assay is less sensitive than either the BEC or the BHP assays. PMID- 24794138 TI - Life-history parameters of the Colorado potato beetle, Leptinotarsa decemlineata, on seven commercial cultivars of potato, Solanum tuberosum. AB - The Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), is an important pest of potato, Solanum tuberosum L. (Solanales: Solanaceae), crops in the Ardabil region of Iran. In this research, the life history parameters of L. decemlineata were investigated on seven potato cultivars, namely Agria, Aozonia, Diamant, Cosmus, Kondor, Morene, and Savalan, in a greenhouse at 23 +/- 1 degrees C and 55 +/- 5% RH under a natural photoperiod. The results indicated that the development time of larvae was longest on Savalan (18.3 days) among the tested potato cultivars. The survival rates (egg to adult) on Savalan and Morene were significantly lower than on the other studied cultivars. L. decemlineata reared on Savalan had the lowest fecundity (286.3 eggs/female) among the tested potato cultivars. The oviposition period of females was significantly shorter on Savalan and Diamant than on Kondor, Aozonia, Morene, Agria, and Cosmus. The values of intrinsic rate of natural increase and population growth rate were lowest on Savalan (0.055 and 1.056, respectively). The generation time and doubling time were significantly longest on Savalan (69.5 and 12.7 days, respectively). Based on these results, it can be concluded that Savalan is the least suitable cultivar for L. decemlineata among the ones tested. These results can be useful in integrated management of L. decemlineata in potato fields. PMID- 24794137 TI - DFT study of the Lewis acid mediated synthesis of 3-acyltetramic acids. AB - The synthesis of 3-acyltetramic acids by C-acylation of pyrrolidine-2,4-diones was studied by density functional theory (DFT). DFT was applied to the mycotoxin tenuazonic acid (TeA), an important representative of these bioactive natural compounds. Lewis acid mediated C-acylation in combination with previous pH neutral domino N-acylation-Wittig cyclization can be used for the efficient preparation of 3-acyltetramic acids. Nevertheless, quite harsh conditions are still required to carry out this synthetic step, leading to unwanted isomerization of stereogenic centers in some cases. In the presented study, the reaction pathway for the C-acetylation of (5S,6S-5-s-butylpyrrolidine-2,4-dione was studied in terms of mechanism, solvent effects, and Lewis acid activation, in order to obtain an appropriate theoretical model for further investigations. Crucial steps were identified that showed rather high activation barriers and rationalized previously reported experimental discoveries. After in silico optimization, aluminum chlorides were found to be promising Lewis acids that promote the C-acylation of pyrrolidine-2,4-diones, whereas calculations performed in various organic solvents showed that the solvent had only a minor effect on the energy profiles of the considered mechanisms. This clearly indicates that further synthetic studies should focus on the Lewis-acidic mediator rather than other reaction parameters. Additionally, given the results obtained for different reaction routes, the stereochemistry of this C-acylation is discussed. It is assumed that the formation of Z-configured TeA is favored, in good agreement with our previous studies. PMID- 24794140 TI - Importance of persistent elevation of cardiac biomarkers in atrial fibrillation: a RE-LY substudy. AB - OBJECTIVES: To evaluate the prognostic importance of transient or persistent elevations of cardiac troponin-I (cTnI) and N-terminal-B-type natriuretic peptide (NT-proBNP) in atrial fibrillation (AF). METHODS: Plasma samples were obtained at randomisation and after 3 months in 2514 patients with AF in the RE-LY trial; median follow-up was 2.0 years. Patients were grouped based on levels at the two time points according to detectable cTnI levels (>=0.01 ug/L) or NT-proBNP levels above median (>=778 ng/L). These groups were related to occurrence of stroke or cardiovascular events evaluated with Cox models adjusting for established risk factors. RESULTS: The proportion of patients with detectable cTnI levels at both time points was 48.5%, at one time point 28.5% and at neither time point 21.0%. Patients with detectable cTnI at both time points had substantially higher rates of stroke compared with those with transient elevations and those with no elevation at either time point (p<0.005, effect of cTnI). Persistent elevation of either or both cardiac biomarkers at baseline and 3 months was associated with a higher risk for cardiovascular events and mortality (p<0.0001). Prognostic prediction improved most with the use of repeated measurements of both cardiac biomarkers simultaneously (p<0.05) and achieved C-statistic 0.644 for stroke compared with 0.611 for CHADS2-score. CONCLUSIONS: Persistent elevation of troponin and NT-proBNP indicates a worse prognosis than transient elevations or no elevations of either marker. Prognostication of stroke, death and thromboembolic events is improved by the use of repeated determinations of cardiac biomarkers. TRIAL REGISTRATION NUMBER: http://www.clinicaltrials.gov, NCT00262600. PMID- 24794139 TI - The contribution of educational class in improving accuracy of cardiovascular risk prediction across European regions: The MORGAM Project Cohort Component. AB - OBJECTIVE: To assess whether educational class, an index of socioeconomic position, improves the accuracy of the SCORE cardiovascular disease (CVD) risk prediction equation. METHODS: In a pooled analysis of 68 455 40-64-year-old men and women, free from coronary heart disease at baseline, from 47 prospective population-based cohorts from Nordic countries (Finland, Denmark, Sweden), the UK (Northern Ireland, Scotland), Central Europe (France, Germany, Italy) and Eastern Europe (Lithuania, Poland) and Russia, we assessed improvements in discrimination and in risk classification (net reclassification improvement (NRI)) when education was added to models including the SCORE risk equation. RESULTS: The lowest educational class was associated with higher CVD mortality in men (pooled age-adjusted HR=1.64, 95% CI 1.42 to 1.90) and women (HR=1.31, 1.02 to 1.68). In men, the HRs ranged from 1.3 (Central Europe) to 2.1 (Eastern Europe and Russia). After adjustment for the SCORE risk, the association remained statistically significant overall, in the UK and Eastern Europe and Russia. Education significantly improved discrimination in all European regions and classification in Nordic countries (clinical NRI=5.3%) and in Eastern Europe and Russia (NRI=24.7%). In women, after SCORE risk adjustment, the association was not statistically significant, but the reduced number of deaths plays a major role, and the addition of education led to improvements in discrimination and classification in the Nordic countries only. CONCLUSIONS: We recommend the inclusion of education in SCORE CVD risk equation in men, particularly in Nordic and East European countries, to improve social equity in primary prevention. Weaker evidence for women warrants the need for further investigations. PMID- 24794141 TI - The single-ventricle patient population: a current and future concern a population-based study in the North of England. AB - OBJECTIVE: To estimate the size and characteristics of the UK population with single-ventricle physiology, and predict future population growth. METHODS: The surviving population with single-ventricle physiology in Northern England (resident population 2.9 million) was identified from our clinical database and the Northern Congenital Abnormality Survey (NorCAS). Conditions included double inlet ventricle, tricuspid atresia, mitral atresia, hypoplastic left heart syndrome and other unbalanced defects. Fetal diagnoses, terminations of pregnancy and surgical interventions were reviewed. Childhood and adult prevalence of single-ventricle physiology were calculated. Current and future National population figures were estimated using expected mortality derived from literature. RESULTS: 80 children and 48 adults with single-ventricle physiology were identified in the NorCAS region. The most frequent underlying condition in childhood was hypoplastic left heart, and among adults was double inlet ventricle. All children over 5 years of age had completed a Fontan repair (89%) or had a Glenn anastomosis. Seven adults had not undergone a Glenn shunt or Fontan procedure. Of those patients over 30 years of age (n=12), 50% were New York Heart Association (NYHA) functional class 3, compared to 3% of those under 30 years (p=0.001). Regional childhood and adult prevalence of single-ventricle physiology was 16 and 2 per 100 000, respectively. CONCLUSIONS: The current UK single-ventricle population is composed of around 1040 adults and 1700 children. Adult numbers will increase by over 60% in the next decade with the proportion in NHYA functional class 3 set to double. PMID- 24794142 TI - Time reproduction during high and low attentional tasks in Alzheimer's Disease. "A watched kettle never boils". AB - A wealth of empirical evidence suggests that directing attention to temporal processing increases perceived duration, whereas drawing attention away from it has the opposite effect. Our work investigates this phenomenon by comparing perceived duration during a high attentional and a low attentional task in Alzheimer's Disease (AD) patients since these participants tend to show attentional deficits. In the high attentional task, AD patients and older adults were asked to perform the interference condition of the Stroop test for 15s while in the low attentional task, they had to fixate on a cross for the same length of time. In both conditions, participants were not aware they would be questioned about timing until the end of the task when they had to reproduce the duration of the previously-viewed stimulus. AD patients under-reproduced the duration of previously-exposed stimulus in the high attentional relative to the low attentional task, and the same pattern was observed in older adults. Due to their attentional deficits, AD patients might be overwhelmed by the demand of the high attentional task, leaving very few, if any, attentional resources for temporal processing. PMID- 24794143 TI - Modelling time-resolved two-dimensional electronic spectroscopy of the primary photoisomerization event in rhodopsin. AB - Time-resolved two-dimensional (2D) electronic spectra (ES) tracking the evolution of the excited state manifolds of the retinal chromophore have been simulated along the photoisomerization pathway in bovine rhodopsin, using a state-of-the art hybrid QM/MM approach based on multiconfigurational methods. Simulations of broadband 2D spectra provide a useful picture of the overall detectable 2D signals from the near-infrared (NIR) to the near-ultraviolet (UV). Evolution of the stimulated emission (SE) and excited state absorption (ESA) 2D signals indicates that the S1 -> SN (with N >= 2) ESAs feature a substantial blue-shift only after bond inversion and partial rotation along the cis -> trans isomerization angle, while the SE rapidly red-shifts during the photoinduced skeletal relaxation of the polyene chain. Different combinations of pulse frequencies are proposed in order to follow the evolution of specific ESA signals. These include a two-color 2DVis/NIR setup especially suited for tracking the evolution of the S1 -> S2 transitions that can be used to discriminate between different photochemical mechanisms of retinal photoisomerization as a function of the environment. The reported results are consistent with the available time-resolved pump-probe experimental data, and may be used for the design of more elaborate transient 2D electronic spectroscopy techniques. PMID- 24794144 TI - Endoplasmic reticulum protein 29 protects cortical neurons from apoptosis and promoting corticospinal tract regeneration to improve neural behavior via caspase and Erk signal in rats with spinal cord transection. AB - Following spinal cord injury (SCI), limit spontaneous functional recovery often emerged. However, the neuronal mechanisms associated with this phenomenon still remains obscure. By using proteomics analysis, endoplasmic reticulum protein 29 (ERp29) was discovered to increase in the motor cortexes of spinal cord transection (SCT) rats for 28 days post-operation (dpo) compared with in 14dpo. Then, the change in the expression of ERp29 was confirmed by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot. To determine the role of ERp29 in the recovery of locomotor functions following SCT, lentiviral vectors were used to up- and downregulate the expression level of ERp29. Here, we found that cortical neurons in vitro with high level of ERp29 expression exhibited a significant proliferation, characterized by smaller size of soma and more extensive axon outgrowth, compared with neurons used as control, while ERp29 silence got the opposite results. In vivo, Lentivirus was inject into the cerebral cortex following SCT at thoracic level 10, which resulted in an increase number of neuronal nuclei(NeuN)-positive cells and less apoptotic cells. Moreover, increased PKC-gamma immunoreactivity density was also found in the spinal cord T9 level compared with control rats. This was associated with a great functional improvement, indicated by Basso, Beattie, Bresnahan (BBB) locomotor rating scale. Lastly, we verified that ERp29 acts as a regulator by regulating a group of genes related with cell survival and apoptosis, involving in caspase and Erk, but not PI3K. Our findings showed that ERp29 can improve locomotor function by promoting neuronal survival and axonal regeneration in SCT rats via caspase and Erk signal pathway. PMID- 24794145 TI - Neurochemical properties of the synapses between the parabrachial nucleus-derived CGRP-positive axonal terminals and the GABAergic neurons in the lateral capsular division of central nucleus of amygdala. AB - The lateral capsular division of central nucleus of amygdala (CeC) contains neurons using gamma-amino butyric acid (GABA) as the predominant neurotransmitter and expresses abundant calcitonin gene-related peptide (CGRP)-positive terminals. However, the relationship between them has not been revealed yet. Using GAD67 green fluorescent protein (GFP) knock-in mouse, we investigated the neurochemical features of synapses between CGRP-positive terminals and GABAergic neurons within CeC and the potential involvement of CGRP1 receptor by combining fluorescent in situ hybridization for CGRP1 receptor mRNA with immunofluorescent histochemistry for GFP and CGRP. The ultrastructures of these synapses were investigated with pre-embedding electron microscopy for GFP and CGRP. We found that some GABAergic neurons in the CeC received parabrachial nucleus (PBN) derived CGRP innervations and some of these GABAergic neurons can be activated by subcutaneous injection of formalin. Moreover, more than 90 % GABAergic neurons innervated by CGRP-positive terminal also express CGRP1 receptor mRNA. The CGRP-positive fibers made symmetric synapses onto the GABAergic somata, and asymmetric synapses onto the GABA-LI dendritic shafts and spines. This study provides direct ultrastructural evidences for the synaptic contacts between CGRP-positive terminals and GABAergic neurons within the CeC, which may underlie the pain-related neural pathway from PBN to CeC and be involved in the chronic pain modulation. PMID- 24794147 TI - CR1 in Alzheimer's disease. AB - The complement component receptor 1 gene (CR1), which encodes a type-I transmembrane glycoprotein, has recently been identified as one of the most important risk genes for late-onset Alzheimer's disease (LOAD). In this article, we reviewed the recent evidence concerning the role of CR1 in LOAD. First, we introduced the structure, localization and physiological function of CR1 in humans. Afterward, we summarized the relation of CR1 polymorphisms with LOAD risk. Finally, we discussed the possible impact of CR1 on the pathogenesis of AD including amyloid-beta pathology, tauopathy, immune dysfunction and glial mediated neuroinflammation. We hope that a more comprehensive understanding of the role that CR1 played in AD may lead to the development of novel therapeutics for the prevention and treatment of AD. PMID- 24794148 TI - Elution of High-affinity (>10-9 KD) Antibodies from Tissue Sections: Clues to the Molecular Mechanism and Use in Sequential Immunostaining. AB - Inconsistent results obtained with published methods for the elution of antibodies from tissue sections prompted the assessment of both old and new methods in combination with monoclonal rabbit antibodies of known, increased affinity (above 1*10(-9) KD). We tested an acidic (pH 2) glycine buffer, a 6 M urea hot buffer and a 2-Mercaptoethanol, SDS buffer (2-ME/SDS). Some antibodies were not removed by the glycine pH 2 or 6 M urea hot buffers, indicating that antibodies survive much harsher conditions than previously believed. We found that the elution is dependent upon the antibody affinity and is reduced by species-specific crosslinking via a dimeric or Fab fragments of a secondary antibody. The high affinity bond of exogenous streptavidin with the endogenous biotin can be removed by 6 M urea but not by the other buffers. 2-ME/SDS buffer is superior to glycine pH 2 and 6 M urea hot elution buffers for all antibodies because of its irreversible effect on the structure of the antibodies. It also has a mild retrieving effect on some antigens present on routinely treated sections and no detrimental effect on the immunoreactivity of the tissue. Therefore, 2-ME/SDS buffer is the method of choice to perform multiple rounds of immunostaining on a single routine section. PMID- 24794149 TI - Clinically important changes in individual and composite measures of rheumatoid arthritis activity: thresholds applicable in clinical trials. AB - OBJECTIVE: Thresholds of minimal clinically important improvement (MCII) are needed to plan and interpret clinical trials. We estimated MCIIs for the rheumatoid arthritis (RA) activity measures of patient global assessment, pain score, Health Assessment Questionnaire Disability Index (HAQ), Disease Activity Score-28 (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). METHODS: In this prospective longitudinal study, we studied 250 patients who had active RA. Disease activity measures were collected before and either 1 month (for patients treated with prednisone) or 4 months (for patients treated with disease modifying medications or biologics) after treatment escalation. Patient judgments of improvement in arthritis status were related to prospectively assessed changes in the measures. MCIIs were changes that had a specificity of 0.80 for improvement based on receiver operating characteristic curve analysis. We used bootstrapping to provide estimates with predictive validity. RESULTS: At baseline, the mean (+/-SD) DAS28-ESR (erythrocyte sedimentation rate) was 6.16+/-1.2 and mean SDAI was 38.6+/-14.8. Improvement in overall arthritis status was reported by 167 patients (66.8%). Patients were consistent in their ratings of improvement versus no change or worsening, with receiver operating characteristic curve areas >=0.74. MCIIs with a specificity for improvement of 0.80 were: patient global assessment -18, pain score -20, HAQ 0.375, DAS28-ESR -1.2, DAS28-CRP (C-reactive protein) -1.0, SDAI -13, and CDAI 12. CONCLUSIONS: MCIIs for individual core set measures were larger than previous estimates. Reporting the proportion of patients who meet these MCII thresholds can improve the interpretation of clinical trials in RA. PMID- 24794150 TI - Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFalpha therapy. PMID- 24794151 TI - Aiming for SDAI remission versus low disease activity at 1 year after inclusion in ESPOIR cohort is associated with better 3-year structural outcomes. AB - OBJECTIVES: Using data for patients with early rheumatoid arthritis (RA) from the ESPOIR cohort, we aimed to evaluate the impact of remission versus low disease activity (LDA) by the Simple Disease Activity Index (SDAI) at 1 year on 3-year structural damage assessed by the modified Sharp-van der Heijde total score (mTSS) and functional impairment assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). METHODS: We included 625 patients from the ESPOIR cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and had an SDAI score at 1 year. mTSS and HAQ-DI scores were compared at 3 years for patients with SDAI remission or LDA status at 1 year. A linear mixed model was used to assess the independent effect of SDAI status at 1 year on mTSS and HAQ-DI at 3 years. RESULTS: Of the 625 patients included (mean (SD) age 48.5 (12.1) years; 491 (78.6%) were women), 121 (19.4%) were in SDAI remission and 223 (35.7%) in LDA at 1 year. The mean (SD) mTSS and HAQ-DI score at 3 years was 9.6 (9.2) and 0.23 (0.42), respectively, for patients in remission at 1 year and 15.8 (16.1) and 0.43 (0.52), respectively, for patients with LDA (both p<0.05). Multivariate analysis revealed an association of remission rather than LDA status at 1 year and reduced mTSS score (p=0.005) but not HAQ-DI score (p=0.4) at 3 years. CONCLUSIONS: Aiming for SDAI remission rather than LDA at 1 year leads to better radiographic outcomes at 3 years in early RA patients. PMID- 24794152 TI - Alexithymia in schizophrenia: associations with neurocognition and emotional distress. AB - While alexithymia, or difficulties identifying and describing affect, has been commonly observed in schizophrenia, little is known about its causes and correlates. To test the hypothesis that deficits in emotion identification and expression result from, or are at least related to, deficits in neurocognition and affective symptoms, we assessed alexithymia using the Toronto Alexithymia Scale (TAS-20), symptoms using the Positive and Negative Syndrome Scale (PANSS), and neurocognition using the MATRICS battery among 65 adults with schizophrenia spectrum disorders in a non-acute phase of illness. Partial correlations controlling for the effects of social desirability revealed that difficulty identifying feelings and externally oriented thinking were linked with greater levels of neurocognitive deficits, while difficulty describing feelings was related to heightened levels of emotional distress. To explore whether neurocognition and affective symptoms were uniquely related to alexithymia, a multiple regression was conducted in which neurocognitive scores and affective symptoms were allowed to enter to predict overall levels of alexithymia after controlling for social desirability. Results revealed both processing speed and anxiety uniquely contributed to the prediction of the total score on the TAS-20. Results suggest that dysfunctions in both cognitive and affective processes may be related to alexithymia in schizophrenia independently of one another. PMID- 24794146 TI - Cognitive reserve and Alzheimer's disease. AB - Alzheimer's disease (AD), as a neurodegenerative process caused by widespread senile plaques and neurofibrillary tangles, is faced with an increasingly higher incidence as the global aging develops. Cognitive reserve (CR) hypothesis is proposed to elucidate the disjunction between cognitive performance and the pathological level of AD, positing that some life span experiences will lend protection from AD pathological insults. We provide an overview on recent studies involved in validation of the hypothesis as well as the association between AD and CR proxies, such as educational attainment and quality, occupational activity, leisure activity, general intelligence, and enriched environment. We further discuss some potential mechanisms by which CR proxy acts against AD pathological insults including neuroplasticity, neurogenesis, and locus coeruleus noradrenergic (LC/NA) system. Finally, we review the applications of CR theory for AD prevention and therapy, particularly through physical activity and cognitive training strategy. We believe that a better knowledge of the relationship between AD and CR, accompanied by a successful transition of research accomplishments into practice, will impart much relief to individuals suffering from AD. PMID- 24794153 TI - Depression and treatment outcome in anorexia nervosa. AB - The aim of this study was to compare the immediate and long-term effect of a cognitive-behavior therapy program for anorexia nervosa inpatients with and without concomitant Major Depressive Episodes (MDE). The program has been adapted from the "enhanced" form of Cognitive Behavior Therapy (CBT) for eating disorders. Sixty-three consecutive underweight adult patients with severe eating disorder were treated with inpatient CBT. MDE was assessed with the structured clinical interview for DSM-IV. The Eating Disorder Examination, and the Brief Symptom Inventory were recorded at entry, at the end of treatment, and 6 and 12 months later. MDE was present in 60.3% of participants. No significant differences were observed in the demographic and baseline clinical variables between patients with and without MDE. Significant improvements in weight, and in eating disorder and general psychopathology were showed. There were no differences between participants with and without MDE in terms of treatment outcome, and the severity of depression was not associated with changes in global Eating Disorder Examination score. These findings suggest that a diagnosis of MDE does not influence the outcome of inpatient treatment for anorexia nervosa patients, and that the severity of depression cannot be used to predict the success or failure of such treatment. PMID- 24794154 TI - The role of 5-HTTLPR polymorphism in alcohol craving experience. AB - The way in which genetic risk mediates the development of craving in alcohol dependence is still relatively unknown. The authors sought to clarify the extent to which alcohol craving could be predicted by a relevant polymorphism in the promoter region of the gene encoding the 5-HT transporter (5-HTTLPR). A sample of 101 alcohol-dependent patients admitted for alcohol treatment was recruited for the study. At admission, blood samples were taken for DNA extraction and alcohol craving information was collected with a composite measure. The 5-HTT polymorphism was genotyped. Alcohol dependent patients who were homozygous for the long allele (LL) self-reported higher scores of craving when compared to patients that were homozygous for the short allele (SS). However, the results were not statistically significant. Also, no significant associations were observed between the 5-HTTLPR genotype and other drinking variables. No 5-HTTLPR genotype effects were observed on alcohol craving experience in a sample of alcohol-dependent outpatients. PMID- 24794155 TI - Obsessed not to forget: lack of retrieval-induced suppression effect in obsessive compulsive disorder. AB - The aim of the present study was to investigate the role of executive functions in resolving memory interference in a clinical sample of patients with obsessive compulsive disorder (OCD). Retrieval of memories has been shown to involve some form of executive act that diminishes the accessibility of rival memory traces, leading to retrieval-induced forgetting (RIF). These executive control processes might suppress unwanted thoughts and irrelevant memories during competitive retrieval. We assessed RIF with the retrieval practice paradigm among 25 OCD patients and 25 healthy controls matched for age and education. Retrieval of target memories led to enhancement of target memory recall in both groups, but suppression of related memories (RIF) occurred only among controls. Our results suggest that suppression of irrelevant, interfering memories during competitive recall is impaired in OCD. PMID- 24794157 TI - Integrating primary care in cancer survivorship programs: models of care for a growing patient population. PMID- 24794156 TI - Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke. AB - Stroke is a devastating neurological disorder and one of the leading causes of death and serious disability. After cerebral ischemia, revascularization in the ischemic boundary zone provides nutritive blood flow as well as various growth factors to promote the survival and activity of neurons and neural progenitor cells. Enhancement of angiogenesis and the resulting improvement of cerebral microcirculation are key restorative mechanisms and represent an important therapeutic strategy for ischemic stroke. In the present study, we tested the hypothesis that post-stroke angiogenesis would be enhanced by omega-3 polyunsaturated fatty acids (n-3 PUFAs), a major component of dietary fish oil. To this end, we found that transgenic fat-1 mice that overproduce n-3 PUFAs exhibited long-term behavioral and histological protection against transient focal cerebral ischemia (tFCI). Importantly, fat-1 transgenic mice also exhibited robust improvements in revascularization and angiogenesis compared to wild type littermates, suggesting a potential role for n-3 fatty acids in post-stroke cerebrovascular remodeling. Mechanistically, n-3 PUFAs induced upregulation of angiopoietin 2 (Ang 2) in astrocytes after tFCI and stimulated extracellular Ang 2 release from cultured astrocytes after oxygen and glucose deprivation. Ang 2 facilitated endothelial proliferation and barrier formation in vitro by potentiating the effects of VEGF on phospholipase Cgamma1 and Src signaling. Consistent with these findings, blockade of Src activity in post-stroke fat-1 mice impaired n-3 PUFA-induced angiogenesis and exacerbated long-term neurological outcomes. Taken together, our findings strongly suggest that n-3 PUFA supplementation is a potential angiogenic treatment capable of augmenting brain repair and improving long-term functional recovery after cerebral ischemia. PMID- 24794158 TI - Treatment-related mortality with everolimus in cancer patients. AB - INTRODUCTION: The overall incidence and odds of fatal adverse events (FAEs) after exposure to everolimus are not well defined. We performed a comprehensive meta analysis of published randomized controlled trials (RCTs) to determine the role of everolimus in treatment-related mortality in patients with cancer. METHODS: PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs of everolimus either alone or in combination with another agent compared with the control arm without everolimus and that reported deaths from an adverse event from January 1966 to July 2013. The primary objective was to determine the difference of FAEs between everolimus-treated patients and control group patients. RESULTS: In total, 2,997 patients with multiple solid tumors from nine RCTs were included. The overall incidence of FAEs in cancer patients treated with everolimus was 0.7% (95% CI 0.3%-1.1%) compared with 0.4% (95% CI 0.0%-0.7%) in cancer patients who did not receive everolimus. The odds ratio of FAEs was greater in everolimus-treated patients (Peto odds ratio = 3.80, 95% CI 1.59-9.07, p = .003). In subgroup analyses, no significant difference was found in the incidence or odds of FAEs by everolimus administration (alone or in combination) or tumor type (breast cancer vs. nonbreast cancer; p = .63). CONCLUSION: In patients with cancer, everolimus is associated with a small but significant increase in the odds of a treatment-related fatal events. PMID- 24794159 TI - Measures of outcome in metastatic breast cancer: insights from a real-world scenario. AB - No gold standard treatment exists for metastatic breast cancer (MBC). Clinical decision making is based on knowledge of prognostic and predictive factors that are extrapolated from clinical trials and, sometimes, are not reliably transferable to a real-world scenario. Moreover, misalignment between endpoints used in drug development and measures of outcome in clinical practice has been noted. The roles of overall survival (OS) and progression-free survival (PFS) as primary endpoints in the context of clinical trials are the subjects of lively debate. Information about these parameters in routine clinical practice is potentially useful to design new studies and/or to interpret the results of clinical research. This study analyzed the impact of patient and tumor characteristics on the major measures of outcome across different lines of treatment in a cohort of 472 patients treated for MBC. OS, PFS, and postprogression survival (PPS) were analyzed. The study showed how biological and clinical characteristics may have different prognostic value across different lines of therapy for MBC. After first-line treatment, the median PPS of luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2)-positive groups was longer than 12 months. The choice of OS as a primary endpoint for clinical trials could not be appropriate with these subtypes. In contrast, OS could be an appropriate endpoint when PPS is expected to be low (e.g., triple-negative subtype after the first line; other subtypes after the third line). The potential implications of these findings are clinical and methodological. PMID- 24794160 TI - Factors associated with lack of response to valproic acid monotherapy in juvenile myoclonic epilepsy. AB - PURPOSE: To determine factors associated with lack of response to valproic acid (VPA) in juvenile myoclonic epilepsy (JME). METHOD: Retrospective analysis of clinical and EEG data of 201 patients with JME who had at least 3 years follow up was performed. Psychiatric evaluation was performed using ICD-10 by structured clinical interview. Patients were divided into two groups: VPA responders (seizure free for 2 or more years) and those with lack of response to VPA. Effect size for non-response and correlations for variables significantly different between the groups was performed, the findings were confirmed by ROC curves. RESULTS: The mean duration of follow up was 7.75 (range 3-12) years; 55.2% were males. Focal semiologic features were noted is 16%. EEG was abnormal in 67%; focal EEG abnormalities were noted in 32.8%. Coexisting psychiatric disorders (PDs) were found in 33.3%. Lack of response to VPA was noted in 19%. Diagnosis of PDs and focal EEG abnormalities significantly increased the risk of VPA non responsiveness by 5.54 (95% CI of 2.60-11.80; p<0.0001) and 3.01 times respectively (95% CI of 1.40-6.47; p<0.008). Diagnosis of PDs showed significant correlation (r=0.332; p<0.0001) and association (AUC 0.700; p<0.0001) with lack of response to VPA. Though focal EEG abnormalities increased the chances, it did not correlate with lack of response to VPA. CONCLUSION: Lack of response to VPA was noted 19% of patients with JME. Coexisting PDs showed significant correlation and association with lack of response to VPA. PMID- 24794161 TI - A novel TSC2 mutation causing tuberless tuberous sclerosis. PMID- 24794162 TI - Brain connectivity in West syndrome. AB - PURPOSE: Hypsarrhythmia, the pathognomonic EEG pattern of West syndrome, is typically characterized by a high amplitude, arrhythmic, and asynchronous pattern. While this severely aberrant pattern would suggest severe abnormalities in connectivity, coherence has not yet been systematically assessed in hypsarrhythmia. METHODS: We evaluated the EEGs of 28 infants, 12 with infantile spasms with hypsarrhythmia and 16 similarly age control infants for coherence and spectral power. RESULTS: Children with infantile spasms and hypsarrhythmia EEGs had marked abnormalities in coherence and spectral power compared to normal children of similar ages. During sleep increases in delta, theta, alpha and beta coherences were seen, particularly at long inter-electrode distances while at short inter-electrode distances coherences were decreased in the theta and beta range, particularly in the frontal region. The enhanced coherences at long inter electrode distances suggest that during sleep in children with infantile spasms widely spread cortical region do not have functional differentiation whereas in the frontal lobe there is reduced functional connectivity and integration of local cortical regions. Children with continued seizures and developmental delay showed persistent abnormalities in coherence. CONCLUSION: This study demonstrates that hypsarrhythmic EEGs have marked abnormalities in coherence spectral power and such abnormalities may be related to cognitive impairment. PMID- 24794163 TI - Safe use of repetitive transcranial magnetic stimulation in patients with implanted vagus nerve stimulators. AB - Vagus nerve stimulation (VNS) and repetitive transcranial stimulation (rTMS) devices are FDA cleared for therapeutic use in treatment resistant depression. Since VNS systems have ferromagnetic components and large-scale safety testing has not been done, the implanted VNS device is considered a contraindication for rTMS therapy. This contraindication should not be considered absolute, as VNS components typically lie outside the electromagnetic field generated by an rTMS treatment coil. We solicited information from clinicians at several academic medical centers through an informal survey about their use of rTMS for depressed patients with implanted VNS systems, and reviewed relevant safety issues with one rTMS device manufacturer. rTMS clinical practices may use special consent procedures and take additional precautions to enhance safety in these situations. Specific recommendations are provided for minimizing risks (heating or movement of VNS components and unintended change in VNS stimulation parameters) when delivering rTMS to patients with implanted VNS systems. PMID- 24794164 TI - Anti-epileptogenic effect of high-frequency stimulation in the thalamic reticular nucleus on PTZ-induced seizures. AB - BACKGROUND: Deep brain stimulation, specifically high-frequency stimulation (HFS), is an alternative and promising treatment for intractable epilepsies; however, the optimal targets are still unknown. The thalamic reticular nucleus (TRN) occupies a key position in the modulation of the cortico-thalamic and thalamo-cortical pathways. OBJECTIVE: We determined the efficacy of HFS in the TRN against tonic-clonic generalized seizures (TCGS) and status epilepticus (SE), which were induced by scheduled pentylenetetrazole (PTZ) injections. METHODS: Male Wistar rats were stereotactically implanted and assigned to three experimental groups: Control group, which received only PTZ injections; HFS-TRN group, which received HFS in the left TRN prior to PTZ injections; and HFS-Adj group, which received HFS in the left adjacent nuclei prior to PTZ injections. RESULTS: The HFS-TRN group reported a significant increase in the latency for development of TCGS and SE compared with the HFS-Adj and Control groups (P < 0.009). The number of PTZ-doses required for SE was also significantly increased (P < 0.001). Spectral analysis revealed a significant decrease in the frequency band from 0.5 Hz to 4.5 Hz of the left motor cortex in the HFS-TRN and HFS-Adj groups, compared to the Control group. Conversely, HFS-TRN provoked a significant increase in all frequency bands in the TRN. EEG asynchrony was observed during spike-wave discharges by HFS-TRN. CONCLUSION: These data indicate that HFS-TRN has an anti-epileptogenic effect and is able to modify seizure synchrony and interrupt abnormal EEG recruitment of thalamo-cortical and, indirectly, cortico thalamic pathways. PMID- 24794165 TI - Graphene-based nanobiocatalytic systems: recent advances and future prospects. AB - Graphene-based nanomaterials are particularly useful nanostructured materials that show great promise in biotechnology and biomedicine. Owing to their unique structural features, exceptional chemical, electrical, and mechanical properties, and their ability to affect the microenvironment of biomolecules, graphene-based nanomaterials are suitable for use in various applications, such as immobilization of enzymes. We present the current advances in research on graphene-based nanomaterials used as novel scaffolds to build robust nanobiocatalytic systems. Their catalytic behavior is affected by the nature of enzyme-nanomaterial interactions and, thus, the availability of methods to couple enzymes with nanomaterials is an important issue. We discuss the implications of such interactions along with future prospects and possible challenges in this rapidly developing area. PMID- 24794166 TI - Evaluation of the single cervical skin test and interferon gamma responses to detect Mycobacterium bovis infected cattle in a herd co-infected with Mycobacterium avium subsp. paratuberculosis. AB - This study reports the performance of the single intradermal tuberculin (SIT) test and the interferon-gamma (IFN-gamma) assay for Mycobacterium bovis in a cattle herd with high prevalence of paratuberculosis (PTB). A total of 58/350 animals were selected for necropsy based on one or more of the following criteria: positive to SIT, IFN-gamma, a breeding cow that seroconverted to PTB and showed signs compatible with a wasting disease. Infection status was determined by post mortem diagnostic tests that included histopathology examination, mycobacterial cultures and PCR identification for M. bovis and Mycobacterium avium subsp. paratuberculosis (MAP). In 7/58 animals primary tuberculosis (TB) lesions, affecting only the retropharyngeal and/or mediastinal lymph nodes, were found; 3/7 animals were found SIT positive. PTB was confirmed in 35/58 animals, of which 30 had seroconverted and 14 had typical clinical signs. 45/58 animals were IFN-gamma(+) using the most stringent criterion (cut off point >= 0.05); however, IFN-gamma test was only positive in 33 animals when using a higher threshold (cut-off point >= 0.1). Three animals co-infected also showed extensive TB and diffuse PTB lesions. These results show that the combined use of SIT and IFN-gamma, as interpreted using official guidelines, detected all confirmed cases of TB. Individually, the sensitivity of the SIT was inadequate to diagnose TB-positive animals with an advanced stage of PTB. The large number of IFN-gamma(+) animals with no visible TB lesion could be due, in part, to some protection conferred by prior infection with MAP. PMID- 24794167 TI - Isolated transient myoclonus in the elderly-cortical vs. subcortical. PMID- 24794168 TI - Neurophobia among general practice trainees: the evidence, perceived causes and solutions. AB - INTRODUCTION: As general practice (GP) is the main source of referrals to neurologists, neurology education for GP trainees is important. We investigated the existence of neurophobia, contributing factors and potential prevention strategies among GP trainees. METHODS: In a questionnaire survey interest, knowledge, confidence and perceived difficulty in neurology were compared with different medical specialties. Reasons for difficulty with neurology, postgraduate neurology education experience, learning methods and suggested teaching improvements were examined. RESULTS: Of 205 GP trainees, 118 (58%) completed the questionnaire. Threshold analyses justified categorical intervals for the Likert responses. Trainees recorded poorer knowledge (p<0.001), less confidence (p<0.001) and more perceived difficulty (p<0.001) with neurology than with any other medical specialty. GP trainees had less interest in neurology than any other medical specialty (Duncan test, p<0.001). There was a similar gradation in difficulty and confidence perception across medical specialties. Hospital and community-based neurology teaching was graded as "poor" or "very poor" by over 60% of GP trainees. There were multiple perceived causes of neurophobia, including neuroanatomy and poor quality teaching. More organised clinical teaching and referral guidance were suggested to address GP neurophobia. CONCLUSIONS: Neurophobia is common among GP trainees in Northern Ireland. GP trainees have clear and largely uniform ideas on improving their neurology education. GP training posts should reflect the importance of neurology within the GP curriculum. PMID- 24794169 TI - Career attitudes of first-year veterinary students before and after a required course on veterinary careers. AB - Careers in Veterinary Medicine is a required, one-credit-hour course at the North Carolina State University College of Veterinary Medicine (NCSU-CVM), which meets once weekly during veterinary students' first semester. Lectures in this course are presented by one or more veterinarians representing diverse career areas. A voluntary, anonymous survey was distributed before the first class meeting in 2011 (PRE) and at the end of the semester (POST) to assess if students' career interests changed during the semester. The survey collected basic demographic data and students' preferences (on a Likert scale) for 17 veterinary career paths. Out of 63 students, 36 (57%) in the POST survey said that their career interests had changed during the semester, and 17 of the 26 students (65%) who gave a reason credited the careers course as one factor in reconsidering their career choice. Only 3 of the 17 career paths had statistically significant PRE/POST survey differences in Likert response frequency (equine practice, pathology, and wildlife medicine), but both informal discussions with students and responses to open-ended survey questions indicated that many students valued the introduction to unfamiliar veterinary career areas. Careers in Veterinary Medicine is a vital component of recent career-planning initiatives in the college, which will be especially important to veterinary students as they face continued changes in the profession, such as the increased debt load of the new graduate and the threat of veterinary workforce oversupply. PMID- 24794170 TI - Collaborative quiz-based teaching strategy in histology. AB - In the present article we introduce a teaching strategy used in a histology course with first-year students in the first term of their studies at the Faculty of Veterinary Medicine at Huanghuai University, China. Forty students were randomly divided into two sections (n=20/section). Students in the first section were taught using a collaborative quiz-based strategy (the experimental section), and students in the second section were taught using a traditional teaching strategy (the control section). To assess achievement of learning, a final examination was carried out at the end of the course. To determine students' attitudes toward the teaching strategy used, a questionnaire was conducted at the end of the term. Results showed that students preferred the collaborative quiz based teaching strategy. The final-examination scores of students in the experimental section were significantly higher than those of students in the control section (p<.05), which indicates that the collaborative quiz-based strategy results in better performance on examinations compared to the traditional histology course. PMID- 24794171 TI - Optimal production of 4-deoxy-L-erythro-5-hexoseulose uronic acid from alginate for brown macro algae saccharification by combining endo- and exo-type alginate lyases. AB - Algae are considered as third-generation biomass, and alginate is the main component of brown macroalgae. Alginate can be enzymatically depolymerized by alginate lyases into uronate monomers, such as mannuronic acid and guluronic acid, which are further nonenzymatically converted to 4-deoxy-L-erythro-5 hexoseulose uronic acid (DEH). We have optimized an enzymatic saccharification process using two recombinant alginate lyases, endo-type Alg7D and exo-type Alg17C, for the efficient production of DEH from alginate. When comparing the sequential and simultaneous additions of Alg7D and Alg17C, it was found that the final yield of DEH was significantly higher when the enzymes were added sequentially. The progress of saccharification reactions and production of DEH were verified by thin layer chromatography and gas chromatography-mass spectrometry, respectively. Our results showed that the two recombinant enzymes could be exploited for the efficient production of DEH that is the key substrate for producing biofuels from brown macro algal biomass. PMID- 24794172 TI - Pretreatment solution recycling and high-concentration output for economical production of bioethanol. AB - The purpose of this study was to enhance the economic efficiency of producing bioethanol. Pretreatment solution recycling is expected to increase economic efficiency by reducing the cost of pretreatment and the amount of wastewater. In addition, the production of high-concentration bioethanol could increase economic efficiency by reducing the energy cost of distillation. The pretreatment conditions were 95 degrees C, 0.72 M NaOH, 80 rpm twin-screw speed, and flow rate of 90 mL/min at 18 g/min of raw biomass feeding for pretreatment solution recycling. The pretreatment with NaOH solution recycling was conducted five times. All of the components and the pretreatment efficiency were similar, despite reuse. In addition, we developed a continuous biomass feeding system for production of high-concentration bioethanol. Using this reactor, the bioethanol productivity was investigated using various pretreated biomass feeding rates in a simultaneous saccharification and fermentation (SSF) process. The maximum ethanol concentration, yield, and productivity were 74.5 g/L, 89.5%, and 1.4 g/L h, respectively, at a pretreated biomass loading of approximately 25% (w/v) with an enzyme dosage of 30 FPU g/cellulose. The results presented here constitute an important contribution toward the production of bioethanol from Miscanthus. PMID- 24794173 TI - Ethanol production from sunflower meal biomass by simultaneous saccharification and fermentation (SSF) with Kluyveromyces marxianus ATCC 36907. AB - The lignocellulosic materials are considered promising renewable resources for ethanol production, but improvements in the processes should be studied to reduce operating costs. Thus, the appropriate enzyme loading for cellulose saccharification is critical for process economics. This study aimed at evaluating the concentration of cellulase and beta-glucosidase in the production of bioethanol by simultaneous saccharification and fermentation (SSF) of sunflower meal biomass. The sunflower biomass was pretreated with 6% H2SO4 (w/v), at 121 degrees C, for 20 min, for hemicellulose removal and delignificated with 1% NaOH. SSF was performed with Kluyveromyces marxianus ATCC 36907, at 38 degrees C, 150 rpm, for 72 h, with different enzyme concentrations (Cellulase Complex NS22086-10, 15 and 20 FPU/gsubstrate and beta-Glucosidase NS22118, with a cellulase to beta-glucosidase ratio of 1.5:1; 2:1 and 3:1). The best condition for ethanol production was cellulase 20 FPU/gsubstrate and beta-glucosidase 13.3 CBU/gsubstrate, resulting in 27.88 g/L ethanol, yield of 0.47 g/g and productivity of 0.38 g/L h. Under this condition the highest enzymatic conversion of cellulose to glucose was attained (87.06%). PMID- 24794174 TI - Female sexual subjectivity and verbal consent to receiving oral sex. AB - Women are less likely than men are to report receiving oral sex from their partners. Elements of sexual subjectivity may have implications for women's communication of consent to specific sexual acts. Sexually active women (n = 237) between 18 and 71 years of age (M = 28.85 years) completed an online survey measuring sociodemographic variables, entitlement to pleasure from partner, self efficacy in achieving sexual pleasure, and consent communication at last receptive oral sex event. Participants were predominantly White (84.8%, n = 201) and in exclusive or monogamous sexual relationships (54.9%, n = 130). The authors used a 4-step test of mediation to determine whether self-efficacy in achieving sexual pleasure mediated the relation between entitlement to pleasure from partner and verbal consent communication. Self-efficacy emerged as a significant predictor of verbal consent communication (p <.01) in the fourth step, while entitlement to pleasure dropped out of the model (p >.05), indicating full mediation. Therefore, entitlement to pleasure predicted verbal consent to oral sex as a function of self-efficacy in achieving sexual pleasure. Sex-positive educational interventions may improve disparities between men and women in receiving oral sex from their partners. Results of this study offer insight into the ways in which culture-level forces affect interpersonal and intraindividual sexual health behaviors. PMID- 24794180 TI - Outcomes in preterm infants. AB - Preterm birth is defined as birth before 37 completed weeks gestation, and it is estimated that each day, across the world over 41,000 infants are born before this gestational age. The risk of adverse consequences declines with increasing gestational age. While this paper focuses on the consequences of preterm birth, the adverse consequences for infants born at 38 and 39 weeks gestation are also of a higher risk than those for infants born at 40 weeks gestation, with the neonatal mortality risk increasing again in infants born beyond the 42nd week of gestation. PMID- 24794182 TI - Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. METHODS: We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real time polymerase chain reaction. RESULTS: We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. CONCLUSIONS: Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host. PMID- 24794183 TI - Adoptive cellular immunotherapy for the treatment of patients with breast cancer: a meta-analysis. AB - BACKGROUND: To evaluate the therapeutic efficacy of dendritic cells (DC) alone, cytokine-induced killer (CIK) cells alone and the combination of DC and CIK cells in the treatment of breast cancer, we performed a systemic review of the relevant published clinical studies, collectively referred to as DC-CIK cell therapy. METHODS: Six hundred thirty-three patients with breast cancer were assigned to cohorts, and a meta-analysis was conducted. RESULTS: The treatment of breast cancer with DC-CIK cells was associated with a significantly improved 1-year survival (P = 0.0001). The Karnofsky performance status scale of the patients treated with DC-CIK cells was significantly improved compared with that of the non-DC-CIK group (P < 0.0001). The percentage of T cells (CD3(+), CD4(+) and CD4(+)CD8(+)), CD16(+) monocytes, and CD3(+)CD56(+) natural killer T cells in the peripheral blood of cancer patients was significantly increased (P <= 0.05), whereas the percentage of CD4(+)CD25(+) regulatory T cells was not significantly decreased (P = 0.32) in the DC-CIK treatment group compared with the non-DC-CIK group. The levels of interleukin-2, interleukin-12, tumor necrosis factor-alpha, interferon-gamma, and nucleolar organizer region protein in the peripheral blood of cancer patients, which reflect immune function, were significantly increased (P < 0.001) after DC-CIK cell treatment. Furthermore, after DC-CIK treatment, the average levels of the alpha-fetoprotein, cancer antigen embryonic antigen and carbohydrate antigen tumor markers were decreased (P < 0.00001). CONCLUSIONS: DC CIK cell therapy markedly prolongs survival time, enhances immune function, and improves the efficacy of the treatment of breast cancer patients. PMID- 24794181 TI - Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential. AB - BACKGROUND AIMS: Cord blood (CB) and amniotic fluid (AF) could represent new and attractive mesenchymal stromal cell (MSC) sources, but their potential therapeutic applications are still limited by lack of standardized protocols for isolation and differentiation. In particular, chondrogenic differentiation has never been deeply investigated. METHODS: MSCs were obtained from CB and AF samples collected during cesarean sections at term and compared for their biological and differentiation properties, with particular interest in cartilage differentiation, in which quantitative real-time polymerase chain reaction and immunohistochemical analyses were performed to evaluate the expression of type 2 collagen, type 10 collagen, SRY-box9 and aggrecan. RESULTS: We were able to isolate MSCs from 12 of 30 (40%) and 5 of 20 (25%) CB and AF units, respectively. Fluorescence in situ hybridization analysis indicated the fetal origin of isolated MSC strains. Both populations expressed mesenchymal but not endothelial and hematopoietic markers, even though we observed a lower expression of human leukocyte antigen (HLA) I in CB-MSCs. No differences in proliferation rate and cell cycle analysis could be detected. After osteogenic induction, both populations showed matrix mineralization and typical marker expression. Under chondrogenic conditions, pellets derived from CB-MSCs, in contrast with AF-MSCs pellets, were significantly larger, showed cartilage-like morphology and resulted positive for chondrocyte-associated markers, such as type 2 collagen, type 10 collagen, SRY-box9 and aggrecan. CONCLUSIONS: Our results show that CB-MSCs and AF-MSCs collected at term differ from each other in their biological and differentiation properties. In particular, only CB-MSCs showed a clear chondrogenic potential and thus could represent an ideal candidate for cartilage tissue engineering. PMID- 24794184 TI - Bariatric surgery interest around the world: what Google Trends can teach us. AB - BACKGROUND: Bariatric surgery may prove an effective weight loss option for those struggling with severe obesity, but it is difficult to determine levels of interest in such procedures at the population level through traditional approaches. Analysis of Google Trend information may give providers and healthcare systems useful information regarding Internet users' interest in bariatric procedures. The objective of this study was to gather Google Trend information on worldwide Internet searches for "bariatric surgery", "gastric bypass", "gastric sleeve", "gastric plication", and "lap band" from 2004-2012 and to explore temporal relationships with relevant media events, economic variations, and policy modifications. METHODS: Data were collected using Google Trends. Trend analyses were performed using Microsoft Excel Version 14.3.5 and Minitab V.16.0. RESULTS: Trend analyses showed that total search volume for the term "bariatric surgery" has declined roughly 25% since January 2004, although interest increased approximately 5% from 2011 to 2012. Interest in lap band procedures declined 30% over the past 5 years, while "gastric sleeve" has increased 15%. Spikes in search numbers show an association with events such as changing policy and insurance guidelines and media coverage for bariatric procedures. CONCLUSION: This report illustrates that variations in Internet search volume for terms related to bariatric surgery are multifactorial in origin. Although it is impossible to ascertain if reported Internet search volume is based on interest in potentially undergoing bariatric surgery or simply general interest, this analysis reveals that search volume appears to mirror real world events. Therefore, Google Trends could be a way to supplement understanding about interest in bariatric procedures. PMID- 24794185 TI - Comment on: High-risk alcohol use after weight loss surgery. PMID- 24794186 TI - Comment on: Anemia, iron and vitamin B12 deficiencies after sleeve gastrectomy compared to Roux-en-Y gastric bypass: A meta-analysis. PMID- 24794187 TI - Revisional sleeve gastrectomy can be a safe and efficacious procedure. PMID- 24794188 TI - A curious onset of Raynaud's phenomenon after gastric bypass: a case report. PMID- 24794189 TI - Comment on: The role of endoscopic stents in the management of chronic anastomotic and staple line leaks and chronic strictures after bariatric surgery. PMID- 24794190 TI - Laparoscopic management of ischemic gastric perforation after banded plication for obesity. PMID- 24794191 TI - Zinc interaction with struvite during and after mineral formation. AB - Sorption of Zn with struvite was assessed both during and after mineral formation at pH 9.0 for 1-100 MUM (0.065-6.54 mg L(-1)) aqueous Zn. The Zn loadings of recovered solids were lower when Zn was present during struvite precipitation compared to when Zn was added to struvite-bearing solutions. X-ray absorption fine structure spectroscopy confirmed that Zn added to struvite-bearing solutions at concentrations<=5 MUM sorbed as both octahedral and tetrahedral complexes (Zn O 1.98-2.03 A), with evidence for bidentate configuration (Zn-P 3.18 A). Bidentate complexes were incorporated into the near-surface structure, contributing to distortion of the struvite nu3 PO4(3-) band in the Fourier transform infrared spectra. At Zn concentrations>5 MUM, tetrahedral monodentate adsorbates (Zn-O 1.98 A) dominated, transitioning to a Zn-phosphate precipitate at 100 MUM. When Zn is present during struvite precipitation, octahedral monodentate sorbates detected at 1 MUM (Zn-O 2.08-2.10 A; Zn-P 3.60-3.64 A) polymerized at 5-50 MUM, ultimately forming a Zn-hydroxide precipitate at 100 MUM. The lowest initial Zn concentrations (0.065 mg L(-1)) and resultant solid loadings from precipitation experiments (13 mg kg(-1)) are consistent with those reported for struvite recovered from wastewater, suggesting that similar Zn sorption processes may occur in more complex systems. PMID- 24794192 TI - Synergetic chemical coupling controls the uniformity of carbon nanotube microstructure growth. AB - Control of the uniformity of vertically aligned carbon nanotube structures (CNT "forests"), in terms of both geometry and nanoscale morphology (density, diameter, and alignment), is crucial for applications. Many studies report complex and sometimes unexplained spatial variations of the height of macroscopic CNT forests, as well as variations among micropillars grown from lithographically patterned catalyst arrays. We present a model for chemically coupled CNT growth, which describes the origins of synergetic growth effects among CNT micropillars in proximity. Via this model, we propose that growth of CNTs is locally enhanced by active species that are catalytically produced at the substrate-bound nanoparticles. The local concentration of these active species modulates the growth rate of CNTs, in a spatially dependent manner driven by diffusion and local generation/consumption at the catalyst sites. Through experiments and numerical simulations, we study how the uniformity of CNT micropillars can be influenced by their size and spacing within arrays and predict the widely observed abrupt transition between tangled and vertical CNT growth by assigning a threshold concentration of active species. This mathematical framework enables predictive modeling of spatially dependent CNT growth, as well as design of catalyst patterns to achieve engineered uniformity. PMID- 24794193 TI - Seasonality of soil erosion under mediterranean conditions at the Alqueva Dam watershed. AB - The Alqueva reservoir created the largest artificial lake of Western Europe in 2010. Since then, the region has faced challenges due to land-use changes that may increase the risk of erosion and shorten the lifetime of the reservoir, increasing the need to promote land management sustainability. This paper investigates the aspect of seasonality of soil erosion using a comprehensive methodology that integrates the Revised Universal Soil Loss Equation (RUSLE) approach, geographic information systems, geostatistics, and remote-sensing. An experimental agro-silvo pastoral area (typical land-use) was used for the RUSLE factors update. The study confirmed the effect of seasonality on soil erosion rates under Mediterranean conditions. The highest rainfall erosivity values occurred during the autumn season (433.6 MJ mm ha(-1) h(-1)), when vegetation cover is reduced after the long dry season. As a result, the autumn season showed the highest predicted erosion (9.9 t ha(-1)), contributing 65 % of the total annual erosion. The predicted soil erosion for winter was low (1.1 t ha(-1)) despite the high rainfall erosivity during that season (196.6 MJ mm ha(-1) h( 1)). The predicted annual soil loss was 15.1 t ha(-1), and the sediment amount delivery was 4,314 * 10(3) kg. Knowledge of seasonal variation would be essential to outline sustainable land management practices. This model will be integrated with World Overview of Conservation Approaches and Technologies methods to support decision-making in that watershed, and it will involve collaboration with both local people and governmental institutions. PMID- 24794194 TI - Mapping ecosystem services for land use planning, the case of Central Kalimantan. AB - Indonesia is subject to rapid land use change. One of the main causes for the conversion of land is the rapid expansion of the oil palm sector. Land use change involves a progressive loss of forest cover, with major impacts on biodiversity and global CO2 emissions. Ecosystem services have been proposed as a concept that would facilitate the identification of sustainable land management options, however, the scale of land conversion and its spatial diversity pose particular challenges in Indonesia. The objective of this paper is to analyze how ecosystem services can be mapped at the provincial scale, focusing on Central Kalimantan, and to examine how ecosystem services maps can be used for a land use planning. Central Kalimantan is subject to rapid deforestation including the loss of peatland forests and the provincial still lacks a comprehensive land use plan. We examine how seven key ecosystem services can be mapped and modeled at the provincial scale, using a variety of models, and how large scale ecosystem services maps can support the identification of options for sustainable expansion of palm oil production. PMID- 24794195 TI - Crystal structure and thermodynamic properties of d-lactate dehydrogenase from Lactobacillus jensenii. AB - The thermostable d-lactate dehydrogenase from Lactobacillus jensenii (Ljd-LDH) is a key enzyme in the production of the d-form of lactic acid from pyruvate concomitant with the oxidation of NADH to NAD(+). The polymers of d-lactic acid are used as biodegradable bioplastics. The crystal structures of Ljd-LDH and in complex with NAD(+) were determined at 2.13 and 2.60A resolutions, respectively. The Ljd-LDH monomer consists of the N-terminal substrate-binding domain and the C terminal NAD-binding domain. The Ljd-LDH forms a homodimeric structure, and the C terminal NAD-binding domain mostly enables the dimerization of the enzyme. The NAD cofactor is bound to the GxGxxG NAD-binding motif located between the two domains. Structural comparisons of Ljd-LDH with other d-LDHs reveal that Ljd-LDH has unique amino acid residues at the linker region, which indicates that the open-close dynamics of Ljd-LDH might be different from that of other d-LDHs. Moreover, thermostability experiments showed that the T50(10) value of Ljd-LDH (54.5 degrees C) was much higher than the commercially available d-lactate dehydrogenase (42.7 degrees C). In addition, Ljd-LDH has at least a 7 degrees C higher denaturation temperature compared to commercially available d-LDHs. PMID- 24794196 TI - 3D silk fibroin scaffold incorporating titanium dioxide (TiO2) nanoparticle (NPs) for tissue engineering. AB - The present study deals with fabrication of scaffolds composing of silk fibroin and TiO2 NPs fabricated using a salt-leaching process. At first instance, the TiO2 NPs were prepared by using sol-gel synthesis, affording to have average diameter of 77+/-21MUm. Furthermore, the aqueous solutions of silk fibroin were mixed with 0.2%, 2.0% and 4.0% of TiO2 NPs and salt-leaching process was introduced which resulted in creation of porous scaffolds modified with TiO2 NPs. The presence of TiO2 NPs in scaffolds was confirmed by VP-FE-SEM-EDS, TGA and XRD. The presence of TiO2 NPs influenced in decrease in pore size and swelling behavior of composite scaffolds. The resultant mechanical property of scaffolds was improved upon the introduction of TiO2 NPs. Moreover, cell cytotoxicity results for 1, 3 and 7 days; revealed no toxic behavior to osteoblasts. However, a mild toxicity to NIH 3T3 fibroblasts was observed with the scaffolds containing 4.0% TiO2 NPs. The cell fixation results from 1 and 7 days of incubation indicated the attachment, spreading and subsequent proliferation of fibroblasts. However, these findings were independent to the amount of TiO2 NPs in scaffolds. PMID- 24794197 TI - Substitution of Thr(55) by Gly and Lys(48) by Asp in OsTrx20 using site-directed mutagenesis. AB - Thioredoxins are small (12-13kDa) ubiquitous proteins containing a redox active disulfide bridge. The primary structure of one of the rice Trx isoforms, OsTrx20, in which Thr is substituted for the largely conserved Gly in position 55 in the active site and Lys is substituted for the conserved Asp/Asn in position 48 is considerably different with other h-type Trx isoforms. In order to probe the functional roles of Thr-55 and Lys-48 in OsTrx20, Thr was replaced with Gly and Lys with Asp using site-directed mutagenesis. The wild type OsTrx20 as well as single mutants T55GOsTrx20, K48DOsTrx20 and the double mutant T55G-K48DOstrx20 were heterologously expressed in Escherichia coli and purified. The changes in the ability to reduce insulin for OsTrx20 and mutants as well as OsTrx23 which has a Trx typical active site were monitored in the pH range 6.5-8. The results showed that whereas the activity of wild type OsTrx20 is dependent on pH and decreases remarkably at high pH values, the activities of mutants T55GOsTrx20, K48DOsTrx20, T55G-K48DOsTrx20 and wild type OsTrx23 slightly change under different pH conditions. These results support the significant involvement of residues Thr-55 and Lys-48 in instability of OsTrx20 activity under pH variations. PMID- 24794198 TI - Conversion of fat-containing waste from the margarine manufacturing process into bacterial polyhydroxyalkanoates. AB - A fat-containing waste produced from the margarine manufacturing process was tested as a low cost carbon source for cultivation of different polyhydroxyalkanoates (PHAs) producing bacterial strains, including Cupriavidus necator, Comamonas testosteroni and several Pseudomonas strains. The margarine waste was mainly composed of free fatty acids (76wt.%), namely mystiric, oleic, linoleic and stearic acids. In preliminary shake flask experiments, several strains were able to grow on the margarine waste, but C. necator reached the highest PHA content in the biomass (69wt.%). This strain was selected for batch bioreactor experiments, wherein it reached a cell dry weight of 11.2g/L with a polymer content of 56wt.%. The culture produced 6.4g/L of polyhydroxybutyrate, P3(HB), within 20h of cultivation, which corresponds to a volumetric productivity of 0.33gPHA/Lh. The P3(HB) polymer produced by C. necator from the margarine waste had a melting point of 173.4 degrees C, a glass transition temperature of 7.9 degrees C and a crystallinity of 56.6%. Although the bioprocess needs to be optimized, the margarine waste was shown to be a promising substrate for P(3HB) production by C. necator, resulting in a polymer with physical and chemical properties similar to bacterial P(3HB) synthesized from other feedstocks. PMID- 24794199 TI - Crosslinked carboxymethyl starch: one step synthesis and sorption characteristics. AB - Crosslinked carboxymethyl starch (cCMS) hydrogels were synthesized in a simple one step process using various crosslinking agent content - dichloroacetic acid (DCA) with the constant monochloroacetic acid and DCA/anhydroglucosidic unit (AGU) 1.75:1 molar ratio whereas DCA/AGU was changed in a range 0.15-1.0mol/AGU. The degree of substitution (DS=0.4-0.9), and reaction efficiency were evaluated. Moreover, swellability in water and aqueous solutions was determined. Adsorption tests for Fe(II) cation as a function of cCMS crosslinking degree, sorbent dose and time were performed in autogenic pH (ca. 7.0). For comparison four other divalent metal cations were tested. Adsorption efficiency was up to 98% for Fe(II), 96% for Ca(II) and above 99.7% for Cu(II), Cd(II) and Pb(II). PMID- 24794200 TI - Relationship between the initial rate of protein aggregation and the lag period for amorphous aggregation. AB - Lag period is an inherent characteristic of the kinetic curves registered for protein aggregation. The appearance of a lag period is connected with the nucleation stage and the stages of the formation of folding or unfolding intermediates prone to aggregation (for example, the stage of protein unfolding under stress conditions). Discovering the kinetic regularities essential for elucidation of the protein aggregation mechanism comprises deducing the relationship between the lag period and aggregation rate. Fandrich proposed the following equation connecting the duration of the lag phase (tlag) and the aggregate growth rate (kg) in the amyloid fibrillation: kg=const/tlag. To establish the relationship between the initial rate of protein aggregation (v) and the lag period (t0) in the case of amorphous aggregation, the kinetics of dithithreitol-induced aggregation of holo-alpha-lactalbumin from bovine milk was studied (0.1M Na-phosphate buffer, pH 6.8; 37 degrees C). The order of aggregation with respect to protein (n) was calculated from the dependence of the initial rate of protein aggregation on the alpha-lactalbumin concentration (n=5.3). The following equation connecting v and t0 has been proposed: v(1/n)=const/(t0-t0,lim), where t0,lim is the limiting value of t0 at high concentrations of the protein. PMID- 24794201 TI - Optimization of the Esperanza window trap for the collection of the African onchocerciasis vector Simulium damnosum sensu lato. AB - A simple inexpensive trap (Esperanza window trap) was shown recently to collect significant numbers of Simulium ochraceum sensu lato, a major vector of Onchocerca volvulus in Mesoamerica. Here, we report studies optimizing this trap for the collection of Simulium damnosum s.l., the major vector of O. volvulus in Africa. A shortened, blue and black striped version of the Esperanza window trap, when baited with a combination of CO2 and worn trousers, rivalled human landing collections in the number of S. damnosum s.l. females collected. Traps baited with a commercially available human skin lure and CO2 resulted in collections that were not significantly different than those obtained from traps baited with worn trousers and CO2. This suggests that the Esperanza window trap may offer a replacement for human landing collections for monitoring onchocerciasis transmission in Africa. PMID- 24794202 TI - Automatic implantable cardiac defibrillator implantation may precipitate effort induced thrombosis in young athletes: a case report and literature review. AB - Upper extremity deep vein thrombosis (DVT) is a common finding after implantation of an automatic implantable cardiac defrillator (AICD). We describe the case of a patient who developed a left upper extremity DVT 4.5 months after implantation of an AICD and was found to have a lead-induced stenosis with possible underlying Paget-Schroetter syndrome (PSS) in the midbrachiocephalic vein on venography. While his symptoms resolved after the combination of pharmacomechanical thrombolysis, angioplasty, and anticoagulation, his long-term management is complicated by the presence of both PSS and lead-induced stenosis. Herein, we discuss his presentation, treatment, and future management options. PMID- 24794203 TI - Can left ventricular function be assessed on non-ECG-gated CT? AB - To evaluate whether non-gated computed tomography (CT) can assess left ventricular (LV) function, 101 patients with both CT and echocardiography were selected, with ejection fraction <50% on echocardiography used as a reference standard. CTs were blindly reevaluated, and qualitative assessment of LV dysfunction on CT correlated with echocardiographic dysfunction, odds ratio of 21.0 (95% confidence interval=6.55-71.0), specificity of 86% (56/65). Systolic and diastolic images were identified on CT, and the ratio of systolic to diastolic LV internal diameters and ratio of LV to RV internal diameter were determined, both showing correlation with LV dysfunction on echocardiography (P<.0001). Non-gated CT can be used to predict LV dysfunction. PMID- 24794204 TI - The effect of lower body weight support on arterial wave reflection in healthy adults. AB - Body weight support (WS) during treadmill exercise is used to rehabilitate orthopedic/neurological patients. WS lowers musculoskeletal strain and load. It compresses the lower body and increases intrathoracic volume. We studied short term effects of WS on wave reflection indices using applanation tonometry during progressive WS of 25%, 50%, and 75% of body weight in 25 healthy men. WS decreased mean heart rate from 79 to 69 beats/min (P < .001). Peripheral and central mean arterial, systolic, and pulse pressures (PP) remained unchanged. There was a trend toward lower peripheral and central diastolic pressure. PP amplification ratio decreased significantly (P = .005). Reflected wave characteristics: Augmented pressure and index increased in a stepwise manner with WS (both P < .001). Both ejection duration and systolic duration of the reflected pressure wave (Atr) increased progressively (both P < .001). The round-trip travel time (Deltatp) was unchanged. Left ventricular workload and oxygen demand: Left ventricular wasted pressure energy increased (P < .001), and the subendocardial viability ratio decreased (P = .005), whereas the tension time index remained unchanged. In normal men, WS acutely decreases the PP amplification ratio, increases the amplitude and duration of the reflected aortic pressure wave, and increases measures of wasted left ventricular pressure energy and oxygen demand. PMID- 24794205 TI - Lung age is related to carotid structural alterations in hypertensive subjects. AB - Hypertensive patients exhibit higher cardiovascular risk and reduced lung function compared with the general population. Whether this association stems from the coexistence of two highly prevalent diseases or from direct or indirect links of pathophysiological mechanisms is presently unclear. This study investigated the association between lung function and carotid features in non smoking hypertensive subjects with supposed normal lung function. Hypertensive patients (n = 67) were cross-sectionally evaluated by clinical, hemodynamic, laboratory, and carotid ultrasound analysis. Forced vital capacity, forced expired volume in 1 second and in 6 seconds, and lung age were estimated by spirometry. Subjects with ventilatory abnormalities according to current guidelines were excluded. Regression analysis adjusted for age and prior smoking history showed that lung age and the percentage of predicted spirometric parameters associated with common carotid intima-media thickness, diameter, and stiffness. Further analyses, adjusted for additional potential confounders, revealed that lung age was the spirometric parameter exhibiting the most significant regression coefficients with carotid features. Conversely, plasma C reactive protein and matrix-metalloproteinases-2/9 levels did not influence this relationship. The present findings point toward lung age as a potential marker of vascular remodeling and indicate that lung and vascular remodeling might share common pathophysiological mechanisms in hypertensive subjects. PMID- 24794206 TI - MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. AB - MicroRNAs (miRs), as essential gene expression regulators, modulate cardiovascular development and disease and thus they are emerging as potential biomarkers and therapeutic targets in cardiovascular disease, including hypertension. We assessed the expression levels of the microRNAs miR-9 and miR 126 in 60 patients with untreated essential hypertension and 29 healthy individuals. All patients underwent two-dimensional echocardiography and 24-hour ambulatory blood pressure monitoring. MicroRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly lower miR-9 (9.69 +/- 1.56 vs 41.08 +/- 6.06; P < .001) and miR-126 (3.88 +/- 0.47 vs 8.96 +/ 1.69; P < .001) expression levels compared with healthy controls. In hypertensive patients, miR-9 expression levels showed a significant positive correlation (r = 0.437; P < .001) with left ventricular mass index. Furthermore, both miR-9 (r = 0.312; P = .015) and miR-126 (r = 0.441; P < .001) expression levels in hypertensive patients showed significant positive correlations with the 24-hour mean pulse pressure. Our data reveal that miR-9 and miR-126 are closely related to essential hypertension in humans, as they show a distinct expression profile in hypertensive patients relative to healthy individuals, and they are associated with clinical prognostic indices of hypertensive target-organ damage in hypertensive patients. Thus, they may possibly represent potential biomarkers and candidate therapeutic targets in essential hypertension. PMID- 24794207 TI - Adiponectin is better predictor of subclinical atherosclerosis than liver function tests in patients with nonalcoholic fatty liver disease. AB - Adiponectin has recently been considered as a possible link between liver dysfunction and atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD). The present study was designed to evaluate the relation between circulating adiponectin and arterial stiffness parameters, such as pulse wave velocity (PWV) and aortic augmentation index (AI), in patients with hepatic steatosis. The study group consisted of 52 subjects with NAFLD. PWV and AI were performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). Metabolic parameters, homeostasis model assessment-insulin resistance, and adiponectin levels were determined. Adiponectin was significantly, positively associated with AI (r = 0.467; P < .0001) and with PWV (r = 0.348; P = .011). No association between arterial stiffness parameters and liver function tests was observed. In a multiple linear regression analysis, adiponectin remained a significant predictor of PWV even after controlling for age, gender, and MAP. Serum adiponectin levels were significantly associated with indices of subclinical atherosclerosis, such as PWV and AI in patients with NAFLD. This association was independent of age, gender, and blood pressure level and suggests an active role of adiponectin in the pathophysiology of vascular disease in this particular population group. PMID- 24794208 TI - Hip and low back pain in the presence of femoral anteversion. A case report. AB - A change in hip morphology, such as femoral anteversion may be a factor in patients with lower quadrant pain. This case study highlights the importance of angle of torsion assessment and consideration of a patient's individual angle in designing rehabilitation programs. A patient who had a four year history of hip pain and a one year history of low back pain, in the presence of femoral anteversion is presented. She was successfully treated by altering her lower limb position as well as performing exercises in this alignment. PMID- 24794209 TI - ADHD treatment and pregnancy. AB - There is increasing recognition that ADHD is a common condition, not only in children and teenagers but also in adults. This has led to a rapid rise in the number of women of childbearing age who are being treated for this condition. Against the background of concerns about the use of medication of any kind during pregnancy and breastfeeding, it is remarkable that there is so little information available on the effects of ADHD medication on the fetus and newborn. The impulsivity associated with ADHD might lead to an increased rate of unplanned pregnancy. Although treating ADHD during pregnancy and lactation might have negative effects on the baby, suspension of treatment or inadequate treatment could also place both mother and baby at risk. Pharmacodynamic and pharmacokinetic changes during pregnancy could affect both the efficacy and the concentration of medication. Again, there is almost no guidance available. The US Food and Drug Administration has classified ADHD medications as being "pregnancy category C", implying that there is insufficient information to confirm either harm or lack of harm. From the limited information that has been published, it would appear that the risk of fetal malformation, at least with methylphenidate, is very low and that the amounts of medication excreted in breast milk and consumed by the infant are very small. Three questions that both clinicians and patients are likely to ask are the following. Should ADHD medication be stopped before, during or after pregnancy, or should it be continued throughout? Should ADHD medication doses be adjusted during the course of the pregnancy or after delivery? Should breastfeeding be encouraged or discouraged? Discontinuing ADHD treatment could put both mother and baby at risk. This has to be balanced against the possible risks to the baby of continuing treatment. Although the data remain inadequate, the risk of the latter appears to be quite small, at least for methylphenidate. However, there is recent evidence that the rates of fetal loss both through abortion and through miscarriage are increased with methylphenidate. Discussions about ADHD treatment with women of childbearing age should be balanced, open and honest, acknowledging the lack of information on the possible risks to the offspring of continuing treatment, while also drawing attention to the possible risks to both mother and child of discontinuing treatment. PMID- 24794210 TI - Cardiotoxicity of systemic agents used in breast cancer. AB - Several breast cancer therapies can lead to cardiovascular toxicity: drugs such anthracyclines can cause permanent damage, anti-HER2 agents may cause transitory and reversible cardiac dysfunction and others, such as those used in endocrine therapy, primarily disturb lipid metabolism. Considering the seriousness of these complications, trials are now being conducted to address cardiotoxicity associated with new drugs; however, to fully understand their toxicity profiles, longer follow-up is needed. In this review, we compile the information available about cardiac toxicity related to well-established systemic breast cancer treatments, as well as newer drugs, including antiangiogenics, mTOR inhibitors and novel anti-HER2 agents. We also describe current and next generation cardiac biomarkers and functional tests that can optimize treatment and reduce and prevent the incidence of treatment-related cardiotoxicity. PMID- 24794211 TI - [Evaluation of the in vitro susceptibility pattern of clinical isolates of Trichophyton mentagrophytes and Trichophyton rubrum in Santiago, Chile]. AB - BACKGROUND: Dermatophytes are a group of keratinophilic fungi able to produce dermatophytosis or tinea infections. In Chile, Trichophyton rubrum and Trichophyton mentagrophytes are the ones most commonly isolated in adults, while Microsporum canis is found among children. Treatment of these infections is usually with topical or oral antifungals, such as griseofulvin or azole derivatives (clotrimazole, itraconazole, fluconazole), allylamines (terbinafine) or new drugs that are available. AIMS: Evaluation of the in vitro susceptibility of dermatophytes to five antifungal agents and the comparison of the susceptibility pattern with that of previous years. METHODS: Sixty-two clinical isolates of dermatophyte fungi were studied (March-June 2010). The CLSI M38-A2 micromethod was used. RESULTS: Fluconazole MIC values for T. rubrum and T. mentagrophytes varied between 0.25 and 1 MUg/ml; MIC range to clotrimazole, terbinafine and itraconazole was 0.03-0.06 MUg/ml, and MIC values for griseofulvin were 0.015-0.03 MUg/ml. No statistically significant differences were found between susceptibility patterns, except for fluconazole. CONCLUSIONS: Fluconazole was less active in comparison with other drugs tested (0.25-1 MUg/ml). None of the isolates were resistant to any of the drugs, and no changes in the susceptibility pattern were observed when comparing the results with data previously reported concerning dermatophytes in Chile. PMID- 24794212 TI - [A case of mycotic keratitis due to Fusarium solani in Valdivia, Chile]. AB - BACKGROUND: Keratomycosis is one of the most prevalent ophthalmic infections, which needs a specific treatment depending on the nature of the infecting fungus. The prognosis is usually severe and depends on an early diagnosis and suitable therapy. CASE REPORT: We describe a case of keratitis due to Fusarium solani in a patient from a rural area, who, between May and October 2011, suffered a corneal trauma caused by dust particles in Valdivia, Chile. On two occasions, direct examination of eye scrapes revealed abundant septate hyphae. All cultures were positive for the same fungus, which was identified as Fusarium solani by phenotypic characterization and sequencing of ribosomal nuclear genes. The patient was initially treated with amphotericin B and afterwards successfully responded to a treatment with oral and intravenous voriconazole, although corneal opacity persisted. CONCLUSIONS: Although keratomycosis in Chile is rare, its diagnostic particularities must be taken into consideration to establish the most effective treatment. Thus, a rapid visualization of the fungus in the lesion, an efficient isolation of the etiologic agent in pure culture is essential, as well as its rapid identification, which requires the use of molecular sequencing techniques in the case of Fusarium species. PMID- 24794214 TI - Pregnancy in inherited and acquired cardiomyopathies. AB - Cardiomyopathy encompasses a wide spectrum of heart muscle disease, which can have an impact on the patient's ability to sustain the increased cardiac workload of pregnancy. Pregnancy can also unmask previously unknown cardiomyopathy. The outcome for both mother and baby is often related to the patient's functional class prior to pregnancy, and a multidisciplinary approach to managing this challenging group of patients is pivotal. PMID- 24794213 TI - Candida norvegensis fungemia in a liver transplant recipient. AB - BACKGROUND: The incidence of candidemia due to non-Candida albicans Candida species has been progressively increasing in recent years. The use of fluconazole as antifungal prophylaxis has been described as a risk factor for the development of infections by fluconazole resistant Candida strains. We report a case of Candida norvegensis bloodstream infection in a liver transplant recipient. CASE REPORT: A 61-year-old man, who received a third liver allograft and became worse with the onset of ischemic cholangiopathy and recurrent episodes of cholangitis, was admitted to our hospital due to the development of intra-abdominal abscesses. He received multiple antibiotic schemes, and after 3 months he was discharged, maintaining parenteral antibiotic at home. While he was on fluconazole prophylaxis, a breakthrough candidemia due to C. norvegensis occurred. In vitro susceptibilities of the isolate to several antifungal agents were as follows: amphotericin B MIC 0.5 mg/l, flucytosine 64 mg/l, fluconazole 64 mg/l, itraconazole 4 mg/l, voriconazole 0.75 mg/l, and caspofungin 0.047 mg/l. He was treated with anidulafungin with resolution of candidemia. CONCLUSIONS: The use of fluconazole for antifungal prophylaxis may lead to the emergence of fluconazole resistant Candida infections, with C. norvegensis being a possible emerging pathogen in organ transplant recipients. PMID- 24794215 TI - Recombinant herpesvirus glycoprotein G improves the protective immune response to Helicobacter pylori vaccination in a mouse model of disease. AB - Alphaherpesviruses, which have co-evolved with their hosts for more than 200 million years, evade and subvert host immune responses, in part, by expression of immuno-modulatory molecules. Alphaherpesviruses express a single, broadly conserved chemokine decoy receptor, glycoprotein G (gG), which can bind multiple chemokine classes from multiple species, including human and mouse. Previously, we demonstrated that infection of chickens with an infectious laryngotracheitis virus (ILTV) mutant deficient in gG resulted in altered host immune responses compared to infection with wild-type virus. The ability of gG to disrupt the chemokine network has the potential to be used therapeutically. Here we investigated whether gG from ILTV or equine herpesvirus 1 (EHV-1) could modulate the protective immune response induced by the Helicobacter pylori vaccine antigen, catalase (KatA). Subcutaneous immunisation of mice with KatA together with EHV-1 gG, but not ILTV gG, induced significantly higher anti-KatA IgG than KatA alone. Importantly, subcutaneous or intranasal immunisation with KatA and EHV-1 gG both resulted in significantly lower colonization levels of H. pylori colonization following challenge, compared to mice vaccinated with KatA alone. Indeed, the lowest colonization levels were observed in mice vaccinated with KatA and EHV-1 gG, subcutaneously. In contrast, formulations containing ILTV gG did not affect H. pylori colonisation levels. The difference in efficacy between EHV 1 gG and ILTV gG may reflect the different spectrum of chemokines bound by the two proteins. Together, these data indicate that the immuno-modulatory properties of viral gGs could be harnessed for improving immune responses to vaccine antigens. Future studies should focus on the mechanism of action and whether gG may have other therapeutic applications. PMID- 24794216 TI - Thrombotic and bleeding events after coronary stenting according to clopidogrel and aspirin platelet reactivity: VerifyNow French Registry (VERIFRENCHY). AB - BACKGROUND: Dual antiplatelet therapy, comprising aspirin and clopidogrel, is recommended in patients undergoing coronary stenting to avoid the occurrence of stent thrombosis and others ischaemic events. Interindividual response to clopidogrel varies, however, with poor response associated with an increased risk of ischaemic events. New assays are available for testing aspirin and clopidogrel response routinely at the bedside. AIM: To evaluate the prognostic value of testing antiplatelet response in an intermediate-risk population undergoing stent implantation. METHODS: We prospectively assessed clopidogrel and aspirin response using the VerifyNow assay at the time of coronary stenting in 1001 patients who presented with stable coronary disease or non-ST-segment elevation acute coronary syndrome. The main ischaemic endpoint was the composite of definite and probable stent thrombosis, cardiovascular death or spontaneous myocardial infarction at one year. The safety endpoint was major bleeding. RESULTS: Overall, 36.0% of patients had high on-clopidogrel platelet reactivity (OCR) and 8.6% had high on aspirin platelet reactivity (OAR). The main ischaemic composite endpoint occurred in 3.9% of patients with high vs. 2.3% of patients with normal OCR (hazard ratio 1.66, 95% confidence interval 0.78-3.54; P=0.18). Definite or probable stent thrombosis occurred in 1.1% of patients with high vs. 0.3% of patients with normal OCR (P=0.86). There was no significant difference in ischaemic endpoints according to OAR and there was no difference in rates of major bleeding between patients with high versus normal on-treatment platelet reactivity. CONCLUSIONS: On-treatment platelet reactivity was not associated with 1-year ischaemic or bleeding events in an intermediate-risk population undergoing stent implantation. PMID- 24794218 TI - The refinement of genetic predictors of multiple sclerosis. AB - A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p = 4.08*10(-10)). The predictive performance of the model including all currently known MS associations (area under the curve = 79.7%, 95%CI = 72.4%-87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction. PMID- 24794219 TI - [Optimized hemodilution (OHD) with hydroxyethyl starch : A blood-sparing technique for surgical treatment of dysgnathia]. PMID- 24794217 TI - Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment. AB - OBJECTIVE: The immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA. DESIGN: We used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients' peripheral blood. RESULTS: In contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen experienced effector memory cell phenotype and were capable of producing IFN gamma. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg. CONCLUSION: Our data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival. PMID- 24794220 TI - [Optimized hemodilution (OHD) with hydroxyethyl starch : A blood-sparing technique for surgical treatment of dysgnathia]. AB - Optimized hemodilution. To avoid blood transfusions, the method of optimized hemodilution (OHD) was developed. OHD consists of preoperative hypervolemic hemodilution with 500 ml hydroxyethyl starch (HES) and consecutive volume replacement with HES in the case of intraoperative intravasal fluid loss. This study verifies the efficacy of OHD. Results. Mono- and bimaxillary operations (n=213) performed between January 1995 and May 1999 were evaluated retrospectively with respect to reduction of blood transfusions due to application of OHD. The average blood loss in the OHD group (n=127) was 593 ml, and no blood transfusion was required. In contrast, the control group (n=86) showed an average blood loss of 738 ml, and 15% of these patients (n=13) required transfusion of a total of 18 blood units. Based on our results, provision of autologous blood is only necessary for patients who do not receive OHD. The costs of fluid replacement and transfusion are increased by a factor of 5.7 when OHD is not used. Discussion. OHD should be preferably used in cases of elective surgery on patients with good cardiopulmonary health. It is an easy to handle infusion regimen, which does not require additional monitoring, has no risk of infection, and results in a significant cost reduction. PMID- 24794221 TI - [Complications of orthognathic surgery : Report on 50 years experience]. AB - Background. During the past few decades, orthognathic surgery has become routine in oral and maxillofacial surgery. As these surgical interventions are elective, the goal is a low complication rate. The aim of this study was to analyze the intraoperative and postoperative complications after orthognathic surgery without considering orthodontic relapse. Patients and methods. The medical files of 507 patients were reviewed who had been treated in the department of oral maxillofacial surgery at the Martin-Luther-Universitat in Halle-Wittenberg during a period of 51 years. The indication for orthognathic surgery was mandibular hyperplasia in 314 cases (61.9%), mandibular hypoplasia in 69 cases (13.6%), mandibular hyperplasia with a frontal open bite in 53 cases (10.5%), maxillary hyperplasia with a cleft in 30 cases (5.9%), maxillary hyperplasia in 22 cases (4.3%), severe laterognathia in 10 cases (2.1%),and isolated frontal open bite in 9 cases (1.5%). The surgical procedures were as follows: bilateral sagittal split osteotomy (n=336, 66%), Le Fort I osteotomy (n=29, 5.9%), bimaxillary osteotomy (n=35, 6.3%), and segment osteotomy (n=107, 21.1%). Rigid fixation was used in 147 patients. Results. In 55% of the patients a postoperative neurosensory deficit of the inferior alveolar nerve was observed, which was only found in 28% after 1 year. Inflammatory wound healing was found in 5.3% of the patients. Conclusion. Due to antibiotic perioperative prophylaxis and modern rigid osteosynthesis devices, orthognathic surgery has become a routine method in maxillofacial surgery with predictable surgical results. PMID- 24794222 TI - [Wavy incisions for soft palate repair]. AB - Purpose. The problem with primary soft palate repair is shortness of the soft palate and a soft tissue deficit in this region. The authors introduce a modification of the intravelar veloplasty allowing lengthening of the soft palate at the time of primary closure. Methods. The "soft palate wavy incision procedure" combines a wavy or undulating type of incision at the velar cleft margins with intravelar veloplasty. In 12 patients with complete clefts of the palate, postoperative breathing and speech was analyzed 3 years later. The investigator did not know whether a modification of the common procedure had been performed in these patients or not. Results. It was found that the soft palate wavy line procedure is easy to perform and closure in three layers is possible even in wide clefts of the soft palate. No postoperative fistula was observed. An average lengthening of the soft palate of about 56% (24-83%) was achieved, measured immediately at the end of surgery. Three years later the patients have good speech results following this technique. Conclusions. Experience has shown that the soft palate wavy incision procedure is straightforward, safe, and easy. It seems that this technique leads to better results than classic intravelar veloplasty. This paper is only a first report, and further investigations are necessary. PMID- 24794224 TI - [Not Available]. PMID- 24794223 TI - [Interdisciplinary treatment of ameloblastic fibro-odontoma in a 3 1/2 year old child : Case report covering a follow-up period of over 21 years]. AB - Background. This report deals with a 3 1/2 year old patient with an ameloblastic fibro-odontoma of the frontal part and left corpus of the mandible. The tumor had become symptomatic 2 months prior to admittance by a local, painless swelling of the bone and the mobility of teeth. The initial findings and the progress of the disease led to the preliminary diagnosis of a malignant mesenchymal tumor. Its extent and aggressive growth prompted a continuity resection of the mandible and immediate reconstruction with a costal autograft. The definitive histological diagnosis was an ameloblastic fibro-odontoma. The patient was followed up over a period of 21 1/2 years. Therapy. Further treatment included an iliac crest onlay graft, followed by autotransplantation of three third molars into both transplants. Two of the wisdom teeth had to be replaced by dental implants because of ankylosis and infra-occlusal positioning. The prosthetic rehabilitation was carried out by a bar attachment and a partial cover denture. This report supports the concept of the interdisciplinary treatment of patients with tumors that occur during the growth phase. PMID- 24794225 TI - Development of a new nanofiber scaffold for use with stem cells in a third degree burn animal model. AB - The combination of mesenchymal stem cells (MSCs) and nanotechnology to promote tissue engineering presents a strategy for the creation of new substitutes for tissues. Aiming at the utilization of the scaffolds of poly-d,l-lactic acid (PDLLA) associated or not with Spirulina biomass (PDLLA/Sp) in skin wounds, MSCs were seeded onto nanofibers produced by electrospinning. These matrices were evaluated for morphology and fiber diameter by scanning electron microscopy and their interaction with the MSCs by confocal microscopy analysis. The biomaterials were implanted in mice with burn imitating skin defects for up to 7 days and five groups were studied for healing characteristics. The scaffolds demonstrated fibrous and porous structures and, when implanted in the animals, they tolerated mechanical stress for up to two weeks. Seven days after the induction of lesions, a similar presence of ulceration, inflammation and fibrosis among all the treatments was observed. No group showed signs of re-epithelization, keratinization or presence of hair follicles on the lesion site. In conclusion, although there was no microscopical difference among all the groups, it is possible that more prolonged analysis would show different results. Moreover, the macroscopic analysis of the groups with the scaffolds showed better cicatrization in comparison with the control group. PMID- 24794226 TI - Response to the letter to the editor: 'Scarring in partial thickness burns in children'. PMID- 24794227 TI - Patient experiences living with split thickness skin grafts. AB - The standard of care for deep burns is autologous split thickness skin grafting. Although adequate to resurface a deep wound, the resulting skin is chronically abnormal. The purpose of this study was to describe the experience of patients with split thickness skin grafts to help guide future investigations related to skin regeneration. In this study, an interpretive description qualitative methodology was employed. Subjects participated in a two-part single patient interview that was recorded and transcribed. A nurse with experience in clinical burn care coded and interpreted the data. Participants were recruited through presentation to a university based outpatient burn clinic for follow up from autologous split thickness skin grafting. Eight male patients and four female patients 20-62 years old ranging 2-29 months post-skin grafting were enrolled in the study. The most significant concerns voiced by patients were identified and organized into five themes: (1) a new normal, (2) split thickness skin graft symptoms, (3) appearance of new skin, (4) coping, and (5) participation in future clinical trials. Participants reported that the abnormalities related to their split thickness skin grafts were significant enough that they would be willing to participate in a future clinical trial investigating new cell-based therapies. PMID- 24794229 TI - Prevalence of sexual problems and associated distress among lesbian and heterosexual women. AB - Prevalence studies on female sexual problems among heterosexual samples have been conducted extensively across different countries. However, relatively little is known regarding prevalence of sexual problems in lesbians. The present study aimed to assess and compare the frequency of self-perceived sexual problems and associated levels of distress in lesbians and heterosexual women. In all, 390 lesbians and 1,009 heterosexual women completed an online survey. The authors assessed the frequency of self-perceived sexual problems in lesbians and heterosexual women, over the past 6 months, as well as the associated levels of distress. Main results suggested that, after controlling for distress levels, sexual pain was the most frequent sexual problem reported by lesbians and heterosexual women. Also, when distress was considered a significant decrease on prevalence rates of sexual problems were found for both lesbians and heterosexual women. Current findings emphasize the role of associated levels of distress to self-perceived sexual problems in women, regardless of sexual orientation. In addition, results suggest that length of relationship play a major role on sexual problems. Overall, data indicated a relatively similar pattern in prevalence of sexual problems in lesbians and heterosexual women. PMID- 24794228 TI - Self-burning - a rare suicide method in Switzerland and other industrialised nations - a review. AB - News items reporting self-immolation by Tibetans have been on the increase in recent years. After examining the corpse of a Swiss man who had committed suicide by deliberate self-burning, we wondered how often this occurs in Switzerland. The Federal Statistics Office (FSO) does not register self-burning specifically so no official national data on this form of suicide are available. However, we had access to the data from a Swiss National Science Foundation (SNSF) project Suicides in Switzerland between 2000 and 2010, which collected information on all (4885) cases of suicide investigated by the various institutes of forensic medicine. From this data pool we extracted 50 cases (1.02%) of suicide by self burning, in order to determine the details and to identify the possible reasons for choosing this method. To look at our results in the light of studies from other countries, we searched the literature for studies that had also retrospectively examined suicide by self-immolation based on forensic records. Our results showed that, on the whole, personal aspects of self-burning in Switzerland do not differ from those in other industrialised nations. Some data, including religious and sociocultural background, were unfortunately missing - not only from our study but also from the similar ones. In our opinion, the most important prevention strategy is to make healthcare professionals more aware of this rare method of suicide. PMID- 24794231 TI - Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation. AB - Cyclin Y, a membrane associated cyclin, is capable of binding and activating CDK14. Here we report that human cyclin Y (CCNY) is a phosphoprotein in vivo and that phosphorylation of CCNY by CDK14 triggers its ubiquitination and degradation. Inactivation of either CDK14 or Cul1 results in accumulation of CCNY. An in vivo and in vitro mapping of CCNY phosphorylation sites by mass spectrometry revealed that the flanking regions of the conserved cyclin box are heavily phosphorylated. Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex. Mutation of serine to alanine at these two sites stabilized CCNY and enhanced the activity of CCNY/CDK14 on phosphorylation of LRP6. Our results provide insight into autoregulation of the cyclin Y/CDK14 pair in CDK14 activation and cyclin Y turnover which is a process that is involved in membrane proximal signaling. PMID- 24794230 TI - Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis. AB - Apolipoprotein E (ApoE) functions as a ligand in receptor-mediated endocytosis of lipoprotein particles and has been demonstrated to play a role in antigen presentation. To explore the contribution of ApoE during autoimmune central nervous system (CNS) demyelination, we examined the clinical, cellular immune function, and pathologic consequences of experimental autoimmune encephalomyelitis (EAE) induction in ApoE knockout (ApoE(-/-)) mice. We observed reduced clinical severity of EAE in ApoE(-/-) mice in comparison to WT mice that was concomitant with an early reduction of dendritic cells (DCs) followed by a reduction of additional innate cells in the spinal cord at the peak of disease without any differences in axonal damage. While T cell priming was enhanced in ApoE(-/-) mice, reduced severity of EAE was also observed in ApoE(-/-) recipients of encephalitogenic wild type T cells. Expression of ApoE during EAE was elevated within the CNS of wild type mice, particularly by innate cells such as DCs. Overall, ApoE promotes clinical EAE, likely by mediation of inflammation localized within the CNS. PMID- 24794232 TI - Calcium entry via TRPV1 but not ASICs induces neuropeptide release from sensory neurons. AB - Inflammatory mediators induce neuropeptide release from nociceptive nerve endings and cell bodies, causing increased local blood flow and vascular leakage resulting in edema. Neuropeptide release from sensory neurons depends on an increase in intracellular Ca(2+) concentration. In this study we investigated the role of two types of pH sensors in acid-induced Ca(2+) entry and neuropeptide release from dorsal root ganglion (DRG) neurons. The transient receptor potential vanilloid 1 channel (TRPV1) and acid-sensing ion channels (ASICs) are both H(+) activated ion channels present in these neurons, and are therefore potential pH sensors for this process. We demonstrate with in situ hybridization and immunocytochemistry that TRPV1 and several ASIC subunits are co-expressed with neuropeptides in DRG neurons. The activation of ASICs and of TRPV1 led to an increase in intracellular Ca(2+) concentration. While TRPV1 has a high Ca(2+) permeability and allows direct Ca(2+) entry when activated, we show here that ASICs of DRG neurons mediate Ca(2+) entry mostly by depolarization-induced activation of voltage-gated Ca(2+) channels and only to a small extent via the pore of Ca(2+)-permeable ASICs. Extracellular acidification led to the release of the neuropeptide calcitonin gene-related peptide from DRG neurons. The pH dependence and the pharmacological profile indicated that TRPV1, but not ASICs, induced neuropeptide secretion. In conclusion, this study shows that although both TRPV1 and ASICs mediate Ca(2+) influx, TRPV1 is the principal sensor for acid-induced neuropeptide secretion from sensory neurons. PMID- 24794234 TI - [The 2nd Swiss Veterinarians' Days Convention from 14 - 16 May in Interlaken]. PMID- 24794233 TI - The role of serum C-reactive protein measured by high-sensitive method in thyroid disease. AB - The aim of this study was the evaluation of serum C-reactive protein (CRP) concentration as a marker of the inflammatory state in many different thyroid diseases and its dependence on the stage and duration of disease. We conducted a retrospective analysis of 444 randomly selected patients with different kinds of thyroid disease (106 men and 338 women, ranging 18-72 years of age; mean 56.2 +/- 5.0 years; median 52 years). Group 1 (G1) comprised 250 patients with hyperthyroidism. Group 2 (G2) consisted of 72 euthyroid patients. Group 3 (G3) consisted of 122 patients with hypothyroidism. Free T4, free T3, and thyrotropin (TSH) levels were measured using the electrochemiluminescent method. Human serum thyroglobulin autoantibodies (Tg-Abs), thyroperoxidase autoantibodies (TPO-Abs), and autoantibodies against the thyrotropin receptor (TSHR-Abs) levels were measured by radioimmunoassay. The high-sensitive CRP (Hs-CRP) level (reference range <3 mg/L) was determined with a highly sensitive latex-based immunoassay. The mean value of Hs-CRP in G1 was 3.6 +/- 2.8 mg/L, in G2 2.5 +/- 1.5 mg/L and in G3 5.9 +/- 5.8 mg/L. Hs-CRP (in mg/L) medians, interquartile and the total ranges in G1 were 3.0 (2.0 [0.1-21.0] 4.0); in G2: 2.3 [1.8 (0.2-9.2) 3.2]; and in G3: 4.3 [2.2 (0.3-31.5) 7.8]. We found statistically significant differences (Kruskal-Wallis test) in serum Hs-CRP values between G1 and G2 (P = 0.007), G1 and G3 (P = 0.001), G2 and G3 (P < 0.001). In G1, statistically significant correlation was confirmed between Hs-CRP and Tg-Abs (r = -0.22, P = 0.0016), CRP and TPO-Abs (r = -0.26, P < 0.001), and also between Hs-CRP and TSHR-Abs (r = 0.18, P = 0.02). In the remaining cases, differences between Hs-CRP and TSH levels (r = -0.09, P = 0.16) were not statistically significant. In G2, no statistically significant correlation was observed: Hs-CRP and Tg-Abs (r = -0.18, P = 0.13), Hs-CRP and TPO-Abs (r = -0.17, P = 0.15), Hs-CRP and TSH (r = 0.01, P = 0.91), Hs-CRP and TSHR-Abs (r = -0.19, P = 0.17). In G3, a statistically significant correlation was confirmed between Hs-CRP and Tg-Abs (r = 0.22, P = 0.012), Hs-CRP and TSH (r = -0.28, P = 0.001). No statistically significant correlation was observed between Hs-CRP and TPO-Abs (r = 0.20, P = 0.06) and between Hs-CRP and TSHR-Abs (r = -0.23, P = 0.11). Hs-CRP is increased in various types of hypothyroidism. This is particularly relevant in postpartum thyroiditis and in patients after radioiodine treatment. The impact of this situation on human health requires further research, however, one might assume that some types of thyroid disease may lead to systemic inflammatory reactions that are reflected in elevated CRP levels. PMID- 24794235 TI - Computed tomography of the abdomen of calves during the first 105 days of life: I. Reticulum, rumen, omasum and abomasum. AB - Computed tomographic (CT) images of the reticulum, rumen, omasum and abomasum of five healthy Holstein-Friesian bull calves were compared with anatomical transverse cadaver sections of the same calves. The calves were scanned in the transverse plane from the 5th thoracic vertebra to the sacrum six times three weeks apart from birth to 105 days of age. Multiplanar reconstruction was used to create images in sagittal and dorsal planes. After subjective assessment of various anatomical structures, the rumen, omasum and abomasum as well as the ruminal strata (gas cap, fibre mat and fluid phase) were measured. After the last CT scan, all calves were euthanised, and four were kept at -18 degrees C in sternal position for 14 days. Transverse sections 1.0 to 1.5 cm thick were made from two calves and dorsal and sagittal sections were made from one calf each using a band saw. The CT images and anatomical slices were compared and the structures on the CT images identified. Very clear CT images were obtained from the reticulum, rumen, omasum and abomasum and there was excellent agreement between images and anatomical slices. PMID- 24794236 TI - Computed tomography of the abdomen of calves during the first 105 days of life: II. Liver, spleen, and small and large intestines. AB - Computed tomography (CT) findings of the liver, spleen and intestines of five healthy calves during six examinations in the first 105 days of life were compared with corresponding cadaver slices. The liver was located in the right hemiabdomen adjacent to the diaphragm and right abdominal wall. The caudal vena cava was seen dorsomedially and the portal vein further ventrally. The umbilical vein was seen running from the navel to the liver in all calves in the first scan and in four calves in the second scan. The spleen ran dorsoventrally adjacent to the costal part of the left abdominal wall and appeared sickle-shaped on transverse images. Differentiation of small and large intestines was only possible when the former contained fluid content and the latter gaseous content. The small intestine was in the left hemiabdomen dorsal to the abomasum and caudodorsal to the rumen at the first two examinations. Growth of the forestomachs caused displacement of the small intestine to the right and toward the ventral abdomen caudal to the liver and adjacent to the right abdominal wall. The large intestine was located caudodorsally, and the typical features of the spiral colon were apparent in the dorsal plane. The location of the caecum varied from dorsal to the spiral colon to adjacent to the right abdominal wall with the apex always pointing caudally. The rectum was easily identified in the pelvic region. The size, volume and density of the described organs throughout the study are shown in several tables. PMID- 24794237 TI - Computed tomography of the abdomen of calves during the first 105 days of life: III. Urinary tract and adrenal glands. AB - Computed tomographic (CT) findings of the urinary tract and adrenal glands of five healthy male calves in the first 105 days of life were compared with corresponding cadaver slices. The structures seen on CT images were identified using the corresponding cadaver slices. CT produced exact images of the kidneys, urinary bladder, urethra and adrenal glands, but reliable images of the ureters were only obtained near the renal hilus. There was excellent agreement between the structures on the CT images and the tissue slices. The structure and vessels of the kidneys, the origin of the ureters, the location, size and content of the urinary bladder and the course of the urethra in the pelvis and penis were evident on images. The size and volume of the kidneys and the length and width of the adrenal glands increased significantly during the study, but the ureteral and urethral diameters changed little. PMID- 24794243 TI - Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. AB - BACKGROUND: Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. METHODS: Patients with previously untreated, non-metastatic, stage II III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1.5 [2.0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0.2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. FINDINGS: 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43.7%, 95% CI 38.1-49.4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36.9%, 31.3-42.4) without carboplatin (odds ratio 1.33, 95% CI 0.96-1.85; p=0.107). Of the patients with triple-negative breast cancer, 84 (53.2%, 54.4-60.9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36.9%, 29.4 44.5) of 157 without (p=0.005). Of the patients with HER2-positive tumours, 45 (32.8%, 25.0-40.7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36.8%, 28.7-44.9) of 136 without (p=0.581; test for interaction p=0.015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0.031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2.0 to 1.5. INTERPRETATION: The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. FUNDING: GlaxoSmithKline, Roche, and Teva. PMID- 24794244 TI - Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology. AB - Cocktail effects and synergistic interactions of chemicals in mixtures are an area of great concern to both the public and regulatory authorities. The main concern is whether some chemicals can enhance the effect of other chemicals, so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chemical toxicants: pesticides, metal ions and antifouling compounds. The aim of the review is to determine 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chemicals tend to induce synergy, and 4) which physiological mechanisms might be responsible for this synergy. Synergy is here defined as mixtures with minimum two-fold difference between observed and predicted effect concentrations using Concentration Addition (CA) as a reference model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixtures included in the data compilation on frequency. The difference between observed and predicted effect concentrations was rarely more than 10-fold. For pesticides, synergistic mixtures included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degradation of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixtures the pattern in terms of chemical groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chemicals are rare and often occur at high concentrations. Addressing the cumulative rather than synergistic effect of co-occurring chemicals, using standard models as CA, is therefore regarded as the most important step in the risk assessment of chemical cocktails. PMID- 24794245 TI - Distinct expression pattern of miRNAs in Marek's disease virus infected-chicken splenic tumors and non-tumorous spleen tissues. AB - MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. Emerging evidence suggests that differential miRNA expression is associated with viral infection and tumorigenesis. Recently discovered microRNAs in the Marek's disease virus (MDV) genome have been suggested to have regulatory roles during MDV oncogenesis. To gain more insight into the molecular mechanisms of the tumorigenesis of MDV, we used microarrays to screen host and viral miRNAs that were sensitive to infection by MDV. Microarray analysis showed significant differential expression of 79 miRNAs, which was confirmed by qRT-PCR analysis. These data suggest that differentially expressed miRNAs may have major roles in MDV-induced tumorigenesis. In addition, we found two clades of chicken miRNAs had increased expression in splenic tumors and non-tumorous spleen tissues from GA infected chickens. Thus, the expression of these miRNAs can be considered signatures for MDV infection and tumorigenesis. PMID- 24794246 TI - Comparative analyses of humoral and cell-mediated immune responses upon vaccination with different commercially available single-dose porcine circovirus type 2 vaccines. AB - The objective of this study was to compare the induction of humoral and cell mediated immune responses by four commercially available single-dose porcine circovirus type 2 (PCV-2) vaccines. A total of 50 3-week-old piglets were assigned to five groups (10 pigs per group). Four commercial PCV-2 vaccines were administered according to the manufacturer's instructions and the piglets were observed for 154 days post vaccination (dpv). Inactivated chimeric PCV-1-2 vaccines induced higher levels of PCV-2-specific neutralizing antibodies (NA) and interferon-gamma-secreting cells (IFN-gamma-SC) in pigs than did the other three commercial PCV-2 vaccines. The proportions of CD4(+) cells were significantly higher in animals vaccinated with inactivated chimeric PCV-1-2 and PCV-2 vaccines than in animals vaccinated with the two subunit vaccines. To our knowledge, this is the first comparison of humoral and cell-mediated immunity induced by four commercial single-dose PCV-2 vaccines under the same conditions. The results of this study demonstrated quantitative differences in the induction of humoral and cell-mediated immunity following vaccination. PMID- 24794247 TI - Opinions of Spanish pig producers on the role, the level and the risk to public health of antimicrobial use in pigs. AB - Antimicrobial use is a major driver of antimicrobial resistance and prescribers (physicians and veterinarians) and end users (patients, food producers and pet owners) are the cornerstones of this scenario. Intensive pig farming is a livestock activity that has a high antimicrobial use. This study is based on the opinions of pig producers. The study was done at national level and comprised two independent cross-sectional surveys using a questionnaire-based methodology and face-to-face interviews carried out between April and October, 2010. The collected data, which consisted of opinions of producers on 48 farrow-to-finish farms and 62 finisher farms, showed that, irrespective of farm type, pig producers in Spain have an imperfect knowledge of the main use of antimicrobials. Antimicrobials are perceived as valuable cost-effective tools for animal health and husbandry and there is little concern among pig producers about the harmful effects on public health of on-farm antimicrobial use. PMID- 24794248 TI - Attenuation of microglial and neuronal activation in the brain by ICV minocycline following myocardial infarction. AB - Following myocardial infarction, microglia, the immune cells in the central nervous system, become activated in the hypothalamic paraventricular nucleus (PVN) suggesting inflammation in this nucleus. Little is known about other brain nuclei. In the present study, we investigated whether the rostral ventrolateral medulla (RVLM), the nucleus tractus solitarius (NTS) and the periaqueductal grey (PAG), regions known to have important cardiovascular regulatory functions, also show increased microglial activation and whether this coincides with increased neuronal activity. We also investigated whether minocycline inhibited microglial activation and whether this also affected neuronal activity and cardiac function. Compared to controls there was a significant increase in the proportion of activated microglia and neuronal activation in the PVN, RVLM, NTS and PAG, 12weeks following myocardial infarction (P<0.001). Intracebroventricular infusion of minocycline (beginning one week prior to infarction) significantly attenuated the increase in microglial activation by at least 50% in the PVN, RVLM, PAG and NTS, and neuronal activation was significantly reduced by 50% in the PVN and virtually abolished in the PAG, RVLM and NTS. Cardiac function (percent fractional shortening) was significantly reduced by 55% following myocardial infarction but this was not ameliorated by minocycline treatment. The results suggest that following myocardial infarction, inflammation occurs in brain nuclei that play key roles in cardiovascular regulation and that attenuation of this inflammation may not be sufficient to ameliorate cardiac function. PMID- 24794249 TI - Genetics of vasovagal syncope. AB - INTRODUCTION: Vasovagal syncope (VVS) is the most frequent type of syncope and affects about 25% of the population. The role of genetic factors in VVS has long been debated. In this review we will discuss the current evidence that strongly suggests a major genetic component. CLINICAL GENETIC STUDIES: Family aggregation studies have consistently shown that individuals with VVS more frequently have affected family members with VVS than unaffected controls. Clear evidence for the relevance of genetic factors was provided by a twin study that showed significantly higher concordance rates in monozygous compared to dizygous twins for frequent syncope and syncope associated with typical vasovagal triggers. Analysis of the family history of the concordant monozygous twins revealed that complex inheritance is operative in the majority but rarer families with autosomal dominant inheritance also exist. Several autosomal dominant families have been described in the literature with the largest including 30 affected individuals. MOLECULAR GENETIC STUDIES: Candidate gene association studies have so far been disappointing as they have revealed either negative or unconfirmed results. However, in an autosomal dominant family the first locus for VVS was identified on chromosome 15q26. The underlying gene has not been identified yet. CONCLUSION: Genetic factors play a role in VVS. Most cases follow complex inheritance; autosomal dominant inheritance occurs less frequently. Identification of the underlying genes will improve our understanding of pathophysiology and may lead to new therapeutic strategies. PMID- 24794250 TI - Urinary nerve growth factor as an oncologic biomarker for prostate cancer aggressiveness. AB - OBJECTIVES: We investigated urinary nerve growth factor (NGF) as a novel urinary biomarker for high-grade prostate cancer (PCa). METHODS AND MATERIALS: After institutional review board approval for a prospective pilot study, we enrolled men at the preoperative visit before robotic-assisted radical prostatectomy. Demographics, urinary flow parameters, and urine samples were collected. Urinary NGF and urinary creatinine were obtained in the translational science laboratory. Pathologic and postoperative demographics were collected after surgery. NGF is the primary outcome variable (dependent variable). The pathologic Gleason score (ordinal variable <=6, 7, and <=8) served as an independent grouping variable. Multivariate analysis using a general linear model was conducted to investigate associations between independent variables and NGF (dependent variable) after adjusting for urinary concentration and volume. RESULTS: We enrolled and analyzed urine samples and pathologic data from 115 subjects. Patient pathology included 24% (n = 28) Gleason score 6 or less, 68% (n = 78) Gleason score 7, and 8% (n = 9) Gleason score 8 or greater. Perineural invasion was more prevalent in higher grade disease (P<0.001). The median NGF level was 24.1 pg/ml (range: 0.16-270.5 pg/ml) and was transformed to the log base 10 scale. Total bladder volume, urinary creatinine level, prostate-specific antigen level, and diabetes were correlated with the Log NGF. In a general linear model, adjusting for bladder volume and urinary creatinine, increasing Log10 NGF was associated with higher Gleason score (Gleason category <=6, 7, and >=8; P = 0.003). CONCLUSIONS: Urinary NGF may be a biomarker for higher-grade PCa. Our pilot study suggests further investigation is warranted to determine whether urinary NGF could provide unique additional information in patients with PCa. PMID- 24794252 TI - Screening for colorectal cancer: the role of CT colonography. AB - Colorectal cancer, which is the third most frequent cancer and the cancer with the second highest mortality rate, frequently develops on a pre-existing adenomatous polyps whose slow growth and malignant degeneration can be identified and controlled by effective screening. Although most lesions can be detected and resected during optical colonoscopy (OC), the cost, risk and poor acceptance of this technique by the general population means that it is reserved for high-risk or very high-risk individuals. The fecal occult blood test (FOBT) (such as the Hemoccult((r))) is proposed for intermediate-risk individuals between 50 and 75 years old. However, despite the improvements that have been made in this method, sensitivity is low, and although it is simple, it is too rarely used. CT colonography (virtual colonoscopy) is proposed in case of failure, additional risk factors or refusal of optical colonoscopy in high-risk patients or in the presence of a positive FOBT. It should also be proposed as an alternative to the FOBT test to patients who accept the constraints of this technique. PMID- 24794251 TI - Infiltration of CD3+ and CD68+ cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. AB - OBJECTIVES: Urothelial carcinoma (UC) aggressiveness is determined by tumor inherent molecular characteristics, such as molecular subtypes, as well as by host reactions directed toward the tumor. Cell types responsible for the host's response include tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). The aim of the present investigation was to explore the immunological response in relation to UC molecular subtypes and to evaluate the prognostic effect of TIL and TAM counts in tissue sections from muscle-invasive (MI) tumors. METHODS AND MATERIALS: Tissue microarrays with 296 tumors spanning all pathological stages and grades were analyzed with antibodies for CD3, CD8, FOXP3, CD68, and CD163. Cases were classified into the following molecular subtypes: urobasal, genomically unstable, and squamous cell carcinoma-like using a combination of immunohistochemistry and histology. The Cox regression and Kaplan-Meier analyses were performed with progression-free survival and disease specific survival as end points. RESULTS: UC molecular subtypes demonstrate different degrees of immunological responses; the urobasal subtype induces a weak response, the genomically unstable subtype induces an intermediate response, and the squamous cell carcinoma-like subtype induces a strong response. These subtype specific responses are independent of tumor stage and include both TILs and TAMs. The presence of infiltrating CD3(+) TILs was significantly associated with good prognosis in the MI cases (P<0.01). This positive association was modulated by the presence of CD68(+) TAMs. The strongest association with poor survival was observed for a high ratio between CD68 and CD3 (P = 7*10(-5)). CONCLUSION: UC molecular subtypes induce immunological responses at different levels. A high CD68/CD3 ratio identifies a bad prognosis group among MI UC cases. PMID- 24794253 TI - Liver, lung and peritoneal metastases in colorectal cancers: is the patient still curable? What should the radiologist know. AB - Regardless of the advances in chemotherapy, the only curative treatment for colorectal metastases is surgery, which must be complete and excise all of the metastatic sites of disease. Thanks to advances in neoadjuvant chemotherapy and also to alternative techniques, such as radiofrequency ablation, however, surgical treatments have become available to a larger number of patients and have improved patient survival. The aim of this article is to describe the different treatment strategies for colorectal metastases and to examine the role of imaging in defining the resect ability of these metastases. The key factors in the radiological report in the initial and post-chemotherapy assessments are described. PMID- 24794256 TI - Screening of dioxin-like compounds by complementary evaluation strategy utilising ELISA, micro-EROD, and HRGC-HRMS in soil and sediments from Montevideo, Uruguay. AB - Polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDF) are persistent, toxic, and bioaccumulate in the environment. Due to their high analytical costs, these compounds are hardly regulated and mostly not monitored in the Third World. To overcome this, bioassays have been proposed as low-cost alternative methods. Two of the most established bioanalytical tools, the dioxin antibody-based enzyme linked immunosorbent assay ELISA and the micro-EROD bioassay are evaluated and compared to high resolution gas chromatography and high resolution mass spectrometry (HRGC/HRMS) analytical methodology. The methods were tested using thirteen soils and sediment samples selected from diverse sites in Montevideo, Uruguay. The WHO2005 total toxic equivalent (WHO2005-TEQ) of soils ranged from 2.4 to 2212 (ng WHO2005-TEQ/kg dry sample) and from 0.14 to 9.4 (ng WHO2005 TEQ/kg dry sample) in sediments. This study shows significant contamination related to dioxin-like compounds, particularly in sites where uncontrolled burnings were carried out. ELISA and micro-EROD bioassay correlated well with HRGC/HRMS, R Spearman 0.773 and 0.913, respectively and were highly correlated to each other, R Spearman 0.879. Preliminary threshold values of bioassay toxic equivalents of 330 (ng/kg dry sample) for the micro-EROD bioassay and 220 (ng/kg dry sample) for ELISA are proposed. PMID- 24794257 TI - Performance of the N/TERT epidermal model for skin sensitizer identification via Nrf2-Keap1-ARE pathway activation. AB - Animal testing of chemical ingredients for cosmetic purposes is prohibited. Therefore there is an urgent need for in vitro models to identify chemical allergens. In human skin, keratinocytes (KCs) are abundantly present and are key players in initiation of allergic contact dermatitis. One of the pathways that has been shown to be induced by sensitizers is the Keap1-Nrf2-ARE pathway. In this study we compared the response of four keratinocyte-based models including (a) primary human KCs, (b) N/TERT monolayer cultures, (c) the Leiden Epidermal models (LEMs) and (d) the N/TERT epidermal models (NEMs). All keratinocyte-based models were subjected to chemical exposure of the sensitizer 2,4 dinitrochlorobenzene (DNCB) and irritant Sodium dodecyl sulfate (SDS) at nontoxic concentrations. Activation of the Keap1-Nrf2-ARE pathway was evaluated by measuring Nrf2 protein levels as well as nuclear translocation and activation of transcriptional targets of Nrf2. Results show that the Keap1-Nrf2-ARE pathway is activated by the sensitizer DNCB in monolayer keratinocytes and as well as the LEMs and NEMs and not by the irritant SDS. Collectively our data demonstrate that the N/TERT models respond similarly as primary KCs and could therefore serve as an alternative model for skin sensitizer identification, thereby overcoming the need for primary skin tissue. PMID- 24794258 TI - Toll-like receptor (TLR)-1/2 triggering of multiple myeloma cells modulates their adhesion to bone marrow stromal cells and enhances bortezomib-induced apoptosis. AB - In multiple myeloma (MM), the malignant plasma cells usually localize to the bone marrow where they develop drug resistance due to adhesion to stromal cells and various environmental signals. Hence, modulation of this interaction is expected to influence drug sensitivity of MM cells. Toll-like receptor (TLR) ligands have displayed heterogeneous effects on B-cell malignancies and also on MM cells in a few recent studies, but effects on adhesion and drug sensitivity of myeloma cells in the context of bone marrow stromal cells (BMSCs) have never been investigated. In the present study, we explored the modulatory effects of TLR1/2 ligand (Pam3CSK4) on adhesion of human myeloma cells to BMSCs. It is shown that TLR1/2 triggering has opposite effects in different HMCLs on their adhesion to BMSCs. Fravel, L363, UM-6, UM-9 and U266 showed increased adhesion to BMSC in parallel with an increased surface expression of integrin molecules alpha4 and alphaVbeta3. OPM-1, OPM-2 and NCI-H929 showed a dose-dependent decrease in adhesion upon TLR activation following a downregulation of beta7 integrin expression. Importantly, TLR1/2 triggering increased cytotoxic and apoptotic effects of bortezomib in myeloma cells independent of the effect on stromal cell adhesion. Moreover, the apoptosis-enhancing effect of Pam3CSK4 paralleled induction of cleaved caspase-3 protein in FACS analysis suggesting a caspase dependent mechanism. Our findings uncover a novel role of TLR activation in MM cells in the context of bone marrow microenvironment. Stimulation of TLR1/2 bypasses the protective shield of BMSCs and may be an interesting strategy to enhance drug sensitivity of multiple myeloma cells. PMID- 24794259 TI - Kinetics of DNA tile dimerization. AB - Investigating how individual molecular components interact with one another within DNA nanoarchitectures, both in terms of their spatial and temporal interactions, is fundamentally important for a better understanding of their physical behaviors. This will provide researchers with valuable insight for designing more complex higher-order structures that can be assembled more efficiently. In this report, we examined several spatial factors that affect the kinetics of bivalent, double-helical (DH) tile dimerization, including the orientation and number of sticky ends (SEs), the flexibility of the double helical domains, and the size of the tiles. The rate constants we obtained confirm our hypothesis that increased nucleation opportunities and well-aligned SEs accelerate tile-tile dimerization. Increased flexibility in the tiles causes slower dimerization rates, an effect that can be reversed by introducing restrictions to the tile flexibility. The higher dimerization rates of more rigid tiles results from the opposing effects of higher activation energies and higher pre-exponential factors from the Arrhenius equation, where the pre-exponential factor dominates. We believe that the results presented here will assist in improved implementation of DNA tile based algorithmic self-assembly, DNA based molecular robotics, and other specific nucleic acid systems, and will provide guidance to design and assembly processes to improve overall yield and efficiency. PMID- 24794260 TI - Historical perspectives on the impact of n-3 and n-6 nutrients on health. AB - Current public advice from the Food and Nutrition Board (FNB) about essential fatty acids (EFA) has limited quantitative details about three processes: (1) similar dynamics for n-3 linolenic and n-6 linoleic polyunsaturated fatty acids (PUFA) in maintaining 20- and 22-carbon n-3 and n-6 highly unsaturated fatty acids (HUFA) in tissues; (2) different dynamics for tissue n-3 and n-6 HUFA during formation and action of hormone-like eicosanoids; (3) simultaneous formation of non-esterified fatty acids (NEFA) and low density lipoprotein (LDL) from very low density lipoprotein (VLDL) formed from excess food energy and secreted by the liver. This report reviews evidence that public health may benefit from advice to eat less n-6 nutrients, more n-3 nutrients and fewer calories per meal. Explicit data for linoleic acid fit an Estimated Average Requirement (EAR) near 0.1 percent of daily food energy (en%) meeting needs of half the individuals in a group, a Recommended Dietary Allowance (RDA) near 0.5 en% meeting needs of 97-98 percent of individuals, and a Tolerable Upper Intake Level (UL) near 2 en% having no likely risk of adverse health effects. Quantitative tools help design and monitor explicit interventions that could beneficially replace imprecise advice on "healthy foods" with explicit preventive nutrition. PMID- 24794261 TI - Attributing the benefits of individual components in a multicomponent intervention: a familiar challenge in comprehensive geriatric care. PMID- 24794263 TI - Use of porous space maintainers in staged mandibular reconstruction. AB - The success of mandibular reconstructions depends not only on restoring the form and function of lost bone but also on the preservation of the overlying soft tissue layer. In this case study, 5 porous polymethylmethacrylate space maintainers fabricated via patient-specific molds were implanted initially to maintain the vitality of the overlying oral mucosa during staged mandibular reconstructions. Three of the 5 patients healed well; the other 2 patients developed dehiscences, likely due to a thin layer of soft tissue overlying the implant. The results presented provide evidence that a larger investigation of space maintainers fabricated using this method is warranted. PMID- 24794262 TI - Epidemiologic trends in head and neck cancer and aids in diagnosis. AB - Head and neck squamous cell carcinoma is the sixth most common cancer worldwide predominately associated with tobacco use. Changing cause and increased incidence in oropharyngeal carcinomas is associated with high-risk types of human papilloma virus and has an improved survival. Optical devices may augment visual oral examination; however, their lack of specificity still warrants tissue evaluation/biopsy. Histologic factors of oral carcinomas are critical for patient management and prognostic determination. Clinical biomarkers are still needed to improve early detection, predict malignant transformation, and optimize therapies. PMID- 24794264 TI - Pitfalls in determining head and neck surgical margins. AB - Accurate assessment of surgical margins in the head and neck is a challenge. Multiple factors may lead to inaccurate margin assessment such as tissue shrinkage, nonstandardized nomenclature, anatomic constraints, and complex three dimensional specimen orientation. Excision method and standard histologic processing techniques may obscure distance measurements from the tumor front to the normal tissue edge. Arbitrary definitions of what constitutes a "close" margin do not consider the prognostic significance of resection dimensions. In this article we review some common pitfalls in determining margin status in head and neck resection specimens as well as highlight newer techniques of molecular margin assessment. PMID- 24794265 TI - Chemotherapy for oral and maxillofacial tumors: an update. AB - Surgery is the primary intervention in oral and maxillofacial tumors and under ideal circumstances is curative. There is no evidence to support the use of induction or adjuvant chemotherapy in initial therapy of early stage tumors. Locally advanced tumors, non-resectable tumors as well as recurrence in early stage disease, need a multi-modality therapeutic approach involving chemotherapy. Palliative chemotherapy plays an important role in the treatment patients with metastatic oral and maxillofacial tumors. Chemotherapy and targeted agents plays an important role in the treatment of patients with rare oral and maxillofacial tumors such as sarcomas, lymphomas, and giant cell tumors. PMID- 24794266 TI - Oral surgery in patients undergoing chemoradiation therapy. AB - Oral health care in patients undergoing chemotherapy and/or radiation therapy can be complex. Care delivered by a multidisciplinary approach is timely and streamlines the allocation of resources to provide prompt care and to attain favorable outcomes. A hospital dentist, oral and maxillofacial surgeon, and a maxillofacial prosthodontist must be involved early to prevent avoidable oral complications. Prevention and thorough preparation are vital before the start of chemotherapy and radiation therapy. Oral complications must be addressed immediately and, even with the best management, can cause delays and interruption in treatment, with serious consequences for the outcome and prognosis. PMID- 24794267 TI - The role of bisphosphonates in medical oncology and their association with jaw bone necrosis. AB - Bisphosphonates, synthetic analogues to inorganic pyrophosphates found in the bone matrix, inhibit bone resorption. Bisphosphonates and their related effects on the jaw have been established since 2001. The pathogenesis of bisphosphonate related osteonecrosis of the jaw (BRONJ) is multifactorial and still under investigation. Currently, drugs with mechanisms of action involving remodeling suppression, osteoclast depression, and decreasing angiogenesis are under investigation for causing BRONJ-like symptoms. Further studies are needed to determine the effective length of use of biphosponates and the efficacy of drug holidays to prevent BRONJ. PMID- 24794268 TI - Nuclear medicine imaging studies in the diagnosis of head and neck disease. AB - Nuclear medicine studies have a role in the evaluation of drug induced osteonecrosis of the jaw (DIONJ). In this article, we discuss the current and future applications within nuclear medicine appropriate for evaluation of DIONJ. The emphasis of this article is positron emission tomography (PET) imaging, specifically, with 18F-fluoro-deoxy-glucose (FDG). PMID- 24794269 TI - Pharmacologic modalities in the treatment of osteoradionecrosis of the jaw. AB - Managing osteoradionecrosis (ORN) of the facial bones is a challenge in maxillofacial head and neck surgery. Changes in understanding of ORN of the jaws has led to new studies using novel therapeutic modalities to manage this disorder. These treatment regimens may allow medical management to replace major reconstructive surgery for some patients who have already undergone chemoradiotherapy or combined modality therapy for head and neck cancer. PMID- 24794270 TI - Magnetic resonance imaging (MRI) in the diagnosis of head and neck disease. AB - Magnetic resonance imaging (MRI) is the modality of choice to identify intracranial or perineural spread from a head and neck primary tumor. Perineural spread is a form of metastatic disease in which primary tumors spread along neural pathways. Orbital cellulitis is a sight-threatening, and potentially life threatening condition. Urgent imaging is performed to assess the anatomic extent of disease, including postseptal, cavernous sinus, and intracranial involvement, and identify orbital abscesses that require exploration and drainage. MRI is useful in the evaluation of the brachial plexus. PMID- 24794271 TI - Adjunctive technologies in the management of head and neck pathology. PMID- 24794272 TI - Stenting for pulmonary artery stenosis complicated by univentricular physiology: subanalysis of JPIC stent survey. AB - BACKGROUND AND PURPOSE: Stent implantation is an important treatment option for pulmonary artery stenosis (PS), even if complicated by univentricular physiology (UVP). However, there is paucity of evidence concerning not only its hemodynamic and morphologic indications but also on markers for its optimal target attainment in UVP. The purpose of this study was to evaluate the acute outcome and factors associated with efficacy of stenting for PS complicating UVP. METHODS AND SUBJECTS: A subanalysis was performed using the data of the Japanese Society of Pediatric Interventional Cardiology (JPIC) stent survey. We analyzed the morphologic and hemodynamic data of 11 patients with UVP who underwent stenting for PS. We defined "a 50% increase in the minimum lumen diameter (MLD)" as "morphologically effective," and "an achievement of 0 mmHg pressure gradient" as "hemodynamically effective." We analyzed the success rate for each criterion and determined factors which may have contributed to hemodynamic effectiveness. RESULTS: Stenting was morphologically effective in all patients, while it was hemodynamically effective in 6/11 (55%). The percent diameter stenosis after stenting was significantly lower in the "hemodynamically effective" group (2.5 +/ 5.5% vs 19.6 +/- 13.1%, p=0.017). The cutoff value of percent diameter stenosis after stenting to "hemodynamically effective" was 14.6%; the sensitivity was 80% and the specificity was 100% (area under the curve 0.825, p=0.021). CONCLUSIONS: The percent diameter stenosis after stenting significantly contributed to achieving a "0 mmHg" pressure gradient, while in order to achieve a "0 mmHg" pressure gradient, the residual percent diameter stenosis should be less than around 15%. PMID- 24794273 TI - Impediments to academic performance of bisexual college students. AB - OBJECTIVE: To investigate health-related impediments to academic success for bisexual college students. PARTICIPANTS: Respondents to the Fall 2011 American College Health Association-National College Health Assessment II (ACHA-NCHA II) survey who self-identified as bisexual, heterosexual, gay, or lesbian. METHODS: Secondary analyses of the ACHA-NCHA II data were conducted to compare the experiences of bisexual students with both each other (bisexual men and bisexual women) and those of their nonbisexual counterparts (heterosexual and gay/lesbian students). RESULTS: Bisexual college students are a large and distinct sexual minority group. On all measures with the exception of discrimination, bisexual college students reported the strongest threats to academic success of all sexual orientations. CONCLUSIONS: Given the unique impediments for bisexual students, college health professionals should consider specifically addressing needs for bisexual students, bisexual women in particular. PMID- 24794274 TI - Synthesis, characterization, crystal structures and biological activity of set of Cu(II) benzothiazole complexes: artificial nucleases with cytotoxic activities. AB - A series of Cu(II) complexes with ligand frames based on quinoline derivatives appended with a benzothiazole substituent has been isolated. The complexes, Cu(Q(oBt))(NO3)2(H2O)?CH3OH (1?CH3OH), Cu(8OHQ(oBt))Cl2?CH3OH (2?CH3OH), Cu(8OQ(oBt))Cl(CH3OH)?CH3OH (3?CH3OH) and [Cu(8OH1/2Q(oBt))(CH3OH)(NO3)]2(NO3) (4) have been characterized by single crystal X-ray diffraction, IR and UV visible spectroscopies, and elemental analysis. The ligand frame within the set of complexes differs in the substituent on the quinoline ring: complex 1 remains unsubstituted at this position while complexes 2-4 have a substituted OH group. In complex 2, the bound phenol remains protonated while in 3 it is a phenolato group. Complex 4 contains two complexes within the unit cell and one NO3(-) giving rise to an overall 'half-protonation'. The interaction between complexes 1 3 with CT-DNA was investigated using fluorescence emission spectroscopy and revealed 2 and 3 strongly intercalate DNA with Kapp values of 1.47*10(7)M(-1) and 3.09*10(7)M(-1), respectively. The ability of complexes 1-3 to cleave SC-DNA was monitored using gel electrophoresis. Each complex exhibits potent, concentration dependent nuclease activity forming single and double-nicked DNA as low as 10MUM. The nuclease activity of complexes 1-3 is primarily dependent on (1)O2 species while .OH radicals play a secondary role in the cleavage by complexes 2 and 3. The cytotoxic effects of 1-3 were examined using HeLa cells and show cell death in the micromolar range. The distribution of cell cycle stages remains unchanged when complexes are present indicating DNA damage may be occurring throughout the cell cycle. PMID- 24794275 TI - Carotid angioplasty and stenting is safe and effective for treatment of recurrent stenosis after eversion endarterectomy. AB - OBJECTIVE: This study was conducted to determine the efficiency and long-term durability of percutaneous transluminal angioplasty and carotid artery stenting in carotid restenosis (CR) treatment after eversion endarterectomy, with emphasis on variables that could influence the outcome. METHODS: We analyzed 319 patients (220 asymptomatic and 99 symptomatic) who underwent carotid angioplasty from 2002 until 2012 for CR that occurred after eversion endarterectomy. During this period, 7993 eversion endarterectomies were done for significant carotid artery stenosis. Significant CR was detected by ultrasound examination and confirmed by digital subtraction angiography or multidetector computed tomography angiography. After angioplasty (with or without stenting), color duplex ultrasound imaging was done after 1 month, 6 months, 1 year, and annually thereafter. End points encompassed myocardial infarction, stroke, and cardiovascular death (fatal myocardial infarction, fatal cardiac failure, fatal stroke), and also puncture site hematoma and recurrent restenosis. Primary end points were analyzed as early results (<=30 days after the procedure), and secondary end points were long-term results (>30 days). Variables and risk factors influencing the early-term and long-term results were also analyzed. Median follow-up was 49.8 +/- 22.8 months (range, 17-121 months). RESULTS: All but one procedure ended with a technical success (99.7%). In the early postoperative period, transient ischemic attack occurred in 2.8% of the patients and stroke in 1.6%, followed by one lethal outcome (0.3%). Stent thrombosis occurred in one patient (0.3%) several hours after the angioplasty, followed by urgent surgery and graft interposition. In the long-term follow-up, there were no transient ischemic attacks or strokes, non neurologic mortality was 3.13%, and the recurrent restenosis rate was 4.4%. The rate of non-neurologic outcomes during the follow-up was significantly higher in asymptomatic patients than in symptomatic patients (4.54% vs 0%; P = .034). The statically highest rate of transient ischemic attack was verified in patients in whom Precise (Cordis Corporation, New Brunswick, NJ) stents was used (12.2%) and a Spider Fx (Covidien, Dublin, Ireland) cerebral protection device (12.5%) was used. Female gender, coronary artery disease, plaque calcifications, and smoking history were associated with an adverse outcome after angioplasty. CONCLUSIONS: Carotid artery stenting is safe and reliable procedure for CR after eversion endarterectomy treatment, with low rate of postprocedural complications. Type of stent and cerebral embolic protection device may influence the rate of postprocedural neurologic ischemic events. PMID- 24794276 TI - Comparison of the impact of open and endovascular abdominal aortic aneurysm repair on renal function. AB - OBJECTIVE: The impact of any intervention on renal function is a crucial determinant of outcome. Open (OR) and endovascular (EVAR) abdominal aortic aneurysm (AAA) repair can affect renal function during the short and longer term. This study aimed to directly compare the effect of those different types of aneurysm repair during a period of 2 years. METHODS: This was a nested case control study including patients undergoing either OR or EVAR of an infrarenal AAA. Three groups were included: OR, EVAR with suprarenal endograft fixation, and EVAR with infrarenal fixation. These were matched for age (within 2 years), sex, AAA size (within 1 cm), hypertension, smoking, and proximal neck diameter (within 5 mm). The primary end point was change in estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration formula at baseline, 6 months, 12 months, and 2 years. RESULTS: A total of 225 patients were included [(45 ORs matched vs 90 suprarenal and 90 infrarenal fixation EVARs; 35 women (16%); age, 71 +/- 8 years; AAA size, 6.4 +/- 1 cm]. Groups did not differ significantly in terms of diabetes, hypercholesterolemia, or baseline eGFR (P = .89). On average, those undergoing OR lost a mean 5.39 mL/min/1.73 m(2) (P = .48) within 1 year and 5.49 units (P = .42) after 2 years. The suprarenal fixation patients lost 5.58 units (P = .002) after 1 year and 6.57 units (P = .001) after 2 years. Finally, the infrarenal fixation patients lost 0.53 unit (P = .74) after 1 year and 2.24 units (P = .22) after 2 years. CONCLUSIONS: OR and suprarenal fixation EVAR are associated with significant declines in renal function during 2 years, in contrast to infrarenal EVAR fixation. The patterns of eGFR decline in OR and suprarenal fixation EVAR are not similar, suggesting different causal mechanisms. PMID- 24794277 TI - Prospective, randomized study of cutting balloon angioplasty versus conventional balloon angioplasty for the treatment of hemodialysis access stenoses. AB - OBJECTIVE: The aim of this trial was to compare the rates of patency achieved by cutting and conventional balloon angioplasty to treat hemodialysis access stenoses. METHODS: End-stage renal failure patients (at three tertiary referral centers) with significant hemodialysis access stenoses were prospectively randomized to have percutaneous transluminal angioplasty (PTA) by either cutting or conventional balloons. Patients with more than one hemodynamically significant stenosis were excluded. Kaplan-Meier method was used to compare the primary assisted patency rates for the two groups. RESULTS: The study randomized 623 patients into two groups, and the duration of follow-up was 15 +/- 3 months. In the cutting balloon angioplasty group, the clinical success rate was 89% (282 of 316 stenoses). In the conventional balloon angioplasty group, the clinical success rate was 86% (265 of 307 stenoses; P = .637). Assisted primary patency for cutting PTA was statistically significantly higher at 6 months and 1 year (86% and 63%) than that for conventional PTA (56% and 37%, respectively; P = .037) in the treatment of stenosis of the graft-to-vein anastomosis. In the venous stenosis subgroup, equivalent primary assisted patency at 6 months and 1 year was observed for cutting PTA (84% and 55%) and conventional PTA (70% and 46%, respectively; P = .360). In the intragraft stenosis subgroup, primary assisted patency was equivalent at 6 months and 1 year for cutting PTA (67% and 39%) and conventional PTA (62% and 49%, respectively; P = .371). In the arterial anastomotic stenosis subgroup, assisted primary patency at 6 months and 1 year was equivalent for cutting PTA (70% and 30%) and conventional PTA (75% and 33%, respectively; P = .921). CONCLUSIONS: Cutting balloon angioplasty proved to be a safe and effective treatment of graft-to-vein anastomotic stenosis, with significantly higher patency than that of conventional balloon angioplasty. PMID- 24794278 TI - Endovascular aortic aneurysm repair surveillance may not be necessary for the first 3 years after an initially normal duplex postoperative study. AB - OBJECTIVE: We have previously shown that duplex ultrasonography (DU) may replace computed tomography angiography (CTA) as the primary surveillance tool for endovascular aortic aneurysm repair (EVAR). Current Society for Vascular Surgery practice guidelines suggest that if CTA does not document endoleak, aneurysm sac enlargement, or limb stenosis by 12 months after EVAR, surveillance studies may be performed annually. The purpose of this study was to determine whether the time to the second surveillance DU study can be safely postponed to 3 years after EVAR if the initial study finding is normal. METHODS: Between 1998 and 2013, DU surveillance was performed in our accredited noninvasive vascular laboratory at 1 week, 6 months, and annually after 410 EVARs (follow-up: mean, 35 months; range, 0.5-151 months). DU was used to measure sac diameter, intrasac endoleak peak systolic velocities (PSVs), and PSVs within endograft limbs. If an endoleak, limb stenosis, or increase in sac size was documented, DU surveillance was performed more frequently or CTA was performed, followed by intervention if appropriate. RESULTS: On the basis of DU surveillance, 113 patients (28%) were diagnosed with either endoleak or graft limb stenosis during the follow-up period. There were 95 patients (23%) with 118 endoleaks (15 [13%] type I, 90 [76%] type II, 11 [9%] type III, 2 [2%] type IV). There were 18 (4%) patients with limb stenosis defined as PSV >300 cm/s. Intervention was performed in 32 (28%) of the 113 patients with endoleak or limb stenosis, or in 8% of the total group (32 of 410), during the follow-up period of 0.5 to 151 months. Only 2.2% of the patients (7 of 325) with an initially normal finding on post-EVAR DU went on to develop endoleak or limb stenosis that required intervention during 3-year follow-up compared with 25% of patients (21 of 85) with an initially abnormal finding on post-EVAR DU (P = .0001). CONCLUSIONS: These findings suggest that follow-up DU surveillance can be postponed until 3 years after EVAR if the initial result of surveillance DU is normal (no endoleak, sac enlargement, stenosis), with minimal risk of an adverse clinical event. PMID- 24794280 TI - Silylamide complexes of chromium(II), manganese(II), and cobalt(II) bearing the ligands N(SiHMe2)2 and N(SiPhMe2)2. AB - Bis(dimethylsilyl)amide and bis(dimethylphenylsilyl)amide complexes of the divalent transition metals chromium, manganese, and cobalt were synthesized. Dimeric, donor-free {Mn[N(SiHMe2)2]2}2 could be obtained via two different pathways, a salt metathesis route (utilizing MnCl2(thf)1.5 and LiN(SiHMe2)2) and a transsilylamination protocol (utilizing Mn[N(SiMe3)2]2(thf) and HN(SiHMe2)2). Addition of 1,1,3,3-tetramethylethylendiamine (tmeda) to {Mn[N(SiHMe2)2]2}2 yielded the monomeric adduct Mn[N(SiHMe2)2]2(tmeda). The syntheses of Cr[N(SiHMe2)2]2(tmeda), Co[N(SiMe3)2][N(SiHMe2)2](tmeda), and Co[N(SiHMe2)2]2(tmeda) were achieved by transsilylamination from Cr[N(SiMe3)2]2(tmeda) and {Co[N(SiMe3)2]2}2(MU-tmeda), respectively. Bis(dimethylphenylsilyl)amide complexes Mn[N(SiMe2Ph)2]2, Cr[N(SiMe2Ph)2]2, and Co[N(SiMe2Ph)2]2(thf) were obtained via salt metathesis employing MCl2(thf)x (M = Cr, Mn, Co) with equimolar amounts of LiN(SiMe2Ph)2 in n-hexane. Treatment of CrCl2 with LiN(SiMe2Ph)2 in thf gave Cr[N(SiMe2Ph)2]2(thf)2, featuring an almost square planar trans-coordination. All complexes were examined by elemental analyses, DRIFT and UV-vis spectroscopy, as well as X-ray structure analysis, paying particular attention to secondary M---SiH beta-agostic and M---pi(arene) interactions. Magnetic moments were determined by Evans' method. PMID- 24794281 TI - Physician payment mechanisms, hospital length of stay and risk of readmission: evidence from a natural experiment. AB - We provide an analysis of the effect of physician payment methods on their hospital patients' length of stay and risk of readmission. To do so, we exploit a major reform implemented in Quebec (Canada) in 1999. The Quebec Government introduced an optional mixed compensation (MC) scheme for specialist physicians working in hospital. This scheme combines a fixed per diem with a reduced fee for services provided, as an alternative to the traditional fee-for-service system. We develop a model of a physician's decision to choose the MC scheme. We show that a physician who adopts this system will have incentives to increase his time per clinical service provided. We demonstrate that as long as this effect does not improve his patients' health by more than a critical level, they will stay more days in hospital over the period. At the empirical level, we estimate a model of transition between spells in and out of hospital analog to a difference in-differences approach. We find that the hospital length of stay of patients treated in departments that opted for the MC system increased on average by 4.2% (0.28 days). However, the risk of readmission to the same department with the same diagnosis does not appear to be overall affected by the reform. PMID- 24794279 TI - Sorting out a promiscuous superfamily: towards cadherin connectomics. AB - Members of the cadherin superfamily of proteins are involved in diverse biological processes such as morphogenesis, sound transduction, and neuronal connectivity. Key to cadherin function is their extracellular domain containing cadherin repeats, which can mediate interactions involved in adhesion and cell signaling. Recent cellular, biochemical, and structural studies have revealed that physical interaction among cadherins is more complex than originally thought. Here we review work on new cadherin complexes and discuss how the classification of the mammalian family can be used to search for additional cadherin-interacting partners. We also highlight some of the challenges in cadherin research; namely, the characterization of a cadherin connectome in biochemical and structural terms, as well as the elucidation of molecular mechanisms underlying the functional diversity of nonclassical cadherins in vivo. PMID- 24794282 TI - Impact of vitreomacular adhesion on ranibizumab mono- and combination therapy for neovascular age-related macular degeneration. AB - PURPOSE: To investigate the influence of vitreomacular adhesion on the efficacy of pro re nata (PRN) ranibizumab monotherapy and verteporfin photodynamic therapy (PDT) combination therapy for neovascular age-related macular degeneration. DESIGN: Post hoc analysis of prospective randomized 12-month multicenter clinical trial data. METHODS: PATIENT POPULATION: Total of 255 treatment-naive patients with subfoveal choroidal neovascularization. OBSERVATION PROCEDURE: Assessment of the vitreomacular interface on monthly optical coherence tomography with division of patients into the following categories according to continuous 1-year grading: posterior vitreous detachment (n=154), dynamic release of vitreomacular adhesion (n=32), stable vitreomacular adhesion (n=51). MAIN OUTCOME MEASURES: Mean best corrected visual acuity (BCVA) letter and central retinal thickness changes at month 12 in the vitreomacular interface groups. RESULTS: Mean BCVA changes at month 12 were +3.5 (posterior vitreous detachment), +4.3 (release of vitreomacular adhesion), and +6.3 (vitreomacular adhesion) in patients receiving monotherapy (P=.767), and +0.1 (posterior vitreous detachment), +6.6 (release of vitreomacular adhesion), and +9.2 (vitreomacular adhesion) in patients receiving combination therapy (P=.009). Mean central retinal thickness changes were -113 MUm (posterior vitreous detachment), -89 MUm (release of vitreomacular adhesion), and -122 MUm (vitreomacular adhesion) in monotherapy (P=.725) and -121 MUm (posterior vitreous detachment), -113 MUm (release of vitreomacular adhesion), and -113 MUm (vitreomacular adhesion) in combination therapy (P=.924). Mean ranibizumab retreatments during 12 months were 4.9 (posterior vitreous detachment), 6.6 (release of vitreomacular adhesion), and 5.3 (vitreomacular adhesion) in monotherapy (P=.018) and 4.7 (posterior vitreous detachment), 5.2 (release of vitreomacular adhesion), and 5.8 (vitreomacular adhesion) in combination therapy (P=.942). CONCLUSION: This study adds evidence that the vitreomacular interface status impacts functional outcomes and retreatment requirements. Patients with posterior vitreous detachment achieve acceptable results with fewer injections in PRN monotherapy, but lose potential vision gain with PDT. Patients with other vitreomacular interface configurations may potentially achieve optimized vision outcomes by combination of antiangiogenic treatment and vaso-occlusive PDT. PMID- 24794283 TI - Intracameral triamcinolone acetonide in glaucoma surgery: a prospective randomized controlled trial. AB - PURPOSE: To evaluate the efficacy and safety of intracameral triamcinolone acetonide (TA) in glaucoma surgery. DESIGN: Prospective randomized clinical trial. METHODS: SETTING: Institutional-Wills Eye Hospital. STUDY POPULATION: Patients undergoing trabeculectomy (with or without cataract surgery) or tube shunt surgery. INTERVENTION: Patients were randomized to receive intracameral TA or balanced salt solution at the end of surgery. Follow-up time was 6 months. MAIN OUTCOME MEASURES: Intraocular pressure, visual acuity, inflammation measured by slit-lamp examination and laser flare meter, cataract grading, bleb appearance, dry eye scores, use of supplemental medical therapy, surgical success, and rate of complications. RESULTS: Seventy-seven patients were enrolled in the study, including 37 in the TA group and 40 in the control group. There were no significant differences in success rates between the 2 groups (P=.60). Intraocular pressure and medication use were similar between the groups for each follow-up visit. Dry eye scores were lower in the TA group at month 1 (P=.042), while flare scores were higher in the TA group on day 1 (P=.015) but lower at month 1 (P=.044). The complication rates were higher in the TA group on day 1 (P=.04). All other outcome measures were similar for both groups. CONCLUSIONS: Intracameral TA did not affect the success rates or change the complication rates of glaucoma surgery. PMID- 24794284 TI - Gray hyper-reflective subretinal exudative lesions in exudative age-related macular degeneration. AB - PURPOSE: To investigate the effects of ranibizumab 0.5 mg on gray hyper reflective subretinal lesions diagnosed by spectral-domain optical coherence tomography (SD OCT) in patients with exudative age-related macular degeneration (AMD). DESIGN: Retrospective interventional study. METHODS: Data from 28 consecutive patients affected with neovascular AMD that presented subretinal hyper-reflective lesions as visualized by SD OCT were collected. Gray hyper reflective subretinal lesion characteristics were analyzed before and after intravitreal ranibizumab 0.5 mg injection. RESULTS: Thirty eyes of 28 patients (5 male, 23 female, aged 57-91 years) were included. At study entry, gray lesion was associated with exudative features in 24 of 30 eyes (80%), including subretinal fluid (SRF) in 20 of 30 eyes (67%) and retinal cystoid spaces in 11 of 30 eyes (37%). Twenty-four eyes with exudative features at study entry received prompt treatment; 6 eyes without exudative features at study entry received deferred treatment (after 1 month observation), when exudative signs emerged (SRF in 3/6 eyes and retinal cystoid spaces in 5/6 eyes). Ninety-three percent of the gray lesions responded to ranibizumab treatment at 2 months and 77% at 6 months. Gray hyper-reflective subretinal lesion thickness was significantly reduced after treatment at both 2 months (from 482+/-116 MUm to 367+/-102 MUm, P<.0001) and 6 months (from 482+/-116 MUm to 369+/-71 MUm, P<.0001). CONCLUSION: Our findings suggest that gray hyper-reflective subretinal lesions might be considered as a qualitative criterion for retreatment of exudative AMD. They may represent an early sign of active choroidal neovascularization, and should prompt to early treatment. PMID- 24794285 TI - The Maccabi Glaucoma Study: prevalence and incidence of glaucoma in a large israeli health maintenance organization. AB - PURPOSE: To investigate the prevalence and incidence of glaucoma in a large health maintenance organization (HMO) in Israel. DESIGN: A population-based retrospective cohort study, conducted using electronic medical database. METHODS: Collected data included personal and medical characteristics. SETTING: Maccabi Healthcare Services, the second-largest HMO in Israel, insuring 2 million members and serving 25% of the population with a nationwide distribution. STUDY POPULATION: Maccabi members from January 2003 to December 2010. MAIN OUTCOME MEASURES: Prevalence and incidence of glaucoma according to the International Classification of Diseases, 9th revision, Clinical Modification diagnostic codes. RESULTS: A total of 15,708 prevalent glaucoma patients were identified among active members of Maccabi in December 2010. A total of 15,332 (97.6%) were 40 years or older, with a point prevalence of 2.2%. Prevalence of glaucoma was strongly associated with age, ranging from 0.28% at age 40-50 to 9.2% among elderly aged 80 or above. The 5 most prevalent diagnoses were open-angle glaucoma (1.61%), exfoliation glaucoma (0.20%), unspecified glaucoma (0.17%), angle closure (0.11%), and normal tension glaucoma (0.06%). We identified 6674 incident glaucoma patients diagnosed between 2003 and 2010. The observed incidence density rate among 40+-year-old members was 1.84 (1.79-1.88) new cases per 1000 person years. Median age at diagnosis was 64 years old. The risk of glaucoma was similar between sexes up to age 70 years, and was significantly (P<.01) higher in men in older ages. CONCLUSIONS: Glaucoma affects nearly 10% of the elderly population in Maccabi, with the highest risk of diagnosis at age 70-74. Since glaucoma leads to irreversible vision loss, the present estimates of morbidity should be of significant concern. PMID- 24794286 TI - Effect of deep brain stimulation in rats selectively bred for reduced prepulse inhibition. AB - BACKGROUND: Sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle reaction (ASR), is disturbed in certain neuropsychiatric disorders, such as schizophrenia, obsessive compulsive disorder, and Tourette's syndrome (TS). Deep brain stimulation (DBS) of the centromedian-parafascicular complex (CM-Pf), globus pallidus internus (in rats the entopeduncular nucleus - EPN), and the ventral striatum (in rats the nucleus accumbens - NAC) has been used for treatment in TS. OBJECTIVE: We tested whether DBS of these regions would alleviate breeding-induced low PPI in rats. METHODS: Rats with breeding-induced low and high PPI were bilaterally implanted with electrodes in the CM-Pf, the EPN, or the NAC. After two weeks, they were stimulated or sham stimulated for epochs of 6 days (in the EPN with a current of 20% below the individual threshold for stimulation-induced side effects, in the NAC or CM-Pf with 100 MUA and 150 MUA). On the 6th day the rats were tested for PPI of ASR. RESULTS: Stimulation in the CM-Pf with 150 MUA significantly alleviated PPI, while NAC stimulation was less effective. In PPI low rats electrode implantation in the EPN already improved PPI, while subsequent stimulation had no additional effect. Startle reaction of PPI low rats was not affected by stimulation of either region. CONCLUSION: The CM-Pf and the EPN are important for the modulation of sensorimotor gating in rats with breeding-induced low PPI. These rats may therefore be useful to further investigate the pathophysiological mechanisms of deficient sensorimotor gating and also mechanisms of action of DBS in these circumstances. PMID- 24794288 TI - Differentially expressed genes in the cuticle and hemolymph of the silkworm, Bombyx mori, injected with the fungus Beauveria bassiana. AB - The most important pathogenic fungus of the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), is Beauveria bassiana (Balsamo-Crivelli ) Vuillemin (Hypocreales: Clavicipitaceae), which causes significant damage to sericulture production. Therefore, diagnosing fungal disease and developing new control measures are crucial to silk production. To better understand the responsive and interactive mechanisms between the host silkworm and this fungus, variations in silkworm gene expression were investigated using the suppression subtractive hybridization method following the injection of B. bassiana conidia. Two cDNA libraries were constructed, and 140 cDNA clones were isolated. Of the 50 differentially expressed genes identified, 45 (112 clones) were identified in the forward library, and 5 (28 clones) were identified in the reverse library. Expression profiling of six of these genes by quantitative polymerase chain reaction (qPCR) verified that they were induced by the fungal challenge. The present study provides insight into the interaction between lepidopteran insects and pathogenic fungi. PMID- 24794287 TI - A novel model incorporating two variability sources for describing motor evoked potentials. AB - OBJECTIVE: Motor evoked potentials (MEPs) play a pivotal role in transcranial magnetic stimulation (TMS), e.g., for determining the motor threshold and probing cortical excitability. Sampled across the range of stimulation strengths, MEPs outline an input-output (IO) curve, which is often used to characterize the corticospinal tract. More detailed understanding of the signal generation and variability of MEPs would provide insight into the underlying physiology and aid correct statistical treatment of MEP data. METHODS: A novel regression model is tested using measured IO data of twelve subjects. The model splits MEP variability into two independent contributions, acting on both sides of a strong sigmoidal nonlinearity that represents neural recruitment. Traditional sigmoidal regression with a single variability source after the nonlinearity is used for comparison. RESULTS: The distribution of MEP amplitudes varied across different stimulation strengths, violating statistical assumptions in traditional regression models. In contrast to the conventional regression model, the dual variability source model better described the IO characteristics including phenomena such as changing distribution spread and skewness along the IO curve. CONCLUSIONS: MEP variability is best described by two sources that most likely separate variability in the initial excitation process from effects occurring later on. The new model enables more accurate and sensitive estimation of the IO curve characteristics, enhancing its power as a detection tool, and may apply to other brain stimulation modalities. Furthermore, it extracts new information from the IO data concerning the neural variability-information that has previously been treated as noise. PMID- 24794289 TI - Can serious games be incorporated with conventional treatment of children with cerebral palsy? A review. AB - The use of video games in rehabilitation is becoming more popular to clinicians. These games are embedded in off-the-shelf commercial entertainment applications or especially-developed for clinical purposes. Treatment of cerebral palsy (CP) children is a challenging task for clinicians. Lack of motivation and progress monitoring are two important factors clinicians need to deal with. The use of serious games (SG), sometimes referred to as Virtual Rehabilitation (VR), could therefore be an interesting adjuvant to conventional treatment for these patients. This is however a new discipline and many scientific issues remain to be solved. The aim of this paper is to describe available conventional treatment for CP children together with the level of evidence of each approach. A systematic review of the use of SG in rehabilitation is then conducted. 31 papers (7 randomized clinical trials, 16 cohort studies and 8 single-cases studies) were selected and analyzed, and their level of evidence compared to the conventional treatment. These studies reported outcomes for 352 patients. In summary, this review shows that it is difficult to compare those studies despite the large amount of patients. This is due to the lack of standardization in patient rehabilitation strategy and to the use of various clinical scales and scores. This non-standardization in patient follow-up between previously-published works make evidence-based conclusions difficult to obtain in order to support these techniques objectively. The use of SG for rehabilitation purposes currently meets similar issues. This paper proposes standardization strategies in order to improve treatment comparison and SG use in rehabilitation. PMID- 24794290 TI - The association between behavioural and emotional problems and age in adults with Down syndrome without dementia: Examining a wide spectrum of behavioural and emotional problems. AB - The literature on the association between behavioural and emotional problems and ageing in adults with Down syndrome (DS) without dementia is limited and has generally not reported on a wide range of behavioural and emotional problems. This research aimed to extend the field by examining the associations between age and a wide spectrum of behavioural and emotional problems in adults with DS without dementia. A preliminary analysis of the association between potential covariates and behavioural and emotional problems was also undertaken. Parents and caregivers completed a questionnaire on behavioural and emotional problems for 53 adults with DS aged between 16 and 56 years. Twenty-eight adults with DS and their caregivers were part of a longitudinal sample, which provided two time points of data approximately four years apart. Additionally, 25 participants with DS and their caregivers were from a cross sectional sample, which provided one time point of data. Random effects regression analyses were used to examine the patterns in item scores for behavioural and emotional problems associated with age. No significant associations between age and the range or severity of any behavioural and emotional items were found. This suggested a more positive pattern for ageing adults with DS than has been previously described. Given that behavioural and emotional problems were not associated with age, investigation into other factors that may be associated with the behavioural and emotional difficulties for adults with DS is discussed. PMID- 24794291 TI - Normal range and regional heterogeneity of myocardial perfusion in healthy human myocardium: assessment on dynamic perfusion CT using 128-slice dual-source CT. AB - Information about myocardial perfusion in healthy hearts is essential for evaluating patients with ischemic heart disease. The purpose of this study was to determine the range and regional variability of myocardial perfusion in normal volunteers on dynamic perfusion computed tomography (CT). Myocardial perfusion was assessed in 19 healthy volunteers (age 33-60 years; 11 men) at rest and during adenosine-induced hyperemia using a 128-slice dual-source CT scanner. Data were quantified as cc/cc/min for the transmural myocardium based on a 17-segment American Heart Association model. Mean myocardial blood flows (MBF) were 1.73 +/- 0.33 cc/cc/min during adenosine-induced hyperemia, 0.83 +/- 0.21 cc/cc/min at rest, and perfusion reserve was 2.20 +/- 0.53. Regional variability was 17 +/- 5% for hyperemic perfusion, 18 +/- 7% for resting, and 21 +/- 6 % for perfusion reserve. Although statistically insignificant, perfusion in the septum was lower at rest and during hyperemia than in other regions. Women tended to have lower perfusion during hyperemia (1.65 +/- 0.40 vs. 1.79 +/- 0.28 cc/cc/min, P = 0.40), and higher perfusion at rest than men (0.91 +/- 0.27 vs. 0.77 +/- 0.15 cc/cc/min, P = 0.23), resulting in lower perfusion reserve (1.86 +/- 0.31 vs. 2.45 +/- 0.53, P = 0.11). This small cohort of healthy volunteers study reveals normal myocardial perfusion parameter on dynamic perfusion CT as follows: mean MBF is 1.73 +/- 0.33 cc/cc/min during hyperemia, 0.83 +/- 0.21 cc/cc/min at rest, and perfusion reserve is 2.20 +/- 0.53. And the study also demonstrates considerable regional heterogeneity of the myocardial perfusion. PMID- 24794292 TI - Dose reduction for coronary calcium scoring with hybrid and model-based iterative reconstruction: an ex vivo study. AB - PURPOSE: To determine the influence of dose reduction on coronary calcium scoring using hybrid and model-based iterative reconstruction (IR) techniques. METHODS: Fifteen ex vivo hearts were scanned in a phantom representing an average adult person at routine dose and three levels of dose reduction; 27, 55 and 82% reduced dose, respectively. All images were reconstructed using filtered back-projection (FBP), hybrid IR (iDose4, levels 1, 4 and 7) as well as model-based IR iterative model reconstruction (IMR, levels 1, 2 and 3). Agatston, mass and volume scores found with iDose4 and IMR were compared to FBP reconstruction (routine dose) as well as objective image quality. RESULTS: With FBP calcium scores remained unchanged at 82% reduced dose. With IR Agatston scores differed significantly at routine dose, using IMR level 3 and iDose4 level 7, and at 82% reduced dose, using IMR levels 1-3 and iDose4 level 7. The maximum median difference was 5.3%. Mass remained unchanged at reduced dose levels while volume was significantly lower at 82% reduced dose with IMR (maximum median difference 5.0%). Objective image quality improved with IR, at 82% reduced dose the CNR of iDose4 level 7 was similar to the reference dose CNR, and IMR levels 1-3 resulted in an even higher CNR. CONCLUSION: Calcium scores were not affected by radiation-dose reduction with FBP and low levels of hybrid IR. Objective image quality increased significantly using hybrid and model-based IR. Therefore low level hybrid IR has the potential to reduce radiation-dose of coronary calcium scoring with up to 82%. PMID- 24794293 TI - Evidence of myocardial scarring and microvascular obstruction on cardiac magnetic resonance imaging in a series of patients presenting with myocardial infarction without obstructed coronary arteries. AB - Patients with acute chest pain, electrocardiographic ST-elevation and significant elevation of cardiac troponin but without obstructive coronary artery disease represent a diagnostic and therapeutic dilemma. Cardiac magnetic resonance imaging (CMR) can elucidate underlying alternative causes of troponin elevation including detection of (minor) myocardial infarction (MI) by identifying myocardial scarring as delayed enhancement. Of 77 patients, who were admitted between March 2009 and December 2012 with electrocardiographic (ECG) and biochemical evidence of acute MI without obstructive coronary artery disease, 45 patients underwent CMR that showed in 11/77 (14%) late gadolinium enhancement (LGE), compatible with myocardial scarring. We analyzed clinical, echocardiographic, and CMR data of these patients. Elevated troponin I levels were observed in all patients (median 1.3 ng/l, IQR 0.44-187) with median peak creatinine phosphokinase of 485 U/l (IQR 234-618). Echocardiographic wall motion abnormalities were detected in 8/11 (73%) patients; in 75% of these segments, ECG abnormalities were observed in corresponding leads. CMR detected LGE in the inferior (4/11), the inferolateral (5/11), the inferoseptal (2/11), the anterior (3/11), apical (3/11) and in the lateral segments (2/11). In addition, in all but two patients, these segments matched ECG abnormalities in corresponding leads. CMR identified microvascular obstruction in 4/11 (36%) patients. Patients with clinical, ECG, and biochemical signs of acute MI but unobstructed coronary arteries may have CMR-detectable myocardial scars. Information on myocardial scarring may help to make the diagnosis and draw therapeutic consequences. This case series underlines the value of contrast-enhanced CMR for myocardial tissue characterization. PMID- 24794294 TI - Neural pathways for the detection and discrimination of conspecific song in D. melanogaster. AB - BACKGROUND: During courtship, male Drosophila melanogaster sing a multipart courtship song to female flies. This song is of particular interest because (1) it is species specific and varies widely within the genus, (2) it is a gating stimulus for females, who are sensitive detectors of conspecific song, and (3) it is the only sexual signal that is under both neural and genetic control. This song is perceived via mechanosensory neurons in the antennal Johnston's organ, which innervate the antennal mechanosensory and motor center (AMMC) of the brain. However, AMMC outputs that are responsible for detection and discrimination of conspecific courtship song remain unknown. RESULTS: Using a large-scale anatomical screen of AMMC interneurons, we identify seven projection neurons (aPNs) and five local interneurons (aLNs) that outline a complex architecture for the ascending mechanosensory pathway. Neuronal inactivation and hyperactivation during behavior reveal that only two classes of interneurons are necessary for song responses--the projection neuron aPN1 and GABAergic interneuron aLN(al). These neurons are necessary in both male and female flies. Physiological recordings in aPN1 reveal the integration of courtship song as a function of pulse rate and outline an intracellular transfer function that likely facilitates the response to conspecific song. CONCLUSIONS: These results reveal a critical pathway for courtship hearing in male and female flies, in which both aLN(al) and aPN1 mediate the detection of conspecific song. The pathways arising from these neurons likely serve as a critical neural substrate for behavioral reproductive isolation in D. melanogaster. PMID- 24794295 TI - Chemosensory communication of gender through two human steroids in a sexually dimorphic manner. AB - Recent studies have suggested the existence of human sex pheromones, with particular interest in two human steroids: androstadienone (androsta-4,16,-dien-3 one) and estratetraenol (estra-1,3,5(10),16-tetraen-3-ol). The current study takes a critical step to test the qualification of the two steroids as sex pheromones by examining whether they communicate gender information in a sex specific manner. By using dynamic point-light displays that portray the gaits of walkers whose gender is digitally morphed from male to female [1, 2], we show that smelling androstadienone systematically biases heterosexual females, but not males, toward perceiving the walkers as more masculine. By contrast, smelling estratetraenol systematically biases heterosexual males, but not females, toward perceiving the walkers as more feminine. Homosexual males exhibit a response pattern akin to that of heterosexual females, whereas bisexual or homosexual females fall in between heterosexual males and females. These effects are obtained despite that the olfactory stimuli are not explicitly discriminable. The results provide the first direct evidence that the two human steroids communicate opposite gender information that is differentially effective to the two sex groups based on their sexual orientation. Moreover, they demonstrate that human visual gender perception draws on subconscious chemosensory biological cues, an effect that has been hitherto unsuspected. PMID- 24794296 TI - Environmental consistency determines the rate of motor adaptation. AB - BACKGROUND: The motor system has the remarkable ability not only to learn but also to learn how fast it should learn. However, the mechanisms behind this ability are not well understood. Previous studies have posited that the rate of adaptation in a given environment is determined by Bayesian sensorimotor integration based on the amount of variability in the state of the environment. However, experimental results have failed to support several predictions of this theory. RESULTS: We show that the rate at which the motor system adapts to changes in the environment is primarily determined not by the degree to which environmental change occurs but by the degree to which the changes that do occur persist from one movement to the next, i.e., the consistency of the environment. We demonstrate a striking double dissociation whereby feedback response strength is predicted by environmental variability rather than consistency, whereas adaptation rate is predicted by environmental consistency rather than variability. We proceed to elucidate the role of stimulus repetition in speeding up adaptation and find that repetition can greatly potentiate the effect of consistency, although unlike consistency, repetition alone does not increase adaptation rate. By leveraging this understanding, we demonstrate that the rate of motor adaptation can be modulated over a range that encompasses a 20-fold increase from lowest to highest. CONCLUSIONS: Understanding the mechanisms that determine the rate of motor adaptation could lead to the principled design of improved procedures for motor training and rehabilitation. Regimens designed to control environmental consistency and repetition during training might yield faster, more robust motor learning. PMID- 24794297 TI - HSP70 transgene directed motion to nuclear speckles facilitates heat shock activation. AB - Association and disassociation of gene loci with respect to specific nuclear compartments accompany changes in gene expression, yet little is known concerning the mechanisms by which this occurs or its functional consequences. Previously, we showed that tethering acidic activators to a peripheral chromosome site led to movement of the chromosome site away from the nuclear periphery, but the physiological relevance of this movement was unclear [1]. Nuclear speckles, or interchromatin granule clusters, are enriched in factors involved in RNA processing [2], and the association of a subset of active genes at their periphery suggests speckles may play a role in gene expression [3, 4]. Here, we show an actin-dependent association of HSP70 transgenes with nuclear speckles after heat shock. We visualized HSP70 transgenes moving curvilinearly toward nuclear speckles over ~0.5-6 MUm distances at velocities of 1-2 MUm min(-1). Chromatin stretching in the direction of movement demonstrates a force-generating mechanism. Transcription in nearly all cases increased noticeably only after initial contact with a nuclear speckle. Moreover, blocking new HSP70 transgene/speckle association by actin depolymerization prevented significant heat shock-induced transcriptional activation in transgenes not associated with speckles, although robust transcriptional activation was observed for HSP70 transgenes associated with nuclear speckles. Our results demonstrate the existence of a still-to-be-revealed machinery for moving chromatin in a direct path over long distances toward nuclear speckles in response to transcriptional activation; moreover, this speckle association enhances the heat shock activation of these HSP70 transgenes. PMID- 24794298 TI - Inefficient double-strand break repair in murine rod photoreceptors with inverted heterochromatin organization. AB - BACKGROUND: DNA double-strand break (DSB) repair is crucial for the maintenance of genomic stability, and chromatin organization represents one important factor influencing repair efficiency. Mouse rod photoreceptors with their inverted heterochromatin organization containing a single large chromocenter in the middle of the nucleus provide a unique model system to study DSB repair in heterochromatin of living animals. RESULTS: We observed that adult rod photoreceptors repair only half of the induced DSBs within 1 day after damage induction, a defect that is neither observed in any other cell type of the adult retina nor in rod photoreceptor precursor cells of postnatal day 4 mice. We show that adult wild-type rods are deficient in a repair pathway involving ATM, a protein that promotes heterochromatic DSB repair by phosphorylating KAP1 and facilitating heterochromatin relaxation. Of note, we observed that rods fail to robustly accumulate active ATM at DSBs, exhibit low KAP1 levels, and display high levels of SPOC1, a factor suppressing KAP1 phosphorylation. Collectively, this results in dramatically reduced KAP1 phosphorylation and the inability to repair heterochromatic DSBs. CONCLUSIONS: Because the distinct heterochromatic structure of rods focuses transmitting light to enable vision at low photon levels, the inability to phosphorylate KAP1 and the failure to relax heterochromatin could serve to maintain this structure and the functionality of rods in the presence of DSBs. Collectively, our findings show that the unique chromatin organization of adult rods renders them incapable to efficiently repair heterochromatic DSBs, providing evidence that heterochromatin affects mammalian DSB repair in vivo. PMID- 24794299 TI - Contact angle at the leading edge controls cell protrusion rate. AB - Plasma membrane tension and the pressure generated by actin polymerization are two antagonistic forces believed to define the protrusion rate at the leading edge of migrating cells [1-5]. Quantitatively, resistance to actin protrusion is a product of membrane tension and mean local curvature (Laplace's law); thus, it depends on the local geometry of the membrane interface. However, the role of the geometry of the leading edge in protrusion control has not been yet investigated. Here, we manipulate both the cell shape and substrate topography in the model system of persistently migrating fish epidermal keratocytes. We find that the protrusion rate does not correlate with membrane tension, but, instead, strongly correlates with cell roundness, and that the leading edge of the cell exhibits pinning on substrate ridges-a phenomenon characteristic of spreading of liquid drops. These results indicate that the leading edge could be considered a triple interface between the substrate, membrane, and extracellular medium and that the contact angle between the membrane and the substrate determines the load on actin polymerization and, therefore, the protrusion rate. Our findings thus illuminate a novel relationship between the 3D shape of the cell and its dynamics, which may have implications for cell migration in 3D environments. PMID- 24794301 TI - Did the classical concept of meconium according to Aristotle induce not only the fetus into sleep, but also us, researchers and clinicians? Introduction. PMID- 24794300 TI - Ecdysone mediates the development of immunity in the Drosophila embryo. AB - Beyond their role in cell metabolism, development, and reproduction, hormones are also important modulators of the immune system. In the context of inflammatory disorders, systemic administration of pharmacological doses of synthetic glucocorticoids (GCs) is widely used as an anti-inflammatory treatment [1, 2]. However, not all actions of GCs are immunosuppressive, and many studies have suggested that physiological concentrations of GCs can have immunoenhancing effects [3-7]. For a more comprehensive understanding of how steroid hormones regulate immunity and inflammation, a simple in vivo system is required. The Drosophila embryo has recently emerged as a powerful model system to study the recruitment of immune cells to sterile wounds [8] and host-pathogen dynamics [9]. Here we investigate the immune response of the fly embryo to bacterial infections and find that the steroid hormone 20-hydroxyecdysone (20-HE) can regulate the quality of the immune response and influence the resolution of infection in Drosophila embryos. PMID- 24794302 TI - The aetiology of meconium-stained amniotic fluid: pathologic hypoxia or physiologic foetal ripening? (Review). AB - INTRODUCTION: Despite the many efforts to study the (patho)physiology of meconium release before delivery, it still remains an indistinct subject. Some studies have reported a relationship between hypoxia and MSAF, whilst others have not. The most common association found however, is between MSAF and the term of gestation. METHODS: MEDLINE, EMBASE and the Cochrane library were electronically searched. Papers about the (patho)physiology of meconium-stained amniotic fluid in English were included. Papers about management strategies were excluded (see elsewhere this issue). RESULTS: Different theories have been proposed including acute or chronic hypoxia, physiologic foetal ripening and peripartum infection. CONCLUSION: We suggest that meconium-stained amniotic fluid should be regarded as a symptom rather than a syndrome becoming more prevalent with increasing term and which might be associated with higher levels of infection or asphyxia. PMID- 24794303 TI - Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation. AB - BACKGROUND: Sparse knowledge exists on the differences in cardiac function between term and preterm infants. This study examines the impact of heart size, gestational age and postnatal maturation on myocardial function. AIM: To assess and compare serial echocardiographic indices of myocardial function in term and moderately preterm infants. METHODS: Longitudinal, prospective, observational echocardiographic cohort study of 45 healthy term infants examined at day three and at 12-20weeks postnatal age and 53 moderately preterm infants (gestational age 31-35weeks) examined at day three and at term equivalent (4-10weeks postnatal age). OUTCOMES: Primary: Systolic mitral and tricuspid annular plane excursions and annular peak systolic pulsed wave tissue Doppler (pwTDI) velocities. Secondary: Indices normalized for heart size. RESULTS: On day three, all indices were higher in the term than in the preterm infants whereas normalized systolic pwTDI velocities were lower in the term infants and normalized excursions showed no difference. All indices increased with advanced postnatal age. The indices in term infants on day three were lower than in preterm infants at term equivalent, with and without normalization. After postnatal maturation in both groups, all indices were higher in the term group (except left pwTDI), whereas normalized indices showed no consistent pattern. CONCLUSIONS: Myocardial function indices increased with gestational age at birth and more profoundly with postnatal maturation. Serial examinations of non-normalized and normalized myocardial function indices showed no sustained differences between the preterm and the term infants. Normalization by heart size may be of value when assessing myocardial function in infants. PMID- 24794305 TI - Consequences of meconium stained amniotic fluid: what does the evidence tell us? AB - BACKGROUND: Meconium stained amniotic fluid (MSAF) is common and associated with meconium aspiration syndrome (MAS). Other consequences of meconium passage before birth are less well understood. METHODS: We reviewed the literature for original papers reporting on outcomes associated with MSAF. FINDINGS: Among preterm infants MSAF is more prevalent than previously believed and is associated with higher neonatal morbidity. Intrauterine exposure to meconium is associated with inflammation of tissues of the lung, chorionic plate and umbilical vessels and through various mechanisms may contribute to neonatal morbidity, independent of MAS. No compelling evidence supported an association between MSAF and increased neurological impairment, including early seizure activity. PMID- 24794304 TI - Maternal sensitivity and infant autonomic and endocrine stress responses. AB - BACKGROUND: Early environmental exposures may help shape the development of the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis, influencing vulnerability for health problems across the lifespan. Little is known about the role of maternal sensitivity in influencing the development of the ANS in early life. AIMS: To examine associations among maternal sensitivity and infant behavioral distress and ANS and HPA axis reactivity to the Repeated Still-Face Paradigm (SFP-R), a dyadic stress task. STUDY DESIGN: Observational repeated measures study. SUBJECTS: Thirty-five urban, sociodemographically diverse mothers and their 6-month-old infants. OUTCOME MEASURES: Changes in infant affective distress, heart rate, respiratory sinus arrhythmia (RSA), and T wave amplitude (TWA) across episodes of the SFP-R were assessed. A measure of cortisol output (area under the curve) in the hour following cessation of the SFP R was also obtained. RESULTS: Greater maternal insensitivity was associated with greater infant sympathetic activation (TWA) during periods of stress and tended to be associated with greater cortisol output following the SFP-R. There was also evidence for greater affective distress and less parasympathetic activation (RSA) during the SFP-R among infants of predominantly insensitive mothers. CONCLUSIONS: Caregiving quality in early life may influence the responsiveness of the sympathetic and parasympathetic branches of the ANS as well as the HPA axis. Consideration of the ANS and HPA axis systems together provides a fuller representation of adaptive versus maladaptive stress responses. The findings highlight the importance of supporting high quality caregiving in the early years of life, which is likely to promote later health. PMID- 24794306 TI - Maternal physical activity mode and fetal heart outcome. AB - BACKGROUND: Maternal leisure-time physical activity (LTPA) improves cardiac autonomic function in the fetus. The specific physical activity attributes (e.g., mode) that produce this benefit are not well understood. AIM: To determine if more time spent performing non-continuous LTPA during pregnancy is significantly associated with lower fetal heart rate (HR) and increased heart rate variability (HRV). STUDY DESIGN: This paper presents a retrospective analysis of previously reported data. Fetal magnetocardiograms (MCG) were recorded from 40 pregnant women at 36-wk gestational age. OUTCOME MEASURES: Metrics of fetal HR and HRV, self-reported min of continuous and non-continuous LTPA performed during the 3 months preceding the 36-wk assessment point and covariates (maternal weight change pre to 36-wk, age, and resting HR and fetal activity state during MCG recordings. RESULTS: Positive correlations were significant (p<0.05) between min of continuous LTPA, the time domain metrics that describe fetal overall HRV, short-term HRV and a frequency domain metric that reflects vagal activity. Time spent in non-continuous LTPA was positively correlated (p<0.05) with two HRV metrics that reflect fetal overall HRV. In the multiple regression analyses, minutes of non-continuous LTPA remained associated with fetal vagal activity (p<0.05) and the relationships between minutes of non-continuous LTPA and fetal overall HRV (p<0.005) persisted. CONCLUSION: These data suggest non-continuous physical activity provides unique benefits to the fetal autonomic nervous system that may give the fetus an adaptive advantage. Further studies are needed to understand the physiological mechanisms and long-term health effects of physical activity (both non-continuous and continuous) performed during pregnancy to both women and their offspring. PMID- 24794307 TI - Maternal thyrotrophin in euthyroid women is related to meconium stained amniotic fluid in women who deliver at or over 41 weeks of gestation. AB - BACKGROUND: Maternal thyroid dysfunction is of known influence on pregnancies in the preterm period. However little is known about its effect on term and post term pregnancies. Meconium stained amniotic fluid (MSAF) is known to occur preferentially in (post)term pregnancies. AIMS: To assess a possible independent relation between maternal thyroid function and MSAF. STUDY DESIGN AND SUBJECTS: 1051 women, in whom thyroid function was assessed at each trimester, were followed prospectively (delivery >=37weeks). We compared the difference in mean TSH and FT4 between women with (152) and without (899) MSAF using one way ANOVA. Thyroid function was assessed in subgroups regarding gestational age. Finally we performed multiple logistic regression analysis with MSAF as dependent variable and TSH as independent variable adjusting for various confounders. RESULTS: Maternal thyroid function was not associated with the incidence of MSAF when analysing all deliveries >=37weeks. However, in the "at-risk" group for MSAF (>41weeks), multiple logistic regression showed an independent relation between MSAF and TSH (O.R.: 1.61, 95% CI: 1.10-2.43). CONCLUSIONS: The present study shows that in women delivering >=41weeks of gestation, higher TSH is independently related to MSAF. PMID- 24794308 TI - Characterization and management of dermatologic adverse events with the NovoTTF 100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma. AB - The NovoTTF-100A System (NovoTTFTM Therapy, Novocure Inc.) is a device that delivers alternating electric fields (TTFields) to tumor cells and interferes with mitosis. It is approved for use as monotherapy for the treatment of recurrent glioblastoma (rGB). TTFields are delivered through insulated transducer arrays applied onto the shaved scalp and connected to a battery-operated field generator. The occurrence of dermatologic adverse events (dAEs) is primarily due to the continuous contact between the array-related components and the scalp for periods of 3-4 days (together with other risk factors). These dAEs may include allergic and irritant dermatitis, mechanical lesions, ulcers, and skin infection. The incidence of dAEs in the phase III trial (n = 116) was 16% (2% grade 2, 0% grade 3/4); the post-marketing surveillance program (n = 570) revealed 156 (21.8%) dAEs with some patients reporting more than one event. Prophylactic strategies for dAEs include proper shaving and cleansing of the scalp and array relocation. Treatment-based strategies are AE-specific and include topical or oral antibiotics, topical corticosteroids, and isolation of affected skin areas from adhesives and pressure. The addition of skin care strategies to the NovoTTF 100A System use will maximize adherence to therapy while maintaining quality of life, all of which contribute to the therapeutic benefit of NovoTTF Therapy in rGB. PMID- 24794309 TI - New insights into the expression profile and function of micro-ribonucleic acid in human spermatozoa. AB - OBJECTIVE: To characterize the microRNA (miRNA) expression profile in spermatozoa from human fertile individuals and their implications in human fertility. DESIGN: The expression levels of 736 miRNAs were evaluated using TaqMan arrays. Ontologic analyses were performed to determine the presence of enriched biological processes among their targets. SETTING: University research and clinical institutes. PATIENT(S): Ten individuals with normal seminogram, standard karyotype, and proven fertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Expression levels of 736 miRNAs, presence of enriched metabolic routes among their targets, homogeneity of the population, influence of demographic features in the results, presence of miRNA stable pairs, and best miRNA normalizing candidates. RESULT(S): A total of 221 miRNAs were consistently present in all individuals, 452 were only detected in some individuals, and 63 did not appear in any sample. The ontologic analysis of the 2,356 potential targets of the ubiquitous miRNAs showed an enrichment of processes related to cell differentiation, development, morphogenesis, and embryogenesis. None of the miRNAs were significantly correlated with age, semen volume, sperm concentration, motility, or morphology. Correlations between samples were statistically significant, indicating a high homogeneity of the population. A set of 48 miRNA pairs displayed a stable expression, a particular behavior that is discussed in relationship to their usefulness as fertility biomarkers. Hsa-miR-532-5p, hsa-miR 374b-5p, and hsa-miR-564 seemed to be the best normalizing miRNA candidates. CONCLUSION(S): Human sperm contain a stable population of miRNAs potentially related to embryogenesis and spermatogenesis. PMID- 24794310 TI - International Federation of Fertility Societies Surveillance 2013: preface and conclusions. AB - Surveillance is a triennial worldwide compendium of national rules and regulations for assisted reproductive technology. It was last published in 2010. PMID- 24794311 TI - Long-term influence of combined oral contraceptive use on the clinical course of relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To assess the long-term effects of combined oral contraceptives (COCs) on the clinical course of relapsing-remitting multiple sclerosis (RRMS), focusing on disability progression and evolution to secondary-progressive multiple sclerosis (SPMS). DESIGN: Retrospective and exploratory study. SETTING: Academic medical center. PATIENT(S): A total of 174 women with clinically confirmed MS; of these, 33 had evolved to SPMS at the time of enrollment in the study, whereas 141 still had a relapsing-remitting form of disease. INTERVENTION(S): Women were interviewed to obtain gynecologic and obstetric history. MAIN OUTCOME MEASURE(S): Expanded Disability Status Scale (EDSS); Multiple Sclerosis Severity Score (MSSS); annualized relapse rate; evolution to SPMS. RESULT(S): Mean+/-SD duration of disease was 14.3+/-9.8 years. Compared with non-users of COCs, COC users had lower EDSS scores and MSSS only in the subset of the population with prior or current immunomodulatory treatment. Nonuse of COCs was a predictor of disease evolution in SPMS, whether treated or not with immunomodulatory drugs. The annualized relapse rate was not influenced by COC use. No differences in EDSS scores and evolution to SPMS depending on COC formulation were detected. CONCLUSION(S): Our results suggest that COC use is associated with a less severe disease and less severe evolution. Whether different doses or types of progestin may have different effects remains to be defined. PMID- 24794312 TI - Decreased expression of SAM68 in human testes with spermatogenic defects. AB - OBJECTIVE: To assess the expression patterns of SAM68 in the testes of azoospermic patients with normal and abnormal spermatogenesis. DESIGN: Retrospective study and in vitro study. SETTING: University hospital. PATIENT(S): Testicular biopsies of azoospermic men with normal spermatogenesis (OAZ; n=20), with maturation arrest at the spermatocyte stage (MA; n=20), and with Sertoli cell-only syndrome (SCOS; n=10). INTERVENTION(S): No interventions with patients. Knockdown of Sam68 was performed in the GC-2spd(ts) cell line. MAIN OUTCOME MEASURE(S): SAM68 expression was analyzed using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry analysis in tissues. Moreover, Sam68 was knocked down in GC 2spd(ts) cells. Cell viability was measured using the MTT assay, and the apoptosis rate was detected using flow cytometry with the Annexin V-FITC kit. RESULT(S): Using qRT-PCR, the expression level of testicular SAM68 mRNA in MA and SCOS patients was statistically reduced compared with in OAZ patients. In addition, using qRT-PCR, Western blot, and immunohistochemistry analyses, mRNA and protein expressions of SAM68 were absent or barely detectable in testicular tissues in 45% (9 of 20) of patients with MA and in all patients with SCOS. Furthermore, decreased expression of Sam68 suppressed germ cell proliferation and induced apoptosis in transfected GC-2spd(ts) cells. CONCLUSION(S): Deficient SAM68 expression was observed in the human testis with MA at the spermatocyte stage and SCOS. These results may offer new perspectives on the molecular basis of abnormal spermatogenesis. PMID- 24794313 TI - Treatment for couples with unexplained infertility: the female partner at the end of reproductive years. PMID- 24794314 TI - Ethnicity as a determinant of ovarian reserve: differences in ovarian aging between Spanish and Indian women. AB - OBJECTIVE: To investigate differences in ovarian reserve markers (antimullerian hormone [AMH] and antral follicle count [AFC]) in Indian and Spanish women. DESIGN: Cross-sectional study. SETTING: In vitro fertilization (IVF) clinics. PATIENT(S): Infertile Spanish (n=229) and Indian (n=236) women who underwent controlled ovarian stimulation for IVF from January to October 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Data on ovarian reserve markers and results after ovarian stimulation were collected. RESULT(S): The mean age of women undergoing their first or second IVF cycle was significantly higher in Spanish than in Indian women (37.5+/-3.3 years vs. 31.5+/-3.8 years). Despite this 6-year age gap, AFCs were similar (9.5+/-4.7 vs. 9.9+/-4.6), as were day 3 FSH levels (7.5+/-4.5 IU/L vs. 6.9+/-2.3 IU/L). AMH levels were slightly lower in Spanish women (1.6+/-1.7 ng/mL vs. 2.5+/-1.6 ng/mL). Multivariate regression analysis showed that being Indian decreased AFC by 2.3, such that AFC in Indian women was similar to that in Spanish women 6.3 years older (95% confidence interval 3.39-1.10). CONCLUSION(S): Similar ovarian reserve markers and ovarian response were observed in women with a 6-year age difference in favor of the Spanish, suggesting ethnic differences in ovarian aging. Further research is needed to understand whether these differences are genetically induced or are caused by other variables, such as nutrition. Our results may help clinicians to counsel infertile women when discussing assisted reproductive technology outcomes according to age and ethnic background. PMID- 24794315 TI - Ultrasound mapping system for the surgical management of deep infiltrating endometriosis. AB - OBJECTIVE: To assess the accuracy of transvaginal sonography (TVS) in defining size and location of deep infiltrating endometriosis (DIE) with laparoscopic/histologic confirmation. DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): One hundred four women with suspected DIE on the basis of TVS. INTERVENTION(S): Patients with DIE underwent TVS evaluation before laparoscopic surgery. An accurate mapping of the extent of the disease was recorded during TVS and at laparoscopy. This new mapping system was developed to assess the extent of endometriosis by measuring the size and depth of the lesions at the various pelvic locations. MAIN OUTCOME MEASURE(S): Surgical and histologic confirmation of the ultrasonographic data to evaluate the presence and location of DIE and creation of a new mapping methodology for detecting DIE by TVS. RESULT(S): Depending on the different location of the lesions, the accuracy of TVS ranged from 76%-97%. The lowest sensitivity (59%) and accuracy (76%) were obtained for TVS in the diagnosis of vaginal endometriosis, whereas the greatest accuracy (97%) was shown in detecting bladder lesions and Douglas obliteration. CONCLUSION(S): This new ultrasound mapping system is accurate for detecting the extent of DIE and may be useful for preoperative planning and intraoperative management of symptomatic patients with DIE. PMID- 24794316 TI - Human oocyte cryopreservation with slow freezing versus vitrification. Results from the National Italian Registry data, 2007-2011. AB - OBJECTIVE: To compare mature human oocytes cryopreservation with slow freezing (SF) and vitrification (VT) in infertile couples. DESIGN: Retrospective study of national Italian data submitted during the period 2007-2011. SETTING: National ART registry. PATIENT(S): Infertile patients with supernumerary oocytes. INTERVENTION(S): Thawing or warming of cryopreserved oocytes and ICSI. MAIN OUTCOME MEASURE(S): oocyte survival, fertilization, implantation and clinical pregnancy rate between SF and VT. RESULT(S): A total of 14,328 cycles with 11,599 transfers, 1,850 pregnancies, 1,168 deliveries and 1,342 babies born were analyzed from 146 reporting centers (range of cycles 1-1,255 per center). The SF oocytes' survival rate was lower than in VT (51.1% vs. 63.1%). Fertilization rate was significantly higher in SF than in VT (SF 71.6% vs. VT 70.1%). VT showed a significantly higher pregnancy rate, both per started cycle (14.4% vs. 12.0%) and per transfer (18.0% vs. 14.8%), and implantation rate (9.5% vs. 8.1%) than SF. However, the range and median pregnancy rate per started cycle were, respectively, 0%-50% and 7.7% in SF and 0%-100% and 6.7% in VT. CONCLUSION(S): VT showed a statistically significant higher performance than SF. As with other ART procedures, the results are not homogeneous among clinics and protocols, but the confirm the clinical value of oocyte cryopreservation in infertile patients. PMID- 24794317 TI - Insights on managing the older couple with unexplained infertility and normal ovarian reserve. PMID- 24794318 TI - What makes them split? Identifying risk factors that lead to monozygotic twins after in vitro fertilization. AB - OBJECTIVE: To identify the incidence, risk factors, and obstetric/perinatal outcomes associated with monozygotic twins (MZTs) after IVF. DESIGN: Nested case control. SETTING: University-based center. PATIENT(S): The IVF cycles eventuating in pregnancy from 2000-2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The MZT incidence, chorionicity/zygosity, pregnancy/neonatal outcome. RESULT(S): Of 6,223 gestations, 131 MZTs were diagnosed (2.1% incidence; 2.0% in autologous and 2.7% in donor IVF cycles), 10 were dichorionic, and 121 were monochorionic. Controlling for all risk factors, young oocyte age, extended culture (noncleavage embryos transferred on/after day 4), and year of IVF treatment cycle were significantly associated with MZT. When assessing factors associated with specific MZT placentation, day 3 assisted hatching correlated more with dichorionic MZT, whereas extended culture and advanced day 5 embryonic stage correlated with monochorionic MZT. Comparing monozygotic to dizygotic multigestation outcomes, MZT fared worse; however, once controlling for triplet gestation, only gestational age at delivery remained significantly compromised in the monozygotic group. CONCLUSION(S): After IVF the incidence of MZT is high, with young oocyte age, year of treatment, and extended culture (or embryo stage at transfer) conferring greatest risk. Regarding MZT type, assisted reproductive technology (ART) procedures may influence the timing of embryonic splitting (i.e., division in early embryonic development may be influenced by zona pellucida [ZP] manipulation whereas later splitting may occur during delayed implantation). Poor obstetric/perinatal outcome is significantly impacted by the presence of an "extra" fetus, as high-order multiple gestation concurrent with an MZT conveyed the worst prognosis. PMID- 24794319 TI - Mechanical energy assessment of adult with Down syndrome during walking with obstacle avoidance. AB - The aim of this study is analyzing the differences between plane walking and stepping over an obstacle for two groups of healthy people and people with Down syndrome and then, evaluating the movement efficiency between the groups by comprising of their mechanical energy exchanges. 39 adults including two groups of 21 people with Down syndrome (age: 21.6 +/- 7 years) and 18 healthy people (age: 25.1 +/- 2.4 years) participated in this research. The test has been done in two conditions, first in plane walking and second in walking with an obstacle (10% of the subject's height). The gait data were acquired using quantitative movement analysis, composed of an optoelectronic system (Elite2002, BTS) with eight infrared cameras. Mechanical energy exchanges are computed by dedicated software and finally the data including spatiotemporal parameters, mechanical energy parameters and energy recovery of gait cycle are analyzed by statistical software to find significant differences. Regards to spatiotemporal parameters velocity and step length are lower in people with Down syndrome. Mechanical energy parameters particularly energy recovery does not change from healthy people to people with Down syndrome. However, there are some differences in inter group through plane walking to obstacle avoidance and it means people with Down syndrome probably use their residual abilities in the most efficient way to achieve the main goal of an efficient energy recovery. PMID- 24794320 TI - Perceiving and acting in depth in Williams syndrome and typical development. AB - Individuals with the neurodevelopmental disorder Williams syndrome (WS) often report difficulty processing and acting in depth, such as crossing roads or reaching for objects; however little research attention has been directed at understanding depth perception and action in depth in WS and whether deficits in depth perception have an ocular or perceptual root in this group. This study assessed the extent and relationship of deficits in stereopsis (binocular, three dimensional vision) and actions performed in depth in WS, as well as in typically developing participants (TD) matched for non-verbal ability. Stereoacuity was age appropriate in the TD group but at the level of a TD three year old in WS; one third of the WS group did not show evidence of stereopsis. When monocularly acting in depth there was no difference between the WS and TD groups. When binocularly acting in depth the WS group that did not exhibit stereopsis were significantly poorer than the TD group and the WS group that exhibited stereopsis. When assessing the relationship between stereoacuity and action in depth, stereoacuity negatively correlated with binocular action in depth for the WS group with stereopsis, but not the TD group. Therefore, no deficits in monocular depth perception in WS were evidenced, yet significant deficits are exhibited in binocular depth perception and action. Importantly action in depth under binocular viewing may be a useful gross screening measure for stereodeficits in WS. Remediation of depth perception deficits in WS could train further understanding of monocular cues to compensate for poor stereopsis. PMID- 24794321 TI - Improving fine motor activities of people with disabilities by using the response stimulation strategy with a standard keyboard. AB - The principle of this study was to use the finger-pressing position detection program (FPPDP) with a standard keyboard to improve the fine motor activities of disabled people through environmental stimulation. The FPPDP is a software solution which turns a standard keyboard into a finger-pressing position detector. By using this technique, this study tried to find out whether two students with developmental disabilities would be able to effectively perform fine motor activities through the triggering of environmental stimulation. This study was based on an ABAB design and the results showed that both participants demonstrated an obvious increase in terms of their willingness to perform target responses during the intervention phases. The practical and developmental implications of the findings are discussed. PMID- 24794322 TI - Toward a deeper characterization of the social phenotype of Williams syndrome: The association between personality and social drive. AB - Previous research has robustly established a Williams syndrome (WS) specific personality profile, predominantly characterized a gregarious, people-oriented, and tense predisposition. Extending this work, the aims of the current, cross sectional study were two-fold: (1) to elucidate the stability of personality characteristics in individuals with WS and typically developing (TD) comparisons across development, and (2) to explore the personality attributes that may be related to the respective profiles of social functioning characterizing the two groups, which is currently poorly understood. The sample comprised of participants with WS and TD matched on chronological age. The test battery included the Multidimensional Personality Questionnaire (MPQ) and the Salk Institute Sociability Questionnaire (SISQ), an index of real-life social behavior. The main results showed that compared to the TD individuals, the WS group were consistently rated higher in Social Closeness, and this trait remained stable across development. Interpersonal behaviors were best predicted by Social Closeness in WS and by Social Potency in TD. Regression analysis highlighted that while a central motive underlying the increased drive toward social interaction in individuals with WS pertains to a desire to form affectionate relationships, TD individuals by contrast are motivated by a desire to exert social influence over others (leadership, social-dominance) and Well-Being (positive emotional disposition). In conclusion, these findings provide novel insight into social motivational factors underpinning the WS social behavior in real life, and contribute toward a deeper characterization of the WS affiliative drive. We suggest potential areas for behavioral intervention targeting improved social adjustment in individuals with WS. PMID- 24794323 TI - Importance of contrast-enhanced fluid-attenuated inversion recovery imaging to detect paradoxical expansion of tuberculoma. AB - Tuberculosis is a significant public health problem that continues to be a major cause of morbidity and mortality worldwide. Tuberculous meningoencephalitis (TM) is the most common extrapulmonary lesion in tuberculosis. A 41-year-old female was thought to have TM. Tests to confirm the TM diagnosis were initially negative, including tuberculosis PCR and adenosine deaminase level in serum and cerebrospinal fluid (CSF). Anti-tuberculous medication and intravenous steroids were administered to her on the basis of brain imaging and lactate dehydrogenase electrophoresis in CSF, suggestive of the diagnosis of TM. Her neurological problems improved rapidly following treatment. Serologic and CSF markers were positive in PCR and culture after 60 days. Radiological findings are often nonspecific and TM is difficult to diagnose without an increased index of suspicion. The detection of paradoxical expansion of tuberculoma is very important in the maintenance of medication. Magnetic resonance imaging was used to detect paradoxical expansion of the tuberculoma using various methods, such as contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) imaging. CE FLAIR imaging conspicuously showed paradoxical expansion of the tuberculoma. If patients present with clear meningitis, without any identified pathogen, there is a need to constantly and scrupulously check for TM, including with the use of CE FLAIR brain imaging. PMID- 24794324 TI - Audit of pediatric transfusion practices in a tertiary care hospital. AB - OBJECTIVE: To perform a retrospective audit of transfusion practices, in order to study the appropriate and inappropriate usage of different blood components in pediatric population. METHODS: The present study, conducted over a period of 3 mo analyzed all the episodes of transfusions and divided them into appropriate and inappropriate according to the type of blood components, the requesting departments and the clinical indication of transfusion. Data was reviewed according to the British Committee for Standards in Hematology and American Association of Blood Bank guidelines. RESULTS: A total of 2,145 units of hemocomponents were transfused to children, including 1,181 units of red cell concentrates, 566 units of platelet concentrates/platelet rich plasma, 118 units of whole blood and 280 units of fresh frozen plasma in 1,819 episodes. Appropriate usage of blood components was 59.65%. Whole blood was most appropriately transfused (82.9%). Appropriate indications outnumbered inappropriate requisitions in Department of Pediatric Medicine (70.38 %), Nursery (82.54 %) and Thalassemia day care centre (55.63%). Red cell concentrate was most appropriately indicated in anemias (73.14%) and inappropriately in cases of surgeries (53.6%). Platelets were used more appropriately in all clinical indications. Whole blood was transfused most appropriately (100%) in double venous exchange therapy. Most appropriate indication of fresh frozen plasma usage was coagulopathy (42.57%). CONCLUSIONS: As the appropriate usage (59.65%) of blood components was low in the present study, regular auditing of transfusion practices from time to time is indicated. This not only helps guide their judicious use but also serves to evaluate and decrease their inappropriate usage. PMID- 24794325 TI - Prevention of blindness due to retinopathy of prematurity: a national movement. AB - Retinopathy of Prematurity (ROP) has been a blinding disorder and a preventable cause of childhood blindness. With growing interest in pediatric ophthalmology and vitreo-retinal subspecialty, ROP has become increasingly recognized in India. Recently, with rise in number of children admitted to NICU's across India, there has been an increase in number of preterm babies with ROP due to variable neonatal practices. An effort to prevent the disease was taken up by WHO and Ministry of Health & Family Welfare by conducting workshops across India piloted by R.P. Centre, AIIMS. These workshops have gone a long way in spreading awareness amongst both neonatologists and ophthalmologists in paired sessions. Both neonatologists and ophthalmologists complemented each other, discussed ROP prevention and issued ROP screening and good neonatal care guidelines which were different from the American guidelines. Treatment strategies have also undergone a huge change from cryotherapy and laser to anti-vascular endothelial growth factor (Anti-VEGF) drugs which have shown promising results, although caution is to be taken due to lack of data on long-term safety. Overall impact of these workshops led to inclusion of ROP in priority list of blindness control programme of Government of India. Still, ROP prevention needs integration of both governmental and non-governmental agencies, each sharing the load in a complementing way aiding in downward trends of ROP cases. PMID- 24794326 TI - Recurrent severe ulcers due to seizures. PMID- 24794327 TI - Sleep duration and daytime sleepiness in Indian adolescents: is there a gender difference? PMID- 24794328 TI - Green urine secondary to methylene blue. PMID- 24794329 TI - Reliability of reagent strips for semi-quantitative measurement of glucosuria in a neonatal intensive care setting. AB - BACKGROUND: Glucosuria in preterm infants is often measured using a visually readable reagent strip, e.g., when monitoring total parenteral nutrition or during sepsis or when treating with corticosteroids. However, the specific circumstances in a neonatal intensive care unit (NICU), such as the use of diapers and the high temperature in incubators, could affect its reliability. OBJECTIVES: To evaluate the reliability of the semi-quantitative measurement of glucosuria under the specific circumstances of a NICU setting. METHODS: Nine hundred assessments of artificially supplemented (contrived) urine samples, intended to simulate pathological specimens, were performed under the following varying conditions: environmental temperature (21 degrees C and 34 degrees C); different times of contact of the urine with the diaper; and using two different methods of collecting urine from the diaper. Each reagent strip was read independently by three observers. The test strips scores were categorized as 0, 1+, 2+, 3+, or 4+ in ascending degree of glucosuria. RESULTS: Agreement was excellent under all the different conditions (temperature, weighted kappa (kappa(w)) = 0.92; method of urine collection, kappa(w) = 0.88; time, p = 0.266). Inter-observer reliability was very good (multi-rater kappa = 0.81). The deviation between the different conditions was seldom larger than one category (2.9%). The reagent strip readings were concordant with the true urinary glucose concentrations in 79.0% of assessments. The discordance was never larger than one category. CONCLUSION: The reliability of the semi-quantitative measurement of glucosuria in newborn infants using reagent strips is good, even under the conditions of a NICU. Changes in the rating of reagent strips of more than one category are most likely to be beyond measurement error. PMID- 24794330 TI - Differential expression of CD45 isoforms in canine leukocytes. AB - CD45 is one of the most abundant molecules expressed on the white blood cell surface in various mammals. In this study, we investigated the differential expression of CD45 isoforms in normal canine white blood cells. It has been shown that all canine nucleated blood cells express CD45. We characterized two major isoforms of canine CD45 derived from alternative splicing: a higher molecular weight isoform, CD45RA, and a lower molecular weight isoform, CD45RO. The nucleotide sequences of the two isoforms were identical, except for the region corresponding to a part in the extracellular domain. Flow cytometry analysis using an antibody that recognizes CD45RA, but not CD45RO, revealed that granulocytes did not express CD45RA, and monocytes express low levels of CD45RA. We further analyzed the expression levels of CD45RA in each lymphocyte subpopulation and found that the expression of CD45RA on CD21+ B cells was uniform. On the other hand, expression of CD45RA on CD3+ T cells was variable. Upon stimulation of lymphocytes with Con A, the CD45RA+ fraction increased, indicating that not only the phenotypes but also the activation status influences the isoform expression pattern of CD45. Our finding provides a basic knowledge of the expression of canine CD45, which could be a tool to study lymphocytes with various phenotypes, developmental stages, and activation status. PMID- 24794331 TI - Shrinkage temperature and anti-calcification property of triglycidylamine crosslinked autologous tissue. AB - Since bioprosthetic valve dysfunction may arise due to histological calcification in the crosslinking process by glutaraldehyde (GA), non-GA crosslinking reagents have been investigated. We compared the efficacy of triglycidylamine (TGA), a newly synthesized epoxy compound, and GA as crosslinking reagents for the treatment of autologous tissues. We assessed the strength of crosslinked tissues using shrinkage temperature (Ts) measured by differential scanning calorimetry. We also conducted subdermal allografting of the crosslinked pericardium and thoracic aorta in rats, and verified the anti-calcification efficacy of TGA by histological evaluations with von Kossa stain, and immunological evaluations using tenascin-C (TN-C) or matrix metalloproteinase-9 (MMP-9). TGA treatment resulted in slower increases in Ts of the pericardium, and it required 9-12 h to reach Ts achieved by GA. In subdermal implantation of rat tissues, calcium content was lower in the TGA group than in the GA groups (p < 0.005). The expression site of TN-C and MMP-9 differed from the primary location of calcium deposition in the thoracic aorta treated with TGA suggesting a different underlying mechanism in calcification between GA and TGA crosslinking. In conclusion, TGA crosslinking in the allograft showed superior anti-calcification effect as compared to brief treatment by GA, although TGA crosslinking process was slow. PMID- 24794332 TI - Author response. PMID- 24794333 TI - [Asthma and COPD - 2 illnesses with similarities and differences]. PMID- 24794334 TI - [Fundamentals of chronic inflammatory lung diseases (asthma, COPD, fibrosis)]. AB - Since three decades the prevalence of chronic inflammatory lung diseases (asthma, COPD, fibrosis) are worldwide increasing. In Switzerland about 5 % of the population develops asthma, while in other countries it affects up to 20 % (Maori: New Zealand). Today, asthma is the most frequent cause from absence from school and work, and significantly reduces life quality of the patients and their families. COPD, or the smoker's lung, is the 4th most frequent cause of death worldwide and in the Western society affects mainly cigarette smokers and ex smokers, while in developing countries it is a diseases linked to open fire cocking with most patients being middle aged women. In both diseases only the symptoms can be controlled by muscle relaxing and anti-inflammatory drugs, but there is no cure available. The third chronic inflammatory lung disease is fibrosis which is increasing with the aging population. As indicated by the terminology "chronic inflammatory lung disease" it is widely assumed that the major cause of these diseases is chronic inflammation occurring in different segments of the lung. This hypothesis is now challenged as increasing evidence from clinical and experimental studies that suggest a much different pathogenesis. There is evidence that the inflammation may come second and tissue structural changes are already pre-set during embryogenesis and may become the major driver for the development of chronic inflammatory lung diseases later in life. The mechanism of this pre-disposition is largely unknown and the difficult to perform investigations have only started in recent years. This review aims to provide an overview of key studies published in the past 2 years on clinical and experimental research. PMID- 24794335 TI - [Differences and similarities in the evaluation and diagnostic workup]. AB - Chronic obstructive pulmonary disease (COPD) and asthma share common clinical characteristics such as cough and dyspnea. Therefore both diseases are sometimes difficult to distinguish clinically but extended medical history and diagnostic tests usually allow their differentiation. This is important because the therapeutic approach differs between the two diseases. In many cases spirometric testing including bronchodilatation is useful to differentiate between COPD and Asthma and can also be performed by the general practitioner. Apart from spirometry, additional diagnostic tests are presented that facilitate differentiation between COPD and Asthma. PMID- 24794336 TI - [The significance of an allergological examination in asthma and COPD]. AB - Of the two most common obstructive lung diseases - bronchial asthma and chronic obstructive pulmonary disease (COPD) - asthma is clearly associated with a possible allergic background, therefore an allergological examination should be included in the work-up of this disease. COPD on the other hand is usually not expected to be linked with an atopic diathesis. Medical history, clinical manifestations, the presence of other atopic diseases, prick tests and measurement of specific IgE antibodies in the serum provide an indication of an allergic genesis of the obstructive pulmonary disease. Bronchial asthma can be roughly divided into an allergic phenotype (TH2-weighted) and a non-allergic phenotype (non-TH2-weighted). The TH2- weighted form leads to an infiltration of eosinophils into the bronchial wall allowing the possibility of a higher concentration of nitrogen oxide in the exhaled air (FeNO measurement) to be detected. In addition to the differentiation between allergic and non-allergic bronchial obstruction, an evaluation of symptoms associated with the workplace (work related asthma) must take place. Furthermore, questions about an intolerance to aspirin (aspirin - exacerbated respiratory disease) or exercise induced symptoms (exercise-induced asthma) should be asked. After a careful interpretation of clinical symptoms and findings in allergy tests, an allergologist can analyze the usefulness of a specific immunotherapy (SIT). For children who suffer from allergic rhinoconjunctivitis, an early SIT can prevent the shift to inflammation of the lower respiratory tract (asthma). Due to the overlapping pathophysiology and symptomatology between bronchial asthma and chronic obstructive pulmonary disease an allergological examination should be considered also in COPD patients. PMID- 24794337 TI - [Asthma and COPD in the workplace]. AB - Obstructive lung diseases are frequent in the Swiss general population. The course of these diseases can be influenced by several factors encountered in the workplace. The impact of these factors can be limited by engineered and administrative controls and then by the utilization of personal protective equipment. Surveillance programs aim to identify individuals with early symptoms of occupational disease. A change of workplace is indicated if the occupational exposures lead to a frequent exacerbation of a respiratory disorder. PMID- 24794338 TI - [Treatment of bronchial asthma and COPD]. AB - 4 clinical phenotypes can be differentiated in asthma and COPD. Apart from routine treatment strategies, phenotyp-specific options in treatment are important to optimise therapy in these patients. Identification of phenotypes and re-evaluation of patients not responding to treatment in the practitioners practise belong in the hand of the pneumologist as well as treatment of severe asthma. Acute severe asthma attacks have become rare in Swiss hospitals. Despite this progress, asthma control in our patients can still be improved. In COPD, any effort of primary respectively secondary smoking prevention is important. PMID- 24794339 TI - [Management of an acute exacerbation of asthma and COPD]. AB - Asthma and chronic obstructive airways disease are chronic pulmonary diseases which have a high prevalence world-wide. Both conditions can deteriorate acutely and potentially put patients into life-threatening situations. Management of an acute exacerbation starts in the emergency consultation-setting and ends only once the longterm management has been thoroughly assessed and optimised in order to prevent future exacerbations. Exacerbation frequency is strongly associated with long-term morbidity and mortality in both diseases. Recent data have shown that short-course systemic steroids (5 days) for the treatment of an acute exacerbation of COPD are as successful as long-course treatments (14 days) in preventing exacerbations during the subsequent 6 months. Similarly the targeted use of antibiotics is discussed in this review. PMID- 24794340 TI - [Impact of exercise, sport and rehabilitation therapy in asthma and COPD]. AB - Patients with chronic obstructive pulmonary disease (COPD) and Asthma share increased physical inactivity as a characteristic and risk factor for the aggravation of their symptoms and marker of their health condition, respectively. Physical inactivity may be objectively measured by means of accelerometry superior to questionnaires. Physical inactivity is the reason for a reduced endurance capacity and a reduction of strength with concomitant decrease of skeletal muscle mass aggravating inflammation as a common pathophysiologic soil. Endurance training is recommended in the form of continuous and interval training having similar effects on endurance capacity executed on either a bike or as walking in patients with COPD und Asthma. Walking inherits the potential additional benefit of a reduction of fall risk which needs additional scientific evidence. This holds true especially for elderly subjects. Strength training is important because of the frequently atrophied skeletal musculature, which triggers the increase of the exercise-induced ventilation by early lactate acidosis and thereby aggravates dyspnea during exercise. An important aspect of therapy is the maintenance of the individualized training after discharge from hospital in the domestic environment taking into consideration training facilities, encounter groups and social circumstances. The objective measurement of physical activity has the potential to guide and control therapy. Because of the frequently present cardio-metabolic comorbidities the assessment of the exercise capacity as well an evaluation of nutrition should be included into a holistic therapeutical approach. An optimized bronchospasmolytic and anti inflammatory therapy is the basis for a sufficient response to exercise training. In patients with asthma, a warm-up phase of at least 15 min prior to exercise is recommended. Redundant fear of exercise-induced attacks of asthma shall be avoided by doing so. If necessary, additional psychological support should be given. PMID- 24794341 TI - [Sleep disorders in asthma and chronic obstructive pulmonary disease (COPD)]. AB - Sleep disturbances (SD) are a frequent finding in patients with asthma and chronic obstructive pulmonary disease (COPD) and have a negative impact on quality of life and the clinical course of the disease. The causes of SD are multiple and include for example respiratory symptoms and comorbidities. On the other hand sleep goes along with multiple physiological changes in respiration, so that sleep itself interacts with asthma and COPD. This interaction favors respiratory symptoms and may lead to hypoxemia and hypercapnia. A further complication of the respiratory situation and the clinical course can be found in asthma and COPD patients with coexisting obstructive sleep apnea syndrome (OSAS). Due to the heterogeneity of SD in asthma and COPD, a detailed patient survey is the most important diagnostical tool. Based on the survey further technical examinations should be considered. Treatment strategies for the reduction of SD in asthma and COPD include an optimized medication and treatment of comorbidities. If indicated oxygen therapy, positive pressure breathing and pulmonary rehabilitation can contribute. PMID- 24794342 TI - Effects of benzo[a]pyrene on whole cytochrome P450-involved molecular responses in the marine medaka Oryzias melastigma. AB - Despite being a strong toxicant for aquatic ecosystems, the effect of benzo[a]pyrene (B[a]P) on whole cytochrome P450 (CYP) biotransformation mechanisms has not been deeply investigated in aquatic organisms. To understand the mode of action of B[a]P on CYP molecular responses in fish, we analyzed the full spectrum of cyp genes and the activities of enzymes that are involved in detoxification and antioxidant defense systems after exposure to different concentrations of B[a]P over different time courses in the marine medaka, Oryzias melastigma. Upon B[a]P exposure, we found significant downregulation of cyp genes associated with steroidogenesis with decreased concentrations of actual hormones including estradiol (E2) and testosterone (11-KT), indicating that B[a]P-treated groups were closely associated with the dysfunction of hormone synthesis in a dose-dependent manner. In addition, B[a]P exposure strongly influenced transcriptional levels of antioxidant-related genes and their enzyme activities. Based on these results, we suggest that B[a]P induced the CYPs-involved systematic biotransformation mechanism with oxidative stress in the juvenile marine medaka, resulting in changes of endogenous hormonal levels and transcriptional levels of several steroidogenic metabolism-related CYPs. PMID- 24794343 TI - Integrating multiple bioassays to detect and assess impacts of sublethal exposure to metal mixtures in an estuarine fish. AB - Estuaries are natural sinks for a wide range of urban, industrial and agricultural contaminants that accumulate at potentially toxic but non-lethal concentrations, yet we know relatively little about the long-term impacts of toxicants at these levels on aquatic organisms. In this study, we present an integrated, multi-pronged approach to detect and assess the impacts to estuarine fish of exposure to sublethal concentrations of metal mixtures. Our aims were to (1) examine the effects of sublethal metal exposure on the embryonic development of Galaxias maculatus, an estuarine spawning fish native to southeastern Australia, (2) determine whether sublethal exposure during development has knock on effects on larval behaviour, and (3) establish whether a signature of metal exposure during embryogenesis can be detected in larval otoliths ("ear bones"). G. maculatus eggs are fertilised in water but develop aerially, in direct contact with estuarine sediments. We were thus also able to explore the relative importance of two exposure pathways, water and sediment. Embryos were exposed to two concentrations of a metal mixture containing Cu, Zn and Pb in water (during fertilisation) and on spiked sediments (during development), using a fully crossed experimental design. Overall, we found that exposure to the metal mixture reduced embryo survival and slowed embryonic development, resulting in poorer quality larvae that exhibited a reduced phototactic response. Differences in exposure to metals between treatment and control embryos were also permanently recorded in the developing otoliths. Combined these three approaches have the potential to be a powerful novel bioassessment tool as they provide a means of identifying a history of metal exposure during the embryonic period and linking it to suboptimal early growth and performance traits which could have long term fitness consequences. PMID- 24794344 TI - [Re-inhalation of carbon dioxide due to not detecting the absence of inspiratory expiratory valves during the daily revision of the anesthetic station]. PMID- 24794345 TI - [Reply to article: "Contribution of neuromonitoring to the safety of tracheal extubation after total thyroidectomy. Prospective study with needle electrodes"]. PMID- 24794346 TI - The nematode Caenorhabditis elegans: a versatile model for the study of proteotoxicity and aging. AB - Toxicity arising from protein misfolding and aggregation (proteotoxicity) is tightly mechanistically linked to the emergence of late-onset neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Why these maladies manifest in late stages of life and what mechanisms protect the young organism from disease are key enigmas. The nematode Caenorhabditis elegans offers key advantages that enable systematic exploration of many cell biological and functional aspects of neurodegeneration-linked proteotoxicity. Here we review the abundantly used nematode-based proteotoxicity models and delineate common techniques for the measurement of protein aggregation and rate of proteotoxicity. We also discuss the advantages offered by the worm for genetic screening, drug development and for the exploration of the links between proteotoxicity and the aging process. PMID- 24794349 TI - The banjo lesson: Henry Ossawa Tanner. PMID- 24794350 TI - Cancer care shows signs of strain as patients live longer. PMID- 24794351 TI - Stroke risk may be increased after shingles episodes. PMID- 24794359 TI - Mental disorders in childhood: shifting the focus from behavioral symptoms to neurodevelopmental trajectories. PMID- 24794360 TI - Research into rare diseases of childhood. PMID- 24794361 TI - Preventing health care-associated harm in children. PMID- 24794362 TI - Promise and perils of the Affordable Care Act for children. PMID- 24794363 TI - A piece of my mind. More than "a case of fragile X". PMID- 24794364 TI - Maternal pertussis immunization: can it help infants? PMID- 24794365 TI - The genetic and environmental contributions to autism: looking beyond twins. PMID- 24794366 TI - Building blocks: the child health theme issue. PMID- 24794367 TI - Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. AB - IMPORTANCE: Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539. PMID- 24794369 TI - Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. AB - IMPORTANCE: Maternal immunization with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine could prevent infant pertussis. OBJECTIVE: To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine. DESIGN, SETTING, AND PARTICIPANTS: Phase 1-2, randomized, double-blind, placebo-controlled, clinical trial conducted from 2008 to 2012. Forty-eight pregnant women aged 18 to 45 years received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks' gestation, with crossover immunization postpartum. INTERVENTIONS: Tdap vaccination at 30 to 32 weeks' gestation or postpartum. MAIN OUTCOMES AND MEASURES: Primary outcomes were maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months. Secondary outcomes were antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months' postpartum, and in infants at birth, at 2 months, and after the third and fourth doses of DTaP. RESULTS: No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%-91.0%]) and 12 (80% [95% CI, 51.9%-95.7%]) pregnant and postpartum women, respectively (P > .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%-54.9%]) and 11 (73.3% [95% CI, 44.9%-92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1-70.1] and 9.1 EU/mL [95% CI, 4.6-17.8], respectively; P < .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1-90.8] and 14.0 EU/mL [95% CI, 7.3-26.9], respectively; P < .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4-29.6] and 5.3 EU/mL [95% CI, 3.0-9.4], respectively; P < .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP. CONCLUSIONS AND RELEVANCE: This preliminary assessment did not find an increased risk of adverse events among women who received Tdap vaccine during pregnancy or their infants. For secondary outcomes, maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00707148. PMID- 24794368 TI - Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. AB - IMPORTANCE: Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE: To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS: The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS: Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES: The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS: The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE: Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294684. PMID- 24794370 TI - The familial risk of autism. AB - IMPORTANCE: Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved. OBJECTIVE: To provide estimates of familial aggregation and heritability of ASD. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort including 2,049,973 Swedish children born 1982 through 2006. We identified 37,570 twin pairs, 2,642,064 full sibling pairs, 432,281 maternal and 445,531 paternal half sibling pairs, and 5,799,875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained. MAIN OUTCOMES AND MEASURES: The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors. RESULTS: In the sample, 14,516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100,000 person years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7 412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64). CONCLUSIONS AND RELEVANCE: Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children. PMID- 24794372 TI - Idiopathic short stature: a clinical review. AB - IMPORTANCE: Approximately 2% of children are defined as having short stature. Deciding when to pursue recombinant human growth hormone therapy to increase adult height is controversial. OBJECTIVE: To review the management of children with idiopathic short stature, including diagnostic evaluation and therapeutic options. EVIDENCE REVIEW: Systematic literature search of PubMed, Embase, and the Cochrane Library databases. For height outcome, articles were limited to studies reporting adult height and to systematic reviews. FINDINGS: Recombinant human growth hormone therapy of children with idiopathic short stature increases height in some children. The estimated mean gain in adult height is 5.2 cm (2 in). The cost-benefit ratio is controversial. Treatment with growth hormone appears safe in the short term, while data on long-term effects are limited because studies of long-term efficacy were not powered to determine safety. CONCLUSIONS AND RELEVANCE: Growth hormone treatment may be considered in some children with idiopathic short stature. PMID- 24794373 TI - Breastfeeding and antiepileptic drugs. PMID- 24794374 TI - A child with a white pupil. PMID- 24794371 TI - Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. AB - IMPORTANCE: Despite concern about an "epidemic," there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups. OBJECTIVE: To estimate changes in the prevalence of type 1 and type 2 diabetes in US youth, by sex, age, and race/ethnicity between 2001 and 2009. DESIGN, SETTING, AND PARTICIPANTS: Case patients were ascertained in 4 geographic areas and 1 managed health care plan. The study population was determined by the 2001 and 2009 bridged-race intercensal population estimates for geographic sites and membership counts for the health plan. MAIN OUTCOMES AND MEASURES: Prevalence (per 1000) of physician-diagnosed type 1 diabetes in youth aged 0 through 19 years and type 2 diabetes in youth aged 10 through 19 years. RESULTS: In 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52). In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88 1.97). In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62) and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47) and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians). Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%) increase in type 1 diabetes over 8 years. In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37). In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49). In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51); 1.06 per 1000 among black youth (95% CI, 0.93-1.22); 0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88); and 0.17 per 1000 among white youth (95% CI, 0.15-0.20). Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians. Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%) overall increase in type 2 diabetes. CONCLUSIONS AND RELEVANCE: Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased. Further studies are required to determine the causes of these increases. PMID- 24794375 TI - Four-year follow-up of children born to women in a randomized trial of prenatal DHA supplementation. PMID- 24794376 TI - Cholesterol testing among children and adolescents during health visits. PMID- 24794377 TI - Discharges against medical advice. PMID- 24794378 TI - Drugs for the treatment of obesity. PMID- 24794379 TI - Drugs for the treatment of obesity--reply. PMID- 24794380 TI - Discharges against medical advice--reply. PMID- 24794384 TI - Physiology for children. PMID- 24794385 TI - JAMA patient page. Short stature. PMID- 24794386 TI - Zinc and copper distribution in swine wastewater treated by anaerobic digestion. AB - Swine wastewater contain high levels of metals, such as copper and zinc, which can cause a negative impact on the environment. Anaerobic digestion is a process commonly used to remove carbon, and can act on metal availability (e.g., solubility or oxidation state). The present study aimed to evaluate the influence of anaerobic digestion on total Zn and Cu contents, and their chemical fractioning due to the biodegradation of the effluent over different hydraulic retention times (HRTs). The sequential extraction protocol proposed by the Community Bureau of Reference (BCR), plus two additional fractions, was the method chosen for this study of Cu and Zn distribution evaluation in swine wastewater. The Zn and Cu concentrations in raw swine manure were 63.58 +/- 27.72 mg L(-1) and 8.98 +/- 3.99 mg L(-1), respectively. The metal retention capacity of the bioreactor decreased when the HRT was reduced from 17.86 d to 5.32 d. Anaerobic digestion had a direct influence on zinc and copper distribution when raw manure (RM) and digested manure (DM) were compared. The reducible fraction showed a reduction of between 3.17% and 7.84% for Zn and between 2.52% and 11.92% for Cu when DM was compared with RM. However, the metal concentration increased in the oxidizable fraction of DM, viz. from 3.01% to 10.64% for Zn and from 4.49% to 16.71% for Cu, thus demonstrating the effect of anaerobic conditions on metal availability. PMID- 24794387 TI - Development of policies for Natura 2000 sites: a multi-criteria approach to support decision makers. AB - The aim of this study is to present a methodology to support decision makers in the choice of Natura 2000 sites needing an appropriate management plan to ensure a sustainable socio-economic development. In order to promote sustainable development in the Natura 2000 sites compatible with nature preservation, conservation measures or management plans are necessary. The main issue is to decide when only conservation measures can be applied and when the sites need an appropriate management plan. We present a case study for the Italian Region of Umbria. The methodology is based on a multi-criteria approach to identify the biodiversity index (BI), and on the development of a human activities index (HAI). By crossing the two indexes for each site on a Cartesian plane, four groups of sites were identified. Each group corresponds to a specific need for an appropriate management plan. Sites in the first group with a high level both of biodiversity and human activities have the most urgent need of an appropriate management plan to ensure sustainable development. The proposed methodology and analysis is replicable in other regions or countries by using the data available for each site in the Natura 2000 standard data form. A multi-criteria analysis is especially suitable for supporting decision makers when they deal with a multidimensional decision process. We found the multi-criteria approach particularly sound in this case, due to the concept of biodiversity itself, which is complex and multidimensional, and to the high number of alternatives (Natura 2000 sites) to be assessed. PMID- 24794388 TI - Changing vessel routes could significantly reduce the cost of future offshore wind projects. AB - With the recent emphasis on offshore wind energy Coastal and Marine Spatial Planning (CMSP) has become one of the main frameworks used to plan and manage the increasingly complex web of ocean and coastal uses. As wind development becomes more prevalent, existing users of the ocean space, such as commercial shippers, will be compelled to share their historically open-access waters with these projects. Here, we demonstrate the utility of using cost-effectiveness analysis (CEA) to support siting decisions within a CMSP framework. In this study, we assume that large-scale offshore wind development will take place in the US Mid Atlantic within the next decades. We then evaluate whether building projects nearshore or far from shore would be more cost-effective. Building projects nearshore is assumed to require rerouting of the commercial vessel traffic traveling between the US Mid-Atlantic ports by an average of 18.5 km per trip. We focus on less than 1500 transits by large deep-draft vessels. We estimate that over 29 years of the study, commercial shippers would incur an additional $0.2 billion (in 2012$) in direct and indirect costs. Building wind projects closer to shore where vessels used to transit would generate approximately $13.4 billion (in 2012$) in savings. Considering the large cost savings, modifying areas where vessels transit needs to be included in the portfolio of policies used to support the growth of the offshore wind industry in the US. PMID- 24794389 TI - Oil removal from runoff with natural sorbing filter fillers. AB - The aim of this paper was to investigate the ability of Lithuanian sheep wool waste and reeds (Phragmites australis) to absorb oil from runoff when it flows through filters filled with these materials. The third material that was analysed, the synthetic sorbent Fibroil, was chosen for comparing the results. The laboratory experiments were performed in several stages, with the following being filtrated: tap water with a diesel admixture, road runoff contaminated with oils, and also suspended solids. The significance of this work is due to the high runoff filtering rate (~10 m/h) and high oil concentrations in the runoff (50-230 mg/L) used in the experiment. In these cases the use of sorbents is limited. Wool waste and reed (Phragmites australis) fillers are quite efficient (98-99%) in oil removal from runoff at a 10 m/h filtering rate. However, wool fillers clog up quickly. Reeds of the genus Phragmites australis are a natural source for the production of oil sorbents. The results obtained in this experimental work can be used in the design of equipment for the treatment of oil-contaminated runoff from gas stations as well as sullage from roads and tunnels. PMID- 24794390 TI - Evaluation of enhanced soil washing process and phytoremediation with maize oil, carboxymethyl-beta-cyclodextrin, and vetiver grass for the recovery of organochlorine pesticides and heavy metals from a pesticide factory site. AB - An innovative ex situ soil washing technology was developed in this study to remediate organochlorine pesticides (OCPs) and heavy metals in a mixed contaminated site. Elevated temperature (60 degrees C) combined with ultrasonication (40 kHz, 20 min) at 50 mL L(-1) maize oil and 45 g L(-1) carboxylmethyl-beta-cyclodextrin were effective in extracting pollutants from the soil. After two successive washing cycles, the removal efficiency rates for total OCPs, mirex, endosulfans, chlordanes, Cd, and Pb were approximately 94.7%, 87.2%, 98.5%, 92.3%, 91.6%, and 87.3%, respectively. Cultivation of vetiver grass and addition of nutrients for 3 months further degraded 34.7% of the residual total OCPs and partially restored the microbiological functions of the soil. This result was indicated by the significant increase in the number, biomass C, N, and functioning diversity of soil microorganisms (p < 0.05). After the treatment, the residual OCPs and heavy metals existed as very slowly desorbing fraction and residual fraction, as evaluated by Tenax extraction combined with a first-three compartment model and sequential extraction. Moreover, the secondary environmental risk of residual pollutants in the remediated soil was at an acceptable level. The proposed combined cleanup strategy proved to be effective and environmentally friendly. PMID- 24794391 TI - Methylene blue modulates adhesion molecule expression on microvascular endothelial cells. AB - OBJECTIVE AND DESIGN: As methylene blue (MB) has been recently proposed to preserve blood pressure in case of vasoplegic syndrome and shock, an entity directly related to systemic inflammation, we aimed to elucidate the effect of MB on the expression of adhesion-molecules in endothelial-cells. MATERIALS AND TREATMENT: Human microvascular endothelial-cells (HuMEC-1) were treated with 10, 30 or 60 uM MB for 30 min and 2 h each. Additionally, the treated HuMEC-1 were co cultured with either human peripheral blood mononuclear cells (PBMCs) or Jurkat cells (human T-lymphocytes) for 2 h. METHODS: HuMEC-1 were analyzed after MB treatment and after co-culture experiments for expression of different adhesion molecules (ICAM-1, VCAM-1, L-selectin, E-selectin) via FACS measurement and western blot analysis. The supernatants of the experiments were analyzed with regard to the soluble forms of the adhesion molecules. RESULTS: We found that MB is able to modulate the expression of adhesion-molecules on EC. Administration of MB increases the expression of E-selectin and VCAM-1 depending on the dosage and time of exposure. ICAM-1 measurements provide evidence that different circulating blood cells can differently alter the adhesion-molecule expression on EC after MB exposure. CONCLUSION: Our results provide evidence regarding the immunomodulatory effect of MB upon endothelial-cells after inflammation. PMID- 24794392 TI - Interleukins as markers of inflammation in malignant and benign thyroid disease. AB - BACKGROUND: Thyroid disorders, including thyroid cancer and autoimmune thyroid diseases, have been closely associated with inflammation. OBJECTIVE: This study aims to investigate the role of inflammation in thyroid disease by assessing serum cytokine levels in patients with malignant and benign thyroid conditions. METHODS: Serum levels of ten interleukins (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL 7, IL-8, IL-10, IL-12 and IL-13) were quantitatively determined in 20 patients with thyroid cancer, 38 patients with benign thyroid disease and 50 healthy controls by multiplex technology. RESULTS: Serum IL-1beta, IL-2, IL-4, IL-5 and IL-6 levels were strongly associated with each other. IL-10 and IL-12 correlated with IL-1beta, IL-5, IL-6, and with each other. Age was inversely correlated with serum levels of IL-2, IL-4 and IL-13. A positive correlation between T3 and IL-13 levels was also observed. Significantly higher levels of IL-6, IL-7, IL-10 and IL 13, as well as significantly lower levels of IL-8 were observed in patients with benign and malignant thyroid disease compared to controls. The combination of IL 13 and IL-8 in a two-marker panel was highly efficient in discriminating thyroid disorders (AUC 0.90). CONCLUSIONS: Malignant and benign thyroid conditions are associated with altered expression levels of interleukins, supporting the association between thyroid disease and underlying inflammatory processes. PMID- 24794393 TI - Intestinal macrophages and dendritic cells: what's the difference? AB - Mononuclear phagocytes (MPs) in the murine intestine, comprising dendritic cells (DCs) and macrophages (Mphis), perform disparate yet complementary immunological functions. Functional analyses of these distinct MP subsets have been complicated by the substantial overlap in their surface phenotypes. Here, we review recent findings that have enabled more accurate definition of these MP subsets. We discuss these recent advances in the context of the current understanding of the functions of DCs and Mphis in the maintenance of intestinal homeostasis, and how their functions may alter when homeostasis is disrupted. PMID- 24794394 TI - Silencing herpes simplex virus type 1 capsid protein encoding genes by siRNA: a promising antiviral therapeutic approach. AB - Herpes simplex virus type 1 (HSV-1), a member of the herpesviridae, causes a variety of human viral diseases globally. Although a series of antiviral drugs are available for the treatment of infection and suppression of dissemination, HSV-1 remains highly prevalent worldwide. Therefore, the development of novel antiviral agents with different mechanisms of action is a matter of extreme urgency. During the proliferation of HSV-1, capsid assembly is essential for viral growth, and it is highly conserved in all HSV-1 strains. In this study, small interfering RNAs (siRNAs) against the HSV-1 capsid protein were screened to explore the influence of silencing capsid expression on the replication of HSV-1. We designed and chemically synthesized siRNAs for the capsid gene and assessed their inhibitory effects on the expression of target mRNA and the total intracellular viral genome loads by quantitative real-time PCR, as well as on the replication of HSV-1 via plaque reduction assays and electron microscopy. Our results showed that siRNA was an effective approach to inhibit the expression of capsid protein encoding genes including UL18, UL19, UL26, UL26.5, UL35 and UL38 in vitro. Interference of capsid proteins VP23 (UL18) and VP5 (UL19) individually or jointly greatly affected the replication of clinically isolated acyclovir resistant HSV-1 as well as HSV-1/F and HSV-2/333. Plaque numbers and intracellular virions were significantly reduced by simultaneous knockdown of UL18 and UL19. The total intracellular viral genome loads were also significantly decreased in the UL18 and UL19 knockdown groups compared with the viral control. In conclusion, interfering with UL18 and UL19 gene expression could inhibit HSV-1 replication efficiently in vitro. Our research offers new targets for an RNA interference-based therapeutic strategy against HSV-1. PMID- 24794395 TI - Disrupted resting-state functional connectivity in minimally treated chronic schizophrenia. AB - OBJECTIVE: The pathophysiology of chronic schizophrenia may reflect long term brain changes related to the disorder. The effect of chronicity on intrinsic functional connectivity patterns in schizophrenia without the potentially confounding effect of antipsychotic medications, however, remains largely unknown. METHOD: We collected resting-state fMRI data in 21 minimally treated chronic schizophrenia patients and 20 healthy controls. We computed regional functional connectivity strength for each voxel in the brain, and further divided regional functional connectivity strength into short-range regional functional connectivity strength and long-range regional functional connectivity strength. General linear models were used to detect between-group differences in these regional functional connectivity strength metrics and to further systematically investigate the relationship between these differences and clinical/behavioral variables in the patients. RESULTS: Compared to healthy controls, the minimally treated chronic schizophrenia patients showed an overall reduced regional functional connectivity strength especially in bilateral sensorimotor cortex, right lateral prefrontal cortex, left insula and right lingual gyrus, and these regional functional connectivity strength decreases mainly resulted from disruption of short-range regional functional connectivity strength. The minimally treated chronic schizophrenia patients also showed reduced long-range regional functional connectivity strength in the bilateral posterior cingulate cortex/precuneus, and increased long-range regional functional connectivity strength in the right lateral prefrontal cortex and lingual gyrus. Notably, disrupted short-range regional functional connectivity strength mainly correlated with duration of illness and negative symptoms, whereas disrupted long-range regional functional connectivity strength correlated with neurocognitive performance. All of the results were corrected using Monte-Carlo simulation. CONCLUSIONS: This exploratory study demonstrates a disruption of intrinsic functional connectivity without long-term exposure to antipsychotic medications in chronic schizophrenia. Furthermore, this disruption was connection-distance dependent, thus raising the possibility for differential neural pathways in neurocognitive impairment and psychiatric symptoms in schizophrenia. PMID- 24794396 TI - Prevalence of HPV infection among clinically healthy Italian males and genotype concordance between stable sexual partners. AB - BACKGROUND: HPV is one of the most common sexually transmitted infections. However little is known about its prevalence in the male population and concordance with female partners. OBJECTIVES: This cross-sectional study aimed to: (a) investigate HPV prevalence and genotype distribution among a series of stable male sexual partners of CIN/HPV positive women and (b) assess HPV infection and type-specific concordance between partners. STUDY DESIGN: 378 stable and monogamous male partners of CIN/HPV positive women were selected. Of these, 238 cases were enrolled at the same time as their female partner. All the subjects were tested by the Linear Array HPV genotyping assay. RESULTS: Overall, 153/378 men (40.5%) and 122/238 women (51.3%) were positive for at least one of the 37 HPV types detectable by the assay used. Among the HPV-positive participants, 69 of the 378 men (18.2%) and 54 of the 238 women (22.7%) harboured multiple genotypes. 75 couples (31.5%) were concordantly HPV positive, while 102 couples (42.9%) were concordantly negative (Kappa value: 0.491, p<0.0001). Among the couples in which both partners were HPV positive, 68% harboured at least one genotype in common. Results from a GEE model evidenced that when the male partner tested HPV positive for at least one genotype, this had a significant effect on the positivity of their relative female partner (p<0.0001). CONCLUSIONS: We evidenced a high prevalence of HPV male infections and a moderate concordance between partners. However, we observed a significant HPV type-specific correlation between partners, which is unlikely to be coincidental. PMID- 24794397 TI - The need for a sequencing-based assay to supplement the Abbott m2000 RealTime HCV Genotype II assay: a 1 year analysis. AB - BACKGROUND: Hepatitis C (HCV) genotyping is important for treatment planning. The Abbott m2000 RealTime HCV Genotype II assay is a PCR-based assay targeting specific regions of the 5'NCR gene for genotypes 1-6, and the NS5b gene for subgenotypes 1a/1b. However, not all genotypes can be resolved, with results being reported as: 'indeterminate', 'mixed', 'genotype X reactivity with Y', or just the major genotype 1 alone. OBJECTIVES AND STUDY DESIGN: To assess the supplementary testing required for these unresolved HCV genotypes, these samples were tested further using an in-house core/E1 sequencing assay. The resulting genotypes/subgenotypes were assigned using phylogenetic analysis with reference HCV genotype sequences. Additional testing was conducted using the INNO-LiPA HCV II assay for truly mixed genotypes. RESULTS: Out of 1052 samples tested, 89 (8.5%) underwent further sequencing to determine the HCV genotype: 16 that were 'indeterminate' on the m2000, were mostly genotype 2s and 3s by sequencing; 12 that were 'mixed', were mostly one of the genotypes reported in the mixture; 7 that were 'X reactivity with Y', were usually genotype X; 54 that gave just a major genotype 1 result were mostly 1a, with some 6 and 1b, and a few 1c. For three truly mixed genotypes, additional testing using the VERSANT((r)) HCV Genotype Assay (LiPA) 2.0, showed two mixed 1 and 3, and one indistinguishable 6c 6l genotypes. CONCLUSIONS: The Abbott m2000 RealTime HCV Genotype II assay can resolve most (~90%) HCV genotypes. However in 9-10% of cases, to fully resolve the genotype, additional testing is required. PMID- 24794398 TI - Survey of congenital cytomegalovirus (cCMV) knowledge among medical students. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) is a leading cause of congenital infection worldwide and the most common congenital infection in the United States, affecting 30,000-40,000 US newborns each year and causing permanent disabilities in 8000-10,000. In contrast to how commonly it occurs, physicians and medical students have little knowledge of cCMV. OBJECTIVES: To test the hypothesis medical students have little awareness about cCMV infection, and to collect data on medical students' knowledge about cCMV. The long-term goal of this project is to establish medical student awareness of cCMV infection and educate students about available treatments and strategies for prevention in at risk populations. STUDY DESIGN: Medical students at one institution were surveyed by questionnaire to assess their knowledge of cCMV. Responses were described, quantified, and compared between groups. RESULTS: 751 surveys were sent and 422 completed responses were received. Respondents were well distributed over all 4 medical school (MS) class years. Only 34% MS1 had heard of cCMV compared to 100% MS2-4 (P<0.0001). All MS2-4 who reported being "very familiar" with CMV learned about it in medical school, 80% in one lecture. MS1 respondents were significantly less knowledgeable about cCMV than MS2-MS4 respondents. CONCLUSION: A baseline lack of knowledge about cCMV was documented in first year medical students. A sharp increase in knowledge of cCMV occurred between MS1 and MS2 years, likely due to preclinical medical student curriculum. However, significant knowledge gaps regarding transmission and treatment were observed in all MS years, representing opportunities for medical education. PMID- 24794399 TI - Making the case for RT-PCR for the diagnosis of H1N1. PMID- 24794400 TI - Redox and epigenetic regulation of the APE1 gene in the hippocampus of piglets: The effect of early life exposures. AB - Oxidative stress via redox reactions can regulate DNA repair pathways. The base excision repair (BER) enzyme apurinic/apyrimidinic endonuclease 1 (APE1) is a key player in the redox regulation of DNA repair. Environmental factors can alter the methylation of DNA repair genes, change their expression and thus modulate BER activity and susceptibility to oxidative DNA damage. Therefore, we hypothesized that epigenetic modifications play a role in the redox regulation of APE1 in hippocampi of newborns and investigated the effect of supplementation of pregnant sows with a diet enriched in antioxidants and other nutrients on oxidative stress, DNA methylation and DNA repair in their offspring. High levels of 8-oxo 7,8-dihydro-2'-deoxyguanosine (8-oxodG) and low levels of glutathione were detected in control piglets after birth compared with supplemented piglets, indicating the presence of oxidative stress. In control animals, this oxidative stress was associated with genomic DNA demethylation, decreased APE1 promoter methylation, increased APE1 expression and with slightly but not statistically significant increased BER-related DNA incision activity. Supplementation of piglets with antioxidants and other nutrients significantly lowered 8-oxodG levels compared to control animals, which was accompanied by overall lower APE1 promoter methylation and enhanced APE1 expression at day 7-28 after birth in supplemented piglets, although DNA incision activity was not significantly different between groups. Preliminary attempts to study the interaction between redox and epigenetic regulatory mechanisms revealed an inverse correlation between APE1 expression and methylation of CpG-sites 11 and 13 in the promoter region, which according to Genomatix "MatInspector" are located in the core binding sites of redox-sensitive transcription factors. We are the first to study methylation of the APE1 promoter and its role in mediating the functional effects of redox reactions induced by oxidative stress. Epigenetic and redox mechanisms may interact in regulating APE1-related DNA repair processes, involving redox sensitive TFs. PMID- 24794401 TI - The DNA damage response: the omics era and its impact. AB - The emergence of high density technologies monitoring the genome, transcriptome and proteome in relation to genotoxic stress have tremendously enhanced our knowledge on global responses and dynamics in the DNA damage response, including its relation with cancer and aging. Moreover, '-omics' technologies identified many novel factors, their post-translational modifications, pathways and global responses in the cellular response to DNA damage. Based on omics, it is currently estimated that thousands of gene(product)s participate in the DNA damage response, recognizing complex networks that determine cell fate after damage to the most precious cellular molecule, DNA. The development of next generation sequencing technology and associated specialized protocols can quantitatively monitor RNA and DNA at unprecedented single nucleotide resolution. In this review we will discuss the contribution of omics technologies and in particular next generation sequencing to our understanding of the DNA damage response and the future prospective of next generation sequencing, its single cell application and omics dataset integration in unraveling intricate DNA damage signaling networks. PMID- 24794404 TI - The evolving role of the NAD+/nicotinamide metabolome in skin homeostasis, cellular bioenergetics, and aging. AB - Human skin is exposed to daily environmental insults, particularly solar radiation, that triggers a range of molecular responses. These perturbations to the normal homeostatic state can lead to cellular dysfunction and, ultimately, impacts tissue integrity and accelerates skin aging (photoaging). One of the responses is increased oxidative stress which has been shown to disrupt cellular bioenergetics. This can be detected by depletion of the nucleotide energy metabolites NAD+ and ATP as both an acute transient decrease and, over time, a more permanent chronic reduction due in part to cumulative damage of mitochondria. NAD+ and its primary precursor nicotinamide have been known for some time to impact skin homeostasis based on linkages to dietary requirements, treatment of various inflammatory conditions, photoaging, and prevention of cancer. Cellular NAD+ pools are known to be lower in aged skin and treatment with nicotinamide is hypothesized to restore these levels, thereby mitigating cellular bioenergetics dysfunction. In dermal fibroblasts, nicotinamide is able to protect against oxidative stress to glycolysis, oxidative phosphorylation as well as increase mitochondrial efficiency via sirtuin-dependent selective mitophagy. Recent research has found that NAD+ cellular pools are more dynamic than previously thought, oscillating in tandem with free nicotinamide, and serves as a regulatory point and feedback loop in cellular metabolism regulation, maintenance of mitochondrial efficiency, and circadian rhythmicity. Since UV-induced oxidative stress in skin can disrupt these processes, continued molecular understanding of the role of NAD+ and nicotinamide in skin biology is important to identify interventions that would help maintain its normal homeostatic functions and efficient cellular bioenergetics. PMID- 24794402 TI - Ribonucleotides in DNA: origins, repair and consequences. AB - While primordial life is thought to have been RNA-based (Cech, Cold Spring Harbor Perspect. Biol. 4 (2012) a006742), all living organisms store genetic information in DNA, which is chemically more stable. Distinctions between the RNA and DNA worlds and our views of "DNA" synthesis continue to evolve as new details emerge on the incorporation, repair and biological effects of ribonucleotides in DNA genomes of organisms from bacteria through humans. PMID- 24794403 TI - Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform. AB - Anti-cancer topoisomerase I (Top1) inhibitors (camptothecin and its derivatives irinotecan and topotecan, and indenoisoquinolines) induce lethal DNA lesions by stabilizing Top1-DNA cleavage complex (Top1cc). These lesions are repaired by parallel repair pathways including the tyrosyl-DNA phosphodiesterase 1 (TDP1) related pathway and homologous recombination. As TDP1-deficient cells in vertebrates are hypersensitive to Top1 inhibitors, small molecules inhibiting TDP1 should augment the cytotoxicity of Top1 inhibitors. We developed a cell based high-throughput screening assay for the discovery of inhibitors for human TDP1 using a TDP1-deficient chicken DT40 cell line (TDP1-/-) complemented with human TDP1 (hTDP1). Any compounds showing a synergistic effect with the Top1 inhibitor camptothecin (CPT) in hTDP1 cells should either be a TDP1-related pathway inhibitor or an inhibitor of alternate repair pathways for Top1cc. We screened the 400,000-compound Small Molecule Library Repository (SMLR, NIH Molecular Libraries) against hTDP1 cells in the absence or presence of CPT. After confirmation in a secondary screen using both hTDP1 and TDP1-/- cells in the absence or presence of CPT, five compounds were confirmed as potential TDP1 pathway inhibitors. All five compounds showed synergistic effect with CPT in hTDP1 cells, but not in TDP1-/- cells, indicating that the compounds inhibited a TDP1-related repair pathway. Yet, in vitro gel-based assay revealed that the five compounds did not inhibit TDP1 catalytic activity directly. We tested the compounds for their ability to inhibit poly(ADP-ribose)polymerase (PARP) because PARP inhibitors are known to potentiate the cytotoxicity of CPT by inhibiting the recruitment of TDP1 to Top1cc. Accordingly, we found that the five compounds inhibit catalytic activity of PARP by ELISA and Western blotting. We identified the most potent compound (Cpd1) that offers characteristic close to veliparib, a leading clinical PARP inhibitor. Cpd1 may represent a new scaffold for the development of PARP inhibitors. PMID- 24794405 TI - Sensitive electrochemical microbial biosensor for p-nitrophenylorganophosphates based on electrode modified with cell surface-displayed organophosphorus hydrolase and ordered mesopore carbons. AB - A novel electrochemical microbial biosensor for the rapid monitoring of p nitrophenyl-substituted organophosphates (OPs) compounds based on glass carbon electrode (GCE) modified with both ordered mesopore carbons (OMCs) and cell surface-expressed organophosphorus hydrolase (OPH) (OPH-bacteria/OMCs/GCE) was described in this paper. The genetically engineered Escherichia coli strain surface displayed mutant OPH (S5) with improved enzyme activity and favorable stability was constructed using a newly identified N-terminal of ice nucleation protein as an anchoring motif, which can be used directly without further time consuming enzyme-extraction and purification, thereafter greatly improved the stability of the enzyme. Compared to OPH-bacteria modified GCE (OPH bacteria/GCE), the OPH-bacteria/OMCs/GCE not only significantly enhanced the current response but also reduced the oxidation overpotential towards oxidizable p-nitrophenol (p-NP), which was the hydrolysate of p-nitrophenyl-substituted OPs. Under the optimized experimental conditions, at +0.84 V (vs. SCE), the current time curve was performed with varying OPs concentration. The current response was linear with paraoxon concentration within 0.05-25 MUM. Similarly, linear range of 0.05-25 MUM was found for parathion, and 0.08-30 MUM for methyl parathion. The low limits of detection were evaluated to be 9.0 nM for paraoxon, 10nM for parathion and 15 nM for methyl parathion (S/N=3). Thus, a highly specific, sensitive and rapid microbial biosensor was established, which holds great promise for on-site detection of trace p-nitrophenyl-substituted OPs. PMID- 24794406 TI - Accurate resistivity mouse brain mapping using microelectrode arrays. AB - Electrical impedance spectroscopy measurements were performed in post-mortem mice brains using a flexible probe with an embedded micrometric electrode array. Combined with a peak resistance frequency method this allowed obtaining intrinsic resistivity values of brain tissues and structures with submillimetric resolution. Reproducible resistivity measurements are reported, which allows the resistivity in the cortex, ventricle, fiber tracts, thalamus and basal ganglia to be differentiated. Measurements of brain slices revealed resistivity profiles correlated with the local density of cell bodies hence allowing to discriminate between the different cortical layers. Finally, impedance measurements were performed on a model of cauterized mouse brain evidencing the possibility to measure the spatial extent and the degree of the tissue denaturation due to the cauterization. PMID- 24794407 TI - Paper-based electroanalytical devices for in situ determination of salicylic acid in living tomato leaves. AB - Detection of phytohormones in situ has gained significant attention due to their critical roles in regulating developmental processes and signaling for defenses in plants at low concentration. As one type of plant hormones, salicylic acid has recently been found to be one of pivotal signal molecules for physiological behaviors of plants. Here we report the application of paper-based electroanalytical devices for sensitively in situ detection of salicylic acid in tomato leaves with the sample volume of several microliters. Specifically, disposable working electrodes were fabricated by coating carbon tape with the mixture of multiwall carbon nanotubes and nafion. We observed that the treatment of the modified carbon tape electrodes with oxygen plasma could significantly improve electrochemical responses of salicylic acid. The tomato leaves had a punched hole of 1.5mm diameter to release salicylic acid with minor influence on continuous growth of tomatoes. By incorporating the tomato leaf with the paper based analytical device, we were able to perform in situ determination of salicylic acid based on its electrocatalytic oxidation. Our experimental results demonstrated that the amounts of salicylic acid differed statistically in normal, phytoene desaturase (PDS) gene silent and diseased (infected by Botrytis cinerea) tomato leaves. By quantifying salicylic acid at the level of several nanograms in situ, the simple paper-based electroanalytical devices could potentially facilitate the study of defense mechanism of plants under biotic and abiotic stresses. This study might also provide a sensitive method with spatiotemporal resolution for mapping of chemicals released from living organisms. PMID- 24794408 TI - Identification of novel helper epitope peptides of Survivin cancer-associated antigen applicable to developing helper/killer-hybrid epitope long peptide cancer vaccine. AB - We identified novel helper epitope peptides of Survivin cancer antigen, which are presented to both HLA-DRB1*01:01 and DQB1*06:01. The helper epitope also contained three distinct Survivin-killer epitopes presented to HLA-A*02:01 and A*24:02. This 19 amino-acids epitope peptide (SU18) induced weak responses of Survivin-specific CD4(+) and CD8(+) T cells though it contained both helper and killer epitopes. To enhance the vaccine efficacy, we synthesized a long peptide by conjugating SU18 peptide and another DR53-restricted helper epitope peptide (SU22; 12 amino-acids) using glycine-linker. We designated this artificial 40 amino-acids long peptide containing two helper and three killer epitopes as Survivin-helper/killer-hybrid epitope long peptide (Survivin-H/K-HELP). Survivin H/K-HELP allowed superior activation of IFN-gamma-producing CD4(+) Th1 cells and CD8(+) Tc1 cells compared with the mixture of its component peptides (SU18 and SU22) in the presence of OK-432-treated monocyte-derived DC (Mo-DC). Survivin-H/K HELP-pulsed Mo-DC pretreated with OK-432 also exhibited sustained antigen presentation capability of stimulating Survivin-specific Th1 cells compared with Mo-DC pulsed with a mixture of SU18 and SU22 short peptides. Moreover, we demonstrated that Survivin-H/K-HELP induced a complete response in a breast cancer patient with the induction of cellular and humoral immune responses. Thus, we believe that an artificially synthesized Survivin-H/K-HELP will become an innovative cancer vaccine. PMID- 24794409 TI - Nonenzymatic oxygenated metabolites of alpha-linolenic acid B1- and L1 phytoprostanes protect immature neurons from oxidant injury and promote differentiation of oligodendrocyte progenitors through PPAR-gamma activation. AB - Phytoprostanes (PhytoP's) are formed in higher plants from alpha-linolenic acid via a nonenzymatic free radical-catalyzed pathway and act as endogenous mediators capable of protecting cells from damage under various conditions related to oxidative stress. Humans are exposed to PhytoP's, as they are present in relevant quantities in vegetable food and pollen. The uptake of PhytoP's through the olfactory epithelium of the nasal mucosa, upon pollen grain inhalation, is of interest as the intranasal pathway is regarded as a direct route of communication between the environment and the brain. On this basis, we sought to investigate the potential activities of PhytoP's on immature cells of the central nervous system, which are particularly susceptible to oxidative stress. In neuroblastoma SH-SY5Y cells, used as a model for undifferentiated neurons, B1-PhytoP's, but not F1-PhytoP's, increased cell metabolic activity and protected them from oxidant damage caused by H2O2. Moreover, B1-PhytoP's induced a moderate depolarization of the mitochondrial inner membrane potential. These effects were prevented by the PPAR-gamma antagonist GW9662. When SH-SY5Y cells were induced to differentiate toward a more mature phenotype, they became resistant to B1-PhytoP activities. B1 PhytoP's also influenced immature cells of an oligodendroglial line, as they increased the metabolic activity of oligodendrocyte progenitors and strongly accelerated their differentiation to immature oligodendrocytes, through mechanisms at least partially dependent on PPAR-gamma activity. However, B1 PhytoP's did not protect oligodendrocyte progenitors against oxidant injury. Taken together, these data suggest that B1-PhytoP's, through novel mechanisms involving PPAR-gamma, can specifically affect immature brain cells, such as neuroblasts and oligodendrocyte progenitors, thereby conferring neuroprotection against oxidant injury and promoting myelination. PMID- 24794410 TI - Reevaluation of the rate constants for the reaction of hypochlorous acid (HOCl) with cysteine, methionine, and peptide derivatives using a new competition kinetic approach. AB - Activated white cells use oxidants generated by the heme enzyme myeloperoxidase to kill invading pathogens. This enzyme utilizes H2O2 and Cl(-), Br(-), or SCN(-) to generate the oxidants HOCl, HOBr, and HOSCN, respectively. Whereas controlled production of these species is vital in maintaining good health, their uncontrolled or inappropriate formation (as occurs at sites of inflammation) can cause host tissue damage that has been associated with multiple inflammatory pathologies including cardiovascular diseases and cancer. Previous studies have reported that sulfur-containing species are major targets for HOCl but as the reactions are fast the only physiologically relevant kinetic data available have been extrapolated from data measured at high pH (>10). In this study these values have been determined at pH 7.4 using a newly developed competition kinetic approach that employs a fluorescently tagged methionine derivative as the competitive substrate (k(HOCl + Fmoc-Met), 1.5 * 10(8)M(-1)s(-1)). This assay was validated using the known k(HOCl + NADH) value and has allowed revised k values for the reactions of HOCl with Cys, N-acetylcysteine, and glutathione to be determined as 3.6 * 10(8), 2.9 * 10(7), and 1.24 * 10(8)M(-1)s(-1), respectively. Similar experiments with methionine derivatives yielded k values of 3.4 * 10(7)M( 1)s(-1) for Met and 1.7 * 10(8)M(-1)s(-1) for N-acetylmethionine. The k values determined here for the reaction of HOCl with thiols are up to 10-fold higher than those previously determined and further emphasize the critical importance of reactions of HOCl with thiol targets in biological systems. PMID- 24794411 TI - Analysis of the antimicrobial effects of nonthermal plasma on fungal spores in ionic solutions. AB - The antimicrobial efficiency of reactive species-based control strategies is significantly affected by the dynamics of reactive species in the biological environment. Atmospheric-pressure nonthermal plasma is an ionized gas in which various reactive species are produced. The various levels of antimicrobial activity may result from the dynamic interaction of the plasma-generated reactive species with the environment. However, the nature of the interaction between plasma and environments is poorly understood. In this study, we analyzed the influence of the ionic strength of surrounding solutions (environment) on the antimicrobial activity of plasma in relation to the plasma-generated reactive species using a model filamentous fungus, Neurospora crassa. Our data revealed that the presence of sodium chloride (NaCl) in the background solution attenuated the deleterious effects of plasma on germination, internal structure, and genomic DNA of fungal spores. The protective effects of NaCl were not explained exclusively by pH, osmotic stability, or the level of reactive species in the solution. These were strongly associated with the ionic strength of the background solution. The presence of ions reduced plasma toxicity, which might be due to a reduced access of reactive species to fungal spores, and fungal spores were inactivated by plasma in a background fluid of nonionic osmolytes despite the low level of reactive species. Our results suggest that the surrounding environment may affect the behavior of reactive species, which leads to different biological consequences regardless of their quantity. Moreover, the microbicidal effect of plasma can be synergistically regulated through control of the microenvironment. PMID- 24794412 TI - Saturated fat intake modulates the association between an obesity genetic risk score and body mass index in two US populations. AB - Combining multiple genetic variants related to obesity into a genetic risk score (GRS) might improve identification of individuals at risk of developing obesity. Moreover, characterizing gene-diet interactions is a research challenge to establish dietary recommendations to individuals with higher predisposition to obesity. Our objective was to analyze the association between an obesity GRS and body mass index (BMI) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) population, focusing on gene-diet interactions with total fat and saturated fatty acid (SFA) intake, and to replicate findings in the Multi-Ethnic Study of Atherosclerosis (MESA) population. Cross-sectional analyses included 783 white US participants from GOLDN and 2,035 from MESA. Dietary intakes were estimated with validated food frequency questionnaires. Height and weight were measured. A weighted GRS was calculated on the basis of 63 obesity-associated variants. Multiple linear regression models adjusted by potential confounders were used to examine gene-diet interactions between dietary intake (total fat and SFA) and the obesity GRS in determining BMI. Significant interactions were found between total fat intake and the obesity GRS using these variables as continuous for BMI (P for interaction=0.010, 0.046, and 0.002 in GOLDN, MESA, and meta analysis, respectively). These association terms were stronger when assessing interactions between SFA intake and GRS for BMI (P for interaction=0.005, 0.018, and <0.001 in GOLDN, MESA, and meta-analysis, respectively). SFA intake interacts with an obesity GRS in modulating BMI in two US populations. Although determining the causal direction requires further investigation, these findings suggest that potential dietary recommendations to reduce BMI effectively in populations with high obesity GRS would be to reduce total fat intake mainly by limiting SFAs. PMID- 24794414 TI - Nucleic acids nanotechnology. PMID- 24794413 TI - Monitoring charge flux to quantify unusual ligand-induced ion channel activity for use in biological nanopore-based sensors. AB - The utility of biological nanopores for the development of sensors has become a growing area of interest in analytical chemistry. Their emerging use in chemical analysis is a result of several ideal characteristics. First, they provide reproducible control over nanoscale pore sizes with an atomic level of precision. Second, they are amenable to resistive-pulse type measurement systems when embedded into an artificial lipid bilayer. A single binding event causes a change in the flow of millions of ions across the membrane per second that is readily measured as a change in current with excellent signal-to-noise ratio. To date, ion channel-based biosensors have been limited to well-behaved proteins. Most demonstrations of using ion channels as sensors have been limited to proteins that remain in the open, conducting state, unless occupied by an analyte of interest. Furthermore, these proteins are nonspecific, requiring chemical, biochemical, or genetic manipulations to impart chemical specificity. Here, we report on the use of the pore-forming abilities of heat shock cognate 70 (Hsc70) to quantify a specific analyte. Hsc70 reconstitutes into phospholipid membranes and opens to form multiple conductance states specifically in the presence of ATP. We introduce the measurement of "charge flux" to characterize the ATP regulated multiconductance nature of Hsc70, which enables sensitive quantification of ATP (100 MUM-4 mM). We believe that monitoring protein-induced charge flux across a bilayer membrane represents a universal method for quantitatively monitoring ion-channel activity. This measurement has the potential to broaden the library of usable proteins in the development of nanopore-based biosensors. PMID- 24794415 TI - Thyroid carcinoma surgery in children and adolescents - 15 years experience surgery of pediatric thyroid carcinoma. AB - OBJECTIVES: The purpose of this study is to evaluate the characteristics of thyroid gland surgery focusing on malignancies at the pediatric age with the main concern on treatment results and complications in extensive primary treatment. METHODS: The records of all patients 18 years and younger with surgically treated thyroid diseases in the Prague Hospital, Motol, between 1991 and 2006 were retrospectively reviewed. RESULTS: Thyroid surgery was performed on 148 pediatric patients (including 56 carcinomas). The youngest patient involved in the study was seven years old, the oldest patient 18 years old (mean 13.7 years). Most frequent histological cancer type was PTC (42 cases, 75%). Follicular cancer was diagnosed in five cases (8.9%) and medullar cancer in nine cases (16.1%). A prophylactic thyroidectomy was performed in three cases (5.4%) without clinical signs of thyroid tumor with diagnosed RET gene mutation. CONCLUSIONS: We consider total thyroidectomy with subsequent radioiodine ablation and TSH suppression as the basic approach in the treatment protocol of pediatric WDTC. The observed 100% recurrence-free and overall survival together with a low incidence of postoperative complications strongly supports the idea of a total thyroidectomy with selective neck dissection in the treatment of metastases of WDTC and MTC. PMID- 24794416 TI - Response to the Letter to the Editor regarding: Parental perception of speech and tongue mobility in three-year olds after neonatal frenotomy. PMID- 24794417 TI - Correlates of human immunodeficiency virus/sexually transmitted infection (HIV/STI) testing and disclosure among HIV-negative collegiate men who have sex with men. AB - OBJECTIVE: To determine the extent to which personal, behavioral, and environmental factors are associated with human immunodeficiency virus/sexually transmitted infection (HIV/STI) testing and disclosure. PARTICIPANTS: Nine hundred thirty HIV-negative collegiate men who have sex with men (MSM) who completed an online survey about alcohol use and sexual behavior. METHODS: Correlates of testing and disclosure significant in bivariate analyses (p < .05) were grouped into personal, behavioral, or environmental factors and entered into multivariable logistic regression models. RESULTS: About half of participants tested for HIV (51.9%) and for STIs (45.8%) at least annually. Over half (57.8%) of participants always/almost always discussed HIV status with new sex partners; 61.1% with new unprotected sex partners. Personal and behavioral factors (age and outness) explained differences in testing, and the behavioral factor (routine testing) explained differences in disclosure. CONCLUSIONS: Collegiate MSM should be supported in coming out, encouraged to engage in routine testing, and counseled on discussing HIV/STI status with potential sex partners. PMID- 24794418 TI - Antigen specific immune enhancement of innate and acquired immunity by pearl in ashed form. AB - The present study evaluated mineral compound, pearl in ashed form [PAF], for its potential as oral immunomodulator. ICP-MS, atomic absorption spectroscopy, CHNS analysis and XRD analysis were used for characterization of PAF. Surface antigen markers (TLR-2/4 and CD-80/86) were studied by flow cytometry. At dose concentration of 25, 50, 100 and 500 MUg/kg body wt., administrated orally for 10 days, TLR-2 expression on murine peritoneal macrophage increased while TLR-4 expression was reduced as compared to control. There was an increase in OVA and mitogen (Con-A) specific lymphocyte proliferation in OVA immunized mice. Also, level of both Th1 (IL-2/IFN-gamma) and Th2 (IL-4/IL-10) cytokines, and level and titer of total IgG, IgG1, IgG2a and IgG2b of OVA immunized mice significantly increased. The level of Inflammatory cytokines (IL-1beta and TNF-alpha) did not increase significantly. Enhancement in T and B cell immune responses may be possibly due to significantly enhanced expression of CD-80 and CD-86 co stimulatory signals as observed using flow cytometry. Also, enhanced phagocytic activity and DTH response exhibit stimulatory effect of PAF on innate and cell mediated immune response. Histopathological analysis of liver, kidney and spleen and analysis of other toxicity parameters, such as effect on body weight, lymphoid organ weight and cellularity, revealed PAF to exhibit no toxic effects. PAF seems to be a promising balanced Th1 and Th2 directing immunomodulator, possibly activating TLR2 through TIR domain-containing adaptor inducing interferon beta (TRIF)-dependent pathway that leads to T-cell activation and promotes effective immune responses and may find useful application clinically. PMID- 24794419 TI - Exacerbations in non-COPD patients: recognition? PMID- 24794420 TI - Test-retest reliability of muscle vibration effects on postural sway. AB - The effect of alterations in the processing of proprioceptive signals, on postural control, has been studied using muscle vibration effects. However, reliability and agreement of muscle vibration have still to be addressed. This study aimed to assess intra- and interday reliability and agreement of vibration effects of lumbar paraspinal and triceps surae muscles in a non-selected sample of 20 subjects, standing on solid surface and on foam. We used mean position and velocity of Centre of Pressure (CoP), during and after vibration to quantify the effect of muscle vibration. We also calculated the ratio of vibration effects on the lumbar paraspinal and triceps surae muscles (proprioceptive weighting). Displacement of the CoP during vibration showed good reliability (ICCs>0.6), and proprioceptive weighting of displacement fair to good reliability (0.52-0.73). Agreement measures were poor, with most CV's ranging between 18% and 36%. Change in CoP velocity appeared not to be reliable. Balance recovery, when based on CoP position and calculated a short period after cessation of vibration, showed good reliability. According to this study, displacement during vibration, proprioceptive weighting and selected recovery variables are the most reliable indicators of the response to muscle vibration. PMID- 24794421 TI - Infective endocarditis: old problem, new guidelines and still much to learn. PMID- 24794422 TI - E-cigarette awareness and perceived harmfulness: prevalence and associations with smoking-cessation outcomes. AB - BACKGROUND: Electronic cigarettes, or e-cigarettes, are increasingly advertised as replacements for regular cigarettes or cessation aids for smokers. PURPOSE: To describe the prevalence and correlates of e-cigarette awareness and perceived harmfulness among U.S. adults and analyze whether these variables are associated with smokers' past-year quit attempts and intention to quit. METHODS: Data were obtained from the Health Information National Trends Survey (HINTS 4 Cycle 2), conducted from October 2012 to January 2013. Data analyses were performed from June to August 2013. RESULTS: Overall, 77% of respondents were aware of e cigarettes. Of these, 51% believed e-cigarettes were less harmful than cigarettes. Younger, white (compared with Hispanic), more educated respondents and current or former smokers (compared with non-smokers) were more likely to be aware of e-cigarettes. Among those who were aware of e-cigarettes, younger; men (compared with women); white (compared with African-American); more educated respondents; and current smokers (compared with former and non-smokers) were more likely to believe that e-cigarettes were less harmful. [corrected]. CONCLUSIONS: Overall e-cigarette awareness increased whereas the proportion of smokers who perceived less harm of e-cigarettes declined compared with earlier surveys. However, awareness and perceived harm of e-cigarettes did not show evidence of promoting smoking cessation at the population level. PMID- 24794423 TI - Carryover effects of cyclical stretching of the digits on hand function in stroke survivors. AB - OBJECTIVE: To investigate the longevity and cumulative impact of multiple sessions of passive, cyclical stretching of the digits on hand function in subacute stroke survivors. DESIGN: Before-after trial with intervention repeated on 3 consecutive days. SETTING: Research laboratory. PARTICIPANTS: Individuals (N=27) with moderate to severe hand impairment, 2 to 6 months (subacute, n=12) and >7 months (chronic, n=15) poststroke. INTERVENTIONS: Subjects wore an actuated glove orthosis that cyclically moved their fingers and thumb from a relaxed/flexed posture into neutral extension for 30 minutes on 3 consecutive days. MAIN OUTCOME MEASURES: Three hand-specific tasks from the Graded Wolf Motor Function Test, Box and Block Test (BBT), grip strength, and lateral pinch strength. Recordings were taken before stretching and at 3 time points, each separated by 30 minutes after completion of stretching on each day. RESULTS: Significant improvement was observed immediately after the stretching for both groups. Improvements in the subacute group were largely maintained up to 1 hour poststretching, with significant carryover from day to day for some outcomes measures such as the BBT (P=.006) and grip strength (P=.012). In contrast, improvements after stretching for the chronic group were transient, with the changes largely dissipating over time and no significant cumulative effect across days. CONCLUSIONS: Cyclical stretching of the digits had a lasting and reinforcing effect on improving hand motor control for subacute stroke survivors. Incorporation of cyclical stretching before active hand therapy may prove to be a beneficial treatment for stroke survivors, especially during the subacute phase of recovery. PMID- 24794424 TI - A scoping review of the use of elastic therapeutic tape for neck or upper extremity conditions. AB - STUDY DESIGN: Scoping review. INTRODUCTION: Elastic therapeutic tape is a relatively new intervention for treating a variety of injuries; however, there is little evidence to support its effectiveness for neck or upper extremity conditions. PURPOSE OF THE STUDY: This scoping review examines current evidence on the recommended application, purpose and effectiveness of elastic therapeutic tape for treating neck or upper extremity conditions. METHODS: A scoping review was conducted to examine the evidence in 14 peer-reviewed published articles that reported on the use of elastic therapeutic tape for neck or upper extremity conditions. RESULTS: Six studies reported statistically significant changes to pain with the use of elastic therapeutic tape. Only three studies found statistically significant changes to range of motion. CONCLUSIONS: Elastic therapeutic tape may play a role in reducing short-term neck and upper extremity pain, however future high quality studies that contribute to the evidence base for its use are needed. LEVEL OF EVIDENCE: N/A. PMID- 24794425 TI - How pervasive are circadian oscillations? AB - Circadian oscillations play a critical role in coordinating the physiology, homeostasis, and behavior of biological systems. Once thought to only be controlled by a master clock, recent high-throughput experiments suggest many genes and metabolites in a cell are potentially capable of circadian oscillations. Each cell can reprogram itself and select a relatively small fraction of this broad repertoire for circadian oscillations, as a result of genetic, environmental, and even diet changes. PMID- 24794426 TI - Early changes of left ventricular geometry and deformational analysis in obese subjects without cardiovascular risk factors: a three-dimensional and speckle tracking echocardiographic study. AB - Subclinical myocardial dysfunction has been identified in obese subjects without cardiovascular risks factors and has been defined as "obesity cardiomyopathy". We evaluated left ventricular (LV) function and geometry in obese patients by using a 3 dimensional echocardiography (3DE). We also aimed to look at the influence of ventricular geometry upon functional parameters of the LV by using 3D speckle tracking imaging (3D-STI). 30 consecutive and asymptomatic obese cases (OB group) with no comorbidities were prospectively enrolled. The control group included 30 healthy volunteers (HS group), matched for age and sex. All subjects underwent 3DE and 3D-STI. Ventricular geometry was evaluated with the LV sphericity index (LV SpI) and the LV diastolic volume to mass ratio (LV EDV/Mass ratio). LV Mass was significantly increased in OB group and the LV EDV/Mass ratio had a significantly lower mean value in this group (p < 0.001 and p = 0.002, respectively). LV SpI was significantly reduced in obese subjects (p < 0.001). A significant reduction in longitudinal (GLS), radial (GRS) and area strain (GAS) was observed in OB group (p = 0.001 for all) while circumferential mechanic (GCS) was not different between the two groups (p = 0.052). LV EDV to mass ratio was significantly related to GLS (r = -0.298, p = 0.022) and GAS (r = -0.289, p = 0.026). On multivariate analysis, GRS and GAS were independently related to LV SpI (beta = 0.222, p = 0.031 and beta = -0.222, p = 0.034, respectively). Geometrical and structural ventricular remodeling negatively influences functional properties of the LV in obese subjects without cardiovascular risks factors. Further studies are needed to assess the prognostic value of our findings. PMID- 24794427 TI - Circular distribution pattern of plant modulars and endophagous herbivory within tree crowns: the impact of roadside light conditions. AB - The circular distributions of plant modulars (branches, leaves) and endophagous herbivory (mines, galls) were investigated within the crowns of four dominant Fagaceae trees in a subtropical evergreen broadleaf forest at Jiulianshan National Nature Reserve, Jiangxi, China. The hypothesis is that more plant modulars and more endophagous herbivory should occur in the crown area perpendicular to the roads. Circular statistical techniques were used to verify new patterns of the impact of roads on plants and insects. The results confirmed that the roadside light environments had larger impacts on the circular distribution patterns of plant modulars than those of leaf herbivores. For herbivores, the impact of light was larger on mine distribution than on gall distribution. The branches of all four tree species were concentrated in the direction perpendicular to the roads. In the preferred direction, branches were longer and higher. More leaves, more mines, and more galls were found surrounding the preferred branch direction. In general, leaf miners and leaf gallers preferred leaves in the sun over those in the shade; however, leaf gallers had a lower degree of preference for sun than leaf miners. Different endphagous insects also showed clear interspecific differences in sun/shade leaf selection. PMID- 24794428 TI - Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. AB - A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism. PMID- 24794429 TI - Patterns of somatically acquired amplifications and deletions in apparently normal tissues of ovarian cancer patients. AB - Little is understood about the occurrence of somatic genomic alterations in normal tissues and their significance in the context of disease. Here, we identified potential somatic copy number alterations (pSCNAs) in apparently normal ovarian tissue and peripheral blood of 423 ovarian cancer patients. There were, on average, two to four pSCNAs per sample detectable at a tissue-level resolution, although some individuals had orders of magnitude more. Accordingly, we estimated the lower bound of the rate of pSCNAs per cell division. Older individuals and BRCA mutation carriers had more pSCNAs than others. pSCNAs significantly overlapped with Alu and G-quadruplexes, and the affected genes were enriched for signaling and regulation. Some of the amplification/deletion hotspots in pan-cancer genomes were hot spots of pSCNAs in normal tissues as well, suggesting that those regions might be inherently unstable. Prevalence of pSCNA in peripheral blood predicted survival, implying that mutations in normal tissues might have consequences for cancer patients. PMID- 24794430 TI - FANCD2 binds CtIP and regulates DNA-end resection during DNA interstrand crosslink repair. AB - The Fanconi anemia (FA) pathway is critically involved in the maintenance of hematopoietic stem cells and the suppression of carcinogenesis. A key FA protein, FANCD2, is monoubiquitinated and accumulates in chromatin in response to DNA interstrand crosslinks (ICLs), where it coordinates DNA repair through mechanisms that are still poorly understood. Here, we report that CtIP protein directly interacts with FANCD2. A region spanning amino acids 166 to 273 of CtIP and monoubiquitination of FANCD2 are both essential for the FANCD2-CtIP interaction and mitomycin C (MMC)-induced CtIP foci. Remarkably, both FANCD2 and CtIP are critical for MMC-induced RPA2 hyperphosphorylation, an event that accompanies end resection of double-strand breaks. Collectively, our results reveal a role of monoubiquitinated FANCD2 in end resection that depends on its binding to CtIP during ICL repair. PMID- 24794431 TI - A pSMAD/CDX2 complex is essential for the intestinalization of epithelial metaplasia. AB - The molecular mechanisms leading to epithelial metaplasias are poorly understood. Barrett's esophagus is a premalignant metaplastic change of the esophageal epithelium into columnar epithelium, occurring in patients suffering from gastroesophageal reflux disease. Mechanisms behind the development of the intestinal subtype, which is associated with the highest cancer risk, are unclear. In humans, it has been suggested that a nonspecialized columnar metaplasia precedes the development of intestinal metaplasia. Here, we propose that a complex made up of at least two factors needs to be activated simultaneously to drive the expression of intestinal type of genes. Using unique animal models and robust in vitro assays, we show that the nonspecialized columnar metaplasia is a precursor of intestinal metaplasia and that pSMAD/CDX2 interaction is essential for the switch toward an intestinal phenotype. PMID- 24794432 TI - Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. AB - Historically, spontaneous deletions and insertions have provided means to probe germline developmental genetics in Drosophila, mouse and other species. Here, induced pluripotent stem cell (iPSC) lines were derived from infertile men with deletions that encompass three Y chromosome azoospermia factor (AZF) regions and are associated with production of few or no sperm but normal somatic development. AZF-deleted iPSC lines were compromised in germ cell development in vitro. Undifferentiated iPSCs transplanted directly into murine seminiferous tubules differentiated extensively to germ-cell-like cells (GCLCs) that localized near the basement membrane, demonstrated morphology indistinguishable from fetal germ cells, and expressed germ-cell-specific proteins diagnostic of primordial germ cells. Alternatively, all iPSCs that exited tubules formed primitive tumors. iPSCs with AZF deletions produced significantly fewer GCLCs in vivo with distinct defects in gene expression. Findings indicate that xenotransplantation of human iPSCs directs germ cell differentiation in a manner dependent on donor genetic status. PMID- 24794433 TI - TRIM27/MRTF-B-dependent integrin beta1 expression defines leading cells in cancer cell collectives. AB - For collective invasion, cancer cells form cohesive groups comprised of leading cells (LCs) at the forefront and following cells (FCs) at the rear. However, the molecular mechanisms that define LCs and FCs remain elusive. Here, we demonstrated that LCs, but not FCs, upregulated the expression of integrin beta1 after the loss of intercellular adhesion. The LC-specific expression of integrin beta1 was posttranscriptionally regulated by the TRIM27/MRTF-B complex in response to the loss of intercellular adhesion, thereby regulating the stability and translation of integrin beta1 mRNA via microRNA-124 in LCs. Accordingly, depletion of TRIM27 and MRTF-B abrogated the upregulation of integrin beta1 in LCs and blocked the invasion of cancer cell groups in vitro and in vivo. Therefore, our findings revealed that the specific function of LCs was defined by intrinsic mechanisms related to the presence of the cell's free surface, providing insights into the regulation of intratumor heterogeneity. PMID- 24794434 TI - FANCD2 and CtIP cooperate to repair DNA interstrand crosslinks. AB - The resolution of DNA interstrand crosslinks (ICLs) requires a complex interplay between several processes of DNA metabolism, including the Fanconi anemia (FA) pathway and homologous recombination (HR). FANCD2 monoubiquitination and CtIP dependent DNA-end resection represent key events in FA and HR activation, respectively, but very little is known about their functional relationship. Here, we show that CtIP physically interacts with both FANCD2 and ubiquitin and that monoubiquitinated FANCD2 tethers CtIP to damaged chromatin, which helps channel DNA double-strand breaks generated during ICL processing into the HR pathway. Consequently, CtIP mutants defective in FANCD2 binding fail to associate with damaged chromatin, which leads to increased levels of nonhomologous end-joining activity and ICL hypersensitivity. Interestingly, we also observe that CtIP depletion aggravates the genomic instability in FANCD2-deficient cells. Thus, our data indicate that FANCD2 primes CtIP-dependent resection during HR after ICL induction but that CtIP helps prevent illegitimate recombination in FA cells. PMID- 24794436 TI - A positive role for PERIOD in mammalian circadian gene expression. AB - In the current model of the mammalian circadian clock, PERIOD (PER) represses the activity of the circadian transcription factors BMAL1 and CLOCK, either independently or together with CRYPTOCHROME (CRY). Here, we provide evidence that PER has an entirely different function from that reported previously, namely, that PER inhibits CRY-mediated transcriptional repression through interference with CRY recruitment into the BMAL1-CLOCK complex. This indirect positive function of PER is consistent with previous data from genetic analyses using Per deficient or mutant mice. Overall, our results support the hypothesis that PER plays different roles in different circadian phases: an early phase in which it suppresses CRY activity, and a later phase in which it acts as a transcriptional repressor with CRY. This buffering effect of PER on CRY might help to prolong the period of rhythmic gene expression. Additional studies are required to carefully examine the promoter- and phase-specific roles of PER. PMID- 24794435 TI - Metabolic resource allocation in individual microbes determines ecosystem interactions and spatial dynamics. AB - The interspecies exchange of metabolites plays a key role in the spatiotemporal dynamics of microbial communities. This raises the question of whether ecosystem level behavior of structured communities can be predicted using genome-scale metabolic models for multiple organisms. We developed a modeling framework that integrates dynamic flux balance analysis with diffusion on a lattice and applied it to engineered communities. First, we predicted and experimentally confirmed the species ratio to which a two-species mutualistic consortium converges and the equilibrium composition of a newly engineered three-member community. We next identified a specific spatial arrangement of colonies, which gives rise to what we term the "eclipse dilemma": does a competitor placed between a colony and its cross-feeding partner benefit or hurt growth of the original colony? Our experimentally validated finding that the net outcome is beneficial highlights the complex nature of metabolic interactions in microbial communities while at the same time demonstrating their predictability. PMID- 24794437 TI - MicroRNA targeting of CoREST controls polarization of migrating cortical neurons. AB - The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis. PMID- 24794438 TI - Balance between apical membrane growth and luminal matrix resistance determines epithelial tubule shape. AB - The morphological stability of biological tubes is crucial for the efficient circulation of fluids and gases. Failure of this stability causes irregularly shaped tubes found in multiple pathological conditions. Here, we report that Drosophila mutants of the ESCRT III component Shrub/Vps32 exhibit a strikingly elongated sinusoidal tube phenotype. This is caused by excessive apical membrane synthesis accompanied by the ectopic accumulation and overactivation of Crumbs in swollen endosomes. Furthermore, we demonstrate that the apical extracellular matrix (aECM) of the tracheal tube is a viscoelastic material coupled with the apical membrane. We present a simple mechanical model in which aECM elasticity, apical membrane growth, and their interaction are three vital parameters determining the stability of biological tubes. Our findings demonstrate a mechanical role for the extracellular matrix and suggest that the interaction of the apical membrane and an elastic aECM determines the final morphology of biological tubes independent of cell shape. PMID- 24794440 TI - Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. AB - Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFbeta1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4. PMID- 24794439 TI - Plac8 links oncogenic mutations to regulation of autophagy and is critical to pancreatic cancer progression. AB - Mutations in p53 and RAS potently cooperate in oncogenic transformation, and correspondingly, these genetic alterations frequently coexist in pancreatic ductal adenocarcinoma (PDA) and other human cancers. Previously, we identified a set of genes synergistically activated by combined RAS and p53 mutations as frequent downstream mediators of tumorigenesis. Here, we show that the synergistically activated gene Plac8 is critical for pancreatic cancer growth. Silencing of Plac8 in cell lines suppresses tumor formation by blocking autophagy, a process essential for maintaining metabolic homeostasis in PDA, and genetic inactivation in an engineered mouse model inhibits PDA progression. We show that Plac8 is a critical regulator of the autophagic machinery, localizing to the lysosomal compartment and facilitating lysosome-autophagosome fusion. Plac8 thus provides a mechanistic link between primary oncogenic mutations and the induction of autophagy, a central mechanism of metabolic reprogramming, during PDA progression. PMID- 24794441 TI - Interleukin-17D mediates tumor rejection through recruitment of natural killer cells. AB - The process of cancer immunoediting generates a repertoire of cancer cells that can persist in immune-competent hosts. In its most complex form, this process begins with the elimination of highly immunogenic unedited tumor cells followed by the escape of less immunogenic edited cells. Although edited tumors can release immunosuppressive factors, it is unknown whether unedited tumors produce cytokines that enhance antitumor function. Utilizing gene microarray analysis, we found the cytokine interleukin 17D (IL-17D) was highly expressed in certain unedited tumors but not in edited mouse tumor cell lines. Moreover, forced expression of IL-17D in edited tumor cells induced rejection by stimulating MCP-1 production from tumor endothelial cells, leading to the recruitment of natural killer (NK) cells. NK cells promoted M1 macrophage development and adaptive immune responses. IL-17D expression was also decreased in certain high-grade and metastatic human tumors, suggesting that it can be targeted for tumor immune therapy. PMID- 24794442 TI - Escargot restricts niche cell to stem cell conversion in the Drosophila testis. AB - Stem cells reside within specialized microenvironments, or niches, that control many aspects of stem cell behavior. Somatic hub cells in the Drosophila testis regulate the behavior of cyst stem cells (CySCs) and germline stem cells (GSCs) and are a primary component of the testis stem cell niche. The shutoff (shof) mutation, characterized by premature loss of GSCs and CySCs, was mapped to a locus encoding the evolutionarily conserved transcription factor Escargot (Esg). Hub cells depleted of Esg acquire CySC characteristics and differentiate as cyst cells, resulting in complete loss of hub cells and eventually CySCs and GSCs, similar to the shof mutant phenotype. We identified Esg-interacting proteins and demonstrate an interaction between Esg and the corepressor C-terminal binding protein (CtBP), which was also required for maintenance of hub cell fate. Our results indicate that niche cells can acquire stem cell properties upon removal of a single transcription factor in vivo. PMID- 24794444 TI - Analysis of imprinted IGF2/H19 gene methylation and expression in normal fertilized and parthenogenetic embryonic stem cells of pigs. AB - To determine whether the genomic imprinting can be maintained during the process of embryonic stem (ES) cell derivation from pig blastocysts, mRNA and DNA methylation at the IGF2/H19 imprinting control region in putative ES cells derived from in vitro fertilized (IVF) and parthenogenetic (PG) embryos were investigated. In the present study, one IVF- and three PG ES-like cell lines were established and analyzed for cellular characteristics such as pluripotent marker expression and differentiation capacity. The results showed that these putative ES cells derived from pig blastocysts fulfilled the general "stemness" criteria. The expression of the H19 gene was significantly greater in PG blastocysts than IVF blastocysts, but there were greater amounts of IGF2 in IVF than PG blastocysts. Of these putative ES cell lines, one PG line had less H19 gene expression than a IVF ES cell line while the other two PG lines had much greater expression of the H19 gene than the IVF line. In contrast, the IGF2 gene was upregulated in the same PG cell line relative to the other two PG cell lines and transcript abundance was similar to IVF ES-like cells. Despite the variable amounts of mRNA among the PG cell lines, the IGF2/H19 gene had a differentially methylated region (DMR) 3 was typically un-methylated in all PG cells, and hemi methylated in the IVF cells. These findings indicated that the mRNA of H19 and IGF2 genes is susceptible to in vitro environments during the process of ES cell derivation from blastocysts but DNA methylation status at this region was well maintained. These altered gene expressions may not be associated with the methylation of the imprinting control region at this locus. Therefore, with their uni-parental genotype, the pluripotent differentiation potentials of PG ES cells could be a valuable tool for understanding genomic imprinting in embryonic development. PMID- 24794443 TI - CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer. AB - Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf(+/-) tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf(+/-) tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression. PMID- 24794445 TI - Gene expression and localization of 20alpha-hydroxysteroid dehydrogenase (HSD) in reproductive tissues during early pregnancy of cattle. AB - The enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the conversion of progesterone to its inactive form, 20alpha-hydroxyprogesterone, and this enzyme has an important role in the regulation of luteal function in mammals. It has previously been determined that the 20alpha-HSD gene is primarily expressed by large luteal cells during the late stage of the estrous cycle. In the present study, the amounts of mRNA were determined in cultured cells of the corpus luteum (CL) cells. The localization of 20alpha-HSD was also determined in ovaries, placenta, and endometrium during early pregnancy. The amount of 20alpha HSD mRNA in cultured luteal cells increased with time and by treatment with the luteolysis agent prostaglandin F2alpha (PGF2alpha). Immunofluorescence assays detected increased protein in cultured luteal cells. The 20alpha-HSD mRNA and protein were present in the ovaries, placenta, and endometrium on Days 30, 60, and 90 of pregnancy. In particular, gene expression was much greater in the ovary than in the placenta and endometrium. Immuno-histochemical analysis indicated that bovine 20alpha-HSD was primarily localized in ovarian large luteal cells, placental cytotrophoblast villus, and glandular epithelial cells of the endometrium during early pregnancy. Furthermore, in situ analyses demonstrated colocalization of 20alpha-HSD mRNA and protein. Taken together, results of the present study indicate that 20alpha-HSD mRNA and protein are co-localized in large luteal cells, the placenta, and the endometrium during early pregnancy, suggesting that 20alpha-HSD regulates mechanisms involved in the maintenance of early pregnancy. PMID- 24794446 TI - A commercial box for dog semen transport: What happens inside when the environmental temperature is increasing? AB - Environmental temperatures may influence the temperature inside commercial transport boxes during semen shipment and thereby storage conditions of diluted dog semen. To evaluate the temperature changes inside boxes and their influence on sperm quality, split semen samples (n=8) were placed in Neopor boxes((r)) exposed for 48h to room temperature (RT) (Box 1), 40 degrees C for 6h and then kept at RT (Box 2) or 40 degrees C (Box 3). A fourth subsample was kept at 4-5 degrees C in a refrigerator (control). Inside Box 1 temperature initially decreased to <3 degrees C before it stabilized at 7-8 degrees C, while in Box 2 no decrease occurred and temperature was at 7-8 degrees C for 48 h. Temperature inside Box 3 was at 14-15 degrees C for 24h and, thereafter, increased to 36.1 degrees C. Analysis of sperm motility (CASA) and viability (PI and FITC-PNA) after 24 and 48 h revealed marked sensitivity of dog spermatozoa to temperature fluctuations (Box 1). A constant storage temperature of 7-8 degrees C (Box 2) provided the most desirable semen quality in terms of motility, viability, as well as osmotic resistance when samples were stored for 48 h. Furthermore, results indicate that during 24h preservation a storage temperature of 14-16 degrees C may provide optimum conditions for maintenance of sperm viability and function. An increase of the inside temperature to >30 degrees C (Box 3) resulted in an almost complete loss in sperm integrity. In conclusion, results suggest a revision of current recommendations for storage temperature of diluted dog semen. Boxes for semen transport should be prepared depending on the expected environmental temperatures. PMID- 24794447 TI - Intrathecal sufentanil for coronary artery bypass grafting. AB - CONTEXT: Cardiac surgery patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. OBJECTIVE: Evaluate the effect of adding intrathecal sufentanil to general anesthesia on hemodynamics. DESIGN: Prospective, randomized, not blinded study, after approval by local ethics in Research Committee. SETTING: Monocentric study performed at Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil. PATIENTS: 40 consenting patients undergoing elective coronary artery bypass, both genders. EXCLUSION CRITERIA: Chronic kidney disease; emergency procedures; reoperations; contraindication to spinal block; left ventricular ejection fraction less than 40%; body mass index above 32kg/m(2) and use of nitroglycerin. INTERVENTIONS: Patients were randomly assigned to receive intrathecal sufentanil 1MUg/kg or not. Anesthesia induced and maintained with sevoflurane and continuous infusion of remifentanil. MAIN OUTCOME MEASURES: Hemodynamic variables, blood levels of cardiac troponin I, B-type natriuretic peptide, interleukin-6 and tumor necrosis factor alfa during and after surgery. RESULTS: Patients in sufentanil group required less inotropic support with dopamine when compared to control group (9.5% vs 58%, p=0.001) and less increases in remifentanil doses (62% vs 100%, p=0.004). Hemodynamic data at eight different time points and biochemical data showed no differences between groups. CONCLUSIONS: Patients receiving intrathecal sufentanil have more hemodynamical stability, as suggested by the reduced inotropic support and fewer adjustments in intravenous opioid doses. PMID- 24794448 TI - Comparison of the effect of sevoflurane and propofol on oxygenation during gradual transition to one-lung ventilation. AB - BACKGROUND: It is known that hypoxic pulmonary vasoconstriction increases as a result of intermittent regional hypoxic challenges. The aim of this study was to compare the effects of sevoflurane and propofol on oxygenation and shunt fraction during one-lung ventilation in a novel model of hypoxic preconditioning before one-lung ventilation. METHODS: Sixteen Wistar-albino rats were anesthetized intra peritoneally before venous and arterial cannulations and tracheotomized. The animals were randomly allocated to receive either sevoflurane 2% or 10mg/kg/h propofol infusion and ventilated with 100% oxygen at an inspiratory rate of 80 breaths/min for 30min. Three cycles of one-lung ventilation and two-lung ventilation were performed and one-lung ventilation was continued for 15min. Arterial blood gas samples were obtained as follows: after cannulation and tracheotomy, following 30min of treatment with sevoflurane or propofol, and at the 5th and 15th min of one-lung ventilation. RESULTS: The PaO2 levels were higher and shunt fractions were lower in rats receiving propofol compared to rats treated with sevoflurane but the difference was not significant; the two groups were comparable in terms of PaCO2. CONCLUSIONS: The similar effects of sevoflurane and propofol on PaO2 during one-lung ventilation following hypoxic preconditioning may be due to other causes beside the inhibition of hypoxic pulmonary vasoconstriction. Gradual transition to one-lung ventilation is a novel technique for preconditioning experiments for one-lung ventilation. PMID- 24794449 TI - In vitro evaluation of antimicrobial features of vasopressors. AB - BACKGROUND: Drugs administered as intravenous infusion may be contaminated during several stages of production or preparation. However studies focusing on antibacterial effects of vasopressor drugs are very rare. This study investigates the in vitro antimicrobial activity of the clinically used forms of vasopressors. MATERIALS AND METHODS: In vitro antimicrobial activities of vasopressor drugs of different concentrations were investigated by using the micro dilution technique. Microorganisms used in the test were Escherichia coli ATCC 25922, Yersinia pseudotuberculosis ATCC 911, Pseudomonas aeruginosa ATCC 10145, Listeria monocytogenes ATCC 43251, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, Bacillus cereus 702 Roma, Mycobacterium smegmatis ATCC607, Candida albicans ATCC 60193, and Saccharomyces cerevisiae RSKK 251. Antibacterial assays were performed in Mueller-Hinton broth at pH 7.3 and antifungal assays were performed in buffered Yeast Nitrogen Base at pH 7.0. RESULTS: Two different dopamine preparations showed antimicrobial activity. No other study drug showed any antimicrobial activity. CONCLUSIONS: In our opinion, dopamine's antibacterial effects may be advantageous for inhibiting the spread of bacterial contamination during the preparation of the infusion solutions. However, it is important that strict guidelines regarding the need for sterile equipment and deliverables be adhered to during all procedures performed in the intensive care units. PMID- 24794450 TI - The comparison of levobupivacaine in continuous or single dose spinal anesthesia for transurethral resection of prostate surgery. AB - BACKGROUND: The aim of the study is to compare the efficacy of levobupivacaine induced continuous spinal anesthesia (CSA) versus single dose spinal anesthesia (SDSA) in patients who are planned to undergo transurethral prostate resection. METHODS: Sixty years or older, ASA I-II or III, 50 patients were included in the study. 12.5mg 0.5% levobupivacaine were administered intrathecally in SDSA group. In CSA group, initially 2mL of 0.25% levobupivacaine were administered through spinal catheter. In order to achieve sensory block level at T10 dermatome, additional 1mL of 0.25% levobupivacaine were administered through the catheter in every 10min. Hemodynamic parameters and block characteristics were recorded. Preoperative and postoperative blood samples of the patients were drawn to determine plasma cortisone and plasma epinephrine levels. RESULTS: CSA technique provided better hemodynamic stability compared to SDSA technique particularly 90min after intrathecal administration. The rise in sensory block level was rapid and the time to reach surgical anesthesia was shorter in SDSA group. Motor block developed faster in SDSA group. In CSA group, similar anesthesia level was achieved by using lower levobupivacaine dose and which was related to faster recovery. Although, both techniques were effective in preventing surgical stress respond, postoperative cortisone levels were suppressed more in SDSA group. CONCLUSION: CSA technique with 0.25% levobupivacaine can be used as a regional anesthesia method for elderly patients planned to have TUR-P operation. PMID- 24794451 TI - Effects of elevated artificial pneumoperitoneum pressure on invasive blood pressure and levels of blood gases. AB - BACKGROUND AND OBJECTIVE: to evaluate the clinical, hemodynamic, gas analysis and metabolic repercussions of high transient pressures of pneumoperitoneum for a short period of time to ensure greater security for introduction of the first trocar. METHODS: sixty-seven patients undergoing laparoscopic procedures were studied and randomly distributed in P12 group: n=30 (intraperitoneal pressure [IPP] 12mmHg) and P20 group: n=37 (IPP of 20mmHg). Mean arterial pressure (MAP) was evaluated by catheterization of the radial artery; and through gas analysis, pH, partial pressure of oxygen (PaO2), partial pressure of CO2 (PaCO2), bicarbonate (HCO3) and alkalinity (BE) were evaluated. These parameters were measured in both groups at time zero before pneumoperitoneum (TP0); at time 1 (TP1) when IPP reaches 12mmHg in both groups; at time 2 (TP2) after five min with IPP=12mmHg in P12 and after 5min with IPP=20mmHg at P20; and at time 3 (TP3) after 10min with IPP=12mmHg in P12 and with return of IPP from 20 to 12mmHg, starting 10min after TP1 in P20. Different values from those considered normal for all parameters assessed, or the appearance of atypical organic phenomena, were considered as clinical changes. RESULTS: there were statistically significant differences in P20 group in MAP, pH, HCO3 and BE, but within normal limits. No clinical and pathological changes were observed. CONCLUSIONS: high and transient intra-abdominal pressure causes changes in MAP, pH, HCO3 and BE, but without any clinical impact on the patient. PMID- 24794452 TI - In vitro evaluation of antimicrobial features of sugammadex. AB - BACKGROUND: Drugs administered by intravenous routes may be contaminated during several stages of production or preparation. Sugammadex is a modified gamma cyclodextrin. While research into the antibacterial effects of varieties of cyclodextrin is available, there are no studies focusing on the antibacterial effects of sugammadex. This study investigates the in vitro antimicrobial activity of sugammadex. MATERIALS AND METHODS: The in vitro antimicrobial activity of sugammadex was investigated using the broth microdilution method. The pH of the test solution was determined using a pH meter. The test microorganisms included Staphylococcus aureus ATCC 29213, Enterococcus fecalis ATCC 29212, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. In the second phase of the study 100mg/mL sugammadex (50MUg) was contaminated with test microorganisms (50MUg), including S. aureus ATCC 29213, E. fecalis ATCC 29212, E. coli ATCC 25922 and P. aeruginosa ATCC 27853, left to incubate for 24h and then the bacterial production in sugammadex was evaluated. RESULTS: The pH of the test solutions ranged between 7.25 and 6.97. Using the microdilution method, sugammadex had no antibacterial effect on S. aureus, E. fecalis, E. coli and P. aeruginosa at any concentration. In the second phase of the study bacterial production was observed after 24h in 100mg/mL sugammadex contaminated with the test microorganisms S. aureus, E. fecalis, E. coli and P. aeruginosa. CONCLUSIONS: Sugammadex had no antimicrobial effect on the test microorganisms, S. aureus, E. fecalis, E. coli and P. aeruginosa. Care should be taken that sterile conditions are maintained in the preparation of sugammadex; that the same sugammadex preparation not be used for more than one patient; and that storage conditions are adhered to after sugammadex is put into the injector. PMID- 24794453 TI - Anesthetic considerations for robotic cystectomy: a prospective study. AB - BACKGROUND AND OBJECTIVES: Robotic cystectomy is rapidly becoming a part of the standard surgical repertoire for the treatment of prostate cancer. Our aim was to describe respiratory and hemodynamic challenges and the complications observed in robotic cystectomy patients. PATIENTS: Sixteen patients who underwent robotic surgery between December 2009 and January 2011 were prospectively enrolled. Main outcome measures were non-invasive monitoring, invasive monitoring and blood gas analysis performed at supine (T0), Trendelenburg (T1), Trendelenburg+pneumoperitoneum (T2), Trendelenburg-before desufflation (T3), Trendelenburg (after desufflation) (T4), and supine (T5) positions. RESULTS: There were significant differences between T0-T1 and T0-T2 with lower heart rates. The mean arterial pressure value at T1 was significantly lower than T0. The central venous pressure value was significantly higher at T1, T2, T3, and T4 than at T0. There was no significant difference in the PET-CO2 value at any time point compared with T0. There were no significant differences in respiratory rate at any time point compared with T0. The mean f values at T3, T4, and T5 were significantly higher than T0. The mean minute ventilation at T4 and T5 were significantly higher than at T0. The mean plateau pressures and peak pressures at T1, T2, T3, T4, and T5 were significantly higher than the mean value at T0. CONCLUSIONS: Although the majority of patients generally tolerate robotic cystectomy well and appreciate the benefits, anesthesiologists must consider the changes in the cardiopulmonary system that occur when patients are placed in Trendelenburg position, and when pneumoperitoneum is created. PMID- 24794454 TI - Knowledge of anaesthesiologists in Recife with respect to potential risks in the operating room-cross-sectional study. AB - OBJECTIVES: the health care should be a safe act, free of adverse events. However, in daily practice an excessive exposure to factors that endanger the health of the professional is observed. The surgical center stands out as one of the sites where the professional involved is more vulnerable. This environment is the anaesthesiologist's workplace, and this professional must deal with its potential complicators. This study aimed to evaluate the knowledge of anaesthesiologists in Recife on various situations of risk in the workplace. METHOD: a cross-sectional study in which structured questionnaires, completed voluntarily and anonymously by the anesthesiologist itself, were applied to assess the knowledge of the potential risks in the operating room. Data were analyzed using Epi Info version 7. RESULTS: a total of 162 anaesthesiologists responded to the questionnaire, 38.02% of these professionals registered at Cooperative of Anaesthesiologists of Pernambuco. Of these, 3.7% read the manual of the Committee on Hospital Infection Control (Comissao de Controle de Infeccao Hospitalar) of their institution and 40.74% chose the correct option, "technical director", as responsible for ensuring proper working conditions. Of the total, 5.56% stated that the anaesthetics' pollution index in the operating theater was monitored. Only 1.85% of the sample was subjected to periodic screening for tuberculosis. By analyzing the hypothetical situation of contamination with a patient with hepatitis C, only 43.83% knew that there is no effective post exposure prophylaxis. CONCLUSION: educational campaigns should be implemented to improve the knowledge of health professionals and clarify institutions and professionals' rights and duties. PMID- 24794455 TI - Total spinal block after lumbar plexus block: a case report. AB - Lumbar plexus block (LPB) is a suitable method for elder patients for lower extremity surgery. Many complications could be seen during LPB, but not as many as central block. In this case report, we aimed to report a total spinal block, an unusual complication. LPB with sciatic block was planned for a male patient, 76 years old, scheduled for total knee replacement due to gonarthrosis. The patient became unconscious after psoas compartment block with Chayen technique for LPB. The operation ended at 145th minute. The patient was admitted to intensive care unit until postoperative second day and discharged to home on fifth day of surgery. Main concern of patient monitorization should be an anesthesiologist. In this manner, we conclude that contacting to the patient should be ensured during these procedures. PMID- 24794456 TI - Transient unilateral combined paresis of the hypoglossal nerve and lingual nerve following intubation anesthesia. AB - Nerve damage may occur in the pharyngolaryngeal region during general anesthesia. The most frequently injured nerves are the hypoglossal, lingual and recurrent laryngeal. These injuries may arise in association with several factors, such as laryngoscopy, endotracheal intubation and tube insertion, cuff pressure, mask ventilation, the triple airway maneuver, the oropharyngeal airway, manner of intubation tube insertion, head and neck position and aspiration. Nerve injuries in this region may take the form of an isolated single nerve or of paresis of two nerves together in the form of hypoglossal and recurrent laryngeal nerve palsy (Tapia's syndrome). However, combined injury of the lingual and hypoglossal nerves following intubation anesthesia is a much rarer condition. The risk of this damage can be reduced with precautionary measures. We describe a case of combined unilateral nervus hypoglossus and nervus lingualis paresis developing after intubation anesthesia. PMID- 24794457 TI - Anesthesia for a child with Walker-Warburg syndrome. AB - BACKGROUND AND OBJECTIVES: Walker-Warburg Syndrome is a rare, autosomal recessive congenital muscular dystrophy manifested by central nervous system, eye malformations and possible multisystem involvement. The diagnosis is established by the presence of four criteria: congenital muscular dystrophy, type II lissencephaly, cerebellar malformation, and retinal malformation. Most of the syndromic children die in the first three years of life because of respiratory failure, pneumonia, seizures, hyperthermia and ventricular fibrillation. CASE REPORT: The anesthetic management of a two-months-old male child listed for elective ventriculo-peritoneal shunt operation was discussed. CONCLUSIONS: A careful anesthetic management is necessary due to the multisystem involvement. We reported anesthetic management of a two-months-old male child with Walker-Warburg Syndrome who was listed for elective ventriculo-peritoneal shunt operation. PMID- 24794458 TI - Venipuncture-related lateral antebrachial cutaneous nerve injury: what to know? AB - BACKGROUND AND OBJECTIVES: Venipuncture is one of the most common procedures performed in daily anesthetic practice. Though usually innocuous, peripheral nerve injuries with serious sequelae have been described following venipuncture. We present a case of venipuncture-related lateral antebrachial cutaneous nerve injury, alongside the essential diagnostic and prognostic information for day to day practice. CASE: 27-Year old male who underwent venipuncture of the right antecubital fossa with a 20-gauge needle, for routine metabolic assessment. The patient suffered a shooting, electric-type pain traveling on the lateral side of the forearm, from the antecubital fossa proximally, to the right lateral wrist and base of the right thumb. After 24h, the patient still experienced shooting, electric-type pain that was rated as 8/10 at the right distal lateral arm, right lateral wrist and base of the thumb, accompanied by paresthesia. The literature was reviewed and the patient was counseled regarding published outcomes of these type of injuries. At follow-up, the patient stated that the dysesthesia subsided approximately 3-4 weeks after initial injury, and reported no remaining neurologic deficits. CONCLUSIONS: Peripheral nerve injuries have been described after venipuncture, but the literature is limited. Nerves in the antecubital fossa classically lie on a plane just beneath, and in close proximity to, the veins, making them susceptible to injury during phlebotomy; also it has been shown that there is a large range of anatomic variation, suggesting that even a non-traumatic, satisfactory venipuncture can directly damage these nerves. Anesthesiologists must be aware of this possible complication, diagnosis and prognostication to adequately counsel patients in the event that this complication occurs. PMID- 24794459 TI - Do the severity and the body region of injury correlate with long-term outcome in the severe traumatic patient? AB - BACKGROUND AND OBJECTIVES: To investigate if the Injury Severity Score (ISS) and the Abbreviated Injury Score (AIS) are correlated with the long-term quality of life in severe trauma patients. METHODS: Patients injured from 2005 to 2007 with an ISS>=15 were surveyed 16-24 months after injury. The Health Assessment Questionnaire (HAQ-DI) was used for measuring the functional status and the Short Form-12 (SF-12) was used for measuring the health status divided into its two components, the PCS (Physical Component Summary) and the MCS (Mental Component Summary). The results of the questionnaires were compared with the ISS and AIS components. Results of the SF-12 were compared with the values expected from the general population. RESULTS: Seventy-four patients filled the questionnaires (response rate 28%). The mean scores were: PCS 42.6+/-13.3; MCS 49.4+/-1.4; HAQ DI 0.5+/-0.7. Correlation was observed with the HAQ-DI and the PCS (Spearman's Rho: -0.83; p<0.05) and no correlation between the HAQ-DI and the MCS neither between the MCS and PCS (Spearman's Rho=-0.21; and 0.01 respectively). The cutaneous-external and extremities-pelvic AIS punctuation were correlated with The PCS (Spearman's Rho: -0.39 and -0.34, p<0.05) and with the HAQ-DI (Spearman's Rho: 0.31 and 0.23; p<0.05). The physical condition compared with the regular population was worse except for the groups aged between 65-74 and 55-64. CONCLUSIONS: Patients with extremities and pelvic fractures are more likely to suffer long-term disability. The severity of the external injuries influenced the long-term disability. PMID- 24794460 TI - Change Pain Latin America--new initiative established to enhance management of patients with chronic pain in Latin America. PMID- 24794461 TI - Contraction versus contracture and centronuclear myopathy versus central part myopathy in malignant hyperthermia. PMID- 24794462 TI - The optimal value of BMI for the lowest risk of osteoporosis in postmenopausal women aged 40-88 years. AB - The aim of this paper is to establish the optimal values of the body mass index (BMI) which would indicate the most favourable preservation of the bone mineral density in postmenopausal women. The material consists of the data of 369 healthy women aged between 40 and 88 years (mean age 67.84, SD=6.70) inhabitants of Wroclaw, which were followed up between 2001 and 2006. The absolute measure of bone mineral density (BMD) of the femoral neck was assessed using dual energy X ray absorptiometry (DEXA), expressed in g/(100mm(2)) and was transformed to T score values. According to the value of BMI, the women were divided into eight groups, the reference group with value between 18.0 and 21.9kg/m(2) and seven other groups beginning with the value 22.0 with a 2-point interval. Postmenopausal status was defined according to the occurrence of menstruation within the last 360 days. The women with osteopenia and osteoporosis were pooled together and comprised the risk group, whereas the other women comprised the normal group (T-score values above -1.0). The adjusted odds ratio showed the highest value for intervals between 24.0 and 25.9 units of BMI, and the lowest value for interval 26.0-27.9 units of BMI. The Youden index showed the lowest value in the 26.0-27.9BMI kg/m(2) interval. For our sample the optimal value of BMI, with the lowest risk of osteopenia and/or osteoporosis was the value of 26.9kg/m(2). A further increase of BMI does not result in a favourable effect on the bones, it rather intensifies negative phenomena in the body resulting in the onset of many diseases. PMID- 24794463 TI - Cytokinins for immunity beyond growth, galls and green islands. AB - Cytokinins are essential plant hormones that control almost every aspect of plant growth and development. Their function in mediating plant susceptibility to fungal biotrophs and gall-causing pathogens is well known. Here we highlight the interaction between cytokinins and salicylic acid pathways. Furthermore, we discuss ways in which cytokinin signaling could crosstalk with plant immune networks. Some of these networks are modulated by pathogens to propagate disease, whereas others help the host to mitigate an infection. PMID- 24794464 TI - Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arterial remodeling, increased right ventricular systolic pressure (RVSP), vasoconstriction and inflammation. The heritable form of PAH (HPAH) is usually (>80%) caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene. Existing treatments for PAH typically focus on the end-stage sequelae of the disease, but do not address underlying mechanisms of vascular obstruction and blood flow and thus, in the long run, have limited effect because they treat the symptoms rather than the cause. Over the past decade, improved understanding of the molecular mechanisms behind the disease has enabled us to consider several novel therapeutic pathways. These include approaches directed toward BMPR2 gene expression, alternative splicing, downstream BMP signaling, metabolic pathways and the role of estrogens and estrogenic compounds in BMP signaling. It is likely that, ultimately, only one or two of these pathways will generate meaningful treatment options, however the potential benefits to PAH patients are still likely to be significant. PMID- 24794465 TI - Inhibition of Factor XI activity as a promising antithrombotic strategy. AB - Prevention and treatment of thromboembolic disorders with minimal bleeding risk remains a significant unmet medical need. Studies in Factor XI (FXI)-deficient humans and experimental animal models suggest that targeting FXI in humans provides antithrombotic benefits with reduced bleeding liability compared with current standard of care. In this review, we describe an exciting era in the discovery and development of antithrombotic agents as multiple therapeutic modalities for FXI(a) inhibition progress through preclinical and clinical development. PMID- 24794466 TI - The push-off test: development of a simple, reliable test of upper extremity weight-bearing capability. AB - STUDY DESIGN: Longitudinal clinical measurement study. INTRODUCTION: The push-off test (POT) is a novel and simple measure of upper extremity weight-bearing that can be measured with a grip dynamometer. There are no published studies on the validity and reliability of the POT. The relationship between upper extremity self-report activity/participation and impairment measures remain an unexplored realm. PURPOSE: The primary purpose of this study is to estimate the intra and inter-rater reliability and construct validity of the POT. The secondary purpose is to estimate the relationship between upper extremity self-report activity/participation questionnaires and impairment measures. METHODS: A convenience sample of 22 patients with wrist or elbow injuries were tested for POT, wrist/elbow range of motion (ROM), isometric wrist extension strength (WES) and grip strength; and completed two self-report activity/participation questionnaires: Disability of the Arm, Shoulder and the Hand (DASH) and Work Limitations Questionnaire (WLQ-26). POT's inter and intra-rater reliability and construct validity was tested. Pearson's correlations were run between the impairment measures and self-report questionnaires to look into the relationship amongst them. RESULTS: The POT demonstrated high inter-rater reliability (ICC affected = 0.97; 95% C.I. 0.93-0.99; ICC unaffected = 0.85; 95% C.I. 0.68-0.94) and intra-rater reliability (ICC affected = 0.96; 95% C.I. 0.92-0.97; ICC unaffected = 0.92; 95% C.I. 0.85-0.97). The POT was correlated moderately with the DASH (r = -0.47; p = 0.03). While examining the relationship between upper extremity self-reported activity/participation questionnaires and impairment measures the strongest correlation was between the DASH and the POT (r = -0.47; p = 0.03) and none of the correlations with the other physical impairment measures reached significance. At-work disability demonstrated insignificant correlations with physical impairments. CONCLUSION: The POT test provides a reliable and easily administered quantitative measure of ability to bear the load through an injured arm. Preliminary evidence supports a moderate relationship between loading bearing measured by the POT and upper extremity function measured by the DASH. LEVEL OF EVIDENCE: 1b. PMID- 24794467 TI - Loss of chance in medical negligence. AB - Occasionally accidents and complications occur during anaesthesia and perioperative care that result in injury to the patient. Unfortunately, this is sometimes due to a breach in the anaesthetist's duty of care to the patient. Sometimes, rather than being the cause of immediate damage, the act or omission results in an alteration in the prognosis of the complaint or increased risk of complications related to the complaint. This avenue for a negligence action is known as 'loss of chance of a better outcome' and has been the subject of much legal argument in Australia in recent years. A recent High Court of Australia decision is widely seen as having 'closed the door' to, or at least made it difficult for the patient to succeed in, loss of chance cases. Many anaesthetists may not be familiar with the concept of 'loss of chance'. This review will explore the concept of loss of chance and the manner in which Australian courts have dealt with it before and after Tabet v Gett from the perspective of the anaesthetist. PMID- 24794468 TI - Determinants of the relationship between cost and survival time after elective adult cardiac surgery. AB - Cardiac surgery is increasingly performed on elderly patients with multiple comorbid conditions, but the determinants of the relationship between cost and survival time after cardiac surgery for patients with a serious cardiac condition remain uncertain. Using the long-term outcome data of a cohort study on adult cardiac surgical patients, the relationship between cost and survival time after cardiac surgery from a hospital service perspective was determined. The total cost for each patient was estimated by the costs of the surgical procedures, intra-aortic balloon pump utilisation, operating theatre utilisation, blood products, intensive care unit stay and cumulative hospital stay up to a median follow-up time of 30 months. Of the 2131 patients considered in this study, a total cost >A$100,000 per life-year after cardiac surgery was observed only in 171 patients (8.0%, 95% confidence interval 6.9 to 9.3%). Age, Charlson Comorbidity Index and EuroSCORE were all related to the cost per life-year after cardiac surgery, but EuroSCORE (odds ratio 1.26 per score increment, 95% confidence interval 1.18 to 1.35, P=0.001) was, by far, the most important determinant and explained 32% of the variability in cost per life-year after cardiac surgery. Patients with a high EuroSCORE were associated with a substantially longer length of intensive care unit stay and cumulative hospital stay, as well as a shorter survival time after cardiac surgery compared to patients with a lower EuroSCORE. Of all the subgroups of patients examined, only patients with a EuroSCORE >5 were consistently associated with a cost >A$100,000 per life-year (cost per life-year $183,148, 95% confidence interval 125, 394 to 240, 902). PMID- 24794469 TI - Cerebral oximetry to reduce perioperative morbidity. AB - The use of cerebral oximetry to guide intraoperative management has been shown to improve patient outcomes in cardiac surgery. This pilot trial assessed the feasibility of performing a similar study of outcome in patients over the age of 70 years undergoing non-cardiac surgery. Patients over the age of 70 years undergoing total knee or hip arthroplasty or bowel resection surgery were randomly assigned to have cerebral oximetry values monitored (intervention group) or not monitored (control) while under general anaesthesia. Indicators of proof of concept were: rate of complications, rate of cerebral desaturation, relationship between cerebral desaturation and complications, and anaesthetist response to cerebral desaturation. Forty patients were recruited and randomised to a control group (n=20) or an intervention group (n=20). The proportion of the study population who had a complication was 40% (95% confidence interval [CI] 26% to 55%). Cerebral desaturation (<75% of baseline) occurred in only two patients (5.0% (CI 1.4% to 16%)), one in each group, and neither of those patients recorded a complication. Changes to anaesthetic management on the basis of cerebral oximetry values occurred in only two patients in the intervention group (10% (CI 2.8% to 30%)). Maintenance of cerebral oximetry values appeared to be closer to baseline in the intervention group than in the control group but this difference was not significant (P=0.15). Our results indicated that complications occurred frequently in the study population but did not appear to be associated with cerebral desaturation events. These findings do not support a larger intervention study using the current study population. PMID- 24794470 TI - Monitoring temperature in children undergoing anaesthesia: a comparison of methods. AB - Children undergoing anaesthesia are prone to hypothermia. Perioperative monitoring of patient temperature is, therefore, standard practice. Postoperative temperature is regarded as a key anaesthetic performance indicator in Australian hospitals. Many different methods and sites of temperature measurement are used perioperatively. It is unclear to what degree these methods might be interchangeable. The aim of this study was to determine the relationships between temperatures measured at different sites in anaesthetised children. Two hundred children, 0 to 17 years, undergoing general anaesthesia for elective non-cardiac surgery, were prospectively recruited. Temperature measurements were taken in the operating theatre concurrently at the nasopharynx, tympanic membranes, temporal artery, axilla and skin (chest). Patient age and weight were documented. Temperatures varied according to site of measurement. The mean difference from nasopharyngeal temperature to temperatures at left and right tympanic, temporal, axillary and cutaneous sites were +0.24 degrees C, +0.24 degrees C, +0.35 degrees C, -0.38 degrees C and -1.70 degrees C, respectively. Levels of agreement to nasopharyngeal temperature were similar at tympanic, temporal and axillary sites. Tympanic and temporal temperatures were superior to axillary temperatures for detection of mild hypothermia (<36 degrees C). Skin temperature showed a large variation from nasopharyngeal measurements. Our findings indicate that measured temperatures vary between sites. Understanding these variations is important for interpreting temperature readings. PMID- 24794471 TI - Validation of the vascular pedicle width as a diagnostic aid in critically ill patients with pulmonary oedema by novice non-radiology physicians-in-training. AB - Assessing intravascular volume status in the critically ill patient remains a challenge for intensivists, and the accuracy of such estimation based on bedside examination alone is reported to be nearly a coin toss. In this retrospective study we sought to validate a previously recommended chest radiographic vascular pedicle width (VPW) >=70 mm for identifying cardiogenic pulmonary oedema (CPO). We additionally assessed whether novice physicians-in-training can reliably measure the VPW. The study included intensive care patients with an existing pulmonary artery catheter. Three independent raters performed measurements of VPW from chest radiographs obtained within three hours of pulmonary artery occlusion pressure measurements. In 80 patients enrolled, a VPW cut-off of >=70 mm had a 55% sensitivity, 88% specificity, 81% positive predictive value, 69% negative predictive value and 73% accuracy for identifying patients with CPO. Receiver operating characteristic curve analysis showed an area under the curve of 0.72 (95% confidence interval 0.61 to 0.84) for VPW in discriminating CPO from non cardiogenic pulmonary oedema. Kappa statistics for inter-rater reliability showed Kappa=0.41, 0.42 and 0.85 for each pair of the three raters. In conclusion, the previously accepted VPW cut-off of >=70 mm is reasonably accurate in discriminating CPO from non-cardiogenic pulmonary oedema. VPW can be measured by physicians-in-training with a comparable performance to previous studies utilising expert radiologists. PMID- 24794472 TI - A technique of placing cuffed endotracheal tubes through in situ paediatric laryngeal mask airways. AB - If tracheal intubation is not possible using direct laryngoscopy, one option is to use a laryngeal mask airway (LMA) through which an endotracheal tube (ETT) can be passed. In children, however, the size of an uncuffed ETT that can pass through the lumen of an LMA is sometimes too small for the trachea, resulting in gas leakage around the ETT. Using a cuffed ETT may reduce the gas leak but withdrawal of the LMA is then prevented by the pilot balloon. In this study, the largest sizes of cuffed and uncuffed MallinckrodtTM ETTs that could pass with ease through various sizes of paediatric ClassicTM and ProSealTM LMAs were documented. For cuffed ETTs, withdrawal of the LMA was made possible by simply cutting off the pilot balloon. The ETT cuff-inflating mechanism was then repaired by passing a 20 or 22 gauge cannula into the cut end of the inflating tubing. The proximal end of the cannula was then connected to a one-way valve or a three-way stopcock. This technique of cutting off the pilot balloon of the cuffed ETT made it possible to use paediatric cuffed ETTs in exchange for the LMAs tested. The task was easy to perform. Subsequent repair of the cuff-inflation tubing was effective and could withstand high pressures. These findings indicate that it is possible to pass cuffed ETTs through paediatric LMA lumens, which can provide ventilation without gas leaks, unlike uncuffed ETTs. PMID- 24794473 TI - Effect of magnetic resonance imaging on core body temperature in anaesthetised children. AB - Children undergoing magnetic resonance imaging (MRI) often require general anaesthesia (GA). Children under GA are at risk of decreases in body temperature. This risk may be greater during MRI due to MRI scanners requiring cool ambient temperatures. Conversely, radiofrequency radiation emitted by MRI scanners is absorbed by the patient as heat energy, creating a risk of an increase in body temperature. The aim of this study was to determine the proportion of anaesthetised children undergoing an MRI scan who develop hyperthermia or hypothermia, and the risk factors associated with temperature changes in these children. Pre-scan and post-scan tympanic temperatures were obtained from 193 children (aged three months to six years) undergoing an MRI procedure under GA. No active warming or cooling devices were used during the MRI scans. The median duration for anaesthesia was 42 minutes (35 to 57 minutes). Fifty-two percent of children were hypothermic after their scan, while no subjects were hyperthermic after their scan. The mean (+/- standard deviation) pre-scan temperature was 36.2 degrees C+/-0.5 degrees C, and the mean (+/- standard deviation) post-scan temperature was 35.9 degrees C+/-0.6 degrees C (an overall mean temperature decrease of 0.28 degrees C was observed [95% confidence interval, -0.36 degrees C to -0.19 degrees C], P <0.001). In conclusion, core body temperature was found to decrease slightly during an MRI scan under GA. These results suggest that more focus is needed regarding the cooling effects of GA agents during MRI, as opposed to the heating effects of the MRI scanner. PMID- 24794474 TI - Hybrid measurement to achieve satisfactory precision in perioperative cardiac output monitoring. AB - Advanced haemodynamic monitoring employing minimally invasive cardiac output measurement may lead to significant improvements in patient outcomes in major surgery. However, the precision (scatter) of measurement of available generic technologies has been shown to be unsatisfactory with percentage error of agreement with bolus thermodilution (% error) of 40% to 50%. Simultaneous measurement and averaging by two or more technologies may reduce random measurement scatter and improve precision. This concept, called the hybrid method, was tested by comparing accuracy and precision of measurement relative to bolus thermodilution using combinations of three component methods. Thirty patients scheduled for either elective cardiac surgery or liver transplantation were studied. Agreement with simultaneous bolus thermodilution of hybrid combinations of continuous thermodilution (QtCCO) or VigeleoTM/FloTracTM pulse contour measurement (QtFT) with pulmonary Capnotracking (QtCO2) was assessed pre- and post-cardiopulmonary bypass or pre- and post-reperfusion of the donor liver and compared with that of the component methods alone. Hybridisation of QtCO2 (% error 42.2) and QtCCO (% error 51.3) achieved significantly better precision (% error 31.3) than the component methods (P=0.0004) and (P=0.0195). Due to poor inherent precision of QtFT (% error 82.8), hybrid combination of QtFT with QtCO2 did not result in better precision than QtCO2 alone. Hybrid measurement can approach a 30% error, which is recommended as the upper limit for acceptability. This is a practical option where at least one component method, such as Capnotracking, is automated and does not increase the cost or complexity of the measurement process. PMID- 24794475 TI - Effect of statins on insulin requirements during non-cardiac surgery. AB - Statins are thought to potentially impair glucose metabolism, increasing plasma glucose concentration. The effect of prolonged statin use on glucose metabolism among outpatients is thus well established. However, the impact of statin use on glucose concentrations and insulin requirements during surgery remains poorly characterised and may very well differ considering the substantial hyperglycaemic stress response to surgery. We conducted a study to test the hypothesis that patients taking statins preoperatively require more intraoperative insulin than non-users. We analysed 173 adults having major non-cardiac surgery who participated in the Dexamethasone, Light Anaesthesia and Tight Glucose Control Trial between 2007 and 2010. We compared statin and non-statin users on total amount of intraoperative insulin to maintain plasma glucose concentration within 4.4 to 6.1 mmol/l using the inverse propensity score weighting method. Sixty seven patients were statin users and 106 were non-statin users. The estimated ratio of geometric means between the statin users and the non-users was 1.45 (95% confidence interval: 0.93, 2.26, statin versus non-statin, P=0.11). The total amount of intraoperative insulin usage did not differ significantly among patients taking different types of statins (P=0.50). While the total amount of intraoperative insulin used was not statistically different between the statin users and non-users, we observed a potentially important trend toward insulin resistance intraoperatively among statin users during major non-cardiac surgery. This result is consistent with non-operative settings and cardiac surgery. Further investigation is essential to determine whether this effect is real and, if so, determine which specific statins are more associated with insulin resistance. PMID- 24794476 TI - Long-term outcomes of minor troponin elevations in the intensive care unit. AB - The aim of our study is to determine the short-term and long-term outcomes of intensive care unit (ICU) patients with minor troponin elevations. The retrospective study compared ICU patients with peak troponin elevation less than 0.1 ng/ml to those with only negative tests during their hospital stay. Data were gathered from ICUs at Beth Israel Deaconess Medical Center between 2001 and 2008. A total of 4224 patients (2547 controls and 1677 positives) were analysed. The primary outcome was mortality at one year. Secondary outcomes were 30-day mortality and hospital and ICU lengths of stay. After adjusting for age, sex, Simplified Acute Physiology Score, Sequential Organ Failure Assessment and combined Elixhauser score, we found that minor troponin elevations (peak troponin elevation between 0.01 and 0.09 ng/ml) were associated with a higher one-year mortality (Hazard Ratio 1.22, P <0.001 for binary troponin presence; Hazard Ratio 1.03, P <0.001 for each 0.01 ng/ml troponin increment). This relationship held for the subgroup of seven-day post-discharge survivors (Hazard Ratio 1.26, P <0.001). Minor elevations of troponin also significantly increased the net reclassification index over traditional risk markers for mortality prediction (net reclassification score 0.12, P <0.001). Minor troponin elevation was also associated with 30-day mortality (odds ratio 1.33, P=0.003). Importantly, troponin testing did not increase the adjusted mortality odds (P=0.9). Minor elevations in troponin substantially increase one-year, all-cause mortality in a stepwise fashion; it was also independently associated with 30-day mortality. We propose that minor elevations in troponin should not be regarded as clinically unimportant, but rather be included as a prognostic element if measured. We recommend prospective ICU studies to assess prognostic value of routine troponin determination. PMID- 24794477 TI - Comparison of the effect of propofol and sevoflurane anaesthesia on acute and chronic postoperative pain after hysterectomy. AB - There is some evidence that propofol may reduce acute postoperative pain; however, the results are inconsistent. Furthermore, there is a paucity of information about the type of anaesthesia and chronic pain. This study was designed to evaluate the hypothesis that propofol reduces acute and chronic postoperative pain compared with sevoflurane. In a randomised, prospective, double-blind trial, we assigned 80 patients having open total abdominal hysterectomy surgery to anaesthesia with either sevoflurane or propofol. Anaesthesia was titrated to clinical needs and bispectral index values to between 40 and 60. Postoperative pain was managed with pethidine and diclofenac. Acute postoperative pain for 24 hours and chronic postoperative pain at one and three months after surgery were evaluated. The Hospital Anxiety and Depression Scale was used to evaluate patient anxiety and depression after one and three months. There were no significant differences between the groups for opioid consumption or opioid-induced side-effects. Pain scores in the first four hours were significantly higher in the sevoflurane group. Persistent surgical pain was observed less frequently (7 out of 40 patients in the propofol group and 21 out of 40 in the sevoflurane group at three months post-surgery, P <0.01) and pain scores were lower at one and three months in the propofol group (0.78+/-0.55 versus 2.23+/-0.73 for the sevoflurane group at three months post-surgery, P <0.01). Anxiety and depression scores were significantly lower in the propofol group at three months. In this study, general anaesthesia with propofol was associated with reduced early acute postoperative and persistent pain, compared to sevoflurane-based anaesthesia, among patients undergoing open abdominal hysterectomy. PMID- 24794478 TI - Low-cost high-fidelity anaesthetic simulation. AB - Simulation has been advocated as a useful training tool, and specific manikin simulators have been developed for use in this role. Debriefing and repetition have been identified as key to achieving educational goals and, while the technical features of manikin simulators can influence simulation outcomes, their cost and infrastructure requirements reduce their suitability for smaller healthcare facilities. We describe a local solution using biomedical calibration machines and modified basic manikins already available in our institution to form a high-fidelity anaesthetic simulator at minimal cost. This was effective in running high-fidelity, team-based in situ simulations and 'can't intubate, can't oxygenate' assessments for anaesthetic trainees. Though equipment in other centres may differ both in availability or suitability for simulation, the option we describe or similar may offer a low-cost solution for peripheral centres to run limited high-fidelity scenarios on a regular basis. PMID- 24794479 TI - Comparison of electromyography and kinemyography during recovery from non depolarising neuromuscular blockade. AB - In this study, two commercially available quantitative neuromuscular function monitoring techniques, electromyography (EMG) and kinemyography (KMG), were compared with respect to repeatability and accuracy during late recovery from neuromuscular blockade. Train-of-four (TOF) ratios were recorded in 30 patients using KMG and EMG at the adductor pollicis muscle. Measurements were taken on the same hand using the Datex-Ohmeda NeuroMuscular Transmission monitor (GE Healthcare, Helsinki, Finland). Instrumental precision was evaluated using the coefficient of repeatability, while accuracy was assessed using the bias and limits of agreement. The coefficients of repeatability were similar for both techniques (0.035 for KMG and 0.043 for EMG), indicating a similar level of precision. KMG overestimated the TOF ratios measured with EMG with a bias of 0.11 (95% limits of agreement: -0.13 to 0.35). At a TOF ratio of 0.90 the bias was 0.08 (95% limits of agreement: -0.08 to 0.25). This means that at a TOF ratio of 0.90 measured with KMG will be approximately equivalent to a TOF ratio of 0.80 measured with EMG at the adductor pollicis muscle, but it may indeed be as low as 0.65 or as high as 1.00. Therefore, TOF ratios measured by KMG and EMG cannot be used interchangeably. PMID- 24794480 TI - Platypnoea-orthodeoxia syndrome post laparoscopic surgery in a patient with a patent foramen ovale. AB - Platypnoea-orthodeoxia syndrome has the pathognomonic clinical findings of dyspnoea and arterial hypoxaemia relieved by recumbency. We report on a patient who presented with platypnoea-orthodeoxia syndrome post laparoscopic surgery. Platypnoea-orthodeoxia syndrome is an important diagnosis to consider when investigating hypoxia without an obvious cause. PMID- 24794481 TI - Severe bleeding after jugular central venous line insertion in a patient under rivaroxaban. PMID- 24794482 TI - A misdiagnosed case of symptomatic hyponatraemia. PMID- 24794483 TI - Serum metalloproteinases 2 and 9 as predictors of mortality in patients with septic shock. PMID- 24794484 TI - Fulminant hepatitis and multisystem organ failure following yellow fever vaccination: description of a fatal case. PMID- 24794485 TI - A simple remedy to help suppress coughing during cataract surgery under local anaesthesia. PMID- 24794486 TI - Tracheal mucosal flap: a look in time can prevent it climb! PMID- 24794487 TI - Reply to the letter "Mean platelet volume as a surrogate marker of inflammation in systemic lupus erythematosus". PMID- 24794488 TI - Survival rates and risk factors for mortality in systemic lupus erythematosus patients in a Chinese center. AB - This paper aims to study the survival and risk factors affecting the long-term prognosis of Chinese patients with systemic lupus erythematosus (SLE). We collected clinical data of 1,072 SLE patients at the time of diagnosis. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazard regression model for the risk factors affecting prognosis. Of the original 1,072 recruited SLE patients, 665 (570 females and 95 males) were successfully followed up. Mean follow-up was 5.47 +/- 4.62 years. Mean age of onset was 29.4 +/- 13.4 years. Eighty-one patients did not survive during follow up; infection, followed by cardiovascular disease, renal failure and SLE disease activity were the leading causes of death. The 5- and 10-year survival rates were 91.2 and 79.6 %, respectively. Moreover, the 5-year survival rates of female and male patients were 92.6 and 81.6 % respectively, and the 10-year survival rates were 80.8 and 62.3 %, respectively. Univariate analyses indicated that male gender, older age of onset, hypertension, increased blood creatinine levels, and high-density lipoprotein cholesterol at the time of diagnosis of SLE were risk factors for all-cause mortality. After adjusting for potential confounders by multivariate analysis, male gender, older age of onset, and high SLEDAI scores at the time of diagnosis were independent risk factors for all-cause mortality in SLE patients. The long-term survival of Chinese SLE patients is comparable to that of other countries. Older age of onset, high disease activity, and decline in renal function are independent risk factors for mortality in patients with SLE. PMID- 24794489 TI - Hypophosphatemic osteomalacia induced by tenofovir in HIV-infected patients. AB - Tenofovir disoproxil fumarate (TDF) is an adenine analogue reverse transcription inhibitor widely used in first-line treatment of human immunodeficiency virus (HIV) infection and also in hepatitis B virus infection. Its use has been linked to sporadic Fanconi syndrome, renal failure and bone disease. We present the clinical characteristics of tenofovir-induced osteomalacia, discuss bone biopsy findings, describe predisposing factors and compare our results with other reported cases. We describe five cases of hypophosphatemic osteomalacia induced by TDF and recorded at the rheumatology service of a university hospital between 2010 and 2014. We also report the characteristics of bone biopsies of this pathology, which have not been previously described. We include a review of published cases of proximal renal tubulopathy (PRT) and osteomalacia induced by TDF (PubMed 1995-2014; keywords: osteomalacia, tenofovir, Fanconi syndrome, hypophosphatemic osteomalacia, proximal renal tubulopathy, bone biopsy). Five HIV patients who developed hypophosphatemic osteomalacia under TDF treatment (>5 years) presented increasing bone pain and a progressive inability to walk without assistance as a result of multiple insufficiency fractures. Bone biopsy performed in three patients after tetracycline labelling showed increased osteoid thickness, confirming osteomalacia. A literature review retrieved 17 publications on this condition, including 53 cases: 26 patients developed isolated PRT, 25 presented PRT and with multiple insufficiency fractures and two presented isolated bone disease, including osteomalacia and osteoporosis. Rheumatologists should be alert to this complication in patients receiving tenofovir. The main complaint reported by these patients is diffuse pain, predominantly in the lower limbs, indicating multiple stress fractures. Serum phosphate and appropriate screening for abnormal proximal tubule function should be monitored. Bone scintigraphy should be carried out in cases of limb pain before the occurrence of more severe complications. PMID- 24794490 TI - Tailored approach to early psoriatic arthritis patients: clinical and ultrasonographic predictors for structural joint damage. AB - This study aims to identify the clinical predictors of arthritis in patients with psoriasis and to evaluate the use of musculoskeletal ultrasonography (US) as a predictor for inflammatory structural progression in psoriatic patients. Measures of association (odds ratio (OR)) were tested, in a prospective, cohort 1-year follow-up study, between structural deterioration and the presence of baseline inflammation, or its persistence. One hundred twenty-six psoriatic patients were prospectively evaluated both clinically and by US at 0, 6, and 12 months for synovitis/ joint damage, enthesitis, and onychopathy. X-ray was performed at 0 and 12 months. One hundred twelve sex and age-matched pasoriatic patients without histories of musculoskeletal symptoms were included as control group. Structural deterioration was observed in 47% of the 5,292 evaluated joints. Clinical variables associated with arthritis risk: BMI > 25 (OR = 1.7), body surface area (OR = 1.13), family history (OR = 5.72) and nail involvement (OR = 2.25). BMI > 30 was significantly correlated (P < 0.01) with shorter time for the onset of arthritis. Baseline synovial score/PD score >= 2 was associated with increased risk of structural progression: OR = 1.98 versus 2.61 versus 2.66 (P < 0.001) for the clinical versus US-gray scale (GS) versus US-power Doppler (PD) evaluation, respectively. An increased probability for structural progression in the presence of enthesitis was observed (OR = 2.79 and 3.50) for both US-GS and US-PD, whereas OR was 2.46 for clinical examination. Onychopathy was associated with structural joint damage (OR = 2.30). In multivariate logistic regression analysis, persistent of synovitis/enthesitis at 6 months of therapy was predictive of subsequent structural progression. Family history of psoriatic arthritis, large BMI (>25), high percentage of psoriatic body surface area, and nail involvement were significantly associated with early onset psoriatic arthritis. Baseline GS score of >=2, PD score of >=2, presence of enthesitis, enhanced vascularity at enthesitis, higher GUESS score, and onychopathy, all at base line as well as persistent synovitis and enthesitis at 6 months are predictors of progressive early psoriatic arthritis. Regular ultrasonographic monitoring of these patients is mandatory to assess the progression of their arthritis status. PMID- 24794491 TI - Cyclophosphamide and methotrexate in Susac's Syndrome: a successful sequential therapy in a case with involvement of the cerebellum. AB - Susac's Syndrome (SS) is a rare disease with unknown aetiology due to a microangiopathy affecting the precapillary arterioles of the brain, retina, cochlea and semicircular canals. Neurological manifestations, visual dysfunction and hearing loss represent the classical clinical triad of SS. Diagnosis is confirmed by laboratory investigations, neuroimaging findings, fluoroangiography and inner-ear studies. An early treatment with steroids and immunosuppressors limits the sequelae of disease. We report a case of SS in which the clinical triad occurred in a very short period of time. Brain MRI showed the involvement of cerebellum, this representing a rare neuroradiological finding in SS. A full remission of disease was obtained by using corticosteroids and cyclophosphamide in the acute-subacute phase and methotrexate as maintenance therapy. This latter has never been used before in SS. PMID- 24794492 TI - Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. AB - The aim of this study was to explore whether the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) play a role in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). MEDLINE and EMBASE database searches and subsequent manual searches were utilized to identify articles in which C677T and A1298C MTHFR polymorphisms were evaluated in RA patients taking MTX. A meta analysis was conducted to identify associations between MTHFR polymorphisms and MTX toxicity. Twelve studies comprising a total of 2,288 RA patients were included in our meta-analysis. Meta-analysis revealed an association between the overall toxicity of MTX and the MTHFR 677TT genotype (odds ratio [OR] = 1.615, 95 % confidence interval [CI] = 1.185-2.200, p = 0.002). Stratification by ethnicity indicated an association between the MTHFR 677TT genotype and the overall toxicity of MTX in East Asians (OR = 1.583, 95 % CI = 1.075-2.331, p = 0.020). The toxicity of MTX also was found to be associated with the TT genotype in patients taking folate (OR = 1.893, 95 % CI = 1.283-2.793, p = 0.001). Stratification by toxicity type indicated an association between the MTHFR 677TT genotype and any adverse effects (OR = 1.716, 95 % CI = 1.127-2.612, p = 0.012). Meta-analysis stratified by toxicity type indicated an association between the MTHFR 1298CC genotype and any adverse effects (OR = 0.501, 95 % CI = 0.284-0.886, p = 0.017). The results of our meta-analysis suggest that the MTHFR C677T and A1298C polymorphisms are associated with MTX toxicity in RA patients. PMID- 24794493 TI - The value of FDG-PET in the diagnosis of thromboangiitis obliterans--a case series. AB - Thromboangiitis obliterans (TAO) is an inflammatory vascular disease affecting dominantly the vessels of the extremities and is etiologically strongly associated with tobacco consumption. Different imaging techniques are generally used to exclude potential differential diagnoses. We investigated the value of (18) F-flourodeoxyglucose positron emission tomography ([(18) F]FDG-PET) in the diagnosis of TAO. All consecutive patients with diagnosed TAO between Nov 2001 and Nov 2003 at our institution who underwent [(18) F]FDG-PET in the diagnostic workup were analyzed retrospectively. Whole-body scans were conducted after a fasting period of at least 6 h and blood glucose levels lower than 180 mg/dl. The primary endpoint was defined as significantly increased vascular FDG uptake. Tracer uptake was visually determined and, in accordance with strength, divided into grades 0 to 3. In total, ten patients were statistically evaluated. The median patient age at the date of the first [(18) F]FDG-PET was 41.5 years. Repetitive FDG-PET imaging was performed in seven out of ten patients (70 %). The endpoint was objectified in one of the initial examinations (10 %) and in another one out of seven follow-up scans (14.3 %). One positive [(18) F]FDG-PET was observed in the pelvic vessels and the other in the infrapopliteal arteries. Therefore, increased tracer uptake could be observed in two examinations on two different patients (both with grade 3 tracer uptake) out of 17 conducted [(18) F]FDG-PETs in total. The [(18) F]FDG-PET was not a suitable investigative procedure for the diagnosis of TAO in the present patient cohort. PMID- 24794494 TI - The conserved transmembrane proteoglycan Perdido/Kon-tiki is essential for myofibrillogenesis and sarcomeric structure in Drosophila. AB - Muscle differentiation requires the assembly of high-order structures called myofibrils, composed of sarcomeres. Even though the molecular organization of sarcomeres is well known, the mechanisms underlying myofibrillogenesis are poorly understood. It has been proposed that integrin-dependent adhesion nucleates myofibrils at the periphery of the muscle cell to sustain sarcomere assembly. Here, we report a role for the gene perdido (perd, also known as kon-tiki, a transmembrane chondroitin proteoglycan) in myofibrillogenesis. Expression of perd RNAi in muscles, prior to adult myogenesis, can induce misorientation and detachment of Drosophila adult abdominal muscles. In comparison to controls, perd depleted muscles contain fewer myofibrils, which are localized at the cell periphery. These myofibrils are detached from each other and display a defective sarcomeric structure. Our results demonstrate that the extracellular matrix receptor Perd has a specific role in the assembly of myofibrils and in sarcomeric organization. We suggest that Perd acts downstream or in parallel to integrins to enable the connection of nascent myofibrils to the Z-bands. Our work identifies the Drosophila adult abdominal muscles as a model to investigate in vivo the mechanisms behind myofibrillogenesis. PMID- 24794495 TI - Mice deficient for the epidermal dermokine beta and gamma isoforms display transient cornification defects. AB - Expression of the human dermokine gene (DMKN) leads to the production of four dermokine isoform families. The secreted alpha, beta and gamma isoforms have an epidermis-restricted expression pattern, with Dmkn beta and gamma being specifically expressed by the granular keratinocytes. The delta isoforms are intracellular and ubiquitous. Here, we performed an in-depth characterization of Dmkn expression in mouse skin and found an expression pattern that was less complex than in humans. In particular, mRNA coding for the delta family were absent. Homozygous mice null for the Dmkn beta and gamma isoforms had no obvious phenotype but only a temporary scaly skin during the first week of life. The pups null for the Dmkn beta and gamma isoforms had smaller keratohyalin granules and their cornified envelopes were more sensitive to mechanical stress. At the molecular level, amounts of profilaggrin and filaggrin monomers were reduced whereas amino acid components of the natural moisturizing factor were increased. In addition, the electrophoretic mobility of involucrin was modified, suggesting post-translational modifications. Finally, the mice null for the Dmkn beta and gamma isoforms strongly overexpressed Dmkn alpha. These data are evocative of compensatory mechanisms relevant to the temporary phenotype. Overall, we improved the knowledge of Dmkn expression in mouse and highlighted a role for Dmkn beta and gamma in cornification. PMID- 24794496 TI - Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia. AB - Defects in SLX4, a scaffold for DNA repair nucleases, result in Fanconi anemia (FA), due to the defective repair of inter-strand DNA crosslinks (ICLs). Some FA patients have an SLX4 deletion removing two tandem UBZ4-type ubiquitin-binding domains that are implicated in protein recruitment to sites of DNA damage. Here, we show that human SLX4 is recruited to sites of ICL induction but that the UBZ deleted form of SLX4 in cells from FA patients is not. SLX4 recruitment does not require either the ubiquitylation of FANCD2 or the E3 ligases RNF8, RAD18 and BRCA1. We show that the first (UBZ-1) but not the second UBZ domain of SLX4 binds to ubiquitin polymers, with a preference for K63-linked chains. Furthermore, UBZ 1 is required for SLX4 recruitment to ICL sites and for efficient ICL repair in murine fibroblasts. The SLX4 UBZ-2 domain does not bind to ubiquitin in vitro or contribute to ICL repair, but it is required for the resolution of Holliday junctions in vivo. These data shed light on SLX4 recruitment, and they point to the existence of currently unidentified ubiquitylated ligands and E3 ligases that are crucial for ICL repair. PMID- 24794497 TI - Second phalanx shortening osteotomy. An innovative technique for long second toe syndrome. AB - Long second-toe syndrome, although frequent and disabling, has been little described. Current surgical techniques often lead to loss of function. Based on anatomical and biomechanical observations, the present study reports a second phalanx shortening osteotomy technique. The procedure is relatively non-invasive, involving self-stabilizing segment resection osteotomy of the second phalanx. Results for the first 23 feet undergoing the procedure were analyzed retrospectively. Assessment comprised clinical examination, radiography and AOFAS and FAAM scores. Mean follow-up was 19+/-9.9 months. Second phalanx shortening osteotomy proved reliable, respecting the biomechanics of the toe. PMID- 24794498 TI - Medium-term osteolysis with the Wallaby I(r) deep-dished total knee prosthesis. AB - BACKGROUND: Highly congruent total knee prostheses were introduced in the 1990s in the hope of decreasing polyethylene wear, thereby minimising loosening and particle-induced peri-prosthetic osteolysis. Despite promising long-term outcomes, substantial rates of aseptic loosening were reported with conventional gamma-irradiated polyethylene inserts, suggesting that highly reticulated polyethylene should be used instead. We assessed medium-term outcomes of the Wallaby I(r) total knee prosthesis with a deep-dished tibial insert made of conventional gamma-irradiated polyethylene. HYPOTHESIS: We hypothesised that the deep-dished Wallaby I(r) prosthesis was associated with similar or lower rates of aseptic loosening and peri-prosthetic osteolysis compared to posterior-stabilised prostheses. MATERIALS AND METHODS: At our institution, 121 consecutive patients underwent total knee arthroplasty (TKA) with a deep-dished cemented prosthesis (Wallaby I(r), Sulzer/Centerpulse, Zurich, Switzerland) between 2001 and 2005. Among them, 89 had complete follow-up data over a 4-year period and a mean follow up of 96 months. We retrospectively analysed the clinical and radiographic IKS scores in these 89 patients. RESULTS: Osteolysis with aseptic loosening required revision TKA of 10 knees after a mean follow-up of 81 months. Mean 9-year prosthesis survival was 88+/-17%. Four inserts exhibited evidence of delamination. A fracture of the postero-medial aspect of the tibial baseplate beneath a zone of insert wear was found in 1 knee and gross mobility of the insert on the baseplate in 6 knees. The other 79 patients had good clinical and radiographic outcomes with a mean range of active knee flexion of 108+/-15 degrees . DISCUSSION: The medium-term outcomes in our study were inferior to those reported with posterior-stabilised tibial components. Sporadic variations in polyethylene quality may explain the cases of osteolysis (shelf oxidation). In addition, the increased shear stresses related to the deep-dish design may increase backside wear, thereby compromising insert fixation to the baseplate. We believe the Wallaby I(r) prosthesis should no longer be used, and we recommend computed tomography follow-up of patients harbouring this prosthesis. LEVEL OF EVIDENCE: Level IV (retrospective study). PMID- 24794499 TI - The posterior malleolar fracture: a parachute injury not to be overlooked. AB - INTRODUCTION: Isolated posterior tibial malleolar fracture, which concerns parachutists in particular, is rare and often overlooked. The present study sought to identify clinical and paraclinical factors able to improve diagnosis and treatment. HYPOTHESIS: Marginal posterior malleolar fracture is under diagnosed due to lack of awareness and difficulty of diagnosis. Delayed diagnosis may impair functional prognosis. MATERIAL AND METHOD: A multicenter retrospective study included 12 cases of isolated marginal posterior malleolar fracture in military parachutists between 2006 and 2011. Clinical and paraclinical data were collected from medical files and a questionnaire administered in consultation or by telephone. RESULTS: Diagnosis was initially overlooked in 75% of cases due to non-specific clinical presentation and the low sensitivity of plain radiographs. Diagnostic delay impaired functional outcome. DISCUSSION: Symptomatology, other than medial retromalleolar pain, is misleading. The Ottawa Ankle Rules should not be used in this particular form of trauma. X-ray should include a lateral view in 50 degrees external rotation. CT provides a useful complement. Delayed diagnosis puts the patient at risk of impaired functional prognosis. LEVEL OF EVIDENCE: IV (retrospective study). PMID- 24794501 TI - TEMPORARY REMOVAL: Optimization of recombinant Pseudomonas putida proline dehydrogenase purification in aqueous two-phase systems using response surface methodology. AB - The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24794500 TI - High yield soluble bacterial expression and streamlined purification of recombinant human interferon alpha-2a. AB - Interferon alpha-2a (IFNA2) is a member of the Type I interferon cytokine family, known for its antiviral and anti-proliferative functions. The role of this family in the innate immune response makes it an attractive candidate for the treatment of many viral and chronic immune-compromised diseases. Recombinant IFNA2 is clinically used to modulate hairy cell leukemia as well as hepatitis c. Historically, IFNA2 has been purified from human leukocytes as well as bacterial expression systems. In most cases, bacterial expression of IFNA2 resulted in inclusion body formation, or required numerous purification steps that decreased the protein yield. Here, we describe an expression and purification scheme for IFNA2 using a pET-SUMO bacterial expression system and a single purification step. Using the SUMO protein as the fusion tag achieved high soluble protein expression. The SUMO tag was cleaved with the Ulp1 protease leaving no additional amino acids on the fusion terminus following cleavage. Mass spectrometry, circular dichroism, 2D heteronuclear NMR, and analytical ultracentrifugation confirmed the amino acid sequence identity, secondary and tertiary protein structures, and the solution behavior of the purified IFNA2. The purified protein also had antiviral and anti-proliferative activities comparable to the WHO International Standard, NIBSC 95/650, and the IFNA2 standard available from PBL Assay Science. Combining the expression and purification protocols developed here to produce IFNA2 on a laboratory scale with the commercial fermenter technology commonly used in pharmaceutical industry may further enhance IFNA2 yields, which will promote the development of interferon-based protein drugs to treat various disorders. PMID- 24794502 TI - The causal effect of family income on child health in the U.K. AB - Recent studies examining the effect of family income on child health have been unable to account for the endogeneity of income. Using data from a British cohort study, we address this gap by exploiting exogenous variation in local labour market characteristics to instrument for family income. We estimate the causal effect of family income on different measures of child health and explore the role of potential transmission mechanisms. We find that income has a very small but significant causal effect on subjective child health and no significant effect on chronic health conditions, apart from respiratory illnesses. Using the panel structure, we show that the timing of income does not matter for young children. Moreover, our results provide further evidence that parental health does not drive a spurious relationship between family income and child health. Our study implies that financial transfers are unlikely to deliver substantial improvements in child health. PMID- 24794503 TI - Levels of soluble TNF-RII are increased in serum of patients with primary progressive multiple sclerosis. AB - The levels of soluble tumor necrosis factor receptor II (sTNF-RII) were determined in serum of 161 untreated multiple sclerosis (MS) patients with different clinical forms and 46 healthy controls (HC) by ELISA. Our results show that serum sTNF-RII levels were significantly increased in patients with primary progressive MS (PPMS) compared with other MS forms and HC. Although sTNF-RII levels significantly increased over a 2-year follow-up period in a subgroup of PPMS patients, they could not discriminate between patients with and without disability progression. Additional studies are needed to further implicate sTNF RII in patients with PPMS. PMID- 24794504 TI - No association of IFI16 (interferon-inducible protein 16) variants with susceptibility to multiple sclerosis. AB - IFI16 encodes a nucleic acid-sensor which detects latent EBV and triggers inflammasome activation. We analysed IFI16 variants in two multiple sclerosis (MS) case-control cohorts from Italy and Spain; results were combined with a previous study. A risk variant for celiac disease/rheumatoid arthritis, a polymorphic exon 7 duplication, and a copy number variant (CNV) in the 5' region were genotyped. No significant association was detected, although heterogeneity was noted for the 5' CNV in the Italian plus GeneMSA cohorts and the Spanish sample. Thus, IFI16 variants do not contribute to MS susceptibility, although some heterogeneity may exist for the 5' CNV. PMID- 24794505 TI - Acoustic emission localization in beams based on time reversed dispersion. AB - The common approach for the localization of acoustic emission sources in beams requires at least two measurements at different positions on the structure. The acoustic emission event is then located by evaluating the difference of the arrival times of the elastic waves. Here a new method is introduced, which allows the detection and localization of multiple acoustic emission sources with only a single, one point, unidirectional measurement. The method makes use of the time reversal principle and the dispersive behavior of the flexural wave mode. Whereas time-of-arrival (TOA) methods struggle with the distortion of elastic waves due to phase dispersion, the method presented uses the dispersive behavior of guided waves to locate the origin of the acoustic emission event. Therefore, the localization algorithm depends solely on the measured wave form and not on arrival time estimation. The method combines an acoustic emission experiment with a numerical simulation, in which the measured and time reversed displacement history is set as the boundary condition. In this paper, the method is described in detail and the feasibility is experimentally demonstrated by breaking pencil leads on aluminum beams and pultruded carbon fiber reinforced plastic beams according to ASTM E976 (Hsu-Nielsen source). It will be shown, that acoustic emissions are successfully localized even on anisotropic structures and in the case of geometrical complexities such as notches, which lead to reflections, and cross sectional changes, which affect the wave speed. The overall relative error in localizing the acoustic emission sources was found to be below 5%. PMID- 24794506 TI - Ultrasonic monitoring of malolactic fermentation in red wines. AB - The progress of malolactic fermentation in red wines has been monitored by using ultrasonic techniques. The evolution of ultrasonic velocity of a tone burst 1MHz longitudinal wave was measured, analyzed and compared to those parameters of oenological interest obtained simultaneously by analytical methods. Semi industrial tanks were used during measurements pretending to be in real industrial conditions. Results showed that the ultrasonic velocity mainly changes as a result of the conversion by lactic acid bacteria of malic acid into lactic acid and CO2. Overall, the present study has demonstrated the potential of the ultrasonic technique in monitoring the malolactic fermentation process. PMID- 24794507 TI - Acoustical characterization of polysaccharide polymers tissue-mimicking materials. AB - Tissue-mimicking phantoms play a crucial role in medical ultrasound research because they can simulate biological soft tissues. In last years, many types of polymeric tissues have been proposed and characterized from an acoustical and a thermal point of view, but, rarely, a deep discussion about the quality of the measurements, in terms of the uncertainty evaluation, has been reported. In this work, considering the necessity to develop laboratory standards for the measurement of ultrasonic exposure and dose quantities, a detailed description of the experimental apparatuses for the sound speed and the attenuation coefficient measurements is given, focusing the attention on the uncertainty evaluation both of the results and analysis algorithms. In particular, this algorithm reveals a novel empirical relation, fixing a limit to the energy content (therefore limits the number of cycles) of the three parts in which the authors have proposed to divide the acoustical signal. Furthermore, the realisation of multi-components phantoms, Agar and Phytagel based tissue-mimicking gels along with others long chain molecules (dextrane or polyvinyl alcohol) and scattering materials (silicon carbide and kieselguhr) are investigated. This paper reports accurate speed of sound and attenuation coefficient measurements. Speed of sound is measured by a pulse-echo technique in far-field condition, using an optical glass buffer rod; while attenuation coefficient is determined by an insertion technique, using demineralized water as reference material. The experimental sound speed results are subjected to an overall estimated relative uncertainty of about 1.5% and the attenuation coefficient uncertainty is less than 2.5%. For the development of laboratory standards, a detailed analysis of the measurement uncertainty is fundamental to make sample properties comparable. The authors believe this study could represent the right direction to make phantoms characterizations referable and traceable. PMID- 24794508 TI - Effects of red blood cell aggregates dissociation on the estimation of ultrasound speckle image velocimetry. AB - Ultrasound speckle image of blood is mainly attributed by red blood cells (RBCs) which tend to form RBC aggregates. RBC aggregates are separated into individual cells when the shear force is over a certain value. The dissociation of RBC aggregates has an influence on the performance of ultrasound speckle image velocimetry (SIV) technique in which a cross-correlation algorithm is applied to the speckle images to get the velocity field information. The present study aims to investigate the effect of the dissociation of RBC aggregates on the estimation quality of SIV technique. Ultrasound B-mode images were captured from the porcine blood circulating in a mock-up flow loop with varying flow rate. To verify the measurement performance of SIV technique, the centerline velocity measured by the SIV technique was compared with that measured by Doppler spectrograms. The dissociation of RBC aggregates was estimated by using decorrelation of speckle patterns in which the subsequent window was shifted as much as the speckle displacement to compensate decorrelation caused by in-plane loss of speckle patterns. The decorrelation of speckles is considerably increased according to shear rate. Its variations are different along the radial direction. Because the dissociation of RBC aggregates changes ultrasound speckles, the estimation quality of SIV technique is significantly correlated with the decorrelation of speckles. This degradation of measurement quality may be improved by increasing the data acquisition rate. This study would be useful for simultaneous measurement of hemodynamic and hemorheological information of blood flows using only speckle images. PMID- 24794509 TI - A novel unsplit perfectly matched layer for the second-order acoustic wave equation. AB - When solving acoustic field equations by using numerical approximation technique, absorbing boundary conditions (ABCs) are widely used to truncate the simulation to a finite space. The perfectly matched layer (PML) technique has exhibited excellent absorbing efficiency as an ABC for the acoustic wave equation formulated as a first-order system. However, as the PML was originally designed for the first-order equation system, it cannot be applied to the second-order equation system directly. In this article, we aim to extend the unsplit PML to the second-order equation system. We developed an efficient unsplit implementation of PML for the second-order acoustic wave equation based on an auxiliary-differential-equation (ADE) scheme. The proposed method can benefit to the use of PML in simulations based on second-order equations. Compared with the existing PMLs, it has simpler implementation and requires less extra storage. Numerical results from finite-difference time-domain models are provided to illustrate the validity of the approach. PMID- 24794510 TI - MalarImDB: an open-access literature-based malaria immunology database. AB - The Malaria Immunology Database (MalarImDB, www.malarimdb.org) is a novel literature-based database of host mediators in blood-stage malaria. We designed this open-access online tool because intensive malaria research has resulted in a dazzling complexity of host mediators with pathogenic or protective functions. MalarImDB allows comparisons between expression levels in humans, expression levels in murine models, and functional data from experimental treatments in mice. The database is equipped with multiple search engines to retrieve information from many published studies. The search output is visualized schematically in tables, thereby revealing similarities and disparities. Thus, the primary aim of this database is to present a clear overview of the currently available data about malaria and to simplify literature searches. PMID- 24794511 TI - A quick and efficient method to generate mammalian stable cell lines based on a novel inducible alphavirus DNA/RNA layered system. AB - We report a new method to generate high-expressing mammalian cell lines in a quick and efficient way. For that purpose, we developed a master cell line (MCL) containing an inducible alphavirus vector expressing GFP integrated into the genome. In the MCL, recombinant RNA levels increased >4,600-fold after induction, due to a doxycycline-dependent RNA amplification loop. The MCL maintained inducibility and expression during 50 passages, being more efficient for protein expression than a conventional cell line. To generate new cell lines, mutant LoxP sites were inserted into the MCL, allowing transgene and selection gene exchange by Cre-directed recombination, leading to quick generation of inducible cell lines expressing proteins of therapeutic interest, like human cardiotrophin-1 and oncostatin-M at several mg/l/24 h. These proteins contained posttranslational modifications, showed bioactivity, and were efficiently purified. Remarkably, this system allowed production of toxic proteins, like oncostatin-M, since cells able to express it could be grown to the desired amount before induction. These cell lines were easily adapted to growth in suspension, making this methodology very attractive for therapeutic protein production. PMID- 24794512 TI - Interest of targeting either cortical area Brodmann 9 or 46 in rTMS treatment for depression: a preliminary randomized study. AB - OBJECTIVE: To assess the interest of specifically targeting Brodmann Areas (BA) 9 or 46 for rTMS treatment of depression. METHODS: Patients with Treatment Resistant Depression were randomly assigned to two treatment groups to receive either rTMS on BA 9 or on BA 46. Each patient underwent 10 sessions of 1Hz-rTMS for 2weeks. The Hamilton and Montgomery-Asberg Depression Rating Scales (HDRS, MADRS) were used under blind conditions to assess the therapeutic response (50% improvement). A Wilcoxon signed-rank test was used to compare the depression rating scales scores obtained before and after the 10 rTMS sessions for each of the two groups. The therapeutic results in the two groups were compared using the Mann-Whitney-Wilcoxon test. We also reported the effect sizes using Hedges's g. RESULTS: Fifteen patients were included. Stimulation of both BA 9 (n=7) and BA 46 (n=8) led to similar therapeutic responses in the two groups (with moderate effect size), such as the mean decrease in HDRS (BA 9: p=0.015; BA 46: p=0.010) and MADRS (BA 9: p=0.042; BA 46: p=0.038) scores. CONCLUSION: Our results do not come out in favor of one or the other BA. SIGNIFICANCE: Stimulation of BA 9 and BA 46 appears to be equally effective in the treatment of depression. PMID- 24794513 TI - Clinical classification and neuro-vestibular evaluation in chronic dizziness. AB - OBJECTIVE: This study attempts to clarify the clinical characteristics of chronic dizziness and its relationships with specific vestibular, oculomotor, autonomic and psychiatric dysfunctions. METHODS: 73 Patients with idiopathic chronic dizziness were recruited and classified based on history taking and clinical examination into the following four clinical subgroups; vestibular migraine (VM), dysautonomia, psychogenic, and unspecified groups. They were also evaluated using oculomotor, otolithic and autonomic function tests, and psychologic investigation. RESULTS: Patients in the VM group showed a high proportion of abnormality on smooth pursuit and otolithic function testing compared to the other groups. The dysautonomia group revealed significant abnormalities in sympathetic and cardiovagal autonomic function, while the psychogenic group had a high frequency of abnormality in sympathetic autonomic testing and in Beck's anxiety inventory scale. The unspecified group showed abnormalities on saccade, smooth pursuit and autonomic function testing. CONCLUSIONS: Clinical classification of patients with chronic dizziness was relevant and they showed a correlation with disease-specific abnormal results in oculomotor, otolithic, autonomic function and psychology testing. SIGNIFICANCE: Appropriate diagnostic investigation based on precise clinical diagnosis of chronic dizziness reduces the need for extensive laboratory testing, neuroimaging, and other low-yield tests. PMID- 24794514 TI - An automated and fast approach to detect single-trial visual evoked potentials with application to brain-computer interface. AB - OBJECTIVE: This study aims (1) to develop an automated and fast approach for detecting visual evoked potentials (VEPs) in single trials and (2) to apply the single-trial VEP detection approach in designing a real-time and high-performance brain-computer interface (BCI) system. METHODS: The single-trial VEP detection approach uses common spatial pattern (CSP) as a spatial filter and wavelet filtering (WF) a temporal-spectral filter to jointly enhance the signal-to-noise ratio (SNR) of single-trial VEPs. The performance of the joint spatial-temporal spectral filtering approach was assessed in a four-command VEP-based BCI system. RESULTS: The offline classification accuracy of the BCI system was significantly improved from 67.6+/-12.5% (raw data) to 97.3+/-2.1% (data filtered by CSP and WF). The proposed approach was successfully implemented in an online BCI system, where subjects could make 20 decisions in one minute with classification accuracy of 90%. CONCLUSIONS: The proposed single-trial detection approach is able to obtain robust and reliable VEP waveform in an automatic and fast way and it is applicable in VEP based online BCI systems. SIGNIFICANCE: This approach provides a real-time and automated solution for single-trial detection of evoked potentials or event-related potentials (EPs/ERPs) in various paradigms, which could benefit many applications such as BCI and intraoperative monitoring. PMID- 24794515 TI - Changes in corticospinal transmission following 8weeks of ankle joint immobilization. AB - OBJECTIVES: Joint immobilization has previously been shown to modulate corticospinal excitability. The present study investigated changes in the excitability of distinct fractions of the corticospinal pathway by means of conditioning the H-reflex with transcranial magnetic stimulation (TMS) of the primary motor cortex (Hcond). This method allows assessment of transmission in fast (monosynaptic) and slow(er) (polysynaptic) corticospinal pathways. METHODS: 9 subjects underwent 8weeks of unilateral ankle joint immobilization during daytime, 7 subjects served as controls. The measures obtained before and after immobilization included stretch- and H-reflexes assessing excitability of the spinal reflex circuitries, TMS recruitment curves estimating overall changes in corticospinal excitability, and Hcond. RESULTS: TMS recruitment curves showed an overall increase in corticospinal excitability following immobilization. Importantly, Hcond revealed significant facilitation of conditioned reflexes, but only for longer conditioning intervals, suggesting that immobilization increased excitability only of slower, indirect corticospinal pathways. No changes were observed in the control group. Immobilization had no significant effects on spinal reflex measures. CONCLUSIONS: 8weeks of ankle joint immobilization was accompanied by pathway-specific modulation of corticospinal transmission. SIGNIFICANCE: It is particularly interesting that fast corticospinal projections were unaffected as these are involved in controlling many, if not most, movements in humans. PMID- 24794516 TI - Differential effects of optic media opacities on simultaneous multifocal pattern electroretinograms and visual evoked potentials. AB - OBJECTIVE: To identify potential confounds in the comparison of simultaneously acquired multifocal electroretinograms (mfPERGs) and visual evoked potentials (mfVEPs) to pattern reversal stimulation. METHODS: With VERIS Science 5.1.10X monocular mfPERGs and mfVEPs were recorded simultaneously to optimised pattern reversal stimulation for a reference condition and two filter conditions, i.e. blur and 8% luminance transmission, in two separate experiments in participants with normal vision. The impact of the filter conditions on mfPERG amplitude (P50 and N95 peaks), mfVEP-magnitude (root-mean-squares and signal-to-noise-ratios), and on the response timing was assessed. RESULTS: Blur reduced mfPERG P50 and N95 amplitudes to 16%, 21%, and mfVEP magnitude to 82%. Decreasing stimulus luminance to 8% reduced only the mfPERG (P50 to 72% and N95 to 74%), but delayed both mfPERG and mfVEP responses by 5.3 and 4.6ms, respectively. CONCLUSIONS: Comparatively minor stimulus manipulations, mimicking optic media opacities, had a differential effect on mfPERGs and mfVEPs magnitudes. SIGNIFICANCE: Simultaneous mfPERG/mfVEP recordings are a promising approach to compare retinal and cortical function, but caution must be exerted in the interpretation of response differences due to incongruent response characteristics. PMID- 24794517 TI - Shutting down sensorimotor interference unblocks the networks for stimulus processing: an SMR neurofeedback training study. AB - OBJECTIVE: In the present study, we investigated how the electrical activity in the sensorimotor cortex contributes to improved cognitive processing capabilities and how SMR (sensorimotor rhythm, 12-15Hz) neurofeedback training modulates it. Previous evidence indicates that higher levels of SMR activity reduce sensorimotor interference and thereby promote cognitive processing. METHODS: Participants were randomly assigned to two groups, one experimental (N=10) group receiving SMR neurofeedback training, in which they learned to voluntarily increase SMR, and one control group (N=10) receiving sham feedback. Multiple cognitive functions and electrophysiological correlates of cognitive processing were assessed before and after 10 neurofeedback training sessions. RESULTS: The experimental group but not the control group showed linear increases in SMR power over training runs, which was associated with behavioural improvements in memory and attentional performance. Additionally, increasing SMR led to a more salient stimulus processing as indicated by increased N1 and P3 event-related potential amplitudes after the training as compared to the pre-test. Finally, functional brain connectivity between motor areas and visual processing areas was reduced after SMR training indicating reduced sensorimotor interference. CONCLUSIONS: These results indicate that SMR neurofeedback improves stimulus processing capabilities and consequently leads to improvements in cognitive performance. SIGNIFICANCE: The present findings contribute to a better understanding of the mechanisms underlying SMR neurofeedback training and cognitive processing and implicate that SMR neurofeedback might be an effective cognitive training tool. PMID- 24794518 TI - Homozygous deletion of six genes including corneodesmosin on chromosome 6p21.3 is associated with generalized peeling skin disease. AB - BACKGROUND: Peeling skin syndrome (PSS) is a rare autosomal recessive form of ichthyosis showing skin exfoliation. PSS is divided into acral and generalized PSS, and the latter is further classified into non-inflammatory type (PSS type A) and inflammatory type (PSS type B). PSS type B is now called peeling skin disease (PSD). Different loss-of-function mutations in the corneodesmosin (CDSN) gene have been reported to cause PSD. OBJECTIVE: The aim of this study was to determine genetic basis of disease in a 14-year-old Japanese patient with PSD. METHODS AND RESULTS: Immunohistochemical study showed lack of corneodesmosin (CDSN) in the skin, and standard PCR for genomic DNA failed to amplify CDSN product, suggesting CDSN defect. Multiplex ligation-dependent probe amplification and genomic quantitative real-time PCR analyses detected large homozygous deletion of 59,184bp extending from 40.6kb upstream to 13.2kb downstream of CDSN, which included 6 genes (TCF19, CCHCR1, PSORS1C2, PSORS1C1, CDSN and C6orf15). The continuous gene lost did not result in additional clinical features. Inverted repeats with 85% similarity flanking the deletion breakpoint were considered to mediate the deletion by non-homologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication. Parents were clinically unaffected and were heterozygote carriers of the same deletion, which was absent in 284 ethnically matched control alleles. We also developed simple PCR method, which is useful for detection of this deletion. CONCLUSION: Although 5 other genes were also deleted, homozygous deletion of CDSN was considered to be responsible for this PSD. PMID- 24794519 TI - Photoinhibition of germination in grass seed--implications for prairie revegetation. AB - Germination photoinhibition is not a recognized cause of revegetation failure; yet prolonged sunlight exposure can inhibit germination of several grass species. This research addressed susceptibility to photoinhibition of selected native grass species used to restore Canadian prairies, and reclamation treatments to alter environmental conditions in order to release seeds from photoinhibition. Under laboratory conditions effects of photoinhibition were tested on the ability of seeds to germinate at low water potential and effects of daily alternating temperatures and nitrates to break photoinhibition. Whether surficial mulch can release seeds from photoinhibition was assessed in a field experiment. Germination photoinhibition was evident in Festuca hallii and Koeleria macrantha seeds even under very low irradiances. The prolonged exposure to light decreased germination rates and ability of seeds to germinate at low water potentials. Daily fluctuating temperatures released a fraction of Bromus carinatus and Elymus trachycaulus seeds from photoinhibition yet did not improve F. hallii or K. macrantha germinability. Nitrates failed to break seed photoinhibition in all species tested. In the field experiment, mulched F. hallii seeds (covered with an erosion control blanket) showed a tenfold increase in germination percentages relative to seeds exposed to direct sunlight, indicating the facilitative effects of mulching on attenuation of the light environment. We conclude that germination photoinhibition as a cause of emergence failures in land reclamation where seed is broadcast or shallow seeded should be recognized and germination photoinhibition included in the decision making process to select revegetation seeding techniques. PMID- 24794520 TI - Perchlorate reduction by hydrogen autotrophic bacteria in a bioelectrochemical reactor. AB - The autotrophic hydrogen reduction of perchlorate was investigated in batch modes in a proton-exchange membrane bioelectrochemical reactor. The phylogenic characterization of hydrogen-autotrophic perchlorate-reducing cultures in the cathode cell mainly included the genera Aureibacter tunicatorum, Fulvivirga kasyanovii, Thermotalea metallivorans (T), bacterium WHC2-6, and Thauera sp. Q20 C. The suitable H2SO4 supplement concentration was identified to be between 0.04 and 0.05 mol L(-1) in the anode cell. The perchlorate reduction was affected by the sludge concentration in the cathode cell, current intensity, and initial perchlorate concentration. The removal efficiency of perchlorate positively correlated with the current intensity, and the current intensity of 20, 40, 50, and 60 mA corresponded to removal efficiencies of 95.03, 96.29, 97.56 and 98.99%, respectively. When the current intensity was sufficient for hydrogen production, the kinetics of the perchlorate reduction conformed to a zero-order kinetics model, and the maximum specific substrate utilization rates for perchlorate (Vmax) ranged from 5.52 to 14.34 mg ClO4(-) g(-1) volatile suspended solid (VSS) h(-1). PMID- 24794521 TI - Effects of inoculum source and co-digestion strategies on anaerobic digestion of residues generated in the treatment of waste vegetable oils. AB - This work aims at selecting a suitable strategy to improve the performance of the anaerobic digestion of residues generated in the treatment of waste vegetable oils (WVO). Biochemical methane potential (BMP) assays were conducted at 35 degrees C to evaluate the effects of substrate mix ratio between a mixture of WVO residues (M) and pig manure (PM) co-digesting by using different inocula. Inoculum from an industrial digester fed with organic waste from hotels, restaurants and catering leftovers (HORECA) showed higher methanogenic activity (55.5 mLCH4 gVS(-1) d(-1)) than municipal wastewater treatment plant (mWWTP) inoculum (42.6 mL CH4 gVS(-1) d(-1)). Furthermore, the results showed that the resistance to WVO residues toxicity was higher for the HORECA sludge than for the mWWTP sludge. HORECA inoculum produced more biogas in all the assays. Moreover, the resulting biogas was of better quality, containing an average of 71.1% (SD = 1.6) methane compared to an average of 69.5% (SD = 1.2) methane for test with mWWTP sludge. The maximum degradation rate occurred at the higher PM mix ratio (M/PM:1/3), reaching 26.7 +/- 4.3 mLCH4 gVS(-1) d(-1) for mWWTP inoculum, versus 42.0 +/- 1,5 mLCH4 gVS(-1) d(-1) achieved for HORECA inoculum. A high reduction of volatile solids (between 70% and 81%) was obtained with both inocula at all M/PM ratios assayed (1/0, 1/3, 1/1 and 3/1 v/v) but, bearing in mind the operation of a full-scale anaerobic plant, the optimal scenario assayed corresponds to the ratio M/PM: 1/3 v/v where shorter lag periods will make it possible to operate at lower hydraulic retention times. PMID- 24794522 TI - Porto-caval shunt or Abernethy malformation. PMID- 24794523 TI - How to establish a bioinformatics postgraduate degree programme--a case study from South Africa. AB - The Research Unit in Bioinformatics at Rhodes University (RUBi), South Africa, offers a Masters of Science in Bioinformatics. Growing demand for bioinformatics qualifications results in applications from across Africa. Courses aim to bridge gaps in the diverse backgrounds of students who range from biologists with no prior computing exposure to computer scientists with no biology background. The programme is evenly split between coursework and research, with diverse modules from a range of departments covering mathematics, statistics, computer science and biology, with emphasis on application to bioinformatics research. The early focus on research helps bring students up to speed with working as a researcher. We measure success of the programme by the high rate of subsequent entry to PhD study: 10 of 14 students who completed in the years 2011-2013. PMID- 24794524 TI - Approaching human language with complex networks. AB - The interest in modeling and analyzing human language with complex networks is on the rise in recent years and a considerable body of research in this area has already been accumulated. We survey three major lines of linguistic research from the complex network approach: 1) characterization of human language as a multi level system with complex network analysis; 2) linguistic typological research with the application of linguistic networks and their quantitative measures; and 3) relationships between the system-level complexity of human language (determined by the topology of linguistic networks) and microscopic linguistic (e.g., syntactic) features (as the traditional concern of linguistics). We show that the models and quantitative tools of complex networks, when exploited properly, can constitute an operational methodology for linguistic inquiry, which contributes to the understanding of human language and the development of linguistics. We conclude our review with suggestions for future linguistic research from the complex network approach: 1) relationships between the system level complexity of human language and microscopic linguistic features; 2) expansion of research scope from the global properties to other levels of granularity of linguistic networks; and 3) combination of linguistic network analysis with other quantitative studies of language (such as quantitative linguistics). PMID- 24794526 TI - Dark matter. AB - The evidence for the dark matter (DM) of the hot big bang cosmology is about as good as it gets in natural science. The exploration of its nature is now led by direct and indirect detection experiments, to be complemented by advances in the full range of cosmological tests, including judicious consideration of the rich phenomenology of galaxies. The results may confirm ideas about DM already under discussion. If we are lucky, we also will be surprised once again. PMID- 24794525 TI - Synthesis and anti-influenza virus activity of 4-oxo- or thioxo-4,5 dihydrofuro[3,4-c]pyridin-3(1H)-ones. AB - A target-free approach was applied to discover anti-influenza viral compounds, where influenza infected Madin-Darby canine kidney cells were treated 7500 different small organic chemicals individually and reduction of virus-induced cytopathic effect was measured. One of the hit compounds was (Z)-1-((5-fluoro-1H indol-3-yl)methylene)-6-methyl-4-thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-one (15a) with half-maximal effective concentrations of 17.4-21.1MUM against influenza A/H1N1, A/H3N2 and B viruses without any cellular toxicity at 900MUM. To investigate the structure-activity relationships, two dozens of the hit analogs were synthesized. Among them, 15g, 15j, 15q, 15s, 15t and 15x had anti influenza viral activity comparable or superior to that of the initial hit. The anti-influenza viral compounds efficiently suppressed not only viral protein level of the infected cells but also production of viral progeny in the culture supernatants in a dose-dependent manner. Based on a mode-of-action study, they did not affect virus entry or RNA replication. Instead, they suppressed viral neuraminidase activity. This study is the first to demonstrate that dihydrofuropyridinones could serve as lead compounds for the discovery of alternative influenza virus inhibitors. PMID- 24794527 TI - Plastidial transporters KEA1, -2, and -3 are essential for chloroplast osmoregulation, integrity, and pH regulation in Arabidopsis. AB - Multiple K(+) transporters and channels and the corresponding mutants have been described and studied in the plasma membrane and organelle membranes of plant cells. However, knowledge about the molecular identity of chloroplast K(+) transporters is limited. Potassium transport and a well-balanced K(+) homeostasis were suggested to play important roles in chloroplast function. Because no loss of-function mutants have been identified, the importance of K(+) transporters for chloroplast function and photosynthesis remains to be determined. Here, we report single and higher-order loss-of-function mutants in members of the cation/proton antiporters-2 antiporter superfamily KEA1, KEA2, and KEA3. KEA1 and KEA2 proteins are targeted to the inner envelope membrane of chloroplasts, whereas KEA3 is targeted to the thylakoid membrane. Higher-order but not single mutants showed increasingly impaired photosynthesis along with pale green leaves and severely stunted growth. The pH component of the proton motive force across the thylakoid membrane was significantly decreased in the kea1kea2 mutants, but increased in the kea3 mutant, indicating an altered chloroplast pH homeostasis. Electron microscopy of kea1kea2 leaf cells revealed dramatically swollen chloroplasts with disrupted envelope membranes and reduced thylakoid membrane density. Unexpectedly, exogenous NaCl application reversed the observed phenotypes. Furthermore, the kea1kea2 background enables genetic analyses of the functional significance of other chloroplast transporters as exemplified here in kea1kea2Na(+)/H(+) antiporter1 (nhd1) triple mutants. Taken together, the presented data demonstrate a fundamental role of inner envelope KEA1 and KEA2 and thylakoid KEA3 transporters in chloroplast osmoregulation, integrity, and ion and pH homeostasis. PMID- 24794529 TI - Flight-crash events in turbulence. AB - The statistical properties of turbulence differ in an essential way from those of systems in or near thermal equilibrium because of the flux of energy between vastly different scales at which energy is supplied and at which it is dissipated. We elucidate this difference by studying experimentally and numerically the fluctuations of the energy of a small fluid particle moving in a turbulent fluid. We demonstrate how the fundamental property of detailed balance is broken, so that the probabilities of forward and backward transitions are not equal for turbulence. In physical terms, we found that in a large set of flow configurations, fluid elements decelerate faster than accelerate, a feature known all too well from driving in dense traffic. The statistical signature of rare "flight-crash" events, associated with fast particle deceleration, provides a way to quantify irreversibility in a turbulent flow. Namely, we find that the third moment of the power fluctuations along a trajectory, nondimensionalized by the energy flux, displays a remarkable power law as a function of the Reynolds number, both in two and in three spatial dimensions. This establishes a relation between the irreversibility of the system and the range of active scales. We speculate that the breakdown of the detailed balance characterized here is a general feature of other systems very far from equilibrium, displaying a wide range of spatial scales. PMID- 24794528 TI - Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. AB - GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia. PMID- 24794530 TI - Metaxins 1 and 2, two proteins of the mitochondrial protein sorting and assembly machinery, are essential for Bak activation during TNF alpha triggered apoptosis. AB - The proteins Bax and Bak are central in the execution phase of apoptosis; however, little is known about the partners involved in the control of this complex process. Here, we show that mitochondrial Bak is incorporated into a VDAC2/Mtx1/Mtx2 multi-protein complex in both resting and dying cells. VDAC2 is a porin that has previously been described as a partner of Bak while Mtx1 and Mtx2 are two proteins of the mitochondrial sorting and assembly machinery (SAM) that have been implicated in TNF-induced apoptosis. We show that, after the induction of apoptosis, Bak switches from its association with Mtx2 and VDAC2 to interact with Mtx1. PMID- 24794531 TI - Early NADPH oxidase-2 activation is crucial in phenylephrine-induced hypertrophy of H9c2 cells. AB - Reactive oxygen species (ROS) produced by different NADPH oxidases (NOX) play a role in cardiomyocyte hypertrophy induced by different stimuli, such as angiotensin II and pressure overload. However, the role of the specific NOX isoforms in phenylephrine (PE)-induced cardiomyocyte hypertrophy is unknown. Therefore we aimed to determine the involvement of the NOX isoforms NOX1, NOX2 and NOX4 in PE-induced cardiomyocyte hypertrophy. Hereto rat neonatal cardiomyoblasts (H9c2 cells) were incubated with 100 MUM PE to induce hypertrophy after 24 and 48h as determined via cell and nuclear size measurements using digital imaging microscopy, electron microscopy and an automated cell counter. Digital-imaging microscopy further revealed that in contrast to NOX1 and NOX4, NOX2 expression increased significantly up to 4h after PE stimulation, coinciding and co-localizing with ROS production in the cytoplasm as well as the nucleus. Furthermore, inhibition of NOX-mediated ROS production with apocynin, diphenylene iodonium (DPI) or NOX2 docking sequence (Nox2ds)-tat peptide during these first 4h of PE stimulation significantly inhibited PE-induced hypertrophy of H9c2 cells, both after 24 and 48h of PE stimulation. These data show that early NOX2 mediated ROS production is crucial in PE-induced hypertrophy of H9c2 cells. PMID- 24794533 TI - Hypoxia differentially regulates muscle oxidative fiber type and metabolism in a HIF-1alpha-dependent manner. AB - Loss of skeletal muscle oxidative fiber types and mitochondrial capacity is a hallmark of chronic obstructive pulmonary disease and chronic heart failure. Based on in vivo human and animal studies, tissue hypoxia has been hypothesized as determinant, but the direct effect of hypoxia on muscle oxidative phenotype remains to be established. Hence, we determined the effect of hypoxia on in vitro cultured muscle cells, including gene and protein expression levels of mitochondrial components, myosin isoforms (reflecting slow-oxidative versus fast glycolytic fibers), and the involvement of the regulatory PPAR/PGC-1alpha pathway. We found that hypoxia inhibits the PPAR/PGC-1alpha pathway and the expression of mitochondrial components through HIF-1alpha. However, in contrast to our hypothesis, hypoxia stimulated the expression of slow-oxidative type I myosin via HIF-1alpha. Collectively, this study shows that hypoxia differentially regulates contractile and metabolic components of muscle oxidative phenotype in a HIF-1alpha-dependent manner. PMID- 24794534 TI - de novo computational enzyme design. AB - Recent advances in systems and synthetic biology as well as metabolic engineering are poised to transform industrial biotechnology by allowing us to design cell factories for the sustainable production of valuable fuels and chemicals. To deliver on their promises, such cell factories, as much as their brick-and-mortar counterparts, will require appropriate catalysts, especially for classes of reactions that are not known to be catalyzed by enzymes in natural organisms. A recently developed methodology, de novo computational enzyme design can be used to create enzymes catalyzing novel reactions. Here we review the different classes of chemical reactions for which active protein catalysts have been designed as well as the results of detailed biochemical and structural characterization studies. We also discuss how combining de novo computational enzyme design with more traditional protein engineering techniques can alleviate the shortcomings of state-of-the-art computational design techniques and create novel enzymes with catalytic proficiencies on par with natural enzymes. PMID- 24794535 TI - Protein engineering of cellulases. AB - This review covers the topic of protein engineering of cellulases, mostly after 2009. Two major trends that are identified in this work are: first, the increased importance of results from computational protein engineering to drive ideas in the field, as experimental ideas and results often are still scarce, and, second, the further development of helper proteins for cellulose hydrolysis, such as lytic polysaccharide monooxygenase (LPO). The discussion in this work focuses both on improved attributes of cellulases and on the domains of cellulase that have been improved. PMID- 24794532 TI - P21-activated kinase in inflammatory and cardiovascular disease. AB - P-21 activated kinases, or PAKs, are serine-threonine kinases that serve a role in diverse biological functions and organ system diseases. Although PAK signaling has been the focus of many investigations, still our understanding of the role of PAK in inflammation is incomplete. This review consolidates what is known about PAK1 across several cell types, highlighting the role of PAK1 and PAK2 in inflammation in relation to NADPH oxidase activation. This review explores the physiological functions of PAK during inflammation, the role of PAK in several organ diseases with an emphasis on cardiovascular disease, and the PAK signaling pathway, including activators and targets of PAK. Also, we discuss PAK1 as a pharmacological anti-inflammatory target, explore the potentials and the limitations of the current pharmacological tools to regulate PAK1 activity during inflammation, and provide indications for future research. We conclude that a vast amount of evidence supports the idea that PAK is a central molecule in inflammatory signaling, thus making PAK1 itself a promising prospective pharmacological target. PMID- 24794536 TI - Synthetic analog and digital circuits for cellular computation and memory. AB - Biological computation is a major area of focus in synthetic biology because it has the potential to enable a wide range of applications. Synthetic biologists have applied engineering concepts to biological systems in order to construct progressively more complex gene circuits capable of processing information in living cells. Here, we review the current state of computational genetic circuits and describe artificial gene circuits that perform digital and analog computation. We then discuss recent progress in designing gene networks that exhibit memory, and how memory and computation have been integrated to yield more complex systems that can both process and record information. Finally, we suggest new directions for engineering biological circuits capable of computation. PMID- 24794539 TI - Quadruplex nanostructures of d(TGGGGT): influence of sodium and potassium ions. AB - The Tetrahymena telomeric repeat sequence d(TG4T) contains only guanine (G) and thymine (T) bases and has medical and nanotechnological applications because of its ability to self-assemble into stiff tetra-molecular parallel-stranded G quadruplexes. The hexadeoxynucleotide d(TG4T) was studied using atomic force microscopy (AFM) on the highly oriented pyrolytic graphite surface and differential pulse (DP) voltammetry at a glassy carbon electrode. The d(TG4T) single-strands self-assembled into G-quadruplex structures, very fast in K(+) ions solution and slowly in Na(+) ions containing solution. The G-quadruplex structures were detected in AFM by the adsorption of small spherical aggregates and by DP voltammetry by the G oxidation peak decrease and G-quartets oxidation peak occurrence, in a time and K(+) ions concentration dependent manner. In the presence of Na(+) ions, the d(TG4T) single-strands also slowly self-assembled into higher-order nanostructures, detected by AFM as short nanowires and nanostructured films that were never observed in K(+) ions containing solution. PMID- 24794538 TI - Signaling specificity in the Akt pathway in biology and disease. AB - Akt/PKB is a key master regulator of a wide range of physiological functions including metabolism, proliferation, survival, growth, angiogenesis and migration and invasion. The Akt protein kinase family comprises three highly related isoforms encoded by different genes. The initial observation that the Akt isoforms share upstream activators as well as several downstream effectors, together with the high sequence homology suggested that their functions were mostly redundant. By contrast, an increasing body of evidence has recently uncovered the concept of Akt isoform signaling specificity, supported by distinct phenotypes displayed by animal strains genetically modified for each of the three genes, as well as by the identification of isoform-specific substrates and association with discrete subcellular locations. Given that Akt is regarded as a promising therapeutic target in a number of pathologies, it is essential to dissect the relative contributions of each isoform, as well as the degree of compensation in pathophysiological function. Here we summarize our view of how Akt selectivity is achieved in the context of subcellular localization, isoform specific substrate phosphorylation and context-dependent functions in normal and pathophysiological settings. PMID- 24794540 TI - "Eating for two": excessive gestational weight gain and the need to change social norms. PMID- 24794541 TI - Health insurance coverage and racial disparities in breast reconstruction after mastectomy. AB - BACKGROUND: Breast reconstruction after mastectomy offers clinical, cosmetic, and psychological benefits compared with mastectomy alone. Although reconstruction rates have increased, racial/ethnic disparities in breast reconstruction persist. Insurance coverage facilitates access to care, but few studies have examined whether health insurance ameliorates disparities. METHODS: We used the Nationwide Inpatient Sample for 2002 through 2006 to examine the relationships between health insurance coverage, race/ethnicity, and breast reconstruction rates among women who underwent mastectomy for breast cancer. We examined reconstruction rates as a function of the interaction of race and the primary payer (self-pay, private health insurance, government) while controlling for patient comorbidity, and we used generalized estimating equations to account for clustering and hospital characteristics. FINDINGS: Minority women had lower breast reconstruction rates than White women (adjusted odds ratio [AOR], 0.57 for African American; AOR, 0.70 for Hispanic; AOR, 0.45 for Asian; p < .001). Uninsured women (AOR, 0.33) and those with public coverage were less likely to undergo reconstruction (AOR, 0.35; p < .001) than privately insured women. Racial/ethnic disparities were less prominent within insurance types. Minority women, whether privately or publicly insured, had lower odds of undergoing reconstruction than White women. Among those without insurance, reconstruction rates did not differ by race/ethnicity. CONCLUSIONS: Insurance facilitates access to care, but does not eliminate racial/ethnic disparities in reconstruction rates. Our findings-which reveal persistent health care disparities not explained by patient health status-should prompt efforts to promote both access to and use of beneficial covered services for women with breast cancer. PMID- 24794542 TI - A survey of health behaviors in minority women in pregnancy: the influence of body mass index. AB - BACKGROUND: An effective behavioral intervention for gestational weight gain in minority obese women needs to incorporate their baseline health behaviors and nutrition patterns. The objective of this study was to compare racial/ethnic differences in health behaviors and nutrition in pregnant obese and non-obese minorities. METHODS: A face-to-face, 75-item survey was administered to 94 women (46% non-obese, 54% obese; 71% Black, 29% Hispanic) at a prenatal visit to an inner-city clinic. Television watching, exercise, and nutrition were compared between obese and non-obese women and racial/ethnic differences were compared within each body mass index (BMI) category using chi-square and Fisher's exact tests. Interactions between BMI category and race/ethnicity for each health behavior were examined. FINDINGS: More obese women described their nutrition as "fair" or "poor" (36% vs. 15%; p = .02) and missed more meals per day (21% vs. 6%; p = .03) compared with non-obese women. Obese Blacks were less likely to improve their nutrition during pregnancy compared with obese Hispanics (28% vs. 58%; p = .08). Non-obese Blacks watched more television (p = .03) and exercised less during pregnancy (p = .04) than non-obese Hispanics. Except for dairy products, there were no differences in daily nutrition (fruit, soda, vegetables, chips) among the BMI categories and racial/ethnic groups; however, fewer than 50% of all participants consumed fruits and vegetables every day. There was an interaction between BMI category and race/ethnicity: Obese Hispanics exercised less before pregnancy (p = .02), but exercised more during pregnancy (p = .01) compared with non-obese Hispanics. CONCLUSIONS: Interventions for gestational weight gain in obese women may have greater success if they considered racial/ethnic differences in health behaviors, especially related to exercise. PMID- 24794543 TI - Maternal depression, pregnancy intention, and return to paid work after childbirth. AB - BACKGROUND: Maternal depression is an important public health issue for women, their families, and their employers. Previous studies have examined the impact of leave duration on maternal depression, but none have studied the association between maternal depression and the pace of return to paid work. We examine herein the relationship between maternal depression and return to work, and the moderating effects of pregnancy intention. METHODS: We utilized data from the Listening to Mothers II Survey collected from January 20 through February 21, 2006. The woman had to be 18 to 45 years old, speak English, and have given birth in 2005 to a live singleton baby in a U.S. hospital. Our analyses were limited to women who worked for an employer during pregnancy (n = 882). The primary outcome was return to paid work at the time of the interview and the analyses utilized Cox proportional hazard models. FINDINGS: In combination, intending the baby and being depressed suppressed return to paid work. Nondepressed mothers with unintended pregnancies returned to work the soonest. Compared with mothers who were not depressed and with unintended pregnancy, the risk ratio of returning to paid work (0.70) was significantly lower for mothers who were depressed and had an intended pregnancy. Mothers who were not depressed and with intended pregnancy also had a significantly lower risk ratio (0.60) of returning to paid work than those who were not depressed and with unintended pregnancy. CONCLUSION: Primary care providers and policy makers can use these findings to support employed women in their childbearing years. PMID- 24794544 TI - Potential for a stress reduction intervention to promote healthy gestational weight gain: focus groups with low-income pregnant women. AB - BACKGROUND: Prepregnancy body mass index and excessive gestational weight gain (GWG) are associated with adverse maternal and infant outcomes. Because stress contributes to obesity and eating behaviors, stress reduction interventions during pregnancy may be a novel way to influence GWG, positively affect maternal and infant outcomes, and address the obesity epidemic intergenerationally. METHODS: Our research team is developing a mindfulness-based stress reduction and nutrition intervention for low-income, overweight and obese pregnant women, with healthy GWG as the primary outcome measure. To inform development of the intervention, we conducted focus groups with our target population. Focus group transcripts were analyzed for themes related to sources and importance of stress, relationship between stress and eating, and motivation for a stress reduction pregnancy intervention. FINDINGS: Fifty-nine low-income pregnant women from the San Francisco Bay Area participated in focus groups and completed a questionnaire. The vast majority of women (80%) reported experiencing significant stress from a variety of sources and most recognized a relationship between stress and eating in their lives. CONCLUSIONS: This at-risk population seems to be extremely interested in a stress reduction intervention to support healthy GWG during pregnancy. The women in our groups described high levels of stress and a desire for programs beyond basic dietary recommendations. These findings inform practitioners and policymakers interested in pregnancy as a "window of opportunity" for behavior change that can affect the metabolic and weight trajectory both for women and their offspring. PMID- 24794545 TI - Physician adherence to U.S. Preventive Services Task Force mammography guidelines. AB - BACKGROUND: In 2009, the U.S. Preventive Services Task Force (USPSTF) guidelines for screening mammography changed significantly, and are now in direct conflict with screening guidelines of other major national organizations. The extent to which physicians in different primary care specialties adhere to current USPSTF guidelines is unknown. METHODS: We conducted a cross-sectional web-based survey completed by 316 physicians in internal medicine, family medicine (FM), and gynecology (GYN) from February to April 2012. Survey items assessed respondents' breast cancer screening recommendations in women of different ages at average risk for breast cancer. We used descriptive statistics to generate response distribution for survey items, and logistic regression models to compare responses among specialties. FINDINGS: The response rate was 55.0% (316/575). A majority of providers in internal medicine (65%), FM (64%), and GYN (92%) recommended breast cancer screening starting at age 40 versus 50. A majority of providers in internal medicine (77%), FM (74%), and GYN (98%) recommended annual versus biennial screening. Gynecologists were significantly more likely than both internists and family physicians to recommend initial mammography at age 40 (p <= .0001) and yearly mammography (p = .0003). There were no other differences by respondent demographic. CONCLUSIONS: Primary care providers, especially gynecologists, have not implemented USPSTF guidelines. The extent to which these findings may be driven by patient versus provider preferences should be explored. These findings suggest that patients are likely to receive conflicting breast cancer screening recommendations from different providers. PMID- 24794546 TI - Self-reported physical activity patterns among low-income Latina women in Arizona. AB - BACKGROUND: Adherence to recommendations for physical activity (PA) among adults in the United States is reported as poor, particularly among low-income Latinos. In particular, Latina women are at increased risk for inactivity and chronic illness, but national health survey reports aggregate data across demographic strata, limiting descriptive information that could guide targeted PA promotion. The purpose of the study was to determine PA patterns among a low-income group of Latina women in the southwestern United States. METHODS: As part of a large community intervention trial to increase cancer prevention behaviors, PA data were collected from 1,006 Latina women using a modified version of the Arizona Activity Frequency Questionnaire. FINDINGS: The weekly PA mean across all exercise types was calculated to be 9.3 +/- 16.4 hours, which is substantially higher than the daily PA recommendation of 30 minutes most days of the week. The highest daily PA means were associated with occupational activities: Cleaning, 2.7 hours; walking, 2.5 hours; lifting, 1.9 hours; and light yard work, 1.0 hours. CONCLUSIONS: In this sample of low-income Latina women, the average PA hours per week exceed the current PA recommendations. Data collection instruments used in this population could more accurately assess PA if they included a wider range of activities and specific questions about work-related activity. PMID- 24794547 TI - Left ventricular noncompaction cardiomyopathy: three decades of progress. PMID- 24794548 TI - Chronic Takotsubo syndrome with acute exacerbations in decompensated chronic heart failure: surgical cardiac sympathectomy may have a role? PMID- 24794549 TI - 2014 global geographic analysis of mortality from ischaemic heart disease by country, age and income: statistics from World Health Organisation and United Nations. AB - BACKGROUND: Ischaemic heart disease (IHD) is the leading cause of death worldwide and its prevention is a public health priority. METHOD: We analysed worldwide IHD mortality data from the World Health Organisation as of February 2014 by country, age and income. Age-standardised mortality rates by country were calculated. We constructed a cartogram which is an algorithmically transformed world map that conveys numbers of deaths in the form of spatial area. RESULTS: Of the countries that provided mortality data, Russia, the United States of America and Ukraine contributed the largest numbers of deaths. India and China were estimated to have even larger numbers of deaths. Death rates from IHD increase rapidly with age. Crude mortality rates appear to be stable whilst age-standardised mortality rates are falling. Over half of the world's countries (113/216) have provided IHD mortality data for 2008 or later. Of these, 13 countries provided data in 2012. No countries have yet provided 2013 data. Of the 103 remaining countries, 24 provided data in 2007 or earlier, and 79 have never provided data in the ICD9 or ICD10 format. CONCLUSIONS: In the countries for which there are good longitudinal data, predominantly European countries, recent years have shown a continuing decline in age-standardised IHD mortality. However, the progressive aging of populations has kept crude IHD mortality high. It is not known whether the pattern is consistent globally because many countries have not provided regular annual data including wealthy countries such as the United Arab Emirates and large countries such as India and China. PMID- 24794550 TI - Undescribed origin of the left main coronary artery from the right sinus of Valsalva: an explanation of nonexistent myocardial ischemia? PMID- 24794551 TI - Proinsulin and IGFBP-1 predicts mortality in an elderly population. AB - BACKGROUND: High IGFBP-1 in elderly subjects is related to all-cause and cardiovascular (CV) mortality. We studied the relation of IGFBP-1 to cardiometabolic risk factors and cardiovascular and all-cause mortality, and also the impact of proinsulin and insulin on this association in an unselected elderly primary health care population. HYPOTHESIS: Our hypothesis was that proinsulin and insulin may have an impact on the association of high IGFBP-1 levels with all cause and CV-mortality in elderly. DESIGN, SETTING AND PARTICIPANTS: A cross sectional and prospective study was carried out in a rural Swedish population. 851 persons aged 66-81 years were evaluated by medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples, and were followed prospectively for up to 12 years. RESULTS: At baseline, in a multivariate analysis, IGFBP-1 was associated with gender, N-terminal proBNP (NT pro-BNP), blood glucose, body mass index (BMI), insulin and proinsulin, estimated glomerular filtration rate (eGFR) and haemoglobin (Hb). During the follow-up period there were 230 deaths (27%), of which 134 (16%) were due to CV mortality. When divided into tertiles there was a significant difference for CV mortality and all-cause mortality between tertiles of IGFBP-1 and proinsulin. For insulin there was a significant difference only for all-cause mortality. After adjustment for well-known risks factors, proinsulin and IGFBP-1 had significant impact on all-cause mortality but only proinsulin on CV mortality. CONCLUSION: Only proinsulin is an independent predictor for both all-cause mortality and CV mortality when comparing IGFBP-1, insulin, and proinsulin as prognostic biomarkers for CV and all-cause mortality in an elderly population. PMID- 24794552 TI - Protein kinase C in enhanced vascular tone in diabetes mellitus. AB - Diabetes mellitus (DM) is a complex syndrome which leads to multiple dysfunctions including vascular disorders. Hyperglycemia is considered to be a key factor responsible for the development of diabetic vascular complications and can mediate their adverse effects through multiple pathways. One of those mechanisms is the activation of protein kinase C (PKC). This important regulatory enzyme is involved in a signal transduction of several vascular functions including vascular smooth muscle contractility. Many studies have shown that hyperglycemia in DM results in oxidative stress. Overproduction of reactive oxygen species (ROS) by different oxidases and the mitochondrial electron transport chain (ETC), advanced glycation end products, polyol pathway flux, and hyperglicemia-induced rising in diacylglycerol (DAG) contribute to the activation of PKC. Activation of endothelial PKC in DM leads to endothelium-dependent vasodilator dysfunction. The main manifestations of this are inhibition of vasodilatation mediated by nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostacyclin, and activation of vasoconstriction mediated by endothelin-1 (ET-1), prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Activated PKC in DM also increases vascular endothelial growth factor (VEGF) expression and activates NADPH oxidases leading to raised ROS production. On the other hand, PKC in DM is involved in enhancement of vascular contractility in an endothelium-independent manner by inactivation of K(+) channels and Ca(2+) sensitization of myofilaments in vascular smooth muscle cells. This shows that PKC is a potential therapeutic target for treating vascular diabetic complications. PMID- 24794553 TI - Influence of left ventricular remodeling on atrial fibrillation recurrence and cardiovascular hospitalizations in patients undergoing rhythm-control therapy. AB - BACKGROUND: Atrial fibrillation (AF) patients with left ventricular hypertrophy (LVH) and diastolic dysfunction may derive benefit from being in sinus rhythm but no data are available to support this strategy in them. We sought to investigate effect of left ventricular remodeling on cardiovascular outcomes in AF patients undergoing rhythm control strategy. METHODS: We identified 1088 patients with echocardiographic data on left ventricular mass (LVM) enrolled in the AFFIRM trial. Using the American Society of Echocardiography (ASE) criteria, patients were divided into 4 categories: 1) normal geometry, 2) concentric remodeling, 3) eccentric hypertrophy, and 4) concentric hypertrophy. The primary endpoint was AF recurrence and the secondary endpoint was cardiovascular hospitalization (CVH). RESULTS: In rhythm control arm, median time to recurrence in patients with concentric LVH was 13.3 months (95% CI 8.2-24.5) vs. 28.3 months (95% CI 20.2 48.6) in patients without LVH. Concentric left ventricular hypertrophy (LVH) was independently predictive of AF recurrence (HR 1.49, 95% CI 1.10-2.01, p=0.01) in rhythm control arm, but not in overall population or rate control arm. Both concentric and eccentric LVH were independently predictive of cardiovascular hospitalization (CVH) in the overall population, with respective HRs of 1.36 (1.04-1.78, p=0.03) and 1.38 (1.02-1.85, p=0.04). CONCLUSION: Concentric LVH is predictive of AF recurrences when a predominantly pharmacologic rhythm-control strategy is employed. Different patterns of LVH seem to be important determinants of outcomes (AF recurrence and CVH). These findings may have important clinical implications for the management of patients with AF and LVH. Further studies are warranted to confirm our findings. PMID- 24794554 TI - The pitfalls of managing thrombosis of an AbsorbTM-treated bifurcation. PMID- 24794555 TI - Reply to the letter to the editor: "ventricular fibrillation and takotsubo syndrome: which one was first?". PMID- 24794556 TI - Pacemaker, implantable cardioverter defibrillator, CRT, CRT-D, psychological difficulties and quality of life. PMID- 24794557 TI - The growing burden of cardiovascular diseases in China. PMID- 24794558 TI - Correspondence letter by Mkrtchyan and Fratz regarding article "aortic biomechanics by magnetic resonance: early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?". PMID- 24794559 TI - Social Security and divorce or death benefits storyboard (S(2)D(2)BS): an interactive participant learning exercise. AB - Using the concept of an interactive or living storyboard, the author discusses the use of seven case narratives constructed for the sole purpose of teaching introductory gerontology or geriatric students about the distribution of Social Security benefits after spousal death. Additional information is included pertaining to Social Security benefits payable to divorced persons after the death of the former spouse, including the status of married same-sex couples. Narratives include representations of a male breadwinner model couple, a two earner couple who have similar/dissimilar earnings prior to retirement, a divorced couple with a remarriage after a death, a gay couple with and without children, and a female primary breadwinner couple. Updated information from the Social Security Administration, as well as information on game preparation, scripts, and debriefing questions are included. PMID- 24794560 TI - A putative bifunctional histidine kinase/phosphatase of the HWE family exerts positive and negative control on the Sinorhizobium meliloti general stress response. AB - The EcfG-type sigma factor RpoE2 is the regulator of the general stress response in Sinorhizobium meliloti. RpoE2 activity is negatively regulated by two NepR type anti-sigma factors (RsiA1/A2), themselves under the control of two anti-anti sigma factors (RsiB1/B2) belonging to the PhyR family of response regulators. The current model of RpoE2 activation suggests that in response to stress, RsiB1/B2 are activated by phosphorylation of an aspartate residue in their receiver domain. Once activated, RsiB1/B2 become able to interact with the anti-sigma factors and release RpoE2, which can then associate with the RNA polymerase to transcribe its target genes. The purpose of this work was to identify and characterize proteins involved in controlling the phosphorylation status of RsiB1/B2. Using in vivo approaches, we show that the putative histidine kinase encoded by the rsiC gene (SMc01507), located downstream from rpoE2, is able to both positively and negatively regulate the general stress response. In addition, our data suggest that the negative action of RsiC results from inhibition of RsiB1/B2 phosphorylation. From these observations, we propose that RsiC is a bifunctional histidine kinase/phosphatase responsible for RsiB1/B2 phosphorylation or dephosphorylation in the presence or absence of stress, respectively. Two proteins were previously proposed to control PhyR phosphorylation in Caulobacter crescentus and Sphingomonas sp. strain FR1. However, these proteins contain a Pfam:HisKA_2 domain of dimerization and histidine phosphotransfer, whereas S. meliloti RsiC harbors a Pfam:HWE_HK domain instead. Therefore, this is the first report of an HWE_HK-containing protein controlling the general stress response in Alphaproteobacteria. PMID- 24794561 TI - Aggregation interplay between variants of the RepA-WH1 prionoid in Escherichia coli. AB - The N-terminal domain (winged-helix domain, or WH1) of the Pseudomonas pPS10 plasmid DNA replication protein RepA can assemble into amyloid fibers in vitro and, when expressed in Escherichia coli, leads to a unique intracellular amyloid proteinopathy by hampering bacterial proliferation. RepA-WH1 amyloidosis propagates along generations through the transmission of aggregated particles across the progeny, but it is unable to propagate horizontally as an infectious agent and is thus the first synthetic bacterial prionoid. RepA-WH1 amyloidosis is promoted by binding to double-stranded DNA (dsDNA) in vitro, and it is modulated by the Hsp70 chaperone DnaK in vivo. Different mutations in the repA-WH1 gene result in variants of the protein with distinct amyloidogenic properties. Here, we report that intracellular aggregates of the hyperamyloidogenic RepA with an A31V change in WH1 [RepA-WH1(A31V)] are able to induce and enhance the growth in vivo of new amyloid particles from molecules of wild-type RepA-WH1 [RepA WH1(WT)], which otherwise would remain soluble in the cytoplasm. In contrast, RepA-WH1(DeltaN37), a variant lacking a clear amyloidogenic sequence stretch that aggregates as conventional inclusion bodies (IBs), can drive the aggregation of the soluble protein into IBs only if expressed at high molar ratios over RepA WH1(WT). The cytotoxic bacterial intracellular prionoid RepA-WH1 thus exhibits a hallmark feature of amyloids, as characterized in eukaryotes: cross-aggregation between variants of the same protein. PMID- 24794562 TI - Genetic analysis of the assimilation of C5-dicarboxylic acids in Pseudomonas aeruginosa PAO1. AB - There is a wealth of information on the genetic regulation and biochemical properties of bacterial C4-dicarboxylate transport systems. In sharp contrast, there are far fewer studies describing the transport and assimilation of C5 dicarboxylates among bacteria. In an effort to better our understanding on this subject, we identified the structural and regulatory genes necessary for the utilization of alpha-ketoglutarate (alpha-KG) in Pseudomonas aeruginosa PAO1. The PA5530 gene, encoding a putative dicarboxylate transporter, was found to be essential for the growth of P. aeruginosa PAO1 on both alpha-KG and glutarate (another C5-dicarboxylate). Metabolite analysis confirmed that the PA5530 gene was necessary for the uptake of extracellular alpha-KG. Like other substrate inducible transporter genes, expression of the PA5530 gene was induced by extracellular C5-dicarboxylates. It was later found that the expression of the PA5530 gene was driven solely by a -24/-12 promoter recognized by the alternative sigma factor RpoN. Surprisingly, the enhancer binding protein MifR, which is known to have an essential role in biofilm development, was required for the expression of the PA5530 gene. The MifR protein is homologous to other transcriptional regulators involved in dicarboxylate assimilation, suggesting that MifR might interact with RpoN to activate the expression of the PA5530 gene in response to extracellular C5-dicarboxylates, especially alpha-KG. The results of this study provide a framework for exploring the assimilation of alpha-KG in other pseudomonads. PMID- 24794563 TI - NtrBC and Nac contribute to efficient Shigella flexneri intracellular replication. AB - Shigella flexneri two-component regulatory systems (TCRS) are responsible for sensing changes in environmental conditions and regulating gene expression accordingly. We examined 12 TCRS that were previously uncharacterized for potential roles in S. flexneri growth within the eukaryotic intracellular environment. We demonstrate that the TCRS EvgSA, NtrBC, and RstBA systems are required for wild-type plaque formation in cultured epithelial cells. The phenotype of the NtrBC mutant depended in part on the Nac transcriptional regulator. Microarray analysis was performed to identify S. flexneri genes differentially regulated by the NtrBC system or Nac in the intracellular environment. This study contributes to our understanding of the transcriptional regulation necessary for Shigella to effectively adapt to the mammalian host cell. PMID- 24794564 TI - Novel MntR-independent mechanism of manganese homeostasis in Escherichia coli by the ribosome-associated protein HflX. AB - Manganese is a micronutrient required for activities of several important enzymes under conditions of oxidative stress and iron starvation. In Escherichia coli, the manganese homeostasis network primarily constitutes a manganese importer (MntH) and an exporter (MntP), which are regulated by the MntR dual regulator. In this study, we find that deletion of E. coli hflX, which encodes a ribosome associated GTPase with unknown function, renders extreme manganese sensitivity characterized by arrested cell growth, filamentation, lower rate of replication, and DNA damage. We demonstrate that perturbation by manganese induces unprecedented influx of manganese in DeltahflX cells compared to that in the wild type E. coli strain. Interestingly, our study indicates that the imbalance in manganese homeostasis in the DeltahflX strain is independent of the MntR regulon. Moreover, the influx of manganese leads to a simultaneous influx of zinc and inhibition of iron import in DeltahflX cells. In order to review a possible link of HflX with the lambda phage life cycle, we performed a lysis-lysogeny assay to show that the Mn-perturbed DeltahflX strain reduces the frequency of lysogenization of the phage. This observation raises the possibility that the induced zinc influx in the manganese-perturbed DeltahflX strain stimulates the activity of the zinc-metalloprotease HflB, the key determinant of the lysis lysogeny switch. Finally, we propose that manganese-mediated autophosphorylation of HflX plays a central role in manganese, zinc, and iron homeostasis in E. coli cells. PMID- 24794565 TI - Expression of each cistron in the gal operon can be regulated by transcription termination and generation of a galk-specific mRNA, mK2. AB - The gal operon of Escherichia coli has 4 cistrons, galE, galT, galK, and galM. In our previous report (H. J. Lee, H. J. Jeon, S. C. Ji, S. H. Yun, H. M. Lim, J. Mol. Biol. 378: 318-327, 2008), we identified 6 different mRNA species, mE1, mE2, mT1, mK1, mK2, and mM1, in the gal operon and mapped these mRNAs. The mRNA map suggests a gradient of gene expression known as natural polarity. In this study, we investigated how the mRNAs are generated to understand the cause of natural polarity. Results indicated that mE1, mT1, mK1, and mM1, whose 3' ends are located at the end of each cistron, are generated by transcription termination. Since each transcription termination is operating with a certain frequency and those 4 mRNAs have 5' ends at the transcription initiation site(s), these transcription terminations are the basic cause of natural polarity. Transcription terminations at galE-galT and galT-galK junctions, making mE1 and mT1, are Rho dependent. However, the terminations to make mK1 and mM1 are partially Rho dependent. The 5' ends of mK2 are generated by an endonucleolytic cleavage of a pre-mK2 by RNase P, and the 3' ends are generated by Rho termination 260 nucleotides before the end of the operon. The 5' portion of pre-mK2 is likely to become mE2. These results also suggested that galK expression could be regulated through mK2 production independent from natural polarity. PMID- 24794566 TI - Effects of (p)ppGpp on the progression of the cell cycle of Caulobacter crescentus. AB - Bacteria must control the progression of their cell cycle in response to nutrient availability. This regulation can be mediated by guanosine tetra- or pentaphosphate [(p)ppGpp], which are synthesized by enzymes of the RelA/SpoT homologue (Rsh) family, particularly under starvation conditions. Here, we study the effects of (p)ppGpp on the cell cycle of Caulobacter crescentus, an oligotrophic bacterium with a dimorphic life cycle. C. crescentus divides asymmetrically, producing a motile swarmer cell that cannot replicate its chromosome and a sessile stalked cell that is replication competent. The swarmer cell rapidly differentiates into a stalked cell in appropriate conditions. An artificial increase in the levels of (p)ppGpp in nonstarved C. crescentus cells was achieved by expressing a truncated relA gene from Escherichia coli, encoding a constitutively active (p)ppGpp synthetase. By combining single-cell microscopy, flow cytometry approaches, and swarming assays, we show that an increase in the intracellular concentration of (p)ppGpp is sufficient to slow down the swarmer-to stalked cell differentiation process and to delay the initiation of chromosome replication. We also present evidence that the intracellular levels of two master regulators of the cell cycle of C. crescentus, DnaA and CtrA, are modulated in response to (p)ppGpp accumulation, even in the absence of actual starvation. CtrA proteolysis and DnaA synthesis seem indirectly inhibited by (p)ppGpp accumulation. By extending the life span of the motile nonreproductive swarmer cell and thus promoting dispersal and foraging functions over multiplication under starvation conditions, (p)ppGpp may play a central role in the ecological adaptation of C. crescentus to nutritional stresses. PMID- 24794567 TI - The terminal oxidase cbb3 functions in redox control of magnetite biomineralization in Magnetospirillum gryphiswaldense. AB - The biomineralization of magnetosomes in Magnetospirillum gryphiswaldense and other magnetotactic bacteria occurs only under suboxic conditions. However, the mechanism of oxygen regulation and redox control of biosynthesis of the mixed valence iron oxide magnetite [FeII(FeIII)2O4] is still unclear. Here, we set out to investigate the role of aerobic respiration in both energy metabolism and magnetite biomineralization of M. gryphiswaldense. Although three operons encoding putative terminal cbb3-type, aa3-type, and bd-type oxidases were identified in the genome assembly of M. gryphiswaldense, genetic and biochemical analyses revealed that only cbb3 and bd are required for oxygen respiration, whereas aa3 had no physiological significance under the tested conditions. While the loss of bd had no effects on growth and magnetosome synthesis, inactivation of cbb3 caused pleiotropic effects under microaerobic conditions in the presence of nitrate. In addition to their incapability of simultaneous nitrate and oxygen reduction, cbb3-deficient cells had complex magnetosome phenotypes and aberrant morphologies, probably by disturbing the redox balance required for proper growth and magnetite biomineralization. Altogether, besides being the primary terminal oxidase for aerobic respiration, cbb3 oxidase may serve as an oxygen sensor and have a further role in poising proper redox conditions required for magnetite biomineralization. PMID- 24794569 TI - Endoscopic repair of tears of the superficial layer of the distal triceps tendon. AB - PURPOSE: The purpose of this study was to evaluate the results after endoscopic repair of partial superficial layer triceps tendon tears. METHODS: Fourteen patients treated surgically between July 2005 and December 2012 were studied prospectively for 12 months. Indication for surgery was a partial detachment of the triceps tendon from the olecranon that was proved by magnetic resonance imaging (MRI) in all cases. Ten of these patients had chronic olecranon bursitis. All patients were treated with endoscopic surgery including bursectomy and repair of the distal triceps tendon with double-loaded suture anchors. Clinical examination of the patients as well as functional and subjective scores (Mayo Elbow Performance Index [MEPI], Disabilities of the Arm, Shoulder and Hand Score [Quick DASH]) were obtained preoperatively and postoperatively at 6 and 12 months. An isokinetic strength measurement and MRI were performed preoperatively and 12 months after surgery. RESULTS: All 14 patients were completely evaluated. The MEPI and Quick DASH Score improved significantly after the repair at all postoperative examinations. The MEPI gained 29 points, up to 96 points at last follow-up (P < .05), and the Quick DASH Score went down 15.6 points after 12 months to 4.5 points (P < .05). Maximum extension power improved 55.8%, up to 94.7% at last follow-up compared with the contralateral side. Using MRI, we found one reruptured partial tear of the triceps tendon that did not require revision surgery. DISCUSSION: Although triceps tendon ruptures are generally uncommon, partial superficial tears might be more common than previously described. Once the diagnosis is made, endoscopic repair is a method leading to good clinical results with improved function of the affected elbow. CONCLUSIONS: Endoscopic repair of superficial tears of the triceps tendon is able to restore function and strength and leads to excellent clinical results after 1 year. Strength recovers to nearly that of the contralateral side, and serious complications appear to be infrequent. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24794570 TI - Arthroscopic and magnetic resonance arthrogram features of Kim's lesion in posterior shoulder instability. AB - PURPOSE: The purpose of this study was to describe the anatomic features of the glenoid and labrum for shoulders with and without Kim's lesions, as well as define the sensitivity, specificity, and reliability of magnetic resonance arthrogram for the detection of these lesions and determine the interobserver reliability of Kim's classification for posterior labral tears. METHODS: A retrospective, blinded analysis of 41 shoulders was performed. Twenty-one shoulders composed the Kim's lesion group. Three observers measured glenoid and chondrolabral retroversion and anterior and posterior labral height. The shoulders were classified as 1 of 3 types according to Kim's classification. RESULTS: There were no differences in glenoid version, chondrolabral version, glenoid depth, and labral height between the groups. The sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing Kim's lesions were 85.7%, 75%, 78.3%, and 83.3%, respectively. The kappa values for interobserver reliability for detecting and classifying Kim's lesions were 0.739 (substantial) and 0.329 (fair), respectively. CONCLUSIONS: Patients with incomplete posteroinferior labral tears have similar retroversion (bony and soft tissue) and labral height to patients without posterior shoulder instability. The sensitivity, specificity, and reliability of magnetic resonance arthrogram for detecting these lesions are substantial. The interobserver reliability of Kim's classification is fair. LEVEL OF EVIDENCE: Level IV, retrospective case-control study. PMID- 24794568 TI - Streptococcus pyogenes polymyxin B-resistant mutants display enhanced ExPortal integrity. AB - The ExPortal protein secretion organelle in Streptococcus pyogenes is an anionic phospholipid-containing membrane microdomain enriched in Sec translocons and postsecretion protein biogenesis factors. Polymyxin B binds to and disrupts ExPortal integrity, resulting in defective secretion of several toxins. To gain insight into factors that influence ExPortal organization, a genetic screen was conducted to select for spontaneous polymyxin B-resistant mutants displaying enhanced ExPortal integrity. Whole-genome resequencing of 25 resistant mutants revealed from one to four mutations per mutant genome clustered primarily within a core set of 10 gene groups. Construction of mutants with individual deletions or insertions demonstrated that 7 core genes confer resistance and enhanced ExPortal integrity through loss of function, while 3 were likely due to gain of function and/or combinatorial effects. Core resistance genes include a transcriptional regulator of lipid biosynthesis, several genes involved in nutrient acquisition, and a variety of genes involved in stress responses. Two members of the latter class also function as novel regulators of the secreted SpeB cysteine protease. Analysis of the most frequently isolated mutation, a single nucleotide deletion in a track of 9 consecutive adenine residues in pstS, encoding a component of a high-affinity Pi transporter, suggests that this sequence functions as a molecular switch to facilitate stress adaptation. Together, these data suggest the existence of a membrane stress response that promotes enhanced ExPortal integrity and resistance to cationic antimicrobial peptides. PMID- 24794571 TI - Medium-term (5-year) comparison of the functional outcomes of combined anterior cruciate ligament and posterolateral corner reconstruction compared with isolated anterior cruciate ligament reconstruction. AB - PURPOSE: To present a 5-year comparison of the functional outcomes of combined anterior cruciate ligament (ACL) and posterolateral corner (PLC) reconstruction with those of isolated ACL reconstruction. METHODS: All patients were reviewed clinically and completed knee function questionnaires prospectively, by use of the International Knee Documentation Committee (IKDC) 2000, Knee Injury and Osteoarthritis Outcome Score (KOOS), and Lysholm scoring systems, preoperatively and at 1, 2, and 5 years postoperatively. Patients who underwent combined ACL-PLC reconstruction were identified and reviewed. These patients had intact lateral collateral ligaments. A comparison group was created from a group of patients who underwent isolated ACL reconstruction. The ACL group was selected to have the same profile with regard to age, sex, and meniscal procedure. RESULTS: There were 25 patients in the ACL-PLC group and 100 in the ACL group. All patients underwent restoration of their PLC function as shown on dial testing. The preoperative values for all KOOS measures and the Lysholm score were significantly lower in the ACL-PLC group than in the ACL group (P < .001). The IKDC score was not significantly different. All knee scores showed a significant improvement in both groups postoperatively at 1, 2, and 5 years (P < .001). At 5 years, the KOOS symptoms subscore (P < .001), KOOS pain subscore (P < .001), KOOS sports subscore (P < .001), KOOS quality-of-life subscore (P < .05), KOOS activities-of-daily living subscore (P < .001), aggregate score for all KOOS parameters (P < .001), and Lysholm score (P < .001) were significantly lower in the ACL-PLC group than in the ACL group. At 5 years, the IKDC scores were not significantly different. All patients in the ACL-PLC group resumed preinjury employment, and 23 of 25 had resumed sports. CONCLUSIONS: Combined ACL-PLC injuries have greater morbidity than isolated ACL injuries. However, return to work and sporting activity is possible in most cases after combined ACL-PLC reconstruction. The KOOS for sport outcomes suggests that sports were resumed at lower functional levels. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 24794572 TI - Post-exposure therapy of filovirus infections. AB - Filovirus infections cause fatal hemorrhagic fever characterized by the initial onset of general symptoms before rapid progression to severe disease; the most virulent species can cause death to susceptible hosts within 10 days after the appearance of symptoms. Before the advent of monoclonal antibody (mAb) therapy, infection of nonhuman primates (NHPs) with the most virulent filovirus species was fatal if interventions were not administered within minutes. A novel nucleoside analogue, BCX4430, has since been shown to also demonstrate protective efficacy with a delayed treatment start. This review summarizes and evaluates the potential of current experimental candidates for treating filovirus disease with regard to their feasibility and use in the clinic, and assesses the most promising strategies towards the future development of a pan-filovirus medical countermeasure. PMID- 24794573 TI - Structure of the Na,K-ATPase regulatory protein FXYD2b in micelles: implications for membrane-water interfacial arginines. AB - FXYD2 is a membrane protein responsible for regulating the function of the Na,K ATPase in mammalian kidney epithelial cells. Here we report the structure of FXYD2b, one of two splice variants of the protein, determined by NMR spectroscopy in detergent micelles. Solid-state NMR characterization of the protein embedded in phospholipid bilayers indicates that several arginine side chains may be involved in hydrogen bond interactions with the phospholipid polar head groups. The structure and the NMR data suggest that FXYD2b could regulate the Na,K-ATPase by modulating the effective membrane surface electrostatics near the ion binding sites of the pump. PMID- 24794574 TI - Searching for religion and mental health studies required health, social science, and grey literature databases. AB - OBJECTIVE: To determine the optimal databases to search for studies of faith sensitive interventions for treating depression. STUDY DESIGN AND SETTING: We examined 23 health, social science, religious, and grey literature databases searched for an evidence synthesis. Databases were prioritized by yield of (1) search results, (2) potentially relevant references identified during screening, (3) included references contained in the synthesis, and (4) included references that were available in the database. We assessed the impact of databases beyond MEDLINE, EMBASE, and PsycINFO by their ability to supply studies identifying new themes and issues. We identified pragmatic workload factors that influence database selection. RESULTS: PsycINFO was the best performing database within all priority lists. ArabPsyNet, CINAHL, Dissertations and Theses, EMBASE, Global Health, Health Management Information Consortium, MEDLINE, PsycINFO, and Sociological Abstracts were essential for our searches to retrieve the included references. Citation tracking activities and the personal library of one of the research teams made significant contributions of unique, relevant references. Religion studies databases (Am Theo Lib Assoc, FRANCIS) did not provide unique, relevant references. CONCLUSION: Literature searches for reviews and evidence syntheses of religion and health studies should include social science, grey literature, non-Western databases, personal libraries, and citation tracking activities. PMID- 24794575 TI - Validation study in four health-care databases: upper gastrointestinal bleeding misclassification affects precision but not magnitude of drug-related upper gastrointestinal bleeding risk. AB - OBJECTIVE: To evaluate the accuracy of disease codes and free text in identifying upper gastrointestinal bleeding (UGIB) from electronic health-care records (EHRs). STUDY DESIGN AND SETTING: We conducted a validation study in four European electronic health-care record (EHR) databases such as Integrated Primary Care Information (IPCI), Health Search/CSD Patient Database (HSD), ARS, and Aarhus, in which we identified UGIB cases using free text or disease codes: (1) International Classification of Disease (ICD)-9 (HSD, ARS); (2) ICD-10 (Aarhus); and (3) International Classification of Primary Care (ICPC) (IPCI). From each database, we randomly selected and manually reviewed 200 cases to calculate positive predictive values (PPVs). We employed different case definitions to assess the effect of outcome misclassification on estimation of risk of drug related UGIB. RESULTS: PPV was 22% [95% confidence interval (CI): 16, 28] and 21% (95% CI: 16, 28) in IPCI for free text and ICPC codes, respectively. PPV was 91% (95% CI: 86, 95) for ICD-9 codes and 47% (95% CI: 35, 59) for free text in HSD. PPV for ICD-9 codes in ARS was 72% (95% CI: 65, 78) and 77% (95% CI: 69, 83) for ICD-10 codes (Aarhus). More specific definitions did not have significant impact on risk estimation of drug-related UGIB, except for wider CIs. CONCLUSIONS: ICD-9 CM and ICD-10 disease codes have good PPV in identifying UGIB from EHR; less granular terminology (ICPC) may require additional strategies. Use of more specific UGIB definitions affects precision, but not magnitude, of risk estimates. PMID- 24794576 TI - Triumphs, trials, and tribulations of the global response to MERS coronavirus. PMID- 24794578 TI - Competitive healthcare and the elderly: handle with care. PMID- 24794579 TI - Occupational stress, bullying and resilience in old age. AB - Our working years increasingly extend into the late 60s and may soon include the 70s for some people. Thus the question whether work stress has a cumulative effect in older age, and whether older employees are more vulnerable to certain sources of work stress, such as bullying in the work place, is becoming increasingly relevant. We review some of the mechanisms, which translate cumulative stress at work into ill health, particularly in older age, and summarise what is known about the effect of age-specific stress, taking age related bullying as an example. PMID- 24794577 TI - Asthma genetics and personalised medicine. AB - Unbiased genetic approaches, especially genome-wide association studies, have identified novel genetic targets in the pathogenesis of asthma, but so far these targets account for only a small proportion of the heritability of asthma. Recognition of the importance of disease heterogeneity, the need for improved disease phenotyping, and the fact that genes involved in the inception of asthma are likely to be different from those involved in severity widens the scope of asthma genetics. The identification of genes implicated in several causal pathways suggests that genetic scores could be used to capture the effect of genetic variations on individuals. Gene-environment interaction adds another layer of complexity, which is being successfully explored by epigenetic approaches. Pharmacogenetics is one example of how gene-environment interactions are already being taken into account in the identification of drug responders and non-responders, and patients most susceptible to adverse effects. Such applications represent one component of personalised medicine, an approach that places the individual at the centre of health care. PMID- 24794580 TI - Neuropsychiatric aspects of dementia. AB - Dementia affects approximately 6.5% of people over the age of 65. Whilst cognitive impairment is central to the dementia concept, neuropsychiatric symptoms are invariably present at some stage of the illness. Neuropsychiatric symptoms result in a number of negative outcomes for the individual and their caregivers and are associated with higher rates of institutionalization and mortality. A number of factors have been associated with neuropsychiatric symptoms including neurobiological changes, dementia type, and illness severity and duration. Specific patient, caregiver and environmental factors are also important. Neuropsychiatric symptoms can be broadly divided into four clusters: psychotic symptoms, mood/affective symptoms, apathy, and agitation/aggression. Neuropsychiatric symptoms tend to persist over time although differing symptom profiles exist at various stages of the illness. Assessment should take into account the presenting symptoms together with an appreciation of the myriad of likely underlying causes for the symptoms. A structured assessment/rating tool can be helpful. Management should focus on non-pharmacological measures initially with pharmacological approaches reserved for more troubling symptoms. Pharmacological approaches should target specific symptoms although the evidence base for pharmacological management is quite modest. Any medication trial should include an adequate appreciation of the risk-benefit profile in individual patients and discussion of these with both the individual and their caregiver. PMID- 24794581 TI - The warm temperature acclimation protein (Wap65) has an important role in the inflammatory response of turbot (Scophthalmus maximus). AB - Wap65 is a molecule similar to the mammalian hemopexin that is a serum glycoprotein produced mainly by the liver with high affinity to heme. Its primary role is participating in iron metabolism scavenging heme that is released into the plasma and transporting it to the liver. It has been reported an important role of hemopexin in the inflammation as an acute-phase protein and its production is up-regulated by pro-inflammatory cytokines. There are also some evidences suggesting this immune-induction in fish Wap65 genes. Most teleost species presents two Wap65 genes but their physiological functions have not been completely elucidated; in fact, the transcriptional patterns of Wap65 genes to stimulatory treatments are variable and contradictory. In the present study two Wap65 genes, Wap65-1 and Wap65-2, have been characterized for the first time in turbot (Scophthalmus maximus). Their constitutive expression and differential modulation by thermal treatments, immune challenges (bacterial and viral), as well as iron supplementation, have been investigated. Both genes were mainly expressed in liver, but they were detected in all tested tissues. Whereas Wap65-1 and Wap65-2 were up-regulated by temperature rise and bacterial challenge, VHSV infection inhibited the expression of both genes. Moreover, iron-dextran administration induced only the overexpression of Wap65-1. Interestingly, these induction were observed in head kidney buy not in liver. The effect of Wap65 protein purified from turbot serum by hemin-agarose affinity chromatography was also studied to demonstrate a possible anti-inflammatory role, analyzing its inhibitory effect on leucocytes migration induced by zymosan injection to the peritoneal cavity. PMID- 24794582 TI - The role of hybridization in improving the immune response and thermal tolerance of abalone. AB - Recently, frequent death of cultured abalone drew our attention to the stress tolerance of abalone. Hybridization is an effective way of genetic improvement in aquaculture, which can introduce improved traits to the hybrids. In this study, we challenged the hybrids between Haliotis discus hannai and Haliotis gigantea, and their parents with bacteria (vibrio harveyi, vibrio alginolyticus and vibrio parahemolyticus), then held them at 20 degrees C and 28 degrees C, survival rates of the parental populations and hybrid populations were recorded. Then we tested the immune responses and thermal-induced responses of the four populations at different temperatures. Total hemocyte count (THC), respiratory burst, superoxide dismutase activity (SOD), acid phosphatase activity (ACP), alkaline phosphatase activity (AKP), myeloperoxidase activity (MPO), and HSP70 expression were determined on day 1 and day 7 of the temperature exposure. Results showed higher survival rates of the hybrids than their parents against bacteria challenge. For immune parameters, THCs were evaluated at 28 degrees C, while increased THC was also observed in H. discus hannai ? * H. gigantea ? (DG) and H. discus hannai ? * H. discus hannai ? (DD) at 12 degrees C (day 7); at 28 degrees C, respiratory burst was activated (day 1 and 7), while SOD activity first rose then fell over 7-days exposure; AKP activity was elevated at 12 degrees C and 28 degrees C (day 1), most notably in DG, and an increased level of ACP was observed in DG at 28 degrees C (day 7); MPO activity was suppressed at 12 degrees C and 28 degrees C on day 1, but recovered on day 7. For HSP70, increased HSP70 levels were observed in all populations at 28 degrees C (day 1), and DD got the lowest HSP70 level after 7-days exposure at 28 degrees C. Overall, the results suggest that temperature changes could significantly affect the physiological status of abalone, and hybrids may be more resistant to disease and thermal stresses than their parents. PMID- 24794583 TI - Antimicrobial activity of trout hepcidin. AB - Hepcidin is an antimicrobial peptide and a hormone produced mostly the liver. It is a cysteine-rich peptide with a highly conserved beta-sheet structure. Recently, we described the hepcidin expression in liver of rainbow trout and its inducibility by iron overloading and lipopolysaccharide (LPS). Thus, in this work, we focused in analyzing the importance of the peptide conformation associated to its oxidative state in the antimicrobial activity. This peptide showed a alpha-helix conformation in reduced state and the characteristic beta sheet conformation in the oxidized state. Antimicrobial activity assays showed that the oxidized peptide is more effective than the reduced peptide against Escherichia coli and the important salmon fish pathogen Piscirickettsia salmonis. In addition, confocal analysis of P. salmonis culture exposed to trout hepcidin coupled with rhodamine revealed the intracellular location of this peptide and Sytox permeation assay showed that membrane disruption is not the mechanism of its antimicrobial action. Moreover, a conserved ATCUN motif was detected in the N terminus of this peptide. This sequence has been described as a small metal binding site that has been implicated in DNA cleavage. In this work we proved that this peptide is able to induce DNA hydrolysis in the presence of ascorbate and CuCl2. When the same experiments were carried out using a variant with truncated N-terminus no DNA hydrolysis was observed. Our results suggest that correct folding of hepcidin is required for its antimicrobial activity and most likely the metal-binding site (ATCUN motif) present in its N-terminus is involved in the oxidative damage to macromolecules. PMID- 24794585 TI - Neural evidence for sequential selection of object features. AB - Behavioral and neural evidence suggests that attention selects entire objects, amplifying all of their features regardless of task relevance. A new magnetoencephalography (MEG) study by Schoenfeld et al. elucidates the time course of this selection, showing that object features are activated sequentially, with attention spreading from task-relevant to task-irrelevant modules. PMID- 24794584 TI - Randomized trial outcomes of a TTM-tailored condom use and smoking intervention in urban adolescent females. AB - Smoking and sexual risk behaviors in urban adolescent females are prevalent and problematic. Family planning clinics reach those who are at most risk. This randomized effectiveness trial evaluated a transtheoretical model (TTM)-tailored intervention to increase condom use and decrease smoking. At baseline, a total of 828 14- to 17-year-old females were recruited and randomized within four urban family planning clinics. Participants received TTM or standard care (SC) computerized feedback and stage-targeted or SC counseling at baseline, 3, 6 and 9 months. Blinded follow-up telephone surveys were conducted at 12 and 18 months. Analyses revealed significantly more consistent condom use in the TTM compared with the SC group at 6 and 12, but not at 18 months. In baseline consistent condom users (40%), significantly less relapse was found in the TTM compared with the SC group at 6 and 12, but not at 18 months. No significant effects for smoking prevention or cessation were found, although cessation rates matched those found previously. This TTM-tailored intervention demonstrated effectiveness for increasing consistent condom use at 6 and 12 months, but not at 18 months, in urban adolescent females. This intervention, if replicated, could be disseminated to promote consistent condom use and additional health behaviors in youth at risk. PMID- 24794588 TI - Welcoming global progress in achieving heart health. PMID- 24794586 TI - Population-based survival analyses of central nervous system tumors from 1994 to 2008. An up-dated study in the temozolomide-era. AB - The present population-based study describes the survival of malignant central nervous system (CNS) tumors diagnosed during 15 years. Also, we obtained individual data regarding the use of temozolomide to analyze the impact of this drug on the survival of patients diagnosed with glioblastoma. From 1994 to 2008, a total of 679 incident cases of primary CNS tumors were reported by the Girona Cancer Registry after excluding 39 cases diagnosed by death certificate only. Number of cases and the corresponding proportion for each CNS histological subtype in the study population were: 25 oligodendroglial and oligoastrocytics (3.7%), 22 ependymal tumors (3.2%), 24 embryonal (3.5%), 372 astrocytic (54.8%), 1 choroid plexus (0.1%) and 235 without histological confirmation (34.6%). Observed survival after 5 years since diagnosis for the histological subtype were: 58.8%; 47.5%; 37.0%; 14.5% and 6.5%, respectively (p<0.001). Survival of patients diagnosed with glioblastoma according to temozolomide treatment (yes/no) was 60.8% vs. 13.6% and 5.9% vs. 2.5% after 1 and 5 years since diagnosis, respectively. Short-term survival was higher for patients diagnosed with glioblastoma and treated with temozolomide than patients not treated with temozolomide. PMID- 24794589 TI - Australia's role in improving global cardiovascular health. PMID- 24794590 TI - Dementia in Aboriginal and Torres Strait Islander people. PMID- 24794591 TI - Senate Committee recommendations for antipsychotic use in people with dementia. PMID- 24794593 TI - Prescribing statins: the real issues. PMID- 24794594 TI - The First 1000 Days: catalysing equity outcomes for Aboriginal and Torres Strait Islander children. PMID- 24794595 TI - Getting mental health reform back on track: a leadership challenge for the new Australian Government. PMID- 24794596 TI - Dipeptidyl peptidase-4 inhibitors and cardiovascular safety. PMID- 24794597 TI - headspace - Australia's innovation in youth mental health: who are the clients and why are they presenting? PMID- 24794598 TI - headspace - Australia's innovation in youth mental health: who are the clients and why are they presenting? PMID- 24794599 TI - Reply headspace - Australia's innovation in youth mental health: who are the clients and why are they presenting? PMID- 24794600 TI - National guidelines for the management of absolute cardiovascular disease risk. PMID- 24794601 TI - Psychotropics and challenging behaviour in people with an intellectual disability. PMID- 24794603 TI - Guidelines fall short on bariatric surgery. Reply. PMID- 24794602 TI - Guidelines fall short on bariatric surgery. PMID- 24794604 TI - The case for CBT over antidepressants. PMID- 24794605 TI - Register4: an Australian web-enabled resource created by the National Breast Cancer Foundation to facilitate and accelerate cancer research. PMID- 24794606 TI - A quack heard around the world. PMID- 24794607 TI - A quack heard around the world. Reply. PMID- 24794609 TI - Dementia prevalence and incidence among the Indigenous and non-Indigenous populations of the Northern Territory. AB - OBJECTIVE: To estimate the prevalence and incidence of dementia in Northern Territory Indigenous and non-Indigenous populations. DESIGN, SETTING AND PARTICIPANTS: Four data sources were used to identify clients with a diagnosis of dementia, from 1 January 2008 to 31 December 2011. The data sources included hospital admissions, aged care services, primary care and death registration. A capture-recapture method was used to estimate prevalence and incidence, including both diagnosed and unknown cases. MAIN OUTCOME MEASURES: Prevalence and incidence of dementia among the NT Indigenous and non-Indigenous populations. RESULTS: In 2011, the estimated prevalence in the NT Indigenous population aged 45 years and over was 3.7 per 100, and 1.1 per 100 in the corresponding NT non-Indigenous population. The age-adjusted prevalence for the NT Indigenous population was 6.5 per 100, compared with the NT non-Indigenous prevalence of 2.6 per 100, which was similar to the national rate. The prevalence rate ratios of NT Indigenous to NT non-Indigenous men and women, respectively, were: 6.5 and 5.5 for the 45-64-years age group, 4.0 and 4.1 for those aged 65-74 years and 2.1 and 1.9 for those aged 75 years and over. The age-adjusted incidence among the NT Indigenous population aged 45 years and over (27.3 per 1000 person-years) was higher than that among the NT non-Indigenous population (10.7 per 1000 person-years). CONCLUSION: The NT Indigenous population has a much higher prevalence and incidence of dementia and younger onset of disease compared with their non-Indigenous counterparts. The results highlight the urgent need for interventions to moderate the emerging impact of dementia in the Australian Indigenous population. PMID- 24794610 TI - Population density predicts outcome from out-of-hospital cardiac arrest in Victoria, Australia. AB - OBJECTIVE: To examine the impact of population density on incidence and outcome of out-of-hospital cardiac arrest (OHCA). DESIGN, SETTING AND PARTICIPANTS: Data were extracted from the Victorian Ambulance Cardiac Arrest Registry for all adult OHCA cases of presumed cardiac aetiology attended by the emergency medical service (EMS) between 1 January 2003 and 31 December 2011. Cases were allocated into one of five population density groups according to their statistical local area: very low density (<= 10 people/km(2)), low density (11-200 people/km(2)), medium density (201-1000 people/km(2)), high density (1001-3000 people/km(2)), and very high density (> 3000 people/km(2)). MAIN OUTCOME MEASURES: Survival to hospital and survival to hospital discharge. RESULTS: The EMS attended 27 705 adult presumed cardiac OHCA cases across 204 Victorian regions. In 12 007 of these (43.3%), resuscitation was attempted by the EMS. Incidence was lower and arrest characteristics were consistently less favourable for lower population density groups. Survival outcomes, including return of spontaneous circulation, survival to hospital and survival to hospital discharge, were significantly poorer in less densely populated groups (P < 0.001 for all comparisons). When compared with very low density populations, the risk-adjusted odds ratios of surviving to hospital discharge were: low density, 1.88 (95% CI, 1.15-3.07); medium density, 2.49 (95% CI, 1.55-4.02); high density, 3.47 (95% CI, 2.20-5.48) and very high density, 4.32 (95% CI, 2.67-6.99). CONCLUSION: Population density is independently associated with survival after OHCA, and significant variation in the incidence and characteristics of these events are observed across the state. PMID- 24794611 TI - Occupational injury risk among Australian paramedics: an analysis of national data. AB - OBJECTIVE: To identify the occupational risks for Australian paramedics, by describing the rate of injuries and fatalities and comparing those rates with other reports. DESIGN AND PARTICIPANTS: Retrospective descriptive study using data provided by Safe Work Australia for the period 2000-2010. The subjects were paramedics who had been injured in the course of their duties and for whom a claim had been made for workers compensation payments. MAIN OUTCOME MEASURES: Rates of injury calculated from the data provided. RESULTS: The risk of serious injury among Australian paramedics was found to be more than seven times higher than the Australian national average. The fatality rate for paramedics was about six times higher than the national average [corrected].On average, every 2 years during the study period, one paramedic died and 30 were seriously injured in vehicle crashes. Ten Australian paramedics were seriously injured each year as a result of an assault. The injury rate for paramedics was more than two times higher than the rate for police officers. CONCLUSIONS: The high rate of occupational injuries and fatalities among paramedics is a serious public health issue. The risk of injury in Australia is similar to that in the United States. While it may be anticipated that injury rates would be higher as a result of the nature of the work and environment of paramedics, further research is necessary to identify and validate the strategies required to minimise the rates of occupational injury for paramedics. PMID- 24794612 TI - A general medical short-stay unit is not more efficient than a traditional model of care. AB - OBJECTIVES: To assess the efficiency of a short-stay unit (SSU) for undifferentiated medical patients and evaluate its effect on the overall efficiency of a general medicine department. DESIGN, SETTING AND PATIENTS: Retrospective study of all general medical patients admitted to the SSU at Flinders Medical Centre, South Australia, during its 5 years of operation (2005 2009), compared with 4 years before its institution and 2 years after its closure. MAIN OUTCOME MEASURES: Relative stay index (RSI); inhospital mortality; readmissions within 7 and 28 days. RESULTS: 23 790 general medical patients were admitted overall, and 10 764 of these (45.2%) were admitted to the SSU. The RSI for the SSU during its years of operation was 0.79, compared with 1.34 for the long-stay unit. The overall RSI for the department did not improve during those years and was not significantly different to the periods before or after. CONCLUSIONS: We found no evidence that an SSU for undifferentiated medical patients creates bed capacity. It does, however, appear to be safe. PMID- 24794613 TI - Rapid eye movement behaviour disorder. PMID- 24794614 TI - A multisystem granulomatous disease: necrobiotic xanthogranuloma with hepatic involvement. PMID- 24794615 TI - The answer was not a pineapple. PMID- 24794616 TI - Artificial heart. 1953. PMID- 24794617 TI - Infection rates after open tibial fractures: are they decreasing? PMID- 24794618 TI - When does hip fracture surgery fail? AB - INTRODUCTION: Hip fractures remain the most common orthopaedic injury requiring hospital admission. Failed surgery for any cause carries a higher morbidity, mortality, and healthcare-related cost. The aims of this study were to determine risk factors for surgical complications of hip fracture surgery, when they occurred and their effect on mortality. PATIENTS AND METHODS: From a prospectively collected consecutive database of 795 hip fractures admitted between July 2007 and June 2008, all surgical and non-surgical complications were identified as well as re-operation for any cause and mortality in the 4 years since surgery. RESULTS: Fifty-five (6.9%) patients were found to have developed a surgical complication requiring further intervention. Risk factors included younger age, smoking and cannulated screw fixation. Cannulated screw fixation was associated with a 30.9% rate of re-operation. Post-operative medical complication occurred in 21.8%. It was associated with a 78.5% mortality at 4 years with a median time to mortality of 58 days (95% CI 0-120 days). CONCLUSIONS: Mechanical failure was the most common reason for cannulated screw re-operation. Hip hemiarthroplasty most commonly failed by infection. Inter-trochanteric and sub trochanteric fracture fixation had very low failure rates. Post-operative medical complications, but not surgical complications, were associated with a higher mortality rate. PMID- 24794619 TI - Use of sourdough fermentation and mixture of wheat, chickpea, lentil and bean flours for enhancing the nutritional, texture and sensory characteristics of white bread. AB - This study aimed at investigating the addition of legume (chickpea, lentil and bean) flours to wheat flour bread. Type I sourdough containing legumes or wheat legume flours were prepared and propagated (back slopped) in laboratory, according to traditional protocols that are routinely used for making typical Italian breads. Based on kinetic of acidification and culture-dependent data, the wheat-legume sourdough was further characterized and selected for bread making. As determined by RAPD-PCR and partial sequencing of 16S rDNA gene analyses, lactic acid bacteria in wheat-legume sourdough included Lactobacillus plantarum, Lactobacillus sanfranciscensis, Leuconostoc mesenteroides, Lactobacillus fermentum, Weissella cibaria, Lactobacillus pentosus, Lactobacillus coryneformis, Lactobacillus rossiae, Lactobacillus brevis, Lactobacillus parabuchneri and Lactobacillus paraplantarum. Two breads containing 15% (w/w) of legume (chickpea, lentil and bean) flours were produced using selected wheat-legume sourdough (WLSB) and traditional wheat sourdough (WSB). Compared to wheat yeasted bread (WYB), the level of total free amino acids (FAA) was higher in WSB and WLSB. Phytase and antioxidant activities were the highest in WLSB. Compared to bread WYB, the addition of legume flours decreased the in vitro protein digestibility (IVPD) (WYB versus WSB). However, the dough fermentation with WSLB favored an increase of IVPD. According to the levels of carbohydrates, dietary fibers and resistant starch, WSB and WLSB showed lower values of hydrolysis index (HI) compared to WYB. As showed by texture and image analyses and sensory evaluation of breads, a good acceptability was found for WSB and, especially, WLSB breads. PMID- 24794621 TI - Symmetry perception in bamboo sharks (Chiloscyllium griseum) and Malawi cichlids (Pseudotropheus sp.). AB - Several species have been shown to perceive symmetry as a measure of superior genetic quality, useful for assessing potential mates or mediating other visual activities such as the selection of food sources. The current study assessed whether Pseudotropheus sp. and Chiloscyllium griseum, two fish species from distantly related groups, possess symmetry perception. In alternative two choice experiments, individuals were tested for spontaneous preferences and trained to discriminate between abstract symmetrical and asymmetrical stimulus pairs. Pair discriminations were followed by extensive categorization experiments. Transfer tests elucidated whether bilaterally symmetrical and rotationally symmetrical stimuli could be distinguished. Sharks were also tested for the degree of dissimilarity between two symbols that could still be detected. While sharks showed both a spontaneous preference for symmetry as well as remarkable discrimination abilities by succeeding in all of the presented tasks, cichlids showed no spontaneous preference, had difficulties in discriminating between symbols and performed poorly in the categorization experiments. Sharks distinguished between bilaterally and rotationally symmetrical stimuli and easily differentiated between a four-armed cross (all arms 90 degrees apart) and a cross where one of the arms was only 45 degrees spaced from the one next to it. Performance did not decline when the separation was extended to 70 degrees , but was significantly reduced at an 80 degrees separation. Results indicate that the ability for symmetry perception varies across fish species and individuals, whereby some can detect even subtle differences in this respect. PMID- 24794622 TI - The immune potential and immunopathology of cytokine-producing B cell subsets: a comprehensive review. AB - B lymphocytes are generally recognized for their potential to mediate humoral immunity by producing different antibody isotypes and being involved in opsonization and complement fixation. Nevertheless, the non-classical, antibody independent immune potential of B cell subsets has attracted much attention especially in the past decade. These B cells can release a broad variety of cytokines (such as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-alpha, IFN-gamma, TNF alpha, TGF-beta, LT), and can be classified into distinct subsets depending on the particular cytokine profile, thus emerging the concept of cytokine-producing B cell subsets. Although there is still controversy surrounding the key cell surface markers, intracellular factors and cellular origins of cytokine-producing B cell subsets, accumulating evidence indicates that these B cells are endowed with great potential to regulate both innate and adaptive arms of immune system though releasing cytokines. On the one hand, they promote immune responses through mounting Th1/Th2/Th17 and neutrophil response, inducing DC maturation and formation of lymphoid structures, increasing NK cell and macrophage activation, enhancing development of themselves and sustaining antibody production. On the other hand, they can negatively regulate immune responses by suppressing Th cell responses, inhibiting Tr1 cell and Foxp3(+) Treg differentiation, impairing APC function and pro-inflammatory cytokine release by monocytes, and inducing CD8(+) T cell anergy and CD4(+) T cell apoptosis. Therefore, cytokine-producing B cell subsets have multifunctional functions in health and diseases, playing pathologic as well as protective roles in autoimmunity, infection, allergy, and even malignancy. In this review, we revisit the history of discovering cytokine producing B cells, describe the identification of cytokine-producing B cell subsets, introduce the origins of cytokine-producing B cell subsets as well as molecular and cellular mechanisms for their differentiation, and summarize the recent progress made toward understanding the unexpectedly complex and potentially opposing roles of cytokine-producing B cells in immunological disorders. PMID- 24794623 TI - Inhibitory effect of N-acetyl cysteine and ascorbic acid on the development of myringosclerosis: an experimental study. AB - OBJECTIVES: This study investigated the effects of ascorbic acid and N-acetyl cysteine (NAC) antioxidants on the development of myringosclerosis (MS) in an experimental model. METHODS: Myringotomies were performed in the ears of 15 guinea pigs, and Spongostan pieces were placed on the perforated regions of the tympanic membrane. The subjects were divided randomly into three groups and treated with three different solutions on the Spongostan-group 1: (control, 0.9% saline), group 2 (ascorbic acid), and group 3 (NAC). On day 15 after treatment, specimens from the tympanic membranes were obtained and examined via light microscopy. Sclerosis and inflammation scores and the tympanic membrane thicknesses were evaluated. Immunohistochemical methods were used to evaluate the expression of VEGF, TGF-beta, iNOS, and IL1-beta in all groups. RESULTS: Lower sclerosis and inflammation scores and reduced tympanic membrane thicknesses were observed in groups treated with NAC or ascorbic acid compared with the control group. Immunohistochemical studies revealed significantly less expression of VEGF, TGF-beta, and iNOS in groups 2 and 3 compared with group 1. Additionally, IL1-beta expression was significantly less in group 3 than in group 1. Compared with group 1, group 2 animals exhibited reduced inflammation in the lamina propria, fewer active fibroblasts, less leukocyte infiltration, and decreased thickness of the vessels; group 3 animals exhibited decreased numbers of active fibroblasts and collagen fibers in the lamina propria. CONCLUSIONS: Inflammation scores, cellular infiltration, and expression of VEGF, TGF-beta, and iNOS were reduced by ascorbic acid and/or NAC treatments, thereby decreasing MS development. Decreased expression of IL1-beta was observed only in animals treated with NAC. PMID- 24794620 TI - Cultivation-independent analysis of microbial communities on Austrian raw milk hard cheese rinds. AB - "Vorarlberger Bergkase" (VB) is an Austrian artisanal hard cheese produced from raw cow's milk. The composition of its rind microbiota and the changes in the microbial communities during ripening have not previously been investigated. This study used 16S and 18S rRNA gene cloning and sequencing to characterize the bacterial and fungal communities of seven pooled cheese rind samples taken in seven different ripening cellars of three Austrian dairy facilities. A total of 408 clones for 16S and 322 clones for 18S rRNA gene libraries were used for taxonomic classification, revealing 39 bacterial and seven fungal operational taxonomic units (OTUs). Bacterial OTUs belonged to four different phyla. Most OTUs were affiliated to genera often found in cheese, including high numbers of coryneforms. The most abundant OTU from 16S rRNA gene libraries showed highest similarity to Halomonas. Young cheese rinds were dominated by Actinobacteria or Proteobacteria, particularly by Halomonas and Brevibacterium aurantiacum, while Staphyloccocus equorum was most abundant in old cheeses. The most abundant 18S rRNA OTU had highest similarity to the filamentous fungus Scopulariopsis brevicaulis. Pairwise correlation analyses revealed putative co-occurrences between a number of OTUs. It was possible to discriminate the different cheese rind microbiota at the community-level by facility affiliation and ripening time. This work provides insights into the microbial composition of VB cheese rinds and might allow the processing- and ripening conditions to be improved to enhance the quality of the product. PMID- 24794624 TI - Social support and lifestyle vs. medical diabetes self-management in the diabetes study of Northern California (DISTANCE). AB - BACKGROUND: In chronic illness self-care, social support may influence some health behaviors more than others. PURPOSE: Examine social support's association with seven individual chronic illness self-management behaviors: two healthy "lifestyle" behaviors (physical activity, diet) and five more highly skilled and diabetes-specific (medical) behaviors (checking feet, oral medication adherence, insulin adherence, self-monitored blood glucose, primary care appointment attendance). METHODS: Using cross-sectional administrative and survey data from 13,366 patients with type 2 diabetes, Poisson regression models estimated the adjusted relative risks (ARR) of practicing each behavior at higher vs lower levels of social support. RESULTS: Higher emotional support and social network scores were significantly associated with increased ARR of both lifestyle behaviors. Both social support measures were also associated with increased ARR for checking feet. Neither measure was significantly associated with other medical behaviors. CONCLUSIONS: Findings suggest that social support diminished in importance as self-care progresses from lifestyle to more skilled "medical" behaviors. PMID- 24794625 TI - Anaerobic 4-chlorophenol mineralization in an enriched culture under iron reducing conditions. AB - We enriched an anaerobic, soil-free 4-chlorophenol (4-CP)-degrading culture under iron-reducing conditions. The [ring-(14)C(U)]4-CP tracer experiment showed that 65 MUM 4-CP mineralized to CO2 and CH4 through phenol, 4-hydroxybenzoate, and benzoate intermediates over 60 days. 16S rRNA gene analyses suggested the involvement of Dehalobacterium in the 4-CP dechlorination in the culture. PMID- 24794626 TI - Stable accumulation of seed storage proteins containing vaccine peptides in transgenic soybean seeds. AB - There has been a significant increase in the use of transgenic plants for the large-scale production of pharmaceuticals and industrial proteins. Here, we report the stable accumulation of seed storage proteins containing disease vaccine peptides in transgenic soybean seeds. To synthesize vaccine peptides in soybean seeds, we used seed storage proteins as a carrier and a soybean breeding line lacking major seed storage proteins as a host. Vaccine peptides were inserted into the flexible disordered regions in the A1aB1b subunit three dimensional structure. The A1aB1b subunit containing vaccine peptides in the disordered regions were sorted to the protein storage vacuoles where vaccine peptides are partially cleaved by proteases. In contrast, the endoplasmic reticulum (ER)-retention type of the A1aB1b subunit containing vaccine peptides accumulated in compartments that originated from the ER as an intact pro-form. These results indicate that the ER may be an organelle suitable for the stable accumulation of bioactive peptides using seed storage proteins as carriers. PMID- 24794627 TI - Differentiation of iPSCs into insulin-producing cells via adenoviral transfection of PDX-1, NeuroD1 and MafA. AB - AIMS: The aim of this study was to evaluate the effect of PDX-1 (pancreatic and duodenal homeobox-1), NeuroD1 (neurogenic differentiation-1) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homolog A) in the differentiation of induced pluripotent stem cells (iPSCs) into insulin-producing cells and to explore this new approach of cell transplantation therapy for type 1 diabetes in mice. METHODS: iPSCs were infected with adenovirus (Ad-Mouse PDX-1-IRES-GFP, Ad Mouse NeuroD1-IRES-GFP and Ad-Mouse Mafa-IRES-GFP) and then differentiated into insulin-producing cells in vitro. RT-PCR was applied to detect insulin gene expression, immunofluorescence to identify insulin protein, and mouse insulin enzyme-linked immunosorbent assay (ELISA) was used to evaluate the amount of insulin at different concentration of glucose. Insulin-producing cells were transplanted into the liver parenchyma of diabetic mice. Immunohistochemistry, intraperitoneal glucose tolerance test (IPGTT) and fasting blood glucose (FBG) were performed to assess the function of insulin-producing cells. RESULTS: Insulin biosynthesis and secretion were induced in iPSCs and insulin-producing cells were responsive to glucose in a dose-dependent manner. Gene expression of the three-gene-modified embryoid bodies (EBs) was similar to the mouse pancreatic beta cell line MIN6. Transplantation of insulin-producing cells into type I diabetic mice resulted in hyperglycemia reversal. CONCLUSIONS: The insulin producing cells we obtained from three-gene-modified EBs may be used as seed cells for tissue engineering and may represent a cell replacement strategy for the production of beta cells for the treatment of type 1 diabetes. PMID- 24794628 TI - A close look at the mammalian blastocyst: epiblast and primitive endoderm formation. AB - During early development, the mammalian embryo undergoes a series of profound changes that lead to the formation of two extraembryonic tissues--the trophectoderm and the primitive endoderm. These tissues encapsulate the pluripotent epiblast at the time of implantation. The current model proposes that the formation of these lineages results from two consecutive binary cell fate decisions. The first controls the formation of the trophectoderm and the inner cell mass, and the second controls the formation of the primitive endoderm and the epiblast within the inner cell mass. While early mammalian embryos develop with extensive plasticity, the embryonic pattern prior to implantation is remarkably reproducible. Here, we review the molecular mechanisms driving the cell fate decision between primitive endoderm and epiblast in the mouse embryo and integrate data from recent studies into the current model of the molecular network regulating the segregation between these lineages and their subsequent differentiation. PMID- 24794630 TI - 'Hybrid' processing strategies for expanding and improving the synthesis of renewable bioproducts. AB - The versatile functionality of microbial biocatalysts offers a promising solution to the growing need to replace conventional, petroleum-derived fuels, chemicals, and materials with sustainable alternatives from renewable biomass. Whereas metabolic pathway engineering and strain optimization have greatly expanded the range of attainable bioproducts, it is by coupling microbial biosynthesis with traditional chemical conversions that the diversity of products that can ultimately be derived from biomass is truly beginning to reach its full potential. As will be the focus of this short review, such 'hybrid' strategies are now facilitating the generation of new and useful value-added bioproducts from renewable sources, the likes of which have previously been unattainable via biological routes alone. PMID- 24794631 TI - Biomining-biotechnologies for extracting and recovering metals from ores and waste materials. AB - The abilities of acidophilic chemolithotrophic bacteria and archaea to accelerate the oxidative dissolution of sulfide minerals have been harnessed in the development and application of a biotechnology for extracting metals from sulfidic ores and concentrates. Biomining is currently used primarily to leach copper sulfides and as an oxidative pretreatment for refractory gold ores, though it is also used to recover other base metals, such as cobalt, nickel and zinc. Recent developments have included using acidophiles to process electronic wastes, to extract metals from oxidized ores, and to selectively recover metals from process waters and waste streams. This review describes the microorganisms and mechanisms involved in commercial biomining operations, how the technology has developed over the past 50 years, and discusses the challenges and opportunities for mineral biotechnologies in the 21st century. PMID- 24794634 TI - Novel gas chromatographic detector utilizing the localized surface plasmon resonance of a gold nanoparticle monolayer inside a glass capillary. AB - This paper presents the design, assembly, and evaluation of a novel gas chromatographic detector intended to measure the absorbance of the localized surface plasmon resonance (LSPR) of a gold nanoparticle monolayer in response to eluted samples from a capillary column. Gold nanoparticles were chemically immobilized on the inner wall of a glass capillary (i.d. 0.8 mm, length = 5-15 cm). The eluted samples flowed through the glass capillary and were adsorbed onto a gold nanoparticle surface, which resulted in changes in the LSPR absorbance. The LSPR probing light source used a green light-emitting diode (LED; lambda(center) = 520 nm), and the light traveled through the glass wall of the capillary with multiple total reflections. The changes in the light intensity were measured by a photodiode at the rear of the glass capillary. The sensitivity of this detector can be improved by using a longer spiral glass capillary. The detector is more sensitive when operated at a lower temperature and at a slower carrier velocity. The calibration lines of 8 preliminary test compounds were all linear (R(2) > 0.99). The detection limits (3sigma) ranged from 22 ng (n-butanol) to 174 ng (2-pentanone) depending on the volatility of the chemicals and the affinity to the citrate lignads attached to the gold nanoparticle surface. This detector consumed a very low amount of energy and could be operated with an air carrier gas, which makes this detector a promising option for portable GC or MUGC. PMID- 24794632 TI - A two-tier Golgi-based control of organelle size underpins the functional plasticity of endothelial cells. AB - Weibel-Palade bodies (WPBs), endothelial-specific secretory granules that are central to primary hemostasis and inflammation, occur in dimensions ranging between 0.5 and 5 MUm. How their size is determined and whether it has a functional relevance are at present unknown. Here, we provide evidence for a dual role of the Golgi apparatus in controlling the size of these secretory carriers. At the ministack level, cisternae constrain the size of nanostructures ("quanta") of von Willebrand factor (vWF), the main WPB cargo. The ribbon architecture of the Golgi then allows copackaging of a variable number of vWF quanta within the continuous lumen of the trans-Golgi network, thereby generating organelles of different sizes. Reducing the WPB size abates endothelial cell hemostatic function by drastically diminishing platelet recruitment, but, strikingly, the inflammatory response (the endothelial capacity to engage leukocytes) is unaltered. Size can thus confer functional plasticity to an organelle by differentially affecting its activities. PMID- 24794629 TI - Eph- and ephrin-dependent mechanisms in tumor and stem cell dynamics. AB - The erythropoietin-producing hepatocellular (Eph) receptors comprise the largest family of receptor tyrosine kinases (RTKs). Initially regarded as axon-guidance and tissue-patterning molecules, Eph receptors have now been attributed with various functions during development, tissue homeostasis, and disease pathogenesis. Their ligands, ephrins, are synthesized as membrane-associated molecules. At least two properties make this signaling system unique: (1) the signal can be simultaneously transduced in the receptor- and the ligand expressing cell, (2) the signaling outcome through the same molecules can be opposite depending on cellular context. Moreover, shedding of Eph and ephrin ectodomains as well as ligand-dependent and -independent receptor crosstalk with other RTKs, proteases, and adhesion molecules broadens the repertoire of Eph/ephrin functions. These integrated pathways provide plasticity to cell microenvironment communication in varying tissue contexts. The complex molecular networks and dynamic cellular outcomes connected to the Eph/ephrin signaling in tumor-host communication and stem cell niche are the main focus of this review. PMID- 24794633 TI - Collier/OLF/EBF-dependent transcriptional dynamics control pharyngeal muscle specification from primed cardiopharyngeal progenitors. AB - In vertebrates, pluripotent pharyngeal mesoderm progenitors produce the cardiac precursors of the second heart field as well as the branchiomeric head muscles and associated stem cells. However, the mechanisms underlying the transition from multipotent progenitors to distinct muscle precursors remain obscured by the complexity of vertebrate embryos. Using Ciona intestinalis as a simple chordate model, we show that bipotent cardiopharyngeal progenitors are primed to activate both heart and pharyngeal muscle transcriptional programs, which progressively become restricted to corresponding precursors. The transcription factor COE (Collier/OLF/EBF) orchestrates the transition to pharyngeal muscle fate both by promoting an MRF-associated myogenic program in myoblasts and by maintaining an undifferentiated state in their sister cells through Notch-mediated lateral inhibition. The latter are stem cell-like muscle precursors that form most of the juvenile pharyngeal muscles. We discuss the implications of our findings for the development and evolution of the chordate cardiopharyngeal mesoderm. PMID- 24794635 TI - Acculturation and Latino adolescent mental health: integration of individual, environmental, and family influences. AB - In order to address the mental health disparities that exist for Latino adolescents in the United States, psychologists must understand specific factors that contribute to the high risk of mental health problems in Latino youth. Given the significant percentage of Latino youth who are immigrants or the children of immigrants, acculturation is a key factor in understanding mental health among this population. However, limitations in the conceptualization and measurement of acculturation have led to conflicting findings in the literature. Thus, the goal of the current review is to examine and critique research linking acculturation and mental health outcomes for Latino youth, as well as to integrate individual, environmental, and family influences of this relationship. An integrated theoretical model is presented and implications for clinical practice and future directions are discussed. PMID- 24794636 TI - Structural and energetic analysis to provide insight residues of CYP2C9, 2C11 and 2E1 involved in valproic acid dehydrogenation selectivity. AB - Docking and molecular dynamics (MD) simulation have been two computational techniques used to gain insight about the substrate orientation within protein active sites, allowing to identify potential residues involved in the binding and catalytic mechanisms. In this study, both methods were combined to predict the regioselectivity in the binding mode of valproic acid (VPA) on three cytochrome P 450 (CYP) isoforms CYP2C9, CYP2C11, and CYP2E1, which are involved in the biotransformation of VPA yielding reactive hepatotoxic intermediate 2-n-propyl-4 pentenoic acid (4nVPA). There are experimental data about hydrogen atom abstraction of the C4-position of VPA to yield 4nVPA, however, there are not structural evidence about the binding mode of VPA and 4nVPA on CYPs. Therefore, the complexes between these CYP isoforms and VPA or 4nVPA were studied to explore their differences in binding and energetic stabilization. Docking results showed that VPA and 4nVPA are coupled into CYPs binding site in a similar conformation, but it does not explain the VPA hydrogen atom abstraction. On the other hand, MD simulations showed a set of energetic states that reorient VPA at the first ns, then making it susceptible to a dehydrogenation reaction. For 4nVPA, multiple binding modes were observed in which the different states could favor either undergo other reaction mechanism or ligand expulsion from the binding site. Otherwise, the energetic and entropic contribution point out a similar behavior for the three CYP complexes, showing as expected a more energetically favorable binding free energy for the complexes between CYPs and VPA than with 4nVPA. PMID- 24794637 TI - A cyclin-like protein, ClgA, regulates development in Aspergillus nidulans. AB - A cyclin-like protein from Aspergillus nidulans, ClgA, was identified. Its cyclin like subunit shares 28.3% identity to Saccharomyces cerevisiae Clg1. Deletion of clgA slightly influenced fungal growth, but repressed asexual development and made it more sensitive to temperature variations. It also downregulated expression of brlA, abaA and wetA, which are critically responsible for asexual development. Sexual development was impaired in the DeltaclgA mutant. Its related genes, veA and nosA, were expressed weakly in the DeltaclgA mutant, while nsdD expression showed the opposite behavior. Generally, ClgA functioned differently from other reported cyclins in development of A. nidulans. PMID- 24794638 TI - Alexithymia and adult attachment representations: associations with the five factor model of personality and perceived relationship adjustment. AB - Several studies have demonstrated associations between alexithymia, adult attachment styles, personality traits, and relationship adjustment. Only two studies, however, have explored associations between alexithymia and attachment representations. As part of a larger investigation of maternal and infant attachment, the current study explored this association in a sample of 97 pregnant women; in addition, measures of alexithymia and domains of the five factor model (FFM) of personality were compared in predicting attachment security, assessed with the Adult Attachment Interview Coherence of Mind mind scale, and perceived relationship adjustment. Alexithymia negatively predicted coherence of mind; the domains of the FFM did not add significantly to the prediction. The Openness-to-Experience domain predicted relationship adjustment better than alexithymia. Contrary to findings from studies that assessed adult attachment styles, coherence of mind was unrelated to relationship adjustment and the FFM. The results suggest that alexithymia does not uniquely predict relationship adjustment beyond the domains of the FFM. PMID- 24794639 TI - Personality traits associated with suicidal behaviors in patients with depression: the CRESCEND study. AB - The aim of the current study was to identify personality traits associated with suicidal behavior in patients with depression. Of the 1183 patients screened for an observational cohort study of depression, 334 (28.2%) who completed the Temperament and Character Inventory (TCI) were included in these analyses. To minimize the effect of current mood state, the TCI was performed 12 weeks after initiation of treatment, and we adjusted for the severity of depression. Of the 344 participants, 59 had a lifetime history of at least one suicide attempt, 37 had a lifetime history of multiple suicide attempts, and 5 attempted suicide during the 12-week study period. At baseline, patients with a lifetime history of at least one suicide attempt, a lifetime history of multiple suicide attempts, and a suicide attempt during the study period expressed more serious current suicidal ideation than did those without such a history, despite the absence of differences among the groups in the severity of depressive and anxiety symptoms. Of the seven personality scales of the TCI, lower scores on the self-directedness scale of the character dimension were associated with a history of at least one suicide attempt (OR [95% CI], 0.91 [0.87-0.96]; p<0.001), a history of multiple suicide attempts (0.91 [0.86-0.97]; p=0.003), and suicide attempts during study period (0.80 [0.69-0.94]; p=0.006). These findings suggest that depressed patients with a history of suicidal behavior differ from non-attempters with regard to personality traits, especially the character dimension of self directedness. It is noteworthy that this result emerged after controlling for the effect of current mood state. PMID- 24794640 TI - Adolescent insanity revisited: course and outcome in early-onset schizophrenia spectrum psychoses in an 8-year follow-up study. AB - OBJECTIVES: Despite inclusion of adolescent insanity-a concept proposed by Thomas Clouston in late XIX century-into the broader nosological entity of dementia praecox, the uniqueness of early psychosis is still discussed. The aim of the current study is the assessment of course and outcome in the large sample of early-onset psychosis subjects. METHOD: Of 299 patients hospitalized in the period 1998-2008 in an adolescent psychiatry ward with schizophrenia spectrum diagnosis 158 completed a follow-up interview. Data concerning current diagnosis, further admissions, current treatment status and occupational and relationship outcome were analyzed after a mean of 8 years of follow-up. RESULTS: Mean age at the index admission and the follow-up was 16.6 +/- 1.2 and 24.5 +/- 3.0 years respectively. After the subsequent discharge almost all subjects (97%) at least briefly continued psychiatric treatment and 75% of patients had been readmitted. Overall diagnostic stability was 42%. For schizophrenia spectrum disorders and schizophrenia diagnostic stability was 72% and 78%, respectively. At the follow up assessment 119 (77.3%) of the traced subjects declared current psychiatric treatment and 110 (73.3%) were receiving pharmacotherapy. Almost half of the subjects (48%) were employed or studying and more than a third (35.8%) remained in a stable relationship. Different distributions of baseline diagnoses were observed in males and females, and the latter showed a better outcome. CONCLUSION: Early-onset psychoses were characterized by limited diagnostic stability, a necessity for further treatment and hospitalizations and significant percentage of unfavorable functional outcomes. Baseline diagnosis of acute and transient psychotic disorders and female gender were associated with an overall better outcome. PMID- 24794641 TI - Exaggerating, mislabeling or simulating obsessive-compulsive symptoms: case reports of patients claiming to have obsessive-compulsive disorder. AB - BACKGROUND: There are no reported cases of factitious or simulated obsessive compulsive disorder (OCD). However, over the last years, our clinic has come across a number of individuals that seem to exaggerate, mislabel or even intentionally "produce" obsessive and/or compulsive symptoms in order to be diagnosed with OCD. METHODS: In this study, experienced clinicians working on a university-based OCD clinic were requested to provide clinical vignettes of patients who, despite having a formal diagnosis of OCD, were felt to display non genuine forms of this condition. RESULTS: Ten non-consecutive patients with a self-proclaimed diagnosis of OCD were identified and described. Although patients were diagnosed with OCD according to various structured interviews, they exhibited diverse combinations of the following features: (i) overly technical and/or doctrinaire description of their symptoms, (ii) mounting irritability, as the interviewer attempts to unveil the underlying nature of these descriptions; (iii) marked shifts in symptom patterns and disease course; (iv) an affirmative "yes" pattern of response to interview questions; (v) multiple Axis I psychiatric disorders; (vi) cluster B features; (vii) an erratic pattern of treatment response; and (viii) excessive or contradictory drug-related side effects. CONCLUSIONS: In sum, reliance on overly structured assessments conducted by insufficiently trained or naive personnel may result in invalid OCD diagnoses, particularly those that leave no room for clinical judgment. PMID- 24794642 TI - Psychopathology and quality of life among patients with comorbidity between schizophrenia spectrum disorder and obsessive-compulsive disorder: no evidence for a "schizo-obsessive" subtype. AB - BACKGROUND: Epidemiological studies have found that obsessive-compulsive disorder (OCD) is estimated to occur in up to 12% of patients with schizophrenia. Furthermore, several etiopathogenic mechanisms have been postulated for understanding this co-occurrence. Whether this subgroup of "schizo-obsessive" patients may be posed as a clinical entity with a distinct psychopathological and functioning profile remains unclear. METHOD: A sample of adult patients who met DSM-IV criteria for both schizophrenia/schizoaffective disorder and OCD (n=30) was compared with a "non-OCD schizophrenic" group (n=37) and another subset of "non-schizophrenic OCD" patients (n=30). The Positive and Negative Syndrome Scale (PANSS), the Scale to Assess Unawareness of Mental Disorder (SUMD), the Yale Brown Obsessive-Compulsive Scale (Y-BOCS), the Brown Assessment of Beliefs Scale (BABS), the Clinical Global Severity scale (CGI), the Quality of Life Scale (QLS), and the Beck's Depression Inventory (BDI) were used. RESULTS: We found that "schizo-obsessive" subjects did not show significant differences in any outcome measures when compared to the "non-OCD schizophrenic" group. Furthermore, statistical analyses also revealed that the "non-schizophrenic OCD" group tended to have lower severity of psychopathology as well as greater quality of life than both psychotic groups. CONCLUSIONS: These findings indicate that comorbidity between schizophrenia/schizoaffective disorder and OCD does not comprise a distinct clinical entity, particularly when compared to "non-OCD schizophrenia" disorder. Discrepancies among previous studies may be justified by methodological divergences. PMID- 24794643 TI - Outcomes of blastocysts biopsied and vitrified once versus those cryopreserved twice for euploid blastocyst transfer. AB - Trophectoderm biopsy with comprehensive chromosome screening (CCS) has been shown to increase implantation and pregnancy rates. Some patients desire CCS on previously cryopreserved blastocysts, resulting in blastocysts that are thawed/warmed, biopsied, vitrified and then warmed again. The effect of two cryopreservation procedures and two thawing/warming procedures on outcomes has not been effectively studied. Cycles were divided into two groups: group 1 patients underwent a cryopreserved embryo transfer with euploid blastocysts that were vitrified and warmed once; group 2 patients had a cryopreserved embryo transfer of a euploid blastocyst that was cryopreserved, thawed/warmed, biopsied, vitrified and warmed. Groups 1 and 2 included 85 and 17 women aged 35.6 +/- 3.9 and 35.3 +/- 4.9 years, respectively (not significantly different). Blastocyst survival in group 1 (114/116, 98.3%) and survival of second warming in group 2 (21/24, 87.5%) was significantly different (P = 0.0354). There was no difference between biochemical (68.2% and 62.5%) and clinical (61.2% and 56.3%) pregnancy rates, implantation rate (58.4% and 52.4%) and live birth/ongoing pregnancy rate (54.0% and 47.6%) between groups 1 and 2, respectively. Although it is unconventional to thaw/warm, biopsy, revitrify and rewarm blastocysts for cryopreserved embryo transfer, the results indicate that outcomes are not compromised. Trophectoderm biopsy and screening the embryos for chromosomal abnormalities has been reported to increase implantation and pregnancy rates. There is a category of patients requesting chromosomal screening on previously cryopreserved blastocysts. This scenario requires blastocysts to be thawed/warmed, biopsied, cryopreserved, and thawed/warmed again. The effect of double cryopreservation procedures and double thawing/warming procedures on pregnancy is unknown. Patients were divided into two groups, group 1 underwent a cryopreserved embryo transfer with a chromosomally normal blastocyst that was vitrified and warmed once and group 2 included patients that had a cryopreserved embryo transfer of a chromosomally normal blastocyst that was cryopreserved, thawed/warmed, biopsied, vitrified, and rewarmed. A total of 85 and 17 women aged 35.6 +/- 3.9 and 35.3 +/- 4.9 years were included in groups 1 and 2, respectively. The survival rate for group 1 (114 of 116, 98.3%) compared with the second warming for group 2 (21 of 24, 87.5%) was significantly higher. There was no difference between biochemical (68.2% and 62.5%), and clinical pregnancies (61.2% and 56.3%), implantation (58.4% and 52.4%), and live birth/ongoing rates (54.0% and 47.6%) between groups 1 and 2. Although it is unconventional to twice cryopreserve and twice thaw/warm a blastocyst, our results indicate that outcomes are not compromised. PMID- 24794645 TI - Serosurveillance of Schmallenberg virus in Switzerland using bulk tank milk samples. AB - Infections with Schmallenberg virus (SBV), a novel Orthobunyavirus transmitted by biting midges, can cause abortions and malformations of newborns and severe symptoms in adults of domestic and wild ruminants. Understanding the temporal and spatial distribution of the virus in a certain territory is important for the control and prevention of the disease. In this study, seroprevalence of antibodies against SBV and the spatial spread of the virus was investigated in Swiss dairy cattle applying a milk serology technique on bulk milk samples. The seroprevalence in cattle herds was significantly higher in December 2012 (99.5%) compared to July 2012 (19.7%). This high between-herd seroprevalence in cattle herds was observed shortly after the first detection of viral infections. Milk samples originating from farms with seropositive animals taken in December 2012 (n=209; mean 160%) revealed significantly higher S/P% ratios than samples collected in July 2012 (n=48; mean 103.6%). This finding suggests a high within herd seroprevalence in infected herds which makes testing of bulk tank milk samples for the identification farms with past exposures to SBV a sensitive method. It suggests also that within-herd transmission followed by seroconversion still occurred between July and December. In July 2012, positive bulk tank milk samples were mainly restricted to the western part of Switzerland whereas in December 2012, all samples except one were positive. A spatial analysis revealed a separation of regions with and without positive farms in July 2012 and no spatial clustering within the regions with positive farms. In contrast to the spatial dispersion of bluetongue virus, a virus that is also transmitted by Culicoides midges, in 2008 in Switzerland, the spread of SBV occurred from the western to the eastern part of the country. The dispersed incursion of SBV took place in the western part of Switzerland and the virus spread rapidly to the remaining territory. This spatial pattern is consistent with the hypothesis that transmission by Culicoides midges was the main way of spreading. PMID- 24794644 TI - Mucosal vaccines against respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in infants, young children, immune-compromised and elderly populations worldwide. Natural RSV infection in young children does not elicit long-lasting immunity and individuals remain susceptible to repeated RSV infections throughout life. Because RSV infection is restricted to the respiratory tract, an RSV vaccine should elicit mucosal immunity at upper and lower respiratory tracts in order to most effectively prevent RSV reinfection. Although there is no safe and effective RSV vaccine available, significant progress has been recently made in basic RSV research and vaccine development. This review will discuss recent advances in the identification of a new neutralizing antigenic site within the RSV fusion (F) protein, understanding the importance of mucosal immune responses against RSV infection, and the development of novel mucosal vaccination strategies. PMID- 24794646 TI - Risk factors associated with the presence of Varroa destructor in honey bee colonies from east-central Argentina. AB - Varroa destructor is considered one of the major threats for worldwide apiculture. Damage caused by varroa mite includes body weight loss, malformation and weakening of the bees. It was also suggested as the main cause associated with colony winter mortality and as an important vector for several honey bee viruses. Little is known about multiple factors and their interaction affecting V. destructor prevalence in apiaries from South America. The aim of this study was to identify risk factors associated with V. destructor prevalence in east central Argentina. Parasitic mite infestation level and colony strength measures were evaluated in 63 apiaries distributed in 4 different regions in east-central Argentina in a cross sectional study. Data regarding management practices in each apiary were collected by means of a questionnaire. A mixed-effects logistic regression model was constructed to associate management variables with the risk of achieving mite infestation higher than 3%. Colonies owned by beekeepers who indicated that they did not monitor colonies after mite treatment (OR=2.305; 95% CI: 0.944-5.629) nor disinfect hives woodenware material (OR=2.722; 95% CI: 1.380 5.565) were associated with an increased risk of presenting high intensity infestation with V. destructor (>3%). On the other hand, beekeepers who reported replacing more than 50% of the queens in their operation (OR=0.305; 95% CI: 0.107 0.872), feeding colonies protein substitute containing natural pollen (OR=0.348; 95% CI: 0.129-0.941) and feeding colonies High Fructose Corn Syrup (HFCS) (OR=0.108; 95% CI: 0.032-0.364), had colonies that were less likely to have V. destructor infestations above 3%, than beekeepers who did not report using these management practices. Further research should be conducted considering that certain management practices were associated to mite infestation level in order to improve the sanitary condition in the colonies. Epidemiological studies provide key information to design surveillance programs against one the major threat to worldwide beekeeping. PMID- 24794647 TI - Body borne loads impact walk-to-run and running biomechanics. AB - The purpose of this study was to perform a biomechanics-based assessment of body borne load during the walk-to-run transition and steady-state running because historical research has limited load carriage assessment to prolonged walking. Fifteen male military personnel had trunk and lower limb biomechanics examined during these locomotor tasks with three different load configurations (light, ~6 kg, medium, ~20 kg, and heavy, ~40 kg). Subject-based means of the dependent variables were submitted to repeated measures ANOVA to test the effects of load configuration. During the walk-to-run transition, the hip decreased (P=0.001) and knee increased (P=0.004) their contribution to joint power with the addition of load. Additionally, greater peak trunk (P=0.001), hip (P=0.001), and knee flexion (P<0.001) moments and trunk flexion (P<0.001) angle, and reduced hip (P=0.001) and knee flexion (P=0.001) posture were evident during the loaded walk-to-run transition. Body borne load had no significant effect (P>0.05) on distribution of lower limb joint power during steady-state running, but increased peak trunk (P<0.001), hip (P=0.001), and knee (P=0.001) flexion moments, and trunk flexion (P<0.001) posture were evident. During the walk-to-run transition the load carrier may move joint power production distally down the kinetic chain and adopt biomechanical profiles to maintain performance of the task. The load carrier, however, may not adopt lower limb kinematic adaptations necessary to shift joint power distribution during steady-state running, despite exhibiting potentially detrimental larger lower limb joint loads. As such, further study appears needed to determine how load carriage impairs maximal locomotor performance. PMID- 24794648 TI - Individuals with chronic ankle instability exhibit decreased postural sway while kicking in a single-leg stance. AB - Individuals with chronic ankle instability (CAI) usually experience deficits in balance control, which increase displacement in the body's center of pressure (COP) when they balance on a single leg. Little is known, however, about whether or not these individuals use the strategies of postural adjustment properly, especially during functional tasks that may predispose them to ankle sprain. The aim of this study was to investigate anticipatory (APA) and compensatory (CPA) postural adjustments in individuals with and without CAI as they kick a ball while standing in a single-leg stance with their ankle in neutral and supinated positions. COP displacements were calculated and their magnitudes (range) analyzed during APA and CPA intervals and over the duration of the whole task, represented by the COP area of sway and mean velocity. The CAI group exhibited a significant decrease in CPA and area of sway over the whole task, relative to controls. These results suggest that the decreased balance sway could be caused by the need for further stabilization of the ankle in more unstable postures to prevent recurrent sprain. Our findings could help clinicians to better understand the strategies of postural adjustments in individuals with CAI, and may assist and motivate new investigations into balance control interventions in such individuals, as well as proactively address recurrent ankle sprain conditions. PMID- 24794649 TI - Academic detailing to teach aging and geriatrics. AB - Geriatric education is a required component of internal medicine training. Work hour rules and hectic schedules have challenged residency training programs to develop and utilize innovative teaching methods. In this study, the authors examined the use of academic detailing as a teaching intervention in their residents' clinic and on the general medicine inpatient wards to improve clinical knowledge and skills in geriatric care. The authors found that this teaching method enables efficient, directed education without disrupting patient care. We were able to show improvements in medical knowledge as well as self-efficacy across multiple geriatric topics. PMID- 24794651 TI - Managing information overload. PMID- 24794652 TI - Copayments for general practice visits. PMID- 24794653 TI - Linking data to improve health outcomes. PMID- 24794656 TI - Doctors' "judgements" and parents' "wishes": ethical implications in conflict situations. PMID- 24794657 TI - General practice: are we equipped for the future? PMID- 24794658 TI - The newer contraceptive pills and venous thromboembolism risk. PMID- 24794659 TI - Murray to the Mountains intern training program: involvement of small health services. PMID- 24794660 TI - The role of oncology nurse practitioners in current oncology practice and lessons for Australia. PMID- 24794661 TI - New Delhi metallo-beta-lactamase-producing enterobacteriaceae in an Australian child who had not travelled overseas. PMID- 24794662 TI - Caveat emptor: the corruption of open access scientific publishing. PMID- 24794663 TI - It's time for clinical guidelines to enter the digital age. PMID- 24794664 TI - The utility of genetics in inherited cancer. PMID- 24794665 TI - Growing the clinical academic workforce: the case for structured academic training programs for junior doctors. PMID- 24794666 TI - Changes in alcohol consumption in pregnant Australian women between 2007 and 2011. PMID- 24794667 TI - Prevention of fetal alcohol spectrum disorders must include maternal treatment. PMID- 24794668 TI - Pathways to enhancing the quality of stroke care through national data monitoring systems for hospitals. PMID- 24794669 TI - Pathways to enhancing the quality of stroke care through national data monitoring systems for hospitals. Reply. PMID- 24794670 TI - Proportionate research funding based on relative burden of conditions of communication and swallowing. PMID- 24794671 TI - Safer hours for doctors and improved safety for patients. AB - An increasing weight of evidence is demonstrating that sleep deprivation and circadian rhythm disruption in doctors are associated with human error and harm to both patients and doctors. The increasing junior doctor workforce entering the hospital system in Australia provides a rare opportunity for workplace and roster reforms. There are cultural, educational and industrial challenges to reforming working hours. Any changes should be evidence-based and monitored to ensure that training for junior doctors and patient care are not compromised. PMID- 24794672 TI - The desire and capability of Australian general practitioners to change their working hours. AB - OBJECTIVE: To explore factors associated with general practitioners' desire to work less and their success in making that change. DESIGN, PARTICIPANTS AND SETTING: Waves 3 and 4 (conducted in 2010 and 2011) of a national longitudinal survey of Australian doctors in clinical practice (Medicine in Australia: Balancing Employment and Life). Of the broader group of medical practitioners in the survey, there were 3664 and 3436 GP completers in Waves 3 and 4, respectively. MAIN OUTCOME MEASURES: The association between the desire to reduce hours and doctor, job and geographic characteristics; the association between predictors of the capability to reduce hours and these same doctor, job and geographic characteristics. RESULTS: Over 40% of GPs stated a preference to reduce their working hours. Characteristics that predicted this preference were being middle-aged, being female, working >= 40 hours per week (all P < 0.01), and being on call (P = 0.03). Factors associated with not wanting to reduce working hours were being in excellent health, being satisfied or very satisfied with work (both P < 0.01), and not being a partner in a practice (P < 0.01 for a number of alternative options [ie, associates, contractors and locums]). Of those who wanted to reduce working hours, 26.8% successfully managed to do so in the subsequent year (where reduction was defined as reducing hours by at least 5 per week). Predictors of successfully reducing hours were being younger, female and working >= 40 hours per week (all P < 0.01). CONCLUSION: A number of factors appear to determine both the desire of GPs to reduce hours and their subsequent success in doing so. Declining working hours have contributed to the perceived shortage in GPs. Therefore, designing policies that address not just the absolute number of medical graduates but also their subsequent level of work may alleviate some of the pressures on the Australian primary health care system. PMID- 24794673 TI - Predictors of variation in colorectal cancer care and outcomes in New South Wales: a population-based health data linkage study. AB - OBJECTIVE: To identify predictors of variation in colorectal cancer care and outcomes in New South Wales. DESIGN, SETTING AND PATIENTS: Multilevel logistic regression analysis using a linked population-based dataset based on the records of patients with cancer of the colon, rectosigmoid junction or rectum who were registered in 2007 and 2008 by the NSW Central Cancer Registry and treated in 105 hospitals in NSW. MAIN OUTCOME MEASURES: Six outcome measures (30-day mortality, 28-day emergency readmission, prolonged length of stay, 30-day wound infection, 90-day venous thromboembolism, 1-year mortality) and five care process measures (discussion at multidisciplinary team [MDT] meeting, documented cancer stage, recorded pathological stage, treatment within 31 days of decision to treat, treatment within 62 days of referral). RESULTS: We analysed data for 6890 people. There was wide variation between hospitals in care process measures, even after adjusting for patient and hospital factors. Older adults were less likely to be discussed at an MDT meeting and receive treatment within suggested time frames (all P < 0.001 for colon cancer). Increasing patient age, greater extent of disease, higher Charlson comorbidity score and resection after emergency admission consistently showed strong evidence of an association with poor outcomes. Much of the variation between hospitals in outcome measures was accounted for by patient characteristics. CONCLUSIONS: Patient characteristics should be included in risk-adjustment models for comparing outcomes between hospitals and for quantifying hospital variation. Further exploration of the reasons why certain hospitals and patients appear to be at risk of poorer care is needed. PMID- 24794674 TI - Survival, mortality and morbidity outcomes after oesophagogastric cancer surgery in New South Wales, 2001-2008. AB - OBJECTIVES: To examine the relationship between hospital volume and patient outcomes for New South Wales hospitals performing oesophagectomy and gastrectomy for oesophagogastric cancer. DESIGN, SETTING AND PATIENTS: A retrospective, population-based cohort study of NSW residents diagnosed with a new case of invasive oesophageal or gastric cancer who underwent oesophagectomy or gastrectomy between 2001 and 2008 in NSW hospitals using linked de-identified data from the NSW Central Cancer Registry, the National Death Index and the NSW Admitted Patient Data Collection. A higher-volume hospital was defined as one performing > 6 relevant procedures per year. MAIN OUTCOME MEASURES: Odds ratios for > 21-day length of stay, 28-day unplanned readmission, 30-day mortality and 90-day mortality, and hazard ratios (HRs) for 5-year absolute and conditional survival. RESULTS: Oesophagectomy (908 patients) and gastrectomy (1621 patients) were undertaken in 42 and 84 hospitals, respectively, between 2001 and 2008. Median annual hospital volume ranged from 2 to 4 for oesophagectomies and ranged from 2 to 3 for gastrectomies. Controlling for known confounders, no associations between hospital volume and > 21-day length of stay and 28-day unplanned readmission were found. Overall 30-day mortality was 4.1% and 4.4% for oesophagectomy and gastrectomy, respectively. Five-year absolute survival was significantly better for patients who underwent oesophagectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.28 [95% CI, 1.10-1.49]; P = 0.002) and for those with localised gastric cancer who underwent gastrectomy in higher-volume hospitals (adjusted HR for lower-volume hospitals, 1.83 [95% CI, 1.28-2.61]; P = 0.001). CONCLUSIONS: These data support initial surgery for oesophagogastric cancer in higher-volume hospitals. PMID- 24794675 TI - Emergency contraception in Australia: the desired source of information versus the actual source of information. AB - OBJECTIVE: To determine long-term trends in emergency contraception (EC) management by general practitioners in Australia. DESIGN, SETTING AND PARTICIPANTS: Data from April 2000 to March 2012 were drawn from the BEACH (Bettering the Evaluation and Care of Health) program, a continuous cross sectional survey of GP activity. We analysed consultations involving EC management, unwanted pregnancy management and emergency contraceptive pill (ECP) prescribing per 1000 GP encounters with women aged 14-54 years. Summary statistics were calculated with 95% confidence intervals. RESULTS: In 2000-2001, GPs managed EC problems at a rate of 5.50 per 1000 encounters (95% CI, 4.37 6.63). From 2004, after the ECP became available over the counter (OTC) in pharmacies, EC management, which includes ECP prescription, progressively declined. By 2011-2012, only 1.43 EC problems were managed per 1000 encounters (95% CI, 0.84-2.02) and only 0.48 ECP prescriptions were provided per 1000 encounters (95% CI, 0.14-0.82). Yet the management rate of unwanted pregnancy problems stayed relatively constant (rate in 2000-2001, 0.95 per 1000 encounters; 95% CI, 0.40-1.50; rate in 2011-2012, 0.88 per 1000 encounters; 95% CI, 0.41 1.36). CONCLUSION: Low rates of EC management by GPs since ECP became available OTC suggest that women may be obtaining information on EC elsewhere. Further investigation is needed to uncover the sources of this information and its acceptability and application by Australian women. PMID- 24794676 TI - Using automated text messages to monitor adverse events following immunisation in general practice. AB - OBJECTIVE: To assess the performance of SmartVax, a prototypic active monitoring system for adverse events following immunisation (AEFI) using short message service (SMS) text messages and clinical data extracted from commercially available medical practice management software. DESIGN, SETTING AND PARTICIPANTS: Between 11 November 2011 and 10 June 2013, adult patients and parents of paediatric patients receiving routine vaccinations in general practice were sent an SMS by SmartVax enquiring if they had experienced any AEFI and requesting a reply by SMS. Attempts were made to telephone patients who did not reply by SMS. MAIN OUTCOME MEASURES: The proportion of patients sent an SMS who replied by SMS, and the proportion of respondents indicating possible AEFI. RESULTS: Of 3281 vaccinated patients, 3226 (98.3%) had a mobile telephone number on record and were sent an SMS. Of 2342 patients (72.6%; 95% CI, 70.0%-75.1%) who responded by SMS, 264 (11.3%; 95 CI, 9.9%-12.7%) reported possible AEFI. The response rate was >= 70% for both paediatric and adult patients. Eighty-per cent of SMS replies were received within 2 hours of transmission of the query SMS. There was no significant difference in the proportion reporting possible AEFI between patients who replied by SMS and those who did not respond by SMS but were subsequently contacted by a telephone call (P = 0.99). CONCLUSIONS: More than 70% of patients responded by SMS to an SMS query about whether they had any vaccine reactions, with the data received in near real-time. Active surveillance of AEFI using SMS has the capacity to complement existing passive reporting systems, potentially permitting more rapid identification of emerging safety signals. PMID- 24794677 TI - Internet slimming, thyrotoxicosis and the liver. PMID- 24794679 TI - Australian doctors and war. 1941. PMID- 24794680 TI - Isolation and substrate specificity of an adenine nucleoside phosphorylase from adult Schistosoma mansoni. AB - An adenine nucleoside phosphorylase (ANP, EC none) activity was identified and partially purified from extracts of Schistosoma mansoni by chromatofocussing column chromatography and molecular sieving. The enzyme is distinct from purine nucleoside phosphorylase (PNP, EC 2.4.2.1). ANP is specific for adenine nucleosides which includes adenosine analogs modified in the aglycone, pentose or both moieties. (e.g. 2'-deoxyadenosine, 5'-deoxy-5'-methylthioadenosine, 5'-deoxy 5'-iodo-2-fluoroadenosine, etc.) The enzyme is also distinct from the mammalian 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP, EC 2.4.2.28) in that it is able of the phosphorolysis of 2'-deoxyadenosine while mammalian MTAP cannot. Because of ANP unique substrate specificity, the enzyme could play a role as a target for chemotherapy of these parasites. Cytotoxic analogs may be designed as subversive substrates that are selectively activated only by the schistosomal ANP. PMID- 24794681 TI - Defining risk factors and presentations of allergic reactions to platelet transfusion. PMID- 24794682 TI - Allergen-specific IgE is not detectable in the bronchial mucosa of nonatopic asthmatic patients. PMID- 24794683 TI - Component-resolved diagnosis of wheat flour allergy in baker's asthma. PMID- 24794684 TI - The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever. AB - BACKGROUND: Sensitization to profilins and other cross-reacting molecules might hinder proper specific immunotherapy (SIT) prescription in polysensitized patients with pollen-related allergic rhinitis (AR). In these patients, component resolved diagnosis (CRD) might modify SIT prescription by improving the identification of the disease-eliciting pollen sources. OBJECTIVES: We sought to measure the effect of CRD on SIT prescription in children with pollen-related AR. METHODS: Children (n = 651) with moderate-to-severe pollen-related AR were recruited between May 2009 and June 2011 in 16 Italian outpatient clinics. Skin prick test (SPT) reactivity to grass, cypress, olive, mugwort, pellitory, and/or Betulaceae pollen was considered clinically relevant if symptoms occurred during the corresponding peak pollen season. IgE sensitization to Phl p 1, Phl p 5, Bet v 1, Cup a 1, Art v 1, Ole e 1, Par j 2, and Phl p 12 (profilin) was measured by using ImmunoCAP. SIT prescription was modeled on SPT responses first and then remodeled considering also CRD according to GA(2)LEN-European Academy of Allergology and Clinical Immunology guidelines and the opinions of 14 pediatric allergists. RESULTS: No IgE to the respective major allergens was detected in significant proportions of patients with supposed clinically relevant sensitization to mugwort (45/65 [69%]), Betulaceae (146/252 [60%]), pellitory (78/257 [30%]), olive (111/390 [28%]), cypress (28/184 [15%]), and grass (56/568 [10%]). IgE to profilins, polcalcins, or both could justify 173 (37%) of 464 of these SPT reactions. After CRD, the SPT-based decision on SIT prescription or composition was changed in 277 (42%) of 651 or 315 (48%) of 651 children according to the European or American approach, respectively, and in 305 (47%) of 651 children according to the opinion of the 14 local pediatric allergists. CONCLUSIONS: In children with pollen-related AR, applying CRD leads to changes in a large proportion of SIT prescriptions as opposed to relying on clinical history and SPT alone. The hypothesis that CRD-guided prescription improves SIT efficacy deserves to be tested. PMID- 24794686 TI - Immunologic response and safety in birch pollen sublingual versus oral vestibule immunotherapy: a pilot study. PMID- 24794685 TI - Host natural killer immunity is a key indicator of permissiveness for donor cell engraftment in patients with severe combined immunodeficiency. AB - BACKGROUND: Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. OBJECTIVE: To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. METHODS: A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK(+) (n = 24) and NK(-) (n = 53) forms of SCID. RESULTS: Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK(-)SCID were more likely to survive than NK(+) recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK(+)SCID required additional transplantation procedures compared with only 8% of children with NK( )SCID (P < .005). CONCLUSIONS: NK(-)SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution. PMID- 24794687 TI - Detection and quantification of periodontal pathogens in smokers and never smokers with chronic periodontitis by real-time polymerase chain reaction. AB - BACKGROUND: The purpose of the present investigation is to compare the presence and number of periodontal pathogens in the subgingival microbiota of smokers versus never-smokers with chronic periodontitis and matched probing depths (PDs) using real-time polymerase chain reaction (RT-PCR). METHODS: Forty current smokers and 40 never-smokers, matched for age, sex, and mean PD of sampling site, were included in this investigation. A full-mouth periodontal examination was performed, and a pooled subgingival plaque sample was collected from the deepest site in each quadrant of each participant. To confirm smoking status, expired carbon monoxide (CO) concentrations were measured with a CO monitor. The presence and quantification of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola were determined using RT-PCR. RESULTS: Smokers had greater overall mean PD (P = 0.001) and attachment loss (P = 0.006) and fewer bleeding on probing sites (P = 0.001). An association was observed between smoking status and the presence of A. actinomycetemcomitans (P <0.001). The counts of A. actinomycetemcomitans (P <0.001), P. gingivalis (P = 0.042), and T. forsythia (P <0.001) were significantly higher in smokers. CONCLUSIONS: Smokers showed significantly greater amounts of P. gingivalis, A. actinomycetemcomitans, and T. forsythia than never-smokers. There was a significant association between smoking and the presence of A. actinomycetemcomitans. PMID- 24794689 TI - Crestal bone level changes around immediately placed implants: a systematic review and meta-analyses with at least 12 months' follow-up after functional loading. AB - BACKGROUND: Immediate implant placement (IIP) is a successful treatment and has the advantages of reducing time and increasing patient satisfaction. However, achieving predictable esthetic results with IIP presents a challenge because of naturally occurring bone loss postextraction. Therefore, the focused question of this systematic review is: What is the effect of IIP on crestal bone level (CBL) changes after at least 12 months of functional loading? METHODS: Extensive literature review of the Cochrane and MEDLINE electronic databases and a manual search up to November 2012 identified eligible studies. Two reviewers independently assessed the study data and methodologic quality using data extraction and assessment forms. RESULTS: Electronic and manual searches identified 648 relevant publications. A total of 57 articles satisfied the inclusion criteria. Sixteen studies had test and control groups; therefore, meta analyses could be performed. The results demonstrated better CBL preservation around IIP compared with implant placement in healed/native bone at 12 months [CBL difference of -0.242 (95% confidence interval [CI], -0.403 to -0.080; P = 0.003)]. Similarly, platform switching around IIP showed better results compared with non-platform switching (CBL difference of -0.770 [95% CI, -1.153 to -0.387; P <0.001]). There was no difference in mean CBL changes with regard to one-stage or two-stage IIP protocol (-0.017 [95% CI, -0.249 to 0.216; P = 0.85]) or the use of immediate or delayed immediate implant loading (0.002 [95% CI, -0.269 to 0.272; P = 0.99]). CONCLUSIONS: Meta-analyses showed less CBL loss around IIP compared with implant placement in healed bone. Platform-switched implants showed greater crestal bone preservation than non-platform-switched implants. There was no significant difference in CBL with one- versus two-stage placement or use of immediate versus delayed IIP loading. Although there were statistically significant differences favoring IIP, the small differences may not be clinically relevant. Although IIP showed favorable outcomes for CBL changes, these results should be interpreted with caution because of high heterogeneity among studies. PMID- 24794688 TI - Vitamin D status and 5-year changes in periodontal disease measures among postmenopausal women: the Buffalo OsteoPerio Study. AB - BACKGROUND: Vitamin D is hypothesized to prevent periodontal disease progression through its immune-modulating properties and its role in maintaining systemic calcium concentrations. The authors investigated associations between plasma 25 hydroxyvitamin D [25(OH)D] (collected 1997 to 2000) and the 5-year change in periodontal disease measures from baseline (1997 to 2000) to follow-up (2002 to 2005) among 655 postmenopausal women in a Women's Health Initiative Observational Study ancillary study. Exploratory analyses were conducted in 628 women who also had 25(OH)D measures at follow-up. METHODS: Four continuous measures of the 5 year change in periodontal disease were assessed using alveolar crest height (ACH), clinical attachment level (CAL), probing depth (PD), and percentage of gingival sites that bled on assessment. Linear regression was used to estimate beta-coefficients, standard errors, and P values corresponding to change in periodontal disease (a 1-mm change in ACH, CAL, or PD or a 1-unit change in the percentage of gingival sites that bled) for a 10-nmol/L difference in 25(OH)D. Models were adjusted for age, education, dental visit frequency, smoking, diabetes status, current medications affecting bone health, baseline measures of periodontal disease, body mass index, and recreational physical activity. RESULTS: No statistically significant associations were observed between baseline 25(OH)D and change in periodontal disease measures, overall or in a subset (n = 442) of women with stable 25(OH)D concentrations [25(OH)D change <20 nmol/L from baseline to follow-up]. RESULTS also did not vary significantly in analyses that were stratified by baseline periodontal disease status. CONCLUSIONS: No association between baseline 25(OH)D and the subsequent 5-year change in periodontal disease measures was observed. Vitamin D status may not influence periodontal disease progression. More studies are needed to confirm these results. PMID- 24794690 TI - Elective removal of cervical cerclage and onset of spontaneous labor. AB - OBJECTIVE: To determine the time interval between elective removal of cervical cerclage and onset of spontaneous labor. METHODS: A retrospective cohort study was conducted between January 2005 and December 2012 at a tertiary care hospital in Lisbon, Portugal. All singleton pregnancies with a McDonald or Shirodkar cerclage electively removed at 36-37 weeks were evaluated for the time interval between cerclage removal and spontaneous labor. Delivery within 72 hours after cerclage removal was compared between patients with elective cerclage and those with non-elective cerclage. In the non-elective group, a sub-analysis of the results for ultrasound- and physical examination-indicated cerclage was performed. RESULTS: Thirty-eight women were included. The time interval between cerclage removal and spontaneous labor did not differ significantly between the elective and the non-elective group (15.6+/-7.6 vs 10.9+/-7.4 days; P=0.063). A higher incidence of delivery 72 hours after cerclage removal was seen in the non elective group but this was not significant (P=0.061). There were no differences regarding the time interval from elective removal of cervical cerclage to onset of spontaneous labor between ultrasound-indicated and physical examination indicated cerclage. CONCLUSION: Regardless of the indication for cervical cerclage, the probability of delivery soon after elective cerclage removal is low. PMID- 24794691 TI - Accidental electrocution in pregnancy. PMID- 24794692 TI - Role of reminder by text message in enhancing postnatal clinic attendance. PMID- 24794693 TI - Outcome of obstetric anal sphincter injuries in terms of persisting endoanal ultrasonographic defects and defecatory symptoms. AB - OBJECTIVE: To determine the prevalence of persisting endoanal ultrasonographic defects among women with obstetric anal sphincter injuries (OASIS), and the incidence of defecatory symptoms. METHODS: In a prospective study in Enschede, Netherlands, women with OASIS were enrolled between 2007 and 2012. Three months after surgical repair, all women had an endoanal ultrasound, and data were collected on gas and fecal incontinence, soiling, and fecal urgency. RESULTS: Overall, 99 women were included. At follow-up, 35 (35.4%) women had a persisting defect of the external anal sphincter on ultrasound, and 5 women (5.1%) also had a persisting defect of the internal anal sphincter. Overall, 35 (35.4%) women had one or more defecatory complaints-predominantly involuntary loss of gas and fecal urgency. Overall, 22 of 35 (63.0%) women with and 13 of 64 (20.3%) women without a persisting defect on ultrasound had defecatory complaints. The number of defecatory symptoms showed a positive correlation with severity of injury. Women with a persisting defect had a threefold higher risk of defecatory complaints as compared with women who had a successful repair (odds ratio, 6.6; 95% confidence interval, 2.6-16.6). CONCLUSION: The results emphasize the importance of adequate repair of OASIS and demonstrate that repair can be difficult or underestimated. PMID- 24794694 TI - Neuropsychological and psychiatric assessments following bilateral deep brain stimulation of the subthalamic nucleus in Japanese patients with Parkinson's disease. AB - The physical benefits of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well documented, but the mental benefits are uncertain, particularly in Japanese patients. This study evaluated the clinical and neuropsychological characteristics before and after STN-DBS surgery in Japanese PD patients. PD patients (n=13, age 67.0 +/- 7.8 years) were evaluated pre-surgery (baseline) and at 1 and 6 months post-surgery by two trained psychiatrists. The motor symptoms were assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. The neuropsychological and psychiatric tests performed were the Mini-Mental State Examination, the Wisconsin Card Sorting Test (WCST), the Verbal Fluency Test (VFT), the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale (HAM-A). The UPDRS motor score (p<0.001) and HAM-A score (p=0.004) showed significant improvement at 1 month post-surgery, but a significant decline was observed in the WCST total error (p=0.005) and the semantic VFT score (p<0.001). The phonetic VFT also showed a substantial decline (p=0.015) at 1 month post-surgery. At 6 months post-surgery, the improvement in the UPDRS motor score was maintained, and the scores on the neuropsychological and psychiatric tests had returned to baseline. Although bilateral STN-DBS did not appear to have long-term effects on neuropsychological and psychiatric outcomes, the microlesion effects associated with STN-DBS appear to increase the risk of transient cognitive and psychiatric complications. These complications should be monitored by careful observation of neurological and psychiatric symptoms. PMID- 24794695 TI - Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha. AB - OBJECTIVE: Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. PATIENTS AND METHODS: Data were collected through a review of patients' medical records. RESULTS: The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. CONCLUSIONS: In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population. PMID- 24794696 TI - [Comparison of two opioids with different kinetics for intravenous analgesia in outpatient multiple third molar avulsions]. AB - INTRODUCTION: We had for aim to compare the effects of intra-operative opioid analgesia according to the drug kinetics. PATIENTS AND METHODS: We conducted a prospective, controlled, randomized, double-blinded trial including 60 patients scheduled for ambulatory multiple third molar avulsion. The general anesthesia, performed with propofol and analgesia was a target-controlled infusion of either remifentanil or sufentanil. The anesthesia was set to reach an optimal bispectral index and adjusted to a clinical target throughout the procedure. The main endpoints were: postoperative request for morphine and other opioids; postoperative pain; postoperative adverse effects of opioids. RESULTS: In the post-operative care unit (French acronym PACU), patients who received remifentanil were extubated earlier (17 vs. 26 min.), but had more pain and required twice more morphine for analgesia (6 vs. 3 mg), than those who had received sufentanil. However, the need for post-surgery oral opioid intake was greater in the sufentanil group, so the overall postoperative opioid consumption and patient satisfaction were identical in both groups. The time spent in the PACU was also identical for both groups. DISCUSSION: Using an ultra-short kinetic opioid such as remifentanil does not seem useful, since the shorter delay before extubation is compensated by a greater need for morphine in the PACU. PMID- 24794697 TI - In meta-analyses of proportion studies, funnel plots were found to be an inaccurate method of assessing publication bias. AB - OBJECTIVE: To assess the utility of funnel plots in assessing publication bias (PB) in meta-analyses of proportion studies. STUDY DESIGN AND SETTING: Meta analysis simulation study and meta-analysis of published literature reporting peri-operative mortality after abdominal aortic aneurysm (AAA) repair. Data for the simulation study were stochastically generated. A literature search of Medline and Embase was performed to identify studies for inclusion in the published literature meta-analyses. RESULTS: The simulation study demonstrated that conventionally constructed funnel plots (log odds vs. 1/standard error [1/SE]) for extreme proportional outcomes were asymmetric despite no PB. Alternative funnel plots constructed using study size rather than 1/SE showed no asymmetry for extreme proportional outcomes. When used in meta-analyses of the mortality of AAA repair, these alternative funnel plots highlighted the possibility for conventional funnel plots to demonstrate asymmetry when there was no evidence of PB. CONCLUSION: Conventional funnel plots used to assess for potential PB in meta-analyses are inaccurate for meta-analyses of proportion studies with low proportion outcomes. Funnel plots of study size against log odds may be a more accurate way of assessing for PB in these studies. PMID- 24794698 TI - Risk-difference curves can be used to communicate time-dependent effects of adjuvant therapies for early stage cancer. AB - OBJECTIVES: To describe the use of risk-difference curves for communicating time dependent absolute treatment effects. STUDY DESIGN AND SETTING: Three examples based on individual patient data meta-analyses for adjuvant treatments for early stage breast cancer are presented. Unit record datasets were re-created from the published Kaplan-Meier curves and numbers at risk or person-years at risk. Risk difference curves, with corresponding 95% confidence bands, are presented and discussed. RESULTS: Risk-difference curves are useful for communicating the results from trials of adjuvant treatments for early-stage cancer when standard measures of the absolute treatment effect for survival data (ie, difference-in mean and difference-in-median survival) can be difficult to estimate. They also avoid the problem of "evolving selection bias", which can affect interval specific hazard ratio (HR)s in trials with long follow-up and where the participants are heterogeneous with respect to prognosis. CONCLUSION: Clinical epidemiologists should consider reporting risk-difference curves in addition to Kaplan-Meier curves and the HR. PMID- 24794699 TI - We need another guideline. PMID- 24794700 TI - Imaging RNA Polymerase II transcription sites in living cells. AB - Over the past twenty years, exciting developments in optical and molecular imaging approaches have allowed researchers to examine with unprecedented resolution the spatial organization of transcription sites in the nucleus. An attractive model that has developed from these studies is that active genes cluster to preformed transcription factories that contain multiple active RNA polymerases and transcription factor proteins required for efficient mRNA biogenesis. However, this model has been extensively debated in part due to the fact transcription factories and their features have only been documented in fixed cells. In this review, we will focus on recent live-cell imaging studies that are changing our understanding of transcription factories. PMID- 24794702 TI - Insulin analogues for recurrent severe hypoglycaemia. PMID- 24794701 TI - SMC complexes link gene expression and genome architecture. AB - The structural maintenance of chromosomes (SMC) complexes are associated with transcriptional enhancers, promoters and insulators, where they contribute to the control of gene expression and genome structure. We review here recent insights into the interlinked roles of SMC complexes in gene expression and genome architecture. Among these, we note evidence that SMC complexes play important roles in the regulation of genes that control cell identity. We conclude by reviewing diseases associated with SMC mutations. PMID- 24794703 TI - Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial. AB - BACKGROUND: Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin. METHODS: In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged >=18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996. FINDINGS: Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0.51 episodes (95% CI 0.19-0.84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11-48; p=0.010). INTERPRETATION: Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins. FUNDING: Novo Nordisk A/S. PMID- 24794704 TI - Usefulness of the Shock Index as a secondary triage tool. AB - INTRODUCTION: Secondary triage at a major incident allows for a more detailed assessment of the patient. In the UK, the Triage Sort (TSO) is the preferred method, combining GCS, systolic BP (SBP) and RR to categorise Priority 1 casualties. The Shock Index (SI) is calculated by dividing HR by SBP (HR/SBP). This study examines whether SI is better at predicting need for life-saving intervention (LSI) following trauma than TSO. METHODS: A prospective observational study was undertaken. Physiological data and interventions performed in the Emergency Department and operating theatre were prospectively collected for 482 consecutive adult trauma patients presenting to Camp Bastion, Afghanistan, over a 6-month period. A patient was deemed to have required LSI if they received any intervention from a set described previously. RESULTS: Complete data were available for 345 patients (71.6%). Of these, 203 (58.8%) were gold standard P1, and 142 (41.2%) were non-P1. The TSO predicted need for LSI with a sensitivity of 58.6% (95% CI 51.8% to 65.4%) and specificity of 88.7% (95% CI 83.5% to 93.9%). Using an SI cut-off >0.75 provided greater sensitivity of 70.0% (95% CI 63.6% to 76.3%) while maintaining an acceptably high (although lower than TSO) specificity of 74.7% (95% CI 67.5% to 81.8%). At this SI cut-off, there was evidence of a difference between TSO and SI in terms of the way in which patients were triaged (p<0.0001). DISCUSSION: Our study showed that a SI >0.75 more accurately predicted the need for LSI, while maintaining acceptable specificity. SI may be more useful than TSO for secondary triage in a mass-casualty situation; this relationship in civilian trauma should be examined to clarify whether these results can be more widely translated into civilian practice. PROJECT REGISTRATION NUMBER: RCDM/Res/Audit/1036/12/0050. PMID- 24794705 TI - Dopamine ups and downs in vulnerability to addictions: a neurodevelopmental model. AB - Addictions are commonly presaged by problems in childhood and adolescence. For many individuals this starts with the early expression of impulsive risk-taking, social gregariousness, and oppositional behaviors. Here we propose that these early diverse manifestations reflect a heightened ability of emotionally salient stimuli to activate dopamine pathways that foster behavioral approach. If substance use is initiated, these at-risk youth can also develop heightened responses to drug-paired cues. Through conditioning and drug-induced sensitization, these effects strengthen and accumulate, leading to responses that exceed those elicited by other rewards. At the same time, cues not paired with drug become associated with comparatively lower dopamine release, accentuating further the difference between drug and non-drug rewards. Together, these enhancing and inhibiting processes steer a pre-existing vulnerability toward a disproportionate concern for drugs and drug-related stimuli. Implications for prevention and treatment are discussed. PMID- 24794706 TI - Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. AB - Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD L1), suggesting a mechanism of immune escape for TPCs. PMID- 24794709 TI - Management of cardiovascular diseases during pregnancy. Foreword. PMID- 24794708 TI - Smokeless tobacco use in pregnancy: an integrative review of the literature. AB - OBJECTIVES: To systematically critique and summarise the available evidence on the outcomes of smokeless tobacco use in pregnancy to inform the public health response. METHODS: In March 2013, a search was conducted of observational studies where the exposure to smokeless tobacco during pregnancy and maternal, placental and/or neonatal outcomes was assessed. Two reviewers extracted data and completed quality assessment of the literature utilizing the Agency for Healthcare Research and Quality criteria (West et al. 2002). RESULTS: The search resulted in 211 articles, 21 (10%) of which met the final criteria for integrative review. Ten (10) of the studies are from India, seven (7) from Sweden, two (2) from Alaska and one (1) each from South Africa and Pakistan. CONCLUSIONS: Many studies lacked sufficient power to estimate precise risks. Most reports were hindered by imprecise measures of exposure and lack of confounding variable control. However, there were indications that maternal smokeless tobacco use increases rates of stillbirth, low birth weight and alters the male:female live birth ratio. Maternal smokeless tobacco use may not be safe for mother or foetus. PMID- 24794707 TI - MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. AB - Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ~50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease. PMID- 24794710 TI - Management of cardiovascular diseases during pregnancy. AB - The prevalence of cardiovascular diseases (CVDs) in women of childbearing age is rising. The successes in medical and surgical treatment of congenital heart disease have led to an increasing number of women at childbearing age presenting with problems of treated congenital heart disease. Furthermore, in developing countries and in immigrants from these countries, rheumatic valvular heart disease still plays a significant role in young women. Increasing age of pregnant women and increasing prevalence of atherosclerotic risk factors have led to an increase in women with coronary artery disease at pregnancy. Successful management of pregnancy in women with CVDs requires early diagnosis, a thorough risk stratification, and appropriate management by a multidisciplinary team of obstetricians, cardiologists, anesthesiologists, and primary care physicians. The following review is based on the recent European guidelines on the management of CVDs during pregnancy, which aim at providing concise and simple recommendations for these challenging problems. PMID- 24794711 TI - Adults' perceptions of genetic counseling and genetic testing. AB - PURPOSE: This study described the perceptions of genetic counseling and testing of adults (N = 116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. METHODS: Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. RESULTS: Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. CONCLUSIONS: Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles. PMID- 24794712 TI - In situ monitoring of structural changes during formation of 30S translation initiation complex by energy dissipation measurement using 27-MHz quartz-crystal microbalance. AB - Ribosome is a bionanomachine that facilitates an orderly translation process during protein synthesis in living cells. Real-time monitoring of conformational changes in ribosomal subunits in aqueous solution is important to understand the regulatory mechanism of protein synthesis, because conformational changes in ribosome in E. coli have been predicted to operate the switch from translation initiation to an elongation process during translation. We performed an energy dissipation measurement by using a quartz-crystal microbalance-admittance (QCM-A) technique for in situ monitoring of conformational changes in pre-30S translation initiation complex in response to the binding of fMet-tRNA(fMet) in aqueous solution. The addition of fMet-tRNA(fMet) caused changes in the physical property (increased dehydration and elasticity) in 30S ribosomal subunit in the presence of mRNA and IF2/guanosine 5'-triphosphate (GTP) on the QCM plate. Furthermore, two sequential changes triggered by the addition of fMet-tRNA(fMet) were observed in 30S ribosomal subunit bound to mRNA in the presence of IF2/GTP and IF3. These observations suggest that the structural changes in 30S ribosomal subunit caused by the binding of fMet-tRNA(fMet) with IF2/GTP in the presence of IF3 could act as a switch to regulate the orderly processing in the construction of translation initiation complex, because the structural distinction can be a guidepost in the process for the relevant biomolecules. PMID- 24794713 TI - Mangiferin regulates interleukin-6 and cystathionine-b-synthase in lipopolysaccharide-induced brain injury. AB - Mangiferin has been extensively applied in different fields due to its anti inflammatory properties. However, the precise mechanism used by mangiferin on lipopolysaccharide (LPS)-induced inflammation has not been elucidated. Here, we discuss the potential mechanism of mangiferin during a LPS-induced brain injury. Brain injury was induced in ICR mice via intraperitoneal LPS injection (5 mg/kg). Open- and closed-field tests were used to detect the behaviors of mice, while immunoblotting was performed to measure the expression of interleukin-6 (IL-6) and cystathionine-b-synthase (CBS) in the hippocampus after mangiferin was orally administered (p.o.). Mangiferin relieved LPS-induced sickness 6 and 24 h after LPS injection; in addition, this compound suppressed LPS-induced IL-6 production after 24 h of LPS induction as well as the downregulation of LPS-induced CBS expression after 6 and 24 h of LPS treatment in the hippocampus. Therefore, mangiferin attenuated sickness behavior by regulating the expression of IL-6 and CBS. PMID- 24794714 TI - Association between current asthma and secondhand smoke exposure in vehicles among adults living in four US states. AB - OBJECTIVE: Many states have implemented laws prohibiting tobacco smoking in indoor public places. However, private settings remain a major source of secondhand smoke (SHS) exposure for many people. We assessed the association between current asthma and SHS exposure in vehicles among adult never-smokers in Indiana, Kentucky, Louisiana and Mississippi. METHODS: Data came from the 2011 Behavioral Risk Factor Surveillance System, a state-based telephone survey of US adults aged >=18 years. Analyses were restricted to states (n=4) that administered an optional SHS module. Prevalence of self-reported asthma and past 7-day SHS exposure in vehicles was calculated by demographics, voluntary smoke free vehicle rules and SHS exposure in homes, public places and workplaces. Logistic regression was used to assess the adjusted association between asthma and SHS exposure in vehicles. RESULTS: Among 17 863 never-smoking adults, 7.4% reported having current asthma, whereas 12.3% reported past 7-day SHS exposure in vehicles. Among adults with asthma, SHS exposure in vehicles was lower among those with voluntary smoke-free rules compared with those without voluntary smoke free rules (9.5% vs 56.7%, p<0.0001). Following adjustment, adults exposed to SHS in a vehicle had a higher odds of having current asthma compared with unexposed adults (OR=2.01, 95% CI 1.18 to 3.40). CONCLUSIONS: Never-smoking adults recently exposed to SHS in a vehicle had higher odds of having current asthma compared with unexposed adults. Efforts are warranted to warn about the dangers of SHS and to encourage voluntary smoke-free rules in vehicles, especially among adults with asthma. PMID- 24794715 TI - How adolescents view the tobacco endgame and tobacco control measures: trends and associations in support among 14-15 year olds. AB - BACKGROUND AND AIMS: Adolescents represent the next generation and have the greatest amount to gain from the tobacco endgame. They will provide the future momentum to achieve the tobacco endgame, thus it is important that their views on interventions are monitored. We examined support among 14-15-year-old New Zealanders for tobacco endgame goals and measures, and trends in this support from 2009 to 2012. METHODS: This study used data from an annual survey of over 25 000 Year 10 students (14-15 year olds) undertaken by Action on Smoking and Health New Zealand. We assessed support for five tobacco control goals and measures: living in a smoke-free country; having fewer tobacco retail outlets; not selling tobacco in 10 years' time; implementing outdoor smoking bans; and raising the price of tobacco. RESULTS: Support for living in a smoke-free country was 59%, while support for a ban on all tobacco sales in 10 years' time was 57% in the most recent survey year. Most respondents supported each of the tobacco control measures and gave strongest support to having fewer places where tobacco could be sold (71% in 2012). Support for the other two tobacco control measures in the most recent year ranged from 59% to 64% and had increased over time, in most cases significantly. Support was strongest among non-smokers and declined as participants' smoking frequency increased. CONCLUSIONS: Young people support New Zealand's smoke-free goal and interventions that could help achieve it; this evidence should galvanise policy action, which remains out of step with public opinion. PMID- 24794716 TI - Stereoselective synthesis of perdeuterated phytanic acid, its phospholipid derivatives and their formation into lipid model membranes for neutron reflectivity studies. AB - We describe a straightforward method, for synthesis of large scale (gram quantities) of highly deuterated phytanic acid from commercially available phytol while preserving the stereochemistry around the chiral centres. The subsequent synthesis of tail-deuterated analogues of the archeabacterial membrane lipids 1,2 di(3RS,7R,11R-phytanyl)-sn-glycero-3-phosphocholine (DPEPC) and 1,2-di(3RS,7R,11R phytanoyl)-sn-glycero-3-phosphocholine (DPhyPC) from perdeuterated phytanic acid is also described. Both lipids were employed in construction of two different model membranes, namely Langmuir monolayers and a tethered bilayer membrane (TBM) on a solid substrate, characterised by pressure area isotherm and neutron reflectometry techniques. At 10 mN/m pressure the head-group thickness of both monolayers was similar while the thickness of the tail region was significantly larger for tail-deuterated DPhyPC, which was evident from a smaller area per molecule. At 20 mN/m the thickness of the head and tail regions in both lipids was comparable, yet the area per molecule of tail-deuterated DPhyPC was 10% smaller than tail-deuterated DPEPC. In the TBM bilayer model membrane, the thickness of the lipid tails in both inner and outer leaflets was 8.2 A, giving a total of 16.4 A. Deuteration enabled unambiguous determination of the relative proportion of the hydrogenous tether, phospholipid and subphase. PMID- 24794718 TI - Endonucleases: new tools to edit the mouse genome. AB - Mouse transgenesis has been instrumental in determining the function of genes in the pathophysiology of human diseases and modification of genes by homologous recombination in mouse embryonic stem cells remains a widely used technology. However, this approach harbors a number of disadvantages, as it is time-consuming and quite laborious. Over the last decade a number of new genome editing technologies have been developed, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas). These systems are characterized by a designed DNA binding protein or RNA sequence fused or co-expressed with a non-specific endonuclease, respectively. The engineered DNA binding protein or RNA sequence guides the nuclease to a specific target sequence in the genome to induce a double strand break. The subsequent activation of the DNA repair machinery then enables the introduction of gene modifications at the target site, such as gene disruption, correction or insertion. Nuclease mediated genome editing has numerous advantages over conventional gene targeting, including increased efficiency in gene editing, reduced generation time of mutant mice, and the ability to mutagenize multiple genes simultaneously. Although nuclease-driven modifications in the genome are a powerful tool to generate mutant mice, there are concerns about off-target cleavage, especially when using the CRISPR/Cas system. Here, we describe the basic principles of these new strategies in mouse genome manipulation, their inherent advantages, and their potential disadvantages compared to current technologies used to study gene function in mouse models. This article is part of a Special Issue entitled: From Genome to Function. PMID- 24794719 TI - Rapamycin protects against Abeta-induced synaptotoxicity by increasing presynaptic activity in hippocampal neurons. AB - The mammalian target of rapamycin (mTOR) is involved in the regulation of learning and memory. Recently, rapamycin has been shown to be neuroprotective in models for Alzheimer's disease in an autophagy-dependent manner. Here we show that rapamycin exerts neuroprotection via a novel mechanism that involves presynaptic activation. Rapamycin increases the frequency of miniature excitatory postsynaptic currents and calcium transients of rat hippocampal primary neurons by a mechanism that involves the up regulation of SV2, a presynaptic vesicular protein linked to neurotransmitter release. Under these conditions, rapamycin treated hippocampal neurons are resistant to the synaptotoxic effect induced by Abeta oligomers, suggesting that enhancers of presynaptic activity can be therapeutic agents for Alzheimer's disease. PMID- 24794720 TI - The effect of nitroglycerin on the IUD insertion experience in nulliparous women: a pilot study. AB - OBJECTIVE: Concern about pain during placement of an intrauterine device (IUD) represents a barrier to use, especially among nulliparous women. We hypothesized that nitroglycerin gel applied vaginally 30 min prior to IUD placement would reduce insertion-related pain. STUDY DESIGN: We designed a randomized, double blinded, placebo-controlled pilot study to evaluate the efficacy and tolerability of 0.5-mg nitroglycerin gel (1 mL) or identical placebo gel applied vaginally in nulliparous women 30 min prior to IUD placement. The study was limited to women who opted for the levonorgestrel-releasing intrauterine system. Subjects completed a series of 100-mm visual analogue scales at several time points. The primary outcome was subject-reported pain with passage of the IUD through the cervix. Secondary outcomes included subject-reported pain at other time points, provider-reported ease of insertion, side effects, adverse events and need for additional dilation. RESULTS: A total of 24 women were randomized. Baseline characteristics were similar between groups. The mean pain score with IUD deployment was 55.0 mm [standard deviation (SD) = 29.7 mm] in the placebo group and 57.4 mm (SD 22.1 mm) in the nitroglycerin group (p=.82). There was no difference in ease of insertion reported by providers. Two subjects required dilation, one in each group. CONCLUSION: Vaginal administration of 0.5-mg nitroglycerin gel 30 min prior to IUD placement does not appear to decrease patient-reported procedural pain among nulliparous women or ease of insertion for providers. PMID- 24794722 TI - Engineering redox balance through cofactor systems. AB - Redox balance plays an important role in the production of enzymes, pharmaceuticals, and chemicals. To meet the demands of industrial production, it is desirable that microbes maintain a maximal carbon flux towards target metabolites with no fluctuations in redox. This requires functional cofactor systems that support dynamic homeostasis between different redox states or functional stability in a given redox state. Redox balance can be achieved by improving the self-balance of a cofactor system, regulating the substrate balance of a cofactor system, and engineering the synthetic balance of a cofactor system. This review summarizes how cofactor systems can be manipulated to improve redox balance in microbes. PMID- 24794723 TI - Expression of exogenous DNA methyltransferases: application in molecular and cell biology. AB - DNA methyltransferases might be used as powerful tools for studies in molecular and cell biology due to their ability to recognize and modify nitrogen bases in specific sequences of the genome. Methylation of the eukaryotic genome using exogenous DNA methyltransferases appears to be a promising approach for studies on chromatin structure. Currently, the development of new methods for targeted methylation of specific genetic loci using DNA methyltransferases fused with DNA binding proteins is especially interesting. In the present review, expression of exogenous DNA methyltransferase for purposes of in vivo analysis of the functional chromatin structure along with investigation of the functional role of DNA methylation in cell processes are discussed, as well as future prospects for application of DNA methyltransferases in epigenetic therapy and in plant selection. PMID- 24794724 TI - Kinase mTOR: regulation and role in maintenance of cellular homeostasis, tumor development, and aging. AB - Serine/threonine protein kinase mTOR regulates the maintenance of cellular homeostasis by coordinating transcription, translation, metabolism, and autophagy with availability of amino acids, growth factors, ATP, and oxygen. The mTOR kinase is a component of two protein complexes, mTORC1 and mTORC2, which are different in their composition and regulate different cellular processes. An uncontrolled activation of the mTOR kinase is observed in cells of the majority of tumors, as well as in diabetes and neurodegenerative and some other diseases. At present, inhibitors of the kinase complex mTORC1 are undergoing clinical trials. This review focuses on different aspects of the regulation of the mTORC1 and mTORC2 complexes, on their role in the regulation of protein synthesis, metabolism, and autophagy, as well as on using mTOR inhibitors for treatment of tumors and slowing of aging. PMID- 24794725 TI - Pectin methylesterase-generated methanol may be involved in tobacco leaf growth. AB - Plant leaves undergo a sink-source modification of intercellular macromolecular transport during the transition from carbon import to carbon export. After assessing the role of metabolite signaling in gene regulation in Nicotiana tabacum sink and source leaves, we observed increased pectin methylesterase (PME) mediated methanol generation in immature leaves. Using suppression subtractive hybridization (SSH), we identified a number of genes whose activity changes from sink to source leaves. The most abundant SSH-identified genes appeared to be sensitive to methanol. We hypothesize that tobacco leaf maturation and the sink source transition are accompanied by a change in mRNA levels of genes that function in methanol-dependent cell signaling. PMID- 24794726 TI - Hepatitis B virus can be inhibited by DNA methyltransferase 3a via specific zinc finger-induced methylation of the X promoter. AB - In this work we explored whether DNA methyltransferase 3a (Dnmt3a) targeted to the HBV X promoter (XP) causes epigenetic suppression of hepatitis B virus (HBV). The C-terminus of Dnmt3a (Dnmt3aC) was fused to a six-zinc-finger peptide specific to XP to form a fused DNA methyltransferase (XPDnmt3aC). The binding and methyl-modifying specificity of XPDnmt3aC were verified with an electrophoretic mobility shift assay and methylation-specific PCR, respectively. XP activity and HBV expression were clearly downregulated in HepG2 cells transfected with plasmid pXPDnmt3aC. The injection of XPDnmt3aC into HBV transgenic (TgHBV) mice also showed significant inhibition, leading to low serum HBV surface protein (HBsAg) levels and a reduced viral load. Thus, XPDnmt3aC specifically silenced HBV via site-selective DNA methylation delivered by zinc-finger peptides. This study establishes the foundation of an epigenetic way of controlling HBV-related diseases. PMID- 24794721 TI - Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. AB - BACKGROUND: Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing remitting multiple sclerosis. METHODS: We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score <=5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 MUg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. FINDINGS: We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0.397 (95% CI 0.328-0.481) in the placebo group versus 0.256 (0.206-0.318) in the every 2 weeks group and 0.288 (0.234-0.355) in the every 4 weeks group (rate ratio for every 2 weeks group 0.644, 95% CI 0.500-0.831, p=0.0007; rate ratio for the every 4 weeks group 0.725, 95% CI 0.565-0.930, p=0.0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. INTERPRETATION: After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. FUNDING: Biogen Idec. PMID- 24794727 TI - Mitochondria-targeted antioxidants prevent TNFalpha-induced endothelial cell damage. AB - Increased serum level of tumor necrosis factor alpha (TNFalpha) causes endothelial dysfunction and leads to serious vascular pathologies. TNFalpha signaling is known to involve reactive oxygen species (ROS). Using mitochondria targeted antioxidant SkQR1, we studied the role of mitochondrial ROS in TNFalpha induced apoptosis of human endothelial cell line EAhy926. We found that 0.2 nM SkQR1 prevents TNFalpha-induced apoptosis. SkQR1 has no influence on TNFalpha dependent proteolytic activation of caspase-8 and Bid, but it inhibits cytochrome c release from mitochondria and cleavage of caspase-3 and its substrate PARP. SkQ analogs lacking the antioxidant moieties do not prevent TNFalpha-induced apoptosis. The antiapoptotic action of SkQR1 may be related to other observations made in these experiments, namely SkQR1-induced increase in Bcl-2 and corresponding decrease in Bax as well as p53. These results indicate that mitochondrial ROS production is involved in TNFalpha-initiated endothelial cell death, and they suggest the potential of mitochondria-targeted antioxidants as vasoprotectors. PMID- 24794728 TI - Search for ligand of N-acetylglucosaminyl-N-acetylmuramyl dipeptide using its peptide mimetic. AB - The method for searching for ligands exerting an adjuvant effect is described. The method involves isolation of polysomes using an immobilized peptide mimetic of N-acetylglucosaminyl-N-acetylmuramyl dipeptide (GMDP) - RN-peptide. After the affinity chromatography and washing, RN-peptide complexes with the target sequences were dissociated with guanidine hydrochloride. The obtained mRNA was used for cDNA synthesis and subsequent cloning in an expression vector. Further studies showed the effectiveness of this method. Clones interacting with the peptide were selected using biotinylated RN-peptide. It was found that all clones encode a sequence identical to the protein YB-1. Recombinant antibodies against protein YB-1 were selected from a phage display human scFv library. Using these antibodies, we determined the binding constant of RN-peptide to protein YB-1. Competitive analysis showed that RN-peptide and GMDP compete for the same portion of YB-1 at molar ratio 1 : 12. PMID- 24794729 TI - Inhibition of oxidative hemolysis in erythrocytes by mitochondria-targeted antioxidants of SkQ series. AB - In the present work we studied the effect of antioxidants of the SkQ1 family (10 (6'-plastoquinonyl)decyltriphenylphosphonium) on the oxidative hemolysis of erythrocytes induced by a lipophilic free radical initiator 2,2'-azobis(2,4 dimethylvaleronitrile) (AMVN) and a water-soluble free radical initiator 2,2' azobis(2-methylpropionamidine) dihydrochloride (AAPH). SkQ1 was found to protect erythrocytes from hemolysis, 2 MUM being the optimal concentration. Both the oxidized and reduced SkQ1 forms exhibited protective properties. Both forms of SkQ1 also inhibited lipid peroxidation in erythrocytes induced by the lipophilic free radical initiator AMVN as detected by accumulation of malondialdehyde. However, in the case of induction of erythrocyte oxidation by AAPH, the accumulation of malondialdehyde was not inhibited by SkQ1. In the case of AAPH induced hemolysis, the rhodamine-containing analog SkQR1 exerted a comparable protective effect at the concentration of 0.2 MUM. At higher SkQ1 and SkQR1 concentrations, the protective effect was smaller, which was attributed to the ability of these compounds to facilitate hemolysis in the absence of oxidative stress. We found that plastoquinone in the oxidized form of SkQ1 could be reduced by erythrocytes, which apparently accounted for its protective action. Thus, the protective effect of SkQ in erythrocytes, which lack mitochondria, proceeded at concentrations that are two to three orders of magnitude higher than those that were active in isolated mitochondria. PMID- 24794730 TI - Study on ATP concentration changes in cytosol of individual cultured neurons during glutamate-induced deregulation of calcium homeostasis. AB - For the first time, simultaneous monitoring of changes in the concentration of cytosolic ATP ([ATP]c), pH (pHc), and intracellular free Ca2+ concentration ([Ca2+]i) of the individual neurons challenged with toxic glutamate (Glu) concentrations was performed. To this end, the ATP-sensor AT1.03, which binds to ATP and therefore enhances the efficiency of resonance energy transfer between blue fluorescent protein (energy donor) and yellow-green fluorescent protein (energy acceptor), was expressed in cultured hippocampal neurons isolated from 1 2-day-old rat pups. Excitation of fluorescence in the acceptor protein allowed monitoring changes in pHc. Cells were loaded with fluorescent low-affinity Ca2+ indicators Fura-FF or X-rhod-FF to register [Ca2+]i. It was shown that Glu (20 uM, glycine 10 uM, Mg2+-free) produced a rapid acidification of the cytosol and decrease in [ATP]c. An approximately linear relationship (r(2) = 0.56) between the rate of [ATP]c decline and latency of glutamate-induced delayed calcium deregulation (DCD) was observed: higher rate of [ATP]c decrease corresponded to shorter DCD latency period. DCD began with a decrease in [ATP]c of as much as 15.9%. In the phase of high [Ca2+]i, the plateau of [ATP]c dropped to 10.4% compared to [ATP]c in resting neurons (100%). In the presence of the Na+/K+ ATPase inhibitor ouabain (0.5 mM), glutamate-induced reduction in [ATP]c in the phase of the high [Ca2+]i plateau was only 36.6%. Changes in [ATP]c, [Ca2+]i, mitochondrial potential, and pHc in calcium-free or sodium-free buffers, as well as in the presence of the inhibitor of Na+/K+-ATPase ouabain (0.5 mM), led us to suggest that in addition to increase in proton conductivity and decline in [ATP]c, one of the triggering factors of DCD might be a reversion of the neuronal plasma membrane Na+/Ca2+ exchange. PMID- 24794731 TI - Glutathionylation of the alpha-subunit of Na,K-ATPase from rat heart by oxidized glutathione inhibits the enzyme. AB - A partially purified Na,K-ATPase preparation from rat heart containing alpha1- and alpha2-isoforms of the enzyme was shown to include both subunits in S glutathionylated state. Glutathionylation of the alpha1-subunit (but not of the alpha2-subunit) was partially removed when the preparation was isolated in the presence of dithiothreitol. The addition of oxidized glutathione irreversibly inhibited both isoforms. Inhibition of the enzyme containing the alpha1-subunit was biphasic, and the rate constants of the inhibition were 3745 +/- 360 and 246 +/- 18 M(-1).min(-1). ATP, ADP, and AMP protected the Na,K-ATPase against inactivation by oxidized glutathione. PMID- 24794732 TI - Chemosensory signaling systems that control bacterial survival. AB - Recent studies have revealed that several Gram-negative species utilize variations of the well-known chemotaxis signaling cascade to switch lifestyles in order to survive environmental stress. The two survival strategies covered in this review are the development of dormant cyst cells and biofilm formation. Each of these structures involves exopolysaccharide-mediated cell-cell interactions, which result in multicellular communities that confer resistance to stress conditions such as desiccation and antibiotics. This review is centered on recent advances in the understanding of phosphate flow and novel output signals in chemosensory signaling pathways that are involved in cyst formation and biofilms. PMID- 24794733 TI - A comparative rapid and sensitive method to screen l-asparaginase producing fungi. AB - Fungi are well known to produce various industrial enzymes and secondary metabolites with different colours. Fungi producing l-asparaginase enzyme are conventionally screened on medium containing phenol red (PR). The contrast between enzyme-hydrolysed zone and unhydrolysed l-asparagine is not very evident and distinct in medium containing PR and bromothymol blue (BB) due to coloured secondary metabolite production. Thus, PR and BB limit and affect the detection and screening method. In the present investigation, an improved method for screening is reported by comparing with PR and BB, wherein methyl red (MR) is incorporated as pH indicator. The enzyme activity was distinctly observed (red and light-yellow) in MR incorporated medium compared to PR and BB. PMID- 24794734 TI - Dusted community: piloting a virtual peer-to-peer support community for people with an asbestos-related diagnosis and their families. AB - Individuals with an asbestos-related diagnosis and their carers face burdens including debilitating and life-limiting physical symptoms and medico-legal stressors. Feelings of social isolation are common. Increasing social connectedness can lead to increased feelings of personal empowerment and may inhibit chronic stress responses. The authors report on the development, via a process of participatory action research, of an online peer-to-peer support group, and the first 30-day test phase of this virtual community. Initial indications are that individuals with an asbestos-related diagnosis and their carers can benefit, in psychosocial terms, from membership of an on-line support group comprised of experientially similar others. PMID- 24794735 TI - Colistin resistance in Klebsiella pneumoniae. AB - Increasing use of colistin for multidrug-resistant Gram-negative bacterial infections has led to the emergence of colistin resistance in Klebsiella pneumoniae in several countries worldwide, including Europe (especially Greece), and colistin resistance rates are continually increasing. Heteroresistance rates, which were significantly higher than resistance rates, were found to be important. Although the mechanism underlying resistance is unclear, it has been suggested that it is related to lipopolysaccharide modification via diverse routes. Several factors have been reported as being associated with colistin resistance, with improper use and patient-to-patient transmission being most often cited. Total infections and infection-related mortality from colistin resistant K. pneumoniae are high, but currently there are no established treatment regimens. However, several combination regimens that are mainly colistin-based have been found to be successful for treating such infections. PMID- 24794736 TI - Genetic and structural insights into plasmid-mediated extended-spectrum beta lactamase activity of CTX-M and SHV variants among pathogenic Enterobacteriaceae infecting Indian patients. AB - Resistance to third-generation cephalosporins (3GCs) mediated by extended spectrum beta-lactamases (ESBLs) in pathogenic Enterobacteriaceae is considered a major public health threat in India. This study deals with the detection of plasmid-mediated blaCTX-M, blaSHV and blaOXA genes, understanding their contribution to the ESBL phenotype, and their molecular interaction with 3GCs. More than 87% of isolates showed 3GC resistance, with ESBL production in 60.0% of Escherichia coli and 47.7% of Klebsiella pneumoniae. Molecular characterisation revealed the presence of blaCTX-M-15 (29.8%), blaCTX-M-truncated (1.3%), blaCTX-M 27 (0.7%), blaSHV-1 (20.5%), blaSHV-11 (2.0%), blaSHV-42 (0.7%) and blaOXA-1 (9.9%), among which blaCTX-M variants and blaSHV-42 were ESBLs. Phylogenetic analysis predicted strong selection pressure on all blaCTX-M variants, blaSHV-11 and blaSHV-42. The instability index and Gibbs free folding energy change (DeltaDeltaG) predicted decreased stability of SHV-11 and SHV-42. Mutations of CTX-M-truncated, SHV-11 and SHV-42 located in the core region of the enzymes were found to be functional/pathogenic in nature. The catalytic pockets of CTX-M-15 and SHV-42 had the greatest molecular surface area, which might explain their expanded substrate spectrum towards oxyimino-cephalosporins. Molecular dynamics analysis indicated different structural flexibility of CTX-M-truncated compared with the other enzymes. Amino acid alterations resulted in a change of orientation of catalytic residues of class A beta-lactamases that might affect their catalytic processes. Molecular interactions revealed higher catalytic efficiency (DeltaG and Km) of CTX-M-15, CTX-M-truncated, CTX-M-27, SHV-11 and SHV 42 compared with their respective wild-types. This study provides useful insights into ESBL production of pathogenic Enterobacteriaceae in India that might help in the development of new antibiotics. PMID- 24794737 TI - Advancements in the field of personality development. AB - A summary is provided what the fields of personality and developmental psychology had to offer each other the past decade, reflected in the eleven contributions enclosed in this special issue. Strengths and opportunities to further advance the field are identified, including the extension of general trait with maladaptive trait models, the use of alternative methods to assess personality, and the adoption of configural approaches to describe traits in individuals, beyond more traditional person-centered approaches. PMID- 24794738 TI - Special funding schemes for innovative medical devices in French hospitals: the pros and cons of two different approaches. AB - Financing innovative medical devices is an important challenge for national health policy makers, and a crucial issue for hospitals. However, when innovative medical devices are launched on the European market there is generally little clinical evidence regarding both efficacy and safety, both because of the flaws in the European system for regulating such devices, and because they are at an early stage of development. To manage the uncertainty surrounding the reimbursement of innovation, several European countries have set up temporary funding schemes to generate evidence about the effectiveness of devices. This article explores two different French approaches to funding innovative in hospital devices and collecting supplementary data: the coverage with evidence development (CED) scheme introduced under Article L. 165-1-1 of the French Social Security Code; and national programs for hospital-based research. We discuss pros and cons of both approaches in the light of CED policies in Germany and the UK. The CED policies for devices share common limitations. Thus, transparency of CED processes should be enhanced and decisions need to be made in a timely way. Finally, we think that closer collaboration between manufacturers, health authorities and hospitals is essential to make CED policies more operational. PMID- 24794739 TI - CaCO3 templated micro-beads and -capsules for bioapplications. AB - Porous CaCO3 vaterite microparticles have been introduced a decade ago as sacrificial cores and becoming nowadays as one of the most popular templates to encapsulate bioactive molecules. This is due to the following beneficial features: i) mild decomposition conditions, ii) highly developed surface area, and iii) controlled size as well as easy and chip preparation. Such properties allow one to template and design particles with well tuned material properties in terms of composition, structure, functionality -- the parameters crucially important for bioapplications. This review presents a recent progress in utilizing the CaCO3 cores for the assembly of micrometer-sized beads and capsules with encapsulated both small drugs and large biomacromolecules. Bioapplications of all the particles for drug delivery, biotechnology, and biosensing as well as future perspectives for templating are addressed. PMID- 24794740 TI - Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user. AB - The conversion of levamisole to aminorex in horses was first described in 2009 and, for the first time, confirmed in humans two years later by our laboratory. Aminorex and levamisole interfere with serotonin metabolism and both are proven cause of potentially fatal idiopathic pulmonary hypertension (IPH). Because most of the world's seizures of illicit cocaine is now contaminated with levamisole, this raises the possibility that users of levamisole adulterated cocaine users may be at risk for IPH. Here we describe the first case of IPH in a user of levamisole-contaminated cocaine. Levamisole and aminorex were both identified and quantified in hair and other biological specimens by means gas chromatography/mass spectrometry system (levamisole: urine, 75.05ng/mL; blood, 15.05ng/mL; brain, >0.15ng/g; liver, >0.15ng/g; hair, 12.15ngmg; aminorex: urine, 38.62ng/mL; blood, 8.92ng/mL, brain >0.15ng/g; liver, 0.15ng/g; hair 7.35ng/mg; cocaine, benzoylecgonine, morphine, 6-acetylmorphine, methadone, 2-ethylidine-1, 5-dimetil-3, 3 diphenylpyrrolidine were also detected). Moreover histological changes associated with IPH were observed in the lung. As IPH produces relatively non-specific symptoms in its early stages, this index case may serve as a harbinger of many more cases to come. It should also alert clinicians to the possibility that their patient may be suffering from this relatively rare disorder. PMID- 24794741 TI - Sex estimation from the talus in a Thai population. AB - Previous research on sex estimation from the tarsals has shown that the talus is the most sexually dimorphic tarsal bone in most populations. In order to assess the sexing potential of the talus in a Thai population, 252 skeletons (126 male, 126 female) from the Chiang Mai University Skeletal Collection were measured. The sample represents Thai people who come from the local Chiang Mai area and who died within the past ten years. Ten measurements were taken on the left and right tali from each skeleton. Seven of these measurements are similar, or identical, to measurements used by other researchers. Three experimental measurements were also taken. Logistic regression equations were calculated for each measurement, and for pairs of measurements. The individual measurements were also examined using ROC analysis. Averaging the results from both sides, the individual measurements with the highest correct allocation accuracies based on logistic regression analysis were trochlear length (88.2%), trochlear breadth (87.3%), talar length (85.5%), and inferior articular surface length (84.5%). The ROC results followed a similar pattern, with Area Under the Curve values as follows: trochlear length (0.952), inferior articular surface length (0.937), trochlear breadth (0.935), and talar length (0.914). When pairs of measurements were considered by means of logistic regression, four equations produced predicted allocation accuracies greater than 90% - three from the right talus, and one from the left. The highest accuracy on both sides resulted from a combination of the two most sexually dimorphic individual measurements of trochlear length and trochlear breadth. Together, they produced predicted allocation accuracies of 91.3% on the right side, and 91.4% on the left side. Unlike many past studies that have found talar length to be the most sexually dimorphic measurement of the talus, our study found trochlear length and breadth to be the most accurate measurements for distinguishing the sexes. Researchers developing sexing equations for use with other populations should consider including trochlear length and breadth in their analyses. PMID- 24794742 TI - Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. AB - A series of novel thiazolidin-4-one analogues, characterized by different substitution patterns at positions C-2 and N-3 of the thiazolidin-4-one scaffold for anti-HIV-1 activity has been investigated. Most of the compounds showed anti HIV-1 activity at micromolar concentrations when tested in TZM-bl cells in vitro. Among the thirty-three compounds tested, compound 16 was the most potent inhibitor of HIV-1 replication against HIV-1IIIB, HIV-1ADA5, HIV-1UG070 and HIV 1VB59 (EC50=0.02, 0.08, 0.08 and 0.08 MUM, respectively) with selectivity index (SI=6940, 1735, 1692 and 1692) against tested viral strains, respectively. The results of the present study suggested that the substitution of the nitro group at 6' position of the C-2 phenyl ring and 4,6-dimethylpyridin-2-yl at the N-3 position of thiazolidin-4-one had a major impact on the anti-HIV-1 activity and was found to lower cytotoxicity. The substitution of the heteroaryl ring with bromo group and bicyclic heteroaryl ring at N-3 thiazolidin-4-one was found to lower anti-HIV-1 activity and increase cytotoxicity. The undertaken docking studies thus facilitated the identification of crucial interactions between the HIV-1 RT enzyme and thiazolidin-4-one inhibitors, which can be used to design new potential inhibitors. PMID- 24794743 TI - Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75. AB - HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their beta-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50=0.826 MUg/mL) and high therapeutic index (TI>242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low- to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains. PMID- 24794744 TI - Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors. AB - Structure-activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF3 phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility. PMID- 24794746 TI - Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy. AB - Matriptase is a serine protease implicated in cancer invasion and metastasis. Expression of matriptase is frequently dysregulated in human cancers and matriptase has been reported to activate latent growth factors such as hepatocyte growth factor/scatter factor, and proteases such as urokinase plasminogen activator suggesting that matriptase inhibitors could have therapeutic potential in treatment of cancer. Here we report a structure-based approach which led to the discovery of selective and potent matriptase inhibitors with benzene as central core having 1,3,5 tri-substitution pattern. X-ray crystallography of one of the potent analogs in complex with matriptase revealed strong hydrogen bonding and salt-bridge interactions in the S1 pocket, as well as strong CH-pi contacts between the P2/P4 cyclohexyl and Trp215 side-chain. An additional interaction of the pendant amine at cyclohexyl with Gln175 side-chain results in substantial improvement in matriptase inhibition and selectivity against other related serine proteases. Compounds 15 and 26 showed tumor growth inhibition in a subcutaneous DU-145 prostate cancer mouse model. These compounds could be useful as tools to further explore the biology of matriptase as a drug target. PMID- 24794745 TI - Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP. AB - The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2-5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCalpha with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. PMID- 24794747 TI - Novel aromatic-polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase. AB - Three types of aromatic-polyamine conjugates (6a-6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone-polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values from 1.50 to 11.13 MUM. Anthracene-polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC50 values from 0.016 to 0.657 MUM. A Lineweaver-Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 MUM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD. PMID- 24794748 TI - The pterocarpanquinone LQB-118 inhibits tumor cell proliferation by downregulation of c-Myc and cyclins D1 and B1 mRNA and upregulation of p21 cell cycle inhibitor expression. AB - The incidence of cancer grows annually worldwide and in Brazil it is the second cause of death. The search for anti-cancer drugs has then become urgent. It depends on the studies of natural and chemical synthesis products. The antitumor action of LQB-118, a pterocarpanquinone structurally related to lapachol, has been demonstrated to induce mechanisms linked to leukemia cell apoptosis. This work investigated some mechanisms of the in vitro antitumor action of LQB-118 on prostate cancer cells. LQB-118 reduced the expression of the c-Myc transcription factor, downregulated the cyclin D1 and cyclin B1 mRNA levels and upregulated the p21 cell cycle inhibitor. These effects resulted in cell cycle arrest in the S and G2/M phases and inhibition of tumor cell proliferation. LQB-118 also induced programmed cell death of the prostate cancer cells, as evidenced by internucleosomal DNA fragmentation and annexin-V positive cells. Except the cell cycle arrest in the S phase and enhanced c-Myc expression, all the mechanisms observed here for the in vitro antitumor action of LQB-118 were also found for Paclitaxel, a traditional antineoplastic drug. These findings suggest new molecular mechanisms for the LQB-118 in vitro antitumor action. PMID- 24794749 TI - Regulation of responsiveness of phosphorescence toward dissolved oxygen concentration by modulating polymer contents in organic-inorganic hybrid materials. AB - Platinum(II) octaethylporphyrin (PtOEP)-loaded organic-inorganic hybrids were obtained via the microwave-assisted sol-gel condensation with methyltrimethoxysilane and poly(vinylpyrrolidone). From transparent and homogeneous hybrid films, the strong phosphorescence from PtOEP was observed. Next, the resulting hybrids were immersed in the aqueous buffer, and the emission intensity was monitored by changing the dissolved oxygen level in the buffer. When the hybrid with relatively-higher amount of the silica element, the strong phosphorescence was observed even under the aerobic conditions. In contrast, the emission from the hybrids with lower amounts of the silica element was quenched under the hypoxic conditions. This is, to the best of our knowledge, the first example to demonstrate that the responsiveness of the phosphorescence intensity of PtOEP in hybrid films to the dissolved oxygen concentration in water can be modulated by changing the percentage of the contents in the material. PMID- 24794750 TI - Probing linker design in citric acid-ciprofloxacin conjugates. AB - A series of structurally related citric acid-ciprofloxacin conjugates was synthesised to investigate the influence of the linker between citric acid and ciprofloxacin on antibacterial activities. Minimum inhibitory concentrations (MICs) were determined against a panel of reference strains and clinical isolates of bacteria associated with infection in humans and correlated with the DNA gyrase inhibitory activity. The observed trend was rationalised by computational modelling. PMID- 24794751 TI - Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 MUM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 MUM. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated. PMID- 24794752 TI - Local daily temperatures, thermal seasons, and suicide rates in Finland from 1974 to 2010. AB - OBJECTIVES: Suicide peaks in late spring and October are still seen in Finland among many countries. Weather factors have been suggested as explanations for these peaks, although with inconsistent results. Since the exact timing of these peaks varies each year, the length of daylight and changes in it seem inadequate as an explanation. We hypothesized that ambient temperature and the timing of thermal seasons might associate with suicide rate. METHODS: Suicide rates from three areas across Finland (N = 10,802) were analyzed with Poisson regression in six different models against variables calculated from the local ambient daily temperature, diurnal temperature range, and the duration from the onset of thermal seasons. Separate models for men and women were constructed. RESULTS: The temperature change over 5 days associated with the suicide rate of men in Helsinki region, or in other words, the lower the suicide rate was, the higher the temperature decrease had been. For women, the results were more inconsistent. CONCLUSIONS: Our study is in line with some earlier studies which imply that impairment of thermoregulation might exist among suicide victims. PMID- 24794753 TI - Axon regeneration in C. elegans. AB - Single axon transection by laser surgery has made Caenorhabditis elegans a new model for axon regeneration. Multiple conserved molecular signaling modules have been discovered through powerful genetic screening. In vivo imaging with single cell and axon resolution has revealed unprecedented cellular dynamics in regenerating axons. Information from C. elegans has greatly expanded our knowledge of the molecular and cellular mechanisms of axon regeneration. PMID- 24794754 TI - Sex-specific role of a glutamate receptor subtype in a pacemaker nucleus controlling electric behavior. AB - Electric communication signals, produced by South American electric fish, vary across sexes and species and present an ideal opportunity to examine the bases of signal diversity, and in particular, the mechanisms underlying sexually dimorphic behavior. Gymnotiforms produce electric organ discharges (EOD) controlled by a hindbrain pacemaker nucleus (PN). Background studies have identified the general cellular mechanisms that underlie the production of communication signals, EOD chirps and interruptions, typically displayed in courtship and agonistic contexts. Brachyhypopomus gauderio emit sexually dimorphic signals, and recent studies have shown that the PN acquires the capability of generating chirps seasonally, only in breeding males, by modifying its glutamatergic system. We hypothesized that sexual dimorphism was caused by sexual differences in the roles of glutamate receptors. To test this hypothesis, we analyzed NMDA and AMPA mediated responses in PN slice preparations by field potential recordings, and quantified one AMPA subunit mRNA, in the PNs of males and females during the breeding season. In situ hybridization of GluR2B showed no sexual differences in quantities between the male and female PN. Functional responses of the PN to glutamate and AMPA, on the other hand, showed a clear cut sexual dimorphism. In breeding males, but not females, the PN responded to glutamate and AMPA with bursting activity, with a temporal pattern that resembled the pattern of EOD chirps. In this study, we have been successful in identifying cellular mechanisms of sexual dimorphic communication signals. The involvement of AMPA receptors in PN activity is part of the tightly regulated changes that account for the increase in signal diversity during breeding in this species, necessary for a successful reproduction. PMID- 24794755 TI - Characterization of in-stent neointimal tissue components following drug-eluting stent implantation according to the phase of restenosis using a 40-MHz intravascular ultrasound imaging system. AB - BACKGROUND AND PURPOSE: It is known that drug-eluting stents (DESs) are associated with in-stent restenosis (ISR). However, the characteristics of neointimal tissue components according to the mechanism and time course of DES ISR have not been fully examined. The aim of this study was to characterize the in-stent neointimal tissue components according to the phase of restenosis using radiofrequency signals from 40-MHz intravascular ultrasound (IVUS), called iMAP IVUS (Boston Scientific Corp., Fremont, CA, USA). METHODS: IVUS examinations were performed in 37 angina patients (37 lesions) who underwent repeated percutaneous coronary intervention (PCI) for the treatment of DES ISR. The patients were divided into two groups according to the phase of restenosis: the early ISR group (E-IRS; <=1 year) and the late ISR group (L-ISR; >1 year). RESULTS: There were 18 patients in the E-ISR group and 19 patients in the L-ISR group. The mean follow up period between stent implantation and repeated PCI was 8.0+/-2.2 months in the E-IRS group and 40.4+/-23.9 months in the L-ISR group. The percentage of lipid components and relative necrotic volume were greater in the L-ISR group than in the E-ISR group (5.77+/-1.81% vs. 4.51+/-1.71%, p<0.05 and 12.20+/-2.97% vs. 8.61+/-2.33%, p<0.001, respectively). Furthermore, there was a positive correlation between the follow-up duration after DES implantation in the L-ISR group and the presence of a necrotic plaque component (r=0.49, p<0.05). CONCLUSIONS: There were differences in the neointimal plaque characteristics after DES implantation according to the phase of restenosis. This information may lead to a better understanding of the mechanisms of DES ISR. PMID- 24794756 TI - Markers of metabolic and cardiovascular health in adults: Comparative analysis of DEXA-based body composition components and BMI categories. AB - OBJECTIVES: To investigate how body composition components fit body mass index (BMI) categories and whether they could be considered as markers of metabolic and cardiovascular health. DESIGN: Prospective study. SETTING: A center for preventive medicine. PARTICIPANTS: Six hundred and sixteen consecutive outpatients: mean age of 56.0+/-10.0 years; 74.6% aged >=50 years and 61.4% were females. MEASUREMENTS: Fat mass (FM) and muscle mass (MM) were obtained by dual energy X-ray absorptiometry analyses. Metabolically unhealthy individuals were defined as people with biological features of dyslipidemia, hyperuricemia, diabetes, and/or hepatitis steatosis. Documented hypertension and/or atherosclerosis of one major artery, at least, defined individuals with cardiovascular complications. RESULTS: According to BMI categories, 45.8% of the sample was of normal weight, while 19.2% and 16.5% were classified as overweight and obese. A total of 78.0% and 86.3% of overweight and obese individuals were metabolically unhealthy respectively, 46.8% and 52.6% of subjects classified into normal and underweight BMI categories were also diagnosed. Cardiovascular complications mainly concerned the two highest BMI groups (78.2%). In multifactorial analyses the overweight and obese BMI categories were predictive of health outcomes [respectively, odds ratio (OR)=8.05, 95% confidence interval (CI): 4.23-12.07 and 5.74, 95% CI: 3.41-8.98]. FM and MM indexes were significantly associated with metabolic (OR=1.30, 95% CI: 1.19-1.47; and 0.84, 95% CI: 0.78-0.91) and cardiovascular (OR=1.22, 95% CI: 1.13-1.32; and 0.72, 95% CI: 0.65-0.80) health respectively, and FM/MM (respectively, OR=15.45, 95% CI: 11.77-20.17; and 16.61, 95% CI: 10.49-21.33) as well. CONCLUSION: Our findings suggest that FM and MM readouts are important measurements of nutritional status and they extend the analysis of its impact on health outcomes to all BMI categories. Moreover, they highlight the interest of measuring body composition in medical check-ups to predict metabolic and cardiovascular diseases. PMID- 24794757 TI - The role of integrated backscatter intravascular ultrasound in characterizing bare metal and drug-eluting stent restenotic neointima as compared to optical coherence tomography. AB - BACKGROUND: To evaluate the role of integrated backscatter intravascular ultrasound (IB-IVUS) in assessing the morphology of neointima in bare-metal stent (BMS) and drug-eluting stent (DES) restenosis as compared to the gold-standard, optical coherence tomography (OCT). METHODS: A total of 120 cross-sections were evaluated by IB-IVUS and OCT at five cross-sections from 24 patients (24 lesions): at the minimal lumen area (MLA) and at 1 and 2mm proximal and distal to the MLA site in 24 lesions (9 treated with DES and 15 treated with BMS). IB-IVUS and OCT findings were analyzed according to the time at which restenosis was identified (early <12 months and late >=12 months) and the stent type. RESULTS: IB-IVUS was found to correctly characterize the neointima of both BMS and DES in stent restenosis (ISR) as compared to OCT. The overall agreement between the pattern of ISR neointima by IB-IVUS and that by OCT was excellent (kappa=0.85, 95% CI 0.76-0.94). Late DES ISR was characterized by more non-homogeneous, low backscatter and lipid-laden neointima, as compared to the BMS equivalent (BMS vs. DES, 45.0% vs. 80.0%, p<0.01; 51.7% vs. 85.0%, p=0.008; 33.3% vs. 65.0%, p<0.01, respectively). CONCLUSIONS: IB-IVUS assessment of the ISR neointima pattern appears to provide similar information as the gold-standard OCT in patients with stable angina. Both modalities suggested that late DES restenosis is characterized by a non-homogeneous lipid-laden neointima. PMID- 24794758 TI - New scoring system (APACHE-HF) for predicting adverse outcomes in patients with acute heart failure: evaluation of the APACHE II and Modified APACHE II scoring systems. AB - BACKGROUND: No scoring system for assessing acute heart failure (AHF) has been reported. METHODS AND RESULTS: Data for 824 AHF patients were analyzed. The subjects were divided into an alive (n=750) and a dead group (n=74). We constructed a predictive scoring system based on eight significant APACHE II factors in the alive group [mean arterial pressure (MAP), pulse, sodium, potassium, hematocrit, creatinine, age, and Glasgow Coma Scale (GCS); giving each one point], defined as the APACHE-HF score. The patients were assigned to five groups by the APACHE-HF score [Group 1: point 0 (n=70), Group 2: points 1 and 2 (n=343), Group 3: points 3 and 4 (n=294), Group 4: points 5 and 6 (n=106), and Group 5: points 7 and 8 (n=11)]. A higher optimal balance was observed in the APACHE-HF between sensitivity and specificity [87.8%, 63.9%; area under the curve (AUC)=0.779] at 2.5 points than in the APACHE II (47.3%, 67.3%; AUC=0.558) at 17.5 points. The multivariate Cox regression model identified belonging to Group 5 [hazard ratio (HR): 7.764, 95% confidence interval (CI) 1.586-38.009], Group 4 (HR: 6.903, 95%CI 1.940-24.568) or Group 3 (HR: 5.335, 95%CI 1.582-17.994) to be an independent predictor of 3-year mortality. The Kaplan-Meier curves revealed a poorer prognosis, including all-cause death and HF events (death, readmission HF), in Group 5 and Group 4 than in the other groups, in Group 3 than in Group 2 or Group 1, and in Group 2 than in Group 1. CONCLUSIONS: The new scoring system including MAP, pulse, sodium, potassium, hematocrit, creatinine, age, and GCS (APACHE-HF) can be used to predict adverse outcomes of AHF. PMID- 24794759 TI - Three-dimensional architectural and structural analysis--a transition in concept and design from Delaire's cephalometric analysis. AB - The aim of this study was to present a systematic sequence for three-dimensional (3D) measurement and cephalometry, provide the norm data for computed tomography based 3D architectural and structural cephalometric analysis, and validate the 3D data through comparison with Delaire's two-dimensional (2D) lateral cephalometric data for the same Korean adults. 2D and 3D cephalometric analyses were performed for 27 healthy subjects and the measurements of both analyses were then individually and comparatively analyzed. Essential diagnostic tools for 3D cephalometry with modified definitions of the points, planes, and measurements were set up based on a review of the conceptual differences between two and three dimensions. Some 2D and 3D analysis results were similar, though significant differences were found with regard to craniofacial angle (C1-F1), incisal axis angles, cranial base length (C2), and cranial height (C3). The discrepancy in C2 and C3 appeared to be directly related to the magnification of 2D cephalometric images. Considering measurement discrepancies between 2D and 3D Delaire's analyses due to differences in concept and design, 3D architectural and structural analysis needs to be conducted based on norms and a sound 3D basis for the sake of its accurate application and widespread adoption. PMID- 24794760 TI - Comparison of dexmedetomidine/fentanyl with midazolam/fentanyl combination for sedation and analgesia during tooth extraction. AB - Dexmedetomidine is an alpha2-adrenergic receptor agonist that causes minimal respiratory depression compared with alternative drugs. This study investigated whether combined dexmedetomidine/fentanyl offered better sedation and analgesia than midazolam/fentanyl in dental surgery. Sixty patients scheduled for unilateral impacted tooth extraction were randomly assigned to receive either dexmedetomidine and fentanyl (D/F) or midazolam and fentanyl (M/F). Recorded variables were patient preoperative anxiety scores, vital signs, visual analogue scale (VAS) pain scores, Observer's Assessment of Alertness/Sedation Scale (OAAS) scores after drug administration, surgeon and patient degree of satisfaction, and the duration of analgesia after surgery. The OAAS scores were significantly lower for patients administered D/F compared to those who received M/F. The duration of analgesia after the surgical procedure was significantly longer in patients who received D/F (5.3 h) than in those who received M/F (4.1 h; P=0.017). The number of surgeons satisfied with the level of sedation/analgesia provided by D/F was significantly higher than for M/F (P=0.001). Therefore, dexmedetomidine/fentanyl appears to provide better sedation, stable haemodynamics, surgeon satisfaction, and postoperative analgesia than midazolam/fentanyl during office-based unilateral impacted tooth extraction. PMID- 24794761 TI - The combined effects of undersized drilling and implant macrogeometry on bone healing around dental implants: an experimental study. AB - This study investigated the effect of undersized preparations with two different implant macrogeometries. There were four experimental groups: group 1, conical implant with an undersized osteotomy of 3.2mm; group 2, conical implant with an undersized osteotomy of 3.5mm; group 3, cylindrical implant with an undersized osteotomy of 3.2mm; group 4, cylindrical implant with an undersized osteotomy of 3.5mm. Implants were placed in one side of the sheep mandible (n=6). After 3 weeks, the same procedure was conducted on the other side; 3 weeks later, euthanasia was performed. All implants were 4mm*10mm. Insertion torque was recorded for all implants during implantation. Retrieved samples were subjected to histological sectioning and histomorphometry. Implants of groups 1 and 2 presented significantly higher insertion torque than those of groups 3 and 4 (P<0.001). No differences in bone-to-implant contact or bone area fraction occupied were observed between the groups at 3 weeks (P>0.24, and P>0.25, respectively), whereas significant differences were observed at 6 weeks between groups 1 and 2, and between groups 3 and 4 (P<0.01). Undersized drilling affected the biological establishment of bone formation around both dental implant macrogeometries. PMID- 24794762 TI - Role of computed tomography angiography in the diagnosis of vascular stenosis in head and neck microvascular free flap reconstruction. AB - The aim of this study was to evaluate the role of computed tomography angiography (CTA) in the diagnosis of vascular stenosis at the vascular pedicle of head and neck microvascular free flaps. A prospective study was done of 65 consecutive patients (49 male, 16 female; mean age 55 years) who had undergone head and neck microvascular free flap reconstruction. All patients underwent 64-slice CTA of the carotid artery. Post-processing with volume rendering reconstruction of CTA images was done. There was excellent inter-observer agreement (weighted kappa=0.82, 95% confidence interval (CI) 0.74-0.93) in grading of the degree of vascular stenosis. The true sensitivity of CTA for diagnosis of stenosis of the vascular pedicle to the flap was 63% (95% CI 63-100%). Patients with failed flaps showed complete occlusion (n=2) on CTA and underwent a replacement flap procedure. Patients with failing flaps showed severe stenosis (n=6) of the vascular pedicle on CTA and underwent revision surgery. There was no change in the degree of stenosis on follow-up CTA for patients with moderate stenosis (n=9). CTA is a reliable, non-invasive, high-quality imaging tool for the diagnosis and grading of vascular stenosis of the vascular pedicle of head and neck microvascular free flaps. PMID- 24794763 TI - A cohort study of patients with juvenile idiopathic arthritis and arthritis of the temporomandibular joint: outcome of arthrocentesis with and without the use of steroids. AB - The purpose of this study was to evaluate the effects of intra-articular temporomandibular joint (TMJ) treatment in patients with juvenile idiopathic arthritis (JIA). The inclusion criteria were met by 21 patients (38 joints). Joints were randomly selected for either arthrocentesis alone (n=17) or arthrocentesis with the additional use of triamcinolone hexacetonide (n=21) using a closed single-needle system. Measurements of pain and function were performed at baseline and at follow-up after 3 and 8 months. Pain on opening and lateral excursion improved significantly after injections. Pain decreased significantly from baseline to first and second control on a visual analogue scale (VAS) for overall pain (49-18-8) and overall function (41-19-4). Significant improvement was recorded for pain on palpation of muscles and joints. There was no statistically significant difference between the treatment modalities, with or without glucocorticoid injection. Arthrocentesis in the TMJ treatment of patients with JIA may be beneficial and steroids had no additional effect. Further studies are needed to evaluate the long-term effects on the TMJ structures and on condylar growth from arthrocentesis and intra-articular steroid injections. PMID- 24794764 TI - Point: Mammography, breast cancer, and overdiagnosis: the truth versus the whole truth versus nothing but the truth. PMID- 24794765 TI - Counterpoint: Overdiagnosis in breast cancer screening. PMID- 24794766 TI - Data-driven hiring in radiology. PMID- 24794767 TI - Posterior Communicating Artery Compromise in Coil Embolization of Posterior Communicating Artery Aneurysms. AB - PURPOSE: Whether the posterior communicating artery (PcomA) can be safely compromised during endovascular treatment of a PcomA aneurysm is a matter of debate. Here we present clinical and radiologic outcomes, given this scenario. METHODS: From data prospectively accrued between January 2004 and December 2012, records of 44 patients harboring 46 PcomA aneurysms were retrieved. All had suffered PcomA compromise in the course of endovascular coil embolization. Patients/aneurysms were stratified into those with complete (Group A) and incomplete (Group B) compromise depending on the degree of PcomA flow limitation documented by postembolization ipsilateral internal carotid artery angiography. Clinical and radiologic outcomes were accordingly assessed. RESULTS: All affected vessels were hypoplastic PcomA variants (PcomA/P1 ratio, <= 1.0), with exception of a single dominant PcomA (PcomA/P1 ratio, 1.1). In Group A (23 patients, 23 aneurysms), no PcomA compromise-related infarction was evident, whereas in Group B (21 patients, 23 aneurysms), two ischemic events occurred. One patient suffered thalamic infarction, although patency of the PcomA was adequate in a follow-up angiogram, and another experienced a transient ischemic attack. CONCLUSION: Our findings suggest that obstructed flow in hypoplastic PcomA variants during coil embolization of PcomA aneurysms carries no major consequence. However, incomplete compromise of the PcomA may be a source of delayed thromboembolic infarction. PMID- 24794768 TI - Heart disease in pregnancy: ischaemic heart disease. AB - Coronary artery disease and in particular acute coronary syndromes in pregnancy are increasing with high risk of mortality and significant morbidity. Whilst women with atherosclerotic risk factors are at greater risk of developing problems in pregnancy, it is important to remember that women can develop problems even in the absence of atherosclerosis-secondary to thrombosis or coronary dissection. A low threshold to investigate women with chest pain is paramount, and women with raised troponin levels should be investigated seriously. Acute coronary syndromes should be managed using an invasive strategy where possible and women should not have coronary angiography withheld for fear of foetal harm. This article aims to review the limited available data of coronary artery disease in pregnancy and give practical advice on the management of stable and acute coronary disease, with particular emphasis on the latter. PMID- 24794770 TI - Optimization of 2-(3-(arylalkyl amino carbonyl) phenyl)-3-(2-methoxyphenyl)-4 thiazolidinone derivatives as potent antitumor growth and metastasis agents. AB - A series of 2,3-diaryl-4-thiazolidinone derivatives were synthesized and evaluated for their antiproliferative properties against two well-known cancer cell lines (A549 as human lung cancer and MDA-MB-231 as human breast cancer). Structure activity relationship (SAR) analysis resulted in the discovery of 2-(3 (arylalkyl amino carbonyl)phenyl)-3-(2-methoxy-phenyl)-4-thiazolidinone derivatives with high potent inhibitory effects on the proliferation of both cancer cell lines. Furthermore, several compounds with potent antiproliferative activities displayed excellent inhibitory activities on migration with an IC50 of about 0.05 MUM on MDA-MB-231 cells in two different migration assays. In particular, compound 39 was indicated to suppress tumor growth and metastasis as well as promote survival rate. Intriguingly, this series of analogs have been indicated to inhibit tumor cell proliferation through inducing cell cycle arrest. These results suggested that the new series of 2-(3-(arylalkyl amino carbonyl)phenyl)-3-(2-methoxyphenyl)-4-thiazolidinone derivatives could be regarded and developed as novel highly potential anticancer agents in the future. PMID- 24794769 TI - Synthesis of amino acid appended indoles: appreciable anti-fungal activity and inhibition of ergosterol biosynthesis as their probable mode of action. AB - Rationally designed compounds consisting of mono- and di-peptide appendages on bis-indole template were synthesized in appreciable yield. Some of these compounds exhibited significant antifungal activities against Candida albicans with their MIC80 in MUg/ml range. However, when used in combination with azoles, the antifungal activities of the azoles were considerably enhanced. The growth inhibition appeared to be specific to the fungal cells and mammalian cells were not affected by these compounds. It is shown that these compounds lower ergosterol levels in the fungal cells and probably act by targeting lanosterol 14alpha-demethylase, a key enzyme in the sterol biosynthetic pathway of C. albicans. The compounds do not appear to directly act on the fungal cell wall. Hence, the sensitivity of the fungal cells to these compounds cannot be attributed to cell wall damage and consequent accumulation of the compounds in the cell, though defects in cell wall due to defective sterol biosynthesis cannot be completely ruled out. PMID- 24794771 TI - DNA condensation by copper(II) complexes and their anti-proliferative effect on cancerous and normal fibroblast cells. AB - In our search towards copper(II) based anticancer compounds, copper(II) complexes [Cu(bitpy)2](ClO4)21, [Cu(bitpy)(phen)](NO3)22 and [Cu(bitpy)(NO3)](NO3) 3 were synthesized and characterized. All the three complexes contain the tridentate ligand bitpy, which bears biologically relevant benzimidazolyl head group, as one of the ligands. Because of the presence of the planar benzimidazolyl group in the bitpy ligand, the complexes exhibited intercalative mode of binding with DNA. The DNA binding constant, K(b), for complexes 1, 2 and 3 were determined to be (1.84 +/- 0.32) * 10(4), (1.83 +/- 0.57) * 10(4) and (1.87 +/- 0.21) * 10(4) M(-1) respectively. All the three complexes possessed DNA condensing ability. The DNA condensing ability of the complexes was in the order 2 > 1 > 3. The DNA condensation induced by these three complexes was found to be reversed in the presence of 1 M NaCl. In vitro cytotoxicity of three complexes was tested against osteosarcoma MG63 cell line as well as normal fibroblast NIH3T3 cell line by MTT reduction assay. Complexes 1 and 2 were found to be highly toxic towards MG63 than NIH3T3 cell line and both these complexes brought about cell death in the MG 63 cell line due to apoptosis. Whereas, complex 3 exhibited almost equal toxic effect towards both MG63 and NIH3T3 cell lines. Based on the fact that both complexes 1 and 2 brought about reversible condensation of DNA and induced apoptosis in osteosarcoma MG-63 cell line, it is hypothesized that they might possess potential pharmaceutical applications. PMID- 24794772 TI - Exploration of the dihydropyrimidine scaffold for the development of new potential anti-inflammatory agents blocking prostaglandin E2 synthase-1 enzyme (mPGES-1). AB - Agents targeting microsomal prostaglandin E2 synthase-1 (mPGES-1) would inhibit only PGE2 production induced by inflammatory stimuli and thus could represent a valuable alternative to non-steroidal anti-inflammatory drugs (NSAIDs) as they should be free from the severe side effects of the classic anti-inflammatory drugs. Although several mPGES-1 inhibitors have been so far identified, none of them is currently in clinical trials, therefore the discovery of new molecular platforms, able to interfere with this interesting target, is urgently required. Here, we report the results of a focused collection of dyhidropyrimidin-2(1H)-one based molecules projected by Virtual Screening computational techniques. The key interactions with the receptor counterpart were introduced as a qualitative filter for the selection of the most promising compounds. The biological data obtained are consistent with the computer-aided suggestions and disclosed two interesting molecules showing in vitro mPGES-1 inhibitory activity in the low MUM range. PMID- 24794773 TI - Synthesis of N-benzenesulfonamide-1H-pyrazoles bearing arylsulfonyl moiety: novel celecoxib analogs as potent anti-inflammatory agents. AB - The reaction of arylsulfones 11a-d with hydrazonoyl chloride derivative 13 furnished celecoxib analogs 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-1 yl)benzenesulfonamides 15a-d, respectively. Oximes 16a, b and hydrazones 17a, b were prepared by reacting sulfones 11a, b with hydroxyl amine and phenyl hydrazine, respectively. The anti-inflammatory activity of the synthesized compounds showed that, 5-(4-bromophenyl)-4-(phenylsulfonyl)pyrazole 15c and 5-(4 bromophenyl)-4-(4-tolylsulfonyl)pyrazole 15d exhibited excellent anti inflammatory activity with ED50 = 68 +/- 2.2 and 51 +/- 0.7 MUM/kg, respectively, higher than that of celecoxib (ED50 = 86 +/- 1.1 MUM/kg) after 3 h with acceptable ulcer index. In addition, the LD50 of 15c and 15d is 7.1 mM/kg for each, and 9.8 mM/kg for celecoxib. Compound 15d appeared selectivity index (COX 2/COX-1) almost the half of celecoxib while 15c is non-selective for COX-2. Compound 15c with ED50 = 80 +/- 2.8 MUM/kg showed a significant analgesic activity when compared with celecoxib (ED50 = 70 +/- 3.9 MUM/kg) after 2 h whereas 15b (ED50 = 50 +/- 1.2 MUM/kg) and 15d (ED50 = 69 +/- 2.7 MUM/kg) seemed to be more potent than celecoxib (ED50 = 156 +/- 4.8 MUM/kg) but with a shorter duration (0.5 h). PMID- 24794774 TI - HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression. AB - RET gene is crucial for the development of enteric nervous system, and dys regulation of RET expression causes Hirschsprung disease. HOXB5 regulates RET transcription, and perturbations in transcriptional regulation by HOXB5 caused reduced RET expression and defective enteric nervous system development in mice. The mechanisms by which HOXB5 regulate RET transcription are unclear. Thus, unraveling the regulatory mechanisms of HOXB5 on RET transcription could lead to a better understanding of the etiology of Hirschsprung disease. In this study, we identified and confirmed HOXB5 binding to the multi-species conserved sequence (MCS+9.7) in the first intron of the RET gene. We developed a RET mini-gene reporter system, and showed that MCS+9.7 enhanced HOXB5 trans-activation from RET promoter in human neuroblastoma SK-N-SH cells and in chick embryos. The deletion of HOXB5 binding site interfered with HOXB5 trans-activation. Furthermore, transfection of HOXB5 induced endogenous RET transcription, enhanced the co precipitation of TATA-box binding protein with the transcription start site of RET, and induced histone H3K4 trimethylation in chromatin regions upstream and downstream of RET transcription start site. In conclusion, (i) HOXB5 physically interacted with MCS+9.7 and enhanced RET transcription, (ii) HOXB5 altered chromatin conformation and histone modification of RET locus, which could facilitate the formation of transcription complex, and enhance RET transcription, (iii) expression of RET was mediated by a complex regulatory network of transcription factors functioning in a synergistic, additive and/or independent manners. Hence, dys-regulation of RET expression by HOXB5 could result in insufficient RET expression and Hirschsprung disease. PMID- 24794781 TI - The cardiovascular health status of minority female nursing assistants working in long-term care: a pilot study. AB - OBJECTIVE: To describe the cardiovascular disease (CVD) status of nursing assistants (NAs) working in long-term care. BACKGROUND: Most research with NAs focus on work-related outcomes despite NAs' potentially high risk for CVD. METHODS: Baseline data from a pilot physical activity (PA) and diet focused health promotion study were used to describe NAs CVD risk. Objective (blood pressure, lipid panel, PA levels, body mass index) and subjective (depressive symptoms) data from 39 NAs were used to provide a CVD assessment. RESULTS: Twenty nine (76.3%) participants had at least three CVD risk factors. Specifically, 18% of participants were hypertensive, 89% of participants were overweight/obese, 90% of participants had hyperlipidemia and 97% of participants did not meet PA guidelines. CONCLUSION: The data suggest NAs working in long-term care have multiple CVD risk factors. Future research should consider PA and diet focused worksite health promotion (WHP) interventions to decrease their CVD risks. PMID- 24794782 TI - The prognostic use of serum concentrations of cardiac troponin-I, CK-MB and myoglobin in patients with idiopathic dilated cardiomyopathy. AB - OBJECTIVE: To examine the association between survival and serum concentrations of cTnI, CK-MB, and myoglobin in patients with idiopathic dilated cardiomyopathy (IDC). BACKGROUND: It has been suggested that elevated circulating biomarkers of myocardial damage such as cardiac troponin-I (cTnI), creatine kinase MB (CK-MB) and myoglobin are independent risk factors for mortality in patients with heart failure, and recent studies, although limited, showed that there was a potential association between cTnI and the prognosis of patients with dilated cardiomyopathy (DCM). METHODS: A cohort study was undertaken in 310 patients with IDC. Standard demographic information, transthoracic echocardiography, and routine blood tests were obtained shortly after hospital admission. Outcome was assessed with all-cause mortality. RESULTS: Among the 310 patients studied, 61 (19.7%) died during a mean follow-up of 2.2 years. There was a significant difference in the all-cause mortality rate between patients with serum cTnI >0.05 ng/mL and with cTnI <= 0.05 ng/mL (37.5% vs 15%, log-rank chi(2) = 18.423, P < 0.001). After adjustment for other factors associated with prognosis at baseline, serum cTnI >0.05 ng/mL, QRS duration, NYHA functional class and systolic blood pressure predicted all-cause mortality in patients with IDC. There was no association between circulating CK-MB and myoglobin levels and all-cause mortality in the studied IDC patients. CONCLUSION: Serum concentrations of cTnI but not CK-MB or myoglobin are an independent predictor of all-cause mortality in patients with IDC. PMID- 24794783 TI - Delayed multifocal recurrent stress-induced cardiomyopathy after antidepressants withdrawal. AB - Stress-induced cardiomyopathy is an acute disease characterized by a large left ventricular apical dyskinesia ("apical ballooning"), triggered by intense emotional or physical stress, acute illnesses or, rarely, by alcohol or opiates withdrawal. Connection to stress and apical asynergy suggest a catecholamine mediated pathogenesis. We recently observed a typical apical stress-induced cardiomyopathy, arising two weeks after a long-lasting antidepressant treatment withdrawal and recurring, a week later, with evidence of inferior wall akinesia. The reported case has several unusual features: 1) both episodes were not preceded by relevant triggering event (except antidepressant discontinuation); 2) early heterozonal relapse was observed; 3) the latency between antidepressant discontinuation and stress-induced cardiomyopathy onset is unusually long. The lack of relevant triggering stress and the evidence of multifocal asynergies could support the hypothesis of a non-catecholaminergic pathogenesis. Moreover, the long latency after antidepressant withdrawal may suggest that prolonged antidepressant treatments may have delayed pathological consequences, possibly related to their known neuroplastic effects. PMID- 24794785 TI - Prolonged anticoagulant activity of rivaroxaban in a polymorbid elderly female with non-convulsive epileptic state. AB - OBJECTIVES AND BACKGROUND: Rivaroxaban, an oral direct factor Xa-inhibitor was non-inferior to adjusted dose warfarin in the prevention of stroke and embolism among patients with atrial fibrillation (AF) in the ROCKET-AF trial and has been approved for stroke prevention in AF. CASE REPORT: A 88-years-old female (body mass-index = 19.95) with AF, hypertension and diabetes mellitus, hospitalized because of heart failure and a non-convulsive epileptic state, was treated by valproate, mirtazepin, nebivolol, digitoxin, lisinopril, gliclazide and amlodipine. Irrespective of renal insufficiency, rivaroxaban 15 mg/d was started. After 3 days rivaroxaban was stopped because of concerns about the bleeding risk. Coagulation tests 28 h after rivaroxaban-intake showed INR 2.26, PT 35%, aPTT 38.3 s and anti-Factor Xa-activity 2.00 U/ml. Explanations for the prolonged anticoagulant activity of rivaroxaban comprise renal failure, the low body-mass index, the advanced age and drug-drug interactions of rivaroxaban with mirtazepin, valproate and amlodipine. CONCLUSION: Health care providers should consider renal function, concomitant medication, polymorbidity and age prior to prescribing rivaroxaban. Care has to be taken when prescribing rivaroxaban to patients who are different from those included in the ROCKET AF trial. PMID- 24794784 TI - Patient ventilator asynchrony in critically ill adults: frequency and types. AB - BACKGROUND: Patient ventilator asynchrony (PVA) occurs frequently, but little is known about the types and frequency of PVA. Asynchrony is associated with significant patient discomfort, distress and poor clinical outcomes (duration of mechanical ventilation, intensive care unit and hospital stay). METHODS: Pressure time and flow-time waveform data were collected on 27 ICU patients using the Noninvasive Cardiac Output monitor for up to 90 min per subject and blinded waveform analysis was performed. RESULTS: PVA occurred during all phases of ventilated breaths and all modes of ventilation. The most common type of PVA was Ineffective Trigger. Ineffective trigger occurs when the patient's own breath effort will not trigger a ventilator breath. The overall frequency of asynchronous breaths in the sample was 23%, however 93% of the sample experienced at least one incident of PVA during their observation period. Seventy-seven percent of subjects experienced multiple types of PVA. CONCLUSIONS: PVA occurs frequently in a variety of types although the majority of PVA is ineffective trigger. The study uncovered previously unidentified waveforms that may indicate that there is a greater range of PVAs than previously reported. Newly described PVA, in particular, PVA combined in one breath, may signify substantial patient distress or poor physiological circumstance that clinicians should investigate. PMID- 24794786 TI - Correlation between postprandial bile acids and body fat mass in healthy normal weight subjects. AB - BACKGROUND: Bile acids (BAs) play important roles in glucose regulation and energy homeostasis via G protein-coupled receptors, such as enteroendocrine L cell TGR5. The aim of the present study was to investigate the relationship between postprandial BA levels and body composition after ingestion of a standard test meal. METHODS: Eleven healthy subjects of normal weight (body-mass index, 22.0 +/- 1.6 kg/m(2) [mean +/- SD]), ingested a 400-kcal test meal, and blood samples were obtained from them before ingestion and every 30 min for 120 min after ingestion. The BA fractions were measured with high-performance liquid chromatography. To evaluate body composition, body impedance analysis was performed 1h before ingestion of the test meal. RESULTS: Concentrations of both total BA and total glycine-conjugated BA (GCBA) at 30, 60, 90, and 120 min after test-meal ingestion were significantly higher than those at baseline. The body mass index was correlated with total GCBA at baseline. Moreover, body fat mass was correlated with total GCBA at 30 min (r=-0.688, P=0.019) and 60 min (r= 0.642, P=0.033) and with total BA at 30 min (r=-0.688, P=0.019) and 60 min (r= 0.642, P=0.033). CONCLUSION: The postprandial BA response is inversely related with body fat mass in healthy subjects of normal weight. PMID- 24794787 TI - Classification of reasons for rejection of biological specimens based on pre preanalytical processes to identify quality indicators at a university hospital clinical laboratory in Turkey. AB - OBJECTIVES: Specific types of error should be identified and corrected in each laboratory to ensure quality results. The objectives of this study were: DESIGN AND METHODS: Data on rejected biological specimens in the laboratory information system from January 2013 to January 2014 were analyzed. SSRs according to the type of pre-preanalytical error and collection area were determined. RESULTS: In total, 971,780 biological specimens were received during the period and 26,070 (2.7%) specimens were rejected based on our laboratory rejection criteria. The most frequent reason for the rejection was the clotted specimen (55.8% of total rejections), followed by inadequate volume (29.3% of total rejections). Most of the clotted specimens were received from adult hospital inpatient services (54.3%), followed by pediatric hospital inpatient services (26.8%). High rates of inadequate volume were also observed in samples originating from adult and pediatric hospital inpatient services, especially in the premature, neonatal, intensive care, and oncology units. CONCLUSIONS: The SSR of clotted specimens was selected as the QI for the preanalytical phase in our laboratory. The selected QI will help to define the effects of our specific interventions and corrective actions, and thus allow monitoring of quality improvement in our hospitals. PMID- 24794788 TI - Multiplex microfluidic paper-based immunoassay for the diagnosis of hepatitis C virus infection. AB - Hepatitis C virus (HCV) infection is a serious and rising global healthcare problem. One critical challenge to tackle this disease is the lack of adequate diagnosis. Here, we develop a multiplex microfluidic paper-based immunoassay, as a novel diagnostic approach, to detect human IgG antibody against HCV (anti-HCV). The paper substrate, highly flammable nitrocellulose (NC), is patterned under ambient temperature by craft punch patterning (CPP) to generate multiple test zones. On the basis of superior merits of patterned paper, this new diagnostic approach demonstrates the key novelty to unprecedentedly combine segmented diagnostic assays into a single multiplex test. The generated diagnostic results are not only informative but can be rapidly and cost-effectively delivered. It would significantly transform the clinical pathway for unwitting individuals with HCV infection. This work highlights the promising role of microfluidic paper based immunoassays in tackling the diagnostic challenge for the HCV pandemic as well as other diseases. PMID- 24794789 TI - Mucinous cystic neoplasm of common hepatic duct. PMID- 24794790 TI - Clinical nutrition guidelines of the French Speaking Society of Clinical Nutrition and Metabolism (SFNEP): Summary of recommendations for adults undergoing non-surgical anticancer treatment. AB - Up to 50% of patients with cancer suffer from weight loss and undernutrition (as called cachexia) even though it is rarely screened or properly handled. Patients' prognosis and quality of life could be greatly improved by simple and inexpensive means encompassing nutritional status assessment and effective nutritional care. These guidelines aim to give health professionals and patients practical and up to-date advice to manage nutrition in the principal situations encountered during the cancer course according to the type of tumour and treatment (i.e. radio and/or chemotherapy). Specific suggestions are made for palliative and elderly patients because of specific risks of undernutrition and related comorbidities in this subset. Levels of evidence and grades of recommendations are detailed as stated by current literature and consensus opinion of clinical experts in each field. PMID- 24794791 TI - 67 laminin receptor promotes the malignant potential of tumour cells up regulating lysyl oxidase-like 2 expression in cholangiocarcinoma. AB - BACKGROUND: 67 laminin receptor (67LR) plays an important role in the invasion and metastasis of cholangiocarcinoma, but its mechanism remains unclear. AIMS: We investigated the clinical significance of 67LR and its relation to lysyl oxidase like 2 (LOXL2) in 67LR-mediated invasion and metastasis in cholangiocarcinoma. METHODS: The clinical significance of 67LR and LOXL2 expression and the prognosis of patients were investigated in 73 cancerous and 32 paracancerous tissues by immunohistochemistry. The impact of LOXL2 on invasion, metastasis and 67LR expression was evaluated in cholangiocarcinoma cells by shRNA or expressed plasmid transfection. RESULTS: Expression of 67LR was recognized in 35.62% cholangiocarcinoma tissue, and none in paracancerous tissues. LOXL2 was positively correlated with expression of 67LR. Expression of 67LR or LOXL2 in cholangiocarcinomas was significantly associated with lymph node metastasis, differentiation and poor overall survival. Cox analysis showed that 67LR can act as an independent prognostic biomarker of prognosis in cholangiocarcinoma patients. Expression of LOXL2 decreased by knockdown of 67LR and increased by overexpression of 67LR in cholangiocarcinoma cells. Knockdown of LOXL2 reduced invasion and metastasis in vitro and in vivo. CONCLUSION: 67LR may regulate the expression of LOXL2 to promote invasion and metastasis in cholangiocarcinoma cells. It could be used as an independent prognostic marker in cholangiocarcinoma patients. PMID- 24794792 TI - The prevalence of adverse events associated with double-balloon enteroscopy from a single-centre dataset in Japan. AB - BACKGROUND: There are few comprehensive reports detailing the prevalence of major adverse events associated with a double-balloon enteroscopy procedure. METHODS: We retrospectively investigated the prevalence of major adverse events in 538 patients (262 males and 276 females; median age, 65 years; age range, 12-95 years) who underwent double-balloon enteroscopy at our Institution between April 2008 and October 2011. RESULTS: Of the 17 adverse events recorded (3.2%), acute pancreatitis (n=5; 0.9%) occurred during both diagnostic (n=3) and therapeutic (n=2) anterograde double-balloon enteroscopy, and all of them were treated conservatively. For these cases, the average duration of the examination was 135 min, which was longer than for the other patients (97 min) (P=0.046). Intestinal bleeding (1.3%) was observed in 6 cases after endoscopic polypectomy and in 1 case following a biopsy procedure during a diagnostic double-balloon enteroscopy. The prevalence rates of intestinal perforation and other complications were 0.2% and 0.7%, respectively. CONCLUSIONS: The rate of adverse events associated with double-balloon enteroscopy was high compared to that associated with conventional upper/lower gastrointestinal endoscopy (0.042%/0.078%). The occurrence of acute pancreatitis may be significantly dependent on the duration of double-balloon enteroscopy examination. PMID- 24794793 TI - Imaging strategies before beginning treatment of colorectal liver metastases. AB - The management of colorectal intrahepatic metastases before resection is multidisciplinary and radiologists and nuclear medicine specialists play a major role. In accordance with the French National Guide for appropriate use of diagnostic imaging, the approach should be multimodal: a chest-abdomen and pelvic (CAP) CT scan and hepatic MRI are mandatory while PET-CT provides important additional information, in particular on intra-abdominal extrahepatic metastases. This multimodal approach emphasizes the importance of early and appropriate use of imaging in these patients, as well as the central role of multidisciplinary meetings in oncology. PMID- 24794794 TI - Inhibition of the connexin 43 elevation may be involved in the neuroprotective activity of leptin against brain ischemic injury. AB - Leptin is a multifunctional hormone produced by the ob gene and is secreted by adipocytes that regulate food intake and energy metabolism. Numerous studies demonstrated that leptin is a novel neuroprotective effector, however, the mechanisms are largely unknown. Herein, we demonstrate the protective activities of leptin after ischemic stroke and provide the first evidence for the involvement of the connexin 43 (Cx43) in leptin-mediated neuroprotection. We found that leptin treatment reduces the infarct volume, improves animal behavioral parameters, and inhibits the elevation of Cx43 expression in vivo. In vitro, leptin reverses ischemia-induced SY5Y and U87 cells Cx43 elevation, secreted glutamate levels in medium and SY5Y cell death, these roles could be abolished by leptin receptor blocker. Additionally, leptin administration upregulated the extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation. Moreover, ERK1/2 inhibitors pretreatment reversed the effects of leptin on Cx43 expression, glutamate levels and cell apoptosis. In conclusion, the present study demonstrated that leptin can reduce the Cx43 expression and cell death both in vivo and in vitro via ERK1/2 signaling pathway. This result provides a novel regulatory signaling pathway of the neuroprotective effects of leptin and may contribute to ischemic brain injury prevention and therapy. PMID- 24794795 TI - Axitinib sensitization of high Single Dose Radiotherapy. AB - BACKGROUND AND PURPOSE: Single Dose Radiation Therapy (SDRT) provides remarkably high rates of control even for tumors resistant to fractionated radiotherapy. SDRT tumor control depends on acute acid sphingomyelinase-mediated endothelial cell injury and monoclonal antibodies targeting Vascular Endothelial Cell Growth Factor (VEGF) signaling radiosensitized tumor endothelium when delivered immediately prior to irradiation. Here we evaluate the ability of the oral VEGF receptor inhibitor, axitinib, to sensitize tumor endothelium and increase tumor control with SDRT. METHODS AND MATERIALS: Axitinib was added to primary cultured endothelial cells, or administered orally to Sv129/BL6 mice bearing radiosensitive MCA/129 sarcoma or radioresistant B16F1 melanoma flank tumors, followed by SDRT. Endothelial apoptosis was assessed by TUNEL assay or bis benzamide staining. Mice with irradiated tumors were followed for 90days to evaluate the impact of axitinib on SDRT tumor control. RESULTS: Pre-treatment with axitinib increased acute endothelial cell apoptosis following SDRT in vitro, and in vivo for both MCA/129 and B16F1 tumors. Axitinib correspondingly increased SDRT tumor growth delay and complete response rate (by 40%) for both tumors. Administration precisely 1h before SDRT was critical for radiosensitization. CONCLUSIONS: Axitinib radiosensitizes tumor endothelial cells and enhances tumor cure with SDRT, which may permit dose de-escalation and significantly expand the range of clinical indications for SDRT. PMID- 24794796 TI - Performance of rapid hepatitis C virus antibody assays among high- and low-risk populations. AB - BACKGROUND: Rapid tests for the detection of antibodies to hepatitis C virus (anti-HCV) can facilitate access to diagnosis. OBJECTIVES: This study aimed to evaluate the performance of rapid tests for anti-HCV detection in the sera, whole blood, and oral fluid samples from individuals with different endemicity profiles and risk behaviors. STUDY DESIGN: Three groups donated biological samples that were tested using three anti-HCV rapid tests (WAMA, Bioeasy and OraSure): (I) suspected cases of hepatitis C, (II) individuals who were living in remote areas in Brazil and (III) crack users and beauty professionals. Reproducibility, repeatability and cross-reactivity to other infectious agents (dengue, HIV, malaria, and syphilis) were also evaluated. RESULTS: In group I, specificities varied from 93.75% to 100% and sensitivities varied from 76.03% to 93.84% according to the EIA results. When anti-HCV/HCV RNA-reactive sera samples were considered true-positive HCV cases, the sensitivities and specificities varied from 86.3% to 99.09% and 93.75% to 100%, respectively. In group II, the OraSure rapid test presented the best performance. In group III, the Bioeasy assay performed best using saliva and whole blood and the OraSure assay performed best using oral fluid samples. The reproducibility and repeatability of the WAMA and Bioeasy tests were excellent. The level of concordance between the HCV EIAs and the rapid tests using samples that were reactive for other infectious agents varied from 82.35% to 100% for the WAMA assay and 94.11% to 100% for the Bioeasy assay. CONCLUSION: All of the rapid tests could be used to identify active HCV infection among individuals with different endemicity profiles and risk behaviors. PMID- 24794797 TI - Fracture of titanium nitride-coated femoral component after total knee arthroplasty. AB - We report a case of fracture of a titanium nitride-coated femoral component 3 years after primary total knee arthroplasty (TKA). The fracture was at the medial condylar area just posterior to the medial peg of the femoral component. The backside of the broken medial condylar portion of the femoral component was devoid of cement. Debonding of the component is a possible cause of the stress fracture. To our knowledge, this is the first case report of the fracture of the femoral component manufactured from titanium alloy. LEVEL OF EVIDENCE: IV. PMID- 24794798 TI - Classification of radiation effects for dose limitation purposes: history, current situation and future prospects. AB - Radiation exposure causes cancer and non-cancer health effects, each of which differs greatly in the shape of the dose-response curve, latency, persistency, recurrence, curability, fatality and impact on quality of life. In recent decades, for dose limitation purposes, the International Commission on Radiological Protection has divided such diverse effects into tissue reactions (formerly termed non-stochastic and deterministic effects) and stochastic effects. On the one hand, effective dose limits aim to reduce the risks of stochastic effects (cancer/heritable effects) and are based on the detriment adjusted nominal risk coefficients, assuming a linear-non-threshold dose response and a dose and dose rate effectiveness factor of 2. On the other hand, equivalent dose limits aim to avoid tissue reactions (vision-impairing cataracts and cosmetically unacceptable non-cancer skin changes) and are based on a threshold dose. However, the boundary between these two categories is becoming vague. Thus, we review the changes in radiation effect classification, dose limitation concepts, and the definition of detriment and threshold. Then, the current situation is overviewed focusing on (i) stochastic effects with a threshold, (ii) tissue reactions without a threshold, (iii) target organs/tissues for circulatory disease, (iv) dose levels for limitation of cancer risks vs prevention of non life-threatening tissue reactions vs prevention of life-threatening tissue reactions, (v) mortality or incidence of thyroid cancer, and (vi) the detriment for tissue reactions. For future discussion, one approach is suggested that classifies radiation effects according to whether effects are life threatening, and radiobiological research needs are also briefly discussed. PMID- 24794800 TI - Is it helpful to give older people with cancer the same chance at rehabilitation as older general medical patients? AB - Although the complexity of age combined with a cancer diagnosis can result in unmet supportive care needs there are seldom resources to assess or address such needs for older people with cancer (OPWC). The purpose of this project was to trial a service to improve the care for OPWC through (1) an expanded supportive care screening process and (2) capacity building of subacute ambulatory care services (SACS) staff to increase referrals to community-based rehabilitation. METHODS/DESIGN: Collaboration between allied health (AH) staff at an inner city general hospital with a large cancer service, a cancer specialist hospital, and a SACS service in Melbourne, Australia, developed an AH geriatric screening assessment (GSA) tool. Parallel to this process training was provided to SACS staff in relation to working with OPWC. Although close to one half (44%) of SACS staff who participated in this program (n = 22) had over 6 years' experience, 32% had not worked with OPWC. Prior to training, 81% did not feel confident in their knowledge about working with this cohort. After their training 72% were more confident about normal aging and implications for care of OPWC. Of the 491 patients screened, 80% were older than age 65, however, only 25 resided in the SACS catchment area. More than one third of these did not have clear rehabilitation needs, and the remainder were not referred due to ongoing medical issues. Less than one half of the patients in the catchment area were discussed in a Multi-disciplinary Meeting (MDM) but all were referred to allied health and assessed using the GSA. Although this project did not result in referrals of OPWC to SACS the training program for SACS staff was a success and allied health assessments were improved to include GSA factors. The complexity of care for OPWC was further highlighted through interviews with staff involved with the study. PMID- 24794799 TI - Reduced quenching and extraction time for mammalian cells using filtration and syringe extraction. AB - In order to preserve the in vivo metabolite levels of cells, a quenching protocol must be quickly executed to avoid degradation of labile metabolites either chemically or biologically. In the case of mammalian cell cultures cultivated in complex media, a wash step previous to quenching is necessary to avoid contamination of the cell pellet with extracellular metabolites, which could distort the real intracellular concentration of metabolites. This is typically achieved either by one or multiple centrifugation/wash steps which delay the time until quenching (even harsh centrifugation requires several minutes for processing until the cells are quenched) or filtration. In this article, we describe and evaluate a two-step optimized protocol based on fast filtration by use of a vacuum pump for quenching and subsequent extraction of intracellular metabolites from CHO (Chinese hamster ovary) suspension cells, which uses commercially available components. The method allows transfer of washed cells into liquid nitrogen within 10-15s of sampling and recovers the entire extraction solution volume. It also has the advantage to remove residual filter filaments in the final sample, thus preventing damage to separation columns during subsequent MS analysis. Relative to other methods currently used in the literature, the resulting energy charge of intracellular adenosine nucleotides was increased to 0.94 compared to 0.90 with cold PBS quenching or 0.82 with cold methanol/AMBIC quenching. PMID- 24794801 TI - Bacterial resistance of self-assembled surfaces using PPOm-b-PSBMAn zwitterionic copolymer - concomitant effects of surface topography and surface chemistry on attachment of live bacteria. AB - Three well-defined diblock copolymers made of poly(sulfobetaine methacrylate) (poly(SBMA)) and poly(propylene oxide) (PPO) groups were synthesized by atom transfer radical polymerization (ATRP) method. They were physically adsorbed onto three types of surfaces having different topography, including smooth flat surface, convex surface, and indented surface. Chemical state of surfaces was characterized by XPS while the various topographies were examined by SEM and AFM. Hydrophilicity of surfaces was dependent on both the surface chemistry and the surface topography, suggesting that orientation of copolymer brushes can be tuned in the design of surfaces aimed at resisting bacterial attachment. Escherichia coli, Staphylococcus epidermidis, Streptococcus mutans and Escherichia coli with green fluorescent protein (E. coli GFP) were used in bacterial tests to assess the resistance to bacterial attachment of poly(SBMA)-covered surfaces. Results highlighted a drastic improvement of resistance to bacterial adhesion with the increasing of poly(SBMA) to PPO ratio, as well as an important effect of surface topography. The chemical effect was directly related to the length of the hydrophilic moieties. When longer, more water could be entrapped, leading to improved anti-bacterial properties. The physical effect impacted on the orientation of the copolymer brushes, as well as on the surface contact area available. Convex surfaces as well as indented surfaces wafer presented the best resistance to bacterial adhesion. Indeed, bacterial attachment was more importantly reduced on these surfaces compared with smooth surfaces. It was explained by the non-orthogonal orientation of copolymer brushes, resulting in a more efficient surface coverage of zwitterionic molecules. This work suggests that not only the control of surface chemistry is essential in the preparation of surfaces resisting bacterial attachment, but also the control of surface topography and orientation of antifouling moieties. PMID- 24794802 TI - Comparison of positron emission tomography/computed tomography with classical contrast-enhanced computed tomography in the initial staging of Hodgkin lymphoma. AB - We compared initial computed tomography (CT) and positron emission tomography (PET)/CT in 96 patients with Hodgkin lymphoma (HL), assessing the role of baseline PET/CT in stage migration and treatment selection. The number of patients with stage I, II, III and IV disease based on CT versus PET/CT was: 5 vs. 7, 49 vs. 37, 28 vs. 22 and 14 vs. 30, respectively. In 33 (34%) patients, PET/CT changed HL stage: 27 (28%) were upstaged and six (6.3%) downstaged. Upstaging was caused by detection of new extranodal involvements (47 sites in 26 patients): bone marrow (10 patients), spleen (five patients) and lung (two patients). In nine patients>=2 further coexisting locations were detected. Downstaging resulted from the absence of fluorodeoxyglucose (18F-FDG) uptake in enlarged nodes (>15 mm) in the abdomen and pelvis. PET/CT modified HL stage in 34% of patients leading to treatment modification in the majority. Our results indicate that PET/CT should be mandatory in the initial staging of HL. PMID- 24794803 TI - XRCC3 Thr241Met (rs861539) polymorphism and leukemia risk: unresolved controversy. PMID- 24794804 TI - ABT-199 partners with azacitidine to contest myeloid malignancies. PMID- 24794805 TI - Is Bcl-2 a valid target in the treatment of indolent non-Hodgkin lymphoma? PMID- 24794806 TI - Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome. AB - There is no effective treatment for relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a phase I dose escalation trial of SAR103168, a novel multi-targeted kinase inhibitor with activity against the Src kinase family, the BCR-Abl kinase and several angiogenic receptor kinases. Twenty-nine patients 18-83 years old were treated with SAR103168. Pharmacokinetics was characterized by plasma peak concentration (Cmax) at the end of the infusion, followed by a biphasic decline in the elimination profile. Adverse events were as expected for the patient population and there were no individual toxicities specific to SAR103168. Due to the unpredictable nature of drug exposure, the sponsor decided to discontinue the study prior to reaching the maximum tolerated dose. PMID- 24794807 TI - CCR4+T cell recruitment to the skin in mycosis fungoides: potential contributions by thymic stromal lymphopoietin and interleukin-16. AB - Mycosis fungoides (MF) is characterized by skin accumulation of CCR4+CCR7- effector memory T cells; however the mechanism for their recruitment is not clearly identified. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that triggers Th2 immunity and is associated with T cell recruitment to the skin in atopic dermatitis. Interleukin-16 (IL-16) is a chemoattractant and growth factor for CD4+T cells. We hypothesized that TSLP and IL-16 could contribute to recruitment of malignant T cells in MF. We found elevated TSLP and IL-16 in very early stage patients' plasma and skin biopsies, prior to elevation in CCL22. Both TSLP and IL-16 induced migratory responses of CCR4+TSLPR+CD4+CCR7 CD31+cells, characteristic of malignant T cells in the skin. Co-stimulation also resulted in significant proliferative responses. We conclude that TSLP and IL-16, expressed at early stages of disease, function to recruit malignant T cells to the skin and contribute to their enhanced proliferation. PMID- 24794808 TI - Impact of dietary supplements, obesity and treatment initiation on serum vitamin D levels in patients with lymphoma. PMID- 24794809 TI - Epstein-Barr virus-associated diffuse large B-cell lymphoma arising in atrial myxoma: a proposal for a modified therapeutic approach. PMID- 24794810 TI - Granulocyte-colony stimulating factor response is superior to neutropenia duration in predicting the risk of infection after high-dose chemotherapy for myeloma and lymphoma. AB - The patient granulocyte-colony stimulating factor (G-CSF) response is represented by the leukocyte peak in the blood induced by a single dose of G-CSF after chemotherapy, and is correlated with subsequent neutropenic infection risk. General patterns for a meaningful risk group stratification, have not yet been determined. Two independent data sets including a total of 306 cases with myeloma or lymphoma and autologous blood stem cell transplant were available. An infection susceptibility curve plotted according to ranked G-CSF responses from a multicenter study reproduced and validated a curve from the previous single center. Two trend changes were seen within these curves at around 11,000 and 22,000 leukocytes/MUL, which separated three groups with a high, medium and low risk of infection. While G-CSF response is related to the consecutive duration of neutropenia, it retains additional independent predictive information for infection risk (p<0.0001) and, more important, is a tool available before the onset of the critical period. PMID- 24794812 TI - Oxidative regeneration of toluene-saturated natural zeolite by gaseous ozone: the influence of zeolite chemical surface characteristics. AB - In this study, the effect of zeolite chemical surface characteristics on the oxidative regeneration of toluene saturated-zeolite samples is investigated. A Chilean natural zeolite (53% clinoptilolite, 40% mordenite and 7% quartz) was chemically modified by acid treatment with hydrochloric acid and by ion-exchange with ammonium sulphate. Thermal pre-treatments at 623 and 823K were applied and six zeolite samples with different chemical surface characteristics were generated. Chemical modification of natural zeolite followed by thermal out gassing allows distinguishing the role of acidic surface sites on the regeneration of exhausted zeolites. An increase in Bronsted acid sites on zeolite surface is observed as a result of ammonium-exchange treatment followed by thermal treatment at 623K, thus increasing the adsorption capacity toward toluene. High ozone consumption could be associated to a high content of Lewis acid sites, since these could decompose ozone into atomic active oxygen species. Then, surface oxidation reactions could take part among adsorbed toluene at Bronsted acid sites and surface atomic oxygen species, reducing the amount of adsorbed toluene after the regenerative oxidation with ozone. Experimental results show that the presence of adsorbed oxidation by-products has a negative impact on the recovery of zeolite adsorption capacity. PMID- 24794811 TI - Mechanisms of genome instability induced by RNA-processing defects. AB - The role of normal transcription and RNA processing in maintaining genome integrity is becoming increasingly appreciated in organisms ranging from bacteria to humans. Several mutations in RNA biogenesis factors have been implicated in human cancers, but the mechanisms and potential connections to tumor genome instability are not clear. Here, we discuss how RNA-processing defects could destabilize genomes through mutagenic R-loop structures and by altering expression of genes required for genome stability. A compelling body of evidence now suggests that researchers should be directly testing these mechanisms in models of human cancer. PMID- 24794813 TI - Macrocyclic receptors immobilized to monodisperse porous polymer particles by chemical grafting and physical impregnation for strontium capture: a comparative study. AB - Separation of strontium is of great significance for radioactive waste treatment and environmental remediation after nuclear accidents. In this work, a novel class of adsorbent (Crown-g-MPPPs) was synthesized by chemical grafting a macrocyclic ether receptor to monodisperse porous polymer particles (MPPPs) for strontium adsorption. Meanwhile, a counterpart material (Crown@MPPPs) with the receptor molecules immobilized to the MPPPs substrate by physical impregnation was prepared. To investigate how the immobilization manner and distribution of the receptors influence the adsorption ability, a comparative study on the adsorption behaviour of the two materials towards Sr(II) in HNO3 media was accomplished. Due to the shorter diffusion path and covalently-bonded structure, Crown-g-MPPPs showed faster adsorption kinetics and better stability for cycle use. While Crown@MPPPs had the advantages of facile synthesis and higher adsorption capacity, owing to the absence of conformational constraint to form complexation with Sr(II). Kinetic functions (Lagergren pseudo-first-order/pseudo second-order functions) and adsorption isotherm models (Langmuir/Freundlich models) were used to fit the experimental data and examine the adsorption mechanism. On this basis, a chromatographic process was proposed by using Crown@MPPPs for an effective separation of Sr(II) (91%) in simulated high level liquid waste (HLLW). PMID- 24794814 TI - Black water sludge reuse in agriculture: are heavy metals a problem? AB - Heavy metal content of sewage sludge is currently the most significant factor limiting its reuse in agriculture within the European Union. In the Netherlands most of the produced sewage sludge is incinerated, mineralizing the organic carbon into the atmosphere rather than returning it back to the soil. Source separation of black water (toilet water) excludes external heavy metal inputs, such as industrial effluents and surface run-offs, producing sludge with reduced heavy metal content that is a more favorable source for resource recovery. The results presented in this paper show that feces is the main contributor to the heavy metal loading of vacuum collected black water (52-84%), while in sewage the contribution of feces is less than 10%. To distinguish black water from sewage in the sludge reuse regulation, a control parameter should be implemented, such as the Hg and Pb content that is significantly higher in sewage sludge compared to black water sludge (from 50- to 200-fold). The heavy metals in feces and urine are primarily from dietary sources, and promotion of the soil application of black water sludge over livestock manure and artificial fertilizers could further reduce the heavy metal content in the soil/food cycle. PMID- 24794815 TI - Protective role of oligomeric proanthocyanidin complex against hazardous nodularin-induced oxidative toxicity in Carassius auratus lymphocytes. AB - Nodularin (NOD) is a hazardous material widely detected in water blooms. Fish immune cells are extremely vulnerable to NOD-induced oxidative stress. Oligomeric proanthocyanidin complex (OPC), extracted from grapeseed, was used as an antioxidant to eliminate reactive oxygen species and prevent apoptotic effects. Carassius auratus lymphocytes were treated with different concentrations (0, 10, 100, and 1,000 MUg/L) of OPC and a constant dose (100 MUg/L) of NOD for 12h in vitro. OPC inhibited mitosis by decreasing intracellular levels of oxidative stress, regulating antioxidant enzymes (CAT, SOD, GPx, GR, and GST), mediating bcl-2 family proteins, and deactivating caspase-3. Glutathione (GSH) levels in group V (NOD 100 MUg/L; OPC 1,000 MUg/L) showed a twofold increase compared with corresponding levels in group II (NOD 100 MUg/L). Structure parameters of NOD and NOD-GSH were calculated using SYBYL 7.1 software. ClogP and HINK logP values of NOD-GSH decreased by 10.4- and 2.3-fold, respectively, compared with corresponding values of NOD. OPC-stimulated GSH can lower the lipophilicity and polarity of NOD. OPC, as a protective agent, can alleviate NOD-induced toxicity in C. auratus lymphocytes by regulating oxidative stress and inducing NOD-GSH detoxification. PMID- 24794817 TI - Open letter to Prime Minister David Cameron on food poverty in the UK. PMID- 24794816 TI - Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study. AB - BACKGROUND: Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia. METHODS: In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2-8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809. FINDINGS: Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0.0004). Bayesian analysis predicted that 3.8 g would result in a 1.5-times increase and 7.5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3.5-6 g resulted in a sustained and significant (p<0.0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes. INTERPRETATION: Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted. FUNDING: Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre. PMID- 24794818 TI - Nicotinamide in Friedreich's ataxia: useful or not? PMID- 24794819 TI - Feedback on difficulties raised by the interpretation of serological tests for the diagnosis of Lyme disease. AB - OBJECTIVES: We had for objectives: i) to evaluate the accuracy of serologic testing for Lyme borreliosis performed in a private medical laboratory (PML); ii) to evaluate the impact of these tests on the practices of infectious diseases specialists (IDS). PATIENTS AND METHOD: This study was performed in two steps: i) retrospective study of patients followed in a university hospital infectious diseases outpatient clinic for suspected Lyme borreliosis, tested (ELISA and Western blot) by both the PML and the National Reference Center (NRC); ii) national survey on IDS practices concerning patients consulting for suspected Lyme borreliosis. RESULTS: Between July 2008 and July 2011, 128 patients consulting for suspected Lyme borreliosis were tested by both laboratories. Serological tests came back positive in 91% of cases from the PML versus 8% of cases from the NRC. Lyme borreliosis was the IDS's final diagnosis for 3.6% of patients. The survey on practices revealed that: i) the modal duration of consultation for suspected Lyme borreliosis was 30-60 minutes; ii) for 33% of patients, serologic test results performed at the PML were the only reason to suspect Lyme borreliosis; iii) 60% of patients had no indication for antibiotics. CONCLUSION: The serological test performed in the PML were positive most of the time, but were not confirmed by tests performed at the NRC. This discrepancy lead to multiple and prolonged consultations in infectious diseases clinics, and discordance in the indications for antibiotics. PMID- 24794820 TI - Risk factors for quinolone-resistance in women presenting with Escherichia coli acute pyelonephritis. AB - In France, according to the National Epidemiology Observatory of Bacterial Resistance to Antibiotics, 15.3% of outpatient urinary Escherichia coli isolates were fluoroquinolone-resistant in 2010. This puts to question the relevance of empirical fluoroquinolone therapy for community-acquired acute pyelonephritis (APN), potentially severe infections. OBJECTIVES: We had for aim to identify individual risk factors for quinolone-resistant E. coli in community-acquired APN. PATIENTS AND METHODS: A retrospective cohort study of 344 adult female patients presenting with E. coli APN was conducted at the Roanne and Saint Etienne hospital emergency departments, from January 2011 to February 2012. We studied the demographic, administrative, and clinical factors. E. coli strains with intermediate susceptibility on the antibiogram were considered as resistant. RESULTS: There was 23% of isolates that were resistant to nalidixic acid and 17.4% to ofloxacin. Complicated APN was not a significant risk factor (univariate analysis). Three risk factors of resistance to nalidixic acid and ofloxacin were independent (multivariate analysis): fluoroquinolone use in the previous 3 months, hospitalization in the previous 6 months, and stay in a long-term care facility. The resistance to ofloxacin reached 30.6% if at least 1 of these risk factors was present; it was 9% when none of the factors were present. CONCLUSIONS: These results suggest that local recommendations for the empirical therapy of APN should be reviewed. The limitations of our study require backing up our results with prospective multicentric studies that could lead to drafting new national recommendations. PMID- 24794821 TI - Elevated sexual risk behaviors among postincarcerated young African American males in the South. AB - The dramatic racial disparities in the rates of HIV/STIs(sexually transmitted infections) among African Americans make understanding broader structural factors that increase the risk for HIV/STIs crucial. The current study of young 564 African American men attending STI clinics investigated whether those who had ever been incarcerated reported recent sexual behaviors relatively more risky than their counterparts who had never been incarcerated. Participants were recruited from clinics treating STIs in three southern U.S. cities. Males 15 to 23 years of age who identified as Black/African American and reported recent (past 2 months) sexual activity were eligible. Linear mixed-effects models and generalized estimating equation models were used to assess associations between baseline incarceration history and sexual risk behavior over a 6-month follow-up period. Mean age was 19.6 years (SD = 1.87). At baseline, 240 (42.6%) men reported history of incarceration. Incarceration history predicted several risk behaviors over a 6-month follow-up period. Compared with those with no incarceration history, men previously incarcerated reported a desire to conceive a pregnancy (beta = .40, p = .02), were less likely to have used a condom at last sex act (odds ratio = .91, p = .02) and were more likely to have used drugs and alcohol before sex in the past 2 months (beta = .69, p < .001; beta = .41, p < .001). A history of incarceration may influence the sexual risk behavior of young African American males. Prevention programs and interventions should intensify support for postincarceration African American males to help mitigate this behavior. PMID- 24794823 TI - Renal cell carcinoma after chernobyl: on the role of radiation vs. late detection. PMID- 24794822 TI - Dating, marriage, and parenthood for HIV-positive heterosexual Puerto Rican men: normalizing perspectives on everyday life with HIV. AB - HIV-positive men are living long and healthier lives while managing HIV as a chronic illness. Although research has extensively documented the experiences of illness of people living with HIV, dating, marriage, and fatherhood among heterosexual Latino men has not been examined. To address this gap, this study used a qualitative study design to examine patterns and strategies for dating, marriage, and parenthood among 24 HIV-positive heterosexual Puerto Rican men living in Boston. The findings in our study indicate that an HIV diagnosis does not necessarily deter men from having an active sexual life, marrying, or having children. In fact, for some of the men, engaging in these social and life changing events is part of moving on and normalizing life with HIV; these men planned for, achieved, and interpreted these events in the context of establishing normalcy with HIV. Although the HIV diagnosis discouraged some men from engaging in sexual relations, getting married, or having children, others fulfilled these desires with strategies aimed to reconciling their HIV status in their personal life, including dating or marrying HIV-positive women only. Additional important themes identified in this study include the decision to disclose HIV status to new sexual partners as well as the decision to accept the risk of HIV transmission to a child or partner in order to fulfill desires of fatherhood. Understanding the personal struggles, decision-making patterns, and needs of HIV-positive heterosexual men can aid in designing interventions that support healthy living with HIV. PMID- 24794825 TI - Methodological approach to the intracrine study and estimation of DHEA and DHEA-S using liquid chromatography-tandem mass spectrometry (LC-MS/MS). AB - A reliable and sensitive method for analyzing steroids using liquid chromatography tandem mass spectrometry (LC-MS/MS) is required for research concerning dehydroepiandrosterone (DHEA), which plays a central role in steroid hormone biosynthesis and metabolism. Furthermore, after the first proposal of the concept of intracrine DHEA, stable isotope tracer analysis, which is useful for structural recognition as well as determination of steroids, has been required to evaluate physiological action and hormone biosynthesis/metabolism in target organs. We describe sample processing and analysis methods for simultaneous quantification of multiple hormones, including DHEA, in serum, saliva and tissue using LC-MS/MS. A derivatization technique compatible with each functional group for measuring 3beta-hydroxy-5-enes, such as DHEA and 5alpha/5beta-steroids, with high sensitivity and specificity is also described. Finally, we describe a newly developed method for intracrine research using stable isotope-labeled (13)C steroid substrates with tracer analysis of their metabolites by LC-MS/MS.This article is part of a Special Issue entitled'Essential role of DHEA'. PMID- 24794826 TI - Activation cross sections for production of 7Be by proton and deuteron induced reactions on 9Be: protons up to 65 MeV and deuterons up to 50 MeV. AB - Experimental cross section data for the production of (7)Be by (9)Be(d,x)(7)Be reactions are presented for the first time at deuteron energies up to 50 MeV. For the (9)Be(p,x)(7)Be reaction values up to 65 MeV are presented and compared to literature values. The cross sections were measured using an activation method in stacked foil irradiations followed by gamma-ray spectroscopy. Thick target yields were calculated and discussed in comparison with other (7)Be producing reactions. The cross section data calculated with the latest versions of the TALYS code (TENDL2012 and TENDL2013 libraries) are discussed. PMID- 24794824 TI - DHEA and cognitive function in the elderly. AB - The adrenal prohormone dehydroepiandrosterone (DHEA) and its sulphate conjugate (DHEAS) steadily decrease with age by 10% per decade reaching a nadir after the age of 80. Both DHEA and DHEAS (DHEA/S) exert many biological activities in different tissues and organs. In particular, DHEA and DHEAS are produced de novo in the brain, hence their classification as neurosteroids. In humans, the brain to-plasma ratios for DHEA and DHEAS are 4-6.5 and 8.5, respectively, indicating a specific neuroendocrine role for these hormones. DHEA/S stimulates neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion. Together with antioxidant, anti-inflammatory and anti glucocorticoid properties, it has been hypothesized a neuroprotective effect for DHEA/S. We conducted an accurate research of the literature using PubMed. In the period of time between 1994 and 2013, we selected the observational human studies testing the relationship between DHEA/S and cognitive function in both sexes. The studies are presented according to the cross-sectional and longitudinal design and to the positive or neutral effects on different domains of cognitive function. We also analysed the Clinical Trials, available in the literature, having cognitive domains as the main or secondary outcome. Although the cross sectional evidence of a positive association between DHEA/S and cognitive function, longitudinal studies and RCTs using DHEA oral treatment (50mg/day) in normal or demented adult-older subjects, have produced conflicting and inconsistent results. In summary, the current data do not provide clear evidence for the usefulness of DHEA treatment to improve cognitive function in adult-older subjects. This article is part of a Special Issue entitled 'Essential role of DHEA'. PMID- 24794828 TI - Sarcopenia: there is a need for some steps forward. PMID- 24794827 TI - The ABCB1-C3435T polymorphism likely acts as a risk factor for resistance to antiepileptic drugs. AB - Previous studies have attempted to confirm the association between the ABCB1 C3435T polymorphism and drug-resistant epilepsy and produced discordant findings. A meta-analysis was conducted to assess the role of the C3435T polymorphism in drug-resistance in epilepsy. Databases were obtained from PubMed, Embase, the Chinese Wanfang, CNKI, and Chongqing VIP database, and all relevant studies were compiled up to February 2013. Odds ratios (ORs) were calculated using models of both fixed- and random-effects for comparisons of alleles and genotypes. Subgroup meta-analyses were carried out based on epilepsy subtype, age, therapeutic regimen, definition of drug-responsiveness and drug-resistance using alleles and genotypes models. Publication bias was tested by Begg's test and inverted funnel plot, and heterogeneity was checked by Cochran's Q statistic and the inconsistency index (I2). Cumulative meta-analyses were adopted to test the robustness of the findings. A total of 38 association studies including a total of 8716 subjects, 4037 drug-resistant patients and 4679 drug-responsive epilepsy patients were pooled in this meta-analysis. The association of ABCB1-C3435T with risk of drug-resistance was significant in the overall population (T allele vs. C allele, OR: 1.21; 95%CI: 1.06-1.39; P=0.006) and in Caucasians, adults, groups treated with various drugs, a '>10 seizures in a year' group based on resistance and a '>=2 years seizure free' group based on response subgroup analysis. The ABCB1-C3435T polymorphism is likely to act as a risk factor for resistance to antiepileptic drugs that needs to be confirmed through further studies. PMID- 24794829 TI - Residential relocations among older people over the course of more than 10 years. AB - OBJECTIVE: The objective of this study was to describe the rates of residential relocations over the course of 10.5 years and evaluate differences in these relocation rates according to gender and decedent status. DESIGN: Prospective, longitudinal study with monthly telephone follow-up for up to 126 months. SETTING: Greater New Haven, CT. PARTICIPANTS: There were 754 participants, aged 70 years or older, who were initially community-living and nondisabled in their basic activities of daily living. MEASUREMENTS: Residential location was assessed during monthly interviews and included community, assisted living facility, and nursing home. A residential relocation was defined as a change of residential location for at least 1 week and included relocations within (eg, community community) or between (community- assisted living) locations. We calculated the rates of relocations per 1000 patient-months and evaluated differences by gender and decedent status. RESULTS: Sixty-six percent of participants had at least one residential relocation (range 0-12). Women had lower rates of relocations from nursing home to community (rate ratio [RR] 0.59, P = .02); otherwise, there were no gender differences. Decedents had higher rates of relocation from community to assisted living (RR 1.71, P = .002), from community to nursing home (RR 3.64, P < .001), between assisted living facilities (RR 3.65, P < .001), and from assisted living to nursing home (RR 2.5, P < .001). In decedents, relocations from community to nursing home (RR 3.58, P < .001) and from assisted living to nursing home (RR 3.3, P < .001) were most often observed in the last year of life. CONCLUSIONS: Most older people relocated at least once during 10.5 years of follow-up. Women had lower rates of relocation from nursing home to community. Decedents were more likely to relocate to a residential location providing a higher level of assistance, compared with nondecedents. Residential relocations were most common in the last year of life. PMID- 24794830 TI - A recurrent 'hot spot' glycine substitution mutation, G2043R in COL7A1, induces dominant dystrophic epidermolysis bullosa associated with intracytoplasmic accumulation of pro-collagen VII. PMID- 24794831 TI - Updating and correcting the description of MVK mutations identified in Chinese patients with disseminated superficial actinic porokeratosis. PMID- 24794834 TI - In memorium, Chester Monroe Edelmann, Jr., MD December 26, 1930-September 19, 2013. PMID- 24794833 TI - Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis. AB - BACKGROUND: Higher doses of erythropoiesis-stimulating agents (ESA) have been associated with an increased risk of adverse outcomes in adults with chronic kidney disease (CKD) and end-stage kidney disease (ESRD), but to our knowledge no trials have been performed in children. We examined the association between ESA dose and all-cause mortality in a prevalent pediatric dialysis population. METHODS: Retrospective cohort study utilizing national data on all prevalent dialysis patients aged <18 years from the Centers for Medicare and Medicaid Services' 2005 ESRD Clinical Performance Measures (CPM) project, linked to 18 month mortality records from the United States Renal Data System. Multivariate Cox proportional hazards regression was performed to determine the risk of mortality by mean weekly ESA dose. RESULTS: Eight-hundred and twenty-nine children were included in the analysis; 7 % died during follow-up. A higher proportion of patients receiving ESA doses in the highest category (erythropoietin >=350 units/kg/week or darbepoetin >=1.5 units/kg/week) died (50 % vs 28 %, p = 0.002), and also demonstrated a trend toward lower hemoglobin (11.0 vs 11.4 g/dL, p = 0.05). In multivariate analysis, patients receiving the highest dose of ESA demonstrated an increased risk of mortality (hazard ratio 3.37; p value <0.01). CONCLUSION: Higher ESA dose is independently associated with mortality in children on chronic dialysis. PMID- 24794835 TI - Review of cognitive performance in hoarding disorder. AB - Hoarding disorder is characterized by extreme difficulty letting go of objects other people would routinely discard or give away, such that the home becomes dysfunctionally cluttered with possessions. Specific cognitive processes, such as decision-making, categorization, and attention, have been hypothesized to contribute to the overvaluing of objects. This review synthesizes the evidence related to those propositions and other executive functioning processes that have received research attention. In this paper, we are primarily interested in cognitive processes that can be, but are not always, studied using performance tasks. Compared to both healthy controls and clinical controls, participants with clinical levels of compulsive hoarding show replicable performance deficits in several areas: planning/problem-solving decisions, visuospatial learning and memory, sustained attention/working memory, and organization. Categorization/concept formation, visuospatial processing, and inhibitory control require further investigation and more detailed testing methods to address inconsistencies in reported findings. Many studies fail to account for potential confounds presented by comorbid depression and between-group differences in age, a problem that should be rectified in future research on this topic. The article concludes with recommendations for a research agenda to better understand contributors to abnormal valuing of objects in hoarding disorder. PMID- 24794836 TI - National action plan to combat antimicrobial resistance in Taiwan. PMID- 24794837 TI - Reading and listening to music increase resting energy expenditure during an indirect calorimetry test. AB - Indirect calorimetry is often done early in the morning in a fasting state, with the subject unshowered and abstained from caffeine or other stimulants. Subjects often fall asleep, resulting in measurement of a sleeping metabolic rate rather than a resting metabolic rate. The objective of this study was to determine whether listening to self-selected relaxing music or reading an electronic device or magazine affects resting energy expenditure (REE) during measurement in healthy adults. A randomized trial comparing three different conditions (ie, resting, reading, and listening to music) was performed. Sixty-five subjects (36 female and 29 male) were used in final data analysis. Inclusion criteria included healthy subjects between the ages of 18 and 50 years with a stable weight. Exclusion criteria included pregnant or lactating women or use of medications known to affect metabolism. Results showed that reading either a magazine or an electronic device significantly increased REE by 102.7 kcal/day when compared with resting (P<0.0001); however, there was no difference in REE between the electronic device and magazine. Listening to self-selected relaxing music increased REE by 27.6 kcal/day compared with rest (P=0.0072). Based on our results, we recommend subjects refrain from reading a magazine or electronic device during an indirect calorimetry test. Whether or not the smaller difference found while listening to music is practically significant would be a decision for the indirect calorimetry test administrator. PMID- 24794838 TI - Structural basis for phosphorylation-dependent recruitment of Tel2 to Hsp90 by Pih1. AB - Client protein recruitment to the Hsp90 system depends on cochaperones that bind the client and Hsp90 simultaneously and facilitate their interaction. Hsp90 involvement in the assembly of snoRNPs, RNA polymerases, PI3-kinase-like kinases, and chromatin remodeling complexes depends on the TTT (Tel2-Tti1-Tti2), and R2TP complexes-consisting of the AAA-ATPases Rvb1 and Rvb2, Tah1 (Spagh/RPAP3 in metazoa), and Pih1 (Pih1D1 in humans)-that together provide the connection to Hsp90. The biochemistry underlying R2TP function is still poorly understood. Pih1 in particular, at the heart of the complex, has not been described at a structural level, nor have the multiple protein-protein interactions it mediates been characterized. Here we present a structural and biochemical analysis of Hsp90-Tah1-Pih1, Hsp90-Spagh, and Pih1D1-Tel2 complexes that reveal a domain in Pih1D1 specific for binding CK2 phosphorylation sites, and together define the structural basis by which the R2TP complex connects the Hsp90 chaperone system to the TTT complex. PMID- 24794839 TI - Development of an Ussuri catfish Pseudobagrus ussuriensis skin cell line displaying differential cytopathic effects to three aquatic animal viruses. AB - An Ussuri catfish Pseudobagrus ussuriensis skin (UCS) cell line was developed and subcultured for more than 60 passages. UCS cells consisted of mostly epithelial like cells and multiplied well in TC199 medium supplemented with 10% fetal bovine serum at 25 degrees C. Chromosome analysis revealed that most UCS cells had a normal diploid karyotype with 2n=52. UCS cells showed differential cytopathic effects (CPEs) after inoculation of spring viremia of carp virus (SVCV, a negative-strand RNA virus), grass carp reovirus (GCRV, a multi-segmented double stranded RNA virus) and Rana grylio virus (RGV, a large double-stranded DNA virus), and were indicative of high sensitivities to these three aquatic animal viruses by a virus titration study. The CPE caused by SVCV appeared as rounded and granular cells, grape-like clusters and small lytic plaques. Characteristic CPE containing plaque-like syncytia was induced by GCRV. RGV-infected cells produced typical CPE characterized by cells shrinkage and aggregation, formation of clear plaques and cell sheet detachment. Furthermore, significant fluorescent signals were observed after UCS cells were transfected with green fluorescent protein reporter plasmids, and the development of CPE induced by a recombinant RGV, DeltaTK-RGV, in UCS cells was illustrated using a combination of light and fluorescence microscopy. The data from this study suggested that UCS cell line can potentially serve as a useful tool for the comparison study of different aquatic animal viruses and the isolation of some newly emerging viruses in Ussuri catfish farming. PMID- 24794840 TI - Empowerment and its associations in schizophrenia: a cross-sectional study. AB - Empowerment denotes a sense of personal competence which is considered an essential requisite of fair outcome in schizophrenia. The current study assessed empowerment along with other relevant variables in patients with schizophrenia and a comparison group. Hierarchical multiple linear regression analysis identified independent living skills survey score and perceived social support as predicting empowerment in patients with schizophrenia, suggesting a correlational relationship. Empowerment could be a treatment goal in schizophrenia and independent living skills as well as perceived social support could be the mediating factors. PMID- 24794841 TI - Carbon monoxide poisoning as a cause of death and differential diagnosis in the forensic practice: a retrospective study, 2000-2010. AB - This study presents the epidemiology and the postmortem forensic aspects in cases with a carboxihemoglobin (COHb) analysis, from autopsies performed at the Forensic Pathology Department of the Centre Branch of the National Institute of Legal Medicine and Forensic Sciences of Portugal. Between January 2000 and December 2010, 69 COHb analyses were requested in our institution. In approximately 70% of the situations, circumstantial information included a Carbon Monoxide (CO) source at the death scene. More than half of the cases presented thermal lesions, cherry-red lividity, and cherry-red blood and viscera coloration were found in, approximately, 30% of the cases. Fourteen cases were recorded as CO poisonings. The highest number of poisonings occurred in 2000, with most of the cases in winter (53.8%), in 51-60 years-old male individuals. 69.2% of the poisonings were accidental and the remainder were suicides, being fires the most frequent sources of CO (38.5%). Cherry-red lividity was present in 61.5% of the cases, and all of them presented cherry-red blood and viscera coloration. Older individuals and those with thermal lesions presented lower COHb levels, and politrauma was the most frequent cause of death among the negative cases. It is possible to conclude that the forensic aspects of CO poisonings interact in a complex way, and differential diagnosis is not straightforward. This study also emphasizes the role played by public prevention campaigns and improvement of heating appliances in reducing the number of accidental CO poisonings, and the importance of preventing urban and forest fires, the major source of CO among us. PMID- 24794842 TI - Focussing on the future: survey results on the image capture of patterned cutaneous injuries. AB - An investigator who is involved in assessing the likelihood of physical abuse must make a decision as to whether the injury seen matches the explanation given. In some instances the pattern of these injuries can give the investigator a possible link to the cause of the injury. Photographic imaging is used to record the patterned cutaneous injuries (PCI) and to facilitate forensic interpretation. The current method of capturing PCI often results in some form of distortion that causes a change to the shape of the patterned injury. The Dermatological Patterned Injury Capture and Analysis (DePICA) research group was formed to assess current image capture methods and practices. An online survey was set up to assess the value of localised imaging protocols and training specific to imaging PCI and was made available to law enforcement professionals, forensic investigators and hospital staff. 80 participants responded to the survey. The majority of the survey participants have had training in medical or forensic photography, however 66 (83%) have not had specific training in how to photograph PCI. 41 (51%) of the participants responded that they always use a rigid scale and 34 (43%) position the camera so that it is perpendicular to the scale and injury. Comments made about the quality of images obtained and produced raises concerns about how much knowledge those initiating such images have about image relevance in criminal cases. It is evident that a clear and comprehensive guide to photographing PCIs is required to improve the quality of the photographic evidence that is collected. PMID- 24794843 TI - Death due to fulminant neuroleptic malignant syndrome induced by low doses of haloperidol: a rare case. AB - The paper reports on a rare case of fulminant neuroleptic malignant syndrome (NMS) with several risk factors, typical manifestation and rapid death induced by low doses of haloperidol. The pathological findings, pathogenesis, clinical manifestations, diagnostic criteria, risk factors and other features of NMS are discussed. The importance of forensic pathologists being aware of the possibility of NMS as the cause of death in people taking antipsychotic drugs is stressed. PMID- 24794844 TI - Commemorative tattoos as markers for anniversary reactions and suicide. AB - Anniversary reactions include physical and/or psychiatric responses to the anniversary of the death of a person who was significant to the decedent. In the most extreme cases this may result in suicide. Two cases of suicide are reported to demonstrate the association with specific commemorative tattoos. Case 1: A 19 year-old man was found hanging by the neck by an electric flex in a shed. A commemorative tattoo had the name of his brother who had committed suicide by hanging in the same shed 9 years and 2 days previously. Case 2: A 47-year-old woman was found hanging by the neck by a rope attached to a metal beam in a shed at her home address. A commemorative tattoo had the name of her daughter who had committed suicide by hanging in the same shed 1 year and 5 days previously. Tattooing may record significant life events and so may be useful in a forensic context in helping to identify an unknown decedent. In cases of apparent suicide, correlating the details of a tattoo at autopsy with the available history or the date of death may also provide useful information that helps to clarify reasons for the event, as well as providing data on the incidence of significant anniversary reactions involving lethal self harm. PMID- 24794845 TI - 7208 Victims of domestic and public violence; an exploratory study based on the reports of assaulted individuals reporting to the police. AB - In this study, the data of 7208 victims (children and adults) of domestic and public violence were analysed after they reported this to the police in Amsterdam, the Netherlands. In this analysis the characteristics of these intentional injuries were collected and compared. Despite some significant differences, there is no clear, specific way to distinguish between public and domestic violence. Therefore, it is more efficient for doctors to limit their focus to the differences between accidental and intentional injuries. PMID- 24794846 TI - The chronological age estimation of third molar mineralization of Han population in southwestern China. AB - The purpose of the study was to estimate the chronology of third molar mineralization in Han population of southwestern China and find its unique characteristics so that it would provide a reference in several legal cases like forensic age estimation. The study used Demirjian's staging method to study 2192 orthopantomograms of 984 male and 1208 female subjects aged between 8 and 25 years. The statistical data was analyzed by Student's t test and ANOVA. The conclusions of the study are: (1) The chronological mineralization age of third molars of Han population in Southwestern China is similar to the Turkish and the Japanese, was earlier than the Austrian and Han of South China, but later than the Spanish. (2) The mineralization timing of the third molars between two sides in maxilla or mandible has no significant differences in the same gender group. (3) There is no significant difference in mineralization of third molars between male and female, except for tooth 48 in Demirjian's stage E. (4) The mineralization of third molar in maxilla is earlier than mandible. PMID- 24794847 TI - Intimate partner violence during pregnancy in Urmia, Iran in 2012. AB - BACKGROUND: In spite of enough prevalence data on Intimate Partner Violence (IPV) during pregnancy from many countries, there are still some regions such as the Middle East with relatively limited data. The purpose of research was to investigate the magnitude of IPV during pregnancy in an Iranian community. METHODS: Thirty hundred fifty women during their postpartum period were invited to participate in a cross-sectional population-based study, but 10.6% of them refused participation. The data was compiled using the Abuse Assessment Screen questionnaire. RESULTS: Of the 313 women, 55.9% reported violence during pregnancy. All types of violence were detected in victims during pregnancy, including psychological violence (43.5%), physical violence (10.2%), and sexual violence (17.2%). Intimate partner violence during pregnancy was significantly associated with lower education of the husbands (PR 1.64; 95% CI 1.15-2.36), un employment of the husbands (PR 1.36; 95% CI 1.12-1.64), marriage duration of 5-9 years (PR 0.95; 95% CI 0.74-1.20) and gravidity of two (PR 0.80; 95% CI 0.59 1.08). CONCLUSION: The reported prevalence of IPV before and during pregnancy in this sample is substantially higher than estimates of exposure to violence in other parts of the globe, even the East Mediterranean region which has the highest prevalence estimation in the globe. PMID- 24794848 TI - Accuracy in certification of cause of death in a tertiary care hospital--a retrospective analysis. AB - Every physician is duty bound to issue a "Cause of Death" certificate in the unfortunate event death of his/her patient. Incomplete and inaccurate entry in these certificates poses difficulty in obtaining reliable information pertaining to causes of mortality, leads to faulty public health surveillance, and causes hindrance in research. This study intends to evaluate the completeness and accuracy of Medical Certification of Cause of Death in our Institute and to formulate strategy to improve the quality of reporting of cause of death. During the period from January 2012 to December 2012, a total of 151 certificates of cause of death were issued by the faculty members of various departments. Maximum number of death certificates were issued for patients in the extremes of the age <10 years (n = 42, 27.82%) and in >60 years (n = 46, 30.46%). The various inadequacies observed by us are as follows: 40 (26.49%) cases had inaccurate cause of death, interval between onset and terminal event was missing in 94 (62.25%) cases, in 68 (45.03%)cases the seal with registration number of the physician was not available on the certificate, incomplete antecedent & underlying cause of death was found in 35 (23.18%) & 84 (55.63%) cases, in 66 (43.71%) cases there was use of abbreviations and the handwriting was illegible in 79(52.32%) cases. PMID- 24794849 TI - Retrospective study of positive physical torture cases in Cairo (2009 & 2010). AB - Torture is the most serious violation of a person's fundamental right to personal integrity and a pathological form of human interaction. In this study, the prevalence of torture in Cairo during the years 2009 & 2010 is 10.97% of the total number of cases examined at the medico legal authority of Egypt in Zenhom (11.29% in 2010 & 10.36% in 2009). The number of cases under this study is 367 (175 cases in 2009, 192 cases in 2010). Torture is more prevalent in the year 2010 than in the year 2009. The largest prevalence of torture was found in the area of south Cairo (120 cases; 32.7%) while the least was found in the area of west Cairo (50 cases; 13.6%). The victims included 336 males (91.6%) and 31 females (8.4%) with male to female ratio 10.8: 1. The most commonly affected age group in the studied victims was the age group of the third decade (171 cases; 46.6%) while the least was the age group above the sixth decade (6 cases; 1.6%). The most commonly affected site of injury was head & neck (243 cases; 66.2%) while the least was abdomen (17 cases; 4.6%). The most common type of injury was bruises (258 cases; 70.3%) while the least was electrocution (5 cases; 1.4%). Regarding the causal instrument, the most commonly used instrument was blunt object (333 cases; 90.7%) while the least was electric current (5 cases; 10%). Hitting with a stick leaving the characteristic shape of elongated abrasion & bruises was found in 35 cases (9.5%) and characteristic lesion of handcuff, which is blunt trauma wounds around wrists or ankles, was found in 68 cases (18.5%). There was one case of hair torture (0.3%) & 5 cases of sexual torture (1.5%). Permanent infirmity left in victims was positive in 24 cases (6.5%) and negative in 343 cases (93.5%) while deformity left in victims was positive in 10 cases (3%) and negative in 357 cases (97%). All permanent infirmity cases were male. Of the 24 cases of permanent infirmity, 83.3% were subjected to blunt trauma and 79.2% were injured in the upper limbs & this is statistically significant. PMID- 24794850 TI - Chemically pretreating slaughterhouse solid waste to increase the efficiency of anaerobic digestion. AB - The combined effect of temperature and pretreatment of the substrate on the anaerobic treatment of the organic fraction of slaughterhouse solid waste was studied. The goal of the study was to evaluate the effect of pretreating the waste on the efficiency of anaerobic digestion. The effect was analyzed at two temperature ranges (the psychrophilic and the mesophilic ranges), in order to evaluate the effect of temperature on the performance of the anaerobic digestion process for this residue. The experiments were performed in 6 L batch reactors for 30 days. Two temperature ranges were studied: the psychrophilic range (at room temperature, 18 degrees C average) and the mesophilic range (at 37 degrees C). The waste was pretreated with NaOH before the anaerobic treatment. The result of pretreating with NaOH was a 194% increase in the soluble chemical oxygen demand (COD) with a dose of 0.6 g NaOH per g of volatile suspended solids (VSS). In addition, the soluble chemical oxygen demand/total chemical oxygen demand ratio (sCOD/tCOD) increased from 0.31 to 0.7. For the anaerobic treatment, better results were observed in the mesophilic range, achieving 70.7%, 47% and 47.2% removal efficiencies for tCOD, total solids (TS), and volatile solids (VS), respectively. PMID- 24794851 TI - Deletion of plant-specific sugar residues in plant N-glycans by repression of GDP D-mannose 4,6-dehydratase and beta-1,2-xylosyltransferase genes. AB - Production of pharmaceutical glycoproteins, such as therapeutic antibodies and cytokines, in plants has many advantages in safety and reduced costs. However, plant-made glycoproteins have N-glycans with plant-specific sugar residues (core beta-1,2-xylose and alpha-1,3-fucose) and a Lewis a (Le(a)) epitope, Galbeta(1 3)[Fucalpha(1-4)]GlcNAc. Because it is likely that these sugar residues and glycan structures are immunogenic, many attempts have been made to delete them. Previously, we reported the simultaneous deletion of the plant-specific core alpha-1,3-fucose and alpha-1,4-fucose residues in Le(a) epitopes by repressing the GDP-D-mannose 4,6-dehydratase (GMD) gene, which is associated with GDP-L fucose biosynthesis, in Nicotiana benthamiana plants (rGMD plants, renamed to DeltaGMD plants) (Matsuo and Matsumura, Plant Biotechnol. J., 9, 264-281, 2011). In the present study, we generated a core beta-1,2-xylose residue-repressed transgenic N. benthamiana plant by co-suppression of beta-1,2-xylosyltransferase (DeltaXylT plant). By crossing DeltaGMD and DeltaXylT plants, we successfully generated plants in which plant-specific sugar residues were repressed (DeltaGMDDeltaXylT plants). The proportion of N-glycans with deleted plant specific sugar residues found in total soluble protein from DeltaGMDDeltaXylT plants increased by 82.41%. Recombinant mouse granulocyte/macrophage-colony stimulating factor (mGM-CSF) and human monoclonal immunoglobulin G (hIgG) harboring N-glycans with deleted plant-specific sugar residues were successfully produced in DeltaGMDDeltaXylT plants. Simultaneous repression of the GMD and XylT genes in N. benthamiana is thus very useful for deleting plant-specific sugar residues. PMID- 24794852 TI - Atomic-structural synergy for catalytic CO oxidation over palladium-nickel nanoalloys. AB - Alloying palladium (Pd) with other transition metals at the nanoscale has become an important pathway for preparation of low-cost, highly active and stable catalysts. However, the lack of understanding of how the alloying phase state, chemical composition and atomic-scale structure of the alloys at the nanoscale influence their catalytic activity impedes the rational design of Pd-nanoalloy catalysts. This work addresses this challenge by a novel approach to investigating the catalytic oxidation of carbon monoxide (CO) over palladium nickel (PdNi) nanoalloys with well-defined bimetallic composition, which reveals a remarkable maximal catalytic activity at Pd:Ni ratio of ~50:50. Key to understanding the structural-catalytic synergy is the use of high-energy synchrotron X-ray diffraction coupled to atomic pair distribution function (HE XRD/PDF) analysis to probe the atomic structure of PdNi nanoalloys under controlled thermochemical treatments and CO reaction conditions. Three dimensional (3D) models of the atomic structure of the nanoalloy particles were generated by reverse Monte Carlo simulations (RMC) guided by the experimental HE XRD/PDF data. Structural details of the PdNi nanoalloys were extracted from the respective 3D models and compared with the measured catalytic properties. The comparison revealed a strong correlation between the phase state, chemical composition and atomic-scale structure of PdNi nanoalloys and their catalytic activity for CO oxidation. This correlation is further substantiated by analyzing the first atomic neighbor distances and coordination numbers inside the nanoalloy particles and at their surfaces. These findings have provided new insights into the structural synergy of nanoalloy catalysts by controlling the phase state, composition and atomic structure, complementing findings of traditional density functional theory studies. PMID- 24794853 TI - Domestic sexual violence and sexual problems among gynecology outpatients: an example from Turkey. AB - Domestic violence is a universal problem, and sexual violence in marriage, in particular, is a hidden form of it. This descriptive, cross-sectional study was conducted to determine to the prevalence of domestic sexual violence by husbands, the prevalence of sexual problems, and the relation of these among married women attending a gynecology outpatient clinic. This study was performed in a university hospital in Turkey and data were collected February-April 2009. The study sample consisted of 200 married women, 53% of whom reported having been exposed to at least one type of domestic sexual violence behaviors by their husbands. Among those behaviors, the rate of marital rape was 33%. The frequency of experiencing any sexual problem was 82%. Women expressed that they mostly had orgasmic problems, and their husbands had premature ejaculation problems. The majority of women who reported sexual violence reported experiencing sexual problems; the frequency of sexual problems was higher in the participants who did (94.3%) than in those who did not report (68.1%) sexual violence (p < .001). Bad sexual harmony (Odds ratio [OR] = 13.50, 95% confidence interval [CI] = 3.87 47.01) and experiencing sexual problems (OR = 12.67, 95% CI = 3.78-42.35) were strongly related to sexual violence in marriage. The results also revealed that the prevalence of sexual violence and sexual problems among those married women who attended gynecology clinics was considerable, even though they did not report this to the health care provider as a problem. PMID- 24794854 TI - The limited right to alter memory. PMID- 24794855 TI - The use of virtual reality simulation to determine potential for endoscopic surgery skill acquisition. AB - BACKGROUND: Efficient acquisition of endoscopic technique is essential for high level care in surgical practice. In contrast to similar substantial risk industries, there is no standard instrument capable of detecting the potential of surgical residency candidates to develop such skills. MATERIAL AND METHODS: We used the Simbionix "Lapmentor" Virtual reality simulator basic skills tasks 1, 5 and 6 to establish baseline performance of 17 subjects lacking surgical experience, then divided them into two groups. One group trained on the Lapmentor, a validated trainer. The second group trained on a video box trainer using 3 FLS tasks, which correlate with real OR performance. After completing the training program, each group was tested on its training modality and correlations were sought between performance in the screening tasks and final scores in both groups. RESULTS: Time in Lapmentor task 1 showed significant correlations with total FLS scores (R 0.807 P 0.015), in addition to other benchmark parameters. With the Lapmentor group, time on task 5 demonstrated correlation with itself on the final scores (R 0.794 P 0.011). CONCLUSIONS: Time in the Lapmentor task 1 demonstrates correlations with FLS scores, which translate to better OR performance. The Lapmentor thus shows potential to be used as a screening test for surgical talent. PMID- 24794856 TI - Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia. AB - Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls. SPG11 patients'-derived neurons exhibited downregulation of specific axonal-related genes, decreased neurite complexity and accumulation of membranous bodies within axonal processes. Altogether, these data point towards axonal pathologies in human neurons with SPG11 mutations. To further corroborate spatacsin function, we investigated human pluripotent stem cell-derived neurons and mouse cortical neurons. In these cells, spatacsin was located in axons and dendrites. It colocalized with cytoskeletal and synaptic vesicle (SV) markers and was present in synaptosomes. Knockdown of spatacsin in mouse cortical neurons evidenced that the loss of function of spatacsin leads to axonal instability by downregulation of acetylated tubulin. Finally, time-lapse assays performed in SPG11 patients'-derived neurons and spatacsin-silenced mouse neurons highlighted a reduction in the anterograde vesicle trafficking indicative of impaired axonal transport. By employing SPG11 patient-derived forebrain neurons and mouse cortical neurons, this study provides the first evidence that SPG11 is implicated in axonal maintenance and cargo trafficking. Understanding the cellular functions of spatacsin will allow deciphering mechanisms of motor cortex dysfunction in autosomal-recessive hereditary spastic paraplegia. PMID- 24794857 TI - A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity. AB - Mutations in LRRK2 are one of the primary genetic causes of Parkinson's disease (PD). LRRK2 contains a kinase and a GTPase domain, and familial PD mutations affect both enzymatic activities. However, the signaling mechanisms regulating LRRK2 and the pathogenic effects of familial mutations remain unknown. Identifying the signaling proteins that regulate LRRK2 function and toxicity remains a critical goal for the development of effective therapeutic strategies. In this study, we apply systems biology tools to human PD brain and blood transcriptomes to reverse-engineer a LRRK2-centered gene regulatory network. This network identifies several putative master regulators of LRRK2 function. In particular, the signaling gene RGS2, which encodes for a GTPase-activating protein (GAP), is a key regulatory hub connecting the familial PD-associated genes DJ-1 and PINK1 with LRRK2 in the network. RGS2 expression levels are reduced in the striata of LRRK2 and sporadic PD patients. We identify RGS2 as a novel interacting partner of LRRK2 in vivo. RGS2 regulates both the GTPase and kinase activities of LRRK2. We show in mammalian neurons that RGS2 regulates LRRK2 function in the control of neuronal process length. RGS2 is also protective against neuronal toxicity of the most prevalent mutation in LRRK2, G2019S. We find that RGS2 regulates LRRK2 function and neuronal toxicity through its effects on kinase activity and independently of GTPase activity, which reveals a novel mode of action for GAP proteins. This work identifies RGS2 as a promising target for interfering with neurodegeneration due to LRRK2 mutations in PD patients. PMID- 24794858 TI - Next generation sequencing techniques in neurological diseases: redefining clinical and molecular associations. AB - The development of next-generation sequencing technologies has allowed for the identification of several new genes and genetic factors in human genetics. Common results from the application of these technologies have revealed unexpected presentations for mutations in known disease genes. In this review, we summarize the major contributions of exome sequencing to the study of neurodegenerative disorders and other neurological conditions and discuss the interface between Mendelian and complex neurological diseases with a particular focus on pleiotropic events. PMID- 24794859 TI - Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype. AB - Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism-epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management. PMID- 24794860 TI - Genotoxic damage of benzo[a]pyrene in cultured sea bream (Sparus aurata L.) hepatocytes: harmful effects of chronic exposure. AB - The large majority of studies on the genotoxic hazard of PAHs polluted water widely applied the ENA assay as versatile tool in large number of wild and farmed aquatic species. Nuclear abnormalities are commonly considered to be a direct consequence of genotoxic lesions in DNA macromolecule, and such evaluation might be helpful in identifying the genotoxic damage induced by the most harmful PAHs such as B[a]P. Regarding at the fish species subjected to aquaculture, most of the toxicological data come from wild fish and mainly focus on freshwater fish, but very little is known for other marine major aquacultured species. The gilthead sea bream (Sparus aurata L.) is the most economically important sparid species cultured along the Mediterranean costs, and it has been proved a very sensitive species to acute B[a]P exposure. However, further investigation is needed on several other types of genotoxic assessments, especially for chronic effects. This work was totally based on an in vitro model for chronic toxicity, using long-term S. aurata hepatocytes in primary culture, continuously exposed to low levels of BaP, over a prolonged period of time, to provide evidences for latent toxicity response. We aimed to investigate the kind of nuclear damage in gilthead sea bream hepatocytes continuously exposed to B[a]P sublethal doses. Cells were exposed to several B[a]P concentrations (10 MUg/mL, 1 MUg/mL, 1 ng/mL, 1 pg/mL) for two exposure times (24 and 72 h), and then tested both for apoptosis induction and for nuclear abnormalities by immunofluorescence analysis. The presence of severe nuclear damage, revealed cells progressing towards abnormal genotypes, due to a series of aberrant mitosis followed by unequal distribution of chromosomal content. The nuclear atypia (NA) more frequently observed were: a) micronuclei (MN); b) nuclear buds or blebs (NBUDs); c) notched nuclei; d) lobed nuclei; e) nuclei with nucleoplasmic bridge (NPBs); f) nuclei squashed, with a residual nuclear membrane; g) open nuclei, with membrane tape unrolled; and h) apoptotic bodies. Our results showed at medium-low doses a sustained genotoxic response, whose potency increased with the exposure time, becoming apparent as apoptosis induction, both by cell surface and nuclear changes. At the lowest doses, the longer was B[a]P exposure, greater was the involvement on masses of replicating cells, establishing the connection between the escape from apoptosis and the selection of tumoral cell evolution. In view of these results, there is no evidence of a threshold dose below which B[a]P was found not to be genotoxic in sea bream cultured hepatocytes. PMID- 24794861 TI - Key joint kinematic characteristics of the gait of fallers identified by principal component analysis. AB - It has been reported that fallers have a higher risk of subsequent falls than non fallers. Therefore, if the differences between the movements of recent fallers and non-fallers can be identified, such could be regarded as the basis of the high risk of falling of the former. The objective of the present study was the identification of the key joint kinematic characteristics of human gait related to the risk of falling while walking on level ground. For this purpose, joint kinematics data obtained from 18 recent fallers and 19 non-fallers were analyzed using principal component analysis (PCA). The PCA was conducted using an input matrix constructed from the time-normalized average and standard deviation of the lower limb joint angles on three planes (101 data*2 parameters*3 angles*3 planes). The PCA revealed that only the 5th principal component vector (PCV 5) among the 23 generated PCVs was related to the risk of falling (p<0.05, ES=0.71). These findings as well as those of previous studies suggest that the joint kinematics of PCV 5 is the key characteristic that affects the risk of falling while walking. We therefore recombined the joint kinematics corresponding to PCV 5 and concluded that the variability of the joint kinematics for fallers was larger than that for non-fallers regardless of the joint. These observations as well as the findings of previous studies suggest that the risk of falling can be reduced by reducing the variability of the joint kinematics using an intervention such as external cues or a special garment. PMID- 24794862 TI - Prognostic significance of novel 18F-FDG PET/CT defined tumour variables in patients with oesophageal cancer. AB - PURPOSE: (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) combined with computed tomography (PET/CT) is now established as a routine staging investigation of oesophageal cancer (OC). The aim of the study was to determine the prognostic significance of PET/CT defined tumour variables including maximum standardised uptake value (SUVmax), tumour length (TL), metastatic length of disease (MLoD), metabolic tumour volume (MTV), total lesion glycolysis (TLG) and total local nodal metastasis count (PET/CT LNMC). MATERIALS AND METHODS: 103 pre-treatment OC patients (76 adenocarcinoma, 25 squamous cell carcinoma, 1 poorly differentiated and 1 neuroendocrine tumour) were staged using PET/CT. The prognostic value of the measured tumour variables were tested using log-rank analysis of the Kaplan-Meier method and Cox's proportional hazards method. Primary outcome measure was survival from diagnosis. RESULTS: Univariate analysis showed all variables to have strong statistical significance in relation to survival. Multivariate analysis demonstrated three variables that were significantly and independently associated with survival; MLoD (HR 1.035, 95% CI 1.008-1.064, p=0.011), TLG (HR 1.002, 95% CI 1.000-1.003, p=0.018) and PET/CT LNMC (HR 0.048-0.633, 95% CI 0.005-2.725, p=0.015). CONCLUSION: MLoD, TLG, and PET/CT LNMC are important prognostic indicators in OC. This is the first study to demonstrate an independent statistical association between TLG, MLoD and survival by multivariable analysis, and highlights the value of staging OC patients with PET/CT using functional tumour variables. PMID- 24794863 TI - Correlation between morphological expansion and impairment of intra- and prelesionary motility in inflammatory small bowel lesions in patients with Crohn's disease - preliminary data. AB - INTRODUCTION: The aim of this study is to investigate if alterations of intra- and prelesionary motility in inflamed small-bowel segments correlate with length, wall-thickness and prelesionary dilatation of inflammatory small bowel lesions in patients suffering from Crohn's disease assessed with MRI. METHODS AND MATERIALS: This retrospective IRB approved study included 25 patients (12 males, 18-77y) with inflammatory lesions examined using (MRE) magnetic resonance imaging enterography. Cine MRE was performed using a coronal 2D steady-state free precession sequence (TR 2.9, TE 1.25) on a 1.5T MRI scanner. Small bowel motility was examined using a dedicated MR-motility assessment software (Motasso, Vers. 1.0, Sohard AG, Bern, Switzerland). Motility patterns (contraction frequency, relative occlusion rate and mean diameter) were assessed in correlation to wall thickness, length and prelesionary dilatation of the lesions. Statistical analysis was performed by calculation of the Pearson's-Correlation coefficient. RESULTS: The length of the inflammatory segments, the wall thickening and prelesionary dilatation did not correlate with the frequency of the contractions (r=0.17, p=0.477; r=0.316, p=0.123; r=0.161, p=0.441) or the impairment of luminal occlusion (r=0.274, p=0.184; r=0.199, p=.0339; r=0.015, p=0.945) and only the prelesionary dilatation (r=0.410, p=0.042) correlated to the mean luminal diameter of the segment. CONCLUSION: The degree of motility impairment within inflammatory small bowel lesions does not significantly correlate with the extent of the lesion but with the motility measured in prelesionary, non-affected segments, suggesting an interdependent functional aspect of inflammation even in morphologically non-affected small bowel segments. PMID- 24794864 TI - Magnetic resonance imaging of cervical carcinoma using an endorectal surface coil. AB - INTRODUCTION: The objective of this trial is to investigate the diagnostic value of magnetic resonance imaging (MRI) with an endorectal surface coil for precise local staging of patients with histologically proven cervical cancer by comparing the radiological, clinical, and histological results. MATERIALS AND METHODS: Women with cervical cancer were recruited for this trial between February 2007, and September 2010. All the patients were clinically staged according to the FIGO classification and underwent radiological staging by MRI that employed an endorectal surface coil. The staging results after surgery were compared to histopathology in all the operable patients. RESULTS: A total of 74 consecutive patients were included in the trial. Forty-four (59.5%) patients underwent primary surgery, whereas 30 (40.5%) patients were inoperable according to FIGO and underwent primary radiochemotherapy. The mean age of the patients was 50.6 years. In 11 out of the 44 patients concordant staging results were obtained by all three staging modalities. Thirty-two of the 44 patients were concordantly staged by FIGO and histopathological examination, while only 16 were concordantly staged by eMRI and histopathological examination. eMRI overstaged tumors in 14 cases and understaged them in 7 cases. CONCLUSIONS: eMRI is applicable in patients with cervical cancer, yet of no benefit than staging with FIGO or standard pelvic MRI. The most precise preoperative staging procedure still appears to be the clinical examination. PMID- 24794865 TI - Three-dimensional contrast enhanced ultrasound score and dynamic contrast enhanced magnetic resonance imaging score in evaluating breast tumor angiogenesis: correlation with biological factors. AB - OBJECTIVE: To explore the clinical value of three-dimensional contrast enhanced ultrasound (3D-CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) score systems in evaluating breast tumor angiogenesis by comparing their diagnostic efficacy and correlation with biological factors. METHODS: 3D CEUS was performed in 183 patients with breast tumors by Esaote Mylab90 with SonoVue (Bracco, Italy), DCE-MRI was performed on a dedicated breast magnetic resonance imaging (DBMRI) system (Aurora Dedicated Breast MRI Systems, USA) with a dedicated breast coil. 3D-CEUS and DCE-MRI score systems were created based on tumor perfusion and vascular characteristics. Microvessel density (MVD), vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-2, MMP-9) expression were measured by immunohistochemistry. RESULTS: Pathological results showed 35 benign and 148 malignant breast tumors. MVD (P=0.000, r=0.76), VEGF (P=0.000, r=0.55), MMP-2 (P=0.000, r=0.39) and MMP-9 (P=0.000, r=0.41) expression were all significantly different between benignity and malignancy. Regarding 3D CEUS 4 points as cutoff value, the sensitivity, specificity and accuracy were 85.1%, 94.3% and 86.9%, respectively, and correlated well with MVD (P=0.000, r=0.50), VEGF (P=0.000, r=0.50), MMP-2 (P=0.000, r=0.50) and MMP-9 (P=0.000, r=0.66). Taking DCE-MRI 5 points as cutoff value, the sensitivity, specificity and accuracy were 86.5%, 94.3% and 88.0%, respectively and also correlated well with MVD (P=0.000, r=0.52), VEGF (P=0.000, r=0.44), MMP-2 (P=0.000, r=0.42) and MMP-9 (P=0.000, r=0.35). CONCLUSIONS: 3D-CEUS score system displays inspiring diagnostic performance and good agreement with DCE-MRI scoring. Moreover, both score systems correlate well with MVD, VEGF, MMP-2 and MMP-9 expression, and thus have great potentials in tumor angiogenesis evaluation. PMID- 24794866 TI - Quantifying thigh muscle co-activation during isometric knee extension contractions: within- and between-session reliability. AB - Muscle co-activation around the knee is important during ambulation and balance. The wide range of methodological approaches for the quantification of co activation index (CI) makes comparisons across studies and populations difficult. The present study determined within- and between-session reliability of different methodological approaches for the quantification of the CI of the knee extensor and flexor muscles during maximum voluntary isometric contractions (MVICs). Eight healthy volunteers participated in two repeated testing sessions. A series of knee extension MVICs of the dominant leg with concomitant torque and electromyographic (EMG) recordings were captured. CI was calculated utilizing different analytical approaches. Intraclass correlation coefficient (ICC) showed that within-session measures displayed higher reliability (ICC>0.861) and lower variability (Coefficient of variation; CV<21.8%) than between-session measures (ICC<0.645; CV>24.2%). A selection of a 500ms or larger window of RMS EMG activity around the PT delivered more reliable and less variable results than other approaches. Our findings suggest that the CI can provide a reliable measure for comparisons among conditions and is best utilized for within-session experimental designs. PMID- 24794867 TI - Insights into the structure and function of ciliary and flagellar doublet microtubules: tektins, Ca2+-binding proteins, and stable protofilaments. AB - Cilia and flagella are conserved, motile, and sensory cell organelles involved in signal transduction and human disease. Their scaffold consists of a 9-fold array of remarkably stable doublet microtubules (DMTs), along which motor proteins transmit force for ciliary motility and intraflagellar transport. DMTs possess Ribbons of three to four hyper-stable protofilaments whose location, organization, and specialized functions have been elusive. We performed a comprehensive analysis of the distribution and structural arrangements of Ribbon proteins from sea urchin sperm flagella, using quantitative immunobiochemistry, proteomics, immuno-cryo-electron microscopy, and tomography. Isolated Ribbons contain acetylated alpha-tubulin, beta-tubulin, conserved protein Rib45, >95% of the axonemal tektins, and >95% of the calcium-binding proteins, Rib74 and Rib85.5, whose human homologues are related to the cause of juvenile myoclonic epilepsy. DMTs contain only one type of Ribbon, corresponding to protofilaments A11-12-13-1 of the A-tubule. Rib74 and Rib85.5 are associated with the Ribbon in the lumen of the A-tubule. Ribbons contain a single ~5-nm wide filament, composed of equimolar tektins A, B, and C, which interact with the nexin-dynein regulatory complex. A summary of findings is presented, and the functions of Ribbon proteins are discussed in terms of the assembly and stability of DMTs, ciliary motility, and other microtubule systems. PMID- 24794868 TI - alpha1-adrenergic receptor signaling in osteoblasts regulates clock genes and bone morphogenetic protein 4 expression through up-regulation of the transcriptional factor nuclear factor IL-3 (Nfil3)/E4 promoter-binding protein 4 (E4BP4). AB - Several studies have demonstrated that the alpha1-adrenergic receptor (AR) plays an important role in regulating cell growth and function in osteoblasts. However, the physiological role of alpha1-AR signaling in bone metabolism is largely unknown. In this study, the stimulation of phenylephrine (PHE), a nonspecific alpha1-AR agonist, increased the transcriptional factor Nfil3/E4BP4 and led to the rhythmic expression of bone morphogenetic protein 4 (Bmp4) in MC3T3-E1 osteoblastic cells. We also showed that Bmp4 mRNA expression peaked in bone near zeitgeber time 8 in a 24-h rhythm. Furthermore, the expression of Nfil3 and Bmp4 displayed a circadian pattern with opposing phases, which suggested that Nfil3 repressed the expression of the Bmp4 gene during a circadian cycle. On a molecular level, both loss-of-function and gain-of-function experiments demonstrated that Nfil3/E4BP4 negatively regulated Bmp4 expression in osteoblasts. Furthermore, the systemic administration of PHE increased the expression of Nfil3 mRNA in bone, whereas it decreased that of Bmp4 mRNA. The expression of Bmp4 mRNA was decreased significantly by exposure to PHE, and this was concomitant with the increase in Nfil3 binding to the D-box-containing Bmp4 promoter region in MC3T3-E1 cells, which indicates that the expression of Nfil3 by alpha1-AR signaling can bind directly to the Bmp4 promoter and inhibit Bmp4 expression in osteoblasts. Our results suggest that alpha1-AR signaling regulates clock genes and Bmp4 expression in osteoblasts. Moreover, alpha1-AR signaling negatively regulated Bmp4 expression by up-regulating the transcriptional factor Nfil3/E4BP4 in osteoblasts. PMID- 24794870 TI - Role of autophagy in cisplatin resistance in ovarian cancer cells. AB - Cisplatin-based treatment is the first line chemotherapy for several cancers including ovarian cancer. The development of cisplatin resistance results in treatment failure, but the underlying mechanisms are not fully understood. Here we show that the induction of autophagy plays an important role in cisplatin resistance in ovarian cancer cells. Specifically, we show that cisplatin resistance is correlated with autophagy induction in a panel of ovarian cancer cells but not in immortalized human ovarian surface epithelial cells. Mechanistically, cisplatin treatment activates ERK and subsequently promotes autophagy. The inhibition of ERK activation with MEK inhibitors or knockdown of ERK expression with siRNA decreases cisplatin-induced autophagy and subsequently sensitizes ovarian cancer cells to cisplatin-induced apoptosis. In ovarian cancer cells that have developed acquired cisplatin resistance, both ERK activation and autophagy induction are increased. Importantly, knockdown of ERK or inhibition of autophagy promotes cisplatin-induced apoptosis in acquired cisplatin-resistant cells. Collectively, our data indicate that ERK-mediated autophagy can lead to cisplatin resistance and suggest that cisplatin resistance can be overcome by inhibition of autophagy in ovarian cancer cells. PMID- 24794869 TI - The VgrG proteins are "a la carte" delivery systems for bacterial type VI effectors. AB - The bacterial type VI secretion system (T6SS) is a supra-molecular complex akin to bacteriophage tails, with VgrG proteins acting as a puncturing device. The Pseudomonas aeruginosa H1-T6SS has been extensively characterized. It is involved in bacterial killing and in the delivery of three toxins, Tse1-3. Here, we demonstrate the independent contribution of the three H1-T6SS co-regulated vgrG genes, vgrG1abc, to bacterial killing. A putative toxin is encoded in the vicinity of each vgrG gene, supporting the concept of specific VgrG/toxin couples. In this respect, VgrG1c is involved in the delivery of an Rhs protein, RhsP1. The RhsP1 C terminus carries a toxic activity, from which the producing bacterium is protected by a cognate immunity. Similarly, VgrG1a-dependent toxicity is associated with the PA0093 gene encoding a two-domain protein with a putative toxin domain (Toxin_61) at the C terminus. Finally, VgrG1b-dependent killing is detectable upon complementation of a triple vgrG1abc mutant. The VgrG1b-dependent killing is mediated by PA0099, which presents the characteristics of the superfamily nuclease 2 toxin members. Overall, these data develop the concept that VgrGs are indispensable components for the specific delivery of effectors. Several additional vgrG genes are encoded on the P. aeruginosa genome and are not linked genetically to other T6SS genes. A closer inspection of these clusters reveals that they also encode putative toxins. Overall, these associations further support the notion of an original form of secretion system, in which VgrG acts as the carrier. PMID- 24794871 TI - p27 protein protects metabolically stressed cardiomyocytes from apoptosis by promoting autophagy. AB - p27(Kip1) (p27), a key regulator of cell division, has been implicated in autophagy of cancer cells. However, its role in autophagy, the evolutionarily conserved catabolic process that enables cells to remove unwanted proteins and damaged organelles, had not been examined in the heart. Here we report that ectopic delivery of a p27 fusion protein (TAT-p27) was sufficient to induce autophagy in neonatal rat ventricular cardiomyocytes in vitro, under basal conditions and after glucose deprivation. Conversely, lentivirus-delivered shRNA against p27 successfully reduced p27 levels and suppressed basal and glucose deprived levels of autophagy in cardiomyocytes in vitro. Glucose deprivation mimics myocardial ischemia and induces apoptosis in cardiomyocytes. During glucose deprivation, TAT-p27 inhibited apoptosis, whereas down-regulation of p27 decreased survival of cardiomyocytes. However, inhibition of autophagy by pharmacological (3-methyladenine, chloroquine, or bafilomycin A1) or genetic approaches (siRNA-mediated knockdown of Atg5) sensitized cardiomyocytes to glucose deprivation-induced apoptosis, even in the presence of TAT-p27. TAT-p27 was also able to provoke greater levels of autophagy in resting and fasting cardiomyocytes in vivo. Further, TAT-p27 enhanced autophagy and repressed cardiomyocytes apoptosis, improved cardiac function, and reduced infarct size following myocardial infarction. Again, these effects were lost when cardiac autophagy in vivo was blocked by chloroquine. Taken together, these data show that p27 positively regulates cardiac autophagy in vitro and in vivo, at rest and after metabolic stress, and that TAT-p27 inhibits apoptosis by promoting autophagy in glucose-deprived cardiomyocytes in vitro and in post-myocardial infarction hearts in vivo. PMID- 24794872 TI - Trapping of Vibrio cholerae cytolysin in the membrane-bound monomeric state blocks membrane insertion and functional pore formation by the toxin. AB - Vibrio cholerae cytolysin (VCC) is a potent membrane-damaging cytolytic toxin that belongs to the family of beta barrel pore-forming protein toxins. VCC induces lysis of its target eukaryotic cells by forming transmembrane oligomeric beta barrel pores. The mechanism of membrane pore formation by VCC follows the overall scheme of the archetypical beta barrel pore-forming protein toxin mode of action, in which the water-soluble monomeric form of the toxin first binds to the target cell membrane, then assembles into a prepore oligomeric intermediate, and finally converts into the functional transmembrane oligomeric beta barrel pore. However, there exists a vast knowledge gap in our understanding regarding the intricate details of the membrane pore formation process employed by VCC. In particular, the membrane oligomerization and membrane insertion steps of the process have only been described to a limited extent. In this study, we determined the key residues in VCC that are critical to trigger membrane oligomerization of the toxin. Alteration of such key residues traps the toxin in its membrane-bound monomeric state and abrogates subsequent oligomerization, membrane insertion, and functional transmembrane pore-formation events. The results obtained from our study also suggest that the membrane insertion of VCC depends critically on the oligomerization process and that it cannot be initiated in the membrane-bound monomeric form of the toxin. In sum, our study, for the first time, dissects membrane binding from the subsequent oligomerization and membrane insertion steps and, thus, defines the exact sequence of events in the membrane pore formation process by VCC. PMID- 24794873 TI - Circadian regulation of Tshb gene expression by Rev-Erbalpha (NR1D1) and nuclear corepressor 1 (NCOR1). AB - Thyroid hormones (TH) are critical for development, growth, and metabolism. Circulating TH levels are tightly regulated by thyroid-stimulating hormone (TSH) secretion within the hypothalamic-pituitary-thyroid axis. Although circadian TSH secretion has been well documented, the mechanism of this observation remains unclear. Recently, the nuclear corepressor, NCOR1, has been postulated to regulate TSH expression, presumably by interacting with thyroid hormone receptors (THRs) bound to TSH subunit genes. We report herein the first in vitro study of NCOR1 regulation of TSH in a physiologically relevant cell system, the TalphaT1.1 mouse thyrotroph cell line. Knockdown of NCOR1 by shRNA adenovirus increased baseline Tshb mRNA levels compared with scrambled control, but surprisingly had no affect on the T3-mediated repression of this gene. Using ChIP, we show that NCOR1 enriches on the Tshb promoter at sites different from THR previously identified by our group. Furthermore, NCOR1 enrichment on Tshb is unaffected by T3 treatment. Given that NCOR1 does not target THR on Tshb, we hypothesized that NCOR1 targeted Rev-Erbalpha (NR1D1), an orphan nuclear receptor that is a potent repressor of gene transcription and regulator of metabolism and circadian rhythms. Using a serum shock technique, we synchronized TalphaT1.1 cells to study circadian gene expression. Post-synchronization, Tshb and Nr1d1 mRNA levels displayed oscillations that inversely correlated with each other. Furthermore, NR1D1 was enriched at the same locus as NCOR1 on Tshb. Therefore, we propose a model for Tshb regulation whereby NR1D1 and NCOR1 interact to regulate circadian expression of Tshb independent of TH negative regulation. PMID- 24794874 TI - Contribution of pyruvate phosphate dikinase in the maintenance of the glycosomal ATP/ADP balance in the Trypanosoma brucei procyclic form. AB - Trypanosoma brucei belongs to a group of protists that sequester the first six or seven glycolytic steps inside specialized peroxisomes, named glycosomes. Because of the glycosomal membrane impermeability to nucleotides, ATP molecules consumed by the first glycolytic steps need to be regenerated in the glycosomes by kinases, such as phosphoenolpyruvate carboxykinase (PEPCK). The glycosomal pyruvate phosphate dikinase (PPDK), which reversibly converts phosphoenolpyruvate into pyruvate, could also be involved in this process. To address this question, we analyzed the metabolism of the main carbon sources used by the procyclic trypanosomes (glucose, proline, and threonine) after deletion of the PPDK gene in the wild-type (Deltappdk) and PEPCK null (Deltappdk/Deltapepck) backgrounds. The rate of acetate production from glucose is 30% reduced in the Deltappdk mutant, whereas threonine-derived acetate production is not affected, showing that PPDK function in the glycolytic direction with production of ATP in the glycosomes. The Deltappdk/Deltapepck mutant incubated in glucose as the only carbon source showed a 3.8-fold reduction of the glycolytic rate compared with the Deltapepck mutant, as a consequence of the imbalanced glycosomal ATP/ADP ratio. The role of PPDK in maintenance of the ATP/ADP balance was confirmed by expressing the glycosomal phosphoglycerate kinase (PGKC) in the Deltappdk/Deltapepck cell line, which restored the glycolytic flux. We also observed that expression of PGKC is lethal for procyclic trypanosomes, as a consequence of ATP depletion, due to glycosomal relocation of cytosolic ATP production. This illustrates the key roles played by glycosomal and cytosolic kinases, including PPDK, to maintain the cellular ATP/ADP homeostasis. PMID- 24794875 TI - Cloning, expression and methylation analysis of piwil2 in half-smooth tongue sole (Cynoglossus semilaevis). AB - piwi is an important regulator gene in germ cell division during spermatogenesis. piwi homologous genes are involved in gametogenesis and germline specification, and knocking down these genes could affect germ cell meiotic progression. To understand the function of piwi-related genes in spermatogenesis, we cloned a Piwi-subfamily member (piwil2 gene) from the gonad of Cynoglossus semilaevis. The full-length of piwil2 cDNA was 3314bp, including a 3162bp open reading frame (ORF), a 60bp 5'-UTR, along with a 92bp 3'-UTR, and encoded a predicted protein of 1053 amino acid residues. Phylogenetic analysis showed that the PIWIL2 putative protein belonged to the Argonaute protein family, and Piwi-subfamily, with typical PAZ and Piwi domains. Ultrathin sections of different gonadal stages, and real-time quantitative PCR showed that the relative expression of the piwil2 gene couldn't be detected until day 95 (95days) larvae, when germ cell divided rapidly in C. semilaevis. The piwil2 transcripts were more abundant in gonads of males and neo-males than in females, and weakly expressed in other tissues and organs. Compared with the relative expression of piwil2 in gonads, the CpG methylation levels were significantly higher in females. Chromosomal fluorescence in situ hybridization (FISH) showed that the piwil2 gene was located on the Z sex chromosome of C. semilaevis. These results suggest that piwil2 plays an important role in spermatogenesis of C. semilaevis. PMID- 24794876 TI - Coronary vasomotion one year after drug-eluting stent implantation: comparison of everolimus-eluting and paclitaxel-eluting coronary stents. AB - First-generation drug-eluting stents (DES) have been associated with impaired localized coronary vasomotion and delayed endothelialization. We aimed to compare coronary vasomotion after implantation of a newer-generation everolimus-eluting stent (EES), with a first-generation paclitaxel-eluting stent (PES). Coronary vasomotion was studied in 19 patients with EES and 13 with PES. Vasomotor response was measured proximally and distally to the stent and in a remote vessel (reference segment). Quantitative coronary angiography was performed offline. Endothelium independent vasomotion did not differ significantly between the two groups. EES showed significant vasodilatation while PES showed vasoconstriction at both proximal (+4.5 +/- 3.6 vs -4.2 +/- 6.9, p < 0.001) and distal (+4.6 +/- 7.9 vs -4.8 +/- 9.3, p = 0.003) segments. The reference segment did not show any significant difference in vasodilatation between the two groups (+9.8 +/- 6.4 vs +7.2 +/- 5.2, p = 0.17). Endothelium-dependent vasomotion at adjacent stent segments is relatively preserved after EES implantation while vasoconstriction was observed after PES implantation. PMID- 24794877 TI - Electrocardiogram abnormalities and risk of cardiovascular mortality and all cause mortality in old age: the Kahrizak Elderly Study (KES). AB - Resting electrocardioghic (ECG) abnormalities might be value for mortality prediction. The aim of this study is to evaluate whether ECG abnormalities are associated with increased mortality in older residents of Kahrizak Charity Foundation (KCF). A total of 247 participants >=60-years of KES were enrolled in this study. Adjudicated all cause mortality was collected over 3 years between 2006 and 2009. The subjects were classified as having major, minor or no ECG abnormalities according to the Minnesota Code. The addition of ECG to risk factors were examined to predict cardiovascular diseases (CVD) and all-cause mortality by using Cox proportional hazards regression models. At baseline, 104(42.1%) had major ECG abnormalities and 73(29.6%) had minor abnormalities. During a median follow-up of 3.2 years, 73 participants died from all-cause mortality and 31 deaths from CVD. Major ECG abnormalities were associated with an increased risk of CVD mortality in all models. The associations between minor ECG abnormalities at baseline and CVD mortality were not statistically significant. After adjustment for age and sex, Body mass index (BMI), smoking, diabetes, hypertension (HTN), hyperlipidemia and history of CVD, the participants with the major ECG abnormalities had higher risks of CVD mortality (HR: 3.12(95% CI, 1.02 9.57) and all-cause mortality (HR: 2.45(95% CI, 1.23-4.85) compared with those with normal ECG. PMID- 24794878 TI - Statins role in the prevention and treatment of sepsis. AB - Sepsis is a complex disease with typically poor outcomes. While the onset of sepsis is typically infectious, the detrimental consequences follow pathogen toxin release that produces activation of numerous cytokines and a pro inflammatory response. These same cytokines also stimulate activation of coagulation and inhibit natural fibrinolysis. Despite decades of research targeted against these pathways the development of sepsis and mortality in patients with sepsis remains high. While statins were developed for reducing cholesterol in patients with atherosclerotic disease, we now know they have a number of other properties which may be helpful in the prevention and treatment of sepsis. Statins have demonstrated the ability to reduce a number of pro inflammatory cytokines known to be detrimental in the development and progression of sepsis. Statins have also demonstrated the ability to limit the coagulation response and promote fibrinolysis in the setting of sepsis. Based on these encouraging pharmacologic properties of statins a number of trials have been conducted evaluating the impact of statins on the prevention and treatment of sepsis. Most of the trials to date have been retrospective cohort trials, with very few prospective randomized trials. While some trials fail to demonstrate a benefit of statins, most trials suggest a reduction in the development of sepsis and/or other important sepsis related outcomes. While the laboratory and early clinical experience with statins are encouraging, randomized controlled trials will be need to fully define the role of statins in the prevention and treatment of sepsis. PMID- 24794879 TI - Treatment response heterogeneity in the predominant negative symptoms of schizophrenia: analysis of amisulpride vs placebo in three clinical trials. AB - BACKGROUND: The extent of heterogeneity in response to the psychopharmacological treatment of negative symptoms is unknown. AIMS: To examine the extent of heterogeneity in response to the treatment of predominantly negative symptoms of schizophrenia. METHOD: Data were analyzed from three clinical trials that compared placebo or amisulpride for up to 60days. Trial participants had predominantly negative symptoms of schizophrenia (n=485). Heterogeneity of percentage reduction on the Scale for the Assessment of Negative Symptoms (SANS) was examined with trajectory-group based modeling followed by descriptive statistics and the prediction of trajectory group membership with logistic regression modeling. Analyses were repeated separately for the placebo and amisulpride groups. RESULTS: Trajectory group-based modeling identified groups of non- (n=297, 61.2%), gradual-moderate (n=135, 27.8%) and rapid- (n=53, 10.9%) responders. At baseline compared to non-responders, rapid-responders had consistently significantly (p<.05) higher SANS total and subscale scores. Percent SANS improvement at endpoint was greatest for the rapid-responders group, a finding that replicated stratifying by placebo and amisulpride treatment groups. Similarly, in the total sample and stratifying by placebo and amisulpride groups, dropout was not significantly associated with trajectory group membership. CONCLUSIONS: Trajectories of treatment response to the psychopharmacological medication of the negative symptoms of schizophrenia demonstrate substantial heterogeneity. Approximately half of the patients included in our analysis showed little improvement, and the most severely ill at baseline responded the most. PMID- 24794880 TI - Testing a modification of cognitive adaptation training: streamlining the model for broader implementation. AB - Cognitive adaptation training (CAT) is a home-based, manualized treatment that utilizes environmental supports to improve target behaviors and functional outcomes in persons with schizophrenia. Although clinical trials have shown CAT to be effective across functional, clinical, and treatment adherence domains, when the intervention is withdrawn clients experience significant declines. The aim of the current study was to test a modified version of CAT, which decreases the duration of intensive CAT intervention while utilizing ongoing case management-supported CAT to maintain the fundamental components of the treatment. Twenty-three people participated in an outcome study of the modified version of CAT, evaluating improvements after 4months of CAT specialist intervention and after an additional 5months of case manager support. Analysis revealed significant improvements in adaptive functioning, psychiatric symptomatology, and goal attainment, which were maintained throughout case management follow-up. This suggests that an intervention that has previously demonstrated good functional outcomes in randomized trials might sustain its impacts in an abbreviated format with support from existing case managers. PMID- 24794881 TI - Antipsychotic treatment with quetiapine increases the cortical silent period. AB - RATIONALE: Measurement of motor cortex excitability with single and paired pulse transcranial magnetic stimulation has become an established method for in vivo characterization of the effects of central-acting drugs. The comparison of drug free and medicated patients with schizophrenia suggests an association of neuroleptics intake and prolongation of the cortical silent period (CSP). However all available data come from cross-sectional non-randomized studies. Thus it is not clear whether the observed difference is an effect of medication or reflects differences in disease severity or both. OBJECTIVES: We aimed to investigate whether the CSP or other parameters of cortical excitability change, when cortical excitability is measured in drug-free patients with acute psychosis before and after 3week intake of the atypical neuroleptic quetiapine. METHODS: Different parameters of cortical excitability were studied in 24 drug-free patients with acute psychosis before and after 3weeks of treatment with a mean dose of 352+/-199mg quetiapine. RESULTS: We observed a significant prolongation of the cortical silent period (CSP) after three week treatment with quetiapine. Other parameters of cortical excitability such as motor threshold (MT), short intracortical inhibition (SICI) and intracortical facilitation (ICF) remained unaffected. There was a significant improvement in clinical parameters (PANS, GAF) but no significant correlation between clinical improvement and changes in cortical excitability. CONCLUSIONS: These longitudinal data are in line with previous reports from cross-sectional studies. The excitability changes induced by three-week intake of quetiapine in acute psychotic patients confirm the notion that neuroleptic treatment is associated with an increase in CSP. PMID- 24794882 TI - A competitive PCR assay confirms the association of a copy number variation in the VIPR2 gene with schizophrenia in Han Chinese. AB - Evidence from genetic studies has revealed that genome-wide rare copy number variations (CNVs) are risk factors for neurodevelopmental disorders and this evidence has given rise to a new understanding of disease etiology, including that of schizophrenia (SCZ). Recent studies have indicated that duplication in the vasoactive intestinal peptide receptor-2 (VIPR2) gene confers the susceptibility to SCZ in Caucasians, but so far this finding has still not been confirmed in Chinese populations. In this study, we investigated the association between CNVs in VIPR2 and SCZ risk in an independent case-control study of Han Chinese using 1035 cases and 1535 controls. The CNVs were genotyped using the multiplex fluorescence competitive PCR method. In contrast with a common genotype (2-copy), a microduplication variant genotype (3-copy) was only carried by SCZ patients (4/1035). This finding indicated that CNVs in VIPR2 may impose a significantly increased risk of SCZ in Han Chinese (P=0.02646, OR=infinity, 95% CI=1.327-infinity). Thus, our results suggest that carriers of microduplication genotypes of VIPR2 are predisposed to SCZ in Han Chinese. PMID- 24794883 TI - Hippocampus and amygdala volumes in children and young adults at high-risk of schizophrenia: research synthesis. AB - BACKGROUND: Studies have reported hippocampal and amygdala volume abnormalities in schizophrenic patients. It is necessary to explore the potential for these structures as early disease markers in subjects at high risk (HR) of schizophrenia. METHODS: We performed a review of 29 magnetic resonance imaging (MRI) studies measuring hippocampal and amygdala volumes in subjects at HR for schizophrenia. We reclassified subjects in 3 new HR categories: presence of only risk symptoms (psychotic moderate symptoms), presence of only risk factors (genetic, developmental or environmental), and presence of combined risk symptoms/factors. RESULTS: Hippocampal volume reductions were detected in subjects with first episode (FE) of psychosis, in all young adults and in adolescents at HR of schizophrenia. The loss of tissue was mainly located in the posterior part of hippocampus and the right side seems more vulnerable in young adults with only risk symptoms. Instead, the anterior sector seems more involved in HR subjects with genetic risks. Abnormal amygdala volumes were found in FE subjects, in children with combined risk symptoms/factors and in older subjects using different inclusion criteria, but not in young adults. CONCLUSION: Hippocampal and amygdala abnormalities may be present before schizophrenia onset. Further studies should be conducted to clarify whether these abnormalities are causally or effectually related to neurodevelopment. Shape analysis could clarify the impact of environmental, genetic, and developmental factors on the medial temporal structures during the evolution of this disease. PMID- 24794885 TI - Primary pyomyositis and disseminated septic pulmonary emboli: a reactivated staphylococcal infection? AB - Staphylococcal pyomyositis is a severe invasive soft tissue infection with high mortality rate that is increasingly being recognized even in temperate climates. In most cases predisposing factors are identified that include either source of skin penetration or/and impaired host immunocompetence. A case of primary, community-acquired pyomyositis of the left iliopsoas muscle in a 59-year-old immunocompetent woman, which was complicated with septic pulmonary emboli within 24h after hospital admission, is presented. The patient was subjected to abscess drainage under computed tomography guidance. Both pus aspiration and blood cultures revealed methicillin-susceptible Staphylococcus aureus. Given the absolute absence of predisposing factors and a remote history of staphylococcal osteomyelitis in the same anatomical region 53 years ago, reactivation of a staphylococcal soft tissue infection was postulated. Systematic review of the literature revealed a few interesting cases of reactivated staphylococcal infection after decades of latency, although the exact pathophysiological mechanisms still need to be elucidated. PMID- 24794884 TI - Prevalence of lipodystrophy and risk factors for dyslipidemia in HIV-infected children in Brazil. AB - The aim of present study was to describe the frequency of lipodystrophy syndrome associated with HIV (LSHIV) and factors associated with dyslipidemia in Brazilian HIV infected children. HIV infected children on antiretroviral treatment were evaluated (nutritional assessment, physical examination, and laboratory tests) in this cross-sectional study. Univariate analysis was performed using Mann-Whitney test or Fisher's exact test followed by logistic regression analysis. Presence of dyslipidemia (fasting cholesterol >200mg/dl or triglycerides >130mg/dl) was the dependent variable. 90 children were enrolled. The mean age was 10.6 years (3-16 years), and 52 (58%) were female. LSHIV was detected in 46 children (51%). Factors independently associated with dyslipidemia were: low intake of vegetables/fruits (OR=3.47, 95%CI=1.04-11.55), current use of lopinavir/ritonavir (OR=2.91, 95%CI=1.11-7.67). In conclusion, LSHIV was frequently observed; inadequate dietary intake of sugars and fats, as well as current use of lopinavir/ritonavir was associated with dyslipidemia. PMID- 24794886 TI - Effects of Leukoreduction and Premedication With Acetaminophen and Diphenhydramine in Minimizing Febrile Nonhemolytic Transfusion Reactions and Allergic Transfusion Reactions During and After Blood Product Administration: A Literature Review With Recommendations for Practice. AB - Transfusion-related reactions cause unwanted interruptions in blood-product administration and potential complications for patients. The most common reactions are febrile nonhemolytic transfusion reactions (FNHTRs) and allergic transfusion reactions (ATRs). The presence of leukocytes in blood products has been associated with these reactions, and efficacy of leukoreduction in minimizing FNHTRs and ATRs has recently been investigated. In addition, premedication with acetaminophen and diphenhydramine is the most widely used practice in minimizing FNHTRs and ATRs, yet the benefit of this is not supported by research. The aim of this systematic literature review was to evaluate the potential benefits of both of these interventions in minimizing FNHTRs and ATRs and provide recommendations for practice. We found moderate quality evidence with strong recommendations for the practice of leukoreduction in minimizing FNHTRs but not ATRs. We did not find evidence to support the use of premedications in minimizing transfusion-related reactions, and we question the need for this practice in settings where leukoreduction is used. PMID- 24794887 TI - Central Venous Catheter Flushing Recommendations: A Systematic Evidence-Based Practice Review. AB - BACKGROUND: Treatment for many children with blood disorders or cancer includes the use of central venous catheters (CVCs). Few prospective studies have been conducted to address flushing guidelines in pediatric hematology oncology patients. Eighteen pediatric hematology oncology units were surveyed regarding current CVC flushing policies and procedures. Results reported extreme variations in CVC flush procedures, which instigated this systematic review. AIMS: The purpose of this project was to critically review current literature and expert opinion regarding CVC flushing practice in the hopes of reporting standardized recommendations. Dissemination of consistent recommendations may reduce practice variability and complications associated with CVCs as well as increase patient and family confidence and competence in providing CVC care. METHODS: Literature searches used PubMed, Medline, CINAHL, National Guidelines Clearinghouse, and Cochrane Database of Systematic Reviews. Multiple reviewers evaluated results relevant to CVC flushing procedures. Studies excluded were those that included neonates, peripheral intravenous catheters, dialysis catheters, and valved catheters. RESULTS: Evaluation of 5 randomized controlled trials, 3 observational studies, 2 systematic reviews, 7 guidelines, and 1 literature review using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and Appraisal of Guidelines for Research & Evaluation II (AGREE II) tools, an overall low level of evidence, and weak recommendation for practice was concluded. CONCLUSION: Weak recommendation for daily flushing of noninfusing Broviac/Hickman catheters and accessed implanted ports may be made. There was not sufficient evidence for heparin volume or concentration recommendations. No recommendations can be reported for peripherally inserted central venous catheters. Further research is indicated for CVC flushing procedures in pediatric hematology oncology patients. PMID- 24794888 TI - Keratoplasty outcomes: are we making advances? PMID- 24794889 TI - Nationwide population-based cohort study on the association of acute coronary syndrome in patients with malignancies. AB - AIMS/INTRODUCTION: Patients with malignancy are suggestive of having a tendency toward an association with vascular thrombosis risk. The aim of this study was to evaluate the possible relationship between malignancy and the risk of acute coronary syndrome (ACS) in Taiwan. MATERIALS AND METHODS: We used data from the National Health Insurance (NHI) system of Taiwan to assess the issue. Cox proportional hazards regression analysis was conducted to estimate the effects of malignancy on the risk of ACS. RESULTS: ACS risk in patients with malignancies was marginally significantly greater when adjusted for age, sex (hazard ratio (HR) = 1.09, 95 % confidence interval (CI) = 0.99-1.20), and comorbidities (HR = 1.03, 95 % CI = 0.93-1.13). A subgroup analysis indicated that patients with prostate cancer and head and neck cancer (HEENT) had a significantly higher risk of ACS (HR = 1.30, 95 % CI = 1.01-1.67; HR = 3.03, 95 % CI = 1.47-6.50). CONCLUSIONS: We suggest careful surveillance of ACS symptoms and regular electrocardiography during follow-up of these patients. However, further large scale studies for patients with prostate and HEENT cancer and cancer survivors (especially from post-hormone or radiotherapy) are needed. PMID- 24794891 TI - Affordable Care Act--cautious optimism is the order of the day. PMID- 24794890 TI - Alteration in fasting glucose after prolonged treatment with a thiazide diuretic. AB - AIMS: Thiazide diuretics are recommended as first line antihypertensive treatment, but may contribute to new onset diabetes. We aimed to describe change in fasting glucose (FG) during prolonged thiazide treatment in an observational setting. METHODS: We conducted an observational, non-randomized, open label, follow-up study of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. We enrolled previous participants from the PEAR or PEAR-2 studies with at least 6 months of continuous treatment with either hydrochlorothiazide (HCTZ) or chlorthalidone. Linear regression was used to identify associations with changes in FG after prolonged thiazide and thiazide like diuretic treatment. RESULTS: A total of 40 participants were included with a mean 29 (range 8-72) months of thiazide treatment. FG increased 6.5 (SD 13.0) mg/dL during short-term thiazide treatment and 3.6 (SD 15.3) mg/dL FG during prolonged thiazide treatment. Increased FG at follow-up was associated with longer thiazide treatment duration (beta=0.34, p=0.008) and lower baseline FG (beta=-0.46, p=0.02). beta blocker treatment in combination with prolonged thiazide diuretic treatment was also associated with increased FG and increased 2 h glucose obtained from OGTT. CONCLUSIONS: Our results indicate that prolonged thiazide treatment duration is associated with increased FG and that overall glycemic status worsens when thiazide/thiazide-like diuretics are combined with beta blockers. PMID- 24794892 TI - Diplopia and driving: a problematic issue. AB - The aim of this article was to review the literature regarding diplopia and driving license and to review the West European legislations about this topic, in order to obtain appropriate indications for hospitals specialists and patients. A systematic review of articles published about diplopia and driving was performed. In addition a review of West European national legislations about driving license regulations for medical illnesses was performed, in addition to the European Union Directive on driving licenses. In the literature, the presence of diplopia has not been considered a reliable predictor of the safety of driving behavior, or it has not appeared to be a contraindication for driving according to some authors who were unable to demonstrate significant differences on driving simulator performance between subjects with chronic stable diplopia and control subjects. Nevertheless, in all western European legislations, acute diplopia constitutes an important limitation for driving, thus making the knowledge of current regulations fundamental for specialists involved in managing patients with diplopia. Ophthalmologists and maxillofacial/head and neck surgeons, may advise patients before hospital discharge about current legislations in their respective countries. PMID- 24794893 TI - Quaternized starch-based carrier for siRNA delivery: from cellular uptake to gene silencing. AB - RNAi therapeutics is a powerful tool for treating diseases by sequence-specific targeting of genes using siRNA. Since its discovery, the need for a safe and efficient delivery system for siRNA has increased. Here, we have developed and characterized a delivery platform for siRNA based on the natural polysaccharide starch in an attempt to address unresolved delivery challenges of RNAi. Modified potato starch (Q-starch) was successfully obtained by substitution with quaternary reagent, providing Q-starch with cationic properties. The results indicate that Q-starch was able to bind siRNA by self-assembly formation of complexes. For efficient and potent gene silencing we monitored the physical characteristics of the formed nanoparticles at increasing N/P molar ratios. The minimum ratio for complete entrapment of siRNA was 2. The resulting complexes, which were characterized by a small diameter (~30 nm) and positive surface charge, were able to protect siRNA from enzymatic degradation. Q-starch/siRNA complexes efficiently induced P-glycoprotein (P-gp) gene silencing in the human ovarian adenocarcinoma cell line, NCI-ADR/Res (NAR), over expressing the targeted gene and presenting low toxicity. Additionally, Q-starch-based complexes showed high cellular uptake during a 24-hour study, which also suggested that intracellular siRNA delivery barriers governed the kinetics of siRNA transfection. In this study, we have devised a promising siRNA delivery vector based on a starch derivative for efficient and safe RNAi application. PMID- 24794895 TI - A novel strategy for the treatment of chronic wounds based on the topical administration of rhEGF-loaded lipid nanoparticles: In vitro bioactivity and in vivo effectiveness in healing-impaired db/db mice. AB - Lipid nanoparticles are currently receiving increasing interest because they permit the topical administration of proteins, such as recombinant human epidermal growth factor (rhEGF), in a sustained and effective manner. Because chronic wounds have become a major healthcare burden, the topical administration of rhEGF-loaded lipid nanoparticles, namely solid lipid nanoparticles (SLN) and nanostructured lipid carries (NLC), appears to be an interesting and suitable strategy for the treatment of chronic wounds. Both rhEGF-loaded lipid nanoparticles were prepared through the emulsification-ultrasonication method; however, the NLC-rhEGF preparation did not require the use of any organic solvents. The characterisation of the nanoparticles (NP) revealed that the encapsulation efficiency (EE) of NLC-rhEGF was significantly greater than obtained with SLN-rhEGF. The in vitro experiments demonstrated that gamma sterilisation is a suitable process for the final sterilisation because no loss in activity was observed after the sterilisation process. In addition, the proliferation assays revealed that the bioactivity of the nanoformulations was even higher than that of free rhEGF. Finally, the effectiveness of the rhEGF loaded lipid nanoparticles was assayed in a full-thickness wound model in db/db mice. The data demonstrated that four topical administrations of SLN-rhEGF and NLC-rhEGF significantly improved healing in terms of wound closure, restoration of the inflammatory process, and re-epithelisation grade. In addition, the data did not reveal any differences in the in vivo effectiveness between the different rhEGF-loaded lipid nanoparticles. Overall, these findings demonstrate the promising potential of rhEGF-loaded lipid nanoparticles, particularly NLC-rhEGF, for the promotion of faster and more effective healing and suggest their future application for the treatment of chronic wounds. PMID- 24794896 TI - Lipid and polymer nanoparticles for drug delivery to bacterial biofilms. AB - Biofilms are matrix-enclosed communities of bacteria that show increased antibiotic resistance and the capability to evade the immune system. They can cause recalcitrant infections which cannot be cured with classical antibiotic therapy. Drug delivery by lipid or polymer nanoparticles is considered a promising strategy for overcoming biofilm resistance. These particles are able to improve the delivery of antibiotics to the bacterial cells, thereby increasing the efficacy of the treatment. In this review we give an overview of the types of polymer and lipid nanoparticles that have been developed for this purpose. The antimicrobial activity of nanoparticle encapsulated antibiotics compared to the activity of the free antibiotic is discussed in detail. In addition, targeting and triggered drug release strategies to further improve the antimicrobial activity are reviewed. Finally, ample attention is given to advanced microscopy methods that shed light on the behavior of nanoparticles inside biofilms, allowing further optimization of the nanoformulations. Lipid and polymer nanoparticles were found to increase the antimicrobial efficacy in many cases. Strategies such as the use of fusogenic liposomes, targeting of the nanoparticles and triggered release of the antimicrobial agent ensured the delivery of the antimicrobial agent in close proximity of the bacterial cells, maximizing the exposure of the biofilm to the antimicrobial agent. The majority of the discussed papers still present data on the in vitro anti-biofilm activity of nanoformulations, indicating that there is an urgent need for more in vivo studies in this field. PMID- 24794894 TI - Amphiphilic beads as depots for sustained drug release integrated into fibrillar scaffolds. AB - Native extracellular matrix (ECM) is a complex fibrous structure loaded with bioactive cues that affects the surrounding cells. A promising strategy to mimicking native tissue architecture for tissue engineering applications is to engineer fibrous scaffolds using electrospinning. By loading appropriate bioactive cues within these fibrous scaffolds, various cellular functions such as cell adhesion, proliferation and differentiation can be regulated. Here, we report on the encapsulation and sustained release of a model hydrophobic drug (dexamethasone (Dex)) within beaded fibrillar scaffold of poly(ethylene oxide terephthalate)-poly(butylene terephthalate) (PEOT/PBT), a polyether-ester multiblock copolymer to direct differentiation of human mesenchymal stem cells (hMSCs). The amphiphilic beads act as depots for sustained drug release that is integrated into the fibrillar scaffolds. The entrapment of Dex within the beaded structure results in sustained release of the drug over the period of 28days. This is mainly attributed to the diffusion driven release of Dex from the amphiphilic electrospun scaffolds. In vitro results indicate that hMSCs cultured on Dex containing beaded fibrillar scaffolds exhibit an increase in osteogenic differentiation potential, as evidenced by increased alkaline phosphatase (ALP) activity, compared to the direct infusion of Dex in the culture medium. The formation of a mineralized matrix is also significantly enhanced due to the controlled Dex release from the fibrous scaffolds. This approach can be used to engineer scaffolds with appropriate chemical cues to direct tissue regeneration. PMID- 24794897 TI - A new injectable liquid crystal system for one month delivery of leuprolide. AB - An injectable liquid crystal-forming system (LCFS) was prepared by using sorbitan monooleate (SMO) as a new liquid crystal-forming material for injections, and its potential use of clinically available sustained-release formulation was evaluated. LCFS was prepared using SMO mixed with phosphatidyl choline and tocopherol acetate, and contained 3.75 mg of leuprolide acetate as a monthly dose in 90 MUl in liquid form. The semi-solid mesophase was formed from the liquid LCFS when it contacted water. The mesophase showed typical characteristics of the liquid crystalline phase, which was classified as the hexagonal phase. The safety of the LCFS was studied by an in vitro extraction colony assay and by examining the injection site in rats and white rabbits after an autopsy. Both in vitro release test and in vivo pharmacokinetic and pharmacodynamic studies showed a sustained release of leuprolide. When compared with a commercial depot formulation of leuprolide, the LCFS showed a similar AUClast value and significantly reduced initial burst with sufficient suppression of testosterone after subcutaneous injections in rats and dogs. The LCFS can serve as a new type of sustained-release injection formulation for its safety, ease of preparation, and sustained release properties. PMID- 24794898 TI - Engineering and evaluating drug delivery particles in microfluidic devices. AB - The development of new and improved particle-based drug delivery is underpinned by an enhanced ability to engineer particles with high fidelity and integrity, as well as increased knowledge of their biological performance. Microfluidics can facilitate these processes through the engineering of spatiotemporally highly controlled environments using designed microstructures in combination with physical phenomena present at the microscale. In this review, we discuss microfluidics in the context of addressing key challenges in particle-based drug delivery. We provide an overview of how microfluidic devices can: (i) be employed to engineer particles, by providing highly controlled interfaces, and (ii) be used to establish dynamic in vitro models that mimic in vivo environments for studying the biological behavior of engineered particles. Finally, we discuss how the flexible and modular nature of microfluidic devices provides opportunities to create increasingly realistic models of the in vivo milieu (including multi-cell, multi-tissue and even multi-organ devices), and how ongoing developments toward commercialization of microfluidic tools are opening up new opportunities for the engineering and evaluation of drug delivery particles. PMID- 24794899 TI - Breakthrough discoveries in drug delivery technologies: the next 30 years. AB - What if we could open the 2044 special issue of the Journal of Controlled Release? Which drug delivery technologies will have led the field? Which ones will have successfully reached the marketplace? In attempting to answer these questions, we selected a few recent technologies and concepts that could, in our opinion, play a crucial role in coming years. In each case, emblematic papers are cited to introduce and discuss the selected topic. PMID- 24794900 TI - EPR: Evidence and fallacy. AB - The enhanced permeability and retention (EPR) of nanoparticles in tumors has long stood as one of the fundamental principles of cancer drug delivery, holding the promise of safe, simple and effective therapy. By allowing particles preferential access to tumors by virtue of size and longevity in circulation, EPR provided a neat rationale for the trend toward nano-sized drug carriers. Following the discovery of the phenomenon by Maeda in the mid-1980s, this rationale appeared to be well justified by the flood of evidence from preclinical studies and by the clinical success of Doxil. Clinical outcomes from nano-sized drug delivery systems, however, have indicated that EPR is not as reliable as previously thought. Drug carriers generally fail to provide superior efficacy to free drug systems when tested in clinical trials. A closer look reveals that EPR-dependent drug delivery is complicated by high tumor interstitial fluid pressure (IFP), irregular vascular distribution, and poor blood flow inside tumors. Furthermore, the animal tumor models used to study EPR differ from clinical tumors in several key aspects that seem to make EPR more pronounced than in human patients. On the basis of this evidence, we believe that EPR should only be invoked on a case-by case basis, when clinical evidence suggests the tumor type is susceptible. PMID- 24794901 TI - Controlled drug delivery systems: past forward and future back. AB - Controlled drug delivery technology has progressed over the last six decades. This progression began in 1952 with the introduction of the first sustained release formulation. The 1st generation of drug delivery (1950-1980) focused on developing oral and transdermal sustained release systems and establishing controlled drug release mechanisms. The 2nd generation (1980-2010) was dedicated to the development of zero-order release systems, self-regulated drug delivery systems, long-term depot formulations, and nanotechnology-based delivery systems. The latter part of the 2nd generation was largely focused on studying nanoparticle formulations. The Journal of Controlled Release (JCR) has played a pivotal role in the 2nd generation of drug delivery technologies, and it will continue playing a leading role in the next generation. The best path towards a productive 3rd generation of drug delivery technology requires an honest, open dialog without any preconceived ideas of the past. The drug delivery field needs to take a bold approach to designing future drug delivery formulations primarily based on today's necessities, to produce the necessary innovations. The JCR provides a forum for sharing the new ideas that will shape the 3rd generation of drug delivery technology. PMID- 24794902 TI - Multifunctional envelope-type nano device for controlled intracellular trafficking and selective targeting in vivo. AB - Nanomedicine is expected to be a basic technology for using nucleic acids as a drug, in which treating the cause of diseases represent the ultimate therapy. However, a sophisticated delivery system is required for efficient delivery of RNA/DNA, since these compounds need precise control of intracellular trafficking as well as biodistribution. Here we report on the use of a multifunctional envelope-type nano device (MEND) which is capable of intracellular trafficking such as endosomal escape, delivery to mitochondria, as well as active targeting to selective tissues/cells in vivo. In this review, we focused on the controlled intracellular trafficking of antigens for advanced immunotherapy, and then introduced a mitochondrial delivery system as an organelle targeting system for unmet medical needs. We also provide a successful in vivo delivery of siRNA to the liver based on a newly designed pH-responsive cationic lipid. Finally we will discuss an important role of an active targeting system using a peptide ligand to adipose vasculature. These progresses in drug delivery system will break through the barriers exist in our body, tissues and cells and open a window for future Nanomedicine. PMID- 24794903 TI - Mechanisms for antidiabetic effect of gingerol in cultured cells and obese diabetic model mice. AB - There have been studies on health beneficial effects of ginger and its components. However, there still remain certain aspects that are not well defined in their anti-hyperglycemic effects. Our aims were to find evidence of possible mechanisms for antidiabetic action of [6]-gingerol, a pungent component of ginger, employing a rat skeletal muscle-derived cell line, a rat-derived pancreatic beta-cell line, and type 2 diabetic model animals. The antidiabetic effect of [6]-gingerol was investigated through studies on glucose uptake in L6 myocytes and on pancreatic beta-cell protective ability from reactive oxygen species (ROS) in RIN-5F cells. Its in vivo effect was also examined using obese diabetic db/db mice. [6]-Gingerol increased glucose uptake under insulin absent condition and induced 5' adenosine monophosphate-activated protein kinase phosphorylation in L6 myotubes. Promotion by [6]-gingerol of glucose transporter 4 (GLUT4) translocation to plasma membrane was visually demonstrated by immunocytochemistry in L6 myoblasts transfected with glut4 cDNA-coding vector. [6]-Gingerol suppressed advanced glycation end product-induced rise of ROS levels in RIN-5F pancreatic beta-cells. [6]-Gingerol feeding suppressed the increases in fasting blood glucose levels and improved glucose intolerance in db/db mice. [6] Gingerol regulated hepatic gene expression of enzymes related to glucose metabolism toward decreases in gluconeogenesis and glycogenolysis as well as an increase in glycogenesis, thereby contributing to reductions in hepatic glucose production and hence blood glucose concentrations. These in vitro and in vivo results strongly suggest that [6]-gingerol has antidiabetic potential through multiple mechanisms. PMID- 24794904 TI - Azithromycin. AB - Azithromycin is an azalide, a subclass of macrolide antibiotics. It is derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered. It prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome and thus inhibits translation of mRNA. Azithromycin is used to treat or prevent certain bacterial infections, most often those causing middle ear infections, strep throat, pneumonia, typhoid, bronchitis, and sinusitis. In recent years, it has been used primarily to prevent bacterial infections in infants and those with weaker immune systems. It is also effective against certain sexually transmitted infections, such as nongonococcal urethritis, chlamydia, and cervicitis. Recent studies have indicated it also to be effective against late-onset asthma, but these findings are controversial and not widely accepted. The present study gives a comprehensive profile of azithromycin, including detailed physico-chemical properties, nomenclature, formulae, methods of preparation, and methods of analysis (including compendial, electrochemical, spectroscopic, and chromatographic methods of analysis). Developed validated stability-indicating (HPLC and biodiffusion assay methods under accelerated acidic, alkaline, and oxidative conditions, in addition to effect of different types of light, temperature, and pH. Detailed clinical applications also presented (mechanism of action, ADME profile, clinical uses and doses, side effects, and drug interactions). Each of the above stages includes appropriate figures and tables. More than 80 references were given as a proof of the above-mentioned studies. PMID- 24794905 TI - Cefdinir. AB - Cefdinir is a third-generation oral cephalosporin antibiotic. Nomenclature, formulae, elemental analysis, and appearance of the drug are mentioned. The uses and applications and the several methods described for its preparation of the drug are outlined. The profile contains the physical characteristics including: pKa value, solubility, X-ray powder diffraction, melting point, and differential scanning calorimetry. The ultraviolet spectrum, vibrational spectrum, nuclear magnetic resonance ((1)H and (13)C NMR) spectra and the mass spectrum and fragmentation patterns of cefdinir together with the corresponding figures and/or tables are all produced. This profile includes the monographs of the Japanese pharmacopeia and the United States pharmacopeia. The several reported analytical methods that had been reported of the analysis of cefdinir include: spectrophotometric, polarographic, voltammetric, and chromatographic methods. The pharmacokinetics and stability of the drug are also provided. About 80 references are listed at end of this comprehensive profile. PMID- 24794906 TI - Curcumin. AB - Curcumin and its two related compounds, that is, demethoxycurcumin and bis demethoxycurcumin (curcuminoids) are the main secondary metabolites of Curcuma longa and other Curcuma spp. Curcumin is commonly used as coloring agent as well as food additive; curcumin has also shown some therapeutic activities. This review summarizes stability of curcumin in solutions, spectroscopy characteristics of curcumin (UV, IR, Raman, MS, and NMR), polymorphism forms, method of analysis in both of biological and nonbiological samples, and metabolite studies of curcumin. For analysis of curcumin and its related compounds in complex matrices, application of LC-MS/MS is recommended. PMID- 24794907 TI - Dasatinib. AB - Dasatinib (Sprycel(r)), a second-generation TKI, has been shown to be effective as an anticancer drug in the treatment of patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib. Several methods of gefitinib synthesis are included in this review. UV spectroscopy of dasatinib showed a lambdamax of approximately 320-330nm, and IR spectroscopy principal peaks were observed at 3418 (NH), 3200 (OH), 1620 (CO), 1582 (CC and CN), 1513 (CHCH) cm(-1). Characteristic NH peaks were observed in nuclear magnetic resonance (NMR) spectroscopy at 11.47 and 9.88ppm. The molecular mass was observed at m/z=487.3((35)Cl) and 488.9((37)Cl) (molecular weight=487.15) and the fragmentation pattern was studied using ion trap mass spectrometry. In addition, different analytical methods for determination of dasatinib are also described in this review. Pharmacokinetically, dasatinib is rapidly absorbed after oral administration where the solubility is dependent on pH. Dasatinib extensively binds to human plasma proteins by approximately 96%. In leukemic patient, the calculated apparent volume of distribution for dasatinib was 2502L and the estimated elimination half-life was approximately 3-5h. Dasatinib is metabolized in humans markedly by CYP3A4 to active metabolites and by phase II drug metabolizing enzymes, such as UDP glucuronosyltransferase. Dasatinib is mainly eliminated via the feces (85%), of which relatively small amount of dasatinib is excreted unchanged as intact drug (19%). Most of the adverse effects associated with dasatinib therapy are mild to moderate in severity and are usually reversible and manageable with appropriate intervention, such as cardiac failure, hypertension, and coronary artery disease. PMID- 24794908 TI - Gefitinib. AB - Gefitinib (Iressa(r)) is a selective inhibitor of epidermal growth factor, a growth factor that plays a pivotal role in the control of cell growth, apoptosis, and angiogenesis. Gefitinib is clinically used for the treatment of chemoresistant non-small cell lung cancer patients. Gefitinib is freely soluble in dimethylsulphoxide but slightly soluble in methanol and ethanol. Several methods of gefitinib synthesis are included in this review. UV spectroscopy of gefitinib showed a lambdamax of approximately 331nm, whereas IR spectroscopy principal peaks were observed at 3400cm(-1) (NH), 2956cm(-1) (CH2, CH, alkyl), 1625cm(-1) (CC, CN), 1500cm(-1) (HCCH, aryl), 1110cm(-1) (CO), 1028cm(-1) (CF). In addition, different analytical methods for determination of gefitinib are also described in this review. Pharmacokinetically, after oral administration, gefitinib is slowly absorbed with bioavailability of approximately 60% in human. Gefitinib is metabolized extensively in the liver into five metabolites by cytochrome P450s, primarily by CYP3A4 and to a lesser extent by CYP3A5 and CYP2D6. Gefitinib is eliminated mainly hepatically with total plasma clearance of 595mL/min after intravenous administration. Most of the adverse effects associated with gefitinib therapy are mild to moderate in severity and are usually reversible and manageable with appropriate intervention, such as diarrhea, dry skin, rash, nausea, and vomiting. PMID- 24794909 TI - Imatinib mesylate. AB - Imatinib (INN), marketed by Novartis as Gleevec (United States) or Glivec (Europe/Australia/Latin America), received Food & Drug Administration (FDA) approval in May 2001 and is a tyrosine kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia. Like all tyrosine kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme. Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy-only cancer cells are killed through the drug's action. In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action and is often cited as a paradigm for research in cancer therapeutics. This study presents a comprehensive profile of imatinib, including detailed nomenclature, formulae, physico-chemical properties, methods of preparation, and methods of analysis (including compendial, electrochemical, spectroscopic, and chromatographic methods of analysis). Spectroscopic and spectrometric analyses include UV/vis spectroscopy, vibrational spectroscopy, nuclear magnetic resonance spectrometry ((1)H and (13)C NMR), and mass spectrometry. Chromatographic methods of analyses include electrophoresis, thin layer chromatography, and high-performance liquid chromatography. Preliminary stability investigations for imatinib have established the main degradation pathways, for example, oxidation to N-oxide under oxidative stress conditions. Stability was also carried out for the formulation by exposing to different temperatures 0 degrees C, ambient temperature, and 40 degrees C. No remarkable change was found in the drug content of formulation. This indicates that the drug was stable at the above optimized formulation. Stability studies under acidic and alkaline conditions have established the following main degradation products: alpha-(4-Methyl-1-piperazinyl)-3'-{[4-(3-pyridyl)-2-pyrimidinyl] amino}-p-tolu-p toluid-ide methanesulfonate and 4-(4-methylpiperazin-1-ylmethyl)-benzoic acid. The main degradation products under oxidation conditions, that is, 4-[(4-methyl-4 oxido-piperazin-1-yl)-methyl]-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino) phenyl]-enzamide, 4-[(4-methyl-1-oxido-piperazin-1-yl)-methyl]-N-[4-methyl-3-(4 pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide, and 4-[(4-methyl-1,4-dioxido piperazin-1-yl)-methyl]-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino) phenyl]-enzamide. Clinical application studies for pharmacodynamics, pharmacokinetics, mechanism of action, and clinical uses of the drug were also presented. Each of the above stages includes appropriate figures and tables. More than 50 references were given as proof of the above-mentioned studies. PMID- 24794910 TI - Moxifloxacin hydrochloride. AB - A comprehensive profile of moxifloxacin HCl with 198 references is reported. A full description including nomenclature, formulae, elemental analysis, and appearance is included. Methods of preparation for moxifloxacin HCl, its intermediates, and derivatives are fully described. In addition, the physical properties, analytical methods, stability, uses and applications, and pharmacology of moxifloxacin HCl are also discussed. PMID- 24794911 TI - Pravastatin sodium. AB - Pravastatin sodium is an [HMG-CoA] reductase inhibitor and is a lipid-regulating drug. This monograph includes the description of the drug: nomenclature, formulae, elemental composition, solubility, appearance, and partition coefficient. The uses and the methods that have been reported for the synthesis of this drug are described. The physical methods that were used to characterize the drug are the X-ray powder diffraction pattern, thermal methods, melting point, and differential scanning calorimetry. This chapter also contains the following spectra of the drug: the ultraviolet spectrum, the vibrational spectrum, the nuclear magnetic resonance spectra, and the mass spectrum. The compendial methods of analysis include the British Pharmacopoeia and the United States Pharmacopoeia methods. Other methods of analysis that are included in this profile are spectrophotometric, electrochemical, polarographic, voltammetric and chromatographic, and immunoassay methods. The chapter also contains the pharmacokinetics, metabolism, stability, and articles that reviewed pravastatin sodium manufacturing, characterization, and analysis. One hundred and sixty-two references are listed at the end of this comprehensive profile. PMID- 24794912 TI - Vardenafil dihydrochloride. AB - Vardenafil (VAR) is synthetic, highly selective, and potent inhibitor of phosphodiesterase-5 which competitively inhibits cyclic guanosine monophosphate (cGMP) hydrolysis and thus increases cGMP levels. It is clinically approved for treatment of erectile dysfunction in men, including diabetic and postprostatectomy patients. Several methods of VAR synthesis are included in this review. UV spectroscopy of VAR showed a lambdamax of approximately 270nm, and IR spectroscopy principal peaks were observed at 3420 (NH), 1724 (CO), 1600 (CC, and CN), 1491 (CHCH) cm(-1). Characteristic carbonyl (CO) carbon was observed in nuclear magnetic resonance spectroscopy at 162.44ppm. The molecular mass was observed at m/z=488.9 (molecular weight=488.2) and the fragmentation pattern was studied using ion trap mass spectrometry. In addition, different analytical methods for determination of vardenafil are also described in this profile. Pharmacokinetic properties of VAR have great impact on efficacy. VAR is rapidly absorbed and slowly metabolized, with an absolute bioavailability of 15%. It is extensively metabolized by CYP3A4 into several metabolites, the most pharmacologically active of which is N-desethyl VAR (M1). The elimination half life of VAR and M1 is about 4-5h. VAR is primarily excreted as metabolites in the feces and to a small extent in urine. VAR is generally well tolerated, with a favorable safety profile and few transient side effects, including headache, flushing, dyspepsia, and rhinitis. PMID- 24794913 TI - Preface to volume 39. PMID- 24794914 TI - [Current state of neonatal extracorporeal membrane oxygenation in Colombia: description of the first cases]. AB - Extracorporeal membrane oxygenation is considered a rescue therapy and complex vital support with benefits in cardiorespiratory diseases during neonatal period that fulfil the characteristics of being reversible in neonates older than 34 weeks. The criteria for patient selection and its prompt use are critical for the final result. Even though new alternatives for management of hypoxemic respiratory failure in full term and almost full term neonates have decreased its use, congenital diaphragmatic hernia continues being a complex disease where it can have some applicability. Even though our experience is beginning, constant training will make of extracorporeal membrane oxygenation an option for complex patients in whom maximum therapy fails. This is a report of the first neonatal cases of hypoxemic respiratory failure managed at Fundacion Cardiovascular de Colombia. PMID- 24794915 TI - Structural isomers of Ti2O4 and Zr2O4 anions identified by slow photoelectron velocity-map imaging spectroscopy. AB - High-resolution anion photoelectron spectra are reported for the group 4 metal dioxide clusters Ti2O4(-) and Zr2O4(-). Slow photoelectron velocity-map imaging (SEVI) spectroscopy of cryogenically cooled, mass-selected anions yields photoelectron spectra with submillielectronvolt resolution, revealing extensive and well-resolved vibrational progressions. By comparison of the spectra with Franck-Condon simulations, we have identified the C(2v) and C(3v) isomers as the ground states of Ti2O4(-) and Zr2O4(-) anions, respectively. Minor contributions from the C(2h) isomer of Ti2O4(-) and the C(2v) isomer of Zr2O4(-) are also seen. The SEVI spectra yield upper bounds for the adiabatic detachment energies, as well as vibrational frequencies for various modes of the neutral Ti2O4 and Zr2O4 species. PMID- 24794916 TI - Molecular evolution tracks macroevolutionary transitions in Cetacea. AB - Cetacea (whales, dolphins, and porpoises) is a model group for investigating the molecular signature of macroevolutionary transitions. Recent research has begun to reveal the molecular underpinnings of the remarkable anatomical and behavioral transformation in this clade. This shift from terrestrial to aquatic environments is arguably the best-understood major morphological transition in vertebrate evolution. The ancestral body plan and physiology were extensively modified and, in many cases, these crucial changes are recorded in cetacean genomes. Recent studies have highlighted cetaceans as central to understanding adaptive molecular convergence and pseudogene formation. Here, we review current research in cetacean molecular evolution and the potential of Cetacea as a model for the study of other macroevolutionary transitions from a genomic perspective. PMID- 24794917 TI - Anxiety and psychological stress before prenatal screening in first-time mothers who conceived through IVF/ICSI or spontaneously. AB - Mothers' general anxiety, anxiety about the well-being of the child and psychological stress before prenatal testing was studied by comparing women who conceived through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with women who conceived naturally. Before the first trimester screening test for Down's syndrome, a group of 51 women who conceived through IVF/ICSI and a group of 54 women who conceived spontaneously completed the State Scale of the State-Trait Anxiety Inventory (S-Anxiety; Spielberger, 1983), the Fear of Bearing a Physically or Mentally Handicapped Child Subscale of the Pregnancy-related Anxiety Questionnaire (PRAQ-R; Huizink et al., 2004), the Psychological Stress Measure (PSM; Lemyre & Tessier, 1988), and the Prenatal Psychosocial Profile (PPP; Curry, Campbell, & Christian, 1994). Women who conceived through IVF/ICSI had more elevated levels of general anxiety and psychological stress than the women who conceived naturally; however, no difference was observed between the two groups for anxiety specifically related to the health of the child. These results underline the need to monitor women's emotional state after conception via IVF/ICSI-when counseling usually ends-and around the time of the first trimester screening. Counseling might thus be extended. PMID- 24794918 TI - When Action Observation Facilitates Visual Perception: Activation in Visuo-Motor Areas Contributes to Object Recognition. AB - Recent evidence suggests an interaction between the ventral visual-perceptual and dorsal visuo-motor brain systems during the course of object recognition. However, the precise function of the dorsal stream for perception remains to be determined. The present study specified the functional contribution of the visuo motor system to visual object recognition using functional magnetic resonance imaging and event-related potential (ERP) during action priming. Primes were movies showing hands performing an action with an object with the object being erased, followed by a manipulable target object, which either afforded a similar or a dissimilar action (congruent vs. incongruent condition). Participants had to recognize the target object within a picture-word matching task. Priming-related reductions of brain activity were found in frontal and parietal visuo-motor areas as well as in ventral regions including inferior and anterior temporal areas. Effective connectivity analyses suggested functional influences of parietal areas on anterior temporal areas. ERPs revealed priming-related source activity in visuo-motor regions at about 120 ms and later activity in the ventral stream at about 380 ms. Hence, rapidly initiated visuo-motor processes within the dorsal stream functionally contribute to visual object recognition in interaction with ventral stream processes dedicated to visual analysis and semantic integration. PMID- 24794920 TI - Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition. AB - Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children. PMID- 24794921 TI - Identification and characterization of suppressor mutants of spl11- mediated cell death in rice. AB - Lesion mimic mutants have been used to dissect programmed cell death (PCD) and defense-related pathways in plants. The rice lesion-mimic mutant spl11 exhibits race nonspecific resistance to the bacterial pathogen Xanthomonas oryzae pv. oryzae and the fungal pathogen Magnaporthe oryzae. Spl11 encodes an E3 ubiquitin ligase and is a negative regulator of PCD in rice. To study the regulation of Spl11-mediated PCD, we performed a genetic screen and identified three spl11 cell death suppressor (sds) mutants. These suppressors were characterized for their resistance to X. oryzae pv. oryzae and M. oryzae and for their expression of defense-related genes. The suppression of the cell-death phenotypes was generally correlated with reduced expression of defense-related genes. When rice was challenged with avirulent isolates of M. oryzae, the disease phenotype was unaffected in the sds mutants, indicating that the suppression might be Spl11 mediated pathway specific and may only be involved in basal defense. In addition, we mapped one of the suppressor mutations to a 140-kb interval on the long arm of rice chromosome 1. Identification and characterization of these sds mutants should facilitate our efforts to elucidate the Spl11-mediated PCD pathway. PMID- 24794919 TI - Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations. AB - Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses. PMID- 24794922 TI - Accuracy of initial clinical diagnosis of acute bacterial meningitis in children from a malaria-endemic area of Papua New Guinea. AB - BACKGROUND: The diagnosis of acute bacterial meningitis (ABM) is challenging in resource-limited settings where cerebral malaria and viral encephalitis are also common. METHODS: To assess the accuracy of an initial clinical diagnosis of ABM in a malaria-endemic area of Papua New Guinea (PNG), a retrospective chart review of hospitalized children aged 2 months to 10 years was conducted. RESULTS: Of the 481 eligible children, 240 had an initial clinical diagnosis of ABM that was confirmed independently by trained research staff under standardized conditions, with laboratory support in only 84 (17.5%; 84/481). When compared with the final laboratory-confirmed diagnosis, an initial diagnosis of ABM had a sensitivity, specificity, positive predictive value and negative predictive value of 76% (95% CI 66-85%), 56% (95% CI 51-61%), 27% (95% CI 21-33) and 92% (95% CI 87-95%), respectively. There was discordance between initial and final diagnosis of ABM in 196 children; 176 initially considered to have ABM had an alternative diagnosis, while 20 without an initial diagnosis of ABM were confirmed to have ABM. CONCLUSION: These data show that initial misdiagnosis of ABM is common in a malaria-endemic area of PNG. A diagnostic algorithm using standardized assessment for meningeal irritation, coma and malaria parasitological testing needs further evaluation in this setting. PMID- 24794923 TI - Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. AB - Despite progress, combination therapy of different functional drugs to increase the efficiency of anticancer treatment still remains challenges. An amphiphilic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-lysine) triblock copolymer decorated with deoxycholate (mPEsG-b-PLG-b-PLL/DOCA) was synthesized and developed as a nanovehicle for the co-delivery of anticancer drugs: doxorubicin (DOX) and paclitaxel (PTX). The amphiphilic copolymer spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and the blank nanoparticles possessed excellent stability. Three different domains of the copolymer performed distinct functions: PEG outer corona provided prolonged circulation, middle biodegradable and hydrophilic PLG shell was designed for DOX loading through electrostatic interactions, and hydrophobic deoxycholate modified PLL served as the container for PTX. In vitro cytotoxicity assays against A549 human lung adenocarcinoma cell line demonstrated that the DOX + PTX co-delivered nanoparticles (Co-NPs) exhibited synergistic effect in inducing cancer cell apoptosis. Ex vivo DOX fluorescence imaging revealed that Co-NPs had highly efficient targeting and accumulation at the implanted site of A549 xenograft tumor in vivo. Co-NPs exhibited significantly higher antitumor efficiency in reducing tumor size compared to free drug combination or single drug-loaded nanoparticles, while no obvious side effects were observed during the treatment, indicating this co-delivery system with different functional antitumor drugs provides the clinical potential in cancer therapy. PMID- 24794924 TI - Targeting efficiency of RGD-modified nanocarriers with different ligand intervals in response to integrin alphavbeta3 clustering. AB - Receptor change induced by ligand binding is a new issue to face in the field of targeted delivery. Receptor clustering, the main pattern of receptor changes, decreases the affinity between ligand and receptor due to the redistribution of receptor position. In an attempt to respond to such challenge, we designed and constructed three RGD-modified nanocarriers with different ligand intervals: stealth liposomes modified with the monomeric RGD (moRGD-LP), dimeric RGD (diRGD LP) and a special dimeric RGD with a linker between two cyclic RGD motifs (P diRGD-LP). The alphavbeta3-positive and -negative tumor cells (Melanoma B16 and MCF-7) were used as the cell models. As a result, P-diRGD-LP demonstrated strongest interaction with B16 cells in surface plasmon resonance study and highest cellular uptake in B16 cells in real-time confocal analysis. The enhanced endocytosis of P-diRGD-LP was found to be alphavbeta3-mediated and P-diRGD-LP increased the involvement of the clathrin-dependent pathway. Importantly, P-diRGD LP demonstrated the best targeting effect in B16-tumor bearing mice in both in vivo and ex vivo near-infrared fluorescent images, about 2.4-fold that of moRGD LP and 2.8-fold that of diRGD-LP at 3 h. Further, we validated integrin alphavbeta3 clustering on B16 cells via a single-molecule imaging by a total internal reflection fluorescence microscopy. Finally, the 3D models of alphavbeta3 clustering suggested a receptor interval within 41.916-65.779 A, while the molecular computation revealed an RGD ligand interval of 20.944 A, 42.753 A and 78.196 A for diRGD-LP, P-diRGD-LP and moRGD-LP, respectively, confirming the best matching between clustered alphavbeta3 and P-diRGD-LP. In conclusion, P-diRGD-LP could achieve higher targeting to alphavbeta3-positive tumor via the enhanced interaction based on the better ligand-receptor compatibility. The design of targeted nanocarriers against receptor clustering might provide new insight into the nanotechnology-based anticancer therapy. PMID- 24794925 TI - The epigenetic promotion of osteogenic differentiation of human adipose-derived stem cells by the genetic and chemical blockade of histone demethylase LSD1. AB - Human adipose-derived stem cells (hASCs) are a highly attractive source in bone tissue engineering. It has become increasingly clear that chromatin regulators play an important role in cell fate determination. However, how osteogenic differentiation of hASCs is controlled by epigenetic mechanisms is not fully understood. Here we use genetic tools and chemical inhibitors to modify the epigenetic program of hASCs and identify lysine-specific demethylase 1 (LSD1), a histone demethylase that specifically catalyzes demethylation of di- and mono- methyl histone H3 lysine 4 (H3K4me2/1), as a key regulator in osteogenic differentiation of hASCs. Specifically, we demonstrated that genetic depletion of LSD1 with lentiviral strategy for gene knockdown promoted osteogenic differentiation of hASCs by cell studies and xenograft assays. At the molecular level, we found that LSD1 regulates osteogenesis-associated genes expression through its histone demethylase activity. Significantly, we demonstrated LSD1 demethylase inhibitors could efficiently block its catalytic activity and epigenetically boost osteogenic differentiation of hASCs. Altogether, our study defined the functional and biological roles of LSD1 and extensively explored the effects of its enzymatic activity in osteogenic differentiation of hASCs. A better understanding of how LSD1 influences on osteogenesis associated epigenetic events will provide new insights into the modulation of hASCs based cell therapy and improve the development of bone tissue engineering with epigenetic intervention. PMID- 24794926 TI - Live cells imaging using a turn-on FRET-based BODIPY probe for biothiols. AB - We designed a red-emitting turn-on FRET-based molecular probe 1 for selective detection of cysteine and homocysteine. Probe 1 shows significant fluorescence enhancement after cleavage of the 2, 4-dinitrobenzensulfonyl (DNBS) unit from the fluorophore upon thiols treatment. The precursor of probe 1, BNM153, is a moderate quantum yield FRET dye which contributes a minimum emission leakage from its donor part. We synthesized this assembly by connecting a low quantum yield (less than 1%) BODIPY donor to a high quantum yield BODIPY acceptor via a 1, 3 triazine bridge system. It is noteworthy that the majority of the non-radiative energy loss of donor (BDN) was converted to the acceptor (BDM)'s fluorescence output with minimum leaks of donor emission. The fluorescence sensing mechanism of probe 1 was illustrated by fluorescence spectroscopy, kinetic measurements, HPLC-MS analysis and DFT calculations. Probe 1 is pH-independent at the physiological pH range. Finally, live cells imaging demonstrated the utility of probe 1 as a biosensor for thiols. PMID- 24794927 TI - A fast and powerful tree-based association test for detecting complex joint effects in case-control studies. AB - MOTIVATION: Multivariate tests derived from the logistic regression model are widely used to assess the joint effect of multiple predictors on a disease outcome in case-control studies. These tests become less optimal if the joint effect cannot be approximated adequately by the additive model. The tree structure model is an attractive alternative, as it is more apt to capture non additive effects. However, the tree model is used most commonly for prediction and seldom for hypothesis testing, mainly because of the computational burden associated with the resampling-based procedure required for estimating the significance level. RESULTS: We designed a fast algorithm for building the tree structure model and proposed a robust TREe-based Association Test (TREAT) that incorporates an adaptive model selection procedure to identify the optimal tree model representing the joint effect. We applied TREAT as a multilocus association test on >20 000 genes/regions in a study of esophageal squamous cell carcinoma (ESCC) and detected a highly significant novel association between the gene CDKN2B and ESCC ([Formula: see text]). We also demonstrated, through simulation studies, the power advantage of TREAT over other commonly used tests. AVAILABILITY AND IMPLEMENTATION: The package TREAT is freely available for download at http://www.hanzhang.name/softwares/treat, implemented in C++ and R and supported on 64-bit Linux and 64-bit MS Windows. CONTACT: yuka@mail.nih.gov SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24794928 TI - A systems-level integrative framework for genome-wide DNA methylation and gene expression data identifies differential gene expression modules under epigenetic control. AB - MOTIVATION: There is a growing number of studies generating matched Illumina Infinium HumanMethylation450 and gene expression data, yet there is a corresponding shortage of statistical tools aimed at their integrative analysis. Such integrative tools are important for the discovery of epigenetically regulated gene modules or molecular pathways, which play key roles in cellular differentiation and disease. RESULTS: Here, we present a novel functional supervised algorithm, called Functional Epigenetic Modules (FEM), for the integrative analysis of Infinium 450k DNA methylation and matched or unmatched gene expression data. The algorithm identifies gene modules of coordinated differential methylation and differential expression in the context of a human interactome. We validate the FEM algorithm on simulated and real data, demonstrating how it successfully retrieves an epigenetically deregulated gene, previously known to drive endometrial cancer development. Importantly, in the same cancer, FEM identified a novel epigenetically deregulated hotspot, directly upstream of the well-known progesterone receptor tumour suppressor pathway. In the context of cellular differentiation, FEM successfully identifies known endothelial cell subtype-specific gene expression markers, as well as a novel gene module whose overexpression in blood endothelial cells is mediated by DNA hypomethylation. The systems-level integrative framework presented here could be used to identify novel key genes or signalling pathways, which drive cellular differentiation or disease through an underlying epigenetic mechanism. AVAILABILITY AND IMPLEMENTATION: FEM is freely available as an R-package from http://sourceforge.net/projects/funepimod. PMID- 24794929 TI - A comparison of algorithms for the pairwise alignment of biological networks. AB - MOTIVATION: As biological inquiry produces ever more network data, such as protein-protein interaction networks, gene regulatory networks and metabolic networks, many algorithms have been proposed for the purpose of pairwise network alignment-finding a mapping from the nodes of one network to the nodes of another in such a way that the mapped nodes can be considered to correspond with respect to both their place in the network topology and their biological attributes. This technique is helpful in identifying previously undiscovered homologies between proteins of different species and revealing functionally similar subnetworks. In the past few years, a wealth of different aligners has been published, but few of them have been compared with one another, and no comprehensive review of these algorithms has yet appeared. RESULTS: We present the problem of biological network alignment, provide a guide to existing alignment algorithms and comprehensively benchmark existing algorithms on both synthetic and real-world biological data, finding dramatic differences between existing algorithms in the quality of the alignments they produce. Additionally, we find that many of these tools are inconvenient to use in practice, and there remains a need for easy-to use cross-platform tools for performing network alignment. PMID- 24794930 TI - Structural and energetic determinants of tyrosylprotein sulfotransferase sulfation specificity. AB - MOTIVATION: Tyrosine sulfation is a type of post-translational modification (PTM) catalyzed by tyrosylprotein sulfotransferases (TPST). The modification plays a crucial role in mediating protein-protein interactions in many biologically important processes. There is no well-defined sequence motif for TPST sulfation, and the underlying determinants of TPST sulfation specificity remains elusive. Here, we perform molecular modeling to uncover the structural and energetic determinants of TPST sulfation specificity. RESULTS: We estimate the binding affinities between TPST and peptides around tyrosines of both sulfated and non sulfated proteins to differentiate them. We find that better differentiation is achieved after including energy costs associated with local unfolding of the tyrosine-containing peptide in a host protein, which depends on both the peptide's secondary structures and solvent accessibility. Local unfolding renders buried peptide-with ordered structures-thermodynamically available for TPST binding. Our results suggest that both thermodynamic availability of the peptide and its binding affinity to the enzyme are important for TPST sulfation specificity, and their interplay results into great variations in sequences and structures of sulfated peptides. We expect our method to be useful in predicting potential sulfation sites and transferable to other TPST variants. Our study may also shed light on other PTM systems without well-defined sequence and structural specificities. AVAILABILITY AND IMPLEMENTATION: All the data and scripts used in the work are available at http://dlab.clemson.edu/research/Sulfation. PMID- 24794931 TI - MSstats: an R package for statistical analysis of quantitative mass spectrometry based proteomic experiments. AB - MSstats is an R package for statistical relative quantification of proteins and peptides in mass spectrometry-based proteomics. Version 2.0 of MSstats supports label-free and label-based experimental workflows and data-dependent, targeted and data-independent spectral acquisition. It takes as input identified and quantified spectral peaks, and outputs a list of differentially abundant peptides or proteins, or summaries of peptide or protein relative abundance. MSstats relies on a flexible family of linear mixed models. AVAILABILITY AND IMPLEMENTATION: The code, the documentation and example datasets are available open-source at www.msstats.org under the Artistic-2.0 license. The package can be downloaded from www.msstats.org or from Bioconductor www.bioconductor.org and used in an R command line workflow. The package can also be accessed as an external tool in Skyline (Broudy et al., 2014) and used via graphical user interface. PMID- 24794932 TI - Bioclojure: a functional library for the manipulation of biological sequences. AB - MOTIVATION: BioClojure is an open-source library for the manipulation of biological sequence data written in the language Clojure. BioClojure aims to provide a functional framework for the processing of biological sequence data that provides simple mechanisms for concurrency and lazy evaluation of large datasets. RESULTS: BioClojure provides parsers and accessors for a range of biological sequence formats, including UniProtXML, Genbank XML, FASTA and FASTQ. In addition, it provides wrappers for key analysis programs, including BLAST, SignalP, TMHMM and InterProScan, and parsers for analyzing their output. All interfaces leverage Clojure's functional style and emphasize laziness and composability, so that BioClojure, and user-defined, functions can be chained into simple pipelines that are thread-safe and seamlessly integrate lazy evaluation. AVAILABILITY AND IMPLEMENTATION: BioClojure is distributed under the Lesser GPL, and the source code is freely available from GitHub (https://github.com/s312569/clj-biosequence). PMID- 24794933 TI - unifiedWMWqPCR: the unified Wilcoxon-Mann-Whitney test for analyzing RT-qPCR data in R. AB - MOTIVATION: Recently, De Neve et al. proposed a modification of the Wilcoxon-Mann Whitney (WMW) test for assessing differential expression based on RT-qPCR data. Their test, referred to as the unified WMW (uWMW) test, incorporates a robust and intuitive normalization and quantifies the probability that the expression from one treatment group exceeds the expression from another treatment group. However, no software package for this test was available yet. RESULTS: We have developed a Bioconductor package for analyzing RT-qPCR data with the uWMW test. The package also provides graphical tools for visualizing the effect sizes. AVAILABILITY AND IMPLEMENTATION: The unifiedWMWqPCR package and its user documentation can be obtained through Bioconductor. PMID- 24794934 TI - Mirin: identifying microRNA regulatory modules in protein-protein interaction networks. AB - Exploring microRNA (miRNA) regulations and protein-protein interactions could reveal the molecular mechanisms responsible for complex biological processes. Mirin is a web-based application suitable for identifying functional modules from protein-protein interaction networks regulated by aberrant miRNAs under user defined biological conditions such as cancers. The analysis involves combining miRNA regulations, protein-protein interactions between target genes, as well as mRNA and miRNA expression profiles provided by users. Mirin has successfully uncovered oncomirs and their regulatory networks in various cancers, such as gastric and breast cancer. AVAILABILITY AND IMPLEMENTATION: Mirin is freely available at http://mirin.ym.edu.tw/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24794935 TI - Validating the strategies analysis diagram: assessing the reliability and validity of a formative method. AB - The Strategies Analysis Diagram (SAD) is a recently developed method to model the range of possible strategies available for activities in complex sociotechnical systems. Previous applications of the new method have shown that it can effectively identify a comprehensive range of strategies available to humans performing activity within a particular system. A recurring criticism of Ergonomics methods is however, that substantive evidence regarding their performance is lacking. For a method to be widely used by other practitioners such evaluations are necessary. This article presents an evaluation of criterion referenced validity and test-retest reliability of the SAD method when used by novice analysts. The findings show that individual analyst performance was average. However, pooling the individual analyst outputs into a group model increased the reliability and validity of the method. It is concluded that the SAD method's reliability and validity can be assured through the use of a structured process in which analysts first construct an individual model, followed by either another analyst pooling the individual results or a group process pooling individual models into an agreed group model. PMID- 24794936 TI - Bioanalytical chromatographic method validation according to current regulations, with a special focus on the non-well defined parameters limit of quantification, robustness and matrix effect. AB - Method validation is a mandatory step in bioanalysis, to evaluate the ability of developed methods in providing reliable results for their routine application. Even if some organisations have developed guidelines to define the different parameters to be included in method validation (FDA, EMA); there are still some ambiguous concepts in validation criteria and methodology that need to be clarified. The methodology to calculate fundamental parameters such as the limit of quantification has been defined in several ways without reaching a harmonised definition, which can lead to very different values depending on the applied criterion. Other parameters such as robustness or ruggedness are usually omitted and when defined there is not an established approach to evaluate them. Especially significant is the case of the matrix effect evaluation which is one of the most critical points to be studied in LC-MS methods but has been traditionally overlooked. Due to the increasing importance of bioanalysis this scenario is no longer acceptable and harmonised criteria involving all the concerned parties should be arisen. The objective of this review is thus to discuss and highlight several essential aspects of method validation, focused in bioanalysis. The overall validation process including common validation parameters (selectivity, linearity range, precision, accuracy, stability...) will be reviewed. Furthermore, the most controversial parameters (limit of quantification, robustness and matrix effect) will be carefully studied and the definitions and methodology proposed by the different regulatory bodies will be compared. This review aims to clarify the methodology to be followed in bioanalytical method validation, facilitating this time consuming step. PMID- 24794937 TI - Multi-mycotoxin analysis in dairy products by liquid chromatography coupled to quadrupole orbitrap mass spectrometry. AB - A new analytical method was developed and validated for simultaneous analysis of 58 mycotoxins in dairy products. Response surface methodology was employed to optimize a quick, easy, cheap, effective, rugged, and safe (QuEChERS) sample preparation method. Ultrahigh-performance liquid chromatography and electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC/ESI Q Orbitrap) was used for the separation and detection of all the analytes. The method was validated by taking into consideration the guidelines specified in Commission Decision 2002/657/EC and 401/2006/EC. The extraction recoveries were in a range of 86.6-113.7%, with coefficient of variation <6.2%. The 58 compounds could be detected in the 0.001-100 MUg kg(-1) concentration range, with correlation coefficient >0.99. The limits of detection for the analytes are in the range 0.001-0.92 MUg kg(-1). The repeatability was lower than 6.4%. This method has been successfully applied on screening of mycotoxins in commercial dairy product samples, and it is very useful for fast screening of different food contaminants. PMID- 24794938 TI - Identification of effective combinatorial markers for quality standardization of herbal medicines. AB - Quality standardization of herbal medicines (HMs) is an important task with great challenges. Selection of abundant compounds as markers is currently a major approach for the quality control of HMs; however, such marker compounds are irrelevant to the bioactivities in many cases. Taking Lycoridis Radiatae Bulbus (LRB) as an example, we proposed a universal strategy to identify the effective combinatorial markers (ECMs) that are representative of the bioactivities of HMs, and took them as chemical markers for quality standardization. Fingerprinting and quantification were employed to find out the common components in various batches of medicines. The contribution of each common compound to the overall bioactivity was determined through fingerprint-bioactivity modeling, which based on the absolute quantification of each compound and the acetylcholinesterase (AChE) inhibitory activity of LRB. Two most effective compounds, ungerimine and galanthamine, were therefore proposed as ECMs. Interestingly, these two compounds could synergistically inhibit AChE. This approach demonstrated its strong advantage of the bioactivity relevant quality assessment when compared with conventional methods. And the success of applying this ECMs-based method to the quality assessment of unknown LRB samples proved that our approach was reliable and reproducible. In conclusion, this approach is not only useful for the bioactivity relevant quality control of HMs but also helpful for the discovery of ECMs as new drug candidates. PMID- 24794939 TI - Water analysis of the sixteen environmental protection agency-polycyclic aromatic hydrocarbons via solid-phase nanoextraction-gas chromatography/mass spectrometry. AB - The growing concern with a sustainable environment poses a new challenge to analytical chemists facing the routine monitoring of polycyclic aromatic hydrocarbons (PAHs) in water samples. The new method presented here meets several features of green analytical chemistry. PAHs are extracted from 500 MUL of water sample with 1 mL of a gold nanoparticles aqueous solution and released with 100 MUL of organic solvents for subsequent analysis via gas chromatography/mass spectrometry. The relative standard deviations of the overall procedure ranged from 2.4 (acenaphthene) to 7.8% (dibenz[a,h]anthracene). The limits of detection were excellent as well and varied from 4.94 (fluoranthene) to 65.5 ng L(-1) (fluorene). The excellent analytical figures of merit, the simplicity of the experimental procedure, the short analysis time and the reduced solvent consumption demonstrate the potential of this approach for the routine monitoring of the sixteen priority pollutants via and environmentally friendly methodology. PMID- 24794941 TI - Two-dimensional semi-parametric alignment of chromatograms. AB - We present a comprehensive alignment algorithm that extends the semi-parametric approach to two dimensions. The algorithm is based on modeling shifts with a two dimensional "warp function" such that the sample chromatogram - its shifts corrected with the warp function - is adjusted to the reference chromatogram by minimizing the squared intensity difference. A warp function approach has the advantage that overlapping peaks are easily dealt with compared to other proposed two-dimensional algorithms. Another advantage is that missing peaks are allowed if the absence of these peaks has little numerical effect on the warp function computation and if these peaks occur between existing peaks. Performance of the algorithm is demonstrated using GC*GC data from three batches of three diesel oil samples and LC-MS data from a mouse breast cancer data set. PMID- 24794940 TI - Comparative metabolomics analysis on hematopoietic functions of herb pair Gui Xiong by ultra-high-performance liquid chromatography coupled to quadrupole time of-flight mass spectrometry and pattern recognition approach. AB - The compatibility of Angelicae Sinensis Radix (Danggui, DG) and Chuanxiong Rhizoma (Chuanxiong, CX), a famous herb pair Gui-Xiong (GX), can produce synergistic and complementary hematopoiesis. In present study, global metabolic profiling with ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) combined with pattern recognition method was performed to discover the underlying hematopoietic regulation mechanisms of DG, CX and GX on hemolytic and aplastic anemia rats (HAA) induced by acetyl phenylhydrazine (APH) and cyclophosphamide (CP). Thirteen endogenous metabolites contributing to the separation of model group and control group were tentatively identified. The levels of LPCs including lysoPC (18:0), lysoPC (20:4), lysoPC (16:0) and lysoPC (18:2), sphinganine, nicotinic acid, thiamine pyrophosphate, phytosphingosine, and glycerophosphocholine increased significantly (p<0.05) in HAA, while the levels of oleic acid, 8,11,14 eicosatrienoic acid, ceramides (d18:1/14:0), and 17a-hydroxypregnenolone decreased significantly (p<0.05) in comparison with control rats. Those endogenous metabolites were chiefly involved in thiamine metabolism and sphingolipid metabolism. The metabolic deviations could be regulated closer to normal level after DG, CX and GX intervention. In term of hematopoietic function, GX was the most effective as shown by the relative distance in PLS-DA score plots and relative intensity of metabolomic strategy, reflecting the synergic action between DG and CX. The relative distance calculation was firstly used in metabolomics for semi-quantization. PMID- 24794942 TI - Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry to identify contaminants in water: an insight on environmental forensics. AB - Ultra-high pressure liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QqTOF-MS) acquiring full scan MS data for quantification, and automatic data dependent information product ion spectra (IDA-MS/MS) without any predefinition of the ions by the user was checked for identifying organic contaminants in water samples. The use of a database with more than 2000 compounds achieved high confidence results for a wide number of contaminants based upon retention time, accurate mass, isotopic pattern and MS/MS library searching. More than 20 contaminants, mostly pharmaceuticals, but also mycotoxins and polyphenols were unambiguously identified. Furthermore, the combination of statistical data analysis using principal component analysis (PCA) followed by empirical formula calculation, on-line database searching and MS/MS fragment ion interpretation achieves not only the successful detection of unknown contaminants but also the selection of those relevant to different types of waters. Unknown compounds, such as C20H34O3, were identified in waste water showing the prospects of this technique. A group of 42 currently used pesticides were selected as target compounds to evaluate the quantitative possibilities. Mean recoveries and percentage relative standard deviation (RSD) were 48-79% (4-20% RSD). The limit of detections ranged from 0.02 to 2 ng L(-1), with a validated limit of quantification of 2 ng L(-1) for water after solid-phase (SPE) isolation and concentration. The quantitative data obtained using UHPLC-QqTOF-MS were compared with those obtained using conventional LC-MS/MS with a triple quadrupole (QqQ). PMID- 24794943 TI - A method for the analysis of perfluorinated compounds in environmental and drinking waters and the determination of their lowest concentration minimal reporting levels. AB - A trace analytical method was developed for the determination of seventeen specific perfluorinated chemicals (PFCs) in environmental and drinking waters. The objectives were to optimize an isotope-dilution method to increase the precision and accuracy of the analysis of the PFCs and to eliminate the need for matrix-matched standards. A 250 mL sample of environmental or drinking water was buffered to a pH of 4, spiked with labeled surrogate standards, extracted through solid phase extraction cartridges, and eluted with ammonium hydroxide in methyl tert-butyl ether: methanol solution. The sample eluents were concentrated to volume and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The lowest concentration minimal reporting levels (LCMRLs) for the seventeen PFCs were calculated and ranged from 0.034 to 0.600 ng/L for surface water and from 0.033 to 0.640 ng/L for drinking water. The relative standard deviations (RSDs) for all compounds were <20% for all concentrations above the LCMRL. The method proved effective and cost efficient and addressed the problems with the recovery of perfluorobutanoic acid (PFBA) and other short chain PFCs. Various surface water and drinking water samples were used during method development to optimize this method. The method was used to evaluate samples from the Mississippi River at New Orleans and drinking water samples from a private residence in that same city. The method was also used to determine PFC contamination in well water samples from a fire training area where perfluorinated foams were used in training to extinguish fires. PMID- 24794944 TI - Effects of stroke education using an animated cartoon and a manga on elementary school children. AB - BACKGROUND: Stroke education for the youth is expected to reduce prehospital delay by informing the bystander of appropriate action to take and providing knowledge to prevent onset of stroke in future. Previously, we developed effective teaching materials consisting of an animated cartoon and a Manga for junior high school students. The aim of this study was to evaluate the feasibility and effectiveness of our educational materials for stroke education taught by schoolteachers to elementary school children. METHODS: Using our teaching materials, a 30-minute lesson was given by trained general schoolteachers. Questionnaires on stroke knowledge (symptoms and risk factors) and action to take on identification of suspected stroke symptoms were filled out by school children before, immediately after, and at 3 months after completion of the lesson. RESULTS: A total of 219 children (aged 10 or 11 years) received the stroke lesson. Stroke knowledge significantly increased immediately after the lesson compared with before (symptoms, P < .001; risk factors, P < .001); however, correct answer rates decreased at 3 months immediately after completion of the lesson (symptoms, P = .002; risk factors, P = .045). The proportion of the number of children calling emergency medical service on identifying stroke symptoms was higher immediately after the lesson than baseline (P = .007) but returned to the baseline at 3 months after the lesson. CONCLUSIONS: Stroke lesson by schoolteachers using our teaching materials consisting of an animated cartoon and a Manga that was previously used for junior high school students was feasible for elementary school children. However, revision of the materials is required for better retention of stroke knowledge for children. PMID- 24794945 TI - Outcome and risk factors presented in old patients above 80 years of age versus younger patients after ischemic stroke. AB - BACKGROUND: Older patients are associated with increased stroke prevalence, worse outcome, and risk of undertreatment in comparison with younger patients. The aim of the present study was to compare risk factor distribution and functional outcome in stroke survivors older and younger than 80 years. METHODS: The analysis was based on consecutive patients admitted within 6 hours after stroke onset and discharged with ischemic stroke, surviving at least 3 months after ictus. To prevent bias, the analysis was based on a registry from before implementation of tissue plasminogen activator treatment; all patients received stroke unit care in accordance with the guidelines. The population was dichotomized into patients aged less than 80 years and 80 years of age or older. Modified Rankin Scale (mRS) score and Barthel Index (BI) were used to assess 3 month and 1-year outcome. RESULTS: Patients 80 years of age or older presented with significantly more severe strokes than younger patients, median Scandinavian Stroke Scale score 39 vs 42 (P = .003). Median mRS score before stroke was significantly higher in patients aged 80 years or older (P < .001) and remained high 3 months and 1 year after ictus (P < .001); the BI was equivalently lower (P < .001). The decline in function was comparable between groups. Patients 80 years of age or older of whom the majority were women (P < .001) presented with atrial fibrillation (P < .001), and hypertension (P = .005). CONCLUSIONS: Risk factors vary significantly with age, suggesting different stroke mechanisms. Patients older than 80 years experience more severe strokes and frequently have minor impairments before stroke. The increase in impairment after stroke is comparable with what is observed in younger patients, suggesting that good recovery after stroke may also be expected in older patients. PMID- 24794946 TI - Computer tomography for prediction of cognitive outcomes after ischemic cerebrovascular events. AB - BACKGROUND: The aim of this study was to evaluate whether parameters noted on a single, acute computed tomographic (CT) scan, are associated with significant cognitive impairment (SCogI), and can help in the prediction of SCogI 3-6 months after stroke or transient ischemic attack (TIA). METHODS: Patients with a recent (<=14 days) ischemic stroke or TIA, without preexisting dementia, underwent noncontrast CT scan within 24 hours of admission. A formal neuropsychologic battery was administered 3-6 months from index stroke. SCogI was defined as moderate cognitively impaired, not demented (CIND) (>=3 domains impaired), and dementia diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Logistic regression models were used to examine associations between CT parameters and SCogI. Receiver operating characteristic analysis with an area under the curve (AUC) was performed to assess discriminatory ability of radiological parameters for SCogI. RESULTS: In all, 318 patients were included: 250 (78.6 %) with ischemic stroke and 68 (21.4%) with TIA; the mean age was 59.8 (+/-11.4) years. At 3-6 months, 76 (23.9 %) had SCogI (67 CIND moderate and 9 dementia). The presence of significant atrophy (P = .02) and chronic infarcts (P = .03) were associated with SCogI at 3-6 months. A significant increase in AUC was noted after addition of summarized CT results to a clinical score derived from age and baseline Montreal Cognitive Assessment (cutoff 21 of 22) for detection of SCogI: .83 (.78-.89) to .86 (.82-.91); P = .03. CONCLUSIONS: CT parameters are independently associated with SCogI at 3-6 months after an ischemic cerebrovascular event and may be a clinically useful component in predicting for SCogI after stroke. PMID- 24794947 TI - Cerebral dural sinus thrombosis associated with adenomyosis: a case report. AB - We report a case of cerebral venous thrombosis (CVT) associated with a giant adenomyosis. At admission, the patient demonstrated generalized seizures and consciousness disturbance. Brain fluid-attenuated inversion recovery magnetic resonance imaging revealed a localized, high-intensity region in the left frontal lobe. Subsequent brain angiography showed that right internal carotid angiograms display abrupt termination of the anterior half of the superior sagittal sinus and a filling defect in the lateral part of the left transverse sinus. The patient complicated with iron deficiency anemia (IDA) and adenomyosis with higher levels of serum carbohydrate antigen 125 (CA125) and d-dimer. After 1 year from onset, intermittent severe menalgia and headache persisted, and blood examination revealed abnormal values; the patient was receiving oral medications. Finally, adenomyosis resection was performed with a favorable outcome, and no recurrence was observed during the 2-year follow-up period. We conclude that IDA and increased CA125 levels may have promoted hypercoagulability and CVT. This report emphasizes the possible relationship between CVT and adenomyosis. PMID- 24794948 TI - Painless hypoglossal palsy as an isolated symptom of spontaneous carotid dissection. AB - Spontaneous internal carotid artery dissection (sICAD) occurs annually in 2.5 to 3 per 100,000 presenting with signs of ischemic events in the majority of cases. In contrast, lower cranial nerve palsy due to peripheral nerve affection is seldom the presenting clinical sign. In symptomatic cases (>90%), sICAD is most commonly accompanied by local pain. We report a case of a 49-year old woman with a left sICAD presenting with isolated ipsilateral hypoglossal palsy as the sole clinical sign. Compared to other cases, local pain was absent and other cranial nerves were not affected. Further, sICAD could not be detected in repeated Doppler-/Duplex-sonography, but magnetic resonance imaging and MR-angiography only. PMID- 24794949 TI - Sleep disturbances after cerebral infarction: role of depression and fatigue. AB - BACKGROUND: Poststroke sleep disturbances (PSSDs) are frequent and reported to be associated with unfavorable clinical outcomes. PSSDs appear to be related to a multitude of factors including lesion location and environmental causes. Moreover, depression and fatigue, which frequently develop in stroke patients may also contribute to PSSD development. The purpose of this study was to evaluate the prevalence and characteristics of PSSDs and factors related to PSSDs including depression and fatigue in hospitalized stroke patients. METHODS: Patients who were hospitalized with acute stroke at the Asan Medical Center were evaluated. The quality (Verran-Snyder-Halpern [VSH] Sleep Scale score), duration and latency of night-time sleep, the frequency of waking after sleep onset, and daytime sleepiness were evaluated during the hospitalization period. To validate the self-reported night-time sleep, an actigraphy was performed in a subset of patients. The location, circulation, and laterality of each lesion were determined from brain magnetic resonance images obtained within 7 days of stroke onset. Depression and fatigue were assessed using the Beck Depression Inventory and the Fatigue Severity Scale, respectively. For environmental factors, the duration of hospitalization and the number of other patients in the same room were recorded. Univariate, multiple regression, and multiple logistic regression analyses were used to evaluate predictors of PSSD development. RESULTS: A total of 282 patients completed the study. The mean age of the patients was 62.3 (+/ 12.76) years and 58.9% of them were male. Sixty patients (21.3%) reported sleep duration less than 6 hours/night and 110 (39.0%) reported more daytime sleepiness than before the stroke. In 54 patients who agreed to wear an actigraph, self reported sleep duration was significantly correlated with time in bed measured with an actigraph (r = .407, P = .002) and, VSH Sleep Scale score and sleep efficiency in actigraphy were also significantly correlated (r = .305, P = .026). Quality of night-time sleep was independently related to cortical lesion location (P = .002), diabetes mellitus (P = .020), and depression (P < .001), whereas increased daytime sleepiness was independently associated with subcortical lesion location (P = .031), fatigue (P = .001), and quality of night-time sleep (P = .001). CONCLUSIONS: PSSDs are common in hospitalized stroke patients. The most powerful factor predicting night-time sleep disturbances in stroke patients was depression. Cortical brain lesion and diabetes mellitus were also associated with night-time sleep disturbances. On the other hand, although poststroke daytime sleepiness is in part caused by night-time sleep disturbance, it is more closely associated with fatigue and subcortical lesion location. PMID- 24794950 TI - Rosenbergiella australoborealis sp. nov., Rosenbergiella collisarenosi sp. nov. and Rosenbergiella epipactidis sp. nov., three novel bacterial species isolated from floral nectar. AB - The taxonomic status of nine strains of the family Enterobacteriaceae isolated from floral nectar of wild Belgian, French, South African and Spanish insect pollinated plants was investigated following a polyphasic approach. Confirmation that these strains belonged to the genus Rosenbergiella was obtained from comparative analysis of partial sequences of the 16S rRNA gene and other core housekeeping genes (atpD [ATP synthase beta-chain], gyrB [DNA gyrase subunit B] and rpoB [RNA polymerase beta-subunit]), DNA-DNA reassociation data, determination of the DNA G+C content and phenotypic profiling. Two strains belonged to the recently described species Rosenbergiella nectarea, while the other seven strains represented three novel species within the genus Rosenbergiella. The names Rosenbergiella australoborealis sp. nov. (with strain CdVSA 20.1(T) [LMG 27954(T)=CECT 8500(T)] as the type strain), Rosenbergiella collisarenosi sp. nov. (with strain 8.8A(T) [LMG 27955(T)=CECT 8501(T)] as the type strain) and Rosenbergiella epipactidis sp. nov. (with strain 2.1A(T) [LMG 27956(T)=CECT 8502(T)] as the type strain) are proposed. Additionally, the description of the genus Rosenbergiella is updated on the basis of new phenotypic and molecular data. PMID- 24794951 TI - The role of sentinel node biopsy in male breast cancer. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is a standard procedure in women with breast cancer. The risk of morbidity related to axillary lymph node dissection (ALND) is similar for men and women with breast cancer and SLNB could minimize this risk. METHODS: Between January 2004 and August 2013, 25 men with primary breast cancer were operated on at the Bacs-Kiskun County Teaching Hospital. These were reviewed retrospectively. SLNB was performed following lymphoscintigraphy with intraoperative gamma probe detection and blue dye mapping. RESULTS: SLNB was successful in all 16 male patients (100 %), in whom it was attempted. The SLNs were negative in 4 cases (25 %) and were involved in 12. Intraoperative imprint cytology was positive in 9 of the 12 involved cases (75 %) and resulted immediate completion ALND. In 7 patients, the intraoperative imprint cytology was negative, with 3 false-negative results that resulted in delayed completion ALND. After a median follow-up of 48 months, there was only one axillary recurrence after ALND and none in the SLNB group. CONCLUSIONS: SLNB is successful and accurate in male breast cancer patients too. Although compared to women a larger proportion of men have positive nodes, for men with negative nodes, ALND-related morbidity may be reduced by SLNB. We recommend SLNB in male patients with breast cancer and clinically negative axilla. PMID- 24794952 TI - Assessment of the Ki67 labeling index: a Japanese validation ring study. AB - BACKGROUND: A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples. PATIENTS AND METHODS: This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2 negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study. RESULTS: For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (rho: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of <13.25 % and in those with a Ki67 labeling index of >13.25 % (kappa = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining. CONCLUSION: The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel. PMID- 24794953 TI - Epigenetics and muscle dysfunction in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease and a major leading cause of morbidity and mortality worldwide. In COPD, comorbidities, acute exacerbations, and systemic manifestations negatively influence disease severity and progression regardless of the respiratory condition. Skeletal muscle dysfunction, which is one of the commonest systemic manifestations in patients with COPD, has a tremendous impact on their exercise capacity and quality of life. Several pathophysiological and molecular underlying mechanisms including epigenetics (the process whereby gene expression is regulated by heritable mechanisms that do not affect DNA sequence) have been shown to participate in the etiology of COPD muscle dysfunction. The epigenetic modifications identified so far in cells include DNA methylation, histone acetylation and methylation, and noncoding RNAs such as microRNAs. Herein, we first review the role of epigenetic mechanisms in muscle development and adaptation to environmental factors in several models. Moreover, the epigenetic events reported so far to be potentially involved in muscle dysfunction and mass loss of patients with COPD are also discussed. Furthermore, the different expression profile of several muscle-enriched microRNAs in the diaphragm and vastus lateralis muscles of patients with COPD are also reviewed from results recently obtained in our group. The role of protein hyperacetylation in enhanced muscle protein catabolism of limb muscles is also discussed. Future research should focus on the full elucidation of the triggers of epigenetic mechanisms and their specific downstream biological pathways in COPD muscle dysfunction and wasting. PMID- 24794954 TI - The role of proteases and inflammatory molecules in triggering neovascular age related macular degeneration: basic science to clinical relevance. AB - Age-related macular degeneration (AMD) causes severe vision impairment in aged individuals. The health impact and cost of the disease will dramatically increase over the years, with the increase in the aging population. Currently, antivascular endothelial growth factor agents are routinely used for managing late-stage AMD, and recent data have shown that up to 15%-33% of patients do not respond to this treatment. Henceforth, there is a need to develop better treatment options. One avenue is to investigate the role proteases and inflammatory molecules might have in regulating and being regulated by vascular endothelial growth factor. Moreover, emerging data indicate that proteases and inflammatory molecules might be critical in the development and progression of AMD. This article reviews recent literature that investigates proteases and inflammatory molecules involved in the development of AMD. Gaining insights into the proteolytic and inflammatory pathways associated with the pathophysiology of AMD could enable the development of additional or alternative drug strategies for the treatment of AMD. PMID- 24794955 TI - Changes in the etiology of valvular heart disease in the rapidly aging Korean population. AB - BACKGROUND: The aim of this study is to assess the changes in the causes of valvular heart disease between 2006 and 2011 in Korea. METHODS: Data were collected from the Korean National Health Insurance Service from 2006 through 2011. These data consisted of primary diagnoses related to valvular heart disease regardless of other conditions. Valvular heart disease included non-rheumatic mitral valve disorders, non-rheumatic aortic valve disorders, rheumatic mitral valve disorders, and rheumatic aortic valve disorders. RESULTS: Overall, the age standardized cumulative prevalence of non-rheumatic valvular heart disease was 70.6 per 100,000 persons in 2006 and 110.3 in 2011. This represented an increase from 42.2 to 65.2 in women and from 28.4 to 45.1 in men. In particular, there was a greater increase in prevalence in patients aged 65 years or older compared with groups aged 20-44 years or 45-64 years for both genders. The age-standardized cumulative prevalence of rheumatic valve disease did not change dramatically between 2006 and 2011. CONCLUSIONS: The overall age-standardized cumulative prevalence of non-rheumatic valvular heart diseases increased between 2006 and 2011, especially in individuals older than 65 years. These changes should be considered in future designs of cardiovascular healthcare services in countries with a rapidly aging population. PMID- 24794956 TI - Complement activation products C5a and sC5b-9 are associated with low-grade inflammation and endothelial dysfunction, but not with atherosclerosis in a cross sectional analysis: the CODAM study. PMID- 24794957 TI - Effect of acute aerobic exercise on serum BDNF levels in patients with Chagas heart disease. PMID- 24794958 TI - Reduction in myocardial infarction incidence: focus on socioeconomic disparities. PMID- 24794959 TI - ATF3 regulates multiple targets and may play a dual role in cardiac hypertrophy and injury. PMID- 24794960 TI - Cardiac biomarkers in Takotsubo cardiomyopathy. PMID- 24794961 TI - Fixed combination dual antiplatelet therapy and the risk of stent thrombosis. PMID- 24794962 TI - Aortic dissection in a patient with a dilated aortic root following tetralogy of Fallot repair. PMID- 24794963 TI - Life-threatening haemorrhagic pericarditis associated with rivaroxaban. PMID- 24794964 TI - Insulin resistance and endothelial function in children and adolescents. AB - AIMS: Insulin resistance (IR) impairs cellular response to insulin due to a dysfunction in glucose metabolism, associated with an increased cardiovascular risk. The aim of our study was to investigate the relationship among homeostasis model assessment index (HOMA index), endothelial function and vascular morphology in order to better stratify cardiovascular risk in children and adolescents. METHODS: A total of 150 children and adolescents (55 pre-pubertal, mean age 10.4 +/- 3.1 years) were enrolled. Anthropometric [body mass index (BMI), waist circumference (WC)], laboratory [blood lipids, inflammatory markers, insulinemia, glycemia], HOMA index and ultrasound parameters [flow-mediated dilatation (FMD), common carotid intima-media thickness (cIMT) and antero-posterior diameter of infra-renal abdominal aorta (APAO)] were assessed. RESULTS: cIMT was positively related to age (r=0.274, p<0.01), BMI (r=0.318, p<0.01), WC (r=0.315, p<0.01) and triglycerides (r=0.230, p<0.01). APAO measurements showed a linear positive correlation with age (r=0.435, p<0.01), BMI (r=0.505, p<0.01), WC (r=0.487, p<0.01), triglycerides (r=0.280, p<0.01), C-reactive protein (r=0.209, p<0.05), fasting insulin (r=0.378, p<0.01) and HOMA index (r=0.345, p<0.01). FMD was inversely related to age (r=-0.251, p<0.01), rough BMI (r=-0.318, p<0.01), WC (r= 0.340, p<0.01), fasting insulin (r=-0.281, p<0.01) and HOMA index (r=-0.282, p<0.01). Multiple regression analysis found no influence of HOMA index on APAO and cIMT. HOMA index was an independent predictor for brachial artery FMD worsening after the statistical adjustment. CONCLUSION: HOMA index increase induced a worsening in endothelial function since childhood. PMID- 24794965 TI - Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner. AB - BACKGROUND: Takotsubo cardiomyopathy (TCM) is characterized by regional left ventricular dysfunction that cannot be explained by an occlusive lesion in a coronary artery. Catecholamines are implicated in the pathogenesis of TCM but the mechanisms involved are unknown. Because the endogenous and the most commonly used exogenous catecholamines have well defined adrenoceptor subtype affinities, inferences can be made about the importance of each adrenoceptor subtype based on the ability of different catecholamines to induce TCM. We therefore studied which of five well-known catecholamines, that differ in receptor subtype affinity, are able to induce TCM-like cardiac dysfunction in the rat. METHODS: 255 rats received intraperitoneally isoprenaline (beta1/beta2-adrenoceptor agonist), epinephrine (beta1/beta2/alpha-adrenoceptor agonist), norepinephrine (beta1/alpha adrenoceptor agonist), dopamine (alpha/beta1/beta2-adrenoceptor agonist) or phenylephrine (alpha-adrenoceptor agonist). Each catecholamine was given in five different doses. We measured blood pressure through a catheter inserted in the right carotid artery and studied cardiac morphology and function by echocardiography. RESULTS: All catecholamines induced takotsubo-like cardiac dysfunction. Isoprenaline induced low blood pressure and predominantly apical dysfunction whereas the other catecholamines induced high blood pressure and basal dysfunction. In another set of experiments, we continuously infused hydralazine or nitroprusside to rats that received epinephrine or norepinephrine to maintain systolic blood pressure < 120 mm Hg. These rats developed akinesia of the apex instead of the base. Infusion of phenylephrine to maintain blood pressure > 120 mm Hg after isoprenaline administration prevented apical TCM-like dysfunction. CONCLUSIONS: Catecholamine-induced takotsubo-like cardiac dysfunction appears to be afterload dependent rather than depend on stimulation of a specific adrenergic receptor subtype. PMID- 24794966 TI - Appropriate use of transesophageal echocardiography at a primary care medical center. PMID- 24794968 TI - Mode of death in chronic systolic heart failure: Chagas cardiomyopathy versus systemic arterial hypertension. PMID- 24794967 TI - Group III/IV muscle afferents impair limb blood in patients with chronic heart failure. AB - OBJECTIVE: To better understand the hemodynamic and autonomic reflex abnormalities in heart-failure patients (HF), we investigated the influence of group III/IV muscle afferents on their cardiovascular response to rhythmic exercise. METHODS: Nine HF-patients (NYHA class-II, mean left ventricular ejection-fraction: 27 +/- 3%) performed single leg knee-extensor exercise (25/50/80% peak-workload) under control conditions and with lumbar intrathecal fentanyl impairing MU-opioid receptor-sensitive muscle afferents. RESULTS: Cardiac-output (Q) and femoral blood-flow (QL) were determined, and arterial/venous blood samples collected at each workload. Exercise-induced fatigue was estimated via pre/post-exercise changes in quadriceps strength. There were no hemodynamic differences between conditions at rest. During exercise, Q was 8-13% lower with Fentanyl-blockade, secondary to significant reductions in stroke volume and heart rate. Lower norepinephrine spillover during exercise with Fentanyl revealed an attenuated sympathetic outflow that likely contributed to the 25% increase in leg vascular conductance (p<0.05). Despite a concomitant 4% reduction in blood pressure, QL was 10-14% higher and end-exercise fatigue attenuated by 30% with Fentanyl-blockade (p<0.05). CONCLUSION/PRACTICE/IMPLICATIONS: Although group III/IV muscle afferents play a critical role for central hemodynamics in HF-patients, it also appears that these sensory neurons cause excessive sympatho-excitation impairing QL which likely contributes to the exercise intolerance in this population. PMID- 24794969 TI - Control of hypertension in China: challenging. PMID- 24794970 TI - Generation and application of a 293 cell line stably expressing bovine interferon gamma. AB - A stable mammalian cell line expressing highly active bovine interferon-gamma (BoIFN-gamma) was generated using Flp recombinase-mediated integration. This recombinant 293 cell line (B1) efficiently secreted FLAG-tagged BoIFN-gamma protein into the culture supernatant, as determined by ELISA and Western blot. The recombinant BoIFN-gamma exhibited high anti-viral activity, suggesting that the 293 cells expressed BoIFN-gamma that structurally and biologically resembled the natural protein. Two monoclonal antibodies (mAbs) with high affinity for the 293 cell-expressed BoIFN-gamma were identified using this cell line, and these mAbs can be used for the development of diagnostic kits. Thus, this work demonstrates the successful generation of a 293 cell line that produces large quantities of highly active BoIFN-gamma and demonstrates its potential application in the research of bovine infectious diseases. PMID- 24794971 TI - Eliciting antibiotics active against the ESKAPE pathogens in a collection of actinomycetes isolated from mountain soils. AB - The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a major threat for human health. In recent years, genome sequencing has unveiled many poorly expressed antibiotic clusters in actinomycetes. Here, we report a well-defined ecological collection of >800 actinomycetes obtained from sites in the Himalaya and Qinling mountains, and we used these in a concept study to see how efficiently antibiotics can be elicited against MDR pathogens isolated recently from the clinic. Using 40 different growth conditions, 96 actinomycetes were identified - predominantly Streptomyces - that produced antibiotics with efficacy against the MDR clinical isolates referred to as ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and/or Enterobacter cloacae. Antimicrobial activities that fluctuated strongly with growth conditions were correlated with specific compounds, including borrelidin, resistomycin, carbomethoxy-phenazine, and 6,7,8- and 5,6,8-trimethoxy-3-methylisocoumarin, of which the latter was not described previously. Our work provided insights into the potential of actinomycetes as producers of drugs with efficacy against clinical isolates that have emerged recently and also underlined the importance of targeting a specific pathogen. PMID- 24794972 TI - Identification and characterization of an acyl-CoA dehydrogenase from Pseudomonas putida KT2440 that shows preference towards medium to long chain length fatty acids. AB - Diverse and elaborate pathways for nutrient utilization, as well as mechanisms to combat unfavourable nutrient conditions make Pseudomonas putida KT2440 a versatile micro-organism able to occupy a range of ecological niches. The fatty acid degradation pathway of P. putida is complex and correlated with biopolymer medium chain length polyhydroxyalkanoate (mcl-PHA) biosynthesis. Little is known about the second step of fatty acid degradation (beta-oxidation) in this strain. In silico analysis of its genome sequence revealed 21 putative acyl-CoA dehydrogenases (ACADs), four of which were functionally characterized through mutagenesis studies. Four mutants with insertionally inactivated ACADs (PP_1893, PP_2039, PP_2048 and PP_2437) grew and accumulated mcl-PHA on a range of fatty acids as the sole source of carbon and energy. Their ability to grow and accumulate biopolymer was differentially negatively affected on various fatty acids, in comparison to the wild-type strain. Inactive PP_2437 exhibited a pattern of reduced growth and PHA accumulation when fatty acids with lengths of 10 to 14 carbon chains were used as substrates. Recombinant expression and biochemical characterization of the purified protein allowed functional annotation in P. putida KT2440 as an ACAD showing clear preference for dodecanoyl CoA ester as a substrate and optimum activity at 30 degrees C and pH 6.5-7. PMID- 24794973 TI - Oxidative stress mediated Ca(2+) release manifests endoplasmic reticulum stress leading to unfolded protein response in UV-B irradiated human skin cells. AB - BACKGROUND: Exposure of skin to ultraviolet (UV) radiation, an environmental stressor induces number of adverse biological effects (photodamage), including cancer. The damage induced by UV-irradiation in skin cells is initiated by the photochemical generation of reactive oxygen species (ROS) and induction of endoplasmic reticulum (ER) stress and consequent activation of unfolded protein response (UPR). OBJECTIVE: To decipher cellular and molecular events responsible for UV-B mediated ER stress and UPR activation in skin cells. METHODS: The study was performed on human skin fibroblast (Hs68) and keratinocyte (HaCaT) cells exposed to UV-B radiations in lab conditions. Different parameters of UVB induced cellular and molecular changes were analyzed using Western-blotting, microscopic studies and flow cytometry. RESULTS: Our results depicted that UV-B induces an immediate ROS generation that resulted in emptying of ER Ca(2+) stores inducing ER stress and activation of PERK-peIF2alpha-CHOP pathway. Quenching ROS generation by anti-oxidants prevented Ca(2+) release and subsequent induction of ER stress and UPR activation. UV-B irradiation induced PERK dependent G2/M phase cell cycle arrest in Hs68 and G1/S phase cell cycle arrest in HaCaT. Also our study reflects that UV-B exposure leads to loss of mitochondrial membrane potential, activation of apoptotic cascade as evident by AnnexinV/PI staining, decreased expression of Bcl-2 and increased cleavage of PARP-1 protein. CONCLUSION: UV-B induced Ca(2+) deficit within ER lumen was mediated by immediate ROS generation. Insufficient Ca(2+) concentration within ER lumen developed ER stress leading to UPR activation. These changes were reversed by use of anti oxidants which quench ROS. PMID- 24794974 TI - In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. AB - Obesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. IUGR mice developed obesity and glucose intolerance with aging. Strikingly, offspring of IUGR male mice also developed glucose intolerance. Here, we show that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5' UTR region. We found the same epigenetic signature in the sperm of their progenitors, F1 males. Our data indicate that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring. PMID- 24794977 TI - Molecular mapping of an adult plant stem rust resistance gene Sr56 in winter wheat cultivar Arina. AB - KEY MESSAGE: This article covers detailed characterization and naming of QSr.sun 5BL as Sr56 . Molecular markers linked with adult plant stem rust resistance gene Sr56 were identified and validated for marker-assisted selection. The identification of new sources of adult plant resistance (APR) and effective combinations of major and minor genes is well appreciated in breeding for durable rust resistance in wheat. A QTL, QSr.sun-5BL, contributed by winter wheat cultivar Arina providing 12-15 % reduction in stem rust severity, was reported in an Arina/Forno recombinant inbred line (RIL) population. Following the demonstration of monogenic segregation for APR in the Arina/Yitpi RIL population, the resistance locus was formally named Sr56. Saturation mapping of the Sr56 region using STS (from EST and DArT clones), SNP (9 K) and SSR markers from wheat chromosome survey sequences that were ordered based on synteny with Brachypodium distachyon genes in chromosome 1 resulted in the flanking of Sr56 by sun209 (SSR) and sun320 (STS) at 2.6 and 1.2 cM on the proximal and distal ends, respectively. Investigation of conservation of gene order between the Sr56 region in wheat and B. distachyon showed that the syntenic region defined by SSR marker interval sun209-sun215 corresponded to approximately 192 kb in B. distachyon, which contains five predicted genes. Conservation of gene order for the Sr56 region between wheat and Brachypodium, except for two inversions, provides a starting point for future map-based cloning of Sr56. The Arina/Forno RILs carrying both Sr56 and Sr57 exhibited low disease severity compared to those RILs carrying these genes singly. Markers linked with Sr56 would be useful for marker-assisted pyramiding of this gene with other major and APR genes for which closely linked markers are available. PMID- 24794976 TI - Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action. AB - Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here, we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R null mice exhibit low bone mass owing to elevated circulating leptin, whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R null mice exhibit high bone mass owing to a differentiation shift from marrow adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant because bone mass is reduced in orexin null and OX1R2R double null mice but enhanced in orexin-overexpressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin yang dual regulation and highlight orexin as a therapeutic target for osteoporosis. PMID- 24794978 TI - Identification of quantitative trait loci controlling linolenic acid concentration in PI483463 (Glycine soja). AB - KEY MESSAGE: The QTLs controlling alpha-linolenic acid concentration from wild soybean were mapped on nine soybean chromosomes with various phenotypic variations. New QTLs for alpha-linolenic acid were detected in wild soybean. Alpha-linolenic acid (ALA) is a polyunsaturated fatty acid desired in human and animal diets. Some wild soybean (Glycine soja) genotypes are high in ALA. The objective of this study was to identify quantitative trait loci (QTLs) controlling ALA concentration in a wild soybean accession, PI483463. In total, 188 recombinant inbred lines of F5:6, F5:7, and F5:8 generations derived from a cross of wild soybean PI483463 (~15 % ALA) and cultivar Hutcheson (~9 % ALA) were planted in four environments. Harvested seeds were used to measure fatty acid concentration. Single nucleotide polymorphism markers of the universal soybean linkage panel (USLP 1.0) and simple sequence repeat markers were used for molecular genotyping. Nine putative QTLs were identified that controlled ALA concentration by model-based composite interval mapping and mapped to different soybean chromosomes. The QTLs detected in four environments explained 2.4-7.9 % of the total phenotypic variation (PV). Five QTLs, qALA5_3, qALA6_1, qALA14_1, qALA15_1, and qALA17_1, located on chromosomes 5, 6, 14, 15, and 17 were identified by model-based composite interval mapping and composite interval mapping in two individual environments. Among them, qALA6_1 showed the highest contribution to the PV with 10.0-10.2 % in two environments. The total detected QTLs for additive and epistatic effects explained 52.4 % of the PV for ALA concentration. These findings will provide useful information for understanding genetic structure and marker-assisted breeding programs to increase ALA concentration in seeds derived from wild soybean PI483463. PMID- 24794975 TI - Transcriptional coregulators: fine-tuning metabolism. AB - Metabolic homeostasis requires that cellular energy levels are adapted to environmental cues. This adaptation is largely regulated at the transcriptional level, through the interaction between transcription factors, coregulators, and the basal transcriptional machinery. Coregulators, which function as both metabolic sensors and transcriptional effectors, are ideally positioned to synchronize metabolic pathways to environmental stimuli. The balance between inhibitory actions of corepressors and stimulatory effects of coactivators enables the fine-tuning of metabolic processes. This tight regulation opens therapeutic opportunities to manage metabolic dysfunction by directing the activity of cofactors toward specific transcription factors, pathways, or cells/tissues, thereby restoring whole-body metabolic homeostasis. PMID- 24794980 TI - Systematic review of hyperbaric oxygen therapy for the treatment of non neurological soft tissue radiation-related injuries. AB - PURPOSE: The purpose of this paper was to provide an evidence-based evaluation of the safety and effectiveness of hyperbaric oxygen therapy (HBOT) for the treatment of non-neurological soft tissue radiation-related injuries (STRI). METHODS: Systematic searches of medical bibliographic databases, the Internet, and lists of references were conducted in December 2010 and April 2013 to identify relevant primary studies. Inclusion and classification of papers was resolved through the application of a predetermined protocol. Information on both the safety and effectiveness of HBOT was analyzed. RESULTS: Forty-one articles were included, with 11 comparing HBOT to a regimen without HBOT. Comparative evidence varied considerably in methodological quality, and numerous limitations were identified. Absolute data showed that serious adverse events after HBOT were rare, while more common adverse events were minor and self-limiting. Compared to observation, conventional, or sham therapies, evidence of benefit in clinical outcomes was shown for HBOT for radiation proctitis and wounds in irradiated soft tissue of the head and neck, but not for postirradiation soft tissue edema or radiation cystitis. Clinical outcomes differed little between HBOT and argon plasma coagulation for radiation proctitis and between HBOT and hyaluronic acid for radiation cystitis. CONCLUSIONS: HBOT is a safe intervention which may offer clinical benefits to patients suffering from radiation proctitis and non neurological STRI of the head and neck. However, differing clinical responses across STRI demonstrate a need for further well-designed clinical trials to validate the use of HBOT for individual STRI, both as an adjunct to conventional treatments and relative to definitive treatments. PMID- 24794981 TI - Characteristic vibrational frequencies of toxic polychlorinated dibenzo-dioxins and -furans. AB - The possibility to monitor in real-time the emission of dioxins produced by incineration of waste or by industrial processes is nowadays a necessity considering the high toxicity of these compounds, their persistence in the environment and their ability to bio-accumulate in the food chain. Recently it has been demonstrated the potentiality of detecting dioxins in carbon tetrachloride via MIR Quantum Cascade Lasers. A fundamental step in real time monitoring of dioxins emission is the possibility to recognize the most toxic congeners within complex mixtures and at low concentrations. Taking into account the lack of spectroscopic data about these very toxic environmental pollutants and the necessity to monitor their emissions we have recorded infrared spectra of 13 of the 17 most toxic congeners of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzo-furans (PCDFs) dissolved in carbon tetrachloride. In this way we have obtained a small database that we have used to test the ability of a linear regression algorithm to recognize each congener and its relative concentration in complex mixtures of these compounds. PMID- 24794982 TI - Thyroid hormone disrupting activities of sediment from the Guanting Reservoir, Beijing, China. AB - In the present study, yeast bioassays were used to evaluate and characterize the thyroid receptor (TR) disrupting activities of the organic extracts and elutriates of the sediments from the Guanting Reservoir, Beijing, China. An accelerated solvent extraction was used to separate the organic extracts, which were subjected to a yeast bioassay. The organic extracts could affect thyroid hormone signaling by decreasing the binding of the thyroid hormone. The TR antagonistic activity equivalents (TEQbio) referring to amiodarone hydrochloride were calculated and the observed TEQbio-organic extracts ranged from 25.4 +/- 3.7 to 176.9 +/- 18.0 MUg/g. Elutriate toxicity tests using the modified yeast bioassay revealed that the elutriates also significantly antagonized the TR, with the TEQbio-elutriates ranging from N.D. to 7.8 +/- 0.8 MUg/L. To characterize the toxic compounds, elutriates were extracted by using a C18 cartridge or treated with ethylenediaminetetraacetic acid (EDTA, 30 mg/L). The results suggested that the addition of EDTA eliminated over 74.3% of the total effects, and the chemical analysis revealed that heavy metals, some of which exhibited TR disrupting potency, for example Zn and Cd, were detectable with higher concentrations in the elutriates. Thus, the cause(s) of toxicity in the elutriate appear to be partly related to the heavy metals. PMID- 24794983 TI - Effects of PbCl2 on selective catalytic reduction of NO with NH3 over vanadia based catalysts. AB - The effects of PbCl2 on the selective catalytic reduction of NO with NH3 over vanadia-based catalysts were studied with BET, XRD, SEM, XPS, NH3-TPD, NH3 chemisorption, FT-IR and catalytic activity measurements. The results showed that PbCl2 deactivated the catalysts to a very high extent. The doping of PbCl2 could decrease the surface acidity, especially that of Bronsted acid sites. XPS characterization reveals that the presence of PbCl2 resulted in the transformation of V(5+) into V(4+), which decreased the reducibility of vanadia species. Based on the analysis of physical and chemical properties of the catalysts, the PbCl2-poisoning mechanism model of the vanadia-based SCR catalysts was proposed. PMID- 24794984 TI - Tailored zeolites for the removal of metal oxyanions: overcoming intrinsic limitations of zeolites. AB - This review aims to present a global view of the efforts conducted to convert zeolites into efficient supports for the removal of heavy metal oxyanions. Despite lacking affinity for these species, due to inherent charge repulsion between zeolite framework and anionic species, zeolites have still received considerable attention from the scientific community, since their versatility allowed tailoring them to answer specific requirements. Different processes for the removal and recovery of toxic metals based on zeolites have been presented. These processes resort to modification of the zeolite surface to allow direct adsorption of oxyanions, or by combination with reducing agents for oxyanions that allow ion-exchange with the converted species by the zeolite itself. In order to testify zeolite versatility, as well as covering the wide array of physicochemical constraints that oxyanions offer, chromium and arsenic oxyanions were selected as model compounds for a review of treatment/remediation strategies, based on zeolite modification. PMID- 24794985 TI - Bioremediation of chlorimuron-ethyl-contaminated soil by Hansschlegelia sp. strain CHL1 and the changes of indigenous microbial population and N-cycling function genes during the bioremediation process. AB - Long-term and excessive application of the herbicide chlorimuron-ethyl has led to soil degradation and crop rotation barriers. In the current study, we isolated bacterial strain Hansschlegelia sp. CHL1, which can utilize chlorimuron-ethyl as its sole carbon and energy source, and investigated its application in soil bioremediation. Indigenous microbial populations and N-cycling function in the soil were also investigated during the bioremediation process by monitoring the copy numbers of bacterial and fungal marker genes, as well as N-cycling functional genes (nifH, amoA, nirS, and nirK). Results showed that >95% of chlorimuron-ethyl could be degraded within 45 days in soils inoculated with CHL1. Inoculation at two time points resulted in a higher remediation efficiency and longer survival time than a single inoculation. At the end of the 60-day incubation, the copy numbers of most indicator genes were recovered to the level of the control, even in the single-inoculation soils. A double inoculation was necessary for recovery of nifH. However, the abundance of nirK and ammonia oxidizing bacterial genes were significantly inhibited regardless of inoculum. The results suggested that CHL1 is effective for the remediation of chlorimuron ethyl-contaminated soil, and could partially reduce the toxic effects of chlorimuron-ethyl on soil microorganisms. PMID- 24794986 TI - Health care cost in Switzerland: quantity- or price-driven? AB - In Switzerland, per capita health care costs vary substantially from canton to canton and rise considerably and steadily from year to year. Since costs are equal to the product of quantities and prices, the question arises whether regional cost variations and cost increase over time are quantity- or price driven. Depending on the answer, the containment of health care costs must be approached differently. This article examines the cost of mandatory health insurance in Switzerland for the period from 2004 to 2010 and breaks it down into quantity and price effects. The main result of the cross-section analysis reveals that regional cost differences are mainly due to quantity differences. Similarly, the longitudinal analysis shows that the cost increase across all health care services is primarily caused by increasing per capita quantities. Any attempt to contain costs must therefore focus primarily on the extent of medical care utilization, and the key challenge to be met is how to identify medical care services which do not have a positive effect on patients' health status. PMID- 24794987 TI - Physicians' brain drain in Greece: a perspective on the reasons why and how to address it. AB - This review study explores the "brain drain" currently evident amongst physicians in Greece, which is closely linked to the country's severe financial woes. In particular, it shows that the Greek healthcare labour market offers few opportunities and thus physicians are forsaking their homeland to seek jobs abroad. The main causes generating or greatly inflating the brain drain of Greek physicians are unemployment, job insecurity, income reduction, over-taxation, together with limited budgets for research institutes. It is argued that, to stop the evolving mass exodus of skilled medical staff, policy-makers should implement fiscal and human-centred approaches, thoroughly safeguarding both the right of skilled Greek physicians to work in their homeland with motivation and dignity, but also of Greek citizens to continue receiving high-quality healthcare by skilled physicians at times when this is mostly needed. PMID- 24794990 TI - Technique helps target microRNA. PMID- 24794991 TI - Researchers identify stem cell origin of AML. PMID- 24794992 TI - Teaming up to engage the immune system. PMID- 24794993 TI - CT scans predict response to cancer therapy. PMID- 24794994 TI - E-cigarettes linked to smoking among teens. PMID- 24794996 TI - Q&A: Mikala Egeblad on tumor microenvironment. AB - Mikala Egeblad, PhD, who studies tumor microenvironment at New York's Cold Spring Harbor Laboratory, talks about how a tumor's microenvironment may affect therapeutic responses and disease metastasis, as well as future research directions in the field. PMID- 24794997 TI - Tracking CTCs may improve cancer treatment. PMID- 24794998 TI - Advanced prostate cancer is distinguished by cholesteryl ester accumulation. AB - Cholesteryl ester accumulates in PTEN-null prostate cancer cells and supports growth and invasion. PMID- 24795008 TI - Finding the right balance of BRAF inhibition in melanoma. AB - Paradoxical activation of the mitogen-activated protein kinase pathway can cause secondary malignancies in patients treated with inhibitors of BRAF(V600) proteins. Characterization of a patient with concurrent BRAF-mutant melanoma and NRAS-mutant leukemia treated intermittently with combined BRAF and MEK inhibition provides new insights into the potential clinical and molecular effects of this therapeutic strategy. PMID- 24795009 TI - MTOR mutations in the crosshairs of targeted therapy. AB - The identification of genetic lesions that affect tumor sensitivity to targeted therapies is a major objective of precision medicine. Two reports in this issue combine tumor genome analyses with functional characterization to uncover activating mutations in MTOR that confer sensitivity to a clinically used mTOR inhibitor. PMID- 24795010 TI - From breaking bad to worse: exploiting homologous DNA repair deficiency in cancer. AB - DNA repair deficiencies are common among cancer cells and represent a potential vulnerability that might be exploited by targeting compensatory repair pathways. However, the identification of synthetically lethal combinations of DNA repair defects, although of significant clinical relevance, has been somewhat anecdotal. Although numerous models have been proposed to explain synthetic lethality among DNA repair mutations, we have only a limited understanding of why a given mutation should render cells sensitive to another. In this issue of Cancer Discovery, Dietlein and colleagues define a general connection between mutations in genes involved in homologous recombination and sensitivity to inhibitors of non-homologous end joining. In doing so, they provide a mechanism to demarcate a set of seemingly diverse tumors that may be highly responsive to established DNA repair-targeted therapeutics. PMID- 24795011 TI - Paths of resistance to EGFR inhibitors: is NF enough? AB - Although the majority of patients with EGFR-mutant lung cancer respond well to EGF receptor (EGFR) tyrosine kinase inhibitors (TKI), all patients eventually develop resistance. The mechanism of acquired resistance is still unknown for a considerable subset of cases. This study reveals the NF1 tumor suppressor gene as a new mediator of resistance to EGFR TKIs and provides a mechanistic rationale for developing combination therapies. PMID- 24795013 TI - Prophylactic surgery recommended for BRCA1 carriers. PMID- 24795012 TI - T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. AB - Cancer immunotherapy has great promise, but is limited by diverse mechanisms used by tumors to prevent sustained antitumor immune responses. Tumors disrupt antigen presentation, T/NK-cell activation, and T/NK-cell homing through soluble and cell surface mediators, the vasculature, and immunosuppressive cells such as myeloid derived suppressor cells and regulatory T cells. However, many molecular mechanisms preventing the efficacy of antitumor immunity have been identified and can be disrupted by combination immunotherapy. Here, we examine immunosuppressive mechanisms exploited by tumors and provide insights into the therapies under development to overcome them, focusing on lymphocyte traffic. PMID- 24795014 TI - BRAF inhibitor resistance can be overcome by blocking autophagy. AB - ER stress-induced autophagy confers resistance to BRAF inhibitors in BRAF-mutant melanoma. PMID- 24795015 TI - Epigenetic mechanisms underlie resistance to NOTCH inhibition in T-ALL. AB - T-ALL cells can become resistant to gamma-secretase inhibitors through reversible epigenetic alterations. PMID- 24795016 TI - The putative tumor suppressor ZMYND11 recognizes H3.3K36me3. AB - ZMYND11 represses gene expression by binding H3.3K36me3 and preventing transcription elongation. PMID- 24795017 TI - Hepatitis B viral insertion generates an oncogenic long noncoding RNA. AB - A hepatitis B virus (HBV)-human chimeric transcript is detectable in 23.3% of HBV associated HCCs. PMID- 24795018 TI - Genome sequencing reveals somatic evolution in murine SCLC. AB - Genomic analysis identifies deregulated PTEN signaling as a driver of murine SCLC progression. PMID- 24795019 TI - UV-induced inflammation drives melanoma progression. AB - UV-induced inflammation promotes angiotropism and metastasis in melanoma. PMID- 24795020 TI - LXR agonism inhibits metastatic melanoma through activation of ApoE. AB - Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models. PMID- 24795021 TI - Serpins shield tumor cells from antimetastatic brain defenses. AB - Serpin expression in tumors facilitates brain metastasis by blocking the effects of plasmin. PMID- 24795022 TI - Angiogenesis-related gene mutations drive a subset of angiosarcomas. AB - Recurrent mutations in PTPRB and PLCG1 were identified in angiosarcomas. PMID- 24795023 TI - C-terminal AKT phosphorylation by CDK2-cyclin A or mTOR activates AKT. AB - CDK2-cyclin A2 or mTOR activate AKT via phosphorylation of the C-terminal residues S477 and T479. PMID- 24795024 TI - Sentinel-node biopsy offers benefit in melanoma. PMID- 24795025 TI - SAICAR binding activates PKM2 protein kinase activity. AB - SAICAR-mediated PKM2 protein kinase activity is necessary for EGF-induced cancer cell proliferation. PMID- 24795026 TI - Study increases molecular understanding of bladder cancer. PMID- 24795027 TI - Developing world faces growing cancer burden. PMID- 24795028 TI - Studies weigh cost, effectiveness of mammography. PMID- 24795029 TI - Childhood cancer incidence up, mortality down. PMID- 24795031 TI - Idelalisib has activity in mantle cell lymphoma. AB - The PI3Kdelta inhibitor idelalisib was effective in heavily pretreated patients with mantle cell lymphoma. PMID- 24795032 TI - IL15 is linked to antitumor immune responses in colorectal cancer. AB - IL15 deletion in colorectal cancer is associated with reduced lymphocyte proliferation and poor outcome. PMID- 24795033 TI - Sliding mode output feedback control based on tracking error observer with disturbance estimator. AB - For a class of systems who suffers from disturbances, an original output feedback sliding mode control method is presented based on a novel tracking error observer with disturbance estimator. The mathematical models of the systems are not required to be with high accuracy, and the disturbances can be vanishing or nonvanishing, while the bounds of disturbances are unknown. By constructing a differential sliding surface and employing reaching law approach, a sliding mode controller is obtained. On the basis of an extended disturbance estimator, a creative tracking error observer is produced. By using the observation of tracking error and the estimation of disturbance, the sliding mode controller is implementable. It is proved that the disturbance estimation error and tracking observation error are bounded, the sliding surface is reachable and the closed loop system is robustly stable. The simulations on a servomotor positioning system and a five-degree-of-freedom active magnetic bearings system verify the effect of the proposed method. PMID- 24795034 TI - Limit cycle analysis of active disturbance rejection control system with two nonlinearities. AB - Introduction of nonlinearities to active disturbance rejection control algorithm might have high control efficiency in some situations, but makes the systems with complex nonlinearity. Limit cycle is a typical phenomenon that can be observed in the nonlinear systems, usually causing failure or danger of the systems. This paper approaches the problem of the existence of limit cycles of a second-order fast tool servo system using active disturbance rejection control algorithm with two fal nonlinearities. A frequency domain approach is presented by using describing function technique and transfer function representation to characterize the nonlinear system. The derivations of the describing functions for fal nonlinearities and treatment of two nonlinearities connected in series are given to facilitate the limit cycles analysis. The effects of the parameters of both the nonlinearity and the controller on the limit cycles are presented, indicating that the limit cycles caused by the nonlinearities can be easily suppressed if the parameters are chosen carefully. Simulations in the time domain are performed to assess the prediction accuracy based on the describing function. PMID- 24795035 TI - Low ileocecal valve pressure is significantly associated with small intestinal bacterial overgrowth (SIBO). AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is a significant and increasingly recognized syndrome. While the development may be multifactorial, impairment of the ileocecal valve (ICV), small bowel motility, and gastric acid secretion have been hypothesized to be risk factors. ICV dysfunction remains largely unexplored using standard technology. The wireless motility capsule (WMC) that evaluates pressure, pH, and temperature throughout the GI tract provides the ability to assess these parameters. AIMS: The primary aims of this study were to assess the relationship of ICV pressures, small bowel transit time (SBTT) and intestinal pH with lactulose hydrogen breath testing (LBT) results in subjects with suspected SIBO. METHODS: We retrospectively studied consecutive patients referred to our institution for WMC and LBT from 2010-2012. Ileocecal junction pressures (IJP), as a surrogate for ICV pressures, were defined as the highest pressure over a 4-min window prior to the characteristic ileocecal pH drop. SBTT and pH were calculated and compared with LBT results. RESULTS: Twenty-three patients underwent both WMC and LBT, with positive results observed in 15 (65.2%). IJP were significantly higher in LBT(-) negative vs. LBT(+) (79.9 vs. 45.1, p < 0.01). SBTT was significantly longer in LBT(+) versus LBT(-) (5.82 vs. 3.81 h, p = 0.05). Among LBT(+) subjects, gastric pH was significantly higher versus LBT(-) subjects (2.76 vs. 1.63, p = 0.01). There was poor correlation between IJP and other parameters (SBTT, small bowel pH, and gastric pH). CONCLUSIONS: Low IJP is significantly associated with SIBO. While this is physiologically plausible, to our knowledge, this is the first study to make this connection. Prolonged SBTT and higher pH are also independently associated with SIBO. Our findings add value of the WMC test as a diagnostic tool in patients with functional gastrointestinal complaints and suggest re-focus of attention on the ileocecal valve as a prominent player in intestinal disorders. PMID- 24795037 TI - Intestinal benign glomus tumor: description and review of the literature. PMID- 24795036 TI - Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model. AB - BACKGROUND/AIMS: Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis. METHODS: C57BL/6 wild-type (WT) and caspase 3 knock out (Casp3 (-/ )) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis. Thereafter, liver injury, liver fibrosis and hepatocellular apoptosis were quantified in liver sections. Additionally, expression of proteins associated with liver inflammation and fibrogenesis was analyzed. RESULTS: WT mice fed MCD diet showed marked activation of caspase 3 in hepatocytes, in conjunction with steatohepatitis and increased hepatic triglyceride levels, hepatocyte ballooning, inflammation and fibrosis. Casp3 (-/-) mice fed the MCD diet showed similar serum aminotransferase levels and NAFLD activity scores (NAS) compared with WT MCD-fed mice. However, Casp3 (-/ ) mice on the MCD diet showed a marked reduction in expression of transcripts for profibrogenic genes, which translated into reduced hepatic collagen deposition. These changes were associated with decreased levels of apoptosis, and a significant reduction in the expression of cytokines involved in inflammatory signaling. Casp3 (-/-) mice on the MCD showed a reduction in expression of chemokine receptor 2 (CCR2) leading to ameliorated infiltration of inflammatory lymphocyte antigen 6 complex, locus C1 (Ly6c) positive monocytes. CONCLUSION: These findings support a prominent role for hepatocyte caspase 3 activation in NASH-related apoptosis, fibrogenesis and fibrosis which in part is mediated via CCR2-dependent infiltration of Ly6c positive monocytes. PMID- 24795038 TI - The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence. AB - Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside" approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence. PMID- 24795039 TI - Should all fluid collections in delayed phase of acute necrotizing pancreatitis labeled as walled-off pancreatic necrosis? PMID- 24795041 TI - Cell penetrating peptides: efficient vectors for delivery of nanoparticles, nanocarriers, therapeutic and diagnostic molecules. AB - Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficult challenge. The cellular membrane is very effective in its role as a selectively permeable barrier. While it is essential for cell survival and function, also presents a major barrier for intracellular delivery of cargo such as therapeutic and diagnostic agents. In recent years, cell-penetrating peptides (CPPs), that are relatively short cationic and/or amphipathic peptides, received great attention as efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo such as plasmid DNA (pDNA), small interfering RNA (siRNAs), drugs, and nanoparticulate pharmaceutical carriers. This review discusses the various uptake mechanisms of these peptides. Furthermore, we discuss recent advances in the use of CPP for the efficient delivery of nanoparticles, nanocarriers, DNA, siRNA, and anticancer drugs to the cells. In addition, we have been highlighting new results for improving endosomal escape of CPP-cargo molecules. Finally, pH-responsive and activable CPPs for tumor-targeting therapy have been described. PMID- 24795040 TI - Cost-effectiveness of chemoprevention with proton pump inhibitors in Barrett's esophagus. AB - BACKGROUND: Proton pump inhibitors (PPIs) may reduce the risk of esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus. PPIs are prescribed for virtually all patients with Barrett's esophagus, irrespective of the presence of reflux symptoms, and represent a de facto chemopreventive agent in this population. However, long-term PPI use has been associated with several adverse effects, and the cost-effectiveness of chemoprevention with PPIs has not been evaluated. AIM: The purpose of this study was to assess the cost-effectiveness of PPIs for the prevention of EAC in Barrett's esophagus without reflux. METHODS: We designed a state-transition Markov microsimulation model of a hypothetical cohort of 50-year-old white men with Barrett's esophagus. We modeled chemoprevention with PPIs or no chemoprevention, with endoscopic surveillance for all treatment arms. Outcome measures were life-years, quality-adjusted life years (QALYs), incident EAC cases and deaths, costs, and incremental cost-effectiveness ratios. RESULTS: Assuming 50% reduction in EAC, chemoprevention with PPIs was a cost effective strategy compared to no chemoprevention. In our model, administration of PPIs cost $23,000 per patient and resulted in a gain of 0.32 QALYs for an incremental cost-effectiveness ratio of $12,000/QALY. In sensitivity analyses, PPIs would be cost-effective at $50,000/QALY if they reduce EAC risk by at least 19%. CONCLUSIONS: Chemoprevention with PPIs in patients with Barrett's esophagus without reflux is cost-effective if PPIs reduce EAC by a minimum of 19%. The identification of subgroups of Barrett's esophagus patients at increased risk for progression would lead to more cost-effective strategies for the prevention of esophageal adenocarcinoma. PMID- 24795042 TI - Does phosphate enhance the natural attenuation of crude oil in groundwater under defined redox conditions? AB - After a crude oil spill caused by a broken pipeline in 2009 to a gravel aquifer in southern France, degradation processes under various redox conditions progressively established, but at rates that predict a long life-time of the source under natural attenuation after partial source removal. In this study, we aimed at identifying the rate-limiting factors for each redox condition, with special emphasis on phosphate as limiting nutrient. The study was conducted in laboratory microcosms assembled with material collected on site: sediments, water from monitoring wells, oil and microbial sludge. Redox conditions were promoted by adding electron acceptors (either oxygen, nitrate, limonite (FeO(OH)), cryptomelane (K(Mn(4+),Mn(2+))8O16), or sulfate). For each condition, the role of phosphate was studied by repeated additions for up to 290days. The results showed a very strong stimulation of aerobic and denitrifying rates of oil degradation by phosphate, provided that oxygen and nitrate were repeatedly supplied. Phosphate caused also a marked stimulation of methanogenic degradation, and a relatively small stimulation of metal reduction. These anaerobic processes started only after marked lag phases, and phosphate shortened the lag phase for methanogenic degradation. Degradation of aromatic and aliphatic hydrocarbons with less than 8 carbons, including benzene, was confirmed even under unstimulated conditions. It is concluded that degradation rates at the site are limited by both, availability of electron acceptors and availability of phosphate needed for promoting microbial growth. PMID- 24795043 TI - Adapter protein Shc regulates Janus kinase 3 phosphorylation. AB - Although constitutive activation of Janus kinase 3 (Jak3) leads to different cancers, the mechanism of trans-molecular regulation of Jak3 activation is not known. Previously we reported that Jak3 interactions with adapter protein p52ShcA (Shc) facilitate mucosal homeostasis. In this study, we characterize the structural determinants that regulate the interactions between Jak3 and Shc and demonstrate the trans-molecular mechanism of regulation of Jak3 activation by Shc. We show that Jak3 autophosphorylation was the rate-limiting step during Jak3 trans-phosphorylation of Shc where Jak3 directly phosphorylated two tyrosine residues in Src homology 2 (SH2) domain and one tyrosine residue each in calponin homology 1 (CH1) domain and phosphotyrosine interaction domain (PID) of Shc. Direct interactions between mutants of Jak3 and Shc showed that although FERM domain of Jak3 was sufficient for binding to Shc, CH1 and PID domains of Shc were responsible for binding to Jak3. Functionally Jak3 was autophosphorylated under IL-2 stimulation in epithelial cells. However, Shc recruited tyrosine phosphatases SHP2 and PTP1B to Jak3 and thereby dephosphorylated Jak3. Thus we not only characterize Jak3 interaction with Shc, but also demonstrate the molecular mechanism of intracellular regulation of Jak3 activation where Jak3 interactions with Shc acted as regulators of Jak3 dephosphorylation through direct interactions of Shc with both Jak3 and tyrosine phosphatases. PMID- 24795044 TI - Substrate specificity and kinetic characterization of peptidoglycan O acetyltransferase B from Neisseria gonorrhoeae. AB - The O-acetylation of the essential cell wall polymer peptidoglycan is a major virulence factor identified in many bacteria, both Gram-positive and Gram negative, including Staphylococcus aureus, Bacillus anthracis, Neisseria gonorrhoeae, and Neisseria meningitidis. With Gram-negative bacteria, the translocation of acetyl groups from the cytoplasm is performed by an integral membrane protein, PatA, for its transfer to peptidoglycan by O-acetyltransferase PatB, whereas a single bimodal membrane protein, OatA, appears to catalyze both reactions of the process in Gram-positive bacteria. Only phenotypic evidence existed in support of these pathways because no in vitro biochemical assay was available for their analysis, which reflected the complexities of investigating integral membrane proteins that act on a totally insoluble and heterogeneous substrate, such as peptidoglycan. In this study, we present the first biochemical and kinetic analysis of a peptidoglycan O-acetyltransferase using PatB from N. gonorrhoeae as the model system. The enzyme has specificity for muropeptides that possess tri- and tetrapeptide stems on muramyl residues. With chitooligosaccharides as substrates, rates of reaction increase with increasing degrees of polymerization to 5/6. This information will be valuable for the identification and development of peptidoglycan O-acetyltransferase inhibitors that could represent potential leads to novel classes of antibiotics. PMID- 24795047 TI - Association between domestic violence and miscarriage: a population-based cross sectional study among women of childbearing ages, Sivas, Turkey. AB - Violence against women is a global issue, with ramifications for the reproductive health of women. The current study examined the relation of domestic violence (DV) to miscarriage among women who were victimized during their last pregnancy. The study was conducted in Sivas city center, in Turkey. Associations between self-reported DV and miscarriage were analyzed using multiple regression modeling. Physical and/or sexual DV during the last pregnancy was reported by 10.0% and 6.2% of women, respectively. Women who experienced physical violence were 2.5 times as likely (Odds Ratio (OR) = 2.47, 95% confidence interval [CI]: 1.37-4.84, p = .003) to have experienced a miscarriage than women who did not report physical violence. These findings suggest that victims who experience physical violence during the last pregnancy may be more likely to experience miscarriage. Preventing DV, especially physical violence, may, therefore, be beneficial for avoiding adverse pregnancy outcomes. PMID- 24795046 TI - Cancer-relevant splicing factor CAPERalpha engages the essential splicing factor SF3b155 in a specific ternary complex. AB - U2AF homology motifs (UHMs) mediate protein-protein interactions with U2AF ligand motifs (ULMs) of pre-mRNA splicing factors. The UHM-containing alternative splicing factor CAPERalpha regulates splicing of tumor-promoting VEGF isoforms, yet the molecular target of the CAPERalpha UHM is unknown. Here we present structures of the CAPERalpha UHM bound to a representative SF3b155 ULM at 1.7 A resolution and, for comparison, in the absence of ligand at 2.2 A resolution. The prototypical UHM/ULM interactions authenticate CAPERalpha as a bona fide member of the UHM family of proteins. We identify SF3b155 as the relevant ULM-containing partner of full-length CAPERalpha in human cell extracts. Isothermal titration calorimetry comparisons of the purified CAPERalpha UHM binding known ULM containing proteins demonstrate that high affinity interactions depend on the presence of an intact, intrinsically unstructured SF3b155 domain containing seven ULM-like motifs. The interplay among bound CAPERalpha molecules gives rise to the appearance of two high affinity sites in the SF3b155 ULM-containing domain. In conjunction with the previously identified, UHM/ULM-mediated complexes of U2AF(65) and SPF45 with SF3b155, this work demonstrates the capacity of SF3b155 to offer a platform for coordinated recruitment of UHM-containing splicing factors. PMID- 24795048 TI - Certain surfactants significantly enhance the activity of antibiotics in the mouse model of MTB and drug resistant MTB infection and effectively remove the bacteria from a pulmonary cavity in human ex-vivo study. AB - Surfactants have the potential to overcome natural resistance of MTB to antibiotics which is mediated by barriers that impede the penetration of drugs to their targets. A major component of this barrier is trehalose dimycolate (TDM) which surrounds the bacteria with a thick lipid shield. In this study dodecyl maltoside (DDM) was evaluated for this purpose. This surfactant is an excellent cellular permeabilizing agent with associated low toxicity. The administration of the surfactant as an aerosol into the lungs of the infected mice achieved a 5-10 times enhancement of the isoniazid (INH) treatment gauged by the reduction of the colony forming units. This study also established proof of principle that surfactants alone applied as an aerosol can reduce the bacteria count in lungs infected with MTB. The potential of the surfactant in the therapy of human cavitary TB was also investigated using a surgically removed lung from a patient with extreme drug resistant MTB (XDR-TB). A cavity in this lung was flushed with DDM solution ex-vivo. The procedure readily removed the bacteria, excessive amounts of TDM and necrotic tissue from the cavity. These studies demonstrate that DDM can disrupt the layers of TDM and free embedded MTB and, consequently, surfactants have promise as a proficient modality for the treatment of pulmonary MTB. PMID- 24795045 TI - PA1b inhibitor binding to subunits c and e of the vacuolar ATPase reveals its insecticidal mechanism. AB - The vacuolar ATPase (V-ATPase) is a 1MDa transmembrane proton pump that operates via a rotary mechanism fuelled by ATP. Essential for eukaryotic cell homeostasis, it plays central roles in bone remodeling and tumor invasiveness, making it a key therapeutic target. Its importance in arthropod physiology also makes it a promising pesticide target. The major challenge in designing lead compounds against the V-ATPase is its ubiquitous nature, such that any therapeutic must be capable of targeting particular isoforms. Here, we have characterized the binding site on the V-ATPase of pea albumin 1b (PA1b), a small cystine knot protein that shows exquisitely selective inhibition of insect V-ATPases. Electron microscopy shows that PA1b binding occurs across a range of equivalent sites on the c ring of the membrane domain. In the presence of Mg.ATP, PA1b localizes to a single site, distant from subunit a, which is predicted to be the interface for other inhibitors. Photoaffinity labeling studies show radiolabeling of subunits c and e. In addition, weevil resistance to PA1b is correlated with bafilomycin resistance, caused by mutation of subunit c. The data indicate a binding site to which both subunits c and e contribute and inhibition that involves locking the c ring rotor to a static subunit e and not subunit a. This has implications for understanding the V-ATPase mechanism and that of inhibitors with therapeutic or pesticidal potential. It also provides the first evidence for the position of subunit e within the complex. PMID- 24795049 TI - Improving antitubercular drug susceptibility testing with liquid media. AB - Liquid media such as the mycobacteria growth indicator tube (MGIT) are widely used for antitubercular drug susceptibility testing (DST) but may cause discordant or invalid results due to ordinary bacterial contamination or mixed mycobacterial colonies. To overcome the drawbacks of DST with MGIT (DSTMGIT), an experiment with a modified method that incorporated a subculture step on the Lowenstein-Jensen (LJ) media with positively identified liquid media of MGIT (modified DSTMGIT) was performed. For 307 samples identified as Mycobacterium tuberculosis complex from 2010 to 2012, DSTMGIT and modified DSTMGIT were performed for isoniazid, rifampin, streptomycin, and ethambutol using BACTEC MGIT 960. Those results were compared to the results of DST with the solid media, LJ (DSTLJ). We obtained drug susceptibility test results from 287 (93.5%) specimens; however, 20 (6.5%) specimens showed invalid results with error messages from the system using DSTMGIT. Thirteen (65.0%) of the 20 invalid DSTMGIT results were made valid using a modified form of DSTMGIT. DSTMGIT and the modified DSTMGIT methods had 41 (14.3%) discordant results to the reference method , DSTLJ. Also, five of these samples were falsely identified as multidrug-resistant. The percent of discordant results was similar between DSTMGIT and the modified DSTMGIT (P=0.624), but the bacterial contamination or mycobacterial mixture rate was significantly lower in the modified DSTMGIT (P=0.029). Modified DSTMGIT can reduce bacterial contamination or mixed mycobacterial cultures and can be useful for samples with discordant or invalid DST results. PMID- 24795050 TI - Morphological manifestations of the atypical mycobacteriosis caused by nontuberculous mycobacteria in the HIV infected patients. AB - Infection with atypical mycobacteria (MAC) is a well-known complication of AIDS that typically occurs only in people with advanced immunodeficiency. We studied tissues from 13 patients with HIV and atypical mycobacterial infection who died in St Petersburg Russia from 2009-2012. Three patterns of disease were identified that suggest effects of host resistance. The first pattern was in people paucibacillary disease. They had positive blood cultures and histologic changes consistent with mycobacterial infection, but no stainable acid fast bacilli (AFB). The second group had disseminated infection in many organs including the lungs with extensive necrosis with many AFB. Finally, the third group had massive infection of many organs, but not the lungs, and only minimal necrosis. These observations suggest significant heterogeneity in atypical mycobacterial infections. PMID- 24795052 TI - Simvastatin attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. AB - AIM: Traumatic brain injury (TBI) leads to important and deleterious inflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. After TBI, the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation. In this study, we hypothesized that the activation of cerebral vascular endothelial cells plays a crucial role in the pathogenesis of inflammation and outcome after TBI. It may represent a key cellular target for statin therapy. METHODS: In our study, cortical contusions were induced, and the effect of continuous treatment of simvastatin on behavior and inflammation in adult rats following experimental TBI was evaluated. The treatment group received 15 mg/kg of simvastatin daily for 3 days. Neurological function was assessed with the grip test. RESULTS: The results showed that the non-treatment control group had a significantly greater increase in ICAM-1 expression from pre-injury to the post-injury 72 h time point as compared to the expression in treatment group. The treatment group had better neurological function as evidenced in a grip test performed from baseline to 72 h. The analysis of a western blot test and pathology also demonstrated reduced ICAM-1 expression and a smaller area of damage and tissue loss. CONCLUSION: Our findings suggest that simvastatin could attenuate the activation of cerebral vascular endothelial inflammatory response and decrease the loss of neurological function and brain tissue. PMID- 24795051 TI - Knockdown of hypoxia-inducible factor-1 alpha reduces proliferation, induces apoptosis and attenuates the aggressive phenotype of retinoblastoma WERI-Rb-1 cells under hypoxic conditions. AB - BACKGROUND: Hypoxia-inducible factor-1 alpha (HIF-1alpha) plays a critical role in tumor cell adaption to hypoxia by inducing the transcription of numerous genes. The role of HIF-1alpha in malignant retinoblastoma remains unclear. We analyzed the role of HIF-1alpha in WERI-Rb-1 retinoblastoma cells under hypoxic conditions. METHODS: CoCl2 (125 mmol/L) was added to the culture media to mimic hypoxia. HIF-1alpha was silenced using siRNA. Gene and protein expression were measured by semi-quantitative RT-PCR and Western blotting. Cell cycle and apoptosis were analyzed by flow cytometry. Cell proliferation, adhesion and invasion were assayed using MTT, Transwell invasion, and cell adhesion assays respectively. RESULT: Hypoxia significantly upregulated HIF-1alpha protein expression and the HIF-1alpha target genes VEGF, GLUT1, and Survivin mRNA. HIF 1alpha mRNA expression was not affected by hypoxia. Transfection of the siRNA expression plasmid pRNAT-CMV3.2/Neo-HIF-1alpha silenced HIF-1alpha by approximately 80% in hypoxic WERI-Rb-1 cells. The knockdown of HIF-1alpha under hypoxic conditions downregulated VEGF, GLUT1, and Survivin mRNA. It also inhibited proliferation, promoted apoptosis, induced the G0/G1 phase cell cycle arrest, and reduced the adhesion and invasion of WERI-Rb-1 cells. CONCLUSION: HIF 1alpha plays a major role in the survival and aggressive phenotype of retinoblastoma cells under hypoxic conditions. Targeting HIF-1alpha may be a promising therapeutic strategy for human malignant retinoblastoma. PMID- 24795053 TI - Tert-butylhydroquinone protects the spinal cord against inflammatory response produced by spinal cord injury. AB - Antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown in our previous studies to play an important role in protection against spinal cord injury (SCI) induced inflammatory response. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), a novel Nrf2 activator, can protect the spinal cord against SCI-induced inflammatory damage. Adult male Sprague-Dawley rats were subjected to laminectomy at T8-T9 and compression with a vascular clip. Three groups were analyzed: a sham group, a SCI group, and a SCI+rhEPO group (n=16 per group). We measured Nrf2 and nuclear factor kappa B (NF-kappaB) binding activities by an electrophoretic mobility shift assay (EMSA). We also measured the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin 6 (IL-6) by an enzyme-linked immunosorbent assay (ELISA); we also measured hindlimb locomotion function by the Basso, Beattie, and Bresnahan (BBB) rating, spinal cord edema by wet/dry weight method, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis. The results showed that the induction of the Nrf2 activity by tBHQ markedly decreased NF-kappaB activation and inflammatory cytokines production in the injured spinal cord. Administration of tBHQ also significantly attenuated SCI induced hindlimb locomotion deficits, spinal cord edema, and apoptosis. To conclude, pre-treatment with tBHQ could attenuate the spinal cord inflammatory response after SCI. PMID- 24795054 TI - Toll-like receptor 2 promotes invasion by SGC-7901 human gastric carcinoma cells and is associated with gastric carcinoma metastasis. AB - Toll-like receptors (TLRs) play a key role in cancer metastasis. The biological role of TLR2 in invasion and metastasis in gastric carcinoma cells and gastric carcinoma is not clear; therefore, we aimed to investigate the biological role of TLR2 in invasion by SGC-7901 human gastric carcinoma cells and to determine whether TLR2 is associated with gastric carcinoma metastasis. RT-PCR, real-time PCR, flow cytometry, and western blotting showed that TLR2 activation significantly increased TLR2 expression at the mRNA and protein levels and notably promoted the transcription of genes related to angiogenesis and invasion, such as VEGF-C and MMP-9. The invasive capacity of SGC-7901 cells was strikingly advanced by TLR2 stimulation on Transwell invasion assay. IL-6 in the supernatants of cultured SGC-7901 cells was increased under the condition of TLR2 stimulation and reduced after TLR2 blockade by ELISA. Combined with clinicopathological parameters, the expression of TLR2 protein examined by immunohistochemical analysis was higher in gastric carcinoma tissues than in adjacent non-cancerous tissues (p<0.001). There was a significant relationship between TLR2 expression and lymph node metastasis (p<0.01), distant metastasis (p<0.01). There was no significant correlation between gastric carcinoma and age (p>0.05), sex (p>0.05), or degree of differentiation (p>0.05). These findings indicate that TLR2 may participate in the progression and metastasis of human gastric carcinoma and provide a new therapeutic target against metastasis of gastric carcinoma. PMID- 24795055 TI - Association of interferon-gamma inducible protein-10 pretreatment level and sustained virological response in HCV-positive Egyptian patients. AB - BACKGROUND: The response to antiviral therapy in HCV infected patients depends on several predictive factors; however, the ability to achieve sustained virological response is still limited to around 60% of the patients infected with the HCV-4 genotype. Increased serum and intrahepatic interferon -gamma inducible protein 10 (IP-10) levels in patients with chronic hepatitis C have been described. The aim of the work was to study the impact of pretreatment serum IP-10 level on the antiviral treatment outcome in a group of Egyptian patients infected with HCV. MATERIALS AND METHODS: The study included 80 treatment naive HCV patients. Serum IP-10 levels were determined by an enzyme linked immunosorbent assay before therapy was introduced. Serum samples were examined twice by Real-Time PCR after complete course of therapy for detection of HCV RNA; at the end of the antiviral therapy and six months later to detect sustained virological response (SVR). RESULTS: 57 patients (71%) achieved SVR while 23 (29%) patients were non responders (NR). Pretreatment serum IP-10 levels were significantly lower in patients who achieved SVR than in NR (p=0.000). CONCLUSION: Low pretreatment serum IP-10 is a favorable predictive of response to antiviral HCV therapy in Egyptian patients. PMID- 24795056 TI - Analysis of the Ten-Eleven Translocation 2 (TET2) gene mutation in myeloproliferative neoplasms. AB - Loss-of-function mutations in the putative tumor suppressor gene, Ten-Eleven Ttranslocation 2(TET2), have been identified recently in myeloproliferative neoplasms (MPNs). The present study analyzed the TET2 gene in 99 MPNs patients. The overall TET2 mutational frequency was 12.1% (22.2% in polycythemia vera (PV), 9.7% in essential thrombocythemia (ET), 18.2% in primary myelofibrosis (PMF,) and 0% in unclassified MPNs), and 11 mutations (p.Lys95Asnfs*18, p.Gln967Asnfs*40, p.Lys1022Glufs*4, p.Asp1314Metfs*49, p.Gln1534Alafs*43, p.Tyr1618Leufs*4, p.Leu1609Glufs*45, p.Gly1735*, Q599R, c.3409+1G>T, c.4044+2insT) were identified. All the patients with TET2 mutation were accompanied by the JAK2 V617F mutation. The existence of the TET2 mutation was not related to the patient's age, hematologic indices, JAK2 V617F allele burden, frequencies of organomegaly, marrow fibrosis, or thrombotic/hemorrhagic complications in entire MPN patients. However, tendencies toward higher JAK2 V617F allele burdens (88.0+/-4.3% vs. 19.1+/-28.7%, P=0.034) and higher Hct (47.4+/-5.4% vs. 25.5+/-6.2%, P=0.037) were detected in PMF patients harboring TET2 mutations. Moreover, a significantly higher frequency of organomegaly was identified in ET patients harboring the TET2 mutation (50% vs. 19.6%, P=0.018). The TET2 mutation most likely contributes to clinical phenotypes and shows a high accompanying rate with JAK2 V617F; larger scale studies involving more MPN patients are needed. PMID- 24795057 TI - An efficient protocol for the generation of monocyte derived dendritic cells using serum-free media for clinical applications in post remission AML patients. AB - Protocols for the generation of dendritic cells (DCs) using serum as a supplementation of culture media leads to reactions due to animal proteins and disease transmissions. Several types of serum-free media (SFM), based on "good manufacture practices" (GMP), have recently been used and seem to be a viable option. The aim of this study was to evaluate the results of the differentiation, maturation, and function of DCs from Acute Myeloid Leukemia patients (AML), generated in SFM and medium supplemented with autologous serum (AS). DCs were analyzed by phenotype characteristics, viability, and functionality. The results showed the possibility of generating viable DCs in all the conditions tested. In patients, the X-VIVO 15 medium was more efficient than the other media tested in the generation of DCs producing IL-12p70 (p=0.05). Moreover, the presence of AS led to a significant increase of IL-10 by DCs as compared with CellGro (p=0.05) and X-Vivo15 (p=0.05) media, both in patients and donors. We concluded that SFM was efficient in the production of DCs for immunotherapy in AML patients. However, the use of AS appears to interfere with the functional capacity of the generated DCs. PMID- 24795058 TI - Relationship between AHSP gene expression, beta/alpha globin mRNA ratio, and clinical severity of the beta-thalassemia patients. AB - BACKGROUND: Alpha hemoglobin stabilizing protein (AHSP) is a chaperone-like molecule specialized for erythroid series which binds to free alpha-globin chain. According to this characteristic, AHSP can be considered an important factor which reduces beta thalassemia symptoms. MATERIALS AND METHODS: Reticulocytes RNA extraction and a subsequent cDNA synthesis were performed, followed by Relative qRT-PCR for AHSP, alpha, and beta globin chain genes. The beta actin gene was used as an endogenous reference as well. The relationship between AHSP gene expression, disease severity, and the beta/alpha globin mRNA ratio was studied among different homozygote beta-thalassemia patients (mild, moderate and severe) and compared with minor thalassemia and the normal population. RESULTS: Analysis of the beta-globin/alpha-globin mRNA ratio has shown that disease severity enhanced with a decrease in this proportion. Evaluation of the correlation between AHSP gene expression and the average of the beta-globin/alpha-globin expression ratio indicated a significant but indirect relationship in considered groups. Our results demonstrated that the AHSP gene expression increases in accordance with augmentation of clinical symptoms. CONCLUSIONS: Although one of the main reasons for reduced clinical severity in homozygote beta-thalassemia can be the high level of AHSP gene expression as a chaperon molecule, our findings indicated that AHSP gene expression decreased in a mild category as compared to that in severe and moderate groups. PMID- 24795059 TI - Association between thrombelastography system and vascular obstructions and hemorrhage: a two-year follow-up study of elderly Chinese patients. AB - OBJECTIVES: This study was designed to test the hypothesis that prior thrombelastography (TEG) indices are associated with subsequent vascular obstructions and hemorrhage events in aged populations, as well as to obtain knowledge about the distribution of TEG indices in elderly Chinese patients. METHODS: We conducted a two-year follow-up study. The study population consisted of patients older than 65 years who had TEG in the Chinese PLA General Hospital between January 2007 and December 2010. Four hundred and three patients were enrolled in our study. They received TEG measurements upon being enrolled in this study. We collected information on demographics, clinical examinations, and outcomes during the observational period. Structural equation modeling (SEM) was used to analyze the relationship between "synthesized" TEG parameter indices and the outcome via an indicator pathway. RESULTS: We found that in the "model of hemorrhage" (adjusted by confounding of anticoagulants), the model fit indices with chi-square/df = 9.555/7, CFI of 0.997, TLI of 0.994, and standardized root mean square residual (SRMR) of 0.034; while in the "model of vascular obstruction events" (adjusted by confounding of Anticoagulants), the model fit indices with chi-square/df = 6.070/7, CFI of 1.000, TLI of 1.002, and standardized root mean square residual (SRMR) of 0.000. The "model of vascular obstruction events" showed that the "synthesized" TEG parameter was significantly associated with vascular obstruction events, while this significance was not found in the "model of hemorrhage". CONCLUSIONS: Previous TEG indices are significantly associated with the subsequent vascular obstruction events in the elderly population. Future study can test this association and provide more information for clinical use. PMID- 24795060 TI - Oxidants and anti-oxidants status in acne vulgaris patients with varying severity. AB - Acne vulgaris is a common dermatological disorder with a multifactorial pathogenesis. Oxidative status has been implicated in the pathogenesis of several skin diseases, including acne. This study was aimed to investigate the levels of oxidative stress biomarkers in acne vulgaris patients with varying severities. The study involved 156 patients with acne and 46 healthy human controls. Based on clinical examination, patients were grouped into 3 subgroups as follows: mild, moderate, and severe acne. Oxidative stress was examined by measuring plasma levels of catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC), and malondialdehyde (MDA). Plasma levels of MDA in acne patients were significantly higher as compared with that of the controls, whereas activities of the antioxidant enzymes SOD and CAT were lower. Moreover, TAC was also low in acne patients as compared with that of the controls. Higher MDA levels in the severe acne subgroup as compared with that of the mild and moderate subgroups were also observed. Furthermore, in the severe acne subgroup, a significant negative correlation was observed between MDA and CAT levels. The data suggests that oxidative stress plays a key role in acne progress and may be employed as a biomarker index to assess the disease's activity and to monitor its treatment. PMID- 24795061 TI - Verrucous herpes of the scrotum presenting clinically as verrucous squamous cell carcinoma: case report and review of the literature. AB - We report a case of a 36-year-old man with acquired immunodeficiency syndrome (AIDS) and an enlarging scrotal mass presumed to be of malignant origin but found to be a rare instance of verrucous herpes simplex type 2 infection of the scrotum. We also review the literature on this subject and discuss pathogenesis of the disease. PMID- 24795062 TI - A Korean patient with glutaric aciduria type 1 with a novel mutation in the glutaryl CoA dehydrogenase gene. AB - Mutations in the glutaryl-CoA dehydrogenase gene can result in Glutaric aciduria type 1(GA 1) by accumulation of glutaric acid, 3-hydroxyglutaric acid (3-OH-GA), and glutarylcarnitine (C5DC). GA 1 is characterized by macrocephaly, subdural hemorrhage (SDH), and dystonic movement disorder after acute encephalopathic crisis. We report a Korean patient with GA1 and a novel mutation. A 16-month-old boy presented with SDH, macrocephaly, and developmental delay. In the neurologic examination, the patient had mild axial hypotonia, but otherwise normal neurologic functions. The brain MRI showed large amounts of bilateral SDH and high signal intensity in both basal ganglia and thalamus. Metabolic screening tests detected highly elevated urinary GA levels but 3-OH-glutaric acid was normal. C5DC was 0.94 MUM/L (reference range < 0.3 MUM/L). The patient had compound heterozygous mutations of the GCDH gene: p.Arg257Gln (c.770G>A) and p.Cys308Arg (c.922T>C). p.Cys308Arg is a novel mutation; reports of p.Arg257Gln were also rare both in Caucasians and Asian populations. In summary, we hereby report one Korean patient with GA1 with clinical, biochemical, and radiologic characteristics confirmed by genetic analysis. PMID- 24795063 TI - Primary splenic angiosarcoma associated with anemia, leukocytosis and thrombocytopenia. AB - Primary angiosarcoma of the spleen is a rare neoplasm arising from endothelial cells. It is an aggressive neoplasm with a poor prognosis. We report a case of 61 year-old Caucasian man who presented with shortness of breath, anemia, leukocytosis, and thrombocytopenia. Ultrasound Sonogram (US) and Computed Tomography (CT) scans revealed a massively enlarged spleen with numerous enhancing hypodense lesions. The spleen was adherent to the omentum, retroperitoneum, and tail of the pancreas. Image-guided Fine Needle Aspiration (FNA) revealed an atypical spindle cell lesion. Resection of the spleen and attached tail of pancreas was performed. Histological examination and immunohistochemical studies revealed a diffuse vascular malignant neoplasm with features of angiosarcoma. The patient appeared disease free after resection. He died within 5 months of unknown etiology. PMID- 24795064 TI - Tenosynovial giant cell tumors lacking giant cells: report of diagnostic pitfalls. AB - Tenosynovial giant cell tumors are a group of neoplastic disorders that involve synovium-lined tendon sheaths, synovial joints, and adjacent soft tissue. They are divided into localized and diffuse subtypes. TSGCTs have well-established clinical and histological diagnostic criteria; however, the subtypes and nomenclature can be confusing. They also pose diagnostic challenges when they occur in atypical locations or without multinucleated giant cells. With the possibility for systemic targeted therapy in relapsing pigmented villonodular tenosynovitis and diffuse-type giant cell tumor, accurate diagnosis and subtyping of TSGCTs is increasingly important. We report two cases of TSGCTs in order to elucidate the diagnostic nomenclature, clinicopathological features, differential diagnosis, and diagnostic pitfalls. Recent advancements in the pathogenesis and targeted therapy of TSGCTs are also discussed. PMID- 24795065 TI - First identified Korean family with Sotos syndrome caused by a novel intragenic mutation in NSD1. AB - Sotos syndrome (SS) is a congenital overgrowth syndrome. NSD1 mutations are identifiable in most SS patients. There have been a few reports of familial inheritance of SS worldwide, but no familial cases have been reported in Korea. A 6-month-old girl had tall stature and macrocephaly with mild ventricular enlargement, and showed mild delay in motor and language development. Her mother also had tall stature and a long narrow face. The baby and her mother were suspected of having familial SS. Chromosome 5q35 microdeletion was first ruled out by fluorescence in situ hybridization analysis, and direct sequencing of NSD1 revealed a novel heterozygous mutation in exon 22 (c.6356delA; p.Asp2119Valfs*31). This report describes, for the first time, a Korean family with two generations of SS resulting from a novel intragenic NSD1 mutation. PMID- 24795066 TI - Brief communication: detection of clinical Klebsiella pneumoniae isolates from China containing transferable quinolone resistance determinants exhibiting resistance to both aminoglycoside and beta-lactams. AB - Though aminoglycosides are routinely used clinically as antimicrobial agents for the treatment of severe infections due to Klebsiella pneumoniae, resistance to the same is an increasing problem. One such resistance mechanism is the production of 16S rRNA methylases. The objective of the current study was to investigate the prevalence and molecular epidemology of 16S rRNA methylase genes among 43 K. pneumoniae isolates (each of which had at least one PQMR gene and ciprofloxacin minimum inhibitory concentration greater than 0.25) recovered from nine tertiary hospitals in China. Our results suggest great genetic variation in terms of 16S rRNA methylase gene of K. pneumoniae hosts containing at least one PQMR gene. This further reinforces the clinical and systemic urgency required to characterize and block their transmission routes. PMID- 24795067 TI - Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial. AB - BACKGROUND: Alternative therapeutic options are needed for patients with systemic lupus erythematosus (SLE) not adequately controlled with or intolerant to traditional treatments. This study evaluated the efficacy of Acthar(r) Gel (ACTH(1-39)) for reducing active SLE severity among patients receiving underlying conventional maintenance therapies. METHODS: Ten females (mean age = 49 yrs, disease duration = 7 yrs, Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2 K] = 10) currently on maintenance self-administered ACTH(1-39) gel 1 mL (80 U/mL) for 7-15 days and were assessed weekly for 28 days. Outcome measures included Physician and Patient Global Assessments, SLEDAI-2 K, Lupus Quality of Life scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, erythrocyte sedimentation rate, and C-reactive protein. Student's t-test compared data obtained at days 7, 14, and 28 with those from baseline. RESULTS: The primary endpoint of SLEDAI-2 K improvement was reached at all observation times (p < 0.05) and statistically significant improvements were observed for most other parameters. No treatment-related serious or unexpected adverse events were observed. CONCLUSIONS: The trial results reveal that among SLE patients in need of therapeutic alternatives, ACTH(1-39) gel may provide significant disease activity reduction. PMID- 24795068 TI - The beneficial effect of plasmapheresis in mixed connective tissue disease with coexisting antiphospholipid syndrome. AB - The authors report a rare case of a female patient with mixed connective tissue disease (MCTD) with coexisting antiphospholipid syndrome (APS). Five years after the diagnosis of MCTD high concentrations of anticardiolipin (anti-CL) and anti beta2-glycoprotein (anti-beta2GPI) autoantibodies were present in the patient's serum without thrombotic events. Epstein-Barr virus (EBV) reactivation provoked APS, with the clinical manifestations of livedo reticularis, digital gangrene and leg ulcers. Skin biopsy from the necrotic area showed multiple fibrin microthrombi in the superficial vessels. Corticosteroid pulse therapy, and plasma exchange in combination with synchronized cyclophosphamide was administered, which led to improvement of the digital gangrenes, while no new lesions developed. The number of CD27high plasma cells decreased, and the previous high levels of autoantibodies also normalized in the peripheral blood. In the case of MCTD with coexisting APS combination therapy, including plasmapheresis has beneficial effects. PMID- 24795069 TI - Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia. AB - We investigated the effectiveness and tolerability of azacitidine in patients with World Health Organization-defined myelodysplastic syndromes, or acute myeloid leukemia with 20-30% bone marrow blasts. Patients were treated with azacitidine, with one of three dosage regimens: for 5 days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 days (AZA 7); all 28-day cycles. Overall response rates were 39.4%, 67.9%, and 51.3%, respectively, and median overall survival (OS) durations were 13.2, 19.1, and 14.9 months. Neutropenia was the most common grade 3-4 adverse event. These results suggest better effectiveness-tolerability profiles for 7-day schedules. PMID- 24795070 TI - The GNAS1 gene in myelodysplastic syndromes (MDS). AB - GNAS1 gene is located at the long arm of chromosome 20 (q13.32). GNAS1 gene deletion has never been investigated in MDS. A GNAS1 activating mutation (R201) was recently found in MDS. We applied FISH and DHPLC plus sequencing to investigate GNAS1 gene in MDS cases with and without del(20q) at karyotype. PMID- 24795071 TI - Efficacy of a non-updated, Matrix-C-based equine influenza subunit-tetanus vaccine following Florida sublineage clade 2 challenge. AB - Assessing the ability of current equine influenza vaccines to provide cross protection against emerging strains is important. Horses not vaccinated previously and seronegative for equine influenza based on haemagglutination inhibition (HI) assay were assigned at random to vaccinated (n=7) or non vaccinated (control, n=5) groups. Vaccination was performed twice four weeks apart with a 1 ml influenza subunit (A/eq/Prague/1/56, A/eq/Newmarket/1/93, A/eq/Newmarket/2/93), tetanus toxoid vaccine with Matrix-C adjuvant (EquilisPrequenza Te). All the horses were challenged individually by aerosol with A/eq/Richmond/1/07 three weeks after the second vaccination. Rectal temperature, clinical signs, serology and virus excretion were monitored for 14 days after challenge. There was no pain at the injection site or increases in rectal temperature following vaccination. Increases in rectal temperature and characteristic clinical signs were recorded in the control horses. Clinical signs were minimal in vaccinated horses. Clinical (P=0.0345) and total clinical scores (P=0.0180) were significantly lower in the vaccinated than in the control horses. Vaccination had a significant effect on indicators of viraemia - the extent (P=0.0006) and duration (P=<0.0001) of virus excretion and the total amount of virus excreted (AUC, P=0.0006). Vaccination also had a significant effect (P=0.0017) on whether a horse was positive or negative for virus excretion during the study. Further research is needed to fully understand the specific properties of this vaccine that may contribute to its cross-protective capacity. PMID- 24795072 TI - Correlation between diabetic retinopathy severity and elevated skin autofluorescence as a marker of advanced glycation end-product accumulation in type 2 diabetic patients. AB - AIMS: We evaluated skin autofluorescence (AF) as a marker of tissue advanced glycation end-product (AGE) accumulation and examined whether it was related to the prevalence and severity of diabetic retinopathy (DR) and of diabetic macular edema (DME) in patients with type 2 diabetes mellitus (DM). METHODS: This study included 138 type 2 DM patients consisting of 31 patients with proliferative DR, 71 patients with non-proliferative DR, and 36 patients without retinopathy, in addition to 111 non-DM control subjects. At the time of skin AF and HbA1c measurement, self-assessed duration of DM was also determined. DR and DME stages were classified according to international guidelines. RESULTS: Skin AF was significantly increased in patients with DM as compared with non-DM controls. Furthermore, skin AF was correlated with the severity of DR, whereas single measurement of HbA1c and self-assessed DM duration were not. None of these 3 factors showed a correlation with DME prevalence or severity. CONCLUSIONS: Skin AF levels, which can be measured non-invasively on a screening basis without skin biopsy or blood sampling, have a greater predictive ability for the presence and severity of DR than single measurement of HbA1c or self-assessed DM duration in patients with type 2 DM. PMID- 24795074 TI - Assessment of implementation fidelity in diabetes self-management education programs: a systematic review. AB - OBJECTIVE: As diabetes requires extensive self-care, self-management education is widely recommended to enhance the effectiveness and reduce the costs of treatment. While a variety of diabetes self-management (DSM) programs are available, the conditions for their effective implementation are not well documented. This paper reviews the literature on implementation fidelity (IF), the degree to which programs are delivered as intended, as a factor influencing the effectiveness of diabetes education. METHODS: Medical, psychological and educational research databases were searched to identify published studies on diabetes education describing the implementation process. Studies detailing the intervention adherence/fidelity/integrity were included to assess the way key elements of IF were addressed. RESULTS: From an initial 418 abstracts, 20 published papers were retained for an in-depth analysis focusing on the components of IF. Intervention content was mainly assessed through observation, whereas intervention dose was more often assessed through self-report measures. Only one study addressed the relationship between IF and intervention effectiveness. CONCLUSION: Despite the importance of IF to achieve program outcomes, IF of DSM programs remains largely under-investigated. PRACTICE IMPLICATIONS: The results of this review suggest that reports on DSM education should systematically describe how the program was implemented. The impact of IF on program outcomes needs further investigation. PMID- 24795073 TI - Does improving patient-practitioner communication improve clinical outcomes in patients with cardiovascular diseases? A systematic review of the evidence. AB - OBJECTIVE: To conduct a systematic literature review appraising the effects of interventions to improve patient-practitioner communication on cardiovascular related clinical outcomes. METHODS: Databases were searched up to March 27, 2013 to identify eligible studies that included interventions to improve patient and/or practitioner communication skills and assessment of a cardiovascular related clinical outcome in adults >=18 years of age. RESULTS: Fifteen papers were reviewed: the primary focus in seven studies was the patient; seven included a practitioner-focused intervention and one targeted both. Two patient-focused and two practitioner-focused studies demonstrated a beneficial effect of the intervention compared to a control group. Patient-focused studies were designed to improve patients' information-seeking and question-asking skills with their practitioner. Practitioner-focused studies were designed to either improve practitioner's general patient-centered communication or risk communication skills. CONCLUSION: Few interventions targeting patient-practitioner communication have assessed the impact on cardiovascular-related clinical outcomes, limiting the ability to determine effectiveness. Additional rigorous research supported by theoretical frameworks and validated measurement is needed to understand the potential of patient-practitioner communication to improve cardiovascular-related clinical outcomes. PRACTICE IMPLICATIONS: Investments in communication skills trainings in medical education and practice are needed in order to attain the full potential of patient-centered care on cardiovascular related clinical outcomes. PMID- 24795075 TI - Near-infrared optical imaging of cancer vascular remodeling after antiangiogenic therapy. AB - BACKGROUND: Near-infrared diffuse optical imaging (DOSI) has been recently accepted as a method to assess tumor vascularity and oxygenation by measuring tissue hemoglobin (Hb) concentration. It is expected that DOSI could be used to monitor changes in vascularity after antiangiogenic therapy. METHODS: A patient with advanced breast cancer was treated with single-agent bevacizumab followed by addition of weekly paclitaxel to it. DOSI was performed in the tumor-bearing breast and contralateral normal breast at baseline, 3, 6, 12, 24 h, and then daily for 1 week. Images of a tumor-to-normal ratio of tHb (rtHb) were constructed for identifying a tumor lesion. RESULTS: Serial images of rtHb showed a tumor lesion which corresponded to a hot spot. The level of rtHb rapidly decreased within several hours after administration of single-agent bevacizumab and then persisted at low levels during treatment. From day 2, the value of rtHb gradually increased and peaked on day 5. CONCLUSION: This trend may be explained considering sequential images of rtHb indicating the inhibition of angiogenesis due to antiangiogenic therapy. We conducted a clinical study using single-agent bevacizumab followed by neoadjuvant chemotherapy in primary breast cancer patients to understand vascular remodeling after antiangiogenic agent at very early time points using DOSI. PMID- 24795076 TI - p53 gene therapy of human breast carcinoma: using a transferrin-modified silica nanoparticles. AB - BACKGROUND: Nanoparticles have an enormous potential for development in biomedical applications, such as gene or drug delivery. In our study, we examined the efficacy of p53 gene therapy in human breast carcinoma (MCF-7) cells using silica nanoparticles (SiNPs) supplemented with transferrin. METHODS: MCF-7 cells were exposed to transferrin-SiNPs-p53 in vitro, and the growth inhibition rate, expression of p53 and bax, and induction of apoptosis were measured 48 h later. RESULTS: Treatment of MCF-7 cells with transferrin-SiNPs-p53 resulted in 60.7 % growth inhibition. Wild-type p53 expression and an increase in bax expression were observed following transfection with transferrin-SiNPs-p53, and 20.5 % of the treated MCF-7 cells were apoptotic. In vivo, the MCF-7 tumor transplanted into nude mice grew to 5-6 mm in diameter. Following growth of the tumor to this size, transferrin-SiNPs-p53 was locally applied to the peripheral tumor (day 0) and then applied once every 5 days for a total of six times. During the administration period, tumor growth did not occur, and the mean tumor volume on the last day of administration (day 25) was 10.0 % of that in the saline control group. CONCLUSION: These results suggest that p53 gene therapy via transferrin modified silica nanoparticles is an effective strategy for treatment of breast carcinoma. PMID- 24795077 TI - Validated UPLC method for determination of unbound bile acids in colesevelam HCl tablets. AB - A simple, precise and accurate gradient reverse-phase ultra-performance liquid chromatographic method was developed for the quantitative determination of bile acids [glycocholic acid (GCA), glycochenodeoxycholic acid (GCDA) and taurodeoxycholic acid (TDCA)) in in vitro bile acid-binding study of Welchol tablets. The method was developed using Phenomenex Kinetex C18 (50 * 2.10 mm, 1.7 um) column with mobile phase containing a gradient mixture of solvent A consisting of 0.02 M tetrabutylammonium phosphate (pH 7.5) and solvent B consists acetonitrile. The eluted compounds were monitored at 210 nm and the runtime was within 2 min. The binding parameter constants of Colesevelam HCl tablets 625 mg were determined using the Langmuir approximation at pH 6.8 by UPLC. The method is selective and capable of detecting bile acids in the presence of placebo matrix. The method has been validated with a lower limit of quantitation of 0.01 mM for bile acids. A linear response function was established for the range of concentrations 0.01-30.0 mM (r > 0.99) for GCA, GCDA and TDCA. The intra- and interday precision values for bile acids met the acceptance as per Food and Drug Administrations guidelines. The developed method was applied to in vitro bile acid-binding studies of Colesevelam HCl tablets. PMID- 24795078 TI - Impurity profiling and a stability-indicating UPLC method development and validation for the estimation of related impurities of halobetasol propionate in halobetasol propionate 0.05% (w/w) cream. AB - A simple, short and stability-indicating reverse phase-ultra-performance liquid chromatography method was developed and validated for the quantitative determination of related impurities of halobetasol propionate in halobetasol propionate 0.05% cream formulation. The proposed method was developed on an ACQUITY UPLCTM BEH Phenyl (2.1 * 100 mm, 1.7 um) column at 40 degrees C with a mobile phase containing a gradient mixture of potassium hydrogen phosphate buffer and acetonitrile and methanol as modifiers with a runtime of 13.0 min at a monitored wavelength of 242 nm. A simple preparative method and liquid chromatography-mass spectrometry-compatible UPLC method also were developed for the isolation and identification of impurities and degradation products. The drug was subjected to forced-degradation conditions and found to degrade significantly. The stability-indicating capability of the developed method is established by analyzing forced-degradation samples in which the spectral purity of halobetasol propionate is ascertained along with the separation of degradation products from the analyte peak. The developed method was validated as per International Conference on Harmonization guidelines. The developed method is precise (%relative standard deviation <2.0) and is capable of detecting and quantifying all the six impurities at a level of 0.01 and 0.03%, respectively, with respect to test concentration. The wide linearity range, sensitivity, accuracy, short retention time and simple mobile phase imply that the method is suitable for routine quantification of halobetasol propionate and its related substances. PMID- 24795079 TI - Mucosal immunity and probiotics in fish. AB - Teleost mucosal immunity has become the subject of unprecedented research studies in recent years because of its diversity and defining characteristics. Its immune repertoire is governed by the mucosa-associated lymphoid tissues (MALT) which are divided into gut-associated lymphoid tissues (GALT), skin-associated lymphoid tissues (SALT), and gill-associated lymphoid tissues (GIALT). The direct contact with its immediate environment makes the mucosal surfaces of fish susceptible to a wide variety of pathogens. The inherent immunocompetent cells and factors in the mucosal surfaces together with the commensal microbiota have pivotal role against pathogens. Immunomodulation is a popular prophylactic strategy in teleost and probiotics possess this beneficial feature. Most of the studies on the immunomodulatory properties of probiotics in fish mainly discussed their impacts on systemic immunity. In contrast, few of these studies discussed the immunomodulatory features of probiotics in mucosal surfaces and are concentrated on the influences in the gut. Significant attention should be devoted in understanding the relationship of mucosal immunity and probiotics as the present knowledge is limited and are mostly based on extrapolations of studies in humans and terrestrial vertebrates. In the course of the advancement of mucosal immunity and probiotics, new perspectives in probiotics research, e.g., probiogenomics have emerged. This review affirms the relevance of probiotics in the mucosal immunity of fish by revisiting and bridging the current knowledge on teleost mucosal immunity, mucosal microbiota and immunomodulation of mucosal surfaces by probiotics. Expanding the knowledge of immunomodulatory properties of probiotics especially on mucosal immunity is essential in advancing the use of probiotics as a sustainable and viable strategy for successful fish husbandry. PMID- 24795080 TI - White spot syndrome virus strains of different virulence induce distinct immune response in Cherax quadricarinatus. AB - In this study, we identified three white spot syndrome virus (WSSV) strains (WSSV CN01, WSSV-CN02 and WSSV-CN03) with significant differences in virulence. Among them, WSSV-CN01 caused significant higher and earlier mortality in redclaw crayfish Cherax quadricarinatus, thus was determined as high-virulent, while WSSV CN02 and WSSV-CN03 were moderate-virulent and low-virulent. By investigating the total number of the circulating haemocytes and the activity of immune relative enzymes, we demonstrated that the different virulent WSSV strains induced distinct immune response in the host. Notably, a dramatic reduction of circulating haemocytes was observed in the crayfish infected with WSSV-CN01 and WSSV-CN02 but not WSSV-CN03. Further analysis revealed that cell death induced by WSSV-CN01 and WSSV-CN02 might be responsible for the decrease of circulating haemocytes. PMID- 24795081 TI - Histopathology and stress biomarkers in the clam Venerupis philippinarum from the Venice Lagoon (Italy). AB - The aim of this study was to evaluate the histomorphology and the stress response in the bivalve Venerupis philippinarum sampled in four differently polluted sites of the Venice Lagoon (Palude del Monte, Marghera, Ca' Roman and Val di Brenta). This species is often used as bioindicator of environmental pollution since it can bioaccumulate a large variety of pollutants because of its filter feeding. Chemical analyses for heavy metals (Cd, Cu, Hg and Pb) and polycyclic aromatic hydrocarbons (PAHs) were performed on whole soft tissues of V. philippinarum. The histological evaluation of clams revealed the presence of Perkinsus sp. infection in animals from all sites, although a very high prevalence of parasites was evidenced in clams from Ca' Roman. Perkinsus sp. were systemically distributed in the mantle, in the intestine and digestive gland, in gonads and gills. The trophozoites of Perkinsus sp. were found isolated or in cluster surrounded by a heavy hemocitical response. Haemocytes always exhibited an immunopositivity to cytochrome P4501A (CYP1A), heat shock protein 70 (HSP70), 4-hydroxy-2-nonenal (HNE) and nitrotyrosine (NT) antibodies. The digestive gland of animals from Palude del Monte showed the highest malondialdehyde (MDA) concentration, whereas clams from Ca' Roman exhibited the highest quantity of metallothioneins. PMID- 24795082 TI - Sex-response differences of immunological and histopathological biomarkers in gill of Prochilodus argenteus from a polluted river in southeast Brazil. AB - The fish gill is in direct and standing contact with the immediate external environment and, therefore, is highly vulnerable to aquatic pollutants. In this study, Prochilodus argenteus were caught at two different points in Sao Francisco river. The first point is located near Tres Marias dam, while the second is placed downstream the Abaete river. Chemical approaches showed the presence of metals contamination in the first point. Thus, the main goal of this study was to investigate the possible toxic effects of these contaminants and the likely use of biomarkers on fish gills. Biometric data of length and weight of fish were obtained in order to calculate the condition factor as an organismal biomarker. The histological changes in gills and alterations in mucous and rodlet cells occurrence were detected microscopically and evaluated with quantitative analyses. Myeloperoxidase (MPO) and Eosinophil Peroxidase (EPO) were also assessed in fish gill. The analysis of the water and sediment samples revealed the presence of metals at the two points. As and Cd were detected at higher concentrations at point 1. The presence of lamellar cell hyperplasia, lamellar fusion, lamellar edema and inflammatory foci varied according to the point. Additionally, mucous and rodlet cells and MPO and EPO activities showed variability according to the environmental conditions. Furthermore, with exception of lamellar hyperplasia and eosinophil peroxidase activity, all others parameters showed sex-variation responses. At the first point, male fish showed a chronical inflammation in gills due to the lowest activity of MPO and EPO, as well as low occurrence of inflammatory foci and glycoprotein secretion by mucous cells, while female fish presented an opposite pattern of response to the same environmental conditions. Therefore, we suggest the use of such biomarkers in future monitoring of aquatic systems, taking into account the sex-variation responses. PMID- 24795083 TI - In defence of 'dye therapy'. AB - Worldwide, healthcare is facing enormous problems with the continuing rise of drug-resistant infectious diseases. In view of the scarcity of new antimicrobial agents and the withdrawal of many pharmaceutical houses from the fray, alternative approaches are required. One of these is photoantimicrobial chemotherapy, which is highly effective across the range of microbial pathogens and does not suffer from resistance. However, there is a lack of uptake of this approach by healthcare providers and the pharmaceutical industry alike. It is seldom recalled that, unlike anticancer photodynamic therapy, the development of photoantimicrobial agents has evolved from the antiseptic 'dye therapy' in common use until the widespread introduction of the penicillin class in the mid-1940s. Cationic biological dyes such as methylene blue, crystal violet and acriflavine were effective in local wound therapy and today provide a sound basis for light activated antimicrobial therapeutics. It is proposed that such 'safe' dyes are introduced as locally administered photoantimicrobials, especially in order to conserve valuable conventional antibacterial drugs. PMID- 24795084 TI - Developments in the management of central nervous system tumours. PMID- 24795085 TI - Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease. AB - Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-beta (Abeta1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD. PMID- 24795086 TI - Insulin secretion from beta cells in intact mouse islets is targeted towards the vasculature. AB - AIMS/HYPOTHESIS: We set out to test the hypothesis that insulin secretion from beta cells is targeted towards the vasculature. METHODS: The spatial location of granule fusion was identified by live-cell two-photon imaging of mouse pancreatic beta cells within intact islets, using sulforhodamine B labelling. Three dimensional (3D) immunofluorescence of pancreatic slices was used to identify the location of proteins associated with neuronal synapses. RESULTS: We demonstrated an asymmetric, non-random, distribution of sites of insulin granule fusion in response to glucose and focal targeting of insulin granule secretion to the beta cell membrane facing the vasculature. 3D immunofluorescence of islets showed that structural proteins, such as liprin, piccolo and Rab2-interacting molecule, normally associated with neuronal presynaptic targeting, were present in beta cells and enriched at the vascular face. In contrast, we found that syntaxin 1A and synaptosomal-associated protein 25 kDa (SNAP25) were relatively evenly distributed across the beta cells. CONCLUSIONS/INTERPRETATION: Our results show that beta cells in situ, within intact islets, are polarised and target insulin secretion. This evidence for an 'endocrine synapse' has wide implications for our understanding of stimulus-secretion coupling in healthy islets and in disease. PMID- 24795088 TI - High-quality DNA from fingernails for genetic analysis. AB - The availability of high-quality germline DNA is an important prerequisite for a variety of genetic analyses. We have shown previously that fingernail clippings provide an optimal source of autologous, constitutional DNA for PCR-based applications. However, most existing protocols for nucleic acid purification from nails do not provide sufficiently high yields of pure and intact DNA for more demanding downstream analyses such as next generation sequencing (NGS). We have extensively tested and systematically modified a number of different protocols for DNA purification from nail material to optimize the yield and quality. The integrity of DNA was determined by PCR amplification of short (<300 bp), mid range (>400 bp), and long-range (>2 kb) sequences using different target genes. Among the methods tested, the Prepfiler Forensic DNA Extraction kit was identified as the most appropriate approach to isolation of high-quality DNA from nail clippings. A standardized input of 20 mg nail material (1 to 10 pieces of fingernail clippings) yielded a mean of 1 MUg DNA (range, 0.5 to 2.3 MUg). Subsequent PCR-analysis revealed efficient amplifiability of short and mid-range targets in 93% and 90%, and long-range fragments in 60% of the samples tested. The adequacy for next generation sequencing applications was demonstrated by successful high-resolution HLA-typing in ten transplant recipients. Hence, the protocol presented facilitates the exploitation of fingernail material even for demanding genomic analyses both in research and diagnostics. PMID- 24795087 TI - Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes. AB - Autophagy is a lysosomal degradation pathway recycling intracellular long-lived proteins and damaged organelles, thereby maintaining cellular homeostasis. In addition to inflammatory processes, autophagy has been implicated in the regulation of adipose tissue and beta cell functions. In obesity and type 2 diabetes autophagic activity is modulated in a tissue-dependent manner. In this review we discuss the regulation of autophagy in adipose tissue and beta cells, exemplifying tissue-specific dysregulation of autophagy and its implications for the pathophysiology of obesity and type 2 diabetes. We will highlight common themes and outstanding gaps in our understanding, which need to be addressed before autophagy could be envisioned as a therapeutic target for the treatment of obesity and diabetes. PMID- 24795089 TI - Compositional biases among synonymous substitutions cause conflict between gene and protein trees for plastid origins. AB - Archaeplastida (=Kingdom Plantae) are primary plastid-bearing organisms that evolved via the endosymbiotic association of a heterotrophic eukaryote host cell and a cyanobacterial endosymbiont approximately 1,400 Ma. Here, we present analyses of cyanobacterial and plastid genomes that show strongly conflicting phylogenies based on 75 plastid (or nuclear plastid-targeted) protein-coding genes and their direct translations to proteins. The conflict between genes and proteins is largely robust to the use of sophisticated data- and tree heterogeneous composition models. However, by using nucleotide ambiguity codes to eliminate synonymous substitutions due to codon-degeneracy, we identify a composition bias, and dependent codon-usage bias, resulting from synonymous substitutions at all third codon positions and first codon positions of leucine and arginine, as the main cause for the conflicting phylogenetic signals. We argue that the protein-coding gene data analyses are likely misleading due to artifacts induced by convergent composition biases at first codon positions of leucine and arginine and at all third codon positions. Our analyses corroborate previous studies based on gene sequence analysis that suggest Cyanobacteria evolved by the early paraphyletic splitting of Gloeobacter and a specific Synechococcus strain (JA33Ab), with all other remaining cyanobacterial groups, including both unicellular and filamentous species, forming the sister-group to the Archaeplastida lineage. In addition, our analyses using better-fitting models suggest (but without statistically strong support) an early divergence of Glaucophyta within Archaeplastida, with the Rhodophyta (red algae), and Viridiplantae (green algae and land plants) forming a separate lineage. PMID- 24795090 TI - International Committee for Monitoring Assisted Reproductive Technologies world report: Assisted Reproductive Technology 2006. AB - STUDY QUESTION: What are the access, effectiveness and safety of assisted reproductive technology (ART) worldwide in 2006? SUMMARY ANSWER: ART access, effectiveness and safety vary markedly among countries. Overall, there was an increase in the use of ICSI, single embryo transfer (SET) and frozen embryo transfer (FET). There was a decline in the multiple delivery rate (DR) and preterm birth rate. WHAT IS KNOWN ALREADY: ART is widely practiced worldwide and there is a need for its continuous monitoring to improve the comprehensiveness and quality of ART data and services. STUDY DESIGN, SIZE, DURATION: This is a retrospective, cross-sectional survey of ART cycles undertaken worldwide in 2006. PARTICIPANTS, SETTING, METHODS: A total of 2352 clinics in 56 countries provided data. Data were analyzed at a country and regional level. The forms for data collection were developed by the International Committee Monitoring Assisted Reproductive Technologies (ICMART) and sent to each country or regional ART register. MAIN RESULTS AND THE ROLE OF CHANCE: A total of >1,050,300 initiated cycles resulted in an estimated >256,668 babies. The overall pregnancy rates (PRs) and DRs per aspiration for IVF were 30.7 and 22.8%, respectively, and for ICSI 29.7 and 20.0%, respectively. The PRs and DRs for FETs were 26.4 and 17.8%, respectively. Multiple DR per PR were 22.2% for twins and 1.5% for triplets following fresh IVF/ICSI and 16.4% for twins and 0.8% for triplets for FETs. Ovarian hyperstimulation syndrome complicated >4585 cycles (0.6%). Access to ART varied from 11 to 3988 cycles per million population. ICSI comprised 66.0% of all initiated cycles, FET 27.4% and SET 20.7%. Perinatal mortality rate was 25.2 per 1000 births for fresh IVF/ICSI and 17.5 per 1000 for FETs. LIMITATIONS, REASONS FOR CAUTION: 44.6% of the countries provided incomplete data. Quality of data varies among individual countries and is dependant on the policy of the local regulatory authority for monitoring ART clinics. Continuous efforts are needed to improve comprehensiveness and quality of data collected. WIDER IMPLICATIONS OF THE FINDINGS: Adopting the policy of SET, FET and the cessation of transferring more than two embryos should be widely applied. ICMART will continue helping countries and regions to establish their own ART registries. STUDY FUNDING/COMPETING INTEREST(S): ICMART receives financial support from medical societies: European Society for Human Reproduction and Embryology (ESHRE), American Society for Reproduction Medicine (ASRM), Fertility Society of Australia (FSA), Japan Society for Reproductive Medicine (JSRM), Latin American Network for Reproductive Medicine (REDLARA) and Middle East Fertility Society (MEFS) and Society for Assisted Reproductive Technology (SART). All authors have no conflict of interest in relation to this work. We declare no support or financial relationship with any organizations or any activities that could appear to have influenced the submitted work. PMID- 24795091 TI - Semen analysis and prediction of natural conception. AB - STUDY QUESTION: Do two semen analyses predict natural conception better than a single semen analysis and will adding the results of repeated semen analyses to a prediction model for natural pregnancy improve predictions? SUMMARY ANSWER: A second semen analysis does not add helpful information for predicting natural conception compared with using the results of a single semen analysis and addition of the second analysis to a prediction model for natural conception did not improve predictions. WHAT IS KNOWN ALREADY: A major problem with semen analyses is the large variability of results within an individual. High-quality evidence is lacking on how many semen analyses need to be performed during the fertility workup to achieve an accurate prediction of conception. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cohort study of 897 consecutive couples presenting with subfertility in two university hospitals in the period 2002-2004 in the Netherlands. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: The laboratories scored sperm parameters according to the 1999 WHO criteria. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of *200. All assessments were performed by trained laboratory technicians. Follow-up started at the completion of the infertility workup and ended after 12 months. Primary end-point was natural conception resulting in an ongoing pregnancy. We constructed models for three strategies for the prediction of natural conception, using univariable and multivariable Cox hazard regression analyses. We evaluated the performance of the three strategies by comparing goodness-of-fit, discrimination and calibration. First, we analysed the semen parameters only. Secondly, we analysed the semen parameters in addition to the multivariable Hunault prediction model. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 897 couples, 132 (15%) achieved a pregnancy by natural conception. Using the results of a single semen analysis only, the calculated probabilities of natural conception within 12 months across the study population ranged from 0.12 to 0.38, with a median of 0.16 (IQR: 0.16-0.17). Using the results of two semen analyses did not lead to a better goodness-of-fit. Discriminative capacity was rather poor, with an area under the ROC curve (AUC) ranging from 0.51 to 0.56. Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration. Using the results of two semen analyses in combination with the Hunault model did not significantly increase goodness-of-fit compared with using a single semen analysis. The Hunault model with the addition of the semen parameters fitted the data significantly better than the Hunault model itself (difference in -2 Log likelihood: 13; 3 df; P = 0.002). Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration. LIMITATIONS, REASONS FOR CAUTION: The academic setting possibly explains the relatively low natural conception rates, with only 15% achieving a natural conception within 1 year. Men with azoospermia were excluded. WIDER IMPLICATIONS OF THE FINDINGS: Performing more than one semen analysis will not increase the prognostic power of the test in clinical practice. Adding the first semen analysis to the Hunault model for the prediction of natural conception improved performance significantly compared with using the Hunault model alone. External validation, in other populations, should follow to confirm our conclusions, and to evaluate the generalizability or transportability of the extended Hunault model. STUDY FUNDING/COMPETING INTEREST(S): No external funding was involved in this study. None of the authors has any conflict of interest to declare. PMID- 24795093 TI - Platelet-rich plasma: applications in dermatology. AB - In recent years, the use of platelet-rich plasma has increased notably in a range of diseases and settings. Uses of these products now go beyond skin rejuvenation therapy in patients with facial ageing. Good outcomes for other dermatological indications such as skin ulcers and, more recently, alopecia have been reported in case series and controlled studies. However, these indications are not currently included in the labeling given that stronger scientific evidence is required to support their real benefits. With the increased use of these products, dermatologists need to become familiar with the underlying biological principles and able to critically assess the quality and outcomes of the studies of these products in different skin diseases. PMID- 24795092 TI - Clinical efficacy of intravenous doripenem in patients with acute biliary tract infection: a multicenter, randomized, controlled trial with imipenem/cilastatin as comparator. AB - BACKGROUND: We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of intravenous doripenem (DRPM) in patients with biliary tract infection requiring biliary drainage in comparison with imipenem/cilastatin (IPM/CS). METHODS: After the initial collection of bile, patients were randomly assigned by the registration system of the Clinical Research Organization to receive intravenous drip infusion of DRPM 0.5 g or IPM/CS 0.5 g three times daily in a randomized, open-label manner. RESULTS: A total of 127 patients were enrolled in the trial (DRPM 62, IPM/CS 65). The characteristics of the 122 patients evaluated for efficacy were well balanced, except for the percentage of patients previously receiving antimicrobials, which was higher in the DRPM group than in the IPM/CS group. The clinical response rate was not significantly different between the DRPM group (93.1 %, 54/58 patients) and the IPM/CS group (93.8 %, 60/64). Non-inferiority assessment using confidence intervals demonstrated the non-inferiority of DRPM-IPM/CS. The incidence of adverse events, for which a causal relationship with either treatment was not ruled out, was 3.3 % (2/60) in the DRPM group and 3.1 % (2/65) in the IPM/CS group, and none was serious. CONCLUSIONS: The clinical efficacy of DRPM in treating moderate or severe biliary tract infection requiring drainage was comparable to that of IPM/CS. DRPM was associated with no serious adverse events and a low incidence of adverse events. The results of this trial demonstrate that DRPM is a useful therapeutic option for moderate or severe biliary tract infection. PMID- 24795094 TI - Impact of the RHANI Wives intervention on marital conflict and sexual coercion. AB - OBJECTIVE: To assess the effects of the RHANI (Reducing HIV among Non-Infected) Wives intervention on marital conflict and intimate partner violence (IPV) in urban India. METHODS: A 2-armed cluster-randomized controlled trial (7 intervention, 6 control clusters) of the RHANI Wives intervention was conducted with 220 women contending with a history of IPV and/or husband's drunken behavior. Participants were surveyed at baseline and 4.5-month follow-up. Outcome measures included marital conflict (arguments with husband in past 3 months), marital IPV (physical or sexual violence from husband in past 3 months), and marital sexual coercion (husband forcing sex at last sex). Intention-to-treat logistic generalized linear mixed models were used to determine intervention impact. RESULTS: One-third (35.0%) of participants reported physical or sexual abuse from their husband in the past 3 months, and 58.6% reported that their husband was drunk in the past 30 days. Intention-to-treat analyses indicated time*treatment reductions in marital conflict (risk ratio [RR] 0.4; 90% confidence interval [CI], 0.1-0.9; P=0.06) and marital sexual coercion (RR 0.2; 90% CI, 0.05-0.9; P=0.08), but not IPV. CONCLUSION: The findings suggest the potential utility of this intervention in reducing marital conflict and sexual coercion among women in urban India. ClinicalTrials.gov: NCT01592994. PMID- 24795095 TI - Predicting cardioembolic stroke with the B-type natriuretic peptide test: a systematic review and meta-analysis. AB - BACKGROUND: We performed a systematic review and meta-analysis to evaluate the value of B-type natriuretic peptide (BNP) in differentiating cardioembolic (CE) stroke from other subtypes of ischemic stroke. METHODS: We searched the EMBASE, MEDLINE, and Cochrane databases and reference lists of relevant articles published in April 2013. We selected original studies reporting the performance of BNP or N-terminal probrain natriuretic peptide (NT-proBNP) in diagnosing CE stroke and summarized test performance characteristics using forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random-effect models. RESULTS: Data from 2958 patients with ischemic stroke were retrieved from 16 studies. Of these, 1024 (34.6%) patients had a final diagnosis of CE stroke. Overall, the mean diagnostic odds ratio (DOR) of BNP for CE stroke was 15.8 (95% confidence interval [CI]: 9.92-25.20). Even after adjustment for multiple clinical predictors, serum natriuretic peptide levels showed a strong association with CE stroke (pooled adjusted DOR, 12.7; 95% CI: 7.32-22.0). The sensitivity and specificity of BNP for CE stroke were .78 (95% CI: .71-.87) and .83 (95% CI: .77-.87), respectively. A single BNP-negative result may be sufficient to exclude a diagnosis of CE stroke in low-prevalence (<20%) settings. Subgroup analysis showed that NT-proBNP had a slightly higher specificity (.87; 95% CI: .77-.93) and better capability for exclusion diagnosis. There was a lack of homogeneity in the timing of measurement and BNP assay method. CONCLUSIONS: BNP has reasonable accuracy in the diagnosis of CE stroke and may be a useful marker for the early detection in patients who may benefit from preventive anticoagulation therapy. PMID- 24795096 TI - Diffusion-weighted imaging at b1000 for identifying intracerebral hemorrhage: preliminary sensitivity, specificity, and inter-rater variability. AB - BACKGROUND: Noncontrast computed tomography (NCCT) is the gold standard to detect intracerebral hemorrhage (ICH) and ischemic stroke (IS) in patients presenting with acute focal syndromes. Diffusion-weighted magnetic resonance imaging (DW MRI) obtained at b1000 is highly sensitive to identify acute IS but its sensitivity and specificity to detect ICH has not been systematically studied. METHODS: Patients with a diagnosis of ICH on NCCT were prospectively enrolled and underwent DW-MRI at b1000. Patients with suspected ischemia and a negative NCCT served as controls. All diffusion-weighted imaging (DWI) scans were evaluated blindly by 4 experienced raters. Sensitivity, specificity, and inter-rater variability of the DWI b1000 scans for detection of ICH were determined. RESULTS: In this preliminary pilot study, 15 patients with ICH and 17 patients with IS were included. All ICH lesions seen on NCCT showed a typical pattern on DW-MRI at b1000 with a hypointense core surrounded by a hyperintense rim. ICH volumes and size were similar on NCCT and MRI. All cases of IS were identified on the DWI scans but none were apparent on NCCT. The mean sensitivity and specificity of DW MRI at b1000 for ICH were 94% and 93.5%, respectively, and the inter-rater variability for ICH detection on DWI was excellent (kappa = .84). CONCLUSIONS: DW MRI at b1000 has a diagnostic yield similar to NCCT for detecting ICH and superior to NCCT for detecting IS. Therefore, DW-MRI may be considered as the initial screening tool for imaging patients presenting with focal neurologic symptoms suggestive of stroke. PMID- 24795097 TI - Exported mycoplasmal proteins: proteome of extracellular membrane vesicles of Acholeplasma laidlawii PG8. PMID- 24795098 TI - The spectral-kinetic indicators of relaxation processes following the electron stabilization into the acceptor compartment of photosynthetic RCs of bacteria. PMID- 24795099 TI - Stress-induced changes in membrane sterols in wheat roots. PMID- 24795100 TI - Isolation of luminescence system from the luminescent fungus Neonothopanus nambi. PMID- 24795101 TI - Identification of additional telomerase component of the yeast H. polymorpha is a step towards understanding the complex at the atomic level. PMID- 24795102 TI - Functional significance of the human nucleolar protein SURF6, the key member of the SURF6 protein family in eukaryotes. PMID- 24795103 TI - Repair of apurinic/apyrimidinic sites in single-stranded DNA initiated by tyrosyl DNA phosphodiesterase 1. PMID- 24795104 TI - Isolation and properties of fibrinolytic subtilisin-like serine protease secreted by the Bacillus subtilis strain B-2805. PMID- 24795105 TI - The rate of transcription in Arabidopsis chloroplasts depends on activity of alternative electron transfer pathway in mitochondria. PMID- 24795106 TI - The combination of ribavirin and ozeltamivir effectively inhibits reproduction of influenza A virus resistant to rimantadine (amantadine) in vitro and in vivo. PMID- 24795107 TI - iTRAQ-based quantitative proteomics study on the neuroprotective effects of extract of Acanthopanax senticosus harm on SH-SY5Y cells overexpressing A53T mutant alpha-synuclein. AB - Extract of Acanthopanax senticosus harms (EAS) has been shown to have neuroprotective effects on Parkinson's disease (PD) cell model against alpha synuclein overexpression and toxicity. However, studies of its anti-PD mechanism are challenging, owing to the complex pathophysiology of PD, and complexity of EAS with multiple constituents acting on different proteomic pathways. Here, we have investigated the proteomic profiles and potential biomarkers in a cell model of A53T mutant alpha-synuclein (A53T-alpha-Syn) overexpression after treatment of EAS. Using an iTRAQ (isobaric tags for relative and absolute quantitation)-based proteomics research approach, we identified 3425 modulated proteins, out of which 84 were found to be altered by A53T-alpha-Syn and considered as potential biomarkers. After treatment with EAS, the group showed the tendency to correct the abnormal expressions of 16 proteins out of 84 potential biomarkers, which were associated with the formation of Lewy body, mitochondrial energy metabolism, protein synthesis and apoptosis, etc. This study indicated that EAS might be a promising candidate for prevention or treatment of PD by regulating the related proteomic pathways in A53T-alpha-Syn transgenic SH-SY5Y cells. PMID- 24795108 TI - Apomorphine attenuates ethanol-induced neurodegeneration in the adult rat cortex. AB - Apomorphine, therapeutically used for Parkinson's disease, is a dopamine D1/D2 receptor agonist that has been determined to be a potent antioxidant and to prevent the reaction of free radicals in the brain. Alcohol is a neurotoxic agent that induces neurodegeneration possibly through the generation of free radicals. In this study, we investigated the antioxidant potential of apomorphine upon ethanol-induced neurodegeneration in the cortex of adult rats. Ethanol-induced apoptotic neurodegeneration was measured via the suppression of Bcl-2, the induction of Bax, the release of cytochrome C and the activation of caspase-9 and caspase-3. Moreover, ethanol-induced elevated levels of cleaved PARP-1 indicated exaggerated neuronal DNA damage. Our results demonstrated the neuroprotective effect of apomorphine by reversing the ethanol-induced apoptotic trend as observed by the increased expression of Bcl-2, down regulation of Bax, inhibition of mitochondrial cytochrome C release and inhibition of activated caspase-9 and caspase-3. Moreover, apomorphine treatment further decreased the expression of cleaved PARP-1 to reveal a reduction in ethanol-induced neuronal damage. Immunohistochemical analysis and Nissl staining also revealed neuroprotective effect of apomorphine after ethanol-induced neuronal cell death. In this study, our results indicated that apomorphine at doses of 1 and 5mg/kg has neuroprotective effects for ethanol-induced neuronal damage. Finally, we can conclude that apomorphine has effective therapeutic potential to protect the brain against ethanol-induced neurotoxicity. PMID- 24795110 TI - Control of crystalline proton-conducting pathways by water-induced transformations of hydrogen-bonding networks in a metal-organic framework. AB - Structure-defined metal-organic frameworks (MOFs) are of interest because rational design and construction allow us to develop good proton conductors or possibly control the proton conductivity in solids. We prepared a highly proton conductive MOF (NH4)2(adp)[Zn2(ox)3].nH2O (abbreviated to 1.nH2O, adp: adipic acid, ox: oxalate, n = 0, 2, 3) having definite crystal structures and showing reversible structural transformations among the anhydrate (1), dihydrate (1.2H2O), and trihydrate (1.3H2O) phases. The crystal structures of all of these phases were determined by X-ray crystallography. Hydrogen-bonding networks consisting of ammonium ions, water molecules, and carboxylic acid groups of the adipic acids were formed inside the two-dimensional interlayer space in hydrated 1.2H2O and 1.3H2O. The crystal system of 1 or 1.2H2O (P21/c, No. 14) was changed into that of 1.3H2O (P1, No. 2), depending on water content because of rearrangement of guests and acidic molecules. Water molecules play a key role in proton conduction as conducting media and serve as triggers to change the proton conductivity through reforming hydrogen-bonding networks by water adsorption/desorption processes. Proton conductivity was consecutively controlled in the range from ~10(-12) S cm(-1) (1) to ~10(-2) S cm(-1) (1.3H2O) by the humidity. The relationships among the structures of conducting pathways, adsorption behavior, and proton conductivity were investigated. To the best of our knowledge, this is the first example of the control of a crystalline proton conducting pathway by guest adsorption/desorption to control proton conductivity using MOFs. PMID- 24795109 TI - The role of nitric oxide on visual-evoked potentials in MPTP-induced Parkinsonism in mice. AB - The present study aimed to elucidate visual evoked potentials (VEP) changes in MPTP induced Parkinson's disease (PD) and investigate the possible benefical effects of neuronal (n) and inducible (i) nitric oxide synthase (NOS) inhibitors on altered VEPs, lipid peroxidation and apoptosis. 3 months old C57BL/6 mice were randomly divided into 6 groups which included control (C), 7-nitra indazole treated (7-NI), S-methylisothiourea (SMT) treated, 1,2,3,6-tetrahydropyridine (MPTP) treated, 7-NI+MPTP treated and SMT+MPTP treated. Motor activity of mice was evaluated via the pole test. At the end of the experimental period VEPs were recorded, brain and retina tissues were removed for biochemical analysis. Dopaminergic neuron death at substantia nigra (SN) was determined by immunohistochemical analysis of tyrosine hydroxylase (TH). Immunohistochemical staining was also performed to determine iNOS and nNOS in all tissue sections. Mice with experimental PD exhibited decreased motor activity. Dopaminergic cell death at pars compacta of SN (SNpc) was significantly increased in MPTP treated group compared to control. Diminished Parkinsonism symptoms were observed in 7 NI+MPTP and SMT+MPTP groups. Treatment with 7-NI and SMT decreased dopaminergic cell death in MPTP treated mice. Caspase-3 activity, nitrite/nitrate and 4 hydroxynonenal (4-HNE) levels were significantly increased in SN of MPTP treated mice compared to control. Treatment with 7-NI and SMT significantly decreased elevated caspase-3 activity, nitrite/nitrate and 4-HNE levels in SN of MPTP treated mice. No significant difference in above parameters were observed in the retina. VEP latencies were significantly prolonged in MPTP group compared to control group. 7-NI and SMT treatment caused a significant decrease in VEP latencies in MPTP treated mice compared to none treated MPTP group. This data shows that 7-NI and SMT improves prolonged VEP latencies. The protective effects of 7-NI and SMT on VEP alterations can be related to decreased dopaminergic cell death and reduced lipid peroxidation. PMID- 24795111 TI - Chemotherapy-induced hand-foot syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. AB - Chemotherapy-induced hand-foot syndrome and nail changes are common complications of many classic chemotherapeutic agents and the newer molecular targeted therapies. They significantly impact patient quality of life, and frequently necessitate chemotherapy dose intensity modification or reduction. We aim to describe the epidemiology, pathogenesis, clinical presentation, and current evidence-based treatment options for these entities. PMID- 24795112 TI - Cardiovascular risk functions: usefulness and limitations. PMID- 24795113 TI - Comments on the 2013 ESC guidelines on the management of stable coronary artery disease. PMID- 24795114 TI - Comments on the ESC guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the european society for the study of diabetes. PMID- 24795115 TI - Impact of using different SCORE tables for estimating cardiovascular risk. AB - INTRODUCTION AND OBJECTIVES: In Spain, various SCORE tables are available to estimate cardiovascular risk: tables for low-risk countries, tables calibrated for the Spanish population, and tables that include high-density lipoprotein values. The aim of this study is to assess the impact of using one or another SCORE table in clinical practice. METHODS: In a cross-sectional study carried out in two primary health care centers, individuals aged 40 to 65 years in whom blood pressure and total cholesterol levels were recorded between March 2010 and March 2012 were selected. Patients with diabetes or a history of cardiovascular disease were excluded. Cardiovascular risk was calculated using SCORE for low-risk countries, SCORE with high-density lipoprotein cholesterol, and the calibrated SCORE. RESULTS: Cardiovascular risk was estimated in 3716 patients. The percentage of patients at high or very high risk was 1.24% with SCORE with high density lipoprotein cholesterol, 4.73% with the low-risk SCORE, and 15.44% with the calibrated SCORE (P<.01). Treatment with lipid-lowering drugs would be recommended in 10.23% of patients using the calibrated SCORE, 3.12% of patients using the low-risk SCORE, and 0.67% of patients using SCORE with high-density lipoprotein cholesterol. CONCLUSIONS: The calibrated SCORE table classifies a larger number of patients at high or very high risk than the SCORE for low-risk countries or the SCORE with high-density lipoprotein cholesterol. Therefore, its use would imply treating more patients with lipid-lowering medication. Validation studies are needed to assess the most appropriate SCORE table for use in our setting. PMID- 24795116 TI - Prognostic value of body mass index and waist circumference in patients with chronic heart failure (Spanish REDINSCOR Registry). AB - INTRODUCTION AND OBJECTIVES: To analyze the association between higher body mass index and waist circumference, and the prognostic values of both indicators in total and cardiac mortality in patients with chronic heart failure. METHODS: The study included 2254 patients who were followed up for 4 years. Obesity was classified as a body mass index >=30 and overweight as a body mass index of 25.0 29.9. Central obesity was defined as waist circumference >=88 cm for women and >=102cm for men. Independent predictors of total and cardiac mortality were assessed in a multivariate Cox model adjusted for confounding variables. RESULTS: Obesity was present in 35% of patients, overweight in 43%, and central obesity in 60%. Body mass index and waist circumference were independent predictors of lower total mortality: hazard ratio=0.84 (P<.001) and hazard ratio=0.97 (P=.01), respectively, and lower cardiac death (body mass index, hazard ratio=0.84, P<.001; waist circumference, hazard ratio=0.97, P=.01). The interaction between body mass index and waist circumference (hazard ratio=1.001, P<.01) showed that the protective effect of body mass index was lost in patients with a waist circumference >120cm. CONCLUSIONS: Mortality was significantly lower in patients with a high body mass index and waist circumference. The results also showed that this protection was lost when these indicators over a certain limit. PMID- 24795117 TI - Clinical benefit of cardiac resynchronization therapy with a defibrillator in patients with an ejection fraction > 35% estimated by cardiac magnetic resonance. AB - INTRODUCTION AND OBJECTIVES: Cardiac resynchronization therapy with a defibrillator prolongs survival and improves quality of life in advanced heart failure. Traditionally, patients with ejection fraction > 35 estimated by echocardiography have been excluded. We assessed the prognostic impact of this therapy in a group of patients with severely depressed systolic function as assessed by echocardiography but with an ejection fraction > 35% as assessed by cardiac magnetic resonance. METHODS: We analyzed consecutive patients admitted for decompensated heart failure between 2004 and 2011. The patients were in functional class II-IV, with a QRS >= to 120 ms, ejection fraction <= 35% estimated by echocardiography, and a cardiac magnetic resonance study. We included all patients (n=103) who underwent device implantation for primary prevention. Ventricular arrhythmia, all-cause mortality and readmission for heart failure were considered major cardiac events. The patients were divided into 2 groups according to systolic function assessed by magnetic resonance. RESULTS: The 2 groups showed similar improvements in functional class and ejection fraction at 6 months. We found a nonsignificant trend toward a higher risk of all cause mortality in patients with systolic function <= 35% at long-term follow-up. The presence of a pattern of necrosis identified patients with a worse prognosis for ventricular arrhythmias and mortality in both groups. CONCLUSIONS: We conclude that cardiac resynchronization therapy with a defibrillator leads to a similar clinical benefit in patients with an ejection fraction <= 35% or > 35% estimated by cardiac magnetic resonance. Analysis of the pattern of late gadolinium enhancement provides additional information on arrhythmic risk and long-term prognosis. PMID- 24795118 TI - Characteristics and outcomes of transposition of great arteries in the neonatal period. AB - INTRODUCTION AND OBJECTIVES: Transposition of the great arteries is a prevalent congenital heart defect with a high survival rate and a good long-term outcome, especially if managed with early surgical intervention during the neonatal period. In this study, our main objective was to describe patient characteristics and outcomes and to identify possible predictors of early and long-term morbidity and mortality. METHODS: Retrospective analysis through review of clinical and surgical charts of patients with transposition of the great arteries admitted to the service of neonatology during 2000-2011. RESULTS: The study included 136 patients; 119 of them had undergone corrective surgery during the neonatal period. Patients were divided into 3 groups: group I, 81 cases of isolated transposition; group II, 24 cases with ventricular septal defect; and group III, 31 with "complex" transposition of the great arteries. The overall postoperative survival was 96.7% (115 of 119 patients); no patients from group I died after surgery. Duration of surgery, intubation, inotropic treatment, and length of stay were higher in patients in groups II and III. The overall survival rate after an average of 6 years of follow-up was 90.4% 123 of 136 patients, with no deaths after discharge in group I. The most frequent residual defect during cardiac follow-up was supravalvular pulmonary stenosis, in 33 of 113 patients that had follow-up data. CONCLUSIONS: In our study, the survival rate was high in patients with transposition of great arteries and especially in those undergoing arterial switch. The number of subsequent residual heart defects was low. PMID- 24795119 TI - Update on ischemic heart disease and critical care cardiology. AB - This article summarizes the main developments reported in 2013 on ischemic heart disease, together with the most important innovations in the management of acute cardiac patients. PMID- 24795120 TI - Update on cardiac imaging techniques 2013. AB - Cardiac imaging is a cornerstone of diagnosis in heart conditions, and an essential tool for assessing prognosis and establishing treatment decisions. This year, echocardiography stands out as a guide in interventional procedures and in choosing the size of the prosthesis. It is also proving to be a valuable technique in low-flow, low-gradient aortic stenosis. Three-dimensional echocardiography is advancing our knowledge of cardiac anatomy and valvular measurements. The parameters indicating tissue deformation have predictive power in valve disease and in the follow-up of drug-induced cardiotoxicity. Single photon emission computed tomography and positron emission tomography are proving useful in ischemic heart disease and in the diagnosis of cardiac inflammation and infections. The role of computed tomography has been strengthened in noninvasive coronary angiography, the emergency room management of chest pain, assessment of chronic occlusions, and morphologic study of coronary plaque. Cardiac magnetic resonance imaging remains the gold standard for tissue characterization in ischemic heart disease and cardiomyopathies, and is assuming a greater role in stress studies and in the assessment of myocardial viability. PMID- 24795123 TI - Acute coronary syndromes. New diagnostic strategies and treatment. PMID- 24795124 TI - The epidemiology of coronary heart disease. AB - Understanding the societal impact and trends of coronary heart disease through basic epidemiological measures is essential to evaluate treatment effectiveness and organize resource distribution. In the following narrative review, data are presented on the prevalence, incidence, and prognosis of coronary heart disease in general and of acute coronary syndrome in particular. PMID- 24795125 TI - Giant posterior left ventricular pseudoaneurysm. PMID- 24795126 TI - Pseudodextrocardia secondary to diaphragmatic hernia. PMID- 24795127 TI - An unusual case of single coronary artery. PMID- 24795128 TI - Usefulness of genetic diagnosis in a woman with hypertrophic cardiomyopathy and the desire for motherhood. PMID- 24795129 TI - Use of antithrombotic therapy according to CHA2DS2-VASc score in patients with atrial fibrillation in primary care. PMID- 24795130 TI - Glycemic control using individualized targets among diabetic patients in Spain: a population-based study. PMID- 24795131 TI - Wolff-Parkinson-White syndrome: could a normal PJ interval exclude bundle branch block? PMID- 24795132 TI - Appropriate use criteria for cardiopulmonary exercise testing in patients with cardiac resynchronization devices. PMID- 24795133 TI - Appropriate use criteria for cardiopulmonary exercise testing in patients with cardiac resynchronization devices. Response. PMID- 24795134 TI - Comments on the analysis of telephone calls to a heart failure unit: reasons for the call and resource use. PMID- 24795135 TI - Comments on the analysis of telephone calls to a heart failure unit: reasons for the call and resource use. Response. PMID- 24795136 TI - Massive left ventricular calcification: related to endomyocardial fibrosis or idiopathic? PMID- 24795137 TI - Atrial fibrillation in cryptogenic stroke: new tools needed for diagnosis? PMID- 24795138 TI - Massive left ventricular calcification: related to endomyocardial fibrosis or idiopathic? Response. PMID- 24795140 TI - Can we predict mutant neoepitopes in human cancers for patient-specific vaccine therapy? PMID- 24795141 TI - The dose-dependent tumor targeting of antibody-IFNgamma fusion proteins reveals an unexpected receptor-trapping mechanism in vivo. AB - Cytokines often display substantial toxicities at low concentrations, preventing their escalation for therapeutic treatment of cancer. Fusion proteins comprising cytokines and recombinant antibodies may improve the anticancer activity of proinflammatory cytokines. Murine IFNgamma was appended in the diabody format at the C-terminus of the F8 antibody, generating the F8-IFNgamma fusion protein. The F8 antibody is specific for the extra-domain A (EDA) of fibronectin, a tumor associated antigen that is expressed in the vasculature and stroma of almost all tumor types. Tumor-targeting properties were measured in vivo using a radioiodinated preparation of the fusion protein. Therapy experiments were performed in three syngeneic murine models of cancer [F9 teratocarcinoma, WEHI 164 fibrosarcoma, and Lewis lung carcinoma (LLC)]. F8-IFNgamma retained the biologic activity of both the antibody and the cytokine moiety in vitro, but, unlike the parental F8 antibody, it did not preferentially localize to the tumors in vivo. However, when unlabeled F8-IFNgamma was administered before radioiodinated F8-IFNgamma, a selective accumulation at the tumor site was observed. F8-IFNgamma showed dose-dependent anticancer activity with a clear superiority over untargeted recombinant IFNgamma. The anticancer activity was potentiated by combining with F8-IL4 without additional toxicities, whereas combination of F8-IFNgamma with F8-TNF was lethal in all mice. Unlike other antibody-cytokine fusions, the use of IFNgamma as payload for anticancer therapy is associated with a receptor-trapping mechanism, which can be overcome by the administration of a sufficiently large amount of the fusion protein without any detectable toxicity at the doses used. PMID- 24795143 TI - Antibiotic prophylaxis for vesicoureteral reflux--answers, yet questions. PMID- 24795142 TI - Antimicrobial prophylaxis for children with vesicoureteral reflux. AB - BACKGROUND: Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. METHODS: In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. RESULTS: Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. CONCLUSIONS: Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.). PMID- 24795144 TI - Functional anatomy and ion regulatory mechanisms of the antennal gland in a semi terrestrial crab, Ocypode stimpsoni. AB - Brachyuran crabs from diverse habitats show great differences in their osmoregulatory processes, especially in terms of the structural and physiological characteristics of the osmoregulatory organs. In crustaceans, the antennal glands are known to be important in osmoregulation, and they play a functional role analogous to that of the vertebrate kidney. Nevertheless, the detailed structure and function of the antennal glands in different species have rarely been described. The aim of this study is to investigate the role of the antennal gland in ion regulation by examining the ultrastructure of the cells and the distribution of the ion regulatory proteins in each cell type in the antennal gland of a semi-terrestrial crab. The results showed that Na(+), K(+)-ATPase activity significantly increased in the antennal gland after a 4-day acclimation in dilute seawater and returned to its original (day 0) level after 7 days. Three major types of cells were identified in the antennal gland, including coelomic cells (COEs), labyrinthine cells (LBRs) and end-labyrinthine cells (ELBRs). The proximal tubular region (PT) and distal tubular region (DT) of the antennal gland consist of LBRs and COEs, whereas the end tubular region (ET) consists of all three types of cells, with fewer COEs and more ELBRs. We found a non-uniform distribution of NKA immunoreactivity, with increasing intensity from the proximal to the distal regions of the antennal gland. We summarise our study with a proposed model for the urine reprocessing pathway and the role of each cell type or segment of the antennal gland. PMID- 24795145 TI - Aggresome formation is regulated by RanBPM through an interaction with HDAC6. AB - In conditions of proteasomal impairment, the build-up of damaged or misfolded proteins activates a cellular response leading to the recruitment of damaged proteins into perinuclear aggregates called aggresomes. Aggresome formation involves the retrograde transport of cargo proteins along the microtubule network and is dependent on the histone deacetylase HDAC6. Here we show that ionizing radiation (IR) promotes Ran-Binding Protein M (RanBPM) relocalization into discrete perinuclear foci where it co-localizes with aggresome components ubiquitin, dynein and HDAC6, suggesting that the RanBPM perinuclear clusters correspond to aggresomes. RanBPM was also recruited to aggresomes following treatment with the proteasome inhibitor MG132 and the DNA-damaging agent etoposide. Strikingly, aggresome formation by HDAC6 was markedly impaired in RanBPM shRNA cells, but was restored by re-expression of RanBPM. RanBPM was found to interact with HDAC6 and to inhibit its deacetylase activity. This interaction was abrogated by a RanBPM deletion of its LisH/CTLH domain, which also prevented aggresome formation, suggesting that RanBPM promotes aggresome formation through an association with HDAC6. Our results suggest that RanBPM regulates HDAC6 activity and is a central regulator of aggresome formation. PMID- 24795146 TI - H3K79 methylation: a new conserved mark that accompanies H4 hyperacetylation prior to histone-to-protamine transition in Drosophila and rat. AB - During spermiogenesis, haploid spermatids undergo extensive chromatin remodeling events in which histones are successively replaced by more basic protamines to generate highly compacted chromatin. Here we show for the first time that H3K79 methylation is a conserved feature preceding the histone-to-protamine transition in Drosophila melanogaster and rat. During Drosophila spermatogenesis, the Dot1 like methyltransferase Grappa (Gpp) is primarily expressed in canoe stage nuclei. The corresponding H3K79 methylation is a histone modification that precedes the histone-to-protamine transition and correlates with histone H4 hyperacetylation. When acetylation was inhibited in cultured Drosophila testes, nuclei were smaller and chromatin was compact, Gpp was little synthesized, H3K79 methylation was strongly reduced, and protamines were not synthesized. The Gpp isoform Gpp-D has a unique C-terminus, and Gpp is essential for full fertility. In rat, H3K79 methylation also correlates with H4 hyperacetylation but not with active RNA polymerase II, which might point towards a conserved function in chromatin remodeling during the histone-to-protamine transition in both Drosophila and rat. PMID- 24795147 TI - GRASP65 controls the cis Golgi integrity in vivo. AB - GRASP65 and GRASP55 are peripheral Golgi proteins localized to cis and medial/trans cisternae, respectively. They are implicated in diverse aspects of protein transport and structure related to the Golgi complex, including the stacking of the Golgi stack and/or the linking of mammalian Golgi stacks into the Golgi ribbon. Using a mouse model, we interfered with GRASP65 by homologous recombination and confirmed its absence of expression. Surprisingly, the mice were healthy and fertile with no apparent defects in tissue, cellular or subcellular organization. Immortalized MEFs derived from the mice did not show any growth or morphological defects. However, despite the normal appearance of the Golgi ribbon, a fluorescence recovery after photobleaching assay revealed functional discontinuities specific to the cis cisternal membrane network. This leads to a strong change in the plasma membrane GSII lectin staining that was also observed in certain mutant tissues. These findings substantiate the role of GRASP65 in continuity of the cis Golgi network required for proper glycosylation, while showing that neither this continuity nor GRASP65 itself are essential for the viability of a complex organism. PMID- 24795148 TI - EphA receptors regulate prostate cancer cell dissemination through Vav2-RhoA mediated cell-cell repulsion. AB - Metastatic prostate cancer cells display EphB receptor-mediated attraction when they contact stromal fibroblasts but EphA-driven repulsion when they contact one another. The impact of these 'social' interactions between cells during cancer cell invasion and the signalling mechanisms downstream of Eph receptors are unclear. Here we show that EphA receptors regulate prostate cancer cell dissemination in a 2D dispersal assay and in a 3D cancer cell spheroid assay. We show that EphA receptors signal via the exchange factor Vav2 to activate RhoA and that both Vav2 and RhoA are required for prostate cancer cell-cell repulsion. Furthermore, we find that in EphA2/EphA4, Vav2 or RhoA siRNA-treated cells, contact repulsion can be restored by partial microtubule destabilisation. We propose that EphA-Vav2-RhoA-mediated repulsion between contacting cancer cells at the tumour edge could enhance their local invasion away from the primary tumour. PMID- 24795149 TI - Christianity's commitments to nurturing and protecting children: biblical foundations: children are neighbors worthy of love and respect. PMID- 24795150 TI - Comorbid epilepsy and psychogenic non-epileptic seizures: how well do patients and caregivers distinguish between the two. AB - PURPOSE: To determine whether patients with comorbid epilepsy and psychogenic nonepileptic seizure (PNES) and their caregivers can distinguish between these two events at least one year after initial diagnosis, and to investigate factors associated with correct identification. METHODS: Adult patients with at least a one year diagnosis of both epilepsy and PNES, confirmed through video electroencephalography (VEEG), were selected. Patients and a caregiver of their choice were interviewed and shown videos containing the patients' epileptic and PNES events. Variables associated with correct identification of events by patients and their caregivers were evaluated. RESULTS: Twenty-four patients participated in the study. Mean time between VEEG diagnosis and enrollment in the study was 26.8 months (+/-12.4). Six of patients correctly distinguished between the events shown. Factors associated with correct identification were the absence of intellectual disability, unremitted PNES, and a degree of preserved awareness during the PNES event. Twelve caregivers correctly distinguished between the events shown. Factors associated with correct identification among caregivers were the presentation of only one epileptic seizure type in the patient, and the participation of the caregiver during VEEG monitoring and communication of PNES diagnosis to the patient. CONCLUSION: A significant proportion of patients with epilepsy and PNES and their caregivers seem to be unable to discriminate between these events a year after diagnosis. These findings have implications for both clinical follow-up and research involving this population. Future research should further investigate methods that would allow patients and their caregivers to better distinguish between these two events. PMID- 24795152 TI - Discussion. PMID- 24795151 TI - Low Glycemic Index Treatment in pediatric refractory epilepsy: the first Middle East report. AB - PURPOSE: Intractable epilepsy is a challenging aspects of pediatric epilepsy. This study was conducted to determine the efficacy and tolerability of Low Glycemic Index Treatment (LGIT) in pediatric patients referred to a Children's Hospital in Iran with intractable epilepsy. METHODS: We studied 42 children with refractory epilepsy aged between 1.5 and 17 years of age, from October 2009 to April 2011 in the pediatric neurology department of Mofid Children's Hospital. Patient information on clinical status, seizure type, and baseline frequency, blood and urine biochemistry, neuro-imaging and the EEG were collected. LGIT was initiated on an outpatient basis and the diet was composed of 65% fat, 25% protein and 10% carbohydrate (40-60 g), and the glycemic index of foods was limited to below 50. RESULTS: 84% of patients were categorized as having more than one seizure per day at study entry, with the remaining children as experiencing over one seizure per week. A greater than 50% seizure reduction was observed in 71.4% of the patients after the second week, in 73.8% at the end of the first month and in 77.8% at the end of the second month. In 30% of the patients a mild increase in blood urea nitrogen (BUN) was detected. The most important reasons for discontinuation of LGIT were restrictiveness, lack of satiation and excessive meat in this diet. No significant complications were observed during the administration of the diet. CONCLUSION: LGIT is a safe and effective adjuvant antiepileptic therapy and may be used as an alternative to the ketogenic diet in conditions when this diet cannot be used. PMID- 24795153 TI - C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization. AB - BACKGROUND: High-sensitivity C-reactive protein (hsCRP) and brain natriuretic peptide (BNP) have been shown to be independent predictors of adverse cardiovascular outcomes and increased risk of secondary interventions or limb loss in patients with peripheral arterial disease (PAD). To assist clinicians in decision-making about treatment approaches and predicting postprocedure mortality and morbidity, we retrospectively examined patients with preprocedure hsCRP and BNP levels who underwent elective angioplasty or stent placement for lower extremity PAD. METHODS: The study period was from January 1, 2007, to December 31, 2012, and patients were included who had angioplasty or stenting for PAD. Minimal required follow-up for study inclusion was at least one postoperative ankle-brachial index, contrast angiography, or duplex imaging of the treated limb. Events of interest included major adverse limb events (MALE), defined as target vessel revascularization, amputation, or disease progression by 1 year, and major adverse cardiovascular events (MACE; stroke, myocardial infarction, or death) by 2 years. Elevated/abnormal values for our biomarkers of interest were established by the upper limits of our institution's clinical laboratory reference range (hsCRP, >0.80 mg/dL; BNP, >100 pg/mL). RESULTS: A total of 159 limbs in 118 patients were included in analysis (42% men; median age [range], 64 [42-87] years). All limbs were symptomatic (Rutherford classification: 1-6). Iliac artery revascularization without other adjunct lower extremity intervention was performed in 60% of the limbs. High hsCRP levels (>0.80 mg/dL) were present in 32 patients (27%) and high BNP values (>100 pg/mL) in 24 patients (20%). Kaplan-Meier analysis with log-rank comparison demonstrated that elevated hsCRP levels were associated with MALE but only in limbs receiving interventions distal to the iliac arteries (P = .005). High BNP levels did not affect MALE rates (P = .821). Conversely, both elevated BNP levels (hazard ratio, 5.6; 95% confidence interval [CI], 2.0-5.8; P = .001) and hsCRP levels (hazard ratio, 2.9; 95% CI, 1.1-7.6; P = .034) predicted MACE at 2 years in the presence of confounders in Cox proportional hazards multivariate analysis. Patients with high preintervention values of hsCRP and BNP were 10.6 times (95% CI, 2.6-42.9; P = .001) more likely to experience MACE than were patients with normal hsCRP and BNP values. CONCLUSIONS: After lower extremity endovascular interventions, elevated preprocedural hsCRP levels are associated with MALE (femoral-popliteal interventions), and elevated levels of hsCRP and BNP are associated with late cardiovascular events. PMID- 24795154 TI - Limbic system mGluR5 availability in cocaine dependent subjects: a high resolution PET [(11)C]ABP688 study. AB - Cocaine self-administration decreases type 5 metabotropic glutamate receptor (mGluR5) tissue concentrations in laboratory rats during early abstinence. These changes are thought to influence the drug's reinforcing properties and the ability of drug-related cues to induce relapse. Here, our goal was to measure brain regional mGluR5 availability in recently abstinent cocaine dependent humans. Participants meeting DSM-IV diagnostic criteria for current cocaine dependence (n=9) were recruited from the general population. mGluR5 availability (binding potential, non-displaceable; BPND) was measured with high-resolution positron emission tomography (PET HRRT) and [(11)C]ABP688. Compared to age- and sex-matched healthy controls (n=9), cocaine dependent subjects showed significantly lower BPND values in the ventral (bilateral: -28.2%, p=0.011), associative (right: -21.4%, p=0.043), and sensorimotor striatum (bilateral: 21.7%, p=0.045), amygdala (left: -26%, p=0.046) and insula (right: -23.3%, p=0.041). Among the cocaine users, receptor availabilities were related to abstinence (range: 2 to 14days). The longer the duration of abstinence, the lower the BPND values in the sensorimotor striatum (r=-0.71, p=0.034), left amygdala (r=-0.73, p=0.026) and right insula (r=-0.67, p=0.046). Compared to healthy controls, BPND values were significantly reduced in those who tested negative for cocaine on the PET test session in the ventral (p=0.018) and sensorimotor striatum (p=0.017), left amygdala (p=0.008), and right insula (p=0.029), but not in those who tested positive. Together, these results provide evidence of time related mGluR5 alterations in striatal and limbic regions in humans during early cocaine abstinence. PMID- 24795155 TI - Evaluating dipolar source localization feasibility from intracerebral SEEG recordings. AB - Stereo-electroencephalography (SEEG) is considered as the golden standard for exploring targeted structures during pre-surgical evaluation in drug-resistant partial epilepsy. The depth electrodes, inserted in the brain, consist of several collinear measuring contacts (sensors). Clinical routine analysis of SEEG signals is performed on bipolar montage, providing a focal view of the explored structures, thus eliminating activities of distant sources that propagate through the brain volume. We propose in this paper to exploit the common reference SEEG signals. In this case, the volume propagation information is preserved and electrical source localization (ESL) approaches can be proposed. Current ESL approaches used to localize and estimate the activity of the neural generators are mainly based on surface EEG/MEG signals, but very few studies exist on real SEEG recordings, and the case of equivalent current dipole source localization has not been explored yet in this context. In this study, we investigate the influence of volume conduction model, spatial configuration of SEEG sensors and level of noise on the ESL accuracy, using a realistic simulation setup. Localizations on real SEEG signals recorded during intracerebral electrical stimulations (ICS, known sources) as well as on epileptic interictal spikes are carried out. Our results show that, under certain conditions, a straightforward approach based on an equivalent current dipole model for the source and on simple analytical volume conduction models yields sufficiently precise solutions (below 10mm) of the localization problem. Thus, electrical source imaging using SEEG signals is a promising tool for distant brain source investigation and might be used as a complement to routine visual interpretations. PMID- 24795156 TI - A three-way parallel ICA approach to analyze links among genetics, brain structure and brain function. AB - Multi-modal data analysis techniques, such as the Parallel Independent Component Analysis (pICA), are essential in neuroscience, medical imaging and genetic studies. The pICA algorithm allows the simultaneous decomposition of up to two data modalities achieving better performance than separate ICA decompositions and enabling the discovery of links between modalities. However, advances in data acquisition techniques facilitate the collection of more than two data modalities from each subject. Examples of commonly measured modalities include genetic information, structural magnetic resonance imaging (MRI) and functional MRI. In order to take full advantage of the available data, this work extends the pICA approach to incorporate three modalities in one comprehensive analysis. Simulations demonstrate the three-way pICA performance in identifying pairwise links between modalities and estimating independent components which more closely resemble the true sources than components found by pICA or separate ICA analyses. In addition, the three-way pICA algorithm is applied to real experimental data obtained from a study that investigate genetic effects on alcohol dependence. Considered data modalities include functional MRI (contrast images during alcohol exposure paradigm), gray matter concentration images from structural MRI and genetic single nucleotide polymorphism (SNP). The three-way pICA approach identified links between a SNP component (pointing to brain function and mental disorder associated genes, including BDNF, GRIN2B and NRG1), a functional component related to increased activation in the precuneus area, and a gray matter component comprising part of the default mode network and the caudate. Although such findings need further verification, the simulation and in-vivo results validate the three-way pICA algorithm presented here as a useful tool in biomedical data fusion applications. PMID- 24795157 TI - The birth of the (gay) clinic. AB - We apply and extend Philo (2000)'s arguments about Foucault's Birth of the Clinic as an inspiration for health geography and the study of governance of gays. Philo identified three spaces through which he argued disease is framed: disease tabled, embodied, and institutionalized. These focus attention on the spatialities through which the medical gaze is power-laden. We adopt this framework empirically through an historical geography of an urban public health system engaged with sexually transmitted infections (STIs) in the "homosexual" population of Seattle, Washington in the 1970s. It reveals the interaction of homophobia, heteronormativity and resistances across places typically understudied in queer historical geography. Our findings also extend this framework, however, by revealing other spaces that were important in the urban politics of sexual health: the gay city, the gay doctor, and the gay community. We suggest, therefore, that these and other spaces may be helpful in other health geographies interested in the dynamics of sexuality, governmentality, and urban public health. PMID- 24795158 TI - Neural activation abnormalities during self-referential processing in schizophrenia: an fMRI study. AB - Impairments in self-awareness contribute to disability in schizophrenia. Studies have revealed activation abnormalities in schizophrenia in cortical midline structures associated with self-reference. We used functional magnetic resonance imaging to compare activation throughout the brain in people with schizophrenia and healthy controls (Kelly et al., 2002) while they indicated whether trait adjectives described attributes of themselves, their mother or a former president of the United States. Blood oxygenation level dependent signal in each condition was compared to resting fixation. Patients were less likely and slower to endorse positive self-attributes, and more likely and quicker to endorse negative self attributes than controls. Activation abnormalities reported previously in cortical midline structures were again noted. In addition, patients showed greater signal increases in frontal, temporal gyri and insula, and smaller signal decreases in posterior regions than healthy controls when thinking about themselves. Group differences were less evident when subjects were thinking about their mothers and tended to go in the opposite direction when thinking about a president. Many of the areas showing abnormality have been shown in other studies to differ between patients and controls in structure and with other activation paradigms. We suggest that general neuropathology in schizophrenia alters the neural system configurations associated with self-representation. PMID- 24795159 TI - Sequential targeted therapy after pazopanib therapy in patients with metastatic renal cell cancer: efficacy and toxicity. AB - INTRODUCTION/BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy. PATIENTS AND METHODS: Patients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented. RESULTS: Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti-VEGF- and everolimus treated patients, respectively (P = .021). CONCLUSION: In this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi. PMID- 24795160 TI - Fatty and lean red meat consumption in China: differential association with Chinese abdominal obesity. AB - AIM: We examined the longitudinal association between red meat (RM) consumption and the risk of abdominal obesity in Chinese adults. METHODS AND RESULTS: Our data are from 16,822 adults aged 18-75 in the China Health and Nutrition Survey from 1993 to 2011. We assessed RM intake with three 24-h dietary recalls. We defined abdominal obesity as a waist circumference (WC) >=85 centimeters (cm) for men and >=80 cm for women. Multilevel mixed-effect regression models showed that men experienced WC increases of 0.74 cm (95% confidence interval [CI]: 0.39-1.09) from a higher total intake of fresh RM and 0.59 cm (95% CI: 0.24-0. 95) from a higher intake of fatty fresh RM but 0.14 cm (95% CI: -0.39 to 0.66) from a higher intake of lean fresh RM in the top quartile versus non-consumers when adjusted for potential confounders. In contrast, after additional adjustment for baseline WC, the odds ratios of abdominal obesity in men were attenuated for total fresh RM (1.25 [95% CI: 1.06-1.47]) and fatty fresh RM (1.22 [95% CI: 1.03-1.44]) but were still not affected by lean fresh RM (0.95 [95% CI: 0.75-1.22]). Women also showed a positive association of fatty fresh RM intake with abdominal obesity. CONCLUSION: Greater intake of fatty fresh RM was significantly associated with higher WC (men only) and abdominal obesity risk in Chinese adults. The gender specific differential association of fatty versus lean fresh RM warrants further study. PMID- 24795161 TI - Life threatening causes of syncope: channelopathies and cardiomyopathies. AB - Syncope is common, has a high recurrence rate and carries a risk of morbidity and, dependent on the cause, mortality. Although the majority of patients with syncope have a benign prognosis, syncope as a result of cardiomyopathy or channelopathy carries a poor prognosis. In addition, the identification of these disorders allows for the institution of treatments, which are effective at reducing the risk of both syncope and mortality. It is for these reasons that the identification of a cardiomyopathy or channelopathy in patients with syncope is crucial. This review article will describe the characteristics of common cardiomyopathies and channelopathies and their investigation. PMID- 24795163 TI - A home-based program of transcutaneous electrical nerve stimulation and task related trunk training improves trunk control in patients with stroke: a randomized controlled clinical trial. AB - BACKGROUND: Impaired trunk motor control is common after stroke. Combining transcutaneous electrical nerve stimulation (TENS) with task-related trunk training (TRTT) has been shown to enhance the recovery of lower limb motor function. OBJECTIVE: This study investigated whether combining TENS with TRTT would enhance trunk control after stroke. Methods. Thirty-seven subjects with stroke were recruited into a randomized controlled clinical trial. Subjects were randomly assigned to any one of the three 6-week home-based training groups: (1) TENS + TRTT, (2) placebo TENS + TRTT, or (3) control without active training. The outcome measures included isometric peak trunk flexion torque and extension torque; forward seated and lateral seated reaching distance to the affected and unaffected side; and Trunk Impairment Scale (TIS) scores. All outcome measures were assessed at baseline, after 3 and 6 weeks of training, and 4 weeks after training ended at follow-up. RESULTS: Both the TENS + TRTT and the placebo-TENS + TRTT groups had significantly greater improvements in isometric peak trunk flexion torque and extension torque, lateral seated reaching distance to affected and unaffected side, and TIS score than the control group after 3 weeks of training. The TENS + TRTT group had significantly greater and earlier improvement in its mean TIS score than the other 2 groups. CONCLUSIONS: Home-based TRTT is effective for improving trunk muscle strength, sitting functional reach and trunk motor control after stroke in subjects without somatosensory deficits. The addition of TENS to the trunk augments the effectiveness of the exercise in terms of TIS scores within the first 3 weeks of training. PMID- 24795162 TI - The impact of dynamic balance measures on walking performance in multiple sclerosis. AB - BACKGROUND: Static posture imbalance and gait dysfunction are common in individuals with multiple sclerosis (MS). Although the impact of strength and static balance on walking has been examined, the impact of dynamic standing balance on walking in MS remains unclear. OBJECTIVE: To determine the impact of dynamic balance, static balance, sensation, and strength measures on walking in individuals with MS. METHODS: Fifty-two individuals with MS (27 women; 26 relapsing-remitting; mean age = 45.6 +/- 10.3 years; median Expanded Disability Status Scale score = 3.5) participated in posturography testing (Kistler-9281 force plate), hip flexion, hip extension, ankle dorsiflexion strength (Microfet2 hand-held dynamometer), sensation (Vibratron II), and walk velocity (Optotrak Motion Analysis System). Analyses included, Mann-Whitney, Spearman correlation coefficients, and multiple regression. RESULTS: All measures were abnormal in individuals with MS when compared with norms (P < .05). Static balance (eyes open, feet together [EOFT]), anterior-posterior (AP) dynamic sway, and hip extension strength were strongly correlated with walking velocity (AP sway r = 0.68; hip extension strength r = 0.73; EOFT r = -0.40). Together, AP dynamic sway (rhor = 0.71; P < .001), hip extension strength (rhor = 0.54; P < .001), and EOFT static balance (rhor = -0.41; P = .01) explained more than 70% of the variance in walking velocity (P < .001). CONCLUSIONS: AP dynamic sway affects walking performance in MS. A combined evaluation of dynamic balance, static balance, and strength may lead to a better understanding of walking mechanisms and the development of strategies to improve walking. PMID- 24795164 TI - Characteristics of replacement breeding cattle trade in Great Britain. AB - The movements of replacement breeding cattle have been implicated in the spread of many economically important cattle diseases. In this analysis, records from the Cattle Tracing System database were used to investigate the frequency and characteristics of replacement breeding cattle trade in Great Britain. During the 2006 calendar year, an estimated 48.7 per cent of beef herds and 47.8 per cent of dairy herds purchased at least one replacement breeding animal. Open beef herds purchased an average of 7.2 replacement animals (median: 4, range: 1-819) from 3.6 source herds (median: 2, range: 1-114), while open dairy herds purchased an average of 13.7 replacement animals (median: 7, range: 1-827) from 5.2 source herds (median: 3, range: 1-146). The most common animal types purchased by beef and dairy herds were open heifers and open lactating cows, respectively. Although the movements of purchased replacement breeding cattle accounted for only 13 per cent of individual movements in the between-herd contact network, they had a disproportionately strong influence on the risk of disease spreading through the industry as evidenced by their high betweenness centrality scores. These results emphasise the importance of ensuring that good biosecurity programmes are in place to prevent disease transmission. PMID- 24795165 TI - Impact of Schmallenberg virus on British sheep farms during the 2011/2012 lambing season. AB - British sheep farmers were invited to complete a questionnaire about the impact of Schmallenberg virus (SBV) on animal health, welfare and their own emotional wellbeing during the 2011-2012 lambing season, through Defra and Farming Industry websites, letters to farmers who had requested SBV laboratory tests and advertisement at Sheep 2012. The 494 responders included SBV confirmed (positive by RT-PCR) (n=76), SBV suspected by farmer (n=140) or SBV not suspected (n=278). Percentage of barren ewes was similar across SBV groups, however, lamb and ewe losses were higher on responder farms where SBV was confirmed or suspected. The median percentages of all lambs born (and lambs born deformed ) that died within one week of birth was 10.4 per cent (5.5 per cent), 7.0 per cent (2.9 per cent) and 5.3 per cent (0 per cent), respectively, on SBV confirmed, suspected and not suspected farms (P<0.001). Eight to 16 per cent of SBV confirmed or suspected farms reported lamb mortality of >=40 per cent. Farmer perceived impact was greater where SBV was confirmed or suspected (P<0.001): 25 per cent reported a high impact on emotional wellbeing (4 per cent of SBV not suspected), 13 per cent reported a high impact on flock welfare and financial performance and 6 per cent were less likely to farm sheep next year because of SBV (<2 per cent in SBV not suspected). Overall, SBV impact has been large relative to reported sheep loss. PMID- 24795167 TI - Meat quality and fatty acid profile of Brazilian goats subjected to different nutritional treatments. AB - This study evaluated the effect of feed restriction and goat genotype on meat quality. Three genotypes (Brazilian native breed Caninde; Brazilian native breed Moxoto; and F1 Boer crossbred animals obtained by crossing Boer bucks with local breed does) and three different feeding regimens (ad libitum fed, AL; restricted fed at 75% of the ad libitum, R.75; or restricted fed at 50% of the average ad libitum intake, R.50) were used. There was no difference (P>0.05) in chemical composition, total and soluble collagen, and shear force of the Longissimus lumborum muscle among genotypes. However, AL had greater amounts of soluble collagen and crude protein in the muscle (P<0.05) than R.75. No difference (P>0.05) was observed for the myofibrillar fragmentation index. The goat genotype presented few differences in their fatty acid profiles. However, goats fed ad libitum had a more favorable fatty acid profile for human health with greater concentrations of oleic acid, unsaturated fatty acids, and conjugated linoleic acid. PMID- 24795166 TI - Culturable fungal endophytes in roots of Enkianthus campanulatus (Ericaceae). AB - Roots of plants in the genus Enkianthus, which belongs to the earliest diverging lineage in the Ericaceae, are commonly colonized by arbuscular mycorrhizal (AM) fungi. We documented the community of fungal root endophytes associated with Enkianthus species using a culture-based method for better understanding the members of root-colonizing fungi, except for AM fungi. Fungal isolates were successfully obtained from 610 out of 3,599 (16.9 %) root segments. Molecular analysis of fungal cultures based on ribosomal internal transcribed spacer (ITS) sequences yielded 63 operational taxonomical units (OTUs: 97 % sequence similarity cutoff) from 315 representative isolates. Further phylogenetic analysis showed that most (296 isolates) belonged to Ascomycota and were either members of Helotiales (Dermataceae, Hyaloscyphaceae, Phialocephala and Rhizoscyphus ericae aggregate), Oidiodendron, or other Pezizomycotina. Twenty three out of 63 OTUs, which mainly consisted of Leotiomycetes, showed high similarities with reference sequences derived from roots of other ericaceous plants such as Rhododendron. The results indicated that Enkianthus houses variable root mycobionts including putative endophytic and mycorrhizal fungi in addition to AM fungi. PMID- 24795168 TI - Comparison of left ventricular function following first ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention in men versus women. AB - Previous data reported worse outcomes in female patients after acute ST elevation myocardial infarction (STEMI), related at least in part to less aggressive and nonparallel treatment. We investigated the presence of gender differences in left ventricular (LV) systolic and diastolic function in patients presenting with first STEMI, treated with primary percutaneous coronary intervention (PCI). Study population included 187 consecutive patients (81% men) presenting with STEMI and treated by primary PCI and guideline-based medications. Their mean age was 58 +/- 10 years. All patients underwent a comprehensive echocardiographic evaluation within 3 days of admission. Female patients were older (62 +/- 11 vs 59 +/- 10 years, p = 0.006), with more co-morbidities and longer symptom duration (490 +/- 436 vs 365 +/- 437 minutes, p = 0.013). Echocardiography demonstrated that female patients had significantly lower LV systolic function (47 +/- 8% vs 45 +/- 8%, p = 0.03), lower septal and lateral e' velocities, higher average E/e' ratio (all p <0.001), elevated systolic pulmonary artery pressure (p = 0.03), and worse diastolic dysfunction (p = 0.007). No significant changes were present in left atrial volumes. In a logistic multivariate analysis model, female gender emerged as an independent predictor of septal e' <8 cm/s (odds ratio 10.11, 95% confidence interval 1.23 to 82.32, p = 0.002) and E/average e' ratio >15 (odds ratio 6.47, 95% confidence interval 1.63 to 25.61, p = 0.008). In conclusion, female patients undergoing primary PCI for first STEMI demonstrated worse systolic and diastolic LV function, despite receiving similar treatment as male patients. PMID- 24795169 TI - Impact of cardiac rehabilitation on angiographic outcomes after drug-eluting stents in patients with de novo long coronary artery lesions. AB - Cardiac rehabilitation (CR) can reduce cardiovascular mortality and morbidity in coronary artery disease. Long coronary artery lesions may be associated with adverse outcomes after drug-eluting stent (DES) implantation. The purpose of this study was to evaluate angiographic outcomes after a comprehensive CR program in patients with DESs for long coronary artery lesions. A total of 576 patients treated with DESs for long (>=25 mm) coronary lesions were enrolled in this prospective CR registry. Comprehensive CR programs were successfully performed in 288 patients (50%). The primary end point was in-stent late luminal loss at the 9 month angiographic follow-up. There were few significant differences between the CR and non-CR groups in terms of baseline characteristics, including clinical, angiographic, and procedural variables. The rate of in-stent late luminal loss in the CR group was 35% less than in the usual care group (0.19 +/- 0.33 mm in CR vs 0.29 +/- 0.45 mm in non-CR, difference 0.08 mm, 95% confidence interval 0.01 to 0.16, p = 0.02) at the 9-month follow-up. After propensity-matched analysis (224 pairs), the results were consistent (0.18 +/- 0.31 mm in CR vs 0.28 +/- 0.41 mm in non-CR, difference 0.10 mm, 95% confidence interval 0.02 to 0.18, p = 0.02). The CR group showed a significant improvement in the overall risk profile compared with the non-CR group, including current smoking, biochemical profiles, depression, obesity, and exercise capacity. In conclusion, the comprehensive CR program significantly reduced late luminal loss after DES implantation for long coronary lesions. This may be associated with significant improvements in exercise capacity and overall risk profile. PMID- 24795170 TI - Real-time polymerase chain reaction correlates well with clinical diagnosis of Clostridium difficile infection. AB - AIM: To determine the clinical utility of a rapid molecular assay for Clostridium difficile infection (CDI) in an acute hospital setting. METHODS: From March to September 2011, stool specimens from inpatients in two acute hospitals with suspected CDI were tested prospectively by routine cell culture cytotoxin neutralization assay (CCNA), real-time polymerase chain reaction (PCR) using the GeneXpert (Cepheid Inc., Sunnyvale, CA, USA), and a dual testing algorithm [glutamate dehydrogenase (GDH)/toxin enzyme immuno-assay, Premier, Launch Diagnostics, Longfield, UK]. All patients with positive PCR, CCNA or discrepant results were reviewed by a multi-disciplinary team (treating clinician, gastroenterologist, microbiologist and infection control nurse). RESULTS: C. difficile detection rates were 11.7% (PCR), 6% (CCNA) and 13.8% (GDH). Out of 1034 stool specimens included in the study, 974 (94.1%) had concordant CCNA and PCR results. Eighty-nine percent (886/985) had concordant CCNA, PCR and GDH results, and 94.4% (930/985) had concordant GDH and PCR results. Using clinical diagnosis as the reference, PCR had sensitivity of 99.1%, specificity of 98.9%, positive predictive value (PPV) of 91.9% and negative predictive value (NPV) of 99.9%. CCNA on a single sample had sensitivity of 51%, specificity of 99.4%, PPV of 91.9% and NPV of 94.3%. GDH had sensitivity of 83.8%, specificity of 94.5%, PPV of 64.7% and NPV of 97.9%. Almost twice as many patients were positive by PCR compared with CCNA (121 vs 62); 54/59 of those with discrepant results were clinically confirmed as CDI. CONCLUSION: Rapid diagnosis of CDI using PCR was timely, accurate and correlated well with clinical diagnosis. PMID- 24795171 TI - Increased initial cement-bone interlock correlates with reduced total knee arthroplasty micro-motion following in vivo service. AB - Aseptic loosening of cemented tibial components in total knee arthroplasty (TKA) has been related to inadequate cement penetration into the trabecular bone bed during implantation. Recent postmortem retrieval work has also shown there is loss of interlock between cement and bone by resorption of trabeculae at the interface. The goal of this study was to determine if TKAs with more initial interlock between cement and bone would maintain more interlock with in vivo service (in the face of resorbing trabeculae) and have less micro-motion at the cement-bone interface. The initial (created at surgery) and current (after in vivo service) cement-bone interlock morphologies of sagittal implant sections from postmortem retrieved tibial tray constructs were measured. The implant sections were then functionally loaded in compression and the micro-motion across the cement-bone interface was quantified. Implant sections with less initial interdigitation between cement and bone and more time in service had less current cement-bone interdigitation (r(2)=0.86, p=0.0002). Implant sections with greater initial interdigitation also had less micro-motion after in vivo service (r(2)=0.36, p=0.0062). This work provides direct evidence that greater initial interlock between cement and bone in tibial components of TKA results in more stable constructs with less micro-motion with in vivo service. PMID- 24795173 TI - Metabolic heterogeneity during preimplantation development: the missing link? AB - BACKGROUND: Most tissues in the body rely on the presence of gap junctions in order to couple their component cells electrically and metabolically via intercellular transport of ions, metabolites and signalling agents. As a result, cells within tissues achieve a high degree of, 'metabolic homogeneity' which enables them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues. Unusually, the developing mammalian preimplantation embryo does not form functional gap junctions until it has divided into 8 or more cells. We discuss the implications of this 'missing link' during the first few days of development for the maintenance of homogeneity between embryonic cells and for the co-ordination of the embryonic response to intrinsic genetic damage and external environmental signals. METHODS: No systematic review has been carried out. The physiology of preimplantation development and the general nature of gap junctions have been reviewed briefly before examining experimental evidence which addresses the following points: (i) whether there are functional differences between early blastomeres; (ii) when during preimplantation development the embryo is most sensitive to environmental perturbation and (iii) the consequences for early embryos of ablating gap junction formation and function. RESULTS AND CONCLUSIONS: General conclusions are confounded by species differences, especially in the timing of embryonic genome activation (EGA) and the extent of intrinsic genotypic and phenotypic variation (low in embryos from inbred mice; high in human embryos). Nevertheless, we propose that the absence of gap junctions requires cleavage stage mammalian embryos to behave cell autonomously in a metabolic sense, contributes to their heightened sensitivity to environmental perturbation compared with the later stages of preimplantation development and poses more problems in the early human embryo, where there is a high degree of heterogeneity between the blastomeres. We argue that the legacy of metabolic heterogeneity, in part generated by the absence of gap junctions, is 'rescued' by the onset of apoptosis following EGA. In the context of human-assisted conception, since early embryos lacking gap junctions are more sensitive to environmental stress during cleavage, this would support transfer to the natural environment as early as possible after fertilization. PMID- 24795172 TI - Hyperlipidemia affects multiscale structure and strength of murine femur. AB - To improve bone strength prediction beyond limitations of assessment founded solely on the bone mineral component, we investigated the effect of hyperlipidemia, present in more than 40% of osteoporotic patients, on multiscale structure of murine bone. Our overarching purpose is to estimate bone strength accurately, to facilitate mitigating fracture morbidity and mortality in patients. Because (i) orientation of collagen type I affects, independently of degree of mineralization, cortical bone's micro-structural strength; and, (ii) hyperlipidemia affects collagen orientation and MUCT volumetric tissue mineral density (vTMD) in murine cortical bone, we have constructed the first multiscale finite element (mFE), mouse-specific femoral model to study the effect of collagen orientation and vTMD on strength in Ldlr(-/-), a mouse model of hyperlipidemia, and its control wild type, on either high fat diet or normal diet. Each uCT scan-based mFE model included either element-specific elastic orthotropic properties calculated from collagen orientation and vTMD (collagen density model) by experimentally validated formulation, or usual element-specific elastic isotropic material properties dependent on vTMD-only (density-only model). We found that collagen orientation, assessed by circularly polarized light and confocal microscopies, and vTMD, differed among groups and that microindentation results strongly correlate with elastic modulus of collagen density models (r(2)=0.85, p=10(-5)). Collagen-density models yielded (1) larger strains, and therefore lower strength, in simulations of 3-point bending and physiological loading; and (2) higher correlation between mFE-predicted strength and 3-point bending experimental strength, than density-only models. This novel method supports ongoing translational research to achieve the as yet elusive goal of accurate bone strength prediction. PMID- 24795174 TI - Is the denervation or hyperinnervation of the cardiac sympathetic nerve in the subepicardium related to unexpected cardiac death? AB - BACKGROUND: Past studies have reported that abnormal innervation of cardiac sympathetic nerve can cause sudden cardiac death through the arrythmogenesis; however, the severe cardiac sympathetic degeneration does not necessarily cause clinical problems. This study aimed to examine whether denervation or hyperinnervation of cardiac sympathetic nerves in the subepicardium is associated with unexpected cardiac death (UCD). METHODS: Cardiac tissues of 278 forensic autopsy cases within 48 h after death were analyzed by double-staining immunohistochemistry for tyrosine hydroxylase and neurofilament. The density of nerve fascicles and the degeneration rate in the subepicardium of the left ventricular anterior wall were compared between the UCD group and the non-UCD group. RESULTS: The density of nerve fascicles was lower in the SCD group (median: 51.9/cm(2)) than in the non-SCD group (median: 58.9/cm(2)); however, the difference was not significant (P = .08). The degeneration rate was higher in the SCD group (median: 0.19) than in the non-SCD group (median: 0.17), but again, the difference was not significant (P = .43). The multiple logistic regression model did not show a significant association between the incidence of UCD and the density of nerve fascicles or the degeneration rate. CONCLUSIONS: It cannot be concluded that the denervation or hyperinnervation of cardiac sympathetic nerves in the subepicardium is related to UCD. Abnormal innervation of cardiac sympathetic nerves in the subepicardium may not have a substantial effect on UCD, compared to other arrhythmogenic factors. PMID- 24795175 TI - Stimulant mechanisms of cathinones - effects of mephedrone and other cathinones on basal and electrically evoked dopamine efflux in rat accumbens brain slices. AB - Mephedrone, an erstwhile "legal high", and some non-abused cathinones (ethcathinone, diethylpropion and bupropion) were tested for stimulant effects in vitro, through assessing their abilities to increase basal and electrically evoked dopamine efflux in rat accumbens brain slices, and compared with cocaine and amphetamine. We also tested mephedrone against cocaine in a dopamine transporter binding study. Dopamine efflux was electrically evoked and recorded using voltammetry in the rat accumbens core. We constructed concentration response curves for these cathinones for effects on basal dopamine levels; peak efflux after local electrical stimulation and the time-constant of the dopamine decay phase, an index of dopamine reuptake. We also examined competition between mephedrone or cocaine and [(125)I]RTI121 at the dopamine transporter. Mephedrone was less potent than cocaine at displacing [(125)I]RTI121. Mephedrone and amphetamine increased basal levels of dopamine in the absence of electrical stimulation. Cocaine, bupropion, diethylpropion and ethcathinone all increased the peak dopamine efflux after electrical stimulation and slowed dopamine reuptake. Cocaine was more potent than bupropion and ethcathinone, while diethylpropion was least potent. Notably, cocaine had the fastest onset of action. These data suggest that, with respect to dopamine efflux, mephedrone is more similar to amphetamine than cocaine. These findings also show that cocaine was more potent than bupropion and ethcathinone while diethylpropion was least potent. Mephedrone's binding to the dopamine transporter is consistent with stimulant effects but its potency was lower than that of cocaine. These findings confirm and further characterize stimulant properties of mephedrone and other cathinones in adolescent rat brain. PMID- 24795176 TI - The morphogenetic effect of bacterial endotoxin lipopolysaccharide on the functioning of the reproductive system in rats. PMID- 24795177 TI - The first reconstruction of the late glacial plant communities on the Yamal Peninsula based on plant macrofossils. PMID- 24795178 TI - The possible role of microorganisms in humus formation in soils. PMID- 24795179 TI - Temperature behavior of the cladoceran Simocephalus vetulus O.F. Muller, 1776 (Crustacea, Cladocera) from the Rybinsk water reservoir. PMID- 24795181 TI - Impact of climate change on the physiological condition of passerine birds during migration. PMID- 24795180 TI - The use of an individual-based model to clarify the role of biological information in daphnia population dynamics. PMID- 24795182 TI - A discovery of a cave lion (Panthera spelaea Goldfuss, 1810) skeleton in Russia. PMID- 24795183 TI - Polymeric lactose fermentation genes in the yeast Kluyveromyces lactis: A new locus LAC3. PMID- 24795184 TI - Vocalization with the mouth closed as a mechanism of generation of the low frequency sound signal in great gerbil (Mammalia, Rodentia). PMID- 24795185 TI - Long-term morphogenetic aftereffects of muskrat acclimatization in Western Siberia. PMID- 24795186 TI - Growth, production, metabolism, and adaptations of high-latitude marine fish. PMID- 24795187 TI - Phylogenetic relationships and subgeneric taxonomy of toad-headed agamas Phrynocephalus (Reptilia, Squamata, Agamidae) as determined by mitochondrial DNA sequencing. PMID- 24795188 TI - Sensory elements and innervation in the freshwater bryozoan Cristatella mucedo lophophore. PMID- 24795189 TI - Molecular and cytogenetic evidence for the occurrence of the East European vole Microtus rossiaemeridionalis (Arvicolinae, Rodentia) in the North of West Siberia. PMID- 24795190 TI - Disproportional heteromorphism of male gametes in the bivalve mollusk Mactra chinensis is related to genetic divergence of this species. PMID- 24795191 TI - Thyroid hormones in the skeletogenesis and accessory sources of endogenous hormones in Xenopus laevis (Amphibia; Anura) ontogeny: Experimental evidence. AB - Skeletal development was studied in normal and goitrogen-treated Xenopus laevis tadpoles reared under thyroid hormone (TH) deficiency. Early stages of skeletal development proceed similarly in both groups. Later stages are retarded or completely arrested in goitrogen-treated tadpoles. After goitrogen-treated tadpoles were transferred into pure water or into a medium containing both goitrogen and exogenous TH, tadpoles resumed development. Consequently, late stages of skeletogenesis are TH-dependent and TH-induced. Athyroid X. laevis "giant tadpoles" described in literature differ from goitrogen-arrested tadpoles in that they have features which require TH to appear. The appearance of TH depended features in giant tadpoles indicates the occurrence of the additional sources of TH other than thyroid gland. PMID- 24795192 TI - Diazotrophic and cellulolytic component of the internal food chains in the voles Microtus rossiaemeridionalis and Clethrionomys glareolus depending on the feeding specialization. PMID- 24795193 TI - Within- and between-population polymorphism of the mtDNA control region of the speckled ground squirrel (Spermophilus suslicus). PMID- 24795194 TI - The use of DNA SCAR markers for differentiation of Kamchatka mykiss (Parasalmo (Oncorhynchus) mykiss). PMID- 24795195 TI - The effect of MP-3 on mouse peritoneal macrophage respiratory boost activity and production of IL-1beta and TNF-alpha under in vivo stress. PMID- 24795196 TI - How to avoid mucocele formation under pedicled nasoseptal flap. PMID- 24795197 TI - Alkaline pH in middle meatus in cases of chronic rhinosinusitis. AB - STUDY TYPE: Prospective and observational study. METHODS: The study group was divided in two groups consisted of 50 normal subjects (100 meati) and 50 patients (100 meati) of chronic rhinosinusitis (CRS). All subjects underwent nasal endoscopy along with measurement of the pH of the middle meatus using a portable pH monitoring device. Statistical analysis was done to compare mean pH of normal middle meatus with the diseased one. RESULTS: The mean pH of normal 100 middle meati was measured to be 7.35(+/-0.82). The mean pH of 100 middle meatii in CRS patients was higher 7.81(+/-0.83) and was found to be statistically significant (p=0.00011). CONCLUSION: Alkaline pH (7.81) was observed in the middle meatus of CRS patients. PMID- 24795198 TI - Regional cerebral blood flow changes associated with focal electrically administered seizure therapy (FEAST). AB - INTRODUCTION: Use of electroconvulsive therapy (ECT) is limited by cognitive disturbance. Focal electrically-administered seizure therapy (FEAST) is designed to initiate focal seizures in the prefrontal cortex. To date, no studies have documented the effects of FEAST on regional cerebral blood flow (rCBF). METHODS: A 72 year old depressed man underwent three single photon emission computed tomography (SPECT) scans to capture the onset and resolution of seizures triggered with right unilateral FEAST. We used Bioimage Suite for within-subject statistical analyses of perfusion differences ictally and post-ictally compared with the baseline scan. RESULTS: Early ictal increases in regional cerebral blood flow (rCBF) were limited to the right prefrontal cortex. Post-ictally, perfusion was reduced in bilateral frontal and occipital cortices and increased in left motor and precuneus cortex. CONCLUSION: FEAST appears to triggers focal onsets of seizure activity in the right prefrontal cortex with subsequent generalization. Future studies are needed on a larger sample. PMID- 24795199 TI - Therapy of hepatitis C--back to the future. PMID- 24795202 TI - United States private schools have higher rates of exemptions to school immunization requirements than public schools. AB - OBJECTIVE: To compare medical, religious, and personal belief immunization exemption rates between private and public schools in US. STUDY DESIGN: Exemption rates were calculated using the Centers for Disease Control and Prevention School Immunization Assessment Surveys for the 2009-2010 school year excluding states with incomplete survey data. Standardized exemption rates weighted on enrollments in public and private schools were calculated. Differences in exemption rates between public and private schools were tested using Wilcoxon signed rank test. RESULTS: The overall state exemption rate was higher in US private than public schools, 4.25% (SD 4.27) vs 1.91% (1.67), P = .0001 and private schools had higher exemption rates for all types of exemptions; medical 0.58% (0.71) vs 0.34% (0.34) respectively (P = .0004), religious 2.09% (3.14) vs 0.83% (1.05) respectively (P = .0001), and personal belief 6.10% (4.12) vs 2.79% (1.57), respectively (P = .006). Overall exemption rates were significantly higher in states that allowed personal belief exemptions. CONCLUSIONS: Exemption rates were significantly higher in US private than in public schools. Children attending private schools may be at higher risk of vaccine-preventable diseases than public school children. PMID- 24795200 TI - ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. AB - BACKGROUND: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.). PMID- 24795201 TI - Sofosbuvir and ribavirin in HCV genotypes 2 and 3. AB - BACKGROUND: In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection. METHODS: We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus. CONCLUSIONS: Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. (Funded by Gilead Sciences; VALENCE ClinicalTrials.gov number, NCT01682720.). PMID- 24795203 TI - Real life clinic visits do not match the ideals of shared decision making. AB - OBJECTIVE: To use observation to understand how decisions about higher-risk treatments, such as biologics, are made in pediatric chronic conditions. METHODS: Gastroenterology and rheumatology providers who prescribe biologics were recruited. Families were recruited when they had an outpatient appointment in which treatment with biologics was likely to be discussed. Consent/assent was obtained to video the visit. Audio of the visits in which a discussion of biologics took place were transcribed and analyzed. Our coding structure was based on prior research, shared decision making (SDM) concepts, and the initial recorded visits. Coded data were analyzed using content analysis and comparison with an existing model of SDM. RESULTS: We recorded 21 visits that included discussions of biologics. In most visits, providers initiated the decision-making discussion. Detailed information was typically given about the provider's preferred option with less information about other options. There was minimal elicitation of preferences, treatment goals, or prior knowledge. Few parents or patients spontaneously stated their preferences or concerns. An implicit or explicit treatment recommendation was given in nearly all visits, although rarely requested. In approximately one-third of the visits, the treatment decision was never made explicit, yet steps were taken to implement the provider's preferred treatment. CONCLUSIONS: We observed limited use of SDM, despite previous research indicating that parents wish to collaborate in decision making. To better achieve SDM in chronic conditions, providers and families need to strive for bidirectional sharing of information and an explicit family role in decision making. PMID- 24795204 TI - Isolated adult Tillaux fracture: a report of two cases. AB - A fracture of the lateral margin of the distal tibia has commonly been called a Tillaux fracture, which is an avulsion-type fracture that can result from the pull of the anterior inferior tibiofibular ligament. The common mechanism of injury described and observed has been one of external rotation of the foot relative to the tibia. Historically, this fracture pattern has been noted in the pediatric and adolescent populations and classified as a Salter-Harris III fracture through the epiphysis. It has typically occurred in children aged 12 to 14 years and is not commonly seen in adults. We discuss 2 cases of isolated Tillaux fractures in skeletally mature adults, aged 47 and 37 years, a population in which this fracture pattern to our knowledge and after review of the published data has not been described. It is important to recognize these distinct injuries and appropriately treat the pathologic features to prevent further instability and arthritis. PMID- 24795205 TI - Ankle salvage surgery with autologous circular pillar fibula augmentation and intramedullary hindfoot nail. AB - Tibiotalocalcaneal arthrodesis with an intramedullary hindfoot nail is an established procedure for fusion of the ankle and subtalar joints. In cases involving ankle bone loss, such as in failed total ankle replacement, it can be difficult to salvage with sufficient bone restoration stability and a physiologic leg length and avoiding below the knee amputation. In addition to the alternatives of using a structural allograft or metal bone substitution, we describe the use of autologous ipsilateral circular pillar fibula augmentation in tibiotalocalcaneal retrograde nail arthrodesis combined with a ventral (anterior) plate in a prospective series of 6 consecutive cases with a mean follow-up duration of 26 +/- 9.95 (range 12 to 34) months. The 6 patients (3 female and 3 male), with a mean age of 55 +/- 13.89 (range 38 to 73) years were treated with revision surgery of the ankle (1 after talectomy, 5 [83.33%] after failed ankle replacement). The visual analog scale for pain and the American Orthopaedic Foot and Ankle Society hindfoot score were used to assess functional outcome, and radiographs and computed tomography scans were used to determine the presence of fusion. All patients improved clinically from pre- to postoperatively in regard to the mean pain visual analog scale score (from 7.5 to 2.0) and American Orthopaedic Foot and Ankle Society hindfoot score (from 29 to 65 points, of an 86 point maximum for fused joints). Radiologically, no loss in the reduction or misalignment of the hindfoot was detected, and all cases fused solid. One patient (16.67%) required hardware removal. The fixation construct provided good clinical and radiologic outcomes, and we recommend it as an alternative to structural allografts or metallic bone grafts for revision ankle surgery with severe bone loss. PMID- 24795206 TI - Complications after revision surgery of malreduced ankle fractures. AB - Ankle fractures are common orthopedic injuries requiring reduction and cast immobilization or fixation. Fractures fixed in a malreduced (misaligned) position can require revision surgery. However, because this has been a relatively rare occurrence, little is known about the complications that can occur after such surgery. We reviewed all adult closed ankle fractures that underwent revision surgery for technical failure in a regional trauma hospital from January 2007 to January 2010. Those with open fractures and those who required external fixation at any point in their treatment were excluded. Nine patients underwent revision surgery during the study period. Of these 9 patients, 3 (33%) developed a deep infection, all with positive microbiology cultures for methicillin-sensitive Staphylococcus aureus. Each of these patients underwent removal of the metalwork and wound debridement, followed by plastic surgery free flap coverage. In addition to the 3 infection cases, those with noninfected complications included 1 patient (11%) with chronic regional pain syndrome, 1 (11%) with failure of plate fixation, and 1 (11%) with persistent pain requiring arthroscopy and debridement. The overall incidence of complications was 66.67% in this group of 9 patients who had undergone revision surgery for the treatment of a malreduced malleolar ankle fracture. Although our observational study involved a small subset of patients who had undergone surgical repair for ankle fracture, we suggest that if revision surgery will be undertaken, the high incidence of infection and the potential need for plastic surgery should be highlighted during the consent process before the original, open reduction internal fixation procedure. PMID- 24795207 TI - Evaluation of Lauge-Hansen designation of Weber C fractures. AB - Associations between Weber C ankle fractures and pronation external rotation (PER) injuries of the Lauge-Hansen classification have often been incorrectly correlated. The purpose of the present study was to evaluate the Lauge-Hansen designation of Weber C fractures by establishing the proportion of Weber C fractures that are supination external rotation (SER), supination adduction (SA), pronation abduction (PA), PER, and hyperplantarflexion variant fractures. A clinical database of operative ankle fractures treated by the senior author (D.G.L.) was reviewed. The inclusion criteria were patient age older than 16 years, preoperative ankle radiographs, and Weber C fracture designation. A total of 132 patients met the inclusion criteria, and the proportion of PA, PER, SER, SA, and variant fractures among the Weber C fractures was analyzed. PA fractures accounted for 0.8% (n = 1), PER fractures 56.8% (n = 75), SER fractures 35.6% (n = 47), and hyperplantarflexion variant fractures 6.8% (n = 9) of the 132 Weber C fractures. Patients with Weber C-PER fractures were more commonly male (p = .005) and younger (p = .003) and demonstrated a greater fibular fracture height (p < .001) than those with Weber C-SER and Weber C-variant fractures. Our study quantitatively demonstrated that not all Weber C fractures occur secondary to pronation injuries. This distinction is important, because all pronation injuries will demonstrate medial ankle injury, but SER and variant fractures might not. We therefore recommend careful evaluation of the fibular fracture characteristics, including the direction of fracture propagation and the distance from the tibial plafond, when classifying Weber C fractures using the Lauge-Hansen system, because correct classification is vital in preparation for appropriate operative treatment. PMID- 24795208 TI - Evidence-based rationale for percutaneous fixation technique of displaced intra articular calcaneal fractures: a systematic review of clinical outcomes. AB - Displaced intra-articular fractures of the calcaneus are complex and have a high degree of morbidity. Percutaneous fixation techniques have been advocated in an effort to minimize postoperative complications. We performed a systematic review of the clinical outcomes to describe and ascertain the different techniques and clinical outcomes for percutaneous treatment of displaced intra-articular calcaneal fractures. A review was performed using PubMed and Google Scholar, from January 2000 to December 2012, with studies ranging from case reports to prospective studies. The inclusion criteria consisted of percutaneous fixation techniques with objective findings (Sander's classification and Bohler's angle measurements) and clinical outcome scoring and complication and subtalar fusion rates. The exclusion criteria included studies with open or limited open procedures, the use of external fixation, the use of bone substitutes alone, and pathologic or open fractures. Data and evidence with a combination of objective findings and clinical outcomes are lacking. Several techniques for percutaneous fixation have been described, including Schanz pins and Kirschner wires, cannulated screws, arthroscopically guided percutaneous fixation, and application of bone substitute. A myriad of techniques are available for percutaneous intra articular calcaneal fixation. The results from the current data appear to be promising; however, the lack of statistical power and inconsistent documentation have made it difficult to determine any superiority. The complication rates were much lower than those with open procedures, regardless of the technique. The percutaneous fixation technique appears to be a favorable option for displaced intra-articular calcaneal fractures. PMID- 24795209 TI - Effect of sub-chronic intermittent ethanol exposure on spatial learning and ethanol sensitivity in adolescent and adult rats. AB - It has become clear that adolescence is a period of distinct responsiveness to the acute effects of ethanol on learning and other cognitive functions. However, the effects of repeated intermittent ethanol exposure during adolescence on learning and cognition are less well studied, and other effects of repeated ethanol exposure such as withdrawal and chronic tolerance complicate such experiments. Moreover, few studies have compared the effects of repeated ethanol exposure during adolescence and adulthood, and they have yielded mixed outcomes that may be related to methodological differences and/or secondary effects of ethanol on behavioral performance. One emerging question is whether relatively brief intermittent ethanol exposure (i.e., sub-chronic exposure) during adolescence or adulthood might alter learning at a time after exposure when chronic tolerance would be expected, and whether tolerance to the cognitive effects of ethanol might influence the effect of ethanol on learning at that time. To address this, male adolescent and adult rats were pre-treated with sub chronic daily ethanol (five doses [4.0 g/kg, i.p.] or saline at 24-h intervals, across 5 days). Two days after the last pre-exposure, spatial learning was assessed on 4 consecutive days using the Morris water maze. Half of the animals from each treatment cell received ethanol (2.0 g/kg, i.p.) 30 min prior to each testing session and half of the animals received saline. Ethanol pre-exposure altered water maze performance in adult animals but not in adolescents, and acute ethanol exposure impaired learning in animals of both ages independent of pre exposure condition. There was no evidence of cognitive tolerance in animals of either age group. These results indicate that a relatively short period of intermittent ethanol exposure during adulthood, but not adolescence, promotes thigmotaxis in the water maze shortly after pre-exposure but does not induce cognitive tolerance to the effects of ethanol in either age group. PMID- 24795210 TI - ICDs at higher age and clinical risk factors. AB - BACKGROUND: The implantable cardioverter defibrillator (ICD) is effective in preventing sudden cardiac death. However, in elderly patients (aged 75 years or older) the role of ICDs is still not well-defined and controversial. METHODS: We retrospectively analysed all clinical and survival data of all ICD patients who were >=75 years at the date of implantation in the Erasmus MC, Rotterdam, the Netherlands and the University Hospital, Basel, Switzerland. Kaplan-Meier survival analysis was performed, and mortality predictors were identified. Mortality of the cohort was compared with a random sample of patients aged 60-70 years originating from the same database and to an age- and sex-matched cohort of Dutch persons. RESULTS: The study cohort consisted of 179 patients aged 75 years or older who were implanted between February 1999 and July 2008. The median follow-up time was 2.0 (IQR 2.8) years. Survival rates after 1, 2 and 3 years were 87, 82, 75 %, respectively. Survival was similar for primary and secondary prevention. Mortality in this study population could be predicted by combining four clinical risk factors: QRS duration >120 ms, NYHA class > II, renal failure and atrial fibrillation (AF). Survival was worse compared with the group of ICD patients aged 60-70 years and to the age- and sex-matched group of elderly persons. However, survival was not significantly worse when comparing elderly ICD patients without additional risk factors to the general population. CONCLUSIONS: Elderly patients still have an acceptable survival probability independent of prevention indication, certainly if there are no additional clinical risk factors. The presence or absence of additional clinical risk factors should be taken into account when making the decision for implantation, since they strongly correlate with survival. PMID- 24795211 TI - Non-diabetic renal disease in Croatian patients with type 2 diabetes mellitus. AB - AIM: Our study aimed to examine the prevalence of non-diabetic renal disease in selected patients with type 2 diabetes mellitus and to determine important risk factors for non-diabetic renal disease. METHODS: We conducted retrospective analysis of clinical, laboratory and pathohistological data of type 2 diabetes mellitus patients in whom renal biopsies were performed from January 2004 to February 2013 at Dubrava University Hospital Zagreb Croatia (n=80). RESULTS: According to renal biopsy findings, isolated diabetic nephropathy was found in 46.25%, non-diabetic renal disease superimposed on diabetic nephropathy in 17.5% and isolated non-diabetic renal disease in 36.25% of the patients. The most common non-diabetic renal diseases found were: membranous nephropathy, followed by IgA nephropathy and focal segmental glomerulosclerosis. In univariate analysis shorter duration of diabetes, independence of insulin therapy, lower levels of HbA1c and absence of diabetic retinopathy were found to be significant clinical predictors of non-diabetic renal disease. In multivariate analysis only independence of insulin therapy (OR 4.418, 95%CI=1.477-13.216) and absence of diabetic retinopathy (OR 5.579, 95%CI=1.788-17.404) were independent predictors of non-diabetic renal disease. CONCLUSIONS: This study confirmed usefulness of renal biopsy in patients with type 2 diabetes mellitus, due to the high prevalence of non-diabetic renal disease found. Since non-diabetic renal disease are potentially curable, we should consider renal biopsy in selected type 2 diabetes mellitus patients with renal involvement, especially in those with absence of diabetic retinopathy and independence of insulin therapy. PMID- 24795212 TI - Spatio-temporal dynamics of dengue 2009 outbreak in Cordoba City, Argentina. AB - During 2009 the biggest dengue epidemic to date occurred in Argentina, affecting almost half the country. We studied the spatio-temporal dynamics of the outbreak in the second most populated city of the country, Cordoba city. Confirmed cases and the results of an Aedes aegypti monitoring during the outbreak were geolocated. The imported cases began in January, and the autochthonous in March. Thirty-three percent of the 130 confirmed cases were imported, and occurred mainly at the center of the city. The autochthonous cases were more frequent in the outskirts, specially in the NE and SE. Aedes aegypti infestation showed no difference between neighborhoods with or without autochthonous cases, neither between neighborhoods with autochthonous vs. imported cases. The neighborhoods with imported cases presented higher population densities. The majority of autochthonous cases occurred at ages between 25 and 44 years old. Cases formed a spatio-temporal cluster of up to 20 days and 12km. According to a mathematical model that estimates the required number of days needed for transmission according to daily temperature, the number of cases begun to fall when more than 15.5 days were needed. This may be a coarse estimation of mean mosquito survival in the area, provided that the study area is close to the global distribution limit of the vector, and that cases prevalence was very low. PMID- 24795213 TI - Diversity and abundance of mosquito species in relation to their larval habitats in Mizoram, North Eastern Himalayan region. AB - The abundance, richness and diversity of anopheline and culicid mosquitoes associated with their habitats, season, and physico-chemical quality of water were surveyed along six districts of Mizoram, North Eastern Himalayan region. The productivity of permanent and temporary habitat types was quantified by carrying out weekly larval sampling using a standard dipping method for a period of three years. Diversity was estimated using the Shannon index (H'), Evenness index (Heve), similarity measures cluster analysis and MANOVA. In total, 5 genera and 20 species of mosquitoes were identified: Culex quinquefasciatus, Anopheles barbirostris and Anopheles vagus were the most abundant and widely-distributed species, representing 39.71%, 29.39% and 14.52% of total mosquito individuals sampled, respectively. Anopheles sp. diversity was lowest in Lunglei district (H'=0.48) and highest in Aizawl (H'=2.03), whereas Culex sp. diversity was lowest in Lawngtlai (H'=0.38), and highest in Aizawl (H'=2.99) and Kolasib (H'=2.13). This represents the first update on the diversity and geographic distribution of the mosquitoes of Mizoram. Mosquito larvae were present in both temporary and permanent habitats suitable for breeding with monthly variations dependent on rainfall intensity, temperature, humidity and location. Early instars were more abundant significantly (P<0.0001) than late instars among the habitat types in all study sites. The productivity of mosquito larvae was significantly (P<0.0001) higher in ponds especially in permanent than semi-permanent and temporary. Weekly rainfall intensity led to an increase or decrease in anopheline and culicid larval abundance depending on the location. Mosquito diversity was highest in monsoon season (July-September) and lowest in January-March. A. barbirostris, A. vagus and C. quinquefasciatus appear the most likely habitat generalist as it demonstrates both widespread distribution. Abundance and diversity of culicine and anopheline larvae were strongly associated (MANOVA) with pH, temperature, dissolved oxygen, alkalinity, phosphates and chlorides concentration of water. This information will be essential for designing and implementing mosquito larval control programs. PMID- 24795214 TI - Molecular phylogenetics and microsatellite analysis reveal cryptic species of speckled dace (Cyprinidae: Rhinichthys osculus) in Oregon's Great Basin. AB - Speckled dace (Rhinichthys osculus) is a small cyprinid that occurs throughout western North America and is the most commonly occurring fish in Oregon. Because of the high genetic and morphological variation in this species across its range, it has been referred to as a species complex; however, no revision to its taxonomy has occurred since 1984. Here, the phylogenetics and population genetics of speckled dace are examined throughout Oregon's Great Basin to describe genetic variation and infer the geographic boundaries between distinct taxonomic entities and populations. We tested the validity of a putative subspecies, Foskett Spring speckled dace, that occurs in a single spring within Warner Valley in Southeast Oregon and is listed Federally as threatened. Dace were collected from Foskett Spring and all surrounding basins containing speckled dace (Warner, Goose Lake, Lake Abert, Silver Lake, and Malheur), as well as Stinking Lake Spring (located within Malheur), created phylogenetic trees from mitochondrial ND2 and nuclear S7 sequence data, and genotyped eight microsatellite loci for population-level analyses. Three highly divergent clades warrant species-level status: Malheur stream dace, Stinking Lake Spring dace, and dace from the other four basins combined. Although Foskett Spring dace were not monophyletic, substantial population structure occurs at the basin-level and separates Foskett Spring dace from other dace in the surrounding Warner Valley. Thus, we recommend ESU status for the isolated population of speckled dace in Foskett Spring. The high, previously unrecognized, taxonomic diversity within this region indicates a need for a range-wide phylogeographic study of speckled dace and an investigation of the morphological distinctiveness of the putative new species. PMID- 24795215 TI - The phylogeography of Eurasian Fraxinus species reveals ancient transcontinental reticulation. AB - To investigate the biogeographical history of ashes species of the Eurasian section Fraxinus and to test the hypothesis of ancient reticulations, we sequenced nuclear DNA (nETS and nITS, 1075 bp) for 533 samples and scored AFLP for 63 samples of Eurasian ashes within the section Fraxinus. The nITS phylogeny retrieved the classical view of the evolution of the section, whereas nETS phylogeny indicated an unexpected separation of F. angustifolia in two paraphyletic groups, respectively found in southeastern Europe and in the other parts of the Mediterranean basin. In the nETS phylogeny, the former group was closely related to F. excelsior, whereas the later was closely related to F. mandshurica, a species which is restricted nowadays to northeastern Asia. This topological incongruence between the two loci indicated the occurrence of an ancient reticulation between European and Asian ash species. Several other ancient reticulation events between the two European species and the other species of the section were supported by the posterior predictive checking method. Some of these reticulation events would have occurred during the Miocene, when climatic variations may have lead these species to expand their distribution range and come into contact. The recurrent reticulations observed among Eurasian ash species indicate that they should be considered as conspecific taxa, with subspecific status for some groups. Altogether, the results of the present study provide a rare documented evidence for the occurrence of multiple ancient reticulations within a group of temperate tree taxa with modern disjunct distributions in Eurasia. These ancient reticulation events indicate that the speciation process is slow in ashes, necessitating long periods of geographical isolation. The implications for speciation processes in temperate trees with similar life history and reproductive biology are discussed. PMID- 24795216 TI - Psychological distress in an incarcerated juvenile population. AB - BACKGROUND/PURPOSE: This study sought to examine the prevalence and correlates of psychological distress among incarcerated youth in Taiwan using the 5-item Brief Symptom Rating Scale (BSRS-5). METHODS: This cross-sectional census survey study was conducted in 2007 among all the juveniles incarcerated in 23 correctional institutions (n = 1505) in Taiwan using a self-administered anonymous questionnaire. Of the total 1505 participants, 1363 completed the questionnaire (91% response rate). We excluded 494 participants as they were aged either over 17 years or under 12 years. Psychological distress was measured among the final 869 participants using the BSRS-5. Psychological distress was defined as a total score of at least 6 out of 20. Those identified as having psychological distress were then pooled into a case group and compared with control participants without psychological distress. RESULTS: The prevalence of psychological distress was 44.1%. Among the case group, sleep disturbance (36.8%) had the highest prevalence of severe or very severe symptoms, followed by depression (34.7%), and hostility (27.9%). Multivariate logistic regression analysis revealed that correlates of psychological distress included the following: being female; having a poor self rated health status; having joined a gang; having experienced life disturbances prior to the current imprisonment; and having ever had a smoking habit. CONCLUSION: Significant sex differences were found for both the overall BSRS-5, as well as for each individual item of the BSRS-5. Treatment programs and interventions should be carefully tailored to address the mental health needs of juvenile inmates in a sex-specific manner using a multifaceted approach. PMID- 24795217 TI - Contextual factors influencing leisure physical activity of urbanized indigenous adolescents. AB - BACKGROUND/PURPOSE: Indigenous populations suffer from disparities in socioeconomic resources and health status. One approach to addressing these disparities is by targeting modifiable risk factors such as leisure physical activity (LPA). This study investigated and compared factors related to LPA among urbanized indigenous and nonindigenous adolescent students. METHODS: This cross sectional survey comprised fifth to ninth grade indigenous and nonindigenous students (n = 733). The nonindigenous students were matched with indigenous students on sex and academic achievement and used as a reference group. Data were collected through telephone interviews using structured questionnaires. Major items included: demographic characteristics; average time spent watching television per bout; participation in LPA; and stress and depression experiences. RESULTS: With the exception of the duration of television watching per bout, Chi square and independent t tests demonstrated that there were no significant differences between indigenous and nonindigenous adolescents in the selected LPA related factors. Multiple logistic regression analysis including terms investigating interaction between ethnicity and the contextual factors included in this study indicated that the following factors were correlated with LPA participation: age [odds ratio (OR) = 0.82, 95% confidence interval (CI) = 0.71 0.94], male sex (OR = 1.77, 95%CI = 1.19-2.61), total hours spent watching television in the past 2 weeks (OR = 0.79, 95%CI = 0.63-0.99), life satisfaction (OR = 2.25, 95%CI = 1.04-4.90), and exercise enjoyment (OR = 3.40, 95%CI = 1.71 6.74). However, neither indigenous status (OR = 1.03, 95%CI = 0.19-5.79) nor any of the interaction terms reached the significant level. CONCLUSION: No significant ethnic differences were found in LPA participation. LPA was significantly correlated with age, male sex, total time spent watching television, life satisfaction, and enjoyment of exercise. PMID- 24795218 TI - What is hepcidin telling us about the natural history of cystic fibrosis? PMID- 24795219 TI - Anthocyanidins pelargonidin and cyanidin reduce genotoxic stress in mice - possible involvement of aryl hydrocarbon receptor in the process. PMID- 24795220 TI - Expert's comment concerning Grand Rounds case entitled "vertebral column resection for complex congenital kyphoscoliosis and type I split cord malformation" (Hua Hui, Zhen-Xing Zhang, Tuan-Min Yang, Bao-Rong He, Ding-Jun Hao). AB - INTRODUCTION: Comment on a case report on a challenging case of a severe spinal congenital deformity with a type I split spinal cord malformation (SSCM) in a 23 year-old with initial neurological symptoms. MATERIAL AND METHODS: The patient was treated with a halo gravity traction over one month. A posterior vertebral column resection cephalad to the bony spur at T12 was done and moderate frontal and sagittal plane curve correction was achieved without resection of the bony spur. CONCLUSIONS: In conclusion, despite a quite clear recommendation in the current literature to first surgically address the type 1 SSCM prior to correction of any spinal deformity, the authors of the present case chose to leave the bony spur. Still it remains to be seen if in this very case the spur will become clinically apparent in the future or not. As long as larger studies on curve correction without spur resection in SSCM are not available, spur resection prior to any type of curve correction remains the golden standard. PMID- 24795221 TI - Lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies. AB - A feature of neurodegenerative diseases is the intraneuronal accumulation of misfolded proteins. In familial encephalopathy with neuroserpin inclusion bodies (FENIB), mutations in neuroserpin lead to accumulation of neuroserpin polymers within the endoplasmic reticulum (ER) of neurons. Cell culture based studies have shown that ER-associated degradation (ERAD) is involved in clearance of mutant neuroserpin. Here, we investigate how mutant neuroserpin is delivered to ERAD using cell culture and a murine model of FENIB. We show that the ER-lectin OS-9 but not XTP3-B is involved in ERAD of mutant neuroserpin. OS-9 binds mutant neuroserpin and the removal of glycosylation sites leads to increased neuroserpin protein load whereas overexpression of OS-9 decreases mutant neuroserpin. In FENIB mice, OS-9 but not XTP3-B is differently expressed and impairment of ERAD by partial inhibition of the ubiquitin proteasome system leads to increased neuroserpin protein load. These findings show that OS-9 delivers mutant neuroserpin to ERAD by recognition of glycan side chains and provide the first in vivo proof of involvement of ERAD in degradation of mutant neuroserpin. PMID- 24795223 TI - Non-invasive pneumococcal serotypes and antimicrobial susceptibilities in a paediatric hospital in the era of conjugate vaccines. AB - To evaluate the effects of 7-valent pneumococcal conjugate vaccine (PCV7) introduction to the routine childhood immunisation schedule in 2008 and its replacement by PCV13 in 2010 in Ireland, we surveyed the serotypes and antimicrobial susceptibilities of 339 pneumococci associated with carriage and non-invasive infection (NII) in a Dublin paediatric hospital from 2009 to 2012. Furthermore, we compared the distribution of pneumococcal serotypes collected from 2009 to 2012 to 105 NII pneumococci isolated in 2007, the year before conjugate vaccine introduction. PCV7 serotypes declined from 2007 to 2012 as follows: carriage, 67-23% (p=0.0004); conjunctivitis, 58-0% (p<0.0001); non bacteraemic lower respiratory tract infection, 50-19% (p=0.0363) and otitis media 54-27%. Notably, antimicrobial resistant (AMR) PCV7 serotypes showed a significant decrease by the end of the study period (i.e. 2012) (p<0.0001). Compared with 2007 the overall occurrence of serotype 19A increased from 1.9 to 10% in 2010 (p=0.0132) and to 15% in 2011 (p=0.0005). Importantly, serotype 19A declined significantly from 2011 levels to an overall prevalence of 4.8% in 2012 (p=0.0243). Most striking was the significant reduction of AMR 19A (p=0.0195). Conversely, increases were observed in non-vaccine type (NVT) pneumococci in 2009 2012, of which serotypes 11A (n=30), 15B/C (n=17), 22F (n=14), 35Bn=13), non typeable pneumococci (n=13) and 23A (n=12) were the most prevalent. Moreover, an increase in NVT non-susceptible to at least one antimicrobial in 2009-2012 was noted, attributable to serotypes 35B (n=10) and 15A (n=7). In summary, this study has shown that PCV7 and PCV13 introduction has had a positive impact on their target serotypes and antimicrobial resistance amongst pneumococci within a paediatric hospital within a short time period. However, the increase in NVT prevalence highlights the need for continued surveillance. PMID- 24795222 TI - Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers. AB - Maternal embryonic leucine zipper kinase (MELK) is a member of the snf1/AMPK family of protein serine/threonine kinases that has recently gained significant attention in the stem cell and cancer biology field. Recent studies suggest that activation of this kinase is tightly associated with extended survival and accelerated proliferation of cancer stem cells (CSC) in various organs. Overexpression of MELK has been noted in various cancers, including colon, breast, ovaries, pancreas, prostate, and brain, making the inhibition of MELK an attractive therapeutic strategy for a variety of cancers. In the experimental cancer models, depletion of MELK by RNA interference or small molecule inhibitors induces apoptotic cell death of CSCs derived from glioblastoma multiforme and breast cancer, both in vitro and in vivo. Mechanism of action of MELK includes, yet may not be restricted to, direct binding and activation of the oncogenic transcription factors c-JUN and FOXM1 in cancer cells but not in the normal counterparts. Following these preclinical studies, the phase I clinical trial for advanced cancers with OTSSP167 started in 2013, as the first-in-class MELK inhibitor. This review summarizes the current molecular understanding of MELK and the recent preclinical studies about MELK as a cancer therapeutic target. PMID- 24795224 TI - Integrated package approach in delivering interventions during immunisation campaigns in a complex environment in Papua New Guinea: a case study. AB - Papua New Guinea's difficult and varied topography, poor transport infrastructure, changing dynamics of population and economy in recent times and understaffed and poorly financed health service present major challenges for successful delivery of vaccination and other preventative health interventions to both the rural majority and urban populations, thereby posing risks for vaccine preventable disease outbreaks in the country. The country has struggled to meet the vaccination coverage targets required for the eradication of poliomyelitis and elimination of measles. Escalation of inter and intra country migration resulting from major industrial developments, particularly in extraction industries, has substantially increased the risk of infectious disease importation. This case study documents the evolution of immunisation programmes since the introduction of supplementary immunisation activities (SIAs). Single antigen SIAs have advantages and disadvantages. In situations in which the delivery of preventative health interventions is difficult, it is likely that the cost benefit is greater for multiple than for single intervention. The lessons learned from the conduct of single antigen SIAs can be effectively used for programmes delivering multiple SIA antigens, routine immunisations, and other health interventions. This paper describes a successful and cost effective multiple intervention programme in Papua New Guinea. The review of the last SIA in Papua New Guinea showed relatively high coverage of all the interventions and demonstrated the operational feasibility of delivering multiple interventions in resource constrained settings. Studies in other developing countries such as Lesotho and Ethiopia have also successfully integrated health interventions with SIA. In settings such as Papua New Guinea there is a strong case for integrating supplementary immunisation activity with routine immunisation and other health interventions through a comprehensive outreach programme. PMID- 24795225 TI - Protective efficacy of a bacterially produced modular capsomere presenting M2e from influenza: extending the potential of broadly cross-protecting epitopes. AB - Influenza A viruses drift and shift, emerging as antigenically distinct strains that lead to epidemics and pandemics of varying severity. Even epitopes associated with broad cross-protection against different strains, such as the ectodomain of matrix protein 2 (M2e), mutate unpredictably. Vaccine protective efficacy is only ensured when the emerging virus lies within the vaccine's cross protective domain, which is poorly defined in most situations. When virus emerges outside this domain it is essential to rapidly re-engineer the vaccine and hence re-center the cross-protective domain on the new virus. This approach of vaccine re-engineering in response to virus change is the cornerstone of the current influenza control system, based on annual prediction and/or pandemic reaction. This system could become more responsive, and perhaps preventative, if its speed could be improved. Here, we demonstrate vaccine efficacy of a rapidly manufacturable modular capsomere presenting the broadly cross-protecting M2e epitope from influenza. M2e inserted into a viral capsomere at the DNA level was expressed in Escherichia coli as a fusion protein (Wibowo et al., 2013). Immunization of mice with this modular capsomere adjuvanted with conventional aluminum hydroxide induced high (more than 10(5) endpoint titer) levels of M2e specific antibodies that reduced disease severity and viral load in the lungs of challenged mice. The combination of rapid manufacturability of modular capsomere presented in this study, and the established cross-protective efficacy of M2e, allow rapid matching of vaccine to the circulating virus and hence rapid re centering of the vaccine's cross-protective domain onto the virus. This approach synergizes the discussed benefits of broadly cross-protecting epitopes with rapid scale-up vaccine manufacture using microbial cell factories. PMID- 24795226 TI - Designing the epitope flanking regions for optimal generation of CTL epitopes. AB - The flanking amino acids that surround epitopes are critical for effective antigen processing and maintenance of epitope integrity. In the present study, the frequency and characteristics of each amino acid that flanked the peptides generated from the proteasomal degradation of three different subtypes of HIV-1 Gag-p24 were determined. Synthetic flanking regions were designed based on the highest and the lowest frequencies of amino acid with the ideal characteristics at positions upstream and downstream of the proteasomal cleavage site. Peptides were synthesized that contained known CD8+ CTL-epitopes from HIV-1 Gag, CMV pp65, and vaccinia proteins HRP-2, and C16, flanked by amino acid sequences specifically designed to either generate or inhibit the known CD8+ CTL-epitopes. As predicted, the known CD8+ CTL-epitopes were effectively generated from the peptides with synthetic flanking regions specifically designed to promote epitope generation in a proteasome-dependent manner. The majority of the proteasome generated epitopes were cleaved immediately after the C-terminal amino acid of the specific CTL-epitope. The synthetic peptide sequences containing known CD8+ CTL-epitopes with the flanking regions that promote epitope generation were effectively processed and presented to epitope specific CD8+ T-cells resulting in the production of IFN-gamma. These results highlight the importance of flanking regions in promoting efficient antigen processing and presentation. This concept can have important implications in vaccine design and development strategies. PMID- 24795227 TI - An algorithm developed using the Brighton Collaboration case definitions is more efficient for determining diagnostic certainty. AB - The Brighton Collaboration is a global research network focused on vaccine safety. The Collaboration has created case definitions to determine diagnostic certainty for several adverse events. Currently nested within multi-page publications, these definitions can be cumbersome for use. We report the results of a randomized trial in which the case definition for anaphylaxis was converted into a user-friendly algorithm and compared the algorithm with the standard case definition. The primary outcomes were efficiency and accuracy. Forty medical students determined the Brighton Level of diagnostic certainty of a sample case of anaphylaxis using either the algorithm or the original case definition. Most participants in both groups selected the correct Brighton Level. Participants using the algorithm required significantly less time to review the case and determine the level of diagnostic certainty [mean difference=107 s (95% CI: 13 200; p=0.026)], supporting that the algorithm was more efficient without impacting accuracy. PMID- 24795228 TI - European enhanced surveillance of invasive pneumococcal disease in 2010: data from 26 European countries in the post-heptavalent conjugate vaccine era. AB - Streptococcus pneumoniae is a leading cause of severe infectious diseases worldwide. This paper presents the results from the first European invasive pneumococcal disease (IPD) enhanced surveillance where additional and valuable data were reported and analysed. Following its authorisation in Europe in 2001 for use in children aged between two months and five years, the heptavalent pneumococcal conjugate vaccine (PCV7) was progressively introduced in the European Union (EU)/European Economic Area (EEA) countries, albeit with different schemes and policies. In mid-2010 European countries started to switch to a higher valency vaccine (PCV10/PCV13), still without a significant impact by the time of this surveillance. Therefore, this surveillance provides an overview of baseline data from the transition period between the introduction of PCV7 and the implementation of PCV10/PCV13. In 2010, 26 EU/EEA countries reported 21 565 cases of IPD to The European Surveillance System (TESSy) applying the EU 2008 case definition. Serotype was determined in 9946/21565 (46.1%) cases. The most common serotypes were 19A, 1, 7F, 3, 14, 22F, 8, 4, 12F and 19F, accounting for 5949/9946 (59.8%) of the serotyped isolates. Data on antimicrobial susceptibility testing (AST) in the form of minimum inhibitory concentrations (MIC) were submitted for penicillin 5384/21565 (25.0%), erythromycin 4031/21565 (18.7%) and cefotaxime 5252/21565 (24.4%). Non-susceptibility to erythromycin was highest at 17.6% followed by penicillin at 8.9%. PCV7 serotype coverage among children <5 years in Europe, was 19.2%; for the same age group, the serotype coverage for PCV10 and PCV13 were 46.1% and 73.1%, respectively. In the era of pneumococcal conjugate vaccines, the monitoring of changing trends in antimicrobial resistance and serotype distribution are essential in assessing the impact of vaccines and antibiotic use control programmes across European countries. PMID- 24795229 TI - Subolesin: a candidate vaccine antigen for the control of cattle tick infestations in Indian situation. AB - Identification of cross-protective tick vaccine antigens is a challenging area of veterinary research. To address this challenge, a recently identified candidate tick protective antigen, Subolesin (SUB), was targeted in this research. The conservation of subolesin ortholog of Hyalomma anatolicum and Rhipicephalus (Boophilus) microplus across different Indian strains was 98.1-99.4% (within species), while at the amino acid level SUB sequence homology was >=53.2% (between tick species). Recombinant R. (B.) microplus SUB (rBmSu) was produced in Escherichia coli and characterized. Cross-bred cattle male calves (N=10) were immunized with three doses of 100 MUg each of the rBmSu emulsified in 10% Montanide 888 at monthly intervals on days 0, 30 and 60. The control group was injected with PBS in 10% Montanide 888. For the first tick challenge, calves were infested with larvae of R. (B.) microplus generated from 100mg eggs 2 weeks after last immunization (day 75). The immunization resulted in 16.3%, 8.0%, 9.4%, and 26.1% reduction in female tick numbers (DT), weight (DW), oviposition (DO) and egg fertility (DF), respectively, when compared to controls. In the subsequent challenge on day 105, DT, DW, DO and DF were reduced by 9.0%, 4.1%, 8.6%, and 24.2%, respectively, when compared to controls. The vaccine efficacy (E) was equal to 44.0% and 37.2% after the first and second challenges, respectively. The results showed a positive correlation between antibody titers for both total IgG and IgG1 and E in the second but not in the first tick challenge. These results suggested the possibility of developing a SUB-based vaccine for control of cattle tick infestations under Indian conditions. PMID- 24795230 TI - Quinocetone-induced Nrf2/HO-1 pathway suppression aggravates hepatocyte damage of Sprague-Dawley rats. AB - Quinocetone (3-methyl-2-quinoxalin benzenevinylketo-1,4-dioxide, QCT) is a widely used veterinary drug in PR China that promotes feed efficiency and growth of various animals. However, its potential toxicity has been concerned recently. In the present study, we investigated QCT-induced hepatocyte changes and its related mechanism, especially the expression of Nrf2/HO-1 pathway. Oxidative stress induced by QCT in hepatocyte led to DNA damage, inflammation and apoptosis. Nevertheless, hepatocyte has a self-repair system to protect itself from oxidative stress. In the 50 mg/kg/day QCT group, the morphology and function of liver were approximately maintained on normal level, which indicated that the damaged cell might have a self-repair mechanism. Notably, nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway plays a critical role in protecting cells against reactive oxygen species (ROS) generation. However, higher doses of QCT (800 mg/kg/day and 2400 mg/kg/day) inhibited the expression of Nrf2/HO-1 pathway, which resulted in excessive ROS generation and irreversible oxidative DNA damage, inflammation and apoptosis. In conclusion, although QCT-induced oxidative stress activates the expression of Nrf2/HO-1 pathway initially, persistent QCT exposure will inhibit this expression and aggravate hepatocyte damage. Simultaneously, inflammation and apoptosis continues to progress, liver dysfunction and tissue damage will be occurred eventually. PMID- 24795231 TI - Neuroprotective effects of xanthone derivative of Garcinia mangostana against lead-induced acetylcholinesterase dysfunction and cognitive impairment. AB - Lead poisoning is a common environmental toxicity and low level of lead exposure is responsible for neurobehavioral or intelligence defects. This study was designed to investigate the protective effect of a xanthone derivative of Garcinia mangostana against lead-induced acetycholinesterase (AChE) dysfunction and cognitive impairment in mice. ICR mice were exposed to lead acetate (Pb) in drinking water (1%) with or without xanthone co-administration (100 and 200mg/kgBW/day) for 38days. Xanthone possesses a high phenolic content, which is positive correlation with its antioxidant activity (R(2)=0.98). The IC50 of xanthone on scavenging free radical activities, hydroxyl radical, superoxide radical, hydrogen peroxide and nitric oxide in cell-free system were 0.48+/-0.08, 1.88+/-0.09, 2.20+/-0.03 and 0.98+/-0.40mg/mL, respectively. We found that Pb induced AChE dysfunction and memory deficit in a dose dependent manner, indicated by in vitro and in vivo studies. However, xanthone significantly restored AChE activity in the blood and brains of mice and prevented Pb-induced neurobehavioral defect indicators with Forced Swimming and Morris water maze tests. Xanthone treatment improved all indicators compared to the Pb-treated group. In conclusion, xanthone alleviates Pb-induced neurotoxicity, in part, by suppression of oxidative damage and reversing AChE activity with a reduction in learning deficit and memory loss. PMID- 24795232 TI - Reduced scytonemin isolated from Nostoc commune suppresses LPS/IFNgamma-induced NO production in murine macrophage RAW264 cells by inducing hemeoxygenase-1 expression via the Nrf2/ARE pathway. AB - Reduced scytonemin (R-scy) and scytonemin (Scy) isolated from Nostoc commune exhibit anti-tumor and ultraviolet-absorbing properties. In this study, we examined the effects of R-scy and Scy on the induction of nitric oxide (NO) production by lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) in murine macrophage RAW264 cells. While both R-scy and Scy suppressed LPS/IFNgamma-induced NO production, R-scy exhibited a stronger inhibitory effect compared with Scy. To further elucidate the mechanisms underlying the anti-inflammatory effects of R scy, we examined the changes in the intracellular signaling cascade after LPS/IFNgamma stimulation in cells. In addition to the attenuation of LPS/IFNgamma induced upregulation of the inducible isoform of NO synthase, R-scy decreased the activity of nuclear factor-kappaB, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) after LPS/IFNgamma stimulation. R-scy treatment increased heme oxygenase-1 (HO-1) expression by increasing the intracellular levels of reactive oxygen species and thereby activating nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element signaling. The induction of HO-1 by R-scy was inhibited by pretreatment with an antioxidant, N-acetyl-cysteine (NAC), as well as SB203580 and LY294002, inhibitors for p38 MAPK and PI3K/Akt, respectively. Our findings suggest that the anti-inflammatory effects of R-scy could involve both the ROS/PI3K/Akt and the p38 MAPK/Nrf2 signaling pathways. PMID- 24795233 TI - Purple sweet potato color ameliorates kidney damage via inhibiting oxidative stress mediated NLRP3 inflammasome activation in high fat diet mice. AB - Inflammation plays a crucial role in the pathogenesis of obesity. Purple sweet potato color (PSPC) has potential anti-inflammation efficacy. We evaluated the effect of PSPC on kidney injury induced by high fat diet (HFD) and explored the mechanism underlying these effects. The results showed that PSPC (700 mg/kg per day) reduced body weight, ratio of urine albumin to creatinine, inflammatory cell infiltration, and Collagen IV accumulation in mice fed an HFD (60% fat food) for 20 weeks. PSPC significantly reduced the expression level of kidney NLRP3 inflammasome including NLRP3 and ASC and Caspase-1, and resulted in decline of IL 1beta. Moreover, PSPC inhibited the activation of I kappa B kinase beta (IKKbeta) and the nuclear translocation of nuclear factor kappa beta (NF-kappaB). Additionally, PSPC decreased the expression level of oxidative stress-associated AGE receptor (RAGE) and thioredoxin interacting protein (TXNIP) in the upstream of NLRP3 inflammasome. These data imply that the beneficial effects of PSPC on HFD-induced kidney dysfunction and damage are mediated through NLRP3 signaling pathways, suggesting a potential target for the prevention of obesity. PMID- 24795234 TI - Expression of antiviral cytokines in Crandell-Reese feline kidney cells pretreated with Korean red ginseng extract or ginsenosides. AB - The antiviral activity and protective mechanism of Korean red ginseng (KRG) is not well understood. The aim of this study was to investigate the protective mechanism of KRG extract and ginsenosides against feline calicivirus (FCV), a human norovirus surrogate. CRFK cells that were pretreated for 48h with 10MUg/mL of KRG extract or purified ginsenoside Rb1 or Rg1, were inoculated with FCV. RNA extracted from each treated group was examined for the expression of antiviral cytokines, including interferon-alpha (IFN-alpha), interferon-beta (IFN-beta), interferon-omega (IFN-omega), Mx, and zinc finger antiviral protein shorter isoform (ZAPS), by relative real-time reverse transcription-polymerase chain reaction. mRNA expression of IFN-alpha, IFN-beta, IFN-omega, Mx, and ZAPS was significantly induced in the FCV-challenged group pretreated with the KRG extract or ginsenosides, and it was higher than the group treated with FCV alone. Mx protein expression was confirmed by western blotting of CRFK cells pretreated with the ginsenoside Rb1 or with Rg1. Induction of antiviral cytokines contributes to the reduction of the viral titer in CRFK cells pretreated with the KRG extract and purified ginsenosides. In future studies, the antiviral protective mechanism of KRG should be demonstrated using other viruses such as human norovirus. PMID- 24795235 TI - Salmon and king crab trypsin stimulate interleukin-8 and matrix metalloproteinases via protease-activated receptor-2 in the skin keratinocytic HaCaT cell line. AB - Occupational skin symptoms are prevalent among the workers of the seafood processing industry. In this study we investigate the role of salmon (Salmo salar) and king crab trypsin (Paralithodes camtschaticus) as inducers of inflammation in skin via secretion of inflammatory mediators. Human skin keratinocytes (HaCaT cells) were exposed to purified salmon and king crab trypsin. We observed that salmon trypsin enhanced the secretion of IL-8 and MMP-2 and crab trypsin enhanced the secretion of IL-8, MMP-2 and MMP-9 in a dose dependent manner. As protease activated receptors (PAR)-2 in skin are known to play an important role in physiology and pathology, we explored the involvement of these receptors in mediating the release of interleukin (IL)-8 and matrix metalloproteinase (MMP)-2 and -9 subsequent to exposure of skin keratinocytes to salmon and crab trypsin. In addition we observed that salmon and crab trypsin exhibit individual differences in stimulating the release of these inflammatory mediators. Finally, using specific small interfering RNA (siRNA) against PAR-2, we confirmed that the increase in secretion of IL-8, MMP-2 and MMP-9 in skin keratinocytes following exposure to salmon and crab trypsin was mediated via activation of PAR-2. These results suggest that exposure to proteases from the seafood may lead to inflammatory reactions in skin. PMID- 24795236 TI - Comparison of core-shell and totally porous ultra high performance liquid chromatographic stationary phases based on their selectivity towards alfuzosin compounds. AB - This paper focuses on the application of a column classification system based on the Katholieke Universiteit Leuven for the characterization of physicochemical properties of core-shell and ultra-high performance liquid chromatographic stationary phases, followed by the verification of the reliability of the obtained column classification in pharmaceutical practice. In the study, 7 stationary phases produced in core-shell technology and 18 ultra-high performance liquid chromatographic columns were chromatographically tested, and ranking lists were built on the FKUL-values calculated against two selected reference columns. In the column performance test, an analysis of alfuzosin in the presence of related substances was carried out using the brands of the stationary phases with the highest ranking positions. Next, a system suitability test as described by the European Pharmacopoeia monograph was performed. Moreover, a study was also performed to achieve a purposeful shortening of the analysis time of the compounds of interest using the selected stationary phases. Finally, it was checked whether methods using core-shell and ultra-high performance liquid chromatographic columns can be an interesting alternative to the high-performance liquid chromatographic method for the analysis of alfuzosin in pharmaceutical practice. PMID- 24795237 TI - A dextran-bonded stationary phase for saccharide separation. AB - A-saccharide-based stationary phase for hydrophilic interaction liquid chromatography (HILIC) is presented. The method uses carbonyl di-imidazole (CDI) as a cross-linker for dextran in aqueous solution. Different from the traditional immobilized saccharide stationary phase, this method was using a simple way to bond the high molecular of polysaccharide immobilized on the silica gel. The new method avoided the time-consuming process but had a very considerable loading result. With silica-based surface bonded, it will be possible to develop well defined surface modifications that promote the hydrophilic with dextran and high mechanical strength with silica. For all tested compounds, including polar compounds and carbohydrates, this dextran-bonded stationary phase performed well in terms of separation efficiency and column stability, and the retention mechanism matched that of typical HILIC retention. Moreover, good selectivity was achieved in the separation of oligosaccharides and glycopeptides. PMID- 24795238 TI - Kidney failure: are we failing? PMID- 24795239 TI - Dreaming of normoglycaemia with fewer diet restrictions. PMID- 24795240 TI - Salt, hypertension, and proteinuria in diabetic nephropathy. PMID- 24795241 TI - How should patients with adrenal incidentalomas be followed up? PMID- 24795242 TI - Targeting non-alcoholic fatty liver disease through 11-betaHSD1 inhibition. PMID- 24795243 TI - Definition and management of radioactive iodine-refractory differentiated thyroid cancer. PMID- 24795244 TI - Implantable insulin pumps: an effective option with restricted dissemination. PMID- 24795245 TI - Vitamin D, obesity, and risk of diabetes. PMID- 24795246 TI - Subclinical Cushing's syndrome and cardiovascular disease. PMID- 24795247 TI - The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes. PMID- 24795248 TI - The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes. PMID- 24795249 TI - The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes -authors' reply. PMID- 24795250 TI - The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes. PMID- 24795251 TI - Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double blind, placebo-controlled trial. AB - BACKGROUND: Diabetes is a leading cause of chronic kidney disease (CKD) worldwide. Optimum glycaemic control in patients with type 2 diabetes is important to minimise the risk of microvascular and macrovascular complications and to slow the progression of CKD. We assessed the efficacy and safety of empagliflozin as an add-on treatment in patients with type 2 diabetes and CKD. METHODS: We did a phase 3, randomised, double-blind, parallel-group, placebo controlled trial at 127 centres in 15 countries. Patients with HbA1c of 7% or greater to 10% or less were eligible for inclusion. Patients with stage 2 CKD (estimated glomerular filtration rate [eGFR] >=60 to <90 mL/min per 1.73 m(2); n=290) were randomly assigned (1:1:1) to receive empagliflozin 10 mg or 25 mg or placebo once daily for 52 weeks. Patients with stage 3 CKD (eGFR >=30 to <60 mL/min per 1.73 m(2); n=374) were randomly assigned (1:1) to receive empagliflozin 25 mg or placebo for 52 weeks. Randomisation was done with a computer-generated random sequence and stratified by renal impairment, HbA1c, and background antidiabetes medication. Treatment assignment was masked from patients and investigators. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01164501. FINDINGS: In patients with stage 2 CKD, adjusted mean treatment differences versus placebo in changes from baseline in HbA1c at week 24 were -0.52% (95% CI -0.72 to -0.32) for empagliflozin 10 mg and 0.68% (-0.88 to -0.49) for empagliflozin 25 mg (both p<0.0001). In patients with stage 3 CKD, adjusted mean treatment difference versus placebo in change from baseline in HbA1c at week 24 was -0.42% (-0.56 to -0.28) for empagliflozin 25 mg (p<0.0001). In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87%) on placebo (15 severe [16%] and 11 serious [12%]), 86 (88%) on empagliflozin 10 mg (six severe [6%] and six serious [6%]) and 78 (80%) on empagliflozin 25 mg (eight severe [8%] and seven serious [7%]). In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83%) on placebo (15 severe [8%] and 23 serious [12%]) and 156 (83%) on empagliflozin 25 mg (18 severe [10%] and 22 serious [12%]). INTERPRETATION: In patients with type 2 diabetes and stage 2 or 3 CKD, empagliflozin reduced HbA1c and was well tolerated. However, our findings might not be applicable to the general population of patients with type 2 diabetes and renal impairment. FUNDING: Boehringer Ingelheim, Eli Lilly. PMID- 24795252 TI - Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial. AB - BACKGROUND: Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy. METHODS: In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366. FINDINGS: Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0.0002), by hydrochlorothiazide (434 mg per day [306 618], p=0.0003), and to the greatest extent by their combination (306 mg per day [203-461], p<0.0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred. INTERPRETATION: We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy. FUNDING: None. PMID- 24795253 TI - Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. AB - BACKGROUND: Incidental discovery of adrenal masses has increased over the past few years. Mild alterations in cortisol secretion without clinical signs of overt hypercortisolism (subclinical Cushing's syndrome) are a common finding in patients with these tumours. Although metabolic alterations and increased cardiovascular risk have been noted in patients with subclinical Cushing's syndrome, incidence of cardiovascular events and mortality in the long term have not been assessed. We aimed to ascertain the frequency of new cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas, tumours of intermediate phenotype, or those causing subclinical Cushing's syndrome. METHODS: From January, 1995, to September, 2010, consecutive outpatients with adrenal incidentalomas who were referred to the endocrinology unit of S Orsola-Malpighi Hospital, Bologna, Italy, were enrolled into our study. Individuals were assessed every 18-30 months for the first 5 years (mean follow up 7.5 [SD 3.2] years, range 26 months to 15 years). Cortisol concentrations after the 1 mg dexamethasone suppression test (DST) were used to define non secreting (+50 nmol/L) and intermediate phenotype (50-138 nmol/L) adrenal incidentalomas and subclinical Cushing's syndrome (+138 nmol/L). At the end of follow-up, patients were reclassified as having either unchanged or worsened secreting patterns from baseline. FINDINGS: 198 outpatients were assessed; at the end of follow-up, 114 patients had stable non-secreting adrenal incidentalomas, 61 had either a stable intermediate phenotype or subclinical Cushing's syndrome, and 23 had a pattern of secretion that had worsened. By comparison with patients with stable non-secreting adrenal incidentalomas, the incidence of cardiovascular events was higher in individuals with a stable intermediate phenotype or subclinical Cushing's syndrome (6.7% vs 16.7%; p=0.04) and in those with worsened secreting patterns (6.7% vs 28.4%; p=0.02). Cardiovascular events were associated independently with a change (from baseline to the end of follow-up) in cortisol concentrations post DST (hazard ratio 1.13, 95% CI 1.05-1.21; p=0.001). Survival rates for all-cause mortality were lower in patients with either stable intermediate phenotype adrenal incidentalomas or subclinical Cushing's syndrome compared with those with stable non-secreting masses (57.0% vs 91.2%; p=0.005). Factors associated with mortality were age (hazard ratio 1.06, 95% CI 1.01-1.12; p=0.03) and mean concentrations of cortisol post DST (1.10, 1.01-1.19; p=0.04). Compared with patients with stable non-secreting adrenal incidentalomas, unadjusted survival for cardiovascular-specific mortality was lower in patients with either a stable intermediate phenotype or subclinical Cushing's syndrome (97.5% vs 78.4%; p=0.02) and in those with worsened secreting patterns (97.5% vs 60.0%; p=0.01). Cancer mortality did not differ between groups. INTERPRETATION: Even when clinical signs of overt hypercortisolism are not present, patients with adrenal incidentalomas and mild hypercortisolism have an increased risk of cardiovascular events and mortality. FUNDING: None. PMID- 24795254 TI - Inhibition of 11beta-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder. METHODS: We did this phase 1b trial at four centres in Germany and Austria. Participants with non alcoholic fatty liver disease (defined as (1)H magnetic resonance spectroscopy liver-fat content >5.56%), insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2.0 mmol/L.mU/L), BMI greater than 27 kg/m(2), and aged 35-65 years were randomly assigned by interactive voice response system in a 1:1 ratio, stratified for triglyceride concentration (<1.7 mmol/L or >=1.7 mmol/L), to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks. The main exclusion criteria were other liver diseases, aspartate aminotransferase or alanine aminotransferase concentrations of more than two and a half times the upper limit of normal, history of diabetes or bariatric surgery, and use of weight lowering drugs. Participants and investigators were masked to assignment throughout the study. The primary endpoint was change in liver-fat content from baseline to week 12. Efficacy analysis was by modified intention to treat, including all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01277094. FINDINGS: We did this trial between Jan 13, 2011, and March 28, 2012. 41 patients were randomly assigned to RO5093151 and 41 to placebo. 35 patients in the RO5093151 group and 39 in the placebo group were included in the efficacy analysis. Mean liver-fat content decreased in the RO5093151 group (from 16.75% [SD 8.67] to 14.28% [8.89]), but not in the placebo group (from 18.53% [10.00] to 18.46% [10.78], p=0.02 for between group difference). 26 participants (65%) in the RO5093151 group had adverse events, compared with 21 (53%) in the placebo group. The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group vs seven [18%] in the placebo group), and infections and infestations (eight [20%] vs nine [23%]). Nervous system disorders occurred in significantly more patients in the RO5093151 group than in the placebo group (nine [23%] vs two [5%]; p=0.02); all other differences in adverse events were non-significant. One participant (3%) in the placebo group and three participants (8%) in the RO5093151 group had serious adverse events. All serious adverse events were deemed unrelated to study treatment. INTERPRETATION: Inhibition of 11beta-HSD1 by RO5093151 was effective and safe in reducing liver fat content, suggesting that targeting of 11beta-HSD1 might be a promising approach for the treatment of non-alcoholic fatty liver disease. FUNDING: F Hoffmann-La Roche. PMID- 24795255 TI - Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. AB - The global increase in chronic kidney disease (CKD) parallels the obesity epidemic. Obesity conveys a gradual but independent risk of progression of CKD that seems irrespective of the underlying nephropathy. Obesity has been associated with a secondary focal segmental glomerulosclerosis coined obesity related glomerulopathy (ORG). Pathways through which obesity might cause renal disease are not well understood, and early clinical biomarkers for incipient ORG or renal relevant obesity are currently lacking. Recent human and experimental studies have associated ectopic lipid accumulation in the kidney (fatty kidney) with obesity-related renal disease. There is enough growing insight that ectopic lipid--the accumulation of lipid in non-adipose tissue--is associated with structural and functional changes of mesangial cells, podocytes, and proximal tubular cells to propose the development of ORG as a maladaptive response to hyperfiltration and albuminuria. Recent advances in metabolic imaging might validate ectopic lipid as a biomarker and research aid, to help translate novel therapeutics from experimental models to patients. PMID- 24795256 TI - Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders. AB - Recent reports of several bone-derived substances, some of which have hormonal properties, have shed new light on the bone-cardiovascular axis. Deranged concentrations of humoral factors are not only epidemiologically connected to cardiovascular morbidity and mortality, but can also be causally implicated, especially in chronic kidney disease. FGF23 rises exponentially with advancing chronic kidney disease, seems to reach maladaptive concentrations, and then induces left ventricular hypertrophy, and is possibly implicated in the process of vessel calcification. Sclerostin and DKK1, both secreted mainly by osteocytes, are important Wnt inhibitors and as such can interfere with systems for biological signalling that operate in the vessel wall. Osteocalcin, produced by osteoblasts or released from mineralised bone, interferes with insulin concentrations and sensitivity, and its metabolism is disturbed in kidney disease. These bone-derived humoral factors might place the bone at the centre of cardiovascular disease associated with chronic kidney disease. Most importantly, factors that dictate the regulation of these substances in bone and subsequent secretion into the circulation have not been researched, and could provide entirely new avenues for therapeutic intervention. PMID- 24795257 TI - The relationship between the mechanical properties of heel-pad and common clinical measures associated with foot ulcers in patients with diabetes. AB - AIM: The present study aims at investigating the correlation between the mechanical properties of the heel-pad of people with type-2 diabetes and the clinical parameters used to monitor their health and ulceration risk. METHODS: A new device for the in-vivo testing of plantar soft tissues was built and pilot tested. This device consists of an ultrasound probe connected in series with a dynamometer. Loading is applied manually using a ball-screw actuator. A total of 35 volunteers with type-2 diabetes were recruited and the thickness, stiffness of their heel-pads as well as the energy absorbed during loading were assessed. The participants with diabetes also underwent blood tests and measurements of Ankle Brachial Index and Vibration Perception Threshold. RESULTS: Pearson correlation analysis revealed strong correlations between triglycerides and heel-pad stiffness (r=0.675, N=27, p<0.001) and between triglycerides and energy (r= 0.598, N=27, p=0.002). A correlation of medium strength was found between Fasting Blood Sugar (FBS) and stiffness (r=0.408, N=29, p=0.043). CONCLUSIONS: People with type-2 diabetes and high levels of triglycerides and FBS are more likely to have stiffer heel-pads. Increased stiffness could limit the tissues' ability to evenly distribute loads making them more vulnerable to trauma and ulceration. PMID- 24795258 TI - Does dance-based therapy increase gait speed in older adults with chronic lower extremity pain: a feasibility study. AB - A decreased gait speed in older adults can lead to dependency when the individuals are no longer able to participate in activities or do things for themselves. Thirty-seven senior apartment residents (31 females; Mean age=80.6 years; SD=8.9) with lower extremity pain/stiffness participated in a feasibility and preliminary efficacy study of 12 weeks (24 sessions). Healthy-Steps dance therapy compared to a wait-list control group. Small improvements in gait speed ([ES]=0.33) were noted for participants completing 19-24 dance sessions. Improvements in gait speed measured by a 10 Meter Walk Test (0.0517 m/s) exceeded 0.05 m/s, a value deemed to be meaningful in community dwelling older adults. These feasibility study findings support the need for additional research using dance-based therapy for older adults with lower extremity pain. PMID- 24795259 TI - Papillary thyroid cancer: strategies for optimal individualized surgical management. AB - OBJECTIVE: The goal of this article was to describe the optimal individualized surgical management of patients with papillary thyroid cancer (PTC). METHODS: This summary reviews the relevant literature that takes into account description of the context of disease incidence, current practice guidelines, controversies in the management of thyroid resection and management of central neck lymph nodes, alternative methods of treatment, and evidence from the author's institution to support the final recommendations. RESULTS: Combining the rationale for treatment decisions from the Mayo Clinic's surgical management of PTC, plus recently published large institutional series and a meta-analysis of patient outcomes, the recommendations for PTC >1 cm include the following: (1) preoperative ultrasound to identify and map the location of lateral jugular lymph node metastasis; (2) bilateral total or near-total thyroidectomy; (3) routine central neck (compartment VI) lymph node dissection; and (4) inclusion of lateral neck lymph node dissection when indicated. Alterations are advised depending on either the level of expertise or anatomic findings at the time of performing the thyroidectomy and lymph node dissection. CONCLUSIONS: Because all of the data presented from the Mayo Clinic and the literature fall short of Level 1 evidence, these recommendations should not be considered dogmatic nor should they exclude reasonable alternatives that are also presented. PMID- 24795260 TI - Effect of cyclic loading on the vertical microgap of long-span zirconia frameworks supported by 4 or 6 implants. AB - STATEMENT OF PROBLEM: Few studies have investigated the microgap of long-span complete-arch fixed dental prosthesis zirconia frameworks. PURPOSE: The purpose of this study was to evaluate the effects of cyclic loading on the vertical microgap of maxillary 12-unit prostheses supported by 4 implants and on 14-unit prostheses supported by 6 implants. MATERIAL AND METHODS: One-piece zirconia frameworks were fabricated with a computer-aided design/computer-aided manufacturing technique and divided into 2 groups (n=5): a group of 12-unit prostheses and a group of 14-unit prostheses. The vertical microgap between the frameworks and prosthetic abutments was measured with an optical microscope (80*) under 2 reading conditions. Condition 1 (1-screw test): 1A, the screw on implant 1 was tightened and readings were made on all implants; 1B, the screw was changed to implant 4 (implant 6 for the 14-unit group) and readings were made on all implants. Condition 2: the microgap was measured with all screws tightened before cyclic loading (2A). Specimens were submitted to 200 N underwater (37 degrees C) cyclic loading at a 2-Hz frequency for 1*10(6) cycles. Microgap reading condition 2 was repeated after cyclic loading (2B). The data were submitted to a linear mixed-effects model for statistical comparison (alpha=.05). RESULTS: A lower (P<.05) vertical microgap (MUm) was found for the 12-unit group (reading conditions: 1A, 47.93; 1B, 43.83; 2A, 11.77; and 2B, 11.25) compared to the 14 unit group (1A, 94.87; 1B, 112.56; 2A, 21.28; and 2B, 16.90). No differences were found when each group was compared before and after cyclic loading (P>.05). CONCLUSIONS: The vertical microgap was significantly reduced after tightening all the screws in the framework, possibly leading to a nonpassive situation. Longer span frameworks showed an increased microgap. Cyclic loading had no influence on the vertical microgap within each group. PMID- 24795261 TI - A comparison of gingival display with a requested smile, Duchenne smile, grimace of disgust, and funnel-shaped expression. AB - STATEMENT OF PROBLEM: A patient's smile may not elicit the maximum amount of maxillary gingiva. PURPOSE: The purpose of this study was to measure the amount of gingival display with 4 different facial expressions. MATERIAL AND METHODS: Video images of 91 randomly selected adults were evaluated to measure the height of gingival display at the maxillary anterior teeth and first premolars when participants were asked to give their biggest smile (requested smile), make a Duchenne smile, mimic an intense grimace of disgust (grimace), and produce a funnel-shaped expression (funnel). Measurements were compared with the Friedman Test with post hoc comparisons (alpha=.05 for all tests). RESULTS: The intraclass correlation coefficient was (95% CI)=0.913(0.623, 0.984). At the central and lateral incisors, the grimace and funnel expressions produced the greatest amounts of gingival display. At the canines and the first premolars, both smiles (requested and Duchenne) exhibited the largest amount of gingival display of the 4 facial expressions. CONCLUSIONS: Neither smile type revealed a significantly greater amount of gingival display above the maxillary central or lateral incisors but the grimace and funnel facial expressions did (P <=.001). Above the maxillary canines, both smiles displayed a significantly greater amount of gingiva than did the funnel expression (P<.001), but only the Duchenne smile displayed a greater amount than did the grimace expression (P=.05). Superiorly to the maxillary first premolars, both smile types revealed significantly greater amounts of soft tissue when compared with the other 2 facial expressions (P<.001). PMID- 24795262 TI - An in vitro comparison of quantitative percussion diagnostics with a standard technique for determining the presence of cracks in natural teeth. AB - STATEMENT OF PROBLEM: The detection of cracks and fractures in natural teeth is a diagnostic challenge. Cracks are often not visible clinically nor detectable in radiographs. PURPOSE: The purpose of this study was to evaluate the diagnostic parity of quantitative percussion diagnostics, transillumination, clinical microscopy, and dye penetration. MATERIAL AND METHODS: Three independent examiners provided blind testing for the study. Examiner 1 transilluminated 30 extracted teeth and 23 three-dimensional copy replica control teeth and documented any visible cracks. Each tooth was then mounted in acrylic resin with a periodontal ligament substitute. Examiner 2 examined each specimen aided by the clinical microscope and transillumination and documented visible tooth cracks and fractures. Examiners 1 and 3 then independently tested all specimens with a device developed for quantitative percussion diagnostics. All visible cracks/fractures were removed with a water-cooled fine diamond rotary instrument. Crack visibility was enhanced by the use of a clinical microscope, dye penetrant, and accessory transillumination. This disassembly process was video documented/photographed for each specimen. One more quantitative percussion diagnostics testing was administered when the disassembly was complete. RESULTS: Quantitative percussion diagnostics crack detection agreed with the gold standard microscope and transillumination method in 52 of 53 comparisons (98% agreement). Moreover, the method achieved 96% specificity and 100% sensitivity for detecting cracks and fractures in natural teeth. When all tooth cracks were removed, quantitative percussion diagnostics indicated no further structural instability. CONCLUSIONS: Quantitative percussion diagnostics can nondestructively detect cracks and fractures in natural teeth with accuracy similar to that of the clinical microscope, transillumination, and dye penetrant. In addition, the method was able to reveal the presence of many cracks that were not detected by conventional transillumination. PMID- 24795263 TI - Marginal and internal adaptation of ceramic crown restorations fabricated with CAD/CAM technology and the heat-press technique. AB - STATEMENT OF PROBLEM: The accuracy of chairside computer-aided design and computer-aided manufacturing (CAD/CAM) restorations is questionable, and the effect of the die spacer settings is not well stated in the literature. PURPOSE: The purpose of the study was to evaluate the marginal and internal adaptation of E4D crowns fabricated with different spacer thicknesses and to compare these crowns with those fabricated with the heat-press technique. MATERIAL AND METHODS: The E4D system was used to fabricate 30 crowns for the first 3 groups, with different spacer thickness settings: 30 MUm, 60 MUm, and 100 MUm. In the fourth group, 10 lithium disilicate crowns were fabricated with the heat-press technique. The occlusal gap, axial gap, vertical marginal gap, and absolute marginal discrepancy were evaluated by x-ray microtomography. Statistical significance was assessed with the Kruskal-Wallis test (alpha=.05). For post hoc analyses, the Mann-Whitney U test was used alongside the Bonferroni correction for multiple comparisons (alpha=.008). RESULTS: Within the CAD/CAM groups, the 30 MUm spacer thickness resulted in the lowest median axial gap (90.04 MUm), whereas the 60-MUm spacer thickness resulted in the lowest median occlusal gap (152.39 MUm). The median marginal gap values of the CAD/CAM-60 group (49.35 MUm) and CAD/CAM-100 group (46.65 MUm) were lower than those of the CAD/CAM-30 group (55.18 MUm). No significant differences among the CAD/CAM groups were observed for absolute marginal discrepancy. The heat-press group had significantly different values than those of the CAD/CAM groups. CONCLUSION: The spacer thickness and fabrication technique affected the adaptation of ceramic crowns. The heat-press group yielded the best marginal and internal crown adaptation results. The 30- or 60-MUm spacer settings are recommended for the E4D CAD/CAM system. PMID- 24795264 TI - WITHDRAWN: Effect of different dentin cleaning techniques on bond strength and the micromorphology of dentin/self-adhesive resin cement interface. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24795265 TI - Phenotype characteristics of patients with colonic serrated polyposis syndrome: a study of 23 cases. AB - INTRODUCTION: Serrated polyposis syndrome (SPS) is a rare entity characterized by the presence of multiple hyperplastic polyps in the colon and an increased risk of presentation and development of colorectal cancer (CRC). OBJECTIVE: To evaluate the clinical and phenotypical characteristics of patients that present one of the 3 WHO criteria for the diagnosis of SPS diagnosed and treated a tour hospital. PATIENTS AND METHODS: Patients with the diagnosis of SPS during 2005 2012 were revised; 24.208 colonoscopies were performed during this period. Age, sex, family history of CRC (APC/MYH), proximal/mixed/distal phenotype, indication for colonoscopy, number, size, location of the hyperplastic polyps, presence of mixed/adenomatous polyps, CRCI, follow-up and endoscopio/surgical treatment. RESULTS: A total of 23 cases were included (19 male). The median age was 51. A total of 34% had a prior family history of CRC or polpyps. Distal phenotype was more frequent (48%). Another 73% presented synchronous adenomatous polyps, and 26% a CRC. A total of 57% were asymptomatic. Surgery was performed in 9 cases (6 for cancer and 3 for polyposis), and 14 were treated by polypectomy and observation. Eleven patients (47%) presented recurrent/persistent lesions after initial surgical/endoscopic treatment. CONCLUSION: SPS is an heterogeneous syndrome that is variable in the type, size, distribution and number of polyps, and is more common in male smokers with a distal phenotype. The majority of patients also present synchronous adenomatous polyps. These patients require an organized multidisciplinary evaluation. PMID- 24795266 TI - The impact of an advanced certifying examination simulation program on the American Board of Surgery Certifying Examination passage rates. AB - BACKGROUND: The national pass rate for the American Board of Surgery Certifying Examination has decreased in the past 5 years. An individual's ability to pass might be as dependent on his or her handling of the psychology of the examination the "examanship" -because it is about clinical knowledge and judgment. To assess this, we implemented the Advanced Certifying Examination Simulation (ACES) program. The ACES was created as a novel method to simulate the stress of the Certifying Examination and focuses on the examanship of the test. STUDY DESIGN: We compared the outcomes of the ACES program with its predecessor, a conventional mock oral program, as measured by residents' first-time pass rates on the Certifying Examination. First-time Certifying Examination pass rates of 26 residents who went through the ACES program were compared with 30 residents who completed the conventional mock oral program. RESULTS: There was a significant increase in passage rates for residents taking part in the ACES program (100%) compared with residents taking part in the conventional mock oral group (83.3%). The groups were equivalent based on previously determined predictive factors of Certifying Examination success, such as in-training and licensing examination scores. CONCLUSIONS: The ACES program provides feedback on the qualities of examanship: controlling anxiety, expressing a positive attitude, and maintaining a strong and confident voice. By providing a structured, simulated venue where residents can safely gain experience, we believe that ACES might lead to increased first-time passage rates on the American Board of Surgery Certifying Examination. PMID- 24795267 TI - Sustainability and success of the acute care surgery model in the nontrauma setting. AB - BACKGROUND: The use of an acute care surgical model has been shown to improve patient care and efficiency. We propose that it is possible to apply this model to emergency general surgery patients at a nontrauma hospital. With this acute care surgery service, no change in the quality of care will occur, and improvements in quality, cost, and outcomes may be achieved and sustained. STUDY DESIGN: A retrospective review was performed of all emergency surgery operations performed at a tertiary referral community hospital without a trauma service. Data were collected from 1 year before and each year up to 4 years after the implementation of an acute care surgical (ACS) service. RESULTS: There were fewer overall complications with ACS (21% to 12%, p < 0.0001), and a shorter length of stay (6.5 days to 5.7 days, p = 0.0016). Hospital costs fell from $12,009 to $8,306 (p < 0.0001). Post-appendectomy complications decreased (13% to 3.7%, p < 0.0001), length of stay was shorter (3.0 to 2.3 days, p < 0.0001), and hospital costs decreased from $9,392 to $5,872 (p < 0.0001). Post-cholecystectomy complications decreased (21% to 9%, p = 0.012), length of stay was shorter (5.3 to 3.8 days, p = 0.0004), and hospital costs decreased from $12,526 to $9,348 (p < 0.0001). CONCLUSIONS: An acute care surgery service can be successfully implemented at a nontrauma hospital. The improvements seen in outcomes and finances are sustainable over time. This sort of coordinated, consistent care is successful and allows alignment of the goals of surgeons, hospitals, and patients. PMID- 24795268 TI - Long-term pulmonary function after metastasectomy for childhood osteosarcoma: a report from the St Jude lifetime cohort study. AB - BACKGROUND: Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood. STUDY DESIGN: We reviewed the medical records of patients who had pulmonary function tests (PFTs) after metastasectomy for osteosarcoma. Patient, tumor, and treatment variables were abstracted along with PFTs. The PFTs were recorded as a percentage of predicted value and were classified as abnormal for forced vital capacity (FVC) < 80%, forced expiratory volume in 1 second (FEV1) < 80%, total lung capacity (TLC) < 75%, and single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr) < 75%. RESULTS: Twenty-one patients had PFTs performed during follow-up. Mean age at diagnosis of osteosarcoma was 13.2 +/- 4.7 years (SD). Fifteen patients had a single thoracotomy, and 6 patients had >=2 thoracotomies (range 2 to 6). Eighty lesions were resected. Nine patients had <=2 lesions resected and 12 patients had >2 lesions (range 3 to 12) resected. Mean time from the last surgical procedure to measurement of PFTs was 20.3 +/- 9.0 years (SD). Total lung capacity was abnormal for 28.6%, DLCOcorr for 47.4%, FVC for 40%, and FEV1 for 47.6% of the cohort members. Individual PFTs were abnormal in 13.3% (TLC) to 46.7% (DLCOcorr) of patients who had 1 thoracotomy and in 50.0% (DLCOcorr) to 66.7% (FEV1, TLC) of patients with >=2 thoracotomies. The number of thoracotomies was associated with abnormal TLC (p = 0.03). CONCLUSIONS: Patients who underwent pulmonary metastasectomy for osteosarcoma as children often had abnormal PFTs on long-term follow-up, but the reduction in lung volumes and DLCOcorr was relatively mild. Multiple thoracotomies predicted greater impairment of pulmonary function. PMID- 24795269 TI - A preliminary report of acute and subacute arthroscopic repair of the radial ulnohumeral ligament after elbow dislocation in the high-demand patient. AB - PURPOSE: The purpose of this study was to evaluate functional outcomes, range of motion (ROM), elbow stability, and time to return to full activities after acute and subacute arthroscopic repair of a simple elbow dislocation in high-demand patients. METHODS: "High-demand patients" were defined as in-season athletes and individuals who required use of both hands for their profession and believed that they could not miss the 6 weeks of work that may be required with conservative treatment in an elbow brace. We retrospectively reviewed 14 consecutive patients with a simple elbow dislocation who underwent arthroscopic repair of the radial ulnohumeral ligament from 2008-2012. Outcomes measures included the Mayo Elbow Performance Score (MEPS), elbow ROM, elbow stability, and time to return to full activities. Each patient was contacted once by telephone to determine the current activity level and presence of any pain or functional limitations. RESULTS: The mean patient age was 25 years, with telephone follow-up at a mean of 30 months and clinical examination after a minimum of 6 months. The postoperative MEPS was excellent (mean, 99.6; range, 95 to 100) for all 14 patients, and all returned to their preinjury level of function with no restrictions or instability. Final ROM averaged -3 degrees of full extension to greater than 130 degrees of flexion. The mean time to return to full activities in and out of a brace was 2.7 weeks and 6.6 weeks, respectively, in the acute group and 4.6 weeks and 8.9 weeks, respectively, in the subacute group. All patients were satisfied with their outcome. CONCLUSIONS: Conservative management remains the gold standard for most simple elbow dislocations. We believe that certain high-demand patients may be candidates for acute arthroscopic ligamentous repair. Our preliminary data show that acute arthroscopic repair of the radial ulnohumeral ligament is a safe, effective procedure that restores stability to the elbow and allows patients to quickly return to full activities. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24795270 TI - Long-term effect of removal of knee joint loading on cartilage quality evaluated by delayed gadolinium-enhanced magnetic resonance imaging of cartilage. AB - OBJECTIVE: Ankle fracture patients were used as a model to study the long-term effect of the removal of joint loading on knee cartilage quality in human subjects. DESIGN: The knees of 10 patients with ipsilateral ankle fractures were investigated using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) at the time of ankle injury. After 6 weeks' prescribed unloading of the affected leg, but no restrictions regarding knee movement, the cast was removed from the ankle and the patient underwent a second dGEMRIC examination. Physiotherapy was then initiated. A third dGEMRIC examination was performed 4 months after remobilization, and a final examination 1 year after the injury. RESULTS: Baseline T1Gd values for the 10 patients were within a narrow range. No significant change in mean T1Gd was observed after 6 weeks' prescribed unloading, but the T1Gd range had increased significantly. Four months after remobilization, the mean T1Gd was significantly lower than in the previous examinations, and the range remained significantly broader than at baseline. At the 1-year follow-up, the mean T1Gd was almost identical to the value after remobilization, and the T1Gd range still showed a significant increase compared to the baseline investigation. CONCLUSIONS: Removal of knee cartilage loading for 6 weeks resulted in a measurable effect on the cartilage matrix, as evidenced by a broader T1Gd range. A decrease in mean T1Gd was observed 4 months after remobilization. These differences persisted a year after injury compared to baseline. PMID- 24795271 TI - Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein. AB - OBJECTIVE: When endoplasmic reticulum (ER) stress, i.e., the excessive accumulation of unfolded proteins in ER, endangers homeostasis, apoptosis is induced by C/EBP homologous protein (Chop). In osteoarthritis (OA) cartilage, Chop expression and apoptosis increase as degeneration progresses. We investigated the role of Chop in murine chondrocyte apoptosis and in the progression of cartilage degeneration. METHOD: We induced experimental OA in Chop knockout (Chop(-/-)) mice by medial collateral ligament transection and meniscectomy and compared cartilage degeneration, apoptosis, and ER stress in Chop(-/-)- and wild-type (Chop(+/+)) mice. In our in vitro experiments we treated murine Chop(-/-) chondrocytes with the ER stress inducer tunicamycin (TM) and evaluated apoptosis, ER stress, and chondrocyte function. RESULTS: In vivo, the degree of ER stress was similar in Chop(-/-)- and Chop(+/+) mice. However, in Chop(-/-) mice apoptosis and cartilage degeneration were lower by 26.4% and 42.4% at 4 weeks, by 26.8% and 44.9% at 8 weeks, and by 26.9% and 32.3% at 12 weeks after surgery than Chop(+/+) mice, respectively. In vitro, the degree of ER stress induction by TM was similar in Chop(-/-)- and Chop(+/+) chondrocytes. On the other hand, apoptosis was 55.3% lower and the suppression of collagen type II and aggrecan mRNA was 21.0% and 23.3% less, and the increase of matrix metalloproteinase-13 mRNA was 20.0% less in Chop(-/-)- than Chop(+/+) chondrocytes. CONCLUSION: Our results indicate that Chop plays a direct role in chondrocyte apoptosis and that Chop-mediated apoptosis contributes to the progression of cartilage degeneration in mice. PMID- 24795272 TI - The role of small leucine-rich proteoglycans in osteoarthritis pathogenesis. AB - OBJECTIVE: To give an overview of the literature on the role of small leucine rich proteoglycans (SLRPs) in osteoarthritis (OA) pathogenesis. METHOD: A literature search was performed and reviewed using the narrative approach. RESULTS: (1) OA is an organ disease with many tissue types and specific roles for each in the pathogenic process. (2) Key biological functions of SLRPs include interacting with collagens to modulate fibril formation, and binding various cell surface receptors and growth factors to influence cellular functions; (3) Accumulating evidence has demonstrated the involvement of SLRPs in OA pathogenesis, most of which came from SLRP-deficient mice models; (4) Possible mechanisms for SLRPs being involved in OA pathogenic process include their roles in the extracellular collagen network, TGF-beta signaling pathways, subchondral bone, muscle weakness, and the innate immune inflammation; (5) SLRP-deficient mice offer a potential to understand the molecular mechanisms of OA initiation and progression. (6) Targeting SLRPs may offer a new therapeutic modality for OA through controlling and modifying the TGF-beta-ECM system. (7) Monitoring SLRP fragmentation may be a promising biomarker strategy to evaluate OA status. CONCLUSIONS: Recent literature has shown that SLRPs may play an important role in OA pathogenesis. Possible mechanisms by which SLRPs are involved in this process have also been proposed. However, further investigations are needed in this field to better understand its mechanisms, develop treatments to slow down the degenerative process, and explore new approaches for effective and timely diagnosis of OA. PMID- 24795273 TI - Physiological and excessive mechanical compression of articular cartilage activates Smad2/3P signaling. AB - OBJECTIVE: Transforming growth factor beta (TGF-beta) in articular cartilage can signal via two routes, the ALK5/Smad2/3P and the ALK1/Smad1/5/8P route, the first being protective and the latter favoring chondrocyte terminal differentiation. Since biomechanical factors are known to play an essential role in osteoarthritis (OA) initiation and progression, we investigated if excessive mechanical compression can alter TGF-beta signaling in cartilage shifting it from ALK5/Smad2/3P to ALK1/Smad1/5/8P pathway, favoring terminal differentiation of chondrocytes. DESIGN: Articular cartilage explants were harvested from bovine metacarpophalangeal joints. After equilibration, explants were subjected to unconfined dynamic mechanical compression (1 Hz) with 3 MPa (physiological) or 12 MPa (excessive) stress. After different time intervals samples were frozen and mRNA levels of selected genes were examined using real-time polymerase chain reaction. RESULTS: In articular cartilage compressed with 3 MPa and also 12 MPa stress the expression of Smad2/3P responsive genes bSerpine1, bSmad7 and bAlk5 was up-regulated, whereas the expression of Smad1/5/8P responsive gene bId1 was down-regulated. Furthermore, the expression of bTgfb1 was significantly up regulated in both compression groups. When ALK5/Smad2/3P pathway was blocked with a selective ALK4/5/7 inhibitor, the effect of excessive mechanical compression on bSmad7 and bAlk5 expression was prevented. CONCLUSIONS: Here we show that excessive mechanical compression alone is not able to shift TGF-beta signaling toward the ALK1/Smad1/5/8P pathway. In contrast, we show that mechanical compression not only with physiological but also with excessive stress can activate Smad2/3P signaling, which is known to be protective for articular cartilage and to block chondrocyte terminal differentiation. PMID- 24795274 TI - Repetitive allogeneic intraarticular injections of synovial mesenchymal stem cells promote meniscus regeneration in a porcine massive meniscus defect model. AB - OBJECTIVE: A new strategy is required in order to regenerate a meniscus for extensive defects. Synovial mesenchymal stem cells (MSCs) are an attractive cell source for meniscus regeneration due to their high proliferation and chondrogenic potential. We examined the effect of repetitive intraarticular injections of synovial MSCs on meniscus regeneration in a massive meniscal defect of pigs. We followed up the efficacy using MRI evaluation in addition to macroscopic and histological observations. DESIGN: Two weeks before the injection of synovial MSCs, the anterior half of the medial menisci was resected in both knees of pigs. Fifty million allogeneic synovial MSCs were injected into the right knee at 0, 2, and 4 weeks and followed up by sequential MRI. The regenerated meniscus, adjacent articular cartilage, and subchondral bone were evaluated by MRI at 2, 4, 8, 12 and 16 weeks. They were also evaluated macroscopically and histologically at 16 weeks (n = 7). RESULTS: The resected meniscus regenerated significantly better in the MSC group than in the control group based on histological and MRI analyses. Macroscopically, the meniscal defect already appeared to be filled with synovial tissue at 2 weeks. Articular cartilage and subchondral bone at the medial femoral condyle were also significantly more preserved in the MSC group based on MRI, macroscopic, and histological analyses. CONCLUSIONS: Intraarticular injections of allogeneic synovial MSCs appeared to promote meniscus regeneration and provide protection at the medial femoral articular cartilage in a porcine massive meniscal defect model. PMID- 24795275 TI - Hypothalamic evanescent lesion by diffuse large B-cell lymphoma. PMID- 24795276 TI - Cerebral Baylisascaris larva migrans in a cynomolgus macaque (Macaca fascicularis). AB - An incidental, asymptomatic, focal inflammatory lesion was detected in brain cerebrum of an approximately 6-year-old, female cynomolgus macaque from a chronic toxicology study. No gross lesions were noted at necropsy. Microscopically, the lesion contained a cross-section of larvae approximately 70-80 MUm in diameter, a centrally located intestine flanked on either side by large triangular excretory columns, and prominent single lateral cuticular alae. Mixed inflammatory cells of eosinophils, macrophages, and lymphocytes admixed with abundant connective tissue stroma and necrosis surrounded the larvae. Histochemical stains for trichrome revealed significant amount of fibrous connective tissue. The morphology of the larvae was compatible with Baylisascaris spp. Based on the microscopic and histochemical examination, a diagnosis of neural Baylisascaris spp. larva migrans was made. PMID- 24795277 TI - National trends in hospital admissions for asthma exacerbations among pediatric and young adult population in Spain (2002-2010). AB - OBJECTIVE: To assess the changes in incidence, use of mechanical ventilation, length of stay (LOS), costs and mortality of children (0-15 years) and young adults (16-45 years) hospitalized for asthma exacerbations. METHODS: We included patients hospitalized for asthma exacerbations in Spain from 2002 to 2010 (ICD9 CM codes 493.0x-493.9x). The data were collected from the National Hospital Discharge Database (entire population). We calculated the yearly age- and sex specific incidence rates for each of the two groups. RESULTS: We included a total of 12,038 pediatric patients and 2792 young adults hospitalized for asthma exacerbations. Overall crude incidence decreased from 20.5 to 18.7 admissions per 100.000 inhabitants in the pediatric group (p < 0.05), and from 4.12 to 3.68 admissions per 100.000 inhabitants among young adults, from 2002 to 2010 (p < 0.05). By contrast, we detected a significant increase in the use of non-invasive ventilation (NIV) in both groups. The average LOS decreased during the study period, from 3.71 (SD 2.28) to 3.16 (SD 2.11) days (p < 0.05) among pediatric patients and there were not changes among young adults. During the study period, the mean cost per patient decreased from 1558.53 (SD 443.63) to 1378.41 (SD 472.71) euros in the pediatric group (p < 0.05), while increased from 2183.44 (SD 783.15) to 2564.32 (SD 1933.98) euros among young adults (p < 0.05). CONCLUSION: Our results suggest a decrease in the incidence of hospital admissions for asthma exacerbations with concomitant increase in use of NIV in asthmatic patients, both pediatric and young adults patients. Although LOS and mean cost have decreased among pediatric patients, they have not changed and increased, respectively, among young adults. A better management of the disease at primary care services may explain the improvement in the incidence and outcomes. PMID- 24795278 TI - AtMMS21 regulates DNA damage response and homologous recombination repair in Arabidopsis. AB - DNA damage is a significant problem in living organisms and DNA repair pathways have been evolved in different species to maintain genomic stability. Here we demonstrated the molecular function of AtMMS21, a component of SMC5/6 complex, in plant DNA damage response. Compared with wild type, the AtMMS21 mutant plants show hypersensitivity in the DNA damaging treatments by MMS, cisplatin and gamma radiation. However, mms21-1 is not sensitive to replication blocking agents hydroxyurea and aphidicolin. The expression of a DNA damage response gene PARP2 is upregulated in mms21-1 under normal condition, suggesting that this signaling pathway is constitutively activated in the mutant. Depletion of ATAXIA TELANGIECTASIA MUTATED (ATM) in mms21-1 enhances its root growth defect phenotype, indicating that ATM and AtMMS21 may play additive roles in DNA damage pathway. The analysis of homologous recombination frequency showed that the number of recombination events is reduced in mms21-1 mutant. Conclusively, we provided evidence that AtMMS21 plays an important role in homologous recombination for DNA damage repair. PMID- 24795279 TI - The origins and processing of ultra fine anaphase DNA bridges. AB - Ultra-fine DNA bridges (UFBs) are a recently identified class of mitotic DNA structures that cannot be visualized using conventional DNA staining methods (e.g. using DAPI). Their existence can currently only be revealed by immuno fluorescent staining for proteins that bind to them, including PICH and BLM. UFBs become visible in the anaphase of mitosis, and can persist into telophase in rare cases. There are at least three different types of UFBs that can be distinguished according to the chromosomal loci from which they originate. However, it remains largely unknown how these UFBs are generated or resolved in the cell. In this article, we will review our current understanding of different types of UFBs and the potential functional role of the proteins that have been shown to be associated with them. PMID- 24795280 TI - Feasibility of bispectral index monitoring to guide early post-resuscitation cardiac arrest triage. AB - INTRODUCTION: Triage after resuscitation from cardiac arrest is hindered by reliable early estimation of brain injury. We evaluated the performance of a triage model based on early bispectral index (BIS) findings and cardiac risk classes. METHODS: Retrospective evaluation of serial patients resuscitated from cardiac arrest, unable to follow commands, and undergoing hypothermia. Patients were assigned to a cardiac risk group: STEMI, VT/VF shock, VT/VF no shock, or PEA/asystole, and to a neurological dysfunction group, based on the BIS score following first neuromuscular blockade (BISi), and classified as BISi>20, BISi 10 20, or BISi<10. Cause of death was described as neurological or circulatory. RESULTS: BISi in 171 patients was measured at 267(+/-177)min after resuscitation and 35(+/-1.7) degrees C. BISi<10 suffered 82% neurological-cause and 91% overall mortality, BISi 10-20 35% neurological and 55% overall mortality, and BISi>20 12% neurological and 36% overall mortality. 33 patients presented with STEMI, 15 VT/VF-shock, 41 VT/VF-no shock, and 80 PEA/asystole. Among BISi>20 patients, 75% with STEMI underwent urgent cardiac catheterization (cath) and 94% had good outcome. When BISi>20 with VT/VF and shock, urgent cath was infrequent (33%), and 4 deaths (44%) were uniformly of circulatory etiology. Of 56 VT/VF patients without STEMI, 24 were BISi>20 but did not undergo urgent cath - 5(20.8%) of these had circulatory-etiology death. Circulatory-etiology death also occurred in 26.5% BIS>20 patients with PEA/asystole. When BISi<10, a neurological etiology death dominated independent of cardiac risk group. CONCLUSIONS: Neurocardiac triage based on very early processed EEG (BIS) is feasible, and may identify patients appropriate for individualized post-resuscitation care. This and other triage models warrant further study. PMID- 24795281 TI - Immature/total granulocyte ratio: a promising tool to assess the severity and the outcome of post-cardiac arrest syndrome. AB - BACKGROUND: The immature/total granulocyte (I/T-G) ratio increases during severe systemic inflammatory response syndrome. This study evaluated the I/T-G ratio as a predictor of poor outcome after out-of-hospital cardiac arrest (OHCA). METHODS: We conducted a pilot prospective cohort study of patients who were admitted in our intensive care unit (ICU) during a one-year period after post-OHCA resuscitation. I/T-G ratio measurements were obtained from blood samples collected on admission using flow cytometry and the outcomes were ICU mortality and post-cardiac arrest syndrome. RESULTS: Among the 130 patients (76% male, median age 54 [46-67] years), the median I/T-G ratio was 0.85 [0.42-1.98]%. The I/T-G ratio was poorly correlated with the SOFA score and lactate level on day 1 (r=0.25, p=0.005 and r=0.5, p<0.001, respectively). Patients with high I/T-G ratios were more likely to develop post-resuscitation shock (37% vs. 58%, p=0.02). Patients dying from post-resuscitation shock had a higher I/T-G ratio than patients dying from neurological causes (2 [1-4]% vs. 1.2 [0.6-1.2]%, p=0.02). The area under the ROC curve based on the I/T-G ratio was 0.82 for predicting ICU mortality. CONCLUSION: The I/T-G ratio appears to be an accurate predictor of poor outcome. However, the added clinical value of this marker and the possible involvement of immature granulocytes in the pathophysiology of post cardiac arrest syndrome remain to be investigated. PMID- 24795282 TI - Keep your hands on the chest. PMID- 24795283 TI - Combining NSE and S100B with clinical examination findings to predict survival after resuscitation from cardiac arrest. AB - BACKGROUND: Neuron specific enolase (NSE) and astroglial protein S100B are associated with outcome following resuscitation from cardiac arrest. We tested whether NSE and S100B levels are associated with illness severity on hospital arrival, and whether levels are independently associated with survival to hospital discharge after adjusting for initial illness severity. METHODS: Levels of NSE and S100B were obtained at arrival, 6, 12, 24, 48, and 72h after successful resuscitation from cardiac arrest. Clinical data included demographics, Pittsburgh Cardiac Arrest Category (PCAC I-IV) and survival to hospital discharge. Univariable and multivariable predictive models including NSE and S-100B were created to predict survival. ROC analyses were performed to determine sensitivity and specificity of NSE and S-100B at each time interval. RESULTS: Of 77 comatose subjects, 5 did not receive therapeutic hypothermia and were excluded. Mean age was 59 (SD 16) years, with 58% male (N=42), 72% out-of hospital arrest (N=52), and 43% VF/VT. Survival was 36% (N=26). PCAC IV was associated with higher levels of NSE at 24h (p=0.001) and S100B at 24h (p=0.005). In the multivariate analysis, survival was associated with initial S100B level (OR 0.24; 95% CI 0.07-0.86). NSE values>49.5ng/mL at 48h and NSE values>10.59ng/mL at 72h predicted mortality. S100B levels>0.414ng/mL at 72h predicted mortality. CONCLUSIONS: More severe neurologic injury on initial examination is associated with higher levels of NSE and S100B. Elevated levels of S100B immediately following resuscitation were associated with death. Persistently elevated levels of NSE and S100B at 48 and 72h were associated with death. PMID- 24795284 TI - Regional cerebral oxygen saturation after cardiac arrest in 60 patients--a prospective outcome study. AB - INTRODUCTION: Non-invasive near-infrared spectroscopy (NIRS) offers the possibility to determine regional cerebral oxygen saturation (rSO2) in patients with cardiac arrest. Limited data from recent studies indicate a potential for early prediction of neurological outcome. METHODS: Sixty cardiac arrest patients were prospectively enrolled, 22 in-hospital cardiac arrest (IHCA) and 38 out-of hospital cardiac arrest (OHCA) patients respectively. NIRS of frontal brain was started after return of spontaneous circulation (ROSC) during admission to ICU and was continued until normothermia. Outcome was determined at ICU discharge by the Pittsburgh Cerebral Performance Category (CPC) and 6 months after cardiac arrest. RESULTS: A good outcome (CPC 1-2) was achieved in 23 (38%) patients, while 37 (62%) had a poor outcome (CPC 3-5). Patients with good outcome had significantly higher rSO2 levels (CPC 1-2: rSO2 68%; CPC 3-5: rSO2 58%; p<0.01). For good and poor outcome median rSO2 within the first 24h period was 66% and 59% respectively and for the following 16h period 68% and 59% (p<0.01). Outcome prediction by area of rSO2 below a critical threshold of rsO2=50% within the first 40h yielded 70% specificity and 86% sensitivity for poor outcome. CONCLUSION: On average, rSO2 within the first 40h after ROSC is significantly lower in patients with poor outcome, but rSO2 ranges largely overlap between outcome groups. Our data indicate limited potential for prediction of poor outcome by frontal brain rSO2 measurements. PMID- 24795285 TI - Quantifying QRS changes during myocardial ischemia: Insights from high frequency electrocardiography. AB - Over four decades of high frequency electrocardiography research have provided a body of knowledge about QRS changes during myocardial ischemia, and the techniques to measure and quantify them. High-frequency QRS (HFQRS) components, being closely related to the pattern of ventricular depolarization, carry valuable clinical information. Changes in HFQRS amplitude and morphology have been shown to be sensitive diagnostic markers of myocardial ischemia, often superior to measures of ST-T segment changes. Clinical studies in patients undergoing exercise testing have consistently demonstrated the incremental diagnostic value of HFQRS analysis in detection of demand ischemia. In 6 studies that evaluated the HyperQTM technology, the average sensitivity and specificity of HFQRS analysis were 75%+/-6% and 80%+/-6%, respectively, compared to average sensitivity 48%+/-16% and average specificity 70%+/-15% of ST segment analysis. In patients with acute supply ischemia, recent studies characterized and quantified the ischemic HFQRS patterns. HFQRS morphology index was found to be higher in patients with acute coronary syndrome (ACS), compared to non-ischemic, with good sensitivity in patients without ST elevation. These research findings may be translated into commercially-available ECG systems and be used in clinical practice for improved diagnosis and monitoring of myocardial ischemia. PMID- 24795286 TI - Skin contamination leading to falsely elevated fingerprick tobramycin levels in a patient taking dry powder inhaled tobramycin. PMID- 24795287 TI - Stigma and optimism in adolescents and young adults with cystic fibrosis. AB - BACKGROUND: Despite increased life expectancy among patients with cystic fibrosis (CF), few studies have examined coping among adolescents and young adults with CF. Previous research suggests that stigma associated with chronic disease is related to worse physical and psychological health, but optimism may be protective. This study examined stigma and optimism among patients with CF. METHODS: Seventy-two patients with CF (ages 14 to 25) completed a self-report questionnaire assessing stigma, distress, CF-specific quality of life (QoL), and optimism. Objective health data were recorded from patient medical records. RESULTS: Greater stigma was associated with lower pulmonary function, QoL, and optimism. Stigma was positively correlated with distress. Optimism moderated the relationship between stigma and anxiety (p<0.001), and between stigma and emotional functioning (p<0.01). CONCLUSIONS: Stigma is related to worse lung function and psychological health in patients with CF, but higher levels of optimism may act as a protective factor. PMID- 24795288 TI - Timing of income assistance payment and overdose patterns at a Canadian supervised injection facility. PMID- 24795289 TI - Humanistic burden in schizophrenia: a literature review. AB - OBJECTIVES OF THE STUDY AND BACKGROUND: Schizophrenia is a complex disease that affects 1% of the population. This disease has a considerable impact not only on patients' health and well-being but also on their surrounding environment. The costs of the disease's management remain large for individuals and society. While literature on the economic impact of schizophrenia is abundant, few studies have focused on its humanistic burden. This does not only concern patients, but also caregivers, relatives, neighbours and others in a patient's daily life. This burden appears through several dimensions, including treatment side effects and the impact on caregivers and features of the patient's environment. The aim of this review is to consider, compile and describe the humanistic burden of schizophrenia as documented in the literature. MATERIALS AND METHODS: We conducted a literature review assessing the worldwide disease burden of schizophrenia, taking into account all humanistic burden topics. The search considered several databases, including Embase, Medline, Cochrane Library, The German Institute of Medical Documentation and Information (DIMDI) and the ISPOR conference websites. RESULTS: The search identified 200 literature reviews, covering several dimensions of humanistic burden and documenting many issues. Main findings included the high death rates that may be explained by long-lasting negative health habits, disease- and treatment-related metabolic disorders, and consequent increased frequencies of cardiovascular diseases. Co-existing depression was found to have adverse consequence on the course of schizophrenia progression, morbidity and mortality. Cognitive impairment also adds to the burden of schizophrenia. Social impairment is worsened by underestimated stigmatisation and lack of corresponding awareness within the professional and social spheres. Finally, caregiver burden was found to be considerable. DISCUSSION: Humanistic burden among patients with schizophrenia is substantial potentially impacted by co-morbid depressive symptoms, caregiver burden and cognitive impairment. Effects of treatment on humanistic burden in addition to economic burden need to be explored in future trials. PMID- 24795290 TI - Medication supply, healthcare outcomes and healthcare expenses: longitudinal analyses of patients with type 2 diabetes and hypertension. AB - INTRODUCTION: Patients with chronic conditions largely depend on proper medications to maintain health. This study aims to examine, for patients with diabetes and hypertension, whether the appropriateness of the quantity of drug obtained is associated with favorable healthcare outcomes and lower expenses. METHODS: This study utilized a longitudinal design with a seven-year follow-up period from 2002 to 2009 under a universal health insurance program in Taiwan. The patients under study were those aged 18 years or older and newly diagnosed with type 2 diabetes or hypertension in 2002. Generalized estimating equations were performed to examine the relationship between medication supply and health outcomes as well as expenses. RESULTS: The results indicate that while compared with patients with an appropriate medication supply, patients with either an undersupply or an oversupply of medications tended to have poorer healthcare outcomes. The study also found that an excess supply of medications for patients with diabetes or hypertension resulted in higher total healthcare expenses. CONCLUSION: Either an undersupply or an oversupply of medication was associated with unfavorable healthcare outcomes, and that medication oversupply was associated with the increased consumption of health resources. Our findings suggest that improving appropriate medication supply is beneficial for the healthcare system. PMID- 24795291 TI - Health-related quality of life in food-allergic adults from eight European countries. AB - BACKGROUND: Food allergy can impair health-related quality of life (HRQL). Food Allergy Quality of Life Questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ-AF). HRQL has not, to date, been measured across different European countries using a uniform methodology. OBJECTIVE: To translate and validate the FAQLQ-AF for use in 8 European countries (Iceland, The Netherlands, Poland, France, Spain, Italy, Greece, and Sweden). METHODS: The English FAQLQ-AF was translated, back-translated, and compared for use in the 8 relevant European languages. Adults with a perceived food allergy were recruited from outpatient departments and through a community survey. Participants completed the FAQLQ-AF, the Food Allergy Independent Measure, and questions concerning participants' characteristics. Validity of the FAQLQ-AF was analyzed for use in the 8 countries. RESULTS: The FAQLQ-AF had strong construct validity (r > 0.59) and an excellent internal consistency (Cronbach alpha > 0.95) in all countries. Total FAQLQ-AF scores (range 3.2-5.0) were significantly different across participating countries. CONCLUSION: The FAQLQ-AF is a suitable and valid instrument for measuring HRQL in food-allergic adults in Iceland, The Netherlands, Poland, France, Spain, Italy, Greece, and Sweden. The impact of food allergy on HRQL seems to differ among adults from the 8 participating European countries. PMID- 24795293 TI - Measurement of beta-tryptase in postmortem serum, pericardial fluid, urine and vitreous humor in the forensic setting. AB - In the realm of forensic pathology, beta-tryptase measurement for diagnostic purposes is performed in postmortem serum obtained from femoral blood. This may be partially or completely unavailable in some specific cases, such as infant autopsies and severely damaged bodies. The aim of this study was to investigate the usefulness of determining beta-tryptase levels for diagnostic purposes in alternative biological samples. Urine, vitreous humor and pericardial fluid were selected and measured in 94 subjects including: fatal anaphylaxis following contrast material administration (6 cases), hypothermia (10 cases), diabetic ketoacidosis (10 cases), gunshot suicide (10 cases), heroin injection-related deaths (18 cases), trauma (10 cases), sudden death with minimal coronary atherosclerosis (10 cases), severe coronary atherosclerosis without myocardial infarction (10 cases) and severe coronary atherosclerosis with myocardial infarction (10 cases). Postmortem serum and pericardial fluid beta-tryptase levels higher than the clinical reference value (11.4ng/ml) were systematically identified in fatal anaphylaxis following contrast material administration and 6 cases unrelated to anaphylaxis. beta-tryptase concentrations in urine and vitreous humor were lower than the clinical reference value in all cases included in this study. Determination of beta-tryptase in pericardial fluid appears to be a possible alternative to postmortem serum in the early postmortem period when femoral blood cannot be collected during autopsy and biochemical investigations are required to objectify increased beta-tryptase levels. PMID- 24795294 TI - Photochemically induced fluorescence studies of 1,3-diethyl-1,3-diphenylurea as stabilizer and its quantitative determination. AB - The photochemically induced fluorescence (PIF) studies of 1,3-diethyl-1,3 diphenylurea or ethyl centralite (EC) as stabilizer have been carried out under various conditions. Influences of solvent type (water, methanol, acetonitrile and chloroform), oxygen dependence and UV irradiation time on the spectroscopic properties of EC were studied. In order to obtain a better understanding of the photochemical mechanism, products were identified by mass spectrometry study. A novel fluorimetric method has been developed for the determination of EC based on the PIF. The method is based on the use of UV irradiation to produce fluorescent derivatives from EC as a non-fluorescent molecule. The determination is carried out by UV irradiation for 4min through measuring the fluorescence intensity in 354nm when an excitation wavelength of 227nm was used. Parameters related to the analytical signal and to the PIF are optimized. The linear range for determination of EC was 4*10(-8) to 2*10(-6)mol L(-1) and the limit of detection (LOD) was 2*10(-8)mol L(-1) with relative standard deviation (R.S.D.) of 3% (n=5). Finally, the proposed method was successfully applied for the determination of EC in real propellant samples and the acquired results were favorably compared to those obtained with HPLC method. PMID- 24795292 TI - Changing roles of eosinophils in health and disease. AB - OBJECTIVE: To review and highlight the unappreciated roles of eosinophils suggested by recent studies. DATA SOURCES: The literature, unpublished observations, and insights by the authors. STUDY SELECTIONS: Basic studies of mouse models and patient-based clinical studies of disease. RESULTS: Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease. CONCLUSION: Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies. PMID- 24795295 TI - Effects of feeder space allocations during rearing, female strain, and feed increase rate from photostimulation to peak egg production on broiler breeder female performance. AB - A study was conducted to determine if there were differences in female broiler breeder performance of 2 strains that had been subjected to 2 feeder space allocations during the growing period followed by 2 feeding to peak programs. Ross 308 and 708 pullets were reared with a single feeding program to 23 wk of age and with 2 circumferential feeder space allocations (5.3 cm/female or 7.0 cm/female) and then assigned to 2 feed increase programs (slow or fast) from photostimulation to peak egg production. The flock was moved to the laying house with 8.8 cm/female of female feeder space and photostimulated at 23 wk of age when Ross 344 males were added to create 16 pens with 60 females and 7 males each in a 2 * 2 * 2 design. The fast feed increase program significantly increased female BW at 31 wk of age, which could have contributed to an increased female mortality during the summer weather of early lay. The 708 females with 5.3 cm/female feeder space produced smaller eggs at 28 and 30 wk of age. The 708 females exhibited better fertile hatchability than 308 females due to fewer late dead embryos. There were no differences in egg production, fertility, or fertile hatchability due to the main effects of feeding to peak program or growing feeder space, but the slow feed increase from photostimulation to peak production reduced cumulative mortality. PMID- 24795296 TI - Effects of commercial in ovo injection of 25-hydroxycholecalciferol on broiler bone development and mineralization on days 0 and 21 posthatch. AB - The effects of in ovo injection of 25-hydroxycholecalciferol [25(OH)D3] at various dosages on weight, breaking strength, and ash and mineral concentrations of left tibial bones in Ross * Ross 708 broilers on d 0 and 21 posthatch were investigated. Six treatment groups were equally represented on each of 10 tray levels (blocks) of a single-stage incubator. The 6 treatment groups, containing 21 eggs each, were randomly arranged on each tray level with respect to those on other tray levels. A multi-egg injector was used to inject eggs on d 18 of incubation according to their preassigned treatments. The experimental treatments included noninjected and diluent-injected (100 uL of commercial diluent) controls, and those that received 0.15, 0.30, 0.60, or 1.20 ug of 25(OH)D3 in 100 uL of diluent. On d 0 and 21 posthatch, 3 chicks from each treatment replicate group were randomly selected for necropsy and the subsequent extraction of their left tibial bones. Tibia samples were weighed and then subjected to breaking strength and ash concentration analysis. One of the 3 residual bone ash samples in each treatment replicate group was randomly selected, digested, and analyzed for Ca, P, Mg, K, Zn, and Mn concentrations. The relative weight, breaking strength, and percentage ash and mineral concentrations of broiler tibias on d 0 and 21 posthatch were not affected by treatment. However, trend analysis of percentage tibial ash on d 21 revealed a dosage effect (P = 0.068). The results of this study suggest that the in ovo injection of 0.15 to 1.20 ug of 25(OH)D3 on d 18 of incubation did not influence subsequent bone development or mineralization in Ross * Ross 708 broilers on d 0 and 21 posthatch. Nevertheless, further trend analysis suggested that increased dosage levels of 25(OH)D3 above 1.20 ug may have the potential to lead to increases in bone mineralization. PMID- 24795297 TI - Divergent selection for muscle color in broilers. AB - One consumer-related physiological abnormality that is a recent concern for the poultry industry is atypical meat quality. Currently in the processing plant, meat is characterized on appearance such as tears, bruises, discoloration, or missing parts. Unfortunately, this method ignores physical properties such as palatability, texture, tenderness, taste, color, pH, and water-holding capacity (WHC). The growing demand for a convenient, economical, and palatable product has shifted the market toward value-added poultry products. The effect of a meat's physical properties on its marketability and versatility has become apparent to processors attempting to utilize poor quality meat. After 8 generations of divergent selection for muscle color or lightness (L*) in broilers, muscle quality parameters were investigated. The 2 broiler lines divergently selected for high (HMC) and low (LMC) muscle color along with their randombred control line (RBC) were included in the study. Heritability estimates for L* were 0.47 +/ 0.05 and 0.51 +/- 0.05 in the HMC and LMC lines, respectively. For generation 8, the mean L* for the HMC, RBC, and LMC lines were 53.91, 49.70, and 46.86, respectively. Selection for increased L* was found to result in increased breast fillet yellowness (b*), whereas selection for decreased L* resulted in an increase in breast fillet redness (a*). Selection for increased L* has resulted in increased rate of pH decline over time, whereas selection for decreased L* has resulted in a decreased rate of pH decline. The HMC line exhibited a higher percentage fillet drip loss than both the LMC and RBC lines, which did not differ from each other. Overall selection for L* was effective in modifying breast muscle color as well as correlated responses associated with atypical poultry meat such as drip loss and postmortem muscle pH. These selected lines can serve as resource populations for the study of PSE and DFD-like meat in poultry and demonstrate that L* selection could be applied to primary breeding programs as a way to improve or manage muscle quality in pedigree elite lines. PMID- 24795298 TI - Featherless and feathered broilers under control versus hot conditions. 1. Breast meat yield and quality. AB - The improved genetic potential of contemporary commercial broilers cannot be fully expressed under hot conditions that depress growth rate, decrease breast meat yield, and reduce meat quality. The negative heat effects are attributed to the insulating feather coverage, which, under high ambient temperatures (AT), hinders dissipation of the excessive internally produced heat. Accordingly, featherless broilers (sc/sc), their feathered sibs (+/sc), and contemporary broilers (+/+) were subjected to control AT (26 degrees C) and hot AT (32 degrees C) to test the hypothesis that lack of feathers contributes to higher breast muscle yield and better meat quality, especially under hot conditions, and that differences related to lack of feathers are related to cardiovascular capacity. In 2 similar trials, the superior genetic background of the contemporary broilers was manifested under control conditions; their mean BW was about 15% higher than the means of the featherless broilers and their feathered sibs. The hot conditions depressed BW of the 2 feathered groups by approximately 25%, with hardly any effect on featherless broiler BW. Breast meat yield (% of BW) in the featherless broilers was higher than in those with feathers, especially under the hot AT. Furthermore, the featherless broilers were characterized by superior meat quality as indicated by lower drip loss, lower lightness, and higher redness. The superior meat quality of the featherless broilers could be explained by their larger hearts and higher hematocrit values, suggesting superior cardiovascular capacity to supply oxygen and nutrients to the breast muscles. On the practical side, the results clearly indicate that modern featherless broilers can reach normal BW, as well as yield and quality of breast meat, under hot conditions as well. It appears that broiler meat production in hot regions and climates can be substantially improved by introducing the featherless gene into contemporary commercial broiler stocks. This has become more feasible since the recent development of a simple DNA test to identify carriers of the recessive sc mutation. PMID- 24795299 TI - Featherless and feathered broilers under control versus hot conditions. 2. Breast muscle development and growth in pre- and posthatch periods. AB - Breast meat yield (% of BW) of featherless broilers (sc/sc) is higher than that of their feathered sibs (+/sc) and contemporary broilers (+/+) under hot temperature (32 degrees C) conditions. This study tested the hypothesis that the advantage to the featherless broiler condition with respect to breast meat yield and quality is due to differences in muscle development during pre- and posthatch periods. Broilers from the 3 genetic groups were reared under normal (26 degrees C) and hot (32 degrees C) conditions and slaughtered on d 29 and 47. Evaluation of myofiber diameter (mean and distribution) and blood-vessel density in breast muscle sections sampled on these days revealed that the fluctuations in breast muscle yields of the different genetic groups under different temperature conditions and the better muscle growth of the featherless broilers are due to changes in muscle hypertrophy and vascularization. In addition, the featherless broilers presented continuous satellite cell proliferation and a slower rate of differentiation compared with the feathered broilers on immediate posthatch period, suggesting a higher reserve of myogenic progeny cells that will contribute to later muscle hypertrophy. In the embryos, breast muscle yield was higher for the featherless versus feathered counterparts between embryonic day (E) 15 and E20. This was manifested in a shift toward higher myofiber diameters in the featherless embryos on E18, and a higher number of myoblasts, which could be explained by higher insulin-like growth factor-I levels in the muscle tissue and lower triiodothyronine levels in the plasma on E17. Together, the data show the advantage of being featherless under hot conditions with regard to breast muscle growth and hypertrophy, and overall performance. Moreover, featherless embryos had increased breast muscle weight compared with their feathered counterparts, likely due to a higher proliferation rate of myoblasts and higher muscle hypertrophy. PMID- 24795300 TI - Association between polymorphism in the melanocortin 1 receptor gene and E locus plumage color phenotype. AB - The purpose of this study was to investigate the effect of the melanocortin 1 receptor (MC1R) gene on plumage color in chickens. The gene was sequenced in 77 males and 77 females from 13 Spanish breeds, carrying 6 different alleles in the E locus (E*E, E*R, E*WH, E*N, E*B, E*BC), a recessive wheaten (yellowish-white) tester line (E*Y), and a White Leghorn population (heterozygous E*E). A total of 11 significant SNP were detected. Nine of them were nonsynonymous (T212C, G274A, G376A, T398AC, G409A, A427G, C637T, A644C, and G646A, corresponding to amino acid changes Met72Thr, Glu92Lys, Val126Ile, Leu133GlnPro, Ala137Thr, Thr143Ala, Arg213Cys, His215Pro, and Val216Ile), and 2 were synonymous (C69T and C834T). With respect to the significant SNP, 7 had an allelic frequency of 0.5 or greater for some of the alleles at the E locus. These results indicated a significant correlation between MC1R polymorphism and the presence of different alleles at the E locus. All the populations carrying the E*E or E*R alleles, except the Birchen Leonesa, had the G274A polymorphism. Eleven haplotypes were made with 7 of the significant SNP. The distribution of these haplotypes in the different alleles of the E locus showed that each haplotype was predominantly associated to one allele. The number of haplotypes was greatest for the Black Menorca, Birchen Leonesa, and Blue Andaluza breeds, whereas the Quail Castellana and Red-barred Vasca breeds were monomorphic. Our results suggested that the Glu92Lys mutation may be responsible of the activation of the receptor for eumelanin production, being necessary but not sufficient to express the extended black phenotype. They also suggested that the Arg213Cys mutation may be the cause of the loss or the decrease of function of the receptor to produce eumelanin, and the Ala137Thr mutation may be a candidate to attenuate the Glu92Lys effect. The observed co segregation of the E locus alleles and polymorphisms in MC1R confirms that the E locus is equivalent to MC1R. PMID- 24795301 TI - gga-miR-26a targets NEK6 and suppresses Marek's disease lymphoma cell proliferation. AB - MicroRNA (miRNA) are a class of highly conserved, small noncoding RNA that emerge as key posttranscriptional regulators in various neoplastic transformations. Our previous study profiling the miRNA transcriptome in Marek's disease virus (MDV) induced lymphoma revealed many novel and differentially expressed miRNA, including gga-miR-26a, which was downregulated in MDV-infected spleens of chickens. In this study, differential expression of gga-miR-26a between MDV infected and noninfected spleens at 4, 7, 14, 21, and 28 d postinfection was analyzed by real-time PCR. The results showed gga-miR-26a were downregulated in MDV-infected spleens at cytolytic infection, latency, and tumor transformation phases. Subsequent cell proliferation assay revealed cell viability was lower in gga-miR-26a mimic transfection group than that in negative controls. Target genes of gga-miR-26a were identified by luciferase reporter gene assay. The results showed significant interaction between gga-miR-26a and Never In Mitosis Gene A (NIMA)-related kinase 6 (NEK6) gene. Subsequent gain of function experiment and Western blot assay showed that mRNA and protein levels of NEK6 were downregulated after gga-miR-26 mimic was transfected into MDV-transformed lymphoid cell line (MSB-1), indicating that NEK6 was modulated by gga-miR-26a. The expression of NEK6 showed a higher trend in MDV-infected samples including tumorous spleen and MD lymphoma from liver than that in noninfected controls. The results suggested that gga-miR-26a inhibited MSB-1 cell proliferation. Gga-miR-26a and its direct target, NEK6, might play important roles in MDV infection. PMID- 24795302 TI - Drug resistance of Aspergillus fumigatus strains isolated from flocks of domestic geese in Poland. AB - The aim of the study was to determine the in vitro susceptibility of 85 Aspergillus fumigatus strains isolated from domestic geese and from their environment to amphotericin B, clotrimazole, voriconazole, itraconazole, enilconazole, miconazole, ketoconazole, and tioconazole. Samples were collected from clinically healthy birds (oral cavity) and from birds with aspergillosis (lungs and air sacs). The study was carried out using the disk diffusion method according to the Clinical Laboratory and Standards Institute (CLSI) M44-A2 procedure in parallel with the microdilution broth method according to CLSI M38 A2. The disk diffusion method showed that the all of the strains, irrespective of source, were resistant to miconazole. Resistance to the remaining azoles and amphotericin B ranged from 90.6 to 70.6%. Complete susceptibility was noted for voriconazole and enilconazole. Determination of the minimum inhibitory concentration (MIC) confirmed the high resistance of the strains tested to clotrimazole (MIC90 = 16 ug*mL(-1)), amphotericin B (MIC90 = 16 ug*mL(-1)), varied susceptibility to itraconazole (MIC 0.5-8 ug*mL(-1)), and 100% susceptibility to enilconazole and voriconazole. A correlation was noted between the susceptibility of the strains and their source. The highest percentage of resistant strains was noted in isolates from the lungs (100% for amphotericin B and clotrimazole and 35.7% for itraconazole). To the best of our knowledge, this is the first monitoring conducted in Poland in this area of research. PMID- 24795303 TI - Effects of in ovo injection with selenium on immune and antioxidant responses during experimental necrotic enteritis in broiler chickens. AB - This study was conducted to investigate the effects of in ovo injection of Se on modulating the immune system and antioxidant responses in broiler chickens with experimental necrotic enteritis. Broiler eggs were injected at 18 d of embryo age with either 100 MUL of PBS alone or sodium selenite (Na2SeO3) in PBS, providing 0 (SS0), 10 (SS10), or 20 (SS20) MUg of Se/egg. At 14 d posthatch, PBS-treated and uninfected chickens were kept as the control group, whereas the remaining chickens were orally infected with 1.0 * 10(4) sporulated oocysts of Eimeria maxima (SS0, SS10, SS20). At 18 d posthatch, E. maxima-infected chickens were orally infected with 1.0 * 10(9) cfu of Clostridium perfringens. Infected control SS0 group showed significantly decreased BW compared with the uninfected control. However, SS20 group showed significantly increased BW compared with the infected control SS0 group, whereas the BW were similar among uninfected control and infected SS10 and SS20 groups. The SS10 group showed significantly lower intestinal lesions compared with the SS0 group, and oocyst production was decreased in both SS10 and SS20 groups. Serum malondialdehyde level and catalase activity were also decreased in both SS10 and SS20 groups, whereas the superoxide dismutase level was significantly lower in the SS10 group compared with the SS0 group. The SS20 group showed significantly higher levels of transcripts for IL 1beta and IL-6 in intestine, and SS10 and SS20 groups had higher levels of transcripts for IL-8 and inducible nitric oxide synthase expression and decreased glutathione peroxidase 7 mRNA levels compared with the SS0 group. The SS10 and SS20 groups also showed increased serum antibody levels to C. perfringens alpha toxin and NetB toxin compared with the SS0 group. These collective results suggest that the injection of Se into the amniotic cavity of developing eggs may be beneficial for enhancing immune and antioxidant responses in the hatched chickens exposed to the necrotic enteritis-causing pathogens. PMID- 24795304 TI - Kinetic examination of femoral bone modeling in broilers. AB - Lameness in broilers can be associated with progressive degeneration of the femoral head leading to femoral head necrosis and osteomyelitis. Femora from clinically healthy broilers were dissected at 7 (n = 35, 2), 14 (n = 32), 21 (n = 33), 28 (n = 34), and 42 (n = 28) d of age, and were processed for bone histomorphometry to examine bone microarchitecture and bone static and dynamic properties in the secondary spongiosa (IISP) of the proximal femoral metaphysis. Body mass increased rapidly with age, whereas the bone volume to tissue volume ratio remained relatively consistent. The bone volume to tissue volume ratio values generally reflected corresponding values for both mean trabecular thickness and mean trabecular number. Bone metabolism was highest on d 7 when significant osteoblast activity was reflected by increased osteoid surface to bone surface and mineralizing surface per bone surface ratios. However, significant declines in osteoblast activity and bone formative processes occurred during the second week of development, such that newly formed but unmineralized bone tissue (osteoid) and the percentages of mineralizing surfaces both were diminished. Osteoclast activity was elevated to the extent that measurement was impossible. Intense osteoclast activity presumably reflects marked bone resorption throughout the experiment. The overall mature trabecular bone volume remained relatively low, which may arise from extensive persistence of chondrocyte columns in the metaphysis, large areas in the metaphysis composed of immature bone, destruction of bone tissue in the primary spongiosa, and potentially reduced bone blood vessel penetration that normally would be necessary for robust development. Delayed bone development in the IISP was attributable to an uncoupling of osteoblast and osteoclast activity, whereby bone resorption (osteoclast activity) outpaced bone formation (osteoblast activity). Insufficient maturation and mineralization of the IISP may contribute to subsequent pathology of the femoral head in fast-growing broilers. PMID- 24795305 TI - The effect of different dietary levels of canola meal on growth performance, nutrient digestibility, and gut morphology of broiler chickens. AB - This study evaluated the effects of different levels of canola meal in broiler diets on growth performance, nutrient digestibility, and duodenal morphometry. A total of 320 one-day-old Cobb broilers were used in a 35-d experiment. A completely randomized design with 5 levels of canola meal (0, 10, 20, 30, and 40%) as a substitute for soybean meal was used with 8 replicates of 8 birds each. The basal diets were formulated based on corn and soybean meal to meet nutrient requirements of broiler chickens. The levels of canola meal were evaluated with a polynomial regression at 5% of significance. Weight gain and average BW showed a quadratic response (P = 0.03 and P = 0.04, respectively), decreasing with the addition of 40% canola meal. The apparent nutrient digestibility of DM (P < 0.0001), CP (P < 0.0001), and nitrogen-free extract (P < 0.0001) decreased linearly with increased levels of canola meal. A quadratic effect was observed for villus height (P = 0.003), decreasing up to a 20% inclusion of canola meal in the diet and increasing beyond that level. In conclusion, canola meal can be added up to 16.7% in diets for broilers without affecting the key variables of growth performance. It can be added up to 20% with no negative effect on the CP digestibility, but there was a linear decrease in the digestibility of DM and nitrogen-free extract with increased inclusion of canola meal. Additionally, a quadratic response to canola was observed for villus height with a maximum at 23.6% canola meal. PMID- 24795306 TI - Effects of pretransport handling stress on physiological and behavioral response of ostriches. AB - Ostrich (Struthio camelus) production is a relatively young industry and there has been little research on ostrich welfare during pretransport handling and the transportation process. A heavy body with a high center of gravity makes ostriches' handling and transportation problems different from other livestock. The main objective of this study was to investigate the effects of the pretransport holding time duration on ostrich behavior and physiological responses. A second objective was to identify and validate behavioral indicator(s) that could be used to identify stressed birds during pretransport handling. Prior to shipping, twenty-four 2.5-yr-old ostriches were moved into a holding pen. Birds were then individually restrained, hooded, and walked from the holding pen (approximately 12 min/bird) to a sampling pen (visually isolated from the holding pen) where they were weighed and a 10-mL blood sample obtained. A second blood sample was taken from each bird after a 1,100-km transportation. Blood samples were analyzed for concentrations of blood metabolites, enzymes, corticosterone, and white blood cell and differential counts. Behavioral responses and physical damages of ostriches were also recorded before and after transport. Results indicated that birds that spent longer time in the pretransport holding pen had higher pretransport plasma concentrations of aspartate aminotransferase, alanine aminotransferase, sodium, and packed cell volume. Immobile sitting behavior, observed in 5 out of the last 11 birds handled, was positively correlated with higher pretransport handling stress, higher posttransport aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, and glucose concentrations, and transport losses. Knowledge of pretransport handling impacts on ostrich stress and availability of behavioral indicators (e.g., immobile sitting response) could be used to improve handing processes, thereby decreasing potential weight loss, injury, and mortality. PMID- 24795307 TI - A meta-analysis of the feed intake and growth performance of broiler chickens challenged by bacteria. AB - The aim of this meta-analysis was to determine the effect of a bacterial immune challenge (Clostridium spp., Escherichia coli, and Salmonella spp.) on the ADFI, ADG, and nutrient partitioning (maintenance requirements and feed efficiency) of broiler chickens. The database used for the meta-analysis included 65 articles that were published between 1997 and 2012 concerning a total of 86,300 broilers and containing information on the feed intake, protein intake, methionine intake, and weight gain of broilers that were challenged with Clostridium spp., E. coli, or Salmonella spp. and were fed or not fed feed additives. The results of the ADFI and the ADG of the challenged broilers were transformed into values relative to those obtained in control broilers (ADG and ADFI). The meta-analysis involved 3 sequential analyses: graphical, correlation, and variance-covariance analysis. The results obtained for the birds that were challenged with Clostridium spp., E. coli, or Salmonella spp. indicated that the ADFI was reduced by 16, 7, and 9%, respectively, and the ADG was reduced by 40, 10, and 29%, respectively. When the results for the challenged birds that were treated or nontreated were compared, ADFI reductions of 26.0 and 26.5% and ADG reductions of 2.9 and 21.6% were observed, respectively. Regression analyses of the ADG as a function of the protein or methionine intake of the challenged birds suggested that nutrients were diverted to the immune system. The relationship between the ADG and the ADFI was quadratic in the challenged and nontreated or treated broilers, as well as for each disease. The intercept of the regression-based curves for the data from all of the challenges were different from zero and negative (-2.20, -0.70, and 3.37, respectively), indicating that all of the challenges increased the maintenance requirements. In general, this meta-analysis allowed for the quantification of the effects of bacteriological challenges on the maintenance and feed efficiency of broiler chickens, and the knowledge that was generated in this study is applicable to broiler nutrition and for modeling their nutritional requirements. PMID- 24795308 TI - The effects of different thermal treatments and organic acid levels on nutrient digestibility in broilers. AB - Poultry feed is a potential vector for pathogens. Heat processing and organic acid treatments may decontaminate feed and can affect bird performance as well as feed digestibility. The present study was performed to investigate the effect of different thermal treatments including pelleting (P), long-term conditioning at 85 degrees C for 3 min (L), or expanding at 110 degrees C (E110) and 130 degrees C for 3 to 5 s (E130) without or with 0.75 and 1.5% organic acid supplementation (63.75% formic acid, 25.00% propionic acid, and 11.25% water) on performance, nutrient digestibility, and organ weights of broilers. In total, 960 one-day-old broiler chicks were randomly assigned to 8 replicates using a 3 * 4 factorial arrangement. Performance variables were determined, and the relative organ weights and ileal and total amino acid (AA) digestibilities were measured at d 35. The organic acid inclusion linearly improved feed efficiency in the first week (P <= 0.05). The acid inclusion levels and thermal treatments had no significant effect on the performance variables at later intervals of the growing period of the birds. The L group showed the lowest ileal AA and CP digestibility. The inclusion of organic acids had a quadratic effect on total and ileal digestibility of isoleucine (P <= 0.05), whereas it had no significant effect on the ileal digestibility of other AA and nutrients. The relative weights of the jejunum and small intestine were significantly higher in the E130 group compared with P and L (P <= 0.05). In conclusion, our study demonstrated that long-term heat conditioning can decrease ileal nutrient digestibility, whereas pelleting and expansion, independently of organic acid addition, seemed to have no negative impact on broiler performance and nutrient digestibilities. Moreover, adding a blend of organic acids to broiler diets had neither positive nor negative effects on nutrient digestibility and final broiler performance. This indicates the feasibility of short-term thermal treatment and acid supplementation for hygienization of broiler feed without negatively influencing performance. PMID- 24795309 TI - Influence of superdoses of a novel microbial phytase on growth performance, tibia ash, and gizzard phytate and inositol in young broilers. AB - An experiment was conducted to evaluate the influence of a novel microbial phytase on performance, tibia ash, and the content of phytate, phytate esters, and inositol in the gizzard of young broilers. Male Cobb 500 broilers (n = 1,680) were fed 1 of 7 experimental diets: positive control (PC) formulated to meet or exceed nutrient recommendations; PC plus dicalcium phosphate (PC+DCP) formulated to provide Ca and P at 0.10% above the PC; PC plus 500 U/kg of microbial phytase (PC+500); negative control (NC) with Ca and P reduced from the PC by 0.16% and 0.15%, respectively; and the NC plus phytase at 500 (NC+500), 1,000 (NC+1,000), or 1,500 (NC+1,500) U/kg. Diets were fed in crumbled form to 20 birds/pen and 12 replicate pens/diet from d 0 to 21. On d 21, 4 birds/pen were euthanized for collection of right tibias and gizzard digesta for determination of tibia ash and gizzard phytate. In general, broilers fed the NC diet had reduced (P <= 0.05) feed intake and BW gain compared with broilers fed diets supplemented with phytase, but not different than the PC or PC+DCP. Phytase supplementation in the NC diet improved (P <= 0.05) BW gain comparable with or above that of the PC. Feed conversion ratio was improved in broilers fed the NC+1,000 or NC+1,500 compared with broilers fed all other diets. Tibia ash was reduced (P <= 0.05) in broilers fed the NC compared with broilers fed all other diets, and phytase supplementation improved tibia ash comparable with the PC. Phytase supplementation reduced (P <= 0.05) phytate (inositol hexa-phosphate) concentration in the gizzard. Inositol concentration in the gizzard was higher (P <= 0.05) in birds fed NC+1,000 or NC+1,500 compared with all other diets and this was correlated with growth performance (P <= 0.05) rather than tibia ash (P > 0.05). Improvements in feed conversion ratio associated with superdoses of phytase may be attributed to phytate destruction and the provision of inositol. PMID- 24795310 TI - Influence of the in vivo method and basal dietary ingredients employed in the determination of the amino acid digestibility of wheat distillers dried grains with solubles in broilers. AB - As distillers dried grains with solubles (DDGS) become increasingly available, it is important to determine their nutritional value for precise feed formulation. The accurate determination of digestibility is crucial, and it is known that the methods used will affect the values obtained. An experiment was designed to determine and compare the standardized ileal digestibility (SID) of amino acids from wheat DDGS using a semisynthetic diet and a difference method using 4 further diets based on corn, wheat, corn DDGS, and wheat DDGS. Eighty 1-d-old male broilers were fed a commercial starter diet until d 21. Between d 21 and 23, they were fed test diets in order to adapt to those diets before the trial took place between d 24 and 27. The trial period took place between d 24 and 27. Feed intake was measured, excreta collected, and at d 27, all birds were culled and ileal digesta was collected for the determination of apparent ileal digestibility and SID of amino acids. Values determined were similar to those reported elsewhere in the literature, although SID values for lysine were particularly low, being 0.26, 0.27, or 0.32, measured in semisynthetic, corn, or wheat diet backgrounds, respectively. It appeared that diet type employed was influential in the values obtained. The SID values for methionine, cysteine, methionine plus cysteine, and arginine were significantly lower (P < 0.05) when measured in semisynthetic diet backgrounds than wheat- or corn-based diets. It appears that dextrose and possibly purified starch have a detrimental impact on the broiler digestive tract. This may affect all digestibility methodologies in which such a diet base is used. PMID- 24795311 TI - Growth performance, nutrient utilization, and digesta characteristics in broiler chickens fed corn or wheat diets without or with supplemental xylanase. AB - Efficacy of supplemental xylanase on growth performance, nutrient utilization, and digesta characteristics in broiler chickens fed corn- or wheat-based diets was investigated. In experiment 1, 192 male broilers (8 birds/pen; n = 6) were fed 4 diets (corn or wheat without or with 1,250 xylanase units/kg) in 2 phases (starter, d 0-21 and grower, d 22-42). There was no interaction (P > 0.05) between diet and xylanase on performance (d 0-42). Wheat diets resulted (P < 0.01) in better performance than corn diets, whereas xylanase-fed birds had improved (P < 0.01) BW gain (2,457 vs. 2,275 g) and feed per gain (1.677 vs. 1.762) relative to birds not fed xylanase. In experiment 2, TiO2 (0.3%) was added in starter diets used in experiment 1, allocated to 13-d-old broiler chicks (n = 6) housed in cages (6 birds/cage) and fed up to d 21. Excreta samples were obtained from d 17 to 20 and birds were euthanized on d 21 for digesta. Corn diets had a greater concentration (10.7 vs. 9.8%) of insoluble nonstarch polysaccharides (NSP) than wheat diets, which in turn had more than twice the concentration of soluble NSP. There was an interaction (P < 0.03) between diet type and xylanase on jejunal digesta viscosity but not (P > 0.10) on apparent ileal digestibilities of nutrients, cecal volatile fatty acids, and AMEn. In this context, diet type influenced (P < 0.05) cecal volatile fatty acids and retention of nutrients and fiber but did not affect (P = 0.45) AMEn. In contrast, xylanase fed birds showed higher (P < 0.05) ceca digesta acetic acid, apparent ileal digestibilities of nutrients, and retention of components. As a result, birds fed xylanase had higher AMEn (3,059 vs. 2,995 kcal/kg; P < 0.01) compared with birds not fed xylanase. Although wheat diets had superior growth performance, the AMEn was similar in both diets. Xylanase improved growth performance and AMEn independent of diet type, suggesting hydrolysis of both soluble and insoluble NSP. PMID- 24795312 TI - Egg quality and productive performance of laying hens fed different levels of skimmed milk powder added to a diet containing Lactobacillus acidophilus. AB - The current trial was carried out on a commercial poultry farm to study the effect of skim milk powder (SMP) added to a diet containing Lactobacillus acidophilus on performance and egg quality of laying hens from 20 to 49 wk of age. A total of 2,400 Hy-Line W-36 laying hens were housed in 600 unenriched cages (4 hens each) located over 4 tier levels. Animals were assigned to 1 of 3 experimental treatments (0, 3, and 4). The laying hens assigned to treatments 3 and 4 received a diet enriched respectively with 3 and 4% SMP, whereas the animals in treatment 0 were fed a diet without SMP. All diets, moreover, were supplemented with L. acidophilus D2/CSL. Hen performance was determined throughout the experimental period and egg quality was measured on 30 eggs per treatment every week. Results showed that productive performance in terms of egg production, egg weight, and feed conversion ratio was not influenced by SMP at 3 or 4% of the diet. Egg quality was significantly affected by SMP included at 3 or 4% of the diet. Eggs from treatments 3 and 4, in fact, displayed higher shell thickness than those from treatment 0 (P < 0.0001). Likewise, specific gravity, Haugh unit, and shell percentage were significantly affected by the addition of SMP. In conclusion, in our study, SMP added to a diet containing L. acidophilus had no significant effects on the productive parameters of hens during the laying period, whereas significant improvements were found in certain egg quality characteristics. PMID- 24795313 TI - The effects of conjugated linoleic acid on growth performance, carcass traits, meat quality, antioxidant capacity, and fatty acid composition of broilers fed corn dried distillers grains with solubles. AB - This study investigated the effects of dietary supplementation with conjugated linoleic acid (CLA) on the growth performance, carcass traits, meat quality, antioxidant capacity, and fatty acid composition of broilers fed corn dried distillers grains with solubles (DDGS). Four hundred eighty 1-d-old broilers were randomly assigned to 4 groups, consisting of 6 replicates with 20 broilers each. Broilers were allocated 1 of 4 diets and fed for 49 d in a 2 * 2 factorial design. The dietary treatments consisted of 2 levels of DDGS (0 or 15%) and 2 levels of CLA (0 or 1%). The results of growth performance analyses showed that dietary supplementation with 1% CLA, 15% DDGS, or both in broilers had no significant effects on ADG, ADFI, and feed/gain (P > 0.05). Dietary supplementation with 15% DDGS did not significantly affect meat color values, drip loss percentage, pH value at 15 min, crude fat content, or shear force value (P > 0.05). Diets supplemented with 15% DDGS decreased the proportions of saturated fatty acids (P < 0.05) and monounsaturated fatty acids but increased the proportion of polyunsaturated fatty acids of the thigh meat (P < 0.05). Diets supplemented with 1% CLA significantly decreased the abdominal fat percentage (P < 0.05). Supplementation with 1% CLA increased the crude fat content and decreased the color (b*) value and shear force value of the breast meat (P < 0.05). Diets supplemented with 1% CLA increased the total superoxide dismutase activity of the serum, breast meat, and liver, and decreased the malondialdehyde content of the serum and breast meat (P < 0.05). Supplementation with 1% CLA decreased the proportion of monounsaturated fatty acids and increased the proportion of saturated fatty acids (P < 0.05). Accumulation of CLA in the thigh meat was significantly increased (P < 0.05) with increasing CLA level in the diet. In conclusion, dietary supplementation with 1% CLA had positive effects on meat quality, antioxidant capacity, and fatty acid composition of broilers, although it had no significant effect on growth performance. PMID- 24795314 TI - Development of skeletal muscle and expression of myogenic regulatory factors during embryonic development in Jinding ducks (Anas platyrhynchos domestica). AB - The important roles of myogenic regulatory factors (MRF) in mammalian skeletal myogenesis have been well studied, but few equivalent studies have been performed in poultry. The expression pattern of MRF during the embryonic development of skeletal muscle in ducks remains unknown. In this study, we identified Myf5, Myf6, MyoD, and myogenin genes in Jinding ducks (Anas platyrhynchos domestica) and quantified their expression levels in breast muscle (BM) and leg muscle (LM) at embryonic d 13, 17, 21, 25, and 27 by real-time reverse-transcription PCR. Body weight and muscle weight show different developmental patterns. The MRF genes were expressed in both BM and LM, but with different expression patterns. The MyoD gene showed lower expression levels in BM before embryonic d 21 compared with LM, whereas the opposite pattern was found later. The higher expression level of MyoD, as well its lagged expression pattern in BM, suggest that the MyoD gene may be involved in maintaining the development of different muscles. Correlation analysis showed that myogenin gene expression levels were significantly negatively correlated with BW and muscle weight in both BM and LM (P < 0.001), and MyoD and Myf6 gene expression levels were more strongly correlated with muscle weight in LM than in BM. The results of this study provide novel evidence for MRF expression in ducks in embryonic stage- and skeletal muscle-dependent manners, and provide a foundation for understanding the molecular control of skeletal muscle growth in duck breeds. PMID- 24795315 TI - Expression of digestive enzymes and nutrient transporters in Eimeria acervulina challenged layers and broilers. AB - Avian coccidiosis is a disease caused by intestinal protozoa in the genus Eimeria. Clinical signs of coccidiosis include intestinal lesions and reduced feed efficiency and BW gain. This growth reduction may be due to changes in expression of digestive enzymes and nutrient transporters in the intestine. The objective of this study was to examine the differential expression of digestive enzymes, transporters of amino acids, peptides, sugars, and minerals, and an antimicrobial peptide in the small intestine of Eimeria acervulina-infected broilers and layers. Uninfected broilers and layers, in general, expressed these genes at comparable levels. Some differences included 3-fold and 2-fold greater expression of the peptide transporter PepT1 and the antimicrobial peptide LEAP2 (liver expressed antimicrobial peptide 2), respectively, in the jejunum of layers compared with broilers and 17-fold greater expression of LEAP2 in the duodenum of broilers compared with layers. In the duodenum of Eimeria-infected broilers and layers, there was downregulation of aminopeptidase N; sucrase-isomaltase; the neutral, cationic, and anionic amino acid transporters b(o,+)AT/rBAT, B(o)AT, CAT2, and EAAT3; the sugar transporter GLUT2; the zinc transporter ZnT1; and LEAP2. In the jejunum of infected layers there was downregulation of many of the same genes as in the duodenum plus downregulation of PepT1, b(o,+)AT/rBAT, and the y(+) L system amino acid transporters y(+) LAT1 and y(+) LAT2. In the ileum of infected layers there was downregulation of CAT2, y(+)LAT1, the L type amino acid transporter LAT1, and the sugar transporter GLUT1, and upregulation of APN, PepT1, the sodium glucose transporter SGLT4, and LEAP2. In E. acervulina-infected broilers, there were no gene expression changes in the jejunum and ileum. These changes in intestinal digestive enzyme and nutrient transporter gene expression may result in a decrease in the efficiency of protein digestion, uptake of important amino acids and sugars, and disruption of mineral balance that may affect intestinal cell metabolism and Eimeria replication. PMID- 24795316 TI - Body composition and reproductive performance at entry into lay of anno 1980 versus anno 2000 broiler breeder females under fast and slow release from feed restriction. AB - During the 1990s, various disturbances arose affecting broiler breeder females at entry into lay. These disturbances were associated with even slight overfeeding during release of feed restriction in this critical maturation period. The present experiment was carried out to gain some insight into the causes of these disturbances by comparing the effect of fast (FF) and slow (SF) release from feed restriction at entry into lay in 2 broiler breeder populations: B1980, representing the genetic level of 1980, and B2000, the genetic level of 2000. Under the FF treatment, B1980 entered lay 19.2 d earlier than B2000; this increased to 37.4 d earlier under SF. The B1980 population entered lay at virtually the same mean age for SF and FF, whereas B2000 entered lay 15.7 d earlier under the FF. Body weight at first egg were 2,621 g for the B1980 and 3,591 g for B2000. Differences in BW at first egg between feeding treatments within lines were minor. As a percentage of BW, ovary, oviduct, and follicle weights were the same for B1980 and B2000; breast weight was 14.9% for B1980 and 21.2% for B2000; abdominal fat pad weight was 5.37% for B1980 and 2.67% for B2000. Follicle weight and absolute difference in weight between successive follicles was greater in B2000 than in B1980. It is concluded that body fat content does not limit entry into lay, and that threshold BW for onset of sexual maturity of broiler breeder hens increased by about 1,000 g between 1980 and 2000, indicating a tight association between juvenile growth rate and threshold BW for onset of sexual maturity. It is also concluded that disturbances at entry into lay due to overfeeding are not due to smaller differences between successive follicles in B2000 compared with B1980. There are hints, however, that overfeeding may contribute to these disturbances by decreasing differences between successive follicles. PMID- 24795317 TI - Improvements in semen quality, sperm fatty acids, and reproductive performance in aged Cobb 500 breeder roosters fed diets containing dried ginger rhizomes (Zingiber officinale). AB - Exposure to high levels of polyunsaturated fatty acid predisposes spermatozoa to lipid peroxidation, resulting in their decreased fertility. Ginger powder (GP), which is high in antioxidative compounds, was fed to aged breeder roosters to improve their reproductive performance. Seventy-five 52-wk-old Cobb 500 breeder roosters randomly received either 0 (GP0), 15 (GP15), or 30 (GP30) g of GP/kg of diet for 14 consecutive wk, during which time their seminal characteristics were evaluated every 2 wk. At the end of the trial, semen samples were tested for determination of sperm fatty acid (FA) concentration and seminal plasma total antioxidant capacity. Furthermore, sperm penetration was assayed, and using 225 artificially inseminated hens, fertility and hatchability rates were determined. Dietary GP improved sperm forward motility, live sperm percentage, and sperm plasma membrane integrity. These were associated with a decrease in the percentage of abnormal sperm. The seminal TBA reactive species concentration was lower in birds belonging to the GP30 treatment in comparison with those in the GP15 and GP0 treatments. The feeding of GP resulted in overall decreases and increases in sperm saturated and unsaturated FA, respectively. The n-6:n-3 FA ratio of sperm was decreased in the GP30 group in comparison with controls. The highest levels of sperm C20:4(n-6) and C22:6(n-3) FA were recorded in the GP15 and GP30 treatments, respectively. A higher percentage of sperm C22:4(n-6) FA was found in GP-fed roosters. Seminal plasma total antioxidant capacity was considerably improved by the GP15 and GP30 treatments. Further, a higher number of perivitelline membrane sperm penetration holes was recorded for the GP30 treatment in comparison with the GP15 and GP0 treatments. Interestingly, although hatchability, chick quality, and embryonic mortality were not affected by dietary treatment, fertility rate was improved by the feeding of GP. In conclusion, dietary GP improved most of the seminal characteristics evaluated in aged roosters of this study, suggesting that it has potential for use in attenuating age-related subfertility in senescent male commercial broiler breeders. PMID- 24795318 TI - The gastric isthmus from D+ and D- broiler lines divergently selected for digestion efficiency shows histological and morphological differences. AB - Previous results suggested that the gastric function plays a paramount role in digestive efficiency differences between D+ and D- broiler lines divergently selected for AMEn (more feed efficient and less feed efficient, respectively). In this paper we show an histological analysis of the gastric isthmus located between the proventriculus and the gizzard in the D+ and D- lines. Cross-sections were performed using a cryostat (Leica CM30505) and stained with a routine procedure using Mayer's Hematoxylin and Eosin Stain. The surface and shape of the constitutive gastric isthmus tissues were quantified using the image analysis software Image J. The lumen occupied 11% of the whole D- isthmus cross-sectional area against 24% for D+ (P < 0.01). The mucosa relative area (cm(2)/total cross sectional area) was higher in D- than in D+ [47% (D-) and 39% (D+), P < 0.01]. It was significantly more oval and more folded on the lumen side in D- than in D+ chickens; the muscle layer (muscularis mucosae) of the mucosa was relatively more developed in D- than in D+ (16 and 11% of the section, respectively; P < 0.01). A relationship between these observations and increased gastric motility reported in D- compared with D+ is discussed. PMID- 24795319 TI - Prevalence and characterization of Salmonella species in entire steps of a single integrated broiler supply chain in Korea. AB - The purpose of this study was to investigate the distribution of Salmonella species in an integrated broiler supply chain in Korea. A total of 1,214 samples from various steps of an integrated broiler production company including broiler breeder farms, broiler farms, broiler trucks, slaughterhouse, and retail chicken meats were collected and investigated. Salmonella was detected in 195 of the samples. The highest prevalence of Salmonella was observed in broiler transporting trucks (71.43%), followed by the slaughterhouse (63.89%) and broiler farms (16.05%). Salmonella Hadar was the most frequently isolated serotype (83.08%). All Salmonella Hadar isolates investigated in this study with pulsed field gel electrophoresis showed the same XbaI pulsed-field gel electrophoresis pulsotype. PMID- 24795320 TI - Marinade with thyme and orange oils reduces Salmonella Enteritidis and Campylobacter coli on inoculated broiler breast fillets and whole wings. AB - Essential oils have been reported to possess antimicrobial properties and therefore have potential usage as natural antimicrobials in food. In a previous study, thyme orange essential oil combination (TOC) used at the 0.5% level as a dip application on chicken cut-up parts had a significant antibacterial effect against Salmonella and Campylobacter. A study was designed to evaluate the effect of salt-phosphate marinade solution containing 0.5% TOC to 1) reduce Salmonella Enteritidis and Campylobacter coli numbers on broiler breast fillets and whole wings marinated by vacuum tumbling, and 2) reduce cross-contamination of both pathogens between inoculated and uninoculated parts during marination. A total of 52 skinless breast fillets and 52 whole wings were used for the 2 replications. For each replication, each cut-up part was randomly assigned to 1 of 5 groups: treatment 1: uninoculated parts marinated without TOC; treatment 2: inoculated parts marinated without TOC; treatment 3: uninoculated parts marinated with TOC; treatment 4: inoculated parts marinated with TOC; and control: nonmarinated inoculated parts. Samples were dipped in an inoculum containing a mixture of Salmonella Enteritidis and C. coli. The treatment samples were marinated by vacuum tumbling. All samples were immediately evaluated to determine Salmonella Enteritidis and C. coli numbers. Results indicated that TOC at the 0.5% level in the marinade solution applied by vacuum tumbling significantly reduced (P < 0.05) numbers of viable Salmonella Enteritidis by 2.6 and 2.3 log cfu/mL on broiler breast fillets and C. coli by 3.6 and 3.1 log cfu/mL on whole wings. Cross contamination was observed as the uninoculated chicken parts marinated with inoculated parts were positive. However, the number of bacterial cells recovered from the TOC treated samples were significantly lower (P < 0.05) than the numbers recovered from the untreated samples. Marination with a salt phosphate formulation containing 0.5% TOC successfully reduced Salmonella and Campylobacter numbers on poultry products. PMID- 24795321 TI - A genome-wide screen identifies Salmonella Enteritidis lipopolysaccharide biosynthesis and the HtrA heat shock protein as crucial factors involved in egg white persistence at chicken body temperature. AB - Eggs contaminated with Salmonella Enteritidis are an important source of human foodborne Salmonella infections. Salmonella Enteritidis is able to contaminate egg white during formation of the egg within the chicken oviduct, and it has developed strategies to withstand the antimicrobial properties of egg white to survive in this hostile environment. The mechanisms involved in the persistence of Salmonella Enteritidis in egg white are likely to be complex. To address this issue, a microarray-based transposon library screen was performed to identify genes necessary for survival of Salmonella Enteritidis in egg white at chicken body temperature. The majority of identified genes belonged to the lipopolysaccharide biosynthesis pathway. Additionally, we provide evidence that the serine protease/heat shock protein (HtrA) appears essential for the survival of Salmonella Enteritidis in egg white at chicken body temperature. PMID- 24795322 TI - Loads and antimicrobial resistance of Campylobacter spp. on fresh chicken meat in Nueva Ecija, Philippines. AB - This study was performed to determine the prevalence and to semiquantify Campylobacter spp. on chicken meat samples at 4 selected local wet markets in Nueva Ecija, Philippines, and to determine the antimicrobial resistance patterns of the Campylobacter isolates. Out of 120 chicken meat samples, 57 (47.5%) were Campylobacter spp. positive. The majority of isolated Campylobacter strains were identified as Campylobacter coli (54.4%) and 45.6% as Campylobacter jejuni. Most of these positive samples (52.6%) showed a very high quantitative Campylobacter contamination (most probable number > 2,400/g, lower confidence limit 580/g). For antimicrobial resistance testing, 44 C. coli/jejuni isolates were tested using the agar disk diffusion method. Out of these, 77.3% were resistant to ampicillin, followed by ciprofloxacin (70.4%), tetracycline (54.6%), erythromycin (20.2%), and gentamicin (11.4%). Of the isolates, 36.4% (n = 16) were resistant to 1 antimicrobial agent, 34.1% (n = 15) were resistance to 3 antimicrobial agents, 13.6% (n = 6) to 2 antimicrobial agents, 9.1% (n = 4) to 4 antimicrobial agents, and 6.8% (n = 3) to all 5 antimicrobial agents tested. Our data demonstrate a high contamination of fresh chicken meat with Campylobacter spp. at retail in the Philippines. The detected high Campylobacter prevalences and quantitative loads on chicken meat at retail in the Philippines highlight the need to implement efficient intervention measures along the food chain and to encourage sanitary handling of poultry meat. PMID- 24795323 TI - Effect of age at photostimulation on sexual maturation in broiler breeder pullets. AB - Genetic selection programs in broiler stocks have contributed to changes in the responsiveness of the broiler breeder female to nutritional factors. A study was conducted to investigate the effect of photostimulation (PS) age on sexual maturity traits in current broiler breeder pullets. Seven hundred twenty Ross 308 pullets with full access to feed to 1 or 3 wk of age were divided among 8 environmental rooms to 16 wk of age. At this time, 128 pullets (64 per initial feeding treatment) were randomly assigned to individual cages in 8 rooms with 16 pullets per room. Pullets were PS at 17 (PS17), 19 (PS19), 21 (PS21), or 23 (PS23) wk of age by increasing the day length from 8L:16D to 16L:8D (multiple steps). Each hen was dissected on the morning after first oviposition (sexual maturity). Data were analyzed by 2-way ANOVA with additional analysis of covariance analysis done using sexual maturity on BW as a covariate. Sexual maturation occurred later with later PS ages. Rate of sexual maturation was accelerated at later PS ages, although age at PS did not affect variation in age at sexual maturity. Despite a 42 d difference in PS age between the PS17 and PS23 groups, only a 25 d difference existed in mean age at sexual maturity among these groups. Initial egg weight, breast muscle weight, frame size, and abdominal fat pad weight at sexual maturity increased in birds with later PS ages. Covariate analysis indicated that these effects were influenced primarily by increased age and BW at sexual maturity in later PS birds. Pullets PS at 17 wk of age had 11.0 large white ovarian follicles, compared with 14.9 in PS23 birds. Comparison to previous studies demonstrates that the years of genetic selection for growth traits have not changed the interval between PS and sexual maturation. Previous research published on this theme likely had a confounding effect of mean BW on estimates of variation at various PS ages. Photostimulating later presented advantages with regard to development of the reproductive tract; these effects were BW dependent. PMID- 24795324 TI - Effect of a commercial housing system on egg quality during extended storage. AB - Egg producers in the United States are utilizing a variety of commercial egg production systems to provide consumer choice and meet legislative requirements. Consumer egg grades in the United States were developed for conventional cage production, and it is unclear what effect alternative production systems might have on egg quality during retail and consumer home storage. The current study was undertaken to determine what changes in egg quality characteristics occur during extended cold storage for commercially produced conventional cage, enriched colony cage, and cage-free aviary eggs. During 12 wk of cold storage, egg weight, albumen height, Haugh unit, static compression shell strength, vitelline membrane strength and deformation, yolk index, shell dynamic stiffness, and whole egg total solids were monitored. Overall, aviary and enriched eggs were significantly (P < 0.05) heavier than conventional cage. Albumen height and Haugh unit (P < 0.05) were significantly greater for conventional cage than enriched eggs. Static compression shell strength was greatest (P < 0.05) for enriched eggs compared with aviary. No overall housing system effects for yolk measurements, shell dynamic stiffness, or whole egg total solids were observed. Albumen height, Haugh unit, and yolk quality measurements were all greatest at 0 and lowest at 12 wk of storage (P < 0.05). The rate of quality change among the housing systems for each measured attribute at 4, 6, and 12 wk was determined. Other than differences in the change of egg weight at 4 wk, no significant differences in the rate of quality decline were found among the housing systems. The results of the current study indicate that current US egg quality standards should effectively define quality for commercially produced conventional cage, enriched colony cage, and cage-free aviary eggs. PMID- 24795325 TI - Red light is necessary to activate the reproductive axis in chickens independently of the retina of the eye. AB - Photoperiod is essential in manipulating sexual maturity and reproductive performance in avian species. Light can be perceived by photoreceptors in the retina of the eye, pineal gland, and hypothalamus. However, the relative sensitivity and specificity of each organ to wavelength, and consequently the physiological effects, may differ. The purpose of this experiment was to test the impacts of light wavelengths on reproduction, growth, and stress in laying hens maintained in cages and to determine whether the retina of the eye is necessary. Individual cages in 3 optically isolated sections of a single room were equipped with LED strips providing either pure green, pure red or white light (red, green, and blue) set to 10 lx (hens levels). The involvement of the retina on mediating the effects of light wavelength was assessed by using a naturally blind line (Smoky Joe) of chickens. Red and white lights resulted in higher estradiol concentrations after photostimulation, indicating stronger ovarian activation, which translated into a significantly lower age at first egg when compared with the green light. Similarly, hens maintained under red and white lights had a longer and higher peak production and higher cumulative egg number than hens under green light. No significant difference in BW gain was observed until sexual maturation. However, from 23 wk of age onward, birds exposed to green light showed higher body growth, which may be the result of their lower egg production. Although corticosterone levels were higher at 20 wk of age in hens under red light, concentrations were below levels that can be considered indicative of stress. Because no significant differences were observed between blind and sighted birds maintained under red and white light, the retina of the eye did not participate in the activation of reproduction. In summary, red light was required to stimulate the reproductive axis whereas green light was ineffective, and the effects of stimulatory wavelengths do not appear to require a functional retina of the eye. PMID- 24795326 TI - Editorial commentary: the Department of Defense fights the battle against antimicrobial resistance: can the United States win the war? PMID- 24795327 TI - Editorial commentary: What happens in hospitals should stay in hospitals. PMID- 24795328 TI - Drug susceptibility and resistance mutations after first-line failure in resource limited settings. AB - BACKGROUND: The development of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been associated with baseline human immunodeficiency virus (HIV)-1 RNA level (VL), CD4 cell counts (CD4), subtype, and treatment failure duration. This study describes drug resistance and levels of susceptibility after first-line virologic failure in individuals from Thailand, South Africa, India, Malawi, Tanzania. METHODS: CD4 and VL were captured at AIDs Clinical Trial Group (ACTG) A5230 study entry, a study of lopinavir/ritonavir (LPV/r) monotherapy after first-line virologic failure on an NNRTI regimen. HIV drug-resistance mutation associations with subtype, site, study entry VL, and CD4 were evaluated using Fisher exact and Kruskall-Wallis tests. RESULTS: Of the 207 individuals who were screened for A5230, sequence data were available for 148 individuals. Subtypes observed: subtype C (n = 97, 66%) AE (n = 27, 18%), A1 (n = 12, 8%), and D (n = 10, 7%). Of the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively. The number of NRTI mutations was significantly associated with a higher study screening VL and lower study screening CD4 (P < .001). Differences in drug-resistance patterns in both NRTI and NNRTI were observed by site. CONCLUSIONS: The degree of NNRTI and NRTI resistance after first-line virologic failure was associated with higher VL at study entry. Thirty two percent of individuals remained fully susceptible to etravirine and rilpivirine, protease inhibitor resistance was rare. Some level of susceptibility to NRTI remained; however, VL monitoring and earlier virologic failure detection may result in lower NRTI resistance. PMID- 24795329 TI - Wastewater treatment plants release large amounts of extended-spectrum beta lactamase-producing Escherichia coli into the environment. AB - BACKGROUND: The determinants of the spread of extended-spectrum beta-lactamase producing Escherichia coli (ESBLEC) in the community remain unclear. To evaluate its dissemination in the environment, we analyzed the ESBLEC population throughout an urban wastewater network. METHODS: Samples were collected weekly, over a 10-week period, from 11 sites throughout the wastewater network of Besancon city (France). Total E. coli and ESBLEC loads were determined for each sample. As a control, we analyzed 51 clinical ESBLEC isolates collected at our hospital. We genotyped both environmental and clinical ESBLEC by pulsed-field gel electrophoresis and multilocus sequence typing and identified their blaESBL genes by sequencing. RESULTS: The E. coli load was higher in urban wastewater than in hospital wastewater (7.5 * 10(5) vs 3.5 * 10(5) CFU/mL, respectively). ESBLEC was recovered from almost all the environmental samples and accounted for 0.3% of total E. coli in the untreated water upstream from the wastewater treatment plant (WWTP). The ESBLEC load was higher in hospital wastewater than in community wastewater (27 * 10(3) vs 0.8 * 10(3) CFU/mL, respectively). Treatment by the WWTP eliminated 98% and 94% of total E. coli and ESBLEC, respectively. The genotyping revealed considerable diversity within both environmental and clinical ESBLEC and the overrepresentation of some clonal complexes. Most of the sequence types displayed by the clinical isolates were also found in the environment. CTX M enzymes were the most common enzymes whatever the origin of the isolates. CONCLUSIONS: The treatment at the WWTP led to the relative enrichment of ESBLEC. We estimated that >600 billion of ESBLEC are released into the river Doubs daily and the sludge produced by the WWTP, used as fertilizer, contains 2.6 * 10(5) ESBLEC per gram. PMID- 24795330 TI - High percentage of false-positive results for influenza B obtained with a rapid influenza point-of-care test. PMID- 24795331 TI - The antimicrobial resistance monitoring and research (ARMoR) program: the US Department of Defense response to escalating antimicrobial resistance. AB - Responding to escalating antimicrobial resistance (AMR), the US Department of Defense implemented an enterprise-wide collaboration, the Antimicrobial Resistance Monitoring and Research Program, to aid in infection prevention and control. It consists of a network of epidemiologists, bioinformaticists, microbiology researchers, policy makers, hospital-based infection preventionists, and healthcare providers who collaborate to collect relevant AMR data, conduct centralized molecular characterization, and use AMR characterization feedback to implement appropriate infection prevention and control measures and influence policy. A particularly concerning type of AMR, carbapenem-resistant Enterobacteriaceae, significantly declined after the program was launched. Similarly, there have been no further reports or outbreaks of another concerning type of AMR, colistin resistance in Acinetobacter, in the Department of Defense since the program was initiated. However, bacteria containing AMR-encoding genes are increasing. To update program stakeholders and other healthcare systems facing such challenges, we describe the processes and impact of the program. PMID- 24795332 TI - Spectroscopic measurements in scleritis: bluish-red or deep red? AB - PURPOSE: To design a slit-lamp mountable spectrometer for the assessment of ophthalmic patients and to illustrate a potential clinical application by measuring the spectral characteristics of inflamed eyes of differing aetiologies. METHODS: A slit lamp mountable instrument was designed and built, and methods for data analysis developed. Reflectance spectra were recorded from two patients with scleritis, three with non-scleritic red eyes and from two controls with non inflamed eyes. RESULTS: Measurements were reproducible and demonstrated statistically significant differences in the spectral characteristics between the three groups. Spectra from scleritic eyes revealed a relative increase in intensity of long wavelength red light, 650-740 nm, compared with non-scleritic red eyes. These longer wavelengths will be appreciated as dark red. There was no increase in relative intensity in the blue part of the spectrum in scleritic eyes. CONCLUSIONS: Reproducible measurements of the eye were made using an innovative, slit-lamp mountable spectrometer and its functionality demonstrated by differentiating the spectra from eyes with differing pathologies. While intending only to illustrate one potential application; for the cases examined, our results indicate that inflamed scleritic eyes exhibit a longer wavelength red light with no increase in shorter wavelength blue light. Thus our measurements would seem to confirm that the perceived redness of scleritis differs from other red eyes. However, it is a deeper darker red and not a bluish one as traditionally described. PMID- 24795333 TI - Evaluation of various machine learning methods to predict vision-related quality of life from visual field data and visual acuity in patients with glaucoma. AB - BACKGROUND/AIMS: We investigated whether it was useful to use machine learning algorithms to predict patients' vision related quality of life (VRQoL) from visual field (VF) and visual acuity (VA). METHODS: VRQoL was surveyed in 164 glaucomatous patients using the Sumi questionnaire. Their VRQoL score was predicted using machine learning algorithms (Random Forest, gradient boosting, support vector machine) based on total deviation (TD) values from integrated VF (IVF), VA, age and gender. For comparison, VRQoL score was predicted using standard linear regression with mean of IVF, TD values, and VA, and also the stepwise model selection by Akaike Information Criterion. Prediction error was calculated as root mean of the squared prediction error (RMSE) associated with the leave one out cross validation. RESULTS: RMSEs associated with general VRQoL score were smaller for the machine learning algorithms (1.99 to 2.21) compared with the standard linear model and the stepwise model selection (2.35 to 3.20). A similar tendency was found in each individual VRQoL task score. CONCLUSIONS: We found that it was advantageous to use machine learning methods to predict VRQoL accurately. These statistical methods could be used to help clinicians better understand patients' VRQoL without the need for extra tests other than standard VA and VF. PMID- 24795334 TI - Injection frequency and anatomic outcomes 1 year following conversion to aflibercept in patients with neovascular age-related macular degeneration. AB - BACKGROUND/AIM: To evaluate the clinical, anatomic and functional effects of conversion to aflibercept following ranibizumab and/or bevacizumab in patients with neovascular age-related macular degeneration (AMD). METHODS: A retrospective review of patients with neovascular AMD treated with intravitreal ranibizumab and/or bevacizumab who were switched to aflibercept was performed. The primary outcome was change in injection frequency in the year following the change. Secondary outcomes included change in central macular thickness (CMT) at 6 months and 1 year, presence of intraretinal and subretinal fluid at 6 months and visual acuity at 1 year. RESULTS: A total of 109 eyes with neovascular AMD were switched to aflibercept and met inclusion criteria. Overall, aflibercept injection frequency was unchanged with patients receiving 7.4 antivascular endothelial growth factor (VEGF) injections the year prior to conversion compared with 7.2 aflibercept injections in the year following (p=0.47). However, the change to aflibercept was associated with improvement in CMT from 324 to 295 MUm (p=0.0001) at 6 months and 299 MUm (p=0.0047) at 1 year. There was no effect on visual acuity at 1 year. In a subgroup analysis, patients who had received >=10 anti VEGF injections in the year prior had fewer injections (11.1 to 8.4, p<0.0001) and clinic visits (13.9 to 9.6, p<0.0001) as well as a significant decrease in CMT (-35 MUm, p=0.02). CONCLUSIONS: In our population, switching to aflibercept therapy was not associated with a change in injection frequency nor improved visual acuity, but was associated with improved CMT at 6 months and 1 year. In patients who received at least 10 anti-VEGF injections in the year prior, transitioning to aflibercept was associated with a reduced injection frequency and CMT, suggesting potential cost savings in this population. PMID- 24795335 TI - Early initial clinical experience with intravitreal aflibercept for wet age related macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is a degenerative process that leads to severe vision loss. Wet AMD is defined by choroidal neovascularisation, leading to the accumulation of subretinal fluid (SRF), macular oedema (ME), and pigment epithelium detachments (PED). Purpose To evaluate the initial clinical experience of conversion from bevacizumab or ranibizumab to aflibercept in wet AMD patients. METHODS: Records of 250 consecutive wet AMD patients were retrospectively reviewed. Of 250 patients, 29 were naive (with no previous treatment), and 221 were previously treated with bevacizumab (1/3) or ranibizumab (2/3). On average, converted patients received 14 injections every 6 weeks on a treat-and-extend regimen with Avastin or Lucentis before being converted to aflibercept every 7 weeks on average (no loading dose) for three doses. For the purposes of this study, we concentrated on the patients converted to aflibercept since the number of naive patients was too small to draw any conclusion from. Snellen (as logMar) visual acuities, and optical coherence tomography (OCT) were compared predrug and postdrug conversion. RESULTS: Converted patients did not show a significant difference in visual acuity or average OCT thickness from preconversion values; however, small improvements in ME (p=0.0001), SRF (p=0.0001), and PED (p=0.008) grading were noted on average after conversion to aflibercept. CONCLUSIONS: No significant difference in visual outcome or average OCT thickness was observed when switched from bevacizumab or ranibizumab q6 week to aflibercept 7-week dosing, on average. Mild anatomic improvements did occur in converted patients with regard to ME, SRF and PED improvement, on average, after conversion to aflibercept, and aflibercept was injected less frequently. No serious adverse reactions, including ocular infections or inflammation, as well as ocular and systemic effects were noted. PMID- 24795336 TI - Evaluation of a new optical biometry device for measurements of ocular components and its comparison with IOLMaster. AB - OBJECTIVE: To assess the reliability of ocular component measurements with a new optical biometry device (AL-Scan; Nidek) and compare these measurements with those of the IOLMaster (Carl Zeiss Meditec) in patients with cataract. METHODS: Sixty-eight cataractous eyes of 68 patients were included in the prospective study. To assess AL-Scan repeatability and reproducibility, central corneal thickness, anterior chamber depth (ACD), keratometry (K) over 2.4 mm and 3.3 mm diameter, axial length (AL), white to white (WTW), and pupil distance (PD) values were measured by two operators. ACD, K, AL and WTW were also measured with the IOLMaster to investigate the level of agreement. Calculations of intraocular lens (IOL) power were compared between the two devices. RESULTS: AL-Scan measurements were highly repeatable and reproducible, except for WTW and PD. Bland-Altman analysis showed good agreement between devices for AL, ACD and most K values. Compared with the IOLMaster, AL-Scan-derived K values using a diameter of 2.4 mm showed a narrower 95% limit of agreement (LoA) than those obtained with a diameter of 3.3 mm. However, poor agreement of WTW measurements was found. The 95% LoAs between devices for IOL calculations were smaller when based on AL-Scan K measurements using a diameter of 2.4 mm rather than 3.3 mm. CONCLUSIONS: The repeatability and reproducibility of AL-Scan was excellent for all parameters, except WTW and PD. Excluding WTW, good agreement was found between the AL-Scan and IOLMaster. The 2.4-mm diameter K value may be the most reliable choice for calculation of IOL power with the AL-Scan. PMID- 24795337 TI - Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases. AB - AIMS: To analyse clinical characteristics and treatment outcomes of osteosarcoma that developed in survivors of bilateral retinoblastoma. METHODS: Three institutions participated in this retrospective study. Among survivors of bilateral retinoblastoma who were diagnosed and treated between 1995 and 2012, 8 cases (4 male, 4 female) of osteosarcoma were identified. Medical records were thoroughly reviewed. RESULTS: Median age at diagnosis of bilateral retinoblastoma was 8.5 months (range 1.4-18.4 months). Treatment modalities for retinoblastoma were: enucleation+chemotherapy+radiotherapy (n=6); chemotherapy combined with focal therapy (n=1); and chemotherapy+radiotherapy (n=1). Median radiotherapy dose was 46.5 Gy (range 45-54 Gy). Median age at diagnosis of osteosarcoma was 8.9 years (range 5.4-20.3 years). Median interval between retinoblastoma and osteosarcoma was 8.2 years (range 5.0-20.0 years). Tumour locations were femur (n=5), tibia (n=1), mandible (n=1), and nasal cavity (n=1). Two patients presented with lung metastasis. Seven patients received multimodal treatment, and treatment was refused in 1 patient. After diagnosis of osteosarcoma, the patients were followed for a median of 17.3 months (range 4.4-56.4 months). The 2-year overall survival and event-free survival rates were 56.3 +/- 19.9% and 33.3 +/- 18.0%, respectively. At the time of analysis, 5 patients remained alive, and 2 of them were on therapy. Of the 3 surviving patients without evidence of disease, 2 received high dose chemotherapy with autologous peripheral blood stem cell support. CONCLUSIONS: Our data could be used as a basis for future studies aimed at reaching consensus about long term follow-up and treatment guidelines for this genetically susceptible group of patients. PMID- 24795338 TI - Cataract surgery outcomes in adult patients with Down's syndrome. AB - PURPOSE: To describe the outcomes of cataract surgery in adult patients with Down's syndrome at a tertiary eye hospital in Hong Kong. METHODS: Retrospective case-file analysis was performed to identify patients with Downs's syndrome who underwent cataract surgery between January 2002 and December 2012. Morphology of cataract, associated ocular features and surgical and visual outcomes were analysed. RESULTS: Cataract surgery was performed in 33 eyes of 20 patients (12 males, 8 females, mean age 42.9+/-10.6 years) over a 10-year period. Nine patients (9/20, 45.0%) had bilateral cataracts at the time of diagnosis. White cataracts were noted in 12 eyes of 10 patients (12/33, 36.3%) at the time of presentation. Associated ocular problems included myopic maculopathy (18 eyes, 54.5%), keratoconus (12 eyes, 36.3%), nystagmus (2 eyes, 6.0%), corneal scar (2 eyes, 6.0%) and glaucoma (2 eyes, 6.0%). Five eyes (15.1%) underwent extracapsular cataract extraction whereas a phacoemulsification was performed in 28 (84.9%) eyes. Intraocular lens implantation was performed in 32/33 eyes. The most common postoperative complication was posterior capsular opacification (8 eyes, 24.2%). The mean best-corrected visual acuity improved from 0.07+/-0.11 preoperatively to 0.17+/-0.19 at 3 months postoperatively (p=0.000). CONCLUSIONS: A high incidence of bilateral cataracts as well as white cataracts was observed in patients with Down's syndrome in our study. Although the surgical outcomes of cataract surgery were good, the visual outcomes were suboptimal in our cases due to associated ocular comorbidities. PMID- 24795339 TI - LSCHL4 from Japonica Cultivar, which is allelic to NAL1, increases yield of indica super rice 93-11. AB - The basic premise of high yield in rice is to improve leaf photosynthetic efficiency and coordinate the source-sink relationship in rice plants. Quantitative trait loci (QTLs) related to morphological traits and chlorophyll content of rice leaves were detected at the stages of heading to maturity, and a major QTL (qLSCHL4) related to flag leaf shape and chlorophyll content was detected at both stages in recombinant inbred lines constructed using the indica rice cultivar 93-11 and the japonica rice cultivar Nipponbare. Map-based cloning and expression analysis showed that LSCHL4 is allelic to NAL1, a gene previously reported in narrow leaf mutant of rice. Overexpression lines transformed with vector carrying LSCHL4 from Nipponbare and a near-isogenic line of 93-11 (NIL 9311) had significantly increased leaf chlorophyll content, enlarged flag leaf size, and improved panicle type. The average yield of NIL-9311 was 18.70% higher than that of 93-11. These results indicate that LSCHL4 had a pleiotropic function. Exploring and pyramiding more high-yield alleles resembling LSCHL4 for super rice breeding provides an effective way to achieve new breakthroughs in raising rice yield and generate new ideas for solving the problem of global food safety. PMID- 24795340 TI - Ventricular arrhythmias arising from the left ventricular outflow tract below the aortic sinus cusps: mapping and catheter ablation via transseptal approach and electrocardiographic characteristics. AB - BACKGROUND: Ventricular arrhythmias (VAs) originating from the anterosuperior left ventricular outflow tract (LVOT) represent a challenging location for catheter ablation. This study investigates mapping and ablation of VA from anterosuperior LVOT via a transseptal approach. METHODS AND RESULTS: This study included 27 patients with symptomatic VA, of which 13 patients had previous failed ablations. LVOT endocardial 3-dimensional mapping via retrograde transaortic and antegrade transseptal approaches was performed. Previous ECG markers for procedure failure were analyzed. In all patients, earliest activation with low-amplitude potentials was identified at the anterosuperior LVOT 5.1+/-2.8 mm below the aortic cusp and preceded the QRS onset by 39.5+/-7.7 ms only via an antegrade transseptal approach using a reversed S curve. In all patients, pace mapping failed to demonstrate perfect QRS morphology match. The anatomic location was below the left coronary cusp in 16, below the left coronary cusp/right coronary cusp junction in 8, and below the right coronary cusp in 3 patients. Radiofrequency energy resulted in rapid disappearance of VAs in all patients. ECG analysis showed aVL/aVR Q-wave amplitude ratio >1.4 in 7, lead III/II R-wave amplitude ratio >1.1 in 10, and peak deflection index >0.6 in 11 patients. There were no complications or clinical VA recurrence during a mean follow-up of 8.4+/ 2.5 months. CONCLUSIONS: The anterosuperior LVOT can be reached via a transseptal approach with a reversed S curve of the ablation catheter. The rapid effect from radiofrequency energy indicates that the VA is most likely located under the endocardium. Also, previous ECG markers for procedure failure need further investigation. PMID- 24795341 TI - Risk factors for groin/hip injuries in field-based sports: a systematic review. AB - BACKGROUND: Groin/hip injuries are common in the athletic population, particularly in sports requiring kicking, twisting, turning and rapid acceleration and deceleration. Chronic hip, buttock and groin pain account for 10% of all attendances to sports medicine centres. Understanding risk factors for field-based sports (FBS) players is important in developing preventive measures for injury. OBJECTIVE: This systematic review aims to identify and examine the evidence for groin/hip injury risk factors in FBS. METHODS: 14 electronic databases were searched using keywords. Studies were included if they met the inclusion criteria and investigated one or more risk factors with relation to the incidence of groin/hip injuries in FBS. Studies were accumulated and independently analysed by two reviewers under a 12-point quality assessment scale (modified CASP (for cohort study design) assessment scale). Owing to the heterogeneity of studies and measures used, a meta-analysis could not be conducted. As a result risk factors were pooled for analysis and discussion. RESULTS: Of the 5842 potentially relevant studies, 7 high-quality studies were included in this review. Results demonstrated that previous groin/hip injury was the most prominent risk factor, identified across four studies (OR range from 2.6 (95% CI 1.1 to 6.11) to 7.3, (p=0.001)), followed by older age (OR 0.9, p=0.05) and weak adductor muscles (OR 4.28, 95% CI 1.31 to 14.0, p=0.02) each identified in two studies. Eight other significant risk factors were identified once across the included studies. CONCLUSIONS: 11 significant risk factors for groin/hip injury for FBS players were identified. The most prominent risk factor identified was previous groin/hip injury. Future research should include a prospective study of a group of FBS players to confirm a relationship between the risk factors identified and development of groin/hip injuries. PMID- 24795342 TI - Autolytic degradation of ocriplasmin: a complex mechanism unraveled by mutational analysis. AB - Ocriplasmin, a truncated form of plasmin, is commercialized in the USA and in Europe under the trade name Jetrea((r)), and indicated for the treatment of symptomatic vitreomacular adhesion and vitreomacular traction including when associated with macular hole <=400 um, respectively. We have shown in a previous study that ocriplasmin undergoes autolytic degradation when injected in eye vitreous, which leads to its rapid inactivation. In order to investigate this process further, we have introduced in ocriplasmin a variety of amino acid substitutions within or in the immediate vicinity of the three major autolytic cleavage sites. We demonstrate here that autolytic inactivation of ocriplasmin is a sequential process where initial cleavage occurs primarily between residues 156 and 157. Reduction or even blocking of autolysis can be achieved by mutating a limited number of key residues. In this study, we also report the identification of a series of ocriplasmin variants with improved resistance to autolysis and unimpaired catalytic activity. Such variants represent useful tools for the exploration of therapeutic approaches aiming at non-surgical resolution of vitreomacular adhesion. PMID- 24795343 TI - Tumor-targeting properties of novel immunocytokines based on murine IL1beta and IL6. AB - There is an increasing biotechnological interest in 'arming' therapeutic antibodies with bioactive payloads. Many antibody-cytokine fusion proteins (immunocytokines) have been described and some of these biopharmaceuticals have progressed to clinical studies. Here, we describe for the first time the expression and in vivo characterization of immunocytokines based on murine IL1beta and IL6. These potent pro-inflammatory cytokines were fused at the N terminus or at the C-terminus of the monoclonal antibodies F8 (specific to the alternatively-spliced extra-domain A domain of fibronectin, a marker of tumor angiogenesis). All immunocytokines retained the binding properties of the parental antibody and were homogenous, when analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and size-exclusion chromatography, except for the N-terminal fusion of IL1beta which revealed the presence of glycosylated species. When analyzed by quantitative biodistribution analysis using radioiodinated protein preparations, F8 fusions with IL6 revealed a preferential accumulation at the tumor site for both cytokine orientations, whereas IL1beta fusions exhibited lower tumor to organ ratios and a slower blood clearance profile. The fusion proteins with the cytokine payload at the C-terminus were studied in therapy experiments in immunocompetent mice bearing F9 tumors. Immunocytokines based on IL1beta resulted in 10% body weight loss at a 5-ug dose, whereas IL6-based products caused a 5% body weight loss at a 225-ug dose. Both F8 IL1beta and F8-IL6 exhibited a <50% inhibition of tumor growth rate, which was substantially lower than the one previously reported for F8-TNF, a closely related pro-inflammatory immunocytokine. This study indicates that IL6 can be efficiently delivered to the tumor neo-vasculature by fusion with the F8 antibody. While F8-IL6 was not as potent as other F8-based immunocytokines that exhibit similar biodistribution profiles, the fusion protein sheds light on the different roles of pro-inflammatory cytokines in boosting immunity against the tumor. PMID- 24795344 TI - A mutation causing Brugada syndrome identifies a mechanism for altered autonomic and oxidant regulation of cardiac sodium currents. AB - BACKGROUND: The mechanisms of the electrocardiographic changes and arrhythmias in Brugada syndrome (BrS) remain controversial. Mutations in the sodium channel gene, SCN5A, and regulatory proteins that reduce or eliminate sodium current (INa) have been linked to BrS. We studied the properties of a BrS-associated SCN5A mutation in a protein kinase A (PKA) consensus phosphorylation site, R526H. METHODS AND RESULTS: In vitro PKA phosphorylation was detected in the I-II linker peptide of wild-type (WT) channels but not R526H or S528A (phosphorylation site) mutants. Cell surface expression of R526H and S528A channels was reduced compared with WT. Whole-cell INa through all channel variants revealed no significant differences in the steady-state activation, inactivation, and recovery from inactivation. Peak current densities of the mutants were significantly reduced compared with WT. Infection of 2D cultures of neonatal rat ventricular myocytes with WT and mutant channels increased conduction velocity compared with noninfected cells. PKA stimulation significantly increased peak INa and conduction velocity of WT but not mutant channels. Oxidant stress inhibits cardiac INa; WT and mutant INa decreases with the intracellular application of reduced nicotinamide adenine dinucleotide (NADH), an effect that is reversed by PKA stimulation in WT but not in R526H or S528A channels. CONCLUSIONS: We identified a family with BrS and an SCN5A mutation in a PKA consensus phosphorylation site. The BrS mutation R526H is associated with a reduction in the basal level of INa and a failure of PKA stimulation to augment the current that may contribute to the predisposition to arrhythmias in patients with BrS, independent of the precipitants. PMID- 24795346 TI - Posttranscriptional regulation of c-Myc expression in adult murine HSCs during homeostasis and interferon-alpha-induced stress response. AB - Previous studies have established pivotal roles for c-Myc and its homolog N-Myc in hematopoietic stem cell (HSC) maintenance and niche-dependent differentiation. However, it remains largely unclear how c-Myc expression is regulated in this context. Here, we show that HSCs and more committed progenitors express similar levels of c-myc transcripts. Using knock-in mice expressing a functional enhanced green fluorescent protein-c-Myc fusion protein under control of the endogenous c myc locus, c-Myc protein levels were assessed. Although HSCs express low levels of c-Myc protein, its expression increases steadily during progenitor differentiation. Thus, mRNA and protein expression patterns differ significantly in stem/progenitor cells, suggesting that c-Myc expression is largely controlled posttranscriptionally. Moreover, interferon-alpha exposure, which activates dormant HSCs, strongly induces c-Myc expression at the protein level but not at the transcript level. This posttranscriptional mechanism of c-Myc regulation provides the blood system with a rapid way to adjust c-Myc expression according to demand during hematopoietic stress. PMID- 24795347 TI - Blood culture for suspected disseminated tuberculosis. PMID- 24795345 TI - Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine beta-thalassemia. AB - In beta-thalassemia, unequal production of alpha- and beta-globin chains in erythroid precursors causes apoptosis and inhibition of late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Here we used a murine model of beta-thalassemia intermedia (Hbb(th1/th1) mice) to investigate effects of a modified activin receptor type IIB (ActRIIB) ligand trap (RAP-536) that inhibits Smad2/3 signaling. In Hbb(th1/th1) mice, treatment with RAP-536 reduced overactivation of Smad2/3 in splenic erythroid precursors. In addition, treatment of Hbb(th1/th1) mice with RAP-536 reduced alpha-globin aggregates in peripheral red cells, decreased the elevated reactive oxygen species present in erythroid precursors and peripheral red cells, and alleviated anemia by promoting differentiation of late-stage erythroid precursors and reducing hemolysis. Notably, RAP-536 treatment mitigated disease complications of IE, including iron overload, splenomegaly, and bone pathology, while reducing erythropoietin levels, improving erythrocyte morphology, and extending erythrocyte life span. These results implicate signaling by the transforming growth factor-beta superfamily in late stage erythropoiesis and reveal potential of a modified ActRIIB ligand trap as a novel therapeutic agent for thalassemia syndrome and other red cell disorders characterized by IE. PMID- 24795348 TI - Familial transmission of venous thromboembolism: a cohort study of 80 214 Swedish adoptees linked to their biological and adoptive parents. AB - BACKGROUND: Venous thromboembolism (VTE) clusters in families, but the familial risk of VTE has not been determined among adoptees. The aim was to disentangle the contributions of genetic and environmental factors to the familial transmission of VTE. METHODS AND RESULTS: The Swedish Multi-Generation Register was used to follow all Swedish-born adoptees born from 1932 to 2004 (n=80,214) between January 1, 1964, and December 31, 2010, for VTE. The risk of VTE was estimated in adoptees with >=1 biological parent with VTE compared with adoptees without a biological parent with VTE. The risk of VTE was also estimated in adoptees with >=1 adoptive parent with VTE compared with adoptees without an adoptive parent with VTE. Adoptees with >=1 biological parent with VTE (n=137) were more likely to have VTE than adoptees without a biological parent with VTE (standardized incidence ratio) 1.51 (95% confidence interval, 1.27-1.79). The standardized incidence ratio for VTE was highest for adoptees with a biological parent diagnosed with VTE before the age of 50 years (standardized incidence ratio=2.03, 1.24-3.14). In contrast, adoptees with >=1 adoptive parent with VTE (n=156) were not at increased risk of VTE (standardized incidence ratio=1.07, 0.91-1.25). CONCLUSIONS: These novel findings suggest that genetic factors make a stronger contribution to the familial transmission of VTE from parents to offspring than family environmental factors. PMID- 24795350 TI - Affinity enhancement of antibodies: how low-affinity antibodies produced early in immune responses are followed by high-affinity antibodies later and in memory B cell responses. AB - The antibodies produced initially in response to most antigens are high molecular weight (MW) immunoglobulins (IgM) with low affinity for the antigen, while the antibodies produced later are lower MW classes (e.g., IgG and IgA) with, on average, orders of magnitude higher affinity for that antigen. These changes, often termed affinity maturation, take place largely in small B-cell clusters (germinal center; GC) in lymphoid tissues in which proliferating antigen stimulated B cells express the highly mutagenic cytidine deaminase that mediates immunoglobulin class-switching and sequence diversification of the immunoglobulin variable domains of antigen-binding receptors on B cells (BCR). Of the large library of BCR-mutated B cells thus rapidly generated, a small minority with affinity-enhancing mutations are selected to survive and differentiate into long lived antibody-secreting plasma cells and memory B cells. BCRs are also endocytic receptors; they internalize and cleave BCR-bound antigen, yielding peptide-MHC complexes that are recognized by follicular helper T cells. Imperfect correlation between BCR affinity for antigen and cognate T-cell engagement may account for the increasing affinity heterogeneity that accompanies the increasing average affinity of antibodies. Conservation of mechanisms underlying mutation and selection of high-affinity antibodies over the ~200 million years of evolution separating bird and mammal lineages points to the crucial role of antibody affinity enhancement in adaptive immunity. PMID- 24795349 TI - Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort. AB - BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (beta=-0.38; P=4.5*10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis. CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology. PMID- 24795351 TI - Tim-3: an emerging target in the cancer immunotherapy landscape. AB - The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer. PMID- 24795352 TI - Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer. AB - We present the case of a man with metastatic, castration-resistant prostate cancer, who had a complete prostate-specific antigen (PSA) response after 21/2 doses of ipilimumab. His treatment course was complicated by diarrhea and autoimmune hepatitis, both of which resolved within 4 months. Sera and biopsy specimens were accessed, and sera from pretreatment and day 113 were analyzed. Augmented antibody responses were detected against 11 potential tumor antigens, with responses ranging from 5- to 20-fold in day 113 sera compared with baseline. Genes that were targets of a strong antibody response (arbitrarily set at 10-fold or greater increase) were analyzed by real-time PCR for expression in the tumor biopsy cDNA. Of the top 5 genes, only 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) could be identified in the amplified tumor biopsy cDNA. Using an antibody to HIBCH, immunohistochemical analysis documented strong expression of the protein. Together, these data suggest that an augmented antibody response to HIBCH, an antigen that was expressed by the patient's prostate cancer, could have contributed to the clinical response. After 16 months of PSA stability, he discontinued his androgen-suppression therapy. With the return of his testosterone, his PSA increased slightly, likely originating from his intact prostate. He has been disease free for the past 6 years without any additional therapy. PMID- 24795353 TI - Long-term complete remission following radiosurgery and immunotherapy in a melanoma patient with brain metastasis: immunologic correlates. AB - A melanoma patient with brain metastases was treated by gamma-knife radiosurgery and immunotherapy with autologous tumor-lysate-loaded dendritic cells (DC). Ten years after the combined treatment, the patient remains in complete remission. Remarkable immunologic correlates to the clinical development were the transient induction of NY-ESO-1 antibody and the durable expansion of MAGE-A1p161-169 EADPTGHSY-specific CD8+ T cells. Although the induction of NY-ESO-1 antibody most likely resulted from gamma-knife-mediated "auto-vaccination," the persistence of circulating MAGE-A1-specific T cells, which are still detectable ex vivo in the absence of any tumor manifestation, coincides with DC-based vaccination administered monthly until today. PMID- 24795354 TI - Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. AB - The immunoregulatory protein T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates T-cell exhaustion and contributes to the suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases, including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3; however, the role of Tim-3 in modulating the function of these innate effector cells remains unclear, particularly in human diseases. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted, and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels were correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK cell exhaustion marker in advanced melanoma and support the development of Tim-3 targeted therapies to restore antitumor immunity. PMID- 24795355 TI - CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. AB - Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer. PMID- 24795356 TI - Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. AB - The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in non tumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP) conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8+ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. PMID- 24795357 TI - Combination of alphavirus replicon particle-based vaccination with immunomodulatory antibodies: therapeutic activity in the B16 melanoma mouse model and immune correlates. AB - Induction of potent immune responses to self-antigens remains a major challenge in tumor immunology. We have shown that a vaccine based on alphavirus replicon particles (VRP) activates strong cellular and humoral immunity to tyrosinase related protein-2 (TRP2) melanoma antigen, providing prophylactic and therapeutic effects in stringent mouse models. Here, we report that the immunogenicity and efficacy of this vaccine is increased in combination with either antagonist anti CTL antigen-4 (CTLA-4) or agonist anti-glucocorticoid-induced TNF family-related gene (GITR) immunomodulatory monoclonal antibodies (mAb). In the challenging therapeutic setting, VRP-TRP2 plus anti-GITR or anti-CTLA-4 mAb induced complete tumor regression in 90% and 50% of mice, respectively. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine encoded antigen, augmenting, respectively, approximately 4- and 2-fold the TRP2 specific CD8(+) T-cell response and circulating Abs, compared with the vaccine alone. Furthermore, while both mAbs increased the frequency of tumor-infiltrating CD8(+) T cells, anti-CTLA-4 mAb also increased the quantity of intratumor CD4(+)Foxp3(-) T cells expressing the negative costimulatory molecule programmed death-1 (PD-1). Concurrent GITR expression on these cells suggests that they might be controlled by anti-GITR mAbs, thus potentially explaining their differential accumulation under the two treatment conditions. These findings indicate that combining immunomodulatory mAbs with alphavirus-based anticancer vaccines can provide therapeutic antitumor immune responses in a stringent mouse model, suggesting potential utility in clinical trials. They also indicate that tumor-infiltrating CD4(+)Foxp3(-)PD-1(+) T cells may affect the outcome of immunomodulatory treatments. PMID- 24795358 TI - Exposure to a histone deacetylase inhibitor has detrimental effects on human lymphocyte viability and function. AB - Histone deacetylase inhibitors (HDACi) have been reported to increase tumor antigen expression, and have been successfully tested as adjuvants for melanoma immunotherapy in mouse models. In this work, we tested the effects of a pan-HDACi on human lymphocytes and melanoma cell lines. Effects of the pan-HDACi panobinostat (LBH589) on cell viability, cell cycle, apoptosis, and DNA damage were determined in peripheral blood mononuclear cells (PBMC) from 2 healthy donors, 13 patients with metastatic melanoma, 2 bone marrow samples from patients with different malignances, and 12 human melanoma cell lines. Intracellular signaling in lymphocytes, with or without cytokine stimulation, was analyzed by phospho-flow cytometry in one of each type. The IC50 in PBMCs was <20 nmol/L compared with >600 nmol/L in melanoma cell lines; >40% apoptotic cell death in PBMCs versus <10% in melanoma cell lines was seen at the same concentration. Phospho-histone variant H2A.X (pH2A.X) increased 2-fold in healthy donor PBMCs at 1 nmol/L, whereas the same effect in the melanoma cell line M229 required 10 nmol/L. pH2A.X was inhibited slightly in the PBMCs of 3 patients with metastatic melanoma at 1 nmol/L and in the melanoma cell line M370 at 10 nmol/L. Panobinostat inhibited phospho-STAT1/3/5/6, -p38, -ERK, -p53, -cyclin D3, and histone H3 in flow cytometry-gated healthy donor B and T cells, whereas it induced up to 6-fold activation in patients with metastatic melanoma and bone marrow samples. In human lymphocytes, panobinostat alters key lymphocyte activation signaling pathways and is cytotoxic at concentrations much lower than those required for melanoma antitumor activity, resulting in an adverse therapeutic window. PMID- 24795359 TI - Streptavidin: a novel immunostimulant for the selection and delivery of autologous and syngeneic tumor vaccines. AB - Induction of antitumor immunity using autologous tumor proteins is an attractive approach to cancer therapy. However, better methods and stimulants to present these autologous proteins back to the immune system are needed. Here, we identify streptavidin as a novel carrier protein and stimulant, and test the efficacy of both syngeneic (rat) and autologous vaccines (dogs) using streptavidin in combination with reduced soluble tumor proteins. Initial syngeneic vaccine studies in the 9L rat glioma model were used to optimize vaccine dose and selectivity. Cytokine and blood analysis was used to monitor the response. Rats receiving two vaccinations of syngeneic tumor vaccine demonstrated a statistically significant (P < 0.05) survival advantage compared with controls (adjuvant only). Notably, vaccination also led to remission rates of between 30% and 60% in the aggressive 9L glioma model. Antibodies to streptavidin were detected in the serum of vaccinated rats; however, antibody levels did not correlate with the response. The cytokine TNF-alpha was upregulated in vaccine treated rats, whereas ICAM1 was downregulated. After engraftment, vaccinated rats maintained CD4(+), CD8(+) T cells, and total lymphocyte levels closer to normal baseline than those in the controls. Twenty-five dogs treated with autologous vaccine preparations using streptavidin as a stimulant showed no adverse reactions, irrespective of additional chemotherapy and other medications. In this study, we developed a novel method for producing syngeneic and autologous vaccines using streptavidin selectivity and immunogenicity. These vaccines show efficacy in the 9L glioma rat model. Safety was also demonstrated in canine patients presenting with cancer treated with autologous vaccine. PMID- 24795360 TI - Cancer-testis antigen expression in digestive tract carcinomas: frequent expression in esophageal squamous cell carcinoma and its precursor lesions. AB - Cancer-testis (CT) antigens are attractive tumor antigens for cancer immunotherapy. They comprise a group of proteins normally expressed in germ cells and aberrantly activated in a variety of human cancers. The protein expression of eight cancer-testis antigens [MAGEA, NY-ESO-1, GAGE, MAGEC1 (CT7), MAGEC2 (CT10), CT45, SAGE1, and NXF2] was evaluated by immunohistochemistry in 61 esophageal carcinomas (40 adenocarcinoma and 21 squamous cell carcinoma), 50 gastric carcinomas (34 diffuse and 16 intestinal type), and 141 colorectal carcinomas. The highest frequency of expression was found in esophageal squamous cell carcinomas: Positive staining for MAGEA, CT45, CT7, SAGE1, GAGE, NXF2, NY-ESO-1, and CT10 was observed in 57%, 38%, 33%, 33%, 29%, 29%, 19%, and 14% of squamous cell carcinomas, respectively. Similar staining patterns were observed in squamous dysplasias. Expression frequencies of cancer-testis antigens were seen in 2% to 24% of gastroesophageal adenocarcinomas and were not significantly different between adenocarcinomas of the stomach versus the esophagus, or between diffuse and intestinal types of gastric adenocarcinomas. Colorectal cancers did not express NY-ESO-1, CT7, CT10, or GAGE, and only infrequently expressed SAGE1 (0.7%) MAGEA (1.4%), CT45 (3.5%), and NXF2 (8.5%). We conclude that cancer-testis antigens are frequently expressed in esophageal squamous neoplasms. Although cancer-testis antigens are generally considered to be expressed later in tumor progression, they are found in squamous dysplasias, suggesting a potential diagnostic role for cancer-testis antigens in the evaluation of premalignant squamous lesions. PMID- 24795363 TI - Advances and controversies in the pathogenesis and management of primary sclerosing cholangitis. AB - INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic immune-mediated liver disease that results in end-stage liver disease requiring liver transplantation. PSC is closely associated with inflammatory bowel disease (IBD) with 70% of patients with PSC also suffering from IBD. SOURCES OF DATA: Data for this review were obtained from PubMed. AREAS OF AGREEMENT: Historical and genome wide association studies have established a strong human leukocyte antigen (HLA) linkage to PSC and defined specific haplotypes associated with enhanced PSC risk. Fifteen non-HLA loci have been defined in PSC. AREAS OF CONTROVERSY: The biological role of risk loci in PSC and their place in PSC pathogenesis remain speculative but suggest significant interactions with the host microbiome and therapeutic opportunities. GROWING POINTS: Genetics provides a platform to systematically target emerging therapies in PSC. AREAS TIMELY FOR DEVELOPING RESEARCH: Linking PSC genotypes with biology and disease phenotypes paves the way for a personalized medicine approach to manage PSC. PMID- 24795361 TI - Reprogramming tumor-infiltrating dendritic cells for CD103+ CD8+ mucosal T-cell differentiation and breast cancer rejection. AB - Our studies showed that tumor-infiltrating dendritic cells (DC) in breast cancer drive inflammatory Th2 (iTh2) cells and protumor inflammation. Here, we show that intratumoral delivery of the beta-glucan curdlan, a ligand of dectin-1, blocks the generation of iTh2 cells and prevents breast cancer progression in vivo. Curdlan reprograms tumor-infiltrating DCs via the ligation of dectin-1, enabling the DCs to become resistant to cancer-derived thymic stromal lymphopoietin (TSLP), to produce IL-12p70, and to favor the generation of Th1 cells. DCs activated via dectin-1, but not those activated with TLR-7/8 ligand or poly I:C, induce CD8+ T cells to express CD103 (alphaE integrin), a ligand for cancer cells, E-cadherin. Generation of these mucosal CD8+ T cells is regulated by DC derived integrin alphavbeta8 and TGF-beta activation in a dectin-1-dependent fashion. These CD103+ CD8+ mucosal T cells accumulate in the tumors, thereby increasing cancer necrosis and inhibiting cancer progression in vivo in a humanized mouse model of breast cancer. Importantly, CD103+ CD8+ mucosal T cells elicited by reprogrammed DCs can reject established cancer. Thus, reprogramming tumor-infiltrating DCs represents a new strategy for cancer rejection. PMID- 24795364 TI - Platelet-rich plasma in the conservative treatment of painful tendinopathy: a systematic review and meta-analysis of controlled studies. AB - BACKGROUND: Platelet-rich plasma (PRP) seeks to meet the multifaceted demand of degenerated tendons providing several molecules capable of boosting healing. AREAS TIMELY FOR DEVELOPING RESEARCH: PRP is used for managing tendinopathy, but its efficacy is controversial. SOURCES OF DATA: Electronic databases were searched for clinical studies assessing PRP efficacy. Methodological quality was evaluated using the methods described in the Cochrane Handbook for systematic reviews. AREAS OF AGREEMENT: Thirteen prospective controlled studies, comprising 886 patients and diverse tendons were included; 53.8% of studies used identical PRP protocol. AREAS OF CONTROVERSY: Sources of heterogeneity included different comparators, outcome scores, follow-up periods and diverse injection protocols, but not PRP formulation per se. GROWING POINTS: Pooling pain outcomes over time and across different tendons showed that L-PRP injections ameliorated pain in the intermediate-long term compared with control interventions, weighted mean difference (95% CI): 3 months, -0.61 (-0.97, -0.25); 1 year, -1.56 (-2.27, 0.83). However, these findings cannot be applied to the management of individual patients given low power and precision. RESEARCH: Further studies circumventing heterogeneity are needed to reach firm conclusions. Available evidence can help to overcome hurdles to future clinical research and bring forward PRP therapies. PMID- 24795365 TI - Pyruvate-associated acid resistance in bacteria. AB - Glucose confers acid resistance on exponentially growing bacteria by repressing formation of the cyclic AMP (cAMP)-cAMP receptor protein (CRP) complex and consequently activating acid resistance genes. Therefore, in a glucose-rich growth environment, bacteria are capable of resisting acidic stresses due to low levels of cAMP-CRP. Here we reveal a second mechanism for glucose-conferred acid resistance. We show that glucose induces acid resistance in exponentially growing bacteria through pyruvate, the glycolysis product. Pyruvate and/or the downstream metabolites induce expression of the small noncoding RNA (sncRNA) Spot42, and the sncRNA, in turn, activates expression of the master regulator of acid resistance, RpoS. In contrast to glucose, pyruvate has little effect on levels of the cAMP CRP complex and does not require the complex for its effects on acid resistance. Another important difference between glucose and pyruvate is that pyruvate can be produced by bacteria. This means that bacteria have the potential to protect themselves from acidic stresses by controlling glucose-derived generation of pyruvate, pyruvate-acetate efflux, or reversion from acetate to pyruvate. We tested this possibility by shutting down pyruvate-acetate efflux and found that the resulting accumulation of pyruvate elevated acid resistance. Many sugars can be broken into glucose, and the subsequent glycolysis generates pyruvate. Therefore, pyruvate-associated acid resistance is not confined to glucose-grown bacteria but is functional in bacteria grown on various sugars. PMID- 24795366 TI - Metatranscriptome of an anaerobic benzene-degrading, nitrate-reducing enrichment culture reveals involvement of carboxylation in benzene ring activation. AB - The enzymes involved in the initial steps of anaerobic benzene catabolism are not known. To try to elucidate this critical step, a metatranscriptomic analysis was conducted to compare the genes transcribed during the metabolism of benzene and benzoate by an anaerobic benzene-degrading, nitrate-reducing enrichment culture. RNA was extracted from the mixed culture and sequenced without prior mRNA enrichment, allowing simultaneous examination of the active community composition and the differential gene expression between the two treatments. Ribosomal and mRNA sequences attributed to a member of the family Peptococcaceae from the order Clostridiales were essentially only detected in the benzene-amended culture samples, implicating this group in the initial catabolism of benzene. Genes similar to each of two subunits of a proposed benzene-carboxylating enzyme were transcribed when the culture was amended with benzene. Anaerobic benzoate degradation genes from strict anaerobes were transcribed only when the culture was amended with benzene. Genes for other benzoate catabolic enzymes and for nitrate respiration were transcribed in both samples, with those attributed to an Azoarcus species being most abundant. These findings indicate that the mineralization of benzene starts with its activation by a strict anaerobe belonging to the Peptococcaceae, involving a carboxylation step to form benzoate. These data confirm the previously hypothesized syntrophic association between a benzene-degrading Peptococcaceae strain and a benzoate-degrading denitrifying Azoarcus strain for the complete catabolism of benzene with nitrate as the terminal electron acceptor. PMID- 24795367 TI - Development of a functional antibody by using a green fluorescent protein frame as the template. AB - Single-chain variable fragment (scFv) antibodies are widely used as diagnostic and therapeutic agents or biosensors for a majority of human disease. However, the limitations of the present scFv antibody in terms of stability, solubility, and affinity are challenging to produce by traditional antibody screening and expression formats. We describe here a feasible strategy for creating the green fluorescent protein (GFP)-based antibody. Complementarity-determining region 3 (CDR3), which retains the antigen binding activity, was introduced into the structural loops of superfolder GFP, and the result showed that CDR3-inserted GFP displayed almost the same fluorescence intensity as wild-type GFP, and the purified proteins of CDR3 insertion showed the similar binding activity to antigen as the corresponding scFv. Among of all of the CDRs, CDR3s are responsible for antigen recognition, and only the CDR3a insertion is the best format for producing GFP-based antibody binding to specific antigen. The wide versatility of this system was further verified by introducing CDR3 from other scFvs into loop 9 of GFP. We developed a feasible method for rapidly and effectively producing a high-affinity GFP-based antibody by inserting CDR3s into GFP loops. Further, the affinity can be enhanced by specific amino acids scanning and site-directed mutagenesis. Notably, this method had better versatility for creating antibodies to various antigens using GFP as the scaffold, suggesting that a GFP-based antibody with high affinity and specificity may be useful for disease diagnosis and therapy. PMID- 24795368 TI - The transcriptional response of Lactobacillus sanfranciscensis DSM 20451T and its tcyB mutant lacking a functional cystine transporter to diamide stress. AB - As a result of its strong adaptation to wheat and rye sourdoughs, Lactobacillus sanfranciscensis has the smallest genome within the genus Lactobacillus. The concomitant absence of some important antioxidative enzymes and the inability to synthesize glutathione suggest a role of cystine transport in maintenance of an intracellular thiol balance. Diamide [synonym 1,1'-azobis(N,N-dimethylformamide)] disturbs intracellular and membrane thiol levels in oxidizing protein thiols depending on its initial concentration. In this study, RNA sequencing was used to reveal the transcriptional response of L. sanfranciscensis DSM 20451(T) (wild type [WT]) and its DeltatcyB mutant with a nonfunctional cystine transporter after thiol stress caused by diamide. Along with the different expression of genes involved in amino acid starvation, pyrimidine synthesis, and energy production, our results show that thiol stress in the wild type can be compensated through activation of diverse chaperones and proteases whereas the DeltatcyB mutant shifts its metabolism in the direction of survival. Only a small set of genes are significantly differentially expressed between the wild type and the mutant. In the WT, mainly genes which are associated with a heat shock response are upregulated whereas glutamine import and synthesis genes are downregulated. In the DeltatcyB mutant, the whole opp operon was more highly expressed, as well as a protein which probably includes enzymes for methionine transport. The two proteins encoded by spxA and nrdH, which are involved in direct or indirect oxidative stress responses, are also upregulated in the mutant. This work emphasizes that even in the absence of definitive antioxidative enzymes, bacteria with a small genome and a high frequency of gene inactivation and elimination use small molecules such as the cysteine/cystine couple to overcome potential cell damage resulting from oxidative stress. PMID- 24795369 TI - Prevalence, genetic diversity, and host range of tectiviruses among members of the Bacillus cereus group. AB - GIL01, Bam35, GIL16, AP50, and Wip1 are tectiviruses preying on the Bacillus cereus group. Despite the significant contributions of phages in different biological processes, little is known about the dealings taking place between tectiviruses and their Gram-positive bacterial hosts. Therefore, this work focuses on characterizing the interactions between tectiviruses and the B. cereus group by assessing their occurrence and genetic diversity and evaluating their host range. To study the occurrence of tectiviruses in the B. cereus group, 2,000 isolates were evaluated using primers designed to be specific to two variable regions detected in previously described elements. PCR and propagation tests revealed that tectivirus-like elements occurred in less than 3% of the isolates. Regardless of this limited distribution, several novel tectiviruses were found, and partial DNA sequencing indicated that a greater diversity exists within the family Tectiviridae. Analyses of the selected variable regions, along with their host range, showed that tectiviruses in the B. cereus group can be clustered mainly into two different groups: the ones infecting B. anthracis and those isolated from other B. cereus group members. In order to address the host range of some novel tectiviruses, 120 strains were tested for sensitivity. The results showed that all the tested tectiviruses produced lysis in at least one B. cereus sensu lato strain. Moreover, no simple relationship between the infection patterns of the tectiviruses and their diversity was found. PMID- 24795371 TI - Targeted and highly multiplexed detection of microorganisms by employing an ensemble of molecular probes. AB - The vast majority of microscopic life on earth consists of microbes that do not grow in laboratory culture. To profile the microbial diversity in environmental and clinical samples, we have devised and employed molecular probe technology, which detects and identifies bacteria that do and do not grow in culture. The only requirement is a short sequence of contiguous bases (currently 60 bases) unique to the genome of the organism of interest. The procedure is relatively fast, inexpensive, customizable, robust, and culture independent and uses commercially available reagents and instruments. In this communication, we report improving the specificity of the molecular probes substantially and increasing the complexity of the molecular probe set by over an order of magnitude (>1,200 probes) and introduce a new final readout method based upon Illumina sequencing. In addition, we employed molecular probes to identify the bacteria from vaginal swabs and demonstrate how a deliberate selection of molecular probes can identify less abundant bacteria even in the presence of much more abundant species. PMID- 24795372 TI - Comparative biochemical characterization of three exolytic oligoalginate lyases from Vibrio splendidus reveals complementary substrate scope, temperature, and pH adaptations. AB - Marine microbes use alginate lyases to degrade and catabolize alginate, a major cell wall matrix polysaccharide of brown seaweeds. Microbes frequently contain multiple, apparently redundant alginate lyases, raising the question of whether these enzymes have complementary functions. We report here on the molecular cloning and functional characterization of three exo-type oligoalginate lyases (OalA, OalB, and OalC) from Vibrio splendidus 12B01 (12B01), a marine bacterioplankton species. OalA was most active at 16 degrees C, had a pH optimum of 6.5, and displayed activities toward poly-beta-d-mannuronate [poly(M)] and poly-alpha-l-guluronate [poly(G)], indicating that it is a bifunctional enzyme. OalB and OalC were most active at 30 and 35 degrees C, had pH optima of 7.0 and 7.5, and degraded poly(M.G) and poly(M), respectively. Detailed kinetic analyses of oligoalginate lyases with poly(G), poly(M), and poly(M.G) and sodium alginate as substrates demonstrated that OalA and OalC preferred poly(M), whereas OalB preferred poly(M.G). The catalytic efficiency (kcat/Km) of OalA against poly(M) increased with decreasing size of the substrate. OalA showed kcat/Km from 2,130 mg(-1) ml s(-1) for the trisaccharide to 224 mg(-1) ml s(-1) for larger oligomers of ~50 residues, and 50.5 mg(-1) ml s(-1) for high-molecular-weight alginate. Although OalA was most active on the trisaccharide, OalB and OalC preferred dimers. Taken together, our results indicate that these three Oals have complementary substrate scopes and temperature and pH adaptations. PMID- 24795370 TI - Functional genomic characterization of virulence factors from necrotizing fasciitis-causing strains of Aeromonas hydrophila. AB - The genomes of 10 Aeromonas isolates identified and designated Aeromonas hydrophila WI, Riv3, and NF1 to NF4; A. dhakensis SSU; A. jandaei Riv2; and A. caviae NM22 and NM33 were sequenced and annotated. Isolates NF1 to NF4 were from a patient with necrotizing fasciitis (NF). Two environmental isolates (Riv2 and 3) were from the river water from which the NF patient acquired the infection. While isolates NF2 to NF4 were clonal, NF1 was genetically distinct. Outside the conserved core genomes of these 10 isolates, several unique genomic features were identified. The most virulent strains possessed one of the following four virulence factors or a combination of them: cytotoxic enterotoxin, exotoxin A, and type 3 and 6 secretion system effectors AexU and Hcp. In a septicemic-mouse model, SSU, NF1, and Riv2 were the most virulent, while NF2 was moderately virulent. These data correlated with high motility and biofilm formation by the former three isolates. Conversely, in a mouse model of intramuscular infection, NF2 was much more virulent than NF1. Isolates NF2, SSU, and Riv2 disseminated in high numbers from the muscular tissue to the visceral organs of mice, while NF1 reached the liver and spleen in relatively lower numbers on the basis of colony counting and tracking of bioluminescent strains in real time by in vivo imaging. Histopathologically, degeneration of myofibers with significant infiltration of polymorphonuclear cells due to the highly virulent strains was noted. Functional genomic analysis provided data that allowed us to correlate the highly infectious nature of Aeromonas pathotypes belonging to several different species with virulence signatures and their potential ability to cause NF. PMID- 24795373 TI - Mannosylglycerate and di-myo-inositol phosphate have interchangeable roles during adaptation of Pyrococcus furiosus to heat stress. AB - Marine hyperthermophiles accumulate small organic compounds, known as compatible solutes, in response to supraoptimal temperatures or salinities. Pyrococcus furiosus is a hyperthermophilic archaeon that grows optimally at temperatures near 100 degrees C. This organism accumulates mannosylglycerate (MG) and di-myo inositol phosphate (DIP) in response to osmotic and heat stress, respectively. It has been assumed that MG and DIP are involved in cell protection; however, firm evidence for the roles of these solutes in stress adaptation is still missing, largely due to the lack of genetic tools to produce suitable mutants of hyperthermophiles. Recently, such tools were developed for P. furiosus, making this organism an ideal target for that purpose. In this work, genes coding for the synthases in the biosynthetic pathways of MG and DIP were deleted by double crossover homologous recombination. The growth profiles and solute patterns of the two mutants and the parent strain were investigated under optimal growth conditions and also at supraoptimal temperatures and NaCl concentrations. DIP was a suitable replacement for MG during heat stress, but substitution of MG for DIP and aspartate led to less efficient growth under conditions of osmotic stress. The results suggest that the cascade of molecular events leading to MG synthesis is tuned for osmotic adjustment, while the machinery for induction of DIP synthesis responds to either stress agent. MG protects cells against heat as effectively as DIP, despite the finding that the amount of DIP consistently increases in response to heat stress in the nine (hyper)thermophiles examined thus far. PMID- 24795374 TI - Effects of pH and lactate on hydrogen sulfide production by oral Veillonella spp. AB - Indigenous oral bacteria in the tongue coating such as Veillonella have been identified as the main producers of hydrogen sulfide (H2S), one of the major components of oral malodor. However, there is little information on the physiological properties of H2S production by oral Veillonella such as metabolic activity and oral environmental factors which may affect H2S production. Thus, in the present study, the H2S-producing activity of growing cells, resting cells, and cell extracts of oral Veillonella species and the effects of oral environmental factors, including pH and lactate, were investigated. Type strains of Veillonella atypica, Veillonella dispar, and Veillonella parvula were used. These Veillonella species produced H2S during growth in the presence of l cysteine. Resting cells of these bacteria produced H2S from l-cysteine, and the cell extracts showed enzymatic activity to convert l-cysteine to H2S. H2S production by resting cells was higher at pH 6 to 7 and lower at pH 5. The presence of lactate markedly increased H2S production by resting cells (4.5- to 23.7-fold), while lactate had no effect on enzymatic activity in cell extracts. In addition to H2S, ammonia was produced in cell extracts of all the strains, indicating that H2S was produced by the catalysis of cystathionine gamma-lyase (EC 4.4.1.1). Serine was also produced in cell extracts of V. atypica and V. parvula, suggesting the involvement of cystathionine beta-synthase lyase (EC 4.2.1.22) in these strains. This study indicates that Veillonella produce H2S from l-cysteine and that their H2S production can be regulated by oral environmental factors, namely, pH and lactate. PMID- 24795375 TI - Involvement of the global regulator GlxR in 3-hydroxybenzoate and gentisate utilization by Corynebacterium glutamicum. AB - Corynebacterium glutamicum is an industrially important producer of amino acids and organic acids, as well as an emerging model system for aromatic assimilation. An IclR-type regulator GenR has been characterized to activate the transcription of genDFM and genKH operons for 3-hydroxybenzoate and gentisate catabolism and represses its own expression. On the other hand, GlxR, a global regulator of the cyclic AMP (cAMP) receptor protein-fumarate nitrate reductase regulator (CRP-FNR) type, was also predicted to be involved in this pathway. In this study, electrophoretic mobility shift assays and footprinting analyses demonstrated that GlxR bound to three sites in the promoter regions of three gen operons. A combination of site-directed mutagenesis of the biding sites, promoter activity assay, and GlxR overexpression demonstrated that GlxR repressed their expression by binding these sites. One GlxR binding site (DFMx) was found to be located -13 to +8 bp upstream of the genDFM promoter, which was involved in negative regulation of genDFM transcription. The GlxR binding site R-KHx01 (located between positions -11 to +5) was upstream of the genKH promoter sequence and involved in negative regulation of its transcription. The binding site R-KHx02, at which GlxR binds to genR promoter to repress its expression, was found within a footprint extending from positions -71 to -91 bp. These results reveal that GlxR represses the transcription of all three gen operons and then contributes to the synchronization of their expression for 3-hydroxybenzoate and gentisate catabolism in collaboration with the specific regulator GenR. PMID- 24795376 TI - Use of cellulolytic marine bacteria for enzymatic pretreatment in microalgal biogas production. AB - In this study, we designed and evaluated a microalgal pretreatment method using cellulolytic bacteria that naturally degrades microalgae in their native habitat. Bacterial strains were isolated from each of two mollusk species in a medium containing 1% carboxymethyl cellulose agar. We selected nine bacterial strains that had endoglucanase activity: five strains from Mytilus chilensis, a Chilean mussel, and four strains from Mesodesma donacium, a clam found in the Southern Pacific. These strains were identified phylogenetically as belonging to the genera Aeromonas, Pseudomonas, Chryseobacterium, and Raoultella. The cellulase producing capacities of these strains were characterized, and the degradation of cell walls in Botryococcus braunii and Nannochloropsis gaditana was tested with "whole-cell" cellulolytic experiments. Aeromonas bivalvium MA2, Raoultella ornithinolytica MA5, and Aeromonas salmonicida MC25 degraded B. braunii, and R. ornithinolytica MC3 and MA5 degraded N. gaditana. In addition, N. gaditana was pretreated with R. ornithinolytica strains MC3 and MA5 and was then subjected to an anaerobic digestion process, which increased the yield of methane by 140.32% and 158.68%, respectively, over that from nonpretreated microalgae. Therefore, a "whole-cell" cellulolytic pretreatment can increase the performance and efficiency of biogas production. PMID- 24795377 TI - Eutrophication and bacterial pathogens as risk factors for avian botulism outbreaks in wetlands receiving effluents from urban wastewater treatment plants. AB - Due to the scarcity of water resources in the "Mancha Humeda" Biosphere Reserve, the use of treated wastewater has been proposed as a solution for the conservation of natural threatened floodplain wetlands. In addition, wastewater treatment plants of many villages pour their effluent into nearby natural lakes. We hypothesized that certain avian pathogens present in wastewater may cause avian mortalities which would trigger avian botulism outbreaks. With the aim of testing our hypothesis, 24 locations distributed in three wetlands, two that receive wastewater effluents and one serving as a control, were monitored during a year. Sediment, water, water bird feces, and invertebrates were collected for the detection of putative avian pathogenic Escherichia coli (APEC), Salmonella spp., Clostridium perfringens type A, and Clostridium botulinum type C/D. Also, water and sediment physicochemical properties were determined. Overall, APEC, C. perfringens, and C. botulinum were significantly more prevalent in samples belonging to the wetlands which receive wastewater. The occurrence of a botulism outbreak in one of the studied wetlands coincided with high water temperatures and sediment 5-day biochemical oxygen demand (BOD5), a decrease in water redox potential, chlorophyll a, and sulfate levels, and an increase in water inorganic carbon levels. The presence of C. botulinum in bird feces before the onset of the outbreak indicates that carrier birds exist and highlights the risk of botulinum toxin production in their carcasses if they die by other causes such as bacterial diseases, which are more probable in wastewater wetlands. PMID- 24795378 TI - Discovery of ethanol-responsive small RNAs in Zymomonas mobilis. AB - Zymomonas mobilis is a bacterium that can produce ethanol by fermentation. Due to its unique metabolism and efficient ethanol production, Z. mobilis has attracted special interest for biofuel energy applications; an important area of study is the regulation of those specific metabolic pathways. Small RNAs (sRNAs) have been studied as molecules that function as transcriptional regulators in response to cellular stresses. While sRNAs have been discovered in various organisms by computational prediction and experimental approaches, their discovery in Z. mobilis has not yet been reported. In this study, we have applied transcriptome analysis and computational predictions to facilitate identification and validation of 15 novel sRNAs in Z. mobilis. We furthermore characterized their expression in the context of high and low levels of intracellular ethanol. Here, we report that 3 of the sRNAs (Zms2, Zms4, and Zms6) are differentially expressed under aerobic and anaerobic conditions, when low and high ethanol productions are observed, respectively. Importantly, when we tested the effect of ethanol stress on the expression of sRNAs in Z. mobilis, Zms2, Zms6, and Zms18 showed differential expression under 5% ethanol stress conditions. These data suggest that in this organism regulatory RNAs can be associated with metabolic functions involved in ethanol stress responses. PMID- 24795379 TI - Comparison of five bacteriophages as models for viral aerosol studies. AB - Bacteriophages are perceived to be good models for the study of airborne viruses because they are safe to use, some of them display structural features similar to those of human and animal viruses, and they are relatively easy to produce in large quantities. Yet, only a few studies have investigated them as models. It has previously been demonstrated that aerosolization, environmental conditions, and sampling conditions affect viral infectivity, but viral infectivity is virus dependent. Thus, several virus models are likely needed to study their general behavior in aerosols. The aim of this study was to compare the effects of aerosolization and sampling on the infectivity of five tail-less bacteriophages and two pathogenic viruses: MS2 (a single-stranded RNA [ssRNA] phage of the Leviviridae family), Phi6 (a segmented double-stranded RNA [dsRNA] phage of the Cystoviridae family), PhiX174 (a single-stranded DNA [ssDNA] phage of the Microviridae family), PM2 (a double-stranded DNA [dsDNA] phage of the Corticoviridae family), PR772 (a dsDNA phage of the Tectiviridae family), human influenza A virus H1N1 (an ssRNA virus of the Orthomyxoviridae family), and the poultry virus Newcastle disease virus (NDV; an ssRNA virus of the Paramyxoviridae family). Three nebulizers and two nebulization salt buffers (with or without organic fluid) were tested, as were two aerosol sampling devices, a liquid cyclone (SKC BioSampler) and a dry cyclone (National Institute for Occupational Safety and Health two-stage cyclone bioaerosol sampler). The presence of viruses in collected air samples was detected by culture and quantitative PCR (qPCR). Our results showed that these selected five phages behave differently when aerosolized and sampled. RNA phage MS2 and ssDNA phage PhiX174 were the most resistant to aerosolization and sampling. The presence of organic fluid in the nebulization buffer protected phages PR772 and Phi6 throughout the aerosolization and sampling with dry cyclones. In this experimental setup, the behavior of the influenza virus resembled that of phages PR772 and Phi6, while the behavior of NDV was closer to that of phages MS2 and PhiX174. These results provide critical information for the selection of appropriate phage models to mimic the behavior of specific human and animal viruses in aerosols. PMID- 24795380 TI - Temporal dynamics of the cecal gut microbiota of juvenile arctic ground squirrels: a strong litter effect across the first active season. AB - Arctic ground squirrels (Urocitellus parryii) are active for a scant 3 to 5 months of the year. During the active season, adult squirrels compete for mates, reproduce, and fatten in preparation for hibernation, while juvenile squirrels, weaned in early July, must grow and acquire sufficient fat to survive their first hibernation season. During hibernation, the gut microbial community is altered in diversity, abundance, and activity. To date, no studies have examined the gut microbiota of hibernators across the truncated active season. We characterized trends in diversity (454 pyrosequencing), density (flow cytometry), viability (flow cytometry), and metabolism (short-chain fatty acid analysis) of the gut microbial community of juvenile arctic ground squirrels across their first active season at weaning and at 4, 6, 8, and 10 weeks postweaning. At 8 weeks postweaning, the mean bacterial density was significantly higher than that at weaning, and the mean percentage of live bacteria was significantly higher than that at either weaning or 4 weeks postweaning. No significant differences in microbial diversity, total short-chain fatty acid concentrations, or molar proportions of individual short-chain fatty acids were observed among sample periods. The level of variability in gut microbial diversity among squirrels was high across the active season but was most similar among littermates, except at weaning, indicating strong maternal or genetic influences across development. Our results indicate that genetic or maternal influences exert profound effects on the gut microbial community of juvenile arctic ground squirrels. We did not find a correlation between host adiposity and gut microbial diversity during prehibernation fattening, likely due to a high level of variability among squirrels. PMID- 24795381 TI - Beyond the matrix-assisted laser desorption ionization (MALDI) biotyping workflow: in search of microorganism-specific tryptic peptides enabling discrimination of subspecies. AB - A well-accepted method for identification of microorganisms uses matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) coupled to analysis software which identifies and classifies the organism according to its ribosomal protein spectral profile. The method, called MALDI biotyping, is widely used in clinical diagnostics and has partly replaced conventional microbiological techniques such as biochemical identification due to its shorter time to result (minutes for MALDI biotyping versus hours or days for classical phenotypic or genotypic identification). Besides its utility for identifying bacteria, MS-based identification has been shown to be applicable also to yeasts and molds. A limitation to this method, however, is that accurate identification is most reliably achieved on the species level on the basis of reference mass spectra, making further phylogenetic classification unreliable. Here, it is shown that combining tryptic digestion of the acid/organic solvent extracted (classical biotyping preparation) and resolubilized proteins, nano liquid chromatography (nano-LC), and subsequent identification of the peptides by MALDI-tandem TOF (MALDI-TOF/TOF) mass spectrometry increases the discrimination power to the level of subspecies. As a proof of concept, using this targeted proteomics workflow, we have identified subspecies-specific biomarker peptides for three Salmonella subspecies, resulting in an extension of the mass range and type of proteins investigated compared to classical MALDI biotyping. This method therefore offers rapid and cost-effective identification and classification of microorganisms at a deeper taxonomic level. PMID- 24795383 TI - Direct air activation measurements at a 15-MV medical linear accelerator. AB - Direct radiometric determination of (14)N (gamma, n) (13)N air activation was achieved at a 15-MV medical linear accelerator operating in a high-energy photon mode. (13)N was identified by irradiating a gas-tight Marinelli beaker filled with nitrogen gas and later observing the 10-min half-life of the 511-keV positron-electron annihilation line using high-resolution gamma spectroscopy. Quantitative evaluation of the spectral signal yielded a (13)N production rate of 836.8 +/- 32 Bq Gy(-1) in air per 40 * 40 cm(2) field cross section at 100 cm source-surface distance. PMID- 24795382 TI - Bioaccumulation efficiency, tissue distribution, and environmental occurrence of hepatitis E virus in bivalve shellfish from France. AB - Hepatitis E virus (HEV), an enteric pathogen of both humans and animals, is excreted by infected individuals and is therefore present in wastewaters and coastal waters. As bivalve molluscan shellfish are known to concentrate viral particles during the process of filter feeding, they may accumulate this virus. The bioaccumulation efficiencies of oysters (Crassostrea gigas), flat oysters (Ostrea edulis), mussels (Mytilus edulis), and clams (Ruditapes philippinarum) were compared at different time points during the year. Tissue distribution analysis showed that most of the viruses were concentrated in the digestive tissues of the four species. Mussels and clams were found to be more sensitive to sporadic contamination events, as demonstrated by rapid bioaccumulation in less than 1 h compared to species of oysters. For oysters, concentrations increased during the 24-h bioaccumulation period. Additionally, to evaluate environmental occurrence of HEV in shellfish, an environmental investigation was undertaken at sites potentially impacted by pigs, wild boars, and human waste. Of the 286 samples collected, none were contaminated with hepatitis E virus, despite evidence that this virus is circulating in some French areas. It is possible that the number of hepatitis E viral particles discharged into the environment is too low to detect or that the virus may have a very short period of persistence in pig manure and human waste. PMID- 24795384 TI - ESR dating of barite in sulphide deposits formed by the sea-floor hydrothermal activities. AB - Barite is a mineral newly found to be practically useful for electron spin resonance (ESR) dating of sulphide deposits formed by the sea-floor hydrothermal activities. The recent studies for the properties of the ESR dating signal in barite are summarised in the present paper as well as the formulas for corrections for accurate dose-rate estimation are developed including the dose rate conversion factors, shape correction for gamma-ray dose and decay of (226)Ra. Although development of the techniques for ESR dating of barite has been completed, further comparative studies with other dating techniques such as U-Th and (226)Ra-(210)Pb dating are necessary for the technique to be widely used. PMID- 24795385 TI - A report on radioactivity measurements of fish samples from the west coast of Canada. AB - Even though many studies have shown that radioactive caesium levels in fish caught outside of Japan were below experimental detection limits of a few Bq kg( 1), significant public concern has been expressed about the safety of consuming seafood from the Pacific Ocean following the Fukushima-Daiichi nuclear accident. To address the public concerns, samples of commonly consumed salmon and groundfish harvested from the Canadian west coast in 2013 were analysed for radioactive caesium. None of the fish samples analysed in this study contained any detectable levels of (134)Cs and (137)Cs under given experimental setting with the average detection limit of ~2 Bq kg(-1). Using a conservative worst-case scenario where all fish samples would contain (137)Cs exactly at the detection limit level and (134)Cs at half of the detection limit level (to account for much shorter half-life of (134)Cs), the resulting radiation dose for people from consumption of this fish would be a very small fraction of the annual dose from exposure to natural background radiation in Canada. Therefore, fish, such as salmon and groundfish, from the Canadian west coast are of no radiological health concern. PMID- 24795387 TI - Government is accused of back-pedalling on its commitment to "parity of esteem" between mental and physical healthcare. PMID- 24795386 TI - Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX LOX inhibitor licofelone in UPII-SV40T transgenic mice. AB - Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX 2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC. PMID- 24795388 TI - Gestational age at birth and outcomes after neonatal cardiac surgery: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. AB - BACKGROUND: Gestational age at birth is a potentially important modifiable risk factor in neonates with congenital heart disease. We evaluated the relationship between gestational age and outcomes in a multicenter cohort of neonates undergoing cardiac surgery, focusing on those born at early term (ie, 37-38 weeks' gestation). METHODS AND RESULTS: Neonates in the Society of Thoracic Surgeons Congenital Heart Surgery Database who underwent cardiac surgery between 2010 and 2011 were included. Multivariable logistic regression was used to evaluate the association of gestational age at birth with in-hospital mortality, postoperative length of stay, and complications, adjusting for other important patient characteristics. Of 4784 included neonates (92 hospitals), 48% were born before 39 weeks' gestation, including 31% at 37 to 38 weeks. Compared with a 39.5 week gestational age reference level, birth at 37 weeks' gestational age was associated with higher in-hospital mortality, with an adjusted odds ratio (95% confidence interval) of 1.34 (1.05-1.71; P=0.02). Complication rates were higher and postoperative length of stay was significantly prolonged for those born at 37 and 38 weeks' gestation (adjusted P<0.01 for all). Late-preterm births (34-36 weeks' gestation) also had greater mortality and postoperative length of stay (adjusted P<=0.003 for all). CONCLUSIONS: Birth during the early term period of 37 to 38 weeks' gestation is associated with worse outcomes after neonatal cardiac surgery. These data challenge the commonly held perception that delivery at any time during term gestation is equally safe and appropriate and question the related practice of elective delivery of fetuses with complex congenital heart disease at early term. PMID- 24795389 TI - Best on time, not a little early: gestational age and outcomes for neonates with congenital heart disease. PMID- 24795391 TI - An encouraging progress report on the treatment of progeria and its implications for atherogenesis. PMID- 24795392 TI - Molecular pathways: CDK4 inhibitors for cancer therapy. AB - Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G1-S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4 cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. PMID- 24795390 TI - Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. AB - BACKGROUND: Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. METHODS AND RESULTS: We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. CONCLUSIONS: This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747. PMID- 24795393 TI - Influence of standing positions and beam projections on effective dose and eye lens dose of anaesthetists in interventional procedures. AB - More and more anaesthetists are getting involved in interventional radiology procedures and so it is important to know the radiation dose and to optimise protection for anaesthetists. In this study, based on Monte Carlo simulations and field measurements, both the whole-body doses and eye lens dose of anaesthetists were studied. The results showed that the radiation exposure to anaesthetists not only depends on their workload, but also largely varies with their standing positions and beam projections during interventional procedures. The simulation results showed that the effective dose to anaesthetists may vary with their standing positions and beam projections to more than a factor of 10, and the eye lens dose may vary with the standing positions and beam projections to more than a factor of 200. In general, a close position to the bed and the left lateral (LLAT) beam projection will bring a high exposure to anaesthetists. Good correlations between the eye lens dose and the doses at the neck, chest and waist over the apron were observed from the field measurements. The results indicate that adequate arrangements of anaesthesia device or other monitoring equipment in the fluoroscopy rooms are useful measures to reduce the radiation exposure to anaesthetists, and anaesthetists should be aware that they will receive the highest doses under left lateral beam projection. PMID- 24795394 TI - Neutron ESR dosimetry through ammonium tartrate with low Gd content. AB - This paper continues analyses on organic compounds for application in neutron dosimetry performed through electron spin resonance (ESR). Here, the authors present the results obtained by ESR measurements of a blend of ammonium tartrate dosemeters and gadolinium oxide (5 % by weight). The choice of low amount of Gd is due to the need of improving neutron sensitivity while not significantly influencing tissue equivalence. A study of the effect of gadolinium presence on tissue equivalence was carried out. The experiments show that the neutron sensitivity is enhanced by more than an order of magnitude even with this small additive content. Monte Carlo simulations on the increment of energy release due to gadolinium presence were carried, and the results were in good agreement with the experimental data. PMID- 24795395 TI - A method based on Monte Carlo simulation for the determination of the G(E) function. AB - The G(E) function method is a spectrometric method for the exposure dose estimation; this paper describes a method based on Monte Carlo method to determine the G(E) function of a 4" * 4" * 16" NaI(Tl) detector. Simulated spectrums of various monoenergetic gamma rays in the region of 40 -3200 keV and the corresponding deposited energy in an air ball in the energy region of full energy peak were obtained using Monte Carlo N-particle Transport Code. Absorbed dose rate in air was obtained according to the deposited energy and divided by counts of corresponding full-energy peak to get the G(E) function value at energy E in spectra. Curve-fitting software 1st0pt was used to determine coefficients of the G(E) function. Experimental results show that the calculated dose rates using the G(E) function determined by the authors' method are accordant well with those values obtained by ionisation chamber, with a maximum deviation of 6.31 %. PMID- 24795396 TI - Preparation and characterisation of a sol-gel process alpha-Al2O3 polycrystalline detector. AB - This article presents the dosimetric characteristics of alpha-Al2O3 detectors prepared through the sol-gel process, disc pressing and sintering in a highly reducing atmosphere. Comparative tests between the sol-gel process alpha-Al2O3 polycrystalline and anion-defective alpha-Al2O3:C single-crystal detectors indicate that the ones prepared through this approach present good dosimetric characteristics similar to those found in single-crystal detectors, such as a simple glow curve with the main peak at ~198 degrees C (2 degrees C s(-1)), high sensitivity, a detection threshold of 1.7 uGy, linearity of response, low fading, relatively low photon energy dependence, reusability without annealing and good reproducibility. However, the undesirable feature of heating rate dependence of the thermoluminescence (TL) output in alpha-Al2O3:C single crystal is practically non-existent in the sol-gel process alpha-Al2O3 polycrystalline detector. This characteristic renders it useful for the routine processing of large numbers of personal and environmental dosemeters at higher heating rates and also when it comes to the proposal for new approaches to thermal quenching investigation. PMID- 24795398 TI - Regarding effects of bariatric surgery on left ventricular mass index and geometry. PMID- 24795397 TI - Pregravid liver enzyme levels and risk of gestational diabetes mellitus during a subsequent pregnancy. AB - OBJECTIVE: Liver enzymes are independent predictors of type 2 diabetes. Although liver fat content correlates with features of insulin resistance, a risk factor for developing gestational diabetes mellitus (GDM), the relationship between liver enzymes and GDM is unclear. The objective of this study was to assess whether pregravid liver enzyme levels are associated with subsequent risk of GDM. RESEARCH DESIGN AND METHODS: A nested case-control study was conducted among women who participated in the Kaiser Permanente Northern California multiphasic health checkup (1984-1996) and had a subsequent pregnancy (1984-2009). Case patients were 256 women who developed GDM. Two control subjects were selected for each case patient and matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies. RESULTS: Being in the highest quartile versus the lowest quartile of gamma-glutamyl transferase (GGT) levels was associated with a twofold increased risk of subsequent GDM (odds ratio 1.97 [95% CI 1.14-3.42]), after adjusting for race/ethnicity, prepregnancy BMI, family history of diabetes, and alcohol use. This result was attenuated after adjusting for homeostasis model assessment of insulin resistance (HOMA-IR), fasting status, and rate of gestational weight gain. There was significant interaction between GGT and HOMA-IR; the association with GGT was found among women in the highest tertile of HOMA-IR. Aspartate aminotransferase and alanine aminotransferase were not associated with increased GDM risk. CONCLUSIONS: Pregravid GGT level, but not alanine aminotransferase or aspartate aminotransferase level, predicted the subsequent risk of GDM. Markers of liver fat accumulation, such as GGT level, are present years before pregnancy and may help to identify women at increased risk for subsequent GDM. PMID- 24795399 TI - Response to "Regarding effects of bariatric surgery on left ventricular mass index and geometry". PMID- 24795400 TI - Denervation of native kidneys in a renal transplant recipient: one swallow does not make a spring. PMID- 24795402 TI - Blood pressure level and hypertension awareness and control differ by marital status, sex, and ethnicity: a population-based study. AB - BACKGROUND: Population-based studies about factors associated with blood pressure (BP) levels and hypertension awareness and control are lacking in Israel. We aimed to identify covariables of BP level (across the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) categories) and hypertension awareness and control. METHODS: Participants (n = 763; aged 25-74 years) were randomly selected from the population registry and stratified by sex, age, and ethnicity (Arab or Jewish). Sociodemographic, lifestyle, chronic morbidity, drug therapy, and measured anthropometric and BP data were collected. Hypertension was defined as physician diagnosis, antihypertension drug therapy, or systolic BP >=140 mm Hg or diastolic BP >=90 mm Hg. RESULTS: Standardized hypertension prevalence was 32.5%. Age and body mass index were positively associated with being in a higher JNC-7 category. In multivariable analysis, the association between gender and JNC-7 category depended upon marital status. Of those with hypertension (n = 315), 66.0% were aware of their status, and 26.0% exhibited adequate BP control. Using "aware-and controlled" as the outcome reference category, the odds ratio (OR) of being aware and uncontrolled was 1.9 (95% confidence interval (CI) = 1.3-2.9) for 10-year age increment. The OR of being unaware and uncontrolled was 5.6 (95% CI = 2.0-15.8) for Arabs vs. Jews, 5.6 (95% CI = 1.4-22.3) for single/divorced vs. married participants, 3.9 (95% CI = 1.7-9.2) for those with <3 visits to the family physician per year, and 0.1 (95% CI = 0.02-0.4) for those with self-reported cardiovascular disease. CONCLUSIONS: Sociodemographic factors and primary healthcare service utilization are associated with hypertension awareness and control. Specially focused outreach may be needed to improve hypertension awareness among Arabs, certain subgroups not traditionally considered to be at high risk, and those who have less contact with the healthcare system. PMID- 24795404 TI - RCVS Council asked to review its decision on postnominals. PMID- 24795403 TI - A systematic review and meta-analysis of yoga for hypertension. AB - BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate the quality of evidence and the strength of recommendation for yoga as a therapeutic means in the management of prehypertension and hypertension. METHODS: MEDLINE/Pubmed, Scopus, CENTRAL, and IndMED were screened through February 2014 for randomized controlled trials (RCTs) on the effects of yoga interventions (>=8 weeks) compared with usual care or any active control intervention on blood pressure in patients with prehypertension (120-139/80-89 mm Hg) or hypertension (>=140/>=90 mm Hg). Risk of bias was assessed using the Cochrane risk of bias tool; quality of evidence was assessed according to the GRADE recommendations. RESULTS: Seven RCTs with a total of 452 patients were included. Compared with usual care, very low-quality evidence was found for effects of yoga on systolic (6 RCTs, n = 278; mean difference (MD) = -9.65 mm Hg, 95% confidence interval (CI) = -17.23 to -2.06, P = 0.01; heterogeneity: I (2) = 90%, chi(2) = 48.21, P < 0.01) and diastolic blood pressure (6 RCTs, n = 278; MD = -7.22 mm Hg, 95% CI = 12.83 to -1.62, P = 0.01; heterogeneity: I (2) = 92%, chi(2) = 64.84, P < 0.01). Subgroup analyses revealed effects for RCTs that included hypertensive patients but not for RCTs that included both hypertensive and prehypertensive patients, as well as for RCTs that allowed antihypertensive comedication but not for those that did not. More adverse events occurred during yoga than during usual care. Compared with exercise, no evidence was found for effects of yoga on systolic or diastolic blood pressure. CONCLUSIONS: Larger studies are required to confirm the emerging but low-quality evidence that yoga may be a useful adjunct intervention in the management of hypertension. PMID- 24795401 TI - Acute air pollution exposure and blood pressure at delivery among women with and without hypertension. AB - BACKGROUND: Chronic air pollution exposure increases risk for hypertensive disorders of pregnancy, but the effect of acute air pollution exposure on blood pressure during pregnancy is less well known. METHODS: We studied 151,276 singleton term deliveries from the Consortium on Safe Labor (2002-2008) with clinical blood pressure measured at admission to labor/delivery and diagnoses of hypertensive disorders collected from electronic medical records and hospital discharge summaries. Air pollution exposures were estimated for the admission hour and the 4 hours preceding admission using a modified version of the Community Multiscale Air Quality models and observed air monitoring data. Blood pressure was categorized as normal; high normal; and mild, moderate, or severe hypertension based on pregnancy cut points. Adjusted ordinal logistic regression estimated the odds of women having a higher admission blood pressure category as a function of air pollutant, hypertensive disorders, and their interaction effect. RESULTS: Odds of high blood pressure at admission to labor/delivery were increased in normotensive women after exposure to nitrogen oxides (by 0.2%/5 units), sulfur dioxide (by 0.3%/1 unit), carbon monoxide and several air toxics (by 3%-4%/high exposure). The effects were often similar or stronger among women with gestational hypertension and preeclampsia. Exposure to particulate matter <10 MUm increased odds of high blood pressure in women with preeclampsia by 3%/5 units. CONCLUSIONS: Air pollution can influence admission blood pressure in term deliveries and may increase likelihood of preeclampsia screening at delivery admission. PMID- 24795405 TI - New organisation to accredit 'middle-tier' training in Europe. PMID- 24795409 TI - Additional round of testing for horsemeat. PMID- 24795410 TI - Sheep farmers warned of an early hatch of parasites. PMID- 24795411 TI - Contributions recognised at welfare awards. PMID- 24795412 TI - Coping with the conflicts associated with ending an animal's life. PMID- 24795413 TI - Veterinary medicines: product update. PMID- 24795414 TI - Should the tail wag the dog? PMID- 24795415 TI - Disinfection procedures and TB in cats. PMID- 24795416 TI - Bovine TB in goats. PMID- 24795417 TI - Removal of postnominals from the RCVS Register. PMID- 24795418 TI - Advanced practitioner status and old-style certificate holders. PMID- 24795419 TI - Prestun shocks and mis-stuns during conventional slaughter. PMID- 24795420 TI - Prestun shocks and mis-stuns during conventional slaughter. PMID- 24795429 TI - Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. AB - Glioblastoma multiforme (GBM) is one of the most aggressive human brain malignancies. Even with optimal treatment, median survival is less than 6 months for patients with recurrent GBM. Immune-based therapies have the potential to improve patient outcome by supplementing standard treatment. Expression of human cytomegalovirus (CMV) antigens in GBM tissues provides the unique opportunity to target viral antigens for GBM therapy. Here, we report findings of a formal clinical assessment of safety and potential clinical efficacy of autologous CMV specific T-cell therapy as a consolidative treatment for recurrent GBM. From a total of 19 patients with recurrent GBM, CMV-specific T cells were successfully expanded from 13 patients (68.4%), 11 of whom received up to four T-cell infusions. Combination therapy based on T-cell infusion and chemotherapy was well tolerated, and we detected only minor adverse events. The overall survival of these patients since first recurrence ranged from 133 to 2,428 days, with a median overall survival of 403 days. Most importantly, 4 of 10 patients that completed the treatment remained progression free during the study period. Furthermore, molecular profiling of CMV-specific T-cell therapy from these patients revealed distinct gene expression signatures, which correlated with their clinical response. Our study suggests that a combination therapy with autologous CMV-specific T cells and chemotherapy is a safe novel treatment option and may offer clinical benefit for patients with recurrent GBM. PMID- 24795430 TI - High-risk HPV16E6 stimulates hADA3 degradation by enhancing its SUMOylation. AB - Despite significant research, our understanding of the molecular mechanisms of Human Papilloma Virus (HPV) induced cancers remains incomplete. Majority of invasive cervical cancers are caused by high-risk HPV 16 and 18. Two potent HPV oncoproteins, E6 and E7, promote human malignancies by disrupting the activities of key regulators of cell proliferation and apoptosis. Recent investigations have identified hADA3, a transcriptional coactivator protein as a target of high-risk HPV16E6. However, the mechanism of degradation of hADA3 by E6 and its contribution in HPV induced carcinogenesis is poorly understood. Here, we showed that E6-mediated proteolysis of hADA3 is responsible for maintaining low levels of hADA3 in HPV-positive cervical cancer cell lines. We demonstrate that HPV16E6 targets hADA3 for ubiquitin-mediated degradation via E6AP ubiquitin ligase. We also show that hADA3 undergoes accelerated SUMOylation in the presence of HPV16E6. Our data represent the first evidence that hADA3 is posttranslationally modified by SUMOylation, which makes it unstable and establishes a link between SUMOylation and E6-mediated ubiquitination of hADA3. Furthermore, depletion of Ubc9 prevented rapid degradation of hADA3 in E6 expressing cervical cancer cells and overexpression of hADA3 resulted in suppression of proliferation and migration abilities of SiHa cells. Overall, this study underscores the importance of posttranslational modifications in HPV16E6-mediated downregulation of hADA3 thereby unveiling a novel mechanism by which HPV induces oncogenesis. PMID- 24795431 TI - Integrating pathology into human disease modelling--how to eat the elephant. AB - Mouse models are increasingly being used for the study of human disease, and the generation and functional characterisation of new models is underpinned by high throughput phenotyping consortia such as the International Mouse Phenotyping Consortium. A new study by Adissu and colleagues, published in Disease Models & Mechanisms, demonstrates the usefulness of histopathology in providing corroborative information and uncovering novel phenotypes in genetically modified mice in a high-throughput screen. Although pathology is recognised as a valuable tool to enhance our understanding of animal disease models, it has also been systematically under-resourced. This Editorial aims to highlight ways in which the gap between the usefulness of pathology and its perceived inaccessibility can be addressed by considering pragmatic solutions for planning, resourcing and accessing pathology expertise. The role of funding agencies, academic centres and journals in ensuring that the value of pathology is fully recognised and is adequately supported and funded is also discussed. PMID- 24795432 TI - Towards a systems-level understanding of aging and cancer: an interview with Dirk Bohmann. PMID- 24795433 TI - Restoring the balance: immunotherapeutic combinations for autoimmune disease. AB - Autoimmunity occurs when T cells, B cells or both are inappropriately activated, resulting in damage to one or more organ systems. Normally, high-affinity self reactive T and B cells are eliminated in the thymus and bone marrow through a process known as central immune tolerance. However, low-affinity self-reactive T and B cells escape central tolerance and enter the blood and tissues, where they are kept in check by complex and non-redundant peripheral tolerance mechanisms. Dysfunction or imbalance of the immune system can lead to autoimmunity, and thus elucidation of normal tolerance mechanisms has led to identification of therapeutic targets for treating autoimmune disease. In the past 15 years, a number of disease-modifying monoclonal antibodies and genetically engineered biologic agents targeting the immune system have been approved, notably for the treatment of rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although these agents represent a major advance, effective therapy for other autoimmune conditions, such as type 1 diabetes, remain elusive and will likely require intervention aimed at multiple components of the immune system. To this end, approaches that manipulate cells ex vivo and harness their complex behaviors are being tested in preclinical and clinical settings. In addition, approved biologic agents are being examined in combination with one another and with cell based therapies. Substantial development and regulatory hurdles must be overcome in order to successfully combine immunotherapeutic biologic agents. Nevertheless, such combinations might ultimately be necessary to control autoimmune disease manifestations and restore the tolerant state. PMID- 24795434 TI - Preferential attention to animals and people is independent of the amygdala. AB - The amygdala is thought to play a critical role in detecting salient stimuli. Several studies have taken ecological approaches to investigating such saliency, and argue for domain-specific effects for processing certain natural stimulus categories, in particular faces and animals. Linking this to the amygdala, neurons in the human amygdala have been found to respond strongly to faces and also to animals. However, the amygdala's necessary role for such category specific effects at the behavioral level remains untested. Here we tested four rare patients with bilateral amygdala lesions on an established change-detection protocol. Consistent with prior published studies, healthy controls showed reliably faster and more accurate detection of people and animals, as compared with artifacts and plants. So did all four amygdala patients: there were no differences in phenomenal change blindness, in behavioral reaction time to detect changes or in eye-tracking measures. The findings provide decisive evidence against a critical participation of the amygdala in rapid initial processing of attention to animate stimuli, suggesting that the necessary neural substrates for this phenomenon arise either in other subcortical structures (such as the pulvinar) or within the cortex itself. PMID- 24795435 TI - Heritability of the neural response to emotional pictures: evidence from ERPs in an adult twin sample. AB - Affect-modulated event-related potentials (ERPs) are increasingly used to study psychopathology and individual differences in emotion processing. Many have suggested that variation in these neural responses reflects genetically mediated risk. However, to date, no studies have demonstrated genetic contributions to affect-modulated ERPs. The present study therefore sought to examine the heritability of a range of ERPs elicited during affective picture viewing. One hundred and thirty monozygotic and 124 dizygotic twin pairs passively viewed 30 pleasant, 30 neutral and 30 unpleasant images for 6 s each. The early posterior negativity was scored for each subject; in addition, the P300/late positive potential (LPP) was scored in multiple time windows and sites. Results indicate that the centro-parietal P300 (occurring between 300 and 600 ms) is subject to substantial genetic contributions. Furthermore, variance in the P300 elicited by affective stimuli was moderately heritable even after controlling for the P300 elicited by neutral stimuli. Later and more frontal activation (i.e. between 1000 and 3000 ms) also showed evidence of heritablity. Early parietal, and perhaps later frontal portions of the P300/LPP complex, may therefore represent promising neurobehavioral markers of genetically influenced processing of emotional information. PMID- 24795436 TI - The neural correlates of emotion alignment in social interaction. AB - Talking about emotion and sharing emotional experiences is a key component of human interaction. Specifically, individuals often consider the reactions of other people when evaluating the meaning and impact of an emotional stimulus. It has not yet been investigated, however, how emotional arousal ratings and physiological responses elicited by affective stimuli are influenced by the rating of an interaction partner. In the present study, pairs of participants were asked to rate and communicate the degree of their emotional arousal while viewing affective pictures. Strikingly, participants adjusted their arousal ratings to match up with their interaction partner. In anticipation of the affective picture, the interaction partner's arousal ratings correlated positively with activity in anterior insula and prefrontal cortex. During picture presentation, social influence was reflected in the ventral striatum, that is, activity in the ventral striatum correlated negatively with the interaction partner's ratings. Results of the study show that emotional alignment through the influence of another person's communicated experience has to be considered as a complex phenomenon integrating different components including emotion anticipation and conformity. PMID- 24795437 TI - Fear across the senses: brain responses to music, vocalizations and facial expressions. AB - Intrinsic emotional expressions such as those communicated by faces and vocalizations have been shown to engage specific brain regions, such as the amygdala. Although music constitutes another powerful means to express emotions, the neural substrates involved in its processing remain poorly understood. In particular, it is unknown whether brain regions typically associated with processing 'biologically relevant' emotional expressions are also recruited by emotional music. To address this question, we conducted an event-related functional magnetic resonance imaging study in 47 healthy volunteers in which we directly compared responses to basic emotions (fear, sadness and happiness, as well as neutral) expressed through faces, non-linguistic vocalizations and short novel musical excerpts. Our results confirmed the importance of fear in emotional communication, as revealed by significant blood oxygen level-dependent signal increased in a cluster within the posterior amygdala and anterior hippocampus, as well as in the posterior insula across all three domains. Moreover, subject specific amygdala responses to fearful music and vocalizations were correlated, consistent with the proposal that the brain circuitry involved in the processing of musical emotions might be shared with the one that have evolved for vocalizations. Overall, our results show that processing of fear expressed through music, engages some of the same brain areas known to be crucial for detecting and evaluating threat-related information. PMID- 24795438 TI - Pubertal testosterone influences threat-related amygdala-orbitofrontal cortex coupling. AB - Growing evidence indicates that normative pubertal maturation is associated with increased threat reactivity, and this developmental shift has been implicated in the increased rates of adolescent affective disorders. However, the neural mechanisms involved in this pubertal increase in threat reactivity remain unknown. Research in adults indicates that testosterone transiently decreases amygdala-orbitofrontal cortex (OFC) coupling. Consequently, we hypothesized that increased pubertal testosterone disrupts amygdala-OFC coupling, which may contribute to developmental increases in threat reactivity in some adolescents. Hypotheses were tested in a longitudinal study by examining the impact of testosterone on functional connectivity. Findings were consistent with hypotheses and advance our understanding of normative pubertal changes in neural systems instantiating affect/motivation. Finally, potential novel insights into the neurodevelopmental pathways that may contribute to adolescent vulnerability to behavioral and emotional problems are discussed. PMID- 24795439 TI - Using 'hug drugs' to understand affiliative behavior: the value of the social neurochemistry perspective. Commentary on: 'Ecstasy' as a social drug: MDMA preferentially affects responses to emotional stimuli with social content by Wardle, Kirkpatrick, and de Wit (2014). PMID- 24795440 TI - Multimodal frontostriatal connectivity underlies individual differences in self esteem. AB - A heightened sense of self-esteem is associated with a reduced risk for several types of affective and psychiatric disorders, including depression, anxiety and eating disorders. However, little is known about how brain systems integrate self referential processing and positive evaluation to give rise to these feelings. To address this, we combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to test how frontostriatal connectivity reflects long term trait and short-term state aspects of self-esteem. Using DTI, we found individual variability in white matter structural integrity between the medial prefrontal cortex and the ventral striatum was related to trait measures of self esteem, reflecting long-term stability of self-esteem maintenance. Using fMRI, we found that functional connectivity of these regions during positive self evaluation was related to current feelings of self-esteem, reflecting short-term state self-esteem. These results provide convergent anatomical and functional evidence that self-esteem is related to the connectivity of frontostriatal circuits and suggest that feelings of self-worth may emerge from neural systems integrating information about the self with positive affect and reward. This information could potentially inform the etiology of diminished self-esteem underlying multiple psychiatric conditions and inform future studies of evaluative self-referential processing. PMID- 24795441 TI - 'Why should I care?' Challenging free will attenuates neural reaction to errors. AB - Whether human beings have free will has been a philosophical question for centuries. The debate about free will has recently entered the public arena through mass media and newspaper articles commenting on scientific findings that leave little to no room for free will. Previous research has shown that encouraging such a deterministic perspective influences behavior, namely by promoting cursory and antisocial behavior. Here we propose that such behavioral changes may, at least partly, stem from a more basic neurocognitive process related to response monitoring, namely a reduced error detection mechanism. Our results show that the error-related negativity, a neural marker of error detection, was reduced in individuals led to disbelieve in free will. This finding shows that reducing the belief in free will has a specific impact on error detection mechanisms. More generally, it suggests that abstract beliefs about intentional control can influence basic and automatic processes related to action control. PMID- 24795442 TI - Life stress in adolescence predicts early adult reward-related brain function and alcohol dependence. AB - Stressful life events increase vulnerability to problematic alcohol use, and they may do this by disrupting reward-related neural circuitry. This is particularly relevant for adolescents because alcohol use rises sharply after mid-adolescence and alcohol abuse peaks at age 20. Adolescents also report more stressors compared with children, and neural reward circuitry may be especially vulnerable to stressors during adolescence because of prefrontal cortex remodeling. Using a large sample of male participants in a longitudinal functional magnetic resonance imaging study (N = 157), we evaluated whether cumulative stressful life events between the ages of 15 and 18 were associated with reward-related brain function and problematic alcohol use at age 20 years. Higher cumulative stressful life events during adolescence were associated with decreased response in the medial prefrontal cortex (mPFC) during monetary reward anticipation and following the receipt of monetary rewards. Stress-related decreases in mPFC response during reward anticipation and following rewarding outcomes were associated with the severity of alcohol dependence. Furthermore, mPFC response mediated the association between stressful life events and later symptoms of alcohol dependence. These data are consistent with neurobiological models of addiction that propose that stressors during adolescence increase risk for problematic alcohol use by disrupting reward circuit function. PMID- 24795445 TI - Intussusception risk increased after rotavirus vaccination but outweighed by benefits. PMID- 24795443 TI - The quality of adolescents' peer relationships modulates neural sensitivity to risk taking. AB - Adolescents' peer culture plays a key role in the development and maintenance of risk-taking behavior. Despite recent advances in developmental neuroscience suggesting that peers may increase neural sensitivity to rewards, we know relatively little about how the quality of peer relations impact adolescent risk taking. In the current 2-year three-wave longitudinal study, we examined how chronic levels of peer conflict relate to risk taking behaviorally and neurally, and whether this is modified by high-quality peer relationships. Forty-six adolescents completed daily diaries assessing peer conflict across 2 years as well as a measure of peer support. During a functional brain scan, adolescents completed a risk-taking task. Behaviorally, peer conflict was associated with greater risk-taking behavior, especially for adolescents reporting low peer support. High levels of peer support buffered this association. At the neural level, peer conflict was associated with greater activation in the striatum and insula, especially among adolescents reporting low peer support, whereas this association was buffered for adolescents reporting high peer support. Results are consistent with the stress-buffering model of social relationships and underscore the importance of the quality of adolescents' peer relationships for their risk taking. PMID- 24795444 TI - Damage to the default mode network disrupts autobiographical memory retrieval. AB - Functional neuroimaging studies have implicated the default mode network (DMN) in autobiographical memory (AM). Convergent evidence from a lesion approach would help clarify the role of the DMN in AM. In this study, we used a voxelwise lesion deficit approach to test the hypothesis that regions of the DMN are necessary for AM. We also explored whether the neural correlates of semantic AM (SAM) and episodic AM (EAM) were overlapping or distinct. Using the Iowa Autobiographical Memory Questionnaire, we tested AM retrieval in 92 patients with focal, stable brain lesions. In support of our hypothesis, damage to regions within the DMN (medial prefrontal cortex, mPFC; posterior cingulate cortex, PCC; inferior parietal lobule, IPL; medial temporal lobe, MTL) was associated with AM impairments. Within areas of effective lesion coverage, the neural correlates of SAM and EAM were largely distinct, with limited areas of overlap in right IPL. Whereas SAM deficits were associated with left mPFC and MTL damage, EAM deficits were associated with right mPFC and MTL damage. These results provide novel neuropsychological evidence for the necessary role of parts of the DMN in AM. More broadly, the findings shed new light on how the DMN participates in self referential processing. PMID- 24795446 TI - Origin of hepatitis C virus genotype 3 in Africa as estimated through an evolutionary analysis of the full-length genomes of nine subtypes, including the newly sequenced 3d and 3e. AB - We characterized the full-length genomes of nine hepatitis C virus genotype 3 (HCV-3) isolates: QC7, QC8, QC9, QC10, QC34, QC88, NE145, NE274 and 811. To the best of our knowledge, NE274 and NE145 were the first full-length genomes for confirming the provisionally assigned subtypes 3d and 3e, respectively, whereas 811 represented the first HCV-3 isolate that had its extreme 3' UTR terminus sequenced. Based on these full-length genomes, together with 42 references representing eight assigned subtypes and an unclassified variant of HCV-3, and 10 sequences of six other genotypes, a timescaled phylogenetic tree was reconstructed after an evolutionary analysis using a coalescent Bayesian procedure. The results indicated that subtypes 3a, 3d and 3e formed a subset with a common ancestor dated to ~202.89 [95% highest posterior density (HPD): 160.11, 264.6] years ago. The analysis of all of the HCV-3 sequences as a single lineage resulted in the dating of the divergence time to ~457.81 (95% HPD: 350.62, 587.53) years ago, whereas the common ancestor of all of the seven HCV genotypes dated to ~780.86 (95% HPD: 592.15, 1021.34) years ago. As subtype 3h and the unclassified variant were relatives, and represented the oldest HCV-3 lineages with origins in Africa and the Middle East, these findings may indicate the ancestral origin of HCV-3 in Africa. We speculate that the ancestral HCV-3 strains may have been brought to South Asia from Africa by land and/or across the sea to result in its indigenous circulation in that region. The spread was estimated to have occurred in the era after Vasco da Gama had completed his expeditions by sailing along the eastern coast of Africa to India. However, before this era, Arabians had practised slave trading from Africa to the Middle East and South Asia for centuries, which may have mediated the earliest spread of HCV-3. PMID- 24795447 TI - Hepatitis E virus (HEV) protease: a chymotrypsin-like enzyme that processes both non-structural (pORF1) and capsid (pORF2) protein. AB - Hepatitis E virus (HEV), a major cause of acute viral hepatitis across the world, is a non-enveloped, plus-strand RNA virus. Its genome codes three proteins, pORF1 (multifunctional polyprotein), pORF2 (capsid protein) and pORF3 (multi-regulatory protein). pORF1 encodes methyltransferase, putative papain-like cysteine protease, helicase and replicase enzymes. Of these, the protease domain has not been characterized. On the basis of sequence analysis, we cloned and expressed a protein covering aa 440-610 of pORF1, expression of which led to cell death in Escherichia coli BL-21 and Huh7 hepatoma cells. Finally, we expressed and purified this protein from E. coli C43 cells (resistant to toxic proteins). The refolded form of this protein showed protease activity in gelatin zymography. Digestion assays showed cleavage of both pORF1 and pORF2 as observed previously. MS revealed digestion of capsid protein at both the N and C termini. N-terminal sequencing of the ~35 kDa methyltransferase, ~35 kDa replicase and ~56 kDa pORF2 proteins released by protease digestion revealed that the cleavage sites were alanine15/isoleucine16, alanine1364/valine1365 in pORF1 and leucine197/valine198 in pORF2. Specificity of these cleavage sites was validated by site-directed mutagenesis. Further characterization of the HEV protease, carried out using twelve inhibitors, showed chymostatin and PMSF to be the most efficient inhibitors, indicating this protein as a chymotrypsin-like protease. The specificity was further confirmed by cleavage of the chymotrypsin-specific fluorogenic peptide N-succinyl-Leu-Leu-Val-Tyr-7-amido-4-methylcoumarin. Mutational analysis of the conserved serine/cysteine/histidine residues suggested that H443 and C472/C481/C483 are possibly the active site residues. To our knowledge, this is the first direct demonstration of HEV protease and its function. PMID- 24795448 TI - The 2014 Ebola virus disease outbreak in West Africa. AB - On 23 March 2014, the World Health Organization issued its first communique on a new outbreak of Ebola virus disease (EVD), which began in December 2013 in Guinee Forestiere (Forested Guinea), the eastern sector of the Republic of Guinea. Located on the Atlantic coast of West Africa, Guinea is the first country in this geographical region in which an outbreak of EVD has occurred, leaving aside the single case reported in Ivory Coast in 1994. Cases have now also been confirmed across Guinea as well as in the neighbouring Republic of Liberia. The appearance of cases in the Guinean capital, Conakry, and the transit of another case through the Liberian capital, Monrovia, presents the first large urban setting for EVD transmission. By 20 April 2014, 242 suspected cases had resulted in a total of 147 deaths in Guinea and Liberia. The causative agent has now been identified as an outlier strain of Zaire Ebola virus. The full geographical extent and degree of severity of the outbreak, its zoonotic origins and its possible spread to other continents are sure to be subjects of intensive discussion over the next months. PMID- 24795449 TI - Impact of maraviroc-resistant and low-CCR5-adapted mutations induced by in vitro passage on sensitivity to anti-envelope neutralizing antibodies. AB - The aim of this study was to generate maraviroc (MVC)-resistant viruses in vitro using a human immunodeficiency virus type 1 subtype B clinical isolate (HIV-1KP 5) to understand the mechanism(s) of resistance to MVC. To select HIV-1 variants resistant to MVC in vitro, we exposed high-chemokine (C-C motif) receptor 5 (CCR5)-expressing PM1/CCR5 cells to HIV-1KP-5 followed by serial passage in the presence of MVC. We also passaged HIV-1KP-5 in PM1 cells, which were low CCR5 expressing to determine low-CCR5-adapted substitutions and compared the Env sequences of the MVC-selected variants. Following 48 passages with MVC (10 uM), HIV-1KP-5 acquired a resistant phenotype [maximal per cent inhibition (MPI) 24%], whilst the low-CCR5-adapted variant had low sensitivity to MVC (IC50 ~200 nM), but not reduction of the MPI. The common substitutions observed in both the MVC selected and low-CCR5-adapted variants were selected from the quasi-species, in V1, V3 and V5. After 14 passages, the MVC-selected variants harboured substitutions around the CCR5 N-terminal-binding site and V3 (V200I, T297I, K305R and M434I). The low-CCR5-adapted infectious clone became sensitive to anti-CD4bs and CD4i mAbs, but not to anti-V3 mAb and autologous plasma IgGs. Conversely, the MVC-selected clone became highly sensitive to the anti-envelope (Env) mAbs tested and the autologous plasma IgGs. These findings suggest that the four MVC resistant mutations required for entry using MVC-bound CCR5 result in a conformational change of Env that is associated with a phenotype sensitive to anti-Env neutralizing antibodies. PMID- 24795451 TI - Heterozygote Advantage in a Finite Population: Black Color in Wolves. AB - There is a striking color polymorphism for wolves in the Yellowstone National Park where approximately half the wolves are black. The genetic basis for this polymorphism is known, and fitnesses of the genotypes are estimated. These estimates suggest that there is strong heterozygote advantage but substantial asymmetry in the fitness differences of the 2 homozygotes. Theoretically, such fitnesses in a finite population are thought to reduce genetic variation at least as fast as if there were no selection at all. Because the color polymorphism has remained at about the same frequency for 17 years, about 4 generations, we investigated whether this was consistent with the theoretical predictions. Counter to this general expectation of loss, given the initial frequency of black wolves, the theoretical expectation in this case was found to be that the frequency would only decline slowly over time. For example, if the effective population size is 20, then the expected black allele frequency after 4 generations would be 0.191, somewhat less than the observed value of 0.237. However, nearly 30% of the time the expected frequency is 0.25 or greater, consistent with the contemporary observed frequency. In other words and in contrast to general theoretical predictions, because of the short period of time in evolutionary terms and the relatively weak selection at low frequencies, the observed variation and the predicted theoretical variation are not inconsistent. PMID- 24795452 TI - Increased peripheral IL-4 leads to an expanded virtual memory CD8+ population. AB - Memory-phenotype CD8(+) T cells can arise even in the absence of overt Ag stimulation. Virtual memory (VM) CD8(+) T cells are CD8(+) T cells that develop a memory phenotype in the periphery of wild-type mice in an IL-15-dependent manner. Innate CD8(+) T cells, in contrast, are memory-phenotype CD8(+) T cells that develop in the thymus in response to elevated thymic IL-4. It is not clear whether VM cells and innate CD8(+) T cells represent two independent T cell lineages or whether they arise through similar processes. In this study, we use mice deficient in Nedd4-family interacting protein 1 to show that overproduction of IL-4 in the periphery leads to an expanded VM population. Nedd4-family interacting protein 1(-/-) CD4(+) T cells produce large amounts of IL-4 due to a defect in JunB degradation. This IL-4 induces a memory-like phenotype in peripheral CD8(+) T cells that includes elevated expression of CD44, CD122, and Eomesodermin and decreased expression of CD49d. Thus, our data show that excess peripheral IL-4 is sufficient to cause an increase in the VM population. Our results suggest that VM and innate CD8(+) T cells may be more similar than previously appreciated. PMID- 24795453 TI - Myeloid glycosylation defects lead to a spontaneous common variable immunodeficiency-like condition with associated hemolytic anemia and antilymphocyte autoimmunity. AB - Common variable immunodeficiency (CVID), the most frequent symptomatic primary immune deficiency in humans, is a heterogeneous group of immunologic disorders estimated to affect 1:10,000-1:50,000. Although a clear disease etiology remains elusive, a common characteristic of CVID is deficient IgG Ab production in response to infection or vaccination. Patients often also exhibit autoimmune cytopenias with symptoms of abnormal T cell function, including reductions in naive T cells, which correlate with clinical severity. In this study, we discovered that targeted alterations in the glycome of the myeloid lineage lead to spontaneous immunodeficiency characteristic of both humoral and T cell dysfunction regularly found in human CVID. Mice carrying a myeloid-specific knockout of the Mgat2 gene encoding UDP-GlcNAc:alpha-6-d-mannoside beta-1,2-N acetylglucosaminyltransferase II enzyme exhibit deficiencies in IgG responses to both protein and polysaccharide conjugate vaccines. Interestingly, the immunodeficiency is associated with decreased T cell activity because of a persistent autoimmune-mediated depletion of naive T cells, which is induced by changes in erythrocyte surface glycosylation. The N-glycosylation dependent autoepitopes that emerge on erythrocytes lead to autoimmune hemolytic anemia, and the causative auto-IgM cross-reacts with naive T cells despite the lack of glycan change on T cells. These findings demonstrate that alterations in erythrocyte glycosylation trigger the development of autoantibodies directed at both erythrocytes and naive T cells, revealing a possible mechanistic link between the induction of autoimmune hemolytic anemia, the reduction in naive T cells, and poor Ab responses to vaccine in severe CVID patients. PMID- 24795454 TI - KIR/HLA interactions negatively affect rituximab- but not GA101 (obinutuzumab) induced antibody-dependent cellular cytotoxicity. AB - Ab-dependent cellular cytotoxicity (ADCC) mediated by NK cells is regulated by inhibitory killer cell Ig-like receptors (KIRs), which interact with target cell HLA class I. We analyzed how KIR/HLA interactions influence ADCC induced by rituximab and by GA101, a novel type II CD20 Ab glycoengineered for increased FcgRIII binding and ADCC capacity. We found that KIR/HLA interactions strongly and selectively inhibit rituximab-induced in vitro ADCC toward target cells expressing cognate HLA KIR ligands. NK cells of donors carrying all three ligands to inhibitory KIR showed weak activation and target cell depletion capacity when incubated with rituximab and KIR-ligand matched target B cells. In contrast, NK cells from individuals missing one or more KIR ligands activated more strongly and depleted KIR ligand-matched target B cells more efficiently in the presence of rituximab. NK cells expressing a KIR for which the ligand was absent were the main effectors of ADCC in these donors. Notably, the influence of KIR/HLA interactions on NK cell activation was synergistic with the effect of the V158F FCGR3A single nucleotide polymorphism. In contrast, GA101 induced activation of NK cells irrespective of inhibitory KIR expression, and efficiency of target cell depletion was not negatively affected by KIR/HLA interactions. These data show that modification of the Fc fragment to enhance ADCC can be an effective strategy to augment the efficacy of therapeutic mAbs by recruiting NK cells irrespective of their inhibitory KIR expression. PMID- 24795455 TI - Critical role for the NLRP3 inflammasome during acute lung injury. AB - The inflammasome is a key factor in innate immunity and senses soluble pathogen and danger-associated molecular patterns as well as biological crystals (urate, cholesterol, etc.), resulting in expression of IL-1beta and IL-18. Using a standard model of acute lung injury (ALI) in mice featuring airway instillation of LPS, ALI was dependent on availability of NLRP3 as well as caspase-1, which are known features of the NLRP3 inflammasome. The appearance of IL-1beta, a product of NLRP3 inflammasome activation, was detected in bronchoalveolar lavage fluids (BALF) in a macrophage- and neutrophil-dependent manner. Neutrophil derived extracellular histones appeared in the BALF during ALI and directly activated the NLRP3 inflammasome. Ab-mediated neutralization of histones significantly reduced IL-1beta levels in BALF during ALI. Inflammasome activation by extracellular histones in LPS-primed macrophages required NLRP3 and caspase-1 as well as extrusion of K(+), increased intracellular Ca(2+) concentration, and generation of reactive oxygen species. NLRP3 and caspase-1 were also required for full extracellular histone presence during ALI, suggesting a positive feedback mechanism. Extracellular histone and IL-1beta levels in BALF were also elevated in C5a-induced and IgG immune complex ALI models, suggesting a common inflammatory mechanism. These data indicate an interaction between extracellular histones and the NLRP3 inflammasome, resulting in ALI. Such findings suggest novel targets for treatment of ALI, for which there is currently no known efficacious drug. PMID- 24795458 TI - S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes. AB - Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10- and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment. PMID- 24795457 TI - Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes. AB - Peptides that bind poorly to MHC class I molecules often elicit low-functional avidity T cell responses. Peptide modification by altering the anchor residue facilitates increased binding affinity and may elicit T cells with increased functional avidity toward the native epitope ("heteroclitic"). This augmented MHC binding is likely to increase the half-life and surface density of the heteroclitic complex, but precisely how this enhanced T cell response occurs in vivo is not known. Furthermore, the ideal heteroclitic epitope will elicit T cell responses that completely cross-react with the native epitope, maximizing protection and minimizing undesirable off-target effects. Such epitopes have been difficult to identify. In this study, using mice infected with a murine coronavirus that encodes epitopes that elicit high (S510, CSLWNGPHL)- and low (S598, RCQIFANI)-functional avidity responses, we show that increased expression of peptide S598 but not S510 generated T cells with enhanced functional avidity. Thus, immune responses can be augmented toward T cell epitopes with low functional avidity by increasing Ag density. We also identified a heteroclitic epitope (RCVIFANI) that elicited a T cell response with nearly complete cross reactivity with native epitope and demonstrated increased MHC/peptide abundance compared with native S598. Structural and thermal melt analyses indicated that the Q600V substitution enhanced stability of the peptide/MHC complex without greatly altering the antigenic surface, resulting in highly cross-reactive T cell responses. Our data highlight that increased peptide/MHC complex display contributes to heteroclitic epitope efficacy and describe parameters for maximizing immune responses that cross-react with the native epitope. PMID- 24795459 TI - Bored teenagers. PMID- 24795456 TI - Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. AB - Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8(+) T cells. This cross presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum-golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8(+) T cells. Finally, Ag-specific CD8(+) T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8(+) T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node-resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags. PMID- 24795460 TI - The epiknowledge of socially responsible innovation. PMID- 24795461 TI - The wicked problem of socially responsible innovation. PMID- 24795462 TI - Why we still need grant peer review. PMID- 24795463 TI - Response: "Why we still need grant peer review". PMID- 24795464 TI - ICAM-1: isoforms and phenotypes. AB - ICAM-1 plays an important role in leukocyte trafficking, immunological synapse formation, and numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane-bound and soluble ICAM-1 isoforms that arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types are poorly understood. In the generation of ICAM-1-deficient mice, two isoform deficient ICAM-1 mutants were inadvertently produced as a result of alternative splicing. These mice, along with true ICAM-1-deficient mice and newly generated ICAM-1-transgenic mice, have provided the opportunity to begin examining the role of ICAM-1 isoforms (singly or in combination) in various disease settings. In this review, we highlight the sharply contrasting disease phenotypes using ICAM-1 isoform mutant mice. These studies demonstrate that ICAM-1 immunobiology is highly complex but that individual isoforms, aside from the full-length molecule, make significant contributions to disease development and pathogenesis. PMID- 24795465 TI - Check MAIT. AB - The evolutionary conservation of T lymphocyte subsets bearing alphabeta TCRs using invariant alpha-chains is indicative of unique and important functions. Among these T lymphocytes, NKT cells that express an invariant TCRalpha-chain and recognize lipid Ags presented by the nonclassical MHC class I molecule CD1d are probably the most studied. However, a new population of evolutionarily conserved T cells with another invariant TCRalpha rearrangement was recently characterized. These cells, which are very abundant in humans, tend to reside in mucosal tissues and, therefore, were named mucosal-associated invariant T (MAIT) cells. Until recently, little was known about MAIT cells; however, several recent advances in our understanding of MAIT cell characteristics and functions secure their upcoming rise to fame in the immunology field and in clinical practice. PMID- 24795470 TI - Primary human cytomegalovirus infection induces the expansion of virus-specific activated and atypical memory B cells. AB - BACKGROUND: Although neutralizing antibodies play a central role in the control of cytomegalovirus (CMV) dissemination, little is known about the response of B lymphocytes to primary human CMV infection. METHODS: The proportion, phenotype, specificity, and functionality of B-cell subsets were studied in a cohort of pregnant women with primary CMV infection. CMV-seronegative pregnant women, as well as CMV-seronegative and CMV-seropositive healthy adults, were included as controls. RESULTS: Primary CMV infection was associated with a sustained expansion of activated (CD27(+)CD20(+)CD21(low)) and atypical (CD27( )CD20(+)CD21(low)) memory B cells (MBCs). Both subsets expressed an effector phenotype, and their proportions were correlated with viremia. Activated MBCs expressed high levels of activation markers and included high frequencies of tumor necrosis alpha (TNF-alpha)-producing cells, whereas atypical MBCs expressed high levels of inhibitory receptors and had low TNF-alpha responses. Fluorescent labeled antigen experiments indicated that activated and atypical MBCs were enriched in CMV-specific cells. CONCLUSIONS: Primary CMV infection mobilizes a large pool of memory B cells that includes activated and atypical MBCs. The functional regulation of CMV-specific MBCs may limit the production of antibodies and the control of viral dissemination. PMID- 24795471 TI - Point of care testing for malaria using LAMP, loop mediated isothermal amplification. PMID- 24795472 TI - Limitations of staphylokinase as a marker for Staplylococcus aureus invasive infections in humans. PMID- 24795474 TI - A new approach to mitigate biofilm formation on totally implantable venous access ports. PMID- 24795473 TI - Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. AB - BACKGROUND: Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV) infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events. METHODS: We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders. RESULTS: Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes. CONCLUSIONS: Interventional trials to decrease the incidence of non AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137. PMID- 24795476 TI - Interleukin 10 (IL-10)-producing CD1dhi regulatory B cells from Schistosoma haematobium-infected individuals induce IL-10-positive T cells and suppress effector T-cell cytokines. AB - BACKGROUND: Chronic schistosome infections are associated with T-cell hyporesponsiveness and a strong regulatory network. Murine studies have shown that schistosome infections can induce regulatory CD1d(hi) B cells, which inhibit inflammatory responses. Here, we evaluated the influence of regulatory B cells (Bregs) on T-cell cytokines in vitro in human schistosomiasis. METHODS: Gabonese young adults were recruited from areas where Schistosoma haematobium (S.h) infections were high or low endemic. The study participants were categorized as infected or uninfected from an high endemic area or uninfected from a low endemic (nonendemic) area. Their B cells were studied for Breg subset markers and cocultured with allogenic anti-CD3-stimulated CD4(+) T cells, followed by T-cell cytokine analysis. RESULTS: A greater percentage of B cells from S. haematobium infected donors expressed cytoplasmic interleukin 10 (IL-10) and membrane-bound latency-associated peptide/transforming growth factor beta1, compared with uninfected donors. T cells produced less interferon gamma, interleukin 4, and interleukin 17 upon coculture with B cells from schistosome-infected individuals only, while the conversion to CD25(hi)FoxP3(+) and the percentage of IL-10(+) T cells was enhanced. Interestingly, depletion of the prominent IL-10-producing B cell subset, CD1d(hi) cells, resulted in less IL-10(+) T cells in the S. haematobium-infected group, while levels of FoxP3(+) regulatory T cells remained unaffected. CONCLUSIONS: Schistosomes can induce functional Bregs in humans that may be instrumental in general T-cell hyporesponsiveness and may contribute to the increased regulatory milieu found in schistosomiasis. PMID- 24795475 TI - Impact of body mass index on immunogenicity of pandemic H1N1 vaccine in children and adults. AB - Obesity emerged as a risk factor for morbidity and mortality related to 2009 pandemic influenza A (H1N1) infection. However, few studies examine the immune responses to H1N1 vaccine among children and adults of various body mass indices (BMI). Pooling data from 3 trials of unadjuvanted split-virus H1N1 A/California/07/2009 influenza vaccines, we analyzed serologic responses of participants stratified by BMI grouping. A single vaccine dose produced higher hemagglutination inhibition antibody titers at day 21 in obese compared to nonobese adults, but there were no significant differences in responses to H1N1 vaccine among children or adults of various BMI following 2 doses. PMID- 24795477 TI - Reply to Bouchiat et al. PMID- 24795478 TI - Identification of a novel polyomavirus in a pancreatic transplant recipient with retinal blindness and vasculitic myopathy. AB - BACKGROUND: A 33 year-old pancreatic transplant recipient developed weakness, retinal blindness, and necrotic plaques on her face, scalp, and hands. METHODS: A muscle biopsy was analyzed by light and electron microscopy and high-throughput nucleic acid sequencing. RESULTS: The biopsy revealed microthrombosis and viral particles in swollen endothelial cell nuclei. High-throughput sequencing of nucleic acid revealed a novel polyomavirus. In situ hybridization confirmed the presence of the polyomavirus in endothelial cells at sites of myositis and cutaneous necrosis. CONCLUSIONS: New Jersey polyomavirus (NJPyV-2013) is a novel polyomavirus that may have tropism for vascular endothelial cells. PMID- 24795479 TI - Preventing biofilm formation and associated occlusion by biomimetic glycocalyxlike polymer in central venous catheters. AB - The use of catheters and other implanted devices is constantly increasing in modern medicine. Although catheters improve patients' healthcare, the hydrophobic nature of their surface material promotes protein adsorption and cell adhesion. Catheters are therefore prone to complications, such as colonization by bacterial and fungal biofilms, associated infections, and thrombosis. Here we describe the in vivo efficacy of biologically inspired glycocalyxlike antiadhesive coatings to inhibit Staphylococcus aureus and Pseudomonas aeruginosa colonization on commercial totally implantable venous access ports (TIVAPs) in a clinically relevant rat model of biofilm infection. Although noncoated TIVAPs implanted in rats were heavily colonized by the 2 biofilm-forming pathogens with a high percentage of occlusion, coating TIVAPs reduced their initial adherence and subsequently led to 4-log reduction in biofilm formation and reduced occlusion. Our antiadhesive approach is a simple and generalizable strategy that could be used to minimize clinical complications associated with the use of implantable medical devices. PMID- 24795480 TI - Field evaluation of a real-time fluorescence loop-mediated isothermal amplification assay, RealAmp, for the diagnosis of malaria in Thailand and India. AB - BACKGROUND: To eliminate malaria, surveillance for submicroscopic infections is needed. Molecular methods can detect submicroscopic infections but have not hitherto been amenable to implementation in surveillance programs. A portable loop-mediated isothermal amplification assay called RealAmp was assessed in 2 areas of low malaria transmission. METHODS: RealAmp was evaluated in 141 patients from health clinics in India (passive surveillance) and in 127 asymptomatic persons in Thailand (active surveillance). The diagnostic validity, precision, and predictive value of RealAmp were determined using polymerase chain reaction (PCR) as the reference method. A pilot study of RealAmp was also performed on samples from patients presenting at a Thai health center. RESULTS: A total of 96 and 7 positive cases were detected in India and Thailand, respectively, via PCR. In comparison with nested PCR, the sensitivity and specificity of RealAmp in India were 94.8% (95% confidence interval [CI], 88.3%-98.3%) and 100% (95% CI, 92.1%-100%), respectively, with correct identification of all 5 Plasmodium vivax cases. In Thailand, compared with pooled real-time PCR, RealAmp demonstrated 100% sensitivity (95% CI, 59.0%-100%) and 96.7% specificity (95% CI, 91.7%-99.1%). Testing at the health center demonstrated RealAmp's potential to serve as a point of-care test with results available in 30-75 minutes. CONCLUSION: RealAmp was comparable to PCR in detecting malaria parasites and shows promise as a tool to detect submicroscopic infections in malaria control and elimination programs worldwide. PMID- 24795481 TI - HIV-1 infection and antibodies to Plasmodium falciparum in adults. AB - BACKGROUND: Coinfection with human immunodeficiency virus (HIV) may increase susceptibility to malaria by compromising naturally acquired immunity. METHODS: In 339 adults (64% HIV infected), we measured antibodies to Plasmodium falciparum variant surface antigens (VSA) and antibodies that opsonise infected erythrocytes using parasite lines FCR3, E8B, and R29, and antibodies to merozoite antigens AMA 1 and MSP2. We determined the relationship between malaria antibodies, HIV infection, markers of immune compromise, and risk of incident parasitemia. RESULTS: HIV-infected adults had significantly lower mean levels of opsonizing antibody to all parasite lines (P < .0001), and lower levels of antibody to AMA-1 (P = .01) and MSP2 (P < .0001). Levels of immunoglobulin G (IgG) to VSA were not affected by HIV status. Opsonising antibody titres against some isolates were positively correlated with CD4 count. There were negative associations between human immunodeficiency virus type 1 (HIV-1) viral load and opsonizing antibodies to FCR3 (P = .04), and levels of IgG to AMA-1 (P <= .03) and MSP2-3D7 (P = .05). Lower opsonizing antibody levels on enrollment were seen in those who became parasitemic during follow-up, independent of HIV infection (P <= .04 for each line). CONCLUSIONS: HIV-1 infection decreases opsonizing antibodies to VSA, and antibody to merozoite antigens. Opsonizing antibodies were associated with lack of parasitemia during follow up, suggesting a role in protection. PMID- 24795482 TI - A novel I221L substitution in neuraminidase confers high-level resistance to oseltamivir in influenza B viruses. AB - Influenza B viruses with a novel I221L substitution in neuraminidase (NA) conferring high-level resistance to oseltamivir were isolated from an immunocompromised patient after prolonged oseltamivir treatment. METHODS: Enzymatic characterization of the NAs (Km, Ki) and the in vitro fitness of viruses carrying wild-type or mutated (I221L) NA genes were evaluated. Proportions of wild-type and mutated NA genes were directly quantified in the patient samples. Structural characterizations by X-ray crystallography of a wild type and I221L variant NA were performed. RESULTS: The Km and Ki revealed that the I221L variant NA had approximately 84 and 51 times lower affinity for oseltamivir carboxylate and zanamivir, respectively, compared with wild-type NA. Viruses with a wild-type or I221L variant NA had similar growth kinetics in Madin Darby canine kidney (MDCK) cells, and 5 passages in MDCK cells revealed no reversion of the I221L substitution. The crystal structure of the I221L NA and oseltamivir complex showed that the leucine side chain protrudes into the hydrophobic pocket of the active site that accommodates the pentyloxy substituent of oseltamivir. CONCLUSIONS: Enzyme kinetic and NA structural analyses provide an explanation for the high level of resistance to oseltamivir while retaining good fitness of viruses carrying I221L variant NA. PMID- 24795483 TI - Impact of experimental hookworm infection on the human gut microbiota. AB - The interactions between gastrointestinal parasitic helminths and commensal bacteria are likely to play a pivotal role in the establishment of host-parasite cross-talk, ultimately shaping the development of the intestinal immune system. However, little information is available on the impact of infections by gastrointestinal helminths on the bacterial communities inhabiting the human gut. We used 16S rRNA gene amplification and pyrosequencing to characterize, for the first time to our knowledge, the differences in composition and relative abundance of fecal microbial communities in human subjects prior to and following experimental infection with the blood-feeding intestinal hookworm, Necator americanus. Our data show that, although hookworm infection leads to a minor increase in microbial species richness, no detectable effect is observed on community structure, diversity or relative abundance of individual bacterial species. PMID- 24795485 TI - Simulation of macrosegregation in a 2.45-ton steel ingot using a three-phase mixed columnar-equiaxed model. AB - A three-phase mixed columnar-equiaxed solidification model is used to calculate the macrosegregation in a 2.45 ton steel ingot. The main features of mixed columnar-equiaxed solidification in such an ingot can be quantitatively modelled: growth of columnar dendrite trunks; nucleation, growth and sedimentation of equiaxed crystals; thermosolutal convection of the melt; solute transport by both convection and crystal sedimentation; and the columnar-to-equiaxed transition (CET). The predicted as-cast macrostructure and the segregation pattern are in qualitative agreement with the reported experimental results. Parameter study on the numerical grid size and the nucleation of the equiaxed crystals are performed, and some segregation mechanisms are numerically analyzed. Discontinued positive-negative segregation just below the hot top is predicted because of the formation of a local mini-ingot and the subsequent sedimentation of equiaxed grains within the mini-ingot. Quasi A-segregates in the middle radius region between the casting outer surface and the centreline are also found. The quasi A segregates originate from the flow instability, but both the appearance of equiaxed crystals and their interaction with the growing columnar dendrite tips significantly strengthen the segregates. The appearance of equiaxed phase is not a necessary condition for the formation of quasi A-segregates. The quantitative discrepancy between the predicted and experimental results is also discussed. PMID- 24795484 TI - Inverse probability weighting with error-prone covariates. AB - Inverse probability-weighted estimators are widely used in applications where data are missing due to nonresponse or censoring and in the estimation of causal effects from observational studies. Current estimators rely on ignorability assumptions for response indicators or treatment assignment and outcomes being conditional on observed covariates which are assumed to be measured without error. However, measurement error is common for the variables collected in many applications. For example, in studies of educational interventions, student achievement as measured by standardized tests is almost always used as the key covariate for removing hidden biases, but standardized test scores may have substantial measurement errors. We provide several expressions for a weighting function that can yield a consistent estimator for population means using incomplete data and covariates measured with error. We propose a method to estimate the weighting function from data. The results of a simulation study show that the estimator is consistent and has no bias and small variance. PMID- 24795486 TI - ? AB - This theoretical article presents some thoughts on research and intervention's frameworks for the well-being of nursing homes' residents with cognitive deficits associated with dementia. Based on a symbolic interactionism perspective, it examines the relations between the staff (nurses, social worker, rehabilitation worker, homecare employee) and family caregivers, to maintain identity for, by and behalf of the elderly. Adopting a critical perspective on the person-centered care approach for an clearer understanding of the person faced with dementia, the authors call for an integrating framework based on two approaches: a bibliographic approach and the holistic relational prothetic approach, allowing the recognition and support of a positive identity in elders with dementia for critical actions promoting their well-being in nursing homes. PMID- 24795487 TI - Formyl Group Activation of a Bromopyrrole Ester in Suzuki Cross-Coupling Reactions: Application to a Formal Synthesis of Polycitone A and B and Polycitrin A. AB - A new pyrrole building block is described, which allows for the regiospecific synthesis of 2,3,5-trisubstituted pyrroles and 2,3,4,5- tetrasubstituted pyrroles. Optimization studies are presented for the preparation of the pyrrole building block along with the evaluation of various cross-coupling conditions and cross-coupling agents. A short, formal synthesis of the natural products Polycitone A, Polycitone B and Polycitrin A from the pyrrole building block is also described. PMID- 24795488 TI - Robust smoothing of gridded data in one and higher dimensions with missing values. AB - A fully automated smoothing procedure for uniformly-sampled datasets is described. The algorithm, based on a penalized least squares method, allows fast smoothing of data in one and higher dimensions by means of the discrete cosine transform. Automatic choice of the amount of smoothing is carried out by minimizing the generalized cross-validation score. An iteratively weighted robust version of the algorithm is proposed to deal with occurrences of missing and outlying values. Simplified Matlab codes with typical examples in one to three dimensions are provided. A complete user-friendly Matlab program is also supplied. The proposed algorithm - very fast, automatic, robust and requiring low storage -provides an efficient smoother for numerous applications in the area of data analysis. PMID- 24795489 TI - Examining deterrence of adult sex crimes: A semi-parametric intervention time series approach. AB - Motivated by recent developments on dimension reduction (DR) techniques for time series data, the association of a general deterrent effect towards South Carolina (SC)'s registration and notification (SORN) policy for preventing sex crimes was examined. Using adult sex crime arrestee data from 1990 to 2005, the the idea of Central Mean Subspace (CMS) is extended to intervention time series analysis (CMS ITS) to model the sequential intervention effects of 1995 (the year SC's SORN policy was initially implemented) and 1999 (the year the policy was revised to include online notification) on the time series spectrum. The CMS-ITS model estimation was achieved via kernel smoothing techniques, and compared to interrupted auto-regressive integrated time series (ARIMA) models. Simulation studies and application to the real data underscores our model's ability towards achieving parsimony, and to detect intervention effects not earlier determined via traditional ARIMA models. From a public health perspective, findings from this study draw attention to the potential general deterrent effects of SC's SORN policy. These findings are considered in light of the overall body of research on sex crime arrestee registration and notification policies, which remain controversial. PMID- 24795490 TI - Bayesian Variable Selection under the Proportional Hazards Mixed-effects Model. AB - Over the past decade much statistical research has been carried out to develop models for correlated survival data; however, methods for model selection are still very limited. A stochastic search variable selection (SSVS) approach under the proportional hazards mixed-effects model (PHMM) is developed. The SSVS method has previously been applied to linear and generalized linear mixed models, and to the proportional hazards model with high dimensional data. Because the method has mainly been developed for hierarchical normal mixture distributions, it operates on the linear predictor under the Cox type models. The PHMM naturally incorporates the normal distribution via the random effects, which enables SSVS to efficiently search through the candidate variable space. The approach was evaluated through simulation, and applied to a multi-center lung cancer clinical trial data set, for which the variable selection problem was previously debated upon in the literature. PMID- 24795492 TI - The creation of the expected Aboriginal woman drug offender in Canada: Exploring relations between victimization, punishment, and cultural identity. AB - This article illustrates how the Aboriginal female drug user is responded to as an expected offender based on the intersection of her gender, race, and class. Drawing on the findings of a national Canadian study documenting the lived experiences of First Nations, Metis, and Inuit female drug users, we argue that the strengthening of cultural identity can potentially disrupt this expected status at both the individual and social system levels. Within the framework of critical victimology, the challenge then becomes to translate this understanding into praxis. In response, we suggest advancing women's agency at the individual level in the face of disempowering images and practices related to the offender, the victim, and Aboriginality. For change at the system level, we return to Christie's notion of the need to dismantle the stereotypical construction of the Aboriginal female drug user. We illustrate both levels of change with an innovative form of knowledge sharing, which aims to evoke transformation with respect to individual and socially constructed conceptualizations of identity. PMID- 24795491 TI - Cognitive control for language switching in bilinguals: A quantitative meta analysis of functional neuroimaging studies. AB - In a quantitative meta-analysis, using the activation likelihood estimation method, we examined the neural regions involved in bilingual cognitive control, particularly when engaging in switching between languages. The purpose of this study was to evaluate the bilingual cognitive control model based on a qualitative analysis [Abutalebi, J., & Green, D. W. (2008). Control mechanisms in bilingual language production: Neural evidence from language switching studies. Language and Cognitive Processes, 23, 557-582.]. After reviewing 128 peer reviewed articles, ten neuroimaging studies met our inclusion criteria and in each study, bilinguals switched between languages in response to cues. We isolated regions involved in voluntary language switching, by including reported contrasts between the switching conditions and high level baseline conditions involving similar tasks but requiring the use of only one language. Eight brain regions showed significant and reliable activation: left inferior frontal gyrus, left middle temporal gyrus, left middle frontal gyrus, right precentral gyrus, right superior temporal gyrus, midline pre-SMA and bilateral caudate nuclei. This quantitative result is consistent with bilingual aphasia studies that report switching deficits associated with lesions to the caudate nuclei or prefrontal cortex. It also extends the previously reported qualitative model. We discuss the implications of the findings for accounts of bilingual cognitive control. PMID- 24795493 TI - Walphos versus Biferrocene-Based Walphos Analogues in the Asymmetric Hydrogenation of Alkenes and Ketones. AB - Two representative Walphos analogues with an achiral 2,2"-biferrocenediyl backbone were synthesized. These diphosphine ligands were tested in the rhodium catalyzed asymmetric hydrogenation of several alkenes and in the ruthenium catalyzed hydrogenation of two ketones. The results were compared with those previously obtained on using biferrocene ligands with a C2-symmetric 2,2" biferrocenediyl backbone as well as with those obtained with Walphos ligands. The application of one newly synthesized ligand in the hydrogenation of 2 methylcinnamic acid gave (R)-2-methyl-3-phenylpropanoic acid with full conversion and with 92% ee. The same ligand was used to transform 2,4-pentanedione quantitatively and diastereoselectively into (S,S)-2,4-pentanediol with 98% ee. PMID- 24795494 TI - Can CA-125 predict lymph node metastasis in epithelial ovarian cancers in Turkish population? AB - OBJECTIVE: The role of single preoperative serum CA-125 levels in predicting pelvic or paraaortic lymph node metastasis in patients operated for epithelial ovarian cancer has been investigated. METHODS: 176 patients diagnosed with epithelial ovarian carcinoma after staging laparotomy between January 2002 and May 2010 were evaluated retrospectively. RESULTS: The mean, geometric mean, and median of preoperative serum CA-125 levels were 632,6, 200,29, and 191,5 U/mL, respectively. The cut-off value predicting lymph node metastases in the ROC curve was 71,92 U/mL, which is significant in logistic regression analysis (P = 0.005). The preoperative log CA-125 levels were also statistically significant in predicting lymph node metastasis in logistic regression analysis (P = 0.008). CONCLUSIONS: The tumor marker CA-125, which increases with grade independent of the effect of stage in EOC, is predictive of lymph node metastasis with a high rate of false positivity in Turkish population. The high false positive rate may obscure the predictive value of CA-125. PMID- 24795495 TI - Effect of the boundary conditions and influence of the rotational inertia on the vibrational modes of an elastic ring. AB - We present the small-amplitude vibrations of a circular elastic ring with periodic and clamped boundary conditions. We model the rod as an inextensible, isotropic, naturally straight Kirchhoff elastic rod and obtain the vibrational modes of the ring analytically for periodic boundary conditions and numerically for clamped boundary conditions. Of particular interest are the dependence of the vibrational modes on the torsional stress in the ring and the influence of the rotational inertia of the rod on the mode frequencies and amplitudes. In rescaling the Kirchhoff equations, we introduce a parameter inversely proportional to the aspect ratio of the rod. This parameter makes it possible to capture the influence of the rotational inertia of the rod. We find that the rotational inertia has a minor influence on the vibrational modes with the exception of a specific category of modes corresponding to high-frequency twisting deformations in the ring. Moreover, some of the vibrational modes over or undertwist the elastic rod depending on the imposed torsional stress in the ring. PMID- 24795497 TI - A fast all-in-one method for automated post-processing of PIV data. AB - Post-processing of PIV (particle image velocimetry) data typically contains three following stages: validation of the raw data, replacement of spurious and missing vectors, and some smoothing. A robust post-processing technique that carries out these steps simultaneously is proposed. The new all-in-one method (DCT-PLS), based on a penalized least squares approach (PLS), combines the use of the discrete cosine transform (DCT) and the generalized cross-validation, thus allowing fast unsupervised smoothing of PIV data. The DCT-PLS was compared with conventional methods, including the normalized median test, for post-processing of simulated and experimental raw PIV velocity fields. The DCT-PLS was shown to be more efficient than the usual methods, especially in the presence of clustered outliers. It was also demonstrated that the DCT-PLS can easily deal with a large amount of missing data. Because the proposed algorithm works in any dimension, the DCT-PLS is also suitable for post-processing of volumetric three-component PIV data. PMID- 24795498 TI - The association between ace gene variation and aerobic capacity in winter endurance disciplines. AB - The aim of the study was to examine the possible relationship between I/D polymorphism of ACE gene and selected indices of aerobic capacity among male and female athletes practising winter endurance sports. Sixty-six well-trained athletes (female n = 26, male n = 40), aged 18.4 +/- 2.8 years, representing winter endurance sports (cross-country skiing, n = 48; biathlon, n = 8; Nordic combined, n = 10) participated in the study. Genotyping for ACE I/D polymorphism was performed using polymerase chain reaction. Maximal oxygen consumption (VO2max), maximal running velocity (Vmax) and running velocity at anaerobic threshold (VAT4) were determined in an incremental test to volitional exhaustion on a motorized treadmill. The ACE genotype had no significant effect on absolute VO2max, relative VO2max (divided by body mass or fat free body mass), VAT4 or Vmax. No interaction effect of gender x ACE genotype was found for each of the examined aerobic capacity indices. ACE gene variation was not found to be a determinant of aerobic capacity in either female or male Polish, well-trained endurance athletes participating in winter sports. PMID- 24795496 TI - TRANSLATION OF BRAIN ACTIVITY INTO SLEEP. AB - Cytokines including tumor necrosis factor alpha (TNF) play a role in sleep regulation in health and disease. Hypothalamic and cerebral cortical levels of TNF mRNA or TNF protein have diurnal variations with higher levels associated with greater sleep propensity. Sleep loss is associated with enhanced brain TNF. Central or systemic TNF injections enhance sleep. Inhibition of TNF using the soluble TNF receptor, or anti-TNF antibodies, or a TNF siRNA reduces spontaneous sleep. Mice lacking the TNF 55 kD receptor have less spontaneous sleep. Injection of TNF into sleep regulatory circuits, e.g. the hypothalamus, promotes sleep. In normal humans, plasma levels of TNF co-vary with EEG slow wave activity (SWA) and in multiple disease states plasma TNF increases in parallel with sleep propensity. Downstream mechanisms of TNF-enhanced sleep include nitric oxide, adenosine, prostaglandins and activation of nuclear factor kappa B. Neuronal use induces cortical neurons to express TNF and if applied directly to cortical columns TNF induces a functional sleep-like state within the column. TNF mechanistically has several synaptic functions. TNF-sleep data led to the idea that sleep is a fundamental property of neuronal/glial networks such as cortical columns and is dependent upon past activity within such assemblies. This view of brain organization of sleep has profound implications for sleep function that are briefly reviewed herein. PMID- 24795499 TI - The effects of injury prevention warm-up programmes on knee strength in male soccer players. AB - The study investigates the effects of the 11+ and HarmoKnee injury prevention programmes on knee strength in male soccer players. Under-21-year-old players (n=36) were divided equally into: the 11+, HarmoKnee and control groups. The programmes were performed for 24 sessions (20-25 min each). The hamstrings and quadriceps strength were measured bilaterally at 60 degrees .s(-1), 180 degrees .s(-1) and 300 degrees .s(-1). The concentric quadriceps peak torque (PT) of the 11+ increased by 27.7% at 300 degrees .s(-1) in the dominant leg (p<0.05). The concentric quadriceps PT of HarmoKnee increased by 36.6%, 36.2% and 28% in the dominant leg, and by 31.3%, 31.7% and 20.05% at 60 degrees .s(-1), 180 degrees .s(-1) and 300 degrees .s(-1) in the non-dominant leg respectively. In the 11+ group the concentric hamstring PT increased by 22%, 21.4% and 22.1% at 60 degrees .s(-1), 180 degrees .s(-1) and 300 degrees .s(-1), respectively in the dominant leg, and by 22.3%, and 15.7% at 60 degrees .s(-1) and 180 degrees .s(-1), in the non-dominant leg. In the HarmoKnee group the hamstrings in the dominant leg showed an increase in PT by 32.5%, 31.3% and 14.3% at 60 degrees .s(-1), 180 degrees .s(-1) and 300 degrees .s(-1), and in the non-dominant leg hamstrings PT increased by 21.1% and 19.3% at 60 degrees .s(-1) and 180 degrees .s(-1) respectively. The concentric hamstrings strength was significantly different between the 11+ and control groups in the dominant (p=0.01) and non-dominant legs (p=0.02). The HarmoKnee programme enhanced the concentric strength of quadriceps. The 11+ and HarmoKnee programmes are useful warm-up protocols for improving concentric hamstring strength in young professional male soccer players. The 11+ programme is more advantageous for its greater concentric hamstring strength improvement compared to the HarmoKnee programme. PMID- 24795501 TI - Temperament and Anxiety: The Mediating Role of Metacognition. AB - The present study examines a simple model for the relationship between temperament, anxiety and maladaptive metacognition. A clinical sample of patients diagnosed with anxiety disorders (n = 216) completed a set of self-reported questionnaires measuring temperament dimensions, state anxiety and metacognitions. Three temperament traits were included in the hypothesized model: emotional reactivity, perseveration and briskness. A structural equation modeling analysis supported a model in which the relationship between the three temperament traits and anxiety were fully mediated by metacognition. Dissimilar models were identified for the male and female subgroups, and also with reference to individual categories of maladaptive metacognition. The findings support the significance of metacognition as a factor influencing the temperament-anxiety relationship. Moreover, they confirm the roles both of emotional reactivity and of perseveration, being major traits related to anxiety which also turned out to be strongly associated with metacognition. In case of the models for the categories of metacognition, emotional reactivity was associated with negative beliefs, perseveration with negative and positive beliefs, while briskness predicted anxiety independently of metacognition. These results suggest the existence of more specific associations between temperament traits, anxiety, and various types of metacognition. PMID- 24795500 TI - Previous physical activity and body balance in elderly people. AB - The purpose of the research was to evaluate the efficiency of body balance regulation in the elderly and verify whether physical activity in adolescence could influence later physical efficiency. Research was carried out on 62 persons aged between 65 and 96 years of age. Fifty people declared that they undertook physical activity in adolescence, while 12 reported no activity. Stabilographic examinations were performed during trials with open and closed eyes on a horizontally situated platform tilted forward and backward. The centre-of pressure (COP) path length, sway range area and centre-of-pressure velocity (COP velocity) were assessed. The safety margin when a person leans forward and backward was evaluated as well. On a horizontally situated platform, exclusion of visual control in most of the examined participants resulted in a significant increase in values of examined parameters. Tilting the platform caused in both groups an increase in values of all the parameters. These changes were more visible when a trial with eyes closed was performed and the group of active people obtained better results. These people were also able to use the support area more effectively when changing the position of the body. It was found that body balance disorder affects more often elderly people who were less active in adolescence and that with age visual balance control dominates the proprioceptive one. This means that physical activity directed towards, among other things, forming and improving the body balance regulation system is needed at an early age. PMID- 24795502 TI - Nickel-catalyzed cross-electrophile coupling of 2-chloropyridines with alkyl bromides. AB - The synthesis of 2-alkylated pyridines by the nickel-catalyzed cross-coupling of two different electrophiles, 2-chloropyridines with alkyl bromides, is described. Compared to our previously published conditions for aryl halides, this method uses the different, more rigid bathophenanthroline ligand and is conducted at high concentration in DMF solvent. The method displays promising functional group compatibility and the conditions are orthogonal to the Stille coupling. PMID- 24795503 TI - Effect of probiotic (VSL#3) and omega-3 on lipid profile, insulin sensitivity, inflammatory markers, and gut colonization in overweight adults: a randomized, controlled trial. AB - To evaluate the effects of probiotic (VSL#3) and omega-3 fatty acid on insulin sensitivity, blood lipids, and inflammation, we conducted a clinical trial in 60 overweight (BMI > 25), healthy adults, aged 40-60 years. After initial screening the subjects were randomized into four groups with 15 per group. The four groups received, respectively, placebo, omega-3 fatty acid, probiotic VSL#3, or both omega-3 and probiotic, for 6 weeks. Blood and fecal samples were collected at baseline and after 6 weeks. The probiotic (VSL#3) supplemented group had significant reduction in total cholesterol, triglyceride, LDL, and VLDL and had increased HDL (P < 0.05) value. VSL#3 improved insulin sensitivity (P < 0.01), decreased hsCRP, and favorably affected the composition of gut microbiota. Omega 3 had significant effect on insulin sensitivity and hsCRP but had no effect on gut microbiota. Addition of omega-3 fatty acid with VSL#3 had more pronounced effect on HDL, insulin sensitivity and hsCRP. Subjects with low HDL, insulin resistance, and high hsCRP had significantly lower total lactobacilli and bifidobacteria count and higher E. coli and bacteroides count. PMID- 24795504 TI - Aryl hydrocarbon receptor (AhR) modulates cockroach allergen-induced immune responses through active TGFbeta1 release. AB - BACKGROUND: Aryl hydrocarbon receptor (AhR), a multifunctional regulator that senses and responds to environmental stimuli, plays a role in normal cell development and immune regulation. Recent evidence supports a significant link between environmental exposure and AhR in the development of allergic diseases. We sought to investigate whether AhR plays a role in mediating cockroach allergen induced allergic immune responses. METHODS: AhR expression in human lung fibroblasts from asthmatic and healthy individuals and in cockroach extract (CRE) treated human lung fibroblasts (WI-38) was examined. The role of AhR in modulating CRE induced TGFbeta1 production was investigated by using AhR agonist, TCDD, antagonist CH122319, and knockdown of AhR. The role of latent TGFbeta1 binding protein-1 (LTBP1) in mediating TCDD induced active TGFbeta1 release was also examined. RESULTS: AhR expression was higher in airway fibroblasts from asthmatic subjects as compared to healthy controls. AhR in fibroblasts was activated by TCDD with an increased expression of cyp1a1 and cyp1b1. Increased AhR expression was observed in CRE-treated fibroblasts. Importantly, CRE induced TGFbeta1 production in fibroblasts was significantly enhanced by TCDD but inhibited by CH122319. Reduced TGFbeta1 production was further confirmed in fibroblasts with AhR knockdown. Moreover, AhR knockdown inhibited CRE induced fibroblast differentiation. Furthermore, TCDD induced active TGFbeta1 release was significantly inhibited by LTBP1 knockdown. CONCLUSION: These results provide evidence for the role of AhR in modulating cockroach allergen-induced immune responses through controlling the active TGFbeta1 release, suggesting a possible synergistic effect between exposure to allergens and environmental chemicals on the development of allergic diseases. PMID- 24795505 TI - The macrophage inflammatory proteins MIP1alpha (CCL3) and MIP2alpha (CXCL2) in implant-associated osteomyelitis: linking inflammation to bone degradation. AB - Bacterial infections of bones remain a serious complication of endoprosthetic surgery. These infections are difficult to treat, because many bacterial species form biofilms on implants, which are relatively resistant towards antibiotics. Bacterial biofilms elicit a progressive local inflammatory response, resulting in tissue damage and bone degradation. In the majority of patients, replacement of the prosthesis is required. To address the question of how the local inflammatory response is linked to bone degradation, tissue samples were taken during surgery and gene expression of the macrophage inflammatory proteins MIP1alpha (CCL3) and MIP2alpha (CXCL2) was assessed by quantitative RT-PCR. MIPs were expressed predominantly at osteolytic sites, in close correlation with CD14 which was used as marker for monocytes/macrophages. Colocalisation of MIPs with monocytic cells could be confirmed by histology. In vitro experiments revealed that, aside from monocytic cells, also osteoblasts were capable of MIP production when stimulated with bacteria; moreover, CCL3 induced the differentiation of monocytes to osteoclasts. In conclusion, the multifunctional chemokines CCL3 and CXCL2 are produced locally in response to bacterial infection of bones. In addition to their well described chemokine activity, these cytokines can induce generation of bone resorbing osteoclasts, thus providing a link between bacterial infection and osteolysis. PMID- 24795506 TI - Lack of association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and carotid intima-media thickness, carotid plaques, and cardiovascular disease in patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. MATERIAL AND METHODS: 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. RESULTS: No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. CONCLUSION: Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA. PMID- 24795507 TI - Regulating inflammation using acid-responsive electrospun fibrous scaffolds for skin scarless healing. AB - Skin injury in adult mammals brings about a series of events and inflammation in the wounded area is initiated first and provides lots of inflammatory factors, which is critical for the final scar formation. While the postinjured skin of fetus and nude mice heals scarlessly owing to the absence of inflammation or immunodeficient, we designed a feasible acid-responsive ibuprofen-loaded poly(L lactide) (PLLA) fibrous scaffolds via doping sodium bicarbonate to prevent excessive inflammation and achieve scarless healing finally. The morphological results of in vivo experiments revealed that animals treated with acid-responsive ibuprofen-loaded PLLA fibrous scaffolds exhibited alleviative inflammation, accelerated healing process, and regulated collagen deposition via interference in the collagen distribution, the alpha-smooth muscle actin (alpha-SMA), and the basic fibroblast growth factor (bFGF) expression. The lower ratios of collagen I/collagen III and TGF-beta1/TGF-beta3 and higher ratio of matrix metalloproteinase-1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) in acid-responsive ibuprofen-loaded PLLA fibrous scaffolds group were confirmed by real-time qPCR as well. These results suggest that inhibiting the excessive inflammation will result in regular collagen distribution and appropriate ratio between the factors, which promote or suppress the scar formation, then decrease the scar area, and finally achieve the scarless healing. PMID- 24795509 TI - Minimizing preventable deaths: the should be focus in Ethiopian health system. PMID- 24795508 TI - Lessons learned from studies of natural resistance in murine experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is a commonly-used animal model of the human demyelinating disease, multiple sclerosis (MS). Similar to MS, EAE is under genetic control in that certain mouse strains are susceptible to disease induction with myelin antigens, while other strains are resistant. In the past, major efforts studying EAE tended to focus on the mechanism of disease susceptibility pertaining to antigen specificities, disease progression and related cytokines. The basis of EAE resistance, on the other hand, had received relatively little attention. It is our contention that EAE resistance is a tightly regulated process and many lessons can be learned from studying its mechanisms. Initially, this laboratory showed that resistance to EAE induced by MBP in B6 mice and many other strains with different H-2 haplotypes could be reversed in an adoptive transfer system by challenging the recipients with MBP CFA. The disease developed in these mice was very similar to that induced in EAE susceptible mouse strains without the antigenic challenge. This approach of reversing EAE resistance was confirmed by several other laboratories. It was also demonstrated definitively that EAE was mediated by the donor T cells and not by host T cells. Indeed, a "resistant" host environment did not affect the outcome of disease development. The antigenic challenge appeared to induce an anamnestic response in the donor T cells, as the antigen dose used could be as low as only 5ug per mouse. Significantly, the period between adoptive cell transfer and antigenic challenge could be as long as over one year, again indicating that the donor cells persisted in the host for a long period of time. Recently, it has been suggested that EAE resistance can be due to the activities of regulatory T cells (Tregs). Depletion of Tregs with anti-CD25 antibodies prior to immunization with PLP139-151 rendered 30% of resistant B10.S mice to develop EAE. These results were confirmed in SJL.B mice responding to MBP but not in B6 mice responding to the same antigen, suggesting that regulation might vary among EAE resistant mouse strains. In addition, it is noted that while B6 and SJL.B mice are resistant to EAE induction with MBP, these mice are susceptible to disease induction when immunized with MOG, suggesting that EAE susceptibility verses resistance is antigen dependent. This unique mouse model, coupled with advance technologies such as peptide/IA tetramers and microarrays, should provide a powerful tool for further elucidation of the basic mechanisms of EAE resistance. PMID- 24795510 TI - Prevalence of Shigella, Salmonella and Campylobacter species and their susceptibility patters among under five children with diarrhea in Hawassa town, south Ethiopia. AB - BACKGROUND: Diarrhea is the leading cause of morbidity and mortality in under five children in developing countries including Ethiopia. Therefore, up-to-date data on etiologic agent and susceptibility pattern are important for the management of bacterial diarrhea in under-five children, which was the main objective of this study. METHOD: A cross-sectional study was conducted at Hawassa Adare Hospital and Millennium Health Center from June 6 to October 28, 2011. A total of 158 under-five children with diarrhea were selected using convenient sampling technique. Demographic and clinical data were collected using questionnaire. Fecal samples were collected and processed for bacterial isolation, and antimicrobial susceptibility testing following standard bacteriological techniques. RESULT: A total of 158 fecal samples were collected from 81(51.3%) males and 77(48.7%) females of under-five children with diarrhea. Of the 158 fecal samples, 35(22.2%) bacterial pathogens were isolated. The isolated bacteria were Campylobacter species, 20 (12.7%), Shigella species, 11 (7.0%), and Salmonella species, 4 (2.5%). The majority of the isolates were sensitive to chloramphenicol, ciprofloxacin, nalidixic acid and cotrimoxazol and high rate of drug resistance was observed against erythromycin and amoxicillin. CONCLUSIONS: The finding of this study indicates that Campylobacter species were the predominant etiologies and the presence of bacterial isolates resistant to the commonly prescribed drugs for treating diarrhea in children. Therefore, periodic monitoring of etiologic agent with their drug resistant pattern is essential in the management of diarrhea in children. PMID- 24795511 TI - The status of iodine nutrition and iodine deficiency disorders among school children in Metekel Zone, northwest Ethiopia. AB - BACKGROUND: Iodine deficiency disorders are serious public health problems in Ethiopia. The aim of this study was to measure the prevalence and severity of iodine deficiency disorders among school children in Metekel Zone. METHODS: A cross-sectional school based descriptive study was conducted between February 2011 and July 2012. One school containing 750 children aged between 6 and 18 years was randomly selected. Two hundred students from this school were selected by systematic random sampling. Physical examination was made according to WHO goiter classification system; 50 salt samples from households to which the sampled children belonged were tested for iodine using rapid field test kits and titration; a casual urine sample (5 ml) was taken from 30 children to measure urinary iodine spectrophotometrically, and 5 ml venous blood sample were collected from 37 children to measure thyroid relevant blood constituents using ELISA. RESULTS: The total goiter prevalence was 39.5%; 60% of the salt samples contained no iodine. The median urinary iodine concentration ranged from 20.54 - 62.2 (39.9 ug/L). School children who were assessed for thyroid hormones showed 18.92% elevated and 27.03% suppressed TSH levels. CONCLUSION: The study demonstrated that iodine deficiency is still a severe public health problem in Metekel Zone. There is a need to further strengthen the existing controlling and monitoring system in order to achieve proper elimination of IDDs in the community. PMID- 24795513 TI - Analysis of diagnostic value of cytological smear method versus cell block method in body fluid cytology: study of 150 cases. AB - BACKGROUND: Aspiration of serous cavities is a simple and relatively non-invasive technique to achieve diagnosis. Cytologic evaluation of body cavity fluid is diagnostically challenging. METHODS: A total of 150 fluid specimens were examined for conventional cytological smear (CS) and cell block method (CB). Out of 150 fluids, 79 were pleural fluid, 69 were ascitic fluid and 2 pericardial fluid. Each fluid specimen was divided in two equal parts: one part was subjected to conventional smear technique, while the other part was subjected to 10% alcohol acetic acid-formalin cell block technique. Overall morphological details, cellularity, architecture, nuclear and cytoplasmic details were studied in both CS and CB techniques. RESULTS: In this study, the utility of the CB method in the cytodiagnosis of malignant effusions was found to be highly significant as compared to the CS method. The additional yield of malignancy was 10% more as was obtained by the CB method. CONCLUSION: For the final cytodiagnosis of body fluid, there is statistically significant difference between the two techniques. In other words, CB is superior to CS method. PMID- 24795512 TI - Use of complementary and alternative medicine for work related musculoskeletal disorders associated with job contentment in dental professionals: Indian outlook. AB - BACKGROUND: High prevalence rates of work-related musculoskeletal disorders (WRMSD) among dentists have been reported. Complementary and alternative medicine (CAM) therapies can be helpful in managing and preventing work-related musculoskeletal disorders. The purpose of this study was to determine if dental professionals are using CAM for work-related musculoskeletal disorders. Who have greater job satisfaction: dentist who uses Complementary and alternative medicine (CAM) or conventional therapy (CT) as a treatment modality for WRMSD. METHOD: Dentists who registered in Uttar Pradesh state, India under Indian Dental Council, Uttar Pradesh branch (n=1134) were surveyed. Data were analyzed using univariate and bivariate analyses and logistic regression. RESULT: A response rate of 53% (n=601) was obtained, revealing that 82% (n=487) of the respondents suffered from work-related musculoskeletal disorders. The use of complementary and alternative medicine or conventional therapy was reported among 80% (n=390) of the dentists with work-related musculoskeletal disorders. Complementary and alternative medicine users reported greater overall health compared to conventional therapy users (P<0.001). Of those with work-related musculoskeletal disorders, 35.5% (n=172) considered a career change for once, and 4.0% (n=19) reported having left dentistry. CONCLUSION: Complementary and alternative medicine therapies may improve quality of life, reduce work disruptions and enhance job satisfaction for dentists who suffer from work-related musculoskeletal disorders. It is important that dentists incorporate complementary and alternative medicine strategies into practice to facilitate musculoskeletal health that will enable longer and healthier careers, increase productivity, provide safer workplace and prevent musculoskeletal disorders. PMID- 24795514 TI - Predictors of treatment seeking intention among people with cough in East Wollega, Ethiopia based on the theory of planned behavior: a community based cross-sectional study. AB - BACKGROUND: Early treatment seeking for cough is crucial in the prevention and control of Tuberculosis. This study was intended to assess treatment seeking intention of people with cough of more than two weeks, and to identify its predictors. METHODS: A community based cross-sectional study was conducted among 763 individuals with cough of more than two weeks in East Wollega Zone from March 10 to April 16, 2011. Study participants were selected from eighteen villages by cluster sampling method. Data collection instruments were developed according to the standard guideline of the theory of planned behavior. The data were analyzed with SPSS 16.0. Multiple linear regression was used to identify predictors. RESULTS: Mean score of intention was found to be 12.6 (SD=2.8) (range of possible score=3-15). Knowledge (beta=0.14, 95%CI: 0.07-0.2), direct attitude (beta=0.31, 95%CI: 0.25-0.35), belief-based attitude (beta=0.03, 95%CI: 0.02-0.06) and perceived subjective norm (beta=0.22, 95%CI: 0.13-0.31) positively predicted treatment seeking intention. However, perceived behavioral control and control belief were not significantly associated with treatment seeking intention (p>0.05). Being smoker (beta=-0.97, 95%CI:-1.65 (-0.37)) and higher family income (beta=-0.06, 95%CI:-0.07-(-0.01) were significantly associated with lower treatment seeking intention. CONCLUSION: TPB significantly predicted treatment seeking intention among the study participants. Attitude and silent beliefs held by the respondents play an important role and should be given emphasize in prevention and control of Tuberculosis. PMID- 24795515 TI - Preliminary antiplaque efficacy of aloe vera mouthwash on 4 day plaque re-growth model: randomized control trial. AB - BACKGROUND: Due to increasing resistance to antibiotics and rising incidence of oral diseases, there is a need for alternative treatment modalities to combat oral diseases. The aim of the present study was to access the effect of Aloe vera mouthwash on the dental plaque in the experimental period of 4 days and to compare it with the bench mark control chlorhexidine and placebo (saline water). MATERIAL AND METHODS: A total of 300 systemically healthy subjects were randomly allocated into 3 groups: Aloe vera mouthwash group (n=100), control group (=100) chlorhexidene group and saline water-Placebo (n=100). To begin with, Gingival index (GI) and plaque index (PI) were recorded. Then, baseline plaque scores were brought to zero by professionally cleaning the teeth with scaling and polishing. After randomization of the participants into three groups they were refrained from regular mechanical oral hygiene measures. Subjects were asked to swish with respective mouthwash (Aloe vera mouthwash, 0.2%chlorhexidine gluconate mouthwash, or normal saline) as per therapeutic dose for 4 days. RESULTS: The results showed that Aloe vera mouthrinse is equally effective in reducing plaque as Chlorhexidine compared to placebo over a period of 4 days. There was a significant reduction on plaque in Aloe vera and chlorhexidine groups and no statistically significant difference was observed among them (p>0.05). Aloe vera mouthwash showed no side effects. CONCLUSION: The results of the present study indicated that Aloe vera may prove an effective mouthwash due to its ability in reducing dental plaque. PMID- 24795516 TI - Occurrence of urinary tract infection in adolescent and adult women of shanty town in Dhaka City, Bangladesh. AB - BACKGROUND: Urinary tract infection (UTI) is commonly experienced by women of various age groups especially elderly ones. We planned to find out the prevalent microbial strains causing UTI in slum inhabitant adolescent and adult women in Dhaka City, Bangladesh. METHODS AND MATERIALS: Urine sample was collected from 462 UTI suspected female subjects. Pathogenic bacteria were identified using standard microbiological tests, and antimicrobial sensitivity profiles of the pathogens were determined. RESULTS: Bacteriuria was present in 9% of the subjects. A higher incidence (16.8%) of UTI was noted among adult women aged above 19 years. Escherichia coli (69%), Streptococcus spp. (15%) and Pseudomonas aeruginosa (7%) were more frequently isolated from the urine samples compared to Enterococcus faecalis (3%), Staphylococcus aureus (2%), Klebsiella pneumoniae (2%) and Hafnia alvei (2%). The E. coli isolates showed complete resistance to commonly used drugs, and 58% of these isolates were multidrug resistant (MDR). Minimum Inhibitory Concentration (MIC) values for ciprofloxacin ranged between 64ug/ml and 512ug/ml, and the Minimum Bactericidal Concentration (MBC) values against the isolates were 128ug/ml or above. Isolated strains of E. coli exhibited equal extent of ciprofloxacin resistance irrespective of the presence or absence of plasmid in them. CONCLUSION: The extent of drug resistance among the uropathogens if ignored may render them uncontrollable. This study suggests regular monitoring of drug resistance phenotype of the UTI pathogens to reduce the morbidity of female UTI patients and offer better treatment strategy in the healthcare sectors of Bangladesh. PMID- 24795517 TI - Physical activity and pattern of blood pressure in postmenopausal women with hypertension in Nigeria. AB - BACKGROUND: Hormonal changes during menopause have been attributed to hypertension-a common public health concern. This study investigated physical activity (PA) and pattern of blood pressure (BP) in postmenopausal women newly diagnosed with hypertension and referred for treatment at the medicine outpatient clinic of a tertiary health facility in Ibadan, Oyo State, Nigeria. It compared BP pattern and adiposity variables [body mass index (BMI) and waist-hip ratio (WHR)] between two PA groups. METHODS: Purposive sampling technique was used to recruit 220 participants in this cross-sectional survey after obtaining their informed consent. International Physical Activity Questionnaire was used to assess PA level, while a 16-item questionnaire was used to assess socio demographic and clinical profiles of the women. BP, BMI and WHR were assessed using standard measurement procedures. Descriptive statistics of mean +/- standard deviation were used for data summarization and independent t-test was used to compare variables between low level and moderate to vigorous level PA groups. RESULTS: Participants' mean values include: age 61.6 +/- 8.5 years, years since menopause 12.75+/- 8.15, BMI 28.63+/-4.99kg/m(2), WHR 1.11+/-0.08, SBP and DBP 145.9+/-17.9; 93.7+/-11.4 mmHg respectively. Mean values of SBP, DBP, BMI and WHR were higher among participants with low PA compared to those with moderate to vigorous even though the difference was not statistically significant (P>0.05). CONCLUSION: Involvement in moderate to vigorous physical activities among menopausal women in Nigeria should be encouraged. This may reduce hypertension and adiposity with a possible control of cardiovascular disease risk. PMID- 24795518 TI - Prevalence and risk factors of depression in Ethiopia: a review. AB - BACKGROUND: Depression is the most common and disabling mental illness in the globe. It accounts for about 6.5% of the burden of diseases in Ethiopia. Regardless of its severity and relapse rate, there are no synthesized evidences about its prevalence and potential risk factors in Ethiopia. The aim of this review was thus to synthesize scientific information about the prevalence and potential risk factors of depression in Ethiopia. METHODS: Out of 37 papers, 31 were collected from PubMed, Medline and Google Scholar electronic databases, and the remaining six from Addis Ababa University, Department of Psychiatry. But, 13 articles were removed after reading the titles; five after reading the abstracts and two after reading the manuscripts and five of them were duplicates. Finally, 12 papers were reviewed and the pooled prevalence was also computed. RESULTS: The pooled prevalence of depression for the five studies, which had used Composite International Diagnostic Interview (CIDI), was 6.8% (95%, CI: 6.4-7.3); but, it increased to 11% (95% CI: 10.4-11.5) when three other studies that had used other screening tools were included. Demographic variables such as sex, age, marital status, violence, migration and substance use were associated with depression, but not with economic factors. CONCLUSIONS: More attention should be given to socio-demographic risk factors and intimate partner violence, since they are potential risk factors of depression. The prevalence of depression in Ethiopia was also found comparable to that of some high-income countries. PMID- 24795519 TI - The ironies of human mind: a case of Rett syndrome. AB - BACKGROUND: Rett Syndrome (RS) is a chromosome X-linked genetic neurological disorder characterized by developmental regression, particularly in relation to expressive language and use of the hands. It is also associated with profound mental retardation and almost exclusively affects females. CASE DETAILS: A four and a half year old girl reported to our dental OPD for a dental checkup. On complete examination, she was diagnosed to be suffering from Rett syndrome. Preventive therapies and proper oral hygiene instructions were explained to her mother. CONCLUSION: Early diagnosis of such disorders is extremely important along with treatment of patients' problems with love and care to prevent them from further pain and stress. PMID- 24795520 TI - Presence of multiple tendinous insertions of palmaris longus: a unique variation of a retrogressive muscle. AB - BACKGROUND: Palmaris longus, being the most variable muscle of the upper extremity is generally considered important morphologically rather than functionally. The palmar aponeurosis represents the distal part of the tendon of Palmaris longus. CASE DETAILS: We report here a unique case of palmaris longus presenting variation distally as its tendon divides to gain multiple attachments with the fascia covering the abductor pollicis brevis, flexor retinaculum and the tendon of flexor carpi ulnaris. In addition, it also continues as palmar aponeurosis as its normal course. CONCLUSION: Presence of this kind of variation might result in compression of the median and ulnar nerves and may aggravate the complications in case of inflammation of palmar aponeurosis thus mimicking the manifestations of Dupuytren's contracture. PMID- 24795521 TI - HIV patient with mucous membrane pemphigoid: a case report. AB - BACKGROUND: Mucous Membrane Pemphigoid, a new denomination of cicatricial pemphigoid, encompasses a group of chronic subepithelial autoimmune blistering diseases that predominantly affect the oral cavity and the eyes (conjunctivitis and symblepharon). CASE DETAILS: A rare case of Mucous Membrane Pemphigoid (MMP) in a human immunodeficiency virus (HIV) positive patient is discussed with clinicohistopathological presentation. CONCLUSION: Since our patient was HIV positive and had lesions restricted to the oral mucosa with ocular involvement, only topical and intralesional steroids were preferred as the first line of treatment. Systemic corticosteroid therapy raises a concern regarding immunosuppression. PMID- 24795522 TI - Traumatic bone cyst of idiopathic origin? A report of two cases. AB - BACKGROUND: Traumatic bone cyst (TBC) is an uncommon non-epithelial lined cavity of the jaws. Traumatic bone cysts have been reported in the literature under a variety of names: solitary bone cyst, haemorrhagic bone cyst, extravasation cyst and simple bone cyst. The multitude of names applied to this lesion implies the lack of understanding of the true aetiology and pathogenesis. However, the term "traumatic bone cyst" is the most widely used name today (1). CASE DETAILS: A 15 years old male patient presented with a complaint of swelling with mild, intermittent and non-radiating pain in the lower left back teeth region. There was expansion of the buccal cortical plate. Radiograph showed a multilocular lesion straddling between the roots of the teeth. In addition, 21 years old male patient came with a complaint of swelling with mild, continuous pain in the lower left jaw region. OPG showed well defined radiolucency with scalloped borders extending from the periapical region of the 1(st) premolar until the 2(nd) molar. The radiolucency was seen extending between the roots of the involved teeth. CONCLUSION: The majority of TBCs are located in the mandibular body between the canine and the third molar. Clinically, the lesion is asymptomatic in the majority of cases and is often accidentally discovered on routine radiological examination, usually as a unilocular radiolucent area with a "scalloping effect". Since material for histologic examination may be scanty or non-available it is very often difficult for a definite histologic diagnosis to be achieved (1). PMID- 24795523 TI - Do political factors matter in explaining under- and overweight outcomes in developing countries? AB - We construct a rich dataset covering 47 developing countries over the years 1990 2007, combining several micro and macro level data sources to explore the link between political factors and body mass index (BMI). We implement a heteroskedastic generalized ordered logit model allowing for different covariate effects across the BMI distribution and accounting for the unequal BMI dispersion by geographical area. We find that systems with democratic qualities are more likely to reduce under-weight, but increase overweight/obesity, whereas effective political competition does entail double-benefits in the form of reducing both under-weight and obesity. Our results are robust to the introduction of country fixed effects. PMID- 24795524 TI - Development and Implementation of Health and Wellness CBT for Individuals with Depression and HIV. AB - Rates of depression are reported to be between 22-33% in adults with HIV, which is double that of the general population. Depression negatively affects treatment adherence and health outcomes of those with medical illnesses. Further, it has been shown in adults that reducing depression may improve both adherence and health outcomes. To address the issues of depression and non-adherence, Health and Wellness (H&W) Cognitive Behavioral Therapy (CBT) and medication management (MM) treatment strategies have been developed specifically for youth living with both HIV and depression. H&W CBT is based on other studies with uninfected youth and upon research on adults with HIV. H&W CBT uses problem-solving, motivational interviewing, and cognitive-behavioral strategies to decrease adherence obstacles and increase wellness. The intervention is delivered in 14 planned sessions over a 6-month period, with three different stages of CBT. This paper summarizes the feasibility and acceptability data from an open depression trial with 8 participants, 16-24 years of age, diagnosed with HIV and with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of depression, conducted at two treatment sites in the Adolescent Trials Network (ATN). Both therapists and subjects completed a Session Evaluation Form (SEF) after each session, and results were strongly favorable. Results from The Quick Inventory of Depressive Symptomatology-Clinician (QIDS-C) also showed noteworthy improvement in depression severity. A clinical case vignette illustrates treatment response. Further research will examine the use of H&W CBT in a larger trial of youth diagnosed with both HIV and depression. PMID- 24795525 TI - Endocavity Ultrasound Probe Manipulators. AB - We developed two similar structure manipulators for medical endocavity ultrasound probes with 3 and 4 degrees of freedom (DoF). These robots allow scanning with ultrasound for 3-D imaging and enable robot-assisted image-guided procedures. Both robots use remote center of motion kinematics, characteristic of medical robots. The 4-DoF robot provides unrestricted manipulation of the endocavity probe. With the 3-DoF robot the insertion motion of the probe must be adjusted manually, but the device is simpler and may also be used to manipulate external body probes. The robots enabled a novel surgical approach of using intraoperative image-based navigation during robot-assisted laparoscopic prostatectomy (RALP), performed with concurrent use of two robotic systems (Tandem, T-RALP). Thus far, a clinical trial for evaluation of safety and feasibility has been performed successfully on 46 patients. This paper describes the architecture and design of the robots, the two prototypes, control features related to safety, preclinical experiments, and the T-RALP procedure. PMID- 24795526 TI - Looking for synergies between the equilibrium point hypothesis and internal models. PMID- 24795527 TI - Differential evolution of asexual and sexual females in a benign culture environment. AB - Here we report one of the first investigations of evolvability of lifespan and reproduction in metazoans, examining both extrinsic and intrinsic factors. We tested effects on senescence of an environmental variable (simulated lake hydroperiod, the length of time an aquatic habitat is inundated), female reproductive physiology (asexual females that reproduce by ameiosis, versus sexual females reproducing by meiosis), and time in a benign culture environment (minimal, if any, external mortality factors). To do this we established chemostat cultures of the rotifer Brachionus plicatilis s.s., and maintained the cultures for 385 d. Hydroperiod alone or in interaction with the effects of time in the benign environment (season) or reproductive physiology had no significant effect on the net reproductive rate, generation time, or rate of aging. Yet combining animals from both ephemeral and permanent hydroperiods revealed a 26% increase in asexual female lifespan across seasons (23% decrease in the rate of aging) and a 56% increase in asexual fecundity, suggesting that maintenance in benign laboratory conditions leads to slower aging. The relative stasis of traits for sexual females implies an impact of reproductive physiology on evolvability. In addition we found a positive correlation between fecundity and lifespan, suggesting an absence of trade-offs in life history traits in the benign laboratory environment. PMID- 24795528 TI - Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis. AB - The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential. Experiments were performed to determine the effects of WIN on proliferation, cell cycle distribution, and programmed cell death in human osteosarcoma MG63 and Saos-2 cells. Results show that WIN induced G2/M cell cycle arrest, which was associated with the induction of the main markers of ER stress (GRP78, CHOP and TRB3). In treated cells we also observed the conversion of the cytosolic form of the autophagosome marker LC3-I into LC3-II (the lipidated form located on the autophagosome membrane) and the enhanced incorporation of monodansylcadaverine and acridine orange, two markers of the autophagic compartments such as autolysosomes. WIN also induced morphological effects in MG63 cells consisting in an increase in cell size and a marked cytoplasmic vacuolization. However, WIN effects were not associated with a canonical apoptotic pathway, as demonstrated by the absence of specific features, and only the addition of TRAIL to WIN-treated cells led to apoptotic death probably mediated by up-regulation of the tumor suppressor factor PAR-4, whose levels increased after WIN treatment, and by the translocation of GRP78 on cell surface. PMID- 24795529 TI - Complete mitochondrial genomes of Carcinoscorpius rotundicauda and Tachypleus tridentatus (Xiphosura, Arthropoda) and implications for chelicerate phylogenetic studies. AB - Horseshoe crabs (order Xiphosura) are often referred to as an ancient order of marine chelicerates and have been considered as keystone taxa for the understanding of chelicerate evolution. However, the mitochondrial genome of this order is only available from a single species, Limulus polyphemus. In the present study, we analyzed the complete mitochondrial genomes from two Asian horseshoe crabs, Carcinoscorpius rotundicauda and Tachypleus tridentatus to offer novel data for the evolutionary relationship within Xiphosura and their position in the chelicerate phylogeny. The mitochondrial genomes of C. rotundicauda (15,033 bp) and T. tridentatus (15,006 bp) encode 13 protein-coding genes, two ribosomal RNA (rRNA) genes, and 22 transfer RNA (tRNA) genes. Overall sequences and genome structure of two Asian species were highly similar to that of Limulus polyphemus, though clear differences among three were found in the stem-loop structure of the putative control region. In the phylogenetic analysis with complete mitochondrial genomes of 43 chelicerate species, C. rotundicauda and T. tridentatus were recovered as a monophyly, while L. polyphemus solely formed an independent clade. Xiphosuran species were placed at the basal root of the tree, and major other chelicerate taxa were clustered in a single monophyly, clearly confirming that horseshoe crabs composed an ancestral taxon among chelicerates. By contrast, the phylogenetic tree without the information of Asian horseshoe crabs did not support monophyletic clustering of other chelicerates. In conclusion, our analyses may provide more robust and reliable perspective on the study of evolutionary history for chelicerates than earlier analyses with a single Atlantic species. PMID- 24795530 TI - Suppression of E-cadherin mediates gallotannin induced apoptosis in Hep G2 hepatocelluar carcinoma cells. AB - Though gallotannin was known to have anti-oxidant and antitumor activity, the underlying antitumor mechanism of gallotannin still remains unclear. Thus, in the present study, antitumor mechanism of gallotannin was elucidated in hepatocellular carcinoma cells. Gallotannin significantly exerted cytotoxicity against Hep G2 and Chang hepatocellular carcinoma cells with the accumulation of the sub-G1 population and increase of terminal deoxynucleotidyltransferasedUTP nick end labeling (TUNEL) positive cells as an apoptotic feature. Also, gallotannin attenuated the expression of pro-caspase9, pro-caspase3, Bcl2 and integrin beta1 and cleaved poly(ADP)-ribose polymerase (PARP) in Hep G2 and Chang cancer cells. Furthermore, gallotannin suppressed cell repair motility by wound healing assay and also inhibited cell adhesion in Hep G2 cells. Of note, gallotannin attenuated the expression of epithelial cadherin (E-cadherin) to form cell-cell adhesion from the early stage, and also beta-catenin at late phase in Hep G2 cells. Consistently, Immunofluorescence assay showed that E-cadherin or beta-catenin expression was suppressed in a time dependent manner by gallotannin. Furthermore, silencing of E-cadherin by siRNA transfection method enhanced PAPR cleavage, caspase 3 activation and sub G1 population and attenuated the cell adhesion induced by gallotannin in Hep G2 cells. Overall, our findings demonstrate that the disruption of cell adhesion junction by suppression of E cadherin mediates gallotannin enhanced apoptosis in Hep G2 liver cancer cells. PMID- 24795532 TI - Applications of a Kullback-Leibler Divergence for Comparing Non-nested Models. AB - Wang and Ghosh (2011) proposed a Kullback-Leibler divergence (KLD) which is asymptotically equivalent to the KLD by Goutis and Robert (1998) when the reference model (in comparison with a competing fitted model) is correctly specified and when certain regularity conditions hold true. While properties of the KLD by Wang and Ghosh (2011) have been investigated in the Bayesian framework, this paper further explores the property of this KLD in the frequentist framework using four application examples, each fitted by two competing non-nested models. PMID- 24795531 TI - Profiling of microRNAs under wound treatment in Aquilaria sinensis to identify possible microRNAs involved in agarwood formation. AB - Agarwood, a kind of highly valued non-timber product across Asia, is formed only when its resource trees--the endangered genus Aquilaria are wounded or infected by some microbes. To promote the efficiency of agarwood production and protect the wild resource of Aquilaria species, we urgently need to reveal the regulation mechanism of agarwood formation. MicroRNAs (miRNAs) are a group of gene expression regulators with overwhelming effects on a large spectrum of biological processes. However, their roles in agarwood formation remain unknown. This work aimed at identifying possible miRNAs involved in the wound induced agarwood formation. In this study, the high-throughput sequencing was adopted to identify miRNAs and monitor their expression under wound treatment in the stems of A. sinensis. The miR171, miR390, miR394, miR2111, and miR3954 families remained at the reduced level two days after the treatment. 131 homologous miRNAs in the 0.5 h library showed over three-fold variation of read number compared with the control library, of which 12 exhibiting strong expression alterations were further confirmed by real-time quantitative PCR. Target prediction and annotation of the miRNAs demonstrated that the binding, metabolic process, catalytic activity, and cellular process are the most common functions of the predicted targets of these newly identified miRNAs in A.sinensis. The cleaveage sites of three newly predicted targets were verified by 5'RACE. PMID- 24795533 TI - Pleomorphic lobular carcinoma of the male breast with axillary lymph node involvement: a case report and review of literature. AB - BACKGROUND: Carcinoma of the male breast is responsible for less than 1% of all malignancies in men but the incidence is rising. Invasive ductal carcinoma is the most common histological subtype while invasive lobular carcinoma is responsible for only 1.5% of the total cases of which pleomorpic lobular carcinoma is an extremely rare variant. We report the case of a gentleman with node positive, pleomorphic lobular carcinoma of the breast. CASE PRESENTATION: An elderly gentleman with a past history of type 2 diabetes and long term ethanol use presented to us with a self-discovered palpable lump in the left breast. Physical examination revealed bilateral gynaecomastia along with a well circumscribed subareolar mass and palpable lymphadenopathy in the ipsilateral axilla. The breast nodule revealed atypical cells on fine needle aspiration biopsy and the patient underwent a modified radical mastectomy after systemic surveillance was negative for metastatic disease. The lesion was reported as grade III pleomorphic lobular carcinoma with a lack of E-cadherin expression on immunohistochemistry and the neoplastic cells exhibited strong positivity for estrogen receptor in the absence of Her2 gene amplification. Six out of the eleven dissected regional lymph nodes showed evidence of disease. The patient completed 4 cycles of adjuvant chemotherapy without evidence of recurrent disease and was subsequently lost to follow up. CONCLUSIONS: Although invasive lobular carcinomas comprise 12% of all female breast cancers, they are very rare in males due to lack of acini and lobules in the normal male breast. Pleomorphic lobular carcinoma, an aggressive variant of ILC is even rarer in males. Chronic consumption of ethanol by our patient may have resulted in some degree of hepatic impairment with resultant hyperestrogenism. This in theory may have been the cause of his gynaecomastia, resultant breast cancer and is a plausible explanation for development of the invasive lobular subtype in a male. The prognosis and clinicopatholocial features of pleomorphic lobular carcinoma in men are less clearly defined due to its rarity. Additional studies are hence necessary to improve our understanding of this disease in males. PMID- 24795535 TI - Robust stabilization control based on guardian maps theory for a longitudinal model of hypersonic vehicle. AB - A typical model of hypersonic vehicle has the complicated dynamics such as the unstable states, the nonminimum phases, and the strong coupling input-output relations. As a result, designing a robust stabilization controller is essential to implement the anticipated tasks. This paper presents a robust stabilization controller based on the guardian maps theory for hypersonic vehicle. First, the guardian maps theories are provided to explain the constraint relations between the open subsets of complex plane and the eigenvalues of the state matrix of closed-loop control system. Then, a general control structure in relation to the guardian maps theories is proposed to achieve the respected design demands. Furthermore, the robust stabilization control law depending on the given general control structure is designed for the longitudinal model of hypersonic vehicle. Finally, a simulation example is provided to verify the effectiveness of the proposed methods. PMID- 24795534 TI - Epigenetic alteration by DNA-demethylating treatment restores apoptotic response to glucocorticoids in dexamethasone-resistant human malignant lymphoid cells. AB - BACKGROUND: Glucocorticoids (GCs) are often included in the therapy of lymphoid malignancies because they kill several types of malignant lymphoid cells. GCs activate the glucocorticoid receptor (GR), to regulate a complex genetic network, culminating in apoptosis. Normal lymphoblasts and many lymphoid malignancies are sensitive to GC-driven apoptosis. Resistance to GCs can be a significant clinical problem, however, and correlates with resistance to several other major chemotherapeutic agents. METHODS: We analyzed the effect of treatment with the cytosine analogue 5 aza-2' deoxycytidine (AZA) on GC resistance in two acute lymphoblastic leukemia (T or pre-T ALL) cell lines- CEM and Molt-4- and a (B cell) myeloma cell line, RPMI 8226. Methods employed included tissue culture, flow cytometry, and assays for clonogenicity, cytosine extension, immunochemical identification of proteins, and gene transactivation. High throughput DNA sequencing was used to confirm DNA methylation status. CONCLUSIONS: Treatment of these cells with AZA resulted in altered DNA methylation and restored GC-evoked apoptosis in all 3 cell lines. In CEM cells the altered epigenetic state resulted in site-specific phosphorylation of the GR, increased GR potency, and GC-driven induction of the GR from promoters that lie in CpG islands. In RPMI 8226 cells, expression of relevant coregulators of GR function was altered. Activation of p38 mitogen-activated protein kinase (MAPK), which is central to a feed-forward mechanism of site-specific GR phosphorylation and ultimately, apoptosis, occurred in all 3 cell lines. These data show that in certain malignant hematologic B- and T-cell types, epigenetically controlled GC resistance can be reversed by cell exposure to a compound that causes DNA demethylation. The results encourage studies of application to in vivo systems, looking towards eventual clinical applications. PMID- 24795537 TI - Convergence analysis and numerical study of a fixed-point iterative method for solving systems of nonlinear equations. AB - We present a fixed-point iterative method for solving systems of nonlinear equations. The convergence theorem of the proposed method is proved under suitable conditions. In addition, some numerical results are also reported in the paper, which confirm the good theoretical properties of our approach. PMID- 24795538 TI - Numerical modeling of the photothermal processing for bubble forming around nanowire in a liquid. AB - An accurate computation of the temperature is an important factor in determining the shape of a bubble around a nanowire immersed in a liquid. The study of the physical phenomenon consists in solving a photothermic coupled problem between light and nanowire. The numerical multiphysic model is used to study the variations of the temperature and the shape of the created bubble by illumination of the nanowire. The optimization process, including an adaptive remeshing scheme, is used to solve the problem through a finite element method. The study of the shape evolution of the bubble is made taking into account the physical and geometrical parameters of the nanowire. The relation between the sizes and shapes of the bubble and nanowire is deduced. PMID- 24795539 TI - Antimicrobial effects of dental luting glass ionomer cements on Streptococcus mutans. AB - OBJECTIVE: To reduce secondary caries, glass ionomer luting cements are often used for cementing of indirect restorations. This is because of their well-known antimicrobial potential through the release of fluoride ions. The aim of this in vitro study was to investigate the antimicrobial effect of five dental luting cements which were based on glass ionomer cement technology. METHODS: Five different glass ionomer based luting cements were tested for their antimicrobial effects on Streptococcus mutans in two different experimental setups: (i) determination of colony-forming units (CFUs) in a plate-counting assay; (ii) live/dead staining (LDS) and fluorescence microscopy. All experiments were conducted with or without prior treatment of the materials using sterilized human saliva. Antimicrobial effects were evaluated for adherent and planktonic bacteria. Bovine enamel slabs (BES) were used as negative control. BES covered with 0.2% chlorhexidine (CHX) served as positive control. RESULTS: Each of the tested materials significantly reduced the number of initially adhered CFUs; this reduction was even more pronounced after prior incubation in saliva. Antimicrobial effects on adherent bacteria were confirmed by live-dead staining. CONCLUSION: All five luting cements showed an antimicrobial potential which was increased by prior incubation with human saliva, suggesting an enhanced effect in vivo. PMID- 24795540 TI - Assessment on knowledge network sharing capability of industrial cluster based on dempster-shafer theory of evidence. AB - Based on Theory of Evidence and reviewing research papers concerned, a concept model of knowledge sharing network among industrial cluster firms, which can be applied to assess knowledge sharing capacity, has been built. Next, the authors create a set of assessment index systems including twelve subindexes under four principle indexes. In this study, ten experts in the same field were invited to score all the indexes of knowledge sharing capacity concerning one certain industrial cluster. The research result shows relatively high knowledge network sharing capacity among the certain industrial cluster firms. Another conclusion is that the assessment method with Theory of Evidence is feasible to conduct such a research. PMID- 24795541 TI - Modeling of information diffusion in Twitter-like social networks under information overload. AB - Due to the existence of information overload in social networks, it becomes increasingly difficult for users to find useful information according to their interests. This paper takes Twitter-like social networks into account and proposes models to characterize the process of information diffusion under information overload. Users are classified into different types according to their in-degrees and out-degrees, and user behaviors are generalized into two categories: generating and forwarding. View scope is introduced to model the user information-processing capability under information overload, and the average number of times a message appears in view scopes after it is generated by a given type user is adopted to characterize the information diffusion efficiency, which is calculated theoretically. To verify the accuracy of theoretical analysis results, we conduct simulations and provide the simulation results, which are consistent with the theoretical analysis results perfectly. These results are of importance to understand the diffusion dynamics in social networks, and this analysis framework can be extended to consider more realistic situations. PMID- 24795543 TI - Estimation of Contaminant Subslab Concentration in Vapor Intrusion Including Lateral Source-Building Separation. AB - Most current vapor-intrusion screening models employ the assumption of a subsurface homogenous source distribution, and groundwater data obtained from nearby monitoring wells are usually taken to reflect the source concentration for several nearby buildings. This practice makes it necessary to consider the possible influence of lateral source-building separation. In this study, a new way to estimate subslab (nonbiodegradable) contaminant concentration is introduced that includes the influence of source offset with the help of a conformal transform technique. Results from this method are compared with those from a three-dimensional numerical model. Based on this newly developed method, a possible explanation is provided here for the great variation in the attenuation factors of the soil vapor concentrations of groundwater-to-subslab contaminants found in the EPA vapor-intrusion database. PMID- 24795542 TI - Kolaviron improved resistance to oxidative stress and inflammation in the blood (erythrocyte, serum, and plasma) of streptozotocin-induced diabetic rats. AB - AIMS: Bitter kola seed (Garcinia kola, family: Guttiferae) has been used as a social masticatory agent in Africa for several years and is believed to possess many useful medicinal properties. The present study evaluates the antioxidative, anti-inflammatory, and antilipidemic effects of kolaviron (an extract from the Garcinia kola seeds) in the blood of streptozotocin- (STZ) induced diabetic rats. METHODS. Diabetic rats were treated with kolaviron (100 mg/kg b.wt) orally, five times a week for a period of six weeks. Serum glucose and HBA(1C) concentrations were estimated in experimental groups. The activities of antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) (in erythrocytes) as well as plasma concentration of malondialdehyde (MDA), a product of lipid peroxidation, oxygen radical absorbing capacity (ORAC) and ferric reducing antioxidant power (FRAP) were investigated. Serum levels of proinflammatory cytokines and growth factor: interleukin- (IL-) 1, monocyte chemotactic protein-1 (MCP-1), and vascular endothelial growth factor (VEGF), respectively, were also analyzed. RESULTS: Kolaviron treatment markedly improved antioxidant status and abated inflammatory response evidenced by reduction in the levels of proinflammatory cytokines and growth factor, lipid peroxidation product, and the restoration of activities of erythrocyte antioxidant enzymes in the blood of diabetic rats. CONCLUSION: Kolaviron improved antioxidant status, reduced inflammation, and protected against hyperglycemic-induced oxidative damage in the blood of diabetic rats. PMID- 24795544 TI - Modeling Excited States in TiO2 Nanoparticles: On the Accuracy of a TD-DFT Based Description. AB - We have investigated the suitability of Time-Dependent Density Functional Theory (TD-DFT) to describe vertical low-energy excitations in naked and hydrated titanium dioxide nanoparticles. Specifically, we compared TD-DFT results obtained using different exchange-correlation (XC) potentials with those calculated using Equation-of-Motion Coupled Cluster (EOM-CC) quantum chemistry methods. We demonstrate that TD-DFT calculations with commonly used XC potentials (e.g., B3LYP) and EOM-CC methods give qualitatively similar results for most TiO2 nanoparticles investigated. More importantly, however, we also show that, for a significant subset of structures, TD-DFT gives qualitatively different results depending upon the XC potential used and that only TD-CAM-B3LYP and TD-BHLYP calculations yield results that are consistent with those obtained using EOM-CC theory. Moreover, we demonstrate that the discrepancies for such structures originate from a particular combination of defects that give rise to charge transfer excitations, which are poorly described by XC potentials that do not contain sufficient Hartree-Fock like exchange. Finally, we consider that such defects are readily healed in the presence of ubiquitously present water and that, as a result, the description of vertical low-energy excitations for hydrated TiO2 nanoparticles is nonproblematic. PMID- 24795545 TI - Study of plasma modified-PTFE for biological applications: relationship between protein resistant properties, plasma treatment, surface composition and surface roughness. AB - PTFE samples were treated by low-pressure, O2 RF plasmas. The adsorption of BSA was used as a probe for the protein resistant properties. The exposure of PTFE to an O2 plasma leads to an increase in the chamber pressure. OES reveals the presence of CO, CO2 and F in the gas phase, indicating a strong etching of the PTFE surface by the O2 plasma. Furthermore, the high resolution C1s spectrum shows the appearance of CF3, CF and C-CF components in addition to the CF2 component, which is consistent with etching of the PTFE surface. WCA as high as 160 degrees were observed, indicating a superhydrophobic behaviour. AFM Images of surfaces treated at high plasma power showed a increase in roughness. Lower amounts of BSA adsorption were detected on high power, O2 plasma-modified PTFE samples compared to low power, oxygen plasma-modified ones. PMID- 24795546 TI - A European survey on awareness of post-surgical adhesions among gynaecological surgeons. AB - The present survey was conducted among gynaecological surgeons from several European countries to assess the actual knowledge and practice related to post surgical adhesions and measures for reduction. From September 1, 2012 to February 6, 2013, gynaecological surgeons were invited to answer an 18-item online questionnaire accessible through the ESGE website. This questionnaire contained eight questions on care settings and surgical practice and ten questions on adhesion formation and adhesion reduction. Four hundred fourteen surgeons participated; 70.8 % agreed that adhesions are a source of major morbidity. About half of them declared that adhesions represented an important part of their daily medical and surgical work. About two thirds informed their patients about the risk of adhesion. Most cited causes of adhesions were abdominal infections and extensive tissue trauma, and endometriosis and myomectomy surgery. Fewer surgeons expected adhesion formation after laparoscopy (18.9 %) than after laparotomy (40.8 %); 60 % knew the surgical techniques recommended to reduce adhesions; only 44.3 % used adhesion-reduction agents on a regular basis. This survey gives a broad picture of adhesion awareness amongst European gynaecological surgeons, mainly from Germany and the UK. The participants had a good knowledge of factors causing adhesions. Knowledge of surgical techniques recommended and use of anti adhesion agents developed to reduce adhesions need to be improved. PMID- 24795547 TI - Anti-adhesion barrier gels following operative hysteroscopy for treating female infertility: a systematic review and meta-analysis. AB - The aim of this study was to assess the effects of any anti-adhesion barrier gel used after operative hysteroscopy for treating infertility associated with uterine cavity abnormalities. Gynecologists might use any barrier gel following operative hysteroscopy in infertile women for decreasing de novo adhesion formation; the use of any barrier gel is associated with less severe de novo adhesions and lower mean adhesion scores. Nevertheless, infertile women should be counseled that there is at the present no evidence for higher live birth or pregnancy rates. There is a lack of data for the outcome miscarriage. Preclinical studies suggest that the use of biodegradable surgical barriers may decrease postsurgical adhesion formation. Observational studies in the human report conflicting results. We searched the Cochrane Menstrual Disorders and Subfertility Specialized Register (10 April 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1), MEDLINE (1950 to 4 April 2013), EMBASE (1974 to 4 April 2013), and other electronic databases of trials including trial registers, sources of unpublished literature, and reference lists. We handsearched the Journal of Minimally Invasive Gynecology (from 1 January 1992 to 13 April 2013); we also contacted experts in the field. We included the randomized comparisons between any anti-adhesion barrier gel versus another barrier gel, placebo, or no adjunctive therapy following operative hysteroscopy. Primary outcomes were live birth rates and de novo adhesion formation at second-look hysteroscopy. Secondary outcomes were pregnancy and miscarriage rates, mean adhesion scores, and severity of adhesions at second-look hysteroscopy. Two authors independently assessed eligible studies for inclusion and risk of bias, and extracted data. We contacted primary study authors for additional information or other clarification. Five trials met the inclusion criteria. There is no evidence for an effect favoring the use of any barrier gel following operative hysteroscopy for the key outcomes of live birth or clinical pregnancy (risk ratio (RR) 3.0, 95 % confidence interval (CI) 0.35 to 26, P = 0.32, one study, 30 women, very low quality evidence); there were no data on the outcome miscarriage. The use of any gel following operative hysteroscopy decreases the incidence of de novo adhesions at second-look hysteroscopy at 1 to 3 months (RR 0.65, 95 % CI 0.45 to 0.93, P = 0.02, five studies, 372 women, very low quality evidence). The number needed to treat to benefit is 9 (95 % CI 5 to 33). The use of auto-cross-linked hyaluronic acid gel in women undergoing operative hysteroscopy for fibroids, endometrial polyps, or uterine septa is associated with a lower mean adhesion score at second-look hysteroscopy at 3 months (mean difference (MD) -1.44, 95 % CI -1.83 to -1.05, P < 0.00001, one study, 24 women; this benefit is even larger in women undergoing operative hysteroscopy for intrauterine adhesions(MD -3.30, 95 % CI -3.43 to -3.17, P < 0.00001, one study, 19 women). After using any gel following operative hysteroscopy, there are more American Fertility Society 1988 stage I (mild) adhesions (RR 2.81, 95 % CI 1.13 to 7.01, P = 0.03, four studies, 79 women). The number needed to treat to benefit is 2 (95 % CI 1 to 4). Similarly there are less' moderate or severe adhesions' at second-look hysteroscopy (RR 0.25, 95 % CI 0.10 to 0.67, P = 0.006, four studies, 79 women). The number needed to treat to benefit is 2 (95 % CI 1 to 4) (all very low quality evidence). There are some concerns for the non-methodological quality. Only two trials included infertile women; in the remaining three studies, it is not clear whether and how many participants suffered from infertility. Therefore, the applicability of the findings of the included studies to the target population under study should be questioned. Moreover, only one small trial studied the effects of anti-adhesion barrier gels for the key outcome of pregnancy; the length of follow-up was, however, not specified. More well-designed and adequately powered randomized studies are needed to assess whether the use of any anti-adhesion gel affects the key reproductive outcomes in a target population of infertile women. PMID- 24795548 TI - Prioritizing spatial accuracy in high-resolution fMRI data using multivariate feature weight mapping. AB - Although ultra-high-field fMRI at field strengths of 7T or above provides substantial gains in BOLD contrast-to-noise ratio, when very high-resolution fMRI is required such gains are inevitably reduced. The improvement in sensitivity provided by multivariate analysis techniques, as compared with univariate methods, then becomes especially welcome. Information mapping approaches are commonly used, such as the searchlight technique, which take into account the spatially distributed patterns of activation in order to predict stimulus conditions. However, the popular searchlight decoding technique, in particular, has been found to be prone to spatial inaccuracies. For instance, the spatial extent of informative areas is generally exaggerated, and their spatial configuration is distorted. We propose the combination of a non-parametric and permutation-based statistical framework with linear classifiers. We term this new combined method Feature Weight Mapping (FWM). The main goal of the proposed method is to map the specific contribution of each voxel to the classification decision while including a correction for the multiple comparisons problem. Next, we compare this new method to the searchlight approach using a simulation and ultra-high-field 7T experimental data. We found that the searchlight method led to spatial inaccuracies that are especially noticeable in high-resolution fMRI data. In contrast, FWM was more spatially precise, revealing both informative anatomical structures as well as the direction by which voxels contribute to the classification. By maximizing the spatial accuracy of ultra-high-field fMRI results, global multivariate methods provide a substantial improvement for characterizing structure-function relationships. PMID- 24795549 TI - Preparing for adulthood: thousands upon thousands of new cells are born in the hippocampus during puberty, and most survive with effortful learning. AB - The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood. PMID- 24795551 TI - Neural mechanisms of peristalsis in the isolated rabbit distal colon: a neuromechanical loop hypothesis. AB - Propulsive contractions of circular muscle are largely responsible for the movements of content along the digestive tract. Mechanical and electrophysiological recordings of isolated colonic circular muscle have demonstrated that localized distension activates ascending and descending interneuronal pathways, evoking contraction orally and relaxation anally. These polarized enteric reflex pathways can theoretically be sequentially activated by the mechanical stimulation of the advancing contents. Here, we test the hypothesis that initiation and propagation of peristaltic contractions involves a neuromechanical loop; that is an initial gut distension activates local and oral reflex contraction and anal reflex relaxation, the subsequent movement of content then acts as new mechanical stimulus triggering sequentially reflex contractions/relaxations at each point of the gut resulting in a propulsive peristaltic contraction. In fluid filled isolated rabbit distal colon, we combined spatiotemporal mapping of gut diameter and intraluminal pressure with a new analytical method, allowing us to identify when and where active (neurally driven) contraction or relaxation occurs. Our data indicate that gut dilation is associated with propagating peristaltic contractions, and that the associated level of dilation is greater than that preceding non-propagating contractions (2.7 +/- 1.4 mm vs. 1.6 +/- 1.2 mm; P < 0.0001). These propagating contractions lead to the formation of boluses that are propelled by oral active neurally driven contractions. The propelled boluses also activate neurally driven anal relaxations, in a diameter dependent manner. These data support the hypothesis that neural peristalsis is the consequence of the activation of a functional loop involving mechanical dilation which activates polarized enteric circuits. These produce propulsion of the bolus which activates further anally, polarized enteric circuits by distension, thus closing the neuromechanical loop. PMID- 24795550 TI - Feedforward and feedback projections of caudal belt and parabelt areas of auditory cortex: refining the hierarchical model. AB - Our working model of the primate auditory cortex recognizes three major regions (core, belt, parabelt), subdivided into thirteen areas. The connections between areas are topographically ordered in a manner consistent with information flow along two major anatomical axes: core-belt-parabelt and caudal-rostral. Remarkably, most of the connections supporting this model were revealed using retrograde tracing techniques. Little is known about laminar circuitry, as anterograde tracing of axon terminations has rarely been used. The purpose of the present study was to examine the laminar projections of three areas of auditory cortex, pursuant to analysis of all areas. The selected areas were: middle lateral belt (ML); caudomedial belt (CM); and caudal parabelt (CPB). Injections of anterograde tracers yielded data consistent with major features of our model, and also new findings that compel modifications. Results supporting the model were: (1) feedforward projection from ML and CM terminated in CPB; (2) feedforward projections from ML and CPB terminated in rostral areas of the belt and parabelt; and (3) feedback projections typified inputs to the core region from belt and parabelt. At odds with the model was the convergence of feedforward inputs into rostral medial belt from ML and CPB. This was unexpected since CPB is at a higher stage of the processing hierarchy, with mainly feedback projections to all other belt areas. Lastly, extending the model, feedforward projections from CM, ML, and CPB overlapped in the temporal parietal occipital area (TPO) in the superior temporal sulcus, indicating significant auditory influence on sensory processing in this region. The combined results refine our working model and highlight the need to complete studies of the laminar inputs to all areas of auditory cortex. Their documentation is essential for developing informed hypotheses about the neurophysiological influences of inputs to each layer and area. PMID- 24795552 TI - Revealing rembrandt. AB - The power and significance of artwork in shaping human cognition is self-evident. The starting point for our empirical investigations is the view that the task of neuroscience is to integrate itself with other forms of knowledge, rather than to seek to supplant them. In our recent work, we examined a particular aspect of the appreciation of artwork using present-day functional magnetic resonance imaging (fMRI). Our results emphasized the continuity between viewing artwork and other human cognitive activities. We also showed that appreciation of a particular aspect of artwork, namely authenticity, depends upon the co-ordinated activity between the brain regions involved in multiple decision making and those responsible for processing visual information. The findings about brain function probably have no specific consequences for understanding how people respond to the art of Rembrandt in comparison with their response to other artworks. However, the use of images of Rembrandt's portraits, his most intimate and personal works, clearly had a significant impact upon our viewers, even though they have been spatially confined to the interior of an MRI scanner at the time of viewing. Neuroscientific studies of humans viewing artwork have the capacity to reveal the diversity of human cognitive responses that may be induced by external advice or context as people view artwork in a variety of frameworks and settings. PMID- 24795554 TI - Therapeutic potential of neural stem cells: greater in people's perception than in their brains? PMID- 24795555 TI - Basal ganglia vulnerability to oxidative stress. PMID- 24795553 TI - Specialized prefrontal "auditory fields": organization of primate prefrontal temporal pathways. AB - No other modality is more frequently represented in the prefrontal cortex than the auditory, but the role of auditory information in prefrontal functions is not well understood. Pathways from auditory association cortices reach distinct sites in the lateral, orbital, and medial surfaces of the prefrontal cortex in rhesus monkeys. Among prefrontal areas, frontopolar area 10 has the densest interconnections with auditory association areas, spanning a large antero posterior extent of the superior temporal gyrus from the temporal pole to auditory parabelt and belt regions. Moreover, auditory pathways make up the largest component of the extrinsic connections of area 10, suggesting a special relationship with the auditory modality. Here we review anatomic evidence showing that frontopolar area 10 is indeed the main frontal "auditory field" as the major recipient of auditory input in the frontal lobe and chief source of output to auditory cortices. Area 10 is thought to be the functional node for the most complex cognitive tasks of multitasking and keeping track of information for future decisions. These patterns suggest that the auditory association links of area 10 are critical for complex cognition. The first part of this review focuses on the organization of prefrontal-auditory pathways at the level of the system and the synapse, with a particular emphasis on area 10. Then we explore ideas on how the elusive role of area 10 in complex cognition may be related to the specialized relationship with auditory association cortices. PMID- 24795556 TI - Neuroscience of foraging. PMID- 24795557 TI - Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory. AB - The cognitive reserve is the capacity of the brain to maintain normal performance while exposed to insults or ageing. Increasing evidences point to a role for the interaction between inflammatory conditions and cognitive reserve status during Alzheimer's disease (AD) progression. The production of new neurons along adult life can be considered as one of the components of the cognitive reserve. Interestingly, adult neurogenesis is decreased in mouse models of AD and following inflammatory processes. The aim of this work is to reveal the long-term impact of a systemic inflammatory event on memory and adult neurogenesis in wild type (WT) and triple transgenic mouse model of AD (3xTg-AD). Four month-old mice were intraperitoneally injected once with saline or lipopolysaccharide (LPS) and their performance on spatial memory analyzed with the Morris water maze (MWM) test 7 weeks later. Our data showed that a single intraperitoneal injection with LPS has a long-term impact in the production of hippocampal neurons. Consistently, LPS-treated WT mice showed less doublecortin-positive neurons, less synaptic contacts in newborn neurons, and decreased dendritic volume and complexity. These surprising observations were accompanied with memory deficits. 3xTg-AD mice showed a decrease in new neurons in the dentate gyrus compatible with, although exacerbated, the pattern observed in WT LPS-treated mice. In 3xTg AD mice, LPS injection did not significantly affected the production of new neurons but reduced their number of synaptic puncta and impaired memory performance, when compared to the observations made in saline-treated 3xTg-AD mice. These data indicate that LPS treatment induces a long-term impairment on hippocampal neurogenesis and memory. Our results show that acute neuroinflammatory events influence the production of new hippocampal neurons, affecting the cognitive reserve and leading to the development of memory deficits associated to AD pathology. PMID- 24795558 TI - Two families with quadrupedalism, mental retardation, no speech, and infantile hypotonia (Uner Tan Syndrome Type-II); a novel theory for the evolutionary emergence of human bipedalism. AB - Two consanguineous families with Uner Tan Syndrome (UTS) were analyzed in relation to self-organizing processes in complex systems, and the evolutionary emergence of human bipedalism. The cases had the key symptoms of previously reported cases of UTS, such as quadrupedalism, mental retardation, and dysarthric or no speech, but the new cases also exhibited infantile hypotonia and are designated UTS Type-II. There were 10 siblings in Branch I and 12 siblings in Branch II. Of these, there were seven cases exhibiting habitual quadrupedal locomotion (QL): four deceased and three living. The infantile hypotonia in the surviving cases gradually disappeared over a period of years, so that they could sit by about 10 years, crawl on hands and knees by about 12 years. They began walking on all fours around 14 years, habitually using QL. Neurological examinations showed normal tonus in their arms and legs, no Babinski sign, brisk tendon reflexes especially in the legs, and mild tremor. The patients could not walk in a straight line, but (except in one case) could stand up and maintain upright posture with truncal ataxia. Cerebello-vermial hypoplasia and mild gyral simplification were noted in their MRIs. The results of the genetic analysis were inconclusive: no genetic code could be identified as the triggering factor for the syndrome in these families. Instead, the extremely low socio-economic status of the patients was thought to play a role in the emergence of UTS, possibly by epigenetically changing the brain structure and function, with a consequent selection of ancestral neural networks for QL during locomotor development. It was suggested that UTS may be regarded as one of the unpredictable outcomes of self-organization within a complex system. It was also noted that the prominent feature of this syndrome, the diagonal-sequence habitual QL, generated an interference between ipsilateral hands and feet, as in non-human primates. It was suggested that this may have been the triggering factor for the attractor state "bipedal locomotion" (BL), which had visual and manual benefits for our ape-like ancestors, and therefore enhancing their chances for survival, with consequent developments in the psychomotor domain of humans. This was put forward as a novel theory of the evolution of BL in human beings. PMID- 24795559 TI - Decoupling speed and accuracy in an urgent decision-making task reveals multiple contributions to their trade-off. AB - A key goal in the study of decision making is determining how neural networks involved in perception and motor planning interact to generate a given choice, but this is complicated due to the internal trade-off between speed and accuracy, which confounds their individual contributions. Urgent decisions, however, are special: they may range between random and fully informed, depending on the amount of processing time (or stimulus viewing time) available in each trial, but regardless, movement preparation always starts early on. As a consequence, under time pressure it is possible to produce a psychophysical curve that characterizes perceptual performance independently of reaction time, and this, in turn, makes it possible to pinpoint how perceptual information (which requires sensory input) modulates motor planning (which does not) to guide a choice. Here we review experiments in which, on the basis of this approach, the origin of the speed accuracy trade-off becomes particularly transparent. Psychophysical, neurophysiological, and modeling results in the "compelled-saccade" task indicate that, during urgent decision making, perceptual information-if and whenever it becomes available-accelerates or decelerates competing motor plans that are already ongoing. This interaction affects both the reaction time and the probability of success in any given trial. In two experiments with reward asymmetries, we find that speed and accuracy can be traded in different amounts and for different reasons, depending on how the particular task contingencies affect specific neural mechanisms related to perception and motor planning. Therefore, from the vantage point of urgent decisions, the speed-accuracy trade off is not a unique phenomenon tied to a single underlying mechanism, but rather a typical outcome of many possible combinations of internal adjustments within sensory-motor neural circuits. PMID- 24795560 TI - Roles of eIF2alpha kinases in the pathogenesis of Alzheimer's disease. AB - Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha). Evidence is accumulating that persistent eIF2alpha phosphorylation at Ser51 through prolonged overactivation of regulatory kinases occurs in neurodegenerative diseases such as Alzheimer's disease (AD), leading to shutdown of general translation and translational activation of a subset of mRNAs. Recent advances in the development of gene-based strategies and bioavailable inhibitors, which specifically target one of the eIF2alpha kinases, have enabled us to investigate pathogenic roles of dysregulated eIF2alpha phosphorylation pathways. This review provides an overview of animal model studies in this field, focusing particularly on molecular mechanisms by which the dysregulation of eIF2alpha kinases may account for synaptic and memory deficits associated with AD. A growing body of evidence suggests that correcting aberrant eIF2alpha kinase activities may serve as disease-modifying therapeutic interventions to treat AD and related cognitive disorders. PMID- 24795561 TI - Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. AB - Many genes have been implicated in the underlying cause of autism but each gene accounts for only a small fraction of those diagnosed with autism. There is increasing evidence that activity-dependent changes in neuronal signaling could act as a convergent mechanism for many of the changes in synaptic proteins. One candidate signaling pathway that may have a critical role in autism is the PI3K/AKT/mTOR pathway. A major regulator of this pathway is the negative repressor phosphatase and tensin homolog (PTEN). In the current study we examined the behavioral and molecular consequences in mice with neuron subset-specific deletion of PTEN. The knockout (KO) mice showed deficits in social chamber and social partition test. KO mice demonstrated alterations in repetitive behavior, as measured in the marble burying test and hole-board test. They showed no changes in ultrasonic vocalizations emitted on postnatal day 10 or 12 compared to wildtype (WT) mice. They exhibited less anxiety in the elevated-plus maze test and were more active in the open field test compared to WT mice. In addition to the behavioral alterations, KO mice had elevation of phosphorylated AKT, phosphorylated S6, and an increase in S6K. KO mice had a decrease in mGluR but an increase in total and phosphorylated fragile X mental retardation protein. The disruptions in intracellular signaling may be why the KO mice had a decrease in the dendritic potassium channel Kv4.2 and a decrease in the synaptic scaffolding proteins PSD-95 and SAP102. These findings demonstrate that deletion of PTEN results in long-term alterations in social behavior, repetitive behavior, activity, and anxiety. In addition, deletion of PTEN significantly alters mGluR signaling and many synaptic proteins in the hippocampus. Our data demonstrates that deletion of PTEN can result in many of the behavioral features of autism and may provide insights into the regulation of intracellular signaling on synaptic proteins. PMID- 24795563 TI - Fatty acids increase neuronal hypertrophy of Pten knockdown neurons. AB - Phosphatase and tensin homolog (Pten) catalyzes the reverse reaction of PI3K by dephosphorylating PIP3 to PIP2. This negatively regulates downstream Akt/mTOR/S6 signaling resulting in decreased cellular growth and proliferation. Co-injection of a lentivirus knocking Pten down with a control lentivirus allows us to compare the effects of Pten knockdown between individual neurons within the same animal. We find that knockdown of Pten results in neuronal hypertrophy by 21 days post injection. This neuronal hypertrophy is correlated with increased p-S6 and p-mTOR in individual neurons. We used this system to test whether an environmental factor that has been implicated in cellular hypertrophy could influence the severity of the Pten knockdown-induced hypertrophy. Implantation of mini-osmotic pumps delivering fatty acids results in increased neuronal hypertrophy and p-S6/p mTOR staining. These hypertrophic effects were reversed in response to rapamycin treatment. However, we did not observe a similar increase in hypertrophy in response to dietary manipulations of fatty acids. Thus, we conclude that by driving growth signaling with fatty acids and knocking down a critical regulator of growth, Pten, we are able to observe an additive morphological phenotype of increased soma size mediated by the mTOR pathway. PMID- 24795562 TI - mTOR signaling and its roles in normal and abnormal brain development. AB - Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mammalian TOR (mTOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development. PMID- 24795564 TI - Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. AB - Activation of guanylate cyclase-C (GC-C) expressed predominantly on intestinal epithelial cells by guanylin, uroguanylin or the closely related GC-C agonist peptide, linaclotide, stimulates generation, and release of cyclic guanosine 3',5'-monophosphate (cGMP). Evidence that the visceral analgesic effects of linaclotide are mediated by a novel, GC-C-dependent peripheral sensory mechanism was first demonstrated in animal models of visceral pain. Subsequent studies with uroguanylin or linaclotide have confirmed the activation of a GC-C/cGMP pathway leading to increased submucosal cGMP mediated by cGMP efflux pumps, which modulates intestinal nociceptor function resulting in peripheral analgesia. These effects can be reproduced by the addition of exogenous cGMP and support a role for GC-C/cGMP signaling in the regulation of visceral sensation, a physiological function that has not previously been linked to the GC-C/cGMP pathway. Notably, targeting the GC-C/cGMP pathway for treatment of gastrointestinal pain and abdominal sensory symptoms has now been validated in the clinic. In 2012, linaclotide was approved in the United States and European Union for the treatment of adult patients with irritable bowel syndrome with constipation. PMID- 24795565 TI - Hox gene regulation in the central nervous system of Drosophila. AB - Hox genes specify the structures that form along the anteroposterior (AP) axis of bilateria. Within the genome, they often form clusters where, remarkably enough, their position within the clusters reflects the relative positions of the structures they specify along the AP axis. This correspondence between genomic organization and gene expression pattern has been conserved through evolution and provides a unique opportunity to study how chromosomal context affects gene regulation. In Drosophila, a general rule, often called "posterior dominance," states that Hox genes specifying more posterior structures repress the expression of more anterior Hox genes. This rule explains the apparent spatial complementarity of Hox gene expression patterns in Drosophila. Here we review a noticeable exception to this rule where the more-posteriorly expressed Abd-B Hox gene fails to repress the more-anterior abd-A gene in cells of the central nervous system (CNS). While Abd-B is required to repress ectopic expression of abd-A in the posterior epidermis, abd-A repression in the posterior CNS is accomplished by a different mechanism that involves a large 92 kb long non-coding RNA (lncRNA) encoded by the intergenic region separating abd-A and Abd-B (the iab8ncRNA). Dissection of this lncRNA revealed that abd-A is repressed by the lncRNA using two redundant mechanisms. The first mechanism is mediated by a microRNA (mir-iab-8) encoded by intronic sequence within the large iab8-ncRNA. Meanwhile, the second mechanism seems to involve transcriptional interference by the long iab-8 ncRNA on the abd-A promoter. Recent work demonstrating CNS specific regulation of genes by ncRNAs in Drosophila, seem to highlight a potential role for the iab-8-ncRNA in the evolution of the Drosophila Hox complexes. PMID- 24795566 TI - Phagocytic receptors activate and immune inhibitory receptor SIRPalpha inhibits phagocytosis through paxillin and cofilin. AB - The innate immune function of phagocytosis of apoptotic cells, tissue debris, pathogens, and cancer cells is essential for homeostasis, tissue repair, fighting infection, and combating malignancy. Phagocytosis is carried out in the central nervous system (CNS) by resident microglia and in both CNS and peripheral nervous system by recruited macrophages. While phagocytosis proceeds, bystander healthy cells protect themselves by sending a "do not eat me" message to phagocytes as CD47 on their surface ligates immune inhibitory receptor SIRPalpha on the surface of phagocytes and SIRPalpha then produces the signaling which inhibits phagocytosis. This helpful mechanism becomes harmful when tissue debris and unhealthy cells inhibit their own phagocytosis by employing the same mechanism. However, the inhibitory signaling that SIRPalpha produces has not been fully revealed. We focus here on how SIRPalpha inhibits the phagocytosis of the tissue debris "degenerated myelin" which hinders repair in axonal injury and neurodegenerative diseases. We tested whether SIRPalpha inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a) the cytoskeleton generates the mechanical forces that drive phagocytosis and (b) both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPalpha expression was knocked-down by SIRPalpha-shRNA. Further, levels of phagocytosis, paxillin activation, and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPalpha produces by promoting the inactivation of paxillin and cofilin. PMID- 24795567 TI - Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. AB - Alzheimer disease (AD) is the most common cause of dementia in people over 60 years old. The molecular and cellular alterations that trigger this disease are still diffuse, one of the reasons for the delay in finding an effective treatment. In the search for new targets to search for novel therapeutic avenues, clinical studies in patients who used anti-inflammatory drugs indicating a lower incidence of AD have been of value to support the neuroinflammatory hypothesis of the neurodegenerative processes and the role of innate immunity in this disease. Neuroinflammation appears to occur as a consequence of a series of damage signals, including trauma, infection, oxidative agents, redox iron, oligomers of tau and beta-amyloid, etc. In this context, our theory of Neuroimmunomodulation focus on the link between neuronal damage and brain inflammatory process, mediated by the progressive activation of astrocytes and microglial cells with the consequent overproduction of proinflammatory agents. Here, we discuss about the role of microglial and astrocytic cells, the principal agents in neuroinflammation process, in the development of neurodegenerative diseases such as AD. In this context, we also evaluated the potential relevance of natural anti inflammatory components, which include curcumin and the novel Andean Compound, as agents for AD prevention and as a coadjuvant for AD treatments. PMID- 24795568 TI - The role of extracellular Tau in the spreading of neurofibrillary pathology. AB - The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of Alzheimer's disease (AD) and several related disorders collectively known as tauopathies. Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of AD patients, tau pathology spreads following an anatomically defined pattern. Mounting evidence strongly suggests that accumulation of abnormal tau is mediated through spreading of seeds of the protein from cell to cell and point at the involvement of extracellular tau species as the main agent in the interneuronal propagation of neurofibrillary lesions and spreading of tau toxicity throughout different brain regions in these disorders. That would support the concept that pathology initiates in a very small part of the brain many years before becoming symptomatic, spreading progressively to the whole brain within 10-20 years. Understanding the precise molecular mechanism underlying tau propagation is crucial for the development of therapeutics for this devastating disorder. In this work, we will discuss recent research on the role of extracellular tau in the spreading of tau pathology, through synaptic and non-synaptic mechanisms. PMID- 24795569 TI - Star players sidelined in chloride homeostasis in neurons. PMID- 24795570 TI - A new era for functional labeling of neurons: activity-dependent promoters have come of age. AB - Genetic labeling of neurons with a specific response feature is an emerging technology for precise dissection of brain circuits that are functionally heterogeneous at the single-cell level. While immediate early gene mapping has been widely used for decades to identify brain regions which are activated by external stimuli, recent characterization of the promoter and enhancer elements responsible for neuronal activity-dependent transcription have opened new avenues for live imaging of active neurons. Indeed, these advancements provided the basis for a growing repertoire of novel experiments to address the role of active neuronal networks in cognitive behaviors. In this review, we summarize the current literature on the usage and development of activity-dependent promoters and discuss the future directions of this expanding new field. PMID- 24795571 TI - Dopamine-enabled anti-Hebbian timing-dependent plasticity in prefrontal circuitry. AB - Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre-post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post-pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post-pre pairings at 0.1 Hz, deltat = -30 ms), we found that DA applied during post-pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits. PMID- 24795572 TI - Concept learning and the use of three common psychophysical paradigms in the archerfish (Toxotes chatareus). AB - Archerfish are well known for their specialized hunting technique of spitting water at prey located above the water line. This unique ability has made them a popular focus of study as researchers try to understand the mechanisms involved in targeting and spitting. In more recent years, archerfish have also become an increasingly popular model for studying visual discrimination and learning in general. Until now, only the alternative forced-choice (AFC) task has been used with archerfish, however, they may be capable of learning other classical discrimination tasks. As well as providing alternative, and potentially more efficient, means for testing their visual capabilities, these other tasks may also provide deeper insight into the extent to which an organism with no cortex can grasp the concepts underlying these tasks. In this paper, we consider both the matched-to-sample (MTS) and the odd-one-out (OOO) tasks as they require the subject to learn relatively sophisticated concepts rather than a straight, stimulus-reward relationship, of the kind underlying AFC tasks. A variety of line drawings displayed on a monitor were used as stimuli. We first determined if archerfish could complete the MTS and OOO test and then evaluated their ability to be retrained to new stimuli using a 4-AFC test. We found that archerfish were unable to learn the MTS and had only a limited capacity for learning the OOO task. We conclude that the MTS and OOO are impractical as paradigms for behavioral experiments with archerfish. However, the archerfish could rapidly learn to complete an AFC test and select the conditioned stimulus with a high degree of accuracy when faced with four stimuli, making this a powerful test for behavioral studies testing visual discrimination. In addition, the fish were able to learn the concept of oddity under particular training circumstances. This paper adds to the growing evidence that animals without a cortex are capable of learning some higher order concepts. PMID- 24795573 TI - The functional and anatomical dissection of somatosensory subpopulations using mouse genetics. AB - The word somatosensation comes from joining the Greek word for body (soma) with a word for perception (sensation). Somatosensory neurons comprise the largest sensory system in mammals and have nerve endings coursing throughout the skin, viscera, muscle, and bone. Their cell bodies reside in a chain of ganglia adjacent to the dorsal spinal cord (the dorsal root ganglia) and at the base of the skull (the trigeminal ganglia). While the neuronal cell bodies are intermingled within the ganglia, the somatosensory system is in reality composed of numerous sub-systems, each specialized to detect distinct stimuli, such as temperature and touch. Historically, somatosensory neurons have been classified using a diverse host of anatomical and physiological parameters, such as the size of the cell body, degree of myelination, histological labeling with markers, specialization of the nerve endings, projection patterns in the spinal cord and brainstem, receptive tuning, and conduction velocity of their action potentials. While useful, the picture that emerged was one of heterogeneity, with many markers at least partially overlapping. More recently, by capitalizing on advances in molecular techniques, researchers have identified specific ion channels and sensory receptors expressed in subsets of sensory neurons. These studies have proved invaluable as they allow genetic access to small subsets of neurons for further molecular dissection. Data being generated from transgenic mice favor a model whereby an array of dedicated neurons is responsible for selectively encoding different modalities. Here we review the current knowledge of the different sensory neuron subtypes in the mouse, the markers used to study them, and the neurogenetic strategies used to define their anatomical projections and functional roles. PMID- 24795574 TI - Comparative neuronal morphology of the cerebellar cortex in afrotherians, carnivores, cetartiodactyls, and primates. AB - Although the basic morphological characteristics of neurons in the cerebellar cortex have been documented in several species, virtually nothing is known about the quantitative morphological characteristics of these neurons across different taxa. To that end, the present study investigated cerebellar neuronal morphology among eight different, large-brained mammalian species comprising a broad phylogenetic range: afrotherians (African elephant, Florida manatee), carnivores (Siberian tiger, clouded leopard), cetartiodactyls (humpback whale, giraffe) and primates (human, common chimpanzee). Specifically, several neuron types (e.g., stellate, basket, Lugaro, Golgi, and granule neurons; N = 317) of the cerebellar cortex were stained with a modified rapid Golgi technique and quantified on a computer-assisted microscopy system. There was a 64-fold variation in brain mass across species in our sample (from clouded leopard to the elephant) and a 103 fold variation in cerebellar volume. Most dendritic measures tended to increase with cerebellar volume. The cerebellar cortex in these species exhibited the trilaminate pattern common to all mammals. Morphologically, neuron types in the cerebellar cortex were generally consistent with those described in primates (Fox et al., 1967) and rodents (Palay and Chan-Palay, 1974), although there was substantial quantitative variation across species. In particular, Lugaro neurons in the elephant appeared to be disproportionately larger than those in other species. To explore potential quantitative differences in dendritic measures across species, MARSplines analyses were used to evaluate whether species could be differentiated from each other based on dendritic characteristics alone. Results of these analyses indicated that there were significant differences among all species in dendritic measures. PMID- 24795575 TI - What do temporal lobe epilepsy and progressive mild cognitive impairment have in common? AB - Temporal lobe epilepsy (TLE) and mild cognitive impairment (MCI) are both subject to intensive memory research. Memory problems are a core characteristic of both conditions and we wonder if there are analogies which would enrich the two distinct research communities. In this review we focus on memory decline in both conditions, that is, the most feared psychosocial effect. While it is clear that memory decline in MCI is highly likely and would lead to the more severe diagnosis of Alzheimer's disease, it is a debate if TLE is a dementing disease or not. As such, like for MCI, one can differentiate progressive from stable TLE subtypes, mainly depending on the age of onset. Neuroimaging techniques such as volumetric analysis of the hippocampus, entorhinal, and perirhinal cortex show evidence of pathological changes in TLE and are predictive for memory decline in MCI. Several studies emphasize that it is necessary to extend the region of interest-even whole-brain characteristics can be predictive for conversion from MCI to Alzheimer's disease. Electroencephalography is increasingly subject to computational neuroscience, revealing new approaches for analyzing frequency, spatial synchronization, and information content of the signals. These methods together with event-related designs that assess memory functions are highly promising for understanding the mechanisms of memory decline in both TLE and MCI populations. Finally, there is evidence that the potential of such markers for memory decline is far from being exhausted. Similar structural and neurophysiological characteristics are linked to memory decline in TLE and MCI. We raise the hope that interdisciplinary research and cross-talk between fields such as research on epilepsy and dementia, will shed further light on the dementing characteristics of the pathological basis of MCI and TLE and support the development of new memory enhancing treatment strategies. PMID- 24795576 TI - The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats. AB - A novel factor of interest for growth/plasticity in the brain is pregnane xenobiotic receptor (PXR). PXR is a liver factor known for its role in xenobiotic clearance and cholesterol metabolism. It is expressed in the brain, suggesting a potential role for plasticity, particularly involving cholesterol-based steroids and neurosteroids. Mating induces synthesis of neurosteroids in the midbrain Ventral Tegmental Area (VTA) of female rodents, as well as other "plastic" regions of the brain, including the hippocampus, that may be involved in the consolidation of the mating experience. Reducing PXR in the VTA attenuates mating induced biosynthesis of the neurosteroid, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). The 18 kDA translocator protein (TSPO) is one rate-limiting factor for 3alpha,5alpha-THP neurosteroidogenesis. The hypothesis tested was that PXR is an upstream factor of TSPO for neurosteroidogenesis of 3alpha,5alpha-THP in the VTA for lordosis, independent of peripheral glands. First, proestrous rats were administered a TSPO blocker (PK11195) and/or 3alpha,5alpha-THP following infusions of PXR antisense oligonucleotides (AS-ODNs) or vehicle to the VTA. Inhibiting TSPO with PK11195 reduced 3alpha,5alpha-THP levels in the midbrain and lordosis, an effect that could be reversed with 3alpha,5alpha-THP administration, but not AS-ODN+3alpha,5alpha-THP. Second, proestrous, ovariectomized (OVX), or ovariectomized/adrenalectomized (OVX/ADX) rats were infused with a TSPO enhancer (FGIN 1-27) subsequent to AS-ODNs or vehicle to the VTA. PXR AS-ODNs blocked actions of FGIN 1-27 for lordosis and 3alpha,5alpha-THP levels among proestrous > OVX > OVX/ADX rats. Thus, PXR may be upstream of TSPO, involved in neurosteroidogenesis of 3alpha,5alpha-THP in the brain for plasticity. This novel finding of a liver factor involved in behavioral/neural plasticity substantiates future studies investigating factors known for their prominent actions in the peripheral organs, such as the liver, for modulating brain function and its augmentation. PMID- 24795577 TI - Eye movement-related brain activity during perceptual and cognitive processing. PMID- 24795579 TI - Complex neural codes in rat prelimbic cortex are stable across days on a spatial decision task. AB - The rodent prelimbic cortex has been shown to play an important role in cognitive processing, and has been implicated in encoding many different parameters relevant to solving decision-making tasks. However, it is not known how the prelimbic cortex represents all these disparate variables, and if they are simultaneously represented when the task requires it. In order to investigate this question, we trained rats to run the Multiple-T Left Right Alternate (MT LRA) task and recorded multi-unit ensembles from their prelimbic regions. Significant populations of cells in the prelimbic cortex represented the strategy controlling reward receipt on a given lap, whether the animal chose to go right or left on a given lap, and whether the animal made a correct decision or an error on a given lap. These populations overlapped in the cells recorded, with several cells demonstrating differential firing to all three variables. The spatial and strategic firing patterns of individual prelimbic cells were highly conserved across several days of running this task, indicating that each cell encoded the same information across days. PMID- 24795578 TI - The vestibular contribution to the head direction signal and navigation. AB - Spatial learning and navigation depend on neural representations of location and direction within the environment. These representations, encoded by place cells and head direction (HD) cells, respectively, are dominantly controlled by visual cues, but require input from the vestibular system. Vestibular signals play an important role in forming spatial representations in both visual and non-visual environments, but the details of this vestibular contribution are not fully understood. Here, we review the role of the vestibular system in generating various spatial signals in rodents, focusing primarily on HD cells. We also examine the vestibular system's role in navigation and the possible pathways by which vestibular information is conveyed to higher navigation centers. PMID- 24795580 TI - Corticosterone and decision-making in male Wistar rats: the effect of corticosterone application in the infralimbic and orbitofrontal cortex. AB - Corticosteroid hormones, released after stress, are known to influence neuronal activity and produce a wide range of effects upon the brain. They affect cognitive tasks including decision-making. Recently it was shown that systemic injections of corticosterone (CORT) disrupt reward-based decision-making in rats when tested in a rat model of the Iowa Gambling Task (rIGT), i.e., rats do not learn across trial blocks to avoid the long-term disadvantageous option. This effect was associated with a change in neuronal activity in prefrontal brain areas, i.e., the infralimbic (IL), lateral orbitofrontal (lOFC) and insular cortex, as assessed by changes in c-Fos expression. Here, we studied whether injections of CORT directly into the IL and lOFC lead to similar changes in decision-making. As in our earlier study, CORT was injected during the final 3 days of the behavioral paradigm, 25 min prior to behavioral testing. Infusions of vehicle into the IL led to a decreased number of visits to the disadvantageous arm across trial blocks, while infusion with CORT did not. Infusions into the lOFC did not lead to differences in the number of visits to the disadvantageous arm between vehicle treated and CORT treated rats. However, compared to vehicle treated rats of the IL group, performance of vehicle treated rats of the lOFC group was impaired, possibly due to cannulation/infusion-related damage of the lOFC affecting decision-making. Overall, these results show that infusions with CORT into the IL are sufficient to disrupt decision-making performance, pointing to a critical role of the IL in corticosteroid effects on reward-based decision making. The data do not directly support that the same holds true for infusions into the lOFC. PMID- 24795581 TI - The impact of multiple memory formation on dendritic complexity in the hippocampus and anterior cingulate cortex assessed at recent and remote time points. AB - Consolidation processes, involving synaptic and systems level changes, are suggested to stabilize memories once they are formed. At the synaptic level, dendritic structural changes are associated with long-term memory storage. At the systems level, memory storage dynamics between the hippocampus and anterior cingulate cortex (ACC) may be influenced by the number of sequentially encoded memories. The present experiment utilized Golgi-Cox staining and neuron reconstruction to examine recent and remote structural changes in the hippocampus and ACC following training on three different behavioral procedures. Rats were trained on one hippocampal-dependent task only (a water maze task), two hippocampal-dependent tasks (a water maze task followed by a radial arm maze task), or one hippocampal-dependent and one non-hippocampal-dependent task (a water maze task followed by an operant conditioning task). Rats were euthanized recently or remotely. Brains underwent Golgi-Cox processing and neurons were reconstructed using Neurolucida software (MicroBrightField, Williston, VT, USA). Rats trained on two hippocampal-dependent tasks displayed increased dendritic complexity compared to control rats, in neurons examined in both the ACC and hippocampus at recent and remote time points. Importantly, this behavioral group showed consistent, significant structural differences in the ACC compared to the control group at the recent time point. These findings suggest that taxing the demand placed upon the hippocampus, by training rats on two hippocampal-dependent tasks, engages synaptic and systems consolidation processes in the ACC at an accelerated rate for recent and remote storage of spatial memories. PMID- 24795582 TI - Pregnanolone Glutamate, a Novel Use-Dependent NMDA Receptor Inhibitor, Exerts Antidepressant-Like Properties in Animal Models. AB - A number of studies demonstrated a rapid onset of an antidepressant effect of non competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3alpha5beta-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3alphaC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. HIGHLIGHTS: -3alpha5beta-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic like and antidepressant-like properties. PMID- 24795583 TI - Episodic memories in anxiety disorders: clinical implications. AB - The aim of this review is to summarize research on the emerging role of episodic memories in the context of anxiety disorders (AD). The available literature on explicit, autobiographical, and episodic memory function in AD including neuroimaging studies is critically discussed. We describe the methodological diversity of episodic memory research in AD and discuss the need for novel tests to measure episodic memory in a clinical setting. We argue that alterations in episodic memory functions might contribute to the etiology of AD. We further explain why future research on the interplay between episodic memory function and emotional disorders as well as its neuroanatomical foundations offers the promise to increase the effectiveness of modern psychological treatments. We conclude that one major task is to develop methods and training programs that might help patients suffering from AD to better understand, interpret, and possibly actively use their episodic memories in a way that would support therapeutic interventions and counteract the occurrence of symptoms. PMID- 24795584 TI - Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson's disease. AB - CD157, known as bone marrow stromal cell antigen-1, is a glycosylphosphatidylinositol-anchored ADP-ribosyl cyclase that supports the survival and function of B-lymphocytes and hematopoietic or intestinal stem cells. Although CD157/Bst1 is a risk locus in Parkinson's disease (PD), little is known about the function of CD157 in the nervous system and contribution to PD progression. Here, we show that no apparent motor dysfunction was observed in young knockout (CD157 (-/-)) male mice under less aging-related effects on behaviors. CD157 (-/-) mice exhibited anxiety-related and depression-like behaviors compared with wild-type mice. These behaviors were rescued through treatment with anti-psychiatric drugs and oxytocin. CD157 was weakly expressed in the amygdala and c-Fos immunoreactivity in the amygdala was less evident in CD157 (-/-) mice than in wild-type mice. These results demonstrate for the first time that CD157 plays a role as a neuro-regulator and suggest a potential role in pre motor symptoms in PD. PMID- 24795585 TI - Sleep and olfactory cortical plasticity. AB - In many systems, sleep plays a vital role in memory consolidation and synaptic homeostasis. These processes together help store information of biological significance and reset synaptic circuits to facilitate acquisition of information in the future. In this review, we describe recent evidence of sleep-dependent changes in olfactory system structure and function which contribute to odor memory and perception. During slow-wave sleep, the piriform cortex becomes hypo responsive to odor stimulation and instead displays sharp-wave activity similar to that observed within the hippocampal formation. Furthermore, the functional connectivity between the piriform cortex and other cortical and limbic regions is enhanced during slow-wave sleep compared to waking. This combination of conditions may allow odor memory consolidation to occur during a state of reduced external interference and facilitate association of odor memories with stored hedonic and contextual cues. Evidence consistent with sleep-dependent odor replay within olfactory cortical circuits is presented. These data suggest that both the strength and precision of odor memories is sleep-dependent. The work further emphasizes the critical role of synaptic plasticity and memory in not only odor memory but also basic odor perception. The work also suggests a possible link between sleep disturbances that are frequently co-morbid with a wide range of pathologies including Alzheimer's disease, schizophrenia and depression and the known olfactory impairments associated with those disorders. PMID- 24795589 TI - Plastic neuroscience: studying what the brain cares about. AB - Drawing on Allan Newell's "You can't play 20 questions with nature and win," this article proposes that neuroscience needs to go beyond binary hypothesis testing and design experiments that follow what neurons care about. Examples from Lettvin et. al. are used to demonstrate that one can experimentally play with neurons and generate surprising results. In this manner, brains are not confused with persons, rather, persons are understood to do things with their brains. PMID- 24795587 TI - Individual differences in behavioral and cardiovascular reactivity to emotive stimuli and their relationship to cognitive flexibility in a primate model of trait anxiety. AB - High trait anxiety is a risk factor for the development of anxiety disorders. Like the disorders themselves high trait anxiety has marked phenotypic variation at the level of symptomatology and neural circuits, suggesting that there may be different symptoms and distinct neural circuits associated with risk for these disorders. To address these issues, it is essential to develop reliable animal models of trait anxiety in a non-human primate whose brain bears structural and functional similarity to humans. The present study investigated individual variation in responsivity to fearful and anxiety provoking stimuli in the common marmoset monkey. Seven out of 27 animals failed to display discriminative, conditioned cardiovascular and behavioral responses on an auditory fear discrimination task, similar to that seen in high anxious humans and rodents. Their heightened emotionality to a rubber snake was consistent with the hypothesis that they were high in trait-like anxiety. Evidence for phenotypic variation in the high anxiety group was provided by the finding that discrimination failure was predicted early in conditioning by either hyper vigilant scanning to the cues or a reduction in blood pressure to the context, i.e., test apparatus. Given that high trait anxiety in humans can be associated with altered prefrontal cognitive functioning and previously we implicated the marmoset anterior orbitofrontal (antOFC) and ventrolateral prefrontal cortex (vlPFC) in negative emotion regulation, we also tested the marmosets on two tests of cognitive flexibility differentially dependent on these two regions. While the high anxious group did not differ overall in their perseverative performance, the two distinct phenotypes were differentially correlated with reduced perseverative responding on the OFC- and vlPFC-dependent flexibility tests. Together, this study provides a new model of trait anxiety in marmosets amenable to analysis of phenotypic variation and neural circuitry. PMID- 24795588 TI - The causal role between phasic midbrain dopamine signals and learning. PMID- 24795586 TI - Mood disorders in Huntington's disease: from behavior to cellular and molecular mechanisms. AB - Huntington's disease (HD) is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT). HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function. PMID- 24795590 TI - Online transcranial Doppler ultrasonographic control of an onscreen keyboard. AB - Brain-computer interface (BCI) systems exploit brain activity for generating a control command and may be used by individuals with severe motor disabilities as an alternative means of communication. An emerging brain monitoring modality for BCI development is transcranial Doppler ultrasonography (TCD), which facilitates the tracking of cerebral blood flow velocities associated with mental tasks. However, TCD-BCI studies to date have exclusively been offline. The feasibility of a TCD-based BCI system hinges on its online performance. In this paper, an online TCD-BCI system was implemented, bilaterally tracking blood flow velocities in the middle cerebral arteries for system-paced control of a scanning keyboard. Target letters or words were selected by repetitively rehearsing the spelling while imagining the writing of the intended word, a left-lateralized task. Undesired letters or words were bypassed by performing visual tracking, a non lateralized task. The keyboard scanning period was 15 s. With 10 able-bodied right-handed young adults, the two mental tasks were differentiated online using a Naive Bayes classification algorithm and a set of time-domain, user-dependent features. The system achieved an average specificity and sensitivity of 81.44 +/- 8.35 and 82.30 +/- 7.39%, respectively. The level of agreement between the intended and machine-predicted selections was moderate (kappa = 0.60). The average information transfer rate was 0.87 bits/min with an average throughput of 0.31 +/- 0.12 character/min. These findings suggest that an online TCD-BCI can achieve reasonable accuracies with an intuitive language task, but with modest throughput. Future interface and signal classification enhancements are required to improve communication rate. PMID- 24795591 TI - The activity in the contralateral primary motor cortex, dorsal premotor and supplementary motor area is modulated by performance gains. AB - There is growing experimental evidence that the engagement of different brain areas in a given motor task may change with practice, although the specific brain activity patterns underlying different stages of learning, as defined by kinematic or dynamic performance indices, are not well understood. Here we studied the change in activation in motor areas during practice on sequences of handwriting-like trajectories, connecting four target points on a digitizing table "as rapidly and as accurately as possible" while lying inside an fMRI scanner. Analysis of the subjects' pooled kinematic and imaging data, acquired at the beginning, middle, and end of the training period, revealed no correlation between the amount of activation in the contralateral M1, PM (dorsal and ventral), supplementary motor area (SMA), preSMA, and Posterior Parietal Cortex (PPC) and the amount of practice per-se. Single trial analysis has revealed that the correlation between the amount of activation in the contralateral M1 and trial mean velocity was partially modulated by performance gains related effects, such as increased hand motion smoothness. Furthermore, it was found that the amount of activation in the contralateral preSMA increased when subjects shifted from generating straight point-to-point trajectories to their spatiotemporal concatenation into a smooth, curved trajectory. Altogether, our results indicate that the amount of activation in the contralateral M1, PMd, and preSMA during the learning of movement sequences is correlated with performance gains and that high level motion features (e.g., motion smoothness) may modulate, or even mask correlations between activity changes and low-level motion attributes (e.g., trial mean velocity). PMID- 24795592 TI - Twisting tongues to test for conflict-monitoring in speech production. AB - A number of recent studies have hypothesized that monitoring in speech production may occur via domain-general mechanisms responsible for the detection of response conflict. Outside of language, two ERP components have consistently been elicited in conflict-inducing tasks (e.g., the flanker task): the stimulus-locked N2 on correct trials, and the response-locked error-related negativity (ERN). The present investigation used these electrophysiological markers to test whether a common response conflict monitor is responsible for monitoring in speech and non speech tasks. Electroencephalography (EEG) was recorded while participants performed a tongue twister (TT) task and a manual version of the flanker task. In the TT task, people rapidly read sequences of four nonwords arranged in TT and non-TT patterns three times. In the flanker task, people responded with a left/right button press to a center-facing arrow, and conflict was manipulated by the congruency of the flanking arrows. Behavioral results showed typical effects of both tasks, with increased error rates and slower speech onset times for TT relative to non-TT trials and for incongruent relative to congruent flanker trials. In the flanker task, stimulus-locked EEG analyses replicated previous results, with a larger N2 for incongruent relative to congruent trials, and a response-locked ERN. In the TT task, stimulus-locked analyses revealed broad, frontally-distributed differences beginning around 50 ms and lasting until just before speech initiation, with TT trials more negative than non-TT trials; response-locked analyses revealed an ERN. Correlation across these measures showed some correlations within a task, but little evidence of systematic cross task correlation. Although the present results do not speak against conflict signals from the production system serving as cues to self-monitoring, they are not consistent with signatures of response conflict being mediated by a single, domain-general conflict monitor. PMID- 24795593 TI - Brain activation during phonological and semantic processing of Chinese characters in deaf signers. AB - Previous studies found altered brain function in deaf individuals reading alphabetic orthographies. However, it is not known whether similar alterations of brain function are characteristic of non-alphabetic writing systems and whether alterations are specific to certain kinds of lexical tasks. Here we examined differences in brain activation between Chinese congenitally deaf individuals (CD) and hearing controls (HC) during character reading tasks requiring phonological and semantic judgments. For both tasks, we found that CD showed less activation than HC in left inferior frontal gyrus, but greater activation in several right hemisphere regions including inferior frontal gyrus, angular gyrus, and inferior temporal gyrus. Although many group differences were similar across tasks, greater activation in right middle frontal gyrus was more pronounced for the rhyming compared to the meaning task. Finally, within the deaf individuals better performance on the rhyming task was associated with less activation in right inferior parietal lobule and angular gyrus. Our results in Chinese CD are broadly consistent with previous studies in alphabetic languages suggesting greater engagement of inferior frontal gyrus and inferior parietal cortex for reading that is largely independent of task, with the exception of right middle frontal gyrus for phonological processing. The brain behavior correlations potentially indicate that CD that more efficiently use the right hemisphere are better readers. PMID- 24795594 TI - The effects of a single night of sleep deprivation on fluency and prefrontal cortex function during divergent thinking. AB - The dorsal and ventral aspects of the prefrontal cortex (PFC) are the two regions most consistently recruited in divergent thinking tasks. Given that frontal tasks have been shown to be vulnerable to sleep loss, we explored the impact of a single night of sleep deprivation on fluency (i.e., number of generated responses) and PFC function during divergent thinking. Participants underwent functional magnetic resonance imaging scanning twice while engaged in the Alternate Uses Task (AUT) - once following a single night of sleep deprivation and once following a night of normal sleep. They also wore wrist activity monitors, which enabled us to quantify daily sleep and model cognitive effectiveness. The intervention was effective, producing greater levels of fatigue and sleepiness. Modeled cognitive effectiveness and fluency were impaired following sleep deprivation, and sleep deprivation was associated with greater activation in the left inferior frontal gyrus (IFG) during AUT. The results suggest that an intervention known to temporarily compromise frontal function can impair fluency, and that this effect is instantiated in the form of an increased hemodynamic response in the left IFG. PMID- 24795595 TI - Pupillary behavior in relation to wavelength and age. AB - Pupil light reflex can be used as a non-invasive ocular predictor of cephalic autonomic nervous system integrity. Spectral sensitivity of the pupil's response to light has, for some time, been an interesting issue. It has generally, however, only been investigated with the use of white light and studies with monochromatic wavelengths are scarce. This study investigates the effects of wavelength and age within three parameters of the pupil light reflex (amplitude of response, latency, and velocity of constriction) in a large sample of younger and older adults (N = 97), in mesopic conditions. Subjects were exposed to a single light stimulus at four different wavelengths: white (5600 degrees K), blue (450 nm), green (510 nm), and red (600 nm). Data was analyzed appropriately, and, when applicable, using the General Linear Model (GLM), Randomized Complete Block Design (RCBD), Student's t-test and/or ANCOVA. Across all subjects, pupillary response to light had the greatest amplitude and shortest latency in white and green light conditions. In regards to age, older subjects (46-78 years) showed an increased latency in white light and decreased velocity of constriction in green light compared to younger subjects (18-45 years old). This study provides data patterns on parameters of wavelength-dependent pupil reflexes to light in adults and it contributes to the large body of pupillometric research. It is hoped that this study will add to the overall evaluation of cephalic autonomic nervous system integrity. PMID- 24795596 TI - I can see clearly now: the effects of age and perceptual load on inattentional blindness. AB - Attention and awareness are known to be linked (e.g., see Lavie et al., 2014, for a review). However the extent to which this link changes over development is not fully understood. Most research concerning the development of attention has investigated the effects of attention on distraction, visual search and spatial orienting, typically using reaction time measures which cannot directly support conclusions about conscious awareness. Here we used Lavie's Load Theory of Attention and Cognitive Control to examine the development of attention effects on awareness. According to Load Theory, awareness levels are determined by the availability of attentional capacity. We hypothesized that attentional capacity develops with age, and consequently that awareness rates should increase with development due to the enhanced capacity. Thus we predicted that greater rates of inattentional blindness (IB) would be found at a younger age, and that lower levels of load will be sufficient to exhaust capacity and cause IB in children but not adults. We tested this hypothesis using an IB paradigm with adults and children aged 7-8, 9-10, 11-12 and 13 years old. Participants performed a line length judgment task (indicating which arm of a cross is longer) and on the last trial were asked to report whether they noticed an unexpected task-irrelevant stimulus (a small square) in the display. Perceptual load was varied by changing the line-length difference (with a smaller difference in the conditions of higher load). The results supported our hypothesis: levels of awareness increased with age, and a moderate increase in the perceptual load of the task led to greater IB for children but not adults. These results extended across both peripheral and central presentations of the task stimuli. Overall, these findings establish the development of capacity for awareness and demonstrate the critical role of the perceptual load in the attended task. PMID- 24795598 TI - Catch trials in force field learning influence adaptation and consolidation of human motor memory. AB - Force field studies are a common tool to investigate motor adaptation and consolidation. Thereby, subjects usually adapt their reaching movements to force field perturbations induced by a robotic device. In this context, so-called catch trials, in which the disturbing forces are randomly turned off, are commonly used to detect after-effects of motor adaptation. However, catch trials also produce sudden large motor errors that might influence the motor adaptation and the consolidation process. Yet, the detailed influence of catch trials is far from clear. Thus, the aim of this study was to investigate the influence of catch trials on motor adaptation and consolidation in force field experiments. Therefore, 105 subjects adapted their reaching movements to robot-generated force fields. The test groups adapted their reaching movements to a force field A followed by learning a second interfering force field B before retest of A (ABA). The control groups were not exposed to force field B (AA). To examine the influence of diverse catch trial ratios, subjects received catch trials during force field adaptation with a probability of either 0, 10, 20, 30, or 40%, depending on the group. First, the results on motor adaptation revealed significant differences between the diverse catch trial ratio groups. With increasing amount of catch trials, the subjects' motor performance decreased and subjects' ability to accurately predict the force field-and therefore internal model formation-was impaired. Second, our results revealed that adapting with catch trials can influence the following consolidation process as indicated by a partial reduction to interference. Here, the optimal catch trial ratio was 30%. However, detection of consolidation seems to be biased by the applied measure of performance. PMID- 24795599 TI - Maximal discharge rate of motor units determines the maximal rate of force development during ballistic contractions in human. PMID- 24795597 TI - Independent and collaborative contributions of the cerebral hemispheres to emotional processing. AB - Presented is a model suggesting that the right hemisphere (RH) directly mediates the identification and comprehension of positive and negative emotional stimuli, whereas the left hemisphere (LH) contributes to higher level processing of emotional information that has been shared via the corpus callosum. RH subcortical connections provide initial processing of emotional stimuli, and their innervation to cortical structures provides a secondary pathway by which the hemispheres process emotional information more fully. It is suggested that the LH contribution to emotion processing is in emotional regulation, social well being, and adaptation, and transforming the RH emotional experience into propositional and verbal codes. Lastly, it is proposed that the LH has little ability at the level of emotion identification, having a default positive bias and no ability to identify a stimulus as negative. Instead, the LH must rely on the transfer of emotional information from the RH to engage higher-order emotional processing. As such, either hemisphere can identify positive emotions, but they must collaborate for complete processing of negative emotions. Evidence presented draws from behavioral, neurological, and clinical research, including discussions of subcortical and cortical pathways, callosal agenesis, commissurotomy, emotion regulation, mood disorders, interpersonal interaction, language, and handedness. Directions for future research are offered. PMID- 24795600 TI - On the role of the ventral attention system in spatial orienting. PMID- 24795601 TI - Mapping memory binding onto the connectome's temporal dynamics: toward a combined biomarker for Alzheimer's disease. PMID- 24795603 TI - Differential effect of motivational features on training improvements in school based cognitive training. AB - Cognitive training often utilizes game-like motivational features to keep participants engaged. It is unclear how these elements, such as feedback, reward, and theming impact player performance during training. Recent research suggests that motivation and engagement are closely related to improvements following cognitive training. We hypothesized that training paradigms featuring game-like motivational elements would be more effective than a version with no motivational elements. Five distinct motivational features were chosen for examination: a real time scoring system, theme changes, prizes, end-of-session certificates, and scaffolding to explain the lives and leveling system included in the game. One version of the game was created with all these motivational elements included, and one was created with all of them removed. Other versions removed a single element at a time. Seven versions of a game-like n-back working memory task were then created and administered to 128 students in second through eight grade at school-based summer camps in southeastern Michigan. The inclusion of real-time scoring during play, a popular motivational component in both entertainment games and cognitive training, was found to negatively impact training improvements over the three day period. Surprisingly, scaffolding to explain lives and levels also negatively impacted training gains. The other game adjustments did not significantly impact training improvement compared to the original version of the game with all features included. These findings are preliminary and are limited by both the small sample size and the brevity of the intervention. Nonetheless, these findings suggest that certain motivational elements may distract from the core cognitive training task, reducing task improvement, especially at the initial stage of learning. PMID- 24795602 TI - Altered choroid plexus gene expression in major depressive disorder. AB - Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFbeta) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier. PMID- 24795604 TI - A cross-linguistic evaluation of script-specific effects on fMRI lateralization in late second language readers. AB - Behavioral and neuroimaging studies have provided evidence that reading is strongly left lateralized, and the degree of this pattern of functional lateralization can be indicative of reading competence. However, it remains unclear whether functional lateralization differs between the first (L1) and second (L2) languages in bilingual L2 readers. This question is particularly important when the particular script, or orthography, learned by the L2 readers is markedly different from their L1 script. In this study, we quantified functional lateralization in brain regions involved in visual word recognition for participants' L1 and L2 scripts, with a particular focus on the effects of L1 L2 script differences in the visual complexity and orthographic depth of the script. Two different groups of late L2 learners participated in an fMRI experiment using a visual one-back matching task: L1 readers of Japanese who learnt to read alphabetic English and L1 readers of English who learnt to read both Japanese syllabic Kana and logographic Kanji. The results showed weaker leftward lateralization in the posterior lateral occipital complex (pLOC) for logographic Kanji compared with syllabic and alphabetic scripts in both L1 and L2 readers of Kanji. When both L1 and L2 scripts were non-logographic, where symbols are mapped onto sounds, functional lateralization did not significantly differ between L1 and L2 scripts in any region, in any group. Our findings indicate that weaker leftward lateralization for logographic reading reflects greater requirement of the right hemisphere for processing visually complex logographic Kanji symbols, irrespective of whether Kanji is the readers' L1 or L2, rather than characterizing additional cognitive efforts of L2 readers. Finally, brain behavior analysis revealed that functional lateralization for L2 visual word processing predicted L2 reading competency. PMID- 24795605 TI - The effect of musical expertise on the representation of space. AB - Consistent evidence suggests that pitch height may be represented in a spatial format, having both a vertical and a horizontal representation. The spatial representation of pitch height results into response compatibility effects for which high pitch tones are preferentially associated to up-right responses, and low pitch tones are preferentially associated to down-left responses (i.e., the Spatial-Musical Association of Response Codes (SMARC) effect), with the strength of these associations depending on individuals' musical skills. In this study we investigated whether listening to tones of different pitch affects the representation of external space, as assessed in a visual and haptic line bisection paradigm, in musicians and non musicians. Low and high pitch tones affected the bisection performance in musicians differently, both when pitch was relevant and irrelevant for the task, and in both the visual and the haptic modality. No effect of pitch height was observed on the bisection performance of non musicians. Moreover, our data also show that musicians present a (supramodal) rightward bisection bias in both the visual and the haptic modality, extending previous findings limited to the visual modality, and consistent with the idea that intense practice with musical notation and bimanual instrument training affects hemispheric lateralization. PMID- 24795607 TI - Passive listening to preferred motor tempo modulates corticospinal excitability. AB - Rhythms are an essential characteristic of our lives, and auditory-motor coupling affects a variety of behaviors. Previous research has shown that the neural regions associated with motor system processing are coupled to perceptual rhythmic and melodic processing such that the perception of rhythmic stimuli can entrain motor system responses. However, the degree to which individual preference modulates the motor system is unknown. Recent work has shown that passively listening to metrically strong rhythms increases corticospinal excitability, as indicated by transcranial magnetic stimulation (TMS). Furthermore, this effect is modulated by high-groove music, or music that inspires movement, while neuroimaging evidence suggests that premotor activity increases with tempos occurring within a preferred tempo (PT) category. PT refers to the rate of a hypothetical endogenous oscillator that may be indicated by spontaneous motor tempo (SMT) and preferred perceptual tempo (PPT) measurements. The present study investigated whether listening to a rhythm at an individual's PT preferentially modulates motor system excitability. SMT was obtained in human participants through a tapping task in which subjects were asked to tap a response key at their most comfortable rate. Subjects listened a 10-beat tone sequence at 11 log-spaced tempos and rated their preference for each (PPT). We found that SMT and PPT measurements were correlated, indicating that preferred and produced tempos occurred at a similar rate. Crucially, single-pulse TMS delivered to left M1 during PPT judgments revealed that corticospinal excitability, measured by motor-evoked potentials (MEPs), was modulated by tempos traveling closer to individual PT. However, the specific nature of this modulation differed across individuals, with some exhibiting an increase in excitability around PT and others exhibiting a decrease. These findings suggest that auditory-motor coupling induced by rhythms is preferentially modulated by rhythms occurring at a preferred rate, and that individual differences can alter the nature of this coupling. PMID- 24795606 TI - Distant functional connectivity for bimanual finger coordination declines with aging: an fMRI and SEM exploration. AB - Although bimanual finger coordination is known to decline with aging, it still remains unclear how exactly the neural substrates underlying the coordination differ between young and elderly adults. The present study focused on: (1) characterization of the functional connectivity within the motor association cortex which is required for successful bimanual finger coordination, and (2) to elucidate upon its age-related decline. To address these objectives, we utilized functional magnetic resonance imaging (fMRI) in combination with structural equation modeling (SEM). This allowed us to compare functional connectivity models between young and elderly age groups during a visually guided bimanual finger movement task using both stable in-phase and complex anti-phase modes. Our SEM exploration of functional connectivity revealed significant age-related differences in connections surrounding the PMd in the dominant hemisphere. In the young group who generally displayed accurate behavior, the SEM model for the anti phase mode exhibited significant connections from the dominant PMd to the non dominant SPL, and from the dominant PMd to the dominant S1. However, the model for the elderly group's anti-phase mode in which task performance dropped, did not exhibit significant connections within the aforementioned regions. These results suggest that: (1) the dominant PMd acts as an intermediary to invoke intense intra- and inter-hemispheric connectivity with distant regions among the higher motor areas including the dominant S1 and the non-dominant SPL in order to achieve successful bimanual finger coordination, and (2) the distant connectivity among the higher motor areas declines with aging, whereas the local connectivity within the bilateral M1 is enhanced for the complex anti-phase mode. The latter may underlie the elderly's decreased performance in the complex anti-phase mode of the bimanual finger movement task. PMID- 24795608 TI - A dual process for the cognitive control of emotional significance: implications for emotion regulation and disorders of emotion. PMID- 24795609 TI - Habit acquisition in the context of neuronal genomic and epigenomic mosaicism. PMID- 24795610 TI - What can mirror-touch synaesthesia tell us about the sense of agency? PMID- 24795611 TI - Injury of the mammillothalamic tract in patients with thalamic hemorrhage. AB - OBJECTIVE: Injury of the mammillothalamic tract (MTT) has been suggested as one of the plausible pathogenic mechanisms of memory impairment in patients with thalamic hemorrhage; however, it has not been clearly demonstrated so far. We attempted to investigate whether injury of the MTT documented by diffusion tensor tractography following thalamic hemorrhage correlates with cognitive impairment. METHODS: We recruited 22 patients with a thalamic hemorrhage and 20 control subjects. MTTs were reconstructed using the probabilistic tractography method. Patients were classified into two subgroups: reconstructed group, patients whose MTT was reconstructed in the affected hemisphere, and non-reconstructed group, patients whose MTT was not reconstructed. RESULTS: Mammillothalamic tract was reconstructed in 5 (22.7%, reconstructed group) patients in the affected hemisphere and was not reconstructed in the remaining 17 patients (77.3%, non reconstructed group). In addition, the MTT was not reconstructed even in the unaffected hemisphere in four patients (23.5%) in non-reconstructed group. Fractional anisotropy and mean diffusivity values of the affected hemisphere in reconstructed group also did not show significant differences from those in the unaffected hemisphere of reconstructed group and the control group (p > 0.05). However, the tract volume of the affected hemisphere in reconstructed group was significantly lower than that of the unaffected hemisphere in reconstructed group and the control group (p < 0.05). CONCLUSION: A large portion of patients with thalamic hemorrhage appeared to suffer severe injury of the ipsilesional MTT (77.3%) and 18.2% of them appeared to suffer severe injury even in the contralesional MTT. In addition, the remaining 22.7% of patients who had preserved integrity of the ipsilesional MTT appeared to suffer partial injury of the ipsilesional MTT. PMID- 24795612 TI - Cerebral pressure passivity in newborns with encephalopathy undergoing therapeutic hypothermia. AB - We extended our recent modification of the power spectral estimation approach to quantify spectral coherence. We tested both the standard and the modified approaches on simulated data, which showed that the modified approach was highly specific and sensitive to the coupling introduced in the simulation while the standard approach lacked these features. We also applied the modified and standard approaches to quantify the pressure passivity in 4 infants receiving therapeutic hypothermia. This was done by measuring the coupling between continuous cerebral hemoglobin differences and mean arterial blood pressure. Our results showed that the modified approach identified a lower pressure passivity index (PPI, percent time the coherence was above a predefined threshold) than the standard approach (P = 0.0027). PMID- 24795613 TI - Sparse short-distance connections enhance calcium wave propagation in a 3D model of astrocyte networks. AB - Traditionally, astrocytes have been considered to couple via gap-junctions into a syncytium with only rudimentary spatial organization. However, this view is challenged by growing experimental evidence that astrocytes organize as a proper gap-junction mediated network with more complex region-dependent properties. On the other hand, the propagation range of intercellular calcium waves (ICW) within astrocyte populations is as well highly variable, depending on the brain region considered. This suggests that the variability of the topology of gap-junction couplings could play a role in the variability of the ICW propagation range. Since this hypothesis is very difficult to investigate with current experimental approaches, we explore it here using a biophysically realistic model of three dimensional astrocyte networks in which we varied the topology of the astrocyte network, while keeping intracellular properties and spatial cell distribution and density constant. Computer simulations of the model suggest that changing the topology of the network is indeed sufficient to reproduce the distinct ranges of ICW propagation reported experimentally. Unexpectedly, our simulations also predict that sparse connectivity and restriction of gap-junction couplings to short distances should favor propagation while long-distance or dense connectivity should impair it. Altogether, our results provide support to recent experimental findings that point toward a significant functional role of the organization of gap-junction couplings into proper astroglial networks. Dynamic control of this topology by neurons and signaling molecules could thus constitute a new type of regulation of neuron-glia and glia-glia interactions. PMID- 24795614 TI - An extended reinforcement learning model of basal ganglia to understand the contributions of serotonin and dopamine in risk-based decision making, reward prediction, and punishment learning. AB - Although empirical and neural studies show that serotonin (5HT) plays many functional roles in the brain, prior computational models mostly focus on its role in behavioral inhibition. In this study, we present a model of risk based decision making in a modified Reinforcement Learning (RL)-framework. The model depicts the roles of dopamine (DA) and serotonin (5HT) in Basal Ganglia (BG). In this model, the DA signal is represented by the temporal difference error (delta), while the 5HT signal is represented by a parameter (alpha) that controls risk prediction error. This formulation that accommodates both 5HT and DA reconciles some of the diverse roles of 5HT particularly in connection with the BG system. We apply the model to different experimental paradigms used to study the role of 5HT: (1) Risk-sensitive decision making, where 5HT controls risk assessment, (2) Temporal reward prediction, where 5HT controls time-scale of reward prediction, and (3) Reward/Punishment sensitivity, in which the punishment prediction error depends on 5HT levels. Thus the proposed integrated RL model reconciles several existing theories of 5HT and DA in the BG. PMID- 24795615 TI - Saccade learning with concurrent cortical and subcortical basal ganglia loops. AB - The Basal Ganglia (BG) is a central structure involved in multiple cortical and subcortical loops. Some of these loops are believed to be responsible for saccade target selection. We study here how the very specific structural relationships of these saccadic loops can affect the ability of learning spatial and feature-based tasks. We propose a model of saccade generation with reinforcement learning capabilities based on our previous BG and superior colliculus models. It is structured around the interactions of two parallel cortico-basal loops and one tecto-basal loop. The two cortical loops separately deal with spatial and non spatial information to select targets in a concurrent way. The subcortical loop is used to make the final target selection leading to the production of the saccade. These different loops may work in concert or disturb each other regarding reward maximization. Interactions between these loops and their learning capabilities are tested on different saccade tasks. The results show the ability of this model to correctly learn basic target selection based on different criteria (spatial or not). Moreover the model reproduces and explains training dependent express saccades toward targets based on a spatial criterion. Finally, the model predicts that in absence of prefrontal control, the spatial loop should dominate. PMID- 24795616 TI - Integrated platform and API for electrophysiological data. AB - Recent advancements in technology and methodology have led to growing amounts of increasingly complex neuroscience data recorded from various species, modalities, and levels of study. The rapid data growth has made efficient data access and flexible, machine-readable data annotation a crucial requisite for neuroscientists. Clear and consistent annotation and organization of data is not only an important ingredient for reproducibility of results and re-use of data, but also essential for collaborative research and data sharing. In particular, efficient data management and interoperability requires a unified approach that integrates data and metadata and provides a common way of accessing this information. In this paper we describe GNData, a data management platform for neurophysiological data. GNData provides a storage system based on a data representation that is suitable to organize data and metadata from any electrophysiological experiment, with a functionality exposed via a common application programming interface (API). Data representation and API structure are compatible with existing approaches for data and metadata representation in neurophysiology. The API implementation is based on the Representational State Transfer (REST) pattern, which enables data access integration in software applications and facilitates the development of tools that communicate with the service. Client libraries that interact with the API provide direct data access from computing environments like Matlab or Python, enabling integration of data management into the scientist's experimental or analysis routines. PMID- 24795618 TI - libNeuroML and PyLEMS: using Python to combine procedural and declarative modeling approaches in computational neuroscience. AB - NeuroML is an XML-based model description language, which provides a powerful common data format for defining and exchanging models of neurons and neuronal networks. In the latest version of NeuroML, the structure and behavior of ion channel, synapse, cell, and network model descriptions are based on underlying definitions provided in LEMS, a domain-independent language for expressing hierarchical mathematical models of physical entities. While declarative approaches for describing models have led to greater exchange of model elements among software tools in computational neuroscience, a frequent criticism of XML based languages is that they are difficult to work with directly. Here we describe two Application Programming Interfaces (APIs) written in Python (http://www.python.org), which simplify the process of developing and modifying models expressed in NeuroML and LEMS. The libNeuroML API provides a Python object model with a direct mapping to all NeuroML concepts defined by the NeuroML Schema, which facilitates reading and writing the XML equivalents. In addition, it offers a memory-efficient, array-based internal representation, which is useful for handling large-scale connectomics data. The libNeuroML API also includes support for performing common operations that are required when working with NeuroML documents. Access to the LEMS data model is provided by the PyLEMS API, which provides a Python implementation of the LEMS language, including the ability to simulate most models expressed in LEMS. Together, libNeuroML and PyLEMS provide a comprehensive solution for interacting with NeuroML models in a Python environment. PMID- 24795617 TI - Integrating neuroinformatics tools in TheVirtualBrain. AB - TheVirtualBrain (TVB) is a neuroinformatics Python package representing the convergence of clinical, systems, and theoretical neuroscience in the analysis, visualization and modeling of neural and neuroimaging dynamics. TVB is composed of a flexible simulator for neural dynamics measured across scales from local populations to large-scale dynamics measured by electroencephalography (EEG), magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), and core analytic and visualization functions, all accessible through a web browser user interface. A datatype system modeling neuroscientific data ties together these pieces with persistent data storage, based on a combination of SQL and HDF5. These datatypes combine with adapters allowing TVB to integrate other algorithms or computational systems. TVB provides infrastructure for multiple projects and multiple users, possibly participating under multiple roles. For example, a clinician might import patient data to identify several potential lesion points in the patient's connectome. A modeler, working on the same project, tests these points for viability through whole brain simulation, based on the patient's connectome, and subsequent analysis of dynamical features. TVB also drives research forward: the simulator itself represents the culmination of several simulation frameworks in the modeling literature. The availability of the numerical methods, set of neural mass models and forward solutions allows for the construction of a wide range of brain-scale simulation scenarios. This paper briefly outlines the history and motivation for TVB, describing the framework and simulator, giving usage examples in the web UI and Python scripting. PMID- 24795619 TI - High-throughput neuroimaging-genetics computational infrastructure. AB - Many contemporary neuroscientific investigations face significant challenges in terms of data management, computational processing, data mining, and results interpretation. These four pillars define the core infrastructure necessary to plan, organize, orchestrate, validate, and disseminate novel scientific methods, computational resources, and translational healthcare findings. Data management includes protocols for data acquisition, archival, query, transfer, retrieval, and aggregation. Computational processing involves the necessary software, hardware, and networking infrastructure required to handle large amounts of heterogeneous neuroimaging, genetics, clinical, and phenotypic data and meta data. Data mining refers to the process of automatically extracting data features, characteristics and associations, which are not readily visible by human exploration of the raw dataset. Result interpretation includes scientific visualization, community validation of findings and reproducible findings. In this manuscript we describe the novel high-throughput neuroimaging-genetics computational infrastructure available at the Institute for Neuroimaging and Informatics (INI) and the Laboratory of Neuro Imaging (LONI) at University of Southern California (USC). INI and LONI include ultra-high-field and standard field MRI brain scanners along with an imaging-genetics database for storing the complete provenance of the raw and derived data and meta-data. In addition, the institute provides a large number of software tools for image and shape analysis, mathematical modeling, genomic sequence processing, and scientific visualization. A unique feature of this architecture is the Pipeline environment, which integrates the data management, processing, transfer, and visualization. Through its client-server architecture, the Pipeline environment provides a graphical user interface for designing, executing, monitoring validating, and disseminating of complex protocols that utilize diverse suites of software tools and web services. These pipeline workflows are represented as portable XML objects which transfer the execution instructions and user specifications from the client user machine to remote pipeline servers for distributed computing. Using Alzheimer's and Parkinson's data, we provide several examples of translational applications using this infrastructure. PMID- 24795620 TI - Efficient generation of connectivity in neuronal networks from simulator independent descriptions. AB - Simulator-independent descriptions of connectivity in neuronal networks promise greater ease of model sharing, improved reproducibility of simulation results, and reduced programming effort for computational neuroscientists. However, until now, enabling the use of such descriptions in a given simulator in a computationally efficient way has entailed considerable work for simulator developers, which must be repeated for each new connectivity-generating library that is developed. We have developed a generic connection generator interface that provides a standard way to connect a connectivity-generating library to a simulator, such that one library can easily be replaced by another, according to the modeler's needs. We have used the connection generator interface to connect C++ and Python implementations of the previously described connection-set algebra to the NEST simulator. We also demonstrate how the simulator-independent modeling framework PyNN can transparently take advantage of this, passing a connection description through to the simulator layer for rapid processing in C++ where a simulator supports the connection generator interface and falling-back to slower iteration in Python otherwise. A set of benchmarks demonstrates the good performance of the interface. PMID- 24795621 TI - Smaller, softer, lower-impedance electrodes for human neuroprosthesis: a pragmatic approach. AB - Finding the most appropriate technology for building electrodes to be used for long term implants in humans is a challenging issue. What are the most appropriate technologies? How could one achieve robustness, stability, compatibility, efficacy, and versatility, for both recording and stimulation? There are no easy answers to these questions as even the most fundamental and apparently obvious factors to be taken into account, such as the necessary mechanical, electrical and biological properties, and their interplay, are under debate. We present here our approach along three fundamental parallel pathways: we reduced electrode invasiveness and size without impairing signal-to-noise ratio, we increased electrode active surface area by depositing nanostructured materials, and we protected the brain from direct contact with the electrode without compromising performance. Altogether, these results converge toward high resolution ECoG arrays that are soft and adaptable to cortical folds, and have been proven to provide high spatial and temporal resolution. This method provides a piece of work which, in our view, makes several steps ahead in bringing such novel devices into clinical settings, opening new avenues in diagnostics of brain diseases, and neuroprosthetic applications. PMID- 24795623 TI - The role of D-serine and glycine as co-agonists of NMDA receptors in motor neuron degeneration and amyotrophic lateral sclerosis (ALS). AB - The fundamental role of D-serine as a co-agonist at the N-methyl-D-aspartate receptor (NMDAR), mediating both physiological actions of glutamate in long term potentiation and nociception and also pathological effects mediated by excitotoxicty, are well-established. More recently, a direct link to a chronic neurodegenerative disease, amyotrophic lateral sclerosis/motor neuron disease (ALS) has been suggested by findings that D-serine levels are elevated in sporadic ALS and the G93A SOD1 model of ALS (Sasabe et al., 2007, 2012) and that a pathogenic mutation (R199W) in the enzyme that degrades D-serine, D-amino acid oxidase (DAO), co-segregates with disease in familial ALS (Mitchell et al., 2010). Moreover, D-serine, its biosynthetic enzyme, serine racemase (SR) and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated aggregates and promotes apoptosis, all of which processes are attenuated by a D-serine/glycine site NMDAR antagonist. These studies provide considerable insight into the crosstalk between neurons and glia and also into potential therapeutic approaches for ALS. PMID- 24795622 TI - Serine racemase: a key player in apoptosis and necrosis. AB - A fine balance between cell survival and cell death is required to sculpt the nervous system during development. However, an excess of cell death can occur following trauma, exposure to neurotoxins or alcohol, and some developmental and neurodegenerative diseases, such as Alzheimer's disease (AD). N-Methyl-D aspartate receptors (NMDARs) support synaptic plasticity and survival of many neuronal populations whereas inappropriate activation may promote various forms of cell death, apoptosis, and necrosis representing the two extremes of a continuum of cell death processes both "in vitro" and "in vivo." Hence, by identifying the switches controlling pro-survival vs. apoptosis and apoptosis vs. pro-excitotoxic outcome of NMDAR stimulation, NMDAR modulators could be developed that selectively block the cell death enhancing pro-survival signaling or synaptic plasticity mediated by NMDAR. Among these modulators, a role is emerging for the enzyme serine racemase (SR) that synthesizes D-serine, a key co-agonist with glutamate at NMDAR. This review summarizes the experimental evidence from "in vitro" neuronal cultures-with special emphasis on cerebellar granule neurons (CGNs)-and "in vivo" models of neurodegeneration, where the dual role of the SR/D serine pathway as a master regulator of apoptosis and the apoptosis-necrosis shift will be discussed. PMID- 24795624 TI - Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease. AB - We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer's disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-epsilon4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories. PMID- 24795625 TI - Age-related changes to the neural correlates of working memory which emerge after midlife. AB - Previous research has indicated that the neural processes which underlie working memory change with age. Both age-related increases and decreases to cortical activity have been reported. This study investigated which stages of working memory are most vulnerable to age-related changes after midlife. To do this we examined age-differences in the 13 Hz steady state visually evoked potential (SSVEP) associated with a spatial working memory delayed response task. Participants were 130 healthy adults separated into a midlife (40-60 years) and an older group (61-82 years). Relative to the midlife group, older adults demonstrated greater bilateral frontal activity during encoding and this pattern of activity was related to better working memory performance. In contrast, evidence of age-related under activation was identified over left frontal regions during retrieval. Findings from this study suggest that after midlife, under activation of frontal regions during retrieval contributes to age-related decline in working memory performance. PMID- 24795627 TI - Age-related neurochemical changes in the rhesus macaque inferior colliculus. AB - Age-related hearing loss (ARHL) is marked by audiometric hearing deficits that propagate along the auditory pathway. Neurochemical changes as a function of aging have also been identified in neurons along the auditory pathway in both rodents and carnivores, however, very little is known about how these neurochemicals change in the non-human primate. To examine how these compensatory neurochemical changes relate to normal aging and audiometric sensitivity along the auditory pathway, we collected auditory brainstem responses (ABRs) and brain specimens from seven rhesus monkeys spanning in age from 15 to 35 years old, and examined the relationship between click evoked ABR thresholds and the ABR evoked pure tone average (PTA) and changes in the number of parvalbumin and NADPH diaphorase positive cells in the auditory midbrain. We found that the number of parvalbumin positive cells in the central nucleus and the surrounding cortex regions of the inferior colliculus were strongly correlated with advancing age and ABR PTA. We also found that the numbers of NADPHd positive cells in these same regions were not associated with normal aging or changes in the ABR thresholds. These findings suggest that the auditory midbrain undergoes an up regulation of parvalbumin expressing neurons with aging that is related to changes in the processing of frequencies across the audiometric range. PMID- 24795626 TI - Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors. AB - The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include beta-amyloid (Abeta) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Abeta accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease. PMID- 24795628 TI - Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer's disease by deep sequencing. AB - One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Abeta aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Abeta4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4 42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss. PMID- 24795629 TI - Fluid intelligence and brain functional organization in aging yoga and meditation practitioners. AB - Numerous studies have documented the normal age-related decline of neural structure, function, and cognitive performance. Preliminary evidence suggests that meditation may reduce decline in specific cognitive domains and in brain structure. Here we extended this research by investigating the relation between age and fluid intelligence and resting state brain functional network architecture using graph theory, in middle-aged yoga and meditation practitioners, and matched controls. Fluid intelligence declined slower in yoga practitioners and meditators combined than in controls. Resting state functional networks of yoga practitioners and meditators combined were more integrated and more resilient to damage than those of controls. Furthermore, mindfulness was positively correlated with fluid intelligence, resilience, and global network efficiency. These findings reveal the possibility to increase resilience and to slow the decline of fluid intelligence and brain functional architecture and suggest that mindfulness plays a mechanistic role in this preservation. PMID- 24795630 TI - Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study. AB - There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease. PMID- 24795631 TI - Erk5 is a mediator to TGFbeta1-induced loss of phenotype and function in human podocytes. AB - BACKGROUND: Podocytes are highly specialized cells integral to the normal functioning kidney, however, in diabetic nephropathy injury occurs leading to a compromised phenotype and podocyte dysfunction which critically produces podocyte loss with subsequent renal impairment. TGFbeta1 holds a major role in the development of diabetic nephropathy. Erk5 is an atypical mitogen-activated protein (MAP) kinase involved in pathways modulating cell survival, proliferation, differentiation, and motility. Accordingly, the role of Erk5 in mediating TGFbeta1-induced podocyte damage was investigated. METHODS: Conditionally immortalized human podocytes were stimulated with TGFbeta1 (2.5 ng/ml); inhibition of Erk5 activation was conducted with the chemical inhibitor BIX02188 (10 MUM) directed to the upstream Mek5; inhibition of Alk5 was performed with SB431542 (10 MUM); Ras signaling was inhibited with farnesylthiosalicylic acid (10 MUM). Intracellular signaling proteins were investigated by western blotting; phenotype was explored by immunofluorescence; proliferation was assessed with a MTS assay; motility was examined with a scratch assay; barrier function was studied using electric cell-substrate impedance sensing; apoptosis was studied with annexin V-FITC flow cytometry. RESULTS: Podocytes expressed Erk5 which was phosphorylated by TGFbeta1 via Mek5, whilst not involving Ras. TGFbeta1 altered podocyte phenotype by decreasing P-cadherin staining and increasing alpha SMA, as well as reducing podocyte barrier function; both were prevented by inhibiting Erk5 phosphorylation with BIX02188. TGFbeta1-induced podocyte proliferation was prevented by BIX02188, whereas the induced apoptosis was not. Podocyte motility was reduced by BIX02188 alone and further diminished with TGFbeta1 co-incubation. CONCLUSION: These results describe for the first time the expression of Erk5 in podocytes and identify it as a potential target for the treatment of diabetic renal disease. PMID- 24795632 TI - Delirium-biomarkers and genetic variance. PMID- 24795634 TI - Dose and time-dependent sub-chronic toxicity study of hydroethanolic leaf extract of Flabellaria paniculata Cav. (Malpighiaceae) in rodents. AB - Flabellaria paniculata Cav. (Malpighiaceae) is a climbing shrub, the preparations of which are used in the treatment of wounds and ulcers in Nigeria and Ghana. This study investigated the sub-chronic toxicity profile of the hydroethanolic leaf extract of F. paniculata (HLE-FP). HLE-FP was administered p.o. (20, 100, and 500 mg/kg) for 30 and 60 days to different groups of rats. Control animals received 10 ml/kg distilled water. In the group of animals for reversibility study, HLE-FP administration ceased on the 60th day and animals were monitored for a further 15 days. Results showed that oral treatment with HLE-FP for 30 days caused significant (p < 0.05) reductions in weight gain pattern compared to control. These changes were sustained with 60 days treatment. However, no significant (p > 0.05) differences in relative organ weights between control and treatment groups were observed. HLE-FP-treated rats showed significant (p < 0.05) increases in Hb, PCV and RBC on day 30 and significant (p < 0.05) increases in MCV and MCH indices on day 60 compared to control. There were significant (p < 0.05) elevations in serum K(+), urea and creatinine compared to control. The liver function tests showed slight but non-significant alterations in relevant parameters when compared to control. Biochemical findings were supported by histopathological observations of vital organs including the kidney and liver. Toxicities observed in respect of kidney function were irreversible at 15 days of stoppage of treatment. In the acute toxicity study, HLE-FP given p.o. caused no lethality at 5000 mg/kg but behavioral manifestations like restlessness, generalized body tremor, feed, and water refusal were observed. The i.p. LD50 was estimated to be 2951.2 mg/kg. Findings in this study showed that HLE-FP is relatively non-toxic on acute exposure and generally safe on sub-chronic administration, but could be deleterious on the kidneys on prolonged oral exposure at a high dose. Thus, caution should be exercised with its long-term usage. PMID- 24795633 TI - Multifunctional polymeric micelles for delivery of drugs and siRNA. AB - Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell structure have been used as versatile carriers for delivery of drugs as well as nucleic acids. They have gained immense popularity owing to a host of favorable properties including their capacity to effectively solubilize a variety of poorly soluble pharmaceutical agents, biocompatibility, longevity, high stability in vitro and in vivo and the ability to accumulate in pathological areas with compromised vasculature. Moreover, additional functions can be imparted to these micelles by engineering their surface with various ligands and cell-penetrating moieties to allow for specific targeting and intracellular accumulation, respectively, to load them with contrast agents to confer imaging capabilities, and incorporating stimuli-sensitive groups that allow drug release in response to small changes in the environment. Recently, there has been an increasing trend toward designing polymeric micelles which integrate a number of the above functions into a single carrier to give rise to "smart," multifunctional polymeric micelles. Such multifunctional micelles can be envisaged as key to improving the efficacy of current treatments which have seen a steady increase not only in hydrophobic small molecules, but also in biologics including therapeutic genes, antibodies and small interfering RNA (siRNA). The purpose of this review is to highlight recent advances in the development of multifunctional polymeric micelles specifically for delivery of drugs and siRNA. In spite of the tremendous potential of siRNA, its translation into clinics has been a significant challenge because of physiological barriers to its effective delivery and the lack of safe, effective and clinically suitable vehicles. To that end, we also discuss the potential and suitability of multifunctional polymeric micelles, including lipid-based micelles, as promising vehicles for both siRNA and drugs. PMID- 24795635 TI - The iron regulatory capability of the major protein participants in prevalent neurodegenerative disorders. AB - As with most bioavailable transition metals, iron is essential for many metabolic processes required by the cell but when left unregulated is implicated as a potent source of reactive oxygen species. It is uncertain whether the brain's evident vulnerability to reactive species-induced oxidative stress is caused by a reduced capability in cellular response or an increased metabolic activity. Either way, dys-regulated iron levels appear to be involved in oxidative stress provoked neurodegeneration. As in peripheral iron management, cells within the central nervous system tightly regulate iron homeostasis via responsive expression of select proteins required for iron flux, transport and storage. Recently proteins directly implicated in the most prevalent neurodegenerative diseases, such as amyloid-beta precursor protein, tau, alpha-synuclein, prion protein and huntingtin, have been connected to neuronal iron homeostatic control. This suggests that disrupted expression, processing, or location of these proteins may result in a failure of their cellular iron homeostatic roles and augment the common underlying susceptibility to neuronal oxidative damage that is triggered in neurodegenerative disease. PMID- 24795636 TI - Pathophysiology of the Belgrade rat. AB - The Belgrade rat is an animal model of divalent metal transporter 1 (DMT1) deficiency. This strain originates from an X-irradiation experiment first reported in 1966. Since then, the Belgrade rat's pathophysiology has helped to reveal the importance of iron balance and the role of DMT1. This review discusses our current understanding of iron transport homeostasis and summarizes molecular details of DMT1 function. We describe how studies of the Belgrade rat have revealed key roles for DMT1 in iron distribution to red blood cells as well as duodenal iron absorption. The Belgrade rat's pathology has extended our knowledge of hepatic iron handling, pulmonary and olfactory iron transport as well as brain iron uptake and renal iron handling. For example, relationships between iron and manganese metabolism have been discerned since both are essential metals transported by DMT1. Pathophysiologic features of the Belgrade rat provide us with a unique and interesting animal model to understand iron homeostasis. PMID- 24795637 TI - Iron deficiency in the elderly population, revisited in the hepcidin era. AB - Iron deficiency (ID) is relatively common among the elderly population, contributing substantially to the high prevalence of anemia observed in the last decades of life, which in turn has important implications both on quality of life and on survival. In elderly subjects, ID is often multifactorial, i.e., due to multiple concurring causes, including inadequate dietary intake or absorption, occult bleeding, medications. Moreover, because of the typical multimorbidity of aged people, other conditions leading to anemia frequently coexist and make diagnosis of ID particularly challenging. Treatment of ID is also problematic in elderly, since response to oral iron is often slow, with a substantial fraction of patients showing refractoriness and requiring cumbersome intravenous administration. In the last decade, the discovery of the iron regulatory hormone hepcidin has revolutionized our understanding of iron pathophysiology. In this review, we revisit ID among elderly people in the light of the impressive recent advances on knowledge of iron regulation, and discuss how hepcidin may help in diagnosis and treatment of this common clinical condition. PMID- 24795639 TI - Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy. AB - EphrinA1-EphA-receptor signaling is protective during myocardial infarction (MI). The EphA2-receptor (EphA2-R) potentially mediates cardiomyocyte survival. To determine the role of the EphA2-R in acute non-reperfused myocardial injury in vivo, infarct size, inflammatory cell density, NF-kappaB, p-AKT/Akt, and MMP-2 protein levels, and changes in ephrinA1/EphA2-R gene expression profile were assessed 4 days post-MI in B6129 wild-type (WT) and EphA2-R-mutant (EphA2-R-M) mice lacking a functional EphA2-R. Fibrosis, capillary density, morphometry of left ventricular chamber and infarct dimensions, and cardiac function also were measured 4 weeks post-MI to determine the extent of ventricular remodeling. EphA2 R-M infarct size and area of residual necrosis were 31.7% and 113% greater than WT hearts, respectively. Neutrophil and macrophage infiltration were increased by 46% and 84% in EphA2-R-M hearts compared with WT, respectively. NF-kappaB protein expression was 1.9-fold greater in EphA2-R-M hearts at baseline and 56% less NF kappaB after infarction compared with WT. EphA6 gene expression was 2.5-fold higher at baseline and increased 9.8-fold 4 days post-MI in EphA2-R-M hearts compared with WT. EphrinA1 gene expression in EphA2-R-M hearts was unchanged at baseline and decreased by 42% 4 days post-MI compared with WT hearts. EphA2-R-M hearts had 66.7% less expression of total Akt protein and 59% less p-Akt protein than WT hearts post-MI. EphA2-R-M hearts 4 weeks post-MI had increased chamber dilation and interstitial fibrosis and decreased MMP-2 expression and capillary density compared with WT. In conclusion, the EphA2-R is necessary to appropriately modulate the inflammatory response and severity of early injury during acute MI, thereby influencing the progression of ischemic cardiomyopathy. PMID- 24795638 TI - Regulation and roles of bicarbonate transporters in cancer. AB - A unifying feature of solid tumors is a markedly altered pH profile compared to normal tissues. This reflects that solid tumors, despite completely different origins, often share several phenotypic properties with implications for intra- and extracellular pH. These include: a metabolic shift in most cancer cells toward more acid-producing pathways, reflecting both oncogenic signaling and the development of hypoxia in poorly perfused regions of the tumors; the poorly perfused and often highly dense tumor microenvironment, reducing the diffusive flux of acid equivalents compared to that in normal tissues; and the markedly altered regulation of the expression and activity of pH-regulatory transport proteins in cancer cells. While some of these properties of tumors have been well described in recent years, the great majority of the research in this clinically important area has focused on proton transport, in particular via the Na(+)/H(+) exchanger 1 (SLC9A1, NHE1) and various H(+) ATPases. We have, however, recently demonstrated that at least under some conditions, including in vitro models of HER2 positive breast cancer, and measurements obtained directly in freshly dissected human mammary carcinomas, bicarbonate transporters such as the electroneutral Na(+), HCO(-) 3 cotransporter (SLC4A7, NBCn1), are upregulated and play central roles in pH regulation. In this review, we summarize and discuss the current knowledge regarding the regulation and roles of bicarbonate transporters in cancer. Furthermore, we present new analyses of publicly available expression data demonstrating widely altered expression levels of SLC4- and SLC26 family transporters in breast-, lung-, and colon cancer patients, and we hypothesize that bicarbonate transporter dysregulation may have both diagnostic and therapeutic potential in cancer treatment. PMID- 24795640 TI - Inhibition does not affect the timing code for vocalizations in the mouse auditory midbrain. AB - Many animals use a diverse repertoire of complex acoustic signals to convey different types of information to other animals. The information in each vocalization therefore must be coded by neurons in the auditory system. One way in which the auditory system may discriminate among different vocalizations is by having highly selective neurons, where only one or two different vocalizations evoke a strong response from a single neuron. Another strategy is to have specific spike timing patterns for particular vocalizations such that each neural response can be matched to a specific vocalization. Both of these strategies seem to occur in the auditory midbrain of mice. The neural mechanisms underlying rate and time coding are unclear, however, it is likely that inhibition plays a role. Here, we examined whether inhibition is involved in shaping neural selectivity to vocalizations via rate and/or time coding in the mouse inferior colliculus (IC). We examined extracellular single unit responses to vocalizations before and after iontophoretically blocking GABAA and glycine receptors in the IC of awake mice. We then applied a number of neurometrics to examine the rate and timing information of individual neurons. We initially evaluated the neuronal responses using inspection of the raster plots, spike-counting measures of response rate and stimulus preference, and a measure of maximum available stimulus-response mutual information. Subsequently, we used two different event sequence distance measures, one based on vector space embedding, and one derived from the Victor/Purpura D q metric, to direct hierarchical clustering of responses. In general, we found that the most salient feature of pharmacologically blocking inhibitory receptors in the IC was the lack of major effects on the functional properties of IC neurons. Blocking inhibition did increase response rate to vocalizations, as expected. However, it did not significantly affect spike timing, or stimulus selectivity of the studied neurons. We observed two main effects when inhibition was locally blocked: (1) Highly selective neurons maintained their selectivity and the information about the stimuli did not change, but response rate increased slightly. (2) Neurons that responded to multiple vocalizations in the control condition, also responded to the same stimuli in the test condition, with similar timing and pattern, but with a greater number of spikes. For some neurons the information rate generally increased, but the information per spike decreased. In many of these neurons, vocalizations that generated no responses in the control condition generated some response in the test condition. Overall, we found that inhibition in the IC does not play a substantial role in creating the distinguishable and reliable neuronal temporal spike patterns in response to different vocalizations. PMID- 24795642 TI - Overexpression of dilp2 causes nutrient-dependent semi-lethality in Drosophila. AB - Insulin/insulin-like growth factor (IGF) plays an important role as a systemic regulator of metabolism in multicellular organisms. Hyperinsulinemia, a high level of blood insulin, is often associated with impaired physiological conditions such as hypoglycemia, insulin resistance, and diabetes. However, due to the complex pathophysiology of hyperinsulinemia, the causative role of excess insulin/IGF signaling has remained elusive. To investigate the biological effects of a high level of insulin in metabolic homeostasis and physiology, we generated flies overexpressing Drosophila insulin-like peptide 2 (Dilp2), which has the highest potential of promoting tissue growth among the Ilp genes in Drosophila. In this model, a UAS-Dilp2 transgene was overexpressed under control of sd-Gal4 that drives expression predominantly in developing imaginal wing discs. Overexpression of Dilp2 caused semi-lethality, which was partially suppressed by mutations in the insulin receptor (InR) or Akt1, suggesting that dilp2-induced semi-lethality is mediated by the PI3K/Akt1 signaling. We found that dilp2 overexpressing flies exhibited intensive autophagy in fat body cells. Interestingly, the dilp2-induced autophagy as well as the semi-lethality was partially rescued by increasing the protein content relative to glucose in the media. Our results suggest that excess insulin/IGF signaling impairs the physiology of animals, which can be ameliorated by controlling the nutritional balance between proteins and carbohydrates, at least in flies. PMID- 24795641 TI - Multidrug resistance in fungi: regulation of transporter-encoding gene expression. AB - A critical risk to the continued success of antifungal chemotherapy is the acquisition of resistance; a risk exacerbated by the few classes of effective antifungal drugs. Predictably, as the use of these drugs increases in the clinic, more resistant organisms can be isolated from patients. A particularly problematic form of drug resistance that routinely emerges in the major fungal pathogens is known as multidrug resistance. Multidrug resistance refers to the simultaneous acquisition of tolerance to a range of drugs via a limited or even single genetic change. This review will focus on recent progress in understanding pathways of multidrug resistance in fungi including those of most medical relevance. Analyses of multidrug resistance in Saccharomyces cerevisiae have provided the most detailed outline of multidrug resistance in a eukaryotic microorganism. Multidrug resistant isolates of S. cerevisiae typically result from changes in the activity of a pair of related transcription factors that in turn elicit overproduction of several target genes. Chief among these is the ATP binding cassette (ABC)-encoding gene PDR5. Interestingly, in the medically important Candida species, very similar pathways are involved in acquisition of multidrug resistance. In both C. albicans and C. glabrata, changes in the activity of transcriptional activator proteins elicits overproduction of a protein closely related to S. cerevisiae Pdr5 called Cdr1. The major filamentous fungal pathogen, Aspergillus fumigatus, was previously thought to acquire resistance to azole compounds (the principal antifungal drug class) via alterations in the azole drug target-encoding gene cyp51A. More recent data indicate that pathways in addition to changes in the cyp51A gene are important determinants in A. fumigatus azole resistance. We will discuss findings that suggest azole resistance in A. fumigatus and Candida species may share more mechanistic similarities than previously thought. PMID- 24795644 TI - New roles for old enzymes: killer caspases as the engine of cell behavior changes. AB - It has become increasingly clear that caspases, far from being merely cell death effectors, have a much wider range of functions within the cell. These functions are as diverse as signal transduction and cytoskeletal remodeling, and caspases are now known to have an essential role in cell proliferation, migration, and differentiation. There is also evidence that apoptotic cells themselves can direct the behavior of nearby cells through the caspase-dependent secretion of paracrine signaling factors. In some processes, including the differentiation of skeletal muscle myoblasts, both caspase activation in differentiating cells as well as signaling from apoptotic cells has been reported. Here, we review the non apoptotic outcomes of caspase activity in a range of different model systems and attempt to integrate this knowledge. PMID- 24795643 TI - Emerging gene editing strategies for Duchenne muscular dystrophy targeting stem cells. AB - The progressive loss of muscle mass characteristic of many muscular dystrophies impairs the efficacy of most of the gene and molecular therapies currently being pursued for the treatment of those disorders. It is becoming increasingly evident that a therapeutic application, to be effective, needs to target not only mature myofibers, but also muscle progenitors cells or muscle stem cells able to form new muscle tissue and to restore myofibers lost as the result of the diseases or during normal homeostasis so as to guarantee effective and lost lasting effects. Correction of the genetic defect using oligodeoxynucleotides (ODNs) or engineered nucleases holds great potential for the treatment of many of the musculoskeletal disorders. The encouraging results obtained by studying in vitro systems and model organisms have set the groundwork for what is likely to become an emerging field in the area of molecular and regenerative medicine. Furthermore, the ability to isolate and expand from patients various types of muscle progenitor cells capable of committing to the myogenic lineage provides the opportunity to establish cell lines that can be used for transplantation following ex vivo manipulation and expansion. The purpose of this article is to provide a perspective on approaches aimed at correcting the genetic defect using gene editing strategies and currently under development for the treatment of Duchenne muscular dystrophy (DMD), the most sever of the neuromuscular disorders. Emphasis will be placed on describing the potential of using the patient own stem cell as source of transplantation and the challenges that gene editing technologies face in the field of regenerative biology. PMID- 24795645 TI - Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. AB - Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations. Therefore, ASD has traditionally been framed as a behavioral disorder. However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation. While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals. A majority of these brain tissue studies have been published since 2010. The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination. This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD. PMID- 24795647 TI - Receptors for short-chain fatty acids in brush cells at the "gastric groove". AB - In the stomach of rodents clusters of brush cells are arranged at the "gastric groove," immediately at the transition zone from the non-glandular reservoir compartment to the glandular digestive compartment. Based on their taste cell like molecular phenotype it has been speculated that the cells may be capable to sense constituents of the ingested food, however, searches for nutrient receptors have not been successful. In this study, it was hypothesized that the cells may express receptors for short-chain fatty acids, metabolites generated by microorganisms during the storage of ingested food in the murine forestomach, which lacks the acidic milieu of more posterior regions of the stomach and is colonized with numerous microbiota. Experimental approaches, including RT-PCR analysis and immunohistochemical studies, revealed that the majority of these brush cells express the G-protein coupled receptor types GPR41 (FFAR3) and GPR43 (FFAR2), which are activated by short-chain fatty acids. Both, the GPR41 receptor proteins as well as an appropriate G-protein, alpha-gustducin, were found to be segregated at the apical brush border of the cells, indicating a direct contact with the luminal content of this gastric region. The exposure of microvillar processes with appropriate receptors and signaling elements to the gastric lumen suggests that the brush cells may in fact be capable to sense the short-chain fatty acids which originate from fermentation processes during the retention of ingested food in the anterior part of the stomach. PMID- 24795646 TI - Impact of vitamin D on immune function: lessons learned from genome-wide analysis. AB - Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1alpha-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans. PMID- 24795648 TI - Elementary and macroscopic light-induced currents and their Ca(2+)-dependence in the photoreceptors of Periplaneta americana. AB - In a microvillar photoreceptor, absorption of an incident photon initiates a phototransduction reaction that generates a depolarizing light-induced current (LIC) in the microvillus. Although in-depth knowledge about these processes in photoreceptors of the fruitfly Drosophila is available, not much is known about their nature in other insect species. Here, we present description of some basic properties of both elementary and macroscopic LICs and their Ca(2+)-dependence in the photoreceptors of a dark-active species, the cockroach Periplaneta americana. Cockroach photoreceptors respond to single photon absorptions by generating quantum bumps with about 5-fold larger amplitudes than in Drosophila. At the macroscopic current level, cockroach photoreceptors responded to light with variable sensitivity and current waveform. This variability could be partially attributed to differences in whole-cell capacitance. Transient LICs, both elementary and macroscopic, showed only moderate dependence on extracellular Ca(2+). However, with long light pulses, response inactivation was largely abolished and the overall size of LICs increased when extracellular Ca(2+) was omitted. Finally, by determining relative ionic permeabilities from reversals of LICs, we demonstrate that when compared to Drosophila, cockroach light-gated channels are only moderately Ca(2+)-selective. PMID- 24795649 TI - 3D-Geomorphometrics tooth shape analysis in hypodontia. AB - Assessment of tooth morphology is an important part of the diagnosis and management of hypodontia patients. Several techniques have been used to analyze tooth form in hypodontia patients and these have shown smaller tooth dimensions and anomalous tooth shapes in patients with hypodontia when compared with controls. However, previous studies have mainly used 2D images and provided limited information. In the present study, 3D surface-imaging and statistical shape analysis were used to evaluate tooth form differences between hypodontia and control patients. Eighteen anatomical landmarks were recorded on the clinical crown of the lower left first permanent molar of 3D scanned study models of hypodontia and control subjects. The study sample group comprised of 120 hypodontia patients (40 mild, 40 moderate, and 40 severe hypodontia patients) and 40 age- and sex-matched controls. Procrustes coordinates were utilized to scale and superimpose the landmark coordinate data and then were subjected to principal component analysis (PCA). Subsequently, differences in shape as well as size were tested statistically using allometric analysis and MANOVA. Significant interaction was found between the two factor variables "group" and "sex" (p < 0.002). Overall expected accuracies were 66 and 56% for females and males, respectively, in the cross-validated discriminant-analysis using the first 20 PCs. Hypodontia groups showed significant shape differences compared with the control subjects (p < 0.0001). Significant differences in tooth crown shape were also found between sexes (p < 0.0001) within groups. Furthermore, the degree of variation in tooth form was proportional to the degree of the severity of the hypodontia. Thus, quantitative measurement of tooth shape in hypodontia patients may enhance the multidisciplinary management of those patients. PMID- 24795650 TI - Recent advances in the involvement of long non-coding RNAs in neural stem cell biology and brain pathophysiology. AB - Exploration of non-coding genome has recently uncovered a growing list of formerly unknown regulatory long non-coding RNAs (lncRNAs) with important functions in stem cell pluripotency, development and homeostasis of several tissues. Although thousands of lncRNAs are expressed in mammalian brain in a highly patterned manner, their roles in brain development have just begun to emerge. Recent data suggest key roles for these molecules in gene regulatory networks controlling neuronal and glial cell differentiation. Analysis of the genomic distribution of genes encoding for lncRNAs indicates a physical association of these regulatory RNAs with transcription factors (TFs) with well established roles in neural differentiation, suggesting that lncRNAs and TFs may form coherent regulatory networks with important functions in neural stem cells (NSCs). Additionally, many studies show that lncRNAs are involved in the pathophysiology of brain-related diseases/disorders. Here we discuss these observations and investigate the links between lncRNAs, brain development and brain-related diseases. Understanding the functions of lncRNAs in NSCs and brain organogenesis could revolutionize the basic principles of developmental biology and neuroscience. PMID- 24795651 TI - Postural control in strabismic children: importance of proprioceptive information. AB - OBJECTIVE: To examine the effect of proprioceptive information during postural control in strabismic children. METHODS: Postural stability was recorded with a platform (Techno Concept(r)) in 12 strabismic children aged from 4.9 to 10 years and data were compared to that of 12 control age-matched children. Two postural positions were performed: Romberg and Tandem. Two postural conditions: without and with foam pad. We analyzed the surface area, the length, the mean speed of the center of pressure (CoP) and the effect of proprioceptive information. RESULTS: Strabismic children are more instable than control age-matched children. The surface, the length and the mean speed of CoP are significantly higher in strabismic children than in control age-matched children. Both groups are more instable in Tandem position than in Romberg position. Finally, strabismic children use more proprioceptive information than control age-matched children. CONCLUSION: For both Romberg and Tandem position, strabismic children are more instable than control age-matched children. Strabismic children use proprioceptive information more than control age-matched children to control their posture. SIGNIFICANCE: Proprioceptive inputs are important for control posture particularly for strabismic population. PMID- 24795652 TI - Arterial pressure variations as parameters of brain perfusion in response to central blood volume depletion and repletion. AB - RATIONALE: A critical reduction in central blood volume (CBV) is often characterized by hemodynamic instability. Restoration of a volume deficit may be established by goal-directed fluid therapy guided by respiration-related variation in systolic- and pulse pressure (SPV and PPV). Stroke volume index (SVI) serves as a surrogate end-point of a fluid challenge but tissue perfusion itself has not been addressed. OBJECTIVE: To delineate the relationship between arterial pressure variations, SVI and regional brain perfusion during CBV depletion and repletion in spontaneously breathing volunteers. METHODS: This study quantified in 14 healthy subjects (11 male) the effects of CBV depletion [by 30 and 70 degrees passive head-up tilt (HUT)] and a fluid challenge (by tilt back) on CBV (thoracic admittance), mean middle cerebral artery (MCA) blood flow velocity (Vmean), SVI, cardiac index (CI), PPV, and SPV. RESULTS: PPV (103 +/- 89%, p < 0.05) and SPV (136 +/- 117%, p < 0.05) increased with progression of central hypovolemia manifested by a reduction in thoracic admittance (11 +/- 5%, p < 0.001), SVI (28 +/- 6%, p < 0.001), CI (6 +/- 8%, p < 0.001), and MCAVmean (17 +/- 7%, p < 0.05) but not in arterial pressure. The reduction in MCAVmean correlated to the fall in SVI (R (2) = 0.52, p < 0.0001) and inversely to PPV and SPV [R (2) = 0.46 (p < 0.0001) and R (2) = 0.45 (p < 0.0001), respectively]. PPV and SPV predicted a >=15% reduction in MCAVmean and SVI with comparable sensitivity (67/67% vs. 63/68%, respectively) and specificity (89/94 vs. 89/94%, respectively). A rapid fluid challenge by tilt-back restored all parameters to baseline values within 1 min. CONCLUSION: In spontaneously breathing subjects, a reduction in MCAVmean was related to an increase in PPV and SPV during graded CBV depletion and repletion. Specifically, PPV and SPV predicted changes in both SVI and MCAVmean with comparable sensitivity and specificity, however the predictive value is limited in spontaneously breathing subjects. PMID- 24795653 TI - Functional roles of Na(+)/K(+)-ATPase in active ammonia excretion and seawater acclimation in the giant mudskipper, Periophthalmodon schlosseri. AB - The giant mudskipper, Periophthalmodon schlosseri, is an amphibious fish that builds burrows in the mudflats. It can actively excrete ammonia through its gills, and tolerate high environmental ammonia. This study aimed to examine the effects of seawater (salinity 30; SW) acclimation and/or environmental ammonia exposure on the kinetic properties of Na(+)/K(+)-ATPase (Nka) from, and mRNA expression and protein abundance of nka/Nka alpha-subunit isoforms in, the gills of P. schlosseri pre-acclimated to slightly brackish water (salinity 3; SBW). Our results revealed that the Nka from the gills of P. schlosseri pre-acclimated to SBW for 2 weeks had substantially higher affinity to (or lower K m for) K(+) than NH(+) 4, and its affinity to NH(+) 4 decreased significantly after 6-days exposure to 75 mmol l(-1) NH4Cl in SBW. Hence, Nka transported K(+) selectively to maintain intracellular K(+) homeostasis, instead of transporting NH(+) 4 from the blood into ionocytes during active NH(+) 4 excretion as previously suggested. Two nkaalpha isoforms, nkaalpha1 and nkaalpha3, were cloned and sequenced from the gills of P. schlosseri. Their deduced amino acid sequences had K(+) binding sites identical to that of Nkaalpha1c from Anabas testudineus, indicating that they could effectively differentiate K(+) from NH(+) 4. Six days of exposure to 75 mmol l(-1) NH4Cl in SBW, or to SW with or without 50 mmol l(-1) NH4Cl led to significant increases in Nka activities in the gills of P. schlosseri. However, a significant increase in the comprehensive Nkaalpha protein abundance was observed only in the gills of fish exposed to 50 mmol l(-1) NH4Cl in SW. Hence, post translational modification could be an important activity modulator of branchial Nka in P. schlosseri. The fast modulation of Nka activity and concurrent expressions of two branchial nkaalpha isoforms could in part contribute to the ability of P. schlosseri to survive abrupt transfer between SBW and SW or abrupt exposure to ammonia. PMID- 24795654 TI - The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. AB - The physiological roles of the betaine/GABA transporter (BGT1; slc6a12) are still being debated. BGT1 is a member of the solute carrier family 6 (the neurotransmitter, sodium symporter transporter family) and mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. Most of the studies of BGT1 concern its function and regulation in the kidney medulla where its role is best understood. The conditions here are hostile due to hyperosmolarity and significant concentrations of NH4Cl and urea. To withstand the hyperosmolarity, cells trigger osmotic adaptation, involving concentration of a transcriptional factor TonEBP/NFAT5 in the nucleus, and accumulate betaine and other osmolytes. Data from renal cells in culture, primarily MDCK, revealed that transcriptional regulation of BGT1 by TonEBP/NFAT5 is relatively slow. To allow more acute control of the abundance of BGT1 protein in the plasma membrane, there is also post-translation regulation of BGT1 protein trafficking which is dependent on intracellular calcium and ATP. Further, betaine may be important in liver metabolism as a methyl donor. In fact, in the mouse the liver is the organ with the highest content of BGT1. Hepatocytes express high levels of both BGT1 and the only enzyme that can metabolize betaine, namely betaine:homocysteine -S methyltransferase (BHMT1). The BHMT1 enzyme removes a methyl group from betaine and transfers it to homocysteine, a potential risk factor for cardiovascular disease. Finally, BGT1 has been proposed to play a role in controlling brain excitability and thereby represents a target for anticonvulsive drug development. The latter hypothesis is controversial due to very low expression levels of BGT1 relative to other GABA transporters in brain, and also the primary location of BGT1 at the surface of the brain in the leptomeninges. These issues are discussed in detail. PMID- 24795655 TI - Principles of agonist recognition in Cys-loop receptors. AB - Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term "chemoreceptor" emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands. PMID- 24795658 TI - Inner Speech is not so Simple: A Commentary on Cho and Wu (2013). PMID- 24795657 TI - Deficits during Voluntary Selection in Adult Patients with ADHD: New Insights from Single-Trial Coupling of Simultaneous EEG/fMRI. AB - Deficits in executive functions, including voluntary decisions are among the core symptoms of attention deficit/hyperactivity disorder (ADHD) patients. In order to clarify the spatiotemporal characteristics of these deficits, a simultaneous EEG/functional MRI (fMRI) study was performed. Single-trial coupling was used to integrate temporal EEG information in the fMRI analyses and to correlate the trial by trial variation in the different event-related potential amplitudes with fMRI BOLD responses. The results demonstrated that during voluntary selection early electrophysiological responses (N2) were associated with responses in similar brain regions in healthy participants as well as in ADHD patients, e.g., in the medial-frontal cortex and the inferior parietal gyrus. However, ADHD patients presented significantly reduced N2-related BOLD responses compared to healthy controls especially in frontal areas. These results support the hypothesis that in ADHD patients executive deficits are accompanied by early dysfunctions, especially in frontal brain areas. PMID- 24795659 TI - Emotional dysregulation and anxiety control in the psychopathological mechanism underlying drive for thinness. AB - Emotional dysregulation is a process which consists in mitigating, intensifying, or maintaining a given emotion and is the trigger for some psychological disorders. Research has shown that an anxiety control plays an important role in emotional expression and regulation and, in addition, for anorexia nervosa (AN) and, more in general, in drive for thinness. Scientific literature suggests that in AN there is a core of emotional dysregulation and anxiety control. The aim of this study is to explore the roles of emotional dysregulation and anxiety control as independent or third variables in a mediational regression model related to drive for thinness. One hundred fifty-four clinical individuals with anorexia participated in the study and all completed a set of self-report questionnaires: eating disorders inventory version 3 (EDI-3), DERS, and the anxiety control questionnaire. The data confirmed a mediational model in which the relation between emotional dysregulation and drive for thinness is mediated by anxiety control. The current study partially supports a clinical model in which emotional dysregulation is a distal factor in eating disorders while the mediator variable anxiety control is a proximal factor in the psychopathological process underlying it. PMID- 24795656 TI - Meditation as a therapeutic intervention for adults at risk for Alzheimer's disease - potential benefits and underlying mechanisms. AB - Alzheimer's disease (AD) is a chronic, progressive, brain disorder that affects at least 5.3 million Americans at an estimated cost of $148 billion, figures that are expected to rise steeply in coming years. Despite decades of research, there is still no cure for AD, and effective therapies for preventing or slowing progression of cognitive decline in at-risk populations remain elusive. Although the etiology of AD remains uncertain, chronic stress, sleep deficits, and mood disturbance, conditions common in those with cognitive impairment, have been prospectively linked to the development and progression of both chronic illness and memory loss and are significant predictors of AD. Therapies such as meditation that specifically target these risk factors may thus hold promise for slowing and possibly preventing cognitive decline in those at risk. In this study, we briefly review the existing evidence regarding the potential utility of meditation as a therapeutic intervention for those with and at risk for AD, discuss possible mechanisms underlying the observed benefits of meditation, and outline directions for future research. PMID- 24795660 TI - The ties to unbind: age-related differences in feature (un)binding in working memory for emotional faces. AB - In the present study, we investigated age-related differences in the processing of emotional stimuli. Specifically, we were interested in whether older adults would show deficits in unbinding emotional expression (i.e., either no emotion, happiness, anger, or disgust) from bound stimuli (i.e., photographs of faces expressing these emotions), as a hyper-binding account of age-related differences in working memory would predict. Younger and older adults completed different N Back tasks (side-by-side 0-Back, 1-Back, 2-Back) under three conditions: match/mismatch judgments based on either the identity of the face (identity condition), the face's emotional expression (expression condition), or both identity and expression of the face (both condition). The two age groups performed more slowly and with lower accuracy in the expression condition than in the both condition, indicating the presence of an unbinding process. This unbinding effect was more pronounced in older adults than in younger adults, but only in the 2-Back task. Thus, older adults seemed to have a specific deficit in unbinding in working memory. Additionally, no age-related differences were found in accuracy in the 0-Back task, but such differences emerged in the 1-Back task, and were further magnified in the 2-Back task, indicating independent age-related differences in attention/STM and working memory. Pupil dilation data confirmed that the attention/STM version of the task (1-Back) is more effortful for older adults than younger adults. PMID- 24795661 TI - Risky business: rhesus monkeys exhibit persistent preferences for risky options. AB - Rhesus monkeys have been shown to prefer risky over safe options in experiential decision-making tasks. These findings might be due, however, to specific contextual factors, such as small amounts of fluid reward and minimal costs for risk-taking. To better understand the factors affecting decision-making under risk in rhesus monkeys, we tested multiple factors designed to increase the stakes including larger reward amounts, distinct food items rather than fluid reward, a smaller number of trials per session, and risky options with greater variation that also included non-rewarded outcomes. We found a consistent preference for risky options, except when the expected value of the safe option was greater than the risky option. Thus, with equivalent mean utilities between the safe and risky options, rhesus monkeys appear to have a robust preference for the risky options in a broad range of circumstances, akin to the preferences found in human children and some adults in similar tasks. One account for this result is that monkeys make their choices based on the salience of the largest payoff, without integrating likelihood and value across trials. A related idea is that they fail to override an impulsive tendency to select the option with the potential to obtain the highest possible outcome. Our results rule out strict versions of both accounts and contribute to an understanding of the diversity of risky decision-making among primates. PMID- 24795662 TI - A perceptual account of symbolic reasoning. AB - People can be taught to manipulate symbols according to formal mathematical and logical rules. Cognitive scientists have traditionally viewed this capacity-the capacity for symbolic reasoning-as grounded in the ability to internally represent numbers, logical relationships, and mathematical rules in an abstract, amodal fashion. We present an alternative view, portraying symbolic reasoning as a special kind of embodied reasoning in which arithmetic and logical formulae, externally represented as notations, serve as targets for powerful perceptual and sensorimotor systems. Although symbolic reasoning often conforms to abstract mathematical principles, it is typically implemented by perceptual and sensorimotor engagement with concrete environmental structures. PMID- 24795663 TI - Gender and the performance of music. AB - This study evaluates propositions that have appeared in the literature that music phenomena are gendered. Were they present in the musical "message," gendered qualities might be imparted at any of three stages of the music-communication interchange: the process of composition, its realization into sound by the performer, or imposed by the listener in the process of perception. The research was designed to obtain empirical evidence to enable evaluation of claims of the presence of gendering at these three stages. Three research hypotheses were identified and relevant literature of music behaviors and perception reviewed. New instruments of measurement were constructed to test the three hypotheses: (i) two listening sequences each containing 35 extracts from published recordings of compositions of the classical music repertoire, (ii) four "music characteristics" scales, with polarities defined by verbal descriptors designed to assess the dynamic and emotional valence of the musical extracts featured in the listening sequences. 69 musically-trained listeners listened to the two sequences and were asked to identify the sex of the performing artist of each musical extract; a second group of 23 listeners evaluated the extracts applying the four music characteristics scales. Results did not support claims that music structures are inherently gendered, nor proposals that performers impart their own-sex-specific qualities to the music. It is concluded that gendered properties are imposed subjectively by the listener, and these are primarily related to the tempo of the music. PMID- 24795664 TI - Age of acquisition and allophony in Spanish-English bilinguals. AB - This study examines age of acquisition (AoA) in Spanish-English bilinguals' phonetic and phonological knowledge of /l/ in English and Spanish. In English, the lateral approximant /l/ varies in darkness by context [based on the second formant (F2) and the difference between F2 and the first formant (F1)], but the Spanish /l/ does not. Further, English /l/ is overall darker than Spanish /l/. Thirty-eight college-aged adults participated: 11 Early Spanish-English bilinguals who learned English before the age of 5 years, 14 Late Spanish-English bilinguals who learned English after the age of 6 years, and 13 English monolinguals. Participants' /l/ productions were acoustically analyzed by language and context. The results revealed a Spanish-to-English phonetic influence on /l/ productions for both Early and Late bilinguals, as well as an English-to-Spanish phonological influence on the patterning of /l/ for the Late Bilinguals. These findings are discussed in terms of the Speech Learning Model and the effect of AoA on the interaction between a bilingual speaker's two languages. PMID- 24795665 TI - Literacy shapes thought: the case of event representation in different cultures. AB - There has been a lively debate whether conceptual representations of actions or scenes follow a left-to-right spatial transient when participants depict such events or scenes. It was even suggested that conceptualizing the agent on the left side represents a universal. We review the current literature with an emphasis on event representation and on cross-cultural studies. While there is quite some evidence for spatial bias for representations of events and scenes in diverse cultures, their extent and direction depend on task demands, one's native language, and importantly, on reading and writing direction. Whether transients arise only in subject-verb-object languages, due to their linear sentential position of event participants, is still an open issue. We investigated a group of illiterate speakers of Yucatec Maya, a language with a predominant verb-object subject structure. They were compared to illiterate native speakers of Spanish. Neither group displayed a spatial transient. Given the current literature, we argue that learning to read and write has a strong impact on representations of actions and scenes. Thus, while it is still under debate whether language shapes thought, there is firm evidence that literacy does. PMID- 24795667 TI - Action scaling of distance perception is task specific and does not predict "the embodiment of culture": a comment on Soliman, Gibson, and Glenberg (2013). PMID- 24795666 TI - Age-related differences in cerebral blood flow underlie the BOLD fMRI signal in childhood. AB - Functional magnetic resonance imaging (fMRI) has become a premiere technique for studying the development and neural mediation of a wide range of typical and atypical behaviors in children. While the mechanism of the blood oxygen level dependent (BOLD) fMRI signal has been a focus of investigation in the mature brain, it has been largely unexamined in the developing brain. One critical component of the BOLD signal that has been noted to change with age is cerebral blood flow (CBF). Reports of CBF in children based on clinical radioactive tracing methods have found elevated CBF in childhood relative to adulthood, which could affect the BOLD response. This study used non-invasive arterial spin labeling magnetic resonance imaging to study resting state and activity-driven CBF in conjunction with the functional BOLD response in healthy children 8 and 12 years of age and in adults. Participants performed a finger-tapping task to generate robust activation measured in the motor cortex. Quantification of resting state CBF demonstrated higher CBF in 8 year olds and in 12 year olds relative to adults. The absolute increase in CBF between baseline rest and peak response during the motor task was also higher in both child groups compared to adults. In contrast, the relative increase of CBF above baseline, expressed as percent of CBF change, was comparable across groups. The percent of BOLD signal change was also stable across age groups. This set of findings suggests that along with elevated CBF in childhood, other component processes of the BOLD response are also in an elevated state such that together they yield a net BOLD effect that resembles adults. These findings coincide with our previous examination of hemodynamics in primary sensory cortex. Although the magnitude of the BOLD response appears consistent between childhood and adulthood, the underlying physiology and cerebrovascular dynamics that give rise to the BOLD effect differ between immature and mature neural systems. PMID- 24795668 TI - Analyzing average and conditional effects with multigroup multilevel structural equation models. AB - Conventionally, multilevel analysis of covariance (ML-ANCOVA) has been the recommended approach for analyzing treatment effects in quasi-experimental multilevel designs with treatment application at the cluster-level. In this paper, we introduce the generalized ML-ANCOVA with linear effect functions that identifies average and conditional treatment effects in the presence of treatment covariate interactions. We show how the generalized ML-ANCOVA model can be estimated with multigroup multilevel structural equation models that offer considerable advantages compared to traditional ML-ANCOVA. The proposed model takes into account measurement error in the covariates, sampling error in contextual covariates, treatment-covariate interactions, and stochastic predictors. We illustrate the implementation of ML-ANCOVA with an example from educational effectiveness research where we estimate average and conditional effects of early transition to secondary schooling on reading comprehension. PMID- 24795669 TI - Tool use ability depends on understanding of functional dynamics and not specific joint contribution profiles. AB - Researchers in cognitive neuroscience have become increasingly interested in how different aspects of tool use are integrated and represented by the brain. Comparatively less attention has been directed toward tool use actions themselves and how effective tool use behaviors are coordinated. In response, we take this opportunity to consider the mechanical principles of tool use actions and their relationship to motor learning. Using kinematic analysis, we examine both functional dynamics and joint contribution profiles of subjects with different levels of experience in a primordial percussive task. Our results show that the ability to successfully produce stone flakes using the Oldowan method did not correspond with any particular joint contribution profile. Rather, expertise in this tool use action was principally associated with the subject's ability to regulate the functional parameters that define the task itself. PMID- 24795670 TI - Internally- and externally-driven network transitions as a basis for automatic and strategic processes in semantic priming: theory and experimental validation. AB - For the last four decades, semantic priming-the facilitation in recognition of a target word when it follows the presentation of a semantically related prime word has been a central topic in research of human cognitive processing. Studies have drawn a complex picture of findings which demonstrated the sensitivity of this priming effect to a unique combination of variables, including, but not limited to, the type of relatedness between primes and targets, the prime-target Stimulus Onset Asynchrony (SOA), the relatedness proportion (RP) in the stimuli list and the specific task subjects are required to perform. Automatic processes depending on the activation patterns of semantic representations in memory and controlled strategies adapted by individuals when attempting to maximize their recognition performance have both been implicated in contributing to the results. Lately, we have published a new model of semantic priming that addresses the majority of these findings within one conceptual framework. In our model, semantic memory is depicted as an attractor neural network in which stochastic transitions from one stored pattern to another are continually taking place due to synaptic depression mechanisms. We have shown how such transitions, in combination with a reinforcement-learning rule that adjusts their pace, resemble the classic automatic and controlled processes involved in semantic priming and account for a great number of the findings in the literature. Here, we review the core findings of our model and present new simulations that show how similar principles of parameter-adjustments could account for additional data not addressed in our previous studies, such as the relation between expectancy and inhibition in priming, target frequency and target degradation effects. Finally, we describe two human experiments that validate several key predictions of the model. PMID- 24795671 TI - Hand proximity differentially affects visual working memory for color and orientation in a binding task. AB - Observers determined whether two sequentially presented arrays of six lines were the same or different. Differences, when present, involved either a swap in the color of two lines or a swap in the orientation of two lines. Thus, accurate change detection required the binding of color and orientation information for each line within visual working memory. Holding viewing distance constant, the proximity of the arrays to the hands was manipulated. Placing the hands near the to-be-remembered array decreased participants' ability to remember color information, but increased their ability to remember orientation information. This pair of results indicates that hand proximity differentially affects the processing of various types of visual information, a conclusion broadly consistent with functional and anatomical differences in the magnocellular and parvocellular pathways. It further indicates that hand proximity affects the likelihood that various object features will be encoded into integrated object files. PMID- 24795672 TI - Acoustic and non-acoustic factors in modeling listener-specific performance of sagittal-plane sound localization. AB - The ability of sound-source localization in sagittal planes (along the top-down and front-back dimension) varies considerably across listeners. The directional acoustic spectral features, described by head-related transfer functions (HRTFs), also vary considerably across listeners, a consequence of the listener-specific shape of the ears. It is not clear whether the differences in localization ability result from differences in the encoding of directional information provided by the HRTFs, i.e., an acoustic factor, or from differences in auditory processing of those cues (e.g., spectral-shape sensitivity), i.e., non-acoustic factors. We addressed this issue by analyzing the listener-specific localization ability in terms of localization performance. Directional responses to spatially distributed broadband stimuli from 18 listeners were used. A model of sagittal plane localization was fit individually for each listener by considering the actual localization performance, the listener-specific HRTFs representing the acoustic factor, and an uncertainty parameter representing the non-acoustic factors. The model was configured to simulate the condition of complete calibration of the listener to the tested HRTFs. Listener-specifically calibrated model predictions yielded correlations of, on average, 0.93 with the actual localization performance. Then, the model parameters representing the acoustic and non-acoustic factors were systematically permuted across the listener group. While the permutation of HRTFs affected the localization performance, the permutation of listener-specific uncertainty had a substantially larger impact. Our findings suggest that across-listener variability in sagittal-plane localization ability is only marginally determined by the acoustic factor, i.e., the quality of directional cues found in typical human HRTFs. Rather, the non acoustic factors, supposed to represent the listeners' efficiency in processing directional cues, appear to be important. PMID- 24795673 TI - A spiral model of musical decision-making. AB - This paper describes a model of how musicians make decisions about performing notated music. The model builds on psychological theories of decision-making and was developed from empirical studies of Western art music performance that aimed to identify intuitive and deliberate processes of decision-making, a distinction consistent with dual-process theories of cognition. The model proposes that the proportion of intuitive (Type 1) and deliberate (Type 2) decision-making processes changes with increasing expertise and conceptualizes this change as movement along a continually narrowing upward spiral where the primary axis signifies principal decision-making type and the vertical axis marks level of expertise. The model is intended to have implications for the development of expertise as described in two main phases. The first is movement from a primarily intuitive approach in the early stages of learning toward greater deliberation as analytical techniques are applied during practice. The second phase occurs as deliberate decisions gradually become automatic (procedural), increasing the role of intuitive processes. As a performer examines more issues or reconsiders decisions, the spiral motion toward the deliberate side and back to the intuitive is repeated indefinitely. With increasing expertise, the spiral tightens to signify greater control over decision type selection. The model draws on existing theories, particularly Evans' (2011) Intervention Model of dual-process theories, Cognitive Continuum Theory Hammond et al. (1987), Hammond (2007), Baylor's (2001) U-shaped model for the development of intuition by level of expertise. By theorizing how musical decision-making operates over time and with increasing expertise, this model could be used as a framework for future research in music performance studies and performance science more generally. PMID- 24795674 TI - Infants' expectations about gestures and actions in third-party interactions. AB - We investigated 14-month-old infants' expectations toward a third party addressee of communicative gestures and an instrumental action. Infants' eye movements were tracked as they observed a person (the Gesturer) point, direct a palm-up request gesture, or reach toward an object, and another person (the Addressee) respond by grasping it. Infants' looking patterns indicate that when the Gesturer pointed or used the palm-up request, infants anticipated that the Addressee would give the object to the Gesturer, suggesting that they ascribed a motive of request to the gestures. In contrast, when the Gesturer reached for the object, and in a control condition where no action took place, the infants did not anticipate the Addressee's response. The results demonstrate that infants' recognition of communicative gestures extends to others' interactions, and that infants can anticipate how third-party addressees will respond to others' gestures. PMID- 24795675 TI - Storybooks aren't just for fun: narrative and non-narrative picture books foster equal amounts of generic language during mother-toddler book sharing. AB - Parents and children encounter a variety of animals and objects in the early picture books they share, but little is known about how the context in which these entities are presented influences talk about them. The present study investigated how the presence or absence of a visual narrative context influences mothers' tendency to refer to animals as individual characters or as members of a kind when sharing picture books with their toddlers (mean age 21.3 months). Mother-child dyads shared both a narrative and a non-narrative book, each featuring six animals and matched in terms of length and quantity of text. Mothers made more specific (individual-referring) statements about animals in the narrative books, whereas they provided more labels for animals in the non narrative books. But, of most interest, the frequency and proportion of mothers' use of generic (kind-referring) utterances did not differ across the two different types of books. Further coding of the content of the utterances revealed that mothers provided more story-specific descriptions of states and actions of the animals when sharing narrative books and more physical descriptions of animals when sharing non-narrative books. However, the two books did not differ in terms of their elicitation of natural facts about the animals. Overall, although the two types of books encouraged different types of talk from mothers, they stimulated generic language and talk about natural facts to an equal degree. Implications for learning from picture storybooks and book genre selection in classrooms and home reading are discussed. PMID- 24795677 TI - Music feels like moods feel. AB - While it is widely accepted that music evokes moods, there is disagreement over whether music-induced moods are relevant to the aesthetic appreciation of music as such. The arguments against the aesthetic relevance of music-induced moods are: (1) moods cannot be intentionally directed at the music and (2) music induced moods are highly subjective experiences and are therefore a kind of mind wandering. This paper presents a novel account of musical moods that avoids these objections. It is correct to say that a listener's entire mood is not relevant to the aesthetic appreciation of music. However, the experience of mood consists of having different feelings. Music induces feelings that are intentionally directed at the music and clusters of these feelings can be recognized as typical of a specific mood. Therefore, mood-feelings are relevant to the aesthetic appreciation of music. PMID- 24795676 TI - Development of neural mechanisms of conflict and error processing during childhood: implications for self-regulation. AB - Regulation of thoughts and behavior requires attention, particularly when there is conflict between alternative responses or when errors are to be prevented or corrected. Conflict monitoring and error processing are functions of the executive attention network, a neurocognitive system that greatly matures during childhood. In this study, we examined the development of brain mechanisms underlying conflict and error processing with event-related potentials (ERPs), and explored the relationship between brain function and individual differences in the ability to self-regulate behavior. Three groups of children aged 4-6, 7-9, and 10-13 years, and a group of adults performed a child-friendly version of the flanker task while ERPs were registered. Marked developmental changes were observed in both conflict processing and brain reactions to errors. After controlling by age, higher self-regulation skills are associated with smaller amplitude of the conflict effect but greater amplitude of the error-related negativity. Additionally, we found that electrophysiological measures of conflict and error monitoring predict individual differences in impulsivity and the capacity to delay gratification. These findings inform of brain mechanisms underlying the development of cognitive control and self-regulation. PMID- 24795678 TI - Parallel effects of processing fluency and positive affect on familiarity-based recognition decisions for faces. AB - According to attribution models of familiarity assessment, people can use a heuristic in recognition-memory decisions, in which they attribute the subjective ease of processing of a memory probe to a prior encounter with the stimulus in question. Research in social cognition suggests that experienced positive affect may be the proximal cue that signals fluency in various experimental contexts. In the present study, we compared the effects of positive affect and fluency on recognition-memory judgments for faces with neutral emotional expression. We predicted that if positive affect is indeed the critical cue that signals processing fluency at retrieval, then its manipulation should produce effects that closely mirror those produced by manipulations of processing fluency. In two experiments, we employed a masked-priming procedure in combination with a Remember-Know (RK) paradigm that aimed to separate familiarity- from recollection based memory decisions. In addition, participants performed a prime discrimination task that allowed us to take inter-individual differences in prime awareness into account. We found highly similar effects of our priming manipulations of processing fluency and of positive affect. In both cases, the critical effect was specific to familiarity-based recognition responses. Moreover, in both experiments it was reflected in a shift toward a more liberal response bias, rather than in changed discrimination. Finally, in both experiments, the effect was found to be related to prime awareness; it was present only in participants who reported a lack of such awareness on the prime discrimination task. These findings add to a growing body of evidence that points not only to a role of fluency, but also of positive affect in familiarity assessment. As such they are consistent with the idea that fluency itself may be hedonically marked. PMID- 24795679 TI - Joint perceptual decision-making: a case study in explanatory pluralism. AB - Traditionally different approaches to the study of cognition have been viewed as competing explanatory frameworks. An alternative view, explanatory pluralism, regards different approaches to the study of cognition as complementary ways of studying the same phenomenon, at specific temporal and spatial scales, using appropriate methodological tools. Explanatory pluralism has been often described abstractly, but has rarely been applied to concrete cases. We present a case study of explanatory pluralism. We discuss three separate ways of studying the same phenomenon: a perceptual decision-making task (Bahrami et al., 2010), where pairs of subjects share information to jointly individuate an oddball stimulus among a set of distractors. Each approach analyzed the same corpus but targeted different units of analysis at different levels of description: decision-making at the behavioral level, confidence sharing at the linguistic level, and acoustic energy at the physical level. We discuss the utility of explanatory pluralism for describing this complex, multiscale phenomenon, show ways in which this case study sheds new light on the concept of pluralism, and highlight good practices to critically assess and complement approaches. PMID- 24795680 TI - Stability of executive function and predictions to adaptive behavior from middle childhood to pre-adolescence. AB - The shift from childhood to adolescence is characterized by rapid remodeling of the brain and increased risk-taking behaviors. Current theories hypothesize that developmental enhancements in sensitivity to affective environmental cues in adolescence may undermine executive function (EF) and increase the likelihood of problematic behaviors. In the current study, we examined the extent to which EF in childhood predicts EF in early adolescence. We also tested whether individual differences in neural responses to affective cues (rewards/punishments) in childhood serve as a biological marker for EF, sensation-seeking, academic performance, and social skills in early adolescence. At age 8, 84 children completed a gambling task while event-related potentials (ERPs) were recorded. We examined the extent to which selections resulting in rewards or losses in this task elicited (i) the P300, a post-stimulus waveform reflecting the allocation of attentional resources toward a stimulus, and (ii) the SPN, a pre-stimulus anticipatory waveform reflecting a neural representation of a "hunch" about an outcome that originates in insula and ventromedial PFC. Children also completed a Dimensional Change Card-Sort (DCCS) and Flanker task to measure EF. At age 12, 78 children repeated the DCCS and Flanker and completed a battery of questionnaires. Flanker and DCCS accuracy at age 8 predicted Flanker and DCCS performance at age 12, respectively. Individual differences in the magnitude of P300 (to losses vs. rewards) and SPN (preceding outcomes with a high probability of punishment) at age 8 predicted self-reported sensation seeking (lower) and teacher-rated academic performance (higher) at age 12. We suggest there is stability in EF from age 8 to 12, and that childhood neural sensitivity to reward and punishment predicts individual differences in sensation seeking and adaptive behaviors in children entering adolescence. PMID- 24795681 TI - The left inferior parietal lobe represents stored hand-postures for object use and action prediction. AB - Action semantics enables us to plan actions with objects and to predict others' object-directed actions as well. Previous studies have suggested that action semantics are represented in a fronto-parietal action network that has also been implicated to play a role in action observation. In the present fMRI study it was investigated how activity within this network changes as a function of the predictability of an action involving multiple objects and requiring the use of action semantics. Participants performed an action prediction task in which they were required to anticipate the use of a centrally presented object that could be moved to an associated target object (e.g., hammer-nail). The availability of actor information (i.e., presenting a hand grasping the central object) and the number of possible target objects (i.e., 0, 1, or 2 target objects) were independently manipulated, resulting in different levels of predictability. It was found that making an action prediction based on actor information resulted in an increased activation in the extrastriate body area (EBA) and the fronto parietal action observation network (AON). Predicting actions involving a target object resulted in increased activation in the bilateral IPL and frontal motor areas. Within the AON, activity in the left inferior parietal lobe (IPL) and the left premotor cortex (PMC) increased as a function of the level of action predictability. Together these findings suggest that the left IPL represents stored hand-postures that can be used for planning object-directed actions and for predicting other's actions as well. PMID- 24795682 TI - Can Doll therapy preserve or promote attachment in people with cognitive, behavioral, and emotional problems? A pilot study in institutionalized patients with dementia. AB - Doll therapy is a non-pharmacological intervention aimed at reducing behavioral and psychological disorders in institutionalized patients with dementia. This therapy as a care tool has been integrated into the context of long-term care institutions, in which the need to find solutions to cognitive, behavioral and emotional problems showed by people with dementia meets the primary objective of developing good care practices focusing on patients and their needs. In the present work we adopt the Bowlby's theory of attachment to investigate the effectiveness of Doll therapy. The hypothesis that we here propose is that the emotional experience of the person with dementia during Doll therapy activates caregiving and exploration systems together with the attachment one. To test this hypothesis we compared institutionalized patients with dementia undergoing Doll therapy with a control group and assessed measures of the relational dimension with the environment, such as gaze direction, behaviors of exploration, and behaviors of caregiving. We used an experimental protocol consisting of 10 non consecutive sessions structured with the goal of recreating a situation of (1) separation from a known figure and (2) interaction with the environment in order to partially recreate the prototypical phases of the "Strange situation." All sessions were videotaped and analyzed through an observational grid. Results support the effectiveness of Doll therapy in promoting and maintaining the affective-relational dimension of attachment-caregiving and the attentive dimension of exploration in patients with advanced stage of dementia. Thus, our results suggest that the use of Doll therapy promotes clinically significant improvements in the ability to relate with the surrounding world. This may be important for managing and caring for patients with dementia in institutionalized context. PMID- 24795683 TI - Applications of cluster analysis to the creation of perfectionism profiles: a comparison of two clustering approaches. AB - Although traditional clustering methods (e.g., K-means) have been shown to be useful in the social sciences it is often difficult for such methods to handle situations where clusters in the population overlap or are ambiguous. Fuzzy clustering, a method already recognized in many disciplines, provides a more flexible alternative to these traditional clustering methods. Fuzzy clustering differs from other traditional clustering methods in that it allows for a case to belong to multiple clusters simultaneously. Unfortunately, fuzzy clustering techniques remain relatively unused in the social and behavioral sciences. The purpose of this paper is to introduce fuzzy clustering to these audiences who are currently relatively unfamiliar with the technique. In order to demonstrate the advantages associated with this method, cluster solutions of a common perfectionism measure were created using both fuzzy clustering and K-means clustering, and the results compared. Results of these analyses reveal that different cluster solutions are found by the two methods, and the similarity between the different clustering solutions depends on the amount of cluster overlap allowed for in fuzzy clustering. PMID- 24795684 TI - Early modality-specific somatosensory cortical regions are modulated by attended visual stimuli: interaction of vision, touch and behavioral intent. AB - Bimodal interactions between relevant visual and tactile inputs can facilitate attentional modulation at early stages in somatosensory cortices to achieve goal oriented behaviors. However, the specific contribution of each sensory system during attentional processing and, importantly, how these interact with the required behavioral motor goals remains unclear. Here we used electroencephalography and event-related potentials (ERPs) to test the hypothesis that activity from modality-specific somatosensory cortical regions would be enhanced with task-relevant bimodal (visual-tactile) stimuli and that the degree of modulation would depend on the difficulty of the associated sensory-motor task demands. Tactile stimuli were discrete vibrations to the index finger and visual stimuli were horizontal bars on a computer screen, both with random amplitudes. Streams of unimodal (tactile) and crossmodal (visual and tactile) stimuli were randomly presented and participants were instructed to attend to one type of stimulus (unimodal or crossmodal) and responses involved either an indication of the presence of an attended stimulus (detect), or the integration and summation of two stimulus amplitudes using a pressure-sensitive ball (grade). Force amplitude associations were learned in a training session, and no feedback was provided during the task. ERPs were time-locked to tactile stimuli and extracted for early modality-specific components (P50, P100, N140). The P50 was enhanced with bimodal (visual-tactile) stimuli that were attended to. This was maximal when the motor requirements involved integration of the two stimuli in the grade task and when the visual stimulus occurred before (100 ms) the tactile stimulus. These results suggest that visual information relevant for movement modulates somatosensory processing as early as the primary somatosensory cortex (S1) and that the motor behavioral context influences this likely through interaction of top-down attentional and motor preparatory systems with more bottom-up crossmodal influences. PMID- 24795686 TI - Failure to see money on a tree: inattentional blindness for objects that guided behavior. AB - How is it possible to drive home and have no awareness of the trip? We documented a new form of inattentional blindness in which people fail to become aware of obstacles that had guided their behavior. In our first study, we found that people talking on cell phones while walking waited longer to avoid an obstacle and were less likely to be aware that they had avoided an obstacle than other individual walkers. In our second study, cell phone talkers and texters were less likely to show awareness of money on a tree over the pathway they were traversing. Nonetheless, they managed to avoid walking into the money tree. Perceptual information may be processed in two distinct pathways - one guiding behavior and the other leading to awareness. We observed that people can appropriately use information to guide behavior without awareness. PMID- 24795685 TI - The tool in the brain: apraxia in ADL. Behavioral and neurological correlates of apraxia in daily living. AB - Humans differ from other animals in the way they can skilfully and precisely operate or invent tools to facilitate their everyday life. Tools have dominated our home, travel and work environment, becoming an integral step for our motor skills development. What happens when the part of the brain responsible for tool use is damaged in our adult life due to a cerebrovascular accident? How does daily life change when we lose the previously mastered ability to make use of the objects around us? How do patients suffering from compromised tool use cope with food preparation, personal hygiene, grooming, housework, or use of home appliances? In this literature review we present a state of the art for single and multiple tool use research, with a focus on the impact that apraxia (impaired ability to perform tool-based actions) and action disorganization syndrome (ADS; impaired ability to carry out multi-step actions) have on activities of daily living (ADL). Firstly, we summarize the behavioral studies investigating the impact of apraxia and other comorbidity syndromes, such as neglect or visual extinction, on ADL. We discuss the hallmarks of the compromised tool use in terms of the sequencing of action steps, conceptual errors committed, spatial motor control, and temporal organization of the movement. In addition, we present an up to-date overview of the neuroimaging and lesion analyses studies that provide an insight into neural correlates of tool use in the human brain and functional changes in the neural organization following a stroke, in the context of ADL. Finally we discuss the current practice in neurorehabilitation of ADL in apraxia and ADS aiming at increasing patients' independence. PMID- 24795687 TI - Toward a more embedded/extended perspective on the cognitive function of gestures. AB - Gestures are often considered to be demonstrative of the embodied nature of the mind (Hostetter and Alibali, 2008). In this article, we review current theories and research targeted at the intra-cognitive role of gestures. We ask the question how can gestures support internal cognitive processes of the gesturer? We suggest that extant theories are in a sense disembodied, because they focus solely on embodiment in terms of the sensorimotor neural precursors of gestures. As a result, current theories on the intra-cognitive role of gestures are lacking in explanatory scope to address how gestures-as-bodily-acts fulfill a cognitive function. On the basis of recent theoretical appeals that focus on the possibly embedded/extended cognitive role of gestures (Clark, 2013), we suggest that gestures are external physical tools of the cognitive system that replace and support otherwise solely internal cognitive processes. That is gestures provide the cognitive system with a stable external physical and visual presence that can provide means to think with. We show that there is a considerable amount of overlap between the way the human cognitive system has been found to use its environment, and how gestures are used during cognitive processes. Lastly, we provide several suggestions of how to investigate the embedded/extended perspective of the cognitive function of gestures. PMID- 24795688 TI - Visual distraction during word-list retrieval does not consistently disrupt memory. AB - Glenberg et al. (1998) reported that episodic memory is impaired by visual distraction and argued that this effect is consistent with a trade-off between internal and external attentional focus. However, their demonstration that visual distraction impairs memory for lists used 15 consecutive word-lists, with analysis only of mid-list items, and has never been replicated. Experiment 1 (N = 37) replicated their methodology and found the same pattern of impairment for mid list recall, but found no evidence of impairment for other items on the lists. Experiment 2 (N = 64) explored whether this pattern arises because the mid-list items are poorly encoded (by manipulating presentation rate) or because of interference. Experiment 3 (N = 36) also looked at the role of interference whilst controlling for potential item effects. Neither study replicated the pattern seen in Experiment 1, despite reliable effects of presentation rate (Experiment 2) and interference (Experiments 2 and 3). Experiment 2 found no effect of distraction for mid-list items, but distraction did increase both correct and incorrect recall of all items suggestive of a shift in willingness to report. Experiment 3 found no effects of distraction whatsoever. Thus, there is no clear evidence that distraction consistently impairs retrieval of items from lists and therefore no consistent evidence to support the embodied cognition account used to explain the original finding. PMID- 24795689 TI - Phase noise reveals early category-specific modulation of the event-related potentials. AB - Previous studies have found that the amplitude of the early event-related potential (ERP) components evoked by faces, such as N170 and P2, changes systematically as a function of noise added to the stimuli. This change has been linked to an increased perceptual processing demand and to enhanced difficulty in perceptual decision making about faces. However, to date it has not yet been tested whether noise manipulation affects the neural correlates of decisions about face and non-face stimuli similarly. To this end, we measured the ERPs for faces and cars at three different phase noise levels. Subjects performed the same two-alternative age-discrimination task on stimuli chosen from young-old morphing continua that were created from faces as well as cars and were calibrated to lead to similar performances at each noise-level. Adding phase noise to the stimuli reduced performance and enhanced response latency for the two categories to the same extent. Parallel to that, phase noise reduced the amplitude and prolonged the latency of the face-specific N170 component. The amplitude of the P1 showed category-specific noise dependence: it was enhanced over the right hemisphere for cars and over the left hemisphere for faces as a result of adding phase noise to the stimuli, but remained stable across noise levels for cars over the left and for faces over the right hemisphere. Moreover, noise modulation altered the category-selectivity of the N170, while the P2 ERP component, typically associated with task decision difficulty, was larger for the more noisy stimuli regardless of stimulus category. Our results suggest that the category specificity of noise-induced modulations of ERP responses starts at around 100 ms post-stimulus. PMID- 24795690 TI - Consumer Demand for Online Dizziness Information: If You Build it, They may Come. AB - OBJECTIVE: Dizziness is a common reason patients present to doctors, but effective diagnostic tests and treatments for dizziness are underused. The internet is a way to disseminate medical information and is emerging as an intervention platform. The objective of this study was to describe internet searches for dizziness terms to assess the possible consumer demand for internet based dizziness diagnostic and treatment tools. STUDY DESIGN/METHODS: Google AdWords and Google Insights for Search were used for keyword search data on the following generic terms: vertigo, dizzy, dizziness, lightheaded, and lightheadedness. Data collected included keyword ideas (i.e., additional keywords identified by Google as being related search terms), global and US only monthly search frequencies, as well as trends in top searches related to dizziness terms from 2004 to 2012. Keywords suggestive of benign paroxysmal positional vertigo (BPPV) or BPPV processes were identified. RESULTS: Of the five generic dizziness terms, vertigo had the most global searches per month (1.83 million) and lightheadedness had the least (90,500). Four BPPV-specific terms had more than 100,000 global searches per month. Three BPPV terms ("positional vertigo," "benign vertigo," and "benign positional vertigo") have been in the list of top searches related to vertigo every quarter since 2004. CONCLUSION: Substantial demand exists for dizziness information via the internet. Future studies should seek to better characterize the population seeking this information. The magnitude of this potential demand suggests that validated and tested diagnostic and treatment tools could contribute to healthcare efficiencies and patient outcomes. PMID- 24795691 TI - beta1-Blockers Lower Norepinephrine Release by Inhibiting Presynaptic, Facilitating beta1-Adrenoceptors in Normotensive and Hypertensive Rats. AB - Peripheral norepinephrine release is facilitated by presynaptic beta adrenoceptors, believed to involve the beta2-subtype exclusively. However, beta1 selective blockers are the most commonly used beta-blockers in hypertension. Here the author tested the hypothesis that beta1AR may function as presynaptic, release-facilitating auto-receptors. Since beta1AR-blockers are injected during myocardial infarction, their influence on the cardiovascular response to acute norepinephrine release was also studied. By a newly established method, using tyramine-stimulated release through the norepinephrine transporter (NET), presynaptic control of catecholamine release was studied in normotensive and spontaneously hypertensive rats. beta1AR-selective antagonists (CGP20712A, atenolol, metoprolol) reduced norepinephrine overflow to plasma equally efficient as beta2AR-selective (ICI-118551) and beta1+2AR (nadolol) antagonists in both strains. Neither antagonist lowered epinephrine secretion. Atenolol, which does not cross the blood-brain barrier, reduced norepinephrine overflow after adrenalectomy (AdrX), AdrX + ganglion blockade, losartan, or nephrectomy. Atenolol and metoprolol reduced resting cardiac work load. During tyramine stimulated norepinephrine release, they had little effect on work load, and increased the transient rise in total peripheral vascular resistance, particularly atenolol when combined with losartan. In conclusion, beta1AR, like beta2AR, stimulated norepinephrine but not epinephrine release, independent of adrenal catecholamines, ganglion transmission, or renal renin release/angiotensin AT1 receptor activation. beta1AR therefore functioned as a peripheral, presynaptic, facilitating auto-receptor. Like tyramine, hypoxia may induce NET mediated release. Augmented tyramine-induced vasoconstriction, as observed after injection of beta1AR-blocker, particularly atenolol combined with losartan, may hamper organ perfusion, and may have clinical relevance in hypoxic conditions such as myocardial infarction. PMID- 24795693 TI - The relationship of neuropsychological variables to driving status following holistic neurorehabilitation. AB - OBJECTIVE: The main objectives of the present study were to evaluate the cognitive and driving outcomes of a holistic neurorehabilitation program and to examine the relationship between the neuropsychological variables of attention, speed of information processing, and visuospatial functioning and driving outcomes. METHODS: One hundred and twenty-eight individuals with heterogeneous neurological etiologies who participated in a holistic neurorehabilitation program. Holistic neurorehabilitation consisted of therapies focusing on physical, cognitive, language, emotional, and interpersonal functioning, including training in compensatory strategies. Neuropsychological testing was administered at admission and prior to starting driving or program discharge. Subtests of processing speed, working memory, and perceptual reasoning from the Wechsler Adult Intelligence Scale-III and Trail Making Test were included. RESULTS: At the time of discharge, 54% of the individuals returned to driving. Statistical analyses revealed that at the time of discharge: the sample as a group made significant improvements on cognitive measures included in the study; the driving and non-driving groups differed significantly on aspects of processing speed, attention, abstract reasoning, working memory, and visuospatial functions. Further, at the time of admission, the driving group performed significantly better than the non-driving group on several neuropsychological measures. CONCLUSION: Cognitive functions of attention, working memory, visual motor coordination, motor and mental speed, and visual scanning significantly contribute to predicting driving status of individuals after neurorehabilitation. Holistic neurorehabilitation facilitates recovery and helps individuals to gain functional independence after brain injury. PMID- 24795692 TI - Dopamine and the biology of creativity: lessons from Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is characterized by reduced flexibility, conceptualization, and visuo-spatial abilities. Although these are essential to creativity, case studies show emergence of creativity during PD. Knowledge about the role of dopamine in creativity so far only stems from a few case reports. We aim at demonstrating that creativity can be induced by dopaminergic treatments in PD, and tends to disappear after withdrawal of dopamine agonists. METHODS: Eleven consecutive creative PD patients were selected from candidates for subthalamic nucleus deep brain stimulation (STN DBS) surgery, and compared to 22 non-creative control PD patients. Motor disability (UPDRS III), cognition (Frontal score, Mattis scale), and behavior (Ardouin scale) were assessed before surgery and 1 year after. RESULTS: Before surgery, whereas cognitive and motor assessments were similar between groups, dopamine agonist (but not levodopa) dosages were higher in creative patients (p = 0.01). The Ardouin scale revealed also a specific psycho-behavioral profile of creative patients which had higher scores for mania (p < 0.001), hobbyism (p = 0.001), nocturnal hyperactivity (p = 0.041), appetitive functioning (p = 0.003), and ON euphoria (p = 0.007) and lower scores for apathy and OFF dysphoria (p = 0.04 for each). Post-operative motor, cognitive, and behavioral scores as dopaminergic treatment dosages were equivalent between groups. Motor improvement allowed for a 68.6% decrease in dopaminergic treatment. Only 1 of the 11 patients remained creative after surgery. Reduction of dopamine agonist was significantly correlated to the decrease in creativity in the whole population of study (Spearman correlation coefficient rho = 0.47 with confidence index of 95% = 0.16; 0.70, p = 0.0053). CONCLUSION: Creativity in PD is linked to dopamine agonist therapy, and tends to disappear after STN DBS in parallel to reduction of dopamine agonists, which are relatively selective for the mesolimbic D3 dopamine receptors. PMID- 24795695 TI - Diabetes and osteoporosis - cause for concern? PMID- 24795694 TI - A Comprehensive Neurorehabilitation Program Should be an Integral Part of a Comprehensive Stroke Center. PMID- 24795696 TI - Roles of reactive oxygen species in the spermatogenesis regulation. AB - Spermatogenesis is a complex process of male germ cells proliferation and maturation from diploid spermatogonia, through meiosis, to mature haploid spermatozoa. The process involves dynamic interactions between the developing germ cells and their supporting Sertoli cells. The gonadal tissue, with abundance of highly unsaturated fatty acids, high rates of cell division, and variety of testis enzymes results very vulnerable to the overexpression of reactive oxygen species (ROS). In order to address this risk, testis has developed a sophisticated array of antioxidant systems comprising both enzymes and free radical scavengers. This chapter sets out the major pathways of testis generation, the metabolism of ROS, and highlights the transcriptional regulation by steroid receptors of antioxidant stress enzymes and their functional implications. It also deals with of the advantages of the system biology for an antioxidant under steroid control, the major selenoprotein expressed by germ cells in the testis, the phospholipid hydroperoxide glutathione peroxidase (PHGPx/GPx4) having multiple functions and representing the pivotal link between selenium, sperm quality, and species preservation. PMID- 24795697 TI - Ontogeny of neuro-insular complexes and islets innervation in the human pancreas. AB - The ontogeny of the neuro-insular complexes (NIC) and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used double-staining with antibodies specific to pan-neural markers [neuron-specific enolase (NSE) and S100 protein] and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw) 10 onward. Later the density of S100 and NSE-positive fibers increased. In adults, this network was sparse. The islets innervation started to form from gw 14. NSE containing endocrine cells were identified from gw 12 onward. Additionally, S100 positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained NIC and the number of these complexes was reduced in adults. The highest density of NIC is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis. PMID- 24795700 TI - Nuclear factor kappa B is required for the production of infectious human herpesvirus 8 virions. AB - Human herpesvirus 8 (HHV8) infection leads to potent activation of nuclear factor kappa B (NFkappaB) in primary and transformed cells. We used recombinant HHV8 (rKSHV.219) expressing green fluorescent protein under the constitutive cellular promoter elongation factor 2alpha and red fluorescent protein under an early HHV8 lytic gene promoter T1.1 to monitor replication during infection of human foreskin fibroblasts (HF), noting changes in NFkappaB activity. In primary HF, NFkappaB levels do not affect the ability of HHV8 to establish infection or maintain latency. Furthermore, there was no effect on the percent of cells undergoing reactivation from latency, and there were similar numbers of released and cell-associated HHV8 viral particles following reactivation in the presence of inhibitors. Reactivation of HHV8 in latently infected HF in the presence of NFkappaB inhibitors resulted in production of viral particles that did not efficiently establish infection, due to deficiencies in binding and/or entry into normally permissive cells. Exogenous expression of glycoprotein M, an envelope protein involved in viral binding and entry, was able to partially overcome the deficiency induced by NFkappaB inhibitors. Our data indicate that in primary cells, NFkappaB is not required for infection, establishment of latency, or entry into the lytic cycle, but is required for the expression of virion associated genes involved in the initial steps of virion infectivity. These studies suggest that strategies to inhibit NFkappaB may prevent HHV8 spread and should be considered as a potential therapeutic target for preventing HHV8 associated diseases. PMID- 24795699 TI - Mesenchymal stem cells: new players in retinopathy therapy. AB - Retinopathies in human and animal models have shown to occur through loss of pericytes resulting in edema formation, excessive immature retinal angiogenesis, and neuronal apoptosis eventually leading to blindness. In recent years, the concept of regenerating terminally differentiated organs with a cell-based therapy has evolved. The cells used in these approaches are diverse and include tissue-specific endogenous stem cells, endothelial progenitor (EPC), embryonic stem cells, induced pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC). Recently, MSC derived from the stromal fraction of adipose tissue have been shown to possess pluripotent differentiation potential in vitro. These adipose stromal cells (ASC) have been differentiated in a number of laboratories to osteogenic, myogenic, vascular, and adipocytic cell phenotypes. In vivo, ASC have been shown to have functional and phenotypic overlap with pericytes lining microvessels in adipose tissues. Furthermore, these cells either in paracrine mode or physical proximity with endothelial cells, promoted angiogenesis, improved ischemia-reperfusion, protected from myocardial infarction, and were neuroprotective. Owing to the easy isolation procedure and abundant supply, fat derived ASC are a more preferred source of autologous mesenchymal cells compared to bone marrow MSC. In this review, we present evidence that these readily available ASC from minimally invasive liposuction will facilitate translation of ASC research into patients with retinal diseases in the near future. PMID- 24795701 TI - Infectious microbial diseases and host defense responses in Sydney rock oysters. AB - Aquaculture has long been seen as a sustainable solution to some of the world's growing food shortages. However, experience over the past 50 years indicates that infectious diseases caused by viruses, bacteria, and eukaryotes limit the productivity of aquaculture. In extreme cases, these types of infectious agents threaten the viability of entire aquaculture industries. This article describes the threats from infectious diseases in aquaculture and then focuses on one example (QX disease in Sydney rock oysters) as a case study. QX appears to be typical of many emerging diseases in aquaculture, particularly because environmental factors seem to play a crucial role in disease outbreaks. Evidence is presented that modulation of a generic subcellular stress response pathway in oysters is responsible for both resistance and susceptibility to infectious microbes. Understanding and being able to manipulate this pathway may be the key to sustainable aquaculture. PMID- 24795702 TI - Genetic basis for nitrate resistance in Desulfovibrio strains. AB - Nitrate is an inhibitor of sulfate-reducing bacteria (SRB). In petroleum production sites, amendments of nitrate and nitrite are used to prevent SRB production of sulfide that causes souring of oil wells. A better understanding of nitrate stress responses in the model SRB, Desulfovibrio vulgaris Hildenborough and Desulfovibrio alaskensis G20, will strengthen predictions of environmental outcomes of nitrate application. Nitrate inhibition of SRB has historically been considered to result from the generation of small amounts of nitrite, to which SRB are quite sensitive. Here we explored the possibility that nitrate might inhibit SRB by a mechanism other than through nitrite inhibition. We found that nitrate-stressed D. vulgaris cultures grown in lactate-sulfate conditions eventually grew in the presence of high concentrations of nitrate, and their resistance continued through several subcultures. Nitrate consumption was not detected over the course of the experiment, suggesting adaptation to nitrate. With high-throughput genetic approaches employing TnLE-seq for D. vulgaris and a pooled mutant library of D. alaskensis, we determined the fitness of many transposon mutants of both organisms in nitrate stress conditions. We found that several mutants, including homologs present in both strains, had a greatly increased ability to grow in the presence of nitrate but not nitrite. The mutated genes conferring nitrate resistance included the gene encoding the putative Rex transcriptional regulator (DVU0916/Dde_2702), as well as a cluster of genes (DVU0251-DVU0245/Dde_0597-Dde_0605) that is poorly annotated. Follow-up studies with individual D. vulgaris transposon and deletion mutants confirmed high throughput results. We conclude that, in D. vulgaris and D. alaskensis, nitrate resistance in wild-type cultures is likely conferred by spontaneous mutations. Furthermore, the mechanisms that confer nitrate resistance may be different from those that confer nitrite resistance. PMID- 24795698 TI - Peptides and food intake. AB - The mechanisms for controlling food intake involve mainly an interplay between gut, brain, and adipose tissue (AT), among the major organs. Parasympathetic, sympathetic, and other systems are required for communication between the brain satiety center, gut, and AT. These neuronal circuits include a variety of peptides and hormones, being ghrelin the only orexigenic molecule known, whereas the plethora of other factors are inhibitors of appetite, suggesting its physiological relevance in the regulation of food intake and energy homeostasis. Nutrients generated by food digestion have been proposed to activate G-protein coupled receptors on the luminal side of enteroendocrine cells, e.g., the L cells. This stimulates the release of gut hormones into the circulation such as glucagon-like peptide-1 (GLP-1), oxyntomodulin, pancreatic polypeptides, peptide tyrosine tyrosine, and cholecystokinin, which inhibit appetite. Ghrelin is a peptide secreted from the stomach and, in contrast to other gut hormones, plasma levels decrease after a meal and potently stimulate food intake. Other circulating factors such as insulin and leptin relay information regarding long term energy stores. Both hormones circulate at proportional levels to body fat content, enter the CNS proportionally to their plasma levels, and reduce food intake. Circulating hormones can influence the activity of the arcuate nucleus (ARC) neurons of the hypothalamus, after passing across the median eminence. Circulating factors such as gut hormones may also influence the nucleus of the tractus solitarius (NTS) through the adjacent circumventricular organ. On the other hand, gastrointestinal vagal afferents converge in the NTS of the brainstem. Neural projections from the NTS, in turn, carry signals to the hypothalamus. The ARC acts as an integrative center, with two major subpopulations of neurons influencing appetite, one of them coexpressing neuropeptide Y and agouti-related protein (AgRP) that increases food intake, whereas the other subpopulation coexpresses pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript that inhibits food intake. AgRP antagonizes the effects of the POMC product, alpha-melanocyte-stimulating hormone (alpha-MSH). Both populations project to areas important in the regulation of food intake, including the hypothalamic paraventricular nucleus, which also receives important inputs from other hypothalamic nuclei. PMID- 24795703 TI - Mycoloop: chytrids in aquatic food webs. AB - Parasites are ecologically significant in various ecosystems through their role in shaping food web structure, facilitating energy transfer, and controlling disease. Here in this review, we mainly focus on parasitic chytrids, the dominant parasites in aquatic ecosystems, and explain their roles in aquatic food webs, particularly as prey for zooplankton. Chytrids have a free-living zoosporic stage, during which they actively search for new hosts. Zoospores are excellent food for zooplankton in terms of size, shape, and nutritional quality. In the field, densities of chytrids can be high, ranging from 10(1) to 10(9) spores L( 1). When large inedible phytoplankton species are infected by chytrids, nutrients within host cells are transferred to zooplankton via the zoospores of parasitic chytrids. This new pathway, the "mycoloop," may play an important role in shaping aquatic ecosystems, by altering sinking fluxes or determining system stability. The grazing of zoospores by zooplankton may also suppress outbreaks of parasitic chytrids. A food web model demonstrated that the contribution of the mycoloop to zooplankton production increased with nutrient availability and was also dependent on the stability of the system. Further studies with advanced molecular tools are likely to discover greater chytrid diversity and evidence of additional mycoloops in lakes and oceans. PMID- 24795704 TI - Antiviral activity of Ladania067, an extract from wild black currant leaves against influenza A virus in vitro and in vivo. AB - Influenza, a respiratory disease caused by influenza viruses, still represents a major threat to humans and several animal species. Besides vaccination, only two classes of drugs are available for antiviral treatment against this pathogen. Thus, there is a strong need for new effective antivirals against influenza viruses. Here, we tested Ladania067, an extract from the leaves of the wild black currant (Ribes nigrum folium) for potential antiviral activity against influenza A virus in vitro and in vivo. In the range of 0-1 mg/ml the extract showed no cytotoxic effect on three cell lines and a CC50 of 0.5 +/- 0.3 mg/ml, on peripheral blood mononuclear cells. Furthermore, the extract did not influence the proliferative status of human lymphocytes. In contrast, Ladania067 was highly effective (EC50 value: 49.3 +/- 1.1 ng/ml) against the human pandemic influenza virus strain A/Regensburg/D6/09 (H1N1). The extract exhibited an antiviral effect when the virus was pre-incubated prior to infection or when added directly after infection. No antiviral effect was found when infected cells were treated 2, 4, or 8 h after infection, indicating that Ladania067 blocks a very early step in the virus infection cycle. In the mouse infection model we were able to demonstrate that an intranasal application of 500 MUg Ladania067 inhibits progeny virus titers in the lung up to 85% after 24 h. We conclude that the extract from the leaves of the wild black currant may be a promising source for the identification of new molecules with antiviral functions against influenza virus. PMID- 24795705 TI - Recent studies in microbial degradation of petroleum hydrocarbons in hypersaline environments. AB - Many hypersaline environments are often contaminated with petroleum compounds. Among these, oil and natural gas production sites all over the world and hundreds of kilometers of coastlines in the more arid regions of Gulf countries are of major concern due to the extent and magnitude of contamination. Because conventional microbiological processes do not function well at elevated salinities, bioremediation of hypersaline environments can only be accomplished using high salt-tolerant microorganisms capable of degrading petroleum compounds. In the last two decades, there have been many reports on the biodegradation of hydrocarbons in moderate to high salinity environments. Numerous microorganisms belonging to the domain Bacteria and Archaea have been isolated and their phylogeny and metabolic capacity to degrade a variety of aliphatic and aromatic hydrocarbons in varying salinities have been demonstrated. This article focuses on our growing understanding of bacteria and archaea responsible for the degradation of hydrocarbons under aerobic conditions in moderate to high salinity conditions. Even though organisms belonging to various genera have been shown to degrade hydrocarbons, members of the genera Halomonas Alcanivorax, Marinobacter, Haloferax, Haloarcula, and Halobacterium dominate the published literature. Despite rapid advances in understanding microbial taxa that degrade hydrocarbons under aerobic conditions, not much is known about organisms that carry out similar processes in anaerobic conditions. Also, information on molecular mechanisms and pathways of hydrocarbon degradation in high salinity is scarce and only recently there have been a few reports describing genes, enzymes and breakdown steps for some hydrocarbons. These limited studies have clearly revealed that degradation of oxygenated and non-oxygenated hydrocarbons by halophilic and halotolerant microorganisms occur by pathways similar to those found in non-halophiles. PMID- 24795706 TI - Metabolic engineering of yeasts by heterologous enzyme production for degradation of cellulose and hemicellulose from biomass: a perspective. AB - This review focuses on current approaches to metabolic engineering of ethanologenic yeast species for the production of bioethanol from complex lignocellulose biomass sources. The experimental strategies for the degradation of the cellulose and xylose-components of lignocellulose are reviewed. Limitations to the current approaches are discussed and novel solutions proposed. PMID- 24795707 TI - The impact of the pathogen Rhizoctonia solani and its beneficial counterpart Bacillus amyloliquefaciens on the indigenous lettuce microbiome. AB - Lettuce belongs to the most commonly raw eaten food worldwide and its microbiome plays an important role for both human and plant health. Yet, little is known about the impact of potentially occurring pathogens and beneficial inoculants of the indigenous microorganisms associated with lettuce. To address this question we studied the impact of the phytopathogenic fungus Rhizoctonia solani and the biological control agent Bacillus amyloliquefaciens FZB42 on the indigenous rhizosphere and phyllosphere community of greenhouse-grown lettuce at two plant stages. The rhizosphere and phyllosphere gammaproteobacterial microbiomes of lettuce plants showed clear differences in their overall and core microbiome composition as well as in corresponding diversity indices. The rhizosphere was dominated by Xanthomonadaceae (48%) and Pseudomonadaceae (37%) with Rhodanobacter, Pseudoxanthomonas, Dokdonella, Luteimonas, Steroidobacter, Thermomonas as core inhabitants, while the dominating taxa associated to phyllosphere were Pseudomonadaceae (54%), Moraxellaceae (16%) and Enterobacteriaceae (25%) with Alkanindiges, Pantoea and a group of Enterobacteriaceae unclassified at genus level. The preferential occurrence of enterics in the phyllosphere was the most significant difference between both habitats. Additional enhancement of enterics on the phyllosphere was observed in bottom rot diseased lettuce plants, while Acinetobacter and Alkanindiges were identified as indicators of healthy plants. Interestingly, the microbial diversity was enhanced by treatment with both the pathogen, and the co-inoculated biological control agent. The highest impact and bacterial diversity was found by Rhizoctonia inoculation, but FZB42 lowered the impact of Rhizoctonia on the microbiome. This study shows that the indigenous microbiome shifts as a consequence to pathogen attack but FZB42 can compensate these effects, which supports their role as biocontrol agent and suggests a novel mode of action. PMID- 24795708 TI - DNA damage repair machinery and HIV escape from innate immune sensing. AB - Viruses have been long known to perturb cell cycle regulators and key players of the DNA damage response to benefit their life cycles. In the case of the human immunodeficiency virus (HIV), the viral auxiliary protein Vpr activates the structure-specific endonuclease SLX4 complex to promote escape from innate immune sensing and, as a side effect, induces replication stress in cycling cells and subsequent cell cycle arrest at the G2/M transition. This novel pathway subverted by HIV to prevent accumulation of viral reverse transcription by-products adds up to facilitating effects of major cellular exonucleases that degrade pathological DNA species. Within this review we discuss the impact of this finding on our understanding of the interplay between HIV replication and nucleic acid metabolism and its implications for cancer-related chronic inflammation. PMID- 24795709 TI - Antivirulence activity of azithromycin in Pseudomonas aeruginosa. AB - Antibiotics represent our bulwark to combat bacterial infections, but the spread of antibiotic resistance compromises their clinical efficacy. Alternatives to conventional antibiotics are urgently needed in order to complement the existing antibacterial arsenal. The macrolide antibiotic azithromycin (AZM) provides a paradigmatic example of an "unconventional" antibacterial drug. Besides its growth-inhibiting activity, AZM displays potent anti-inflammatory properties, as well as antivirulence activity on some intrinsically resistant bacteria, such as Pseudomonas aeruginosa. In this bacterium, the antivirulence activity of AZM mainly relies on its ability to interact with the ribosome, resulting in direct and/or indirect repression of specific subsets of genes involved in virulence, quorum sensing, biofilm formation, and intrinsic antibiotic resistance. Both clinical experience and clinical trials have shown the efficacy of AZM in the treatment of chronic pulmonary infections caused by P. aeruginosa. The aim of this review is to combine results from laboratory studies with evidence from clinical trials in order to unify the information on the in vivo mode of action of AZM in P. aeruginosa infection. PMID- 24795710 TI - Bacteriophage T7 DNA polymerase - sequenase. AB - An ideal DNA polymerase for chain-terminating DNA sequencing should possess the following features: (1) incorporate dideoxy- and other modified nucleotides at an efficiency similar to that of the cognate deoxynucleotides; (2) high processivity; (3) high fidelity in the absence of proofreading/exonuclease activity; and (4) production of clear and uniform signals for detection. The DNA polymerase encoded by bacteriophage T7 is naturally endowed with or can be engineered to have all these characteristics. The chemically or genetically modified enzyme (Sequenase) expedited significantly the development of DNA sequencing technology. This article reviews the history of studies on T7 DNA polymerase with emphasis on the serial key steps leading to its use in DNA sequencing. Lessons from the study and development of T7 DNA polymerase have and will continue to enlighten the characterization of novel DNA polymerases from newly discovered microbes and their modification for use in biotechnology. PMID- 24795711 TI - Biofilm formation of Clostridium perfringens and its exposure to low-dose antimicrobials. AB - Clostridium perfringens is an opportunistic pathogen that can cause food poisoning in humans and various enterotoxemia in animal species. Very little is known on the biofilm of C. perfringens and its exposure to subminimal inhibitory concentrations of antimicrobials. This study was undertaken to address these issues. Most of the C. perfringens human and animal isolates tested in this study were able to form biofilm (230/277). Porcine clinical isolates formed significantly more biofilm than the porcine commensal isolates. A subgroup of clinical and commensal C. perfringens isolates was randomly selected for further characterization. Biofilm was found to protect C. perfringens bacterial cells from exposure to high concentrations of tested antimicrobials. Exposure to low doses of some of these antimicrobials tended to lead to a diminution of the biofilm formed. However, a few isolates showed an increase in biofilm formation when exposed to low doses of tylosin, bacitracin, virginiamycin, and monensin. Six isolates were randomly selected for biofilm analysis using scanning laser confocal microscopy. Of those, four produced more biofilm in presence of low doses of bacitracin whereas biofilms formed without bacitracin were thinner and less elevated. An increase in the area occupied by bacteria in the biofilm following exposure to low doses of bacitracin was also observed in the majority of isolates. Morphology examination revealed flat biofilms with the exception of one isolate that demonstrated a mushroom-like biofilm. Matrix composition analysis showed the presence of proteins, beta-1,4 linked polysaccharides and extracellular DNA, but no poly-beta-1,6-N-acetyl-D-glucosamine. This study brings new information on the biofilm produced by C. perfringens and its exposure to low doses of antimicrobials. PMID- 24795712 TI - Linking activity and function to ecosystem dynamics in a coastal bacterioplankton community. AB - For bacterial communities containing hundreds to thousands of distinct populations, connecting functional processes and environmental dynamics at high taxonomic resolution has remained challenging. Here we use the expression of ribosomal proteins (%RP) as a proxy for in situ activity of 200 taxa within 20 metatranscriptomic samples in a coastal ocean time series encompassing both seasonal variability and diel dynamics. %RP patterns grouped the taxa into seven activity clusters with distinct profiles in functional gene expression and correlations with environmental gradients. Clusters 1-3 had their highest potential activity in the winter and fall, and included some of the most active taxa, while Clusters 4-7 had their highest potential activity in the spring and summer. Cluster 1 taxa were characterized by gene expression for motility and complex carbohydrate degradation (dominated by Gammaproteobacteria and Bacteroidetes), and Cluster 2 taxa by transcription of genes for amino acid and aromatic compound metabolism and aerobic anoxygenic phototrophy (Roseobacter). Other activity clusters were enriched in transcripts for proteorhodopsin and methylotrophy (Cluster 4; SAR11 and methylotrophs), photosynthesis and attachment (Clusters 5 and 7; Synechococcus, picoeukaryotes, Verucomicrobia, and Planctomycetes), and sulfur oxidation (Cluster 7; Gammaproteobacteria). The seasonal patterns in activity were overlain, and sometimes obscured, by large differences in %RP over shorter day-night timescales. Seventy-eight taxa, many of them heterotrophs, had a higher %RP activity index during the day than night, indicating a strong diel activity rhythm at this coastal site. Emerging from these taxonomically- and time-resolved estimates of in situ microbial activity are predictions of specific ecological groupings of microbial taxa in a dynamic coastal environment. PMID- 24795713 TI - Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. AB - We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases. PMID- 24795714 TI - Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3' Regulatory Region. AB - The Igh locus undergoes an amazing array of DNA rearrangements and modifications during B cell development. During early stages, the variable region gene is constructed from constituent variable (V), diversity (D), and joining (J) segments (VDJ joining). B cells that successfully express an antibody can be activated, leading to somatic hypermutation (SHM) focused on the variable region, and class switch recombination (CSR), which substitutes downstream constant region genes for the originally used CMU constant region gene. Many investigators, ourselves included, have sought to understand how these processes specifically target the Igh locus and avoid other loci and potential deleterious consequences of malignant transformation. Our laboratory has concentrated on a complex regulatory region (RR) that is located downstream of Calpha, the most 3' of the Igh constant region genes. The ~40 kb 3' RR, which is predicted to serve as a downstream major regulator of the Igh locus, contains two distinct segments: an ~28 kb region comprising four enhancers, and an adjacent ~12 kb region containing multiple CTCF and Pax5 binding sites. Analysis of targeted mutations in mice by a number of investigators has concluded that the entire 3' RR enhancer region is essential for SHM and CSR (but not for VDJ joining) and for high levels of expression of multiple isotypes. The CTCF/Pax5 binding region is a candidate for influencing VDJ joining early in B cell development and serving as a potential insulator of the Igh locus. Components of the 3' RR are subject to a variety of epigenetic changes during B cell development, i.e., DNAse I hypersensitivity, histone modifications, and DNA methylation, in association with transcription factor binding. I propose that these changes provide a foundation by which regulatory elements in modules of the 3' RR function by interacting with each other and with target sequences of the Igh locus. PMID- 24795716 TI - Non-Inflammasome Forming NLRs in Inflammation and Tumorigenesis. AB - Aberrant inflammation is an enabling characteristic of tumorigenesis. Thus, signaling cascades that alter inflammatory activation and resolution are of specific relevance to disease pathogenesis. Pattern recognition receptors (PRRs) are essential mediators of the host immune response and have emerged as critical elements affecting multiple facets of tumor pathobiology. The nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins are intracellular PRRs that sense microbial and non-microbial products. Members of the NLR family can be divided into functional sub-groups based on their ability to either positively or negatively regulate the host immune response. Recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively regulate diverse biological pathways associated with both inflammation and tumorigenesis. Understanding the mechanisms underlying the function of these unique NLRs will assist in the rationale design of future therapeutic strategies targeting a wide spectrum of inflammatory diseases and cancer. Here, we will discuss recent findings associated with this novel NLR sub-group and mechanisms by which these PRRs may function to alter cancer pathogenesis. PMID- 24795717 TI - Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation. AB - Affinity maturation of the antibody response is a fundamental process in adaptive immunity during which B-cells activated by infection or vaccination undergo rapid proliferation accompanied by the acquisition of point mutations in their rearranged immunoglobulin (Ig) genes and selection for increased affinity for the eliciting antigen. The rate of somatic hypermutation at any position within an Ig gene is known to depend strongly on the local DNA sequence, and Ig genes have region-specific codon biases that influence the local mutation rate within the gene resulting in increased differential mutability in the regions that encode the antigen-binding domains. We have isolated a set of clonally related natural Ig heavy chain-light chain pairs from an experimentally infected influenza patient, inferred the unmutated ancestral rearrangements and the maturation intermediates, and synthesized all the antibodies using recombinant methods. The lineage exhibits a remarkably uniform rate of improvement of the effective affinity to influenza hemagglutinin (HA) over evolutionary time, increasing 1000 fold overall from the unmutated ancestor to the best of the observed antibodies. Furthermore, analysis of selection reveals that selection and mutation bias were concordant even at the level of maturation to a single antigen. Substantial improvement in affinity to HA occurred along mutationally preferred paths in sequence space and was thus strongly facilitated by the underlying local codon biases. PMID- 24795715 TI - Familial hemophagocytic lymphohistiocytosis: when rare diseases shed light on immune system functioning. AB - The human immune system depends on the activity of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells in order to fight off a viral infection. Understanding the molecular mechanisms during this process and the role of individual proteins was greatly improved by the study of familial hemophagocytic lymphohistiocytosis (FHL). Since 1999, genetic sequencing is the gold standard to classify patients into different subgroups of FHL. The diagnosis, once based on a clinical constellation of abnormalities, is now strongly supported by the results of a functional flow-cytometry screening, which directs the genetic study. A few additional congenital immune deficiencies can also cause a resembling or even identical clinical picture to FHL. As in many other rare human disorders, the collection and analysis of a relatively large number of cases in registries is crucial to draw a complete picture of the disease. The conduction of prospective therapeutic trials allows investigators to increase the awareness of the disease and to speed up the diagnostic process, but also provides important functional and genetic confirmations. Children with confirmed diagnosis may undergo hematopoietic stem cell transplantation, which is the only cure known to date. Moreover, detailed characterization of these rare patients helped to understand the function of individual proteins within the exocytic machinery of CTL, NK, and NKT cells. Moreover, identification of these genotypes also provides valuable information on variant phenotypes, other than FHL, associated with biallelic and monoallelic mutations in the FHL-related genes. In this review, we describe how detailed characterization of patients with genetic hemophagocytic lymphohistiocytosis has resulted in improvement in knowledge regarding contribution of individual proteins to the functional machinery of cytotoxic T- and NK-cells. The review also details how identification of these genotypes has provided valuable information on variant phenotypes. PMID- 24795718 TI - T cell responses to viral infections - opportunities for Peptide vaccination. AB - An effective immune response against viral infections depends on the activation of cytotoxic T cells that can clear infection by killing virus-infected cells. Proper activation of these T cells depends on professional antigen-presenting cells, such as dendritic cells (DCs). In this review, we will discuss the potential of peptide-based vaccines for prevention and treatment of viral diseases. We will describe features of an effective response against both acute and chronic infections, such as an appropriate magnitude, breadth, and quality and discuss requirements for inducing such an effective antiviral immune response. We will address modifications that affect presentation of vaccine components by DCs, including choice of antigen, adjuvants, and formulation. Furthermore, we will describe differences in design between preventive and therapeutic peptide-based vaccines. The ultimate goal in the design of preventive vaccines is to develop a universal vaccine that cross-protects against multiple strains of the virus. For therapeutic vaccines, cross-protection is of less importance, but enhancing existing T cell responses is essential. Although peptide vaccination is successful in inducing responses in human papillomavirus (HPV) infected patients, there are still several challenges such as choosing the right target epitopes, choosing safe adjuvants that improve immunogenicity of these epitopes, and steering the immune response in the desired direction. We will conclude with an overview of the current status of peptide vaccination, hurdles to overcome, and prospects for the future. PMID- 24795721 TI - The role of tumor/dendritic cell interactions in the regulation of anti-tumor immunity: the good, the bad, and the ugly. PMID- 24795719 TI - Know Thyself: NK-Cell Inhibitory Receptors Prompt Self-Tolerance, Education, and Viral Control. AB - Natural killer (NK) cells provide essential protection against viral infections. One of the defining features of this lymphocyte population is the expression of a wide array of variable cell surface stimulatory and inhibitory NK receptors (sNKR and iNKR, respectively). The iNKR are particularly important in terms of NK-cell education. As receptors specific for MHC class I (MHC I) molecules, they are responsible for self-tolerance and adjusting NK-cell reactivity based on the expression level of self-MHC I. The end result of this education is twofold: (1) inhibitory signaling tunes the functional capacity of the NK cell, endowing greater potency with greater education, and (2) education on self allows the NK cell to detect aberrations in MHC I expression, a common occurrence during many viral infections. Many studies have indicated an important role for iNKR and MHC I in disease, making these receptors attractive targets for manipulating NK-cell reactivity in the clinic. A greater understanding of iNKR and their ability to regulate NK cells will provide a basis for future attempts at translating their potential utility into benefits for human health. PMID- 24795720 TI - Role of innate immune response in non-alcoholic Fatty liver disease: metabolic complications and therapeutic tools. AB - Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, both in adults and children. It is characterized by an aberrant lipid storage in hepatocytes, named hepatic steatosis. Simple steatosis remains a benign process in most affected patients, while some of them develop superimposed necroinflammatory activity with a non-specific inflammatory infiltrate and a progression to non-alcoholic steatohepatitis with or without fibrosis. Deep similarity and interconnections between innate immune cells and those of liver parenchyma have been highlighted and showed to play a key role in the development of chronic liver disease. The liver can be considered as an "immune organ" because it hosts non-lymphoid cells, such as macrophage Kupffer cells, stellate and dendritic cells, and lymphoid cells. Many of these cells are components of the classic innate immune system, enabling the liver to play a major role in response to pathogens. Although the liver provides a "tolerogenic" environment, aberrant activation of innate immune signaling may trigger "harmful" inflammation that contributes to tissue injury, fibrosis, and carcinogenesis. Pathogen recognition receptors, such as toll-like receptors and nucleotide oligomerization domain-like receptors, are responsible for the recognition of immunogenic signals, and represent the major conduit for sensing hepatic and non hepatic noxious stimuli. A pivotal role in liver inflammation is also played by cytokines, which can initiate or have a part in immune response, triggering hepatic intracellular signaling pathways. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic alteration traits: insulin resistance, obesity, diabetes, hyperlipidemia, and their compounded combined effects. In this review, we discuss the relevant role of innate immune cell activation in relation to NAFLD, the metabolic complications associated to this pathology, and the possible pharmacological tools. PMID- 24795722 TI - Fish allergens at a glance: variable allergenicity of parvalbumins, the major fish allergens. AB - Fish is a common trigger of severe, food-allergic reactions. Only a limited number of proteins induce specific IgE-mediated immune reactions. The major fish allergens are the parvalbumins. They are members of the calcium-binding EF-hand protein family characterized by a conserved protein structure. They represent highly cross-reactive allergens for patients with specific IgE to conserved epitopes. These patients might experience clinical reactions with various fish species. On the other hand, some individuals have IgE antibodies directed against unique, species-specific parvalbumin epitopes, and these patients show clinical symptoms only with certain fish species. Furthermore, different parvalbumin isoforms and isoallergens are present in the same fish and might display variable allergenicity. This was shown for salmon homologs, where only a single parvalbumin (beta-1) isoform was identified as allergen in specific patients. In addition to the parvalbumins, several other fish proteins, enolases, aldolases, and fish gelatin, seem to be important allergens. New clinical and molecular insights advanced the knowledge and understanding of fish allergy in the last years. These findings were useful for the advancement of the IgE-based diagnosis and also for the management of fish allergies consisting of advice and treatment of fish-allergic patients. PMID- 24795723 TI - Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis. AB - With 1.4 million deaths and 8.7 million new cases in 2011, tuberculosis (TB) remains a global health care problem and together with HIV and Malaria represents one of the three infectious diseases world-wide. Control of the global TB epidemic has been impaired by the lack of an effective vaccine, by the emergence of drug-resistant forms of Mycobacterium tuberculosis (Mtb) and by the lack of sensitive and rapid diagnostics. It is estimated, by epidemiological reports, that one third of the world's population is latently infected with Mtb, but the majority of infected individuals develop long-lived protective immunity, which controls and contains Mtb in a T cell-dependent manner. Development of TB disease results from interactions among the environment, the host, and the pathogen, and known risk factors include HIV co-infection, immunodeficiency, diabetes mellitus, overcrowding, malnutrition, and general poverty; therefore, an effective T cell response determines whether the infection resolves or develops into clinically evident disease. Consequently, there is great interest in determining which T cells subsets mediate anti-mycobacterial immunity, delineating their effector functions. On the other hand, many aspects remain unsolved in understanding why some individuals are protected from Mtb infection while others go on to develop disease. Several studies have demonstrated that CD4(+) T cells are involved in protection against Mtb, as supported by the evidence that CD4(+) T cell depletion is responsible for Mtb reactivation in HIV-infected individuals. There are many subsets of CD4(+) T cells, such as T-helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs), and all these subsets co-operate or interfere with each other to control infection; the dominant subset may differ between active and latent Mtb infection cases. Mtb-specific-CD4(+) Th1 cell response is considered to have a protective role for the ability to produce cytokines such as IFN-gamma or TNF alpha that contribute to the recruitment and activation of innate immune cells, like monocytes and granulocytes. Thus, while other antigen (Ag)-specific T cells such as CD8(+) T cells, natural killer (NK) cells, gammadelta T cells, and CD1 restricted T cells can also produce IFN-gamma during Mtb infection, they cannot compensate for the lack of CD4(+) T cells. The detection of Ag-specific cytokine production by intracellular cytokine staining (ICS) and the use of flow cytometry techniques are a common routine that supports the studies aimed at focusing the role of the immune system in infectious diseases. Flow cytometry permits to evaluate simultaneously the presence of different cytokines that can delineate different subsets of cells as having "multifunctional/polyfunctional" profile. It has been proposed that polyfunctional T cells, are associated with protective immunity toward Mtb, in particular it has been highlighted that the number of Mtb specific T cells producing a combination of IFN-gamma, IL-2, and/or TNF-alpha may be correlated with the mycobacterial load, while other studies have associated the presence of this particular functional profile as marker of TB disease activity. Although the role of CD8 T cells in TB is less clear than CD4 T cells, they are generally considered to contribute to optimal immunity and protection. CD8 T cells possess a number of anti-microbial effector mechanisms that are less prominent or absent in CD4 Th1 and Th17 T cells. The interest in studying CD8 T cells that are either MHC-class Ia or MHC-class Ib-restricted, has gained more attention. These studies include the role of HLA-E-restricted cells, lung mucosal associated invariant T-cells (MAIT), and CD1-restricted cells. Nevertheless, the knowledge about the role of CD8(+) T cells in Mtb infection is relatively new and recent studies have delineated that CD8 T cells, which display a functional profile termed "multifunctional," can be a better marker of protection in TB than CD4(+) T cells. Their effector mechanisms could contribute to control Mtb infection, as upon activation, CD8 T cells release cytokines or cytotoxic molecules, which cause apoptosis of target cells. Taken together, the balance of the immune response in the control of infection and possibly bacterial eradication is important in understanding whether the host immune response will be appropriate in contrasting the infection or not, and, consequently, the inability of the immune response, will determine the dissemination and the transmission of bacilli to new subjects. In conclusion, the recent highlights on the role of different functional signatures of T cell subsets in the immune response toward Mtb infection will be discerned in this review, in order to summarize what is known about the immune response in human TB. In particular, we will discuss the role of CD4 and CD8 T cells in contrasting the advance of the intracellular pathogen in already infected people or the progression to active disease in subjects with latent infection. All the information will be aimed at increasing the knowledge of this complex disease in order to improve diagnosis, prognosis, drug treatment, and vaccination. PMID- 24795725 TI - Human immune responses to dengue virus infection: lessons learned from prospective cohort studies. AB - Dengue virus (DENV) continues to spread globally and is a major cause of morbidity and mortality. Currently, there is no antiviral treatment to diminish severe illness or a vaccine to induce protection from infection. An effective dengue vaccine that protects against all four DENV serotypes is a high priority for endemic countries and several candidates are in development by various United States Federal Agencies and private pharmaceutical companies. Challenges faced by dengue vaccine developers include creating tetravalent formulations that provide tetravalent protection, the lack of a correlate of protective immunity, a changing viral landscape as DENV evolves, and a complex viral-host pathogenesis that can result in a spectrum of illness from subclinical infection to severe hemorrhagic fever. There have been a number of long-term prospective studies on DENV transmission and dengue severity that have provided invaluable information on DENV epidemiology and pathogenesis of this disease. In this section, we will review the critical lessons learned from these studies and their application for dengue vaccine development. PMID- 24795724 TI - Understanding MHC class I presentation of viral antigens by human dendritic cells as a basis for rational design of therapeutic vaccines. AB - Effective viral clearance requires the induction of virus-specific CD8(+) cytotoxic T lymphocytes (CTL). Since dendritic cells (DC) have a central role in initiating and shaping virus-specific CTL responses, it is important to understand how DC initiate virus-specific CTL responses. Some viruses can directly infect DC, which theoretically allow direct presentation of viral antigens to CTL, but many viruses target other cells than DC and thus the host depends on the cross-presentation of viral antigens by DC to activate virus specific CTL. Research in mouse models has highly enhanced our understanding of the mechanisms underlying cross-presentation and the dendritic cells (DC) subsets involved, however, these results cannot be readily translated toward the role of human DC in MHC class I-antigen presentation of human viruses. Here, we summarize the insights gained in the past 20 years on MHC class I presentation of viral antigen by human DC and add to the current debate on the capacities of different human DC subsets herein. Furthermore, possible sources of viral antigens and essential DC characteristics for effective induction of virus-specific CTL are evaluated. We conclude that cross-presentation is not only an efficient mechanism exploited by DC to initiate immunity to viruses that do not infect DC but also to viruses that do infect DC, because cross-presentation has many conceptual advantages and bypasses direct immune modulatory effects of the virus on its infected target cells. Since knowledge on the mechanism of viral antigen presentation and the preferred DC subsets is crucial for rational vaccine design, the obtained insights are very instrumental for the development of effective anti viral immunotherapy. PMID- 24795726 TI - Activating killer cell Ig-like receptors in health and disease. AB - Expression of non-rearranged HLA class I-binding receptors characterizes human and mouse NK cells. The postulation of the missing-self hypothesis some 30 years ago triggered the subsequent search and discovery of inhibitory MHC-receptors, both in humans and mice. These receptors have two functions: (i) to control the threshold for NK cell activation, a process termed "licensing" or "education," and (ii) to inhibit NK cell activation during interactions with healthy HLA class I-expressing cells. The discovery of activating forms of KIRs (aKIR) challenged the concept of NK cell tolerance in steady state, as well as during immune challenge: what is the biological role of the activating KIR, in particular when NK cells express aKIRs in the absence of inhibitory receptors? Recently it was shown that aKIRs also participate in the education of NK cells. However, instead of lowering the threshold of activation like iKIRs, the expression of aKIRs has the opposite effect, i.e., rendering NK cells hyporesponsive. These findings may have consequences during NK cell response to viral infection, in cancer development, and in the initial stages of pregnancy. Here we review the current knowledge of activating KIRs, including the biological concept of aKIR-dependent NK cell education, and their impact in health and disease. PMID- 24795727 TI - Nod-like receptors: key molecular switches in the conundrum of cancer. AB - It is believed the immune system can contribute to oncogenic transformation especially in settings of chronic inflammation, be activated during immunosurveillance to destroy early neoplastic cells before they undergo malignant outgrowth, and finally, can assist growth of established tumors by preventing clearance, remodeling surrounding tissue, and promoting metastatic events. These seemingly opposing roles of the immune system at the different stages of cancer development must all be mediated by innate signaling mechanisms that regulate the overall state of immune activation. Recently, the cytosolic nod like receptor (NLR) pathway of innate immunity has gained a lot of attention in the tumor immunology field due to its known involvement in promoting inflammation and immunity, and conversely, in regulating tissue repair processes. In this review, we present all the current evidence for NLR involvement in the different stages of neoplasia to understand how a single molecular pathway can contribute to conflicting immunological interactions with cancer. PMID- 24795728 TI - SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors. AB - Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8(+) T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1 + 6](-/-) and Slamf[1 + 5 + 6](-/-) B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8(+) T cells slightly increased in the Slamf[1 + 5 + 6](-/ ) , but not in the Slamf[1 + 6](-/-) strain, suggesting that Slamf5 may function as a negative regulator of innate CD8(+) T cell development. Accordingly, Slamf5( /-) B6 mice showed an exclusive expansion of innate CD8(+) T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7(-/-) strain showed an expansion of both splenic innate CD8(+) T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3(-/-) BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZF(hi)) NKT cells and innate CD8(+) T cells significantly increased in the SAP-independent Slamf8(-/-) BALB/c strain. In summary, these results show that NKT and innate CD8(+) T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8(+) T cells. PMID- 24795729 TI - The Critical Role of IL-15-PI3K-mTOR Pathway in Natural Killer Cell Effector Functions. AB - Natural killer (NK) cells were so named for their uniqueness in killing certain tumor and virus-infected cells without prior sensitization. Their functions are modulated in vivo by several soluble immune mediators; interleukin-15 (IL-15) being the most potent among them in enabling NK cell homeostasis, maturation, and activation. During microbial infections, NK cells stimulated with IL-15 display enhanced cytokine responses. This priming effect has previously been shown with respect to increased IFN-gamma production in NK cells upon IL-12 and IL-15/IL-2 co-stimulation. In this study, we explored if this effect of IL-15 priming can be extended to various other cytokines and observed enhanced NK cell responses to stimulation with IL-4, IL-21, IFN-alpha, and IL-2 in addition to IL-12. Notably, we also observed elevated IFN-gamma production in primed NK cells upon stimulation through the Ly49H activation receptor. Currently, the fundamental processes required for priming and whether these signaling pathways work collaboratively or independently for NK cell functions are poorly understood. To identify the key signaling events for NK cell priming, we examined IL-15 effects on NK cells in which the pathways emanating from IL-15 receptor activation were blocked with specific inhibitors. Our results demonstrate that the PI3K-AKT-mTOR pathway is critical for cytokine responses in IL-15 primed NK cells. Furthermore, this pathway is also implicated in a broad range of IL-15-induced NK cell effector functions such as proliferation and cytotoxicity. Likewise, NK cells from mice treated with rapamycin to block the mTOR pathway displayed defects in proliferation, and IFN-gamma and granzyme B productions resulting in elevated viral burdens upon murine cytomegalovirus infection. Taken together, our data demonstrate the requirement of PI3K-mTOR pathway for enhanced NK cell functions by IL-15, thereby coupling the metabolic sensor mTOR to NK cell anti-viral responses. PMID- 24795730 TI - Role of Fused Mycobacterium tuberculosis Immunogens and Adjuvants in Modern Tuberculosis Vaccines. AB - Several approaches have been developed to improve or replace the only available vaccine for tuberculosis (TB), BCG (Bacille Calmette Guerin). The development of subunit protein vaccines is a promising strategy because it combines specificity and safety. In addition, subunit protein vaccines can be designed to have selected immune epitopes associated with immunomodulating components to drive the appropriate immune response. However, the limited antigens present in subunit vaccines reduce their capacity to stimulate a complete immune response compared with vaccines composed of live attenuated or killed microorganisms. This deficiency can be compensated by the incorporation of adjuvants in the vaccine formulation. The fusion of adjuvants with Mycobacterium tuberculosis (Mtb) proteins or immune epitopes has the potential to become the new frontier in the TB vaccine development field. Researchers have addressed this approach by fusing the immune epitopes of their vaccines with molecules such as interleukins, lipids, lipoproteins, and immune stimulatory peptides, which have the potential to enhance the immune response. The fused molecules are being tested as subunit vaccines alone or within live attenuated vector contexts. Therefore, the objectives of this review are to discuss the association of Mtb fusion proteins with adjuvants; Mtb immunogens fused with adjuvants; and cytokine fusion with Mtb proteins and live recombinant vectors expressing cytokines. The incorporation of adjuvant molecules in a vaccine can be complex, and developing a stable fusion with proteins is a challenging task. Overall, the fusion of adjuvants with Mtb epitopes, despite the limited number of studies, is a promising field in vaccine development. PMID- 24795731 TI - Genetic regulation and structural changes during tomato fruit development and ripening. AB - Fruits are an important evolutionary acquisition of angiosperms, which afford protection for seeds and ensure their optimal dispersal in the environment. Fruits can be divided into dry or fleshy. Dry fruits are the more ancient and provide for mechanical seed dispersal. In contrast, fleshy fruits develop soft tissues in which flavor compounds and pigments accumulate during the ripening process. These serve to attract animals that eat them and disseminate the indigestible seeds. Fruit maturation is accompanied by several striking cytological modifications. In particular, plastids undergo significant structural alterations, including the dedifferentiation of chloroplasts into chromoplasts. Chloroplast biogenesis, their remodeling in response to environmental constraints and their conversion into alternative plastid types are known to require communication between plastids and the nucleus in order to coordinate the expression of their respective genomes. In this review, we discuss the role of plastid modifications in the context of fruit maturation and ripening, and consider the possible involvement of organelle-nucleus crosstalk via retrograde (plastid to nucleus) and anterograde (nucleus to plastid) signaling in the process. PMID- 24795732 TI - The role of ubiquitin and the 26S proteasome in plant abiotic stress signaling. AB - Ubiquitin is a small, highly conserved, ubiquitously expressed eukaryotic protein with immensely important and diverse regulatory functions. A well-studied function of ubiquitin is its role in selective proteolysis by the ubiquitin proteasome system (UPS). The UPS has emerged as an integral player in plant response and adaptation to environmental stresses such as drought, salinity, cold and nutrient deprivation. The UPS has also been shown to influence the production and signal transduction of stress-related hormones such as abscisic acid. Understanding UPS function has centered mainly on defining the role of E3 ubiquitin ligases, which are the substrate-recruiting component of the ubiquitination pathway. The recent identification of stress signaling/regulatory proteins that are the subject of ubiquitin-dependent degradation has increased our knowledge of how the UPS facilitates responses to adverse environmental conditions. A brief overview is provided on role of the UPS in modulating protein stability during abiotic stress signaling. E3 ubiquitin ligases for which stress related substrate proteins have been identified are discussed. PMID- 24795734 TI - An update: improvements in imaging perfluorocarbon-mounted plant leaves with implications for studies of plant pathology, physiology, development and cell biology. AB - Plant leaves are optically complex, which makes them difficult to image by light microscopy. Careful sample preparation is therefore required to enable researchers to maximize the information gained from advances in fluorescent protein labeling, cell dyes and innovations in microscope technologies and techniques. We have previously shown that mounting leaves in the non-toxic, non fluorescent perfluorocarbon (PFC), perfluorodecalin (PFD) enhances the optical properties of the leaf with minimal impact on physiology. Here, we assess the use of the PFCs, PFD, and perfluoroperhydrophenanthrene (PP11) for in vivo plant leaf imaging using four advanced modes of microscopy: laser scanning confocal microscopy (LSCM), two-photon fluorescence microscopy, second harmonic generation microscopy, and stimulated Raman scattering (SRS) microscopy. For every mode of imaging tested, we observed an improved signal when leaves were mounted in PFD or in PP11, compared to mounting the samples in water. Using an image analysis technique based on autocorrelation to quantitatively assess LSCM image deterioration with depth, we show that PP11 outperformed PFD as a mounting medium by enabling the acquisition of clearer images deeper into the tissue. In addition, we show that SRS microscopy can be used to image PFCs directly in the mesophyll and thereby easily delimit the "negative space" within a leaf, which may have important implications for studies of leaf development. Direct comparison of on and off resonance SRS micrographs show that PFCs do not to form intracellular aggregates in live plants. We conclude that the application of PFCs as mounting media substantially increases advanced microscopy image quality of living mesophyll and leaf vascular bundle cells. PMID- 24795735 TI - A functional TOC complex contributes to gravity signal transduction in Arabidopsis. AB - Although plastid sedimentation has long been recognized as important for a plant's perception of gravity, it was recently shown that plastids play an additional function in gravitropism. The Translocon at the Outer envelope membrane of Chloroplasts (TOC) complex transports nuclear-encoded proteins into plastids, and a receptor of this complex, Toc132, was previously hypothesized to contribute to gravitropism either by directly functioning as a gravity signal transducer or by indirectly mediating the plastid localization of a gravity signal transducer. Here we show that mutations in multiple genes encoding TOC complex components affect gravitropism in a genetically sensitized background and that the cytoplasmic acidic domain of Toc132 is not required for its involvement in this process. Furthermore, mutations in TOC132 enhance the gravitropic defect of a mutant whose amyloplasts lack starch. Finally, we show that the levels of several nuclear-encoded root proteins are altered in toc132 mutants. These data suggest that the TOC complex indirectly mediates gravity signal transduction in Arabidopsis and support the idea that plastids are involved in gravitropism not only through their ability to sediment but also as part of the signal transduction mechanism. PMID- 24795736 TI - Whole shoot mineral partitioning and accumulation in pea (Pisum sativum). AB - Several grain legumes are staple food crops that are important sources of minerals for humans; unfortunately, our knowledge is incomplete with respect to the mechanisms of translocation of these minerals to the vegetative tissues and loading into seeds. Understanding the mechanism and partitioning of minerals in pea could help in developing cultivars with high mineral density. A mineral partitioning study was conducted in pea to assess whole-plant growth and mineral content and the potential source-sink remobilization of different minerals, especially during seed development. Shoot and root mineral content increased for all the minerals, although tissue-specific partitioning differed between the minerals. Net remobilization was observed for P, S, Cu, and Fe from both the vegetative tissues and pod wall, but the amounts remobilized were much below the total accumulation in the seeds. Within the mature pod, more minerals were partitioned to the seed fraction (>75%) at maturity than to the pod wall for all the minerals except Ca, where only 21% was partitioned to the seed fraction. Although there was evidence for net remobilization of some minerals from different tissues into seeds, continued uptake and translocation of minerals to source tissues during seed fill is as important, if not more important, than remobilization of previously stored minerals. PMID- 24795733 TI - Callose homeostasis at plasmodesmata: molecular regulators and developmental relevance. AB - Plasmodesmata are membrane-lined channels that are located in the plant cell wall and that physically interconnect the cytoplasm and the endoplasmic reticulum (ER) of adjacent cells. Operating as controllable gates, plasmodesmata regulate the symplastic trafficking of micro- and macromolecules, such as endogenous proteins [transcription factors (TFs)] and RNA-based signals (mRNA, siRNA, etc.), hence mediating direct cell-to-cell communication and long distance signaling. Besides this physiological role, plasmodesmata also form gateways through which viral genomes can pass, largely facilitating the pernicious spread of viral infections. Plasmodesmatal trafficking is either passive (e.g., diffusion) or active and responses both to developmental and environmental stimuli. In general, plasmodesmatal conductivity is regulated by the controlled build-up of callose at the plasmodesmatal neck, largely mediated by the antagonistic action of callose synthases (CalSs) and beta-1,3-glucanases. Here, in this theory and hypothesis paper, we outline the importance of callose metabolism in PD SEL control, and highlight the main molecular factors involved. In addition, we also review other proteins that regulate symplastic PD transport, both in a developmental and stress-responsive framework, and discuss on their putative role in the modulation of PD callose turn-over. Finally, we hypothesize on the role of structural sterols in the regulation of (PD) callose deposition and outline putative mechanisms by which this regulation may occur. PMID- 24795737 TI - Plant virus metagenomics: what we know and why we need to know more. PMID- 24795738 TI - Tolerance to drought and salt stress in plants: Unraveling the signaling networks. AB - Tolerance of plants to abiotic stressors such as drought and salinity is triggered by complex multicomponent signaling pathways to restore cellular homeostasis and promote survival. Major plant transcription factor families such as bZIP, NAC, AP2/ERF, and MYB orchestrate regulatory networks underlying abiotic stress tolerance. Sucrose non-fermenting 1-related protein kinase 2 and mitogen activated protein kinase pathways contribute to initiation of stress adaptive downstream responses and promote plant growth and development. As a convergent point of multiple abiotic cues, cellular effects of environmental stresses are not only imbalances of ionic and osmotic homeostasis but also impaired photosynthesis, cellular energy depletion, and redox imbalances. Recent evidence of regulatory systems that link sensing and signaling of environmental conditions and the intracellular redox status have shed light on interfaces of stress and energy signaling. ROS (reactive oxygen species) cause severe cellular damage by peroxidation and de-esterification of membrane-lipids, however, current models also define a pivotal signaling function of ROS in triggering tolerance against stress. Recent research advances suggest and support a regulatory role of ROS in the cross talks of stress triggered hormonal signaling such as the abscisic acid pathway and endogenously induced redox and metabolite signals. Here, we discuss and review the versatile molecular convergence in the abiotic stress responsive signaling networks in the context of ROS and lipid-derived signals and the specific role of stomatal signaling. PMID- 24795739 TI - Polyamines control of cation transport across plant membranes: implications for ion homeostasis and abiotic stress signaling. AB - Polyamines are unique polycationic metabolites, controlling a variety of vital functions in plants, including growth and stress responses. Over the last two decades a bulk of data was accumulated providing explicit evidence that polyamines play an essential role in regulating plant membrane transport. The most straightforward example is a blockage of the two major vacuolar cation channels, namely slow (SV) and fast (FV) activating ones, by the micromolar concentrations of polyamines. This effect is direct and fully reversible, with a potency descending in a sequence Spm(4+) > Spd(3+) > Put(2+). On the contrary, effects of polyamines on the plasma membrane (PM) cation and K(+)-selective channels are hardly dependent on polyamine species, display a relatively low affinity, and are likely to be indirect. Polyamines also affect vacuolar and PM H(+) pumps and Ca(2+) pump of the PM. On the other hand, catabolization of polyamines generates H2O2 and other reactive oxygen species (ROS), including hydroxyl radicals. Export of polyamines to the apoplast and their oxidation there by available amine oxidases results in the induction of a novel ion conductance and confers Ca(2+) influx across the PM. This mechanism, initially established for plant responses to pathogen attack (including a hypersensitive response), has been recently shown to mediate plant responses to a variety of abiotic stresses. In this review we summarize the effects of polyamines and their catabolites on cation transport in plants and discuss the implications of these effects for ion homeostasis, signaling, and plant adaptive responses to environment. PMID- 24795740 TI - Plant responses to Agrobacterium tumefaciens and crown gall development. AB - Agrobacterium tumefaciens causes crown gall disease on various plant species by introducing its T-DNA into the genome. Therefore, Agrobacterium has been extensively studied both as a pathogen and an important biotechnological tool. The infection process involves the transfer of T-DNA and virulence proteins into the plant cell. At that time the gene expression patterns of host plants differ depending on the Agrobacterium strain, plant species and cell-type used. Later on, integration of the T-DNA into the plant host genome, expression of the encoded oncogenes, and increase in phytohormone levels induce a fundamental reprogramming of the transformed cells. This results in their proliferation and finally formation of plant tumors. The process of reprogramming is accompanied by altered gene expression, morphology and metabolism. In addition to changes in the transcriptome and metabolome, further genome-wide ("omic") approaches have recently deepened our understanding of the genetic and epigenetic basis of crown gall tumor formation. This review summarizes the current knowledge about plant responses in the course of tumor development. Special emphasis is placed on the connection between epigenetic, transcriptomic, metabolomic, and morphological changes in the developing tumor. These changes not only result in abnormally proliferating host cells with a heterotrophic and transport-dependent metabolism, but also cause differentiation and serve as mechanisms to balance pathogen defense and adapt to abiotic stress conditions, thereby allowing the coexistence of the crown gall and host plant. PMID- 24795741 TI - When RNA and protein degradation pathways meet. AB - RNA silencing has become a major focus of molecular and biomedical research in the last decade. This mechanism, which is conserved in most eukaryotes, has been extensively studied and is associated to various pathways implicated in the regulation of development, in the control of transposition events, heterochromatin maintenance and also playing a role in defense against viruses. Despite of its importance, the regulation of the RNA silencing machinery itself remains still poorly explored. Recently several reports in both plants and metazoans revealed that key components of RNA silencing, such as RNA-induced silencing complex component ARGONAUTE proteins, but also the endonuclease Dicer are subjected to proteasomal and autophagic pathways. Here we will review these post-translational proteolytic regulations with a special emphasis on plant research and also discuss their functional relevance. PMID- 24795742 TI - Physiological roles of regulated Ire1 dependent decay. AB - Inositol-requiring enzyme 1 (Ire1) is an important transducer of the unfolded protein response (UPR) that is activated by the accumulation of misfolded proteins in the endoplamic reticulum (ER stress). Activated Ire1 mediates the splicing of an intron from the mRNA of Xbp1, causing a frame-shift during translation and introducing a new carboxyl domain in the Xbp1 protein, which only then becomes a fully functional transcription factor. Studies using cell culture systems demonstrated that Ire1 also promotes the degradation of mRNAs encoding mostly ER-targeted proteins, to reduce the load of incoming ER "client" proteins during ER stress. This process was called RIDD (regulated Ire1-dependent decay), but its physiological significance remained poorly characterized beyond cell culture systems. Here we review several recent studies that have highlighted the physiological roles of RIDD in specific biological paradigms, such as photoreceptor differentiation in Drosophila or mammalian liver and endocrine pancreas function. These studies demonstrate the importance of RIDD in tissues undergoing intense secretory function and highlight the physiologic role of RIDD during UPR activation in cells and organisms. PMID- 24795744 TI - Trans-regulation of RNA-binding protein motifs by microRNA. AB - The wide array of vital functions that RNA performs is dependent on its ability to dynamically fold into different structures in response to intracellular and extracellular changes. RNA-binding proteins regulate much of this activity by targeting specific RNA structures or motifs. One of these structures, the 3-way RNA junction, is characteristically found in ribosomal RNA and results from the RNA folding in cis, to produce three separate helices that meet around a central unpaired region. Here we demonstrate that 3-way junctions can also form in trans as a result of the binding of microRNAs in an unconventional manner with mRNA by splinting two non-contiguous regions together. This may be used to reinforce the base of a stem-loop motif being targeted by an RNA-binding protein. Trans interactions between non-coding RNA and mRNA may be used to control the post transcriptional regulatory code and suggests a possible role for some of the recently described transcripts of unknown function expressed from the human genome. PMID- 24795743 TI - Pharmacogenomics and adverse drug reactions in children. AB - Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children. PMID- 24795745 TI - How integration of global omics-data could help preparing for pandemics - a scent of influenza. AB - Pandemics caused by novel emerging or re-emerging infectious diseases could lead to high mortality and morbidity world-wide when left uncontrolled. In this perspective, we evaluate the possibility of integration of global omics-data in order to timely prepare for pandemics. Such an approach requires two major innovations. First, data that is obtained should be shared with the global community instantly. The strength of rapid integration of simple signals is exemplified by Google's(TM) Flu Trend, which could predict the incidence of influenza-like illness based on online search engine queries. Second, omics technologies need to be fast and high-throughput. We postulate that analysis of the exhaled breath would be a simple, rapid and non-invasive alternative. Breath contains hundreds of volatile organic compounds that are altered by infection and inflammation. The molecular fingerprint of breath (breathprint) can be obtained using an electronic nose, which relies on sensor technology. These breathprints can be stored in an online database (a "breathcloud") and coupled to clinical data. Comparison of the breathprint of a suspected subject to the breathcloud allows for a rapid decision on the presence or absence of a pathogen. PMID- 24795746 TI - SDS, a structural disruption score for assessment of missense variant deleteriousness. AB - We have developed a novel structure-based evaluation for missense variants that explicitly models protein structure and amino acid properties to predict the likelihood that a variant disrupts protein function. A structural disruption score (SDS) is introduced as a measure to depict the likelihood that a case variant is functional. The score is constructed using characteristics that distinguish between causal and neutral variants within a group of proteins. The SDS score is correlated with standard sequence-based deleteriousness, but shows promise for improving discrimination between neutral and causal variants at less conserved sites. The prediction was performed on 3-dimentional structures of 57 gene products whose homozygous SNPs were identified as case-exclusive variants in an exome sequencing study of epilepsy disorders. We contrasted the candidate epilepsy variants with scores for likely benign variants found in the EVS database, and for positive control variants in the same genes that are suspected to promote a range of diseases. To derive a characteristic profile of damaging SNPs, we transformed continuous scores into categorical variables based on the score distribution of each measurement, collected from all possible SNPs in this protein set, where extreme measures were assumed to be deleterious. A second epilepsy dataset was used to replicate the findings. Causal variants tend to receive higher sequence-based deleterious scores, induce larger physico-chemical changes between amino acid pairs, locate in protein domains, buried sites or on conserved protein surface clusters, and cause protein destabilization, relative to negative controls. These measures were agglomerated for each variant. A list of nine high-priority putative functional variants for epilepsy was generated. Our newly developed SDS protocol facilitates SNP prioritization for experimental validation. PMID- 24795747 TI - Asymmetric localization of natural antisense RNA of neuropeptide sensorin in Aplysia sensory neurons during aging and activity. AB - Despite the advances in our understanding of transcriptome, regulation and function of its non-coding components continue to be poorly understood. Here we searched for natural antisense transcript for sensorin (NAT-SRN), a neuropeptide expressed in the presynaptic sensory neurons of gill-withdrawal reflex of the marine snail Aplysia californica. Sensorin (SRN) has a key role in learning and long-term memory storage in Aplysia. We have now identified NAT-SRN in the central nervous system (CNS) and have confirmed its expression by northern blotting and fluorescent RNA in situ hybridization. Quantitative analysis of NAT SRN in micro-dissected cell bodies and processes of sensory neurons suggest that NAT-SRN is present in the distal neuronal processes along with sense transcripts. Importantly, aging is associated with reduction in levels of NAT-SRN in sensory neuron processes. Furthermore, we find that forskolin, an activator of CREB signaling, differentially alters the distribution of SRN and NAT-SRN. These studies reveal novel insights into physiological regulation of natural antisense RNAs. PMID- 24795748 TI - Elucidating the interactions between the human gut microbiota and its host through metabolic modeling. AB - Increased understanding of the interactions between the gut microbiota, diet and environmental effects may allow us to design efficient treatment strategies for addressing global health problems. Existence of symbiotic microorganisms in the human gut provides different functions for the host such as conversion of nutrients, training of the immune system, and resistance to pathogens. The gut microbiome also plays an influential role in maintaining human health, and it is a potential target for prevention and treatment of common disorders including obesity, type 2 diabetes, and atherosclerosis. Due to the extreme complexity of such disorders, it is necessary to develop mathematical models for deciphering the role of its individual elements as well as the entire system and such models may assist in better understanding of the interactions between the bacteria in the human gut and the host by use of genome-scale metabolic models (GEMs). Recently, GEMs have been employed to explore the interactions between predominant bacteria in the gut ecosystems. Additionally, these models enabled analysis of the contribution of each species to the overall metabolism of the microbiota through the integration of omics data. The outcome of these studies can be used for proposing optimal conditions for desired microbiome phenotypes. Here, we review the recent progress and challenges for elucidating the interactions between the human gut microbiota and host through metabolic modeling. We discuss how these models may provide scaffolds for analyzing high-throughput data, developing probiotics and prebiotics, evaluating the effects of probiotics and prebiotics and eventually designing clinical interventions. PMID- 24795751 TI - Variation in genes involved in epigenetic processes offers insights into tropically adapted cattle diversity. AB - We evaluated the relevance of the BovineHD Illumina SNP chip with respect to genes involved in epigenetic processes. Genotypes for 729,068 SNP on two tropical cattle breeds of Australia were used: Brahman (n = 2112) and Tropical Composite (n = 2550). We used data mining approaches to compile a list of bovine protein coding genes involved in epigenetic processes. These genes represent 9 functional categories that contain between one (histone demethylases) and 99 (chromatin remodeling factors) genes. A total of 3091 SNP mapped to positions within 3000 bp of the 193 coding regions of those genes, including 113 SNP in transcribed regions, 2738 in intronic regions and 240 in up- or down-stream regions. For all these SNP categories, we observed differences in the allelic frequencies between Brahman and Tropical Composite cattle. These differences were larger than those observed for the entire set of 729,068 SNP (P = 1.79 x 10(-5)). A multidimensional scaling analysis using only the 113 SNP in transcribed regions allowed for the separation of the two populations and this separation was comparable to the one obtained with a random set of 113 SNP (Principal Component 1 r (2) > 0.84). To further characterize the differences between the breeds we defined a gene-differentiation metric based on the average genotypic frequencies of SNP connected to each gene and compared both cattle populations. The 10% most differentiated genes were distributed across 10 chromosomes, with significant (P < 0.05) enrichment on BTA 3 and 10. The 10% most conserved genes were located in 12 chromosomes. We conclude that there is variation between cattle populations in genes connected to epigenetic processes, and this variation can be used to differentiate cattle breeds. More research is needed to fully characterize the use of these SNP and its potential as means to further our understanding of biological variation and epigenetic processes. PMID- 24795752 TI - Association of CTRC and SPINK1 gene variants with recurrent hospitalizations for pancreatitis or acute abdominal pain in lipoprotein lipase deficiency. AB - BACKGROUND: There are important inter-individual variations in the incidence and severity of acute pancreatitis in patients with severe hypertriglyceridemia. Several genes involved in triglyceride-rich lipoprotein metabolism or serine proteases pathways are known to influence the risk of pancreatitis. AIM: To evaluate the association between genes regulating serine proteases, chymotrypsin C (CTRC) and serine peptidase inhibitor kazal type1 (SPINK1), and recurrence of hospitalizations for acute pancreatitis or severe abdominal pain in patients with Lipoprotein Lipase Deficiency (LPLD), a rare and extreme monogenic model of severe hypertriglyceridemia and pancreatitis. METHOD: The CTRC and SPINK1 genes promoter and coding regions sequencing has been performed in a sample of 38 LPLD adults (22 men and 16 women) and 100 controls (53 men and 47 women). Estimation of the association of CTRC and SPINK1 gene variants or combinations of variants with history of hospitalizations for pancreatitis or acute abdominal pain in LPLD was investigated using non-parametric analyses with correction for multiple testing and logistic regression models controlling for age, gender, family history, and life habits. RESULTS: Gene sequencing followed by genotype stratified analyses of the CTRC and SPINK1 genes in LPLD and controls revealed a positive association between recurrence of hospitalizations and the rs545634 (CTRC)-rs11319 (SPINK1) combination [OR = 41.4 (CI: 2.0-848.0); p = 0.016]. In all models, a positive family history of pancreatitis was a significant predictor of recurrent hospitalizations independently of the contribution of SPINK1 or CTRC (p < 0.001). CONCLUSION: These results suggest that a positive family history of pancreatitis and genetic markers in the serine protease pathways could be associated with a risk of recurrent hospitalization for acute pancreatitis in severe hypertriglyceridemia due to LPLD. PMID- 24795753 TI - Expression of microRNAs in bovine and human pre-implantation embryo culture media. AB - MicroRNAs (miRNA) are short non-coding RNAs which act to regulate expression of genes driving numerous cellular processes. These RNAs are secreted within exosomes from cells into the extracellular environment where they may act as signaling molecules. In addition, they are relatively stable and are specifically expressed in association to certain cancers making them strong candidates as biological markers. Moreover, miRNAs have been detected in body fluids including urine, milk, saliva, semen, and blood plasma. However, it is unknown whether they are secreted by embryonic cells into the culture media. Given that miRNAs are expressed throughout embryonic cellular divisions and embryonic genome activation, we hypothesized that they are secreted from the embryo into the extracellular environment and may play a role in the developmental competence of bovine embryos. To test this hypothesis, bovine embryos were cultured individually from day 5 to day 8 of development in an in vitro fertilization system and gene expression of 5 miRNAs was analyzed in both embryos and culture media. Differential miRNA gene expression was observed between embryos that developed to the blastocyst stage and those that failed to develop from the morula to blastocyst stage, deemed degenerate embryos. MiR-25, miR-302c, miR 196a2, and miR-181a expression was found to be higher in degenerate embryos compared to blastocyst embryos. Interestingly, these miRNAs were also found to be expressed in the culture media of both bovine and human pre-implantation embryos. Overall, our results show for the first time that miRNAs are secreted from pre implantation embryos into culture media and that miRNA expression may correlate with developmental competence of the embryo. Expression of miRNAs in in vitro culture media could allow for the development of biological markers for selection of better quality embryos and for subsequent successful pregnancy. PMID- 24795749 TI - Epigenetic control of mobile DNA as an interface between experience and genome change. AB - Mobile DNA in the genome is subject to RNA-targeted epigenetic control. This control regulates the activity of transposons, retrotransposons and genomic proviruses. Many different life history experiences alter the activities of mobile DNA and the expression of genetic loci regulated by nearby insertions. The same experiences induce alterations in epigenetic formatting and lead to trans generational modifications of genome expression and stability. These observations lead to the hypothesis that epigenetic formatting directed by non-coding RNA provides a molecular interface between life history events and genome alteration. PMID- 24795755 TI - Commentary on Shimoyama et al. (2012): three ontologies to define phenotype measurement data. PMID- 24795750 TI - Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. AB - The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5*FAD, and 3*Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression. PMID- 24795754 TI - Stress, genomic adaptation, and the evolutionary trade-off. AB - Cells are constantly exposed to various internal and external stresses. The importance of cellular stress and its implication to disease conditions have become popular research topics. Many ongoing investigations focus on the sources of stress, their specific molecular mechanisms and interactions, especially regarding their contributions to many common and complex diseases through defined molecular pathways. Numerous molecular mechanisms have been linked to endoplasmic reticulum stress along with many unexpected findings, drastically increasing the complexity of our molecular understanding and challenging how to apply individual mechanism-based knowledge in the clinic. A newly emergent genome theory searches for the synthesis of a general evolutionary mechanism that unifies different types of stress and functional relationships from a genome-defined system point of view. Herein, we discuss the evolutionary relationship between stress and somatic cell adaptation under physiological, pathological, and somatic cell survival conditions, the multiple meanings to achieve adaptation and its potential trade-off. In particular, we purposely defocus from specific stresses and mechanisms by redirecting attention toward studying underlying general mechanisms. PMID- 24795756 TI - Detection of large expansions in myotonic dystrophy type 1 using triplet primed PCR. AB - Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease caused by expansion of a CTG trinucleotide repeat in the DMPK gene. Methodology for genetic testing of DM1 is currently not optimal, in particular for the early onset patients in pediatric populations where large expanded (CTG)n alleles are usually common. Individuals who are homozygous for a normal allele and individuals who are heterozygous for one normal and one large expanded allele are indistinguishable by conventional PCR, as both generate a single product of the normal allele. Thus, reflex Southern blot has often been needed to distinguish these cases. With the aim to decrease the need for reflex Southern blot tests, a novel, single-tube CTG repeat primed PCR technology was designed to distinguish the true homozygous patients from the individuals whose large alleles are missed by conventional PCR. The method utilizes two gene-specific primers that flank the triplet repeat region and a third primer set complementary to the repeated region to detect the large alleles. Compared to traditional PCR, this novel Triplet repeat Primed PCR can detect the presence of large expanded alleles with demonstrating a ladder pattern. Using this single-step protocol, 45 specimens were tested. The alleles with sizes~i~85 repeats were determined by the gene specific primers. 13 abnormal alleles, which were missed by conventional PCR, were successfully detected by the Triplet-repeat Primed PCR. All the abnormal alleles were confirmed and measured by Southern Blot analysis. In summary, optimized Triplet-Primed PCR (TP-PCR) can accurately detect the presence of the large expanded alleles. With the ability to distinguish the true homozygous patients from the false negative homozygous individuals, the application of the optimized TP-PCR can significantly reduce the need of Southern Blot tests. PMID- 24795757 TI - miR-191: an emerging player in disease biology. AB - Specific microRNAs have emerged as key players in disease biology by playing crucial role in disease development and progression. This review draws attention to one such microRNA, miR-191 that has been recently reported to be abnormally expressed in several cancers (>20) and various other diseases like diabetes-type 2, Crohn' s, pulmonary hypertension, and Alzheimer' s. It regulates important cellular processes such as cell proliferation, differentiation, apoptosis, and migration by targeting important transcription factors, chromatin remodelers, and cell cycle associated genes. Several studies have demonstrated it to be an excellent biomarker for cancer diagnosis and prognosis leading to two patents already in its kitty. In this first review we summarize the current knowledge of the regulation, functions and targets of miR-191 and discuss its potential as a promising disease biomarker and therapeutic target. PMID- 24795758 TI - Prevalence of Dementia, Emotional State and Physical Performance among Older Adults in the Metropolitan Area of Guadalajara, Jalisco, Mexico. AB - Background. Dementia affects memory, thinking, language, judgment, and behavior. Depression, is common in older adults with dementia. The concomitance of dementia and depression increases disability with impaired activities of daily living (ADL), increasing the chances of institutionalization and mortality. Methods. Cross-sectional study of a population 60 years and older who live in the State of Jalisco, Mexico. A total of 1142 persons were assessed regarding their cognitive function, emotional state, and physical performance. Door-to-door interview technique was assigned in condition with multistage probability random sampling. Cognitive function, depression and functional disability were assessed by applying standardized Minimental State Examination (Folstein), Geriatric Depression Scale, and the Katz index, respectively. Diagnosis of dementia was performed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, the Fourth Edition. Data were analyzed using SPSS software. Results. Prevalence of demency was 9.5% (63.35% women, and 36.7% men). Demency was associated with being woman, being older than 70 years, low level of education, not having the economic benefit of retirement, being single or living without a partner, low level of education, suffering from depression and have functional disability in ADL. Conclusion. Dementia is more common in women and is related to depression and disability. PMID- 24795759 TI - The efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss for postmenopausal women with early breast cancer: a systematic review and meta-analysis. AB - Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL) in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329-21.959, P value = 0.018) and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249-7.143, P value = 0.0002). Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR's than patients with delayed ZOL. PMID- 24795760 TI - Beginning with Our Voices: How the Experiential Stories of First Nations Women Contribute to a National Research Project. AB - The purpose of this paper is to review how the experiential stories of First Nations women contribute to a national research project. The project focuses on how women's healing is impacted by their views about themselves as - and the stigma associated with being - a drug user, involved in crime and an Aboriginal woman. Our project began with three First Nations women on our research team documenting the role of stigma and self-identity in their personal healing journeys from problematically using drugs and being in conflict with the law. In this paper we discuss how key components of feminist research practices, Aboriginal methodology and community-based research helped us position the women's experiential stories in authoritative, recognized and celebrated ways in our study. We illustrate how the women's stories uniquely contributed to the creation of our interview questions and the research project in general. We also discuss how the women personally benefited from writing about and sharing their experiences. Key benefits include the women discovering the impact of the written word, promotion of their healing, personal recognition of their ability to offer hope to women in need, increased self-esteem, and increased appreciation of the importance of sharing their lived experiences with others. Our method of research differs from a conventional western scientific approach to understanding, and as such made important contributions to both the project itself and the women who shared their experiential stories. PMID- 24795761 TI - All the post-genomic world is a stage: the actors and narrators required for translating pharmacogenomics into public health. PMID- 24795762 TI - Pedometer accuracy in slow walking older adults. AB - The purpose of this study was to determine pedometer accuracy during slow overground walking in older adults (Mean age = 63.6 years). A total of 18 participants (6 males, 12 females) wore 5 different brands of pedometers over 3 pre-set cadences that elicited walking speeds between 0.3 and 0.9 m/s and one self-selected cadence over 80 meters of indoor track. Pedometer accuracy decreased with slower walking speeds with mean percent errors across all devices combined of 56%, 40%, 19% and 9% at cadences of 50, 66, and 80 steps/min, and self selected cadence, respectively. Percent error ranged from 45.3% for Omron HJ105 to 66.9% for Yamax Digiwalker 200. Due to the high level of error across the slowest cadences of all 5 devices, the use of pedometers to monitor step counts in healthy older adults with slower gait speeds is problematic. Further research is required to develop pedometer mechanisms that accurately measure steps at slower walking speeds. PMID- 24795764 TI - Medicinal plants in the prevention and treatment of chronic diseases 2013. PMID- 24795763 TI - Effects of chronic electroacupuncture on depression- and anxiety-like behaviors in rats with chronic neuropathic pain. AB - Growing evidence indicates that chronic neuropathic pain is frequently accompanied by an array of psychiatric diseases, such as depression and anxiety. Electroacupuncture (EA), as one therapy of traditional Chinese medicine, has displayed potent antidepressant-like effects in numerous clinical studies. The present study was designed to examine the possible effects of EA on the depressive and anxiety disorders induced by neuropathic pain. A classic rat model of neuropathic pain was produced by chronic constriction injury (CCI) of the sciatic nerve. EA was performed on acupoints "Bai-Hui" (GV20) and unilateral "Yang-Ling-Quan" (GB34). The antidepressive and anxiolytic effects of EA treatment were analyzed using the forced swimming test (FST) and the elevated plus maze (EPM) test, respectively. CCI resulted in remarkable depression- and anxiety-like behaviors, whereas the chronic EA treatment significantly improved the behavioral deficits of CCI rats. Moreover, the phosphorylation level of the NMDA receptor type 1 (NR1) subunit was decreased in the hippocampus of CCI rats. Intriguingly, continuous EA treatment effectively blocked this decrease in the levels of pNR1. These results suggested that EA has antidepressive and anxiolytic effects on rats with neuropathic pain and that this might be associated with restoring the phosphorylation of NR1 in the hippocampus. PMID- 24795765 TI - Administration Dependent Antioxidant Effect of Carica papaya Seeds Water Extract. AB - Carica papaya is widely used in folk medicine as herbal remedy to prevent, protect against, and cure several diseases. These curative properties are based on the presence in different parts of the plant of phytochemical nutrients with antioxidant effect. Seeds are the less exploited part; thus this study is aimed at assessing the antioxidant activities of the C. papaya seeds water extract against hydrogen peroxide (H2O2) oxidative stress in human skin Detroit 550 fibroblasts. C. papaya seeds water extract is not toxic and acts as a potent free radical scavenger, providing protection to Detroit 550 fibroblasts that underwent H2O2 oxidative stress. Data show that (i) the maximum protective effect is achieved by the simultaneous administration of the extract with 1 mM H2O2; (ii) the extract in presence of an oxidative stress does not increase catalase activity and prevents the release of cytochrome C and the inner mitochondrial transmembrane potential (Deltapsi m ) loss; (iii) the extract is more efficient than vitamin C to hamper the oxidative damage; (iv) the purified subfractions of the seeds water extract exert the same antioxidant effect of whole extract. In conclusion, C. papaya seeds water extract is potentially useful for protection against oxidative stress. PMID- 24795766 TI - Study on qi deficiency syndrome identification modes of coronary heart disease based on metabolomic biomarkers. AB - Coronary heart disease (CHD) is one of the most important types of heart disease because of its high incidence and mortality. With the era of systems biology bursting into reality, the analysis of the whole biological systems whether they are cells, tissues, organs, or the whole organisms has now become the norm of biological researches. Metabolomics is the branch of science concerned with the quantitative understandings of the metabolite complement of integrated living systems and their dynamic responses to the changes of both endogenous and exogenous factors. The aim of this study is to discuss the characteristics of plasma metabolites in CHD patients and CHD Qi deficiency syndrome patients and explore the composition and concentration changes of the plasma metabolomic biomarkers. The results show that 25 characteristic metabolites related to the CHD patients comparing with the healthy people, and 4 identifiable variables had significant differences between Qi deficiency and non-Qi deficiency patients. On the basis of identifying the different plasma endogenous metabolites between CHD patients and healthy people, we further prompted the metabolic rules, pathogenesis, and biological essence in Qi deficiency syndrome patients. PMID- 24795767 TI - The Alterations of IL-1Beta, IL-6, and TGF-Beta Levels in Hippocampal CA3 Region of Chronic Restraint Stress Rats after Electroacupuncture (EA) Pretreatment. AB - Immunological reactions induced by proinflammatory cytokines have been involved in the pathogenesis of depressive disorders. Recent studies showed that Electroacupuncture (EA) was able to reduce depressive symptoms; however, the underlying mechanism and its potential targets remain unknown. In the present study, we used a 21-day chronic restraint stress rats as a model to investigate how EA could alleviate depression. Open field test was carried out to evaluate the depressive symptoms at selected time points. At the end of study, immunohistochemistry (IHC) was performed to detect the expressions of IL-1beta, IL-6, and TGF-beta in hippocampal CA3 region. We found that chronic restraint stress significantly decreased behavioral activities, whereas EA stimulation at points Baihui (GV 20) and Yintang (GV 29) showed protective effect during the test period. In addition, the IL-1beta, IL-6, and TGF-beta increased in rats exposed to chronic restraint stress, while EA downregulated the levels of IL 1beta and IL-6. These findings implied that EA pretreatment could alleviate depression through modulating IL-1beta and IL-6 expression levels in hippocampal CA3 region. PMID- 24795768 TI - Hepatoprotective Effects of Silybum marianum (Silymarin) and Glycyrrhiza glabra (Glycyrrhizin) in Combination: A Possible Synergy. AB - Oxidative stress, lipid peroxidation, and transaminase reactions are some of the mechanisms that can lead to liver dysfunction. A time-dependent study was designed to evaluate the ability of silymarin (SLN) and glycyrrhizin (GLN) in different dosage regimens to lessen oxidative stress in the rats with hepatic injury caused by the hepatotoxin carbon tetrachloride. Wistar male albino rats (n = 60) were randomly assigned to six groups. Group A served as a positive control while groups B, C, D, E, and F received a dose of CCl4 (50% solution of CCl4 in liquid paraffin, 2 mL/kg, intraperitoneally) twice a week to induce hepatic injury. Additionally, the animals received SLN and GLN in different doses for a period of six weeks. CCl4 was found to induce hepatic injury by significantly increasing serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and thiobarbituric acid reactive substances while decreasing total protein and the activities of reduced glutathione, superoxide dismutase, and catalase. Treatment with various doses of SLN and GLN significantly reduced ALT, AST, ALP, and TBARS levels and increased GSH, SOD, and CAT levels. Our findings indicated that SLN and GLN have hepatoprotective effects against oxidative stress of the liver. PMID- 24795769 TI - Effects of Chaihu-Shugan-San and Shen-Ling-Bai-Zhu-San on p38 MAPK Pathway in Kupffer Cells of Nonalcoholic Steatohepatitis. AB - This study aimed to investigate the effects of Chaihu-Shugan-San (CSS), Shen-Ling Bai-Zhu-San (SLBZS), and integrated recipe of the above two recipes on inflammatory markers and proteins involved in p38 MAPK pathway in Kupffer cells of NASH rats induced by high fat diet (HFD). Rats were administered at low or high dose of CSS, SLBZS, and integrated recipe except normal group and model group for 16 weeks. The levels of hepatic lipid, TNF- alpha , IL-1, and IL-6 in liver tissues were measured. Kupffer cells were isolated from livers to evaluate expressions of TLR4, p-p38 MAPK, and p38 MAPK by Western blotting. The results showed that the NASH model rats successfully reproduced typical pathogenetic and histopathological features. Levels of hepatic lipid and liver tissues inflammatory factors in high-dose SLBZS group and integrated recipe group were all lower than that of model group decreased observably. Expressions of TLR4, p p38 MAPK, and p38 MAPK in Kupffer cells were decreased in all treatment groups, but there was no significant difference between treatment groups. The high-dose SLBZS group had the lowest expression levels of TLR4, and the most visible downtrend in the expression levels of p-p38 MAPK and p38 MAPK was found in the high-dose integrated recipe group. The ratio of p-p38 MAPK to total p38 MAPK protein was obviously increased in all treatment groups. Therefore, our study showed that the activation of p38 MAPK pathway in Kupffer cells might be related to the release of inflammatory factors such as TNF- alpha , IL-1, and IL-6 in NASH rats. High dose of SLBZS and integrated recipe might work as a significant anti-inflammatory effect in Kupffer cells of NASH rats induced by HFD through suppression of p38 MAPK pathway. It indicated that p38 MAPK pathway may be the possible effective target for the recipes. PMID- 24795771 TI - Beneficial Effects of Fractions of Nardostachys jatamansi on Lipopolysaccharide Induced Inflammatory Response. AB - It has been previously shown that Nardostachys jatamansi (NJ) exhibits anti inflammatory properties against lipopolysaccharide (LPS) challenges. However, the potency of NJ constituents against LPS-induced inflammatory responses has not been examined. In this present study, we determined which NJ extract fractions exhibit inhibitory effects against LPS-induced inflammatory responses. Among the NJ fractions, NJ-1, NJ-3, NJ-4, and NJ-6 inhibited LPS-induced production of NO. The NJ-3, NJ-4, and NJ-6 fractions also inhibited the production of cytokines, such as IL-1 beta , IL-6, and TNF- alpha . However, NJ-1, NJ-3, NJ-4, and NJ-6 showed differential inhibitory mechanisms against LPS-induced inflammatory responses. NJ-1, NJ-3, and NJ-4 inhibited LPS-induced activation of c-jun NH2 terminal kinase (JNK) and p38 but did not affect activation of extracellular signal-regulated kinase (ERK) or NF- kappa B. On the other hand, NJ-6 inhibited activation of MAPKs and NF- kappa B. In addition, in vivo experiments revealed that administration of NJ-1, NJ-3, NJ-4, and NJ-6 reduced LPS-induced endotoxin shock, with NJ-6 especially showing a marked protective effect. Taken together, these results provide the evidence for the potential of selective NJ fractions against LPS-induced inflammation. Thus, it will be advantageous to further isolate and determine single effective compounds from these potent fractions. PMID- 24795772 TI - Effects of 6-Hydroxyflavone on Osteoblast Differentiation in MC3T3-E1 Cells. AB - Osteoblast differentiation plays an essential role in bone integrity. Isoflavones and some flavonoids are reported to have osteogenic activity and potentially possess the ability to treat osteoporosis. However, limited information concerning the osteogenic characteristics of hydroxyflavones is available. This study investigates the effects of various hydroxyflavones on osteoblast differentiation in MC3T3-E1 cells. The results showed that 6-hydroxyflavone (6-OH F) and 7-hydroxyflavone (7-OH-F) stimulated ALP activity. However, baicalein and luteolin inhibited ALP activity and flavone showed no effect. Up to 50 MU M of each compound was used for cytotoxic effects study; flavone, 6-OH-F, and 7-OH-F had no cytotoxicity on MC3T3-E1 cells. Moreover, 6-OH-F activated AKT and serine/threonine kinases (also known as protein kinase B or PKB), extracellular signal-regulated kinases (ERK 1/2), and the c-Jun N-terminal kinase (JNK) signaling pathways. On the other hand, 7-OH-F promoted osteoblast differentiation mainly by activating ERK 1/ 2 signaling pathways. Finally, after 5 weeks of 6-OH F induction, MC3T3-E1 cells showed a significant increase in the calcein staining intensity relative to merely visible mineralization observed in cells cultured in the osteogenic medium only. These results suggested that 6-OH-F could activate AKT, ERK 1/2, and JNK signaling pathways to effectively promote osteoblastic differentiation. PMID- 24795773 TI - A systematic review and meta-analysis of herbal medicine on chronic obstructive pulmonary diseases. AB - Herbal medicine (HM) as an adjunct therapy has been shown to be promising for the chronic obstructive pulmonary disease (COPD). However, the role of herbs in COPD remains largely unexplored. In this present study, we conducted the systematic review to evaluate the efficacy of herbs in COPD. 176 clinical studies with reporting pulmonary function were retrieved from English and Chinese database. Commonly used herbs for acute exacerbations stage (AECOPD) and stable COPD stage (SCOPD) were identified. A meta-analysis conducted from 15 high quality studies (18 publications) showed that HM as an adjunct therapy had no significant improvement in pulmonary function (FEV1, FEV%, FVC, and FEV1/FVC) compared to conventional medicine. The efficacy of the adjunct HM on improving the arterial blood gas (PaCO2 and PaO2) for AECOPD and SCOPD remains inconclusive due to the heterogeneity among the studies. However, HM as an adjunct therapy improved clinical symptoms and quality of life (total score, activity score, and impact score of St. George's Respiratory Questionnaire). Studies with large-scale and double-blind randomized controlled trials are required to confirm the role of the adjunct HM in the management of COPD. PMID- 24795774 TI - Logic regression for provider effects on kidney cancer treatment delivery. AB - In the delivery of medical and surgical care, often times complex interactions between patient, physician, and hospital factors influence practice patterns. This paper presents a novel application of logic regression in the context of kidney cancer treatment delivery. Using linked data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program and Medicare we identified patients diagnosed with kidney cancer from 1995 to 2005. The primary endpoints in the study were use of innovative treatment modalities, namely, partial nephrectomy and laparoscopy. Logic regression allowed us to uncover the interplay between patient, provider, and practice environment variables, which would not be possible using standard regression approaches. We found that surgeons who graduated in or prior to 1980 despite having some academic affiliation, low volume surgeons in a non-NCI hospital, or surgeons in rural environment were significantly less likely to use laparoscopy. Surgeons with major academic affiliation and practising in HMO, hospital, or medical school based setting were significantly more likely to use partial nephrectomy. Results from our study can show efforts towards dismantling the barriers to adoption of innovative treatment modalities, ultimately improving the quality of care provided to patients with kidney cancer. PMID- 24795775 TI - Modeling the impact of climate change on the dynamics of Rift Valley Fever. AB - A deterministic SEIR model of rift valley fever (RVF) with climate change parameters was considered to compute the basic reproduction number R 0 and investigate the impact of temperature and precipitation on R 0. To study the effect of model parameters to R 0, sensitivity and elasticity analysis of R 0 were performed. When temperature and precipitation effects are not considered, R 0 is more sensitive to the expected number of infected Aedes spp. due to one infected livestock and more elastic to the expected number of infected livestock due to one infected Aedes spp. When climatic data are used, R 0 is found to be more sensitive and elastic to the expected number of infected eggs laid by Aedes spp. via transovarial transmission, followed by the expected number of infected livestock due to one infected Aedes spp. and the expected number of infected Aedes spp. due to one infected livestock for both regions Arusha and Dodoma. These results call for attention to parameters regarding incubation period, the adequate contact rate of Aedes spp. and livestock, the infective periods of livestock and Aedes spp., and the vertical transmission in Aedes species. PMID- 24795776 TI - Weighted Lin-Wang tests for crossing hazards. AB - Lin and Wang have introduced a quadratic version of the logrank test, appropriate for situations in which the underlying survival distributions may cross. In this note, we generalize the Lin-Wang procedure to incorporate weights and investigate the performance of Lin and Wang's test and weighted versions in various scenarios. We find that weighting does increase statistical power in certain situations; however, none of the procedures was dominant under every scenario. PMID- 24795777 TI - Giant extra-hepatic thrombosed portal vein aneurysm: a case report and review of the literature. AB - BACKGROUND: Extrahepatic Portal vein aneurysm (EPVA) is a rare finding that may be associated with different complications, e.g. thrombosis, rupture, portal hypertension and compression of adjacent structures. It is being diagnosed more frequently with the advent of modern cross-sectional imaging. Our review of the English literature disclosed 13 cases of thrombosed EPVA. CASE PRESENTATION: A 50 years-old woman presented with acute abdominal pain but no other symptom. She had no relevant medical history. Palpation of the right upper quadrant showed tenderness. Laboratory tests were unremarkable. A computed tomography showed portal vein aneurysm measuring 88 * 65 mm with thrombosis extending to the superior mesenteric and splenic vein. The patient was treated conservatively with anticoagulation therapy. She was released after two weeks and followed on an outpatient basis. At two months, she reported decreased abdominal pain and her physical examination was normal. A computed tomography was performed showing a decreased thrombosis size and extent, measuring 80 * 55 mm. CONCLUSIONS: Although rare, surgeons should be made aware of this entity. Complications are various. Conservative therapy should be chosen in first intent in most cases. We reported the case of the second largest thrombosed extra-hepatic PVA described in the literature, treated by anticoagulation therapy with a good clinical and radiological response. PMID- 24795778 TI - Archaeometric classification of ancient human fossil bones, with particular attention to their carbonate content, using chemometrics, thermogravimetry and ICP emission. AB - BACKGROUND: The potential of coupling chemometric data processing techniques to thermal analysis for formulating an "archaeometric" classification of fossil bones was investigated. Moreover, the possibility of integrating the outcomes of this approach with the results of inductively coupled plasma (ICP) emission spectroscopy for an anthropological interpretation of the observed patterns was also examined. RESULTS: Several fossil bone samples coming from the necropolis of El Geili, in the middle Nile, an important archaeological site, were first of all subjected to thermogravimetric (TG) and derivative thermogravimetric (DTG) analysis and the main steps of the curves were analyzed. This allowed fossil bone samples to be differentiated, both by means of classical bidimensional and chemometric representations, namely Principal Component Analysis (PCA). In particular, two clusters were observed, attributable to samples of different antiquity. In addition, inductively coupled plasma (ICP) emission spectroscopy showed that the samples in the cluster corresponding to more recent burials are characterized by a higher Zn content, suggesting a more varied diet. CONCLUSIONS: The experimental data obtained using thermogravimetry (TG-DTG) allows us to differentiate all the fossil bone samples analyzed into two separate clusters and to interpret this differentiation in terms of the observed transitions. PMID- 24795779 TI - Diffusion tensor MRI as a biomarker in axonal and myelin damage. AB - Diffusion tensor imaging has been used extensively as a research tool to understand the structural changes associated with white matter pathology. Using water diffusion as the basis to construct anatomic details, diffusion tensor imaging offers the potential to identify structural and functional adaptations before gross anatomical changes, such as lesions and tumors, become apparent on conventional MRI. Over the past 10 years, further parameters, such as axial and radial diffusivity, have been developed to characterize white matter changes specific to axons and myelin. In this paper, the potential application and outstanding issues on the use of diffusion tensor imaging directional diffusivity as a biomarker in axonal and myelin damage in neurological disorders will be reviewed. PMID- 24795780 TI - A Stress Model for Couples Parenting Children With Autism Spectrum Disorders and the Introduction of a Mindfulness Intervention. AB - Parents of children with autism spectrum disorders (ASD) are at an increased risk for acute and chronic stress compared to parents of children with other developmental disabilities and parents of children without disabilities. It is plausible that the stressors of having a child with ASD affect the couple relationship; however, few researchers have focused on this dynamic within these families. In this article, we seek to develop a model for how stress operates in families with children with ASD. In developing this new stress model, we describe the characteristics of ASD, discuss stressors that are pronounced in families of children with ASD as supported by the literature, and highlight the limitations of Perry's (2004) model in application to this population. Our expanded stress model includes the addition of parenting couple resources and parenting couple outcomes. Finally, we demonstrate how to apply the model using a mindfulness intervention to promote positive outcomes and strengthen the couple relationship. PMID- 24795781 TI - Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity. AB - BACKGROUND: Antiprogestin compounds have been shown to be effective in blocking the growth of ovarian cancer cells of different genetic backgrounds. Herein we studied the anti-ovarian cancer effect of a series of antiprogestins sharing the chemical backbone of the most characterized antiprogestin, mifepristone, but with unique modifications in position C-17 of the steroid ring. We assessed the effect of mifepristone-like antiprogestins on the growth of ovarian cancer cells sensitive to the standard combination therapy cisplatin-paclitaxel or made double resistant upon six cycles of pulse-selection with the drugs used at clinically relevant concentrations and exposure times. METHODS: IGROV-1 and SKOV-3 cells were pulsed with 20 MUM cisplatin for 1 h followed by 100 nM paclitaxel for 3 h once a week for six weeks. The cells that did not die and repopulate the culture after the chemotherapies were termed Platinum-Taxane-EScape cells (PTES). Parental cells were compared against their PTES derivatives in their responses to further platinum-taxane treatments. Moreover, both ovarian cancer cells and their PTES siblings were exposed to escalating doses of the various antiprogestin derivatives. We assessed cell growth, viability and sub-G1 DNA content using microcapillary cytometry. Cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1) and cleavage of downstream caspase-3 substrate PARP were used to assess whether cell fate, as a consequence of treatment, was limited to cytostasis or progressed to lethality. RESULTS: Cells subjected to six pulse-selection cycles of cisplatin-paclitaxel gave rise to sibling derivatives that displayed ~2-7 fold reduction in their sensitivities to further chemotherapy. However, regardless of the sensitivity the cells developed to the combination cisplatin-paclitaxel, they displayed similar sensitivity to the antiprogestins, which blocked their growth in a dose-related manner, with lower concentrations causing cytostasis, and higher concentrations causing lethality. CONCLUSIONS: Antiprogestins carrying a backbone similar to mifepristone are cytotoxic to ovarian cancer cells in a manner that does not depend on the sensitivity the cells have to the standard ovarian cancer chemotherapeutics, cisplatin and paclitaxel. Thus, antiprogestin therapy could be used to treat ovarian cancer cells showing resistance to both platinum and taxanes. PMID- 24795783 TI - Optimal Decisions for Organ Exchanges in a Kidney Paired Donation Program. AB - The traditional concept of barter exchange in economics has been extended in the modern era to the area of living-donor kidney transplantation, where one incompatible donor-candidate pair is matched to another pair with a complementary incompatibility, such that the donor from one pair gives an organ to a compatible candidate in the other pair and vice versa. Kidney paired donation (KPD) programs provide a unique and important platform for living incompatible donor-candidate pairs to exchange organs in order to achieve mutual benefit. In this paper, we propose novel organ allocation strategies to arrange kidney exchanges under uncertainties with advantages, including (i) allowance for a general utility based evaluation of potential kidney transplants and an explicit consideration of stochastic features inherent in a KPD program; and (ii) exploitation of possible alternative exchanges when the originally planned allocation cannot be fully executed. This allocation strategy is implemented using an integer programming (IP) formulation, and its implication is assessed via a data-based simulation system by tracking an evolving KPD program over a series of match runs. Extensive simulation studies are provided to illustrate our proposed approach. PMID- 24795782 TI - Bridging neuroscience and clinical psychology: cognitive behavioral and psychophysiological models in the evaluation and treatment of Gilles de la Tourette syndrome. AB - Cognitive neuroscience and clinical psychology have long been considered to be separate disciplines. However, the phenomenon of brain plasticity in the context of a psychological intervention highlights the mechanisms of brain compensation and requires linking both clinical cognition and cognitive psychophysiology. A quantifiable normalization of brain activity seems to be correlated with an improvement of the tic symptoms after cognitive behavioral therapy in patients with Gilles de la Tourette syndrome (GTS). This article presents broad outlines of the state of the current literature in the field of GTS. We present our clinical research model and methodology for the integration of cognitive neuroscience in the psychological evaluation and treatment of GTS to manage chronic tic symptoms. PMID- 24795784 TI - Quantification of Arterial Wall Inhomogeneity Size, Distribution, and Modulus Contrast Using FSI Numerical Pulse Wave Propagation. AB - Changes in aortic wall material properties, such as stiffness, have been shown to accompany onset and progression of various cardiovascular pathologies. Pulse Wave velocity (PWV) and propagation along the aortic wall have been shown to depend on the wall stiffness (i.e. stiffer the wall, higher the PWV), and can potentially enhance the noninvasive diagnostic techniques. Conventional clinical methods involve a global examination of the pulse traveling between femoral and carotid arteries, to provide an average PWV estimate. Such methods may not prove effective in detecting wall focal changes as entailed by a range of cardiovascular diseases. A two-way-coupled fluid-structure interaction (FSI) simulation study of pulse wave propagation along inhomogeneous aortas with focal stiffening and softening has previously proved the model reliable. In this study, simulations are performed on inhomogeneous aortic walls with hard inclusions of different numbers, size and modulus in order to further characterize the effects of focal hardening on pulse wave propagation. Spatio-temporal maps of the wall displacement were used to analyze the regional pulse wave propagations and velocities. The findings showed that the quantitative markers -such as PWVs and r2 s on the pre-inclusion forward, reflected and post-inclusion waves, and the width of the standing wave- as well as qualitative markers -such as diffracted reflection zone versus single reflection wave- allow the successful and reliable distinction between the changes in inclusion numbers, size and modulus. Future studies are needed to incorporate the wall softening and physiologically-relevant wall inhomogeneities such as those seen in calcifications or aneurysms. PMID- 24795785 TI - Taking the Kidney Personally: The Quest for Novel Antigens of Idiopathic Membranous Nephropathy through Proteomic Approaches - Per Ardua Ad Astra? PMID- 24795786 TI - Commensurate Priors for Incorporating Historical Information in Clinical Trials Using General and Generalized Linear Models. AB - Assessing between-study variability in the context of conventional random-effects meta-analysis is notoriously difficult when incorporating data from only a small number of historical studies. In order to borrow strength, historical and current data are often assumed to be fully homogeneous, but this can have drastic consequences for power and Type I error if the historical information is biased. In this paper, we propose empirical and fully Bayesian modifications of the commensurate prior model (Hobbs et al., 2011) extending Pocock (1976), and evaluate their frequentist and Bayesian properties for incorporating patient level historical data using general and generalized linear mixed regression models. Our proposed commensurate prior models lead to preposterior admissible estimators that facilitate alternative bias-variance trade-offs than those offered by pre-existing methodologies for incorporating historical data from a small number of historical studies. We also provide a sample analysis of a colon cancer trial comparing time-to-disease progression using a Weibull regression model. PMID- 24795787 TI - QUANTIFYING ALTERNATIVE SPLICING FROM PAIRED-END RNA-SEQUENCING DATA. AB - RNA-sequencing has revolutionized biomedical research and, in particular, our ability to study gene alternative splicing. The problem has important implications for human health, as alternative splicing may be involved in malfunctions at the cellular level and multiple diseases. However, the high dimensional nature of the data and the existence of experimental biases pose serious data analysis challenges. We find that the standard data summaries used to study alternative splicing are severely limited, as they ignore a substantial amount of valuable information. Current data analysis methods are based on such summaries and are hence sub-optimal. Further, they have limited flexibility in accounting for technical biases. We propose novel data summaries and a Bayesian modeling framework that overcome these limitations and determine biases in a non parametric, highly flexible manner. These summaries adapt naturally to the rapid improvements in sequencing technology. We provide efficient point estimates and uncertainty assessments. The approach allows to study alternative splicing patterns for individual samples and can also be the basis for downstream analyses. We found a several fold improvement in estimation mean square error compared popular approaches in simulations, and substantially higher consistency between replicates in experimental data. Our findings indicate the need for adjusting the routine summarization and analysis of alternative splicing RNA-seq studies. We provide a software implementation in the R package casper. PMID- 24795788 TI - ESTIMATION METHOD OF THE HOMODYNED K-DISTRIBUTION BASED ON THE MEAN INTENSITY AND TWO LOG-MOMENTS. AB - The homodyned K-distribution appears naturally in the context of random walks and provides a useful model for the distribution of the received intensity in a wide range of non-Gaussian scattering configurations, including medical ultrasonics. An estimation method for the homodyned K-distribution based on the first moment of the intensity and two log-moments (XU method), namely the X and U-statistics previously studied in the special case of the K-distribution, is proposed as an alternative to a method based on the first three moments of the intensity (MI method) or the amplitude (MA method), and a method based on the signal-to-noise ratio (SNR), the skewness and the kurtosis of two fractional orders of the amplitude (labeled RSK method). Properties of the X and U statistics for the homodyned K-distribution are proved, except for one conjecture. Using those properties, an algorithm based on the bisection method for monotonous functions was developed. The algorithm has a geometric rate of convergence. Various tests were performed to study the behavior of the estimators. It was shown with simulated data samples that the estimations of the parameters 1/alpha and 1/(kappa + 1) of the homodyned K-distribution are preferable to the direct estimations of the clustering parameter alpha and the structure parameter kappa (with respective relative root mean squared errors (RMSEs) of 0.63 and 0.13 as opposed to 1.04 and 4.37, when N = 1000). Tests on simulated ultrasound images with only diffuse scatterers (up to 10 per resolution cell) indicated that the XU estimator is overall more reliable than the other three estimators for the estimation of 1/alpha, with relative RMSEs of 0.79 (MI), 0.61 (MA), 0.53 (XU) and 0.67 (RSK). For the parameter 1/(kappa + 1), the relative RMSEs were equal to 0.074 (MI), 0.075 (MA), 0.069 (XU) and 0.100 (RSK). In the case of a large number of scatterers (11 to 20 per resolution cell), the relative RMSEs of 1/alpha were equal to 1.43 (MI), 1.27 (MA), 1.25 (XU) and 1.33 (RSK), and the relative RMSEs of 1/(kappa + 1) were equal to 0.14 (MI), 0.16 (MA), 0.17 (XU) and 0.20 (RSK). The four methods were also tested on simulated ultrasound images with a variable density of periodic scatterers to test images with a coherent component. The addition of noise on ultrasound images was also studied. Results showed that the XU estimator was overall better than the three other ones. Finally, on the simulated ultrasound images, the average computation times per image were equal to 6.0 ms (MI), 8.0 ms (MA), 6.8 ms (XU) and 500 ms (RSK). Thus, a fast, reliable, and novel algorithm for the estimation of the homodyned K-distribution was proposed. PMID- 24795789 TI - The available SRL3 deletion strain of Saccharomyces cerevisiae contains a truncation of DNA damage tolerance protein Mms2: Implications for Srl3 and Mms2 functions. AB - A screen of the commercially available collection of haploid deletion mutants of Saccharomyces cerevisiae for spontaneous mutator mutants newly identified a deletion of SRL3. This gene had been previously isolated as a suppressor of lethality of checkpoint kinase deletions if overexpressed. We found DNA damage sensitivity and extended checkpoint arrests to be associated with this strain. However, when crossed to wild-type, a mutant gene conferring these phenotypes was found to segregate from the SRL3 deletion. The mutation was identified as a C terminal truncation of Mms2, an E2 ubiquitin conjugating enzyme involved in error free replicative bypass of lesions. This confirmed an earlier report that Mms2 may be required to restrain error-prone polymerase zeta activity and underscored that residues of the C-terminus are necessary for Mms2 function. Srl3, on the other hand, does not appear to influence DNA damage sensitivity or spontaneous mutability if deleted. However, the absence of these phenotypes does not contradict its likely role as a positive regulator of dNTP levels. PMID- 24795790 TI - Evaluation of the Dawson College Shooting Psychological Intervention: Moving Toward a Multimodal Extensive Plan. AB - In 2006, following the shooting at Dawson College, the authorities implemented an intervention plan. This provided an opportunity to analyze the responses to services offered, and afforded a learning opportunity, which led to the proposal of an extensive multimodal short- and long-term psychological plan for future needs. Both quantitative and qualitative data were gathered 18 months after the event, involving the participation of 948 students and staff. Mental health problems and the perception of services offered after the shooting were investigated, using standardized measures. Second, focus groups and individual interviews were conducted among a subgroup of participants (support team members; teachers and employees; students and parents) and permitted to gather data on services received and services required. Individual report of events, the extent of psychological impact and services offered and received were analyzed in terms of the following dimensions: intervention philosophy, training, ongoing offer of services and finally, detection and outreach. A significant incidence of disorders and a high rate of exacerbation of preexisting mental disorders were observed within the 18 months following the shooting. Postimmediate and short term intervention appeared adequate, but the long-term collective vision toward community support and availability of mental health services were lacking. Lessons learned from this evaluation and other school shootings suggest that preparedness and long-term community responses are often overlooked. A multimodal extensive plan is proposed based on a theoretical model from which interventions strategies could be drawn. PMID- 24795791 TI - Lactobacillus rhamnosus GG: An Updated Strategy to Use Microbial Products to Promote Health. AB - It is now widely appreciated that probiotics exert their beneficial effects through several mechanisms, including inhibitory effects on pathogens, maintenance of the balance of intestinal microbiota, and regulation of immune responses and intestinal epithelial homeostasis. A significant area of progress has come from observations that specific products derived from probiotics mediate their mechanism(s) of action. This review focuses on new insights into the well studied probiotic bacterium Lactobacillus rhamnosus GG (LGG). The biologic consequences of LGG-derived products enhance LGG adherence to intestinal epithelial cells and protect intestinal epithelial cells from injury through regulating several signaling pathways. Thus, LGG-derived products may provide novel approaches for health and disease prevention and treatment, especially for intestinal inflammatory disorders. However, compared to LGG functional proteins predicted by analysis of LGG genome sequences, the number of identified LGG derived products is limited. As more mechanistic evidence becomes available to characterize the relationship between probiotics and host cellular responses, the development of more therapeutics from naturally derived or modified probiotics may be part of our future. PMID- 24795792 TI - Human tumor xenograft models for preclinical assessment of anticancer drug development. AB - Xenograft models of human cancer play an important role in the screening and evaluation of candidates for new anticancer agents. The models, which are derived from human tumor cell lines and are classified according to the transplant site, such as ectopic xenograft and orthotopic xenograft, are still utilized to evaluate therapeutic efficacy and toxicity. The metastasis model is modified for the evaluation and prediction of cancer progression. Recently, animal models are made from patient-derived tumor tissue. The patient-derived tumor xenograft models with physiological characters similar to those of patients have been established for personalized medicine. In the discovery of anticancer drugs, standard animal models save time and money and provide evidence to support clinical trials. The current strategy for using xenograft models as an informative tool is introduced. PMID- 24795793 TI - A rapid method for estimating the levels of urinary thiobarbituric Acid reactive substances for environmental epidemiologic survey. AB - Malondialdehyde (MDA), used as an oxidative stress marker, is commonly assayed by measuring the thiobarbituric acid reactive substances (TBARS) using HPLC, as an indicator of the MDA concentration. Since the HPLC method, though highly specific, is time-consuming and expensive, usually it is not suitable for the rapid test in large-scale environmental epidemiologic surveys. The purpose of this study is to develop a simple and rapid method for estimating TBARS levels by using a multiple regression equation that includes TBARS levels measured with a microplate reader as an independent variable. Twelve hour urine samples were obtained from 715 subjects. The concentration of TBARS was measured at three different wavelengths (fluorescence: lambda-ex 530 nm and lambda-ex 550 nm; lambda-ex 515 nm and lambda-ex 553 nm; and absorbance: 532 nm) using microplate reader as well as HPLC. 500 samples were used to develop a regression equation, and the remaining 215 samples were used to evaluate the validity of the regression analysis. The induced multiple regression equation is as follows: TBARS level (MUM) = -0.282 + 1.830 * (TBARS level measured with a microplate reader at the fluorescence wavelengths lambda-ex 530 nm and lambda-em 550 nm, MUM) -0.685 * (TBARS level measured with a microplate reader at the fluorescence wavelengths lambda-ex 515 nm and lambda-em 553 nm, MUM) + 0.035 * (TBARS level measured with a microplate reader at the absorbance wavelength 532 nm, MUM). The estimated TBARS levels showed a better correlation with, and are closer to, the corresponding TBARS levels measured by HPLC compared to the values obtained by the microplate method. The TBARS estimation method reported here is simple and rapid, and that is generally in concordance with HPLC measurements. This method might be a useful tool for monitoring of urinary TBARS level in environmental epidemiologic surveys with large sample sizes. PMID- 24795794 TI - Inhallation of e-Cigarette Cartridge Solution Aggravates Allergen-induced Airway Inflammation and Hyper-responsiveness in Mice. AB - Electronic cigarettes (e-cigarettes) are becoming increasingly popular worldwide and their cellular effects warrant further evaluation. In this study, we investigated the effects of an e-cigarette cartridge solution on allergen related asthmatic airway inflammation (AI) and airway hyperresponsiveness (AHR), when it is delivered by intratracheal route in mice. Asthmatic AI and AHR were induced by systemic sensitization to ovalbumin (OVA) followed by intratracheal, intraperitoneal, and aerosol allergen challenges in BALB/c mice. The cartridge solution of e-cigarette (containing 16 mg/ml nicotine) was diluted 50 times and 100 MUl of the diluted solution was intratracheally instilled to OVA-sensitized (OVA-S) mice two times a week for 10 weeks. Long-term e-cigarette inhalation elicited no remarkable changes in the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase enzymes in serum, however, increased infiltration of inflammatory cells including eosinophils, into airways from blood, aggravated the asthmatic AI and AHR, and stimulated the production of cytokines such as interleukin (IL)-4, IL-5 and IL-13, and OVA specific IgE production. Our data suggest that the inhalation of e-cigarette solutions can function as an important factor to exacerbate the allergy-induced asthma symptoms. Further studies are needed to address the effects of e-cigarette solutions on human health. PMID- 24795795 TI - Licochalcone Suppresses LXRalpha-Induced Hepatic Lipogenic Gene Expression through AMPK/Sirt1 Pathway Activation. AB - Licochalcone (LC), a major phenolic retrochalcone from licorice, has anti inflammatory activity. This study investigated the effects of licochalcone A (LCA) and licochalcone E (LCE) on Liver X receptor-alpha (LXRalpha)-mediated lipogenic gene expression and the molecular mechanisms underlying those effects. LCA and LCE antagonized the ability of LXRalpha agonists (T0901317 or GW3965) to increase sterol regulatory element binding protein-1c (SREBP-1c) expression and thereby inhibited target gene expression (e.g., FAS and ACC) in HepG2 cells. Moreover, treatment with LCA and LCE impaired LXRalpha/RXRalpha-induced CYP7A1 LXRE-luciferase (CYP7A1) transactivation. The AMPK-Sirt1 signaling pathway is an important regulator of energy metabolism and, therefore, a potential therapeutic target for metabolic diseases, including hepatic steatosis. We found here that LCE increased AMPK phosphorylation and Sirt1 expression. We conclude that LC inhibits SREBP-1c-mediated hepatic lipogenesis via activation of the AMPK/Sirt1 signaling pathway. PMID- 24795796 TI - A Probiotic Preparation Duolac-Gold Ameliorates Dextran Sulphate Sodium-induced Mouse Colitis by Downregulating the Expression of IL-6. AB - Probiotics are live microorganisms that confer a health benefit on the host. Duolac-Gold is a mixture of six probiotic bacteria containing three species of Bifidobacteria, two species of Lactobacillus, and Streptococcus thermophilus [corrected]. The aim of this study was to assess the anti-inflammatory effects of Duolac-Gold in an inflammatory bowel disease (IBD) mouse model. IBD was induced by administering 1.5% dextran sulfate sodium (DSS) for 10 days. After induction of DSS-induced colitis, Duolac-Gold was orally administered at three different concentrations. Interestingly, Duolac-Gold treatment accelerated IBD healing, and anti-inflammatory activity was assessed by weight loss, length of the colon, and a microscopic damage score by histology. The expression of inflammatory related cytokines was measured in colon tissues and serum. Of these cytokines, the expression of interleukin-6 decreased remarkably after Duolac-Gold treatment. Taken together, these results suggest that Duolac-Gold treatment is effective in IBD healing by regulating IL-6. PMID- 24795797 TI - Expression and Characterization of Truncated Recombinant Human Cytochrome P450 2J2. AB - The human cytochrome P450 2J2 catalyzes an epoxygenase reaction to oxidize various fatty acids including arachidonic acid. In this study, three recombinant enzyme constructs of P450 2J2 were heterologously expressed in Escherichia coli and their P450 proteins were successfully purified using a Ni(2+)-NTA affinity column. Deletion of 34 amino acid residues in N-terminus of P450 2J2 enzyme (2J2 D) produced the soluble enzyme located in the cytosolic fraction. The enzymatic analysis of this truncated protein indicated the typical spectral characteristics and functional properties of P450 2J2 enzyme. P450 2J2-D enzymes from soluble fraction catalyzed the oxidation reaction of terfenadine to the hydroxylated product. However, P450 2J2-D enzymes from membrane fraction did not support the P450 oxidation reaction although it displayed the characteristic CO-binding spectrum of P450. Our finding of these features in the N-terminal modified P450 2J2 enzyme could help understand the biological functions and the metabolic roles of P450 2J2 enzyme and make the crystallographic analysis of the P450 2J2 structure feasible for future studies. PMID- 24795798 TI - Association between Urinary Bisphenol A and Waist Circumference in Korean Adults. AB - Bisphenol A (BPA) is widely used in the production of polycarbonate plastics, epoxy resins, and food and beverage containers. In the present study, we aimed to investigate the relationship between urinary concentrations of BPA and waist circumference in Korean adults. A total of 1,030 Korean adults (mean age, 44.3 +/ 14.6 years) were enrolled in the study on the integrated exposure to hazardous materials for safety control, conducted by the Ministry of Food and Drug Safety from 2010 to 2012. Abdominal obesity was defined as having a waist circumference of at least 90 cm and 85 cm for men and women, respectively. The participants were divided into 4 groups according to the urinary BPA concentration quartile. Waist circumference was significantly higher among subjects with a urinary BPA concentration in the highest quartile relative to those in the lowest quartile (p = 0.0071). Linear regression analysis revealed a significant positive association between urinary BPA concentrations and body mass index, body fat, after adjusting for potential confounders. Moreover, subjects with urinary BPA concentrations in the fourth quartile were more likely to be obese compared to those with urinary BPA concentrations in the first quartile (odds ratio, 1.938; 95% CI: 1.314~2.857; p for trend = 0.0106). These findings provide evidence for a positive association between urinary BPA concentration and waist circumference in Korean adults. PMID- 24795799 TI - Inhibitory Activities of Palmatine from Coptis chinensis Against Helicobactor pylori and Gastric Damage. AB - Helicobacter pylori (H. pylori) is the most important factor of gastric disease in clinical practice. Moreover, smoking, stress and a poor diet may be additive factors for gastric damage. With these factors, increasing infection of H. pylori triggers gastritis, gastric ulcers and gastric cancer. To develop a new protective agent, we are concerned with plant-derived extract. The extract of Coptis chinensis (C. chinensis) and its constituents were investigated to assess their protective activities against gastric damage. The C. chinensis extract showed a scavenging effect against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals, inhibition of H. pylori colonization and antiulcerogenic activities in rat. In particular, palmatine derived from C. chinensis was found to be the novel protective agent. It is better than the C. chinensis extract, berberine, a well-known constituent of C. chinensis. We suggest that palmatine from the root cortex of C. chinensis may be a good candidate for the development of new pharmaceuticals to prevent gastric disease. PMID- 24795800 TI - Hepatoprotective effect of aged black garlic extract in rodents. AB - In this study, we investigated the hepatoprotective effects of aged black garlic (ABG) in rodent models of liver injury. ABG inhibited carbon tetrachloride induced elevation of aspartate transaminase (AST) and alanine transaminase (ALT), which are markers of hepatocellular damage, in SD rats. D-galactosamineinduced hepatocellular damage was also suppressed by ABG treatment. However, ABG does not affect the elevation of alkaline phosphatase (ALP), a marker of hepatobilliary damage, in rats treated with carbon tetrachloride or D-galactosamine. We also examined the effect of ABG on high-fat diet (HFD)-induced fatty liver and subsequent liver damage. ABG had no significant effect on body weight increase and plasma lipid profile in HFD-fed mice. However, HFD-induced increase in AST and ALT, but not ALP, was significantly suppressed by ABG treatment. These results demonstrate that ABG has hepatoprotective effects and suggest that ABG supplementation might be a good adjuvant therapy for the management of liver injury. PMID- 24795801 TI - Studies on the toxicity and distribution of indium compounds according to particle size in sprague-dawley rats. AB - OBJECTIVES: The use of indium compounds, especially those of small size, for the production of semiconductors, liquid-crystal panels, etc., has increased recently. However, the role of particle size or the chemical composition of indium compounds in their toxicity and distribution in the body has not been sufficiently investigated. Therefore, the aim of this study was to examine the effects of particle size and the chemical composition of indium compounds on their toxicity and distribution. METHODS: Male Sprague-Dawley rats were exposed to two different-sized indium oxides (average particle sizes under 4,000 nm [IO_4000] and 100 nm [IO_100]) and one nano-sized indium-tin oxide (ITO; average particle size less than 50 nm) by inhalation for 6 hr daily, 5 days per week, for 4 weeks at approximately 1 mg/m(3) of indium by mass concentration. RESULTS: We observed differences in lung weights and histopathological findings, differential cell counts, and cell damage indicators in the bronchoalveolar lavage fluid between the normal control group and IO- or ITO-exposed groups. However, only ITO affected respiratory functions in exposed rats. Overall, the toxicity of ITO was much higher than that of IOs; the toxicity of IO_4000 was higher than that of IO_100. A 4-week recovery period was not sufficient to alleviate the toxic effects of IO and ITO exposure. Inhaled indium was mainly deposited in the lungs. ITO in the lungs was removed more slowly than IOs; IO_4000 was removed faster than IO_100. IOs were not distributed to other organs (i.e., the brain, liver, and spleen), whereas ITO was. Concentrations of indium in the blood and organ tissues were higher at 4 weeks after exposure. CONCLUSIONS: The effect of particle size on the toxicity of indium compounds was not clear, whereas chemical composition clearly affected toxicity; ITO showed much higher toxicity than that of IO. PMID- 24795802 TI - Early-life estrogens and prostate cancer in an animal model. AB - While early-life estrogens are thought to play a physiologic role in prostate gland development, inappropriate estrogenic exposures either in dose, type or temporally can reprogram the prostate gland and increase susceptibility to abnormal prostate growth with aging including carcinogenesis. This review discusses the evidence for developmental estrogenic reprogramming that leads to adult prostate disease in a rat model. We propose that estrogen imprinting of the prostate is mediated through both structural reorganization of the gland early in life and epigenomic reprogramming that permits life-long memory of the inappropriate developmental exposures including heightened sensitivity to rising estradiol levels with aging. Complex interactions between early epigenetic programming and later-life experiences results in an emergence of multiple epigenomic outcomes, with some contributing to carcinogenesis with aging. PMID- 24795803 TI - Relative impact of 3- and 5-hydroxyl groups of cytosporone B on cancer cell viability. AB - A novel and the shortest route, thus far, for preparing cytosporone B (Csn-B) is reported. Csn-B and two analogs were used to probe the importance of hydroxyl groups at the 3- and 5-positions of the Csn-B benzene ring in inhibiting the viability of human H460 lung cancer and LNCaP prostate cancer cells, inducing H460 cell apoptosis, and interacting with the NR4A1 (TR3) ligand-binding domain (LBD). These studies indicate that Csn-B and 5-Me-Csn-B, having a phenolic hydroxyl at the 3-position of their aromatic rings, had similar activities in inhibiting cancer cell viability and in inducing apoptosis, whereas 3,5-(Me)2-Csn B was unable to do so. These results are in agreement with ligand-binding experiments showing that the interaction with the NR4A1 LBD required the presence of the 3-hydroxyl group. PMID- 24795804 TI - FP Tethering: a screening technique to rapidly identify compounds that disrupt protein-protein interactions. AB - Tethering is a screening technique for discovering small-molecule fragments that bind to pre-determined sites via formation of a disulphide bond. Tethering screens traditionally rely upon mass spectrometry to detect disulphide bind formation, which requires a time-consuming liquid chromatography step. Here we show that Tethering can be performed rapidly and inexpensively using a homogenous fluorescence polarization (FP) assay that detects displacement of a peptide ligand from the protein target as an indirect readout of disulphide formation. We apply this method, termed FP Tethering, to identify fragments that disrupt the protein-protein interaction between the KIX domain of the transcriptional coactivator CBP and the transcriptional activator peptide pKID. PMID- 24795805 TI - Antimicrobial resistant bacteria in wild mammals and birds: a coincidence or cause for concern? AB - BACKGROUND: The emergence and dissemination of antimicrobial resistance (AMR) is a growing concern to public and animal health. The contribution attributable to wildlife remains unclear. In this study two unrelated wildlife species herring gulls (Larus argentatus) and a hybrid deer (Cervus elaphus x Cervus nippon) were investigated for the presence of Escherichia coli expressing an AMR phenotype. FINDINGS: Bacterial isolates resistant to beta-lactam compounds were identified in both animal species and the production of functional beta-lactamase was confirmed using nitrocefin. The prevalence of resistant isolates was higher in herring gulls (87%) compared to deer (31%). Resistance to this class of antibiotic was found only in non-pathogenic E. coli in herring gulls and in both pathogenic and non-pathogenic E. coli strains in deer. CONCLUSIONS: The presence of AMR in wildlife has implications for public health, food safety and potable water source protection among others. PMID- 24795806 TI - Epidermal growth factor receptor inhibitor therapy for recurrent respiratory papillomatosis. AB - The epidermal growth factor pathway has been implicated in various tumors, including human papillomavirus (HPV) lesions such as recurrent respiratory papillomatosis (RRP). Due to the presence of epidermal growth factor receptors in RRP, epidermal growth factor receptor (EGFR) inhibitors have been utilized as adjuvant therapy. This case series examines the response to EGFR inhibitors in RRP. Four patients with life-threatening RRP were treated with EGFR inhibitors. Operative frequency and anatomical Derkay scores were calculated prior to, and following EGFR inhibitor treatment via retrospective chart review. The anatomical Derkay score decreased for all four patients after initiation of EGFR inhibitor therapy. In one patient, the operative frequency increased after switching to an intravenous inhibitor after loss of control with an oral inhibitor. In the other patients there was a greater than 20% decrease in operative frequency in one and a more than doubling in the time between procedures in two. This study suggests that EGFR inhibitors are a potential adjuvant therapy in RRP and deserve further study in a larger number of patients. PMID- 24795807 TI - Policies to increase the social value of science and the scientist satisfaction. An exploratory survey among Harvard bioscientists. AB - Basic research in the biomedical field generates both knowledge that has a value per se regardless of its possible practical outcome and that has the potential to produce more practical benefits. Policies can increase the benefit potential to society of basic biomedical research by offering various kinds of incentives to basic researchers. In this paper we argue that soft incentives or "nudges" are particularly promising. However, to be well designed, these incentives must take into account the motivations, goals and views of the basic scientists. In the paper we present the results of an investigation that involved more than 300 scientists at Harvard Medical School and affiliated institutes. The study shows that basic researchers' support for soft incentives is such that the transformative value of fundamental investigations can be increased without affecting the spirit of the basic research and scientists' work satisfaction. After discussing the findings, we suggest a few examples of nudges and discuss one in more detail. PMID- 24795808 TI - Characterization of a SAM-dependent fluorinase from a latent biosynthetic pathway for fluoroacetate and 4-fluorothreonine formation in Nocardia brasiliensis. AB - Fluorination has been widely used in chemical synthesis, but is rare in nature. The only known biological fluorination scope is represented by the fl pathway from Streptomyces cattleya that produces fluoroacetate (FAc) and 4 fluorothreonine (4-FT). Here we report the identification of a novel pathway for FAc and 4-FT biosynthesis from the actinomycetoma-causing pathogen Nocardia brasiliensis ATCC 700358. The new pathway shares overall conservation with the fl pathway in S. cattleya. Biochemical characterization of the conserved domains revealed a novel fluorinase NobA that can biosynthesize 5'-fluoro-5' deoxyadenosine (5'-FDA) from inorganic fluoride and S-adenosyl-l-methionine (SAM). The NobA shows similar halide specificity and characteristics to the fluorination enzyme FlA of the fl pathway. Kinetic parameters for fluoride ( K m 4153 MUM, k cat 0.073 min (-1)) and SAM ( K m 416 MUM, k cat 0.139 min (-1)) have been determined, revealing that NobA is slightly (2.3 fold) slower than FlA. Upon sequence comparison, we finally identified a distinct loop region in the fluorinases that probably accounts for the disparity of fluorination activity. PMID- 24795809 TI - Case report: retained gutta-percha as a cause for persistent maxillary sinusitis and pain. AB - Dental sources of infection can produce acute and chronic maxillary sinusitis. In some cases, the source of the infection may be related to the presence of endodontic materials in the oral cavity. In this article, we report a case of retained gutta-percha in the maxillary sinus resulting in chronic sinusitis. PMID- 24795810 TI - The putative mechanisms underlying testosterone and cardiovascular risk. AB - The use of testosterone supplementation therapy (TST) is increasing primarily in men with symptomatic hypogonadism. While TST has been shown to have numerous benefits, as its use increases, the role on cardiovascular health must be explored. Previous evidence showed no adverse cardiovascular risks associated with TST use; however, more recent studies suggest that there may be an associated risk. The exact mechanism by which TST may contribute to cardiovascular risk has not been elucidated. Numerous mechanisms have been proposed which include testosterone's effect on thromboxane A2 receptors, vascular adhesion molecule 1 receptors, erythropoiesis, and obstructive sleep apnea, all of which can ultimately lead to atherogenesis and increased cardiovascular risk. PMID- 24795811 TI - Fracture healing and lipid mediators. AB - Lipid mediators regulate bone regeneration during fracture healing. Prostaglandins and leukotrienes are well-known lipid mediators that regulate inflammation and are synthesized from the Omega-6 fatty acid, arachidonic acid. Cyclooxygenase (COX-1 or COX-2) and 5-lipoxygenase (5-LO) catalyze the initial enzymatic steps in the synthesis of prostaglandins and leukotrienes, respectively. Inhibition or genetic ablation of COX-2 activity impairs fracture healing in animal models. Genetic ablation of COX-1 does not affect the fracture callus strength in mice, suggesting that COX-2 activity is primarily responsible for regulating fracture healing. Inhibition of cyclooxygenase activity with nonsteroidal anti-inflammatory drugs (NSAIDs) is performed clinically to reduce heterotopic ossification, although clinical evidence that NSAID treatment impairs fracture healing remains controversial. In contrast, inhibition or genetic ablation of 5-LO activity accelerates fracture healing in animal models. Even though prostaglandins and leukotrienes regulate inflammation, loss of COX-2 or 5 LO activity appears to primarily affect chondrogenesis during fracture healing. Prostaglandin or prostaglandin analog treatment, prostaglandin-specific synthase inhibition and prostaglandin or leukotriene receptor antagonism also affect callus chondrogenesis. Unlike the Omega-6-derived lipid mediators, lipid mediators derived from Omega-3 fatty acids, such as resolvin E1 (RvE1), have anti inflammatory activity. In vivo, RvE1 can inhibit osteoclastogenesis and limit bone resorption. Although Omega-6 and Omega-3 lipid mediators have clear-cut effects on inflammation, the role of these lipid mediators in bone regeneration is more complex, with apparent effects on callus chondrogenesis and bone remodeling. PMID- 24795812 TI - Combination therapy for osteoporosis: a reappraisal. AB - Combinations of anabolic and antiresorptive agents have potential to improve bone density and bone strength more than either agent alone. A large number of relatively small clinical trials have been performed evaluating combinations of PTH1-34 or PTH1-84 with a variety of antiresorptives, including hormone/estrogen therapy, raloxifene, alendronate (Aln), risedronate, ibandronate, zoledronic acid and denosumab (Dmab). Most of the studies evaluate dual-X-ray densitometry outcomes, with a few trials reporting volumetric bone mineral density (BMD) by quantitative computed tomography followed by finite element modeling of bone strength. None of the studies has been powered to assess differences in fracture incidence between combination therapy and monotherapy. BMD outcomes vary depending on the timing of introduction of the anabolic agent (before, during or after antiresorptive treatment), as well as according to the specific anabolic and antiresorptive used. Furthermore, effects of combination therapies are site dependent. The most consistent effect of combining antiresorptive agents with parathyroid hormone (PTH) is a superior hip BMD outcome compared with PTH alone. This is most evident when PTH is combined with a bisphosphonate or Dmab. In contrast to findings in the hip, in the majority of studies there is no benefit to spine BMD with combination therapy when compared with monotherapy. The two exceptions to this are when PTH is combined with Dmab and when PTH is given as monotherapy first for 9 months followed by the addition of Aln and continuation of PTH as combination treatment. On the basis of what we now know, in patients on bisphosphonates who suffer hip fractures or who have very low hip BMD, strong consideration should be given to starting teriparatide and continuing a bisphosphonate (possibly switching to zoledronic acid or even Dmab) to maximize hip BMD and strength. Furthermore, in treatment-naive individuals with very severe osteoporosis, such as those with spine and hip fractures, combination therapy with PTH and Dmab or PTH followed by combination treatment with a potent bisphosphonate or Dmab should be considered to maximize early increases in BMD. PMID- 24795814 TI - Inhibition of sclerostin in the management of osteoporosis: results of a phase 2 clinical trial meet expectations. PMID- 24795813 TI - Targeting RANKL in metastasis. AB - Acting through its cognate receptor, receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival. Preclinical data have now firmly established that blockade of tumor induced osteoclastogenesis by RANKL inhibition will not only protect against bone destruction but will also inhibit the progression of established bone metastases and delay the formation of de novo bone metastases in cancer models. In patients with bone metastases, skeletal complications are driven by increased osteoclastic activity and may result in pathological fractures, spinal cord compression and the need for radiotherapy to the bone or orthopedic surgery (collectively known as skeletal-related events (SREs)). Denosumab, a fully human monoclonal antibody against RANKL, has been demonstrated to prevent or delay SREs in patients with solid tumors that have metastasized to bone. In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts. For example, RANKL also stimulates metastasis via activity on RANK expressing cancer cells, resulting in increased invasion and migration. Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells. This review describes these distinct but potentially overlapping mechanisms by which RANKL may promote metastases. PMID- 24795815 TI - Pulmonary function decline in firefighters and non-firefighters in South Korea. AB - OBJECTIVES: The purpose of this study was to evaluate and compare changes to pulmonary function among firefighters and non-firefighters who were exposed to harmful substances in their work environments. METHODS: Firefighters (n = 322) and non-firefighters (n = 107) in Daegu who received a pulmonary function test in 2008 and 2011 as well as a regular health examination were included. Repeated measures ANOVA was performed to evaluate the pulmonary function of the two groups over the three-year period. RESULTS: After adjusting for age, height, body mass index, duration of exposure, physical activity, and smoking, which were statistically different between the two groups and known risk factors of pulmonary function, the forced expiratory volume in one s FEV1, forced vital capacity FVC, and FEV1/FVC% over the 3 year period were significantly lower among firefighters compared with non-firefighters. CONCLUSIONS: Evaluating the working environment of firefighters is difficult; however, our study revealed that pulmonary function declined in firefighters. Thus, more effort should be made to prevent and manage respiratory diseases early by preforming strict and consistent pulmonary function tests in firefighters. PMID- 24795817 TI - Optimization of Conditions for In Vitro Culture of the Microphallid Digenean Gynaecotyla adunca. AB - In vitro cultivation of digeneans would aid the development of effective treatments and studies of the biology of the parasites. The goal of this study was to optimize culture conditions for the trematode, Gynaecotyla adunca. Metacercariae of the parasite from fiddler crabs, Uca pugnax, excysted in trypsin, were incubated overnight to permit fertilization, and were cultured in different conditions to find those that resulted in maximum worm longevity and egg production. When cultured in media lacking serum, worms lived longer in Hanks balanced salt solution and Dulbecco's Modified Eagle medium/F-12 (DME/F-12) than in RPMI-1640 but produced the most eggs in DME/F-12. Worm longevity and egg production increased when worms were grown in DME/F-12 supplemented with 20% chicken, horse, or newborn calf serum but the greatest number of eggs was deposited in cultures containing horse or chicken serum. Horse serum was chosen over chicken serum due to the formation of a precipitate in chicken serum. The optimal concentration of horse serum with respect to egg production ranged from 5 to 20%. Infectivity of eggs deposited by worms in culture was tested by feeding eggs to mud snails, Ilyanassa obsoleta. None of these snails produced G. adunca cercariae. PMID- 24795816 TI - Lesion of the Subfornical Organ attenuates Neuronal Activation of the Paraventricular Nucleus in response to Angiotensin II in normal rats. AB - INTRODUCTION/HYPOTHESIS: The subfornical organ, one of the central circumventricular organs, has been shown to mediate many of the effects of circulating angiotensin II (AngII). Where these signals are processed downstream is not fully understood. The SFO does indeed project to prominent cardiovascular regulatory centers such as the paraventricular nucleus (PVN), of whose neurons are activated by central AngII. We reasoned that AngII sensed at the SFO would cause neuronal activation at downstream hypothalamic areas such as the median preoptic nucleus and paraventricular nucleus, and as such would be diminished in animals with lesions of the SFO. MATERIALS AND METHODS: To test this hypothesis, groups of rats underwent either SFO lesion (SFOx) or sham operation. Five days later rats were instrumented with radiotelemetry transducers for monitoring of mean arterial pressure (MAP) and venous catheters for infusions. MAP and heart rate were measured continuously. After a 4 day control period, infusion of AngII (0.575 ug/kg/min) was begun for a period of 2 hours. Rats were then sacrificed and brains were processed for neuronal Fos expression. RESULTS: AngII produced Fos expression in the SFO, MnPO and PVN of sham rats. Fos expression was greatly attenuated in the PVN of SFOx rats. CONCLUSION: These results support our hypothesis, suggesting that AngII sensitive neurons of the SFO can mediate neuronal activation in the PVN. PMID- 24795818 TI - Costs and Quality of Life in Diabetic Macular Edema: Canadian Burden of Diabetic Macular Edema Observational Study (C-REALITY). AB - Purpose. To characterize the economic and quality of life burden of diabetic macular edema (DME) in Canadian patients. Patients and Methods. 145 patients with DME were followed for 6 months with monthly telephone interviews and medical chart reviews at months 0, 3, and 6. Visual acuity in the worst-seeing eye was assessed at months 0 and 6. DME-related healthcare costs were determined over 6 months, and vision-related (National Eye Institute Visual Functioning Questionnaire) and generic (EQ-5D) quality of life was assessed at months 0, 3, and 6. Results. Mean age of patients was 63.7 years: 52% were male and 72% had bilateral DME. At baseline, visual acuity was categorized as normal/mild loss for 63.4% of patients, moderate loss for 10.4%, and severe loss/nearly blind for 26.2%. Mean 6-month DME-related costs/patient were as follows: all patients (n = 135), $2,092; normal/mild loss (n = 88), $1,776; moderate loss (n = 13), $1,845; and severe loss/nearly blind (n = 34), $3,007. Composite scores for vision related quality of life declined with increasing visual acuity loss; generic quality of life scores were highest for moderate loss and lowest for severe loss/nearly blind. Conclusions. DME-related costs in the Canadian healthcare system are substantial. Costs increased and vision-related quality of life declined with increasing visual acuity severity. PMID- 24795820 TI - Nutrigenomics: definitions and advances of this new science. AB - The search for knowledge regarding healthy/adequate food has increased in the last decades among the world population, researchers, nutritionists, and health professionals. Since ancient times, humans have known that environment and food can interfere with an individual's health condition, and have used food and plants as medicines. With the advance of science, especially after the conclusion of the Human Genome Project (HGP), scientists started questioning if the interaction between genes and food bioactive compounds could positively or negatively influence an individual's health. In order to assess this interaction between genes and nutrients, the term "Nutrigenomics" was created. Hence, Nutrigenomics corresponds to the use of biochemistry, physiology, nutrition, genomics, proteomics, metabolomics, transcriptomics, and epigenomics to seek and explain the existing reciprocal interactions between genes and nutrients at a molecular level. The discovery of these interactions (gene-nutrient) will aid the prescription of customized diets according to each individual's genotype. Thus, it will be possible to mitigate the symptoms of existing diseases or to prevent future illnesses, especially in the area of Nontransmissible Chronic Diseases (NTCDs), which are currently considered an important world public health problem. PMID- 24795821 TI - Poor Reporting of Outcomes Beyond Accuracy in Point-of-Care Tests for Syphilis: A Call for a Framework. AB - Background. Point-of-care (POC) diagnostics for syphilis can contribute to epidemic control by offering a timely knowledge of serostatus. Although accuracy data on POC syphilis tests have been widely published, few studies have evaluated broader outcomes beyond accuracy that impact patients and health systems. We comprehensively reviewed evidence and reporting of these implementation research outcomes (IROs), and proposed a framework to improve their quality. Methods. Three reviewers systematically searched 6 electronic databases from 1980 to 2014 for syphilis POC studies reporting IROs. Data were abstracted and findings synthesised narratively. Results. Of 71 studies identified, 38 documented IROs. IROs were subclassified into preference (7), acceptability (15), feasibility (15), barriers and challenges (15), impact (13), and prevalence (23). Using our framework and definitions, a pattern of incomplete documentation, inconsistent definitions, and lack of clarity was identified across all IROs. Conclusion. Although POC screening tests for syphilis were generally favourably evaluated across a range of outcomes, the quality of evidence was compromised by inconsistent definitions, poor methodology, and documentation of outcomes. A framework for standardized reporting of outcomes beyond accuracy was proposed and considered a necessary first step towards an effective implementation of these metrics in POC diagnostics research. PMID- 24795822 TI - The Validity and Reliability of the Sinhala Translation of the Patient Health Questionnaire (PHQ-9) and PHQ-2 Screener. AB - The Patient Health Questionnaire (PHQ-9) was adapted and translated into Sinhala. Sample consisted of 75 participants diagnosed with MDD according to DSM-IV criteria and 75 gender matched controls. Concurrent validity was assessed by correlating total score of PHQ-9 with that of Centre for Epidemiological Studies Depression Scale (CESD). The Structured Clinical Interview for DSM-IV (SCID-II) conducted by a psychiatrist was the gold standard. Mean age of the sample was 33.0 years. There were 91 females (60.7%). There was significant difference in the mean PHQ-9 scores between cases (14.71) and controls (2.55) (P < 0.001). The specificity of the categorical algorithm was 0.97; the sensitivity was 0.58. Receiver operating characteristic (ROC) analysis found that cut-off score of >=10 had sensitivity of 0.75 and specificity of 0.97. The area under the curve (AOC) was 0.93. The sensitivity of the two-item screener (PHQ-2) was 0.80 and the specificity was 0.97. Cronbach's alpha was 0.90. The PHQ-9 is a valid and reliable instrument for diagnosing MDD in a non-Western population. The threshold algorithm is recommended for screening rather than the categorical algorithm. The PHQ-2 screener has good sensitivity and specificity and is recommended as a quick screening instrument. PMID- 24795823 TI - Avian influenza surveillance in the danube delta using sentinel geese and ducks. AB - Highly pathogenic avian influenza (HPAI) H5N1 virus incursions from migrating birds have occurred multiple times in Romania since 2005. Beginning in September 2008 through April 2013, seasonal sentinel surveillance for avian influenza A viruses (AIVs) using domestic geese (Anser cygnoides) and ducks (Anas platyrhynchos) in the Danube Delta was established by placing 15 geese and 5 ducks at seven sites. Tracheal and cloacal swabs, and sera collections (starting in 2009) were taken monthly. We studied a total of 580 domestic birds and collected 5,520 cloacal and tracheal swabs from each and 2,760 sera samples. All swabs were studied with real-time reverse transcription polymerase chain reaction (rRT-PCR) for evidence of AIV. Serological samples were studied with hemagglutination inhibition assays against avian H5, H7, and H9 influenza viruses. From 2009 to 2013, 47 swab specimens from Cot Candura, Enisala, and Saon screened positive for AIV; further subtyping demonstrated that 14 ducks and 20 geese had cloacal evidence of H5N3 carriage. Correspondingly, 4 to 12 weeks after these molecular detections, sentinel bird sera revealed elevated HI titers against H5 virus antigens. We posit that domestic bird surveillance is an effective method to conduct AIV surveillance among migrating birds in delta areas. PMID- 24795824 TI - Correlations between MRI and Information Processing Speed in MS: A Meta-Analysis. AB - Objectives. To examine relationships between conventional MRI measures and the paced auditory serial addition test (PASAT) and symbol digit modalities test (SDMT). Methods. A systematic literature review was conducted. Included studies had >=30 multiple sclerosis (MS) patients, administered the SDMT or PASAT, and measured T2LV or brain atrophy. Meta-analysis of MRI/information processing speed (IPS) correlations, analysis of MRI/IPS significance tests to account for reporting bias, and binomial testing to detect trends when comparing correlation strengths of SDMT versus PASAT and T2LV versus atrophy were conducted. Results. The 39 studies identified frequently reported only significant correlations, suggesting reporting bias. Direct meta-analysis was only feasible for correlations between SDMT and T2LV (r = -0.45, P < 0.001) and atrophy in patients with mixed-MS subtypes (r = -0.54, P < 0.001). Familywise Holm-Bonferroni testing found that selective reporting was not the source of at least half of significant results reported. Binomial tests (P = 0.006) favored SDMT over PASAT in strength of MRI correlations. Conclusions. A moderate-to-strong correlation exists between impaired IPS and MRI in mixed MS populations. Correlations with MRI were stronger for SDMT than for PASAT. Neither heterogeneity among populations nor reporting bias appeared to be responsible for these findings. PMID- 24795825 TI - Influence of second-trimester ultrasound markers for Down syndrome in pregnant women of advanced maternal age. AB - The objective of the present study was to evaluate the influence of second trimester ultrasound markers on the incidence of Down syndrome among pregnant women of advanced maternal age. This was a retrospective cohort study on 889 singleton pregnancies between the 14th and 30th weeks, with maternal age >= 35 years, which would undergo genetic amniocentesis. The second-trimester ultrasound assessed the following markers: increased nuchal fold thickness, cardiac hyperechogenic focus, mild ventriculomegaly, choroid plexus cysts, uni- or bilateral renal pyelectasis, intestinal hyperechogenicity, single umbilical artery, short femur and humerus length, hand/foot alterations, structural fetal malformation, and congenital heart disease. To investigate differences between the groups with and without markers, nonparametric tests consisting of the chi square test or Fisher's exact test were used. Moreover, odds ratios with their respective 95% confidence intervals were calculated. Out of the 889 pregnant women, 131 (17.3%) presented markers and 758 (82.7%) did not present markers on the second-trimester ultrasound. Increased nuchal fold (P < 0.001) and structural malformation (P < 0.001) were the markers most associated with Down syndrome. The presence of one marker increased the relative risk 10.5-fold, while the presence of two or more markers increased the risk 13.5-fold. The presence of markers on the second-trimester ultrasound, especially thickened nuchal fold and structural malformation, increased the risk of Down syndrome among pregnant women with advanced maternal age. PMID- 24795826 TI - A case of acute psychosis in an adolescent male. AB - Primary hyperparathyroidism (PHPT) is a disorder of calcium homeostasis. We report the case of a 17-year-old adolescent male, who presented with an acute psychosis coinciding with severe hypercalcemia and markedly elevated intact parathyroid hormone (iPTH) level and low vitamin D level. A Sestamibi scan showed a positive signal inferior to the left lobe of the thyroid gland. He had only a partial response to the initial medical and psychiatric management. The enlarged parathyroid gland was resected surgically and postoperatively serum calcium and iPTH levels normalized. The histopathology was compatible with a benign adenoma. Patient's acute psychotic symptoms resolved gradually after surgery; however he remained under psychiatric care for the behavioral issues for about 6 months after surgery. While psychosis is a rare clinical manifestation of hypercalcemia secondary to PHPT in pediatric population, it should be considered as a clinical clue in an otherwise asymptomatic pediatric patient. PMID- 24795827 TI - Spontaneous splenic rupture in melanoma. AB - Spontaneous rupture of spleen due to malignant melanoma is a rare situation, with only a few case reports in the literature. This study reports a previously healthy, 30-year-old man who came with chief complaint of acute abdominal pain to emergency room. On physical examination, abdominal tenderness and guarding were detected to be coincident with hypotension. Ultrasonography revealed mild splenomegaly with moderate free fluid in abdominopelvic cavity. Considering acute abdominal pain and hemodynamic instability, he underwent splenectomy with splenic rupture as the source of bleeding. Histologic examination showed diffuse infiltration by tumor. Immunohistochemical study (positive for S100, HMB45, and vimentin and negative for CK, CD10, CK20, CK7, CD30, LCA, EMA, and chromogranin) confirmed metastatic malignant melanoma. On further questioning, there was a past history of a nasal dark skin lesion which was removed two years ago with no pathologic examination. Spontaneous (nontraumatic) rupture of spleen is an uncommon situation and it happens very rarely due to neoplastic metastasis. Metastasis of malignant melanoma is one of the rare causes of the spontaneous rupture of spleen. PMID- 24795828 TI - Diffuse Hepatic and Spleen Uptake of Tc-99m MDP on Bone Scintigraphy Resembling Liver-Spleen Scintigraphy in a Patient of Plasma Cell Tumor. AB - The present case demonstrates a diffuse intense hepatic and, to a lesser degree, spleen, Tc-99m MDP uptake on a routine bone scintigraphy resembling liver-spleen imaging. A 49-year-old female with a history of anaplastic plasma cell tumor and suffering from bone pain was referred for bone scintigraphy to evaluate possible bone metastases. The bone scintigraphy showed diffuse hepatic and spleen uptake of Tc-99m MDP resembling liver-spleen imaging. Furthermore, bone uptake of Tc-99m MDP was significantly diminished and there were no abnormal foci throughout the skeleton. The bone scintigraphy of the present case of an anaplastic plasma cell tumor suggests the possible presence of amyloidosis. PMID- 24795829 TI - The inguinal herniation of the ovary in the newborn: ultrasound and color Doppler ultrasound findings. AB - Inguinal hernias in the newborn age group are seldom encountered. In the affected female patient, the ovaries, fallopian tubes, and the intestines may settle in the hernia sac. The early diagnosis of torsion in cases in which the ovary is herniated into the inguinal canal is of utmost importance in order to give surgery the chance of reduction and correction. In this paper, a case of an ovarian herniation into the inguinal canal without the presence of torsion is being presented, and the place of US and CDUS in the differential diagnosis of the situation is being discussed. PMID- 24795830 TI - Mesenteric lipoblastoma and cervical lipoblastomatosis: ultrasound, elastosonography, and computed tomography findings in two children. AB - Lipoblastomas are benign tumors of the embryonic lipoid cells mainly occurring in infancy and early childhood. They are clinicopathologically distinguished in two forms: the well-circumscribed and localized type and the diffuse, irregularly confined type with infiltrative growth pattern, also called lipoblastomatosis. We report two pediatric cases of a mesentery localized and cervical diffuse lipoblastomas investigated both with ultrasound and computed tomography examinations. PMID- 24795831 TI - A Novel Dual Force Sensing Instrument with Cooperative Robotic Assistant for Vitreoretinal Surgery. AB - Robotic assistants and smart surgical instruments have been developed to overcome many significant physiological limitations faced by vitreoretinal surgeons, one of which is lack of force perception below 7.5 mN. This paper reports the development of a new force sensor based on fiber Bragg grating (FBG) with the ability to sense forces at the tip of the surgical instrument located inside the eye and also provide information about instrument interaction with the sclera. The sclera section provides vital feedback for cooperative robot control to minimize potentially dangerous forces on the eye. Preliminary results with 2*2 degree-of-freedom (DOF) sensor and force scaling robot control demonstrate significant reduction of forces on the sclera. The design and analysis of the sensor is presented along with a simulated robot assisted retinal membrane peeling on a phantom with sclera constraints and audio feedback. PMID- 24795832 TI - Multi-Media Educational Tool Increases Knowledge of Clinical Trials in Uganda. AB - BACKGROUND: Informed consent is premised on the participants' understanding the scope of the research and the associated risks and benefits. The objective was to evaluate the improvement in knowledge in a population unfamiliar with clinical trial concepts about "what it means to be part of a clinical trial" using an innovative educational tool called the 'Speaking Book'. METHODS: This was a randomized controlled trial conducted at a research site in Uganda. 201 participants were randomized to: 1) clinical trials information session control arm, or 2) clinical trials information session followed by instruction in the use of the Speaking Book with a take-home copy (intervention arm). After the session, participants of both groups completed a 22-item multiple-choice test on the rights and responsibilities of participants. Participants returned after one week to complete the same test to assess knowledge retention. The mean pre- and post test score difference was assessed according to trial arm using an unpaired t test of proportions. RESULTS: Ninety-one (90%) participants completed both the initial and follow-up tests in the control arm and 100 (100%) in the intervention arm. The average age of participants was 38 years, 53% were female and 67% were employed; 20% had previously been invited to participate in a clinical trial; of these, 19% had participated. The mean difference in proportion of correct responses from test 1 to test 2 was 2.7% (95%CI 0.3%-5.0%) for the control arm and 11.6% (95%CI 9.3%-13.7%) for the intervention arm (t-score= -5.3, p value<0.0001). CONCLUSION: Participants who had instruction in the use of the Speaking Book had a larger increase in knowledge than those who had no access to this tool. To better engage patients unfamiliar with clinical trial concepts, innovative educational techniques can assist to increase knowledge to make an informed decision about participation in a clinical trial. PMID- 24795833 TI - Cloning, Expression and Purification of L. Donovani Specific Antigen for Serodiagnosis of Visceral Leishmaniasis. AB - BACKGROUND: Rapid diagnostic test using rk39 antigen is widely used for visceral leishmaniasis. However it detects anti-rk39 antibodies in 20-32% of endemic healthy individuals. In search for a better biomarker of infection, we identified a protein of molecular weight 70 kDa (BHUP1), specifically recognized by sera of visceral leishmaniasis (VL) patients. METHODS: The protein was cloned as His tagged fusion protein and purified. We evaluated the sensitivity and specificity of this protein in an enzyme linked immunosorbant assay (ELISA) format in comparison to the rk39 antigen using sera collected from various groups of individuals. RESULTS: The sensitivity of rBHUP1 was 96.5% compared to 98.8% with rk39. For healthy controls from non endemic and endemic regions, the specificity of rBHUP1 was 100% and 95.6% compared to 100% and 84.9% for rk39, respectively. For other infectious diseases such as malaria, tuberculosis, viral fever, etc., specificity of rBHUP1 was as low as 74.5% when compared to 94% of rk39. At six month and one year follow-up, 74% and 22.5% patients tested positive with rBHUP1, respectively, compared to 97% and 77.4% with rk39 antigen. CONCLUSION: Though the high sensitivity and specificity of rBHUP1 antigen for VL and healthy controls would have made it a good diagnostic biomarkers, however, its non-specific reaction with other infectious diseases limit its utility. PMID- 24795834 TI - How the Brain Process Stimulus-Response Conflict? New Insights from Lateralized Readiness Potentials Scalp Topography and Reaction Times. AB - Stimulus-Response Compatibility (SRC) refers to the fact that some tasks are performed easier and better than others because of the way stimuli and responses are paired with each other. To assess the brain responses to stimulus-response conflicts, we investigated the behavioral (accuracy and Reaction Times: RTs) as well as the physiological response (Lateralized Readiness Potentials: LRP) modulations in a positional blocked and a conditional mixed design in twelve university students. Results revealed that the performance was less accurate and the RTs, as well as the LRP onset, were delayed under the mixed conditional design. A greater compatibility effect was also noted on accuracy, RTs and LRP onset latency in the mixed design. Consistent with these findings, smaller peak activation at fronto-central areas suggests that more selective inhibition is needed in a mixed design context. Despite a smaller activation, the topographical distribution is similar in both designs. These results indicate that the translation time between stimulus- and response codes are greater under the mixed instruction, while the similar LRP topography suggests that common neural structures underlie LRPs in response to both type of designs. PMID- 24795835 TI - Quantitative (99m)Tc DTPA renal transplant scintigraphic parameters: assessment of interobserver agreement and correlation with graft pathologies. AB - Various (99m)Tc DTPA scintigraphic quantitative parameters for renal graft function assessment have been recommended, but none is universally accepted. In this study, 439 dynamic renal transplant scintigraphies (DRTS) were retrospectively analysed. In the first set of studies, four observers analysed the 47 random DRTS and interobserver agreement of eleven derived parameters was assessed. In the other set of studies, 181 instances of DRTS, performed on 127 recipients with renal biopsies within five days of each other were selected for correlation with pathology. Hilson's Perfusion index (HI), DeltaP, P:Pl, P:U & T10 were selected for this analysis. The pathologies were categorized into renal vascular compromise (RVC; n = 20), acute tubular necrosis (ATN; n = 40), vascular rejection (VR; n = 34), interstitial rejection (IR; n = 33), normal (NOR; n = 36) and unclassified pathologies (n = 18). A majority of the parameters showed good Intraclass correlation (ICC). HI differentiated well between grafts with RVC and the remainder of the study cohort, (p < 0.0001; AUC = 0.84); at a cut-off > 278, it had 84% sensitivity and 78% specificity (Likelihood ratio = 3.8). At < 278, it had 98% 'negative' predictive value for RVC. HI also showed reasonable association with VR (p = 0.02; AUC = 0.62) and IR (p = 0.009; AUC = 0.65). However, significant overlap of HI values between various subgroups was noted. Other parameters had good ICC but were not effective in differentiating graft pathologies. Of the measured parameters, only HI proved to be useful for the pathological assessment, particularly in the identification of vascular compromise. This parameter, however, has lower specificity in differentiating the other pathologies. PMID- 24795836 TI - PET/CT in the diagnosis of inflammatory bowel disease in pediatric patients: a review. AB - The literature on positron emission tomography and computed tomography using (18)fluoro-deoxyglusose (FDG-PET/CT) in the diagnosis of pediatric inflammatory bowel disease (IBD) is presented. Only five papers representing independent studies were identified and included in this review. Of these, two studies dealt with both stand-alone FDG-PET and FDG-PET/CT, while three were about stand-alone FDG-PET only. No studies could be found that focused on FDG-PET/CT only. The five studies comprised analysis of a total 181 pediatric patients (0-18 years of age). They unanimously indicated that FDG-PET/CT is a versatile method with a diagnostic high sensitivity ranging from 70% to 97%. In conclusion, the pediatric literature on FGD-PET/CT's role in the diagnosis of IBD is very limited. Prospective studies of well characterized populations are needed in order to validate this novel imaging modality in pediatric IBD. PMID- 24795837 TI - Relationship between pretreatment FDG-PET and diffusion-weighted MRI biomarkers in diffuse large B-cell lymphoma. AB - The purpose of this study was to determine the correlation between the (18)F fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm(2)) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson's correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL. PMID- 24795838 TI - Cognitive reserve and clinical expression of Alzheimer's disease: evidence and implications for brain PET imaging. AB - Cognitive reserve (CR) refers to the hypothesized capacity of an adult brain to cope with brain damage in order to minimize symptomatology. The present review is focused on the contribution of brain PET in the understanding of the influence of CR on the disassociation between cognition and degree of Alzheimer's disease (AD) pathology. Theories for the explanation CR-related mechanism as well as PET imaging evidence for the existence of CR are described. Moreover functional imaging studies investigating specific networks for CR both in healthy subjects and AD patients are discussed. Finally implications for amyloid PET imaging are presented. PMID- 24795839 TI - Automated synthesis and dosimetry of 6-deoxy-6-[(18)F]fluoro-D-fructose (6 [(18)F]FDF): a radiotracer for imaging of GLUT5 in breast cancer. AB - 6-Deoxy-6-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) is a promising PET radiotracer for imaging GLUT5 in breast cancer. The present work describes GMP synthesis of 6 [(18)F]FDF in an automated synthesis unit (ASU) and dosimetry calculations to determine radiation doses in humans. GMP synthesis and dosimetry calculations are important prerequisites for first-in-human clinical studies of 6-[(18)F]FDF. The radiochemical synthesis of 6-[(18)F]FDF was optimized and adapted to an automated synthesis process using a Tracerlab FXFN ASU (GE Healthcare). Starting from 30 GBq of cyclotron-produced n.c.a. [(18)F]fluoride, 2.9 +/- 0.1 GBq of 6-[(18)F]FDF could be prepared within 50 min including HPLC purification resulting in an overall decay-corrected radiochemical yield of 14 +/- 3% (n = 11). Radiochemical purity exceeded 95%, and the specific activity was greater than 5.1 GBq/MUmol. Sprague-Dawley rats were used for biodistribution experiments, and dynamic and static small animal PET experiments. Biodistribution studies served as basis for allometric extrapolation to the standard man anatomic model and normal organ absorbed dose calculations using OLINDA/EXM software. The calculated human effective dose for 6-[(18)F]FDF was 0.0089 mSv/MBq. Highest organ doses with a dose equivalent of 0.0315 mSv/MBq in a humans were found in bone. Injection of 370 MBq (10 mCi) of 6-[(18)F]FDF results in an effective whole body radiation dose of 3.3 mSv in humans, a value comparable to that of other (18)F-labeled PET radiopharmaceuticals. The optimized automated synthesis under GMP conditions, the good radiochemical yield and the favorable human radiation dosimetry estimates support application of 6-[(18)F]FDF in clinical trials for molecular imaging of GLUT5 in breast cancer patients. PMID- 24795840 TI - PET brain kinetics studies of (11)C-ITMM and (11)C-ITDM,radioprobes for metabotropic glutamate receptor type 1, in a nonhuman primate. AB - The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL?cm(-3) for (11)C-ITMM and 3.6 mL?cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future. PMID- 24795841 TI - Sexually immature male ERE-Luc reporter mice to assess low dose estrogen-like effects of CdCl2 versus dietary Cd. AB - CdCl2 salt is widely used in exposure oriented studies, while the biological exposure of Cadmium (Cd) occurs mostly through diet. Hence, we designed a in vivo imaging methodology with sexually immature male ERE-Luc reporter mice to test the estrogen-like (EL) effects of Cd as a natural component in wheat and flax bread based diets (containing 17.57 and 49.22 ug/kg Cd concentrations respectively) and CdCl2 per-oral dose of 1 ug/kg/bw/day. Total exposure of ingested and % bioaccumulation of Cd in selected organs were estimated as 547 ng (4.4%), 776 ng (0.3%) and 2131.8 ng (0.1%) corresponding to CdCl2, wheat and flax bread based diet treatments respectively. Cd from CdCl2 bioaccumulated more readily, despite the exposure of Cd is higher with bread based diets. Longitudinal in vivo imaging did not reveal significant changes in luciferase activity. White adipose tissue (WAT) and prostate were identified as novel target organs of Cd. Indeed, the rest of the observed EL effects, endogenous target gene expression and necropsy findings are not consistent to any particular organ or treatment. This implies that, the observed EL effects due to low doses of Cd (either from CdCl2 or dietary form) occur only as subtle changes at the molecular level, but inadequate to cause significant changes at the anatomo-pathological level during the 21 day exposure period. The study demonstrates the sensitivity of the methodology to assess EL effects of food embedded Cd and underlines the limitations of directly extrapolating the results of suspected chemicals in their pure form to dietary exposure scenarios. PMID- 24795842 TI - Positron emission tomography imaging for vascular inflammation evaluation in elderly subjects with different risk factors for cardiovascular diseases. AB - This study was aimed to investigate the usefulness of (18)F-FDG-PET to differentiate vascular inflammation and to determine the effect of rosuvastatin. Eight subjects were recruited and were divided according to their health status in three groups; 3 healthy subjects, 3 patients with hypercholesterolemia and 2 patients with stable angina pectoris. Hypercholesterolemic patients were submitted immediately after their recruitment to rosuvastatin treatment (20 mg/d). Two PET/CT measurements were made throughout the course of the study, one at baseline and the second 12 months later. Our results showed that the ratio of calcified arteries to total analyzed arteries segments were 23%, 36% and 44% for healthy, hypercholesterolemic and stable angina patients respectively. Healthy subjects present, at baseline, a high level of vascular inflammation as measured by (18)F-FDG uptake in both calcified and non-calcified segments of the arteries. This vascular inflammation increases as a function of the cardiovascular risk factors. After the 12-month follow-up period, non-calcified arteries showed a significant increase of (18)F-FDG uptake in both healthy, hypercholesterolemic and stable angina patients. However, the highest increase was noted for the healthy subjects; (50% increase, p<0.0001), while hypercholesterolemic patients under rosuvastatin showed only 25% increase of (18)F-FDG uptake (p<0.0001). This study confirms the usefulness of (18)F-FDG measurement to localize and quantify arterial inflammation in each artery segments and as a function of the CVD risk factors. Rosuvastatin may have a protective effect against arterial inflammation however; other studies with higher rosuvastatin doses (>20 mg/d) are needed to confirm this beneficial effect. PMID- 24795843 TI - The Influence of Disease Perceptions on the Participation of Melanoma Patients and their Partners in Skin Self-Examination Education. AB - By examining differences between patients who enroll or decline to enroll in a partner-based study, future research can benefit and adapt recruitment strategies to reduce sampling biases. This study examined differences between melanoma patients' who either declined or enrolled in an intervention aimed at increasing skin self-examination (SSE) with partner assistance. Specifically, differences were assessed for gender, age, perception of likelihood of getting another melanoma, benefits of early detection, and severity of the disease. Additionally, reasons for declining were examined. Among 368 melanoma patients interviewed during their appointment with the treating physician, 187 enrolled in the study and 181 declined to participate. No significant age or gender differences between enrolled and declined patients were observed. However, enrolled participants had significantly higher reports on the likelihood of getting another melanoma, severity of melanoma, and early detection as being beneficial (p<0.001). Among those declining to participate, males reported being "too busy and can't make follow-up appointments" whereas females reported their "partner won't assist". Results indicate perceptions of the benefits of early detection, the severity of melanoma, and patients' increased risk of developing a melanoma may have influenced patients' decision to participate. Future studies may benefit by highlighting these topics in order to motivate more patients to participant in partner studies. PMID- 24795845 TI - Invasion success of a scarab beetle within its native range: host range expansion versus host-shift. AB - Only recently has it been formally acknowledged that native species can occasionally reach the status of 'pest' or 'invasive species' within their own native range. The study of such species has potential to help unravel fundamental aspects of biological invasions. A good model for such a study is the New Zealand native scarab beetle, Costelytra zealandica (White), which even in the presence of its natural enemies has become invasive in exotic pastures throughout the country. Because C. zealandica still occurs widely within its native habitat, we hypothesised that this species has only undergone a host range expansion (ability to use equally both an ancestral and new host) onto exotic hosts rather than a host shift (loss of fitness on the ancestral host in comparison to the new host). Moreover, this host range expansion could be one of the main drivers of its invasion success. In this study, we investigated the fitness response of populations of C. zealandica from native and exotic flora, to several feeding treatments comprising its main exotic host plant as well as one of its ancestral hosts. Our results suggest that our initial hypothesis was incorrect and that C. zealandica populations occurring in exotic pastures have experienced a host-shift rather than simply a host-range expansion. This finding suggests that an exotic plant introduction can facilitate the evolution of a distinct native host-race, a phenomenon often used as evidence for speciation in phytophagous insects and which may have been instrumental to the invasion success of C. zealandica. PMID- 24795846 TI - Microbial metabolism: optimal control of uptake versus synthesis. AB - Microbes require several complex organic molecules for growth. A species may obtain a required factor by taking up molecules released by other species or by synthesizing the molecule. The patterns of uptake and synthesis set a flow of resources through the multiple species that create a microbial community. This article analyzes a simple mathematical model of the tradeoff between uptake and synthesis. Key factors include the influx rate from external sources relative to the outflux rate, the rate of internal decay within cells, and the cost of synthesis. Aspects of demography also matter, such as cellular birth and death rates, the expected time course of a local resource flow, and the associated lifespan of the local population. Spatial patterns of genetic variability and differentiation between populations may also strongly influence the evolution of metabolic regulatory controls of individual species and thus the structuring of microbial communities. The widespread use of optimality approaches in recent work on microbial metabolism has ignored demography and genetic structure. PMID- 24795844 TI - Microbial TLR Agonists and Humoral Immunopathogenesis in HIV Disease. AB - Although T cells are the primary and most-studied targets of the Human Immunodeficiency Virus (HIV), B cells, especially memory B lymphocytes, are also chronically depleted in the course of HIV disease. Although the lack of CD4+ T cell help may explain these deficiencies, intrinsic defects in B lymphocytes appear to contribute to B cell depletion and reduced antibody (Ab) production in the setting of HIV, especially of some antigens eliciting T cell-independent responses. The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Toll-Like Receptor (TLR) agonists. The association of enhanced systemic levels of TLR agonists and B cell dysfunction in HIV disease is not understood. This review discusses the potential role of microbial TLR agonists in the B cell depletion, enhanced autoantibody production and impaired responses to vaccination observed in HIV infected hosts. Increased microbial translocation in HIV infection may drive B cells to produce autoantibodies and increase susceptibilities of B cells to apoptosis through activation-induced cell death. Determining the mechanisms of B cell perturbations in HIV disease will inform the design of novel strategies of improve immune responses to vaccines, reduce opportunistic infections and slow disease progression. PMID- 24795847 TI - Germination of Acacia harpophylla (Brigalow) seeds in relation to soil water potential: implications for rehabilitation of a threatened ecosystem. AB - Initial soil water conditions play a critical role when seeding is the primary approach to revegetate post-mining areas. In some semi-arid climates, such as the Brigalow Belt Bioregion in eastern Australia, extensive areas are affected by open-cut mining. Together with erratic rainfall patterns and clayey soils, the Brigalow Belt denotes a unique biome which is representative of other water limited ecosystems worldwide. Apart from other environmental stressors, germination is governed by the water potential of the surrounding soil material. While previous studies have confirmed the high tolerance of Brigalow (Acacia harpophylla) seeds to a broad range of temperature and salinity, the question of how soil water potential triggers seed germination remains. In this study, we used three replicates of 50 seeds of Brigalow to investigate germination in relation to water potential as an environmental stressor. Solutions of Polyethylene Glycol (PEG 6000) were applied to expose seeds to nine osmotic water potentials ranging from soil water saturation (0 MPa) and field capacity (-.01 to -.03 MPa) to the permanent wilting point (-1.5 MPa). We measured germinability (number of germinated seeds relative to total number of seeds per lot) and mean germination time (mean time required for maximum germination of a seed lot) to quantify germination. Based on the empirical data of the germination we estimated the parameters of the hydrotime model which simulates timing and success of seed emergence. Our findings indicate that Brigalow seeds are remarkably tolerant to water stress, with germination being observed at a water potential as low as -1.5 MPa. Likewise, the average base water potential of a seed population (hydrotime model) was very low and ranged between -1.533 and -1.451 MPa. In general, Brigalow seeds germinate opportunistically over a broad range of abiotic conditions related to temperature, salinity, and water availability. Direct seeding and germination of native plants on post-mining land may be an effective and economically viable solution in order to re-establish plant communities. However, due to their capacity to reproduce asexually, alternative rehabilitation approaches such as transplantation of whole soil-root compartments may become attractive for restoration ecologists to achieve safe, stable, and non-polluting ecosystems. PMID- 24795848 TI - Landscape fragmentation and pollinator movement within agricultural environments: a modelling framework for exploring foraging and movement ecology. AB - Pollinator decline has been linked to landscape change, through both habitat fragmentation and the loss of habitat suitable for the pollinators to live within. One method for exploring why landscape change should affect pollinator populations is to combine individual-level behavioural ecological techniques with larger-scale landscape ecology. A modelling framework is described that uses spatially-explicit individual-based models to explore the effects of individual behavioural rules within a landscape. The technique described gives a simple method for exploring the effects of the removal of wild corridors, and the creation of wild set-aside fields: interventions that are common to many national agricultural policies. The effects of these manipulations on central-place nesting pollinators are varied, and depend upon the behavioural rules that the pollinators are using to move through the environment. The value of this modelling framework is discussed, and future directions for exploration are identified. PMID- 24795849 TI - A new direction for prenatal chromosome microarray testing: software-targeting for detection of clinically significant chromosome imbalance without equivocal findings. AB - Purpose. To design and validate a prenatal chromosomal microarray testing strategy that moves away from size-based detection thresholds, towards a more clinically relevant analysis, providing higher resolution than G-banded chromosomes but avoiding the detection of copy number variants (CNVs) of unclear prognosis that cause parental anxiety. Methods. All prenatal samples fulfilling our criteria for karyotype analysis (n = 342) were tested by chromosomal microarray and only CNVs of established deletion/duplication syndrome regions and any other CNV >3 Mb were detected and reported. A retrospective full-resolution analysis of 249 of these samples was carried out to ascertain the performance of this testing strategy. Results. Using our prenatal analysis, 23/342 (6.7%) samples were found to be abnormal. Of the remaining samples, 249 were anonymized and reanalyzed at full-resolution; a further 46 CNVs were detected in 44 of these cases (17.7%). None of these additional CNVs were of clear clinical significance. Conclusion. This prenatal chromosomal microarray strategy detected all CNVs of clear prognostic value and did not miss any CNVs of clear clinical significance. This strategy avoided both the problems associated with interpreting CNVs of uncertain prognosis and the parental anxiety that are a result of such findings. PMID- 24795850 TI - Microbial communities respond to experimental warming, but site matters. AB - Because microorganisms are sensitive to temperature, ongoing global warming is predicted to influence microbial community structure and function. We used large scale warming experiments established at two sites near the northern and southern boundaries of US eastern deciduous forests to explore how microbial communities and their function respond to warming at sites with differing climatic regimes. Soil microbial community structure and function responded to warming at the southern but not the northern site. However, changes in microbial community structure and function at the southern site did not result in changes in cellulose decomposition rates. While most global change models rest on the assumption that taxa will respond similarly to warming across sites and their ranges, these results suggest that the responses of microorganisms to warming may be mediated by differences across the geographic boundaries of ecosystems. PMID- 24795851 TI - Oppositional defiant- and conduct disorder-like problems: neurodevelopmental predictors and genetic background in boys and girls, in a nationwide twin study. AB - Background. Previous research has supported gender-specific aetiological factors in oppositional defiant disorder (ODD) and conduct disorder (CD). The aims of this study were to identify gender-specific associations between the behavioural problems-ODD/CD-like problems-and the neurodevelopmental disorders-attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD)-and to investigate underlying genetic effects. Methods. 17,220 twins aged 9 or 12 were screened using the Autism-Tics, AD/HD and other Comorbidities inventory. The main covariates of ODD- and CD-like problems were investigated, and the relative importance of unique versus shared hereditary and environmental effects was estimated using twin model fitting. Results. Social interaction problems (one of the ASD subdomains) was the strongest neurodevelopmental covariate of the behavioural problems in both genders, while ADHD-related hyperactivity/impulsiveness in boys and inattention in girls stood out as important covariates of CD-like problems. Genetic effects accounted for 50%-62% of the variance in behavioural problems, except in CD-like problems in girls (26%). Genetic and environmental effects linked to ADHD and ASD also influenced ODD-like problems in both genders and, to a lesser extent, CD-like problems in boys, but not in girls. Conclusions. The gender-specific patterns should be considered in the assessment and treatment, especially of CD. PMID- 24795852 TI - Does more sequence data improve estimates of galliform phylogeny? Analyses of a rapid radiation using a complete data matrix. AB - The resolution of rapid evolutionary radiations or "bushes" in the tree of life has been one of the most difficult and interesting problems in phylogenetics. The avian order Galliformes appears to have undergone several rapid radiations that have limited the resolution of prior studies and obscured the position of taxa important both agriculturally and as model systems (chicken, turkey, Japanese quail). Here we present analyses of a multi-locus data matrix comprising over 15,000 sites, primarily from nuclear introns but also including three mitochondrial regions, from 46 galliform taxa with all gene regions sampled for all taxa. The increased sampling of unlinked nuclear genes provided strong bootstrap support for all but a small number of relationships. Coalescent-based methods to combine individual gene trees and analyses of datasets that are independent of published data indicated that this well-supported topology is likely to reflect the galliform species tree. The inclusion or exclusion of mitochondrial data had a limited impact upon analyses upon analyses using either concatenated data or multispecies coalescent methods. Some of the key phylogenetic findings include support for a second major clade within the core phasianids that includes the chicken and Japanese quail and clarification of the phylogenetic relationships of turkey. Jackknifed datasets suggested that there is an advantage to sampling many independent regions across the genome rather than obtaining long sequences for a small number of loci, possibly reflecting the differences among gene trees that differ due to incomplete lineage sorting. Despite the novel insights we obtained using this increased sampling of gene regions, some nodes remain unresolved, likely due to periods of rapid diversification. Resolving these remaining groups will likely require sequencing a very large number of gene regions, but our analyses now appear to support a robust backbone for this order. PMID- 24795853 TI - The perception of shape from shading in a new light. AB - How do humans see three-dimensional shape based on two-dimensional shading? Much research has assumed that a 'light from above' bias solves the ambiguity of shape from shading. Counter to the 'light from above' bias, studies of Bayesian priors have found that such a bias can be swayed by other light cues. Despite the persuasive power of the Bayesian models, many new studies and books cite the original 'light from above' findings. Here I present a version of the Bayesian result that can be experienced. The perception of shape-from-shading was found here to be influenced by an external light source, even when the light was obstructed and did not directly illuminate a two-dimensional stimulus. The results imply that this effect is robust and not low-level in nature. The perception of shape from shading is not necessarily based on a hard-wired internal representation of lighting direction, but rather assesses the direction of lighting in the scene adaptively. Here, for the first time, is an experiential opportunity to see what the Bayesian models have supported all along. PMID- 24795854 TI - A probabilistic analysis reveals fundamental limitations with the environmental impact quotient and similar systems for rating pesticide risks. AB - Comparing risks among pesticides has substantial utility for decision makers. However, if rating schemes to compare risks are to be used, they must be conceptually and mathematically sound. We address limitations with pesticide risk rating schemes by examining in particular the Environmental Impact Quotient (EIQ) using, for the first time, a probabilistic analytic technique. To demonstrate the consequences of mapping discrete risk ratings to probabilities, adjusted EIQs were calculated for a group of 20 insecticides in four chemical classes. Using Monte Carlo simulation, adjusted EIQs were determined under different hypothetical scenarios by incorporating probability ranges. The analysis revealed that pesticides that have different EIQs, and therefore different putative environmental effects, actually may be no different when incorporating uncertainty. The EIQ equation cannot take into account uncertainty the way that it is structured and provide reliable quotients of pesticide impact. The EIQ also is inconsistent with the accepted notion of risk as a joint probability of toxicity and exposure. Therefore, our results suggest that the EIQ and other similar schemes be discontinued in favor of conceptually sound schemes to estimate risk that rely on proper integration of toxicity and exposure information. PMID- 24795855 TI - A survey of authors publishing in four megajournals. AB - Aim. To determine the characteristics of megajournal authors, the nature of the manuscripts they are submitting to these journals, factors influencing their decision to publish in a megajournal, sources of funding for article processing charges (APCs) or other fees and their likelihood of submitting to a megajournal in the future. Methods. Web-based survey of 2,128 authors who recently published in BMJ Open, PeerJ, PLOS ONE or SAGE Open. Results. The response rate ranged from 26% for BMJ Open to 47% for SAGE Open. The authors were international, largely academics who had recently published in both subscription and Open Access (OA) journals. Across journals about 25% of the articles were preliminary findings and just under half were resubmissions of manuscripts rejected by other journals. Editors from other BMJ journals and perhaps to a lesser extent SAGE and PLOS journals appear to be encouraging authors to submit manuscripts that were rejected by the editor's journals to a megajournal published by the same publisher. Quality of the journal and speed of the review process were important factors across all four journals. Impact factor was important for PLOS ONE authors but less so for BMJ Open authors, which also has an impact factor. The review criteria and the fact the journal was OA were other significant factors particularly important for PeerJ authors. The reputation of the publisher was an important factor for SAGE Open and BMJ Open. About half of PLOS ONE and around a third of BMJ Open and PeerJ authors used grant funding for publishing charges while only about 10% of SAGE Open used grant funding for publication charges. Around 60% of SAGE Open and 32% of PeerJ authors self-funded their publication fees however the fees are modest for these journals. The majority of authors from all 4 journals were pleased with their experience and indicated they were likely to submit to the same or similar journal in the future. Conclusions. Megajournals are drawing an international group of authors who tend to be experienced academics. They are choosing to publish in megajournals for a variety of reasons but most seem to value the quality of the journal and the speed of the review/publication process. Having a broad scope was not a key factor for most authors though being OA was important for PeerJ and SAGE Open authors. Most authors appeared pleased with the experience and indicated they are likely to submit future manuscripts to the same or similar megajournal which seems to suggest these journals will continue to grow in popularity. PMID- 24795856 TI - Association between in-scanner head motion with cerebral white matter microstructure: a multiband diffusion-weighted MRI study. AB - Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) has emerged as the most popular neuroimaging technique used to depict the biological microstructural properties of human brain white matter. However, like other MRI techniques, traditional DW-MRI data remains subject to head motion artifacts during scanning. For example, previous studies have indicated that, with traditional DW-MRI data, head motion artifacts significantly affect the evaluation of diffusion metrics. Actually, DW-MRI data scanned with higher sampling rate are important for accurately evaluating diffusion metrics because it allows for full-brain coverage through the acquisition of multiple slices simultaneously and more gradient directions. Here, we employed a publicly available multiband DW-MRI dataset to investigate the association between motion and diffusion metrics with the standard pipeline, tract-based spatial statistics (TBSS). The diffusion metrics used in this study included not only the commonly used metrics (i.e., FA and MD) in DW-MRI studies, but also newly proposed inter-voxel metric, local diffusion homogeneity (LDH). We found that the motion effects in FA and MD seems to be mitigated to some extent, but the effect on MD still exists. Furthermore, the effect in LDH is much more pronounced. These results indicate that researchers shall be cautious when conducting data analysis and interpretation. Finally, the motion-diffusion association is discussed. PMID- 24795857 TI - Chemical and biological sensing using liquid crystals. AB - The liquid crystalline state of matter arises from orientation-dependent, non covalent interaction between molecules within condensed phases. Because the balance of intermolecular forces that underlies formation of liquid crystals is delicate, this state of matter can, in general, be easily perturbed by external stimuli (such as an electric field in a display). In this review, we present an overview of recent efforts that have focused on exploiting the responsiveness of liquid crystals as the basis of chemical and biological sensors. In this application of liquid crystals, the challenge is to design liquid crystalline systems that undergo changes in organization when perturbed by targeted chemical and biological species of interest. The approaches described below revolve around the design of interfaces that selectively bind targeted species, thus leading to surface-driven changes in the organization of the liquid crystals. Because liquid crystals possess anisotropic optical and dielectric properties, a range of different methods can be used to read out the changes in organization of liquid crystals that are caused by targeted chemical and biological species. This review focuses on principles for liquid crystal-based sensors that provide an optical output. PMID- 24795858 TI - Double small bowel intussusception complicating bilateral partial nephrectomies. AB - An 11.5-month-old male, diagnosed with bilateral Wilms tumor at 10 months of age, received 6 weeks of chemotherapy and subsequently underwent bilateral partial nephrectomies. On postoperative day 5, he had crampy abdominal pain and bilious vomiting. Abdominal ultrasound confirmed the presence of an intussusception in the right lower quadrant. Laparotomy demonstrated two separate areas of small intestinal intussusception located at jejuno-jejunal and ileo-ileal locations. The patient was successfully treated with manual reduction. A high index of suspicion is necessary to diagnose and treat patients with two different points of intussusception. PMID- 24795860 TI - Corrigendum: involvement of a non-human sialic Acid in human cancer. PMID- 24795859 TI - Antibody therapy for pediatric leukemia. AB - Despite increasing cure rates for pediatric leukemia, relapsed disease still carries a poor prognosis with significant morbidity and mortality. Novel targeted therapies are currently being investigated in an attempt to reduce adverse events and improve survival outcomes. Antibody therapies represent a form of targeted therapy that offers a new treatment paradigm. Monoclonal antibodies are active in pediatric acute lymphoblastic leukemia (ALL) and are currently in Phase III trials. Antibody-drug conjugates (ADCs) are the next generation of antibodies where a highly potent cytotoxic agent is bound to an antibody by a linker, resulting in selective targeting of leukemia cells. ADCs are currently being tested in clinical trials for pediatric acute myeloid leukemia and ALL. Bispecific T cell engager (BiTE) antibodies are a construct whereby each antibody contains two binding sites, with one designed to engage the patient's own immune system and the other to target malignant cells. BiTE antibodies show great promise as a novel and effective therapy for childhood leukemia. This review will outline recent developments in targeted agents for pediatric leukemia including monoclonal antibodies, ADCs, and BiTE antibodies. PMID- 24795861 TI - Targeting PI3K/mTOR Signaling in Cancer. PMID- 24795862 TI - Sorting Out Pandora's Box: Discerning the Dynamic Roles of Liver Microenvironment in Oncolytic Virus Therapy for Hepatocellular Carcinoma. AB - Oncolytic viral therapies have recently found their way into clinical application for hepatocellular carcinoma (HCC), a disease with limited treatment options and poor prognosis. Adding to the many intrinsic challenges of in vivo oncolytic viral therapy, is the complex microenvironment of the liver, which imposes unique limitations to the successful delivery and propagation of the virus. The normal liver milieu is characterized by an intricate network of hepatocytes and non parenchymal cells including Kupffer cells, stellate cells, and sinusoidal endothelial cells, which can secrete anti-viral cytokines, provide a platform for non-specific uptake, and form a barrier to efficient viral spread. In addition, natural killer cells are greatly enriched in the liver, contributing to the innate defense against viruses. The situation is further complicated when HCC arises in the setting of underlying hepatitis virus infection and/or hepatic cirrhosis, which occurs in more than 90% of clinical cases. These conditions pose further inhibitory effects on oncolytic virus (OV) therapy due to the presence of chronic inflammation, constitutive cytokine expression, altered hepatic blood flow, and extracellular matrix deposition. In addition, OVs can modulate the hepatic microenvironment, resulting in a complex interplay between virus and host. The immune system undoubtedly plays a substantial role in the outcome of OV therapy, both as an inhibitor of viral replication, and as a potent mechanism of virus-mediated tumor cell killing. This review will discuss the particular challenges of oncolytic viral therapy for HCC, as well as some potential strategies for modulating the immune system and synergizing with the hepatic microenvironment to improve therapeutic outcome. PMID- 24795864 TI - Protein kinase C Beta in the tumor microenvironment promotes mammary tumorigenesis. AB - Protein kinase C beta (PKCbeta) expression in breast cancer is associated with a more aggressive tumor phenotype, yet the mechanism for how PKCbeta is pro tumorigenic in this disease is still unclear. Interestingly, while it is known that PKCbeta mediates angiogenesis, immunity, fibroblast function and adipogenesis, all components of the mammary tumor microenvironment (TME), no study to date has investigated whether stromal PKCbeta is functionally relevant in breast cancer. Herein, we evaluate mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) induced mammary tumorigenesis in the presence and absence of PKCbeta. We utilize two model systems: one where PKCbeta is deleted in both the epithelial and stromal compartments to test the global requirement for PKCbeta on tumor formation, and second, where PKCbeta is deleted only in the stromal compartment to test its role in the TME. MMTV-PyMT mice globally lacking PKCbeta live longer and develop smaller tumors with decreased proliferation and decreased macrophage infiltration. Similarly, when PKCbeta is null exclusively in the stroma, PyMT-driven B6 cells form smaller tumors with diminished collagen deposition. These experiments reveal for the first time a tumor promoting role for stromal PKCbeta in MMTV-PyMT tumorigenesis. In corroboration with these results, PKCbeta mRNA (Prkcb) is increased in fibroblasts isolated from MMTV-PyMT tumors. These data were confirmed in a breast cancer patient cohort. Combined these data suggest the continued investigation of PKCbeta in the mammary TME is necessary to elucidate how to effectively target this signaling pathway in breast cancer. PMID- 24795863 TI - Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising. AB - The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell's genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process. PMID- 24795865 TI - Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT. PMID- 24795867 TI - Supra-organismal interactions in the human intestine. PMID- 24795866 TI - Implications of free Shiga toxin-converting bacteriophages occurring outside bacteria for the evolution and the detection of Shiga toxin-producing Escherichia coli. AB - In this review we highlight recent work that has increased our understanding of the distribution of Shiga toxin-converting phages that can be detected as free phage particles, independently of Shiga toxin-producing bacteria (STEC). Stx phages are a quite diverse group of temperate phages that can be found in their prophage state inserted within the STEC chromosome, but can also be found as phages released from the cell after activation of their lytic cycle. They have been detected in extraintestinal environments such as water polluted with feces from humans or animals, food samples or even in stool samples of healthy individuals. The high persistence of phages to several inactivation conditions makes them suitable candidates for the successful mobilization of stx genes, possibly resulting in the genes reaching a new bacterial genomic background by means of transduction, where ultimately they may be expressed, leading to Stx production. Besides the obvious fact that Stx phages circulating between bacteria can be, and probably are, involved in the emergence of new STEC strains, we review here other possible ways in which free Stx phages could interfere with the detection of STEC in a given sample by current laboratory methods and how to avoid such interference. PMID- 24795869 TI - A remembrance of Mary ellen avery, m.d. PMID- 24795868 TI - Tissue communication in regenerative inflammatory signaling: lessons from the fly gut. AB - The intestine, as a barrier epithelium, serves in the first line of defense against invading pathogens and damaging agents that enter the body via food ingestion. Maintenance of intestinal homeostasis is therefore key to organismal health. To maintain homeostasis, intestinal stem cells (ISCs) continuously replace lost or damaged intestinal epithelial cells in organisms ranging from Drosophila to humans. Interestingly, intestinal damage upon ingestion of chemicals or pathogenic bacteria leads to an inflammatory response in the Drosophila intestine, which promotes regeneration and predisposes to tumorigenesis. This regenerative inflammatory signaling culminates in proliferation and differentiation of ISCs that replenish the damaged intestinal cells and is regulated by the interplay of conserved cell-cell communication pathways, such as the JNK, JAK/STAT, Wnt/Wingless, Notch, InR, PVR, EGFR, and Hippo. These pathways are induced by signals emanating not only from the damaged intestinal epithelial cells, but also from neighboring tissues associated with the intestinal epithelium, such as the muscles and the trachea, or distant tissues, such as the wounded epidermis and the brain. Here we review tissue communication during homeostasis and regenerative inflammatory signaling in Drosophila focusing on the signals that emanate from non-intestinal epithelial tissues to ensure intestinal integrity. PMID- 24795870 TI - How Mary Ellen Avery Influenced my Career as an Investigator. PMID- 24795871 TI - My tribute to Mary ellen avery. PMID- 24795872 TI - Are there cultural differences in parental interest in early diagnosis and genetic risk assessment for autism spectrum disorder? AB - BACKGROUND: There are many societal and cultural differences between healthcare systems and the use of genetic testing in the US and France. These differences may affect the diagnostic process for autism spectrum disorder (ASD) in each country and influence parental opinions regarding the use of genetic screening tools for ASD. METHODS: Using an internet-based tool, a survey of parents with at least one child with ASD was conducted. A total of 162 participants from the US completed an English version of the survey and 469 participants from France completed a French version of the survey. Respondents were mainly females (90%) and biological parents (94.3% in the US and 97.2% in France). RESULTS: The mean age of ASD diagnosis reported was not significantly different between France (57.5 +/- 38.4 months) and the US (56.5 +/- 52.7 months) (p = 0.82) despite significant difference in the average age at which a difference in development was first suspected [29.7 months (+/-28.4) vs. 21.4 months (+/-18.1), respectively, p = 7 * 10(-4)]. Only 27.8% of US participants indicated that their child diagnosed with ASD had undergone diagnostic genetic testing, whereas 61.7% of the French participants indicated this was the case (p = 2.7 * 10(-12)). In both countries, the majority of respondents (69.3% and 80% from France and the US, respectively) indicated high interest in the use of a genetic screening test for autism. CONCLUSION: Parents from France and the US report a persistent delay between the initial suspicion of a difference in development and the diagnosis of ASD. Significantly fewer US participants underwent genetic testing although this result should be regarded as exploratory given the limitations. The significance of these between country differences will be discussed. PMID- 24795873 TI - Surge Capacity and Capability. A Review of the History and Where the Science is Today Regarding Surge Capacity during a Mass Casualty Disaster. AB - Disasters which include countless killed and many more injured, have occurred throughout recorded history. Many of the same reports of disaster also include numerous accounts of individuals attempting to rescue those in great peril and render aid to the injured and infirmed. The purpose of this paper is to briefly discuss the transition through several periods of time with managing a surge of many patients. This review will focus on the triggering event, injury and illness, location where the care is provided and specifically discuss where the science is today. PMID- 24795874 TI - Public Mental Health - Using the Mental Health Gap Action Program to Put all Hands to the Pumps. AB - Although mental ill health constitutes a huge portion of the Global Burden of Disease (GBD), the majority of people with mental health problems do not receive any treatment, a scenario much worse in developing countries where mental health personnel are in gross short supply. The mhGAP was launched to address this gap, especially by training non-mental health professionals to deliver effective services for selected priority mental health problems. Especially in developing countries, many people with mental health problems consult traditional healers either as a first step in the pathway to biomedical mental health care or as the sole mental health service providers. Bridging the gap between mental health needs and available services in developing countries needs to incorporate traditional healers, who are ubiquitously available, easily accessible, and acceptable to the natives. Even though there are barriers in forging collaborations between traditional and biomedical mental health care providers, with mutual respect, understanding, and adapted training using the mhGAP intervention guide, it should be possible to get some traditional healers to understand the core principles of some priority mental health problems identification, treatment, and referral. PMID- 24795875 TI - Identifying Active Travel Behaviors in Challenging Environments Using GPS, Accelerometers, and Machine Learning Algorithms. AB - BACKGROUND: Active travel is an important area in physical activity research, but objective measurement of active travel is still difficult. Automated methods to measure travel behaviors will improve research in this area. In this paper, we present a supervised machine learning method for transportation mode prediction from global positioning system (GPS) and accelerometer data. METHODS: We collected a dataset of about 150 h of GPS and accelerometer data from two research assistants following a protocol of prescribed trips consisting of five activities: bicycling, riding in a vehicle, walking, sitting, and standing. We extracted 49 features from 1-min windows of this data. We compared the performance of several machine learning algorithms and chose a random forest algorithm to classify the transportation mode. We used a moving average output filter to smooth the output predictions over time. RESULTS: The random forest algorithm achieved 89.8% cross-validated accuracy on this dataset. Adding the moving average filter to smooth output predictions increased the cross-validated accuracy to 91.9%. CONCLUSION: Machine learning methods are a viable approach for automating measurement of active travel, particularly for measuring travel activities that traditional accelerometer data processing methods misclassify, such as bicycling and vehicle travel. PMID- 24795876 TI - Protein sequence classification with improved extreme learning machine algorithms. AB - Precisely classifying a protein sequence from a large biological protein sequences database plays an important role for developing competitive pharmacological products. Comparing the unseen sequence with all the identified protein sequences and returning the category index with the highest similarity scored protein, conventional methods are usually time-consuming. Therefore, it is urgent and necessary to build an efficient protein sequence classification system. In this paper, we study the performance of protein sequence classification using SLFNs. The recent efficient extreme learning machine (ELM) and its invariants are utilized as the training algorithms. The optimal pruned ELM is first employed for protein sequence classification in this paper. To further enhance the performance, the ensemble based SLFNs structure is constructed where multiple SLFNs with the same number of hidden nodes and the same activation function are used as ensembles. For each ensemble, the same training algorithm is adopted. The final category index is derived using the majority voting method. Two approaches, namely, the basic ELM and the OP-ELM, are adopted for the ensemble based SLFNs. The performance is analyzed and compared with several existing methods using datasets obtained from the Protein Information Resource center. The experimental results show the priority of the proposed algorithms. PMID- 24795877 TI - Recombinant nAG (a salamander-derived protein) decreases the formation of hypertrophic scarring in the rabbit ear model. AB - nAG (newt-Anterrior Gradient) protein is the key mediator of regrowth of amputated limbs in salamanders. In a previous work in our lab, a new nAG gene (suitable for humans) was designed and cloned. The cloned vector was transfected into primary human fibroblasts. The expression of nAG in human primary fibroblasts was found to suppress collagen expression. The current study shows that local injection of recombinant nAG reduces scar hypertrophy in the rabbit ear model. This is associated with lower scar elevation index (SEI), lower levels of collagen I & III, higher levels of MMP1, and a higher degree of scar maturation in experimental wounds compared to controls. PMID- 24795878 TI - Removal of cardiopulmonary resuscitation artifacts with an enhanced adaptive filtering method: an experimental trial. AB - Current automated external defibrillators mandate interruptions of chest compression to avoid the effect of artifacts produced by CPR for reliable rhythm analyses. But even seconds of interruption of chest compression during CPR adversely affects the rate of restoration of spontaneous circulation and survival. Numerous digital signal processing techniques have been developed to remove the artifacts or interpret the corrupted ECG with promising result, but the performance is still inadequate, especially for nonshockable rhythms. In the present study, we suppressed the CPR artifacts with an enhanced adaptive filtering method. The performance of the method was evaluated by comparing the sensitivity and specificity for shockable rhythm detection before and after filtering the CPR corrupted ECG signals. The dataset comprised 283 segments of shockable and 280 segments of nonshockable ECG signals during CPR recorded from 22 adult pigs that experienced prolonged cardiac arrest. For the unfiltered signals, the sensitivity and specificity were 99.3% and 46.8%, respectively. After filtering, a sensitivity of 93.3% and a specificity of 96.0% were achieved. This animal trial demonstrated that the enhanced adaptive filtering method could significantly improve the detection of nonshockable rhythms without compromising the ability to detect a shockable rhythm during uninterrupted CPR. PMID- 24795879 TI - Alcohol use, stigmatizing/discriminatory attitudes, and HIV high-risk sexual behaviors among men who have sex with men in China. AB - OBJECTIVE: This research was conducted to assess the correlates of alcohol consumption and HIV/AIDS-related stigmatizing and discriminatory attitudes among men who have sex with men (MSM) in Shandong province, China. METHODS: A cross sectional survey provided demographics, sexual behaviors, illicit drug use, alcohol consumptions, and service utilization. RESULTS: Of 1,230 participants, 82.8% were single, 85.7% aged <35 years, 47.2% had college or higher education, and 11.7% drank alcohol >3 times per week in the past six months. The average total score of stigmatizing and discriminatory attitude was 37.4 +/- 4.4. More frequent episodes of alcohol use were independently associated with higher levels of HIV/AIDS-related stigma and discrimination, unprotected anal sex, bisexual identity, multiple male sex partners, drug use, and lower levels of education. Expressing higher levels of HIV/AIDS-related stigmatizing and discriminatory attitudes was independently associated with alcohol use, unprotected male anal sex, bisexuals, more male sex partners, commercial sex with men, and non-receipt of peer education in the past year. CONCLUSION: HIV/AIDS-related stigmatizing and discriminatory attitudes are common and associated with alcohol use and unprotected sex among MSM. The finding highlights the needs to develop programs that would reduce HIV/AIDS-related stigmatizing and discriminatory attitudes and strengthen alcohol use prevention and risk reduction initiatives among MSM. PMID- 24795880 TI - HIV risk perception among HIV negative or status-unknown men who have sex with men in China. AB - OBJECTIVE: To evaluate HIV risk perception and its associated factors among Chinese MSM. METHODS: A cross-sectional study was conducted among MSM with an HIV negative or unknown status in Beijing, China, between 2011 and 2012. A questionnaire interview was conducted and a blood sample was collected for HIV and syphilis testing. RESULTS: Of 887 MSM who reported they were HIV negative or did not know their HIV status before recruitment, only 7.3% reported a high risk of HIV infection, 28.0% medium risk, 52.2% low risk, and 12.5% no risk. In multivariate logistic regression models using those who reported a medium self perceived risk as a reference group, self-reported high risk of HIV perception was associated with minority ethnicity (odds ratio [OR]: 2.91; 95% confidence interval [CI]: 1.03-8.19), self-reported history of sexually transmitted diseases (OR: 2.27; 95% CI: 1.25-4.10), and HIV testing times since the last HIV testing (OR: 0.47; 95% CI: 0.26-0.84); low self-perceived risk of HIV infection was related to full-time employment (OR: 1.58; 95% CI: 1.15-2.18) and illicit drug use (OR: 0.28; 95% CI: 0.10-0.75). CONCLUSION: The HIV/AIDS epidemic is rapidly rising among Beijing MSM, but more than half MSM did not perceive this risk. PMID- 24795881 TI - A noncellulosomal mannanase26E contains a CBM59 in Clostridium cellulovorans. AB - A multicomponent enzyme-complex prevents efficient degradation of the plant cell wall for biorefinery. In this study, the method of identifying glycoside hydrolases (GHs) to degrade hemicelluloses was demonstrated. The competence of C. cellulovorans, which changes to be suitable for degradation of each carbon source, was used for the method. C. cellulovorans was cultivated into locust bean gum (LBG) that is composed of galactomannan. The proteins produced by C. cellulovorans were separated into either fractions binding to crystalline cellulose or not. Proteins obtained from each fraction were further separated by SDS-PAGE and were stained with Coomassie Brilliant Blue and were detected for mannanase activity. The proteins having the enzymatic activity for LBG were cut out and were identified by mass spectrometry. As a result, four protein bands were classified into glycosyl hydrolase family 26 (GH26) mannanases. One of the identified mannanases, Man26E, contains a carbohydrate-binding module (CBM) family 59, which binds to xylan, mannan, and Avicel. Although mannose and galactose are the same as a hexose, the expression patterns of the proteins from C. cellulovorans were quite different. More interestingly, zymogram for mannanase activity showed that Man26E was detected in only LBG medium. PMID- 24795882 TI - Nonpharmacological strategies to prevent contrast-induced acute kidney injury. AB - Contrast-induced AKI (CI-AKI) has been one of the leading causes for hospital acquired AKI and is associated with independent risk for adverse clinical outcomes including morbidity and mortality. The aim of this review is to provide a brief summary of the studies that focus on nonpharmacological strategies to prevent CI-AKI, including routine identification of at-risk patients, use of appropriate hydration regimens, withdrawal of nephrotoxic drugs, selection of low osmolar contrast media or isoosmolar contrast media, and using the minimum volume of contrast media as possible. There is no need to schedule dialysis in relation to injection of contrast media or injection of contrast agent in relation to dialysis program. Hemodialysis cannot protect the poorly functioning kidney against CI-AKI. PMID- 24795883 TI - Risk factors for HIV/syphilis infection and male circumcision practices and preferences among men who have sex with men in China. AB - OBJECTIVE: To investigate factors associated with HIV infection and the frequency and willingness of male circumcision among men who have sex with men (MSM) in Chengdu city, China. METHODS: A cross-sectional survey provided information on participants' demographics, risk behaviors, circumcision, and uptake of HIV prevention services. RESULTS: Of 570 participants, 13.3% were infected with HIV and 15.9% with syphilis. An estimated 43.0% of respondents reported having unprotected receptive anal intercourse, and 58.9% reported having >=2 male sexual partners in the past 6 months. Multivariable logistic regression revealed that syphilis, more male sex partners, predominantly receptive anal intercourse, and exclusively receptive male sex were associated with HIV infection. Higher level of education and peer education service were inversely associated with HIV infection. Nearly a fifth (18.0%) of participants were circumcised. More than half of uncircumcised participants expressed willingness to be circumcised. CONCLUSION: This study reveals a high prevalence of HIV and syphilis among MSM in Chengdu province of China. The frequency of unprotected receptive anal intercourse and multiple male sexual partnerships highlight the urgency for an effective comprehensive HIV prevention strategy. Although the willingness to accept male circumcision (MC) is high, further research is needed to assess the protective effective of MC among MSM. PMID- 24795884 TI - Short-term esmolol improves coronary artery remodeling in spontaneously hypertensive rats through increased nitric oxide bioavailability and superoxide dismutase activity. AB - The aim of this study was to assess the effects of short-term esmolol therapy on coronary artery structure and function and plasma oxidative stress in spontaneously hypertensive rats (SHR). For this purpose, 14-month-old male SHR were treated for 48 hours with esmolol (SHR-E, 300 MU g/kg/min). Age-matched untreated male SHR and Wistar Kyoto rats (WKY) were used as hypertensive and normotensive controls, respectively. At the end of intervention we performed a histological study to analyze coronary artery wall width (WW), wall-to-lumen ratio (W/L), and media cross-sectional area (MCSA). Dose-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed. We also assessed several plasma oxidative stress biomarkers, namely, superoxide scavenging activity (SOSA), nitrites, and total antioxidant capacity (TAC). We observed a significant reduction in WW (P < 0.001), W/L (P < 0.05), and MCSA (P < 0.01) and improved endothelium-dependent relaxation (AUC(SHR-E) = 201.2 +/- 33 versus AUC(SHR) = 97.5 +/- 21, P < 0.05) in SHR-E compared with untreated SHR; no differences were observed for WW, MCSA, and endothelium-dependent relaxation by ACh at higher concentrations (10(-6) to 10(-4) mol/l) for SHR-E with respect to WKY. SOSA (P < 0.001) and nitrite (P < 0.01) values were significantly higher in SHR-E than in untreated SHR; however, TAC did not increase after treatment with esmolol. Esmolol improves early coronary artery remodeling in SHR. PMID- 24795885 TI - Oxidatively modified proteins in the serous subtype of ovarian carcinoma. AB - Serous subtype of ovarian cancer is considered to originate from fallopian epithelium mucosa that has been exposed to physiological changes resulting from ovulation. Ovulation influences an increased in inflammation of epithelial ovarian cells as results of constant exposure of cells to ROS. The imbalance between ROS and antioxidant capacities, as well as a disruption of redox signaling, causes a wide range of damage to DNA, proteins, and lipids. This study applied spectrophotometric, dinitrophenylhydrazone (DNPH) assay, two-dimensional gel electrophoresis, and Western blot analyses to assess the levels of oxidatively modified proteins in 100 primary serous epithelial ovarian carcinoma and normal/surrounding tissues. These samples were obtained from 56 Caucasian and 44 African-American patients within the age range of 61 +/- 10 years. Analyses showed that the levels of reactive protein carbonyl groups increased as stages progressed to malignancy. Additionally, the levels of protein carbonyls in serous ovarian carcinoma among African Americans are 40% (P < 0.05) higher relative to Caucasian at similar advanced stages. Results suggest that oxidative stress is involved in the modification of carbonyl protein groups, leading to increased aggressiveness of epithelial ovarian tumors and may contribute to the disease's invasiveness among African Americans. PMID- 24795886 TI - Effect of intraocular lens diameter implanted in enucleated porcine eye on intraocular pressure induced by scleral depression. AB - The effect of the diameter of an intraocular lens (IOL) implanted in enucleated porcine eyes on the intraocular pressure induced by scleral depression was investigated. Two IOLs of 6 mm and 7 mm optic diameter were implanted. The intraocular pressure (IOP) was monitored during scleral depression by a transducer placed in the midvitreous through a sclerotomy at 6 o'clock. The area under the curve (AUC) of the IOP changes from the beginning of the indentation to the point when the peripheral retinal surface was observed through the IOL optics was measured. The AUC was significantly larger in eyes with a 6 mm IOL than in eyes with a 7 mm IOL (p < 0.05). The IOP elevation at the endpoint was higher in eyes with the 6 mm IOL than in eyes with the 7 mm IOL. We conclude that the AUC may represent the degree of stress induced by scleral depression. The higher AUC value with the X-60 may be because of the longer distance from the peripheral retina to the edge of the IOL optics. PMID- 24795887 TI - BACs-on-Beads technology: a reliable test for rapid detection of aneuploidies and microdeletions in prenatal diagnosis. AB - The risk of fetal aneuploidies is usually estimated based on high resolution ultrasound combined with biochemical determination of criterion in maternal blood, with invasive procedures offered to the population at risk. The purpose of this study was to investigate the effectiveness of a new rapid aneuploidy screening test on amniotic fluid (AF) or chorionic villus (CV) samples based on BACs-on-Beads (BoBs) technology and to compare the results with classical karyotyping by Giemsa banding (G-banding) of cultured cells in metaphase as the gold standard technique. The prenatal-BoBs kit was used to study aneuploidies involving chromosomes 13, 18, 21, X, and Y as well as nine microdeletion syndromes in 321 AF and 43 CV samples. G-banding of metaphase cultured cells was performed concomitantly for all prenatal samples. A microarray-based comparative genomic hybridization (aCGH) was also carried out in a subset of samples. Prenatal-BoBs results were widely confirmed by classical karyotyping. Only six karyotype findings were not identified by Prenatal-BoBs, all of them due to the known limitations of the technique. In summary, the BACs-on-Beads technology was an accurate, robust, and efficient method for the rapid diagnosis of common aneuploidies and microdeletion syndromes in prenatal samples. PMID- 24795888 TI - Influence of radiofrequency surgery on architecture of the palatine tonsils. AB - Radiofrequency surgery is a widely used modern technique for submucosal volume reduction of the tonsils. So far there is very limited information on morphologic changes in the human tonsils after radiofrequency surgery. We performed histopathological study of tonsillectomy specimens after previous bipolar radiofrequency induced thermotherapy (RFITT). A total of 83 patients underwent bipolar RFITT for hypertrophy of palatine tonsils. Tonsil volume reduction was measured by 3D ultrasonography. Five patients subsequently underwent tonsillectomy. Profound histopathological examination was performed to determine the effect of RFITT on tonsillar architecture. All tonsillectomy specimens showed the intact epithelium, intact germinal centers, normal vascularization, and no evidence of increased fibrosis. No microscopic morphological changes in tonsillectomy specimens after bipolar RFITT were observed. RFITT is an effective submucosal volume reduction procedure for treatment of hypertrophic palatine tonsils with no destructive effect on microscopic tonsillar architecture and hence most probably no functional adverse effect. PMID- 24795889 TI - Preparation of naringenin/ beta-cyclodextrin complex and its more potent alleviative effect on choroidal neovascularization in rats. AB - Choroidal neovascularization (CNV) is characterized by abnormal blood vessels growing from the choroid. Current remedies for CNV have not shown favorable therapeutic efficacy. It is urgent to identify and develop more safe and potent anti-CNV agents via multiple technologies. We previously showed that the natural product naringenin attenuated CNV. However, naringenin has poor water solubility and low bioavailability. Here, we prepared the beta-cyclodextrin (beta-CD) complex of naringenin and characterized it using infrared spectra and X-ray diffraction analyses. Determination of content and solubility in the complex showed that naringenin accounted for 20.53% in the complex and its solubility was increased by more than 10-fold. Using a laser-induced CNV model in rats we demonstrated that naringenin/beta-CD complex more significantly reduced CNV area than naringenin alone in rats. Furthermore, naringenin and its beta-CD complex significantly inhibited the mRNA and protein expression of VEGF, COX-2, PI3K, p38MAPK, MMP-2, and MMP-9 in retina and choroid tissues. Naringenin/beta-CD complex showed more significant inhibitory effect on VEGF and COX-2 expression than naringenin. These results collectively indicated that naringenin/beta-CD complex could be a promising therapeutic option for CNV and that the beneficial effects could be linked to the anti-inflammatory properties of naringenin. PMID- 24795890 TI - Peripheral leukocyte apoptosis in patients with Parkinsonism: correlation with clinical characteristics and neuroimaging findings. AB - Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson's disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using (99m)Tc-TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression. PMID- 24795891 TI - Characterization of genipin-modified dentin collagen. AB - Application of biomodification techniques to dentin can improve its biochemical and biomechanical properties. Several collagen cross-linking agents have been reported to strengthen the mechanical properties of dentin. However, the characteristics of collagen that has undergone agent-induced biomodification are not well understood. The objective of this study was to analyze the effects of a natural cross-linking agent, genipin (GE), on dentin discoloration, collagen stability, and changes in amino acid composition and lysyl oxidase mediated natural collagen cross-links. Dentin collagen obtained from extracted bovine teeth was treated with three different concentrations of GE (0.01%, 0.1%, and 0.5%) for several treatment times (0-24 h). Changes in biochemical properties of NaB(3)H4-reduced collagen were characterized by amino acid and cross-link analyses. The treatment of dentin collagen with GE resulted in a concentration- and time-dependent pigmentation and stability against bacterial collagenase. The lysyl oxidase-mediated trivalent mature cross-link, pyridinoline, showed no difference among all groups while the major divalent immature cross-link, dehydro dihydroxylysinonorleucine/its ketoamine in collagen treated with 0.5% GE for 24 h, significantly decreased compared to control (P < 0.05). The newly formed GE induced cross-links most likely involve lysine and hydroxylysine residues of collagen in a concentration-dependent manner. Some of these cross-links appear to be reducible and stabilized with NaB(3)H4. PMID- 24795892 TI - Effects of chlorophenoxy herbicides and their main transformation products on DNA damage and acetylcholinesterase activity. AB - Persistent pesticide transformation products (TPs) are increasingly being detected among different environmental compartments, including groundwater and surface water. However, there is no sufficient experimental data on their toxicological potential to assess the risk associated with TPs, even if their occurrence is known. In this study, the interaction of chlorophenoxy herbicides (MCPA, mecoprop, 2,4-D and dichlorprop) and their main transformation products with calf thymus DNA by UV-visible absorption spectroscopy has been assessed. Additionally, the toxicity of the chlorophenoxy herbicides and TPs was also assessed evaluating the inhibition of acetylcholinesterase activity. On the basis of the results found, it seems that AChE is not the main target of chlorophenoxy herbicides and their TPs. However, the results found showed that the transformation products displayed a higher inhibitory activity when compared with the parent herbicides. The results obtained in the DNA interaction studies showed, in general, a slight effect on the stability of the double helix. However, the data found for 4-chloro-2-methyl-6-nitrophenol suggest that this transformation product can interact with DNA through a noncovalent mode. PMID- 24795893 TI - A first assessment of Mycobacterium tuberculosis genetic diversity and drug resistance patterns in twelve Caribbean territories. AB - With the exception of some French-speaking islands, data on tuberculosis (TB) in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug resistance patterns. Of the 480 isolates, 40 (8.3%) isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P = 0.02), and Guyana (27.5%; P < 0.0001), while it was significantly lower in Jamaica (2.4%; P = 0.03) than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster), while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial) and ongoing links (trade, tourism, and migratory flows) with European countries with which they shared a common past. PMID- 24795894 TI - Development and characterization of liposomal doxorubicin hydrochloride with palm oil. AB - The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 +/- 0.8 and 0.22 +/- 1.3 and zeta potentials of about -31 and -32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37 degrees C. Comparing cytotoxicity and cellular uptake of LUV with Caelyx(R) on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes. PMID- 24795895 TI - Cardiac phosphoproteomics during remote ischemic preconditioning: a role for the sarcomeric Z-disk proteins. AB - Remote ischemic preconditioning (RIPC) induced by brief ischemia/reperfusion cycles of remote organ (e.g., limb) is cardioprotective. The myocardial cellular changes during RIPC responsible for this phenomenon are not currently known. The aim of this work was to identify the activation by phosphorylation of cardiac proteins following RIPC. To achieve our aim we used isobaric tandem mass tagging (TMT) and reverse phase nanoliquid chromatography tandem spectrometry using a Linear Trap Quadropole (LTQ) Orbitrap Velos mass spectrometer. Male C57/Bl6 mice were anesthetized by an intraperitoneal injection of Tribromoethanol. A cuff was placed around the hind limb and inflated at 200 mmHg to prevent blood flow as confirmed by Laser Doppler Flowmetry. RIPC was induced by 4 cycles of 5 min of limb ischemia followed by 5 min of reperfusion. Hearts were extracted for phosphoproteomics. We identified approximately 30 phosphoproteins that were differentially expressed in response to RIPC protocol. The levels of several phosphoproteins in the Z-disk of the sarcomere including phospho-myozenin-2 were significantly higher than control. This study describes and validates a novel approach to monitor the changes in the cardiac phosphoproteome following the cardioprotective intervention of RIPC and prior to index ischemia. The increased level of phosphorylated sarcomeric proteins suggests they may have a role in cardiac signaling during RIPC. PMID- 24795896 TI - Targeting spleen tyrosine kinase-Bruton's tyrosine kinase axis for immunologically mediated glomerulonephritis. AB - The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended. PMID- 24795898 TI - Consistency and Recanting of Ever-Smoking Status Reported by Self and Proxy Respondents One Year Apart. AB - The study examined consistency of reports concerning current and prior smoking behaviors. Data came from the 2002-2003 Tobacco Use Supplement to the Current Population Survey, where the current smoking behaviors and smoking history were reported by self- and proxy-respondents on two occasions, one year apart. The ever-smoking status is reported consistently, overall: Kappa coefficient is 0.78 with the corresponding 95% confidence interval given by (0.77, 0.78). One specific type of inconsistency of prior reports was assessed for respondents who were identified as never smokers at the latter assessment and former or current smokers at the earlier assessment. Based on the survey logistic regression that controls for multiple respondent characteristics and survey administration method, the estimated prevalence of such inconsistent self-reports is 9.0%, and prevalence of inconsistent proxy-reports is 5.4%. In addition, prevalence of recanting, i.e., future reporting never smoking for respondents who previously claimed to be a former or a current smoker was assessed. The recanting was shown to be most prevalent with respect to proxy-reports and former smokers: overall prevalence of recanting was estimated to be in the range 13% - 19% for current smokers, and 27% - 46% for former smokers. Our findings indicate that while, unexpectedly, proxy-respondents are more likely to report the ever-smoking status consistently than do self-respondents, the proxies are also more likely to incorrectly report never smoking in the future for smokers especially regarding adolescents and young adults. Therefore, the observed higher level of consistency for proxy-respondents may be due to proxies' incorrect knowledge which leads to consistent yet ambiguous responses. PMID- 24795897 TI - Effects of subchronic exposure to N,N-diethyl-m-toluamide on selected biomarkers in common carp (Cyprinus carpio L.). AB - DEET (N,N-diethyl-m-toluamide) is the most common active ingredient in the insect repellents commonly detected in European groundwater. The aim of this study was to investigate the effect of subchronic DEET exposure on biochemical and haematological parameters, antioxidant enzymes, including catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, and the amount of thiobarbituric acid reactive substances (TBARS) in common carp (Cyprinus carpio L.). Two specific proinflammatory and anti-inflammatory cytokine genes were selected to assess an immunological status of the fish. Fish were exposed for 28 days to three concentrations of DEET (1.0 ug/L, 0.1 mg/L, and 1.0 mg/L) where 1 ug/L is corresponding to the concentration found in the environment. DEET had a significant (P < 0.05) effect on increased RBC, decreased mean corpuscular volume (MCV), and mean corpuscular haemoglobin value (MCH) compared to control groups in the concentration of 1 mg/L. A significant decline (P < 0.05) in triacylglycerols (TAG) in plasma was found in the concentration of 1 mg/L compared to the control groups. The parameters of oxidative stress in tissues of common carp were weekly affected and immunological parameters were not affected. PMID- 24795899 TI - Exploratory analysis of urinary metabolites of phosphorus-containing flame retardants in relation to markers of male reproductive health. AB - The use of phosphorus-containing flame retardants (PFRs) has increased over the past decade. Widespread human exposure has been reported, but information on the safety or potential health risks of PFRs is lacking. We assessed the relationship between urinary concentrations of two PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPHP)] and semen quality, sperm motion parameters, and serum hormone levels in 33 men. BDCPP and DPHP concentrations were significantly greater in urine samples collected in the afternoon compared to those collected in the morning (p <0.05). In multivariable models, a number of statistically significant or suggestive associations were observed between the reproductive health measures and both PFR metabolites. While the study was limited by a small sample size, these results warrant further investigation in a larger study population. Additional studies on sources, pathways, and routes of PFR exposure, along with research on toxicokinetics and exposure measure utility, are also needed. PMID- 24795901 TI - Primary care is first-contact care. PMID- 24795902 TI - 40 years of helping family physicians refine their care. PMID- 24795903 TI - Chest pain--tools to improve your in-office evaluation. PMID- 24795905 TI - Beyond chronic pain: how best to treat psychological comorbidities. PMID- 24795906 TI - USPSTF: What's recommended, what's not. PMID- 24795907 TI - PURLs: Finally, a way to relieve cancer-related fatigue. PMID- 24795908 TI - Blisters on an elderly woman's toes. PMID- 24795909 TI - Clinical Inquiry: what are the benefits and risks of inhaled corticosteroids for COPD? PMID- 24795910 TI - Vomiting, abdominal pain, compulsive bathing--Dx? PMID- 24795911 TI - How often does otitis media cause fever? PMID- 24795912 TI - Addressing the unique issues of student athletes with ADHD. PMID- 24795913 TI - PURLs: A simple way to reduce catheter-associated UTIs. PMID- 24795914 TI - Latin America's resources: blessing or curse? PMID- 24795915 TI - Lily Jan. PMID- 24795916 TI - Professor Donald Lee 1931-2013. PMID- 24795917 TI - Mediastinal and base of skull pancreatic pseudocyst. PMID- 24795918 TI - Rupture of splenic artery pseudoaneurysm. PMID- 24795919 TI - New US patent for potential treatment of multidrug-resistant tuberculosis. PMID- 24795920 TI - New mechanism of action discovered for anticarcinogenic natural compound. PMID- 24795921 TI - Team demonstrates the rational design of drugs from RNA sequence. PMID- 24795922 TI - [Update intensive care]. PMID- 24795923 TI - I spy apraxic eyes in spinocerebellar ataxia type 2: a false-negative ataxia panel. PMID- 24795924 TI - Reply: To PMID 23598458. PMID- 24795925 TI - Laparoscopic rectopexy for solitary rectal ulcer syndrome without overt rectal prolapse. A case report and review of the literature. AB - Solitary rectal ulcer syndrome is a rare clinical entity. Several treatment options has been described. However, there is no consensus yet on treatment algorithm and standard surgical procedure. Rectopexy is one of the surgical options and it is generally performed in patients with solitary rectal ulcer accompanied with overt prolapse. Various outcomes have been reported for rectopexy in the patients with occult prolapse or rectal intussusception. In the literature; outcomes of laparoscopic non-resection rectopexy procedure have been reported in the limited number of case or case series. No study has emphasized the outcomes of laparoscopic non-resection rectopexy procedure in the patients with solitary rectal ulcer without overt prolapse. In this report we aimed to present clinical outcomes of laparoscopic non-resection posterior suture rectopexy procedure in a 21-year-old female patient with solitary rectal ulcer without overt prolapse. PMID- 24795926 TI - [ Thrombolytic therapy in acute occlusions of peripheral arteries]. AB - Atherosclerotic occlusions of the abdominal aorta and arteries of the lower limbs are the commonest pathology of the arterial system. General growth of primary reconstructive operations on the abdominal aorta and peripheral arteries is accompanied and followed by the increased number of patients presenting with various postoperative complications of a specific character, such as early and late re-occlusions of the postoperative segments. Besides, currently important remains the problem concerning effective and safe management of acute occlusions of peripheral arteries not subjected to reconstruction. One of the promising methods of treatment for acute arterial occlusion is thrombolytic therapy. Presented herein is a review of the literature concerning the state of the art of thrombolytic therapy in acute occlusions of peripheral arteries. PMID- 24795927 TI - [Cognitive reserve, cognitive impairment and possibilities of their pharmacological correction]. PMID- 24795929 TI - [Primary systemic vasculitis and damages of the central nervous system]. PMID- 24795928 TI - [The interhemispheric asymmetry in normalcy and pathology]. AB - The article reviews various issues of the interhemispheric asymmetry in normal people in the context of ontogenetic, morphological, neurobiochemical and functional aspects. The significance of this phenomenon in different pathological states of the central nervous system (CNS) is highlighted. Special attention is drawn to the dysfunction of the right and left hemispheres and interhemispheric interactions in normalcy and CNS pathology. PMID- 24795930 TI - [Bulimia nervosa: problems of clinical differentiation]. PMID- 24795931 TI - [Current strategy of treatment of cognitive impairment: potential points of application of drugs used for treatment of cognitive functions]. AB - The article reviews the literature on the diagnosis and treatment of cognitive impairment in the aspect of activity of main functional systems involved in functioning of the higher mental functions, cortical/subcortical interactions, afferent activating pattern of the reticular system and the cerebral blood flow system. The role of the latter is considered in frames of the concept of the neurovascular unit. Main points of application of drugs used for treatment of cognitive functions, including those which exert an effect on the capillary blood flow, are defined. PMID- 24795932 TI - Pathology of US porcine epidemic diarrhea virus strain PC21A in gnotobiotic pigs. AB - To understand the progression of porcine epidemic diarrhea virus infection, we inoculated gnotobiotic pigs with a newly emerged US strain, PC21A, of the virus. At 24-48 hours postinoculation, the pigs exhibited severe diarrhea and vomiting, fecal shedding, viremia, and severe atrophic enteritis. These findings confirm that strain PC21A is highly enteropathogenic. PMID- 24795934 TI - Medical management of first-trimester abortion. PMID- 24795933 TI - Incorporating research and evaluation into pandemic influenza vaccination preparedness and response. PMID- 24795935 TI - Figure out future needs and goals before breaking ground on your new facility. PMID- 24795936 TI - AGA's approach to the microbiome. PMID- 24795938 TI - Proceedings of the 18th Interdisciplinary Czech-Slovak Toxicology Conference,TOXCON June 19-21, 2013, Hradec Kralove, Czech Republic. PMID- 24795937 TI - Special issue dedicated to Dr. Mamoru Tamura. PMID- 24795939 TI - Are implementation science advances and digital technology developments important in sports medicine? Sports Medicine Australia thinks so. PMID- 24795940 TI - Can the "turn-of-the-nut" method improve cortical screw fixation? AB - OBJECTIVES: To determine the angular rotation that maximizes screw tension without sacrificing screw pullout force yet minimizing loss of screw purchase. METHODS: Three pairs of human humeri in each of the 3 groups (osteopenic, osteoporotic, and normal) underwent screw tension and pullout protocols. For screw tension, 3.5-mm screws were tightened into a strain gauge-instrumented plate until screw stripping occurred. Insertion torque, screw tension, and screw rotation were measured. For pullout, 3.5-mm screws were inserted until the head contacted the plate, additionally rotated (90, 180, 270, or 360 degrees), and then pulled out. A generalized linear and latent mixed model was used to check for significant associations (P < 0.05). RESULTS: Mean (95% confidence interval) peak screw tension occurred at 286 degrees (95% confidence interval, 261-311 degrees) beyond screw seating. Screw tension significantly increased at 90-135 degrees but not after 180 degrees. At 270 degrees, 39% of the screws had already reached their peak ability to compress the plate. Peak screw torque lagged behind peak screw tension by 31 +/- 50 degrees, and in seeking peak screw torque, a loss of 104 +/- 115 N in screw tension resulted. Screw pullout force was greatest at 90 degrees, but it was not significantly different from that of the other angle groups. CONCLUSIONS: Screw rotation at 180 degrees provides screw tension and pullout strength statistically similar to those at greater rotations but without the loss of purchase associated with greater rotations. PMID- 24795941 TI - Model guideline for state ignition interlock programs. PMID- 24795942 TI - The Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, USA. PMID- 24795943 TI - When the blood flow becomes bright. PMID- 24795944 TI - Introduction of a university-based counselling service for older adults. AB - AIM: Despite the growing number of older adults in Australia, many do not access counselling, partly because of the lack of trained mental health professionals for older people. This paper describes an innovative solution for providing counselling services to older adults, and geropsychology training to postgraduate psychology students. METHOD: A university-based counselling clinic for older adults was described - an outreach service for older adults living in the community or in residential aged care facilities in metropolitan Melbourne, Australia. RESULTS: Over its first 13 months, the clinic provided a total of 266 sessions of counselling to 57 clients (41 living in residential aged care), and involved six postgraduate students. CONCLUSION: This paper describes the potential benefits of the clinic for clients and students and the resources needed to support this model of service delivery. Thus, it provides a blueprint for other universities for developing similar services for older adults. PMID- 24795945 TI - Minimally invasive transforaminal interbody fusion surgery for the old fracture of the thoracolumbar junction. AB - STUDY DESIGN: Retrospective analysis of the clinical outcomes of 15 patients with the old thoracolumbar junction fracture treated by minimally invasive surgery (MIS) transforaminal interbody fusion surgery. OBJECTIVE: To investigate the efficacy and safety of MIS for the old fracture of the thoracolumbar junction in a pilot study. SUMMARY OF BACKGROUND DATA: MIS have demonstrated efficacy in the treatment of lumbar degenerative diseases. There is some controversy regarding the ideal management of thoracolumbar fractures, especially those without an associated neurologic deficit. Reports concerning MIS for old thoracolumbar junction fracture with chronic pain are quite rare. METHODS: A total of 15 MIS fusion, performed between October 2006 and May 2011, were examined in a retrospective study. The clinical and radiological data were collected and analyzed. Fusion levels were T10-T11 (2 patients), T11-T12 (5 patients), T12-L1 (6 patients), L1-L2 (2 patients). Clinical outcome was assessed using the visual analogue scale and the Oswestry disability index. Radiographic evaluation of the lumbar spine was performed at the second day and 12 months postoperatively. RESULTS: The average follow-up period was 26.3 months, with a minimum of 17 months. The mean operating time, intraoperative blood loss, and x-ray exposure time were 125+/-31 minutes, 226+/-45 mL, and 47+/-12 seconds, respectively. At last followup,the visual analogue scale for back pain and the Oswestry disability index decreased significantly postoperatively from 7.4+/-2.3 to 1.8+/-0.6 (P<0.01) and from 38.9+/-7.1 to 13.5+/-4.5 (P<0.01), respectively. The average Cobb angle was improved from 19.1-15.1 degrees in this series. No significant correction of local kyphosis was found postoperatively (P>0.05). Radiographic evaluation showed satisfactory bony union at the fixed level in all cases except for 2 patients. There were no other major complications at last follow-up. CONCLUSIONS: MIS transforaminal interbody fusion is a safe and effective procedure for old thoracolumbar junction fracture with chronic pain. Improvement of kyphosis is limited and occurrence of nonunion is relatively high. PMID- 24795946 TI - Medical supermarkets, preferably without Whole Foods' prices. PMID- 24795947 TI - Does lumbar disk degeneration increase segmental mobility in vivo? Segmental motion analysis of the whole lumbar spine using kinetic MRI. AB - STUDY DESIGN: This is a retrospective analysis of lumbar segmental motion using Kinetic magnetic resonance imaging(KMRI). OBJECTIVE: The aim of the study was to investigate lumbar segmental motion in functional (ie, standing weight-bearing flexion and extension) positions and examine the effects of lumbar disk degeneration on lumbar segmental motion. SUMMARY OF BACKGROUND DATA: Various biomechanical studies using cadaveric specimens have demonstrated the effects of disk degeneration on lumbar motion. However, the studies did not determine the effect of disk degeneration on segmental motion in the functional, living spine. METHODS: Segmental range of motion (ROM) was calculated and disk degeneration was graded in patients who had undergone KMRI in weight-bearing neutral, 60 degrees of flexion, and 20 degrees of extension. Patients (n=262) were categorized as having normal disks (n=94), single-level degeneration at L4-L5 (n=28) or L5-S1 (N=71), or double-level degeneration at L4-L5-S1 (N=69). Angular ROM, contribution (%)of each segment to total lumbar motion, and contribution of motion from upper (L1-L3) and lower (L4-S1) lumbar levels were compared. RESULTS: Mean ROMo f the lumbar spine in the normal group was 41.3+/-13.3 degrees. The L4 L5 degeneration group (36.1+/-12.4 degrees) and the L4-L5-S1 degeneration group (37.1+/-12.5 degrees) showed significantly decreased total lumbar ROM compared with the normal group. The ROM in upper lumbar segments was significantly larger than that in the lower segments in the normal group and similar in the degeneration groups. The contribution of L5-S1 to total lumbar motion was the smallest of all segments, and no significant difference was found between all groups. CONCLUSIONS: In functional positions assessed utilizing weight bearing KMRI, segmental motion at levels with degenerated disks was decreased. The contribution of upper lumbar segments to the total lumbar motion was not smaller than that of the lower segments. The L5-S1 level showed the smallest ROM in lumbar motion. PMID- 24795948 TI - The distributed medical home model, from video box to mailbox. PMID- 24795949 TI - The retrospective analysis of the effect of balloon kyphoplasty to the adjacent segment fracture in 171 patients. AB - STUDY DESIGN: Analysis of the adjacent-segment fractures in 171 balloon kyphoplasty (BK)-performed patients. OBJECTIVE: The purpose of this study was to investigate the risk factors for new symptomatic vertebral compression fractures (VCF) after BK. SUMMARY OF BACKGROUND DATA: Although there are many studies about the incidence and possible risk factors for occurrence of adjacent-level fractures, there is no consensus on the increased risk of adjacent-level fractures after BK. METHODS: We performed a retrospective analysis of 171 patients treated with percutaneous kyphoplasty. The follow-up period was 41.04+/ 21.78 months. The occurrence of new symptomatic VCF was recorded after the procedure. We evaluated the variables of patient age and sex, the amount of injected cement, the initial kyphotic angle (KA) of VCF, the change of the KA after BK, the severity of osteoporosis, and the percentage of height restoration of the vertebral body. Furthermore, possible risk factors were reported for new symptomatic VCFs. RESULTS: The only 2 factors identified as being significantly associated with adjacent-level fractures were the sex (P=0.001) of the patient and the preoperative KA (P=0.013). The patients with new symptomatic compression fracture had higher initial KA than those without fractures. The female group had higher risk than the male group in occurrence of the new vertebra fractures. The severity of the osteoporosis (low bone mineral density) was not a determinant in occurrence of the new VCF after BK. CONCLUSIONS: If the patients experience severe or mild back pain with higher preoperative KA, especially in the first 2 months, then they deserve detailed radiologic examination. To avoid subsequent fracture in the same or adjacent level, vertebral body should be filled adequately and sagittal balance should be obtained with KA correction. BK alone did not influence the incidence of subsequent VCF. PMID- 24795950 TI - [Sight in the elderly -- an underappreciated art in ophthalmology]. PMID- 24795951 TI - [Justified actions for disjunction for disloyal competition breach clause]. PMID- 24795952 TI - [Tax returns: the risk facing salaried physicians]. PMID- 24795953 TI - [Substance monograph on ochratoxin A: Opinion of the Commission on Human Biomonitoring UBA]. PMID- 24795954 TI - Three uncommon KEL alleles in one family with unusual Kell phenotypes explain a 35-year old conundrum. AB - BACKGROUND: Kell is a complex blood group system comprising 35 antigens. Kell antigens are absent from rare red cells of the Ko (null) phenotype and expressed only weakly in the Kmod phenotype. Molecular analysis of three uncommon KEL alleles elucidated the obscure pattern of inheritance of Kell antigens in one family. MATERIALS AND METHODS: Standard serological methods were employed. All exons, flanking intronic sequence and introns 15 and 16 of KEL were sequenced from genomic DNA. cDNA was obtained from erythroid cells cultured from progenitor cells isolated from peripheral blood. RESULTS: The Kmod propositus was heterozygous for two KEL mutations: c.2107G>A, p.Gly703Arg and a synonymous mutation, c.1719C>T, in the codon for p.573Gly. Sequencing of cDNA revealed that c.1719C>T caused skipping of exon 16, resulting in a silent allele. Her KEL:3,-4 brother was heterozygous for KEL*03/04 and c.1719C/T. CONCLUSION: A synonymous mutation caused complete exon skipping, despite being located 16 bases downstream of the 3' splice site, resulting in a null KEL allele. The combined effects of two mod alleles, one responsible for KEL3 expression and the other for p.Gly703Arg, were probably responsible for an unexpected KEL:3,-4 phenotype. PMID- 24795955 TI - Associations between birth weight and attention-deficit/hyperactivity disorder symptom severity: indirect effects via primary neuropsychological functions. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) has a range of aetiological origins which are associated with a number of disruptions in neuropsychological functioning. This study aimed to examine how low birth weight, a proxy measure for a range of environmental complications during gestation, predicted ADHD symptom severity in preschool-aged children indirectly via neuropsychological functioning. METHODS: A total of 197 preschool-aged children were recruited as part of a larger longitudinal study. Two neuropsychological factors were derived from NEPSY domain scores. One, referred to as 'Primary Neuropsychological Function,' was loaded highly with Sensorimotor and Visuospatial scores. The other, termed 'Higher-Order Function' was loaded highly with Language and Memory domain scores. Executive functioning split evenly across the two. Analyses examined whether these neuropsychological factors allowed for an indirect association between birth weight and ADHD symptom severity. RESULTS: As both factors were associated with symptom severity, only the Primary Neuropsychological Factor was associated with birth weight. Furthermore, birth weight was indirectly associated to symptom severity via this factor. CONCLUSIONS: These data indicate that birth weight is indirectly associated with ADHD severity via disruption of neuropsychological functions that are more primary in function as opposed to functions that play a higher-order role in utilising and integrating the primary functions. PMID- 24795956 TI - A prospective study of heart rate and externalising behaviours in young children. AB - BACKGROUND: Low heart rate predicts externalising and delinquent behaviour in adults, adolescents and school-age children. In younger children the evidence is less clear. Moreover, the specificity of the relation between the autonomic nervous system and different forms of externalising behaviour is uncertain. We investigated the longitudinal relation between resting mean heart rate and different externalising behaviours. METHODS: In 412 children of the Generation R Study, we measured resting mean heart rate at 14 months. At 3 years, child problem behaviour was assessed by the mother with the Child Behavior Checklist. In a gift delay task, we observed whether children were compliant and whether they lied about their noncompliance. The association of heart rate with behaviour was contrasted with the effect of harsh parenting. RESULTS: In our main analysis, we examined the association between heart rate and reported and observed child behaviour. For comparison, the association of heart rate with behaviour was contrasted with the effect of harsh parenting. Mean heart rate was positively associated with Anxious/Depressed scale scores (beta = .1, 95% CI = 0.01; 0.2, p = .04), but not with Aggressive Behaviour (beta = .02; 95% CI = -0.1; 0.1, p = .8) nor Attention Problem scale scores (beta = .08, 95% CI = -0.3; 0.5, p = .8). We could not demonstrate an association between mean heart rate and noncompliance during the gift delay task (OR = 1.14, 95% CI = 0.9; 1.1, p = .2), but lower heart rate predicted higher odds of the child lying (OR = 0.56, 95% CI = 0.3; 0.9, p = .03). In contrast, harsh parenting was associated with mother-reported Aggressive Behaviour (beta = .7, 95% CI = 0.4; 0.9, p < .001) and Attention Problems (beta = .2, 95% CI = 0.1; 0.3, p < .001), but not with observed lying (OR = 1.03, 95% CI = 0.8; 1.4, p = .8). CONCLUSIONS: Lower resting mean heart rate at age 14 months predicts low anxiety symptoms and higher odds of lying at age 3 years. Low resting mean heart rate may be less an indicator of early childhood aggression than of fearless behaviour. PMID- 24795957 TI - Bifactor latent structure of ADHD/ODD symptoms: predictions of dual pathway/trait-impulsivity etiological models of ADHD. AB - OBJECTIVE: To determine if ADHD/ODD symptoms are better represented by a bifactor model of disruptive behavior [general disruptive behavior factor along with specific inattention (IN), specific hyperactivity/impulsivity (HI), and specific oppositional defiant disorder (ODD) factors] than an ADHD-IN, ADHD-HI, and ODD three-factor model. METHOD: Mothers' and fathers' ratings of ADHD-IN, ADHD-HI, and ODD symptoms in a community sample of 4,658 children and adolescents (53% female) from Brazil, Thailand, and the US were used to evaluate the measurement models. RESULTS: The bifactor model of disruptive behavior provided a better fit than the three factor model. The bifactor model also occurred with mothers' and fathers' ratings of male and female children and adolescents. CONCLUSIONS: Consistent with predictions derived from recently articulated dual-pathway and trait-impulsivity models of externalizing liability, and from behavioral genetics studies indicating near complete overlap in vulnerability to ADHD and ODD, ADHD and ODD symptoms arose from a single, general disruptive behavior factor, which accounted for all of the variance in HI subscale scores and over half of the variance IN and ODD subscales. Thus, IN, HI, and ODD subscale scores strongly reflect a general disruptive behavior factor - not the specific content of their respective constructs. PMID- 24795958 TI - Eye movements reveal the dynamic simulation of speed in language. AB - This study investigates how speed of motion is processed in language. In three eye-tracking experiments, participants were presented with visual scenes and spoken sentences describing fast or slow events (e.g., The lion ambled/dashed to the balloon). Results showed that looking time to relevant objects in the visual scene was affected by the speed of verb of the sentence, speaking rate, and configuration of a supporting visual scene. The results provide novel evidence for the mental simulation of speed in language and show that internal dynamic simulations can be played out via eye movements toward a static visual scene. PMID- 24795959 TI - You get what you need: an examination of purpose- based inheritance reasoning in undergraduates, preschoolers, and biological experts. AB - This set of seven experiments examines reasoning about the inheritance and acquisition of physical properties in preschoolers, undergraduates, and biology experts. Participants (N = 390) received adoption vignettes in which a baby animal was born to one parent but raised by a biologically unrelated parent, and they judged whether the offspring would have the same property as the birth or rearing parent. For each vignette, the animal parents had contrasting values on a physical property dimension (e.g., the birth parent had a short tail; the rearing parent had a long tail). Depending on the condition, the distinct properties had distinct functions ("function-predictive") were associated with distinct habitats ("habitat-predictive"), or had no implications ("non-predictive"). Undergraduates' bias to view properties as inherited from the birth parent was reduced in the function- and habitat-predictive conditions. This result indicates a purpose-based view of inheritance, whereby animals can acquire properties that serve a purpose in their environment. This stance was not found in experts or preschoolers. We discuss the results in terms of how undergraduates' purpose based inheritance reasoning develops and relates to larger-scale misconceptions about Darwinian evolutionary processes, and implications for biology education. PMID- 24795960 TI - Tuning the colloidal stability in ionic liquids by controlling the nanoparticles/liquid interface. AB - To shed light on the origin of colloidal stability in ionic liquids,we focus on a model colloidal system (maghemite nanoparticles) in which surface charge and counterion nature can be controlled at will. We thus evidence the crucial role of interfacial features on dispersion quality in a standard ionic liquid, ethylammonium nitrate. PMID- 24795962 TI - Directed colloidal self-assembly in toggled magnetic fields. AB - Suspensions of paramagnetic colloids are driven to phase separate and self assemble by a toggled magnetic field. Initially, all suspensions form network structures that span the sample cell. When the magnetic field is toggled, this network structure coarsens diffusively for a time that scales exponentially with frequency. Beyond this break through time, suspensions cease diffusive coarsening and undergo an apparent instability. The magnetic field drives suspensions to condense into dispersed, domains of bodycentered tetragonal crystals. Within these domains the crystalline order depends on the pulse frequency. Because the scaling of the break through time with respect to frequency is exponential, the steady state limit corresponding to an infinite pulse frequency is kinetically arrested and the equilibrium state is unreachable. These experiments show that there is an out-of-equilibrium pathway that can be used to escape a kinetically arrested state as well as a diverging time scale for phase separation as the critical frequency for condensation is approached. Rather than fine tuning the strength of the interactions among particles, a simple annealing scheme - toggling of the magnetic field - is used to create a broad envelope for assembly of ordered particle structures. PMID- 24795961 TI - A new injectable in situ forming hydroxyapatite and thermosensitive chitosan gel promoted by Na2CO3. AB - A new injectable in situ forming hydroxyapatite and thermosensitive chitosan gel (chitosan/HA/Na2CO3 gel) promoted by Na2CO3 was preliminarily synthesized. This study was the first to use Na2CO3 as coagulant to construct the chitosan thermosensitive gel. The sol-gel phase transition, degradation, and morphology of the gel were examined. We found that chitosan/HA/Na2CO3 sol with 1.4% Na2CO3 has a suitable gelation time (9 min) and degradation rate. SEM images of the dried gel show a porous netlike framework. TEM, EDS, and XRD were combined to confirm the presence of hydroxyapatite. In vitro cell culture was performed by using rat bone mesenchymal stem cells (rBMSCs). rBMSCs survived well on the chitosan gel scaffold that formed in vitro and in vivo, indicating that the chitosan gel was a suitable substrate for the attachment and proliferation of rBMSCs. Subcutaneous implantation of the chitosan gel formed in situ into a nude mouse revealed that the chitosan gel loaded with rBMSCs could lead to angiogenesis. PMID- 24795963 TI - Dynamic interfacial behavior of viscoelastic aqueous hyaluronic acid: effects of molecular weight, concentration and interfacial velocity. AB - An aqueous hyaluronic acid (HA(aq)) pericellular coat, when mediating the tactile aspect of cellular contact inhibition, has three tasks: interface formation, mechanical signal transmission and interface separation. To quantify the interfacial adhesive behavior of HA(aq), we induce simultaneous interface formation and separation between HA(aq) and a model hydrophobic, hysteretic Si SAM surface. While surface tension gamma remains essentially constant, interface formation and separation depend greatly on concentration (5 <= C <= 30 mg mL( 1)), molecular weight (6 <= MW <= 2000 kDa) and interfacial velocity (0 <= V <= 3 mm s(-1)), each of which affect shear elastic and loss moduli G' and G'', respectively. Viscoelasticity dictates the mode of interfacial motion: wetting dewetting, capillary necking, or rolling. Wetting-dewetting is quantified using advancing and receding contact angles theta(A) and theta(R), and the hysteresis between them, yielding data landscapes for each C above the [MW, V] plane. The landscape sizes, shapes, and curvatures disclose the interplay, between surface tension and viscoelasticity, which governs interfacial dynamics. Gel point coordinates modulus G and angular frequency omega appear to predict wetting dewetting (G < 75 omega0.2), capillary necking (75 omega0.2 < G < 200 omega0.075) or rolling (G > 200omega0.075). Dominantly dissipative HA(aq) sticks to itself and distorts irreversibly before separating, while dominantly elastic HA(aq) makes contact and separates with only minor, reversible distortion. We propose the dimensionless number (G'V)/(omega(r)gamma), varying from 10(-5) to 10(3) in this work, as a tool to predict the mode of interface formation-separation by relating interfacial kinetics with bulk viscoelasticity. Cellular contact inhibition may be thus aided or compromised by physiological or interventional shifts in [C, MW, V], and thus in (G'V)/(omega(r)gamma), which affect both mechanotransduction and interfacial dynamics. These observations, understood in terms of physical properties, may be broadened to probe interfacial dynamics of other viscoelastic aqueous biopolymers. PMID- 24795964 TI - Fabrication and photoactivity of a tunable-void SiO2-TiO2 core-shell structure on modified SiO2 nanospheres by grafting an amphiphilic diblock copolymer using ARGET ATRP. AB - SiO2-based composites have important applications in various technological fields. In this work, a tunablevoid SiO2-TiO2 core-shell structure was successfully prepared for the first time using SiO2-polymethyl methacrylate (PMMA)-polyoligo(ethylene glycol)methyl ether methacrylate (PO(EO)nMA) (n = 2, 5, and 8). An amphiphilic copolymer was used as the template, and calcination was performed using tetrabutyl titanate (TBT) as the titanium source. SiO2-PMMA-b PO(EO)nMA microspheres were first synthesized through activators regenerated by electron transfer-atom transfer radical polymerization. Methyl methacrylate and O(EO)nMA were grafted with different EO unit numbers onto the surface of the halogen functional group of SiO2. TBT was hydrolyzed along with the PO(EO)nMA chain through hydrogen bonding, and then the SiO2-TiO2 core-shell structure was acquired through calcination to remove the polymer. Simultaneously, amorphous TiO2 crystallized during calcination. A series of characterizations indicated that the amphiphilic block copolymer was grafted onto SiO2 mesoparticle surfaces, the titania samples existed only in the anatase phase, and the prepared SiO2-TiO2 had hierarchically nanoporous structures. The gradient hydrophilicity of the PMMA b-PO(EO)nMA copolymer template facilitated the hydrolysis of TBT molecules along the PO(EO)nMA to PMMA segments, thereby tuning the space between the core and the shell. In addition, the space was about 6 nm when the EO number was 2, and the space was about 10 nm when the EO numbers were 5 and 8. The photocatalytic activities of the SiO2-TiO2 materials were tested on the photodegradation of methyl orange. PMID- 24795965 TI - Formation of divalent ion mediated anionic disc bicelle-DNA complexes. AB - Disc-shaped bicelles are formed by mixing long-chain lipids with short-chain lipids at suitable molar ratios and they have a relatively uniform size, typically around a few tens of nanometers in diameter. Different from the typically formulated cationic or anionic liposome-DNA complexes, which are used as nonviral vectors for improving the transfection efficiency of gene therapy, a novel way of packing the DNA can be developed by using the much smaller disc-like bicelles. We demonstrate that anionic lipid bicelle-ion-DNA (AB-DNA) complexes can be formed with the help of divalent ions. Multi-stacked AB-DNA complexes can be formed with diameters of around 50-100 nm and lengths of around 50-150 nm as revealed by TEM. Using the anionic lipid-DNA complexes has the advantage of lower cytotoxicity than using cationic lipids. The interaction of DNA with anionic bicelles was investigated by SAXS. It was found that the anionic bicelle could not form stable complexes with DNA at low calcium ion concentrations, such as 1 mM. The AB-DNA complexes can be formed in the investigated range of 10 mM to 100 mM calcium ion concentrations. However, for an equal anionic lipid charge and DNA charge system, an ion-membrane phase (multilamellar vesicles) would gradually appear as the calcium ion concentration is increased above a critical concentration. It indicates that DNA could be packed closer at above the critical divalent ion concentration. If more DNA is added to such a two-phase coexistence system (originally with the total anionic lipid charge equal to that of DNA), the ion-membrane phase could be transformed into the AB-DNA complexes. As a result, more DNA can be packed in the form of AB-DNA complexes at above the critical calcium ion concentration. PMID- 24795966 TI - Flow properties of MK-based geopolymer pastes. A comparative study with standard Portland cement pastes. AB - Geopolymers are presented in many studies as alternatives to ordinary Portland cement. Previous studies have focused on their chemical and mechanical properties, their microstructures and their potential applications, but very few have focussed on their rheological behaviour. Our work highlights the fundamental differences in the flow properties, which exist between geopolymers made from metakaolin and Ordinary Portland Cement (OPC). We show that colloidal interactions between metakaolin particles are negligible and that hydrodynamic effects control the rheological behaviour. Metakaolin-based geopolymers can then be described as Newtonian fluids with the viscosity controlled mainly by the high viscosity of the suspending alkaline silicate solution and not by the contribution of direct contacts between metakaolin grains. This fundamental difference between geopolymers and OPC implies that developments made in cement technology to improve rheological behaviour such as plasticizers will not be efficient for geopolymers and that new research directions need to be explored. PMID- 24795967 TI - Proceedings of the Second IEEE International Conference on Computational Advances in Bio and Medical Sciences (ICCABS 2012): Bioinformatics, February 23-25, 2012, Las Vegas, Nevada. PMID- 24795968 TI - Proceedings of The Second Workshop on Data Mining of Next-Generation Sequencing in conjunction with the 2012 IEEE International Conference on Bioinformatics and Biomedicine, October 4-7, 2012, Philadelphia, PA. PMID- 24795969 TI - Proceedings of IX Nestle Nutrition Conference. Maternal obesity: reproduction, pregnancy, and offspring outcomes, November 8-9, 2012, Mexico City, Mexico. PMID- 24795970 TI - Proceedings of International Consultation on Urologic Diseases: Urethral Strictures, International Consultation on Urethral Strictures, in conjunction with the Societe Internationale d'Urologie (SIU) World Meeting, 13-16 October 2010, Marrakech, Morocco. PMID- 24795971 TI - Abstracts of the XVIII PASPCR 2013: Advances in Melanocyte and Melanoma Biology, September 8-11, 2013, Madison, WI. PMID- 24795972 TI - Abstracts of the 18th Meeting of the European Society for Pigment Cell Research, September 9-12, 2013, Lisbon, Portugal. PMID- 24795973 TI - Special issue in memory of Bob Ham: a pioneer in waste management. PMID- 24795974 TI - Proceedings of an International conference: Modeling & Design of Molecular Materials-MDMM 2012, September 10-14, 2012, Wroclaw, Poland. PMID- 24795975 TI - Abstracts of the German Skin Cancer Congress and ADO annual meeting, September 26 28, 2013, Essen, Germany. PMID- 24795977 TI - Proceedings of the Tenth International Nanomedicine and Drug Delivery Symposium, December 6-7, 2012, Atlantic City, NJ. PMID- 24795976 TI - Proceedings of the ISWA World Solid Waste Congress, October 7-11, 2013, Vienna, Austria. PMID- 24795978 TI - Pairing of cholesterol with oxidized phospholipid species in lipid bilayers. AB - We claim that (1) cholesterol protects bilayers from disruption caused by lipid oxidation by sequestering conical shaped oxidized lipid species such as 1 palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PZPC) away from phospholipid, because cholesterol and the oxidized lipid have complementary shapes and (2) mixtures of cholesterol and oxidized lipids can self-assemble into bilayers much like lysolipid-cholesterol mixtures. The evidence for bilayer protection comes from molecular dynamics (MD) simulations and dynamic light scattering (DLS) measurements. Unimodal size distributions of extruded vesicles (LUVETs) made up of a mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and PZPC containing high amounts of PZPC are only obtained when cholesterol is present in high concentrations. In simulations, bilayers containing high amounts of PZPC become porous, unless cholesterol is also present. The protective effect of cholesterol on oxidized lipids has been observed previously using electron paramagnetic resonance (EPR) and electron microscopy imaging of vesicles. The evidence for the pairing of cholesterol and PZPC comes mainly from correlated 2-D density and thickness plots from simulations, which show that these two molecules co-localize in bilayers. Further evidence that the two molecules can cohabitate comes from self-assembly simulations, where we show that cholesterol-oxidized lipid mixtures can form lamellar phases at specific concentrations, reminiscent of lysolipid-cholesterol mixtures. The additivity of the packing parameters of cholesterol and PZPC explains their cohabitation in a planar bilayer. Oxidized lipids are ubiquitously present in significant amounts in high- and low-density lipoprotein (HDL and LDL) particles, diseased tissues, and in model phospholipid mixtures containing polyunsaturated lipids. Therefore, our hypothesis has important consequences for cellular cholesterol trafficking; diseases related to oxidized lipids, and to biophysical studies of phase behaviour of cholesterol containing phospholipid mixtures. PMID- 24795979 TI - Free energy change for insertion of charged, monolayer-protected nanoparticles into lipid bilayers. AB - Charged, monolayer-protected gold nanoparticles (AuNPs) with core diameters smaller than 10 nm have recently emerged as a prominent class of nanomaterial for use in targeted drug delivery and biosensing. In particular, recent experimental studies showed that AuNPs protected by a binary mixture of purely hydrophobic and anionic, end-functionalized alkanethiol ligands were able to spontaneously penetrate through cell membranes via a non-endocytic, non-disruptive mechanism. The critical step in the penetration process is a fusion step during which the AuNPs insert into the hydrophobic core of the bilayer. This fusion step is driven by hydrophobic forces as inserted AuNPs minimize their exposed hydrophobic surface area and thereby lower their free energy compared to particles in the bulk. Here, we explore the effect of the large parameter space of composition, size, ligand length, morphology, and hydrophobicity strength on the change in the free energy upon insertion. Using a newly developed implicit bilayer, implicit solvent simulation model, our work shows that there is a size cutoff for insertion that has a strong dependence on surface composition and ligand chemistry. Our results agree well with previous experimental findings for a particular value of the hydrophobicity strength. This work provides physical insight that may be used to both understand the insertion of AuNPs into bilayers and guide the design of monolayers to either encourage or inhibit insertion. PMID- 24795980 TI - Gastroesophageal reflux guidelines: the European experience. PMID- 24795981 TI - Lessons from Leon. PMID- 24795982 TI - Noncompliance with NASPGHAN-ESPGHAN practice guidelines for GER in Europe: is there a point? PMID- 24795983 TI - The fast dynamics of cavitation bubbles within water confined in elastic solids. AB - Many applications such as ultrasonic cleaning or sonochemistry use the ability of bubbles to oscillate and drive liquid flow. But bubbles have also received attention in porous media, where drying may cause cavitation, a phenomenon occurring in plant tissues. Here we explore the dynamics of cavitation bubbles when the liquid is fully entrapped in an elastic solid, using light scattering, laser strobe photography and high speed camera recordings. Our experiments show unexpectedly fast bubble oscillations in volume. They depend on the confinement size and elasticity, which we explain with a simple model where liquid compressibility is a key parameter. We also observe rich non-spherical dynamics, with ejection away from the walls and bubble fragmentation, which reveal extreme fluid motion at short timescales. PMID- 24795984 TI - Response. PMID- 24795985 TI - Response. PMID- 24795986 TI - Efficacy and safety of an oral somatostatin DNA vaccine without antibiotic resistance gene in promoting growth of piglets. AB - This study aimed to evaluate the efficacy and safety of an oral DNA vaccine against somatostatin (SS) (pGS/2SS-asd, encoding two copies of somatostatin genes) mediated by attenuated Salmonella choleraesuis C500 without antibiotic resistance gene on piglets growth. A total of 50 piglets were uniformly divided into five groups. The animals in the first three groups were orally given vaccine in dose of either 5 9 1010, 5 9 109 or 5 9 108 colony-forming units (CFU).The remaining two groups were orally administered with either bacteria C500(containing pVAX-asd plasmid without somatostatin gene) or phosphate buffered saline (PBS) as controls. The results indicated that the vaccine induced SS specific antibodies in a dose-dependent pattern. Compared with the PBS control, animals in the high-dose group showed lower SS levels and higher growth hormone (GH) levels in sera. Average daily gain of animals in the high dose group was increased by 32.88% and 26.46% during 4 and 8 weeks,respectively. Anti-SS antibodies were positively correlated with either GH levels or average daily gain at week 8 after primary immunization (P < 0.05). Faecal,soil and water samples originating from immunized piglets and surrounding environment were collected. The target gene (the fusion gene GS/2SS) of C500(pGS/2SS-asd) was not detected by PCR amplification in these samples,indicating that the surrounding environment was not contaminated by residual recombinant bacteria. In conclusion, the vaccine without antibiotic resistance gene is attributable to improve growth performance of piglets through an influence on GH secretion. Moreover, the immunization did not contaminate the surrounding environment of animals. PMID- 24795987 TI - Administration of sulfatide to ameliorate type I diabetes in non-obese diabetic mice. AB - The endogenous glycosphingolipid sulfatide is a ligand for CD1d-restricted type II natural killer T (NKT) lymphocytes. Through the action of these cells,sulfatide treatment has been shown to modulate the immune response in mouse models for autoimmune diseases, infections and tumour immunity. Sulfatide exists naturally in different organs including the pancreas, where sulfatide colocalizes with insulin within the Langerhans islet b-cells, targets for the immune destruction in type 1 diabetes (T1D). Human T1D patients, but not patients with type 2 diabetes nor healthy individuals, have autoantibodies against sulfatide in serum, suggesting that sulfatide induces an immune response in the natural course of T1D in humans. Here, we investigate sulfatide as an autoantigen and a modulator of autoimmune disease in the murine model forT1D, the non-obese diabetic (NOD) mice. We demonstrate that aged NOD mice displayed serum autoantibody reactivity to sulfatide; however, this reactivity did not correlate with onset of T1D. Repeated administration of sulfatide did not result in an increase in serum reactivity to sulfatide. Moreover, a multidose sulfatide treatment of female NOD mice initiated at an early (5 weeks of age),intermediate (8 weeks of age) or late (12 weeks of age) phase of T1D progression did not influence the incidence of disease. Thus, we demonstrate that a fraction of NOD mice develop autoantibody reactivity to sulfatide; however, we fail to demonstrate that sulfatide treatment reduces the incidence of T1D in this mouse strain. PMID- 24795988 TI - Special issues from High 1: KSBMB Winter Workshop. PMID- 24795989 TI - Retraction notice to "PBOX-15 induces apoptosis and improves the efficacy of oxaliplatin in human colorectal cancer cell lines" [Eur. J. Pharmacol. 714(1-3) (2013) 379-387]. PMID- 24795990 TI - Management of traumatic digital amputations. PMID- 24795991 TI - Guide to the slit lamp. PMID- 24795992 TI - Calcium pyrophosphate deposition. PMID- 24795993 TI - In memoriam: Janet D. Rowley, MD (April 5, 1925-December 17, 2013). PMID- 24795994 TI - Protective role of edaravone against neomycin-induced ototoxicity in zebrafish. AB - Aminoglycosides such as neomycin are one of the most commonly prescribed types of antibiotics worldwide. However, these drugs appear to generate free radicals within the inner ear, which can result in permanent hearing loss. We evaluated the effects of edaravone, a neuroprotective agent, on neomycin-induced ototoxicity in transgenic zebrafish. The 5-day post fertilization (dpf) zebrafish larvae were exposed to 125 MUM neomycin and various concentrations of edaravone for 1 h. Hair cell survival was calculated as average numbers of the hair cells in the control group, which was not exposed to neomycin. Ultrastructural changes were evaluated using a scanning electron microscope (SEM) and transmission electron microscope (TEM). Edaravone protected against neomycin-induced hair cell loss in the neuromasts (1000 MUM: 11.6 +/- 1.1 cells, neomycin only: 5.5 +/- 0.5 cells; n = 10, P<0.05) and decreased the TUNEL reaction for detecting apoptosis. In ultrastructural analysis, structures of mitochondria and hair cells within neuromasts were preserved in zebrafish exposed to 125 MUM neomycin and 1000 MUM edaravone for 1 h. Edaravone protected against neomycin-induced hair cell loss by preventing apoptosis. PMID- 24795995 TI - Gene flow and the maintenance of species boundaries. AB - Hybrid zones are regions where individuals from genetically differentiated populations meet and mate, resulting in at least some offspring of mixed ancestry. Patterns of gene flow (introgression) in hybrid zones vary across the genome, allowing assessment of the role of individual genes or genome regions in reproductive isolation. Here, we document patterns of introgression between two recently diverged species of field crickets. We sampled at a very fine spatial scale and genotyped crickets for 110 highly differentiated single nucleotide polymorphisms (SNPs) identified through transcriptome scans. Using both genomic and geographic cline analysis, we document remarkably abrupt transitions (<100 m) in allele frequencies for 50 loci, despite high levels of gene flow at other loci. These are among the steepest clines documented for any hybridizing taxa. Furthermore, the cricket hybrid zone provides one of the clearest examples of the semi-permeability of species boundaries. Comparisons between data from the fine scale transect and data (for the same set of markers) from sampling a much larger area in a different region of the cricket hybrid zone reveal consistent patterns of introgression for individual loci. The consistency in patterns of introgression between these two distant and distinct regions of the hybrid zone suggests that strong selection is acting to maintain abrupt discontinuities within the hybrid zone and that genomic regions with restricted introgression likely include genes that contribute to nonecological prezygotic barriers. PMID- 24795996 TI - Ancient mitochondrial DNA and the genetic history of Eurasian beaver (Castor fiber) in Europe. AB - After centuries of human hunting, the Eurasian beaver Castor fiber had disappeared from most of its original range by the end of the 19th century. The surviving relict populations are characterized by both low genetic diversity and strong phylogeographical structure. However, it remains unclear whether these attributes are the result of a human-induced, late Holocene bottleneck or already existed prior to this reduction in range. To investigate genetic diversity in Eurasian beaver populations during the Holocene, we obtained mitochondrial control region DNA sequences from 48 ancient beaver samples and added 152 modern sequences from GenBank. Phylogeographical analyses of the data indicate a differentiation of European beaver populations into three mitochondrial clades. The two main clades occur in western and eastern Europe, respectively, with an early Holocene contact zone in eastern Europe near a present-day contact zone. A divergent and previously unknown clade of beavers from the Danube Basin survived until at least 6000 years ago, but went extinct during the transition to modern times. Finally, we identify a recent decline in effective population size of Eurasian beavers, with a stronger bottleneck signal in the western than in the eastern clade. Our results suggest that the low genetic diversity and the strong phylogeographical structure in recent beavers are artefacts of human hunting associated population reductions. While beaver populations have been growing rapidly since the late 19th century, genetic diversity within modern beaver populations remains considerably reduced compared to what was present prior to the period of human hunting and habitat reduction. PMID- 24795997 TI - Neutral and selective processes shape MHC gene diversity and expression in stocked brook charr populations (Salvelinus fontinalis). AB - The capacity of an individual to battle infection is an important fitness determinant in wild vertebrate populations. The major histocompatibility complex (MHC) genes are crucial for a host's adaptive immune system to detect pathogens. However, anthropogenic activities may disrupt natural cycles of co-evolution between hosts and pathogens. In this study, we investigated the dynamic sequence and expression variation of host parasite interactions in brook charr (Salvelinus fontinalis) in a context of past human disturbance via population supplementation from domestic individuals. To do so, we developed a new method to examine selection shaping MHC diversity within and between populations and found a complex interplay between neutral and selective processes that varied between lakes that were investigated. We provided evidence for a lower introgression rate of domestic alleles and found that parasite infection increased with domestic genomic background of individuals. We also documented an association between individual MHC alleles and parasite taxa. Finally, longer cis-regulatory minisatellites were positively correlated with MHC II down-regulation and domestic admixture, suggesting that inadvertent selection during domestication resulted in a lower immune response capacity, through a trade-off between growth and immunity, which explained the negative selection of domestic alleles at least under certain circumstances. PMID- 24795998 TI - Resequencing studies of nonmodel organisms using closely related reference genomes: optimal experimental designs and bioinformatics approaches for population genomics. AB - Decreasing costs of next-generation sequencing (NGS) experiments have made a wide range of genomic questions open for study with nonmodel organisms. However, experimental designs and analysis of NGS data from less well-known species are challenging because of the lack of genomic resources. In this work, we investigate the performance of alternative experimental designs and bioinformatics approaches in estimating variability and neutrality tests based on the site-frequency-spectrum (SFS) from individual resequencing data. We pay particular attention to challenges faced in the study of nonmodel organisms, in particular the absence of a species-specific reference genome, although phylogenetically close genomes are assumed to be available. We compare the performance of three alternative bioinformatics approaches - genotype calling, genotype-haplotype calling and direct estimation without calling genotypes. We find that relying on genotype calls provides biased estimates of population genetic statistics at low to moderate read depth (2-8X). Genotype-haplotype calling returns more accurate estimates irrespective of the divergence to the reference genome, but requires moderate depth (8-20X). Direct estimation without calling genotypes returns the most accurate estimates of variability and of most SFS tests investigated, including at low read depth (2-4X). Studies without species-specific reference genome should thus aim for low read depth and avoid genotype calling whenever individual genotypes are not essential. Otherwise, aiming for moderate to high depth at the expense of number of individuals, and using genotype-haplotype calling, is recommended. PMID- 24795999 TI - Recruitment of fat cell precursors during high fat diet in C57BL/6J mice is fat depot specific. AB - OBJECTIVE: The study aims to explore long-term dietary effects on increases in body mass and fat depot enlargement through the recruitment of early in life labeled progenitor cells to the adipolineage. METHODS: Neonate male C57BL/6J (B6) mice were injected intraperitoneally with BrdU. From 4 until 30 weeks of age they were fed either low fat diet (LFD) or high fat diet (HFD). BrdU-labeled cells were analyzed by flow cytometric and immunohistochemical assays after 10 days and 4, 8, 16, and 30 weeks. RESULTS: Mice fed HFD were heavier than mice fed LFD with the most dramatic disparity recorded between week 16 and 30. BrdU-bearing cells showed the decrease in the percentage content of labeled cells in inguinal (iWAT), epididymal (eWAT) and bone marrow (BM) tissues, regardless diets. However, iWAT collected from animals on HFD showed significant increase in labeled-cells at week 16th, which coincides with robust increase in inguinal but not epididymal fat weight between 16 and 30 weeks age. CONCLUSIONS: Cells labeled with BrdU during neonate life of B6 mice persist in fat tissues for long period of time and are recruited to the adipocyte lineage in a favorable (obesogenic) environment in iWAT but not in eWAT. PMID- 24796000 TI - Is overweight and class I obesity associated with increased health claims costs? AB - OBJECTIVES: Evaluate the relationship between body mass index (BMI) and health claims costs over the last decade, assess the strength and nature of the relationship between BMI and costs, and identify comorbidities that may drive any increased costs. METHODS: Using 2001-2011 claims data for employees participating in annual health appraisals, annual paid claims costs were calculated. One-part negative binomial models were fit to evaluate the relationship between BMI and costs, controlling for age, gender, race/ethnicity, and calendar year period. RESULTS: The relationship between increasing BMI and increasing health claims costs is gradual and starts already at a BMI of 19. The nature of the relationship did not change notably over time. The most important obesity-related comorbidities, expressed as percent increase in cost per BMI unit, was cardiovascular disease (males 10.53, 95% CI [6.46, 14.77], females 4.27, 95% CI [1.25, 7.38), while cardiovascular agents (7.23, 95% CI [6.08, 8.39]) were the most important driver of pharmacy costs. CONCLUSION: In contrast to recent evidence relating to effects on mortality, we observed a gradual increase in health claims costs starting at the low end of the recommended BMI range. PMID- 24796001 TI - To the Editor. PMID- 24796002 TI - Reply: To PMID 23584702. PMID- 24796003 TI - To the Editor. PMID- 24796004 TI - Reply: To PMID 23591531. PMID- 24796005 TI - To the Editor. PMID- 24796006 TI - Reply: To PMID 23609121. PMID- 24796008 TI - What will happen to Medicare? PMID- 24796009 TI - QNU meets with health minister on midwifery-led models. PMID- 24796007 TI - Complement receptors C5aR and C5L2 are associated with metabolic profile, sex hormones, and liver enzymes in obese women pre- and postbariatric surgery. AB - OBJECTIVE: Obesity is associated with metabolic dysfunction with sex differences and chronic, low-grade inflammation.We proposed that hepatic expression of immune complement C3 related receptors (C3aR, C5aR, and C5L2) would be associated with pre- or postmenopausal status and metabolic profile in severely obese women. We hypothesized that C5L2/C5aR ratio, potentially influencing the ASP/C5L2 metabolic versus C5a/C5aR immune response, would predict metabolic profiles after weight loss surgery. MATERIALS AND METHODS: Fasting plasma (hormone, lipid, and enzyme analysis) and liver biopsies (RT-PCR gene expression) were obtained from 91 women during surgery. RESULTS: Hepatic C5L2 mRNA expression was elevated in pre- versus postmenopausal women (P < 0.01) and correlated positively with circulating estradiol, estrone, ApoB, ApoA1, ApoA1/B, waist circumference, age, and LDL-C (all P < 0.05).While plasma ASP was lower in pre- versus postmenopausal women (P < 0.01), the hepatic C5L2/C5aR mRNA ratio was increased (P < 0.001) and correlated positively with estrone (P < 0.01) and estradiol (P < 0.001) and negatively with circulating ApoB and liver enzymes ALT, AST, and GGT (all P < 0.05). Over 12 months postoperatively, liver enzymes in low C5L2/C5aR mRNA ratio group remained higher (ALP and ALT, P < 0.05, AST and GGT, P < 0.001 2-way ANOVA). CONCLUSION: C5L2-C5aR association with other mediators including estrogens may contribute to hepatic metabolic and inflammatory function. PMID- 24796011 TI - State government proposes to reduce safety standards. PMID- 24796010 TI - 'Award modernisation'--just another club to whack nurses and midwives. PMID- 24796012 TI - What your employer must provide if you are impaired. PMID- 24796013 TI - When it comes to healthcare quality, should titles matter? PMID- 24796014 TI - Public quality reporting: a plea for consistency. PMID- 24796015 TI - Why QI plus IP is more than alphabet soup. PMID- 24796016 TI - Only a 50% adherence rate to infection control in ICUs. PMID- 24796017 TI - Patient education: Orphan trains and the best interest of the child. PMID- 24796018 TI - An ambulance-safety how-to. Federal partners plan guidebook, demo truck to share best ideas. PMID- 24796019 TI - [Genitourinary tumor]. PMID- 24796020 TI - [ I.Renal cell carcinoma]. PMID- 24796021 TI - [II. Urothelial carcinoma-current topics and treatment for non-muscle invasive bladder cancer-]. PMID- 24796022 TI - [III. Prostate cancer]. PMID- 24796023 TI - [IV. Testis cancer]. PMID- 24796024 TI - [Bacterimia due to Rhodotorula mucilaginosa related catheters]. PMID- 24796025 TI - [Lewy body dementia]. PMID- 24796026 TI - [Regulation of ribosome function and disease]. PMID- 24796027 TI - The editor's offering. PMID- 24796028 TI - The Rubicon Foundation. PMID- 24796029 TI - To the Editor. PMID- 24796030 TI - Author reply: To PMID 24371331. PMID- 24796031 TI - Current world literature. Immunosuppression. PMID- 24796032 TI - Current world literature. Cellular transplantation. PMID- 24796033 TI - Philip John Rushmer: West Auckland GP leaves fitting legacy for patients. PMID- 24796034 TI - The uptake of particulate matter by endothelial cells. PMID- 24796035 TI - Prenatal and postnatal growth and development of the central nervous system of the pig. PMID- 24796036 TI - The effect of undernutrition on the postnatal development of the brain and cord in pigs. PMID- 24796037 TI - Variation in the long-tailed field-mouse (Apodemus sylvaticus (L>)) in the Channel Islands. PMID- 24796038 TI - Hypothalamic pathways for independent release of vasopressin and oxytocin. PMID- 24796040 TI - The dynamics of burrowing in Ensis (Bibalvia). PMID- 24796039 TI - The release of vasopressin without oxytocin in response to haemorrhage. PMID- 24796041 TI - [Cognitive impairment in earthquake brain injury treated with comprehensive program of acupuncture and rehabilitation: a randomized controlled trial]. AB - OBJECTIVE: To explore the comprehensive program of integrated Chinese and western medicine in the treatment of cognitive impairment in earthquake brain injury. METHODS: The multi-central randomized controlled trial was adopted. The qualified subjects were randomized into an acupuncture + rehabilitation group (38 cases) and a rehabilitation group (35 cases). In the acupuncture + rehabilitation group, acupuncture, hyperbaric oxygen (HBO) and cognitive rehabilitation training were combined as the comprehensive program of integrated Chinese and western medicine in the treatment. In the rehabilitation group, HBO and cognitive rehabilitation training were adopted. The efficacy and safety were assessed. RESULTS: (1) After treatment of 2 months, the intelligent state, cognitive function and activity of daily life of patients were improved in the both groups (all P < 0.01). (2) After treatment of 2 months, the score of MMSE and the score of activity of daily life were (24.11 +/- 4.08) and (75.45 +/- 13.95) in the acupuncture + rehabilitation group, which were more significant as compared with (17.05 +/- 43.84), (66.06 +/- 12.75) in the rehabilitation group, respectively (both P < 0.01). In 6-month follow-up visit after treatment, the cognitive function and activity of daily life were improved continuously in the acupuncture + rehabilitation group, which was more significant as compared with the rehabilitation group (P < 0.01, P < 0.05). CONCLUSION: The integrated Chinese and western medicine of acupuncture, HBO and cognitive rehabilitation training is safe and effective in the treatment of cognitive impairment in earthquake brain injury. The therapeutic effect is more advantageous as compared with the simple rehabilitation program of western medicine. PMID- 24796042 TI - [Allergic rhinitis treated with acupuncture and the triple-strong stimulation therapy at dazhui (GV 14): a randomized controlled trial]. AB - OBJECTIVE: To evaluate the impacts on the short-term efficacy and the long-term prevention of recurrence of allergic rhinitis treated with the triple-strong stimulation at Dazhui (GV 14) so as to provide the convenient and long-term effective therapy of acupuncture and moxibustion for allergic rhinitis. METHODS: One hundred and twenty cases of allergic rhinitis were randomized into an acupuncture group, an acupuncture + medication group and a triple-strong stimulation group, 40 cases in each one. In the acupuncture group, acupuncture was applied at Dazhui (GV 14), Fengchi (GB 20), Baihui (GV 20), Yintang (GV 29) and the others, stimulating with reinforcing manipulation for the deficiency and reducing manipulation for the excess, once every day. In the acupuncture + medication group, on the basis of acupuncture therapy, claritin (loratadine tablets) was supplemented for oral administration, 10 mg, once every two days, continuously for 30 days. In the triple-strong stimulation group, on the basis of acupuncture therapy, the strong needling, strong cupping and strong moxibustion were applied at Dazhui (GV 14). This combined therapy was given once every day in the first 3 days and once every two days afterwards. The 10 day treatment made one session, at the interval of 3 days between the sessions and totally 3 sessions were required in the three groups. Separately, before treatment, after treatment and in 6 months after treatment, the changes of symptom and physical sign score and value of single item symptom including nasal itching, nasal blockage, sneezing and rhinorrhea were observed in the patients of the three groups. And the long-term clinical efficacy was compared among the three groups. RESULTS: The symptom and physical sign score and the value of single item symptom were all reduced in the three groups after treatment and in 6 months after treatment (P < 0.001, P < 0.01, P < 0.05). The results in the triple-strong stimulation group were superior to the other two groups (all P < 0.05). In the triple-strong stimulation group, the total effective rate was 92.5% (36/40) in the follow-up of 6 months after treatment, which was better than 60.5% (23/38) in the acupuncture group and 69.2% (27/39) in the acupuncture + medication group (both P < 0.01). CONCLUSION: The combined therapy of acupuncture and the triple strong stimulation at Dazhui (GV 14) achieves the reliable and effective result in the clinical treatment of allergic rhinitis and displays the good role on the prevention from long-term recurrence. PMID- 24796043 TI - [Primary dysmenorrhea treated with staging acupoint catgut embedment therapy: a randomized controlled trial]. AB - OBJECTIVE: To observe the short-term and long-term efficacies on primary dysmenorrhea treated with staging acupoint embedment therapy. METHODS: Seventy cases of primary dysmenorrhea were randomized into an embedment therapy group and a fenbid group, 35 cases in each one. In the embedment therapy group, the embedment therapy was applied twice during the menstrual cycle, one treatment 3 days before menstruation and one treatment during the 12th-14th days of menstruation, respectively. Guanyuan (CV 4), Zigong (EX-CA 1), Diji (SP 8) and Ciliao (BL 32) were the main acupoints in the treatment 3 days before menstruation. Shenshu (BL 23), Ganshu (BL 18) and Pishu (BL 20) were the main acupoints in the treatment during menstruation. In the fenbid group, fenbid was prescribed for oral administration, 0.3 g each time, twice a day, starting 3 days before menstruation till pain was relieved. The treatment of one menstrual cycle was one session. The continuous treatment of 3 menstrual cycles was required. The short-term and long-term efficacies were evaluated at the end of the 3rd cycle and in 3 months after the treatment terminal. The dysmenorrhea score was used to evaluate the efficacy. Visual analogue scale (VAS) and SF-36 were for the assessment of pain degree and life quality. RESULTS: (1) The total effective rate was 91.4% (32/35) in the embedment therapy group after the 3 menstrual cycles, which was better than 74.3% (26/35) in the fenbid group (P < 0.01). In the follow up stage, the total effective rate was 91.4% (32/35) in the embedment therapy group, which was better than 40.0% (14/35) in the fenbid group (P < 0.01). (2) The differences were not significant in dysmenorrhea score and VAS score after the 1st and 2nd menstrual cycle treatments between the two groups (all P > 0.05). In the 3rd menstrual cycle and the follow-up stage, the dysmenorrhea score and VAS score were reduced obviously in the embedment therapy group as compared with those in the fenbid group (P < 0.05, P < 0.01). The rebound effect occurred in the follow-up stage in the fenbid group. (3) In the 3rd menstrual cycle and the follow-up stage, the improvement in the total score of life quality of the embedment therapy group was superior apparently to the fenbid group (P < 0.05, P < 0. 01). CONCLUSION: The staging acupoint embedment therapy achieves the superior short-term and long-term efficacies as compared with the oral administration of fenbid in the treatment of primary dysmenorrhea. As the symptoms of dysmenorrhea and pain are relieved, the life quality is improved. PMID- 24796044 TI - [Effects of jingjin acupuncture on fine activity of hemiplegic hand in recovery period of stroke]. AB - OBJECTIVE: To observe improved effects of Jingjin acupuncture on fine activity of hemiplegic hand in recovery period of stroke. METHODS: Fifty cases were randomly divided into an observation group and a control group, 25 cases in each one. Regular western medicine treatment, rehabilitation training and regular acupuncture (in which Shuigou (GV 26), Baihui (GV 20), Neiguan (PC 6), etc. were selected) were applied in both groups. Additionally, muscles in palm side of affected hand, dorsal metacarpophalangeal joints and proximal interphalangeal joints were treated with acupuncture in the observation group, once every other day and electroacupuncture was applied when arrival of qi was acquired. Baxie (EX UE 9) in the affected hand were needled in the control group, and electroacupuncture was added when arrival of qi was acquired. Ten days of treatment was considered a treatment course, and after two courses Lindmark score, Brunnstrom movement function grade, joint range of hand and Barthel index (BI) were observed in two groups. RESULTS: Compared before the treatment, the Lindmark score in two groups were both improved after the treatment (both P < 0.01). Compared with the control group, the motor coordination ability, sensory function and total score of Lindmark in observation group were obviously improved (differences before and after treatment: 8.24 +/- 3.07 vs 6.84 +/- 2.43, 3.52 +/- 2.33 vs 2.16 +/- 2.12, 11.76 +/- 3.55 vs 9.00 +/- 3.62, all P < 0.05). The Brunnstrom movement function grade was significantly improved in both groups after treatment (both P < 0.01), which was more obvious in the observation group (P < 0.05). The joint range of hemiplegic hand was improved in both groups after treatment (both P < 0.01), which was more obvious in the observation group [differences before and after treatment: (25.35 +/- 10.91) degrees vs (18.65 +/- 7.86) degrees, p < 0.05]. The score of BI was also significantly improved after treatment in two groups (both P < 0.01). CONCLUSION: The Jingjin acupuncture could effectively improve fine activity of hemiplegic hand in recovery period of stroke prove daily life ability. PMID- 24796045 TI - [Effects of syndrome-differentiation acupuncture on life quality in patients with functional dyspepsia]. AB - OBJECTIVE: To observe effects of syndrome-differentiation acupuncture on life quality in patients with functional dyspepsia (FD) in order to evaluate its clinical efficacy. METHODS: One hundred and five cases of FD were randomly divided into a syndrome-differentiation acupuncture group, a regular acupuncture group and a non-acupoint group, 35 cases in each one. Zhongwan (CV 12), Tianshu (ST 25), Zusanli (ST 36) were selected as main acupoints in the syndrome differentiation acupuncture group. After syndrome differentiation, Danzhong (CV 17) and Zhangmen (LR 13) were added for those with stagnation of liver qi; Pishu (BL 20) and Weishu (BL 21) were added for those with deficiency of spleen-stomach qi; Qimen (LR 14) and Taichong (LR 3) were added for liver-qi invading stomach and Yinlingquan (SP 9) and Neiting (ST 44) were added for dampness-heat blocking stomach. The selection of acupoints in the regular acupuncture group was the same as main acupoints in the syndrome-differentiation acupuncture group. The points 10 mm lateral to the main acupoints were selected in the non-acupoint group. The treatment was given once a day, six days as a treatment course and totally two courses were required. The symptom total score, health-related quality of life survey (SF-36) and Nepean dyspepsia index (NDI) were evaluated before and after the treatment as well as one month after the treatment (follow-up visit), respectively. The efficacy was also assessed. RESULTS: After the treatment, the total effective rate was 87.5% (28/32) in the syndrome-differentiation acupuncture group, which was superior to 74.2% (23/31) in the regular acupuncture group and 20.7% (6/29) in the non-acupoint group (P < 0.05, P < 0.01). Compared before the treatment, the SF-36, NDI and symptom total score after the treatment and in the follow-up visit were all obviously improved in the syndrome differentiation acupuncture group and regular acupuncture group (all P < 0.05), which was the most obvious in the syndrome-differentiation acupuncture group [after the treatment, SF-36: 84.54 +/- 5.93 vs 81.44 +/- 6.22, 63.46 +/- 6.59; NDSI: 18.94 +/- 9.30 vs 21.23 +/- 8.39, 43.93 +/- 11.26; NDLQI: 71.42 +/- 7.23 vs 63.11 +/- 7.06, 54.87 +/- 6.00; symptom total score: 22.06 +/- 15.80 vs 32.52 +/- 16.88, 47.97 +/- 10.92]; the improvement in the regular acupuncture group was more obvious than that in the non-acupoint group (P < 0.01, P < 0.05). Compared before the treatment, only NDSI score was improved in the non-acupoint group after the treatment (P < 0.05). CONCLUSION: The syndrome-differentiation acupuncture could obviously improve patient's life quality in the treatment of FD, which is an effective therapy for FD. PMID- 24796046 TI - [Effects of warm needling combined with zhangmo decoction on endometrial receptivity in patient with ovulation induction]. AB - OBJECTIVE: To explore the effects of warm needling combined with Zhangmo decoction (see text) on endometrial receptivity in patients with clomiphene (CC) induced ovulation. METHODS: One hundred and sixty cases were randomly divided into a CC group (group A), a CC+ progynova group (group B), a CC+ Zhangmo decoction group (group C) and a CC+ Zhangmo decoction + warm needling group (group D), 40 cases in each one. In the Group A, CC alone was applied. In the group B, progynova was jointly used on the 8th day of menstrual cycle. In the Group C, Zhangmo decoction was jointly used on the 5th day of menstrual cycle. In the group D, based on treatment of the Zhangmo decoction, warm needling was applied at Guanyuan (CV 4), Zhongji (CV 3) and Zigong (EX-CA 1) etc. The endometrial thickness and type, pulsatility index (PI), resistance index (RI), ratio of S/D on day of human chorionic gonadotropin (HCG) and pregnancy rate were observed in fou groups. RESULTS: The PI, RI and S/D in the group C and D were obviously lower than those in group A and B (all P < 0.01). The endometrial thickness was (7.7 +/- 1.49) mm in group B, (8.2 +/- 1.54) mm in group C and (8.9 +/- 1.51) mm in group D, which were significantly different from (6.4 5 +/- 1.26) mm in the group A (all P < 0.01) also there was a significant difference between group C and D (P < 0.05). The rate of endometrial type A was 65.0% in the group D, which was significantly higer than 27.5% in the group A, 32.5% in the group B and 35.0% in the group C (all P < 0.01). The pregnancy rate was 30.0% in the group D, which was obviously higher than 12.5% in the group A, 15.0% in the group B and 17.5% in the group C (P < 0.05). The endometrial thickness and rate of endometrial type A in the pregnant were obviously higher than those in the non pregnant (both P < 0.01) while PI, RI and S/D was lower than those in the non pregnant (P < 0.01, P < 0.05). CONCLUSION: Warm needing combined with Zhangmo decoction could improve endometrial thickness, morphology and uterine spiral artery to improve pregnancy rate, which has superior effect to clomiphene, clomiphene combined with progynova and clomiphene combined with Zhangmo decoction. PMID- 24796047 TI - [Effects and efficacy observation of acupuncture on serum 5-HT in patients with diarrhea-predominant irritable bowel syndrome]. AB - OBJECTIVE: To evaluate the clinical efficacy of acupuncture for treatment of diarrhea-predominant irritable bowel syndrome and discuss its action mechanism. METHODS: Fifty-seven cases were randomly divided into two groups. The acupuncture group (29 cases) was treated with acupuncture at Taichong (LR 3), Zusanli (ST 36) and Sanyinjiao (SP 6) etc., once a day and 5 times per week. The medication group (28 cases) was treated with oral administration of pinaverium (50 mg each time, 3 times a day) and live combined bifidobacterium and lactobacillus tablet (4 tablets each time, 3 times a day). Four weeks were taken as a treatment course in both groups. Before and after treatment ELISA method was applied to measure the level of serum 5-HT of the patients in two groups. The scores of clinical symptoms were observed before treatment, after one and four weeks of treatment and 3 months after treatment, respectively. RESULTS: The level of serum 5-HT was significantly reduced in the acupuncture group and medication group (P < 0.01, P < 0.05), which had no statistical difference between two groups (P > 0.05). Compared with the medication group, the scores of clinical symptoms were obviously improved in the acupuncture group after one and four weeks of treatment and 3 months after treatment (P < 0.01, P < 0.05). The total effective rate was 89.66% (26/29) in the acupuncture group, which was superior to 67.85% (19/28) in the medication group (P < 0.05). CONCLUSION: The efficacy of acupuncture is superior to that of medicine in the treatment of diarrhea-predominant irritable bowel syndrome. The acupuncture treatment could reduce the visceral sensitivity, improve the intestinal motility and regulate the imbalance of brain-intestine interactive function. PMID- 24796048 TI - [Efficacy observation on the combination of acupuncture and Chinese medication in prevention of the recurrence of endometriosis after laparoscopic surgery]. AB - OBJECTIVE: To evaluate the efficacy and safety of acupuncture-moxibustion combined with modified Mojie tablet (see text) in the prevention of the recurrence of endometriosis (EMS) after laparoscopic surgery. METHODS: After laparoscopic surgery, 120 cases of EMS were randomized into an acupuncture moxibustion group, a western medication group, a Chinese medication group and a combined therapy of acupuncture-moxibustion and Chinese medication group (combined therapy group), 30 cases in each one. In the acupuncture-moxibustion group, acupuncture was applied at Xuehai (SP 10), Sanyinjiao (SP 6) and Guanyuan (CV 4); the isolated moxibustion with ginger was used at Guanyuan (CV 4), once a day, twice a week. In the western medication group, gestrinone was prescribed for oral administration, 2.5 mg, once a day, twice a week. In the Chinese medication group, the self-prepared Mojie tablet were prescribed for oral administration. In the combined therapy group, acupuncture, moxibustion and modified Mojie tablet for oral administration were used in combination. The therapeutic methods were same as the acupuncture-moxibustion group and the Chinese medication group. Totally, the treatment of 3 months was required. Separately, before treatment, after treatment, in 3 months after treatment and in 6 months after treatment, EHP 5 score (endometriosis health profile-5), the abdominal/vaginal ultrasound examination, serum CA125 detection and safety index (ALT detection) were compared in patients among 4 groups. RESULTS: In 3 and 6 months after treatment, the positive rates of EHP-5 score were 0% (0/30) in the combined therapy group and 0% (0/30) in the acupuncture-moxibuston group, which were all lower significantly than 13.3% (4/30) in the western medication group (both P < 0.05). In follow-up stage of 6 months after treatment, there was no recurrence case in abdominal lviginal ultrasound examination in the combined therapy group, which was lower than 13.3% (4/30) in the western medication group (P < 0.05); the serum CA125 detection in the combined therapy group did not find any abnormal case, which was lower than 16.7% (5/30) in the western medication group (P < 0.05). At the end of treatment session and in the follow-up stage of 3 months after treatment, the abnormal rate of ALT were 20.0% (6/30) and 13.3% (4/30) in the western medication group, which were higher than those in any of the rest groups (P < 0.05). In the follow-up stage of 6 months after treatment, there were 3 abnormal cases of ALT in the western medication group, but which was not different significantly as compared with the rest groups (P > 0.05). CONCLUSION: Acupuncture and moxibustion combined with modified Mojie tablet effectively prevent from the recurrence of EMS after laparoscopic surgery and improve the life quality of the patients. This combined therapy brings less damage on the liver as compared with the western medication of gestrinone and indicates its definite efficacy and safety. PMID- 24796049 TI - [Research on correlation between lung and large intestine based on meridian and acupoint palpation in patients with bronchial asthma]. AB - OBJECTIVE: To explore correlation between lung and large intestine and the two meridians under pathological condition in the view of meridian theory. METHODS: Ninety-six cases of bronchial asthma were applied palpation at the running course of 12 regular meridians under the elbow and knees and back-shu points. And abnormal reactions were recorded, the affected meridians and back-shu points were discovered. RESULTS: The abnormal reactions most frequently appeared on the Lung Meridian, followed by the Large Intestine Meridian, the Spleen Meridian, the Liver Meridian, the Stomach Meridian and the Triple Energizer Meridian. And the unusual reaction of the back-shu points most frequently appeared on Feishu (BL 13), and Dachangshu (BL 25) and Pishu (BL 21) followed as the next two. CONCLUSION: The existence of correlation between the Lung Meridian and the Large Intestine Meridians under pathological condition can be proved through meridian and acupoint palpation on bronchial asthma patients. PMID- 24796050 TI - [Effect of different acupoint prescriptions on prevention and treatment of stress gastric ulcer]. AB - OBJECTIVE: To investigate the effects of different acupoint combination on prevention and treatment of stress gastric ulcer and to search for a better acupoint combination. METHODS: The theoretical basis and experimental research on treatment of stomach diseases with the combination of he-(sea) points and front mu points as well as back-shu points and front-mu points are analyzed in this article. RESULTS: The combination of he-sea points and front-mu points is suitable to be applied on acute diseases, febrile diseases and diseases of fu organs. While the combination of back-shu points and front-mu points is more applicable on chronic gastric diseases. CONCLUSION: It is proved that the combination of he-sea point (Zusanli ST 36) and front-mu point (Zhongwan CV 12) has reliable effect on prevention and treatment of stress gastric ulcer. PMID- 24796051 TI - [Effect on surface electromyography of deltoid in periarthritis patients under acupuncture stimulation]. AB - OBJECTIVE: To explore the objective evaluation index of acupuncture effect through study on the differences of surface electromyography of deltoid before and after acupuncture at some specific points. METHODS: Twenty-six cases of periarthritis were treated with acupuncture at Jianyu (LI 15), Jianqian (Extra), Jianliao (TE 14) and Binao (LI 14). The treatment was given once every other day, six treatments were required. The deltoid myoelectricity indices were collected and analyzed before treatment, after treatment and after 5 s manipulations at each acupoint. RESULTS: Compared with the deltoid myoelectricity before treatment, there were statistically significant differences in the 2nd, 3rd and 5th manipulations during the acupuncture stimulation at Jianqian (Extra), the 2nd, 3rd and 6th manipulations at Binao ( LI 14) (all P < 0.05) and all the 6 manipulations at Jianyu (LI 15) (all P < 0.05). However, there was no statistically significant difference in all the 6 manipulations at Jianliao (TE 14) (all P > 0.05). And the differences of deltoid surface myoelectricity before and after the 6 acupuncture treatments were all with statistic significance (all P < 0.05). CONCLUSION: A certain therapeutic effect can be found in treatment of periarthritis with acupuncture. And the effect at Jianyu (LI 15) is proved to be the most obvious. Jianqian (Extra) and Binao (LI 14) are considered as the second obvious. While no significant effect can be found at Jianliao (TE 14). PMID- 24796052 TI - [Nineteen cases of panic disorder treated with muscular needling tech nique at Neiguan (PC 6)]. PMID- 24796053 TI - [Protective mechanism of acupuncture-moxibustion on hippocampal neuron mitochondria in rats with Alzheimer's disease]. AB - OBJECTIVE: To observe effects of acupuncture and moxibustion on ultrastructure and silent information regulator 1 (SIR1) in hippocampal neuron mitochondria in rats with Alzheimer's disease (AD) in order to explore its possible effective mechanism during the process of protecting mitochondria. METHODS: Eighty Wistar rats were randomly divided into a normal group, a sham operation group, a model group and an acupuncture group, 20 rats in each one. The AD model was established in the model group and acupuncture group with injection of Amyloid beta Protein Fragment1-14 (Abeta1-42) into the hippocampus. Acupuncture and moxibustion was applied at "Baihui" (GV 20) and "Shenshu" (BL 23) in the acupuncture group, once a day, seven days as a treatment course and totally two course were required. The rest groups were all fed with normal diet, without any treatment. The transmission electron microscopy, immunohistochemistry and immunoblotting technique were respectively adapted to measure ultrastructure and level of STR1 in hippocampal neuron mitochondria in AD rats. RESULTS: Compared with the model group, the ultrastructure in hippocampal neuron mitochondria in the acupuncture group was effectively improved. The average optical density of SIR1 in hippocampus was 0.21 +/- 0.10 and the gray value was 136.82 +/- 47.42 in the model group, which were obviously lower than 0.47 +/- 0.09 and 281.44 +/- 57.98 in the normal group (both P < 0.01). However, levels of SIR1 in the acupuncture group, they were 0.32 +/- 0.11 and 199.52 +/- 58.12, which were significantly increased compared with those in the model group (both P < 0.05). CONCLUSION: The reinforcing-kidney and regulating-Governor Vessel method of acupuncture and moxibustion for AD could improve ultrastructure of mitochondria and increase levels of SIR1 to achieve the aim of recovering injury of mitochondria and protecting function of mitochondria. PMID- 24796054 TI - [Effects of mild moxibustion on imbalance of Th1/Th2 in rabbits with atherosclerosis and its regulating rules]. AB - OBJECTIVE: To observe effects of mild moxibustion and lovastatin on immunologic function in rabbits with chronic hyperlipidaemia and atherosclerosis (AS) to initially explain regulating rules of mild moxibustion on immunologic function. METHODS: Among thirty-two Japanese male big-ear rabbits, 8 rabbits were randomly selec ted as a blank group, the rest 24 rabbits were fed with method of endothelial injury and high-fat diet to establish AS model. The blank group was raised with normal diet and free water. After ten weeks of model establishment, the rest 24 rabbits were randomly divided into a model group, a moxibustion group and a medicine group, eight rabbits in each one. Moxibustion was applied at "Shenque" (CV 8) and "Zusanli" (ST 36) for 10 min per acupoint per day in the moxibustion group, while intragastric administration of 3.6 mg/kg lovastatin capsule was applied in the medicine group. After treatment, serum was acquired. Spectrophotometry method was adapted to measure cholesterol (TC) and high-density lipoprotein (HDL-C) and evaluated atherosclerosis index (AI), while enzyme-linked immunosorbent assay method was used to measure interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). RESULTS: (1) The serum TC and HDL-C in the model group were significantly higher than those in the blank group, moxibustion group and medicine group (all P < 0.01). The mean value of AI was 1.683 +/- 0.486 in the moxibustion group, which was obviously lower than 20.301 +/- 4.022 in the model group (P < 0.01). (2) The ratio of Th1/Th2 was 0.569 +/- 0.143 in the moxibustion group and 0.445 +/- 0.079 in the medicine group, which were significantly lower than 0.917 +/- 0.255 in the model group (both P < 0.01), but there was no statistically significant difference between the moxibustion group and the medicine group (P > 0.05). CONCLUSION: The moxibustion for AS could reduce atherosclerosis index, influence drift and bias of helper T cell and regulate balance between humoral immunity and cellular immunity. As a result, status of relative balance of immunity is acquired, which could slow down the development of atherosclerosis and process of thrombus burst. PMID- 24796055 TI - [Bloodletting at ear apex combined with acupoint application at Yongquan (KI 1) for 21 cases of hordeolum]. PMID- 24796056 TI - [Acupuncture for 160 cases of constipation]. PMID- 24796057 TI - [Efficacy on analgesia with electric stimulation of long-term retaining needle after laparoscopic cholecystectomy]. AB - OBJECTIVE: To observe the clinical effect of electric stimulation of long-term retaining needle on analgesia after laparoscopic cholecystectomy (LC) and the impacts on the post-surgical flatus time. METHODS: Under static absorptive composite general anesthesia, 90 cases of LC were randomized into three groups, 30 cases in each one. In the control group, the analgesia was not applied after LC. In the analgesia-pumper group, the patient controlled intravenous analgesia (PCIA) was used. In the needle-retaining group, the electric acupuncture stimulator was used. The needles were inserted transversely at Riyue (GB 24), Qichong (ST 30) and Yanglingquan (GB 34) and fixed with sterile sticker. Separately, in 8 h and 24 h after surgery, the electric acupuncture stimulation with disperse-dense wave, 2 Hz/100 Hz frequency was applied continuously for 30 min. Visual analogue scale (VAS), adverse reactions such as vomiting and nausea and the postoperative flatus time in 2, 4, 8, 12, 24 and 36 h after surgery were observed and recorded in the three groups. RESULTS: In 2, 4, 8, 12 and 24 h after surgery, VAS scores in the needle-retaining group and the analgesia-pumper group were all lower than those in the control group (P < 0.05, P < 0.01). The analgesia effect at the above time points in the needle-retaining group was better than that in the analgesia-pumper group (all P < 0.05). There was not adverse reaction in the needle-retaining group. But there were 3 cases of somnolence, 6 cases of nausea and 3 cases of vomiting in the analgesia-pumper group, and 2 cases of nausea and 1 case of vomiting in the control group. The flatus time was quite earlier in the needle-retaining group as compared with the other two groups [(14.77 +/- 4.99) h vs (18.50 +/- 4.22) h, P < 0.01; (14.77 +/- 4.99) h vs (18.17 +/- 4.69) h, P < 0.05]. CONCLUSION: The electric stimulation of long-term retaining needle is safe and effective in analgesia after LC. It avoids the adverse reactions of analgesics and promotes postoperative flatus. PMID- 24796058 TI - [Wrist-ankle needling for 32 cases of dysfunctional uterine bleeding]. PMID- 24796059 TI - [Clinical observation on cervical type cervical spondylosis treated with sword like needle and chiropractic spinal manipulation]. AB - OBJECTIVE: To compare the difference in the efficacy on cervical type of cervical spondylosis (CS) between the combined treatment of sword-like needle and chiropractic spinal manipulation (the combined therapy) and the simple chiropractic spinal manipulation. METHODS: One hundred and thirty-eight cases of cervical type of CS were randomized into a combined therapy group (76 cases) and a simple chiropractic spinal manipulation group (62 cases). In the combined therapy group, the sword-like needle therapy was applied at Fengchi (GB 20), Tianzhu (BL 10) and Jiaji (EX-B 2) C3-C5. The chiropractic spinal manipulation was used in combination. In the chiropractic spinal manipulation group, the simple chiropractic spinal manipulation was adopted. The treatment was given once every other day in the two groups, 10 days made one session. One session of treatment was required. Visual analog scale (VAS) score was observed before and after treatment in the two groups and the efficacies were compared between the two groups. RESULTS: VAS score after treatment was reduced obviously as compared with that before treatment in the patients of the two groups (both P < 0.01) and VAS score after treatment in the combined therapy group was lower than that in the simple chiropractic spinal manipulation group (1.50 +/- 0.58 vs 1.87+/-1.05, P < 0.01). In the combined therapy group, 48 cases were cured, 20 cases remarkably effective, 8 cases improved and 0 case failed. In the chiropractic spinal manipulation group, 30 cases were cured, 16 cases remarkably effective, 15 cases improved and 1 case failed. The overall efficacy in the combined therapy group was better than that in the chiropractic spinal manipulation (P < 0.05). CONCLUSION: The sword-like needle therapy combined with chiropractic spinal manipulation relieve effectively pain in cervical type of CS and the efficacy is superior to the simple chiropractic spinal manipulation. PMID- 24796060 TI - [Eleven cases of avascular necrosis of femoral head treated with moxibustion and acupuncture]. PMID- 24796061 TI - [Fifty-three cases of scapular muscle fasciitis treated by Pizhen (sword-like needle)]. PMID- 24796062 TI - [Standardized management of acupuncture-moxibustion clinic in Singapore General Hospital]. AB - The standardized management of acupuncture-moxibustion in Singapore General Hospital is introduced. With gradual improvement of outpatient infrastructure, re training of medical staff, strict disinfection of manipulation, periodical inspection of medical instruments, unified management of writing, saving and processing in medical records and public education of TCM knowledge, a standardized management system in accordance with modernized hospital is gradually established. As a result, efficiency and quality of clinical treatment is continuously increasing. From April of 1998 to December of 2012, a total of 74 654 times of treatment were performed, and treatment amount per day is gradually increased. The unusual condition of acupuncture is avoided. Periodical strict inspection of joint committee authenticated by domestic and overseas medical health organization is repeatedly passed and accepted. Additionally, three clinical researches funded by Singapore Health-care Company are still in progress in acupuncture-moxibustion department. PMID- 24796063 TI - [On-site quality control of acupuncture randomized controlled trial: design of content and checklist of quality control based on PICOST]. AB - To effectively guarantee quality of randomized controlld trial (RCT) of acupuncture and develop reasonable content and checklist of on-site quality control, influencing factors on quality of acupuncture RCT are analyzed and scientificity of quality control content and feasibility of on-site manipulation are put into overall consideration. Based on content and checklist of on-site quality control in National 11th Five-Year Plan Project Optimization of Comprehensive Treatment Plan for TCM in Prevention and Treatment of Serious Disease and Clinical Assessment on Generic Technology and Quality Control Research, it is proposed that on-site quality control of acupuncture RCT should be conducted with PICOST (patient, intervention, comparison, out come, site and time) as core, especially on quality control of interveners' skills and outcome assessment of blinding, and checklist of on-site quality control is developed to provide references for undertaking groups of the project. PMID- 24796064 TI - [Two cases of accidental bleeding induced by acupuncture near eyes]. PMID- 24796065 TI - [Vertigo caused by auricular sticking therapy]. PMID- 24796066 TI - [Question discussion on Theories of Different Schools of Acupuncture and Moxibustion, "the twelfth five-year plan" teaching material]. AB - The several questions in Theories of Acupuncture and Moxibustion of Different Schools, "the twelfth five-year plan" teaching material, are analyzed and discussed. The expression of DOU Han-qing on "playing a role of meridians, collaterals, qi and blood" is not so accurate, which is suggested to modify as "attaching the importance to needles". "Theory of heaven, human being and earth" "theory of acupuncture on qi regulation" and "the eight therapeutic methods in treatment of disease" in Jinzhenfu (Ode to Golden Needles) are valuable academically and suggested to be supplemented. The expression of XI Hong on "reinforcing and reducing technique by following or against the running course of meridian" and the expression of XU Feng on "the magic turtle eight techniques" are not concrete. It is required to elaborate them in detail. These questions are put forward and needed to discuss with the editors so as to perfect the teaching material. PMID- 24796067 TI - [Discussion on XU Shu-wei's clinical application of moxibustion]. AB - The experiences and features of XU Shu-wei's clinical application of moxibustion is studied in this article with method of review research. XU Shu-wei attached great importance on yangqi and the functions of spleen and kidney. At the same time, warming-reinforcing method was recommended in treatment as well. Not only treatment with medicine was emphasized, but also moxibustion was encouraged to be applied in clinic. A warming-reinforcing method with moxibustion was recommended for diseases such as yinzheng (yin syndrome), yin-du (extreme yin syndrome), yang deficiency syndrome, stroke, prolapse of anus and furuncles on back. Flexible moxibustion methods were applied based on differentiation of syndromes. Various acupoints and moxibustion manipulations were selected according to different conditions. With the proved therapeutic effect, XU Shu-wei was held as the forerunner of warming-reinforcing method in the acupuncture history of China. Meanwhile, he also made certain contribution on the establishment of the Wenbu Xuepai (the warming-reinforcing school) in the Ming Dynasty (1368-1644). PMID- 24796068 TI - [Thirty-two cases of narcolepsy treated by acupuncture of regulatimg nutrient qi and defense qi]. PMID- 24796069 TI - [Scientific practice of Chengjiang Acupuncture School in the Republic of China]. AB - Under the influence of Chinese medicine scientization, Chengjiang Acupuncture School, which was originated in the Republic of China (1912 - 1949), has also undergone a series of scientific practice. The Chengjiang School established scientific research, education and medical organizations such as the Research Society of China Acupuncture-Moxibustion, China Acupuncture-Moxibustion School, Training School of China Acupuncture-Moxibustion and Sanatorium of Acupuncture Moxibustion. Zhenjiu Zazhi (Journal of Acupuncture-Moxibustion) was established, and monographs and textbooks such as Zhongguo Zhenjiu Zhiliaoxue (Therapeutics of Chinese Acupuncture-Moxibustion) and Zhongguo Zhenjiuxue Jiangyi (Lectures on Chinese Acupuncture-Moxibustion) were published. Meanwhile, based on clinical practice, large members of acupuncture personnel with scientific literacy emerged. Therefore, it is held that the scientization of Chengjiang School has performed a profound influence on the development of modern acupuncture moxibustion. PMID- 24796070 TI - [Interpretation on small needles in Neijing (internal classic)]. PMID- 24796071 TI - [Explaination on "selecting the acupoint of affected meridian when sydrome is neither excess nor deficiency"]. PMID- 24796072 TI - [Meta analysis on acupuncture-moxibustion for amblyopia [correction of agrypnia] ]. AB - The effectiveness and safety of acupuncture-moxibustion for the treatment of agrypnia was systematically reviewed. The clinical randomized controlled trial (RCT) of acupuncture-moxibustion for agrypnia were collected. The literature and document on acupuncture-moxibustion RCT for the treatment of agrypnia that published from January of 2001 to March of 2012 was searched with computer in PubMed, CNKI, Wanfang and VIP database. According to Cochrane Handbook 5. 1. 0, the bias risk and quality assessment were performed on every included trial and RevMan 5. 0 software was applied to make the Meta analysis. Totally 14 researches were included, involving 2662 cases. The Meta analysis showed that the differences of total effective rate between acupuncture-moxibustion and clinical routine treatment were significant [RR = 1.16, 95% CI (1.12, 1.19), Z = 9.32, P < 0.000 01]. The results indicate that total effective rate of acupuncture moxibustion for agrypnia is obviously superior to that of clinical routine treatment, meaning clinical efficacy of acupuncture-moxibustion is served credit. PMID- 24796073 TI - [Smoking, a risk factor in diabetes]. PMID- 24796074 TI - [Diabetes and tobacco, a dangerous combination]. AB - Smoking is a worldwide health problem. In regular smokers, the risk of developing type 2 diabetes is high. In people with diabetes, smoking significantly worsens microangiopathic, cardio- and cerebrovascular complications.Therefore, helping people with diabetes or at risk of diabetes to give up smoking is crucial. PMID- 24796075 TI - [Smoking cessation and weight gain. From one addiction to another?]. AB - TWeight gain is a common side effect of smoking cessation. Psychological support and physical activity are essential. Medication-based methods can help the withdrawal less difficult. However, research must continue into the mechanisms involved. PMID- 24796076 TI - [Learning how not to smoke anymore]. AB - Understanding tobacco addiction and the behavioural factors involved in continuing to smoke via acquired psychological mechanisms, provides the caregiver with immediate tools to use. Smokers must be assured of their total freedom in their decision to continue or to stop smoking by a nurse who is better trained in tobacco addiction and cognitive behavioural therapies. PMID- 24796077 TI - [The role of the tobacco addiction nurse in hospitals]. AB - The tobacco addiction nurse plays a major role in the management of tobacco withdrawal. A multi-disciplinary team offers greater efficiency in the management of tobacco withdrawal. PMID- 24796078 TI - Every end has a new beginning. PMID- 24796079 TI - Vitamin C: a wound healing perspective. AB - Vitamin C, also known as ascorbic acid (AA), is involved in all phases of wound healing. In the inflammatory phase it is required for neutrophil apoptosis and clearance. During the proliferative phase, AA contributes towards synthesis, maturation, secretion and degradation of collagen. Deficiencies affect the maturation phase by altering collagen production and scar formation. The body strives to maintain homeostasis of AA, thereby ensuring availability for collagen synthesis. After wounding, plasma and tissue levels of AA diminish and, as a consequence, supplements may be useful for healing, although levels beyond saturation are excreted Clinicians need to be aware of both the nutritional status of patients with either acute or chronic wounds and the possibility of any AA deficiency which may hinder healing. PMID- 24796080 TI - Diabetic foot ulcer management: the podiatrist's perspective. AB - Diabetic foot complications result from two broad pathologies-neuropathic and neuro-ischaemic feet. It is important for diabetic patients to have at least a yearly review of foot ulcer risk factors, and they should have a corresponding risk classification agreed based on this assessment. Diabetic foot ulcer assessment should include a wound classification tool, which can give an indication of wounds at greater risk of non-healing or amputation. The treatment of diabetic foot ulcers should be part of a comprehensive care plan that should also include treatment of infection, frequent debridement (if deemed appropriate by a skilled specialist clinician), biomechanical offloading, blood glucose control and treatment of comorbidities. Clinicians should base dressing selection on the wound's location, size and depth, amount of exudate, presence of infection or necrosis and the condition of the surrounding tissue. PMID- 24796081 TI - Using larval therapy in the community setting. AB - The NHS is driven by quality targets that permeate all specialties and care settings, and by the need for safety, efficiency and patient-centred care. Efficient care pathways need to be safe and indicated, and should offer measurable advantages and patient benefits as well as giving a treatment end point. Complex wounds require very careful management from the multidisciplinary team and present clinicians with intricate challenges to promote cost-effective wound healing. Wound bed preparation and debridement need to be as effective and as non-traumatic as possible. Larval therapy removes devitalised tissue effectively with minimal tissue trauma, and early intervention results in cost effective wound care in the patient's own surroundings and can prevent admission to hospital for surgical debridement. This article discusses the history of, and evidence for, larval therapy, its cost effectiveness and the different presentations of larval therapy and their various benefits. PMID- 24796082 TI - Holistic wound assessment in primary care. AB - Wound care is expensive and can cause immeasurable stress and inconvenience to patients and their significant others. It is therefore in the best interest of the patient, their significant others and the NHS as a whole that wounds are expertly assessed, managed and healed in the quickest timeframe possible. Nurses play a pivotal role in the process of accurate holistic wound assessment, evaluation and treatment. This article aims to help further develop and enhance both professional and clinical wound care assessment and evaluation skills. Pertinent wound care literature is critically reviewed and the crucial nature and important components of comprehensive wound assessment for facilitating the highest possible quality wound care to patients are presented alongside recommendations regarding how the enhanced knowledge and skills could be applied into everyday wound care practice. PMID- 24796083 TI - Why don't patients adhere to compression therapy? AB - This article explores the psychological influences on patients and their choices over adopting (or not) the advice of health-care professionals (HCPs) with regard to their own health. The article will examine some key theories by reviewing studies as well as examining how the patient-HCP relationship has evolved over time to try and improve patient adherence. Although specifically focusing on the area of venous leg ulcers and compression therapy, the theories relate to many health conditions. Despite health advice and compression treatments being the cornerstone of ulcer prevention and recurrence when adhered to, patient adherence levels are often persistently poor, both anecdotally and via clinical study. This article attempts to explain what influences a patient's adherence. PMID- 24796084 TI - Drawtex: breaking the vicious circle of cellular and molecular imbalances. AB - Uncontrolled cellular and molecular activity in the inflammatory phase of healing will determine whether a wound becomes chronic. Assessment and interventions designed to remove the barriers to healing are essential in order to break the vicious cycle and to kick-start healing in chronic wounds. This product focus gives an overview of the inflammatory phase of the wound healing continuum; discusses how the imbalance of matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases occurs; how this imbalance manifests itself clinically within the wound; and what health professionals can do in order to tip the balance in favour of healing. It discusses a new wound dressing, Drawtex, which combines three modes of action to maintain a moist wound environment in order to debride, manage exudate and reduce bioburden by locking harmful proteases into its core. Case studies are presented where Drawtex has been used to achieve healing in wounds that were not responding to treatment. PMID- 24796085 TI - [Neurological diseases and neurovascular unit (NVU)]. PMID- 24796086 TI - [Epidemiology of dementia: the Hisayama study]. AB - A prospective cohort study has been conducted in the elderly of the town of Hisayama in Japan since 1985 to elucidate the trends in the prevalence of dementia and examine risk and protective factors for dementia in the general Japanese population. We revealed that the prevalence of all-cause dementia and Alzheimer's disease significantly increased from 1985 to 2005. In our prospective study, diabetes was associated with significantly increased risk of Alzheimer's disease and vascular dementia, while midlife and late-life hypertensions were significant risk factors for vascular dementia but not for Alzheimer's disease. Meanwhile, physical activity and a dietary pattern which was roughly correspondent to a customary Japanese diet were associated with lower risk of dementia in our population. PMID- 24796087 TI - [Early detection and prevention of dementia]. AB - Dementia is about 15% aged 65 and over people now, and is regarded as the common disease. Early symptoms, such as forgetfulness, tend to be overlooked. Alzheimer type dementia is now possible to treat with medication. Therefore, early diagnosis and early treatment are required. Prevention of dementia is also expected and dementia checkup attracts attention. Although there was little data with high evidence, I introduced some reports about dementia prevention including our data. Dementia prevention is an important issue and establishment of evidence is desired in the near future. PMID- 24796088 TI - [Prevention of dementia on the basis of modification of lifestyle and management of lifestyle-related diseases: a review]. AB - Recent observational longitudinal studies have indicated the association of cognition with lifestyle and lifestyle-related diseases, which can affect timely through the life as protective or risk factors. In particular, inappropriate lifestyle including diet and exercise induces lifestyle-related diseases such as hypertension, diabetes, dyslipidemia, obesity, cigarette smoking which promote cognitive decline and the occurrence of dementia as vascular risk factors. On the other hand, education during early life, occupational exposure during mid-life, and diet with green leafy vegetables and fish oil, and leisure activities including hobbies, social activities, and physical activities during later life could maintain or accelerate the cognitive reserve function. On the basis of modification of lifestyle and management of lifestyle-related diseases, therefore, we should prevent cognitive decline and the occurrence of dementia to achieve healthy aging society. PMID- 24796089 TI - [Alzheimer's disease and vascular dementia]. AB - Alzheimer's disease (AD) and vascular dementia (VaD) are the two major forms of dementia in the elderly, and they had been separated categorically on the basis of pathogenetic mechanisms and clinical operationalized criteria. However, it was claimed that this strict separation might steered toward the overdiagnosis of vascular dementia, this dichotomy has been reevaluated in the light of recent epidemiological and neuropathological knowledge. Cerebrovascular disease (CVD) is now considered as one of the vascular risk factors to the onset and evolution of Alzheimer's disease. Futhermore, the term "AD with CVD" has been used to classify patients fulfilling the clinical criteria for possible AD and who also present clinical or brain imaging evidence of relevant CVD. PMID- 24796090 TI - [Insulin resistance and cognitive function]. AB - Risk of Alzheimer disease is increased in patients with diabetes. Insulin resistance is identified as a pathogenic mechanism of impaired cognitive dysfunction. Amyloid beta oligomers cause impaired insulin signaling at IRS-1 via mechanisms of TNFalpha and JNK activation. Attenuation of PI-3 kinase pathway is also involved in the hyper-phosphorylation of Tau. Impairment of orexin function is connected to the age related insulin resistance and shortening of life expectancy. Synapse deterioration and loss via these mechanisms underlying defective brain insulin signaling result in cognitive dysfunction. Stimulation of insulin signaling is a developing therapeutic approach in Alzheimer disease. Nasal insulin administration, thiazolidinedione, and GLP-1 receptor agonist possess neuronal protective effects in the treatment of mild cognitive dysfunction. Further identification of the pathogenic mechanism connecting between Alzheimer disease and insulin resistance contributes to development of novel therapeutics in Alzheimer disease. PMID- 24796091 TI - [Brain renin-angiotensin-aldosterone system and cognitive function]. AB - The presence of hypertension and other vascular risk factors such as diabetes mellitus is known to be associated with the decreased cognitive function. Blood pressure-lowering with antihypertensive agents was suggested to reduce the risk of dementia or cognitive decline. The renin-angiotensin-aldosterone system plays a role not only in the cardiovascular system including blood pressure regulation, but also in the central nervous system. The possible beneficial effects of ARB and ACE inhibitor on cognitive function are also becoming highlighted in the clinical field. This article reviews the effects of regulation of activation of angiotensin II receptor subtypes, and ACE2/angiotensin- (1-7)/Mas receptor on ischemic brain damage and cognitive function. PMID- 24796092 TI - [Omega-3 fatty acids and cognition]. AB - Docosahexaenoic acid, the most abundant omega3 fatty acid in the brain, plays a role in cognitive development, learning ability, neuronal membrane plasticity, synaptogenesis, and neurogenesis, all of which are involved in synaptic transmission and the well-being of normal brain functions, and search on the functionality is still in progress. Establishment of prevention and treatment of neuropsychiatric illnesses, such as dementia is not easy, but from numerous basic and epidemiological studies, increase of omega3 fatty acid dietary intake is reported likely to prevent the onset of dementia. This paper is outlined the relevance of cognitive function and omega3 fatty acids, especially docosahexaenoic acid, and the possibility of preventive effect of the fatty acid on dementia. PMID- 24796093 TI - [Sex hormones and cognitive function]. AB - Endogenous estrogen is considered to be protective against cognitive dysfunction. However, clinical trials examining the efficacy of hormone replacement therapy (HRT) in postmenopausal women showed rather deteriorating effects of HRT on cognitive function and dementia, resulting in the recommendation of no use of HRT for the prevention of dementia. By contrast, recent advances in androgen research have suggested the effects of androgen on cognitive function in older men with mild cognitive impairment, pending the mechanistic clarification and clinical trials. Also, the protective role of androgen in cognitive and physical function in older women has been highlighted. Recent topics on the relationship between sex hormones and cognitive function were overviewed in this paper. PMID- 24796094 TI - [Cognitive function in eating disorders]. AB - Eating disorders are characterized by uncontrolled eating behaviors. The core psychopathology is expressed in a variety of ways: body image distortion, preoccupation with food and weight, fear of weight gain, and so on. Brain-imaging techniques provide many opportunities to study neural circuits related symptoms in eating disorder. The present article focuses studies about functional magnetic resonance imaging (fMRI) of eating disorders. Studies of anorexia nervosa suggest 1) relationship between amygdala activation and fear of weight gain, 2) relationship between prefrontal cortex activity and cognitive flexibility. Studies of bulimic eating disorder (bulimia nervosa, binge eating disorder, and so on) suggest 1) relationship between brain reward system and overeating, 2) relationship between prefrontal cortex activity and impulse control. PMID- 24796095 TI - [Clinical diagnosis]. AB - The commonly followed definition of dementia is the one described by the International Statistical Classification of Diseases, 10th Revision (ICD-10, World Health Organization) or the Diagnostic and Statistical Manual of Mental Disorders (DSM-V, American Psychiatric Association). The most important aspect in the diagnosis of dementia is the assessment of overall mental and functions, including living environment, activities of daily living, cognition, mental status, and behavior. Physicians should diagnose dementia on the basis of not only cognitive test results or radiological findings but also other available information, including that obtained from the families or caregivers. Tests for the quantitative evaluation of cognitive function and dementia include the Mini Mental State Examination (MMSE), Hasegawa Dementia Scale Revised (HDS-R), Clinical Dementia Rating (CDR), and Wechsler Memory Scale-Revised (WMS-R). PMID- 24796096 TI - [Electroencephalography, a potential biomarker for early diagnosis of dementia]. AB - Early diagnosis at the prodromal stage of dementing illnesses is an important topic of current clinical research. Remarkable advances of biomarker for the early diagnosis have done with structural MRI imaging, metabolic/amyloid PET imaging, and cerebrospinal fluid analysis. However, there still remains a need to develop an efficient, low cost, portable, noninvasive method. Electrophysiological measurements are promising for this point and they have the highest time resolution for reflecting brain dynamics in cognition. Unfortunately, the classification of cognitive impaired subjects at individual level revealed a moderate accuracy with electrophysiological markers. However, cortical functional activity change preceding anatomical and metabolic changes can only be assessed by electrophysiological measurements. Improvement of the accuracy for the early diagnosis of cognitive decline is expected. PMID- 24796097 TI - [Imaging diagnosis of dementia]. AB - The role of neuroimaging in the diagnosis of dementia diseases is overviewed. In the clinical practice, screening imaging examinations such as X-ray CT and MRI of the brain are useful to exclude cerebrovascular disorders, brain tumors, subdural hematomas, and normal pressure hydrocephalus from neurodegenerative disorders. After differentiating those disorders, the regional distribution patterns of atrophy, neuronal injury, or functional impairment detected by morphological MRI, perfusion SPECT, or 18F-FDG PET are useful for the differential diagnosis of neurodegenerative diseases. Cardiac scintigraphy by 123I- MIBG, dopamine transporter imaging, and amyloid imaging give us pathology specific information such as cardiac autonomic dysfunction mainly by Lewy body disease, nigral degeneration with parkinson's syndrome, and amyloid deposition with Alzheimer's disease. Those structural, functional, and pathology specific neuroimaging tools can be used not only for the early diagnosis, but also for tracing disease progression in understanding the relationship between life style diseases and dementia, and developing disease modifying therapies. PMID- 24796098 TI - [Hypertension]. AB - Hypertension is well known to one of the risk factors to reduce cognitive function, however, it is still unclear whether anti-hypertensive therapy is effective to prevent development of dementia or Alzheimer's disease. Epidemiological studies suggested antihypertensive therapy from the middle-age could reduce risk of dementia. The meta-analysis including HYVET also suggested blood pressure lowering from the elderly might be also effective to prevent development of dementia. The network meta-analysis and the cohort study using mega-data bank suggested ARB might be effective to prevent development of dementia or Alzheimer's disease compared to administration with other anti hypertensive drugs. Although the further major clinical investigation is required, anti-hypertensive treatment might be useful to manage hypertensive patients with dementia. PMID- 24796099 TI - [Preventive strategy for cognitive decline in elderly with diabetes mellitus]. AB - Diabetes increases the risk of cognitive decline including vascular dementia and Alzheimer's disease. Preventive strategy for cognitive impairment is thus needed in elderly with diabetes. To avoid brain injury in diabetic elderly patients, management of hypoglycemia, hyperglycemia, fluctuation of blood glucose, insulin resistance, and cerebral vessel disease is crucial. Recent clinical trials show hyperglycemia should be controlled with HbA1c of 7.2-7.4% for prevention of newly onset of dementia in the elderly. In contrast, little is known for target glucose levels in diabetic elderly combined with demented disease. Careful insight of hypoglycemia seems more important in the elderly. Now, a variety of pharmacological agents for treatment of diabetes is available and it seems clear that a comprehensive approach will be required in order to achieve healthy brain function. PMID- 24796100 TI - [Lipid abnormality]. AB - Vascular dementia is caused by stroke, so primary and secondary prevention for stroke is extremely important. Effects of statins on stroke prevention in patients are reported from recent randomized controlled trials. Hypercholesterolemia in midlife are related to an increased risk of Alzheimer's disease (AD) in later life. During the past decade, effects of statins for patients with AD are controversial in many subsequent original studies. Accordingly, it remains unknown whether statin therapy have a preventive effect on cognitive decline in patients with AD. As a possible mechanism, hypercholesterolemia may be associated with the progression of AD pathology. As another possible mechanism hypercholesterolemia may be associated with hypoperfusion through the progression of atherosclerosis. PMID- 24796101 TI - [Metabolic syndrome]. AB - Considerable attention has focused on the prevention of dementia in terms of non genetic risk factors, including midlife obesity, especially visceral obesity associated with hyperglycemia, hypertension, and hypercholesterolemia. Accumulating evidence has indicated that the increased insulin resistance in relation to visceral fat accumulation is potential risk of Alzheimer's disease (AD) and vascular dementia. Reducing the accumulating visceral fat may contribute to reduce the risk of on set and progression of AD and vascular dementia. Treatment with renin-angiotensin system blockers in hypertension might slow the rate of cognitive decline in patients with AD by modulating insulin resistance. PMID- 24796102 TI - [Brain atrophy and cognitive impairment in patients with chronic kidney disease]. AB - Many recent reports have shown that prevalence of brain atrophy (BA) and cognitive impairment (CI) increases in patients with chronic kidney disease (CKD), and is also associated with the severity of kidney dysfunction. Various risk factors such as dialysis-related factors, oxidative stress, anemia, brain ischemia, and uremic toxins are considered to involve in these conditions. We recently reported that CI in CKD mice were ameliorated by the treatment with tempol, an antioxidant drug, thorough inhibition of oxidative stress in the brain. Moreover, it has been reported that renal transplantation are effective in the improvement of CI; however, increase in hemodialysis by frequent hemodialysis had failed to improve CI in CKD patients. Further evidences are required to elucidate the pathogenesis of BA and CI in CKD. PMID- 24796103 TI - [Ischemic heart disease, heart failure, and their effects on cognitive function]. AB - Recent studies have shown that ischemic heart disease and heart failure are closely associated with cognitive impairment via injury of the small cerebral arteries. On the other hand, these factors are suggested to be associated with Alzheimer's disease as well as vascular dementia. This review paper focuses on the role of ischemic heart disease and heart failure as risk factors for cognitive impairment, and summarizes current knowledge on the relationships between vascular risk factors and Alzheimer's disease pathology. PMID- 24796104 TI - [Cognitive function in patients with chronic obstructive pulmonary disease]. AB - It is increasingly recognized that COPD is a multi-component disease, but little attention has been paid to its effects on cognition. Cognitive dysfunction is associated with increased disability of daily living and mortality. However, it remains to be elucidated in COPD. Our main findings are: 1) cognitive dysfunction in patients with COPD is related to the grade of activity of daily livings and hypoxemia, especially in exercise-induced hypoxemia; 2) cognitive impairment such as perception, attention and short memory are impaired; 3) attention function determined by Trail Making Test is improved by O2 inhalation with the increase in the prefrontal cortex oxygenation; 4) by 8 week exercise training, cognitive function in COPD is improved with the increase in the prefrontal circulation. PMID- 24796105 TI - [Liver diseases]. AB - Hepatic encephalopathy is frequently accompanied by reversible cognitive impairment, while chronic acquired hepatocerebral degeneration is a rare irreversible neurological disorder in patients with liver cirrhosis, characterized by parkinsonism and cognitive decline. Patients with Wilson disease can also present cognitive deficits. Recently, it was reported that non-alcoholic fatty liver disease (NAFLD) might be a risk factor for cognitive impairment. There may be the links among obesity, type 2 diabetes mellitus, NAFLD, insulin resistance and cognitive impairment. Reduced liver biosynthesis of docosahexaenoic acid (DHA) might also contribute to cognitive decline in Alzheimer's disease. The associations between chronic liver diseases and cognitive impairment need further investigation. PMID- 24796107 TI - [Central nervous system infection presenting with cognitive impairment]. AB - In diabetes mellitus, various complications are caused by microvascular damage caused by a long-term hyperglycosemic state. In diabetes mellitus, the prevalence of the infectious disease is high and is easy to become severe. And, central nervous system infection is one of the most important causes of cognitive impairment. We want to show about some important central nervous system infections which affect to cognitive functions. PMID- 24796106 TI - [Locomotive syndrome]. AB - Both cognitive impairment (CI) and osteoarthritis (OA) are top-ranked causes of disability requiring support, but there have been no previous reports on the association between CI and OA. We aimed to investigate the association between mild cognitive impairment (MCI) and the occurrence and progression of OA of the knee among men and women who participated in the research on osteoarthritis/osteoporosis against disability (ROAD) study. Of 1,690 participants at the baseline, 1,384 individuals (81.9%; 466 men, 918 women) completed the second survey including knee radiography 3 years later. Baseline presence of MCI was significantly associated with the incidence of knee OA (vs. non-occurrence of knee OA; OR 4.90, p < 0.05). PMID- 24796108 TI - [Sleep disorders]. AB - Some sleep disorders and sleep problems are reported as risk of dementia. It is reported that 50-80% of idiopathic REM sleep behavior had a later conversion to a synucleinopathy, thus this parasomnia is regarded as early marker of Parkinson disease, dementia with Lewy bodies and multiple system atrophy. Obstructive sleep apnea syndrome causes reversible decline of cognitive functions in children and adults, and it increases the risk of dementia and mild cognitive impairment in elderly women. A decrease of amplitude of circadian activity rhythm and habitual long sleep duration (> or = 9 hours) are reported to increase the risk of dementia in elderly people. Some reports indicate that hypnotic use may be a risk factor of dementia. However, it is not cleared whether insomnia itself related with dementia or not, since no study evaluated the risk of insomnia without hypnotic treatment. PMID- 24796109 TI - [Periodontal disease]. AB - It has been shown that the inflammatory pathways are activated in the brains of patients with Alzheimer disease (AD), and the use of anti-inflammatory drugs reduces risk to develop AD. It is understood that molecules involved in this inflammation promote pathological processes leading to AD, whereas other molecules work to protect neuron/brain function from toxicity found in AD pathogenesis. Periodontal disease is one of the diseases causing inflammation and recent lines of evidence show the link between these two diseases. In this paper, relationship between periodontitis and AD will be reviewed and the possible mechanisms, by which periodontitis may affect the onset and progression of AD, will be discussed. PMID- 24796110 TI - [Alcohol-related dementia]. AB - Excessive alcohol use is associated with health problems for the elderly in combination with their chronic conditions. One such complication, alcohol-related dementia (ARD) is brought about by direct or indirect ethanol intoxication, and coexisting nutritional deficiency, liver disease, cerebrovascular disease and traumatic brain injury. The elderly people with ARD have been underestimated and underdiagnosed. In these older alcoholics, atrophic changes, lacunar infarcts and deep white matter lesions of the brain are evident and are associated not only with their cognitive decline, but also with their frailty, leading to high morbidity and mortality ratio. Although lifelong abstinence can recover patients with ARD to temporally lull, aging, the severity of alcohol dependence, and the concomitant nutritional, physical and environmental factors can all impact negatively their outcome. Therefore, a comprehensive approach to lifestyle factors is recommended so that they can minimize preventable risks and maintain health status. Nursing home placement may be an appropriate treatment option for some refractory, long-term patients with ARD. PMID- 24796111 TI - [Recent progress and prospects for research on urate efflux transporter ABCG2]. AB - ABCG2 is a high-capacity urate exporter. Two frequent variants, Q126X and Q141K are a nonfunctional and half-functional variant, respectively. The estimated ABCG2 dysfunction based on the combination of Q126X and Q141K haplotype raises gout/hyperuricemia risk. ABCG2 dysfunction accounts for about 80% of gouty patients. Severe ABCG2 dysfunction particularly increased the risk of early-onset gout. Hyperuricemia has been clinically classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. A major cause of'overproduction' hyperuricemia is not true overproduction of urate but rather'extra-renal urate underexcretion' by common ABCG2 dysfunction. As ABCG2 dysfunction is a main cause of gout, ABCG2 research will provide a new approach for prevention and treatment of gout. PMID- 24796112 TI - [The 41st Scientific Meeting: perspectives of internal medicine ; lessons from the disaster of the Great East Japan earthquake; 1. Preface]. PMID- 24796113 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 2. The common ground of internal medicine and disaster medicine]. PMID- 24796114 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 3. Medical disease learned from the Great East Japan earthquake--feature, treatment and prevention--; 1) The Great East Japan earthquake and cardiovascular diseases]. PMID- 24796115 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 3. Medical disease learned from the Great East Japan earthquake--feature, treatment and prevention--; 2) Respiratory diseases]. PMID- 24796116 TI - [The 41st Scientific Meeting: perspectives of internal medicine lessons from the disaster of the Great East Japan earthquake; 3. Medical disease learned from the Great East Japan earthquake--feature, treatment and prevention--; 3) Digestive diseases]. PMID- 24796117 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake: 3. Medical disease learned from the Great East Japan earthquake--feature, treatment and prevention--; 4) Status of medical care on dialysis patients and patients with chronic life-style related diseases after Great East-Japan earthquake: lesson from our experiences in Fukushima and future perspectives]. PMID- 24796118 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 3. Medical disease learned from the Great East Japan earthquake--feature, treatment and prevention-; 5) Total management for infectious diseases]. PMID- 24796119 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake: 3. Medical disease learned from the Great East Japan earthquake--feature, treatment and prevention--; 6) Radiation disaster and internal medicine]. PMID- 24796120 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 4. Proposal of an effective internal medical care against disaster; 1) Role of general practitioner]. PMID- 24796121 TI - [The 41st Scientific Meeting: perspectives of internal medicine: lessons from the disaster of the Great East Japan earthquake; 4. proposal of an effective internal medical care against disaster; 2) Disaster response in dialysis patients]. PMID- 24796122 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake: 4. Proposal of an effective internal medical care against disaster; 3) An appropriate management of geriatric disorders following Japan catastrophic disaster and tsunami 2011]. PMID- 24796123 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 4. Proposal of an effective internal medical care against disaster; 4) Disaster-tolerant internal medical care: efficient use of ICT]. PMID- 24796124 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 5. Panel discussion; The role and cooperation of physicians in great disasters: proposals]. PMID- 24796125 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake: 5. Panel discussion: 1) Medical transportation for patients requiring artificial ventilation]. PMID- 24796126 TI - [The 41st Scientific Meeting: perspectives of internal medicine; lessons from the disaster of the Great East Japan earthquake; 6. Conclusion]. PMID- 24796127 TI - [Programs for continuing medical education: a session; 1. Advances in endoscopic therapy for small intestinal lesions using double-balloon endoscopy]. PMID- 24796128 TI - [Programs for continuing medical education: a session; 2. Current therapy for chronic hepatitis C]. PMID- 24796129 TI - [Programs for continuing medical education: a session; 3. Dementia: diagnosis and therapy]. PMID- 24796130 TI - [Programs for continuing medical education: a session: 4. The pathogenesis and update for the treatments of Parkinson's disease]. PMID- 24796131 TI - [Programs for continuing medical education: a session; 5. Diagnosis and treatment of water disorder]. PMID- 24796132 TI - [Programs for continuing medical education: a session; 6. Differential diagnosis and treatment of adrenal incidentaloma]. PMID- 24796133 TI - [Programs for continuing medical education: a session; 7. Recent trends in treatment of diabetes mellitus]. PMID- 24796134 TI - [Programs for continuing medical education: a session; 8. Pharmacotherapy of rheumatoid arthritis--interleukin-6 blocker made in Japan]. PMID- 24796135 TI - [Programs for continuing medical education: a session; 9. Using vital signs to diagnose the emergency patients]. PMID- 24796136 TI - [Programs for continuing medical education: B session; 1. The pathophysiology of heart failure--is it the disease of the heart?]. PMID- 24796137 TI - [Programs for continuing medical education: B session; 2. Recent progress in diagnosis, treatment and prevention of coronary artery disease]. PMID- 24796138 TI - [Programs for continuing medical education: B session; 3. Management of COPD and bronchial asthma]. PMID- 24796139 TI - [Programs for continuing medical education: B session; 4. Progress in lung cancer therapy]. PMID- 24796140 TI - [Programs for continuing medical education: B session: 5. Channels, transporters, and kidney diseases]. PMID- 24796141 TI - [Programs for continuing medical education: B session; 6. Metabolic syndrome and chronic kidney disease]. PMID- 24796142 TI - [Programs for continuing medical education: B session 7. Progress in treatment for hematologic diseases]. PMID- 24796143 TI - [Programs for continuing medical education: B session; 8. Progress in clinical management for pneumonia--present situation and future perspectives in Japanese elderly society]. PMID- 24796144 TI - [Programs for continuing medical education: B session; 9. Revisit medical interviewing as a basic clinical competence]. PMID- 24796145 TI - [Case report; Disseminated Mycobacterium abscessus infection with hemophagocytic syndrome during treatment of chronic lymphocytic leukemia]. PMID- 24796146 TI - [Case report; Selective serotonin reuptake inhibitor induced QT prolongation and ventricular fibrillation in acute myocardial infarction]. PMID- 24796147 TI - [Case report; Small cell neuroendocrine carcinoma of the esophagus producing parathyroid hormone-related peptide with humoral hypercalcemia]. PMID- 24796148 TI - [Case report; Chorea as the first manifestation of systemic lupus erythematosus associated with anti-phospholipid syndrome]. PMID- 24796149 TI - [Cutting-edge of medicine; management of heart failure with biomarkers--how to interpret the JHFS(Japanese Heart Failure Society) statement for BNP use]. PMID- 24796150 TI - [Cutting-edge of medicine; the prospects of novel anti-obesity drugs]. PMID- 24796151 TI - Do children prefer mentalistic descriptions? AB - Against a long tradition of childhood realism (Piaget, 1929), A. S. Lillard and J. H. Flavell (1990) found that 3-year-olds prefer to characterize people by their mental states (beliefs, desires, emotions) than by their visible behaviors. In this exploratory study, we extend this finding to a new cohort of 3-year-olds, examine how these preferences change from 3-4 years, and explore relationships with theory of mind and parental mind-mindedness. The results showed a developmental change and a possible cohort difference: at 3 years, children in the sample preferred behavioral descriptions, although by 4 years of age, they preferred mentalistic ones. Interestingly, mentalistic preferences were unrelated to theory of mind or parental mind-mindedness, concurrently or over time. Perspective-taking skills at 3 years, however, predicted an increase in mentalistic responses from 3 years to 4 years. Possible explanations for each finding are discussed. PMID- 24796152 TI - Do differences make the heart grow fonder? Associations between differential peer experiences on adolescent sibling conflict and relationship quality. AB - Though it is known that different familial relationships influence one another (e.g., Yu & Gamble, 2008) the influence of outside relationships (i.e., peers) on family dynamics (i.e., sibling relationships) is less clear. Thus, the authors examined the association differential peer experiences had on the conflict frequency, conflict intensity, and relationship quality of the sibling relationship. A 1-year longitudinal design measured first-born siblings in Grades 8, 10, and 12 along with their second-born siblings. In the first year, participants were brought to the university to complete questionnaires and in the following year, siblings again participated by completing online questionnaires at home. Results partially confirmed the study hypotheses that adolescents would show greater sibling conflict and poorer relationship quality with greater peer group differences, revealing that when peer group differences between siblings were greater, the youngest siblings reported more intense sibling conflicts (pe = -.10 p < .05), the oldest siblings reported greater relationship positivity (pe = .13 p < .05), and the oldest second-borns reported greater relationship negativity (pe = -.12 p < .10). These findings underscore the importance of investigating siblings' differential experiences beyond familial influence to focus on outside sources to better understand developmental fluctuations in siblings' relationships. PMID- 24796153 TI - Mixed-grade rejection and its association with overt aggression, relational aggression, anxious-withdrawal, and psychological maladjustment. AB - The authors examined the associations between mixed-grade rejection (rejection by peers in a different school grade), anxious-withdrawal, aggression, and psychological adjustment in a middle school setting. Participants were 181 seventh-grade and 180 eighth-grade students (M age = 13.20 years, SD = 0.68 years) who completed peer nomination and self-report measures in their classes. Analyses indicated that in general, same- and mixed-grade rejection were related to overt and relational aggression, but neither type was related to anxious withdrawal. Mixed-grade rejection was associated uniquely and negatively with self-esteem for seventh-grade boys, while increasing the loneliness associated with anxious-withdrawal. The results suggest that school-wide models of peer relations may be promising for understanding the ways in which different peer contexts contribute to adjustment in middle school settings. PMID- 24796154 TI - Linking immigrant parents' educational expectations and aspirations to their children's school performance. AB - The authors examined the relationships of parental expectations and aspirations for their children's educational attainment to children's academic performance in school among 783 immigrant-origin children aged 5-18 years in Canada. The results of hierarchical regression analyses, after accounting for student and family background characteristics, indicated that immigrant parents' expectations and aspirations for their children's educational attainment were positively linked to immigrant-origin children's academic performance in school. Implications of these findings are briefly discussed. PMID- 24796155 TI - Deviation from zeitgeist and motivation in the intergenerational transmission of individualistic and collectivistic values in East Germany and Shanghai, China. AB - Intergenerational intrafamilial transmission is a process by which acquired information passes from parent to offspring. The authors examined mechanisms of intergenerational transmission of individualistic and collectivistic values in 216 families with 1 adolescent child in 2 societies: East Germany and the Shanghai region in China. To clarify the impact of transmission from mother and father to son or daughter, this study analyzed the filter model by U. Schonpflug and L. Bilz (2009), including zeitgeist concerning value climate in the social context, each family member's deviation from the zeitgeist, and the familial motivation to transmit. The 2-dimensional structure (individualism and collectivism) of 10 values of the Portrait Value Questionnaire (Schwartz, Lehmann, & Rocca, 1999) differed somewhat in the 2 regions for adolescents and their fathers, but not for mothers. In East Germany, no significant direct transmission of value orientation was observed, whereas in Shanghai, fathers transmitted individualism and collectivism values. Family motivation impacted significantly on the child's value orientation in both regions. The zeitgeist measure had no significant influence on the transmission process whereas deviation from zeitgeist did. The gender of the child determined the level and transmission of collectivism, but not the transfer of individualism. PMID- 24796156 TI - Coping with negative emotions: connections with adolescents' academic performance and stress. AB - The authors assessed connections among adolescents' emotional dispositions, negative academic affect, coping strategies, academic stress, and overall grade point average (GPA). A total of 119 ninth through 12th-grade students completed assessments for (a) overall positive and negative moods, (b) GPA, and (c) academically related variables involving stress, negative emotions, and engaged and disengaged coping strategies. Greater negative academic affect and disengaged coping were related to lower GPAs, and disengaged coping mediated the connection between negative academic affect and GPA. By contrast, higher academic stress was related to students' overall moods, negative academic affect, and disengaged coping; disengaged coping mediated the connection between academic stress and negative overall moods. Discussion focused on the especially problematic nature of disengaged academic coping. PMID- 24796157 TI - The construction of symmetry in children and adults. AB - The development of the concept of symmetry is important to an overall understanding of cognitive development in children and to spatial cognition in particular. Age differences in the construction of the 3 types of symmetry (bilateral, translational, and radial) were investigated in children and adults engaged in block construction. Children 2-4.5 years old produced bilateral symmetry in low frequencies independent of their precise vertical alignment of blocks. Children 4-12 years old and adults produced all 3 types of symmetry. The hypothesis predicting the sequence and frequency of the 3 types of symmetry based on an analysis of spatial complexity was partially supported. Bilateral symmetry was produced at significantly higher frequencies than the other 2 types across all age groups. Children 5-12 years old produced adult levels of bilateral symmetry while children 9-12 years old reached adult levels of construction of translational and radial symmetry. PMID- 24796158 TI - Marital satisfaction and quality of father-child interactions: the moderating role of child gender. AB - The authors aimed to investigate the prospective links between normative variation in fathers' marital satisfaction and the observed quality of father toddler interactions, as well as the moderating role of child gender in these associations. Sixty-three fathers reported on their marital satisfaction when their children were 15 months of age, and were observed interacting with their child at 18 months. The results suggested that marital satisfaction was positively associated with the quality of father-son interactions, while no relations emerged among fathers of girls. These findings reiterate the importance of marital relationships for the quality of fathers' parenting, while reaffirming previous suggestions that the role of child gender in the marriage-parenting connections requires further investigation. PMID- 24796159 TI - The differential impact of parental warmth on externalizing problems among triangulated adolescents. AB - Triangulation is a family-wide process in which children are inappropriately involved in interparental conflict, placing them at heightened risk for adjustment problems. A common form of triangulation occurs by parents pressuring their children to take sides, which may result in feelings of being torn between parents. Externalizing behaviors in particular may develop as adolescents feel caught in the middle of conflict and forced to choose a side. However, the nature of the triadic process of triangulation may be impacted by dyadic-level relationships within the family. The authors thus explored how positive parenting processes may alter the relations between triangulation and adolescent externalizing problems. Mothers, fathers, and adolescents (n = 301 families) provided assessments of adolescent externalizing problems, triangulation, and maternal and paternal warmth. Analyses revealed a 3-way interaction among triangulation and maternal and paternal warmth predicting adolescent externalizing problems; child gender also moderated these relations. Among highly triangulated youth, boys displayed increased externalizing problems when both parents exhibited low or high warmth, whereas girls showed increased behavior problems in the context of low maternal but high paternal warmth. These findings indicate the importance of examining the broader family context and gender when considering the impact of triangulation during adolescence. PMID- 24796160 TI - Bullying behaviors and victimization experiences among adolescent students: the role of resilience. AB - The role of resilience in the relationship between bullying behaviors, victimization experiences, and self-efficacy was examined. Participants were 393 (191 young men, 202 young women) adolescents (M age = 15.88 years, SD = 0.64 years) from schools in Coimbatore, India, who completed scales to assess bullying behaviors and victimization experiences, resilience, and self-efficacy. Multigroup structural equation modeling, with separate groups created according to participant gender, revealed that resilience mediated the relationship between bullying behaviors and self-efficacy in young men. Young men engaged in bullying behaviors and experienced victimization more frequently than young women. The findings of the study have implication for designing intervention programs to enhance resilience among adolescents and young adults to enable them to manage bullying behaviors. PMID- 24796161 TI - Staying alone or getting attached: development of the motivations toward romantic relationships during adolescence. AB - The authors present the initial validation of a romantic relationship motivation scale, enabling the level of self-determined involvement in romantic relationships during adolescence to be examined. The inclusion of Self Determination Theory (E. L. Deci & R. M. Ryan, 2000) in the motivational constructs enhances the developmental perspective regarding adolescent romantic involvement. The scale was administered to 284 adolescents (163 girls and 121 boys, age 14-19 years) with a self-esteem scale and some questions about their romantic experiences to provide some elements of external validation. The results confirmed the 4-factor structure: intrinsic motivation, identified regulation, external regulation, and amotivation, which follow the self-determination continuum, previously highlighted in friendship motivation. As hypothesized, adolescents became more self-determined with age and girls were more self determined than boys. Other findings show specific links between motivation for romantic relationships, self-esteem and romantic experiences. It highlights the importance of considering adolescents' motivations when exploring their romantic relationships. PMID- 24796162 TI - Does future-oriented thinking predict adolescent decision making? AB - A number of theorists, as well as plain common sense, suggest that future oriented thinking (FOT) should be involved in decision making; therefore, the development of FOT should be related to better quality decision making. FOT and quality of the decision making were measured in adolescents as well as adults in 2 different experiments. Though the results of the first experiment revealed an increase in quality of decision making across adolescence into adulthood, there was no relationship between FOT and decision making. In the second experiment, FOT predicted performance on a more deliberative decision-making task independent of age, but not performance on the Iowa Gambling Task (IGT). Performance on the IGT was instead related to emotion regulation. The study's findings suggest that FOT can be related to reflective decision making but not necessarily decision making that is more intuitive. PMID- 24796163 TI - Nigerian Centenary Award beneficiary: Professor Kelsey Atangamuerimo Harrison. PMID- 24796164 TI - Traditional versus birth attendants in provision of maternity care: call for paradigm shift. PMID- 24796165 TI - Components of maternal healthcare delivery system contributing to maternal deaths in Malawi: a descriptive cross-sectional study. AB - In Malawi, it has been observed that some women are dying even when they reach a comprehensive emergency obstetric care facility where the quality is expected to be high and the maternal mortality low. The objective of this study was to describe shortcomings within the maternal healthcare delivery system that might have contributed to maternal deaths in the district of Lilongwe. Retrospectively, 14 maternal deaths that occurred between January 1, 2011 and June 30, 2011 were reviewed. Interviews were conducted with healthcare workers who provided care to the deceased women. Triangulated data from the respective medical charts and interview transcripts were analyzed using a directed approach to content analysis. Excerpts were categorized according to three main components of the maternal healthcare delivery system: skill birth attendant (SBA), enabling environment (EE) and referral system (RS). Most of the shortcomings identified were grouped under SBA. They included inadequate clinical workups and monitoring, missed and incorrect diagnoses, delayed or incorrect treatment, delayed referrals and transfers, patients not being stabilized before being referred and outright negligence. The SBA component should be investigated further. Interventions based on evidence from these investigations may have a positive impact on maternal mortality. PMID- 24796166 TI - Evaluating the benefits of incorporating traditional birth attendants in HIV prevention of mother to child transmission service delivery in Lilongwe, Malawi. AB - The objective of our intervention was to examine the benefits of incorporating traditional birth attendants (TBA) in HIV Prevention of Mother to Child Transmission (PMTCT) service delivery. We developed a training curriculum for TBAs related to PMTCT and current TBA roles in Malawi. Fourteen TBAs and seven TBA assistants serving 4 urban health centre catchment areas were assessed, trained and supervised. Focus group discussions with the TBAs were conducted after implementation of the program. From March 2008 to August 2009, a total of 4017 pregnant women visited TBAs, out of which 2133 (53.1%) were directly referred to health facilities and 1,884 (46.9%) women delivered at TBAs and subsequently referred. 168 HIV positive women were identified by TBAs. Of these, 86/168 (51.2%) women received nevirapine and 46/168 (27.4%) HIV exposed infants received nevirapine. The challenges in providing PMTCT services included lack of transportation for referrals and absence of a reporting system to confirm the woman's arrival at the health center. Non-disclosure of HIV status by patients to the TBAs resulted in inability to assist nevirapine uptake. TBAs, when trained and well-supervised, can supplement efforts to provide PMTCT services in communities. PMID- 24796167 TI - Barriers to skilled birth attendance: a survey among mothers in rural Gambia. AB - The objectives of this cross-sectional survey were to identify the most important barriers for use of skilled attendance during childbirth by women in rural Gambia. We also assessed information received during antenatal care, preparations made prior to childbirth, and experiences and perceptions that may influence the use of skilled birth attendance in rural Gambia. The most frequently stated barriers for giving birth in a health facility were not having enough time to go (75%), and lack of transport (29%). The majority of the women (83%) stated that they preferred having a health worker attending their childbirth. More than seventy percent of the participants gave birth attended by a traditional birth attendant, but only 27% had intended to give birth at home. Sixty-four percent had made advance arrangements for the childbirth. Only 22% were informed about expected time of birth during antenatal care. Our findings suggest that the participants hold the knowledge and motivation that is necessary if practices are to be changed. Interventions aiming at ensuring timely transport of women to health facilities seem key to increased use of skilled birth attendants. PMID- 24796168 TI - Prevalence and correlates of maternal anemia in rural Sidama, Southern Ethiopia. AB - In order to assess the prevalence and correlates of prenatal anemia, a survey was conducted among 700 randomly selected pregnant women in rural Sidama, Southern Ethiopia. The prevalences of anemia, Iron Deficiency (ID) and ID anemia were 31.6%, 17.4% and 8.7%, respectively. The burden of anemia was significantly high among illiterates, women devoid of self-income, lowlanders, multiparas and women aged 25-34 years. Women who weren't on iron-folate supplementation had 1.90 (95% Confidence Interval (CI): 1.14-3.19) times increased odds of anemia. Anemia was associated with ID, zinc deficiency and elevated C-reactive protein with odds ratio of 2.46 (95% CI: 1.63-3.73), 2.29 (95% CI: 1.62-3.23) and 1.98 (95% CI: 1.12-3.47) respectively; however, it was not associated with vitamin A deficiency. Though ID was a significant correlate of anemia, only 11.8% of anemia was attributable to it. Zinc, iron and vitamin A deficiencies did not show synergistic interaction in associating with anemia. PMID- 24796169 TI - Estimating the influence of maternal height on under-five mortality in Nigeria. AB - This study uses a nationally representative data sample to assess the effect of maternal height as an intergenerational influence on under-five mortality. Data from the 2003 and 2008 Nigerian Demographic Health Survey (NDHS) (n = 41,005) selecting women aged 15 to 49 yrs whose most recent births were within 5 years (n = 23,568), were analyzed. The outcome measure was under-five mortality. Independent variables included maternal height categorized as > or = 63 inch, 61 62.9 inch, 59.1-60.9 inch, < 59.1 inch. Confounding factors were controlled for. A multivariable logistic regression was used to obtain odds ratio estimates along with their respective confidence interval. After adjusting for confounding factors, we found that each 1 inch increase in maternal height, was associated with a decreased odds of mortality OR 0.98 (95% CI 0.97-0.99). The OR of under five mortality when comparing women > or = 63 inch versus women < 59.1 inch was 1.13 (95% CI 0.98-1.31). The population attributable fraction of child death due to maternal short stature was 0.36. PMID- 24796170 TI - Non-surgical adult male circumcision using the PrePex device: task-shifting from physicians to nurses. AB - The Republic of Rwanda is implementing a program of voluntary male circumcision (MC) to reduce HIV transmission but lacks the infrastructure for conventional surgical MC on a nationwide scale. Nonsurgical MC using the PrePex device was first assessed in 5 subjects on an inpatient basis. Subsequent procedures were on an outpatient basis. Physicians performed 100 outpatient procedures (Phase 1 of this study) and trained nurses in the technique; the nurses then independently performed 47 procedures (Phase 2). All subjects achieved complete circumcision and healing within 6 weeks. There were no cases of infection or bleeding. In Phase 1, one case of transient moderate diffuse edema occurred. In Phase 2, no adverse events were reported. Thus, outcomes of MC performed by nurses using the PrePex device were not inferior to outcomes achieved by physicians, suggesting that task-shifting MC by this method from physicians to nurses is feasible in Rwanda. PMID- 24796171 TI - Current and predicted fertility using Poisson regression model: evidence from 2008 Nigerian Demographic Health Survey. AB - Nigeria with persistent high growth rate is among top ten most populous countries. Monitoring key mechanisms of population dynamics particularly fertility in Nigeria is long overdue. Periodical availability of data on fertility and other demographic indices is scarce, hence this study. Our objective was to build a non-linear model to identify fertility determinants and predict fertility using women's background characteristics. We used 2008 Nigeria Demography and Health Survey dataset consisting of 33,385 women with 31.4% from urban area. Fertility was measured using children ever born (CEB) and fitted into multi-factors additive Poisson regression models. Respondents mean age was 28.64 +/- 9.59 years, average CEB of 3.13 +/- 3.07 but higher among rural women than urban women (3.42 +/- 3.16 vs 2.53 +/- 2.79). Women aged 20-24years were about twice as likely to have higher CEB as those aged 15-19 years (IRR = 2.06, 95% CI: 1.95-2.18). Model with minimum deviance was selected and was used to predict CEB by the woman. PMID- 24796172 TI - Contraceptive discontinuation and switching among Ghanaian women: evidence from the Ghana Demographic and Health Survey, 2008. AB - This study identifies factors associated with contraceptive discontinuation and switching among Ghanaian women of reproductive age, using data from 1,378 female respondents of the 2008 Ghana Demographic and Health Survey. Logistic regression models were used to determine relationships between key socio-demographic factors and user status. Discontinued use occurred among 56% of ever users and switching among 55% of current users. The IUD was most abandoned (70%) and its use was associated with almost twice the odds of discontinuation (OR = 1.97; 95% CI (1.04, 3.75)). Having a history of terminated pregnancy significantly predicted both discontinuation (OR = 1.36; 95% CI (1.03, 1.79) and switching (OR = 1.78; 95% CI (1.16, 2.73)) and intention to limit births significantly predicted lower discontinuation (OR = 0.71; 95% CI (0.52, 0.96)). Counseling services emphasizing contraceptive options and reinforcing switching are critically needed to reduce unwanted pregnancies that may result from poor method use and discontinuation especially among post-abortion clients and IUD users. PMID- 24796173 TI - The effect of educational intervention on family planning knowledge, attitudes, and practices among married women in a military barrack in northern Nigeria. AB - Army barracks in Nigeria have low contraceptive prevalence rates (CPRs) and many children per family. The aim of this interventional study, involving 963 married women, is to determine the impact of health education on family planning knowledge, attitudes, and practices among married barrack women. The intervention group attended a 50-minute health talk and demonstrations on family planning methods. In the intervention group, the mean knowledge score rose significantly, from 5.5 points to 7.8 points post-intervention (t = -16.7281, p = 0.0000, df = 460). In addition, the CPR increased significantly, from 11.8% at baseline to 22.4% post-intervention (McNemar's chi2 = 125.41, p = 0.0000). Such significant changes were not noted in the control group. We conclude that health education is an effective intervention for improving knowledge about and attitudes towards contraceptives and their use among married women in military barracks in Nigeria. Intense and sustained health education is therefore recommended in addressing the low CPR in Nigeria. PMID- 24796174 TI - Predictors of contraceptive use among female adolescents in Ghana. AB - Adolescent girls in Ghana still face a number of challenges accessing reproductive/sexual health services despite efforts to improve their accessibility. This paper explores the key socio-demographic factors associated with contraceptive use amongst adolescent girls in Ghana using the 2008 Ghana Demographic and Health Survey (GDHS). Data from the 2008 GDHS was analyzed. Socio demographic variables were selected to assess their interaction with contraceptive use. Multivariable regression analyses were performed. Odds ratios and confidence intervals were computed. Place of residence and marital status were the most important predictors of contraceptive use among sexually active adolescents. Rural residents were less likely to use contraceptives compared to urban residents (OR 0.32, CI 0.12-0.84, p = 0.021) as well as married respondents compared to their unmarried peers (OR 0.27, 95% CI 0.11-0.67, p = 0.005). The accessibility of reproductive/sexual health services needs to be improved and promoted in rural areas and among married adolescent women. PMID- 24796175 TI - Gender based violence and its effects on women's reproductive health: the case of Hatcliffe, Harare, Zimbabwe. AB - Gender based violence (GBV) negatively impacts on women's reproductive health (R.H) and is contrary to human rights and RH statutory instruments. The study triangulates quantitative and qualitative research methods with women in the reproductive age group being the target group. The study noted that 95% of the respondents experienced physical violence, 31% rape by a stranger, 92% spousal rape and 65% forced marriages. Socio-cultural, religious, economic and policy implementation factors underlie a culture of silence that prevails among the victims of GBV. The study recommends economic empowerment of women and information, education, counselling pertaining to the negative effects of GBV to both males and females. There is need for education about grievance procedures and scaling up of policy enforcement in order to curb the gruesome effects of GBV. PMID- 24796176 TI - Mother-child communication about sexual health, HPV and cervical cancer among antenatal clinic attendees in Johannesburg, South Africa. AB - Parent-child communication about sexual health is considered an effective strategy for encouraging safe sexual practices among youth. This study used a brief survey to examine mother-child communication among 86 antenatal clinic attendees in Johannesburg, South Africa. Eighty-five percent of mothers reported having enough information to discuss HIV/AIDS prevention with their children, while only 36% reported having enough information to discuss HPV/cervical cancer prevention. Thirty-seven percent of mothers who reported being comfortable discussing HIV/sexual health with their child actually discussed these topics with their child; while 58% of mothers who reported being comfortable did not discuss HIV/sexual health with their child. Future research and program planning efforts should focus on identifying the best strategies to educate South African mothers on HPV and cervical cancer, so that mothers can effectively communicate their knowledge about these topics to their children. PMID- 24796177 TI - The knowledge base and acceptability of prenatal diagnosis by pregnant women in Ibadan. AB - This cross-sectional study evaluated knowledge and acceptability of prenatal diagnosis among 500 pregnant women at the University College Hospital, Ibadan. Most participants were aged 25-34 years, self-employed, Muslim, monogamy, secondary school leavers, on income of < naira10,000.00 (US$ 67.00)/month. Attitudinal mean score was dependent on age (p = 0.006), educational attainment (p = 0.001), marital status (p = 0.025) and religion (p = 0.012). Knowledge mean score was influenced by marital status (p = 0.028). Overall, acceptance of prenatal diagnosis was high. There was a direct correlation between acceptance and educational attainment: 41.5%, 31.50%, 19%, 19% of women who agreed to have prenatal diagnosis had tertiary, secondary school, primary school and no formal education respectively. Determinants of acceptability were age, educational attainment, marital status and religion. Being married significantly affected knowledge scores, while tertiary education, being divorced, unskilled and self employed positively influenced attitude towards prenatal diagnosis. PMID- 24796178 TI - Prevalence and determinants of adherence to highly active antiretroviral therapy amongst people living with HIV/AIDS in a rural setting in south-south Nigeria. AB - Adherence to HAART is necessary to achieve the best virologic response and lower the risk of drug resistance amongst People living with HIV/AIDS (PLHIV). However, there is limited documentation of adherence amongst patients on HAART in the south-south region of Nigeria. This study aimed to determine the prevalence and determinants of adherence to HAART amongst PLHIV in a rural setting in Cross River State. A descriptive cross-sectional study was conducted among 393 patients on HAART attending the Heart to Heart centre Ugep using an interviewer administered questionnaire. Adherence was measured via self report and patients were termed adherent if they took at least 95% of prescribed doses. The self reported adherence rate based on a one week recall was 50.4%. The main reason for skipping doses were being busy (50.6%), simply forgetting to take medications (43.8%) and religious constraints (16%). Perceived improved health status [OR 2.7; CI: 1.37-5.39], Non use of herbal remedies, [OR 1.8; 95% CI: 1.23- 2.64] and ARV regimens devoid of dietary instructions [OR 1.49; 95% CI: 1.07- 2.06] were significant predictors of adherence. The adherence rate reported in this study was low. Appropriate adherence enhancing intervention strategies targeted at use of simplified ARV regimens and discouraging herbal use is strongly recommended. PMID- 24796179 TI - Utilization of HIV testing and counseling in Ghana: implications for universal coverage. AB - HIV testing and counselling (HTC) is a gateway to all systems of AIDS-related care. This study examined national programme data to highlight gaps in HTC service utilization, regional differences and differential use of various HTC programs in Ghana in the period, 2007-2010. Analysis showed HTC increased rapidly across the country, however the increase was not uniform across the 10 regions. Also huge differential use of current HTC programs (Diagnostic Centre (DCs), Know Your Status campaigns (KYS) and PMTCT Centres) emphasized differential preferences of various testing programmes. Testing through KYS was substantially higher than testing done at DCs. However, HIV positive test rates at DCs were comparatively higher across the regions than those of KYS. KYS thus attracts and conducts huge numbers of HIV tests, yet it captures relatively low HIV positives. A well structured and more targeted expansion of facility-based HTC services to capture most vulnerable population groups is needed. PMID- 24796180 TI - Group psychological therapy in obstetric fistula care: a complementary recipe for the accompanying mental ill health morbidities? AB - The objective of this study is to determine the impact of group psychological therapy (GPT) on the mental health of obstetric fistula patients. It was a comparative pre and post intervention design. All patients had GPT prior to surgery and mental health assessment conducted before and after surgical repair. There was a significant reduction in proportion of those with severe mental health status after surgery. Specifically, the proportion of those with depression score of 4 and above reduced from 71.7% to 43.4%, and those with score of less than 4 increased from 28.3 to 56.6 percent. There was a significant reduction in those with very low self-esteem from 65.0% to 18.3%. Suicidal ideation reduced generally; severe (15.0 to 0%), moderate (16.7 to 5.0%) and mild (25.0 to 21.7%) and those without increased (43.3 to 73.3%). In conclusion, GPT is a useful adjunct to OF care as it improves their overall mental health status. PMID- 24796181 TI - The prevalence of polycystic ovary morphology among women attending a new teaching hospital in southern Nigeria. AB - The aim of this study was to determine the prevalence of polycystic ovary morphology (PCO) among Nigerian women attending for pelvic ultrasound. This was a retrospective study of the ultrasound scan findings of all women who attended for pelvic ultrasound scan at a new teaching hospital in southern Nigeria from the commencement of ultrasound services on 1 March to 31 July 2010. The main indication for the scans was infertility (52.7%), and the commonest finding was fibroid (44.6%). Polycystic ovary morphology was present in 12.2% of the women. On average women with PCO were younger (30.3 v 35.0 years) and more likely to present with amenorrhea (33.3 v 7.6%) than women without PCO, but there was no other statistically significant differences between the two groups. This study suggests that Nigerian women have a low incidence of PCO morphology. PMID- 24796182 TI - [Expression profile of osteogenic-related genes during spontaneous calcification of rat bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To analyze the expression profile changes of osteogenic-related genes during spontaneous calcification of rat bone marrow mesenchymal stem cells (BMSCs). METHODS: BMSCs were isolated from 3-day-old healthy Sprague Dawley rats; cells at the 4th generation were used to establish the spontaneous calcification model in vitro. Spontaneous calcification process was recorded by inverted phase contrast microscope observation and alizarin red staining after 7 and 14 days of culture. For gene microarray analysis, cell samples were collected at 0, 7, and 14 days after culture; the differentially expressed genes were analyzed by bioinformatics methods and validated by real-time quantitative PCR (RT-qPCR) assay. RESULTS: Rat BMSCs calcified spontaneously in vitro. When cultured for 7 days, the cells began to aggregate and were weakly positive for alizarin red staining. After 14 days of culture, obvious cellular aggregation and typical mineralized nodules were observed, the mineralized nodules were brightly positive for alizarin red staining. A total of 576 gene probe-sets expressed differentially during spontaneous calcification, corresponding 378 rat genes. Among them, 359 gene probe-sets expressed differentially between at 0 and 7 days, while only 13 gene probe-sets expressed differentially between at 7 and 14 days. The 378 differentially expressed genes were divided into 6 modes according to their expression profiles. Moreover, according to their biological functions, differentially expressed genes related to bone cell biology could be classified into 7 major groups: angiogenesis, apoptosis, bone-related genes, cell cycle, development, cell communication, and signal pathways related to osteogenic differentiation. In cell cycle group, 12 down-regulated genes were linked with each other functionally. Matrix metalloproteinase 13 (Mmp13), secreted phosphoprotein 1 (Spp1), Cxcl12, Mmp2, Mmp3, Apoe, and Itga7 had more functional connections with other genes. The results of genes Spp1, Mgp, Mmp13, Wnt inhibitory factor 1, Cxcl12, and cyclin A2 by RT-qPCR were consistent with that of gene microarray. CONCLUSION: The first 7 days after rat BMSCs were seeded are a key phase determining the fate of spontaneous calcification. Multiple genes related with cell communication, bone-related genes, cell cycle, transforming growth factor-beta signaling pathway, mitogen-activated protein kinase signaling pathway, and Wnt signaling pathway are involved during spontaneous calcification. PMID- 24796183 TI - [Preliminary study on transgenic cell sheet with cartilage-derived morphogenetic protein]. AB - OBJECTIVE: To construct a transgenic cell sheet of cartilage-derived morphogenetic protein 1 (CDMP1) by adenovirus vector in vitro and to identify its biological activity. METHODS: The bone mesenchymal stem cells (BMSCs) were isolated from bone marrow of 1-month-old rabbit, and cultured in vitro. The 3rd 6th generation of BMSCs were used for experiment. The experiment was divided into 3 groups: BMSCs transfected by adenovirus (Ad)-cytomegalovirus (CMV)-human CDMP1 (hCDMP1)-internal ribosome entry site (IRES)-enhanced green fluorescent protein (EGFP) in group A, BMSCs transfected by Ad-CMV-EGFP in group B, and untransfected BMSCs in group C. The expression of green fluorescence was observed in 3 groups under fluorescent inverted microscope. MTT assay was used to detect the proliferation of the cells. The cell sheet was obtained by means of temperature responsive culture dish for 14 days. The morphological and HE staining observations of the cell sheet were carried out. RT-PCR and Western blot were used to detect the expressions of hCDMP1 and collagen type II at gene and protein levels, while alcian blue staining was used to detect the expression of glycosaminoglycans (GAG). RESULTS: Bright green fluorescence was observed in transfected cells at 72 hours under fluorescent inverted microscope, and the transfection efficiency was up to 90%. MTT assay showed approximate S-shaped growth curves in 3 groups, showing no significant difference in the absorbance (A) value among 3 groups within 9 days (P > 0.05). The three-dimensional cell sheets were successfully harvested in vitro. The RT-PCR and Western blot showed that there were positive expressions of hCDMPl and collagen type II in group A and negative expression in other 2 groups. HE staining and alcian blue staining showed that there were rich fibrous tissues, mass extracellular matrix, and dark blue metachromatic granules in group A, but there was less fibrous tissues and no specific blue metachromatic granules in other 2 groups; and the positive expression area was significantly lower and gray scale of GAG was significantly higher in group A than that in groups B and C (P < 0.05). CONCLUSION: A transgenic cell sheet of exogenous recombinant hCDMP1 by adenovirus vector can express collagen type II and GAG, so it has chondrogenic capacity. This technology that overcomes limitations in traditional tissue engineering, such as low cell-attachment efficiency and inflammatory reaction, may be a new tissue engineering approach for hard tissue reconstruction and is hopeful to build a large density of tissue engineered cartilage. PMID- 24796184 TI - [Chondrogenesis of bone marrow mesenchymal stem cells induced by transforming growth factor beta3 gene in Diannan small-ear pigs]. AB - OBJECTIVE: To observe transforming growth factor beta3 (TGF-beta3) gene expression and the chondrogenesis of bone marrow mesenchymal stem cells (BMSCs) after TGF-beta3 gene is transfected into BMSCs of Diannan small-ear pig. METHODS: Recombinant adenovirus 5 (rAd5) was extracted as gene vector and packed into recombinant adenovirus rAd5-TGF-beta3, double enzyme digestion and PCR identification were performed. BMSCs were isolated and cultured from bone marrow of 2-month-old Diannan small-ear pigs (weighing, 12-15 kg), and the 2nd generation of BMSCs were harvested for experiments. The experiments were divided into 3 groups. BMSCs were transfected with rAd5-TGF-beta3 as experimental group and with empty vector as control group, and non-transfected BMSCs were used as blank control group. The transfection efficiency of exogenous gene was identified by flow cytometry, TGF-beta3 protein expression by immunofluorescence and Western blot. The cell morphology of experimental group was observed by inverted phase contrast microscope, and the expression of collagen type II in each group was detected by Western blot. RESULTS: The rAd5-TGF-beta3 recombinant adenovirus was successfully constructed and transfected into BMSCs. Green fluorescence was observed by immunofluorescence microscope. Flow cytometry test showed the best transfection at 72 hours (transfection efficiency of 84.86%). Immunofluorescence staining showed that the expression of TGF-beta3 protein was obvious at 72 hours; Western blot showed that there was a TGF-beta3 positive band with a relative molecular mass of 30 x 10(3), while the control group and blank control group had no positive band. Obvious chondrogenic differentiation was observed in the experimental group after transfection in vitro, while the control group and blank control group had no obvious chondrogenic differentiation. Western blot showed that there was collagen type II positive band with a relative molecular mass of 130 x 10(3) at 21 days after culture, while the control group and blank control group had no positive band. CONCLUSION: rAd5-TGF-beta3 gene can be successfully transfected into BMSCs via adenovirus vectors, and stable expression of TGF-beta3 protein can be observed, enhancing BMSCs differentiation into chondrocytes, which may provide an experimental basis for gene therapy of joint cartilage defects. PMID- 24796185 TI - [Experimental study on vascular endothelial growth factor 165 gene-modified rat hair follicle stem cells mediated by lentiviral vector]. AB - OBJECTIVE: To obtain rat hair follicle stem cells (rHFSCs) which can constantly and highly express vascular endothelial growth factor 165 (VEGF165), and to observe the expression of VEGF165 gene in rat HFSCs. METHODS: The cirri skin of 1 week-old Sprague Dawley rat was harvested and digested by using combination of Dispase and type IV collagenases. The bulge was isolated under microscope. The rHFSCs were cultured by tissue block method. After purified by rapid adhering on collagen type IV, the growth curve of different generations rHFSCs was drawn. The cells were identified by immunofluorescence staining and real time quantitative PCR (RT-qPCR) analysis that tested the expression level of correlated genes. Lentivirus of pLV-internal ribosome entry site (IRES)-VEGF165-enhanced green fluorescent protein (EGFP) (experimental group) and pLV-IRES-EGFP empty vector (control group) was packaged by calcium transfected method and the rHFSCs were transfected. The green fluorescent protein expression was observed by inverted fluorescence microscope, and VEGF165 mRNA and protein expressions were detected using RT-PCR and Western blot. RESULTS: The rHFSCs which were isolated, cultured, and purified were like the "slabstone", and had strong adhesion ability and colony formation ability. The purified cells were in latent growth phase at 2-3 days; they were in exponential growth phase at 5-6 days. The expressions of cytokeration 15 (CK15), integrin alpha6, and integrin beta1 (markers of HFSCs) were positive by immunocytochemistry. The RT-qPCR analysis showed that CK15, CK19, integrin alpha6, and integrin beta1 expressed highly, but CD34 (a marker of epidermal stem cells) and CK10 (a marker of keratinocyte) expressed lowly. After 14 days, the transfection efficiency was up to 85.76% +/- 1.91%. RT-PCR analysis and Western blot showed that VEGF165 mRNA and protein expressions were positive in experimental group, and were negative in control group. CONCLUSION: The rHFSCs with high purity and strong proliferation ability can be obtained by using microscope combined with tissue cultivation and rapid cell adhesion on collagen type IV. The rHFSCs with high expression of VEGF165 can be successfully obtained by lentiviral transfection. This method provides good seeding cells for tissue engineering to construct artificial hair follicles, blood vessels, and skins. PMID- 24796186 TI - [Three-dimensional culture and morphological observation of human eccrine sweat gland cells]. AB - OBJECTIVE: To investigate the three-dimensional (3D) culture and morphology of human eccrine sweat gland cells. METHODS: The human eccrine sweat gland cells were isolated from normal abdominal full thickness skin by digestion of type II collagenase, and cultured in defined-keratinocyte serum free medium supplemented with 5 ng/mL recombinant human epidermal growth factor, 25 mg/mL bovine pituitary extract, 100 U/mL penicillin, and 100 microg/mL streptomycin at 37 degrees C in a humidified atmosphere of 5%CO2/95% air incubator. When the cell fusion reached above 80%, the cells were harvested and the concentration was adjusted to 1 x 10(5) cells/mL. The mixture of 0.3 mL cell suspension and 0.3 mL Matrigel basement-membrane matrix was cultured in 12-well plate. The cell growth was observed under an inverted phase contrast microscope. At 14 days after culture, frozen sections were prepared and were stained with HE to observe the cells morphology, and immunohistochemical analysis was used to detect the antigen expressions of cytokeratin 7 (CK7) and CK19. RESULTS: Inverted phase contrast microscope observation showed that many free eccrine sweat gland tissues were seen after digestion of type II collagenase; eccrine sweat gland cells grew adhering to the wall at 3-5 days and continued division for 2-3 weeks to form single ring around the block sweat glands; cellular senescence were observed after 3-4 weeks. During the process of 3D culture, the single eccrine sweat gland cell divided into 2-4 cells after 2-3 days, and these cells subsequently formed small cell clusters, tubular-like structures and finally spheric-like shapes. After cultured for about 2 weeks, there was crack in part of the gelled mixture or liquefaction occurred. HE staining of frozen sections of the 3D cultures showed some of the tubular-like structures composed of 1-2 layers of epithelial cells, which were similar to the secretion part and the duct part of the eccrine sweat gland. Immunohistochemical analysis showed that CK7 and CK19 antigens expressed positively in the cells. CONCLUSION: Human eccrine sweat gland cells cultured in Matrigel can form the 3D structures which simulate the morphology of eccrine sweat glands in vivo. PMID- 24796187 TI - [Experimental study on gradient of nerve growth factor immobilized conduits promoting peripheral nerve regeneration in rats]. AB - OBJECTIVE: To study the effect of the loaded concentration gradient of nerve growth factor (NGF) immobilized conduit on rat peripheral nerve defect repair. METHODS: The peripheral nerve conduits made of poly (epsilon-caprolactone)-block poly (L-lactide-co-epsilon-caprolactone) were prepared with uniform loads or concentration gradient loads by combining differential absorption of NGF/silk fibroin (SF) coating, and the gradient of NGF was immobilized in the nerve conduits. ELISA method was used to exam the NGF release for 12 weeks in vitro. Twenty-four male Sprague Dawley rats (weighing, 220-250 g) were selected to establish the right sciatic nerve defect model (14 mm in length) and randomly divided into 4 groups according to repair methods. The transected nerve was bridged by a blank conduit without NGF in group A, by a conduit containing uniform loads of NGF in group B, by a conduit concentration gradient loads of NGF in group C, and by the autogenous nerve segment in group D. The gross observation, electrophysiological examination, histological observation, and transmission electron microscope observation were carried out to assess the nerve regeneration at 12 weeks after surgery. RESULTS: The cumulative release amount of NGF was (14.2 +/- 1.4) ng/mg and (13.7 +/- 1.3) ng/mg in gradient of NGF loaded conduits and uniform NGF loaded conduits respectively at 12 weeks, showing no significant difference (t = 0.564, P=0.570). All the animals survived to completion of the experiment; plantar ulcers occurred at 4 days, which healed at 12 weeks; groups C and D were better than groups A and B in ulcerative healing. At 12 weeks after surgery, the compound muscle action potential of group A was significantly lower than that of groups B, C, and D (P < 0.05), and group B was significantly lower than groups C and D (P < 0.05), but no significant difference was found between groups C and D (P > 0.05). The axon density of group C was significantly higher that of groups A, B, and D (P < 0.05); group D was significantly higher than groups A, B, and C, and group C was significantly higher than groups A and B in the axon number, axon diameter, and area of muscle fiber (P < 0.05); the thickness of myelin sheath of groups C and D was significantly larger than that of groups A and B (P < 0.05), but no significant difference was found between groups C and D (P > 0.05). CONCLUSION: Gradient of NGF loaded nerve condnits for rat sciatic nerve defect has similar results to autogenous nerve, with a good bridge, which can promote the sciatic nerve regeneration, improve the myelinization of the regenerating nerve, and accelerate the function reconstruction of the regenerating nerve. PMID- 24796189 TI - [Research progress of co-culture system for constructing vascularized tissue engineered bone]. AB - OBJECTIVE: To review the research progress of the co-culture system for constructing vascularized tissue engineered bone. METHODS: The recent literature concerning the co-culture system for constructing vascularized tissue engineered bone was reviewed, including the selection of osteogenic and endothelial lineages, the design and surface modification of scaffolds, the models and dimensions of the co-culture system, the mechanism, the culture conditions, and their application progress. RESULTS: The construction of vascularized tissue engineered bone is the prerequisite for their survival and further clinical application in vivo. Mesenchymal stem cells (owning the excellent osteogenic potential) and endothelial progenitor cells (capable of directional differentiation into endothelial cell) are considered as attractive cell types for the co-culture system to construct vascularized tissue engineered bone. The culture conditions need to be further optimized. Furthermore, how to achieve the clinical goals of minimal invasion and autologous transplantation also need to be further studied. CONCLUSION: The strategy of the co-culture system for constructing vascularized tissue engineered bone would have a very broad prospects for clinical application in future. PMID- 24796188 TI - [Application progress of seed cells in tissue engineered nerve]. AB - OBJECTIVE: To summarize the applications of Schwann cells (SCs), stem cells, and genetically modified cells (GMCs) in repair of peripheral nerve defects. METHODS: The literature of original experimental study and clinical research related with SCs, stem cells, and GMCs was reviewed and analyzed. RESULTS: SCs play a key role in repair of peripheral nerve defects; the stem cells can be induced to differentiate into SCs, which can be implanted into nerve conduits to promote the repair of peripheral nerve defect; genetically modified technology can enhance the function of SCs and different stem cells, which has been regarded as a new option for tissue engineered nerve. CONCLUSION: Although great progress has been made in tissue engineered nerve recently, mostly limited to the experimental stage. The research of seed cells in application of tissue engineered nerve need be studied deeply. PMID- 24796190 TI - [Research progress of skeletal myoblasts for cardiac repair]. AB - OBJECTIVE: To review the recent research progress of skeletal myoblasts for cardiac repair. METHODS: The related literature about skeletal myoblasts for cardiac repair was reviewed, analyzed, and summarized. RESULTS: The results of animal experiments and clinical studies have shown that skeletal myoblasts been transplanted into the regional myocardial infarction area in different ways can improve cardiac function. But there are some challenges such as high loss rate of skeletal myoblasts and resulting in ventricular arrhythmias. CONCLUSION: Further studies can improve the safety and effectiveness of skeletal myoblasts for cardiac repair in the future. PMID- 24796191 TI - [Clinical research of resection of mandibular benign tumors and primary reconstruction with autogenous bone graft via an intraoral approach]. AB - OBJECTIVE: To investigate the clinical outcomes of resection of mandibular benign tumors and primary reconstruction with autogenous bone graft via an intraoral approach. METHODS: Fifteen patients with mandibular benign tumors were treated between January 2009 and September 2012. There were 7 males and 8 females, aged from 18 to 45 years (mean, 30 years). The pathological diagnosis identified 11 cases of ameloblastoma, 3 cases of odontogenic keratocyst, and 1 case of odontogenic myxoma. According to the Urken's CRBS (Condyle, Ramus, Body, Symphysis) classification criteria based on the location of the mandibular defect, there were 3 cases of body type (B type), 3 cases of ramus type (R type), and 9 cases of body and ramus type (BR type). The surgeries were performed via an intraoral approach, except 1 patient with the lesion at the level of sigmoid notch via an auxiliary preauricular incision. To fix the bone grafts to the dissected mandibular defects, reconstructive titanium plates were used, either indirectly according to the computer aided design/computer aided manufacturing mandibular models before surgery (9 patients) or directly according to the exposed mandibles during surgery (6 patients). The patients received benign mandibular tumor resection and primary autogenous bone graft reconstruction with free iliac bones (11 cases) or vascularized fibular flaps (4 cases). The mandibular inferior alveolar nerves were preserved in 6 cases. RESULTS: Primary healing of incision was obtained in 14 patients, while secondary healing in 1 patient suffering from bone graft infection. All the patients were followed up 1 4 years (mean, 2.5 years). At last follow-up, no patients showed facial nerve damage; occlusion of remaining teeth was similar to preoperative conditions; the chewing function was satisfactory; mouth opening was 30-35 mm (mean, 33 mm); and swallowing and speaking functions were normal. Only slight extraoral scars caused by the auxiliary incision and the transbuccal appliances were observed, and all the patients were satisfied with the facial appearance. Lower lip numbness was relived in patients with preserved inferior alveolar nerves. There was no tumor recurrence during follow-up period. CONCLUSION: The intraoral approach is a feasible and proper approach for resection of benign mandibular tumors and primary reconstruction with autogenous bone grafts, with the advantages of inconspicuous facial scars, minimum damage to the facial nerve, and expectable aesthetic appearance. PMID- 24796192 TI - [Arthroscopic treatment of Snyder II type of superior labrum anterior and posterior injury by absorbable anchors through anterior and posterior approach]. AB - OBJECTIVE: To evaluate the effectiveness of arthroscopic treatment of superior labrum anterior and posterior (SLAP) injury by absorbable anchors through anterior and posterior approach. METHODS: Between January 2010 and August 2012, 28 patients with Snyder II type of SLAP injury underwent arthroscopic operation by absorbable anchors through anterior and posterior approach. There were 15 males and 13 females, aged from 30 to 45 years (mean, 36.5 years). The left shoulder was involved in 12 cases and the right shoulder in 16 cases. All patients had a clear history of trauma. The disease duration ranged from 2 weeks to 3 years (median, 13 months). The results of O'Brien test and Speed test were positive in 25 cases and 26 cases respectively. Shoulder pain visual analogue scale (VAS) was 7.6 +/- 1.4. The Constant score of shoulder joint function was 60.2 +/- 4.3. RESULTS: Operation was successfully completed, and the incision healed well in all cases, with no complication. The follow-up time ranged from 12 to 36 months (mean, 24.5 months). The symptoms of shoulder joint interlocking, snapping, and instability disappeared. The joint pain was significantly improved. At 12 months after surgery, Constant score of shoulder joint function was 92.7 +/ 4.5, showing significant difference when compared with preoperative score (t = 30.279, P = 0.000); the shoulder pain VAS score was 1.1 + 0.9, showing significant difference when compared with preoperative score (t = 23.810, P = 0.000). At 1 year after operation, MRI examination showed complete healing in 25 cases, and high signal in 3 cases, but the pain and activity were significantly improved. CONCLUSION: Arthroscopic treatment of SLAP injury by absorbable anchors through anterior and posterior approach has the advantages of less injury, small incision, and quick recovery, so it is an ideal operation method. PMID- 24796193 TI - [Type C2 proximal humeral fracture fixation using locking-plate with an intramedullary fibular allograft]. AB - OBJECTIVE: To investigate the clinical results of locking-plate with an intramedullary fibular allograft for type C2 proximal humeral fracture fixation. METHODS: Between January 2011 and August 2012, 16 patients with proximal humeral fractures (AO type C2) were treated by locking-plate with an intramedullary fibular allograft. The clinical data were retrospectively analysed. There were 5 males and 11 females with an average age of 64 years (range, 55-70 years). The injury causes were falling injury in 12 cases, traffic accident injury in 3 cases, and sports injury in 1 case. The duration between injury and operation ranged from 2 to 6 days (mean, 4.5 days). The imaging data were used to judge the fracture healing, and to measure the neck-shaft angle and the height of humeral head; the disability of arm, shoulder, and hand (DASH) score, short-form 36 health survey scale (SF-36), and Neer score were used to evaluate the function of the shoulder after surgery. RESULTS: Primary healing of incision was obtained in all patients; no complication of vascular and nerve injury occurred. Sixteen cases were followed up 12-24 months (mean, 18 months). All fractures healed at 18 24 weeks (mean, 20 weeks). No complication occurred as follows: re-displacement, necrosis, rejection reaction, and loosening or extraction of screws. At last follow-up, the neck-shaft angle was 126.6-136.9 degrees (mean, 132.5 degrees), showing a little lost when compared with intraoperative angle (130.5-138.0 degrees, 134.0 degrees on average). At 12 months after surgery, the height loss of humeral head was 1.8-4.6 mm (mean, 2.0 mm); the passive anteflexion of the shoulder was 130-160 degrees (mean, 148 degrees); the active anteflexion was 120 145 degrees (mean, 136 degrees); the external rotation was 30-65 degrees (mean, 56 degrees); the internal rotation was 15-25 degrees (mean, 19 degrees). And the DASH score was 2-53 (mean, 12); the SF-36 score was 50-95 (mean, 89). According to Neer score for shoulder function, the results were excellent in 10 cases, good in 4 cases, fair in 1 case, and poor in 1 case, with an excellent and good rate of 87.5%. CONCLUSION: Locking-plate with an intramedullary fibular allograft for type C2 proximal humeral fracture fixation has satisfactory clinical results because of stable fixation, high clinical outcome scores, and low internal fixation failure. PMID- 24796194 TI - [Intra-articular radioulnar ligament reconstruction for chronic instability of distal radioulnar joint]. AB - OBJECTIVE: To evaluate the effectiveness of intra-articular radioulnar ligament reconstruction in the treatment of chronic instability of the distal radioulnar joint. METHODS: Between January 2006 and June 2012, the intraarticular radioulnar ligament reconstruction was used to treat chronic instability of the distal radioulnar joint in 12 patients. Of 12 cases, 8 were males and 4 were females with an average age of 37.3 years (range, 22-54 years). The causes of injury were tumble in 9 patients, traffic accident in 2 patients, and sprain in 1 patient. The average time from initial injury to operation was 6.2 months (range, 2-13 months). The pain and function of the wrists were assessed with Patient-Rated Wrist Evaluation (PRWE) (27.5 +/- 4.7). Broadening of the distal radioulnar joint space was seen on the anteroposterior radiograph in all the patients. Lateral view showed dorsal instability in 10 patients and palmar instability in 2 patients. There was no radial fracture, ulnar fractures or degeneration of the distal radioulnar joint. RESULTS: All patients achieved primary healing of incision. No complication of deep infection or nerve injury occurred. They were followed up from 12 to 30 months (mean, 20.6 months). Pain and the clicking sound of the wrists disappeared; grip strength increased; the range of motion values of the wrist and forearm were restored. PRWE score was 5.8 +/- 2.1 at last follow up, showing significant difference when compared with preoperative score (t = 14.215, P = 0.000). Imaging examination showed good appositions of the distal radioulnar joint, with no dislocation or subluxation. CONCLUSION: Intra-articular radioulnar ligament reconstruction can rebuild the anatomic stability of the distal radioulnar joint, which does not damage the adjacent structures of the joints and can obtain satisfactory function of the reconstructed joint. It is a good choice for chronic instability of the distal radioulnar joint without articular degeneration. PMID- 24796195 TI - [Articular external fixation for chronic dorsal instability of distal radioulnar joint]. AB - OBJECTIVE: To discuss the clinical result of extrinsic radioulnar tether combined with anchoring nail fixation for treating chronic dorsal instability of the distal radioulnar joint (DRUJ). METHODS: Between July 2011 and December 2012, 6 patients with chronic dorsal instability of the DRUJ were treated with extrinsic radioulnar tether combined with anchoring nail fixation. There were 1 male and 5 females with the average age of 27.3 years (range, 22-35 years). All of 6 patients had a wrist trauma history. The average disease duration was 4.8 years (range, 6 months to 15 years). Radiographs were taken postoperatively to observe the anchoring nail loosening. The stress test and forearm rotation test were used to evaluate the function of DRUJ. The complications, the grip power, range of motion, and visual analogue scale (VAS) scores were recorded at last follow-up. And the joint function was evaluated by disability of arm, shoulder, and hand (DASH) score. RESULTS: Primary healing of incision was obtained in all cases, without any complications such as infection and ulnar neck fracture. All 6 patients were followed up 6-24 months (mean, 13.7 months). Stability was achieved in all patients. Radiographs showed that the joint space was widened and dislocation of the ulnar head was improved at 3 and 6 months after operation. The results of the stress test and forearm rotation test were negative. At last follow-up, the grip power, DASH score, VAS score, and range of motion of the wrist were significantly improved when compared with preoperative ones (P < 0.05). CONCLUSION: Extrinsic radioulnar tether combined with anchoring nail fixation is an easy method of surgical revision to treat chronic dorsal instability of DRUJ, which can maintain the stability and protect the blood supply of triangular fibrocartilage complex. PMID- 24796196 TI - [Effect of reformative acetabular centralization technology on leg-length inequality in total hip arthroplasty]. AB - OBJECTIVE: To investigate the application value of acetabular centralization technology for correction of leg-length inequality in total hip arthroplasty (THA). METHODS: Between June 2001 and January 2012, 147 cases of abnormal acetabular center were treated. Of them, 68 cases underwent routine THA (control group), and 79 cases underwent acetabular reconstruction by fossae ovalis oriented centralized technology in THA (test group). There was no significant difference in gender, age, side, pathogeny, acetabular rotation center indexs, difference of relative and absolute leg-length, and Harris score between 2 groups before operation (P > 0.05). The hip joint function was evaluated by Harris score; the difference of relative leg-length was measured by tape; the difference of absolute leg-length and the horizontal and vertical distances of actual and true rotation center were also measured on the X-ray films by software. RESULTS: The patients were followed up 8-26 months (mean, 8.3 months) in the test group, and 6-33 months (mean, 9.7 months) in the control group. Sciatic nerve injury occurred in 2 cases (1 in each group, respectively), lower extremity deep venous thrombosis in 7 cases (3 in test group and 4 in control group), and hip joint dislocation in 2 cases (control group); the other patients had no related complications. The difference of relative leg-length and Harris score in test group were significantly better than in control group (P < 0.05), and significant difference was also found when compared with preoperative one in 2 groups (P < 0.05). The horizontal and vertical distances of actual and the true rotation center in test group was significantly better than those in control group at immediate after operation on the X-ray films (P < 0.05); and significant differences were also found when compared with preoperative ones in 2 groups (P < 0.05). At 6 months after operation, the absolute leg-length difference in test group was significantly better than that in control group (P < 0.05); and significant difference was also found when compared with preoperative one in 2 groups (P < 0.05). CONCLUSION: The fossae ovalis oriented acetabular centralized technology in THA can significantly correct abnormal hip center of rotation, thus reduce the relative and absolute leg-length inequality and improve the life quality of the patients. PMID- 24796197 TI - [Mid-term results of total hip arthroplasty for osteoarthritis secondary to hip sepsis]. AB - OBJECTIVE: To evaluate mid-term results of total hip arthroplasty (THA) for treatment of osteoarthritis secondary to hip sepsis. METHODS: Between February 2003 and January 2009, 62 patients (62 hips) with osteoarthritis secondary to hip sepsis underwent THA. There were 32 males and 30 females with an average age of 39.9 years (range, 18-67 years). The original infection included pyogenic arthritis in 40 hips and tuberculosis in 22 hips. After infection, 35 patients underwent nonoperative treatment, and 27 patients received operative management. The average time interval between initial infection and THA was 28.7 years (range, 12-53 years). The preoperative Harris hip score was 24.6 +/- 9.2. The Trendelenburg sign was positive in all hips. Leg discrepancy was observed in 25 cases, and the mean discrepancy of bilateral lower extremities was 3.8 cm (range, 2.6-6.5 cm) preoperatively. All hips had no evidence of active hip sepsis. RESULTS: All patients were followed up 72 months on average (range, 54-115 months). Intraoperative complications included sciatic nerve injury (2 cases) and femoral shaft fractures (2 cases); postoperative complications included hip anterior dislocation (1 case) and periprosthetic infection (1 case). At last follow-up, 1 hip, 5 hips, 18 hips, and 38 hips were found to have severe pain, moderate pain, slight pain, and no pain respectively. Claudication occurred in 30 patients (mild in 19, moderate in 8, and severe in 3). The Trendelenburg sign was positive in 18 hips. After THA, only 5 patients had a leg length discrepancy of 2.9 cm on average (range, 2.6-3.5 cm). The Harris score was significantly increased to 82.3 +/- 11.4 at last follow-up when compared with preoperative one (t = -31.241, P=0.000). The results of subjective satisfaction were very satisfactory in 43 cases, satisfactory in 12 cases, unsatisfactory in 4 cases, and unsatisfactory at all in 3 cases. No sign of aseptic loosening of prosthesis was found during follow-up period. Roentgenographic results showed no radiolucent line or osteolysis in the other patients except 2 patients having local radiolucent. After THA, 12 hips had heterotopic ossification. CONCLUSION: The mid term clinical and radiographic results of THA for treatment of osteoarthritis secondary to hip sepsis are good, with the advantages of high satisfactory rate, good function recovery, and low complication incidence. PMID- 24796198 TI - [Tibial Inlay reconstruction of medial collateral ligament using Achilles allograft]. AB - OBJECTIVE: To evaluate the clinical results of the tibial Inlay technique for the medial collateral ligament (MCL) reconstruction using Achilles tendon allograft in recovery of medial instability of the knee. METHODS: Between January 2011 and December 2012, 21 patients underwent tibial Inlay reconstruction of the MCL using Achilles tendon allograft, and the clinical data were retrospectively analyzed. There were 13 males and 8 females with a mean age of 32 years (range, 19-62 years). Injury was caused by sports in 15 cases and by traffic accident in 6 cases. The disease duration ranged from 15 days to 3 months (mean, 1.5 months). According to International Knee Documentation Committee (IKDC) criteria, 5 cases were classified as degree II and 16 cases as degree III. The results of the valgus stress test were positive in all patients. The complications were observed after operation; IKDC subjective knee score and Lysholm score were used to assess the knee function. RESULTS: Bone block fracture occurred in 1 case during operation. Primary healing of incision was obtained in the other cases except 1 case having unhealing incision who was healed after skin grafting. No complications of knee joint stiffness, vascular nerve injury, and infection occurred. All patients were followed up 7-29 months (mean, 18.5 months). At last follow-up, the results of the valgus stress test were negative in 20 cases, and positive (degree I) in 1 case; the other patients had no knee extension or flexion limitation except 1 patient having 15 degrees flexion limitation. The Lysholm score was significantly improved from 45.4 +/- 13.6 to 87.5 +/- 9.4, the IKDC 2000 subjective score was significantly improved from 46.5 +/- 14.0 to 88.4 +/- 9.3 at last follow-up (P < 0.05). MRI showed that the reconstructed MCL was continuous. CONCLUSION: The short-term clinical results of the tibial Inlay technique for MCL reconstruction using Achilles tendon allograft are satisfactory. The Inlay technique for MCL reconstruction can provide good medial stability of the knee, but the lorg-term effectiveness needs further follow-up. PMID- 24796199 TI - [A comparative study on treatment of thoracolumbar fracture with injured vertebra pedicle instrumentation and cross segment pedicle instrumentation]. AB - OBJECTIVE: To compare the effective of short-segment pedicle instrumentation with bone grafting and pedicle screw implanting in injured vertebra and cross segment pedicle instrumentation with bone grafting in injured vertebra for treating thoracolumbar fractures. METHODS: A prospective randomized controlled study was performed in 40 patients with thoracolumbar fracture who were in accordance with the inclusive criteria between June 2010 and June 2012. Of 40 patients, 20 received treatment with short-segment pedicle screw instrumentation with bone grafting and pedicle screw implanting in injured vertebra in group A, and 20 received treatment with cross segment pedicle instrumentation with bone grafting in injured vertebra in group B. There was no significant difference in gender, age, affected segment, disease duration, Frankel grade, Cobb angle, compression rate of anterior verterbral height, visual analogue scale (VAS) score, and Japanese Orthopaedic Association (JOA) score between 2 groups before operation (P > 0.05). The operation time, blood loss, Cobb angle, compression rate of anterior vertebral height, loss of disc space height, Frankel grade, VAS and JOA scores were compared between 2 groups. RESULTS: There was no significant difference in the operation time and blood loss between 2 groups (P > 0.05). Primary healing of incision was obtained in all patients, and no early complication of infection or lower limb vein thrombus occurred. Forty patients were followed up 12-16 months (mean, 14.8 months). No breaking or displacement of internal fixation was observed. The improvement of Frankel grading score was 0.52 +/- 0.72 in group A and 0.47 +/- 0.63 in group B, showing no significant difference (t = 0.188, P = 0.853) at 12 months after operation. The Cobb angle, compression rate of anterior verterbral height, and VAS score at 1 week and 12 months, and JOA score at 12 months were significantly improved when compared with preoperative ones in 2 groups (P < 0.05). No significant difference was found in Cobb angle, disc space height, VAS score, and JOA score between 2 groups at each time point (P > 0.05), but the compression rate of anterior verterbral height in group A was significantly lower than that in group B (P < 0.05). The loss of disc space height next to the internal fixation or the injured vertebra was observed in 2 groups at 12 months, but showing no significant difference (P > 0.05). CONCLUSION: Compared with cross segment pedicle instrumentation, short-segment pedicle screw instrumentation with bone grafting and pedicle screw implanting in injured vertebra can recover and maintain the affected vertebra height in treating thoracolumbar fractures, but it could not effectively prevent degeneration of adjacent segments and the loss of kyphosis correction degree. PMID- 24796200 TI - [Combination of high porous polyethylene lower eyelid spacers and lateral tarsal strip procedure for reconstruction of eyelid closure function in paralytic lagophthalmus after facial palsy]. AB - OBJECTIVE: To evaluate the effectivness of using high porous polyethylene lower eyelid spacers (Medpor LES) combined with the lateral tarsal-strip procedure for reconstruction of the eyelid closure function in paralytic lagophthalmus after facial palsy. METHODS: Between March 2008 and December 2012, 32 patients (32 eyelids) with hypophasis in facial palsy which all sorts of causes lead to were treated with Medpor LES combined with the lateral tarsal-strip procedure. Of 32 cases, 20 were male and 12 were female, aged from 20 to 72 years (mean, 46.8 years). The left eye was involved in 18 cases and the right eye in 14 cases with a disease duration of 1.5 months to 2 years (mean, 4.4 months). All the patients were shown as lower eyelid ectropion, lower eyelid retraction, exposure keratitis, and corneal ulcer, but no obvious upper eyelid retraction was observed. RESULTS: Primary healing of incision was obtained in all patients. The edema time of the eyelid was from 5 days to 3 weeks (mean, 2 weeks). Conjunctival edema appeared in 4 cases after 2 weeks of operation, which was cured after expectant treatment. The patients were followed up 5-8 months (mean, 6 months). At 1 week, 3 and 6 months after operation, the height of palpebral fissure was reduced, and the degree of lagophthalmus and low eyelid retraction were significantly corrected (P < 0.05), but no significant difference among different time points after operation (P > 0.05). Outer canthus displacement occurred in 3 cases at 1 month postoperatively, and was cured after the lateral tarsal strip procedure. No lower eyelid ectropion, corneal exposure, or Medpor LES displacement and exposure occurred during follow-up. CONCLUSION: Medpor LES combined with the lateral tarsal-strip procedure has good effectiveness for reconstruction of eyelid closure function in most cases of paralytic lagophthalmus after facial palsy. PMID- 24796201 TI - [Effectiveness of improved interosseous dorsal artery reversed island flap for dorsal skin and soft tissue defect of hand]. AB - OBJECTIVE: To discuss the effectiveness of improved interosseous dorsal artery reversed island flap to repair dorsal skin and soft tissue defect of the hand. METHODS: Between March 2009 and September 2012, 29 cases of dorsal skin and soft tissue defects were treated with improved interosseous dorsal artery reversed island flap. Of 29 cases, there were 17 males and 12 females, aged 23-71 years (mean, 47 years); and the left hand was involved in 12 cases and the right hand in 17 cases. There were 11 cases of avulsion injury, 9 cases of crushing injury, 5 cases of strangulation injury, and 2 cases of traffic accident injury; the interval of injury and admission was 1-7 hours (mean, 4 hours). Two patients had scar contracture. The locations of soft tissue defects were dorsal hands in 21 cases, first webs in 5 cases, and dorsal thumb in 3 cases. The size of soft tissue defects ranged from 4 cm x 3 cm to 10 cm x 8 cm. One-stage repair was performed in 11 cases, and two-stage repair in 18 cases. The size of flaps ranged from 5.5 cm x 4.5 cm to 12.0 cm x 10.0 cm. The donor sites were sutured directly or repaired by skin grafting. RESULTS: All flaps survived, and wounds healed in first stage. And the grafted skins at donor sites all survived, and incisions all healed in first stage. Twenty-six patients were followed up 3 months-3 years (mean, 19.5 months). Bulky flap was observed in 3 cases, and defatted operation was performed after 6 months; the other flaps had good appearance and texture, and wrist function was normal. According to total angle of motion (TAM) systematic evaluation, the results were excellent in 17 cases, good in 6 cases, and fair in 3 cases at 3 months after operation. CONCLUSION: Improved interosseous dorsal artery reversed island flap has the advantages of easy-to obtain, simple operation, and high survival rate of flaps, so it is an effective method to repair dorsal skin and soft tissue defect of the hand. PMID- 24796202 TI - [Research and application of multipoint centralization method in removal of small foreign body]. AB - OBJECTIVE: To introduce a new method to remove the small foreign body in the hand or foot, and to discuss its feasibility and effectiveness. METHODS: Between May 2007 and March 2012, 78 patients with small foreign bodies embedded in the soft tissue of the hand or foot were treated with the method. There were 51 males and 27 females, aged from 7 to 69 years with an average of 32.5 years. The hand, wrist, and foot were involved in 48, 6, and 24 cases respectively. Foreign body type included fiberglass (57 cases), thorn (11 cases), iron (5 cases), bamboo thorn (2 cases), fishbone (2 cases), and metal needles (1 case). The time between injury and operation was 30 minutes to 16 days (mean, 2.6 days). The position and range of the foreign body were defined using the multipoint centralization method before removal surgery. The skin was cut according multipoint connection for finding small foreign body under a microscope. RESULTS: All foreign bodies were successfully removed. The mean operation time was 6 minutes (range, 3-22 minutes). Healing of incision by first intention was obtained in all cases; no blood circulation disorders or infection occurred. All the patients were followed up 3 months-3 years (mean, 9 months). The distal limb had no feeling or movement disorders. CONCLUSION: Removal of small foreign body in soft-tissue using multipoint centralization method is safe and effective. PMID- 24796203 TI - [Biofilm and role of icaA, icaD, and accumulation-associated protein in Staphylococcus epidermidis isolated in breast surgery]. AB - OBJECTIVE: To investigate biofilm formation on the surface of silica gel by breast surgery clinical specimens of Staphylococcus epidermidis and to analyze the relationship between biofilm formation and icaA, icaD, and accumulation associated protein (aap) gene. METHODS: Between December 2011 and January 2013, 44 strains of Staphylococcus epidermidis were isolated from the clinical specimens of the female patients who had no symptom of infection. The icaA, icaD, and aap genes were detected by PCR and 4 genotypic groups were divided: icaA+ icaD+/aap+ group (group A), icaA+ icaD+/aap- group (group B), icaA- icaD-/aap+ group (group C), and icaAicaD/aap group (group D). Biofilms mass was semi quantified by semi-quantitative adherence assay after 8, 12, 24, 30, and 36 hours of incubation. The thickness of biofilms was measured by confocal laser scanning microscope (CLSM) at 12 and 24 hours after incubation. The ultrastructure of biofilms was observed by scanning electron microscope (SEM) at 24 hours after incubation. RESULTS: PCR test showed that 13 strains were icaA+ icaD+/ aap+ (group A), 12 strains were icaA+ icaD+/aap- (group B), 16 strains were icaA- icaD /aap+ (group C), and 3 strains were icaA- icaD-/aap- (group D). In 29 strains which had bacterial biofilm formation (65.9%), there were 13 strains in group A, 7 strains in group B, 9 strains in group C, and 0 in group D. The result of semi quantitative adherence assay showed no significant difference in the absorbance (A) values among 4 groups at 8 hours (P > 0.05). The A values of groups A, B, and C were significantly higher than that of group D at 12-36 hours, and group A was significantly higher than groups B and C (P < 0.05), but there was no significant difference between groups B and C (P > 0.05). The results of CLSM showed that the thickness of biofilm in groups A, B, and C was significantly larger than that in group D at 12 and 24 hours after incubation (P < 0.05), and the thickness of biofilm in group A was significantly larger than that in groups B and C (P < 0.05), but there was no significant difference between groups B and C (P > 0.05). The result of SEM showed that the mature biofilm could be observed on the surface of silica gel in groups A, B, and C, and the ultrastructure of biofilms in group A were the most abundant and extensive among 3 groups. The ultrastructure of biofilm in group B was similar to that in group C. No obvious biofilms formed in group D. CONCLUSION: icaA, icaD, and aap genes all play key roles in the process for biofilm formation of Staphylococcus epidermidis. Futhermore, aap gene enhance the ability of biofilm-forming when aap and ica genes coexist, so the biofilm forming ability of icaA+ icaD+/aap+ is strongest. PMID- 24796204 TI - [Progress in treatment of pubic symphysis diastasis]. AB - OBJECTIVE: To summarize the progress in treatment of pubic symphysis diastasis. METHODS: Related literature concerning treatment of pubic symphysis diastasis was extensively reviewed and comprehensively analyzed in terms of anatomy, biomechanics, and treatment. RESULTS: There are many fixation methods for treatment of pubic symphysis diastasis, which aims at restoring the stability of the anterior pelvic ring. External fixator is often used as a temporary fixation; tension band wire has been abandoned due to its poor biomechanical stability; screw loosening and plate breakage often appears when a single reconstruction plate is used; box plate significantly increases the biomechanical stability of anterior pelvic ring but it leads to a considerable surgical trauma; locking plate has been used for pubic symphysis diastasis recently, especially for osteoporotic fractures; percutaneous cannulated screw has the advantages of less trauma, less bleeding, and good stability, so it is good choice for treatment of pubic symphysis diastasis. CONCLUSION: There is no uniform standards about the treatment of pubic symphysis diastasis, but the minimally invasive treatment is an undeniable trend. Percutaneous cannulated screw has achieved satisfactory effectiveness, however, its biomechanical stability and anatomic channels need to be further studied. PMID- 24796205 TI - [Application status and research progess of alginate dressings]. AB - OBJECTIVE: To review the application status and research progress of alginate dressings. METHODS: The related home and abroad literature was reviewed, and the relevant product standards and regulations were summarized. RESULTS: Alginate dressings have been widely used in clinical because of the characteristics of anti-infection and promoting wound healing. It is mainly used on the wound surface and filled in the wound. Pure alginate dressing is limited in promoting wound healing. A large number of studies are devoted to promoting the activity with other polymer composite to get better dressing. In addition, the industry standards and regulation of alginate dressing products are also gradually improved and standardized. CONCLUSION: Alginate dressing, as an advanced bio dressing, whose effectiveness has been confirmed, its derivative dressings are also continuously expanding. PMID- 24796206 TI - Expression of CD163, interleukin-10, and interferon-gamma in oral squamous cell carcinoma: mutual relationships and prognostic implications. AB - Tumor-associated macrophages (TAMs) and their associated inflammatory cytokines represent the major inflammatory component of the stroma of many tumors and can affect prognosis in the case of neoplasms. The objective of this study was to determine the prognostic significance of CD163(+) cells, interleukin-10 (IL-10), and interferon-gamma (IFN-gamma) in oral lesions associated with oral squamous cell carcinoma (OSCC). The levels of CD163, IFN-gamma, and IL-10 in the tissue samples of 240 patients with OSCC and 58 patients with other oral lesions were assessed by immunohistochemistry. Individuals with low IFN-gamma levels, high IL 10 levels, and low CD163 levels were of special concern with respect to OSCC progression. We found that high levels of CD163, or a combination of low IFN gamma levels, high IL-10 levels, and low CD163 levels, were associated with poorer overall survival (OS). CD163(+) cells provide better predictive power for OS in comparison with traditional markers, such as clinical stage and lymph node metastasis. Therefore, CD163(+) cells may be effective prognostic predictors of OSCC. IL-10 may also indicate poor outcomes when IFN-gamma secretion is low and the cells are CD163(-) . PMID- 24796207 TI - The triglyceride to high-density lipoprotein ratio identifies children who may be at risk of developing cardiometabolic disease. AB - AIM: It is important to develop simple, reliable methods to identify high-risk individuals who may benefit from intervention. This study investigated the association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio and cardiometabolic risk, cardiorespiratory fitness and physical activity in children. METHODS: Anthropometric, biochemical parameters, cardiorespiratory fitness and accelerometry determined physical activity were assessed in 155 children (80 girls) from 10 to 14 years of age from Bedfordshire, UK. Participants were grouped into high and low TG/HDL ratio groups, according to published thresholds. MANCOVA and logistic regression were used in the analysis. RESULTS: Cardiometabolic risk factor levels were significantly higher in participants with a high TG/HDL ratio (p < 0.05). The odds of having high waist circumference (OR = 13.99; 95% CI 2.93, 69.25), elevated systolic blood pressure (5.27; 1.39, 20.01), high non-HDL cholesterol (19.47; 4.42, 85.81) and >=2 cardiometabolic risk factors (15.32; 3.10, 75.79) were higher in participants with a high TG/HDL ratio. The TG/HDL ratio values were significantly lower in those with high cardiorespiratory fitness (p = 0.01), but there was no association with physical activity. CONCLUSION: These findings support the use of the TG/HDL ratio to identify children with cardiometabolic risk factors who may be at risk of developing cardiometabolic disease. PMID- 24796208 TI - Serial changes in myocardial function in preterm infants over a four week period: the effect of gestational age at birth. AB - BACKGROUND: Myocardial performance is impaired in the first days of life in preterm infants but improves by day 5. Tissue Doppler imaging (TDI) is a novel and reliable means of assessing myocardial performance. OBJECTIVE: To investigate myocardial performance using TDI and shortening fraction (SF) in preterm infants of different gestational age groups and serial changes in these parameters in first four weeks of life. Study design Infants less than 36 weeks of gestation were divided into group 1 (24-27 weeks, n=8), group 2 (28-31 weeks, n=12) and group 3 (32-35 weeks, n=13). Infants with severe congenital malformations, a hypoxic insult at birth, and those on inotropic support were excluded. Echocardiograms were performed at 36-48 hours, 2 weeks and 4 weeks of life. Left ventricular (LV) SF, systolic (S'), early diastolic (E') and late diastolic (A') TDI velocities were assessed. We analyzed the data using a repeated-measures ANOVA. RESULTS: Thirty three infants underwent serial TDI and SF measurements. There was an increase in LV S' (p=.02) and E' (.01) velocities in group 2 , and in group 3 (p=.03 for S' and p=.04 for E'), but no significant increase in group 1 (p=.48 for S' and .32 for E'). At each study point, there was significant difference in myocardial performance between group 1 and 3 for each of the parameters (p<.05). There was no significant increase in SF over time in any of the groups. CONCLUSION: We describe a serial increase in myocardial performance in infants of 28 weeks gestation and above. While there was no change in myocardial performance among the most extremely preterm infants, this may have been the result of small sample size of the group. PMID- 24796209 TI - Gross motor development in full-term Greek infants assessed by the Alberta Infant Motor Scale: reference values and socioeconomic impact. AB - OBJECTIVE: The aims of this study were to investigate gross motor development in Greek infants and establish AIMS percentile curves and to examine possible association of AIMS scores with socioeconomic parameters. METHODS: Mean AIMS scores of 1068 healthy Greek full-term infants were compared at monthly age level with the respective mean scores of the Canadian normative sample. In a subgroup of 345 study participants, parents provided, via interview, information about family socioeconomic status. Multiple linear regression analysis was performed to evaluate the relationship of infant motor development with socioeconomic parameters. RESULTS: Mean AIMS scores did not differ significantly between Greek and Canadian infants in any of the 19 monthly levels of age. In multiple linear regression analysis, the educational level of the mother and also whether the infant was being raised by grandparents/babysitter were significantly associated with gross motor development (p=0.02 and p<0.001, respectively), whereas there was no significant correlation of mean AIMS scores with gender, birth order, maternal age, paternal educational level and family monthly income. CONCLUSIONS: Gross motor development of healthy Greek full-term infants, assessed by AIMS during the first 19months of age, follows a similar course to that of the original Canadian sample. Specific socioeconomic factors are associated with the infants' motor development. PMID- 24796210 TI - Metabolomic analysis reveals a unique urinary pattern in normozoospermic infertile men. AB - Normozoospermic infertility has become a common and important health problem worldwide. We designed this metabolomic case-control study to investigate the possible mechanism and urinary biomarkers of normozoospermic infertility. Normozoospermic infertile cases (n = 71) and fertile controls (n = 47) were recruited. A urinary metabolome pattern could discriminate normozoospermic infertile cases from fertile controls. A total of 37 potential biomarkers were identified; these have functionally important roles in energy production, antioxidation, and hormone regulation in spermatogenesis. This gave rise to a combined biomarker pattern of leukotriene E4, 3-hydroxypalmitoylcarnitine, aspartate, xanthosine, and methoxytryptophan pointing to a diagnostic capability (AUC = 0.901, sensitivity = 85.7%, and specificity = 86.8%) in a ROC model; these markers may highlight keynote events of normozoospermic infertility. Stalled medium- and long-chain fatty acid metabolism with improved ketone body metabolism, plus decreased levels of malate and aspartate could result in citrate cycle alterations via a malate-aspartate shuttle in ATP generation in spermatogenesis. Inhibitory alterations in the normal hormone-secreting activity in spermatogenesis were suggested in normozoospermic infertility. Folate deficiency and oxidative stress may jointly impact infertile patients. The disruption of eicosanoid metabolism and xanthine oxidase system, which were tightly associated with energy metabolism and oxidative stress, was also a potential underlying mechanism. In addition, depression might be associated with normozoospermic infertility via neural activity-related metabolites. This study suggests that the urinary metabolome can be used to differentiate normozoospermic infertile men from fertile individuals. Potential metabolic biomarkers derived from these analyses might be used to diagnose what remains a somewhat idiopathic condition and provide functional insights into its pathogenesis. PMID- 24796211 TI - Structural evolution of atomically precise thiolated bimetallic [Au(12+n)Cu32(SR)(30+n)]4- (n = 0, 2, 4, 6) nanoclusters. AB - A series of all-thiol stabilized bimetallic Au-Cu nanoclusters, [Au(12+n)Cu32(SR)(30+n)](4-) (n = 0, 2, 4, 6 and SR = SPhCF3), are successfully synthesized and characterized by X-ray single-crystal analysis and density functional theory (DFT) calculations. Each cluster consists of a Keplerate two shell Au12@Cu20 core protected by (6 - n) units of Cu2(SR)5 and n units of Cu2Au(SR)6 (n = 0, 2, 4, 6) motifs on its surface. The size and structural evolution of the clusters is atomically controlled by the Au precursors and countercations used in the syntheses. The clusters exhibit similar optical absorption properties that are not dependent on the number of surface Cu2Au(SR)6 units. Although DFT suggests an electronic structure with an 18-electron superatom shell closure, the clusters display different thermal stabilities. [Au(12+n)Cu32(SR)(30+n)](4-) clusters with n = 0 and 2 are more stable than those with n = 4 and 6. Moreover, an oxidation product of the clusters, [Au13Cu12(SR)20](4-), is structurally identified to gain insight into how the clusters are oxidized. PMID- 24796212 TI - Arylboronate ester based diazeniumdiolates (BORO/NO), a class of hydrogen peroxide inducible nitric oxide (NO) donors. AB - Here, we report the design, synthesis, and evaluation of arylboronate ester based diazeniumdiolates (BORO/NO), a class of nitric oxide (NO) donors activated by hydrogen peroxide (H2O2), a reactive oxygen species (ROS), to generate NO. We provide evidence for the NO donors' ability to permeate bacteria to produce NO when exposed to H2O2 supporting possible applications for BORO/NO to study molecular mechanisms of NO generation in response to elevated ROS. PMID- 24796213 TI - 3D imaging of enzymes working in situ. AB - Today, development of slowly digestible food with positive health impact and production of biofuels is a matter of intense research. The latter is achieved via enzymatic hydrolysis of starch or biomass such as lignocellulose. Free label imaging, using UV autofluorescence, provides a great tool to follow one single enzyme when acting on a non-UV-fluorescent substrate. In this article, we report synchrotron DUV fluorescence in 3-dimensional imaging to visualize in situ the diffusion of enzymes on solid substrate. The degradation pathway of single starch granules by two amylases optimized for biofuel production and industrial starch hydrolysis was followed by tryptophan autofluorescence (excitation at 280 nm, emission filter at 350 nm). The new setup has been specially designed and developed for a 3D representation of the enzyme-substrate interaction during hydrolysis. Thus, this tool is particularly effective for improving knowledge and understanding of enzymatic hydrolysis of solid substrates such as starch and lignocellulosic biomass. It could open up the way to new routes in the field of green chemistry and sustainable development, that is, in biotechnology, biorefining, or biofuels. PMID- 24796214 TI - Informing the Australian government on AT policies: ARATA's experiences. AB - This article describes the development and dissemination of an evidence-based Policy Statement and Background Papers by the Australian Rehabilitation and Assistive Technology Association (ARATA). An experienced project team was engaged to conduct literature reviews and member consultations, develop resources and implement a targeted advocacy strategy that included a policy launch and meetings with government officials. The Policy Statement and Background Papers have enabled ARATA to represent the views of Assistive Technology (AT) Practitioners in consultations around the National Disability Insurance Scheme and other AT related inquiries. In ARATA's experience, developing a policy statement and disseminating it through a targeted advocacy strategy is an effective way for a not-for-profit professional organisation to influence government policy. IMPLICATIONS FOR REHABILITATION: AT practitioners must consider political factors in working towards effective policies to support their practice. To be effective at a systemic level, AT practitioners must develop political awareness and an understanding of the drivers of policy. This case study provides a blueprint for AT practitioners and organisations in tackling policy change. PMID- 24796215 TI - Distance learning and telemedicine. PMID- 24796216 TI - Improvement of strain discrimination by combination of superantigen profiles, PFGE, and RAPD for Staphylococcus aureus isolates from clinical samples and food poisoning cases. AB - Staphylococcus aureus is one of the major bacterial species that may cause clinical infection and food-poisoning cases. Strains of this bacterial species may produce a series of superantigens (SAgs) (i.e., staphylococcal enterotoxins [SEs], staphylococcal enterotoxin-like toxins, and toxic shock syndrome toxin). In this study, S. aureus strains from clinical samples and food-poisoning cases in Taiwan were collected; their SAg profiles, and SmaI digestion patterns determined by pulsed-field gel electrophoresis (PFGE), were then analyzed. Results showed that their SAg gene profiles and SmaI digestion patterns of chromosomal DNA were highly diverse. Although PFGE has been used as a criterion standard for typing of S. aureus strains, and the SAg profiles have been used in combination with PFGE for typing of S. aureus strains, we found that strains grouped in these combined patterns could be further discriminated by the random amplified polymorphic DNA (RAPD) method. Thus, the combined use of SAg profiles, PFGE, and RAPD patterns permits high discrimination for typing of S. aureus strains from not only the clinical samples but also the food-poisoning cases. Such a combined method may be used as a highly accurate approach for epidemiological study and tracing of the contamination origin of staphylococcal infections either in hospitals or food-poisoning cases. PMID- 24796217 TI - In vitro activity of the siderophore monosulfactam BAL30072 against contemporary Gram-negative pathogens from New York City, including multidrug-resistant isolates. AB - The in vitro activity of BAL30072 was assessed against clinical isolates from NYC hospitals, including isolates from a citywide surveillance study and a collection of isolates with well-characterised resistance mechanisms. BAL30072 was the most active beta-lactam against Pseudomonas aeruginosa (MIC50/90, 0.25/1 MUg/mL), Acinetobacter baumannii (MIC50/90, 4/>64 MUg/mL) and KPC-possessing Klebsiella pneumoniae (MIC50/90, 4/>64 MUg/mL). Combining BAL30072 with meropenem resulted in a >= 4-fold decrease in the BAL30072 MIC90 both for A. baumannii and K. pneumoniae. For isolates with a BAL30072 MIC>4 MUg/mL, addition of a sub-MIC concentration of colistin resulted in a four-fold decrease in the BAL30072 MIC in 44% of P. aeruginosa, 82% of A. baumannii and 23% of K. pneumoniae. Using sub-MIC concentrations, BAL30072 plus colistin was bactericidal against 4 of 11 isolates in time-kill studies. BAL30072 MICs were frequently lower for P. aeruginosa and K. pneumoniae when tested using Mueller-Hinton agar versus Iso-Sensitest agar or Mueller-Hinton broth. Against the well-characterised isolates, reduced susceptibility to BAL30072 correlated with mexA and mexX expression (P. aeruginosa), adeB expression (A. baumannii) and presence of SHV-type ESBLs (A. baumannii and K. pneumoniae). BAL30072 shows promising activity against contemporary Gram-negatives, including MDR P. aeruginosa, A. baumannii and K. pneumoniae. Enhanced activity was often present when BAL30072 was combined with meropenem or colistin. BAL30072 MICs were influenced by the testing method, particularly for P. aeruginosa and K. pneumoniae. Further in vivo studies are warranted to determine the potential clinical utility of BAL30072 alone and combined with other agents. PMID- 24796218 TI - Pharmacokinetic/pharmacodynamic evaluation of sulbactam against Acinetobacter baumannii in in vitro and murine thigh and lung infection models. AB - Acinetobacter baumannii is a pathogen that has become globally associated with nosocomial infections. Sulbactam, a potent inhibitor of beta-lactamases, was previously shown to be active against A. baumannii strains in vitro and effective against A. baumannii infections. However, a pharmacokinetic/pharmacodynamic (PK/PD) analysis of sulbactam against A. baumannii infections has not yet been performed. This is necessary because optimisation of dosing regimens should be based on PK/PD analysis. Therefore, in vitro and in vivo PK/PD analyses of sulbactam were performed using murine thigh and lung infection models of A. baumannii to evaluate the pharmacokinetics and pharmacodynamics of sulbactam. Sulbactam showed time-dependent bactericidal activity in vitro against A. baumannii. The PK/PD index that best correlated with its in vivo effects was the time that the free drug concentration remained above the minimum inhibitory concentration (fT>MIC) both in the thigh (R(2)=0.95) and lung (R(2)=0.96) infection models. Values of fT>MIC for a static effect and 1, 2 and 3log10 kill, respectively, were 21.0%, 32.9%, 43.6% and 57.3% in the thigh infection model and 20.4%, 24.5%, 29.3% and 37.3% in the lung infection model. Here we report the in vitro and in vivo time-dependent activities of sulbactam against A. baumannii infection and demonstrate that sulbactam was sufficiently bactericidal when an fT>MIC of >60% against A. baumannii thigh infection and >40% against A. baumannii lung infection was achieved. PMID- 24796219 TI - Haloperidol blocks dorsal striatum activity but not analgesia in a placebo paradigm. AB - Although placebo analgesia has been associated with an engagement of the endogenous opioid system there is growing evidence from neuropharmacological studies for an involvement of additional neurotransmitter systems. An increased dopaminergic neurotransmission in the ventral basal ganglia that has been found during placebo analgesia suggests a role for the dopaminergic system (Scott et al., 2007). It is, however, unclear whether striatal dopaminergic activity is causally involved in this type of analgesia. This study aimed at exploring the functional role of the dopaminergic system in placebo analgesia. To this end, we investigated the effect of the dopamine D2/D3 receptor antagonist haloperidol on behavioral and neural measures of placebo analgesia using functional magnetic resonance imaging (fMRI) in healthy volunteers. We found that 2 mg haloperidol p.o. significantly reduced the correlation between dorsal striatum activity and the individual placebo response, but had no significant effect on placebo analgesia at the behavioral or neural level, as indexed by activity in sensory or pain-modulatory brain regions. Our study therefore suggests that dopaminergic neurotransmission might not be causally involved in placebo analgesia but is related to phenomena associated with placebo analgesia such as reward processing and learning. PMID- 24796220 TI - Validation of the Greek Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain. AB - BACKGROUND: The Douleur Neuropathique 4 questionnaire (DN4) was developed by the French Neuropathic Pain Group and is a simple and objective tool, primarily designed to screen for neuropathic pain. The aim of our study is to validate the DN4 in the Greek language. METHODS: The study was set up as a prospective observational study. Two pain specialists independently examined patients and diagnosed them with neuropathic, nociceptive, or mixed pain, according to the International Association for the Study of Pain (IASP) definitions. A third and a fourth physician administered the DN4 questionnaire to the patients. RESULTS: Out of the 237 patients who met our inclusion criteria and had identical diagnoses regarding the type of pain, 123 were diagnosed with neuropathic, 59 with nociceptive, and 55 with mixed pain. Among patients with identical diagnoses of neuropathic or nociceptive pain, using a receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.92. A cutoff point of equal or greater than 4 resulted in a sensitivity of 93% and a specificity of 78%. Among patients suffering from pain with neuropathic element (neuropathic or mixed pain) or pain with no neuropathic element (nociceptive pain), using a ROC curve analysis, the AUC was 0.89. A cutoff point of equal or greater than 4 resulted in a sensitivity of 89% and a specificity of 78%. CONCLUSION: The Greek version of DN4 is a valid tool for discriminating between neuropathic and nociceptive pain conditions in daily practice. PMID- 24796221 TI - Babylon tower. PMID- 24796222 TI - Run for your life! PMID- 24796223 TI - Facile fabrication of superhydrophobic surface with excellent mechanical abrasion and corrosion resistance on copper substrate by a novel method. AB - A novel method for controllable fabrication of a superhydrophobic surface with a water contact angle of 162 +/- 1 degrees and a sliding angle of 3 +/- 0.5 degrees on copper substrate is reported in this Research Article. The facile and low-cost fabrication process is composed from the electrodeposition in traditional Watts bath and the heat-treatment in the presence of (heptadecafluoro 1,1,2,2-tetradecyl) triethoxysilane (AC-FAS). The superhydrophobicity of the fabricated surface results from its pine-cone-like hierarchical micro nanostructure and the assembly of low-surface-energy fluorinated components on it. The superhydrophobic surface exhibits high microhardness and excellent mechanical abrasion resistance because it maintains superhydrophobicity after mechanical abrasion against 800 grit SiC sandpaper for 1.0 m at the applied pressure of 4.80 kPa. Moreover, the superhydrophobic surface has good chemical stability in both acidic and alkaline environments. The potentiodynamic polarization and electrochemical impedance spectroscopy test shows that the as prepared superhydrophobic surface has excellent corrosion resistance that can provide effective protection for the bare Cu substrate. In addition, the as prepared superhydrophobic surface has self-cleaning ability. It is believed that the facile and low-cost method offer an effective strategy and promising industrial applications for fabricating superhydrophobic surfaces on various metallic materials. PMID- 24796224 TI - Delivery of nitric oxide to the interior of mammalian cell by carbon nanotube: MD simulation. AB - Computer simulations have been performed to study the nanoindentation of phospholipid bilayer by the single-walled armchair carbon nanotube, filled with the nitric oxide molecules. The process has been simulated by means of molecular dynamics (MD) technique at physiological temperature T = 310 K with a constant pulling velocity of the nanotube. The force acting on the nanotube during membrane penetration has been calculated. We show that the indentation by carbon nanotube does not permanently destroy the membrane structure (self-sealing of the membrane occurs). The mobility of nitric oxide molecules during the membrane nanoindentation is discussed. PMID- 24796225 TI - Unravelling of the health effects of polyphenols is a complex puzzle complicated by metabolism. AB - Plant metabolism creates complex mixtures of polyphenols in plant foods. Epidemiology and human trials reduced this complexity, by studying specific foods; subclasses of polyphenols; individual polyphenols, or total antioxidant capacity (TAC). This implies the following assumptions: (1) a limited number of potent polyphenols exists; (2) well-defined natural potent mixtures of polyphenols exist; (3) polyphenols share a common biological activity (e.g. antioxidant activity). To find potent polyphenols (1st assumption), in vitro screening has been widely applied, but most published results are of limited use because metabolism, changing biological activity profoundly, has frequently not been considered. The abundant anecdotal evidence for natural potent mixtures of polyphenols (2nd assumption) on the internet is very hard to verify. Additionally, cross-cultural studies have revealed the potency of e.g. cocoa. Polyphenols share the antioxidant phenolic group which inspired researchers to measure their antioxidant activity, thus greatly reducing complexity (3rd assumption). Unfortunately, the elegant antioxidant hypothesis has to be rejected, because poor absorption and extensive metabolism annihilate any contribution to the endogenous body antioxidants. In conclusion, the above assumptions are hard to verify, and no quick answers are to be expected. Future research should focus on structure-activity relations at nanomolar levels and explore metabolomics. PMID- 24796226 TI - High job strain is associated with inflammatory markers of disease in young long haul bus drivers. AB - Atherosclerosis is an inflammatory disease. The study was aimed to investigate the association between job strain and inflammation markers and to examine factors contributing to high strain. The long-haul bus drivers (n = 825) were recruited from a Taiwanese transportation company. The psychosocial work environment was measured by a validated job content questionnaire (JCQ). Plasma high sensitivity C-reactive protein (hs-CRP) and homocysteine (Hcy) were analyzed as inflammation markers. Job strain effects and its interaction with age were analyzed by logistic regression. Explained variance (Nagelkerke R square) was applied to select important stressors. The crude and adjusted odds ratio (OR) for the effect of high strain on high hs-CRP and Hcy were not significant. However, there was significant interaction between job strain and age (p = .014). The significantly increased risk of high strain on high hs-CRP was found among drivers younger than 35 years old (OR = 2.71), but not in driver groups age 35 to 49 and older than 50. The contributing factors to high strain were varied among the 3 age groups. The 3 stressors found for young drivers were having rest time less than 8 hours between 2 shifts, being physically inactive during leisure time, and frequent driving more than 12 hours a day. Job strain interacted with age influenced hs-CRP levels. The risk of inflammatory disease markers only increased in high strained group of young drivers. Appropriate work shift systems should be implemented to increase off-duty time, reduce sleep restrictions, and increase physical activity during leisure time. PMID- 24796227 TI - Coaching for workers with chronic illness: evaluating an intervention. AB - Working with chronic illness may present challenges for individuals-for instance, managing symptoms at work, attaining accommodations, and career planning while considering health limitations. These challenges may be stressful and lead to strains. We tested a 12-week, 6-session, phone-based coaching intervention designed to help workers manage these challenges and reduce strains. Using theories of stress and resources, we proposed that coaching would help boost workers' internal resources and would lead to improved work ability perceptions, exhaustion and disengagement burnout, job self-efficacy, core self-evaluations, resilience, mental resources, and job satisfaction, and that these beneficial effects would be stable 12 weeks after coaching ended. Fifty-nine full-time workers with chronic illnesses were randomly assigned to either a coaching group or a waitlisted control group. Participants completed online surveys at enrollment, at the start of coaching, after coaching ended, and 12 weeks postcoaching. Compared with the control group, the coaching group showed significantly improved work ability perceptions, exhaustion burnout, core self evaluations, and resilience-yet no significant improvements were found for job self-efficacy, disengagement burnout, or job satisfaction. Indirect effects of coaching on work ability, exhaustion and disengagement burnout, and job satisfaction were observed through job self-efficacy, core self-evaluations, resilience, and mental resources. Results indicated that the positive effects of coaching were stable 12 weeks after coaching ended. Results suggest that this coaching intervention was helpful in improving the personal well-being of individuals navigating challenges associated with working and managing chronic illness. PMID- 24796228 TI - Why do employees worry about their jobs? A meta-analytic review of predictors of job insecurity. AB - We used psychological contract theory as a framework to meta-analytically review subjective and objective predictors of employees' perceived job insecurity. Seventy-six samples from 68 studies were included in our review. Results revealed that lower levels of job insecurity are associated with having an internal locus of control, lower amounts of role ambiguity and role conflict, greater amounts of organizational communication, less organizational change, younger employees, and white-collar and permanent work. Moderator analyses further revealed that relations between job insecurity and age, gender, education, and formal contracts are moderated by unemployment rates, countries of origin, and type of job insecurity measure. We discuss theoretical and practical implications for psychological contract theory and occupational health, and offer directions for future research. PMID- 24796229 TI - Hiding behind confusion: pleural empyema caused by Parvimonas micra. PMID- 24796230 TI - Incidence of clinically significant percutaneous spinal cord stimulator lead migration. AB - OBJECTIVE: To examine the incidence of percutaneous spinal cord stimulator lead migration, given current hardware and surgical technique. MATERIALS AND METHODS: We retrospectively reviewed records of patients who underwent spinal cord stimulator implantation with percutaneous leads at our institution from 2008 through 2011. We determined the number of patients who required surgical revision for clinically significant lead migration. RESULTS: Clinically significant lead migration requiring surgical revision occurred in three of 143 patients (2.1%) with primary SCS system implants utilizing percutaneous-type leads. CONCLUSIONS: The rate of lead migration observed in our practice was considerably lower than previously published estimates of clinically significant lead migration or revision for lead migration (13%-22%). However, our study did not determine the reason for the decreased rate, which may be influenced by current hardware and implant techniques. PMID- 24796231 TI - Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN J). AB - AIM: Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon-like peptide-1 receptor agonist that affects the histological findings in patients with non-alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy-proven NASH. METHODS: After lifestyle modification intervention for 24 weeks, subjects whose hemoglobin A1c levels failed to improve to less than 6.0% and/or whose alanine aminotransferase levels were not lower than baseline, received liraglutide at 0.9 mg/body per day for 24 weeks. RESULTS: Of 27 subjects, 26 completed the lifestyle modification intervention. Nineteen subjects received liraglutide therapy for 24 weeks. Body mass index, visceral fat accumulation, aminotransferases and glucose abnormalities improved significantly. Repeated liver biopsy was performed in 10 subjects who continued liraglutide therapy for 96 weeks. Six subjects showed decreased histological inflammation as determined by NASH activity score and stage determined by Brunt classification. We saw no significant adverse events during therapy with liraglutide. CONCLUSION: Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance. PMID- 24796232 TI - Mental dysfunctions in dystonia-plus syndromes. AB - With the increasing understanding of the involvement of basal ganglia circuits in the functions of movement, cognition, emotion and motivation, the network model of dystonia posits a plausible mechanism for the co-occurrence of mental dysfunctions in dystonia-plus syndromes. Genetic mutations that alter the production of neurotransmitters and receptors can potentially affect the function of these interconnecting circuits and yield non-motor symptoms as well. This article reviews the psychiatric findings in dystonia-plus syndromes reported thus far in the literature, both in animal models and human subjects. Based on this innovative understanding of the pathophysiology, implications to treatment of combined motor and non-motor symptoms (i.e. mental dysfunctions) are also briefly discussed. PMID- 24796233 TI - Color vision impairment in Parkinson's disease. PMID- 24796234 TI - Application of the University Of Pennsylvania Smell Identification Test (traditional Chinese version) for detecting olfactory deficits in early Parkinson's disease in a Taiwanese cohort. AB - BACKGROUND: Olfactory dysfunction is a non-motor feature of Parkinson's disease (PD) that appears at an early stage. The University of Pennsylvania Smell Identification Test (UPSIT) is the most widely used test for olfactory dysfunction, with multiple language versions available, including one in Traditional Chinese (UPSIT-TC). However, the UPSIT-TC has rarely been applied to the elderly population or patients with PD in Taiwan. OBJECTIVE: The present study aimed to establish normative data in a Taiwanese cohort and evaluate the efficacy of the UPSIT-TC for detecting olfactory deficits in early PD. METHODS: The UPSIT-TC was administered to 161 healthy Taiwanese subjects divided into four age groups: 40-49, 50-59, 60-69, and 70-79 years. Furthermore, 30 patients with PD with less than 2 years disease duration were examined with the UPSIT-TC. RESULTS: The normative data from this cohort were lower than expected, deviating from North American norms by 2.5 to 5 points. The deviation was more prominent with advanced age. The PD group had a significantly lower mean UPSIT-TC score than the age- and gender-matched control group (p < 0.0001). With a cutoff score of 29.5, the sensitivity and specificity of the UPSIT-TC for the diagnosis of olfactory dysfunction in early PD was 86% and 70%, respectively. The subjects with PD, advanced age, and shorter education had significantly lower UPSIT-TC scores (p < 0.0001). CONCLUSIONS: The UPSIT-TC effectively detected hyposmia in early PD in the Taiwanese cohort. Despite the modification of UPSIT-TC items, a discrepancy was found between the Taiwanese and North American norms. PMID- 24796235 TI - Sleep disorders in Parkinson's disease. AB - Sleep disorders in patients with Parkinson's disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD. PMID- 24796236 TI - Prognostic markers of sarcoidosis: an analysis of patients from everyday pneumological practice. AB - INTRODUCTION: Although sarcoidosis is a well-known disease, sarcoidosis patient outcome and the role of prognostic markers in everyday practice have not yet been well described. Therefore, the goal of the present study was to analyse the fate of sarcoidosis patients and the factors influencing the disease's behaviour in routine practice. METHODS: The study was a retrospective analysis of 306 consecutive patients (181 females and 125 males; median age 45 years) diagnosed with sarcoidosis in the years 2003-2012. RESULTS: Through the use of uniparametric analysis, it was determined that the stage of the disease, organ involvement, CD4/CD8 ratio in the bronchoalveolar lavage fluid (BALF), serum and urine calcium levels, smoking, and pulmonary functions had a significant influence on spontaneous sarcoidosis resolution. Multiparametric analysis revealed that spontaneous resolution was significantly positively influenced by female gender, a less advanced disease stage, a higher CD4/CD8 ratio in the BALF, lymphocytosis in the BALF and normal pulmonary functions at diagnosis. During follow-up, only three patients died. The causes of death were respiratory failure with pneumonia (n = 2) and heart attack caused by sarcoidosis heart involvement (n = 1). CONCLUSION: The data show sarcoidosis as a disorder with high variability in clinical and laboratory findings but with good general prognosis. PMID- 24796237 TI - Reducing health disparities: the social role of medical schools. AB - INTRODUCTION: Medical education based on the principles of social medicine can contribute toward reducing health disparities through the "creation" of doctors who are more involved in community programs. PURPOSE: This study compared the social medicine orientation of graduates from various medical schools in Israel. METHODS: The authors conducted an online cross-sectional survey in May 2011 among physicians who are graduates of Israeli medical schools. RESULTS: The study included 1050 physicians practicing medicine in Israel: 36% who are graduates from the Hebrew University, 26% from Tel Aviv University, 22% from the Technion and 16% from Ben-Gurion University. A greater percentage of physicians who studied either at the Technion or Ben-Gurion are working or have worked in the periphery (~50% vs. ~30% at the Hebrew and Tel Aviv Universities). Among Ben Gurion graduates, 47% are active in social medicine programs vs. 34-38% from other schools. Among physicians active in social medicine programs, 32% of Ben Gurion alumni estimated that their medical education greatly influenced their social medicine involvement vs. 8-15% from other schools. Hebrew University alumni described their studies as more research-oriented. In contrast, Ben-Gurion graduates described their studies as more social medicine-oriented and they exhibited more positive attitudes about the role of physicians in reducing health disparities. DISCUSSION: Social medicine-oriented medical education induces a socialization process reinforcing human values regarding doctor-patient relationships and produces positive attitudes among future doctors about social involvement. Findings emphasize the need to develop educational programs with this orientation and to strengthen medical schools in the periphery. PMID- 24796238 TI - Students improve patient care and prepare for professional practice: an interprofessional community-based study. AB - BACKGROUND: We report on an education model that enables students to contribute to practice while experiencing the realities of complex team-working in the community. AIMS: The study considers how interprofessional learning impacts on patient care and service delivery. METHOD: A qualitative study using a realist approach. The views of practice-staff, patients and facilitators on how student team learning impacted on practice was obtained through focus groups, interviews and an e-questionnaire and compared to student analysis as feedback forms. RESULTS: Staff from six Primary Health Care Teams (n = 23) stated that the student teams had offered solutions to improve the quality of patient care and on organisational systems. The positive value of the student work was confirmed by the course facilitators (n = 8). In addition, practitioners were propelled to maintain high professional standards. Patients (n = 23) recalled benefits directly attributable to the student work confirmed by the 434 student feedback forms. CONCLUSION: Undergraduate interprofessional student teams in mid-training can support and help practice teams, and this subsequently benefits patient care. This practice-based interprofessional learning model offers learning, which is theory-based, and supports positive student contributions. This learning fits today's requirements for positive outcomes from education when mapped against the Kirkpatrick or the NHS (UK) education outcomes framework. PMID- 24796239 TI - The transition to a teaching hospital: patient satisfaction before and after the introduction of medical students. AB - BACKGROUND: Several studies have explored the effect of the presence of medical students on patient satisfaction. However, nearly all of these studies took place in hospitals where medical students had been involved in patient care for many years. Less is known about patients' perceptions of care in a hospital moving toward becoming a teaching facility with undergraduate students. No research has explored patient satisfaction before and after the introduction of medical students. OBJECTIVE: To assess patient satisfaction as an indicator of quality of care (QoC) from the patients' perspective, before and after the presence of medical students in a general hospital setting. METHODS: This observational, cross-sectional study was conducted at Hospital Universitario-Fundacion Santa Fe de Bogota (HU-FSFB) in Bogota, Colombia. The study had two phases. In 2006, prior to HU-FSBF becoming a teaching hospital, 385 subjects were asked to fill out a closed-question questionnaire addressing patients' satisfaction and perception of QoC provided by attending physicians. During the second period in 2009, 372 patients answered the same questionnaire when medical students were involved in their care. RESULTS: Patients' perceptions of QoC provided by attending physicians improved in five aspects when medical students were present: friendliness (p = 0.003), competence providing medical care (p = 0.049), quality of information provided (p = 0.025), amount of time spent with the patient (p < 0.001) and availability to personally provide care (p < 0.001). Overall patient satisfaction also significantly increased (p < 0.001). CONCLUSIONS: The presence of medical students does not negatively affect patients' perceptions of QoC, on the contrary, these results provide evidence of improved patient satisfaction in several aspects of care when medical students were involved. The relevance of this study lies in its unique way of comparing patient satisfaction before and after the introduction of medical students. This setting helps elucidate the real effect of the presence of medical students on patient satisfaction. PMID- 24796240 TI - Differential expression of a novel gene EaF82a in green and yellow sectors of variegated Epipremnum aureum leaves is related to uneven distribution of auxin. AB - EaF82, a gene identified in previous studies of the variegated plant Epipremnum aureum, exhibited a unique expression pattern with greater transcript abundance in yellow sectors than green sectors of variegated leaves, but lower abundance in regenerated pale yellow plants than in green plants derived from leaf tissue culture. Studies of its full-length cDNA and promoter region revealed two members with only the EaF82a expressed. Immunoblotting confirmed that EaF82a encodes a 12 kDa protein and its accumulation consistent with its gene expression patterns in different color tissues. Transient expression of EaF82a-sGFP fusion proteins in protoplasts showed that EaF82a seems to be present in the cytosol as unidentified spots. Sequence motif search reveals a potential auxin responsive element in promoter region. Using transgenic Arabidopsis seedlings carrying EaF82a promoter driving the bacterial uidA (GUS) gene, an increased GUS activity was observed when IAA (indole-3-acetic acid) concentration was elevated. In E. aureum, EaF82a is more abundant at the site where axillary buds emerge and at the lower side of bending nodes where more IAA accumulates relative to the upper side. The measurement of endogenous IAA levels in different color tissues revealed the same pattern of IAA distribution as that of EaF82a expression, further supporting that EaF82a is an IAA responsive gene. EaF82a expression in etiolated transgenic Arabidopsis seedlings responded to IAA under the influence of light suggesting a microenvironment of uneven light condition affects the EaF82a transcript levels and protein accumulation in variegated leaves. PMID- 24796241 TI - Effect of increasing levels of seven tree species extracts added to a high concentrate diet on in vitro rumen gas output. AB - This study was conducted to investigate the effects of increasing levels of extracts of Byrsonima crassifolia, Celtis pallida, Enterolobium cyclocarpum, Fraxinus excelsior, Ficus trigonata, Phoradendrom brevifolium and Prunus domestica on in vitro gas production (GP) and ruminal fermentation of a high concentrate diet. Plant extracts were prepared at 1 g dry matter (DM)/8 mL of solvent mixture (methanol : ethanol : water, 1:1:8) and added at levels of 0, 0.6, 1.2 and 1.8 mL/g DM of a high concentrate diet. In vitro GP was recorded at 2, 4, 6, 8, 10, 12, 24, 48 and 72 h of incubation. Increasing addition of extracts linearly increased (P < 0.001), the GP24 , GP48 and GP72 (mL/g DM), and linearly decreased (P < 0.001), the discrete GP lag time. Moreover, increasing extract doses linearly increased (P < 0.001) the asymptotic GP and decreased (P < 0.001) the rate of GP. GP6 was not impacted by treatments and GP12 increased linearly (P = 0.01) with increasing addition of extracts. Rumen pH declined linearly (P < 0.05) with increasing doses of extracts added. As no interactions (P > 0.05) occurred between the extracts and doses, it could be conclude that all extracts positively modified rumen fermentation at doses of 1.2 to 1.8 mL extract/g diet DM. PMID- 24796242 TI - Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. AB - BACKGROUND: The most common cystic fibrosis-associated mutation, the deletion of phenylalanine 508 (F508del), results in channels with poor membrane expression and impaired function. VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking. METHODS: The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments. RESULTS: VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported. CONCLUSIONS: The results from these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels. PMID- 24796243 TI - Evidence for trade-offs in detoxification and chemosensation gene signatures in Plutella xylostella. AB - BACKGROUND: Detoxification genes have been associated with insecticide adaptation in the diamondback moth, Plutella xylostella. The link between chemosensation genes and adaptation, however, remains unexplored. To gain a better understanding of the involvement of these genes in insecticide adaptation, the authors exposed lines of P. xylostella to either high uniform (HU) or low heterogeneous (LH) concentrations of permethrin, expecting primarily physiological or behavioral selection respectively. Initially, 454 pyrosequencing was applied, followed by an examination of expression profiles of candidate genes that responded to selection [cytochrome P450 (CYP), glutathione S-transferase (GST), carboxylesterase (CarE), chemosensory protein (CSP) and odorant-binding protein (OBP)] by quantitative PCR in the larvae. Toxicity and behavioral assays were also conducted to document the effects of the two forms of exposure. RESULTS: Pyrosequencing of the P. xylostella transcriptome from adult heads and third instars produced 198,753 reads with 52,752,486 bases. Quantitative PCR revealed overexpression of CYP4M14, CYP305B1 and CSP8 in HU larvae. OBP13, however, was highest in LH. Larvae from LH and HU lines had up to five- and 752-fold resistance levels respectively, which could be due to overexpression of P450s. However, the behavioral responses of all lines to a series of permethrin concentrations did not vary significantly in any of the generations examined, in spite of the observed upregulation of CSP8 and OBP13. CONCLUSION: Expression patterns from the target genes provide insights into behavioral and physiological responses to permethrin and suggest a new avenue of research on the role of chemosensation genes in insect adaptation to toxins. PMID- 24796244 TI - A comprehensive study to explore differences in mycotoxin patterns from agro ecological regions through maize, peanut, and cassava products: a case study, Cameroon. AB - A total of 420 samples were collected from agrarian households. Whereas 51% (215/420) of the samples were contaminated with one or more toxins, the contamination rates for maize, peanut, and cassava products were 74, 62, and 24%, respectively. The fumonisins (20-5412 MUg/kg), aflatoxin B1 (6-645 MUg/kg), roquefortine C (1-181 MUg/kg), and deoxynivalenol (27-3842 MUg/kg) were the most prevalent contaminants in maize. For peanut samples, aflatoxin B1 (6-125 MUg/kg) and ochratoxin A (0.3-12 MUg/kg) were the main contaminants, whereas aflatoxin B1 (6-194 MUg/kg) and penicillic acid (25-184 MUg/kg) were detected in the cassava products. Exposures calculated through maize intake for fumonisin B1 and aflatoxin B1 were several-fold higher (2-5 for fumonisin B1 and 10(4)-10(5) for aflatoxin B1) than the health-based guidance values of 2 MUg/kg bw/day and 0.15 ng/kg bw/day, respectively. The study design constitutes a good model that can be implemented in other sub-Saharan African countries. PMID- 24796245 TI - Selective ultrasonic imprinting for micropattern replication on predefined area. AB - Conventional micro/nano patterning processes generally use rectangular patterned molds, so that the pattern replications are usually performed in a corresponding rectangular region. In this study, a selective patterning method based on ultrasonic imprinting is developed to replicate micropatterns on predefined areas with arbitrary profiles. To replicate micropatterns on predefined areas, the conventional ultrasonic imprinting process is modified by placing a profiled metal mask between a target film and an ultrasonic horn. Ultrasonic waves are then selectively transferred to the target film through the mask film, from which micropatterns can be replicated onto the predefined areas. For the implementation of the proposed selective imprinting process, the effects of the mask size and shape are experimentally investigated in terms of the replication characteristics of micropatterns. This selective imprinting process is further applied to micropattern replications on arbitrarily profiled areas. In these applications, the effects of the mask film and imprinting conditions are also discussed in terms of the replication quality in both the masked and the unmasked regions. PMID- 24796246 TI - Measurement of cylindrical Rayleigh surface waves using line-focused PVDF transducers and defocusing measurement method. AB - Line-focused PVDF transducers and defocusing measurement method are applied in this work to determine the dispersion curve of the Rayleigh-like surface waves propagating along the circumferential direction of a solid cylinder. Conventional waveform processing method has been modified to cope with the non-linear relationship between phase angle of wave interference and defocusing distance induced by a cylindrically curved surface. A cross correlation method is proposed to accurately extract the cylindrical Rayleigh wave velocity from measured data. Experiments have been carried out on one stainless steel and one glass cylinders. The experimentally obtained dispersion curves are in very good agreement with their theoretical counterparts. Variation of cylindrical Rayleigh wave velocity due to the cylindrical curvature is quantitatively verified using this new method. Other potential applications of this measurement method for cylindrical samples will be addressed. PMID- 24796247 TI - Pitfalls in the experimental recording of ultrasonic (backscatter) polar scans for material characterization. AB - The ultrasonic polar scan (UPS), either in transmission, reflection or backscatter mode, is a promising non-destructive testing technique for the characterization of composites, providing information about the mechanical anisotropy, the viscoelastic damping, the surface roughness, and more. At present, the technique is merely being used for qualitative purposes. The limited quantitative exploration and use of the technique can be primarily ascribed to limitations of current theoretical models as well as the difficulty to perform accurate, and more importantly, reproducible UPS experiments. Over the last years, we have identified several potential pitfalls in the experimental implementation of the technique which severely deteriorate the accurateness and reproducibility of a UPS. In this paper, we make an inventory of the most important difficulties, illustrate each of them by a real experiment and present a feasible mediation, either numerical or experimental in nature. Once the experimental set-up is fine-tuned to overcome these pitfalls, it is expected that the recording of high-level UPS experiments, in combination with numerical computations, will facilitate the technique to become a fully quantitative non destructive characterization method. PMID- 24796248 TI - Mandatory use of checklists for reporting guidelines. PMID- 24796250 TI - Photosynthesis: response to high temperature stress. AB - Global warming has led to increased temperature of the earth which is a major abiotic stress posing a serious threat to the plants. Photosynthesis is amongst the plant cell functions that is highly sensitive to high temperature stress and is often inhibited before other cell functions are impaired. The primary sites of targets of high temperature stress are Photosystem II (PSII), ribulose-1,5 bisphosphate carboxylase/oxygenase (Rubisco) while Cytochrome b559 (Cytb559) and plastoquinone (PQ) are also affected. As compared to PSII, PSI is stable at higher temperatures. ROS production, generation of heat shock proteins, production of secondary metabolites are some of the consequences of high temperature stress. In this review we have summarized the physiological, biochemical and molecular aspects of high temperature stress on the process of photosynthesis, as well as the tolerance and adaptive mechanisms involved. PMID- 24796249 TI - On-the-fly decoding luminescence lifetimes in the microsecond region for lanthanide-encoded suspension arrays. AB - Significant multiplexing capacity of optical time-domain coding has been recently demonstrated by tuning luminescence lifetimes of the upconversion nanoparticles called 'tau-Dots'. It provides a large dynamic range of lifetimes from microseconds to milliseconds, which allows creating large libraries of nanotags/microcarriers. However, a robust approach is required to rapidly and accurately measure the luminescence lifetimes from the relatively slow-decaying signals. Here we show a fast algorithm suitable for the microsecond region with precision closely approaching the theoretical limit and compatible with the rapid scanning cytometry technique. We exploit this approach to further extend optical time-domain multiplexing to the downconversion luminescence, using luminescence microspheres wherein lifetimes are tuned through luminescence resonance energy transfer. We demonstrate real-time discrimination of these microspheres in the rapid scanning cytometry, and apply them to the multiplexed probing of pathogen DNA strands. Our results indicate that tunable luminescence lifetimes have considerable potential in high-throughput analytical sciences. PMID- 24796254 TI - Prolonged administration of antidepressant drugs leads to increased binding of [(3)H]MPEP to mGlu5 receptors. AB - Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs. PMID- 24796256 TI - Ciproxifan improves working memory through increased prefrontal cortex neural activity in sleep-restricted mice. AB - Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders. However, few works have tried to identify their cognitive effects after sleep restriction and their impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction in a shaker apparatus that prevents sleep by transient (20-40 ms) up and down movements. Number of stimulations (2-4), and delay between 2 stimulations (100 200 ms) were randomized. Each sequence of stimulation was also randomly administered (10-30 s interval) for 20 consecutive hours during light (8 h) and dark (12 h) phases. Immediately after 20 h-sleep restriction, mice were injected with H3 antagonist (ciproxifan 3 mg/kg ip) and submitted 30-min later to a working memory (WM) task using spatial spontaneous alternation behaviour. After behavioural testing, brains were perfused for Fos immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8+/-1.4% to 9.2+/-2.7%, p<0.001) and was followed by sleep rebound (58.2+/ 5.9%, p<0.05). Sleep restriction did not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5 s) inter-trial intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles, ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of Fos labelling in prelimbic, infralimbic and cingulate 2 cortex. In conclusion, ciproxifan at 3 mg/kg enhanced WM in sleep restricted mice through specific modulation of prefrontal cortex areas. PMID- 24796255 TI - Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior. AB - The neural factors underlying individual differences in susceptibility to chronic stress remain poorly understood. Preclinical studies demonstrate that mouse strains vary greatly in anxiety-related responses to chronic stress in a manner paralleled by differential stress-induced changes in glutamatergic signaling in the basolateral amygdala (BLA). Previous work has also shown that alterations in the amygdala gene expression of the GluN1 NMDA and the GluK1 kainate receptors are associated with stress-induced alterations in anxiety-like behavior in the C57BL/6J mouse strain. Using in vivo behavioral pharmacological and ex vivo physiological approaches, the aim of the current study was to further elucidate changes in glutamate neurotransmission in the BLA caused by stress and to test the functional roles of GluN1 and GluK1 in mediating stress-related changes in behavior. Results showed that stress-induced alterations in anxiety-like behavior (light/dark exploration test) were absent following bilateral infusion of the GluK1 agonist ATPA into the BLA. Intra-BLA infusion of the competitive NMDA antagonist AP5 produced a generalized behavioral disinhibition/locomotor hyperactivity, irrespective of stress. Slice electrophysiological recordings showed that ATPA augmented BLA GABAergic neurotransmission and that stress increased the amplitude of network-dependent spontaneous excitatory postsynaptic currents and amplitude of GABAergic miniature inhibitory postsynaptic currents in BLA. These findings could indicate stress-induced BLA glutamatergic neuronal network hyperexcitability and a compensatory increase in GABAergic neurotransmission, suggesting that GluK1 agonism augmented GABAergic inhibition to prevent behavioral sequelae of stress. Current data could have implications for developing novel therapeutic approaches, including GluK1 agonists, for stress related anxiety disorders. PMID- 24796257 TI - The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex. AB - Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1-2 min, and hindered SD induction and expansion for the following 15-30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use. PMID- 24796258 TI - Whole genome prediction of bladder cancer risk with the Bayesian LASSO. AB - To build a predictive model for urothelial carcinoma of the bladder (UCB) risk combining both genomic and nongenomic data, 1,127 cases and 1,090 controls from the Spanish Bladder Cancer/EPICURO study were genotyped using the HumanHap 1M SNP array. After quality control filters, genotypes from 475,290 variants were available. Nongenomic information comprised age, gender, region, and smoking status. Three Bayesian threshold models were implemented including: (1) only genomic information, (2) only nongenomic data, and (3) both sources of information. The three models were applied to the whole population, to only nonsmokers, to male smokers, and to extreme phenotypes to potentiate the UCB genetic component. The area under the ROC curve allowed evaluating the predictive ability of each model in a 10-fold cross-validation scenario. Smoking status showed the highest predictive ability of UCB risk (AUCtest = 0.62). On the other hand, the AUC of all genetic variants was poorer (0.53). When the extreme phenotype approach was applied, the predictive ability of the genomic model improved 15%. This study represents a first attempt to build a predictive model for UCB risk combining both genomic and nongenomic data and applying state-of-the art statistical approaches. However, the lack of genetic relatedness among individuals, the complexity of UCB etiology, as well as a relatively small statistical power, may explain the low predictive ability for UCB risk. The study confirms the difficulty of predicting complex diseases using genetic data, and suggests the limited translational potential of findings from this type of data into public health interventions. PMID- 24796259 TI - Construction and characterization of external cavity diode lasers for atomic physics. AB - Since their development in the late 1980s, cheap, reliable external cavity diode lasers (ECDLs) have replaced complex and expensive traditional dye and Titanium Sapphire lasers as the workhorse laser of atomic physics labs. Their versatility and prolific use throughout atomic physics in applications such as absorption spectroscopy and laser cooling makes it imperative for incoming students to gain a firm practical understanding of these lasers. This publication builds upon the seminal work by Wieman, updating components, and providing a video tutorial. The setup, frequency locking and performance characterization of an ECDL will be described. Discussion of component selection and proper mounting of both diodes and gratings, the factors affecting mode selection within the cavity, proper alignment for optimal external feedback, optics setup for coarse and fine frequency sensitive measurements, a brief overview of laser locking techniques, and laser linewidth measurements are included. PMID- 24796260 TI - Reaction mechanisms of small-molecule activation by amidoditetrylynes R(2)N-EE NR(2) (E = Si, Ge, Sn). AB - The calculated reaction profiles using density functional theory at the BP86/TZVPP level for the reaction of small molecules with amidoditetrylynes R2N EE-NR2 (E = Si, Ge, Sn) are discussed. Four projects are presented that feature the virtue of cooperation between theory and experiment. First, the calculated reaction paths for hydrogenation of the model systems (Me2N)EEL(NMe2) (E = Si, Ge, Sn), which possess E-E single bonds, are examined. The results for the germanium model systems are compared with hydrogenation of the real system L(?)GeGeL(?) where L(?) = NAr*(SiMe3) (Ar* = C6H2{C(H)Ph2}2Me-2,6,4). The second project introduced the multiply bonded amidodigermyne L(??)GeGeL(??), which carries the extremely bulky substituents L(??) = N(Ar(??))(SiPr(i)3), where Ar(??) = C6H2{C(H)Ph2}2Pr(i)-2,6,4. The theoretical reaction profile for dihydrogen addition to L(??)GeGeL(??) is discussed. Hydrogenation gives L(??)(H)GeGe(H)L(??) as the product, which is in equilibrium with the hydrido species Ge(H)L(??). The latter germanium hydride and tin homologue Sn(H)L(??) were found to be effective catalysts for hydroboration reactions, which is the topic of the third project. Finally, the calculated reaction course for the reduction of CO2 to CO with the amidodigermyne L(?)GeGeL(?) is discussed. PMID- 24796261 TI - Using gas modifiers to significantly improve sensitivity and selectivity in a cylindrical FAIMS device. AB - Recent reports describing enhanced performance when using gas additives in a DMS device (planar electrodes) have indicated that comparable benefits are not attainable using FAIMS (cylindrical electrodes), owing to the non-homogeneous electric fields within the analyzer region. In this study, a FAIMS system (having cylindrical electrodes) was modified to allow for controlled delivery of gas additives. An experiment was carried out that illustrates the important distinction between gas modifiers present as unregulated contaminants and modifiers added in a controlled manner. The effect of contamination was simulated by adjusting the ESI needle position to promote incomplete desolvation, thereby permitting ESI solvent vapor into the FAIMS analyzer region, causing signal instability and irreproducible CV values. However, by actively controlling the delivery of the gas modifier, reproducible CV spectra were obtained. The effects of adding different gas modifiers were examined using 15 positive ions having mass-to-charge (m/z) values between 90 and 734. Significant improvements in peak capacity and increases in ion transmission were readily attained by adding acetonitrile vapor, even at trace levels (<=0.1%). Increases in signal intensity were greatest for the low m/z ions; for the six lowest molecular weight species, signal intensities increased by ~10- to over 100-fold compared with using nitrogen without gas additives, resulting in equivalent or better signal intensities compared with ESI without FAIMS. These results confirm that analytical benefits derived from the addition of gas modifiers reported with a uniform electric field (DMS) also are observed using a non-homogenous electric field (FAIMS) in the analyser region. PMID- 24796262 TI - Detecting and removing data artifacts in Hadamard transform ion mobility-mass spectrometry measurements. AB - Applying Hadamard transform multiplexing to ion mobility separations (IMS) can significantly improve the signal-to-noise ratio and throughput for IMS coupled mass spectrometry (MS) measurements by increasing the ion utilization efficiency. However, it has been determined that fluctuations in ion intensity as well as spatial shifts in the multiplexed data lower the signal-to-noise ratios and appear as noise in downstream processing of the data. To address this problem, we have developed a novel algorithm that discovers and eliminates data artifacts. The algorithm employs an analytical approach to identify and remove artifacts from the data, decreasing the likelihood of false identifications in subsequent data processing. Following application of the algorithm, IMS-MS measurement sensitivity is greatly increased and artifacts that previously limited the utility of applying the Hadamard transform to IMS are avoided. Figure ? PMID- 24796263 TI - Family, money, and health: regional differences in the determinants of life satisfaction over the life course. AB - We examine how family, money, and health explain variation in life satisfaction over the life cycle across seven global regions using data from the World Values Survey. With a life domain approach, we study whether the importance of the life domains varies by region and age groups and whether the variation explained by each factor is due to the magnitude or prevalence of each factor. Globally, family, money, and health explain a substantial fraction of life satisfaction, increasing from 12 percent in young adulthood to 15 percent in mature adulthood. Health is the most important factor, and its importance increases with age. Income is unimportant above age 50. Remarkably, the contribution of family is small across ages. Across regions health is most important in the wealthier, and income in the poorer regions of the world. Family explains a substantial fraction of life satisfaction only in Western Europe and Anglophone countries. Findings highlight that the population-level importance of family, money, and health in explaining variation in life satisfaction across regions is mainly attributable to the individual-level life satisfaction differences between people of different statuses rather than differences in the distribution of various states such as poor health across regions. PMID- 24796264 TI - The dynamic association between same-sex contact and educational attainment. AB - Previous studies have shown that sexual minorities and heterosexuals differ in the level of success in educational attainment. Because these studies treated sexual orientation as a static trait, they could not address how the dynamic aspect of sexual orientation impacts educational attainment. This study seeks to answer this question while focusing on sexual contact as an indicator of sexual orientation and highest educational degree obtained by young adulthood as an attainment outcome. Ordered logistic regression analysis was conducted using US data (the National Longitudinal Study of Adolescent Health or "Add Health," Waves 1-4). Among women, those who report same-sex contact obtain lower educational degrees than those without such contact regardless of its timing and continuity. Among men, those who report their first same-sex contact in young adulthood obtain higher degrees than others. These associations are explained by self exploratory attitudes, depressive symptoms, and academic performance and expectations. These results help understand how same-sex sexual development creates opportunities and constraints in the educational attainment process, thereby extending the existing attainment literature, which concentrates on implications of heterosexual development. PMID- 24796265 TI - Childbearing desires of childless men and women: when are goals adjusted? AB - This paper examines the concept of desired future fertility. Childbearing desires are often conceptualized in the literature as representing an individual's ideal future fertility where there are no constraints or obstacles to achieve the desired outcome. As such, childbearing desires, unlike fertility intentions, are thought to be relatively unaffected by changing life circumstances. Using a theoretically driven model incorporating goal adjustment, we test whether desires of childless men and women do in fact change over time. Using data from the Household, Income and Labour Dynamics in Australia (HILDA) survey (2001-2010) we specifically investigate whether changing life circumstances do effect a change in childbearing desires. We find that age is strongly related to adjusting childbearing desires, as is relationship formation. Desires are however, not greatly influenced by short-term shocks such as an episode of poor health or unemployment, although these events have different effects for women and for men. Overall, the findings are consistent with psychological theories of goal adjustment, that is, individuals will revise their desires for having children if they perceive that their desires are not likely to be fulfilled. PMID- 24796266 TI - A life course perspective on socioeconomic inequalities in health: a critical review of conceptual frameworks. AB - Social scientists and public health researchers have long known that social position is related to health and that socioeconomic inequalities in health persist in later life. Increasingly, a life course perspective is adopted to understand the socioeconomic position (SEP)-health dynamic. This paper critically reviews the conceptual perspectives underlying empirical research seeking to better understand socioeconomic inequalities in health in the context of the life course. I comment on the contributions of this work, but also its limitations. In particular, I note the emphasis on understanding the mechanisms linking SEP to health, to the exclusion of research on the institutional and structural factors associated with socioeconomic inequalities over the life course. I also critique the relative absence of gender in this work, and how, by not linking individual experiences to the social policy contexts that shape resources and opportunities, the proximal, rather than the structural or institutional determinants of health are emphasized. I suggest that moving forward, a return to some of the key tenets of life course theory, including contributions from the comparative welfare states literature, may better inform life course analyses of socioeconomic inequalities in health. Specific suggestions for life scholarship are discussed. PMID- 24796267 TI - Divergent population structure and climate associations of a chromosomal inversion polymorphism across the Mimulus guttatus species complex. AB - Chromosomal rearrangement polymorphisms are common and increasingly found to be associated with adaptive ecological divergence and speciation. Rearrangements, such as inversions, reduce recombination in heterozygous individuals and thus can protect favourable allelic combinations at linked loci, facilitating their spread in the presence of gene flow. Recently, we identified a chromosomal inversion polymorphism that contributes to ecological adaptation and reproductive isolation between annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus. Here we evaluate the population genetic structure of this inverted region in comparison with the collinear regions of the genome across the M. guttatus species complex. We tested whether annual and perennial M. guttatus exhibit different patterns of divergence for loci in the inverted and noninverted regions of the genome. We then evaluated whether there are contrasting climate associations with these genomic regions through redundancy analysis. We found that the inversion exhibits broadly different patterns of divergence among annual and perennial M. guttatus and is associated with environmental variation across population accessions. This study is the first widespread population genetic survey of the diversity of the M. guttatus species complex. Our findings contribute to a greater understanding of morphological, ecological, and genetic evolutionary divergence across this highly diverse group of closely related ecotypes and species. Finally, understanding species relationships among M. guttatus sp. has hitherto been stymied by accumulated evidence of substantial gene flow among populations as well as designated species. Nevertheless, our results shed light on these relationships and provide insight into adaptation in life history traits within the complex. PMID- 24796268 TI - Individual differences in forced-choice recognition memory: partitioning contributions of recollection and familiarity. AB - In forced-choice recognition memory, two different testing formats are possible under conditions of high target-foil similarity: Each target can be presented alongside foils similar to itself (forced-choice corresponding; FCC), or alongside foils similar to other targets (forced-choice noncorresponding; FCNC). Recent behavioural and neuropsychological studies suggest that FCC performance can be supported by familiarity whereas FCNC performance is supported primarily by recollection. In this paper, we corroborate this finding from an individual differences perspective. A group of older adults were given a test of FCC and FCNC recognition for object pictures, as well as standardized tests of recall, recognition, and IQ. Recall measures were found to predict FCNC, but not FCC performance, consistent with a critical role for recollection in FCNC only. After the common influence of recall was removed, standardized tests of recognition predicted FCC, but not FCNC performance. This is consistent with a contribution of only familiarity in FCC. Simulations show that a two-process model, where familiarity and recollection make separate contributions to recognition, is 10 times more likely to give these results than a single-process model. This evidence highlights the importance of recognition memory test design when examining the involvement of recollection and familiarity. PMID- 24796269 TI - Clinicopathologic and molecular characterization of myeloid neoplasms harboring isochromosome 17(q10). PMID- 24796270 TI - Why don't they accept non-invasive ventilation?: insight into the interpersonal perspectives of patients with motor neurone disease. AB - OBJECTIVES: Although non-invasive ventilation (NIV) can benefit survival and quality of life, it is rejected by a substantial proportion of people with motor neurone disease (MND). The aim of this study was to understand why some MND patients decline or withdraw from NIV. METHOD: Nine patients with MND (male = 7, mean age = 67 years) participated in this study. These patients, from a cohort of 35 patients who were offered NIV treatment to support respiratory muscle weakness, did not participate in NIV treatment when it was clinically appropriate. Semi-structured interviews and interpretative phenomenological analysis (IPA) were employed to explore these patient's experience of MND and their thoughts and understanding of NIV treatment. RESULTS: Using IPA, four themes were identified: preservation of the self, negative perceptions of NIV, negative experience with health care services, and not needing NIV. Further analysis identified the fundamental issue to be the maintenance of perceived self, which was interpreted to consist of the sense of autonomy, dignity, and quality of life. CONCLUSIONS: The findings indicate psychological reasons for disengagement with NIV. The threat to the self, the sense of loss of control, and negative views of NIV resulting from anxiety were more important to these patients than prolonging life in its current form. These findings suggest the importance of understanding the psychological dimension involved in decision making regarding uptake of NIV and a need for sensitive holistic evaluation if NIV is declined. Statement of contribution What is already known on this subject? Non-invasive ventilation is widely used as an effective symptomatic therapy in MND, yet about a third of patients decline the treatment. Psychological disturbance generated by NIV use leads to negative experiences of the treatment. Decision-making about treatment potentials is complex and unique to each individual affected by perceived impact of disease. What does this study add? A decision concerning NIV uptake was influenced by perceived impact on individuals' sense of self. Sense of self was influenced by the maintenance of autonomy, dignity, and quality of life. Individuals' sense of self was identified to have been challenged by the disease, NIV, and their experience of health care service. PMID- 24796271 TI - Chronic kidney disease and the aging population. PMID- 24796272 TI - Tryptamine functionalized reduced graphene oxide for label-free DNA impedimetric biosensing. AB - A novel simple protocol of synthesizing tryptamine-functionalized reduced graphene oxide (TRA-rGO) was proposed to fabricate label-free electrochemical impedance DNA biosensor. TRA was anchored to rGO with its indole ring via pi stacking interaction. The morphology, conductivity and interaction of TRA-rGO were characterized by atomic force microscopy, high resolution transmission electron microscopy, cyclic voltammetry, electrochemical impedance spectroscopy (EIS) as well as Raman and fluorescence spectroscopy. The amino-substituted oligonucleotide probe was conjugated to TRA by cross-linker glutaraldehyde for preparing an electrochemical biosensing platform. The DNA hybridization reaction of oligonucleotide probe with target DNA was monitored by EIS. Under optimum conditions, the proposed biosensor exhibited high sensitivity and low detection limit for detecting complementary oligonucleotide. The target oligonucleotide could be quantified in a wide range of 1.0 * 10(-12)-1.0 * 10(-7)M with low detection limit of 5.2 * 10(-13)M (S/N=3). PMID- 24796273 TI - Design of a timed and controlled release osmotic pump system of atenolol. AB - The objective of the article was to design a novel timed and controlled release osmotic pump (TCOP) containing atenolol as an active pharmaceutical ingredient and compare with a bilayer-core osmotic pump (BCOP) of atenolol. Different from BCOP, a modulating barrier was added to delay the drug release and obtain desired lag time (Tlag). The influences of the amount of pore-forming agent and modulating barrier, coating weight gain on the lag time (Tlag) and drug release rate (Rt) of TCOP were investigated. The central composite design-response surface methodology (RSM) was applied to optimize the formulation. Rhodamine B was added to modulating barrier to determine the release process of modulating barrier. A method used to correct the release profiles with a certain lag time by DeltaTlag and interpolating was applied to compare TCOP with BCOP. Tlag was directly proportional to the amount of modulating barrier and coating weight gain, but inversely related to the amount of pore forming agent, which were contrary to the effects on Rt. The optimal formulation including 60 mg PEO WSR N80, 3 g PEG 4000 and 6% coating weight gain could obtain a 3.59-h Tlag. According to the release of Rhodamine B, the modulating barrier was completely pushed out at ~5.0 h, longer than 3.59 h, therefore, atenolol along with remaining modulating barrier was released together between 3.59 and 5.0 h. By comparing with BCOP, the release profiles subtracting the part of lag time had no significant difference, yet Rt of TCOP presented a slight decrease. PMID- 24796274 TI - Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan. AB - Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs. PMID- 24796275 TI - A Valsalva leak-point pressure of >100 cmH2O is associated with greater success in AdVanceTM sling placement for the treatment of post-prostatectomy urinary incontinence. AB - OBJECTIVES: To determine if there is a Valsalva leak-point pressure (VLPP) threshold that predicts for retro-urethral transobturator sling (RTS) success in men with post-prostatectomy urinary incontinence (UI). PATIENTS AND METHODS: The preoperative urodynamic parameters of all patients undergoing RTS (AdVanceTM) sling surgery over the last 5 years were analysed and compared with the postoperative outcomes. The sling was defined as having been successful if the patient no longer had to wear pads or merely used a pad to provide a sense of security. RESULTS: In all, 46 men with a mean (range) age of 65 (45-83) years, underwent AdVanceTM sling surgery. 10 men had undergone holmium laser enucleation of the prostate, one a transurethral resection of the prostate and 35 radical prostatectomy. 11 men had a VLPP of <=100 cmH2O. Of these 11 men, three had no, or minimal, improvement in their leakage and all three required a secondary procedure (artificial urinary sphincter, AUS). In the 35 men with a VLPP of >100 cmH2O there were three failures. One of these was successfully salvaged with a repeat sling, another with an AUS and one with ProACTTM balloons. The hazard ratio (HR) for failure with a VLPP of <=100 cmH20 compared with a VLPP of >100 cmH2O was 4 (95% confidence interval 0.68-23.7). CONCLUSION: A VLPP of >100 cmH2O has a high degree of predictability for success for AdVanceTM sling placement for men with post-prostatectomy UI. PMID- 24796276 TI - In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors. AB - Infiltration of a neoplasm with tumor-associated macrophages (TAMs) is considered an important negative prognostic factor and is functionally associated with tumor vascularization, accelerated growth, and dissemination. However, the ontogeny and differentiation pathways of TAMs are only incompletely characterized. Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified. We propose that, akin to various MU subtypes in nonmalignant tissues, local proliferation and CSF1 play a vital role in the homeostasis of TAMs. PMID- 24796277 TI - Biased agonism at G protein-coupled receptors: the promise and the challenges--a medicinal chemistry perspective. AB - Historically, determination of G protein-coupled receptor (GPCR) ligand efficacy has often been restricted to identifying the ligand as an agonist or antagonist at a given signaling pathway. This classification was deemed sufficient to predict compound efficacy at all signaling endpoints, including the therapeutically relevant one(s). However, it is now apparent that ligands acting at the same GPCR can stabilize multiple, distinct, receptor conformations linked to different functional outcomes. This phenomenon, known as biased agonism, stimulus bias, or functional selectivity offers the opportunity to separate on target therapeutic effects from side effects through the design of drugs that show pathway selectivity. However, the medicinal chemist faces numerous challenges to develop biased ligands, including the detection and quantification of biased agonism. This review summarizes the current state of the field of research into biased agonism at GPCRs, with a particular focus on efforts to relate biased agonism to ligand structure. PMID- 24796278 TI - Why Is the L-Shaped Structure of X2...X2 (X = F, Cl, Br, I) Complexes More Stable Than Other Structures? AB - Five different structures (L- and T-shaped (LS, TS), parallel (P), parallel displaced (PD), and linear (L)) of (X2)2 dimers (X = F, Cl, Br, I, N) have been investigated at B97-D3, M06-2X, DFT-SAPT, and CCSD(T) levels. The Qzz component of the quadrupole moment of all dihalogens, which coincides with the main rotational axis of the symmetry of the molecule, has been shown to be positive, whereas that of dinitrogen is negative. All of these values correlate well with the most positive value of the electrostatic potential, which, for dihalogens, reflects the magnitude of the sigma-hole. The LS structure is the most stable structure for all dihalogen dimers. This trend is the most pronounced in the case of iodine and bromine; for dinitrogen dimer, the LS, TS, and PD structures are comparably stable. The dominant stabilization energy for dihalogen dimers is dispersion energy, followed by Coulomb energy. In the case of dinitrogen dimer, it is only the dispersion energy. At short distances, the Coulomb (polarization) energy for dihalogen dimers is more attractive for the LS structure; at larger distances, the TS structure is more favorable, as dispersion and induction energies are systematically more stable for the TS structure. For all dimers and all distances, the long-range electrostatic energy covering the interactions of multipole moments is the most attractive for the TS structure. In the case of dihalogen dimers, the preference of the LS structure over the others, resulting from the concert action of Coulomb, dispersion, and induction energies, is explained by the presence of a sigma-hole. In the case of dinitrogen, comparable stability of LS, TS, and PD structures is obtained, as all are dominantly stabilized by dispersion energy. PMID- 24796279 TI - Administration of anti-CD20 mAb is highly effective in preventing but ineffective in treating chronic graft-versus-host disease while preserving strong graft versus-leukemia effects. AB - Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome, and donor B cells play important roles in augmenting its pathogenesis. B cell depleting anti-CD20 mAb has been administered before or after cGVHD onset for preventing or treating cGVHD in the clinic. Although administration before onset appeared to be more effective, the effect is variable and sometimes minimal. Here, we used 2 mouse cGVHD models to evaluate the preventive and therapeutic effect of anti-CD20 mAb. With the model of DBA/2 donor to MHC-matched BALB/c recipient, 1 intravenous injection of anti-CD20 mAb (40 mg/kg) the following day or on day 7 after hematopoietic cell transplantation when serum autoantibodies were undetectable effectively prevented induction of cGVHD and preserved a strong graft-versus-leukemia (GVL) effect. The separation of GVL effect from GVHD was associated with a significant reduction of donor CD4(+) T cell proliferation and expansion and protection of host thymic medullary epithelial cells. Anti-CD20 mAb administration also prevented expansion of donor T cells and induction of cGVHD in another mouse model of C57BL/6 donor to MHC-mismatched BALB/c recipients. In contrast, administration of anti-CD20 mAb after GVHD onset was not able to effectively deplete donor B cells or ameliorate cGVHD in either model. These results indicate that administration of anti-CD20 mAb before signs of cGVHD can prevent induction of autoimmune-like cGVHD while preserving a GVL effect; there is little effect if administered after cGVHD onset. This provides new insights into clinical prevention and therapy of cGVHD with B cell-depleting reagents. PMID- 24796281 TI - Predictive value of circulating angiopoietin-2 for endothelial damage-related complications in allogeneic hematopoietic stem cell transplantation. AB - Endothelial cell damage has been reported to be associated with noninfectious transplant-related complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among these, noninfectious transplant-related complications with endothelial cell damage (TRC-EC) include sinusoidal occlusive syndrome, transplant-associated microangiopathy, intestinal transplant-associated microangiopathy, capillary leak syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage. Because angiopoietin-2 (ANG2) plays an essential role in the endothelial cell damage of various inflammatory disorders, we hypothesized that ANG2 may also play a critical role in TRC-EC. We retrospectively estimated the incidence of TRC-EC and evaluated the association with ANG2 level at transplant. We studied 153 consecutive adult patients who underwent allo-HSCT at our institution between 2000 and 2012. Median patient age was 49 years (range, 16 to 68 years). With a median follow-up of 55 months, 3 year overall survival for all patients was 55%. The incidence of TRC-EC at day 100 was significantly higher in the high-ANG2 group (>=2000 pg/mL; n = 36) than in the low-ANG2 group (<2000 pg/mL; n = 117) (70% [95% confidence interval {CI}, 55% to 84%] versus 16% [95% CI, 11% to 24%]; P < .001). Multivariate analysis revealed that high ANG2 level at transplant was independently associated with higher risk of TRC-EC (hazard ratio, 6.01; 95% CI, 3.16 to 11.43; P < .001) and shorter overall survival (hazard ratio, 2.23; 95% CI, 1.66 to 4.48; P = .002). These results suggest that ANG2 level at transplant may be a useful marker for predicting the risk of TRC-EC after allo-HSCT. Prospective studies are warranted to validate our results. PMID- 24796282 TI - A prototype axial ultrasound needle guide to reduce epidural bone contact. AB - We have developed an ultrasound probe through the centre of which an epidural needle can pass, intended to reduce the rate of contact between bone and needle during epidural insertion. We tested the ability of this probe to identify the lumbar interspace, using A-mode ultrasound, in a submerged plastic model, a porcine phantom and five human volunteers. In the plastic model, the minimum echo representing the interspace was only 8.8% of the maximum echo from the 'bone'. In the porcine model, the echo variations between the interspace and L3 were up to 48% and the needle was safely inserted into the interspace without bone contact under guidance. The human study also showed that the maximum bone echo was at least three times stronger than the interspace echo. Axial ultrasound guidance, with the needle passing through the probe, offers a method for reducing bone contact during epidural insertion. PMID- 24796280 TI - Treatment with a rho kinase inhibitor improves survival from graft-versus-host disease in mice after MHC-haploidentical hematopoietic cell transplantation. AB - Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT) and the main cause of nonrelapse mortality during the first 100 days post-transplant. Although GVHD can be prevented by extensive removal of mature donor T cells from the donor hematopoietic stem cell population, doing so eliminates any potential allogeneic graft-versus-tumor (GVT) effect also mediated by donor T cells and results in unacceptable rates of cancer relapse. One potential solution to this problem of separating GVHD development from a GVT response is to prevent T cell-mediated GVHD in the intestinal tract (IT) while preserving systemic antihost alloreactivity of donor T cells that target residual tumor cells expressing host alloantigens. We examined the ability of the anti-inflammatory rho kinase inhibitor, fasudil, given orally and intraperitoneally, to prevent GVHD in a C3H > B6C3F1 mouse model of MHC-haploidentical bone marrow transplantation. Fasudil treated recipients of anti-thy-1 mAb + C' treated bone marrow (ATBM) cells plus T cells had a 73% 90-day survival compared with 25% among untreated ATBM + T cell recipients (P < .0001). Severe initial weight loss was similar in the 2 groups, but less diarrhea was observed among treated animals, and fasudil-treated survivors recovered more weight than untreated survivors. Skin inflammation occurred and resolved between weeks 2 and 8 with similar severity and kinetics in both treated and untreated surviving animals, indicating persistent alloreactivity. Day 10 post-transplantation splenocytes from fasudil-treated mice, containing mature donor T cells, and day 98 splenocytes, containing mature donor and de novo thymus-derived T cells, exhibited alloreactivity against host parental antigens, as assessed by in vitro IFN-gamma production and rounds of allostimulated proliferation, respectively. These data support the idea that targeted treatment of the IT with rho kinase inhibitors can ameliorate lethal GVHD while preserving systemic alloreactivity. The results also suggest that similar mechanisms of IT-specific tolerance or resistance to GVHD operate in fasudil-treated and untreated long-term survivors of allogeneic ATBM + T cells. PMID- 24796283 TI - Fast and reversible insertion of carbon dioxide into zirconocene-alkoxide bonds. A mechanistic study. AB - In two consecutive equilibria the compound (Cp*)2Zr(OMe)2 undergoes insertion of CO2 to form the mono- and bis-hemicarbonates. Both equilibria are exothermic but entropically disfavoured. Magnetisation transfer experiments gave kinetic data for the first equilibrium showing that the rate of insertion is overall second order with a rate constant of 3.20 +/- 0.12 M(-1) s(-1), which is substantially higher than those reported for other early transition metal alkoxides, which are currently the best homogeneous catalysts for dimethyl carbonate formation from methanol and CO2. Activation parameters for the insertion reaction point to a highly ordered transition state and we interpret that as there being a substantial interaction between the CO2 and the metal during the C-O bond formation. This is supported by DFT calculations showing the lateral attack by CO2 to have the lowest energy transition state. PMID- 24796284 TI - Pilot study on the validity of the pupillographic sleepiness test in children and adolescents. AB - OBJECTIVE: To report preliminary validation data for the pupillographic sleepiness test (PST) in children and adolescents. METHODS: Twelve patients (13.1+/-4.4 years of age) underwent the multiple sleep latency test (MLST) and three PSTs at 09:00, 11:00, and 13:00 on one single day. Correlations were tested between mean sleep latency and gender-adjusted z-values of the natural logarithm of the pupillary unrest index (zlnPUI). RESULTS: Spearman's correlation (P-value) between the zlnPUI values obtained at 09:00 and 11:00 with the MSL was rS = 0.641 (0.025) and r = -0.553 (0.062). CONCLUSION: There was satisfactory agreement between PST and the MLST, which is similar to what is found in adults. The PST may be promising for the evaluation of daytime sleepiness in children and adolescents, and should be further evaluated in future studies. PMID- 24796285 TI - Nightmares in narcolepsy: underinvestigated symptom? AB - OBJECTIVE: Besides main disease symptoms, disturbing dreams are often found in narcoleptics and may contribute to disturbed sleep. Our main goal was to study different types of oneiric activity in narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (N). METHODS: We have analyzed the medical history of 118 narcoleptics (64 men, 86 with NC, 32 with N, mean age 41.6+/-15 years). Their most frequent dreams were divided into four groups: (A) low recall/mundane dreams, (B) vivid dreams without disturbing negative emotion, (C) nightmares, (D) reduction of nightmares, possibly by medication. Associations with other features of the disease were statistically analyzed. RESULTS: Nightmares were found in one third of the patients, proportionally distributed in N and NC groups; not negatively charged vivid dreams appeared more frequently in NC patients (P<0.005). No/mundane dreams occurred with higher prevalence in men (48%) than in women (20%), (P<0.005), without any significant influence of age. Occurrence of nightmares was significantly higher in patients with REM sleep behavior (P<0.05), but lower in patients with obstructive sleep apnea (P<0.005). Polysomnographic correlation of N and NC nightmare groups showed more wakefulness (P<0.05) and higher percentage of NREM1 stage (P<0.05) in NC patients with nightmares. CONCLUSION: Compared with the general population, nightmares seem to be significantly more prevalent in both NC and N, and they are not sufficiently investigated and treated. The neurobiological basis of narcolepsy and patients' dreaming activities appear to be closely related. PMID- 24796286 TI - Prognostic implication of obstructive sleep apnea diagnosed by post-discharge sleep study in patients presenting with acute coronary syndrome. AB - OBJECTIVE: We aimed to determine the prognostic implications of obstructive sleep apnea (OSA) diagnosed during the recovery phase of acute coronary syndrome (ACS). METHODS: Patients presenting with ACS and treated with percutaneous coronary intervention were recruited prospectively for a home-based sleep study within 30 days of hospital discharge. Major adverse cardiac and cerebrovascular events (MACCEs) assessed included cardiac death, myocardial infarction, stroke, unplanned revascularization, and hospitalization for heart failure. RESULTS: Of the 85 patients recruited, 68 successfully completed the study. The median time from percutaneous coronary intervention to sleep study was 14 days (interquartile range: 7.5-27 days). OSA was diagnosed in 24 patients (35.3%) (apnea-hypopnea index > or =15). A drug-eluting stent was implanted into the target lesion in 45 patients (66.2%). None of the study patients had received treatment for OSA. At 24-month follow-up, the MACCE incidence was 34.9% in the OSA group and 5.1% in the non-OSA group (P=0.008, log-rank test). After adjusting for the possible confounding effect of age, gender, coronary intervention indications, hypertension, smoking, and body mass index, OSA remained an independent predictor of MACCEs (adjusted hazard ratio, 6.95; 95% confidence interval, 1.17-41.4; P=0.033). CONCLUSION: OSA diagnosed in patients treated with percutaneous coronary intervention for ACS by post-discharge sleep studies conducted 2 weeks after percutaneous coronary intervention was independently associated with MACCEs at 24-month follow-up. PMID- 24796287 TI - Pattern separation of emotional information in hippocampal dentate and CA3. AB - Emotional arousal, mediated by the amygdala, is known to modulate episodic memories stored by the hippocampus, a region involved in pattern separation (the process by which similar representations are independently stored). While emotional modulation and pattern separation have been examined independently, this study attempts to link the two areas of research to propose an alternative account for how emotion modulates episodic memory. We used an emotional discrimination task designed to tax pattern separation of emotional information by concurrently varying emotional valence and similarity of stimuli. To examine emotional modulation of memory at the level of hippocampal subfields, we used high-resolution fMRI (1.5 mm isotropic) of the medial temporal lobe. Consistent with prior reports, we observed engagement of the hippocampal dentate gyrus (DG) and CA3 during accurate discrimination of highly similar items (behavioral correlate of pattern separation). Furthermore, we observed an emotional modulation of this signal (negative > neutral) specific to trials on which participants accurately discriminated similar emotional items. The amygdala was also modulated by emotion, regardless of the accuracy of discrimination. Additionally, we found aberrant amygdala-hippocampal network activity in a sample of adults with depressive symptoms. In this sample, amygdala activation was enhanced and DG/CA3 activation was diminished during emotional discrimination compared to those without depressive symptoms. Depressive symptom severity was also negatively correlated with DG/CA3 activity. This study suggests a novel mechanistic account for how emotional information is processed by hippocampal subfields as well as how this network may be altered in mood disorders. PMID- 24796288 TI - Peripheral Blood Mononuclear Cell ABCA1 Transcripts and Protein Expression in Acute Myocardial Infarction. AB - BACKGROUND: ATP binding cassette transporter-A1 (ABCA1) facilitates the formation of high density lipoprotein (HDL). HDL due to its anti-atherosclerotic, anti inflammatory and anti-thrombotic activities provides protection against atherothrombosis or myocardial infarction (MI). The aim was to investigate the role of peripheral blood mononuclear cell (PBMNC) ABCA1 expression in MI. METHODS: The participants comprised 29 males with acute MI (AMI) and 20 healthy controls. AMI patients were normotensive, not on statins, with triglycerides < 200mg/dl and categorized into AMI with type 2 diabetes (T2DM) (N = 12) and without T2DM (N = 17). The PBMNC ABCA1 mRNA transcripts were analysed by quantitative real-time polymerase chain reaction (qRTPCR) and protein by enzyme linked immunosorbent assay (ELISA). RESULTS: PBMNC ABCA1 mRNA transcript and protein levels were not significantly different in AMI patients or when sub grouped into with/without T2DM, as compared to controls. ABCA1 protein correlated positively with HDL-cholesterol (r = 0.655, p = 0.021) in AMI patients with T2DM and negatively with age (r = - 0.525, p = 0.031) in AMI patients without T2DM and it was more strongly associated in latter group with smoking and alcohol habit. CONCLUSION: In the present study, the effects of metabolites of diabetes and ischemia were observed on PBMNC ABCA1 protein and thus on HDL-C in AMI patients. Further influence of risk factors such as smoking and alcohol consumption observed in the present study can be evaluated in larger sample size. The control of these cardiovascular associated risk factors may increase stability of PBMNC ABCA1 protein and thus HDL-C levels. PMID- 24796289 TI - Typologies of alcohol consumption on a Saturday night among young adults. AB - BACKGROUND: Alcohol policies and interventions seek to curtail risky single occasion drinking (RSOD) and the negative health and public order consequences. Yet RSOD behaviors are not easily defined since people can drink excessively at a variety of locations and drink a range of products. The current study examines the presence and correlates of different typologies or classes of drinking behavior on 1 Saturday night to facilitate a nuanced policy response to harmful drinking. METHODS: Data from 1,883 adults aged 18 to 30 were collected using an online survey. Latent class analysis was used to categorize respondents into mutually exclusive classes based on the quantity, type, and unit cost of alcohol consumed plus location of alcohol consumption on the past Saturday night. Significant correlates and predictors of latent class membership were then identified using regression analysis. RESULTS: Seven distinct classes were identified that represent qualitatively distinct profiles of Saturday night drinking behavior among young adults. Multivariate analyses indicated that alcohol risk (measured using the Alcohol Use Disorder Identification Test), age, and recent (past 12 months) stimulant use were strong predictors of heavier drinking. The heaviest drinkers also consumed some of the cheapest alcohol and consumed alcohol at multiple locations over the course of the night. CONCLUSIONS: Given the large degree of heterogeneity among drinking behaviors, policy makers need to be cognizant that alcohol type and drinking location-specific policies may be less effective in targeting some groups of the population. PMID- 24796290 TI - Characterization of prostate neuroendocrine cancers and therapeutic management: a literature review. AB - OBJECTIVES: Neuroendocrine prostate cancers (NEPCs) are rare. The current lack of consensus for clinical, biological and pathological characterization as well as therapeutic approach makes the management of those tumors a clinical challenge. This literature review aims to summarize available data on the characterization and management of patients with prostate cancer with a neuroendocrine element. We try to identify major controversies and uncertainties in order to understand all aspects of this particular entity. METHODS: We searched for all articles published and registered in the MEDLINE database before 31 November 2013 with the following search terms: (('prostatic neoplasms' (MeSH Terms)) AND ('carcinoma, neuroendocrine' (MeSH Terms)) OR ('carcinoma, small cell' (MeSH Terms))) AND (English (Language)). RESULTS: Case reports, letters or comments were excluded. We then selected relevant articles from titles and abstracts. Overall, 278 articles published between 1976 and November 2013 were identified. No definition of NEPC seems to be clearly established. Natural history of the disease reveals poor prognosis with median survival of up to 10 to 13 months. Histological characterization appears difficult. Serum markers could be helpful with some controversies in terms of prognostic significance. Concerning management, the majority of patients received local treatment combined with chemotherapy in case of early and localized disease. Few clinical trials described strategy for metastatic disease. CONCLUSIONS: The exploration of the different pathways implicated in the neuroendocrine differentiation of prostate cancers is essential for the comprehension of castration-resistance mechanisms. It will enable the identification of optimal therapeutic strategies for which no recommendation is currently established. Inclusion in prospective clinical trials appears necessary to identify the adequate strategy. PMID- 24796292 TI - Southern Society for Clinical Investigation 2014 Founders' Medal acceptance: an academic career--it takes a village. PMID- 24796291 TI - Role of interferon alpha in endothelial dysfunction: insights into endothelial nitric oxide synthase-related mechanisms. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the production of autoantibodies against nuclear antigens such as double stranded DNA. Lupus predominantly affects women (ratio, 9:1). Moreover, premenopausal women with SLE are 50 times more likely to have a myocardial infarction. Although specific risk factors for advanced cardiovascular complications have not been identified in this patient population, endothelial dysfunction is highly prevalent. Recent studies show that the type I interferon signature gene expression coincides with impaired brachial artery flow-mediated dilation and diminished endothelial progenitor cell circulation, both markers of impaired endothelial function. Although many factors promote the development of vascular endothelial dysfunction, all pathways converge on the diminished activity of endothelial nitric oxide synthase (eNOS) and loss of nitric oxide (NO) bioavailability. Studies examining the effects of type I interferons on eNOS and NO in SLE are missing. This literature review examines the current literature regarding the role of type I interferons in cardiovascular disease and its known effects on regulators of eNOS and NO bioavailability that are important for proper endothelial cell function. PMID- 24796294 TI - Development of a regression model to predict copper toxicity to Daphnia magna and site-specific copper criteria across multiple surface-water drainages in an arid landscape. AB - The water effect ratio (WER) procedure developed by the US Environmental Protection Agency is commonly used to derive site-specific criteria for point source metal discharges into perennial waters. However, experience is limited with this method in the ephemeral and intermittent systems typical of arid climates. The present study presents a regression model to develop WER-based site specific criteria for a network of ephemeral and intermittent streams influenced by nonpoint sources of Cu in the southwestern United States. Acute (48-h) Cu toxicity tests were performed concurrently with Daphnia magna in site water samples and hardness-matched laboratory waters. Median effect concentrations (EC50s) for Cu in site water samples (n=17) varied by more than 12-fold, and the range of calculated WER values was similar. Statistically significant (alpha=0.05) univariate predictors of site-specific Cu toxicity included (in sequence of decreasing significance) dissolved organic carbon (DOC), hardness/alkalinity ratio, alkalinity, K, and total dissolved solids. A multiple regression model developed from a combination of DOC and alkalinity explained 85% of the toxicity variability in site water samples, providing a strong predictive tool that can be used in the WER framework when site-specific criteria values are derived. The biotic ligand model (BLM) underpredicted toxicity in site waters by more than 2-fold. Adjustments to the default BLM parameters improved the model's performance but did not provide a better predictive tool compared with the regression model developed from DOC and alkalinity. PMID- 24796293 TI - A population of progenitor cells in the basal and intermediate layers of the murine bladder urothelium contributes to urothelial development and regeneration. AB - BACKGROUND: Homeostatic maintenance and repair of the bladder urothelium has been attributed to proliferation of keratin 5-expressing basal cells (K5-BC) with subsequent differentiation into superficial cells. Recent evidence, however, suggests that the intermediate cell layer harbors a population of progenitor cells. We use label-retaining cell (LRC) methodology in conjunction with a clinically relevant model of uropathogenic Escherichia coli (UPEC)-induced injury to characterize urothelial ontogeny during development and in response to diffuse urothelial injury. RESULTS: In the developing urothelium, proliferating cells were dispersed throughout the K5-BC and intermediate cells layers, becoming progressively concentrated in the K5-BC layer with age. When 5-bromo-2 deoxyuridine (BrdU) was administered during urothelial development, LRCs in the adult were found within the K5-BC, intermediate, and superficial cell layers, the location dependent upon time of labeling. UPEC inoculation resulted in loss of the superficial cell layer followed by robust proliferation of K5-BCs and intermediate cells. LRCs within the K5-BC and intermediate cell layers proliferated in response to injury. CONCLUSIONS: Urothelial development and regeneration following injury relies on proliferation of K5-BC and intermediate cells. The existence and proliferation of LRCs within both the K5-BC and intermediate cell layers suggests the presence of two populations of urothelial progenitor cells. PMID- 24796295 TI - ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer. AB - PURPOSE: ERG expression has been proposed to signify molecular subtype of PCA. However, its significance in early onset prostate cancer (PCA) is not characterized. MATERIALS AND METHODS: ERG protein expression was investigated in a cohort of 121 men diagnosed with localized PCA at <50 years of age with a mean follow-up time of 65.7 months. ERG was correlated to patients' outcome and clinical-pathological parameters using univariate and multivariate analysis. RESULTS: ERG expression was detected in 76/118 (64.4 %) analyzable patients' samples and showed interfocal heterogeneity (differences between foci) in 17/118 (14.4 %) patients. There was significant association between ERG expression and Gleason score (p = 0.022), but not with any other clinical-pathologic parameter, including pre-surgical PSA levels, tumor volume, pathological stage, surgical margin or lymph-vascular invasion. ERG had significant effect on the rate of biochemical relapse following radical prostatectomy, with ERG positive patients showing higher relapse rates vs. ERG negative patients (p = 0.007). However, considering time till biochemical relapse post-radical prostatectomy, ERG expression showed positive insignificant trends (p = 0.071). Notably, and of great significance, in this cohort of early onset disease, none of the ERG negative PCA patients exhibited biochemical relapse. CONCLUSION: The study results suggest that ERG expression may be of added prognostic value in localized prostate cancer in patients with early onset PCA. However, the issue of ERG interfocal heterogeneity observed may require the evaluation of several tumor foci to assess ERG status per case. Incorporating ERG status into existing nomograms may be of added prognostic value in patients with early onset PCA. PMID- 24796296 TI - Reduced graphene oxide supported piperazine in aminocatalysis. AB - Reduced graphene oxide (rGO) has been used as a support for piperazine to provide a heterogeneous bifunctional organocatalyst (rGO-NH) that is able to efficiently promote vintage organic transformations such as Knoevenagel, Michael and aldol reactions. The obtained results suggest a significant role of the support in the course of these reactions. PMID- 24796297 TI - microRNAs 424 and 503 are mediators of the anti-proliferative and anti-invasive action of the thyroid hormone receptor beta. AB - The thyroid hormone receptors (TRs) mediate tumor suppressive effects in hepatocarcinoma and breast cancer cells. Here we show that incubation of hepatocarcinoma SK-hep1 cells expressing TRb with the thyroid hormone T3 induces transcription of the polycistronic message coding for microRNAs 424 and 503. TRb binds to the promoter region of these miRNAs and T3 induces an exchange of corepressors and coactivators inducing histone acetylation and transcriptional stimulation. We have validated cell cycle components as targets of these miRNAs. Overexpression of miR-424 mimicked the repressive effect of T3 on cell proliferation, growth in suspension, migration and invasion. Knockdown of miR-424 or miR-503 reduced the inhibitory effect of the hormone. T3 increased miR-424 and miR-503 in breast cancer cells expressing TRb, and this induction is also involved in the anti-invasive effects of the hormone. Furthermore, miR-424 or miR 503 depletion enhanced extravasation to the lungs of hepatocarcinoma cells injected in the tail vein of mice. The levels of these miRNAs were reduced in xenograft tumors formed in hypothyroid nude mice that are more invasive. Therefore, miR-424 or miR-503 mediate anti-proliferative and anti-invasive actions of TRb both in cultured cells and in vivo. PMID- 24796299 TI - Extraction of fucoxanthin from raw macroalgae excluding drying and cell wall disruption by liquefied dimethyl ether. AB - Macroalgae are one of potential sources for carotenoids, such as fucoxanthin, which are consumed by humans and animals. This carotenoid has been applied in both the pharmaceutical and food industries. In this study, extraction of fucoxanthin from wet brown seaweed Undaria pinnatifida (water content was 93.2%) was carried out with a simple method using liquefied dimethyl ether (DME) as an extractant in semi-continuous flow-type system. The extraction temperature and absolute pressure were 25 degrees C and 0.59 MPa, respectively. The liquefied DME was passed through the extractor that filled by U. pinnatifida at different time intervals. The time of experiment was only 43 min. The amount of fucoxanthin could approach to 390 MUg/g dry of wet U. pinnatifida when the amount of DME used was 286 g. Compared with ethanol Soxhlet and supercritical CO2 extraction, which includes drying and cell disruption, the result was quite high. Thus, DME extraction process appears to be a good method for fucoxanthin recovery from U. pinnatifida with improved yields. PMID- 24796298 TI - Marine bioactives and potential application in sports. AB - An enriched diet with antioxidants, such as vitamin E, vitamin C, beta-carotene and phenolic compounds, has always been suggested to improve oxidative stress, preventing related diseases. In this respect, marine natural product (MNP), such as COX inhibitors, marine steroids, molecules interfering with factors involved in the modulation of gene expression (such as NF-kappaB), macrolides, many antioxidant agents, thermogenic substances and even substances that could help the immune system and that result in the protection of cartilage, have been recently gaining attention. The marine world represents a reserve of bioactive ingredients, with considerable potential as functional food. Substances, such as chitin, chitosan, n-3 oils, carotenoids, vitamins, minerals and bioactive peptides, can provide several health benefits, such as the reduction of cardiovascular diseases, anti-inflammatory and anticarcinogenic activities. In addition, new marine bioactive substances with potential anti-inflammatory, antioxidant and thermogenic capacity may provide health benefits and performance improvement, especially in those who practice physical activity, because of their increased free radical and Reacting Oxygen Species (ROS) production during exercise, and, particularly, in athletes. The aim of this review is to examine the potential pharmacological properties and application of many marine bioactive substances in sports. PMID- 24796300 TI - Development of pedigree classification using microsatellite and mitochondrial markers for Giant grouper broodstock (Epinephelus lanceolatus) management in Taiwan. AB - Most giant groupers in the market are derived from inbred stock. Inbreeding can cause trait depression, compromising the animals' fitness and disease resistance, obligating farmers to apply increased amounts of drugs. In order to solve this problem, a pedigree classification method is needed. Here, microsatellite and mitochondrial DNA were used as genetic markers to analyze the genetic relationships among giant grouper broodstocks. The 776-bp fragment of high polymorphic mitochondrial D-loop sequence was selected for measuring sibling relatedness. In a sample of 118 giant groupers, 42 haplotypes were categorized, with nucleotide diversity (pi) of 0.00773 and haplotype diversity (HD) of 0.983. Furthermore, microsatellites were used for investigation of parentage. Six out of 33 microsatellite loci were selected as markers based on having a high number of alleles and compliance with Hardy-Weinberg equilibrium. Microsatellite profiles based on these loci provide high variability with low combined non-exclusion probability, permitting practical use in aquaculture. The method described here could be used to improve grouper broodstock management and lower the chances of inbreeding. This approach is expected to lead to production of higher quality groupers with higher disease resistance, thereby reducing the need for drug application. PMID- 24796301 TI - Pathophysiological effects of synthetic derivatives of polymeric alkylpyridinium salts from the marine sponge, Reniera sarai. AB - Polymeric 3-alkylpyridinium salts (poly-APS) are among the most studied natural bioactive compounds extracted from the marine sponge, Reniera sarai. They exhibit a wide range of biological activities, and the most prominent among them are the anti-acetylcholinesterase and membrane-damaging activity. Due to their membrane activity, sAPS can induce the lysis of various cells and cell lines and inhibit the growth of bacteria and fungi. Because of their bioactivity, poly-APS are possible candidates for use in the fields of medicine, pharmacy and industry. Due to the small amounts of naturally occurring poly-APS, methods for the synthesis of analogues have been developed. They differ in chemical properties, such as the degree of polymerization, the length of the alkyl chains (from three to 12 carbon atoms) and in the counter ions present in their structures. Such structurally defined analogues with different chemical properties and degrees of polymerization possess different levels of biological activity. We review the current knowledge of the biological activity and toxicity of synthetic poly-APS analogues, with particular emphasis on the mechanisms of their physiological and pharmacological effects and, in particular, the mechanisms of toxicity of two analogues, APS12-2 and APS3, in vivo and in vitro. PMID- 24796302 TI - In vitro assessment of marine Bacillus for use as livestock probiotics. AB - Six antimicrobial-producing seaweed-derived Bacillus strains were evaluated in vitro as animal probiotics, in comparison to two Bacillus from an EU-authorized animal probiotic product. Antimicrobial activity was demonstrated on solid media against porcine Salmonella and E. coli. The marine isolates were most active against the latter, had better activity than the commercial probiotics and Bacillus pumilus WIT 588 also reduced E. coli counts in broth. All of the marine Bacillus tolerated physiological concentrations of bile, with some as tolerant as one of the probiotics. Spore counts for all isolates remained almost constant during incubation in simulated gastric and ileum juices. All of the marine Bacillus grew anaerobically and the spores of all except one isolate germinated under anaerobic conditions. All were sensitive to a panel of antibiotics and none harbored Bacillus enterotoxin genes but all, except B. pumilus WIT 588, showed some degree of beta-hemolysis. However, trypan blue dye exclusion and xCELLigence assays demonstrated a lack of toxicity in comparison to two pathogens; in fact, the commercial probiotics appeared more cytotoxic than the majority of the marine Bacillus. Overall, some of the marine-derived Bacillus, in particular B. pumilus WIT 588, demonstrate potential for use as livestock probiotics. PMID- 24796303 TI - Eunicellin-based diterpenoids, hirsutalins N-R, from the formosan soft coral Cladiella hirsuta. AB - New eunicellin-type hirsutalins N-R (1-5), along with two known eunicellins, (6 and 7) were isolated from the soft coral Cladiella hirsuta. The structures of the metabolites were determined by extensive spectroscopic analysis. Cytotoxic activity of compounds 1-7 against the proliferation of a limited panel of cancer cell lines was measured. The in vitro anti-inflammatory activity of compounds 1-7 was evaluated by measuring their ability in suppressing superoxide anion generation and elastase release in fMLP/CB-induced human neutrophils. PMID- 24796304 TI - Marinopyrrole derivatives as potential antibiotic agents against methicillin resistant Staphylococcus aureus (III). AB - The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2-4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA. Here, we report a novel fluoro derivative of marinopyrrole A (1e) showing an improved profile of potency, less susceptibility to serum inhibition, as well as rapid and concentration-dependent killing of MRSA. PMID- 24796305 TI - Antiplatelet and anticoagulant effects of diterpenes isolated from the marine alga, Dictyota menstrualis. AB - Cardiovascular diseases represent a major cause of disability and death worldwide. Therapeutics are available, but they often have unsatisfactory results and may produce side effects. Alternative treatments based on the use of natural products have been extensively investigated, because of their low toxicity and side effects. Marine organisms are prime candidates for such products, as they are sources of numerous and complex substances with ecological and pharmacological effects. In this work, we investigated, through in vitro experiments, the effects of three diterpenes (pachydictyol A, isopachydictyol A and dichotomanol) from the Brazilian marine alga, Dictyota menstrualis, on platelet aggregation and plasma coagulation. Results showed that dichotomanol inhibited ADP- or collagen-induced aggregation of platelet-rich plasma (PRP), but failed to inhibit washed platelets (WP). In contrast, pachydictyol A and isopachydictyol A failed to inhibit the aggregation of PRP, but inhibited WP aggregation induced by collagen or thrombin. These diterpenes also inhibited coagulation analyzed by the prothrombin time and activated partial thromboplastin time and on commercial fibrinogen. Moreover, diterpenes inhibited the catalytic activity of thrombin. Theoretical studies using the Osiris Property Explorer software showed that diterpenes have low theoretical toxicity profiles and a drug score similar to commercial anticoagulant drugs. In conclusion, these diterpenes are promising candidates for use in anticoagulant therapy, and this study also highlights the biotechnological potential of oceans and the importance of bioprospecting to develop medicines. PMID- 24796307 TI - Four new Jacaranone analogs from the fruits of a Beibu Gulf mangrove Avicennia marina. AB - Four new jacaranone analogs, marinoids F-I (1-4), were isolated from the fruits of a Beibu Gulf mangrove Avicennia marina. The structures were elucidated based on analysis of spectroscopic data. Marinoids F and G are shown to be diastereoisomers of chlorocornoside, a new halogen containing marine secondary metabolite. The antioxidant activity of the isolates was evaluated using a cellular antioxidant assay, and 4 showed good antioxidant activity (EC50 = 26 MUM). PMID- 24796306 TI - Gram-negative marine bacteria: structural features of lipopolysaccharides and their relevance for economically important diseases. AB - Gram-negative marine bacteria can thrive in harsh oceanic conditions, partly because of the structural diversity of the cell wall and its components, particularly lipopolysaccharide (LPS). LPS is composed of three main parts, an O antigen, lipid A, and a core region, all of which display immense structural variations among different bacterial species. These components not only provide cell integrity but also elicit an immune response in the host, which ranges from other marine organisms to humans. Toll-like receptor 4 and its homologs are the dedicated receptors that detect LPS and trigger the immune system to respond, often causing a wide variety of inflammatory diseases and even death. This review describes the structural organization of selected LPSes and their association with economically important diseases in marine organisms. In addition, the potential therapeutic use of LPS as an immune adjuvant in different diseases is highlighted. PMID- 24796308 TI - New benzoxazine secondary metabolites from an arctic actinomycete. AB - Two new secondary metabolites, arcticoside (1) and C-1027 chromophore-V (2), were isolated along with C-1027 chromophore-III and fijiolides A and B (3-5) from a culture of an Arctic marine actinomycete Streptomyces strain. The chemical structures of 1 and 2 were elucidated through NMR, mass, UV, and IR spectroscopy. The hexose moieties in 1 were determined to be d-glucose from a combination of acid hydrolysis, derivatization, and gas chromatographic analyses. Arcticoside (1) and C-1027 chromophore-V (2), which have a benzoxazine ring, inhibited Candida albicans isocitrate lyase. Chromophore-V (2) exhibited significant cytotoxicity against breast carcinoma MDA-MB231 cells and colorectal carcinoma cells (line HCT-116), with IC50 values of 0.9 and 2.7 MUM, respectively. PMID- 24796309 TI - The effect of maternal body mass index on fetal growth: use of individualized growth assessment and two-level linear modeling. AB - PURPOSE: To determine the effect of maternal body mass index on fetal growth using individualized growth assessment and two-level linear modeling. METHODS: A retrospective review of biometry in the second and third trimesters from 246 normal, term singleton fetuses was performed. Four to eight biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur diaphysis length (FDL) measurements per fetus were available and used to determine second trimester growth rates. Expected third-trimester size trajectories were generated from these data and Percent Deviations [%Dev = ((observed - expected)/expected) * 100] were calculated. Two-level linear modeling was used to determine %Dev slopes and the effect of body mass index (BMI) on these slopes. Relationships between individual second- and third-trimester slopes and BMI were evaluated using linear regression. RESULTS: Linear regression analysis of second-trimester growth indicated no significant relationships between the fetal growth rate and the BMI in the second trimester [R(2) (adj): 0.0% to 1.0% except AC in one subgroup (5.6%)]. Regression analysis did not indicate a significant relationship (adj R(2) : 0%-0.2%) between BMI and third-trimester %Dev slopes for any anatomic parameter. Two-level statistical modeling showed no effect of BMI on BPD, AC, or FDL growth and only a moderate effect on the HC growth in the third trimester. CONCLUSIONS: Our findings indicate that the maternal BMI does not have an effect on fetal growth in either the second or the third trimester as determined with individualized growth assessment. PMID- 24796310 TI - Neuromagnetic brain responses to other person's eye blinks seen on video. AB - Eye blinks, typically occurring 15-20 times per minute, rarely capture attention during face-to-face interaction. To determine the extent to which eye blinks affect the viewer's brain activity, we recorded magnetoencephalographic brain responses to natural blinks, and to the same blinks slowed down to 38% of the original speed. The stimuli were presented on video once every 2.3-6.2 s. As a control, we presented two horizontal black bars moving with the same time courses and the same extent as the eyelids in the blink video. Both types of blinks and bars elicited clear responses peaking at about 200 ms in the occipital areas, with no systematic differences between hemispheres. For the bars, these main responses were (as expected) weaker (by 24%) and later (by 33 ms) to slow-motion than normal-speed stimuli. For blinks, however, the responses to both normal speed and slow-motion stimuli were of the same amplitude and latency. Our results demonstrate that the brain not only responds to other persons' eye blinks, but that the responses are as fast and of equal size even when the blinks are considerably slowed down. We interpret this finding to reflect the increased social salience of the slowed-down blinks that counteracted the general tendency of the brain to react more weakly and more slowly to slowly- vs. quickly-changing stimuli. This finding may relate to the social importance of facial gestures, including eye blinks. PMID- 24796311 TI - Primary lipoma arborescens of the knee may involve the development of early osteoarthritis if prompt synovectomy is not performed. AB - BACKGROUND: Primary lipoma arborescens (LA) is a rare, benign intra-articular hyperplastic tumor that has been associated with osteoarthritis (OA). The aim of this study was to determine whether prompt synovectomy could avoid progressive joint degeneration in cases of primary LA of the knee. MATERIALS AND METHODS: A review of currently available literature about the disease was carried out. The clinical, histological and radiological records of a series of nine knees with primary LA diagnosed and treated between 2002 and 2012 were retrospectively reviewed. Eight of the knees had histological confirmation of LA and none had evidence of condropathy on the initial magnetic resonance image or degenerative changes at the initial radiographic examination. RESULTS: At the final follow-up no evidence of OA was found in the three knees that underwent synovectomy when symptoms did not last more than 1 year. The five knees in which synovectomy was delayed developed progressive joint degeneration. CONCLUSION: In this series, primary LA of the knee involved the development of early osteoarthritis when prompt synovectomy was not performed. Timely synovectomy is strongly recommended, if not mandatory. LEVEL OF EVIDENCE: IV. PMID- 24796312 TI - A retrospective analysis of the cost of hospitalizations for sickle cell disease with crisis in England, 2010/11. AB - BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder which may result in a broad range of complications including recurring and severe episodes of pain--sickle 'crises'--which require frequent hospitalizations. We assessed the cost of hospitalizations associated with SCD with crisis in England. METHODS: Hospital Episodes Statistics data for all hospital episodes in England between 2010 and 2011 recording Sickle Cell Anaemia with Crisis as primary diagnosis were used. The total cost of admissions and exceeded length of stay due to SCD were assessed using Healthcare Resource Groups tariffs. The impact of patients' characteristics on SCD admissions costs and the likelihood of incurring extra bed days were also examined. RESULTS: In 2010-11, England had 6077 admissions associated with SCD with crisis as primary diagnosis. The total cost for these admissions for commissioners was L18,798 255. The cost of admissions increases with age (children admissions costs 50% less than adults). Patients between 10 and 19 years old are more likely to stay longer in hospital compared with others. CONCLUSION: SCD represents a significant cost for commissioners and the NHS. Further work is required to assess how best to manage patients in the community, which could potentially lead to a reduction in hospital admissions and length of stay, and their associated costs. PMID- 24796313 TI - One-step purification of twin-strep-tagged proteins and their complexes on strep tactin resin cross-linked with bis(sulfosuccinimidyl) suberate (BS3). AB - Affinity purification of Strep-tagged fusion proteins on resins carrying an engineered streptavidin (Strep-Tactin) has become a widely used method for isolation of protein complexes under physiological conditions. Fusion proteins containing two copies of Strep-tag II, designated twin-Strep-tag or SIII-tag, have the advantage of higher affinity for Strep-Tactin compared to those containing only a single Strep-tag, thus allowing more efficient protein purification. However, this advantage is offset by the fact that elution of twin Strep-tagged proteins with biotin may be incomplete, leading to low protein recovery. The recovery can be dramatically improved by using denaturing elution with sodium dodecyl sulfate (SDS), but this leads to sample contamination with Strep-Tactin released from the resin, making the assay incompatible with downstream proteomic analysis. To overcome this limitation, we have developed a method whereby resin-coupled tetramer of Strep-Tactin is first stabilized by covalent cross-linking with Bis(sulfosuccinimidyl) suberate (BS3) and the resulting cross-linked resin is then used to purify target protein complexes in a single batch purification step. Efficient elution with SDS ensures good protein recovery, while the absence of contaminating Strep-Tactin allows downstream protein analysis by mass spectrometry. As a proof of concept, we describe here a protocol for purification of SIII-tagged viral protein VPg-Pro from nuclei of virus-infected N. benthamiana plants using the Strep-Tactin polymethacrylate resin cross-linked with BS3. The same protocol can be used to purify any twin Strep-tagged protein of interest and characterize its physiological binding partners. PMID- 24796314 TI - A guide to reading health care news stories. AB - From April 16, 2006, through May 30, 2013, a team of reviewers from HealthNewsReview.org, many of whom were physicians, evaluated the reporting by US news organizations on new medical treatments, tests, products, and procedures. After reviewing 1889 stories (approximately 43% newspaper articles, 30% wire or news services stories, 15% online pieces [including those by broadcast and magazine companies], and 12% network television stories), the reviewers graded most stories unsatisfactory on 5 of 10 review criteria: costs, benefits, harms, quality of the evidence, and comparison of the new approach with alternatives. Drugs, medical devices, and other interventions were usually portrayed positively; potential harms were minimized, and costs were ignored. Our findings can help journalists improve their news stories and help physicians and the public better understand the strengths and weaknesses of news media coverage of medical and health topics. PMID- 24796315 TI - Stumped; the Achilles of laparoscopic appendectomy. PMID- 24796316 TI - Unusual structural features in the lysozyme derivative of the tetrakis(acetato)chloridodiruthenium(II,III) complex. AB - The reaction between the paddle-wheel tetrakis(acetato)chloridodiruthenium(II,III) complex, [Ru2(MU-O2CCH3)4Cl] and hen egg-white lysozyme (HEWL) was investigated through ESI-MS and UV/Vis spectroscopy and the formation of a stable metal-protein adduct was unambiguously demonstrated. Remarkably, the diruthenium core is conserved in the adduct while two of the four acetate ligands are released. The crystal structure of this diruthenium-protein derivative was subsequently solved through X-ray diffraction analysis to 2.1 A resolution. The structural data are in agreement with the solution results. It was found that HEWL binds two diruthenium moieties, at Asp101 and Asp119, respectively, with the concomitant release of two acetate ligands from each diruthenium center. PMID- 24796317 TI - Mutational analysis of bone marrow mesenchymal stromal cells in myeloid malignancies. PMID- 24796319 TI - Forty-five year trends in overweight and obesity in an indigenous arctic Inuit Society in transition and spatiotemporal trends. AB - OBJECTIVES: Overweight and obesity associate with increased morbidity and premature death. Westernization of societies heralds rising obesity rates. A steep increase in body mass index (BMI) and overweight in Greenland from 1963 to 1998 led us to follow-up on height, weight, BMI, and rates of overweight among populations in Greenland and assess time trends between different stages of transition. METHODS: BMI was calculated from height and weight measured on Inuit and non-Inuit aged 50 through 69 years surveyed in 1963, 1998, and 2008 in Ammassalik district in East Greenland and in 1998 and 2008 in the capital Nuuk in West Greenland. RESULTS: A total of 1,186 were surveyed in 1963 (52 men/63 women), 1998 (309/226), and 2008 (297/239). BMI increased with time (P < 0.001; 1963/1998/2008 23.3/24.3/26.2 kg/m(2) ). In addition, BMI increased with urbanization in Inuit men (P = 0.001; settlements/town/city, in 1998, 23.9/24.9/25.5 kg/m(2) ; in 2008, 25.0/26.0/27.0 kg/m(2) ) while not in Inuit women (P = 0.18). The number of overweight Inuit (BMI >27 kg/m(2) ) increased with time in men (4.0/25.6/33.2% in 1963/1998/2008, P = 0.001) and in women (13.6/30.7/37.3%, P = 0.001). BMI was above 30 kg/m(2) in 2.0/10.8/17.5% of all Inuit men in 1963/1998/2008 (P = 0.003) and in 8.3%/23.0/24.5% of all Inuit women (P = 0.02) respectively. CONCLUSIONS: Overweight and obesity rates rise with time and with societal transition in Greenland. Settlements and town are catching up with the city where the rate of increase is diminishing, although there were gender differences. PMID- 24796318 TI - Beyond individual differences: are working memory and inhibition informative specifiers within ASD? AB - Findings on working memory (WM) and inhibition in children with autism spectrum disorders (ASD) are contradictory and earlier studies largely ignored individual differences. As WM and inhibition seem to be related, children who experience WM deficits might also experience inhibition deficits. Moreover, these children possibly form a distinct subgroup, differing on other variables, such as cognitive functioning, symptom severity, behavior, and attention deficit hyperactivity disorder (ADHD) characteristics. We studied a large sample of children with and without ASD (8-12 years, IQ > 80) with classic experimental tasks (n-back task, ASD n = 77, control n = 45; stop task, ASD n = 74, control n = 43), and explored individual differences. The ASD group made more errors on the n-back task with increasing WM load, and had longer stop signal reaction times on the stop task when compared with controls. However, only 6 % of the ASD group showed both WM and inhibition deficits, and 71 % showed no deficits. Parents of children with WM and/or inhibition deficits tended to report more conduct problems on the disruptive behavior disorder rating scale. ADHD characteristics did not influence performance. Some children used medication during testing, which seemingly influenced stop task performance, but excluding these data did not change the main findings. Large individual differences in cognitive functioning are present, even within children with ASD with average or above average intelligence. However, whether individual differences in specific cognitive domains, such as WM and inhibition are as informative as individual differences in diagnosis, comorbidity, and general cognitive functioning, calls for future research. PMID- 24796321 TI - Efficient hybrid plasmonic polymer solar cells with Ag nanoparticle decorated TiO2 nanorods embedded in the active layer. AB - A hybrid plasmonic polymer solar cell, in which plasmonic metallic nanostructures (such as Ag, Au, and Pt nanoparticles) are embedded in the active layer, has been under intense scrutiny recently because it provides a promising new approach to enhance the efficiency of the device. We propose a brand new hybrid plasmonic nanostructure, which combines a plasmonic metallic nanostructure and one dimensional semiconductor nanocrystals, to enhance the photocurrent of the device through a strong localized electric field and an enhanced charge transport channel. We demonstrate that when Ag nanoparticle decorated TiO2 nanorods were introduced into the active layer of polymer-fullerene based bulk heterojunction solar cells, the photocurrent significantly increased to 14.15 mA cm(-2) from 6.51 mA cm(-2) without a decrease in the open voltage; thus, the energy conversion efficiency was dramatically enhanced to 4.87% from 2.57%. PMID- 24796320 TI - FR-190997, a nonpeptide bradykinin B2-receptor partial agonist, is a potent and efficacious intraocular pressure lowering agent in ocular hypertensive cynomolgus monkeys. AB - Preclinical Research FR-190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnaminoacetyl]-N-methylamino]benzyloxy]-2-methyl-4- (2-pyridylmethoxy) quinoline), a nonpeptide bradykinin (BK) B2-receptor-selective agonist, represents a novel class of ocular hypotensive agents. FR-190997 exhibited a high affinity for the human cloned B2-receptor (Ki = 9.8 nM) and a relatively high potency (EC50 = 155 nM) for mobilizing intracellular Ca(2+) ([Ca(2+)]i) in human ocular cells from nonpigmented ciliary epithelium; trabecular meshwork [h-TM]; ciliary muscle [h-CM] that are involved in regulating intraocular pressure (IOP). Unlike BK, FR-190997 behaved as a partial agonist (Emax = 38-80%) in these cells and its [Ca(2+)]i-mobilizing effects were blocked by the B2-receptor-selective antagonists (HOE-140, Ki = 0.8-7 nM; WIN-64338, Ki = 157-425 nM). FR-190997 stimulated the production of prostaglandins (PGs) in h-CM and h-TM cells (EC50 = 15-19 nM; Emax = 27-33%); an effect that was reduced by the cyclooxygenase-2 inhibitor bromfenac, and by HOE-140. FR-190997 also induced pro-matrix metalloproteinase (MMP)-1 and MMP-3 release from h-CM cells. FR-190997 significantly lowered IOP (37% [P < 0.001] with 30 MUg, 24 h post-topical ocular dosing) in ocular hypertensive eyes of conscious Cynomolgus monkeys. This effect was reduced by bromfenac and completely blocked by a B2-antagonist. FR-190997 primarily stimulated uveoslceral outflow (UVSO) of aqueous humor (2.6 to 3.9-fold above baseline). In conclusion, FR-190997 is a B2-receptor selective partial agonist that activates phospholipase C, mobilizes [Ca(2+)]; induces PG and pro MMP production, and that profoundly lowers IOP by promoting UVSO in ocular hypertensive Cynomolgus monkey eyes. PMID- 24796322 TI - Influence of antioxidant compounds, total sugars and genetic background on the chilling injury susceptibility of a non-melting peach (Prunus persica (L.) Batsch) progeny. AB - BACKGROUND: To identify genotypes with good organoleptic properties, antioxidant rich content and low susceptibility to chilling injury (CI), fruits from 130 peach cultivars were studied over three consecutive years. Pomological traits, l ascorbic acid, flavonoids, total phenolics, relative antioxidant capacity (RAC) and sugars were determined. Major symptoms of CI developed at 5 degrees C, such as leatheriness, flesh browning, bleeding and loss of flavor, were evaluated. RESULTS: The population exhibited wide phenotypic variation in agronomic and biochemical traits. Six genotypes with high total phenolics, RAC, flavonoids and total sugars were selected. The progeny also showed variability for all evaluated CI symptoms, and 16 genotypes showed considerably lower susceptibility to CI. After 2 weeks of cold storage, leatheriness and bleeding were the main CI symptoms observed, whereas flesh browning was predominant after 4 weeks. CONCLUSION: It was possible to find varieties with high phenolic concentration and relatively low or intermediate CI susceptibility (22, 33, 68, 80, 81, 96 and 120). However, the correlations observed between CI and phenolic contents highlight their potential influence on susceptibility to internal browning. This relationship should be considered in the current breeding programs to select cultivars with high bioactive compound contents, health-enhancing properties and good postharvest performance. PMID- 24796323 TI - Dual-frequency calcium-responsive MRI agents. AB - Responsive or smart magnetic resonance imaging (MRI) contrast agents are molecular sensors that alter the MRI signal upon changes in a particular parameter in their microenvironment. Consequently, they could be exploited for visualization of various biochemical events that take place at molecular and cellular levels. In this study, a set of dual-frequency calcium-responsive MRI agents are reported. These are paramagnetic, fluorine-containing complexes that produce remarkably high MRI signal changes at the (1)H and (19)F frequencies at varying Ca(2+) concentrations. The nature of the processes triggered by Ca(2+) was revealed, allowing a better understanding of these complex systems and their further improvement. The findings indicate that these double-frequency tracers hold great promise for development of novel functional MRI methods. PMID- 24796324 TI - Involvement of interleukin-17A-induced hypercontractility of intestinal smooth muscle cells in persistent gut motor dysfunction. AB - BACKGROUND AND AIM: The etiology of post-inflammatory gastrointestinal (GI) motility dysfunction, after resolution of acute symptoms of inflammatory bowel diseases (IBD) and intestinal infection, is largely unknown, however, a possible involvement of T cells is suggested. METHODS: Using the mouse model of T cell activation-induced enteritis, we investigated whether enhancement of smooth muscle cell (SMC) contraction by interleukin (IL)-17A is involved in postinflammatory GI hypermotility. RESULTS: Activation of CD3 induces temporal enteritis with GI hypomotility in the midst of, and hypermotility after resolution of, intestinal inflammation. Prolonged upregulation of IL-17A was prominent and IL-17A injection directly enhanced GI transit and contractility of intestinal strips. Postinflammatory hypermotility was not observed in IL-17A deficient mice. Incubation of a muscle strip and SMCs with IL-17A in vitro resulted in enhanced contractility with increased phosphorylation of Ser19 in myosin light chain 2 (p-MLC), a surrogate marker as well as a critical mechanistic factor of SMC contractility. Using primary cultured murine and human intestinal SMCs, IkappaBzeta- and p38 mitogen-activated protein kinase (p38MAPK) mediated downregulation of the regulator of G protein signaling 4 (RGS4), which suppresses muscarinic signaling of contraction by promoting inactivation/desensitization of Galphaq/11 protein, has been suggested to be involved in IL-17A-induced hypercontractility. The opposite effect of L-1beta was mediated by IkappaBzeta and c-jun N-terminal kinase (JNK) activation. CONCLUSIONS: We propose and discuss the possible involvement of IL-17A and its downstream signaling cascade in SMCs in diarrheal hypermotility in various GI disorders. PMID- 24796325 TI - The effects of extra-somatic weapons on the evolution of human cooperation towards non-kin. AB - Human cooperation and altruism towards non-kin is a major evolutionary puzzle, as is 'strong reciprocity' where no present or future rewards accrue to the co operator/altruist. Here, we test the hypothesis that the development of extra somatic weapons could have influenced the evolution of human cooperative behaviour, thus providing a new explanation for these two puzzles. Widespread weapons use could have made disputes within hominin groups far more lethal and also equalized power between individuals. In such a cultural niche non cooperators might well have become involved in such lethal disputes at a higher frequency than cooperators, thereby increasing the relative fitness of genes associated with cooperative behaviour. We employ two versions of the evolutionary Iterated Prisoner's Dilemma (IPD) model--one where weapons use is simulated and one where it is not. We then measured the performance of 25 IPD strategies to evaluate the effects of weapons use on them. We found that cooperative strategies performed significantly better, and non-cooperative strategies significantly worse, under simulated weapons use. Importantly, the performance of an 'Always Cooperate' IPD strategy, equivalent to that of 'strong reciprocity', improved significantly more than that of all other cooperative strategies. We conclude that the development of extra-somatic weapons throws new light on the evolution of human altruistic and cooperative behaviour, and particularly 'strong reciprocity'. The notion that distinctively human altruism and cooperation could have been an adaptive trait in a past environment that is no longer evident in the modern world provides a novel addition to theory that seeks to account for this major evolutionary puzzle. PMID- 24796326 TI - Detection of early age-related macular degeneration using novel functional parameters of the focal cone electroretinogram. AB - The focal cone electroretinogram is a sensitive marker for macular disease, but have we unlocked its full potential? Typically assessment of waveform parameters is subjective and focuses on a small number of locations (e.g. the a-wave). This study evaluated the discriminatory and diagnostic potential of 4 conventional and 15 novel, objectively determined, parameters in patients with early Age-related Macular Degeneration. Focal cone electroretinograms were recorded in 54 participants with early Age-related Macular Degeneration (72.9+/-8.2 years) and 54 healthy controls (69+/-7.7 years). Conventional a and b wave amplitudes and implicit times were measured and compared to novel parameters derived from both the 1st and 2nd derivatives and the frequency-domain power spectrum of the electroretinogram.Statistically significant differences between groups were shown for all conventional parameters, the majority of 1st and 2nd derivative parameters and the power spectrum at 25 and 30 Hz. Receiver operating characteristics showed that both conventional and 1st and 2nd derivative implicit times had provided the best diagnostic potential. A regression model showed a small improvement over any individual parameter investigated. The non conventional parameters enhanced the objective evaluation of the focal electroretinogram, especially when the amplitude was low. Furthermore, the novel parameters described here allow the implicit time of the electroretinogram to be probed at points other than the peaks of the a and b waves. Consequently these novel analysis techniques could prove valuable in future electrophysiological investigation, detection and monitoring of Age-related Macular Degeneration. PMID- 24796327 TI - Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits. AB - PURPOSE: To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. METHODS: The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. RESULTS: The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs. CONCLUSIONS: Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases. PMID- 24796328 TI - A meta-analysis of the relationship between RARbeta gene promoter methylation and non-small cell lung cancer. AB - BACKGROUND: Hypermethylation of CpG islands in tumor suppressor gene plays an important role in carcinogenesis. Many studies have demonstrated that hypermethylation in promoter region of RARbeta gene could be found with high prevalence in tumor tissue and autologous controls such as corresponding non tumor lung tissue, sputum and plasma of the NSCLC patients. But with the small number subjects included in the individual studie, the statistical power is limited. Accordingly, we performed this meta-analysis to further asses the relationship of methylation prevalence between the cancer tissue and atuologous controls (corresponding non-tumor lung tissue, sputum and plasma). METHODS: The published articles about RARbeta gene promoter hypermethyltion were identified using a systematic search strategy in PubMed, EMBASE and CNKI databases. The pooled odds ratio (OR) of RARbeta promoter methylation in lung cancer tissue versus autologous controls were calculated. RESULTS: Finally, eleven articles, including 1347 tumor tissue samples and 1137 autologous controls were included in this meta-analysis. The pooled odds ratio of RARbeta promoter methylation in cancer tissue was 3.60 (95%CI: 2.46-5.27) compared to autologous controls with random-effect model. Strong and significant correlation between tumor tissue and autologous controls of RARbeta gene promoter hypermethylation prevalence across studies (Correlation coefficient 0.53) was found. CONCLUSION: RARbeta promoter methylation may play an important role in carcinogenesis of the NSCLC. With significant methylation prevalence correlation between tumor tissue and autologous of this gene, methylation detection may be a potential method for searching biomarker for NSCLC. PMID- 24796329 TI - Diagnosis and surgical treatment of renal hydatid disease: a retrospective analysis of 30 cases. AB - Echinococcosis (CE) is an infection which is caused by the larval stage of a tapeworm and is endemic in stockbreeding regions of developing countries. The kidney is the most commonly affected organ in the urinary tract. However, reports on renal hydatid disease are limited in the literature, and usually there are no specific clinical characteristics and promising operative methods. The purpose of this study is to assess the most appropriate surgical technique for the patient with urinary tract CE. We retrospectively analyzed thirty patients with renal hydatid cysts who received different surgical treatments in the urology department of the First Affiliated Hospital of Xinjiang Medical University from February 1985 to April 2010. Twenty patients were males and ten were females. The diagnostic accuracy was 74%, 87.5%, and 66.6% respectively by using of ultrasound, CT, and laboratory tests. Thirty patients were followed up for 1-15 years after surgery. One patient experienced a recurrence of renal CE. The ultrasound, CT, and immunological tests are an important means of diagnosis. The surgical treatment principle of renal hydatid should be based on residual renal function, hydatid cyst size, number, location, and surgical techniques to determine the surgical plan to retain the renal function. PMID- 24796330 TI - Economic Evaluation of a Steroid-Eluting Sinus Implant following Endoscopic Sinus Surgery for Chronic Rhinosinusitis. AB - OBJECTIVE: This study aimed to evaluate the cost-effectiveness of a mometasone steroid-eluting sinus implant compared to a nonsteroid-eluting sinus implant following endoscopic sinus surgery (ESS) for chronic rhinosinusitis. STUDY DESIGN: Economic evaluation using a decision tree model. SETTING: Academic and nonacademic otolaryngology practices. SUBJECTS: Patients with refractory chronic rhinosinusitis undergoing ESS. METHODS: The economic perspective was the health care third party payer. Effectiveness and probability data were obtained from a single meta-analysis of 2 randomized, double-blind, controlled trials. Costs were obtained from the Centers for Medicare & Medicaid Services database and wholesale pharmaceutical pricing. Multiple sensitivity analyses were performed including a probabilistic sensitivity analysis. Comparative treatment groups were (1) placement of the mometasone steroid-eluting sinus implant following ESS and (2) placement of a nonsteroid-eluting implant following ESS. The primary outcome was cost per postoperative intervention avoided within 60 days after ESS. RESULTS: The mean cost for the steroid-eluting and nonsteroid-eluting sinus implant strategies were $1,572.91 and $365.18, respectively. The steroid-eluting strategy incremental cost-effectiveness ratio was $5,489.68. The sensitivity analysis demonstrated a 74.3%, 87.2%, and 90.5% certainty that the steroid-eluting implant strategy is cost-effective at willingness-to-pay thresholds of $10,000, $25,000, and $50,000, respectively. CONCLUSION: Results from this economic evaluation suggest that placement of a mometasone steroid-eluting sinus implant into the ethmoid cavity following ESS for refractory chronic rhinosinusitis is a cost effective intervention for preventing a postoperative intervention within 60 days after surgery. PMID- 24796331 TI - Etiology and Time to Presentation of Unilateral Vocal Fold Paralysis. AB - OBJECTIVE: To determine the etiology, laterality, and time to presentation of unilateral vocal fold paralysis (UVFP) at a tertiary care institution over 10 years. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: All patients seen between 2002 and 2012 by the Department of Otolaryngology at the Washington University School of Medicine (WUSM), with a diagnosis of unilateral vocal fold paralysis, were included. Medical records were reviewed for symptom onset date, presentation date(s), and etiology of UVFP. RESULTS: Of the patients, 938 met inclusion criteria and were included. In total, 522 patients (55.6%) had UVFP due to surgery; 158 (16.8%) were associated with thyroid/parathyroid surgery, while 364 (38.8%) were due to nonthyroid surgery. Of the patients, 416 (44.4%) had nonsurgical etiologies, 124 (13.2%) had idiopathic UVFP, and 621 (66.2%) had left-sided UVFP. The diagnosis was more common on the left side in cases of intrathoracic surgeries and malignancies, as expected, but also in idiopathic, carotid endarterectomy, intubation, and skull base tumors. In total, 9.8% of patients presented first to an outside otolaryngologist at a median time of 2.1 months after onset, but these patients presented to WUSM at a median time of 9.5 months. Overall, 70.6% of patients presented to a WUSM otolaryngologist within 3 months of onset. CONCLUSION: Iatrogenic injury remains the most common cause of UVFP. Thyroidectomy remains the leading cause of surgery-related UVFP. Patients are typically seen within 3-4 months of onset; however, a significant delay exists for those referred to WUSM. PMID- 24796332 TI - NPM1 silencing reduces tumour growth and MAPK signalling in prostate cancer cells. AB - The chaperone nucleophosmin (NPM1) is over-expressed in the epithelial compartment of prostate tumours compared to adjacent healthy epithelium and may represent one of the key actors that support the neoplastic phenotype of prostate adenocarcinoma cells. Yet, the mechanisms that underlie NPM1 mediated phenotype remain elusive in the prostate. To better understand NPM1 functions in prostate cancer cells, we sought to characterize its impact on prostate cancer cells behaviour and decipher the mechanisms by which it may act. Here we show that NPM1 favors prostate tumour cell migration, invasion and colony forming. Furthermore, knockdown of NPM1 leads to a decrease in the growth of LNCaP-derived tumours grafted in Nude mice in vivo. Such oncogenic-like properties are found in conjunction with a positive regulation of NPM1 on the ERK1/2 (Extracellular signal-Regulated Kinases 1/2) kinase phosphorylation in response to EGF (Epidermal Growth Factor) stimulus, which is critical for prostate cancer progression following the setting of an autonomous production of the growth factor. NPM1 could then be a target to switch off specifically ERK1/2 pathway activation in order to decrease or inhibit cancer cell growth and migration. PMID- 24796333 TI - Preoperative atrial fibrillation predicts mortality and morbidity after aortic valve replacement. AB - OBJECTIVES: Atrial fibrillation (AF) is the commonest cardiac arrhythmia, becoming increasingly prevalent as the population ages. There is conflicting information around whether AF is associated with adverse outcomes after aortic valve replacement (AVR) from the few studies that have investigated this. We compared the characteristics and outcomes of patients undergoing AVR with their history of AF. METHODS: Isolated AVR patients at Auckland City Hospital 2005-2012 were divided into those with and without preoperative AF for comparative analyses. RESULTS: Of 620 consecutive patients, 19.2% (119) had permanent or paroxysmal AF preoperatively. Patients with AF were significantly older (70.5 vs 63.4 years, P < 0.001) and were more likely to be New Zealand European (82.4 vs 68.1%, P = 0.004). They also had higher prevalence of NYHA class III-IV (55.4 vs 37.4%, P = 0.004), inpatient operation (62.1 vs 48.3%, P = 0.008), history of stroke (10.9 vs 5.0%, P = 0.031), lower creatinine clearance (73 vs 82, P = 0.001) and higher EuroSCORE II (5.2 vs 3.4%, P < 0.001). Operative mortality (6.7 vs 2.0%, P = 0.012) and composite morbidity (27.7 vs 16.5%, P = 0.006) were also higher in patients with AF. After adjusting for significant variables, preoperative AF remained an independent predictor of operative mortality with an odds ratio of 3.44 (95% confidence interval 1.29-9.13), composite morbidity of 1.79 (1.05-3.04) and a mortality during follow-up hazards ratio of 2.36 (1.44 3.87). CONCLUSIONS: AF was associated with several cardiovascular and cardiac surgery risk factors, but remained independently associated with short- and long term mortality. AF should be incorporated into cardiac surgery risk models and surgical AF ablation may be considered with AVR. PMID- 24796334 TI - Impact of closed minimal extracorporeal circulation on microvascular tissue perfusion during surgical aortic valve replacement: intravital imaging in a prospective randomized study. AB - OBJECTIVES: Closed minimal extracorporeal circulation (MECC) systems currently do not represent the standard of surgical care for open-heart surgery. Yet, considering the beneficial results reported for coronary artery bypass graft (CABG) surgery, we used an MECC system in aortic valve replacement (AVR) and analysed the effects on intraoperative microvascular perfusion in comparison with conventional open extracorporeal circulation (CECC). METHODS: In the current study, we analysed alterations in microvascular perfusion at 4 predefined time points (T1-T4) during surgical AVR utilizing orthogonal polarization spectral (OPS) imaging. Twenty patients were randomized for being operated on utilizing either MECC or CECC. Changes in functional capillary density (FCD, cm/cm(2)), mircovascular blood flow velocity (mm/s) and vessel diameter (MUm) were analysed by a blinded investigator. RESULTS: After the start of extracorporeal circulation and aortic cross-clamping (T2), both groups showed a significant drop in FCD, but with a significantly higher FCD in the MECC group (153.1 +/- 15.0 cm/cm2 in the CECC group vs 160.8 +/- 12.2 cm/cm2 in the MECC group, P = 0.034). During the late phase of the cardiopulmonary bypass (CPB) (T3), the FCD was still significantly depressed in both treatment groups (153.5 +/- 14.6 cm/cm2 in the CECC group, P <0.05 vs 'T1'; 159.5 +/- 12.4 cm/cm2 in the MECC group, P <0.05 versus 'T1'). After termination of CPB (T4), the FCD recovered in both groups to baseline values. Microvascular blood flow velocity tended to remain at a higher level in the MECC group, whereas haemodilution during CPB was significantly reduced in the MECC group. CONCLUSIONS: The use of MECC in AVR did not affect procedural safety and, resulted in beneficial preservation of microvascular blood flow velocity and significantly reduced haemodilution during CPB. In contrast to CABG surgery, the use of MECC did not improve FCD during surgical AVR. Clinical advantages possibly resulting from attenuated haemodilution and preservation of microvascular blood flow velocity require further validation in larger patient cohorts. PMID- 24796335 TI - Identification of patients with gout: elaboration of a questionnaire for epidemiological studies. AB - OBJECTIVES: In France, the prevalence of gout is currently unknown. We aimed to design a questionnaire to detect gout that would be suitable for use in a telephone survey by non-physicians and assessed its performance. METHODS: We designed a 62-item questionnaire covering comorbidities, clinical features and treatment of gout. In a case-control study, we enrolled patients with a history of arthritis who had undergone arthrocentesis for synovial fluid analysis and crystal detection. Cases were patients with crystal-proven gout and controls were patients who had arthritis and effusion with no monosodium urate crystals in synovial fluid. The questionnaire was administered by phone to cases and controls by non-physicians who were unaware of the patient diagnosis. Logistic regression analysis and classification and regression trees were used to select items discriminating cases and controls. RESULTS: We interviewed 246 patients (102 cases and 142 controls). Two logistic regression models (sensitivity 88.0% and 87.5%; specificity 93.0% and 89.8%, respectively) and one classification and regression tree model (sensitivity 81.4%, specificity 93.7%) revealed 11 informative items that allowed for classifying 90.0%, 88.8% and 88.5% of patients, respectively. CONCLUSIONS: We developed a questionnaire to detect gout containing 11 items that is fast and suitable for use in a telephone survey by non-physicians. The questionnaire demonstrated good properties for discriminating patients with and without gout. It will be administered in a large sample of the general population to estimate the prevalence of gout in France. PMID- 24796336 TI - The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. AB - OBJECTIVE: To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. METHODS: We conducted a retrospective cohort study using 2005-2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. RESULTS: We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP>10 mg/L compared with <1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR>42 mm/h compared with <14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol >=60 mg/dL (1.6 mmol/L) compared with <40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. CONCLUSIONS: This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk. PMID- 24796338 TI - Barking up the right tree at last: another step closer to a universal definition of bleeding. PMID- 24796337 TI - Advanced chronic kidney disease in patients undergoing transcatheter aortic valve implantation: insights on clinical outcomes and prognostic markers from a large cohort of patients. AB - AIM: The aim of this study was to determine the effects of advanced chronic kidney disease (CKD) on early and late outcomes after transcatheter aortic valve implantation (TAVI), and to evaluate the predictive factors of poorer outcomes in such patients. METHODS AND RESULTS: This was a multicentre study including a total of 2075 consecutive patients who had undergone TAVI. Patients were grouped according the estimated glomerular filtration rate as follows: CKD stage 1-2 (>=60 mL/min/1.73 m(2); n = 950), stage 3 (30-59 mL/min/1.73 m(2); n = 924), stage 4 (15-29 mL/min/1.73 m(2); n = 134) and stage 5 (<15 mL/min/1.73 m2 or dialysis; n = 67). Clinical outcomes were evaluated at 30-days and at follow-up (median of 15 [6-29] months) and defined according to the VARC criteria. Advanced CKD (stage 4-5) was an independent predictor of 30-day major/life-threatening bleeding (P = 0.001) and mortality (P = 0.027), and late overall, cardiovascular and non-cardiovascular mortality (P < 0.01 for all). Pre-existing atrial fibrillation (HR: 2.29, 95% CI: 1.47-3.58, P = 0.001) and dialysis therapy (HR: 1.86, 95% CI: 1.17-2.97, P = 0.009) were the predictors of mortality in advanced CKD patients, with a mortality rate as high as 71% at 1-year follow-up in those patients with these 2 factors. Advanced CKD patients who had survived at 1-year follow-up exhibited both a significant improvement in NYHA class (P < 0.001) and no deterioration in valve hemodynamics (P = NS for changes in mean gradient and valve area over time). CONCLUSIONS: Advanced CKD was associated with a higher rate of early and late mortality and bleeding events following TAVI, with AF and dialysis therapy determining a higher risk in these patients. The mortality rate of patients with both factors was unacceptably high and this should be taken into account in the clinical decision-making process in this challenging group of patients. PMID- 24796339 TI - Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI Randomized Controlled Trial. AB - AIMS: Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for ~2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. CONCLUSIONS: Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury. PMID- 24796341 TI - Psychometric evaluation of the Short Form 36 Health Survey (SF-36) and the World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF) for patients with schizophrenia. AB - Quality-of-life (QoL) instruments measure the overall health status of people with schizophrenia, for whom the activities of daily life are often difficult. However, information on the psychometric properties of scores from the Short Form 36 Health Survey (SF-36) and the World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF), 2 commonly used generic QoL instruments in this population, is limited. Thus, we used a multitrait-multimethod analysis plus confirmatory factor analysis (CFA) to examine their psychometric properties. To test the reliability of their scores, we used methods of absolute reliability (standard error of measurement [SEM] and smallest real difference [SRD]) and relative reliability (i.e., intraclass correlation coefficient [ICC]). We recruited 100 patients with schizophrenia from a psychiatric hospital in southern Taiwan. All participants filled out the SF-36 and the WHOQOL-BREF at baseline and 2 weeks later. The participants' QoL scores were lower than those of the Taiwan general population (ps < .01), and CFA indicated that the constructs of QoL scores for the SF-36 (comparative fit index [CFI] = .918; incremental fit index [IFI] = .919; Tucker-Lewis index [TLI] = .885) and the WHOQOL-BREF (CFI = .967; IFI = .967; TLI = .900) were acceptable. The SEM and SRD analyses suggested that the total scores of the SF-36 (SEM% = 10.03%; SRD% = 27.80%) and of the WHOQOL BREF (SEM% = 5.55%; SRD% = 15.40%) were reliable. Also, our results demonstrated that the WHOQOL-BREF scores were more reliable and valid than the SF-36 scores for assessing people with schizophrenia. The scores of both questionnaires were valid and reliable and detected different aspects of QOL in the population with schizophrenia. PMID- 24796340 TI - Association of cyclooxygenase-2 genetic variant with cardiovascular disease. AB - AIM: A genetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial. METHODS AND RESULTS: The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 * 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 * 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers. CONCLUSION: The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin. PMID- 24796343 TI - The heritability of psychopathic personality in 14- to 15-year-old twins: a multirater, multimeasure approach. AB - Until now, no study has examined the genetic and environmental influences on psychopathic personality across different raters and method of assessment. Participants were part of a community sample of male and female twins born between 1990 and 1995. The Child Psychopathy Scale and the Antisocial Process Screening Device were administered to the twins and their parents when the twins were 14-15 years old. The Psychopathy Checklist: Youth Version (PCL:YV) was administered and scored by trained testers. Results showed that a 1-factor common pathway model was the best fit for the data. Genetic influences explained 69% of the variance in the latent psychopathic personality factor, while nonshared environmental influences explained 31%. Measurement-specific genetic effects accounted for between 9% and 35% of the total variance in each of the measures, except for PCL:YV, where all genetic influences were in common with the other measures. Measure-specific nonshared environmental influences were found for all measures, explaining between 17% and 56% of the variance. These findings provide further evidence of the heritability in psychopathic personality among adolescents, although these effects vary across the ways in which these traits are measured, in terms of both informant and instrument used. PMID- 24796344 TI - Short-Term Assessment of Risk and Treatability (START): systematic review and meta-analysis. AB - This article describes a systematic review of the psychometric properties of the Short-Term Assessment of Risk and Treatability (START) and a meta-analysis to assess its predictive efficacy for the 7 risk domains identified in the manual (violence to others, self-harm, suicide, substance abuse, victimization, unauthorized leave, and self-neglect) among institutionalized patients with mental disorder and/or personality disorder. Comprehensive terms were used to search 5 electronic databases up to January 2013. Additional articles were located by examining references lists and hand-searching. Twenty-three papers were selected to include in the narrative review of START's properties, whereas 9 studies involving 543 participants were included in the meta-analysis. Studies about the feasibility and utility of the tool had positive results but lacked comparators. START ratings demonstrated high internal consistency, interrater reliability, and convergent validity with other risk measures. There was a lack of information about the variability of START ratings over time. Its use in an intervention to reduce violence in forensic psychiatric outpatients was not better than standard care. START risk estimates demonstrated strong predictive validity for various aggressive outcomes and good predictive validity for self harm. Predictive validity for self-neglect and victimization was no better than chance, whereas evidence for the remaining outcomes is derived from a single, small study. Only 3 of the studies included in the meta-analysis were rated to be at a low risk of bias. Future research should aim to investigate the predictive validity of the START for the full range of adverse outcomes, using well-designed methodologies, and validated outcome tools. PMID- 24796345 TI - Stroke service: how can we improve and measure outcomes? Consensus summary from a global stroke forum. AB - The success of acute stroke treatment is first and foremost time-dependent, and the need for improvement in acute stroke management is demonstrated by the fact that only a minority of patients gain access to treatment - in particular, intravenous recombinant tissue plasminogen activator (IV tPA) - within the necessary time window. Standards of acute stroke care vary widely both regionally and nationally; consequently, various healthcare organizations have undertaken initiatives to measure and improve quality of care. To date, most quality measures have been process-based, focusing primarily on metrics of patient care in the acute hospital-based setting (e.g., time to recombinant tPA administration). Therefore, there remains a need for metrics designed to assess how improvements in process translate into patient outcomes. A global forum was convened to share best practice and provide consensus recommendations on core metrics for measuring improvements in access to care and patient outcomes. Recommendations for core metrics of patient outcomes include hospital-based outcomes (e.g., neurological status at 24 h, ambulatory status at discharge) and post-discharge outcomes (e.g., modified Rankin Scale score at 30 and/or 90 days). Recommendations for best practice relating to aspects of people, process, and technology involved in the stroke treatment pathway that may help provide improvements in these core outcome measures are also outlined. PMID- 24796346 TI - An observational study to compare the contents and quality of information furnished in CDSCO ADR reporting form, yellow card, medwatch and blue form by the healthcare professionals. AB - BACKGROUND: Spontaneous adverse drug reaction (ADR) reporting form is a vital tool for collecting information about ADRs, which helps in establishing the causal assessment and generating a signal. This is feasible if quality information is translated into the reporting form by health care professional (HCPs). Hence, present study was carried out to compare efficiency of HCPs in translating suspected ADR information in the spontaneous reporting forms and to compare the ADR reporting forms of different countries and their duration of training in pharmacovigilance. METHODS: In a cross-sectional study, 50 doctors, 50 Nurses and 50 Pharmacists were asked to fill different reporting forms (CDSCO form, Medwatch, Yellow card and the Blue form) using different simulated ADR case reports. Filled forms were analysed for their contents, information captured and time taken to fill these forms. They were also asked about their training and exposure to pharmacovigilance related activities. RESULTS: All the spontaneous ADR reporting forms had 24-26 data elements to furnish information. Information regarding dechallenge was lacking in the Yellow card and Blue form. Blue form also lacked the information on rechallenge. Overall nurses took longer time to fill all the ADR reporting forms as compared to the doctors and pharmacists. Majority of HCPs missed to fill reporter's information in all the forms. CONCLUSION: Study suggested that the quality of information translated by the HCPs needs improvement for which they should be sensitized periodically on the basic elements of pharmacovigilance. PMID- 24796347 TI - Information on adverse events in randomised clinical trials assessing drug interventions published in four medical journals with high impact factors. AB - BACKGROUND: The impact of the extension of the Consolidated Standards of Reporting Trials (CONSORT) statement, which was published in 2004 and aimed to improve the quality of the safety information presented in clinical trials, remains uncertain. OBJECTIVE: To assess the incorporation of the CONSORT statement extension's recommendations in randomised clinical trials (RCTs) evaluating drug therapies published in high-impact medical journals. METHODS: Using Medline, 122 RCTs published in 2009 were selected from BMJ, JAMA, Lancet, and NEJM. A structured form was used to identify the harms information reported in the RCTs, following the recommendations of the CONSORT statement extension. RESULTS: The most frequently met CONSORT recommendation was the mention of harms in the title or abstract of the paper (72.1% of the papers analysed); the least met recommendation was the reporting of how the harms information was collected (10.7%). The studies that focused on harms presented better information on safety, but only 10.8% met all recommendations in the CONSORT statement. CONCLUSION: The adverse event information was insufficient for the RCTs published in four high-impact medical journals five years after the publication of the extension of the CONSORT statement. PMID- 24796348 TI - Guidewire retention following central venous catheterisation: a human factors and safe design investigation. AB - BACKGROUND: Central Venous Catheterisation (CVC) has occasionally been associated with cases of retained guidewires in patients after surgery. In theory, this is a completely avoidable complication; however, as with any human procedure, operator error leading to guidewires being occasionally retained cannot be fully eliminated. OBJECTIVE: The work described here investigated the issue in an attempt to better understand it both from an operator and a systems perspective, and to ultimately recommend appropriate safe design solutions that reduce guidewire retention errors. METHODS: Nine distinct methods were used: observations of the procedure, a literature review, interviewing CVC end-users, task analysis construction, CVC procedural audits, two human reliability assessments, usability heuristics and a comprehensive solution survey with CVC end-users. RESULTS: The three solutions that operators rated most highly, in terms of both practicality and effectiveness, were: making trainees better aware of the potential guidewire complications and strongly emphasising guidewire removal in CVC training, actively checking that the guidewire is present in the waste tray for disposal, and standardising purchase of central line sets so that differences that may affect chances of guidewire loss is minimised. CONCLUSIONS: Further work to eliminate/engineer out the possibility of guidewires being retained is proposed. PMID- 24796349 TI - Palivizumab and respiratory syncytial virus disease: selling sickness for future? AB - Over the past two decades Russia has gone through dramatic "democratic" changes resulting in unprecedented deterioration of health, loss of lives and extinction of population. The health system turned into a ridiculous monster of poorly organized business exploiting reminiscent social values of the past to build profits on selling sickness-for-all in consumer culture. We present facts and conclude that introduction of palivizumab into clinical practice for the most vulnerable patient category was done without confirmation of efficacy, without pharmacoeconomics evaluations, without any precautionary measures in a country with undeveloped pharmacovigilance system. The situation calls for immediate action of responsible authorities and the society as a whole. PMID- 24796350 TI - Births and male:female birth ratio in Scandinavia and the United Kingdom after the Windscale fire of October 1957. AB - AIMS: The Windscale (UK) fire of 1957 carried radioactive fallout according to the then prevailing wind patterns, in a North-Easterly direction across the Nordic countries, toward Norway. The male:female ratio at birth (M/F) is known to be increased after parental exposure to ionising radiation due to foetal losses that affect female more than male pregnancies. This study was carried out in order to ascertain whether the Windscale fire had any effects on M/F and birth rates in the United Kingdom and Scandinavia. METHODS: Annual live births by gender were obtained from a World Health Organization dataset. The null hypothesis was that there were no significant changes in M/F or in births in temporal association with the 1957 Windscale event in abovementioned countries. RESULTS: There were no significant effects on the UK and most of Scandinavia but there was a significant rise in M/F for Norway and Finland with an aggregate deficit of around 4000 births in each country. CONCLUSIONS: A recent study suggests that the plume from the reactor extended further east than previously believed. This study confirms that contamination from the Windscale fire had a negligible impact on the UK (as measured by birth effects) but had a significant impact on births in Norway and Sweden. PMID- 24796351 TI - Optimization and utilization of Agrobacterium-mediated transient protein production in Nicotiana. AB - Agrobacterium-mediated transient protein production in plants is a promising approach to produce vaccine antigens and therapeutic proteins within a short period of time. However, this technology is only just beginning to be applied to large-scale production as many technological obstacles to scale up are now being overcome. Here, we demonstrate a simple and reproducible method for industrial scale transient protein production based on vacuum infiltration of Nicotiana plants with Agrobacteria carrying launch vectors. Optimization of Agrobacterium cultivation in AB medium allows direct dilution of the bacterial culture in Milli Q water, simplifying the infiltration process. Among three tested species of Nicotiana, N. excelsiana (N. benthamiana * N. excelsior) was selected as the most promising host due to the ease of infiltration, high level of reporter protein production, and about two-fold higher biomass production under controlled environmental conditions. Induction of Agrobacterium harboring pBID4-GFP (Tobacco mosaic virus-based) using chemicals such as acetosyringone and monosaccharide had no effect on the protein production level. Infiltrating plant under 50 to 100 mbar for 30 or 60 sec resulted in about 95% infiltration of plant leaf tissues. Infiltration with Agrobacterium laboratory strain GV3101 showed the highest protein production compared to Agrobacteria laboratory strains LBA4404 and C58C1 and wild-type Agrobacteria strains at6, at10, at77 and A4. Co-expression of a viral RNA silencing suppressor, p23 or p19, in N. benthamiana resulted in earlier accumulation and increased production (15-25%) of target protein (influenza virus hemagglutinin). PMID- 24796352 TI - Emergence of collective modes and tri-dimensional structures from epithelial confinement. AB - Many in vivo processes, including morphogenesis or tumour maturation, involve small populations of cells within a spatially restricted region. However, the basic mechanisms underlying the dynamics of confined cell assemblies remain largely to be deciphered and would greatly benefit from well-controlled in vitro experiments. Here we show that confluent epithelial cells cultured on finite population-sized domains, exhibit collective low-frequency radial displacement modes as well as stochastic global rotation reversals. A simple mathematical model, in which cells are described as persistent random walkers that adapt their motion to that of their neighbours, captures the essential characteristics of these breathing oscillations. As these epithelia mature, a tri-dimensional peripheral cell cord develops at the domain edge by differential extrusion, as a result of the additional degrees of freedom of the border cells. These results demonstrate that epithelial confinement alone can induce morphogenesis-like processes including spontaneous collective pulsations and transition from 2D to 3D. PMID- 24796353 TI - Risk factors for post-operative pulmonary complications after gastrectomy for gastric cancer. AB - BACKGROUND: Post-operative pulmonary complications (PPCs) negatively affect patients' quality of life and can be life-threatening. Predictors of PPCs have been evaluated in patients who underwent various operations, but few studies have specifically focused on gastrectomy. METHODS: We retrospectively studied 1,053 patients with gastric adenocarcinoma who underwent radical gastrectomy with lymphadenectomy in our hospital between 1999 and 2011. Post-operative pulmonary complications were defined as conditions such as pneumonia, macroscopic atelectasis, pneumothorax, and acute respiratory distress syndrome that developed within 30 d after surgery. We evaluated the relations between PPCs and pre operative or intra-operative factors and assessed risk factors for PPCs after gastrectomy. RESULT: A total of 49 (4.7%) patients had PPCs. On univariate analysis, PPCs were significantly associated with male gender (p=0.024), predicted vital capacity (VC) (p=0.020), a lower pre-operative serum albumin concentration (p=0.023), open surgery (p=0.007), total gastrectomy (p<0.001), combined resection of another organ (p=0.001), extended operating time (p<0.001), higher operative bleeding volume (p<0.001), intra-operative or post-operative blood transfusion (p=0.009), and pathologic tumor stage (p=0.003). On multivariable analysis, extended operating time (odds ratio [OR], 3.21, 95% confidence interval [CI] 1.46-7.07; p=0.004), total gastrectomy (OR, 2.65, 95% CI 1.25-5.59; p=0.011) and predicted VC (OR, 2.42, 95% CI 1.01-5.85; p=0.049) were independent risk factors. These three factors also were independent risk factors for post-operative pneumonia (total gastrectomy OR, 2.64, 95% CI 1.32-5.30; p=0.006); extended operating time OR, 2.54, 95% CI 1.24-5.19; p=0.011; and predicted VC OR, 2.41, 95% CI 1.01-5.75; p=0.048). CONCLUSION: Extended operating time, total gastrectomy, and predicted VC were independent predictors of PPCs, particularly pneumonia, in patients with gastric cancer who underwent gastrectomy. In patients with restrictive pulmonary dysfunction who are scheduled to undergo total gastrectomy, reduced lymphadenectomy or the avoidance of combined resection should be considered to shorten the operating time. PMID- 24796354 TI - The potential impact of the revision of the Basic World Federation Medical Education Standards. AB - BACKGROUND: The World Federation of Medical Education has released a revised version of their Basic Medical Education Standards. This paper compares the original and revised versions following an external review of a medical school based on the original version, and indicates potential implications of the changes for making judgements about the quality of medical education. METHODS: A comparative analysis was conducted of the original and revised standards, producing a list of changes, through either "strengthened" or "new" standards or guidance for their interpretation. The potential impact of the changes on the writing of a report for this external review was then considered. RESULTS: The revised standards have more specific requirements for curriculum design, clinical placements, research training and the support and participation of students. In order to meet the revised standards, medical schools may need to invest substantially in acquiring in-house medical education expertise and better prepared teaching and research staff. CONCLUSION: The bar appears to have been raised substantially in the revised standards document. While individually the changes appear sound, the overall impact, particularly in the developing world, may be substantial. PMID- 24796355 TI - Clinical communication skills learning outcomes among first year medical students are consistent irrespective of participation in an interview for admission to medical school. AB - BACKGROUND: Although contentious most medical schools interview potential students to assess personal abilities such as communication. AIMS: To investigate any differences in clinical communication skills (CCS) between first year students admitted to UQ medical school with or without an admissions interview. METHODS: A retrospective analysis of 1495 student assessment scores obtained after structured communication skills training (CCS) between 2007 and 2010. RESULTS: The average assessment score was 3.76 ([95% CI, 3.73-3.78]) and adjusting for student characteristics, showed no main effect for interview (p = 0.89). The strongest predictor of scores was gender with females achieving significantly higher scores (3.91 [95% CI, 3.54-4.28] vs. 3.76 [95% CI, 3.39 4.13]; p <= 0.001). CONCLUSIONS: Data show no differences in post-training assessment measures between students who were interviewed during selection or not. Further research about the quality and retention of communications skills after training is warranted. PMID- 24796356 TI - Comments on "Twelve tips for teaching with ultrasound in the undergraduate curriculum". PMID- 24796357 TI - How we developed Doctors Speak Up: an evidence-based language and communication skills open access resource for International Medical Graduates. AB - BACKGROUND: Some International Medical Graduates (IMGs) need to develop language and communication skills for patient-centred care but have limited opportunities to do so. AIM: To develop an evidence-based, language and communication skills web resource for IMG doctors and supervisors, focussing on culturally challenging patient interviews. METHODS: Forty-eight IMGs participated in four practice OSCEs. We video-recorded the interactions and applied discourse analytic methods to investigate salient language and communication features. RESULTS: The findings from the OSCE workshops showed that many participants demonstrated aspects of patient-centred interviewing but were hindered by limited interactional competence to elicit information and negotiate behaviours as well as a limited repertoire of English grammar, vocabulary, and phonological phrasing for effective interaction. These findings guided the choice of content and pedagogy for the development of the web-based resource Doctors Speak Up. CONCLUSION: Evaluation and uptake of the Doctors Speak Up website confirm the demand for a resource combining targeted communication skills and language instruction. Over 19 500 users visited the website between March 2012 and November 2013. PMID- 24796358 TI - Career-long learning: relationship between cognitive and metacognitive skills. AB - OBJECTIVES: Physicians need metacognitive skills including reflection and goal generation for effective lifelong learning (LLL). These skills are not readily assessed and may not correlate with cognitive skills. We examined early-career physicians' metacognition and relationships between metacognitive skills, cognitive skills, and orientation toward LLL. METHODS: Pediatric fellows at UCSF document career progress in annual Individual Development Plans (IDPs). To assess metacognitive skills, we scored narratives in IDPs with a Reflective Ability Rubric (RAR) and goal setting with a SMART Goal Rubric (SMART-GR: consists of global IDP score and four IDP domain subscores). To assess cognitive skills, we collected American Board of Pediatrics scores (ABP), and to measure orientation toward LLL, fellows completed the Jefferson Scale (JeffSPLL). We used Spearman's correlation to examine relationships between scores. RESULTS: About 57/66 (86%) fellows participated. Mean scores were: RAR 2.4 +/- 1.3 (scale 0-6); SMART-GR global IDP 2.8 +/- 1.0, (1-5); JeffSPLL 46.3 +/- 3.9 (14-56); and ABP 559.4 +/- 75.7. RAR scores correlated significantly with SMART-GR scores but metacognitive measures did not correlate with ABP scores. CONCLUSIONS: Our study suggests early-career physicians may have limited metacognitive skills; cognitive and metacognitive skills do not correlate; and orientation toward LLL does not predict metacognitive skills. Thus, we need improved methods to teach and assess metacognition. PMID- 24796359 TI - Workplace immersion in the final year of an undergraduate medicine course: the views of final year students and recent graduates. AB - BACKGROUND: Most medical schools require formal competence assessment of students immediately prior to graduation, but variation exists in the approach to endpoint assessments. This article reports perceptions of senior students and graduates from a school with a six-year program which has introduced final year workplace immersion placements following a barrier examination at the end of the penultimate Year 5. METHODS: Final year students (22) and recent graduates (4) attended focus groups and in-depth interviews exploring their perceptions of the value of the curriculum experience during the final two years, the structure and timing of assessment, and their preparation for internship. FINDINGS: Participants felt that the penultimate year was more pressured, and focused on passing "artificial" examinations. In contrast, the final year was more relaxed, building skills for postgraduate work and later career development. As a result, students felt well prepared for internship with some indication that the self directed nature of the final year promoted a lifelong learning approach. CONCLUSION: The final year workplace immersion model was regarded positively by senior students of this medical school. This model may be a better way of preparing students to be junior doctors than a traditional final year heavy on theoretical learning and assessment. PMID- 24796360 TI - Failure to intercalate: a scapegoat for decreasing involvement in academic medicine? PMID- 24796361 TI - Core competencies in teaching and training for doctors in Scotland: a review of the literature and stakeholder survey. AB - BACKGROUND: The UK General Medical Council requires all registered doctors to be competent in all areas of their work, including teaching and training. AIMS: The current research sought consensus on core competencies for all consultants and GPs involved in teaching and training in Scotland. METHOD: A draft list of 80 competencies was developed from the literature and made available as a survey to all consultants and GPs with teaching roles and all final year speciality trainees working in Scotland. Respondents rated the importance of each competency and provided free text comments. RESULTS: There were 1026 responses. Eighteen competencies were rated as "high priority", and are recommended as a baseline for all doctors involved in teaching and training; 55 were rated as "medium priority", and are recommended in relation to specific teaching and training roles; and 7 were rated as "low priority". Free text responses suggested the topic was controversial and emotive, and emphasised the importance of further work to engage trainers. CONCLUSIONS: The findings appeared to have face validity, and it was felt these could be used as the basis for developing a "Scottish Trainer Framework" for doctors and others involved in teaching and training in Scotland. PMID- 24796362 TI - Silent mentors. PMID- 24796363 TI - The highs and lows of general practice--Using highly abnormal clinical findings and investigation results in general practice training. PMID- 24796364 TI - TELEMOLD project: oximetry and exercise telemonitoring to improve long-term oxygen therapy. AB - BACKGROUND: Standard assessment of long-term oxygen therapy (LTOT) prescription involves hospital-based clinical tests. However, there is some evidence suggesting that oxygen demand during daily activities may not be correctly estimated by such tests, when compared with continuous ambulatory oximetry. The authors describe the results of a study aiming to evaluate the clinical relevance of a home telemonitoring system in LTOT optimization. SUBJECTS AND METHODS: Thirty-five chronic respiratory failure patients were monitored in real time with an oximeter sensor and an accelerometer. Signals were sent via Bluetooth((r)) (Bluetooth SIG, Kirkland, WA) to a mobile phone and then via 3G or general packet radio service to a server. Continuous and secure access to data was established through an Internet site. RESULTS: Each patient was monitored an average of 7.6 +/- 4.5 days (total, 83 +/- 67 h). Valid records were on average 65 +/- 24%. Records of rest, activity, and sleep time per patient were, on average, 28 +/- 21%, 7 +/- 6%, and 59 +/- 25%, respectively. Significant desaturation during rest, activity, and sleep was found in 2, 26, and 9 patients, respectively. Patients' ratings of the user-friendliness of the equipments, assessed by questionnaire, were fairly good (76% reported it as easy/very easy). CONCLUSIONS: Our study suggests that a telemonitoring system combining oximetry and physical activity evaluation might contribute to a more adequate oxygen prescription, mainly during daily activities. PMID- 24796365 TI - Experiences of functional electrical stimulation (FES) and ankle foot orthoses (AFOs) for foot-drop in people with multiple sclerosis. AB - Abstract Purpose: A constructivist phenomenological study explored impacts of ankle foot orthoses (AFOs) or functional electrical stimulation (FES) on people with foot-drop from multiple sclerosis (MS). Method: Focus groups following topic guides were analysed using interpretative phenomenological analysis, with researcher reflexivity, participant verification and peer checking of analysis. Participants with sustained use of the devices (under 2 y) were invited from two quantitative studies that (a) investigated immediate FES effects (n = 12) and (b) compared habitual use of AFO (n = 7) or FES (n = 6). Two focus groups addressed AFO (n = 4) and FES (n = 6) experiences. Results: Similar numbers of positive and negative aspects were described for AFO and FES. Both reduced fatigue, improved gait, reduced trips and falls, increased participation, and increased confidence; greater balance/stability was reported for AFOs, and increased walking distance, fitness and physical activity for FES. Barriers to both included avoiding reliance on devices and implications for shoes and clothing; a non-normal gait pattern was reported for AFO, and difficulties of application and limitations in the design of FES. However, participants felt the positives outweighed the negatives. Conclusions: Participants felt benefits outweighed the drawbacks for AFO and FES; greater understanding of user preferences and satisfaction may increase likelihood of usage and efficacy. Implications for Rehabilitation Interventions to reduce the impacts of foot-drop in people with multiple sclerosis (MS) are important to optimise physical activity participation and participation in life; they include ankle foot orthoses (AFOs) and functional electrical stimulation (FES). Research is lacking regarding user satisfaction and perceived outcomes, therefore, two separate focus groups were conducted from a constructivist phenomenological perspective to explore the impacts of AFOs (n = 4) and FES (n = 6) on people with foot-drop from MS. Some similar positive aspects of AFO and FES use were described, including reduced fatigue, improved gait and fewer trips and falls, while common barriers included finding the device cumbersome, uncomfortable, and inconvenient, with some psychological barriers to their use. On balance, the impacts of the devices on improving activities and participation were more important for participants than practical barriers, highlighting the importance of combining understanding of individual experiences and preferences with clinical decision-making when prescribing a device to manage foot-drop. PMID- 24796367 TI - The future of leadership. PMID- 24796366 TI - High levels of Staphylococcus aureus contamination in Chinese-style roast pork. AB - Chinese roasted pork has been implicated as a major source of food poisoning caused by Staphylococcus aureus. Establishing the source, either as contaminants from raw meat or from food handlers, could facilitate drafting more appropriate guidelines for better prevention of food poisoning. To determine the rate and source of staphylococcal contamination, roasted pork purchased from 50 sui-mei shops in Hong Kong was sampled for presence of S. aureus by enrichment and subsequent culture. Isolates were characterized for methicillin sensitivity, spa type, and presence of Panton-Valentine leukocidin (PVL) and staphylococcal enterotoxins (SEs). Methicillin-resistant isolates were confirmed by presence of mecA and SCCmec type and sensitivity to vancomycin investigated. S. aureus was isolated from 25 (50%) samples, with 3 yielding two colony types. Of the 28 isolates, 3 were resistant to cefoxitin, but only 2 were mecA positive and belonged to SCCmec type V. The mecA negative isolate also lacked mecC, but had a penicillin minimum inhibitory concentration of 10 mg/L. A livestock-associated spa type (t034) was only observed in one methicillin-sensitive strain, all other isolates appearing to be of human origin, with 30% belonging to t189. One isolate was PVL positive and five carried genes for classical SEs. The high rate of staphylococcal contamination observed was probably associated with food handlers, as the strains belonged to spa types previously reported in clinical and nasal carriage isolates. The presence of enterotoxins in 18% of isolates confirms the risk of food poisoning associated with this product and emphasizes the need for improved guidelines for handling after preparation. Use of refrigerated display areas should be considered. PMID- 24796368 TI - Insulin pump-associated adverse events in children and adolescents--a prospective study. AB - BACKGROUND: Intensive insulin regimens are now the mainstay of modern, type 1 diabetes mellitus management. Insulin pumps (CSII) are a key technique used. Although there has been considerable study of outcomes, there are few recent data on CSII-associated adverse events (AEs) and their incidence and characteristics. SUBJECTS AND METHODS: Phone calls to our 24-h diabetes support service were screened for CSII-associated AEs. Phone interviews were conducted with the parent/patient, within 96 h of the event. Interviews explored AE characteristics and the role of the user, as well as questions relating to outcome and the impact to the family and patient. Comparisons were made with clinic CSII patients not reporting an AE. RESULTS: Over a 16-week study period, 50 confirmed AEs occurred in 45 of 405 (11.1%) patients. This was annualized to an AE incidence of 40 AEs/100 person-years. Pump malfunction and infusion set/site failures were the most common events reported, occurring in 27 (54.0%) and 18 (36.0%) AEs, respectively. A user- or education-related issue was implicated in 22 (44.0%) events. Pump replacement occurred in 19 of 50 occurrences (38.0%). Additionally, 16 (32.0%) reported a hospital admission or emergency department attendance as a consequence. When compared with those on CSII not reporting an AE, AEs were associated with age <10 years (odds ratio=3.2 [95% confidence interval, 1.7-6.1]) but not with gender, glycosylated hemoglobin, diabetes duration, or pumping duration. CONCLUSIONS: This is the first prospective study to look at AEs in modern-generation insulin pumps. AEs appear common and should be anticipated. Their origin is multifactorial, with the pump, associated consumables, and the user all being important factors. Ongoing support and anticipatory education are essential to minimize pump-associated AEs and their impact. PMID- 24796369 TI - Coadministration of a Na+-H+ exchange inhibitor and sodium bicarbonate for the treatment of asphyxia-induced cardiac arrest in piglets. AB - BACKGROUND: The present study tested the hypothesis that addition of an inhibitor of Na(+)/H(+) exchanger (NHE1) to sodium bicarbonate might improve the response to base therapy from prolonged asphyxial cardiac arrest in piglets. METHODS: Asphyxial cardiac arrest was induced by endotracheal tube clamping. Animals were randomly assigned to four study groups: (i) vehicle control, (ii) administration of sabiporide (NHE1 inhibitor), (iii) administration of sodium bicarbonate, and (iv) administration of sabiporide and sodium bicarbonate. RESULTS: Administration of sodium bicarbonate alone did not affect survival, hemodynamic measures, and regional blood flow to critical tissues such as brain, heart, kidney, liver, and spleen. In contrast, sabiporide given alone or combined with sodium bicarbonate improved these. Furthermore, treatment with sabiporide reduced accumulation of neutrophils, reduced cytokine production in the lung, and reduced plasma levels of cardiac troponin-I, alanine aminotransferase, aspartate aminotransferase, and urea. In addition, the combined use of sabiporide and sodium bicarbonate had more profound reduction in interleukin (IL)-6 and IL-10, compared to sabiporide alone. CONCLUSION: These results suggest that addition of sabiporide to the administration of sodium bicarbonate might improve hemodynamic response and dampen the inflammatory cascade noted with cardiac arrest, and therefore being an attractive option in the treatment of cardiac arrest. PMID- 24796371 TI - Association of vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia. AB - BACKGROUND: Vitamin D and its receptor (VDR) have important roles in perinatal lung development. The aim of this study was to investigate the relationship between VDR gene polymorphism and bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: VDR Fok I, Bsm I, Apa I, and Taq I polymorphisms were genotyped using restriction fragment length polymorphism in 109 preterm infants (47 with BPD, 62 without BPD). RESULTS: In univariate analysis, Ff (odds ratio (OR) = 3.937, P = 0.022, 95% confidence interval (CI) = 1.22-12.69) and ff (OR = 5.23, P = 0.004, 95% CI = 1.69-16.23) genotypes of Fok I were associated with the increased risk of BPD; whereas tt genotype of Taq 1 was associated with a protective effect against BPD (OR = 0.30, P = 0.04, 95% CI = 0.09-0.94). In multivariate logistic regression analysis, variant Fok 1 genotype increased risk of BPD (OR = 4.11, 95% CI = 1.08-15.68, P = 0.038) independent of patent ductus arteriosus, sepsis, mechanical ventilation, and surfactant treatment. Taq 1, Bsm 1, and Apa 1 polymorphisms did not have any effect. CONCLUSION: After adjusting for multiple confounders, VDR Fok 1 polymorphism was associated with the increased frequency of BPD. Further studies are needed to assess the contribution of VDR signaling to the pathogenesis of BPD and to determine if VDR polymorphisms may be suitable for identifying infants at high risk for BPD. PMID- 24796370 TI - Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve. AB - BACKGROUND: Bicuspid aortic valve (BAV) is the most common type of congenital heart disease (CHD) and has a proposed genetic etiology. BAV is categorized by cusp fusion, with right-left (R-L) cusp fusion being associated with additional CHD, and right-noncoronary cusp (R-NC) fusion being associated with aortic valve dysfunction. Loss of murine Gata5, which encodes a cardiac transcription factor, results in a partially penetrant R-NC BAV, and we hypothesize that mutations in GATA5 are associated with R-NC BAV in humans. METHODS: A cohort of 78 BAV patients (50 with isolated BAV and 28 with associated aortic coarctation) was analyzed using Sanger sequencing to identify GATA5 sequence variants. Biochemical assays were performed to identify functional deficits of identified sequence variants. RESULTS: We identified two rare heterozygous nonsynonymous variants, p.Gln3Arg and p.Leu233Pro, for a frequency of 2.6% (2/78). Both individuals with nonsynonymous variants had BAV and aortic coarctation, one R-L and one R-NC subtype. Of the nonsynonymous variants, only p.Gln3Arg demonstrated decreased transcriptional activity in vitro. CONCLUSION: Rare sequence variants in GATA5 are associated with human BAV. Our findings suggest a genotype-phenotype correlation in regards to associated CHD but not cusp fusion. PMID- 24796372 TI - Testicular failure in a patient with G6PC3 deficiency. AB - BACKGROUND: Glucose-6-phosphatase-beta (G6PC3) deficiency is characterized by congenital neutropenia and variable developmental disorders, including those of the cardiovascular system and the urogenital system (e.g., cryptorchidism) and a peculiar visibility of subcutaneous veins. METHODS: A patient with clinical findings suggestive of G6PC3 deficiency was investigated. Genetic, hematopathologic, immunologic, and endocrine work-up were performed. RESULTS: The reported patient had binucleotide deletion mutation in G6PC3 and displayed the full spectrum of clinical manifestations associated with G6PC3 deficiency including neutropenia. The reported patient had normal bone marrow cellularity without increased apoptosis, and his neutrophils displayed normal respiratory burst activity. Endocrine work-up revealed low testosterone levels, which did not respond to human chorionic gonadotropin stimulation, extremely elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and undetectable anti-Mullerian hormone, all of which are suggestive of testicular failure or anorchia. CONCLUSION: Our report extends the knowledge about this syndrome and suggests a role for G6PC3 in testicular differentiation and formation. Urogenital dysmorphism could indeed be unrelated to G6PC3 and secondary to consanguinity. However, given the similar description of urogenital anomalies in previous reports of this syndrome, the dysmorphism in our patient is likely related. PMID- 24796373 TI - Effects of less-invasive surfactant administration on oxygenation, pulmonary surfactant distribution, and lung compliance in spontaneously breathing preterm lambs. AB - BACKGROUND: A new technique was proposed to administer surfactant to spontaneous breathing preterm infants by placing a thin catheter through the vocal cords. This technique was not studied with respect to oxygenation, gas exchange, surfactant distribution, and lung mechanics. We tested the technique of less invasive surfactant administration (LISA) in a spontaneous breathing preterm lamb model. METHODS: Preterm lambs (n = 12) of 133-134 d gestational age were randomized to the following three groups: (i) continuous positive airway pressure (CPAP) only, (ii) CPAP + LISA, and (iii) intubation and mechanical ventilation with surfactant administration. Surfactant was labeled with samarium oxide. During the next 180 min, blood gas analyses were performed. Postmortem, lungs were removed and surfactant distribution was assessed, and pressure-volume curves were performed. RESULTS: Pao2 in the LISA-treated lambs was significantly higher than in the lambs that exclusively received CPAP. Moreover, Pao2 values were similar between the LISA-treated and the intubated lambs. Overall, surfactant deposition was less in the LISA lambs, with significantly less surfactant distributed to the right upper lobe. Lung compliance was better in the intubated lambs compared with the LISA-treated lambs, although this did not reach significance. CONCLUSION: LISA improved oxygenation, similar to conventional surfactant application techniques, despite lower surfactant deposition and lung compliance. PMID- 24796374 TI - Bifacial peptide nucleic acid as an allosteric switch for aptamer and ribozyme function. AB - We demonstrate herein that bifacial peptide nucleic acid (bPNA) hybrid triplexes functionally substitute for duplex DNA or RNA. Structure-function loss in three non-coding nucleic acids was inflicted by replacement of a duplex stem with unstructured oligo-T/U strands, which are bPNA binding sites. Functional rescue was observed on refolding of the oligo-T/U strands into bPNA triplex hybrid stems. Bifacial PNA binding was thus used to allosterically switch-on protein and small-molecule binding in DNA and RNA aptamers, as well as catalytic bond scission in a ribozyme. Duplex stems that support the catalytic site of a minimal type I hammerhead ribozyme were replaced with oligo-U loops, severely crippling or ablating the native RNA splicing function. Refolding of the U-loops into bPNA triplex stems completely restored splicing function in the hybrid system. These studies indicate that bPNA may have general utility as an allosteric trigger for a wide range of functions in non-coding nucleic acids. PMID- 24796375 TI - Acceptor-donor-acceptor oligomers containing dithieno[3,2-b:2',3'-d]pyrrole and thieno[2,3-c]pyrrole-4,6-dione units for solution-processed organic solar cells. AB - New acceptor-donor-acceptor (A-D-A) oligomers (1 and 2) containing a central dithieno[3,2-b:2',3'-d]pyrrole unit and end-capping thieno[2,3-c]pyrrole-4,6 dione groups have been synthesized and characterized. Bulk heterojunction solar cells were prepared together with PC61BM and PC71BM, and the best results were obtained for the latter acceptor using 1,8-diiodooctane as an additive. Photovoltaic devices containing these oligomers achieved high external quantum efficiencies up to 50%. PMID- 24796376 TI - Benchmarking quantum chemical methods for the calculation of molecular dipole moments and polarizabilities. AB - The calculation of molecular electric moments, polarizabilities, and electrostatic potentials is a widespread application of quantum chemistry. Although a range of wave function and density functional theory (DFT) methods have been applied in these calculations, combined with a variety of basis sets, there has not been a comprehensive evaluation of how accurate these methods are. To benchmark the accuracy of these methods, the dipole moments and polarizabilities of a set of 46 molecules were calculated using a broad set of quantum chemical methods and basis sets. Wave function methods Hartree-Fock (HF), second-order Moller-Plesset (MP2), and coupled cluster-singles and doubles (CCSD) were evaluated, along with the PBE, TPSS, TPSSh, PBE0, B3LYP, M06, and B2PLYP DFT functionals. The cc-pVDZ, cc-pVTZ, aug-cc-pVDZ, aug-cc-pVTZ, and Sadlej cc-pVTZ basis sets were tested. The aug-cc-pVDZ, Sadlej cc-pVTZ, and aug-cc-pVTZ basis sets all yield results with comparable accuracy, with the aug-cc-pVTZ calculations being the most accurate. CCSD, MP2, or hybrid DFT methods using the aug-cc-pVTZ basis set are all able to predict dipole moments with RMSD errors in the 0.12-0.13 D range and polarizabilities with RMSD errors in the 0.30-0.38 A(3) range. Calculations using Hartree-Fock theory systematically overestimated dipole moments and underestimate polarizabilities. The pure DFT functionals included in this study (PBE and TPSS) slightly underestimate dipole moments and overestimate polarizability. Polarization anisotropy and implications for charge fitting are discussed. PMID- 24796377 TI - Editorial Comment from Dr Sato to Relationship between plasma melatonin levels and the efficacy of selective serotonin reuptake inhibitors treatment on premature ejaculation. PMID- 24796378 TI - Inhibition of acidic sphingomyelinase reduces established hepatic fibrosis in mice. AB - AIM: Liver fibrosis occurs as a result of several chronic liver diseases and leads to portal hypertension, cirrhosis and liver failure, often requiring liver transplantation. Activated hepatic stellate cells (HSC) are known to contribute to liver fibrosis, but currently there are no effective therapies for the treatment of established liver fibrosis. Activation of the acidic sphingomyelinase (ASM) has been shown to be involved in HSC activation. In the present study we investigated whether treatment with the ASM inhibitor, amitriptyline (TCA), could prevent and/or reverse fibrosis induced in mice by carbon tetrachloride (CCl4 ). METHODS: Mice were treated with CCl4 for 8 weeks to induce fibrosis. Concurrently, mice received drinking water with or without 180 mg/L TCA. RESULTS: Mice receiving TCA in the water had decreased hepatic collagen deposition and reduced liver mRNA expression of the fibrogenic mediators, transforming growth factor (TGF)-beta1, tissue inhibitor of matrix metalloproteinase-1, collagen and tumor necrosis factor-alpha. TCA treatment also reduced HSC activation determined by alpha-smooth muscle actin staining. In a separate set of experiments, mice were treated with CCl4 for 5 weeks prior to treatment with TCA, to test whether TCA had any effect on established fibrosis. Remarkably, in mice with established fibrosis, treatment with TCA significantly reduced collagen deposition, HSC activation, and prevented portal hypertension and improved hepatic architecture. Treatment of isolated HSC in vitro with TCA completely inhibited TGF-beta1-induced collagen expression and platelet-derived growth factor-beta-beta-induced proliferation. CONCLUSION: The data suggest that ASM is a critical signaling component in HSC for the development of liver fibrosis and represents an important therapeutic target. PMID- 24796379 TI - Structural elucidation of sulfaquinoxaline metabolism products and their occurrence in biological samples using high-resolution Orbitrap mass spectrometry. AB - Four previously unreported metabolism products of sulfaquinoxaline (SQX), a widely used veterinary medicine, were isolated and analyzed using liquid chromatography coupled to high-resolution Orbitrap mass spectrometry. Metabolites were structurally elucidated, and a fragmentation pathway was proposed. The combination of high-resolution MS(2) spectra, linear ion trap MS(2), in-source collision-induced dissociation (CID) fragmentation, and photolysis were used to analyze SQX and its metabolites. All metabolism products identified showed a similar fragmentation pattern to that of the original drug. Differential product ions were produced at m/z 162 and 253 which contain the radical moiety with more 16 Da units than sulfaquinoxaline. This occurs by a hydroxyl attachment to the quinoxaline moiety. With the exception of two low-intensity compounds, all the mass errors were below 5.0 ppm. The distribution of these metabolites in some animal species are also presented and discussed. PMID- 24796380 TI - 5-hydroxymethyl-2-furfural and derivatives formed during acid hydrolysis of conjugated and bound phenolics in plant foods and the effects on phenolic content and antioxidant capacity. AB - A common protocol for the extraction of phenolic aglycons or bound phenolics in plants generally involves hydrothermal hydrolysis in an aqueous methanol or ethanol solution containing 2-4 N HCl. However, as shown in the present study, this process also forms 5-(hydroxymethyl)furan-2-carbaldehyde (HMF) and its derivative products 5-(methoxymethyl)furan-2-carbaldehyde (MMF) and 5 (ethoxymethyl)furan-2-carbaldehyde (EMF), as identified by HPLC-DAD-ESI-MS/MS and NMR. These compounds are commonly misidentified as phenolics due to similar UV absorption at 280 nm. In this study, production of HMF, MMF, and EMF was shown to be dependent on the solvent condition and duration and temperature of hydrolysis. Fruits and vegetables produced HMF more readily than grains. HMF and its derivatives were subjected to various spectrophotometric antioxidant assays [2 diphenyl-1-picryhydrazyl radical scavenging activity (DPPH), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbing capacity (ORAC)] and displayed antioxidant activity mainly in the ORAC assay. Results of this study help avoid overestimation of phenolic content and antioxidant activities of plant foods. PMID- 24796382 TI - Exploring the radical nature of a carbon surface by electron paramagnetic resonance and a calibrated gas flow. AB - While the first Electron Paramagnetic Resonance (EPR) studies regarding the effects of oxidation on the structure and stability of carbon radicals date back to the early 1980s the focus of these early papers primarily characterized the changes to the structures under extremely harsh conditions (pH or temperature)(1 3). It is also known that paramagnetic molecular oxygen undergoes a Heisenberg spin exchange interaction with stable radicals that extremely broadens the EPR signal(4-6). Recently, we reported interesting results where this interaction of molecular oxygen with a certain part of the existing stable radical structure can be reversibly affected simply by flowing a diamagnetic gas through the carbon samples at STP(7). As flows of He, CO2, and N2 had a similar effect these interactions occur at the surface area of the macropore system. This manuscript highlights the experimental techniques, work-up, and analysis towards affecting the existing stable radical nature in the carbon structures. It is hoped that it will help towards further development and understanding of these interactions in the community at large. PMID- 24796381 TI - Reasons for limiting drinking in an HIV primary care sample. AB - BACKGROUND: Heavy drinking among individuals with HIV is associated with major health concerns (liver disease, medication nonadherence, immune functioning), but little is known about cognitive-motivational factors involved in alcohol consumption in this population, particularly reasons for limiting drinking. METHODS: Urban HIV primary care patients (N = 254; 78.0% male; 94.5% African American or Hispanic) in a randomized trial of brief drinking-reduction interventions reported on reasons for limiting drinking, alcohol consumption, and alcohol dependence symptoms prior to intervention. RESULTS: Exploratory factor analysis indicated 3 main domains of reasons for limiting drinking: social reasons (e.g., responsibility to family), lifestyle reasons (e.g., religious/moral reasons), and impairment concerns (e.g., hangovers). These factors evidenced good internal consistency (alphas = 0.76 to 0.86). Higher scores on social reasons for limiting drinking were associated with lower typical quantity, maximum quantity, and binge frequency (ps < 0.01), and higher scores on lifestyle reasons were associated with lower maximum quantity, binge frequency, and intoxication frequency (ps < 0.01). In contrast, higher scores on impairment concerns were associated with more frequent drinking and intoxication, and higher risk of alcohol dependence (ps < 0.05), likely because dependent drinkers are more familiar with alcohol-induced impairment. CONCLUSIONS: The current study is the first to explore reasons for limiting drinking among individuals with HIV and how these reasons relate to alcohol involvement. This study yields a scale that can be used to assess reasons for limiting drinking among HIV-positive drinkers and provides information that can be used to enhance interventions with this population. Discussing social and lifestyle reasons for limiting drinking among less extreme drinkers may support and validate these patients' efforts to limit engagement in heavy drinking; discussion of impairment reasons for limiting drinking may be a way to engage dependent drinkers in efforts to decrease their alcohol consumption. PMID- 24796383 TI - Galanin-like peptide (GALP) neurone-specific phosphoinositide 3-kinase signalling regulates GALP mRNA levels in the hypothalamus of males and luteinising hormone levels in both sexes. AB - Galanin-like peptide (GALP) neurones participate in the metabolic control of reproduction and are targets of insulin and leptin regulation. Phosphoinositide 3 kinase (PI3K) is common to the signalling pathways utilised by both insulin and leptin. Therefore, we investigated whether PI3K signalling in neurones expressing GALP plays a role in the transcriptional regulation of the GALP gene and in the metabolic control of luteinising hormone (LH) release. Accordingly, we deleted PI3K catalytic subunits p110alpha and p110beta via conditional gene targeting (cKO) in mice (GALP-p110alpha/beta cKO). To monitor PI3K signalling in GALP neurones, these animals were also crossed with Cre-dependent FoxO1GFP reporter mice. Compared to insulin-infused control animals, the PI3K-Akt-dependent FoxO1GFP nuclear exclusion in GALP neurones was abolished in GALP-p110alpha/beta cKO mice. We next used food deprivation to investigate whether the GALP-neurone specific ablation of PI3K activity affected the susceptibility of the gonadotrophic axis to negative energy balance. Treatment did not affect LH levels in either sex. However, a significant genotype effect on LH levels was observed in females. By contrast, no genotype effect on LH levels was observed in males. A sex-specific genotype effect on hypothalamic GALP mRNA was observed, with fed and fasted GALP-p110alpha/beta cKO males having lower GALP mRNA expression compared to wild-type fed males. Finally, the effects of gonadectomy and steroid hormone replacement on GALP mRNA levels were investigated. Compared to vehicle-treated mice, steroid hormone replacement reduced mediobasal hypothalamus GALP expression in wild-type and GALP-p110alpha/beta cKO animals. In addition, within the castrated and vehicle-treated group and compared to wild-type mice, LH levels were lower in GALP-p110alpha/beta cKO males. Double immunofluorescence using GALP Cre/R26-YFP mice showed androgen and oestrogen receptor co-localisation within GALP neurones. Our data demonstrate that GALP neurones are direct targets of steroid hormones and that PI3K signalling regulates hypothalamic GALP mRNA expression and LH levels in a sex-specific fashion. PMID- 24796385 TI - Electrolyte-gated colloidal nanoplatelets-based phototransistor and its use for bicolor detection. AB - Colloidal nanocrystals are appealing candidates for low cost optoelectronic applications because they can combine the advantages of both organic materials, such as their easy processing, and the excellent performance of inorganic systems. Here, we report the use of two-dimensional colloidal nanoplatelets for photodetection. We show that the nanoplatelets photoresponse can be enhanced by two to three orders of magnitude when they are incorporated in an all solid electrolyte-gated phototransistor. We extend this technique to build the first colloidal quantum dot-based bicolor detector with a response switchable between the visible and near-IR. PMID- 24796384 TI - Spiradenocarcinoma, cylindrocarcinoma and spiradenocylindrocarcinoma: a clinicopathological study of nine cases. AB - AIMS: To elucidate diagnostic criteria for spiradenocarcinoma, cylindrocarcinoma and spiradenocylindrocarcinoma, and to emphasize correlations between clinical behaviour and variable morphological patterns. METHODS AND RESULTS: We investigated the clinicopathological and immunophenotypic features of nine cases. There were five men and four women, with ages ranging from 58 years to 82 years. The tumour size varied from 10 mm to 50 mm. The head and neck were most commonly involved. Three cases of spiradenocarcinoma and three cases of cylindrocarcinoma showed a salivary gland-type basal cell adenocarcinoma-like pattern, low-grade (BCAC-LG) and/or high grade (BCAC-HG). The remaining three cases of spiradenocarcinoma showed adenocarcinoma in situ, with invasive adenocarcinoma being seen in one of these cases. PAS staining revealed loss of the PAS-positive hyaline sheath in malignant zones of cylindrocarcinoma. p53 staining was variably positive in the malignant components of all cases. Follow-up was available for all patients, ranging from 5 months to 107 months. Two patients died of disease, one experienced recurrence, and one died of an unrelated cause. CONCLUSIONS: Patients with BCAC-LG have a better prognosis. BCAC-HG is more likely to be found in cylindrocarcinoma, and its clinical behaviour seems to be more aggressive. Close follow-up for early detection of recurrence and metastases is strongly recommended. PMID- 24796386 TI - Accessory vein obliteration criteria for immature fistulae: a modest proposal for an old paradigm. AB - Venous stenosis and/or presence of accessory vein (av) are the two most common causes of early fistula failure. While treatment of stenosis is better defined, there are no clear criteria for obliteration of the av. Often, interventionalists rely on visual assessment of flow through the av and its diameter (significant if > 1/3 of the main fistula diameter) for intervention. The purpose of this study was to establish objective criteria for the management of av. Various computational fluid dynamics simulations were performed to analyze blood flow in the arteriovenous fistula (AVF). av of different diameters and angles was then added at various locations in the AVF and comparison of simulation results was undertaken. The computational model revealed that when the av was 33% of the diameter of the AVF, flow in av was only 7%. When diameter of the av was increased to 50% and 66% of the diameter of the AVF, flow through the av was 10% and 31% of the flow in main AVF, respectively. Location or angle of take-off of av did not alter flow. This report provides objective information regarding criteria for av obliteration. It needs to be further validated in randomized clinical trials. PMID- 24796387 TI - Relationship between angiotensin-converting enzyme gene polymorphism and respiratory distress syndrome in premature neonates. AB - OBJECTIVE: The aim of this study was to investigate the possible relationship between angiotensin-converting enzyme (ACE) gene polymorphism (D/D and I/D genotypes) and respiratory distress syndrome (RDS) in preterm neonates. STUDY DESIGN: Our study included 120 preterm neonates (<37 weeks of gestation) with RDS (the patient group) and 120 preterm neonates without RDS (the control group). Blood samples were obtained from patients and control groups, and ACE gene polymorphism was analysed using the polymerase chain reaction method. RESULTS: D/D genotype was highly significant in the patient group compared with the control group (48.3% of RDS group vs 20% of the control group, P < 0.001). Meanwhile, I/D and I/I genotypes were significantly higher in the control group (75% and 5% of the control group vs 50% and 1.7% of the patient group, P < 0.001). D/D genotype was highly significant in neonates with bronchopulmonary dysplasia (BPD) compared with I/D genotype (P = 0.001). CONCLUSION: Our results may suggest that D/D genotype is associated with increased risk of RDS and BPD development in preterm neonates. PMID- 24796389 TI - Tropical Medicine & International Health June 2014. PMID- 24796390 TI - Synthesis and antifungal activity of benzamidine derivatives carrying 1,2,3 triazole moieties. AB - Eighteen novel benzamidine derivatives containing 1,2,3-triazole moieties were synthesized. The in vitro and in vivo fungicidal acitivities of the title compounds and the arylamidine intermediates against Colletotrichum lagenarium and Botrytis cinerea were tested. The synthesized benzamidines exhibited weak antifungal activities in vitro against the tested fungi, but some of the compounds showed excellent activities in vivo to the same strains. Among the compounds tested, 9b showed 79% efficacy in vivo against C. lagenarium at a concentration of 200 MUg/mL, and the efficacy of compound 16d (90%) toward the same strain was even superior than that of the commercial fungicide carbendazim (85%). PMID- 24796391 TI - Codeine in mothers and children: where are we now? PMID- 24796392 TI - Resistance to phytopathogens e tutti quanti: placing plant quantitative disease resistance on the map. PMID- 24796393 TI - Changes in antioxidants are critical in determining cell responses to short- and long-term heat stress. AB - Heat stress can have deleterious effects on plant growth by impairing several physiological processes. Plants have several defense mechanisms that enable them to cope with high temperatures. The synthesis and accumulation of heat shock proteins (HSPs), as well as the maintenance of an opportune redox balance play key roles in conferring thermotolerance to plants. In this study changes in redox parameters, the activity and/or expression of reactive oxygen species (ROS) scavenging enzymes and the expression of two HSPs were studied in tobacco Bright Yellow-2 (TBY-2) cells subjected to moderate short-term heat stress (SHS) and long-term heat stress (LHS). The results indicate that TBY-2 cells subjected to SHS suddenly and transiently enhance antioxidant systems, thus maintaining redox homeostasis and avoiding oxidative damage. The simultaneous increase in HSPs overcomes the SHS and maintains the metabolic functionality of cells. In contrast the exposure of cells to LHS significantly reduces cell growth and increases cell death. In the first phase of LHS, cells enhance antioxidant systems to prevent the formation of an oxidizing environment. Under prolonged heat stress, the antioxidant systems, and particularly the enzymatic ones, are inactivated. As a consequence, an increase in H2 O2 , lipid peroxidation and protein oxidation occurs. This establishment of oxidative stress could be responsible for the increased cell death. The rescue of cell growth and cell viability, observed when TBY-2 cells were pretreated with galactone-gamma-lactone, the last precursor of ascorbate, and glutathione before exposure to LHS, highlights the crucial role of antioxidants in the acquisition of basal thermotolerance. PMID- 24796394 TI - Third-degree burn from cooled radiofrequency ablation of medial branch nerves for treatment of thoracic facet syndrome. AB - Radiofrequency ablation of medial branch nerves is considered a safe and effective treatment for chronic facet joint pain in the cervical, thoracic, and lumbosacral spine. Cooled radiofrequency ablation (C-RFA) is gaining popularity over conventional thermal radiofrequency ablation (RFA) in pain management. However, complications of C-RFA have not been reported in the literature. We present a first report of third-degree skin burn resulting from C-RFA electrode use for the treatment of facet syndrome. A 61-year-old woman (BMI of 21.8 kg/m(2) ) with thoracic facet syndrome underwent C-RFA of the T1-4 medial branch nerves (Thoracool System, Baylis Medical Company, Montreal, QC, Canada). Lesioning at the superior-lateral aspect of the thoracic transverse processes at each level was performed. During lesioning of the T2 MBN on the T3 transverse process, skin blanching 15 mm in diameter was noted around the introducer needle with patient complaints of severe, localized pain. Postprocedurally the skin injury at this level worsened in appearance, with a 20 mm * 4 mm skin defect, which took nearly 5 months to heal. With C-RFA, internally cooled electrodes are capable of creating large volume spherical lesions, a size advantage over conventional RFA. Although C-RFA lesion size may overcome the anatomic variability of target nerve location and potentially improve pain outcomes, added vigilance is required in thin patients and in anatomic regions of minimal subcutaneous tissue between the lesion target and the dermis. Skin burns at the site of the RF electrode are a potential risk under such conditions. PMID- 24796396 TI - Electronic cigarettes: time for an accurate and evidence-based debate. PMID- 24796395 TI - Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. AB - Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo. PMID- 24796397 TI - A 0.05 BAC limit in the United States: an important challenge for policy, health and safety. PMID- 24796398 TI - An argument for prioritizing drivers above the current illegal limit in the United States. PMID- 24796399 TI - A better path to progress on drunk driving. PMID- 24796401 TI - Commentary on Sims et al. (2014) and Langley et al. (2014): mass media campaigns require adequate and sustained funding to change population health behaviours. PMID- 24796400 TI - Response to commentaries on 0.05 blood alcohol concentration (BAC) limit. PMID- 24796404 TI - Use and reimbursement of off-label drugs in pediatric anesthesia: the Italian experience. AB - BACKGROUND: Most of the drugs used in anesthesia are off-label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market). OBJECTIVE: Define a list of medicinal products commonly used off-label in pediatrics anesthesia to be reimbursed by Italian National Health System. METHODS AND RESULTS: We hereby describe the methodological framework used to allow reimbursed use of a list of medicinal products, widely used off-label in pediatric patients, ensuring the best therapeutic results with the lowest possible risk for children. A task force of pediatric anesthesiologists from Italy petitioned the Italian Medicines Agency (AIFA) to allow a number of commonly utilized but off-label drugs for pediatric anesthesia to be reimbursed for specific indications. For each drug, both the supporting literature and expert opinion were used, and the resulting list of drugs allowed to be used/reimbursed officially by AIFA was significantly expanded. This paper documents one approach to the problem of off-label use of drugs for pediatric patients that can be a model for future efforts. CONCLUSION: Continuous efforts are needed from government institutions and sponsors on drug development and on drug approval process in pediatrics, as research on drug effectiveness and safety is mandatory in children as in adults. At the same time, clinicians must become more familiar with the drug-approval process, participate to sponsored trials, and perform ztrials themselves. PMID- 24796405 TI - Multichannel intraesophageal impedance pattern of children with aerophagia. AB - BACKGROUND: Childhood aerophagia is defined by the Rome III criteria as two or more of the following symptoms; air swallowing, abdominal distension due to intraluminal air, or repetitive belching and/or flatus. The aim of this study was to determine the multichannel intraesophageal impedance (MII) pattern in children suffering from aerophagia. METHODS: We compared the MII tracings of five children with aerophagia according to Rome III criteria (three girls, median age 7 years) to five controls (three girls, median age 8 years). Controls underwent MII for symptoms of gastro-esophageal reflux, and had normal findings. Liquid swallows (LS), air swallows (AS), mixed swallows (MS) and supragastric belching (SGB) were recorded. Meals were excluded from the analysis. All MII parameters were separately analyzed in the upright and recumbent position. All data are reported as median number of events per hour. KEY RESULTS: There was no difference in the total number of LS and MS between the two groups. However, the total number of AS in patients was significantly higher than in controls (26/h vs 5.5/h, p < 0.05) but only in the upright position (46/h vs 8.2 in control group, p < 0.05). SGB was noted only in patients with aerophagia (2.6/h vs 0/h, p < 0.01). CONCLUSIONS & INFERENCES: Children suffering from aerophagia have a specific MII pattern with an increased frequency of air swallows in the upright position and supragastric belching. MII may be used as a tool to confirm diagnosis of aerophagia in children. PMID- 24796406 TI - Descriptions and interpretations of the ACCORD-Lipid trial in the news and biomedical literature: a cross-sectional analysis. AB - The lipid component of the Action to Control Cardiovascular Risk in Diabetes (ACCORD-Lipid) trial was a landmark, publicly funded study demonstrating that fenofibrate, when added to statin therapy, was not associated with improved cardiovascular outcomes among patients with diabetes mellitus. We performed a cross-sectional study of all articles describing the results of ACCORD-Lipid in the news and biomedical literature in the 15 months following its publication. For articles published in biomedical journals, we determined whether there was an association between authors' conflicts of interest and trial interpretation. We identified 67 news articles and 141 biomedical journal articles discussing ACCORD Lipid. Approximately 30% of news and biomedical journal articles described fenofibrate as ineffective, whereas nearly 20% concluded it was effective. Among articles making a recommendation, approximately 50% of news and 67% of biomedical journal articles supported continued fibrate use. Authors with conflicts of interest were more likely to describe fenofibrate as effective (27.1% vs 8.9%; relative risk, 3.03; 95% CI, 1.22-7.50; P = .008) and support continued fibrate use (77.4% vs 45.8%; 1.69; 1.07-2.67; P = .006). The ACCORD-Lipid trial was described inconsistently in news and biomedical journal articles, possibly creating uncertainty among patients and physicians. In addition, conflicts of interest were associated with more favorable trial interpretation. PMID- 24796407 TI - Chemically induced synaptic activity between mixed primary hippocampal co cultures in a microfluidic system. AB - Primary neuronal cultures are an invaluable in vitro tool for examining the fundamental physiological changes that occur in diseases of the central nervous system. In this work, we have used a microfluidic device to grow twin cultures of primary hippocampal neuronal/glia cells which are synaptically connected but environmentally isolated. Immunocytochemical staining, for beta-III-Tubulin and synaptophysin, indicated that the two neuronal populations were physically connected and that synapses were present. By dispensing predefined volumes of fluids into the device inlets, one culture was chemically stimulated and the consequent increase in neuronal activity in the opposing culture was monitored using calcium imaging. To optimise the experimental procedures, we validated a numerical model that estimates the concentration distribution of substances under dynamic fluidic conditions, proposing that no cross contamination of chemical stimuli occurred during the experiments. Calcium imaging and local chemical stimulation were used to confirm synaptic connectivity between the cultures. Chemical stimulation of one population, using KCl or glutamate, resulted in a significant increase of calcium events in both neurons and astrocytes of the connected population. The integration of the system and techniques described here presents a novel methodology for probing the functional synaptic connectivity between mixed primary hippocampal co-cultures, creating an in vitro testing platform for the high-throughput investigation of synaptic activity modulation either by novel compounds or in in vitro disease models. PMID- 24796408 TI - Activation of a carbonyl compound by halogen bonding. AB - Using a prototypical Diels-Alder reaction as benchmark, we show that dicationic halogen-bond donors are capable of activating a neutral organic substrate. By various comparison experiments, the action of traces of acid or of other structural features of the halogen-bond donor not related to halogen bonding are excluded with high certainty. PMID- 24796409 TI - Childhood wheeze phenotypes show less than expected growth in FEV1 across adolescence. AB - RATIONALE: Better characterization of childhood wheeze phenotypes using newer statistical methods provides a basis for addressing the heterogeneity of childhood asthma. Outcomes of these phenotypes beyond childhood are unknown. OBJECTIVES: To determine if adolescent respiratory symptoms, lung function, and changes in lung function over adolescence differ by childhood wheeze phenotypes defined through latent class analysis. METHODS: A prospective birth cohort (Melbourne Atopy Cohort Study) followed 620 high allergy-risk children, recording respiratory symptoms and spirometry at 12 and 18 years. Regression analyses identified relationships between wheeze phenotypes (never/infrequent, early transient, early persistent, intermediate onset, and late onset) and lung function, change in lung function (12-18 yr), respiratory symptoms, and asthma. The baseline classification was never/infrequent wheeze. MEASUREMENTS AND MAIN RESULTS: Deficits in expected growth of lung function, measured by change in prebronchodilator FEV1 between 12 and 18 years, were found for early persistent (reduced 290 ml; 95% confidence interval [CI], 82-498), intermediate-onset (reduced 210 ml; 95% CI, 62-359), and late-onset wheeze (reduced 255 ml; 95% CI, 69-442). Intermediate-onset wheezers had persistent FEV1 deficit after bronchodilator at 18 years (reduced 198 ml; 46,350). Current asthma risk was increased for all phenotypes except early transient, which was also not associated with lung function deficits at 12 or 18 years. CONCLUSIONS: Persistent wheeze phenotypes in childhood were associated with reduced growth in prebronchodilator FEV1 over adolescence. Intermediate-onset wheezers showed irreversible airflow limitation by 18 years. Conversely, early transient wheeze was a benign condition with no sequelae for respiratory health by age 18. PMID- 24796410 TI - Factors influencing the peripheral venous catheter survival in critically ill children in a pediatric intensive care unit. AB - OBJECTIVES: To study the duration of the peripheral venous catheter access and the effect of variables such as intravenous fluid, medications and blood products on the life span of the catheter in authors' pediatric intensive care unit. METHODS: All peripheral intravenous lines established in sick children aged 1 mo to 15 y admitted to authors' intensive care were included and details of cannula gauge, insertion site, sampling, drugs administered and the mode of administration were noted. The cannulas were monitored regularly for signs of infiltration till removal. The time of insertion and removal along with the reason for termination was noted and the life span was calculated. Mann Whitney test was used to test for differences in median survival time with respect to drugs administered and Kaplan Meir survival analysis was used to compare the survival of the cannula at different time periods for each drug. RESULTS: One hundred seventy four catheters were placed on 102 children aged 1 mo to 15 y over a period of 2 mo; of which 63 got infiltrated. The mean life span of the catheter was 39 + 24.4 h. Administration of phenytoin (13.2 vs. 40 h, p = 0.000) and mannitol (14.5 vs. 80 h, p = 0.034) significantly decreased the survival and infusion of blood (66.5 vs. 31.5 h, p = 0.002) prolonged the survival of the catheters. CONCLUSIONS: The catheters in the index study lasted on an average for 39 h. Phenytoin, mannitol, blood and blood products were found to significantly influence the survival of the catheters. PMID- 24796412 TI - Successfully treated fingertip necrosis in an infant with primary Raynaud phenomenon. PMID- 24796411 TI - Predictors of altered sensorium at admission in children with diabetic ketoacidosis. AB - OBJECTIVE: To predict factors causing altered sensorium at admission in children with diabetic ketoacidosis (DKA). METHODS: This retrospective study was done on 139 children with DKA who presented to Pediatric Emergency of a tertiary care hospital between January 2008 and November 2012. The case records were reviewed and information regarding personal details, clinical features, biochemical parameters and outcome was recorded. Statistical analyses were performed in small STATA version 12. Variables associated with altered sensorium in bivariate analysis (P < 0.05) were selected for inclusion in the multivariable logistic regression model. RESULTS: Mean age was 8.04 +/- 4.1 y; Male: Female ratio 0.75:1. The newly diagnosed diabetics were 54.6 % whereas rest were known diabetics. Eighty one percent children in severe DKA, 63 % moderate DKA and 18 % mild DKA had altered sensorium at admission. Univariate analysis revealed significant P values (P < 0.05) for pH and degree of dehydration. Results of final multivariate logistic regression revealed significant P values for pH (for pH 7.1-7.2, AOR-5.47, 95 % CI-1.24-24.1, P = 0.025 and for pH <7.1, AOR-14.19, 95 % CI - 4.13-48.7, P = 0.001) using pH >7.2 as the reference category. CONCLUSIONS: Alteration in sensorium in children at initial admission with DKA is associated to low blood pH. ROC curve suggested good discrimination of pH for prediction of altered sensorium. The exact pathophysiologic mechanism of how low pH alters sensorium in DKA is still unknown and requires further studies. PMID- 24796413 TI - Advances in management of neonatal seizures. AB - Seizures are more common in the neonatal period than any other time in the human lifespan. A high index of suspicion for seizures should be maintained for infants who present with encephalopathy soon after birth, have had a stroke, central nervous system (CNS) infection or intracranial hemorrhage or have a genetic or metabolic condition associated with CNS malformations. Complicating the matter, most neonatal seizures lack a clinical correlate with only subtle autonomic changes and often no clinical indication at all. Over the last three decades, several tools have been developed to enhance the detection and treatment of neonatal seizures. The use of electroencephalography (EEG) and the later development of amplitude-integrated EEG (aEEG), allows for Neurologists and non Neurologists alike, to significantly increase the sensitivity of seizure detection. When applied to the appropriate clinical setting, time to diagnosis and start of therapy is greatly reduced. Phenobarbital maintains the status of first-line therapy in worldwide use. However, newer anti-epileptic agents such as, levetiracetam, bumetanide, and topiramate are increasingly being applied to the neonatal population, offering the potential for seizure treatment with a significantly better side-effect profile. Seizures in premature infants, continue to confound clinicians and researchers alike. Though the apparent seizure burden is significant and there is an association between seizures and adverse outcomes, the two are not cleanly correlated. Compounding the issue, GABA-ergic anti epileptic drugs are not only less effective in this age group due to reversed neuronal ion gradients but may cause harm. Selecting an appropriate treatment group remains a challenge. PMID- 24796414 TI - The mechanochemistry of cytoskeletal force generation. AB - In this communication, we propose a model to study the non-equilibrium process by which actin stress fibers develop force in contractile cells. The emphasis here is on the non-equilibrium thermodynamics, which is necessary to address the mechanics as well as the chemistry of dynamic cell contractility. In this setting, we are able to develop a framework that relates (a) the dynamics of force generation within the cell and (b) the cell's response to external stimuli to the chemical processes occurring within the cell, as well as to the mechanics of linkage between the stress fibers, focal adhesions and extracellular matrix. PMID- 24796416 TI - A multiplex PCR assay for simultaneous detection of Escherichia coli O157:H7, Bacillus cereus, Vibrio parahaemolyticus, Salmonella spp., Listeria monocytogenes, and Staphylococcus aureus in Korean ready-to-eat food. AB - A multiplex polymerase chain reaction (PCR) assay was developed for simultaneous detection of Escherichia coli O157:H7, Bacillus cereus, Vibrio parahaemolyticus, Salmonella spp., Listeria monocytogenes, and Staphylococcus aureus in various Korean ready-to-eat foods. The six specific primer pairs for multiplex PCR were selected based on the O157 antigen (rfbE) gene of E. coli O157:H7, the DNA gyrase subunit B (gyrB) gene of B. cereus, the toxin regulatory protein (toxR) gene of V. parahaemolyticus, the invasion protein A (invA) gene of Salmonella spp., the hemolysin (hly) gene of L. monocytogenes, and the thermonuclease (nuc) gene of S. aureus. The 16S rRNA gene was targeted as an internal control gene in the presence of bacterial DNA. The specificity and sensitivity assays for multiplex primer pairs were investigated by testing different strains. When this multiplex PCR assay was applied to evaluate the validity of detecting six foodborne pathogens in artificially inoculated several ready-to-eat food samples, the assay was able to specifically simultaneously detect as few as 1 colony-forming unit/mL of each pathogen after enrichment for 12 h. Their presence in naturally contaminated samples also indicates that the developed multiplex PCR assay is an effective and informative supplement for practical use. PMID- 24796415 TI - IL-21 induces IL-22 production in CD4+ T cells. AB - Interleukin (IL)-22 produced by innate lymphoid cells (ILCs) and CD4+ T cells plays an important role in host defence and mucosal homeostasis, thus it is important to investigate the mechanisms that regulate IL-22 production. We investigated the regulation IL-22 production by CD4+ T cells. Here we show that IL-21 triggers IL-22, but not IL-17 production by CD4+ T cells. STAT3, activated by IL-21, controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Moreover, IL-21 and AhR signalling in T cells control IL-22 production and the development of dextran sodium sulphate induced colitis in ILC-deficient mice. Thus, we have identified IL-21 as an inducer of IL-22 production in CD4+ T cells in vitro and in vivo. PMID- 24796418 TI - Transient gene expression in tobacco using Gibson assembly and the Gene Gun. AB - In order to target a single protein to multiple subcellular organelles, plants typically duplicate the relevant genes, and express each gene separately using complex regulatory strategies including differential promoters and/or signal sequences. Metabolic engineers and synthetic biologists interested in targeting enzymes to a particular organelle are faced with a challenge: For a protein that is to be localized to more than one organelle, the engineer must clone the same gene multiple times. This work presents a solution to this strategy: harnessing alternative splicing of mRNA. This technology takes advantage of established chloroplast and peroxisome targeting sequences and combines them into a single mRNA that is alternatively spliced. Some splice variants are sent to the chloroplast, some to the peroxisome, and some to the cytosol. Here the system is designed for multiple-organelle targeting with alternative splicing. In this work, GFP was expected to be expressed in the chloroplast, cytosol, and peroxisome by a series of rationally designed 5' mRNA tags. These tags have the potential to reduce the amount of cloning required when heterologous genes need to be expressed in multiple subcellular organelles. The constructs were designed in previous work(11), and were cloned using Gibson assembly, a ligation independent cloning method that does not require restriction enzymes. The resultant plasmids were introduced into Nicotiana benthamiana epidermal leaf cells with a modified Gene Gun protocol. Finally, transformed leaves were observed with confocal microscopy. PMID- 24796419 TI - Facile fabrication of hierarchical ZnCo2O4/NiO core/shell nanowire arrays with improved lithium-ion battery performance. AB - We report a facile and controllable strategy for the fabrication of three dimensional (3D) ZnCo2O4/NiO core/shell nanowire arrays (ZCO/NiO NWs) on nickel (Ni) foam substrates by a simple, cost-effective, two-step, solution-based method. Ultra-thin NiO nanosheets are revealed to grow uniformly on the porous ZnCo2O4 nanowires with many interparticle mesopores, resulting in the formation of 3D core/shell nanowire arrays with hierarchical architecture. In comparison with the pristine ZnCo2O4 nanowire arrays (ZCO NWs), the ZCO/NiO NWs exhibit significantly improved Li storage properties, in terms of higher capacity, enhanced rate capability and improved cycling stability when applied as binders and additive-free anode materials for lithium-ion batteries. The superior Li storage performance of the ZCO/NiO NWs could be attributed to the synergetic effect between the ZnCo2O4 core and the NiO shell, as well as its unique hierarchical architecture, which ensures a large specific surface area and good conductivity. Our results may offer very useful guidelines in scrupulously designing 3D core/shell nanowire-array electrodes using cheap, earth-abundant materials in energy storage applications. PMID- 24796422 TI - Therapeutic potential of thiazolidinedione-8 as an antibiofilm agent against Candida albicans. AB - Candida albicans is known as a commensal microorganism but it is also the most common fungal pathogen in humans, causing both mucosal and systemic infections. Biofilm-associated C. albicans infections present clinically important features due to their high levels of resistance to traditional antifungal agents. Quorum sensing is closely associated with biofilm formation and increasing fungal pathogenicity. We investigated the ability of the novel bacterial quorum sensing quencher thiazolidinedione-8 (S-8) to inhibit the formation of, and eradication of mature C. albicans biofilms. In addition, the capability of S-8 to alter fungal adhesion to mammalian cells was checked. S-8 exhibited specific antibiofilm and antiadhesion activities against C. albicans, at four- to eightfold lower concentrations than the minimum inhibitory concentration (MIC). Using fluorescence microscopy, we observed that S-8 dose-dependently reduces C. albicans-GFP binding to RAW macrophages. S-8 at sub-MICs also interfered with fungal morphogenesis by inhibiting the yeast-to-hyphal form transition. In addition, the tested agent strongly affected fungal cell wall characteristics by modulating its hydrophobicity. We evaluated the molecular mode of S-8 antibiofilm and antiadhesion activities using real-time RT-PCR. The expression levels of genes associated with biofilm formation, adhesion and filamentation, HWP1, ALS3 and EAP1, respectively, were dose-dependently downregulated by S-8. Transcript levels of UME6, responsible for long-term hyphal maintenance, were also significantly decreased by the tested agent. Both signaling pathways of hyphal formation-cAMP-PKA and MAPK-were interrupted by S-8. Their upstream general regulator RAS1 was markedly suppressed by S-8. In addition, the expression levels of MAPK cascade components CST20, HST7 and CPH1 were downregulated by S-8. Finally, transcriptional repressors of filament formation, TUP1 and NRG1, were dramatically upregulated by our compound. Our results indicate that S-8 holds a novel antibiofilm therapeutic mean in the treatment and prevention of biofilm associated C. albicans infections. PMID- 24796423 TI - Power and control in interactions between journalists and health-related industries: the view from industry. AB - The mass media is a major source of health information for the public, and as such the quality and independence of health news reporting is an important concern. Concerns have been expressed that journalists reporting on health are increasingly dependent on their sources--including representatives of industries responsible for manufacturing health-related products--for story ideas and content. Many critics perceive an imbalance of power between journalists and industry sources, with industry being in a position of relative power, however the empirical evidence to support this view is limited. The analysis presented here--which is part of a larger study of industry-journalist relationships--draws on in-depth, semi-structured interviews with representatives of health-related industries in Australia to inductively examine their perceptions of power relations between industry and journalists. Participants painted a picture in which journalists, rather than themselves, were in a position to control the nature, extent, and outcome of their interactions with industry sources. Our results resonate with the concept of "mediatisation" as it has been applied in the domain of political reporting. It appears that, from the perspective of industry representatives, the imposition of media logic on health-related industries may inappropriately influence the information that the public receives about health-related products. PMID- 24796424 TI - A random blend: the self in Philip Larkin's poems "Ambulances" and "The Building". AB - In two of his great poems, "Ambulances" and "The Building," Philip Larkin considers a deep fear about human individuality. The fear is that the human self is contingent and disjunctive, lacking any integrity or unity. The arrival of an ambulance on an urban curb and a visit to the hospital are the occasion of reflection on this form of human fragility. But more significant, the ambulance and the hospital are imagined as contexts in which the contingency of the human individual is brought out and laid before us. PMID- 24796425 TI - Odd complaints and doubtful conditions: norms of hypochondria in Jane Austen and Catherine Belling. AB - In her final fragmentary novel Sanditon, Jane Austen develops a theme that pervades her work from her juvenilia onward: illness, and in particular, illness imagined, invented, or self-inflicted. While the "invention of odd complaints" is characteristically a token of folly or weakness throughout her writing, in this last work imagined illness is also both a symbol and a cause of how selves and societies degenerate. In the shifting world of Sanditon, hypochondria is the lubricant for a society bent on turning health into a commodity. As a result, people's rationality and their moral character come under attack. Catherine Belling's recent subtle study, A Condition of Doubt: The Meanings of Hypochondria, unveils hypochondria's discursive and cultural character. Running sharply against the tenor of Austen's treatment, however, she argues in defense of the rationality of hypochondriacs; the notion that the condition may involve morally significant defects is not entertained; any connection to the commercialization of health care is muted. Here, I contrast Austen's morally and epistemically negative rendering of her hypochondriacal characters in Sanditon with Belling's efforts to create a sympathetic understanding of people with hypochondria. I will argue that, despite time gaps and genre differences, joint consideration of these texts can help bioethicists better appreciate how medicine can intensify, pathologize, and exploit anxieties about illness and death, thus adding to the challenges of living well in the face of mortality and morbidity. PMID- 24796427 TI - A retrospective analysis of surgical site infections after chlorhexidine-alcohol versus iodine-alcohol for pre-operative antisepsis. AB - BACKGROUND: Surgical site infection (SSI) is the most common hospital-acquired infection in the Netherlands. There is little evidence in regard to differences in the efficacy of pre-operative topical antisepsis with iodine-alcohol as compared with chlorhexidine-alcohol for preventing SSI. METHODS: We conducted a retrospective analysis at a single center, involving all patients who underwent breast, colon, or vascular surgery in 2010 and 2011, in which pre-operative disinfection of the skin was done with iodine-alcohol in 2010 and with chlorhexidine-alcohol in 2011. Demographic characteristics, surgical parameters, and rates of SSI were compared in the two groups of patients. Subgroup analyses were done for wound classification, wound type, and type of surgery performed. Associations of patient characteristics with SSI were also investigated. Data were analyzed with chi(2) tests, Student t-tests, and logistic regression analysis. RESULTS: No statistically significant difference was found in the rates of SSI in the two study groups, at 6.1% for the patients who underwent antisepsis with iodine-alcohol and 3.8% for those who underwent disinfection with chlorhexidine-alcohol (p=0.20). After multivariable analysis, an odds ratio (OR) of 0.68 (95% confidence interval [CI] 0.30-1.47) in favor of chlorhexidine alcohol was found. Male gender, acute surgery, absence of antibiotic prophylaxis, and longer hospital length of stay (LOS) were all associated with SSI after pre operative topical antisepsis. CONCLUSION: In this single-center study conducted over a course of one year with each of the preparations investigated, no difference in the rate of SSI was found after an instantaneous protocol change from iodine-alcohol to chlorhexidine-alcohol for pre-operative topical antisepsis. PMID- 24796428 TI - Diffusional kurtosis imaging reveals a distinctive pattern of microstructural alternations in idiopathic generalized epilepsy. AB - OBJECTIVES: Idiopathic generalized epilepsy (IGE) arises from paroxysmal dysfunctions of the thalamo-cortical network. One of the hallmarks of IGE is the absence of visible abnormalities on routine magnetic resonance imaging (MRI). However, recent quantitative MRI studies showed cortical-subcortical structural abnormalities in IGE, but the extent of abnormalities has been inconsistent in the literature. The inconsistencies may be associated with complex microstructural abnormalities in IGE that are not completely detectable using conventional diffusion tensor imaging methods. The goal of this study was to investigate white-matter (WM) microstructural abnormalities in patients with IGE using diffusional kurtosis imaging (DKI). MATERIALS AND METHODS: We obtained DKI and volumetric T1-weighted images from 14 patients with IGE and 25 matched healthy controls. Using tract-based spatial statistics, we performed voxel-wise group comparisons in the parametric maps generated from DKI: mean diffusivity (MD), fractional anisotropy (FA), and mean kurtosis (MK), and in probabilistic maps of WM volume generated by voxel-based morphometry. RESULTS: We observed that conventional microstructural measures (MD and FA) revealed WM abnormalities in thalamo-cortical projections, whereas MK disclosed a broader pattern of WM abnormalities involving thalamo-cortical and cortical-cortical projections. CONCLUSIONS: Even though IGE is traditionally considered a 'non-lesional' form of epilepsy, our results demonstrated pervasive thalamo-cortical WM microstructural abnormalities. Particularly, WM abnormalities shown by MK further extended into cortical-cortical projections. This suggests that the extent of microstructural abnormalities in thalamo-cortical projections in IGE may be better assessed through the diffusion metrics provided by DKI. PMID- 24796429 TI - Deployment of remote advanced electrocardiography for improved cardiovascular risk assessment in career firefighters. AB - INTRODUCTION: Firefighters perform strenuous muscular work while wearing heavy, encapsulating personal protective equipment in high temperature environments, under chaotic and emotionally stressful conditions. These factors can precipitate sudden cardiac events in firefighters with underlying cardiovascular disease. The purpose of this pilot study was to deploy and explore the feasibility of the resting "advanced" 12-lead electrocardiogram (A-ECG) as a remote firefighter risk assessment tool for improved assessment of cardiac risk. MATERIALS AND METHODS: Conventional 12-lead resting electrocardiograms (ECGs) were collected for 5 min by using high-fidelity PC-based ECG hardware and software while subjects (n=21) rested comfortably. Raw data from the ECG system were securely transported via a secure network to a server where they were archived and processed. Authorized personnel performed both conventional ECG and A-ECG analyses from each digital recording, generating A-ECG "scores" in a blinded fashion. A separate cohort of firefighters (n=6) was trained to administer the A-ECG and rated the system's usability and frequency of technical problems. RESULTS: Of the 21 uniformed personnel who completed testing, only 1 had a positive A-ECG score for coronary artery disease, which was subsequently confirmed by a cardiologist. All other subjects were classified as healthy by A-ECG. Firefighters trained to administer the A-ECG responded favorably in rating the usability of the system. CONCLUSIONS: We have demonstrated that a new technology, A-ECG, can be deployed for remote firefighter risk assessment being performed by firefighters themselves and interpreted centrally. This simple, time- and cost-effective approach can help identify individuals potentially at increased risk for line-of-duty death due to underlying cardiovascular disease. PMID- 24796430 TI - Changes in the bacterial community of soil from a neutral mine drainage channel. AB - Mine drainage is an important environmental disturbance that affects the chemical and biological components in natural resources. However, little is known about the effects of neutral mine drainage on the soil bacteria community. Here, a high throughput 16S rDNA pyrosequencing approach was used to evaluate differences in composition, structure, and diversity of bacteria communities in samples from a neutral drainage channel, and soil next to the channel, at the Sossego copper mine in Brazil. Advanced statistical analyses were used to explore the relationships between the biological and chemical data. The results showed that the neutral mine drainage caused changes in the composition and structure of the microbial community, but not in its diversity. The Deinococcus/Thermus phylum, especially the Meiothermus genus, was in large part responsible for the differences between the communities, and was positively associated with the presence of copper and other heavy metals in the environmental samples. Other important parameters that influenced the bacterial diversity and composition were the elements potassium, sodium, nickel, and zinc, as well as pH. The findings contribute to the understanding of bacterial diversity in soils impacted by neutral mine drainage, and demonstrate that heavy metals play an important role in shaping the microbial population in mine environments. PMID- 24796431 TI - Superiority of total white blood cell count over other leukocyte differentials for predicting long-term outcomes in patients with non-ST elevation acute coronary syndrome. AB - CONTEXT: Leukocytes have been found to be the predictor of outcome following acute coronary syndrome (ACS). OBJECTIVE: We sought to determine the relationship between leukocyte differentials and developing major adverse cardiac events (MACE) in patients with non-ST elevation ACS (NSTE-ACS). MATERIALS AND METHODS: A total of 490 consecutive patients were enrolled, and MACE incidence was evaluated at long-term follow-up period. RESULTS: Total white blood cell (WBC) was higher in subjects occurring MACE. Moreover, elevated total WBC, >=7.5 * 10(3)/uL, independently predicted MACE. DISCUSSION AND CONCLUSION: Elevated admission total WBC can predict long-term MACE in NSTE-ACS patients better than other differentials. PMID- 24796432 TI - Development of RNA interference-based therapeutics and application of multi target small interfering RNAs. AB - RNA interference (RNAi) has been proven in recent years to be a newly advanced and powerful tool for development of therapeutic agents toward various unmet medical needs such as cancer, in particular, a great attention has been paid to the development of antineoplastic agents. Recent success in clinical trials related to RNAi-based therapeutics on cancer and ocular disease has validated that small interfering RNAs (siRNAs) constitute a new promising class of therapeutics. Currently, a great wealth of multi-target based siRNA structural modifications is available for promoting siRNA-mediated gene silencing with low side effects. Here, the latest developments in RNAi-based therapeutics and novel structural modifications described for siRNAs--in particular multi-target siRNAs- are reviewed. PMID- 24796433 TI - The neuropathology of schizophrenia: new insights from postmortem studies. PMID- 24796434 TI - Permanent post concussion symptoms after mild head injury: a systematic review of age and gender factors. AB - BACKGROUND: Older age and female gender are known factors in the development of persisting post concussion symptoms (PCS) following mild head injury (MHI). Very few studies however have examined these variables in permanent PCS. OBJECTIVE: This systematic review empirically examines the extent to which such factors pertain to this group. METHODS: Systematic electronic data base searches identified all long-term studies of two types: first, those with correlations between age or gender and outcome; second, those providing the mean ages or gender mixes of samples selected for poor outcome and samples not selected for such. RESULTS: Twenty studies from 1341 abstracts were ultimately analysed. Correlation studies showed poorer outcome to be associated with both older age (3/4 studies) and female gender (2/4 studies). Those with poor long-term outcome had a significantly higher mean age (40.6) than non- selected patients (32.5). The proportion of men in selected samples (54.8%) was significantly lower than those in non-selected ones (66.5%). CONCLUSIONS: Older age is a strong vulnerability factor in the development of permanent PCS and female gender is a significant one. PMID- 24796435 TI - Philosophy of mind: coming to terms with traumatic brain injury. AB - INTRODUCTION: Patients and their families struggle with accepting changes in personality after traumatic brain injury (TBI). A neuroanatomic understanding may assist with this process. OBJECTIVES: We briefly review the history of the Western conceptualization of the Self, and discuss how neuroscience and changes in personality wrought by brain injuries modify and enrich our understanding of our selves and our patients. CONCLUSION: The sense of self, while conflated with the concept of a "soul" in Western thinking, is more rationally considered a construct derived from neurophysiologic structures. The self or personality therefore often changes when the brain changes. A neuroanatomic perspective can help patients, families, and clinicians accept and cope with the sequellae of TBI. PMID- 24796436 TI - Clinically important improvements in motor function are achievable during inpatient rehabilitation by stroke patients with severe motor disability: a prospective observational study. AB - BACKGROUND: A good motor outcome after stroke is often equated with independence in functional performance. However, for patients with severe motor disability a good outcome is unlikely, but an important change may be achievable. OBJECTIVE: Determine if patients admitted to inpatient rehabilitation with severe motor disability can achieve clinically important improvements in motor function. METHODS: A prospective observational study of 239 patients with stroke admitted to inpatient rehabilitation in Brisbane, Australia was conducted. On admission and discharge, participants were assessed using the motor items of the Functional Independence Measure (m-FIM). The importance of change achieved on the m-FIM was evaluated according to: 1) a statistical significant outcome; 2) achievement of a MCID based on a physician-anchored rating of change; and 3) shift in disability status e.g., severe to moderate disability. RESULTS: Patients with severe motor disability achieved a significant improvement in motor function (p < 0.001), which saw up to 83% achieve a MCID and 85% shift out of 'severe' to either moderate or mild motor disability on discharge from inpatient rehabilitation. CONCLUSION: This study demonstrates that patients admitted to inpatient rehabilitation with severe motor disability can achieve clinically important improvements in motor function on discharge from inpatient rehabilitation. PMID- 24796437 TI - An organizational approach to reducing and preventing restraint and seclusion use with people with acquired brain injury. AB - INTRODUCTION: Seclusion, restraint (S/R) and coercive practices are used across human service populations, settings, with people of all ages. Their use has been increasingly scrutinized by the public, federal government and the media. Alternatives, interventions, and organizational approaches to these forms of containment are now emerging and advancing practice. AIM/PURPOSE: This article provides an overview of the work conducted to reduce the use of coercion restraint, seclusion and other invasive practices in behavioral health settings that often include the defacto admission of persons with Acquired Brain Injury (ABI). The article also examines treatment culture factors that can exacerbate behavior dysfunction and how to moderate such challenges to prevent the use of S/R procedures among people with ABI. CONCLUSION: Seclusion and restraint can be avoided and greatly reduced in settings serving people with ABI. When S/R use is recognized as an inadequate organizational response to harmful behavior that maintains patterns of aggression or harm, leadership-driven core strategies can be implemented to disrupt the behavioral sequence. The Six Core Strategies(c) provide a prevention based framework to anticipate challenge, intervene early, and analyze the factors that contribute to maintaining the cycle of violence if S/R is used. PMID- 24796438 TI - Post-coma persons with multiple disabilities use assistive technology for their leisure engagement and communication. AB - BACKGROUND: Interventions for post-coma persons, who have emerged from a minimally conscious state but present with extensive neuro-motor impairment and lack of or minimal verbal skills, need to promote occupation and communication through the use of assistive technology. OBJECTIVE: These two studies were aimed at assessing two technology-aided programs to promote leisure engagement and communication for three post-coma participants with multiple disabilities. METHODS: Study I assessed a program to allow a woman and a man with extensive neuro-motor impairment and lack of speech to switch on music and videos, make requests to caregivers, and send messages to (communicate with) relevant partners and receive messages from those partners. Study II assessed a program to allow a post-coma woman with extensive motor impairment and reduced verbal behavior to activate music, videos and requests, send and receive messages, and make telephone calls. RESULTS: Data showed that both programs were successful. The participants of Study I managed leisure engagement, requests, as well as text messaging. The participant of Study II showed consistent leisure engagement, text messaging, and telephone calls. CONCLUSIONS: Assistive technology can be profitably used to provide post-coma persons with multiple disabilities relevant leisure and communication opportunities. PMID- 24796439 TI - Issues of cultural diversity in acquired brain injury (ABI) rehabilitation. AB - INTRODUCTION: With the general population in the United States becoming increasingly diverse, it is important for rehabilitation professionals to develop the capacity to provide culturally sensitive treatment. This is especially relevant when working with minority populations who have a higher risk for brain injury and poorer rehabilitation outcomes. OBJECTIVES: This article presents a number of clinical vignettes to illustrate how cultural factors can influence behavior in patients recovering from brain injury, as well as rehabilitation staff. The main objectives are to raise awareness among clinicians and stimulate research ideas by highlighting some real world examples of situations where a specialized, patient-centered approach needs to consider factors of cultural diversity. CONCLUSION: Because one's own world view impacts the way we see the world and interpret behavior, it is important to understand one's own ethnocentrism when dealing with a diverse population of patients with brain injury where behavioral sequelae are often expected. Being able to see behavior after brain injury with an open mind and taking into account cultural and contextual factors is an important step in developing culturally competent rehabilitation practices. PMID- 24796440 TI - Reliability and validity of the extended timed-get-up-and-go test in patients with bilateral vestibular loss. AB - BACKGROUND: The aim of his study was to evaluate the reliability and validity of the Expanded Timed Get-up-and-Go (ETGUG) test in patients with bilateral vestibular loss (BVL). METHODS: 21 BVL patients (58 +/- 14 years) were recruited and measured twice by two raters. After a one hour break ETGUG was repeated by the first rater. 21 age matched controls (CON; 58 +/- 14 years) were measured once by the first rater. All time scores of the ETGUG for the separate tasks and gait speed calculated from tasks 3 and 5 were analysed to determine relative and absolute reliability, smallest detectable change (SDC) and discriminatory capabilities. RESULTS: The ETGUG scores showed good to excellent inter-rater (ICC2,1 = 0.85-0.97) and test-retest reliability (ICC3,1 = 0.86-0.98) following log-transformation for tasks 2-6. Task1 scored fair r = 0.46-0.68. The SDCs were small (SDC = 0.05-0.21 seconds). Bland-Altman plots demonstrated good agreement between the measurements. There were significant differences between BVL and CON in ETGUG scores for tasks 1, 3, 4, 5, 6 & overall time. Task 2 showed no difference between the groups. BVL patients walked slower compared to the age matched controls. DISCUSSION: Good reliability of the ETGUG in BVL and an indication for the discriminatory capabilities for the separate tasks suggest that the ETGUG could facilitate the study of functional deficits in BVL patients. Good reliability, small measurement error and values of SDC warrant the further utilisation of the ETGUG for the evaluation of physical functioning in BVL patients. PMID- 24796442 TI - Team models in neurorehabilitation: structure, function, and culture change. AB - INTRODUCTION: Neurorehabilitation requires a team effort. Over time the nature of teams has evolved from single discipline work through multi-disciplinary and inter-disciplinary teams to trans-disciplinary teams. However, there are inconsistencies in the literature and clinical practice as to the structure and function of these team models. Each model engenders advantages over its predecessor and unless the models are well understood clinicians may labor in a model that is less efficacious than the most transcendent model. OBJECTIVES: To define and examine the models of single discipline care, multi-disciplinary teams, inter-disciplinary teams, and trans-disciplinary teams and to review in depth trans-disciplinary teams as the most advanced team model. This paper will also consider professional roles and integration across disciplines as well as the crucial topics of staff selection, attendance in rounds and the nature of rounds, staff physical plant assignments, and leadership responsibilities. Leadership responsibilities that will be addressed include scope of practice and role release, peer pressure, and culture change issues. CONCLUSIONS: The trans disciplinary model is the gold standard for teams in neurorehabilitation because they entail more integrated service delivery than do other teams. Trans disciplinary teams also represent a more persons-centered approach. To initiate a trans-disciplinary model, team members must have excellent communication and shared decision making including persons with brain injury. Leadership must address staff selection, scope of practice and role-release. Otherwise, the model will fail due to peer pressure and institutional or program cultural variables. PMID- 24796441 TI - Trunk kinematics during walking in persons with multiple sclerosis: the influence of body weight support. AB - BACKGROUND: Although body weight supported (BWS) treadmill training (TT) leads to some improvements in walking ability, it has not been proven that it is more effective than other walking therapies in persons with multiple sclerosis (PwMS). One possible explanation could be that BWSTT focuses on the cyclic movement of the lower extremities while the trunk is passively suspended in the harness. OBJECTIVE: This study aimed to assess the 3 dimensional trunk and pelvis movements during BWS treadmill walking. METHODS: 14 PwMS and 14 healthy persons (8 male/20 female; age 23 to 59 years) walked with 0%, 10%, 20%, 30%, 50% and 70% BWS. After a familiarization period, kinematic electromagnetic tracking (Polhemus LibertyTM 240/16) of the trunk and pelvis movements was applied. Statistical analysis consisted of a repeated measures ANOVA with simple contrasts (SPSS 20). RESULTS: This study shows that BWS walking leads in general to smaller maximum trunk and pelvis movement amplitudes compared with walking without BWS, this with exception of the pelvis anterior-posterior movement in healthy subjects. CONCLUSION: These data help to identify and isolate the effect of different BWS levels in PwMS and in healthy persons and suggest to use BWS lower than 30% for treadmill training. PMID- 24796443 TI - The Behavioural Assessment of Self-Structuring (BASS): psychometric properties in a post-acute brain injury rehabilitation programme. AB - BACKGROUND: Jackson et al. (this edition) argue that structure is an important component in reducing the handicaps caused by cognitive impairments following acquired brain injury and that post-acute neuropsychological brain injury rehabilitation programmes should not only endeavour to provide structure but also aim to develop self-structuring. However, at present there is no standardized device for assessing self-structuring. OBJECTIVE: To provide preliminary analysis of the psychometric properties of the Behavioural Assessment of Self-Structuring (BASS) staff rating scale (a 26 item informant five point rating scale based on the degree of support client requires to achieve self-structuring item). METHODS: BASS data was utilised for clients attending residential rehabilitation. Reliability (inter-rarer and intra-rater), validity (construct, concurrent and discriminate) and sensitivity to change were investigated. RESULTS: Initial results indicate that the BASS has reasonably good reliability, good construct validity (via principal components analysis), good discriminant validity, and good concurrent validity correlating well with a number of other outcome measures (HoNOS; NPDS, Supervision Rating Scale, MPAI, FIM and FAM). The BASS did not correlate well with the NPCNA. Finally, the BASS was shown to demonstrate sensitivity to change. CONCLUSIONS: Although some caution is required in drawing firm conclusions at the present time and further exploration of the psychometric properties of the BASS is required, initial results are encouraging for the use of the BASS in assessing rehabilitation progress. These findings are discussed in terms of the value of the concept of self-structuring to the rehabilitation process for individuals with neuropsychological impairments consequent on acquired brain injury. PMID- 24796444 TI - Effects of type of health insurance coverage on colorectal cancer survival in Puerto Rico: a population-based study. AB - Colorectal cancer represents a major health problem and an important economic burden in Puerto Rico. In the 1990's, the Commonwealth of Puerto Rico implemented a health care reform through the privatization of the public health system. The goal was to ensure access to health services, eliminate disparities for medically indigent citizens and provide special coverage for high-risk conditions such as cancer. This study estimates the 5-year relative survival rate of colorectal cancer and the relative excess risk of death in Puerto Rico for 2004-2005, by type of health insurance coverage; Government Health Plan vs. Non-Government Health Plan. Colorectal cancer in advanced stages was more common in Government Health Plan patients compared with Non-Government Health Plan patients (44.29% vs. 40.24 had regional extent and 13.58% versus 10.42% had distant involvement, respectively). Government Health Plan patients in the 50-64 (RR = 6.59; CI: 2.85 15.24) and >=65 (RR = 2.4; CI: 1.72-4.04) age-groups had the greater excess risk of death compared with Non-Government Health Plan patients. Further studies evaluating the interplay of access to health services and the barriers affecting the Government Health Plan population are warranted. PMID- 24796446 TI - CT and MRI features of patients with diastematomyelia. AB - OBJECTIVE: To evaluate computed tomography (CT) and magnetic resonance imaging (MRI) features in patients with diastematomyelia and to investigate clinical characteristics of this lesion. STUDY DESIGN: A retrospectively study. SETTING: The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University. METHODS: A total of 82 diastematomyelia cases were retrospectively studied. All the patients underwent neurological examinations as well as MRI and CT of the spine. A self-established neurological functional grading system was used, and posterior tibial nerve somatosensory cortical-evoked potential (PTNSCEP) was measured to assess the neurological status of the patients. Imaging features of symmetry of splitting, presence of septum, location of lesion and number of split segments were studied. The neurological functional grading, PTNSCEP, and imaging findings were then analyzed and compared, and the difference was considered to be significant if P-value was lower than 0.05. RESULTS: Neurological functional grading and latency of PTNSCEP were significantly different but related in terms of symmetry of splitting, presence of septum and location of lesion. Although no significant differences were present in the number of split segments, the severity of the neurological functional grading and PTNSCEP impairment were not related to the number of split segments. CONCLUSION: The imaging features in diastematomyelia are characteristic and relate well with the clinical manifestations according to neurological functional grading and PTNSCEP measurement, except the number of split segments. PMID- 24796445 TI - Knowledge translation and implementation in spinal cord injury: a systematic review. AB - OBJECTIVE: To conduct a systematic review examining the effectiveness of knowledge translation (KT) interventions in changing clinical practice and patient outcomes. METHODS: MEDLINE/PubMed, CINAHL, EMBASE and PsycINFO were searched for studies published from January 1980 to July 2012 that reported and evaluated an implemented KT intervention in spinal cord injury (SCI) care. We reviewed and summarized results from studies that documented the implemented KT intervention, its impact on changing clinician behavior and patient outcomes as well as the facilitators and barriers encountered during the implementation. RESULTS: A total of 13 articles featuring 10 studies were selected and abstracted from 4650 identified articles. KT interventions included developing and implementing patient care protocols, providing clinician education and incorporating outcome measures into clinical practice. The methods (or drivers) to facilitate the implementation included organizing training sessions for clinical staff, introducing computerized reminders and involving organizational leaders. The methodological quality of studies was mostly poor. Only 3 out of 10 studies evaluated the success of the implementation using statistical analyses, and all 3 reported significant behavior change. Out of the 10 studies, 6 evaluated the effect of the implementation on patient outcomes using statistical analyses, with 4 reporting significant improvements. The commonly cited facilitators and barriers were communication and resources, respectively. CONCLUSION: The field of KT in SCI is in its infancy with only a few relevant publications. However, there is some evidence that KT interventions may change clinician behavior and improve patient outcomes. Future studies should ensure rigorous study methods are used to evaluate KT interventions. PMID- 24796447 TI - Quantitative magnetic resonance imaging analysis correlates with surgical outcome of cervical spinal cord injury without radiologic evidence of trauma. AB - STUDY DESIGN: Prospective study. OBJECTIVES: To investigate whether pre- and post operative changes of signal intensity (SI) and transverse area (TA) of the spinal cord on T2-weighted magnetic resonance imaging (MRI) reflect the surgical outcome in patients with spinal cord injury (SCI) without radiologic evidence of trauma (SCIWORET). SETTING: The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. METHODS: In 36 consecutive prospective patients, MRI was performed pre-operatively and 3 months post-operatively. The Japanese Orthopaedic Association (JOA) scale and the American Spinal Cord Injury Association (ASIA) motor score (AMS) were used to quantify neurologic status at admission and at least 12-month follow-up. Pre- and post-operative TA, range of signal intensity (RSI), grayscale of signal intensity (GSI) and prevertebral hyperintensities (PVHs) were measured using the image analysis software. Pre operative status and post-operative recovery were assessed in relation to MRI parameters pre- and post-operatively using univariate and multivariate analysis. RESULTS: Pre-operative JOA and AMS score negatively correlates RSI, GSI and PVH. There was no significant correlation between pre-operative TA and pre-operative JOA and AMS. Recovery rate with JOA negatively correlates pre-operative RSI, post operative RSI, pre-operative GSI, post-operative GSI and PVH. There was a significant negative correlation between recovery rate with AMS and pre-operative RSI, post-operative GSI and PVH. From these results of multivariate stepwise regression analysis, the predictors of surgical outcomes are pre-operative GSI and pre-operative RSI. CONCLUSION: Quantitative MRI analysis may provide reliable information for the prediction of the initial neurological status and surgical outcome of patients with SCIWORET. PMID- 24796449 TI - The development of the NZ-based international upper limb surgery registry. AB - STUDY DESIGN: Implementation study. OBJECTIVES: To describe the development and potential value of the New Zealand (NZ) upper limb surgery registry and report the demographic and spinal cord injury characteristics of individuals with tetraplegia collated to date. SETTING: Multi Center-coordinated from Burwood Spinal Unit, NZ. METHODS: Following discussions with eight international units, clinical information and outcomes measures were agreed upon for use in this specific population. To implement this consensus, a web-based upper limb surgery registry was developed in NZ. Inclusion criteria included referral to a hand clinic for clinical assessment for suitability for tendon transfer surgery. Clinical data were collected regardless of acceptance of surgery thereby creating a self-selected control group. Twenty-eight years of retrospective NZ data was entered into the registry, as well as 3 years of prospective data collected in NZ. RESULTS: From 1982 to 2013, a total of 357 persons with tetraplegia were assessed as suitable for surgery. Of those, 223 individuals underwent surgery and 134 declined the intervention(s). The prospective group currently comprises 55 assessments with 23 surgery individuals and 32 who have declined surgery to date. CONCLUSION: Clinical information is now available within a web-based registry for all individuals reviewed in hand clinics from when upper limb surgery was first introduced. A broad range of outcomes of interest can easily be reported directly from the registry. The self-selected control group will allow comparative studies to be explicitly linked to the specific interventions of interest. PMID- 24796448 TI - Gene expression profile of type II spinal cord decompression sickness. AB - STUDY DESIGN: This study was an experimental, controlled, animal study. OBJECTIVE: This study was to determine the changes of molecular pathology in spinal cord decompression sickness (SC-DCS) based on a rabbit model of SC-DCS with the aid of an all-gene expression profile chip. SETTING: Qingdao, Shandong Province, China. METHODS: A gene expression profile chip containing 43 803 genes was used to compare the gene expressions in the spinal cords of four male New Zealand white rabbits in the SC-DCS and control groups, respectively. Selected differentially expressed genes were identified with quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. RESULTS: The chip hybridization results showed that the SC DCS group had nine upregulated and seventeen downregulated genes, compared with the control group. These genes were mainly related to inflammation, ion channels, the cell cycle, material transfer and apoptosis. The qRT-PCR results showed that parathyroid hormone and tumor necrosis factor alpha (TNF-alpha) genes were upregulated compared with the control group (P<0.01). However, the acyl-CoA synthetase and voltage-gated channel genes were downregulated (P<0.05). The immunohistochemical staining results confirmed that there were significantly greater expression levels of TNF-alpha in the spinal cord tissues of the SC-DCS group compared with the control group. CONCLUSIONS: The spinal cord lesions of SC DCS involve multiple gene changes in the rabbit; however, the significance of these findings needs further research. Meanwhile, the gene expression profile chip results provide us with a better understanding of the pathogenesis of DCS. PMID- 24796450 TI - Health-related quality of life in patients with traumatic spinal cord injury in Estonia. AB - OBJECTIVES: To describe health-related quality of life (HRQoL) in persons with traumatic spinal cord injury (TSCI) and to assess factors that affect HRQoL. STUDY DESIGN: Cross-sectional. METHODS: Eighty Estonian-speaking TSCI patients from the Estonian TSCI database were included in the study. The RAND-36 questionnaire, the Life Orientation Test, the Emotional State Questionnaire and the Brief Social Support Questionnaire were used. RESULTS: There were 66 men and 14 women; the mean age was 38.9+/-14.8 years. The mean time that had elapsed since injury was 4.2 years. According to the RAND-36 scales, the lowest scores were given for physical health-related domains, followed by the energy/fatigue and the general health domains. The regression analysis adjusted to age and gender revealed that age, employment and category of the American Spinal Injury Association (ASIA) Impairment Scale during the acute phase of injury were significant factors in predicting physical functioning (P<0.001). Age, depression and general anxiety were significant predictors of emotional well-being (P<0.001). Age and depression were independently associated with general health (P<0.001). CONCLUSION: As expected, physical functioning and physical role limitation were the most pronounced deficits in HRQoL. Compared with data from other countries, all scores for the RAND-36 scales are lower in Estonian TSCI patients. The HRQoL following TSCI is affected by severity of injury, depression, age and employment status. PMID- 24796452 TI - Air- and water-tolerant rare earth guanidinium BINOLate complexes as practical precatalysts in multifunctional asymmetric catalysis. AB - Shibasaki's REMB catalysts (REMB; RE = Sc, Y, La-Lu; M = Li, Na, K; B = 1,1'-bi-2 naphtholate; RE/M/B = 1/3/3) are among the most enantioselective asymmetric catalysts across a broad range of mechanistically diverse reactions. However, their widespread use has been hampered by the challenges associated with their synthesis and manipulation. We report here the self-assembly of novel hydrogen bonded rare earth metal BINOLate complexes that serve as bench-stable precatalysts for Shibasaki's REMB catalysts. Incorporation of hydrogen-bonded guanidinium cations in the secondary coordination sphere leads to unique properties, most notably, improved stability toward moisture in solution and in the solid state. We have exploited these properties to develop straightforward, high-yielding, and scalable open-air syntheses that provide rapid access to crystalline, nonhygroscopic complexes from inexpensive hydrated RE starting materials. These compounds can be used as precatalysts for Shibasaki's REMB frameworks, where we have demonstrated that our system performs with comparable or improved levels of stereoselectivity in several mechanistically diverse reactions including Michael additions, aza-Michael additions, and direct Aldol reactions. PMID- 24796453 TI - [To establish a concept of whole course management of prevention and treatment of colorectal cancer]. PMID- 24796451 TI - Sodium hyaluronate-CNTF gelatinous particles promote axonal growth, neurogenesis and functional recovery after spinal cord injury. AB - OBJECTIVES: Currently, effective therapeutic strategy for spinal cord injury (SCI) is not clinically available. To establish a better method that may help repair the injured spinal cord, sodium hyaluronate-ciliary neurotrophic factor (CNTF) gelatinous particles were generated. METHODS: A segment of spinal cord tissue was excised to form a 2.5-mm-long cavity at thoracic level in an adult rat, and sodium hyaluronate-CNTF gelatinous particles were implanted into the lesion cavity. The recovery of the injured spinal cord was evaluated by immunohistochemistry, nerve tracing, electrophysiological test and Basso-Beattie Bresnahan locomotor rating scale. RESULTS: Open-field locomotion of the sodium hyaluronate-CNTF rats was significantly enhanced up to 12 weeks postoperation. Together with the evidence of enhanced cortical motor evoked potentials and cortical somatosensory evoked potentials in the sodium hyaluronate-CNTF group, these findings suggested a powerful functional recovery component. Immunohistochemical analyses suggested that the functional recovery might be attributable partly to an increase in axonal regrowth as well as in replenishment of beta-tubulin-III-positive neuron-like cells. CONCLUSION: Sodium hyaluronate CNTF gelatinous particles may provide an effective method for treating SCI. PMID- 24796454 TI - [2-deoxy-D-glucose modified supermagnetic iron oxide nanoparticles enhance the contrasting effect on MRI of human lung adenocarcinoma A549 tumor in nude mice]. AB - OBJECTIVE: To evaluate the role of 2-deoxy-D-glucose (2-DG) modified supermagnetic iron oxide nanoparticles (SPIO) (gamma-Fe2O3@DMSA-DG NPs) in tumor detection as a magnetic resonance imaging (MRI) contrast agent. METHODS: gamma Fe2O3@DMSA-DG NPs was prepared. The degree of A549 cells targeted absorption of gamma-Fe2O3@DMSA-DG NPs was detected by Prussian blue staining, colorimetric assay, T2W and multi-echo sequence MRI. gamma-Fe2O3@DMSA NPs was used as a control agent, and free D-glucose as a competitive inhibitor. Human lung adenocarcinoma A549 xenograft tumor was prepared in nude mice. Sterile aqueous suspension of gamma-Fe2O3@DMSA NPs or gamma-Fe2O3@DMSA-DG NPs was injected into the tail vein of nude mice. Before and 6, 12, 24, 48 h after injection, MRI imaging of the mice was performed. T2 signal intensity of the tumor, brain, liver and thigh skeletal muscles, and T2 values of the tumors were measured. RESULTS: The average diameter of the particles was about 10 nm, and there were no significant differences between the diameters of gamma-Fe2O3@DMSA NPs and gamma- Fe2O3@DMSA-DG NPs. The IR spectra showed the C-N retractable vibration peak at gamma-Fe2O3@DMSA-DG NPs surface, indicating that 2-DG was conjugated to the gamma Fe2O3@DMSA NPs. The Prussian blue staining, colorimetric assay, MRI T2 signal intensity and T2 values revealed that gamma-Fe2O3@DMSA-DG NPs were significantly more absorbed by A549 cells at growth peak than gamma-Fe2O3@DMSA NPs, and the absorption of gamma-Fe2O3@DMSA-DG NP was inhibited by free D-glucose. The results of in vivo examination showed that before and at 6, 12, 24, 48 h after injection of gamma-Fe2O3@DMSA-DG NPs, the mean T2 signal intensities of the tumors were (326.00 +/- 16.26)s, (276.40 +/- 5.13)s, (268.40 +/- 30.58)s, (240.40 +/- 25.93)s, (262.20 +/- 30.04)s, respectively, and the T2 values of the tumors were (735.80 +/- 20.93) ms, (645.80 +/- 69.58) ms, (615.00 +/- 124.61) ms, (570.60 +/- 67.78) ms, and (537.80 +/- 105.29) ms, respectively. However, before and at 6, 12, 24, 48 h after injection of gamma-Fe2O3@DMSA NPs, the mean T2 signal intensities of the tumors were (335.60 +/- 4.93)s, (290.80 +/- 5.93)s, (273.40 +/ 15.08)s, (327.40 +/- 16.65)s, and (313.20 +/- 20.45)s, respectively, and T2 values were (686.00 +/- 21.44)ms, (617.80 +/- 69.93)ms, (645.20 +/- 85.89)ms, (669.40 +/- 13.72)ms, and (608.80 +/- 61.90)ms, respectively. The T2 signal intensity and T2 value of the tumors were not declined generally after injection. The liver T2 signal intensity was decreased after injection of both gamma Fe2O3@DMSA-DG NPs and gamma-Fe2O3@DMSA NPs, and T2 signal intensity of the brain and muscle did not show significant changes. CONCLUSIONS: gamma-Fe2O3@DMSA-DG NPs has an ability to target glucose receptors overexpressed in tumors, and may serve as a MRI contrast agent for tumor detection. PMID- 24796455 TI - [Effect of antisense miR-224 on gastric cancer cell proliferation and apoptosis]. AB - OBJECTIVE: To observe the effects of miR-224 antisense oligonucleotide (ASO) on the proliferation and apoptosis of gastric cancer cells in vitro and vivo. METHODS: The expression of miR-224 in the cancer tissues and their adjacent tissues in 120 gastric cancer patients were detected by real-time quantitative PCR. The biological effects of miR-224 ASO on human gastric cancer SGC7901 cells was assessed by MTT assay, clone formation assay, flow cytometry and in vivo experiment in nude mice. RESULTS: Compared with the control group (0.50 +/- 0.07), miR-224 ASO significantly reduced the miR-224 mRNA expression in the cancer patients (0.09 +/- 0.01, P < 0.05). MTT assay results showed that the survival rate of gastric cells at 24 h, 48 h and 72 h was 53.6%, 59.1% and 70.1% in the miR-224 ASO group, and 12.3%, 17.4% and 24.7%, respectively, in the control group (P < 0.05 for all). Clone formation assay revealed that clone formation rate in the miR-224 ASO group was (5.33 +/- 0.74)%, significantly lower than the (33.33 +/- 8.38)% in the control group (P < 0.05). Flow cytometry indicated that the apoptotic index was (15.68 +/- 1.46)% in the miR-224 ASO group and (3.36 +/- 0.88)% in the control group (P < 0.01). In addition, the expressions of Bcl2 mRNA and protein were 1.05 +/- 0.04 and 0.21 +/- 0.03 in the miR-224 ASO group, significantly lower than that in the control group (4.87 +/- 0.96 and 0.88 +/- 0.09, P < 0.01). The in vivo study further showed that the tumor volume in the experimental group is significantly smaller than that in the control group (P = 0.01). CONCLUSIONS: MiR-224 is overexpressed in human gastric cancer. Reducing the expression of miR-224 can effectively inhibit the growth and promote apoptosis of gastric cancer cells. miR-224 may become a new target for the regulation of gene expression in gastric cancer. PMID- 24796456 TI - [Establishment and characterization of dual-color fluorescence nude mouse models of glioma]. AB - OBJECTIVE: To establish red-green dual-color fluorescence glioma model in nude mice and to explore its practical values. METHODS: CM-DiI-stained rat glioma C6 cells (C6-CM- DiI cells) expressing red fluorescence were inoculated into the brain of athymic nude mice expressing green fluorescence protein (NC-C57BL/6J EGFP). Then the whole-body dual-color fluorescence imaging was detected dynamically. Finally whole brains of the tumor-bearing mice were removed and 5 um thick serial frozen slices were made. Light microscopy, fluorescence microscopy and confocal laser scanning microscopy were performed to observe the transplanted tumor tissue structure and fluorescent cells. RESULTS: Tumor mass with red fluorescence increased gradually under continuous in-vivo fluorescence imaging monitoring. Under the fluorescence microscope, cells with red, green and yellow fluorescence were observed in the frozen sections of transplanted tumor tissue and the mutual structural relationship among them could be defined. The tumor cells migration, implantation and cell fusion between transplanted tumor cells and host cells could be observed. It could be distinguished according to the fluorescence, that blood vessels of tumor-origin displayed red fluorescence, blood vessels of host-origin displayed green fluorescence and mosaic blood vessels appeared yellow fluorescence. It was depicted that host innate astrocytes and oligodendrocytes in the microenvironment at the tumor periphery could be activated and dedifferentiated into nestin-positive cells. CONCLUSIONS: In contrast to traditional animal model, the dual-color fluorescence imaging of nude mouse models of glioma possesses enormous advantages in investigating tumor mass in-vivo fluorescence imaging, tumor cells migration and metastasis, tumor angiogenesis and reactive activation of host innate cells in the microenvironment at tumor periphery, thus, has highly practical application value. PMID- 24796457 TI - [Effect of CD133(+) cells on the radiosensitivity of rectal cancer cells]. AB - OBJECTIVE: To investigate the effect of CD133(+) cells on radiosensitivity of rectal cancer cells. METHODS: In vitro experiments: CD133(+) cells were purified with Immunomagnetic beads from human rectal cancer cell line SW480 cells and annexin V/PI staining was used to determine apoptosis in CD133(+) and CD133(-) cells. In vivo experiments: Transplanted rectal tumor was established in 30 nude mice using primarily established SW480 cells. The tumor cells were divided into CD133-high and CD133-low groups based on the immunohistochemical staining of CD133 expression of the tumor cells. The tumor size after irradiation was recorded every three days. RESULTS: CD133(+) cells had a much lower percentage of apoptosis after radiation exposure compared with CD133(-) cells [(12.6 +/- 3.2) % vs. (38.8 +/- 6.7) %, P < 0.01]. In vivo experiment showed that the normalized tumor size of CD133-high group (3.00 +/- 0.32) became significantly larger than that of the CD133-low group(2.55 +/- 0.29) at the ninth day and this difference lasted until the observation end (P < 0.05). CONCLUSIONS: CD133(+) cells have a radioresistant effect on rectal cancer cells and may become a potential therapeutic target in the radiotherapy of rectal cancer. PMID- 24796458 TI - [Prospective analysis of the risk factors and clinical indications of dissection of lymph node posterior to right recurrent laryngeal nerve in 283 cases of papillary thyroid carcinoma]. AB - OBJECTIVE: To investigate the risk factors for metastasis and clinical indications for dissection of lymph node posterior to right recurrent laryngeal nerve (LN-prRLN) in papillary thyroid carcinoma (PTC). METHODS: A prospective analysis including 283 consecutive patients with PTC who underwent total thyroidectomy with routine central lymph node dissection (CLND) in our hospital from Jan. 2010 to Jan. 2012 was performed. The right paratracheal lymph nodes in the central compartment lymph nodes (CCLN) were divided into the anterior (level VIa) and posterior (level VIb) compartments by recurrent laryngeal nerve (RLN), and were removed respectively. The complications and recurrences were recorded with a follow-up of 3 months to 3 years. RESULTS: CCLN metastases were present in 47.7% (135/283) of the patients, and level VIb metastases were present in 27.2% (77/283) of the patients. The incidence of level VIb metastasis was 20.5% (58/283) in level VIa-positive patients, while 6.7% (19/283) in level VIa negative patients. Complications of level VIb dissection were found in 4.9% (14/283) of all patients. 2.1% (6/283) of all patients were diagnosed with regional recurrence during the 3-year follow-up. Univariate analysis revealed that level VIb metastasis was significantly associated with tumor size, number, extrathyroidal invasion, clinical nodal stage, level VIa and lateral lymph node metastases. Multivariate analysis revealed that tumor larger than 1 cm, multifocality, extrathyroidal invasion, level VIa and lateral lymph node metastases were independent risk factors for level VIb metastasis. CONCLUSIONS: Lymph node posterior to right recurrent laryngeal nerve can be the only site of metastasis from PTC without other cervical compartment involvements. Therefore, routine intraoperative detection of these nodes may be necessary for patients with right PTC, and dissection should be considered when a right-side PTC tumor is larger than 1 cm, multifocality, with extrathyroidal invasion or cervical nodal metastases. PMID- 24796459 TI - [Value of MR diffusion-weighted imaging in diagnosis and outcome prediction for uterine cervical cancer]. AB - OBJECTIVE: To investigate the clinical application of diffusion weighted imaging (DWI) in uterine cervical cancer and the apparent diffusion coefficient (ADC) value in diagnosis and predicting treatment response. METHODS: Twenty-eight patients with advanced primary cervical cancer confirmed by pathology and 10 cases of normal uterine cervix as control were recruited in this prospective clinical trial. To analyze the correlation between tumor volume measured in DWI and tumor maximum diameter measured according to the RECIST criteria. To compare the ADC value differences among the uterine cervical cancer, uterine myometrium, and normal uterine cervix. To compare the ADC values in 17 cancer patients before and after treatment. RESULTS: The illustration of tumor boundary in DWI was superior to conventional T2WI and post-enhancement T1WI. The DWI with higher b value (2000 s/mm(2)) had a better signal-to-noise ratio. The tumor volume measured in DWI has good correlation with tumor maximum diameter according to RECIST criteria (r = 0.759, P < 0.01). When b = 800 s/mm(2), the ADC values of the uterine cervical cancer, uterine myometrium, and normal uterine cervix were (9.85 +/- 1.55)*10(-3) mm(2)/s, (14.20 +/- 2.80)*10(-3) mm(2)/s, and (14.14 +/- 0.45) *10(-3) mm(2)/s. When b = 2000 s/mm(2), the ADC values of the uterine cervical cancer, uterine myometrium and normal uterine cervix were (7.38 +/- 0.98)*10(-3) mm(2)/s, (8.52 +/- 2.38)*10(-3) mm(2)/s, and (8.60 +/- 0.63)*10(-3) mm(2)/s, respectively. There were significant differences between the cervical cancer and normal cervix or uterine myometrium (P < 0.001 for both). When b = 800 s/mm(2), the ADC value was (9.85 +/- 1.55)*110(-3) mm(2)/s before and (13.41 +/- 2.93)*10(-3) mm(2)/s after treatment (P < 0.001). When b = 2000 s/mm(2), the ADC value was (7.38 +/- 0.98)*10(-3) mm(2)/s before and (8.93 +/- 1.92)*10(-3) mm(2)/s after treatment (P = 0.008). Univariate logistic regression analysis showed that 25% ADC, 50%ADC, and 75%ADC in the tumor ADC value histogram before treatment were significantly correlated to the treatment outcome of cervical cancer (P < 0.05 for all). Multivariate regression analysis showed that 25%ADC, 50%ADC, and 75%ADC in the tumor ADC value histogram before treatment were not significantly correlated to the treatment outcome of cervical cancer (P > 0.05 for all). The values of ROC curves were 25%ADC = 0.818, 50%ADC = 0.775, and 75%ADC = 0.716 (P > 0.05), however, the 25% ADC showed a relatively stronger statistical power. CONCLUSIONS: DWI helps to confirm the morphology and exact target zone of the tumor for radiotherapy. DWI volume measurement is well correlated with RECIST criteria, particularly in volume measurement of irregular tumors. ADC value has a potential in quantitatively monitoring treatment response and predicting outcome of cervical cancers. PMID- 24796460 TI - [Relationship between expression of mTOR and prognosis of early stage non-small cell lung cancer]. AB - OBJECTIVE: To investigate the influence of mTOR expression on prognosis of early stage NSCLC. METHODS: One-hundred and thirty-eight patients who underwent radical surgery for early stage NSCLC in our hospital from Janurary 2002 to December 2006 were included in this study. There were 83 males and 55 females, in an average age of 65.8 years, for both genders). The influence of age, gender, tumor typing, pathological grading, pathological staging and mTOR expression on patients' survival were analyzed by univariate and multivariate analyses. RESULTS: The 5 year survival rate of the 138 cases was 44.8%. Immunohistochemical examination showed that mTOR-positive cases accounted for 101 while mTOR-negative cases accounted for 37. The 5-year survival rate of mTOR-positive patients was 32.7% and that of mTOR-negative patients was 56.4% (P = 0.019). Univariate analysis showed that mTOR expression, pathological staging and N1 lymph node metastasis were identified as significant prognostic factors, and were correlated to prognosis (P < 0.05 for all). Multivaraite analysis showed that pathological staging, mTOR expression, N1 lymph node involvement were identified as independent prognostic factors for patients with early NSCLC (P < 0.05 for all). CONCLUSIONS: Our findings suggest that overexpression of mTOR indicates a poor prognosis for NSCLC. mTOR, pathological stage and N1 lymph node metastasis are independent prognostic factors in early stage NSCLC. PMID- 24796461 TI - [Serum anti-Ku86: a potential biomarker for early detection of hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the clinical value of serum anti-Ku86 in early detection of hepatocellular carcinoma (HCC). METHODS: Expression levels of Ku86 protein in HCC and adjacent normal liver tissues were detected by Western blotting. Serum anti-Ku86 level in 83 patients with early HCC and 124 patients with liver cirrhosis were detected by enzyme-linked immunosorbent assay (ELISA). Chemiluminescence was used to measure the serum level of alpha-fetoprotein (AFP). RESULTS: Expression of Ku86 protein in HCC was increased when compared with the adjacent normal liver tissues (0.21 +/- 0.05 vs. 0.08 +/- 0.02, P < 0.01). Serum anti-Ku86 level was significantly elevated in HCC patients compared with that in liver cirrhosis patients (0.47 +/- 0.22 vs. 0.22 +/- 0.06 Abs at 450 nm, P < 0.01), but there was no significant difference between HBV infection and HCV infection in HCC patients (0.51 +/- 0.19 vs. 0.47 +/- 0.24, P = 0.267). Of note, serum anti-Ku86 level was significantly decreased after surgical resection of the tumors in the 30 HCC cases tested (P < 0.01). The results of ROC analysis indicated a better performance of anti-Ku86 (0.857) than AFP (0.739) for early detection of HCC. In 83 HCC patients, the positive rate of anti-Ku86 was 61.4% (51/83), significantly higher than that of the AFP positive rate (27.7%, 23/83). The anti-Ku86 level was positive in 37 of 60 HCC cases with negative AFP. Combination assay of AFP and anti-Ku86 could detect 60 of 83 HCC cases (72.3%, 60/83). There was no significant correlation of anti-Ku86 and AFP (r = 0.156, P = 0.161). CONCLUSIONS: Serum anti-Ku86 level is significantly elevated and is not related to HBV and HCV infection in HCC patients. Serum anti-Ku86 antibody may be a potential biomarker for early detection of HCC, and can be used in combination with AFP in clinics. PMID- 24796462 TI - [Methylation of ER and ER gene and its significance in primary and relapsed/metastatic lesions of breast cancer]. AB - OBJECTIVE: To investigate the different expressions of ER and ER gene status between primary and relapsed/metastatic lesions and their clinical significance. METHODS: ER and ER gene status of primary and relapse/metastatic breast cancer masked in 70 metastatic breast cancer patients were assessed by determination of methylation status by immunohistochemistry (IHC) and methylation specific polymerase chain reaction (MSP), respectively. RESULTS: Positive rate of ER in the primary breast cancers was 64.3%, and in the relapse/metastatic lesions was 41.4% (P < 0.05). There were six patients whose positive ER status was changed to negative, among them the ER gene status was changed from demethylation to hypermethylation in four cases. Another four patients with negative ER status changed to positive, and their ER gene hypermethylation changed to ER demethylation status. CONCLUSIONS: The discordance of ER expression status in primary and relapse/metastatic lesions of breast cancer might be related to DNA methylation status. PMID- 24796463 TI - [Trastuzumab administered concurrently with anthracycline-containing adjuvant regimen for breast cancer]. AB - OBJECTIVE: To investigate the safety and efficacy of trastuzumab administered concurrently with anthracycline-containing adjuvant regimen for breast cancer. METHODS: It is a prospective, randomized and controlled trial. Participants were randomized to receive trastuzumab administered concurrently or sequentially with anthracycline-containing adjuvant regimen. The primary endpoint was cardiac safety. The second endpoints were disease-free survival (DFS) and overall survival (OS). RESULTS: One hundred and nine breast cancer patients were enrolled and randomized in this trial. Fifty-five participants received trastuzumab administered concurrently with anthracycline-containing adjuvant regimen and 54 patients received trastuzumab administered sequentially with anthracycline. The primary cardiac event was asymptomatic decrease in the left ventricular ejection fraction (LVEF). There was no significant difference between concurrent and sequential groups in cardiac event rates (9.1% vs13.0%, P = 0.556), neither of LVEF values at basline or at 3, 6, 9 and 12 months during trastuzumab treatment (P > 0.05). Four patients (7.3%) in the concurrent group suffered local recurrences or distant metastases, and 6 participants (11.1%) in the sequential group had distant metastases. There was no significant difference between the two groups in DFS (P = 0.724). There was no death in both groups. CONCLUSIONS: Trastuzumab administered concurrently with anthracycline is a safe adjuvant regimen for breast cancer and does not increase cardiac events. Further research is needed to determine the efficacy of this treatment regimen. PMID- 24796464 TI - [Efficacy and safety evaluation of gemcitabine combined with oxaliplatin in lymphoma patients after failure of multiple chemotherapy regimens]. AB - OBJECTIVE: To evaluate the efficacy and safety of gemcitabine combined with oxaliplatin (GEMOX) in lymphoma patients after failure of multiple chemotherapy regimens. METHODS: The clinical data of 27 lymphoma patients, who received GEMOX regimen after failure of two or more prior chemotherapy regimens, were retrospectively reviewed. The predictive factors related to the clinical efficacy of GEMOX regimen were explored. RESULTS: The efficacy could be evaluated in 24 patients. Complete response was obtained in 4 patients (16.7%), partial response in 7 patients (29.1%), stable disease in 6 patients (25.0%), and progressive disease in 7 patients (29.1%), with an overall response rate of 45.8%. Among the eleven CR and PR patients, four patients were with diffuse large B cell lymphoma, four patients with Hodgkin's lymphoma, one with peripheral T cell lymphoma, one with mantle cell lymphoma and one with gastric mucosa-associated lymphoid tissue lymphoma. The median PFS time of the whole group was 8 months (95%CI, 1.6-14.4 months). For 11 CR and PR patients who had response to the GEMOX regimen, the median PFS time was 19 months (95%CI, 11.1-26.8 months). Major adverse response was hematologic toxicity. Among them, grade III or IV neutropenia appeared in 16 patients (59.3%), and grade III or IV thrombocytopenia appeared in 11 patients (40.7%). The sensitivity to the last chemotherapy was related to the efficacy of GEMOX regimen. The response rate was 83.3% in patients who had response to the last chemotherapy, and only 31.2% in the patients who failed to the last chemotherapy (P = 0.001). CONCLUSIONS: GEMOX regimen can get a better response rate in lymphoma patients after failure of multiple chemotherapy regimens, and with a good tolerance and acceptable safety. Some patients can get long-term survival. Patients sensitive to the last chemotherapy are more likely to benefit from GEMOX regimen. PMID- 24796465 TI - [Effect of number of metastatic lymph nodes and metastatic lymph node ratio on the prognosis in patients with adenocarcinoma of the esophagogastric junction after curative resection]. AB - OBJECTIVE: To analyze the effects of number of positive lymph nodes and metastatic lymph node ratio (LNR) in evaluation of recurrence risk and overall survival in patients with adenocarcinoma of the esophagogastric junction (AEG) after curative resection. METHODS: Clinical data of 337 AEG patients who underwent curative resection in our hospital were retrospectively reviewed. The pN stage was categorized based on the number of metastatic lymph nodes and LNR stage, and was determined by the best cutoff approach at log-rank test. Univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model were used to analyze the effects of pN and LNR on recurrence-free survival and overall survival of these patients. Receiver operating characteristic (ROC) curves were plotted to compare the accuracy of prognosis prediction with pN and LNR. RESULTS: The 5-year recurrence-free survival rate and overall survival rate for all patients were 25.5% and 29.9%, respectively. The 5 year recurrence-free survival rates were 47.6%, 23.2%, 17.1% and 5.7% for pN0, pN1, pN2, and pN3, respectively, (P < 0.001) and the 5-year overall survival rates were 53.3%, 28.9%, 18.9% and 7.3%, respectively (P < 0.001). The 5-year recurrence-free survival rates were 47.6%, 24.3%, 11.4% and 2.0% for LNR0, LNR1, LNR2, and LNR3, respectively (P < 0.001), and the 5-year overall survival rates were 53.3%, 28.5%, 15.0%, 2.6%, respectively (P < 0.001). Univariate analysis showed that tumor size, macroscopic type, degree of differentiation, pT, pN, LNR and TNM stage were significantly associated with RFS and OS (P < 0.05). Cox multivariate analysis showed that either pN or LNR was independent risk factor for RFS and OS (P < 0.001). When pN and LNR were entered into the Cox hazard ratio model as covariates at the same time, LNR remained as an independent prognosis factor for RFS and OS (P < 0.001), but pN was not (P > 0.05). ROC curves showed that the area under the curve of LNR stage was larger than that of pN stage in prediction of both RFS and OS, however the differences were not statistically significant (P > 0.05). CONCLUSIONS: LNR is an independent risk factor associated with the prognosis of AEG patients. The value of LNR in prediction of recurrence hazard and overall survival was better than that of pN stage. It offers some helpful suggestions for AEG patients risk classification, allowing clinicians to develop a reasonable treatment. PMID- 24796466 TI - [Adenoid cystic carcinoma of the breast:report of 25 cases]. AB - OBJECTIVE: To explore the clinical features, management approach and treatment outcomes for adenoid cystic carcinoma (ACC) of the breast. METHODS: The clinicopathological data of 25 patients with breasts ACC treated in our hospital from years 1990 to 2012 were retrospectively reviewed and their prognosis was analyzed. RESULTS: The median age of these 25 patients was 53 years (ranged from 31 to 81 years). With the exception of one male case, all patients were female including 17 cases of postmenopausal women. The most frequent presenting symptom is breast lumps, most (48.0%) were in the upper outer quadrant and areola area of the breast. Core needle biopsy was performed in five patients. The specimen finding were adenoids in three and invasive carcinoma in two cases. Axillary lymph node dissection was performed in 23 patients. Only two patients had histologically positive lymph nodes (3 of 14 and 2 of 20). Expression of ER and PR in 14 cases was detected by immunohistochemistry, showing one PR-positive and three ER-positive cases. The median follow-up of the 25 cases was 118 months (ranged from 12 to 244 months). Two patients died of lung metastases at 3 and 10 years after the surgery, respectively. CONCLUSIONS: Due to the complexity of the histology of ACC, adequate sampling of specimens is essential for accurate diagnosis. ACC of the breast is a rare disease with a relatively good prognosis. The low incidence of axillary lymph node metastasis suggests that axillary node dissection is not recommended as a routine procedure. Breast ACC are often with negative ER and PR expression, and the value of adjuvant therapy needs to be further investigated. PMID- 24796467 TI - [Value of postoperative radiochemotherapy for thoracic esophageal squamous cell carcinoma with lymph node metastasis]. AB - OBJECTIVE: To retrospectively compare the efficacy of postoperative radiotherapy (RT) alone with that of postoperative radiotherapy with concurrent chemotherapy (CRT) for thoracic esophageal squamous cell carcinoma (EPC) with positive lymph nodes, and to evaluate the clinical value of RT + CRT. METHODS: 304 EPC patients underwent esophagectomy with three-field lymph node dissection had pathological lymph node metastases, but no hematogenous distant metastasis. Among them, 140 cases underwent postoperative RT alone, and 164 cases underwent postoperative CRT. The dose of irradiation was 50 Gy, and the chemotherapy regimen was taxol and cis-platinum, and a cycle was 21 days. RESULTS: The 1-, 3- and 5-year total survival rates of the whole group were 90.1%, 56.6% and 43.3%, respectively, with a median survival time of 49.7 months. The 5-year overall survival rates of the CRT and RT groups were 47.4% and 38.6%, respectively (P = 0.030), with a median survival time of 53.5 and 41.7 months, respectively (P = 0.030). The overall survival rates of the patients who underwent 1, 2, 3, 4 cycles of chemotherapy were 24.4%, 53.0%, 58.1% and 43.3%, respectively (P = 0.007). Among them, the 5 year total survival rate of patients with 2-4 cycles of chemotherapy was significantly better than that of patients who underwent one cycle of chemotherapy (P = 0.001). Univariate analysis showed that number of metastatic lymph nodes, pT stage, therapeutic regimen and number of chemotherapy cycles were significantly correlated with the prognosis of the patients (P < 0.05 for all). Multivariate analysis showed that number of metastatic lymph nodes, pT stage, and number of chemotherapy cycles were independent prognostic factors of the patients (P < 0.05 for all). Early toxic effects including neutropenia, radiation esophagitis, and gastrointestinal effects were significantly more severe in the CRT group than that in the RT group (P < 0.05), however, there were no significant differences of late toxic effects between the two groups (P > 0.05). CONCLUSION: Postoperative CRT for thoracic EPC with positive lymph nodes can improve the survival rate, with tolerable adverse effects. PMID- 24796468 TI - [Discussion on reconstruction of the postoperative defect after oral floor carcinoma resection]. AB - OBJECTIVE: To explore the reconstruction approaches and indications in repairing of postoperative defect after resection of oral floor carcinoma. METHODS: To review the clinical data of 106 patients with oral floor carcinoma treated by radical resection with simultaneous reconstruction in the Department of Head and Neck Surgery at our hospital from July 2003 to March 2013, and to evaluate the advantages and disadvantages of various repair methods. RESULTS: The patients were followed up for 2 months to 10 years. Their 3-year survival rate was 63.6% (42/66) and 5-year survival rate was 57.7% (30/52). One case had sternocleidomastoid myocutaneous flap necrosis, and was successfully repaired with elective pectoralis major myocutaneous flap. Another one case showed partial strap muscle flap necrosis, and the wound was well healed after debridement and dressing changes. Three cases of free flap crisis because of poor blood supply were successfully cured by flap emergency exploration. The rest were well healed. The eating and language function of the patients could meet the general needs of life. CONCLUSIONS: At the time of radical resection of oral floor carcinoma, an appropriate repair method should be selected according to many factors such as disease conditions, defect size, patients' physical constitution, etc. Generally, adjacent pedicle flap is not recommended. Prosthodontics membrane, free forearm flap, free anterolateral thigh flap, pectoralis major myocutaneous flap and free fibula flap can basically meet the need of repair of the postoperative defect after resection of oral floor carcinoma, therefore, are recommended. PMID- 24796469 TI - [Analysis of results of endoscopic screening of esophageal, gastric cardia and gastric cancers in high risk population]. AB - OBJECTIVE: To summarize the results of endoscopic screening of esophageal, gastric cardiac and gastric cancers in the high-risk population, and analyze the influencing factors such as age, gender and biopsy rate on their detection and early diagnosis rates. METHODS: Nine high incidence cities and counties of esophageal cancer in Henan province were included in this study. People aged 40 69 years were set to the target population. Excluding contraindications for gastroscopy, in accordance with the national technical scheme of early cancer diagnosis and treatment, gastroscopic screening and biopsy pathology for human esophageal, cardiac and gastric cancers were carried out. RESULTS: During the 3 year period, a total of 40 156 subjects were screened. Among them, 18 459 cases of various precancerous lesions (46.0%) were detected. The cancer detection rate was 2.3% (916 cases), including 763 cases of early cancers. The diagnosis rate of early cancers was 83.3%. Precancerous lesions were detected in 9297 cases (23.2%) for esophagus and 9162 cases (22.8%) for gastric cardia as well as stomach, respectively. CONCLUSIONS: The results of this study demonstrate that endoscopic screening is feasible for early detection, diagnosis and treatment of esophageal, gastric cardia and gastric cancers among high risk population in high incidence area. Exploration analysis of relevant affecting factors may help to further improve the screening project for early diagnosis and treatment of those cancers. PMID- 24796470 TI - Complications of herpes zoster in cancer patients. AB - Cancer patients tend to have a higher incidence of herpes zoster (HZ), but little is known about their risk of HZ complications. We conducted a retrospective study of 424 newly diagnosed hematologic (HM, n = 140) and solid tumor malignancy (STM, n = 284) patients who developed HZ between January 2001 and December 2006 to measure the frequency and identify risk factors of HZ complications. Patients were adult members of Kaiser Permanente Northern California. HZ diagnosis and complications were confirmed by medical chart review. HM patients with HZ tended to have more HZ complications than STM patients (34% vs 23%, p = 0.02), largely due to more frequent non-pain complications. On multivariate analysis, older age and being male were associated with a higher risk of HZ complications in HM patients; more advanced cancer stage was associated with HZ complications in STM patients. HZ complications are frequent and can present extra disease burden in cancer patients who develop HZ. PMID- 24796471 TI - Overcoming obstacles to health: how can we achieve equality? PMID- 24796472 TI - Clinical outcomes of patient mobility in a neuroscience intensive care unit. AB - BACKGROUND: Patients treated in a neuroscience intensive care unit (NICU) are often viewed as too sick to tolerate physical activity. In this study, mobility status in NICU was assessed, and factors and outcomes associated with mobility were examined. METHODS: Using a prospective design, daily mobility status, medical history, demographics, Acute Physiology and Chronic Health Evaluation (APACHE) III score, and clinical outcomes were collected by medical records and database review. Depression, anxiety, and hostility were assessed before NICU discharge. Analyses included comparative statistics and multivariable modeling. RESULTS: In 228 unique patients, median (minimum, maximum) age was 64.0 (20, 95) years, 66.4% were Caucasian, and 53.6% were men. Of 246 admissions, median NICU stay was 4 (1, 61) days; APACHE III score was 56 (16, 145). Turning, range of motion, and head of bed of >30 degrees were uniformly applied (n = 241), but 94 patients (39%) never progressed; 94 (39%) progressed to head of bed of >45 degrees or dangling legs, 29 (12%) progressed to standing or pivoting to chair, and 24 (10%) progressed to walking. Female gender (p = .019), mechanical ventilation (p < .001), higher APACHE score (p = .004), and 30-day mortality (p = .001) were associated with less mobility. In multivariable modeling, greater mobility was associated with longer unit stay (p < .001) and discharge to home (p < .001). Psychological profile characteristics were not associated with mobility level. CONCLUSION: Nearly 40% of patients never progressed beyond bed movement, and only 10% walked. Although limited mobility progression was not associated with many patient factors, it was associated with poorer clinical outcomes. Implementation and evaluation of a progressive mobility protocol are needed in NICU patients. VIDEO ABSTRACT: For more insights from the authors, see Supplemental Digital Content 1, at http://link.lww.com/JNN/A10. PMID- 24796473 TI - Ethical dilemmas around the dying patient with stroke: a qualitative interview study with team members on stroke units in Sweden. AB - In Sweden, individuals affected by severe stroke are treated in specialized stroke units. In these units, patients are attended by a multiprofessional team with a focus on care in the acute phase of stroke, rehabilitation phase, and palliative phase. Caring for patients with such a large variety in condition and symptoms might be an extra challenge for the team. Today, there is a lack of knowledge in team experiences of the dilemmas that appear and the consequences that emerge. Therefore, the purpose of this article was to study ethical dilemmas, different approaches, and what consequences they had among healthcare professionals working with the dying patients with stroke in acute stroke units. Forty-one healthcare professionals working in a stroke team were interviewed either in focus groups or individually. The data were transcribed verbatim and analyzed using content analysis. The ethical dilemmas that appeared were depending on "nondecisions" about palliative care or discontinuation of treatments. The lack of decision made the team members act based on their own individual skills, because of the absence of common communication tools. When a decision was made, the healthcare professionals had "problems holding to the decision." The devised and applied plans could be revalued, which was described as a setback to nondecisions again. The underlying problem and theme was "communication barriers," a consequence related to the absence of common skills and consensus among the value system. This study highlights the importance of palliative care knowledge and skills, even for patients experiencing severe stroke. To make a decision and to hold on to that is a presupposition in creating a credible care plan. However, implementing a common set of values based on palliative care with symptom control and quality of life might minimize the risk of the communication barrier that may arise and increases the ability to create a healthcare that is meaningful and dignified. PMID- 24796474 TI - Post-lumbar puncture headache: a review of issues for nursing practice. AB - Headache is the most common complication after lumbar puncture. This narrative review explores the literature to determine strategies for preventing headache and provide evidence-based nursing care to adults with post-lumbar puncture headache. Multiple findings regarding prevention and relieving of post-lumbar puncture headache were identified and summarized under the headings "Needle Design and LP Technical Procedure," "Bed Rest and Early Mobilization," "Posture and Head Position," "Cerebral Vasoconstriction," "Hydration and Seal of the Puncture Site," and "Patient Characteristics." Despite the amount of articles, no widely accessible nursing practice guidelines were found. It has been shown that several treatments with insufficient or low levels of evidence supporting their efficacy are still being used (e.g., prolonged bed rest, special postures in bed, additional fluid intake, and caffeine intake). A clear recommendation regarding using atraumatic, small-sized needles. Further research is needed to support nursing with stronger evidence. PMID- 24796475 TI - Neuroscience nursing research: trend analysis from 1989 to 2010. AB - This study extends an earlier investigation (DiIorio et al., 2004) regarding neuroscience studies published in four nursing journals over the period from 1989 to 2000. A literature review was conducted from 2001 to 2010 with the same search strategy performed by DiIorio from 1989 to 2000. A trend analysis comparing the articles published in the period of 2001-2008 with those published from 1993 to 2000 (odds ratio [OR], 95% confidence interval [CI]) was performed. From 1989 to 2010, a total of 607 articles were published, 2.2 articles per month. A significantly increased number of publications on neuroscience nursing research have emerged comparing 2001-2008 versus 1993-2000 (OR = 2.1, 95% CI [1.22, 3.29]; p = .00). From 1989 to 2000, neurological problems were the predominant object of study (389 articles, 64.1%), followed by neurotrauma problems (156, 25.7%) and those neurosurgical problems (31, 5.1%). Moreover, a progressive reduction of studies focusing on neurological problems (OR = 0.42, 95% CI [0.26, 0.68]; p = .00) has emerged comparing 2001-2008 versus 1993-2000. The setting chosen for the study from 1989 to 2000 was mainly hospitals (211, 34.8%) followed by long-term care (125, 20.6%) and the home environment (77, 12.7%). Over the years (2001- 2008 vs. 1993-2000), studies performed at the home level were lower (OR = 0.27, 95% CI [0.15, 0.47]; p = .00), whereas those carried out at the hospital level and at the long-term care level have increased. Research in neuroscience nursing has continued to grow in the last decade, involving more patients who are mainly women. In the coming years, quasiexperimental, experimental, or complex intervention designs, involving the various care settings and along the trajectories of illnesses of patients who have an acute phase but especially in a long-term phase, are needed. PMID- 24796477 TI - Intrafacility transportation of patients with acute brain injury. AB - Patients with acute brain injury (ABI) frequently require diagnostic and therapeutic procedures in the areas located outside of the intensive care unit. Transports can be risky for critically ill patients with ABI. Secondary brain injury can occur during the transport from causes such as ischemia, hypotension, hypoxia, hypercapnia, and cerebral edema. Preparation and implementation of preventive procedures including pretransport assessment, monitoring during transport, and posttransport examination and documentation for transports of patients with ABI deem to be necessary. The purpose of this article is to review the typical risks associated with the transports of the patients with ABI out of the intensive care unit and to propose the strategies that can be used to minimize the risks of secondary brain injury. PMID- 24796478 TI - A journey of suffering: living with amyotrophic lateral sclerosis in South Korea. AB - Amyotrophic lateral sclerosis presents significant challenges for patients because of the devastating disease characteristics and the fact that there is no treatment available. In this article, we explored the illness experiences from the perspectives of patients with amyotrophic lateral sclerosis in the sociocultural context of South Korea. Fifteen patients were observed and interviewed between September 2009 and July 2010 in the metropolitan area of South Korea. We used an ethnographic approach for data collection and analysis. The meta-theme generated was "a journey of suffering," and three themes emerged: (a) off the course, (b) drifting, and (c) on a new boat. Participants experienced multidimensional suffering as the disease progressed. Healthcare professionals should understand that, for many patients, this disease is a process or a series of experiences rather than a single diagnosis. This knowledge would allow healthcare providers to help patients prepare for those needs that arise as the disease worsens. PMID- 24796480 TI - Vulgarisin A, a new diterpenoid with a rare 5/6/4/5 ring skeleton from the Chinese medicinal plant Prunella vulgaris. AB - Vulgarisin A (1), a new diterpenoid with an unprecedented 5/6/4/5 fused tetracyclic ring skeleton, has been isolated from the medicinal plant Prunella vulgaris Linn. Its structure was characterized by extensive spectroscopic methods, and the absolute configuration was secured by single crystal X-ray diffraction analysis. Compound 1 showed weak cytotoxicity against human lung carcinoma A549 cells with an IC50 value of 57.0 MUM. PMID- 24796479 TI - Learning and control of exploration primitives. AB - Animals explore novel environments in a cautious manner, exhibiting alternation between curiosity-driven behavior and retreats. We present a detailed formal framework for exploration behavior, which generates behavior that maintains a constant level of novelty. Similar to other types of complex behaviors, the resulting exploratory behavior is composed of exploration motor primitives. These primitives can be learned during a developmental period, wherein the agent experiences repeated interactions with environments that share common traits, thus allowing transference of motor learning to novel environments. The emergence of exploration motor primitives is the result of reinforcement learning in which information gain serves as intrinsic reward. Furthermore, actors and critics are local and ego-centric, thus enabling transference to other environments. Novelty control, i.e. the principle which governs the maintenance of constant novelty, is implemented by a central action-selection mechanism, which switches between the emergent exploration primitives and a retreat policy, based on the currently experienced novelty. The framework has only a few parameters, wherein time scales, learning rates and thresholds are adaptive, and can thus be easily applied to many scenarios. We implement it by modeling the rodent's whisking system and show that it can explain characteristic observed behaviors. A detailed discussion of the framework's merits and flaws, as compared to other related models, concludes the paper. PMID- 24796482 TI - Improving pain assessment in the NICU: a quality improvement project. AB - Pain assessment documentation was inadequate because of the use of a subjective pain assessment strategy in a tertiary level IV neonatal intensive care unit (NICU). The aim of this study was to improve consistency of pain assessment documentation through implementation of a multidimensional neonatal pain and sedation assessment tool. The study was set in a 60-bed level IV NICU within an urban children's hospital. Participants included NICU staff, including registered nurses, neonatal nurse practitioners, clinical nurse specialists, pharmacists, neonatal fellows, and neonatologists. The Plan Do Study Act method of quality improvement was used for this project. Baseline assessment included review of patient medical records 6 months before the intervention. Documentation of pain assessment on admission, routine pain assessment, reassessment of pain after an elevated pain score, discussion of pain in multidisciplinary rounds, and documentation of pain assessment were reviewed. Literature review and listserv query were conducted to identify neonatal pain tools. Survey of staff was conducted to evaluate knowledge of neonatal pain and also to determine current healthcare providers' practice as related to identification and treatment of neonatal pain. A multidimensional neonatal pain tool, the Neonatal Pain, Agitation, and Sedation Scale (N-PASS), was chosen by the staff for implementation. Six months and 2 years following education on the use of the N PASS and implementation in the NICU, a chart review of all hospitalized patients was conducted to evaluate documentation of pain assessment on admission, routine pain assessment, reassessment of pain after an elevated pain score, discussion of pain in multidisciplinary rounds, and documentation of pain assessment in the medical progress note. Documentation of pain scores improved from 60% to 100% at 6 months and remained at 99% 2 years following implementation of the N-PASS. Pain score documentation with ongoing nursing assessment improved from 55% to greater than 90% at 6 months and 2 years following the intervention. Pain assessment documentation following intervention of an elevated pain score was 0% before implementation of the N-PASS and improved slightly to 30% 6 months and 47% 2 years following implementation. Identification and implementation of a multidimensional neonatal pain assessment tool, the N-PASS, improved documentation of pain in our unit. Although improvement in all quality improvement monitors was noted, additional work is needed in several key areas, specifically documentation of reassessment of pain following an intervention for an elevated pain score. PMID- 24796481 TI - Tea consumption and risk of head and neck cancer. AB - BACKGROUND: The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage. METHODS: Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking. RESULTS: A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93-0.99; OR for ?5 cups per day = 0.60, 95% CI: 0.39-0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88 0.98; OR for ?5 cups per day = 0.32, 95% CI: 0.16-0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea. CONCLUSIONS: This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC. PMID- 24796483 TI - A new trigonometric spline approach to numerical solution of generalized nonlinear Klien-Gordon equation. AB - The generalized nonlinear Klien-Gordon equation plays an important role in quantum mechanics. In this paper, a new three-time level implicit approach based on cubic trigonometric B-spline is presented for the approximate solution of this equation with Dirichlet boundary conditions. The usual finite difference approach is used to discretize the time derivative while cubic trigonometric B-spline is applied as an interpolating function in the space dimension. Several examples are discussed to exhibit the feasibility and capability of the approach. The absolute errors and Linfinity error norms are also computed at different times to assess the performance of the proposed approach and the results were found to be in good agreement with known solutions and with existing schemes in literature. PMID- 24796484 TI - Continuing a cancer treatment despite tumor growth may be valuable: sunitinib in renal cell carcinoma as example. AB - BACKGROUND: The US FDA and the EMA have approved seven agents for the treatment of renal cell carcinoma, primarily based on differences in progression-free survival (PFS). Because PFS is an arbitrary endpoint we hypothesized that an analysis would demonstrate the growth rate of tumors remained constant at the time of RECIST-defined disease progression. METHODS: We previously estimated the growth (g) and regression (d) rates and the stability of g using data from the Phase III trial comparing sunitinib and interferon. RESULTS: Sufficient data were available and rate constants statistically valid in 321 of 374 patients randomized to sunitinib. Median d was 0*0052 days(-1); in 53 patients no tumor growth was recorded. Median g was 0*00082 days(-1) and was stable for a median of 275 days on therapy, remaining stable beyond 300, 600 and 900 days in 122, 65 and 27 patients, respectively. A possible increase in g while receiving sunitinib could be discerned in only 18 of 321 patients. Given a median g of 0*00082 days( 1) the estimated median time to a second progression were sunitinib continued past RECIST-defined progression was 7.3 months. At 100, 200, and 300 days after starting therapy, an estimated 47%, 27%, and 13% of tumor remains sunitinib sensitive and could explain a RECIST-defined response to a new TKI. CONCLUSION: Prolonged stability of g with sunitinib suggests continued sunitinib beyond RECIST-defined progression may provide a beneficial outcome. Randomized trials in patients whose disease has "progressed" on sunitinib are needed to test this hypothesis. PMID- 24796486 TI - Editorial comment from Dr Lucarelli and Dr Ditonno to Impact of graft nephrectomy on outcomes of second kidney transplantation. PMID- 24796485 TI - Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2 modified protein-producing renal carcinoma cells. AB - Some cancer cells can survive under glucose deprivation within the microenvironment of a tumor. Recently, we reported that N-linked (beta-N acetylglucosamine)2 [N-GlcNAc2]-modified proteins induce G2/M arrest and cell death under glucose deprivation. Here, we investigated whether such a response to glucose deprivation contributes to the survival of renal cell carcinomas, which are sensitive to nutritional stress. Specifically, we analyzed seven renal carcinoma cell lines. Four of these cell lines produced N-GlcNAc2-modified proteins and led G2/M-phase arrest under glucose deprivation, leading to cell death. The remaining three cell lines did not produce N-GlcNAc2-modified proteins and undergo G1/S-phase arrest under glucose deprivation, leading to survival. The four dead cell lines displayed significant up-regulation in the UDP-GlcNAc biosynthesis pathway as well as increased phosphorylation of p53, which was not observed in the surviving three cell lines. In addition, the four dead cell lines showed prolonged up-regulated expression of ATF3, which is related to unfolded protein response (UPR), while the surviving three cell lines showed only transient up-regulation of ATF3. In this study, we demonstrated that the renal carcinoma cells which accumulate N-GlcNAc2-modified proteins under glucose deprivation do not survive with abnormaly prolonged UPR pathway. By contrast, renal carcinoma cells that do not accumulate N-GlcNAc2-modified proteins under these conditions survive. Morover, we demonstrated that buformin, a UPR inhibitor, efficiently reduced cell survival under conditions of glucose deprivation for both sensitive and resistant phenotypes. Further studies to clarify these findings will lead to the development of novel chemotherapeutic treatments for renal cancer. PMID- 24796487 TI - Penning ionization electron spectroscopy of hydrogen sulfide by metastable helium and neon atoms. AB - The dynamics of the Penning ionization of hydrogen sulfide molecules by collision with helium and metastable neon atoms, occurring in the thermal energy range, has been studied by analyzing the energy spectra of the emitted electrons obtained in our laboratory in a crossed beam experiment. These spectra are compared with the photoelectron spectra measured by using He(I) and Ne(I) photons under the same experimental conditions. In this way we obtained the negative energy shifts for the formation of H2S(+) ions in the first three accessible electronic states by He*(2(3,1)S1,0) and Ne*((3)P2,0) Penning ionization collisions: the 2b1 (X(2)B1) fundamental one, the first 5a1 (A(2)A1), and the second 2b2 (B(2)B2) excited states, respectively. The recorded energy shifts indicate that in the case of He* and Ne*-H2S the autoionization dynamics depends on the features of the collision complex and is mainly driven by an effective global attraction that comes from a balance among several non covalent intermolecular interaction components. This suggests that the Penning ionization should take place, in a specific range of intermolecular distances, as we have already observed in the case of Penning ionization of water molecules [Brunetti, B. G.; Candori, P.; Falcinelli, S.; Pirani, F.; Vecchiocattivi, F. J. Chem. Phys. 2013, 139, 164305-1-164305-8]. PMID- 24796488 TI - Oxygen and hydrogen isotope composition of silage water. AB - Silage is an important dietary water source that influences the oxygen and hydrogen isotopic composition of domestic herbivores and their products. Silage sampled fresh from the silo had (18)O- and (2)H-depleted tissue water when compared with fresh pasture grass sampled around midday during the silage-making seasons. During exposure in the feed bunk, silage water became increasingly enriched in (18)O and (2)H. When delta(18)O was plotted against delta(2)H, the slope of the regression was less during daytime than during night-time. Exposure to (18)O- and (2)H-enriched or -depleted water vapor inside sealed glass containers led to strong changes in the isotope composition of silage water. The results resembled predictions from the Craig-Gordon isotope model of evaporation. The atmospheric conditions during exposure (relative humidity, exposure time, and isotopic composition of the air vapor) in the feed bunk thus strongly affect the isotopic composition of silage water ingested by domestic herbivores. PMID- 24796489 TI - A case of lichen planus pigmentosus that was recalcitrant to topical treatment responding to pigment laser treatment. AB - Lichen planus pigmentosus is a rare variant of lichen planus for which no effective treatment is currently available. Patients usually present with hyperpigmented, dark brown macules on sun-exposed areas or flexural folds. Here we describe a 50-year-old Chinese woman who had biopsy-confirmed lichen planus pigmentosus that was recalcitrant to a variety of topical treatments, but responded to treatment with a pigment laser. PMID- 24796490 TI - Quantitating metabolites in protein precipitated serum using NMR spectroscopy. AB - Quantitative NMR-based metabolite profiling is challenged by the deleterious effects of abundant proteins in the intact blood plasma/serum, which underscores the need for alternative approaches. Protein removal by ultrafiltration using low molecular weight cutoff filters thus represents an important step. However, protein precipitation, an alternative and simple approach for protein removal, lacks detailed quantitative assessment for use in NMR based metabolomics. In this study, we have comprehensively evaluated the performance of protein precipitation using methanol, acetonitrile, perchloric acid, and trichloroacetic acid and ultrafiltration approaches using 1D and 2D NMR, based on the identification and absolute quantitation of 44 human blood metabolites, including a few identified for the first time in the NMR spectra of human serum. We also investigated the use of a "smart isotope tag," (15)N-cholamine for further resolution enhancement, which resulted in the detection of a number of additional metabolites. (1)H NMR of both protein precipitated and ultrafiltered serum detected all 44 metabolites with comparable reproducibility (average CV, 3.7% for precipitation; 3.6% for filtration). However, nearly half of the quantified metabolites in ultrafiltered serum exhibited 10-74% lower concentrations; specifically, tryptophan, benzoate, and 2-oxoisocaproate showed much lower concentrations compared to protein precipitated serum. These results indicate that protein precipitation using methanol offers a reliable approach for routine NMR-based metabolomics of human blood serum/plasma and should be considered as an alternative to ultrafiltration. Importantly, protein precipitation, which is commonly used by mass spectrometry (MS), promises avenues for direct comparison and correlation of metabolite data obtained from the two analytical platforms to exploit their combined strength in the metabolomics of blood. PMID- 24796491 TI - Harnessing implementation science to improve care quality and patient safety: a systematic review of targeted literature. AB - BACKGROUND: Getting greater levels of evidence into practice is a key problem for health systems, compounded by the volume of research produced. Implementation science aims to improve the adoption and spread of research evidence. A linked problem is how to enhance quality of care and patient safety based on evidence when care settings are complex adaptive systems. Our research question was: according to the implementation science literature, which common implementation factors are associated with improving the quality and safety of care for patients? METHODS: We conducted a targeted search of key journals to examine implementation science in the quality and safety domain applying PRISMA procedures. Fifty-seven out of 466 references retrieved were considered relevant following the application of exclusion criteria. Included articles were subjected to content analysis. Three reviewers extracted and documented key characteristics of the papers. Grounded theory was used to distil key features of the literature to derive emergent success factors. RESULTS: Eight success factors of implementation emerged: preparing for change, capacity for implementation-people, capacity for implementation-setting, types of implementation, resources, leverage, desirable implementation enabling features, and sustainability. Obstacles in implementation are the mirror image of these: for example, when people fail to prepare, have insufficient capacity for implementation or when the setting is resistant to change, then care quality is at risk, and patient safety can be compromised. CONCLUSIONS: This review of key studies in the quality and safety literature discusses the current state-of-play of implementation science applied to these domains. PMID- 24796492 TI - A meta-analysis of topiramate's effects for individuals with alcohol use disorders. AB - BACKGROUND: Influenced by several trials and reviews highlighting positive outcomes, topiramate is increasingly prescribed as a treatment for alcohol use disorders (AUDs). The only previously published meta-analysis of topiramate for AUDs was limited by a sample of only 3 randomized, placebo-controlled trials (RCTs). METHODS: A systematic search identified 7 RCTs (including a total of 1,125 participants) that compared topiramate to placebo for the treatment for AUDs. This meta-analysis estimated the overall effects of topiramate on abstinence, heavy drinking, craving, and gamma-glutamyltranspeptidase (GGT) outcomes and included several sensitivity analyses to account for the small sample of studies. RESULTS: Overall, the small to moderate effects favored topiramate, although the effect on craving was not quite significantly different from 0. The largest effect was found on abstinence (g = 0.468, p < 0.01), followed by heavy drinking (g = 0.406, p < 0.01), GGT (g = 0.324, p = 0.02), and craving (g = 0.312, p = 0.07) outcomes. Sensitivity analyses did not change the magnitude or direction of the results, and tests did not indicate significant publication bias. The small sample size did not allow for examination of specific moderators of the effects of topiramate. CONCLUSIONS: Topiramate can be a useful tool in the treatment of AUDs. Its efficacy, based on the current sample of studies, seems to be of somewhat greater magnitude than that of the most commonly prescribed medications for AUDs (naltrexone and acamprosate). Further research will help to identify the contexts in which topiramate is most beneficial (e.g., dose, concurrent psychotherapy, patient characteristics). PMID- 24796493 TI - Autoimmune hepatitis-like reaction developing in a patient treated with interferon-beta1a. PMID- 24796494 TI - Exfoliation of Egyptian Blue and Han Blue, two alkali earth copper silicate-based pigments. AB - In a visualized example of the ancient past connecting with modern times, we describe the preparation and exfoliation of CaCuSi4O10 and BaCuSi4O10, the colored components of the historic Egyptian blue and Han blue pigments. The bulk forms of these materials are synthesized by both melt flux and solid-state routes, which provide some control over the crystallite size of the product. The melt flux process is time intensive, but it produces relatively large crystals at lower reaction temperatures. In comparison, the solid-state method is quicker yet requires higher reaction temperatures and yields smaller crystallites. Upon stirring in hot water, CaCuSi4O10 spontaneously exfoliates into monolayer nanosheets, which are characterized by TEM and PXRD. BaCuSi4O10 on the other hand requires ultrasonication in organic solvents to achieve exfoliation. Near infrared imaging illustrates that both the bulk and nanosheet forms of CaCuSi4O10 and BaCuSi4O10 are strong near infrared emitters. Aqueous CaCuSi4O10 and BaCuSi4O10 nanosheet dispersions are useful because they provide a new way to handle, characterize, and process these materials in colloidal form. PMID- 24796495 TI - Tunable protease-activatable virus nanonodes. AB - We explored the unique signal integration properties of the self-assembling 60 mer protein capsid of adeno-associated virus (AAV), a clinically proven human gene therapy vector, by engineering proteolytic regulation of virus-receptor interactions such that processing of the capsid by proteases is required for infection. We find the transfer function of our engineered protease-activatable viruses (PAVs), relating the degree of proteolysis (input) to PAV activity (output), is highly nonlinear, likely due to increased polyvalency. By exploiting this dynamic polyvalency, in combination with the self-assembly properties of the virus capsid, we show that mosaic PAVs can be constructed that operate under a digital AND gate regime, where two different protease inputs are required for virus activation. These results show viruses can be engineered as signal integrating nanoscale nodes whose functional properties are regulated by multiple proteolytic signals with easily tunable and predictable response surfaces, a promising development toward advanced control of gene delivery. PMID- 24796496 TI - Microbial biofilm formation: a need to act. PMID- 24796497 TI - Ln(IO3)3 (Ln = Ce, Nd, Eu, Gd, Er, Yb) polycrystals as novel photocatalysts for efficient decontamination under ultraviolet light irradiation. AB - Ln(IO3)3 (Ln = Ce, Nd, Eu, Gd, Er, Yb) polycrystals were hydrothermally synthesized using lanthanide nitrate or lanthanide oxide and iodic acid as precursors. X-ray diffraction was used to characterize the crystal structures of the Ln(IO3)3 products. Scanning electron microscopy was carried out to observe the microscopic morphologies. The lattice spacings were studied by high resolution transmission electron microscopy and selected area electron diffraction. We evaluated the photocatalytic efficiency by decomposing methyl orange dye under ultraviolet light irradiation, and the Ln(IO3)3 products show excellent photocatalytic properties. To rule out the effect of photosensitization, 2,4-dichlorophenol was also photodegraded. As one of the key factors of photocatalysis, ultraviolet-visible diffuse reflectance spectra of the Ln(IO3)3 samples were also studied, and all products have strong absorption in the ultraviolet region. PMID- 24796498 TI - Vasodilatory effects of the selective GPER agonist G-1 is maximal in arteries of postmenopausal women. AB - G-protein-coupled estrogen receptors (GPERs) have been proposed to mediate estrogen-mediated vasodilation. The presence of GPER-dependent vasodilation in human resistance-sized arteries (HRAs) or its signal transduction pathways have not been investigated. HRAs in subcutaneous fat tissues (biopsies from postmenopausal women (PMW), age-matched men (M) and pregnant women (PGW)) were mounted for in vitro isometric force recording. Vasodilation induced by G-1 (selective GPER-agonist, 3 MUM) from HRAs pre-contracted with norepinephrine amounted to 40+/-5% in PMW, significantly larger than those obtained from M (20+/ 5%) or PGW (20+/-5%). L-NAME (nitric oxide (NO) synthase inhibitor) abolished these relaxations in PGW, attenuated them in PMW and had no effect in M. Immunohistochemical analysis confirmed the presence of GPER in both smooth muscle and endothelial cells of HRA with maximum expression in PGW. In cultured human umbilical vein endothelial cells (HUVECs), G-1 increased NO-synthesis concentration-dependently through higher expressions of endothelial NO-synthase (eNOS) and through enhanced phosphorylation of eNOS on Ser(1177). In conclusion, GPER vasodilates human resistance arteries through various activating mechanisms of the eNOS-signaling pathway. PMID- 24796499 TI - X chromosome parental origin and aortic stiffness in turner syndrome. AB - INTRODUCTION: Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome (TS). Impaired aortic stiffness may prove to have clinical prognostic value in TS as is the case in other diseases such as Marfan syndrome, diabetes and hypertension. Additionally, the parental origin of the X chromosome in TS may influence aortic stiffness. OBJECTIVE: To assess the relation between X chromosome parental origin and aortic stiffness in TS patients. METHODS: Twenty-four subjects with TS participated in this cross sectional study at a tertiary care centre. The parental origin of the X chromosome was determined. Cardiac-gated multidetector computerized tomography (MDCT) was performed and distensibility of the ascending aorta (AA), a measure of aortic stiffness, was calculated. RESULTS: Fourteen women were Xm (maternal origin) and 10 were Xp (paternal origin) for their inheritance of the single X chromosome. Age, body size, blood pressure and AA areas were similar in the two groups. However, the calculated AA distensibility was significantly lower in the Xm group (2.8 +/- 1.1 mm/Hg) than in the Xp group (4.1 +/- 1.5 mm/Hg); P < 0.05. Conclusion This study demonstrates that TS subjects that inherit their single X chromosome from their mother (Xm) have a significantly stiffer aorta compared with the TS with a paternally originating X chromosome (Xp), consistent with a potentially greater risk for cardiovascular complications. These findings suggest that parental chromosomal analysis and aortic stiffness measurements would be useful for the risk assessment and clinical management of TS patients. PMID- 24796501 TI - Identification of novel sphingolipid-binding motifs in mammalian membrane proteins. AB - Specific interactions between transmembrane proteins and sphingolipids is a poorly understood phenomenon, and only a couple of instances have been identified. The best characterized example is the sphingolipid-binding motif VXXTLXXIY found in the transmembrane helix of the vesicular transport protein p24. Here, we have used a simple motif-probability algorithm (MOPRO) to identify proteins that contain putative sphingolipid-binding motifs in a dataset comprising proteomes from mammalian organisms. From these motif-containing candidate proteins, four with different numbers of transmembrane helices were selected for experimental study: i) major histocompatibility complex II Q alpha chain subtype (DQA1), ii) GPI-attachment protein 1 (GAA1), iii) tetraspanin-7 TSN7, and iv), metabotropic glutamate receptor 2 (GRM2). These candidates were subjected to photo-affinity labeling using radiolabeled sphingolipids, confirming all four candidate proteins as sphingolipid-binding proteins. The sphingolipid binding motifs are enriched in the 7TM family of G-protein coupled receptors, predominantly in transmembrane helix 6. The ability of the motif-containing candidate proteins to bind sphingolipids with high specificity opens new perspectives on their respective regulation and function. PMID- 24796500 TI - Spectrum of Cav1.4 dysfunction in congenital stationary night blindness type 2. AB - Defective retinal synaptic transmission in patients affected with congenital stationary night blindness type 2 (CSNB2) can result from different dysfunction phenotypes in Cav1.4 L-type calcium channels. Here we investigated two prototypical Cav1.4 variants from either end of the functional spectrum. Using whole-cell and single-channel patch-clamp techniques, we provide analysis of the biophysical characteristics of the point mutation L860P and the C-terminal truncating mutation R1827X. L860P showed a typical loss-of-function phenotype attributed to a reduced number of functional channels expressed at the plasma membrane as implied by gating current and non-stationary noise analyses. This phenotype can be rationalized, because the inserted proline is predicted to break an amphipatic helix close to the transmembrane segment IIIS1 and thus to reduce channel stability and promote misfolding. In fact, L860P was subject to an increased turnover. In contrast, R1827X displayed an apparent gain-of-function phenotype, i.e., due to a hyperpolarizing shift of the IV-curve and increased single-channel activity. However, truncation also resulted in the loss of functional C-terminal modulation and thus unmasked calcium-dependent inactivation. Thus R1827X failed to support continuous calcium influx. Current inactivation curtails the dynamic range of photoreceptors (e.g., when adapting to variation in illumination). Taken together, the analysis of two representative mutations that occur in CSNB2 patients revealed fundamental differences in the underlying defect. These may explain subtle variations in the clinical manifestation and must be taken into account, if channel function is to be restored by pharmacochaperones or related approaches. PMID- 24796502 TI - A proapoptotic peptide conjugated to penetratin selectively inhibits tumor cell growth. AB - The peptide KLA (acetyl-(KLAKLAK)2-NH2), which is rather non toxic for eukaryotic cell lines, becomes active when coupled to the cell penetrating peptide, penetratin (Pen), by a disulfide bridge. Remarkably, the conjugate KLA-Pen is cytotoxic, at low micromolar concentrations, against a panel of seven human tumor cell lines of various tissue origins, including cells resistant to conventional chemotherapy agents but not to normal human cell lines. Live microscopy on cells possessing fluorescent labeled mitochondria shows that in tumor cells, KLA-Pen had a strong impact on mitochondria tubular organization instantly resulting in their aggregation, while the unconjugated KLA and pen peptides had no effect. But, mitochondria in various normal cells were not affected by KLA-Pen. The interaction with membrane models of KLA-Pen, KLA and penetratin were studied using dynamic light scattering, calorimetry, plasmon resonance, circular dichroism and ATR-FTIR to unveil the mode of action of the conjugate. To understand the selectivity of the conjugate towards tumor cell lines and its action on mitochondria, lipid model systems composed of zwitterionic lipids were used as mimics of normal cell membranes and anionic lipids as mimics of tumor cell and mitochondria membrane. A very distinct mode of interaction with the two model systems was observed. KLA-Pen may exert its deleterious and selective action on cancer cells by the formation of pores with an oblique membrane orientation and establishment of important hydrophobic interactions. These results suggest that KLA-Pen could be a lead compound for the design of cancer therapeutics. PMID- 24796503 TI - Improvement of pulmonary surfactant activity by introducing D-amino acids into highly hydrophobic amphiphilic alpha-peptide Hel 13-5. AB - The high costs of artificial pulmonary surfactants, ranging in hundreds per kilogram of body weight, used for treating the respiratory distress syndrome (RDS) premature babies have limited their applications. We have extensively studied soy lecithins and higher alcohols as lipid alternatives to expensive phospholipids such as DPPC and PG. As a substitute for the proteins, we have synthesized the peptide Hel 13-5D3 by introducing D-amino acids into a highly lipid-soluble, basic amphiphilic peptide, Hel 13-5, composed of 18 amino acid residues. Analysis of the surfactant activities of lipid-amphiphilic artificial peptide mixtures using lung-irrigated rat models revealed that a mixture (Murosurf SLPD3) of dehydrogenated soy lecithin, fractionated soy lecithin, palmitic acid (PA), and peptide Hel 13-5D3 (40:40:17.5:2.5, by weight) superior pulmonary surfactant activity than a commercially available pulmonary surfactant (beractant, Surfacten(r)). Experiments using ovalbumin-sensitized model animals revealed that the lipid-amphiphilic artificial peptide mixtures provided significant control over an increase in the pulmonary resistance induced by premature allergy reaction and reduced the number of acidocytes and neutrophils in lung-irrigated solution. The newly developed low-cost pulmonary surfactant system may be used for treatment of a wide variety of respiratory diseases. PMID- 24796504 TI - The structure of Lactobacillus brevis surface layer reassembled on liposomes differs from native structure as revealed by SAXS. AB - The reassembly of the S-layer protein SlpA of Lactobacillus brevis ATCC 8287 on positively charged liposomes was studied by small angle X-ray scattering (SAXS) and zeta potential measurements. SlpA was reassembled on unilamellar liposomes consisting of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine and 1,2-dioleoyl-3 trimethylammonium-propane, prepared by extrusion through membranes with pore sizes of 50nm and 100nm. Similarly extruded samples without SlpA were used as a reference. The SlpA-containing samples showed clear diffraction peaks in their SAXS intensities. The lattice constants were calculated from the diffraction pattern and compared to those determined for SlpA on native cell wall fragments. Lattice constants for SlpA reassembled on liposomes (a=9.29nm, b=8.03nm, and gamma=84.9 degrees ) showed a marked change in the lattice constants b and gamma when compared to those determined for SlpA on native cell wall fragments (a=9.41nm, b=6.48nm, and gamma=77.0 degrees ). The latter are in good agreement with values previously determined by electron microscopy. This indicates that the structure formed by SlpA is stable on the bacterial cell wall, but SlpA reassembles into a different structure on cationic liposomes. From the (10) reflection, the lower limit of crystallite size of SlpA on liposomes was determined to be 92nm, corresponding to approximately ten aligned lattice planes. PMID- 24796505 TI - Abdominal collateral vein as an unconventional vascular access for hemodialysis in patient with central vein occlusion. AB - A 65-year-old female patient with chronic kidney disease stage 5 and a history of spleen neoplasm with dissemination within peritoneum is presented. During 5 years of hemodialysis therapy, bilateral occlusion of brachiocephalic and iliac vein developed as a consequence of vein catheterization. An attempt to cannulate inferior vena cava was unsuccessful. A cannulation of dilated collateral abdominal veins with dialysis needles allowed to perform several hemodialysis sessions in the patient. PMID- 24796506 TI - Prognostic comparison of proliferation markers and World Health Organization 1973/2004 grades in urothelial carcinomas of the urinary bladder. AB - European treatment guidelines of non-muscle-invasive urothelial carcinoma of the urinary bladder are strongly dependent on grade, but grading reproducibility is wanting. Protocolized proliferation features such as Mitotic Activity Index (MAI), Ki-67, and phosphohistone H3 are prognostic and reproducible. The objective of this population-based study was to compare proliferation biomarkers with each other and with World Health Organization (WHO) 1973/2004 grades with regard to prediction of stage progression. A total of 193 primary non-muscle invasive urothelial carcinomas were analyzed using WHO73/04 grades and measurement of the proliferation markers mentioned above. Sensitivities, specificities, and positive and negative predictive values with confidence intervals (CIs) were estimated with regard to progression prediction. Kaplan Meier survival curves were made, and the hazard ratio and Harrell's C-index with 95% CIs, P values, and adjusted C-index for stage progression or not of WHO73, WHO04, and the proliferation markers were calculated. The median follow-up time was 75 months (range, 1-127). A total of 111 patients (52%) experienced recurrence within 5 years, and 14 patients (7%) progressed. High values of MAI predicted stage progression with a positive predictive value of 0.22 (95% CI, 0.12-0.37). The positive predictive value of Ki-67 and phosphohistone H3 were 0.15 (both 95% CIs, 0.07-0.29) and comparable to that of the WHO04. The prognostic value of MAI was strongest, exceeding that of the other proliferation markers and the WHO grading systems. In conclusion, in non-muscle-invasive urinary bladder urothelial carcinomas, proliferation biomarkers have prognostic value, possibly exceeding that of the WHO classifications. PMID- 24796507 TI - New-onset pancytopenia: a diagnostic approach-reply. PMID- 24796508 TI - A rare cause of chronic cough: solitary glandular papilloma of the lung. PMID- 24796509 TI - Looking at faces from different angles: Europeans fixate different features in Asian and Caucasian faces. AB - Race categorization of faces is a fast and automatic process and is known to affect further face processing profoundly and at earliest stages. Whether processing of own- and other-race faces might rely on different facial cues, as indicated by diverging viewing behavior, is much under debate. We therefore aimed to investigate two open questions in our study: (1) Do observers consider information from distinct facial features informative for race categorization or do they prefer to gain global face information by fixating the geometrical center of the face? (2) Does the fixation pattern, or, if facial features are considered relevant, do these features differ between own- and other-race faces? We used eye tracking to test where European observers look when viewing Asian and Caucasian faces in a race categorization task. Importantly, in order to disentangle centrally located fixations from those towards individual facial features, we presented faces in frontal, half-profile and profile views. We found that observers showed no general bias towards looking at the geometrical center of faces, but rather directed their first fixations towards distinct facial features, regardless of face race. However, participants looked at the eyes more often in Caucasian faces than in Asian faces, and there were significantly more fixations to the nose for Asian compared to Caucasian faces. Thus, observers rely on information from distinct facial features rather than facial information gained by centrally fixating the face. To what extent specific features are looked at is determined by the face's race. PMID- 24796510 TI - A theory divided: current representations of the anchoring theory of lightness contradict the original's core claims. AB - The anchoring theory of lightness perception (Gilchrist et al., Psychological Review 106 (1999) 795-834) has been described as one of the most successful approaches to lightness perception. Yet, not only does the original proposal contain serious gaps and inconsistencies, later expressions of the theory, which was never formally revised, seem to contradict the original claims while leaving the gaps unresolved. These problems call into question the theory's viability. PMID- 24796511 TI - Children's cognitive representation of the mathematical number line. AB - Learning of the mathematical number line has been hypothesized to be dependent on an inherent sense of approximate quantity. Children's number line placements are predicted to conform to the underlying properties of this system; specifically, placements are exaggerated for small numerals and compressed for larger ones. Alternative hypotheses are based on proportional reasoning; specifically, numerals are placed relative to set anchors such as end points on the line. Traditional testing of these alternatives involves fitting group medians to corresponding regression models which assumes homogenous residuals and thus does not capture useful information from between- and within-child variation in placements across the number line. To more fully assess differential predictions, we developed a novel set of hierarchical statistical models that enable the simultaneous estimation of mean levels of and variation in performance, as well as developmental transitions. Using these techniques we fitted the number line placements of 224 children longitudinally assessed from first to fifth grade, inclusive. The compression pattern was evident in mean performance in first grade, but was the best fit for only 20% of first graders when the full range of variation in the data are modeled. Most first graders' placements suggested use of end points, consistent with proportional reasoning. Developmental transition involved incorporation of a mid-point anchor, consistent with a modified proportional reasoning strategy. The methodology introduced here enables a more nuanced assessment of children's number line representation and learning than any previous approaches and indicates that developmental improvement largely results from midpoint segmentation of the line. PMID- 24796512 TI - Ethnic variation in breastfeeding and complimentary feeding in the Republic of Ireland. AB - Early nutrition plays a pivotal role in long-term health. The World Health Organization (WHO) recommends exclusive breastfeeding during the first six months of life, with the gradual introduction of solids after this period. However, studies in the Republic of Ireland (ROI) have shown poor compliance with guidelines. The ROI continues to have one of the lowest breastfeeding rates worldwide. Our objective was to analyse differences in breastfeeding and complimentary feeding behaviours between Irish and non-Irish mothers residing in the ROI, as well as the role of acculturation on these behaviours, using the national longitudinal study, Growing Up in Ireland (GUI). Mothers (n = 11,134) residing in the ROI were interviewed when their infants were nine months of age. The percentage of Irish mothers who initiated breastfeeding was 49.5%, as opposed to 88.1% among the non-Irish cohort (p < 0.001). Breastfeeding initiation reduced from 89.4% of non-Irish mothers who had arrived within the last year to five years ago to 67.5% for those who had arrived 11 to >20 years ago (p < 0.001). Our results indicate that cultural differences are an important factor in shaping patterns of infant feeding in the ROI. Reviewing existing support and education policies for parents is required to achieve the implementation of desirable infant feeding practices. PMID- 24796513 TI - Exploring the high lipid production potential of a thermotolerant microalga using statistical optimization and semi-continuous cultivation. AB - A recently isolated thermotolerant microalga Desmodesmus sp. F2 has the traits of becoming potential biodiesel feedstock, such as high growth rate, high lipid content, and quick precipitation. Its overall lipid productivity was 113 mg/L/d when grown under non-optimal conditions using batch cultivation. A two-step response surface methodology was adopted to optimize its cultivation conditions. The overall lipid productivity was increased to 263 mg/L/d when the cells were grown under the optimized conditions of 6.6mM initial nitrogen level and 6 days nitrogen depletion treatment in 700 MUmol/m(2)/s light intensity at 35 degrees C using batch cultivation. Fed-batch and semi-continuous cultivations were employed to further increase its lipid productivity to 213 and 302 mg/L/d, respectively. The 302 mg/L/d is the highest overall lipid productivity of microalgae ever reported in the literature. This study provides the information required for the design and operation of photobioreactors for large scale outdoor cultivation of this species. PMID- 24796514 TI - Visualization of dyed NAPL concentration in transparent porous media using color space components. AB - Finding a correlation between image pixel information and non-aqueous phase liquid (NAPL) saturation is an important issue in bench-scale geo-environmental model studies that employ optical imaging techniques. Another concern is determining the best dye color and its optimum concentration as a tracer for use in mapping NAPL zones. Most bench scale flow studies employ monochromatic gray scale imaging to analyze the concentration of mostly red dyed NAPL tracers in porous media. However, the use of grayscale utilizes a third of the available information in color images, which typically contain three color-space components. In this study, eight color spaces consisting of 24 color-space components were calibrated against dye concentration for three color-dyes. Additionally, multiple color space components were combined to increase the correlation between color-space data and dyed NAPL concentration. This work is performed to support imaging of NAPL migration in transparent synthetic soils representing the macroscopic behavior of natural soils. The transparent soil used in this study consists of fused quartz and a matched refractive index mineral-oil solution that represents the natural aquifer. The objective is to determine the best color dye concentration and ideal color space components for rendering dyed sucrose-saturated fused quartz that represents contamination of the natural aquifer by a dense NAPL (DNAPL). Calibration was achieved for six NAPL zone lengths using 3456 images (24 color space components*3 dyes*48 NAPL combinations) of contaminants within a defined criteria expressed as peak signal to noise ratio. The effect of data filtering was also considered and a convolution average filter is recommended for image conditioning. The technology presented in this paper is fast, accurate, non-intrusive and inexpensive method for quantifying contamination zones using transparent soil models. PMID- 24796515 TI - Transport of bare and capped zinc oxide nanoparticles is dependent on porous medium composition. AB - Zinc oxide (ZnO) nanoparticles are one of the most frequently used nanoparticles in industry and hence are likely to be introduced to the groundwater environment. The mobility of these nanoparticles in different aquifer materials has not been assessed. While some studies have been published on the transport of ZnO nanoparticles in individual porous media, these studies do not generally account for varying porous medium composition both within and between aquifers. As a first step towards understanding the impact of this variability, this paper compares the transport of bare ZnO nanoparticles (bZnO-NPs) and capped ZnO nanoparticles, coated with tri-aminopropyltriethoxysilane (cZnO-NPs), in saturated columns packed with glass beads, fine grained sand and fine grained calcite, at near-neutral pH and groundwater salinity levels. With the exception of cZnO-NPs in sand columns, ZnO nanoparticles are highly immobile in all three types of studied porous media, with most retention taking place near the column inlet. Results are in general agreement with DLVO theory, and the deviation in experiments with cZnO-NPs flowing through columns packed with sand is linked to variability in zeta potential of the capped nanoparticles and sand grains. Therefore, differences in surface charge of nanoparticles and porous media are demonstrated to be key drivers in nanoparticle transport. PMID- 24796516 TI - Understanding disorders of sexual development. AB - Studies estimate that the incidence of genital anomalies could be as high as 1 in 300 births. While it is rare for an infant to present with truly ambiguous genitalia, it is plausible that the pediatric nurse will encounter a patient with disorders of sexual development in his or her career. Cases of disorders of sexual development are challenging due to complexities of diagnosis, gender assignment, uncertain outcomes, treatment options, and psychosocial stressors. This article discusses the evaluation and management of children with disorders of sexual development and the nurse's role as child advocate and family educator. PMID- 24796517 TI - Posttraumatic feeding disorder in low birth weight young children: a nested case control study of a home-based intervention program. AB - Low birth weight infants (LBW) are reported to be at risk for posttraumatic feeding disorder (PTFD). In this study, we evaluated the outcome of an intervention program for infants with PTFD. LBW infants with PTFD (N=21) completed feeding behavior questionnaires at entry and after completing the program and were compared to a matched control group. PTFD group infants showed a significantly high rate of food disorder symptoms at entry but not at follow-up compared to the control group. The intervention program for PTFD infants resulted in reduced feeding disorder symptoms. PMID- 24796518 TI - The new DSM-5 and its impact on the mental health care of children. AB - The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5), the premier resource in the diagnosis of mental health conditions, was published in June 2013. It contains many new diagnoses as well as changes to both the names and criteria for longstanding conditions. It is essential for pediatric nurses to understand the changes so that they can communicate effectively and advocate responsibly for their patients and families. This article discusses the changes, the criticisms voiced about them, and the implications for the pediatric nurse. PMID- 24796519 TI - Development of an efficient trapping system for New Zealand flower thrips, Thrips obscuratus. AB - BACKGROUND: New Zealand flower thrips (NZFT), Thrips obscuratus (Crawford), is an economic pest of various horticultural crops in New Zealand and is recognised as a quarantine pest globally. Two chemical attractants (ethyl nicotinate and 6 pentyl-2H-pyran-2-one), three dispensers, three trap designs and four trap heights were investigated to determine the most effective method for monitoring NZFT. Phenology of NZFT at two locations was compared. RESULTS: 6-Pentyl-2H-pyran 2-one in a polyethylene bag dispenser was the most attractive lure formulation and exhibited high stability in release rate trials. There was no difference in NZFT catch between vertical-panel and cross-panel traps, but both caught significantly more than delta traps. However, both types of panel trap had unacceptably high by-catch of native insects. Catch of thrips increased with height from 0 to 3 m. Phenology of NZFT showed similar population trends at both locations, but with a timing difference of around 50 days. CONCLUSIONS: Delta traps containing 6-pentyl-2H-pyran-2-one in a polyethylene bag at 2 m above the ground is the recommended method for monitoring NZFT, significantly improving the sensitivity, accuracy and labour input compared with prior methods. Long-term monitoring of NZFT could lead to more accurate economic damage thresholds and timing for when to apply insecticides. (c) 2014 Society of Chemical Industry. PMID- 24796520 TI - Molecular and cellular mechanisms of heterotopic ossification. AB - Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients' lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone. PMID- 24796521 TI - Biology of spermatogenesis--the challenges ahead. PMID- 24796522 TI - Biology of spermatogenesis. PMID- 24796523 TI - Influential factors in the response to salvage radiotherapy after radical prostatectomy. AB - OBJECTIVE: To analyze the influential factors in the response in prostatectomized patients with subsequent biochemical relapse (BCR) and treated with salvage radiotherapy (RTP). MATERIAL AND METHODS: We analyzed 313 patients with pT2/pT3 prostate cancer who were receiving salvage therapy due to biochemical relapse (from a series of 1,310 radical prostatectomies between 1989-2012). Of the 313 patients; 159 (50.8%) only received androgen deprivation (AD), 63 (20.1%) Radiotherapy (RTP) plus concomitant AD and 91 (29.1%) only RTP. Of these, 57 (62.6%) have maintained complete response and 34 (37.4%) had failure response with post-RTP BCR. RESULTS: Study of the group treated exclusively with salvage RTP. Ninety-one patients were treated with salvage RTP. Median follow-up was 6.4 years and median to recurrence 11 months. Post-RTP biochemical relapse-free survival (PRBRFS) was 68 +/- 7% and 30 +/- 10% in 5 to 10 years. Median PRBRFS was 7.3 years (6.3-8.3). Initial PSA (HR: 1.08; 95% CI: 1.01-1.1 P=.02) with best PSA cut-off point PSA>20 ng/ml (HR: 13.6; 95% CI: 2.1-86 P=.005) and PSA pre-RTP (HR: 1.9; 95% CI: 1.2-3.3; P=.009), best PSA cut-off point PSA preRTP 0.92 ng/ml (HR: 4.5; 95% CI: 1.3-15.6; P=.01) showed independent influence in the response in the multivariate study. PRBRFS at 5 years, 81 +/- 9% versus 58 +/- 9% with initial PSA <20 or >20 ng/ml (P=.03). PRBRFS at 5 years, 93 +/- 5% versus 53 +/- 10% according to PSA pre-RTP <0.9 or >0.9 ng/ml (P=.02). CONCLUSIONS: In patients treated with salvage RTP after radical prostatectomy, the preoperative PSA>20 ng/ml and PSA preRTP>0.92 ng/ml shows an independent influence on the response. PMID- 24796524 TI - Stress urinary incontinence surgery with sling MiniArc: a 4-year results. AB - OBJETIVES: The aim of this publication is to describe retrospectively the results of the surgical technique of AMS MiniArc for the treatment of female urinary incontinence, evaluate its results at 4 years follow-up. MATERIAL AND METHODS: We present a retrospective cohort study of 135 patients, 110 (81.5%) had urinary incontinence and 25 (18.5%) mixed urinary incontinence. All these procedures were performed with local anesthesia and in "out patient surgery". Patients were monitored in the outpatient clinic at 6 months (control 1), one year (control 2) and annually (control 3, 4, and 5). During the following up, clinical history was made in every woman with ICIQ-SF questionnaire, that included a fourth question to evaluate the degree of satisfaction after surgery, as well as physical examination. We considered objective cure when negative stress with full bladder. We use the SPSS program (V19.0) for statistical analysis of the results. RESULTS: The mean follow-up was of 59 months (range from 33 to 72 months). When evaluating the success rate of anti-incontinence surgery, 86.7% of patients showed objective cured (80.8% with MUI and 89.2% with SUI). The ICIQ-SF decreased average of 12.7 points, 85.7% patients were very or fairly satisfied. CONCLUSION: The AMS MiniArc is an optim anti-incontinence procedure a medium term. But the results should be interpreted with caution given the limitations of the study. PMID- 24796525 TI - Nonempirical calculations of the one-bond (29)Si-(13)C spin-spin coupling constants taking into account relativistic and solvent corrections. AB - The computational study of the one-bond (29)Si-(13)C spin-spin coupling constants has been performed at the second-order polarization propagator approximation (SOPPA) level in the series of 60 diverse silanes with a special focus on the main factors affecting the accuracy of the calculation including the level of theory, the quality of the basis set, and the contribution of solvent and relativistic effects. Among three SOPPA-based methods, SOPPA(MP2), SOPPA(CC2), and SOPPA(CCSD), the best result was achieved with SOPPA(CCSD) when used in combination with Sauer's basis set aug-cc-pVTZ-J characterized by the mean absolute error of calculated coupling constants against the experiment of ca 2 Hz in the range of ca 200 Hz. The SOPPA(CCSD)/aug-cc-pVTZ-J method is recommended as the most accurate and effective computational scheme for the calculation of (1)J(Si,C). The slightly less accurate but essentially more economical SOPPA(MP2)/aug-cc-pVTZ-J and/or SOPPA(CC2)/aug-cc-pVTZ-J methods are recommended for larger molecular systems. It was shown that solvent and relativistic corrections do not play a major role in the computation of the total values of (1)J(Si,C); however, taking them into account noticeably improves agreement with the experiment. The rovibrational corrections are estimated to be of about 1 Hz or 1-1.5% of the total value of (1)J(Si,C). PMID- 24796526 TI - [Importance of an emergency medical care system in the recovery of cardiac arrest]. PMID- 24796527 TI - Heart calcification (idiopathic cardiac osseous metaplasia): a case report. PMID- 24796528 TI - Self-identities and durability of biosystems via their abstracting capacity. AB - Any surviving organism is unique in abstracting and holding its self-identity as experiencing and processing different individual events of a concrete nature. The organism that can survive maintains its self-identity as abstracting its own durability as a class property out of those different individual events to be met and processed. Rather, the organism has the internal propensity of making its own actualization durable while processing the material resources available that are individually distinguishable. Biology is distinctive as compared to physics in availing itself of the synthesis of organization with use of the material act of measurement as a form of abstraction. PMID- 24796529 TI - Sonographic appearance of uterine lymphoma: case report and review of the literature. AB - Uterine lymphoma is rare and tends to be misdiagnosed due to lack of specific radiologic features. Few reports have been published on the sonographic characteristics of uterine lymphoma. We present a case report of uterine lymphoma manifested by a fast growing uterus and describe the sonographic findings. PMID- 24796530 TI - DNA barcoding detected improper labelling and supersession of crab food served by restaurants in India. AB - BACKGROUND: Detection of improper labelling of raw and processed seafood is of global importance for reducing commercial fraud and enhancing food safety. Crabs are crustaceans with intricate morphological as well as genetic divergence among species and are popular as seafood in restaurants. Owing to the high number of crab species available, it can be difficult to identify those included in particular food dishes, thus increasing the chance of supersession. DNA barcoding is an advanced technology for detecting improper food labelling and has been used successfully to authenticate seafood. RESULTS: This study identified 11 edible crab species from India by classical taxonomy and developed molecular barcodes with the cytochrome c oxidase I (COI) gene. These barcodes were used as reference barcodes for detecting any improper labelling of 50 restaurant crab samples. Neighbour-joining tree analysis with COI barcodes showed distinct clusters of restaurant samples with respective reference species. The study demonstrated 100% improper labelling of restaurant samples to cover up acts of inferior crab supersession. CONCLUSION: DNA barcoding successfully identified 11 edible crabs in accordance with classical taxonomy and discerned improper crab food labelling in restaurants of India. PMID- 24796532 TI - Proliferation of oogonia and folliculogenesis in the viviparous teleost Ilyodon whitei (Goodeidae). AB - Oogonial proliferation in fishes is an essential reproductive strategy to generate new ovarian follicles and is the basis for unlimited oogenesis. The reproductive cycle in viviparous teleosts, besides oogenesis, involves development of embryos inside the ovary, that is, intraovarian gestation. Oogonia are located in the germinal epithelium of the ovary. The germinal epithelium is the surface of ovarian lamellae and, therefore, borders the ovarian lumen. However, activity and seasonality of the germinal epithelium have not been described in any viviparous teleost species regarding oogonial proliferation and folliculogenesis. The goal of this study is to identify the histological features of oogonial proliferation and folliculogenesis during the reproductive cycle of the viviparous goodeid Ilyodon whitei. Ovaries during nongestation and early and late gestation were analyzed. Oogonial proliferation and folliculogenesis in I. whitei, where intraovarian gestation follows the maturation and fertilization of oocytes, do not correspond to the late oogenesis, as was observed in oviparous species, but correspond to late gestation. This observation offers an example of ovarian physiology correlated with viviparous reproduction and provides elements for understanding the regulation of the initiation of processes that ultimately result in the origin of the next generation. These processes include oogonia proliferation and development of the next batch of germ cells into the complex process of intraovarian gestation. PMID- 24796531 TI - Differentiation-associated genes regulated by c-Jun and decreased in the progression of esophageal squamous cell carcinoma. AB - Transcription factor c-Jun plays a key role in controlling epithelium cell proliferation, apoptosis and differentiation. However, molecular mechanism and biological functions of c-Jun in squamous differentiation and the progression of esophageal squamous cell carcinoma (ESCC) remain elusive. In this study, we found that c-Jun bound directly to the promoter region, and activated the transcription of differentiation-associated genes including cystatin A, involucrin and SPRR3 in vivo. Ectopic expression of c-Jun enhanced SPRR3 transactivation in KYSE450 cells. Conversely, TAM67, a dominant negative mutant of c-Jun, inhibited SPRR3 transactivation. c-Jun increased expression of SPPR3 mainly via a PKC/JNK pathway in response to TPA in KYSE450 cells. Furthermore, c-Jun was remarkably reduced in esophageal cancer. Interestingly, cystatin A, involucrin and SPRR3 were significantly downregulated as well, and associated with differentiation grade. Expression of c-Jun was correlated with the expression of these genes in normal epithelium and ESCC. Importantly, the expression of these genes was remarkably decreased during the malignant transformation from normal epithelium to low-grade intraepithelial neoplasia (LGIN) or high-grade intraepithelial neoplasia (HGIN). The expression of cystatin A and involucrin was significantly reduced from LGIN to HGIN. These results suggest c-Jun was involved in the regulation of differentiation-associated genes in ESCC. These genes might serve as the potential markers in distinguishing normal epithelium from esophageal squamous intraepithelial neoplasia. PMID- 24796534 TI - Clinical Application of the DiversiLab Microbial Typing System Using Repetitive Sequence-Based PCR for Characterization of Helicobacter pylori in Japan. AB - We evaluated the DiversiLab (DL) system with universal primers, a semiautomated repetitive extragenic palindromic sequence-based polymerase chain reaction (PCR) (rep-PCR) system, for the characterization of Helicobacter pylori in Japan. All 135 isolates from Japanese patients with gastric cancer (GC, n = 55) or non-GC (n = 80) were used and subjected to the drug susceptibility examinations (amoxicillin, AMPC; metronidazole, MNZ; and clarithromycin, CAM) by E-test. There were 28 MNZ-resistant (20.7%), 35 CAM-resistant (25.9%), and 16 MNZ/CAM-resistant (11.9%) isolates. DL rep-PCR fingerprinting analysis at the level of 95% similarity revealed five major groups (A-E) and the other including 45 isolates. The occupation rates of GC-derived isolates in groups B (54.2%) and E (58.8%) were higher than in the other groups: A (26.7%), C (28.6%), D (30.0%), and the other (40.0%). Relative higher occupation rates of drug resistants, such as MNZ-, CAM- and double MNZ/CAM-resistant isolates, were observed in groups B (45.8%), C (42.6%), and D (40%). Five of eight GC-derived isolates with MNZ/CAM resistance were significantly assigned to group B (P = 0.0312, chi(2) -test). These results suggest that the isolates classified in group B have a potential to contribute to the development of severe gastric disorders. The DL system, rapid and high sensitive technology, would be widely available in clinical laboratory for pathological and epidemiological analyses even in H. pylori. PMID- 24796533 TI - Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy. AB - While much of cancer immunology research has focused on anti-tumor immunity both systemically and within the tumor microenvironment, little is known about the impact of pre-existing malignancy on pathogen-specific immune responses. Here, we sought to characterize the antigen-specific CD8+ T cell response following a bacterial infection in the setting of pre-existing pancreatic adenocarcinoma. Mice with established subcutaneous pancreatic adenocarcinomas were infected with Listeria monocytogenes, and antigen-specific CD8+ T cell responses were compared to those in control mice without cancer. While the kinetics and magnitude of antigen-specific CD8+ T cell expansion and accumulation was comparable between the cancer and non-cancer groups, bacterial antigen-specific CD8+ T cells and total CD4+ and CD8+ T cells in cancer mice exhibited increased expression of the coinhibitory receptors BTLA, PD-1, and 2B4. Furthermore, increased inhibitory receptor expression was associated with reduced IFN-gamma and increased IL-2 production by bacterial antigen-specific CD8+ T cells in the cancer group. Taken together, these data suggest that cancer's immune suppressive effects are not limited to the tumor microenvironment, but that pre-existing malignancy induces phenotypic exhaustion in T cells by increasing expression of coinhibitory receptors and may impair pathogen-specific CD8+ T cell functionality and differentiation. PMID- 24796535 TI - Experimental and theoretical insights into photochemical transformation kinetics and mechanisms of aqueous propylparaben and risk assessment of its degradation products. AB - The kinetics and mechanisms of ultraviolet photochemical transformation of propylparaben (PPB) were studied. Specific kinetics scavenging experiments coupled with quantum yield determinations were used to distinguish the roles of various reactive species induced by self-sensitized and direct photolysis reactions, and the excited triplet state of PPB ((3) PPB*) was identified as the most important species to initiate the photochemical degradation of PPB in aquatic environments. The computational results of time-resolved absorption spectra proved that (3) PPB* is a highly reactive electron acceptor, and a head to-tail hydrogen transfer mechanism probably occurs through electron coupled with proton transfer. Physical quenching by, or chemical reaction of (3) PPB* with, O2 was confirmed as a key step affecting the initial PPB transformation pathways and degradation mechanisms. The transformation products were identified and the toxicity evolutions of PPB solutions during photochemical degradation under aerobic and anaerobic conditions were compared. The results indicate that anaerobic conditions are more likely than aerobic conditions to lead to the elimination and detoxification of PPB but less likely to lead to PPB mineralization. PMID- 24796536 TI - Cytokine imbalance in irritable bowel syndrome: a systematic review and meta analysis. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology; although infection and inflammation have recently been considered as important etiologic agents. A recent meta-analysis showed correlations between cytokine [interleukin-10 (IL-10) and tumor necrosis factor (TNF)] gene polymorphisms and IBS; however, it is still unknown whether patients with IBS have different cytokine profiles compared to healthy population. METHODS: To determine the relationships between serum/plasma levels or mucosal expression of IL-10/TNF-alpha and IBS, we conducted a systematic review and meta analysis based on case-control studies retrieved from PubMed and EMBASE search through August 2013. Standardized mean difference (SMD) was generated by using the inverse variance method. Heterogeneity was assessed based on I(2) values. KEY RESULTS: Serum/plasma levels of TNF-alpha tended to be higher in IBS vs controls (p = 0.09); this reached significance in IBS subtypes vs controls and in female patients with IBS. However, serum/plasma levels of IL-10 were not significantly different in IBS patients vs controls. Further analysis of serum/plasma IL-10 levels in IBS subtypes did not show any difference; however, analysis based on gender showed a significantly lower serum/plasma IL-10 levels in male patients with IBS vs male controls (p = 0.02). Colonic IL-10 mRNA had a significantly lower expression in IBS vs control (p = 0.001). CONCLUSIONS & INFERENCES: There is an imbalance of proinflammatory TNF-alpha, and anti-inflammatory IL-10, cytokines in IBS. Stratifying IBS patients based on cytokine profile may represent an opportunity for personalized treatment of this condition. PMID- 24796538 TI - Protecting group free synthesis of urea-linked glycoconjugates: efficient synthesis of beta-urea glycosides in aqueous solution. AB - A method for the protecting group free synthesis of beta-urea-linked glycoconjugates has been developed. The one step process, involving reactions between urea and D-glucose, N-acetyl-D-glucosamine or D-xylose in acidic aqueous solution, furnishes the corresponding beta-urea glycosides in modest yields. This simple and efficient procedure is applicable to the synthesis of beta-urea tethered amino acid-carbohydrate conjugates. PMID- 24796537 TI - Peripheral surgical wounding and age-dependent neuroinflammation in mice. AB - Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of beta-amyloid (Abeta) have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Abeta accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), Iba1 positive cells (the marker of microglia activation), CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-alpha, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients. PMID- 24796540 TI - Autophagy plays a protective role as an anti-oxidant system in human T cells and represents a novel strategy for induction of T-cell apoptosis. AB - Autophagy is an intracellular degradation system that plays an important role in T-cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy-defective naive CD4(+) T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4(+) T cells had lower autophagic activity than naive CD4(+) T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti-oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T-cell death, which could be a novel strategy for induction of T-cell apoptosis. PMID- 24796539 TI - Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer. AB - BACKGROUND: Family history of prostate cancer is a well-recognized risk factor. Previous linkage studies have reported a putative prostate cancer susceptibility locus at chromosome 17q21-22. SPOP (Speckle-type POZ protein) maps to the 17q21 22 candidate linkage region and is one of the most frequently mutated genes in sporadic prostate cancers. METHODS: We performed targeted next generation sequencing to analyze 2009 exons from 202 genes in a candidate linkage region on chromosome 17q21-22 using 94 unrelated familial prostate cancer cases from the University of Michigan Prostate Cancer Genetics Project (n=54) and Johns Hopkins University (n=40) including the exons and UTRs of SPOP. RESULTS: We identified a novel SPOP missense mutation (N296I) in a man with prostate cancer diagnosed at age 43. This mutation completely segregates with prostate cancer affection status among the men in this family. The N296I mutation resides within the evolutionarily conserved Bric-a-brac, Tramtrack, Broad-complex (BTB) domain, involved in recruiting targets to Cul3 for degradation. Analysis of the prostate tumor from this individual verified the presence of heterozygous N296I as well as an ERG fusion. CONCLUSIONS: We have discovered a novel mutation in SPOP that tracks with prostate cancer within a family and is predicted to be deleterious. Taken together, our results implicate SPOP as a candidate gene for hereditary prostate cancer. PMID- 24796541 TI - Rates and predictors of renewed quitting after relapse during a one-year follow up among primary care patients. AB - BACKGROUND: Most people who quit smoking relapse within a year of quitting. Little is known about what prompts renewed quitting after relapse or how often this results in abstinence. PURPOSE: This study seeks to identify rates, efficacy, and predictors of renewed quit attempts after relapse during a 1-year follow-up. METHODS: Primary care patients in a comparative effectiveness trial of smoking cessation pharmacotherapies reported daily smoking every 6-12 weeks for 12 months to determine relapse, renewed quitting, and 12-month abstinence rates. RESULTS: Of 894 known relapsers, 291 (33%) renewed quitting for at least 24 h, and 99 (34%) of these were abstinent at follow-up. The average latency to renewed quitting was 106 days and longer latencies predicted greater success. Renewed quitting was more likely for older, male, less dependent smokers, and later abstinence was predicted by fewer depressive symptoms and longer past abstinence. CONCLUSIONS: Renewed quitting is common and produces meaningful levels of cessation. PMID- 24796542 TI - Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology. AB - Three causal genes for idiopathic basal ganglia calcification (IBGC) have been identified. Most recently, mutations in PDGFRB, encoding a member of the platelet derived growth factor receptor family type beta, and PDGFB, encoding PDGF-B, the specific ligand of PDGFRbeta, were found implicating the PDGF-B/PDGFRbeta pathway in abnormal brain calcification. In this study, we aimed to identify and study mutations in PDGFRB and PDGFB in a series of 26 patients from the Mayo Clinic Florida Brain Bank with moderate to severe basal ganglia calcification (BCG) of unknown etiology. No mutations in PDGFB were found. However, we identified one mutation in PDGFRB, p.R695C located in the tyrosine kinase domain, in one BGC patient. We further studied the function of p.R695C mutant PDGFRbeta and two previously reported mutants, p.L658P and p.R987W PDGFRbeta in cell culture. We show that, in response to PDGF-BB stimulation, the p.L658P mutation completely suppresses PDGFRbeta autophosphorylation, whereas the p.R695C mutation results in partial loss of autophosphorylation. For the p.R987W mutation, our data suggest a different mechanism involving reduced protein levels. These genetic and functional studies provide the first insight into the pathogenic mechanisms associated with PDGFRB mutations and provide further support for a pathogenic role of PDGFRB mutations in BGC. PMID- 24796543 TI - A double-dose hepatitis B vaccination schedule in travelers presenting for late consultation. AB - BACKGROUND: Vaccination against hepatitis B virus (HBV) is recommended for all travelers visiting HBV-endemic countries. However, travelers often present with insufficient time for the standard HBV vaccine schedule (SVS). We examined seroprotection against HBV following an alternative two-visit vaccination schedule (TVS) with currently available vaccine products, and completion rates with this TVS. METHODS: A retrospective cohort study was conducted in three travel clinics in British Columbia, Canada. Adults >=20 years old traveling to an HBV-endemic country, and unable to complete the standard or rapid HBV vaccination schedule before departure, were offered a TVS that consisted of a double dose of HBV vaccine at day 0, followed by a single dose in 4 to 12 months. Immunity to HBV [anti-HBV surface antigen (HBs) >=10 mIU/mL] was determined 1 to 6 months following the final dose of HBV vaccine. Logistic regression modeling was used to assess correlates of seroprotection. We also determined completion rate with this TVS at two clinics. RESULTS: In total, 117 participants (age range, 21-81 years, median age 57) met the inclusion criteria. Of these, 97 (82.9%) were immune after the TVS. Immunity was demonstrated in 93.1% of patients <50 years old and 79.5% of patients >=50 years old. Increasing age was associated with reduced odds of developing immunity to HBV using the TVS [adjusted odds ratio = 0.954, 95% confidence interval (CI): 0.904, 1.008]. The completion rate of the TVS was 32.6% over a 12-month period. Completion rates varied between clinics (23.5% vs 48.4%, p < 0.001), suggesting that clinic-specific follow-up policies were important. CONCLUSION: Seroprotection with completion of this TVS was similar to or exceeded that published in the literature for the SVS by age. However, even with a TVS, completion rates were low, underscoring the importance of follow-up. Further research is needed to determine whether travelers are protected prior to completion of this TVS. PMID- 24796544 TI - Bromeliad treefrogs as phoretic hosts of ostracods. AB - Aquatic organisms can use many methods of dispersal among discrete freshwater habitats, and phoresy is an important but poorly understood mechanism. Tank bromeliads are small and unconnected habitats used by many animals, and some of them use phoresy for dispersal. Ostracods living in bromeliads used treefrogs as phoretic hosts for dispersal. We investigated the distribution of phoretic ostracods among body parts of treefrogs (Scinax littoreus and Scinax perpusillus), the prevalence and intensity of ostracods (Elpidium sp.) between Scinax species, and the prevalence and mean intensity of ostracods among the frogs in wet vs. dry seasons in two inselbergs areas at Rio de Janeiro State (Brazil). There were significant differences among the body parts occupied by ostracods and between the Scinax species. Seasonal differences were found only for S. littoreus showing greater abundance during the wet season. Additionally, we record Scinax cuspidatus and Thoropa miliaris as new phoretic hosts for Elpidium sp. to use phoresy. PMID- 24796545 TI - Hippocampal slow EEG frequencies during NREM sleep are involved in spatial memory consolidation in humans. AB - The hypothesis that sleep is instrumental in the process of memory consolidation is currently largely accepted. Hippocampal formation is involved in the acquisition of declarative memories and particularly of spatial memories. Nevertheless, although largely investigated in rodents, the relations between spatial memory and hippocampal EEG activity have been scarcely studied in humans. Aimed to evaluate the effects of spatial learning on human hippocampal sleep EEG activity, we recorded hippocampal Stereo-EEG (SEEG) in a group of refractory epilepsy patients undergoing presurgical clinical evaluation, after a training on a spatial navigation task. We observed that hippocampal high-delta (2-4 Hz range) activity increases during the first NREM episode after learning compared to the baseline night. Moreover, the amount of hippocampal NREM high-delta power was correlated with task performance at retest. The effect involved only the hippocampal EEG frequencies inasmuch no differences were observed at the neocortical electrodes and in the traditional polysomnographic measures. The present findings support the crucial role of hippocampal slow EEG frequencies during sleep in the memory consolidation processes. More generally, together with previous results, they suggest that slow frequency rhythms are a fundamental characteristic of human hippocampal EEG during both sleep and wakefulness, and are related to the consolidation of different types of memories. PMID- 24796546 TI - Choosing a screening method for cervical cancer: Papanicolaou testing alone or with human papillomavirus testing. PMID- 24796547 TI - Alkyne cycloaddition to a titanocene oxide as a route to cyclopentadienyl modification. AB - Addition of terminal or internal alkynes to a base-free titanocene oxide results in synthesis of the corresponding oxometallocyclobutene. With appropriate cyclopentadienyl substitution, these compounds undergo reversible C-C reductive elimination offering a unique approach to cyclopentadienyl modification. PMID- 24796548 TI - Enhancement of the HIF-1alpha/15-LO/15-HETE axis promotes hypoxia-induced endothelial proliferation in preeclamptic pregnancy. AB - Preeclampsia (PE) is an extremely serious condition in pregnant women and the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiological factors of this disorder remain elusive. The increased release of 15-hydroxyeicosatetraenoic acid (15-HETE) in the placenta of preeclamptic patients has been studied, but its exact role in PE pathogenesis remains unknown. Mounting evidence shows that PE is associated with placental hypoxia, impaired placental angiogenesis, and endothelial dysfunction. In this study, we confirmed the upregulated expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and 15-lipoxygenase-1/2 (15-LO-1/2) in patients with PE. Production of the arachidonic acid metabolite, 15-HETE, also increased in the preeclamptic placenta, which suggests enhanced activation of the HIF-1alpha-15-LO-15-HETE axis. Furthermore, this study is the first to show that the umbilical cord of preeclamptic women contains significantly higher serum concentrations of 15-HETE than that of healthy pregnant women. The results also show that expression of 15 LO-1/2 is upregulated in both human umbilical vein endothelial cells (HUVECs) collected from preeclamptic women and in those cultured under hypoxic conditions. Exogenous 15-HETE promotes the migration of HUVECs and in vitro tube formation and promotes cell cycle progression from the G0/G1 phase to the G2/M + S phase, whereas the 15-LO inhibitor, NDGA, suppresses these effects. The HIF-1alpha/15 LO/15-HETE pathway is therefore significantly associated within the pathology of PE. PMID- 24796549 TI - Prediction of potential cancer-risk regions based on transcriptome data: towards a comprehensive view. AB - A novel integrative pipeline is presented for discovery of potential cancer susceptibility regions (PCSRs) by calculating the number of altered genes at each chromosomal region, using expression microarray datasets of different human cancers (HCs). Our novel approach comprises primarily predicting PCSRs followed by identification of key genes in these regions to obtain potential regions harboring new cancer-associated variants. In addition to finding new cancer causal variants, another advantage in prediction of such risk regions is simultaneous study of different types of genomic variants in line with focusing on specific chromosomal regions. Using this pipeline we extracted numbers of regions with highly altered expression levels in cancer condition. Regulatory networks were also constructed for different types of cancers following the identification of altered mRNA and microRNAs. Interestingly, results showed that GAPDH, LIFR, ZEB2, mir-21, mir-30a, mir-141 and mir-200c, all located at PCSRs, are common altered factors in constructed networks. We found a number of clusters of altered mRNAs and miRNAs on predicted PCSRs (e.g.12p13.31) and their common regulators including KLF4 and SOX10. Large scale prediction of risk regions based on transcriptome data can open a window in comprehensive study of cancer risk factors and the other human diseases. PMID- 24796550 TI - A novel newborn rat kernicterus model created by injecting a bilirubin solution into the cisterna magna. AB - BACKGROUND: Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague Dawley (SD) rats. METHODS: On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pH = 8.5) was injected into the CM at 10 ug/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test. RESULTS: The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (P<0.001). The early and late mortality of the bilirubin-treated rats were both dramatically higher than those of the controls (P = 0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test. CONCLUSION: By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are available. PMID- 24796551 TI - Genetic characterization of emerging coxsackievirus A12 associated with hand, foot and mouth disease in Qingdao, China. AB - To characterize the genetic properties of coxsackievirus A12 (CVA12) strains isolated from hand, foot and mouth disease (HFMD) patients in Qingdao during 2008 2011, the complete genome and VP1 coding region were sequenced and analyzed. Phylogenetic analysis showed that all strains from China clustered into three different branches, suggesting multiple lineages of CVA12 co-circulating in Asia. Sequence analysis indicated a monophyletic group only when the P1 region was examined, indicating possible recombination between CVA12 and other HEV-A serotypes. The emergence of CVA12 involved in an HFMD outbreak in China is a public-health issue. PMID- 24796552 TI - A high degree of African streak virus diversity within Nigerian maize fields includes a new mastrevirus from Axonopus compressus. AB - The A-strain of maize streak virus (MSV-A; genus Mastrevirus, family Geminiviridae), the causal agent of maize streak disease, places a major constraint on maize production throughout sub-Saharan Africa. In West-African countries such as Nigeria, where maize is not cultivated year-round, this MSV strain is forced to overwinter in non-maize hosts. In order to both identify uncultivated grasses that might harbour MSV-A during the winter season and further characterise the diversity of related maize-associated streak viruses, we collected maize and grass samples displaying streak symptoms in a number of Nigerian maize fields. From these we isolated and cloned 18 full mastrevirus genomes (seven from maize and 11 from various wild grass species). Although only MSV-A isolates were obtained from maize, both MSV-A and MSV-F isolates were obtained from Digitaria ciliaris. Four non-MSV African streak viruses were also sampled, including sugarcane streak Reunion virus and Urochloa streak virus (USV) from Eleusine coacana, USV from Urochloa sp., maize streak Reunion virus (MSRV) from both Setaria barbata and Rottboellia sp., and a novel highly divergent mastrevirus from Axonopus compressus, which we have tentatively named Axonopus compressus streak virus (ACSV). Besides the discovery of this new mastrevirus species and expanding the known geographical and host ranges of MSRV, we have added D. ciliaris to the list of uncultivated species within which Nigerian MSV-A isolates are possibly able to overwinter. PMID- 24796553 TI - Transcriptional analysis of ORF amv133 of Amsacta moorei entomopoxvirus. AB - The open reading frame (ORF) amv133 of Amsacta moorei entomopoxvirus, encodes a putative lipase gene. Its temporal expression pattern was characterized by RT-PCR and found to start at 6 h postinfection (h p.i.) and reach a maximum level at 48 h p.i. While the ORF has a late promoter motif, the inhibition of viral DNA synthesis by Ara-C failed to inhibit transcription, but a general inhibitor of protein synthesis prevented its transcription, indicating that amv133 is an intermediate gene. 5'-RACE analysis showed that transcription was initiated at position -77 relative to the translational start site. To determine the size of the promoter, several truncations were generated and cloned upstream of the firefly luciferase reporter gene. The resulting constructs were tested in a dual assay. A fragment that contained 115 bp relative to the transcription start site exhibited optimum promoter length. PMID- 24796554 TI - Characterization of a thermophilic bacteriophage of Geobacillus kaustophilus. AB - GBK2 is a bacteriophage, isolated from a backyard compost pile, that infects the thermophile Geobacillus kaustophilus. GBK2 has a circularly permuted genome of 39,078 bp with a G+C content of 43 %. Annotation of the genome reveals 62 putative open reading frames (ORFs), 25 of which (40.3 %) show homology to known proteins and 37 of which (59.7 %) are proteins with unknown functions. Twelve of the identified ORFs had the greatest homology to genes from the phage SPP1, a phage that infects the mesophile Bacillus subtilis. The overall genomic arrangement of GBK2 is similar to that of SPP1, with the majority of GBK2 SPP1 like genes coding for proteins involved in DNA replication and metabolism. PMID- 24796555 TI - Mutational modifications of hepatitis A virus proteins 2B and 2C described for cell culture-adapted and attenuated virus are present in wild-type virus populations. AB - Studies have identified certain mutations in the 2B and 2C proteins of hepatitis A virus (HAV) as being essential for efficient growth in cultured cells, and it is assumed that these mutations contribute to the attenuated phenotype. We found that mutations supporting cell culture growth already exist in wild-type HAV populations. This suggests that these variants are not entirely generated de novo but are selected from the wild-type population. In a prolonged case of hepatitis A, we found that sequences associated with cell culture adaptation predominated later in infection. This might suggest selection of an attenuated virus population during a prolonged clinical infection. PMID- 24796556 TI - Pathways into living alone in mid-life: diversity and policy implications. AB - This paper adopts a life course approach to investigate the pathways into living alone in mid-life in Britain and how these vary by gender and socio-economic status. The rise in the proportion of people living alone over the past three decades has been well documented. However, much of the focus of the existing literature has been on either people living solo in young adulthood or in later life. Mid-life has received surprising little scholarly attention, despite the fact that living arrangements in mid-life are changing rapidly, and that household composition and socio-economic circumstances in the period immediately prior to retirement are strongly associated with living arrangements and associated sources of support in later life. This paper therefore aims to fill this gap. We begin with a review of previous research on living alone and present a conceptual framework of the pathways into living alone in mid-life. Data from the United Kingdom Household Longitudinal Survey (UKHLS) are used to analyse the partnership and parenthood histories and socio-economic characteristics of those currently living alone in mid-life. The findings indicate that the dissolution of a marriage with children is the dominant pathway into mid-life solo-living, but that there is also a substantial group of never partnered men living alone. These never partnered men are split between those with low and high socio-economic status. Distinguishing between different groups of individuals living alone in mid-life is important for policy as these groups of men and women will have different social and financial resources as they enter later life. Mid-life men living alone who have not had children, have no educational qualifications, are not economically active and who live in rented housing are likely to be most at risk of needing a social and economic 'safety net' in old age. PMID- 24796557 TI - Material deprivation or minimal education? Social class and crime in an egalitarian welfare state. AB - Research on social class and crime is dominated by perspectives that assume socioeconomic disadvantage to exert causal influence on offending. As an alternative approach, the present study examined hypotheses derived from a social selection perspective which treats intergenerational continuity in antisocial propensity as the primary source of socioeconomic differences in criminal activity. Under this theory, individual characteristics of the parents influence their personal socioeconomic attainment as well as the behavioral traits they pass on to their children. Consistent with both of these perspectives, longitudinal data tracking Finnish males born in 1987 (n=21,513) showed strong negative associations between family socioeconomic status (SES) and offspring rates of criminal offending. In critical support for the selection perspective: (1) these association were linear rather than discrete, (2) parents' educational attainment accounted for most of the association between the occupational measure of family SES and crime, and (3) measures of offspring criminal propensity mediated a substantial share of these effects. Adolescent educational marginalization emerged as the key factor linking childhood socioeconomic status to the risk of criminal offending in emerging adulthood. We discuss the implications of this finding for social influence and social selection models of explanation. PMID- 24796558 TI - Immigrants' initial steps in Germany and their later economic success. AB - In line with the emerging research that acknowledges the importance of the process character of immigrants' labour market integration, this paper examines the existence of path dependencies of early employment trajectories on later labour market outcomes. Theoretically we are interested in establishing whether career trajectories provide a distinct signal, used by both employers and employees: a signal that operates apart and beyond the accumulation of host country relevant resources, especially, host-country labour market experience or training. The analyses are performed with the help of a unique dataset comprised of recent immigrants from the former Soviet Union in Germany. Sequence analysis techniques and multivariate regressions are applied. Results show that starting in higher-status employment leaves a distinguishable imprint on immigrants' later occupational standings, even after the returns to the skills associated with early trajectories are taken into account. At the same time, initial career trajectories do not have any direct effect on wages, apart from the pay-off to relevant skills acquired while pursuing these careers. The findings are discussed in concurrence with the human capital and signalling theories. PMID- 24796559 TI - Civic involvement across the life course: moving beyond age-based assumptions. AB - This paper critically examines factors which, over time and context, are linked to civic involvement for individuals, age groups, and cohorts. We begin by critiquing current age- and cohort-related civic involvement canons and norms by extracting and evaluating rationales for why such activity in two particular periods of life-early adulthood and old age-is assumed to be good for individuals and for society. Then, employing elements of a life course perspective, we consider an alternative approach to civic involvement-one that emphasizes dynamic trajectories and the significant degree of variability within individuals, age groups and cohorts resulting in a very different set of assumptions about individual choice and activity. We close by discussing the utility of this alternative approach for research, policy, and practice regarding civic involvement. PMID- 24796560 TI - The long reach of childhood. Childhood experiences influence close relationships and loneliness across life. AB - This paper intends to gain insight into the role of childhood relationships and experiences within the parental home for the formation and meaning of later family relationships and loneliness. Particularly, childhood attachment to mother and father and stressful childhood experiences were studied in their association with satisfaction in the romantic relationship, the quality of adult family ties and the perceived quality of the social network, i.e. loneliness in adulthood. Based on data from the Netherlands Kinship Panel Study (N=3980) structural equation models were estimated to predict adult relationships and loneliness with childhood experiences. Positive attachment experiences with parents, such as reliability, closeness and supportiveness during childhood were associated with greater satisfaction in the romantic relationship, stronger family ties and less loneliness, whereas stressful childhood experiences, such as conflicts and violence negatively predicted the quality of adult relationships. Life span theoretical perspectives, such as attachment theory are discussed as useful unifying framework to study social relationships, their interconnectedness and association with outcome during all phases of life. PMID- 24796561 TI - Adolescent behavior and achievement, social capital, and the timing of geographic mobility. AB - This paper examines the relationship between geographic mobility and adolescent academic achievement and behavior problems. Specifically, it addresses how the effects of moving differ by age and how social capital moderates the impact of moving on children (aged 6 to 15). Children's behavior problems and academic achievement test scores were compared across four survey waves of the National Longitudinal Survey of Youth (2000, 2002, 2004, and 2006) and matched to data from their mothers' reports from the National Longitudinal Survey of Youth 1979. The findings indicate that the negative behavioral effects of geographic mobility on adolescents are most pronounced for individuals relocating to a new city, county, or state as opposed to those moving locally (i.e., within the same city). Furthermore, as suggested by a life-course perspective, the negative effects of moving on behavior problems decrease as children get older. The results also show that several social capital factors moderate the effects of moving on behavior but not achievement. PMID- 24796562 TI - Azospirillum brasilense ameliorates the response of Arabidopsis thaliana to drought mainly via enhancement of ABA levels. AB - Production of phytohormones is one of the main mechanisms to explain the beneficial effects of plant growth-promoting rhizobacteria (PGPR) such as Azospirillum sp. The PGPRs induce plant growth and development, and reduce stress susceptibility. However, little is known regarding the stress-related phytohormone abscisic acid (ABA) produced by bacteria. We investigated the effects of Azospirillum brasilense Sp 245 strain on Arabidopsis thaliana Col-0 and aba2-1 mutant plants, evaluating the morphophysiological and biochemical responses when watered and in drought. We used an in vitro-grown system to study changes in the root volume and architecture after inoculation with Azospirillum in Arabidopsis wild-type Col-0 and on the mutant aba2-1, during early growth. To examine Arabidopsis development and reproductive success as affected by the bacteria, ABA and drought, a pot experiment using Arabidopsis Col-0 plants was also carried out. Azospirillum brasilense augmented plant biomass, altered root architecture by increasing lateral roots number, stimulated photosynthetic and photoprotective pigments and retarded water loss in correlation with incremented ABA levels. As well, inoculation improved plants seed yield, plants survival, proline levels and relative leaf water content; it also decreased stomatal conductance, malondialdehyde and relative soil water content in plants submitted to drought. Arabidopsis inoculation with A. brasilense improved plants performance, especially in drought. PMID- 24796563 TI - One-stage hip reconstruction in children with cerebral palsy: long-term results at skeletal maturity. AB - PURPOSE: Hip subluxation is common in children with cerebral palsy (CP). Surgery is indicated in case of pain or progressive increase of Reimers index on radiographs. Peri-iliac osteotomy combined with femoral osteotomy is one of the numerous operative techniques available, but results at skeletal maturity remain unclear. The purpose of this radiological study was to report the long-term results of this procedure. MATERIALS AND METHODS: Twenty hips in 20 children were retrospectively evaluated at skeletal maturity. Mean age at surgery was 8.1 years and follow-up averaged 9.1 years. All patients underwent Dega acetabuloplasty, soft-tissue release and femoral-shortening varus derotation osteotomy without open reduction. Reimers index, acetabular angle (AA) and neck-shaft angle (NSA) were compared on preoperative, postoperative and latest follow-up radiographs. RESULTS: Dega osteotomy significantly improved the AA and the correction remained stable at maturity. The NSA significantly decreased postoperatively (153 degrees 115 degrees ), but recurrence of the valgus deformity (130 degrees ) of the proximal femur was observed at maturity. Consequently, Reimers index followed the same evolution. No case of osteonecrosis was reported but one hip dislocated and one subluxated during follow-up. CONCLUSION: Progressive recurrence of the valgus deformity of the proximal femur, attributable to adductors spasticity and gluteus medius weakness, led to a significant increase in the Reimers index. However, hip coverage remained >70 % at maturity in 90 % of the hips. This one-stage procedure without hip dislocation efficaciously corrected acetabulum dysplasia and successfully treated neurological hips in CP patients. LEVEL OF EVIDENCE IV: retrospective study. PMID- 24796566 TI - Ectopically expressed sweet pepper ferredoxin PFLP enhances disease resistance to Pectobacterium carotovorum subsp. carotovorum affected by harpin and protease mediated hypersensitive response in Arabidopsis. AB - Plant ferredoxin-like protein (PFLP) is a photosynthesis-type ferredoxin (Fd) found in sweet pepper. It contains an iron-sulphur cluster that receives and delivers electrons between enzymes involved in many fundamental metabolic processes. It has been demonstrated that transgenic plants overexpressing PFLP show a high resistance to many bacterial pathogens, although the mechanism remains unclear. In this investigation, the PFLP gene was transferred into Arabidopsis and its defective derivatives, such as npr1 (nonexpresser of pathogenesis-related gene 1) and eds1 (enhanced disease susceptibility 1) mutants and NAHG-transgenic plants. These transgenic plants were then infected with the soft-rot bacterial pathogen Pectobacterium carotovorum subsp. carotovorum (Erwinia carotovora ssp. carotovora, ECC) to investigate the mechanism behind PFLP-mediated resistance. The results revealed that, instead of showing soft-rot symptoms, ECC activated hypersensitive response (HR)-associated events, such as the accumulation of hydrogen peroxide (H2 O2 ), electrical conductivity leakage and expression of the HR marker genes (ATHSR2 and ATHSR3) in PFLP-transgenic Arabidopsis. This PFLP-mediated resistance could be abolished by inhibitors, such as diphenylene iodonium (DPI), 1-l-trans-epoxysuccinyl-leucylamido-(4-guanidino) butane (E64) and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), but not by myriocin and fumonisin. The PFLP-transgenic plants were resistant to ECC, but not to its harpin mutant strain ECCAC5082. In the npr1 mutant and NAHG transgenic Arabidopsis, but not in the eds1 mutant, overexpression of the PFLP gene increased resistance to ECC. Based on these results, we suggest that transgenic Arabidopsis contains high levels of ectopic PFLP; this may lead to the recognition of the harpin and to the activation of the HR and other resistance mechanisms, and is dependent on the protease-mediated pathway. PMID- 24796565 TI - Antifibrinolytic mechanisms in acute airway injury after sulfur mustard analog inhalation. AB - Acute lung injury in response to mustard gas (sulfur mustard [SM]) inhalation results in formation of fibrin casts, which obstruct the airway. The objective of this study was to identify fibrinolytic pathways that could be contributing to the persistence of airway casts after SM exposure. Rats were exposed to the SM analog, 2-chloroethyl ethyl sulfide, via nose-only aerosol inhalation. At 4 and 18 hours after exposure, animals were killed and airway-capillary leak estimated by measuring bronchoalveolar lavage fluid (BALF) protein and IgM content. The fibrin clot-degrading and plasminogen-activating capabilities of BALF were also assessed by activity assays, whereas Western blotting was used to determine the presence and activities of plasminogen activator inhibitor-1, thrombin activatable fibrinolytic inhibitor and alpha2-antiplasmin. Measurement of tissue specific steady-state mRNA levels was also conducted for each fibrinolytic inhibitor to assess whether its synthesis occurs in lung or at extrapulmonary sites. The results of this study demonstrate that fibrin-degrading and plasminogen-activating capabilities of the airways become impaired during the onset of 2-chloroethyl ethyl sulfide-induced vascular leak. Findings of functionally active reservoirs of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and alpha2-antiplasmin in BALF indicate that airway fibrinolysis is inhibited at multiple levels in response to SM. PMID- 24796567 TI - Demonstrating a multi-drug resistant Mycobacterium tuberculosis amplification microarray. AB - Simplifying microarray workflow is a necessary first step for creating MDR-TB microarray-based diagnostics that can be routinely used in lower-resource environments. An amplification microarray combines asymmetric PCR amplification, target size selection, target labeling, and microarray hybridization within a single solution and into a single microfluidic chamber. A batch processing method is demonstrated with a 9-plex asymmetric master mix and low-density gel element microarray for genotyping multi-drug resistant Mycobacterium tuberculosis (MDR TB). The protocol described here can be completed in 6 hr and provide correct genotyping with at least 1,000 cell equivalents of genomic DNA. Incorporating on chip wash steps is feasible, which will result in an entirely closed amplicon method and system. The extent of multiplexing with an amplification microarray is ultimately constrained by the number of primer pairs that can be combined into a single master mix and still achieve desired sensitivity and specificity performance metrics, rather than the number of probes that are immobilized on the array. Likewise, the total analysis time can be shortened or lengthened depending on the specific intended use, research question, and desired limits of detection. Nevertheless, the general approach significantly streamlines microarray workflow for the end user by reducing the number of manually intensive and time-consuming processing steps, and provides a simplified biochemical and microfluidic path for translating microarray-based diagnostics into routine clinical practice. PMID- 24796568 TI - The narcissism epidemic: commentary on modernity and narcissistic personality disorder. AB - Comments on the original article by Paris (see record 2012-18549-001) regarding narcissistic personality disorder. The current authors agree with Paris that modern life is making people more narcissistic. In fact, the authors demonstrate with this commentary, the case for increasing narcissism is even stronger than presented in his article. An explain that expressing individualism and lack of social support play key roles in this increase. However, the current authors question the idea that therapy is building narcissism. PMID- 24796569 TI - Ruminations on narcissistic personality disorder. AB - Comments on the original article by Paris (see record 2012-18549-001) which provides an interesting and provocative overview of the diagnosis, etiology, and treatment of narcissistic personality disorder (NPD). In this commentary, the author focuses on several assessment issues for narcissism, as well as NPD in particular. PMID- 24796570 TI - Narcissism and its discontents. AB - Comments on the original article by Paris (see record 2012-18549-001) on the topic of narcissism and modernity. It is a wide-ranging, ambitious, and, at times, provocative discussion of issues related to putative cultural influences on the etiology, development, and exacerbation of narcissism. Among the most important issues raised by Paris is the need for well-conducted longitudinal research on the development of narcissism so that the etiological mechanisms underlying this oftentimes-deleterious condition might be uncovered. However, there are a number of ongoing debates in the literature that make much of his proposal premature. This commentary addresses a few of these debate issues. PMID- 24796571 TI - Response to commentaries: modernity and narcissistic personality disorder. AB - Replies to comments by Twenge, Miller, and Campbell (see record 2014-16207-001), Trull (see record 2014-16207-002), and Wright (see record 2014-16207-003) on the original article by Paris (see record 2012-18549-001) on the topic of narcissism and modernity. The current author would like to thank all three commentators for focusing on points in the original article that need clarification. Wright (2014) underlines the problem of precisely defining narcissism, arguing that research cannot progress until we agree on the meaning of the construct. Trull (2014) makes the useful point that cohort changes in narcissism do not translate into changes in the prevalence of NPD. Finally, Twenge, Miller, and Campbell (2014) are leaders in the empirical study of narcissism and NPD. The current author is pleased that they agree with some of his conclusions. However, they should not consider the case for dramatic increases in trait narcissism to be settled. PMID- 24796572 TI - Electrical magnetochiral anisotropy in a bulk chiral molecular conductor. AB - So far, no effect of chirality on the electrical properties of bulk chiral conductors has been observed. Introduction of chiral information in tetrathiafulvalene precursors represents a powerful strategy towards the preparation of crystalline materials in which the combination of chirality and conducting properties might allow the observation of the electrical magnetochiral anisotropy effect. Here we report the synthesis by electrocrystallization of both enantiomers of a bulk chiral organic conductor based on an enantiopure tetrathiafulvalene derivative. The enantiomeric salts crystallize in enantiomorphic hexagonal space groups. Single crystal resistivity measurements show metallic behaviour for the enantiopure salts down to 40 K, in agreement with band structure calculations. We describe here the first experimental evidence of electrical magnetochiral anisotropy in these crystals, confirming the chiral character of charge transport in our molecular materials. PMID- 24796576 TI - Novel parvovirus from the worm lizard Trogonophis wiegmanni - First virus ever detected in amphisbaenian hosts. AB - To explore the diversity of some DNA viruses in reptiles, a continuous screening is going on, in our laboratory, by PCR using different consensus primers designed for the detection of the most conserved genome regions of adeno-, herpes- and parvoviruses. The test material consists essentially of dead specimens collected randomly from private pet owners, local pet shops, or at occasional exotic pet fairs. Here we report the partial sequence of a putative novel parvovirus obtained from a dead checkerboard worm lizard (Trogonophis wiegmanni) that had been wild-caught in its native habitat. An in-house-developed PCR with consensus primers targeting the gene of the parvoviral capsid protein was used. Other PCRs, intended to detect certain large DNA viruses, remained negative. The sequence of the PCR product indicated the presence of a hitherto unknown parvovirus in the internal organs of the checkerboard worm lizard. In phylogeny reconstruction, the novel sequence clustered with the members of the Dependovirus genus of the Parvoririnae subfamily, closest to the branch of snake adeno-associated virus. Since we could not demonstrate the presence of a potential helper virus, the putative amphisbaenian parvovirus supposedly can replicate autonomously. This is the first virus infection ever detected in any members of the suborder Amphisbaenia, and only the third parvoviral sequence obtained from any reptilian host. PMID- 24796577 TI - The role of speech prosody and text reading prosody in children's reading comprehension. AB - BACKGROUND: Text reading prosody has been associated with reading comprehension. However, text reading prosody is a reading-dependent measure that relies heavily on decoding skills. Investigation of the contribution of speech prosody - which is independent from reading skills - in addition to text reading prosody, to reading comprehension could provide more insight into the general role of prosody in reading comprehension. AIMS: The current study investigates how much variance in reading comprehension scores is explained by speech prosody and text reading prosody, after controlling for decoding, vocabulary, and syntactic awareness. SAMPLE: A battery of reading and language assessments was performed by 106 Dutch fourth-grade primary school children. METHODS: Speech prosody was assessed using a storytelling task and text reading prosody by oral text reading performance. Decoding skills, vocabulary, syntactic awareness, and reading comprehension were assessed using standardized tests. RESULTS: Hierarchical regression analyses showed that text reading prosody explained 6% of variance and that speech prosody explained 8% of variance in reading comprehension scores, after controlling for decoding, vocabulary, and syntactic awareness. Phrasing was the significant factor in both speech and text reading. When added in consecutive order, phrasing in speech added 5% variance to phrasing in reading. In contrast, phrasing in reading added only 3% variance to phrasing in speech. CONCLUSIONS: The variance that speech prosody explained in reading comprehension scores should not be neglected. Speech prosody seems to facilitate the construction of meaning in written language. PMID- 24796578 TI - In-situ TEM observation of the response of ultrafine- and nanocrystalline-grained tungsten to extreme irradiation environments. AB - The accumulation of defects, and in particular He bubbles, can have significant implications for the performance of materials exposed to the plasma in magnetic confinement nuclear fusion reactors. Some of the most promising candidates for deployment into such environments are nanocrystalline materials as the engineering of grain boundary density offers the possibility of tailoring their radiation resistance properties. In order to investigate the microstructural evolution of ultrafine- and nanocrystalline-grained tungsten under conditions similar to those in a reactor, a transmission electron microscopy study with in situ 2 keV He(+) ion irradiation at 950 degrees C has been completed. A dynamic and complex evolution in the microstructure was observed including the formation of defect clusters, dislocations and bubbles. Nanocrystalline grains with dimensions less than around 60 nm demonstrated lower bubble density and greater bubble size than larger nanocrystalline (60-100 nm) and ultrafine (100-500 nm) grains. In grains over 100 nm, uniform distributions of bubbles and defects were formed. At higher fluences, large faceted bubbles were observed on the grain boundaries, especially on those of nanocrystalline grains, indicating the important role grain boundaries can play in trapping He and thus in giving rise to the enhanced radiation tolerance of nanocrystalline materials. PMID- 24796580 TI - Synthesis, characterization, and metal ion coordination of a multichromophoric highly luminescent polysulfurated pyrene. AB - We have designed a new multichromophoric system based on a tetra(phenylthio)pyrene core appended with four terpyridine units. The system behaves as a molecular antenna that collects light with the peripheral units and funnels the energy to the very highly luminescent core. The addition of metals ions to the investigated system can not only switch the direction of the intramolecular energy transfer, but also control the formation of three dimensional nanoscopic objects in a dual function. PMID- 24796579 TI - In silico prediction of mutant HIV-1 proteases cleaving a target sequence. AB - HIV-1 protease represents an appealing system for directed enzyme re-design, since it has various different endogenous targets, a relatively simple structure and it is well studied. Recently Chaudhury and Gray (Structure (2009) 17: 1636 1648) published a computational algorithm to discern the specificity determining residues of HIV-1 protease. In this paper we present two computational tools aimed at re-designing HIV-1 protease, derived from the algorithm of Chaudhuri and Gray. First, we present an energy-only based methodology to discriminate cleavable and non cleavable peptides for HIV-1 proteases, both wild type and mutant. Secondly, we show an algorithm we developed to predict mutant HIV-1 proteases capable of cleaving a new target substrate peptide, different from the natural targets of HIV-1 protease. The obtained in silico mutant enzymes were analyzed in terms of cleavability and specificity towards the target peptide using the energy-only methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence. PMID- 24796581 TI - Parents and prevention: a systematic review of interventions involving parents that aim to prevent body dissatisfaction or eating disorders. AB - OBJECTIVE: To systematically review the literature on interventions involving parents that aim to prevent body dissatisfaction or eating disorders in children, and provide directions for future research by highlighting current gaps. METHOD: The literature was searched for articles using key concepts: parents, prevention and eating disorders or disordered eating or body dissatisfaction. All English language publications between 1992 and 2013 were searched across a range of academic databases. Studies were reviewed if they: (i) delivered an intervention designed to reduce eating disorders or body dissatisfaction or their risk factors, in children or adolescents; (ii) provided some intervention component for parents; and (iii) included some outcome measure of intervention effectiveness on disordered eating or body dissatisfaction. A scoring matrix based on the Critical Appraisal Skills Program (CASP) screening questions was used to assess each study's sample representativeness, relevance and data quality. RESULTS: From 647 novel records uncovered by the search, 20 separate studies met inclusion criteria. The CASP scoring matrix revealed eight studies provided no relevant data, four relevant and eight highly relevant data on the effects of involving parents in prevention programs. Two of four high-quality studies reported that parental involvement significantly improved child outcomes on measures of body dissatisfaction or disordered eating. DISCUSSION: Although a greater focus on engaging and retaining parents is needed, this review demonstrates that a small number of prevention studies with parents have led to significant reductions in risk of body image and eating problems, and future research is indicated. PMID- 24796582 TI - An epidemiological and environmental study of Shiga toxin-producing Escherichia coli in India. AB - Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens of worldwide importance, but a shortage of data exists for STEC isolation from India. Therefore, an epidemiological and environmental study that covers a large geographic area in north India was conducted. Ruminant stool samples (n=650) were collected from 59 dairies. Meat samples (n=450) were collected from local abattoirs and the main slaughterhouse of the region. Additionally, 600 human cases of diarrhea and hemolytic uremic syndrome were screened for STEC. Isolates were characterized for the virulence gene profiles and for the serogroups and were submitted to molecular typing by the multilocus variable-number tandem repeat analysis (MLVA). Overall, 12.3% of animal stool samples and 6.3% of mutton samples (n=160) were positive for STEC. Additionally, STEC were isolated from 1.7% and 1.6% of watery (n=290) and bloody (n=310) stool specimens, respectively. Animal stool isolates were significantly more prevalent in hilly areas (p<0.05) than in plain areas. Polymerase chain reaction demonstrated the presence of stx1, stx2, hly, espP, saa, toxB, and iha genes in 117 (83.5%), 94 (67.1%), 77 (55%), 33 (23%), 62 (44.2%), 29 (20.7%), and 51 (36%) of the isolates, respectively. Five new serogroups (O55, O33, O173, O165, and O136) are being reported for the first time from India. Four isolates from serogroup O103 were found in mutton and stool specimens of cattle and humans (n=160). One isolate from serogroup O104 was isolated from a mutton sample. MLVA suggested the potential transmission of STEC from contaminated meat and bovine sources. This study confirms the frequent contamination of mutton samples (24%), whereas chicken and pork samples were negative for STEC. This study demonstrates the presence of STEC that carry a large repertoire of virulence genes and the potential transmission of STEC from contaminated mutton and animal stools in north India. PMID- 24796584 TI - Cancer, infection and disturbances of the integrity of tissue homeostasis: the most significant triggers for molecular mimicry and autoimmunity in dermatology? PMID- 24796585 TI - [The difference and similarity of obesity hypoventilation syndrome and obstructive sleep apnea hypopnea syndrome]. PMID- 24796586 TI - [Diagnosis and treatment of overlap syndrome]. PMID- 24796583 TI - Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma. AB - The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment. PMID- 24796587 TI - [Slow eye movement analysis in patients with obstructive sleep apnea/hypopnea syndrome]. AB - OBJECTIVE: To determine whether slow eye movement (SEM) analysis performed comparably to standard sleep onset criteria at the multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) in patients with obstructive sleep apnea/hyponea syndrome (OSAHS). METHODS: We compared SEM latencies with sleep latencies upon analysis of MSLT and MWT recordings artificially, in a population of 20 severe OSAHS patients that randomly underwent the 2 tests 2 days apart. They all answered the Epworth Sleepiness Scale. RESULTS: Mean SEM latency was different from standard sleep onset in the MSLT [(4.2 +/- 1.9) min vs (5.3 +/ 2.0) min, P < 0.001], and the MWT [(12 +/- 10) min vs (13 +/- 10) min, P < 0.001]. Mean SEM latency correlated significantly with the sleep latency at the MSLT (r = 0.958, P < 0.001) and at the MWT (r = 0.997, P < 0.001). Finally, the Epworth Sleepiness Scale score correlated with SEM latency at the MSLT (r = 0.580, P = 0.007), but not at the MWT. CONCLUSIONS: SEM latency was different from sleep latency that detected from EEG, but they correlated significantly with each other, thus providing a simplified way to evaluate sleepiness. PMID- 24796588 TI - [A long-term follow-up of the correlation between obstructive sleep apnea hypopnea syndrome and multiple organ diseases]. AB - OBJECTIVE: To explore the correlation between obstructive sleep apnea hypopnea syndrome (OSAHS) and multiple organ diseases. METHODS: Home-visit questionnaires were performed in 1 868 subjects (956 male, 912 female) with an average age of (79 +/- 5) years, and a prospective follow-up was performed for a period of 20 years with annual medical examinations. Multiple organ diseases included hypertension, coronary heart disease, stroke, diabetes, pulmonary heart disease, renal insufficiency and erythrocytosis. The subjects were grouped by the diagnosis of OSAHS. RESULTS: Among the 1 868 subjects, 598 (32.0%) were diagnosed with OSAHS, and 1 270 (68.0%) of non-OSAHS as the control group. By the end of follow-up, in the OSAHS group there were 477 (79.8%) cases with hypertension, 337 (56.4%) cases with coronary heart disease, 167 (27.9%) cases with stroke, 76 (12.7%) cases with diabetes, 37 (6.2%) cases with pulmonary heart disease, 73 (12.2%) cases with renal insufficiency and 211(35.3%) cases with erythrocytosis, all of which were significantly higher than those of the control group [323(25.4%), 315 (24.8%), 95 (7.5%), 69 (5.4%), 40 (3.2%), 58 (4.6%), 30 (2.4%), P < 0.01]. The number of diseases in the OSAHS group was also higher than that in the control group (P < 0.05) . CONCLUSION: The incidence of multiple organ diseases was remarkably higher in the OSAHS group than that in the control group, which indicated that OSAHS was a risk factor for multiple organ diseases. These diseases in OSAHS patients may be related to hypoxia caused by OSAHS, endocrine and metabolic disorders, unhealthy lifestyles and arteriosclerosis. PMID- 24796589 TI - [Candidemia combined with bacterial bloodstream infection: analysis of clinical features and associated risk factors]. AB - OBJECTIVE: To investigate the clinical characteristics of and risk factors for candidemia combined with bacterial bloodstream infection(BSI) by retrospective analysis of cases. METHOD: The clinical data of cases diagnosed as candidemia combined with BSI confirmed by blood culture were compared with those of cases with mono-candidemia in Beiing Tongren Hospital from January 2009 to December 2011. A logistic regression analysis was performed to investigate the independent risk factors. RESULTS: Forty-two cases diagnosed as candidemia were analyzed including 14 cases of candidemia combined with BSI and 28 cases of mono candidemia. Ten strains of gram-positive cocci and 4 strains of gram-negative bacilli were isolated from candidemia combined with BSI group.Six strains of C.albicans, 4 strains of C.glabrata, 3 strains of C.tropicalis and 1 strain of C.krosei were isolated. There was no C.parapsilosis isolated from candidemia combined with BSI group but 9 strains in the mono-candidemia group. The septic shock rate of the candidemia combined with BSI group was higher than that of the mono-candidemia group (12/14 vs 7/28, P = 0.000). The mortality rate of the candidemia combined with BSI group was higher than that of the mono-candidemia group (10/14 vs 15/28), but the difference did not reach statistical significance (P = 0.266).Four factors were found statistically different by univariate analysis, including hospitalization more than 4 weeks (P = 0.001), bacteremia before candidemia(P = 0.005), hematological tumor (P = 0.01) and abdominal infection (P = 0.001). Multivariate analysis showed that hospitalization more than 4 weeks was the independent risk factor. CONCLUSION: Gram-positive cocci were the predominant species and septic shock was more common in candidemia combined with BSI. Hospitalization more than 4 weeks was the independent risk factor for candidemia combined with BSI. PMID- 24796590 TI - [The value of simplified pulmonary embolism severity index and biomarkers in evaluating pulmonary embolism prognosis]. AB - OBJECTIVE: To evaluate the value of simplified pulmonary embolism severity index (sPESI) , brain natriuretic peptide (BNP) and high-sensitivity troponin I (hs TnI) in predicting the short-term and long-term prognosis of patients with acute pulmonary embolism. METHODS: We collected the clinical data of 162 consecutive patients with acute pulmonary embolism in The First Affiliated Hospital of Dalian Medical University from January of 2010 to September of 2012. Hospital death, shock, mechanical ventilation and cardiopulmonary resuscitation were defined as the primary endpoints while death within 38 months as the secondary endpoint. The correlations between sPESI,BNP and hs-TnI, and the primary and secondary endpoints in the overall cohort and hemodynamically stable subgroup were analyzed respectively. RESULTS: BNP, hs-TnI and sPESI were independent predictors in multivariate regression of the primary endpoints in the overall cohort. The area under ROC curve and the risk odds ratio of them were 0.87, 8.16;0.91, 6.09 and 0.78 , 14.07 respectively.Only BNP and sPESI were independent predictors in multivariate regression of the primary endpoints in hemodynamically stable subgroup.Only sPESI was an independent risk factor in COX regression of the secondary endpoint. The combination of BNP and hs-TnI further improved the positive predictive value (44.4%), while the negative predictive value was unaffected(97.8%). There was no adverse event in patients with low score of sPESI and single-positive or negative combination of BNP and hs-TnI. CONCLUSION: sPESI could reflect overall risk of pulmonary embolism.It had a high value in the evaluation of pulmonary embolism prognosis, especially for long-term prognosis.It should be integrated into the risk stratification strategy of pulmonary embolism.In the evaluation of short-term prognosis, BNP and hs-TnI were the best indicators, and the combination of BNP, hs-TnI and sPESI could further improve the prognostic value. PMID- 24796591 TI - [Effects of docosahexaenoic acid on hypoxia-induced pulmonary arterial hypertension]. AB - OBJECTIVE: To investigate the effects of docosahexaenoic acid (DHA) on hypoxia induced pulmonary arterial hypertension(PAH) and the mechanism. METHODS: PAH was induced by chronic intermittent hypoxia for 21 days in vivo. Forty male Sprague Dawley rats were randomly divided into 4 groups (n = 10, each):a normal control group, DHA-treated groups in normoxia and hypoxia, and a PAH group. At the end of study, mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy and the index of wall thickness of small pulmonary artery (WT% and WA%) among groups were compared. The changes of pulmonary arterial smooth muscle cell (PASMC) proliferation were determined by MTT in vitro. Migration assay was performed using the Boyden chamber. Real-time quantitative PCR was performed to quantify mRNA levels of the smooth muscle cell phenotype markers SM-alpha-actin, calponin and SM 22alpha under normoxic or hypoxic conditions, in the absence or presence of DHA. RESULTS: DHA treatment significantly lowered mPAP [(22.7 +/- 1.8) mmHg (1 mmHg = 0.133 kPa)], reduced thickening of small pulmonary artery wall [WT%:(21.6 +/- 4.1)%, WA%: (52.0 +/- 2.9)% ] and alleviated ventricular hypertrophy (34.2 +/ 2.2) % compared to those of the hypoxic group (P < 0.05). DHA inhibited the proliferation, migration and phenotype switching of PASMCs induced by hypoxia in vitro. CONCLUSION: DHA therapy reduced mPAP in a rat model of hypoxia-induced PAH and this effect was linked with inhibition of pulmonary vascular remodelling. PMID- 24796592 TI - [The interaction of chronic intermittent hypoxemia with peripheral blood cells]. PMID- 24796593 TI - [Progress of research on composite evaluation methods of diaphragmatic dysfunction]. PMID- 24796594 TI - [Research progress of pulmonary tuberculosis local immune]. PMID- 24796595 TI - [Innate lymphoid cells and asthma]. PMID- 24796596 TI - [Research development of the use of electronic cigarettes in smoking cessation]. PMID- 24796597 TI - Charge-transfer-featured materials-promising hosts for fabrication of efficient OLEDs through triplet harvesting via triplet fusion. AB - A charge-transfer-featured naphthalimide derivative with a small exchange energy but a lower lying (3)pipi* state than (3)CT state is found to contribute to triplet harvesting through a P-type rather than an E-type delayed fluorescence, and could act as a quite promising host to achieve highly efficient OLEDs. PMID- 24796599 TI - Impaired acquisition of goal-directed action in healthy aging. AB - According to dual-system theories, instrumental learning is supported by dissociable goal-directed and habitual systems. Previous investigations of the dual-system balance in healthy aging have yielded mixed results. To further investigate this issue, we compared performance of young (17-24 years) and older (69-84 years) adults on an instrumental learning task. Following the initial learning phase, the behavioral autonomy of the motivational significance of the instrumental outcome was assessed with an outcome-devaluation test and slips-of action test. The present study provides evidence for a disrupted dual-system balance in healthy aging, as reflected in reduced outcome-induced conflict during acquisition, as well as in impaired performance during the test stage, during which participants had to flexibly adjust their actions to changes in the current desirability of the behavioral outcome. These findings will be discussed in relation to previous aging studies into habitual and goal-directed control, as well as other cognitive impairments, challenges that older adults may face in everyday life, and to the neurobiological basis of the developmental pattern of goal-directed action across the lifespan. PMID- 24796598 TI - Building tasks from verbal instructions: an EEG study on practice trial exposure and task structure complexity during novel sequences of behavior. AB - Configuring the mind to perform a novel task is an effortful process and one that is related to differences in general intelligence. Previous research has suggested that when participants are given instructions for a future task, representations of the rules contained in the instructions can influence subsequent behavior, even when the rules are not necessary to perform the upcoming task. One hypothesis for the continued activation of rule representations suggests that the practice trials participants perform before the experimental trials may instantiate the unnecessary task rules into participants' mental model of the task (i.e., the task space). To test this hypothesis, EEGs were recorded as participants (N = 66) completed a multirule task designed to contrast the effects of increasing task structure complexity and practice trial exposure. The results showed that, as was predicted, performance is significantly poorer when more task rules are specified in the task instructions. Practice trials with the extra rule did not affect task performance, indicating that an unacted verbal instruction is sufficient to incorporate the rule into participants' mental model of the task. The EEG results showed that instruction complexity was linked to a phasic increase in frontal theta synchronization but reduced posterior alpha and beta desynchronization. These changes in synchronization occurred during a time period of low intertrial phase coherence and suggest that participants were "checking the task rules" amidst a trial. This transient neural activity may reflect compensatory mechanisms for dealing with increased mind-wandering that is more likely to occur in complex tasks. PMID- 24796600 TI - Impact of mono- and disubstitution on the colorimetric dynamic covalent switching chalcone/flavanone scaffold. AB - The effect of aryl substitution on various aspects of the interconversion of ortho-hydroxychalcones and flavanones has been studied using multiple spectroscopic techniques. Derivatization of the core scaffold predictably alters the midpoint pH of this equilibration process suggesting its viability for application as a functional colorimetric molecular switch. PMID- 24796601 TI - Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease. AB - INTRODUCTION: Only +/- 50% of patients with type 1 von Willebrand disease (VWD) have recognized molecular defects and diagnosis still rests on demonstrating low plasma von Willebrand factor (VWF) protein/function. However, no generalized consensus exists regarding the type and number of VWF variables that should be considered for diagnosis. AIM: To compare the quantitative impact of four different criteria to diagnose type 1 VWD. METHODS: We tested four laboratory criteria on 4298 laboratory studies during a 5-year period. The first was the National Heart, Lung, and Blood Institute recommendation, which diagnoses type 1 VWD with plasma VWF antigen (VWF:Ag) and VWF ristocetin cofactor (VWF:RCo) < 30 IU dL(-1) and possible VWD/'low VWF' with values between 30 and 50 IU dL(-1) . Second, diagnosis was established when two of three variables, VWF:Ag, VWF:RCo, VWF collagen binding assay (VWF:CB), were <= 2.5th percentile. Diagnostic criterion for possible VWD/'low VWF' using percentiles was also described. The third criterion (European Group on von Willebrand Disease, EUVWD), uses a plasma level of VWF:RCo (or VWF:CB) <= 40 IU dL(-1) for diagnosis. Finally, the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCBVWD) diagnoses VWD if VWF:Ag or VWF:RCo are <= 40 IU dL(-1) . RESULTS: The three assays had high correlation and excellent agreement at levels < 120 IU dL(-1) . The National Heart, Lung, and Blood Institute recommendation was followed to diagnose 122 (2.8%) patients with type 1 VWD and 704 (16.4%) with possible VWD/'low VWF.' Using percentiles, the diagnosis of type 1 VWD increased to 280 (6.5%) patients; 169 (3.9%) patients had possible VWD and 180 (4.2%) patients had 'low VWF.' Diagnoses using EUVWD and ZPMCBVWD criteria increased to 339 (7.9%) and 357 (8.3%) patients, respectively. DISCUSSION: Identical data, analyzed using different criteria, led to almost three-fold difference (2.8-8.3%) in diagnostic rate. This increase is mostly explained by increasing the cut-off values of VWF measurements from < 30 to ~ 40 IU dL(-1) . Further refinement of the laboratory diagnosis of type 1 VWD is a priority. PMID- 24796602 TI - Accessory lateral rectus in a patient with normal ocular motor control. AB - Although supernumerary extraocular muscles are common in monkeys and other species, they are relatively rare in humans and typically are noted in the context of childhood strabismus. We present a case of an incidentally found unilateral accessory lateral rectus muscle in a 51-year-old woman with normal ocular motor control. In this patient, the accessory lateral rectus was approximately 10% the size of a normally sized lateral rectus muscle. It originated from the orbital apex, traveled between the optic nerve and the lateral rectus and attached to the superolateral aspect of the globe. This unique case demonstrates that accessory lateral rectus in humans may have no impact on eye movement and ocular alignment. PMID- 24796603 TI - Editorial Comment from Dr Amano to Relationship between plasma melatonin levels and the efficacy of selective serotonin reuptake inhibitors treatment on premature ejaculation. PMID- 24796604 TI - Acylazetine as a dienophile in bioorthogonal inverse electron-demand Diels-Alder ligation. AB - A new bioorthogonal N-acylazetine tag, suitable for tetrazine mediated inverse electron-demand Diels-Alder conjugation, is developed. The tag is small and achiral. We demonstrate the usefulness of N-acylazetine-tetrazine based bioorthogonal chemistry in two-step activity-based protein profiling. The performance of the new tetrazinophile in the labeling of catalytically active proteasome subunits was comparable to that of the more sterically demanding norbornene tag. PMID- 24796605 TI - Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage. AB - OBJECTIVES: Aneurysmal subarachnoid hemorrhage (SAH) is frequently associated with delayed neurological deterioration (DND). Several studies have shown that DND is not always related to vasospasm and ischemia. Experimental and clinical studies have recently documented that it is possible to diagnose and separate cerebral ischemia and mitochondrial dysfunction bedside. The study explores whether cerebral biochemical variables in SAH patients most frequently exhibit a pattern indicating ischemia or mitochondrial dysfunction. METHODS: In 55 patients with severe SAH, intracerebral microdialysis was performed during neurocritical care with bedside analysis and display of glucose, pyruvate, lactate, glutamate, and glycerol. The biochemical patterns observed were compared to those previously described in animal studies of induced mitochondrial dysfunction as well as the pattern obtained in patients with recirculated cerebral infarcts. RESULTS: In 29 patients, the biochemical pattern indicated mitochondrial dysfunction while 10 patients showed a pattern of cerebral ischemia, six of which also exhibited periods of mitochondrial dysfunction. Mitochondrial dysfunction was observed during 5162 h. An ischemic pattern was obtained during 688 h. Four of the patients (40%) with biochemical signs of ischemia died at the neurosurgical department as compared with three patients (10%) in the group of mitochondrial dysfunction. CONCLUSIONS: The study documents that mitochondrial dysfunction is a common cause of disturbed cerebral energy metabolism in patients with SAH. Mitochondrial dysfunction may increase tissue sensitivity to secondary adverse events such as vasospasm and decreased cerebral blood flow. The separation of ischemia and mitochondrial dysfunction bedside by utilizing microdialysis offers a possibility to evaluate new therapies. PMID- 24796606 TI - Highly stable hysteresis-free carbon nanotube thin-film transistors by fluorocarbon polymer encapsulation. AB - We report hysteresis-free carbon nanotube thin-film transistors (CNT-TFTs) employing a fluorocarbon polymer (Teflon-AF) as an encapsulation layer. Such fluorocarbon encapsulation improves device uniformity with excellent operation stability in air and even in water. The fluoropolymers possess high hydrophobicity for efficient removal of water molecules from the vicinity of nanotubes, which are known to induce charge trapping. In addition, the strong dipole associated with the carbon-fluorine bonds can provide effective screening of the charge carriers in nanotubes from various trap states in the substrate. We also report on the extended applications of encapsulation with Teflon-AF for the realization of dual-gate CNT-TFTs, where one gate is used to control the threshold voltage and the other to switch the device. The fluorocarbon encapsulation technique presents a promising approach for enhanced device reliability, which is critical for future system-level electronics based on CNTs. PMID- 24796607 TI - UHPLC quantification of sotolon in white wine. AB - Sotolon (4,5-dimethyl-3-hydroxy-2,5-dihydrofuran-2-one) is a volatile compound involved in the atypical aging of dry white wine, causing an irreversible defect when it exceeds 7-8 MUg L(-1), and it might be adopted as a chemical marker of oxidative aging. An easier and sensitive ultrahigh-pressure liquid chromatography method for its determination in white wine is reported. The sample preparation is based on the liquid/liquid extraction by dichloromethane and the purification by solid phase extraction of the redissolved dry sample. This method showed good linearity and intermediate repeatability (<0.7 MUg L(-1)), high recovery (>89.5%), and low detection limit (0.029 MUg L(-1)). This method was usefully applied to 30 Italian sparkling and still white wine samples, where sotolon was not detected in most of them and exceeded the perception threshold only in one sparkling wine (13 MUg L(-1)). The proposed method could be used to further investigate the aging/storage conditions and the chemical-physical parameters affecting its formation in wine. PMID- 24796608 TI - Advances in prenatal diagnostics. PMID- 24796609 TI - Short-term prediction of preeclampsia: how close are we? PMID- 24796610 TI - Clinical applications of biomarkers in preeclampsia. AB - Preeclampsia remains a significant cause of maternal morbidity and mortality worldwide. Prediction, diagnosis and management continue to be challenging but advances in the understanding of the pathophysiological processes underlying the disease has enabled identification of multiple biomarkers, some of which aid prediction of those at risk. Even in isolation, some of these biomarkers have demonstrated sufficient test performance for incorporation into clinical practice. A combination of the most promising biomarkers and clinical factors may improve risk prediction, and aid diagnosis and subsequent management through development of integrated clinical risk models. This article aims to review the literature relating to biomarkers in preeclampsia and summarize the possible clinical applications of these findings. PMID- 24796611 TI - Fetal fibronectin as a biomarker of preterm labor: a review of the literature and advances in its clinical use. AB - Spontaneous preterm birth (sPTB) is a challenge in obstetrics today, and is the leading cause of neonatal morbidity and mortality. The ability to predict preterm birth had, until recently, been poor. The biomarker fetal fibronectin (fFN), found at the maternal-fetal interface, when present in high concentrations in cervicovaginal fluid, has been shown to increase the risk of sPTB in symptomatic and asymptomatic women. Recently, further research has been performed into the applicability of such a test to clinical practice, and its effects on management decisions and patient outcomes. Owing to its high negative predictive value, a negative fFN result has been shown to reduce unnecessary interventions, change patient management and reduce healthcare costs, by allowing early reassurance and return to normal care pathways, while care can be concentrated on those at risk. The development of a bedside quantitative fFN test has shown promise to further improve the positive predictive abilities of fFN, as have combined predictive models with cervical length and fFN. PMID- 24796612 TI - Telomere length analysis and preterm infant health: the importance of assay design in the search for novel biomarkers. AB - Preterm infants develop an 'aged' phenotype in comparison with term-born infants, one component of which is adverse metabolic health and, therefore, long-term health follow-up is warranted to identify morbidity. In light of this, the identification and use of biomarkers to aid with prognosis would be a welcome development. Telomeres are repeat sequences at the ends of each chromosome arm known to shorten as a consequence of cellular aging, and in relation to several disease conditions. The hypothesis that expreterm infants manifest alterations in telomere attrition rate is, therefore, one of interest. Analysis of telomere length maybe a plausible technique to predict prognosis in relation to preterm birth, and early life environmental and nutritional exposures. In this article, we review the literature on telomere length analysis in the preterm infant population and examine the tools available to measure telomere length. PMID- 24796613 TI - What does next-generation sequencing mean for prenatal diagnosis? AB - The ability to gain genetic information from the fetus in the mother's blood during pregnancy has been a long desired goal of research in prenatal medicine. The detection of fetal DNA in maternal blood, coupled with the development of the powerful techniques of next-generation sequencing finally transferred this analysis into clinical practice. Following the commercial introduction of noninvasive prenatal testing for aneuploidies, there has been a very strong demand, which has fostered an extreme rapid development and improvement of technology. Publications in this field are so numerous so that it is challenging to keep up with the latest state of the art. Here, we describe the current basic concepts of cell-free DNA-based noninvasive prenatal testing, give an overview of the currently commercially available tests and the chromosomal aberrations that can be identified. We also present current and future concepts for the implementation of cell-free DNA testing into clinical care. PMID- 24796614 TI - Fetal lung maturity testing: the end of an era. AB - Respiratory distress syndrome is a major cause of neonatal morbidity and mortality that is most commonly caused by a deficiency in lung surfactant in premature infants. Therefore, laboratory tests were developed to measure the presence and/or concentration of lung surfactant in amniotic fluid in order to estimate maturity of the fetal lung. Although these tests were once widely employed, their utilization by physicians has decreased in recent years. Several studies have shown that demonstration of a mature fetal lung index by antenatal testing does not improve neonatal outcomes. Instead, decreased respiratory and nonrespiratory morbidities are most highly correlated with gestational age of the fetus. Therefore, fetal lung maturity testing may have passed the point of being clinically useful. PMID- 24796615 TI - Biomarkers in frontotemporal dementia. PMID- 24796616 TI - Ten-gene biomarker panel: a new hope for ovarian cancer? PMID- 24796619 TI - Clinical implications of different biomarkers in elderly patients with heart failure. AB - AIMS: The aim of this article was to determine the importance of neuroendocrine and inflammatory biomarkers in elderly patients (>70 years) with heart failure (HF). METHODS: In this retrospective and observational study, TNF-alpha, IL-6, IL 18, Fas (Apo1), BNP, C-reactive protein and cystatin C values were calculated, as well as the relationship between them and the clinical evolution of patients. RESULTS: A total of 124 patients (mean age +/- standard deviation: 83+/-5 years) were included. After a mean follow-up of 2.4 years, 40.3% of patients were hospitalized for HF and 15.3% of patients died. Those patients who were hospitalized for HF compared with those that did not were hospitalized for HF showed higher values of IL-6 (9.8+/-13.1 vs 4.65+/-5.8 pg/ml; p=0.003) and those who died compared with those who are alive higher values of IL-18 (437.1+/-137.4 vs 299.7+/-167.2 pg/ml; p=0.01), C-reactive protein (12.6+/-19.4 vs 6.1+/-9.4 mg/l; p=0.03), BNP (704.2+/-428.6 vs 418.5+/-410.6 pg/ml; p=0.008) and cystatin C (1.76+/-0.6 vs 1.45+/-0.5 mg/l; p=0.04). In the multivariate analysis, only IL-18 (hazard ratio: 1.4; 95% CI: 1.05-1.8; p=0.027) remained as an independent predictor for mortality. CONCLUSION: In elderly patients with HF, the determination of biomarkers may be helpful to establish those patients at higher risk. PMID- 24796620 TI - Urinary excretion of liver-type FABP as a new clinical marker for the progression of obstructive nephropathy. AB - AIM: The aim of this article was to investigate the performance and predictive value of urinary liver-type FABP (uL-FABP) and urinary NGAL (uNGAL) for renal function and prognosis in obstructive nephropathy (ON). PATIENTS & METHODS: A total of 108 ON patients and urine samples were collected. An ELISA was used to determine the uL-FABP and uNGAL levels. A total of 90 patients completed the 1 year follow-up and were used to evaluate the predictive value of uL-FABP and uNGAL for the renal prognosis in ON. RESULTS: During the 1-year renal function follow-up, the uL-FABP level was significantly correlated with poor prognosis. When the preoperative uL-FABP and uNGAL or 72-h postoperative uL-FABP and uNGAL levels were combined, the areas under the curve for renal prognosis were 0.968 and 0.952, respectively. CONCLUSION: uL-FABP was helpful for the prediction of renal prognosis in ON. The combination of uL-FABP and uNGAL increased the accuracy of prediction. PMID- 24796621 TI - Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation. AB - AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Disturbances in cardiac potassium conductance are considered as one of the disease mechanisms in AF. We aimed to investigate if mutations in potassium channel beta-subunits KCNE2 and KCNE3 are associated with early-onset lone AF. METHODS & RESULTS: The coding regions of KCNE2 and KCNE3 were bidirectionally sequenced in 192 unrelated patients diagnosed with early-onset lone AF (<40 years). Two nonsynonymous missense mutations were identified in KCNE2 (M23L and I57T). Both mutations were absent in a healthy control group (n=1500 alleles). Electrophysiological investigations were performed for both mutations in combination with candidate pore-forming alpha-subunits KV7.1, KV11.1, KV4.3 and KV1.5. A significant gain-of-function effect was observed upon coexpression with KV7.1 and KV7.1+KCNE1. Confocal imaging found no differences in subcellular localization. No disease-suspected mutations were identified in KCNE3. CONCLUSION: We identified two KCNE2 gain-of-function missense mutations that seem to increase the susceptibility of early-onset lone AF. These results confirm previous findings indicating that gain-of-function in the slow delayed rectifier potassium current might be involved in the pathogenesis of AF. PMID- 24796622 TI - An evaluation of chromogranin A versus gastrin and progastrin in gastrinoma diagnosis and control. AB - AIM: The value of chromogranin A (CgA) versus gastrin and progastrin in diagnosis and control of gastrinoma patients is not settled because the peptides circulate as variable mixtures. We have addressed this complexity using defined sequence specific assays. PATIENTS & METHODS: Six assays were applied to plasma from 40 gastrinoma patients to measure alpha-amidated gastrins, glycine-extended gastrins, the total progastrin product, and assays for CgA sequence (340-348) and the 'total' CgA product. RESULTS: The gastrin/progastrin parameters did not add to the diagnosis beyond that of alpha-amidated gastrins, except in one patient. All gastrin parameters correlated otherwise closely. The CgA results differed. Thus, 11 patients had normal CgA concentrations. By contrast, all total CgA concentrations were elevated but correlated only moderately to gastrin. CONCLUSION: Assays measuring alpha-amidated gastrins have high diagnostic value except for singular patients in whom only progastrin was elevated. By contrast, CgA measurements are not valid in diagnosis or control of gastrinomas. PMID- 24796623 TI - Association between higher expression of YB-1 and poor prognosis in early-stage extranodal nasal-type natural killer/T-cell lymphoma. AB - AIM: A recent study shows that YB-1-related biomarkers affect the prognosis of patients with natural killer/T-cell lymphoma (NKTCL). The aim of this study was to determine whether there is an association between YB-1 expression and the prognosis of patients with early-stage extranodal nasal-type NKTCL. MATERIALS & METHODS: To clarify the roles of YB-1 in early-stage extranodal nasal-type NKTCL, we used immunohistochemical studies to examine YB-1 expression in 36 early-stage extranodal nasal-type NKTCL specimens. RESULTS: Subsequently, YB-1 expression was correlated with clinicopathologic parameters. Higher expression of YB-1 was associated with an increased potential for relapse, poor disease-free survival and reduced overall survival. DISCUSSION: Higher expression of YB-1 could be an independent risk factor for poor prognosis in patients with early-stage extranodal nasal-type NKTCL. Understanding the biology of YB-1-mediated pathways may lead to novel therapeutic strategies for early-stage extranodal nasal-type NKTCL. PMID- 24796625 TI - UV curable lens production using molecular weight controlled PEEK based acrylic oligomer (Ac-PEEK). AB - We produced UV curable lenses with properties blocking short wave UV light. In the UV-curable formulations, we used an oligomer (Ac-PEEK) with another urethan oligomer (Mw = 2000). Radically active, molecular weight controlled Ac-PEEK was obtained by reacting 2-hydroxyl ethyl methacrylate with molecular- weight- controlled and isocyanate terminated PEEK (Mn = 4500). We characterized all synthesized monomer, oligomer and optical materials with UV/Vis spectrophotometer with interferogram, elemental analyser, mass spectrophotometer, proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermal gravimetric analyzer, differential scanning calorimeter, scanning electron microscopy and gas chromatography. Results suggested that newly synthesized oligomer with the structure of PEEK absorbs short wave UV-light. Ageing tests [ISO 11979-5, Ophthalmic implants-intraocular lenses (IOL)-Part 5: Biocompatibility] performed on the IOL materials were successful. High contact angle of the obtained lenses suggests that all lenses were hydrophobic and SEM results revealed that lenses are morphologically homogeneous. Based on all positive properties just mentioned, we safely conclude that the lenses produced in this study are very promising for IOL production. PMID- 24796624 TI - Growing recognition of the role for rare missense substitutions in breast cancer susceptibility. AB - Most cancer susceptibility genes function as tumor suppressors; accordingly, the focus of mutation screening in breast cancer families has been to identify protein-truncating mutations. However, it is now clear that, for some breast cancer susceptibility genes, a significant proportion of the burden of disease comes from rare missense substitutions. Among genes that have been extensively evaluated, BRCA1, BRCA2, PALB2 and BRIP1 stand as examples where the majority of mutations lead to protein truncation;TP53 provides a counter example, where the majority of pathogenic variants are missense substitutions. In ATM and CHEK2, missense substitutions are probably equally or more important in terms of their frequency and attributable risk. Therefore, ongoing efforts to identify new susceptibility genes should not ignore missense variation. PMID- 24796626 TI - Capillary action: enrichment of retention and habitation of cells via micro channeled scaffolds for massive bone defect regeneration. AB - The development of a biomaterial substitute that can promote bone regeneration in massive defects has remained as a significant clinical challenge even using bone marrow cells or growth factors. Without an active, thriving cell population present throughout and stable anchored to the construct, exceptional bone regeneration does not occur. An engineered micro-channel structures scaffold within each trabecular has been designed to overcome some current limitations involving the cultivation and habitation of cells in large, volumetric scaffolds to repair massive skeletal defect. We created a scaffold with a superior fluid retention capacity that also may absorb bone marrow cells and provide growth factor-containing body fluids such as blood clots and/or serum under physiological conditions. The scaffold is composed of 3 basic structures (1) porous trabecular network (300-400 MUm) similar to that of human trabecular bones, (2) micro-size channels (25-70 MUm) within each trabecular septum which mimic intra-osseous channels such as Haversian canals and Volkmann's canals with body fluid access, diffusion, nutritional supply and gas exchange, and (3) nano size pores (100-400 nm) on the surface of each septum that allow immobilized cells to anchor. Combinatorial effects of these internal structures result in a host-adapting construct that enhances cell retention and habitation throughout the 3 cm-height and 4 cm-length bridge-shaped scaffold. PMID- 24796627 TI - Investigating the surface reactivity of SiO2-TiO2-CaO-Na2O/SrO bioceramics as a function of structure and incubation time in simulated body fluid. AB - This study focuses on evaluating the biocompatibility of a SiO2-TiO2-CaO-Na2O/SrO glass and glass-ceramic series. Glass and ceramic samples were synthesized and characterized using X-ray diffraction. Each material was subject to maturation in simulated body fluid over 1, 7 and 30 days to describe any changes in surface morphology. Calcium phosphate (CaP) deposition was observed predominantly on the Na(+) containing amorphous and crystalline materials, with plate-like morphology. The precipitated surface layer was also observed to crystallize with respect to maturation, which was most evident in the amorphous Na(+) containing glasses, Ly N and Ly-C. The addition of Sr(2+) greatly reduced the solubility of all samples, with limited CaP precipitation on the amorphous samples and no deposition on the crystalline materials. The morphology of the samples was also different, presenting irregular plate-like structures (Ly-N), needle-like deposits (Ly-C) and globular-like structures (Ly-S). Cell culture analysis presented a significant increase in cell viability with the Na(+) materials, 134%, while the Sr(2+) containing glasses, 60-80% and ceramics, 60-85% presented a general reduction in cell viability, however these reductions were not significant. PMID- 24796628 TI - Tumor necrosis factor-beta Nco1 polymorphism and susceptibility to sepsis following major elective surgery. AB - BACKGROUND: Post-operative sepsis remains a substantial cause of morbidity and mortality. In injured patients, that a polymorphism of the gene for tumor necrosis factor-beta (TNF-beta) has been related to the development of sepsis. Genetic factors may also have a role in etio-pathogenesis of sepsis following surgery. We investigated the relationship of the polymorphism of the gene for TNF beta and the serum concentration of TNF-alpha to the development of sepsis after elective major surgery. METHODS: The study population consisted of 211 patients undergoing major elective surgery. The NcoI polymorphism of TNF-beta was studied in genomic DNA through the analysis of restriction fragments of Nco1-digested DNA with the polymerase chain reaction (PCR). All patients were followed for 1 mo after surgery for any evidence of sepsis. Serum concentrations of TNF-alpha were measured pre- and post-operatively by enzyme linked immunosorbent assay (ELISA). Genotypes of TNF-beta and the production of TNF-alpha were related to the occurrence of sepsis. RESULTS: Post-operative sepsis developed in 21.8% (n=46) of the patients. The overall mortality was 4.2% (n=9). The overall allele frequency of the TNF-beta genotype was 0.32 for TNFB1 and 0.68 for TNFB2. Within the TNF beta genotype, 11.84% (n=25) of the patients were homozygous recessive for TNFB1, 41.23% (n=87) were heterozygous, with TNFB1/TNFB2, and 46.91% (n=99) were homozygous dominant for TNFB2. The incidence of post-operative sepsis was significantly (p=0.01) higher in patients homozygous for the TNFB2 allele. When compared with patients carrying at least one TNFB1 allele (TNFB1 homozygous and heterozygous genotype), the TNFB2 homozygous genotype was associated with an odds ratio (OR) of 2.60 (p=0.005; 95% CI 1.32-5.15) for the development of sepsis. As compared with that for the heterozygous genotype, the OR for the homozygous TNFB2 genotype was 3.00 (p=0.003; 95% CI 1.39-6.44). In patients with post-operative sepsis, serum concentrations of TNF-alpha were significantly higher (p=0.02) in TNFB2 homozygous individuals than in those of individuals of the other TNF-beta genotypes. CONCLUSION: The development of sepsis was associated with a greater capacity to produce TNF-alpha after surgery. The Nco1 polymorphism of the TNF beta gene was associated with the development of post-operative sepsis with an increased serum concentration of TNF-alpha. In patients without post-operative sepsis, polymorphism of the TNF-beta gene was not related to different levels of TNF-alpha production. This indicates an association between polymorphism of the TNF-beta gene and post-operative sepsis, suggesting the TNFB2/B2 genotype as a high-risk factor for the development of sepsis after elective surgery. PMID- 24796629 TI - Three novel quantitative trait loci for skin thickness in swine identified by linkage and genome-wide association studies. AB - Skin is the largest organ in the pig body and plays a key role in protecting the body against pathogens and excessive water loss. Deciphering the genetic basis of swine skin thickness would enrich our knowledge about the skin. To identify the loci for porcine skin thickness, we first performed a genome scan with 194 microsatellite markers in a White Duroc * Erhualian F2 intercross. We identified three genome-wide significant QTL on pig chromosomes (SSC) 4, 7 and 15 using linkage analysis. The most significant QTL was found on SSC7 with a small confidence interval of ~5 cM, explaining 23.9 percent of phenotypic variance. Further, we conducted a genome-wide association study (GWAS) using Illumina PorcineSNP60 Beadchips for the F2 pedigree and a population of Chinese Sutai pigs. We confirmed significant QTL in the F2 pedigree and replicated QTL on SSC15 in Chinese Sutai pigs. A meta-analysis of GWASs on both populations detected a genomic region associated with skin thickness on SSC4. GWAS results were generally consistent with QTL mapping. Identical-by-descent analysis defined QTL on SSC7 in a 683-kb region harboring an interesting candidate gene: HMGA1. On SSC15, the linkage disequilibrium analysis showed a haplotype block of 2.20 Mb that likely harbors the gene responsible for skin thickness. Our findings provide novel insights into the genetic basis of swine skin thickness, which would benefit further understanding of porcine skin function. PMID- 24796631 TI - A second look at Emmonsia infection can make the difference. PMID- 24796630 TI - Angiotensin receptors as sensitive markers of acute bronchiole injury after lung transplantation. AB - BACKGROUND: Although lung transplantation is the only means of survival for patients with end-stage pulmonary disease, outcomes from this intervention are inferior to other solid organ transplants. The reason for the poor outcomes may be linked to an early reaction, such as primary graft dysfunction, and associated with marked inflammatory response, bronchiole injury, and later fibrotic responses. Mediators regulating these effects include angiotensin II and matrix metalloproteinases (MMPs). METHODS: We investigated changes to these mediators over the course of cardiopulmonary bypass (CPB) and up to 72 h after lung transplantation, using immunohistochemistry, Western blot, and ELISA techniques. RESULTS: We found 4- and 16-fold increases in plasma angiotensin II and MMP-9, respectively, from pre-CPB to post-CPB. MMP-9 levels remained elevated 1 h after transplantation. MMP-2 levels were elevated 6-24 h after lung transplantation. Type 2 angiotensin II receptor (ATR2) expression was 3.5-fold higher in bronchoalveolar cells 1-6 h after transplantation than in controls. CONCLUSIONS: The study suggests that the combination of cardiopulmonary bypass and lung transplantation is associated with early changes in the angiotensin II receptor system and in MMPs, and that altered expression of these mediators may be a useful marker to examine pathological changes that occur in lungs during transplant surgery. PMID- 24796632 TI - Synthesis and antifungal evaluation of a series of maleimides. AB - BACKGROUND: Maleimides, both natural and synthesised, have good biological activities. In a continuous effort to discover new maleimides with good antifungal activities, the authors have synthesised a series of 3,4-dichloro-, 3 methyl and non-substituted maleimides based on previous studies. The compounds were biologically evaluated against the fungal pathogen Sclerotinia sclorotiorum. RESULTS: Of the 63 compounds evaluated, 25 compounds had interesting inhibitory potency with EC50 < 10 ug mL(-1). N-(3,5-Dichlorophenyl)-3,4-dichloromaleimide (EC50 = 1.11 ug mL(-1)) and N-octyl-3-methylmaleimide (EC50 = 1.01 ug mL(-1)) were more potent than the commercial fungicide dicloran (EC50 = 1.72 ug mL(-1)). The results showed that compounds exhibiting log P values within the range 2.4 3.0 displayed the best results in terms of fungicidal activity, and this seemed, therefore, to be the optimum range for this physicochemical parameter. CONCLUSION: The present work demonstrates that some maleimides can be used as potential lead compounds for developing novel antifungal agents against S. sclerotiorum. PMID- 24796634 TI - Validation of a venous thromboembolism risk assessment model in gynecologic oncology. AB - OBJECTIVES: Gynecologic oncology patients undergoing surgery are at an increased risk for venous thromboembolism (VTE). We attempted to validate a VTE risk assessment model in gynecologic oncology patients. METHODS: All gynecologic oncology patients who underwent a laparotomy for the diagnosis or suspicion of gynecologic malignancy from 2004 to 2010 were included. Demographic, surgicopathologic, and complication data were collected. VTE was based on the symptomatic diagnosis. Data for the Caprini risk assessment model (RAM) was used to score and stratify patients on their risk for VTE. RESULTS: 1123 gynecologic oncology patients were included within this study. Ovarian cancer was the most common diagnosis (39%) with a median age of 56.1. All patients received SCDs with 40% receiving double prophylaxis. The overall incidence of VTE was 3.3%, with lower extremity deep venous thrombosis (DVT) n=17 and pulmonary embolism (PE) n=20. Complication rates were similar in each group. Based on the Caprini scoring model 92% of patients scored in the "Highest Risk" category. The Caprini RAM accurately predicted all 37 VTEs, all of which scored in the "Highest Risk" category. The percentage of patients that received double prophylaxis increased with time from 12% in 2004 to 63% in 2010. Importantly, 25 of the 37 VTEs (68%) did not receive double prophylaxis. CONCLUSIONS: The use of the Caprini RAM accurately predicted patients at the highest risk of experiencing VTE. Considering accurate identification of patients allows proper administration of double prophylaxis, we recommend the use of this scoring model preoperatively in patients undergoing surgery for gynecologic malignancies. PMID- 24796633 TI - Prospective quality of life outcomes following robotic surgery in gynecologic oncology. AB - PURPOSE: To characterize the health-related quality of life (HRQL) of patients undergoing robotic surgery for the treatment of gynecologic cancers. METHODS: 211 patients completed a quality of life questionnaire before surgery. Postoperative questionnaires, consisting of the same assessment with the addition of postoperative questions, were given at 1 week, 3 weeks, 3, 6, and 12 months after surgery. The Functional Assessment of Cancer Therapy-General (FACT-G) and its subscales were used to evaluate HRQL. Patient-rated body image was evaluated using the Body Image Scale. Statistical significance was measured by the Wilcoxon signed-rank test. Minimally important difference (MID) values were analyzed to evaluate clinical significance. RESULTS: Overall HRQL and body image decreased at 1 week after surgery and returned to baseline by 3 weeks. Physical and functional well-being decreased at 1 week after surgery and returned to baseline by 3 months after surgery. However, using MID criteria, physical well-being returned to baseline by 3 weeks. Social well-being did not change significantly. Emotional well-being increased immediately by 1 week after surgery. CONCLUSION: Patient reported HRQL outcomes following robotic surgery for the treatment of gynecologic cancers suggests a rapid return to pre-surgery values. PMID- 24796635 TI - The use of a three-dimensional cell culture model to investigate host-pathogen interactions of Francisella tularensis in human lung epithelial cells. AB - Francisella tularensis inhalation results in bacterial interaction with numerous lung cell types, including those of the epithelium. This work investigates a three-dimensional cell-culture system to characterise the epithelial response to F. tularensis. Immortalised human pneumocytes (A549s) grown in rotating-wall vessel (RWV) bioreactors display an in vivo-like phenotype, which has been confirmed to be driven by specific transcriptional events (8454 genes, p <= 0.05). These data support the RWV model as a more in vivo-like culture system to investigate the lung epithelium, compared to monolayer counterparts. RWV-cultured A549s were infected with F. tularensis SchuS4 and LVS and intracellular replication mapped over 22 h compared to monolayer cells. The RWV-cultured A549s were more resistant to SchuS4 and LVS infection (p <= 0.05). Transcriptomics identified 2086 genes (p <= 0.05) as candidates for host-pathogen interactions which result in the observed increase in resistance of the RWV-cultured A549 cells. Gene and pathway analysis identified processes involved in MMP modulation, endocytosis, mucin production and the complement pathway amongst others. The role of these pathways during infection was further characterised using chemical inhibitors. This work has revealed several new hypotheses worthy of further testing in order to understand the epithelial host response to F. tularensis infection. PMID- 24796637 TI - Fraud and plagiarisim in school and career. AB - Between 0% and 94% of university students acknowledge having committed academic fraud. Its forms are varied: cheating on examinations, submitting someone else's work, plagiarism, false citations, false reporting on experiments, tests or findings in the medical history and physical examination, unfair behavior toward fellow students, and many others. The consequences of academic fraud include learning corruption, useless efforts by students and faculty, incorrect performance evaluations and unfair selection for jobs. Since this can be a prelude to future fraud as doctors or researches, the prevalence, risk factors, motivations, clinical appearances, detection and prevention of the disease of academic fraud are here reviewed. PMID- 24796636 TI - Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns Project. AB - BACKGROUND: Central serotonergic (5-HT) function is implicated in pathways to alcohol dependence, including dysphoria manifested by symptoms of anxiety and depression. However, little is known about genetic variation in central 5-HT function and its potential impact on temperament and behavior in persons with a family history of alcoholism (FH+). METHODS: We tested 314 healthy young adults (23.5 years of age, 57% female; 193 FH- and 121 FH+) enrolled in the Oklahoma Family Health Patterns project, a study of alcoholism risk in relation to temperament and behavioral dyscontrol. Dysphoria was assessed using the Eysenck neuroticism and Beck depression scales, and Cloninger's Tridimensional Personality Questionnaire. Risk taking was assessed with the Iowa Gambling Task (IGT) and Balloon Analogue Response Task (BART). All subjects were genotyped for a functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4). RESULTS: FH+ subjects with the gain-of-function 5 HTTLPR genotype scored higher in neuroticism, harm avoidance, and symptoms of depression (p-values <= 0.03). No effect of 5-HTTLPR genotype was seen in FH-. FH+ carriers of the gain-of-function 5-HTTLPR genotype played to minimize their frequency of losses in the IGT, whereas FH- carriers played a balanced strategy (p < 0.003). No 5-HTTLPR effects were seen in the BART. Results were unaffected by sex, education, drug use, and antisocial characteristics. CONCLUSIONS: The functional 5-HTTLPR polymorphism predicted significant variation in negative moods and poorer affect regulation in FH+ persons, with possible consequences for behavior, as seen in a simulated gambling task. This pattern may contribute to a drinking pattern that is compensatory for such affective tendencies. PMID- 24796638 TI - Hemophagocytic lymphohistiocytosis associated with viral infections: Diagnostic challenges and therapeutic dilemmas. AB - Hemophagocytic lymphohistiocytosis is a frequently fatal clinicopathologic syndrome in which an uncontrolled and ineffective immune response leads to severe hyperinflammation. It may occur as either a familial disorder or a sporadic condition in association with a variety of triggers: infections, malignancies, autoimmune diseases, and acquired immune deficiencies. However, the most consistent association is with viral infections, especially Epstein-Barr virus. The main clinical features are fever, liver dysfunction, coagulation abnormalities and pancytopenia. Early diagnosis and treatment are important to reducing mortality, but the diagnosis is difficult because of the rarity of the syndrome and the lack of specificity of the clinical findings. Treatment should be directed towards treating the underlying disease and to suppressing the exaggerated inflammatory response through the use of immunosuppressive agents. PMID- 24796639 TI - [Woman with facial hypertrichosis]. PMID- 24796640 TI - Prevalence of sarcopenia in a media and long stay Unit. AB - BACKGROUND: Sarcopenia is characterized by the loss of skeletal muscle mass and strength and represents a risk factor for frailty, loss of independence and physical disabilities. This study aimed to assess the prevalence of sarcopenia in a population of patients admitted to a media and long-stay unit. PATIENTS AND METHODS: Descriptive, cross-sectional observational study that included 166 patients over 18 years who were admitted consecutively for a year to palliative care, convalescence or rehabilitation. Administrative and anthropometric data were recorded. Sarcopenia detection was performed by assessing the strength in the scapular and pelvic girdle muscles, grip strength in the hands, muscle mass and physical functional capacity. RESULTS: The overall prevalence of sarcopenia was 77.6%. Most patients had severe sarcopenia (91.2%), with reduced levels of the 3 assessed parameters: muscle strength (88.2%), muscle mass (85.5%) and physical performance (94.70%). CONCLUSION: The prevalence of sarcopenia in patients admitted to our media and long-stay unit is higher than that reported in noninstitutionalized populations, and often has a significant degree of severity. PMID- 24796641 TI - Senile primary aldosteronism associated with adrenal carcinoma. PMID- 24796642 TI - The contributions of anthropology and mitochondrial DNA analysis to the identification of the human skeletal remains of the Australian outlaw Edward 'Ned' Kelly. AB - This paper details the anthropological and genetic analyses that contributed to the identification of the notorious Australian outlaw ('bushranger') Edward ('Ned') Kelly. In 1880 at the age of 25, Kelly was hanged and buried at the former Melbourne Gaol in Victoria, Australia. In 1929, the remains of executed prisoners (including those of Kelly) were haphazardly disinterred following the demolition of parts of the Melbourne Gaol and haphazardly reinterred in three distinct "pits" at the Pentridge Prison. In 1999 the Pentridge Prison was sold for commercial development and subsequently in 2008 and 2009 the human remains of prisoners were recovered. A total of 41 cases of unidentified human skeletal remains from Pentridge were examined using traditional anthropological techniques. At least one representative sample from each of the remains (mostly clavicles) from all three pits was selected for DNA analysis. Comparative ante mortem reference samples were also located. Given the antiquity and condition of remains recovered from Pentridge, and the 130 years that had passed since Kelly's execution, mitochondrial DNA analysis was chosen as a suitable DNA analysis tool to examine the Pentridge cases to assist in the inclusion or exclusion of remains as being those of Ned Kelly. Only one of the Pentridge cases (Pen14) matched the HV1/HV2 mitochondrial DNA haplotype of the reference sample. Additional anthropological analyses indicated a number of pathological features that provided support that the remains of Pen14 are those of Edward ("Ned") Kelly. PMID- 24796643 TI - Stereochemical diversity of {MNO}(10) complexes: molecular orbital analyses of nickel and copper nitrosyls. AB - The great majority of {NiNO}(10) complexes are characterized by short Ni-N(O) distances of 1.60-1.65 A and linear NO units. Against this backdrop, the {CuNO}(10) unit in the recently reported [Cu(CH3NO2)5(NO)](2+) cation (1) has a CuNO angle of about 120 degrees and a very long 1.96 A Cu-N(O) bond. According to DFT calculations, metal-NO bonding in 1 consists of a single Cu(dz(2))-NO(pi*) sigma-interaction and essentially no metal(dpi)-NO(pi*) pi-bonding, which explains both the bent CuNO geometry and the long, weak Cu-N(O) bond. This sigma interaction is strongly favored by a ligand trans to the NO; indeed such a trans ligand may be critical for the existence and stability of a {CuNO}(10) unit. By contrast, {NiNO}(10) complexes exhibit a strong avoidance of such trans ligands. Thus, a five-coordinate {NiNO}(10) complex appears to favor a trigonal bipyramidal structure with the NO in an equatorial position, as in the case of [Ni(bipy)2(NO)](+) (6). An unusual set of Ni(d)-NO(pi*) orbital interactions accounts for the strongly bent NiNO geometry for this complex. PMID- 24796644 TI - An electrically driven, ultrahigh-speed, on-chip light emitter based on carbon nanotubes. AB - The integration of high-speed light emitters on silicon chips is an important issue that must be resolved in order to realize on-chip or interchip optical interconnects. Here, we demonstrate the first electrically driven ultrafast carbon nanotube (CNT) light emitter based on blackbody radiation with a response speed (1-10 Gbps) that is more than 10(6) times higher than that of conventional incandescent emitters and is either higher than or comparable to that of light emitting diodes or laser diodes. This high-speed response is explained by the extremely fast temperature response of the CNT film, which is dominated by the small heat capacity of the CNT film and its high heat dissipation to the substrate. Moreover, we experimentally demonstrate 140 ps width pulsed light generation and real-time optical communication. This CNT-based emitter with the advantages of ultrafast response speeds, a small footprint, and integration on silicon can enable novel architectures for optical interconnects, photonic, and optoelectronic integrated circuits. PMID- 24796645 TI - On the natural fate of maleic hydrazide. Kinetic aspects of the photochemical and microbiological degradation of the herbicide. AB - Kinetic and mechanistic aspects of the photochemical and microbiological degradation of the herbicide Maleic Hydrazide (MH) have been studied. Riboflavin (Rf, vitamin B2) was employed as a main photosensitizer whereas Humic Acid (HA) was included as a second sensitizer in order to more closely simulate natural environmental conditions. MH quenches excited singlet and triplet states of Rf, with rate constants close to the diffusion limit. The herbicide and dissolved molecular oxygen competitively quench triplet excited Rf. As a consequence the reactive oxygen species (ROS), superoxide radical anion (O2(-.)), hydrogen peroxide (H2O2) and singlet molecular oxygen (O2((1)Deltag)) are produced by electron- and energy-transfer processes, respectively, as demonstrated by auxiliary experiments employing selective auxiliary quenchers and the exclusive O2((1)Deltag) generator Rose Bengal (RB). As a global result, the photodegradation of Rf is retarded, whereas MH is degraded by the generated ROS. The bacteria Pseudomonas aeruginosa (Ps) and Bacillus subtilis (Bs), recognized as contaminants surface-water and soil and microbial antagonists of phytopathogenic, were used in the microbiological experiments. Results of the individual incubation of both bacteria in in the presence of MH indicate a stimulation on the Ps growth, implying the biodegradation of the herbicide, whereas MH only exerted a bacteriostatic effect on Bs. PMID- 24796646 TI - Transcranial direct current stimulation and simultaneous functional magnetic resonance imaging. AB - Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses weak electrical currents administered to the scalp to manipulate cortical excitability and, consequently, behavior and brain function. In the last decade, numerous studies have addressed short-term and long-term effects of tDCS on different measures of behavioral performance during motor and cognitive tasks, both in healthy individuals and in a number of different patient populations. So far, however, little is known about the neural underpinnings of tDCS-action in humans with regard to large-scale brain networks. This issue can be addressed by combining tDCS with functional brain imaging techniques like functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). In particular, fMRI is the most widely used brain imaging technique to investigate the neural mechanisms underlying cognition and motor functions. Application of tDCS during fMRI allows analysis of the neural mechanisms underlying behavioral tDCS effects with high spatial resolution across the entire brain. Recent studies using this technique identified stimulation induced changes in task-related functional brain activity at the stimulation site and also in more distant brain regions, which were associated with behavioral improvement. In addition, tDCS administered during resting-state fMRI allowed identification of widespread changes in whole brain functional connectivity. Future studies using this combined protocol should yield new insights into the mechanisms of tDCS action in health and disease and new options for more targeted application of tDCS in research and clinical settings. The present manuscript describes this novel technique in a step-by-step fashion, with a focus on technical aspects of tDCS administered during fMRI. PMID- 24796648 TI - IL-33 promotes airway remodeling and is a marker of asthma disease severity. AB - OBJECTIVE: To investigate the function of interleukin-33 (IL-33) in the asthmatic airway remodeling and the relationship between IL-33 and asthma severity. METHODS: IL-33 levels, sputum eosinophils percentage (EOS%), pulmonary function and total immunoglobulin (IgE) were measured for 45 patients with asthma and 40 non-allergic controls. Asthma severity was assessed. The expressions of IL-33 and reticular basement membrane (RBM) on bronchial biopsy specimens from eight asthma patients and eight non-allergic controls were observed after hematoxylin-eosin staining (HE) and immunohistochemical staining. In vitro experiments, real-time polymerase chain reactions and western blotting analysis were used to identify the specific effects of IL-33 administration. RESULTS: Serum IL-33 levels in patients with asthma were higher than those in non-allergic controls. Moreover, in asthmatic patients, serum IL-33 levels were negatively correlated to forced expiratory volume in one second (FEV1, % predicted), and positively correlated to asthma severity. Increased expression of IL-33 and RBM thickening were observed on bronchial biopsy specimens obtained from patients with asthma. Serum IL-33 levels were positively correlated to basement membrane thickness. The production of fibronectin1 and type I collagen in human lung fibroblasts (HLF-1) increased at 24 h after IL-33 treatment in vitro. Pre-treatment with anti-ST2 antibody or fluticasone propionate (FP) suppressed the production of fibronectin1 and types I collagen induced by IL-33. CONCLUSIONS: IL-33 is a marker of asthma severity, and may contribute to airway remodeling in asthma by acting on human lung fibroblasts. PMID- 24796647 TI - CCL11 as a potential diagnostic marker for asthma? AB - OBJECTIVE: Asthma is an inflammatory airway disease characterized by airway eosinophilia, in which CCL11 (eotaxin) plays a crucial role. The aim of study is to determine the elevation of CCL11 levels in bronchoalveolar lavage fluid (BALF), blood, exhaled breath condensate (EBC) and sputum in asthma patients and to identify which medium yields the most significant change in CCL11 level. METHODS: The databases of PubMed, Embase and Cochrane Centre Register of Controlled Trials were systematically searched from inception to September 2013. Controlled clinical trials that focused on CCL11 concentrations in asthma patients and controls, and their correlations with other asthma indicators were obtained. Data were analysed using Stata 12.0. RESULTS: Thirty studies were included in this investigation. CCL11 levels in blood, EBC and sputum were significantly higher in asthma patients than in healthy subjects. Sputum CCL11 concentrations were significantly elevated in unstable asthma patients versus stable asthma patients and in uncontrolled asthma patients versus partially controlled asthma patients. CCL11 levels in sputum and blood were negatively correlated with the lung function as measured by FEV1% predicted, and were positively correlated with BALF, EBC and sputum eosinophil counts. Similarly, CCL11 concentrations were positively correlated with eosinophil cationic protein in EBC, blood and sputum as well as with interleukin-5 in sputum and fractional exhaled nitric oxide in EBC. Steroid treatment had no significant effect on CCL11 levels. CONCLUSIONS: CCL11 is a potentially useful biomarker for the diagnosis and assessment of asthma severity and control, especially in sputum. CCL11 is crucial in eosinophil chemoattraction and activation in asthma pathogenesis. Further studies using anti-CCL11 approaches are needed to confirm a role for CCL11 in asthma pathogenesis particularly in patients with more severe disease. PMID- 24796649 TI - Methacholine challenge is insufficient to exclude bronchial hyper-responsiveness in a symptomatic military population. AB - BACKGROUND: Bronchial hyper-responsiveness in a military population has been evaluated by direct and indirect challenge methods. We hypothesized that negative methacholine challenge testing (MCT) was not sufficient to exclude significant bronchial hyper-responsiveness in a symptomatic military population with exertional dyspnea. The purpose of our study was to identify bronchial hyper responsiveness in symptomatic military recruits and active duty personnel with normal baseline spirometry and negative pharmacologic bronchoprovocation testing. METHODS: We performed a retrospective single center electronic chart review of symptomatic service members with a negative MCT who completed a subsequent exercise challenge test (ECT). RESULTS: ECT was positive in 45 (26.4%) of 171 subjects (98 recruits). Subjects with a positive ECT had lower baseline forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC than those with a negative ECT, and these differences were statistically significant. The mean drop in FEV1 with exercise challenge positive patients was 17.9 +/- 9.2%, and the mean drop in FEV1 with MCT was significantly greater in exercise challenge positive patients (-9.5 +/- 5.5 vs. -7.6 +/- 5.5, p = 0.042). Exercise-induced bronchoconstriction (EIB) was observed in 41% of all recruits who subsequently did not complete training. Only 1 recruit subject of 28 with EIB completed training. CONCLUSIONS: Methacholine challenge is an insufficient screening test to detect bronchial hyper-responsiveness in a symptomatic military population. In military recruits, EIB is associated with training failure. PMID- 24796650 TI - In-school asthma management and physical activity: children's perspectives. AB - OBJECTIVE: Regular physical activity (PA) is an important component of pediatric asthma management. No studies have examined how in-school asthma management influences PA from children's perspectives. The aim of this study was to explore children's perceptions of the impact of in-school asthma management on PA. METHODS: Qualitative interviews with 23 inner-city minority children with asthma (aged 8-10 yrs; 12 girls, 11 boys) were conducted in 10 Bronx, New York elementary schools. Sampling continued until saturation was reached. Interviews were recorded, transcribed and independently coded for common themes. RESULTS: Interviews produced five themes representing students' perceptions about (1) asthma symptoms during in-school PA; (2) methods to control asthma episodes during school PA; (3) methods to prevent asthma episodes during school; (4) limited accessibility of asthma medications; and (5) negative feelings about asthma and medication use. The majority of students experienced asthma symptoms while performing PA during school. Primary methods of managing asthma symptoms were sitting out during activity, drinking water, and visiting the nurse. Students lacked awareness or adherence to action plans to prevent or control asthma. Students reported limited access to medication during school and feelings of embarrassment and/or concerns of teasing when medicating in front of others. CONCLUSIONS: Our results indicate inappropriate in-school management of asthma symptoms, poor asthma control, lack of accessible medication, and stigma around publicly using asthma medication. Thus, students often missed or were withheld from PA. Interventions to improve in-school asthma care must consider ways to address these issues. PMID- 24796651 TI - Novel LC-MS2 product dependent parallel data acquisition function and data analysis workflow for sequencing and identification of intact glycopeptides. AB - Data dependent acquisition (DDA) of higher collision energy dissociation (HCD) MS(2) followed by electron transfer dissociation (ETD)-MS(2) upon detection of glycan-specific oxonium is one of the better approaches in current LC-MS(2) analysis of intact glycopeptides. Although impressive numbers of glycopeptide identification by a direct database search have been reported, false positives remained high and difficult to determine. Even in cases when the peptide backbones were correctly identified, the exact glycan moieties were often erroneously assigned. Any attempt to fit the best glycosyl composition match by mass only is problematic particularly when the correct monoisotopic precursor cannot be determined unambiguously. Taking advantage of a new trihybrid Orbitrap configuration, we experimented with adding in a parallel ion trap collision induced dissociation (CID)-MS(2) data acquisition to the original HCD-product dependent (pd)-ETD function. We demonstrated the feasibility and advantage of identifying the peptide core ion directly from edited HCD-MS(2) data as an easy way to reduce false positives without compromising much sensitivity in intact glycopeptide positive spectrum matches. Importantly, the additional CID-MS(2) data allows one to validate the glycan assignment and provides insight into possible glycan modifications. Moreover, it is a viable alternative to deduce the glycopeptide backbone particularly in cases when the peptide backbone cannot be identified by ETD/HCD. The novel HCD-pd-CID/ETD workflow combines the best possible decision tree dependent MS(2) data acquisition modes currently available for glycoproteomics within a rapid Top Speed DDA duty cycle. Additional informatics can conceivably be developed to mine and integrate the rich information contained within for simultaneous N- and O-glycopeptide analysis. PMID- 24796653 TI - Decreased miR-146 expression in peripheral blood mononuclear cells is correlated with ongoing islet autoimmunity in type 1 diabetes patients 1miR-146. AB - BACKGROUND: Type 1 diabetes mellitus (T1D) is a common autoimmune disease mediated by autoimmune attack against pancreatic beta-cells. It has been reported that dysregulation of microRNAs (miRNAs) may contribute to the pathogenesis of autoimmune diseases, including T1D. The aim of the present study was to identify pathogenic miRNAs in peripheral blood mononuclear cells (PBMC) of T1D patients. METHODS: Global miRNA and mRNA expression was profiled in PBMC from 12 patients with newly diagnosed T1D and 10 normal controls. Differently expressed miRNAs were validated in an independent set of patients and controls. The dynamic changes in miRNA and target gene expression were analyzed in T1D patients treated with either a short (6 months) or long (12-24 months) course of insulin. The association between miRNA expression and serum glutamic acid decarboxylase antibody (GADA) titers was also investigated. RESULTS: Compared with normal controls, there were 26 miRNAs and 1218 genes differently expressed in PBMC of patients with newly diagnosed T1D. The greatest downregulation was for miR-146a (48% decrease; P < 0.05). Expression of its target genes, predicted to be tumor necrosis factor receptor-associated factor 6 (TRAF6), B cell CLL/lymphoma 11A (BCL11A), syntaxin 3 (STX3) and numb homolog (NUMB), was upregulated. Moreover, T1D patients on long-course insulin and optimized glucose control had sustained low expression of miR-146. Interestingly, decreased miR-146a expression was significantly associated with high serum GADA titers (P < 0.05). CONCLUSIONS: The results suggest that dysregulation of miR-146 expression in PBMC may be associated with the ongoing autoimmune imbalance in T1D patients. PMID- 24796652 TI - Characterization of nitrogen and water status in oat leaves using optical sensing approach. AB - BACKGROUND: Optical sensing is a potential tool to estimate plant N status, but soil water deficits may interefere with forming a clear relationship. A greenhouse study was conducted with oat plants treated with three water regimes and four N levels to determine whether optical sensing could be used to estimate leaf N and relative water content (RWC). RESULTS: Leaf N was strongly correlated with reflectance at 550 nm and at around 705 nm, and N treatments caused a red edge peak shift to lower wavelength. The ratio of the first derivative reflectance at 741-696 nm (FDRE) was identified to be a good estimator of leaf N at jointing (R(2) = 0.90) and heading (R(2) = 0.86) stages across water treatments. Leaf N also had a stronger association with the red-edge position (REP) at both stages (R(2) = 0.83 and 0.78), or with the ratio R4 (R760/R550) at jointing (R(2) = 0.88), than with chlorophyll meter (SPAD) readings. Under water stress, the predictive accuracy of leaf N increased with these reflectance indices, but decreased using SPAD readings. CONCLUSION: The results indicate that specific reflectance indices of FDRE, REP and R4 may be used for a rapid and non destructive estimation of oat plant N status over a range of water regimes. PMID- 24796654 TI - Adenine formation without HCN. AB - From a historic point of view adenine was always presumed to be the product of HCN pentamerization. In this work a new mechanism for adenine synthesis in the gas phase without HCN is proposed. The concept of retrosynthetic analysis was employed to create a tautomer of adenine, which can be reached from previously observed interstellar molecules C3NH and HNCNH and its isomer H2NCN. MP2/6 311++G(2d,2p) calculations were performed to calculate the Gibbs free energy of the minimum and the transition state (TS) structures involved in the six step mechanism. This new mechanism requires a smaller number of steps, the reaction energy is twice as exergonic, and the rate determining TS is lower in energy than the corresponding ones proposed elsewhere in the literature. PMID- 24796655 TI - Adolescent risk-taking and resting state functional connectivity. AB - The existing literature on the role of emotion regulation circuits (amygdala prefrontal cortex) in the adolescent brain yields mixed results, particularly on the role of these regions in the context of reward sensitivity and risk-taking behavior sensitivity and risk-taking behavior. Here, we examined functional connectivity in the resting state in 18 risk-taking (RT) adolescents compared with 18 non-risk-taking (NRT) adolescents as defined by the Youth Risk Behavior Surveillance Survey. Separate seed-based correlations with bilateral amygdala and bilateral nucleus accumbens used as the seed were performed to determine functional connectivity using functional magnetic resonance imaging (fMRI). The results showed greater connectivity between the amygdala (seed region) and the right middle frontal gyrus, left cingulate gyrus, left precuneus and right inferior parietal lobule in RT adolescents than in NRT adolescents. Likewise, there was greater connectivity between the nucleus accumbens (seed region) and the right middle frontal gyrus in RT adolescents compared with NRT adolescents. These findings suggest that risk-taking behavior in adolescents is associated with hyperconnectivity during the resting state in networks associated with emotion regulation, reward sensitivity, executive control, and the default mode. PMID- 24796656 TI - [Basic concepts for network meta-analysis]. AB - Systematic reviews and meta-analyses have long been fundamental tools for evidence-based clinical practice. Initially, meta-analyses were proposed as a technique that could improve the accuracy and the statistical power of previous research from individual studies with small sample size. However, one of its main limitations has been the fact of being able to compare no more than two treatments in an analysis, even when the clinical research question necessitates that we compare multiple interventions. Network meta-analysis (NMA) uses novel statistical methods that incorporate information from both direct and indirect treatment comparisons in a network of studies examining the effects of various competing treatments, estimating comparisons between many treatments in a single analysis. Despite its potential limitations, NMA applications in clinical epidemiology can be of great value in situations where there are several treatments that have been compared against a common comparator. Also, NMA can be relevant to a research or clinical question when many treatments must be considered or when there is a mix of both direct and indirect information in the body of evidence. PMID- 24796657 TI - Should every patient diagnosed with a phaeochromocytoma have a 123 I-MIBG scintigraphy? AB - Localization of phaeochromocytomas and paragangliomas (PPGLs) should involve functional imaging as anatomical imaging modalities can either fail to locate the tumour or can be suboptimal due to an anatomical abnormality or previous surgery. Functional imaging is particularly useful to fully delineate the extent of disease using the whole-body scan and the evaluation of multifocality, metastatic or recurrent disease. An increasing number of radiolabeled tracers have become available for tumour visualization during the past decade. (123) I-meta iodobenzylguanidine scintigraphy is the most widely used functional imaging modality, and its sensitivity to identify chromaffin cell tumours varies from 85 to 88% for phaeochromocytomas and 56-76% for paragangliomas, while specificity ranges between 70 and 100% and 84-100%, respectively. PMID- 24796658 TI - A living biosensor model to dynamically trace glucocorticoid transcriptional activity during development and adult life in zebrafish. AB - Glucocorticoids (GCs) modulate many cellular processes through the binding of the glucocorticoid receptor (GR) to specific responsive elements located upstream of the transcription starting site or within an intron of GC target genes. Here we describe a transgenic fish line harboring a construct with nine GC-responsive elements (GREs) upstream of a reporter (EGFP) coding sequence. Transgenic fish exhibit strong fluorescence in many known GC-responsive organs. Moreover, its enhanced sensitivity allowed the discovery of novel GC-responsive tissue compartments, such as fin, eyes, and otic vesicles. Long-term persistence of transgene expression is seen during adult stages in several organs. Pharmacological and genetic analysis demonstrates that the transgenic line is highly responsive to drug administration and molecular manipulation. Moreover, reporter expression is sensitively and dynamically modulated by the photoperiod, thus proving that these fish are an in vivo valuable platform to explore GC responsiveness to both endogenous and exogenous stimuli. PMID- 24796660 TI - "Signs of Suicide" shows promise as a middle school suicide prevention program. AB - Although the Signs of Suicide (SOS) suicide prevention program has been implemented at both the middle and high school levels, its efficacy has been demonstrated previously only among high school students. The current study evaluated SOS implemented in high military impact middle schools. Compared to controls, SOS participants demonstrated improved knowledge about suicide and suicide prevention, and participants with pretest ideation reported fewer suicidal behaviors at posttest than controls with pretest ideation. These results provide preliminary evidence for SOS's efficacy as a suicide prevention program for middle school students. PMID- 24796659 TI - Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen. AB - Fetoplacental endothelial cells reside under physiological normoxic conditions (~2-8% O2) in vivo. Under such conditions, cells are believed to sense O2 changes primarily via hypoxia inducible factor 1 alpha (HIF1A). However, little is known regarding the role of HIF1A in fetoplacental endothelial function under physiological normoxia. We recently reported that physiological chronic normoxia (PCN; 20-25 day, 3% O2) enhanced FGF2- and VEGFA-stimulated proliferation and migration of human umbilical vein endothelial cells (HUVECs) via the MEK/ERK1/2 and PI3K/AKT1 pathways compared to standard cell culture normoxia (SCN; ambient O2: ~21% O2). Here, we investigated the action of HIF1A in regulating these cellular responses in HUVECs. HIF1A adenovirus infection in SCN-cells increased HIF1A protein expression, enhanced FGF2- and VEGFA-stimulated cell proliferation by 2.4 and 2.0-fold respectively, and promoted VEGFA-stimulated cell migration by 1.4-fold. HIF1A adenovirus infection in SCN-cells did not affect either basal or FGF2- and VEGFA-induced ERK1/2 activation, but it decreased basal AKT1 phosphorylation. Interestingly, HIF1A knockdown in PCN-cells via specific HIF1A siRNA transfection did not alter FGF2- and VEGFA-stimulated cell proliferation and migration, or ERK1/2 activation; however, it inhibited FGF2-induced AKT1 activation by ~50%. These data indicate that HIF1A differentially regulates cell proliferation and migration, and ERK1/2 and AKT1 activation in PCN- and SCN HUVECs. These data also suggest that HIF1A critically regulates cell proliferation and migration in SCN-, but not in PCN-HUVECs. PMID- 24796661 TI - Mothers' depressive symptoms predict both increased and reduced negative reactivity: aversion sensitivity and the regulation of emotion. AB - This study examined whether, as mothers' depressive symptoms increase, their expressions of negative emotion to children increasingly reflect aversion sensitivity and motivation to minimize ongoing stress or discomfort. In multiple interactions over 2 years, negative affect expressed by 319 mothers and their children was observed across variations in mothers' depressive symptoms, the aversiveness of children's immediate behavior, and observed differences in children's general negative reactivity. As expected, depressive symptoms predicted reduced maternal negative reactivity when child behavior was low in aversiveness, particularly with children who were high in negative reactivity. Depressive symptoms predicted high negative reactivity and steep increases in negative reactivity as the aversiveness of child behavior increased, particularly when high and continued aversiveness from the child was expected (i.e., children were high in negative reactivity). The findings are consistent with the proposal that deficits in parenting competence as depressive symptoms increase reflect aversion sensitivity and motivation to avoid conflict and suppress children's aversive behavior. PMID- 24796662 TI - A perceptually completed whole is less than the sum of its parts. AB - How efficiently do people integrate the disconnected image fragments that fall on their eyes when they view partly occluded objects? In the present study, I used a psychophysical summation-at-threshold technique to address this question by measuring discrimination performance with both isolated and combined features of physically fragmented but perceptually complete objects. If visual completion promotes superior integration efficiency, performance with a visually completed object should exceed what would be expected from performance with the individual object parts shown in isolation. Contrary to this prediction, results showed that discrimination performance with both static and moving versions of physically fragmented but perceptually complete objects was significantly worse than would be expected from performance with their constituent parts. These results present a challenge for future theories of visual completion. PMID- 24796663 TI - Impact of thyroid autoantibodies on functional outcome in patients with acute ischemic stroke. AB - BACKGROUND: Recent studies have shown that thyroid autoantibodies contribute to the development of cerebrovascular diseases, including atherosclerosis, moyamoya disease, and even arterial dissection, induced by immune-mediated endothelial dysfunction on the cerebral vasculature. The aim of this study was to investigate the impact of thyroid autoantibodies on functional outcome in patients with acute ischemic stroke. METHODS: We reviewed the patients with acute ischemic stroke who consecutively underwent thyroid autoantibody tests. We divided the patients into positive thyroid autoantibody (PAB) and negative thyroid autoantibody (NAB) groups. Demographic profiles, risk factors, stroke subtypes, laboratory results, and functional outcomes were compared between the 2 groups. We performed the multivariate analysis to determine whether thyroid autoantibodies were independently associated with functional outcome. RESULTS: Of the 763 patients, 121 (15.9%) were of the PAB group. Compared with the NAB group, higher baseline National Institutes of Health Stroke Scale score (P = .001) and prevalence of large-artery atherosclerosis (P = .014) were found in the PAB group. The PAB group had significantly higher proportion of unfavorable outcome at 3 months (modified Rankin Scale score >= 3) than the NAB group (P = .002). On multiple regression analysis, lower tri-iodothyronine level (odds ratio [OR] .985, 95% confidence interval [CI] .976-.995, P = .002) and PABs (OR 1.661, 95% CI 1.013 2.724, P = .044) were significant and independent predictors of unfavorable outcome. CONCLUSIONS: This study showed that elevated thyroid autoantibodies were independently associated with unfavorable outcome in patients with acute ischemic stroke. We speculate that immune-mediated vascular damage may contribute to the increased risk of unfavorable outcome by providing insufficient cerebral blood flow to the ischemic area. PMID- 24796664 TI - Increased expression of sorcin is associated with multidrug resistance in leukemia cells via up-regulation of MDR1 expression through cAMP response element binding protein. AB - Sorcin, a 22 kDa Ca(2+) binding protein, was first identified in a vincristine resistant Chinese hamster lung cell line, and was later demonstrated to be involved in the development of multidrug-resistance (MDR) phenotypes in a variety of human cancer cell lines. However, the exact role of sorcin in MDR cells is yet to be fully elucidated. Here we explored the role of sorcin in the development of MDR in leukemia cells, and revealed that the expression level of sorcin was directly correlated to the expression of MDR1/P-glycoprotein (P-gp). In addition, it was shown that sorcin induced the expression of MDR1/P-gp through a cAMP response element (CRE) between -716 and -709 bp of the mdr1/p-gp gene. Furthermore, overexpression of sorcin increased the phosphorylation of CREB1 and the binding of CREB1 to the CRE sequence of mdr1/p-gp promoter, and induced the expression of MDR1/P-gp. These findings suggested that sorcin induces MDR1/P-gp expression markedly through activation of the CREB pathway and is associated with the MDR phenotype. The new findings may be helpful for understanding the mechanisms of MDR in human cancer cells, prompting its further investigation as a molecular target to overcome MDR. PMID- 24796665 TI - Alpha-lipoic acid protects against cisplatin-induced ototoxicity via the regulation of MAPKs and proinflammatory cytokines. AB - Cisplatin is an effective antineoplastic drug that is widely used to treat various cancers; however, it causes side effects such as ototoxicity via the induction of apoptosis of hair cells in the cochlea. Alpha-lipoic acid (ALA) has been reported to exert a protective effect against both antibiotic-induced and cisplatin-induced hearing loss. Therefore, this study was conducted to (1) elucidate the mechanism of the protective effects of ALA against cisplatin induced ototoxicity using in vitro and ex vivo culture systems of HEI-OC1 auditory cells and rat cochlear explants and (2) to gain additional insight into the apoptotic mechanism of cisplatin-induced ototoxicity. ALA pretreatment significantly reduced apoptotic cell death of the inner and outer hair cells in cisplatin-treated organ of Corti explants and attenuated ototoxicity via marked inhibition of the increase in the expression of IL-1beta and IL-6, the phosphorylation of ERK and p38, the degradation of IkappaBalpha, the increase in intracellular levels of ROS, and the activation of caspase-3 in cisplatin-treated HEI-OC1 cells. This study represents the first histological evaluation of the organ of Corti following treatment with ALA, and these results indicate that the protective effects of ALA against cisplatin-induced ototoxicity are mediated via the regulation of MAPKs and proinflammatory cytokines. PMID- 24796666 TI - The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a. AB - Gastric carcinoma is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate. However, the mechanism underling gastric cancer is still not fully understood. Here in the present study, we identify the RNA-binding protein PCBP2 as an oncogenic protein in human gastric carcinoma. Our results show that PCBP2 is up-regulated in human gastric cancer tissues compared to adjacent normal tissues, and that high level of PCBP2 predicts poor overall and disease-free survival. Knockdown of PCBP2 in gastric cancer cells inhibits cell proliferation and colony formation in vitro, whereas opposing results are obtained when PCBP2 is overexpressed. Our in vivo subcutaneous xenograft results also show that PCBP2 can critically regulate gastric cancer cell growth. In addition, we find that PCBP2-depletion induces apoptosis in gastric cancer cells via up-regulating expression of pro-apoptotic proteins and down-regulating anti apoptotic proteins. Mechanically, we identify that miR-34a as a target of PCBP2, and that miR-34a is critically essential for the function of PCBP2. In summary, PCBP2 promotes gastric carcinoma development by regulating the level of miR-34a. PMID- 24796667 TI - PLCepsilon1: a potential target of RNA interference therapy for gastric cancer. AB - Phospholipase C epsilon 1 (PLCepsilon1) has been recently identified as a novel potential biomarker for gastric cancer because of its critical role in inflammation and tumorigenesis. Until now, there are no further reports to investigate the feasibility of gene therapy by suppressing PLCepsilon1 expression for gastric cancer. In this study, a small interfering RNA (shRNA) targeting PLCepsilon1 was firstly transfected into gastric cancer cells in order to silence PLCepsilon1 expression. Both mRNA and protein expression of PLCepsilon1 in gastric cancer cells significantly reduced by RT-PCR and Western blotting analysis. Moreover, subsequent results revealed that PLCepsilon1 shRNA depressed the in vitro and in vivo growth of gastric cancer cells by using MTT assay and tumor xenograft experiment. Furthermore, after PLCepsilon1 shRNA transfection, the expression of proinflammatory molecules including tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase 2 (COX-2), interleukin (IL)-6 and chemokine (C-X-C motif) ligand (CXCL)-1 were unaffected, but only chemokine (C-C motif) ligand (CCL)-2 expression decreased in the gastric cancer cells. It is implied that PLCepsilon1 may inhibit the growth of gastric cancer cells via CCL-2 protein mediated pathway. These results suggest that PLCepsilon1 might be an alternative molecular target for gastric cancer gene therapy. PMID- 24796668 TI - 6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia. AB - Recently, increased attention has been directed towards medicinal extracts as potential new drug candidates for dementia. Ginger has long been used as an important ingredient in cooking and traditional herbal medicine. In particular, ginger has been known to have disease-modifying effects in Alzheimer's disease (AD). However, there is no evidence of which constituents of ginger exhibit therapeutic effects against AD. A growing number of experimental studies suggest that 6-shogaol, a bioactive component of ginger, may play an important role as a memory-enhancing and anti-oxidant agent against neurological diseases. 6-Shogaol has also recently been shown to have anti-neuroinflammatory effects in lipopolysaccharide (LPS)-treated astrocytes and animal models of Parkinson's disease, LPS-induced inflammation and transient global ischemia. However, it is still unknown whether 6-shogaol has anti-inflammatory effects against oligomeric forms of the Abeta (AbetaO) in animal brains. Furthermore, the effects of 6 shogaol against memory impairment in dementia models are also yet to be investigated. In this study, we found that administration of 6-shogaol significantly reduced microgliosis and astrogliosis in intrahippocampal AbetaO injected mice, ameliorated AbetaO and scopolamine-induced memory impairment, and elevated NGF levels and pre- and post-synaptic marker in the hippocampus. All these results suggest that 6-shogaol may play a role in inhibiting glial cell activation and reducing memory impairment in animal models of dementia. PMID- 24796669 TI - Allograft inflammatory factor-1 stimulates chemokine production and induces chemotaxis in human peripheral blood mononuclear cells. AB - Allograft inflammatory factor-1 (AIF-1) is expressed by macrophages, fibroblasts, endothelial cells and smooth muscle cells in immune-inflammatory disorders such as systemic sclerosis, rheumatoid arthritis and several vasculopathies. However, its molecular function is not fully understood. In this study, we examined gene expression profiles and induction of chemokines in monocytes treated with recombinant human AIF (rhAIF-1). Using the high-density oligonucleotide microarray technique, we compared mRNA expression profiles of rhAIF-1-stimulated CD14(+) peripheral blood mononuclear cells (CD14(+) PBMCs) derived from healthy volunteers. We demonstrated upregulation of genes for several CC chemokines such as CCL1, CCL2, CCL3, CCL7, and CCL20. Next, using ELISAs, we confirmed that rhAIF 1 promoted the secretion of CCL3/MIP-1alpha and IL-6 by CD14(+) PBMCs, whereas only small amounts of CCL1, CCL2/MCP-1, CCL7/MCP-3 and CCL20/MIP-3alpha were secreted. Conditioned media from rhAIF-1stimulated CD14(+) PBMCs resulted in migration of PBMCs. These findings suggest that AIF-1, which induced chemokines and enhanced chemotaxis of monocytes, may represent a molecular target for the therapy of immune-inflammatory disorders. PMID- 24796670 TI - Rapamycin alleviates cisplatin-induced ototoxicity in vivo. AB - BACKGROUND: Cisplatin-induced ototoxicity affects a high percentage of new cancer patients worldwide. The detailed mechanism of cisplatin-induced ototoxicity is not completely understood. We investigated whether rapamycin could protect rats from cisplatin-induced ototoxicity. METHODS: Forty-eight male Wistar rats were randomly divided into six groups. Three groups were intraperitoneally (IP) infused with cisplatin at a dose of 16 mg/kg and immediately injected with either dimethylsulfoxide (DMSO), rapamycin, or chloroquine (CQ). The remaining three groups were treated with rapamycin, CQ, or saline alone. The auditory brainstem response (ABR) test was performed to detect the rats' hearing status. Serum was isolated to measure the level of the oxidative marker malondialdehyde (MDA), the basilar membrane was prepared to count the outer hair cell loss, and soft tissue samples extracted from the cochleae were lysed to analyze the microtubule associated protein light chain 3 (LC3) and Beclin-1. RESULTS: The rapamycin treatment significantly attenuated cisplatin-induced hearing loss, decreased oxidative stress, and alleviated the hair cell damage that was associated with the upregulation of the LC3-II/GAPDH ratio and increased Beclin-1 expression. CONCLUSION: Our results demonstrated that rapamycin has an otoprotective effect; it attenuates cisplatin-induced ototoxicity, probably by attenuating oxidative damage and inducing autophagy. PMID- 24796671 TI - The Cj0588 protein is a Campylobacter jejuni RNA methyltransferase. AB - TlyA proteins belong to 2'-O-methyltransferases. Methylation is a common posttranscriptional RNA modification. The Campylobacter jejuni Cj0588 protein belongs to the TlyA(I) protein family and is a rRNA methyltransferase. Methylation of ribosomal RNA catalyzed by Cj0588 appears to have an impact on the biology of the cell. Presence of the cj0588 gene in bacteria appears to be important for ribosome stability and virulence properties. Absence of the Cj0588 protein causes accumulation of the 50S ribosomal subunits, reduction in the amount of functional 70S ribosomes and confers increase resistance to capreomycin. PMID- 24796672 TI - omega-Hydroxyundec-9-enoic acid induces apoptosis through ROS-mediated endoplasmic reticulum stress in non-small cell lung cancer cells. AB - omega-Hydroxyundec-9-enoic acid (omega-HUA), a hydroxyl unsaturated fatty acid derivative, is involved in the antifungal activity of wild rice (Oryza officinalis). Here, we investigated the anti-cancer activity of omega-HUA on a non-small cell lung cancer (NSCLC) cell line. omega-HUA increased apoptosis and induced cleavages of caspase-6, caspase-9, and poly (ADP-ribose) polymerase (PARP). omega-HUA treatment significantly induced endoplasmic reticulum (ER) stress response. Suppression of CHOP expression and inhibiting ER stress by 4 phenylbutyrate (4-PBA) significantly attenuated the omega-HUA treatment-induced activation of caspase-6, caspase-9, and PARP, and subsequent apoptotic cell death, indicating a role for ER stress in omega-HUA-induced apoptosis. In addition, cells subjected to omega-HUA exhibited significantly increased quantity of reactive oxygen species (ROS), and the ROS scavenger N-acetyl-L-cysteine (NAC) inhibited omega-HUA-induced apoptotic cell death and ER stress signals, indicating a role for ROS in ER stress-mediated apoptosis in omega-HUA-treated cells. Taken together, these results suggest that sequential ROS generation and ER stress activation are critical in omega-HUA treatment-induced apoptosis and that omega-HUA represents a promising candidate for NSCLC treatment. PMID- 24796673 TI - Interleukin-10 blocks in vitro replication of human cytomegalovirus by inhibiting the virus-induced autophagy in MRC5 cells. AB - BACKGROUND: Interleukin-10 is an important cytokine that regulates immune response. Previous studies have shown that human cytomegalovirus can trigger cell autophagy during the early stages of infection. To our knowledge, whether IL-10 inhibits HCMV-induced autophagy and virus replication has not been studied previously. OBJECTIVES: We investigated whether IL-10 affects cell viability and autophagy under the conditions of starvation and HCMV infection by using the MRC5 cell line. We also explored the role of IL-10-mediated autophagy on HCMV replication. RESULTS: Our data showed that IL-10 inhibited the autophagic flux of the MRC5 cells irrespective of starvation or HCMV infection, and suppressed HCMV replication. The promotion of autophagy with either a pharmacological inducer (rapamycin), or a technique to over-express the BECN1 gene reversed the effect of IL-10 on virus replication. Furthermore, the PI3K/Akt signal pathway was activated when the cells were pretreated with IL-10. CONCLUSIONS: Our results indicated that IL-10 can suppress HCMV replication by inhibiting autophagy in host cells during the early stages of infection. PMID- 24796675 TI - Genomic analysis and expression investigation of caleosin gene family in Arabidopsis. AB - Caleosin is a common lipid-droplet surface protein, which has the ability to bind calcium. Arabidopsis (Arabidopsis thaliana) is considered a model organism in plant researches. Although there are growing researches about caleosin in the past few years, a systemic analysis of caleosins in Arabidopsis is still scarce. In this study, a comprehensive investigation of caleosins in Arabidopsis was performed by bioinformatics methods. Firstly, eight caleosins in Arabidopsis are divided into two types, L-caleosin and H-caleosin, according to their molecular weights, and these two types of caleosin have many differences in characteristics. Secondly, phylogenetic tree result indicates that L-caleosin may evolve from H-caleosin. Thirdly, duplication pattern analysis shows that segmental and tandem duplication are main reasons for Arabidopsis caleosin expansion with the equal part. Fourthly, the expression profiles of caleosins are also investigated in silico in different organs and under various stresses and hormones. In addition, based on promoter analysis, caleosin may be involved in calcium signal transduction and lipid accumulation. Thus, the classification and expression analysis of caleosin genes in Arabidopsis provide facilities to the research of phylogeny and functions in this gene family. PMID- 24796674 TI - Computational design of a sulfoglucuronide derivative fitting into a hydrophobic pocket of dengue virus E protein. AB - We performed first-principles calculations based on the ab initio fragment molecular orbital method on dengue virus envelope protein with a hydrophobic ligand, octyl-beta-D-glucose to develop an entry inhibitor. As several polar amino acid residues are present at the edge of the pocket, the glucose moiety was chemically modified with hydrophilic groups. Introduction of both sulfated and carboxylated groups on glucose enhanced not only binding affinity to the protein but also inhibition of dengue virus entry. Octyl-2-O-sulfo beta-D-glucuronic acid may serve as a molecular probe to study the dengue virus entry process. PMID- 24796676 TI - Neurotropic and neuroprotective activities of the earthworm peptide Lumbricusin. AB - We recently isolated a polypeptide from the earthworm Lumbricus terrestris that is structurally similar to defensin, a well-known antibacterial peptide. An 11 mer antibacterial peptide (NH2-RNRRWCIDQQA), designated Lumbricusin, was synthesized based on the amino acid sequence of the isolated polypeptide. Since we previously reported that CopA3, a dung beetle peptide, enhanced neuronal cell proliferation, we here examined whether Lumbricusin exerted neurotropic and/or neuroprotective effects. Lumbricusin treatment induced a time-dependent increase (~51%) in the proliferation of human neuroblastoma SH-SY5Y cells. Lumbricusin also significantly inhibited the apoptosis and decreased viability induced by treatment with 6-hydroxy dopamine, a Parkinson's disease-mimicking agent. Immunoblot analyses revealed that Lumbricusin treatment increased ubiquitination of p27(Kip1) protein, a negative regulator of cell-cycle progression, in SH-SY5Y cells, and markedly promoted its degradation. Notably, adenoviral-mediated over expression of p27(Kip1) significantly blocked the antiapoptotic effect of Lumbricusin in 6-hydroxy dopamine-treated SH-SY5Y cells. These results suggest that promotion of p27(Kip1) degradation may be the main mechanism underlying the neuroprotective and neurotropic effects of Lumbricusin. PMID- 24796677 TI - Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection. AB - RATIONALE: Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial. OBJECTIVES: To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-gamma) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion. METHODS: Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-gamma responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT. RESULTS: Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-gamma responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-gamma responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters. CONCLUSIONS: TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-gamma production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease. PMID- 24796679 TI - Case studies of the perceptions of women with high risk congenital heart disease successfully completing a pregnancy. AB - PURPOSE: Women even with moderate to severe congenital heart disease (CHD) seek motherhood despite posing significant health risks to themselves and their infant. This study explored their motivations and perceptions and compared them to those of women with low risk CHD who conceived. PROCEDURES: Twenty women over 18 years with CHD who had a successful pregnancy were recruited, half of whom were identified as having a high risk cardiac abnormality. They completed a questionnaire and a semi-structured interview following which a thematic analysis was employed. Their medical records and clinical status were also reviewed and their current cardiac status graded by their attending cardiologist. FINDINGS: Women with high risk (moderate to severe) CHD (n=10) appeared to have similar motivations for conceiving as women with low-risk (mild) CHD (n=10). Their decision to conceive seemed based on their own and at times unrealistic perceptions of the consequences of their CHD. CONCLUSIONS: Women with mild or more severe CHD had similar motivations to conceive tending to down play the seriousness of their CHD. Their drive for motherhood appeared to be stronger than the drive for self care. It behoves clinicians, both obstetricians and cardiologists caring for women with high risk CHD to be knowledgeable of the effects of the CHD on the pregnancy and the impact of the pregnancy on the cardiac status. PMID- 24796678 TI - The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs. AB - BACKGROUND: Gene expression studies of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine genes. Studies of patients with Aicardi Goutieres syndrome, commonly cited as a single gene model for SLE, have suggested that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing studies of SLE patients have been performed. This study was designed to define altered expression of coding and non-coding RNAs and to detect globally altered RNA processing in SLE. METHODS: Purified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA seq. Quantitative RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA. RESULTS: We found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs, but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes. We further identified increased circulating endotoxin in SLE patients. CONCLUSIONS: Monocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci, inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a new potential disease mechanism. PMID- 24796680 TI - Endoscopic radial artery harvesting does not compromise graft patency for coronary artery bypass graft: a meta analysis of 2782 patients. AB - BACKGROUND: Endoscopic radial artery harvesting is a favourable harvesting technique which provides excellent cosmetic result and low incidence of incision related complications, however the impact of this technique on graft quality is less well-explained. We sought to evaluate the impact of harvesting technique on graft patency and relevant clinical outcomes in patients undergoing coronary artery bypass graft (CABG). METHOD: A systematic literature search was conducted to identify publications containing comparisons between different sampling skills in CABG, data was extracted and analysed with Revman, Downs and Black score was applied to evaluate the methodological quality of included studies. RESULT: Ten studies containing 2782 patients were undertaken, the quality was generally acceptable. Pooled analysis results indicate endoscopic radial artery harvesting was associated with a lower incidence of wound infection and a similar incidence of haematoma formation compared with open harvesting. The difference in graft patency and all-cause mortality was insignificant between two cohorts. CONCLUSION: Endoscopic radial artery harvesting is a safe technique and provides equivalent graft patency as compared with open harvesting, further investigation is required to confirm the aforementioned conclusion and evaluate the impact of harvesting technique on hand sensory and motor function. PMID- 24796682 TI - "This is my first time"--the way of the fearless. PMID- 24796681 TI - Psychological therapies for the management of chronic and recurrent pain in children and adolescents. AB - BACKGROUND: This is an update of the original Cochrane review first published in Issue 1, 2003, and previously updated in 2009 and 2012. Chronic pain affects many children, who report severe pain, disability, and distressed mood. Psychological therapies are emerging as effective interventions to treat children with chronic or recurrent pain. This update focuses specifically on psychological therapies delivered face-to-face, adds new randomised controlled trials (RCTs), and additional data from previously included trials. OBJECTIVES: There were three objectives to this review. First, to determine the effectiveness on clinical outcomes of pain severity, disability, depression, and anxiety of psychological therapy delivered face-to-face for chronic and recurrent pain in children and adolescents compared with active treatment, waiting-list, or standard medical care. Second, to evaluate the impact of psychological therapies on depression and anxiety, which were previously combined as 'mood'. Third, we assessed the risk of bias of the included studies and the quality of outcomes using the GRADE criteria. SEARCH METHODS: Searches were undertaken of CENTRAL, MEDLINE, EMBASE, and PsycINFO. We searched for further RCTs in the references of all identified studies, meta-analyses, and reviews. Trial registry databases were also searched. The date of most recent search was January 2014. SELECTION CRITERIA: RCTs with at least 10 participants in each arm post-treatment comparing psychological therapies with active treatment, standard medical care, or waiting-list control for children or adolescents with episodic, recurrent or persistent pain were eligible for inclusion. Only trials conducted in person (face-to-face) were considered. Studies that delivered treatment remotely were excluded from this update. DATA COLLECTION AND ANALYSIS: All included studies were analysed and the quality of outcomes were assessed. All treatments were combined into one class, psychological treatments. Pain conditions were split into headache and non headache. Both conditions were assessed on four outcomes: pain, disability, depression, and anxiety. Data were extracted at two time points; post-treatment (immediately or the earliest data available following end of treatment) and at follow-up (between three and 12 months post-treatment). MAIN RESULTS: Seven papers were identified in the updated search. Of these papers, five presented new trials and two presented follow-up data for previously included trials. Five studies that were previously included in this review were excluded as therapy was delivered remotely. The review thus included a total of 37 studies. The total number of participants completing treatments was 2111. Twenty studies addressed treatments for headache (including migraine); nine for abdominal pain; two for mixed pain conditions including headache pain, two for fibromyalgia, two for recurrent abdominal pain or irritable bowel syndrome, and two for pain associated with sickle cell disease.Analyses revealed psychological therapies to be beneficial for children with chronic pain on seven outcomes. For headache pain, psychological therapies reduced pain post-treatment and at follow-up respectively (risk ratio (RR) 2.47, 95% confidence interval (CI) 1.97 to 3.09, z = 7.87, p < 0.01, number needed to treat to benefit (NNTB) = 2.94; RR 2.89, 95% CI 1.03 to 8.07, z = 2.02, p < 0.05, NNTB = 3.67). Psychological therapies also had a small beneficial effect at reducing disability in headache conditions post-treatment and at follow-up respectively (standardised mean difference (SMD) -0.49, 95% CI 0.74 to -0.24, z = 3.90, p < 0.01; SMD -0.46, 95% CI -0.78 to -0.13, z = 2.72, p < 0.01). No beneficial effect was found on depression post-treatment (SMD -0.18, 95% CI -0.49 to 0.14, z = 1.11, p > 0.05). At follow-up, only one study was eligible, therefore no analysis was possible and no conclusions can be drawn. Analyses revealed a small beneficial effect for anxiety post-treatment (SMD 0.33, 95% CI -0.61 to -0.04, z = 2.25, p < 0.05). However, this was not maintained at follow-up (SMD -0.28, 95% CI -1.00 to 0.45; z = 0.75, p > 0.05).Analyses revealed two beneficial effects of psychological treatment for children with non-headache pain. Pain was found to improve post-treatment (SMD 0.57, 95% CI -0.86 to -0.27, z = 3.74, p < 0.01), but not at follow-up (SMD 0.11, 95% CI -0.41 to 0.19, z = 0.73, p > 0.05). Psychological therapies also had a beneficial effect for disability post-treatment (SMD -0.45, 95% CI -0.71 to 0.19, z = 3.40, p < 0.01), but this was not maintained at follow-up (SMD -0.35, 95% CI -0.71 to 0.02, z = 1.87, p > 0.05). No effect was found for depression or anxiety post-treatment (SMD -0.07, 95% CI -0.30 to 0.17, z = 0.54, p > 0.05; SMD 0.15, 95% CI -0.36 to 0.07, z = 1.33, p > 0.05) or at follow-up (SMD 0.06, 95% CI -0.16 to 0.28, z = 0.53, p > 0.05; SMD 0.05, 95% CI -0.24 to 0.33, z = 0.32, p > 0.05). AUTHORS' CONCLUSIONS: Psychological treatments delivered face-to-face are effective in reducing pain intensity and disability for children and adolescents (<18 years) with headache, and therapeutic gains appear to be maintained, although this should be treated with caution for the disability outcome as only two studies could be included in the follow-up analysis. Psychological therapies are also beneficial at reducing anxiety post-treatment for headache. For non headache conditions, psychological treatments were found to be beneficial for pain and disability post-treatment but these effects were not maintained at follow-up. There is limited evidence available to estimate the effects of psychological therapies on depression and anxiety for children and adolescents with headache and non-headache pain. The conclusions of this update replicate and add to those of the previous review which found that psychological therapies were effective in reducing pain intensity for children with headache and non-headache pain conditions, and these effects were maintained at follow-up for children with headache conditions. PMID- 24796683 TI - Data, data, on the server: challenges in applying data analysis to operating room management. PMID- 24796684 TI - The Scarlet "A". PMID- 24796685 TI - Double papillary fibroelastoma: beautiful, innocent flowers in the left heart. AB - Papillary fibroelastoma is a rare, benign tumor, and multiple papillary fibroelastomas are even more uncommon. In an asymptomatic patient scheduled for carotid endarterectomy, transthoracic echocardiography discovered a fibroelastoma on the mitral valve. Then, transesophageal echocardiography showed another fibroelastoma on the aortic valve. Because he also needed a right coronary artery bypass, the patient underwent surgical excision of both masses. Fibroelastomas are not always as innocent as they seem, and surgical excision is necessary because of their potential for systemic or coronary embolization. Transoesophageal echocardiography may improve the diagnosis of multiple papillary fibroelastomas. PMID- 24796686 TI - Re: Martinez-Garcia R, Ubeda-Sansano MI, Diez-Domingo J, Perez-Hoyos S, Gil-Salom M. It is time to abandon "expected bladder capacity." Systematic review and new models for children's normal maximum voided volumes. Neurourol Urodyn 2014;33:1092-8. PMID- 24796687 TI - Identification of specific Y chromosomes associated with increased prostate cancer risk. AB - BACKGROUND: Evidence supports the possibility of a role of the Y chromosome in prostate cancer, but controversy exists. METHODS: A novel analysis of a computerized population-based resource linking genealogy and cancer data was used to test the hypothesis of a role of the Y chromosome in prostate cancer predisposition. Using a statewide cancer registry from 1966 linked to a computerized genealogy representing over 1.2 million descendants of the Utah pioneers, 1,000 independent sets of males, each set hypothesized to share the same Y chromosome as represented in genealogy data, were tested for a significant excess of prostate cancer. RESULTS: Multiple Y chromosomes representing thousands of potentially at-risk males were identified to have a significant excess risk for prostate cancer. CONCLUSIONS: This powerful and efficient in silico test of an uncommon mode of inheritance has confirmed evidence for Y chromosome involvement in prostate cancer. PMID- 24796688 TI - A large pericardiophrenic collateral in a patient with Budd-Chiari syndrome. PMID- 24796689 TI - Reply to Ruzza. PMID- 24796690 TI - Age-gender considerations on survival in patients undergoing radial artery grafting. PMID- 24796691 TI - Voice disorder in cystic fibrosis patients. AB - Cystic fibrosis is a common autosomal recessive disorder with drastic respiratory symptoms, including shortness of breath and chronic cough. While most of cystic fibrosis treatment is dedicated to mitigating the effects of respiratory dysfunction, the potential effects of this disease on vocal parameters have not been systematically studied. We hypothesized that cystic fibrosis patients, given their characteristic respiratory disorders, would also present dysphonic symptoms. Given that voice disorders can severely impair quality of life, the identification of a potential cystic fibrosis-related dysphonia could be of great value for the clinical evaluation and treatment of this disease. We tested our hypothesis by measuring vocal parameters, using both objective physical measures and the GRBAS subjective evaluation method, in male and female cystic fibrosis patients undergoing conventional treatment and compared them to age and sex matched controls. We found that cystic fibrosis patients had a significantly lower vocal intensity and harmonic to noise ratio, as well as increased levels of jitter and shimmer. In addition, cystic fibrosis patients also showed higher scores of roughness, breathiness and asthenia, as well as a significantly altered general grade of dysphonia. When we segregated the results according to sex, we observed that, as a group, only female cystic fibrosis patients had significantly lower values of harmonic to noise ratio and an abnormal general grade of dysphonia in relation to matched controls, suggesting that cystic fibrosis exerts a more pronounced effect on vocal parameters of women in relation to men. Overall, the dysphonic characteristics of CF patients can be explained by dysfunctions in vocal fold movement and partial upper airway obstruction, potentially caused by the accumulation of mucus and chronic cough characteristic of CF symptomatology. Our results show that CF patients exhibit significant dysphonia and suggest they may potentially benefit from voice therapy as a parallel treatment strategy. PMID- 24796692 TI - Using the whole body as a sucker: combining respiration and feeding with an attached lifestyle in hill stream loaches (Balitoridae, Cypriniformes). AB - Small fishes living in fast-flowing rivers face a harsh environment as they can easily be swept away by the rapid currents. To survive such circumstances, teleosts evolved a wide variety of attachment mechanisms, based on friction, negative pressure or both. Balitorinae (Balitoridae, Cypriniformes) are exceptional in using their whole body as an adhesive apparatus. We investigated the morphological adaptations of Balitorinae by studying the osteology and myology of four species (Beaufortia leveretti, Sewellia lineolata, Pseudogastromyzon myersi, and Gastromyzon punctulatus) using clearing and staining, serial cross-sections and CT-scanning. A kinematic analysis was performed to study the respiration and feeding mechanisms and to identify key structures in these mechanisms. Our research showed that the whole body of Balitorinae acts as a suction disc, with friction-enhancing structures (unculi) on the thickened anterior rays of the paired fins. The abruptly rising head profile, supported by the extremely enlarged lacrimal bone and the flat ventral body surface facilitate effective substrate attachment. During attachment, the pelvic girdle is pulled anterodorsally, suggesting the formation of a negative pressure underneath the body. Detachment by water inflow underneath the body is prevented by three mechanisms. 1) Barbels control the water inflow by detachment and reattachment to the substrate. 2) Most water present underneath the body is removed during inspiration. 3) Excess water is regularly removed by movements of the posterior pectoral fin rays. The balitorine body is thus modified as such that it allows effective attachment, while not impairing respiration. Comparison with other teleosts living in similar environments shows that most species use more locally concentrated modifications of the paired fins and/or the mouth for attachment. The high diversity in teleostean adhesive apparatuses and associated myological modifications suggest a substantial functional convergent evolution, without necessarily highly convergent anatomical adaptations. PMID- 24796693 TI - The complex morphology of reactive astrocytes controlled by fibroblast growth factor signaling. AB - Astrocytes are the most abundant cell-type of the human brain and play a variety of roles in brain homeostasis and synaptic maturation, under normal conditions. However, astrocytes undergo dramatic pathological changes in response to brain injury, such as reactive gliosis and glial scar formation. Although abnormal hypertrophy and massive proliferation of astrocytes are obvious, the molecular identity and cues that dictate the structural changes in reactive astrocytes remain unclear. This study proposes that fibroblast growth factor (FGF) signaling is responsible for making astrocyte morphology more complex and hypertrophic in response to an inflammatory stimulus such as lipopolysaccharide. Primary astrocytes isolated from perinatal brains developed more branches in the presence of FGF8 or lesser branches in the presence of FGF2. Introduction of the constitutively active form of the FGF receptor 3 (caFGFR3) into the brain increases the structural complexity, with greater glial fibrillary acidic protein level in astrocytes, while overexpression of a dominant-negative form of FGFR3 (dnFGFR3) reduces it. Treatment of FGF8 facilitated the wound-healing process of primary astrocytes in vitro by changing their morphology, indicating that the FGF signal may control the responsiveness of astrocytes in injury conditions. Finally, the blockade of FGF signaling by introducing dnFGFR3 at the site of reactive gliosis reduces astrocyte branch formation and minimizes hypertrophic responses during reactive gliosis. Taken together, these results indicate that FGF8-FGFR3 signaling controls structural changes in astrocytes during reactive gliosis, under pathogenic conditions. PMID- 24796694 TI - Phytochemical composition, antioxidant activity and HPLC fingerprinting profiles of three Pyrola species from different regions. AB - The present study was performed to investigate the variation of phytochemical composition, antioxidant activity and High Performance Liquid Chromatography (HPLC) fingerprinting profiles of three Pyrola species. Thirteen samples (eight P. decorata, three P. calliantha and two P. renifolia) were collected from different regions in China. The tannin, hyperoside and quercetin contents of all samples were determined by reverse-phase HPLC and varied within the range 9.77 34.75, 0.34-2.16 and 0.062-0.147 mg/g dry weigh, respectively. Total flavonoid content was evaluated and varied within the range 16.22-37.82 mg/g dry weight. Antioxidant activity was determined by DPPH assay, with IC50 ranging from 7.96 to 50.33 ug/ml, ABTS*+ and FRAP assay, within the range 612.66-1021.05 and 219.64 398.12 umol equiv. Trolox/g, respectively. These results revealed that there were significant variations in phytochemical profiles and antioxidant activity among all samples. Due to the higher phytochemical content and significant antioxidant activity, P. calliantha was selected as the most valuable species, and the P. calliantha sample from Left banner of Alxa even possessed the strongest antioxidant activity among all the thirteen samples. Futhermore, Emei Mountain was proved to be the most suitable region for producing P. decorata. Moreover, in order to further evaluate the diversities and quality of Pyrola, HPLC fingerprint analysis coupled with hierarchical cluster and discrimination analyses were introduced to establish a simple, rapid and effective method for accurate identification, classification and quality assessment of Pyrola. Thirteen samples were divided into three groups consistent with their morphological classification. Two types of discriminant functions were generated and the ratio of discrimination was 100%. This method can identify different species of Pyrola and the same species from different regions of origin. Also, it can be used to compare and control the quality of Pyrola and other natural products prepared from them. PMID- 24796695 TI - Synthesis and evaluation of fluorine-substituted phenyl acetate derivatives as ultra-short recovery sedative/hypnotic agents. AB - BACKGROUND: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. METHODOLOGY/PRINCIPAL FINDINGS: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and gamma-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. CONCLUSIONS/SIGNIFICANCE: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness. PMID- 24796697 TI - Recurrent late-onset sepsis in the neonatal intensive care unit: incidence, clinical characteristics and risk factors. AB - We aimed to characterize the incidence, clinical features, risk factors and outcomes of recurrent late-onset sepsis (LOS) in the neonatal intensive care unit (NICU). All neonates with LOS from the NICU of a tertiary-level teaching hospital in northern Taiwan between 2004 and 2011 were enrolled for analyses. A case control study was performed to determine risk factors for recurrence. Of 713 neonates with LOS, 150 (21.0%) experienced recurrence and 48 (6.7%) had >1 recurrences; c. two-thirds of recurrent LOS occurred in infants with birth weight (BW)?1500 g or gestational age (GA)?30 weeks. The recurrent LOS episodes were significantly more severe and had a higher sepsis-attributable mortality rate than the first episodes. The overall in-hospital mortality rate was 30.7% for neonates with recurrent LOS and 7.8% for those with single LOS (odds ratio (OR), 5.22; 95% CI, 3.28-8.30). When both BW and GA were controlled, neonates with recurrent LOS had a significantly prolonged hospitalization compared with the controls (median 109 vs. 84 days, p<0.001). After multivariate logistic regression, longer duration of total parenteral nutrition (TPN; OR, 1.30; 95% CI, 1.10-1.52 for every 10-day increment), presence of congenital anomalies (OR, 2.64; 95% CI, 1.10-6.35) and neurological co-morbidities (OR, 4.14; 95% CI, 1.14 15.10) were identified as the independent risk factors for LOS recurrence. We concluded that c. one-fifth of neonates with LOS had recurrence, which significantly resulted in prolonged hospitalization and increased mortality. Longer TPN administration, presence of congenital anomalies and neurological co morbidities are independently associated with recurrent LOS. PMID- 24796696 TI - Inhibition of U4 snRNA in human cells causes the stable retention of polyadenylated pre-mRNA in the nucleus. AB - Most human pre-mRNAs contain introns that are removed by splicing. Such a complex process needs strict control and regulation in order to prevent the expression of aberrant or unprocessed transcripts. To analyse the fate of pre-mRNAs that cannot be spliced, we inhibited splicing using an anti-sense morpholino (AMO) against U4 snRNA. As a consequence, splicing of several selected transcripts was strongly inhibited. This was accompanied by the formation of enlarged nuclear speckles containing polyadenylated RNA, splicing factors and the nuclear poly(A) binding protein. Consistently, more polyadenylated pre-mRNA could be isolated from nucleoplasmic as well as chromatin-associated RNA fractions following U4 inhibition. Further analysis demonstrated that accumulated pre-mRNAs were stable in the nucleus and that nuclear RNA degradation factors did not re-localise to nuclear speckles following splicing inhibition. The accumulation of pre-mRNA and the formation of enlarged speckles were sensitive to depletion of the 3' end processing factor, CPSF73, suggesting a requirement for poly(A) site processing in this mechanism. Finally, we provide evidence that the pre-mRNAs produced following U4 snRNA inhibition remain competent for splicing, perhaps providing a biological explanation for their stability. These data further characterise processes ensuring the nuclear retention of pre-mRNA that cannot be spliced and suggest that, in some cases, unspliced transcripts can complete splicing sometime after their initial synthesis. PMID- 24796698 TI - Suicide: an existentialist reconceptualization. AB - The phenomenon of suicide is one of the primary concerns for mental health professions. The health-care literature is dominated by discussions that focus variously on local and national suicide prevention policies, on the assessment of those individuals judged to be at risk of committing suicide as well as the appropriateness and efficacy of interventions for those who express suicidal ideation and display suicidal behaviours. What appear less frequently in the literature, however, are critical analyses of the concept of suicide and, in particular, critical reflections on the manner in which the concept of suicide has been, and continues to be, understood or 'framed'. In an attempt to respond to this apparent omission, this paper will suggest that the work of Albert Camus, and his philosophical work The Myth of Sisyphus in particular, can be understood as providing a significant reconceptualization and reframing of suicide. In doing so, it will be suggested that Camus's work not only challenges how the concept of suicide has traditionally been situated within the context of mental illness, but can also be understood as challenging the efficacy of the interventions that have been associated with an understanding of suicide within that context. PMID- 24796699 TI - Reactive aggression and peer victimization from pre-kindergarten to first grade: accounting for hyperactivity and teacher-child conflict. AB - BACKGROUND: The role of reactive aggression in the development of peer victimization remains unclear due in part to a failure to account for confounding problems of behavioural undercontrol (e.g., hyperactivity). As well, the school social context has rarely been examined to see whether these risks are mediated by relationships with teachers. AIMS: This study tests the prospective relations between reactive aggression, hyperactivity, victimization, and teacher-child (T C) relationship, to determine whether conflict mediates the relationships between externalizing problems and victimization. SAMPLE: A sample of 1,114 Australian students were followed from pre-kindergarten through first grade. METHODS: Cross lagged path analyses were conducted, with comparison of gender-moderating models and autocorrelation models. Full-information maximum likelihood was deployed to account for missingness. RESULTS: Best fitting models found that the relationship of early externalizing problems to later victimization was mediated by T-C conflict. No evidence of victimization increasing externalizing problems nor gender differences were observed. T-C conflict in kindergarten predicted subsequent increases in victimization, reactive aggression, and hyperactivity. CONCLUSIONS: Understanding the processes whereby externalizing problems confer risk of victimization involves understanding the whole social context of classrooms, including relationships with teachers. Finer-grained research is needed to better understand how peer dynamics may be influenced by observation of T-C relationships. Pre-service teacher education needs to ensure a focus on the potential social impact of teacher's relationships with students. PMID- 24796700 TI - Free-breathing 3D late gadolinium enhancement imaging of the left ventricle using a stack of spirals at 3T. AB - PURPOSE: To develop navigator-gated free-breathing 3D spiral late gadolinium enhancement (LGE) imaging of the left ventricle at 3T and compare it with conventional breath-hold 2D Cartesian imaging. MATERIALS AND METHODS: Equivalent slices from 3D spiral and multislice 2D Cartesian acquisitions were compared in 15 subjects in terms of image quality (1, nondiagnostic to 5, excellent), sharpness (1-3), and presence of artifacts (0-2). Blood signal-to-noise ratio (SNR), blood/myocardium contrast-to-noise ratio (CNR), and quantitative sharpness were also compared. RESULTS: All 3D spiral scans were completed faster than an equivalent 2D Cartesian short-axis stack (85 vs. 230 sec, P < 0.001). Image quality was significantly higher for 2D Cartesian images than 3D spiral images (3.7 +/- 0.87 vs. 3.4 +/- 1.05, P = 0.03) but not for mid or apical slices specifically. There were no significant differences in qualitative and quantitative sharpness (95% confidence interval [CI]: 1.91 +/- 0.67 vs. 1.93 +/- 0.69, P = 0.83 and 95% CI: 0.41 +/- 0.07 vs. 0.40 +/- 0.09, P = 0.25, respectively), artifact scores (95% CI: 0.16 +/- 0.37 vs. 0.40 +/- 0.58, P = 0.16), SNR (95% CI: 121.5 +/- 55.3 vs. 136.4 +/- 77.9, P = 0.13), and CNR (95% CI: 101.6 +/- 48.4 vs. 102.7 +/- 61.8, P = 0.98). Similar enhancement ratios (0.65 vs. 0.62) and volumes (13.8 vs. 14.1cm(3) ) were measured from scar regions of three patients. CONCLUSIO: Navigator-gated 3D spiral LGE imaging can be performed in significantly and substantially shorter acquisition durations, although with some reduced image quality, than multiple breath-hold 2D Cartesian imaging while providing higher resolution and contiguous coverage. PMID- 24796701 TI - Low susceptibility of invasive red lionfish (Pterois volitans) to a generalist ectoparasite in both its introduced and native ranges. AB - Escape from parasites in their native range is one of many mechanisms that can contribute to the success of an invasive species. Gnathiid isopods are blood feeding ectoparasites that infest a wide range of fish hosts, mostly in coral reef habitats. They are ecologically similar to terrestrial ticks, with the ability to transmit blood-borne parasites and cause damage or even death to heavily infected hosts. Therefore, being highly resistant or highly susceptible to gnathiids can have significant fitness consequences for reef-associated fishes. Indo-Pacific red lionfish (Pterois volitans) have invaded coastal habitats of the western tropical and subtropical Atlantic and Caribbean regions. We assessed the susceptibility of red lionfish to parasitic gnathiid isopods in both their native Pacific and introduced Atlantic ranges via experimental field studies during which lionfish and other, ecologically-similar reef fishes were caged and exposed to gnathiid infestation on shallow coral reefs. Lionfish in both ranges had very few gnathiids when compared with other species, suggesting that lionfish are not highly susceptible to infestation by generalist ectoparasitic gnathiids. While this pattern implies that release from gnathiid infestation is unlikely to contribute to the success of lionfish as invaders, it does suggest that in environments with high gnathiid densities, lionfish may have an advantage over species that are more susceptible to gnathiids. Also, because lionfish are not completely resistant to gnathiids, our results suggest that lionfish could possibly have transported blood parasites between their native Pacific and invaded Atlantic ranges. PMID- 24796703 TI - Comparison of xTAG respiratory virus panel and Verigene Respiratory Virus Plus for detecting influenza virus and respiratory syncytial virus. AB - BACKGROUND: Nucleic acid amplification tests have allowed simultaneous detection of multiple respiratory viruses. METHODS: We compared the results of a liquid bead array xTAG Respiratory Virus Panel (RVP; (Luminex Corporation, Toronto, Canada) and a solid microarray Verigene Respiratory Virus Plus (RV+; Nanosphere, Northbrook, IL) for the detection of influenza A virus (INF A), influenza B virus (INF B), and respiratory syncytial virus (RSV) in 170 respiratory specimens from hospitalized patients. RESULTS: Overall, xTAG RVP demonstrated sensitivities and specificities of 97.6 and 100% for INF A, 100 and 99.4% for INF B, and 100 and 100% for RSV, while the Verigene RV+ test sensitivities and specificities were 95.1 and 98.5%, 100.0 and 99.4%, and 97.1 and 100%, respectively. There were no significant differences in the area under the curves between the two assays for each virus (P = 0.364 for INF A, P = 1.000 for INF B, P = 0.317 for RSV). Comparing the results of two assays, discordant results were present mostly due to subtype assignments and identification of coinfections. The detection of viruses was not significantly different (P = 1.000) and the virus/subtype assignment showed good agreement with kappa coefficients of 0.908. CONCLUSION: The xTAG RVP and Verigene RV+ showed high sensitivities and specificities, and good overall agreement in detection and identification of INF and RSV. These assays can be used in clinical settings for a reliable detection of respiratory viruses found commonly in hospitalized patients. PMID- 24796702 TI - Mutation update for GNE gene variants associated with GNE myopathy. AB - The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ~4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials. PMID- 24796704 TI - A refined method for estimating the size of the potential blood donor pool in Australia. AB - BACKGROUND: To be eligible to donate blood, potential donors must meet certain eligibility criteria to ensure safety to the donor and to the blood supply. In Australia, there is no reliable estimate of the size of the donor-eligible population. This study uses a refinement to a published method to determine the population prevalence of donor-exclusion factors and subsequently estimates the size of the potential donor pool in Australia. STUDY DESIGN AND METHODS: A total of 70 donor-exclusion factors (in addition to age) were identified. The donor eligible population was estimated by subtracting the prevalence of the exclusion factors from the total population. Prevalence of the donor-exclusion factors was adjusted for age, deferral period, and overlap of multiple conditions. Overlap was adjusted by extending a published random-probability model according to known association of epidemiologic data on overlapping conditions. RESULTS: The most prevalent (deferral period-adjusted) donor-exclusion factor among the 16- to 80 year-old Australian population was variant Creutzfeldt-Jakob disease-related travel risk (6.8%) followed by upper respiratory tract infections (6.4%). After exclusion of all factors, and accounting for overlapping factors, 62% of 16- to 80-year-olds or 47.3% of the total population were donor eligible in Australia. CONCLUSION: We developed a refined method for estimating the size of the donor eligible population. Applying this method to Australia, we estimate that approximately 10.7 million people (62% of the 16- to 80-year-olds) were eligible to donate blood in Australia in 2012. PMID- 24796705 TI - Convecting particle diffusion in a binary particle system under vertical vibration. AB - We studied the separation behaviour of binary granular particles in a vertically vibrated container. The final separation of the binary particle system exhibited the Brazil-Nut (BN) effect, though it was not complete. Particle convection occurred, and four different typical convection modes were observed when the frequency f changed from 20 Hz to 80 Hz at constant dimensionless acceleration Gamma = 4piAf(2)/g. However, when Gamma changed from 2 to 4 at constant f, the system's convection mode stayed almost the same. In our experiments, one type of particle generally moved much faster than the other, so the former was termed the 'convecting' particle, and the latter was termed the 'non-convecting' particle. To study the separation results qualitatively, we divided the system into vertical layers and calculated the mass distribution of the binary particles along the z axis. The results showed that when f increased at constant Gamma or Gamma decreased at constant f, the convecting particles, usually the smaller and lighter ones, distributed less to the top side and more to the bottom side of the container. Finally, to explain the experimental results, we derived a mass conservation equation for the convecting particles considering simultaneous convection and diffusion. The equation described the experimental results well. We also analysed the effects of f, Gamma, diameter ratio, density ratio, etc., on the final separation results. PMID- 24796707 TI - [Psychiatric psychotherapeutic interventions in breast cancer inpatients: a contribution to liaison-consultation psychiatry]. AB - BACKGROUND: Psychosocial stress and psychopathological abnormalities are expected in cancer patients at a frequency of 30-60%. Apart from decreased quality of life psychological factors may cause a negative impact on treatment compliance and on the subsequent biological course of tumor development. MATERIALS AND METHODS: This study examined the association of different psychiatric and psychotherapeutic interventions in liaison-consultation psychiatry with the four psychopathological dimensions derived by factor analysis based on the items of psycho-oncological basic documentation in a group of 141 breast cancer patients without pre-existing mental disorders who were inpatients of a gynecologic cancer centre. In addition information concerning subjective stress experience was collected with the distress thermometer. RESULTS: The plausible fit of the various psychiatric and psychotherapeutic interventions due to the psychopathological dimensions and due to the subjective experience of stress could be demonstrated. Those intervention variables that were associated with an improvement of the psychological state could be described as well. The findings showed that improvement or at least stability of the psychological state was regularly associated with completion of oncological treatment in the relevant index inpatient stay. In addition it was found that the interventions offered could contribute to improved psychological well-being in the subgroup of patients without mental disorders particularly in normal grief reactions. CONCLUSION: Despite methodological limitations this investigation contributes to describing relevant psychopathological syndromes in a group of breast cancer patients without pre-existing mental disorders and the goodness of fit of the different psychiatric and psychotherapeutic interventions. Finally the study confirmed the assumption that stabilization of the mental state may help to avoid treatment interruptions in an oncological inpatient setting and therefore decrease the likelihood that reduced psychological well-being can negatively impact the biological course of tumor development. PMID- 24796709 TI - The socioeconomic origins of physical functioning among older U.S. adults. AB - Mounting evidence finds that adult health reflects socioeconomic circumstances (SES) in early life and adulthood. However, it is unclear how the health consequences of SES in early life and adulthood accumulate-for example, additively, synergistically. This study tests four hypotheses about how the health effects of early-life SES (measured by parental education) and adult SES (measured by own education) accumulate to shape functional limitations, whether the accumulation differs between men and women, and the extent to which key mechanisms explain the accumulation. It uses data from the 1994-2010 Health and Retirement Study on U.S. adults 50-100 years of age (N=24,026). The physical functioning benefits of parental and own education accumulated additively among men. While the physical functioning benefits generally accumulated among women, the functioning benefits from one's own education were dampened among women with low-educated mothers. The dampening partly reflected a strong tie between mothers' education level and women's obesity risk. Taken together, the findings reveal subtle differences between men and women in the life course origins of physical functioning. They also shed light on a key mechanism-obesity-that may help explain why a growing number of studies find that early-life SES is especially important for women's health. PMID- 24796708 TI - Biomechanical and psychosocial occupational exposures: joint predictors of post retirement functional health in the French GAZEL cohort. AB - OBJECTIVES: Biomechanical and psychosocial occupational exposures are seldom considered simultaneously and over extended follow-up in occupational epidemiologic studies, although there is some evidence that combined exposures have interactive effects on workers' health during working life. Given high prevalence of functional disability among retirees, research on earlier-life determinants of subsequent functional outcomes can help shape workplace policies and practices. This study investigates whether health effects of combined occupational exposures during working life are observed after individuals retire and are no longer exposed. METHODS: Analyses were conducted among retirees in the French GAZEL occupational cohort (n=9168). Cumulative exposure during working life to eight biomechanical strains and to one or more reports of psychosocial job strain (high-demand, low-control work) were assessed as predictors of three outcomes: difficulty with physical functioning, role limitations due to physical difficulties, and bodily pain. Individuals were classified by joint exposure to both biomechanical and psychosocial constraints. We modeled risk ratios (RR) between exposure to biomechanical and psychosocial factors at work (separately and in combination) and disability after retirement, and we calculated the relative excess risk due to interaction (RERI) to test whether combined effects departed from additivity. RESULTS: Both psychosocial and biomechanical exposures during working life were independent predictors of the three functional health outcomes. Compared with individuals who had neither biomechanical nor psychosocial exposures, in fully adjusted log-binomial models of the combined effects of biomechanical and psychosocial exposure, among those with low biomechanical exposures, the RR for physical functioning difficulties associated with psychosocial exposures was 1.18 (95% CI 1.01, 1.37). Among those with the highest levels of biomechanical exposures, RR was 1.42 (95% CI 1.21, 1.65) among those with low psychosocial exposures and 1.91 (95% CI 1.61, 2.26) among those with high psychosocial exposures. The two exposure types were modestly super additive, with an RERI of 0.32 (95% CI 0.00, 0.62) between those with the highest and lowest levels of biomechanical exposures; if the effects were strictly additive, we would have expected an RERI of 0. For the other two outcomes results were similar, although there was no significant departure from additivity. Some effects varied in magnitude by gender. CONCLUSION: Across the sample, combined biomechanical and psychosocial occupational exposures during working life appear to have additive or perhaps interactive effects on functional health in retirement. However, the relationship is less straightforward among women. Improving overall working conditions may lessen future disability among retirees. PMID- 24796710 TI - Ideal ages for family formation among immigrants in Europe. AB - This paper investigates ideal ages for marriage and parenthood among immigrants from over 160 countries origins living in 25 European countries. Ideals regarding the timing of family formation are indicative of how individuals perceive the family life course and provide insight into family-life aspirations and the meaning attached to these transitions. Using data from the European Social Survey (Round 3, 2006; N=6330) and a cross-classified multilevel modeling approach, we investigate associations between the influences of the dominant family formation timing patterns in countries of origin and settlement, individual-level characteristics, and ideal ages. We make innovative use of a standard demographic measure, the singulate mean age of marriage, to measure family formation patterns. Results suggest that residential context influences are associated with the timing ideals of all migrants, but origin influences seem to be associated with the ideals of only the most recent migrants. PMID- 24796711 TI - Influences of family structure experiences on the risk of premarital sexual initiation during adolescence in Cameroon. AB - The link between family structure experiences and premarital sexual initiation in sub-Saharan African settings has been investigated using primarily the socialization perspective. This article tests additional hypotheses using the perspectives of change and duration of exposure. The analyses are based on time dependent retrospective data on family living arrangements from a sample of 1182 individuals aged 12-24 years old, drawn from the Cameroon Family and Health Survey. From the socialization perspective for both females and males: living without both biological parents does not necessarily increase the probability of premarital sexual initiation during adolescence; the timing of family structure experiences is an important factor to consider in life course transitions; and other relatives play a protective role during adolescence, especially among females living in mother-only families. Findings also provide some support for the instability and change hypothesis as well as for the duration of exposure conjecture: a change from other family structure types to a both biological parents structure between age 6 and age 12 (change perspective) and living with the biological mother only at all the time (duration of exposure perspective) are associated with lower risks of premarital sexual initiation during adolescence among females. Our results have implications for preventing risky sexual behaviours during adolescence. PMID- 24796712 TI - The influence of working later in life on memory functioning. AB - This article examines the influence of work status on subsequent memory trajectories in later years. Using a subsample of 8165 older adults who participated in the Health and Retirement Study and were 65 years or older in 2002, we examined work status and memory functioning after controlling for age and demographic characteristics. In growth curve analyses, work status predicted the rate of immediate memory decline from 2002 to 2006 with full-time employed individuals showing less immediate memory decline after controlling for age. However, work status categories were not associated with subsequent age-adjusted delayed memory trajectories. The findings from these growth curve analyses support the hypothesis that working late in life helps to impede immediate memory declines that often occur in later years. PMID- 24796713 TI - Individualization, opportunity and jeopardy in American women's work and family lives: a multi-state sequence analysis. AB - Life course sociologists are increasingly concerned with how the general character of biographies is transformed over historical time--and with what this means for individual life chances. The individualization thesis, which contends that contemporary biographies are less predictable, less orderly and less collectively determined than were those lived before the middle of the 20th century, suggests that life courses have become both more internally dynamic and more diverse across individuals. Whether these changes reflect expanding opportunities or increasing jeopardy is a matter of some debate. We examine these questions using data on the employment, marital and parental histories, over the ages of 25-49, for five birth cohorts of American women (N=7150). Our results show that biographical change has been characterized more by growing differences between women than by increasing complexity within individual women's lives. Whether the mounting diversity of work and family life paths reflects, on balance, expanding opportunities or increasing jeopardy depends very much on the social advantages and disadvantages women possessed as they entered their prime working and childrearing years. PMID- 24796714 TI - Effectiveness of an oral health educational program on community-dwelling older people with xerostomia. AB - AIM: The purpose of the present study was to evaluate the changes in oral health and function through an oral health educational program for the independent older people with xerostomia. METHODS: Community-dwelling older people with xerostomia aged over 65 years who participated in a preliminary comprehensive health survey in 2011 were recruited for the educational program. A total of 47 participants were randomly assigned into two groups, the intervention group (n = 26) and the control group (n = 21). The intervention group attended a 90-min oral health education program every 2 weeks for 3 months. The program consisted of oral hygiene instruction, facial and tongue muscle exercise, and salivary gland massage. The control group was provided only general information about oral health. The assessments of oral function, such as oral diadochokinesis of articulation, swallowing, taste threshold and salivary flow rate, were carried out before and after 3 months with or without intervention. RESULTS: A total of 38 participants (21 of intervention group and 17 of control group) completed the study protocol. In the intervention group, resting salivation significantly improved after the program. The second and third cumulated Repetitive Saliva Swallowing Test times significantly improved in the intervention group. The threshold for bitterness significantly lowered in the intervention group, whereas the sour threshold significantly heightened in the control group after 3 months (P < 0.05). CONCLUSIONS: The present study suggests that the educational program targeting oral function improvement is effective among the independent older population. PMID- 24796715 TI - Myocardial infarction and functional outcome assessment in pigs. AB - Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One important prerequisite is a good understanding of all safety and efficacy aspects obtained in a large animal model that validly reflect the human scenario of myocardial infarction (MI). Pigs are widely used in this regard since their cardiac size, hemodynamics, and coronary anatomy are close to that of humans. Here, we present an effective protocol for using the porcine MI model using a closed-chest coronary balloon occlusion of the left anterior descending artery (LAD), followed by reperfusion. This approach is based on 90 min of myocardial ischemia, inducing large left ventricle infarction of the anterior, septal and inferoseptal walls. Furthermore, we present protocols for various measures of outcome that provide a wide range of information on the heart, such as cardiac systolic and diastolic function, hemodynamics, coronary flow velocity, microvascular resistance, and infarct size. This protocol can be easily tailored to meet study specific requirements for the validation of novel cardioregenerative biologics at different stages (i.e. directly after the acute ischemic insult, in the subacute setting or even in the chronic MI once scar formation has been completed). This model therefore provides a useful translational tool to study MI, subsequent adverse remodeling, and the potential of novel cardioregenerative agents. PMID- 24796716 TI - The Bu4NI-catalyzed alfa-acyloxylation of ketones with benzylic alcohols. AB - The Bu4NI-catalyzed reaction of ketones with benzylic alcohols was achieved, leading to alfa-acyloxycarbonyl compounds in moderate to good yields. This metal free procedure featured the employment of facilely and commercially available starting materials and TBHP as a clean oxidant with high atom economy. PMID- 24796717 TI - Inhibition of STAT6 during vaccination with formalin-inactivated RSV prevents induction of Th2-cell-biased airway disease. AB - The pattern of immune response to a vaccine antigen can influence both efficacy and adverse events. Th2-cell-deviated responses have been implicated in both human and murine susceptibility to enhanced disease following formalin inactivated (FI) vaccines for measles and RSV. In this study, we used the Th2 cell-deviated murine model of FI-RSV vaccination to test the ability of a dominant negative, cell-penetrating peptide inhibitor of STAT6 (STAT6 inhibitory peptide (IP)) to modulate the vaccine-induced predisposition to exaggerated inflammation during later RSV infection. Intranasal delivery of STAT6-IP in BALB/c mice at the time of distal intramuscular FI-RSV vaccination (Early Intervention) markedly decreased vaccine-enhanced, Th2-cell-dependent pathology upon subsequent RSV challenge. Administration of the STAT6-IP at the time of RSV challenge (Late Intervention) had no effect. Following RSV challenge, the STAT6 IP-treated mice in the Early Intervention group had lower airway eosinophils, increased lung IFN-gamma levels, as well as increased IFN-gamma-secreting CD4(+) and CD8(+) cells in the lungs. Our findings demonstrate the feasibility of targeting intracellular signaling pathways as a new way to modulate vaccine induced responses. PMID- 24796718 TI - Kenneth Wade (1932-2014). PMID- 24796719 TI - IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. AB - Central nervous system (CNS) autoimmunity is regulated by the balance of pro inflammatory cytokines and IL-10. Here we identify the transcriptional regulator Blimp1 as crucial to induce IL-10 in inflammatory T helper cells. Pre-committed Th17 cells respond to IL-27 and IL-12 by upregulating Blimp1 and adopt a Tr-1 like phenotype characterized by IL-10 and IFN-gamma production. Accordingly, Blimp1-deficient effector T cells fail to produce IL-10, and deficiency in Tr-1 cell function leads to uncontrolled Th17 cell-driven CNS pathology without the need to stabilize the Th17 phenotype with IL-23. IL-23 counteracts IL-27 and IL 12-mediated effects on Tr-1-development reinforcing the pro-inflammatory phenotype of Th17 cells. Thus, the balance of IL-23 vs IL-12/IL-27 signals into CD4(+) effector T cells determines whether tissue inflammation is perpetuated or resolves. PMID- 24796720 TI - Hotspots of climate change impacts in sub-Saharan Africa and implications for adaptation and development. AB - Development efforts for poverty reduction and food security in sub-Saharan Africa will have to consider future climate change impacts. Large uncertainties in climate change impact assessments do not necessarily complicate, but can inform development strategies. The design of development strategies will need to consider the likelihood, strength, and interaction of climate change impacts across biosphere properties. We here explore the spread of climate change impact projections and develop a composite impact measure to identify hotspots of climate change impacts, addressing likelihood and strength of impacts. Overlapping impacts in different biosphere properties (e.g. flooding, yields) will not only claim additional capacity to respond, but will also narrow the options to respond and develop. Regions with severest projected climate change impacts often coincide with regions of high population density and poverty rates. Science and policy need to propose ways of preparing these areas for development under climate change impacts. PMID- 24796721 TI - High-frequency EEG activity in epileptic encephalopathy with suppression-burst. AB - OBJECTIVE: We explored high-frequency activity in the suppression-burst (SB) pattern of interictal electroencephalogram (EEG) in early infantile epileptic encephalopathy including Ohtahara syndrome (OS) and early myoclonic encephalopathy (EME) to investigate the pathophysiological characteristics of SB. METHODS: Subjects included six patients with the SB EEG pattern related to OS or EME (Group SB). The results were evaluated in comparison to trace alternant (TA) observed during the neonatal period in nine patients to rule out possible nonspecific relationships between high-frequency activity and periodic EEG patterns (Group TA). EEG was digitally recorded with a sampling rate of 500Hz and the analysis was performed in each of the particular bipolar channel-pairs. We visually selected 20 typical consecutive burst sections and 160 inter-burst sections for comparison from the sleep record of each patient and performed the time-frequency analysis. We investigated the maximum frequencies of power enhancement in each derivation in both groups. RESULTS: In Group SB, a significant increase in power at a frequency of 80-150Hz was observed in association with the bursts, particularly in the bilateral parieto-occipital derivations, in all patients. In Group TA, on the contrary, no significant increase in high-frequency power was found. The maximum frequencies of power enhancement were significantly higher in Group SB than in Group TA (p<0.001 by repeated-measures ANOVA). CONCLUSION: Interictal high frequencies of up to 150Hz were detected in the suppression-burst EEG patterns in epileptic encephalopathy in early infancy. Further studies will be necessary to identify the role of the interictal high-frequency activity in the pathophysiology of such early epileptic encephalopathy. PMID- 24796722 TI - Episodic tremors representing cortical myoclonus are characteristic in Angelman syndrome due to UBE3A mutations. AB - OBJECTIVE: Neurological manifestations including psychomotor developmental delay and epilepsy in patients with Angelman syndrome caused by ubiquitin protein ligase E3A (UBE3A) mutations has been considered similar but is relatively milder than that in patients with deletion-type Angelman syndrome. This makes the diagnosis of the former subgroup often difficult. We here characterized epilepsy, specifically the types of tremulous movement, in 4 patients (age, 3-38years) with Angelman syndrome caused by UBE3A mutations. METHODS: Ictal electroencephalography was used to record episodic tremors in all study patients. Jerk-locked averaging was performed using digital electroencephalography and surface electromyogram data from patients who were monitored for 24h. RESULTS: All patients had tremors in the limbs, head, and trunk, which resulted in 2 patients falling backward. These tremors lasted several seconds, and could emerge in clusters for hours in older patients. In addition, the tremors coincided with 7-8Hz rhythmic activity with a frontocentral predominance, diffuse spike-wave bursts, or no apparent change on electroencephalography. In 2 patients, these tremors were confirmed as cortical myoclonus using jerk-locked averaging. The other seizure types were isolated generalized myoclonus and tonic seizures. None of the patients experienced atypical absence seizures. Levetiracetam therapy was effective in controlling the myoclonic events in 2 of the 3 patients. CONCLUSION: Semirhythmic myoclonus is common in patients with Angelman syndrome caused by UBE3A mutations, and such myoclonic events are often life disabling. The preserved expression of gamma-aminobutyric acid type A receptor subunit genes located proximal to UBE3A might explain the low prevalence of absence seizures in this population. PMID- 24796724 TI - Evaluation of three herbicide resistance genes for use in genetic transformations and for potential crop protection in algae production. AB - Genes conferring resistance to the herbicides glyphosate, oxyfluorfen and norflurazon were developed and tested for use as dominant selectable markers in genetic transformation of Chlamydomonas reinhardtii and as potential tools for the protection of commercial-scale algal production facilities against contamination by organisms sensitive to these broad-spectrum herbicides. A synthetic glyphosate acetyltransferase (GAT) gene, when fitted with a strong Chlamydomonas promoter, conferred a 2.7*-fold increase in tolerance to the EPSPS inhibitor, glyphosate, in transgenic cells compared with progenitor WT cells. A mutant Chlamydomonas protoporphyrinogen oxidase (protox, PPO) gene previously shown to produce an enzyme insensitive to PPO-inhibiting herbicides, when genetically engineered, generated transgenic cells able to tolerate up to 136* higher levels of the PPO inhibitor, oxyfluorfen, than nontransformed cells. Genetic modification of the Chlamydomonas phytoene desaturase (PDS) gene-based gene sequences found in various norflurazon-resistant organisms allowed production of transgenic cells tolerant to 40* higher levels of norflurazon than nontransgenic cells. The high efficiency of all three herbicide resistance genes in producing transgenic cells demonstrated their suitability as dominant selectable markers for genetic transformation of Chlamydomonas and, potentially, other eukaryotic algae. However, the requirement for high concentrations of glyphosate and its associated negative effects on cell growth rates preclude its consideration for use in large-scale production facilities. In contrast, only low doses of norflurazon and oxyfluorfen (~1.5 MUm and ~0.1 MUm, respectively) are required for inhibition of cell growth, suggesting that these two herbicides may prove effective in large-scale algal production facilities in suppressing growth of organisms sensitive to these herbicides. PMID- 24796726 TI - Deuterium and hydrogen tunneling in the hydrogenation of 4-oxocyclohexa-2,5 dienylidene. AB - 4-Oxocyclohexa-2,5-dienylidene is a highly reactive triplet ground state carbene that is hydrogenated in solid H2, HD, and D2 at temperatures as low as 3 K. The mechanism of the insertion of the carbene into dihydrogen was investigated by IR and EPR spectroscopy and by kinetic studies. H or D atoms were observed as products of the reaction with H2 and D2, respectively, whereas HD produces exclusively D atoms. The hydrogenation shows a very large kinetic isotope effect and remarkable isotope selectivity, as was expected for a tunneling reaction. The experiments, therefore, provide clear evidence for both hydrogen tunneling and the rare deuterium tunneling in an intermolecular reaction. PMID- 24796725 TI - The increasing prevalence of reported diagnoses of childhood psychiatric disorders: a descriptive multinational comparison. AB - The objective of this study is to compare the time trend of reported diagnoses of autism spectrum disorder (ASD), hyperkinetic disorder, Tourette's syndrome, and obsessive-compulsive disorder across four countries after standardizing the study period, diagnostic codes used to define the conditions and statistical analyses across countries. We use a population-based cohort, including all live-born children in Denmark, Finland, Sweden and Western Australia, from January 1, 1990, through December 31, 2007 and followed through December 31, 2011. The main outcome measure is age-specific prevalence of diagnoses reported to population based registry systems in each country. We observe an increase in age-specific prevalence for reported diagnoses of all four disorders across birth-year cohorts in Denmark, Finland, Sweden, and (for ASD) Western Australia. Our results highlight the increase in the last 20 years in the number of children and families in contact with health care systems for diagnosis and services for an array of childhood neuropsychiatric disorders, a phenomenon not limited to ASD. Also, the age of diagnosis of the studied disorders was often much higher than what is known of the typical age of onset of symptoms, and we observe limited leveling off in the incidence rate with increasing age. PMID- 24796727 TI - The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials. AB - BACKGROUND: Tumors may exploit the coagulation system to enhance the survival and dissemination of cancer cells. Some studies have suggested that heparin and low molecular weight heparin (LMWH) have antitumor effects. We reported a previous meta-analysis that suggested a modest improvement in overall survival with the use of LMWH in patients with cancer. Herein, we present the results of an updated systematic review and meta-analysis. OBJECTIVE: To evaluate the effect of LMWH as compared with placebo or no anticoagulant on the overall survival in patients with solid cancers. METHODS: We conducted a systematic review and meta-analysis of randomized trials evaluating the use of LMWH vs. placebo or no anticoagulant in cancer patients without venous thrombosis. A meta-analysis was conducted with a random-effects model, and data were analyzed by the use of odds ratios (ORs) and relative risks (RRs) calculated for 1-year overall mortality. RESULTS: We identified 724 potentially relevant studies, nine of which met our inclusion criteria, and reported data on 1-year overall mortality. Studies were heterogeneous regarding types of cancer and interventions, and included 5987 patients, 98.4% of whom had advanced-stage disease (III and IV). There was no discernible effect on mortality with the use of LMWH (pooled OR 0.87, 95% CI 0.70 1.08; RR 0.94, 95% CI 0.86-1.04). CONCLUSIONS: In contrast to the previous study, these results did not show a survival benefit in cancer patients receiving LMWH. The effect of LMWH on overall survival in patients with limited-stage disease still is unknown. PMID- 24796728 TI - Can the new cervical cancer screening and management guidelines be simplified? PMID- 24796729 TI - Interlaboratory comparison study on lead in blood, in external quality assessment schemes since 1996: a progress report. AB - In 1992, at the request of the French labor ministry, an External Quality Control for lead in whole blood (F-EQCPbB) came into being. After 15 years (1996-2011), the ministry wished to exploit the database collected with a sufficient number of laboratories. Indeed, the number of participating laboratories had decreased from 73 to 41. However, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread of the results over the entire range of tested PbB (9 and 700 ug/l). So, it was that in laboratories having participated for >10 years, the good scores rose between 1996 and 2011 from 49% to 93%. To sum up, analysis has shown progressive and highly pronounced diminution of CVs (%) for all the ranges having undergone testing. We have observed increasing use of inductively coupled plasma with mass spectrometry (from 9% in 2005 to 29% in 2011) and decreasing use of electrothermal atomic absorption spectrometry. That said, and provided that they are based on the same degree of expertise in metrology, on all tested concentrations the two analytical techniques yield results that are not statistically different. Thanks to the F EQCPbB, laboratories have enhanced their proficiency and registered demonstrably improved performance. PMID- 24796730 TI - Tailoring self-organized nanostructured morphologies in kilometer-long polymer fiber. AB - While nanowires and nanospheres have been utilized in the design of a diverse array of nanoscale devices, recent schemes frequently require nanoscale architectures of higher complexity. However, conventional techniques are largely unsatisfactory for the production of more intricate nanoscale shapes and patterns, and even successful fabrication methods are incompatible with large scale production efforts. Novel top-down, iterative size reduction (ISR)-mediated approaches have recently been shown to be promising for the production of high throughput cylindrical and spherical nanostructures, though more complex architectures have yet to be created using this process. Here we report the presence of a hitherto-undescribed transitory region between nanowire and nanosphere transformation, where a diverse array of complex quasi one-dimensional nanostructures is produced by Rayleigh-Plateau instability-mediated deformation during the progress of a combined ISR/thermal instability technique. Temperature based tailoring of architecturally diverse, indefinitely long, globally parallel, complex nanostructure arrays with high uniformity and low size variation facilitates the development of in-fiber or free-standing nanodevices with significant advantages over on-chip devices. PMID- 24796731 TI - Biological and metabolic response in STS-135 space-flown mouse skin. AB - There is evidence that space flight condition-induced biological damage is associated with increased oxidative stress and extracellular matrix (ECM) remodeling. To explore possible mechanisms, changes in gene expression profiles implicated in oxidative stress and in ECM remodeling in mouse skin were examined after space flight. The metabolic effects of space flight in skin tissues were also characterized. Space Shuttle Atlantis (STS-135) was launched at the Kennedy Space Center on a 13-day mission. Female C57BL/6 mice were flown in the STS-135 using animal enclosure modules (AEMs). Within 3-5 h after landing, the mice were euthanized and skin samples were harvested for gene array analysis and metabolic biochemical assays. Many genes responsible for regulating production and metabolism of reactive oxygen species (ROS) were significantly (p < 0.05) altered in the flight group, with fold changes >1.5 compared to AEM control. For ECM profile, several genes encoding matrix and metalloproteinases involved in ECM remodeling were significantly up-/down-regulated following space flight. To characterize the metabolic effects of space flight, global biochemical profiles were evaluated. Of 332 named biochemicals, 19 differed significantly (p < 0.05) between space flight skin samples and AEM ground controls, with 12 up-regulated and 7 down-regulated including altered amino acid, carbohydrate metabolism, cell signaling, and transmethylation pathways. Collectively, the data demonstrated that space flight condition leads to a shift in biological and metabolic homeostasis as the consequence of increased regulation in cellular antioxidants, ROS production, and tissue remodeling. This indicates that astronauts may be at increased risk for pathophysiologic damage or carcinogenesis in cutaneous tissue. PMID- 24796732 TI - Contribution of the hydration force to vesicle adhesion on titanium oxide. AB - Titanium oxide is a biocompatible material that supports vesicle adhesion. Depending on experimental parameters, adsorbed vesicles remain intact or rupture spontaneously. Vesicle rupture has been attributed to electrostatic attraction between vesicles and titanium oxide, although the relative contribution of various interfacial forces remains to be clarified. Herein, we investigated the influence of vesicle surface charge on vesicle adsorption onto titanium oxide and observed that electrostatic attraction is insufficient for vesicle rupture. Following this line of evidence, a continuum model based on the DLVO forces and a non-DLVO hydration force was applied to investigate the role of different interfacial forces in modulating the lipid-substrate interaction. Within an experimentally significant range of conditions, the model shows that the magnitude of the repulsive hydration force strongly influences the behavior of adsorbed vesicles, thereby supporting that the hydration force makes a strong contribution to the fate of adsorbed vesicles on titanium oxide. The findings are consistent with literature reports concerning phospholipid assemblies on solid supports and nanoparticles and underscore the importance of the hydration force in influencing the behavior of phospholipid films on hydrophilic surfaces. PMID- 24796735 TI - [RL-RVG inhibits proliferation and promotes apoptosis of lung cancer cells in vitro]. AB - OBJECTIVE: To infect lung adenocarcinoma A549 cells with recombinant LaSota strain Newcastle disease virus (NDV) vaccine expressing the rabies virus glycoprotein (rL-RVG), and explore the effect of rL-RVG on proliferation and apoptosis of lung cancer cells. METHODS: A549 cells were infected with the rL-RVG and then detected for the expressions of RVG and NDV proteins by Western blotting. The cell proliferation was examined by MTT assay and apoptosis index and cell early apoptosis were respectively detected by TUNEL and annexin V FITC/PI staining combined with flow cytometry. The expression of pro-apoptotic protein caspase-3 was observed by Western blotting. The LaSota strain of NDV was used as control group and PBS was the blank control. RESULTS: Both RVG and NDV proteins were stably expressed in A549 cells infected with rL-RVG. MTT assay results showed that cell proliferation was significantly inhibited, and the inhibition rate of the rL-RVG group was higher than that of LaSota group. The apoptosis of A549 cells were promoted by rL-RVG infection. Flow cytometry revealed that the early apoptotic cells of the rL-RVG group increased as compared with the other two groups (P<0.05). Consistently, TUNEL assay showed the apoptotic index increased in the rL-RVG group as compared with the other two groups (P<0.05). Western blotting demonstrated that the expression of the pro apoptotic protein caspase-3 was up-regulated. However, when we added specific broad-spectrum caspase inhibitor Z-VAD-FMK, the expression of the caspase-3 protein was obviously reduced. CONCLUSION: The rL-RVG is stably expressed in the infected A549 cells. The rL-RVG inhibits lung cancer cell growth and promote cell apoptosis, and the effect of rL-RVG is better than the wild LaSota strain. PMID- 24796734 TI - Pulse oximetry-derived respiratory rate in general care floor patients. AB - Respiratory rate is recognized as a clinically important parameter for monitoring respiratory status on the general care floor (GCF). Currently, intermittent manual assessment of respiratory rate is the standard of care on the GCF. This technique has several clinically-relevant shortcomings, including the following: (1) it is not a continuous measurement, (2) it is prone to observer error, and (3) it is inefficient for the clinical staff. We report here on an algorithm designed to meet clinical needs by providing respiratory rate through a standard pulse oximeter. Finger photoplethysmograms were collected from a cohort of 63 GCF patients monitored during free breathing over a 25-min period. These were processed using a novel in-house algorithm based on continuous wavelet-transform technology within an infrastructure incorporating confidence-based averaging and logical decision-making processes. The computed oximeter respiratory rates (RRoxi) were compared to an end-tidal CO2 reference rate (RRETCO2). RRETCO2 ranged from a lowest recorded value of 4.7 breaths per minute (brpm) to a highest value of 32.0 brpm. The mean respiratory rate was 16.3 brpm with standard deviation of 4.7 brpm. Excellent agreement was found between RRoxi and RRETCO2, with a mean difference of -0.48 brpm and standard deviation of 1.77 brpm. These data demonstrate that our novel respiratory rate algorithm is a potentially viable method of monitoring respiratory rate in GCF patients. This technology provides the means to facilitate continuous monitoring of respiratory rate, coupled with arterial oxygen saturation and pulse rate, using a single non invasive sensor in low acuity settings. PMID- 24796733 TI - STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth. AB - The dismal 5-year survival (<5%) for pancreatic cancer (PanCA) underscores the need for developing effective therapeutic options. Recent studies from our laboratory have shown that Nexrutine(r) (Nx), a bark extract from Phellodendron amurense exhibits excellent anticancer activity in human pancreatic cancer cells through inhibition of inflammatory signaling via STAT3/NFkappaB/Cox-2. Given the apparent high oxidative stress and autophagic activity in pancreatic tumors, we investigated the potential of Nx to modulate autophagy, reactive oxygen species (ROS), and their crosstalk. Our results show that Nx inhibits autophagy and decreases ROS generation. Pharmacological inhibition of autophagy led to decreased ROS generation and proliferation with no significant effect on apoptosis. Further, using combination index analysis we also found that combination of late-stage autophagy inhibitor with Nx exhibited a moderate synergistic to additive effect. Additionally, genetic or pharmacological inactivation of STAT3 reduced LC3-II levels and expression indicating a possible role for STAT3 in transcriptional regulation of autophagy. Since both inflammatory and oxidative stress signaling activate STAT3, our data implicates that STAT3 plays a vital role in the regulation of autophagy through its contributions to the positive feedback loop between ROS and autophagy. Overall, our findings reveal an important role for STAT3/LC3/ROS in Nx-mediated anti pancreatic cancer effects. PMID- 24796736 TI - [TRAIL inhibits proliferation and promotes apoptosis of 3AO ovarian cancer cells]. AB - OBJECTIVE: To investigate the effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on the proliferation of ovarian carcinoma 3AO cells in vitro and its molecular mechanism. METHODS: Ovarian carcinoma 3AO cells were incubated with 12.5, 25.0, 50.0 ng/mL TRAIL proteins for 72 hours, respectively. At 24, 48 and 72 hours, the cells were collected to observe the morphological change under an inverted microscope, detect the cell proliferation using methyl thiazolyl tetrazolium (MTT) assay, the apoptosis rate and cell cycle using flow cytometry (FCM), the morphological features of apoptotic cells using TdT-mediated dUTP nick end labeling (TUNEL) and the expression of caspase-3 protein using Western blotting. RESULTS: The growth of 3AO cells was inhibited by different concentrations of TRAIL (P<0.05). Morphological change of 3AO cells was clearly observed. TRAIL protein at 25 and 50 ng/mL significantly induced 3AO cell apoptosis and cell cycle arrest. With the treatment time went by, the percentage of cells at G1 phase increased and cells at S and G2/M phase decreased. The expression of caspase-3 protein was raised by TRAIL. No significant differences were noted in the apoptosis rate and the expression of caspase-3 protein between the 25 and 50 ng/mL TRAIL groups (P>0.05). CONCLUSION: TRAIL protein could promote the apoptosis of 3AO cells through inhibiting cell growth cycle, blocking DNA synthesis and activating caspase-3. PMID- 24796737 TI - [Effect of all-trans retinoic acid on cerebral ischemia injury and regulatory T cell accounts in stroke mice]. AB - OBJECTIVE: To investigate the cerebral infarct volume 24 hours after transient middle cerebral artery occlusion (tMCAO) and the proportion of CD4+;CD25+;Foxp3+; regulatory T cells (Tregs) in splenocytes in diverse periods after all-trans retinoic acid (ATRA) treatment in mice, so as to explore whether ATRA have the protection against cerebral ischemia damage in mice through intervening Treg differentiation. METHODS: Sixty male Kunming mice were randomly divided into two groups, i.e. pretreatment (n=40) and post-treatment (n=20) groups. Each group was against divided into two subgroups, i.e. tMCAO combined with ATRA treatment group, tMCAO combined with DMSO control group. Pretreatment groups: mice were treated intraperitoneally with ATRA (10 mg/kg) dissolved in 100 mL/L DMSO or equivalent volume of 100 mL/L DMSO daily for 7 days (n=20/group). Ten mice in each group were sacrificed and the proportion of Tregs in splenocytes was analyzed by flow cytometry (FCM) after 7-day pretreatment. The other 10 mice in each group were subjected to tMCAO by modified monofilament method. Neurologic deficit score (NDS) was recorded and the infarct volume was assessed by 2, 3, 5 triphenyltetrazolium chloride(TTC) staining 24 hours after tMCAO. The mice in post-treatment groups were treated intraperitoneally with ATRA (10 mg/kg) or equivalent volume of 100 mL/L DMSO immediately after the reperfusion of tMCAO modeling (n=10/group). NDS and infarct volume were assessed and the proportion of Tregs in splenocytes was analyzed 24 hours after tMCAO. RESULTS: ATRA pretreatment for 7 days failed to improve neurologic function deficit (P>0.05) and to reduce the cerebral infarct volume (P>0.05) 24 hours after tMCAO in mice. ATRA post-treatment could markedly improve neurologic function (P<0.05) and reduce the cerebral infarct volume (P<0.05) 24 hours after tMCAO. However, neither ATRA pretreatment nor post-treatment had effect on the proportion of Tregs in the splenocytes of mice (P>0.05). CONCLUSION: ATRA administered before tMCAO for 7 days failed to protect brain against ischemic damage. ATRA administered immediately following tMCAO induced cerebral protective effect 24 hours after tMCAO. The results suggest that Tregs change is not involved in the neuroprotection mechanism of ATRA. PMID- 24796738 TI - [Preparation of the recombinant lentiviral expression vector targeting human Wnt5a gene and its inhibitory effect on melanoma cell invasion]. AB - OBJECTIVE: To construct a recombinant lentiviral vector expressing small-hairpin RNA (shRNA) targeting human Wnt5a gene and investigate its silencing effect on WM793B human melanoma invasion. METHODS: Based on the sequence of human Wnt5a gene in GenBank, Wnt5a siRNA was designed and synthesized. The single-stranded primers were annealed to double-stranded oligonucleotide sequences and subcloned into linear pLKO.1 lentiviral plasmid digested by enzyme to produce pLKO.1 shWnt5a lentiviral vector. After being identified by PCR and sequencing, plasmid pLKO.1-shWnt5a was transfected into HEK293T cells to package lentiviral particles. Human malenoma WM793B cells were infected by the lentiviral particles. Expression of shWnt5a in WM793B cells was detected using Western blotting. Then the Transwell(TM); invasion assay was performed to assess its effect on melanoma cell invasion. RESULTS: Lentivirus expressing shWnt5a was successfully constructed and WM793B(Wnt5a-);, a strain of melanoma cells with low expression of Wnt5a was also established. Transwell(TM); invasion assay revealed that cell migration was inhibited in Wnt5a-inhibited melanoma cells. CONCLUSION: Down regulated Wnt5a expression exerts a significant inhibitory effect on the invasion of melanoma cells. PMID- 24796739 TI - [Infusion of ex vivo expanded homologous CD4+;CD25+; regulatory T cells promotes the susceptibility to tumor in mice]. AB - OBJECTIVE: To study the effects of adoptive transfer of ex vivo expanded homologous CD4+;CD25+; regulatory T cells (Tregs) on antitumor immunity in mice and explore the potential risk of this therapeutic method. METHODS: Marine CD4+;CD25+; Tregs were separated from spleens by magnetic activated cell sorting (MACS) and expanded by anti-CD3/CD28-coated microbeads and 1 000 U/mL interleukin 2 (IL-2) in vitro. The purity of fresh and expanded Tregs was determined by FACS. The cells were collected after two rounds of expansion (7 days each), and suppressive activity of expanded Tregs was tested by the mixed lymphocyte reaction (MLR) in vitro. Thereafter, the BALB/c mice were intravenously injected with 1 * 107 expanded Tregs and 24 hours later, they were inoculated intravenously with 1 * 106; B16;F10; tumor cells. The mice injected with tumor cells only were set as the control group. Fourteen days later, the percentage of CD4+;CD25+;Foxp3+; Tregs in peripheral blood was analyzed by flow cytometry and the numbers of pulmonary metastases were counted. Results The purity of expanded Tregs decreased from (96.3 +/- 2.88)% to (87.73 +/- 2.35)% compared with fresh Tregs, but there was no significant difference in the suppressive activity between fresh Tregs and expanded Tregs (P>0.05). The number of tumor nodules in lung of BALB/c mice was significantly elevated from 14 +/- 5 to 73 +/- 9 after injected 1 * 107; expanded Tregs compared with the control group (P=0.007), and the same with the mice that were inoculated with 2 * 106; B16;F10; cells alone (P=0.230). What's more, the number of pulmonary metastases was significantly raised from 70 +/- 15 to over 300 (P<0.01) in 5 * 105; B16;F10; inoculated C57BL/6 mice if they were injected previously with 8 * 106; expanded Tregs. The percentage of Foxp3+; Tregs in peripheral blood significantly increased in the experimental group as compared with normal mice and control group (P<0.05). Conclusion Adoptive transfer of ex vivo expanded Tregs can induce the immune tolerance and inhibit the antitumor immunity at the same time. There was a potential risk in the clinical application of Tregs. PMID- 24796740 TI - [Effect of RNF2 knockdown on apoptosis and radiosensitivity in glioma U87 cells]. AB - OBJECTIVE: To investigate the effect of RING finger protein 2 (RNF2) knockdown on the biological characteristics and radiosensitivity in glioma U87 cells. METHODS: Plasmids containing shRNA targeting RNF2 were transfected into U87 cells. Real time quantitative PCR (qRT-PCR) and Western blotting were respectively applied to detect the mRNA and protein level of RNF2. MTT assay was used to detect cell proliferation. Cell cycle and apoptosis were measured by flow cytometry combined with annexin V-FITC/PI staining in the control and RNF2 knockdown cells. Apoptosis was also detected after X-ray radiation. RESULTS: Both shRNAs efficiently inhibited RNF2 expression in U87 cells. Cell proliferation was obviously depressed in RNF2 knockdown cells. The percentage of cells decreased in S phase (shRNA-NC: 27.31 +/- 1.35; shRNF2-1: 16.72 +/- 2.90; shRNF2-3: 10.35 +/- 1.33) and increased in G1 phase (shRNA-NC: 56.13 +/- 1.80; shRNF2-1: 76.32 +/- 3.11; shRNF2-3: 80.45 +/- 2.83). More cell apoptosis was observed in RNF2 knockdown cells. After X ray radiation, the apoptosis rate was significantly raised in RNF2 knockdown cells (shRNA-NC: 20.88 +/- 0.64; shRNF2-1: 39.69 +/- 0.57; shRNF2-3: 47.82 +/- 0.45). CONCLUSION: Knockdown of RNF2 can inhibit cell proliferation, induce cell cycle arrest and promote apoptosis in U87 cells. RNF2 knockdown can obviously increase the sensitivity of U87 cells to X ray radiation. PMID- 24796741 TI - [Expression and activity identification of a fusion protein for promoting adenovirus infection efficiency of dendritic cells]. AB - OBJECTIVE: To construct a prokaryotic expression plasmid for CT40L, express the target protein in E. coli, purity the CT40L fusion protein and verify its antigenicity. METHODS: Gene sequences of Coxsackie and adenovirus receptor (CAR), bacteriophage T4 fibritin and mouse CD40L were found out in GenBank. Then functional domains of three molecules were linked to form a fusion sequence which was then optimized for prokaryotic expression. The optimized sequence was cloned into prokaryotic expression vector pET42a(+) to construct the recombinant expression vector pET42a-CT40L. The recombinant vector was transformed into BL21 (DE3) and the fusion protein CT40L/GST was induced by IPTG. The fusion protein was then subjected to purification using GST affinity chromatography and to identification of the immune activity using Western blotting and ELISA. RESULTS: The recombinant expression vector was verified correct by double digestion with Nco I and EcoR I. After IPTG induction, SDS-PAGE showed that the relative molecular mass of the fusion protein was about 78 kDa and that the purity of the purified protein reached 90%. Western blotting and ELISA demonstrated that the purified fusion protein had a valid antigenicity. CONCLUSION: The prokaryotic expression plasmid pET42a-Ct40L was successfully constructed and expressed in E. coli, and the purified fusion protein was proved to have a good antigenicity. PMID- 24796742 TI - [Prokaryotic expression and function detection of Mycobacterium tuberculosis Hsp16.3]. AB - OBJECTIVE: To construct a prokaryotic expression vector of Mycobacterium tuberculosis (MTB) small heat shock protein Hsp16.3, express and purify the fusion protein of His-Hsp16.3, and identify its function. METHODS: Hsp16.3 gene was amplified from H37Rv DNA by PCR, and then cloned into prokaryotic expression vector Pet28a. The positive recombinant plasmid Pet28a-Hsp16.3 was selected and identified by double enzyme digestion and sequencing. Then the recombinant plasmid of correct sequence was transformed into E.coli BL21 (DE3), and induced by IPTG. The expressed recombinant protein was analyzed by SDS-PAGE and Western blotting; the fusion protein was purified by Hislink spin protein purification system, and then detected for its concentration; real-time quantitative PCR (qRT PCR) was used to determine the expressions of IL-10 and IFN-gamma in mouse peritoneal macrophages treated by the purified fusion protein of different concentrations. Meanwhile, the blank control group and positive control group were set up and compared. RESULTS: Double enzyme digestion and sequencing showed that the recombinant plasmid Pet28a-Hsp16.3 was successfully constructed, and SDS PAGE and Western blotting revealed that the fusion protein was expressed in E.coli BL21(DE3). Moreover, qRT-PCR showed that the purified fusion protein when added to the mouse peritoneal macrophage cells could significantly promote the produce of IFN-gamma and restrain the expression of IL-10. CONCLUSION: MTB Hsp16.3 was successfully cloned, expressed and purified. His-Hsp16.3 could significantly promote the produce of IFN-gamma and restrain the expression of IL 10. PMID- 24796744 TI - [The expression of C-type lectin-like domain of DNGR-1 molecules of Chinese rhesus macaques in E.coli]. AB - OBJECTIVE: To obtain the nucleotide sequence and express the C-type lectin-like domain (CTLD) of C-type lectin domain family 9, member A (Clec9A) gene of Chinese rhesus macaques. METHODS: The complete coding region of rhesus macaque Clec9A gene was amplified by sequence specific RT-PCR and sub-cloned into the pGEM-T vector and sequenced. Recombinant plasmid pET-32a-CTLD was constructed to express the CTLD region of CLEC9A in BL21 (DE3) cells under IPTG induction. The recombinant protein was identified by SDS-PAGE and Western blotting. RESULTS: The 726 bp complete coding sequence of Clec9A gene was obtained. Sequencing and sequence alignments showed that rhesus macaque Clec9A gene shared 95.0% and 73.1% nucleotide identities and 91.7% and 57.3% amino acid identities with humans and mice, respectively. In vitro expression of CTLD resulted in a protein with Mr; of 32 000. Western blotting revealed that the protein had the similar antigenicity with human DNGR-1. CONCLUSION: The Clec9A gene of Chinese rhesus macaques is highly similar to that of humans and could code a protein with the antigenicity of human CTLD protein. PMID- 24796743 TI - [Over-expression of human SPRY2 promotes the proliferation and survival of HEK293T cells]. AB - OBJECTIVE: To construct a recombinant expression vector pDC315/hSPRY2 carrying human SPRY2 (hSPRY2) gene, and transfect the recombinant plasmid into human embryonic kidney HEK293T cells to express the target protein, and thus explore preliminarily the effect of hSPRY2 on the proliferation and survival of HEK293T cells. METHODS: The recombinant adenoviral vector expressing hSPRY2 was constructed and transfected into HEK293T cells in vitro. The expression of hSPRY2 target protein in the transfected cells was identified by Western blot analysis. The effect of hSPRY2 on the proliferation and survival of HEK293T cells in a serum-free condition was tested using CCK-8 assay. RESULTS: The recombinant expression vector pDC315/hSPRY2 was constructed, and the target protein hSPRY2 was expressed in the transfected HEK293T cells. The proliferation and survival rates of HEK293T cells transfected with pDC315/hSPRY2 were significantly higher than those transfected with pDC315/EGFP (P<0.05). CONCLUSION: The recombinant expression vector for hSPRY2 was successfully constructed and its expression was demonstrated in the transfected HEK293T cells. Over-expression of SPRY2 promoted the proliferation and survival of HEK293T cells. PMID- 24796745 TI - [The expression of human IL-1beta gene containing human erythropoietin signal peptide in HepG2 cells]. AB - OBJECTIVE: To construct two lentiviruses secreting human IL-1beta through either classical or nonclassical pathway and analyze their expressions in HepG2 cells after packaging lentiviruses and infecting hepatoma carcinoma HepG2 cells. METHODS: Human full-length IL-1beta gene and chimeric gene containing human erythropoietin(EPO) signal peptide and mature IL-1beta protein coding sequence were respectively amplified from pIRES2-EGFP-proIL-1beta and pIRES2-EGFP-epoIL 1beta using PCR. The sequences were subsequently cloned into lentiviral expression vector pLenti6/V5 to construct pLenti6/V5-proIL-1beta, which expressed IL-1beta through nonclassical pathway, and pLenti6/V5-epoIL-1beta, which expressed IL-1beta through signal-peptide mediated classical pathway. Lentiviruses expressing human IL-1beta through either classical or nonclassical pathway were packaged in HEK293T cells using a three-plasmid packaging system, and then these viruses were used to infect HepG2 cells. The level of IL-1beta in both cytoplasm and culture supernatant were detected by sandwich ELISA and Western blotting. RESULTS: pLenti6/V5-proIL-1beta expressing human full-length IL 1beta gene and pLenti6/V5-epoIL-1beta expressing human EPO signal peptide and mature IL-1beta gene were successfully constructed and confirmed through enzymatic assay and DNA sequencing. The lentiviruses expressing IL-1beta through different pathways were prepared using a three-plasmid packaging system in HEK293T cells. Compared with the cells infected with control virus, levels of supernatant and cytoplasmic IL-1beta in the cells infected with two lentiviruses expressing IL-1beta through different pathways were markedly elevated (P<0.01). However, level of mature IL-1beta in supernatant of HepG2/epoIL-1beta cells was much higher than that of HepG2/proIL-1beta cells, while total IL-1beta level in cytoplasm of HepG2/proIL-1beta cells was significantly higher than that in HepG2/epoIL-1beta cells. CONCLUSION: Both classical and nonclassical pathway secretion vectors could express human IL-1beta in HepG2 cells, but EPO signal peptide mediated classical pathway secreted much higher mature IL-1beta than that of nonclassical pathway. PMID- 24796746 TI - [Mechanism of cardiac function changes in rat models of Sjogren's syndrome based on Keap1-Nrf2/ARE signaling pathways]. AB - OBJECTIVE: To investigate the mechanism underlying the changes in the cardiac function in rat models of Sjogren's syndrome (SS) based on Kelch-like ECH associated protein 1 (Keap1)-Nrf2/ARE signaling pathways. METHODS: Thirty male Wistar rats were randomly divided into two groups, normal control (NC) group and SS model group, with 15 in each. The rats in the model group were injected with the complete Freund's adjuvant plus homologous antigen of submandibular gland (0.2 mL mixture) into bilateral posterior paw metatarsus. The body mass, water intake, submandibular gland index, spleen index, and histological changes of the glands were observed 30 days after inflammation was induced. Cardiac function was assessed using invasive hemodynamic monitoring. Meanwhile, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and total antioxidant capacity (TAC), IL-18, IL-35 were detected using ELISA; ROS and reactive nitrogen species (RNS), glutathione (GSH), thioredoxin (TrX) protein were determined using immunohistochemical staining. The expressions of Keap 1, nuclear factor erythroid 2-related factor (Nrf2), macrophage activating factor (Maf) antioxidant responsive element (ARE) mRNAs were detected using real-time fluorescent quantitative PCR (qRT-PCR); the levels of heme oxygenase-1 (HO-1), gamma-glutamic acid and a half long glycine synthetase (gamma-GCS) proteins in cardiac tissue were examined using Western blotting. RESULTS: Compared with the NC group, the model group presented reduced body mass, submandibular gland index and spleen index (P<0.05), increased water intake (P<0.01), heart rate (HR), heart index (HI), left ventricular systolic pressure (LVSP) and left ventricular diastolic pressure (LVEDP) (P<0.05), and decreased left ventricular +/-dp/dtmax (P<0.05). Compared with the NC group, the model group had increased IL-18, MDA, RNS, TAC, ROS levels, and Keap1, Maf, Nfr2 mRNAs, HO-1, gamma-GCS protein expressions in the heart tissue, while TrX, GSH, IL-5 and SOD levels decreased significantly (P<0.01). CONCLUSION: The immune imbalance in SS rats may be related with the up-regulated levels of Keap1, Maf, Nfr2 mRNAs, HO-1, gamma-GCS. PMID- 24796747 TI - [Protective effect and mechanism of IL-17 monoclonal antibody on mice with viral myocarditis]. AB - OBJECTIVE: To explore the protective effects of interleukin-17 monoclonal antibody (IL-17 mAb) on viral myocarditis (VMC) mice and its possible molecular mechanisms. METHODS: Ninety BALB/c mice were randomly divided into 4 groups: normal control group (n=15), model group (n=25), isotype control group (n=25) and IL-17 mAb group (n=25). Mice in model, isotype control and IL-17 mAb groups were inoculated with 0.1 mL Eagle's solution containing Coxsackievirus B3 (CVB3) intraperitoneally; and those in normal control group were treated with 0.1 mL Eagle's solution without CVB3. On the day 3 and 5 after inoculation, mice in isotype control and IL-17 mAb groups received intragastric administration of 100 MUg non-specific IgG antibody and IL-17 mAb, respectively. On day 7 postinoculation, 5 mice were killed in each group, and the hearts were removed. Virus titer was detected using Reed-Muench method, and CVB3 mRNA copy number was measured by real-time quantitative PCR. All mice were killed on day 14 after weighing body mass (BM). The mortality was compared among groups. Serum was separated and serum cardiac troponin I (cTnI) concentration was detected using ELISA. The heart was removed and weighed to calculate heart index (HM/BM). Histological sections of heart were stained with hematoxylin-eosin and myocardial histopathologic scores were counted under optical microscope. The expression of nuclear factor-kappaB (NF-kappaB) p65 was examined by Western blotting. Myocardial interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels were detected by ELISA. RESULTS: The HM/BM, serum cTnI concentration, NF kappaB p65 expression level and myocardial IL-6 and TNF-alpha contents in model group were higher than those in normal control group (P<0.01). In comparison with model and isotype control groups, mortality, HM/BM, serum cTnI concentration, myocardial histopathologic scores, virus titer, CVB3 mRNA copy number, NF-kappaB p65 expression level, and myocardial IL-6 and TNF-alpha contents in IL-17 mAb group were significantly reduced (P<0.05 or 0.01). There was no difference in the above indicators between isotype control group and model group(P>0.05). CONCLUSION: IL-17 mAb can improve myocardial injury in VMC mice, and the mechanisms are associated with the inhibition of viral replication and NF-kappaB activation. PMID- 24796748 TI - [The expression of human IL-37 in E.coli and preparation and characterization of mouse anti-IL-37 antibody]. AB - OBJECTIVE: To construct a prokaryotic expression system for interleukin-37 (IL 37) and prepare its polyclonal antibody. METHODS: The gene encoding mature interleukin-37 (IL-37m) was amplified by PCR and subcloned into prokaryotic expression vector pET28a. Then the recombinant plasmid pET28a/IL-37m was transformed into E.coli Rosetta and expressed under IPTG induction. The recombinant IL-37m was purified through Ni2+;-NT agarose gel column and the purified recombinant IL-37m was used as immunogen to immunize the BALB/c mouse. The titer and specificity of the mouse anti-IL-37 antibody were analyzed by ELISA, Western blotting and immunohistochemical staining, respectively. RESULTS: The recombinant IL-37 was successfully expressed and purified, and the mouse anit IL-37 antibody was successfully prepared. ELISA showed that the titer of the antiserum was 1:128 000. Western blot analysis revealed that the antibody reacted with IL-37 specifically. Immunohistochemical staining detection manifested the antibody could recognize the native IL-37. CONCLUSION: The mouse anti-IL-37 antibody with high titer and specificity was successfully prepared. PMID- 24796749 TI - [Prognostic value of IL-10 expression in tumor tissues of breast cancer patients]. AB - OBJECTIVE: To evaluate the prognostic value of IL-10 expression in breast cancer patients and determine the correlation between IL-10 expression and clinicopathological features of breast cancer. METHODS: Paraffin sections were retrospectively collected from 130 patients of stage I-III breast cancer who received surgery between January 2000 and December 2002 in the Chinese PLA General Hospital. The protein expression of IL-10 in the primary lesions was detected by immunohistochemistry to analyze the correlations of IL-10 expression with clinicopathological variables and prognosis. RESULTS: IL-10 was found expressed in the cytoplasm of both tumor cells and stromal cells. Higher IL-10 expression in tumor cell cytoplasm was associated with lower T grade (P=0.012), higher SBR grade (P=0.004), positive ER (P=0.007), negative vascular invasion (P=0.034). The multivariant COX regression analysis showed that higher IL-10 expression in tumor cell cytoplasm was associated with better disease-free survival (HR=0.443, P=0.022) and that higher density of IL-10+; in stromal cell cytoplasm was associated with overall survival (HR=0.411, P=0.051). CONCLUSION: IL-10 expression level in breast tumor cells and stromal cells can be used as a predictor of breast cancer prognosis. Low expression of IL-10 is associated with poor survival outcome. PMID- 24796750 TI - [Post-transplant cell immune reconstitution in humanized NOD/SCID mice]. AB - OBJECTIVE: To investigate the cell immune reconstitution in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice by the transplantation of human umbilical cord blood (HUCB) CD34+; cells. Methods CD34+; cells were isolated from HUCB by magnetic activated cell sorting (MACS), and then were transplanted into NOD/SCID mice following the irradiation of sublethal doses via the lateral tail vein. Human CD45+; CD3+; CD56+; cell populations in the peripheral blood of mice were dynamically analyzed by flow cytometry (FCM) 4, 6, 8 and 10 weeks after transplantation. After 10 weeks, the expression of human ALU gene was detected by PCR in the bone marrow of mice, and the expressions of human CD3+; CD56+; cells were examined by immunohistochemical staining in the spleen tissues. RESULTS: After irradiation, the nucleated cells and giant cells in the marrow cavity of NOD/SCID mice were reduced significantly or completely demolished. The effect of myeloablative pretreatment was ideal. Human CD45+; CD3+; CD56+; cells were found by FCM in the peripheral blood of all surviving mice in transplantation group 4, 6, 8, and 10 weeks after the transplantation. The population of the human lymphocytes varied over time, peaked at the 8th week, and remained at a high level later. At the 10th week, the human ALU sequence could be detected in the bone marrow of all surviving mice in transplantation group, and human CD3+; CD56+; cells could be observed in the spleen tissues. All mice which received no transplantation died within 2 weeks after irradiation. CONCLUSION: The hu-SRC-NOD/SCID model was successfully established in irradiation induced NOD/SCID mice by the transplantation of HUCB CD34+; cells, and its cell immune system was effectively rebuilt. PMID- 24796751 TI - [Expression, purification and hIgG-binding activity identification of truncated Streptococcus suis factor H-binding protein]. AB - OBJECTIVE: To construct a prokaryotic expression vector of the His-tagged truncated factor H-binding protein (Fhb) fragments, Fhb-N (amino acids 45-344aa) and Fhb-C (amino acids 345-644aa), of Streptococcus suis serotype 2, express it in E.coli BL21 (DE3) in order to acquire high-purity recombinant protein, and finally identify the binding activity with human serum IgG (hIgG). METHODS: Fhb-N gene and Fhb-C gene were amplified using the primers designed according to 05ZYH33 genome sequences and cloned into the expression vector pET28a+ to construct recombinant plasmids. The plasmids were transformed into E.coli BL21 (DE3) and induced to express by IPTG. The recombinant proteins were purified by nickel affinity chromatography and identified by Western blotting. The hIgG was purified from human serum by HiTrap protein G HP column in accordance with the manufacturer's instructions. In addition, the specific binding to hIgG was identified by Western blotting and biolayer Interferometry (BLI). RESULTS: The prokaryotic expression vector of His-Fhb-N and His-Fhb-C was constructed, and the target proteins were expressed, purified and identified. The specific binding activity with hIgG was identified and the binding region was found located on the Fhb-N(45-344aa). CONCLUSION: His-Fhb-N can specifically bind to hIgG, which will help us to further study the role of Fhb-hIgG interaction in the pathogenesis of Streptococcus suis. PMID- 24796752 TI - Molecular characterization and expression analysis of ATP-gated P2X7 receptor involved in Japanese flounder (Paralichthys olivaceus) innate immune response. AB - ATP-gated P2X7 receptor (P2RX7) channel is a key component for purinergic signaling and plays important roles in the innate immune response in mammals. However, the expression, molecular properties and immune significances of P2RX7 in lower vertebrates are still very limited. Here we identified and characterized a novel bony fish P2RX7 homologue cDNA, termed poP2RX7, in Japanese flounder (Paralichthys olivaceus). PoP2RX7 protein shares about 60-88% sequence similarity and 45-78% sequence identity with known vertebrate P2RX7 proteins. Phylogenetic analysis placed poP2RX7 and other P2RX7 proteins within their own cluster apart from other P2RX members. While the functional poP2RX7 channel shares structural features in common with known P2RX7 homologs, electrophysiological studies revealed that BzATP, the more potent agonist for known mammalian and fish P2RX7s, shows similar potency to ATP in poP2RX7 activation. poP2RX7 mRNA constitutively expressed in all examined tissues from unstimulated healthy Japanese flounder with dominant expression in hepatopancreas and the lowest expression in head kidney, trunk kidney, spleen and gill. poP2RX7 mRNA expression, however, was significantly induced in Japanese flounder head kidney primary cells by Poly(I:C) and bacterial endotoxin LPS stimulations. In vivo experiments further revealed that poP2RX7 gene expression was substantially up-regulated by immune challenge with infectious bacteria Edwardsiella tarda and Vibrio anguillarum. Moreover, activation of poP2RX7 results in an increased gene expression of multifunctional cytokines IL-1beta and IL-6 in the head kidney primary cells. Collectively, we identified and characterized a novel fish P2RX7 homolog which is engaged in Japanese flounder innate immune response probably through modulation of pro inflammatory cytokines expression. PMID- 24796753 TI - Garlic attenuates cardiac oxidative stress via activation of PI3K/AKT/Nrf2-Keap1 pathway in fructose-fed diabetic rat. AB - BACKGROUND: Cardiovascular complication due to diabetes has remained a major cause of death. There is an urgent need to intervene the cardiac complications in diabetes by nutritional or pharmacological agents. Thus the present study was designed to find out the effectiveness of garlic on cardiac complications in insulin-resistant diabetic rats. METHODS AND RESULTS: SD rats were fed high fructose (65%) diet alone or along with raw garlic homogenate (250 mg/kg/day) or nutrient-matched (65% corn starch) control diet for 8 weeks. Fructose-fed diabetic rats showed cardiac hypertrophy, increased NFkB activity and increased oxidative stress. Administration of garlic significantly decreased (p<0.05) cardiac hypertrophy, NFkB activity and oxidative stress. Although we did not observe any changes in myocardial catalase, GSH and GPx in diabetic heart, garlic administration showed significant (p<0.05) increase in all three antioxidant/enzymes levels. Increased endogenous antioxidant enzymes and gene expression in garlic treated diabetic heart are associated with higher protein expression of Nrf2. Increased myocardial H2S levels, activation of PI3K/Akt pathway and decreased Keap levels in fructose-fed heart after garlic administration might be responsible for higher Nrf2 levels. CONCLUSION: Our study demonstrates that raw garlic homogenate is effective in reducing cardiac hypertrophy and fructose-induced myocardial oxidative stress through PI3K/AKT/Nrf2-Keap1 dependent pathway. PMID- 24796754 TI - Pyometra: a rare cause of acute peritonitis. PMID- 24796755 TI - Editorial comment from Dr Morley and Dr Zaslau to Non-bladder conditions in female Taiwanese patients with interstitial cystitis/hypersensitive bladder syndrome. PMID- 24796756 TI - The effect of magnification on sonographically measured nerve cross-sectional area. AB - INTRODUCTION: The primary aim of this investigation was to determine whether use of write-zoom magnification affects sonographically determined cross-sectional area (CSA) of peripheral nerves. METHODS: CSAs of the median (MN) and posterior interosseous (PIN) nerves were measured in 22 limbs from 11 asymptomatic volunteers using both standard imaging and write-zoom magnification. CSA measurements were repeated on the same images 1 week later. RESULTS: The average CSA of write-zoomed images for the MN was significantly larger at both measurement sessions (week 1: 11.1 mm(2) write-zoom vs. 10.0 mm(2) standard, P = 0.019; week 2: 11.8 mm(2) vs. 10.4 mm(2), P = 0.023). Similar differences were noted for the PIN (week 1: 2.3 mm(2) vs. 1.9 mm(2), P = 0.002; week 2: 2.5 mm(2) vs. 1.9 mm(2), P = 0.001). CONCLUSIONS: Write-zoom magnification may significantly increase the measured CSA of peripheral nerves. These changes appear to be more substantial when smaller nerves are measured. PMID- 24796757 TI - Therapeutic potential of and treatment with boceprevir/telaprevir-based triple therapy in HIV/chronic hepatitis C co-infected patients in a real-world setting. AB - The aim of this study was to assess the therapeutic potential of telaprevir (TPV)/boceprevir (BOC)-based triple-therapy in a complete cohort of HIV/chronic hepatitis C co-infected patients (HIV/HCV). Moreover, a case series of four HIV/HCV genotype (HCV-GT)1 patients with rapid virologic response (RVR), who received only 28 weeks of BOC-based triple-therapy (BOCW28), was reported. 290/440 HIV-positive patients with positive HCV serology had at least one visit during the past 2 years, 142/290 had target detectable HCV-RNA with 64% (82/142) carrying HCV-GT1. While 18 HIV/HCV-GT1 displayed contraindications, 45% (64/142) of HIV/HCV were eligible for triple-therapy. Insufficiently controlled HIV infection despite combined antiretroviral therapy (cART) (HIV-RNA <50 copies/mL: 73% vs. 22%; p<0.001) and liver cirrhosis (31% vs. 8%; p=0.025) were overrepresented among patients with contraindications for triple-therapy. Low treatment uptake rates (39% (25/64)) during the first 2 years of triple-therapy availability suggest that its benefit in HIV/HCV co-infected patients might fall short of expectations. Modification of cART or TPV dose adjustment would have been necessary in 61% and 84% of HIV/HCV-GT1 on cART eligible for triple-therapy using TPV and BOC, respectively, suggesting that drug-drug interactions with cART complicate management in the majority of patients. All four BOCW28 patients achieved a sustained virologic response. Prospective studies are necessary to validate our observations on the shortening of treatment duration in HIV/HCV-GT1 with RVR. PMID- 24796758 TI - HIV+ men need reproductive counseling too: Assessing childbearing goals and provider communication among HIV+ male patients in Rio de Janeiro, Brazil. AB - We assessed reported communication with HIV providers about reproductive plans among HIV+ men in Rio de Janeiro, Brazil, and factors associated with having had such communication. A total of N=311 HIV+ men (18-50 years) receiving HIV care at one of six public primary care clinics in Rio de Janeiro between 2008-2009 were surveyed. We used descriptive statistics, and multivariate logistic regression to identify factors associated with communication about childbearing with an HIV provider. HIV+ male patients (mean age=42.7 years, 57% mixed race; 23% bisexual, 51% married/committed partner, 61% with at least one biological child, 77% on ART) reported accepting attitudes of HIV and childbearing (51%), the desire (39%), and/or intention (19%) to have a future child, and reported communication with the HIV provider (14%) or their primary partner (28%) about having children. There were no significant differences between the responses of HIV+ heterosexual and bisexual men on the above outcomes. Men who discussed childbearing with their HIV provider were more likely to have accepting attitudes about HIV and childbearing [AOR 2.8, 95%CI (1.2-6.4), p=0.014], and intend to have a child [AOR 2.6, 95% CI (1.2-5.6), p=0.018], but less likely to have discussed this topic with their partner [AOR 0.32 (0.15-0.68), p=0.003]. Among men reporting communication, 40% (17/42) reported advice against having a child. An unmet need for collaborative, nonjudgmental, and provider-initiated communication about childbearing goals exists for HIV+ men in clinical care. PMID- 24796760 TI - Irrelevant speech does not interfere with serial recall in early blind listeners. AB - Phonological working memory is known be (a) inversely related to the duration of the items to be learned (word-length effect), and (b) impaired by the presence of irrelevant speech-like sounds (irrelevant-speech effect). As it is discussed controversially whether these memory disruptions are subject to attentional control, both effects were studied in sighted participants and in a sample of early blind individuals who are expected to be superior in selectively attending to auditory stimuli. Results show that, while performance depended on word length in both groups, irrelevant speech interfered with recall only in the sighted group, but not in blind participants. This suggests that blind listeners may be able to effectively prevent irrelevant sound from being encoded in the phonological store, presumably due to superior auditory processing. The occurrence of a word-length effect, however, implies that blind and sighted listeners are utilizing the same phonological rehearsal mechanism in order to maintain information in the phonological store. PMID- 24796761 TI - Annulus fibrosus cell characteristics are a potential source of intervertebral disc pathogenesis. AB - In the end stage of intervertebral disc degeneration, cartilage, bone, endothelial cells, and neurons appear in association with the worsening condition. The origin of the abnormal cells is not clear. This study investigated the properties of progenitor cells in the annulus fibrosus (AF) using one in vitro and two in vivo models. Cultivation of rabbit AF cells with chondrogenic media significantly increased expressions of collagen and aggrecan. Upon exposure to osteogenic conditions, the cultures showed increased mineralization and expression of osteopontin, runx2, and bmp2 genes. Two models were used in the in vivo subcutaneous implantation experiments: 1) rabbit AF tissue in a demineralized bone matrix (DBM) cylinder (DBM/AF), and, 2) rat intact and needle punctured lumbar discs. Bone formation in the AF tissue was detected and hypertrophic chondrocytes and osteoblasts were present 1 month after implantation of the DBM/AF to nude mice. In addition to collagen I and II, immunostaining shows collagen X and osteocalcin expression in DBM/AF specimens 4 months after implantation. Similar changes were detected in the injured discs. Almost the entire needle punctured disc had ossified at 6 months. The results suggest that AF cells have characteristics of progenitor cells and, under appropriate stimuli, are capable of differentiating into chondrocytes and osteoblasts in vitro as well as in vivo. Importantly, these cells may be a target for biological treatment of disc degeneration. PMID- 24796762 TI - Preeclampsia is associated with a deficiency of lipoxin A4, an endogenous anti inflammatory mediator. AB - OBJECTIVE: To test whether lipoxin A4 (LXA4) deficiency results in preeclampsia. DESIGN: Prospective experimental study. SETTING: Patient and animal research facilities. ANIMAL(S): Sprague-Dawley rats. INTERVENTION(S): We measured LXA4 and its biosynthetic enzymes, blocked the LXA4 signaling pathway, treated experimental rats with preeclampsia with LXA4, and detected inflammatory factors, FPR2/ALX, and 11beta-HSD2 to systematically test whether lack of LXA4 results in preeclampsia. MAIN OUTCOME MEASURE(S): We measured serum levels of LXA4 and inflammatory factors using enzyme-linked immunosorbent assay; detected LXA4 biosynthetic enzymes, inflammatory factors, FPR2/ALX, and 11beta-HSD2 mRNA expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR; and localized protein expression using immunohistochemistry. RESULT(S): FPR2/ALX and LXA4 and its biosynthetic enzymes were found to be decreased in women with preeclampsia. Replenishing LXA4 improved the symptoms of lipopolysaccharide-induced rats with preeclampsia, while blocking LXA4 signaling resulted in preeclampsia. LXA4 significantly reduced interleukin-6 (IL-6), tumor necrosis factor-alpha, and IFN-gamma but increased IL-10, LXA4 up-regulated 11beta-HSD2. CONCLUSION(S): A deficiency of LXA4 may result in preeclampsia, which might be ascribed to a reduction in inflammation response, oxidative stress, and regulation of 11beta-HSD2. PMID- 24796763 TI - Live birth from a 46-year-old using fresh autologous oocytes through in vitro fertilization. AB - OBJECTIVE: To report a live birth with IVF from a 46-year-old woman using autologous oocytes. DESIGN: Case report. SETTING: Reproductive endocrinology and infertility private practice and ambulatory IVF center. PATIENT(S): One 46-year old nulligravid woman. INTERVENTION(S): IVF with fresh ET. MAIN OUTCOME MEASURE(S): Live birth after IVF. RESULT(S): A 46-year-old with antimullerian hormone (AMH) level less than 0.16 conceived through IVF using autologous oocytes. A total of seven oocytes were retrieved, from which four embryos were transferred at the cleavage stage, resulting in a pregnancy and delivery of a healthy male infant weighing 1,580 g at 31 and 3/7 weeks' estimated gestational age. CONCLUSION(S): The prognosis for a live birth from IVF in a patient with very advanced reproductive age, particularly with an undetectable AMH level using autologous oocytes, remains extremely poor. This case should be interpreted with caution so as to not provide false hope to women aged 45 and above. PMID- 24796764 TI - A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T). AB - OBJECTIVE: To determine the optimal infertility therapy for women at the end of their reproductive potential. DESIGN: Randomized clinical trial. SETTING: Academic medical centers and private infertility center in a state with mandated insurance coverage. PATIENT(S): Couples with >= 6 months of unexplained infertility; female partner aged 38-42 years. INTERVENTION(S): Randomized to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. MAIN OUTCOME MEASURE(S): Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment. RESULT(S): We randomized 154 couples to receive CC/IUI (N = 51), FSH/IUI (N = 52), or immediate IVF (N = 51); 140 (90.9%) couples initiated treatment. The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatments, 110 (71.4%) of 154 couples had conceived a clinically recognized pregnancy, and 46.1% had delivered at least one live-born baby; 84.2% of all live-born infants resulting from treatment were achieved via IVF. There were 36% fewer treatment cycles in the IVF arm compared with either COH/IUI arm, and the couples conceived a pregnancy leading to a live birth after fewer treatment cycles. CONCLUSION(S): A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group. CLINICAL TRIAL REGISTRATION NUMBER: NCT00246506. PMID- 24796765 TI - Common variants in the CYP2C19 gene are associated with susceptibility to endometriosis. AB - OBJECTIVE: To follow-up previous studies highlighting a possible role for cytochrome P450, family 2, subfamily C, 19 (CYP2C19) in susceptibility to endometriosis by searching for additional variants in the CYP2C19 gene that may be associated with the disease. DESIGN: Case-control study. SETTING: Academic research. SUBJECT(S): The cases comprised 2,271 women with surgically confirmed endometriosis; the controls comprised 939 women with self-report of no endometriosis and 1,770 unscreened population samples. INTERVENTION(S): Sequencing of the CYP2C19 region and follow-up of 80 single nucleotide polymorphisms (SNPs) in two case-control samples. MAIN OUTCOME MEASURE(S): Allele frequency differences between cases and controls. RESULT(S): Sequencing of the CYP2C19 gene region resulted in the detection of a large number of known and novel SNPs. Genotyping of 80 polymorphic SNPs in 901 endometriosis cases and 939 controls resulted in study-wide significant association signals for SNPs in moderate or complete linkage disequilibrium with rs4244285, a functional SNP in exon 5 that abrogates CYP2C19 function through the creation of an alternative splice site. Evidence of association was also detected for another functional SNP in the CYP2C19 promoter, rs12248560, which was highlighted in our previous study. CONCLUSION(S): Functional variants in CYP2C19 may contribute to endometriosis susceptibility in both familial and sporadic cases. PMID- 24796766 TI - A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders. AB - OBJECTIVE: To evaluate whether pretreatment dehydroepiandrosterone (DHEA) supplementation improves ovarian response markers, ovarian response to standard low-dose gonadotropin stimulation, and in vitro fertilization (IVF) outcomes in poor responders. DESIGN: Randomized, double-blind, placebo-controlled pilot study. SETTING: Tertiary reproductive medicine unit. PATIENT(S): Thirty-two women with anticipated poor ovarian response. INTERVENTION(S): Randomization into DHEA group (n=16) receiving GNC (25 mg three times a day) or placebo (n=16) starting from at least 12 weeks before the scheduled IVF treatment according to a computer generated randomization list. MAIN OUTCOME MEASURE(S): Measurement of monthly ovarian response markers, including antral follicle count (AFC), serum antimullerian hormone (AMH), and follicle-stimulating hormone (FSH) levels; comparison of ovarian response to a standard dose of gonadotropin stimulation at week 8 and IVF outcomes; and AFC after 12 weeks (primary outcome). RESULT(S): The DHEA supplementation resulted in statistically significantly higher serum DHEA-S, free androgen index, and follicular DHEA-S levels. No statistically significant differences in the ovarian response markers (AFC, AMH, or FSH), the ovarian response to standard-dose gonadotropin stimulation, or IVF outcomes were found between the two groups. CONCLUSION(S): No statistically significant improvement in ovarian response markers, ovarian response to standard dose gonadotropin stimulation, or IVF outcomes was found in poor responders receiving pretreatment DHEA. CLINICAL TRIAL REGISTRATION NUMBER: HKCTR-1149 (www.hkclinicaltrials.com) and NCT01915186 (www.ClinicalTrials.org). PMID- 24796767 TI - Is it possible to change phenotype progression in Crohn's disease in the era of immunomodulators? Predictive factors of phenotype progression. AB - OBJECTIVES: Crohn's disease (CD) induces cumulative structural damage, initially characterized by a non-stenosing non-penetrating behavior (B1) with progression over time to a fibro-stenosing (B2) and/or penetrating phenotype (B3). Our aim was to assess the long-term evolution of disease behavior of CD and determine what factors predict phenotype progression. METHODS: This was a study based on prospectively collected data from a CD database in an inflammatory bowel disease outpatient clinic. B1 corresponds to a non-stenosing non-penetrating disease, B2 to a stenosing behavior, and B3 to a penetrating one. RESULTS: Seven hundred and thirty-six patients with CD (368 female) were followed up for 12.3 years (+/- 8.4), with 87.0% of them exhibiting B1 phenotype at diagnosis. Of these patients, 28.5% progressed to B2 phenotype and 23.5% to B3. Fifty percent of the patients started azathioprine treatment before phenotype change and 13.9% started anti tumor necrosis factor-alpha (anti-TNFalpha) treatment before phenotype change. Monotherapy with azathioprine before phenotype change as well as combination therapy with azathioprine/anti-TNFalpha before phenotype change delayed disease progression (B1-B2 or B3) in comparison with patients who did not receive treatment (P<0.001). The hazard ratio (HR) for disease progression was lower for both monotherapy with azathioprine (HR: 0.15, P<0.001) or combination therapy with anti-TNFalpha (HR: 0.33, P<0.001). Upper gastrointestinal tract involvement, male gender, and steroid use were associated with an early progression of phenotype from B1 to B2 or B3 (P<0.001). The HR for disease progression was higher in patients who used steroids without criteria of dependence or resistance (HR: 2.67, P<0.001) and was even higher in patients with criteria of dependence or resistance (HR: 6.44, P<0.001). Longer delays between CD diagnosis and beginning of therapy with azathioprine and/or anti-TNFalpha were associated with disease progression. The longer the duration of treatment, the less likely the disease progression. CONCLUSIONS: Monotherapy with azathioprine before behavior change as well as combination therapy with azathioprine and anti-TNFalpha before behavior change delays phenotype progression of CD, whereas upper gastrointestinal tract involvement, male gender, and steroid use with or without criteria of steroid dependence are associated with a higher risk for disease progression. PMID- 24796768 TI - First multicenter study of modified release phosphatidylcholine "LT-02" in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine refractory courses. AB - OBJECTIVES: Phosphatidylcholine is a key component of the mucosal barrier. Treatment with modified release phosphatidylcholine aims to improve the impaired barrier function. The primary objective is to evaluate the efficacy of LT-02, a newly designed modified release phosphatidylcholine formula, in a multicenter setting. METHODS: This is a double-blinded, randomized, placebo-controlled, superiority study conducted in 24 ambulatory referral centers in Germany, Lithuania, and Romania. A total of 156 patients with an inadequate response to mesalazine, a disease activity score (Simple Clinical Colitis Activity Index (SCCAI)) of >= 5, and bloody diarrhea underwent treatment with 0, 0.8, 1.6, or 3.2 g LT-02. The primary end point was defined a priori as changes in SCCAI from baseline to the end of treatment. The primary statistical model was a general linear least-squares model. The study was funded by the sponsor Lipid Therapeutics, Heidelberg, Germany, and registered at http://clinicaltrials.gov/show/NCT01011322. RESULTS: Baseline characteristics and dropouts were well balanced between all groups. The primary analyses revealed an SCCAI drop of 33.3% in the placebo group (from 9.0 to 6.0 points) compared with 44.3% in the 0.8 g LT-02 (from 8.8 to 4.9, P>0.05) and 40.7% in the 1.6 g groups (from 8.6 to 5.1, P>0.05). The 3.2 g group improved 51.7% from 8.5 to 4.1 (P=0.030 in comparison with placebo). The remission rate was 15% (6/40) in the placebo group compared with 31.4% (11/35) in the highest LT-02 dose group (P=0.089). Mucosal healing was achieved in 32.5% of placebo patients compared with 47.4% of LT-02 patients (P=0.098); the rates for histologic remission were 20% compared with 40.5%, respectively (P=0.016). There were 17 (48.6%) treatment emergent adverse events in the highest dose group (and 0 serious adverse events (SAEs)) compared with 22 (55%) in the placebo group (4 SAEs). CONCLUSIONS: The primary end point analysis showed a statistically significant improvement in disease activity during LT-02 treatment in comparison with placebo. The drug was found to be very safe. PMID- 24796769 TI - Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn's disease: post hoc analysis of a randomized controlled trial. AB - OBJECTIVES: Cost-effective guidance of therapeutic strategy in Crohn's disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by radioimmunoassay (RIA). This study investigated implications of using other techniques for this purpose. METHODS: This is a post hoc analysis of randomized clinical trial including 66 Crohn's disease patients with IFX failure in whom IFX and anti-IFX Ab measurements by RIA had been used for therapeutic guidance. Samples were additionally assessed by enzyme-linked immunosorbent assay (ELISA), homogeneous mobility shift assay (HMSA), and functional cell-based reporter gene assay (RGA). RESULTS: IFX detection was comparable between assays (82% RIA, 76% ELISA, 88% HMSA, and 74% RGA), and it correlated significantly (Pearson's r=0.91-0.97, P<0.0001). However, IFX concentrations varied systematically between all pair of assays except RIA-RGA. Anti-IFX Ab detection was variable (27% RIA, 9% ELISA, 33% HMSA, and 11% RGA), but correlated significantly (Pearson's r=0.77-0.96; P<0.0001). Anti-IFX Abs detected by RIA and HMSA were often from sera without drug-neutralizing activity (RGA). Assays agreed on classification of underlying mechanism for treatment failure in most cases (79-94%). The majority (74-88%) failed IFX owing to pharmacodynamic problems, or had noninflammatory pathophysiology for symptoms resembling relapse. Applied threshold for therapeutic vs. subtherapeutic IFX level influenced classifications. The four different assays did not differ in terms of the ability to predict response to interventions defined by the algorithm. CONCLUSIONS: Despite variable analytical properties, common assays result in similar classifications and interventions in patients with IFX treatment failure, and with comparable clinical outcomes. Implications are, however, profound for the minority classified differently. PMID- 24796770 TI - Long-term progression of retinal vasculitis in Behcet patients using a fluorescein angiography scoring system. AB - BACKGROUND: To evaluate the long-time progression of retinal vasculitis in Behcet patients using the fluorescein angiography (FA) scoring system. METHODS: Retrospective study was conducted for 71 eyes of 43 patients who met the study criteria. All patients completed at least 2 years of follow-up. FA was taken during the periods of active retinal vasculitis and the quiescent phase, and analyzed using a FA scoring system. Among nine categories, the four most prevalent FA signs were evaluated: optic disc hyperfluorescence (score 0-3), macular edema (score 0-4), retinal vascular staining and/or leakage (score 0-7), and capillary leakage (score 0-10). RESULTS: Mean number of total active inflammations was 2.6 +/- 1.5 times during mean 55.0 +/- 20.0 months. Mean scores at the first active inflammation were 1.8 +/- 1.0 for optic disc hyperfluorescence, 2.4 +/- 1.0 for macular edema, 5.3 +/- 2.1 for retinal vascular staining and/or leakage, and 5.8 +/- 3.2 for capillary leakage. Mean total FA score was 17.4 +/- 6.8. Mean scores at the first quiescent phase were 0.6 +/- 0.4 for optic disc hyperfluorescence, 1.1 +/- 1.2 for macular edema, 3.8 +/- 1.9 for retinal vascular staining and/or leakage, and 3.5 +/- 3.5 for capillary leakage. Mean total FA score was 9.1 +/- 5.0. Mean scores for each active inflammation and quiescent phase were not significantly changed, and mean FA scores were significantly reduced in quiescent phase (P = 0.003 for optic disc hyperfluorescence, P = 0.005 for macular leakage, P = 0.010 for retinal vascular staining and/or leakage, P = 0.008 for capillary leakage, and P = 0.018 for total FA score; paired t-test). CONCLUSIONS: Retinal vasculitis of Behcet patients did not significantly progress during long-term follow-up. PMID- 24796771 TI - Partial lamellar keratoplasty for peripheral corneal disease using a graft from the glycerin-preserved corneoscleral rim. AB - BACKGROUND: To evaluate the feasibility of partial lamellar keratoplasty (LK) for treatment of peripheral corneal disease (PCD) using a graft from the corneoscleral rim preserved in glycerin. METHODS: Patients who underwent LK for PCD at Shandong Eye Hospital from January 2006 to December 2012 were included. Corneoscleral rims of donor grafts, out of which the corneal buttons had been punched and used for penetrating keratoplasty, were preserved in glycerin and used for LK procedures. A trephine of 7.5-8.0 mm was used to mark the central cornea. An excision was made according to the size of the lesions, after which a partial ring-shaped corneoscleral graft was transplanted to repair the peripheral cornea. Visual acuity, refractive astigmatism, and complications were monitored. RESULTS: There were 26 patients (28 eyes), including 15 patients with Terrien's marginal degeneration, eight with Mooren's ulcer, two with Wegener's granulomatosis, and one with peripheral corneal ulcer. The mean follow-up was 15 months (range, 6-36 months). Uncorrected visual acuity was improved by a mean of 3.17 Snellen chart lines (P = 0.010), and best spectacle-corrected visual acuity was improved by a mean of 0.85 Snellen chart lines (P = 0.045) at 6 months after surgery. The refractive astigmatism decreased by 5.1 +/- 8.6 diopters (P = 0.003). Two patients suffering graft ulcers (recurrence) were successfully treated by a second partial LK. No graft rejection occurred. CONCLUSIONS: Partial LK using a graft from the corneoscleral rim appears to be effective in the treatment of patients with PCD. This approach saves the donor graft, which is important in the countries or regions with scarcity of donor tissue. PMID- 24796772 TI - English sentence optotypes for measuring reading acuity and speed--the English version of the Radner Reading Charts. AB - PURPOSE: To develop 28 short sentence optotypes for the English version of the Radner Reading Charts that are as comparable as possible in number and length of words, as well as in difficulty and syntactical construction. METHODS: Thirty four English sentences were constructed following the method used for other Radner Reading Charts to obtain "sentence optotypes" with comparable structure and the same lexical and grammatical difficulty. Best comparable sentences were statistically selected and standardized in 50 volunteers. Reading speed and the number of errors were determined. Validity was analyzed with a 124-word long 4th grade paragraph of the Florida Comprehensive Assessment Test(r). Computerized measurements of reading parameters were performed with the RADNER Reading Device (RAD-RD(c); in conjunction with a PC and microphone). RESULTS: The mean reading speed obtained with the 28 selected short sentences was 201.53 +/- 35.88 words per minute (wpm), as compared to 215.01 +/- 30.37 wpm for the long paragraph. The mean reading times were 4.30 +/- 0.79 s and 35.26 +/- 4.85 s, respectively. The mean number of reading errors was 0.11 +/- 0.34. The correlation between the short sentences and the long paragraph was high (r = 0.76; p < 0.05; n = 50). Reliability analyses yielded an overall Cronbach's alpha coefficient of 0.9743. CONCLUSION: The present study indicates that the 28 selected English sentence optotypes are comparable in terms of both lexical difficulty as well as in reading length, and it demonstrates the validity and reliability of such sentences as test items for determining reading parameters such as reading acuity and speed. PMID- 24796773 TI - Series of lead oxide hydroxide nitrates obtained by adjusting the pH values of the reaction systems. AB - A series of lead(II) nitrates have been synthesized by a hydrothermal method and adjusting the pH values of the reaction systems. Pb20O6(OH)16(NO3)12 and Pb2O(OH)NO3, crystallize in the centrosymmetric space group P1 and Pbca, respectively. The structure of Pb20O6(OH)16(NO3)12 features infinite cationic chains of [Pb20O6(OH)16]infinity running along c axis, and the nitrate groups as the counterions reside between adjacent chains, while the structure of Pb2O(OH)NO3 can be described as alternate stacking of cationic [Pb2O(OH)]infinity layers with anionic [NO3](-) layers along [001] direction by the weak Pb-O bonds, forming a 3D framework with 1D tunnels of 12-member rings (MRs). [Pb4(OH)4](NO3)4, crystallizing in the noncentrosymmetric space group Cc, has been studied as the nonlinear optical material for the first time. The second harmonic generation (SHG) measurement indicates that the SHG responses of [Pb4(OH)4](NO3)4 are 0.7 times that of KDP. Theoretical calculations confirmed the SHG efficiency of [Pb4(OH)4](NO3)4 originates from the cooperative effect of NO3(-) groups and lead oxygen polyhedras in the structure. Meanwhile, the relationship between pH value and ratio of Pb/OH(-) in the molecules presents a positive correlation, which results in the diversity of these structures under different pH value. PMID- 24796774 TI - Chemotherapy-induced polyneuropathy: major agents and assessment by questionnaires. AB - Chemotherapy-induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. Therefore, the aim of this MiniReview was to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant differences between the neuropathic pain scales, which are most commonly used for assessing CIPN. PMID- 24796776 TI - [Editor's commentary. Clinical registries are needed!]. PMID- 24796775 TI - Processing anomalous anaphors. AB - Previous researchers have demonstrated that readers may engage in shallow, or incomplete, processing when the semantic overlap between current information and previously encountered information is high. The present study investigated whether these effects would occur during processing of unambiguous noun phrase anaphors, for which there was only a single possible antecedent. Participants read passages containing anaphors that were correct, incorrect but highly related, or incorrect and low-related, with respect to previously encountered information. The time required to process the anaphor was a function of the goodness of fit between the anaphor and the antecedent; anaphors that were incorrect but highly related to the antecedent were processed more quickly than those that were incorrect and low-related. This occurred regardless of the distance between the anaphor and the antecedent. However, reading times results from a spillover sentence indicated that readers subsequently validated the anaphor against the information in memory, resulting in continued processing difficulty for both the incorrect-high- and -low-related anaphor conditions. The results are consistent with a three-stage comprehension model in which information is activated, integrated on the basis of its goodness of fit with the contents of working memory, and then validated against information in long-term memory. PMID- 24796777 TI - [Patient registries from the view of health policy]. AB - Integrated health data management and disease registries which are able to support evidence-based decision making are of critical importance for health policy. Data provided by disease registries are used for the development of health strategy, planning of preventive activities, capacity-building in health care provision, improving health care quality, and planning clinical trials. Disease registries monitoring epidemiology, natural history of diseases, treatment outcomes and the detection of adverse reactions are requested not only by policy-makers, but public health authorities and health care providers, too. Registries for rare diseases are of critical importance for developing network between reference centres and developing and evaluating new drugs. Data and information need for decision-making in public services and the protection of health data of individuals require a careful balance that needs to be taken into account when considering disease registries. PMID- 24796778 TI - [Importance of the National Childhood Cancer Registry in the field of paediatric oncology care in Hungary]. AB - National Childhood Cancer Registry has been operated since 1971 by the Hungarian Paediatric Oncology Network. This Registry collects data on epidemiology, treatment modalities and effectiveness, as well as late follow-up of childhood cancers. An internet-based paediatric cancer registration and communication system for the Hungarian Paediatric Oncology Network has been introduced in April, 2010. The National Childhood Cancer Registry contains data of all paediatric cancer patients (0-18 yrs) who have insurance covered by the Hungarian Social Security Card. Creation (1971) and operation of the National Childhood Cancer Registry have been very important steps in the field of childhood oncology to evaluate the efficiency of paediatric oncology treatments as well as maximize return on medical investment. PMID- 24796779 TI - [National Myocardial Infarction Registry of Hungary]. AB - The authors delineate the circumstances of the creation of the National Myocardial Infarction Registry program. This web-based program started in January 1, 2010 as a "pilot" study with the voluntary participation of 12 centres. As a result of professional consensus, the number of participating institutions has continuously increased and, since March 1, 2013, data supply has become obligatory for hospitals treating patients with myocardial infarction. In December, 2013 a new modification of certain health and health insurance related acts such as Act XLVII/1997 regulated the operation of National Myocardial Infraction Registry. At present 65 institutions provide data regularly. The number of patients with myocardial infarction in the database was 24308 in January 1, 2014. The authors summarize the data which accumulated during almost four years of functioning of the National Myocardial Infarction Registry Program. The incidence of myocardial infarction was defined by reviewing the number of pre hospital and hospital cases in five districts of the capital and Szabolcs-Szatmar Bereg County of Hungary. Reviewing the records patients with ST-elevation and non ST-elevation myocardial infarction revealed that treatment of 91% of ST-elevation patients occurred in hospitals with cardiac catheterization laboratory, and 82% of patients had primary percutaneous coronary intervention. In-hospital, 30-day and 1-year mortality were defined for patients treated for both types of myocardial infarction. Based on national and international experience, the authors emphasize that professional characteristics of patient care can only be assessed using specific patient registries and these data are essential in the development of an efficient health-care system. PMID- 24796780 TI - [Primary Spinal Tumor Registry at the National Centre for Spinal Disorders]. AB - Primary spinal tumors are rare diseases. Primary spinal tumor registry would be useful to help decision making in this complex field of spine surgery. In this article the authors present the latest findings from the Primary Spinal Tumor Registry at the National Centre for Spinal Disorders, Hungary. The registry is based on a novel database management software, the REDCap electronic data capture system. It contains data of 323 patients treated surgically during an 18-year period. Among the 126 malignant tumors, the most frequent was chordoma (61 cases). In the case of benign tumors schwannoma showed the largest prevalence (45 cases). The authors conclude that due to the rarity of the disease and the complexity of the management, multicenter, prospective registries are required to provide high level of evidence. The structure of the Primary Spinal Tumor Registry in the National Centre for Spinal Disorders in Hungary is optimal for user-friendly, fast and secure data collection providing a prospective database for scientific researches and clinical follow-up. PMID- 24796781 TI - [Past, present, future and benefits of "Tauffer", the Hungarian obstetric registry]. AB - Since more than 80 years, the Hungarian obstetric database, called Tauffer registry, shows the evolution as well as professional and organizational issues of the Hungarian obstetrics. The system, renewed in 1994, provides detailed on line information about obstetric events in the website owned by the National Institute for Quality and Organizational Development in Healthcare and Medicines. Although a significant overlap between Tauffer registry and other databases exists, these databases improve the efficacy of Tauffer registry and they provide additional information on obstetric events. Tauffer registry is publicly available for anyone and its data can be used by professionals and professional managers. The author presents 3 examples to demonstrate the practical use of professional indicators obtained from Tauffer registry. PMID- 24796782 TI - [Establishment and functioning of the Vascular Registry in Hungary]. AB - Randomized controlled trials provide the best evidence in clinical trials; however, they do have limitations. In order to evaluate the effectiveness of treatments, population based registries may also yield useful information about the actual practice and they may enable users to carry out a dynamic follow-up. To evaluate the outcome of vascular procedures, the Vascular Registry in Hungary has been established in 2002. This article presents the establishment and functioning of the Vascular Registry and provides information about scientific results obtained during the past years. The Vascular Registry is an internet based database with on-line input. The backup server is provided by the National Institute for Quality and Organizational Development in Healthcare and Medicines. The database collects data in three different fields: interventions for carotid artery, aneurysm (any type) and lower extremity vascular diseases. Twenty five vascular surgical units record interventions in the registry, which corresponds to two thirds of the whole activity. Since joining the Vascunet Group of the European Society for Vascular Surgery, the registry has contributed to several publications based on evaluation of a large common dataset in different fields of vascular surgery. A validation process has been recently performed which confirmed the internal and external validity of the database. The authors conclude that despite unsolved problems related to financing issues, the Vascular Registry has proved to be a useful tool during the past years. In order to take advantage of the registry to its fullest, measures should be taken to achieve a more complete data recording, increase publication activity on the national dataset, improve the flow of information during operation and develop a system of regular feedback. PMID- 24796783 TI - [Hungarian Arthroplasty Registry]. AB - The authors present the internet based Hungarian Arthroplasty Registry that was introduced in 2007. All departments involved in prosthesis implantation in Hungary have already registered and, therefore, data entry is available. However, data entry is far from 100 percent. The fully completed registry would be very important in order to be recognised at international forums. Until now 51 387 cases have been entered into the database. The datasheets can be saved after completion, the data and the correlations can be analysed and graphically displayed. This is a good tool to have data on prosthesis survival, surgical interventions and complications. PMID- 24796784 TI - [Hungarian Hypertension Registry]. AB - Today, hypertension is considered endemic throughout the world. The number of individuals with high blood pressure and the increasing risk, morbidity and mortality caused by hypertension despite modern therapy do not decrease sufficiently. Hypertension has become a public health issue. Prevention and effective care require integrated datasets about many features, clinical presentation and therapy of patients with hypertension. The lack of this database in Hungary prompted the development of the registry which could help to provide population-based data for analysis. Data collection and processing was initiated by the Hungarian Society of Hypertension in 2002. Data recording into the Hungarian Hypertension Registry was performed four times (2002, 2005, 2007, 2011) and the registry currently contains data obtained from 108,473 patients. Analysis of these data indicates that 80% of the patients belong to the high or very high cardiovascular risk group. The registry provides data on cardiovascular risk of the hypertensive populations and the effectiveness of antihypertensive therapy in Hungary. Based on international experience and preliminary analysis of data from the Hungarian Hypertension Registry, establishment of hypertension registry may support the effectiveness of public health programs. A further step would be needed for proper data management control and the application of professional principles of evidence-based guidelines in the everyday practice. PMID- 24796785 TI - Effect of low-magnitude whole-body vibration combined with alendronate in ovariectomized rats: a random controlled osteoporosis prevention study. AB - BACKGROUND: Alendronate (ALE) is a conventional drug used to treat osteoporosis. Low-magnitude whole-body vibration (WBV) exercise has been developed as a potential treatment for osteoporosis. The aim of this study was to investigate whether low-magnitude WBV could enhance the protective effect of ALE on bone properties in ovariectomized rats. METHODS: A total of 128 Sprague-Dawley rats were randomly divided into five groups (SHAM, OVX+VEH, OVX+WBV, OVX + ALE, OVX+WBV+ALE). The level of WBV applied was 0.3 g at 45-55 Hz for 20 min/day, 5 day/week and for 3 months. ALE was administered in dose of 1 mg/Kg once a week. Every four weeks eight rats from each group were sacrificed and their blood and both tibiae were harvested. The expression of osteocalcin and CTX in serum was measured by enzyme-linked immunosorbent assay (ELISA) and the tibiae were subjected to metaphyseal three-point bending and MUCT analysis. RESULTS: Osteocalcin rose after ovariectomy and was not appreciably changed by either alendronate or WBV alone or in combination. Alendronate treatment significantly prevented an increase in CTX. WBV alone treatment did not alter this effect. Compared with the OVX+WBV group, nearly all tested indices such as the BV/TV, TV apparent, Tb.N, Tb.Th, and Conn.D were higher in the OVX+ALE group at week 12.Compared with the OVX+WBV group, certain tested indices such as BV/TV, TV apparent, Tb.N, and Con.D, were higher in the OVX+WBV+ALE group at week 12. At week 12, tibiae treated with WBV+ALE exhibited a significantly higher Fmax compared to the OVX+VEH group, and a significant difference was also found in energy absorption between the OVX+WBV+ALE and OVX+VEH groups. CONCLUSIONS: Compared with the WBV, ALE was more effective at preventing bone loss and improved the trabecular architecture. However, WBV enhanced the effect of alendronate in ovariectomized rats by inducing further improvements in trabecular architecture. PMID- 24796786 TI - Glucose controls morphodynamics of LPS-stimulated macrophages. AB - Macrophages constantly undergo morphological changes when quiescently surveying the tissue milieu for signs of microbial infection or damage, or after activation when they are phagocytosing cellular debris or foreign material. These morphofunctional alterations require active actin cytoskeleton remodeling and metabolic adaptation. Here we analyzed RAW 264.7 and Maf-DKO macrophages as models to study whether there is a specific association between aspects of carbohydrate metabolism and actin-based processes in LPS-stimulated macrophages. We demonstrate that the capacity to undergo LPS-induced cell shape changes and to phagocytose complement-opsonized zymosan (COZ) particles does not depend on oxidative phosphorylation activity but is fueled by glycolysis. Different macrophage activities like spreading, formation of cell protrusions, as well as phagocytosis of COZ, were thereby strongly reliant on the presence of low levels of extracellular glucose. Since global ATP production was not affected by rewiring of glucose catabolism and inhibition of glycolysis by 2-deoxy-D-glucose and glucose deprivation had differential effects, our observations suggest a non metabolic role for glucose in actin cytoskeletal remodeling in macrophages, e.g. via posttranslational modification of receptors or signaling molecules, or other effects on the machinery that drives actin cytoskeletal changes. Our findings impute a decisive role for the nutrient state of the tissue microenvironment in macrophage morphodynamics. PMID- 24796787 TI - Losartan improved antioxidant defense, renal function and structure of postischemic hypertensive kidney. AB - Ischemic acute renal failure (ARF) is a highly complex disorder involving renal vasoconstriction, filtration failure, tubular obstruction, tubular backleak and generation of reactive oxygen species. Due to this complexity, the aim of our study was to explore effects of Angiotensin II type 1 receptor (AT1R) blockade on kidney structure and function, as well as oxidative stress in spontaneously hypertensive rats (SHR) after renal ischemia reperfusion injury. Experiments were performed on anaesthetized adult male SHR in the model of ARF with 40 minutes clamping the left renal artery. The right kidney was removed and 40 minutes renal ischemia was performed. Experimental groups received AT1R antagonist (Losartan) or vehicle (saline) in the femoral vein 5 minutes before, during and 175 minutes after the period of ischemia. Biochemical parameters were measured and kidney specimens were collected 24 h after reperfusion. ARF significantly decreased creatinine and urea clearance, increased LDL and lipid peroxidation in plasma. Treatment with losartan induced a significant increase of creatinine and urea clearance, as well as HDL. Lipid peroxidation in plasma was decreased and catalase enzyme activity in erythrocytes was increased after losartan treatment. Losartan reduced cortico-medullary necrosis and tubular dilatation in the kidney. High expression of pro-apoptotic Bax protein in the injured kidney was downregulated after losartan treatment. Our results reveal that angiotensin II (via AT1R) mediates the most postischemic injuries in hypertensive kidney through oxidative stress enhancement. Therefore, blockade of AT1R may have beneficial effects in hypertensive patients who have developed ARF. PMID- 24796788 TI - Alterations in regulatory T cell subpopulations seen in preterm infants. AB - Regulatory T cells are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens. The purpose of this study was to measure the percentages of two different regulatory T cells subpopulations, identified by the presence or absence of CD31 (Recent thymic emigrants and peripherally induced naive regulatory T cells), in term and preterm infant cord blood. We report the association of prenatal factors, intrauterine exposure to lipopolysaccharide and inflammation and the percentages of these regulatory T cell subpopulations in term and preterm infants. Cord blood samples were collected from both term and preterm infants and mononuclear cells isolated over a Ficoll-Hypaque cushion. Cells were then stained with fluorochrome-labeled antibodies to characterize regulatory T cell populations and analyzed with multi color flow cytometry. Cord blood plasma C-reactive protein, and lipopolysaccharide were also measured. Placental pathology was also examined. We report a gestational age-dependent difference in the percentage of total regulatory T cells, in which preterm infants of lower gestational ages have an increased percentage of regulatory T cells. We report the presence of two populations of regulatory T cells (CD31+ and CD31-) in cord blood of term and preterm infants and their association with different maternal and fetal characteristics. Factors associated with differences in the percentage of CD31- Tregs included the use of prenatal antibiotics, steroids and magnesium sulfate. In addition, the percentage of CD31- Tregs was significantly higher in cord blood of preterm pregnancies associated with inflammation and prenatal lipopolysaccharide exposure. The peripheral Treg pool of preterm infants could be altered by prenatal exposure to inflammation and chorioamnionitis; however, the clinical implications of this finding are not yet understood. PMID- 24796790 TI - Human S100A9 potentiates IL-8 production in response to GM-CSF or fMLP via activation of a different set of transcription factors in neutrophils. AB - Inflammation is highly regulated by various agents. Unexpectedly, we report here that the damage-associated molecular pattern S100A9 protein, a potent neutrophil activator and inducer of cytokine production in monocytes, is not a direct activator of cytokine production in human neutrophils. However, S100A9 primed IL 8 production in fMLP- and GM-CSF-stimulated neutrophiles via NF-kappaB and CREB 1, and NF-kappaB, STAT3 and STAT5, respectively. Pharmacological inhibition confirmed the importance of these transcription factors by significantly decreasing IL-8 production. This is the first time that a different set of transcription factors are shown to be involved in S100A9-primed neutrophils in response to proinflammatory agonist. PMID- 24796789 TI - Alterations in connexin 43 during diabetic cardiomyopathy: competition of tyrosine nitration versus phosphorylation. AB - BACKGROUND: Cardiac conduction abnormalities are observed early in the progression of type 1 diabetes (T1D), but the mechanism(s) involved are undefined. Connexin 43, a critical component of ventricular gap junctions, depends on tyrosine phosphorylation status to modulate channel conductance; changes in connexin 43 content, distribution, and/or phosphorylation status may be involved in cardiac rhythm disturbances. We tested the hypothesis that cardiac content and/or distribution of connexin 43 is altered in a rat model of T1D cardiomyopathy, investigating a mechanistic role for tyrosine. METHODS: Electrocardiographic analyses were conducted during the progression of diabetic cardiomyopathy in rats dosed with streptozotocin (STZ; 65 mg/kg) 3, 7, and 35 days after the induction of diabetes. Following functional analyses, we conducted immunohistochemical and immunoprecipitation studies to assess alterations in connexin 43. RESULTS: There was significant evidence of ventricular conduction abnormalities (QRS complex, Q-T interval) as early as 7 days after STZ, persisting throughout the study. Connexin 43 levels were increased 7 days after STZ and remained elevated throughout the study. Connexin 40 content was unchanged relative to controls throughout the study. Changes in connexin 43 distribution were also observed: connexin 43 staining was dispersed from myocyte short axis junctions. Connexin 43 tyrosine phosphorylation declined during the progression of diabetes, with concurrent increases in tyrosine nitration. CONCLUSIONS: The data suggest that changes in connexin 43 content and distribution occur during experimental diabetes and likely contribute to alterations in cardiac function, and that oxidative modification of tyrosine-mediated signaling may play a mechanistic role. PMID- 24796791 TI - Identification of a novel insect neuropeptide, CNMa and its receptor. AB - To identify ligands for orphan GPCRs, we searched novel neuropeptide genes in the Drosophila melanogaster genome. Here, we describe CNMa, a novel cyclic neuropeptide that is a highly potent and selective agonist for the orphan GPCR, CG33696 (CNMaR). Phylogenetic analysis revealed that arthropod species have two paralogous CNMaRs, but many taxa retain only one. Drosophila CNMa potently activates CNMaR-2 from Apis mellifera, suggesting both receptors are functional. Although CNMa is conserved in most arthropods, Lepidoptera lack the CNMa gene. However, they retain the CNMaR gene. Bombyx CNMaR showed low sensitivity to Drosophila CNMa, hinting toward the existence of additional CNMaR ligand(s). PMID- 24796792 TI - Using avian surveillance in Ecuador to assess the imminence of West Nile virus incursion to Galapagos. AB - Infectious disease emergence represents a global threat to human, agricultural animal and wildlife health. West Nile virus (WNV) first emerged in the Americas in 1999 following its introduction to New York from the Old World. This flavivirus rapidly spread across much of North America, causing human, equine and avian mortalities and population declines of multiple wild bird species. It has now spread to Central and South America, and there is concern that the virus will reach the Galapagos Islands, a UNESCO World Heritage Site famous for its unique biodiversity, with potentially catastrophic results. Here, we use wild bird surveillance to examine the current WNV status in the Galapagos Islands and around the Ecuadorian city of Guayaquil (the main air and sea port serving Galapagos). We conducted serosurveys of wild birds on three Galapagos Islands (Baltra, San Cristobal and Santa Cruz) with direct transport links to the South American continent. In addition, dead birds killed by car collisions on Santa Cruz were tested for WNV infection. On mainland Ecuador, serosurveys of wild birds were conducted at three sites around Guayaquil. No evidence of WNV seropositivity or infection was detected. Although wider testing is recommended on the mainland, the study highlights a limit of WNV spread within South America. Our results indicate the continued absence of WNV on Galapagos and suggest the current likelihood of human-mediated transport of WNV to Galapagos to be low. The risk of emergence will almost certainly increase over time, however, and stringent biosecurity and surveillance measures should be put in place to minimise the risk of the introduction of WNV (and other alien pathogens) to Galapagos. PMID- 24796793 TI - Cognitive-behavioral screening in elderly patients with new-onset epilepsy before treatment. AB - OBJECTIVES: Cognitive comorbidity at epilepsy onset reflects disease severity and provides a baseline estimate of reserve capacities with regard to the effects of epilepsy and its treatment. Given the high incidence of epilepsy at an older age, this study analyzed objective and subjective cognition as well as quality of life in elderly patients with new-onset focal epilepsy before initiation of anti epileptic treatment. MATERIALS AND METHODS: A total of 257 untreated patients (60 95 years of age) with new-onset epilepsy underwent objective assessment of executive function (EpiTrack) and performed subjective ratings of cognition (Portland Neurotoxicity Scale) and quality of life (QoL; QOLIE-31). RESULTS: According to age-corrected norms, 58% of patients (N=257) demonstrated deficits in executive function; major determinants were cerebrovascular etiology, neurological comorbidity, and higher body mass index. Subjective ratings indicated deficits in up to 27% of patients. Self-perceived deficits were associated with neurological, cardiovascular, and/or psychiatric comorbidity, whereas poorer QoL was related to neurological comorbidity and female gender. Objectively assessed executive functions correlated with subjective social functioning, energy, motor function, and vigilance. CONCLUSIONS: We found a relatively high QoL, a low rate of subjective impairment, but a high incidence of objective executive deficits in untreated elderly patients with new-onset epilepsy. Neurological status and body mass index, rather than seizure frequency or severity, were risk factors for cognitive impairment. Given the relevance of cognition in the course of epilepsy and its treatment, routine screening before treatment initiation is highly recommended. PMID- 24796794 TI - 19F NMR spectroscopy monitors ligand binding to recombinantly fluorine-labelled b'x from human protein disulphide isomerase (hPDI). AB - We report a protein-observe (19)F NMR-based ligand titration binding study of human PDI b'x with Delta-somatostatin that also emphasises the need to optimise recombinant protein fluorination when using 5- or 6-fluoroindole. This study highlights a recombinant preference for 5-fluoroindole over 6-fluoroindole; most likely due to the influence of fluorine atomic packing within the folded protein structure. Fluorination affords a single (19)F resonance probe to follow displacement of the protein x-linker as ligand is titrated and provides a dissociation constant of 23 +/- 4 MUM. PMID- 24796795 TI - Division of the stapedial tendon results in noise-induced damage to the inner ear. AB - BACKGROUND: The effect of division of the stapedial tendon on susceptibility to noise-induced inner ear damage has not been previously studied. This study aimed to evaluate the effects of noise exposure following division of the stapedial tendon in guinea pigs. MATERIAL AND METHODS: Ten adult albino guinea pigs were used. The stapedial tendon of each right ear was cut. The stapedial tendon in each left ear was left intact and these ears served as a control group. DPOAEs and ABR tests were performed before and 10 days after noise exposure. The animals were exposed to a 110-dB noise stimulus for 6 h in a silent room a week after surgery. Cochleas of the animals were removed, and inner and outer hair cells were examined under a light microscope. RESULTS: We found that noise exposure adversely affected DPOAE measurements at all frequencies except 2 KHz in experimental ears. Noise exposure also produced significantly elevated ABR thresholds in experimental ears at 2, 4, 8, and 16 KHz. On histopathological examination, we found a significantly greater prevalence of apoptotic cells in the experimental ears. CONCLUSIONS: Based on these findings, we can conclude that after division of the stapedial tendon, noise exposure may cause damage to the inner ear. This is the first study in the English literature that demonstrates the potential protective effect of the stapedial tendon against acoustic damage. PMID- 24796796 TI - Modularized construction of general integrated circuits on individual carbon nanotubes. AB - While constructing general integrated circuits (ICs) with field-effect transistors (FETs) built on individual CNTs is among few viable ways to build ICs with small dimension and high performance that can be compared with that of state of-the-art Si based ICs, this has not been demonstrated owing to the absence of valid and well-tolerant fabrication method. Here we demonstrate a modularized method for constructing general ICs on individual CNTs with different electric properties. A pass-transistor-logic style 8-transistor (8-T) unit is built, demonstrated as a multifunctional function generator with good tolerance to inhomogeneity in the CNTs used and used as a building block for constructing general ICs. As an example, an 8-bits BUS system that is widely used to transfer data between different systems in a computer is constructed. This is the most complicated IC fabricated on individual CNTs to date, containing 46 FETs built on six individual semiconducting CNTs. The 8-T unit provides a good basis for constructing complex ICs to explore the potential and limits of CNT ICs given the current imperfection in available CNT materials and may also be developed into a universal and efficient way for constructing general ICs on ideal CNT materials in the future. PMID- 24796797 TI - Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes. AB - Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFkappaB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose- and time-dependent fashion. Inhibition of this IL-8 production was also observed at the transcriptional level. In addition, 17-DMAG treatment blunted BP IgG-mediated upregulation of NFkappaB activity and was associated with Hsp70 induction. This study provides important insights that Hsp90 is involved as crucial regulator in anti-BP180 IgG-induced production of keratinocyte-derived IL-8. By adding to the knowledge of the multimodal anti inflammatory effects of Hsp90 blockade, our data further support the introduction of Hsp90 inhibitors into the clinical setting for treatment of autoimmune diseases, especially for BP. PMID- 24796798 TI - Effects of heat stress on antioxidant defense system, inflammatory injury, and heat shock proteins of Muscovy and Pekin ducks: evidence for differential thermal sensitivities. AB - Rising temperatures are severely affecting the mortality, laying performance, and meat quality of duck. Our aim was to investigate the effect of acute heat stress on the expression of heat shock proteins (HSPs: HSP90, 70, 60, 40, and 10) and inflammatory factors (nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) and antioxidant enzyme activity (superoxide dismutase (SOD), malondialdehybe (MDA), catalase (CAT), total antioxidant capacity (T-AOC)) in livers of ducks and to compare the thermal tolerance of Pekin and Muscovy ducks exposed to acute heat stress. Ducks were exposed to heat at 39 +/- 0.5 degrees C for 1 h and then returned to 20 degrees C for 1 h followed by a 3-h recovery period. The liver and other tissues were collected from each individual for analysis. The mRNA levels of HSPs (70, 60, and 40) increased in both species, except for HSP10, which was upregulated in Muscovy ducks and had no difference in Pekin ducks after heat stress. Simultaneously, the mRNA level of HSP90 decreased in the stress group in both species. Morphological analysis indicated that heat stress induced tissue injury in both species, and the liver of Pekin ducks was severely damaged. The activities of several antioxidant enzymes increased in Muscovy duck liver, but decreased in Pekin duck. The mRNA levels of inflammatory factors were increased after heat stress in both duck species. These results suggested that heat stress could influence HSPs, inflammatory factors expression, and the activities of antioxidant enzymes. Moreover, the differential response to heat stress indicated that the Muscovy duck has a better thermal tolerance than does the Pekin duck. PMID- 24796799 TI - Liver enzyme elevations within 3 months of diagnosis of inflammatory bowel disease and likelihood of liver disease. AB - BACKGROUND: Inflammatory bowel disease-associated liver diseases (IBD-LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and an overlap syndrome. Prospective unbiased multicenter data regarding the frequency of IBD-LD in patients with pediatric inflammatory bowel disease (IBD) are lacking. We examined early alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) elevations in children diagnosed as having IBD and assessed the likelihood of IBD-LD. METHODS: Data collected from the prospective observational Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry enrolling children of age <16 years within 30 days of diagnosis. AIH, PSC, and overlap syndrome were diagnosed using local institutional criteria. RESULTS: A total of 1569 subjects had liver enzymes available. Of the total, 757 had both ALT and GGT, 800 had ALT only (no GGT), and 12 had GGT only (no ALT). Overall, 29 of 1569 patients (1.8%) had IBD-LD. IBD-LD was diagnosed in 1 of 661 (0.15%) of patients with both ALT and GGT <= 50 IU/L compared with 21 of 42 (50%) of patients with both ALT and GGT > 50 (odds ratio 660, P < 0.0001). Of the 29 patients with IBD-LD, 21 had PSC, 2 had AIH, and 6 had overlap syndrome. IBD-LD was more common in patients with ulcerative colitis and IBD-unclassified (indeterminate colitis) than in those with Crohn disease (4% vs 0.8%, respectively, P < 0.001). CONCLUSIONS: Elevation of both ALT and GGT within 90 days after the diagnosis of IBD is associated with a markedly increased likelihood of IBD-LD. Both ALT and GGT levels should be measured in all of the pediatric patients newly diagnosed as having IBD. PMID- 24796800 TI - Reporting outcome measures in trials of infant colic. AB - OBJECTIVES: Infant colic (IC), with an estimated prevalence of 5% to 25%, has a high impact on health care costs. Furthermore, reported negative sequelae are disturbed parent-infant interaction, increased susceptibility to abdominal pain, and even child abuse. Its etiology remains unknown, leading to a wide variety in interventions. We hypothesize that definitions and outcome measures in studies on IC will be heterogeneous as well. Our objective is to systematically assess how definitions and outcome measures are reported in randomized controlled trials (RCTs) of IC. METHODS: CENTRAL, Embase, and MEDLINE/PubMed were searched from inception to December 2012. English-language systematic reviews (SRs) and RCTs concerning IC in children ages 0 to 9 months were included. Bibliographies of included SRs were searched for additional articles. Quality was assessed using the Delphi list. RESULTS: A total of 1702 studies were found; 55 articles were included (16 SRs, 39 RCTs). In 39 trials, we found 20 different definitions for IC, 11 different definitions for improvement, 28 different interventions, and 19 different outcomes. Fifty-one percent of the trials were of good methodological quality. All of the trials used parental diaries; only 31% stated that their instrument was validated. CONCLUSIONS: Too many different definitions and outcome measures for IC are used in RCTs. Only a minority of the trials reported parental perception as primary outcome. Uniform definitions, outcomes, and validated instruments are needed to make a comparison between intervention studies possible. PMID- 24796801 TI - Research and the promotion of child health: a position paper of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. AB - Children comprise one-fifth of Europe's population. Promoting child health and development is of key importance for society and its future. This position paper highlights opportunities of investing in gastrointestinal, liver, and nutritional research to promote child health and delineates priorities for research. Investing in child health plays a key role in the promotion of population health, well-being, and disease prevention lifelong, with large health economic benefits. Major opportunities for improving knowledge and translational application arise from recent scientific and technological developments, for example, the long-term impact of early environmental cues interacting with genes. Personalised approaches to therapy and prevention should be enhanced. Deciphering the microbiome and its effects on functions can help in promoting long-term health. Epigenetic research can help to understand how early environmental factors influence later gastrointestinal and hepatic health and disease. A linked nutrition and physical activity strategy can promote health and prevent nutritional deficiencies, inactivity, and chronic noncommunicable diseases, such as diabetes, to ensure optimal health and cognition. Special attention should be devoted to populations with low socioeconomic status, migrant background, and ethnic minorities, and to critical life periods, including pregnancy, lactation, infancy, and childhood. Improved understanding of optimal nutrition and on maintaining gut and liver homeostasis throughout childhood will help prevent chronic diseases in later life. PMID- 24796802 TI - Endoscopic necrosectomy in children. AB - Acute pancreatitis in children is rarely complicated by the development of necrosis. Although endoscopic transluminal necrosectomy is evolving as the standard of care in adults, its feasibility in the pediatric population has not been established. We hereby report the first case series of children with necrotizing pancreatitis successfully treated with endoscopic therapy. We believe the use of fully covered self-expanding metallic stents in the cystgastrostomy may reduce the number of transluminal necrosectomy sessions for large necrotic collections in children. PMID- 24796804 TI - Preventing bloodstream infection in patients receiving home parenteral nutrition. AB - Patients receiving home parenteral nutrition (HPN) are at particularly high risk of meticillin-sensitive Staphylococcus aureus (MSSA) catheter-related bloodstream infections (CRBSI). We developed a multidisciplinary enhanced care pathway encompassing a number of minimal cost interventions involving line/exit site care, training for staff and parents, multidisciplinary discharge planning, and monitoring compliance. Implementation reduced the mean rates of MSSA CRBSI (from 0.93, 95% CI 0.25-1.61, to 0.23, 95% CI -0.06 to 0.52, per 1000 parenteral nutrition [PN] days) and all-cause CRBSI (from 1.98, 95% CI 0.77-3.19, to 0.45, 95% CI 0.10-0.80, per 1000 PN days). A similar approach could be applied to preventing health care-associated infections in other complex, vulnerable patient groups. PMID- 24796803 TI - Fecal microbial therapy: promises and pitfalls. AB - A rapidly expanding range of diverse human diseases is now associated with perturbations to the gastrointestinal microbiome. Fecal microbial transplant (FMT) has been used with high rates of efficacy to treat gastrointestinal microbiome perturbation associated with recurrent Clostridium difficile infection, and is now being considered for other indications. Here we discuss the gut microbiome, review published and ongoing studies using FMT as a treatment modality for human disease, consider the regulatory aspects of FMT, and outline some factors that should be considered in patients in whom this therapeutic strategy is being contemplated. PMID- 24796805 TI - Pediatric constipation in the emergency department: evaluation, treatment, and outcomes. AB - OBJECTIVES: Limited knowledge exists surrounding the pharmacologic management of pediatric constipation in the emergency department (ED) setting and the success of interventions. Our primary objective was to determine whether enema administration is associated with 7-day ED revisits for persistent symptoms. Secondary objectives focused on assessing other predictors of ED revisits. METHODS: We conducted a retrospective cohort study of children <18 years old, diagnosed as having constipation (International Classification of Diseases-10 codes F98.1 nonorganic encopresis, K59.0 constipation) in a pediatric ED in Toronto, Canada, between November 2008 and October 2010. RESULTS: A total of 3592 visits were included; 6% (n = 225) were associated with a revisit. Children with revisits more frequently had vomiting (28% vs 17%, P = 0.001), more pain (5.7 +/- 3.6 vs 4.6-3.6 of 10, P = 0.01), and underwent more blood tests (19% 05, 11%, 95% confidence interval [CI] of the difference 3%-14%] and diagnostic imaging (62% vs 47%, 95% CI of the difference 9%-22%). Children administered an enema were 1.54 times more likely to revisit the ED than those who did not receive an enema (8.6% vs 5.5%, 95% CI of the difference 1.1%-5.2%, P = 0.001). Type of enema administered varied by age (P < 0.001). Regression analysis identified the following independent predictors of revisits: diagnostic imaging (odds ratio [OR] 1.54, 95% CI 1.15-2.06), vomiting (OR 1.45, 95% CI 1.07-1.98), enema administration (OR 1.40, 95% CI 1.05-1.88), and significant medical history (OR 1.26, 95% CI 1.04-1.53). CONCLUSIONS: Enema administration and diagnostic imaging are associated with revisits in children diagnosed with constipation. Their role in the ED management of pediatric constipation requires further evaluation. PMID- 24796806 TI - A candidate gene association study for nine economically important traits in Italian Holstein cattle. AB - We genotyped 58 single nucleotide polymorphisms (SNPs) in 25 candidate genes in about 800 Italian Holstein sires. Fifty-six (minor allele frequency >0.02) were used to evaluate their association with single traits: milk yield (MY), milk fat yield (FY), milk protein yield (PY), milk fat percentage (FP), milk protein percentage (PP), milk somatic cell count (MSCC); and complex indexes: longevity, fertility and productivity-functionality type (PFT), using deregressed proofs, after adjustment for familial relatedness. Thirty-two SNPs were significantly associated (proportion of false positives <0.05) with different traits: 16 with MSCC, 15 with PY, 14 with MY, 12 with PFT, eight with longevity, eight with FY, eight with PP, five with FP and two with fertility. In particular, a SNP in the promoter region of the PRLR gene was associated with eight of nine traits. DGAT1 polymorphisms were highly associated with FP and FY. Casein gene markers were associated with several traits, confirming the role of the casein gene cluster in affecting milk yield, milk quality and health traits. Other SNPs in genes located on chromosome 6 were associated with PY, PP, PFT, MY (PPARGC1A) and MSCC (KIT). This latter association may suggest a biological link between the degree of piebaldism in Holstein and immunological functions affecting somatic cell count and mastitis resistance. Other significant SNPs were in the ACACA, CRH, CXCR1, FASN, GH1, LEP, LGB (also known as PAEP), MFGE8, SRC, TG, THRSP and TPH1 genes. These results provide information that can complement QTL mapping and genome-wide association studies in Holstein. PMID- 24796807 TI - Giant scaffolding protein AHNAK1 interacts with beta-dystroglycan and controls motility and mechanical properties of Schwann cells. AB - The profound morphofunctional changes that Schwann cells (SCs) undergo during their migration and elongation on axons, as well as during axon sorting, ensheathment, and myelination, require their close interaction with the surrounding laminin-rich basal lamina. In contrast to myelinating central nervous system glia, SCs strongly and constitutively express the giant scaffolding protein AHNAK1, localized essentially underneath the outer, abaxonal plasma membrane. Using electron microscopy, we show here that in the sciatic nerve of ahnak1(-) (/) (-) mice the ultrastructure of myelinated, and unmyelinated (Remak) fibers is affected. The major SC laminin receptor beta-dystroglycan co immunoprecipitates with AHNAK1 shows reduced expression in ahnak1(-) (/) (-) SCs, and is no longer detectable in Cajal bands on myelinated fibers in ahnak1(-) (/) (-) sciatic nerve. Reduced migration velocity in a scratch wound assay of purified ahnak1(-) (/) (-) primary SCs cultured on a laminin substrate indicated a function of AHNAK1 in SC motility. This was corroborated by atomic force microscopy measurements, which revealed a greater mechanical rigidity of shaft and leading tip of ahnak1(-) (/) (-) SC processes. Internodal lengths of large fibers are decreased in ahnak1(-) (/) (-) sciatic nerve, and longitudinal extension of myelin segments is even more strongly reduced after acute knockdown of AHNAK1 in SCs of developing sciatic nerve. Together, our results suggest that by interfering in the cross-talk between the transmembrane form of the laminin receptor dystroglycan and F-actin, AHNAK1 influences the cytoskeleton organization of SCs, and thus plays a role in the regulation of their morphology and motility and lastly, the myelination process. PMID- 24796808 TI - The relation between motor function of stroke patients and diffusion tensor imaging findings for the corticospinal tract. AB - Although the corticospinal tract (CST) is a major neural tract for motor function, the detailed role of the CST has not been clearly elucidated. We investigated relations between motor function of patients with chronic hemiparetic stroke and diffusion tensor imaging (DTI) findings for the CST. We recruited 82 consecutive chronic stroke patients. Medical Research Council, Modified Brunnstrom Classification, and Functional Ambulatory Category were used in measurement of the affected side. All motor functions showed positive correlations with fractional anisotropy (FA) and fiber number (FN) ratios (p<0.05). With regard to Medical Research Council, shoulder abductor (r=0.70, 0.68), elbow flexor (r=0.75, 0.72), finger flexor (r=0.73, 0.74), and finger extensor (r=0.69, 0.77) showed strong correlations with FA and FN ratios. Modified Brunnstrom Classification (r=0.70, 0.73) also showed strong correlation. According to our findings, it appears that the CST is related to motor function of upper and lower extremities, with particular relation to motor function of upper extremities, including the hand, compared with other motor functions. PMID- 24796809 TI - Anti-inflammatory cytokine interleukin-10 increases resistance to brain ischemia through modulation of ischemia-induced intracellular Ca2+ response. AB - It is suggested that anti-inflammatory cytokine interleukin-10 (IL-10) mediates the delayed protective effects through activation of Jak-Stat3, PI3K-Akt and NF kappaB signaling pathways. However, our previous experiments have demonstrated that IL-10 is capable to exert the rapid neuroprotective action through modulation of hypoxia-induced intracellular Ca(2+) ([Ca(2+)]i) response. The first purpose of the present study was to evaluate the neuroprotective effects of IL-10 using three models of the ischemic insults in rats: permanent middle cerebral artery occlusion, ischemia in acute hippocampal slices in vitro and ischemia in cultured hippocampal cells in vitro. The second purpose of the study was to elucidate a role of [Ca(2+)]i changes in the mechanisms underlying IL-10 elicited protection of neurons and astrocytes from ischemia-induced death in cultures of primary hippocampal cells. The data presented here shown that anti inflammatory cytokine IL-10 is capable to induce a resistance of the brain cells to ischemia-evoked damages in in vivo and in vitro models of the ischemic insults in rats. This protective effect in cultured hippocampal cells is developed rapidly after application of IL-10 and strongly associated with the IL-10 elicited elimination of [Ca(2+)]i response to ischemia. Thus, our results provide the evidence that anti-inflammatory cytokine IL-10, in addition to an activation of the canonical signaling pathways, is capable to exert the rapid neuroprotective effects through transcription-independent modulation of ischemia induced intracellular Ca(2+) responses in the brain cells. PMID- 24796810 TI - The amyloid-beta degradation pattern in plasma--a possible tool for clinical trials in Alzheimer's disease. AB - Amyloid beta (Abeta) is the main component of plaques, the central neuropathological hallmark in Alzheimer's disease (AD). Abeta is derived from the amyloid precursor protein (APP) by beta- and gamma-secretase-mediated cleavages. A large number of Abeta peptides are found in cerebrospinal fluid and these peptides are produced in specific metabolic pathways, which are important for diagnosis, in drug development and to explore disease pathogenesis. To investigate whether a similar pattern could be found also in blood samples, an immunoprecipitation (IP) based method for enrichment of Abeta peptides from human plasma was developed. The peptides were analyzed using matrix-assisted-laser desorption/ionization time-of-flight/time-of-flight mass spectrometry for Abeta profiling and selected reaction monitoring (SRM) for MS quantification of Abeta1 38, Abeta1-40 and Abeta1-42 using tripe quadrupole MS. Sixteen N- or C-terminally truncated Abeta peptides were reproducibly detected in human plasma, of which 11 were verified by tandem MS. In a pilot study including 9 AD patients and 10 controls, where Abeta1-38, Abeta1-40 and Abeta1-42 were quantified using SRM, no AD-associated change in plasma levels of the peptides were observed. Using MS based measurement techniques, we show that several Abeta peptides can be monitored in a single analysis and the developed methods have the potential to be used as a read out in clinical trials of drugs affecting APP processing or Abeta homeostasis. PMID- 24796811 TI - The influence of gender, age and treatment time on brain oxidative stress and memory impairment induced by D-galactose in mice. AB - Chronic exposure to d-galactose (d-gal) serves as a model for age-related oxidative damage and cognitive dysfunction. However, methods used, including the dose and treatment time of d-gal as well as the gender, age and strain of animals used, vary greatly among published articles. In this study, we investigate the effect of gender, age and treatment time on brain oxidative stress and spatial memory deficits induced by d-gal in mice, respectively. Eight-week-old female mice injected with 100mg/kg d-gal per day, for 6 weeks, did not show spatial memory impairment or high levels of hydroxyl radical, protein carbonyl and malondialdehyde in brain homogenates, although brain reactive oxygen species were increased when compared with saline control mice. In contrast, both 8-week-old male mice and 24-week-old female mice receiving 100mg/kg d-gal for 6 weeks, or 8 week-old female mice receiving 100mg/kg d-gal for 10 weeks showed spatial memory deficits and significant increases in the above oxidative markers, compared with their corresponding controls. These results demonstrate that d-gal-induced brain oxidative stress and spatial memory impairment are dependent upon exposure time of d-gal, plus gender and age of the animals used. The findings can serve as a useful guide for successfully establishing d-gal induced age-related oxidative damage models. PMID- 24796812 TI - GABAB receptor dependent modulation of sharp wave-ripple complexes in the rat hippocampus in vitro. AB - Sharp wave-ripple complexes (SPW-R) are observed in vivo during resting immobility, consummatory behavior and during slow wave sleep, and they have been proposed to support memory consolidation. It has been suggested that GABAergic cells play important roles in controlling incidence of sharp waves and of ripple frequency. We report here that the GABAB agonist baclofen reversibly suppresses SPW-R activity in rat hippocampal slices, presumably affecting the strength of neuronal coupling in the associative network of area CA3. The effect is specific as the GABAB receptor antagonist CGP55846 prevents this effect; however, CGP55846 application had no major effect on incidence of SPW-R. Interestingly, repetitive stimulation in the presence of baclofen is able to induce SPW-R activity, which only appears after washout of baclofen. Our findings suggest that GABA levels through activation of GABAB receptors may be involved in the transition from theta-gamma to SPW-R working mode in the hippocampus. PMID- 24796813 TI - Impact of indomethacin on neuroinflammation and hippocampal neurogenesis in aged mice. AB - Age-induced neuroinflammation could be a contributing factor to the restricted neurogenesis in aged mice. Indomethacin, a common non-steroidal anti-inflammatory drug, has been demonstrated to partially restore neurogenesis under pathophysiological inflammation-associated conditions in adult C57BL/6 mice. This study investigated whether indomethacin is able to decrease age-related neuroinflammation in the hippocampus (24-month-old mice) and thereby stimulate neurogenesis. During hippocampal aging, the transcript expression of pro inflammatory cytokines (Tnfalpha, Il-1alpha, Il-1beta), the chemokine Mip-1alpha, and markers for activated astrocytes (Gfap, Lcn2, but not Vim and Serpina3n) and microglia (Iba1, F4/80, Cd68, Cd86) significantly increased. Treatment with indomethacin significantly decreased COX-1 and COX-2 transcript expression. Of the age-related inflammatory mediators, only Gfap and Iba1 were affected by indomethacin treatment in the hippocampus, with a significantly reduced transcript expression being detected for both markers. Neurogenesis was unaffected by indomethacin. Thus, our data reveal that administration of indomethacin to aged mice is not able to effectively decrease neuroinflammation and promote neurogenesis. PMID- 24796814 TI - Chronic repetitive transcranial magnetic stimulation enhances GABAergic and cholinergic metabolism in chronic unpredictable mild stress rat model: 1H-NMR spectroscopy study at 11.7T. AB - Gamma-animobutyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. Deficits in GABA-containing neurons are consistently reported in psychiatric disease, particularly in the prefrontal cortex and hippocampus. Repetitive transcranial magnetic stimulation (rTMS) that use magnetic field to stimulate focal cortical regions with electrical current have a potential therapeutic effects with non-invasive and painless method. In this study, we used chronic unpredictable mild stress (CUMS) rat model of depression to investigate the behavioral and neurochemical alterations. Furthermore, chronic rTMS treatment effect on neurochemical profile in prefrontal cortex and hippocampus of rats were assessed. The CUMS induced significant reductions in absolute sucrose intake and sucrose preference. In addition, high resolution (1)H-NMR spectra from brain extracts revealed significantly reduced prefrontal and hippocampal GABA levels in CUMS rats compared to control. The behavioral and neurochemical changes were reversed by chronic rTMS treatment. Furthermore, chronic rTMS treatments results in differential effects on different brain regions. Our results suggest specific and regionally different metabolic response to chronic rTMS treatment in animal model of depression. PMID- 24796815 TI - Understanding conversion disorders: back to Freud's theory. PMID- 24796816 TI - Novel transgenic technology reveals several molecular adaptations and potential therapeutic targets in the direct pathway in levodopa-induced dyskinesia. PMID- 24796817 TI - The therapeutic process in psychological treatments for eating disorders: a systematic review. AB - OBJECTIVE: For eating disorders, a vast number of investigations have demonstrated the efficacy of psychological treatments. However, evidence supporting the impact of therapeutic process aspects on outcome (i.e., process outcome research) has not been disentangled. METHOD: Using the Generic Model of Psychotherapy (GMP) to organize various process aspects, a systematic literature search was conducted on psychological treatment studies for anorexia nervosa, bulimia nervosa, binge-eating disorder, and eating disorders not otherwise specified. RESULTS: Improved outcomes resulted for family-based treatment compared to individual treatment, for individual compared to group treatment, booster sessions, and positive patient expectations (GMP contract aspect); for nutritional counseling and exercising but not exposure with response prevention as adjunct interventions (therapeutic operations); for highly motivated patients and, to a lesser extent, for therapeutic alliance (therapeutic bond); as well as for rapid response and longer overall treatment duration (temporal patterns). Regarding other GMP aspects, studies on self-relatedness were completely lacking and in-session impacts were rarely investigated. DISCUSSION: As most studies assessed only a limited number of process aspects, the ability to draw conclusions about their overall impact regarding outcome is rather limited. Therefore, future process-outcome research is needed beyond investigations of treatment efficacy for eating disorders. PMID- 24796818 TI - Super-stretchable graphene oxide macroscopic fibers with outstanding knotability fabricated by dry film scrolling. AB - Graphene oxide (GO) has recently become an attractive building block for fabricating graphene-based functional materials. GO films and fibers have been prepared mainly by vacuum filtration and wet spinning. These materials exhibit relatively high Young's moduli but low toughness and a high tendency to tear or break. Here, we report an alternative method, using bar coating and drying of water/GO dispersions, for preparing large-area GO thin films (e.g., 800-1200 cm(2) or larger) with an outstanding mechanical behavior and excellent tear resistance. These dried films were subsequently scrolled to prepare GO fibers with extremely large elongation to fracture (up to 76%), high toughness (up to 17 J/m(3)), and attractive macroscopic properties, such as uniform circular cross section, smooth surface, and great knotability. This method is simple, and after thermal reduction of the GO material, it can render highly electrically conducting graphene-based fibers with values up to 416 S/cm at room temperature. In this context, GO fibers annealed at 2000 degrees C were also successfully used as electron field emitters operating at low turn on voltages of ca. 0.48 V/MUm and high current densities (5.3 A/cm(2)). Robust GO fibers and large-area films with fascinating architectures and outstanding mechanical and electrical properties were prepared with bar coating followed by dry film scrolling. PMID- 24796819 TI - Zucker Diabetic Fatty rats exhibit hypercoagulability and accelerated thrombus formation in the Arterio-Venous shunt model of thrombosis. AB - INTRODUCTION: Diabetes is a significant risk factor for thrombosis. The present study aimed at assessing coagulability, platelet reactivity, and thrombogenicity of the diabetic female Zucker Diabetic Fatty (ZDF) rat model and its relevance in studying antithrombotic mechanisms. MATERIALS AND METHODS: The basal coagulant state in ZDF rats was evaluated by clotting times, thromboelastography, and thrombin generation assay. A 14-day treatment with dapagliflozin in ZDF rats was pursued to investigate if glycemic control can improve coagulability. Thrombus formation in the Arterio-Venous (A-V) shunt model and the FeCl3-induced arterial thrombosis model was studied, with the antithrombotic effect of apixaban in the former model further investigated. RESULTS: ZDF rats exhibited significantly shortened clotting times, enhanced thrombin generation, and decreased fibrinolysis at baseline. Effective glycemic control achieved with dapagliflozin did not improve any of these parameters. ZDF rats displayed accelerated thrombus formation and were amenable to apixaban treatment in the A-V shunt model albeit with less sensitivity than normal rats. ZDF rats exhibited less platelet aggregation in response to ADP, collagen and PAR-4, and attenuated thrombotic response in the FeCl3 model. CONCLUSIONS: ZDF rats are at a chronic hypercoagulable and hypofibrinolytic state yet with compromised platelet reactivity. They display accelerated and attenuated thrombosis in the A-V shunt and FeCl3 model of thrombosis, respectively. Results shed new light on the pathophysiology of the ZDF rat model and illustrate its potential value in translational research on anticoagulant agents in diabetics. Caution needs to be exerted in utilizing this model in assessing antiplatelet mechanisms in diabetes associated atherothrombosis. PMID- 24796820 TI - Brief prenatal ethanol exposure alters behavioral sensitivity to the kappa opioid receptor agonist (U62,066E) and antagonist (Nor-BNI) and reduces kappa opioid receptor expression. AB - BACKGROUND: Approximately 10 to 15% of women consume alcohol (ethanol [EtOH]) during pregnancy in the United States. Even low amounts of EtOH consumption during pregnancy can elicit long-term consequences. Prenatal experience with as few as 3 drinks has been associated with increase problem drinking in adulthood. Such effects are corroborated in rodents; however, the underlying neural adaptations contributing to this effect are not clear. In the current set of experiments, we investigated whether changes in EtOH responding following prenatal EtOH exposure involved kappa opioid receptor activation and expression. METHODS: Sprague-Dawley rats were prenatally exposed to low levels of alcohol (1.0 g/kg) during late gestation (gestational days 17 to 20 [GD17-20]) via intragastric intubation of pregnant dams. Following birth, EtOH intake, kappa- and mu-opioid-induced place conditioning, and kappa opioid receptor expression in mesolimbic brain regions were assessed in infant rats (postnatal days 14 to 15 [PD14-15]) that were offspring of dams given EtOH, vehicle, or untreated, during pregnancy. RESULTS: Animals exposed to prenatal alcohol drank more alcohol later in life and exhibited significant changes in the kappa opioid system. While control subjects found kappa opioid activation aversive, animals exposed to EtOH prenatally exhibited either no aversion or appetitive responding. Further analysis revealed that synaptosomal kappa opioid receptor expression was significantly decreased in brain areas implicated in responding to EtOH. CONCLUSIONS: Overall, these data suggest that prenatal EtOH affects kappa opioid function and expression and that these changes may be involved in increased drinking later in life. PMID- 24796822 TI - Improvements in dental care using a new mobile app with cloud services. AB - BACKGROUND/PURPOSE: Traditional dental care, which includes long-term oral hygiene maintenance and scheduled dental appointments, requires effective communication between dentists and patients. In this study, a new system was designed to provide a platform for direct communication between dentists and patients. METHODS: A new mobile app, Dental Calendar, combined with cloud services specific for dental care was created by a team constituted by dentists, computer scientists, and service scientists. This new system would remind patients about every scheduled appointment, and help them take pictures of their own oral cavity parts that require dental treatment and send them to dentists along with a symptom description. Dentists, by contrast, could confirm or change appointments easily and provide professional advice to their patients immediately. In this study, 26 dentists and 32 patients were evaluated by a questionnaire containing eight dental-service items before and after using this system. Paired sample t test was used for statistical analysis. RESULTS: After using the Dental Calendar combined with cloud services, dentists were able to improve appointment arrangements significantly, taking care of the patients with sudden worse prosthesis (p < 0.05). Patients also achieved significant improvement in appointment reminder systems, rearrangement of appointments in case of sudden worse prosthesis, and establishment of a direct relationship with dentists (p < 0.05). CONCLUSION: Our new mobile app, Dental Calendar, in combination with cloud services, provides efficient service to both dentists and patients, and helps establish a better relationship between them. It also helps dentists to arrange appointments for patients with sudden worsening of prosthesis function. PMID- 24796821 TI - Proactive infection control measures to prevent nosocomial transmission of vancomycin-resistant enterococci in Hong Kong. AB - BACKGROUND/PURPOSE: The study describes a proactive infection control approach to prevent nosocomial transmission of vancomycin-resistant enterococci (VRE) and tests if this approach is effective for controlling multiple-drug resistant organisms in a nonendemic setting. METHODS: In response to the increasing prevalence of VRE in Hong Kong since 2011, we adopted a multifaceted assertive approach in our health care network. This included active surveillance culture, extensive contact tracing, directly observed hand hygiene in conscious patients before they received meals and medications, stringent hand hygiene and environmental cleanliness, and an immediate feedback antimicrobial stewardship program. We report the occurrence of VRE outbreaks in our hospital after institution of these measures and compared with the concurrent occurrence in other public hospitals in Hong Kong. RESULTS: Between July 1, 2011 and November 13, 2013, VRE was identified in 0.32% (50/15,851) of admission episodes by active surveillance culture. The risk of VRE carriage was three times higher in patients with a history of hospitalization outside our hospital networks in the past 3 months (0.56% vs. 0.17%; p = 0.001) compared with those who were not. Extensive contact tracing involving 3277 patient episodes was performed in the investigation for the 25 VRE index patients upon whom implementation of contact precautions was delayed (more than 48 hours of hospitalization). One episode of VRE outbreak was identified in our hospital network, compared with the 77 VRE outbreaks reported in the other hospital networks (controls) without these proactive infection control measures. CONCLUSION: Our multifaceted assertive proactive infection control approach can minimize the nosocomial transmission and outbreak of VRE in a nonendemic area. PMID- 24796823 TI - Muller-Weiss disease - review of current knowledge. AB - Muller-Weiss disease (MWD) is a complex idiopathic foot condition of the adult tarsal navicular characterised by progressive navicular fragmentation and talo navicular joint destruction leading to mid and hind foot pain and deformit. This article reviews, the current literature regarding this condition and discusses the surgical treatment options. PMID- 24796824 TI - The impact of risk assessment on the implementation of venous thromboembolism prophylaxis in foot and ankle surgery. AB - BACKGROUND: The purpose of this prospective study was to determine whether the more frequently quoted procedure and patient specific risk factors have any impact in the implementation of venous thromboembolism (VTE) prophylaxis following foot and ankle surgery. METHODS: Two hundred and sixteen patients were included in the study. A variety of operative procedures was carried out with the common denominator being a below knee cast for at least 4 weeks and nonweightbearing for an average of 6 weeks in 130 patients. The remainder of the patients (88) had hallux surgery not requiring a cast and were allowed to weightbear. No patient received any form of thromboprophylaxis postoperatively. All patients were subjected to compression ultrasonography for deep vein thrombosis (DVT) between 2 and 6 weeks postoperatively. RESULTS: There was a 5.09% incidence of VTE (0.9% pulmonary embolism) overall. As no VTE (neither DVT nor pulmonary embolus) developed in the hallux subgroup, i.e. patients not requiring immobilization and were allowed to weightbear, the incidence of VTE in the cast/nonweightbearing group was 8.46%. The results are descriptive and only statistically analyzed where possible, as the sample size of the VTE group was small. There was no significant difference in number of risk factors and no association between gender in the VTE and non VTE groups. 90.9% of patients in the VTE group had a total risk factor score of 5 or more and 73.7% of patients in the non VTE group had a total risk factor score of 5 or more. The average timing to the diagnosis of VTE in this current study was 33.1 days. CONCLUSIONS: In view of the unacceptable incidence of VTE and the average total risk factor score of 5 or more (for which thromboprophylaxis is recommended) in the majority of the patients, the authors feel that the routine use of thromboprophylaxis in foot and ankle surgery requiring nonweightbearing in combination with short leg cast immobilization, is warranted. This prophylaxis should continue until the patient regains adequate mobility either by weightbearing (in or out of the cast) or removal of cast immobilization (weightbearing or nonweightbearing), usually between 28 and 42 days. PMID- 24796825 TI - An anatomical and cadaveric study examining the risk of sural nerve injury in percutaneous Achilles tendon repair using the Achillon device. AB - BACKGROUND: Percutaneous Achilles tendon repairs are gaining in popularity. This study aims to quantify the risk of sural nerve injury when using the Achillon device. METHODS: The Achillon device was instrumented into 15 cadaveric specimens and through dissection the rate of sural nerve puncture and the position of the sural nerve in relation to the Achilles tendon was documented. RESULTS: The sural nerve was found lateral to the Achilles tendon insertion point over a range of 14.3mm and crossed the lateral border of the Achilles tendon over a range of 57.7mm. The sural nerve was punctured a total of 6 times and in 4 out of 15 cadaveric specimens (27%). Four out of the 6 punctures occurred when the Achillon device was instrumented distally. CONCLUSIONS: The sural nerve displays a highly variable anatomical course and there is a risk of puncture during percutaneous Achilles tendon repair using the Achillon device. PMID- 24796826 TI - Anabolic androgenic steroids reverse the beneficial effect of exercise on tendon biomechanics: an experimental study. AB - BACKGROUND: The effect of anabolic androgenic steroids on tendons has not yet been fully elucidated. Aim of the present study was the evaluation of the impact of anabolic androgenic steroids on the biomechanical and histological characteristics of Achilles tendons. METHODS: Twenty-four male Wistar rats were randomized into four groups with exercise and anabolic steroids (nandrolone decanoate) serving as variables. Protocol duration was 12 weeks. Following euthanasia, tendons' biomechanical properties were tested with the use of a modified clamping configuration. Histological examination with light and electron microscopy were also performed. RESULTS: In the group of anabolic steroids and exercise the lowest fracture stress values were observed, while in the exercise group the highest ones. Histological examination by light and electron microscopy revealed areas of collagen dysplasia and an increased epitendon in the groups receiving anabolic steroids and exercise. CONCLUSIONS: These findings suggest that anabolic androgenic steroids reverse the beneficial effect of exercise, thus resulting in inferior maximal stress values. PMID- 24796827 TI - Open talar dislocations without associated fractures. AB - AIM: Total dislocation of the talus first reported in 1680. It is a rare injury and without associated fractures is even rarer. Is generally considered to be one of the most disabling ankle injuries and occurs after high energy trauma. The primary goal of our study is the retrospective evaluation of complete talar extrusion without associated fractures and immediate reimplantation. MATERIALS AND METHODS: In the past nine years, nine patients with mean age 31.7 years were admitted to our center with a complete open talar extrusion. The dislocated talus was reduced and held in place with two Steinmann pins placed from the inferior aspect of the calcaneus, through the talus and into the inferior aspect of the tibia. An external fixator was used to stabilize the limb. The mean follow up time was 21.1 months. At the last follow up visit, six patients were evaluated both radiographically and functionally with the AOFAS score. RESULTS: Six patients were free of complications and the mean AOFAS Ankle-Hindfoot Scale score at the time of the last follow up visit was 82.5. Two patients had an infection, one had avascular necrosis of the talus and one had signs of subtalar joint arthritis. Two patients had to undergo arthrodesis. CONCLUSIONS: It is important to attempt reimplantation of the talus since a good final outcome is to be expected. Even in the case of a catastrophic complication this technique will ensure adequate bone stock for additional surgical procedures. PMID- 24796828 TI - Comparison between tenocutaneous suture and Kessler suture techniques in treating acute closed Achilles tendon rupture. AB - BACKGROUND: To compare the effectiveness of tenocutaneous suture and conventional Kessler suture techniques in treating acute closed Achilles tendon rupture. METHODS: A total of 33 patients with acute closed Achilles tendon rupture who were admitted to our hospital from February 1998 to December 2008 underwent repair with either a tenocutaneous suture or Kessler suture technique. All patients were followed up for 1-5 years (mean, 3 years). RESULTS: According to the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale, the excellence rate was 91% in the Kessler suture group and 98% in the tenocutaneous suture group, with a significant difference between groups. CONCLUSION: Our tenocutaneous suture technique is an effective method for treating Achilles tendon rupture. It has certain advantages compared with the conventional incision method and is worthy of wide clinical application. PMID- 24796829 TI - Contribution of a new electrophysiologic test to Morton's neuroma diagnosis. AB - BACKGROUND: Morton's neuroma causes metatarsalgia due to the interdigital neuropathy. The small nerve diameter compromises their evaluation in image studies. To overcome this problem we propose a new electrophysiological test. METHODS: We conducted a prospective case-control study performing a orthodromic electroneurography using subdermal electrodes in controls and patients to assess the validity. Additionally all patients were tested with magnetic resonance. Some patients required surgery and subsequent histological evaluation. RESULTS: The new ENG procedure showed higher sensitivity and specificity. Methodological standardization was easy and the test was well tolerated by the subjects. CONCLUSIONS: Our test demonstrated remarkable diagnostic efficiency, and also was able to identify symptomatic patients undetected by magnetic resonance, which underlines the lack of correlation between the size and intensity of the lesion. This new electrophysiological method appears to be a highly sensitivity, well tolerated, simple and low-cost for Morton's neuroma diagnosis. PMID- 24796830 TI - Are locking plates better than non-locking plates for treating distal tibial fractures? AB - BACKGROUND: Locking and non-locking plates has been used for distal tibia fracture osteosynthesis. Sufficient evidence to favor one implant over the other is lacking in the current literature. Our aim is to compare them in terms of fracture healing, alignment, functional outcome, complications. METHODS: Sixty eight patients operated on using a percutaneous plate were retrospectively reviewed. They were divided into two groups: in group 1 (28 patients) a 4.5mm narrow conventional dynamic compression plate (DCP) was used. In group 2 (40 patients) a titanium locked compression plate (LCP) was used. RESULTS: Mean time to union was 16.2 and 15.4 weeks for group 1 and 2, respectively (p=0.618). 11 patients (39.3%) in group 1 and 4 patients (10%) in group 2 showed malalignment (p=0.016). AOFAS scores at follow up were 89 and 88 in groups 1 and 2, respectively. Implant removal was necessary in 9 cases (32.1%) and 4 cases (10%) in group 1 and group 2, respectively (p=0.042). Three patients (10.7%) in group 1 and three patients (7.5%) in group 2 had an infection. CONCLUSIONS: Both plating systems have similar results in terms of time to union, infection, and AOFAS scores. The LCP seems superior with respect to alignment and the need for implant removal. PMID- 24796831 TI - Non-irradiated frozen structural allograft in reconstructive surgeries of the hindfoot and midfoot. AB - BACKGROUND: A few studies investigating the use of structural allograft in foot and ankle surgery are available. The purpose of this study is to analyze the clinical, functional and radiological results of patients treated with non irradiated frozen structural bone allograft. METHODS: We analyzed 20 reconstructive surgeries of the hindfoot and midfoot performed between April 2004 and April 2010. The mean follow up period was 45.4 months. The results were evaluated according to AOFAS score, X-ray (allograft consolidation, alignment preservation, and allograft collapse or re-absorption), and complications. RESULTS: We observed a 48-point mean improvement of AOFAS ankle and hindfoot score (17 cases), and a 53-point mean improvement of AOFAS midfoot score (3 cases). The mean bone consolidation time was 75 days. No graft fracture and no cases of non-union were seen. CONCLUSION: This treatment is a good option to treat severe defects or fill sequelae deformities. PMID- 24796832 TI - Impact of fibular torsion and rotation on chronic ankle instability. AB - BACKGROUND: The fibula is known not to involve in transmission of weight but known simply as an ankle stabilizer. However, its main function in stabilizing the ankle remains obscure. Since the fibula has an impact on torsion and rotation of the ankle, its effect on lateral ankle instability should be investigated. MATERIALS AND METHODS: Twenty patients with lateral ankle instability (Group 1) and 19 healthy volunteers (Group 2) were included in the study. The tibiofibular and talofibular relationships were evaluated using MRI images. Fibular torsion and rotation angles were calculated using a new method. Range of motion of the ankle joint was investigated while the knee was at flexion (90 degrees ) and extension (0 degrees ). The comparisons performed between the 2 groups and independent from the groups were statistically evaluated and, the p value of <0.05 was considered as statistically significant. RESULTS: A significant difference was found between the two groups for age (p<0.05). There were no statistically significant differences between the right and left sides for all measurements in the group 1 and 2 (p>0.05). There was a statistically significant difference between the two groups in dorsal flexion when the knee is at flexion (90 degrees ) and extension (0 degrees ) position. There was also a statistically significant difference between the two groups in plantar flexion which was measured while the knee was at extension (0 degrees ) position. No statistically significant difference was found between both groups in terms of fibular torsion and rotation. However, independent from the groups when the patients were divided into 2 groups according to whether the fibula localized posteriorly or not, in patients with posteriorly localized fibula it was demonstrated that the fibular torsion and rotation was increased significantly. CONCLUSION: We did not detect any relationship between fibular torsion and rotation and ankle instability. However, independent from the groups when the patients were divided into 2 groups according to whether the fibula localized posteriorly or not, we realized that in patients with posteriorly localized fibula, fibular torsion and rotation significantly increased. This finding did not explain the cause of instability. However, it may gain significance with new further studies regarding ankle instability. PMID- 24796833 TI - Clinical and oncological outcomes after surgical excision of pigmented villonodular synovitis at the foot and ankle. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare benign neoplastic disease of the synovium of joints and tendon sheaths, which may be locally aggressive. It can be broadly classified into localised disease or more diffuse forms, with the latter more prone to recurrence after surgical excision. We describe our experience in the management of foot and ankle PVNS, focusing on the diffuse type. METHODS: Patients with PVNS were identified from a histology database from 2000 to 2010 at the University Hospitals of Leicester. The primary aim was to determine oncological outcomes and evaluate clinical outcomes with the Toronto Extremity Salvage Score (TESS) and the American Academy of Foot and Ankle Surgeons (AOFAS) scores. RESULTS: 30 patients, 16 males and 14 females with a mean age of 37+/-15 years, who underwent surgery, were identified. There were 22 nodular PVNS and 8 diffuse PVNS. The diffuse PVNS was more likely to be in the hindfoot (75%, 6/8), of which 50% (3/6) had osteoarthritis at presentation. The localised PVNS was mostly located in the forefoot (91%, 20/22). None of the localised PVNS had a recurrence. The surgical recurrence rate in this series was similar to the pooled recurrence rate from the literature [12.5% (1/8) compared to 12.2% (6/49)]. The mean TESS and AOFAS scores were 86 and 78, respectively. CONCLUSIONS: Diffuse PVNS is more likely to occur in the hindfoot and nodular PVNS is more common in the forefoot. Aggressive synovectomy alone is an effective treatment for diffuse PVNS, with good oncological and clinical outcomes. PMID- 24796834 TI - Arthroscopic triple fusion joint preparation using two lateral portals: a cadaveric study to evaluate efficacy and safety. AB - BACKGROUND: Arthroscopic triple fusion has several advantages over open techniques, but its use has yet to become widespread. Preliminary published techniques use five portals with neurovascular risk. Our aim was to assess the safety and efficacy of an alternative lateral two portal technique. METHODS: Four cadaveric hindfeet were arthroscopically prepared for a triple fusion using two lateral portals. The distance to relevant subcutaneous nerves was measured as well as the prepared joint surface percentage. RESULTS: Mean distance from mid lateral portal to the nearest sural nerve branch was 22.3mm (range 20-24mm) and from the dorsolateral portal to the intermediate branch of the superficial peroneal nerve was 7.8mm (range 4-11mm). Mean percentages of joint preparation were 63% (talar head), 62% (navicular), 75% (calcaneum) and 74% (cuboid). CONCLUSIONS: Two lateral arthroscopic portals allow adequate joint preparation for triple fusion procedures. The proximity of subcutaneous nerves is important to appreciate when using these portals. PMID- 24796835 TI - Treatment of diabetic foot complications with hyperbaric oxygen therapy: a retrospective experience. AB - BACKGROUND: The aim of this study is to evaluate the role of hyperbaric oxygen in the treatment of diabetic foot ulcers. METHODS: We performed a retrospective observational study of all patients with diabetic foot ulcers treated at the Institution's hyperbaric chamber between January 2010 and August 2012. Patient data was obtained upon patient hospital visit and prospective clinical record consultation. RESULTS: Twenty-six foot lesions including 13 foot ulcers Wagner grade 2 or greater and 13 amputation stump ulcers were submitted to hyperbaric oxygen therapy between January 2010 and August 2012 in our Institution. Of these, 23 foot lesions completed treatment and complete epithelialization of the primary lesion was achieved in 15 (65%). The mean healing period since the first hyperbaric oxygen therapy session was 16 weeks. Above-ankle amputations were performed in 3 limbs and transmetatarsal amputations in 2 limbs. CONCLUSION: Hyperbaric oxygen may be associated with ulcer healing in selected diabetic foot ulcers with impaired cicatrization. PMID- 24796836 TI - Biomechanical comparison of first metatarsophalangeal joint arthrodeses using triple-threaded headless screws versus partially threaded lag screws. AB - BACKGROUND: Triple-threaded, cannulated headless screws of varying thread diameters and pitch are designed to maintain thread length across the arthrodesis plane, provide joint compression, and reduce countersinking. This study tested the biomechanical fixation strength of conventional partially threaded lag screws compared to triple-threaded headless screws in first metatarsophalangeal joint arthrodesis. METHODS: First metatarsophalangeal joint arthrodesis using a crossed screw technique was performed on 11 paired, preserved cadaver first rays with two 4.0-mm triple-threaded, cannulated headless screws or two 4.0-mm partially threaded, cannulated lag screws. The constructs were tested to failure through dorsally directed cantilever bending. RESULTS: The triple-threaded, cannulated headless screws displayed significantly greater bending stiffness (p=0.017) and failure load (p=0.040) during load-to-failure testing compared to the partially threaded, cannulated lag screws. CONCLUSIONS: Triple-threaded, cannulated headless screws may be a viable alternative to partially threaded lag screws in first metatarsophalangeal arthrodesis. PMID- 24796837 TI - Fashioning autologous bone graft from the fibula in the transfibular approach to open ankle arthrodesis. AB - Open ankle arthrodesis is one of the primary operations for disabling ankle arthrosis. The transfibular lateral approach to ankle fusion is a common approach for open ankle arthrodesis. Autologous bone graft can be harvested from the osteotomised fibula. We describe a safe technique of taking graduated slices of fibula bone graft, which allows optimal fibula length excision and are suitable in shape to pack into defects at the fusion site. PMID- 24796838 TI - Review of the treatment of distal tibia metaphyseal fractures; plating versus intramedullary nailing: a systematic review of recent evidence. PMID- 24796839 TI - Response to 'letter to the editor' by Mahmood and Kumar. PMID- 24796840 TI - Reconstruction of an extensive soft tissue and bone defect of the first metatarsal with the use of Masquelet technique: a case report. AB - The literature regarding reconstruction of foot bone defects is limited. The purpose of this study is to present a case report with an extensive bone defect of the first metatarsal bone which was treated with the use of the induced membrane technique. A 53-year-old man, with comminuted foot grade IIIb open fracture was treated with the Masquelet procedure. At 14 months follow-up, clinical and radiological assessment of the foot revealed osseous healing and no signs of infection, osteolysis or hardware failure. At 18 months follow-up, the patient had no pain and returned to his usual daily activities. The Masquelet procedure provides an effective method of treatment of extensive bone defects of the foot. It can restore the normal length and metatarsal arch minimizing the risk of complications that occurs with other surgical procedures. LEVEL OF EVIDENCE: Level V, case report. PMID- 24796841 TI - Large foot schwannoma with bone invasion - a case report. AB - A rare case of a large foot schwannoma with an intraosseous component is presented. Due to suspicion of malignancy, an amputation had previously been proposed. When the patient presented to us, the prolonged clinical course as well as some elements of the imaging exams suggested benignancy and we decided for complete tumor excision. Intraoperative findings supported the benign character of the neoplasm and pathology would later confirm the diagnosis of a benign schwannoma. The outcome, at 18 months of follow-up was a fully functional limb. Recurrence must still be considered but malignant transformation is very rare in a solitary schwannoma and can be discounted. Solitary benign schwannomas have a negligible malignization potential independently of their size or osseous component. When benignancy is considered, primary total tumor excision, as part of a staged procedure, is a safe approach. It allows for a thorough pathologic examination and eventually for a definitive treatment. PMID- 24796842 TI - Foreign body granulomatous reaction associated with polyethelene 'Fiberwire((r))' suture material used in Achilles tendon repair. AB - Repair of acute Achilles tendon rupture is a common procedure. There are many accepted surgical techniques; suture selection is largely due to surgeon preference. We present a case report of a granulomatous reaction to suture material following Achilles tendon repair. 'Fiberwire((r))' is an increasingly popular suture material for the repair of tendons and ligamentous structures; the polyethelene braided structure with silicone and polyester coating provides high tensile strengths and good handling characteristics. Eight months following uneventful Achilles tendon repair surgery in an otherwise fit and well patient, pain, swelling and loss of function was noted. She required revision surgery with debridement and reconstruction of the tendo Achillis with flexor hallucis longus tendon transfer. Histology revealed a granulomatous reaction with giant cell response surrounding sections of the suture. Both the silicone coating of Fiberwire((r)) and polyethylene core have the potential to cause a severe granulomatous reaction. We would advise caution in the use of this suture for tendo Achillis repair, and use the readily available alternatives. PMID- 24796843 TI - Checkrein deformity due to extensor hallucis longus hypotrophy treated with extensor digitorum longus tendon transfer. AB - Checkrein deformity is a relatively rare condition caused by hypotrophy or adhesion of a tendon after a lower leg injury. The occurrence of this condition due to the dysfunction of the extensor hallucis longus (EHL) is extremely rare. Only a few related case reports have been published, and Z-lengthening of the EHL tendon was performed for almost all patients. We report a case of checkrein deformity due to EHL hypotrophy. The patient was involved in a traffic accident 7 years ago. He sustained left tibial and fibular closed diaphyseal fractures and underwent minimally invasive plate osteosynthesis. He continued to have left great toe symptoms characterized by dorsiflexion of the great toe during ankle plantarflexion. The EHL had become an insufficient power source because of considerable hypotrophy. Therefore, a tendon transfer using the extensor digitorum longus to the second toe was performed as a primary treatment. PMID- 24796844 TI - Successful arthroscopic decompression and synthetic grafting of a posterior talar cyst: a case report. AB - We describe the endoscopic management of a large talar cyst using synthetic allograft gel. Three and a half years later the patient has returned to sport and repeat MRI demonstrates no further collapse of the cyst. PMID- 24796845 TI - Cancer vaccines: Trafficking of tumor-specific T cells to tumor after therapeutic vaccination. AB - Cancer vaccines can induce robust activation of tumor-specific CD8(+) T cells that can destroy tumors. Understanding the mechanism by which cancer vaccines work is essential in designing next-generation vaccines with more potent therapeutic activity. We recently reported that short peptides emulsified in poorly biodegradable, Incomplete Freund's Adjuvant (IFA) primed CD8(+) T cells that did not localize to the tumor site but accumulated at the persisting, antigen-rich vaccination site. The vaccination site eventually became a T cell graveyard where T cells responded to chronically released gp100 peptide by releasing cytokines, including interferon-gamma (IFN-gamma), which in turn upregulated Fas ligand (FasL) on host cells, causing apoptosis of Fas(+) T cells. T cells that escaped apoptosis rapidly became exhausted, memory formation was poor, and therapeutic impact was minimal. Replacing the non-biodegradable IFA based formulation with water-based, short-lived formulation in the presence of immunostimulatory molecules allowed T cells to traffic to tumors, causing their regression. In this review, we discuss recent advances in immunotherapeutic approaches that could enhance vaccine-primed immune cells fitness and render the tumor microenvironment more accessible for immune cell infiltration. PMID- 24796846 TI - LRP1-dependent pepsin clearance induced by 2'-hydroxycinnamaldehyde attenuates breast cancer cell invasion. AB - 2'-Hydroxycinnamaldehyde inhibits breast cancer cell invasion. This study examined whether 2'-hydroxycinnamaldehyde, acting as a Michael acceptor, interferes with the ligand binding of low-density lipoprotein receptor-related protein 1 to mediate breast cancer cell invasion. Low-density lipoprotein receptor-related protein 1, one of the direct molecular targets of 2' hydroxycinnamaldehyde, is a multifunctional endocytic receptor. Changes in the thiol oxidation status of cell surface receptor proteins may function as a molecular switch, influencing ligand(s) binding. The oxidation status of extracellular cysteine thiol groups in MCF-7 and MDA-MB-231 cells was examined using a fluorescence-activated cell sorter with thiol-specific fluorescent probes; Matrigel invasion and wound-healing assays were performed to determine the effects of 2'-hydroxycinnamaldehyde on in vitro cell migration. The molecular mechanisms by which 2'-hydroxycinnamaldehyde acts were evaluated by transient knockdown using siRNA or inhibition of low-density lipoprotein receptor-related protein 1 by receptor-associated protein treatment. 2'-Hydroxycinnamaldehyde increased alpha-2-macroglobulin binding to low-density lipoprotein receptor related protein 1, which was alleviated by pretreatment of cells with N acetylcystein. 2'-Hydroxycinnamaldehyde decreased the extracellular pepsin concentration significantly in a low-density lipoprotein receptor-related protein 1- and alpha-2-macroglobulin-dependent manner. The anti-invasive effect of 2' hydroxycinnamaldehyde was mitigated with receptor-associated protein pretreatment, suggesting that low-density lipoprotein receptor-related protein 1 is essential for the effects of 2'-hydroxycinnamaldehyde. From these data, we suggest that 2'-hydroxycinnamaldehyde increases the cysteine thiol oxidation status of low-density lipoprotein receptor-related protein 1 extracellular domains, which results in alpha-2-macroglobulin ligand binding stimulation. Therefore, pepsin clearance in a low-density lipoprotein receptor-related protein 1-alpha-2-macroglobulin-dependent manner might be an important molecular mechanism in 2'-hydroxycinnamaldehyde exerting its anti-invasive action on breast cancer cells. Furthermore, our data may provide an opportunity to promote the importance of the thiol oxidation status of cell surface receptor proteins for regulating cellular signaling pathways that are important in cancer progression. PMID- 24796847 TI - Cyclic AMP and the regeneration of retinal ganglion cell axons. AB - In this paper we present a brief review of studies that have reported therapeutic benefits of elevated cAMP on plasticity and regeneration after injury to the central nervous system (CNS). We also provide new data on the cellular mechanisms by which elevation of cyclic adenosine monophosphate (cAMP) promotes cytokine driven regeneration of adult CNS axons, using the visual system as the experimental model. cAMP is a second messenger for many intracellular signalling pathways. Elevation of cAMP in the eye by intravitreal injection of the cell permeant analogue (8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphate; CPT-cAMP), when added to recombinant ciliary neurotrophic factor (rCNTF), significantly enhances rCNTF-induced regeneration of adult rat retinal ganglion cell (RGC) axons into peripheral nerve (PN) grafted onto transected optic nerve. This effect is mediated to some extent by protein kinase A (PKA) signalling, but CPT-cAMP also acts via PI3K/Akt signalling to reduce suppressor of cytokine signalling protein 3 (SOCS3) activity in RGCs. Another target for cAMP is the exchange protein activated by cAMP (Epac), which can also mediate cAMP-induced axonal growth. Here we describe some novel results and discuss to what extent the pro-regenerative effects of CPT-cAMP on adult RGCs are mediated via Epac as well as via PKA-dependent pathways. We used the established PN-optic nerve graft model and quantified the survival and regenerative growth of adult rat RGCs after intravitreal injection of rCNTF in combination with a selective activator of PKA and/or a specific activator of Epac. Viable RGCs were identified by betaIII tubulin immunohistochemistry and regenerating RGCs retrogradely labelled and quantified after an injection of fluorogold into the distal end of the PN grafts, 4 weeks post-transplantation. The specific agonists of either PKA or Epac were both effective in enhancing the effects of rCNTF on RGC axonal regeneration, but interestingly, injections that combined rCNTF with both agonists were significantly less effective. The results are discussed in relation to previous CPT-cAMP studies on RGCs, and we also consider the need to modulate cAMP levels in order to obtain the most functionally effective regenerative response after CNS trauma. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID- 24796848 TI - Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys. AB - d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) versus serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anticocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT, and NE, and the role of manipulating NE release potency on abuse-related or anticocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT versus NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5 fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anticocaine effects of the compound with highest selectivity to release DA/5HT versus NE (PAL-542) were tested in an assay of cocaine versus food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggests that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE versus DA/5HT does not improve anticocaine efficacy. PMID- 24796849 TI - Positive smoking outcome expectancies mediate the association between negative affect and smoking urge among women during a quit attempt. AB - Ecological momentary assessment was used to examine associations between negative affect, positive smoking outcome expectancies, and smoking urge during the first 7 days of a smoking quit attempt. Participants were 302 female smokers who enrolled in an individually tailored smoking cessation treatment study. Multilevel mediation analysis was used to examine the temporal relationship among the following: (a) the effects of negative affect and positive smoking outcome expectancies at 1 assessment point (e.g., time j) on smoking urge at the subsequent time point (e.g., time j + 1) in Model 1; and, (b) the effects of negative affect and smoking urge at time j on positive smoking outcome expectancies at time j + 1 in Model 2. The results from Model 1 showed a statistically significant effect of negative affect at time j on smoking urge at time j + 1, and this effect was mediated by positive smoking outcome expectancies at time j, both within- and between-participants. In Model 2, the within participant indirect effect of negative affect at time j on positive smoking outcome expectancies at time j + 1 through smoking urge at time j was nonsignificant. However, a statistically significant indirect between participants effect was found in Model 2. The findings support the hypothesis that urge and positive smoking outcome expectancies increase as a function of negative affect, and suggest a stronger effect of expectancies on urge as opposed to the effect of urge on expectancies. PMID- 24796850 TI - Drunk personality: reports from drinkers and knowledgeable informants. AB - Existing literature supports the five-factor model (FFM) of personality (i.e., Extraversion, Agreeableness, Conscientiousness, Emotional Stability, and Intellect or Openness) as a comprehensive representation of stable aspects of mood, affect, and behavior. This study evaluated the FFM as a framework for both self-perceptions of drunkenness (i.e., individual changes in mood, affect, and behavior associated with one's own intoxication), as well "drinking buddies'" perceptions of their friends' drunkenness (i.e., changes in mood, affect, and behavior associated with friends' intoxication) and the association of reported sober-to-drunk differences with negative alcohol-related consequences. College student drinkers (N = 374; 187 drinking buddy pairs) reported on their sober and drunk levels of the 5 factors, as well as those of their drinking buddies. Buddies completed parallel assessments for themselves and their friends to ensure rater agreement. All participants completed assessments of harmful alcohol outcomes experienced within the past year. Regardless of reporter, differences between drunken and sober states were found across all 5 factors and agreement between self and informant reports was consistently significant and comparable across sober and drunk conditions. Low levels of drunk Conscientiousness and drunk Emotional Stability were associated with experiencing more alcohol-related consequences, even when controlling for sober factor levels and binge-drinking frequency. Findings support the use of the FFM as a clinically relevant framework for organizing differences in personality expression associated with intoxication and the validity of self-reports of drunk personality. PMID- 24796851 TI - Expression of neuron-specific enolase in multiple myeloma and implications for clinical diagnosis and treatment. AB - OBJECTIVE: To determine the expression of neuron-specific enolase (NSE) in patients with multiple myeloma (MM) and to evaluate its clinical value as a tumor marker and, an indicator of disease progression and treatment efficacy. METHODS: Using electrochemiluminescence immunoassay (ECLIA), we measured the serum levels of NSE in 47 healthy subjects (control group), 25 patients with small cell lung cancer (lung cancer group), and 52 patients with MM (MM group). For the MM group, serum NSE levels were measured and other disease indicators and related symptoms were monitored before and after chemotherapy. The relationship between NSE expression and other MM-related factors was analyzed. In addition, immunohistochemical staining was performed on bone marrow biopsy specimens from patients with MM. RESULTS: In the control group, serum NSE levels were within the normal range as previously reported, while the lung cancer group and the untreated MM group exhibited NSE levels that were significantly higher relative to the control group (P<0.05). The difference in NSE expression between the lung cancer group and untreated MM group was statistically significant (P<0.05). NSE levels were significantly decreased in MM patients after chemotherapy and were positively correlated with an MM disease index [beta-2 microglobulin (beta2-MG)]. Changes in NSE were not related to the response rate to chemotherapy but rather were correlated with progression-free survival. CONCLUSIONS: Patients with MM may have increased serum NSE levels, and changes in NSE may provide insight into treatment efficacy of chemotherapy and disease progression. Perhaps NSE expression is a viable biomarker for MM and can be a useful reference for the design and adjustment of clinical MM treatment programs. PMID- 24796852 TI - Sensitivity of arterial spin labeling perfusion MRI to pharmacologically induced perfusion changes in rat kidneys. AB - PURPOSE: To investigate whether arterial spin labeling (ASL) MRI is sensitive to changes by pharmacologically induced vasodilation and vasoconstriction in rat kidneys. MATERIALS AND METHODS: Changes in renal cortical blood flow in seven rats were induced by adenosine infusion (vasodilation) and L-NAME injection (vasoconstriction). All imaging studies were performed on a 3 Tesla scanner using a FAIR-TrueFISP sequence for the ASL implementation. The acquisition time for each ASL scan was 6 min. Cortical perfusion rates were calculated using regions of interest analysis, and the differences in perfusion rates during baseline, vasodilation, and vasoconstriction were compared and assessed for statistical significance. RESULTS: Compared with the baseline, an average of 94 mL/100 g/min increase and 157 mL/100 g/min decrease in cortical perfusion was observed following adenosine infusion and L-NAME administration, respectively. The changes in cortical perfusion were significant between baseline and vasodilation (P < 0.05), baseline and vasoconstriction (P < 0.01), and vasodilation and vasoconstriction (P < 0.01). CONCLUSION: ASL is sensitive to pharmacologically induced perfusion changes in rat kidneys at doses comparable to current use. The preliminary results suggest the feasibility of ASL for investigating renal blood flow in a variety of rodent models. PMID- 24796853 TI - A single pathophysiological pathway in Takotsubo cardiomyopathy: Catecholaminergic stress. AB - BACKGROUND: Takotsubo cardiomyopathy (TTC) continues to be under-diagnosed, due to its varying presentation, with potentially serious consequences if treatment is delayed. AIMS: To demonstrate the consistent involvement of catecholaminergic stress in TTC, regardless of the trigger. METHODS: Between 01 July 2009 and 31 August 2013, patients managed in our centre for thoracic pain syndrome, with or without troponin release, were followed up prospectively. TTC was diagnosed from the apical ballooning seen on left ventricular imaging (angiography or transthoracic echocardiography) in the absence of a significant coronary artery lesion. Triggers (emotional trauma, surgical stress and beta2-mimetic intoxication) were recorded; catecholamine-secreting tumours were screened for with a urinary methoxylate-derivative assay. RESULTS: TTC was diagnosed in 40 out of 2754 (1.5%) patients with thoracic pain syndrome, with or without troponin release. Triggers were emotional trauma (n=29, 72.5%), surgical stress (n=5, 12.5%), adrenergic intoxication (n=3, 7.5%) and catecholaminergic tumour (n=3, 7.5%). Mean left ventricular ejection fraction at admission was 38.0 +/- 15.7%. Eight (20%) patients initially showed cardiogenic shock. In-hospital mortality was 7.5%, with no deaths from cardiogenic causes. Thirty-five (94.6%) of the survivors had recovered a normal left ventricular ejection fraction (> 55%) by discharge. CONCLUSION: Whatever the trigger, the common denominator in TTC is catecholaminergic stress. Classically suggested after emotional trauma, TTC may also be induced by surgical stress or endogenous or iatrogenic beta2-mimetic intoxication. The various contexts all have a similarly excellent cardiovascular prognosis if treated early. PMID- 24796854 TI - Image-based simulation of urethral distensibility and flow resistance as a function of pelvic floor anatomy. AB - AIMS: The goal of this study is to develop an image-based model of urethral distention and resistance in women with and without SUI. METHODS: A biomechanical vector force model was created to simulate the mechanical deformation of pelvic floor structures during cough and Valsalva in order to measure urethral distension and predict flow resistance patterns. Dynamic MRI images were used to create a spatial model to construct an accurate representation of tissue thickness and location, which was combined with tissue property values (MATLAB 2011a, MathWorks, Natick, MA). Spatial profiles were created to demonstrate the effects of hypermobility and tissue property variability on distensibility and flow resistance along the urethra. Sensitivity analyses were conducted to demonstrate the relationship between flow resistance and various tissue properties. RESULTS: The average distension for incontinent cases (3.8 mm) was significantly greater than that of continent cases (2.6 mm) (t = 3.3083, df = 8, P < 0.01), corresponding to a 70% drop in average resistance to urine flow. Sensitivity analyses demonstrated that the stiffness and contractility of the vagina and urethra had the greatest effect on continence. CONCLUSIONS: We present a novel, 2-dimensional biomechanical model of female stress urinary incontinence (SUI) that relates the effects of various factors such as tissue elasticity, pelvic floor structure, and muscle activation. A better understanding of the pathophysiology underlying SUI has potential implications for the creation of novel targeted treatments. PMID- 24796855 TI - Catalase mimic property of Co3O4 nanomaterials with different morphology and its application as a calcium sensor. AB - The applications of inorganic nanomaterials as biomimetic catalysts are receiving much attention because of their high stability and low cost. In this work, Co3O4 nanomaterials including nanoplates, nanorods, and nanocubes were synthesized. The morphologies and compositions of the products were characterized by scanning electron microscopy, transmission electron microscopy, and X-ray diffraction. The catalytic properties of Co3O4 nanomaterials as catalase mimics were studied. The Co3O4 materials with different morphology exhibited different catalytic activities in the order of nanoplates > nanorods > nanocubes. The difference of the catalytic activities originated from their different abilities of electron transfer. Their catalytic activities increased significantly in the presence of calcium ion. On the basis of the stimulation by calcium ion, a biosensor was constructed by Co3O4 nanoplates for the determination of calcium ion. The biosensor had a linear relation to calcium concentrations and good measurement correlation between 0.1 and 1 mM with a detection limit of 4 MUM (S/N = 3). It showed high selectivity against other metal ions and good reproducibility. The proposed method was successfully applied for the determination of calcium in a milk sample. PMID- 24796857 TI - Identification of a Pantoea biosynthetic cluster that directs the synthesis of an antimicrobial natural product. AB - Fire Blight is a destructive disease of apple and pear caused by the enteric bacterial pathogen, Erwinia amylovora. E. amylovora initiates infection by colonizing the stigmata of apple and pear trees, and entering the plants through natural openings. Epiphytic populations of the related enteric bacterium, Pantoea, reduce the incidence of disease through competition and antibiotic production. In this study, we identify an antibiotic from Pantoea ananatis BRT175, which is effective against E. amylovora and select species of Pantoea. We used transposon mutagenesis to create a mutant library, screened approximately 5,000 mutants for loss of antibiotic production, and recovered 29 mutants. Sequencing of the transposon insertion sites of these mutants revealed multiple independent disruptions of an 8.2 kb cluster consisting of seven genes, which appear to be coregulated. An analysis of the distribution of this cluster revealed that it was not present in any other of our 115 Pantoea isolates, or in any of the fully sequenced Pantoea genomes, and is most closely related to antibiotic biosynthetic clusters found in three different species of Pseudomonas. This identification of this biosynthetic cluster highlights the diversity of natural products produced by Pantoea. PMID- 24796856 TI - Network dysfunction in Alzheimer's disease: refining the disconnection hypothesis. AB - Much effort in recent years has focused on understanding the effects of Alzheimer's disease (AD) on neural function. This effort has resulted in an enormous number of papers describing different facets of the functional derangement seen in AD. A particularly important tool for these investigations has been resting-state functional connectivity. Attempts to comprehensively synthesize resting-state functional connectivity results have focused on the potential utility of functional connectivity as a biomarker for disease risk, disease staging, or prognosis. While these are all appropriate uses of this technique, the purpose of this review is to examine how functional connectivity disruptions inform our understanding of AD pathophysiology. Here, we examine the rationale and methodological considerations behind functional connectivity studies and then provide a critical review of the existing literature. In conclusion, we propose a hypothesis regarding the development and spread of functional connectivity deficits seen in AD. PMID- 24796858 TI - Functional characterization of the Xanthophyllomyces dendrorhous farnesyl pyrophosphate synthase and geranylgeranyl pyrophosphate synthase encoding genes that are involved in the synthesis of isoprenoid precursors. AB - The yeast Xanthophyllomyces dendrorhous synthesizes the carotenoid astaxanthin, which has applications in biotechnology because of its antioxidant and pigmentation properties. However, wild-type strains produce too low amounts of carotenoids to be industrially competitive. Considering this background, it is indispensable to understand how the synthesis of astaxanthin is controlled and regulated in this yeast. In this work, the steps leading to the synthesis of the carotenoid precursor geranylgeranyl pyrophosphate (GGPP, C20) in X. dendrorhous from isopentenyl pyrophosphate (IPP, C5) and dimethylallyl pyrophosphate (DMAPP, C5) was characterized. Two prenyl transferase encoding genes, FPS and crtE, were expressed in E. coli. The enzymatic assays using recombinant E. coli protein extracts demonstrated that FPS and crtE encode a farnesyl pyrophosphate (FPP, C15) synthase and a GGPP-synthase, respectively. X. dendrorhous FPP-synthase produces geranyl pyrophosphate (GPP, C10) from IPP and DMAPP and FPP from IPP and GPP, while the X. dendrorhous GGPP-synthase utilizes only FPP and IPP as substrates to produce GGPP. Additionally, the FPS and crtE genes were over expressed in X. dendrorhous, resulting in an increase of the total carotenoid production. Because the parental strain is diploid, the deletion of one of the alleles of these genes did not affect the total carotenoid production, but the composition was significantly altered. These results suggest that the over expression of these genes might provoke a higher carbon flux towards carotenogenesis, most likely involving an earlier formation of a carotenogenic enzyme complex. Conversely, the lower carbon flux towards carotenogenesis in the deletion mutants might delay or lead to a partial formation of a carotenogenic enzyme complex, which could explain the accumulation of astaxanthin carotenoid precursors in these mutants. In conclusion, the FPS and the crtE genes represent good candidates to manipulate to favor carotenoid biosynthesis in X. dendrorhous. PMID- 24796859 TI - Disappearance of GFP-positive hepatocytes transplanted into the liver of syngeneic wild-type rats pretreated with retrorsine. AB - BACKGROUND AND AIM: Green fluorescent protein (GFP) is a widely used molecular tag to trace transplanted cells in rodent liver injury models. The differing results from various previously reported studies using GFP could be attributed to the immunogenicity of GFP. METHODS: Hepatocytes were obtained from GFP-expressing transgenic (Tg) Lewis rats and were transplanted into the livers of wild-type Lewis rats after they had undergone a partial hepatectomy. The proliferation of endogenous hepatocytes in recipient rats was inhibited by pretreatment with retrorsine to enhance the proliferation of the transplanted hepatocytes. Transplantation of wild-type hepatocytes into GFP-Tg rat liver was also performed for comparison. RESULTS: All biopsy specimens taken seven days after transplantation showed engraftment of transplanted hepatocytes, with the numbers of transplanted hepatocytes increasing until day 14. GFP-positive hepatocytes in wild-type rat livers were decreased by day 28 and could not be detected on day 42, whereas the number of wild-type hepatocytes steadily increased in GFP-Tg rat liver. Histological examination showed degenerative change of GFP-positive hepatocytes and the accumulation of infiltrating cells on day 28. PCR analysis for the GFP transgene suggested that transplanted hepatocytes were eliminated rather than being retained along with the loss of GFP expression. Both modification of the immunological response using tacrolimus and bone marrow transplantation prolonged the survival of GFP-positive hepatocytes. In contrast, host immunization with GFP-positive hepatocytes led to complete loss of GFP positive hepatocytes by day 14. CONCLUSION: GFP-positive hepatocytes isolated from GFP-Tg Lewis rats did not survive long term in the livers of retrorsine pretreated wild-type Lewis rats. The mechanism underlying this phenomenon most likely involves an immunological reaction against GFP. The influence of GFP immunogenicity on cell transplantation models should be considered in planning in vivo experiments using GFP and in interpreting their results. PMID- 24796860 TI - Stereoselectivity of chiral drug transport: a focus on enantiomer-transporter interaction. AB - Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism and elimination. Many literature works presenting important aspects related to stereochemistry of drug metabolism are available. However, there is very little literature on stereoselectivity of chiral drug transport and enantiomer-transporter interaction. In recent years, the experimental research within this field showed good momentum. Herein, an up-to date review on this topic was presented. Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Proteins (MRP), P-glycoprotein (P-gp), Organic Anion Transporters (OATs), Organic Anion Transporting Polypeptides (OATPs), Organic Cation Transporters (OCTs), Peptide Transport Proteins (PepTs), Human Proton Coupled Folate Transporter (PCFT) and Multidrug and Toxic Extrusion Proteins (MATEs), have been reported to exhibit either positive or negative enantio selective substrate recognition. The approaches utilized to study chirality in enantiomer-transporter interaction include inhibition experiments of specific transporters in cell models (e.g. Caco-2 cells), transport study using drug resistance cell lines or transgenic cell lines expressing transporters in wild type or variant, the use of transporter knockout mice, pharmacokinetics association of single nucleotide polymorphism in transporters, pharmacokinetic interaction study of racemate in the presence of specific transporter inhibitor or inducer, molecule cellular membrane affinity chromatography and pharmacophore modeling. Enantiomer-enantiomer interactions exist in chiral transport. The strength and/or enantiomeric preference of stereoselectivity may be species or tissue-specific, concentration-dependent and transporter family member-dependent. Modulation of specific drug transporter by pure enantiomers might exhibit opposite stereoselectivity. Further studies with integrated approaches will open up new horizons in stereochemistry of pharmacokinetics. PMID- 24796861 TI - One-pot organocatalytic enantioselective Michael-Michael-aldol-Henry reaction cascade. A facile entry to the steroid system with six contiguous stereogenic centers. AB - An expedited method has been developed for the enantioselective synthesis of highly functionalized steroid systems containing six contiguous stereogenic centers with high enantioselectivities (99% ee). The one-pot methodology comprises a cascade of organocatalytic Michael-Michael-aldol-Henry reactions of 7 nitrohept-3-en-2-one and 5-(1-methyl-2,5-dioxocyclopentyl)pent-2-enal. The structure and absolute configuration of the products were confirmed by X-ray analyses of appropriate products. PMID- 24796863 TI - Effectiveness of cooking to reduce norovirus and infectious F-specific RNA bacteriophage concentrations in Mytilus edulis. AB - AIMS: The aim of this study was to determine if domestic cooking practices can reduce concentrations of norovirus (NoV) and F-specific RNA (FRNA) bacteriophage in experimentally contaminated mussels. METHODS AND RESULTS: Mussels (n = 600) contaminated with NoV and FRNA bacteriophage underwent four different cooking experiments performed in triplicate at ~70 degrees C and >90 degrees C. Concentrations of infectious FRNA bacteriophage (using a plaque assay) were compared with concentrations of FRNA bacteriophage and NoV determined using a standardised RT-qPCR. Initial concentrations of infectious FRNA bacteriophage (7.05 log10 PFU g(-1) ) in mussels were not significantly reduced in simmering water (~70 degrees C); however, cooking at higher temperatures (>90 degrees C) reduced infectious FRNA bacteriophage to undetected levels within 3 min. Further investigation determined the time required for a 1-log reduction of infectious FRNA bacteriophage at 90 degrees C to be 42 s therefore a >3-log reduction in infectious virus can be obtained by heating mussel digestive tissue to 90 degrees C for 126 s. CONCLUSIONS: Domestic cooking practices based on shell opening alone do not inactivate infectious virus in mussels, however, cooking mussels at high temperatures is effective to reduce infectious virus concentrations and the risk of illness in consumers. SIGNIFICANCE AND IMPACT OF THE STUDY: The data will contribute towards evidence-based cooking recommendations for shellfish to provide a safe product for human consumption. PMID- 24796862 TI - Resveratrol and its metabolites bind to PPARs. AB - Resveratrol, a modulator of several signaling proteins, can exert off-target effects involving the peroxisome proliferator-activated receptor (PPAR) transcription factors. However, evidence for the direct interaction between this polyphenol and PPARs is lacking. Here, we addressed the hypothesis that resveratrol and its metabolites control aspects of PPAR transcriptional activity through direct interaction with PPARs. Bioaffinity chromatographic studies with the immobilized ligand-binding domains (LBDs) of PPARgamma and PPARalpha and isothermal titration calorimetry allowed the binding affinities of resveratrol, resveratrol 3-O-glucuronide, resveratrol 4-O-glucuronide, and resveratrol 3-O sulfate to both PPAR-LBDs to be determined. Interaction of resveratrol, resveratrol 3-O-glucuronide, and resveratrol 4-O-glucuronide with PPARgamma-LBD occurred with binding affinities of 1.4, 1.1, and 0.8 MUM, respectively, although only resveratrol bound to the PPARalpha-LBD with a binding affinity of 2.7 MUM. Subsequently, X-ray crystallographic studies were carried out to characterize resveratrol binding to the PPARgamma-LBD at the molecular level. The electron density map from the crystal structure of the complex between PPARgamma-LBD and resveratrol revealed the presence of one molecule of resveratrol bound to the LBD of PPARgamma, with the ligand occupying a position close to that of other known PPARgamma ligands. Transactivation assays were also performed in HepG2 cells, with the results showing that resveratrol was not a PPAR agonist but instead was able to displace rosiglitazone from PPARgamma and Wy-14643 from PPARalpha with IC50 values of (27.4+/-1.8) MUM and (31.7+/-2.5) MUM, respectively. We propose that resveratrol acts as a PPAR antagonist through its direct interaction with PPARgamma and PPARalpha. PMID- 24796864 TI - The effects of separate and combined dietary weight loss and exercise on fasting ghrelin concentrations in overweight and obese women: a randomized controlled trial. AB - OBJECTIVE: Compensatory metabolic changes that accompany weight loss, for example, increased ghrelin, contribute to weight regain and difficulty in long term weight loss maintenance; however, the separate effects of long-term caloric restriction and exercise on total circulating ghrelin in humans are unknown. DESIGN: A 12-month randomized controlled trial comparing: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 45 min/day, 5 days/week ('exercise'; n = 117); iii) dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle-change control (n = 87). PARTICIPANTS: 439 overweight or obese postmenopausal women (50 75 y). MEASUREMENTS: Fasting total serum ghrelin was measured by radioimmunoassay at baseline and 12 months. Fasting serum leptin, adiponectin and insulin were also measured. RESULTS: Fasting total ghrelin significantly increased in the diet + exercise arm (+7.4%, P = 0.008) but not in either the diet (+6.5%, P = 0.07) or exercise (+1.0%, P = 0.53) arms compared with control. Greater weight loss was associated with increased ghrelin concentrations, regardless of intervention. Neither baseline ghrelin nor body composition modified the intervention effects on changes in total ghrelin. The 12-month change in total ghrelin was inversely associated with changes in leptin, insulin and insulin resistance, and positively associated with change in adiponectin. CONCLUSIONS: Greater weight loss, achieved through a reduced calorie diet or exercise, is associated with increased total ghrelin concentrations in overweight or obese postmenopausal women. PMID- 24796865 TI - CaMKII binding to GluN2B is differentially affected by macromolecular crowding reagents. AB - Binding of the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B controls long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning and memory. Regulation of this interaction is well-studied biochemically, but not under conditions that mimic the macromolecular crowding found within cells. Notably, previous molecular crowding experiments with lysozyme indicated an effect on the CaMKII holoenzyme conformation. Here, we found that the effect of molecular crowding on Ca2+/CaM-induced CaMKII binding to immobilized GluN2B in vitro depended on the specific crowding reagent. While binding was reduced by lysozyme, it was enhanced by BSA. The ATP content in the BSA preparation caused CaMKII autophosphorylation at T286 during the binding reaction; however, enhanced binding was also observed when autophosphorylation was blocked. Importantly, the positive regulation by nucleotide and BSA (as well as other macromolecular crowding reagents) did not alleviate the requirement for CaMKII stimulation to induce GluN2B binding. The differential effect of lysozyme (14 kDa) and BSA (66 kDa) was not due to size difference, as both dextran-10 and dextran-70 enhanced binding. By contrast, crowding with immunoglobulin G (IgG) reduced binding. Notably, lysozyme and IgG but not BSA directly bound to Ca2+/CaM in an overlay assay, suggesting a competition of lysozyme and IgG with the Ca2+/CaM-stimulus that induces CaMKII/GluN2B binding. However, lysozyme negatively regulated binding even when it was instead induced by CaMKII T286 phosphorylation. Alternative modes of competition would be with CaMKII or GluN2B, and the negative effects of lysozyme and IgG indeed also correlated with specific or non-specific binding to the immobilized GluN2B. Thus, the effect of any specific crowding reagent can differ, depending on its additional direct effects on CaMKII/GluN2B binding. However, the results of this study also indicate that, in principle, macromolecular crowding enhances CaMKII binding to GluN2B. PMID- 24796866 TI - Role of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) in the antibacterial immunity of Marsupenaeus japonicus. AB - The Toll/Toll-like receptor (TLR) signaling pathway has an important role in the innate immunity of animals. Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein that functions as an adaptor protein for the Toll/TLR and bone morphogenetic protein signaling pathways. ECSIT is also a key component in the macrophage bactericidal activity of mammals. However, the function of ECSIT in crustaceans remains unclear. In this study, we cloned and identified a functional ECSIT homologue, MjECSIT 1, from kuruma shrimp Marsupenaeus japonicus. The complementary DNA of MjEcsit 1 is 1442 base pairs long, with an open reading frame of 1221 base pairs that encodes a 407-residue polypeptide. Transcripts of MjEcsit 1 are detected in hemocytes, gills, hepatopancreas, stomach, heart, intestines, testes, and ovaries. Such transcripts are upregulated by Gram-positive bacteria (Staphylococcus aureus) and Gram negative bacteria (Vibrio anguillarum) injections. The knockdown of MjEcsit 1 by double-stranded RNA injection increases the sensitivity of M. japonicus to S. aureus challenge and weakens the bacterial clearance ability of M. japonicus in vivo. In addition, suppressing MjEcsit 1 restrains the upregulation of two anti lipopolysaccharide factors by S. aureus injection. The results indicate that MjECSIT 1 is important in the antibacterial immunity of M. japonicus. PMID- 24796867 TI - Future prospects for prophylactic immune stimulation in crustacean aquaculture - the need for improved metadata to address immune system complexity. AB - Future expansion of the crustacean aquaculture industry will be required to ensure global food security. However, this expansion must ensure: (a) that natural resources (including habitat use and fish meal) are sustainably exploited, (b) that the socio-economic development of producing nations is safeguarded, and (c) that the challenge presented by crustacean diseases is adequately met. Conventionally, the problem of disease in crustacean aquaculture has been addressed through prophylactic administration of stimulants, additives or probiotics. However, these approaches have been questioned both experimentally and philosophically. In this review, we argue that real progress in the field of crustacean immune stimulants has now slowed, with only incremental advances now being made. We further contend that an overt focus on the immune effector response has been misguided. In light of the wealth of new data reporting immune system complexity, a more refined approach is necessary - one that must consider the important role played by pattern recognition proteins. In support of this more refined approach, there is now a much greater requirement for the reporting of essential metadata. We propose a broad series of recommendations regarding the 'Minimum Information required to support a Stimulant Assessment experiment' (MISA guidelines) to foster new progression within the field. PMID- 24796868 TI - Cloning and characterization of two different L-type lectin genes from the Chinese mitten crab Eriocheir sinensis. AB - L-type lectins contain a leguminous lectin domain and bind to high-mannose type oligosaccharides. In the secretory pathway, L-type lectins play crucial functions in the trafficking, sorting, and targeting of maturing glycoproteins. This study identified two novel L-type lectins, designated as EsERGIC-53 and EsVIP36, from the Chinese mitten crab Eriocheir sinensis. The complete nucleotide sequence of ERGIC-53 cDNA was 1955 bp, containing a 1506 bp open reading frame (ORF) encoding a putative protein of 501 deduced amino acids. The full-length cDNA of VIP36 was 3474 bp with a 984 bp ORF encoding a 327-amino acid peptide. The deduced ERGIC-53 and VIP36 proteins contained a putative signal peptide and an L-type lectin-like domain. Phylogenetic analysis showed that ERGIC-53 and VIP36 belonged to different clades of L-type lectin family. Reverse transcription PCR showed that ERGIC-53 and VIP36 were expressed in all tested tissues. Quantitative real-time RT-PCR analysis revealed that ERGIC-53 and VIP36 transcripts in hepatopancreas were significantly induced at various time points after infection with lipopolysaccharide (LPS), peptidoglycan (PGN), Staphylococcus aureus, Vibrio parahaemolyticus, and Aeromonas hydrophila. A bacterium-binding experiment showed that both ERGIC-53 and VIP36 could bind to different microbes. Sugar binding assay revealed that these lectins could also bind to the glycoconjugates of bacteria surface, such as LPS, PGN, d-Mannose, and N-Acetyl-d-mannosamine. Moreover, these two L-type lectins agglutinated bacteria in a calcium-dependent manner, and both exerted the ability of facilitating the clearance of injected bacteria V. parahaemolyticus in the crab. Our results suggested that ERGIC-53 and VIP36 functioned as pattern recognition receptors in the immune system of E. sinensis. PMID- 24796869 TI - Obstructed bi-leaflet prosthetic mitral valve imaging with real-time three dimensional transesophageal echocardiography. AB - Real-time three-dimensional transesophageal echocardiography (RT3D-TEE) can provide unique visualization and better understanding of the relationship among cardiac structures. Here, we report the case of an 85-year-old woman with an obstructed mitral prosthetic valve diagnosed promptly by RT3D-TEE, which clearly showed a leaflet stuck in the closed position. The opening and closing angles of the valve leaflets measured by RT3D-TEE were compatible with those measured by fluoroscopy. Moreover, RT3D-TEE revealed, in the ring of the prosthetic valve, thrombi that were not visible on fluoroscopy. RT3D-TEE might be a valuable diagnostic technique for prosthetic mitral valve thrombosis. PMID- 24796870 TI - PTSD symptom clusters are differentially associated with components of the acquired capability for suicide. AB - Previous research has established the link between posttraumatic stress disorder (PTSD) and suicidal behavior. In the current study, constructs proposed to explain this relationship were examined, applying the framework of the interpersonal-psychological theory of suicide (IPTS). Relationships between acquired capability for suicide (ACS; i.e., fearlessness about death [FAD] and pain tolerance) and specific PTSD symptom clusters were explored. In a sample of 334 trauma-exposed undergraduates, anxious arousal and FAD were negatively associated, and numbing and pain tolerance were positively associated. Results establish a foundation for investigating the role of ACS in understanding observed relationships between suicidal behavior and PTSD symptoms. PMID- 24796871 TI - Csa2, a member of the Rbt5 protein family, is involved in the utilization of iron from human hemoglobin during Candida albicans hyphal growth. AB - Csa2 is a member of both the Candida albicans Rbt5 protein family and the Common in Fungal Extracellular Membranes (CFEM) protein superfamily. CFEM proteins are characterized by an internal domain containing eight equally spaced cysteine residues. Csa2 is involved in iron uptake from hemoglobin and heme proteins; however, its precise role is unclear. Here, we provide quantitative evidence of the involvement of Csa2 in the utilization of iron from human hemoglobin during C. albicans hyphal growth. The ability of the hyphal form of the wild-type (wt), a homozygote csa2Delta mutant, and a complemented strain of C. albicans to utilize hemoglobin as an iron source under iron-restricted conditions was examined through growth studies and a crystal violet-staining assay. Hemoglobin binding activity was assessed indirectly using a hemoglobin-sensitized tube method. Although hyphal growth of the wt and csa2Delta/Delta::CSA2 strains was completely recovered when a high concentration of human hemoglobin was added to the iron-restricted culture medium, the recovery of the csa2Delta/Delta mutant was significantly diminished. Furthermore, hemoglobin binding was impaired in the csa2Delta/Delta mutant compared with the wt and csa2Delta/Delta::CSA2 strains, revealing that Csa2 is involved in the utilization of hemoglobin as an iron source by the hyphal form of C. albicans. PMID- 24796872 TI - Winter climate change affects growing-season soil microbial biomass and activity in northern hardwood forests. AB - Understanding the responses of terrestrial ecosystems to global change remains a major challenge of ecological research. We exploited a natural elevation gradient in a northern hardwood forest to determine how reductions in snow accumulation, expected with climate change, directly affect dynamics of soil winter frost, and indirectly soil microbial biomass and activity during the growing season. Soils from lower elevation plots, which accumulated less snow and experienced more soil temperature variability during the winter (and likely more freeze/thaw events), had less extractable inorganic nitrogen (N), lower rates of microbial N production via potential net N mineralization and nitrification, and higher potential microbial respiration during the growing season. Potential nitrate production rates during the growing season were particularly sensitive to changes in winter snow pack accumulation and winter soil temperature variability, especially in spring. Effects of elevation and winter conditions on N transformation rates differed from those on potential microbial respiration, suggesting that N-related processes might respond differently to winter climate change in northern hardwood forests than C-related processes. PMID- 24796873 TI - Deep neck infection with descending necrotizing mediastinitis presenting as empyema thoracis. PMID- 24796874 TI - Age and socioeconomic inequalities in health: examining the role of lifestyle choices. AB - The role of lifestyle choices in explaining how socioeconomic inequalities in health vary with age has received little attention. This study explores how the income and education gradients in both important lifestyle choices and self assessed health (SAH) vary with age. Repeated cross-sectional data from Norway (n=25,016) and logistic regression models are used to track the income and education gradients in physical activity, smoking, consumption of fruit and vegetables and SAH over the age range 25-79 years. The education gradient in smoking, the income gradient in consumption of fruit and vegetables and the education gradient in physical activity among males become smaller at older ages. Physical activity among females is the only lifestyle indicator in which the income and education gradients grow stronger at older ages. In conclusion, this study shows that income and education gradients in lifestyle choices may not remain constant, but vary with age, and such variation could be important in explaining corresponding age patterns of inequality in health. PMID- 24796875 TI - Factors of change and cumulative factors in self-rated health trajectories: a systematic review. AB - In Western societies, self-rated health (SRH) inequalities have increased over the past decades. Longitudinal studies suggest that the SRH trajectories of disadvantaged populations are declining at a faster rate than those of advantaged populations, resulting in an accumulation of (dis)advantages over the life course, as postulated by the Cumulative Advantage/Disadvantage (CAD) model. The objectives of this study are to conduct a systematic review of the factors influencing SRH trajectories in the adult population and to assess to what extent the findings support the CAD model. Based on the inclusion criteria, 36 articles, using 15 nationally representative databases, were reviewed. The results show that young age, high socioeconomic position and marital transitions (entering a partnership) are advantageous factors of change in SRH trajectories. However, evidence for cumulative influences supporting the CAD model remains limited: gender, ethnicity, education and employment status are only moderately associated with growing influences over time, and the cumulative influences of income, occupation, age and marital status are weak. In conclusion, this systematic review provides consolidated evidence on the factors influencing SRH trajectories, though the inclusion of only 15 nationally representative databases may limit the generalization of the results. PMID- 24796876 TI - Marrying after arriving: The role of individuals' networks for immigrant choice of partner's origin. AB - This paper analyses the impact of social networks on the transition to marriage among recently arrived, single, immigrants in Spain. Our hypothesis states that the existence of individual networks at the moment of arrival strongly influences partner selection. Using the 2007 Spanish National Immigration Survey we apply competing risk models to estimate the likelihood of endogamous or exogamous marriage, for men and women separately. The analysis shows that among immigrant men and women, the presence of relatives or friends from their home-country at the time of arrival increases the probability of marriage to a co-national. Correspondingly, immigrants who obtained Spanish citizenship before migrating present higher chances of intermarriage, as they are likely to have more contact with the host society. PMID- 24796877 TI - Pathways to adulthood and changes in health-promoting behaviors. AB - The transition to adulthood in the US has become increasingly diverse over the last fifty years, leaving young adults without a normative pathway to adulthood. Using Waves I and III of the National Longitudinal Study of Adolescent Health (N=7803), I draw from a cumulative advantages/disadvantages (CAD) perspective to examine the relationships between union formation, parenthood, college attendance, full-time employment, home-leaving, and changes in health-promoting behaviors between adolescence and young adulthood. I find that men and women who marry, cohabit, or attend college during the transition from adolescence to young adulthood report fewer losses in healthy behaviors over time. When the sample is divided into mutually exclusive "pathways to adulthood", two higher-risk groups emerge for both men and women: single parents and those transitioning into fulltime work without attending college or forming families. These groups experience greater losses in healthy behaviors over time even after adjusting for family of origin characteristics and may be at long-term risk for persistently low engagement in health-promoting behaviors. PMID- 24796878 TI - Evaluation of spatial memory and locomotor activity during hypercortisolism induced by the administration of dexamethasone in adult male rats. AB - In neurosurgery practice glucocorticoids are commonly used. Steroids may have central nervous system side effects affecting whole body, including steroid induced mental agitation and psychosis. In experimental and clinical studies conducted by using dexamethasone (DEX), it has been reported that DEX adversely affects learning and memory skills. Unfortunately, there are yet no clinically accepted clinical approaches to prevent DEX-induced cognitive dysfunction. In this experimental study it was aimed to investigate the effect of chronic DEX administration on learning-memory and locomotor behaviors in adult male Sprague Dawley rats. In addition, it was also aimed to explore the potential favorable contribution of melatonin (MEL) and vitamin C (Vit C) having antioxidant and neuroprotective properties to the effects of DEX on learning-memory and locomotor behaviors. For this purpose, rats were injected 10mg/kg DEX intraperitoneally, both alone and in combination with MEL (40 mg/kg) and Vit C (100mg/kg), for 9 days, and the animals were tested using the radial arm maze and open field apparatus. The test results revealed that DEX caused a significant decrease in spatial memory and locomotor activities and MEL and Vit C failed to reverse losses in these activities. Furthermore, DEX led to a gradual weight loss that reached 30% of the initial weight at 9th day of the injection. DEX administration causes a generalized loss of behavioral activity of rats. Experimental studies devised to investigate effects of DEX should take into account this DEX-induced generalized behavioral loss when assessing the effects of DEX on learning and memory skills. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 24796879 TI - Estrogen regulates the expression of Ndrg2 in astrocytes. AB - N-myc downstream-regulated gene 2 (Ndrg2) is a newly identified molecule that is mainly expressed in astrocytes within the central nervous system (CNS) and is involved in the proliferation and activation of astrocytes. 17beta-estradiol (E2) is one of the most important circulating hormones, and in the CNS, astrocytes are a target and potential mediator of the action of E2. Our most recent study found that DPN, an estrogen receptor (ER) beta-specific agonist, activated the Ndrg2 promoter and elevated endogenous NDRG2 protein expression in MCF7, HSG and T-47D cells. However, whether E2 regulates Ndrg2 expression in astrocytes remains unknown. Here, we conducted both in vivo and in vitro experiments and found that ERbeta co-localized with NDRG2 in astrocytes. Furthermore, in primary cultured astrocytes, we demonstrated that E2 up-regulated Ndrg2 mRNA and protein expression in a dose- and time-dependent manner and that the ERbeta agonist DPN but not the ERalpha agonist PPT up-regulated Ndrg2 expression. In vivo, we found that in the hippocampus of adult ovariectomized (OVX) female mice, Ndrg2 mRNA and protein expression were significantly decreased compared with those in normal adult female mice. After the OVX mice received continuous subcutaneous injections of 50MUg/kg E2, 100MUg/kg E2 or the ERbeta agonist DPN for 10 days, the Ndrg2 expression significantly increased compared with that of the OVX mice. Our results indicate that E2 may affect astrocytes by regulating Ndrg2 expression. PMID- 24796881 TI - Impaired methylation modifications of FZD3 alter chromatin accessibility and are involved in congenital hydrocephalus pathogenesis. AB - Congenital hydrocephalus is heterogeneous in its etiology, and in addition to a genetic component, has been shown to be caused by environmental factors. Until now, however, no methylation alterations of target genes have been connected with congenital hydrocephalus in humans. Frizzled 3(FZD3) is a planar cell polarity (PCP) gene required for PCP signaling. Partial restoration of frizzled 3 activities in FZD3 mutant mice results in hydrocephalus. To analyze the possible roles of epigenetic modifications of the FZD3 gene in congenital hydrocephalus pathogenesis, DNA methylation in the promoter region of FZD3 was assayed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Gene expression and chromatin accessibility were also determined to assess the role of methylation alterations. Our study found methylation levels of the FZD3 gene were increased in congenital hydrocephalus, especially in males (10.57 +/- 3.90 vs. 7.08 +/- 0.94, p=0.001). Hypermethylation of FZD3 increased congenital hydrocephalus risk, with an odds ratio of 10.125 (p=0.003). Aberrant methylation modification of FZD3 altered both chromatin structure in this region and FZD3 expression levels. Totally, aberrant methylation modification of the FZD3 gene increases the risk of congenital hydrocephalus by altering chromatin structure and disturbing gene expression. PMID- 24796880 TI - HIF-1alpha/COX-2 expression and mouse brain capillary remodeling during prolonged moderate hypoxia and subsequent re-oxygenation. AB - Dynamic microvascular remodeling maintains an optimal continuous supply of oxygen and nutrients to the brain to account for prolonged environmental variations. The objective of this study was to determine the relative time course of capillary regression during re-oxygenation after exposure to prolonged moderate hypoxia and expression of the primary signaling factors involved in the process. Four-month old male C57BL/6 mice were housed and maintained in a hypobaric chamber at 290 Torr (0.4 atm) for 21 days and allowed to recover at normoxia (room air) for up to 21 days. The mice were either decapitated or perfused in-situ and brain samples collected were either homogenized for Western blot analysis or fixed and embedded in paraffin for immunohistochemistry. Hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and erythropoietin (EPO) expression were increased during hypoxic exposure and diminished during subsequent re-oxygenation. However, cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2) were both elevated during hypoxia as well as subsequent re-oxygenation. Significantly increased capillary density at the end of the 3rd week of hypoxia regressed back toward normoxic baseline as the duration of re-oxygenation continued. In conclusion, elevated COX-2 and Ang-2 expression during hypoxia where angiogenesis occurs and re-oxygenation, when micro-vessels regress, identifies these proteins as vascular remodeling molecules crucial for angioplasticity. PMID- 24796882 TI - A one-pot approach to bio-synthesize globotriose and its derivatives from simpler substrates. AB - Globotriose is involved in numerous pathogenic processes and drug development strategies. Recent studies have demonstrated that globotriosylceramide could be used in colon cancer therapy and as a crucial indicator for susceptibility to HIV 1 infection. Therefore, the cost-effective and facile approaches for large-scale production of globotiose as potential drugs are highly required. Here, a multi enzyme one-pot system containing a galactokinase (SpGalK, E.C.2.7.1.6), a UDP glucose pyrophosphorylase (SpGalU, E.C.2.7.7.9), a alpha-1,4 galactosyltransferase (LgtC, E.C. 2.4.1.44) and a commercial inorganic pyrophosphatase (PPase, EC 3.6.1.1) was designed to achieve globotriose on preparative scales. This method exploits a cheaper initial substrate, galactose, for donor UDP-galactose production. More importantly, the substrate specificity of SpGalK and SpGalU is highly promiscuous and various UDP-galactose derivatives obtained could be used as the donor substrates for LgtC. This pointcut of rapid preparation of globotriose derivatives is proposed for the first time. Finally, three globotriose analogs were achieved by this one-pot multi-enzyme system in our study. PMID- 24796883 TI - Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non intercalative DNA-binding topoisomerase II-specific catalytic inhibitor. AB - We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R(3) group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4 diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships. PMID- 24796884 TI - Investigation of amino acid conjugates of (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro 1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one (DW2282) as water soluble anticancer prodrugs. AB - The amino acid-conjugates (1a-k) with eleven amino acids attached to primary amine of (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl imidazolidin-2-one (DW2282, 1) were prepared and studied for their prodrug characteristics and anti-cancer activity against SW620 cell line. All the amino acid derivatives showed not only improved water solubility but also displayed potent anti-cancer activity in vitro. Among these amino acid-conjugates the compounds, DW2282-L-Ala (1b), DW2282-L-Phe (1e), DW2282-L-Leu (1g) and DW2282-L Met (1h) showed good reconversion within 8 h (104.76%, 84.03%, 95.02% and 78.34%, respectively) to the parent drug in human plasma. In addition, the compounds 1e, 1g and 1j also showed good bioavailability profile along with potent in vivo anticancer activity. PMID- 24796885 TI - Cell dynamics in Hertwig's epithelial root sheath and surrounding mesenchyme in mice irradiated to the head. AB - OBJECTIVE: To investigate the mechanisms that cause damage to root formation as a result of irradiation to the mouse head, morphological changes in molar dental roots and cell dynamics in Hertwig's epithelial root sheath (HERS), and surrounding mesenchymal tissue were examined. MATERIALS AND METHODS: To perform the experiments, 5-day-old C57BL/6 mice were randomly divided into three groups: the control group (0 Gy) and irradiated groups (10 and 20 Gy). Micro-CT analysis, HE staining, immunohistochemistry analysis, and TUNEL assay were then performed. RESULTS: Roots in irradiated mice were dose-dependently shorter than those of control mice. Cells located outside the root dentin, with abnormal morphology in irradiated mice, were positive for an odontoblast marker. HERS fragmentation occurred earlier in irradiated mice than in control mice, and HERS was trapped by the calcified apical tissue. A dose-dependent reduction in the number of proliferating cells within the apical dental pulp and periapical periodontal ligament surrounding HERS was observed in irradiated mice. Apoptotic cells in the dental pulp and periodontal ligament surrounding HERS were hardly seen. CONCLUSIONS: These results indicate that the early disappearance of HERS and the proliferative suppression of the surrounding mesenchymal cells, which was induced by irradiation, caused dental root malformation. PMID- 24796886 TI - Examining the relation of osteochondral lesions of the talus to ligamentous and lateral ankle tendinous pathologic features: a comprehensive MRI review in an asymptomatic lateral ankle population. AB - Given the frequency and burden of ankle sprains, the pathologic features identified on magnetic resonance imaging (MRI) scans are widely known in the symptomatic population. Ankle MRI pathologic features in the asymptomatic population, however, are poorly understood. Such examinations are rarely undertaken unless an ankle has been injured or is painful. We report the systematic MRI findings from the reports of 108 consecutive asymptomatic lateral ankles (104 patients). Our purpose was to (1) report the prevalence of osteochondral lesions of the talus (OLTs) and pathologic features of the medial and lateral ligaments, peroneal tendons, and superior peroneal retinaculum (SPR); (2) correlate the presence of OLTs with the pathologic features of the medial and lateral ligaments, peroneal tendons, and SPR; and (3) correlate ligamentous discontinuity with the peroneal pathologic features, OLTs, and SPR pathologic features. A total of 16 OLTs (14.81%) were present (13 medial and 3 lateral). Of the 16 patients with OLTs, 8 (50.00%) had concomitant peroneal pathologic findings. Healthy medial and lateral ligaments were noted in 41 patients (37.96%), and ligamentous discontinuity was grade I in 25 (23.15%), II in 32 (29.63%), III in 5 (4.63%), and grade IV in 5 patients (4.63%). A weak positive correlation was found between attenuation or tears of the superficial deltoid and medial OLTs (phi coefficient = 0.23, p = .0191) and a moderate positive correlation between tears of the posterior talofibular ligament and lateral OLTs (phi coefficient = 0.30, p = .0017). Additionally, a moderate positive correlation between ligamentous discontinuity and tendinopathy of the peroneus brevis was noted [Spearman's coefficient(106) = 0.29, p = .0024]. These findings add to the evidence of concomitant pathologic features in the asymptomatic population. To definitively assess causation and evaluate the clinical evolution of radiologic findings, future, prospective, longitudinal cohort studies are necessary. PMID- 24796887 TI - Staged reconstruction of a multiplane post-traumatic deformity: a case report. AB - Damaging effects of joint function can occur after fractures of the lower extremity that have healed with an angular malunion. Surgical techniques have been described to restore the normal mechanics and establish a plantigrade foot, including osteotomy and fusion. In the present report, we describe a unique case of a 17-year-old male who had initially experienced a severe injury to his left lower extremity and foot when he had been run over by a jeep. Originally, a Lisfranc injury with navicular and cuboid fractures were surgically corrected. He had also sustained an extra-articular distal tibial and fibular fracture, which had been conservatively managed. Seven months after the initial incident, he underwent 3-staged reconstructive surgery because of a malaligned valgus ankle with fibular malunion and a painful collapsing pes planovalgus deformity. A supramalleolar tibial osteotomy with fibular lengthening was first performed, followed by triple arthrodesis with removal of hardware and then syndesmosis repair. The present report discusses our clinical evaluation and surgical technique for this multiplanar post-traumatic deformity. PMID- 24796888 TI - Plantar measurements to determine success of surgical correction of Stage IIb adult acquired flatfoot deformity. AB - Adult acquired flatfoot deformity is a degenerative disease causing medial arch dysfunction. Surgical correction has typically involved tendon reconstruction with calcaneal osteotomy; however, the postoperative changes have not been fully characterized. The present study assessed the success of surgical correction of Stage IIb adult acquired flatfoot deformity through changes in plantar pressures and patient-generated outcome scores. With Institutional Review Board approval, 6 participants were evaluated before and after surgery using pedobarography, the Foot and Ankle Outcome Score, and the Medical Outcomes Study 36-item short-form questionnaire. The plantar pressures were recorded using a TekScan HRMat((r)) during walking and in a 1- and 2-foot stance. The resulting contour maps were segmented into 9 regions, with the peak pressure, normalized force, and arch index calculated. Surgical effects were analyzed using paired t tests. Postoperatively, the Foot and Ankle Outcome Score and Medical Outcomes Study 36 item short-form questionnaire scores increased significantly from 180 +/- 78 to 360 +/- 136 (p < .03) and 47 +/- 18 to 71 +/- 19 (p = .06), respectively. During the 2-foot stance, the normalized force had increased significantly in the lateral midfoot (p < .03), although no significant differences were found in peak pressures. No significant differences were observed in the 1-foot stance. During walking, the normalized force increased significantly in the lateral mid- and forefoot (p < .05). The peak pressure increased significantly in the lateral forefoot (p < .01). The arch index values demonstrated no significant changes. The increased questionnaire scores indicated that surgical correction improved the self-perceived health of the participants. Lateral shifts in the peak pressure and normalized force suggest that forefoot and midfoot loading is altered postoperatively, consistent with the goal of offloading the dysfunctional arch. Thus, the present study has demonstrated that surgical treatment of adult acquired flatfoot deformity can be accurately assessed using patient-reported outcome measures and plantar pressures. PMID- 24796889 TI - Differentiation between Staphylococcus aureus and coagulase-negative Staphylococcus species by real-time PCR including detection of methicillin resistants in comparison to conventional microbiology testing. AB - BACKGROUND: Staphylococcus aureus has long been recognized as a major pathogen. Methicillin-resistant strains of S. aureus (MRSA) and methicillin-resistant strains of S. epidermidis (MRSE) are among the most prevalent multiresistant pathogens worldwide, frequently causing nosocomial and community-acquired infections. METHODS: In the present pilot study, we tested a polymerase chain reaction (PCR) method to quickly differentiate Staphylococci and identify the mecA gene in a clinical setting. RESULTS: Compared to the conventional microbiology testing the real-time PCR assay had a higher detection rate for both S. aureus and coagulase-negative Staphylococci (CoNS; 55 vs. 32 for S. aureus and 63 vs. 24 for CoNS). Hands-on time preparing DNA, carrying out the PCR, and evaluating results was less than 5 h. CONCLUSIONS: The assay is largely automated, easy to adapt, and has been shown to be rapid and reliable. Fast detection and differentiation of S. aureus, CoNS, and the mecA gene by means of this real-time PCR protocol may help expedite therapeutic decision-making and enable earlier adequate antibiotic treatment. PMID- 24796890 TI - Halogen- and hydrogen-bonded salts and co-crystals formed from 4-halo-2,3,5,6 tetrafluorophenol and cyclic secondary and tertiary amines: orthogonal and non orthogonal halogen and hydrogen bonding, and synthetic analogues of halogen bonded biological systems. AB - Co-crystallisation of, in particular, 4-iodotetrafluorophenol with a series of secondary and tertiary cyclic amines results in deprotonation of the phenol and formation of the corresponding ammonium phenate. Careful examination of the X-ray single-crystal structures shows that the phenate anion develops a C=O double bond and that the C-C bond lengths in the ring suggest a Meissenheimer-like delocalisation. This delocalisation is supported by the geometry of the phenate anion optimised at the MP2(Full) level of theory within the aug-cc-pVDZ basis (aug-cc-pVDZ-PP on I) and by natural bond orbital (NBO) analyses. With sp(2) hybridisation at the phenate oxygen atom, there is strong preference for the formation of two non-covalent interactions with the oxygen sp(2) lone pairs and, in the case of secondary amines, this occurs through hydrogen bonding to the ammonium hydrogen atoms. However, where tertiary amines are concerned, there are insufficient hydrogen atoms available and so an electrophilic iodine atom from a neighbouring 4-iodotetrafluorophenate group forms an I???O halogen bond to give the second interaction. However, in some co-crystals with secondary amines, it is also found that in addition to the two hydrogen bonds forming with the phenate oxygen sp(2) lone pairs, there is an additional intermolecular I???O halogen bond in which the electrophilic iodine atom interacts with the C=O pi-system. All attempts to reproduce this behaviour with 4-bromotetrafluorophenol were unsuccessful. These structural motifs are significant as they reproduce extremely well, in low-molar-mass synthetic systems, motifs found by Ho and co-workers when examining halogen-bonding interactions in biological systems. The analogy is cemented through the structures of co-crystals of 1,4-diiodotetrafluorobenzene with acetamide and with N-methylbenzamide, which, as designed models, demonstrate the orthogonality of hydrogen and halogen bonding proposed in Ho's biological study. PMID- 24796891 TI - Evaluation of influence of single nucleotide polymorphisms in cytochrome P450 2B6 on substrate recognition using computational docking and molecular dynamics simulation. AB - In this study, we investigated the influence of single nucleotide polymorphisms on the conformation of mutated cytochrome P450 (CYP) 2B6 proteins using molecular dynamics (MD) simulation. Some of these mutations influence drug metabolism activities, leading to individual variations in drug efficacy and pharmacokinetics. Using computational docking, we predicted the structure of the complex between the antimalarial agent artemether and CYP2B6 whose conformations were obtained by MD simulation. The simulation demonstrated that the entire structure of the protein changes even when a single residue is mutated. Moreover, the structural flexibility is affected by the mutations and it may influence the enzyme activity. The results suggest that some of the inactive mutants cannot recognize artemether due to structural changes caused by the mutation. PMID- 24796892 TI - The biogeography of trophic cascades on US oyster reefs. AB - Predators can indirectly benefit prey populations by suppressing mid-trophic level consumers, but often the strength and outcome of trophic cascades are uncertain. We manipulated oyster reef communities to test the generality of potential causal factors across a 1000-km region. Densities of oyster consumers were weakly influenced by predators at all sites. In contrast, consumer foraging behaviour in the presence of predators varied considerably, and these behavioural effects altered the trophic cascade across space. Variability in the behavioural cascade was linked to regional gradients in oyster recruitment to and sediment accumulation on reefs. Specifically, asynchronous gradients in these factors influenced whether the benefits of suppressed consumer foraging on oyster recruits exceeded costs of sediment accumulation resulting from decreased consumer activity. Thus, although predation on consumers remains consistent, predator influences on behaviour do not; rather, they interact with environmental gradients to cause biogeographic variability in the net strength of trophic cascades. PMID- 24796893 TI - Evidence overview for shunting, patching, type of endarterectomy and anesthesia during carotid surgery. AB - Carotid endarterectomy has been shown to reduce the risk for stroke in patients with symptomatic or selected asymptomatic severe internal carotid artery stenosis. Although the basic aims of surgery are always the same, the exact techniques used to achieve them vary between surgeons. This paper summarizes the current evidence based optimal technical management of patients with an indication for carotid surgery, focusing on shunt use, patching, eversion versus longitudinal endarterectomy, and type of anesthesia applied. For each subtopic discuss, the text is accompanied by a table summarizing the key points. PMID- 24796894 TI - Identifying the high-risk carotid plaque. AB - With the benefit of hindsight, most symptomatic (67%) and most asymptomatic patients (88%) who were treated medically in the randomized trials were never destined to suffer a stroke. As a consequence of a growing awareness that only a relative minority of patients actually benefit from surgery or stenting, there has been much debate about how contemporary imaging and serum biomarkers might be used to identify the patient with the "high-risk for stroke" plaque in whom to target surgery or stenting in the future. This is particularly important for patients with asymptomatic carotid disease in whom 95% of carotid surgical procedures are ultimately unnecessary. Even if the procedural risk could be reduced to zero, 93% of all interventions would still prove to be unnecessary. This paper reviews the rationale underlying the need to identify "high-risk for stroke" patients in whom to target invasive therapies. It reviews the pathophysiology of the unstable carotid plaque and how such a lesion might be identified using contemporary imaging modalities and serum biomarkers. PMID- 24796895 TI - Strategies for optimizing the safety of carotid stenting in the hyperacute period after onset of symptoms. AB - The majority of patients with symptomatic carotid artery stenosis will benefit from early intervention with carotid endarterectomy (CEA). Carotid artery stenting (CAS) can be an alternative to CEA in selected cases. This paper will deal with the technical aspects of CAS in the emergency setting, including the use of embolic protection devices and will also discuss the pharmacologic management and treatment of complications. A review of the literature will be presented. PMID- 24796897 TI - Carotid and coronary disease management prior to open and endovascular aortic surgery. What are the current guidelines? AB - Several bodies produce broadly concurring and updated guidelines for the evaluation and treatment of cardiovascular disease in both surgical and non surgical patients. Recent developments include revised recommendations on preoperative stress testing, referral for possible coronary revascularization and medical management. It is recognized that non-invasive cardiac tests are relatively poor at predicting perioperative risk, and "prophylactic" coronary revascularization has a limited role. The planned aortic intervention (open or endovascular repair) also influences preoperative management. Patients presenting for elective abdominal aortic aneurysm (AAA) repair should only be referred for cardiological testing if they have active symptoms of coronary artery disease (CAD), known CAD and poor functional exercise capacity, or multiple risk factors for CAD. Coronary revascularization before AAA surgery should be limited to patients with established indications, so cardiac stress testing should only be performed if it would change management i.e. the patient is a candidate for and would benefit from coronary revascularization. When endovascular aortic repair is planned, it is reasonable to proceed to surgery without further cardiac stress testing or evaluation unless otherwise indicated. All non-emergency patients require medical optimization, but perioperative beta blockade benefits only certain patients. Some of the data informing recent guidelines have been questioned and some guidelines are being revised. Current guidelines do not specifically address the management of patients with known or suspected carotid artery disease who may require aortic surgery. For these patients, an individualized approach is required. This review considers recent guidelines. Algorithms for investigation and management based on their recommendations are included. PMID- 24796896 TI - Ultrasound surveillance after CAS and CEA: what's the evidence? AB - AIM: The rationale of clinical and Duplex ultrasound (DUS) surveillance after carotid endarterectomy (CEA) and carotid artery stenting (CAS) is the detection of recurrent stenoses and the prevention of future carotid-related cerebral ischemic events. This paper addresses the evidence for this approach. METHODS: The multicenter randomized controlled trials (RCTs) published between 1990 and 2013 were reviewed with respect to DUS surveillance intervals, recurrent stenoses rates and recurrent ipsilateral stroke rates. In addition a Medline literature search from January 1990 until February 2014 was performed by use of the following keywords: "surveillance"; "carotid endarterectomy"; "carotid stenting"; "carotid artery surveillance"; "carotid artery stenosis". Finally we analyzed all carotid-related guidelines published between 2006 and 2013 for recommendations on DUS surveillance after CEA or CAS. RESULTS: Nine RCT protocols (NASCET, ECST, ACST, ACAS, CAVATAS, SAPPHIRE, EVA-3S, CREST, and SPACE) showed similar follow-up intervals (at 1 month, 3 or 4 and at 6, and 12 months after CAS and CEA, then at least once a year). The incidence of a recurrent carotid stenosis (>=50%) or occlusion ranged around 6% four years after CEA or CAS. The annual incidence of any ipsilateral cerebral ischemic event was about 1% and 0.5% after CEA for a symptomatic or an asymptomatic stenosis respectively. Since the overall incidence of carotid recurrent stenosis and postprocedural strokes is low, DUS is questioned as necessary for all patients after CEA and CAS in prospective single center series. However, certain subgroups of patients (women, diabetics, patients with dyslipidemia, smokers) might have increased rates of restenosis after CEA or CAS. Data on DUS surveillance intervals following CAS is rare. Three out of 21 identified guidelines recommend long-term DUS surveillance, as the benefits are considered to exceed the risks. However, the level of evidence for any recommendation on DUS surveillance is consistently low. CONCLUSION: Our literature review reveals only little evidence to support routine DUS after CEA within short intervals. Currently a practice with one periprocedural DUS and one DUS after 12 months after CEA seems to be reasonable. In patients with an ipsilateral restenosis>=50%, contralateral disease progression>=50% and in patients who are considered to be at higher risk of restenosis further DUS surveillance seems appropriate. Due to inconsistent long-term data on surveillance after CAS imaging at 6 months and then annually seems reasonable. Further studies on DUS surveillance are necessary. PMID- 24796898 TI - Open repair for aortic occlusive disease: indication, techniques, results, tips and tricks. AB - AIM: The aim of this article was to review indications, techniques, and outcomes of a series of open repair for aortic occlusive disease. METHODS: Between 1991 and 2013, 1071 patients (917 men, 154 women; mean age 62.6 years) underwent open repair for aortoiliac occlusive disease. According to TASC II classification, 123 patients (11.5%) had type B lesions, 343 (32%) type C, and 605 (56.5%) type D. Among type D lesions, 138 patients had Leriche's Syndrome with complete aortic occlusion. Nine hundred and eight aortobifemoral bypasses, 114 axillo-bifemoral bypasses, 42 aortic endarterectomies with patch aortoplasty, and 7 thoracobifemoral bypasses were performed. Associated endarterectomy of abdominal aorta was required in 191 patients (18.5%), of the femoral arteries in 297 (28.7%). RESULTS: Perioperatively mortality was 0.6%; perioperative morbidity included cardiac (3.4% of patients), respiratory (2.6%), as well as acute renal insufficiency (2.6%). There were 26 (2.5%) cases of intraoperative distal embolization, 9 (0.8%) of acute graft thrombosis and 9 (0.8%) of bleeding requiring surgical revision within the first 24 hours after surgery. Sixty-one groin complications were reported in 57 patients (5.3%). During a mean follow-up time of 74 months (range 1-264), calculated actuarial occlusion-free survival at 12, 24, and 36 months was 94.8%, 91.8% and 87.2%, respectively. The limb-salvage rate in patients with critical limb ischemia was 87.3%. There were 11 (1%) graft infections. CONCLUSION: Open repair is a ductile strategy and may be tailored according to the patient clinical condition and disease anatomy. Long-term patency is excellent with low perioperative mortality and reasonable morbidity rates. PMID- 24796899 TI - Chimney grafts in aortic occlusive disease. AB - The aim of this article was to present juxtavisceral aortic occlusive disease with particular reference to a novel therapeutic approach, namely protected stenting by means of so called chimney grafts. The juxta renal aortic occlusion is the last aortoiliac occlusive lesion not to be stented routinely because of the risk for trash and/or need for overstenting of vital aortic side branches. The risk for trash also exists in open repair which makes it particularly challenging in this setting. The patients have advanced atherosclerosis and are poor risks for major surgery. A safe endovascular approach is therefore desirable. These lesions are either predominantly thrombotic or heavily calcified plaques. The thrombotic lesions can be stented under protection of the visceral branches by temporary occlusion balloons. The calcified lesions, on the other hand, require overstenting of the visceral vessels that then need to be preserved by chimney grafts. These endovascular procedures are complex and time consuming but they are associated with less surgical trauma and hence improved morbidity, mortality and recovery. The median term results of chimney grafts are encouraging, although more patients and longer follow-up are still needed. PMID- 24796900 TI - Challenging access in endovascular repair of infrarenal aortic aneurysms. AB - Endovascular repair has revolutionized the treatment of infrarenal aortic aneurysms. However, its application is still limited in patients with challenging access conditions such as small-caliber vessels, iliac tortuosity, excessive calcification or occlusive disease. The underlying manuscript addresses the crucial role of preoperative access vessel evaluation and summarizes recent developments in endograft manufacturing and surgical techniques allowing for coping with hostile access conditions. Furthermore, alternative access routes and complication management are discussed. PMID- 24796901 TI - The current endovascular therapeutic spectrum for short neck and juxtarenal aneurysms. AB - Endovascular treatment of short neck infrarenal and juxtarenal abdominal aortic aneurysms (AAA) is feasible. Many different techniques have been used, including standard stent-grafts with or without adjuncts as endoanchors or chimney grafts, fenestrated stent-grafts or even newer concepts like the multilayer flow modulating stent. The purpose of this article was to describe the techniques, the indications and results of the various endovascular methods to treat short neck infrarenal and juxtarenal AAA. PMID- 24796902 TI - Fenestrated and branched stent-grafting after previous open or endovascular aortic surgery. AB - AIM: Aim of the study was to review our experience with fenestrated and branched stent-grafts to treat juxtarenal (JAA) and thoracoabdominal (TAAA) aortic aneurysms after previous open or endovascular aortic surgery. METHODS: A prospectively maintained database including all consecutive patients with JAA or TAAA treated with fenestrated/branched stent-grafts after previous open or endovascular aortic surgery within the period March 2002-November 2013 was analyzed. Evaluated outcomes included initial technical success, operative mortality and morbidity and late procedure-related events with regard to survival, target vessel patency, and re-intervention. RESULTS: A total of 122 patients (110 male, 12 female; mean age mean age 70+/-9.5 years) were treated. Median time interval from previous aortic surgery to current fenestrated/branched stent-grafting was 80 months (range 3-261 months). Seventy-seven (63.1%) patients had previous open infrarenal aortic surgery, 33 (27%) had previous endovascular abdominal aortic aneurysm repair (EVAR), nine (7.4%) had previous open thoracic aortic surgery, and three (2.5%) had previous endovascular thoracic aortic repair (TEVAR). Indication for current treatment was a JAA in 65 (53.3%) patients and a TAAA in 57 (46.7%) patients. Technical success was achieved in 115 (94.3%) patients. Seven patients were considered as technical failure (open conversion; N.=1, target vessel loss; N.=6). Operative target vessel perfusion success rate with endovascular means was 98.5% (391/397). Intraoperative technical difficulties due to pre-existing stent-graft/surgical graft were encountered in 28 (23%) patients (access, N.=12; target vessel catheterisation, N.=16). Thirty day operative mortality was 4.1% (5/122), with zero mortality in 65 JAA, and 8.8% (5/57) in TAAA, respectively. Cause of death was multiple organ failure (N.=3), acute gastrointestinal bleeding (N.=1), and subdural hematoma (N.=1). Major complications occurred in 20 (16.4%) patients. Median hospital stay was 7 days (range 3-50 days), and mean ICU stay 1.5+/-3.2 days. Mean follow-up was 22.5+/-21 months. All-cause late mortality was encountered in 23 patients, including one aneurysm-related mortality. Estimated survival was 91.2+/-3%, 83.3+/-4.2% and 81.1+/-4.6% at one, two and three years, respectively. During follow-up, eight target vessels occluded. Estimated target vessel patency was 97.2+/-1.1%, and 96.3+/-1.2% at one and three years, respectively. Reintervention during follow-up was required in 13 (10.6%) cases accounting for an estimated freedom from reintervention of 91.6+/-3.1%, and 82.1+/-5.4% at one and three years, respectively. CONCLUSION: Fenestrated and branched stent-grafting represents a feasible option for the repair of JAA and TAAA after prior endovascular or open aortic surgery. Despite increased technical difficulties it is associated with high technical success rate and is advantageous in terms of mortality and morbidity compared to redo open aortic surgery. PMID- 24796903 TI - Endoleaks after EVAR and TEVAR: indications for treatment and techniques. AB - Endoleaks after endovascular aortic repair (EVAR) are a common cause of treatment failure and secondary interventions. Endoleak classification is important to determine both prognosis as well as need for treatment. With increasingly complex endovascular aortic procedures, endoleak classification according to the original classification has become more difficult. A classification into direct and indirect endoleaks as well as precise anatomical description is often more pragmatic. This manuscript outlines mechanisms of endoleak formation and their treatment. PMID- 24796904 TI - Anatomic changes of target vessels after fenestrated and branched aortic aneurysm repair. AB - AIM: Objective of this study was to evaluate the anatomic changes of the stented target vessels after endovascular repair of complex aortic aneurysms. METHODS: Between July 2011 and December 2013, 53 aortic aneurysms were treated in our department with fenestrated and branched stent-graft devices. Forty-two of these patients were pre- and postoperatively scanned with a high resolution computer tomography (CT) (Cook Zenith(r) fenestrated or branched, Australia Pty. Ltd., Brisbane, Australia: N.=19; AnacondaTM fenestrated, Vascutek, Glasgow, Scotland, UK: N.=23). The other 11 out of the 53 patients did not receive a CT scan, because of a pre-existing renal failure. In the CT scans we retrospectively evaluated the anatomic vessel deviation at the origin of the target vessel and the vessel shift distal to the stent. For the first measurement the CT scans were loaded into OsiriX MD(r), and the pre- and postoperative angles of the target vessels were measured and subtracted. For matching, the CT-scans were normalized at vertebral body lumbar 2. The second measured angle was the maximal measured angle distal to the target vessel stent-graft. RESULTS: Altogether, 113 target vessels were stented (celiac trunk [CT] 15, superior mesenteric arteries [SMA] 26, renal arteries [RA] 72), with 97 balloon-expandable PTFE stents: 90 Atrium V12 (Maquet Getinge group, Hudson, NH, USA), 7 BeGrafts (Bentley InnoMed, Hechingen, Germany) and 16 self-expandable fluency PTFE stents (Bard, Karlsruhe, Germany). The mean anatomic deviation at the target vessel origin was 28+/-17.3 and the mean vessel shift distal to the stent was 36.3+/-18.8. There were no significant differences between the main device and the target vessel stent types. CONCLUSION: Fenestrated and branched stent-graft solutions for aortic aneurysm repair induce changes of the target vessel anatomy. We did not observe significant differences between the several devices. PMID- 24796905 TI - Techniques to reduce radiation and contrast volume during EVAR. AB - There is a large variability observed in the literature regarding radiation exposure and contrast volume injection during endovascular aortic repair (EVAR). Reducing both in order to decrease their respective toxicities must be a priority for the endovascular therapist. Radiation dose reduction requires a strict application of the "as low as reasonably achievable" principles. Firstly, all X ray system settings should be defaulted to low dose, and fluoroscopic time reduced as much as possible. Digital subtraction angiography runs should be replaced by recorded fluoroscopy runs when possible. Magnification should be avoided, whereas collimation should be systematic to minimize scatter radiation and focus only on the area of interest. Advanced imaging modes can also contribute to dose reduction. For instance, image fusion can facilitate endovascular navigation, and allow table and C-arm positioning without fluoroscopy. In our experience, routine use of image fusion during EVAR significantly reduces both radiation exposure and contrast volumes during complex EVAR. To make these imaging modes useable in real life settings, the X-ray system should be fully controlled by the operator from table side. Reducing iodinated contrast volume, while maintaining image quality, can also be achieved through the use of automated contrast injectors. Additionally, alternative contrast agents, like carbon dioxide (CO2) and gadolinium, have also been evaluated and can be used in specific cases. Contrast-enhanced ultrasound and intravascular ultrasonography are currently developed as potential alternatives to both iodinated contrast use and X-ray during EVAR. Lastly, specific education and training of operators in radiation protection are essential. PMID- 24796906 TI - Acute aortic syndromes: definition, prognosis and treatment options. AB - Acute aortic syndromes (AAS) are life-threatening vascular conditions of the thoracic aorta presenting with acute pain as the leading symptom in most cases. The incidence is approximately 3-5/100,000 in western countries with increase during the past decades. Clinical suspicion for AAS requires immediate confirmation with advanced imaging modalities. Initial management of AAS addresses avoidance of progression by immediate medical therapy to reduce aortic shear stress. Proximal symptomatic lesions with involvement of the ascending aorta are surgically treated in the acute setting, whereas acute uncomplicated distal dissection should be treated by medical therapy in the acute period, followed by surveillance and repeated imaging studies. Acute complicated distal dissection requires urgent invasive treatment and thoracic endovascular aortic repair has become the treatment modality of choice because of favorable outcomes compared to open surgical repair. Intramural hematoma, penetrating aortic ulcers, and traumatic aortic injuries of the descending aorta harbor specific challenges compared to aortic dissection and treatment strategies are not as uniformly defined as in aortic dissection. Moreover these lesions have a different prognosis. Once the acute period of aortic syndrome has been survived, a lifelong medical treatment and close surveillance with repeated imaging studies is essential to detect impending complications which might need invasive treatment within the short-, mid- or long-term. PMID- 24796907 TI - Uncomplicated type B dissections: which patients should be treated? Lessons learned from the recent literature. AB - The management of type B aortic dissection is complex and decision-making is often based on physician experience and subjective clinical judgment. Thoracic endovascular aortic repair is considered first-line therapy for complicated type B aortic dissection but whether this should be performed in uncomplicated cases has been a matter of debate. Randomized controlled trials have demonstrated the long-term benefit of endovascular treatment to prevent aortic-related mortality, however pre-emptive surgery may not be the solution for all patients because of the occurrence of adverse events such death, stroke and paraplegia. Morphological and false lumen characteristics including aortic diameter, the position, size and number of entry tears and false lumen thrombus volume have been shown to serve as predictors of outcome and may be used to identify high-risk patients. Functional imaging methods such as magnetic resonance and echocardiography are evolving and may be able to provide the clinically-relevant structural, hemodynamic and biomechanical information that is needed for accurate risk stratification of individual patients. A patient-specific approach designed to intervene only in patients that are at high risk of developing complications should improve the long-term outcome of these patients. PMID- 24796908 TI - Do we need long-term follow-up after EVAR and TEVAR or can we simplify surveillance protocols? AB - Endovascular repair is an increasingly preferred treatment modality for aortic pathology. Concerns regarding durability and postimplant complications have let to recommendations for rigorous surveillance regimens which are not entirely data driven. Besides the costs of an excessive imaging follow-up protocol, deleterious effects may arise from repeated contrast administration and radiation exposure. Due to improvements in selection, planning and execution, coupled with technical improvements in devices, reported complications following endovascular repair have gradually decreased since the pivotal reports. Although late failure may be multifactorial and therefore not totally preventable with any surveillance regimen, patients may be stratified according to the expected risk (balanced by the potential benefit gained with surveillance) and be offered an individualized surveillance program. In this review, we aimed to describe current strategies for surveillance, modern outcomes after abdominal and thoracic endovascular repair, and proposed risk-adapted strategies for postoperative surveillance. PMID- 24796909 TI - Spinal cord ischemia in open and endovascular thoracoabdominal aortic aneurysm repair: new concepts. AB - For more than half a century ischemic spinal cord injury (SCI) and consecutively permanent paraplegia remained the most devastating complication after open and endovascular thoracoabdominal aortic aneurysm (TAAA) repair. Various neuroprotective strategies (e.g., motor-/somatosensory evoked potential monitoring and cerebrospinal fluid drainage) used as adjuncts have lowered the SCI; maybe most importantly, the modern collateral network (CN) has begun to replace the classic understanding of spinal cord blood supply implying several consequences. Reliable non-invasive tools to monitor cord perfusion to detect imminent spinal cord malperfusion, ischemia and forthcoming neurologic injury (particularly early postoperatively) is not available, neither is a reliable strategy to prevent ischemic injury during distal circulatory arrest and after segmental artery occlusion. Currently, two promising new concepts--potentially advancing spinal protection in open and endovascular TAAA repair--address these issues: 1) non-invasive real-time monitoring of the paraspinous CN-oxygenation via near-infrared spectroscopy (NIRS) as an alternative to the demanding direct neuromonitoring; and 2) preconditioning of the CN as minimally invasive, endovascular "first stage" to increase the resilience of spinal cord perfusion prior to definite aortic repair. This article illustrates both concepts discussing: 1) the clinical application of thoracic and lumbar collateral NIRS monitoring to indirectly detect spinal cord hypoperfusion; and 2) minimally invasive selective segmental artery coil-embolization (MISACE) for (arteriogenic) preconditioning of the CN prior to extensive open or endovascular staged TAAA repair. PMID- 24796910 TI - Late rupture after EVAR: a new trend? AB - AIM: Endovascular aortic repair (EVAR) is an adequate therapy for abdominal aortic aneurysms (AAA). Late aortic ruptures caused by endoleaks after EVAR still remain a critical issue. The aim of this study was to assess the causes of ruptured aortic aneurysms after EVAR in a single center study. METHODS: All patients, who were treated in our University hospital with a ruptured juxtra- or infrarenal AAA between January 2011 and October 2013, were included in this retrospective analysis. RESULTS: Thirty patients with ruptured infra- or juxtrarenal aneurysms were treated in this time frame. Six out of these 30 patients had previous EVAR repair. The median maximal aneurysm diameter of these post-EVAR patients was 82 (75-95) mm. The median time between primary EVAR and rupture was 42.5 (14-99) months. Three patients with type Ia endoleaks were treated by stent removal and conventional aortic reconstruction. In two patients with type II endoleak the bleeding was controlled by occluding the back bleeding lumbar arteries. One type III endoleak was sealed by an additional stent-graft implantation into the right iliac artery. CONCLUSION: We observed a considerable number of patients with a ruptured AAA after EVAR. Surprisingly, we observed two ruptured aneurysms due to type II endoleaks. PMID- 24796911 TI - Optimizing the pharmacotherapy of vascular surgery patients by medication reconciliation. AB - AIM: Medication errors may occur at any stage during the medication process and can lead to preventable adverse drug events and patients' harm. Pharmacists' support for reconcilable medication has been shown to be effective, rectifying errors and inaccuracies of the drug treatment and in the increase of medication safety. However, none of the previous studies focused on vascular patients. We investigated the nature and frequency of drug-related problems (DRPs) including the amount of potentially inappropriate medication (PIM) prescribed for elderly patients suffering from vascular diseases and the influence of pharmacists in the improvement of cardiovascular medication. METHODS: After the patients' routine admission process, medication reconciliation was performed. Therefore, a pharmacist obtained an accurate medication use history. The patients' drug therapy was critically screened for DRPs and referring to this, intervention was made by the pharmacist and communicated to the physician if necessary. Potentially inappropriate medication in the elderly was reviewed through a retrospective analysis using the Priscus-List. DRPs were documented anonymously and classified. RESULTS: We identified 138 DRPs among 105 patients. Sixty-five patients experienced at least 1 DRP, accordingly 1.3 DRPs per patient. In total, 43 unintended discrepancies between current medication and admission medication were detected with an overall rate of 0.41 per patient; 100 interventions were made of which 56 resulted in explicit recommendations for prescription changes. Drug classes frequently affected by DRPs were antihypertensive in 23.9%, antithrombotic agents in 19.3% and lipid lowering agents in 12.1%. In a retrospective analysis of the home medication, 12 definite PIM were identified in 49 elderly patients. CONCLUSION: DRPs are common in the medication of vascular surgery patients and may be improved by pharmacists. PMID- 24796912 TI - A new shunting concept to prevent lower limb ischemia/reperfusion injury in prolonged fenestrated stent-graft procedures. AB - AIM: Complex endovascular procedures to treat thoracoabdominal aortic aneurysms (TAAA) can be time consuming and therefore comprise the risk of lower limb ischemia with subsequent reperfusion injury and compartment syndrome. Aim of this study was to evaluate a new protective method to prevent these postoperative problems. METHODS: In order to maintain blood perfusion to both legs during prolonged endovascular aortic procedures we developed a shunting technique with two additional 7 French (Fr) sheaths in both superficial femoral arteries. We evaluated the perfusion technique in 5 patients with fenestrated endovascular aortic aneurysms repair (FEVAR). First, we measured the flow in the 7 Fr sheaths; second, we clinically controlled the lower limb for developing compartment syndrome. Third we measured creatinine kinase (CK) as marker for postoperative muscular damage. RESULTS: In 5 male patients (median age 77, range 59-80 years) undergoing endovascular TAAA repair, the perfusion technique was feasible. The median flow per catheter was 102 mL/min (range 61-156.5 mL/min) and monophasic with a mean arterial blood pressure of 71 mmHg (range 56-82 mmHg). No patient developed a compartment syndrome. The CK levels were only lightly elevated. CONCLUSION: This simple perfusion technique allows adequate lower limb perfusion during prolonged complex endovascular aortic procedures. PMID- 24796913 TI - Acute ischemia and bypass occlusion: current options. AB - AIM: Acute limb ischemia (ALI) and bypass occlusion are vascular emergencies and require immediate decisions and therapy. There are a lot of options, and the vascular therapist should be able to provide multiple alternatives. In this article we give on overview over the actual therapeutic options and present the data of a retrospective analysis of bypass occlusions. METHODS: Therapeutic options of ALI are discussed according to the current literature. For the retrospective study, patients with acute or subacute occlusion of below knee alloplastic bypass were included. Endpoints of the study were secondary patency and limb salvage rate. A prognostic index was calculated to estimate the specific risk. RESULTS: We analyzed 262 bypass occlusions; 161 patients were male. The majority of patients (N.=249) presented with threatened limb at readmission. After one year, 2/3 of the bypasses showed a reocclusion. Introducing the therapy with bypass thrombolysis enhanced the prognosis significantly. Of the factors examined, cardiac and renal insufficiency had a significant poor influence, whereas therapy with Coumadin enhanced the prognosis in terms of patency. The prognostic index was calculated using the factors identified as relevant in the multivariate analysis. DISCUSSION: Despite all new technical tools, ALI and bypass occlusion is still associated with a significant risk for limb loss and mortality. Endovascular procedures are excellent options. The prognostic index may be a helpful tool in estimating the patency or risk of limb loss. PMID- 24796914 TI - Management of peripheral arterial disease and the diabetic foot. AB - The management of peripheral arterial disease (PAD) in patients with diabetic foot ulceration (DFU) is complex and there is a lack of robust evidence to guide definitive treatment strategies. Due to the distinct differences in etiology, disease distribution and treatment outcomes patients with diabetes, PAD and foot ulceration should be considered separately from those without diabetes. There is no randomized trial data to compare angioplasty and surgical bypass for revascularization in patients with DFU and PAD and the decision of whether, and how, to revascularize should be taken by experienced surgeons, in a multidisciplinary setting. Revascularization is only part of a treatment regimen which includes aggressive management of infection, neuropathy, foot deformity and cardiovascular risk. The burden and challenge of DFU in the context of PAD is continuing to increase and new research studies should be targeted specifically towards this ever-expanding group of patients. PMID- 24796915 TI - Current techniques and strategies for anesthesia in patients undergoing peripheral bypass surgery. AB - Peripheral arterial disease is an illness with a high prevalence in Europe and North America. The disease is associated with a significant impact on quality of life. Despite advanced medical and endovascular treatments, surgery is often indicated to prevent the consequences of ischemic injury. Usually, these patients do have significant comorbidities resulting in an increased risk for anesthesia related complications. While general anesthesia is commonly used for the majority of the patients, local and regional anesthesia (RA) offer several possible advantages such as stable cardiovascular hemodynamic perioperative course, improved postoperative pain relief and prevention of chronic postsurgical pain syndromes. This review will discuss perioperative management, available evidence regarding general anesthesia and various regional anesthetic techniques for peripheral vascular surgery, and the current advises regarding anticoagulants and RA. No definitive conclusions can be drawn from the existing literature with respect to superiority of general or neuraxial anesthesia or even RA. Maybe the profits lie in the combination of techniques, a strategy, to overcome the risks of one and use the benefits of the other technique. From circumstantial evidence, it is most likely that the experience of the anesthetic and surgical team is one of the major determinants of perioperative complications independent from the individual anesthesia technique. PMID- 24796916 TI - Homografts and extra-anatomical reconstructions for infected vascular grafts. AB - Managing graft infections is a challenge in vascular surgery. The incidence of vascular graft infections varies between 2% and 6%. The number of patients treated by means of implantation of artificial prostheses is constantly growing. The treatment of vascular graft infections remains controversial. This article discusses in-situ repair and the role of extra-anatomic routes. Homografts present the lowest rate of reinfection with acceptable rates of degradation and aneurysm formation. Silvergrafts and synthetic grafts coated with antimicrobials show similar early and late mortality rates, but higher reinfection rates. The outcome extra-anatomic bypass surgery seems to be improved in actual series compared with historical results but their disadvantages (limited patency, higher rate of amputations as well as high rates of reintervention combined with higher early mortality) are obvious. PMID- 24796917 TI - Popliteal artery entrapment syndrome. AB - Intermittent claudication is frequently encountered in vascular surgical practice in atherosclerotic patients. However, it may also be observed in a younger subset of patients without any cardiovascular risk factors and can represent a challenging diagnosis. Popliteal artery entrapment syndrome is rare but can cause intermittent claudication in young people. There is a lack of consensus about optimal strategies or diagnosis and management, particularly for variants such as functional popliteal entrapment. Since the first description in 1959, knowledge of the pathology and the underlying anatomic abnormalities was advanced through sporadic publications of case reports and small case series, but popliteal artery entrapment syndrome still remains a rare anatomic abnormality. It can be difficult to differentiate from other causes of lower limb pain in young patients, and diagnosis can be challenging. We propose to review clinical symptomatology, classification, radiological diagnosis and treatment of popliteal entrapment syndrome. PMID- 24796918 TI - Popliteal artery aneurysm: when open, when endo? AB - The purpose of this article was to obtain a more clear view in the management of popliteal artery aneurysms (PAAs). When do we need to treat it and how is it best treated? After going through multiple review articles and case reports concerning this matter, we came to the following conclusions. Repair of a PAA is indicated when it reaches a postero-anterior diameter of 3 cm (at higher risk for thrombosis) or becomes symptomatic (mild claudication or severe ischemic symptoms). Whether the repair is then performed in an endovascular (Endovascular repair) or open way (Open repair), depends on the personal experience and clinical evaluation of the surgeon. PMID- 24796919 TI - CT angiography to evaluate hemodynamic changes in popliteal artery aneurysms during flexion and extension of the knee joint. AB - AIM: The aim of this study was to find out which characteristics of an asymptomatic popliteal artery aneurysm (PAA) will increase the risk for acute thrombosis. METHODS: This was a single-center prospective study of consecutive patients with asymptomatic PAAs presenting from January 2010 to April 2012. Computed tomography angiography was used to perform measurements of the PAA during 0o extension and 90o flexion of the knee. After semi-automated segmentation of the popliteal artery (PA) lumen, a center lumen line (CLL) was automatically constructed. RESULTS: The study included 16 asymptomatic PAAs. Median lumen area of the PA was directly proximal and distal of the PAA 57 mm2 (IQR, 44-87 mm2) and 46 mm2 (IQR, 32-66 mm2) in extension vs. 51 mm2 (IQR, 38-73 mm2) and 38 mm2 (IQR, 30-62 mm2) during 90o flexion, respectively (P=0.007) and (P=0.03). The median of the greatest decrease in lumen area after flexion and extension of the knee was 36 mm (IQR, 28-48 mm) in PAAs>=30 mm compared with 11 mm (IQR, 4-18 mm) in PAAs<30 mm (P<0.05). The proximal angulation was a median 48 degrees in extension (IQR, 27-61o) and 75 degrees during flexion (IQR, 46-99o; P=0.02). Distal angulation was a median of 31 degrees (IQR, 21-42o) after extension vs. 62 degrees (IQR, 33-81o) during flexion (P=0.03). CONCLUSION: Knee bending in patients with PAAs will lead to a reduction in the lumen area of the PAA and a change in the degree of angulation of the PAA. A significant decrease in lumen area was seen in PAAs>=30 mm compared with PAAs<30 mm after flexion of the knee. PMID- 24796920 TI - Facts that every vascular surgeon needs to know about the diabetic foot. AB - This paper describes important aspects of the diabetic foot which the vascular surgeon needs to understand to efficiently manage the diabetic foot. Firstly, it emphasises the three main pathologies which come together in the diabetic foot, namely neuropathy, ischemia and immunopathy, the latter predisposing to infection. As a result of neuropathy, the signs and symptoms of tissue breakdown, infection and ischemia may be minimal. Nevertheless the pathology emanating from such clinical events proceeds rapidly without the body being aware of it and the end stage of tissue death and necrosis is quickly reached. It is important to have a prompt system of evaluation and intervention to prevent the rapid progression to necrosis. Thus, secondly, the paper describes a simple rapid assessment of the diabetic foot, which comprises inspection, palpation and sensory testing and leads on to a modern classification and staging of the diabetic foot. This classifies six subdivisions of the diabetic foot: foot with neuropathic ulceration, Charcot foot, neuroischemic foot, critically ischemic foot, acutely ischemic foot and renal ischemic foot and six stages in the natural history of each of these subdivisions: normal foot, high risk foot, ulcerated foot, infected foot, necrotic foot and unsalvageable foot. Thirdly, it describes modern management of the diabetic foot, emphazising wound care and revascularization within the context of a multidisciplinary care team that provides integrated care focused in a diabetic foot clinic, to which patients with diabetes should have easy and rapid access. Members of the team include podiatrist, nurse, orthotist, physician, radiologist and surgeons. PMID- 24796921 TI - Nutrient free flaps with vascular bypasses for extremity salvage in patients with chronic limb ischemia. AB - AIM: Treatment of severe wounds remains a surgical challenge in patients with critical limb ischemia (CLI). In some patients with end stage disease a combined arterial and venous vascular bypass together with immediate or subsequent free soft tissue transfer can become necessary to salvage the limb. The aim of this paper was to develop an algorithm of differential approaches of interdisciplinary reconstructions with bypasses and free flaps for leg salvage. METHODS: From our experiences with over 76 patients receiving a vascular bypass and a free microsurgical tissue transfer, we analyzed the various configurations of possible vascular constellations and treatment options. We derived an algorithm for the combined interdisciplinary surgical approach. RESULTS: We found the surgical technique to be one of the main predictors for the final outcome and categorized the various options and vascular configurations in combination with free flaps to salvage extremities. The overall complication rate with more than 20% revisional surgeries is higher than in routine free flap transfer for reconstructions in patient without CLI. We observed 3 failures (4%) with complete flap loss and bypass occlusion and found 3 patients (4%) with initially successful reconstructions to have secondary amputations within 6 to 18 months postoperatively. CONCLUSION: Given the multitude of concomitant diseases in patients with serious wounds and CLI the distinct choice of the individual reconstructive vascular/flap-procedure has to be thoroughly selected. Any treatment decision against revascularization must be made only with proper and adequate diagnosis based on proper and sufficient diagnostic imaging techniques following an interdisciplinary discussion of possible options for limb salvage. Based on our experience with a large series of this type of combined revascularization-flap reconstruction we developed a specific algorithm of surgical variants of bypass-free flap arterial and venous reconstructions that is presented in this paper. PMID- 24796922 TI - Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy. AB - AIMS: Chronic cyclosporine (CsA) treatment induces autophagic cell death characterized by excessive autophagosome formation and decreased autophagic clearance. In this study, we evaluated the influence of ginseng treatment on autophagy in chronic CsA nephropathy. METHODS: Mice were treated with CsA (30 mg/kg) with or without Korean red ginseng (KRG) extract (0.2, 0.4 g/kg) for 4 weeks. The effect of KRG on CsA-induced autophagosome formation was measured using phospholipid-conjugated form of LC3-II, beclin-1, and autophagic vacuoles were visualized with electron microscopy. Autophagic clearance was evaluated by accumulation of p62/sequestosome 1 (p62) and ubiquitin, then double immunolabeling for p62 and either LC3-II or ubiquitin. To demonstrate the association between the effects of KRG treatment on autophagy and apoptosis, double immunolabelling for LC3-II and active caspase-3 was performed. Multiple autophagy pathways were also examined. RESULTS: KRG co-treatment significantly decreased the expression of LC3-II, beclin-1, and the number of autophagic vacuoles compared with the CsA group, and these changes were accompanied by improvements in renal dysfunction and fibrosis. CsA-induced accumulation of p62 and ubiquitin was also decreased by KRG treatment, and these proteins were colocalized with LC3-II and with each other. KRG treatment simultaneously reduced the expression of both active caspase-3 and LC3-II in the injured area. KRG treatment during chronic CsA nephropathy induced the expression of AKT/mTOR, which is a pathway that inhibits autophagy, and reduced AMPK expression. CONCLUSION: Ginseng treatment attenuated CsA-induced excessive autophagosome formation and autophagic aggregates. These findings suggest that ginseng has a renoprotective effect against CsA-induced autophagic cell death. PMID- 24796923 TI - Biological instability in a chlorinated drinking water distribution network. AB - The purpose of a drinking water distribution system is to deliver drinking water to the consumer, preferably with the same quality as when it left the treatment plant. In this context, the maintenance of good microbiological quality is often referred to as biological stability, and the addition of sufficient chlorine residuals is regarded as one way to achieve this. The full-scale drinking water distribution system of Riga (Latvia) was investigated with respect to biological stability in chlorinated drinking water. Flow cytometric (FCM) intact cell concentrations, intracellular adenosine tri-phosphate (ATP), heterotrophic plate counts and residual chlorine measurements were performed to evaluate the drinking water quality and stability at 49 sampling points throughout the distribution network. Cell viability methods were compared and the importance of extracellular ATP measurements was examined as well. FCM intact cell concentrations varied from 5*10(3) cells mL(-1) to 4.66*10(5) cells mL(-1) in the network. While this parameter did not exceed 2.1*10(4) cells mL(-1) in the effluent from any water treatment plant, 50% of all the network samples contained more than 1.06*10(5) cells mL(-1). This indisputably demonstrates biological instability in this particular drinking water distribution system, which was ascribed to a loss of disinfectant residuals and concomitant bacterial growth. The study highlights the potential of using cultivation-independent methods for the assessment of chlorinated water samples. In addition, it underlines the complexity of full scale drinking water distribution systems, and the resulting challenges to establish the causes of biological instability. PMID- 24796924 TI - Strong association between insulin-mediated glucose uptake and the 2-hour, not the fasting plasma glucose concentration, in the normal glucose tolerance range. AB - AIM: The aim of this study was to examine the relationship between whole-body insulin-mediated glucose disposal and the fasting plasma glucose concentration in nondiabetic individuals. RESEARCH DESIGN AND METHODS: Two hundred fifty-three nondiabetic subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance received a 75-g oral glucose tolerance test and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-hour plasma glucose concentrations in each group. RESULTS: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2-hour plasma glucose (PG; r = 0.40, P < .0001) but not with the fasting PG. When IFG and NGT individuals were stratified based on their 2-hour PG concentration, the increase in 2-hour PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals. CONCLUSION: The present results indicate the following: 1) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; 2) the large variability in TGD in IFG and NGT individuals is related to the 2-hour PG concentration; and 3) after adjustment for the 2-hour proglucagon concentration, IFG subjects have comparable TGD with NGT individuals. PMID- 24796926 TI - Accuracy of adrenal imaging and adrenal venous sampling in predicting surgical cure of primary aldosteronism. AB - CONTEXT: The accurate distinction between unilateral and bilateral adrenal disease in patients with primary aldosteronism (PA) guides surgical management. Adrenal venous sampling (AVS), the criterion standard localization procedure, is not readily available at many centers throughout the world. OBJECTIVE: The objective of the study was to determine factors most consistent with surgically curable PA. DESIGN: This was a retrospective observational study. SETTING: The study was conducted at the Mayo Clinic (Rochester, Minnesota), a tertiary referral center. PATIENTS: All patients who underwent unilateral adrenalectomy for treatment of PA between January 1993 and December 2011 participated in the study. INTERVENTION: The intervention in the study was unilateral adrenalectomy. MAIN OUTCOME MEASURES: Variables associated with the prediction of unilateral disease were measured. RESULTS: Over 19 years, 263 patients underwent unilateral adrenalectomy for the treatment of PA. Long-term postoperative follow-up was obtained in 143 patients (54.4%). The overall effective cure rate of PA was 95.5% in those patients sent for adrenalectomy for presumptive unilateral disease. In patients with cured PA, defined as the resolution of autonomous aldosterone secretion, hypertension was cured in 53 (41.7%) and improved in 59 (46.5%) patients. PA was not cured with unilateral adrenalectomy in six patients (4.2%). Adrenal imaging and AVS were concordant to the surgically documented side in 58.6% and 97.1% of the patients, respectively. Although there was no statistically significant difference in mean age between the inaccurate vs the accurate adrenal imaging group, we found that the minimum age in the former was 35.1 years. CONCLUSIONS: Using adrenal imaging and AVS, the effective surgical cure rate for PA was 95.5%. Although the overall accuracy of computed tomography and magnetic resonance imaging in detecting unilateral adrenal disease was poor at 58.6%, adrenal imaging performed well in those patients younger than 35 years of age. PMID- 24796925 TI - Patterns of adiponectin expression in term pregnancy: impact of obesity. AB - CONTEXT: Adiponectin (adpN) production is down-regulated in several situations associated with insulin resistance. The hypoadiponectinemia, which develops in late pregnancy, suggests a role of adpN in pregnancy-induced insulin resistance. OBJECTIVE: In obese pregnancy there is a decreased systemic adpN, which results from down-regulation of gene expression in adipose tissue. SETTING AND DESIGN: One hundred and thirty-three women with uncomplicated pregnancies and a wide range in pre-gravid body mass index (18-62 kg/m(2)) were recruited at term for a scheduled cesarean delivery. Maternal blood, placenta, and sc abdominal adipose tissue were obtained in the fasting state. DNA methylation was analyzed by MBD based genome-wide methylation sequencing and methyl-specific PCR of placenta and maternal adipose tissue. mRNA and protein expression were characterized by real time RT-PCR and immunodetection. Plasma adpN, leptin, and insulin were assayed by ELISA. RESULTS: Maternal adipose tissue was the prominent site of adpN gene expression with no detectable mRNA or protein in placenta. In obese women, adipose tissue adpN mRNA was significantly decreased (P < .01) whereas DNA methylation was significantly increased (P < .001) compared with lean women. The decreased adipose tissue expression resulted in normal-weight women having significantly greater plasma adpN compared with the severely obese (12.8 +/- 4.3 ng/mL vs 8.6 +/- 3.1, P < .001). Plasma adpN was negatively correlated with maternal body mass index (r = -0.28, P < .001) and homeostasis model assessment indices of insulin sensitivity (r = -0.32, P < .001) but not with gestational weight gain. CONCLUSIONS: Maternal adipose tissue is the primary source of circulating adpN during pregnancy. Further, based on our results, the placenta does not synthesize adiponectin at term. Obesity in pregnancy is associated with negative regulation of adpN adipose expression with increase in adpN DNA methylation associated with lower mRNA concentrations and hypoadiponectinemia. Maternal hypoadiponectinemia may have functional consequences in down-regulating biological signals transmitted by adpN receptors in various tissues, including the placenta. PMID- 24796927 TI - Novel biomarkers of androgen deficiency from seminal plasma profiling using high resolution mass spectrometry. AB - CONTEXT: The seminal plasma is made of secretions from the testis, the epididymis, and the male accessory glands, which are dependent on the presence of androgenic stimuli. OBJECTIVE: The objective of this study was to identify new seminal biomarkers for secundary male hypogonadism using proteomic profiling. DESIGN: Seminal plasma samples from patients affected by secundary hypogonadism and normogonadal controls were analyzed by an LTQ Orbitrap XL hybrid mass spectrometer and data were evaluated using bioinformatic tools. SETTING: The study was performed at a clinical research center. SUBJECTS: Twenty male patients, aged 25-55 years, affected by secundary hypogonadic were studied. Ten patients were reevaluated after 6 months of T replacement therapy (TRT). Ten normogonadic men were enrolled as a control group. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The list of absent proteins in the samples of hypogonadic patients and identified after TRT was studied. Bioinformatic tools were used to functionally annotate the panel of androgen-dependent proteins. The interaction network of the differentially expressed proteins was built in silico, including the androgen receptor. RESULTS: A lower number of proteins was identified in hypogonadic patients compared with normogonadal men. Among the 61 proteins identified in normogonadal men, 33 proteins were absent in hypogonadic patients. Fourteen of 33 absent proteins were identified in seminal samples after 6 months of TRT. Functional annotation analysis revealed that binding and enzymatic activities are mainly deficient in male hypogonadism. Seven of 14 differentially expressed proteins can fall into one large protein-protein interaction network, which directly involves the androgen receptor. CONCLUSION: A high resolution mass spectrometry-based proteomic approach was first used to describe the alterations of seminal seminal proteome in secundary male hypogonadism. These proteins represent putative physiological in vivo targets for androgen deficiency. PMID- 24796929 TI - Estradiol affects extracellular leptin:adiponectin ratio in human breast tissue in vivo. AB - CONTEXT: Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue. OBJECTIVE: To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer. SETTING AND DESIGN: Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated. RESULTS: In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P < .05) and positively correlated with leptin (r = 0.37; P < .05) and leptin:adiponectin ratio (r = 0.38; P < .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P < 0.05) and decreased leptin (P < .01) and the leptin:adiponectin ratio (P < .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P < .01) and adiponectin lower (P < .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P < .05). CONCLUSIONS: Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention. PMID- 24796928 TI - Transforming growth factor-beta induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis. AB - CONTEXT: TGF-beta is believed to play a major role in the etiology of peritoneal endometriosis. In tumors, TGF-beta induces the metabolic conversion of glucose to lactate via glycolysis, a process referred to as the "Warburg effect." Lactate increases cell invasion, angiogenesis, and immune suppression, all crucial steps in the development of endometriosis. OBJECTIVE: The aim of this study was to determine whether TGF-beta induces a "Warburg-like" effect in peritoneal endometriosis. DESIGN: The study was informed by human tissue analysis and cel culture. SETTING: The study was conducted at the university research institute. PATIENTS OR OTHER PARTICIPANTS: We studied women undergoing surgical investigation for endometriosis. INTERVENTIONS: Concentrations of lactate and TGF beta1 in peritoneal fluid (n = 16) were measured by commercial assay. Expression of genes implicated in glycolysis was measured in endometrial and peritoneal biopsies (n = 31) by quantitative RT-PCR and immunohistochemistry. The effect of TGF-beta1 on primary human peritoneal mesothelial cells (n = 6) and immortalized mesothelial (MeT-5A) cells (n = 3) was assessed by quantitative RT-PCR, Western blot, and commercial assays. MAIN OUTCOME MEASURES: Lactate, TGF-beta1, and markers of glycolysis were measured. RESULTS: Concentrations of lactate in peritoneal fluid paralleled those of TGF-beta1, being significantly higher in women with endometriosis compared to women without (P < .05). Endometriosis lesions expressed higher levels of glycolysis-associated genes HIF1A, PDK1, and LDHA than eutopic endometrium, and adjacent peritoneum had higher levels of HIF1A and SLC2A1 than peritoneum from women without disease (P < .05 to P < .001). Exposure of mesothelial cells to TGF-beta1 increased production of lactate (P < .05), increased HIF1A mRNA (P < .05), and protein, and increased concentrations of mRNAs encoded by glycolysis-associated genes (LDHA, PDK1, SLC2A1; P < .05). CONCLUSIONS: A change in the metabolic phenotype of endometriosis lesions and peritoneal mesothelium in women with endometriosis may favor development of endometriosis. PMID- 24796930 TI - Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine. AB - CONTEXT: An increased need for T4 has been described in patients with different gastrointestinal disorders. However, there is a lack of systematic studies assessing the need for T4 in hypothyroid patients with lactose intolerance, a widespread and often occult disorder. OBJECTIVE: The objective of the study was to assess the replacement T4 dose required in hypothyroid patients with lactose intolerance. DESIGN: This was a cohort study. SETTING: The study was conducted at an outpatient endocrinology unit in a University Hospital. PATIENTS: The replacement T4 dose has been analyzed, from 2009 to 2012, in 34 hypothyroid patients due to Hashimoto's thyroiditis and lactose intolerance and being noncompliant with a lactose-free diet. MAIN OUTCOME MEASURE: An individually tailored T4 dose was measured. RESULTS: In all patients with isolated Hashimoto's thyroiditis, target TSH (median TSH 1.02 mU/L) was obtained at a median T4 dose of 1.31 MUg/kg/d. In patients with lactose intolerance, only five of 34 patients reached the desired TSH (median TSH 0.83 mU/L) with a similar T4 dose (1.29 MUg/kg/d). In the remaining 29 patients, the T4 dose was progressively increased and the target TSH (median TSH 1.21 mU/L) was attained at a median T4 dose of 1.81 MUg/kg/d (+38%, P < .0001). In six of these patients, other gastrointestinal disorders were diagnosed, and their median T4 requirement was higher (2.04 MUg/kg/d; +55%; P = .0032). In the remaining 23 patients with isolated lactose intolerance, a median T4 dose of 1.72 MUg/kg/d (+31% P < .0001) has been required to attain pharmacological thyroid homeostasis. CONCLUSIONS: These findings show that lactose intolerance significantly increased the need for oral T4 in hypothyroid patients. PMID- 24796931 TI - Sex steroids in relation to sexual and skeletal maturation in obese male adolescents. AB - BACKGROUND: Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting. OBJECTIVES: To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence. METHODS: Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatography-tandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays. RESULTS: Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages. CONCLUSION: Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys. PMID- 24796933 TI - Stem cell therapies in the management of diabetic retinopathy. AB - Diabetic retinopathy is the leading cause of blindness in the working population. We now understand that the pathogenesis of the disease contains both a neurodegenerative and vasodegenerative component. Yet despite this, current treatment is still limited to combating the proliferative end stage component of the disease rather than addressing its underlying causes. In recent years, much basic research has focused on demonstrating the potential that several classes of stem cells have in conferring both neuro- and vasoprotection on the diabetic retina. Further, progress has been made in using stem cells to stimulate both neuro and vascular regeneration. This review will discuss the current understanding as to what mechanisms underlie diabetic retinopathy while highlighting the types of stem cells which offer hope as potential novel therapies for diabetic retinopathy, including those that are now in clinical trial. PMID- 24796934 TI - Risks and benefits of statin use in young people with type 1 diabetes. AB - Cardiovascular disease (CVD) is the primary cause of mortality in patients with type 1 diabetes (T1D). Despite advances in the management of microvascular complications of T1D, there is a lack of similar progress in reduction of macrovascular complications. Dyslipidemia is one of the major contributory factors for macrovascular complications in T1D, but the literature suggests significant under-treatment of this risk factor in children and adolescents with diabetes. Statins have shown to be both effective and safe in young people with familial hypercholesterolemia and adults with diabetes mellitus, but the role for statins in children and adolescent with T1D remains unclear and controversial. In this review, we will summarize the risks and benefits of statin use in young people with T1D. PMID- 24796935 TI - Expression of histone deacetylase-1 and p300 in aristolochic acid nephropathy models. AB - Aristolochic acid nephropathy (AAN) is mainly caused by aristolochic acid I (AAI), but the actual mechanism is still uncertain. The current study explored the correlation among the expression of Smad7, p300, histone deacetylase-1 (HDAC1) and the development of AAN using transmission electron microscopy (TEM), RT-PCR, and western blotting in the AAN mouse model and in the AAN cell model. TEM revealed that the renal tubular epithelial cells from the AAI-treated mice presented organelle damages and nuclear deformation. We found that a certain dose of AAI caused renal fibrosis and induced renal tubular epithelial cells to differentiate into myofibroblasts. There was a gradual increase in the expression of HDAC1 mRNA and protein observed using RT-PCR and western blotting in the AAN cell model compared with the control group. Gradual decrease in the expression of Smad7 and p300 mRNA and protein was revealed in the AAN mouse and cell models compared with the control group. These results suggest that AAI dose dependently contributed to the development of AAN, and HDAC1 and p300 participate in the modulation of TGF-beta/Smad pathway-mediated renal interstitial fibrosis. PMID- 24796936 TI - Improvement of virtual screening results by docking data feature analysis. AB - In this study, we propose a novel approach to evaluate virtual screening (VS) experiments based on the analysis of docking output data. This approach, which we refer to as docking data feature analysis (DDFA), consists of two steps. First, a set of features derived from the docking output data is computed and assigned to each molecule in the virtually screened library. Second, an artificial neural network (ANN) analyzes the molecule's docking features and estimates its activity. Given the simple architecture of the ANN, DDFA can be easily adapted to deal with information from several docking programs simultaneously. We tested our approach on the Directory of Useful Decoys (DUD), a well-established and highly accepted VS benchmark. Outstanding results were obtained by DDFA not only in comparison with the conventional rankings of the docking programs used in this work but also with respect to other methods found in the literature. Our approach performs with similar good results as the best available methods, which, however, also require substantially more computing time, economic resources, and/or expert intervention. Taken together, DDFA represents an automatic and highly attractive methodology for VS. PMID- 24796938 TI - Retracted: Sirt3 activation attenuated oxidized low-density lipoprotein-induced human umbilical vein endothelial cells' apoptosis by sustaining autophagy by Luo, X, Yang, Z, Zheng, S, Cao, Y and Wu, Y. AB - The above article, published online on 05 May 2014 in Wiley Online Library (http://onlinelibrary.wiley.com/doi/10.1002/cbin.10291/full), has been retracted by agreement between the authors, the journal Editor, Sergio Schenkman, and John Wiley & Sons Ltd. The retraction has been agreed because the authors discovered that the results of section 3 in this paper were irreproducible. In addition, Zhiqiang Yang, a co-author, states conflict of interest in this paper. The authors and publisher apologize for any inconvenience. Reference Luo X, Yang Z, Zheng S, Cao Y, Wu Y (2014) Sirt3 activation attenuated oxidized low-density lipoprotein induced human umbilical vein endothelial cells' apoptosis by sustaining autophagy. Cell Biol Int, https://doi.org/10.1002/cbin.10291. PMID- 24796937 TI - Leukoreduced blood transfusion does not increase circulating soluble markers of inflammation: a randomized controlled trial. AB - BACKGROUND: Transfused blood may have immunomodulatory and proinflammatory effects. We report the first randomized study exploring whether leukoreduced red blood cell (RBC) transfusion increases circulating proinflammatory mediators, markers of neutrophil activation, and the acute-phase response in critically ill adults. STUDY DESIGN AND METHODS: Eighty-four patients were recruited from six general intensive care units in the United Kingdom as part of a laboratory study nested within a parallel-group randomized trial comparing restrictive and liberal leukoreduced RBC transfusion strategies in critically ill patients aged more than 55 years with measured hemoglobin concentrations of not more than 90 g/L (ClinicalTrials.gov NCT00944112). Forty-one patients received transfusion and 43 did not receive transfusion. Plasma was sampled at baseline, 6 hours, and 24 hours after randomization or transfusion, and concentrations of interleukin (IL) 1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12-p70, interferon-gamma, tumor necrosis factor-alpha, human neutrophil elastase, soluble L-selectin, and C reactive protein were measured using cytokine bead array analysis and an enzyme linked immunosorbent assay. RESULTS: Patients who received transfusion did not have significantly different inflammatory biomarker plasma concentrations at the time points compared to those who did not receive transfusion, with the exception of IL-8 concentrations at 24 hours, which were reduced in the transfused group (p = 0.02). After adjustment for baseline inflammatory biomarker concentrations, there were no significant differences between patients who received transfusion and those who did not. CONCLUSION: Concentrations of measured biomarkers were not significantly increased during the first 24 hours after leukoreduced RBC transfusion. These data do not support the contention that leukoreduced RBC transfusion is associated with a proinflammatory response in the general adult critically ill population. PMID- 24796939 TI - The submerged printing of cells onto a modified surface using a continuous flow microspotter. AB - The printing of cells for microarray applications possesses significant challenges including the problem of maintaining physiologically relevant cell phenotype after printing, poor organization and distribution of desired cells, and the inability to deliver drugs and/or nutrients to targeted areas in the array. Our 3D microfluidic printing technology is uniquely capable of sealing and printing arrays of cells onto submerged surfaces in an automated and multiplexed manner. The design of the microfluidic cell array (MFCA) 3D fluidics enables the printhead tip to be lowered into a liquid-filled well or dish and compressed against a surface to form a seal. The soft silicone tip of the printhead behaves like a gasket and is able to form a reversible seal by applying pressure or backing away. Other cells printing technologies such as pin or ink-jet printers are unable to print in submerged applications. Submerged surface printing is essential to maintain phenotypes of cells and to monitor these cells on a surface without disturbing the material surface characteristics. By printing onto submerged surfaces, cell microarrays are produced that allow for drug screening and cytotoxicity assessment in a multitude of areas including cancer, diabetes, inflammation, infections, and cardiovascular disease. PMID- 24796940 TI - Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea. AB - BACKGROUND: More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. METHODS: Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc(99) m liver-spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake, <10% uptake, decreased but >=10% uptake, and normal. RESULTS: Mean age (N = 40) was 9.1 yrs, range 2.3-17.0. After 3 yrs of treatment, 13 (33%) had uptake on LS scan. These 13 children were younger (median age 6.0 vs. 10.6 yrs, P = 0.008), had a higher HbF at baseline (mean 10.2% vs. 5.8%, P = 0.004) and after 3 yrs (22.9% vs. 13.9%, P < 0.001), achieved MTD more rapidly (median 288 vs. 358 d, P = 0.021), and were more likely to have baseline splenic uptake (P < 0.001). CONCLUSIONS: Hydroxyurea at MTD is associated with preserved or improved splenic filtrative function, with 33% demonstrating LS scan uptake after 3 yrs. Younger age, higher %HbF, and baseline splenic function are associated with a favorable outcome. PMID- 24796941 TI - Aqueous synthesis of multidentate-polymer-capping Ag2Se quantum dots with bright photoluminescence tunable in a second near-infrared biological window. AB - A new strategy for fabricating water-dispersible Ag2Se quantum dots (QDs) is presented. A multidentate polymer (MDP) was synthesized and used as a capping agent for Ag2Se QDs. The MDP-capping Ag2Se QDs were synthesized in aqueous solution at room temperature, which are highly photoluminescent in a second near infrared (NIR-II) biological window and possess good photostability. These readily prepared NIR-II fluorescent nanoprobes have great potential for biomedical applications, especially useful for in vivo imaging. PMID- 24796942 TI - High throughput identification and quantification of anabolic steroid esters by atmospheric solids analysis probe mass spectrometry for efficient screening of drug preparations. AB - Recent developments in ambient mass spectrometry (AMS), such as atmospheric solids analysis probe (ASAP) mass spectrometry, open a whole new range of possibilities to screen for drug preparations. In this study, the potential of ASAP for the rapid identification and quantification of anabolic steroid esters has been evaluated. These compounds are known to be used both in human and in food producing animals to enhance performances and to improve the rate of growth, respectively. Using a triple quadrupole (QqQ) MS instrument, mechanism of ionization and fragmentation in both positive and negative mode were studied for a range of 21 selected steroid esters (based on testosterone, estradiol, nandrolone, and boldenone) which highlighted common neutral mass loss of 96.1, thus allowing rapid screening in minutes to reveal steroid ester presence with minimal sample preparation. Ester identification is further achieved through an efficient 2 min workflow on a QqQ MS instrument. Moreover, the use of isotope labeled internal standards permitted the quantification of the corresponding steroid esters in selected reaction monitoring (SRM) mode, for the first time in ASAP. This approach was successfully applied for characterization of oily commercial preparations. These results open new perspectives in hormone (and drug) rapid analysis by ASAP-MS in the near future. PMID- 24796943 TI - [Bipolar disorders in DSM-5]. AB - BACKGROUND: In spring 2013 the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) edited by the American Psychiatric Association was published. The DSM-5 has also brought some important changes regarding bipolar disorders. OBJECTIVES: The goal of this manuscript is to review the novelties in DSM-5 and to evaluate the implications of these changes. MATERIALS AND METHODS: The diagnostic criteria as well as the additional remarks provided in the running text of DSM-5 were carefully appraised. RESULTS: For the first time diagnostic criteria are provided for disorders which up to now have been considered as subthreshold bipolar disorders. Furthermore, mixed episodes were eliminated and instead a mixed specifier was introduced. An increase in goal directed activity/energy is now one of the obligatory symptoms for a (hypo)manic episode. Diagnostic guidance is provided as to when a (hypo)manic episode that has developed during treatment with an antidepressant has to be judged to be causally related to antidepressants and when this episode has only occurred coincidentally with antidepressant use. CONCLUSIONS: While some of the novelties are clearly useful, e.g. addition of increased goal-directed activity/energy as obligatory symptom for (hypo)manic episodes, this remains to be demonstrated for others, such as the definition of various subthreshold bipolar disorders. PMID- 24796944 TI - Regeneration of posterior segments and terminal structures in the bearded fireworm, Hermodice carunculata (Annelida: Amphinomidae). AB - Like many other annelids, bearded fireworms, Hermodice carunculata, are capable of regenerating posterior body segments and terminal structures lost to amputation. Although previous research has examined anterior regeneration in other fireworm species, posterior regenerative ability in fireworms remains poorly studied. As the morphology of the anal lobe (a small, fleshy terminal structure of unknown function) has been used to distinguish East and West Atlantic H. carunculata populations, there is a more imminent need to understand the morphology and organization of tissues in specimens undergoing posterior regeneration, and the timeframe in which significant developmental changes occur. To further investigate this phenomenon, we amputated the posterior segments of living H. carunculata specimens collected from the Gulf of Mexico and monitored posterior regeneration over a 6-month study period. Although many aspects of posterior regeneration in H. carunculata are consistent with the findings of other annelid regeneration studies, histological analysis revealed that once formed, anal lobe morphology remains relatively unchanged at all stages of posterior regeneration; East Atlantic morphotypes were not observed in the West Atlantic specimens studied here. Additionally, we found that the ventral nerve chord, which is partially responsible for the regeneration of lost body parts in polychaete annelids, terminates within the anal lobe, suggesting that this structure may play a role in the formation of new segments. PMID- 24796945 TI - New procedure for rapid identification of microorganisms causing urinary tract infection from urine samples by mass spectrometry (MALDI-TOF). AB - INTRODUCTION: Matrix assisted laser desorption/ionization-time of flight (MALDI TOF) mass spectrometry is widely established as a technique in clinical microbiology laboratories for the identification of microorganisms. Using this technique, it is also possible to obtain the identification of microorganisms from untreated urine samples. METHODS: In this study, a differential centrifugation protocol and a criterion for validation of the results in order to achieve microbial identification from untreated urine samples are proposed. Additionally, the sensitivity of the analytical procedure in monobacterial urine samples has been evaluated. RESULTS: A 90% sensitivity (confidence interval of 81.96%-94.84%) was obtained in urine samples with bacterial counts of >=1*10(5)CFU/ml, and it was possible to improve the percentages of direct identifications from urine samples with bacterial counts of <1*10(5)CFU/ml. CONCLUSION: It is concluded that the MALDI-TOF system is both fast and reliable in the identification of individual microorganisms from untreated urine samples with counts of >=1*10(5)CFU/ml. PMID- 24796946 TI - Brave new world - towards a forensic science profession. PMID- 24796947 TI - A preliminary investigation into the use of alginates for the lifting and enhancement of fingermarks in blood. AB - Recent studies have reported the use of alginate in the lifting and subsequent enhancement of footwear marks in blood. A study was set up to assess the use of such a method in the treatment of fingermarks in blood on a variety of porous, non-porous and semi-porous surfaces. Other variables included ageing of the fingermarks in blood and the application of chemicals prior to or post-alginate lifting. All different variations were compared to direct chemical treatment of the substrate. The results demonstrated that alginate is not compatible with certain substrates (e.g. glass and tile). On substrates that were compatible with alginate (e.g. fabric and paper), the enhanced fingermarks on the alginate cast and the enhanced fingermarks on the post-alginate substrates appeared, overall, inferior compared to direct chemical enhancement without the use of alginate. A further variation using water-based protein stains directly mixed with the alginate appeared to provide enhancement directly on the substrate as well as simultaneous lifting and enhancing the fingermarks in blood on the alginate cast. PMID- 24796948 TI - Exploring the recovery and detection of messenger RNA and DNA from enhanced fingermarks in blood. AB - Often in the examination of bloodstained fingermarks discussion occurs around whether to prioritise the fingerprint evidence or focus on the biological evidence. Collecting a sample for genetic profiling may result in the loss of ridge detail that could have been used for fingerprint comparison. Fingermark enhancement and recovery methods along with sample collection methods could also compromise downstream genetic analysis. Previous forensic casework has highlighted circumstances where, after enhancement had been performed, it would have been extremely valuable to both identify the body fluid and generate a DNA profile from the same sample. We enhanced depletion series of fingermarks made in blood, using single treatments consisting of aqueous amido black, methanol-based amido black, acid yellow and leucocrystal violet, and exposure to long wave UV light. We then extracted the DNA and RNA for profiling, to assess the recovery and detection of genetic material from the enhanced fingermarks. We have shown that genetic profiling of bloodstained fingermarks can be successful after chemical enhancement; however it may still be necessary to prioritise evidence types in certain circumstances. From our results it appears that even with visible bloodstained fingermarks, leucocrystal violet can reduce the effectiveness of subsequent messenger RNA profiling. Aqueous amido black and acid yellow also have adverse effects on messenger RNA profiling of depleted fingermarks with low levels of cellular material. These results help with forensic decision-making by expanding knowledge of the extent of the detrimental effects of blood-enhancement reagents on both DNA profiling and body fluid identification using messenger RNA profiling. PMID- 24796949 TI - Assessment of the methodology for estimating ridge density in fingerprints and its forensic application. AB - In recent times, some studies have explored the forensic application of dermatoglyphic traits such as the epidermal ridge breadth or ridge density (RD) toward the inference of sex and population from fingerprints of unknown origin, as it has been demonstrated that there exist significant differences of fingerprints between sexes and between populations. Part of the population differences found between these studies could be of methodological nature, due both to the lack of standardisation in the position of the counting area, as well as to the differences in the method used for obtaining the fingerprint. Therefore, the aim of this study was to check whether there are differences between the RD of fingerprints depending on where the counting area is placed and how the fingerprints are obtained. Fingerprints of each finger were obtained from 102 adult Spanish subjects (50 females and 52 males), using two methods (plain and rolled). The ridge density of each fingerprint was assessed in five different areas of the dactylogram: two closer to the core area (one on the radial and the other on the ulnar side), two closer to the outermost area of each of the sides (radial and ulnar), and another one in the proximal region of the fingertip. Regardless of the method used and of the position of the counting area, thumbs and forefingers show a higher RD than middle, ring, and little fingers in both sexes, and females present a higher RD than males in all areas and fingers. In both males and females, RD values on the core region are higher than those on the outer region, irrespective of the technique of fingerprinting used (rolled or plain). Regardless of the sex and location of the count area (core or outer), the rolled fingerprints exhibit RD greater than that of the plain ones in both radial and proximal areas, whereas the trend is inverted in the ulnar area, where rolled fingerprints demonstrate RD lesser than that of the plain ones. Therefore, in order for the results of different studies to be comparable, it is necessary to standardise the position of the count area and to use the same method of obtaining the fingerprint, especially when involving a forensic application. PMID- 24796950 TI - Cognitive bias in forensic anthropology: visual assessment of skeletal remains is susceptible to confirmation bias. AB - An experimental study was designed to examine cognitive biases within forensic anthropological non-metric methods in assessing sex, ancestry and age at death. To investigate examiner interpretation, forty-one non-novice participants were semi randomly divided into three groups. Prior to conducting the assessment of the skeletal remains, two of the groups were given different extraneous contextual information regarding the sex, ancestry and age at death of the individual. The third group acted as a control group with no extraneous contextual information. The experiment was designed to investigate if the interpretation and conclusions of the skeletal remains would differ amongst participants within the three groups, and to assess whether the examiners would confirm or disagree with the given extraneous context when establishing a biological profile. The results revealed a significant biasing effect within the three groups, demonstrating a strong confirmation bias in the assessment of sex, ancestry and age at death. In assessment of sex, 31% of the participants in the control group concluded that the skeleton remains were male. In contrast, in the group that received contextual information that the remains were male, 72% concluded that the remains were male, and in the participant group where the context was that the remains were of a female, 0% of the participants concluded that the remains were male. Comparable results showing bias were found in assessing ancestry and age at death. These data demonstrate that cognitive bias can impact forensic anthropological non-metric methods on skeletal remains and affects the interpretation and conclusions of the forensic scientists. This empirical study is a step in establishing an evidence base approach for dealing with cognitive issues in forensic anthropological assessments, so as to enhance this valuable forensic science discipline. PMID- 24796951 TI - Configural and featural information in facial-composite images. AB - Eyewitnesses are often invited to construct a facial composite, an image created of the person they saw commit a crime that is used by law enforcement to locate criminal suspects. In the current paper, the effectiveness of composite images was investigated from traditional feature systems (E-FIT and PRO-fit), where participants (face constructors) selected individual features to build the face, and a more recent holistic system (EvoFIT), where they 'evolved' a composite by repeatedly selecting from arrays of complete faces. Further participants attempted to name these composites when seen as an unaltered image, or when blurred, rotated, linearly stretched or converted to a photographic negative. All of the manipulations tested reduced correct naming of the composites overall except (i) for a low level of blur, for which naming improved for holistic composites but reduced for feature composites, and (ii) for 100% linear stretch, for which a substantial naming advantage was observed. Results also indicated that both featural (facial elements) and configural (feature spacing) information were useful for recognition in both types of composite system, but highly detailed information was more accurate in the feature-based than in the holistic method. The naming advantage of linear stretch was replicated using a forensically more-practical procedure with observers viewing an unaltered composite sideways. The work is valuable to police practitioners and designers of facial-composite systems. PMID- 24796952 TI - Analysis of illicit dietary supplements sold in the Italian market: identification of a sildenafil thioderivative as adulterant using UPLC-TOF/MS and GC/MS. AB - Identification of pharmaceutical active ingredients sildenafil and tadalafil and the characterization of a dimethylated thio-derivative of sildenafil, called thioaildenafil or thiodimethylsildenafil, in illicit dietary supplements were described. A multi-residual ultra-performance liquid chromatography-time of flight mass spectrometry (UPLC-TOF/MS) method was developed to screen for the presence of the phosphodiesterase-5 (PDE-5) inhibitors sildenafil, tadalafil, and vardenafil and their analogues thioaildenafil and thiohomosildenafil in powders and pharmaceutical dosage forms. The study was developed in connection with an operation supervised by the Italian Medicines Agency (A.I.F.A.), aimed to monitor dietary supplements in the Italian market. In two of the eleven specimens under investigation, high-resolution mass spectrometry (HR-MS) allowed the identification of the PDE-5 inhibitors sildenafil and tadalafil, while another specimen proved to contain a unapproved dimethylated thioderivative of sildenafil, thioaildenafil or thiodimethylsildenafil, identified for the first time in Italy as adulterant in food supplements. PMID- 24796953 TI - Limitations and recommendations for successful DNA extraction from forensic soil samples: a review. AB - Soil is commonly used in forensic casework to provide discriminatory power to link a suspect to a crime scene. Standard analyses examine the intrinsic properties of soils, including mineralogy, geophysics, texture and colour; however, soils can also support a vast amount of organisms, which can be examined using DNA fingerprinting techniques. Many previous genetic analyses have relied on patterns of fragment length variation produced by amplification of unidentified taxa in the soil extract. In contrast, the development of advanced DNA sequencing technologies now provides the ability to generate a detailed picture of soil microbial communities and the taxa present, allowing for improved discrimination between samples. However, DNA must be efficiently extracted from the complex soil matrix to achieve accurate and reproducible DNA sequencing results, and extraction efficacy is highly dependent on the soil type and method used. As a result, a consideration of soil properties is important when estimating the likelihood of successful DNA extraction. This would include a basic understanding of soil components, their interactions with DNA molecules and the factors that affect such interactions. This review highlights some important considerations required prior to DNA extraction and discusses the use of common chemical reagents in soil DNA extraction protocols to achieve maximum efficacy. Together, the information presented here is designed to facilitate informed decisions about the most appropriate sampling and extraction methodology, relevant both to the soil type and the details of a specific forensic case, to ensure sufficient DNA yield and enable successful analysis. PMID- 24796954 TI - Distinguishing between forensic science and forensic pseudoscience: testing of validity and reliability, and approaches to forensic voice comparison. AB - In this paper it is argued that one should not attempt to directly assess whether a forensic analysis technique is scientifically acceptable. Rather one should first specify what one considers to be appropriate principles governing acceptable practice, then consider any particular approach in light of those principles. This paper focuses on one principle: the validity and reliability of an approach should be empirically tested under conditions reflecting those of the case under investigation using test data drawn from the relevant population. Versions of this principle have been key elements in several reports on forensic science, including forensic voice comparison, published over the last four-and-a half decades. The aural-spectrographic approach to forensic voice comparison (also known as "voiceprint" or "voicegram" examination) and the currently widely practiced auditory-acoustic-phonetic approach are considered in light of this principle (these two approaches do not appear to be mutually exclusive). Approaches based on data, quantitative measurements, and statistical models are also considered in light of this principle. PMID- 24796955 TI - Three-dimensional gamma analysis of dose distributions in individual structures for IMRT dose verification. AB - Our purpose in this study was to implement three-dimensional (3D) gamma analysis for structures of interest such as the planning target volume (PTV) or clinical target volume (CTV), and organs at risk (OARs) for intensity-modulated radiation therapy (IMRT) dose verification. IMRT dose distributions for prostate and head and neck (HN) cancer patients were calculated with an analytical anisotropic algorithm in an Eclipse (Varian Medical Systems) treatment planning system (TPS) and by Monte Carlo (MC) simulation. The MC dose distributions were calculated with EGSnrc/BEAMnrc and DOSXYZnrc user codes under conditions identical to those for the TPS. The prescribed doses were 76 Gy/38 fractions with five-field IMRT for the prostate and 33 Gy/17 fractions with seven-field IMRT for the HN. TPS dose distributions were verified by the gamma passing rates for the whole calculated volume, PTV or CTV, and OARs by use of 3D gamma analysis with reference to MC dose distributions. The acceptance criteria for the 3D gamma analysis were 3/3 and 2 %/2 mm for a dose difference and a distance to agreement. The gamma passing rates in PTV and OARs for the prostate IMRT plan were close to 100 %. For the HN IMRT plan, the passing rates of 2 %/2 mm in CTV and OARs were substantially lower because inhomogeneous tissues such as bone and air in the HN are included in the calculation area. 3D gamma analysis for individual structures is useful for IMRT dose verification. PMID- 24796957 TI - Rheology of dense suspensions of elastic capsules: normal stresses, yield stress, jamming and confinement effects. AB - We study the shearing rheology of dense suspensions of elastic capsules, taking aggregation-free red blood cells as a physiologically relevant example. Particles are non-Brownian and interact only via hydrodynamics and short-range repulsive forces. An analysis of the different stress mechanisms in the suspension shows that the viscosity is governed by the shear elasticity of the capsules, whereas the repulsive forces are subdominant. Evidence for a dynamic yield stress above a critical volume fraction is provided and related to the elastic properties of the capsules. The shear stress is found to follow a critical jamming scenario and is rather insensitive to the tumbling-to-tank-treading transition. The particle pressure and normal stress differences display some sensitivity to the dynamical state of the cells and exhibit a characteristic scaling, following the behavior of a single particle, in the tank-treading regime. The behavior of the viscosity in the fluid phase is rationalized in terms of effective medium models. Furthermore, the role of confinement effects, which increase the overall magnitude and enhance the shear-thinning of the viscosity, is discussed. PMID- 24796956 TI - Biliary cirrhosis and sepsis are two risk factors of failure after surgical repair of major bile duct injury post-laparoscopic cholecystectomy. AB - BACKGROUND: Major bile duct injury (MBDI) remains frequent after laparoscopic cholecystectomy (LC) reaching 0.3 to 0.6 % and is associated with a significant mortality rate. The aim of this study was to retrospectively analyze the factors likely to influence the long-term results of surgical repair for MBDI occurring after LC. METHODS: Medical records of patients referred to our referral center from January 1992 to January 2010 for management of bile duct injury following LC were retrospectively analyzed, and patients with MBDI were identified. Clinicopathological factors likely to influence long-term results after surgical repair were assessed by univariate and multivariable analysis. RESULTS: During the study period, 38 patients were treated for MBDI. These 38 patients underwent Roux-en-Y hepaticojejunostomy (HJ) or HJ revision in 25 (66 %) and 13 (34 %) cases, respectively. The median follow-up period was 93 (26-204) months. A Clavien-Dindo post-operative morbidity class >3 occurred in 10 (26 %) cases and was independently associated with a surgical repair performed during a sepsis period (OR = 102.5; IC 95 % [7.12; 11,352], p < 0.007). Long-term results showed that biliary strictures occurred in 5 (13 %) cases and were associated with sepsis (p < 0.006), liver cirrhosis (p < 0.002) and post-operative complications (p < 0.012). Multivariate analysis revealed that only liver cirrhosis remained predictive of stricture (OR = 26.4, 95 % CI [2; 1,018], p < 0.026). CONCLUSION: When MBDI occurs following LC, HJ seems to be the optimal treatment but should not be performed during a sepsis period. Long-term results are significantly altered by the presence of a biliary cirrhosis at time of repair. PMID- 24796958 TI - Optimizing efficiency and operations at a California safety-net endoscopy center: a modeling and simulation approach. AB - BACKGROUND: Improvements in endoscopy center efficiency are needed, but scant data are available. OBJECTIVE: To identify opportunities to improve patient throughput while balancing resource use and patient wait times in a safety-net endoscopy center. SETTING: Safety-net endoscopy center. PATIENTS: Outpatients undergoing endoscopy. INTERVENTION: A time and motion study was performed and a discrete event simulation model constructed to evaluate multiple scenarios aimed at improving endoscopy center efficiency. MAIN OUTCOME MEASUREMENTS: Procedure volume and patient wait time. RESULTS: Data were collected on 278 patients. Time and motion study revealed that 53.8 procedures were performed per week, with patients spending 2.3 hours at the endoscopy center. By using discrete event simulation modeling, a number of proposed changes to the endoscopy center were assessed. Decreasing scheduled endoscopy appointment times from 60 to 45 minutes led to a 26.4% increase in the number of procedures performed per week, but also increased patient wait time. Increasing the number of endoscopists by 1 each half day resulted in increased procedure volume, but there was a concomitant increase in patient wait time and nurse utilization exceeding capacity. By combining several proposed scenarios together in the simulation model, the greatest improvement in performance metrics was created by moving patient endoscopy appointments from the afternoon to the morning. In this simulation at 45- and 40 minute appointment times, procedure volume increased by 30.5% and 52.0% and patient time spent in the endoscopy center decreased by 17.4% and 13.0%, respectively. The predictions of the simulation model were found to be accurate when compared with actual changes implemented in the endoscopy center. LIMITATIONS: Findings may not be generalizable to non-safety-net endoscopy centers. CONCLUSIONS: The combination of minor, cost-effective changes such as reducing appointment times, minimizing and standardizing recovery time, and making small increases in preprocedure ancillary staff maximized endoscopy center efficiency across a number of performance metrics. PMID- 24796959 TI - Endoscopic management is the treatment of choice for bile leaks after liver resection. AB - BACKGROUND: Despite improvements in surgical techniques and postoperative patient care, bile leaks still occur postoperatively in as many as 15% of liver resections (LRs) and are associated with high mortality. There is a paucity of outcome data on endoscopic treatment of complex bile leaks. OBJECTIVE: The aim of this retrospective study was to evaluate the efficacy of interventional endoscopy in the treatment of bile leaks after LR. DESIGN: Retrospective interventional study. SETTING, PATIENTS, AND INTERVENTIONS: Sixty patients with bile leaks after LR were treated endoscopically with or without implantation of endoprostheses by using ERCP. The characteristics of LR, effects of surgical and other nonendoscopic treatment measures, clinical and endoscopic presentation of bile leaks, and outcomes after stent placement were recorded. MAIN OUTCOME MEASURE: Main outcome measure was resolution of leakage or termination of unsuccessful endoscopic leakage therapy. RESULTS: The median age of the observed cohort was 58 years. Sixty-five percent of patients had central and 35% peripheral bile leaks; 55% had resection of an entire hepatic lobe, and 45% underwent segmental resection. The overall success rate of endoscopic therapy was 77%. Although endoscopic therapy was performed in all patients with a mean of 2.6 interventions, 28% underwent additional percutaneous drainage. Success of endoscopic treatment was related to stent implantation. Thirteen patients with unsuccessful endoscopic treatment underwent surgical reintervention, and 1 patient died before surgical intervention. LIMITATIONS: No standardized protocol for stent placement due to retrospective nature of the study. Small sample number with uneven distribution of outcome. CONCLUSIONS: Endoscopic therapy with sphincterotomy and insertion of endoprostheses is effective, even in large postoperative bile leaks and particularly for leaks proximal to the common hepatic duct. Complete resolution of the leakage often necessitates multiple treatment sessions. PMID- 24796960 TI - Risk of advanced lesions at first follow-up colonoscopy in high-risk groups as defined by the United Kingdom post-polypectomy surveillance guideline: data from a single U.S. center. AB - BACKGROUND: The United Kingdom (U.K.) post-adenoma resection guidelines recommend earlier surveillance for patients with 5 or more adenomas or 3 to 4 adenomas of which one is 10 mm or larger compared with U.S. guidelines. OBJECTIVE: To evaluate the effect of using the U.K. guideline on a U.S. cohort of adenoma patients. DESIGN: Single-center, retrospective study. SETTING: Indiana University Hospital and an associated ambulatory surgery center. PATIENTS: A total of 1414 patients with baseline adenoma findings belonging to one of 5 risk categories and with a follow-up colonoscopy more than 200 days later. INTERVENTION: Colonoscopy, polypectomy. MAIN OUTCOME MEASUREMENTS: Incidence of advanced lesions at follow up colonoscopy. RESULTS: Advanced neoplasms at follow-up occurred in 16.3% of patients with 5 or more adenomas including 1 that was 10 mm or larger, 8.6% of patients with 3 or 4 adenomas including 1 that was 10 mm or larger, 5% of those with 5 or more adenomas all smaller than 10 mm, 1.8% of those with 3 or 4 adenomas all smaller than 10 mm, and 1.4% of those with 1 to 2 adenomas smaller than 10 mm. Logistic regression analyses showed that the rate of advanced lesions at first follow-up was increased in persons with 3 or more baseline adenomas and at least 1 that is 10 mm or larger compared with those with 1 to 4 small baseline adenomas. LIMITATIONS: Single-center, retrospective study. CONCLUSIONS: Our results indicate the U.K. guideline predicts higher risk groups for advanced neoplasia at first follow-up. Our study had inadequate power to show better prediction of incident cancer. Additional study of other databases is warranted. PMID- 24796961 TI - Editorial Comment to Growing teratoma syndrome: clinical and radiographic characteristics. PMID- 24796962 TI - Effect of strong electric field on the conformational integrity of insulin. AB - A series of molecular dynamics (MD) simulations up to 1 MUs for bovine insulin monomer in different external electric fields were carried out to study the effect of external electric field on conformational integrity of insulin. Our results show that the secondary structure of insulin is kept intact under the external electric field strength below 0.15 V/nm, but disruption of secondary structure is observed at 0.25 V/nm or higher electric field strength. Although the starting time of secondary structure disruption of insulin is not clearly correlated with the strength of the external electric field ranging between 0.15 and 0.60 V/nm, long time MD simulations demonstrate that the cumulative effect of exposure time under the electric field is a major cause for the damage of insulin's secondary structure. In addition, the strength of the external electric field has a significant impact on the lifetime of hydrogen bonds when it is higher than 0.60 V/nm. The fast evolution of some hydrogen bonds of bovine insulin in the presence of the 1.0 V/nm electric field shows that different microwaves could either speed up protein folding or destroy the secondary structure of globular proteins deponding on the intensity of the external electric field. PMID- 24796963 TI - Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study. AB - The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0.006), 2-year overall survival (OS) (P = 0.005) and 2-year disease-free survival (DFS) rates (P = 0.037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0.04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7.18, 95% confidence interval [CI]: 1.71-30.1; P = 0.007) and shorter OS (hazard ratio [HR]: 0.27, 95% CI: 0.08-0.87; P = 0.029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10.3, 95% CI: 2.49-43.2; P = 0.001) and shorter survival (HR: 0.17, 95% IC: 0.05-0.53; P = 0.002), while the association with DFS was of marginal significance (HR: 1.01; 95% CI: 0.99-1.02; P = 0.06). In summary, low KMT2E expression may predict poor outcome in APL patients. PMID- 24796964 TI - Impact of repeat testing of living kidney donors within 14 days of the transplant procedure: a multicenter retrospective survey. AB - BACKGROUND: A transmission of human immunodeficiency virus (HIV) from a live kidney donor prompted recommendations by the New York State Department of Health and the US Centers for Disease Control and Prevention that all live donors undergo additional screening for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) within 7-14 days of the donation procedure. There are concerns that re-screening will result in delays and cancelled transplants. METHODS: We surveyed live-donor transplant centers in New York State to assess their screening protocols and outcomes. Nine live-donor programs (kidney and liver centers) responded. RESULTS: All but 1 program has a formal repeat screening policy. Overall, no cancellations occurred, but 2 centers experienced transplantation delays, generally as the result of technician and laboratory procedural mistakes necessitating repeat phlebotomy. Testing is typically coordinated with pre-surgical visits, additional laboratory tests, and physical examinations. In the initial evaluation, serology was most frequently used (all 9 centers), with few centers utilizing nucleic acid testing (NAT) (HIV NAT, 1; HBV NAT, 2; HCV NAT, 2). Repeat testing modalities varied: HIV antibody (5, 55%), HIV NAT (8, 88%), hepatitis B surface antigen (5, 55%), hepatitis B surface antibody (2, 22%), hepatitis B core antibody (3, 33%), HBV NAT (3, 33%), HCV antibody (3, 33%), and HCV NAT (5, 55%). CONCLUSION: Most respondents have policies to re-test living donors within 14 days of the transplant procedures. Rarely, centers encountered repeat testing-associated delays, but no cancellations occurred. PMID- 24796965 TI - Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice. AB - The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics. Daumone [(2)-(6R)-(3,5-dihydroxy-6-methyltetrahydropyran-2 yloxy)heptanoic acid], a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival in mammals by mimicking calorie restriction. Daumone (2 mg kg(-1) day(-1) ) was administered orally for 5 months to 24-month-old male C57BL/6J mice. Daumone was found to reduce the risk of death by 48% compared with age-matched control mice, and the increased plasma insulin normally presented in old mice was significantly reduced by daumone. The increased hepatic hypertrophy, senescence-associated beta galactosidase activity, insulin resistance, lipid accumulation, inflammation, oxidative stress, and fibrosis in old mice were significantly attenuated by daumone. From a mechanistic view, daumone reduced the phosphorylation of the IkappaBalpha and upregulation of Rela and Nfkbia mRNA in the livers of old mice. The anti-inflammatory effect of daumone was confirmed in lipopolysaccharide induced liver injury model. Oral administration of daumone improves survival in mice and delivers anti-aging effects to the aged liver by modulating chronic inflammation, indicating that daumone could be developed as an anti-aging compound. PMID- 24796966 TI - Pulmonary metastasectomy secondary to esophageal carcinoma: long-term survival and prognostic factors. AB - BACKGROUND: Lung metastasectomy has become an effective treatment for selected patients with colorectal cancer, renal cancer, and other malignancies; however, limited experience has been reported regarding pulmonary metastasectomy for esophageal carcinoma. We reviewed 23 patients with esophageal cancer who underwent pulmonary metastasectomy and investigated their long-term prognosis and prognostic factors. METHODS: A total of 23 patients who underwent 30 curative pulmonary metastasectomies at Toranomon Hospital, Japan, between 2001 and 2011 were included. Four patients underwent repeated metastasectomy. The overall survival rate was examined by the Kaplan-Meier method and various characteristics were assessed by univariate analysis to identify prognostic factors. RESULTS: The overall 1-, 3-, and 5-year survival rate was 82.6, 46, and 34.1 %, respectively. Median follow-up was 37.4 months (range 1-114 months). Univariate analysis revealed a history of extrapulmonary metastases before pulmonary metastasectomy, poorly differentiated primary esophageal carcinoma, and short disease-free interval (DFI) as unfavorable prognostic factors. Five patients who underwent repeated metastasectomy for recurrent pulmonary metastases survived a mean 58 months (range 24-114 months). The other patients survived a mean 29.4 months (range 1-109 months). CONCLUSIONS: Pulmonary resection for lung metastases from esophageal carcinoma should be considered in selected patients, and repeated metastasectomy should be encouraged. Extrapulmonary metastases before pulmonary metastasectomy, poor differentiation of primary esophageal carcinoma, and short DFI are unfavorable prognostic factors. Due to poor prognosis, metastasectomy in patients with these factors should be more carefully considered before being indicated. PMID- 24796967 TI - The Bethesda system for reporting thyroid cytopathology: a single-center experience over 5 years. AB - BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) was developed to refine fine-needle aspiration (FNA) cytology definitions and improve clinical management. This study evaluates the impact of the BSRTC 5 years after its adoption at a single institution. METHODS: A total of 1,625 patients undergoing thyroidectomy in the pre-BSRTC (Group 1: July 2007-January 2009) and post-BSRTC (Group 2: February 2009-September 2013) periods were reviewed. Cytologic diagnoses in Group 1 included non-diagnostic, benign, follicular neoplasm, suspicious for malignancy and malignant. Atypia/follicular lesion of undetermined significance (AUS/FLUS) was included in Group 2. The proportions of each FNA category and malignancy rate per cytologic diagnosis were compared. RESULTS: Fifty-four percent (187/347) of Group 1 patients had a preoperative FNA versus 61 % (777/1278) in Group 2 (p = 0.02). Group 1 FNA results included 3 % non-diagnostic, 48 % benign, 17 % follicular, 13 % suspicious for cancer, and 19 % cancer. Group 2 results included 3 % non-diagnostic, 36 % benign, 9 % follicular, 8 % suspicious for malignancy, 18 % malignant and 26 % AUS/FLUS. In Group 2, the proportions of benign, follicular and suspicious for malignancy FNAs decreased significantly (p < 0.05). In Group 2, there were more indeterminate FNA diagnoses overall (30 vs. 43 %; p < 0.001). The rate of cancer in suspicious for cancer FNA lesions increased from 44 to 65 % (p = 0.07). The AUS/FLUS malignancy rate was 15 %. CONCLUSIONS: Since the adoption of the BSRTC at our institution, the proportion of indeterminate FNAs has increased; however, the diagnostic accuracy of the suspicious for cancer category improved. We recommend periodic review of the utilization and malignancy rates per cytologic category at each institution to help tailor clinical management. PMID- 24796968 TI - Predictors that influence contralateral prophylactic mastectomy election among women with ductal carcinoma in situ who were evaluated for BRCA genetic testing. AB - BACKGROUND: Patients with ductal carcinoma in situ (DCIS) are at increased risk for developing contralateral breast cancer (CBC). Consequently, more women with DCIS are electing to undergo contralateral prophylactic mastectomy (CPM). We evaluated factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA testing. METHODS: This retrospective study involved 165 women with DCIS referred for genetic counseling between 2003 and 2011. Patient characteristics were age, marital and educational status, tumor markers, nuclear grade, family history of breast cancer (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with CPM election. RESULTS: Of 165 patients, 44 (27 %) underwent CPM. Patients <45 years of age were more likely to elect CPM (p = 0.0098). A BRCA+ mutation was found in 17 patients (10.3 %), and BRCA+ women were more likely to elect CPM than BRCA or untested women (p = 0.0001). Patients who had a family history of OC (57.7 %) were more likely to choose CPM than those with no family history (p = 0.0004). Younger age, BRCA+, and an OC family history remained significant in the multivariate model (p < 0.008). CONCLUSION: The CPM rate among patients with DCIS who undergo genetic counseling is high. Factors associated with increased likelihood of CPM among this group were age, BRCA+, and a family history of OC. Further studies are needed to evaluate patients' perceptions of CBC risk and their role in the likelihood of CPM choice. PMID- 24796969 TI - Fluorescence properties of selected benzo[c]phenanthridines. AB - The fluorescence properties of selected benzo[c]phenanthridines (BPs) were examined. The effect of structure, pH and solvent on the fluorescence properties has been investigated. It was found out that the presence of charged iminium nitrogen significantly decreased the fluorescence of the compounds. The fluorescence (intensity as well as emission spectra shape) of the investigated compounds was significantly dependent on pH as well as used solvent. The utilization in epigenetic modification mechanisms studies as demethylase probe and as possible pH indicator was suggested. PMID- 24796970 TI - Does pharmacological treatment of ADHD in adults enhance parenting performance? Results of a double-blind randomized trial. AB - OBJECTIVE: This study examines the effects of parental lisdexamfetamine (LDX) treatment on parent-child interactions. METHODS: Participants were 30 parents (27% were male) and their children aged 5-12 years, both diagnosed with DSM-IV attention-deficit/hyperactivity disorder (ADHD). Optimal LDX dose (30, 50, or 70 mg/day) was determined for parents during a 3-week open-label titration, followed by a within-subjects trial of the acute impact of LDX and placebo on observable parent-child interactions. Two laboratory-based, parent-child interactions simulating typical family tasks (e.g., homework, joint play) were conducted within 2 weeks, once with the adult on a blinded optimal dose of LDX and once on placebo (phase I). Parents were then randomly assigned to continue blinded treatment with LDX or placebo for another month followed by a third interaction task (phase II) to assess the ongoing effects of LDX on parent-child interactions. The primary outcome was the change in rate of parenting behaviors coded during the parent-child interaction tasks. Secondary outcomes included observed rates of children's inappropriate behaviors during the laboratory tasks and changes in parental ADHD symptom severity (ADHD-Rating Scale). RESULTS: Twenty parents (67%) completed the trial. In phase I, medication was associated with a significant reduction in negative talk by parents (p = 0.0066, d = -0.47). There was a Medication * Task interaction (p = 0.0235) with a reduction in children's negative behaviors in the homework phase only (p = 0.0154, d = -0.58). In phase II, LDX was associated with significant increases in praise by parents (d = 0.81) and reductions in parental commands (d = -0.88) and children's inappropriate behaviors (d = -0.84) (all p-values < 0.05). While not reaching statistical significance, LDX was also associated with large reductions in parental verbalizations (d = -0.82), moderate increases in parental responsiveness (d = 0.55), and large reductions in the ratio of commands to verbalizations during the non-homework task (d = -1.05) (all p-values < 0.10). Significant reductions in parental ADHD symptoms vs. placebo were observed (p < 0.005). Loss of appetite, dry mouth, headaches, and delayed sleep onset were the most common adverse events. CONCLUSIONS: Improvements in parent-child interactions emerged over time with LDX treatment of parental ADHD. Results suggest that pharmacological treatment of parental ADHD may improve outcomes in parents and their children. PMID- 24796971 TI - Local and commissural IC neurons make axosomatic inputs on large GABAergic tectothalamic neurons. AB - Large GABAergic (LG) neurons are a distinct type of neuron in the inferior colliculus (IC) identified by their dense vesicular glutamate transporter 2 (VGLUT2)-containing axosomatic synaptic terminals. Yet the sources of these terminals are unknown. Since IC glutamatergic neurons express VGLUT2, and IC neurons are known to have local collaterals, we tested the hypothesis that these excitatory, glutamatergic axosomatic inputs on LG neurons come from local axonal collaterals and commissural IC neurons. We injected a recombinant viral tracer into the IC which enabled Golgi-like green fluorescent protein (GFP) labeling in both dendrites and axons. In all cases, we found terminals positive for both GFP and VGLUT2 (GFP+/VGLUT2+) that made axosomatic contacts on LG neurons. One to six axosomatic contacts were made on a single LG cell body by a single axonal branch. The GFP-labeled neurons giving rise to the VGLUT2+ terminals on LG neurons were close by. The density of GFP+/VGLUT2+ terminals on the LG neurons was related to the number of nearby GFP-labeled cells. On the contralateral side, a smaller number of LG neurons received axosomatic contacts from GFP+/VGLUT2+ terminals. In cases with a single GFP-labeled glutamatergic neuron, the labeled axonal plexus was flat, oriented in parallel to the fibrodendritic laminae, and contacted 9-30 LG cell bodies within the plexus. Our data demonstrated that within the IC microcircuitry there is a convergence of inputs from local IC excitatory neurons on LG cell bodies. This suggests that LG neurons are heavily influenced by the activity of the nearby laminar glutamatergic neurons in the IC. PMID- 24796973 TI - Intact muscle compartment exposed to botulinum toxin type A shows compromised intermuscular mechanical interaction. AB - INTRODUCTION: We tested the hypothesis that BTX-A diminishes epimuscular myofascial force transmission (EMFT) within an intact muscle compartment. METHODS: The tibialis anterior (TA) and extensor hallucis longus (EHL) muscles were kept at constant length, whereas the position of the extensor digitorum longus (EDL) muscle was changed exclusively. Two groups of Wistar rats were tested: a control group (no BTX-A injected) and a BTX group (0.1 unit of BTX-A injected into the mid-belly of TA). RESULTS: In controls, distally altered EDL position affected EDL distal and proximal forces and proximodistal force differences, indicating substantial EMFT. In the BTX group, EDL forces measured at the most proximal position did not change significantly with altered muscle position, and EDL proximodistal force differences became minimized. CONCLUSIONS: Use of BTX-A diminishes EMFT. It may be relevant clinically that BTX-A compromises intermuscular mechanical interaction, as recent studies have shown that such an interaction plays a role in the abnormal mechanics of spastic muscle. PMID- 24796974 TI - Metabolic monitoring in commercially insured pediatric patients newly initiated to take a second-generation antipsychotic. PMID- 24796972 TI - Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. AB - Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-beta-muricholic acid (T-beta-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-beta-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12alpha-hydroxylated bile acids and increasing intestinal T-beta-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. PMID- 24796975 TI - Bin/Amphiphysin/Rvs (BAR) family members bend membranes in cells. AB - We provide direct evidence that Bin/Amphiphysin/Rvs (BAR) family members bend the steady state membrane architecture of organelles in intact cells. In response to inducible BAR molecular actuators, organelles exhibit distinct changes to the orientation and degree of their membrane curvature. This rapidly inducible system may offer a mechanism by which to better understand the structure-function relationship of intracellular organelles. PMID- 24796976 TI - A new single nucleotide polymorphism in the rabbit (Oryctolagus cuniculus) myostatin (MSTN) gene is associated with carcass composition traits. AB - This study aimed at the identification of genetic variations in the myostatin (MSTN) gene and testing their effects on carcass quality traits. We comparatively sequenced Giant Grey (GG) and New Zealand White (NZW) rabbits that were founders of a cross-bred population. Alignment of our sequence data with the GenBank sequence of the rabbit MSTN gene (Ensembl Gene ID ENSOCUG00000012663) identified three single nucleotide polymorphisms (SNPs). The two novel SNPs (c.-125T>C, c.373+234G>A) and one known SNP (c.747+34C>T) were subsequently analysed for linkage with carcass composition traits in 363 F2 animals of the cross GG * NZW. Significant linkage was found between c.373+234G>A and nine carcass composition traits (P < 0.05). No significant effects were found for c.-125T>C and c.747+34C>T. Because the linked SNP is located in intron 1 and no genetic variation was found in the coding region, further investigations are necessary to understand the functional effect of the c.373+234G>A variant on the variability of the traits. PMID- 24796977 TI - Effects of carbohydrate ingestion on acute leukocyte, cortisol, and interleukin-6 response in high-intensity long-distance running. AB - The purpose of this study was to investigate the effect of ingestion of fluids with different carbohydrate concentrations (0, 1.5, and 7%) on the acute immune stress responses after high-intensity long-distance running. Continuous 18- to 20 km run was performed at 75% of maximal oxygen uptake with carbohydrate supplementation (CHO7%, 7% carbohydrate solution) and low-carbohydrate supplementation (lowCHO1.5%, 1.5% carbohydrate solution) in a randomized, double blind, placebo (PLA) controlled design. Seven recreational runners (4 men and 3 women) completed all 3 trials. Blood was collected at baseline (PRE) and immediately after the run (POST). The running task induced significant (p <= 0.05) increases in leukocyte (white blood cells), neutrophil, and interleukin-6 (IL-6) counts in every trial. There was a significant (p <= 0.05) increase in cortisol with PLA and lowCHO1.5% but not with CHO7%. Increase in total leukocyte and neutrophil concentration was significantly lower with CHO7% compared with PLA (p <= 0.05). Postexercise IL-6 levels were significantly elevated when compared with baseline in all conditions (p <= 0.05). Interleukin-6 (IL-6) concentrations did not differ significantly between trials. LowCHO1.5% sport drink did not significantly differ from PLA in measured variables, which indicated that the amount and rate of carbohydrate ingestion (15 g, 10 g.h) in low-carbohydrate sport drink was not enough to significantly protect from the stress induced by high-intensity long-distance running, whereas the ingestion of CHO7% (45 g.h) blunted the significant cortisol response and significantly decreased the leukocyte response. PMID- 24796978 TI - Influence of variable resistance loading on subsequent free weight maximal back squat performance. AB - The purpose of the study was to determine the potentiating effects of variable resistance (VR) exercise during a warm-up on subsequent free-weight resistance (FWR) maximal squat performance. In the first session, 16 recreationally active men (age = 26.0 +/- 7.8 years; height = 1.7 +/- 0.2 m; mass = 82.6 +/- 12.7 kg) were familiarized with the experimental protocols and tested for 1 repetition maximum (1RM) squat lift. The subjects then visited the laboratory on 2 further occasions under either control or experimental conditions. During these conditions, 2 sets of 3 repetitions of either FWR (control) or VR (experimental) squat lifts at 85% of 1RM were performed; during the experimental condition, 35% of the load was generated from band tension. After a 5-minute rest, 1RM, 3D knee joint kinematics, and vastus medialis, vastus lateralis, rectus femoris, and semitendinosus electromyogram (EMG) signals were recorded simultaneously. No subject increased 1RM after FWR, however, 13 of 16 (81%) subjects increased 1RM after VR (mean = 7.7%; p < 0.01). Lower peak and mean eccentric (16-19%; p <= 0.05) and concentric (12-21%; p <= 0.05) knee angular velocities were observed during the 1RM following VR when compared with FWR, however, no differences in knee flexion angle (1.8 degrees ; p > 0.05) or EMG amplitudes (mean = 5.9%; p > 0.05) occurred. Preconditioning using VR significantly increased 1RM without detectable changes in knee extensor muscle activity or knee flexion angle, although eccentric and concentric velocities were reduced. Thus, VR seems to potentiate the neuromuscular system to enhance subsequent maximal lifting performance. Athletes could thus use VR during warm-up routines to maximize squat performance. PMID- 24796979 TI - Effect of using a suspension training system on muscle activation during the performance of a front plank exercise. AB - The objective of the study was to examine the effect of suspension training on muscle activation during performance of variations of the plank exercise. Twenty one participants took part. All individuals completed 2 repetitions each of 4 different plank exercises that consisted of a floor based plank, or planks with arms suspended, feet suspended, or feet and arms suspended using a TRX Suspension System. During plank performance, muscle activation was recorded from rectus abdominis, external oblique, rectus femoris, and serratus anterior (SA) muscles using electromyography. All planks were performed for a total of 3 seconds. Resulting muscle activation data were amplitude normalized, and root mean square activation was then determined over the full 3 second duration of the exercise. A significant main effect of plank type was found for all muscles. Post hoc analysis and effect size examination indicated that abdominal muscle activation was higher in all suspended conditions compared to the floor based plank. The highest level of abdominal muscle activation occurred in the arms suspended and arms/feet suspended conditions, which did not differ from one another. Rectus femoris activation was greatest during the arms suspended condition, whereas SA activity peaked during normal and feet suspended planks. These results indicate that suspension training as performed in this study seems to be an effective means of increasing muscle activation during the plank exercise. Contrary to expectations, the additional instability created by suspending both the arms and feet did not result in any additional abdominal muscle activation. These findings have implications in prescription and progression of core muscle training programs. PMID- 24796980 TI - Changes in functional movement screen scores over a season in collegiate soccer and volleyball athletes. AB - Changes in many aspects of physical capacity and athletic performance have been documented through the course of a competitive season in collegiate athletes. Movement pattern quality as measured by the functional movement screen (FMS) has recently been linked to performance and injury risk. The purpose of this study was to document the changes in functional movement patterns over a competitive season. Fifty-seven National Collegiate Athletic Association Division II athletes were screened using the FMS as part of the pre and post participation examination for their competitive seasons in 2012. Composite and individual FMS test scores for the preseason and postseason were compared with identified significant changes. The scores were also analyzed for changes in the number of asymmetries present and the frequency of a score of 1 in any of the tests. There were no significant interactions in the main effects for time or sport in the composite FMS scores. However, 4 individual tests did show significant change. The deep squat (Z = -3.260, p = 0.001) and in-line lunge scores (Z = -3.498, p < 0.001) improved across all athletes, and the active straight leg raise (Z = -2.496, p = 0.013) and rotary stability scores (Z = -2.530, p = 0.011) worsened across all athletes. A reduction in the number of asymmetries (chi = 4.258, p = 0.039) and scores of 1 (chi = 26.148, p < 0.001) were also found. Changes in individual fundamental movement patterns occur through the course of a competitive season. PMID- 24796981 TI - Tethered swimming can be used to evaluate force contribution for short-distance swimming performance. AB - The purpose of this study was two-fold: (a) to compare stroke and the physiological responses between maximal tethered and free front crawl swimming and (b) to evaluate the contribution of force exertion for swimming performance over short distances. A total of 34 male swimmers, representing various levels of competitive performance, participated in this study. Each participant was tested in both a 30-second maximal tethered swimming test and a 50-m free swimming test. The tethered force parameters, the swimming speed, stroke (stroke rate [SR]), and the physiological responses (increase in blood lactate concentration [DeltaBLa], heart rate, and rate of perceived exertion) were recorded and calculated. The results showed no differences in stroke and the physiological responses between tethered and free swimming, with a high level of agreement for the SR and DeltaBLa. A strong correlation was obtained between the maximum impulse of force per stroke and the speed (r = 0.91; p < 0.001). Multiple regression analysis revealed that the maximum impulse and SR in the tethered condition explained 84% of the free swimming performance. The relationship between the swimming speed and maximum force tended to be nonlinear, whereas linear relationships were observed with the maximum impulse. This study demonstrates that tethered swimming does not significantly alter stroke and the physiological responses compared with free swimming, and that the maximum impulse per stroke should be used to evaluate the balance between force and the ability to effectively apply force during sprint swimming. Consequently, coaches can rely on tethered forces to identify strength deficits and improve swimming performance over short distances. PMID- 24796982 TI - Passive drag reduction using full-body swimsuits: the role of body position. AB - This study aimed to analyze whether using full-body swimsuits affects the swimmer's body alignment and to what extent changes in the body position are responsible of the passive drag (Dp) reduction experienced by the swimmers when using these swimsuits. Fourteen swimmers performed 20-m towing trials using a full-body synthetic rubber swimsuit, a full-body textile swimsuit, a traditional brief swimsuit, and a traditional brief swimsuit with a pull buoy. In all trials, the speed-specific drag (k = Dp per v), the trunk incline (TI), and the lower limbs incline (LI) were determined. In comparison with both conditions in which a full-body swimsuit was not used, k was significantly lower when using the rubber swimsuit (-8.4 and -12.2% vs. the brief swimsuit with and without pull bouy, respectively), and the textile swimsuit (-6.9 and -10.8% vs. the brief swimsuit with and without pull bouy, respectively). No differences in TI were observed among conditions, whereas LI was significantly higher when using the rubber swimsuit or the brief swimsuit with pull buoy than when using the traditional brief swimsuit. A linear mixed model showed that k can be reduced by increasing LI (that is lifting the lower limbs), by decreasing TI (that is keeping the trunk more horizontal), and by using either the rubber or textile full-body swimsuit rather than the traditional brief swimsuit. In conclusion, full-body swimsuits involve a reduction of a swimmer's passive drag caused by intrinsic properties related to the "material composition" of the swimsuits and also influenced by changes in the swimmer's body position. PMID- 24796984 TI - Tennis for physical health: acute age- and gender-based physiological responses to cardio tennis. AB - This study described physiological and perceptual responses to Cardio tennis for "younger" and "older" adult populations of both sexes for health-related outcomes. Thirty-one active participants, each with prior recreational tennis experience (~2 years) (8 younger and 8 older males, and 7 younger and 8 older females) performed preliminary testing and a 50-minute instructor-led Cardio tennis session. Cardio tennis is a conditioning-based tennis program comprised of warm-up movements, drill-based exercises (set movement and hitting games), and competitive play scenarios. Participants performed the 20-m shuttle run test to determine maximal heart rate (HR) during preliminary testing. Before, after, and 30-minute post Cardio tennis session, HR, blood pressure (BP), rate pressure product (RPP), and capillary blood lactate and glucose were determined. Furthermore, HR and pedometer-derived step counts were measured throughout, while the session was filmed and coded for technical skill. After the session, ratings of perceived exertion, enjoyment, and challenge were obtained. Heart rate, systolic BP, and RPP were significantly increased by Cardio tennis (p <= 0.05), though returned to pre-exercise levels after 30 minutes (p > 0.05). Heart rate and BP did not differ between groups pre- or 30-minute postexercise (p > 0.05); however, these were lower in younger males during and higher in younger females postsession (p <= 0.05). Lactate and glucose concentrations were increased in all groups (p <= 0.05), with lactate being highest in male groups (p <= 0.05), without differences in glucose between groups (p > 0.05). Stroke and step counts were not different between groups (p > 0.05). Ratings of perceived exertion and perceived challenge were lowest in the younger male group compared with all other groups (p <= 0.05). Cardio tennis presents as an effective stimulus to invoke sufficient cardiovascular and metabolic load to benefit health and fitness, though age- and sex-based responses should be considered in prescription. PMID- 24796985 TI - Body fat has no effect on the maximal fat oxidation rate in young, normal, and overweight women. AB - The purpose of this study was to examine how fat mass affects the maximal fat oxidation rates of women. Fourteen active, healthy women (age, 21-31 years) with body composition ranging from 18.6 to 30.0% fat were divided into 2 groups (15 24.9% = lower-fat group; 25-35% = higher-fat group). On day 1, subjects performed a graded exercise test on the treadmill to determine maximal oxygen consumption (VO2max). On day 2, subjects were measured for % fat and performed a maximal fat oxidation test. Fat and carbohydrate oxidation rates were determined using gas exchange analysis. Fat oxidation in absolute (in gram per minute) and relative to fat-free body mass (in milligram per kilogram of fat-free mass per minute) was determined using stoichiometric equations and appropriate energy equivalents. There were no significant differences (p > 0.05) in maximal fat oxidation rates between the women in lower-fat (0.39 +/- 0.10 g.min-1, 8.52 +/- 2.69 mg.kg FFM.min-1) and higher-fat (0.49 +/- 0.13 g.min-1, 10.81 +/- 2.80 mg.kg-1 FFM.min 1) groups. Maximal fat oxidation occurred at an exercise intensity of 55.7 +/- 11.1% and 59.1 +/- 5.4% VO2max for the lower-fat and higher-fat groups, respectively, with no significant difference between groups (p > 0.05). The maximal fat oxidation rate (g.min-1 and mg.kg-1 FFM.min-1) was not significantly correlated with any of the descriptive variables (fat mass, fat-free mass, percent body fat, or VO2max). In conclusion, personal trainers and health practitioners can use the exercise intensities that elicited the highest rate of fat oxidation to prescribe exercise programs to women, despite their body composition, that prevent weight gain and/or promote body fat and body weight loss. PMID- 24796986 TI - Does performing drop jumps with additional eccentric loading improve jump performance? AB - Previous investigators have speculated that applying additional external load throughout the eccentric phase of the jumping movement could amplify the stretch shortening cycle mechanism and modulate jumping performance and jump exercise intensity. The aims of this study, therefore, were to determine the effect of increased eccentric phase loading, as delivered using an elastic device, on drop jumps (DJs) performed from different drop heights. Of specific interest were changes in (a) the kinetics; eccentric and concentric impulse, rate of force development (RFD), concentric velocity and (b) the electromyographic (EMG) activity of leg muscles. In a randomized repeated-measure study, 15 highly resistance trained male subjects performed DJs from 3 heights (20, 35, and 50 cm) under 3 different conditions: body weight only (free DJ) and with elastic bands providing downward force equivalent to 20% (+20% DJ) and 30% (+30% DJ) of body mass. All DJs were recorded using video and force plate data that were synchronized with EMG data. Results demonstrated that using additional tensile load during the airborne and eccentric phases of the DJ could enhance eccentric impulse (p = 0.042) and RFD (p < 0.001) and resulted in small to moderate effect size (ES) increases in quadriceps intergrated EMG across the eccentric phase (0.23 > ES > 0.51). The observed greater eccentric loading, however, did not immediately alter concentric kinetics and jump height nor did it alter muscle activation levels during this phase. The findings indicated that, in addition to the conventional technique of increasing drop height, using a tensile load during the airborne and eccentric phases of the DJ could further improve eccentric loading of DJs. As it has been suggested that eccentric impulse and RFD are indicators of DJ exercise intensity, these findings suggest that the loaded DJs, using additional elastic load, may be an effective technique for improving DJ exercise intensity without acute effects on the jumping performance and neuromuscular activation level in highly trained athletes. PMID- 24796987 TI - Effects of 6 weeks of aerobic exercise combined with conjugated linoleic acid on the physical working capacity at fatigue threshold. AB - The purpose of this study was to examine the effects of conjugated linoleic acid (CLA) supplementation in conjunction with 6 weeks of aerobic exercise training on the physical working capacity at the fatigue threshold (PWCFT), timed sit-ups, and the standing long jump. Thirty-three untrained to moderately trained men (mean +/- SD; age = 21.6 +/- 2.8 years) participated in this double-blind, placebo-controlled study and were randomly assigned to either a CLA (Clarinol A 80; n = 17) or placebo (PLA; sunflower oil; n = 16) group. Before and after 6 weeks of aerobic training (50% VO2peak for 30 minutes, twice per week) and supplementation (8 ml CLA or PLA per day), each subject completed an incremental cycle ergometer test to exhaustion to determine the PWCFT, maximal number of sit ups in 1 minute, and the standing long jump. There were no differences (all p >= 0.23) between the CLA and PLA groups for the analysis of covariance-adjusted posttest mean values for PWCFT, sit-ups, or standing long jump. The PWCFT increased from pre- to posttraining in the CLA (p = 0.003) and PLA (p = 0.003) groups. There were no differences (p > 0.05) from pre- to posttraining for sit ups and standing long jump in either the CLA or PLA groups. There was no effect of CLA on the training-induced increases in PWCFT, nor were there any effects of CLA or aerobic training on the maximum number of sit-ups or standing long jump. Thus, CLA had no ergogenic benefits on this model of aerobic training-induced improvements in neuromuscular fatigue, or on field tests of muscle endurance and power. PMID- 24796988 TI - Oxidation and modification of extracellular matrix and its role in disease. AB - There is accumulating evidence that damage to extracellular materials and particularly the extracellular matrix, can play a major role in multiple human pathologies. In contrast to cells, the extracellular compartment of most biological tissues is relatively poorly equipped to prevent or repair damage caused by oxidation due to lower levels of antioxidant defenses (low molecular mass and enzymatic) and repair systems (both catabolic and enzymatic). The extracellular compartment is therefore likely to be subject to both an increased extent of damage and an overall accumulation of damage due to slow turnover and/or poor repair. The nature and consequences of damage to the extracellular matrix is poorly understood, despite evidence that changes in matrix structure influences not only structural integrity, but also cell adhesion, proliferation, migration and signaling, and cytokine and growth factor binding. In this article the nature of the extracellular matrix is briefly reviewed, together with evidence for the presence of matrix modifications in cardiovascular disease. The oxidants and mechanisms that are known to damage extracellular matrix are reviewed, together with the limited data available to date on how such changes affect structural properties and cellular behavior. PMID- 24796989 TI - Identification, characterization, and biofilm formation of clinical Chryseobacterium gleum isolates. AB - Chryseobacterium gleum is not commonly isolated from clinical source(s). Using 16S rRNA gene sequencing, we identified 15 C. gleum isolates from the Central Region Hospital Alliance, Taiwan, which were all misidentified: 14 as Chryseobacterium indologenes and 1 as Elizabethkingia meningoseptica using the Vitek 2 GN card. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry, a rapid and clinically applicable method, was evaluated for the identification of C. gleum, and the rate of species or probable species level identification reached 13.3% and 86.6%, respectively. Using pulsed-field gel electrophoresis analysis, all C. gleum isolates from central Taiwan were found to be epidemiologically unrelated. The most prevalent sample was urine (35.7%, 5/14), followed by sputum (28.6%, 4/14), whereas 1 isolate was from an unknown source. All of the isolates were susceptible to minocycline, 93.3% susceptible to trimethoprim/sulfamethoxazole, but were completely or highly resistant to the other drugs examined. Biofilm-forming ability was observed in 40.0% (6/15) isolates using the Luria-Bertani broth. To the best of our knowledge, this is the first focusing on exploring clinical C. gleum isolates. PMID- 24796997 TI - Limited genomic consequences of mixed mating in the recently derived sister species pair, Collinsia concolor and Collinsia parryi. AB - Highly selfing species often show reduced effective population sizes and reduced selection efficacy. Whether mixed mating species, which produce both self and outcross progeny, show similar patterns of diversity and selection remains less clear. Examination of patterns of molecular evolution and levels of diversity in species with mixed mating systems can be particularly useful for investigating the relative importance of linked selection and demographic effects on diversity and the efficacy of selection, as the effects of linked selection should be minimal in mixed mating populations, although severe bottlenecks tied to founder events could still be frequent. To begin to address this gap, we assembled and analysed the transcriptomes of individuals from a recently diverged mixed mating sister species pair in the self-compatible genus, Collinsia. The de novo assembly of 52 and 37 Mbp C. concolor and C. parryi transcriptomes resulted in ~40 000 and ~55 000 contigs, respectively, both with an average contig size ~945. We observed a high ratio of shared polymorphisms to fixed differences in the species pair and minimal differences between species in the ratio of synonymous to replacement substitutions or codon usage bias implying comparable effective population sizes throughout species divergence. Our results suggest that differences in effective population size and selection efficacy in mixed mating taxa shortly after their divergence may be minimal and are likely influenced by fluctuating mating systems and population sizes. PMID- 24796999 TI - How drugs are developed and approved by the FDA: current process and future directions. AB - OBJECTIVES: This article provides an overview of FDA's regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future. METHODS: A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates. RESULTS: While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from $868M to $1,241M USD. Several new laws have been enacted, including the FDA Safety and Innovation Act (FDASIA) of 2013, which is designed to improve the drug approval process and enhance access to new medicines. CONCLUSIONS: The FDA's improved processes for drug approval and post market surveillance have achieved the goal of providing patients with timely access to effective drugs while minimizing the risk of drug-related harm. The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years. With the approval of the new FDASIA law, the FDA will continue to improve their processes and, working together with the ACG through the FDA-Related Matters Committee, continue to develop safe and effective drugs for our patients. PMID- 24797000 TI - The FDA and prescription pancreatic enzyme product cost. PMID- 24797001 TI - Image of the month: Hookworm infection observed via a narrow-band imaging system. PMID- 24797006 TI - Utilizing HDL levels to improve detection of celiac disease in patients with iron deficiency anemia. PMID- 24797007 TI - Genome-wide association study identifies two novel genomic regions in irritable bowel syndrome. PMID- 24797008 TI - A comparison of patient satisfaction with sedation between fentanyl/midazolam and meperidine/midazolam in patients undergoing endoscopy. PMID- 24797009 TI - Drastically reduced neoplastic seeding related to radiofrequency ablation for hepatocellular carcinoma. PMID- 24797010 TI - Random colonic mucosal biopsies during colonoscopy performed for chronic diarrhea: differences in practice patterns between gastroenterologists and surgeons in a study of 300 patients. PMID- 24797011 TI - The power of poop: patients getting ahead of their doctors using self administered fecal transplants. PMID- 24797017 TI - Characteristics of the Children's Revised Impact of Event Scale in a clinically referred Dutch sample. AB - Early identification of posttraumatic stress disorder (PTSD) in children is important to offer them appropriate and timely treatment. The Children's Revised Impact of Event Scale (CRIES) is a brief self-report measure designed to screen children for PTSD. Research regarding the diagnostic validity of the CRIES is still insufficient, has been restricted to specific populations, and sample sizes have often been small. This study evaluated the reliability and validity of the 8 item (CRIES-8) and 13-item (CRIES-13) versions of the CRIES in a large clinically referred sample. The measure was completed by 395 Dutch children (7-18 years) who had experienced a wide variety of traumatic events. PTSD was assessed using the Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent version. A cutoff score of 17 on the CRIES-8 and 30 on the CRIES-13 emerged as the best balance between sensitivity and specificity, and correctly classified 78%-81% of all children. The CRIES-13 outperformed the CRIES-8, in that the overall efficiency of the CRIES-13 was slightly superior (.81 and .78, respectively). The CRIES appears to be a reliable and valid measure, which gives clinicians a brief and user-friendly instrument to identify children who may have PTSD and offer them appropriate and timely treatment. PMID- 24797018 TI - Fast Response, vertically oriented graphene nanosheet electric double layer capacitors synthesized from C(2)H(2). AB - The growth and electrical characteristics of vertically oriented graphene nanosheets grown by radio frequency plasma-enhanced chemical vapor deposition from C2H2 feedstock on nickel substrates and used as electrodes in symmetric electric double layer capacitors (EDLC) are presented. The nanosheets exhibited 2.7 times faster growth rate and much greater specific capacitance for a given growth time than CH4 synthesized films. Raman spectra showed that the intensity ratio of the D band to G band versus temperature initially decreased to a minimum value of 0.45 at a growth temperature of 750 degrees C, but increased rapidly with further temperature increase (1.15 at 850 degrees C). The AC specific capacitance at 120 Hz of these EDLC devices increased in a linear fashion with growth temperature, up to 265 MUF/cm(2) (2 MUm high film, 850 degrees C with 10 min growth). These devices exhibited ultrafast frequency response: the frequency response at -45 degrees phase angle reached over 20 kHz. Consistent with the increase in D band to G band ratio, the morphology of the films became less vertical, less crystalline, and disordered at substrate temperatures of 800 degrees C and above. This deterioration in morphology resulted in an increase in graphene surface area and defect density, which, in turn, contributed to the increased capacitance, as well as a slight decrease in frequency response. The low equivalent series resistance varied from 0.07 to 0.08 Omega and was attributed to the significant carbon incorporation into the Ni substrate. PMID- 24797020 TI - Metal-induced crystallization of highly corrugated silicon thick films as potential anodes for Li-ion batteries. AB - Silicon has turned into one of the most promising anodes for high energy rechargeable Li-ion batteries. However, a huge volume expansion during alloying with Li always induces serious pulverization/delamination for microsized electrodes as well as undesired accumulation of solid electrolyte interphase (SEI). Many efforts have focused on various nanoengineering and binding strategies to construct integrated, robust ionic/electronic wiring networks but with a trade-off between active/inactive material ratio and performance retention. Here, we first apply a metal-induced crystallization (AIC) principle for immiscible metal/semiconductor systems (Si/Al bilayers in this work) to prepare microthick Si films consisting of a high density of isolated nanocolumns. This method furthermore brings about low temperature crystallization of initial amorphous Si and conformal coating of ion-conductive oxide to enhance the Li transport kinetics of bulk and interface. Both highly satisfactory capacity retention (1650 mAh/g after 500 cycles) and rate performance (~1000 mAh/g at 8C) are achieved for such thick Si film anodes. This methodology can be used to prepare thick film samples with well-defined nanostructures but free of extra binder and conductive additives. It enables much higher area specific capacity than for inactive-component contained slurry samples and thin film samples. This postdeposition pore-creating can be extended to more alloying or conversion electrodes of thick films for high capacity Li/Na ion batteries. PMID- 24797019 TI - Exogenously delivered heat shock protein 70 displaces its endogenous analogue and sensitizes cancer cells to lymphocytes-mediated cytotoxicity. AB - Hsp70 chaperone is known to stimulate anti-tumour immunity in a variety of cancer models. Here we demonstrated that the addition of purified recombinant Hsp70 to the culture medium facilitated cancer cell cytolysis by lymphocytes. Importantly, exogenous Hsp70 triggered secretion of the intracellular Hsp70 to a cell surface and extracellular milieu, which played a role in cytolysis because down regulation of the endogenous Hsp70 reduced both its presence at the cell surface and the lymphocyte-mediated cytolysis. Inhibitors that target both the ATPase and the peptide-binding domains of Hsp70 molecule potently decreased its anti-tumor effect. Using a variety of cell transport markers and inhibitors, we showed that the exchange of exogenous and intracellular Hsp70 is supported by classical and non-classical transport pathways, with a particular role of lipid rafts in the chaperone's intracellular transport. In conclusion, exogenous Hsp70 can eject endogenous Hsp70, thus exerting anticancer activity. PMID- 24797021 TI - Fluoridonitrosyl complexes of technetium(I) and technetium(II). Synthesis, characterization, reactions, and DFT calculations. AB - A mixture of [Tc(NO)F5](2-) and [Tc(NO)(NH3)4F](+) is formed during the reaction of pertechnetate with acetohydroxamic acid (Haha) in aqueous HF. The blue pentafluoridonitrosyltechnetate(II) has been isolated in crystalline form as potassium and rubidium salts, while the orange-red ammine complex crystallizes as bifluoride or PF6(-) salts. Reactions of [Tc(NO)F5](2-) salts with HCl give the corresponding [Tc(NO)Cl4/5](-/2-) complexes, while reflux in neat pyridine (py) results in the formation of the technetium(I) cation [Tc(NO)(py)4F](+), which can be crystallized as hexafluoridophosphate. The same compound can be synthesized directly from pertechnetate, Haha, HF, and py or by a ligand-exchange procedure starting from [Tc(NO)(NH3)4F](HF2). The technetium(I) cation [Tc(NO)(NH3)4F](+) can be oxidized electrochemically or by the reaction with Ce(SO4)2 to give the corresponding Tc(II) compound [Tc(NO)(NH3)4F](2+). The fluorido ligand in [Tc(NO)(NH3)4F](+) can be replaced by CF3COO(-), leaving the "[Tc(NO)(NH3)4](2+) core" untouched. The experimental results are confirmed by density functional theory calculations on [Tc(NO)F5](2-), [Tc(NO)(py)4F](+), [Tc(NO)(NH3)4F](+), and [Tc(NO)(NH3)4F](2+). PMID- 24797022 TI - Analysis of the torsional storage modulus of human hair and its relation to hair morphology and cosmetic processing. AB - Through measurements of three different hair samples (virgin and treated) by the torsional pendulum method (22 degrees C, 22% RH) a systematic decrease of the torsional storage modulus G' with increasing fiber diameter, i.e., polar moment of inertia, is observed. G' is therefore not a material constant for hair. This change of G' implies a systematic component of data variance, which significantly contributes to the limitations of the torsional method for cosmetic claim support. Fitting the data on the basis of a core/shell model for cortex and cuticle enables to separate this systematic component of variance and to greatly enhance the discriminative power of the test. The fitting procedure also provides values for the torsional storage moduli of the morphological components, confirming that the cuticle modulus is substantially higher than that of the cortex. The results give consistent insight into the changes imparted to the morphological components by the cosmetic treatments. PMID- 24797023 TI - Antioxidant, antimelanogenic, and skin-protective effect of sesamol. AB - Sesame contains high nutritional value and important bioactive lignans which are good for health-promoting effects including sesamol. Sesamol is found in trace amounts in sesame. The biological action from the trace amounts of sesamol found might indicate its efficacy. This paper presents a systematic study of the antimelanogenic and skin-protective effects (antioxidant) of sesamol and positive compounds. The results showed that sesamol had the most scavenging 2,2-Diphenyl-1 picrylhydrazyl hydrate (DPPH.) radical with an IC50 value < 14.48 uM. The antioxidant power (Ferric reducing antioxidant power value) of sesamol at a concentration of 0.1129 uM was 189.88 +/- 17.56 uM FeSO4. Sesamol inhibited lipid peroxidation with an IC50 value of 6.15 +/- 0.2 uM. Moreover, sesamol possessed a whitening effect by inhibition of mushroom tyrosinase at an IC50 value of 1.6 uM and an inhibition of cellular tyrosinase with 23.55 +/- 8.25% inhibition at a concentration of 217.2 uM. Sesamol exhibited high antioxidant and anti-tyrosinase activity compared to the positive control, kojic acid and beta-arbutin. Sesamol from edible sesame seed could therefore have an alternative cosmeceutical purpose. PMID- 24797024 TI - Oxidative stability of cosmetic argan oil: a one-year study. AB - The objective of this work is to determine the chemical stability of cosmetic argan oil (INCI: Argania spinosa kernel oil). The methodology involves the repeated measurement over a 1-year period of the quality metrics used in the cosmetic industry: acid and peroxide value and specific absorbance. During this year, storage is performed at 40 degrees or 25 degrees C to assess the importance of temperature. In this latter case, oil samples have been either protected or exposed to sunlight. In addition, sterol and fatty acid composition is determined to attest argan oil chemical integrity over 1 year. Storage of argan oil at 40 degrees C results in a rapid loss of quality. Stored at 25 degrees C and protected from sunlight, argan oil quality is still satisfactory after 12 months according to the official Moroccan norm, but storage should not be longer than 6 months to fulfill industrial standards. PMID- 24797025 TI - In vitro evaluation of carboxymethylcellulose effectiveness in releasing Candida albicans from skin strips. AB - Development of more effective products for cleansing the skin of microorganisms is enhanced by improved understanding of the mechanisms of attachment, as well as potential removal strategies. This paper describes an in vitro method for use of the cationic exchanger carboxymethylcellulose (CMC) to enhance the removal of the yeast Candida albicans as measured in vitro using human skin tape strippings. Several negatively charged and cationic exchanger compounds were evaluated using a visual release method to determine their ability to prompt release of C. albicans from human skin strips. CMC was further tested using a viable count method to assess its ability to effectively release the yeast from skin strips and to evaluate the effects of pH on CMC performance. CMC microparticles were found to release greater than 95% of bound C. albicans from the skin strips over a broad range of pH values. Interaction of CMC with the overall skin charge appears to result in detachment of C. albicans, a response suggesting that anionic particles may facilitate C. albicans removal from skin. PMID- 24797026 TI - Fucus extract: cosmetic treatment for under-eye dark circles. AB - BACKGROUND: Dark circles around the eyes are a complex issue with two main possible causes, the accumulation of melanin in the skin around the eyes and the accumulation of heme resulting from blood leakage. The free heme produced in this manner is highly cytotoxic, proinflammatory and pro-oxidative. AIMS: To evaluate the effect of Fucus extract on heme oxygenase-1 (HO-1) stimulation activity, and to study its in vitro anti-inflammatory, antioxidative, and collagen stimulation activity. METHODS: The HO-1 stimulation activity was first evaluated at gene level by reverse transcriptase- polymerase chain reaction targeting specific HO-1 gene, and then followed by Western blot in protein level. The in vitro anti inflammatory effect was measured by quantification of interleukin-8 (IL-8) level. The in vitro antioxidative activity was measured. Collagen stimulation activity was quantitatively measured by the amount of deposited collagen I in the extracellular matrix. RESULTS: Fucus extract was identified to have HO-1 stimulation activity at both gene and protein level. By stimulating this enzyme, it promotes the degradation of toxic heme to its protective catabolites (CO, Ferritin, and bilirubin) and reduces the source of dark circles. In addition, Fucus extract showed good anti-inflammatory efficacy. The strong antioxidation property of Fucus extract can reduce eye bags and wrinkles while its collagen boosting activity will potentially reduce fine lines and wrinkles. CONCLUSION: Fucus extract is a novel product that brings a quadruple approach to the treatment of under-eye dark circles. PMID- 24797027 TI - High prevalence of suicide risk in people living with HIV: who is at higher risk? AB - A cross-sectional study was developed to evaluate suicide risk and associated factors in HIV/AIDS patients at a regional reference center for the treatment of HIV/AIDS in southern Brazil. We assessed 211 patients in regard to suicide risk, clinical and sociodemographic characteristics, drug use, depression, and anxiety. Suicide risk was assessed with Mini International Neuropsychiatric Interview, Module C. Multivariate analysis was performed using Poisson regression. Of the total sample, 34.1% were at risk of suicide. In the multivariate analysis, the following variables were independently associated with suicide risk: female gender; age up to 47 years; unemployment; indicative of anxiety; indicative of depression; and abuse or addiction on psychoactive substances. Suicide risk is high in this population. Psychosocial factors should be included in the physical and clinical evaluation, given their strong association with suicide risk. PMID- 24797028 TI - Attitudes toward embryo donation among staff at in vitro fertilization clinics. AB - OBJECTIVE: To examine attitudes towards embryo donation among staff at in vitro fertilization clinics in Sweden. DESIGN: Descriptive questionnaire study. SETTING: University-based in vitro fertilization clinic. SAMPLE: Study participants were the staff at all in vitro fertilization clinics in Sweden. METHODS: A questionnaire with questions regarding different aspects of embryo donation was sent to the 338 healthcare professionals working at Swedish in vitro fertilization clinics. MAIN OUTCOME MEASURES: Attitudes towards embryo donation. RESULTS: A total of 207 persons (61%) responded to the questionnaire. A majority of the respondents (77%) considered that embryo donation to infertile couples should be permitted in Sweden. Most respondents (76%), and especially the men (96%), stated that it should be possible to donate surplus embryos for research. Forty-two percent of the respondents agreed with embryo donation to single women. A majority of respondents stated that special requirements with regard to the recipient's age, medical condition and criminal background should potentially be considered. The women stated that there should be special demands made concerning recipients' tobacco (48%) and alcohol abuse (92%). A majority considered that donors should be anonymous to the recipients (66%), but not to the child (9%). CONCLUSIONS: Swedish in vitro fertilization staff have positive attitudes concerning embryo donation to infertile couples and also the use of surplus embryos for research. PMID- 24797030 TI - Cerebellar stimulation fails to modulate motor cortex plasticity in writing dystonia. AB - BACKGROUND: Primary dystonia is characterized neurophysiologically by reduced inhibitory mechanisms and abnormal regulation of plasticity responses. The potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool in writing dystonia was examined, after the observation that cerebellar stimulation reduces responses to an associative plasticity protocol in healthy subjects. METHODS: Ten patients with writing dystonia completed a two part study (sham and anodal) in which cerebellar stimulation was given simultaneously with paired associative stimulation. Electrophysiological and clinical parameters were measured before and after stimulation. RESULTS: Clinical symptoms were unchanged by cerebellar stimulation. Patients exhibited much variability in the size and direction of their plasticity responses. Excessive or topographically abnormal plasticity responses were not observed. In the subgroup of patients with facilitatory responses to paired associative stimulation in the sham condition, anodal cerebellar stimulation retained its ability to reduce the magnitude of plasticity response. CONCLUSIONS: Our limited understanding of intersubject variability of plasticity responses in writing dystonia currently undermines cerebellar stimulation as a novel treatment in this subset of dystonia. Cerebellar stimulation may be beneficial in other neurological disorders with consistently exaggerated plasticity. PMID- 24797029 TI - Eating behaviors and negative affect in college women's everyday lives. AB - OBJECTIVE: A growing body of research seeks to understand the relationship between mood and eating behaviors. Ecological Momentary Assessment (EMA) methods provide a method for assessing these processes in natural settings. We used EMA to examine the relationship between mood and eating behaviors in everyday life among women with subclinical disordered eating behaviors. METHOD: Participants (N = 127, age M = 19.6 years, BMI M = 25.5) completed five daily EMA reports on palmtop computers for 1 week. Assessments included measures of negative affect (NA) and eating-related behavior during eating (eating large amounts of food, loss of control over eating, and restricting food intake) and noneating episodes (skip eating to control weight/shape). Time-lagged multilevel models tested mood eating behavior relationships. RESULTS: Higher NA did not precede any unhealthy eating and weight control behaviors. However, NA was higher when women reported eating large quantities of food, losing control over eating, and restricting food intake during their most recent eating episode, but not after skipping eating to control weight/shape. DISCUSSION: These findings elucidate the processes in daily life that may influence the development and maintenance of unhealthy eating and weight control behaviors that, in turn, can inform interventions. PMID- 24797031 TI - Practical approaches to probiotics use. AB - Probiotics are microorganisms exerting beneficial effects on the host. They can be ingested through foods or supplements and their inclusion in these products is regulated in Canada by the Health Canada Health Products and Food Branch. The aim of this article is to summarize current evidence from randomized controlled trials and guidelines from Health Canada, the World Health Organization, and internationally recognized expert committees in the hope that it will help practitioners and professionals recommending probiotics to healthy and diseased patients, with a focus on the Canadian setting. From a general perspective, probiotics can be recommended for prevention of diseases that are associated to altered intestinal ecology. Specifically, they can be recommended for prevention of upper respiratory tract infections and pouchitis, for prevention and management of necrotizing enterocolitis, bacterial vaginosis and antibiotic associated diarrhea, including Clostridium difficile infection, and for treatment of atopic eczema in cow's milk allergy and of infectious diarrhea. Additional substantiated probiotic benefits include prevention of hypercholesterolemia, management of constipation, reduction of recurrent urinary tract infections, improvement of irritable bowel syndrome symptoms, and reduction of antibiotics side effects in Helicobacter pylori eradication. Because probiotics are generally recognized as safe and can be removed with antimicrobial agents, their use should be considered in patients of all ages. PMID- 24797032 TI - Aortic distensibility in bicuspid aortic valve patients with normal aortic diameter. AB - OBJECTIVE: Bicuspid aortic valve (BAV) is associated with aortic abnormalities. The ascending aorta tends to dilate and its elasticity deteriorates. The morphology of the BAV and the elasticity of the proximal ascending aorta seem to influence the outcome. This study aimed to determine the distensibility of the ascending aorta with normal diameter in BAV patients and its relation to its morphology. METHODS: This is a cross-sectional study. In the patients with BAV referred for echocardiography, the phenotype was defined as anteroposterior (AP) or mediolateral (ML) leaflet orientations. The aortic distensibility at 5-10 mm above the sinotubular junction was assessed using transthoracic echocardiography in 50 BAV patients, and 50 healthy controls with tricuspid aortic valve (TAV) matched by gender and age. RESULTS: The ascending aorta in BAV patients had less distensibility compared with that in the control subjects (0.00298 +/- 0.0023 versus 0.00805 +/- 0.0028 cm2 dynes-1 * 10-6, respectively, p < 0.001). The ML phenotype of BAVs was more frequent. However, the reduced distensibility was not related to gender and morphology of the valve. CONCLUSIONS: Regardless of the valve morphology and also in the absence of aortic dilation, aortic distensibility is impaired in BAV subjects compared with TAV subjects. This finding supports the idea of an intrinsic aortic wall anomalies underlying the impaired elasticity of the aorta in BAV patients. PMID- 24797033 TI - Involvement of insulin resistance in the protective effect of metformin against alcoholic liver injury. AB - BACKGROUND: Alcoholic liver disease (ALD) continues to be a major cause of morbidity worldwide. The exact mechanisms for ALD pathogenesis are not fully understood. There is currently no known available drug for ALD. Previous studies have suggested that ethanol (EtOH)-induced hepatic insulin resistance, through the inhibition of adenosine monophosphate-activated protein kinase (AMPK) and the expression of adiponectin as well as downstream enzymes, contribute to the development of ALD. This study was to determine the effects of EtOH on AMPK activity as well as the protective effect of metformin. METHODS: Forty male Wistar rats weighing 200 +/- 20 g were randomized into 4 groups (n = 10) as follows: A = control group-rats received rodent chow; B = control + metformin group-rats received metformin (200 mg/kg/d intragastrically [IG]) at 21:00; C = EtOH group-rats were gavaged with alcohol of gradually increasing concentrations (30 to 60%, 5 to 9 g/kg/d) twice a day (9:00 and 16:00); D = EtOH + metformin group-rats received the same amount of EtOH as the rats in group C, and in addition received metformin (200 mg/kg/d IG) at 21:00. After 16 weeks, blood and liver samples were collected for further study. RESULTS: Chronic EtOH consumption led to liver injury both histologically and biochemically accompanied by insulin resistance, reduced AMPK activity, and dysregulation of downstream enzymes. Decreased levels of circulating adiponectin and decreased expression of proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and peroxisome proliferator-activated receptors-alpha (PPAR-alpha) in the hepatic tissue were observed. Treatment with metformin attenuated the severity of liver injury, restored AMPK activity and normalized the expression of acetyl-CoA carboxylase and fatty acid synthase. In addition, metformin also increased the circulating adiponectin and liver adiponectin receptor 2 expression. Furthermore, PGC-1alpha and PPAR-alpha activities were also restored. CONCLUSIONS: EtOH exposure induces hepatic insulin resistance. Metformin improved insulin resistance and reversed liver injury through the activation of AMPK and normalized adiponectin signaling making metformin a promising drug for the treatment of ALD. PMID- 24797034 TI - Controlled multistep synthesis in a three-phase droplet reactor. AB - Channel-fouling is a pervasive problem in continuous flow chemistry, causing poor product control and reactor failure. Droplet chemistry, in which the reaction mixture flows as discrete droplets inside an immiscible carrier liquid, prevents fouling by isolating the reaction from the channel walls. Unfortunately, the difficulty of controllably adding new reagents to an existing droplet stream has largely restricted droplet chemistry to simple reactions in which all reagents are supplied at the time of droplet formation. Here we describe an effective method for repeatedly adding controlled quantities of reagents to droplets. The reagents are injected into a multiphase fluid stream, comprising the carrier liquid, droplets of the reaction mixture and an inert gas that maintains a uniform droplet spacing and suppresses new droplet formation. The method, which is suited to many multistep reactions, is applied to a five-stage quantum dot synthesis wherein particle growth is sustained by repeatedly adding fresh feedstock. PMID- 24797036 TI - Does extracorporeal shock wave lithotripsy cause hearing impairment? AB - OBJECTIVE: To evaluate the possible effects of extracorporeal shock wave lithotripsy (ESWL) on the hearing status of the patients in this prospective controlled study. METHODS: A total of 40 patients with normal hearing function were included to the study. We had 20 patients each in the study group and control group. The treatment parameters were standardized in all 3 sessions in which a total of 3000 shock waves with a rate of 90/min along with a total energy value of 126 J at the fourth energy level have been applied (Dornier Compact Sigma, Medtech, Germany). In addition to the testing of hearing functions and possible cochlear impairment by Transient Evoked Otoacoustic Emissions test at 1.0, 1.4, 2.0, 2.8, and 4.0 kHz frequencies, complications such as ear pain, tinnitus, and hearing loss have been well evaluated in each patient before the procedure and 2 hours and 1 month after the completion of the third session of ESWL in the study group. The same evaluation procedures were performed before the study and after 7-weeks in the control group. RESULTS: Regarding Transient Evoked Otoacoustic Emissions data obtained in study group and control group patients, there was no significant alteration in values obtained after ESWL when compared with the values before the procedure. CONCLUSION: A well-planned ESWL procedure is a safe and effective treatment in urinary stones and causes no detectable harmful effect on the hearing function of treated patients. PMID- 24797035 TI - Biomonitoring and hormone-disrupting effect biomarkers of persistent organic pollutants in vitro and ex vivo. AB - Persistent organic pollutants (POPs) include lipophilic legacy POPs and the amphiphilic perfluorinated alkyl acids (PFAAs). They have long half-lives and bioaccumulate in the environment, animals and human beings. POPs possess toxic, carcinogenic and endocrine-disrupting potentials. Endocrine-disrupting chemicals (EDCs) are compounds that either mimic or block endogenous hormones and thus disrupt the normal hormone homeostasis. Biomonitoring assesses the internal doses of a person to provide information about chemical exposures. Effect biomarkers assess chemicals potential to affect cellular functions in vivo/ex vivo. Human beings are exposed to complex mixtures of chemicals, having individually very different biological potentials and effects. Therefore, the assessment of the combined, integrated biological effect of the actual chemical mixture in human blood is important. In vitro and ex vivo cell systems have been introduced for the assessment of the integrated level of xenobiotic cellular effects in human beings. Ex vivo studies have shown geographical differences in bioaccumulated POP serum levels, being reflected by the combined biomarker effects of the complex mixture extracted from human serum. Xenohormone receptor transactivities can be used as an ex vivo integrated biomarker of POP exposure and effects. Epidemiological and in vitro/ex vivo studies have supported the potential impact of the combined effect of serum POPs on the activity of hormone and/or dioxin receptors as a risk factor for human health. With focus on hormone disruption, this MiniReview will give an update on recent POP-related endocrine-disrupting effects in vitro/ex vivo/in vivo and some related genetic data. PMID- 24797037 TI - Does bone marrow-derived mesenchymal stem cell transfusion prevent antisperm antibody production after traumatic testis rupture? AB - OBJECTIVE: To determine whether transfusion of mesenchymal stem cells (MSCs) could prevent humoral immune response and autoimmunization against sperms after traumatic testis rupture. METHODS: Immunomodulatory properties of MSCs have been evaluated by a prospective cohort on 50 adult BALB/c mice. In each interventional arms of study, controlled testis rupture and surgical repair were exerted. In addition to tissue repair, single dose of 5*10(5) MSCs labeled by green fluorescent protein was delivered intravenously to 20 cases (cell therapy group). After euthanizing, seroconversion of antisperm antibody (ASA) was compared between 2 interventional groups as response of humoral immune system. Lung and testis tissues were examined for green fluorescent protein-positive cells to assess whether presence of stem cells is correlated with seroconversion rates. RESULTS: Six cases had been lost during the study. Fourteen of 16 mice in cell therapy control group formed ASA (87.5%) but 6 of 18 mice (33.3%) in cell therapy group were immunized and formed ASA (P=.002). Transplanted cells were traced in lungs of 55% (n=10) of cell therapy group and none were found in trauma site. Small volume of mice blood was our main limitation to trace seroconversion or quantitative measurement of ASA in each case. CONCLUSION: In this in vivo model of autoimmune infertility, bone marrow-derived MSC transfusion showed immunosuppressive effects on antibody production. Considering immunomodulatory properties of MSCs even in allogeneic settings, novel clinical application should be investigated further. PMID- 24797038 TI - Nucleocytoplasmic transport under stress conditions and its role in HSP70 chaperone systems. AB - BACKGROUND: In eukaryotic cells, molecular trafficking between the nucleus and cytoplasm is a highly regulated process related to cellular homeostasis and cellular signaling. However, various cellular stresses induce the perturbation of conventional nucleocytoplasmic transport pathways, resulting in the nucleocytoplasmic redistribution of many functional proteins. SCOPE OF REVIEW: We describe the recent insights into the mechanism and functions of nuclear import of cytosolic chaperone HSP70 under stress conditions and the cellular distribution and functions of its co-chaperones. MAJOR CONCLUSIONS: Hikeshi mediates the nuclear import of the molecular chaperone HSP70. A few of the regulators of the HSP70 chaperone system also accumulate in the nucleus under heat stress conditions. These proteins function collaboratively to protect cells from stress-induced damage and aid in the recovery of cells from stress. GENERAL SIGNIFICANCE: Studies on the regulation of nucleocytoplasmic transport under several cellular stresses should provide new insights into the fundamental principles of protein homeostasis (proteostasis) in both compartments, the nucleus and cytoplasm. PMID- 24797039 TI - Biogenesis and adhesion of type 1 and P pili. AB - BACKGROUND: Uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs) in approximately 50% of women. These bacteria use type 1 and P pili for host recognition and attachment. These pili are assembled by the chaperone-usher pathway of pilus biogenesis. SCOPE OF REVIEW: The review examines the biogenesis and adhesion of the UPEC type 1 and P pili. Particular emphasis is drawn to the role of the outer membrane usher protein. The structural properties of the complete pilus are also examined to highlight the strength and functionality of the final assembly. MAJOR CONCLUSIONS: The usher orchestrates the sequential addition of pilus subunits in a defined order. This process follows a subunit incorporation cycle which consists of four steps: recruitment at the usher N terminal domain, donor-strand exchange with the previously assembled subunit, transfer to the usher C-terminal domains and translocation of the nascent pilus. Adhesion by the type 1 and P pili is strengthened by the quaternary structure of their rod sections. The rod is endowed with spring-like properties which provide mechanical resistance against urine flow. The distal adhesins operate differently from one another, targeting receptors in a specific manner. The biogenesis and adhesion of type 1 and P pili are being therapeutically targeted, and efforts to prevent pilus growth or adherence are described. GENERAL SIGNIFICANCE: The combination of structural and biochemical study has led to the detailed mechanistic understanding of this membrane spanning nano-machine. This can now be exploited to design novel drugs able to inhibit virulence. This is vital in the present era of resurgent antibiotic resistance. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins. PMID- 24797040 TI - Semantic priming revealed by mouse movement trajectories. AB - Congruency effects are taken as evidence that semantic information can be processed automatically. However, these effects are often weak, and the straightforward association between primes and targets can exaggerate congruency effects. To address these problems, a mouse movement method is applied to scrutinize congruency effects. In one experiment, participants judged whether two numbers were the same ("3?3") or different ("3?5"), preceded by briefly presented pictures with either positive or negative connotations. Participants indicated their responses by clicking a "Same" or "Different" button on the computer screen, while their cursor trajectories were recorded for each trial. The trajectory data revealed greater deviation to unselected buttons in incongruent trials (e.g., "3?5" preceded by a green traffic light picture). This effect was influenced by the type of responses but not by prime durations. We suggest that the mouse movement method can complement the reaction time to study masked semantic priming. PMID- 24797041 TI - Losing oneself upon placement in another's position: the influence of perspective on self-referential processing. AB - Self-referential processing is considered to be an essential index for exploring self-consciousness. However, whether perspective is the determining factor of the self-reference effect (SRE), which is accompanied by self-referential processing, has not been established. The present study aims to address this issue by using a self-reference paradigm, in which the participants perform a self-reference task while adopting different perspectives. Our results showed that trait words presented with the self in the first-person perspective (1PP) were better remembered compared to trait words presented with others. Interestingly, these SREs were decreased and even reversed in the third-person perspective. When the participants viewed themselves based on their friend's perspective, no significant difference was found between the recognition performances of self- and friend-trait words. Moreover, an improved "remember" recognition performance of friend-trait words was found. These findings support the assumption that the 1PP is a necessary factor for self-advantage in self-referential processing. PMID- 24797042 TI - Iodine nutrition status amongst neonates in Kangra district, Himachal Pradesh. AB - Iodine deficiency (ID) is an endemic health problem in Kangra district, Himachal Pradesh (HP) state. ID leads to mental retardation, deaf mutism, squint, dwarfism, spastic diplegia, neurological defects and congenital anomalies. Iodine nutrition status amongst neonates can be assessed by estimating thyroid stimulating hormone (TSH). The present study was conducted with an objective to assess the iodine nutrition status amongst Neonates in Kangra district, HP. All of the hospitals in the district which provide obstetric services were enlisted, of which three were selected for this survey. A total of 613 umbilical cord blood samples of neonates were collected on filter paper and analyzed for TSH. WHO (2007) reported that that a <3% frequency of TSH concentrations above 5 mIU/L in samples collected 3-4 days after birth indicates iodine sufficiency in a population. In our study we found that 73.4% of the neonates had TSH levels of more than 5 mlU/l, thus indicating ID in the population studied. Iodine deficiency continues to be a public health problem in Kangra district, Himachal Pradesh. PMID- 24797043 TI - Reliability of a new hip lateral view to quantify alpha angle in femoroacetabular impingement. AB - BACKGROUND: Radiographic measurement of the alpha angle (AA) in femoroacetabular impingement (FAI) is not well codified and invasive techniques such as MR- or CT arthrography remain the gold standard. Excessive acetabular coverage described in pincer-type FAI can be seen on plain radiographs but has never been quantified and anterior center edge (ACE) angle, described on the false-profile view (FP) to measure anterior acetabular coverage has never been evaluated in FAI. HYPOTHESIS: In this study we wanted to determine if a plain radiograph could efficiently measure AA compared to CT-arthrography and if ACE could quantify the acetabular coverage in FAI. MATERIALS AND METHODS: We developed a hip view combining a lateral view and a FP, called profile view in impingement position (PIP). Twenty six patients operated for FAI had CT-arthrography, PIP and FP. Nineteen control subjects had the PIP. AA were measured twice by three raters and ACE once. We compared AA measured on patients between CT and PIP, on PIP between patients and controls, ACE measured on patients between PIP and FP, and did a reproducibility analysis. Means were compared by paired or unpaired t-tests; reproducibility was measured by intraclass correlation coefficient (ICC). RESULTS: Mean AA was 65.8 degrees (range, 48-85 degrees ) on CT-arthrography and 63.9 degrees (range, 50 87 degrees ) on PIP (P>0.05). ICC for PIP measures were 0.8-0.9 for intra-rater and 0.6-0.9 for inter-rater reliability. Mean AA on PIP in patients was 63.3 degrees (range, 52-87 degrees ) and 44.9 degrees (range, 34-67 degrees ) in controls (P<0.001). Mean ACE was 26.8 degrees (range, 14-41 degrees ) on PIP and 32.8 degrees (range, 18-56 degrees ) on the FP (P=0.015). DISCUSSION: The PIP is a reliable view to measure the AA in FAI as measures on PIP and CT-arthrography were not significantly different with a good reproducibility. All of the painful hips and 2 controls had an AA>50 degrees . PIP was not efficient to measure ACE. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 24797044 TI - The ilio-inguinal approach for recent acetabular fractures: ultrasound evaluation of the ilio-psoas muscle and complications in 24 consecutive patients. AB - INTRODUCTION: The ilio-inguinal approach is used to achieve internal fixation of acetabular fractures. Although the outcomes of this procedure have been extensively reported, information is lacking on potential complications. More specifically, the effect on the ilio-psoas muscle, whose iliac attachments are almost completely released, has not been accurately evaluated. HYPOTHESIS: Endopelvic dissection does not alter the ultrasound structure of the ilio-psoas muscle compared to the normal side at a distance from acetabular internal fixation via the ilio-inguinal approach. PATIENTS AND METHODS: We retrospectively evaluated 26 patients who underwent internal fixation of acetabular fractures via the ilio-inguinal approach between 2006 and 2010. Two patients with multiple injuries died shortly after the procedure, leaving 24 patients with unilateral fractures for the study. In 2012, an observer who was not involved in the surgical treatment of these patients conducted an assessment (Oxford score except in the 8 patients who required revision surgery for arthroplasty and evaluation for a deficit of the lateral femoral cutaneous nerve in the full cohort). At the same time point, ultrasonography was performed to compare ilio-psoas muscle morphology on the two sides. Any other complications (vascular, nervous, or parietal) were recorded. RESULTS: Of the 24 patients, 11 (45%) experienced complications, of whom only 3 required further surgery, 2 with infections that recovered fully after lavage and 1 with a haematoma responsible for compression of the urinary bladder. The lateral femoral cutaneous nerve was injured in 8 (33%) patients, including 4 who had achieved a full recovery at last follow-up. At last follow-up, none of the 24 patients had ultrasound evidence of a significant difference in ilio-psoas muscle size at the lateral window: mean transverse diameter was 51.8+/-0.8mm (range, 44-58 mm) on the operated side versus 51.7+/-0.79 mm (range, 44-59 mm) on the other side (P=0.9). After a mean follow-up of 49 months (range, 31-70 months), the mean Oxford score in the 16 patients who had not required further surgery was 20.5/60 (range, 12-44). DISCUSSION: Our results show that, despite extensive endopelvic dissection, the ilio-inguinal approach has no effect on the ultrasound morphology of the ilio psoas muscle. There is a high risk of injury to the lateral femoral cutaneous nerve that should be disclosed to the patient before the procedure. In contrast, no parietal complications were recorded. In selected patients, the Cole-Stoppa approach is an alternative that spares the lateral femoral cutaneous nerve. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 24797045 TI - Developmental dysplasia of the hip in neonates: evolution of acetabular dysplasia after hip stabilization by brief Pavlik harness treatment. AB - BACKGROUND: The recommended treatment duration in neonates with developmental dysplasia of the hip (DDH) varies depending on whether prolonged Pavlik harness therapy is believed to favourably affect the course of the acetabular dysplasia. According to one theory, several months of additional Pavlik harness therapy after achieving hip reduction contributes to correct the acetabular dysplasia. Another theory holds that hip dislocation induces the acetabular dysplasia, which corrects spontaneously once the femoral head is properly seated in the acetabulum. Here, we evaluated this second theory by studying outcomes after early brief Pavlik harness therapy. HYPOTHESIS: Acetabular dysplasia associated with neonatal hip instability undergoes self-correction provided stable hip reduction is achieved very early after birth. Therefore, the duration of Pavlik harness therapy can be substantially shortened. MATERIALS AND METHODS: We defined hip instability as either reducible hip dislocation or a very easily dislocatable hip with a soft clunk precluding determination of spontaneous hip position as dislocated or reduced. Static and dynamic ultrasound scans were obtained. Patients with ultrasonographic instability (pubo-femoral distance>5mm with less than 50% of coverage) underwent a second physical examination and received treatment. We re-evaluated 42 abnormal hips in 30 patients after a mean follow-up of 6.7 years (range, 5-14 years). Mean age at treatment initiation was 5 days (range, 1-15 days) and mean treatment duration was 34 days (range, 15-75 days). RESULTS: Mean acetabular angle was 20 degrees (range, 12 degrees -30 degrees ) and mean Wiberg's lateral centre-edge angle was 30 degrees (range, 22 degrees 35 degrees ). Blunting of the lateral angle of the bony roof was noted in 8 hips at last follow-up. In 1 patient whose hip was stable clinically but unstable by ultrasonography at 21 days of age, recurrent dislocation occurred at 5 months of age. The Severin class was 1a in all patients. DISCUSSION: Despite continuing controversy about whether hip dislocation induces dysplasia or vice versa, the need for early treatment is universally recognised. The optimal treatment duration, however, remains debated. Proponents of the familial determinism of DDH consider that acetabular shaping is genetically programmed when the femoral head is centred in the acetabular socket. Others advocate routine prolongation of Pavlik harness therapy for 2 months or longer, based on the opinion that this strategy decreases the dislocation recurrence rate and that mechanical hip unloading may promote correction of the dysplasia. Mean treatment duration in our population was 34 days and our sole objective was to treat the instability. The hip was reduced and held in its proper position long enough to allow sufficient capsule and ligament tightening to stabilise the hip. Under these conditions, the acetabular dysplasia underwent self-correction that was not related to treatment duration. CONCLUSION: Very early Pavlik harness therapy to ensure rapid hip reduction and stabilisation optimises the potential of the acetabulum for spontaneous remodelling. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 24797046 TI - Naevoid melanoma masquerading as small cell carcinoma on fine needle aspiration cytology of an axillary metastasis. PMID- 24797047 TI - MiRNAs in peripheral artery disease - something gripping this way comes. AB - Peripheral artery disease (PAD) is a marker disease for generalized atherosclerosis and represents one of the world's major causes of morbidity and mortality. Many studies have tried to gain insight into the molecular mechanisms involved in PAD onset, progression and prognosis. In the last decade, small non coding RNAs, termed miRNAs, have emerged as a major research focus due to their regulating function of multiple gene sets. In the cardiovascular system, miRNAs not only impact on physiological pathways like cardiac development and angiogenesis, but also play an important role in disease mechanisms and progression of myocardial hypertrophy, acute myocardial infarction, heart failure or arrhythmias. New insights lend considerable support to the concept of miRNAs serving as highly sensitive biomarkers and therapeutic targets. To date, a comprehensive understanding of miRNA regulation of angiogenesis and maintenance of vascular integrity in PAD remains less explored. In this review, we discuss current studies and highlight the potential of miRNAs not only to act as a diagnostic tool, but also to facilitate innovative strategies for gene therapy. PMID- 24797048 TI - Polymorphisms XbaI (rs693) and EcoRI (rs1042031) of the ApoB gene are associated with carotid plaques but not with carotid intima-media thickness in patients with diabetes mellitus type 2. AB - BACKGROUND: Apolipoprotein B is a key structural component of all the atherogenic lipoproteins (LDL, VLDL and IDL). Genetic variations of the ApoB gene may affect plasma ApoB and lipid levels, thus influencing atherogenesis. The present study was designed to investigate the association of polymorphisms XbaI (rs693) and EcoRI (rs1042031) of the ApoB gene with plasma ApoB level, lipid levels and the different ultrasound phenotypes of carotid atherosclerosis in patients with diabetes mellitus type 2. PATIENTS AND METHODS: 595 patients with diabetes (399 on statin therapy and 196 without) and 200 healthy controls were enrolled in the study. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Both XbaI (rs693) and EcoRI (rs1042031) genotypes were determined by real-time PCR. RESULTS: Genotype distributions and allele frequencies of the XbaI and EcoRI polymorphisms were not statistically significantly different between diabetic patients and controls. No statistically significant difference in lipid parameters, ApoA1, ApoB, hs-CRP and fibrinogen as well as CIMT was observed in diabetic patients regarding XbaI and EcoRI polymorphisms, even after adjustment for statin treatment. The risk of having plaques on carotid arteries was higher in homozygous carriers of the mutant X + allele (OR = 1.74, p = 0.03) and lower in diabetics carrying mutant E- alleles (OR = 0.48, p = 0.02). Neither XbaI nor EcoRI polymorphism was associated with CIMT or presence of unstable plaques in diabetic patients. Plasma ApoB level was not independently associated with any of the ultrasonographic parameters of carotid atherosclerosis. CONCLUSIONS: Both XbaI and EcoRI polymorphisms were associated with presence of plaques on carotid arteries but not with CIMT or presence of unstable plaques. Plasma ApoB level was not independently associated with ultrasonographic phenotypes of carotid atherosclerosis in patients with diabetes mellitus. PMID- 24797049 TI - Hyperhomocysteinaemia, low folate concentrations and MTHFR C677T mutation in abdominal aortic aneurysm. AB - BACKGROUND: Homocysteine (Hcy) has been implicated in abdominal aortic aneurysm (AAA). However, the association of Hcy, vitamin B12, and folate in patients with AAA has not been studied in China. This study was conducted with the aim to evaluate the relationship of vitamin B12, folic acid, and Hcy levels in AAA. PATIENTS AND METHODS: 463 patients who had AAA were included in this study. 463 control subjects were age- and sex-matched with the patients. In all of the subjects, we evaluated total plasma levels Hcy, vitamin B12, folic acid and the distribution of the C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation. RESULTS: The mean plasma Hcy levels were significantly higher in patients with AAA compared with controls (18.37 +/- 6.97 vs. 12.89 +/- 4.08 MUmol/L, P < 0.001). The frequency of homozygous (TT) genotype in MTHFR C677T mutation was significantly higher in patients with AAA than that in control subjects (19.4 % vs. 11.9 %, P = 0.002). The fasting Hcy correlated negatively with folate (AAA: r = - 0.311, P < 0.01; CONTROL: r = - 0.348, P < 0.01). The aneurysm size was significantly greater (P < 0.001) in patients with hyperhomocysteinemia than that in patients with normal Hcy plasma levels. The size of the AAA had a linear correlation with the plasma Hcy level (r = 0.286; P< 0.001). CONCLUSIONS: Serum folate deficiency and hyperhomocysteinemia were associated with an increased risk of AAA in Northeast China. The homozygous (TT) genotype of MTHFR gene mutation may be a crucial hereditary risk factor in AAA. PMID- 24797050 TI - Triglyceride to high density lipoprotein cholesterol ratio, total cholesterol to high density lipoprotein cholesterol ratio and low ankle brachial index in an elderly population. AB - BACKGROUND: The associations of triglyceride (TG) to high-density lipoprotein cholesterol ratio (HDL-C) and total cholesterol (TC) to HDL-C ratio and low ankle brachial index (ABI) were seldom investigated. PATIENTS AND METHODS: A population based cross-sectional survey was conducted and 2982 participants 60 years and over were recruited. TG, TC, HDL-C, and low-density lipoprotein cholesterol (LDL C) were assessed in all participants. Low ABI was defined as ABI <= 0.9 in either leg. Multiple logistic regression models were applied to study the association between TG/HDL-C ratio, TC/HDL-C ratio and low ABI. RESULTS: The TG/HDL-C ratios for those with ABI > 0.9 and ABI <= 0.9 were 1.28 +/- 1.20 and 1.48 +/- 1.13 (P < 0.0001), while the TC/HDL-C ratios were 3.96 +/- 1.09 and 4.32 +/- 1.15 (P < 0.0001), respectively. After adjusting for age, gender, body mass index, obesity, current drinking, physical activity, hypertension, diabetes, lipid-lowering drugs, and cardiovascular disease history, the odds ratios (ORs) with 95 % confidence intervals (CIs) of low ABI for TG/HDL-C ratio and TC/HDL-C ratio were 1.10 (0.96, 1.26) and 1.34 (1.14, 1.59) in non-smokers. When TC was further adjusted, the ORs (95 % CIs) were 1.40 (0.79, 2.52) and 1.53 (1.21, 1.93) for TG/HDL-C ratio and TC/HDL-C ratio, respectively. Non-linear relationships were detected between TG/HDL-C ratio and TC/HDL-C ratio and low ABI in both smokers and non-smokers. CONCLUSIONS: TC/HDL-C ratio was significantly associated with low ABI in non-smokers and the association was independent of TC, TG, HDL-C, and LDL-C. TC/HDL-C might be considered as a potential biomarker for early peripheral arterial disease screening. PMID- 24797051 TI - Can the scoring of the walking estimated limitation calculated by history (WELCH) questionnaire be simultaneously simplified and improved? AB - BACKGROUND: The WELCH questionnaire includes 4 items (A, B, C and D) and estimates the maximal walking time (MWT) on treadmill in patients with claudication. Its scoring was empirically defined. We aimed to test various methods for scoring to estimate whether the scoring of the WELCH could be improved or simplified. PATIENTS AND METHODS: In 423 patients, we tested 8 methods (from H1 to H8) of weighing D or calculating alpha, beta and gamma in the equation MWT = (alphaA + betaB + gammaC) * D. RESULTS: While the WELCH Pearson r was 0.639 and area under ROC curve for the ability to walk 5 minutes on treadmill was 0.795 for the reference empirical method, tested hypotheses resulted in values ranging 0.566 to 0.661 for the Pearson r values and 0.750 to 0.809 for the areas under ROC curve respectively. CONCLUSIONS: None of the tested methods simultaneously improved the correlation to MWT, remained simple enough to be scored by mental calculation and ranged between intuitive minimal and maximal values. The original empirical scoring seems a good compromise between accuracy and simplicity. PMID- 24797052 TI - Ankle brachial index and pneumoplethysmographic pulse-volume recordings for detection of peripheral arterial disease. AB - BACKGROUND: The measurement of the ankle-brachial index (ABI) is a straightforward method for the detection of atherosclerosis in the lower limbs. Pneumoplethysmographic pulse-volume recordings (PVR) investigations are supposed to be less valid. Thus we compared the sensitivity of ABI and PVR in detection of PAD and its improvement by combining both methods. PATIENTS AND METHODS: 122 consecutive patients admitted for PAD treatment were included. All patients (81 females; mean age 70 +/- 15 years) had angiographic imaging of their peripheral arteries, a standardized personal interview and a determination of the ABI based on the highest (ABI high) and lowest (ABI low) ankle pressure. PVR parameters were oscillometric index (OI) and time to normalisation (TN) after exercise. RESULTS: There was a small variation of ABI with different segmental manifestations of PAD. The OI did not vary with different segmental manifestations. TN was longest in iliac artery manifestation and got shorter with more distal manifestation. Correlation of TN and ABI high and ABI low was low. Sensitivity of ABI high in all legs was 78 %, but only 40 % in isolated crural manifestation. ABI low has higher sensitivities with 87 % in all legs, but a much lower specificity. Combining ABI and TN increases both sensitivity and specificity. The best sensitivity and specificity was seen using ABI low + TN in combination in all kinds of manifestations with 94 % and 96 %, respectively. CONCLUSIONS: Combined assessment of ABI low and TN in post-exercise PVR seems to be a highly sensitive but also specific method to look for PAD compared to ABI high alone. PMID- 24797053 TI - Treatment options of crural pseudoaneurysms. AB - BACKGROUND: Pseudoaneurysms (PAs) of crural arteries represent rare complications of vascular interventions or surgery. Management of crural PAs includes different treatment options, conservative treatment as well as open surgery or endovascular procedures. We reviewed our experience. PATIENTS AND METHODS: We retrospectively analysed all patients who were diagnosed with crural PAs since 2003. We evaluated etiology, treatment and outcome. Endpoints were target vessel patency, vascular re-intervention and limb loss. RESULTS: A total of 30 patients were diagnosed with crural PAs. PA was caused by vascular intervention in 27 patients (90 %): open balloon thrombectomy (n = 25), subfascial endoscopic perforator vein surgery (n = 1) and transcutaneous catheter-assisted thrombus aspiration (n = 1). In 3 patients (10 %) it was caused by orthopaedic surgical procedures. Location of crural PAs were peroneal artery (n = 11; 36.7 %), posterior tibial artery (n = 10; 33.3 %), anterior tibial artery (n = 5; 16.7 %), and tibioperoneal trunk (n = 4; 13.3 %). Treatment of crural PAs included open surgery (n = 3; 10 %), endovascular procedures (n = 13; 43.3 %) such as endograft implantation (n = 9) or coil embolisation (n = 4), and conservative management (n = 14; 46.7 %). After a median follow-up period of 7 months (range: 0 - 46 months) 8 of 9 endografts were occluded, in none of these patients a minor or a major amputation was necessary. None of the surgically, endovascularly and conservatively treated patients needed a re-intervention for crural PA. A major amputation was necessary in 4 patients due to progression of peripheral arterial disease; none was a directly consequence of the crural PA. CONCLUSIONS: Crural PAs are mainly caused by vascular intervention, most frequently by catheter thrombectomy. As a consequence, we recommend fluoroscopic-assisted balloon thrombectomy over a guide wire as routine technique. In many cases of crural PAs, conservative management is sufficient. The choice of treatment of crural PAs depends on size, location and associated symptoms. Endovascular treatment using endografts is limited by poor long-term patency. PMID- 24797054 TI - Critical care of kyphoscoliotic type Ehlers-Danlos syndrome with recurrent vascular emergencies. PMID- 24797055 TI - Thrombosis of palmar and interdigital arteries in the hypereosinophilic syndrome. PMID- 24797056 TI - Extensive arteriovenous malformations in the extremities complicated by cardiac dysfunction. PMID- 24797059 TI - Badly off or better off than them? The impact of relative deprivation and relative gratification on intergroup discrimination. AB - This research examines for the 1st time the effects of relative deprivation and relative gratification, based on social comparison, on implicit and overt forms of discrimination toward the outgroup in a minimal group setting. Study 1 showed that compared to a control condition, relative deprivation and relative gratification enhanced implicit discrimination-measured through variations of linguistic abstraction in intergroup descriptions. Whereas both relative deprivation and relative gratification produced linguistic ingroup favoritism, linguistic productions of relatively deprived groups also conveyed outgroup derogation. Study 2 showed that relatively deprived and relatively gratified groups were overtly discriminatory in intergroup allocations of negative outcomes. The effects of relative deprivation were mediated by perceived intergroup rivalry and, in part, by perceived common fate. Perceived common fate partly accounted for the effects of relative gratification. Study 3 focused on mediators of relative gratification. First, members of relatively gratified (vs. control) groups worried about losing the ingroup advantage, which together worked as sequential mediators of discrimination. Second, relatively gratified groups reported higher existential guilt, which, in turn, was related to expectations of discrimination by the relatively deprived outgroup, and these sequentially mediated the effects of relative gratification. Overall, these studies highlight that both relative deprivation and relative gratification enhance intergroup discrimination and contribute to the understanding of the underlying processes. PMID- 24797058 TI - Comparison of flowrates and voided volumes during non-instrumented uroflowmetry and pressure-flow studies in women with stress incontinence. AB - AIMS: The Blaivas-Groutz nomogram defines voiding obstruction in women using Qmax from the NIF and the maximum detrusor pressure (Pdetmax ) from the PFS. The aim of this study was to understand the relationship between NIF and PFS maximum flow rates in women with stress incontinence. METHODS: We analyzed the UDS of 597 women with stress-dominant urinary incontinence. Each subject underwent a NIF and then a PFS. Mixed model was used to test the hypothesis that the relationship between flow rates and voided volume (VV) were similar for NIF and PFS. RESULTS: There were 452 subjects with both NIF and PFS studies that met the inclusion criteria and had max flow rate (Qmax ) for both NIF and PFS. The mean age was 53. Overall, higher VV were observed during PFS compared to NIF and subjects had higher Qmax with NIF compared to PFS. The relationship between Qmax and VV was significantly different between NIF and PFS (P < 0.004). At 200 ml, NIF Qmax was 14% higher than PFS Qmax and this difference increased to 30% at 700 ml. CONCLUSION: The difference between PFS Qmax and NIF Qmax increases as VV increase. As a result, values from PFS and NIF cannot be used interchangeably as has been suggested in the Blaivas-Groutz nomogram for obstruction in women. PMID- 24797060 TI - Microstructural brain abnormalities of children of idiopathic generalized epilepsy with generalized tonic-clonic seizure: a voxel-based diffusional kurtosis imaging study. AB - PURPOSE: To investigate the diffusion abnormalities in the brain of children with idiopathic generalized epilepsy (IGE) with generalized tonic-clonic seizure (GTCS) by using diffusion kurtosis imaging (DKI). MATERIALS AND METHODS: Twenty one IGE children with GTCS and 16 controls were recruited. DKI was performed and maps of radial diffusivity (lambda? ), axial diffusivity (lambda// ), mean diffusivity (MD), fractional anisotropy (FA), radial kurtosis (K? ), axial kurtosis (K// ) and mean kurtosis (MK) were calculated. Voxel-based analyses were employed to compare diffusion metrics in epilepsy versus the controls. RESULTS: In the case group, MD was found significantly higher in the right temporal lobe, the right occipital lobe, hippocampus, and some subcortical regions, while FA increased in bilateral supplementary motor area and the left superior frontal lobe (false discovery rate corrected P < 0.05). Analysis of lambda? and lambda// showed that the increased MD was mainly due to the elevated lambda// . Significantly decreased MK was also detected in bilateral temporo-occipital regions, the right hippocampus, the left insula, the left post-central area, and some subcortical regions (false discovery rate corrected P < 0.05). In most regions the changed MK were due to the decreased K// . CONCLUSION: The kurtosis parameters (K? , K// , and MK) reflect different microstructural information in the IGE children with GTCS, and this support the value of DKI in studying children GTCS. PMID- 24797061 TI - Atomic layer-by-layer deposition of Pt on Pd nanocubes for catalysts with enhanced activity and durability toward oxygen reduction. AB - An effective strategy for reducing the Pt content while retaining the activity of a Pt-based catalyst is to deposit the Pt atoms as ultrathin skins of only a few atomic layers thick on nanoscale substrates made of another metal. During deposition, however, the Pt atoms often take an island growth mode because of a strong bonding between Pt atoms. Here we report a versatile route to the conformal deposition of Pt as uniform, ultrathin shells on Pd nanocubes in a solution phase. The introduction of the Pt precursor at a relatively slow rate and high temperature allowed the deposited Pt atoms to spread across the entire surface of a Pd nanocube to generate a uniform shell. The thickness of the Pt shell could be controlled from one to six atomic layers by varying the amount of Pt precursor added into the system. Compared to a commercial Pt/C catalyst, the Pd@PtnL (n = 1-6) core-shell nanocubes showed enhancements in specific activity and durability toward the oxygen reduction reaction (ORR). Density functional theory (DFT) calculations on model (100) surfaces suggest that the enhancement in specific activity can be attributed to the weakening of OH binding through ligand and strain effects, which, in turn, increases the rate of OH hydrogenation. A volcano-type relationship between the ORR specific activity and the number of Pt atomic layers was derived, in good agreement with the experimental results. Both theoretical and experimental studies indicate that the ORR specific activity was maximized for the catalysts based on Pd@Pt2-3L nanocubes. Because of the reduction in Pt content used and the enhancement in specific activity, the Pd@Pt1L nanocubes showed a Pt mass activity with almost three-fold enhancement relative to the Pt/C catalyst. PMID- 24797062 TI - Juanlimycins A and B, ansamycin macrodilactams from Streptomyces sp. AB - Ansamycins are a family of macrolactams characterized by an aromatic chromophore with an aliphatic chain (ansa chain) connected back to a nonadjacent position through an amide bond. This family has shown a high degree of druggability exemplified by rifamycins, maytansinoids, and geldanamycins. In this study, the isolation of two novel ansamycin macrodilactams with unprecedented features, juanlimycins A (1) and B (2), from Streptomyces sp. LC6 were reported. The structures of 1 and 2 were assigned on the basis of analysis of NMR spectroscopic data and X-ray single crystal diffraction. PMID- 24797063 TI - Pharmacokinetics of ertapenem in outpatients with complicated urinary tract infections. AB - OBJECTIVES: Ertapenem is a broad-spectrum carbapenem antibiotic used to treat severe bacterial infections. In view of its dosing convenience, it is increasingly used as outpatient therapy. The objective of this study was to determine the pharmacokinetics and renal disposition of ertapenem in outpatients with complicated urinary tract infections. METHODS: Ertapenem was administered as a daily intravenous infusion of 1 g over 30 min. At steady-state, blood and urine samples were collected over one dosing interval. Drug concentrations in serum and urine were determined using a validated liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was used to characterize ertapenem serum and urine profiles. The likelihood of the standard dosing achieving a favourable pharmacokinetic-pharmacodynamic exposure was evaluated using Monte Carlo simulations. RESULTS: Ten adult male patients were studied. Concentration-time profiles of ertapenem in both serum (r(2) =0.997) and urine (r(2) =0.982) were captured satisfactorily. Mean values for volume of distribution, clearance and elimination t1/2 were 4.8 L, 0.7 L/h and 6.1 h, respectively. A high ertapenem concentration (>128 mg/L) could be attained in the urine at 40% of the dosing interval. CONCLUSIONS: The pharmacokinetics of ertapenem in serum and urine were characterized. Our simulations suggested that a sufficiently high ertapenem concentration could be achieved in urine to overcome low to intermediate resistance. Clinical investigations to validate our findings are warranted. PMID- 24797064 TI - Waste water effluent contributes to the dissemination of CTX-M-15 in the natural environment. AB - OBJECTIVES: Multidrug-resistant Enterobacteriaceae pose a significant threat to public health. We aimed to study the impact of sewage treatment effluent on antibiotic resistance reservoirs in a river. METHODS: River sediment samples were taken from downstream and upstream of a waste water treatment plant (WWTP) in 2009 and 2011. Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae were enumerated. PCR-based techniques were used to elucidate mechanisms of resistance, with a new two-step PCR-based assay developed to investigate bla(CTX M-15) mobilization. Conjugation experiments and incompatibility replicon typing were used to investigate plasmid ecology. RESULTS: We report the first examples of bla(CTX-M-15) in UK river sediment; the prevalence of bla(CTX-M-15) was dramatically increased downstream of the WWTP. Ten novel genetic contexts for this gene were identified, carried in pathogens such as Escherichia coli ST131 as well as indigenous aquatic bacteria such as Aeromonas media. The bla(CTX-M-15) gene was readily transferable to other Gram-negative bacteria. We also report the first finding of an imipenem-resistant E. coli in a UK river. CONCLUSIONS: The high diversity and host range of novel genetic contexts proves that evolution of novel combinations of resistance genes is occurring at high frequency and has to date been significantly underestimated. We have identified a worrying reservoir of highly resistant enteric bacteria in the environment that poses a threat to human and animal health. PMID- 24797065 TI - Emergence of Escherichia coli ST131 sub-clone H30 producing VIM-1 and KPC-3 carbapenemases, Italy. PMID- 24797067 TI - Microcin MccPDI reduces the prevalence of susceptible Escherichia coli in neonatal calves. AB - AIMS: Microcin MccPDI-producing Escherichia coli have a fitness advantage in dairy calves. For this project, we determined whether MccPDI is responsible for the in vivo fitness advantage, which is a necessary condition before MccPDI strains can be considered viable candidates for inhibiting pathogenic serovars of E. coli. METHODS AND RESULTS: Neonatal calves were coinoculated with either MccPDI-producing E. coli or MccPDI-knockout mutants in conjunction with a susceptible strain. After 6 days, the MccPDI-producing E. coli-25 strain clearly dominated the E. coli-186 susceptible strain in the inoculated calves (P = 0.003). MccPDI-producing E. coli composed a higher log percentage of the total population of lactose-fermenting bacteria in the faeces (5.51 log CFU per 8.03 log CFU) compared with the knockout strain (2.6 log CFU per 8.23 log CFU) (P = 0.01), and it was more consistently recovered from the lower gastrointestinal tract at the time of necropsy (P = 0.01). CONCLUSION: Our findings support the hypothesis that MccPDI is functional in vivo and it is most likely responsible for a fitness advantage in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: MccPDI producing E. coli strongly inhibit pathogenic E. coli strains in vitro. We show herein that MccPDI functions in vivo, and thus, these strains may be candidate probiotics against pathogenic strains of E. coli. PMID- 24797066 TI - Evolution of a transition state: role of Lys100 in the active site of isocitrate dehydrogenase. AB - An active site lysine essential to catalysis in isocitrate dehydrogenase (IDH) is absent from related enzymes. As all family members catalyze the same oxidative beta-decarboxylation at the (2R)-malate core common to their substrates, it seems odd that an amino acid essential to one is not found in all. Ordinarily, hydride transfer to a nicotinamide C4 neutralizes the positive charge at N1 directly. In IDH, the negatively charged C4-carboxylate of isocitrate stabilizes the ground state positive charge on the adjacent nicotinamide N1, opposing hydride transfer. The critical lysine is poised to stabilize-and perhaps even protonate-an oxyanion formed on the nicotinamide 3-carboxamide, thereby enabling the hydride to be transferred while the positive charge at N1 is maintained. IDH might catalyze the same overall reaction as other family members, but dehydrogenation proceeds through a distinct, though related, transition state. Partial activation of lysine mutants by K(+) and NH4 (+) represents a throwback to the primordial state of the first promiscuous substrate family member. PMID- 24797068 TI - Comparison of periodontal conditions among three elderly populations in Japan and Germany. AB - AIM: There is a growing interest in comparing periodontal conditions between countries. This study compared periodontal disease conditions in three elderly populations- one from Japan and two from Germany. MATERIALS AND METHODS: We compared periodontal data of 70-year-old subjects from the Niigata Study with 65 74-year-old subjects from the Study of Health in Pomerania (SHIP) and from West Germany (DMS III). A total of 489, 399 and 549 dentate subjects were analysed, respectively. Recording protocols were standardized. Linear or logistic models were used to compare Niigata Study with SHIP. RESULTS: Elderly German subjects in SHIP and DMS III had significantly more severe periodontal conditions and fewer remaining teeth compared to those in Niigata Study, though differences were less pronounced for DMS III. German subjects showed a significantly different pattern of various periodontal risk factors compared to Japanese subjects. Even after adjustment for putative periodontal risk factors, SHIP subjects still presented significantly higher adjusted values for most periodontal parameters compared to Niigata Study subjects (p < 0.05). CONCLUSIONS: Periodontitis was more prevalent in SHIP compared with Niigata Study, even after comprehensive risk factor adjustment. Only to a very small extent, differences between studies could be explained by the risk factors explored. PMID- 24797069 TI - Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and alpha-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were gammadelta-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) alpha-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with gammadelta-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP. PMID- 24797070 TI - E2F activators signal and maintain centrosome amplification in breast cancer cells. AB - Centrosomes ensure accurate chromosome segregation by directing spindle bipolarity. Loss of centrosome regulation results in centrosome amplification, multipolar mitosis and aneuploidy. Since centrosome amplification is common in premalignant lesions and breast tumors, it is proposed to play a central role in breast tumorigenesis, a hypothesis that remains to be tested. The coordination between the cell and centrosome cycles is of paramount importance to maintain normal centrosome numbers, and the E2Fs may be responsible for regulating these cycles. However, the role of E2F activators in centrosome amplification is unclear. Because E2Fs are deregulated in Her2(+) cells displaying centrosome amplification, we addressed whether they signal this abnormal process. Knockdown of E2F1 or E2F3 in Her2(+) cells decreased centrosome amplification without significantly affecting cell cycle progression, whereas the overexpression of E2F1, E2F2, or E2F3 increased centrosome amplification in MCF10A mammary epithelial cells. Our results revealed that E2Fs affect the expression of proteins, including Nek2 and Plk4, known to influence the cell/centrosome cycles and mitosis. Downregulation of E2F3 resulted in cell death and delays/blocks in cytokinesis, which was reversed by Nek2 overexpression. Nek2 overexpression enhanced centrosome amplification in Her2(+) breast cancer cells silenced for E2F3, revealing a role for the E2F activators in maintaining centrosome amplification in part through Nek2. PMID- 24797071 TI - Functional amyloids in the mouse sperm acrosome. AB - The acrosomal matrix (AM) is an insoluble structure within the sperm acrosome that serves as a scaffold controlling the release of AM-associated proteins during the sperm acrosome reaction. The AM also interacts with the zona pellucida (ZP) that surrounds the oocyte, suggesting a remarkable stability that allows its survival despite being surrounded by proteolytic and hydrolytic enzymes released during the acrosome reaction. To date, the mechanism responsible for the stability of the AM is not known. Our studies demonstrate that amyloids are present within the sperm AM and contribute to the formation of an SDS- and formic acid-resistant core. The AM core contained several known amyloidogenic proteins, as well as many proteins predicted to form amyloid, including several ZP binding proteins, suggesting a functional role for the amyloid core in sperm-ZP interactions. While stable at pH 3, at pH 7, the sperm AM rapidly destabilized. The pH-dependent dispersion of the AM correlated with a change in amyloid structure leading to a loss of mature forms and a gain of immature forms, suggesting that the reversal of amyloid is integral to AM dispersion. PMID- 24797072 TI - Fidelity of histone gene regulation is obligatory for genome replication and stability. AB - Fidelity of chromatin organization is crucial for normal cell cycle progression, and perturbations in packaging of DNA may predispose to transformation. Histone H4 protein is the most highly conserved chromatin protein, required for nucleosome assembly, with multiple histone H4 gene copies encoding identical protein. There is a long-standing recognition of the linkage of histone gene expression and DNA replication. A fundamental and unresolved question is the mechanism that couples histone biosynthesis with DNA replication and fidelity of cell cycle control. Here, we conditionally ablated the obligatory histone H4 transcription factor HINFP to cause depletion of histone H4 in mammalian cells. Deregulation of histone H4 results in catastrophic cellular and molecular defects that lead to genomic instability. Histone H4 depletion increases nucleosome spacing, impedes DNA synthesis, alters chromosome complement, and creates replicative stress. Our study provides functional evidence that the tight coupling between DNA replication and histone synthesis is reciprocal. PMID- 24797073 TI - Synapsis alters RAG-mediated nicking at Tcrb recombination signal sequences: implications for the "beyond 12/23" rule. AB - At the Tcrb locus, Vbeta-to-Jbeta rearrangement is permitted by the 12/23 rule but is not observed in vivo, a restriction termed the "beyond 12/23" rule (B12/23 rule). Previous work showed that Vbeta recombination signal sequences (RSSs) do not recombine with Jbeta RSSs because Jbeta RSSs are crippled for either nicking or synapsis. This result raised the following question: how can crippled Jbeta RSSs recombine with Dbeta RSSs? We report here that the nicking of some Jbeta RSSs can be substantially stimulated by synapsis with a 3'Dbeta1 partner RSS. This result helps to reconcile disagreement in the field regarding the impact of synapsis on nicking. Furthermore, our data allow for the classification of Tcrb RSSs into two major categories: those that nick quickly and those that nick slowly in the absence of a partner. Slow-nicking RSSs can be stimulated to nick more efficiently upon synapsis with an appropriate B12/23 partner, and our data unexpectedly suggest that fast-nicking RSSs can be inhibited for nicking upon synapsis with an inappropriate partner. These observations indicate that the RAG proteins exert fine control over every step of V(D)J cleavage and support the hypothesis that initial RAG binding can occur on RSSs with either 12- or 23-bp spacers (12- or 23-RSSs, respectively). PMID- 24797074 TI - Binding of the WASP/N-WASP-interacting protein WIP to actin regulates focal adhesion assembly and adhesion. AB - The actin cytoskeleton is essential for cell adhesion and migration, functions important for tumor invasion. In addition to binding N-WASP/WASP, WIP binds and stabilizes F-actin. WIP(-/-) fibroblasts were used to test the role of WIP in F actin function. WIP(-/-) cells had defective focal adhesion (FA), stress fiber assembly, and adherence to substrates, functions that were restored by transduction of wild-type WIP. Protein and mRNA levels of several FA constituents regulated by the myocardin-related transcription factor (MRTF)-serum response factor (SRF) transcription factor complex were reduced in WIP(-/-) fibroblasts. The level of G-actin, which sequesters MRTF in the cytoplasm, was increased, and nuclear localization of MRTF-A and SRF was reduced, in WIP(-/-) fibroblasts. Transfection of an MRTF-A mutant that constitutively translocates to the nucleus or transfection of constitutively active SRF restored FA and stress fiber assembly. Fibroblasts from knock-in mice expressing a WIP mutant that fails to bind actin phenocopied WIP(-/-) fibroblasts. Thus, WIP is a novel regulator of FA assembly and cell adhesion. PMID- 24797075 TI - Distinct transmissibility features of TSE sources derived from ruminant prion diseases by the oral route in a transgenic mouse model (TgOvPrP4) overexpressing the ovine prion protein. AB - Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases associated with a misfolded form of host-encoded prion protein (PrP). Some of them, such as classical bovine spongiform encephalopathy in cattle (BSE), transmissible mink encephalopathy (TME), kuru and variant Creutzfeldt-Jakob disease in humans, are acquired by the oral route exposure to infected tissues. We investigated the possible transmission by the oral route of a panel of strains derived from ruminant prion diseases in a transgenic mouse model (TgOvPrP4) overexpressing the ovine prion protein (A136R154Q171) under the control of the neuron-specific enolase promoter. Sources derived from Nor98, CH1641 or 87V scrapie sources, as well as sources derived from L-type BSE or cattle-passaged TME, failed to transmit by the oral route, whereas those derived from classical BSE and classical scrapie were successfully transmitted. Apart from a possible effect of passage history of the TSE agent in the inocula, this implied the occurrence of subtle molecular changes in the protease-resistant prion protein (PrPres) following oral transmission that can raises concerns about our ability to correctly identify sheep that might be orally infected by the BSE agent in the field. Our results provide proof of principle that transgenic mouse models can be used to examine the transmissibility of TSE agents by the oral route, providing novel insights regarding the pathogenesis of prion diseases. PMID- 24797076 TI - The p21-activated kinase (PAK) family member PakD is required for chemorepulsion and proliferation inhibition by autocrine signals in Dictyostelium discoideum. AB - In Dictyostelium discoideum, the secreted proteins AprA and CfaD function as reporters of cell density and regulate cell number by inhibiting proliferation at high cell densities. AprA also functions to disperse groups of cells at high density by acting as a chemorepellent. However, the signal transduction pathways associated with AprA and CfaD are not clear, and little is known about how AprA affects the cytoskeleton to regulate cell movement. We found that the p21 activated kinase (PAK) family member PakD is required for both the proliferation inhibiting activity of AprA and CfaD and the chemorepellent activity of AprA. Similar to cells lacking AprA or CfaD, cells lacking PakD proliferate to a higher cell density than wild-type cells. Recombinant AprA and CfaD inhibit the proliferation of wild-type cells but not cells lacking PakD. Like AprA and CfaD, PakD affects proliferation but does not significantly affect growth (the accumulation of mass) on a per-nucleus basis. In contrast to wild-type cells, cells lacking PakD are not repelled from a source of AprA, and colonies of cells lacking PakD expand at a slower rate than wild-type cells, indicating that PakD is required for AprA-mediated chemorepulsion. A PakD-GFP fusion protein localizes to an intracellular punctum that is not the nucleus or centrosome, and PakD-GFP is also occasionally observed at the rear cortex of moving cells. Vegetative cells lacking PakD show excessive actin-based filopodia-like structures, suggesting that PakD affects actin dynamics, consistent with previously characterized roles of PAK proteins in actin regulation. Together, our results implicate PakD in AprA/CfaD signaling and show that a PAK protein is required for proper chemorepulsive cell movement in Dictyostelium. PMID- 24797077 TI - The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections. AB - OBJECTIVES: To investigate the utility of beta-D-glucan (BDG) testing in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive fungal infection (IFI), as compared to BAL galactomannan (GM). METHODS: We retrospectively reviewed medical records of 132 consecutive patients at the National Institutes of Health (NIH) in whom BAL BDG testing was performed for diagnosis of pneumonia. Using the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines, we determined which patients had proven or probable IFI, and assessed the diagnostic performance of BAL BDG testing, relative to BAL GM. We also determined the reproducibility of the BDG assay in BAL via repeat testing of patient samples. RESULTS: Ten patients had Pneumocystis pneumonia, and 34 patients had proven/probable IFI, including 14 with invasive aspergillosis (IA). BAL BDG was 100% sensitive for Pneumocystis. Although BAL BDG had similar sensitivity to BAL GM for the diagnosis of IA and IFI, it exhibited inferior specificity. Repeat testing demonstrated poor reproducibility of the BDG assay in BAL but not in serum. CONCLUSIONS: BDG testing exhibits poor specificity and reproducibility in BAL. Identification of the BAL-specific factors that may interfere with the performance of the assay could improve the clinical usefulness of BAL BDG testing. PMID- 24797078 TI - Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) isolates with an elevated vancomycin MIC >=2 mg/L have been increasingly identified in many countries. We aimed to develop a clinical score to predict vancomycin MIC >=2 mg/L in patients with community-onset MRSA bacteraemia. METHODS: This retrospective cohort study enrolled 394 patients with MRSA bacteraemia. Vancomycin MICs of all MRSA isolates were determined by agar dilution method. Clinical characteristics between patients with high (>=2 mg/L) and low (<=1 mg/L) vancomycin MIC MRSA bacteraemia were compared. Independent predictors of high vancomycin MIC isolate infection were identified and used to create a score-based predictive model. RESULTS: Among the 394 study patients, 56 (14.2%) had MRSA isolates with a vancomycin MIC >=2 mg/L. The final regression model included 6 independent predictors: chronic liver disease (adjusted odds ratio [aOR], 2.99; 95% confidence interval [CI], 1.39-6.42), prior recovery of MRSA from respiratory tract specimen (aOR, 2.54; 95% CI, 1.15-5.61), end-stage renal disease (aOR, 2.53; 95% CI, 1.33-4.78), severe sepsis or septic shock on presentation (aOR, 2.39; 95% CI, 1.28-4.44), prior vancomycin exposure (aOR, 2.21; 95% CI, 1.13 4.30), and recent hospitalization within 3 months (aOR, 2.11; 95% CI; 1.01-4.40). All independent predictors had a value of one point. Youden's index statistics indicated a score of >=3 as best cutoff value that had a sensitivity of 69.6% and specificity of 78.4%. CONCLUSIONS: Simple decision rule helps clinicians stratify the risk of high vancomycin MIC MRSA infection when deciding empirical therapy for patients with community-onset infections. PMID- 24797079 TI - C/EBP transcription factors regulate NADPH oxidase in human aortic smooth muscle cells. AB - In atherosclerosis, oxidative stress-induced vascular smooth muscle cells (SMCs) dysfunction is partially mediated by up-regulated NADPH oxidase (Nox); the mechanisms of enzyme regulation are not entirely defined. CCAAT/enhancer-binding proteins (C/EBP) regulate cellular proliferation and differentiation, and the expression of many inflammatory and immune genes. We aimed at elucidating the role of C/EBP in the regulation of Nox in SMCs exposed to pro-inflammatory conditions. Human aortic SMCs were treated with interferon-gamma (IFN-gamma) for up to 24 hrs. Lucigenin-enhanced chemiluminescence, real-time PCR, Western blot, promoter-luciferase reporter analysis and chromatin immunoprecipitation assays were employed to investigate Nox regulation. IFN-gamma dose-dependently induced Nox activity and expression, nuclear translocation and up-regulation of C/EBPalpha, C/EBPbeta and C/EBPdelta protein expression levels. Silencing of C/EBPalpha, C/EBPbeta or C/EBPdelta reduced significantly but differentially the IFN-gamma-induced up-regulation of Nox activity, gene and protein expression. In silico analysis indicated the existence of typical C/EBP sites within Nox1, Nox4 and Nox5 promoters. Transient overexpression of C/EBPalpha, C/EBPbeta or C/EBPdelta enhanced the luciferase level directed by the promoters of the Nox subtypes. Chromatin immunoprecipitation demonstrated the physical interaction of C/EBPalpha, C/EBPbeta and C/EBPdelta proteins with the Nox1/4/5 promoters. C/EBP transcription factors are important regulators of Nox enzymes in IFN-gamma exposed SMCs. Activation of C/EBP may induce excessive Nox-derived reactive oxygen species formation, further contributing to SMCs dysfunction and atherosclerotic plaque development. Pharmacological targeting of C/EBP-related signalling pathways may be used to counteract the adverse effects of oxidative stress. PMID- 24797080 TI - The associations between the family education and mortality of patients on peritoneal dialysis. AB - AIMS: To investigate whether education level of family members predicts all-cause and cardiovascular death and initial-episode peritonitis in patients on peritoneal dialysis (PD). METHODS: A total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic, socioeconomic and laboratory data of patients and the education level of all family members were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of all-cause and cardiovascular mortality, and initial-episode peritonitis with adjustments for recognized traditional factors. RESULTS: There were no significant differences in baseline characteristics between patients with (n = 1752) and without (n = 512) complete education information. According to the highest education level of patients' family, included 1752 patients were divided into four groups, i.e. elementary or lower (15%), middle (27%), high (24%) and more than high school (34%). The family highest education (using elementary school or lower group as reference, hazard ratio and 95% confidence interval of middle school group, high school group and more than high school group was 0.68[0.48-0.96], 0.64[0.45-0.91], 0.66[0.48-0.91], respectively) rather than their average education level or patients' or spouse's education was significantly associated with the higher mortality. Neither patients' nor family education level did correlate to the risk for cardiovascular death or initial episode peritonitis. CONCLUSIONS: Family members' education level was found to be a novel predictor of PD outcome. Family, as the main source of health care providers, should be paid more attention in our practice. PMID- 24797081 TI - Status epilepticus after prolonged umbilical cord occlusion is associated with greater neural injury in [corrected] fetal sheep at term-equivalent. AB - The majority of pre-clinical studies of hypoxic-ischemic encephalopathy at term equivalent have focused on either relatively mild insults, or on functional paradigms of cerebral ischemia or hypoxia-ischemia/hypotension. There is surprisingly little information on the responses to single, severe 'physiological' insults. In this study we examined the evolution and pattern of neural injury after prolonged umbilical cord occlusion (UCO). 36 chronically instrumented fetal sheep at 125-129 days gestational age (term = 147 days) were subjected to either UCO until mean arterial pressure was < = 8 mmHg (n = 29), or sham occlusion (n = 7). Surviving fetuses were killed after 72 hours for histopathologic assessment with acid-fuchsin thionine. After UCO, 11 fetuses died with intractable hypotension and 5 ewes entered labor and were euthanized. The remaining 13 fetuses showed marked EEG suppression followed by evolving seizures starting at 5.8 (6.8) hours (median (interquartile range)). 6 of 13 developed status epilepticus, which was associated with a transient secondary increase in cortical impedance (a measure of cytotoxic edema, p<0.05). All fetuses showed moderate to severe neuronal loss in the hippocampus and the basal ganglia but mild cortical cell loss (p<0.05 vs sham occlusion). Status epilepticus was associated with more severe terminal hypotension (p<0.05) and subsequently, greater neuronal loss (p<0.05). In conclusion, profound UCO in term-equivalent fetal sheep was associated with delayed seizures, secondary cytotoxic edema, and subcortical injury, consistent with the predominant pattern after peripartum sentinel events at term. It is unclear whether status epilepticus exacerbated cortical injury or was simply a reflection of a longer duration of asphyxia. PMID- 24797083 TI - Open abdomen management of intra-abdominal infections: analysis of a twenty-year experience. AB - BACKGROUND: No conclusive results on the efficacy and timing of open abdomen (OA) are available, particularly in the setting of intra-abdominal infections. We analyzed outcomes and risk factors retrospectively in a large series of patients managed with an OA during the past 20 y in an effort to clarify this issue. METHODS: We reviewed the records of 133 patients who underwent treatment with an OA, considering factors related to patient, disease, medical management, and surgical treatment. The end points of the bi-variable analysis were 1-y mortality, calculated from the time of an initial OA procedure, and definitive fascial closure. RESULTS: Most patients (112/133) managed with an OA had one of several types of peritonitis. Many patients had severe clinical conditions (mean Acute Physiology and Chronic Health Evaluation [APACHE] II score was almost 9 points for the study population). With regard to surgical management, the mean (+SD) number of abdominal revisions was 5.9+9.3 during a mean duration of treatment with an OA of 14.3+11.6 d. The overall mortality in the study was 26% (35/133). Bi-variable analysis revealed factors associated with overall mortality to be age, renal and respiratory co-morbidities, edema on an initial chest radiograph, blood pressure, blood glucose and creatinine concentrations; and APACHE II score. The rate of definitive fascial closure was 75% (100/133). Factors associated negatively with fascial closure were respiratory co-morbidity, edema on a first chest radiograph, post-operative mesenteric ischemia as an indication for OA, blood glucose and creatinine concentrations, and duration of an OA. CONCLUSIONS: Patients' pre-operative clinical status influences strongly their response to surgical treatment. The management of OA does not affect adversely the survival of patients with intra-abdominal infections, but factors related to the management of OA (duration of OA) seem to affect the possibility of definitive fascial closure. PMID- 24797082 TI - Mediators of the daily hassles-suicidal ideation link in African American women. AB - Depressive symptoms and hopelessness as mediators of the daily hassles-suicidal ideation link in low-income African American women exposed to intimate partner violence (n = 100) were investigated. As hypothesized, daily hassles, depressive symptoms, and hopelessness were each significantly and positively associated with suicidal ideation. Moreover, the relation between daily hassles and suicidal ideation was, in part, accounted for by depressive symptoms and hopelessness. This study demonstrates the importance of assessing for the presence of these risk factors when determining the likelihood that an abused African American woman will consider suicide. The findings further highlight the value of designing and implementing interventions that target the reduction in depressive symptoms and hopelessness in abused African American women exposed to daily hassles to reduce their suicide risk. PMID- 24797084 TI - Recurrence of nonfamilial cardiac myxoma in the left ventricle: a case report. AB - A left atrial myxoma was found and removed in a 47-year-old woman admitted for acute ischemic cerebrovascular disease, without family history of cardiac tumor. Follow-up echocardiography, 15 months later, demonstrated a new myxoma in the left ventricle. PMID- 24797085 TI - Evaluating a model linking assessed parent factors to four domains of youth risky driving. AB - Motor vehicle collisions are the leading cause of death in youth aged 15-19. Research has consistently shown that driver education programs do not result in safer youth driving. Indeed, the biggest predictor of collisions involving youth is parental history of collisions. The current study examined how parental modeling of and teaching about risky driving behaviors related to youth practices within four domains of risky driving (aggressive, substance use, distracted, moving violations), and evaluated whether the Prototype-Willingness Model explains links from parent to teen driving practices. Participants (N=432) were undergraduate students (mean age 18 years, age range 17-22 years) who had obtained their G2 driver's license within the past year; the G2 driver's license allows youth to drive alone on all municipal roads, with some restrictions on their blood alcohol level and the number of passengers they can carry. Results revealed that parental modeling was more predictive than parental teaching for all domains of risky driving examined. Youth whose parents modeled risky driving behaviors were found to be more likely to have engaged in those risky driving behaviors in the past, as well as to be more willing to engage in the behaviors in the future. The Prototype-Willingness Model was not a good fit to explain these relations. Findings from this study highlight the role parents play in the development of youth risky driving practices. PMID- 24797086 TI - Strong contribution of autumn phenology to changes in satellite-derived growing season length estimates across Europe (1982-2011). AB - Land Surface Phenology (LSP) is the most direct representation of intra-annual dynamics of vegetated land surfaces as observed from satellite imagery. LSP plays a key role in characterizing land-surface fluxes, and is central to accurately parameterizing terrestrial biosphere-atmosphere interactions, as well as climate models. In this article, we present an evaluation of Pan-European LSP and its changes over the past 30 years, using the longest continuous record of Normalized Difference Vegetation Index (NDVI) available to date in combination with a landscape-based aggregation scheme. We used indicators of Start-Of-Season, End-Of Season and Growing Season Length (SOS, EOS and GSL, respectively) for the period 1982-2011 to test for temporal trends in activity of terrestrial vegetation and their spatial distribution. We aggregated pixels into ecologically representative spatial units using the European Landscape Classification (LANMAP) and assessed the relative contribution of spring and autumn phenology. GSL increased significantly by 18-24 days decade(-1) over 18-30% of the land area of Europe, depending on methodology. This trend varied extensively within and between climatic zones and landscape classes. The areas of greatest growing-season lengthening were the Continental and Boreal zones, with hotspots concentrated in southern Fennoscandia, Western Russia and pockets of continental Europe. For the Atlantic and Steppic zones, we found an average shortening of the growing season with hotspots in Western France, the Po valley, and around the Caspian Sea. In many zones, changes in the NDVI-derived end-of-season contributed more to the GSL trend than changes in spring green-up, resulting in asymmetric trends. This underlines the importance of investigating senescence and its underlying processes more closely as a driver of LSP and global change. PMID- 24797087 TI - NADPH oxidase inhibitor, apocynin, improves renal glutathione status in Zucker diabetic fatty rats: a comparison with melatonin. AB - Apocynin (4'-hydroxy-3'-methoxyacetophenone) is the most commonly used NADPH oxidase (Nox) inhibitor. However, its application raises serious controversies, as the compound has been reported to reveal some prooxidative effects. The aim of this study was to elucidate apocynin action on glutathione, the main intracellular antioxidant, metabolism in kidneys of Zucker diabetic fatty (ZDF) rat, a well established model of diabetes type 2. Additionally, apocynin effects were compared with those of melatonin. The experiments were performed on five groups of animals: (1) untreated lean (?/+) ZDF rats, (2) ZDF ?/+ rats treated with apocynin (2 g/l) in drinking water, (3) untreated obese diabetic (fa/fa) ZDF rats, (4) ZDF fa/fa rats treated with apocynin (2 g/l) in drinking water, and (5) ZDF fa/fa rats treated with melatonin (20 mg/l) in drinking water. After 8weeks of the treatment, the following parameters were measured in kidneys: NADPH oxidase activity, the rate of hydroxyl free radicals (HFR) production, GSH and GSSG content and the activities of the enzymes of glutathione metabolism: gamma glutamylcysteine synthetase (GCS), glutathione reductase (GR) and glutathione peroxidase (GPx). Compared to ?/+ controls, ZDF fa/fa rats exhibited increased Nox activity, accelerated HFR generation and dramatically lowered GSH/GSSG ratio accompanied by increased GPx and diminished GCS activities. In case of diabetic animals, apocynin treatment resulted in attenuation of both Nox activity and HFR production, restoration of control GSH/GSSG ratio (due to both an increase in GSH and a decline in GSSG content), normalization of GPx activity and a slight increase in GCS activity. Similar observations were made upon melatonin application to ZDF fa/fa rats. Thus, it is concluded that, in the diabetic model studied, apocynin extends a beneficial effect on renal glutathione homeostasis. The mechanism of this phenomenon involves attenuation of glutathione peroxidase activity, which is overstimulated under conditions of oxidative stress accompanying diabetes. PMID- 24797088 TI - Molecular simulation investigation on the interaction between barrier-to autointegration factor or its Gly25Glu mutant and DNA. AB - In order to understand the binding mechanism between Barrier-to-autointegration factor (BAF) and DNA, two DNA:BAF complexes with wild type (WT) BAF and its Gly25Glu point mutate type (MT) were generated by molecular docking on the basis of the crystal structures of BAF (PDB code: 2ODG, chain A) and DNA (PDB code: 2BZF, chain B and C). Then, molecular dynamics (MD) simulations were performed on the two docked structures, as well as BAF (WT) and BAF (MT). The results show that monomer BAF is more flexible than BAF in DNA:BAF complex, suggesting that DNA is effective to stabilize conformation of BAF, which is in good agreement with the experimental results. Besides, the mutated Glu25 in DNA:BAF (MT) can change the BAF conformation to some extent. With deeper investigation on the DNA:BAF structures, the hydrogen bonds are found to make great contribution to the interaction between DNA and BAF. The hydrogen bonds in DNA:BAF (MT) are fewer than those in DNA:BAF (WT), indicating that the Gly25Glu mutation in BAF has an important effect on the hydrogen bonds in the DNA:BAF complex. Besides, the binding free energy in DNA:BAF (MT) is also higher than that in DNA:BAF (WT). It results from the influence of Glu25 side chain on the orientation of Lys6 and Lys33 in the interface between DNA and BAF. The binding free energy of Lys72, another key residue, decreases a lot in DNA:BAF (MT) anomalously. The decreasing energy causes the destruction of hydrophobic pocket in the binding site between DNA and BAF (MT). Our results are helpful for further experimental investigations. PMID- 24797089 TI - Molecular dynamics, dynamic site mapping, and highthroughput virtual screening on leptin and the Ob receptor as anti-obesity target. AB - Body weight control is a mechanism finely regulated by several hormonal, metabolic, and nervous pathways. The leptin receptor (Ob-R) is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells into the bloodstream, and under normal circumstances, circulating levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neurocircutry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased concentrations lead to opposite effects. Therefore rational design of leptin agonists constitute an appealing challenge in the battle against obesity. In this study, we performed protein-protein docking among the re-built crystal structure of leptin and leptin binding domain (LBD). The obtained complex was used as a starting point to carry out nanosecond-scale molecular dynamics simulations to characterize the key regions in terms of physical-chemical features involved in the protein-protein interaction (dynamic site mapping filtered by means multivariate analysis) and used to carry out a HTVS. The main goal of this study was to suggest guidelines for the rational drug design of new agonists of leptin. Identified hits could be a consistent starting point to carry out in vitro testing. PMID- 24797090 TI - Autotomy of the Visceral mass in the feather star Himerometra robustipinna (Crinoidea, Comatulida). AB - The microanatomy of the attachment sites of the visceral mass to the calyx before and after visceral mass autotomy in the feather star Himerometra robustipinna was investigated. At the aboral site, the visceral mass is linked to the calyx by septa of the aboral coelom and is attached to the tegmen at the peripheral site. The connective tissue of the septa and tegmen contains cells resembling typical juxtaligamental cells of echinoderms, nerve cells, and bundles of axons. Visceral mass autotomy in H. robustipinna can be provoked by mechanical action and occurs relatively rapidly. Immediately after the visceral mass is gripped with forceps, the proximal pinnules are lowered and form a dense cluster covering the calyx. If the visceral mass is held for 20-30 s, the proximal pinnules are raised. At this time, the visceral mass has separated from the calyx and can be easily removed. During autotomy, the aboral coelomic septa are broken under the aboral wall of the subintestinal coelom, and the tegmen is ruptured at the interradii along the periphery of the calyx and at the base of the arms. The juxtaligamental cells probably participate in the alteration of the connective tissue and the breakage of the septa and tegmen. The granules of juxtaligamental cells swell, develop an electron-transparent halo, and are released into the extracellular matrix. In general, our results suggest that separation of the visceral mass in H. robustipinna is characterized by all the features of autotomy. PMID- 24797091 TI - Circadian rhythm in larval release by the crab Rhithropanopeus harrisii: entrainment model. AB - The subtidal crab Rhithropanopeus harrisii has a circadian rhythm in larval release; under constant conditions eggs hatch in the 2-3-h interval after the time of sunset in nontidal estuaries. Eggs that are removed from the female hatch rhythmically, indicating that the circadian rhythm resides in the embryos. The model for entrainment is that mature embryos have functional sensory systems that detect and entrain to environmental cycles. This model was reexamined by confirming that the visual system of advanced embryos responds to light and thus could mediate entrainment to the light/dark cycle. We then determined whether the hatching rhythm of mature embryos that are removed from the female can be entrained to new light/dark cycles. Contrary to expectations, these embryos did not entrain to new cycles. Instead, they remained entrained to the light/dark cycle to which they were exposed when still attached to the female, suggesting that the female entrains the rhythm. Indeed, hatching by embryos collected from the field when they had not yet developed eye pigments, kept in constant conditions attached to their mother, exhibited the circadian hatching rhythm. They could also be entrained to a new photoperiod in the laboratory. The role of the female is further supported by experiments showing that the hatching rhythm in embryos carried by females lacking one but not both eyes can be entrained to a new cycle in the laboratory. Thus, the revised model is that the female perceives the light/dark cycle and entrains the circadian rhythm in the embryos. PMID- 24797092 TI - Interaction of pathogenic vibrio bacteria with the blood clot of the pacific white shrimp, Litopenaeus vannamei. AB - In addition to its roles in hemostasis and wound repair, the blood clot plays an underappreciated role in innate immunity, where the established clot serves as a barrier to microbial penetration into the internal milieu and where the early clot entraps and immobilizes microbes that have entered wounds to the integuments. In this report we document the behavior of the pathogenic gram negative bacterium Vibrio harveyi that has been entrapped in the fabric of the extracellular blood clot of one of its target organisms, the Pacific white shrimp, Litopenaeus vannamei. The freshly entrapped bacteria are held tightly by the clot, losing even Brownian motility, but by 1 h post-entrapment, a fraction of the bacteria have established small domains of fibrinolysis that enlarge progressively, enabling bacteria to escape from the clot's embrace. Escape is dependent on the actions of both serine- and metallo-proteases released from the bacterial cells. PMID- 24797093 TI - Handed behavior in hagfish--an ancient vertebrate lineage--and a survey of lateralized behaviors in other invertebrate chordates and elongate vertebrates. AB - Hagfish represent an ancient lineage of boneless and jawless vertebrates. Among several curious behaviors they exhibit, solitary individuals in one dominant genus of hagfish (Eptatretus spp.) regularly rest in a tightly coiled posture. We present the first systematic treatment of this distinctive behavior. Individual northeastern Pacific hagfish (E. stoutii) exhibited significant handedness (preferred orientation of coiling). However, right-coiling and left-coiling individuals were equally common in the population. Individual hagfish likely develop a preference for one direction by repeating the preceding coiling direction. We also revisit classical accounts of chordate natural history and compare the coiling behavior of Eptatretus with other handed or lateralized behaviors in non-vertebrate chordates, lampreys, and derived vertebrates with elongate bodies. Handed behaviors occur in many of these groups, but they likely evolved independently. In contrast to vertebrates, morphological asymmetries may bias lateralized larval behaviors toward one side in cephalochordates and tunicates. As a consequence, no known handed behavior can be inferred to have existed in the common ancestor of vertebrates. PMID- 24797094 TI - Field study of growth and calcification rates of three species of articulated coralline algae in British Columbia, Canada. AB - Ocean acidification caused by rising atmospheric CO2 is predicted to negatively impact growth and calcification rates of coralline algae. Decreases in coralline abundance may have cascading effects on marine ecosystems and on carbon sequestration worldwide. In this study, we measured growth and calcification rates of three common species of articulated coralline algae (Bossiella plumosa, Calliarthron tuberculosum, and Corallina vancouveriensis) at an intertidal field site in British Columbia. Linear growth rates measured in the field were slow, although Bossiella grew significantly faster (0.22 cm mon-1) than Calliarthron and Corallina (0.17 and 0.15 cm mon-1, respectively). Growth rates in the field were generally slower than growth rates in the laboratory, suggesting that data generated in the laboratory may not be representative of natural field conditions. Growth rates did not decrease as fronds approached their maximum observed size, suggesting that maximum frond size might be determined not by intrinsic factors but by external factors such as wave-induced drag forces. Using growth data, we estimate that the largest observed Bossiella frond (20 cm2) and Calliarthron frond (40 cm2) were about 4- and 11-years-old, respectively, and had deposited approximately 1 and 6 g CaCO3 in that time. Given the great abundance of coralline algae along the coast of British Columbia, deposition rates of CaCO3 are expected to play a significant but poorly characterized role in carbon sequestration. PMID- 24797095 TI - Burrowing behavior in mud and sand of morphologically divergent polychaete species (Annelida: Orbiniidae). AB - Muddy and sandy sediments have different physical properties. Muds are cohesive elastic solids, whereas granular beach sands are non-cohesive porous media. Infaunal organisms such as worms that burrow through sediments therefore face different mechanical challenges that potentially lead to a variety of burrowing strategies and morphologies. In this study we compared three morphologically distinct polychaete species representing different clades in the family Orbiniidae and related differences in their burrowing behaviors and morphologies to their natural environments (mud or sand). Worms burrowed in transparent analogs for muds and sands, and kinematic analysis showed differences both among species and between materials. Leitoscoloplos pugettensis lives in mud and burrows by fracture, using its pointed head to concentrate stress at the tip of the burrow. Naineris dendritica lives in sand and uses its broader head that fluctuates in width over a burrowing cycle to decrease backward slipping in sand, potentially preventing burrow collapse. Orbinia johnsoni lives in sand and uses internal body expansions to pack sand grains, another mechanism to prevent burrow collapse. By combining data from species and materials to obtain a broad range of burrowing velocities, we show that burrowing worms control their velocity by increasing or decreasing their burrowing frequency rather than by altering cycle distance as shown previously for crawling earthworms. This study demonstrates how fairly small evolutionary divergences in morphologies and behaviors facilitate locomotion in environments with different physical constraints. PMID- 24797096 TI - Melatonin production in the sea star Echinaster brasiliensis (Echinodermata). AB - The primary hormone of the vertebrate pineal gland, melatonin, has been identified broadly throughout the tree of life, in animals, plants, and fungi, supporting a deep evolutionary origin for this signaling molecule. However, some key groups have not been studied. Echinoderms, deuterostome animals, are one of these groups. Herein we study the presence of melatonin and enzymes of its pathway in the sea star Echinaster brasiliensis. We demonstrate that E. brasiliensis produces endogenous melatonin, in the gonads, under a circadian pattern with a nocturnal peak of production. We also show that the enzymes arylalkylamine N-acetyltransferase (AANAT) and tryptophan hydroxylase (TPH) are present and are probably regulating the melatonin production. PMID- 24797097 TI - Host differentially expressed genes during association with its defensive endosymbiont. AB - Mutualism, a beneficial relationship between two species, often requires intimate interaction between the host and symbiont to establish and maintain the partnership. The colonial marine bryozoan Bugula neritina harbors an as yet uncultured endosymbiont, "Candidatus Endobugula sertula," throughout its life stages. The bacterial symbiont is the putative source of bioactive complex polyketide metabolites, the bryostatins, which chemically defend B. neritina larvae from predation. Despite the presence of "Ca. Endobugula sertula" in all life stages of the host, deterrent bryostatins appear to be concentrated in reproductive portions of the host colony, suggesting an interaction between the two partners to coordinate production and distribution of the metabolites within the colony. In this study, we identified host genes that were differentially expressed in control colonies and in colonies cured of the symbiont. Genes that code for products similar to glycosyl hydrolase family 9 and family 20 proteins, actin, and a Rho-GDP dissociation inhibitor were significantly downregulated (more than twice) in antibiotic-cured non-reproductive zooids compared to control symbiotic ones. Differential expression of these genes leads us to hypothesize that the host B. neritina may regulate the distribution of the symbiont within the colony via mechanisms of biofilm degradation and actin rearrangement, and consequently, influences bryostatin localization to bestow symbiont-associated protection to larvae developing in the reproductive zooids. PMID- 24797098 TI - Poly(lactic acid) nanoparticles coated with combined WGA and water-soluble chitosan for mucosal delivery of beta-galactosidase. AB - A combinatorial design, physical adsorption of water-soluble chitosan (WSC) to particle surface and covalent conjugation of wheat germ agglutinin (WGA) to WSC, was applied to surface modification of poly(lactic acid) nanoparticles (NPs) for targeted delivery of beta-galactosidase to the intestinal mucosa. All the surface engineered NPs in the size range of 500-600 nm were prepared by a w/o/w solvent diffusion/evaporation technique. beta-Galactosidase encapsulated in these NPs was well protected from external proteolysis and exerted high hydrolytic activity on the permeable lactose. The presence of WSC coating, whether alone or with WGA, highly improved the suspension stability of NPs and tailored the particle surface positively charged. In comparison to NPs modified with WGA or WSC alone, the synergistic action of WGA and WSC greatly enhanced the NP-mucin interactions in vitro. The highest amount of NPs was found in the small intestine at 24 h after oral administration in rats. Notably, calculated half-life of WGA-WSC-NPs in the small intestine was 6.72 h, resulting in 2.1- and 4.3-fold increase when compared to WGA-polyvinylalcohol (PVA)-NPs and WSC-NPs, much longer than that of control PVA-NPs (6.9-fold). These results suggest that NPs with the combined WGA and WSC coating represent promising candidates for efficient mucosal drug delivery as well as biomimetic treatment of lactose intolerance. PMID- 24797099 TI - A pregnancy with discordant fetal and placental chromosome 18 aneuploidies revealed by invasive and noninvasive prenatal diagnosis. AB - This study investigated a pregnancy where the fetus was diagnosed with monosomy 18p by invasive amniocentesis and karyotyping. Additional noninvasive prenatal diagnosis, which detects fetal chromosome abnormalities in the circulating cell free plasma DNA originating from the placenta revealed a related 18p monosomy/18q trisomy, suggesting confined placental mosaicism. Based on recent observations of chromosomal instability in the early preimplantation embryo, this study speculates on the possible embryonic origin(s) of these related but discordant chromosome 18 aneuploidies in the placental and fetal tissues. The findings highlight the potential for both false-positive and -negative noninvasive prenatal diagnosis results in pregnancies where there is either confined placental mosaicism or placental mosaicism. The study investigated a pregnancy involving a fetus with a chromosome disease syndrome called monosomy 18p where part of the short arm of chromosome 18 was missing in the fetal tissues. Using non-invasive prenatal diagnosis which detects fetal chromosome abnormalities in the circulating cell free plasma DNA originating from the placenta, we also detected monosomy 18p as well a related chromosome 18 abnormality involving duplication of the long arm of chromosome 18. This suggested confined placental mosaicism where the constitution of the chromosomes are different between fetal and placental tissues. We speculated that these related chromosome 18 abnormalities arose during preimplantation embryo development, leading to the formation of different chromosome abnormalities observed in the placental and fetal tissues of this pregnancy. Our findings highlight the potential for both false positive and negative non-invasive prenatal diagnosis test results in pregnancies where there is confined placental mosaicism. PMID- 24797100 TI - Effects of chronic gamma-irradiation on growth and survival of the Tohoku hynobiid salamander, Hynobius lichenatus. AB - The Tohoku hynobiid salamanders, Hynobius lichenatus, were chronically irradiated with gamma-rays from embryonic to juvenile stages for 450 days. At 490 MUGy h(-1) or lower dose rates, growth and survival were not significantly affected by irradiation, and any morphological aberrations and histological damages were not observed. At 4600 MUGy h(-1), growth was severely inhibited, and all the individuals died mostly at the juvenile stage. Chronic LD50 was 42 Gy as a total dose. In the liver, the number of hematopoietic cells was significantly reduced in the living juveniles, and these cells disappeared in the dead juveniles. In the spleen, mature lymphocytes were depleted in the living larvae, and almost all the heamtopoietic cells disappeared in the dead juveniles. These results suggest that this salamander died due to acute radiation syndrome, i.e., hematopoietic damage and subsequent sepsis caused by immune depression. The death would be also attributed to skin damage inducing infection. At 18,000 MUGy h(-1), morphological aberrations and severe growth inhibition were observed. All the individuals died at the larval stage due to a multiple organ failure. Chronic LD50 was 28 Gy as a total dose. Assuming that chronic LD50 was 42 Gy at lower dose rates than 4600 MUGy h(-1), a chronic median lethal dose rate could be estimated to be <340 MUGy h(-1) for the whole life (>14 years). These results suggest that, among guidance dose rates, i.e., 4-400 MUGy h(-1), proposed by various organisations and research programmes for protection of amphibians and taxonomic groups or ecosystems including amphibians, most of them would protect this salamander but the highest value may not on the whole life scale. PMID- 24797103 TI - Characterization of new specific copper chelators as potential drugs for the treatment of Alzheimer's disease. AB - The non-controlled redox-active metal ions, especially copper, in the brain of patients with Alzheimer disease (AD) should be considered at the origin of the intense oxidative damage in the AD brain. Several bis(8-aminoquinoline) ligands, such as 1 and PA1637, are able to chelate Cu(2+) with high affinity, and are specific chelators of copper with respect to iron and zinc. They are able to efficiently extract Cu(2+) from a metal-loaded amyloid. In addition, these tetradentate ligands are specific for the chelation of Cu(2+) compared with Cu(+). Consequently, the copper ion is easily released from the bis(8 aminoquinoline) ligand under reductive conditions, and can be trapped again by a protein having some affinity for copper such as human serum albumin (HSA) proteins. In addition, the copper is not efficiently released from [Cu(CQ)2] in reductive conditions. The catalytic production of H2O2 by [Cu(2+)-Abeta(1 28)]/ascorbate is inhibited in vitro by the bis(8-aminoquinoline) 1, suggesting that 1 should be able to play a protective role against oxidative damages induced by copper-loaded amyloids. PMID- 24797102 TI - Role of autophagy in head and neck cancer and therapeutic resistance. AB - Head and neck squamous cell carcinomas (HNSCC) are one of the most common cancers worldwide, accounting for almost 50% of all malignancies in developing nations. Autophagy is a catabolic process involving turnover of long-lived proteins and organelles and is an important mechanism for cell survival under stress conditions. Autophagy has been shown to play a pivotal role in etio-pathogenesis of several cancers. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis, or defective apoptosis rendering immortalized epithelial cells highly tumorigenic. Autophagy has been found to buffer metabolic stress and may help in cell survival; however, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors. Therefore, autophagy acts as a double-edged sword in cancer therapeutics. Role of autophagy in pathophysiology and as a potential cancer therapeutics is a subject of intensive research. This review will focus on the role of autophagy and how it contributes to the pathogenesis and overcoming therapeutic resistance in HNSCC. PMID- 24797101 TI - Next-generation sequencing sheds light on the natural history of hepatitis C infection in patients who fail treatment. AB - High rates of sexually transmitted infection and reinfection with hepatitis C virus (HCV) have recently been reported in human immunodeficiency virus (HIV) infected men who have sex with men and reinfection has also been described in monoinfected injecting drug users. The diagnosis of reinfection has traditionally been based on direct Sanger sequencing of samples pre- and posttreatment, but not on more sensitive deep sequencing techniques. We studied viral quasispecies dynamics in patients who failed standard of care therapy in a high-risk HIV infected cohort of patients with early HCV infection to determine whether treatment failure was associated with reinfection or recrudescence of preexisting infection. Paired sequences (pre- and posttreatment) were analyzed. The HCV E2 hypervariable region-1 was amplified using nested reverse-transcription polymerase chain reaction (RT-PCR) with indexed genotype-specific primers and the same products were sequenced using both Sanger and 454 pyrosequencing approaches. Of 99 HIV-infected patients with acute HCV treated with 24-48 weeks of pegylated interferon alpha and ribavirin, 15 failed to achieve a sustained virological response (six relapsed, six had a null response, and three had a partial response). Using direct sequencing, 10/15 patients (66%) had evidence of a previously undetected strain posttreatment; in many studies, this is interpreted as reinfection. However, pyrosequencing revealed that 15/15 (100%) of patients had evidence of persisting infection; 6/15 (40%) patients had evidence of a previously undetected variant present in the posttreatment sample in addition to a variant that was detected at baseline. This could represent superinfection or a limitation of the sensitivity of pyrosequencing. CONCLUSION: In this high-risk group, the emergence of new viral strains following treatment failure is most commonly associated with emerging dominance of preexisting minority variants rather than reinfection. Superinfection may occur in this cohort but reinfection is overestimated by Sanger sequencing. PMID- 24797104 TI - Prevalence of 25-hydroxyvitamin D deficiency in Korean patients with anemia. AB - BACKGROUND: We investigated the prevalence and risk factors for vitamin D deficiency in Korean patients with anemia. METHODS: We included 200 anemic patients and 300 controls. Anemia was defined according to the WHO criteria. Serum 25-hydroxyvitamin D [25(OH)D] was measured using an electrochemiluminescence immunoassay. We compared serum 25(OH)D levels based on the presence and subtypes of anemia. RESULTS: We found that 91% (182/200) and 87.3% (262/300) of patients exhibited 25(OH)D inadequacies (<20 ng/ml) in the anemic (median hemoglobin (Hb), 9.6 g/dl) and control groups (median Hb 13.8 g/dl), respectively. The prevalence of 25(OH)D deficiency (<12 ng/ml) was significantly higher in the anemic group than in the control group (52.5% (105/200) vs. 25% (75/300), P < 0.0001), with an odds ratio of 3.316 (95% CI, 2.265-4.854; P < 0.0001). The prevalence of 25(OH)D deficiency was not different among anemia subtypes. Female gender and high C-reactive protein (CRP) were associated with vitamin D deficiency in anemic group. CONCLUSIONS: This study demonstrates that vitamin D deficiency is associated with anemia. Therefore, the measurement of serum 25(OH)D levels and appropriate vitamin D supplementation should be considered in anemic patients, particularly in females and patients with high CRP level. PMID- 24797105 TI - Ultrasound-guided anaesthetic blockade of the pelvic limb in calves. AB - This study aimed to describe a suitable acoustic window to facilitate access to the sciatic and femoral nerves in calves and to study the effects of their blockade with local anaesthetics. The neuroanatomical and ultrasound (US) study was performed on the cadavers of 10 calves, and the effects of 2% lidocaine with epinephrine (0.2 mL/kg) were determined in five healthy calves. The sciatic nerve in the cadavers was easily visualised as a hyperechoic band distal to the femoral greater trochanter and caudal to the femoral shaft. The femoral nerve in the cadavers was not easily identified, and was visualised as a hyperechoic oval structure situated immediately medial to the psoas major muscle and lateral to the femoral artery. The sciatic nerve was stained by methylene blue, injected under US guidance, in 9/10 cases, and the femoral nerve was stained in 6/10 cases. Sciatic nerve blockade under US guidance produced adduction of the limb with metatarsophalangeal joint flexion, while the femoral nerve blockade produced reduced weight bearing. The sciatic nerve blockade produced a reduced response to the noxious stimulus, mainly in the phalanges, proximal and distal metatarsus, tarsus and tibia and, following the femoral nerve blockade, in the medial subarea of the femur. However, femoral nerve blockade produced a more variable degree of blockade. In conclusion, US -guided anaesthetic blockade of the sciatic nerve in calves may be considered for surgery in the distal pelvic limb, although further studies are necessary to determine its clinical application. PMID- 24797106 TI - The role of osteonecrosis in canine coronoid dysplasia: arthroscopic and histopathological findings. AB - Coronoid dysplasia (CD) or medial coronoid disease is part of canine elbow dysplasia and eventually results in osteoarthrosis. Although CD was originally attributed to disturbed endochondral ossification, more recent data point to the subchondral bone. The objective of this study was to assess dysplastic bone and cartilage of dogs that underwent unilateral or bilateral arthroscopic subtotal coronoidectomy for the treatment of CD. Arthroscopic findings and histopathology of bone and cartilage removed from elbow joints with CD were compared. The most common arthroscopic finding was fragmentation with softening of the subchondral bone of the central part of the medial coronoid process. In dogs without obvious fragmentation, CD was characterised by bone softening and chondromalacia. During arthroscopic intervention dysplastic bone and cartilage were collected for histopathological assessment. Forty-five slices of formalin-fixed, paraffin embedded bone and cartilage samples were stained using haematoxylin and eosin and evaluated. Histopathological findings primarily consisted of osteonecrosis of subchondral bone with necrosis within the marrow spaces. Histopathological changes in the articular cartilage were characterised by fibrillation, chondrocyte clone formation, and focal cartilage necrosis. The pathology was found primarily in the subchondral bone and not in the articular cartilage. Vascular compromise may play a role in the pathogenesis of osteonecrosis in CD. PMID- 24797107 TI - Effects of stillbirth and dystocia on subsequent reproductive performance in Japanese Black cattle. AB - The objective of this study was to determine the effects of stillbirth and dystocia on subsequent reproductive performance in Japanese Black cattle. Data were collected for 34,763 calvings from 13,186 animals on 826 farms. Stillbirth was associated with a decreased first service conception rate compared to cows with a normal calving (44.4 versus 54.0%, respectively, P < 0.001). Cows with a normal calving required fewer artificial inseminations per conception and had a lower stillbirth rate at subsequent parity than those with stillbirth and dystocia (P < 0.001). Japanese Black cows with stillbirth and dystocia had inferior subsequent reproductive performance compared with those with a normal calving. PMID- 24797108 TI - Renal unit characteristics and patient education practices that predict a high prevalence of home-based dialysis in Australia. AB - AIM: The proportion of patients using home dialysis in Australia varies from 6% to 62% between renal units. The aim of this study was to determine if the variance is attributed to any underlying renal unit factors including pre-end stage education practices. METHODS: An online survey was distributed to all Australian units that offered home dialysis. Logistic regression was performed to estimate the effects of renal unit characteristics on the binary outcome of <30% versus >= 30% of patients using home dialysis, and for >= 10% of patients using home haemodialysis (HHD) dialysis specifically. Prevalent home dialysis rates were sourced from the Australia and New Zealand Dialysis and Transplant Association registry. RESULTS: 33 of 43 units (77%) completed the survey. Factors shown to predict >= 30% of patients using home dialysis were; a metropolitan based renal unit compared with a rural or remote unit (OR 1.08, 95% CI 1.01 1.15), a New South Wales unit compared with other states (OR 1.13, 95% CI 1.04 1.22), and a unit that offered multiple group education sessions per year (OR 1.01, 95% CI 1.01-1.02). A unit that offered >1 h of pre-end stage education per patient, compared with <= 1 h predicted more than 10% of patients on HHD (OR 2.84, 95% CI 1.17-6.90). CONCLUSION: Our data suggest certain pre-end stage education practices are significantly associated with home dialysis rates above the national average. The consistent above average home dialysis rates witnessed in New South Wales appear to be the result of renal unit culture, education strategies and policies that support 'home dialysis first'. PMID- 24797109 TI - Subcellular distribution patterns and elevated expression of GNA11 and GNA14 proteins in the lungs of humans with pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH), a progressive and devastating disease, is characterized by abnormal proliferation of pulmonary artery endothelial and smooth muscle cells. GTP-binding protein subunits, GNA11 and GNA14, transmembrane and intracellular signaling molecules, participate in the regulating endothelial function and vascular development. We followed the expression of GNA11 and GNA14 in human lungs in control and PAH patients using immunohistochemical and Western blot analyses. Both GNA11 and GNA14 were expressed in lung tissue, primarily in artery endothelial and smooth muscle cells. Expression was more pronounced in PAH lung tissues compared with controls. Using immunocytochemistry and laser scanning confocal microscopy, the subcellular distribution of GNA11 and GNA14 in human pulmonary arterial endothelial (HPAECs) and smooth muscle (HPASMCs) cells in culture was investigated. GNA11 was predominantly localized in the cytoplasm and nucleus of HPASMCs, but it was only found in the cytoplasm of HPAECs. On the other hand, GNA14 immunolocalized to the nucleus and cytoplasm of both HPAECs and HPASMCs. Based on bioinformatic analyses, nuclear localization signal and transmembrane topology confirm the different subcellular distributions of GNA11 and GNA14. The data suggest that GNA11 and GNA14 are related to PAH pathogenesis, and help further functional studies of these proteins in this severe disease. PMID- 24797110 TI - Imaging and 3D reconstruction of cerebrovascular structures in embryonic zebrafish. AB - Zebrafish are a powerful tool to study developmental biology and pathology in vivo. The small size and relative transparency of zebrafish embryos make them particularly useful for the visual examination of processes such as heart and vascular development. In several recent studies transgenic zebrafish that express EGFP in vascular endothelial cells were used to image and analyze complex vascular networks in the brain and retina, using confocal microscopy. Descriptions are provided to prepare, treat and image zebrafish embryos that express enhanced green fluorescent protein (EGFP), and then generate comprehensive 3D renderings of the cerebrovascular system. Protocols include the treatment of embryos, confocal imaging, and fixation protocols that preserve EGFP fluorescence. Further, useful tips on obtaining high-quality images of cerebrovascular structures, such as removal the eye without damaging nearby neural tissue are provided. Potential pitfalls with confocal imaging are discussed, along with the steps necessary to generate 3D reconstructions from confocal image stacks using freely available open source software. PMID- 24797111 TI - Introducing conformal prediction in predictive modeling. A transparent and flexible alternative to applicability domain determination. AB - Conformal prediction is introduced as an alternative approach to domain applicability estimation. The advantages of using conformal prediction are as follows: First, the approach is based on a consistent and well-defined mathematical framework. Second, the understanding of the confidence level concept in conformal predictions is straightforward, e.g. a confidence level of 0.8 means that the conformal predictor will commit, at most, 20% errors (i.e., true values outside the assigned prediction range). Third, the confidence level can be varied depending on the situation where the model is to be applied and the consequences of such changes are readily understandable, i.e. prediction ranges are increased or decreased, and the changes can immediately be inspected. We demonstrate the usefulness of conformal prediction by applying it to 10 publicly available data sets. PMID- 24797112 TI - College health as a partner in the care of pediatric cancer survivors. AB - OBJECTIVE: This study reviews an initiative to educate providers on pediatric cancer survivor care and to establish a cancer survivor registry in a college health center. PARTICIPANTS: PARTICIPANTS were University of Georgia (UGA) college health providers. METHODS: Providers attended lectures on survivor care and were encouraged to register on Cancer SurvivorLink. Changes in provider familiarity and practice were measured using baseline and follow-up surveys. A survivor registry was created using health entrance forms and medical records abstraction. RESULTS: Twenty-four providers registered on SurvivorLink, and 16 completed both surveys. Familiarity with survivor care (p = .003) and a survivor health care plan (p = .016) increased. Likelihood to deliver survivor care increased (p = .01). UGA follows 95 survivors; 71 diagnosed at < 21 years. Among survivors diagnosed at < 21 years, 91% reported their diagnosis on entrance forms. CONCLUSIONS: Through education and optimization of health informatics, college health centers can identify and provide survivor care to this medically vulnerable population. PMID- 24797113 TI - Percentiles for left ventricular rotation: comparison of reference values to paediatric patients with pacemaker-induced dyssynchrony. AB - AIM: Left ventricular rotation is an interesting mechanism to investigate patients with heart disease. In children, reference values have to be defined prior to assess pathology. METHODS AND RESULTS: One hundred and seventy-four healthy individuals (0-20 years) were investigated by two-dimensional speckle tracking echocardiography, percentiles were created addressing the amount and time-to-peak values (TTP) of rotational parameters normalized to percentage of cardiac cycle (cc). Patients with right ventricular (RV) pacemaker stimulation were integrated into percentiles describing their rotational delay. Feasibility was 87.4% in healthy individuals (8.5 +/- 6.2 years), 42 patients (13.0 +/- 6.6 years, mean RV-stimulation time: 6.1 +/- 4.3 years) were enrolled. Apical rotation (Rot(ap)) varied and was higher than basal rotation (Rot(bas)) throughout all ages. Peak torsion (Tor(max)) normalized to left ventricle (LV) length (Tor(maxi)) was elevated in early childhood and decreased until adulthood. TTP values revealed greater dispersion between apical and basal rotation at younger age and a decrease during maturation. Patients with RV pacing had decreased Tor(max) (10.0 +/- 6.0 vs. 13.7 +/- 6.6 degrees , P < 0.05), Rot(ap) (6.7 +/- 4.8 vs. 9.3 +/- 5.7 degrees , P < 0.05) and Rot(bas) (-3.3 +/- 2.6 vs. 4.5 +/- 2.7 degrees , P < 0.05). Patients with impaired ejection fraction (EF) had abnormal delays between Rot(ap) and Rot(bas). CONCLUSIONS: Percentile illustrations of LV rotation reveal a high amount and dispersion of Rot(ap) and Tor(maxi) in young children as well as a higher rotational delay compared with older ages. Abnormal delays in RV pacing are associated with reduced EF. PMID- 24797114 TI - Collateral from conus artery competing with the left internal mammary artery graft. PMID- 24797115 TI - NIRS-IVUS-guided implantation of pericardium-covered stents in a giant coronary aneurysm. PMID- 24797116 TI - Oesophageal dilatation due to gastric band detected by echocardiography: a 'chameleon tumour'. PMID- 24797117 TI - Amyloidosis-induced tricuspid stenosis mimicking rheumatic heart disease. PMID- 24797118 TI - Current status of haematopoietic autologous stem cell transplantation in lymphoid malignancies: a European perspective. AB - The use of autologous haematopoietic stem cell transplantation (ASCT) has increased considerably in lymphoid malignancies in the last decade, and it is now considered as the standard of care in particular circumstances. This review aims to present an overview of the current situation with ASCT in lymphoid malignancies in Europe, in terms of both current use and issues. It will also look briefly at ASCT in rarer haematological malignancies and at the future. It is intended as a reflection of opinion from selected centres in Europe and as an aid to understanding for those who are new to the area. The review is based on a series of four preceptorship meetings held in Europe in 2013. PMID- 24797119 TI - Education material for heart failure patients: what works and what does not? AB - Patient education is an important element of care, but evidence with regard to education material is not always apparent, as it is intertwined with educational strategies as components of heart failure management programs. Difficulties have arisen in determining the effectiveness of particular education strategies, as multiple strategies are commonly bundled together and packaged within research protocols. To further complicate this issue, the bundles are diverse, lack precision in describing their components, and report different outcomes. Despite these difficulties, clinicians can utilise a number of proven commonalities to deliver effective education: assessment of learning needs and style, verbal interaction with a healthcare professional, and a selection of multimedia patient education materials. PMID- 24797120 TI - Epidural labor analgesia is associated with a decreased risk of postpartum depression: a prospective cohort study. AB - BACKGROUND: Postpartum depression is a common psychiatric disorder in parturients after delivery. The etiology remains unclear, and multiple factors may be involved. In this study, we investigated whether epidural labor analgesia was associated with a decreased risk of postpartum depression development. METHODS: Two hundred fourteen parturients who were preparing for a vaginal delivery were enrolled in this prospective cohort study. Epidural labor analgesia was performed in 107 of 214 patients on their request. Parturients' mental status was assessed with the Edinburgh Postnatal Depression Scale at 3 days and 6 weeks after delivery. A score of 10 or higher on the scale at 6 weeks was used as an indication of postpartum depression. Parturients' characteristics together with perinatal variables were collected. Multivariate logistic regression analysis was performed to assess an association between the use of epidural analgesia and the occurrence of postpartum depression. RESULTS: Postpartum depression occurred in 14.0% (15 of 107) of parturients who received epidural labor analgesia and in 34.6% (37 of 107) of those who did not (P < 0.001). Use of epidural labor analgesia was associated with a decreased risk of postpartum depression (odds ratio [OR] 0.31, 95% confidence interval [CI], 0.12-0.82, P = 0.018). Attendance at childbirth classes during pregnancy (OR 0.30, 95% CI, 0.12-0.79, P = 0.015) and continued breast-feeding after delivery (OR 0.02, 95% CI, 0.00-0.07, P < 0.001) were also associated with decreased risks of postpartum depression. A high Edinburgh Postnatal Depression Scale score at 3 days postpartum was associated with an increased risk of postpartum depression (OR 1.20, 95% CI, 1.05-1.37, P = 0.009). CONCLUSIONS: Epidural labor analgesia was associated with a decreased risk of postpartum depression. Further study with a large sample size is needed to evaluate the impact of epidural analgesia on the occurrence of postpartum depression. PMID- 24797121 TI - Does anesthetic regimen influence implicit memory during general anesthesia? AB - BACKGROUND: Implicit learning of intraoperative auditory stimuli during general anesthesia is very difficult to quantify but may require the presence of noxious stimulation. We hypothesized that an anesthetic regimen with a low dose of opioid would enhance implicit memory, while a regimen with a high dose of opioid would not. METHODS: One hundred-twenty patients were randomized into 3 groups. All patients were anesthetized with a target-controlled infusion of propofol and remifentanil, targeting a Bispectral Index (BIS) value of 50. The remifentanil effect-site concentration (in ng/mL) was always double that of propofol (in MUg/mL) in the first group and half of that in the second group. Patients in these 2 groups were played a list of 20 words via headphones during surgery. The third group served as control for memory tests and was not played any word during anesthesia. BIS was recorded during word presentation. RESULTS: No statistical difference was found among the 3 groups regarding 3 different memory tests although 67.5% [50.7%; 80.9%] of the patients of the high-opioid group and 72.5% [55.9%; 84.9%] of the low-opioid group had at least 1 episode of BIS >60. CONCLUSIONS: We could not demonstrate the presence of implicit or explicit memorization under propofol-remifentanil anesthesia either with a low- or a high dose opioid anesthetic regimen. PMID- 24797122 TI - Clinical evaluation of a novel system for monitoring surgical hemoglobin loss. AB - BACKGROUND: Accurate measurement of intraoperative blood loss is an important clinical variable in managing fluid resuscitation and avoiding unnecessary transfusion of blood products. In this study, blood lost onto laparotomy sponges during surgical cases was measured using a tablet computer programmed with a unique algorithm modeled after facial recognition technology. In this study, we assessed the accuracy and performance of the system in surgical cases. METHODS: In this prospective, multicenter study, 46 patients undergoing surgery with anticipated significant blood loss contributed laparotomy sponges for hemoglobin (Hb) loss measurement using the Triton System with Feature Extraction Technology (Gauss Surgical, Inc., Los Altos, CA). The Hb loss measured by the new system was compared with that measured by manual rinsing of the sponges. Accuracy was evaluated using linear regression and Bland-Altman analysis. In addition, the new system's calculation of blood volume loss was compared with the gravimetric method of estimating blood loss from intraoperative sponge weights. RESULTS: A significant positive linear correlation was noted between the new system's measurements and the rinsed Hb mass (r = 0.93, P < 0.0001). Bland-Altman analysis revealed a bias of 9.0 g and narrow limits of agreement (-7.5 to 25.5 g) between the new system's measures and the rinsed Hb mass. These limits were within the clinically relevant difference of +/-30 g, which is approximately half of the Hb content of a unit of allogeneic whole blood. Bland-Altman analysis of the estimated blood loss on sponges using the gravimetric method demonstrated a bias of 466 mL (overestimation) with limits of agreement of -171 and 1103 mL, due to the presence of contaminants other than blood on the laparotomy sponges. CONCLUSIONS: The novel mobile monitoring system provides an accurate measurement of Hb mass on surgical sponges as compared with that of manual rinsing measurements and is significantly more accurate than the gravimetric method. Further study is warranted to assess the clinical use of the technology. PMID- 24797123 TI - Spinal cord stimulation reduces mechanical hyperalgesia and restores physical activity levels in animals with noninflammatory muscle pain in a frequency dependent manner. AB - BACKGROUND: Spinal cord stimulation (SCS) is an effective treatment for neuropathic pain, but its effect on chronic muscle pain is unclear. We designed this study to test the effect of SCS in an animal model of noninflammatory muscle pain. METHODS: Male Sprague-Dawley rats were implanted with an epidural SCS lead on the upper lumbar spinal cord (L3-L4) under isoflurane anesthesia (4%). Ten days after implantation, chronic muscle pain was induced by giving 2 injections of pH 4 saline into the left gastrocnemius muscle, 5 days apart. In experiment 1, SCS was delivered daily (6-hour duration/day) for 4 days at one of 4 different frequencies (0 (sham), 4, 60, and 100 Hz) from day 6 to day 9. Paw withdrawal threshold and muscle withdrawal threshold were measured before the first injection, and before and during SCS daily. Physical activity (distance, crossing, stand, and grooming) was assessed before the first injection, before SCS on day 6 and during SCS on day 9. In experiment 2, SCS was delivered (6 hours) on day 6 at either 60 or 100 Hz. Paw withdrawal threshold and muscle withdrawal threshold were assessed before the first injection, before and during SCS on day 6, and daily for the following 3 days (day 7-day 9). RESULTS: Paw withdrawal threshold and muscle withdrawal threshold significantly decreased bilaterally after the second injection of acidic saline. SCS delivered at 60 or 100 Hz significantly reversed the decreased paw withdrawal threshold and muscle withdrawal threshold bilaterally when compared with that of sham SCS, but 4 Hz SCS had no effect on paw withdrawal threshold and muscle withdrawal threshold. SCS (60 or 100 Hz) delivered daily provided a persistently reversed effect, and SCS delivered singly provided a carryover effect for 24 hours. During 60 Hz SCS, the distance traveled and the number of crossings increased significantly when compared with that of sham SCS. CONCLUSIONS: The current study shows that higher frequencies of SCS (60 and 100 Hz) significantly reduce mechanical hyperalgesia of the paw and muscle in an animal model of noninflammatory muscle pain, and 60 Hz SCS restores physical activity levels of animals, not 4 Hz. PMID- 24797124 TI - Biomarkers to decide red blood cell transfusion in newborn infants. AB - Almost 90% of extremely low birthweight infants receive red blood cell (RBC) transfusion during their stay in the neonatal unit (NNU). Currently most NNUs use a combination of clinical signs and laboratory findings such as hemoglobin (Hb), hematocrit (Hct), and cardiorespiratory or ventilation status to decide the need for RBC transfusion. Various other laboratory (lactate, reticulocyte count, RBC volume) and bedside measurements (near infrared spectroscopy and Doppler ultrasound scan) have been investigated to identify a suitable trigger for RBC transfusion in newborn infants. The evidence to apply any of these investigations or measurements to clinical practice is lacking. Further research is required to identify a suitable biomarker for RBC transfusion in newborn infants. PMID- 24797125 TI - Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. AB - Multiple sclerosis is a chronic neuroinflammatory demyelinating disorder of the central nervous system with a strong neurodegenerative component. While the exact etiology of the disease is yet unclear, autoreactive T lymphocytes are thought to play a central role in its pathophysiology. MS therapy is only partially effective so far and research efforts continue to expand our knowledge on the pathophysiology of the disease and to develop novel treatment strategies. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model for MS sharing many clinical and pathophysiological features. There is a broad diversity of EAE models which reflect different clinical, immunological and histological aspects of human MS. Actively-induced EAE in mice is the easiest inducible model with robust and replicable results. It is especially suited for investigating the effects of drugs or of particular genes by using transgenic mice challenged by autoimmune neuroinflammation. Therefore, mice are immunized with CNS homogenates or peptides of myelin proteins. Due to the low immunogenic potential of these peptides, strong adjuvants are used. EAE susceptibility and phenotype depends on the chosen antigen and rodent strain. C57BL/6 mice are the commonly used strain for transgenic mouse construction and respond among others to myelin oligodendrocyte glycoprotein (MOG). The immunogenic epitope MOG35-55 is suspended in complete Freund's adjuvant (CFA) prior to immunization and pertussis toxin is applied on the day of immunization and two days later. Mice develop a "classic" self-limited monophasic EAE with ascending flaccid paralysis within 9 14 days after immunization. Mice are evaluated daily using a clinical scoring system for 25-50 days. Special considerations for care taking of animals with EAE as well as potential applications and limitations of this model are discussed. PMID- 24797127 TI - Body mind therapy group for clients with severe borderline personality disorder. PMID- 24797129 TI - Editorial Comment from Dr Takahashi to Development and validation of a nomogram predicting recurrence risk in women with symptomatic urinary tract infection. PMID- 24797128 TI - Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases. AB - Transforming growth factor beta (TGF-beta) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFbeta-inhibitory molecules. We constructed a plasmid encoding a potent TGF-beta-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-beta. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-beta signaling in the liver and to enhance IL-12 -mediated IFN gamma production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-gamma and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rgamma-/- immunodeficient mice. This effect was associated with downregulation of TGF-beta target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-beta-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. PMID- 24797130 TI - Developmental changes in the skull morphology of common minke whales Balaenoptera acutorostrata. AB - We investigated growth-related and sex-related morphological changes in the skulls of 144 North Pacific common minke whales Balaenoptera acutorostrata. Measurement was conducted at 39 points on the skull and mandible to extract individual allometric equations relating the length and zygomatic width of the skull. The results revealed no significant differences in skull morphology by sex except for width of occipital bone. The size relative to the skull of the anatomical parts involved in feeding, such as the rostrum and mandible, increased after birth. In contrast, the sensory organs and the anatomical regions involved in neurological function, such as the orbit, tympanic bullae, and foramen magnum, were fully developed at birth, and their relative size reduced over the course of development. This is the first study to investigate developmental changes in the skull morphology using more than 100 baleen whale specimens, and we believe the results of this study will contribute greatly to multiple areas of baleen whale research, including taxonomy and paleontology. PMID- 24797131 TI - Reducing food losses by intelligent food logistics. AB - The need to feed an ever-increasing world population makes it obligatory to reduce the millions of tons of avoidable perishable waste along the food supply chain. A considerable share of these losses is caused by non-optimal cold chain processes and management. This Theme Issue focuses on technologies, models and applications to monitor changes in the product shelf life, defined as the time remaining until the quality of a food product drops below an acceptance limit, and to plan successive chain processes and logistics accordingly to uncover and prevent invisible or latent losses in product quality, especially following the first-expired-first-out strategy for optimized matching between the remaining shelf life and the expected transport duration. This introductory article summarizes the key findings of this Theme Issue, which brings together research study results from around the world to promote intelligent food logistics. The articles include three case studies on the cold chain for berries, bananas and meat and an overview of different post-harvest treatments. Further contributions focus on the required technical solutions, such as the wireless sensor and communication system for remote quality supervision, gas sensors to detect ethylene as an indicator of unwanted ripening and volatile components to indicate mould infections. The final section of this introduction discusses how improvements in food quality can be targeted by strategic changes in the food chain. PMID- 24797132 TI - Remote quality monitoring in the banana chain. AB - Quality problems occurring during or after sea transportation of bananas in refrigerated containers are mainly caused by insufficient cooling and non-optimal atmospheric conditions, but also by the heat generated by respiration activity. Tools to measure and evaluate these effects can largely help to reduce losses along the banana supply chain. The presented green life model provides a tool to predict the effect of deviating temperature, relative humidity, and CO2 and O2 gas concentrations on the storage stability of bananas. A second thermal model allows evaluation of the cooling efficiency, the effect of changes in packaging and stowage and the amount of respiration heat from the measured temperature curves. Spontaneous ripening causes higher respiration heat and CO2 production rate. The resulting risk for creation of hot spots increases in positions in which the respiration heat exceeds the available cooling capacity. In case studies on the transport of bananas from Costa Rica to Europe, we validated the models and showed how they can be applied to generate automated warning messages for containers with reduced banana green life or with temperature problems and also for remote monitoring of the ripening process inside the container. PMID- 24797133 TI - Communication techniques and challenges for wireless food quality monitoring. AB - Remote measurement of product core temperature is an important prerequisite to improve the cool chain of food products and reduce losses. This paper examines and shows possible solutions to technical challenges that still hinder practical applications of wireless sensor networks in the field of food transport supervision. The high signal attenuation by water-containing products limits the communication range to less than 0.5 m for the commonly used 2.4 GHz radio chips. By theoretical analysis of the dependency of signal attenuation on the operating frequency, we show that the signal attenuation can be largely reduced by the use of 433 MHz or 866 MHz devices, but forwarding of messages over multiple hops inside a sensor network is mostly unavoidable to guarantee full coverage of a packed container. Communication protocols have to provide compatibility with widely accepted standards for integration into the global Internet, which has been achieved by programming an implementation of the constrained application protocol for wireless sensor nodes and integrating into IPv6-based networks. The sensor's battery lifetime can be extended by optimizing communication protocols and by in-network pre-processing of the sensor data. The feasibility of remote freight supervision was demonstrated by our full-scale 'Intelligent Container' prototype. PMID- 24797134 TI - Shelf life modelling for first-expired-first-out warehouse management. AB - In the supply chain of perishable food products, large losses are incurred between farm and fork. Given the limited land resources and an ever-growing population, the food supply chain is faced with the challenge of increasing its handling efficiency and minimizing post-harvest food losses. Huge value can be added by optimizing warehouse management systems, taking into account the estimated remaining shelf life of the product, and matching it to the requirements of the subsequent part of the handling chain. This contribution focuses on how model approaches estimating quality changes and remaining shelf life can be combined in optimizing first-expired-first-out cold chain management strategies for perishable products. To this end, shelf-life-related performance indicators are used to introduce remaining shelf life and product quality in the cost function when optimizing the supply chain. A combinatorial exhaustive-search algorithm is shown to be feasible as the complexity of the optimization problem is sufficiently low for the size and properties of a typical commercial cold chain. The estimated shelf life distances for a particular batch can thus be taken as a guide to optimize logistics. PMID- 24797135 TI - Improvement in fresh fruit and vegetable logistics quality: berry logistics field studies. AB - Shelf life of fresh fruits and vegetables is greatly influenced by environmental conditions. Increasing temperature usually results in accelerated loss of quality and shelf-life reduction, which is not physically visible until too late in the supply chain to adjust logistics to match shelf life. A blackberry study showed that temperatures inside pallets varied significantly and 57% of the berries arriving at the packinghouse did not have enough remaining shelf life for the longest supply routes. Yet, the advanced shelf-life loss was not physically visible. Some of those pallets would be sent on longer supply routes than necessary, creating avoidable waste. Other studies showed that variable pre cooling at the centre of pallets resulted in physically invisible uneven shelf life. We have shown that using simple temperature measurements much waste can be avoided using 'first expiring first out'. Results from our studies showed that shelf-life prediction should not be based on a single quality factor as, depending on the temperature history, the quality attribute that limits shelf life may vary. Finally, methods to use air temperature to predict product temperature for highest shelf-life prediction accuracy in the absence of individual sensors for each monitored product have been developed. Our results show a significant reduction of up to 98% in the root-mean-square-error difference between the product temperature and air temperature when advanced estimation methods are used. PMID- 24797136 TI - Quality tracing in meat supply chains. AB - The aim of this study was the development of a quality tracing model for vacuum packed lamb that is applicable in different meat supply chains. Based on the development of relevant sensory parameters, the predictive model was developed by combining a linear primary model and the Arrhenius model as the secondary model. Then a process analysis was conducted to define general requirements for the implementation of the temperature-based model into a meat supply chain. The required hardware and software for continuous temperature monitoring were developed in order to use the model under practical conditions. Further on a decision support tool was elaborated in order to use the model as an effective tool in combination with the temperature monitoring equipment for the improvement of quality and storage management within the meat logistics network. Over the long term, this overall procedure will support the reduction of food waste and will improve the resources efficiency of food production. PMID- 24797137 TI - Postharvest treatments of fresh produce. AB - Postharvest technologies have allowed horticultural industries to meet the global demands of local and large-scale production and intercontinental distribution of fresh produce that have high nutritional and sensory quality. Harvested products are metabolically active, undergoing ripening and senescence processes that must be controlled to prolong postharvest quality. Inadequate management of these processes can result in major losses in nutritional and quality attributes, outbreaks of foodborne pathogens and financial loss for all players along the supply chain, from growers to consumers. Optimal postharvest treatments for fresh produce seek to slow down physiological processes of senescence and maturation, reduce/inhibit development of physiological disorders and minimize the risk of microbial growth and contamination. In addition to basic postharvest technologies of temperature management, an array of others have been developed including various physical (heat, irradiation and edible coatings), chemical (antimicrobials, antioxidants and anti-browning) and gaseous treatments. This article examines the current status on postharvest treatments of fresh produce and emerging technologies, such as plasma and ozone, that can be used to maintain quality, reduce losses and waste of fresh produce. It also highlights further research needed to increase our understanding of the dynamic response of fresh produce to various postharvest treatments. PMID- 24797138 TI - Ethylene detection in fruit supply chains. AB - Ethylene is a gaseous ripening phytohormone of fruits and plants. Presently, ethylene is primarily measured with stationary equipment in laboratories. Applying in situ measurement at the point of natural ethylene generation has been hampered by the lack of portable units designed to detect ethylene at necessary resolutions of a few parts per billion. Moreover, high humidity inside controlled atmosphere stores or containers complicates the realization of gas sensing systems that are sufficiently sensitive, reliable, robust and cost efficient. In particular, three measurement principles have shown promising potential for fruit supply chains and were used to develop independent mobile devices: non-dispersive infrared spectroscopy, miniaturized gas chromatography and electrochemical measurement. In this paper, the measurement systems for ethylene are compared with regard to the needs in fruit logistics; i.e. sensitivity, selectivity, long term stability, facilitation of automated measurement and suitability for mobile application. Resolutions of 20-10 ppb can be achieved in mobile applications with state-of-the-art equipment, operating with the three methods described in the following. The prices of these systems are in a range below ?10 000. PMID- 24797139 TI - Two underestimated threats in food transportation: mould and acceleration. AB - Two important parameters are often neglected in the monitoring of perishable goods during transport: mould contamination of fresh food and the influence of acceleration or vibration on the quality of a product. We assert the claim that it is necessary to focus research on these two topics in the context of intelligent logistics in this opinion paper. Further, the technical possibilities for future measurement systems are discussed. By measuring taste deviations, we verified the effect on the quality of beer at different vibration frequencies. The practical importance is shown by examining transport routes and market shares. The general feasibility of a mobile mould detection system is established by examining the measurement resolution of semiconductor sensors for mould related gases. Furthermore, as an alternative solution, we present a concept for a miniaturized and automated culture-medium-based system. Although there is a lack of related research to date, new efforts can make a vital contribution to the reduction of losses in the logistic chains for several products. PMID- 24797140 TI - Radio frequency identification enabled wireless sensing for intelligent food logistics. AB - Future technologies and applications for the Internet of Things (IoT) will evolve the process of the food supply chain and create added value of business. Radio frequency identifications (RFIDs) and wireless sensor networks (WSNs) have been considered as the key technological enablers. Intelligent tags, powered by autonomous energy, are attached on objects, networked by short-range wireless links, allowing the physical parameters such as temperatures and humidities as well as the location information to seamlessly integrate with the enterprise information system over the Internet. In this paper, challenges, considerations and design examples are reviewed from system, implementation and application perspectives, particularly with focus on intelligent packaging and logistics for the fresh food tracking and monitoring service. An IoT platform with a two-layer network architecture is introduced consisting of an asymmetric tag-reader link (RFID layer) and an ad-hoc link between readers (WSN layer), which are further connected to the Internet via cellular or Wi-Fi. Then, we provide insights into the enabling technology of RFID with sensing capabilities. Passive, semi-passive and active RFID solutions are discussed. In particular, we describe ultra wideband radio RFID which has been considered as one of the most promising techniques for ultra-low-power and low-cost wireless sensing. Finally, an example is provided in the form of an application in fresh food tracking services and corresponding field testing results. PMID- 24797141 TI - Development and evaluation of a DAS-ELISA for rapid detection of Tembusu virus using monoclonal antibodies against the envelope protein. AB - Since April 2010, Tembusu virus (TMUV) which is a contagious pathogen of waterfowls, causing symptoms of high fever, loss of appetite and fall in egg production, has been reported in east of China. A double antibody sandwich enzyme linked immunosorbent assay (DAS-ELISA) which detects for TMUV was developed, using two monoclonal antibodies (mAbs) against the TMUV envelope (E) protein. BALB/c mice were immunized with purified recombinant E protein expressed in E. coli. Three hybridoma cell lines designated as 12B1, 10C6 and 2D2, were screened by cell fusion and indirect ELISA for their ability to recognize different linear epitopes on the E protein, and were characterized subsequently. High-affinity mAbs 12B1 and 2D2 were used as capture and detection antibodies, respectively. The reaction conditions for the DAS-ELISA were optimized for TMUV detection. The cross-reactivity of the DAS-ELISA was determined using TMUV, duck plague virus, avian influenza virus subtype H9, Newcastle disease virus, duck hepatitis A virus type 1 and duck reovirus samples. A total of 191 homogenized tissues of field samples were simultaneously detected by DAS-ELISA and by RT-PCR. The former was found to have a high specificity of 99.1% and a sensitivity of 93.1%. These results reveal a positive coincidence between DAS-ELISA and RT-PCR at a coincidence rate of 95.8%. The method developed in this study can be used for the diagnosis of TMUV infection of duck origin. PMID- 24797142 TI - [SAPHO syndrome]. AB - SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare entity characterized by the association of heterogeneous osteoarticular and cutaneous manifestations that have for common denominator an aseptic inflammatory process. The etiopathogeny of this disease is still a matter of debate. Although it has been related to the spondylarthritis family, an infectious origin is suggested. Diagnosis is based on the presence of at least one of the three diagnostic criteria proposed by Kahn. The treatment includes NSAIDs, antibiotics, corticosteroids, methotrexate and more recently the bisphosphonates and the TNFalpha inhibitors. PMID- 24797143 TI - A first step toward the development of a barley NAM population and its utilization to detect QTLs conferring leaf rust seedling resistance. AB - KEY MESSAGE: We suggest multi-parental nested association mapping as a valuable innovation in barley genetics, which increases the power to map quantitative trait loci and assists in extending genetic diversity of the elite barley gene pool. Plant genetic resources are a key asset to further improve crop species. The nested association mapping (NAM) approach was introduced to identify favorable genes in multi-parental populations. Here, we report toward the development of the first explorative barley NAM population and demonstrate its usefulness in a study on mapping quantitative trait loci (QTLs) for leaf rust resistance. The NAM population HEB-5 was developed from crossing and backcrossing five exotic barley donors with the elite barley cultivar 'Barke,' resulting in 295 NAM lines in generation BC1S1. HEB-5 was genetically characterized with 1,536 barley SNPs. Across HEB-5 and within the NAM families, no deviation from the expected genotype and allele frequencies was detected. Genetic similarity between 'Barke' and the NAM families ranged from 78.6 to 83.1 %, confirming the backcrossing step during population development. To explore its usefulness, a screen for leaf rust (Puccinia hordei) seedling resistance was conducted. Resistance QTLs were mapped to six barley chromosomes, applying a mixed model genome-wide association study. In total, four leaf rust QTLs were detected across HEB-5 and four QTLs within family HEB-F23. Favorable exotic QTL alleles reduced leaf rust symptoms on two chromosomes by 33.3 and 36.2 %, respectively. The located QTLs may represent new resistance loci or correspond to new alleles of known resistance genes. We conclude that the exploratory population HEB-5 can be applied to mapping and utilizing exotic QTL alleles of agronomic importance. The NAM concept will foster the evaluation of the genetic diversity, which is present in our primary barley gene pool. PMID- 24797144 TI - Urine sample preparation in 96-well filter plates for quantitative clinical proteomics. AB - Urine is an important, noninvasively collected body fluid source for the diagnosis and prognosis of human diseases. Liquid chromatography mass spectrometry (LC-MS) based shotgun proteomics has evolved as a sensitive and informative technique to discover candidate disease biomarkers from urine specimens. Filter-aided sample preparation (FASP) generates peptide samples from protein mixtures of cell lysate or body fluid origin. Here, we describe a FASP method adapted to 96-well filter plates, named 96FASP. Soluble urine concentrates containing ~10 MUg of total protein were processed by 96FASP and LC-MS resulting in 700-900 protein identifications at a 1% false discovery rate (FDR). The experimental repeatability, as assessed by label-free quantification and Pearson correlation analysis for shared proteins among replicates, was high (R >= 0.97). Application to urinary pellet lysates which is of particular interest in the context of urinary tract infection analysis was also demonstrated. On average, 1700 proteins (+/-398) were identified in five experiments. In a pilot study using 96FASP for analysis of eight soluble urine samples, we demonstrated that protein profiles of technical replicates invariably clustered; the protein profiles for distinct urine donors were very different from each other. Robust, highly parallel methods to generate peptide mixtures from urine and other body fluids are critical to increase cost-effectiveness in clinical proteomics projects. This 96FASP method has potential to become a gold standard for high throughput quantitative clinical proteomics. PMID- 24797145 TI - Time to transplantation as a predictor of hepatocellular carcinoma recurrence after liver transplantation. AB - In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC); it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non-HCC-related death, or last follow-up. The cumulative incidence of HCC recurrence was compared for patients waiting <= 120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%-3.8%] and 5.6% (95% CI = 5.0%-6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting <= 120 days (2.2% versus 3.9%, P = 0.002); however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the institution of a mandatory waiting time after an exception is granted. PMID- 24797146 TI - Neuronal expression of the intermediate conductance calcium-activated potassium channel KCa3.1 in the mammalian central nervous system. AB - The expression pattern and functional roles for calcium-activated potassium channels of the KCa2.x family and KCa1.1 have been extensively examined in central neurons. Recent work indicates that intermediate conductance calcium activated potassium channels (KCa3.1) are also expressed in central neurons of the cerebellum and spinal cord. The current study used immunocytochemistry and GFP linked to KCNN4 promoter activity in a transgenic mouse to determine the expression pattern of KCa3.1 channels in rat or mouse neocortex, hippocampus, thalamus, and cerebellum. KCa3.1 immunolabel and GFP expression were closely matched and detected in both excitatory and inhibitory cells of all regions examined. KCa3.1 immunolabel was localized primarily to the somatic region of excitatory cells in cortical structures but at the soma and over longer segments of dendrites of cells in deep cerebellar nuclei. More extensive labeling was apparent for inhibitory cells at the somatic and dendritic level with no detectable label associated with axon tracts or regions of intense synaptic innervation. The data indicate that KCa3.1 channels are expressed in the CNS with a differential pattern of distribution between cells, suggesting important functional roles for these calcium-activated potassium channels in regulating the excitability of central neurons. PMID- 24797149 TI - Particle segregation in a sedimenting bidisperse soft sphere system. AB - We study the sedimentation process of a binary colloidal soft sphere system where significant overlaps of the particles are possible. We employ estimates of the equation of states in the small and large pressure limit in order to predict the final states of the sedimentation process. Furthermore, Brownian dynamics simulations were performed in order to confirm the predictions and to explore the dynamics of the sedimentation. We observe that the segregation process due to gravity usually consists of multiple steps. Instead of single particles moving upwards or downwards we usually observe that first local segregation occurs, then clusters consisting of particles of one species are formed that finally sink towards their equilibrium position within the final sedimentation profile. The possible final states include complex phases like a phase consisting of large particles on the top and the bottom of the system with small particles in between. We also observe metastable network-like structures. PMID- 24797148 TI - Minimally invasive valve surgery. AB - Cardiac valve surgery is life saving for many patients. The advent of minimally invasive surgical techniques has historically allowed for improvement in both postoperative convalescence and important clinical outcomes. The development of minimally invasive cardiac valve repair and replacement surgery over the past decade is poised to revolutionize the care of cardiac valve patients. Here, we present a review of the history and current trends in minimally invasive aortic and mitral valve repair and replacement, including the development of sutureless bioprosthetic valves. PMID- 24797150 TI - Twin pregnancy among women with pregestational type 1 or type 2 diabetes mellitus. AB - OBJECTIVE: To assess the impact of twin versus singleton pregnancy on obstetric and perinatal outcomes among women with pregestational diabetes mellitus (DM). METHODS: Multicenter retrospective cohort study of women with pregestational DM and twin or singleton pregnancy, conducted in Spain during 2005-2010. Each group included 63 women (type 1 DM, n=39; type 2 DM, n=24). RESULTS: Of 269 565 deliveries, 68 (0.025%) were twins of mothers with pregestational DM, with 28/63 (44.4%) conceptions achieved with assisted reproduction technology. Among women with type 1 DM, hypertensive complications were more common among those with twins than among controls (13% versus 3%, P=0.02); the rate of preterm birth was higher (69% versus 15%, P<0.001); and the rate of admission to the neonatal intensive care unit was higher (51% versus 21%, P=0.005). Twin pregnancy was an independent risk factor for adverse perinatal outcomes regardless of the type of diabetes. CONCLUSION: Twin pregnancy in women with either type of DM dramatically increased the risk of perinatal morbidity. In mothers with type 1 DM, twin pregnancy was more often associated with hypertensive complications than singleton pregnancy. Transfer of more than one embryo should be avoided if ART is needed in a woman with DM. PMID- 24797147 TI - Current understanding of sarcopenia: possible candidates modulating muscle mass. AB - The world's elderly population is expanding rapidly, and we are now faced with the significant challenge of maintaining or improving physical activity, independence, and quality of life in the elderly. Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Muscle loss has been linked with several proteolytic systems, including the ubuiquitin-proteasome, lysosome-autophagy, and tumor necrosis factor (TNF)-alpha/nuclear factor-kappaB (NF-kappaB) systems. Although many factors are considered to regulate age-dependent muscle loss, this gentle atrophy is not affected by factors known to enhance rapid atrophy (denervation, hindlimb suspension, etc.). In addition, defects in Akt-mammalian target of rapamycin (mTOR) and serum response factor (SRF)-dependent signaling have been found in sarcopenic muscle. Intriguingly, more recent studies indicated an apparent functional defect in autophagy- and myostatin-dependent signaling in sarcopenic muscle. In this review, we summarize the current understanding of the adaptation of many regulators in sarcopenia. PMID- 24797151 TI - The venom apparatus in stenogastrine wasps: subcellular features of the convoluted gland. AB - In the wasp venom apparatus, the convoluted gland is the tract of the thin secretory unit, i.e. filament, contained in the muscular reservoir. Previous transmission electron microscope investigation on Stenogastrinae disclosed that the free filaments consist of distal and proximal tracts, from/to the venom reservoir, characterized by class 3 and 2 gland patterns, respectively. This study aims to extend the ultrastructural analysis to the convoluted tract, in order to provide a thorough, subcellular representation of the venom gland in these Asian wasps. Our findings showed that the convoluted gland is a continuation of the proximal tract, with secretory cells provided with a peculiar apical invagination, the extracellular cavity, collecting their products. This compartment holds a simple end-apparatus lined by large and ramified microvilli that contribute to the processing of the secretory product. A comparison between previous and present findings reveals a noticeable regionalization of the stenogastrine venom filaments and suggests that the secretory product acquires its ultimate composition in the convoluted tract. PMID- 24797152 TI - Breath-holding spell and macrocytic anaemia in a toddler. PMID- 24797153 TI - Comparison of two methods of assessing total body water at sea level and increasing high altitude. AB - Fluid retention is a recognized feature of acute mountain sickness. However, accurate assessment of hydration, including the quantification of body water, has traditionally relied on expensive and non-portable equipment limiting its utility in the field setting. We compared the assessment of total body water (TBW) and their relationship to total body weight using two non-invasive methods using the NICas single-frequency bioimpedance analysis (SF-BIA) system and the BodyStat QuadScan 4000 multifrequency BIA system (MF-BIA). TBW measurements were performed at rest at sea level and at high altitude (HA) at 3833 m postexercise and at rest and thereafter at rest at 4450 m and 5129 m on 47 subjects. The average age was 34.5 +/- 9.3 years with an age range of 21-54 years (70.2% male). There were strong correlations between TBW assessment with both methods at sea level (r = 0.90; 95% CI 0.78-0.95: P<0.0001) and at HA (r = 0.92; 0.89-0.94: P<0.0001), however, TBW readings were 0.2 l and 1.91 l lower, respectively, with the NICaS. There was a stronger correlation between TBW and body weight with the QuadScan (r = 0.91; P<0.0001) than with the NICaS (r = 0.83; P<0.0001). The overall agreement between the two TBW methods was good, but the 95% confidence intervals around these agreements were relatively wide. We conclude that there was reasonable agreement between the two methods of BIA for TBW, but this agreement was lower at HA. PMID- 24797154 TI - Rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient: report of the first transplant case and review of the literature. AB - Rhodococcus species are environmental organisms that predominantly cause opportunistic infections in immunocompromised hosts. Rhodococcus equi is the most common species associated with human infections, but there are uncommon but increasing number of cases of infections caused by non-equi Rhodococcus species. We report a case of Rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient, who presented with subacute systemic illness accompanied by severe hepatitis. In the context of this case, we review the literature on Rhodococcus species infections in transplant recipients. PMID- 24797155 TI - Pilot Study of Waterpipe Tobacco Smoking Among US Muslim College Students. AB - Waterpipe smoking is common among the young in Muslim-majority countries despite recent Islamic rulings on tobacco. US Muslim college students, especially immigrants, may be at high risk for smoking, but information is lacking. In this pilot study, respondent-driven sampling was used to sample 156 Muslim college students. Waterpipe smoking was common (44.3%). Leading motivations to smoke were social and perceived low tobacco harm. Independent risk factors among the Muslim students were perception that friends and other students smoked, and ever drank alcohol. Personal belief that waterpipe smoking is prohibited in Islam was not significant. This pilot suggests that Muslim students are at high risk for waterpipe smoking and more definitive studies are needed. PMID- 24797156 TI - Spiritual Well-Being for Increasing Life Expectancy in Palliative Radiotherapy Patients: A Questionnaire-Based Study. AB - Spiritual well-being in patients with an advanced cancer has been found to positively correlate with subjective well-being, lower pain levels, hope and positive mood states, high self-esteem, social competence, purpose in life, and overall quality of life. In this regard, Quran recitation is stated to be an efficient way to increase patient spirituality and also to handle life's everyday challenges. The aim of this study was to investigate the effects of listening, reading, and watching the text of the Holy Quran, called (in this study) Quran recitation, for increasing life expectancy (LE) in palliative radiotherapy patients admitted to Radiotherapy Department of Seyed alshohada Hospital, Isfahan, Iran. A questionnaire-based study was carried out on a total of 89 palliative radiotherapy patients between March 2012 and June 2012. Informed consent was obtained. The patients were requested to complete a standardized questionnaire which was designed based on the European Organization for Research and Treatment of Cancer C30 Scale Quality of Life Questionnaire (EORTC C30 Scale QLQ). A computer program (SPSS version 16.0, Chicago, IL, USA) was used, and data were analyzed by the Wilcoxon test and Spearman's rank correlation. All hypotheses were tested using a criterion level of P = 0.05. There was a significant difference for frequency and duration of Quran recitation among patients, before and after the diagnosis of their cancer (P = 0.03). Using the Spearman's rank correlation, it was found that there was a correlation between Quran recitation and subjective well-being (r = 0.352, P < 0.001). Moreover, there was a correlation between Quran recitation and increasing LE (r = 0.311, P < 0.003). More than 60% of the patients stated that more frequent recitation would lead to more LE and/or greater reassurance. On the basis of the present work, listening, reading, and watching the text of the Holy Quran are useful for increasing LE in palliative radiotherapy patients admitted to Radiotherapy Department. In other words, a benefit of Quran recitation on outcome of radiotherapy for palliative radiotherapy patients was found. PMID- 24797157 TI - Defining phenotypes in asthma: a step towards personalized medicine. AB - Asthma is a common disease with a complex pathophysiology. It can present in various clinical forms and with different levels of severity. Unbiased cluster analytic methods have unravelled several phenotypes in cohorts representative of the whole spectrum of severity. Clusters of severe asthma include those on high dose corticosteroid treatment, often with both inhaled and oral treatment, usually associated with severe airflow obstruction. Phenotypes with concordance between symptoms and sputum eosinophilia have been reported, including an eosinophilic inflammation-predominant group with few symptoms and late-onset disease who have a high prevalence of rhinosinusitis, aspirin sensitivity, and exacerbations. Sputum eosinophilia is also a biomarker that can predict therapeutic responses to antibody-based treatments to block the effects of the T helper (Th)-2 cytokine, interleukin (IL)-5. Low Th2-expression has been predictive of poor therapeutic response to inhaled corticosteroid therapy. Current asthma schedules emphasise a step-up approach to treating asthma in relation to increasing severity, but, in more severe disease, phenotyping or endotyping of asthma will be necessary to determine new treatment strategies as severe asthma is recognized as being a particularly heterogeneous disease. Much less is known about 'non-eosinophilic' asthma. Phenotypic characterisation of corticosteroid insensitivity and chronic airflow obstruction of severe asthma is also needed. Phenotype-driven treatment of asthma will be further boosted by the advent of transcriptomic and proteomic technologies, with the application of systems biology or medicine approaches to defining phenotypes and biomarkers of disease and therapeutic response. This will pave the way towards personalized medicine and healthcare for asthma. PMID- 24797158 TI - Management of asthma and chronic obstructive pulmonary disease with combination inhaled corticosteroids and long-acting beta-agonists: a review of comparative effectiveness research. AB - The value of combination therapy with inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) is well recognized in the management of asthma and chronic obstructive pulmonary disease (COPD). Despite differences in the pharmacological properties between two well-established ICS/LABA products (budesonide/formoterol and fluticasone/salmeterol), data from randomized clinical trials (RCTs) and meta-analyses suggest that these two products perform similarly under RCT conditions. In contrast, a few recently reported real-world comparative effectiveness studies have suggested that there are substantial differences between ICS/LABA combination treatments in terms of clinical and healthcare outcomes in patients with asthma or COPD. The purpose of this article is to provide a brief review of the benefits, as well as the limitations, of comparative effectiveness research (CER) in the therapeutic area of asthma and COPD. We conducted a structured literature review of the current CER studies on ICS/LABA combinations in asthma and COPD. These articles were then used to illustrate the unique challenges of CER studies, providing a summary of study results and limitations. We focus particularly on difficult biases and confounding factors that may be introduced before, during, and after the initiation of therapy. Beyond being a review of these two ICS/LABA combination treatments, this article is intended to help those who wish to assess the quality of CER published projects in asthma and COPD, or guide investigators who wish to design new CER studies for chronic respiratory disease treatments. PMID- 24797159 TI - Apremilast: first global approval. AB - Apremilast (Otezla((r))), an oral small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4), is under development with Celgene Corporation for the treatment of psoriatic arthritis, psoriasis, ankylosing spondylitis, Behcet's syndrome, atopic dermatitis, and rheumatoid arthritis. Apremilast is indicated for the treatment of active psoriatic arthritis in adults. Apremilast has received its first global approval for this indication in the USA. Regulatory submissions for approval in this indication are under review in Canada and Europe. Regulatory filings have also been submitted for apremilast in the treatment of plaque psoriasis in the USA and Europe. This article summarizes the milestones in the development of apremilast leading to its first approval for the treatment of psoriatic arthritis. PMID- 24797160 TI - The activating receptor NKG2D of natural killer cells promotes resistance against enterovirus-mediated inflammatory cardiomyopathy. AB - In enterovirus-induced cardiomyopathy, information regarding the detailed impact of natural killer (NK) cells on the outcome of the disease is limited. We therefore hypothesized that NK cells and certain NK cell receptors determine the different outcome of coxsackievirus B3 (CVB3) myocarditis. Here, we demonstrate in murine models that resistance to chronic CVB3 myocarditis in immunocompetent C57BL/6 mice is characterized by significantly more mature CD11b(high) NK cells, the presence of NKG2D on NK cells, and enhanced NKG2D-dependent cytotoxicity compared to CVB3-susceptible A.BY/SnJ mice. The highly protective role of NKG2D in myocarditis was further proven by in vivo neutralization of NKG2D as well as in NKG2D-deficient mice but was shown to be independent of CD8(+) T-cell dependent immunity. Moreover, the adoptive transfer of immunocompetent C57BL/6 NK cells pre- (day -1) as well as post-infectionem (day +2) displayed the potential to prevent permissive A.BY/SnJ mice from a progressive outcome of CVB3 myocarditis reflected by significantly improved cardiopathology and heart function. Altogether, our results provide firm evidence for a protective role of NKG2D-activated NK cells in CVB3 myocarditis leading to an effective virus clearance, thus offering novel therapeutic options in the treatment of virus induced myocarditis. PMID- 24797161 TI - The natural history of weight percentile changes in the first year of life. PMID- 24797162 TI - Electrically induced torque decrease reflects more than muscle fatigue. AB - The aim of the study was to compare the fatigue induced by different electrical stimulation (ES) protocols. The triceps surae muscle of 8 healthy subjects was fatigued with 4 protocols (30 Hz-500 MUs, 30 Hz-1 ms, 100 Hz-1 ms, and 100 Hz-500 MUs), composed of 60 trains (4 s on-6 s off), delivered at an intensity evoking 30% of maximal voluntary contraction (MVC). Fatigue was quantified by ES and MVC torque decreases. The amplitude of the twitch delivered at the intensity and pulse width used in each fatiguing protocol (twitch at Istim ) was analyzed. All parameters decreased significantly after all protocols. The ES torque decrease correlated positively with the twitch decrease elicited at Istim only for the 30 Hz protocols. Results show that, during the 100-Hz protocols, phenomena not related to the fatigue of the solicited motor units may occur, including changes in the excitability threshold of the axonal terminal branches. PMID- 24797163 TI - Lipid modulatory activities of Cichorium glandulosum Boiss et Huet are mediated by multiple components within hepatocytes. AB - To investigate a possible methodology of exploiting herbal medicine and design polytherapy for the treatment of non-alcoholic fatty liver disease (NAFLD), we have made use of Cichorium glandulosum Boiss et Huet (CG), a traditional Chinese herbal medicine that has been proven to be effective in treating hepatic diseases. Here, we report that the extract of CG effectively reduced lipid accumulation under conditions of lipid overloading in vivo and in vitro (in a rat high-fat diet model and a hepG2 cell model of free fatty acid treatment). CG extract also protected hepatocytes from injury and inflammation to aid its lipid lowering properties (in a rat high-fat diet model and a L02 cell model of acetaminophen treatment). Serum chemistry analysis accompanied by in vitro drug screening confirmed that CG-4, CG-10 and CG-14 are the lipo-effective components of CG. Western blotting analysis revealed that these components can regulate key lipid targets at the molecular level, including CD36, FATP5 and PPAR-alpha, thus the lipid oxidation and lipid absorption pathways. Finally, we adopted the experimental design and statistical method to calculate the best combination proportion (CG-4: CG-10: CG-14 = 2.065: 1.782: 2.153) to optimize its therapeutic effect. PMID- 24797164 TI - SNP discovery in wild and domesticated populations of blue catfish, Ictalurus furcatus, using genotyping-by-sequencing and subsequent SNP validation. AB - Blue catfish, Ictalurus furcatus, are valued in the United States as a trophy fishery for their capacity to reach large sizes, sometimes exceeding 45 kg. Additionally, blue catfish * channel catfish (I. punctatus) hybrid food fish production has recently increased the demand for blue catfish broodstock. However, there has been little study of the genetic impacts and interaction of farmed, introduced and stocked populations of blue catfish. We utilized genotyping-by-sequencing (GBS) to capture and genotype SNP markers on 190 individuals from five wild and domesticated populations (Mississippi River, Missouri, D&B, Rio Grande and Texas). Stringent filtering of SNP-calling parameters resulted in 4275 SNP loci represented across all five populations. Population genetics and structure analyses revealed potential shared ancestry and admixture between populations. We utilized the Sequenom MassARRAY to validate two multiplex panels of SNPs selected from the GBS data. Selection criteria included SNPs shared between populations, SNPs specific to populations, number of reads per individual and number of individuals genotyped by GBS. Putative SNPs were validated in the discovery population and in two additional populations not used in the GBS analysis. A total of 64 SNPs were genotyped successfully in 191 individuals from nine populations. Our results should guide the development of highly informative, flexible genotyping multiplexes for blue catfish from the larger GBS SNP set as well as provide an example of a rapid, low-cost approach to generate and genotype informative marker loci in aquatic species with minimal previous genetic information. PMID- 24797165 TI - Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose. AB - Male C57BL/6J mice treated with D-galactose (DG) were used to examine the effects of ergothioneine (EGT), melatonin (MEL), or their combination (EGT+MEL) on learning and memory abilities. The mice were divided into five groups and injected subcutaneously with DG (0.3 mL of 1% DG/mouse) except for group 1 (normal controls). Group 3 was orally supplemented with EGT [0.5 mg/kg body weight (bw)], group 4 with MEL (10 mg/kg bw, p.o.), and group 5 with EGT+MEL. EGT and MEL were provided daily for 88 days, while DG was provided between days 7 to 56. Active avoidance task and Morris water-maze task were used to evaluate learning and memory abilities. DG treatment markedly increased escape latency and decreased the number of avoidance in the active avoidance test, whereas EGT and MEL alone significantly improved the performance. DG also impaired the learning and memory abilities in the water-maze task, and EGT and MEL alone also significantly improved the performance. EGT+MEL produced the strongest effects in both tasks. EGT and MEL alone markedly decreased beta-amyloid protein accumulation in the hippocampus and significantly inhibited lipid peroxidation and maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of DG-treated mice. MEL alone completely prevented the rise in brain acetylcholine esterase activity induced by DG, whereas EGT and EGT+MEL were only partially effective. Overall, EGT, MEL, and, in particular, the combination of EGT and MEL effectively protect against learning and memory deficits in C57BL/6J mice treated with DG, possibly through attenuation of oxidative damage. PMID- 24797166 TI - Dioecy is associated with higher diversification rates in flowering plants. AB - In angiosperms, dioecious clades tend to have fewer species than their nondioecious sister clades. This departure from the expected equal species richness in the standard sister clade test has been interpreted as implying that dioecious clades diversify less and has initiated a series of studies suggesting that dioecy might be an 'evolutionary dead end'. However, two of us recently showed that the 'equal species richness' null hypothesis is not valid in the case of derived char acters, such as dioecy, and proposed a new test for sister clade comparisons; preliminary results, using a data set available in the litterature, indicated that dioecious clades migth diversify more than expected. However, it is crucial for this new test to distinguish between ancestral and derived cases of dioecy, a criterion that was not taken into account in the available data set. Here, we present a new data set that was obtained by searching the phylogenetic literature on more than 600 completely dioecious angiosperm genera and identifying 115 sister clade pairs for which dioecy is likely to be derived (including > 50% of the dioecious species). Applying the new sister clade test to this new dataset, we confirm the preliminary result that dioecy is associated with an increased diversification rate, a result that does not support the idea that dioecy is an evolutionary dead end in angiosperms. The traits usually associated with dioecy, that is, an arborescent growth form, abiotic pollination, fleshy fruits or a tropical distribution, do not influence the diversification rate. Rather than a low diversification rate, the observed species richness patterns of dioecious clades seem to be better explained by a low transition rate to dioecy and frequent losses. PMID- 24797167 TI - Use of a novel high-resolution magnetic resonance neurography protocol to detect abnormal dorsal root Ganglia in Sjogren patients with neuropathic pain: case series of 10 patients and review of the literature. AB - The diagnosis and treatment of patients with Sjogren syndrome (SS) with neuropathic pain pose several challenges. Patients with SS may experience unorthodox patterns of burning pain not conforming to a traditional "stocking-and glove" distribution, which can affect the face, torso, and proximal extremities. This distribution of neuropathic pain may reflect mechanisms targeting the proximal-most element of the peripheral nervous system-the dorsal root ganglia (DRG). Skin biopsy can diagnose such a small-fiber neuropathy and is a surrogate marker of DRG neuronal cell loss. However, SS patients have been reported who have similar patterns of proximal neuropathic pain, despite having normal skin biopsy studies. In such cases, DRGs may be targeted by mechanisms not associated with neuronal cell loss. Therefore, alternative approaches are warranted to help characterize abnormal DRGs in SS patients with proximal neuropathic pain.We performed a systematic review of the literature to define the frequency and spectrum of SS peripheral neuropathies, and to better understand the attribution of SS neuropathic pain to peripheral neuropathies. We found that the frequency of SS neuropathic pain exceeded the prevalence of peripheral neuropathies, and that painful peripheral neuropathies occurred less frequently than neuropathies not always associated with pain. We developed a novel magnetic resonance neurography (MRN) protocol to evaluate DRG abnormalities. Ten SS patients with proximal neuropathic pain were evaluated by this MRN protocol, as well as by punch skin biopsies evaluating for intraepidermal nerve fiber density (IENFD) of unmyelinated nerves. Five patients had radiographic evidence of DRG abnormalities. Patients with MRN DRG abnormalities had increased IENFD of unmyelinated nerves compared to patients without MRN DRG abnormalities (30.2 [interquartile range, 4.4] fibers/mm vs. 11.0 [4.1] fibers/mm, respectively; p = 0.03). Two of these 5 SS patients whose neuropathic pain resolved with intravenous immunoglobulin (IVIg) therapy had improvement of MRN DRG abnormalities.We have developed a novel MRN protocol that can detect DRG abnormalities in SS patients with neuropathic pain who do not have markers of peripheral neuropathy. We found that SS patients with MRN DRG abnormalities had statistically significant, increased IENFD on skin biopsy studies, which may suggest a relationship between trophic mediators and neuropathic pain. Given that our literature review has demonstrated that many SS neuropathic pain patients do not have a neuropathy, our findings suggest an important niche for this MRN DRG technique in the evaluation of broader subsets of SS neuropathic pain patients who may not have underlying neuropathies. The improvement of MRN DRG abnormalities in patients with IVIg-induced remission of neuropathic pain suggests that our MRN protocol may be capturing reversible, immune-mediated mechanisms targeting the DRG. PMID- 24797169 TI - Bloodstream infections in patients with solid tumors: epidemiology, antibiotic therapy, and outcomes in 528 episodes in a single cancer center. AB - Current information regarding bloodstream infection (BSI) in patients with solid tumors is scarce. We assessed the epidemiology, antibiotic therapy, and outcomes of BSI in these patients. We also compared patients who died with those who survived to identify risk factors associated with mortality. From January 2006 to July 2012 all episodes of BSI in patients with solid tumors at a cancer center were prospectively recorded and analyzed. A total of 528 episodes of BSI were documented in 489 patients. The most frequent neoplasms were hepatobiliary tumors (19%), followed by lung cancer (18%) and lower gastrointestinal malignancies (16%). Many patients had received corticosteroid therapy (41%), and 15% had neutropenia (<500 neutrophils/MUL) at the time of BSI. The most common source of BSI was cholangitis (21%), followed by other abdominal (19.5%) and urinary tract infections (17%). Gram-negative BSI occurred in 55% of cases, mainly due to Escherichia coli (55%), Pseudomonas aeruginosa (18%), and Klebsiella pneumoniae (16%). Among gram-positive BSI (35%), viridans group streptococci were the most frequent causative organisms (22%), followed by Staphylococcus aureus (21%) and Enterococcus species (18%). We identified 61 multidrug-resistant (MDR) organisms (13%), mainly extended-spectrum beta-lactamase-producing Enterobacteriaceae (n = 20) and AmpC-producing Enterobacteriaceae (n = 13). The majority of patients with BSI caused by MDR organisms had received antibiotics (70%), and they had been previously hospitalized (61.4%) more frequently than patients with BSI caused by susceptible strains. Inadequate empirical antibiotic therapy was given to 23% of patients, with a higher proportion in those with BSI due to a MDR strain (69%). Early (<48 h) and overall (30 d) case-fatality rates were 7% and 32%, respectively. The overall case-fatality rate was higher among cases caused by MDR organisms (39.3%). The only independent risk factors for the early case-fatality rate were the endogenous source of BSI (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.06-12.02), shock at presentation (OR, 3.63; 95% CI, 1.63-8.09), and corticosteroid therapy (OR, 3.245; 95% CI, 1.43-7.32). The independent risk factors for overall case-fatality rate were the presence of a chronic advanced cancer (OR, 35.39; 95% CI, 2.48-504.91), shock at presentation (OR, 25.84; 95% CI, 3.73-179.0), and corticosteroid therapy (OR, 6.98; 95% CI, 1.61-30.21).BSI in patients with solid tumors occurred mainly among those with hepatobiliary cancer, and cholangitis was the most frequent source; gram-negative bacilli were the most frequent causative agents. MDR organisms were relatively common, particularly in patients who had previously received antibiotics and had been hospitalized; these patients were frequently treated with inadequate empirical antibiotic therapy and had a poorer outcome. The case-fatality rate of patients with solid tumors and BSI was high and was associated with chronic advanced cancer, corticosteroid therapy, and shock at presentation. PMID- 24797168 TI - Hepatic hydrothorax: clinical features, management, and outcomes in 77 patients and review of the literature. AB - Hepatic hydrothorax is an important and difficult-to-manage complication of cirrhosis and portal hypertension. Here, we aimed to study its clinical features and natural history. Complete clinical data, including outcomes, were abstracted from hospital records of patients with cirrhosis and ascites admitted to University of Texas Southwestern University teaching hospitals from January 2001 to July 2012. Hepatic hydrothorax was diagnosed based on currently accepted clinical characteristics of the disease, including a known diagnosis of cirrhosis, the presence of portal hypertension, pleural fluid analysis, and the absence of primary cardiopulmonary disease.Seventy-seven of 495 (16%) hospitalized cirrhotic patients with pleural effusion (28 female; mean age, 52 yr) met the criteria for diagnosis of hepatic hydrothorax. Resting dyspnea and cough were the most prominent presenting symptoms, occurring in 34% and 22% of patients, respectively. Pleural effusions were most often right-sided (56/77; 73%), followed by left-sided only (13/77; 17%) and bilateral effusions (8/77; 10%); 7 (9%) patients did not have detectable ascites. The mean Model for End Stage Liver Disease (MELD) score at presentation was 16. The serum to pleural fluid albumin gradient (SPAG) was >=1.1 in all 48 patients in whom it was measured. Most patients (64/77; 83%) were managed with diuretics and/or thoracentesis, while 8 (10%) underwent transjugular intrahepatic portosystemic shunt (TIPS) and 5 (7%) underwent liver transplant. A total of 44 of 77 (57%) patients died during a mean follow-up of 12 months. The average time from presentation to death for all patients was 368 days, while for those after TIPS it was 845 days. No deaths were reported in the liver transplant group. The data indicate that a substantial number of patients with hepatic hydrothorax had what may be considered atypical presentations, including left-sided only effusions, or pleural effusion without ascites. Here, we propose that the term "serum to pleural fluid albumin gradient (SPAG)" be used to describe the gradient between serum and pleural fluid albumin levels and suggest that not only is it consistent with the portal hypertensive pathophysiology of hepatic hydrothorax, but also it is a useful criterion for diagnosis of hepatic hydrothorax. Finally, the overall outcome of hepatic hydrothorax was extremely poor, except in those undergoing TIPS or liver transplantation. PMID- 24797170 TI - Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. AB - Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3 hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 +/- 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 <=3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 +/- 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 +/- 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role. PMID- 24797171 TI - Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients. AB - Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by MEditerranean FeVer gene (MEFV) mutations. In Japan, patients with FMF have been previously reported, including a mild or incomplete form. Several factors are presumed to contribute to the variable penetrance and to the phenotypic variability of FMF. We conducted the current study to investigate the correlation of variable clinical presentations and MEFV genotypic distributions in Japanese FMF patients.We analyzed demographic, clinical, and genetic data for 311 FMF patients enrolled in the study. Clinically, we classified FMF into 2 phenotypes: 1) the "typical" form of FMF, and 2) the "atypical" form of FMF according to the Tel Hashomer criteria. Patients with the typical FMF phenotype had a higher frequency of febrile episodes, a shorter duration of febrile attacks, more frequent thoracic pain, abdominal pain, a family history of FMF, and MEFV exon 10 mutations. Conversely, patients with the atypical FMF phenotype had a lower frequency of fever episodes and more frequent arthritis in atypical distribution, myalgia, and MEFV exon 3 mutations. Multivariate analysis showed that the variable associated with typical FMF presentation was the presence of MEFV exon 10 mutations. Typical FMF phenotype frequencies were decreased in patients carrying 2 or a single low-penetrance mutations compared with those carrying 2 or a single high-penetrance mutations (M694I), with an opposite trend for the atypical FMF phenotype. In addition, patients having more than 2 MEFV mutations had a younger disease onset and a higher prevalence of thoracic pain than those carrying a single or no mutations. Thus, MEFV exon 10 mutations are associated with the more typical FMF phenotype. In contrast, more than half of the Japanese FMF patients without MEFV exon 10 mutations presented with an atypical FMF phenotype, indicating that Japanese FMF patients tend to be divided into 2 phenotypes by a variation of MEFV mutations. PMID- 24797173 TI - QTL analysis of body weight and carcass body length traits in an F2 intercross between Landrace and Korean native pigs. AB - Growth traits, such as body weight and carcass body length, directly affect productivity and economic efficiency in the livestock industry. We performed a genome-wide linkage analysis to detect the quantitative trait loci (QTL) that affect body weight, growth curve parameters and carcass body length in an F2 intercross between Landrace and Korean native pigs. Eight phenotypes related to growth were measured in approximately 1000 F2 progeny. All experimental animals were subjected to genotypic analysis using 173 microsatellite markers located throughout the pig genome. The least squares regression approach was used to conduct the QTL analysis. For body weight traits, we mapped 16 genome-wide significant QTL on SSC1, 3, 5, 6, 8, 9 and 12 as well as 22 suggestive QTL on SSC2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16 and 17. On SSC12, we identified a major QTL affecting body weight at 140 days of age that accounted for 4.3% of the phenotypic variance, which was the highest test statistic (F-ratio = 45.6 under the additive model, nominal P = 2.4 * 10(-11) ) observed in this study. We also showed that there were significant QTL on SSC2, 5, 7, 8, 9 and 12 affecting carcass body length and growth curve parameters. Interestingly, the QTL on SSC2, 3, 5, 6, 8, 9, 10, 12 and 17 influencing the growth-related traits showed an obvious trend for co-localization. In conclusion, the identified QTL may play an important role in investigating the genetic structure underlying the phenotypic variation of growth in pigs. PMID- 24797172 TI - Rosai-Dorfman disease of the central nervous system: report of 6 cases and review of the literature. AB - Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is an uncommon benign idiopathic lymphoproliferative disorder. The histologic hallmark of RDD is the finding of emperipolesis displayed by lesional histiocytes. While RDD most commonly affects lymph nodes, extranodal involvement of multiple organs has been reported, including the central nervous system (CNS). However, CNS involvement in RDD is rare and is not well characterized. As a result, therapeutic approaches to CNS involvement in RDD are not well established. Herein we report 6 cases of RDD with isolated CNS involvement and review the literature on RDD with CNS involvement. One of the presented cases exhibited intramedullary involvement of the spinal cord--a very rare form of RDD with CNS involvement. PMID- 24797174 TI - The activating Ly49W and inhibitory Ly49G NK cell receptors display similar affinities for identical MHC class I ligands. AB - The Ly49 receptor family plays an important role in the regulation of murine natural killer (NK) cell effector function. They recognize cell surface-expressed class I MHC (MHC-I) and are functionally equivalent to the killer Ig-related receptors (KIRs) in human NK cells. Ly49s exist in activating and inhibitory forms with highly homologous extracellular domains, displaying greater variability in the stalk regions. Inhibitory Ly49s can recognize self-MHC-I and therefore mediate tolerance to self. The role of activating Ly49 receptors is less clear. Some activating Ly49 receptors have been shown to recognize MHC-I molecules. The binding affinity of activating Ly49 receptors with MHC-I is currently unknown, and we sought to examine the affinities of two highly related receptors, an activating and an inhibitory Ly49 receptor, for their shared MHC-I ligands. The ectodomain of inhibitory Ly49G of the BALB/c mouse strain is highly similar to the Ly49W activating receptor in the nonobese diabetic (NOD) mouse. Recombinant soluble Ly49G and W were expressed, refolded, and analyzed for binding affinity with MHC-I by surface plasmon resonance. We found that Ly49G and Ly49W bound with similar affinity to the same MHC-I molecules. These results are a first determination of an activating Ly49 receptor affinity for MHC-I and show that, unlike prior results obtained with activating and inhibitory KIR receptors, functional homologues to Ly49 receptors, activating and inhibitory Ly49, can recognize common MHC-I ligands, with similar affinities. PMID- 24797175 TI - Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes. AB - Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have explored one of the mechanisms by which diabetes accelerates tumorigenesis in the kidney. Kidney cancer tissue from patients with diabetes showed a higher activity of Akt and decreased in total protein of tuberin compared to kidney cancer patient without diabetes or diabetes alone. In addition, a significant increase in phospho-Akt/tuberin expression was associated with an increase in Ki67 expression and activation of mTOR in kidney tumor with or without diabetes compared to diabetes alone. In addition, decrease in tuberin expression resulted in a significant decrease in protein expression of OGG1 and increased in oxidative DNA damage, 8-oxodG in kidney tissues from patients with cancer or cancer+diabetes. Importantly, these data showed that the majority of the staining of Akt/tuberin/p70S6K phosphorylation was more prominently in the tubular cells. In addition, accumulation of oxidative DNA damage is localized only in the nucleus of tubular cells within the cortex region. These data suggest that Akt/tuberin/mTOR pathway plays an important role in the regulation DNA damage and repair pathways that may predispose diabetic kidneys to pathogenesis of renal cell carcinoma. PMID- 24797176 TI - Sexual violence therapy group in a women's correctional facility: a preliminary evaluation. AB - This pilot study was an evaluation of an 8-week exposure-based therapy group targeting sexual trauma in incarcerated women, an underserved population with high rates of trauma exposure. Preliminary findings from 14 female prisoners showed significant decreases in depressive and anxiety symptoms from pre- to posttreatment. Of the women who were above the screening cutoff for possible posttraumatic stress disorder (PTSD; n = 13), depression (n = 12), and generalized anxiety disorder (GAD; n = 12) at pretreatment, approximately 60% had recovered, meaning they had symptom reductions that placed them below the cutoff at posttreatment (n = 8 for PTSD; n = 8 for depression, and n = 9 for GAD). In addition, 85% of participants reported a clinically significant reduction in depressive symptoms and 50% in GAD symptoms. The findings show promise for successful group treatment of sexual violence sequelae in incarcerated women. PMID- 24797177 TI - Synthesis of a highly efficient BiOCl single-crystal nanodisk photocatalyst with exposing {001} facets. AB - BiOCl is known as a highly efficient photocatalyst for degradation of pollutants. However, effective methods for fabricating BiOCl nanomaterials with well-defined facets are still lacking. In this work, a facile synthetic method was developed for the fabrication of BiOCl nanodisks with exposed {001} facets. The central feature of this approach was the use of water as the hydrolysis agent and ethylene glycol as the crystal growth inhibitor agent to tune the growth of BiOCl nanomaterial. With this approach, the size and shape of BiOCl nanostructures could be effectively tuned through adjusting the volume ratio of ethylene glycol/H2O. In addition, the mechanism of the crystal growth in this fabrication process was elucidated. The as-prepared BiOCl nanodisks with exposed {001} facets exhibited an excellent photocatalytic activity towards Rhodamine B degradation under both ultraviolet and visible light irradiations. These findings shed light on the deep understanding of formation mechanisms of BiOCl nanodisks and provide an efficient and facile method for the synthesis of high active photocatalyst. PMID- 24797178 TI - Noninvasive visualization of respiratory viral infection using bioorthogonal conjugated near-infrared-emitting quantum dots. AB - Highly pathogenic avian influenza A viruses are emerging pandemic threats in human beings. Monitoring the in vivo dynamics of avian influenza viruses is extremely important for understanding viral pathogenesis and developing antiviral drugs. Although a number of technologies have been applied for tracking viral infection in vivo, most of them are laborious with unsatisfactory detection sensitivity. Herein we labeled avian influenza H5N1 pseudotype virus (H5N1p) with near-infrared (NIR)-emitting QDs by bioorthogonal chemistry. The conjugation of QDs onto H5N1p was highly efficient with superior stability both in vitro and in vivo. Furthermore, QD-labeled H5N1p (QD-H5N1p) demonstrated bright and sustained fluorescent signals in mouse lung tissues, allowing us to visualize respiratory viral infection in a noninvasive and real-time manner. The fluorescence signals of QD-H5N1p in lung were correlated with the severity of virus infection and significantly attenuated by antiviral agents, such as oseltamivir carboxylate and mouse antiserum against H5N1p. The biodistribution of QD-H5N1p in lungs and other organs could be easily quantified by measuring fluorescent signals and cadmium concentration of virus-conjugated QDs in tissues. Hence, virus labeling with NIR QDs provides a simple, reliable, and quantitative strategy for tracking respiratory viral infection and for antiviral drug screening. PMID- 24797179 TI - Selective oxidative homo- and cross-coupling of phenols with aerobic catalysts. AB - Simple catalysts that use atom-economical oxygen as the terminal oxidant to accomplish selective ortho-ortho, ortho-para, or para-para homo-couplings of phenols are described. In addition, chromium salen catalysts have been discovered as uniquely effective in the cross-coupling of different phenols with high chemo- and regioselectivity. PMID- 24797182 TI - An effective mobilization strategy for lymphoma patients after failed upfront mobilization with plerixafor. AB - In an otherwise eligible patient, inadequate mobilization of PBSCs is a limiting factor to proceeding with an auto-ASCT. In such situations, plerixafor is commonly added to improve PBSC collection yields along with cytokine (G-CSF alone) or chemomobilization (chemotherapy+G-CSF). Individually, both strategies are proven to be safe and effective. Here we report six patients who underwent successful mobilization with combination chemomobilization plus plerixafor after upfront failure of cytokine mobilization plus plerixafor. The median CD34(+) cell yield after chemomobilization was 2.48 * 10(6)/kg (range 0.99-8.49) after receiving one to two doses of plerixafor. All patients subsequently underwent ASCT without major unforeseen toxicities and engrafted successfully. No significant delays in time to neutrophil recovery were observed. Our experience highlights the safety and effectiveness of chemomobilization with plerixafor after G-CSF plus plerixafor (G+P) failure and suggests this is a viable salvage strategy after initial failed G+P mobilization. PMID- 24797181 TI - A higher number of infused CD34(+) cells has a positive impact on the clinical outcome after related PBSC transplantation. PMID- 24797180 TI - Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. AB - BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with ~85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m(2), alemtuzumab 54 mg/m(2) (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function. PMID- 24797183 TI - Specific abnormalities versus number of abnormalities and cytogenetic scoring systems for outcome prediction after allogeneic hematopoietic SCT for myelodysplastic syndromes. AB - Newer cytogenetic scoring systems for myelodysplastic syndromes (MDSs), like cytogenetic stratification of the revised international prognostic scoring system (IPSS-R) or monosomal karyotype, may also improve outcome prediction after hematopoietic SCT (HCT). We compared the prognostic value of specific cytogenetic abnormalities, IPSS-R karyotype and monosomal karyotype for HCT outcome in 98 patients with MDS and AML post MDS. Higher-risk IPSS-R karyotype, 3q21q26 and transformation to AML before HCT were associated with increased cumulative incidence of relapse (CIR), whereas OS was adversely influenced by del 5q/-5, abnormalities of chromosomes 11 and 17 and cytogenetic IPSS-R very poor category. Karyotype with ?2 abnormalities and no abnormalities of chromosomes 3, 5, 7, 11 and 17 was an independent prognostic factor of lower CIR (hazard ratio (HR)=0.2, P=0.01) and longer OS (HR=0.5, P=0.03). In conclusion, some specific cytogenetic abnormalities and high cytogenetic complexity, as reflected by IPSS-R very poor karyotype, rather than monosomal karyotype, were associated with higher CIR and shorter OS after HCT. Conversely, results were encouraging in patients lacking those abnormalities, who may be very good candidates for HCT. PMID- 24797184 TI - Is there an expiration date for a cord blood unit in storage? PMID- 24797186 TI - Prevalence and correlates of willingness to participate in a rectal microbicide trial among men who have sex with men in Bangkok. AB - Rectal microbicides (RMs) hold promise as a HIV prevention method to reduce transmission among men who have sex with men (MSM). To assess RM trial feasibility in Bangkok, we measured prevalence and correlates of willingness to participate among Thai MSM observational cohort participants. Between April 2006 and December 2010, 1744 MSM enrolled in the Bangkok MSM Cohort Study; at 12 months, RM trial participation willingness was measured. We evaluated correlates of RM trial participation willingness using logistic regression analysis. Participants completing the 12-month visit (81.4%, n = 1419) had a mean age of 27.3 years (SD = 6.1), and 65.5% and 86.1% reported having a steady partner or anal intercourse (AI) in the past four months, respectively. Most (79.1%, n = 1123) participants reported willingness to participate in an RM trial, which, in multivariable analysis, was independently associated with insertive only (adjusted odds ratio [AOR] = 3.25, 95% CI: 1.82-5.81) or receptive/versatile role AI (AOR = 3.07, 95% CI: 1.88-5.01), and being paid for sex (AOR = 12.15, 95% CI: 1.67-88.21) in the past four months, and believing that people with AIDS look sick (AOR = 1.92, 95% CI: 1.23-2.98). Of hypothetical RM trial features to increase enrollment likelihood, the most (91.1%) compelling was that the study be approved by the Thai ethics committee, followed by the study site offering evening hours (88.9%). Reasons not to participate were not wanting a rectal examination (29.5%) or fluid collected from the penis or anus (24.6%) and not wanting the placebo (23.0%). RM trial participation willingness was high, particularly for those with greater HIV acquisition risk, within this Thai MSM cohort, suggesting feasibility of an RM trial. Addressing potential barriers to trial entry may be useful in educational materials to optimize recruitment. PMID- 24797185 TI - Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy. AB - In metachromatic leukodystrophy (MLD), the deficiency of the lysosomal enzyme arylsulfatase A (ARSA) leads to demyelination in the central and peripheral nervous system and ultimately to death. Allogeneic hematopoietic SCT (HSCT) is currently the only treatment for adult and late-onset juvenile MLD, although it is still in question because of insufficient follow-up. We wanted to determine whether HSCT could halt the progression of adult and late-onset juvenile MLD. Four treated unrelated patients and three untreated siblings were included in the study, and followed regularly for up to 18 years after transplantation. The patients were assessed from clinical examination, ARSA enzyme levels, magnetic resonance imaging of the brain and neuropsychological and neurophysiological tests. In the treated patients, ARSA levels were normal up to 18 years after transplantation. The parameters evaluated stabilized and remained stable after a latency period of 12-24 months. Two patients live normal lives, partially in a protected environment. The other two patients stabilized at a low cognitive and functional level. One of the controls is demented, one is in a vegetative state and one died. We conclude that, in comparison with their untreated siblings, HSCT halted the progression of the disease in our treated patients. PMID- 24797187 TI - Occupational therapy in chronic progressive disorders: enhancing function and modifying disease. PMID- 24797188 TI - Occupational therapy's role in preventing acute readmissions. PMID- 24797189 TI - Effectiveness of Cognitive-Functional (Cog-Fun) occupational therapy intervention for young children with attention deficit hyperactivity disorder: a controlled study. AB - OBJECTIVE: The purpose of this study was to examine the effectiveness of the Cognitive-Functional (Cog-Fun) intervention for young children with attention deficit hyperactivity disorder (ADHD). METHOD: Nineteen children ages 5-7 yr diagnosed with ADHD were allocated to treatment and wait-list control groups. After the 12-wk intervention, the control group was crossed over to treatment. Follow-up was conducted 3 mo after treatment. Outcome measures included the Behavior Rating Inventory of Executive Function and the Canadian Occupational Performance Measure. RESULTS: Before crossover, significant differences were found between groups in change scores on the outcome measures. After crossover, no significant differences were found in treatment effects, and significant moderate to large treatment effects were found for both COPM and BRIEF scores. Treatment gains were maintained at follow-up. CONCLUSION: The study supports the effectiveness of the Cog-Fun intervention in improving occupational performance and executive functions in daily life for young children with ADHD. PMID- 24797190 TI - Effects of early intervention on mental or neuromusculoskeletal and movement related functions in children born low birthweight or preterm: a meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis to examine the association between early intervention and mental or neuromusculoskeletal and movement-related functions of children born low birthweight (LBW) or preterm. METHOD: The meta-analysis included 16 studies that yielded 97 effects. Q and I2 values were used to determine heterogeneity. Publication bias was evaluated using Egger's regression intercept test and a funnel plot. RESULTS: The association between early intervention and either mental or neuromusculoskeletal and movement-related functions yielded a significant but small effect size (d = .219, p < .0001). Heterogeneity was statistically insignificant. CONCLUSION: Participation in early intervention programs addressing mental or neuromusculoskeletal and movement related functions in children born LBW or preterm results in significant improvements in these areas. PMID- 24797191 TI - Development, reliability, and validity of the My Child's Play (MCP) questionnaire. AB - OBJECTIVE: This article describes the development, reliability, and validity of My Child's Play (MCP), a parent questionnaire designed to evaluate the play of children ages 3-9 yr. METHOD: The first phase of the study determined the questionnaire's content and face validity. Subsequently, the internal reliability consistency and construct and concurrent validity were demonstrated using 334 completed questionnaires. RESULTS: The MCP showed good internal consistency (alpha = .86). The factor analysis revealed four distinct factors with acceptable levels of internal reliability (Cronbach's alphas = .63-.81) and gender- and age related differences in play characteristics; both findings attest to the tool's construct validity. Significant correlations (r = .33, p < .0001) with the Parent as a Teacher Inventory demonstrate the MCP's concurrent validity. CONCLUSION: The MCP demonstrated acceptable reliability and validity. It appears to be a promising standardized assessment tool for use in research and practice to promote understanding of a child's play. PMID- 24797192 TI - Internal structure of the Children Helping Out: Responsibilities, Expectations, and Supports (CHORES) measure. AB - The purpose of this study was to examine the internal structure of the Children Helping Out: Responsibilities, Expectations, and Supports (CHORES), an assessment of household task participation for children. Rasch analysis was used to examine patterns of item response and scale structure with data collected from caregivers of 132 children and youth ages 6-14 yr with and without disabling conditions. Internal consistency was strong for the total measure and the subscales. The items in both subscales fit the measurement model, and the item difficulty order matched the expected pattern from harder to easier household task performance and degree of caregiver assistance. The sample distribution in the hierarchical continuum showed that younger participants and those with physical disabilities tended to score lower. Some inconsistencies in rating scale use suggest a need for further clarification of the scoring criteria for measurement coherence. PMID- 24797193 TI - Content and construct validity of Here's How I Write (HHIW): A Child's Self Assessment and Goal Setting Tool. AB - OBJECTIVE: We examined content and construct validity of Here's How I Write: A Child's Self-Assessment and Goal Setting Tool, to assess children's perception of their handwriting and set child-directed goals. METHOD: In Study 1, a content validity study, 6 occupational therapists and 2 educators assessed the need for this type of measure and examined the proposed items. Thirty-four occupational therapists and educators then completed an online survey examining the items. Study 2, a construct validity study, compared the self-ratings of 20 children with poor handwriting and 20 children with good handwriting in Grades 2-5 with their teachers' ratings. RESULTS: Results supported test content and indicated freedom from culture and gender bias. The assessment discriminated between good and poor writers. The relationship between teacher and student ratings was significant, although teachers of poor writers rated the children lower than the children rated themselves. CONCLUSION: These studies provide support for the tool's validity. PMID- 24797194 TI - Young adults with developmental coordination disorder: a longitudinal study. AB - We conducted a longitudinal study to assess the continuing influence of developmental coordination disorder (DCD) on quality of life and participation. Ninety-six participants (25 in the DCD group, 30 in the borderline group, and 41 in the control group) ages 22-29 yr who had been screened for DCD 3-4 yr previously completed the Participation in Every Day Activities of Life, the Life Satisfaction Questionnaire, and the World Health Organization Quality of Life (WHOQOL-BREF) instrument. Multivariate analysis of variance revealed a significant between-groups difference, F(7, 95) = 2.89, p = .001, eta = 0.173, and post hoc analyses revealed that participants in the DCD and borderline groups scored lower overall on participation, quality of life, and life satisfaction. Linear regression found the Psychological Health domain of the WHOQOL-BREF to be a significant predictor of life satisfaction (B = 0.533; p = .001). PMID- 24797195 TI - Ergonomic design of a computer mouse for clients with wrist splints. AB - OBJECTIVE: We explored effects of cutaneous feedback and hump position on efficiency and comfort in mouse use with a splint. We also analyzed the relationship between anthropometric measurements (width of hand and length of hand, palm, and index) and the task performance. METHOD: Thirty participants performed a computer task with two forms of mice (front hump and rear hump) and two kinds of wrist splints (dorsal and volar). Movement time and satisfaction scores were recorded. RESULTS: No interaction effect (Hump Position * Splint Type) was found on movement time. Movement time was shorter for rear-hump mouse users than for front-hump mouse users. Movement time was also shorter for wearers of dorsal wrist splints than for wearers of volar wrist splints. Limited differences existed in the satisfaction scores. Participants with a longer index finger had shorter movement time. CONCLUSION: Both dorsal wrist splints and rear hump mice are recommended. Length of index finger positively correlated with task performance. PMID- 24797196 TI - Predictors of motor, daily function, and quality-of-life improvements after upper extremity robot-assisted rehabilitation in stroke. AB - OBJECTIVE: A subgroup of patients benefiting most from robot-assisted therapy (RT) has not yet been described. We examined the predictors of improved outcomes after RT. METHOD: Sixty-six patients with stroke receiving RT were analyzed. The outcome measures were the Fugl-Meyer Assessment (FMA), Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and Stroke Impact Scale (SIS). The potential predictors were age, side of lesion, time since onset, Modified Ashworth Scale (MAS) scores, accelerometer data, Box and Block Test (BBT) scores, and kinematic parameters. RESULTS: BBT scores were predictive of FMA (29%) and MAL (9%-15%) improvements. Reduced shoulder flexion synergy, as measured by less shoulder abduction during forward reach, and MAS-distal were predictive of WMFT-function improvements. MAS-distal was predictive of SIS-physical improvements. Demographic variables did not predict outcomes. CONCLUSION: Manual dexterity was a valuable predictor of motor impairment and daily function after RT. Outcomes at different levels may have different predictors. PMID- 24797197 TI - Interrater reliability and clinical utility of the Personal Care Participation Assessment and Resource Tool (PC-PART) in an inpatient rehabilitation setting. AB - OBJECTIVE: We examined the interrater reliability and clinical utility of the Personal Care Participation Assessment and Resource Tool (PC-PART) in a rehabilitation setting. METHOD: Ninety-six patients were recruited from the caseload of four occupational therapists. Patients were assessed on admission. Clinical utility was based on time to complete assessments. RESULTS: Interrater reliability for the total score was very high (intraclass correlation coefficient = .91). Limits of agreement for the program indicated aggregate data from individual scores were within 1.3 units (range = -1.3 to 0.5) but individual scores would be within 10 units (range = -9.3 to 0.2). The PC-PART took 27 min to complete. CONCLUSION: The PC-PART may have sufficient interrater reliability and clinical utility to evaluate program outcomes. The limits of agreement for rating individuals were relatively large, suggesting that it may be difficult to use the PC-PART to make clinical inferences about an individual patient. PMID- 24797198 TI - One- and three-screen driving simulator approaches to evaluate driving capacity: evidence of congruence and participants' endorsement. AB - OBJECTIVE: We examined the validity of one-screen versus three-screen driving simulators and their acceptability to middle-aged and older drivers. METHOD: Participants aged 40-55 or 65 and older (N = 32) completed simulated drives first with a single monitor and then with a three-monitor setup, followed by pen-and paper measures and an interview. RESULTS: Mean differences between one- and three screen drives were not statistically significant for Starting/Stopping and Passing/Speed. Correlations between the two drives indicated moderate positive linear relationships with moderate agreement. More errors occurred on the one screen simulator for Signal Violation/Right of Way/Inattention, Moving in a Roadway, Turning, and Total Scores. However, for Moving in a Roadway, Turning, and Total Scores, correlations between drives indicated strong positive linear relationships. We found no meaningful correlation between workload, computer comfort, simulator discomfort, and performance on either drive. Participants found driving simulators acceptable. CONCLUSION: Findings support the use of one screen simulators. Participants were favorable regarding driving simulators for assessment. PMID- 24797199 TI - Instrumental activities of daily living performance among people with Parkinson's disease without dementia. AB - OBJECTIVE: To investigate the performance of cognitively demanding instrumental activities of daily living (IADLs) among people with Parkinson's disease (PD) without dementia. METHOD: Seventy-seven participants with PD and 57 participants without PD underwent standardized, performance-based IADL evaluation using the Performance Assessment of Self-care Skills. Activity performance was rated for independence, adequacy, and safety. RESULTS: The PD group had lower independence and adequacy scores than the non-PD group for almost every activity. Medication management, shopping, and sharp utensil use were the activities most sensitive to group differences. In the PD group, older age, lower Mini-Mental State Examination scores, and decreased motor function were associated with poorer IADL performance. CONCLUSIONS: People with relatively early and mild PD demonstrated measurable deficits in the performance of cognitively demanding IADLs. This work highlights the importance of using objective assessments of IADL function to detect early functional changes in people with PD. PMID- 24797200 TI - Research opportunities in the area of early childhood: birth through 5 years. AB - The American Occupational Therapy Association (AOTA) Evidence-Based Practice Project has developed a table summarizing the research opportunities on early childhood. The table provides an overview of the state of current available evidence on interventions within the scope of occupational therapy practice and is based on the systematic reviews from the AOTA Evidence-Based Practice Guidelines Series. Researchers, students, and clinicians can use this information in developing innovative research to answer important questions within the occupational therapy field. PMID- 24797201 TI - Feasibility and effect of a professional education workshop for occupational therapists' management of upper-limb poststroke sensory impairment. AB - OBJECTIVE: We examined the development, implementation, and effectiveness of a theory-based workshop to facilitate knowledge translation for occupational therapists addressing upper-limb poststroke sensory impairments. METHOD: Nineteen therapists participated in a quasi-experimental pretest-posttest study that included an 8-hr evidence-based workshop designed using the Theory of Planned Behavior. We measured changes in knowledge, attitudes, and perceived behavioral control and intended behaviors regarding sensory impairment management, research utilization, and shared decision making. RESULTS: We noted significant changes in knowledge, attitudes, and perceived behavioral control and intended behaviors about sensory impairment management, research utilization, and shared decision making and made recommendations for changes in recruitment strategies, outcome measures, and workshop content. CONCLUSION: A theory-based workshop can potentially affect knowledge, attitudes, and intended behaviors about sensory impairment management, research utilization, and shared decision making. A randomized controlled trial evaluating this intervention is warranted and will potentially improve understanding of methods to facilitate knowledge translation. PMID- 24797202 TI - Using mirror therapy in the home environment: a case report. AB - OBJECTIVE: Mirror therapy (MT) is a potential intervention to improve function after stroke. How to apply this intervention in practice is not clear. This case report illustrates the feasibility and effectiveness of a self-administered home based MT program. METHOD: A home-based MT program was practiced over 5 wk. The participant was encouraged to use MT for 30 min 5*/wk. Therapist contact occurred 1*/wk to monitor performance. An independent evaluator administered three outcome measures pre- and postintervention: Upper Extremity Sensory and Pain sections of the Fugl-Meyer Assessment; Jebsen-Taylor Test of Hand Function, and the Manual Ability Measure-20. RESULTS: The participant engaged in a mean of 39.23 (+/-7.44) min of MT per day and used a variety of the recommended activities. Change scores indicated improvement on all of the included outcome measures. CONCLUSION: This case report suggests that a predominantly self-administered home-based MT program is feasible and effective at improving function after stroke. PMID- 24797203 TI - Occupational therapy and breastfeeding promotion: our role in societal health. AB - Occupational therapists are part of multidisciplinary teams supporting infants with feeding and eating difficulties, including problems related to initiation and continuation of breastfeeding. We have the opportunity to expand our role in breastfeeding promotion by also defining breastfeeding as a child-rearing and health management and maintenance occupation and broadening our clientele to include health and wellness populations. The use of a health promotion approach enables occupational therapy practitioners to better address environmental and contextual barriers to engagement in breastfeeding, barriers also encountered by healthy populations. Healthy People 2020 calls for increased rates of exclusive breastfeeding in the United States, given evidence of the health benefits of breastfeeding for infants, women, and society. Occupational therapists are well positioned to assist individuals, organizations, and populations in establishing habits and routines supportive of continued breastfeeding while lessening environmental and contextual barriers. Occupational therapists should consider emerging practice opportunities as consultants for breastfeeding promotion. PMID- 24797204 TI - Systematic review of studies on measurement properties of instruments for adults published in the American Journal of Occupational Therapy, 2009-2013. AB - OBJECTIVE: We describe the methodological quality of recent studies on instrument development and testing published in the American Journal of Occupational Therapy (AJOT). METHOD: We conducted a systematic review using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist to appraise 48 articles on measurement properties of assessments for adults published in AJOT between 2009 and 2013. RESULTS: Most studies had adequate methodological quality in design and statistical analysis. Common methodological limitations included that methods used to examine internal consistency were not consistently linked to the theoretical constructs underpinning assessments; participants in some test-retest reliability studies were not stable during the interim period; and in several studies of reliability and convergent validity, sample sizes were inadequate. CONCLUSION: AJOT's dissemination of psychometric research evidence has made important contributions to moving the profession toward the American Occupational Therapy Association's Centennial Vision. This study's results provide a benchmark by which to evaluate future accomplishments. PMID- 24797205 TI - Peripartum heart failure caused by left ventricular diastolic dysfunction: a case report. AB - Peripartum cardiomyopathy is a rare but potentially life-threatening condition. The current definition of peripartum cardiomyopathy only includes patients with systolic dysfunction. We describe a 25-year-old nulligravid patient with heart failure, i.e. left ventricular diastolic dysfunction with preserved systolic dysfunction during the third trimester of pregnancy. She complained of dyspnea and was referred to our hospital at 31 weeks of gestation. The patient met the clinical criteria for peripartum cardiomyopathy with the exception of systolic dysfunction. Brain-type natriuretic peptide levels peaked at 1447 pg/dL. The patient responded to therapy for heart failure and showed resolution of her diastolic dysfunction by 1 month postpartum. The case demonstrated the important role of diastolic dysfunction in peripartum heart failure and the possibility of clarifying the pathophysiology of peripartum cardiomyopathy by evaluating diastolic function. Further investigations are needed to provide evidence regarding the clinical role of diastolic dysfunction in peripartum heart failure. PMID- 24797206 TI - Normative data for female adolescents with eating disorders on the Children's Depression Inventory. AB - OBJECTIVE: Given the importance of assessing depressive symptoms and suicidal ideation in adolescents with eating disorders (EDs), the aim was to provide normative data on the Children's Depression Inventory (CDI) for female adolescents presenting for treatment of an ED. METHOD: The data source was the Helping to Outline Paediatric Eating Disorders (HOPE) Project registry (N = 1000), a prospective, ongoing registry study comprising consecutive pediatric tertiary ED referrals. Females (N = 256; 12-17 years) with DSM-5 EDs completed the CDI at intake. RESULTS: Results on the CDI revealed a pattern of increasing depressive scores with age and higher scores among patients with anorexic spectrum disorders. The prevalence of suicidal ideation was high and had the same pattern as CDI scores. The mean score on the CDI in the sample was higher than community samples and clinical samples of adolescents with post-traumatic stress disorder, obsessive compulsive disorder, and other clinical disorders. DISCUSSION: Females adolescents with EDs are at high-risk of depression and suicidal ideation. These data provide information about variation in CDI scores to guide clinicians in interpretation of scores. PMID- 24797207 TI - Second-meal effects of pulses on blood glucose and subjective appetite following a standardized meal 2 h later. AB - This study investigated whether pulses (chickpeas, yellow peas, navy beans, lentils) have an effect on blood glucose (BG) and appetite following a fixed-size meal 2 h later. Over the following 2 h, all pulses lowered BG area under the curve (AUC) and lentils reduced appetite AUC compared with white bread (p < 0.05). Following the meal, BG was lower after lentils and chickpeas at 150 and 165 min, and AUC was lower after lentils compared with white bread (p < 0.05). PMID- 24797208 TI - A longitudinal examination of different etiological pathways to alcohol use and misuse. AB - BACKGROUND: Sher, Grekin, and Williams (2005) pointed out the existence of 4 main etiological, but not mutually exclusive, models that might explain the development of alcohol use and misuse. The aim of the present study was to explore 3 of these 4 pathways in which psychological (personality and drinking motives) and environmental (child maltreatment) variables may play a relevant role: positive affect regulation, negative affect regulation, and deviance proneness. METHODS: Three hundred and fourteen young adults in the 18 to 29 year age range completed different personality, alcohol use, and child maltreatment questionnaires at Time 1. Five years later, they responded to drinking motives, antisocial behavior, alcohol use, and alcohol-related problems questionnaires. RESULTS: The path analyses showed that emotional abuse predicted negative emotionality, which, in turn, prospectively predicted alcohol-related problems through coping-with-depression drinking motives (negative affect regulation). Emotional neglect predicted lesser positive emotionality, and physical abuse predicted unconscientious disinhibition personality characteristics. In turn, these 2 broad personality domains predicted drinking at weekends at Time 2 through enhancement drinking motives (positive affect regulation). Finally, physical neglect predicted disagreeable disinhibition, and both disinhibition domains directly predicted antisocial behavior 5 years later which, in turn, predicted drinking at weekends, drinking on weekdays, and alcohol-related problems (deviance proneness). CONCLUSIONS: The findings describe the specific role of distal (maltreatment and personality) and more proximal (antisocial behavior and drinking motives) variables in the different pathways involved in the development of alcohol use and misuse. PMID- 24797209 TI - Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons. AB - Behavioural flexibility is mediated through the neural circuitry linking the prefrontal cortex and basal ganglia. Here we conduct selective elimination of striatal cholinergic interneurons in transgenic rats by immunotoxin-mediated cell targeting. Elimination of cholinergic interneurons from the dorsomedial striatum (DMS), but not from the dorsolateral striatum, results in enhanced reversal and extinction learning, sparing the acquisition of place discrimination. This enhancement is prevented by infusion of a non-selective muscarinic acetylcholine receptor agonist into the DMS either in the acquisition, reversal or extinction phase. In addition, gene-specific silencing of M4 muscarinic receptor by lentiviral expression of short hairpin RNA (shRNA) mimics the place reversal learning promoted by cholinergic elimination, whereas shRNA-mediated gene silencing of M1 muscarinic receptor shows the normal performance of reversal learning. Our data indicate that DMS cholinergic interneurons inhibit behavioural flexibility, mainly through the M4 muscarinic receptor, suggesting that this role is engaged to the stabilization of acquired reward contingency and the suppression of response switch to changed contingency. PMID- 24797210 TI - A subpubic cartilaginous cyst causing neurological and sexual symptoms in a 69 year-old man. AB - INTRODUCTION: Subpubic cartilaginous cysts (SCCs) are rare. AIM: This is the first reported case of a male patient presenting with neurological and sexual symptoms due to an SCC. METHOD: We describe the clinical history of a patient who reported neuralgic pain, numbness in the groin and base of his penis, and loss of sexual function. RESULTS: A magnetic resonance imaging revealed the presence of an SCC with associated mass effect. A conservative approach was adopted and within 12 months, the cyst had decreased in size and his symptoms had improved. CONCLUSIONS: Men who present with erectile dysfunction and neurological symptoms merit a thorough assessment including appropriate investigation to exclude organic pathology. PMID- 24797211 TI - Resilience in attaining and sustaining sobriety among older lesbians with alcoholism. AB - This phenomenological study illuminates coping among older lesbians with alcoholism. Twenty study participants were recruited through purposive and snowball sampling; each completed 3 interviews structured to gain a deeper understanding of participants' lived experiences. This article focuses on the key situations and people that helped study participants obtain sobriety and stay sober. Five major themes emerged from the data: wake-up calls, impact of formal treatment, impact of 12-step recovery groups, consequences from other sources, and resiliency. Findings support the need for culturally sensitive approaches to practice with this subpopulation of older adults. PMID- 24797212 TI - Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. AB - Immunodeficiency is a severe side effect of radiation therapy, notably at high radiation doses. It may also impact healthy individuals exposed to environmental ionizing radiation. Although it is believed to result from cytotoxicity of bone marrow cells and of immunocompetent cells in the peripheral blood, the response of distinct bone marrow and blood cell subpopulations following exposure to ionizing radiation is not yet fully explored. In this review, we aim to compile the knowledge on radiation sensitivity of immunocompetent cells and to summarize data from bone marrow and peripheral blood cells derived from mouse and human origin. In addition, we address the radiation response of blood stem and progenitor cells. The data indicate that stem cells, T helper cells, cytotoxic T cells, monocytes, neutrophils and, at a high degree, B cells display a radiation sensitive phenotype while regulatory T cells, macrophages, dendritic cells and natural killer cells appear to be more radioresistant. No conclusive data are available for basophil and eosinophil granulocytes. Erythrocytes and thrombocytes, but not their precursors, seem to be highly radioresistant. Overall, the data indicate considerable differences in radiosensitivity of bone marrow and blood normal and malignant cell populations, which are discussed in the light of differential radiation responses resulting in hematotoxicity and related clinical implications. PMID- 24797213 TI - Effect of CPAP treatment on plasma high sensitivity troponin levels in patients with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with an increased prevalence of cardiovascular diseases. New generations of highly sensitive assays for cardiac troponin (hs-cTnT) have been introduced recently, and a number of clinical observations have challenged the notion that troponins are only increased in blood following irreversible necrosis. OBJECTIVE: The aims of this study were to compare the levels of hs-cTnT between a group of healthy controls and a group of patients with OSA without co-existent coronary artery disease, and to assess the possible influence of the treatment with Continuous positive airway pressure (CPAP) on these levels. METHODS: The study population included 200 male participants. The case (n = 133) or control (n = 67) status was defined by an apnea-hypopnea index of 10 or greater. The hs-cTnT assay was validated as reported previously, with a limit of detection of 3 ng/L and an upper reference limit (99th percentile) of 14 ng/L. RESULTS: The proportion of subjects with detectable plasma hs-cTnT was higher in patients with OSA than in controls (61 vs 75%, p = 0.04). In patients, a significant increase in hs-cTnT levels was observed after an effective treatment with CPAP (7.3 +/- 3.4 vs 10.1 +/- 4.9 ng/L; p < 0.01). CONCLUSION: This study shows that the percentage of subjects with detectable hs-cTnT is associated with the presence of OSA. It also evidences that treatment with CPAP is followed by a rise in hs-cTnT concentrations. It is reasonable to suggest that CPAP therapy might induce a potential degree of cardiac stress, resulting in deleterious consequences for the heart. PMID- 24797214 TI - The effectiveness of semantic feature analysis: an evidence-based systematic review. AB - OBJECTIVES: This review examines the effectiveness of semantic feature analysis as an intervention to improve naming abilities for persons with aphasia. METHOD: A systematic search of the literature identified 11 studies that met the pre determined inclusion criteria. Two independent raters evaluated each study for methodological quality and assigned appropriate levels of evidence using the Single Case Experimental Design scale. To determine clinical effectiveness, effect sizes using Cohen's d were calculated if sufficient data were available. Alternatively, percent of non-overlapping data was calculated. RESULTS: Results indicated that methodologically sound research has been conducted to determine the effectiveness of semantic feature analysis for persons with aphasia using single subject research designs. When using Cohen's d, the majority of participants showed a small effect size. However, when percent of non-overlapping data was calculated, a large treatment effect was present for the majority of participants. CONCLUSIONS: Semantic feature analysis was an effective intervention for improving confrontational naming for the majority of participants included in the current review. Further research is warranted to examine generalization effects. PMID- 24797215 TI - Perianal pruritus in dogs with skin disease. AB - BACKGROUND: Perianal pruritus has been reported in dogs with anal sac disease but not in healthy dogs. Some authors describe it as typical of allergy, but there is little evidence in support of this. HYPOTHESIS/OBJECTIVES: The aim was to investigate the association between perianal pruritus and canine atopic dermatitis (CAD), adverse food reaction (ARF) and other skin diseases in dogs. ANIMALS: Two hundred and fifty privately owned dogs with skin disease and without anal sac disease. METHODS: The presence or absence of perianal pruritus, macroscopic and cytological evaluation of the perianal skin surface and the macroscopic appearance of anal sac contents were assessed. Chi-square and Fisher's exact tests were performed to compare the frequency of perianal pruritus with the clinical diagnoses and with clinical and cytological parameters. RESULTS: Perianal pruritus was seen in 39 of 75 dogs with CAD, in 29 of 57 dogs with ARF and in only 24 of 118 dogs with other conditions. The frequency of perianal pruritus in dogs with CAD and/or ARF was significantly higher than that in dogs with other diagnoses (P < 0.0001). No other disease was significantly associated with perianal pruritus. Perianal pruritus was significantly associated with signs of perianal alopecia, erythema, excoriations, lichenification and hyperpigmentation; it was not associated with the presence of bacteria or yeasts or with anal sac impaction. CONCLUSIONS AND CLINICAL IMPORTANCE: Perianal pruritus was seen more frequently in dogs with AFR/CAD than with other dermatological diseases. This is the first study to evaluate perianal pruritus in dogs with skin disease and without anal sac disease. PMID- 24797216 TI - A European network of email and telephone help lines providing information and support on rare diseases: results from a 1-month activity survey. AB - BACKGROUND: Information on rare diseases are often complex to understand, or difficult to access and additional support is often necessary. Rare diseases helplines work together across Europe to respond to calls and emails from the public at large, including patients, health care professionals, families, and students. Measuring the activity of helplines can help decision makers to allocate adequate funds when deciding to create or expand an equivalent service. OBJECTIVE: Data presented are referred to a monthly user profile analysis, which is one of the activities that each helpline has to carry out to be part of the network. This survey aimed to explore the information requests and characteristics of users of rare diseases helplines in different European countries. Another aim was to analyze these data with respect to users' characteristics, helpline characteristics, topics of the inquiries, and technologies used to provide information. With this survey, we measure data that are key for planning information services on rare diseases in the context of the development of national plans for rare diseases. METHODS: A survey was conducted based on all calls, emails, visits, or letters received from November 1 to 30, 2012 to monitor the activity represented by 12 helplines. Data were collected by a common standardized form, using ORPHA Codes for rare diseases, when applicable. No personal data identifying the inquirer were collected. It was a descriptive approach documenting on the number and purpose of inquiries, the number of respondents, the mode of contact, the category of the inquirer in relation to the patient, the inquirer's gender, age and region of residence, the patient's age when applicable, the type and duration of response, and the satisfaction as scored by the respondents. RESULTS: A total of 1676 calls, emails, or letters were received from November 1 to 30, 2012. Inquiries were mostly about specific diseases. An average of 23 minutes was spent for each inquiry. The inquirer was a patient in 571/1676 inquiries (ie, 34.07% of all cases; 95% CI 31.8-36.3). Other inquirers included relatives (520/1676, 31.03%; 95% CI 28.9-33.3), health care professionals (354/1676, 21.12%; 95% CI 19.2-23.1), and miscellaneous inquirers (230/1676, 13.72%; 95% CI 12.1-15.4). Telephone remained the main mode of contact (988/1676, 58.95%; 95% CI 56.6-61.3), followed by emails (609/1676, 36.34%; 95% CI 34.0-38.6). The three main reasons of inquiries were to acquire about information on the disease (682/2242, 30.42%; 95% CI 27.8-32.1), a specialized center/expert (404/2242, 18.02%; 95% CI 15.9-19.6), and social care (240/2242, 10.70%; 95% CI 9.1-12.0). CONCLUSIONS: The helplines service responds to the demands of the public, however more inquiry-categories could be responded to. This leaves the possibility to expand the scope of the helplines, for example by providing assistance to patients when they are reporting suspected adverse drug reactions as provided by Directive 2010/84/EU or by providing information on patients' rights to cross-border care, as provided by Directive 2010/24/EU. PMID- 24797217 TI - Understanding irregular shell formation of Nautilus in aquaria: chemical composition and structural analysis. AB - Irregular shell formation and black lines on the outside of live chambered nautilus shells have been observed in all adult specimens at aquariums and zoos soon after the organisms enter aquaria. Black lines have also been observed in wild animals at sites of broken shell, but continued growth from that point returns to a normal, smooth structure. In contrast, rough irregular deposition of shell continues throughout residence in aquaria. The composition and reasons for deposition of the black material and mitigation of this irregular shell formation is the subject of the current study. A variety of analytical techniques were used, including stable isotope mass spectrometry (SI-MS), inductively coupled plasma mass spectrometry (ICP-MS), micro x-ray fluorescence (uXRF), X-ray diffraction (XRD), and scanning electron microscopy (SEM) based X-ray microanalysis. Results indicate that the black material contains excess amounts of copper, zinc, and bromine which are unrelated to the Nautilus diet. The combination of these elements and proteins plays an important role in shell formation, growth, and strengthening. Further study will be needed to compare the proteomics of the shell under aquaria versus natural wild environments. The question remains as to whether the occurrence of the black lines indicates normal healing followed by growth irregularities that are caused by stress from chemical or environmental conditions. In this paper we begin to address this question by examining elemental and isotopic differences of Nautilus diet and salt water. The atomic composition and light stable isotopic ratios of the Nautilus shell formed in aquaria verses wild conditions are presented. PMID- 24797219 TI - Hole spin coherence in a Ge/Si heterostructure nanowire. AB - Relaxation and dephasing of hole spins are measured in a gate-defined Ge/Si nanowire double quantum dot using a fast pulsed-gate method and dispersive readout. An inhomogeneous dephasing time T2* 0.18 MUs exceeds corresponding measurements in III-V semiconductors by more than an order of magnitude, as expected for predominately nuclear-spin-free materials. Dephasing is observed to be exponential in time, indicating the presence of a broadband noise source, rather than Gaussian, previously seen in systems with nuclear-spin-dominated dephasing. PMID- 24797218 TI - Digital subtraction MR angiography roadmapping for magnetic steerable catheter tracking. AB - PURPOSE: To develop a high temporal resolution MR imaging technique that could be used with magnetically assisted remote control (MARC) endovascular catheters. MATERIALS AND METHODS: A technique is proposed based on selective intra-arterial injections of dilute MR contrast at the beginning of a fluoroscopic MR angiography acquisition. The initial bolus of contrast is used to establish a vascular roadmap upon which MARC catheters can be tracked. The contrast to noise ratio (CNR) of the achieved roadmap was assessed in phantoms and in a swine animal model. The ability of the technique to permit navigation of activated MARC catheters through arterial branch points was evaluated. RESULTS: The roadmapping mode proved effective in phantoms for tracking objects and achieved a CNR of 35.7 between the intra- and extra-vascular space. In vivo, the intra-arterial enhancement strategy produced roadmaps with a CNR of 42.0. The artifact produced by MARC catheter activation provided signal enhancement patterns on the roadmap that experienced interventionalists could track through vascular structures. CONCLUSION: A roadmapping approach with intra-arterial contrast-enhanced MR angiography is introduced for navigating the MARC catheter. The technique mitigates the artifact produced by the MARC catheter, greatly limits the required specific absorption rate, permits regular roadmap updates due to the low contrast agent requirements, and proved effective in the in vivo setting. Inc. PMID- 24797220 TI - Remarkable switch of regioselectivity in Diels-Alder reaction: divergent total synthesis of borreverine, caulindoles, and flinderoles. AB - Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products. PMID- 24797221 TI - Inhibition of cytokine release by mycobacterium tuberculosis phenolic glycolipid analogues. AB - Infection by Mycobacterium tuberculosis causes tuberculosis, a disease characterized by alteration of host innate and adaptive immunity. These processes are mediated by a series of bacterial biomolecules, among which phenolic glycolipids (PGLs) and the related p-hydroxybenzoic acid derivatives have been suggested to play important roles. To probe the importance of structural features of these glycans on cytokine modulation, we synthesized three M. tuberculosis PGL analogues (1-3), which differ from the native glycoconjugates by possessing a simplified lipid algycone. The ability of 1-3 to modulate the release of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, MCP-1) and nitric oxide (NO) was evaluated. None of the compounds stimulated the secretion of these signalling molecules. However, all showed a Toll-like Receptor 2-mediated, concentration-dependent inhibition profile that was related to the methylation pattern on the glycan. PMID- 24797223 TI - Demonstration of persistent contamination of a cooked egg product production facility with Salmonella enterica serovar Tennessee and characterization of the persistent strain. AB - AIMS: The aim of this study was to investigate whether continuous contamination of light pasteurized egg products with Salmonella enterica serovar Tennessee (S. Tennessee) at a large European producer of industrial egg products was caused by persistent contamination of the production facility and to characterize the persistent strains. METHODS AND RESULTS: Seventy-three S. Tennessee isolates collected from products over a 3-year period with intermittent contamination, and 15 control strains were compared by pulsed field gel electrophoresis (PFGE) using two enzymes. Forty-five case isolates distributed throughout the full period were shown to belong to one profile type. Isolates representing different PFGE profiles were all assigned to ST 319 by multilocus sequence typing (MLST). The case isolates did not show a higher ability to form biofilm on a plastic surface than noncase isolates. Characteristically, members of the persistent clone were weak producers of H2 S in laboratory medium. S. Tennessee isolated from the case was able to grow better in pasteurized egg product compared with other serovars investigated. CONCLUSIONS: It was concluded that the contamination was caused by a persistent strain in the production facility and that this strain apparently had adapted to grow in the relevant egg product. SIGNIFICANCE AND IMPACT OF THE STUDY: S. Tennessee has previously been associated with persistence in hatching facilities. This is the first report of persistent contamination of an egg production facility with this serovar. PMID- 24797222 TI - The effect of periodontal therapy on glycaemic control in a Hispanic population with type 2 diabetes: a randomized controlled trial. AB - OBJECTIVE: In the Mexican-American population, the prevalence of Type 2 diabetes mellitus (T2DM) is as high as 50% of the population. This randomized controlled clinical trial was designed to elucidate how treatment of periodontal disease affects HbA1c values in this population. MATERIALS AND METHODS: One hundred and fifty-four T2DM patients with periodontal disease were enrolled in the study. The test group was treated with scaling and root planing (SRP); the control group received oral hygiene instructions. At baseline and 4-6 weeks after therapy, a complete periodontal examination was performed. Blood was collected at baseline and 4 months later for HbA1c levels. RESULTS: One hundred and twenty-six individuals completed the study. Baseline mean +/- SD HbA1c for the test and control groups were 9.0 +/- 2.3% and 8.4 +/- 2.0% respectively. Non-significant difference in HbA1c reductions (0.6 +/- 2.1% and 0.3 +/- 1.7%) was found between test and control groups at 4 months. Comparisons of the periodontal clinical parameters between the test and control groups found significant differences with improved results in the test subjects. CONCLUSIONS: No statistically significant differences were found in the changes of HbA1c levels between test and control groups. Non-surgical periodontal therapy improved the magnitude of change in periodontal parameters as compared to the control subjects. ClinicalTrials.gov Identifier: NCT01128374. PMID- 24797224 TI - Channel selection methods for the P300 Speller. AB - The P300 Speller brain-computer interface (BCI) allows a user to communicate without muscle activity by reading electrical signals on the scalp via electroencephalogram. Modern BCI systems use multiple electrodes ("channels") to collect data, which has been shown to improve speller accuracy; however, system cost and setup time can increase substantially with the number of channels in use, so it is in the user's interest to use a channel set of modest size. This constraint increases the importance of using an effective channel set, but current systems typically utilize the same channel montage for each user. We examine the effect of active channel selection for individuals on speller performance, using generalized standard feature-selection methods, and present a new channel selection method, termed jumpwise regression, that extends the Stepwise Linear Discriminant Analysis classifier. Simulating the selections of each method on real P300 Speller data, we obtain results demonstrating that active channel selection can improve speller accuracy for most users relative to a standard channel set, with particular benefit for users who experience low performance using the standard set. Of the methods tested, jumpwise regression offers accuracy gains similar to the best-performing feature-selection methods, and is robust enough for online use. PMID- 24797225 TI - A hybrid NIRS-EEG system for self-paced brain computer interface with online motor imagery. AB - BACKGROUND: For a self-paced motor imagery based brain-computer interface (BCI), the system should be able to recognize the occurrence of a motor imagery, as well as the type of the motor imagery. However, because of the difficulty of detecting the occurrence of a motor imagery, general motor imagery based BCI studies have been focusing on the cued motor imagery paradigm. NEW METHOD: In this paper, we present a novel hybrid BCI system that uses near infrared spectroscopy (NIRS) and electroencephalography (EEG) systems together to achieve online self-paced motor imagery based BCI. We designed a unique sensor frame that records NIRS and EEG simultaneously for the realization of our system. Based on this hybrid system, we proposed a novel analysis method that detects the occurrence of a motor imagery with the NIRS system, and classifies its type with the EEG system. RESULTS: An online experiment demonstrated that our hybrid system had a true positive rate of about 88%, a false positive rate of 7% with an average response time of 10.36 s. COMPARISON WITH EXISTING METHOD(S): As far as we know, there is no report that explored hemodynamic brain switch for self-paced motor imagery based BCI with hybrid EEG and NIRS system. CONCLUSIONS: From our experimental results, our hybrid system showed enough reliability for using in a practical self-paced motor imagery based BCI. PMID- 24797226 TI - Quantifying human movement across the continuum of care: From lab to clinic to community. AB - The ability to precisely quantify human movement within the laboratory setting provides researchers with data that comprehensively describe movement dysfunction in clinical cohorts. Furthermore, these data can be effectively utilized to identify potential underlying mechanisms as targets for therapeutic intervention. Although the utility of these methodologies is evidenced by the number of laboratories incorporating these techniques to understand clinical pathologies, the direct translation to clinical practice remains elusive and there exists an information gap between researchers studying these populations and the clinicians developing treatment for the individuals. METHOD: Recent technological advancements allow researchers and their clinician counterparts to measure certain elements of human movement outside of the laboratory. Specifically, the use of portable accelerometers allows for calculation of acceleration of the center of mass (COMa) during walking. COMa can be then be used to infer information about force generation by the individual during walking. This information may then be used by researchers to integrate with laboratory based results as well as by clinicians to partner with clinical findings, thus guiding clinical decision making as well as treatment design. The extent to which these types of measurement devices can be used to generate specific data describing human movement away from the lab is in the early stages of investigation, however, the potential for their use is something that could help advance research and patient care in the future. PMID- 24797227 TI - Treatment with Actovegin improves spatial learning and memory in rats following transient forebrain ischaemia. AB - This study aimed to investigate whether Actovegin, which is a deproteinized ultrafiltrate derived from calf blood, demonstrates neuroprotective effects in a rat model of transient global cerebral ischaemia. Forty Sprague Dawley rats were subjected to four-vessel occlusion to induce transient global cerebral ischaemia followed by either saline or Actovegin treatment. Sham operations were performed on 15 rats. Actovegin (200 mg/kg) or saline was administered 6 hrs after carotid artery occlusion and then daily until Day 40. Learning and memory were evaluated using the Morris water maze test over two different 5-day periods, and grip strength testing was also performed to control for potential motor impairments. Rat brains were harvested for histological analysis on Day 68. In comparison to controls, Actovegin-treated rats exhibited a decreased latency to reach the hidden platform on the second learning trial of water maze testing (46.82 +/- 6.18 versus 27.64 +/- 4.53 sec., P < 0.05; 38.3 +/- 8.23 versus 13.37 +/- 2.73 sec., P < 0.01 for the first and second 5-day testing periods, respectively). In addition, Actovegin-treated rats spent more time in the platform quadrant than saline-treated rats during memory trials (P < 0.05). No differences in grip strength were detected. Histological analyses demonstrated increased cell survival in the CA1 region of the hippocampus following Actovegin treatment (left hemisphere, 166 +/- 50 versus 332 +/- 27 cells, P < 0.05; right hemisphere, 170 +/- 45 versus 307 +/- 28 cells, P < 0.05, in saline- versus Actovegin-treated rats, respectively). In rats, Actovegin treatment improves spatial learning and memory following cerebral ischaemia, which may be related to hippocampal CA1 neuroprotection. PMID- 24797228 TI - Triclosan-coated abdominal closure sutures reduce the incidence of surgical site infections after pancreaticoduodenectomy. AB - BACKGROUND: Surgical site infection (SSI) is a serious complication after pancreaticoduodenectomy (PD). To prevent microbial colonization of suture material in operative wounds, triclosan-coated polyglactin sutures with antibacterial activity have been developed recently. Several clinical studies have shown that the use of such suture reduces SSIs in various operations, but its efficacy in PD has not been studied. We evaluated whether the incidence of SSI can be reduced when triclosan-coated sutures are used for abdominal incision closure after PD. METHODS: This controlled clinical trial took place between December 2005 and February 2012 with a total of 198 consecutive patients who had undergone PD. The study group received triclosan-coated polyglactin 910 antimicrobial sutures between March 2009 and February 2012, and the control group received conventional wound closure between January 2005 and February 2009. We compared the rate and types of infections in the two groups. RESULTS: In the study group, age, the incidence of diabetes mellitus, smoking history, and operating time were significantly greater than in the control group. The rates of SSI were 4.5% in the study group and 14.5% in the control group (p=0.037). CONCLUSIONS: The use of triclosan-coated sutures may help reduce the incidence of SSI after PD compared with conventional non-antibiotic sutures. PMID- 24797229 TI - Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents. AB - Quetiapine is an atypical antipsychotic drug with a high permeability, moderate solubility and defined as a Biopharmaceutics Classification System class ll compound. The pharmacokinetics (PK) of the quetiapine immediate-release (IR) formulation has been studied in both adults and children, but the quetiapine extended-release (XR) formulation has only been conducted in adults. The purpose of the current study was to use physiologically based pharmacokinetic modeling (PBPK) quantitatively to predict the PK of the XR formulation in children and adolescents. Using a 'learn and confirm' approach, PBPK models were developed employing in vitro ADME and physicochemical data, clinical PK data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children. These models can predict well the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. The AUC and Cmax ratios (children vs adults) for the different age groups were in reasonable agreement with the observed ratios. In addition, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses. The results from the study can help inform dosing regimens in pediatrics using the quetiapine XR formulation. PMID- 24797230 TI - Effects of exercise training on depression in patients with heart failure: a systematic review and meta-analysis of randomized controlled trials. AB - AIMS: The aim of this review is to assess the effects of exercise training on the symptoms of depression in heart failure (HF) patients. METHODS AND RESULTS: Randomized controlled trials of exercise training in patients with HF and symptoms of depression were identified. The depression data were pooled using meta-analysis, and 19 studies were identified, with a total of 3447 patients, of which 16 (3226 patients) provided data for the meta-analysis. Exercise training demonstrated significant reductions in the symptoms of depression [standardized mean difference (SMD) -0.38, 95% confidence interval (CI) -0.55 to -0.21], and its antidepressive effect was consistent in a number of HF groups, such as in ages under and over 65 years (SMD -0.14, 95% CI -0.22 to -0.07 vs. SMD -0.44, 95% CI -0.61 to -0.27) and EFs of <50% (SMD -0.38, 95% CI -0.56 to -0.20), as well as in a range of interventional strategies, including the aerobic mode (SMD -0.40, 95% CI -0.61 to -0.19), centre, home, or combined setting (SMD -0.61, 95% CI 0.95 to -0.27 vs. SMD -0.25, 95% CI -0.44 to -0.07 vs. SMD -0.13, 95% CI -0.21 to -0.05), and short or longer training programmes (<=12 weeks, SMD -0.50, 95% CI 0.73 to -0.27; 12-26 weeks, SMD -0.47, 95% CI -0.82 to -0.11; >26 weeks, SMD 0.12, 95% CI -0.20 to -0.04). The beneficial effects were preserved when blind design trials were considered (SMD -0.14, 95% CI -0.22 to -0.07). CONCLUSION: Exercise training significantly decreased the symptoms of depression in patients with HF. This benefit remained unclear in cases of HF with a normal EF and combined aerobic and strength training. Random controlled trials are needed to verify the benefit of exercise in these populations, and in very old, asymptomatic, and severe HF patients. PMID- 24797231 TI - Transition metal-catalyzed cycloadditions of cyclopropanes for the synthesis of carbocycles: C-C activation in cyclopropanes. AB - Transition metal-catalyzed cycloadditions of cyclopropanes have been well developed over the past several decades, leading to numerous new types of cycloadditions which are complementary to the traditional cycloadditions for the synthesis of carbocycles. Cycloadditions of vinylcyclopropanes (VCPs) and methylenecyclopropanes (MCPs) constitute two main aspects of this field. VCPs can act either as five-carbon synthons or three-carbon synthons, depending on whether the vinyl substituent is acting as an additional two-carbon synthon or not. As five-carbon synthons, VCPs are involved in [5+1], [5+2], [5+2+1], and [5+1+2+1] cycloadditions. As three-carbon synthons, VCPs are mainly involved in [3+2] and [3+2+1] cycloadditions. MCPs mostly act as three-carbon synthons and can have [3+2] cycloadditions with different pi systems. Other types of cycloadditions involving MCPs are also reviewed, such as [3+1], [3+2+2], and [4+3+2] cycloadditions. Cycloadditions of some other unusual cyclopropane derivatives are also introduced briefly. The cycloadditions of VCPs and MCPs have found applications in total synthesis and some representative molecules are tabulated as selected examples. PMID- 24797232 TI - Probing strongly correlated materials in non-equilibrium: basic concepts and possible future trends in first principle approaches. AB - Time-resolved spectroscopy has an emerging role among modern material characterization techniques. Two powerful theoretical formalisms for systems out of equilibrium (and thus for time-resolved spectroscopy) are Non-Equilibrium Green's Functions (NEGF) and Time-Dependent Density Functional Theory (TDDFT). In this chapter, we offer a perspective (with more emphasis on the NEGF) on their current capability to deal with the case of strongly correlated materials. To this end, the NEGF technique is briefly presented, and its use in time-resolved spectroscopy highlighted. We then show how a linear response description is recovered from NEGF real-time dynamics. This is followed by a review of a recent ab initio NEGF treatment and by a short introduction to TDDFT. With these background notions, we turn to the problem of describing strong correlation effects by NEGF and TDDFT. This is done in terms of model Hamiltonians: using simple lattice systems as benchmarks, we illustrate to what extent NEGF and TDDFT can presently describe complex materials out of equilibrium and with strong electronic correlations. Finally, an outlook is given on future trends in NEGF and TDDFT research of interest to time-resolved spectroscopy. PMID- 24797233 TI - Synthesis, structures, and physical properties of aromatic molecular-bowl hydrocarbons. AB - This chapter summarizes the synthesis, physical properties, structure, and crystal packing of buckybowls. Buckybowls exemplify an intermediate class of polynuclear aromatic compounds between the closed-shell fullerenes and the flat extended arrays of graphene. These warped sheets can be seen as fragments of fullerenes or the end cap of single-walled carbon nanotubes; and, their curvature endows them with physical properties distinct from flat polynuclear hydrocarbons, which opens up unique possibilities for molecular bowls in various organic materials applications. PMID- 24797234 TI - Modification of bipolar lipid conformation at the air/water interface by a single stereochemical variation. AB - This article describes the design and the synthesis of two analogues of archaeal bipolar lipids that differ only by the configuration of a single stereogenic centre on a glyceryl moiety. The corresponding comparative physicochemical study by tensiometry/ellipsometry and atomic force microscopy provided a set of data that points out the effect of this single stereochemical variation. The two epimers revealed different conformations at the air/water interface resulting in a more or less tendency for a bent or a stretched conformation. It strengthens the importance of the stereochemistry in such bipolar lipid packing. PMID- 24797235 TI - Is treatment with trimetazidine beneficial in patients with chronic heart failure? AB - BACKGROUND: Whether additional benefit can be achieved with the use of trimetazidine (TMZ) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of TMZ treatment in CHF patients. METHODS: We searched PubMed, EMBASE, and Cochrane databases through October 2013 and included 19 RCTs involving 994 CHF patients who underwent TMZ or placebo treatment. Risk ratio (RR) and weighted mean differences (WMD) were calculated using fixed or random effects models. RESULTS: TMZ therapy was associated with considerable improvement in left ventricular ejection fraction (WMD: 7.29%, 95% CI: 6.49 to 8.09, p<0.01) and New York Heart Association classification (WMD: 0.55, 95% CI: -0.81 to -0.28, p<0.01). Moreover, treatment with TMZ also resulted in significant decrease in left ventricular end-systolic volume (WMD: -17.09 ml, 95% CI: -20.15 to -14.04, p<0.01), left ventricular end-diastolic volume (WMD: 11.24 ml, 95% CI: -14.06 to -8.42, p<0.01), hospitalization for cardiac causes (RR: 0.43, 95% CI: 0.21 to 0.91, p = 0.03), B-type natriuretic peptide (BNP; WMD: -157.08 pg/ml, 95% CI: -176.55 to -137.62, p<0.01) and C-reactive protein (CRP; WMD: -1.86 mg/l, 95% CI: -2.81 to -0.90, p<0.01). However, there were no significant differences in exercise duration and all-cause mortality between patients treated with TMZ and placebo. CONCLUSIONS: TMZ treatment in CHF patients may improve clinical symptoms and cardiac function, reduce hospitalization for cardiac causes, and decrease serum levels of BNP and CRP. PMID- 24797236 TI - Traditionally produced sauerkraut as source of autochthonous functional starter cultures. AB - Spontaneous sauerkraut fermentation was performed at industrial scale in "Prehrana Inc.", Varazdin, in order to select autochthonous lactic acid bacteria (LAB) which were evaluated according probiotic criteria and tested for their capacity as probiotic starter cultures. At the end of the spontaneous sauerkraut fermentation, total LAB counts reached 9.0*10(5) CFU/ml. This underlines that the need for addition of the well characterised probiotic cultures, in appropriate viable cell counts, would be valuable in probiotic sauerkraut production. Phenotypic characterisation through API 50 CHL and SDS-PAGE of cell protein patterns revealed that Lactobacillus plantarum is predominant LAB strain in homofermentative phase of fermentation. Autochthonous LAB isolates SF1, SF2, SF4, SF9 and SF15 were selected based on the survival in in vitro gastrointestinal tract conditions. RAPD fingerprints indicated that the selected autochthonous LAB were distinct from one another. All of the strains efficiently inhibited the growth of indicator strains and satisfied technological properties such as acidification rate, tolerance to NaCl and viability during freeze-drying. Strains Lb. paraplantarum SF9 and Lb. brevis SF15, identified by AFLP DNA fingerprints, have shown the best properties to be applied as probiotic starter cultures, because of their highest adhesion to Caco-2 cells and expression of specific, protective S-layer proteins of 45 kDa in size. With addition of these strains, probiotic attribute of the sauerkraut will be achieved, including health promoting, nutritional, technological and economic advantages in large scale industrial sauerkraut production. PMID- 24797237 TI - Biomechanics of metastatic disease in the vertebral column. AB - Metastatic disease in the vertebral column compromises the structural stability of the spine leading to increased risk of fracture. The complex patterns of osteolytic and osteoblastic disease within the bony spine have motivated a multimodal approach to better characterize the biomechanics of tumor-involved bone. This review presents our current understanding of the biomechanical behavior of metastatically involved vertebrae, and experimental and computational image-based approaches that have been employed to quantify structural integrity in preclinical models with translation to clinical data sets. PMID- 24797238 TI - A comparison of the analgesia efficacy and side effects of paravertebral compared with epidural blockade for thoracotomy: an updated meta-analysis. AB - OBJECTIVE: The most recent systematic review and meta-analysis comparing the analgesic efficacy and side effects of paravertebral and epidural blockade for thoracotomy was published in 2006. Nine well-designed randomized trials with controversial results have been published since then. The present report constitutes an updated meta-analysis of this issue. SUMMARY OF BACKGROUND: Thoracotomy is a major surgical procedure and is associated with severe postoperative pain. Epidural analgesia is the gold standard for post-thoracotomy pain management, but has its limitations and contraindications, and paravertebral blockade is increasingly popular. However, it has not been decided whether the analgesic effect of the two methods is comparable, or whether paravertebral blockade leads to a lower incidence of adverse side effects after thoracotomy. METHODS: Two reviewers independently searched the databases PubMed, EMBASE, and the Cochrane Library (last performed on 1 February, 2013) for reports of studies comparing post-thoracotomy epidural analgesia and paravertebral blockade. The same individuals independently extracted data from the appropriate studies. RESULT: Eighteen trials involving 777 patients were included in the current analysis. There was no significant difference in pain scores between paravertebral blockade and epidural analgesia at 4-8, 24, 48 hours, and the rates of pulmonary complications and morphine usage during the first 24 hours were also similar. However, paravertebral blockade was better than epidural analgesia in reducing the incidence of urinary retention (p<0.0001), nausea and vomiting (p = 0.01), hypotension (p<0.00001), and rates of failed block were lower in the paravertebral blockade group (p = 0.01). CONCLUSIONS: This meta-analysis showed that PVB can provide comparable pain relief to traditional EPI, and may have a better side-effect profile for pain relief after thoracic surgery. Further high powered randomized trials are to need to determine whether PVB truly offers any advantages over EPI. PMID- 24797239 TI - Synthetic protocol toward fused pyrazolone derivatives via a Michael addition and reductive ring closing strategy. AB - A new class of pyrazolo[3,4-c]pyridine-3,7-dione and pyrazolo[3,4-d]azepine-3,7 dione scaffolds was synthesized via a Michael addition and reductive cyclization strategy. These fused heterocycles were accessed from simple starting materials such as nitroolefins and 3-ethoxycarbonyl(methylene)pyrazoline-5-one. The pyrazolo-fused heterocycles were obtained in good overall yields. PMID- 24797240 TI - Perioperative transfusion-related acute lung injury: the Canadian Blood Services experience. AB - PURPOSE: Transfusion-related acute lung injury (TRALI) is a devastating transfusion-associated adverse event. There is a paucity of data on the incidence and characteristics of TRALI cases that occur perioperatively. We classified suspected perioperative TRALI cases reported to Canadian Blood Services between 2001 and 2012, and compared them to non-perioperative cases to elucidate factors that may be associated with an increased risk of developing TRALI in the perioperative setting. METHODS: All suspected TRALI cases reported to Canadian Blood Services (CBS) since 2001 were reviewed by two experts or, from 2006 to 2012, the CBS TRALI Medical Review Group (TMRG). These cases were classified based on the Canadian Consensus Conference (CCC) definitions and detailed in a database. Two additional reviewers further categorized them as occurring within 72 h from the onset of surgery (perioperative) or not in that period (non perioperative). Various demographic and characteristic variables of each case were collected and compared between groups. RESULTS: Between 2001 and 2012, a total of 469 suspected TRALI cases were reported to Canadian Blood Services; 303 were determined to be within the TRALI diagnosis spectrum. Of those, 112 (38%) were identified as occurring during the perioperative period. Patients who underwent cardiac surgery requiring cardiopulmonary bypass (25.0%), general surgery (18.0%) and orthopedics patients (12.5%) represented the three largest surgical groups. Perioperative TRALI cases comprised more men (53.6% vs. 41.4%, p=0.04) than non-perioperative patients. Perioperative TRALI patients more often required supplemental O2 (14.3% vs. 3.1%, p=0.0003), mechanical ventilation (18.8% vs. 3.1%), or were in the ICU (14.3% vs. 3.7%, p=0.0043) prior to the onset of TRALI compared to non-perioperative TRALI patients. The surgical patients were transfused on average more components than non-perioperative patients (6.0 [SD=8.3] vs. 3.6 [5.2] products per patient, p=0.0002). Perioperative TRALI patients were transfused more plasma (152 vs. 105, p=0.013) and cryoprecipitate (51 vs. 23, p<0.01) than non-perioperative TRALI patients. There was no difference between donor antibody test results between the groups. CONCLUSION: CBS data has provided insight into the nature of TRALI cases that occur perioperatively; this group represents a large proportion of TRALI cases. PMID- 24797241 TI - Prevalence of irregular red blood cell antibodies among healthy blood donors in Delhi population. AB - OBJECTIVES: To evaluate the prevalence of the anti-red blood cell antibodies among healthy blood donors. MATERIAL AND METHODS: Antibody screening of all voluntary blood donor serum was performed as routine immunohematological procedure. Positive sera were further investigated to identify the specificity of irregular erythrocyte antibody by commercially available red cell panel (ID-Dia Panel, Diamed-ID Microtyping System). RESULT: A total of 47,450 donors were screened for the presence of irregular erythrocyte antibodies. A total of forty six donors showed presence of alloantibodies in their serum (46/47,450%, 0.09%), yielding a prevalence of 0.09%. Most frequent alloantibodies identified were of MNS blood group system. The results showed statistically a higher prevalence of RBC alloantibodies in females than in males. CONCLUSION: Screening for presence of alloantibodies in donor blood is important to provide compatible blood products and to avoid transfusion reactions. PMID- 24797242 TI - Comment on: have we reached the limits for the treatment of diabetic nephropathy? PMID- 24797243 TI - Electrical remodeling of preoptic GABAergic neurons involves the Kv1.5 subunit. AB - The electrogenic machinery of an excitable cell can adapt in response to changes in input, genetic deficit or in pathological conditions, however the underlying molecular mechanisms are not understood. In cases of genetic deletion it is commonly observed that a channel subunit from the same family replaces the missing one. We have previously reported that Kv4.2-/- preoptic GABAergic neurons display identical firing characteristics to those of wild-type neurons despite having reduced A-type currents, and that, surprisingly, they present a robust upregulation of a delayed rectifier current, the nature of which is unknown. Here, using pharmacology, qPCR and Western blots we report that, although the wild-type neurons express several Kv subunits, the upregulated current is conducted by the Kv1.5 subunit exclusively. Thus, this study reveals the molecular nature of a novel mechanism of electrical remodeling in central neurons. PMID- 24797244 TI - Prevalence of hypertension in Indian tribes: a systematic review and meta analysis of observational studies. AB - INTRODUCTION: In India there is an increasing trend in hypertension prevalence among the general population. Studies have shown that tribal populations in India are also experiencing this burden. OBJECTIVE: The aim was to estimate the pooled prevalence of primary hypertension among adult tribal populations of India. METHODS: A systematic search was conducted in MEDLINE, IndMed, Web of Science, Google Scholar and major journals for studies published between 1981 and 2011. Two authors independently reviewed the studies, did quality assessment and extracted data in pre-coded spread-sheets. Pooled estimates of prevalence of hypertension were calculated using DerSimonian-Laird random effects model. Subgroup and sensitivity analyses and meta-regression were performed. RESULTS: Twenty studies or 53 subpopulations with 64 674 subjects were included in final review. The pooled estimate of hypertension prevalence was 16.1% (95% CI: 13.5, 19.2). There was significant heterogeneity among the studies (I2 = 99% and Q = 4624.0, df = 53, p<0.001). Subgroup analyses showed that year of study, acculturation status, special features, and BP measurement techniques significantly influenced prevalence, but after meta-regression analyses, 'decade of study' remained the only covariate that significantly and independently influenced prevalence (R2 = 0.57, Q = 119.2, df = 49, p value <0.001). CONCLUSION: An increasing trend was found in the prevalence of hypertension in adult tribal populations across three decades. Although acculturation was probably the underlying agent that caused this increase, other unmeasured factors that need further research were also important. Concerned policy makers should focus on the changing health needs of tribal communities. PMID- 24797245 TI - Effects of exposure to intermittent versus continuous red light on human circadian rhythms, melatonin suppression, and pupillary constriction. AB - Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2) s(-1)), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light. PMID- 24797246 TI - Pharmacotherapeutic agents used in temporomandibular disorders. AB - Depending on the source and character, pharmacotherapy is one of the most commonly used methods to treat temporomandibular disorders in addition to the use of appliances, physiotherapy, behavioral therapy, and surgical interventions. To decide on the appropriate treatment approach for the treatment of temporomandibular disorders, pharmacotherapeutics should be understood in great detail. As for other pain treatments, pharmacotherapy can be used as a monotherapy or combined with other treatment options in temporomandibular disorders. The aim of the present review is to overview the primary analgesics and myorelaxants used in temporomandibular disorders. PMID- 24797248 TI - Superbasic alkyl-substituted bisphosphazene proton sponges: synthesis, structural features, thermodynamic and kinetic basicity, nucleophilicity and coordination chemistry. AB - Herein we describe an easily accessible class of superbasic proton sponges based on the 1,8-bisphosphazenylnaphthalene (PN) proton pincer motif and P-alkyl substituents ranging from methyl (TMPN) to n-butyl (TBPN), isopropyl (TiPrPN) and cyclopentyl (TcyPPN). These neutral bases with a pK(BH)(+) value (MeCN) of ~30 were accessible via a Kirsanov condensation using commercially available 1,8 diaminonaphthalene, and in case of TMPN and TBPN, simple one-pot procedures starting from trisalkylphosphanes can be performed. Furthermore, the known pyrrolidinyl-substituted superbase TPPN previously synthesized via a Staudinger reaction could also be prepared by the Kirsanov strategy allowing its preparation in a larger scale. The four alkyl-substituted proton sponges were structurally characterized in their protonated form; molecular XRD structures were also obtained for unprotonated TiPrPN and TcyPPN. Moreover, we present a detailed description of spectroscopic features of chelating bisphosphazenes including TPPN and its hyperbasic homologue P2-TPPN on which we reported recently. The four alkyl-substituted superbases were investigated with respect to their basic features by computational means and by NMR titration experiments revealing unexpectedly high experimental pK(BH)(+) values in acetonitrile between 29.3 for TMPN and 30.9 for TBPN. Besides their thermodynamic basicity, we exemplarily studied the kinetic basicity of TMPN and TPPN by means of NMR-spectroscopic methods. Furthermore, the competing nucleophilic versus basic properties were examined by reacting the proton sponges with ethyl iodide. Insight into the coordination chemistry of chelating superbases was provided by reacting TMPN with trimethylaluminum and trimethylgallium to give cationic complexes of Group XIII metal alkyls that were structurally characterized. PMID- 24797247 TI - Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study. AB - Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to >= 4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [CI]: 0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95% CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant. CONCLUSION: Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer. PMID- 24797249 TI - Allergen component specific ige measurement with the ImmuliteTM 2000 system: diagnostic accuracy and intermethod comparison. AB - BACKGROUND: The identification of the allergenic molecules, associated to the advances in the field of recombinant allergens, led to the development of a new concept in allergy diagnosis called component-resolved diagnosis. The aim of our study was to evaluate the diagnostic accuracy of different allergen components using the full automatic singleplex quantitative platform ImmuliteTM 2000. METHODS: One hundred ninety-five allergic outpatients (35 to olive pollen, 35 to birch pollen, 35 to profilin, 35 to house dust mites, 35 to peach, and 20 to shrimp) and 20 negative controls were enrolled for the study. Bet v 1, Bet v 2, Ole e 1, Der p 1, Der p 2, Der f 1, Der f 2, Pru p 3, tropomyosin were tested both with ImmuliteTM 2000 and ImmunoCAPTM (Thermo Fisher Scientific, Uppsala, Sweden). RESULTS: Sensitivity of allergen-specific Immunoglobulin E (sIgE) to Ole e 1, Bet v 1, Der p 1, Der p 2, Der f 1, Der f 2, Pen m 1, and Pru p 3 with ImmuliteTM 2000 was 100%, 100%, 77.1%, 94.3%, 71.4%, 94%, 75%, and 97.1%, respectively, and the specificity was 100% for all the allergens. The overall agreement between ImmuliteTM 2000 and ImmunoCAPTM (Thermo Fisher Scientific) platforms was 98.6% (Cohen's kappa = 0.979; confidence interval [CI] 95%: 0.960 0.997). From moderate to strong, positive linear correlations between the assays (r(2) from 0.322 to 0.860, and Spearman's rho from 0.824 to 0.971) were showed. CONCLUSIONS: A high diagnostic accuracy of the sIgE to allergen components measurement with ImmuliteTM 2000 and a high agreement with ImmunoCAPTM platforms were shown in this study. PMID- 24797250 TI - Anterior chamber keratinous horn. AB - A 14-year-old boy presented with a 6-month history of small white masses in his right eye. Examination revealed a white floating fluffy lesion and 2 vegetative hornlike white lesions originating at the periphery of the iris. On ultrasound biomicroscopy, a normal echogenic mass was detected on the inferior iris root and angle, with no posterior chamber or cilliary body involvement. Histopathology following an excisional biopsy revealed keratinous material. There was no recurrence during 10 months of follow-up. PMID- 24797251 TI - Quantifying fibrosis in head and neck cancer treatment: An overview. AB - BACKGROUND: Fibrosis is a common late complication of radiotherapy and/or surgical treatment for head and neck cancers. Fibrosis is difficult to quantify and formal methods of measure are not well recognized. The purpose of this review was to summarize the methods available to quantify neck fibrosis. METHODS: A PubMed search of articles was carried out using key words "neck" and "fibrosis." RESULTS: Many methods have been used to assess fibrosis, however, there is no preferred methodology. Specific to neck fibrosis, most studies have relied upon hand palpation rating scales. Indentation and suction techniques have been used to mechanically quantify neck fibrosis. There is scope to develop applications of ultrasound, dielectric, bioimpedance, and MRI techniques for use in the neck region. CONCLUSION: Quantitative assessment of neck fibrosis is sought after in order to compare treatment regimens and improve quality of life outcomes in patients with head and neck cancer. PMID- 24797252 TI - African American cancer survivors: do cultural factors influence symptom distress? AB - PURPOSE: The purpose of this study was to examine how the cultural factors, stigma, being strong, and religiosity influence symptom distress in African American cancer survivors. METHODS: This descriptive correlational study was designed using the Sociocultural Stress and Coping Framework. Seventy-seven African American cancer survivors, recruited from oncology clinics and the community in North Carolina, completed a questionnaire that consisted of measures of demographic and illness characteristics, the Perceived Stigma Scale, the Ways of Helping Questionnaire, the Religious Involvement Scale, and the Symptom Distress Scale. RESULTS: The two cultural factors that were significantly associated with symptom distress were stigma (beta = .23, p < .05) and organized religion (beta = -.50, p < .05). No significant associations were found between being strong or nonorganized religiosity and symptom distress. The most commonly reported symptoms were fatigue (M = 2.44, SD = 1.20), pain (M = 2.26, SD = 1.43), and insomnia (M = 1.95, SD = 1.25). CONCLUSIONS: The findings of this study indicate that the cultural factors, stigma, and organized religiosity were significantly associated with symptom distress. IMPLICATIONS FOR PRACTICE: The results from this study can be used to guide researchers in developing culturally appropriate interventions aimed at alleviating symptom distress in African American cancer survivors. PMID- 24797253 TI - An ethnographic exploration of postoperative pain experiences among Ghanaian surgical patients. AB - BACKGROUND: The experience of pain associated with surgery has been a challenge for health care professionals for many years, and culture is said to influence pain. PURPOSE: This study focused on patients' experiences of postoperative pain (POP) and factors that affect POP. DESIGN: The study employed qualitative ethnographic principles. METHOD: Data were collected through individual face-to face interviews. Data were saturated after analyzing data from 13 patients from two hospitals in Ghana. FINDINGS: Themes that emerged were the subjective nature of pain, which described pain dimensions and communication; psycho-sociocultural factors, such as personal inclinations and sociocultural background; and health system factors, such as personnel attitudes and health financing. IMPLICATIONS FOR FUTURE RESEARCH AND PRACTICE: Health professionals need to understand the sociocultural effects of pain in order to give effective care. CONCLUSION: The study highlighted the need for patient education and the importance that health care professionals understand context-specific factors that influence POP management. PMID- 24797254 TI - Perceived unsatisfactory care as a barrier to diabetes self-management for Coeur d'Alene tribal members with type 2 diabetes. AB - The prevalence of diabetes and related complications are disproportionally higher in Native Americans. Diabetes self-management (DSM) is instrumental in preventing complications. The results presented here are a part of a larger hermeneutic phenomenology study to explore living with diabetes for one Pacific Northwest tribe. This study identified barriers to DSM within the worldview of the tribal people. Using purposive sampling, 10 Coeur d'Alene tribal members, ages 26 to 86 years, participated in in-depth interviews. Data interpretation used a three-step method leading to integrated themes across the transcripts. Perceived unsatisfactory care emerged as the major barrier to self-management, including communication barriers (distrust, misunderstanding, and educational methods) and organizational barriers (quality of care and access issues). Findings highlight the need to improve cross-cultural communication and calls for different approaches to diabetes education. Our profession is challenged to create new DSM and diabetes educational approaches for acceptable and compassionate cross cultural nursing care. PMID- 24797255 TI - A systematic review of barriers and facilitators to mammography in Hispanic women. AB - PURPOSE: A systematic review of the research on barriers and facilitators to mammography in Latinas was conducted to determine if the challenges faced by these women are unique to this population. METHOD: Medline and CINAHL database searches for the years 2005-2013 were included. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were used to guide this review. RESULTS: Of the 174 articles identified, 18 articles met inclusion criteria. The most consistent findings were that income and education were associated with screening. CONCLUSIONS: Financial barriers and social characteristics were significant predictors of mammography in these studies, which were composed almost exclusively of low-income Latinas. These findings are similar to those found in other populations of low-income women and therefore are not likely unique to Latinas. IMPLICATIONS FOR PRACTICE: It is likely that there is little difference between poor Latinas and other populations of poor, non English-speaking women in barriers and facilitators to mammography. PMID- 24797256 TI - Comparison of infant vitamin D supplement use among Canadian-born, immigrant, and refugee mothers. AB - PURPOSE: This study compares knowledge and practice of infant vitamin D supplementation among immigrant, refugee, and Canadian-born mothers. METHOD: Focus group discussions with 94 mothers of children aged 0 to 3 years recruited from early childhood centers and a refugee health clinic. FINDINGS: Both immigrant and Canadian-born mothers indicated good knowledge and use of infant vitamin D supplementation. In contrast, Canadian government-assisted refugees were less likely to supplement with vitamin D. The main source of information about vitamin D was public health prenatal classes. Many mothers reported inconsistent guidance from health care providers. DISCUSSION AND CONCLUSIONS: Exclusively breastfed infants of refugees may be more at risk of vitamin D deficiency. All mothers require clear recommendations, both in clinical and public health settings. IMPLICATIONS FOR PRACTICE: Mothers, both new Canadian and Canadian-born, require clear and consistent messaging from health professionals. Refugee mothers, however, require more educational support to promote infant vitamin D supplementation. PMID- 24797257 TI - Novel bronchoscopic strategies for the diagnosis of peripheral lung lesions: present techniques and future directions. AB - The diagnosis of the peripheral lung lesion has been a long-standing clinical challenge--balancing accuracy with patient safety. With recent data revealing mortality benefits with lung cancer screening via low-dose computed tomography, now more than ever, clinicians will be challenged with the task of providing the means to provide a safe and minimally invasive method of obtaining accurate tissue diagnostics for the pulmonary nodule. In this review, we present available technologies to aid clinicians in attempts at minimally invasive techniques and the data supporting their use. In addition, we review novel tools under investigation that may further increase yield and provide additional benefit in obtaining an early diagnosis of lung cancer. PMID- 24797260 TI - Mesenchymal stem cell based therapy for osteo-diseases. AB - Stem cell therapy in recent years has gained much attention as the modern therapeutic approach to treat diseases. Mesenchymal stem cells (MSCs) are seen as the most reliable cells applied in therapy over other stem cells because of their versatility. Bone and cartilage diseases (osteo-diseases) are the major target of therapy using MSCs. In this perspective, we have statistically analyzed the data available on clinical trials registry databases regarding the mesenchymal stem cell based therapy for a number of mentioned diseases and paid attention towards the osteodiseases. We report that MSC therapy for osteo-diseases needs optimization in its standards to achieve acceptable results so that we can apply it in daily routine clinical practice. PMID- 24797261 TI - Surface passivation for single-molecule protein studies. AB - Single-molecule fluorescence spectroscopy has proven to be instrumental in understanding a wide range of biological phenomena at the nanoscale. Important examples of what this technique can yield to biological sciences are the mechanistic insights on protein-protein and protein-nucleic acid interactions. When interactions of proteins are probed at the single-molecule level, the proteins or their substrates are often immobilized on a glass surface, which allows for a long-term observation. This immobilization scheme may introduce unwanted surface artifacts. Therefore, it is essential to passivate the glass surface to make it inert. Surface coating using polyethylene glycol (PEG) stands out for its high performance in preventing proteins from non-specifically interacting with a glass surface. However, the polymer coating procedure is difficult, due to the complication arising from a series of surface treatments and the stringent requirement that a surface needs to be free of any fluorescent molecules at the end of the procedure. Here, we provide a robust protocol with step-by-step instructions. It covers surface cleaning including piranha etching, surface functionalization with amine groups, and finally PEG coating. To obtain a high density of a PEG layer, we introduce a new strategy of treating the surface with PEG molecules over two rounds, which remarkably improves the quality of passivation. We provide representative results as well as practical advice for each critical step so that anyone can achieve the high quality surface passivation. PMID- 24797262 TI - Identification of serum cytokine profiles associated with HBeAg seroconversion following antiviral treatment interruption. AB - The major shortcoming of nucleos(t)ide analogue therapy for chronic hepatitis B (CHB) is the frequent requirement for indefinite therapy. Withdrawal of treatment can result in viral rebound with an alanine aminotransferase (ALT) flare leading to hepatic decompensation, while in others this can lead to hepatitis B e antigen (HBeAg) seroconversion. The aim of the study was to identify host immune profiles associated with these different outcomes. Eighteen HBeAg(+) patients, enrolled on a phase III trial with the nucleoside analogue adefovir dipivoxil, were followed for up to 128 weeks. For the first 48 weeks, all patients received continuous therapy. Subsequently, patients experienced cycles of treatment interruptions due to random drug/placebo misallocations. Host immune profiles were characterized by measuring a panel of serum cytokines before, during, and after each cycle of treatment withdrawal. Virus-specific T-cell responses were also determined at these time points in a subset of patients to elucidate the mechanisms utilized to control hepatitis B virus (HBV) replication post-treatment. Significantly, elevated levels of IFN-gamma, IP-10, and IL-2 on-treatment were associated with HBeAg seroconversion after treatment withdrawal. In these patients, treatment interruption induced further increases in serum IFN-gamma levels and marked increases in virus-specific T-cells producing IFN-gamma, but minimal alterations in viremia and ALT. In HBeAg(+) patients with low on-treatment levels of serum IFN-gamma, the interruption of therapy induced significant elevations in HBV-DNA, ALT, IP-10, and increases in virus-specific T-cells producing IL-10. Evaluating on-treatment serum cytokines in concert with virologic and clinical parameters may help to identify CHB patients who can successfully discontinue nucleos(t)ide analogue therapy. PMID- 24797263 TI - Proteomic analysis of the epidermal growth factor receptor (EGFR) interactome and post-translational modifications associated with receptor endocytosis in response to EGF and stress. AB - Aberrant expression, activation, and stabilization of epidermal growth factor receptor (EGFR) are causally associated with several human cancers. Post translational modifications and protein-protein interactions directly modulate the signaling and trafficking of the EGFR. Activated EGFR is internalized by endocytosis and then either recycled back to the cell surface or degraded in the lysosome. EGFR internalization and recycling also occur in response to stresses that activate p38 MAP kinase. Mass spectrometry was applied to comprehensively analyze the phosphorylation, ubiquitination, and protein-protein interactions of wild type and endocytosis-defective EGFR variants before and after internalization in response to EGF ligand and stress. Prior to internalization, EGF-stimulated EGFR accumulated ubiquitin at 7 K residues and phosphorylation at 7 Y sites and at S(1104). Following internalization, these modifications diminished and there was an accumulation of S/T phosphorylations. EGFR internalization and many but not all of the EGF-induced S/T phosphorylations were also stimulated by anisomycin-induced cell stress, which was not associated with receptor ubiquitination or elevated Y phosphorylation. EGFR protein interactions were dramatically modulated by ligand, internalization, and stress. In response to EGF, different E3 ubiquitin ligases became maximally associated with EGFR before (CBL, HUWE1, and UBR4) or after (ITCH) internalization, whereas CBLB was distinctively most highly EGFR associated following anisomycin treatment. Adaptin subunits of AP-1 and AP-2 clathrin adaptor complexes also became EGFR associated in response to EGF and anisomycin stress. Mutations preventing EGFR phosphorylation at Y(998) or in the S(1039) region abolished or greatly reduced EGFR interactions with AP-2 and AP-1, and impaired receptor trafficking. These results provide new insight into spatial, temporal, and mechanistic aspects of EGFR regulation. PMID- 24797264 TI - Identification of small ubiquitin-like modifier substrates with diverse functions using the Xenopus egg extract system. AB - Post-translational modification by SUMO is a highly conserved pathway in eukaryotes that plays very important regulatory roles in many cellular processes. Deregulation of the SUMO pathway contributes to the development and progression of many diseases including cancer. Therefore, identifying additional SUMO substrates and studying how their cellular and biological functions are regulated by sumoylation should provide new insights. Our studies showed that sumoylation activity was significant in Xenopus egg extracts, and that a high level of sumoylation was associated with sperm chromatin when SUMO was incubated with Xenopus egg extracts. By isolating SUMO-conjugated substrates using His-tagged SUMO1 or SUMO2 proteins under denaturing conditions, we identified 346 proteins by mass spectrometry analysis that were not present in control pull-downs. Among them, 167 proteins were identified from interphase egg extracts, 86 proteins from mitotic phase egg extracts, and 93 proteins from both. Thirty-three proteins were pulled down by SUMO1, 85 proteins by SUMO2, and 228 proteins by both. We validated the sumoylation of five candidates, CKB, ATXN10, BTF3, HABP4, and BZW1, by co-transfecting them along with SUMO in HEK293T cells. Gene ontology analysis showed that SUMO substrates identified in this study were involved in diverse biological processes. Additionally, SUMO substrates identified from different cell cycle stages or pulled down by different SUMO homologs were enriched for distinct cellular components and functional categories. Our results comprehensively profile the sumoylation occurring in the Xenopus egg extract system. PMID- 24797265 TI - O-Glycosylation of the N-terminal region of the serine-rich adhesin Srr1 of Streptococcus agalactiae explored by mass spectrometry. AB - Serine-rich (Srr) proteins exposed at the surface of Gram-positive bacteria are a family of adhesins that contribute to the virulence of pathogenic staphylococci and streptococci. Lectin-binding experiments have previously shown that Srr proteins are heavily glycosylated. We report here the first mass-spectrometry analysis of the glycosylation of Streptococcus agalactiae Srr1. After Srr1 enrichment and trypsin digestion, potential glycopeptides were identified in collision induced dissociation spectra using X! Tandem. The approach was then refined using higher energy collisional dissociation fragmentation which led to the simultaneous loss of sugar residues, production of diagnostic oxonium ions and backbone fragmentation for glycopeptides. This feature was exploited in a new open source software tool (SpectrumFinder) developed for this work. By combining these approaches, 27 glycopeptides corresponding to six different segments of the N-terminal region of Srr1 [93-639] were identified. Our data unambiguously indicate that the same protein residue can be modified with different glycan combinations including N-acetylhexosamine, hexose, and a novel modification that was identified as O-acetylated-N-acetylhexosamine. Lectin binding and monosaccharide composition analysis strongly suggested that HexNAc and Hex correspond to N-acetylglucosamine and glucose, respectively. The same protein segment can be modified with a variety of glycans generating a wide structural diversity of Srr1. Electron transfer dissociation was used to assign glycosylation sites leading to the unambiguous identification of six serines and one threonine residues. Analysis of purified Srr1 produced in mutant strains lacking accessory glycosyltransferase encoding genes demonstrates that O GlcNAcylation is an initial step in Srr1 glycosylation that is likely required for subsequent decoration with Hex. In summary, our data obtained by a combination of fragmentation mass spectrometry techniques associated to a new software tool, demonstrate glycosylation heterogeneity of Srr1, characterize a new protein modification, and identify six glycosylation sites located in the N terminal region of the protein. PMID- 24797266 TI - Cord blood CD34+ cells expanded on Wharton's jelly multipotent mesenchymal stromal cells improve the hematopoietic engraftment in NOD/SCID mice. AB - OBJECTIVE: This study aims to investigate the capability of Wharton's jelly multipotent mesenchymal stromal cells (WJ-MSC) to support the in vitro expansion of hematopoietic stem/progenitor cells (HSPC) derived from cord blood (CB) in the absence of exogenous cytokines, and the effect on engraftment of the expanded cells in a mouse model. METHODS: CB-CD34+ cells were seeded on WJ-MSC layer and cultured in HP01 serum-free medium. Day-7 and day-13 expanded cells were transplanted in NOD/SCID mice. After 8 wk, engraftment was evaluated in mouse bone marrow as percentage of human CD45+ cells. RESULTS: CD34+ population was expanded without increasing the differentiation rate. Co-culture increased the expansion of the CD34+ cells by 2.0 and 7.3 times after 7 and 13 d, respectively, and maintained the CD34+ cells up to day 20. In particular, earlier CD34+/CD90+ and CD34+/CD33- subtypes were increased. An advantage of the day-7 co-cultured HSPC in respect of HSPC at day 0 in the engraftment of NOD/SCID mice was obtained both as percentage of mice engrafted (100% vs. 75%) and as percentage of chimerism. CONCLUSIONS: Although the increase in hematopoietic progenitors is not dramatic as in the presence of added cytokines, this study demonstrates the effectiveness of the WJ-MSC not only to preserve the CD34+ population but also to improve the repopulating efficacy of the amplified HSPC, also in the absence of added cytokines and growth factors. PMID- 24797267 TI - Perceived barriers among physicians for stopping non-cost-effective blood-saving measures in total hip and total knee arthroplasties. AB - BACKGROUND: Despite evidence that the blood-saving measures (BSMs) erythropoietin (EPO) and intra- and postoperative blood salvage are not (cost-)effective in primary elective total hip and knee arthroplasties, they are used frequently in Dutch hospitals. This study aims to assess the impact of barriers associated with the intention of physicians to stop BSMs. STUDY DESIGN AND METHODS: A survey among 400 orthopedic surgeons and 400 anesthesiologists within the Netherlands was performed. Multivariate logistic regression was used to identify barriers associated with intention to stop BSMs. RESULTS: A total of 153 (40%) orthopedic surgeons and 100 (27%) anesthesiologists responded. Of all responders 67% used EPO, perioperative blood salvage, or a combination. After reading the evidence on non-cost-effective BSMs, 50% of respondents intended to stop EPO and 53% to stop perioperative blood salvage. In general, barriers perceived most frequently were lack of attention for blood management (90% of respondents), department priority to prevent transfusions (88%), and patient characteristics such as comorbidity (81%). Barriers significantly associated with intention to stop EPO were lack of interest to save money and the impact of other involved parties. Barriers significantly associated with intention to stop perioperative blood salvage were concerns about patient safety, lack of alternatives, losing experience with the technique, and lack of interest to save money. CONCLUSION: Physicians experience barriers to stop using BSMs, related to their own technical skills, patient safety, current blood management policy, and lack of interest to save money. These barriers should be targeted in strategies to make BSM use cost-effective. PMID- 24797268 TI - A 78-year-old female patient with severe resistant hypertension and chronic kidney disease stage 5 treated by renal denervation. PMID- 24797269 TI - The neuralgias: diagnosis and management. AB - The neuralgias are characterized by pain in the distribution of a cranial or cervical nerve. While most often brief, severe, and paroxysmal, continuous neuropathic pain may occur. The most commonly encountered entities include trigeminal, postherpetic, glossopharyngeal, and occipital neuralgia. More unusual cranial neuralgias may occur in periorbital (eg, supraorbital neuralgia) and auricular (eg, nervus intermedius neuralgia) distributions. These disorders may be mimicked by structural and inflammatory/infectious neurologic disease, along with other primary headache disorders (eg, primary stabbing headache). The approach to diagnosis and treatment of this group of headache disorders is reviewed. PMID- 24797270 TI - Diagnostic ultrasound imaging of mouse diaphragm function. AB - Function analysis of rodent respiratory skeletal muscles, particularly the diaphragm, is commonly performed by isolating muscle strips using invasive surgical procedures. Although this is an effective method of assessing in vitro diaphragm activity, it involves non-survival surgery. The application of non invasive ultrasound imaging as an in vivo procedure is beneficial since it not only reduces the number of animals sacrificed, but is also suitable for monitoring disease progression in live mice. Thus, our ultrasound imaging method may likely assist in the development of novel therapies that alleviate muscle injury induced by various respiratory diseases. Particularly, in clinical diagnoses of obstructive lung diseases, ultrasound imaging has the potential to be used in conjunction with other standard tests to detect the early onset of diaphragm muscle fatigue. In the current protocol, we describe how to accurately evaluate diaphragm contractility in a mouse model using a diagnostic ultrasound imaging technique. PMID- 24797272 TI - Bone marrow-derived macrophages incorporate into the endothelium and influence vascular and renal function after irradiation. AB - PURPOSE: We recently demonstrated that endoglin, an ancillary transforming growth factor beta (TGF-beta) receptor, modulates vascular damage and fibrosis formation and influences renal function after kidney irradiation. We also suggested that this was partially accomplished by endoglin-mediated regulation of cytokine production in macrophages. Endoglin is expressed on both endothelial cells and on activated macrophages. Therefore, in the current study, we addressed the respective contribution of altered endoglin levels in the different cellular compartments to the development of kidney toxicity after irradiation. MATERIALS AND METHODS: Female endoglin wild-type (Eng(+/+) or WT) or heterozygous (Eng(+/-) or HET) mice were subjected to total body irradiation (2 * 6 Gy with a 6-hour interval) followed by kidney irradiation (1 * 3 Gy). Recipient mice were then transplanted with 4 * 10E(6) green fluorescent protein heterozygous (GFP(+/-)) bone marrow cells from either Eng(+/+) or Eng(+/-) male donor mice. Chimerism was determined 6 weeks thereafter. Blood samples were taken every 10 weeks after irradiation and at sacrifice at 35 weeks. One kidney was used to isolate macrophages; the other kidney was used for histology and to determine cytokine and chemokine concentrations. RESULTS: In all treatment groups, the majority of infiltrating macrophages were bone marrow-derived and this was not altered by endoglin. Bone marrow cells accumulated in damaged tissue areas in the interstitium, but also incorporated into the vasculature. Reducing endoglin levels in macrophages, but not in the endothelium, led to improved renal function (hematocrit, blood urea nitrogen) after irradiation. This was probably promoted by lowered production of pro-inflammatory cytokines and chemokines in macrophages. Other measurements of tissue toxicity (pericyte coverage, fibrosis, damage score) were not altered by differential endoglin expression. CONCLUSIONS: Endoglin regulates pro-inflammatory macrophage properties thereby influencing vascular and renal function after kidney irradiation. PMID- 24797273 TI - Editorial comment to Estimating age and ethnic variation in the histological prevalence of prostate cancer to inform the impact of screening policies. PMID- 24797271 TI - A toolbox for tuberculosis (TB) diagnosis: an Indian multi-centric study (2006 2008); evaluation of serological assays based on PGL-Tb1 and ESAT-6/CFP10 antigens for TB diagnosis. AB - BACKGROUND: The aim of this multi-centric prospective study in India was to assess the accuracy of a serological test as an additional tool for diagnosing active tuberculosis (ATB). In particular, an assay based on ELISA using a phenolic glycolipid (PGL-Tb1) or a fusion protein (ESAT-6/CFP10) was compared to the tuberculin skin test (TST) and the microbiological results according to HIV status. METHODS: Individuals with and without ATB and HIV infection were enrolled. Serology and TST results were analyzed per se and in combination with the microbiological data. RESULTS: Among the 778 ATB patients, 102 were HIV infected, 316 HIV-uninfected and 360 had an HIV-unknown status. Of the 945 non ATB subjects, 559 were at low risk (community adults) and 386 at high risk of M. tuberculosis exposure. Among those with ATB, the sensitivity of ELISA-PGL-Tb1 for ATB was higher than that of ELISA-ESAT-6/CFP10, both in HIV-infected (72.3% versus 63.7%, p = 0.29) and HIV-uninfected/HIV-unknown groups (40.5% versus 28.6%; p<0.0001), whereas the specificity was around 91% for both tests. Sensitivity for ATB increased when the results of the two ELISA were combined, reaching 75.5% in the HIV-infected and 50.9% in the group of HIV-uninfected/HIV unknown ATB, with a significant decrease of the global specificity (83.9%). Analyzing the ELISA results with the microbiological results, we observed that the sensitivity of both serology tests was independent of the ATB patients' smear microscopy (SM) status and grade. Combining the results of SM with both ELISA, the detection of ATB patients significantly increased (p<0.0001), particularly in those with extrapulmonary TB (up to 45.1%) or HIV infection (up to 83.3%). No significant association was observed between TST and serology results. CONCLUSIONS: In this prospective multi-centric study, the combination of two rapid tests, such as SM and serology, might be useful in detecting ATB, especially in HIV-infected patients. PMID- 24797275 TI - The placentation of eulipotyphla-reconstructing a morphotype of the Mammalian placenta. AB - Placentation determines the developmental status of the neonate, which can be considered as the most vulnerable stage in the mammalian life cycle. In this respect, the different evolutionary and ecological adaptations of marsupial and placental mammals have most likely been associated with the different reproductive strategies of the two therian clades. The morphotypes of marsupial and placental neonates, as well as the placental stem species pattern of Marsupialia, have already been reconstructed. To contribute to a better understanding of the evolution of Placentalia, a histological and ultrastructural investigation of the placenta in three representatives of Eulipotyphla, that is, core insectivores, has been carried out in this study. We studied the Musk shrew (Suncus murinus), the four-toed hedgehog (Atelerix albiventris), and the Iberian mole (Talpa occidentalis). As a result, a eulipotyphlan placental morphotype consisting of a compact and invasive placenta was reconstructed. This supports the widely accepted hypothesis that the stem lineage of Placentalia is characterized by an invasive, either endothelio- or hemochorial placenta. Evolutionary transformations toward a diffuse, noninvasive placenta occurred in the stem lineages of lower primates and cetartiodactyles and were associated with prolonged gestation and the production of few and highly precocial neonates. Compared to the choriovitelline placenta of Marsupialia, the chorioallantoic placenta of Placentalia allows for a more intimate contact and is associated with more advanced neonates. PMID- 24797274 TI - Shiga-like toxin B subunit of Escherichia coli as scaffold for high-avidity display of anti-immunocomplex peptides. AB - Small compounds cannot bind simultaneously to two antibodies, and thus, their immunodetection is limited to competitive formats in which the analyte is indirectly quantitated by measuring the unoccupied antibody binding sites using a competing reporter. This limitation can be circumvented by using phage-borne peptides selected for their ability to specifically react with the analyte antibody immunocomplex, which allows the detection of these small molecules in a noncompetitive format (PHAIA) with increased sensitivity and a positive readout. In an effort to find substitutes for the phage particles in PHAIA, we explore the use of the B subunit of the Shiga-like toxin of Escherichia coli, also known as verotoxin (VTX), as a scaffold for multivalent display of anti-immunocomplex peptides. Using the herbicides molinate and clomazone as model compounds, we built peptide-VTX recombinant chimeras that were produced in the periplasmic space of E. coli as soluble pentamers, as confirmed by multiangle light scattering analysis. These multivalent constructs, which we termed nanopeptamers, were conjugated to a tracer enzyme and used to detect the herbicide-antibody complex in an ELISA format. The VTX-nanopeptamer assays performed with over a 10 fold increased sensitivity and excellent recovery from spiked surface and mineral water samples. The carbon black-labeled peptide-VTX nanopeptamers showed great potential for the development of a lateral-flow test for small molecules with a visual positive readout that allowed the detection of up to 2.5 ng/mL of clomazone. PMID- 24797277 TI - The nursing educator's role in e-learning: a literature review. AB - BACKGROUND: e-Learning is becoming more commonplace in nursing and healthcare professional education. Research has shown that e-learning can be just as effective at helping students achieve cognitive learning objectives as traditional face-to-face courses, provided that certain quality criteria are met. However, the decentralized, asynchronous nature of e-learning precludes spontaneous, personal interaction between the instructor and the learner. In addition to this, learning objectives in nursing and other healthcare professions are not only within the cognitive, but also within the affective and psychomotor domains. OBJECTIVE: This article seeks to answer the following question: How does e-learning transform the role of nurse educators? DESIGN: Narrative literature review. REVIEW METHODS: A comprehensive database search was conducted using the English and German key words "teacher," "educator," "role," "e-learning," and "nursing" to identify literature that examined the role of (nurse) educators in e learning. RESULTS: The search strategy resulted in the inclusion of 40 sources. The majority of the literature is expert opinion and examines the educator's role in e-learning from a theoretical point of view (n=30). There is a paucity of empirical research pertaining directly to the educator's role (n=10). Only four sources deal specifically with the nurse educator's role. CONCLUSIONS: The literature agrees on the need for a new role definition in light of e-learning. This role is more complex than the educator's traditional role. The literature does not provide any indication of how the educator's role can be adapted to the specific needs of online nurse education. There is a need for more empirical research on this subject. PMID- 24797278 TI - Expression of Chlorovirus MT325 aquaglyceroporin (aqpv1) in tobacco and its role in mitigating drought stress. AB - MAIN CONCLUSIONS: A Chlorovirus aquaglyceroporin expressed in tobacco is localized to the plastid and plasma membranes. Transgenic events display improved response to water deficit. Necrosis in adult stage plants is observed. Aquaglyceroporins are a subclass of the water channel aquaporin proteins (AQPs) that transport glycerol along with other small molecules transcellular in addition to water. In the studies communicated herein, we analyzed the expression of the aquaglyceroporin gene designated, aqpv1, from Chlorovirus MT325, in tobacco (Nicotiana tabacum), along with phenotypic changes induced by aqpv1 expression in planta. Interestingly, aqpv1 expression under control of either a constitutive or a root-preferred promoter, triggered local lesion formation in older leaves, which progressed significantly after induction of flowering. Fusion of aqpv1 with GFP suggests that the protein localized to the plasmalemma, and potentially with plastid and endoplasmic reticulum membranes. Physiological characterizations of transgenic plants during juvenile stage growth were monitored for potential mitigation to water dry-down (i.e., drought) and recovery. Phenotypic analyses on drought mimic/recovery of juvenile transgenic plants that expressed a functional aqpv1 transgene had higher photosynthetic rates, stomatal conductance, and water use efficiency, along with maximum carboxylation and electron transport rates when compared to control plants. These physiological attributes permitted the juvenile aqpv1 transgenic plants to perform better under drought-mimicked conditions and hastened recovery following re-watering. This drought mitigation effect is linked to the ability of the transgenic plants to maintain cell turgor. PMID- 24797279 TI - The Moonwalker mouse: new insights into TRPC3 function, cerebellar development, and ataxia. AB - The Moonwalker (Mwk) mouse is a recent model of dominantly inherited cerebellar ataxia. The motor phenotype of the Mwk mouse is due to a gain-of-function mutation in the gene encoding the cation-permeable transient receptor potential channel (TRPC3). This mutation converts a threonine into an alanine in the highly conserved cytoplasmic S4-S5 linker of the channel, affecting channel gating. TRPC3 is highly expressed in cerebellar Purkinje cells and type II unipolar brush cells that both degenerate in the Mwk mouse. Studies of the Mwk mouse have provided new insights into the role of TRPC3 in cerebellar development and disease, which could not have been predicted from the Trpc3 knockout phenotype. Here, the genetic, behavioral, histological, and functional characterization of the Mwk mouse is reviewed. Moreover, the relationship of the Mwk mutant to other cerebellar mouse models and its relevance as a model for cerebellar ataxia are discussed. PMID- 24797280 TI - Limitation of TREC-based newborn screening for ZAP70 Severe Combined Immunodeficiency. PMID- 24797281 TI - Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. AB - Serum alpha-fetoprotein (AFP) has been increasingly recognized as a marker for a poor prognosis after liver transplantation (LT) for hepatocellular carcinoma (HCC). Many published reports, however, have included a large proportion of patients with HCC beyond the Milan criteria, and the effects of incorporating AFP as an exclusion criterion for LT remain unclear. We studied 211 consecutive patients undergoing LT for HCC within the Milan criteria according to imaging under the Model for End-Stage Liver Disease organ allocation system between June 2002 and January 2009. The majority (93.4%) had locoregional therapy before LT. The median follow-up was 4.5 years (minimum = 2 years). The Kaplan-Meier 1- and 5 year patient survival rates were 94.3% and 83.4%, respectively. In a univariate analysis, significant predictors of HCC recurrence included vascular invasion [hazard ratio (HR) = 10, 95% confidence interval (CI) = 3.9-26, P < 0.001], a pathological tumor stage beyond the University of California San Francisco criteria (HR = 4.1, 95% CI = 1.36-12.6, P = 0.01), an AFP level > 1000 ng/mL (HR = 4.5, 95% CI = 1.3-15.3, P = 0.02), and an AFP level > 500 ng/mL (HR = 3.1, 95% CI = 1.04-9.4, P = 0.04). In a multivariate analysis, vascular invasion was the only significant predictor of tumor recurrence (HR = 5.6, 95% CI = 1.9-19, P = 0.02). An AFP level > 1000 ng/mL was the strongest pretransplant variable predicting vascular invasion (odds ratio = 6.8, 95% CI = 1.6-19.1, P = 0.006). The 1- and 5-year rates of survival without recurrence were 90% and 52.7%, respectively, for patients with an AFP level > 1000 ng/mL and 95% and 80.3%, respectively, for patients with an AFP level <= 1000 ng/mL (P = 0.026). Applying an AFP level > 1000 ng/mL as a cutoff would have resulted in the exclusion of 4.7% of the patients fr m LT and a 20% reduction in HCC recurrence. In conclusion, an AFP level > 1000 ng/mL may be a surrogate for vascular invasion and may be used to predict posttransplant HCC recurrence. Incorporating an AFP level > 1000 ng/mL as an exclusion criterion for LT within the Milan criteria may further improve posttransplant outcomes. PMID- 24797282 TI - Prospective observational cohort study of the association between thromboelastometry, coagulation and platelet parameters and bleeding in patients with haematological malignancies- the ATHENA study. AB - Previous studies have shown that total platelet count (TPC) inadequately predicts bleeding in thrombocytopenic patients with haematological malignancies. This prospective cohort study evaluated whether rotational thromboelastometry (ROTEM), coagulation or other platelet parameters were more strongly associated with bleeding than TPC. Adults treated at two UK haematology centres for haematological malignancy were enrolled if they had thrombocytopenia (TPC <= 50 * 10(9) /l) at beginning of, or during treatment (International Standard Randomized Controlled Trial Number 81226121). TPC and bleeding symptoms were recorded daily for up to 30 d or until platelet count recovery, hospital discharge or death. Blood samples were tested thrice weekly using ROTEM, Platelet Function Analyser (PFA)-100((r)) , coagulation and platelet cytometry assays. Bleeding symptoms and TPC from 49/50 enrolled participants who completed the study were recorded on 754/760 study days. Mean platelet volume and PFA-100((r)) closure times were frequently inestimatable because of thrombocytopenia. TPC, absolute immature platelet number (AIPN) and ROTEM maximum clot firmness were significantly associated with bleeding on the day after blood sampling. Only AIPN was associated with bleeding after adjustment of test results for TPC (Odds Ratio 0.52, 95% confidence interval 0.28-0.97; P = 0.038). In a predictive model, AIPN was superior to TPC for predicting bleeding. This study indicates that AIPN may be more clinically useful than TPC at predicting bleeding. PMID- 24797283 TI - Parsing protection and risk for problem behavior versus pro-social behavior among US and Chinese adolescents. AB - This study investigates the different roles played by protective factors and risk factors-and by particular protective and risk factors-when the concern is with accounting for adolescent problem behavior than when the concern is with accounting for adolescent pro-social behavior. The protective and risk factor literature on adolescent problem behavior reveals considerable conceptual and operational ambiguity; an aim of the present study was to advance understanding in this domain of inquiry by providing a systematic conceptualization of protection and risk and of their measurement. Within the systematic framework of Problem Behavior Theory, four protective and four risk factors are assessed in a cross-national study of both problem behavior and pro-social behavior involving large adolescent samples in China (N = 1,368) and the US (N = 1,087), in grades 9, 10, and 11; females 56 %, US; 50 %, China. The findings reveal quite different roles for protection and risk, and for particular protective and risk factors, when the outcome criterion is problem behavior than when it is pro-social behavior. The protective factor, Controls Protection, which engages rule and regulations and sanctions in the adolescent's ecology, emerges as most important in influencing problem behavior, but it plays a relatively minor role in relationship to pro-social behavior. By contrast, Models Protection, the presence of pro-social models in the adolescent's ecology, and Support Protection, the presence of interest and care in that same ecology, have no significant relationship to problem behavior variation, but they are both the major predictors of variation in pro-social behavior. The findings are robust across the samples from the two very diverse societies. These results suggest that greater attention be given to protection in problem behavior research and that a more nuanced perspective is needed about the roles that particular protective and risk factors play in reducing problem behavior and in promoting pro-social behavior. PMID- 24797284 TI - Hierarchical nanoparticle clusters induced by block copolymer self-assembly. AB - The hierarchical relation of microscale structures with those of zoomed-in nanoscale in a composite material is one of the challenging issues. In terms of multiscale regional analogy of fractal, identical motifs are repeated on different size scales. However, idealized packing schemes are typically known to break down beyond a length scale of a few clusters. Here, we propose a new packing scheme - the structural analogy investigated by gold nanoparticle (AuNP) clusters describes a deformed self-similarity in multiscales. The clusters are directly imaged in microscale and in submicroscale using X-ray microscopy (XM) and X-ray nanoscopy (XN) without sample distortion in the hierarchical field-of view up to 600 MUm. We show that the broad-range ordering has the characteristics of a fractal with a dimension (D) between 1 and 2. This D value is smaller in XN scale than in XM scale, indicating dense cluster formation in large scale. The D values are independent from the pathways of cluster growth and compatibility of AuNPs with the polymer template. The nanoparticle cluster growth induced by block copolymer self-assembly is characteristically different from those occurring in free-space where the conventional diffusion- or reaction-limited aggregations are dominant. Our findings provide a new perspective in organic-inorganic hybrid nanomaterials and has broad implications in understanding their structure property relationship for various applications. PMID- 24797285 TI - The impact of a structured pharmacist intervention on the appropriateness of prescribing in older hospitalized patients. AB - BACKGROUND: Throughout the literature, drug-related problems (DRPs), such as medication reconciliation issues and potentially inappropriate prescribing, have been reported to be associated with adverse outcomes in older individuals. Both structured pharmacist review of medication (SPRM) interventions and computerized decision support systems (CDSSs) have been shown to reduce DRPs. OBJECTIVE: The objectives of this study were to (i) evaluate the impact of a specially developed SPRM/CDSS intervention on the appropriateness of prescribing in older Irish hospital inpatients, and (ii) examine the acceptance rates of these recommendations. METHODS: We prospectively reviewed 361 patients, aged >=65 years who were admitted to an Irish university teaching hospital over a 12-month period. At the point of admission, the patients received a SPRM/CDSS intervention, which screened for DRPs. Any DRPs that were identified were then communicated in writing to the attending medical team. The patient's medical records were reviewed again at 7-10 days, or at the point of discharge (whichever came first). RESULTS: Of the 361 patients reviewed, 181 (50.1 %) were female; the median age was 77 years [interquartile range (IQR) 71-83 years). A total of 3,163 (median 9, IQR 6-12) and 4,192 (median 12, IQR 8-15) medications were prescribed at admission and discharge, respectively. The SPRM generated 1,000 recommendations in 296 patients. Of the 1,000 recommendations, 548 (54.8 %) were implemented by the medical teams accordingly. The SPRM/CDSS intervention resulted in an improvement in the appropriateness of prescribing as defined by the medication appropriateness index (MAI), with a statistically significant difference in the median summated MAI at admission (15, IQR: 7-21) and follow-up (12, IQR: 6-18); p < 0.001. However, the SPRM did not result in an improvement in appropriateness of underprescribing as defined by a modified set assessment of care of vulnerable elders (ACOVE) criteria. CONCLUSION: This study indicated that DRPs are prevalent in older Irish hospitalized inpatients and that a specially developed SPRM intervention supported by a CDSS can improve both the appropriateness and accuracy of medication regimens of older hospitalized inpatients. PMID- 24797286 TI - Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis. AB - Osteoporotic fractures are a major cause of morbidity in the elderly population. Since postmenopausal osteoporosis is related to an increase in osteoclastic activity at the time of menopause, inhibitors of bone resorption have genuinely been considered an adequate strategy for prevention and treatment of osteoporosis. Bisphosphonates and selective oestrogen receptor modulators are widely prescribed to treat osteoporosis. However, other antiresorptive drugs have been developed for the management of osteoporosis, with the objective of providing a substantial reduction in osteoporotic fractures at all skeletal sites, combined with an acceptable long-term skeletal and systemic safety profile. Denosumab, a human monoclonal antibody to receptor activator for nuclear factor kappa B ligand, has shown efficacy against vertebral, nonvertebral and hip fractures. Its administration every 6 months as a subcutaneous formulation might significantly influence compliance and persistence to therapy. Additional results regarding long-term skeletal safety (i.e. osteonecrosis of the jaw and atypical diaphyseal femoral fracture) are needed. Odanacatib, a selective cathepsin K inhibitor, is a promising new approach to the inhibition of osteoclastic resorption, with the potential to uncouple bone formation from bone resorption. Results regarding its anti-fracture efficacy are expected in the coming months. PMID- 24797287 TI - Michaela Diamant, 11 April 1962-9 April 2014. PMID- 24797288 TI - Evidence from a single individual that increased plasma GLP-1 and GLP-1 stimulated insulin secretion after gastric bypass are independent of foregut exclusion. PMID- 24797289 TI - A visual grading study for different administered activity levels in bone scintigraphy. AB - INTRODUCTION: The aim of the study is to assess the administered activity levels versus visual-based image quality using visual grading regression (VGR) including an assessment of the newly stated image criteria for whole-body bone scintigraphy. MATERIALS AND METHODS: A total of 90 patients was included and grouped in three levels of administered activity: 400, 500 and 600 MBq. Six clinical image criteria regarding image quality was formulated by experienced nuclear medicine physicians. Visual grading was performed in all images, where three physicians rated the fulfilment of the image criteria on a four-step ordinal scale. The results were analysed using VGR. A count analysis was also made where the total number of counts in both views was registered. RESULTS: The administered activity of 600 MBq gives significantly better image quality than 400 MBq in five of six criteria (P<0.05). Comparing the administered activity of 600 MBq to 500 MBq, four criteria of six show significantly better image quality (P<0.05). The administered activity of 500 MBq gives no significantly better image quality than 400 Mbq (P<0.05). The count analysis shows that none of the three levels of administrated activity fulfil the recommendations by the EANM. CONCLUSION: There was a significant improvement in perceived image quality using an activity level of 600 MBq compared to lower activity levels in whole-body bone scintigraphy for the gamma camera equipment end set-up used in this study. This type of visual-based grading study seems to be a valuable tool and easy to implement in the clinical environment. PMID- 24797290 TI - A rare reason for liver transplantation: hepatic alveoloar echinococcosis. AB - One of the rare indications for liver transplantation is hepatic alveolar echinococcosis (AE). We present a case of hepatic AE with portal vein involvement. PMID- 24797291 TI - Location, location, location! The reality of life for an intestinal stem cell in the crypt. AB - The intestinal crypt has become the archetypal system to understand stem cell behaviour in vivo. Advances in lineage-tracing technology have identified rapidly cycling stem cells at the crypt base with prominent expression of 'marker' genes such as Lgr5. Elegant quantitative analysis of lineage-tracing data has shown that each stem cell within the crypt is in continual neutral competition with the others in order to retain its place in the niche and so prevent differentiation into a specialized lineage. Accordingly, it appears that the regulation of the stem cell pool occurs primarily at the level of the stem cell population, as a simple consequence of competition for the limited space within the niche. However, contradictory data showing that cells located away from the crypt base niche can also sometimes function as stem cells has challenged the notion that stemness is fundamentally cell-extrinsic. Writing in Nature, Ritsma and colleagues have resolved this debate by performing in vivo live-imaging of the crypt base. By tracking individual stem cells over time, they showed that the relative positioning of the cell within the niche stochastically regulates its fate. Stem cells located in close proximity to the crypt base were more likely to persist long-term, but peripheral cells could sometimes move into privileged crypt-base positions. Thus, while many cells within the crypt have stem cell potential, only cells lucky enough to reside in the 'Goldilocks zone' behave as functional stem cells in the long term. The hunt for intestinal stem cells is over: the stem cells are simply found in their niche. PMID- 24797292 TI - Efficacy of chlorine dioxide tablets on inactivation of cryptosporidium oocysts. AB - The ability of chlorine dioxide (ClO2) to achieve 2-log inactivation of Cryptosporidium in drinking water has been documented. No studies have specifically addressed the effects of ClO2 on C. parvum oocyst infectivity in chlorinated recreational water venues (e.g., pools). The aim of this research was to determine the efficacy of ClO2 as an alternative to existing hyperchlorination protocols that are used to achieve a 3-log inactivation of Cryptosporidium in such venues. To obtain a 3-log inactivation of C. parvum Iowa oocysts, contact times of 105 and 128 min for a solution containing 5 mg/L ClO2 with and without the addition of 2.6 mg/L free chlorine, respectively, were required. Contact times of 294 and 857 min for a solution containing 1.4 mg/L ClO2 with and without the addition of 3.6 mg/L free chlorine, respectively, were required. The hyperchlorination control (21 mg/L free chlorine only) required 455 min for a 3 log inactivation. Use of a solution containing 5 mg/L ClO2 and solutions containing 5 or 1.4 mg/L ClO2 with the addition of free chlorine appears to be a promising alternative to hyperchlorination for inactivating Cryptosporidium in chlorinated recreational water venues, but further studies are required to evaluate safety constraints on use. PMID- 24797293 TI - Effect of temperature on development and reproduction of Proprioseiopsis asetus (Acari: Phytoseiidae) fed on asparagus thrips, Thrips tabaci. AB - Thrips tabaci Lindeman (Thysanoptera: Thripidae) is one of the most important pests of asparagus in China. In this study the effects of five constant temperatures (15, 20, 25, 30 and 35 degrees C) on the growth, survivorship and reproduction of Proprioseiopsis asetus (Chant) (Acari: Phytoseiidae) fed on T. tabaci was examined under laboratory conditions. Development time of immatures decreased with increasing temperature. The lower egg-to-adult developmental threshold (T 0) and thermal constant (K) of P. asetus were estimated at 15.2 degrees C and 75.8 degree days by means of a linear model. Fertilized females fed on T. tabaci produced offspring of both sexes, whereas the offspring sex ratio [?/(? + ?)] of P. asetus at 20-35 degrees C was female-biased (0.68-0.78) and not significantly influenced by temperature. Survivorship during immature development was significantly influenced by temperature, and was especially low at 15 degrees C. Pre- and post-oviposition periods of fertilized females shortened with the increase in temperature. The longest oviposition period was 20.4 days, at 25 degrees C, whereas at 15 degrees C the mites did not reproduce. Maximum average life time fecundity and mean daily fecundity was recorded at 25 and 35 degrees C, respectively; the intrinsic rate of increase ranged from 0.05 (20 degrees C) to 0.17 (35 degrees C). The results indicate the capability of P. asetus to develop and reproduce at a broad range of temperatures, especially above 25 degrees C, which can be used for better management of T. tabaci in asparagus. PMID- 24797294 TI - Effect of antimicrobial treatment of acute otitis media on the daily disappearance of middle ear effusion: a placebo-controlled trial. AB - IMPORTANCE: Antimicrobial treatment reduces the symptoms of acute otitis media (AOM). The effect of antimicrobial treatment on the duration of middle ear effusion (MEE) and concomitant hearing impairment is not known. OBJECTIVE: To determine whether the antimicrobial treatment of AOM reduces the duration of MEE. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo controlled trial involved a total of 84 children with AOM between 6 months and 15 years of age. Participants were recruited from September 14, 1999, to January 4, 2000; October 10, 2005, to December 16, 2005; and September 22, 2009, to June 4, 2012, from among children attending an AOM prevention trial and children visiting local outpatient clinics in Oulu, Finland. INTERVENTIONS: Children were randomly allocated to receive either 40 mg/kg of amoxicillin-clavulanate or a placebo mixture per day for 7 days. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the time to the disappearance of MEE as defined by a normal tympanogram finding (A curve) from both ears on 2 consecutive measurement days. Parents performed daily tympanometry at home. The study physician performed tympanometry and otoscopy at study entry, after 3 and 7 days, and then weekly until both ears were healthy. The main secondary outcome measures were the time to normal otoscopy findings and the proportion of children without persistent MEE at 14 days and 2 months. RESULTS: Middle ear effusion disappeared 2.0 weeks (13.7 days) earlier (P = .02) in the antimicrobial group (mean time, 2.7 weeks; 95% CI, 1.7-3.7) than in the placebo group (4.7 weeks; 95% CI, 3.6-5.7). Normal otoscopy findings were observed 1.4 weeks sooner in the antimicrobial group than in the placebo group (P = .02). On day 14, 69% of children in the antimicrobial group and 38% in the placebo group had normal tympanometry findings (number needed to treat, 3.2; 95% CI, 2.0-10.5). On day 60, 2 children (5%) in the antimicrobial group and 10 children (24%) in the placebo group had persistent MEE (P = .01). CONCLUSIONS AND RELEVANCE: Antimicrobial treatment effectively reduced the duration of MEE and possible concomitant hearing impairment in children with AOM. Antimicrobial treatment also reduced the risk for persistent MEE. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01244581. PMID- 24797295 TI - The Second World. PMID- 24797296 TI - Amino acids regulate transgene expression in MDCK cells. AB - Gene expression and cell growth rely on the intracellular concentration of amino acids, which in metazoans depends on extracellular amino acid availability and transmembrane transport. To investigate the impact of extracellular amino acid concentrations on the expression of a concentrative amino acid transporter, we overexpressed the main kidney proximal tubule luminal neutral amino acid transporter B0AT1-collectrin (SLC6A19-TMEM27) in MDCK cell epithelia. Exogenously expressed proteins co-localized at the luminal membrane and mediated neutral amino acid uptake. However, the transgenes were lost over few cell culture passages. In contrast, the expression of a control transgene remained stable. To test whether this loss was due to inappropriately high amino acid uptake, freshly transduced MDCK cell lines were cultivated either with physiological amounts of amino acids or with the high concentration found in standard cell culture media. Expression of exogenous transporters was unaffected by physiological amino acid concentration in the media. Interestingly, mycoplasma infection resulted in a significant increase in transgene expression and correlated with the rapid metabolism of L-arginine. However, L-arginine metabolites were shown to play no role in transgene expression. In contrast, activation of the GCN2 pathway revealed by an increase in eIF2alpha phosphorylation may trigger transgene derepression. Taken together, high extracellular amino acid concentration provided by cell culture media appears to inhibit the constitutive expression of concentrative amino acid transporters whereas L-arginine depletion by mycoplasma induces the expression of transgenes possibly via stimulation of the GCN2 pathway. PMID- 24797297 TI - de novo synthesis of a bacterial toxin/antitoxin system. AB - The prevalence of toxin/antitoxin (TA) systems in almost all genomes suggests they evolve rapidly. Here we show that an antitoxin from a type V system (GhoS, an endoribonuclease specific for the mRNA of the toxin GhoT) can be converted into a novel toxin (ArT) simply by adding two mutations. In contrast to GhoS, which increases growth, the new toxin ArT decreases growth dramatically in Escherichia coli. Transmission electron microscopy analysis revealed that the nucleoid in ArT-producing cells is concentrated and appears hollow. Whole transcriptome profiling revealed ArT cleaves 50 additional transcripts, which shows that the endoribonuclease activity of GhoS has been broadened as it was converted to ArT. Furthermore, we evolved an antitoxin for the new toxin ArT from two unrelated antitoxin templates, the protein-based antitoxin MqsA and RNA-based antitoxin ToxI, and showed that the evolved MqsA and ToxI variants are able to counteract the toxicity of ArT. In addition, the de novo TA system was found to increase persistence, a phenotype commonly associated with TA systems. Therefore, toxins and antitoxins from disparate systems can be interconverted. PMID- 24797298 TI - Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. AB - Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and >=5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of >=3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials. PMID- 24797301 TI - (-)-Epigallocatechin-3-gallate attenuated myocardial mitochondrial dysfunction and autophagy in diabetic Goto-Kakizaki rats. AB - Type 2 diabetes mellitus (T2DM) is a risk factor for heart disease. However, the mechanisms of T2DM involvement in cardiac complications are still unclear. In the present study, we investigated mitochondria-related mechanisms underlying the pathogenesis of myocardial disorders in diabetic Goto-Kakizaki (GK) rats. We found that remarkable myocardial mitochondrial deficiency and dysfunction as well as oxidative stress occurred in the heart of GK rats. In addition, our results suggested that the loss of mitochondria was in response to elevated autophagy and upstream FoxO factors in diabetic myocardium. More importantly, (-) epigallocatechin-3-gallate (EGCG), a polyphenol derived from green tea, successfully improved mitochondrial function and autophagy in the heart of GK rats. Our findings revealed that diabetes-associated myocardial mitochondrial deficiency and dysfunction was associated with enhanced autophagy in myocardium, and EGCG might be a potential agent in preventing and treating myocardial disorders involved in diabetes. PMID- 24797300 TI - Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. AB - The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255. PMID- 24797299 TI - Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. AB - In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum beta2-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov). PMID- 24797302 TI - Boston type I keratoprosthesis assisted with intraprosthetic amniotic membrane (AmniotiKPro sandwich technique). PMID- 24797303 TI - Anatomical study of the iliohypogastric, ilioinguinal, and genitofemoral nerves using high-resolution ultrasound. AB - INTRODUCTION: In this study we aimed to determine whether high-resolution ultrasound (US) can identify the iliohypogastric (IH), ilioinguinal (II), and genitofemoral (GF) nerves and their relations. METHODS: This investigation, initially undertaken in cadavers, was followed by a high-resolution US study in 30 healthy adult volunteers (180 nerves) by 2 musculoskeletal radiologists on separate occasions, using 2 different approaches (proximal to distal and distal to proximal). A 0-3 scale was used to assess nerve visibility. Location and course of the IH, II, and GF nerves and their relations to adjacent anatomical structures were analyzed. RESULTS: Nerves and their terminal branches were better visualized with the distal-to-proximal approach (P < 0.05). Visualization of the terminal branches was possible in up to 60% of volunteers. CONCLUSIONS: High resolution ultrasound (US) can identify the IH, II, and GF nerves at the level of the abdominal wall and the terminal branches in the majority of volunteers. PMID- 24797304 TI - Significance of hypernatremia following the correction of severe hyperglycemia. PMID- 24797305 TI - Predictive value of liver transaminases levels in abdominal trauma. AB - INTRODUCTION: We aimed to evaluate whether hepatic transaminase levels could predict the presence and severity of liver injury following abdominal trauma. METHODS: We performed a retrospective analysis of 75 surgically treated patients and 21 non-surgically treated patients with liver injury who were managed between 2004 and 2012. We retrieved demographic, laboratory, radiologic, and intraoperative data, as well as surgical procedures and the outcome from the patients' medical records. We compared the findings between patients divided into 2 groups according to the severity of liver injury: group 1, including patients with Grade 1 or 2 liver injuries; and group 2, including patients with grade 3 to 5 liver injury. RESULTS: There were 87 (90.6%) males and 9 (9.4%) females. The mean age was 34 years (range, 17-90 years). The overall mortality rate was 14.6% (n = 14). The injury was blunt in 83 patients (86.5%) and penetrating in 13 patients (13.5%). There were multiple traumas in 60 patients (62.5%). Overall, 43 patients (44.8%) had a total of 61 coexisting intraabdominal injuries. The circulating aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (LDH) levels were significantly higher in group 2 than in group 1. CONCLUSIONS: In patients with abdominal trauma, abnormal hepatic transaminase and LDH levels are associated with liver injury. Alanine aminotransferase <=76 U/L, aspartate aminotransferase <130 U/L, and LDH <=410 U/L are predictive of low grade liver injury, and patients with serum liver levels below these levels can be managed conservatively. PMID- 24797306 TI - Atrial fibrillation related to carbon monoxide poisoning in a female patient. PMID- 24797307 TI - Late-life and intergenerational effects of larval exposure to microbial competitors in the burying beetle Nicrophorus vespilloides. AB - Intergenerational effects can have either adaptive or nonadaptive impacts on offspring performance. Such effects are likely to be of ecological and evolutionary importance in animals with extended parental care, such as birds, mammals and some insects. Here, we studied the effects of exposure to microbial competition during early development on subsequent reproductive success in the burying beetle Nicrophorus vespilloides, an insect with elaborate parental care. We found that exposure to high levels of microbial competition both during a female's larval development and during her subsequent reproduction resulted in females rearing smaller broods than those exposed to lower levels of microbial competition. To determine whether these differences arose before or after offspring hatching, a cross-fostering experiment was conducted. Our results demonstrate that the impact of larval competition with microbes for resources extends into adult life and can negatively affect subsequent generations via impacts on the quality of parental care provided after hatching. However, we also find evidence for some positive effects of previous microbial exposure on prehatch investment, suggesting that the long-term results of competition with microbes may include altering the balance of parental investment between prehatch and post-hatch care. PMID- 24797308 TI - Light-intensity physical activity is associated with adiposity in adolescent females. AB - INTRODUCTION: Sedentary behavior (SB) research has relied on accelerometer thresholds to distinguish between sitting/lying time (SLT) and light-intensity physical activity (LIPA). Such methods may misclassify SLT, standing time (StT), and LIPA. This study examines the association between directly measured SB, physical activity (PA), and adiposity in an adolescent female sample. METHODS: Female adolescents (n = 195; mean age, 15.7 yr (SD, 0.9)) had body mass index (BMI) (median, 21.7 kg.m (interquartile range, 5.2 kg.m)) and four-site sum of skinfolds (median, 62.0 mm; interquartile range, 37.1 mm) measured and wore an activPALTM activity monitor for 7 d. SLT, StT, breaks in SLT, and bouts of SLT <30 and >=30 min were determined from activPAL outputs. A threshold of 2997 counts per 15 s determined moderate-to-vigorous PA. All remaining time was quantified as LIPA. Mixed linear regression models examined associations between PA variables, SB variables, and adiposity. RESULTS: Participants spent a mean of 65.3% (SD, 7.1) of the waking day in SLT, 23.0% (SD, 5.3) in StT, 5.6% (SD, 1.5) in LIPA, and 6.1% (SD, 2.4) in moderate-to-vigorous PA. Significant effects for the percentage of LIPA (which excluded StT) with both BMI (beta = -4.38, P = 0.0006) and sum of skinfolds (beta = -4.05, P = 0.006) were identified. Significant effects for breaks in SLT with BMI (beta = -0.30, P = 0.04) were also observed. No additional significant associations were found between activity measures and adiposity. CONCLUSIONS: Increased LIPA (excluding StT) and breaks in SLT were negatively associated with adiposity in this sample, independent of age. Interventional work should examine whether reducing SLT through breaks and increasing LIPA may prevent increases in adiposity in adolescent females. PMID- 24797309 TI - Genome-wide association study identifies quantitative trait loci affecting hematological traits in an F2 intercross between Landrace and Korean native pigs. AB - Changes affecting the status of health and robustness can bring about physiological alterations including hematological parameters in swine. To identify quantitative trait loci (QTL) associated with eight hematological traits (one leukocyte trait, six erythrocyte traits and one platelet trait), we conducted a genome-wide association study using the PorcineSNP60K BeadChip in a resource population derived from an intercross between Landrace and Korean native pigs. A total of 36 740 SNPs from 816 F2 progeny were analyzed for each blood related trait after filtering for quality control. Data were analyzed by the genome-wide rapid association using mixed model and regression (GRAMMAR) approach. A total of 257 significant SNPs (P < 1.36 * 10(-6) ) on SSC3, 6, 8, 13 and 17 were identified for blood-related traits in this study. Interestingly, the genomic region between 17.9 and 130 Mb on SSC8 was found to be significantly associated with red blood cell, mean corpuscular volume and mean corpuscular hemoglobin. Our results include the identification of five significant SNPs within five candidate genes (KIT, IL15, TXK, ARAP2 and ERG) for hematopoiesis. Further validation of these identified SNPs could give valuable information for understanding the variation of hematological traits in pigs. PMID- 24797310 TI - Strategy to enhance the therapeutic effect of doxorubicin in human hepatocellular carcinoma by selenocystine, a synergistic agent that regulates the ROS-mediated signaling. AB - Doxorubicin-based chemotherapy represents one of the most effective ways in combating human cancers. However, its clinical use is limited by severe side effects. Selenocystine (SeC) is a natural available selenoamino acid with novel anticancer efficacy. In this study, we used SeC to sensitize HepG2 human hepatocellular carcinoma (HCC) cells to DOX, and to achieve anticancer synergism in vitro and in vivo. Treatment with DOX dose-dependently reduced HepG2 cell viability through initiating cell apoptosis and strong G2/M phase cell cycle arrest. Mechanistic studies indicated that this sensitization of SeC to DOX was achieved by triggering inactivation of ERK and AKT and DNA damage through reactive oxygen species (ROS) overproduction. Pretreatment with inhibitors of ERK and AKT markedly enhanced combined treatment-induced cell killing, indicating that combined treatment-induced HCC cell killing with ERK- and AKT-dependent manner. Furthermore, inhibition of ROS effectively attenuated combined treatment induced DNA damage and inactivation of ERK and AKT. Additionally, xenograft hepatocellular carcinoma growth was also effectively inhibited by combined treatment through induction of cell apoptosis in vivo. Taken together, our results suggest that the strategy to use SeC and DOX in combination could be a highly efficient way to achieve anticancer synergism against HCC. PMID- 24797311 TI - Native soil fungi associated with compostable plastics in three contrasting agricultural settings. AB - Plastics are used widely as agricultural mulches to suppress weeds and retain soil moisture. Disposal of conventional plastic mulches requires physical removal for disposal in a landfill or incineration. Biodegradable plastic mulches that could be tilled into the soil at the end of a growing season represent an attractive alternative to conventional plastic mulches. In this study, three commercially available mulches labeled as "biodegradable" and one experimental, potentially biodegradable mulch were used during a tomato growing season, and then buried in field soil at three locations for approximately 6 months, as would occur typically in an agricultural setting. Degradation after 6 months in soil was minimal for all but the cellulosic mulch. After removal of mulches from soil, fungi were isolated from the mulch surfaces and tested for their ability to colonize and degrade the same mulches in pure culture. The majority of culturable soil fungi that colonized biodegradable mulches were within the family Trichocomaceae (which includes beneficial, pathogenic, and mycotoxigenic species of Aspergillus and Penicillium). These isolates were phylogenetically similar to fungi previously reported to degrade both conventional and biodegradable plastics. Under pure culture conditions, only a subset of fungal isolates achieved detectable mulch degradation. No isolate substantially degraded any mulch. Additionally, DNA was extracted from bulk soil surrounding buried mulches and ribosomal DNA was used to assess the soil microbial community. Soil microbial community structure was significantly affected by geographical location, but not by mulch treatments. PMID- 24797312 TI - Abatement of styrene waste gas emission by biofilter and biotrickling filter: comparison of packing materials and inoculation procedures. AB - The removal of styrene was studied using two biofilters packed with peat and coconut fibre (BF1-P and BF2-C, respectively) and one biotrickling filter (BTF) packed with plastic rings. Two inoculation procedures were applied: an enriched culture with strain Pseudomonas putida CECT 324 for BFs and activated sludge from a municipal wastewater treatment plant for the BTF. Inlet loads (ILs) between 10 and 45 g m(-3) h(-1) and empty bed residence times (EBRTs) from 30 to 120 s were applied. At inlet concentrations ranging between 200 and 400 mg Nm(-3), removal efficiencies between 70 % and 95 % were obtained in the three bioreactors. Maximum elimination capacities (ECs) of 81 and 39 g m(-3) h(-1) were obtained for the BF1-P and BF2-C, respectively (IL of 173 g m(-3) h(-1) and EBRT of 60 s in BF1-P; IL of 89 g m(-3) h(-1) and EBRT of 90 s in BF2-C). A maximum EC of 52 g m( 3) h(-1) was obtained for the BTF (IL of 116 g m(-3) h(-1), EBRT of 45 s). Problems regarding high pressure drop appeared in the peat BF, whereas drying episodes occurred in the coconut fibre BF. DGGE revealed that the pure culture used for BF inoculation was not detected by day 105. Although two different inoculation procedures were applied, similar styrene removal at the end of the experiments was observed. The use as inoculum of activated sludge from municipal wastewater treatment plant appears a more feasible option. PMID- 24797313 TI - Secreted biomolecules alter the biological identity and cellular interactions of nanoparticles. AB - A nanoparticle's physical and chemical properties at the time of cell contact will determine the ensuing cellular response. Aggregation and the formation of a protein corona in the extracellular environment will alter nanoparticle size, shape, and surface properties, giving it a "biological identity" that is distinct from its initial "synthetic identity". The biological identity of a nanoparticle depends on the composition of the surrounding biological environment and determines subsequent cellular interactions. When studying nanoparticle-cell interactions, previous studies have ignored the dynamic composition of the extracellular environment as cells deplete and secrete biomolecules in a process known as "conditioning". Here, we show that cell conditioning induces gold nanoparticle aggregation and changes the protein corona composition in a manner that depends on nanoparticle diameter, surface chemistry, and cell phenotype. The evolution of the biological identity in conditioned media enhances the cell membrane affinity, uptake, and retention of nanoparticles. These results show that dynamic extracellular environments can alter nanoparticle-cell interactions by modulating the biological identity. The effect of the dynamic nature of biological environments on the biological identity of nanoparticles must be considered to fully understand nano-bio interactions and prevent data misinterpretation. PMID- 24797314 TI - Evidence-based anatomy. AB - Anatomy is a descriptive basic medical science that is no longer considered a research-led discipline. Many publications in clinical anatomy are prevalence studies treating clinically relevant anatomical variations and reporting their frequencies and/or associations with variables such as age, sex, side, laterality, and ancestry. This article discusses the need to make sense of the available literature. A new concept, evidence-based anatomy (EBA), is proposed to find, appraise, and synthetize the results reported in such publications. It consists in applying evidence-based principles to the field of epidemiological anatomy research through evidence synthesis using systematic reviews and meta analyses to generate weighted pooled results. Pooled frequencies and associations based on large pooled sample size are likely to be more accurate and to reflect true population statistics and associations more closely. A checklist of a typical systematic review in anatomy is suggested and the implications of EBA for practice and future research, along with its scope, are discussed. The EBA approach would have positive implications for the future preservation of anatomy as a keystone basic science, for sound knowledge of anatomical variants, and for the safety of medical practice. PMID- 24797315 TI - Porous nickel hydroxide-manganese dioxide-reduced graphene oxide ternary hybrid spheres as excellent supercapacitor electrode materials. AB - This paper reports the first nickel hydroxide-manganese dioxide-reduced graphene oxide (Ni(OH)2-MnO2-RGO) ternary hybrid sphere powders as supercapacitor electrode materials. Due to the abundant porous nanostructure, relatively high specific surface area, well-defined spherical morphology, and the synergetic effect of Ni(OH)2, MnO2, and RGO, the electrodes with the as-obtained Ni(OH)2 MnO2-RGO ternary hybrid spheres as active materials exhibited significantly enhanced specific capacitance (1985 F.g(-1)) and energy density (54.0 Wh.kg(-1)), based on the total mass of active materials. In addition, the Ni(OH)2-MnO2-RGO hybrid spheres-based asymmetric supercapacitor also showed satisfying energy density and electrochemical cycling stability. PMID- 24797316 TI - In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers. AB - INTRODUCTION: We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. METHODS: All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). RESULTS: FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum. CONCLUSIONS: Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. PMID- 24797317 TI - Racial discrimination and posttraumatic stress symptoms as pathways to sexual HIV risk behaviors among urban Black heterosexual men. AB - In light of evidence that racial discrimination and posttraumatic stress symptoms (PTSS) are neither rare nor extraordinary for many Black urban men, we examined the relationship between everyday racial discrimination and sexual HIV risk behaviors in a predominantly low-income sample of 526 urban Black heterosexually identified men; 64% of whom were unemployed and 55% of whom reported a history of incarceration. We tested the hypothesis that PTSS would mediate the relationship between everyday racial discrimination and sexual risk. Participants in the predominantly low-income urban sample ranged in age from 18 to 45 (M = 28.80, SD = 7.57). Three multiple regression models were used to test the study's mediational model. As hypothesized, PTSS mediated the relationship between everyday racial discrimination and sexual risk behaviors. Most participants (97%) reported experiences with everyday racial discrimination. Results empirically support the notion of racial discrimination-based traumatic stress as a pathway to Black heterosexual men's increased sexual risk behaviors. Results also highlighted key demographic differences with older men reporting fewer PTSS and sexual risk behaviors compared with younger men. Incarceration was related to both PTSS and sexual risk, underscoring the role that incarceration may play in Black heterosexual men's adverse health outcomes. Our study highlights the need for more qualitative and quantitative research to understand the nature of PTSS in Black heterosexual men and mechanisms such as substance use that may link traumatic experiences and sexual risk. Future research could also assess experiences with childhood sexual abuse, violence, and incarceration to gain a more in-depth understanding of the sources of traumatic stress in Black heterosexual men's lives. We advocate for the development of community-based individual and structural-level interventions to help Black heterosexual men in urban areas develop effective strategies to cope with racial discrimination-based traumatic stress to reduce sexual HIV risk behaviors in Black communities. PMID- 24797318 TI - A critical appraisal of the evidence for using cardiotocography plus ECG ST interval analysis for fetal surveillance in labor. Part II: the meta-analyses. AB - We appraised the methodology, execution and quality of the five published meta analyses that are based on the five randomized controlled trials which compared cardiotocography (CTG)+ST analysis to cardiotocography. The meta-analyses contained errors, either created de novo in handling of original data or from a failure to recognize essential differences among the randomized controlled trials, particularly in their inclusion criteria and outcome parameters. No meta analysis contained complete and relevant data from all five randomized controlled trials. We believe that one randomized controlled trial excluded in two of the meta-analyses should have been included, whereas one randomized controlled trial that was included in all meta-analyses, should have been excluded. After correction of the uncovered errors and exclusion of the randomized controlled trial that we deemed inappropriate, our new meta-analysis showed that CTG+ST monitoring significantly reduces the fetal scalp blood sampling usage (risk ratio 0.64; 95% confidence interval 0.47-0.88), total operative delivery rate (0.93; 0.88-0.99) and metabolic acidosis rate (0.61; 0.41-0.91). PMID- 24797319 TI - Comments on 'A dose-finding approach based on shrunken predictive probability for combinations of two agents in phase I trials' by Akihiro Hirakawa, Chikuma Hamada, and Shigeyuki Matsui. PMID- 24797320 TI - Response to letter to the editor by Dr Wages et al. PMID- 24797321 TI - Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism. AB - BACKGROUND: It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. METHODS: In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. RESULTS: In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. CONCLUSIONS: Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2. PMID- 24797322 TI - Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence. AB - Senescence is involved in various pathophysiological conditions. Besides loss of retinoblastoma and p53 pathways, little is known about other pathways involved in senescence. Here we identify two calcium channels; inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) (also known as inositol 1,4,5-triphosphate receptor 2 (IP3R2)) and mitochondrial calcium uniporter (MCU) as new senescence regulators in a loss-of-function genetic screen. We show that loss of ITPR2, known to mediate endoplasmic reticulum (ER) calcium release, as well as loss of MCU, necessary for mitochondrial calcium uptake, enable escape from oncogene-induced senescence (OIS). During OIS, ITPR2 triggers calcium release from the ER, followed by mitochondrial calcium accumulation through MCU channels. Mitochondrial calcium accumulation leads to a subsequent decrease in mitochondrial membrane potential, reactive oxygen species accumulation and senescence. This ER-mitochondria calcium transport is not restricted to OIS, but is also involved in replicative senescence. Our results show a functional role of calcium release by the ITPR2 channel and its subsequent accumulation in the mitochondria. PMID- 24797323 TI - Optimizing the grain size distribution of allografts in bone impaction grafting. AB - In bone impaction grafting, allografts in the form of bone chips are used for reconstruction of defects and to induce bone remodeling. Optimizing grain size distribution of this allograft material should help prevent implant subsidence by achieving higher primary stability of the graft. We evaluated the influence of grain size distribution on the mechanical stability of allograft material. Bone tissue was rinsed, and the grain size distribution of the allograft material was determined by performing a sieve analysis. Uniaxial compression tests were carried out before and after a standardized compaction procedure for samples with controlled grain size distribution and a control group. Allografts with controlled grain size distribution showed a yield limit almost twice as high as in the control group after a standardized compaction procedure. A better interlocking between bone particles was observed compared to the control group. Thus, grain size distribution has a major impact on the mechanical stability of bone grafts. By controlling the grain size distribution of allograft material, a tighter packing can be achieved and subsequently implant subsidence of implants could be avoided. PMID- 24797324 TI - Dermatomyositis-like disease in a Rottweiler. AB - BACKGROUND: Canine dermatomyositis is a hereditary disease described in collies and Shetland sheep dogs and their cross-breeds. A similar disease, called dermatomyositis-like disease, has been described occasionally in other breeds but never in the Rottweiler. HYPOTHESIS/OBJECTIVES: We report on the clinicopathological findings associated with dermatomyositis-like disease in a Rottweiler. ANIMAL: A 7-month-old female Rottweiler was referred for dermatological abnormalities, regurgitation and weakness. Cutaneous abnormalities included alopecia, crusting and scaling on the inner surface of the pinnae, the tip of the tail, periorbital and perilabial skin. The dog also presented onychogryphosis and onychalgia. METHODS: Complete blood count, serum biochemistry panel, thoracic radiographs, electromyography, nerve-conduction studies and skin and muscle biopsies were performed. RESULTS: Megaoesophagus, pneumonia, ischaemic dermatopathy and generalized myositis were documented. The final diagnosis was dermatomyositis-like disease. CONCLUSIONS AND CLINICAL IMPORTANCE: This is the first report of dermatomyositis-like disease in a Rottweiler. PMID- 24797325 TI - Commentary: Who is a candidate for testosterone therapy? A synthesis of international expert opinions. AB - INTRODUCTION: Despite increasing use of testosterone therapy (TTh) for men with testosterone deficiency (TD), there remains uncertainty determining who is a candidate for treatment. AIM: The aim if this study was to report the opinions of international experts on TTh, as initially presented at the meeting of the World Meeting on Sexual Medicine in Chicago, United States in August 2012. METHODS: Expert responses to questions regarding the diagnosis of TD based on their own clinical and research experience. RESULTS: All experts emphasized the primacy of symptoms for the diagnosis of TD. Total testosterone (T) thresholds used to identify TD ranged from 350 ng/dL to 400 ng/dL (12-14 nmol/L); however, experts emphasized the diagnostic limitations of this test. Free T was obtained by all, with some valuing this test more than total T for clinical decision making. Only one expert routinely used a screening questionnaire. None used age-adjusted values. Bioavailable T and the free androgen index were not used. Luteinizing hormone (LH) and sex hormone-binding globulin levels were routinely obtained at evaluation. Additional supportive evidence for TD diagnosis included small testicular volume, high androgen receptor CAG repeats, elevated LH, and presence of diabetes or metabolic syndrome. Two T tests were generally obtained but not always required. Some experts did not require morning testing in men 50 years and older. All monitored prostate-specific antigen and hematocrit after initiation of TTh. All but one expert would consider a trial of TTh to a symptomatic man with total T within the normal range. Recent studies suggesting increased cardiovascular risk with T therapy were not found to be credible. CONCLUSIONS: Determining who is a candidate for TTh requires clinical assessment based on symptoms and signs, with confirmatory laboratory evaluation. These expert opinions differed from some published guidelines by the emphasis on symptoms as paramount, recognition of the limitations of total T as a diagnostic test, and the potential utility of a therapeutic trial in symptomatic cases with normal total T concentrations. PMID- 24797326 TI - Functional distinction between NGF-mediated plasticity and regeneration of nociceptive axons within the spinal cord. AB - Successful regeneration after injury requires either the direct reformation of the circuit or the formation of a bridge circuit to provide partial functional return through a more indirect route. Presently, little is known about the specificity of how regenerating axons reconnect or reconstruct functional circuits. We have established an in vivo Dorsal root entry zone (DREZ) model, which in the presence of Nerve Growth Factor (NGF), shows very robust regeneration of peptidergic nociceptive axons, but not other sensory axons. Expression of NGF in normal, non-injured animals leads to robust sprouting of only the peptidergic nociceptive axons. Interestingly, NGF-induced sprouting of these axons leads to severe chronic pain, whereas, regeneration leads to protective-like pain without chronic pain. Using this model we set out to compare differences in behavioral outcomes and circuit features between these two groups. In this study, we examined pre-synaptic and post-synaptic markers to evaluate the relationship between synaptic connections and behavioral responses. NGF-induced sprouting of calcitonin gene-related peptide (CGRP) axons resulted in a significant redistribution of synapses and cFos expression into the deeper dorsal horn. Regeneration of only the CGRP axons showed a general reduction in synapses and cFos expression within laminae I and II; however, inflammation of the hindpaw induced peripheral sensitization. These data show that although NGF-induced sprouting of peptidergic axons induces robust chronic pain and cFos expression throughout the entire dorsal horn, regeneration of the same axons resulted in normal protective pain with a synaptic and cFos distribution similar, albeit significantly less than that shown by the sprouting of CGRP axons. PMID- 24797327 TI - Isoflurane unveils a critical role of glutamate transporter type 3 in regulating hippocampal GluR1 trafficking and context-related learning and memory in mice. AB - Glutamate transporter type 3 (EAAT3) may play a role in cognition. Isoflurane enhances EAAT3 trafficking to the plasma membrane. Thus, we used isoflurane to determine how EAAT3 might regulate learning and memory and the trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, such as GluR1, to the plasma membrane, a fundamental biochemical process for learning and memory. Here, isoflurane increased EAAT3 but did not change GluR1 levels in the plasma membrane of wild-type mouse hippocampus. Isoflurane increased protein phosphatase activity in the wild-type and EAAT3(-/-) mouse hippocampus. Also, isoflurane reduced GluR1 in the plasma membrane and decreased phospho-GluR1 in EAAT3(-/-) mice. The phosphatase inhibitor okadaic acid attenuated these effects. Finally, isoflurane inhibited context-related fear conditioning in EAAT3(-/-) mice but not in wild-type mice. Thus, isoflurane may increase GluR1 trafficking to the plasma membrane via EAAT3 and inhibit GluR1 trafficking via protein phosphatase. Lack of EAAT3 effects leads to decreased GluR1 trafficking and impaired cognition after isoflurane exposure in EAAT3(-/-) mice. PMID- 24797328 TI - Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia. AB - Brain ischemic tolerance is an endogenous protective mechanism activated by a preconditioning stimulus that is closely related to N-methyl-d-aspartate receptor (NMDAR). Glycine transporter type 1 (GlyT-1) inhibitors potentiate NMDAR and suggest an alternative strategy for brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by sarcosine, a GlyT 1 inhibitor, against global cerebral ischemia and its relation to NMDAR. Sarcosine was administered over 7 days (300 or 500 mg/kg/day, ip) before the induction of a global cerebral ischemia model in Wistar rats (male, 8-week-old). It was observed that sarcosine preconditioning reduced cell death in rat hippocampi submitted to cerebral ischemia. Hippocampal levels of glycine were decreased in sarcosine-treated animals, which was associated with a reduction of [(3)H] glycine uptake and a decrease in glycine transporter expression (GlyT-1 and GlyT-2). The expression of glycine receptors and the NR1 and NR2A subunits of NMDAR were not affected by sarcosine preconditioning. However, sarcosine preconditioning reduced the expression of the NR2B subunits of NMDAR. In conclusion, these data demonstrate that sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia and this neuroprotective state is associated with changes in glycine transport and reduction of NR2B containing NMDAR expression. PMID- 24797329 TI - Stereological quantification of olfactory receptor neurons in mice. AB - The total number of olfactory receptor neurons (ORNs) in the mouse main olfactory epithelium (MOE) was estimated using stereological sampling. Noses and skulls of male and female 8-week-old C57BL/6J mice were de-calcified, embedded in paraffin, cut into 10-MUm-thick sections serially at 100-MUm intervals, and processed for immunohistochemistry for the olfactory marker protein (OMP), a specific marker for ORNs. The number of OMP (+) receptor neurons was measured using an optical fractionator with the Stereo-Investigator software. The mean values of the total number of OMP (+) receptor neurons in the unilateral MOE were 5,140,000+/-380,000 in males and 5,210,000+/-380,000 in females, with no significant differences between the sexes. We concluded that the total number of ORNs in the unilateral MOE is approximately 5*10(6) in mice. PMID- 24797330 TI - Distribution of Fos-immunoreactive cells in rat forebrain and midbrain following social defeat stress and diazepam treatment. AB - The anxiolytic diazepam selectively inhibits psychological stress-induced autonomic and behavioral responses without causing noticeable suppression of other central performances. This pharmacological property of diazepam led us to the idea that neurons that exhibit diazepam-sensitive, psychological stress induced activation are potentially those recruited for stress responses. To obtain neuroanatomical clues for the central stress circuitries, we examined the effects of diazepam on psychological stress-induced neuronal activation in broad brain regions. Rats were exposed to a social defeat stress, which caused an abrupt increase in body temperature by up to 2 degrees C. Pretreatment with diazepam (4mg/kg, i.p.) attenuated the stress-induced hyperthermia, confirming an inhibitory physiological effect of diazepam on the autonomic stress response. Subsequently, the distribution of cells expressing Fos, a marker of neuronal activation, was examined in 113 forebrain and midbrain regions of these rats after the stress exposure and diazepam treatment. The stress following vehicle treatment markedly increased Fos-immunoreactive (IR) cells in most regions of the cerebral cortex, limbic system, thalamus, hypothalamus and midbrain, which included parts of the autonomic, neuroendocrine, emotional and arousal systems. The diazepam treatment significantly reduced the stress-induced Fos expression in many brain regions including the prefrontal, sensory and motor cortices, septum, medial amygdaloid nucleus, medial and lateral preoptic areas, parvicellular paraventricular hypothalamic nucleus, dorsomedial hypothalamus, perifornical nucleus, tuberomammillary nucleus, association, midline and intralaminar thalami, and median and dorsal raphe nuclei. In contrast, diazepam increased Fos-IR cells in the central amygdaloid nucleus, medial habenular nucleus, ventromedial hypothalamic nucleus and magnocellular lateral hypothalamus. These results provide important information for elucidating the neural circuitries that mediate the autonomic and behavioral responses to psychosocial stressors. PMID- 24797332 TI - Rivastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice. AB - Rivastigmine is a non-competitive inhibitor of both acetylcholinesterase (AChE) and butylcholinesterase (BuChE) used to treat mild to moderate dementia in Alzheimer's disease (AD) patients. Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients, its ability to improve Behavioral and Psychological Symptoms of Dementia (BPSD) remains unclear. To determine whether rivastigmine treatment antagonizes depression-like behaviors, we chronically administered rivastigmine (0.1-1.0mg/kg) to olfactory bulbectomized (OBX) mice once a day for 2weeks, starting 2weeks after bulbectomy. Chronic treatment at 0.3 or 1.0mg/kg dose dependently and significantly improved depression-like behaviors, as assessed by tail suspension (TST), forced swim (FST), locomotion and novelty-suppressed feeding (NSFT) tests. Importantly, co-administration with WAY-100635 (1.0mg/kg), a 5-HT1A receptor antagonist, but not ketanserin (1.0mg/kg,), a 5-HT2A receptor antagonist, completely blocked rivastigmine induced anti-depressive effects, suggesting that 5-HT1A receptor stimulation mediates this activity. Consistent with this observation, rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a 5-HT1A receptor-dependent manner. Furthermore, enhanced protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis. These effects were blocked by WAY-100635 but not ketanserin treatment. Finally, we confirmed that 5-HT1A but not 5-HT2A receptor stimulation by specific agonists mimicked rivastigmine-induced anti-depression activity and promoted hippocampal neurogenesis. We conclude that, in addition to enhancing the cholinergic system, rivastigmine treatment restores normal function of the hippocampal serotonergic system, an activity that likely ameliorates depressive behaviors in AD patients. PMID- 24797333 TI - The brain structure correlates of individual differences in trait mindfulness: a voxel-based morphometry study. AB - Mindfulness is the state of being attentive to and aware of what is taking place in the present, which is beneficial for reducing stress-related symptoms and improving mental and physical health. Previous studies have demonstrated that meditation practice can improve individuals' mindfulness through modifying functions and structures of multiple brain regions, including the anterior cingulate cortex (ACC), insula, fronto-limbic network, posterior cingulate cortex (PCC), and temporal-parietal junction. However, little is known about the neuroanatomical correlates of trait mindfulness. In the current study, we used voxel-based morphometry to investigate the neural correlates of individual differences in trait mindfulness by correlating the gray matter (GM) volume of each voxel across the whole brain with trait mindfulness measured by the Mindful Attention Awareness Scale in a large sample of young adults (N=247). We found that individuals who were more mindful of the present had greater GM volume in the right hippocampus/amygdala and bilateral ACC, but less GM volume in bilateral PCC and the left orbitofrontal cortex. These results suggest that trait mindfulness is associated with brain regions involved in executive attention, emotion regulation, and self-referential processing, through which mindfulness may exert its beneficial effects on psychological and physical well-being. PMID- 24797331 TI - A tale of two species: Neural integration in zebrafish and monkeys. AB - Selection of a model organism creates tension between competing constraints. The recent explosion of modern molecular techniques has revolutionized the analysis of neural systems in organisms that are amenable to genetic techniques. Yet, the non-human primate remains the gold-standard for the analysis of the neural basis of behavior, and as a bridge to the operation of the human brain. The challenge is to generalize across species in a way that exposes the operation of circuits as well as the relationship of circuits to behavior. Eye movements provide an opportunity to cross the bridge from mechanism to behavior through research on diverse species. Here, we review experiments and computational studies on a circuit function called "neural integration" that occurs in the brainstems of larval zebrafish, primates, and species "in between". We show that analysis of circuit structure using modern molecular and imaging approaches in zebrafish has remarkable explanatory power for details of the responses of integrator neurons in the monkey. The combination of research from the two species has led to a much stronger hypothesis for the implementation of the neural integrator than could have been achieved using either species alone. PMID- 24797334 TI - Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease. AB - This study investigated the effect of naringin, a major flavonoid in grapefruit and citrus fruits, on the degeneration of the nigrostriatal dopaminergic (DA) projection in a neurotoxin model of Parkinson's disease (PD) in vivo and the potential underlying mechanisms focusing on the induction of glia-derived neurotrophic factor (GDNF), well known as an important neurotrophic factor involved in the survival of adult DA neurons. 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the medial forebrain bundle of rat brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. To ascertain whether naringin-induced GDNF contributes to neuroprotection, we further investigated the effects of intranigral injection of neutralizing antibodies against GDNF in the MPP(+) rat model of PD. Our observations demonstrate that naringin could increase the level of GDNF in DA neurons, contributing to neuroprotection in the MPP(+) rat model of PD, with activation of mammalian target of rapamycin complex 1. Moreover, naringin could attenuate the level of tumor necrosis factor-alpha in microglia increased by MPP(+)-induced neurotoxicity in the substantia nigra. These results indicate that naringin could impart to DA neurons the important ability to produce GDNF as a therapeutic agent against PD with anti-inflammatory effects, suggesting that naringin is a beneficial natural product for the prevention of DA degeneration in the adult brain. PMID- 24797336 TI - Small head-to-tail macrocyclic alpha-peptoids. AB - A convenient and efficient methodology for the head-to-tail macrocyclization of small 3-mer, 4-mer, and 5-mer alpha-peptoid acids (9-, 12-, and 15-atom N substituted glycine oligomers) is described. The cyclic trimer has a ccc amide sequence in the crystal structure, whereas the tetramer has ctct and the pentamer has ttccc stereochemistry. NMR analysis reveals rigid structures in solution. These synthetic macrocycles may prove useful in medicinal and materials applications. PMID- 24797335 TI - Association of polymorphisms at HORMAD2 and prognosis in advanced non-small-cell lung cancer patients. AB - BACKGROUND: Cancer-testis (CT) genes are predominantly expressed in the testis and are ectopically activated in a wide range of cancers. The expression of CT antigens has been shown to significantly affect the survival of patients with non small-cell lung cancer (NSCLC). Recently, a genome-wide association study (GWAS) and expression analysis have identified a novel CT gene (HORMAD2) associated with lung cancer risk in Han Chinese people. Thus, the aim of this study is to evaluate the potential prognostic value of HORMAD2 polymorphisms in Han Chinese patients with advanced NSCLC and undergoing first-line platinum-based chemotherapy. MATERIALS AND METHODS: We selected eight single-nucleotide polymorphisms (SNPs) of HORMAD2 with the potential function of affecting the binding of transcription factors, and we genotyped these SNPs in 303 patients with advanced NSCLC using the MassARRAY platform. All patients were treated with first-line platinum-based chemotherapy but without surgery. Log-rank test and Cox proportional hazard models were used for the survival analyses. RESULTS: Four SNPs at HORMAD2 (rs9620953, rs8135823, rs5753025 and rs9625921) were significantly associated with the survival of advanced NSCLC patients. Among these, patients with the rs9620953 T allele had a significantly reduced risk of death compared to those with the C allele (additive model: HR, 0.53, 95%CI, 0.32 0.89, P=0.016; dominant model: HR, 0.50, 95%CI, 0.29-0.84, P=0.010). Similarly, the G allele at rs8135823 could decrease the death risk of NSCLC patients compared to the T allele (additive model: HR, 0.63, 95%CI, 0.41-0.95, P=0.028; dominant model: HR, 0.60, 95%CI, 0.39-0.93, P=0.022). Furthermore, both the rs5753025 C allele and the rs9625921 G allele also decreased the death risk in NSCLC in different genetic models (additive model for rs5753025: HR, 0.80, 95%CI, 0.65-0.98, P=0.032; heterozygote model for rs9625921: HR, 0.71, 95%CI, 0.51-0.99, P=0.040). In the joint effect analyses, we found that patients with one, two, and three to eight favorable alleles had a better survival compared with patients carrying no alleles. CONCLUSIONS: These findings indicate that polymorphisms at the CT gene HORMAD2 might be involved in the prognosis of advanced NSCLC in Han Chinese. Further larger and functional studies are needed to confirm the results. PMID- 24797337 TI - Improved multislice perfusion imaging with velocity-selective arterial spin labeling. AB - PURPOSE: To improve the multislice performance of velocity-selective arterial spin labeling (VS-ASL) imaging for cerebral blood flow (CBF) measurement such that it might be routinely applied for clinical applications with whole brain coverage. MATERIALS AND METHODS: VS-ASL was performed with improvements such as timing optimization, stimulated echo removal, and slice profile sharpening. Each improvement was evaluated in volunteers by measuring temporal noise in the CBF measurement. VS-ASL with all these improvements was performed in 20 patients with Moyamoya disease some of whom also underwent xenon-enhanced CT (xeCT) imaging which was the reference standard for CBF measurement. RESULTS: Sequence timing optimization and inter-slice crosstalk reduction using stimulated echo removal and slice profile sharpening all contributed to reduction of temporal noise. VS ASL imaging with all these improvements performed in Moyamoya disease patients showed significant reduction of temporal noise (P < 0.0001) and increased correlation coefficient with xeCT CBF imaging (from 0.07 to 0.62). CONCLUSION: We demonstrated that timing optimization, stimulated echo removal, and slice profile improvement have a large effect on image quality and robustness of VS-ASL in clinical imaging applications. PMID- 24797338 TI - Macro and small over micro: macromolecules and small molecules that regulate microRNAs. AB - Given the correlation between the deregulation of specific miRNAs and disease onset, it is critical to identify miRNA regulators that effectively control miRNAs involved in the pathogenesis of target diseases. This review provides the latest update on oligonucleotide- and small-molecule-based miRNA regulators, and discusses assays developed to screen for small-molecule regulators. PMID- 24797339 TI - I don't believe it, but i'd better do something about it: patient experiences of online heart age risk calculators. AB - BACKGROUND: Health risk calculators are widely available on the Internet, including cardiovascular disease (CVD) risk calculators that estimate the probability of a heart attack, stroke, or death over a 5- or 10-year period. Some calculators convert this probability to "heart age", where a heart age older than current age indicates modifiable risk factors. These calculators may impact patient decision making about CVD risk management with or without clinician involvement, but little is known about how patients use them. Previous studies have not investigated patient understanding of heart age compared to 5-year percentage risk, or the best way to present heart age. OBJECTIVE: This study aimed to investigate patient experiences and understanding of online heart age calculators that use different verbal, numerical, and graphical formats, based on 5- and 10-year Framingham risk equations used in clinical practice guidelines around the world. METHODS: General practitioners in New South Wales, Australia, recruited 26 patients with CVD/lifestyle risk factors who were not taking cholesterol or blood pressure-lowering medication in 2012. Participants were asked to "think aloud" while using two heart age calculators in random order, with semi-structured interviews before and after. Transcribed audio recordings were coded and a framework analysis method was used. RESULTS: Risk factor questions were often misinterpreted, reducing the accuracy of the calculators. Participants perceived older heart age as confronting and younger heart age as positive but unrealistic. Unexpected or contradictory results (eg, low percentage risk but older heart age) led participants to question the credibility of the calculators. Reasons to discredit the results included the absence of relevant lifestyle questions and impact of corporate sponsorship. However, the calculators prompted participants to consider lifestyle changes irrespective of whether they received younger, same, or older heart age results. CONCLUSIONS: Online heart age calculators can be misunderstood and disregarded if they produce unexpected or contradictory results, but they may still motivate lifestyle changes. Future research should investigate both the benefits and harms of communicating risk in this way, and how to increase the reliability and credibility of online health risk calculators. PMID- 24797340 TI - Clinical relevance of sensitive and quantitative STAT3 mutation analysis using next-generation sequencing in T-cell large granular lymphocytic leukemia. AB - Diagnosis of T-cell large granular lymphocytic leukemia (T-LGL) is often challenging because clinical and laboratory characteristics are overlapping with nonneoplastic conditions. Recently, mutation in the STAT3 gene has been identified as a recurrent genetic abnormality in T-LGL. STAT3 mutation, therefore, represents a promising marker in T-LGL diagnostics. We developed a new quantitative next-generation sequencing assay that allows sensitive analysis of the STAT3 gene. The assay was used to study the utility of STAT3 mutation analysis as a diagnostic tool in T-LGL. The study included 16 T-LGL patients. A total of 15 mutations, including 2 new mutations (G618R and K658R), were detected in 12 patients (75%), with mutation levels ranging from 2.5% to 45.6% mutation positive alleles. Next-generation sequencing detected 50% more mutations than Sanger sequencing. Blood samples from 20 healthy blood donors all tested negative, thus demonstrating the specificity of the assay. The results also indicated that mutation levels in blood and bone marrow are not systematically different, and next-generation sequencing-based STAT3 mutation analysis represents a sensitive method for monitoring residual disease as demonstrated in a patient receiving pentostatin. We demonstrate the clinical relevance of next generation sequencing-based STAT3 mutation analysis, which represents a sensitive and specific diagnostic marker in T-LGL that allows assessment of molecular residual disease, which may improve clinical decision making. PMID- 24797342 TI - Cation-induced band-gap tuning in organohalide perovskites: interplay of spin orbit coupling and octahedra tilting. AB - Organohalide lead perovskites have revolutionized the scenario of emerging photovoltaic technologies. The prototype MAPbI3 perovskite (MA = CH3NH3(+)) has dominated the field, despite only harvesting photons above 750 nm (~1.6 eV). Intensive research efforts are being devoted to find new perovskites with red shifted absorption onset, along with good charge transport properties. Recently, a new perovskite based on the formamidinium cation ((NH2)2CH(+) = FA) has shown potentially superior properties in terms of band gap and charge transport compared to MAPbI3. The results have been interpreted in terms of the cation size, with the larger FA cation expectedly delivering reduced band-gaps in Pb based perovskites. To provide a full understanding of the interplay among size, structure, and organic/inorganic interactions in determining the properties of APbI3 perovskites, in view of designing new materials and fully exploiting them for solar cells applications, we report a fully first-principles investigation on APbI3 perovskites with A = Cs(+), MA, and FA. Our results evidence that the tetragonal-to-quasi cubic structural evolution observed when moving from MA to FA is due to the interplay of size effects and enhanced hydrogen bonding between the FA cations and the inorganic matrix altering the covalent/ionic character of Pb-I bonds. Most notably, the observed cation-induced structural variability promotes markedly different electronic and optical properties in the MAPbI3 and FAPbI3 perovskites, mediated by the different spin-orbit coupling, leading to improved charge transport and red-shifted absorption in FAPbI3 and in general in pseudocubic structures. Our theoretical model constitutes the basis for the rationale design of new and more efficient organohalide perovskites for solar cells applications. PMID- 24797341 TI - Sustained pyridoxine response in primary hyperoxaluria type 1 recipients of kidney alone transplant. AB - Combined liver kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) given that it removes the hepatic source of oxalate production and improves renal allograft survival. However, PH1 patients homozygous for the G170R mutation can develop normal urine oxalate levels with pyridoxine therapy and may be candidates for kidney alone transplant (KTx). We examined the efficacy of pyridoxine therapy following KTx in five patients homozygous for G170R transplanted between September 1999 and July 2013. All patients were maintained on pyridoxine posttransplant. Median age at transplant was 39 years (range 33-67 years). Median follow-up posttransplant was 8.5 years (range 0.2-13.9 years). At the end of follow-up, four grafts were functioning. One graft failed 13.9 years posttransplant due to recurrent oxalate nephropathy following an acute medical illness. After tissue oxalate stores had cleared, posttransplant urine oxalate levels were <0.5 mmol/24 h the majority of times checked. Calcium oxalate crystals were noted in only 3/13 allograft biopsies. This series suggests that a subgroup of PH1 patients demonstrate sustained response to pyridoxine therapy following KTx. Therefore, pyridoxine combined with KTx should be considered for PH1 patients with a homozygous G170R mutation. PMID- 24797343 TI - Signal transducers and activators of transcription (STATs) gene polymorphisms related with susceptibility to rheumatic heart disease in north Indian population. AB - Rheumatic heart disease (RHD) is the most serious complication of heart that comprises inflammatory reactions in heart valves. Cytokines play a critical role in triggering inflammatory reactions and they activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway. Altered signals of STATs play important roles in the balance between proinflammatory and anti-inflammatory cytokines in inflammatory diseases. The aim of the present study was to investigate for the association of polymorphisms related with STAT genes, i.e. STAT3 (rs4796793 C/G) and STAT5b (rs6503691 C/T) with the pathogenesis of RHD. This case-control association study involved 300 healthy controls and 400 RHD patients from North Indian Population. We categorized RHD patients into two subgroups based on involvement of heart valves, mitral valve lesion alone (MVL), and combined valve lesions including mitral valve (CVL). Genotyping was done by RFLP/Taqman probes. We observed that STAT3 CG and GG genotypes were significantly associated with RHD (p=0.030 and p=0.014 respectively), STAT5b CT and TT genotypes were also significantly associated with RHD (p<=0.001). Haplotype analysis revealed that minor alleles of both the variants (Grs4796793Trs6503691) were significantly associated (p<0.0001) with increased risk of the disease susceptibility irrespective of gender or age of onset of the disease. However, the polymorphisms were not involved in severity of RHD as both MVL and CVL patients were equally affected. STAT Grs4796793Trs6503691 carriers may have reduced production of STAT3 leading to damage of heart valves. Thus, STAT genes polymorphisms may be useful markers for the identification of individuals with high risk of RHD in the susceptible population. PMID- 24797344 TI - Comparison of sputum and nasopharyngeal swabs for detection of respiratory viruses. AB - Diagnostic tests for respiratory viral infections use traditionally either nasopharyngeal washes or swabs. Sputum is representative of the lower respiratory tract but is used rarely for viral testing. The aim of this study was to compare the detection rates of respiratory viruses from nasopharyngeal swabs and sputum using a multiplex real-time reverse transcription-polymerase chain reaction (RT PCR). Adults who were admitted or presented to the clinics of Gil Medical Center with acute respiratory symptoms were recruited from 1 November 2012 to 31 March 2013. Paired specimens of nasopharyngeal swabs and sputum were obtained from 154 subjects, and RNA was extracted and tested for 16 different respiratory viruses using the Anyplex II RV16 Detection kit (Seegene, Seoul, Korea). The positive rate was 53% (81/154) for nasopharyngeal swabs and 68% (105/154) for sputum (P < 0.001). One hundred thirty-four viruses were identified for 107 illnesses. Influenza A virus, RSV A, HRV, coronavirus OC43, and adenovirus were detected more frequently in sputum samples than in nasopharyngeal swabs (P < 0.001). Importantly, 12 of 44 (27%) influenza A infections and 11 of 27 (41%) RSV infections were positive in only sputum samples. The detection rates of respiratory viruses from sputum samples were significantly higher than those from nasopharyngeal swabs in adults using real-time multiplex RT-PCR. These findings suggest that sputum would benefit for the detection of respiratory viruses by nucleic acid amplification tests (NAATs) in patients who produce sputum. Further studies are needed to establish standardized RNA extraction methods from sputum samples. PMID- 24797345 TI - Development and application of a loop-mediated isothermal amplification assay for rapid detection of Pythium helicoides. AB - Root rot of poinsettia, caused by Pythium helicoides at high temperatures in hydroponic cultures, has become a serious problem in many parts of the world. We have developed a species-specific, loop-mediated isothermal amplification (LAMP) assay for the rapid diagnosis of this pathogen. The primers were designed using the ribosomal DNA internal transcribed spacer sequence. Primer specificity was established using 40 Pythium species including P. helicoides, 11 Phytophthora species, and eight other soil-borne pathogens. A sensitivity test was carried out using genomic DNA extracted from P. helicoides, and the detection limit was c. 100 fg which is comparable to that of the polymerase chain reaction (PCR). In addition, we tested the ease of pathogen detection in poinsettia roots. The LAMP results were consistent with those from the conventional plating method and showed more sensitivity than the PCR results. Consequently, the LAMP method developed in this study is effective for the rapid and easy detection of P. helicoides. PMID- 24797347 TI - Control of Salmonella Enteritidis in turkeys using organic acids and competitive exclusion product. AB - AIM: To evaluate the use of organic acids (OAs) and competitive exclusion (CE) product administered continuously in the feed and transiently in drinking water on the control of Salmonella enterica subspecie enterica serotype Enteritidis (SE) prior to slaughter. METHODS AND RESULTS: The influence of treatments were evaluated on pH, population of the lactic acid bacteria (LAB) and bacteria of the family Enterobacteriaceae, concentration of volatile fatty acids and SE colonization in the crop and caecum. The birds were challenged with SE 24 h before being slaughtered, and then, the caeca and crop were removed and subjected to SE counts. Continuous administration of OAs reduced the population of bacteria from the Enterobacteriaceae family in both crop and caecum, positively influenced the butyric acid concentration and reduced SE colonization in the caecum. The diet supplemented with CE product positively influenced the quantity of LAB in the crop and caecum, elevated the butyric acid concentration and reduced both Enterobacteriaceae quantity and SE colonization in the caecum. There was no effect from administering the treatments via drinking water on the variables measured. CONCLUSIONS: Continuous supplementation in feed with OAs and CE product reduced SE colonization of the caeca. SIGNIFICANCE AND IMPACT OF THE STUDY: Supplementation of OAs and CE product in diet to turkeys can reduce the SE load, potentially leading to a lower contamination risk of meat during slaughter. PMID- 24797348 TI - A multicentre cohort study of acute heart failure syndromes in Korea: rationale, design, and interim observations of the Korean Acute Heart Failure (KorAHF) registry. AB - AIMS: The Korean Acute Heart Failure registry (KorAHF) aims to evaluate the clinical characteristics, management, hospital course, and long-term outcomes of patients hospitalized for acute heart failure syndrome (AHFS) in Korea. METHODS AND RESULTS: This is a prospective observational multicentre cohort study funded by the Korea National Institute of Health. Patients hospitalized for AHFS in 10 tertiary university hospitals across the country have been consecutively enrolled since March 2011. The study is expected to complete the scheduled enrolment of 5000 patients some time in 2014, and follow-up is planned through 2016. As of April 2012, the interim analysis of 2066 consecutive subjects was performed to understand the baseline characteristics of the population. The mean age was 69 +/ 14 years; 55% were male; and 50% were de novo heart failure. The mean left ventricular ejection fraction (LVEF) was 40 +/- 18%. Ischaemia was both the leading cause (38%) and the most frequent aggravating factor (26%) of AHFS. ACE inhibitors/ARBs and beta-blockers were prescribed at discharge in 65% and 51% of the patients, respectively. In-hospital mortality was 5.2%, and 0.9% of patients received urgent heart transplantation. Low blood pressure and azotaemia were the most important predictors of in-hospital mortality. The post-discharge 30-day and 180-day all-cause mortality were 1.2% and 9.2%, respectively. CONCLUSIONS: Our analysis reveals that the prognosis of AHFS in Korea is poor and that there are specific features, including lower blood pressures at admission and lower rates of heart failure related to hypertension, compared with other registries. Adherence to current guidelines should be improved. PMID- 24797349 TI - Direct application of MALDI-TOF mass spectrometry to cerebrospinal fluid for rapid pathogen identification in a patient with bacterial meningitis. AB - BACKGROUND: Bacterial meningitis is a neurological emergency. Early diagnosis and rapid initiation of antimicrobial therapy are vital. METHODS: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is increasingly used as a rapid and accurate microbial diagnostic method for species identification of pathogens. Although this technology requires a growth step to obtain bacterial colonies for the acquisition of substantial spectra in most cases, it can also be used to analyze clinical specimens such as urine and cerebrospinal fluid for direct bacterial identification. There are very few reports describing the use of MALDI-TOF MS for the direct detection of microorganisms causing bacterial meningitis. RESULTS: We describe a case of bacterial meningitis caused by Klebsiella pneumoniae in which MALDI-TOF MS provided a rapid bacteriological diagnosis, thus enabling early and appropriate treatment. CONCLUSIONS: Identification of microbes based on MALDI-TOF MS is now an important technology in clinical microbiology laboratories that are required to provide a rapid diagnosis of bacterial meningitis. PMID- 24797350 TI - [Not Available]. PMID- 24797351 TI - [Not Available]. PMID- 24797352 TI - Urea-catalyzed N-H insertion-arylation reactions of nitrodiazoesters. AB - The power of hydrogen-bond donor catalysis has been harnessed to elicit and control carbene-like reactivity from nitrodiazoesters. Specifically, select ureas have been identified as effective catalysts for N-H insertion and multicomponent coupling reactions of nitrodiazoesters, anilines, and aromatic nucleophiles, thereby preparing a variety of alpha-aryl glycines in high yield. Experimental and computational studies designed to probe the plausible reaction pathways suggest that difluoroboronate ureas are particularly well-suited to catalyze reactions of nitrodiazoesters with a range of anilines through a polar reaction pathway. Urea-facilitated loss of nitrite followed by addition of a nucleophile conceivably generates the observed aryl glycine products. PMID- 24797353 TI - Occurrence of Tropheryma whipplei during diarrhea in Hajj pilgrims: a PCR analysis of paired rectal swabs. AB - BACKGROUND: Tropheryma whipplei was recently associated with gastroenteritis in children. We hypothesize that T. whipplei may be a contributing microbe in traveller's diarrhea. METHOD: The presence of T. whipplei was investigated by PCR on rectal swab samples of Hajj pilgrims before and after travelling to the Kingdom of Saudi Arabia (KSA). Additionally a rectal swab was performed at the time of diarrhea for some pilgrims. RESULTS: A total of 129 pilgrims underwent rectal swab samples before departure and on return. All pilgrims were negative for T. whipplei before travel. One pilgrim (0.8%) was positive on return but did not reported diarrhea. A total of 30 pilgrims (23.3%) experienced diarrhea during the stay in the KSA. Nine pilgrims with diarrhea underwent the additional rectal swab during their diarrhea episode, two of them were positive for T. whipplei. CONCLUSIONS: This work suggests that T. whipplei may be associated with adult traveller's diarrhea, by finding T. whipplei DNA individuals negative before and after the episode of diarrhea. Further study addressing this issue in larger cohorts of Hajj pilgrims with systematic sampling at the time of diarrheal episode may help to understand the potential role of T. whipplei in traveller's diarrhea. PMID- 24797354 TI - Current drugs in early development for hereditary angioedema: potential for effective treatment. AB - Hereditary angioedema (HAE) through C1 inhibitor deficiency is a rare but important disease. It is characterized by recurrent episodes of angioedema, which commonly affects the skin (in the form of swelling in the extremities, face and genitals) as well as the gastrointestinal tract (abdominal pain attacks). In approximately 1% of cases of angiodema-related swelling, there is obstruction of the upper airway, which is potentially life-threatening. Therefore, HAE due to C1 inhibitor deficiency may be associated with significant morbidity and mortality. Recent research has added to our ever-increasing understanding of the pathogenesis of HAE, which has, in addition, new clinical trials with new therapeutic agents and strategies. The following editorial covers drugs currently under investigation that have the potential to be promising new therapeutic options. While some compounds show promise for the future, there are currently no oral treatments available for the treatment of acute attacks. Furthermore, some of the intravenous therapies currently available require numerous injections and do not always prevent acute attacks. Attenuated androgens also may have problematic side effects, highlighting the need for new treatment options. PMID- 24797355 TI - Sleep changes in smokers before, during and 3 months after nicotine withdrawal. AB - Nicotine may affect sleep by influencing sleep-regulating neurotransmitters. Sleep disorders can increase the risk for depression and substance dependency. To detect the influence of sleep disturbances on the effect of smoking cessation, we investigated polysomnographically (PSG) the sleep of smoking subjects during a period of smoking, during withdrawal and after a period of abstinence from nicotine. Thirty-three smokers (23 male, 10 female, median age 29 years, Fagerstrom Test for Nicotine Dependence score 6.3) were examined during smoking, 24-36 hours after smoking and 3 months after cessation. All subjects had an adaptation night followed by the PSG night. Compared with the smoking state, we found increased arousal index and wake time during nicotine withdrawal. Smokers who later relapsed (11) presented a higher degree of nicotine dependence and more withdrawal symptoms than those who abstained (22) and were characterized by less rapid eye movement (REM) sleep, a longer REM latency as well as by more intense sleep impairments in the subjective sleep rating during the withdrawal. Impairments of sleep during the withdrawal phase may reflect more severe nicotine dependence and may contribute to earlier relapse into smoking behaviours. PMID- 24797356 TI - Reassembling epidemiology: mapping, monitoring and making-up people in the context of HIV prevention in India. AB - This paper explores how the Gates-funded HIV Initiative in India, known as Avahan, produces sociality. Drawing upon ethnographic research conducted between 2006 and 2012, we illustrate how epidemiological surveillance procedures, undergirded by contemporary managerial and entrepreneurial logics, entwine with and become transformed by the everyday practices of men who have sex with men (many of whom sell sex). The coevolution of epidemiology and sociality, with respect to these communities, is explored in relation to: 1) how individual identities are reproduced in association with standardized units of space and time; 2) how knowledge of mapping and enumeration data is employed in the making up of group membership boundaries, revealing how collective interests come to cohere around the project of epidemic prevention; and 3) how knowledge of epidemiological surveillance and procedures provides a basis on which groups collectively realize and execute local security strategies. While monitoring and evaluation (M&E) specialists continually track and standardize the identities, behaviours and social spaces of local populations (through various mapping, typologization and random sampling procedures, which treat space and time as predictable variables), community members simultaneously retranslate and reroute these standardizing processes into "the local" through everyday spatial management practices for health protection. These grounded epidemiologies, we argue, point to vital sites in the co-creation of scientific knowledge-where the quotidian practices of sex workers reassemble epidemiology, continually altering the very objects that surveillance experts are tracking. We further argue that attention to these re-workings can help us unravel the tremendous successes that have been claimed under Avahan in terms of HIV infections averted. PMID- 24797357 TI - Comparison of three molecular assays for the detection of rifampin resistance in Mycobacterium tuberculosis. AB - BACKGROUND: Rifampin (RIF) is the most important first-line antituberculosis drug, and resistance to this drug may result in treatment failures. We evaluated the diagnostic performances of recently introduced, molecular assays for the detection of RIF resistance. METHODS: A total of 100 isolates (50 RIF resistant and 50 RIF susceptible) were studied. Their RIF resistances were determined by conventional drug-susceptibility test. These results were compared with those of three molecular assays: Xpert MTB/RIF assay (MTB is Mycobacterium tuberculosis), Sacace MTB Real-TM resistance, and AdvanSure MDR-TB GenoBlot assay (MDR is multidrug resisitant). RESULTS: Sensitivities for RIF resistance detection of Xpert MTB/RIF assay, Sacace MTB Real-TM resistance, and Advansure GenoBlot assay were 94.0%, 91.8%, and 84.0%, respectively. Their specificities for RIF resistance detection were all 100%. CONCLUSION: Three molecular assays for the detection of RIF resistance have various performances. Xpert MTB/RIF assay shows the highest sensitivity among the three molecular assays and can be an effective choice in clinical laboratories. PMID- 24797358 TI - HCV treatment as prevention in prison: key issues. PMID- 24797359 TI - Synthesis of new lipid-inspired ionic liquids by thiol-ene chemistry: profound solvent effect on reaction pathway. AB - The synthesis of a series of new lipid-inspired ionic liquids through thiol-ene "click" reaction with a single-step process. This synthesis offers considerable promise as an efficient and orthogonal method to construct structurally diverse imidazolium-type ionic liquids with linear and branched cationic tails, as well as versatility in the placement of the sulfur heteroatom. Profound solvent effect in this ene reaction regioselectivity has been observed. PMID- 24797361 TI - Transoral robotic assisted resection of the parapharyngeal space. AB - BACKGROUND: Preliminary case series have reported clinical feasibility and safety of a transoral minimally invasive technique to approach parapharyngeal space masses. With the assistance of the surgical robotic system, tumors within the parapharyngeal space can now be excised safely without neck incisions. A detailed technical description is included. METHODS: After developing compressive symptoms from a parapharyngeal space lipomatous tumor, the patient was referred by his primary otolaryngologist because of poor open surgical access to the nasopharyngeal component of the tumor. RESULTS: Transoral robotic assisted resection of a 54- * 46-mm parapharyngeal space mass was performed, utilizing 97 minutes of robotic surgical time. Pictorial demonstration of the robotic resection is provided. CONCLUSION: Parapharyngeal space tumors have traditionally been approached via transcervical skin incisions, typically including blunt dissection from tactile feedback. The transoral robotic approach offers magnified 3D visualization of the parapharyngeal space that allows for complete and safe resection. PMID- 24797360 TI - Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology. AB - The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue--such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy. PMID- 24797363 TI - Integrating physiotherapists within primary health care teams: perspectives of family physicians and nurse practitioners. AB - The international literature suggests a number of benefits related to integrating physiotherapists into primary health care (PHC) teams. Considering the mandate of PHC teams in Canada, emphasizing healthy living and chronic disease management, a broad range of providers, inclusive of physiotherapists is required. However, physiotherapists are only sparsely integrated into these teams. This study explores the perspectives of "core" PHC team members, family physicians and nurse practitioners, regarding the integration of physiotherapists within Ontario (Canada) PHC teams. Twenty individual semi-structured in-depth interviews were conducted, transcribed verbatim, and then analyzed following an iterative process drawing from an interpretive phenomenological approach. Five key themes emerged which highlighted "how physiotherapists could and do contribute as team members within PHC teams particularly related to musculoskeletal health and chronic disease management". The perceived value of physiotherapists within Ontario, Canada PHC teams was a unanimous sentiment particularly in terms of musculoskeletal health, chronic disease management and maximizing health human resources efficiency to ensure the right care, is delivered by the right practitioner, at the right time. PMID- 24797362 TI - Hyper-activation of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells. AB - Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells. PMID- 24797365 TI - Impact of pulmonary hypertension on exercise performance in patients with interstitial lung disease undergoing evaluation for lung transplantation. AB - BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is a known complication in patients with interstitial lung disease (ILD). Cardiopulmonary exercise testing (CPET) is an essential tool for the assessment of patients with cardiac and pulmonary diseases due to its prognostic and therapeutic implications. Few studies have evaluated the relationship between CPET response and mean pulmonary artery pressures (mPAP) in ILD. The purpose of the present study was to determine and compare the potential correlations between CPET, 6-min walk test (6MWT), pulmonary function testing (PFT) and PH in patients with ILD being evaluated for lung transplantation. METHODS: The present study reviewed patients with ILD who received lung transplantations and had CPETs within 2 years before transplantation, right heart catheterizations, PFTs and 6MWTs within 4 months of CPET. RESULTS: A total of 72 patients with ILD were analysed; 36% had PH. There were significant correlations between mPAP and CPET parameters in patients with PH; but mPAP had no impact on percent of predicted diffusion capacity of the lung for carbon monoxide or 6-min walk distance (6MWD). CPET parameters were able to detect differences between levels of severity of PH through the use of the ratio of minute ventilation to rate of carbon dioxide production (VE/VCO2) and the partial pressure of end-tidal carbon dioxide. CONCLUSIONS: This is the first study that analyses 6MWD, PFT and CPET in patients with ILD awaiting lung transplantation with and without PH. The present study demonstrates the significant impact of PH on exercise capacity and performance in patients with ILD awaiting lung transplantation. PMID- 24797366 TI - IL-8 enhances the angiogenic potential of human bone marrow mesenchymal stem cells by increasing vascular endothelial growth factor. AB - The beneficial effects of mesenchymal stem cells (MSCs) are mediated partly by the paracrine production of cytoprotective and trophic factors. Vascular endothelial growth factor (VEGF) is released from MSCs as a paracrine trophic factor and contributes to the therapeutic effects of the stem cell by regulating angiogenesis and promoting revascularization in injured tissues. Interleukin-8 (IL-8), an inflammatory chemokine with potent proangiogenic properties, is upregulated in the ischemic brain and has been shown to promote homing of bone marrow-derived cells to injured sites. However, the effect of IL-8 on MSCs paracrine function remains unknown. We found that IL-8 induced VEGF production and phosphorylation of Akt and ERK. Both effects could be blocked by inhibitors (LY294002, PD098059) or siRNA-mediated silencing of Akt and ERK in human bone marrow MSCs (hBM-MSCs). IL-8-induced VEGF production in hBM-MSCs significantly increased tube formation on Matrigel compared with basal secreted VEGF. In a rat stroke model, administration of IL-8-treated hBM-MSCs decreased the infarction volume and increased angiogenesis in the ischemic boundary zone compared with hBM MSC treatment alone. In conclusion, IL-8 stimulates VEGF production in hBM-MSCs in part via the PI3K/Akt and MAPK/ERK signal transduction pathways and that administration of IL-8-treated hBM-MSCs increases angiogenesis after stroke. This approach may be used to optimize MSC-based therapies for numerous diseases including stroke, myocardial ischemia, and spinal cord injury. PMID- 24797367 TI - Gyroid nickel nanostructures from diblock copolymer supramolecules. AB - Nanoporous metal foams possess a unique combination of properties - they are catalytically active, thermally and electrically conductive, and furthermore, have high porosity, high surface-to-volume and strength-to-weight ratio. Unfortunately, common approaches for preparation of metallic nanostructures render materials with highly disordered architecture, which might have an adverse effect on their mechanical properties. Block copolymers have the ability to self assemble into ordered nanostructures and can be applied as templates for the preparation of well-ordered metal nanofoams. Here we describe the application of a block copolymer-based supramolecular complex - polystyrene-block-poly(4 vinylpyridine)(pentadecylphenol) PS-b-P4VP(PDP) - as a precursor for well-ordered nickel nanofoam. The supramolecular complexes exhibit a phase behavior similar to conventional block copolymers and can self-assemble into the bicontinuous gyroid morphology with two PS networks placed in a P4VP(PDP) matrix. PDP can be dissolved in ethanol leading to the formation of a porous structure that can be backfilled with metal. Using electroless plating technique, nickel can be inserted into the template's channels. Finally, the remaining polymer can be removed via pyrolysis from the polymer/inorganic nanohybrid resulting in nanoporous nickel foam with inverse gyroid morphology. PMID- 24797368 TI - The complexity of HIV persistence and pathogenesis in the lung under antiretroviral therapy: challenges beyond AIDS. AB - Antiretroviral therapy (ART) represents a significant milestone in the battle against AIDS. However, we continue learning about HIV and confronting challenges 30 years after its discovery. HIV has cleverly tricked both the host immune system and ART. First, the many HIV subtypes and recombinant forms have different susceptibilities to antiretroviral drugs, which may represent an issue in countries where ART is just being introduced. Second, even under the suppressive pressures of ART, HIV still increases inflammatory mediators, deregulates apoptosis and proliferation, and induces oxidative stress in the host. Third, the preference of HIV for CXCR4 as a co-receptor may also have noxious outcomes, including potential malignancies. Furthermore, HIV still replicates cryptically in anatomical reservoirs, including the lung. HIV impairs bronchoalveolar T lymphocyte and macrophage immune responses, rendering the lung susceptible to comorbidities. In addition, HIV-infected individuals are significantly more susceptible to long-term HIV-associated complications. This review focuses on chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, and lung cancer. Almost two decades after the advent of highly active ART, we now know that HIV-infected individuals on ART live as long as the uninfected population. Fortunately, its availability is rapidly increasing in low- and middle-income countries. Nevertheless, ART is not risk-free: the developed world is facing issues with antiretroviral drug toxicity, resistance, and drug-drug interactions, while developing countries are confronting issues with immune reconstitution inflammatory syndrome. Several aspects of the complexity of HIV persistence and challenges with ART are discussed, as well as suggestions for new avenues of research. PMID- 24797369 TI - The role of podoplanin in the biology of differentiated thyroid cancers. AB - Podoplanin (PDPN), a mucin-type transmembrane glycoprotein specific to the lymphatic system is expressed in a variety of human cancers, and is regarded as a factor promoting tumor progression. The purpose of this study was to elucidate the molecular role of PDPN in the biology of thyroid cancer cells. PDPN expression was evaluated in primary thyroid carcinomas and thyroid carcinoma cell lines by RT-qPCR, Western blotting, IF and IHC. To examine the role of podoplanin in determining a cell's malignant potential (cellular migration, invasion, proliferation, adhesion, motility, apoptosis), a thyroid cancer cell line with silenced PDPN expression was used. We observed that PDPN was solely expressed in the cancer cells of 40% of papillary thyroid carcinoma (PTC) tissues. Moreover, PDPN mRNA and protein were highly expressed in PTC-derived TPC1 and BcPAP cell lines but were not detected in follicular thyroid cancer derived cell lines. PDPN knock-down significantly decreased cellular invasion, and modestly reduced cell migration, while proliferation and adhesion were not affected. Our results demonstrate that PDPN mediates the invasive properties of cells derived from papillary thyroid carcinomas, suggesting that podoplanin might promote PTC progression. PMID- 24797370 TI - Dot1-dependent histone H3K79 methylation promotes the formation of meiotic double strand breaks in the absence of histone H3K4 methylation in budding yeast. AB - Epigenetic marks such as histone modifications play roles in various chromosome dynamics in mitosis and meiosis. Methylation of histones H3 at positions K4 and K79 is involved in the initiation of recombination and the recombination checkpoint, respectively, during meiosis in the budding yeast. Set1 promotes H3K4 methylation while Dot1 promotes H3K79 methylation. In this study, we carried out detailed analyses of meiosis in mutants of the SET1 and DOT1 genes as well as methylation-defective mutants of histone H3. We confirmed the role of Set1 dependent H3K4 methylation in the formation of double-strand breaks (DSBs) in meiosis for the initiation of meiotic recombination, and we showed the involvement of Dot1 (H3K79 methylation) in DSB formation in the absence of Set1 dependent H3K4 methylation. In addition, we showed that the histone H3K4 methylation-defective mutants are defective in SC elongation, although they seem to have moderate reduction of DSBs. This suggests that high levels of DSBs mediated by histone H3K4 methylation promote SC elongation. PMID- 24797371 TI - Derivation and osmotolerance characterization of three immortalized tilapia (Oreochromis mossambicus) cell lines. AB - Fish cell cultures are becoming more widely used models for investigating molecular mechanisms of physiological response to environmental challenge. In this study, we derived two immortalized Mozambique tilapia (Oreochromis mossambicus) cell lines from brain (OmB) and lip epithelium (OmL), and compared them to a previously immortalized bulbus arteriosus (TmB) cell line. The OmB and OmL cell lines were generated without or with Rho-associated kinase (ROCK) inhibitor/3T3 feeder layer supplementation. Although both approaches were successful, ROCK inhibitor/feeder layer supplementation was found to offer the advantages of selecting for epithelial-like cell type and decreasing time to immortalization. After immortalization (>= passage 5), we characterized the proteomes of the newly derived cell lines (OmB and OmL) using LCMS and identified several unique cell markers for each line. Subsequently, osmotolerance for each of the three cell lines following acute exposure to elevated sodium chloride was evaluated. The acute maximum osmotolerance of these tilapia cell lines (>700 mOsm/kg) was markedly higher than that of any other known vertebrate cell line, but was significantly higher in the epithelial-like OmL cell line. To validate the physiological relevance of these tilapia cell lines, we quantified the effects of acute hyperosmotic challenge (450 mOsm/kg and 700 mOsm/kg) on the transcriptional regulation of two enzymes involved in biosynthesis of the compatible organic osmolyte, myo-inositol. Both enzymes were found to be robustly upregulated in all three tilapia cell lines. Therefore, the newly established tilapia cells lines represent valuable tools for studying molecular mechanisms involved in the osmotic stress response of euryhaline fish. PMID- 24797372 TI - Transfusion-associated hepatitis before the screening of blood for hepatitis risk factors. AB - BACKGROUND: The true incidence of transfusion-associated hepatitis (TAH) before blood screening is unknown. Our aims were to reevaluate blood recipients receiving unscreened blood and analyze hepatitis viruses circulating more than 45 years ago. STUDY DESIGN AND METHODS: Cryopreserved serum samples from 66 patients undergoing open heart surgery in the 1960s were reevaluated with modern diagnostic tests to determine the incidence of TAH and its virologic causes. RESULTS: In this heavily transfused population receiving a mean of 20 units per patient of predominantly paid-donor blood, 30 of 66 (45%) developed biochemical evidence of hepatitis; of these, 20 (67%) were infected with hepatitis C virus (HCV) alone, four (13%) with hepatitis B virus (HBV) alone, and six (20%) with both viruses. Among the 36 patients who did not develop hepatitis, four (11%) were newly infected with HCV alone, nine (25%) with HBV alone, and one (3%) with both viruses. Overall, 100% of patients with hepatitis and 39% of those without hepatitis were infected with HBV and/or HCV; one patient was also infected with hepatitis E virus. The donor carrier rate for HBV and/or HCV was estimated to be more than 6%; contemporaneously prepared pooled normal human plasma was also contaminated with multiple hepatitis viruses. CONCLUSION: TAH virus infections were a larger problem than perceived 50 years ago and HCV was the predominant agent transmitted. All hepatitis cases could be attributed to HCV and/or HBV and hence there was no evidence to suggest that an additional hepatitis agent existed undetected in the blood supply. PMID- 24797373 TI - The association of spiritual care providers' activities with family members' satisfaction with care after a death in the ICU*. AB - OBJECTIVES: Spiritual distress is common in the ICU, and spiritual care providers are often called upon to provide care for patients and their families. Our goal was to evaluate the activities spiritual care providers' conduct to support patients and families and whether those activities are associated with family satisfaction with ICU care. DESIGN: Prospective cohort study. SETTING: Three hundred fifty-bed tertiary care teaching hospital with 65 ICU beds. SUBJECTS: Spiritual care providers and family members of patients who died in the ICU or within 30 hours of transfer from the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Spiritual care providers completed surveys reporting their activities. Family members completed validated measures of satisfaction with care and satisfaction with spiritual care. Clustered regression was used to assess the association between activities completed by spiritual care providers and family ratings of care. Of 494 eligible patients, 275 family members completed surveys (response rate, 56%). Fifty-seven spiritual care providers received surveys relating to 268 patients, completing 285 surveys for 244 patients (response rate, 91%). Spiritual care providers commonly reported activities related to supporting religious and spiritual needs (>= 90%) and providing support for family feelings (90%). Discussions about the patient's wishes for end-of-life care and a greater number of spiritual care activities performed were both associated with increased overall family satisfaction with ICU care (p < 0.05). Discussions about a patient's end-of-life wishes, preparation for a family conference, and total number of activities performed were associated with improved family satisfaction with decision-making in the ICU (p < 0.05). CONCLUSIONS: Spiritual care providers engage in a variety of activities with families of ICU patients; several are associated with increased family satisfaction with ICU care in general and decision-making in the ICU specifically. These findings provide insight into spiritual care provider activities and provide guidance for interventions to improve spiritual care delivered to families of critically ill patients. PMID- 24797374 TI - Angiotensin II in septic shock: effects on tissue perfusion, organ function, and mitochondrial respiration in a porcine model of fecal peritonitis. AB - OBJECTIVES: To compare effects of norepinephrine and angiotensin II in experimental sepsis on hemodynamics, organ function, and mitochondrial respiration. DESIGN: Randomized, controlled, study. SETTING: University experimental laboratory. SUBJECTS: Twenty-eight anesthetized, mechanically ventilated pigs. INTERVENTIONS: Sixteen pigs were randomized to receive after 12 hours of fecal peritonitis fluid resuscitation and either norepinephrine (group NE; n = 8) or angiotensin II (group AT-II; n = 8) for 48 hours. A separate group (n = 8), treated with enalapril for 1 week before peritonitis and until study end, received fluids and norepinephrine (group E). The blood pressure dose response to angiotensin II was evaluated in additional four nonseptic pigs. MEASUREMENTS AND MAIN RESULTS: Blood pressure target (75-85 mm Hg) was reached in both NE and AT-II, and cardiac output increased similarly (NE: from 64 mL/kg/min [60-79 mL/kg/min] to 139 mL/kg/min [126-157 mL/kg/min]; AT-II from 79 mL/kg/min [65-86 mL/kg/min] to 145 mL/kg/min [126-147 mL/kg/min]; median, interquartile range). Renal plasma flow, prevalence of acute kidney injury, inflammation and coagulation patterns, and mitochondrial respiration did not differ between NE and AT-II. In group E, blood pressure targets were not achieved (mean arterial pressure at study end: NE: 81 mm Hg [76-85 mm Hg]; AT-II: 80 mm Hg [77-84 mm Hg]; E: 53 mm Hg [49-66 mm Hg], p = 0.002, compared to NE), whereas skeletal muscle adenosine triphosphate concentrations were increased. During resuscitation one animal died in groups AT-II and E. CONCLUSIONS: Angiotensin II reversed sepsis induced hypotension with systemic and regional hemodynamic effects similar to those of norepinephrine. Inhibition of angiotensin-converting enzyme before sepsis worsened the hypotension but enhanced skeletal muscle adenosine triphosphate. Modifying the renin-angiotensin system in sepsis should be further evaluated. PMID- 24797375 TI - Lactate clearance is a useful biomarker for the prediction of all-cause mortality in critically ill patients: a systematic review and meta-analysis*. AB - OBJECTIVES: Lactate clearance has been widely investigated for its prognostic value in critically ill patients. However, the results are conflicting. The present study aimed to explore the diagnostic accuracy of lactate clearance in predicting mortality in critically or acutely ill patients. DATA SOURCES: Databases of Medline, Embase, Scopus, and Web of Knowledge were searched from inception to June 2013. STUDY SELECTION: Studies investigating the prognostic value of lactate clearance were defined as eligible. The searched item consisted of terms related to critically ill patients and terms related to lactate clearance. DATA EXTRACTION: The following data were extracted: the name of the first author, publication year, subjects and setting, mean age of study population, sample size, male percentage, mortality of study cohort, definition of clearance, and the initial lactate level. Relative risk was reported to estimate the predictive value of lactate clearance on mortality rate, with relative risk less than 1 indicating that lactate clearance was a protective factor. Meta-analysis of diagnostic accuracy of lactate clearance in predicting mortality was performed by using hierarchical summary receiver operating characteristic model. DATA SYNTHESIS: A total of 15 original articles were included in the study. Because of the significant heterogeneity across studies (I = 61.4%), random-effects model was used to pool relative risks. The pooled relative risk for mortality was 0.38 (95% CI, 0.29-0.50). The overall sensitivity and specificity for lactate clearance to predict mortality were 0.75 (95% CI, 0.58-0.87) and 0.72 (95% CI, 0.61-0.80), respectively. The diagnostic performance improved slightly when meta-analysis was restricted to ICU patients, with sensitivity and specificity of 0.83 (95% CI, 0.67-0.92) and 0.67 (95% CI, 0.59 0.75), respectively. CONCLUSION: Our study demonstrates that lactate clearance is predictive of lower mortality rate in critically ill patients, and its diagnostic performance is optimal for clinical utility. PMID- 24797376 TI - A multicenter, randomized clinical trial of IV iron supplementation for anemia of traumatic critical illness*. AB - OBJECTIVE: To evaluate the efficacy of IV iron supplementation of anemic, critically ill trauma patients. DESIGN: Multicenter, randomized, single-blind, placebo-controlled trial. SETTING: Four trauma ICUs. PATIENTS: Anemic (hemoglobin < 12 g/dL) trauma patients enrolled within 72 hours of ICU admission and with an expected ICU length of stay of more than or equal to 5 days. INTERVENTIONS: Randomization to iron sucrose 100 mg IV or placebo thrice weekly for up to 2 weeks. MEASUREMENTS AND MAIN RESULTS: A total of 150 patients were enrolled. Baseline iron markers were consistent with functional iron deficiency: 134 patients (89.3%) were hypoferremic, 51 (34.0%) were hyperferritinemic, and 64 (42.7%) demonstrated iron-deficient erythropoiesis as evidenced by an elevated erythrocyte zinc protoporphyrin concentration. The median baseline transferrin saturation was 8% (range, 2-58%). In the subgroup of patients who received all six doses of study drug (n = 57), the serum ferritin concentration increased significantly for the iron as compared with placebo group on both day 7 (808.0 ng/mL vs 457.0 ng/mL, respectively, p < 0.01) and day 14 (1,046.0 ng/mL vs 551.5 ng/mL, respectively, p < 0.01). There was no significant difference between groups in transferrin saturation, erythrocyte zinc protoporphyrin concentration, hemoglobin concentration, or packed RBC transfusion requirement. There was no significant difference between groups in the risk of infection, length of stay, or mortality. CONCLUSIONS: Iron supplementation increased the serum ferritin concentration significantly, but it had no discernible effect on transferrin saturation, iron-deficient erythropoiesis, hemoglobin concentration, or packed RBC transfusion requirement. Based on these data, routine IV iron supplementation of anemic, critically ill trauma patients cannot be recommended (NCT 01180894). PMID- 24797377 TI - Basic critical care echocardiography by pulmonary fellows: learning trajectory and prognostic impact using a minimally resourced training model*. AB - OBJECTIVES: The spread of basic critical care echocardiography may be limited by training resources. Another barrier is the lack of information about the learning trajectory and prognostic impact of individual basic critical care echocardiography domains like acute cor pulmonale determination and left ventricular function estimation. We thus developed a minimally resourced training model and studied the latter outcomes. DESIGN: Prospective observational study. SETTING: Twenty-bed medical ICU. SUBJECTS: Echocardiography-naive trainees enrolled in the first year of our Pulmonary Medicine Fellowship Program from September 2012 to September 2013. INTERVENTIONS: We described the learning trajectory in six basic critical care echocardiography domains (adequate views, pericardial effusion, acute cor pulmonale, left ventricular ejection fraction, mitral regurgitation, and inferior vena cava variability) and correlated abnormalities in selected basic critical care echocardiography domains with clinical outcomes (mortality and length of stay). MEASUREMENTS AND MAIN RESULTS: Three-hundred forty-three basic critical care echocardiography scans were done for 318 patients by seven fellows (median of 40 scans per fellow; range, 34-105). Only one-third patients had normal basic critical care echocardiography studies. Accuracy in various basic critical care echocardiography domains was high (> 90%), especially beyond the first 30 examinations. Acute cor pulmonale was associated with ICU mortality when adjusted for Acute Physiology and Chronic Health Evaluation II score and presence of sepsis, whereas mitral regurgitation was associated with longer hospitalization only on univariate analysis. CONCLUSIONS: Basic critical care echocardiography training using minimal resources is feasible. New trainees can achieve reasonable competency in most basic critical care echocardiography domains after performing about 30 examinations within the first year. The relatively high prevalence of abnormalities and the significant association of acute cor pulmonale with ICU mortality support the need for basic critical care echocardiography training. PMID- 24797378 TI - A single institution experience on 314 newly diagnosed advanced Hodgkin lymphoma patients: the role of ABVD in daily practice. AB - Based on the results of clinical trials, there is no global consensus on the optimal first-line therapy for patients with advanced Hodgkin lymphoma (HL) with both ABVD and BEACOPP currently being used. However, the results of clinical trials are usually better than those in daily practice. We thus describe here our experience on 314 advanced classical HL patients treated with ABVD at the Clinical Center of Serbia and associated centers between 1997 and 2008. The median follow-up for all patients was 91 months; the estimated 5-yr event-free survival was 62% and the 5-yr overall survival (OS) 76%. Multivariate Cox regression analysis revealed that patients with IPS >= 3 and extranodal disease involving more than one site have a poorer outcome. The data presented here show on overall improvement in outcome as compared to more previous data and illustrate the problems of treating advanced stage HL outside the setting of a clinical trial. PMID- 24797380 TI - Exercise training as treatment in cancer cachexia. AB - Cachexia is a wasting syndrome that may accompany a plethora of diseases, including cancer, chronic obstructive pulmonary disease, aids, and rheumatoid arthritis. It is associated with central and systemic increases of pro inflammatory factors, and with decreased quality of life, response to pharmacological treatment, and survival. At the moment, there is no single therapy able to reverse cachexia many symptoms, which include disruption of intermediary metabolism, endocrine dysfunction, compromised hypothalamic appetite control, and impaired immune function, among other. Growing evidence, nevertheless, shows that chronic exercise, employed as a tool to counteract systemic inflammation, may represent a low-cost, safe alternative for the prevention/attenuation of cancer cachexia. Despite the well-documented capacity of chronic exercise to counteract sustained disease-related inflammation, few studies address the effect of exercise training in cancer cachexia. The aim of the present review was hence to discuss the results of cachexia treatment with endurance training. As opposed to resistance exercise, endurance exercise may be performed devoid of equipment, is well tolerated by patients, and an anti inflammatory effect may be observed even at low-intensity. The decrease in inflammatory status induced by endurance protocols is paralleled by recovery of various metabolic pathways. The mechanisms underlying the response to the treatment are considered. PMID- 24797381 TI - Functional anatomy and kinematics of the oral jaw system during terrestrial feeding in Periophthalmus barbarus. AB - The Atlantic mudskipper, Periophthalmus barbarus, is an amphibious fish that successfully overcomes the numerous physical challenges of capturing prey in a terrestrial environment. However, it is unclear what changes in the morphology and function of the feeding apparatus contribute to the mudskipper's successful transition from aquatic to terrestrial capture of prey. In particular, how does the mudskipper achieve effective prehension of land-based prey using its percomorph feeding apparatus? To address that question, we performed a morphological analysis of the feeding apparatus of P. barbarus based on microcomputed tomography scanning, histological sectioning, and dissections as well as a kinematic analysis based on high-speed video and X-ray video to quantify the movements of the oral jaw apparatus elements. Our results show that the neurocranium remains in a fixed position relative to the pectoral girdle as the fish pivots over its pectoral fins toward the prey. The premaxilla rotates dorsally and protrudes downward over the prey. The dentary is rotated ventrally over an angle of 120 degrees , which is facilitated by an intramandibular joint. These motions of the neurocranium, premaxilla, and dentary reorient the mouth aperture so it is parallel to the substrate, thereby allowing the jaws to be placed over the prey. The prey is grabbed between the oral teeth or scooped into the mouth primarily via rapid closing motion of the lower jaw. This analysis of P. barbarus clarifies the morphological and kinematic characteristics required by fish to become successful terrestrial feeders at the environmental transition between water and land. PMID- 24797379 TI - Use of a caspase multiplexing assay to determine apoptosis in a hypothalamic cell model. AB - The ability to multiplex assays in studies of complex cellular mechanisms eliminates the need for repetitive experiments, provides internal controls, and decreases waste in costs and reagents. Here we describe optimization of a multiplex assay to assess apoptosis following a palmitic acid (PA) challenge in an in vitro hypothalamic model, using both fluorescent and luminescent based assays to measure viable cell counts and caspase-3/7 activity in a 96-well microtiter plate format. Following PA challenge, viable cells were determined by a resazurin-based fluorescent assay. Caspase-3/7 activity was then determined using a luminogenic substrate, DEVD, and normalized to cell number. This multiplexing assay is a useful technique for determining change in caspase activity following an apoptotic stimulus, such as saturated fatty acid challenge. The saturated fatty acid PA can increase hypothalamic oxidative stress and apoptosis, indicating the potential importance of assays such as that described here in studying the relationship between saturated fatty acids and neuronal function. PMID- 24797382 TI - Around the world with Analytical Chemistry. PMID- 24797383 TI - From (Au5Sn + AuSn) physical mixture to phase pure AuSn and Au5Sn intermetallic nanocrystals with tailored morphology: digestive ripening assisted approach. AB - Here we present digestive ripening facilitated interatomic diffusion for the phase controlled synthesis of homogeneous intermetallic nanocrystals of Au-Sn system. Au and Sn metal nanoparticles synthesized by a solvated metal atom dispersion (SMAD) method are employed as precursors for the fabrication of AuSn and Au5Sn which are Au-rich Au-Sn intermetallic nanocrystals. By optimizing the stoichiometry of Au and Sn in the reaction mixture, and by employing growth directing agents, the formation of phase pure intermetallic AuSn and Au5Sn nanocrystals could be realized. The as-prepared Au and Sn colloidal nanoparticles and the resulting intermetallic nanocrystals are thoroughly characterized by powder X-ray diffraction, transmission electron microscopy (TEM and STEM-EDS), and optical spectroscopy. The results obtained here demonstrate the potential of solution chemistry which allows synthesizing phase pure Au-Sn intermetallics with tailored morphology. PMID- 24797384 TI - Endocarditis and molecular imaging. PMID- 24797385 TI - Do we need PET? PMID- 24797386 TI - Mosquito and sand fly gregarines of the genus Ascogregarina and Psychodiella (Apicomplexa: Eugregarinorida, Aseptatorina)--overview of their taxonomy, life cycle, host specificity and pathogenicity. AB - Mosquitoes and sand flies are important blood-sucking vectors of human diseases such as malaria or leishmaniasis. Nevertheless, these insects also carry their own parasites, such as gregarines; these monoxenous pathogens are found exclusively in invertebrates, and some of them have been considered useful in biological control. Mosquito and sand fly gregarines originally belonging to a single genus Ascogregarina were recently divided into two genera, Ascogregarina comprising parasites of mosquitoes, bat flies, hump-backed flies and fleas and Psychodiella parasitizing sand flies. Currently, nine mosquito Ascogregarina and five Psychodiella species are described. These gregarines go through an extraordinarily interesting life cycle; the mosquito and sand fly larvae become infected by oocysts, the development continues transtadially through the larval and pupal stages to adults and is followed by transmission to the offspring by genus specific mechanisms. In adult mosquitoes, ascogregarines develop in the Malpighian tubules, and oocysts are defecated, while in the sand flies, the gregarines are located in the body cavity, their oocysts are injected into the accessory glands of females and released during oviposition. These life history differences are strongly supported by phylogenetical study of SSU rDNA proving disparate position of Ascogregarina and Psychodiella gregarines. This work reviews the current knowledge about Ascogregarina and Psychodiella gregarines parasitizing mosquitoes and sand flies, respectively. It gives a comprehensive insight into their taxonomy, life cycle, host specificity and pathogenicity, showing a very close relationship of gregarines with their hosts, which suggests a long and strong parasite-host coevolution. PMID- 24797387 TI - Common polymorphic effectors of immunity against hepatitis B and C modulate susceptibility to infection and spontaneous clearance in a Moroccan population. AB - Chronic diseases caused by hepatitis B and C viruses may evolve towards major complications as liver cirrhosis and cancer. Fortunately, only subsets among acutely infected individuals develop a persistent disease suggesting that genetic susceptibility may influence the establishment of chronicity. In the present study we aim to explore variants distribution in genes encoding for important immune response effectors in chronic hepatitis B and C. We intend to identify common features and to establish connections between single nucleotide polymorphisms (SNPs) predisposing to both chronic hepatitis and spontaneous clearance in a Moroccan population. Ten SNPs mapping on seven candidate genes (CD209, TGFbeta-1, CCR5, CCL2, CXCL12, SUMO1 and UBC9) were studied in 544 Moroccan subjects grouped in chronically infected patients, spontaneously resolved individuals, liver disease progressors and healthy controls. Among significant associations found between virus infections and genetic variants, we report for the first time an association of rs4804803 (CD209) A and G variants with susceptibility to HBV infection and spontaneous clearance (p<0.001, OR=3.53, 95% CI 2.155; 5.908, and p<0.001, OR=7.75, 95% CI 4.646-13.114, respectively). Other important, albeit previously unknown, association was found between SUMO1 rs10185956T variant and spontaneous clearance of HCV infection (p=0.002, OR=2.71, 95% CI 1.332-5.869). Our observation, that deserves further confirmation with other SNPs and populations, underlines the involvement of selected immune polymorphisms, among which those in CD209, in the natural history of both chronic hepatitis B and C. PMID- 24797389 TI - Beyond the platelet count: immature platelet fraction and thromboelastometry correlate with bleeding in patients with immune thrombocytopenia. AB - Platelet counts (PC) estimate bleeding risk in Immune Thrombocytopenia (ITP). We investigated whether measures of thromboelastometry and absolute immature platelet fraction (A-IPF) would correlate better with acute bleeding score (ABS) than PC or mean platelet volume (MPV). Simultaneous determination of ABS, complete blood count and thromboelastometry was performed in 141 ITP patients; 112 underwent A-IPF testing. Subgroup analyses were performed for paediatric subjects, PC <60 * 10(9) /l and <30 * 10(9) /l. PC significantly inversely correlated with ABS in all subjects, PC <30 * 10(9) /l and total paediatric cohort. MPV did not correlate with ABS in any subgroup. Thromboelastometry measures of clot firmness, but not PC, significantly correlated with ABS in all subjects with PC <60 * 10(9) /l, and children with PC <60 * 10(9) /l and <30 * 10(9) /l. A-IPF demonstrated stronger correlation with ABS than did PC among all subjects, those with PC <60 * 10(9) /l, all children and children with PC <30 * 10(9) /l (r = -0.37; r = -0.34; r = -0.44; r = -0.60) versus ABS with PC (r = 0.36; ns; r = -0.32; ns). Stronger correlations of both thromboelastometry measures of clot firmness and A-IPF than PC with ABS suggest factors beyond PC, i.e. related to platelet function, contribute to ITP bleeding pathophysiology. Thromboelastometry, A-IPF and ABS can be incorporated into routine or acute visits. PMID- 24797388 TI - A novel antibody against human properdin inhibits the alternative complement system and specifically detects properdin from blood samples. AB - The complement system is an essential part of the innate immune system by acting as a first line of defense which is stabilized by properdin, the sole known positive regulator of the alternative complement pathway. Dysregulation of complement can promote a diversity of human inflammatory diseases which are treated by complement inhibitors. Here, we generated a novel blocking monoclonal antibody (mAb) against properdin and devised a new diagnostic assay for this important complement regulator. Mouse mAb 1340 specifically detected native properdin from human samples with high avidity. MAb 1340 inhibited specifically the alternative complement mediated cell lysis within a concentration range of 1 10 ug/mL. Thus, in vitro anti-properdin mAb 1340 was up to fifteen times more efficient in blocking the complement system as compared to anti-C5 or anti-Ba antibodies. Computer-assisted modelling suggested a three-dimensional binding epitope in a properdin-C3(H2O)-clusterin complex to be responsible for the inhibition. Recovery of properdin in a newly established sandwich ELISA using mAb 1340 was determined at 80-125% for blood sample dilutions above 1?50. Reproducibility assays showed a variation below 25% at dilutions less than 1?1,000. Systemic properdin concentrations of healthy controls and patients with age-related macular degeneration or rheumatic diseases were all in the range of 13-30 ug/mL and did not reveal significant differences. These initial results encourage further investigation into the functional role of properdin in the development, progression and treatment of diseases related to the alternative complement pathway. Thus, mAb 1340 represents a potent properdin inhibitor suitable for further research to understand the exact mechanisms how properdin activates the complement C3-convertase and to determine quantitative levels of properdin in biological samples. PMID- 24797390 TI - The nature of epistemic virtues in the practice of medicine. AB - There is an assumption in virtue epistemology that epistemic virtues are the same in different times and places. In this paper, however, I examine this assumption in the practice of medicine as a paradigm example. I identify two different paradigms of medical practice, one before and the other after the rise of bioethics in 1960s. I discuss the socially defined role and function of physicians and the epistemic goals of medical practice in these two periods to see how these elements affect the necessary epistemic virtues for physicians. I conclude that epistemic virtues of medical practice differ in these two periods according to the differing epistemic goals and the socially defined function of physicians. In the end, I respond to the possible objections to my thesis based on the distinction between skill and virtue. PMID- 24797391 TI - Identification of triacylglycerols in archaelogical organic residues by core shell reversed phase liquid chromatography coupled to electrospray ionization quadrupole-time of flight mass spectrometry. AB - A method based on the use of a Poroshell 120 EC-C18 column (3.0mm*50mm, 2.7MUm) with a high resolution electrospray ionization-quadrupole-time of flight (ESI-Q ToF) tandem mass spectrometer as detection system was optimized for the identification of triacylglycerols (TAGs) in complex archaeological residues. The best performances in chromatographic separation and Q-ToF detection sensitivity were reached by using a mixture of iPrOH/MeOH at a 0.6mL/min flow rate. Triolein (OOO) was eluted in 12.30min and the chromatographic resolution against tripalmitin (PPP) was 1.4. Very good limits of detection and quantification limits were also achieved (LOD<0.03MUg/g LOQ<0.10MUg/g). These achievements were compared with the results provided by traditional particle columns and with the results reported in the recent literature regarding TAGs analysis in archaeological residues. Thanks to the unprecedented chromatographic separation and detection sensitivity attained, it was possible for the first time to perform TAGs researches in archaeological residues and reference materials with a dataset containing more than 500 molecular formula. PMID- 24797392 TI - Can neutral analytes be concentrated by transient isotachophoresis in micellar electrokinetic chromatography and how much? AB - Transient isotachophoresis (tITP) is a versatile sample preconcentration technique that uses ITP to focus electrically charged analytes at the initial stage of CE analysis. However, according to the ruling principle of tITP, uncharged analytes are beyond its capacity while being separated and detected by micellar electrokinetic chromatography (MEKC). On the other hand, when these are charged micelles that undergo the tITP focusing, one can anticipate the concentration effect, resulting from the formation of transient micellar stack at moving sample/background electrolyte (BGE) boundary, which increasingly accumulates the analytes. This work expands the enrichment potential of tITP for MEKC by demonstrating the quantitative analysis of uncharged metal-based drugs from highly saline samples and introducing to the BGE solution anionic surfactants and buffer (terminating) co-ions of different mobility and concentration to optimize performance. Metallodrugs of assorted lipophilicity were chosen so as to explore whether their varying affinity toward micelles plays the role. In addition to altering the sample and BGE composition, optimization of the detection capability was achieved due to fine-tuning operational variables such as sample volume, separation voltage and pressure, etc. The results of optimization trials shed light on the mechanism of micellar tITP and render effective determination of selected drugs in human urine, with practical limits of detection using conventional UV detector. PMID- 24797393 TI - Extending the limits of operating pressure of narrow-bore column liquid chromatography instrumentation. AB - The increase of the operating pressure in Liquid Chromatography, has been one of the crucial steps toward faster and more efficient separations. In the present contribution, it was investigated if the pressure limits for narrow-bore columns (2.1mm ID) could be increased beyond those of commercially available (1300bar) instrumentation without performance loss. Whereas previous studies applying pressures higher than 2000bar were limited to the use of columns with a diameter smaller or equal to 1mm, it is a difficult feat to expand this to 2.1mm ID given that viscous-heating effects increase according to the fifth power of the column radius. A prototype LC set-up was realized, allowing to operate at pressures up to 2600bar (260MPa) for large separation volumes (>5mL). The performance of an in house-built injector was compared at 800bar to commercially available injectors, yielding equal performance but twice the maximum pressure rating. The performance of (coupled) custom columns packed with fully porous and superficially porous particles were assessed at ultra-high-pressure conditions. Increasing the inlet pressure from 800 to 2400bar and scaling the column length proportionally (from 150mm to 450mm), resulted in the theoretically expected linear increase in plate count from 20,000 to 59,000. A maximum plate number of 81,000 was realized using a 600mm long (coupled) column at 2600bar. Viscous-heating effects were diminished by insulating coupled columns and applying an intermediate-cooling strategy in a forced-air oven. PMID- 24797394 TI - Validation of a reverse-phase high-performance liquid chromatography method for the determination of amino acids in gelatins by application of 6-aminoquinolyl-N hydroxysuccinimidyl carbamate reagent. AB - In-house method validation was conducted to determine amino acid composition in gelatin by a pre-column derivatization procedure with the 6-aminoquinolyl-N hydroxysuccinimidyl carbamate reagent. The analytical parameters revealed that the validated method was capable of selectively performing a good chromatographic separation for 18 amino acids in less than 40 min; the overall detection and quantitation limit for amino acids fell into ranges of 5.68-12.48 and 36.0-39.0 pmol/MUl, respectively; the matrix effect was not observed, and the linearity range was 37.5-1000 pmol/MUl. The accuracy (precision and recovery) analyses of the method were conducted under repeatable conditions on different days in random order. Method precision revealed by HorRat values was significantly less than 2, except for histidine with a precision of 2.19, and the method recoveries had a range of 80-115% except for alanine which was recovered at 79.4%. The findings were reproducible and accurately defined, and the method was found to be suited to routine analysis of amino acid composition in gelatin-based ingredients. PMID- 24797395 TI - Fast determination of seven synthetic pigments from wine and soft drinks using magnetic dispersive solid-phase extraction followed by liquid chromatography tandem mass spectrometry. AB - A novel, simple and sensitive method based on the use of magnetic dispersive solid-phase extraction (M-dSPE) procedure combined with ultra-fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS) was developed to determine seven synthetic pigments (tartrazine, amaranth, carmine, sunset yellow, allura red, brilliant blue and erythrosine) in wines and soft drinks. An amino functionalized low degrees of cross-linking magnetic polymer (NH2-LDC-MP) was synthesized via suspension polymerization, and characterized by transmission electron microscopy (TEM). The NH2-LDC-MP was used as the M-dSPE sorbent to remove the matrix from the solution, and the main factors affecting the extraction were investigated in detail. The obtained results demonstrated the higher extraction capacity of NH2-LDC-MP with recoveries between 84.0 and 116.2%. The limits of quantification (LOQs) for the seven synthetic pigments were between 1.51 and 5.0MUg/L in wines and soft drinks. The developed M-dSPE UFLC-MS/MS method had been successfully applied to the real wines and soft drinks for food safety risk monitoring in Zhejiang Province, China. The results showed that sunset yellow was in three out of thirty soft drink samples (2.95-42.6MUg/L), and erythrosine in one out of fifteen dry red wine samples (3.22MUg/L), respectively. It was confirmed that the NH2-LDC-MP was a kind of highly effective M-dSPE materials for the pigments analyses. PMID- 24797396 TI - A multifaceted intervention to improve mental health literacy in students of a multicampus university: a cluster randomised trial. AB - PURPOSE: The aim of the current study was to assess whether a multifaceted intervention could improve mental health literacy, facilitate help seeking and reduce psychological distress and alcohol misuse in students of a multicampus university in Melbourne, Australia. METHODS: In this cluster randomized trial, nine university campuses were paired (some pairs included more than one campus), with one of each pair randomly assigned to either the intervention or control condition. The interventions were designed to be whole-of-campus and to run over 2 academic years with their effectiveness assessed through recruitment of a monitoring sample of students from each campus. Interventions included emails, posters, campus events, factsheets/booklets and mental health first aid training courses. Participants had a 20-min telephone interview at baseline and at the end of academic years 1 and 2. This assessed mental health literacy, help seeking, psychological distress and alcohol use. The primary outcomes were depression and anxiety levels and alcohol use and pertained to the individual level. RESULTS: There were no effects on psychological distress and alcohol use. Recall of intervention elements was greater in the intervention group at the end of year 2. Students in the intervention group were more likely to say they would go to a drug and alcohol centre for alcohol problems at the end of 6 months. CONCLUSION: Although education and awareness may play a role in improving mental health literacy, it is likely that, to achieve changes in psychological distress, interventions would need to be more personalized and intensive. PMID- 24797397 TI - Risk for suicidal behaviors associated with alcohol and energy drink use in the US Army. AB - PURPOSE: Suicidal behaviors have increased in the US Army since 2005. To identify potential interventions for suicide risk, we examined the relationship between alcohol and energy drink use, independently and in combination, and rates of seriously considering and/or attempting suicide in US Army soldiers. METHODS: This study used the DoD Survey of Health Related Behaviors Among Active Duty Military Personnel (DoD HRB), which sampled 10,400 Army soldiers, with 5,927 responses representing 508,088 soldiers. Use of energy drinks in combination with alcohol (A/ED) and average daily amount of alcohol consumption over the past 30 days and history of seriously considering and/or attempting suicide in the past year were assessed via self-report questions. RESULTS: Six percent of Army service members reported either seriously considering and/or attempting suicide in the past year. Twenty-six percent of soldiers reported A/ED. Those who reported the highest level of alcohol use were more likely to have seriously considered and/or attempted suicide. Soldiers who reported daily A/ED were over three times more likely to have reported suicidal ideation or attempts, and even after adjusting for overall alcohol consumption and energy drink use alone remained approximately two times (OR = 1.99) more likely to report suicidality. CONCLUSIONS: Combination alcohol and energy drink use and heavy alcohol use contribute to suicidality and may be targets for potential intervention to address suicide risk. PMID- 24797398 TI - Electromechanical delay of the knee extensor muscles: comparison among young, middle-age and older individuals. AB - The aim of this study was to investigate the effects of the ageing process in the electromechanical delay (EMD), rate of torque development (RTD) and peak torque (PT) of the knee extensor muscles. The volunteers were assigned to three groups: young group (YG - 23.44 +/- 4.74 years, 78.14 +/- 15.11 kg, 1.72 +/- 0.05 m), middle-aged group (MAG - 49.56 +/- 6.06 years, 72.01 +/- 14.07 kg, 1.67 +/- 0.06 m) and elderly group (EG - 68.67 +/- 9.06 years, 67.96 +/- 7.60 kg, 1.64 +/- 0.07 m). The PT and RTD were assessed during maximal voluntary ballistic isometric contractions (MVBIC) in the isokinetic dynamometer. Muscle electrical activity was recorded (EMG) during MVBIC in the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) muscles. The EMD was calculated during the MVBIC, through the time interval between the EMG onset and torque onset. The PT and RTD were higher in the YG than in the MAG (P = 0.02; P = 0.01, respectively) and in the EG (P = 0.002; P = 0.0004, respectively). There were no significant differences in EMD among the three age groups for the VL, VM and RF (P>0.05) muscles. We conclude that age affects the PT and RTD, but not EMD of the VL, VM and RF muscles. PMID- 24797399 TI - Assessment of anti-plasmodial activity of non-hemolytic, non-immunogenic, non toxic antimicrobial peptides (AMPs LR14) produced by Lactobacillus plantarum LR/14. AB - BACKGROUND AND OBJECTIVES: Lactobacillus plantarum strains are known to exhibit an antimicrobial property against bacteria and fungi. In the present investigation, AMPs LR14, antimicrobial peptides produced by L. plantarum strain LR/14, were tested against a protozoan system, Plasmodium falciparum and its non toxic nature was envisaged on a mammalian system. METHODS: Human erythrocytes infected with chloroquine-sensitive and -resistant strains of P. falciparum were treated with purified AMPs LR14. The loss in cell viability was assessed by monitoring the incorporation of [(3)H]-hypoxanthine in the nucleic acid of the parasite. The hemolytic activity of AMPs LR14 was monitored at different concentrations and the investigations into the in vivo toxicity of AMPs LR14 were carried out on a mammalian system (Wistar rat). The level of toxicity in the tissues was visualized by histopathological studies conducted on the liver and kidney of the test and control rats. A study was also undertaken to see the production of antibodies in an animal (rabbit) after it was immunized with AMPs LR14. RESULTS: A loss in cell viability was observed in both test strains of P. falciparum. However, the dose required for inhibition of the chloroquine resistant strain was ~2 times the dose required for the chloroquine-sensitive strain. At these concentrations, no hemolysis of human erythrocytes was observed. The studies conducted on in vivo toxicity of AMPs LR14 suggest that the lethal dose (LD50) is beyond 1,000 mg/kg body weight, suggesting its safe use against microbes and protozoans. Antibodies were also not detected against these peptides, indicating a non-immunogenic nature. CONCLUSION: The data indicate that AMPs LR14 are non-toxic, potent anti-plasmodial peptides causing growth inhibition of P. falciparum without causing hemolysis. These results pave the way for the development of bioactive peptides as therapeutics. PMID- 24797400 TI - Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C. AB - AIMS: Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft-Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys). METHODS: A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations. RESULTS: The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38-94 years) taking dabigatran etexilate was 60 ug/L (range 9-279). The dose corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R (2), 95 % CI) 32 % (9-55), 37 % (12-60), 41 % (16-64) and 47 % (20-69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R (2) values for each equation was not statistically significant (p = 0.74). DISCUSSION: Estimates of renal function using the four equations accounted for 32 47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure. PMID- 24797401 TI - Dose- and time-dependent changes of micronucleus frequency and gene expression in the progeny of irradiated cells: two components in radiation-induced genomic instability? AB - Murine embryonic C3H/10T1/2 fibroblasts were exposed to X-rays at doses of 0.2, 0.5, 1, 2 or 5 Gy. To follow the development of radiation-induced genomic instability (RIGI), the frequency of micronuclei was measured with flow cytometry at 2 days after exposure and in the progeny of the irradiated cells at 8 and 15 days after exposure. Gene expression was measured at the same points in time by PCR arrays profiling the expression of 84 cancer-relevant genes. The micronucleus results showed a gradual decrease in the slope of the dose-response curve between days 2 and 15. The data were consistent with a model assuming two components in RIGI. The first component is characterized by dose-dependent increase in micronuclei. It may persist more than ten cell generations depending on dose, but eventually disappears. The second component is more persistent and independent of dose above a threshold higher than 0.2 Gy. Gene expression analysis 2 days after irradiation at 5 Gy showed consistent changes in genes that typically respond to DNA damage. However, the consistency of changes decreased with time, suggesting that non-specificity and increased heterogeneity of gene expression are characteristic to the second, more persistent component of RIGI. PMID- 24797402 TI - Protothecosis in hematopoietic stem cell transplantation: case report and review of previous cases. AB - Prototheca species are achlorophyllus algae. Prototheca wickerhamii and Prototheca zopfii cause human disease. In immunocompetent individuals, they cause soft tissue infections and olecranon bursitis, but in transplant recipients, these organisms can cause disseminated disease. We report a fatal case of disseminated P. zopfii infection in an hematopoietic stem cell transplant (HSCT) recipient with bloodstream infection and involvement of multiple soft tissue sites. We review all previous cases of protothecosis in HSCT reported in the literature. Protothecosis is uncommon after HSCT, but has a disseminated presentation that is frequently fatal. It is commonly misidentified as a yeast. Tumor necrosis factor-alpha inhibitors and contamination of central venous catheters may contribute to development of protothecosis. Optimal treatment approaches are yet to be defined. New agents such as miltefosine may be possible future therapies. PMID- 24797403 TI - Rapidly derived colorectal cancer cultures recapitulate parental cancer characteristics and enable personalized therapeutic assays. AB - We have developed a simple procedure for deriving pure cultures of growing cancer cells from colorectal cancers, including material refrigerated overnight, for pathological characterization and cytotoxicity assays. Forty-six cancers were processed and cultures set up under varying culture conditions. Use of a Rho kinase (ROCK1) inhibitor markedly increased culture survival, resulting in 80% of samples growing in culture for at least 1 month and beyond. Overnight refrigeration of samples before culture initiation had little effect on success rates, paving the way for cultures to be established for samples collected over wide geographical areas, such as those for clinical trials. Primary cultures demonstrated good correlation for differentiation markers compared to parent cancers, and were highly dynamic in 3D culture. In Matrigel, many colonies formed central lumens, indicating the presence of stem-like cells. Viable colonies in these cultures recapitulated the in vivo generation of carcinoembryonic antigen (CEA)-positive necrotic/apoptotic debris, much of which was derived from abnormal vacuolated dynamic 'bubble cells' that have not previously been described. Although bubble cells morphologically resembled signet ring cells, a rare cancer subtype, immunostaining suggested that they were most likely derived from terminally differentiated enterocytes. Micro-assays showed that drug toxicity could be measured in these cultures within hours and with sensitivity down to a few hundred cells. Primary cultures derived by our method provide valid in vitro avatars for studying the pathology of cancers in vitro and are amenable to pre clinical drug testing, paving the way for personalized cancer treatment. PMID- 24797404 TI - Intracameral dynamic spotlight-assisted cataract surgery in eyes with corneal opacity, small pupil or advanced cataract. PMID- 24797405 TI - Multi-scale analysis of the associations among egg, larval and pupal surveys and the presence and abundance of adult female Aedes aegypti (Stegomyia aegypti) in the city of Merida, Mexico. AB - Despite decades of research, there is still no agreement on which indices of Aedes aegypti (Stegomyia aegypti) (Diptera: Culicidae) presence and abundance better quantify entomological risk for dengue. This study reports the results of a multi-scale, cross-sectional entomological survey carried out in 1160 households in the city of Merida, Mexico to establish: (a) the correlation between levels of Ae. aegypti presence and abundance detected with aspirators and ovitraps; (b) which immature and egg indices correlate with the presence and abundance of Ae. aegypti females, and (c) the correlations amongst traditional Aedes indices and their modifications for pupae at the household level and within medium-sized geographic areas used for vector surveillance. Our analyses show that ovitrap positivity was significantly associated with indoor adult Ae. aegypti presence [odds ratio (OR) = 1.50; P = 0.03], that the presence of pupae is associated with adult presence at the household level (OR = 2.27; P = 0.001), that classic Aedes indices are informative only when they account for pupae, and that window screens provide a significant level of protection against peridomestic Ae. aegypti (OR = 0.59; P = 0.02). Results reinforce the potential of using both positive collections in outdoor ovitraps and the presence of pupae as sensitive indicators of indoor adult female presence. PMID- 24797406 TI - Assessing genetic influences on behavior: informant and context dependency as illustrated by the analysis of attention problems. AB - Assessment of genetic influences on behavior depends on context, informants, and study design: We show (analytically) that, conditional on study design, informant specific genetic variance is included in the genetic variance component or in the environmental variance component. To aid the explanation, we present an illustrative empirical analysis of data from the Netherlands Twin Register. Subjects included 1,571 monozygotic and 2,672 dizygotic 12-year-old twin pairs whose attention problems (AP) were rated by their parents, teachers, and themselves. Heritability estimates (h(2)) of AP were about ~0.75 for same informant ratings (mother, father, and same teacher ratings) and ~0.54 for different informants' ratings (different parents', different teachers', and two twins' self-ratings). Awareness of assessment effects is relevant to research into psychiatric disorders. Differences in assessment can account for age effects, such as a drop in heritability of ADHD symptoms. In genome-wide association studies, effects of rating specific genetic influences will be undetectable. PMID- 24797407 TI - God was born prematurely. PMID- 24797408 TI - Catalytic [3 + 2] annulation of ketimines with alkynes via C-H activation by a cationic iridium(cod) complex. AB - [3 + 2] Annulation of ketimines with internal and terminal alkynes proceeded via C-H activation to give aminoindene derivatives in high yields, which is catalyzed by a cationic iridium complex coordinated with 1,5-cyclooctadiene (cod). PMID- 24797409 TI - The effectiveness of a brief intervention for emotion-focused nurse-parent communication. AB - OBJECTIVE: A child's hospitalization is stressful for both the children and their parents. Nurse-parent communication during stressful hospitalizations requires skilled nurse communicators. Brief methods of training emotion-focused communication for newly licensed nurses are needed, but as yet are rare. The purpose of this study was to evaluate the effectiveness of a validated brief communication training (Four Habits Model) session using simulation for newly licensed pediatric nurses. METHODS: Quantitative and qualitative methods provided data for this experimental study, using a group-by-trials repeated measures ANOVA design. The intervention group participated in a 1-h three-part education simulation session and the control group observed a 1-h video. RESULTS: Compared with the controls, the intervention group improved significantly in four of five areas: preparation, communication skills, relationships, and confidence. Experience level had minimal effect. Over half of the nurses in the intervention group reported using one or more of the Four Habits in clinical practice. CONCLUSIONS: The findings of this study suggest that a 1-h Four Habits communication-training program improves newly licensed nurses' self-perception of their preparation for emotion-focused conversations with parents. PRACTICE IMPLICATIONS: The findings of this study suggest that the Four Habits Model can be useful in communication training with nurses. PMID- 24797410 TI - Site migration in seeking care services from multiple providers is associated with worse clinical outcomes among HIV-infected individuals in Washington, DC. AB - Washington, DC, is a metropolitan city with a severe HIV epidemic and faces challenges in retaining people living with HIV (PLWH) in quality care. This study assessed site migration in seeking care services and its correlates among PLWH in DC. PLWH diagnosed before 2008 and living through the end of 2010 were analyzed. Six scenarios of site migration were examined as patients visited =2, =3, and =4 different providers for their CD4 cell count and/or viral load (VL) tests in the past 3 years from 2008 to 2010 and 2 years from 2009 to 2010, respectively. Of 6480 patients analyzed from 2008 to 2010, 18.4% had CD4 < 200 cells/mm(3), 30.5% had VL > 400 copies/mL, and 76.6% were retained in same care sites; 23.4%, 5.0%, and 0.9% visited =2, =3, and =4 sites in the past 3 years from 2008 to 2010, respectively. Of 5954 patients analyzed from 2009 to 2010, 16.8% had CD4 < 200 cells/mm(3), 29.4% had VL > 400 copies/mL, and 81.9% were retained in same care sites; 18.1%, 3.1%, and 0.6% visited =2, =3, and =4 sites in the past 2 years from 2009 to 2010, respectively. Multivariable logistic regression analyses revealed that migration across six scenarios are consistently associated with CD4 < 200 cells/mm(3) and VL > 400 copies/mL. Site migration was common and associated with lower CD4 and higher VL among PLWH in DC. Frequent migration might be a factor in achieving optimal health outcomes for a subset of patients. Site migration might potentially limit effective delivery of high quality care and treatment services. The preliminary findings underscore the need for further research to assess the predictors of migration and its impact on stage of care. PMID- 24797412 TI - Roles of sirtuins in the regulation of antioxidant defense and bioenergetic function of mitochondria under oxidative stress. AB - In addition to serving as the power house of mammalian cells, mitochondria are crucial for the maintenance of cellular homeostasis in response to physiological or environmental changes. Several lines of evidence suggest that posttranslational modification (PTM) of proteins plays a pivotal role in the regulation of the bioenergetic function of mitochondria. Among them, reversible lysine acetylation of mitochondrial proteins has been established as one of the key mechanisms in cellular response to energy demand by modulating the flux of a number of key metabolic pathways. In this article, we focus on the role of Sirt3 mediated deacetylation in: (1) flexibility of energy metabolism, (2) activation of antioxidant defense, and (3) maintenance of cellular redox status in response to dietary challenge and oxidative stress. We suggest that oxidative stress elicited down-regulation of Sirt3 plays a role in the pathophysiology of diabetes, cardiac hypotrophy, mitochondrial diseases, and age-related diseases. Besides, the physiological role of newly identified lysine acylation mediated by Sirt5 and its biochemical effects on oxidative metabolism are also discussed. Moreover, we have integrated the regulatory function of several protein kinases that are involved in the phosphorylation of mitochondrial enzymes during oxidative stress. Finally, the functional consequence of the synergistic regulation through diverse protein modifications is emphasized on the maintenance of the bioenergetic homeostasis and metabolic adaptation of the animal and human cells. Together, we have provided an updated review of PTM in mitochondrial biology and their implications in aging and human diseases through an intricate regulation of energy metabolism under oxidative stress. PMID- 24797411 TI - Genomic responses to arsenic in the cyanobacterium Synechocystis sp. PCC 6803. AB - Arsenic is a ubiquitous contaminant and a toxic metalloid which presents two main redox states in nature: arsenite [As(III)] and arsenate [As(V)]. Arsenic resistance in Synechocystis sp. strain PCC 6803 is mediated by the arsBHC operon and two additional arsenate reductases encoded by the arsI1 and arsI2 genes. Here we describe the genome-wide responses to the presence of arsenate and arsenite in wild type and mutants in the arsenic resistance system. Both forms of arsenic produced similar responses in the wild type strain, including induction of several stress related genes and repression of energy generation processes. These responses were transient in the wild type strain but maintained in time in an arsB mutant strain, which lacks the arsenite transporter. In contrast, the responses observed in a strain lacking all arsenate reductases were somewhat different and included lower induction of genes involved in metal homeostasis and Fe-S cluster biogenesis, suggesting that these two processes are targeted by arsenite in the wild type strain. Finally, analysis of the arsR mutant strain revealed that ArsR seems to only control 5 genes in the genome. Furthermore, the arsR mutant strain exhibited hypersentivity to nickel, copper and cadmium and this phenotype was suppressed by mutation in arsB but not in arsC gene suggesting that overexpression of arsB is detrimental in the presence of these metals in the media. PMID- 24797413 TI - Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury. AB - The pathological processes that lead to long-term consequences of multiple concussions are unclear. Primary mechanical damage to axons during concussion is likely to contribute to dysfunction. Secondary damage has been hypothesized to be induced or exacerbated by inflammation. The main inflammatory cells in the brain are microglia, a type of macrophage. This research sought to determine the contribution of microglia to axon degeneration after repetitive closed-skull traumatic brain injury (rcTBI) using CD11b-TK (thymidine kinase) mice, a valganciclovir-inducible model of macrophage depletion. Low-dose (1 mg/mL) valganciclovir was found to reduce the microglial population in the corpus callosum and external capsule by 35% after rcTBI in CD11b-TK mice. At both acute (7 days) and subacute (21 days) time points after rcTBI, reduction of the microglial population did not alter the extent of axon injury as visualized by silver staining. Further reduction of the microglial population by 56%, using an intermediate dose (10 mg/mL), also did not alter the extent of silver staining, amyloid precursor protein accumulation, neurofilament labeling, or axon injury evident by electron microscopy at 7 days postinjury. Longer treatment of CD11b-TK mice with intermediate dose and treatment for 14 days with high-dose (50 mg/mL) valganciclovir were both found to be toxic in this injury model. Altogether, these data are most consistent with the idea that microglia do not contribute to acute axon degeneration after multiple concussive injuries. The possibility of longer-term effects on axon structure or function cannot be ruled out. Nonetheless, alternative strategies directly targeting injury to axons may be a more beneficial approach to concussion treatment than targeting secondary processes of microglial-driven inflammation. PMID- 24797417 TI - High thermal robustness of molecularly thin perovskite nanosheets and implications for superior dielectric properties. AB - A systematic study has been conducted to examine the thermal stability of layer by-layer assembled films of perovskite-type nanosheets, (Ca2Nb3O10(-))n (n = 1 10), which exhibit superior dielectric and insulating properties. In-plane and out-of-plane X-ray diffraction data as well as observations by atomic force microscopy and transmission electron microscopy indicated the high thermal robustness of the nanosheet films. In a monolayer film with an extremely small thickness of ~2 nm, the nanosheet was stable up to 800 degrees C, the temperature above which segregation into CaNb2O6 and Ca2Nb2O7 began. The critical temperature moderately decreased as the film thickness, or the number of nanosheet layers, increased, and reached 700 degrees C for seven- and 10-layer films, which is comparable to the phase transformation temperature for a bulk phase of the protonic layered oxide of HCa2Nb3O10.1.5H2O as a precursor of the nanosheet. This thermal stabilization of perovskite-type nanosheets should be associated with restricted nucleation and crystal growth peculiar to such ultrathin 2D bound systems. The stable high-k dielectric response (epsilonr = 210) and highly insulating nature (J < 10(-7) A cm(-2)) remained substantially unchanged even after the nanosheet film was annealed up to 600 degrees C. This study demonstrates the high thermal stability of 2D perovskite-type niobate nanosheets in terms of structure and dielectric properties, which suggests promising potential for future high-k devices operable over a wide temperature range. PMID- 24797418 TI - Orbital presentation of a nasal midline destructive lesion in a young boy. AB - Midline Destructive Lesions (MDL) are well known to cause nasal problems. There is a long differential diagnosis of such lesions. However, in the pediatric population, the 2 main diseases to be aware of are Non-Hodgkin's T-cell lymphoma and granulomatosis with polyangiitis (previously known as Wegener's granulomatosis). The authors present the report of a 15-year-old boy who presented with epiphora, chemosis, and limitation of left abduction. CT scan of his orbits suggested a destructive lesion of the ethmoid sinuses. His laboratory investigations revealed a positive ANCA. The patient underwent endoscopic sinus surgery, and this was characteristic for granulomatosis with polyangiitis. He was treated with systemic steroids and then maintained on cyclophosphamide, which controlled his disease activity. This case highlights the need for ophthalmologists to have a high index of suspicion for MDL and concomitant orbital disease. PMID- 24797416 TI - Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. AB - Periodontitis has been implicated as a risk factor for metabolic disorders such as type 2 diabetes, atherosclerotic vascular diseases, and non-alcoholic fatty liver disease. Although bacteremias from dental plaque and/or elevated circulating inflammatory cytokines emanating from the inflamed gingiva are suspected mechanisms linking periodontitis and these diseases, direct evidence is lacking. We hypothesize that disturbances of the gut microbiota by swallowed bacteria induce a metabolic endotoxemia leading metabolic disorders. To investigate this hypothesis, changes in the gut microbiota, insulin and glucose intolerance, and levels of tissue inflammation were analysed in mice after oral administration of Porphyromonas gingivalis, a representative periodontopathogens. Pyrosequencing revealed that the population belonging to Bacteroidales was significantly elevated in P. gingivalis-administered mice which coincided with increases in insulin resistance and systemic inflammation. In P. gingivalis administered mice blood endotoxin levels tended to be higher, whereas gene expression of tight junction proteins in the ileum was significantly decreased. These results provide a new paradigm for the interrelationship between periodontitis and systemic diseases. PMID- 24797419 TI - Postural response to vibration of triceps surae, but not quadriceps muscles, differs between people with and without knee osteoarthritis. AB - Although proprioceptive impairments are reported in knee osteoarthritis (OA), there has been little investigation of the underlying causes. Muscle spindles make an important contribution to proprioception. This study investigated whether function of quadriceps, triceps surae, and tibialis anterior muscle spindles is altered in individuals with knee OA. Thirty individuals with knee OA (17 females, 66 +/- 7 [mean +/- SD] years) and 30 healthy asymptomatic controls (17 females, 65 +/- 8 years) stood comfortably and blindfolded on a force plate. Mechanical vibration (60 Hz) was applied bilaterally over the quadriceps, triceps surae, or tibialis anterior muscles for the middle 15 s (Vibration) of a 45 s trial (preceded and followed by 15 s Baseline and Recovery periods). Two trials were recorded for each muscle site. Mean anterior-posterior displacement of centre of pressure was analysed. Although there were no differences between groups for trials with vibration applied to the quandriceps or tibialis anterior, participants with knee OA were initially perturbed more by triceps surae vibration and accommodated less to repeated exposure than controls. This indicates that people with knee OA have less potential to detect or compensate for disturbed input to triceps surae, possibly due to an inability to compensate using muscles spindles in the quadriceps muscle. PMID- 24797420 TI - Underdiagnosis of allergic rhinitis in underserved children. PMID- 24797422 TI - Safety and immunogenicity of immunotherapy with Bet v 1-derived contiguous overlapping peptides. PMID- 24797421 TI - Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. AB - BACKGROUND: Autosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. OBJECTIVE: We investigated whether reversions contributed to the variable disease expression. METHODS: Patients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. RESULTS: We identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation. CONCLUSIONS: In patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time. PMID- 24797423 TI - Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Investigations meeting current standards are limited for the effect of house dust mite (HDM) allergy immunotherapy in asthmatic patients. OBJECTIVE: This trial investigated the efficacy and safety of a standardized quality (SQ; allergen standardization method proprietary to the trial sponsor) HDM SLIT-tablet (ALK, Horsholm, Denmark) in adults and adolescents with HDM respiratory allergic disease. This publication reports the results of the endpoints related to asthma. METHODS: Six hundred four subjects 14 years or older with HDM allergic rhinitis and mild-to-moderate asthma were randomized 1:1:1:1 to double-blind daily treatment with one of 3 active doses (1, 3, or 6 SQ-HDM) or placebo. Their use of inhaled corticosteroid (ICS) was standardized and adjusted at baseline and the end of treatment to the lowest dose providing asthma control. The primary end point was a reduction in ICS dose from the individual subject's baseline dose after 1 year of treatment. RESULTS: The primary analysis revealed a mean difference between 6 SQ-HDM and placebo in the reduction in daily ICS dose of 81 MUg (P = .004). Relative mean and median reductions were 42% and 50% for 6 SQ-HDM and 15% and 25% for placebo, respectively. No statistically significant differences were observed for the other assessed asthma parameters, reflecting the intended controlled status of the trial subjects. The most common adverse events were local reactions in the mouth. The rate and severity of adverse events were higher for 3 and 6 SQ-HDM than for 1 SQ-HDM and placebo. CONCLUSION: Efficacy in mild-to-moderate asthma of 6 SQ-HDM relative to placebo was demonstrated by a moderate statistically significant reduction in the ICS dose required to maintain asthma control. All active doses were well tolerated. PMID- 24797424 TI - CRISPR transcriptional repression devices and layered circuits in mammalian cells. AB - A key obstacle to creating sophisticated genetic circuits has been the lack of scalable device libraries. Here we present a modular transcriptional repression architecture based on clustered regularly interspaced palindromic repeats (CRISPR) system and examine approaches for regulated expression of guide RNAs in human cells. Subsequently we demonstrate that CRISPR regulatory devices can be layered to create functional cascaded circuits, which provide a valuable toolbox for engineering purposes. PMID- 24797425 TI - An open, self-controlled study on the efficacy of topical indoxacarb for eliminating fleas and clinical signs of flea-allergy dermatitis in client-owned dogs in Queensland, Australia. AB - BACKGROUND: Canine flea-allergy dermatitis (FAD), a hypersensitivity response to antigenic material in the saliva of feeding fleas, occurs worldwide and remains a common presentation in companion animal veterinary practice despite widespread availability of effective systemic and topical flea-control products. HYPOTHESIS/OBJECTIVES: To evaluate the clinical response in dogs with FAD treated topically with indoxacarb, a novel oxadiazine insecticide. ANIMALS: Twenty-five client-owned dogs in Queensland, Australia diagnosed with pre-existing FAD on the basis of clinical signs, flea-antigen intradermal and serological tests. METHODS: An open-label, noncontrolled study, in which all dogs were treated with topical indoxacarb at 4 week intervals, three times over 12 weeks. RESULTS: Twenty-four dogs completed the study. Complete resolution of clinical signs of FAD was observed in 21 cases (87.5%), with nearly complete resolution or marked improvement in the remaining three cases. Mean clinical scores (Canine Atopic Dermatitis Extent and Severity Index-03) were reduced by 93.3% at week 12. Mean owner-assessed pruritus scores were reduced by 88% by week 12. Mean flea counts reduced by 98.7 and 100% in weeks 8 and 12, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Topical indoxacarb treatment applied every 4 weeks for 12 weeks, without concomitant antipruritic or ectoparasiticide therapy, completely alleviated flea infestations in all dogs and associated clinical signs of FAD in a high proportion of this population of dogs in a challenging flea-infestation environment. PMID- 24797427 TI - Comparative cervical profiles of adult and under-18 front-row rugby players: implications for playing policy. AB - OBJECTIVE: To compare the cervical isometric strength, fatigue endurance and range of motion of adult and under-18 age-grade front-row rugby players to inform the development of a safe age group policy with particular reference to scrummaging. DESIGN: Cross-sectional cohort study. SETTING: 'Field testing' at Murrayfield stadium. PARTICIPANTS: 30 high-performance under-18 players and 22 adult front-row rugby players. OUTCOME MEASURES: Isometric neck strength, height, weight and grip strength. RESULTS: Youth players demonstrated the same height and grip strength as the adult players; however, the adults were significantly heavier and demonstrated substantially greater isometric strength (p<0.001). Only two of the 'elite' younger players could match the adult mean cervical isometric strength value. In contrast to school age players in general, grip strength was poorly associated with neck strength (r=0.2) in front-row players; instead, player weight (r=0.4) and the number of years' experience of playing in the front row (r=0.5) were the only relevant factors in multivariate modelling of cervical strength (R(2)=0.3). CONCLUSIONS: Extreme forces are generated between opposing front rows in the scrum and avoidance of mismatch is important if the risk of injury is to be minimised. Although elite youth front-row rugby players demonstrate the same peripheral strength as their adult counterparts on grip testing, the adults demonstrate significantly greater cervical strength. If older youths and adults are to play together, such findings have to be noted in the development of age group policies with particular reference to the scrum. PMID- 24797426 TI - The intraviral protein interaction network of hepatitis C virus. AB - Hepatitis C virus (HCV) is a global health problem and one of the main reasons for chronic liver diseases such as cirrhosis and hepatocellular carcinoma. The HCV genome is translated into a polyprotein which is proteolytically processed into 10 viral proteins. The interactome of the HCV proteins with the host cell has been worked out; however, it remains unclear how viral proteins interact with each other. We aimed to generate the interaction network of these 10 HCV proteins using a flow-cytometry-based FRET assay established in our laboratory (Banning, C., Votteler, J., Hoffmann, D., Koppensteiner, H., Warmer, M., Reimer, R., Kirchhoff, F., Schubert, U., Hauber, J., and Schindler, M. (2010) A flow cytometry-based FRET assay to identify and analyse protein-protein interactions in living cells. PLoS One 5, e9344). HCV proteins were constructed as fusions with the chromophores CFP and YFP. All HCV fusions were expressed and localized to specific subcellular compartments, indicating that they were functional. FACS FRET measurements identified a total of 20 interactions; 13 of these were previously described and have now been confirmed in living cells via our method. Among the seven novel protein binding pairs, HCV p7 plays a pivotal role. It binds to the HCV capsid protein Core and the two glycoproteins E1 and E2. These interplays were further demonstrated in the relevant context of Huh7.5 liver cells expressing infectious HCV. Our work demonstrates the feasibility of rapidly generating small interaction networks via FACS-FRET and defines the network of intra-HCV protein interactions. Furthermore, our data support an important role of p7 in HCV assembly. PMID- 24797428 TI - The founding of Mauritian endemic coffee trees by a synchronous long-distance dispersal event. AB - The stochastic process of long-distance dispersal is the exclusive means by which plants colonize oceanic islands. Baker's rule posits that self-incompatible plant lineages are unlikely to successfully colonize oceanic islands because they must achieve a coordinated long-distance dispersal of sufficiently numerous individuals to establish an outcrossing founder population. Here, we show for the first time that Mauritian Coffea species are self-incompatible and thus represent an exception to Baker's rule. The genus Coffea (Rubiaceae) is composed of approximately 124 species with a paleotropical distribution. Phylogenetic evidence strongly supports a single colonization of the oceanic island of Mauritius from either Madagascar or Africa. We employ Bayesian divergence time analyses to show that the colonization of Mauritius was not a recent event. We genotype S-RNase alleles from Mauritian endemic Coffea, and using S-allele gene genealogies, we show that the Mauritian allelic diversity is confined to just seven deeply divergent Coffea S-RNase allelic lineages. Based on these data, we developed an individual-based model and performed a simulation study to estimate the most likely number of founding individuals involved in the colonization of Mauritius. Our simulations show that to explain the observed S-RNase allelic diversity, the founding population was likely composed of fewer than 31 seeds that were likely synchronously dispersed from an ancestral mainland species. PMID- 24797429 TI - Getting consent into perspective. AB - This article continues a debate with Gareth Jones about the ethics of anatomy. The article discusses the distinction between direct and indirect reasons to require the deceased's consent prior to anatomical use. Getting this distinction wrong has potentially radical and unwelcome implications for the ethics of many uses of dead bodies. The article then exposes an ambiguity in asking what anatomical uses are ethical: we must distinguish between, on the one hand, who ought to have the power to make decisions and, on the other, how those with power ought to exercise it. It then applies this distinction to the ethics of the public display of bodies for entertainment. PMID- 24797430 TI - The lock-washer: a reconciliation of the RIG-I activation models. AB - RIG-I belongs to a type of intracellular pattern recognition receptors involved in the recognition of viral RNA by the innate immune system. A report by Peisley et al. published in Nature provides the crystal structure of human RIG-I revealing a tetrameric architecture of the RIG-I 2-CARD domain bound by three K63 linked ubiquitin chains, uncovering its activation mechanism for downstream signaling. PMID- 24797431 TI - Identifying specific receptors for cargo-mediated autophagy. AB - Macroautophagy has been implicated in numerous diseases, yet our understanding of the proteins responsible for the turnover of specific cargo by autophagy is limited. In a recent paper published in Nature, Mancias et al. used quantitative proteomics to identify a cohort of autophagosome-enriched proteins, one of which, nuclear receptor coactivator 4 (NCOA4) was shown to be required for the selective delivery of ferritin to the lysosome, ultimately regulating intracellular iron by autophagic turnover of ferritin, or ferritinophagy. PMID- 24797432 TI - Akt: a new activation mechanism. AB - Akt phosphorylation at S473 and T308 has been believed to be the prerequisites for its activation for years. Now, new phosphorylation event on Akt is identified and can trigger Akt activation and lead to its downstream oncogenic events. PMID- 24797433 TI - The IRE1alpha-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic beta-cells. PMID- 24797435 TI - Exposure of children with developmental delay to social determinants of poor health: cross-sectional case record review study. AB - BACKGROUND: Research on child development in general has highlighted the importance that the family environment plays in mediating the pathway between exposure to low socio-economic position (SEP) and child well-being. While child developmental models in intellectual disability have highlighted the interplay between social context, family environment and child development, little empirical work has attempted to formally evaluate the evidence in support of specific mediating pathways between low SEP and child outcomes. METHODS: Secondary analysis of cross-sectional confidentialized needs analysis data collected in three Primary Care Trusts in England covering a total population of 1.25 million people. Case record reviews were undertaken for 46 023 households, 2236 (4.9%) of which contained a child in the target age range with developmental delay. RESULTS: Children with developmental delay, when compared with their non disabled peers, were at significantly increased risk of poorer health outcomes and of being exposed to a wide range of social determinants of poor health. Controlling for between-group differences in exposure to social determinants of poor health reduced the risk of developmental delay being associated with poorer health outcomes by 45% for behaviour problems and 89% for risk of significant harm. For children with developmental delay, parenting difficulties appears to play a particularly significant role in partially mediating the effects of low SEP. CONCLUSIONS: The findings of the present study point to the potential effectiveness of family-focused early intervention to prevent the emergence and escalation of behavioural difficulties and health problems in children with developmental delay. PMID- 24797434 TI - Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma. AB - The tumor suppressor p53 and its signaling pathway play a critical role in tumor prevention. As a direct p53 target gene, the role of glutaminase 2 (GLS2) in tumorigenesis is unclear. In this study, we found that GLS2 expression is significantly decreased in majority of human hepatocellular carcinoma (HCC). Restoration of GLS2 expression in HCC cells inhibits the anchorage-independent growth of cells and reduces the growth of HCC xenograft tumors. Interestingly, we found that GLS2 negatively regulates the PI3K/AKT signaling, which is frequently activated in HCC. Blocking the PI3K/AKT signaling in HCC cells largely abolishes the inhibitory effect of GLS2 on the anchorage-independent cell growth and xenograft tumor growth. The GLS2 promoter is hypermethylated in majority of HCC samples. CpG methylation of GLS2 promoter inhibits GLS2 transcription, whereas reducing the methylation of GLS2 promoter induces GLS2 expression. Taken together, our results demonstrate that GLS2 plays an important role in tumor suppression in HCC, and the negative regulation of PI3K/AKT signaling contributes greatly to this function of GLS2. Furthermore, hypermethylation of GLS2 promoter is an important mechanism contributing to the decreased GLS2 expression in HCC. PMID- 24797436 TI - The contributions and challenges of NINR centers: perspectives of directors. PMID- 24797438 TI - The hare and the tortoise: emphasizing speed can change the evidence used to make decisions. AB - Decision-makers effortlessly balance the need for urgency against the need for caution. Theoretical and neurophysiological accounts have explained this tradeoff solely in terms of the quantity of evidence required to trigger a decision (the "threshold"). This explanation has also been used as a benchmark test for evaluating new models of decision making, but the explanation itself has not been carefully tested against data. We rigorously test the assumption that emphasizing decision speed versus decision accuracy selectively influences only decision thresholds. In data from a new brightness discrimination experiment we found that emphasizing decision speed over decision accuracy not only decreases the amount of evidence required for a decision but also decreases the quality of information being accumulated during the decision process. This result was consistent for 2 leading decision-making models and in a model-free test. We also found the same model-based results in archival data from a lexical decision task (reported by Wagenmakers, Ratcliff, Gomez, & McKoon, 2008) and new data from a recognition memory task. We discuss discuss implications for theoretical development and applications. PMID- 24797437 TI - Imaging of brain tumors with paramagnetic vesicles targeted to phosphatidylserine. AB - PURPOSE: To investigate paramagnetic saposin C and dioleylphosphatidylserine (SapC-DOPS) vesicles as a targeted contrast agent for imaging phosphatidylserine (PS) expressed by glioblastoma multiforme (GBM) tumors. MATERIALS AND METHODS: Gd DTPA-BSA/SapC-DOPS vesicles were formulated, and the vesicle diameter and relaxivity were measured. Targeting of Gd-DTPA-BSA/SapC-DOPS vesicles to tumor cells in vitro and in vivo was compared with nontargeted paramagnetic vesicles (lacking SapC). Mice with GBM brain tumors were imaged at 3, 10, 20, and 24 h postinjection to measure the relaxation rate (R1) in the tumor and the normal brain. RESULTS: The mean diameter of vesicles was 175 nm, and the relaxivity at 7 Tesla was 3.32 (s*mM)(-1) relative to the gadolinium concentration. Gd-DTPA BSA/SapC-DOPS vesicles targeted cultured cancer cells, leading to an increased R1 and gadolinium level in the cells. In vivo, Gd-DTPA-BSA/SapC-DOPS vesicles produced a 9% increase in the R1 of GBM brain tumors in mice 10 h postinjection, but only minimal changes (1.2% increase) in the normal brain. Nontargeted paramagnetic vesicles yielded minimal change in the tumor R1 at 10 h postinjection (1.3%). CONCLUSION: These experiments demonstrate that Gd-DTPA BSA/SapC-DOPS vesicles can selectively target implanted brain tumors in vivo, providing noninvasive mapping of the cancer biomarker PS. PMID- 24797439 TI - The influence of verb-bound syntactic preferences on the processing of syntactic structures. AB - Speakers sometimes repeat syntactic structures across sentences, a phenomenon called syntactic priming. We investigated the influence of verb-bound syntactic preferences on syntactic priming effects in response choices and response latencies for German ditransitive sentences. In the response choices we found inverse preference effects: There were stronger syntactic priming effects for primes in the less preferred structure, given the syntactic preference of the prime verb. In the response latencies we found positive preference effects: There were stronger syntactic priming effects for primes in the more preferred structure, given the syntactic preference of the prime verb. These findings provide further support for the idea that syntactic processing is lexically guided. PMID- 24797441 TI - Can bilinguals see it coming? Word anticipation in L2 sentence reading. AB - Why is it more difficult to comprehend a 2nd (L2) than a 1st language (L1)? In the present article we investigate whether difficulties during L2 sentence comprehension come from differences in the way L1 and L2 speakers anticipate upcoming words. We recorded the brain activity (event-related potentials) of Spanish monolinguals, French-Spanish late bilinguals, and Spanish-Catalan early bilinguals while reading sentences in Spanish. We manipulated the ending of highly constrained sentences so that the critical noun was either expected or not. The expected and unexpected nouns were of different gender so that we could observe potential anticipation effects already on the article. In line with previous studies, a modulation of the N400 effect was observed on the article and the noun, followed by an anterior positivity on the noun. Importantly, this pattern was found in all 3 groups, suggesting that, at least when their 2 languages are closely related, bilinguals are able to anticipate upcoming words in a similar manner as monolinguals. PMID- 24797440 TI - Language and short-term memory: the role of perceptual-motor affordance. AB - The advantage for real words over nonwords in serial recall--the lexicality effect--is typically attributed to support for item-level phonology, either via redintegration, whereby partially degraded short-term traces are "cleaned up" via support from long-term representations of the phonological material or via the more robust temporary activation of long-term lexical phonological knowledge that derives from its combination with established lexical and semantic levels of representation. The much smaller effect of lexicality in serial recognition, where the items are re-presented in the recognition cue, is attributed either to the minimal role for redintegration from long-term memory or to the minimal role for item memory itself in such retrieval conditions. We show that the reduced lexicality effect in serial recognition is not a function of the retrieval conditions, but rather because previous demonstrations have used auditory presentation, and we demonstrate a robust lexicality effect for visual serial recognition in a setting where auditory presentation produces no such effect. Furthermore, this effect is abolished under conditions of articulatory suppression. We argue that linguistic knowledge affects the readiness with which verbal material is segmentally recoded via speech motor processes that support rehearsal and therefore affects tasks that involve recoding. On the other hand, auditory perceptual organization affords sequence matching in the absence of such a requirement for segmental recoding and therefore does not show such effects of linguistic knowledge. PMID- 24797442 TI - Toward an episodic context account of retrieval-based learning: dissociating retrieval practice and elaboration. AB - We tested the predictions of 2 explanations for retrieval-based learning; while the elaborative retrieval hypothesis assumes that the retrieval of studied information promotes the generation of semantically related information, which aids in later retrieval (Carpenter, 2009), the episodic context account proposed by Karpicke, Lehman, and Aue (in press) assumes that retrieval alters the representation of episodic context and improves one's ability to guide memory search on future tests. Subjects studied multiple word lists and either recalled each list (retrieval practice), did a math task (control), or generated associates for each word (elaboration) after each list. After studying the last list, all subjects recalled the list and, after a 5-min delay, recalled all lists. Analyses of correct recall, intrusions, response times, and temporal clustering dissociate retrieval practice from elaboration, supporting the episodic context account. PMID- 24797443 TI - Phonologically driven variability: the case of determiners. AB - Speakers usually produce words in connected speech. In such contexts, the form in which many words are uttered is influenced by the phonological properties of neighboring words. The current article examines the representations and processes underlying the production of phonologically constrained word form variations. For this purpose, we consider determiners whose form is sensitive to phonological context (e.g., in English: a car vs. an animal; in French: le chien 'the dog' vs. l'ane 'the donkey'). Two hypotheses have been proposed regarding how these words are processed. Determiners either are thought to have different representations for each of their surface forms, or they are thought to have only 1 representation while other forms are generated online after selection through a rule-based process. We tested the predictions derived from these 2 views in 3 picture naming experiments. Participants named pictures using determiner adjective-noun phrases (e.g., la nouvelle table 'the new table'). Phonologically consistent or inconsistent conditions were contrasted, based on the phonological onsets of the adjective and the noun. Results revealed shorter naming latencies for consistent than for inconsistent sequences (i.e., a phonological consistency effect) for all the determiner types tested. Our interpretation of these findings converges on the assumption that determiners with varying surface forms are represented in memory with multiple phonological-lexical representations. This conclusion is discussed in relation to models of determiner processing and models of lexical variability. PMID- 24797444 TI - Effects of varied and constant environmental contexts on acquisition and retention. AB - Four experiments examined the decontextualization of memories, the stage of learning in which memories can be recalled in the absence of episodic memory cues. Face-name pairs were studied with video-recorded environmental contexts in the background, and after 5 practice trials, recall of names associated with faces was tested in the absence of the original video context cues. In Experiments 1, 2, and 3, five retrieval practice trials for a pair occurred either always with the original video context (constant context condition) or with a new context on each trial (varied context condition). Final recall was tested either on the same day (Experiments 3 and 4) or 2 days later (Experiments 1 and 2), and either the recall test context for each face was a new (never seen) video (Experiment 1) or there was no context shown at test (Experiments 2, 3, and 4). In the first 3 experiments, acquisition was better for the constant context condition, but on the final recall test, performance was better for pairs learned under varied context conditions. In Experiment 4, which used multiple study trials rather than multiple retrieval practices during acquisition, no differences were found between the constant and varied context conditions, either for acquisition or for final retention. The results show that acquisition trials given in varied contexts can result in decontextualized memories, but only when acquisition involves retrieval practice, rather than simple restudy trials. These results are consistent with the new theory of disuse, but not with the theory of encoding variability. PMID- 24797445 TI - Systemic treatment of HER2-positive metastatic breast cancer: a systematic review. AB - AIM: We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2-positive metastatic breast cancer. METHODS: We reviewed phase 2 and 3 studies in which an anti-HER2 agent was used in one or both arms of the study. While formal meta-analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings. RESULTS: There is strong evidence that the addition of an anti-HER2 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T DM1 or dual anti-HER2 agents are superior to single anti-HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti-HER2 agent confers any benefit over a single cytotoxic, anti-HER2 combination. CONCLUSION: This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting. PMID- 24797446 TI - Systemic treatment of HER2+ metastatic breast cancer: clinical conundrums and future perspectives. AB - Improvements in the treatment of metastatic HER2-positive breast cancer constitute one of the great advances in breast cancer medicine of the last generation. From being a highly aggressive fatal condition, the use of anti-HER2 targeted therapies, in particular trastuzumab, has led to significant improvements in disease outcomes. There are reports of increasing numbers of patients alive and well more than 5 years from diagnosis of metastatic disease. Nevertheless, there remain many complex and clinically difficult scenarios where there is little in the way of randomized evidence or published guidelines to guide decision making. As a companion piece to our review of HER2-targeted therapies in the metastatic setting, we decided to focus on a series of clinical scenarios that fell outside of the standard trial-based settings and where opinions and guidance from experienced clinicians and experts in the field would be considered useful to help develop safe and effective treatment strategies. The following eight cases were put forward by our panel of experts, voted on by their peers to select the most relevant and interesting cases, and the discussions worked on by teams of two followed by review and commentary by another team of two. PMID- 24797447 TI - Interventricular Pacemaker-Mediated Tachycardia during Biventricular Pacing. PMID- 24797448 TI - Facile approach to synthesize g-PAN/g-C3N4 composites with enhanced photocatalytic H2 evolution activity. AB - Novel composites consisting of graphitized polyacrylonitrile (g-PAN) nanosheets grown on layered g-C3N4 sheets were synthesized through a facile one-step thermal condensation of PAN and melamine for the first time. Photoluminescence spectroscopy and the photoelectrochemical measurements reveal that g-PAN nanosheets act as effective electron transfer channels to facilitate charge carrier separation in g-PAN/g-C3N4 composites. The g-PAN/g-C3N4 composites exhibit significantly enhanced visible-light photocatalytic performance for H2 evolution over pristine g-C3N4. The 5.0 wt % g-PAN/g-C3N4 composite has optimal H2 evolution rate of 37 MUmol h(-1), exceeding 3.8 times over pristine g-C3N4. We have proposed a possible mechanism for charge separation and transfer in the g PAN/g-C3N4 composites to explain the enhanced photocatalytic performance. PMID- 24797449 TI - Evidence for a role of the right dorsolateral prefrontal cortex in controlling stimulus-response integration: a transcranial direct current stimulation (tDCS) study. AB - BACKGROUND: Acting coherently upon stimuli requires some kind of integration of stimulus and response features across various distinct cortical feature maps (one aspect of the binding problem). Although the process of feature binding proper seems rather automatic, recent studies revealed that the management of stimulus response bindings is less efficient in populations with impaired cognitive control processes. OBJECTIVE: Here, we investigated whether the cognitive control of stimulus-response feature bindings ("event files") in healthy participants is affected by non-invasive brain stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC)-a main component of the cognitive-control network. METHOD: In different sessions, participants received anodal, cathodal, or sham tDCS (2 mA, 20 min) while performing an audio-visual event-file task assessing the creation and retrieval of stimulus-stimulus and stimulus-response feature bindings. The general findings from this task indicate that performance suffers when some, but not all of the features are repeated (the so-called partial repetition cost). RESULTS: Stimulation over the right, but not the left DLPFC reduced control of stimulus-response bindings and produced outcome patterns similar to those previously observed in autistic children, people with lower fluid intelligence, and older adults. CONCLUSIONS: This finding provides empirical support for a role of the right DLPFC in feature-binding management, which might consist in preventing the stimulus-induced activation of previously created, but now task irrelevant, episodic bindings. From a methodological perspective, the finding may suggest that tDCS could be used as a temporary, reversible "brain lesion" generator in healthy subjects, enabling experimental investigation of how the brain works. PMID- 24797451 TI - Synthesis of labdane diterpenes galanal A and B from (+)-sclareolide. AB - The first chemical synthesis of galanal A and B was achieved by a concise and highly efficient pathway starting from commercially available (+)-sclareolide and features a Wittig reaction and a titanocene-mediated radical cyclization as the key steps. PMID- 24797450 TI - Disease and treatment characteristics do not predict symptom occurrence profiles in oncology outpatients receiving chemotherapy. AB - BACKGROUND: A large amount of interindividual variability exists in the occurrence of symptoms in patients receiving chemotherapy (CTX). The purposes of the current study, which was performed in a sample of 582 oncology outpatients who were receiving CTX, were to identify subgroups of patients based on their distinct experiences with 25 commonly occurring symptoms and to identify demographic and clinical characteristics associated with subgroup membership. In addition, differences in quality of life outcomes were evaluated. METHODS: Oncology outpatients with breast, gastrointestinal, gynecological, or lung cancer completed the Memorial Symptom Assessment Scale before their next cycle of CTX. Latent class analysis was used to identify subgroups of patients with distinct symptom experiences. RESULTS: Three distinct subgroups of patients were identified (ie, 36.1% in Low class; 50.0% in Moderate class, and 13.9% in All High class). Patients in the All High class were significantly younger and more likely to be female and nonwhite, and had lower levels of social support, lower socioeconomic status, poorer functional status, and a higher level of comorbidity. CONCLUSIONS: Findings from the current study support the clinical observation that some oncology patients experience a differentially higher symptom burden during CTX. These high-risk patients experience significant decrements in quality of life. PMID- 24797453 TI - Ultrafast electron and phonon response of oriented and diameter-controlled germanium nanowire arrays. AB - Carrier and phonon dynamics in dense arrays of aligned, single-crystal Ge nanowires (NWs) of controlled diameter are investigated by ultrafast optical pump probe measurements, effective medium calculations, and elasticity analysis. Both a pronounced induced absorption and the amplitude and spectral range of Fabry Perot oscillations observed in the probe signal are predicted for the NW array/air metamaterial by effective medium calculations. Detected temporal oscillations of reflectivity are consistent with excitation of radial breathing mode acoustic phonons by the intense pump pulse. PMID- 24797452 TI - A critical appraisal of the evidence for using cardiotocography plus ECG ST interval analysis for fetal surveillance in labor. Part I: the randomized controlled trials. AB - We reappraised the five randomized controlled trials that compared cardiotocography plus ECG ST interval analysis (CTG+ST) vs. cardiotocography. The numbers enrolled ranged from 5681 (Dutch randomized controlled trial) to 799 (French randomized controlled trial). The Swedish randomized controlled trial (n = 5049) was the only trial adequately powered to show a difference in metabolic acidosis, and the Plymouth randomized controlled trial (n = 2434) was only powered to show a difference in operative delivery for fetal distress. There were considerable differences in study design: the French randomized controlled trial used different inclusion criteria, and the Finnish randomized controlled trial (n = 1483) used a different metabolic acidosis definition. In the CTG+ST study arms, the larger Plymouth, Swedish and Dutch trials showed lower operative delivery and metabolic acidosis rates, whereas the smaller Finnish and French trials showed minor differences in operative delivery and higher metabolic acidosis rates. We conclude that the differences in outcomes are likely due to the considerable differences in study design and size. This will enhance heterogeneity effects in any subsequent meta-analysis. PMID- 24797454 TI - The management of antibody-mediated rejection in the first presensitized recipient of a full-face allotransplant. AB - We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody-mediated rejection (AMR). The recipient is a 45-year-old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti-HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full-face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor-specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA. PMID- 24797455 TI - Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase. AB - Prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a strategy for targeting cancer metabolism. Many NAMPT inhibitors undergo NAMPT catalyzed phosphoribosylation (pRib), a property often correlated with their cellular potency. To understand this phenomenon and facilitate drug design, we analyzed a potent cellularly active NAMPT inhibitor (GNE-617). A crystal structure of pRib-GNE-617 in complex with NAMPT protein revealed a relaxed binding mode. Consistently, the adduct formation resulted in tight binding and strong product inhibition. In contrast, a biochemically equipotent isomer of GNE 617 (GNE-643) also formed pRib adducts but displayed significantly weaker cytotoxicity. Structural analysis revealed an altered ligand conformation of GNE 643, thus suggesting weak association of the adducts with NAMPT. Our data support a model for cellularly active NAMPT inhibitors that undergo NAMPT-catalyzed phosphoribosylation to produce pRib adducts that retain efficient binding to the enzyme. PMID- 24797456 TI - Food preference and copying behaviour in zebra finches, Taeniopygia guttata. AB - As a social species zebra finches might be expected to copy the food choices of more experienced conspecifics. This prediction has been tested previously by presenting observers with two demonstrator birds that differ in some way (e.g., sex, familiarity), each feeding on a different colour food source. However, if the observer subsequently exhibits a preference, it is unclear whether it has copied the choice of one demonstrator or avoided the choice of the other. Furthermore, this choice may actually be influenced by pre-existing preferences, a potential bias that is rarely tested. Here we examine whether apparent copying or avoidance can be explained by pre-existing preferences. In Experiment 1, observers had the opportunity to watch a conspecific forage from one of the two differently coloured food hoppers. In Experiment 2, the observers did not have this opportunity. In both experiments observers were subsequently tested for their food hopper preference and all but one preferred one colour over the other. In Experiment 1 some observers showed evidence for copying, while others seemed to avoid the colour preferred by the demonstrator. In Experiment 2 females generally preferred the white hopper. Pre-existing colour preferences could, therefore, explain the apparent copying/avoidance we observed. This article is part of a Special Issue entitled: Cognition in the wild. PMID- 24797457 TI - Real-time RT-PCR assays for discriminating influenza B virus Yamagata and Victoria lineages. AB - Since the late 1980s, two genetically and antigenically distinct lineages of influenza B virus, namely, B/Victoria/2/87-like (B/Victoria) and B/Yamagata/16/88 like (B/Yamagata), have co-circulated. In this study, one-step real-time reverse transcription-PCR (rRT-PCR) assays were developed to differentiate B/Victoria and B/Yamagata lineages. The assays were evaluated using in vitro transcribed control RNA, isolated viruses, and other respiratory pathogenic viruses, and were shown to have high sensitivity, good linearity (R(2)=0.99), and high specificity. Using the developed rRT-PCR assays, 169 clinical specimens collected between 2010 and 2013 were then tested, resulting in the identification of 20 clinical specimens as positive for influenza B virus. Of these, 14 and 6 samples were identified as positive for the B/Victoria and B/Yamagata lineages, respectively, whereas 149 samples were negative for the influenza B virus. The rRT-PCR assays were also examined using 20 clinical isolates from 20 influenza B virus-positive specimens, revealing that there was no discrepancy between the results from the rRT-PCR assays and the hemagglutination inhibition (HI) test, with the exception that one clinical isolate with different antigenicity could not be discriminated by the HI test. The present results suggest that these highly sensitive and specific assays are useful not only for diagnosing influenza viruses but also for their surveillance. PMID- 24797458 TI - A novel method to produce Influenza A virus matrix protein M1 Capsid Like Particles (CLPs). AB - Avian influenza viruses represent a growing threat for an influenza pandemic. The currently licensed influenza vaccines have inherent drawbacks which has led many research groups to explore different approaches of vaccine development among which Virus Like particles (VLPs) seem like a promising alternative in the near future. Although it is known that the Matrix 1 protein (M1) of influenza plays an essential role in VLP formation and it is documented that M1 is able to form dimers, it is not clear if M1 is capable of forming higher order structures without the interference of other influenza proteins or cell derived envelope. Here, for the first time we have demonstrated that expression of M1 alone is enough to form a Capsid Like Particle (CLP) without the requirement of any other external factor. PMID- 24797460 TI - TaqMan real time RT-PCR assays for detecting ferret innate and adaptive immune responses. AB - The ferret is an excellent model for many human infectious diseases including influenza, SARS-CoV, henipavirus and pneumococcal infections. The ferret is also used to study cystic fibrosis and various cancers, as well as reproductive biology and physiology. However, the range of reagents available to measure the ferret immune response is very limited. To address this deficiency, high throughput real time RT-PCR TaqMan assays were developed to measure the expression of fifteen immune mediators associated with the innate and adaptive immune responses (IFNalpha, IFNbeta, IFNgamma, IL1alpha, IL1beta, IL2, IL4, IL6, IL8, IL10, IL12p40, IL17, Granzyme A, MCP1, TNFalpha), as well as four endogenous housekeeping genes (ATF4, HPRT, GAPDH, L32). These assays have been optimized to maximize reaction efficiency, reduce the amount of sample required (down to 1ng RNA per real time RT-PCR reaction) and to select the most appropriate housekeeping genes. Using these assays, the expression of each of the tested genes could be detected in ferret lymph node cells stimulated with mitogens or infected with influenza virus in vitro. These new tools will allow a more comprehensive analysis of the ferret immune responses following infection or in other disease states. PMID- 24797459 TI - Targeted deep sequencing of HIV-1 using the IonTorrentPGM platform. AB - The characterization of mixed HIV-1 populations is a key question in clinical and basic research settings. This can be achieved through targeted deep sequencing (TDS), where next-generation sequencing is used to examine in depth a sub-genomic region of interest. This study explores the suitability of IonTorrent PGM(LifeTechnologies) for the TDS-based analysis of HIV-1 evolution. Using laboratory reagents and primary specimens sampled at pre-peak viremia the error rates from misincorporation and in vitro recombination were <0.5%. The sequencing error rate was 2- to 3-fold higher in/around homopolymeric tracts, and could be discerned from true polymorphism using bidirectional sequencing. The limit of detection of complex variants was further lowered by using haplotyping. The application of this system was illustrated on primary samples from an individual infected with HIV-1 followed from pre-peak viremia through six months post acquisition. TDS provided an augmented view of the extent of genetic diversity, the covariation among polymorphisms, the evolutionary pathways, and the boundaries of the mutational space explored by the viral swarm. Based on its performance, the system can be applied for the characterization of minor viral variants in support of studies of viral evolution, which can inform the rational design of the next generation of vaccines and therapeutics. PMID- 24797461 TI - Rapid and sensitive detection of Little cherry virus 2 using isothermal reverse transcription-recombinase polymerase amplification. AB - Little cherry virus 2 (LChV2) (genus Ampelovirus) is the primary causal agent of little cherry disease (LCD) in sweet cherry (Prunus avium) in North America and other parts of the world. This mealybug-transmitted virus does not induce significant foliar symptoms in most sweet cherry cultivars, but does cause virus infected trees to yield unevenly ripened small fruits with poor flavor. Most fruits from infected trees are unmarketable. In the present study, an isothermal reverse transcription-recombinase polymerase amplification (RT-RPA) technique was developed using LChV2 coat protein specific primers and probe. Detection of terminally labeled amplicons was achieved with a high affinity lateral flow strip. The RT-RPA is confirmed to be simple, fast, and specific. In comparison, although it retains the sensitivity of RT-PCR, it is a more cost-effective procedure. RT-RPA will be a very useful tool for detecting LChV2 from crude extracts in any growth stage of sweet cherry from field samples. PMID- 24797462 TI - SHARELIFE-One century of life histories in Europe. AB - Welfare state interventions shape our life courses in almost all of their multiply linked domains. In this introduction, we sketch how cross-nationally comparative retrospective data can be fruitfully employed to better understand these links and the long-run effects of the welfare state at the same time. We briefly introduce SHARE, the Survey of Health, Ageing and Retirement in Europe, and SHARELIFE, which collected 30,000 life histories of SHARE respondents from 14 European countries, providing a unique data infrastructure for interdisciplinary research on the various influences of contextual structures on the lives of Europeans during the last century until today. The eight studies in this special issue show that the multidisciplinary cross national approach of SHARELIFE allows a much more detailed understanding of life histories in Europe than was possible before. PMID- 24797463 TI - Jobless now, sick later? Investigating the long-term consequences of involuntary job loss on health. AB - In the light of the current economic crises which in many countries lead to business closures and mass lay-offs, the consequences of job loss are important on various dimensions. They have to be investigated not only in consideration of a few years, but with a long-term perspective as well, because early life course events may prove important for later life outcomes. This paper uses data from SHARELIFE to shed light on the long-term consequences of involuntary job loss on health. The paper distinguishes between two different reasons for involuntary job loss: plant closures, which in the literature are considered to be exogenous to the individual, and lay-offs, where the causal direction of health and unemployment is ambiguous. These groups are separately compared to those who never experienced a job loss. The paper uses eleven different measures of health to assess long-term health consequences of job loss, which has to have occurred at least 25 years before the current interview. As panel data cannot be employed, a large body of variables, including childhood health and socio-economic conditions, is used to control for the initial conditions. The findings suggest that individuals with an exogenous job loss suffer in the long run: men are significantly more likely to be depressed and they have more trouble knowing the current date. Women report poorer general health and more chronic conditions and are also affected in their physical health: they are more likely to be obese or overweight, and to have any limitations in their (instrumental) activities of daily living. In the comparison group of laid-off individuals, controlling for the initial conditions reduces the effects of job loss on health - proving that controlling for childhood conditions is important. PMID- 24797464 TI - Working conditions in mid-life and mental health in older ages. AB - This article illustrates the importance of previous working conditions during mid life (between 40 and 55) for mental health among older retired men and women (60 or older) across 13 European countries. We link information on health from the second wave (2006-2007) of the Survey of Health, Ageing and Retirement in Europe (SHARE) with information on respondents' working life collected retrospectively in the SHARELIFE interview (2008-2009). To measure working conditions, we rely on core assumptions of existing theoretical models of work stress (the demand control-support and the effort-reward imbalance model) and distinguish four types of unhealthy working conditions: (1) a stressful psychosocial work environment (as assessed by the two work stress models) (2) a disadvantaged occupational position throughout the whole period of mid-life, (3) experience of involuntary job loss, and (4) exposure to job instability. Health after labour market exit is measured using depressive symptoms, as measured by the EURO-D depression scale. Main results show that men and women who experienced psychosocial stress at work or had low occupational positions during mid-life had significantly higher probabilities of high depressive symptoms during retirement. Additionally, men with unstable working careers and an involuntary job loss were at higher risks to report high depressive symptoms in later life. These associations remain significant after controlling for workers' health and social position prior mid life. These findings support the assumption that mental health of retirees who experienced poor working conditions during mid-life is impaired. PMID- 24797465 TI - Retrospective explanation of older women's lifetime work involvement: Individual paths around social norms. AB - This paper uses the retrospective questionnaire of the SHARE survey of Europeans aged 50+ to document the career dilemmas faced by women in Europe over the last fifty years. It charts how social transformation was directly experienced by survey respondents: First, it documents career differences of two cohorts in four geographical regions. Second, it compares outcomes faced by career women who had 'gone against the flow' in countries where they were in a minority, with women who had taken the same decision where career was, already, a majority choice. Third, it examines how far individual career choice was affected by the operation of the welfare state. To do that, we employ a multivariate econometric model that treats entry into the labour market and career choice as linked decisions, which are affected by individual circumstances, macroeconomic conditions but also by social policy parameters. We conclude that the same degree of past social policy effort appears to operate differently in different places. This is broadly consistent with the existence of distinct kinds of welfare state in the different parts of Europe. PMID- 24797466 TI - The direct impact of maternity benefits on leave taking: Evidence from complete fertility histories. AB - Maternity leave policies have important effects on several labour market outcomes of women, and are specifically designed to reduce gender differences in the various dimensions of working life and to contrast the negative consequence of fertility decisions. By making use of a unique data set which contains complete work and fertility histories for different European countries, combined with features of maternity leave schemes across countries and over time, we look at the effect of maternity leave benefits on job interruptions after each successive childbirth. The main result of the paper is that maternity leave legislation in Europe effectively increases job protection and female labour market attachment: a more generous paid maternity leave increases the number of weeks employed but not at work, but reduces the number of weeks spent out of the labour market. PMID- 24797467 TI - Adverse effects of widowhood in Europe. AB - I investigate the relationship between widowhood and the financial situation among women aged 50 and above in Europe. The results of the paper are based on the Survey of Health, Ageing and Retirement in Europe, and its retrospective third wave (SHARELIFE). Using retrospective data makes it possible to analyze the dynamics of the adverse effects of widowhood. I estimate both the short run and long run effects of widowhood on financial circumstances, health, and labor force status. I argue that not only the lack of the deceased husband's income, but also the worse health condition and earlier retirement of widows contribute to the unfavorable financial conditions, although these indirect effects are small. I also analyze the role survivors' pensions have in mitigating the adverse effects of widowhood, and provide evidence for varying compensating effects of survivors' pensions in the European countries analyzed. PMID- 24797468 TI - Home-ownership in Europe: How did it happen? AB - We use data from the third wave of the Survey of Health, Ageing and Retirement in Europe (SHARELIFE)(1) to document the different ways individuals first became home-owners across countries and over cohorts over the second half of the 20th century. Focusing on first-time home owners we find that younger cohorts became home-owners earlier and were more likely to do it through credit, less likely to inherit their home directly. Having higher human capital, being employed, married, having children and living in an urban area, all make it more likely to purchase a home with a mortgage. The persistence of family help in accessing home ownership in many countries demonstrates the interrelation between family, market and the state in most of continental Europe. PMID- 24797469 TI - Life insurance investment and stock market participation in Europe. AB - In most European countries life insurance has played a key role in household portfolios, to the extent that it has often been the first asset ever purchased. In this paper we use life history data from a host of European countries to investigate the role of life insurance investment in shaping individuals' attitudes towards participation in stocks and mutual funds. We show that individuals who purchased a life insurance policy are more likely to invest in stocks and mutual funds later. On the one hand, these findings support the notion that life insurance policies play an educational role in financial investment. On the other hand, they are also consistent with behavioural models where economic agents are first concerned with avoiding unacceptable adverse scenarios by purchasing low risk investments, such as life insurance policies, and then invest in riskier assets, such as stocks and mutual funds, to obtain higher economic returns. PMID- 24797470 TI - The influence of living conditions in early life on life satisfaction in old age. AB - This article examines the influence of living conditions in early life on life satisfaction in old age in eleven Western European countries. It combines the influence of individual conditions, for example housing and family background, with country characteristics in the decade of birth. Using pooled data from the second and third wave of the Survey of Health, Ageing and Retirement in Europe, multilevel models show that early life living conditions have an influence on life satisfaction in old age. Furthermore, interaction effects between current and past living conditions show that adverse living conditions strengthen the effect of early life on life satisfaction in later life and therefore are an indication of cumulative inequality over the life course. PMID- 24797471 TI - MicroRNAs as biomarkers of graft outcome. AB - Dramatic improvements in short-term graft outcomes after solid organ transplantation over the past decade have not translated into major improvements in long-term allograft acceptance and patient survival. Innovative approaches to develop individualized therapy for the graft recipient are critically needed and have stimulated active research in the field of biomarker discovery. MicroRNAs (miRNAs) are small non-coding RNAs that function as important regulators of gene and protein expression by RNA interference. They are implicated in many biological processes and diseases. Their characteristics prompted their evaluation as candidate molecular markers to evaluate the transplant patient: their expression profile is specifically altered in pathological conditions, they can be easily detected and quantified in tissues, and they are highly stable in almost all body fluids, allowing the development of non-invasive approaches. We aimed to review the existing knowledge about miRNA biogenesis and function and summarize the recent findings demonstrating their potential use as biomarkers in solid organ transplantation. Although they still need to be validated in larger patient cohorts, miRNAs are not far from being used in transplant clinical practice as usefulness biomarkers. Ongoing multi-center trials should help to further define the clinical utility of miRNA profiles as biomarkers of allograft status and outcome. PMID- 24797473 TI - ICK is essential for cell type-specific ciliogenesis and the regulation of ciliary transport. AB - Cilia and flagella are formed and maintained by intraflagellar transport (IFT) and play important roles in sensing and moving across species. At the distal tip of the cilia/flagella, IFT complexes turn around to switch from anterograde to retrograde transport; however, the underlying regulatory mechanism is unclear. Here, we identified ICK localization at the tip of cilia as a regulator of ciliary transport. In ICK-deficient mice, we found ciliary defects in neuronal progenitor cells with Hedgehog signal defects. ICK-deficient cells formed cilia with mislocalized Hedgehog signaling components. Loss of ICK caused the accumulation of IFT-A, IFT-B, and BBSome components at the ciliary tips. In contrast, overexpression of ICK induced the strong accumulation of IFT-B, but not IFT-A or BBSome components at ciliary tips. In addition, ICK directly phosphorylated Kif3a, while inhibition of this Kif3a phosphorylation affected ciliary formation. Our results suggest that ICK is a Kif3a kinase and essential for proper ciliogenesis in development by regulating ciliary transport at the tip of cilia. PMID- 24797474 TI - Meiotic cohesin STAG3 is required for chromosome axis formation and sister chromatid cohesion. AB - The cohesin complex is essential for mitosis and meiosis. The specific meiotic roles of individual cohesin proteins are incompletely understood. We report in vivo functions of the only meiosis-specific STAG component of cohesin, STAG3. Newly generated STAG3-deficient mice of both sexes are sterile with meiotic arrest. In these mice, meiotic chromosome architecture is severely disrupted as no bona fide axial elements (AE) form and homologous chromosomes do not synapse. Axial element protein SYCP3 forms dot-like structures, many partially overlapping with centromeres. Asynapsis marker HORMAD1 is diffusely distributed throughout the chromatin, and SYCP1, which normally marks synapsed axes, is largely absent. Centromeric and telomeric sister chromatid cohesion are impaired. Centromere and telomere clustering occurs in the absence of STAG3, and telomere structure is not severely affected. Other cohesin proteins are present, localize throughout the STAG3-devoid chromatin, and form complexes with cohesin SMC1beta. No other deficiency in a single meiosis-specific cohesin causes a phenotype as drastic as STAG3 deficiency. STAG3 emerges as the key STAG cohesin involved in major functions of meiotic cohesin. PMID- 24797476 TI - Coselection for resistance to multiple late-generation human therapeutic antibiotics encoded on tetracycline resistance plasmids captured from uncultivated stream and soil bacteria. AB - AIMS: Transmissible plasmids captured from stream and soil bacteria conferring resistance to tetracycline in Pseudomonas were evaluated for linked resistance to antibiotics used in the treatment of human infections. METHODS AND RESULTS: Cells released from stream sediments and soils were conjugated with a rifampicin resistant, plasmid-free Pseudomonas putida recipient and selected on tetracycline and rifampicin. Each transconjugant contained a single 50-80 kb plasmid. Resistance to 11 antibiotics, in addition to tetracycline, was determined for the stream transconjugants using a modification of the Stokes disc diffusion antibiotic susceptibility assay. Nearly half of plasmids conferred resistance to six or more antibiotics. Resistance to streptomycin, gentamicin, and/or ticarcillin was conferred by a majority of the plasmids, and resistance to additional human clinical use antibiotics such as piperacillin/tazobactam, ciprofloxacin and aztreonam was observed. MICs of 16 antibiotics for representative sediment and soil transconjugants revealed large increases, relative to the Ps. putida recipient, for 11 of 16 antibiotics tested, including the expanded spectrum antibiotics cefotaxime and ceftazidime, as well as piperacillin/tazobactam, lomefloxacin and levofloxacin. CONCLUSIONS: Resistance to multiple antibiotics-including those typically used in clinical Pseudomonas and enterobacterial infections-can be conferred by transmissible plasmids in streams and soils. SIGNIFICANCE AND IMPACT OF STUDY: Selective pressure exerted by the use of one antibiotic, such as the common agricultural antibiotic tetracycline, may result in the persistence of linked genes conferring resistance to important human clinical antibiotics. This may impact the spread of resistance to human use antibiotics even in the absence of direct selection. PMID- 24797475 TI - STAG3-mediated stabilization of REC8 cohesin complexes promotes chromosome synapsis during meiosis. AB - Cohesion between sister chromatids in mitotic and meiotic cells is promoted by a ring-shaped protein structure, the cohesin complex. The cohesin core complex is composed of four subunits, including two structural maintenance of chromosome (SMC) proteins, one alpha-kleisin protein, and one SA protein. Meiotic cells express both mitotic and meiosis-specific cohesin core subunits, generating cohesin complexes with different subunit composition and possibly separate meiotic functions. Here, we have analyzed the in vivo function of STAG3, a vertebrate meiosis-specific SA protein. Mice with a hypomorphic allele of Stag3, which display a severely reduced level of STAG3, are viable but infertile. We show that meiocytes in homozygous mutant Stag3 mice display chromosome axis compaction, aberrant synapsis, impaired recombination and developmental arrest. We find that the three different alpha-kleisins present in meiotic cells show different dosage-dependent requirements for STAG3 and that STAG3-REC8 cohesin complexes have a critical role in supporting meiotic chromosome structure and functions. PMID- 24797477 TI - Molecular epidemiological study of hepatitis B virus genotypes in Southwest, China. AB - Hepatitis B virus (HBV) is highly endemic in Southwest China; an area with many ethnic minorities. Information about the genetic distribution of HBV is still limited. In 2010, a multistage cluster sampling method was carried out in the Southwest China. Five hundred forty serum samples of participants were collected. Polymerase chain reaction followed by nucleotide sequencing of parts of the HBV S and C genes was performed. HBV genotype and subgenotype were determined. Recombination analysis was carried out. HBV infectious markers, HBV DNA and mutations in the basic core promoter (BCP) A1762T/G1764A and G1896A were analyzed. The results show us that HBV genotypes C/D recombinant (38.6%), B (31.6%), and C (23.3%), were predominant in Southwest China. C/D4 (96.8%) was endemic in the Tibetan and B2 (43.5%) in Han, and C1 (66.7%) was predominant in the Yi minority. 67.5% (56/83) of genotype C/D was Hepatitis B surface antigen (HBsAg) positive/Hepatitis B e antigen (HBeAg) positive/HBV DNA>=20,000 IU/ml, BCP A1762T/G1764A double mutation was frequent in genotype C and C/D, and G1896A was frequent in B and B/C. Thus, HBV genotypes distribution differed significantly in area and minority in Southwest China. C/D recombinant is endemic in the Tibetan, while B, C genotypes are predominant in Han minority. C/D recombinant exhibits higher frequency with HBeAg positive, high level of HBV DNA and BCP A1762T/G1764A double mutation. PMID- 24797481 TI - Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. AB - Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral "rejuvenating" factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction. PMID- 24797482 TI - Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. AB - In the adult central nervous system, the vasculature of the neurogenic niche regulates neural stem cell behavior by providing circulating and secreted factors. Age-related decline of neurogenesis and cognitive function is associated with reduced blood flow and decreased numbers of neural stem cells. Therefore, restoring the functionality of the niche should counteract some of the negative effects of aging. We show that factors found in young blood induce vascular remodeling, culminating in increased neurogenesis and improved olfactory discrimination in aging mice. Further, we show that GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. The identification of factors that slow the age-dependent deterioration of the neurogenic niche in mice may constitute the basis for new methods of treating age-related neurodegenerative and neurovascular diseases. PMID- 24797483 TI - Pharmacokinetic evaluation of diquafosol tetrasodium for the treatment of Sjogren's syndrome. AB - INTRODUCTION: Dry eye is a multifactorial disease of the ocular surface causing ocular discomfort and visual impairment for the patient. A variety of topical and systemic drugs are available to treat dry eye. Conventional treatments are limited to tear supplementation or improvement of ocular surface inflammation by the use of corticosteroids or cyclosporine A. Treatment of severe dry eye associated with Sjogren's syndrome (SS) is even more challenging and is designed to improve the quality and quantity of tear fluid. Diquafosol tetrasodium , a P2Y2 purinergic receptor agonist, acts via a novel mechanism by activating P2Y2 receptors of the ocular surface. AREAS COVERED: The aim of this review is to summarize the pharmacokinetics, and pharmacological and clinical data of 3% diquafosol tetrasodium ophthalmic solution in patients with dry eye, particularly SS. The mechanisms of impaired ocular surface due to severe dry eye, as defined by the International Dry Eye Workshop, are analyzed. EXPERT OPINION: Diquafosol tetrasodium provides a novel mode of action in dry eye syndrome, including SS, by stimulating the quantity and quality of tear fluid secretion via various mechanisms. In clinical trials, 3% Diquafosol tetrasodium ophthalmic solution demonstrated a good safety profile and exhibited efficacy with clinical improvement of the ocular surface in dry eye including SS. PMID- 24797484 TI - Uric acid levels decrease with fibrosis progression in patients with nonalcoholic fatty liver disease. PMID- 24797485 TI - Treatment adherence in patients with headache. PMID- 24797486 TI - Cochrane, and the truth about gabapentin for migraine. PMID- 24797487 TI - Parenteral treatment of episodic tension-type headache. Is there sufficient evidence? PMID- 24797488 TI - Parenteral treatment of episodic tension-type headache: is there sufficient evidence? A response. PMID- 24797489 TI - Headache in HIV-infected patients: much to consider. PMID- 24797490 TI - Headache toolbox. Behavioral and other nonpharmacologic treatments for headache. PMID- 24797491 TI - Robust trans-amide helical structure of oligomers of bicyclic mimics of beta proline: impact of positional switching of bridgehead substituent on amide cis trans equilibrium. AB - Because homooligomers of 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acid, a bridged beta-proline analogue with a substituent installed at the remote C4 bridgehead position, completely biased the amide cis-trans equilibrium to the cis amide structure, we expected that introduction of a substituent at the C1 bridgehead position adjacent to the carboxylic acid moiety, rather than the remote C4-bridgehead position, would tip the cis-trans amide equilibrium toward trans-amide structure without the aid of hydrogen bonding. Thus, in this work we established an efficient synthetic route to an optically active bicyclic analogue of 1,1-disubstituted beta-proline, bearing a substituent at the C1-bridgehead position. Crystallographic, spectroscopic, and computational studies showed that indeed oligomers of this analogue take a consistent helical structure involving all-trans-amide linkages, independently of the number of residues, from the dimer up to the octamer. Oligomers composed of (R)-beta-amino acid units form an extended left-handed helix with about 2.7 residues per turn and an approximately 4.0 A rise per residue, characterized by complete lack of main-chain hydrogen bonding. This unique helical structure shows some similarity in shape to the trans-amide-based polyproline II (PPII) helix. The present helix was stable in various kinds of solvents such as alcohols. The present work provided a fundamental structural basis for future applications. PMID- 24797492 TI - Validity of and interrater agreement on the LINNEAUS Euro-PC medication safety incident classification system in primary care in Poland. AB - INTRODUCTION: Medication safety incidents occur in all health care sectors and cause considerable morbidity and mortality, with 8.5% of all related incidents reported estimated to occur in primary care. A common incident classification system could facilitate collective learning from the analysis of medication related errors and improve patient safety OBJECTIVE: The objective of this study was to assess the validity of a new classification system of medication safety incidents in primary care in Poland. METHODS: Analysis of data from a descriptive, cross-sectional, self-reported survey on the Learning from International Networks about Errors and Understanding Safety in Primary Care (LINNEAUS Euro-PC) medication safety incident classification for primary care with assessment of 10 case-based clinical scenarios done by doctors and pharmacists form community-based family medicine clinics and pharmacies in Lodz. MAIN OUTCOME MEASURES: The percentages of overall agreement on judgements and a fixed-marginal multirater kappa (kappa) coefficient as statistical measures of interrater agreement for categorical items. RESULTS: The overall agreement levels were: category 1 - 86.3%; category 2 - 85.6%; category 3 - 72.1%; category 4 - 71.8%; and category 5 - 70.4%. The interrater agreement between the 15 evaluators varied as follows: category 1 fixed-marginal kappa = 0.144; category 5 fixed marginal kappa = 0.565; category 3 fixed-marginal kappa = 0.607; category 4 fixed marginal kappa = 0.634; and category 2 fixed-marginal kappa = 0.807. CONCLUSIONS: This is the first known study on levels of agreement on the perception of medication safety incidents and assessment of the validity of a related classification system in primary health care in Poland. Interrater agreement in this study was surprisingly high, but still leaves room for improvement. PMID- 24797493 TI - Regarding "The effects of an exercise and lifestyle intervention program on cardiovascular, metabolic factors and cognitive performance in middle-aged adults with type 2 diabetes: a pilot study. Can J Diabetes 2013;37:214-9". PMID- 24797494 TI - Patient perspectives on discharge from specialist type 2 diabetes care back to primary care: a qualitative study. AB - BACKGROUND: Timely access to specialist care remains a barrier for both patients with type 2 diabetes and their primary care physicians. To improve access to specialists for new patients, an efficient and appropriate discharge process is required. Consideration of patient perspectives is central to developing a smooth care transition, and currently, research in this area is limited. The aim of this study was to explore patients' expectations and experiences surrounding discharge from a specialized diabetes centre back to primary care. METHODS: A qualitative approach was used involving data from one-to-one semistructured interviews. Participants were 12 patients with type 2 diabetes who had been discharged from the Tertiary Care Diabetes Referral Centre in Ottawa, Canada. RESULTS: Participants were uncertain in their initial expectations of specialist care duration. Patients expressed that an explicit discussion of the discharge process had not occurred, and many were unclear about the reason for discharge and plans for appropriate primary care physician follow up. Patients' psychological preparedness for discharge existed on a spectrum from low to high readiness. Many articulated a desire for improved communication surrounding the discharge plan, and some wished to have input into the discharge decision. Although most described their primary care physician positively, some expressed concern over cessation of specialist care. CONCLUSIONS: It is important to prepare patients for discharge from care, and to recognize that individual patients have varying needs and preferences. Further research is warranted to develop effective interventions for improving the discharge process for patients. PMID- 24797495 TI - Once-weekly exenatide as adjunct treatment of type 1 diabetes mellitus in patients receiving continuous subcutaneous insulin infusion therapy. AB - OBJECTIVE: The use of once-weekly exenatide in type 2 diabetes mellitus is well supported, but little is known about its effectiveness in type 1 diabetes. The objective of this study was to determine the clinical efficacy of once-weekly exenatide on glycemic control in patients with type 1 diabetes when added to basal-bolus insulin therapy. METHODS: For this retrospective study, patients with type 1 diabetes, aged 18 years and older, receiving continuous subcutaneous insulin infusion, using a continuous glucose monitoring device or regularly measuring blood glucose levels and receiving 2 mg of exenatide once weekly for at least 3 months were included. Demographic information, glycated hemoglobin (A1C), body weight, body mass index, systolic and diastolic blood pressures, total daily insulin dose, basal and bolus insulin doses, 28-day continuous subcutaneous insulin infusion glucose average and incidence of hypoglycemia were collected at baseline and 3 months after beginning therapy with once-weekly exenatide. RESULTS: An electronic medical record search identified 11 patients with type 1 diabetes who met the inclusion criteria. Comparing baseline and 3 months after initiation of once-weekly exenatide revealed reductions of 0.6% in A1C (p=0.013), 3.7% in body weight (p=0.008), 1.7 kg/m(2) in body mass index (p=0.003), 13% in total daily insulin dose (p=0.011) and 9.3 units in bolus insulin dose (p=0.015). CONCLUSIONS: This study revealed that the addition of once-weekly exenatide to insulin therapy for type 1 diabetes patients leads to significant improvements in A1C, body weight, body mass index and insulin doses. PMID- 24797496 TI - How to offer culturally relevant type 2 diabetes screening: lessons learned from the South asian diabetes prevention program. AB - The literature on diabetes mellitus in the South Asian population clearly states the high-risk status of this group, yet there is a lack of effective models of culturally relevant, community-based screening and education programs for such a group. The South Asian Diabetes Prevention Program (SADPP) was developed to enhance equitable access to diabetes prevention resources for the South Asian communities in Toronto by offering language-specific and culturally relevant services. The SADPP model works through 3 participant education sessions plus an additional attachment and enrolment component. The screening tool that SADPP uses to provide participants with their individual risk score at the first education session is derived from the multiculturally validated Canadian Diabetes Risk Assessment Questionnaire (CANRISK), which has been modified to reflect the distinctive characteristics of the South Asian population. After analyzing the risk scores, 32% of participants were at increased risk, 40% were at high risk, 21% were at very high risk and only 7% were found to be at low risk of diabetes development. Evaluations of the program conducted in 2010 and 2013 revealed that the program is achieving its objectives and that participants increase their knowledge and self-efficacy related to diabetes prevention after program participation. Participants reported that the presentation from the nurse and dietitian, the question-and-answer time, the healthy eating demonstration, the multiple languages of delivery and the convenient location were especially beneficial. Those working in the field are encouraged to adapt this model and to contribute to the development of culturally relevant, community-driven diabetes prevention programs. PMID- 24797497 TI - The ethics of hepatitis C "treatment as prevention" among prisoners. PMID- 24797498 TI - Clinical application evaluation of two fourth-generation human immunodeficiency virus (HIV) screening assays in West China Hospital. AB - BACKGROUND: Fourth-generation human immunodeficiency virus (HIV) screening assays have been used in many laboratories. The Elecsys(r) HIV combi PT assay is a new kind of fourth-generation HIV screening assay developed to allow earlier detection of seroconversion. METHODS: A total of 271,845 routine specimens were detected using the Elecsys(r) HIV combi assay and Elecsys(r) HIV combi PT assay from September 2010 to December 2012 in a large university hospital. Repeatedly, reactive screening samples were confirmed according to recommended confirmatory algorithms. RESULTS: The false-positive rate and positive predictive value (PPV) of two assays are 0.08 and 78.35%, respectively, for the Elecsys(r) HIV combi assay and 0.07 and 82.21% for the Elecsys(r) HIV combi PT assay. Ninety-four percent cases with cutoff index ratio <15.0 were false-positive. When we set the specificity as 95.0 and 99.0%, PPV could increase to 98.7, 99.6, 98.8, and 99.7%, and sensitivity reduced to 99.2, 98.4, 98.5, and 96.8% for the Elecsys(r) HIV combi assay and the Elecsys(r) HIV combi PT assay, respectively. CONCLUSIONS: The Elecsys(r) HIV combi PT assay shows a better performance in specificity than the Elecsys(r) HIV combi assay. Most weakly reactive results were false-positive, this means it still need to be improved and it will need laboratory personnel to communicate with the clinical doctor and patients more properly about the result of the assay. PMID- 24797499 TI - Prophylactic and therapeutic effects of Acanthopanax senticosus Harms extract on murine collagen-induced arthritis. AB - Evidences are accumulating that extract of Acanthopanax senticosus Harms (ASH; syn Eleutherococcus senticosus [Rupr. & Maxim.] Maxim), a shrub native to Northeastern Asia, has antiinflammatory effects. In this study, we examined prophylactic and therapeutic effects of ASH extract (ASHE) on rheumatoid arthritis using collagen-induced arthritis (CIA) mouse model. Acanthopanax senticosus Harms extract was administered before the onset of arthritis in the prophylaxis model. In the therapeutic model, ASHE was administered after the onset of arthritis with or without anti-TNF-alpha antibody. The ASHE treatment showed efficacy before onset of CIA but there was no effect after CIA was established. The ASHE treatment delayed the onset and decreased severity of CIA. In vitro examinations showed that ASHE is an antioxidant and that ASHE suppresses TNF-alpha and interleukin-6 production in human peripheral blood mononuclear cells. The combination therapy with ASHE and anti-TNF-alpha antibody reduced the severity of arthritis compared with anti-TNF-alpha antibody alone. The present study shows that ASHE has prophylactic effect against CIA and support therapeutic effect of anti-TNF-alpha antibody. PMID- 24797501 TI - Interaction of a hydrophobic-functionalized PAMAM dendrimer with bovine serum albumin: thermodynamic and structural changes. AB - The interaction between a hydrophobic-functionalized PAMAM dendrimer (PAMAM-NH2 C12, 25%, G4) and bovine serum albumin (BSA) has been investigated by circular dichroism (CD), UV-vis, and fluorescence spectroscopic methods and molecular modeling. The analysis of the effects of dendrimer complexation on the stability and conformation of BSA indicated that the binding process of the hydrophobic functionalized dendrimer with BSA induced the relatively large changes in secondary structure of protein. Thermal denaturation of BSA, when carried out in the presence of dendrimer, also indicated that this hydrophobic-functionalized dendrimer acted as a structure destabilizer for BSA. The hydrophobic, electrostatic, and hydrogen bonding forces played important roles in the complex formation. The putative binding site of PAMAM-NH2-C12 (25%) dendrimer on BSA was near to domain I and domain II. The effect of hydrophobic modification on the stability and structure of BSA would find useful information on the cytotoxicity of PAMAM dendrimer. PMID- 24797500 TI - Exogenous IGF-1 promotes hair growth by stimulating cell proliferation and down regulating TGF-beta1 in C57BL/6 mice in vivo. AB - OBJECTIVE: Insulin-like growth factor 1 (IGF-1) increases the growth of cultured hair follicles and plays a role in regulating hair migration during the development of hair follicles in transgenic mice. However, the exogenous effect of IGF-1 on hair growth in wild-type mice has not been reported. In the present study, we examined whether IGF-1 was an important regulator of hair follicle growth in wide-type mice in vivo. DESIGN: C57BL/6 mice were injected with different concentrations of IGF-1 on dorsal skin. The treated tissues were analyzed by immunoassay methods for TGF-beta1 and BrdU. RESULTS: Local injection of IGF-1 increased hair follicle number and prolonged the growing phase during the transition from anagen to telogen. Meanwhile, immunology analyses revealed that IGF-1 also stimulated the proliferation of follicle cells in anagen of the matrix and down regulated TGF-beta1 expression in hair follicles. CONCLUSIONS: These observations suggest that IGF-1 is an effective stimulator of hair follicle development in wide-type mice in vivo and may be a promising drug candidate for baldness therapy. PMID- 24797502 TI - Locoregional and free flap reconstruction of the lateral skull base. AB - Lateral temporal bone reconstruction after ablative surgery for malignancy, chronic infection, osteoradionecrosis, or trauma presents a challenge for the reconstructive surgeon. This complexity is due to the 3D nature of the region, potential dural exposure, and the possible need for external surface repair. Successful reconstruction therefore requires achieving separation of the dura, obliteration of volume defect, and external cutaneous repair. There is significant institutional bias on the best method of reconstruction of these defects. In this review, the advantages and disadvantages of reconstructive options will be discussed as well as the potential pitfalls and complications. PMID- 24797503 TI - Interleukin-27 mediates inflammation during chronic disease. AB - The interleukin (IL)-12 family cytokine, IL-27 has been implicated in the pathogenesis of many autoimmune inflammatory disorders, including rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, and ulcerative colitis. Discovered in 2002, IL-27 has been primarily described as an anti inflammatory cytokine with regulatory roles in multiple sclerosis and experimental autoimmune encephalitis. However, recent studies have demonstrated a pro-inflammatory function of IL-27 in both the adaptive and innate immune responses. This review will focus on the proinflammatory nature of IL-27 in chronic inflammatory skin disease and inflammatory bowel disease. PMID- 24797504 TI - A retrospective study of volume doubling time in surgically resected non-small cell lung cancer. AB - BACKGROUND AND OBJECTIVE: Volume doubling time (VDT) contributes to the evaluation of the indeterminate pulmonary nodule, an increasingly frequent problem given the rising use of computed tomography (CT). We aimed to correlate patient and tumour characteristics with VDT and growth rates of primary non-small cell lung cancers (NSCLC). METHODS: Surgically treated NSCLC, which underwent two or more CT scans separated by 25 or more days were studied. Tumour volume was measured using semi-automated volumetric software. VDT and growth rate (1/VDT) were correlated with patient and tumour characteristics. RESULTS: Thirty-six adenocarcinomas (AC), six squamous cell carcinoma (SCC), two large cell and two carcinoids in 46 patients had 109 eligible scans. Median VDT was 191 days (range 9435 to 2256 days); median growth rate was 0.0038 (range -0.0086 to 0.0186). Median growth rate of AC was significantly slower than SCC (0.0034 vs. 0.0103, P = 0.037). Nine AC had VDT >400 days, three of which developed distant metastases. Median growth rate of AC was faster in smokers compared with never-smokers (0.0052 vs. 0.0014, P = 0.02). Growth rate was not related to symptoms at diagnosis (P = 0.16). Less differentiated tumours tended to grow faster than more differentiated (P = 0.0038). Growth curves of 12 multi-imaged tumours conformed best with the exponential model of growth. CONCLUSIONS: NSCLC growth rate appears to be highly variable and related to histological subtype and smoking history, but not the presence of symptoms at diagnosis. Significant growth may be detected in as little as 2 months in NSCLC in smokers. Relatively slow-growing AC can metastasize. PMID- 24797505 TI - Effect of ectopic OCT4 expression on canine adipose tissue-derived mesenchymal stem cell proliferation. AB - Enhancing the proliferative capacity of mesenchymal stem cells (MSCs) is critical for increasing their therapeutic potential in a variety of diseases. We hypothesized that lentivirus-mediated overexpression of canine octamer-binding transcription factor 4 (OCT4) might influence the proliferation of canine adipose tissue-derived MSCs (cATMSCs). cOCT4-cATMSCs were generated by transducing cATMSCs with a cOCT4-lentiviral vector. Increased expression of cOCT4 was confirmed using RT-PCR and immunoblotting. Immunophenotypic characterization using flow cytometry indicated that the CD29, CD44, CD73, CD90, and CD105 surface markers were highly expressed by both cOCT4- and mock-transduced cATMSCs (mock cATMSCs), whereas the CD31 and CD45 markers were absent. We performed the osteogenic differentiation assay to evaluate the effects of cOCT4 overexpression on the osteogenic differentiation potential of cATMSCs. The results showed that cOCT4-cATMSCs had a much higher potential for osteogenic differentiation than mock-cATMSCs. Next, the proliferative capacities of cOCT4- and mock-cATMSCs were evaluated using a WST-1 cell proliferation assay and trypan blue exclusion. cOCT4 cATMSCs showed a higher proliferative capacity than mock-cATMSCs. Cell cycle analysis indicated that overexpression of cOCT4 in cATMSCs induced an increase in the proportion of cells in S and G2/M phases. Consistent with this, immunoblot analysis showed that cyclin D1 expression was increased in cOCT4-cATMSCs. In conclusion, our results indicate that lentivirus-mediated overexpression of cOCT4 increased the proliferative capacity of cATMSCs. OCT4-mediated enhancement of cell proliferation may be a useful method for expanding MSC population rapidly without loss of stemness. PMID- 24797506 TI - Heated relations: temperature-mediated shifts in consumption across trophic levels. AB - A rise in temperature will intensify the feeding links involving ectotherms in food webs. However, it is unclear how the effects will quantitatively differ between the plant-herbivore and herbivore-carnivore interface. To test how warming could differentially affect rates of herbivory and carnivory, we studied trophic interaction strength in a food chain comprised of green algae, herbivorous rotifers and carnivorous rotifers at 10, 15, 20 and 25 degrees C. We found significant warming-induced changes in feeding by both herbivorous and carnivorous rotifers, but these responses occurred at different parts of the entire temperature gradient. The strongest response of the per capita herbivore's ingestion rate occurred due to an increase in temperature from 15 to 20 degrees C (1.9 fold: from 834 to 1611 algal cells per h(-1)) and of the per capita carnivore's ingestion rate from 20 to 25 degrees C (1.6 fold: from 1.5 to 2.5 prey h(-1)). Handling time, an important component of a consumer's functional response, significantly decreased from 15 to 20 degrees C in herbivorous rotifers. In contrast, it decreased from 20 to 25 degrees C in carnivorous rotifers. Attack rates significantly and strongly increased from 10 to 25 degrees C in the herbivorous animals, but not at all in the carnivores. Our results exemplify how the relative forces of top-down control exerted by herbivores and carnivores may strongly shift under global warming. But warming, and its magnitude, are not the only issue: If our results would prove to be representative, shifts in ectotherm interactions will quantitatively differ when a 5 degrees C increase starts out from a low, intermediate or high initial temperature. This would imply that warming could have different effects on the relative forces of carnivory and herbivory in habitats differing in average temperature, as would exist at different altitudes and latitudes. PMID- 24797507 TI - Lesion Explorer: a video-guided, standardized protocol for accurate and reliable MRI-derived volumetrics in Alzheimer's disease and normal elderly. AB - Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimer's disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests(1,2). However, LE's accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs. LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizer's manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors. While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LE's manual procedures. PMID- 24797508 TI - Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. AB - C-type lectin DC-SIGN receptor, encoded by CD209, plays a key role in the infection of dendritic cells by dengue virus (DENV). Because the -336A/G SNP (rs4804803) polymorphism in the promoter of CD209 modulates DC-SIGN expression, we investigated the putative association of this polymorphism with DENV infection and its pathogenesis. A control sample of 72 individuals, rigorously selected through a clinical investigation for absence of past dengue fever (DF) was compared to a sample of 168 patients (156 classical DF; 12 dengue hemorrhagic fever), all residents from Para, Brazil. However, the prevalence of symptoms showed a trend higher in the AA genotype (Wilcoxon test; Z=2.02; p=0.04). Hence, our findings indicate that the G allele downregulates the spectrum of symptoms during the early acute phase of DENV infection, putatively decreasing the viremia, as suggested in the literature. PMID- 24797509 TI - Immunologic characterization suggests reduced alloimmunization in a murine model of thalassemia intermedia. AB - BACKGROUND: Transfusion therapy remains a mainstay of treatment for patients with thalassemia major and to a lesser extent for the less anemic patients with thalassemia intermedia. We have previously reported a role for regulatory T cells (Tregs) in the control of antibody responses in wild-type C57BL/6 (WT) mice exposed to allogeneic red blood cell transfusions. As an initial step to study and characterize immune regulation in thalassemias, we performed an immunologic cell-type characterization of C57BL/6 Hbb(th-1)/Hbb(th-1) mouse model of thalassemia intermedia (Thal) in steady state as well as after transfusions with allogeneic blood. STUDY DESIGN AND METHODS: The myeloid and lymphocyte compartments including Tregs and T helper (Th) responses were analyzed in transfusion naive Thal and WT mouse spleens. The effect of allogeneic transfusions on Treg and global T helper responses was also measured. RESULTS: We found elevated levels and activity of splenic Tregs in Thal mice with lower Th type 1/Th type 2 ratios before as well as after transfusion. Furthermore, pretransfused Thal mice had altered ratios of the splenic myeloid compartment with increased proportion of macrophages but lower frequency of conventional dendritic cells. Surprisingly, transfusions resulted in lower alloimmunization levels in Thal compared to WT mice. CONCLUSION: These data suggest that this experimental model of thalassemia intermedia has an intrinsic alteration in splenic immunoregulation with an increased resistance to alloimmunization, raising the possibility that studying this animal model may help to identify potential immunoregulatory networks to inhibit alloimmunization. PMID- 24797510 TI - Addressing the path-length-dependency confound in white matter tract segmentation. AB - We derive the Iterative Confidence Enhancement of Tractography (ICE-T) framework to address the problem of path-length dependency (PLD), the streamline dispersivity confound inherent to probabilistic tractography methods. We show that PLD can arise as a non-linear effect, compounded by tissue complexity, and therefore cannot be handled using linear correction methods. ICE-T is an easy-to implement framework that acts as a wrapper around most probabilistic streamline tractography methods, iteratively growing the tractography seed regions. Tract networks segmented with ICE-T can subsequently be delineated with a global threshold, even from a single-voxel seed. We investigated ICE-T performance using ex vivo pig-brain datasets where true positives were known via in vivo tracers, and applied the derived ICE-T parameters to a human in vivo dataset. We examined the parameter space of ICE-T: the number of streamlines emitted per voxel, and a threshold applied at each iteration. As few as 20 streamlines per seed-voxel, and a robust range of ICE-T thresholds, were shown to sufficiently segment the desired tract network. Outside this range, the tract network either approximated the complete white-matter compartment (too low threshold) or failed to propagate through complex regions (too high threshold). The parameters were shown to be generalizable across seed regions. With ICE-T, the degree of both near-seed flare due to false positives, and of distal false negatives, are decreased when compared with thresholded probabilistic tractography without ICE-T. Since ICE-T only addresses PLD, the degree of remaining false-positives and false-negatives will consequently be mainly attributable to the particular tractography method employed. Given the benefits offered by ICE-T, we would suggest that future studies consider this or a similar approach when using tractography to provide tract segmentations for tract based analysis, or for brain network analysis. PMID- 24797511 TI - Necrotizing fasciitis in two patients with myelodysplastic syndrome treated with azacitidine. AB - Azacitidine is a novel agent for treating myelodysplastic syndromes (MDS). It has a relatively safe toxicity profile with very few reported skin toxicities. Patients with MDS were prone to get severe infections, especially via respiratory tract, urinary system, and bloodstream. However, necrotizing fasciitis (NF) is a relatively rare event in patients with MDS, and it is hard to diagnose early. Here, we report two MDS cases that developed NF in lower extremities while receiving azacitidine treatment. One of them survives after emergent fasciotomy along with the administration of broad-spectrum antibiotics and intravenous immunoglobulin. PMID- 24797512 TI - Clinical relevance of beta2-glycoprotein-I plasma levels in antiphospholipid syndrome (APS). AB - Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid (aPL) antibodies associated with thrombosis or pregnancy morbidity. The antibodies mainly involved in this disorder are directed against beta2-glycoprotein I (beta2-GPI). beta2-GPI plasma level is usually not reported in studies on APS, because it is not regarded as relevant to the diagnosis and prognosis of APS. Nevertheless its measurement may be important for understanding the pathophysiology of the syndrome. This review summarizes available data from the literature on plasma concentrations of beta2-GPI in patients with different antibody profiles. PMID- 24797513 TI - Three dimensional cultures: a tool to study normal acinar architecture vs. malignant transformation of breast cells. AB - Invasive breast carcinomas are a group of malignant epithelial tumors characterized by the invasion of adjacent tissues and propensity to metastasize. The interplay of signals between cancer cells and their microenvironment exerts a powerful influence on breast cancer growth and biological behavior(1). However, most of these signals from the extracellular matrix are lost or their relevance is understudied when cells are grown in two dimensional culture (2D) as a monolayer. In recent years, three dimensional (3D) culture on a reconstituted basement membrane has emerged as a method of choice to recapitulate the tissue architecture of benign and malignant breast cells. Cells grown in 3D retain the important cues from the extracellular matrix and provide a physiologically relevant ex vivo system(2,3). Of note, there is growing evidence suggesting that cells behave differently when grown in 3D as compared to 2D(4). 3D culture can be effectively used as a means to differentiate the malignant phenotype from the benign breast phenotype and for underpinning the cellular and molecular signaling involved(3). One of the distinguishing characteristics of benign epithelial cells is that they are polarized so that the apical cytoplasm is towards the lumen and the basal cytoplasm rests on the basement membrane. This apico-basal polarity is lost in invasive breast carcinomas, which are characterized by cellular disorganization and formation of anastomosing and branching tubules that haphazardly infiltrates the surrounding stroma. These histopathological differences between benign gland and invasive carcinoma can be reproduced in 3D(6,7). Using the appropriate read-outs like the quantitation of single round acinar structures, or differential expression of validated molecular markers for cell proliferation, polarity and apoptosis in combination with other molecular and cell biology techniques, 3D culture can provide an important tool to better understand the cellular changes during malignant transformation and for delineating the responsible signaling. PMID- 24797514 TI - Skeletal muscle mass and muscular function in master swimmers is related to training distance. AB - It is unknown whether or not the daily swim training distances of master swimmers (MS) affect the observed changes in skeletal muscle mass (SM) and physical function commonly associated with the aging process. Twenty-two male MS aged 52 82 years were divided into two groups based upon training distance: High MS (>3000 meters swim/session and 4.1 times/week; n=11) and moderate MS (1500-2800 meters swim/session and 3.4 times/week; n=11). Eleven age- and body mass index matched older (aged 56-80 years) men served as controls (AMC). Subjects who performed resistance training were excluded in this study. Muscle thickness (MTH) was measured by ultrasound at nine sites on the anterior/posterior aspects of the body (forearm, upper arm, trunk, thigh, and lower leg), and from this, total and segmental SM mass values were estimated. Thigh MTH (anterior:posterior mid-thigh, A50:P50) ratio was calculated to assess the site-specific thigh muscle loss. Straight and zigzag walking performance and maximum knee extension/flexion strength were also measured. Arm SM was greater for high MS and moderate MS than for AMC. Total SM index was higher for high MS than for moderate MS and AMC. A50:P50 ratio was greater for high MS than for AMC. Absolute and relative knee extension strength, but not flexion strength, was greater in high MS than in AMC. The A50:P50 ratio inversely correlated (p<0.05) with zigzag walking time, whereas relative knee extension strength positively correlated (p<0.05) with both straight and zigzag walking performance. Training distance in older MS may be an important factor for maintaining muscle mass and function in the aging process. PMID- 24797515 TI - Identification and differential distribution of CART in the small intestine depending on the diet. AB - This study was aimed at identifying and locating cocaine- and amphetamine regulated transcript (CART) in the small intestine of broilers in relation to the diet. The feeding regime of the chicks was based on diets largely consisting of maize and one of four protein sources: post-extraction soya bean meal (SBM) or non-GM seed meal - meal from traditional variety of soy seeds Glicine max (FFS) and meal from seeds of Lupinus angustifolius (LA) and Lupinus luteus L (LY). The presence of cocaine- and amphetamine-regulated transcript immunoreactive (CART IR) in the wall of the small intestine of the chicks was determined on the basis of staining patterns produced by the immunohistochemical method (IHC). CART-IR structures were found in the myenteric plexus (MP), submucosus plexus (SP), in endomucosal fibres, and fibres innervating miocytes and blood vessels in the muscularis membrane and adipocytes of the white adipose tissue (WAT) located on the perimeter of the serous membrane and single cells of the diffuse neuroendocrine system. Based on microscopic observation and result analysis, the lowest number of CART-IR structures was identified in the group that was fed the SBM-based diet. This study confirms previous observations concerning CART distribution in the gastrointestinal tract (GIT) of animal and broadens current knowledge by inclusion of chicken in the list of CART-positive species. Moreover, this work provides evidence that dietary composition can be a factor that stimulates post-prandial CART secretion in intestinal nerve structures. PMID- 24797516 TI - Structure and function of placental exchange surfaces in goodeid fishes (Teleostei: Atheriniformes). AB - The species of the family Goodeidae have evolved reproductive strategies involving intraovarian gestation, early evacuation of nearly yolk-exhausted embryos from the ovigerous tissue into the ovarian cavity, placental matrotrophy during intraluminal gestation, and the birth of highly developed fry. The inner ovarian lining becomes hypervascularized during gestational periods and functions as the maternal component of the placental association. Embryotrophic liquid is secreted by the inner ovarian epithelium into the ovarian cavity. Comparative electrophoretic analyses of embryotrophe and maternal blood serum provide evidence for the transfer of maternal serum proteins into the embryotrophe. Trophotaeniae, proctodaeal processes of the embryos, provide a surface for nutrient absorption. Endocytic activity was demonstrated by ingestion of unspecific tracer proteins in various species. Moreover, the trophotaenial absorptive cells (TACs) in Ameca splendens ingest various proteins or random copolymers conjugated to colloidal gold as well as radioiodinated proteins in a way that satisfies the criteria of receptor-mediated endocytosis. Several aminopeptidases (APs) on the surface of TACs were identified as protein binding sites as evidenced by inhibition of binding and uptake of marker proteins in the presence of AP substrates or AP inhibitors. Morphological adaptations of the embryonic circulatory system pertaining to nutrient and gas exchange were characterized. The embryonic epidermis comprises two layers of squamous cells closely underlain by a dense capillary net. Efficient gas exchange is facilitated by a thin embryotrophe-blood barrier of both the embryonic skin and the intraovarian lining. PMID- 24797517 TI - The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner. AB - The JmjC domain-containing protein JMJD3/KDM6B catalyses the demethylation of H3K27me3 and H3K27me2. JMJD3 appears to be highly regulated at the transcriptional level and is upregulated in response to diverse stimuli such as differentiation inducers and stress signals. Accordingly, JMJD3 has been linked to the regulation of different biological processes such as differentiation of embryonic stem cells, inflammatory responses in macrophages, and induction of cellular senescence via regulation of the INK4A-ARF locus. Here we show here that JMJD3 interacts with the tumour suppressor protein p53. We find that the interaction is dependent on the p53 tetramerization domain. Following DNA damage, JMJD3 is transcriptionally upregulated and by performing genome-wide mapping of JMJD3, we demonstrate that it binds genes involved in basic cellular processes, as well as genes regulating cell cycle, response to stress and apoptosis. Moreover, we find that JMJD3 binding sites show significant overlap with p53 bound promoters and enhancer elements. The binding of JMJD3 to p53 target sites is increased in response to DNA damage, and we demonstrate that the recruitment of JMJD3 to these sites is dependent on p53 expression. Therefore, we propose a model in which JMJD3 is recruited to p53 responsive elements via its interaction with p53 and speculate that JMJD3 could act as a fail-safe mechanism to remove low levels of H3K27me3 and H3K27me2 to allow for efficient acetylation of H3K27. PMID- 24797519 TI - Electrocatalytic activity of various types of h-BN for the oxygen reduction reaction. AB - The electrocatalytic activities of various types of h-BN, i.e., spin coated BN nanotubes (BNNTs) and BN nanosheets (BNNSs) and sputter deposited BN, on Au electrodes as well as those of BNNS modified glassy carbon (GC) and Pt electrodes for the oxygen reduction reaction (ORR) were examined in O2 saturated 0.5 M H2SO4 solution based on the theoretical prediction that monolayered BN on a metal substrate may act as an electrocatalyst for ORR even though bulk BN is an insulator with a wide band gap. The overpotential for ORR at Au electrodes was reduced by ca. 100, ca. 270, and ca. 150 mV by spin coating of the dispersion of BNNT and liquid exfoliated BNNS, and sputter deposition of BN, respectively, proving the theoretical prediction. On the other hand, no change in the overpotential was observed at the glassy carbon electrode with BNNS modification and the overpotential even increased at the Pt electrode, suggesting that the interaction between BN and Au plays an important role in BN becoming ORR active. PMID- 24797518 TI - Poldip2 knockout results in perinatal lethality, reduced cellular growth and increased autophagy of mouse embryonic fibroblasts. AB - Polymerase-delta interacting protein 2 (Poldip2) is an understudied protein, originally described as a binding partner of polymerase delta and proliferating cell nuclear antigen (PCNA). Numerous roles for Poldip2 have been proposed, including mitochondrial elongation, DNA replication/repair and ROS production via Nox4. In this study, we have identified a novel role for Poldip2 in regulating the cell cycle. We used a Poldip2 gene-trap mouse and found that homozygous animals die around the time of birth. Poldip2-/- embryos are significantly smaller than wild type or heterozygous embryos. We found that Poldip2-/- mouse embryonic fibroblasts (MEFs) exhibit reduced growth as measured by population doubling and growth curves. This effect is not due to apoptosis or senescence; however, Poldip2-/- MEFs have higher levels of the autophagy marker LC3b. Measurement of DNA content by flow cytometry revealed an increase in the percentage of Poldip2-/- cells in the G1 and G2/M phases of the cell cycle, accompanied by a decrease in the percentage of S-phase cells. Increases in p53 S20 and Sirt1 were observed in passage 2 Poldip2-/- MEFs. In passage 4/5 MEFs, Cdk1 and CyclinA2 are downregulated in Poldip2-/- cells, and these changes are reversed by transfection with SV40 large T-antigen, suggesting that Poldip2 may target the E2F pathway. In contrast, p21CIP1 is increased in passage 4/5 Poldip2 /- MEFs and its expression is unaffected by SV40 transfection. Overall, these results reveal that Poldip2 is an essential protein in development, and underline its importance in cell viability and proliferation. Because it affects the cell cycle, Poldip2 is a potential novel target for treating proliferative conditions such as cancer, atherosclerosis and restenosis. PMID- 24797521 TI - Outcomes after living kidney donation: what we still need to know and why. PMID- 24797520 TI - Impact of an altered PROX1 expression on clinicopathology, prognosis and progression in renal cell carcinoma. AB - The transcription factor PROX1 (prospero homeobox 1) has a critical role in the development of various organs, and has been implicated in both oncogenic and tumor-suppressive functions in human cancers. However, the role of PROX1 in the development of renal cell carcinomas (RCCs) has not yet been studied. Here, we reported that PROX1 expression was decreased in human RCC tissues compared with adjacent normal tissues. In RCC tissues, however, poorly differentiated RCC expressed higher PROX1 levels compared with well-differentiated RCC. In addition, the PROX1 immunostaining levels were positively correlated with tumor nuclear grade and lymph node metastasis. Further, high PROX1 expression indicated poor survival for patients. These findings imply that in the different developmental stages of RCC, PROX1 may exert distinct functions according to the specific microenvironment of tumor. Moreover, in vitro experiments revealed that PROX1 overexpression enhanced the proliferation and migration of RCC cells; conversely, PROX1 depletion by siRNA attenuated the proliferation and migration of RCC cells. Collectively, these observations suggest that PROX1 plays an important role in RCC development and progression, and PROX1 may be a novel target for prevention and treatment of RCC. PMID- 24797522 TI - Kidney stones and cardiovascular risk: a meta-analysis of cohort studies. AB - BACKGROUND: Recent epidemiologic evidence suggests an association between kidney stones and incident cardiovascular disease after adjusting for other cardiovascular risk factors, but results are inconsistent. STUDY DESIGN: Meta analysis of cohort studies. SETTING & POPULATION: Patients with kidney stones. SELECTION CRITERIA FOR STUDIES: Cohort studies with data for kidney stones and cardiovascular morbidity identified in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings through February 27, 2014. PREDICTOR: Kidney stones as determined by physician diagnosis, clinical coding, or self-reported scales. OUTCOMES: Cardiovascular disease, coronary heart disease (CHD), and stroke. RESULTS: 6 cohort studies that contained 49,597 patients with kidney stones and 3,558,053 controls, with 133,589 cardiovascular events, were included. Pooled results suggested that kidney stones were associated with an increased adjusted risk estimate for CHD (HR, 1.19; 95% CI, 1.05-1.35; P=0.05; n=6 cohorts) and stroke (HR, 1.40; 95% CI, 1.20-1.64; P<0.001; n=3 cohorts). In particular, kidney stones conferred HRs of 1.29 (95% CI, 1.10-1.52; n=6 cohorts) and 1.31 (95% CI, 1.05-1.65; n=4 cohorts) for myocardial infarction and coronary revascularization, respectively. Moreover, the pooled female cohorts showed a statistically significant association (HR, 1.49; 95% CI, 1.21-1.82; n=4 cohorts), whereas the male cohorts showed no association (HR, 1.15; 95% CI, 0.89-1.50; n=2 cohorts). LIMITATIONS: Results may be limited by substantial heterogeneity, likelihood of residual confounding, and paucity of studies that separately evaluated for effect modification by sex. CONCLUSIONS: Kidney stones were associated with increased cardiovascular risk, including the risk for incident CHD or stroke. There is some suggestion that the risk may be higher in women than men. Further prospective studies are needed to determine whether the association is sex specific. PMID- 24797523 TI - Prospective analysis of after-hour pages to nephrology fellows. PMID- 24797524 TI - Hepatitis C treatment in dialysis patients: is a new dawn approaching? PMID- 24797525 TI - Increased urinary albumin excretion following recovery from thrombotic thrombocytopenic purpura due to acquired ADAMTS13 deficiency. PMID- 24797526 TI - Nitric oxide-releasing quaternary ammonium-modified poly(amidoamine) dendrimers as dual action antibacterial agents. AB - Herein we describe the synthesis of nitric oxide (NO)-releasing quaternary ammonium (QA)-functionalized generation 1 (G1) and generation 4 (G4) poly(amidoamine) (PAMAM) dendrimers. Dendrimers were modified with QA moieties of different alkyl chain lengths (i.e., methyl, butyl, octyl, dodecyl) via a ring opening reaction. The resultant secondary amines were then modified with N diazeniumdiolate NO donors to yield NO-releasing QA-modified PAMAM dendrimers capable of spontaneous NO release (payloads of ~0.75 MUmol/mg over 4 h). The bactericidal efficacy of individual (i.e., non-NO-releasing) and dual action (i.e., NO-releasing) QA-modified PAMAM dendrimers was evaluated against Gram positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria. Bactericidal activity was found to be dependent on dendrimer generation, QA alkyl chain length, and bacterial Gram class for both systems. Shorter alkyl chains (i.e., methylQA, butylQA) demonstrated increased bactericidal activity against P. aeruginosa versus S. aureus for both generations, with NO release markedly enhancing overall killing. PMID- 24797527 TI - Superhydrophobic nitric oxide-releasing xerogels. AB - Superhydrophobic nitric oxide (NO)-releasing xerogels were prepared by spray coating a fluorinated silane/silica composite onto N-diazeniumdiolate NO donor modified xerogels. The thickness of the superhydrophobic layer was used to extend NO release durations from 59 to 105h. The resulting xerogels were stable, maintaining superhydrophobicity for up to 1month (the longest duration tested) when immersed in solution, with no leaching of silica or undesirable fragmentation detected. The combination of superhydrophobicity and NO release reduced viable Pseudomonas aeruginosa adhesion by >2-logs. The killing effect of NO was demonstrated at longer bacterial contact times, with superhydrophobic NO releasing xerogels resulting in 3.8-log reductions in adhered viable bacteria vs. controls. With no observed toxicity to L929 murine fibroblasts, NO-releasing superhydrophobic membranes may be valuable antibacterial coatings for implants as they both reduce adhesion and kill bacteria that do adhere. PMID- 24797528 TI - Ultrastructural organization and micromechanical properties of shark tooth enameloid. AB - The outer part of shark teeth is formed by the hard and mineral-rich enameloid that has excellent mechanical properties, which makes it a very interesting model system for the development of new bio-inspired dental materials. We characterized the microstructure, chemical composition and resulting local mechanical properties of the enameloid from teeth of Isurus oxyrinchus (shortfin mako shark) by performing an in-depth analysis using various high-resolution analytical techniques, including scanning electron microscopy, qualitative energy-dispersive X-ray spectroscopy and nanoindentation. Shark tooth enameloid reveals an intricate hierarchical arrangement of thin (50-80nm) and long (>1MUm) crystallites of fluoroapatite with a high degree of structural anisotropy, which leads to exceptional mechanical properties. Both stiffness and hardness are surprisingly homogeneous in the shiny layer as well as in the enameloid: although both tooth phases differ in structure and composition, they show almost no orientation dependence with respect to the loading direction of the enameloid crystallites. The results were used to determine the structural hierarchy of shark teeth, which can be used as a base for establishing design criteria for synthetic bio-inspired and biomimetic dental composites. PMID- 24797529 TI - Demographic structure, sex ratio and growth rates of southern bluefin tuna (Thunnus maccoyii) on the spawning ground. AB - The demographics of the southern bluefin tuna (SBT) Thunnus maccoyii spawning stock were examined through a large-scale monitoring program of the Indonesian longline catch on the spawning ground between 1995 and 2012. The size and age structure of the spawning population has undergone significant changes since monitoring began. There has been a reduction in the relative abundance of larger/older SBT in the catch since the early 2000s, and a corresponding decrease in mean length and age, but there was no evidence of a significant truncation of the age distribution. Pulses of young SBT appear in the catches in the early- and mid-2000s and may be the first evidence of increased recruitment into the spawning stock since 1995. Fish in these two recruitment pulses were spawned around 1991 and 1997. Size-related variations in sex ratio were also observed with female bias for fish less than 170 cm FL and male bias for fish greater than 170 cm FL. This trend of increasing proportion of males with size above 170 cm FL is likely to be related to sexual dimorphism in growth rates as male length-at age is greater than that for females after age 10 years. Mean length-at-age of fish aged 8-10 years was greater for both males and females on the spawning ground than off the spawning ground, suggesting that size may be the dominant factor determining timing of maturation in SBT. In addition to these direct results, the data and samples from this program have been central to the assessment and management of this internationally harvested stock. PMID- 24797530 TI - Activity-dependent and graded BACE1 expression in the olfactory epithelium is mediated by the retinoic acid metabolizing enzyme CYP26B1. AB - It is well established that environmental influences play a key role in sculpting neuronal connectivity in the brain. One example is the olfactory sensory map of topographic axonal connectivity. While intrinsic odorant receptor signaling in olfactory sensory neurons (OSN) determines anterior-posterior counter gradients of the axonal guidance receptors Neuropilin-1 and Plexin-A1, little is known about stimulus-dependent gradients of protein expression, which correlates with the functional organization of the olfactory sensory map along its dorsomedial (DM)-ventrolateral (VL) axis. Deficiency of the Alzheimer's beta-secretase BACE1, which is expressed in a DM(low)-VL(high) gradient, results in OSN axon targeting errors in a DM > VL and gene dose-dependent manner. We show that expression of BACE1 and the all-trans retinoic acid (RA)-degrading enzyme Cyp26B1 form DM-VL counter gradients in the olfactory epithelium. Analyses of mRNA and protein levels in OSNs after naris occlusion, in mice deficient in the olfactory cyclic nucleotide-gated channel and in relation to onset of respiration, show that BACE1 and Cyp26B1 expression in OSNs inversely depend on neuronal activity. Overexpression of a Cyp26B1 or presence of a dominant negative RA receptor transgene selectively in OSNs, inhibit BACE1 expression while leaving the DM(low) VL(high) gradient of the axonal guidance protein Neuropilin-2 intact. We conclude that stimulus-dependent neuronal activity can control the expression of the RA catabolic enzyme Cyp26B1 and downstream genes such as BACE1. This result is pertinent to an understanding of the mechanisms by which a topographic pattern of connectivity is achieved and modified as a consequence of graded gene expression and sensory experience. PMID- 24797531 TI - Developmental toxicity studies with atrazine and its major metabolites in rats and rabbits. AB - Atrazine (ATR), hydroxyatrazine (OH-ATR), and the three chloro metabolites of ATR (deethylatrazine [DEA], deisopropylatrazine [DIA], diaminochlorotriazine [DACT]) were evaluated for developmental effects in rats and rabbits. Three developmental toxicity studies were conducted on ATR in rats (two studies) and rabbits and a developmental toxicity study was conducted in rats for each of the four ATR metabolites DEA, DIA, DACT, and OH-ATZ. ATR administration by gavage to pregnant rats and rabbits from implantation (gestation day [GD] 6 in rat, GD 7 in rabbit) through closure of the palate (GD 15 in rat and GD 19 in rabbit) did not statistically significantly alter the incidence of developmental abnormalities or malformations at dose levels up to 100 (rat) or 75 (rabbit) mg/kg bw/day. There were no effects on developmental toxicity parameters for DEA, DIA, DACT, or OH ATR at oral dose levels up to 100, 100, 150, or 125 mg/kg bw/day, respectively, with the exception of reductions in fetal body weight by DACT and OH-ATR in the presence of decreased maternal body weight gain. ATR did not adversely affect developmental end points in a two-generation study conducted in rats exposed to dose levels up to 500 ppm (38.7 mg/kg/day) in the diet. The 500-ppm dose level resulted in significantly reduced maternal body weight gain. Overall, data show that neither ATR nor its metabolites statistically significantly affected rat or rabbit embryo-fetal development even at dose levels producing maternal toxicity. PMID- 24797533 TI - Defining the best cut-off value for lymphopenia in diffuse large B cell lymphoma treated with immuno-chemotherapy. PMID- 24797534 TI - Short communication: Viable Mycobacterium avium subspecies paratuberculosis in retail artisanal Coalho cheese from Northeastern Brazil. AB - Mycobacterium avium ssp. paratuberculosis (MAP) is the etiologic agent of paratuberculosis and it potentially plays a role in Crohn's disease. In humans, the main route of transmission of MAP might be the intake of contaminated milk and dairy products. Considering that MAP has already been detected in many types of cheese in different counties, and that Coalho cheese is an important dairy product in northeastern Brazil, the aim of this study was to report the first detection of MAP in retail Coalho cheese in Brazil by PCR and culture. Of 30 retail Coalho cheese samples, 3 (10%) amplified fragments of a similar size to that expected (626 bp) were obtained and viable MAP was recovered by culture from 1 (3.3%) sample. The DNA from the positive culture sample was sequenced and showed 99% identity with the insertion sequence IS900 deposited in GenBank. It was possible to identify the presence of MAP-specific DNA in the analyzed samples for the first time in Brazil, and to recover viable cells from retail Coalho cheese. PMID- 24797535 TI - Biodegradation of biphenyl and 2-chlorobiphenyl by a Pseudomonas sp. KM-04 isolated from PCBs-contaminated coal mine soil. AB - The biphenyl-degrading strain, Pseudomonas sp. KM-04, was isolated from polychlorinated biphenyls-contaminated soil sample obtained from the vicinity of a former coal mine. We herein report that strain KM-04 can use biphenyl as a sole carbon source, and resting cells convert biphenyl to its corresponding metabolic intermediates. Incubation of KM-04 with autoclaved mining-contaminated soil for 10 days in a slurry system reduced the levels of biphenyl and 2-chlorobiphenyl by 98.5 % and 82.3 %, respectively. Furthermore, treatment of a mine-soil microcosm with strain KM-04 for 15 days in a composting system under laboratory conditions reduced the levels of biphenyl and 2-chlorobiphenyl by 87.1 % and 68.7 %, respectively. These results suggest that KM-04 is a potential candidate for the biological removal of biphenyl and its chlorinated derivatives from polychlorinated biphenyl-contaminated mining areas. PMID- 24797536 TI - Characteristic haemodynamic changes of cirrhosis may influence the diagnosis of portopulmonary hypertension. AB - BACKGROUND & AIMS: Diagnosis of portopulmonary hypertension (POPH) is based on the presence of portal hypertension and the same haemodynamic criteria as pulmonary arterial hypertension (PAH). However, the typical hyperdynamic circulation of cirrhosis may have some impact on the diagnosis of POPH. The aim was to compare the haemodynamic pattern of the pulmonary circulation between cirrhotics and non-cirrhotics, including patients with PAH. PATIENTS AND METHODS: 600 patients with cirrhosis [male 77.5%, age 54 (47-60) years, Child A: 14.7%, B: 54.3%, C: 31%] received right heart catheterization. For comparison, 118 non cirrhotic patients [male 60%, age 64 (53-65) years] with right heart catheterization and PCWP <20 mmHg were included. Both were divided into 3 groups, A: absence of pulmonary arterial hypertension; B or intermediate group: MPAP >25 mmHg, PVR 120-240 dyn s cm(-5) and PCWP <15 mmHg (or PCWP >15 mmHg with TPG >=12 mmHg); C: pulmonary arterial hypertension (same criteria as B except PVR >=240 dyn s cm(-5) ). RESULTS: Distribution of patients with cirrhosis was A 583, B 7 and C 10. Prevalence of POPH was 1.7%. Cirrhotics had lower SVR and greater CO than non-cirrhotics (P < 0.05). Interestingly, patients with cirrhosis without PAH (groups A and B) had lower PVR (P < 0.05) when comparing with non-cirrhotics, while no differences in PVR were observed in group C. However, mean TPG was greater in group C of cirrhotics [36.6 mmHg (12.2) vs. 27.1 mmHg (10.1); P = 0.034]. CONCLUSIONS: Patients with cirrhosis have lower PVR. TPG is greater in POPH than PAH. Characteristic haemodynamic changes of cirrhosis may influence the diagnosis of POPH. PMID- 24797537 TI - Assessing the efficacy of candidate mosquito repellents against the background of an attractive source that mimics a human host. AB - Mosquito repellents are used around the globe to protect against nuisance biting and disease-transmitting mosquitoes. Recently, there has been renewed interest in the development of repellents as tools to control the transmission of mosquito borne diseases. We present a new bioassay for the accurate assessment of candidate repellent compounds, using a synthetic odour that mimics the odour blend released by human skin. Using DEET (N,N-diethyl-meta-toluamide) and PMD (p menthane-3,8-diol) as reference compounds, nine candidate repellents were tested, of which five showed significant repellency to the malaria mosquito Anopheles gambiae sensu stricto (Diptera: Culicidae). These included: 2-nonanone; 6-methyl 5-hepten-2-one; linalool; delta-decalactone, and delta-undecalactone. The lactones were also tested on the yellow fever mosquito Aedes aegypti (Stegomyia aegypti) (Diptera: Culicidae), against which they showed similar degrees of repellency. We conclude that the lactones are highly promising repellents, particularly because these compounds are pleasant-smelling, natural products that are also present in human food sources. PMID- 24797538 TI - Molecular cloning, sequence identification, and gene expression analysis of bovine ADCY2 gene. AB - Adenylyl cyclase 2 (ADCY2), a class B member of adenylyl cyclases, is important in accelerating phosphor-acidification as well as glycogen synthesis and breakdown. Given its distinct role in flesh tenderization after butchering, we cloned and sequenced the ADCY2 gene from Yanbian cattle and assessed its expression in bovine tissues. A 2947 bp nucleotide sequence representing the full length cDNA of bovine ADCY2 gene was obtained by 5' and 3' remote analysis computations for gene expression. Analyses of the putative protein sequence showed that ADCY2 had high homology among species, except with the non-mammal Oreochromis niloticus. Gene structural domain analyses in humans and rats indicated that the ADCY2 protein had no flaw; only the transmembrane domain was reduced and the CYCc structure domain was shortened. Assessment of ADCY2 expression in bovine tissues by real-time PCR showed that the highest expression was in the testes, followed by the longissimus dorsi, tensor fasciae latae, and latissimus dorsi. These data will serve as a foundation for further insight into the cattle ADCY2 gene. PMID- 24797540 TI - An exhaustive yet simple virtual screening campaign against Sortase A from multiple drug resistant Staphylococcus aureus. AB - Methicillin resistant Staphylococcus aureus (MRSA) is one of the challenging bacterial pathogen due to its acquired resistance to the beta lactam antibiotics. The Sortase A is an enzyme of Gram-positive bacteria including S. aureus to anchor surface proteins to the cell wall. Sortase A is well studied enzyme and considered as the drug target against MRSA. Sortase A plays active role in anchoring the virulence proteins on the cell wall of the Gram-positive bacteria. The inhibition of Sortase A activity results in the separation of S. aureus from the host cells and ultimately alleviation of the infection. Here, we adapted a structure-based virtual screening protocol which helped in identification of novel potential inhibitors of Sortase A. The protocol involved the docking of a chemical library of druglike compounds with the Sortase A binding site represented by multiple crystal structures. The compounds were ranked by multiple scoring functions and shortlisted for future experimental screening. The method resulted in shortlisting of three compounds as potential novel inhibitors of Sortase A out of a large chemical library. The high rankings of shortlisted compounds estimated by multiple scoring functions showed their binding potential with Sortase A. The results are proved to be a simple yet efficient choice of structure-based virtual screening. The identified compounds are druglike and show high rankings among all set protocols of the virtual screening. We hope that the study would eventually help to expedite the discovery of novel drug candidates against MRSA. PMID- 24797541 TI - Frequency of CYP2C9 and VKORC1 gene polymorphisms and their influence on warfarin dose in Egyptian pediatric patients. AB - INTRODUCTION: Warfarin is a widely used anticoagulant that shows a high inter individual variability in the dose needed to achieve target anticoagulation. In adults, common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex (VKORC1) enzymes, in addition to non-genetic factors, explain this dose variability. In children, data about warfarin pharmacogenetics are limited and inconsistent. METHODS: CYP2C9 (*2 and *3) alleles and the VKORC1 (C1173T and G-1639A) polymorphisms were studied by multiplex real time polymerase chain reaction in 41 pediatric patients who received stable warfarin maintenance dose. RESULTS: The allele frequency of the studied genes was CYP2C9*2 (0.085), CYP2C9*3 (0.12), VKORC1 1173T (0.52), and VKORC1 -1639A (0.54). In univariate analysis, patients' age, weight, and height were significantly (p < 0.0001) associated with warfarin maintenance dose. However, CYP2C9 and VKORC1 gene polymorphisms did not affect warfarin dose. In multivariate analysis, age was found to be the only significant determinant of daily warfarin maintenance dose (p = 0.045). CONCLUSION: Age was the most significant determinant of warfarin dosage in this preliminary study including Egyptian pediatric patients. Further studies involving larger numbers of children are warranted to determine the true impact of genetic factors on warfarin doses in pediatric patients. PMID- 24797543 TI - Impact of a change in antibacterial prophylaxis on bacteremia and hospitalization rates following outpatient autologous peripheral blood stem cell transplantation for multiple myeloma. AB - BACKGROUND: Levofloxacin is routinely used for the prevention of invasive bacterial infections during autologous peripheral blood stem cell transplantation (APBSCT). However, increasing rates of bacterial sepsis were noted at our institution among multiple myeloma (MM) patients undergoing outpatient APBSCT with melphalan-based chemotherapy and levofloxacin prophylaxis. We assessed the impact of a change in antibacterial prophylaxis from oral levofloxacin (Period 1) to sequential oral levofloxacin followed by ertapenem (Period 2). METHODS: Electronic medical records were reviewed to identify MM patients who underwent APBSCT in the outpatient clinic between October 2007 and April 2012. RESULTS: Over a 4.5-year period, 165 outpatient APBSCTs were eligible for the analysis. Fewer overall bacteremias occurred during Period 2 as compared with Period 1 (0.5 cases per 100 person-days vs. 2.4 cases per 100 person-days, P<0.001). In addition, fewer patients were hospitalized for neutropenic fever while receiving sequential prophylaxis (45.7% vs. 75.7% of outpatient APBSCT recipients during Periods 2 and 1, respectively; P<0.001). In Kaplan-Meier analysis, receipt of sequential prophylaxis (Period 2) was significantly associated with overall bacteremia-free survival within 30 days after the APBSCT (P<0.001). No significant differences were seen in the number of patients developing Clostridium difficile infection or ertapenem-resistant gram-negative bacteremia between study periods. CONCLUSION: In conclusion, sequential prophylaxis may effectively prevent episodes of bacteremia and hospitalizations in neutropenic MM outpatient APBSCT recipients. Prospective studies that involve larger numbers of MM patients with extended periods of follow-up are ultimately required to define the safety and efficacy of sequential antibacterial prophylaxis. PMID- 24797544 TI - Study of fluid ingress through clear corneal incisions following phacoemulsification with or without the use of a hydrogel ocular bandage: a prospective comparative randomised study. AB - PURPOSE: To assess the use of a hydrogel ocular bandage (HOB) on clear corneal incisions in phacoemulsification cataract surgery and determine whether HOB reduces ocular surface contaminants ingress after routine surgery. METHODS: In this prospective randomized controlled study, thirty eyes of patients undergoing uneventful phacoemulsification were recruited consecutively and randomly assigned to have a HOB applied to the corneal incision at the end of the surgery or not. At the end of the surgery, trypan blue (TRB) was instilled on the ocular surface, aqueous fluid was aspirated from the anterior chamber (AC) and its optical density was measured using ultraviolet spectrophotometry. The corneal incisions were examined postoperatively using anterior segment optical coherence tomography. Main outcome measures were concentration of TRB in the AC, corneal incision architecture, intraocular pressure (IOP) and Seidel test. RESULTS: All incisions were Seidel negative. The mean IOP in the immediate postoperative period was 18.1 +/- 5.48 mmHg for the intervention group and 16.9 +/- 5.7 mmHg for the control group (p > 0.05). No architectural differences of the incisions between the two groups were noted. The total mean length of the three-step corneal incisions in the two groups was 2261.2 +/- 96.92 MUm and 2263 +/- 119.75 MUm, respectively (p > 0.05). No trace of TRB was detected in any of the samples. CONCLUSION: Proper surgical wound construction without the use of a HOB is efficient in preventing the ingress of fluid through the main corneal incision postoperatively. PMID- 24797542 TI - Improving outcomes in children with sickle cell disease: treatment considerations and strategies. AB - Over the past decades there has been a significant improvement in the care of patients with sickle cell disease (SCD) in high-income countries. However, more needs to be learned about the complex pathophysiology and the factors that contribute to the development of end organ damage from the disease. While antibiotic prophylaxis and appropriate treatment of infections have resulted in a significant reduction of early mortality, management of the painful episodes and prevention of organ damage remain a challenge. Hydroxyurea is the only medication approved as disease-modifying therapy, and bone marrow transplant as curative treatment is not available to most patients. In low-income countries with the highest disease burden, early mortality is high due to limited resources for systematic screening, early diagnosis, and disease management. In order to improve outcomes in patients with SCD in high-income countries, better and widespread implementation of known disease-modifying therapies and the development of newer therapies targeting key pathophysiologic pathways are required. In low-income countries with high disease burden, innovative approaches to develop low-cost diagnostic devices and treatments that can be implemented to scale are needed to combat early mortality from the disease. Sustainable solutions in low-resource settings require evidence-based affordable interventions that can be integrated into primary and secondary healthcare systems. PMID- 24797545 TI - Delirium in the pediatric patient: On the growing awareness of its clinical interdisciplinary importance. PMID- 24797546 TI - Boron-doped carbon-iron nanocomposites as efficient oxygen reduction electrocatalysts derived from carbon dioxide. AB - Developing cost-effective oxygen reduction reaction (ORR) catalysts is pivotal for development of fuel cells. While Fe-N-C catalysts were proposed for ORR, Fe-B C catalysts have not been explored. This work introduces the B-doped carbon catalysts encapsulating iron cores using CO2 as a carbon source. The Fe-B-C catalysts show enhanced ORR activity and durability due to the iron core within the graphitic layers. PMID- 24797547 TI - Discussion. PMID- 24797548 TI - The impact of endovascular aneurysm repair on aortoiliac tortuosity and its use as a predictor of iliac limb complications. AB - OBJECTIVE: Aortoiliac tortuosity is often cited subjectively as a causative factor in iliac limb complications after endovascular aneurysm repair (EVAR); however, evidence on this subject is poor. The aim of this study was to investigate the impact of stent grafting on aortoiliac tortuosity and to explore the role of the tortuosity index (TI) as a predictor of iliac limb complications after EVAR. METHODS: A retrospective case-control study was performed comparing an iliac limb complication group with a control group. Reconstructed computed tomography angiography images were analyzed to calculate TI of the aortoiliac segments. RESULTS: This study included 153 patients, 120 in the control groups (40 Zenith flex [Cook Medical, Bloomington, Ind], 40 Endurant II [Medtronic, Minneapolis, Minn], and 40 Excluder [W. L. Gore and Associates, Flagstaff, Ariz] stent grafts) and 33 in the complications group (13 Zenith flex, 14 Endurant II, 4 Excluder, and 2 Aorfix [Lombard Medical, Oxfordshire, UK] stent grafts). There was a significant reduction in aortic and iliac TI after EVAR. This was greatest with the Zenith Flex compared with Endurant, with the least change in TI seen after Gore Excluder implantation. Iliac limb complications included 10 type Ib endoleaks, one iliac limb modular dislocation, two limbs with insufficient engagement, four occlusions, and 16 iliac limb kinks. There was no significant difference in complication rates between the three stent grafts (Zenith flex, 1.4%; Endurant, 2.9%; Excluder, 1.9%; P = .115). The median time to iliac complication was 14 months (range, 1-90 months). The iliac limb complication group was found to have a significantly increased aortoiliac TI on both preoperative and postoperative computed tomography imaging. CONCLUSIONS: EVAR has a significant effect on aortoiliac tortuosity. Despite the reduction of aortoiliac tortuosity after the insertion of a stent graft, TI may serve as a predictor of iliac limb complications after EVAR. PMID- 24797549 TI - Discussion. PMID- 24797550 TI - Impact of psychological factors on objective ambulatory measures in patients with intermittent claudication. AB - OBJECTIVE: The purpose of this study was to evaluate the difference in objective measures of ambulation and psychosocial factors in patients with intermittent claudication (IC) stratified by type D personality, which incorporates elements of social inhibition and negative affectivity. METHODS: During a 1-year period, routine history and physical examination, ankle-brachial index, and pulse volume recording were performed on IC patients. Questionnaires assessing type D personality and psychosocial factors were also collected. The 6-minute walk test (6MWT) was performed, assessing symptoms and distance walked. Univariate and multivariate methods were used to assess the association between ambulation and type D personality. RESULTS: Seventy-one patients were enrolled (mean age, 62.5 +/- 1.1 years; mean ankle-brachial index, 0.55 +/- 0.03). Mean distance to symptoms and total distance walked were 83.7 +/- 80.1 m and 206.5 +/- 126.3 m, respectively. Type D personality was present in 29.6% of the population (n = 21). On 6MWT, 83.1% of all patients developed symptoms, and 57.4% quit because of symptoms. Univariate analysis of objective measures of ambulation demonstrated lower distance to symptoms in the type D group and trends toward lower total distance walked and quitting the 6MWT. Multivariate models showed increased odds of quitting the 6MWT (odds ratio, 7.71; P = .01) and less total distance walked by an average of 33.2 +/- 13.3 m (P = .02) for the type D group. CONCLUSIONS: Despite equivalent demographic, medical, and psychosocial factors, the type D group was limited in ambulation, suggesting that type D personality is a strong predictor of disease impact in patients with IC. PMID- 24797551 TI - The effect of surgeon specialization on outcomes after ruptured abdominal aortic aneurysm repair. AB - OBJECTIVE: Although mortality after elective abdominal aortic aneurysm (AAA) repair has steadily declined, operative mortality for a ruptured AAA (rAAA) remains high. Repair of rAAA at hospitals with a higher elective aneurysm workload has been associated with lower mortality rates irrespective of the mode of treatment. This study sought to determine the association between surgeon specialization and outcomes after rAAA repair. METHODS: The American College of Surgeons National Surgical Quality Improvement Project database from 2005 to 2010 was used to examine the 30-day mortality and morbidity outcomes of patients undergoing rAAA repair by vascular and general surgeons. Multivariable logistic regression analysis was performed for each death and morbidity, adjusting for all independently predictive preoperative risk factors. Survival curves were compared using the log-rank test. RESULTS: We identified 1893 repairs of rAAAs, of which 1767 (96.1%) were performed by vascular surgeons and 72 (3.9%) were performed by general surgeons. There were no significant differences between patients operated on by general vs vascular surgeons in preoperative risk factors or method of repair. Overall 30-day mortality was 34.3% (649 of 1893). After risk adjustment, mortality was significantly lower in the vascular surgery group compared with the general surgery group (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.30 0.86; P = .011). The risk of returning to the operating room (OR, 0.58; 95% CI, 0.35-0.97; P = .038), renal failure (OR, 0.54; 95% CI, 0.31-0.95; P = .034), and a cardiac complication (OR, 0.53; 95% CI, 0.28-0.99; P = .047) were all significantly less in the vascular surgery group. CONCLUSIONS: Despite similar preoperative risk factors profiles, patients who were operated on by vascular surgeons had lower mortality, less frequent returns to the operating room, and decreased incidences of postoperative renal failure and cardiac events. These data add weight to the case for further centralization of vascular services. PMID- 24797552 TI - A new simple method of converting a retrograde femoral access to an antegrade catheterization. AB - Antegrade puncture is a routinely used technique of obtaining access to the common femoral artery to perform infrainguinal interventions. However, antegrade arterial access can be challenging in the presence of hostile, scarred groins, obesity, or a high common femoral artery bifurcation. A simple method of converting a retrograde femoral access to an antegrade catheterization using an inexpensive and universally available monofilament suture is presented. PMID- 24797554 TI - Hyperphosphatemia induces protective autophagy in endothelial cells through the inhibition of Akt/mTOR signaling. AB - OBJECTIVE: Hyperphosphatemia-induced endothelial dysfunction has been shown to play a pathogenic role in the development of atherosclerosis in chronic kidney disease (CKD) through unclear mechanisms. Emerging evidence indicates that autophagy is involved in the maintenance of normal cardiovascular function. However, it is unclear whether autophagy participates in the molecular mechanism underlying high phosphate (Pi)-induced endothelial dysfunction. METHODS: The autophagy activity was determined by the immunofluorescence staining of the expression of endothelial microtubule-associated protein 1 light chain 3 (LC3) in the 5/6 nephrectomy rat model of CKD and sham-operated control rats. The LC3 II/LC3-I ratio and the activation of the Akt/mammalian target of rapamycin (mTOR) signaling pathway were determined in cultured human microvascular endothelial cell (HMEC-1) endothelial cells that were exposed to a high concentration of Pi with or without the Pi influx blocker phosphonoformic acid, the autophagy inhibitor 3-methyladenine, and the autophagy inducer rapamycin. The impacts of autophagy on Pi-induced apoptotic damage were assessed by flow cytometry. RESULTS: The in vivo rat model of CKD revealed that hyperphosphatemia is associated with increased endothelial LC3 staining. The exposure of HMEC-1 cells to high Pi induced both dose-dependent and time-dependent increases in the LC3 II/LC3-I expression ratio accompanied by the inhibition of the Akt/mTOR signaling pathway. In HMEC-1 cells, high Pi-induced autophagy and the inhibition of Akt/mTOR signaling were reversed by phosphonoformic acid through the blockage of Pi influx. Apoptosis, characterized by the levels of cleaved caspase 3 and poly(ADP-ribose) polymerase, along with autophagy was induced by high Pi, and the inhibition of autophagy by 3-methyladenine significantly aggravated high Pi induced apoptosis. The flow cytometry results confirmed that the blockage of autophagy promoted the apoptosis of endothelial cells. CONCLUSIONS: Hyperphosphatemia induces endothelial autophagy, possibly through the inhibition of the Akt/mTOR signaling pathway, which may play a protective role against high Pi-induced apoptosis. PMID- 24797555 TI - "Off-the-shelf" devices for complex aortic aneurysm repair. AB - BACKGROUND: Fenestrated devices currently require a 3- to 4-week manufacturing period before implantation; as such, there have been efforts to develop "off-the shelf" (OTS) devices to reduce the time before definitive treatment can be accomplished. We examined all patients treated for complex aortic problems at our institution during the past 12 months to evaluate the suitability and early outcomes of the OTS devices vs commercially available endovascular options. METHODS: Between July 2012 and September 2013, patients undergoing aortic aneurysm repair were extracted from a prospectively managed aortic database. Two OTS devices, the Cook (Bloomington, Ind) p-Branch and the Endologix (Irvine, Calif) Ventana device, were being evaluated through clinical trials during this time frame. The custom Cook Zenith fenestrated endovascular (ZFEN) device was also available and approved by the U.S. Food and Drug Administration (FDA) during the study period. RESULTS: Of 224 aortic aneurysms treated at our institution during this period, there were a total of 85 patients with type IV thoracoabdominal aneurysms including juxtarenal aneurysms. Only 23 patients (27%) met anatomic criteria for OTS devices, with 16 patients having these investigational devices implanted. The major exclusion criterion for the p-Branch device was renal axial or circumferential position; the limiting factor for Ventana was infrasuperior mesenteric artery neck length restriction. Five of the patients who would have fit criteria for an OTS device had an FDA-approved (ZFEN) device implanted instead, and two patients opted for open repair as a result of follow-up requirements. An additional 25 patients received custom-designed (ZFEN) devices (n = 30; 35%), whereas 37 (44%) others did not meet criteria for any available endovascular device and were repaired with alternative management strategies. The mean age and maximal aortic diameter of the two cohorts (OTS and ZFEN) were 71.8 years and 72.7 years (P = NS) and 61.3 mm and 58.5 mm (P = NS), respectively. Technical success was 100%, with an overall 30-day mortality of 2.1% (n = 1, ZFEN). Major complications occurred in eight patients (17%; two OTS, six ZFEN). CONCLUSIONS: Whereas OTS device strategies will reduce the waiting times for patients with complex aortic aneurysmal disease, a significant number will still require custom-made device repair until additional device designs become available. Early experience with OTS devices does not demonstrate any significant renal risks; however, the treatment numbers are low and should be interpreted with caution until larger confirmatory studies are published. Further studies comparing the outcomes of these techniques are required to establish the best approach to handle endovascular repair of complex aortic aneurysm. PMID- 24797556 TI - Verbal fluency, naming and verbal comprehension: three aspects of language as predictors of cognitive impairment. AB - OBJECTIVES: To establish the possible relationship among three components of language (verbal fluency, naming and comprehension) and cognitive impairment as well as to determine the usefulness of language assessment tests to predict or monitor the development of cognitive impairment. METHOD: A comparative, descriptive and cross-sectional study was performed on 82 subjects >= 65 years of age who were cognitively assessed with the Mini Mental State Examination and were divided into two groups: Group A comprised of subjects classified as levels 1, 2 and 3 on the Reisberg's Global Deterioration Scale (GDS) and group B comprised of subjects at levels 4 and 5 of the GDS. Language skills were assessed by the Verbal Fluency Test, Boston Naming Test and Token Test. RESULTS: An inverse relationship between performance on language tests and cognitive impairment level was observed with a more pronounced effect observed on fluency and comprehension tests. CONCLUSION: Language assessments, especially fluency and comprehension, were good indicators of cognitive impairment. The use of these assessments as predictors of the degree of cognitive impairment is discussed in-depth. PMID- 24797553 TI - Impact of statin therapy on patients with coronary heart disease and aortic aneurysm or dissection. AB - OBJECTIVE: The impact of statin therapy on cardiovascular outcome in coronary artery disease (CAD) patients with aortic aneurysm or dissection (AD) is still unclear. The aim of this study was to elucidate the effect of statins at discharge to improve outcomes in CAD patients with AD. METHODS: Among 14,834 consecutive patients who underwent first coronary revascularization in the CREDO Kyoto PCI/CABG registry, we identified 699 patients (4.7%) with AD. The primary outcome measure was defined as a composite of all-cause death, myocardial infarction, and stroke. The effect of statin therapy was assessed by a Cox proportional hazards model incorporating clinically relevant factors. RESULTS: The risk for the primary outcome measure was significantly higher in patients with AD (adjusted hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.23 1.66; P < .0001). In patients with AD, 215 patients (31%) had already undergone aneurysm repair, and only 274 patients (39%) were treated with statins at discharge. Patients treated with statins were younger, had higher body mass index, and were more often treated with percutaneous coronary intervention. Heart failure, anemia, and hemodialysis were more prevalent in patients treated without statins. In patients without AD, 7014 patients (50%) were treated with statins. Patients treated with statins were younger and had higher body mass index, and more patients were treated for CAD due to myocardial infarction. Heart failure, prior stroke, hemodialysis, anemia, and malignant disease were more prevalent in patients treated without statins. The use of statins was associated with lower risk for the primary outcome measure in patients with AD (adjusted HR, 0.71; 95% CI, 0.51-0.99; P = .045) as well as in patients without AD (adjusted HR, 0.79; 95% CI, 0.73-0.85; P < .0001). The effect size of statin use was similar between the patients with AD and those without AD (P interaction = .69). CONCLUSIONS: CAD patients with AD had significantly higher long-term risk for cardiovascular events. Statin therapy was associated with lower risk for cardiovascular events in patients with CAD with AD as well as in patients without AD. PMID- 24797557 TI - Characteristics of sugar surfactants in stabilizing proteins during freeze thawing and freeze-drying. AB - Sugar surfactants with different alkyl chain lengths and sugar head groups were compared for their protein-stabilizing effect during freeze-thawing and freeze drying. Six enzymes, different in terms of tolerance against inactivation because of freeze-thawing and freeze-drying, were used as model proteins. The enzyme activities that remained after freeze-thawing and freeze-drying in the presence of a sugar surfactant were measured for different types and concentrations of sugar surfactants. Sugar surfactants stabilized all of the tested enzymes both during freeze-thawing and freeze-drying, and a one or two order higher amount of added sugar surfactant was required for achieving protein stabilization during freeze-drying than for the cryoprotection. The comprehensive comparison showed that the C10-C12 esters of sucrose or trehalose were the most effective through the freeze-drying process: the remaining enzyme activities after freeze-thawing and freeze-drying increased at the sugar ester concentrations of 1-10 and 10-100 MUM, respectively, and increased to a greater extent than for the other surfactants at higher concentrations. Results also indicate that, when a decent amount of sugar was also added, the protein-stabilizing effect of a small amount of sugar ester through the freeze-drying process could be enhanced. PMID- 24797558 TI - Modelling inborn errors of metabolism in zebrafish. AB - The majority of human inborn errors of metabolism are fatal multisystem disorders that lack proper treatment and have a poorly understood mechanistic basis. Novel technologies are required to address this issue, and the use of zebrafish to model these diseases is an emerging field. Here we present the published zebrafish models of inborn metabolic diseases, discuss their validity, and review the novel mechanistic insights that they have provided. We also review the available methods for creating and studying zebrafish disease models, advantages and disadvantages of using this model organism, and successful examples of the use of zebrafish for drug discovery and development. Using a zebrafish to model inborn errors of metabolism in vivo, although still in its infancy, shows promise for a deeper understanding of disease pathomechanisms, onset, and progression, and also for the development of specific therapies. PMID- 24797559 TI - Mitochondrial transporters of the SLC25 family and associated diseases: a review. AB - To date, 14 inherited diseases (including phenotypes) associated to mitochondrial transporters of the SLC25 family have been well characterized biochemically and genetically. They are rare metabolic disorders caused by mutations in the SLC25 nuclear genes that encode mitochondrial carriers, a superfamily of 53 proteins in humans that shuttle a variety of solutes across the mitochondrial membrane. Mitochondrial carriers vary considerably in the nature and size of the substrates they transport, the modes of transport and driving forces. However, their substrate translocation mechanism at the molecular level is thought to be basically the same. Herein, the main structural and functional properties of the SLC25 mitochondrial carriers and the known carrier-related diseases are presented. Two of these disorders, ADP/ATP carrier deficiency and phosphate carrier deficiency, are caused by defects of the two mitochondrial carriers that provide mitochondria with ADP and phosphate, the substrates of oxidative phosphorylation; these disorders therefore are characterized by defective energy production by mitochondria. The mutations of SLC25 carrier genes involved in other cellular functions cause carnitine/acylcarnitine carrier deficiency, HHH syndrome, aspartate/glutamate isoform 1 and 2 deficiencies, congenital Amish microcephaly, neuropathy with bilateral striatal necrosis, congenital sideroblastic anemia, neonatal epileptic encephalopathy, and citrate carrier deficiency; these disorders are characterized by specific metabolic dysfunctions depending on the role of the defective carrier in intermediary metabolism. PMID- 24797560 TI - Pharmacochemistry and integrated pharmacokinetics of six alkaloids after oral administration of huang-lian-jie-du-tang decoction. AB - Pharmacochemistry and integrated pharmacokinetics of six alkaloids (groenlandicine, berberine, palmatine, epiberberine, jatrorrhizine, and columbamine) after oral administration of Huang-Lian-Jie-Du-Tang (HLJDT) decoction were investigated in this paper. The method of plasma pharmacochemistry was applied to predict the potential bioactive components in HLJDT decoction. Based on the accurate molecular weight, 10 components including 2 flavonoids (baicalin and wogonoside), 1 iridoid glycoside (geniposide), and 7 alkaloids (above-mentioned 6 alkaloids and coptisine) were structurally identified. Then, integrated pharmacokinetics of the alkaloids in Sprague-Dawley rats after oral administration of HLJDT decoction was investigated by HPLC method. The results showed that the pharmacokinetic behaviors of the alkaloids were different although their chemical structures were similar. This study developed a method to predict the potential bioactive components in HLJDT decoction and research the pharmacokinetic behaviors of the potential bioactive components. PMID- 24797561 TI - Preliminary investigation of an SOI-based arrayed waveguide grating demodulation integration microsystem. AB - An arrayed waveguide grating (AWG) demodulation integration microsystem is investigated in this study. The system consists of a C-band on-chip LED, a 2 * 2 silicon nanowire-based coupler, a fiber Bragg grating (FBG) array, a 1 * 8 AWG, and a photoelectric detector array. The coupler and AWG are made from silicon-on insulator wafers using electron beam exposure and response-coupled plasma technology. Experimental results show that the excess loss in the MMI coupler with a footprint of 6 * 100 MUm(2) is 0.5423 dB. The 1 * 8 AWG with a footprint of 267 * 381 MUm(2) and a waveguide width of 0.4 MUm exhibits a central channel loss of -3.18 dB, insertion loss non-uniformity of -1.34 dB, and crosstalk level of -23.1 dB. The entire system is preliminarily tested. Wavelength measurement precision is observed to reach 0.001 nm. The wavelength sensitivity of each FBG is between 0.04 and 0.06 nm/dB. PMID- 24797563 TI - Highly water-soluble, porous, and biocompatible boron nitrides for anticancer drug delivery. AB - Developing materials for "Nano-vehicles" with clinically approved drugs encapsulated is envisaged to enhance drug therapeutic effects and reduce the adverse effects. However, design and preparation of the biomaterials that are porous, nontoxic, soluble, and stable in physiological solutions and could be easily functionalized for effective drug deliveries are still challenging. Here, we report an original and simple thermal substitution method to fabricate perfectly water-soluble and porous boron nitride (BN) materials featuring unprecedentedly high hydroxylation degrees. These hydroxylated BNs are biocompatible and can effectively load anticancer drugs (e.g., doxorubicin, DOX) up to contents three times exceeding their own weight. The same or even fewer drugs that are loaded on such BN carriers exhibit much higher potency for reducing the viability of LNCaP cancer cells than free drugs. PMID- 24797564 TI - Intensity of gadolinium enhancement on MRI is useful in differentiation of intracochlear inflammation from tumor. AB - OBJECTIVE: Magnetic resonance imaging is the gold standard in retrocochlear imaging; however, its role in management of inner ear diseases remains poorly defined. In this study, we investigate the utility of MRI in defining the nature of intracochlear pathology. STUDY DESIGN: A retrospective review of 11 patients with inner ear abnormalities on MRI between 2010 and 2013. Patients' diagnosis included cholesteatoma, labyrinthitis, meningitis, and intralabyrinthine schwannoma. SETTING: Tertiary care hospital. MAIN OUTCOME MEASURES: T1, T2, and postcontrast signal intensities were measured within the lesion and normalized in reference to the contralateral normal cochlea. The following ratios were calculated: T1 postgadolinium lesion/contralateral cochlea, T2 lesion/contralateral cochlea and T1 lesion/contralateral cochlea. Statistical analysis was conducted using the unpaired Student's t test using IBM SPSS Statistics version 20.0.0. RESULTS: The relative intensity ratios were useful in defining the nature of inner ear lesion. Normalized T1 postgadolinium lesion intensities were significantly higher in the tumor group (3.98 +/- 0.880 versus 1.71 +/- 0.370, p < 0.0002). Normalized T1 precontrast signal intensities were higher in tumors (1.33 +/- 0.200 versus 0.842 +/- 0.426, p < 0.0626), and T2 values were lower in tumors (0.838 +/- 0.491 versus 1.10 +/- 0.305, p < 0.317); however, these did not reach significance. CONCLUSION: Intensity of gadolinium enhancement on MRI is useful in differentiation of inflammation from tumors; normalized T1 postgadolinium intensity ratio greater than 3 is strongly suggestive of intralabyrinthine tumor. PMID- 24797562 TI - Short-segment fixation through a limited ilioinguinal approach for treating anterior acetabular fractures: a historical-control study. AB - PURPOSE: We evaluated the potential advantages of short-segment fixation of certain anterior acetabular fracture patterns through a limited ilioinguinal approach. METHODS: Two patient groups were studied. The first group comprised 22 patients (20 men, two women; average age 36 years) treated using the short segment fixation protocol through a limited ilioinguinal approach. We modified the use of short pelvic brim plates, spring plates and posterior-column screws as reduction and fixation tools (leaving the distal end of the fracture unfixed) to keep the dissection entirely lateral to the iliac vessels. The second (control) group comprised 31 patients with matched fracture patterns fixed through the standard ilioinguinal approach. All patients were followed up for a minimum of two years. The estimated amount of blood loss (primary outcome measure), operative time, postoperative radiographic assessment of reduction quality and functional score assessment (secondary outcome measures) were compared between groups. RESULTS: The short-segment-fixation group had significantly less blood loss (p < 0.0001) and shorter operative time (p = 0.002) compared with the control group. However, there were no significant differences in the quality of fracture reduction and functional scores between groups at the final follow-up. No major complications were encountered in either group. CONCLUSION: Short segment fixation through a limited ilioinguinal approach is a safe and effective alternative for treating certain patterns of anterior acetabular fractures. Decreased blood loss and shorter operative time with less soft tissue dissection are the main advantages of this approach. PMID- 24797565 TI - Otogenic Brain Abscess Mimicking as Stroke. PMID- 24797566 TI - Safety, efficacy, and hearing preservation using an integrated electro-acoustic stimulation hearing system. AB - OBJECTIVE: To determine the safety, efficacy, and potential for hearing preservation of an electroacoustic hearing system in patients with severe high frequency and moderate low-frequency hearing loss. PATIENTS: Five patients were included in this study with steeply down-sloping sensorineural hearing loss. All patients had a history of hearing aid use and similar hearing in the contralateral ear. Ages ranged from 48 to 69 years. INTERVENTION: All participants were implanted with an electro-acoustic stimulation (EAS) device using a hearing preservation technique. This device integrates electric and acoustic stimulation into a single processor for simultaneous ipsilateral bimodal stimulation. MAIN OUTCOME MEASURE(S): Pure-tone audiograms (PTA) and speech reception thresholds (SRTs) during preoperative evaluation; initial cochlear implant (CI) stimulation; initial EAS stimulation; and at 3, 6, and 12 months poststimulation. Consonant-Nucleus-Consonant (CNC) monosyllables preoperatively and at 3, 6, and 12 months poststimulation. RESULTS: All participants showed preserved hearing in the surgical ear after implantation as measured by PTA and SRT. Significant improvement in speech recognition testing over hearing aid was observed at 3 months with EAS versus 6 months with CI-only stimulation. Facial stimulation occurred in 1 patient and resolved after reprogramming. CONCLUSION: There were no significant complications in this cohort of patients. Adequate hearing preservation was achieved. EAS and CI aided conditions both showed significant improvement over hearing aid with EAS condition achieving significance sooner. PMID- 24797567 TI - Contribution of nonimplanted ear to pitch perception for prelingually deafened cochlear implant recipients. AB - INTRODUCTION: Bimodal stimulation (BMS) has been shown to be beneficial for the performance of pitch ranking in postlingually deafened adults. However, the contribution of nonimplanted ears to pitch perception with respect to duration of hearing aid (HAs) use for prelingually cochlear implantees remained unclear. This study aimed to investigate whether experiences/duration of HAs use in the nonimplanted ear improved pitch perception ability in this population of subjects. MATERIALS AND METHODS: Twenty-nine children with congenital/prelingual deafness of profound degree were studied. Test stimuli consisted of 2 sequential piano tones, ranging from C (256 Hz) to B (495 Hz). Children were asked to identify the pitch relationship between the 2 tones (i.e., same, higher, or lower). RESULTS: Duration of HAs use was the major factor related to the correct rate for pitch perception. Overall correct rate for pitch perception (O) could be best predicted by duration of HAs use (DuA) (O = 0.561XDuA, r = 0. 315, p = 0.002). DISCUSSION: Experiences of HAs use appear to improve pitch perception ability in prelingually cochlear implantees. This suggests that incorporation of HAs use early in life and through the postoperative rehabilitation program for prelingually deafened children with cochlear implants would be beneficial, although an association does not guarantee causality. A longitudinal study is needed to show whether improvement of music performance with duration of HAs use in these children is measurable using auditory evoked potentials. PMID- 24797568 TI - Stitchless fibrin glue-aided facial nerve grafting after cerebellopontine angle schwannoma removal: technique and results in 15 cases. AB - AIM OF THE STUDY: To evaluate the results of facial nerve (FN) grafting using great auricular cable graft and fibrin glue without suturing to palliate FN disruption after removal of large cerebellopontine angle (CPA) vestibular schwannoma (VS) or facial nerve schwannoma (FNS). To assess whether tumor size and origin influenced the results. STUDY DESIGN AND SETTING: Retrospective review of all patients having undergone removal of FNS/VS and needing intraoperative FN repair between 2001 and 2011. INTERVENTION: FN was rehabilitated using great auricular nerve cable graft and fibrin glue (Tisseal) without stitching suture. MAIN OUTCOME MEASURES: All data recorded were reviewed to access age, sex, tumor type, and tumor size according to the Koos classification and presenting symptoms. FN function was evaluated preoperatively and at 18 months using the House-Brackmann (HB) grading system. RESULTS: Among the 595 patients operated for CPA schwannomas in this period, 15 patients (2.5%) underwent FN repair, including 7 cases of FNS and 8 cases of VS. Tumor removal was total in all cases. FN recovery was HB3 in 13 cases (86.7%) and HB4 in 2. The mean time to the first clinical signs of facial reinnervation was 10 months (6-12 mo). No significant relation was found between postoperative facial function and tumor size or type, even if all cases of preoperative FP were noted in FNS. CONCLUSION: Immediate FN reconstruction with fibrin glue-aided greater auricular nerve graft can effectively restore FN function with excellent outcomes. The results seem better than those observed by other authors using sutured grafts or delayed hypoglossal facial nerve anastomosis. PMID- 24797569 TI - A national survey of facial paralysis on the quality of life of patients with acoustic neuroma. AB - OBJECTIVE: The aim of this survey was to objectively quantify the impact of facial palsy on the quality of life of acoustic neuroma patients. METHODS: The Facial Clinimetric Evaluation (FaCE) Scale was emailed to all members of the British Acoustic Neuroma Association (BANA). RESULTS: Of the 880 BANA members contacted, 398 (45.2%) responded, of which, 178 indicated that they had facial paralysis. Surgery for acoustic neuroma accounted for 80% of facial paralysis. Treatment received for facial palsy varied considerably, although 33% reported not receiving any treatment. The commonest single treatment modality wads facial electrical stimulation (41%), followed by facial physiotherapy (39%). The most common surgical procedures were to the eye lid (50%), followed by nerve graft (12%), forehead lift (10%), muscle sling (9%), and face lift (9%). The overall mean total FaCE Scale score was 54.8 (range, 10-100, standard deviation [SD] 21.2). Both facial movement and eye comfort domains had the lowest mean scores of 41.3 (SD, 29.9) and 41.2 (SD 32.6) respectively. The mean total FaCE Scale score of female respondents was statistically lower (p = 0.03) than males (52.6 (SD 21.2) versus 58.8 (SD 20.7) respectively), as were the difference in mean domain scores for facial comfort, eye comfort and social function. The mean total FaCE Scale scores of respondents aged below 40 years were the lowest. Younger patients had the lowest social function domain scores of all age groups. CONCLUSION: Facial paralysis is a significant problem in patients with acoustic neuroma. Based on this survey, treatment for facial paralysis is often not offered and even when given, still leaves the patient with a significantly lowered quality of life. However, it should be remembered that this study has surveyed a skewed patient population and that overall, most acoustic neuroma patients do not suffer with facial paralysis. PMID- 24797570 TI - Detection of relaxin receptor in the dorsoradial ligament, synovium, and articular cartilage of the trapeziometacarpal joint. AB - Basilar thumb osteoarthritis (OA) is postulated to occur due to ligament attenuation of the trapeziometacarpal (TM) joint. Relaxin is a peptide hormone, which loosens ligaments before childbirth, through remodeling of the extracellular matrix via upregulation of matrix metalloproteases (MMPs). We postulated that relaxin family peptide receptor 1 (RXFP-1), the receptor for circulating relaxin, was present in tissues of the TM joint. Ligaments and synovium were sampled from 15 patients during surgery for TM arthritis. We obtained trapezial cartilage from two autopsy donors and four patients. Tissues were fixed, paraffin embedded, and sectioned at 5 um, then were immunostained for RXFP-1, as well as MMP-1, and MMP-13, using rabbit anti-human polyclonal antibodies. Eight DRL samples showed positive immunostaining for relaxin receptor, with 14/15 positively stained in synovium. Greater staining was seen in specimens obtained from women with more severe TM arthritis. Trapezial cartilage demonstrated receptor staining within chondrocytes in the middle and deep zones. Immunostaining for MMPs co-localized with relaxin receptor staining. Relaxin receptors are present at the ligament, cartilage, and synovium of the TM joint, indicating that it is a potential target for relaxin. This suggests that circulating relaxin may impact joint stability. The role of relaxin in cartilage and synovium may be related to its role in collagen regulation as a possible tissue response to OA. PMID- 24797571 TI - Microvesicles derived from human Wharton's jelly mesenchymal stem cells promote human renal cancer cell growth and aggressiveness through induction of hepatocyte growth factor. AB - In our previous study, microvesicles (MVs) released from human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) retard the growth of bladder cancer cells. We would like to know if MVs have a similar effect on human renal cell carcinoma (RCC). By use of cell culture and the BALB/c nu/nu mice xeno-graft model, the influence of MVs upon the growth and aggressiveness of RCC (786-0) was assessed. Cell counting kit-8 (CCK-8) assay, incidence of tumor, tumor size, Ki-67 or TUNEL staining was used to evaluate tumor cell growth in vitro or in vivo. Flow cytometry assay (in vitro) or examination of cyclin D1 expression (in vivo) was carried out to determine the alteration of cell cycle. The aggressiveness was analyzed by Wound Healing Assay (in vitro) or MMP-2 and MMP-9 expression (in vivo). AKT/p-AKT, ERK1/2/p-ERK1/2 or HGF/c-MET expression was detected by real time PCR or western blot. Our data demonstrated that MVs promote the growth and aggressiveness of RCC both in vitro and in vivo. In addition, MVs facilitated the progression of cell cycle from G0/1 to S. HGF expression in RCC was greatly induced by MVs, associated with activation of AKT and ERK1/2 signaling pathways. RNase pre-treatment abrogated all effects of MVs. In summary, induction of HGF synthesis via RNA transferred by MVs activating AKT and ERK1/2 signaling is one of crucial contributors to the pro-tumor effect. PMID- 24797573 TI - Contribution of six risk factors to achieving the 25*25 non-communicable disease mortality reduction target: a modelling study. AB - BACKGROUND: Countries have agreed to reduce premature mortality (defined as the probability of dying between the ages of 30 years and 70 years) from four main non-communicable diseases (NCDs)--cardiovascular diseases, chronic respiratory diseases, cancers, and diabetes--by 25% from 2010 levels by 2025 (referred to as 25*25 target). Targets for selected NCD risk factors have also been agreed on. We estimated the contribution of achieving six risk factor targets towards meeting the 25*25 mortality target. METHODS: We estimated the impact of achieving the targets for six risk factors (tobacco and alcohol use, salt intake, obesity, and raised blood pressure and glucose) on NCD mortality between 2010 and 2025. Our methods accounted for multi-causality of NCDs and for the fact that when risk factor exposure increases or decreases, the harmful or beneficial effects on NCDs accumulate gradually. We used data for risk factor and mortality trends from systematic analyses of available country data. Relative risks for the effects of individual and multiple risks, and for change in risk after decreases or increases in exposure, were from re-analyses and meta-analyses of epidemiological studies. FINDINGS: If risk factor targets are achieved, the probability of dying from the four main NCDs between the ages of 30 years and 70 years will decrease by 22% in men and by 19% in women between 2010 and 2025, compared with a decrease of 11% in men and 10% in women under the so-called business-as-usual trends (ie, projections based on current trends with no additional action). Achieving the risk factor targets will delay or prevent more than 37 million deaths (16 million in people aged 30-69 years and 21 million in people aged 70 years or older) from the main NCDs over these 15 years compared with a situation of rising or stagnating risk factor trends. Most of the benefits of achieving the risk factor targets, including 31 million of the delayed or prevented deaths, will be in low income and middle-income countries, and will help to reduce the global inequality in premature NCD mortality. A more ambitious target on tobacco use (a 50% reduction) will almost reach the target in men (>24% reduction in the probability of death), and enhance the benefits to a 20% reduction in women. INTERPRETATION: If the agreed risk factor targets are met, premature mortality from the four main NCDs will decrease to levels that are close to the 25*25 target, with most of these benefits seen in low-income and middle-income countries. On the basis of mortality benefits and feasibility, a more ambitious target than currently agreed should be adopted for tobacco use. FUNDING: UK MRC. PMID- 24797574 TI - Decisive action to end apathy and achieve 25*25 NCD targets. PMID- 24797576 TI - Interventional cardiology: Outcomes in coronary stent trials--1 year is not enough. PMID- 24797577 TI - Interventional cardiology: Anticoagulation during AF ablation. PMID- 24797572 TI - Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. AB - BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success. METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030. FINDINGS: We estimated that 6.3 million (95% UI 6.0-6.6) children under-5 died in 2013, a 64% reduction from 17.6 million (17.1-18.1) in 1970. In 2013, child mortality rates ranged from 152.5 per 1000 livebirths (130.6 177.4) in Guinea-Bissau to 2.3 (1.8-2.9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6.8% to 0.1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41.6% of under-5 deaths compared with 37.4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1.4 million more child deaths, and rising income per person and maternal education led to 0.9 million and 2.2 million fewer deaths, respectively. Changes in secular trends led to 4.2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone. INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030. FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development. PMID- 24797578 TI - Acute coronary syndromes: Right direction--moving proximally in timing of STEMI care. PMID- 24797579 TI - Life history, predation and flight initiation distance in a migratory bird. AB - Life-history trade-offs occur as a consequence of the compromise between maximization of different components such as the size and the number of clutches. Flight initiation distance (FID) potentially constitutes a general proximate factor influencing such trade-offs reflecting the risks that individuals take. Therefore, greater investment in reproduction occurs at a higher risk of death, resulting in selection for efficient flight morphology. I analysed long-term data on FID in a population of barn swallows Hirundo rustica during 1984-2013 with 2196 records of FID for 1789 individuals. FID had a repeatability of 0.62 (SE = 0.04) and a heritability of 0.48 (SE = 0.07). FID varied between individuals and sites, and it increased over time as climate ameliorated. FID showed a U-shaped relationship with age, with young and very old individuals having the longest FIDs. Barn swallows that arrived early from spring migration, started to breed early and produced many fledglings had the longest FID. Individuals with the longest tails had the longest FID, and individuals with the shortest aspect ratios and wing loadings had the longest FID. Individuals that died from predation had shorter FID than survivors. These findings are consistent with the hypothesis that FID relates directly to life history, with longer FIDs being associated with smaller levels of risk-taking. PMID- 24797580 TI - Ultrasound investigation of vastus medialis oblique muscle architecture: an in vivo study. AB - There is thought to be a link between vastus medialis oblique (VMO) architecture and patellofemoral pain syndrome (PFPS). Historical data are largely derived from older populations, whereas PFPS commonly affects younger populations. The aim of this study was to gather data on VMO architecture in young asymptomatic adults, to provide baseline values for comparison with symptomatic sufferers. VMO maximum fiber angle and insertion ratio were measured with ultrasound. The insertion ratio represents the proportion (%) of the patella which has the muscle fibers attaching to its medial border. Eighty knees from 40 healthy young subjects (18 males, 22 females, and age 20-30) were assessed. Individual Tegner scores were recorded to assess participants' level of physical activity. Results were compared with data in the literature for PFPS sufferers and normal older individuals. Mean fiber angle and insertion ratio were 56.6 degrees and 57.8%, respectively. There was no significant difference between age groups. The insertion ratio was higher among females (61.2% F:53.6% M). There was some evidence of increased fiber angle and decreased insertion ratio with increased Tegner score. There was some overlap in fiber angle between healthy knees in this study and values reported elsewhere for pathological knees. VMO fiber angle and insertion ratio are not age-related. The overlap in fiber angle values between healthy and pathological knees suggests that the cause of PFPS is multifactorial. An individual's VMO architecture may be affected by their physical activity level, which could have important implications for PFPS. PMID- 24797581 TI - Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA Stability. AB - The cancer chemopreventive property of Chinese herb new isolate isorhapontigenin (ISO) and mechanisms underlying its activity have never been explored. Here we demonstrated that ISO treatment with various concentrations for 3 weeks could dramatically inhibit TPA/EGF-induced cell transformation of Cl41 cells in Soft Agar assay, whereas co-incubation of cells with ISO at the same concentrations could elicit G0/G1 cell-cycle arrest without redundant cytotoxic effects on non transformed cells. Further studies showed that ISO treatment resulted in cyclin D1 downregulation in dose- and time-dependent manner. Our results indicated that ISO regulated cyclin D1 at transcription level via targeting JNK/C-Jun/AP-1 activation. Moreover, we found that ISO-inhibited JNK/C-Jun/AP-1 activation was mediated by both upregulation of MKP-1 expression through increasing its mRNA stability and deactivating MKK7. Most importantly, MKP-1 knockdown could attenuate ISO-mediated suppression of JNK/C-Jun activation and cyclin D1 expression, as well as G0/G1 cell cycle arrest and cell transformation inhibition, while ectopic expression of FLAG-cyclin D1 T286A mutant also reversed ISO-induced G0/G1 cell-cycle arrest and inhibition of cell transformation. Our results demonstrated that ISO is a promising chemopreventive agent via upregulating mkp-1 mRNA stability, which is distinct from its cancer therapeutic effect with downregulation of XIAP and cyclin D1 expression. PMID- 24797582 TI - The maturation of antibody technology for the HIV epidemic. AB - Antibodies are one of our most useful biological tools. Indeed, improvements in antibody-based technologies have ushered in a new era of antibody-based therapeutics, research and diagnostic tools. Although improved technologies have led to the development of therapeutic antibodies for treatment of malignancies and inflammatory conditions, the use of advanced antibody technology in the therapy of viral infections is in its infancy. Non-human primate studies have demonstrated that antibodies against the HIV envelope can both prevent viral infection and control viremia. Despite the obvious potential of antibody therapies against HIV, there remain limitations in production and purification capacity that require further research. Recent advances in recombinant antibody technology have led to the development of a range of novel antibody fragments, such as single-domain nanobodies and bispecific antibodies, that are capable of targeting cancer cells to cytotoxic T cells. Novel antibody production techniques have also been designed, allowing antibodies to be obtained from non-mammalian cells, bovine colostrum and the periplasm and cytoplasm of bacteria. These advances may allow large-scale production of HIV antibodies that are capable of protecting against HIV infection or serving as therapeutics that reduce the need for life-long antiretroviral treatment. This review summarises recent advances in antibody-based technologies and discusses the possibilities and challenges of using these advances to design prophylactics and therapeutics against HIV. PMID- 24797584 TI - What do parents need to enhance participation of their school-aged child with a physical disability? A cross-sectional study in the Netherlands. AB - BACKGROUND: The aim was to provide an overview of the number, domains and priority of needs as expressed by parents in supporting participation of their school-aged child with a physical disability. Additionally, this study investigated whether the number of needs within each domain is related to the child's gross motor function level, parent's perceived own general health, family socio-economic status and family type. METHOD: A cross-sectional study with a total of 146 participants (84.9% mothers) who completed a survey including the Family Needs Inventory - Paediatric Rehabilitation, the Gross Motor Function Classification System Family Report Questionnaire, the General Health Questionnaire and a demographic questionnaire. A need has been operationalized as 'a family's, parent's or other family member's expressed desire for information, services and supports related to their family'. Descriptive statistics and correlation analysis were applied. RESULTS: Parents (n = 146; response rate 27%) varied in the number of expressed needs (range 0-124; mean = 35.9; median = 30; SD = 25.6). Highest mean percentage scores were found for the domains 'Laws, regulations and fees' (36%), 'Leisure time' (35.6%) and 'Aids, adaptations, facilities and resources' (33.8%). Seven single needs were expressed by 50% or more of the parents. All domains of needs showed a positive correlation with perceived parental general health. The domains 'Laws, regulations and fees', 'Day care & school', 'Emotional and mental support' and 'Raising my child' correlated negatively with family socio-economic status; and child's gross motor function level correlated positively with the domains 'Aids, adaptations, facilities and resources', 'Practical support at home' and 'Leisure time'. CONCLUSIONS: As parents have a major influence on participation of children with a physical disability, meeting their individual needs should become an objective for service providers and policy makers. Family-centred service might be more effective by putting a greater emphasis on changing the environment. PMID- 24797585 TI - Social support and self-esteem as mediators between stress and antepartum depressive symptoms in rural pregnant women. AB - The purpose of this secondary analysis was to determine whether satisfaction with social support and self-esteem mediated the relationship between antepartum stress and depressive symptoms in women attending prenatal clinics in a rural Southeastern community (N = 318). Path analysis with linear regression indicated that the relationship between antepartum stress and depressive symptoms was partially mediated by higher levels of the internal resources of satisfaction with social support and self-esteem. Self-esteem had a greater influence on the relationship between antepartum stress and depressive symptoms than did satisfaction with social support. These findings suggest further study to determine whether developing culturally tailored interventions that emphasize stress reduction activities in addition to enhancing self-esteem and increasing satisfaction with social support can decrease the burden of antepartum depressive symptoms in rural low-income women. PMID- 24797583 TI - Phorbol myristate acetate, but not CD40L, induces the differentiation of CLL B cells into Ab-secreting cells. AB - In this study, we investigated the capacity of chronic lymphocytic leukemia (CLL) B cells to undergo terminal differentiation into Ig-secreting plasma cells in T cell-independent and T cell-dependent responses. We used a two-step model involving stimulation with phorbol myristate acetate (PMA) and CD40L, together with cytokines (PMA/c and CD40L/c), for 7 days. We describe immunophenotypic modifications, changes in the levels of mRNA and protein for transcription factors and morphological and functional events occurring during the differentiation of CLL B cells into antibody-secreting cells (ASCs). The induction of differentiation differed significantly between the CD40L/c and PMA/c culture systems. The PMA/c culture system allowed CLL B cells to differentiate into IgM-secreting cells with an immunophenotype and molecular profile resembling those of preplasmablasts. By contrast, CD40L/c-stimulated cells had a phenotype and morphology similar to those of activated B cells and resembling those of the CLL B cells residing in the lymph node and bone marrow. These data suggest that the CLL B cells are not frozen permanently at a stage of differentiation and are able to differentiate into ASCs as appropriate stimulation are provided. The data presented here raise questions about the molecular processes and stimulation required for CLL B-cell differentiation and about the inability of CD40 ligand to induce differentiation of the CLL B cells. PMID- 24797586 TI - MAT-CAP: a novel medication assessment tool to explore adherence to clinical practice guidelines in community-acquired pneumonia. AB - BACKGROUND/PURPOSE: Community-acquired pneumonia (CAP) is a disease with high morbidity and mortality. Adherence to clinical practice guidelines (CPGs) in treatment of CAP is associated with favourable outcome. We aimed to develop and validate a medication assessment tool (MAT) to explore adherence to CPG recommendations in patients with CAP admitted to a Norwegian hospital. The tool is named MAT-CAP. METHOD: Sixteen quality indicators (QIs) based on local and international CPGs were developed. Content validity was explored in an expert panel using a two-round modified Delphi technique. QIs demonstrating content valdity were reformulated into review criteria forming the MAT-CAP. Feasibility and adherence to MAT-CAP were explored in a retrospective study using data from electronic patient records of CAP patients admitted to the University Hospital of North Norway Tromso during 2008. Reliability was explored using Cohen's kappa (K) statistics for inter- and intra-observer agreements. RESULTS: Content validity was demonstrated for 15 QIs covering areas as initial empirical treatment, microbiological diagnostics, pathogen specific treatment, dose adjustment according to renal function, switch from intravenous to oral treatment and treatment duration. Overall reliability was excellent with K-values of 0.88 and 0.95 for inter-observer and intra-observer agreements, respectively. Overall applicability was 37.2%, and mean application times were 3.1 and 3.8 min for the two observers. Overall adherence to 812 criteria applied was 59% (range 0-100). CONCLUSIONS: We have demonstrated content validity, feasibility and reliability of a 15-criterion MAT-CAP. Adherence results from applying MAT-CAP criteria pinpointed areas with good clinical performance and areas with improvement potentials. PMID- 24797587 TI - "Psychogenic movement disorders": they are what they are. PMID- 24797588 TI - A re-examination of the MDM2/p53 interaction leads to revised design criteria for novel inhibitors. AB - The general model of epitope-type MDM2 inhibitor was developed based on the structural information on the complexes between MDM2 and various low molecular weight ligands found in the PDB database. Application of this model to our in house library has led us to a new scaffold capable of interrupting protein protein interactions. A synthetic library based on this and related scaffolds resulted in new classes of compounds that possess biochemical and cellular activity and good pharmacokinetic properties. We assume that such general approach to PPI inhibitors design may be useful for the development of inhibitors of various PPI types, including Bcl/XL. PMID- 24797591 TI - Effects of fish oil on cell proliferation and liver injury in an experimental model of acute hepatic injury induced by carbon tetrachloride. AB - OBJECTIVE: We aimed to investigate the effect of fish oil on the hepatic injury and cell cycle phases as well as cellular proliferation- regeneration in a rat model of acute hepatic injury induced by carbon tetrachloride. BACKGROUND: Compensatory cell proliferation and tissue regeneration occurs as an endogenous response following chemical damage to the liver and enable animals to over come the injury. Data related to effect of fish oil on liver injury induced by chemical hepatotoxicants are controversial. METHOD: 60 male Wistar-albino rats were fed either with a diet supplemented with 20% fish oil or standard rat feed for 2 weeks. After an overnight fast, rats in each group were administered either 1 ml/kg carbon tetrachloride or saline intraperitoneally. RESULTS: Fish oil enriched diet significantly enhanced the carbon tetrachloride - associated necroinflammatory damage, ballooning degeneration and the elevation of serum transaminases induced by carbon tetrachloride. Furthermore fish oil diet prevented cell proliferation, increased the proportion of cells in the G0/G1phase concomitant with a decrease in the proportion of cells in the S phase cells. CONCLUSION: Fish oil diet exacerbates the hepatic injury and prevents cell proliferation-regeneration in normal and injured liver cells. Suppression of tissue regeneration by fish oil may lead to progression of the hepatic injury (Tab. 3, Fig. 4, Ref. 31). PMID- 24797592 TI - Protective effect of vitamin B5 (dexpanthenol) on cardiovascular damage induced by streptozocin in rats. AB - OBJECTIVES: This study investigated whether Dexpanthenol (DEX) improves diabetic cardiovascular function and cardiac performance by regulating total oxidant and antioxidant status. METHODS: Diabetes was induced by a single intraperitoneal injection of Streptozocin (50 mg/kg in 1 ml of saline) and treatment groups received DEX (300 mg/kg/day) for 6 weeks. Endothelium (in)dependent relaxation responses were assessed in thoracic aortic rings and coronary vasculature together with alpha receptor and voltage dependant contractile responses of aorta. Myocardial contractility has been recorded by an intra ventricular latex balloon. Total oxidant and antioxidant status were measured from the serum samples. RESULTS: Induction of diabetes resulted in an apparent body weight loss, high blood glucose, endothelial dysfunction and increased serum oxidant status. DEX supplementation restored the endothelial dysfunction, antioxidant status and body weight whereas decreasing blood glucose level. CONCLUSION: Along with the standard therapy of diabetes, DEX can be used as a safe and economical way of adjuvant therapy to diminish the burden of the disease (Tab. 3, Fig. 3, Ref. 30). PMID- 24797575 TI - Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. AB - BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery. METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values. FINDINGS: 292,982 (95% UI 261,017 327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483 407,574) in 1990. The global annual rate of change in the MMR was -0.3% (-1.1 to 0.6) from 1990 to 2003, and -2.7% (-3.9 to -1.5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0.4% (0.2-0.6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956.8 (685.1 1262.8) in South Sudan to 2.4 (1.6-3.6) in Iceland. INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa. FUNDING: Bill & Melinda Gates Foundation. PMID- 24797593 TI - Environmental enrichment exposure restrains the neuronal damage induced by diabetes and stress in the motor cortex of rat brain. AB - OBJECTIVE: The present study was intended to assess the effect of environmental enrichment on the diabetes as well as combined actions of diabetes and stress on the neurons of the motor cortex of rat brain. BACKGROUND: Untreated diabetes mellitus causes severe insults to the neurons of the central nervous system. Treatment with environmental enrichment is known for producing significant and reliable neuronal changes in the neurological disorders of central nervous system. MATERIALS AND METHODS: Male albino rats of Wistar strain, aged 35 days were used. The rats were divided into (A) Normal Control (B) Vehicle Control (C) Diabetic (D) Diabetes+Stress (E)Diabetes+Environmental enrichment (F)Diabetes+Stress+Environmental enrichment (n=6) in each group). Blood glucose levels and body weight was measured before the induction of diabetes, on the 2nd day after induction of diabetes and before sacrifice. After exposure to stress and environmental enrichment diabetic rats were sacrificed (Day 30) and brains were processed for cresyl violet staining. The number of survived neurons in the motor cortex was quantified. RESULTS: Quantification of cresyl violet neurons in the motor cortex showed a significant increase in the number of survived neurons in Diabetes+Environmental enrichment and Diabetes+Stress+Environmental enrichment group rats compared to Diabetes and Diabetes+Stress group rats respectively. CONCLUSION: Findings from the present study indicated that the exposure to environmental enrichment can prevent the amount of the neural damage caused by complications of diabetes and combined actions of diabetes and stress to the neurons of the motor cortex (Fig. 5, Ref. 37). PMID- 24797594 TI - Phosphoinositid signal pathway mediate neurite outgrowth in PC12 cells by staurosporine. AB - OBJECTIVES: In previous studies, we showed that staurosporine uses intracellular calcium ions to affect cell death in PC12 cells. The bulk release of intracellular excessive Ca(2+) from intracellular sources into cytosol contributes to neuronal apoptotic events, which in turn results in neuronal cell death. However, the mechanisms of Ca(2+)-induced neuronal cell death or neurite elongation is still unclear. Therefore, we investigated the relation between phosphoinositid signal pathway, intracellular calcium, and reactive oxygen species on one hand, with staurosporine-induced neurite outgrowth in PC12 cells on the other. RESULTS: The inhibition of phospholipase C or IP3 receptor antagonist or phosphoinositid signal transduction antagonist produced cell death and suppressed neurite outgrowth by staurosporine in PC12 cells. The inhibition of these enzymes and pathway results in an increase in intracellular Ca(2+) although subsequent hydroxyl radical (*OH) production began after inhibitors exposure. *OH production was significantly attenuated in inhibitor supplemented medium treatment, and it was dependent on the intracellular Ca(2+) concentration. These data indicate that staurosporine activates phosphoinositid signal pathway while endoplasmic Ca(2+), and subsequent *OH production are critical events in staurosporine-induced neurite outgrowth in PC12 cells. CONCLUSION: We conclude that the fact that staurosporine mobilizes Ca2+, probably via activating the subcellular compartment, is responsible for staurosporine-induced (Ca2+]i increase during neurite outgrowth in PC12 cells (Fig. 7, Ref. 30). PMID- 24797595 TI - The effects of Hypericum perforatum on hepatic ischemia- -reperfusion injury in rats. AB - BACKGROUND: Ischemia-reperfusion injury (IR) is associated with a high morbidity and mortality. Several agents have been used to protect the liver after IR. We aimed to investigated the effects of the Hypericum perforatum on IR of the liver. METHODS: A total of 62 wistar-albino male rats in 4 groups were used. Sham group (n: 8). Control group (IR, n: 18) was underwent partially liver ischemia and reperfusion (IR). Carboxymethyl cellulose group (CMC n: 18) was given 0.5 % carboxymethyl cellulose before IR for a week. Hypericum perforatum group (HP, n:18) was given 0.5 % carboxymethyl cellulose supplemental the extract of Hypericum perforatum before IR for a week. Blood and liver samples were obtained before ischemia, and 1, 2, 4 hours after the reperfusion. AST, ALT, LDH, TNF alpha, IL-6, MDA and advanced oxidation protein products(AOPP) levels were determined in blood samples. Histological evaluation and tissue MDA, AOPP levels were determined. RESULTS: Blood levels of ALT, TNF-alpha, IL-6 and MDA were significantly low in HP group compared with IR and CMC groups (p < 0.05). There was no difference between the liver injury scrores of IR and CMC groups (p > 0.05). CONCLUSION: [corrected] These results indicate that H. perforatum can protect the liver against IR. As antioxidative agent, Hypericum perforatum has both local and systemic protective effects in ischemia reperfusion injury (Tab. 1, Fig. 4, Ref. 31). PMID- 24797596 TI - The detection of early myocardial changes in asymptomatic diabetic individuals by 99mTc - Myoview gated-SPET and heart rate variability measurement. AB - AIMS: Incidence of early myocardial changes in asymptomatic diabetic individuals is not clearly documented. In the present study, we examined diabetic patients without a history of cardiovascular disease with negative treadmill test and no signs of systolic dysfunction for presence of cardiac autonomic neuropathy established by measurement of heart rate variability (HRV) and (99m)Tc - Myoview gated-SPET. MATERIALS AND METHODS: 47 type I and type II diabetic patients were subjected to prospective study including echocardiography and HRV measurement using the combination of Ewing's testing and spectral analysis. Subsequently, patients underwent treadmill test and stress myocardial perfusion scintigraphy. Additionally, vascular and metabolic parameters were collected. RESULTS: Treadmill test was negative in all patients. Diastolic dysfunction was found in 10 % of T1DM and 11 % of T2DM patients by echocardiography, whereas none of the patients had systolic dysfunction. SPET confirmed hypoperfusion in 35 % T1DM (p=0.01) and in 60 % T2DM (p=0.001). Diagnosis of cardiac autonomic neuropathy based on Ewing's testing and HRV examination was established in 60 % of T1DM patients (p=0.001) and 77 % of T2DM patients (p=0.001). In T1DM group, significant association was found between cardiac autonomic neuropathy (CAN) and frequency of hypoglycaemia (p=0.04). No such correlations were found in patients with T2DM. CONCLUSION: The results of the present study show high incidence of myocardial hypoperfusion and cardiac autonomic neuropathy among asymptomatic diabetic patients, whereas the standard diagnostic approaches including treadmill test and echocardiography failed to show any changes. Therefore, we conclude that diabetic heart disease remains underdiagnosed by standard approaches, but could be detected in asymptomatic patients by more sensitive methods, such as HRV measurement and myocardial scintigraphy (Tab. 2, Fig. 2, Ref. 26). PMID- 24797597 TI - A pilot study of Helicobacter pylori genotypes and cytokine gene polymorphisms in reflux oesophagitis and peptic ulcer disease. AB - Helicobacter pylori causes various diseases such as chronic gastritis, peptic ulcer and gastric cancer. While majority of the people infected with H. pylori is asymptomatic, 15-20 % of them develop such diseases. The main factors, which determine the development of H. pylori related diseases might be bacterial virulence, host genetic and environmental factors.The aim of this study was to reveal the factors that play a role in the disease development in patients with reflux esophagitis and peptic ulcer, infected with Helicobacter pylori. Environmental factors such as medical agents, smoking and body mass index were evaluated. The factors specific to bacteria such as vacA, CagA, babA and iceA virulence genotypes and the host factors such as IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, interferon-gamma, TNF-alpha, ve TGF-beta1 gene polymorphisms were compared between the two groups.H. pylori infected twenty five patients with reflux esophagitis and peptic ulcer were enrolled in the study. There was no statistical difference between the two groups regarding environmental factors. IL-2 -330T +166T (p=0.037) and IL10 -1082A; -819C (p=0.049) gene polymorphisms were significantly more common in the group of patients with peptic ulcer compared to the group with reflux esophagitis. In both groups of patients, either with reflux esophagitis or peptic ulcer, multiple H. pylori virulence genotypes (cagA, vacA, babA) (mean values 74 %, 78 %, 54 % respectively) were observed.In this study, we revealed that cytokine gene polymorphisms may play a role in the development peptic ulcer while H. pylori virulence genotypes seem to be crucial for the development of associated diseases (Tab. 4, Ref. 51). PMID- 24797598 TI - Elevated levels of circulating biomarkers of cell death (nucleosomes) in the patients with plaque psoriasis treated with the Goeckerman regimen. AB - BACKGROUND: Nucleosomes are complexes that are formed during apoptosis. Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation and anti-apoptotic features. Presented study was focused to expression of circulating biomarkers of cell death (circulating nucleosomes, CN) during Goeckerman therapy of psoriasis (UV, PAHs). METHODS: In a group of patients with psoriasis (19), treated with Goeckerman regimen (GR), we evaluated their level of CN, level of chromosomal aberration in peripheral lymphocytes (CA), level of urinary 1 hydroxypyrene (1-OHP) and their value of Psoriasis Area and Severity Index (PASI). RESULTS: Following the treatment, the serum level of CN and urinary level of 1-OHP (p<0.05) were significantly increased (p<0.01). We found significant correlation between CN and urinary level of 1-OHP after GR (r=0.57; p<0.05). Immediately after the treatment we found significantly increased total numbers of abnormal chromosomes (ABB; p<0.01) and structurally abnormal chromosomes (SAB; p<0.05). CONCLUSIONS: We found slightly (but statistically significant) elevated level of circulating biomarkers of cell death (nucleosomes) in patients with plaque psoriasis treated with GR (PAHs, UV radiation). We suppose that elevated level of CN is a result of combination of the positive effects of GR and its weak genotoxic effect (mainly PAHs). Conclusions are supported by significant correlation between CN and urinary level of 1-OHP after GR and significantly elevated level of CA after GR (Tab. 2, Fig. 1, Ref. 28). PMID- 24797599 TI - A meta-analysis of pemetrexed-based doublet compared with pemetrexed alone for the second-line treatment of advanced non-small-cell lung cancer. AB - PURPOSE: This meta-analysis investigated pemetrexed-based doublet compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer. METHODS: Randomized controlled trials which compared pemetrexed based doublet with single-agent pemetrexed in patients as second-line treatment of advanced non-small cell lung cancer were searched. Overall survival (OS) was the primary end point, while secondary end points included progression-free survival, overall response rate, 1-year survival rate, and grade 3 or 4 toxicity. RESULTS: Four eligible randomized clinical trials including 1,084 patients were selected. Meta-analysis demonstrated that pemetrexed-based doublet arm significantly improved the overall response rate (OR=2.70, 95% CI: 1.76-4.15, p=0.000), compared with docetaxel alone group, while there were no significant differences in overall survival (HR=0.88, 95% CI: 0.74-1.04, p=0.132), progression-free survival (HR=0.91, 95% CI: 0.73-1.15, p=0.443), and 1-year survival rate (OR=1.43, 95% CI: 0.85-2.40, p=0.178) between the two arms. However, there were more frequencies of grade 3-4 leucopenia (OR=2.86, 95% CI: 1.32-6.20, p=0.008), neutropenia (OR=2.69, 95% CI: 1.55-4.68, p=0.000) and thrombocytopenia (OR=6.92, 95% CI: 2.51-19.07, p=0.000) in pemetrexed-based doublet group. Grade 3-4 anemia (OR=0.62, 95% CI: 0.33-1.18, p=0.144) and fatigue (OR=1.15, 95% CI: 0.73-1.79, p=0.550) had equivalent incidences in the two groups. CONCLUSIONS: This is the first meta-analysis to compare pemetrexed-based doublet with single-agent pemetrexed in second-line therapy of non-small cell lung cancer. Our meta-analysis suggested that pemetrexed combination chemotherapy was not superior to single-agent arm and was not recommended as the second-line chemotherapy for patients with non-small cell lung cancer (Tab. 2, Fig. 6, Ref. 20). PMID- 24797600 TI - Effect of spa therapy after intervertebral disc surgery in the cervical spine. AB - OBJECTIVE: The aim of this paper is to determine whether standard spa treatment significantly affects disability, functional status, and quality of life of patients after surgery of intervertebral discs in the cervical spine. MATERIAL AND METHODS: The study was performed in patients who underwent an artificial intervertebral disc replacement in the cervical spine.The study involved a group of 88 patients with mean age of 49.49 (range 32 to 74, standard deviation 9.12) while the experimental group consisted of 40 patients who underwent spa treatment with mean age of 49.35 (range 32 to 72, standard deviation 7.69). The control group was not treated by spa treatment, and consisted of 48 patients with mean age of 49.6 (range 36 to 74, standard deviation 8.73). These patients underwent standard medical rehabilitation at rehabilitation departments.Dysfunction of the cervical spine was scaled according to The Neck Disability Index (NDI). Functional status of patients was evaluated by Pulses Profile, and quality of life was evaluated by test of the quality of life according to Spitzer. RESULTS: The statistical evaluation parameter for NDI, Pulses and Spitzer found significant difference at the significance level of 0.01, suggesting that experimental group of patients who received spa treatment during follow-up examination had significantly better results in comparison with the control group. CONCLUSION: As a result of this study we have concluded that after implantation of the artificial intervertebral disc replacement in the cervical spine it is appropriate to recommend spa treatment for its positive effect on disability, functional status, and quality of life (Tab. 3, Fig. 3, Ref. 24). PMID- 24797601 TI - The Derer's biological - cosmic week and the Halberg's circaseptan chronome. AB - There are three common periodic intervals in the life of each human being from time immemorial: the day, the week and the year. The first one is given by the Earth's rotation, the latter one by its revolution around the Sun. These both do have clear biomedical counterparts. The 7-day week, basically linguistically "period of change" (or a similar period, e.g.10 days in Egypt or 8 days in Etrutria) was obviously originally considered mainly as a product of a societal agreement. Two groups of Czechoslovak clinicians-scientists, however, noted in forties of the XXth century an approximately week period in human laboratory data, after similar attempts abroad a few years earlier. In fifties, L.Derer, respecting the mathematical and biological principles in medicine and supported by the mathematician A.Huta, demonstrated the presence of the "6-day" rhythm in blood leukocyte counts in patients with leukemia, treated by cytostatics. Posing the question "Where is it from?", he considered also cosmic influences but was unable to study this issue more deeply due to his premature decease. Two decades later, the "Derer's circaseptans" found wide confirmation not only in human medicine but also in biology. The pioneering role here belongs to Franz Halberg, USA, the godfather of the "circadians" (originally "Halberg's paranoia") since the fifties. The possible geocosmic roots of circaseptans are supposed in the geomagnetic activity from interplanetary space, generating under the influence of the Sun rotation the periods around 6-7 days. This is presently documented, surprisingly, also by analysing the Derer's original data using more advanced, inferentially statistical method - the Halberg cosinor regression. Thus, the optimal approximation has been achieved for the period of 6.75 days - the 4th harmonics of the Bartels solar rotation cycle. Accordingly, the week can be now, after Derer and Halberg, understood also - same as day and year - as a biological - geocosmic phenomenon, a geomagnetic week, genetically acquired in the course of billions years' of evolution, encoded in our chronome. The personality of Ladislav Derer should, in the history of the Czech and Slovak biomedical sciences, be permanenly standing by such giants as the well known Jan Evangelista Purkyne ("Purkinje") or as Bohumil Nemec, discoverer of the mechanism of positive geotropism of plant roots (Fig. 3, Ref. 28). PMID- 24797602 TI - The photocathodic properties of a Pb(Zr(0.2)Ti(0.8))O3 wrapped CaFe2O4 layer on ITO coated quartz for water splitting. AB - Pb(Zr(0.2)Ti(0.8))O3 wrapped CaFe2O4 particles were constructed on ITO coated quartz as a photocathode for efficient water splitting. A photocurrent of 152 MUA cm(-2) was obtained under zero bias vs. Ag/AgCl and 100 mW cm(-2) with the assistance of positive poling and Ag decoration. PMID- 24797603 TI - Evaluation of hydrophobic polyvinyl-alcohol formaldehyde sponges as absorbents for oil spill. AB - Macroporous materials are a class of absorbents used for oil spill cleanup. In this article, novel macroporous and hydrophobic polyvinyl formaldehyde (PVF-H) sponges were prepared by the reaction of stearoyl chloride with hydroxyl groups of hydrophilic PVF sponge at different temperatures. Attenuated total reflectance infrared (ATR-IR) spectroscopy confirmed the successfully anchoring of hydrophobic stearoyl groups on the PVF networks. Scanning electron microscopy (SEM) images demonstrated that the as-prepared PVF-H had interconnected open-cell structures, and mercury intrusion porosimetry indicated that the average pore size ranged from 60 to 90 MUm and porosity was greater than 94.8%. Such PVF-H sponges can absorb oil products effectively, such as toluene, n-hexane, kerosene, soybean oil, hydraulic oil, and crude oil up to 13.7 g.g(-1) to 56.6 g.g(-1), and this level of absorption was approximately 2-4 times higher than that absorbed by commercial polypropylene nonwoven mat. In low-viscosity oils, the samples can reach the saturated absorption amount only in 1 min, but in higher-viscosity oils, absorption equilibrium can be reached in 10 min. In a simulated oil slick system, these macroporous and hydrophobic sponges can still maintain high oil absorption capacities within the range of 14.4 g.g(-1) to 57.6 g.g(-1), whereas a relatively low absorption rate (approximately 20 min) indicated high absorption performance and excellent selectivity in the oil-water mixture. In addition, the absorbed oils were collected effectively only through a simple squeeze. The PVF-H sponges were subjected to 35 absorption-squeeze cycles and exhibited good reusability and 90% recovery for oils. The samples prepared at different temperatures differed in their absorption capacities to some extent. However, this new kind of macroporous and PVF-H sponges had excellent absorption performance on oil products. PMID- 24797604 TI - Comparative safety of periablation anticoagulation strategies for atrial fibrillation: data from a large multicenter study. AB - BACKGROUND: There are a variety of periprocedural anticoagulation strategies for atrial fibrillation (AF) ablation, including the use of dabigatran. It is unclear which strategy is superior. OBJECTIVE: To compare the safety and efficacy of anticoagulation with uninterrupted warfarin, dabigatran, and warfarin with heparin bridging in patients undergoing ablation of AF at four experienced centers. METHODS AND RESULTS: In this retrospective analysis, 882 patients (mean age: 61 +/- 11 years) underwent ablation of AF using uninterrupted warfarin (n = 276), dabigatran (n = 374), or warfarin with heparin bridging (n = 232) for periprocedural anticoagulation. The rate of total complications was 23/276 (8.3%) in the uninterrupted warfarin group, 30/374 (8.0%) in the dabigatran group, and 29/232 (12.5%) in the bridged group (P = 0.15). Major complications were more frequent in the uninterrupted warfarin group 12/276 (4.3%) compared with 3/374 (0.8%) in dabigatran and 6/232 (2.6%) in the bridged group (P = 0.01). The most common major complication was the need for transfusion or occurrence of major bleeding. Minor complications did not differ among the three groups. On multivariate analysis, female gender (odds ratio [OR] 1.93, confidence interval [CI] 1.16-3.19, P = 0.011), bridging heparin (OR 2.13, CI 1.100-3.941, P = 0.016), use of triple antithrombotic therapy (OR 1.77, CI 1.05-2.98, P = 0.033), and prior myocardial infarction (OR 2.40, CI 1.01-5.67, P = 0.046) independently predicted total complications. CONCLUSIONS: When comparing the use of uninterrupted warfarin, dabigatran, and warfarin with heparin bridging in patients undergoing catheter ablation of AF, dabigatran was not associated with increased risk, major complications were more common in the uninterrupted warfarin group, and after adjustment, warfarin with bridging increased total complications. PMID- 24797606 TI - Insulin-like growth factor 1 receptor inhibitors: where do we come from? What are we? Where are we going? PMID- 24797605 TI - A novel variant in the 3' untranslated region of the CDK4 gene: interference with microRNA target sites and role in increased risk of cutaneous melanoma. PMID- 24797607 TI - A randomised comparison of free-handed vs air-Q assisted fibreoptic-guided tracheal intubation in children < 2 years of age. AB - We prospectively compared free-handed and air-QTM assisted fibreoptic-guided tracheal intubation in children < 2 years of age. Eighty healthy children were enrolled and randomly assigned to a technique (free-handed or air-Q assisted) and operator (trainee or attending). Time, number of attempts and manoeuvres required were assessed. There was no difference in median (IQR [range]) time to successful tracheal intubation between the free-handed (52.2 (34.8-67.7 [19.7-108.0]) s), and the air-Q assisted (60.3 (45.5-75.1 [28.1-129.0]) s; p = 0.13) groups, or the number of attempts needed. The air-Q assisted group required fewer manoeuvres to optimise the laryngeal view (median (IQR [range]) 0 (0-1 [0-2])) than the free handed group (1 (1-1 [0-3]); p < 0.001). In conclusion, fibreoptic-guided tracheal intubation times were similar with and without the use of the air-Q, but supraglottic airway devices may be a consideration for their other practical advantages. PMID- 24797608 TI - Spectroscopic investigation of electrochemically charged individual (6,5) single walled carbon nanotubes. AB - Individual single-walled carbon nanotubes (SWNTs) of (6,5) chirality were investigated by means of optical spectroscopy while their charge state was controlled electrochemically. The photoluminescence of the SWNTs was found to be quenched at positive and negative potentials, where the onset and offset varied for each individual SWNT. We propose that differences in the local environment of the individual SWNT lead to a shift of the Fermi energy, resulting in a distribution of the oxidation and reduction potentials. The exciton emission energy was found to correlate with the oxidation and reduction potential. Further proof of a correlation was found by deliberately doping individual SWNTs and monitoring their photoluminescence spectral shift. PMID- 24797609 TI - Summary of Bioethical Prescriptions. PMID- 24797610 TI - Direct-to-consumer genomics on the scales of autonomy. AB - Direct-to-consumer (DTC) genetic services have generated enormous controversy from their first emergence. A dramatic recent manifestation of this is the Food and Drug Administration's (FDA) cease and desist order against 23andMe, the leading provider in the market. Critics have argued for the restrictive regulation of such services, and even their prohibition, on the grounds of the harm they pose to consumers. Their advocates, by contrast, defend them as a means of enhancing the autonomy of those same consumers. Autonomy emerges as a key battle-field in this debate, because many of the 'harm' arguments can be interpreted as identifying threats to autonomy. This paper assesses whether DTC genomic services are a threat to, or instead, an enhancement of, personal autonomy. It deploys Joseph Raz's account of personal autonomy, with its emphasis on choice from a range of valuable options. It then seeks to counter claims that DTC genomics threatens autonomy because it involves manipulation in contravention of consumers' independence or because it does not generate valuable options which can be meaningfully engaged with by consumers. It is stressed that the value of the options generated by DTC genomics should not be judged exclusively from the perspective of medical actionability, but should take into consideration plural utilities. Finally, the paper ends by broaching policy recommendations, suggesting that there is a strong autonomy-based argument for permitting DTC genomic services, and that the key question is the nature of the regulatory conditions under which they should be permitted. The discussion of autonomy in this paper helps illuminate some of these conditions. PMID- 24797611 TI - Remote revascularization of abdominal wall transplants using the forearm. AB - Primary abdominal wall closure following small bowel transplantation is frequently impossible due to contraction of the abdominal domain. Although abdominal wall transplantation was reported 10 years ago this, technique has not been widely adopted, partly due to its complexity, but largely because of concerns that storing the abdominal allograft until the end of a prolonged intestinal transplant procedure would cause severe ischemia-reperfusion injury. We report six cases of combined small bowel and abdominal wall transplantation where the ischemic time was minimized by remotely revascularizing the abdominal wall on the forearm vessels, synchronous to the intestinal procedure. When the visceral transplant was complete, the abdominal wall was removed from the forearm and revascularized on the abdomen (n = 4), or used to close the abdomen while still vascularized on the forearm (n = 2). Primary abdominal wall closure was achieved in all. Mean cold ischemia was 305 min (300-330 min), and revascularization on the arm was 50 min (30-60 min). Three patients had proven abdominal wall rejection, all treated successfully. Immediate revascularization of the abdominal wall allograft substantially reduces cold ischemia without imposing constraints on the intestinal transplant. Reducing storage time may also have benefits with respect to ischemia-reperfusion-related graft immunogenicity. PMID- 24797612 TI - Creatine prevents the imbalance of redox homeostasis caused by homocysteine in skeletal muscle of rats. AB - Homocystinuria is a neurometabolic disease caused by severe deficiency of cystathionine beta-synthase activity, resulting in severe hyperhomocysteinemia. Affected patients present several symptoms including a variable degree of motor dysfunction, being that the pathomechanism is not fully understood. In the present study we investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative stress, namely 2'7'dichlorofluorescein (DCFH) oxidation, levels of thiobarbituric acid-reactive substances (TBARS), antioxidant enzyme activities (SOD, CAT and GPx), reduced glutathione (GSH), total sulfhydryl and carbonyl content, as well as nitrite levels in soleus skeletal muscle of young rats subjected to model of severe hyperhomocysteinemia. We also evaluated the effect of creatine on biochemical alterations elicited by hyperhomocysteinemia. Wistar rats received daily subcutaneous injection of homocysteine (0.3-0.6 MUmol/g body weight), and/or creatine (50mg/kg body weight) from their 6th to the 28th days age. Controls and treated rats were decapitated at 12h after the last injection. Chronic homocysteine administration increased 2'7'dichlorofluorescein (DCFH) oxidation, an index of production of reactive species and TBARS levels, an index of lipoperoxidation. Antioxidant enzyme activities, such as SOD and CAT were also increased, but GPx activity was not altered. The content of GSH, sulfhydril and carbonyl were decreased, as well as levels of nitrite. Creatine concurrent administration prevented some homocysteine effects probably by its antioxidant properties. Our data suggest that the oxidative insult elicited by chronic hyperhomocystenemia may provide insights into the mechanisms by which homocysteine exerts its effects on skeletal muscle function. Creatine prevents some alterations caused by homocysteine. PMID- 24797613 TI - Microbial and Carbohydrate Active Enzyme profile of buffalo rumen metagenome and their alteration in response to variation in the diet. AB - Rumen microbiome represents rich source of enzymes degrading complex plant polysaccharides. We describe here analysis of Carbohydrate Active Enzymes (CAZymes) from 3.5 gigabase sequences of metagenomic data from rumen samples of Mehsani buffaloes fed on different proportions of green or dry roughages to concentrate ration. A total of 2597 contigs encoding putative CAZymes were identified by CAZyme Analysis Toolkit (CAT). The phylogenetic analysis of these contigs by MG-RAST revealed predominance of Bacteroidetes, followed by Firmicutes, Proteobacteria, and Actinobacteria phyla. Moreover, a higher abundance of oligosaccharide degrading and debranching enzymes in buffalo rumen metagenome and that of cellulases and hemicellulases in termite hindgut was observed when we compared glycoside hydrolase (GH) profile of buffalo rumen metagenome with cow rumen, termite hindgut and chicken caecum metagenome. Further, comparison of microbial profile of green or dry roughage fed animals showed significantly higher abundance (p-value<0.05) of various polysaccharide degrading bacterial genera like Fibrobacter, Prevotella, Bacteroides, Clostridium and Ruminococcus in green roughage fed animals. In addition, we found a significantly higher abundance (p-value<0.05) of enzymes associated with pectin digestion such as pectin lyase (PL) 1, PL10 and GH28 in green roughage fed animals. Our study outlines CAZyme profile of buffalo rumen metagenome and provides a scope to study the role of abundant enzyme families (oligosaccharide degrading and debranching enzymes) in digestion of coarse feed. PMID- 24797614 TI - Spatially conserved regulatory elements identified within human and mouse Cd247 gene using high-throughput sequencing data from the ENCODE project. AB - The Cd247 gene encodes for a transmembrane protein important for the expression and assembly of TCR/CD3 complex on the surface of T lymphocytes. Down-regulation of CD247 has functional consequences in systemic autoimmunity and has been shown to be associated with Type 1 Diabetes in NOD mouse. In this study, we have utilized the wealth of high-throughput sequencing data produced during the Encyclopedia of DNA Elements (ENCODE) project to identify spatially conserved regulatory elements within the Cd247 gene from human and mouse. We show the presence of two transcription factor binding sites, supported by histone marks and ChIP-seq data, that specifically have features of an enhancer and a promoter, respectively. We also identified a putative long non-coding RNA from the characteristically long first intron of the Cd247 gene. The long non-coding RNA annotation is supported by manual annotations from the GENCODE project in human and our expression quantification analysis performed in NOD and B6 mice using qRT PCR. Furthermore, 17 of the 23 SNPs already known to be implicated with T1D were observed within the long non-coding RNA region in mouse. The spatially conserved regulatory elements identified in this study have the potential to enrich our understanding of the role of Cd247 gene in autoimmune diabetes. PMID- 24797615 TI - Complete mitochondrial genome of the atlas moth, Attacus atlas (Lepidoptera: Saturniidae) and the phylogenetic relationship of Saturniidae species. AB - Mitochondrial genome (mitogenome) can provide information for genomic structure as well as for phylogenetic analysis and evolutionary biology. In this study, we present the complete mitogenome of the atlas moth, Attacus atlas (Lepidoptera: Saturniidae), a well-known silk-producing and ornamental insect with the largest wing surface area of all moths. The mitogenome of A. atlas is a circular molecule of 15,282 bp long, and its nucleotide composition shows heavily biased towards As and Ts, accounting for 79.30%. This genome comprises 13 protein-coding genes (PCGs), two ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), and an A+T-rich region. It is of note that this genome exhibits a slightly positive AT skew, which is different from the other known Saturniidae species. All PCGs are initiated by ATN codons, except for COI with CGA instead. Only six PCGs use a common stop codon of TAA or TAG, whereas the remaining seven use an incomplete termination codon T or TA. All tRNAs have the typical clover-leaf structure, with an exception for tRNA(Ser)(AGN). The A. atlas A+T-rich region contains non repetitive sequences, but harbors several features common to the Bombycoidea insects. The phylogenetic relationships based on Maximum Likelihood method provide a well-supported outline of Saturniidae, which is in accordance with the traditional morphological classification and recent molecular works. PMID- 24797616 TI - Iron colloids reduce the bioavailability of phosphorus to the green alga Raphidocelis subcapitata. AB - Phosphorus (P) is a limiting nutrient in many aquatic systems. The bioavailability of P in natural waters strongly depends on its speciation. In this study, structural properties of iron colloids were determined and related to their effect on P sorption and P bioavailability. The freshwater green alga Raphidocelis subcapitata was exposed to media spiked with radiolabelled (33)PO4, and the uptake of (33)P was monitored for 1 h. The media contained various concentrations of synthetic iron colloids with a size between 10 kDa and 0.45 MUm. The iron colloids were stabilised by natural organic matter. EXAFS spectroscopy showed that these colloids predominantly consisted of ferrihydrite with small amounts of organically complexed Fe. In colloid-free treatments, the P uptake flux by the algae obeyed Michaelis-Menten kinetics. In the presence of iron colloids at 9 or 90 MUM Fe, corresponding to molar P:Fe ratios between 0.02 and 0.17, the truly dissolved P (<10 kDa) was between 4 and 60% of the total dissolved P (<0.45 MUm). These colloids reduced the P uptake flux by R. subcapitata compared to colloid-free treatments at the same total dissolved P concentration. However, the P uptake flux from colloid containing solutions equalled that from colloid-free ones when expressed as truly dissolved P. This demonstrates that colloidal P did not contribute to the P uptake flux. It is concluded that, on the short term, phosphate adsorbed to ferrihydrite colloids is not available to the green alga R. subcapitata. PMID- 24797617 TI - Testosterone and cardiovascular risk: world's experts take unprecedented action to correct misinformation. PMID- 24797618 TI - The Atraumatic Restorative Treatment (ART) approach can improve oral health for the elderly; myth or reality? PMID- 24797619 TI - Reactive osteocartilaginous metaplasia in denture wearers: a rare trauma-related lesion. AB - OBJECTIVE: To present a case of reactive osteocartilaginous metaplasia (ROCM) in the anterior edentulous mandibular ridge. BACKGROUND: The ROCM secondary to chronic mechanical denture trauma is rare and appears as a focal sometimes painful mass on or near the crest of the edentulous alveolar ridge in long-term denture wearers. The literature review disclosed 24 cases involving more commonly the posterior portion of the mandible. MATERIALS AND METHODS: An 80-year-old female was referred for the evaluation of a painful, submucosal nodule extending into the vestibular mucosa of the anterior edentulous mandibular region. Microscopically, cartilaginous regions exhibiting sparse hyperchromatic or binucleated chondrocytes transitioned into areas of ossification. RESULTS: The diagnosis was ROCM. The presence of osteocartilaginous tissue displaying bizarre histopathological features can create a diagnostic dilemma. CONCLUSION: Complete conservative surgical excision of this lesion has a very good prognosis. Surgical augmentation of the sharp edentulous mandibular ridges might be needed to avoid continuous irritation and possible recurrence. PMID- 24797620 TI - Thermal burn of palate in an elderly diabetic patient. AB - BACKGROUND: Burns of the oral mucosa may be caused by thermal, mechanical, chemical, electrical or radiation injury. Clinically, these burns can produce localised or diffuse areas of tissue damage depending on the severity and extent of the insult. Most oral thermal burns produce erosions or ulcers on the palate or tongue. MATERIALS AND METHODS: A case of palatal burn in a 66-year-old diabetic patient caused by drinking hot cereal is presented. The role of diabetes in causing oral mucosal dysesthesia that predisposed the occurrence of this burn is also discussed. CONCLUSION: Insensate palatal burn as a rare complication of diabetes mellitus is reported here. With the disease being more widespread now, its potential oral complications will be seen with increasing frequency. PMID- 24797622 TI - Priority and emerging pollutants in sewage sludge and fate during sludge treatment. AB - This paper aims at characterizing the quality of different treated sludges from Paris conurbation in terms of micropollutants and assessing their fate during different sludge treatment processes (STP). To achieve this, a large panel of priority and emerging pollutants (n=117) have been monitored in different STPs from Parisian wastewater treatment plants including anaerobic digestion, thermal drying, centrifugation and a sludge cake production unit. Considering the quality of treated sludges, comparable micropollutant patterns are found for the different sludges investigated (in mg/kg DM - dry matter). 35 compounds were detected in treated sludges. Some compounds (metals, organotins, alkylphenols, DEHP) are found in every kinds of sludge while pesticides or VOCs are never detected. Sludge cake is the most contaminated sludge, resulting from concentration phenomenon during different treatments. As regards treatments, both centrifugation and thermal drying have broadly no important impact on sludge contamination for metals and organic compounds, even if a slight removal seems to be possible with thermal drying for several compounds by abiotic transfers. Three different behaviors can be highlighted in anaerobic digestion: (i) no removal (metals), (ii) removal following dry matter (DM) elimination (organotins and NP) and iii) removal higher than DM (alkylphenols - except NP - BDE 209 and DEHP). Thus, this process allows a clear removal of biodegradable micropollutants which could be potentially significantly improved by increasing DM removal through operational parameters modifications (retention time, temperature, pre-treatment, etc.). PMID- 24797623 TI - Evolution of simeprevir-resistant variants over time by ultra-deep sequencing in HCV genotype 1b. AB - Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants. PMID- 24797624 TI - Are intra-articular injections of Hylan G-F 20 efficacious in painful osteoarthritis of the knee? A systematic review & meta-analysis. AB - AIM: To systematically review evidence and perform a meta-analysis of the efficacy of intra-articular (IA) injections of Hylan G-F 20 for the treatment of painful osteoarthritis (OA) of the knee. METHODS: Systematic review of the Embase and PubMed databases up to July 2013 of randomised placebo-controlled trials studying the effect of Hylan G-F 20 in patients with painful knee OA, with a meta analysis of trials reporting visual analogue scores (VAS) for weight-bearing pain in the knees of patients followed up for a minimum of 6 months. RESULTS: Six placebo-controlled randomised trials were identified on systematic review of which two studies met criteria for inclusion in the meta-analysis. Meta-analysis demonstrated that at 6-month follow up, there was no significant difference between Hylan G-F 20 and control in terms of reduction in VAS for weight bearing pain. (Mean Difference - 12.96 (95% CI: -35.48, 9.56). Z tests used to test for overall effect showed that the difference between the two groups was not significant (p = 0.26). DISCUSSION: A significant placebo effect exists for patients receiving IA injections for the treatment of painful knee OA. The withdrawal of fluid from the affected knee prior to any injectable therapy may itself have additional benefits which in isolation have not been studied. This may form the basis of future research. The authors' acknowledge that although limited conclusions can be drawn from the results of this study, the meta analysis presented has not been performed previously and will further contribute to the knowledge on this subject. CONCLUSION: Although Hylan G-F 20 may produce improvement in VAS scores for weight-bearing pain at 6-month follow up in OA knees treated with it, patients should be informed that this may be equivalent to that seen with control treatments. PMID- 24797625 TI - EBC-219: a new diterpene skeleton, crotinsulidane, from the Australian rainforest containing a bridgehead double bond. AB - EBC-219 (4), isolated from Croton insularis (Baill), was established by spectroscopic and DFT methods as the first member of a new diterpene skeletal class, uniquely defined by the presence of a bicyclo[10.2.1] bridgehead olefin. The proposed biogenetic pathway to 4 from the co-isolated natural products EBC 131 (1), EBC-180 (2) and EBC-181 (3) is highly likely. EBC-180 (2) and EBC-181 (3) showed moderate to strong cytotoxic activity against various cancer cell lines. PMID- 24797627 TI - Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating. AB - Intermittent fasting (IF) is an often-used intervention to decrease body mass. In male Sprague-Dawley rats, 24 hour cycles of IF result in light caloric restriction, reduced body mass gain, and significant decreases in the efficiency of energy conversion. Here, we study the metabolic effects of IF in order to uncover mechanisms involved in this lower energy conversion efficiency. After 3 weeks, IF animals displayed overeating during fed periods and lower body mass, accompanied by alterations in energy-related tissue mass. The lower efficiency of energy use was not due to uncoupling of muscle mitochondria. Enhanced lipid oxidation was observed during fasting days, whereas fed days were accompanied by higher metabolic rates. Furthermore, an increased expression of orexigenic neurotransmitters AGRP and NPY in the hypothalamus of IF animals was found, even on feeding days, which could explain the overeating pattern. Together, these effects provide a mechanistic explanation for the lower efficiency of energy conversion observed. Overall, we find that IF promotes changes in hypothalamic function that explain differences in body mass and caloric intake. PMID- 24797626 TI - Fetal alcohol exposure disrupts metabolic signaling in hypothalamic proopiomelanocortin neurons via a circadian mechanism in male mice. AB - Early-life ethanol feeding (ELAF) alters the metabolic function of proopiomelanocortin (POMC)-producing neurons and the circadian expression of clock regulatory genes in the hypothalamus. We investigated whether the circadian mechanisms control the action of ELAF on metabolic signaling genes in POMC neurons. Gene expression measurements of Pomc and a selected group of metabolic signaling genes, Stat3, Sirt1, Pgc1-alpha, and Asb4 in laser-captured microdissected POMC neurons in the hypothalamus of POMC-enhanced green fluorescent protein mice showed circadian oscillations under light/dark and constant darkness conditions. Ethanol programmed these neurons such that the adult expression of Pomc, Stat3, Sirt, and Asb4 gene transcripts became arrhythmic. In addition, ELAF dampened the circadian peak of gene expression of Bmal1, Per1, and Per2 in POMC neurons. We crossed Per2 mutant mice with transgenic POMC-enhanced green fluorescent protein mice to determine the role of circadian mechanism in ELAF-altered metabolic signaling in POMC neurons. We found that ELAF failed to alter arrhythmic expression of most circadian genes, with the exception of the Bmal1 gene and metabolic signaling regulating genes in Per2 mutant mice. Comparison of the ELAF effects on the circadian blood glucose in wild-type and Per2 mutant mice revealed that ELAF dampened the circadian peak of glucose, whereas the Per2 mutation shifted the circadian cycle and prevented the ELAF dampening of the glucose peak. These data suggest the possibility that the Per2 gene mutation may regulate the ethanol actions on Pomc and the metabolic signaling genes in POMC neurons in the hypothalamus by blocking circadian mechanisms. PMID- 24797628 TI - Leptin signaling in the rainbow trout central nervous system is modulated by a truncated leptin receptor isoform. AB - Central leptin (Lep) signaling is important in control of appetite and energy balance in mammals, but information on Lep signaling and physiological roles in early vertebrates is still lacking. To elucidate fish Lep signaling activation and modulation, a long-form Lep receptor (LepRL) and a truncated LepR (LepRT) are functionally characterized from rainbow trout. The receptors generated in alternatively splicing events have identical extracellular and transmembrane domains but differ in the intracellular sequence, both in length and identity. Gene transfection experiments show that LepRL is expressed as a 125-kDa protein in rainbow trout hepatoma cell line RTH-149, whereas LepRT is 100 kDa; both receptors specifically bind Lep. Homogenous Lep induces tyrosine phosphorylation of Janus kinase 2 and signal transducer and activation of transcription 3 in LepRL-expressing RTH-149 cells. This response is diminished in cells coexpressing LepRL and LepRT, suggesting that the LepRT which lacks these kinase-associated motifs competes with the LepRL for Lep availability, thus attenuating the Lep signal. Both receptor genes are highly expressed in the central nervous system. The mRNA levels of LepRT in hypothalamus, but not LepRL, change postprandially, with decreased transcription at 2 hours postfeeding and then elevated at 8 hours, concomitant with changes in proopiomelanocortin-A1 transcription. However, both receptors have no change in mRNA levels during 3 weeks of fasting. These data indicate that LepRT transcription is more likely a mechanism for modulating Lep effects on short-term feed intake than in regulating energy balance in the long term. In vitro and physiological characterization of LepR isoforms indicates divergent Lep signaling modulation patterns among vertebrates with different life histories and metabolic profiles. PMID- 24797629 TI - Intrarenal ghrelin receptor antagonism prevents high-fat diet-induced hypertension in male rats. AB - Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure in response to high-fat diet (HFD) is preceded by significant increases in renal tubular sodium (Na(+)) reabsorption. In normal rats, intrarenal ghrelin infusion increases distal nephron-dependent Na(+) reabsorption via activation of the intrarenal ghrelin receptor (GHSR). This study focusses on the role of intrarenal GHSR-mediated Na(+) reabsorption in HFD induced hypertension. Dahl salt-sensitive rats received standard diet or HFD for 6 weeks. Rats underwent uninephrectomy and osmotic minipump implantation for chronic intrarenal delivery of vehicle (0.25 MUL/h * 28 d), selective GHSR antagonist [D-Lys-3]-growth hormone releasing peptide-6 (0.2MUM/d), or GHSR inverse agonist [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P (SUB-P) (3.6MUM/d). HFD rats with vehicle pumps had significantly increased renal GHSR expression compared with standard diet (0.092 +/- 0.005 vs 0.065 +/- 0.004 arbitrary units; P < .05), whereas acyl ghrelin levels were similar (16.3+/-6.2 vs 15.7+/-8.7 pg/g tissue). HFD rats with vehicle pumps became hypertensive after 2 weeks (P < .05) and showed a significant reduction in 24-hour urine Na(+) before hypertension. At this time, these rats showed an increase in collecting duct alpha-epithelial Na(+) channel, thereby providing a potential mechanism for the excess Na(+) reabsorption. In contrast, HFD rats with [D-Lys-3]-growth hormone releasing peptide-6 or SUB-P pumps never became hypertensive and did not show the reduction in urine Na(+). Because SUB-P blocks the constitutive, but not ghrelin-dependent, activity of the GHSR, and HFD-induced alpha-epithelial Na(+) channel up-regulation was abolished during GHSR antagonism, these data suggest that HFD increases the constitutive activity of renal GHSR to increase Na(+) reabsorption and induce hypertension in rats. PMID- 24797630 TI - Regulation and function of deiodinases during decidualization in female mice. AB - Thyroid dysfunction during human pregnancy is closely related to serious pregnancy outcome. However, the regulation and function of thyroid hormones during early pregnancy are largely unknown. We found that type II deiodinase, an enzyme converting T4 to activated T3, is highly expressed in the mouse uterus on days 3 and 4 of pregnancy. Once the embryo implants into the receptive uterus, type III deiodinase (Dio3), a mainly paternally imprinted gene for inactivating T3, is significantly induced in the stromal cells and accompanied by DNA hypermethylation of intergenic differentially CpG methylation regions in the delta-like 1 homolog-Dio3 imprinting cluster. The concentration of uterine free T3 is actually decreased after embryo implantation. T3 induces Dio3 expression both in vivo and in vitro, suggesting a positive feedback loop. T3 addition or Dio3 knockdown compromises decidualization. These results indicate that the Dio3 mediated local T3 decrease is critical for decidualization of stromal cells during early pregnancy. Furthermore, we found that progesterone regulates Dio3 expression through its cognate receptor both in vivo and in vitro. Additionally, cAMP regulates Dio3 transcription through the protein kinase A-cAMP response element-binding protein pathway. The inhibition of the protein kinase A pathway results in decreased Dio3 expression and impaired decidualization. Dio3 opposite strand (Dio3os) expressed in a similar pattern to Dio3, is transcribed from the opposite strand of Dio3 and fine-tunes Dio3 expression during decidualization. Our data indicate that Dio3 is strongly expressed and tightly controlled during decidualization. PMID- 24797631 TI - The catalytic function of hormone-sensitive lipase is essential for fertility in male mice. AB - In male mice, deficiency of hormone sensitive lipase (HSL, Lipe gene, E.C.3.1.1.3) causes deficient spermatogenesis, azoospermia, and infertility. Postmeiotic germ cells express a specific HSL isoform that includes a 313 amino acid N-terminus encoded by a testis-specific exon (exon T1). The remainder of testicular HSL is identical to adipocyte HSL. The amino acid sequence of the testis-specific exon is poorly conserved, showing only a 46% amino acid identity with orthologous human and rat sequences, compared with 87% over the remainder of the HSL coding sequence, providing no evidence in favor of a vital functional role for the testis-specific N-terminus of HSL. However, exon T1 is important for Lipe transcription; in mouse testicular mRNA, we identified 3 major Lipe transcription start sites, finding numerous testicular transcription factor binding motifs upstream of the transcription start site. We directly explored two possible mechanisms for the infertility of HSL-deficient mice, using mice that expressed mutant HSL transgenes only in postmeiotic germ cells on a HSL-deficient background. One transgene expressed human HSL lacking enzyme activity but containing the testis-specific N-terminus (HSL-/-muttg mice). The other transgene expressed catalytically inactive HSL with the testis-specific N-terminal peptide (HSL-/-atg mice). HSL-/-muttg mice were infertile, with abnormal histology of the seminiferous epithelium and absence of spermatozoa in the epididymal lumen. In contrast, HSL-/-atg mice had normal fertility and normal testicular morphology. In conclusion, whereas the catalytic function of HSL is necessary for spermatogenesis in mice, the presence of the N-terminal testis-specific fragment is not essential. PMID- 24797633 TI - Gestational protein restriction impairs insulin-regulated glucose transport mechanisms in gastrocnemius muscles of adult male offspring. AB - Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet fed rats gained less weight than controls during pregnancy. Male pups from LP diet-fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor substrate-1, and AS160 phosphorylation and impaired glucose transporter type 4 translocation. PMID- 24797632 TI - Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment. AB - Adverse experiences during gestation such as maternal stress and infection are known risk factors for neurodevelopmental disorders, including schizophrenia, autism, and attention deficit/hyperactivity disorder. The mechanisms by which these distinct exposures may confer similar psychiatric vulnerability remain unclear, although likely involve pathways common to both stress and immune responses at the maternal-fetal interface. We hypothesized that maternal stress induced activation of immune pathways within the placenta, the sex-specific maternal-fetal intermediary, may contribute to prenatal stress programming effects on the offspring. Therefore, we assessed for markers indicative of stress induced placental inflammation, and examined the ability of maternal nonsteroidal antiinflammatory drug (NSAID) treatment to ameliorate placental effects and thereby rescue the stress-dysregulation phenotype observed in our established mouse model of early prenatal stress (EPS). As expected, placental gene expression analyses revealed increased levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1beta, specifically in male placentas. NSAID treatment partially ameliorated these EPS effects. Similarly, in adult offspring, males displayed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal NSAID treatment. Fitting with these outcomes and supportive of dopamine pathway involvement, expression of dopamine D1 and D2 receptors was altered by EPS in males. These studies support an important interaction between maternal stress and a proinflammatory state in the long-term programming effects of maternal stress. PMID- 24797634 TI - TRalpha protects against atherosclerosis in male mice: identification of a novel anti-inflammatory property for TRalpha in mice. AB - Hypothyroidism is associated with an increased occurrence of atherosclerosis, suggesting some protective role for thyroid hormones (THs). Hypercholesterolemia is one of the major risk factor to develop this disease. Here, we show that the well-known TH cholesterol lowering effect was dependent on TH nuclear receptor (TR)beta liver activity. But most importantly, TRalpha was also shown to contribute of slowing down atherosclerosis progression via an independent mechanism. Introduction of TRalpha(0/0) deletion in the ApoE(-/-) background accelerated the appearance of plaques. Earlier cholesterol accumulation was detected in aorta macrophages, likely due to impaired cholesterol efflux. The IL 1beta inflammatory cytokine was elevated in serum and macrophages in correlation with an activation of the AKT/nuclear factor kappaB pathway in these cells. Inhibition of AKT prevented inflammation and restored normal cholesterol efflux. Similar low-grade inflammation was identified in TRalpha(0/0) male mice. Thus, the mere absence of TRalpha is associated with elevated levels of cytokines likely responsible for cholesterol accumulation and atherosclerosis. This TRalpha protective activity should be relevant for other inflammatory pathologies. PMID- 24797635 TI - Phosphorylation of CDK2 at threonine 160 regulates meiotic pachytene and diplotene progression in mice. AB - Telomere clustering is a widespread phenomenon among eukaryotes. However, the molecular mechanisms that regulate formation of telomere clustering in mammalian meiotic prophase I, are still largely unknown. Here, we show that CDK2, especially p39(cdk2), as a potential meiosis-specific connector interaction with SUN1 mediates formation of telomere clustering during mouse meiosis. The transition from CDK2 to p-CDK2 also regulates the progression from homologous recombination to desynapsis by interacting with MLH1. In addition, disappearance of CDK2 on the telomeres and of p-CDK2 on recombination sites, were observed in Sun1(-/-) mice and in pachytene-arrested hybrid sterile mice (pwk*C57BL/6 F1), respectively. These results suggest that transition from CDK2 to p-CDK2 plays a critical role for regulating meiosis progression. PMID- 24797636 TI - Transcriptional co-regulation of evolutionarily conserved microRNA/cone opsin gene pairs: implications for photoreceptor subtype specification. AB - The vertebrate retina contains two types of photoreceptor cells, rods and cones, which use distinct types of opsins and phototransduction proteins. Cones can be further divided into several subtypes with differing wavelength sensitivity and morphology. Although photoreceptor development has been extensively studied in a variety of vertebrate species, the mechanism by which photoreceptor subtypes are established is still largely unknown. Here we report two microRNAs (miRNAs), miR 726 and miR-729, which are potentially involved in photoreceptor subtype specification. In the medaka Oryzias latipes, the genes encoding miR-726 and miR 729 are located upstream of the red-sensitive opsin gene LWS-A and the UV sensitive opsin gene SWS1, respectively, and are transcribed in the opposite direction from the respective opsin genes. The miR-726/LWS pair is conserved between teleosts and tetrapods, and the miR-729/SWS1 pair is conserved among teleosts. in situ hybridization analyses and fluorescence reporter assays suggest that these miRNAs are co-expressed with the respective opsins in specific cone subtypes. Potential targets of miR-726 and miR-729 predicted in silico include several transcription factors that regulate photoreceptor development. Functional analyses of cis-regulatory sequences in vivo suggest that transcription of the paired microRNA and opsin genes is co-regulated by common cis-regulatory modules. We propose an evolutionarily conserved mechanism that controls photoreceptor subtype identity through coupling between transcriptional and post transcriptional regulations. PMID- 24797637 TI - Mesh reconstruction of the inguinal ligament with bone anchors following radical oncologic excision: a case series. PMID- 24797638 TI - A comparison of Progrip((r)) and Adhesix ((r)) self-adhering hernia meshes in an onlay model in the rat. AB - BACKGROUND: Atraumatic fixation is a key element of modern hernia repair. Two different concepts of self-adhering meshes were directly compared in this study. Adhesix((r)) (AH) is coated with polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP), whereas Parietene Progrip((r)) (PP) relies on the mechanical principle of micro grips made of polylactic acid (PLA). These meshes are the main competitors in the field. METHODS: AH and PP were tested in Sprague Dawley rats at 14 and 90 days. Four groups were operated (n = 8 animals per group). Two meshes were implanted per animal in an operation model of onlay hernia repair. Dislocation, tissue integration and foreign-body reaction were evaluated. RESULTS: AH dislocated significantly more frequently (every second mesh) at both time points of observation than PP. Tissue integration was good with PP and could not be reliably assessed in AH due to frequent dislocation. Histologic examination revealed only a mild foreign body reaction in all groups. CONCLUSIONS: In our hands, PP (mechanical grip fixation) was superior to hydrogel fixation with PEG and PVP in AH in an onlay model. The reason for dislocation of AH requires further clarification as well as the impact of long-term degradation of the PLA grips. PMID- 24797639 TI - Protecting effect of recycled urban wastes (sewage sludge and wastewater) on ryegrass against the toxicity of pesticides at high concentrations. AB - Degraded landscapes, like those from abandoned mine areas, could be restored by revegetating them with appropriate plant species, after correction for acidity and improvement by adding exogenous organic material. Application of urban wastes to large areas of derelict land helps in the sustainable development of this landscape. However, the development of plant species in these soils could require in the future the management of possible pests or diseases by pesticide applications which could also affect plant yield. Therefore, ryegrass (Lolium perenne L.) was planted in a limed soil from the mining area of Riotinto (SW Spain), using an indoor pot experiment and the effects of amendment with sewage sludge, as well as irrigation with urban wastewater on plant uptake of the insecticide thiacloprid and the fungicide fenarimol were examined. Ryegrass biomass was reduced up to 3-fold by pesticide application. Fenarimol residues were the highest in soil, while those of thiacloprid were lower in soil and higher in ryegrass. Addition of sewage sludge and irrigation with wastewater led to a reduction of pesticide translocation to the aerial plant parts, representing a lower hazard to ryegrass quality grown in this mine soil. PMID- 24797640 TI - Synthesis and reactivity of 4'-deoxypentenosyl disaccharides. AB - 4-Deoxypentenosides (4-DPs) are versatile synthons for rare or higher-order pyranosides, and they provide an entry for structural diversification at the C5 position. Previous studies have shown that 4-DPs undergo stereocontrolled DMDO oxidation; subsequent epoxide ring-openings with various nucleophiles can proceed with both anti or syn selectivity. Here, we report the synthesis of alpha- and beta-linked 4'-deoxypentenosyl (4'-DP) disaccharides, and we investigate their post-glycosylational C5' additions using the DMDO oxidation/ring-opening sequence. The alpha-linked 4'-DP disaccharides were synthesized by coupling thiophenyl 4-DP donors with glycosyl acceptors using BSP/Tf2O activation, whereas beta-linked 4'-DP disaccharides were generated by the decarboxylative elimination of glucuronyl disaccharides under microwave conditions. Both alpha- and beta linked 4'-DP disaccharides could be epoxidized with high stereoselectivity using DMDO. In some cases, the alpha-epoxypentenosides could be successfully converted into terminal l-iduronic acids via the syn addition of 2-furylzinc bromide. These studies support a novel approach to oligosaccharide synthesis, in which the stereochemical configuration of the terminal 4'-DP unit is established at a post glycosylative stage. PMID- 24797641 TI - Out of the woods, a Mayo Clinic emerges: a commentary on the history of Mayo Clinic in Florida. PMID- 24797642 TI - Value and process of curbside consultations in clinical practice: a grounded theory study. AB - OBJECTIVES: To clarify the value and process of the curbside consultation and identify ways to optimize this activity. PARTICIPANTS AND METHODS: We conducted 13 focus groups at an academic medical center and outlying community sites (September 2011 to January 2013), involving a purposive sample of 54 primary care and subspecialist internal medicine and family medicine physicians. Focus group discussions were transcribed and then analyzed using a constant comparative approach to identify benefits, liabilities, mechanisms, and potential improvements related to curbside consultations. RESULTS: We developed a model describing the role and process of the curbside consultation. Focus group participants perceived that curbside consultations add particular value in offering immediate, individualized answers with bidirectional information exchange, and this in turn expedites patient care and elevates patient confidence. Despite the uncompensated interruption and potential risks, experts provide curbside consultations because they appreciate the honor of being asked and the opportunity to help colleagues, expedite patient care, and teach. Key decisions for the initiator (each reflecting a potential barrier) include whom to contact, how to contact that expert, and how to determine availability. Experts decide to accept a request on the basis of personal expertise, physical location, and capacity to commit time and attention. Participants suggested systems-level improvements to facilitate expert selection, clarify expert availability, enhance access to clinical information, and acknowledge the expert's effort. CONCLUSIONS: Curbside consultations play an important role in enhancing communication and care coordination in clinical medicine, but the process can be further improved. Information technology solutions may play a key role. PMID- 24797643 TI - Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease. AB - OBJECTIVE: To determine whether elevated serum polyclonal free light chain (FLC) levels predict mortality in a population of individuals with chronic kidney disease (CKD). PATIENTS AND METHODS: From January 2, 2006, through July 31, 2007, we recruited a cohort of 848 people with CKD who were not receiving renal replacement therapy and did not have monoclonal gammopathy. We measured serum kappa FLC and lambda FLC isotype levels to determine combined FLC (cFLC) levels. The cohort was prospectively followed up for a median of 63 months (interquartile range, 0-93 months). Cox regression analysis was performed to determine variables predictive of mortality. RESULTS: High cFLC levels were an independent risk factor for death (hazard ratio [HR], 2.71; 95% CI, 1.98-3.70; P<.001). Other independent risk factors were age (HR, 1.79; 95% CI, 1.52-2.10; P<.001), South Asian ethnicity (HR, 0.33; 95% CI, 0.14-0.64; P=.02), preexisting cardiovascular disease (HR, 1.59; 95% CI, 1.09-2.31; P=.02), and high-sensitivity C-reactive protein (HR, 1.13; 95% CI, 1.00-1.28; P=.04). Neither estimated glomerular filtration rate nor albuminuria was an independent risk factor for death. CONCLUSION: High cFLC levels independently predict mortality in people with CKD. PMID- 24797644 TI - Risk scores for 30-day mortality after percutaneous coronary intervention: new insights into causes and risk of death. AB - OBJECTIVE: To determine the causes and risk of death after percutaneous coronary interventions (PCIs) and to compare the discriminatory ability of the New York State Risk Score (NYSRS) with the Mayo Clinic Risk Score (MCRS). PATIENTS AND METHODS: We studied in-hospital and 30-day mortality after PCI in 4898 patients treated at Mayo Clinic in Rochester, Minnesota, from January 1, 2007, through December 31, 2010, to validate the NYSRS equation with recalibrated predicted probabilities of death. RESULTS: Of the 4898 patients studied, 93 (1.9%) died during the index hospitalization, and 36 (0.7%) died within 30 days after discharge. For the in-hospital and 30-day mortality, respectively, the area under the receiver operating characteristic curve was 0.92 and 0.88 for the NYSRS and 0.93 and 0.90 for the MCRS, indicating excellent discrimination. The NYSRS model underpredicted event rates when applied in Mayo Clinic data (2.6% observed [127 of 4898 patients] vs 2.3% predicted [114 of 4898 patients]), even after recalibration. The instantaneous hazard over time revealed the highest risk of death in the first 3 days after PCI (daily probability, >0.2%), declined to 0.1% until about day 12, and then decreased below 0.1%. Cardiac causes (mainly myocardial infarction) dominated in the first week (83 of 85 deaths [97.6%]) and then decreased to 59.5% (25 of 42 deaths) between 8 and 30 days after PCI. CONCLUSION: The discriminatory ability of the NYSRS and the MCRS for in-hospital and 30-day mortality after PCI is roughly interchangeable. The risk of death is highest during the first 2 weeks and is dominated by cardiac causes of death. PMID- 24797645 TI - Professionalism: good for patients and health care organizations. AB - Professionalism is an indispensable element in the compact between the medical profession and society that is based on trust and putting the needs of patients above all other considerations. The resurgence of interest in professionalism dates back to the 1980s when health maintenance organizations were formed and proprietary influences in health care increased. Since then, a rich and comprehensive literature has emerged in defining professionalism, including desirable individual attributes and behaviors and how they may be taught, promoted, and assessed. More recently, scholarship has shifted from individual to organizational professionalism. This literature addresses the role that health care organizations can play to establish environments that are conducive to the consistent expression of professionalism by individuals and health care teams. We reviewed interdisciplinary empirical studies from health care effectiveness and outcomes, organizational sciences, positive psychology, and social psychology, finding evidence that organizational and individual professionalism is associated with a wide range of benefits to patients and the organization. We identify actionable organizational strategies and approaches that, if adopted, can foster and promote combined organizational and individual professionalism. In doing so, trust in the medical profession and its institutions can be enhanced, which in turn will reconfirm a commitment to the social compact. PMID- 24797646 TI - Patient-initiated second opinions: systematic review of characteristics and impact on diagnosis, treatment, and satisfaction. AB - The impact of second opinions on diagnosis in radiology and pathology is well documented; however, the value of patient-initiated second opinions for diagnosis and treatment in general medical practice is unknown. We conducted a systematic review of patient-initiated second opinions to assess their impact on clinical outcomes and patient satisfaction and to determine characteristics and motivating factors of patients who seek a second opinion. We searched PubMed, EMBASE, Cochrane, and Academic OneFile databases using Medical Subject Headings (MeSH) indexes and keyword searches. Search terms included referral and consultation, patient-initiated, patient preference, patient participation, second opinion, second review, and diagnosis. Multiple reviewers screened abstracts and articles to determine eligibility and extract data. We assessed risk of bias using the Cochrane Risk of Bias Tool and rated study quality using Cochrane's GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. We screened 1342 abstracts and reviewed full text of 41 articles, identifying 7 articles that reported clinical agreement data and 10 that discussed patient characteristics, motivation, and satisfaction. We found that a second opinion typically confirms the original diagnosis or treatment regimen but that 90% of patients with poorly defined conditions remain undiagnosed. However, 10% to 62% of second opinions yield a major change in the diagnosis, treatment, or prognosis. A larger fraction of patients receive different advice on treatment than on diagnosis. Factors motivating a second opinion include diagnosis or treatment confirmation, dissatisfaction with a consultation, desire for more information, persistent symptoms, or treatment complications. Patients generally believed that second opinions were valuable. Second opinions can result in diagnostic and treatment differences. The literature on patient-initiated second opinions is limited, and the accuracy of the second opinion through follow-up is generally unknown. Standardized methods and outcome measures are needed to determine the value of second opinions, and the potential of second opinions to reduce diagnostic errors merits more rigorous evaluation. PMID- 24797647 TI - Pneumatosis intestinalis with a focus on hyperbaric oxygen therapy. AB - Pneumatosis intestinalis is a rare condition of air in the bowel wall. Pneumatosis intestinalis is most often secondary to another medical condition. The diagnosis is most often made radiologically with a computed tomography scan. The disease severity ranges from benign to life-threatening. Predictors of poor outcomes include pH less than 7.3, bicarbonate level of less than 20 mEq/L, lactate level of more than 2 mmol/L, amylase level of more than 200 U/L, and portal venous gas on imaging. Early recognition of life-threatening signs and symptoms is critical. Treatment options include bowel rest, antibiotics, surgery, and, more recently, the use of hyperbaric oxygen therapy. Hyperbaric oxygen therapy is extremely safe, with no reported complications in the literature when used for pneumatosis intestinalis. When surgery is not emergently needed, symptomatic pneumatosis intestinalis can be safely treated with hyperbaric oxygen with a high likelihood of success without any considerable adverse effects. PMID- 24797648 TI - 75-year-old man with abdominal pain and reflux. PMID- 24797649 TI - Brain machine interface and limb reanimation technologies: restoring function after spinal cord injury through development of a bypass system. AB - Functional restoration of limb movement after traumatic spinal cord injury (SCI) remains the ultimate goal in SCI treatment and directs the focus of current research strategies. To date, most investigations in the treatment of SCI focus on repairing the injury site. Although offering some promise, these efforts have met with significant roadblocks because treatment measures that are successful in animal trials do not yield similar results in human trials. In contrast to biologic therapies, there are now emerging neural interface technologies, such as brain machine interface (BMI) and limb reanimation through electrical stimulators, to create a bypass around the site of the SCI. The BMI systems analyze brain signals to allow control of devices that are used to assist SCI patients. Such devices may include a computer, robotic arm, or exoskeleton. Limb reanimation technologies, which include functional electrical stimulation, epidural stimulation, and intraspinal microstimulation systems, activate neuronal pathways below the level of the SCI. We present a concise review of recent advances in the BMI and limb reanimation technologies that provides the foundation for the development of a bypass system to improve functional outcome after traumatic SCI. We also discuss challenges to the practical implementation of such a bypass system in both these developing fields. PMID- 24797650 TI - The lesser known side-effect of warfarin: warfarin-induced venous limb gangrene. PMID- 24797651 TI - Solomon's Seal, Flamingo Flower, Kousa Dogwood, and Kousa Dogwood by Harold Feinstein. AB - In recognition of the important part that art has had in the Mayo Clinic environment since the original Mayo Building was finished in 1914, Mayo Clinic Proceedings will feature some of the numerous works of art displayed throughout the buildings and grounds on the Mayo Clinic campuses. PMID- 24797652 TI - Adverse events in hospitalized paediatric patients: a systematic review and a meta-regression analysis. AB - RATIONALE, AIMS AND OBJECTIVES: To gain insight into the incidence of paediatric adverse events (AEs); to assess if there are significant differences among study results and to what extent methodological issues can explain them. METHODS: From November 2012 to January 2013, systematic literature searches were conducted on PubMed, Scopus and the Cochrane Library. We selected studies from 1970 onwards that evaluated the incidence of AEs in hospitalized paediatric patients and included a minimum of 1000 patient records with the same definition of AE. Studies that reported only specific AEs or only a specific ward were not considered. Data were extracted on the method of data collection, study design, type of hospital, and the timing of the AE in relation to its discovery and the index admission (time frame). AE incidence and preventability were considered. RESULTS: The pooled incidence of AEs was 2.0% (95% CI: 1.3-3.0%). Five methodological differences among studies were taken into account. Only the time frame of detected events had a statistically significant effect on the incidence of AEs (P<0.0001). The pooled incidence of preventable AEs was 46.2% (95% CI: 35.3-57.5%) with a high variability among studies. CONCLUSIONS: Our meta-analysis confirms that AEs are a major public health issue. Although studies use the same definition of AE, the reported incidence of AEs and preventable AEs varied considerably. To direct prevention efforts properly, studies methodologically more homogeneous and more detailed about the standard of health care provided and the health system organization are needed. PMID- 24797653 TI - Management of cardiac arrest in pregnancy. AB - Cardiac arrest in pregnancy is a rare event in routine obstetric practice, but is increasing in frequency. Resuscitation of cardiac arrest is more complex for pregnant women because of a number of factors unique to pregnancy: the altered physiologic state induced by pregnancy; the requirement to consider both maternal and fetal issues during resuscitation; and the consequent possibility of perimortem caesarean section during resuscitation. These extra considerations create a unique clinical emergency and decision pathway requiring the co ordinated response of medical, obstetric, and neonatal teams. Although many research questions remain in this area, recent consensus has been reached on appropriate resuscitation of a pregnant woman. Centres offering care for birthing women need to be aware of the changing demographics and resuscitation guidelines in this important area, and implement measures to ensure dependable and optimal team responses to maternal cardiac arrest. PMID- 24797654 TI - Successful anti-scavenger receptor class B type I (SR-BI) monoclonal antibody therapy in humanized mice after challenge with HCV variants with in vitro resistance to SR-BI-targeting agents. AB - Hepatitis C virus (HCV)-induced endstage liver disease is currently a major indication for liver transplantation. After transplantation the donor liver inevitably becomes infected with the circulating virus. Monoclonal antibodies (mAbs) against the HCV coreceptor scavenger receptor class B type I (SR-BI) inhibit HCV infection of different genotypes, both in cell culture and in humanized mice. Anti-SR-BI mAb therapy is successful even when initiated several days after HCV exposure, supporting its potential applicability to prevent HCV reinfection of liver allografts. However, HCV variants with reduced SR-BI dependency have been described in the literature, which could potentially limit the use of SR-BI targeting therapy. In this study we show, both in a preventative and postexposure setting, that humanized mice infected with HCV variants exhibiting increased in vitro resistance to SR-BI-targeting molecules remain responsive to anti-SR-BI mAb therapy in vivo. A 2-week antibody therapy readily cleared HCV RNA from the circulation of infected humanized mice. We found no evidence supporting increased SR-BI-receptor dependency of viral particles isolated from humanized mice compared to cell culture-produced virus. However, we observed that, unlike wild-type virus, the in vitro infectivity of the resistant variants was inhibited by both human high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The combination of mAb1671 with these lipoproteins further increased the antiviral effect. CONCLUSION: HCV variants that are less dependent on SR-BI in vitro can still be efficiently blocked by an anti-SR-BI mAb in humanized mice. Since these variants are also more susceptible to neutralization by anti-HCV envelope antibodies, their chance of emerging during anti-SR-BI therapy is severely reduced. Our data indicate that anti-SR-BI receptor therapy could be an effective way to prevent HCV infection in a liver transplant setting. PMID- 24797655 TI - Spectrum analysis of common inherited metabolic diseases in Chinese patients screened and diagnosed by tandem mass spectrometry. AB - BACKGROUND: Information concerning inherited metabolic diseases in China is scarce. We investigated the prevalence and age distributions of amino acid, organic acid, and fatty acid oxidation disorders in Chinese patients. METHODS: Blood levels of amino acids and acylcarnitines (tandem mass spectrometry) were measured in 18,303 patients with suspected inherited metabolic diseases. Diagnosis was based on clinical features, blood levels of amino acids or acylcarnitines, urinary organic acid levels (gas chromatography-mass spectrometry), and (in some) gene mutation tests. RESULTS: Inherited metabolic diseases were confirmed in 1,135 patients (739 males, 396 females). Median age was 12 months (1 day to 59 years). There were 28 diseases: 12 amino acid disorders (580 patients, 51.1%), with hyperphenylalaninemia (HPA) being the most common; nine organic acidemias (408 patients, 35.9%), with methylmalonic acidemia (MMA) as the most common; and seven fatty acid oxidation defects (147 patients, 13.0%), with multiple acyl-coenzyme A dehydrogenase deficiency (MADD) being the most common. Onset was mainly at 1-6 months for citrin deficiency, 0-6 months for MMA, and in newborns for ornithine transcarbamylase deficiency (OTCD). HPA was common in patients aged 1-3 years, and MADD was common in patients >18 years. CONCLUSIONS: In China, HPA, citrin deficiency, MMA, and MADD are the most common inherited disorders, particularly in newborns/infants. PMID- 24797656 TI - Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene. AB - Biotinidase deficiency (BD) is an autosomal recessive disorder resulting in the inability to recycle the vitamin biotin. Individuals with biotinidase deficiency can develop neurological and cutaneous symptoms if they are not treated with biotin. To date, more than 165 mutations in the biotinidase gene (BTD) have been reported. Essentially all the mutations result in enzymatic activities with less than 10% of mean normal serum enzyme activity (profound biotinidase deficiency) with the exception of the c.1330G>C (p.D444H) mutation, which results in an enzyme having 50% of mean normal serum activity and causes partial biotinidase deficiency (10-30% of mean normal serum biotinidase activity) if there is a mutation for profound biotinidase deficiency on the second allele. We now reported eight novel mutations in ten children identified by newborn screening in Michigan from 1988 to the end of 2012. Interestingly, one intronic mutation, c.310-15delT, results in an approximately two-fold down-regulation of BTD mRNA expression by Quantitative real-time reverse-transcription PCR (qRT-PCR). This is the first report of an intronic mutation in the BTD gene with demonstration of its effect on enzymatic activity by altering mRNA expression. This study identified three other mutations likely to cause partial biotinidase deficiency. These results emphasize the importance of full gene sequencing of BTD on patients with biotinidase deficiency to better understand the genotype and phenotype correlation in the future. PMID- 24797657 TI - IQP-GC-101 reduces body weight and body fat mass: a randomized, double-blind, placebo-controlled study. AB - IQP-GC-101 is a patented blend of the standardized extracts of Garcinia cambogia, Camellia sinensis, unroasted Coffea arabica, and Lagerstroemia speciosa. These individual ingredients of IQP-GC-101 have each shown promise in promoting weight loss; however, the efficacy of the blend has not been established. This randomized, placebo-controlled, double-blind, parallel group study conducted over 14 weeks (including a 2-week run-in phase) aimed to investigate the efficacy and safety of IQP-GC-101 in reducing body weight and body fat mass in overweight Caucasian adults. Subjects took three IQP-GC-101 or placebo tablets, twice a day, 30 min before main meals. All subjects also adhered to a 500 kcal/day energy deficit diet with 30% of energy from fat. Ninety-one overweight and mildly obese subjects (46 in the IQP-GC-101 group, 45 in the placebo group) completed the study. After 12-week intervention, IQP-GC-101 resulted in a mean (+/-SD) weight loss of 2.26 +/- 2.37 kg compared with 0.56 +/- 2.34 kg for placebo (pU = 0.002). There was also significantly more reduction in body fat mass, waist circumference, and hip circumference in the IQP-GC-101 group. No serious adverse events were reported. The use of IQP-GC-101 has been shown to result in body weight and body fat reduction in the current study, with good tolerability. PMID- 24797658 TI - Lipid concentration and molar ratio boundaries for the use of isotropic bicelles. AB - Bicelles are model membranes generally made of long-chain dimyristoylphosphatidylcholine (DMPC) and short-chain dihexanoyl-PC (DHPC). They are extensively used in the study of membrane interactions and structure determination of membrane-associated peptides, since their composition and morphology mimic the widespread PC-rich natural eukaryotic membranes. At low DMPC/DHPC (q) molar ratios, fast-tumbling bicelles are formed in which the DMPC bilayer is stabilized by DHPC molecules in the high-curvature rim region. Experimental constraints imposed by techniques such as circular dichroism, dynamic light scattering, or microscopy may require the use of bicelles at high dilutions. Studies have shown that such conditions induce the formation of small aggregates and alter the lipid-to-detergent ratio of the bicelle assemblies. The objectives of this work were to determine the exact composition of those DMPC/DHPC isotropic bicelles and study the lipid miscibility. This was done using (31)P nuclear magnetic resonance (NMR) and exploring a wide range of lipid concentrations (2-400 mM) and q ratios (0.15-2). Our data demonstrate how dilution modifies the actual DMPC/DHPC molar ratio in the bicelles. Care must be taken for samples with a total lipid concentration <=250 mM and especially at q ~ 1.5-2, since moderate dilutions could lead to the formation of large and slow tumbling lipid structures that could hinder the use of solution NMR methods, circular dichroism or dynamic light scattering studies. Our results, supported by infrared spectroscopy and molecular dynamics simulations, also show that phospholipids in bicelles are largely segregated only when q > 1. Boundaries are presented within which control of the bicelles' q ratio is possible. This work, thus, intends to guide the choice of q ratio and total phospholipid concentration when using isotropic bicelles. PMID- 24797659 TI - An 8-month exercise intervention alters frontotemporal white matter integrity in overweight children. AB - In childhood, excess adiposity and low fitness are linked to poor academic performance, lower cognitive function, and differences in brain structure. Identifying ways to mitigate obesity-related alterations is of current clinical importance. This study examined the effects of an 8-month exercise intervention on the uncinate fasciculus, a white matter fiber tract connecting frontal and temporal lobes. Participants consisted of 18 unfit, overweight 8- to 11-year-old children (94% Black) who were randomly assigned to either an aerobic exercise (n = 10) or a sedentary control group (n = 8). Before and after the intervention, all subjects participated in a diffusion tensor MRI scan. Tractography was conducted to isolate the uncinate fasciculus. The exercise group showed improved white matter integrity as compared to the control group. These findings are consistent with an emerging literature suggesting beneficial effects of exercise on white matter integrity. PMID- 24797660 TI - Accelerated identification of halogenated monoterpenes from Australian specimens of the red algae Plocamium hamatum and Plocamium costatum. AB - Two species of red algae belonging to the genus Plocamium, P. hamatum from Moreton Bay, Queensland, and P. costatum, from Pandalowie Bay, South Australia, were investigated to assess their chemical variation and as potential sources of new halogenated monoterpenes. The hyphenated technique HPLC-UV-MS-SPE-NMR was used to assess the algal extracts and to determine its potential for accelerated identification of halogenated monoterpenes generally. A combination of the hyphenated and traditional chromatographic techniques resulted in the isolation and characterization of a total of 10 halogenated monoterpene metabolites, eight of which are reported for the first time. Their structures, including configurations, were determined through interpretation of their 1D and 2D NMR, mass spectrometric, infrared, and X-ray data. The two species of Plocamium produced different secondary metabolites and contained a significant number of new polyhalogenated monoterpenes. The investigation also showed the hyphenated technique HPLC-UV-MS-SPE-NMR to be useful for preliminary investigation of the chemical content of algal extracts. PMID- 24797662 TI - Deer bone extract suppresses articular cartilage damage induced by monosodium iodoacetate in osteoarthritic rats: an in vivo micro-computed tomography study. AB - We evaluated the anti-osteoarthritic effects of deer bone extract on articular cartilage damage by using micro-computed tomography (micro-CT) in monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in rats. Male Wistar rats (6 weeks of age) were randomly divided into 5 groups (10 rats/group): sham control (SC; PBS injection+PBS 1 mL treatment); negative control (NC; MIA injection+PBS 1 mL treatment); positive control (PC; MIA injection+250 mg/kg glucosamine sulfate/chondroitin sulfate mixture treatment); low dose (LDB; MIA injection+250 mg/kg deer bone extract treatment); and high dose (HDB; MIA injection+500 mg/kg deer bone extract treatment). After 50 days of treatment, we observed that the administration of deer bone extract protected against bone destruction and reduced the number of erosion lacunae. When deer bone extract was administered, the trabecular thickness distribution (Tb.Th) (LDB: 75.9 MUm, HDB: 80.7 MUm vs. NC: 48.0 MUm) and the trabecular bone volume fraction ratio (BV/TV) (LDB: 43.8%, HDB: 48.2% vs. NC: 39.1%) were significantly restored. Additionally, the trabecular separation (Tb.Sp) increase caused by MIA was decreased significantly with the administration of deer bone extract (LDB: 73.4 MUm, HDB: 81.2 MUm vs. NC: 112.0 MUm). We concluded that the oral administration of deer bone extract effectively relieved the morphological changes induced by MIA injection in an animal model. PMID- 24797661 TI - Transcriptomic analysis reveals evidence for a cryptic plastid in the colpodellid Voromonas pontica, a close relative of chromerids and apicomplexan parasites. AB - Colpodellids are free-living, predatory flagellates, but their close relationship to photosynthetic chromerids and plastid-bearing apicomplexan parasites suggests they were ancestrally photosynthetic. Colpodellids may therefore retain a cryptic plastid, or they may have lost their plastids entirely, like the apicomplexan Cryptosporidium. To find out, we generated transcriptomic data from Voromonas pontica ATCC 50640 and searched for homologs of genes encoding proteins known to function in the apicoplast, the non-photosynthetic plastid of apicomplexans. We found candidate genes from multiple plastid-associated pathways including iron sulfur cluster assembly, isoprenoid biosynthesis, and tetrapyrrole biosynthesis, along with a plastid-type phosphate transporter gene. Four of these sequences include the 5' end of the coding region and are predicted to encode a signal peptide and a transit peptide-like region. This is highly suggestive of targeting to a cryptic plastid. We also performed a taxon-rich phylogenetic analysis of small subunit ribosomal RNA sequences from colpodellids and their relatives, which suggests that photosynthesis was lost more than once in colpodellids, and independently in V. pontica and apicomplexans. Colpodellids therefore represent a valuable source of comparative data for understanding the process of plastid reduction in humanity's most deadly parasite. PMID- 24797663 TI - Mitochondrial DAMPs induce endotoxin tolerance in human monocytes: an observation in patients with myocardial infarction. AB - Monocyte exposure to mitochondrial Danger Associated Molecular Patterns (DAMPs), including mitochondrial DNA (mtDNA), induces a transient state in which these cells are refractory to further endotoxin stimulation. In this context, IRAK-M up regulation and impaired p65 activity were observed. This phenomenon, termed endotoxin tolerance (ET), is characterized by decreased production of cytokines in response to the pro-inflammatory stimulus. We also show that monocytes isolated from patients with myocardial infarction (MI) exhibited high levels of circulating mtDNA, which correlated with ET status. Moreover, a significant incidence of infection was observed in those patients with a strong tolerant phenotype. The present data extend our current understanding of the implications of endotoxin tolerance. Furthermore, our data suggest that the levels of mitochondrial antigens in plasma, such as plasma mtDNA, should be useful as a marker of increased risk of susceptibility to nosocomial infections in MI and in other pathologies involving tissue damage. PMID- 24797664 TI - Turoctocog alfa (NovoEight(r))--from design to clinical proof of concept. AB - Turoctocog alfa (NovoEight(r)) is a recombinant factor VIII (rFVIII) with a truncated B-domain made from the sequence coding for 10 amino acids from the N terminus and 11 amino acids from the C-terminus of the naturally occurring B domain. Turoctocog alfa is produced in Chinese hamster ovary (CHO) cells without addition of any human- or animal-derived materials. During secretion, some rFVIII molecules are cleaved at the C-terminal of the heavy chain (HC) at amino acid 720, and a monoclonal antibody binding C-terminal to this position is used in the purification process allowing isolation of the intact rFVIII. Viral inactivation is ensured by a detergent inactivation step as well as a 20-nm nano-filtration step. Characterisation of the purified protein demonstrated that turoctocog alfa was fully sulphated at Tyr346 and Tyr1664, which is required for optimal proteolytic activation by thrombin. Kinetic assessments confirmed that turoctocog alfa was activated by thrombin at a similar rate as seen for other rFVIII products fully sulphated at these positions. Tyr1680 was also fully sulphated in turoctocog alfa resulting in strong affinity (low nm Kd ) for binding to von Willebrand factor (VWF). Half-lives of 7.2 +/- 0.9 h in F8-KO mice and 8.9 +/- 1.8 h haemophilia A dogs supported that turoctocog alfa bound to VWF after infusion. Functional studies including thromboelastography analysis of human haemophilia A whole blood with added turoctocog alfa and effect studies in mice bleeding models demonstrated a dose-dependent effect of turoctocog alfa. The non clinical data thus confirm the haemostatic effect of turoctocog alfa and, together with the comprehensive clinical evaluation, support the use as FVIII replacement therapy in patients with haemophilia A. PMID- 24797666 TI - Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats. AB - Vaccination against the highly abused prescription opioid oxycodone has shown pre clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund's adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID- 24797667 TI - FGF23 regulates renal sodium handling and blood pressure. AB - Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regulates the membrane abundance of the Na(+):Cl(-) co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/alphaKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na(+)) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and alphaKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na(+) uptake and membrane abundance of NCC, leading to volume expansion, hypertension, and heart hypertrophy in a alphaKlotho and dietary Na(+)-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and heart hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na(+) reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients. PMID- 24797669 TI - Arbuscular mycorhizal fungi associated with the olive crop across the Andalusian landscape: factors driving community differentiation. AB - BACKGROUND: In the last years, many olive plantations in southern Spain have been mediated by the use of self-rooted planting stocks, which have incorporated commercial AMF during the nursery period to facilitate their establishment. However, this was practised without enough knowledge on the effect of cropping practices and environment on the biodiversity of AMF in olive orchards in Spain. METHODOLOGY/PRINCIPAL FINDINGS: Two culture-independent molecular methods were used to study the AMF communities associated with olive in a wide-region analysis in southern Spain including 96 olive locations. The use of T-RFLP and pyrosequencing analysis of rDNA sequences provided the first evidence of an effect of agronomic and climatic characteristics, and soil physicochemical properties on AMF community composition associated with olive. Thus, the factors most strongly associated to AMF distribution varied according to the technique but included among the studied agronomic characteristics the cultivar genotype and age of plantation and the irrigation regimen but not the orchard management system or presence of a cover crop to prevent soil erosion. Soil physicochemical properties and climatic characteristics most strongly associated to the AMF community composition included pH, textural components and nutrient contents of soil, and average evapotranspiration, rainfall and minimum temperature of the sampled locations. Pyrosequencing analysis revealed 33 AMF OTUs belonging to five families, with Archaeospora spp., Diversispora spp. and Paraglomus spp., being first records in olive. Interestingly, two of the most frequent OTUs included a diverse group of Claroideoglomeraceae and Glomeraceae sequences, not assigned to any known AMF species commonly used as inoculants in olive during nursery propagation. CONCLUSIONS/SIGNIFICANCE: Our data suggests that AMF can exert higher host specificity in olive than previously thought, which may have important implications for redirecting the olive nursery process in the future as well as to take into consideration the specific soils and environments where the mycorrhized olive trees will be established. PMID- 24797670 TI - Reply to letter to the editor. PMID- 24797668 TI - Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. AB - Controversy surrounds the identity, origin, and physiologic role of endogenous cardiomyocyte progenitors in adult mammals. Using an inducible genetic labeling approach to identify small non-myocyte cells expressing cardiac markers, we find that activated endogenous cardioblasts are rarely evident in the normal adult mouse heart. However, myocardial infarction results in significant cardioblast activation at the site of injury. Genetically labeled isolated cardioblasts express cardiac transcription factors and sarcomeric proteins, exhibit spontaneous contractions, and form mature cardiomyocytes in vivo after injection into unlabeled recipient hearts. The activated cardioblasts do not arise from hematogenous seeding, cardiomyocyte dedifferentiation, or mere expansion of a preformed progenitor pool. Cell therapy with cardiosphere-derived cells amplifies innate cardioblast-mediated tissue regeneration, in part through the secretion of stromal cell-derived factor 1 by transplanted cells. Thus, stimulation of endogenous cardioblasts by exogenous cells mediates therapeutic regeneration of injured myocardium. PMID- 24797671 TI - Discriminative and predictive properties of multidimensional prognostic indices of chronic obstructive pulmonary disease: a validation study in Taiwanese patients. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a pulmonary disease with systemic involvement. Several multidimensional indices have been developed to predict long-term outcomes. However, these indices have not been compared and validated in Taiwanese patients with COPD. METHODS: A prospective, observational, hospital-based study was designed, and a total of 621 patients were recruited from May 2006 to December 2011. Patients followed at least 1 year were enrolled and 594 patients eligible for inclusion. Three prognostic indices--the ADO (age, dyspnoea and airflow obstruction), BODEx (body mass index, airflow obstruction, dyspnoea and exacerbations), and CPI (the COPD Prognostic Index)--were validated and the predictive power of each was analysed. RESULTS: The median follow-up of the 594 patients was 33 months (range 1-72 months), and the mortality rate was 19.2% (114 deaths). All indices were significantly predictive for all-cause mortality in our validation cohort. Furthermore, the C statistics of the three indices, indicating their predictive accuracy, were all >0.7 (area under the curve of the CPI 0.718, P < 0.001, ADO 0.702, P < 0.001, BODEx 0.702, P < 0.001). CONCLUSIONS: ADO, BODEx and CPI scores are useful predictors of all-cause mortality with significantly discriminative properties in Taiwanese patients with COPD. PMID- 24797672 TI - Making the invisible visible: bioelectrical impedance analysis demonstrates unfavourable body composition in rheumatoid arthritis patients in clinical practice. AB - OBJECTIVES: To examine differences between the assessment of body composition by body mass index (BMI) and bioelectrical impedance analysis (BIA) in patients with rheumatoid arthritis (RA). METHOD: The body composition of RA patients was assessed during their visit to the outpatient department of a Dutch academic hospital using BMI, fat-free mass index (FFMI), and fat mass index (FMI). FFMI and FMI were determined by single-frequency BIA. RESULTS: Sixty-five consecutive RA patients (83% women, mean age 58 years, median disease duration 7 years) with moderately active disease [mean Disease Activity Score using 28 joint counts (DAS28) = 3.40; mean Rheumatoid Arthritis Disease Activity Index (RADAI) score = 3.49] and moderate disability [mean Health Assessment Questionnaire (HAQ) score = 0.87] were included. Based on BMI, 2% of our study population were underweight, 45% had a healthy body composition, and 54% were overweight or obese. Based on BIA, 18% of the patients showed a low FFMI and 74% had a high or very high FMI. Low FFMI was found in 44% of the women with a normal BMI, and high FMI was found in 40% of the women and 75% of the men with a normal BMI. CONCLUSIONS: A high frequency of unfavourable body composition, predominantly reduced FFMI and elevated FMI, was found in a cohort of RA patients with moderately active disease, turning BMI into an unreliable method for assessment of body composition in RA. BIA, however, might be the preferred method to assess FFMI and FMI in RA patients in clinical practice, as it is easy to use and relatively inexpensive. PMID- 24797673 TI - In ovo carbohydrate supplementation modulates growth and immunity-related genes in broiler chickens. AB - A study was undertaken to investigate the role of in ovo administrated carbohydrates on the expression pattern of growth and immune-related genes. In ovo injections (n = 400) were carried out on the 14th day of incubation into the yolk sac/amnion of the broiler chicken embryos. Expression of growth-related genes: chicken growth hormone (cGH), insulin-like growth factor-I & II (IGF-I & II) and mucin were studied in hepatic and jejunum tissues of late-term embryo and early post-hatch chicks. Expression of candidate immune genes: Interleukin-2, 6, 10 and 12 (IL-2, IL-6, IL-10 and IL-12), Tumour necrosis factor-alpha (TNF-alpha) and Interferon gamma (IFN-gamma) were studied in peripheral blood monocyte cells of in ovo-injected and control birds following antigenic stimulation with sheep RBC (SRBC) or mitogen concanavalin A (Con-A). Glucose injection significantly increased the expression of IGF-II gene during embryonic period and both cGH and IGF-II in early post-hatch period, while ribose-injected chicks had higher expression of IGF-II gene during embryonic stage. Enhanced mucin gene expression was also observed in fructose-injected chicks during embryonic age. Glucose injected chicks had higher expression of IL-6 or IL-10, while those injected with fructose or ribose had higher expression of IL-2, IL-12 and IFN gamma. It is concluded that in ovo supplementation of carbohydrates might help in improving the growth of late-term embryos and chicks. In ovo glucose could modulate humoral related immunity, while fructose or ribose might help in improving the cellular immunity in broiler chickens. PMID- 24797674 TI - A simplified method to measure choroidal thickness using adaptive compensation in enhanced depth imaging optical coherence tomography. AB - PURPOSE: To evaluate a simplified method to measure choroidal thickness (CT) using commercially available enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT). METHODS: We measured CT in 31 subjects without ocular diseases using Spectralis EDI SD-OCT. The choroid-scleral interface of the acquired images was first enhanced using a post-processing compensation algorithm. The enhanced images were then analysed using Photoshop. Two graders independently graded the images to assess inter-grader reliability. One grader re graded the images after 2 weeks to determine intra-grader reliability. Statistical analysis was performed using intra-class correlation coefficient (ICC) and Bland-Altman plot analyses. RESULTS: Using adaptive compensation both the intra-grader reliability (ICC: 0.95 to 0.97) and inter-grader reliability (ICC: 0.93 to 0.97) were perfect for all five locations of CT. However, with the conventional technique of manual CT measurements using built-in callipers provided with the Heidelberg explorer software, the intra- (ICC: 0.87 to 0.94) and inter-grader reliability (ICC: 0.90 to 0.93) for all the measured locations is lower. Using adaptive compensation, the mean differences (95% limits of agreement) for intra- and inter-grader sub-foveal CT measurements were -1.3 ( 3.33 to 30.8) um and -1.2 (-36.6 to 34.2) um, respectively. CONCLUSIONS: The measurement of CT obtained from EDI SD-OCT using our simplified method was highly reliable and efficient. Our method is an easy and practical approach to improve the quality of choroidal images and the precision of CT measurement. PMID- 24797676 TI - Cell labeling and injection in developing embryonic mouse hearts. AB - Testing the fate of embryonic or pluripotent stem cell-derivatives in in vitro protocols has led to controversial outcomes that do not necessarily reflect their in vivo potential. Preferably, these cells should be placed in a proper embryonic environment in order to acquire their definite phenotype. Furthermore, cell lineage tracing studies in the mouse after labeling cells with dyes or retroviral vectors has remained mostly limited to early stage mouse embryos with still poorly developed organs. To overcome these limitations, we designed standard and ultrasound-mediated microinjection protocols to inject various agents in targeted regions of the heart in mouse embryos at E9.5 and later stages of development. Embryonic explant or embryos are then cultured or left to further develop in utero. These agents include fluorescent dyes, virus, shRNAs, or stem cell-derived progenitor cells. Our approaches allow for preservation of the function of the organ while monitoring migration and fate of labeled and/or injected cells. These technologies can be extended to other organs and will be very helpful to address key biological questions in biology of development. PMID- 24797677 TI - Effects of temperature and hydraulic retention time on acetotrophic pathways and performance in high-rate sludge digestion. AB - High-rate anaerobic digestion of organic solids requires rapid hydrolysis and enhanced methanogenic growth rates, which can be achieved through elevated temperature (>55 degrees C) at short hydraulic retention times (HRT). This study assesses the effect of temperatures between 55 degrees C and 65 degrees C and HRTs between 2 and 4 days on process performance, microbial community structure, microbial capability, and acetotrophic pathways in thermophilic anaerobic reactors. Increasing the temperature did not enhance volatile solids (VS) destruction above the base value of 37% achieved at 55 degrees C and 4 days HRT. Stable isotopic signatures (delta13C) revealed that elevated temperature promoted syntrophic acetate oxidation, which accounted for 60% of the methane formation at 55 degrees C, and increasing substantially to 100% at 65 degrees C. The acetate consumption capacity dropped with increasing temperature (from 0.69-0.81 gCOD gVS(-1) d(-1) at 55 degrees C to 0.21-0.35 gCOD gVS(-1) d(-1) at 65 degrees C), based on specific activity testing of reactor contents. Community analysis using 16S rRNA pyrosequencing revealed the dominance of Methanosarcina at 55-60 degrees C. However, a further increase to 65 degrees C resulted in loss of Methanosarcina, with an accumulation of organic acids and reduced methane production. Similar issues were observed when reducing the HRT to 2 days, indicating that temperature<60 degrees C and HRT>3 days are critical to operate these systems stably. PMID- 24797675 TI - Direct evidence for pitavastatin induced chromatin structure change in the KLF4 gene in endothelial cells. AB - Statins exert atheroprotective effects through the induction of specific transcriptional factors in multiple organs. In endothelial cells, statin dependent atheroprotective gene up-regulation is mediated by Kruppel-like factor (KLF) family transcription factors. To dissect the mechanism of gene regulation, we sought to determine molecular targets by performing microarray analyses of human umbilical vein endothelial cells (HUVECs) treated with pitavastatin, and KLF4 was determined to be the most highly induced gene. In addition, it was revealed that the atheroprotective genes induced with pitavastatin, such as nitric oxide synthase 3 (NOS3) and thrombomodulin (THBD), were suppressed by KLF4 knockdown. Myocyte enhancer factor-2 (MEF2) family activation is reported to be involved in pitavastatin-dependent KLF4 induction. We focused on MEF2C among the MEF2 family members and identified a novel functional MEF2C binding site 148 kb upstream of the KLF4 gene by chromatin immunoprecipitation along with deep sequencing (ChIP-seq) followed by luciferase assay. By applying whole genome and quantitative chromatin conformation analysis {chromatin interaction analysis with paired end tag sequencing (ChIA-PET), and real time chromosome conformation capture (3C) assay}, we observed that the MEF2C-bound enhancer and transcription start site (TSS) of KLF4 came into closer spatial proximity by pitavastatin treatment. 3D-Fluorescence in situ hybridization (FISH) imaging supported the conformational change in individual cells. Taken together, dynamic chromatin conformation change was shown to mediate pitavastatin-responsive gene induction in endothelial cells. PMID- 24797678 TI - Medical tourism in plastic surgery: ethical guidelines and practice standards for perioperative care. AB - BACKGROUND: The goal of this review was to identify the safety and medical care issues that surround the management of patients who had previously undergone medical care through tourism medicine. Medical tourism in plastic surgery occurs via three main referral patterns: macrotourism, in which a patient receives treatments abroad; microtourism, in which a patient undergoes a procedure by a distant plastic surgeon but requires postoperative and/or long-term management by a local plastic surgeon; and specialty tourism, in which a patient receives plastic surgery from a non-plastic surgeon. METHODS: The ethical practice guidelines of the American Medical Association, International Society of Aesthetic Plastic Surgery, American Society of Plastic Surgeons, and American Board of Plastic Surgeons were reviewed with respect to patient care and the practice of medical tourism. CONCLUSIONS: Safe and responsible care should start prior to surgery, with communication and postoperative planning between the treating physician and the accepting physician. Complications can arise at any time; however, it is the duty and ethical responsibility of plastic surgeons to prevent unnecessary complications following tourism medicine by adequately counseling patients, defining perioperative treatment protocols, and reporting complications to regional and specialty-specific governing bodies. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24797679 TI - Severe methylenetetrahydrofolate reductase deficiency: clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia. AB - IMPORTANCE: Hereditary spastic paraplegia is a highly heterogeneous group of neurogenetic disorders with pure and complicated clinical phenotypes. No treatment is available for these disorders. We identified 2 unrelated families, each with 2 siblings with severe methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting a complicated form of adult-onset hereditary spastic paraparesis partially responsive to betaine therapy. OBSERVATIONS: Both pairs of siblings presented with a similar combination of progressive spastic paraparesis and polyneuropathy, variably associated with behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy, beginning between the ages of 29 and 50 years. By the time of diagnosis a decade later, 3 patients were ambulatory and 1 was bedridden. Investigations have revealed severe hyperhomocysteinemia and hypomethioninemia, reduced fibroblast MTHFR enzymatic activity (18%-52% of control participants), and 3 novel pathogenic MTHFR mutations, 2 as compound heterozygotes in one family and 1 as a homozygous mutation in the other family. Treatment with betaine produced a rapid decline of homocysteine by 50% to 70% in all 4 patients and, over 9 to 15 years, improved the conditions of the 3 ambulatory patients. CONCLUSIONS AND RELEVANCE: Although severe MTHFR deficiency is a rare cause of complicated spastic paraparesis in adults, it should be considered in select patients because of the potential therapeutic benefit of betaine supplementation. PMID- 24797681 TI - Effect of stepped substrates on the interfacial adhesion properties of graphene membranes. AB - In order to gain a comprehensive understanding of interface adhesion properties involved in adhesion energy and local interface separation between graphene membranes and underlying stepped substrates, we develop an analytic model by considering the total free energy originally from interfacial van der Waals interaction and elastic strain energy stored in the membranes based on an atomic bond-relaxation consideration. It is found that the interface adhesion energy decreases with increasing membrane thickness. Moreover, as compared to the case of a flat substrate surface, the interface adhesion properties of graphene membranes on stepped surfaces are strongly affected by the substrate surface parameters, including step height, vicinal angle, membrane thickness, terrace width and orientation, etc., implying that the topographic fluctuation of graphene is attributed to the various interface separations at different substrate sites. Our predictions agree reasonably well with computer simulations and experimental observations, which suggest that the developed method can be regarded as an effective method to design the interface adhesion of graphene membranes in graphene-based functional device components. PMID- 24797680 TI - Picoinjection of microfluidic drops without metal electrodes. AB - Existing methods for picoinjecting reagents into microfluidic drops require metal electrodes integrated into the microfluidic chip. The integration of these electrodes adds cumbersome and error-prone steps to the device fabrication process. We have developed a technique that obviates the needs for metal electrodes during picoinjection. Instead, it uses the injection fluid itself as an electrode, since most biological reagents contain dissolved electrolytes and are conductive. By eliminating the electrodes, we reduce device fabrication time and complexity, and make the devices more robust. In addition, with our approach, the injection volume depends on the voltage applied to the picoinjection solution; this allows us to rapidly adjust the volume injected by modulating the applied voltage. We demonstrate that our technique is compatible with reagents incorporating common biological compounds, including buffers, enzymes, and nucleic acids. PMID- 24797682 TI - In pursuit of pain: recent advances and future directions in pain assessment in the ICU. PMID- 24797683 TI - Parotiditis secondary to NIV interface. PMID- 24797684 TI - Clinical research in emergency situations in incompetent persons: the situation in Italy. PMID- 24797685 TI - Understanding negative pressure pulmonary edema. PMID- 24797686 TI - Understanding acute kidney injury in sepsis. PMID- 24797687 TI - Comment on Xirouchaki et al.: Impact of lung ultrasound on clinical decision making in critically ill patients. PMID- 24797688 TI - Impact of lung ultrasound on clinical decision making in critically ill patients: response to O'Connor et al. PMID- 24797689 TI - An unusual water-bridged homospin Co(II) single-chain magnet. AB - An unusual water-bridged homospin Co(II) coordination polymer has been successfully assembled, which exhibits slow relaxation of the magnetization at low temperature. PMID- 24797690 TI - Inflammatory activity modulation by hypertonic saline and pentoxifylline in a rat model of strangulated closed loop small bowel obstruction. AB - BACKGROUND: Intestinal obstruction is an abdominal disease associated to mortality, especially if complicated with sepsis. Resuscitation increases survival, although controversies remain concerning to therapeutic strategy. METHODS: To assess the effects of hypertonic saline and pentoxifylline on the inflammatory response and oxidative stress, Wistar rats underwent a laparotomy loop intestinal obstruction and ischemia. After 24 h, the intestinal segment was resected (IO) without any other treatment and resuscitation/pentoxifylline were administered according to the group: Ringer's lactate (RL); hypertonic saline (HS); pentoxifylline (PTX); Ringer's lactate with pentoxifylline (RL + PTX); hypertonic saline with pentoxifylline (HS + PTX) and the control group (CG) that was not submitted to ischemia and obstruction. Mean arterial pressure (MAP) was recorded 4 times, and euthanasia was done 3 h after the resuscitation to obtain lung tissue, for malondialdehyde (MDA) by thiobarbituric acid reactive substances (TBARS) method, inflammatory cytokines were assessed using ELISA and NF-kappaBeta by Western blotting. RESULTS: The initial MAP levels were higher in the RL and HS groups than in the others; however, the last measurement was similar among all the groups. IL-1beta, IL-6 and CINC-1 (Cytokine-Induced Neutrophil Chemoattractant-1) were lower in the HS, PTX and HS + PTX groups compared with the IO and RL groups. IL-10 was lower in the HS + PTX group than in the IO group. NF-kappaB in the HS, PTX and HS + PTX groups were lower than in the IO group; NF kappaB in the HS + PTX group was lower than in the RL group. MDA in the lung was lower in the HS + PTX group compared with other groups. CONCLUSION: Hypertonic saline and pentoxifylline, both alone and in combination, attenuated oxidative stress and the activation of NF-kappaB, leading to a decrease in the inflammatory response. PMID- 24797691 TI - Morphological and functional changes in pituitary-thyroid axis following prolonged exposure of female rats to constant light. AB - Light regulates numerous physiological functions and synchronizes them with the environment, in part by adjusting secretion of different hormones. We hypothesized that constant light (CL) would disturb pituitary-thyroid axis. Our aim was to determine morphological and functional changes in this endocrine system in such extreme conditions and, based on the obtained results, to propose the underlying mechanism(s). Starting from the thirtieth postnatal day, female Wistar rats were exposed to CL (600 lx) for the following 95 days. The controls were maintained under the regular laboratory lighting conditions. After decapitation, pituitaries and thyroids were prepared for further histomorphometric, immunohistochemical, and immunofluorescence examinations. Concentration of thyroid stimulating hormone (TSH), total T4 and T3 (TH) were determined. Thyroid tissue of light-treated rats was characterized by microfollicular structure. We detected no change in total thyroid volume, localization and accumulation of thyroglobulin, thyroid peroxidase, and sodium iodide symporter in the follicular epithelium of CL rats. The volume of follicular epithelium and activation index were increased, while volume of the colloid and serum levels of TH decreased. In the pituitary, the relative intensity of TSH beta-immunofluorescence signal within the cytoplasm of thyrotrophs increased, but their average cell volume and the relative volume density decreased. Serum TSH was unaltered. We conclude that exposure of female rats to CL induced alterations in pituitary-thyroid axis. Thyroid tissue was characterized by microfollicular structure. Serum TH levels were reduced without accompanying increase in serum TSH. We hypothesize that increased secretion and clearance of TH together with unchanged or even decreased hormonal synthesis, resulted in decreased serum TH levels in CL group. We assume this decrease consequently led to increased synthesis and/or accumulation of pituitary TSH. However, decreased average TSH cell volume and relative volume density, together with unchanged serum TSH, point to additional, negative regulation of thyrotrophs. PMID- 24797692 TI - Mental health and social networks in early adolescence: a dynamic study of objectively-measured social interaction behaviors. AB - How are social interaction dynamics associated with mental health during early stages of adolescence? The goal of this study is to objectively measure social interactions and evaluate the roles that multiple aspects of the social environment--such as physical activity and food choice--may jointly play in shaping the structure of children's relationships and their mental health. The data in this study are drawn from a longitudinal network-behavior study conducted in 2012 at a private K-8 school in an urban setting in California. We recruited a highly complete network sample of sixth-graders (n = 40, 91% of grade, mean age = 12.3), and examined how two measures of distressed mental health (self-esteem and depressive symptoms) are positionally distributed in an early adolescent interaction network. We ascertained how distressed mental health shapes the structure of relationships over a three-month period, adjusting for relevant dimensions of the social environment. Cross-sectional analyses of interaction networks revealed that self-esteem and depressive symptoms are differentially stratified by gender. Specifically, girls with more depressive symptoms have interactions consistent with social inhibition, while boys' interactions suggest robustness to depressive symptoms. Girls higher in self-esteem tended towards greater sociability. Longitudinal network behavior models indicate that gender similarity and perceived popularity are influential in the formation of social ties. Greater school connectedness predicts the development of self-esteem, though social ties contribute to more self-esteem improvement among students who identify as European-American. Cross-sectional evidence shows associations between distressed mental health and students' network peers. However, there is no evidence that connected students' mental health status becomes more similar in their over time because of their network interactions. These findings suggest that mental health during early adolescence may be less subject to mechanisms of social influence than network research in even slightly older adolescents currently indicates. PMID- 24797693 TI - Transnational healthcare practices of Romanian migrants in Ireland: inequalities of access and the privatisation of healthcare services in Europe. AB - This article deals with the transnational healthcare practices of Central and Eastern European migrants in Europe, taking the case of Romanian migrants in Ireland. It explores the implications of migrants' transnational healthcare practices for the transformation of citizenship in Europe, more particularly in terms of access to free public healthcare. The article places these practices in the larger perspective of global care chains, seen as including transnational flows of healthcare seekers and healthcare workers that link distant healthcare systems in an emerging European healthcare assemblage. The study adopted a holistic perspective, taking into account both formal and informal practices, as well as the use of healthcare services in both the host and the origin countries of migrants. These were explored during multi-sited fieldwork in Romania and Ireland, conducted between 2012 and 2013, and combining a variety of sources and methods (semi-structured interviews, informal conversations, documentary analysis, etc.). The article explores the links between migrants' transnational healthcare practices and two other important processes: 1) inequalities in access to healthcare services in migrants' countries of origin and of destination; and 2) the contribution of healthcare privatisation to these inequalities. It shows that Romanian migrants' transnational healthcare practices function as strategies of social mobility for migrants, while also reflecting the increasing privatisation of healthcare services in Ireland and Romania. The article argues that these processes are far from specific to Ireland, Romania, and the migration flows uniting them. Rather, they draw our attention to the rise of an unevenly developed European healthcare assemblage and citizenship regime in which patients' movements across borders are closely interlinked with diminishing and increasingly unequal access to public healthcare services. PMID- 24797694 TI - Stem cells with decellularized liver scaffolds in liver regeneration and their potential clinical applications. AB - End-stage hepatic failure is a potentially life-threatening condition for which orthotopic liver transplantation (OLT) is the only effective treatment. However, a shortage of available donor organs for transplantation each year results in the death of many patients waiting for liver transplantation. Cell-based therapies and hepatic tissue engineering have been considered as alternatives to liver transplantation. However, primary hepatocyte transplantation has rarely produced therapeutic effects because mature hepatocytes cannot be effectively expanded in vitro, and the availability of hepatocytes is often limited by shortages of donor organs. Decellularization is an attractive technique for scaffold preparation in stem cell-based liver engineering, as the resulting material can potentially retain the liver architecture, native vessel network and specific extracellular matrix (ECM). Thus, the reconstruction of functional and practical liver tissue using decellularized scaffolds becomes possible. This review focuses on the current understanding of liver tissue engineering, whole-organ liver decellularization techniques, cell sources for recellularization and potential clinical applications and challenges. PMID- 24797695 TI - Wolbachia infection does not alter attraction of the mosquito Aedes (Stegomyia) aegypti to human odours. AB - The insect endosymbiont Wolbachia pipientis (Rickettsiales: Rickettsiaceae) is undergoing field trials around the world to determine if it can reduce transmission of dengue virus from the mosquito Stegomyia aegypti to humans. Two different Wolbachia strains have been released to date. The primary effect of the wMel strain is pathogen protection whereby infection with the symbiont limits replication of dengue virus inside the mosquito. A second strain, wMelPop, induces pathogen protection, reduces the adult mosquito lifespan and decreases blood feeding success in mosquitoes after 15 days of age. Here we test whether Wolbachia infection affects mosquito attraction to host odours in adults aged 5 and 15 days. We found no evidence of reduced odour attraction of mosquitoes, even for those infected with the more virulent wMelPop. This bodes well for fitness and competitiveness in the field given that the mosquitoes must find hosts to reproduce for the biocontrol method to succeed. PMID- 24797696 TI - Chimerization and characterization of a monoclonal antibody with potent neutralizing activity across multiple influenza A H5N1 clades. AB - The persistent evolution and circulation of highly pathogenic avian influenza H5N1 viruses pose a serious threat to global heath and hamper pandemic preparedness through conventional vaccine strategies. Combination passive immunotherapy using non-competing neutralizing antibodies has been proposed as a viable alternative to provide broad protection against drift variants. This necessitates the pre-pandemic production and characterization of potently neutralizing monoclonal antibodies (MAbs). One such antibody, MAb 9F4 was shown to provide heterologous protection against multiple H5N1 clade viruses, including one of the recently designated subclades, namely 2.3.4, through binding to a novel epitope, warranting its further development and characterization as a therapeutic candidate. In this study, the conversion of MAb 9F4 from mouse IgG2b to mouse-human chimeric (xi) IgG1 and IgA1 was achieved. These chimeric MAb versions were found to retain high degrees of binding and neutralizing activity against H5N1. The demonstration that xi-IgA1-9F4 retains a fairly high level of neutralizing activity, which is ~10-fold lower than the corresponding xi-IgG1 isotype, suggests that this MAb could be further developed and engineered for intranasal administration. PMID- 24797697 TI - Interfacial nanodroplets guided construction of hierarchical Au, Au-Pt, and Au-Pd particles as excellent catalysts. AB - Interfacial nanodroplets were grafted to the surfaces of self-sacrificed template particles in a galvanic reaction system to assist the construction of 3D Au porous structures. The interfacial nanodroplets were formed via direct adsorption of surfactant-free emulsions onto the particle surfaces. The interfacial nanodroplets discretely distributed at the template particle surfaces and served as soft templates to guide the formation of porous Au structures. The self variation of footprint sizes of interfacial nanodroplets during Au growth gave rise to a hierarchical pore size distribution of the obtained Au porous particles. This strategy could be easily extended to synthesize bimetal porous particles such as Au-Pt and Au-Pd. The obtained porous Au, Au-Pt, and Au-Pd particles showed excellent catalytic activity in catalytic reduction of 4 nitrophenol. PMID- 24797698 TI - Tracheal intubation of pediatric manikins during ongoing chest compressions. Does Glidescope(r) videolaryngoscope improve pediatric residents' performance? AB - Our objective was to test the ability of pediatric residents to intubate the trachea of infant and child manikins during continuous chest compressions (CC) by means of indirect videolaryngoscopy with Glidescope(r) versus standard direct laryngoscopy. A randomized crossover simulation trial was designed. Twenty-three residents trained to intubate child and infant manikins were eligible for the study. They were asked to perform tracheal intubation in manikins assisted by both standard laryngoscopy and Glidescope(r) while a colleague delivered uninterrupted chest compressions. In the infant cardiac arrest scenario, the median (IQR) total time for intubation was significantly shorter with the Miller laryngoscope [28.2 s (20.4-34.4)] than with Glidescope(r) [38.0 s (25.3-50.5)] (p = 0.021). The number of participants who needed more than 30 s to intubate the manikin was also significantly higher with Glidescope(r) (n = 13) than with the Miller laryngoscope (n = 7, p = 0.01). In the child scenario, the total time for intubation and number of intubation failures were similar with Macintosh and Glidescope(r) laryngoscopes. The participants' subjective difficulty of the procedure was similar for direct and videolaryngoscopy. CONCLUSION: In simulated infant and child cardiac arrest scenarios, pediatric residents are able to intubate the trachea during CC. The videolaryngoscope Glidescope(r) does not improve performance in this setting. PMID- 24797699 TI - Physiopathological effects of Escherichia coli O157:H7 inoculation in weaned calves fed with colostrum containing antibodies to EspB and Intimin. AB - Escherichia coli O157:H7 is responsible for severe intestinal disease and hemolytic uremic syndrome (HUS), a serious systemic complication which particularly affects children. Cattle are the primary reservoir for E. coli O157:H7 and the main source of infection for humans. In this study, we evaluated the ability of transferred maternal colostral antibodies against gamma-Intimin C280 and EspB, to protect young weaned calves from E. coli O157:H7 infection. Hyperimmune colostra were obtained by immunization of pregnant cows with a mix of the mentioned antigens. All vaccinated cows mounted a significant IgG response against gamma-Intimin C280, and EspB in sera and colostra. Colostrum-fed calves also exhibited high serum IgG titers against gamma-Intimin C280 and EspB along with a rise in mucosal gamma-Intimin C280-specific IgG antibodies at recto-anal junction and ileum. Additionally, 70 day-old calves received a challenge with E. coli O157:H7 but no reduction in total bacterial shedding or frequency of E. coli O157:H7 excretion from these calves was observed. Most tissue samples showed granulocyte focal infiltrations of the lamina propria and enterocyte erosion. In conclusion, up to the 70th day, the passively acquired gamma-Intimin-C280 and EspB-IgG antibodies present in sera and recto-anal mucosa reached a titer insufficient to reduce EHEC O157 shedding and damages of experimentally inoculated young calves. PMID- 24797702 TI - Single-cell heterogeneity in suppression of PC12 differentiation by direct microinjection of a differentiation inhibitor, U0126. AB - Phenotypic and genomic heterogeneity among single cells in a cell population leads to inaccuracy and obscuration in research about mammalian cell differentiation. In order to address the problems regarding bulk analysis on heterogeneous cell populations, it is necessary to accurately regulate and analyze changes in differentiating cells at the single-cell level. To investigate the single-cell changes in PC12 neuronal differentiation that occur when inhibited by U0126, an inhibitor of mitogen-activated protein kinase kinase (MEK), we directly injected the chemical into individual target cells and analyzed the outcomes (neurite outgrowth) at the single-cell level. As a result, we could accurately regulate the quantity of U0126 being introduced into each target cell, which was previously not possible using the common method of simply adding the inhibitor to the culture medium. It was possible to analyze the inhibitive effect of U0126 even when the injected quantity was lower than the lower limit for inhibition when added to culture medium (0.1 MUM, identical to 1.2 * 10(8) molecules per cell on dish). In particular, injection of 1.5 * 10(7) molecules into each cell resulted in a 59% decrease of the mean total neurite length. Time-course analysis of neurite outgrowth at the single-cell level using fluorescence staining method showed that the changes in neurite length of differentiating PC12 cells were not homogeneous, but were largely variable across individual target cells. PMID- 24797700 TI - Highly efficient production of a dengue pseudoinfectious virus. AB - Dengue is a major infectious disease that affects people living in tropical and subtropical regions around the world. The causative agents are dengue virus serotype 1, 2, 3, and 4 (DENV1, 2, 3, and 4). Developing a vaccine for dengue is a high priority for public health, but traditional methods have faced numerous obstacles due to the unique immunopathogenesis of dengue virus infection. Here, we report a novel dengue vaccine candidate based on dengue pseudoinfectious virus (PIV) produced by the incorporation of a dengue subgenomic replicon into viral particles in highly efficient packaging cells. The subgenomic replicon was constructed by deleting the capsid protein (C) gene from the dengue viral genome and optimizing the signal peptide sequence of pre-membrane protein (prM) to facilitate the formation of viral particles. Packaging cells were developed for inducible expression of a bi-protein Cpr, where the protein pr is the "pr" segment of viral protein prM that holds the protein C on the endoplasmic reticulum (ER). When the replicon was introduced into the packaging cells, protein C was released from the bi-protein Cpr by a replicon-encoded viral protease. Coordinate expression of viral structural proteins by the replicon and packaging cells led to the incorporation of the replicon into viral particle to produce PIVs. Animal tests showed that the dengue PIV vaccine was highly immunogenic and the immune response protected mice challenged with a hundred-fold LD50 inoculation of dengue virus. The method described here has the potential to be applied to vaccine development for other flaviviruses. PMID- 24797703 TI - The sensitivity of pre-operative axillary staging in breast cancer: comparison of invasive lobular and ductal carcinoma. AB - INTRODUCTION: Axillary ultrasound (AUS) with fine-needle aspiration (FNA) biopsy of abnormal lymph nodes is important for pre-operative staging and planning the surgical management of the axilla. Invasive lobular carcinoma (ILC) metastases are thought to be difficult to detect because the cells are small and on cytology resemble lymphocytes. To investigate this we directly compared the sensitivity of pre-operative axillary staging between ILC and invasive ductal carcinoma (IDC). METHOD: Consecutive patients that presented in a single breast unit with pure IDC between April 2005 and December 2006 and pure ILC between January 2008 and December 2012 were retrospectively identified from pathology records. Pre operative axillary ultrasound and FNA biopsy results were compared with post operative histopathology from the sentinel node biopsy (SNB) or axillary lymph node dissection (ALND). RESULTS: A total of 275 and 142 axillae were identified in the IDC and ILC groups respectively. In the node positive patients there was no significant difference in the sensitivity of AUS (IDC vs. ILC; 58.7% vs. 52.8%). However, there was a significant difference in the sensitivity of ultrasound-guided FNA biopsy of abnormal nodes (IDC vs. ILC; 98.4% vs. 53.6%; p < 0.001). CONCLUSION: AUS has comparative sensitivities between IDC and ILC populations. In contrast, FNA biopsy of abnormal axillary nodes is clearly less sensitive in the ILC group. In these patients, who have abnormal AUS, we suggest that a core biopsy is required to improve the pre-operative staging and prevent unnecessary surgical procedures. PMID- 24797704 TI - Complications of HbH disease in adulthood. PMID- 24797705 TI - Differences in weight loss across different BMI classes: a meta-analysis of the effects of interventions with diet and exercise. AB - BACKGROUND: Lifestyle interventions are effective for weight loss and are recommended for persons with a body mass index (BMI) of 25-40 kg m(-2). However, this group is very heterogeneous, which could influence outcomes from lifestyle interventions. PURPOSE: In this systematic review, differences in 1-year weight change and percentage weight change after lifestyle interventions were investigated for participants varying in initial BMI using meta-analyses. METHOD: Twenty-two interventions with healthy Caucasian adults, a mean BMI between 25 and 40 kg m(-2), a dietary as well as a physical activity component aiming at weight loss, and at least five contact sessions guided by a professional health care provider were selected from a systematic search in the MEDLINE database. Participants in each intervention were divided into one of the three BMI classes: overweight (BMI of 25-29.99 kg m(-2)), class-I obesity (BMI of 30-34.99 kg m( 2)), and class-II obesity (BMI of 35-39.99 kg m(-2)). Differences in weight change and percentage weight change were analyzed and compared among different BMI classes within the same intervention by calculating standardized mean differences. RESULTS: Overweight participants lost 1.1 kg less (p < 0.01) than participants with class-I obesity and 1.5 kg less (p < 0.01) than participants with class-II obesity. For percentage weight change, no significant differences were found among the BMI classes. CONCLUSION: Average weight change during lifestyle interventions only differs to a small extent among people with BMI between 25 and 40 kg m(-2). This implies that these interventions are equally appropriate for these BMI classes. PMID- 24797706 TI - Dissemination of an online theory-based intervention to improve gluten-free diet adherence in coeliac disease: the relationship between acceptability, effectiveness, and attrition. AB - BACKGROUND: Both acceptability and behaviour change data provide important information about the likelihood of success of an intervention when disseminated outside the research context. Despite this, few studies have combined such data for use in ongoing intervention development. PURPOSE: To assess the acceptability and feasibility of an online intervention to improve gluten-free diet (GFD) adherence in coeliac disease, and to examine the relationships with participant characteristics, attrition, and effectiveness to inform ongoing intervention developments to ultimately reduce attrition and improve the reach and effectiveness of the programme. METHODS: All participants completed measures of GFD adherence, theory of planned behaviour variables, psychological symptoms, and demographic and disease characteristics. Acceptability and feasibility ratings were obtained at the conclusion of each of the six intervention modules. Chi square analyses were used to examine differences between completers and non completers, and Spearman's correlations were used to determine the relationships between participant characteristics, effectiveness, and acceptability and feasibility. RESULTS: Participants who rated the early modules less favourably were more likely to drop-out of the intervention. Acceptability and feasibility ratings were also associated with the presence of psychological symptoms, use of adaptive coping strategies, GFD duration, and attitude change. CONCLUSIONS: The findings suggest that changes to the structure and implementation of the intervention may be useful in minimising attrition and maximising effectiveness for future dissemination in a wider coeliac disease population. PMID- 24797707 TI - Dopamine D3 receptor-regulated NR2B subunits of N-methyl-d-aspartate receptors in the nucleus accumbens involves in morphine-induced locomotor activity. AB - AIMS: Dopamine and glutamate receptors are densely expressed in the nucleus accumbens (NAc). Active interactions between these receptors contribute to the development of neuropsychiatric diseases, such as drug addiction and relapse. However, the molecular mechanisms underlying these interactions remain unclear. METHODS: This study established a mouse model of intermittent morphine-induced mouse behavioral sensitization model. Western blot and electrophysiological recording methods were performed to directly identify the affective components of morphine behavioral sensitization. RESULTS: Interval morphine administration could cause significant locomotor sensitization. Hyperlocomotion and behavioral locomotor sensitization were significantly suppressed when ifenprodil (5 mg/kg), a selective NR2B subunit-containing N-methyl-d-aspartate (NMDA) receptor antagonist, or nafadotride (25 MUg/kg), a dopamine D3 receptor (D3R)-preferring antagonist, was coadministered with morphine. Western blot analysis showed that morphine behavioral sensitization induced a region-specific increase in phosphorylation of NR2B (pNR2B) and total levels of NR2B (NR2B) expression in the NAc. Systemically administered nafadotride attenuated behavioral locomotor sensitization induced by morphine and significantly reversed the overexpression of pNR2B and NR2B subunit-containing NMDA receptor in the NAc. NMDA receptor mediated excitatory postsynaptic currents in the NAc were also significantly reduced by nafadotride. CONCLUSIONS: These findings suggest that D3Rs are involved in morphine-induced behavioral locomotor sensitization in mice by regulating the NR2B subunits of NMDA receptors in the NAc. PMID- 24797709 TI - Echinacoside ameliorates D-galactosamine plus lipopolysaccharide-induced acute liver injury in mice via inhibition of apoptosis and inflammation. AB - OBJECTIVE: This study aimed to investigate the protective effects of echinacoside, one of the phenylethanoids isolated from the stems of Cistanche salsa, a Chinese herbal medicine, on D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced acute liver injury in mice. METHODS: We administered GalN (650 mg/kg) together with LPS (30 MUg/kg) to mice by intraperitoneal injection to induce acute liver damage. Echinacoside (60 mg/kg) was given intraperitoneally to mice at 1 h prior to GalN/LPS exposure. Mice were sacrificed at different time points following GalN/LPS treatment, and the liver and blood samples were collected for future analysis. RESULTS: It showed that GalN/LPS treatment produced severe hepatic injury, evidenced by significantly elevated plasma alanine aminotransferase (ALT) levels and abnormal histological changes such as hepatocyte necrosis or apoptosis, hemorrhage, fatty degeneration, and neutrophil infiltration. Notably, pretreatment with echinacoside remarkably improved the survival rate of GalN/LPS-treated mice and attenuated acute hepatotoxicity, as demonstrated by decreased ALT levels and improved histological signs. Echinacoside shows both anti-apoptotic and anti-inflammatory properties, characterized by a substantial inhibition of hepatocyte apoptosis and a significant reduction in the inflammatory markers, including myeloperoxidase, extracellular nucleosomes, high-mobility group box 1, and inflammatory cytokines in the plasma of mice, which may be important mechanisms related to its protective effect. CONCLUSION: Our results suggest that echinacoside can provide a pronounced protection against GalN/LPS-induced acute liver injury in mice, which may complement the available strategies for management of acute liver damage in clinical settings. PMID- 24797710 TI - Weak phylogenetic signal in physiological traits of methane-oxidizing bacteria. AB - The presence of phylogenetic signal is assumed to be ubiquitous. However, for microorganisms, this may not be true given that they display high physiological flexibility and have fast regeneration. This may result in fundamentally different patterns of resemblance, that is, in variable strength of phylogenetic signal. However, in microbiological inferences, trait similarities and therewith microbial interactions with its environment are mostly assumed to follow evolutionary relatedness. Here, we tested whether indeed a straightforward relationship between relatedness and physiological traits exists for aerobic methane-oxidizing bacteria (MOB). We generated a comprehensive data set that included 30 MOB strains with quantitative physiological trait information. Phylogenetic trees were built from the 16S rRNA gene, a common phylogenetic marker, and the pmoA gene which encodes a subunit of the key enzyme involved in the first step of methane oxidation. We used a Blomberg's K from comparative biology to quantify the strength of phylogenetic signal of physiological traits. Phylogenetic signal was strongest for physiological traits associated with optimal growth pH and temperature indicating that adaptations to habitat are very strongly conserved in MOB. However, those physiological traits that are associated with kinetics of methane oxidation had only weak phylogenetic signals and were more pronounced with the pmoA than with the 16S rRNA gene phylogeny. In conclusion, our results give evidence that approaches based solely on taxonomical information will not yield further advancement on microbial eco-evolutionary interactions with its environment. This is a novel insight on the connection between function and phylogeny within microbes and adds new understanding on the evolution of physiological traits across microbes, plants and animals. PMID- 24797712 TI - Hole contacts on transition metal dichalcogenides: interface chemistry and band alignments. AB - MoOx shows promising potential as an efficient hole injection layer for p-FETs based on transition metal dichalcogenides. A combination of experiment and theory is used to study the surface and interfacial chemistry, as well as the band alignments for MoOx/MoS2 and MoOx/WSe2 heterostructures, using photoelectron spectroscopy, scanning tunneling microscopy, and density functional theory. A Mo(5+) rich interface region is identified and is proposed to explain the similar low hole Schottky barriers reported in a recent device study utilizing MoOx contacts on MoS2 and WSe2. PMID- 24797713 TI - Success in the garden-and in research: message from the president. PMID- 24797711 TI - Atrazine and pregnancy outcomes: a systematic review of epidemiologic evidence. AB - Atrazine (ATR) is a commonly used agricultural herbicide that has been the subject of epidemiologic studies assessing its relation to reproductive health problems. This review evaluates both the consistency and the quality of epidemiologic evidence testing the hypothesis that ATR exposure, at usually encountered levels, is a risk factor for birth defects, small for gestational age birth weight, prematurity, miscarriages, and problems of fetal growth and development. We followed the current methodological guidelines for systematic reviews by using two independent researchers to identify, retrieve, and evaluate the relevant epidemiologic literature on the relation of ATR to various adverse outcomes of birth and pregnancy. Each eligible paper was summarized with respect to its methods and results with particular attention to study design and exposure assessment, which have been cited as the main areas of weakness in ATR research. As a quantitative meta-analysis was not feasible, the study results were categorized qualitatively as positive, null, or mixed. The literature on ATR and pregnancy-related health outcomes is growing rapidly, but the quality of the data is poor with most papers using aggregate rather than individual-level information. Without good quality data, the results are difficult to assess; however, it is worth noting that none of the outcome categories demonstrated consistent positive associations across studies. Considering the poor quality of the data and the lack of robust findings across studies, conclusions about a causal link between ATR and adverse pregnancy outcomes are not warranted. PMID- 24797714 TI - Development of new punch shape to replicate scale-up issues in laboratory tablet press II: a new design of punch head to emulate consolidation and dwell times in commercial tablet press. AB - Differences between laboratory and commercial tablet presses are frequently observed during scale-up of tableting process. These scale-up issues result from the differences in total compression time that is the sum of consolidation and dwell times. When a lubricated blend is compressed into tablets, the tablet thickness produced by the commercial tablet press is often thicker than that by a laboratory tablet press. A new punch shape design, designated as shape adjusted for scale-up (SAS), was developed and used to demonstrate the ability to replicate scale-up issues in commercial-scale tableting processes. It was found that the consolidation time can be slightly shortened by changing the vertical curvature of the conventional punch head rim. However, this approach is not enough to replicate the consolidation time. A secondary two-stage SAS punch design and an embossed punch head was designed to replicate the consolidation and dwell times on a laboratory tablet press to match those of a commercial tablet press. The resulting tablet thickness using this second SAS punch on a laboratory tablet press was thicker than when using a conventional punch in the same laboratory tablet press. The secondary SAS punches are more useful tools for replicating and understanding potential scale-up issues. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. PMID- 24797715 TI - Information-based sample size re-estimation in group sequential design for longitudinal trials. AB - Group sequential design has become more popular in clinical trials because it allows for trials to stop early for futility or efficacy to save time and resources. However, this approach is less well-known for longitudinal analysis. We have observed repeated cases of studies with longitudinal data where there is an interest in early stopping for a lack of treatment effect or in adapting sample size to correct for inappropriate variance assumptions. We propose an information-based group sequential design as a method to deal with both of these issues. Updating the sample size at each interim analysis makes it possible to maintain the target power while controlling the type I error rate. We will illustrate our strategy with examples and simulations and compare the results with those obtained using fixed design and group sequential design without sample size re-estimation. PMID- 24797716 TI - Gene expression profiles reveal that chondrogenic progenitor cells and synovial cells are closely related. AB - We showed previously that chondrogenic progenitor cells (CPCs) from the superficial zone of articular cartilage respond vigorously to cartilage wounding by responding chemotactically to cell debris, but the physiologic functions of CPCs remain unclear. To help bridge this knowledge gap we undertook a comparative analysis of gene expression in bovine CPCs, chondrocytes, synovial fibroblasts (synoviocytes), and cells isolated from synovial fluid (SFCs). Analysis of microarrays parsed the four cell types into two distinct groups, one composed only of chondrocytes and the other of CPCs, synoviocytes, and SFCs. The groups differed with respect to metalloendopeptidase, collagen, and cytokine gene expression. Quantitative PCR showed that, relative to chondrocytes, all other cells under-expressed cartilage matrix genes. CPCs significantly over-expressed genes encoding the chemokines interleukin 8 (IL8), and C-C motif ligand 2, while synoviocytes over-expressed the chemokine C-X-C motif Ligand 12. Sulfated glycosaminoglycan deposition in pellet cultures by CPCs was intermediate between chondrocytes and synoviocytes/SFCs. These results indicate that the CPC phenotype more closely resembles synoviocytes and SFCs than chondrocytes. CPCs show a tendency to over-express chemokines that promote immune cell chemotaxis, suggesting they mediate inflammation in response to cartilage wounding. PMID- 24797717 TI - Synthesis and evaluation of novel marine bromopyrrole alkaloid-based derivatives as potential antidepressant agents. AB - Herein, we report synthesis and screening of a series of twenty derivatives of bromopyrrole alkaloids with aroyl hydrazone feature for antidepressant activity by forced swim test (FST), tail suspension test (TST), and actophotometer method. The molecules were further evaluated for in vitro human MAO's inhibitory activities. The tested compounds exhibited moderate to good antidepressant activity compared with standard fluoxetine. Among these, most promising antidepressant derivatives 5b (%DID = 60.48), 5e (%DID = 59), and 5j (%DID = 74.86) reduced immobility duration of 50-70% at 30 mg/kg dose levels in FST. Further, derivative 5b, 5e, and 5j displayed good antidepressant activity with %DID value of 47.50, 46.62, and 52.49, respectively, in TST compared with standard fluoxetine (66.56% DID). Compound 5b showed high in vitro MAO-A potency and selectivity (Ki MAO-A (MUM) = 2.4 +/- 0.99, SI = 0.06) with promising pharmacological activity recognizing its potential as antidepressant lead candidate for further drug development. Study revealed that the presence of halogen atoms such as chlorine and fluorine at ortho- and/or para-position of phenyl ring and N-alkylation of pyrrole core is favored features for antidepressant activity. PMID- 24797718 TI - Importance of adequate decoppering in Wilson's disease. PMID- 24797719 TI - Population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension. AB - OBJECTIVES: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient specific sources of pharmacokinetic variability. DESIGN: Prospective observational cohort study. SETTING: Level 3 neonatal ICU. PATIENTS: Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age. CONCLUSIONS: We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension. PMID- 24797720 TI - Extracorporeal membrane oxygenation-supported cardiopulmonary resuscitation following stage 1 palliation for hypoplastic left heart syndrome. AB - OBJECTIVES: To report on survival from a large multicenter cohort of neonates with hypoplastic left heart syndrome requiring extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation after stage 1 palliation operation. DESIGN: Retrospective analysis of data from the Extracorporeal Life Support Organization data registry (1998 through 2013). We computed the survival to hospital discharge for neonates (age < 30 d) who required extracorporeal membrane oxygenation after stage 1 palliation and evaluated factors associated with mortality using multivariate logistic regression analysis. SETTING: Multicenter data reported to Extracorporeal Life Support Organization registry. PATIENTS: Infants with hypoplastic left heart syndrome after stage 1 palliation who received extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 307 extracorporeal membrane oxygenation runs in the setting of extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation in 293 neonates with hypoplastic left heart syndrome following stage 1 palliation operation. The median age at cannulation was 9 days (interquartile range, 5-14 d). Survival to hospital discharge was 36%. In univariate analysis, gestational age, weight, extracorporeal membrane oxygenation duration, presence of air embolism, hemorrhagic complications, renal failure, and pulmonary complications (pulmonary hemorrhage and pneumothorax) were all associated with nonsurvival. In multivariate analysis, lower body weight at cannulation (odds ratio, 3.9; 95% CI, 1.9-8.3), duration of the extracorporeal membrane oxygenation (odds ratio, 3.4; 95% CI, 1.9-7.3), and renal failure while on extracorporeal membrane oxygenation (odds ratio, 2; 95% CI, 1.2-3.5) increased odds of mortality. CONCLUSIONS: Mortality for neonates with hypoplastic left heart syndrome supported with extracorporeal membrane oxygenation-assisted cardiopulmonary resuscitation after stage 1 palliation is high. Lower body weight, increased duration of extracorporeal membrane oxygenation support, and renal failure increased mortality. PMID- 24797721 TI - Young adult cancer survivors and the challenges of intimacy. AB - The purpose of this study was to explore intimate relationships after a cancer diagnosis, applying constructivist grounded theory to interviews with 55 Canadian young adult cancer survivors. The core category found was the dynamic interplay between participants' experiences of cancer and their intimate relationships. The authors found four themes within this core category: the mental experience of cancer, challenged sexual intimacy, the relationship response to strain (supportive or nonsupportive), and adapted intimacy. This research demonstrates the importance of intimate relationships for young adults along their cancer trajectory, revealing that those relationships are severely strained by a cancer diagnosis and treatment yet help to limit negative consequences. PMID- 24797722 TI - Avian influenza virus vaccines containing Toll-like receptors 2 and 5 ligand adjuvants promote protective immune responses in chickens. AB - Vaccination remains a useful means for the control of avian influenza viruses (AIV) in chickens. Current vaccines can protect chickens from morbidity and mortality. However, they do not eliminate virus shedding into the environment. Therefore, novel measures must be considered in order to enhance the immunogenicity of AIV vaccines, such as through the administration of immunostimulatory compounds. One such group of compounds is Toll-like receptor (TLR) ligands, such as bacterial flagellin, as well as synthetic lipopeptides such as Pam3CSK4. The objective of the present study was to assess the adjuvant potential of TLR2 and TLR5 ligands flagellin and Pam3 respectively. Chickens were vaccinated twice with an inactivated H4N6 AIV vaccine, 14 days apart. Antibody mediated responses were assessed in sera and lacrimal secretions, while cell mediated immune response was assessed by stimulating splenocytes from vaccinated chickens in vitro with the vaccine antigen. To evaluate vaccine efficacy, chickens were challenged with the H4N6 virus, and virus shedding was assessed on day 7 post-challenge. The results suggest that both ligands significantly enhanced antigen-specific IgY antibodies, while only the Pam3 adjuvant induced greater IgM and IgA antibody levels. Chickens receiving the flagellin adjuvant had significantly higher IgY responses, as well as significantly higher hemagglutination-inhibition antibody titers compared to the no adjuvant control. With respect to cell-mediated responses, splenocytes isolated from chickens that received either TLR ligand adjuvant proliferated in response to an in vitro stimulation with vaccine antigens. Lastly, chickens receiving vaccines containing either flagellin or Pam3 adjuvants were partially protected from an experimental AIV challenge and shed significantly less virus compared to controls. Future studies may be aimed at examining the efficacy of Pam3 and flagellin adjuvants for highly pathogenic AIV strains. PMID- 24797723 TI - Abrogation of STAT3 signaling cascade by zerumbone inhibits proliferation and induces apoptosis in renal cell carcinoma xenograft mouse model. AB - Persistent activation of signal transducer and activator of transcription 3 (STAT3) is one of the characteristic features of renal cell carcinoma (RCC) and often linked to its deregulated proliferation, survival, and angiogenesis. In the present report, we investigated whether zerumbone, a sesquiterpene, exerts its anticancer effect through modulation of STAT3 activation pathway. The pharmacological effect of zerumbone on STAT3 activation, associated protein kinases and phosphatase, and apoptosis was investigated using both RCC cell lines and xenograft mouse model. We observed that zerumbone suppressed STAT3 activation in a dose- and time-dependent manner in RCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Pervanadate treatment reversed zerumbone induced downregulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that zerumbone induced the expression of tyrosine phosphatase SHP-1 that correlated with its ability to inhibit STAT3 activation. Interestingly, deletion of SHP-1 gene by siRNA abolished the ability of zerumbone to inhibit STAT3 activation. The inhibition of STAT3 activation by zerumbone also caused the suppression of the gene products involved in proliferation, survival, and angiogenesis. Finally, when administered i.p., zerumbone inhibited STAT3 activation in tumor tissues and the growth of human RCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that zerumbone is a novel blocker of STAT3 signaling cascade and thus has an enormous potential for the treatment of RCC and other solid tumors. PMID- 24797724 TI - Why the (dis)agreement? Family context and child-parent perspectives on health related quality of life and psychological problems in paediatric asthma. AB - BACKGROUND: Children's health-related quality of life (HrQoL) and psychological problems are important outcomes to consider in clinical decision making in paediatric asthma. However, children's and parents' reports often differ. The present study aimed to examine the levels of agreement/disagreement between children's and parents' reports of HrQoL and psychological problems and to identify socio-demographic, clinical and family variables associated with the extent and direction of (dis)agreement. METHODS: The sample comprised 279 dyads of Portuguese children with asthma who were between 8 and 18 years of age (M = 12.13; SD = 2.56) and one of their parents. The participants completed self- and proxy-reported questionnaires on paediatric generic HrQoL (KIDSCREEN-10), chronic generic HrQoL (DISABKIDS-37) and psychological problems (Strengths and Difficulties Questionnaire). Children's and parents' perceptions of family relationships were measured with the Family Environment Scale and the caregiving burden was assessed using the Revised Burden Measure. RESULTS: The child-parent agreement on reported HrQoL and psychological problems was poor to moderate (intraclass correlation coefficients between 0.32 and 0.47). The rates of child parent discrepancies ranged between 52.7% (psychological problems) and 68.8% (generic HrQoL), with 50.5% and 31.5% of the parents reporting worse generic and chronic-generic HrQoL, respectively, and 33.3% reporting more psychological problems than their children. The extent and direction of disagreement were better explained by family factors than by socio-demographic and clinical variables: a greater caregiving burden was associated with increased discrepancies in both directions and children's and parents' perceptions of less positive family relationships were associated with discrepancies in different directions. CONCLUSIONS: Routine assessment of paediatric HrQoL and psychological problems in healthcare and research contexts should include self- and parent reported data as complementary sources of information, and also consider the family context. The additional cost of conducting a more in-depth assessment of paediatric adaptation outcomes can be offset through more efficient allocation of health resources. PMID- 24797725 TI - Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma. AB - Effective treatment as well as prognostic biomarker for malignant esophageal squamous cell carcinoma (ESCC) is urgently needed. The present study was aimed at identifying oncogenic genes involving dysregulated intracellular Ca2+ signaling, which is known to function importantly in cellular proliferation and migration. Tumors from patients with ESCC were found to display elevated expression of Orai1, a store-operated Ca2+ entry (SOCE) channel, and the high expression of Orai1 was associated with poor overall and recurrence-free survival. In contrast to the quiescent nature of non-tumorigenic epithelial cells, human ESCC cells exhibited strikingly hyperactive in intracellular Ca2+ oscillations, which were sensitive to treatments with Orai1 channel blockers and to orai1 silencing. Moreover, pharmacologic inhibition of Orai1 activity or reduction of Orai1 expression suppressed proliferation and migration of ESCC in vitro and slowed tumor formation and growth in in vivo xenografted mice. Combined, these findings provide the first evidence to imply Orai1 as a novel biomarker for ESCC prognostic stratification and also highlight Orai1-mediated Ca2+ signaling pathway as a potential target for treatment of this deadly disease. PMID- 24797726 TI - A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study. AB - BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS: Eligibility criteria included age >= 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks * 4 and every 12 weeks thereafter. RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a >= 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted. PMID- 24797727 TI - Successful pregnancy following assisted reproduction and transmyometrial embryo transfer in a patient with anatomical distortion of the cervical canal. AB - Abstract Presented is the case report of a patient noted to have gross distortion of the internal cervical canal during her attempt at embryo transfer following an in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) procedure. Multiple attempts at cervical dilation were unsuccessful and the patient was ultimately treated by transmyometrial embryo transfer also known as the Towako method. She successfully achieved a singleton pregnancy and delivered at 41 weeks by primary cesarean section because of arrest of cervical dilation. Transmyometrial embryo transfer represents a viable option for patients with cervical stenosis refractory to conventional methods of navigation or severe anatomical distortion of the internal cervical canal. PMID- 24797729 TI - Ferromagnetic sorbents based on nickel nanowires for efficient uptake of mercury from water. AB - This work reports the preparation of ferro-magnetic nickel nanowires (NiNW) coated with dithiocarbamate-functionalized siliceous shells and its application for the uptake of aqueous Hg(II) ions by magnetic separation. NiNW with an average diameter and length of 35 nm and 5 MUm, respectively, were firstly prepared by Ni electrodeposition in an anodic aluminum oxide template. The NiNW surfaces were then coated with siliceous shells containing dithiocarbamate groups via a one-step procedure consisting in the alkaline hydrolytic co-condensation of tetraethoxysilane (TEOS) and a siloxydithiocarbamate precursor (SiDTC). A small amount of these new nanoadsorbents (2.5 mg.L(-1)) removed 99.8% of mercury ions from aqueous solutions with concentration 50 MUg.L(-1) and in less than 24 h of contact time. This outstanding removal ability is attributed to the high affinity of the sulfur donor ligands to Hg(II) species combined with the high surface area to-volume ratio of the NiNW. PMID- 24797728 TI - Prescription of antihypertensive medications during pregnancy in the UK. AB - PURPOSE: This study aimed to describe the management of antihypertensive medications in pregnancy by general practitioners in the UK and compare it with current guidelines. METHODS: We used electronic medical records from The Health Improvement Network database from 1996 to 2010 to identify completed pregnancies. The study cohort included the first pregnancy identified during the study period in women aged 13-49 years. Information on both hypertension diagnoses and prescription of specific antihypertensive medications within the 90 days before the last menstrual period (LMP) and during pregnancy was ascertained from electronic medical records. RESULTS: Among 148,544 eligible pregnancies, we identified 1995 (1.3%) during which the women had pre-existing hypertension diagnosed by the LMP date. Overall, the prevalence of antihypertensive medications during the first trimester was 1.5%; beta-blockers were the most commonly prescribed antihypertensive. Among women with pre-existing hypertension, 36% were prescribed an antihypertensive medication during the 90 days before the LMP. Among those, 9.6% and 22.2% had discontinued their medication by the first and second trimesters, respectively. For contraindicated drugs such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, the corresponding discontinuation rates were around 25% and 70%. Women who switched therapy received preferably either methyldopa or an alpha/beta-blocker. CONCLUSIONS: In this population of UK pregnant women, prescription patterns of antihypertensive medications were dominated by recommended treatments, although some patients continued on contraindicated drugs throughout pregnancy or switched to preferred agents in a delayed fashion. PMID- 24797730 TI - [Parotid involvement in Churg-Strauss syndrome]. AB - INTRODUCTION: Churg-Strauss syndrome is a rare systemic vascularitis. This disease causes eosinophilic tissue infiltration. The most frequent manifestations are cortico-dependent asthma, mono- or polyneuropathy, paranasal sinus polyposis, and digestive and renal dysfunction. Salivary glands are very rarely involved. OBSERVATION: We describe a case of CSS in a patient presenting with bilateral parotid swelling. The morphological study of salivary glands revealed an unusual thickening of the salivary duct walls. DISCUSSION: Salivary gland involvement in Churg and Strauss syndrome can be difficult to demonstrate histologically; it does not usually present in the clinical foreground of the disease, and can be a source of misdiagnosis. The biopsy should be performed in the symptomatic gland, away from any previous corticoid treatment. PMID- 24797732 TI - Effective nanometer airgap of NEMS devices using negative capacitance of ferroelectric materials. AB - Nanoelectromechnical system (NEMS) is seen as one of the most promising candidates for next generation extreme low power electronics that can operate as a versatile switch/memory/sensor/display element. One of the main challenges toward this goal lies in the fabrication difficulties of ultrascaled NEMS required for high density integrated circuits. It is generally understood that fabricating and operating a NEMS with an airgap below a few nanometer will be extremely challenging due to surface roughness, nonideal forces, tunneling, etc. Here, we show that by cascading a NEMS with a ferroelectric capacitor, operating in the negative capacitance regime, the effective airgap can be reduced by almost an order of magnitude, without the need to reduce the airgap physically. This would not only reduce the pull-in voltage to sub-1 V regime, but also would offer a set of characteristics which are difficult/impossible to achieve otherwise. For example, one can reduce/increase the classical travel range, flip the traditional stable-unstable regime of the electrode, get a negative pull-out voltage, and thus, center the hysteresis around zero volt. Moreover, one can also operate the combination as an effective ferroelectric memory with much reduced switching voltages. These characteristics promise dramatic saving in power for NEMS-based switching, memory, and other related applications. PMID- 24797731 TI - [Managing patients with therapeutic antibodies in odontostomatology]. AB - Immunotherapies, particularly therapeutic antibodies, are increasingly used in the treatment of many autoimmune or oncological diseases. Patients treated with therapeutic antibodies may present with an increased risk of infection or of osteonecrosis of the jaws (ONJ). There is currently no consensus on the management of patients treated with therapeutic antibodies. These treatments are mainly used in hospitals, but they have been increasingly prescribed in ambulatory treatment for patients undergoing oral care. It is therefore important to establish therapeutic precautions for these patients. We had for aim to describe these antibody therapies, their indications, their potentially adverse effects in the oral cavity and to review the latest recommendations. PMID- 24797733 TI - Biodegradation mechanisms of iron oxide monocrystalline nanoflowers and tunable shield effect of gold coating. AB - Understanding the relation between the structure and the reactivity of nanomaterials in the organism is a crucial step towards efficient and safe biomedical applications. The multi-scale approach reported here, allows following the magnetic and structural transformations of multicore maghemite nanoflowers in a medium mimicking intracellular lysosomal environment. By confronting atomic scale and macroscopic information on the biodegradation of these complex nanostuctures, we can unravel the mechanisms involved in the critical alterations of their hyperthermic power and their Magnetic Resonance imaging T1 and T2 contrast effect. This transformation of multicore nanoparticles with outstanding magnetic properties into poorly magnetic single core clusters highlights the harmful influence of cellular medium on the therapeutic and diagnosis effectiveness of iron oxide-based nanomaterials. As biodegradation occurs through surface reactivity mechanism, we demonstrate that the inert activity of gold nanoshells can be exploited to protect iron oxide nanostructures. Such inorganic nanoshields could be a relevant strategy to modulate the degradability and ultimately the long term fate of nanomaterials in the organism. PMID- 24797734 TI - Electrochemical supercapacitors from conducting polyaniline-graphene platforms. AB - Energy storage devices such as electrochemical supercapacitors, with high power and energy densities are required to address the colossal energy requirements against the backdrop of global warming and the looming energy crisis. Nanocarbon, particularly two-dimensional graphene and graphene-based conducting polymer composites are promising electrode materials for such energy storage devices. Owing to their environmental stability, the low cost of polymers with high electroactivity and pseudocapacitance, such composite hybrids are expected to have wide implications in next generation clean and efficient energy systems. In this feature article, an overview of current research and important advances over the past four years on the development of conducting polyaniline (PANI)-graphene based composite electrodes for electrochemical supercapacitors are highlighted. Particular emphasis is made on the design, fabrication and assembly of nanostructured electrode architectures comprising PANI and graphene along with metal oxides/hydroxides and carbon nanotubes. Comments on the challenges and perspectives towards rational design and synthesis of graphene-based conducting polymer composites for energy storage are discussed. PMID- 24797735 TI - A Technosol as archives of organic matter related to past industrial activities. AB - To better understand formation, functioning and evolution of a Technosol developing on a former settling pond of iron industry under forest cover, organic matter (OM) of layers along the soil profile was investigated. Spectroscopic and molecular analyses of extractable OM gave information on OM origin and state of preservation. In the surface layer, OM fingerprints indicated fresh input from vegetation while they revealed well preserved anthropogenic compounds related to industrial processes in deeper layers. OM variability and distribution according to the layers recorded deposition cycles of industrial effluents into the pond. Thus, the Technosol can be considered as archives of past industrial activities. The preservation of anthropogenic OM could be connected with mineralogy, high metal contents and particular physical properties of the Technosol. PMID- 24797736 TI - Distribution and risk assessment of quinolone antibiotics in the soils from organic vegetable farms of a subtropical city, Southern China. AB - Organic fertilizer or manure containing antibiotics has been widely used in organic farms, but the distribution and potential impacts of antibiotics to the local environment are not well understood. In this study, four quinolone antibiotics in soil samples (n=69) from five organic vegetable farms in a subtropical city, Southern China, were analyzed using high performance liquid chromatography-tandem mass spectrometry. Our results indicated that quinolone compounds were ubiquitous in soil samples (detection frequency>97% for all compounds), and their concentrations ranged from not detectable to 42.0 MUg/kg. Among the targets, enrofloxacin (ENR) was the dominant compound, followed by ciprofloxacin (CIP) and norfloxacin (NOR). The average total concentrations of four compounds in the soils were affected by vegetable types and species cultivated, decreasing in the order of fruit>rhizome>leaf vegetables. Moreover, the average concentrations of quinolone compounds (except ENR) in open-field soils were higher than those in greenhouse soils. The concentrations of quinolone antibiotics in this study were lower than the ecotoxic effect trigger value (100 MUg/kg) proposed by the Veterinary Medicine International Coordination commission. Risk assessment based on the calculated risk quotients indicated that NOR, CIP, and ENR posed mainly medium to low risks to bacteria. PMID- 24797737 TI - Seasonal variations in the sources of natural and anthropogenic lead deposited at the East Rongbuk Glacier in the high-altitude Himalayas. AB - Lead (Pb) isotopic compositions and concentrations, and barium (Ba) and indium (In) concentrations have been analysed at sub-annual resolution in three sections from a <110 m ice core dated to the 18th and 20th centuries, as well as snow pit samples dated to 2004/2005, recovered from the East Rongbuk Glacier in the high altitude Himalayas. Ice core sections indicate that atmospheric chemistry prior to ~1,953 was controlled by mineral dust inputs, with no discernible volcanic or anthropogenic contributions. Eighteenth century monsoon ice core chemistry is indicative of dominant contributions from local Himalayan sources; non-monsoon ice core chemistry is linked to contributions from local (Himalayan), regional (Indian/Thar Desert) and long-range (North Africa, Central Asia) sources. Twentieth century monsoon and non-monsoon ice core data demonstrate similar seasonal sources of mineral dust, however with a transition to less-radiogenic isotopic signatures that suggests local and regional climate/environmental change. The snow pit record demonstrates natural and anthropogenic contributions during both seasons, with increased anthropogenic influence during non-monsoon times. Monsoon anthropogenic inputs are most likely sourced to South/South-East Asia and/or India, whereas non-monsoon anthropogenic inputs are most likely sourced to India and Central Asia. PMID- 24797738 TI - Priority persistent contaminants in people dwelling in critical areas of Campania Region, Italy (SEBIOREC biomonitoring study). AB - To investigate if protracted living in degraded environments of the Caserta and Naples provinces (Campania Region, Italy) had an impact on exposure of local people, highly toxic persistent contaminants were measured in blood, blood serum, and human milk of a large number of healthy donors. Sampling was carried out from 2008 to 2009. Blood was collected from over 850 20-64-year old donors; by pooling, 84 blood and 84 serum samples were obtained. Milk was donated by 52 mothers: specimens were pooled into six samples. Polychlorodibenzodioxins (PCDDs), polychlorodibenzofurans (PCDFs), and polychlorobiphenyls (PCBs, dioxin like (DL) and non-dioxin-like (Sigma6PCBs)), arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) were measured in serum (organic biomarkers) and blood (metals); these chemicals and polybromobiphenyl ethers (Sigma9PBDEs) were analyzed in milk. PCDD+PCDF, DL-PCB, TEQTOT, and Sigma6PCB concentration ranges (medians) in serum were 6.26-23.1 (12.4), 3.42-31.7 (11.5), 10.0-52.8 (23.9) pgTEQ97/g fat, and 55.5-647 (219) ng/g fat, respectively, while in milk concentration ranges were 5.99-8.77, 4.02-6.15, 10.0-14.2 pgTEQ97/g fat, and 48.7 74.2 ng/g fat. Likewise, As, Cd, Hg, and Pb findings in blood spanned 2.34-13.4 (5.83), 0.180-0.930 (0.475), 1.09-7.60 (2.60), 10.2-55.9 (28.8) MUg/L, respectively; only Pb could be measured in milk (2.78-5.99 MUg/L). Sigma9PBDE levels in milk samples were 0.965-6.05 ng/g fat. Biomarkers' concentrations were found to be compatible with their current values in European countries and in Italy, and consistent with an exposure primarily determined by consumption of commercial food from the large distribution system. Based on relatively higher biomarker values within the hematic biomonitoring database, the following municipalities were flagged as possibly deserving attention for health-oriented interventions: Brusciano and Caivano (As), Giugliano (Hg), Pianura (PCDDs+PCDFs), and Qualiano-Villaricca (As, Hg). The analysis of samples' qualitative variability indicated that biomarker composition was sensitive at municipality level, a feature that can potentially drive interventions for future local risk assessment and/or management measures. PMID- 24797739 TI - Benefits for agriculture and the environment from urban waste. AB - Soluble bio-based substances (SBO) that have been isolated from urban biowaste have recently been reported to enhance plant leaf chlorophyll content and growth. The same SBO have also been shown to enhance the photochemical degradation of organic pollutants in industrial effluent. These findings suggest that SBO may promote either C fixation or mineralization, according to operating conditions. The present work aims to investigate SBO performance, as a function of source material. Thus, three materials have been sampled from a municipal waste treatment plant: (i) the digestate of the anaerobic fermentation of a humid organic fraction, (ii) a whole vegetable compost made from gardening residues and (iii) compost made from a mixture of digestate, gardening residues and sewage sludge. These materials were hydrolyzed at pH13 and 60 degrees C to yield SBO that display different chemical compositions. These products were applied to soil at 30, 145 and 500 kg ha(-1) doses for tomato cultivation. Soil and plant leaf chemical composition, plant growth, leaf chlorophyll content and CO2 exchange rate as well as fruit quality and production rate were measured. Although it did not affect the soil's chemical composition, SBO were found to significantly increase plant photosynthetic activity, growth and productivity up to the maximum value achieved at 145 kg ha(-1). The effects were analyzed as a function of SBO chemical composition and applied dose. The results of this work, compared with those of previous works, indicate that urban biowaste, if properly exploited, may furnish conjugate economic and environmental benefits, within a friendly sustainable ecosystem. PMID- 24797740 TI - [Building on our heritage* Historical Archives of the DDG. The time has come ....]. PMID- 24797742 TI - Sclerotherapy of varicose veins in dermatology. AB - Venous disorders rank among the most frequent diseases in the German population. Early diagnostic investigation and treatment can prevent their progression and may reduce the risk for secondary diseases. The therapeutic spectrum for varicose veins includes conservative as well as interventional and surgical methods. Because it is minimally invasive and well-tolerated, sclerotherapy represents an important treatment method for venous insufficiency, recurrent varicosis and venous malformations. We review the role of sclerotherapy as a treatment option of chronic venous insufficiency in dermatology. PMID- 24797746 TI - Autoantibodies in psoriatic patients treated with anti-TNF-alpha therapy. AB - BACKGROUND: TNF-alpha inhibitors have been associated with induction of autoantibodies and autoimmune diseases. We retrospectively evaluated the incidence of autoantibodies ANA, ENA, anti-dsDNA, the occurrence of clinical symptoms and possibly related treatment failure. PATIENTS AND METHODS: The titers of ANA, ENA and anti-dsDNA were evaluated from blood samples every six months in 128 patients receiving a TNF-alpha inhibitor (adalimumab, etanercept, infliximab). RESULTS: Overall 37% of 128 patients treated with anti-TNF-alpha drug developed autoantibodies, mostly induced by infliximab; 48.48 % of patients who received infliximab presented autoantibodies. One patient developed a drug induced lupus erythematosus. Forty-five patients were switched to one or more additional TNF-alpha inhibitors and 25 developed autoantibodies. CONCLUSIONS: An increased autoantibody titer is not predictive of treatment failure; particular attention to all phenomena suggestive for autoimmunity is needed in patients with a positive autoantibody titer. Further studies are needed to clarify the role of autoantibodies during anti-TNF- alpha therapy. PMID- 24797745 TI - The environment-pathogen-host axis in communicable and non-communicable diseases: recent advances in experimental and clinical research. AB - Allergies and autoimmune diseases are spreading worldwide. Control of infections, on the other hand, remains an issue, even in the post-antibiotic era. Chronic or poorly controlled infections occur in immune compromised individuals such as HIV patients, hospitalized patients exposed to multi-resistant bacteria, or patients on immunosuppressive treatment. They may become an even more emerging issue in an ageing population. At the same time, profound environmental changes such as global warming, urbanization, increasing environmental pollution and novel food engineering technologies may alter the abundance or aggressiveness of allergens/allergen carriers in our environment. Likewise, changes in dietary habits - and possibly also use of antibiotics - have an impact on the composition of our natural microbial flora in the gut, airways and skin, which may alter susceptibility for common diseases, among them allergies, asthma and atopic eczema. At the recently founded Institute of Environmental Medicine of the Technische Universitat Munich, located in Augsburg at the UNIKA-T, experimental, clinical and translational research is focused on the complex interactions of environment, pathogen and host in expression or control of communicable and non communicable diseases. We present our research concept and recent findings in environment - host interactions. PMID- 24797748 TI - Cooperation between the occupational health insurance and physicians practicing occupational dermatology: optimization potential in quality assurance. AB - BACKGROUND: Quality assurance is a task of the medical profession, but it is also a duty of the occupational health insurance (OHI). Data on the interaction quality between physicians practicing occupational dermatology and the OHI are limited. MATERIAL AND METHODS: An online survey was performed in 854 German members of the Working Group on Occupational and Environmental Dermatology in October 2013. Items included demographic data, a judgment on the cooperation between the dermatologists and OHI companies, an economic grading of the current compensation scheme, and prioritization of optimization tasks. RESULTS: 182 members (21.3 % of the invited population) participated in the survey. The cooperation with the OHI companies was judged as "very good" by 10.8 %, as "good" by 56.7 %, as "satisfactory" by 24.2 %, as "sufficient" by 7.0 % and as "inadequate" by 1.3 %. 93.4 % of the interviewed mentioned problems and improvement potentials in the cooperation of their practice or clinic with OHI companies. Main points of criticisms were reimbursement (44.7 %), followed by impairments of the treatment options (36.5 %) and the delay or scope of the treatment in the dermatologist's procedure (29.4 %). CONCLUSIONS: While most physicians practicing occupational dermatology give a positive judgment of their cooperation with OHI companies, quality optimization potentials exist regarding the reimbursement of dermatological services, especially regarding time-intensive counselling in the prevention of occupational skin diseases, in the enablement of diagnostic and therapeutic procedures according to current guidelines and in a timely preventive intervention to use the therapeutic window before chronification of skin diseases may occur. PMID- 24797753 TI - Atrophic dermatofibrosarcoma protuberans: are there specific dermatoscopic features? PMID- 24797757 TI - [11. Heinrich-Teller Lecture at the Embassy of Hungary on November 22, 2013. Why do memorial lectures?]. PMID- 24797758 TI - [Journal club]. PMID- 24797760 TI - Adverse effects of first-degree AV-block in patients with sinus node dysfunction: data from the mode selection trial. AB - BACKGROUND: Patients with a pacing indication and first-degree atrioventricular (AV)-block pose a clinical challenge. The prognostic impact of first-degree AV block in patients with sinus node dysfunction and the impact of pacing in this setting are not known. METHODS: In the Mode Selection Trial (MOST), 2,010 patients with sinus node dysfunction were randomized to either dual-chamber (DDD R) or ventricular (VVI-R) pacing and followed for a median of 33 months. We report on clinical outcomes in patients with first-degree AV-block (PR interval > 200 ms) compared with patients who had a normal PR interval at baseline. RESULTS: Patients with first-degree AV-block (n = 378) were older (median [Q1, Q3]; 76 [70, 82] years vs 73 [66, 79] years, P< 0.0001), more often male (57% vs 49%, P = 0.0049), and had more comorbidity, such as hypertension (66% vs 60%, P = 0.034) and heart failure (24% vs 17%, P = 0.0050) than patients with normal AV conduction (n = 1,159). In multivariable analyses, patients with first-degree AV block were at greater risk of death, stroke, or heart failure hospitalization (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.06-1.61, P = 0.013). A trend towards a higher incidence of atrial fibrillation was seen (HR 1.24, 95% CI 0.98-1.55, P = 0.069). No significant interactions between pacing arm and prolonged versus normal PR were found for any endpoint, and hazard ratios were consistent across subgroups. CONCLUSIONS: First-degree AV-block is associated with more advanced disease but is still an independent predictor of poor clinical outcome. Neither DDD-R nor VVI-R pacing, as employed in MOST, eliminate the negative effects associated with first-degree AV-block. PMID- 24797762 TI - Preparation of mPEG2000-PLA-modified Xingnaojing microemulsion and evaluation in mucosal irritation. AB - Xingnaojing microemulsion (XNJ-M) administered intranasally is used for stroke treatment. Methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) is a block copolymer with surfactant-like properties and good biodegradability and reliable biological safety. In order to investigate the possibility to lower mucosa irritation with XNJ-M, XNJ-M modified by mPEG2000-PLA (XNJ-MM) was prepared. Different ratios of mPEG2000-PLA were synthesized. The structures and properties were confirmed by 1H-NMR, IR, and DSC. The hydrophile-lipophile balance (HLB) value and critical micellar concentration of copolymers were investigated. The in situ toad palate model was adopted to investigate the ciliotoxicity of the copolymers. The XNJ-M and XNJ-MM were prepared by dropping aqueous phase method. Mucosal irritation of different Xingnaojing (XNJ) preparations was studied by behavioral observations including sneezing and scratching nose. The epithelial thickness of nasal mucosa was evaluated and the secretory protein concentration was determined. The results of in situ toad palate model demonstrated that high HLB value mPEG2000-PLA basically showed no ciliotoxicity, while EL-35 had significant dose-dependent ciliotoxicity (P<0.05). The irritating effects of mPEG2000-PLA were significantly lower than EL-35 after seven days of treatment, based on the epithelial thickness of 0.429+/-0.100 mm and 0.700+/-0.035 mm, respectively (P<0.01). The epithelial thickness with XNJ-MM was lower than XNJ-M after seven days of treatment: 0.620+/-0.10 mm vs. 0.809+/-0.153 mm, respectively (P<0.05). The mPEG2000-PLA-modified microemulsion is a promising dosage form of XNJ, based on reduced irritation on nasal mucosa. PMID- 24797761 TI - VEGF promotes osteogenic differentiation of ASCs on ordered fluorapatite surfaces. AB - Vascular endothelial growth factor (VEGF) has been reported to mediate both osteogenesis and angiogenesis in bone regeneration. We previously found an upregulation of VEGF in adipose-derived stem cells (ASCs) when obvious mineralization occurred on a novel fluorapatite (FA)-coated surfaces. This study investigated the effect of FA and VEGF on the growth, differentiation and mineralization of (ASC) grown on ordered FA surfaces. Cells grown on FA and treated with VEGF demonstrated osteogenic differentiation as measured with ALP staining, and obvious mineralization as measured by Alizarin red staining. A combined stimulating effect of FA and VEGF was seen using both indicators. VEGF signaling pathway perturbation using a specific VEGF receptor inhibitor showed the lowest levels of ALP and Alizarin red staining, which was partially rescued when the cells were grown on FA and/or treated with the addition of VEGF. The osteogenic differentiation of ASCs stimulated by these FA surfaces as well as VEGF has been shown to be mediated through, but probably not only, the VEGF signaling pathway. The enhancement of osteogenic differentiation and mineralization supports the potential use of therapeutic VEGF and FA coatings in bone regeneration. PMID- 24797763 TI - Patient-centred, administration friendly medicines for children - an evaluation of children's preferences and how they impact medication adherence. AB - The development of age appropriate paediatric formulations, particularly those suitable for young children, presents challenges with only limited knowledge available on the acceptability of different medicines and how this affects medication adherence. This publication describes studies conducted at Alder Hey Children's Hospital, Liverpool, UK with the aim of determining which factors relating to dose form and organoleptic properties of a medicinal product influence medication adherence in chronically ill children. The research was conducted in two phases comprising 70 chronically ill children aged between 3 and 11 years, 70 primary caregivers, and 33 hospital clinical and technical staff. Phase one, the CHIMP study (children's medication preferences), investigated children's preferences in terms of the organoleptic properties of medicines, and factors which influence these preferences and medication adherence. The data generated in the CHIMP study was used to construct a Medication Adherence Prediction Tool (MedAPT), in the form of a questionnaire, which was the subject of a second study (MedAPT), to qualify the prediction tool, in which adherence predictions derived from children and primary caregiver's questionnaire response data were statistically evaluated against adherence measurement generated from pharmacy medication refill data. The developed MedAPT questionnaire correctly predicted medication adherence/non-adherence in 79.4% of children. It is envisaged that, following further confirmation of the MedAPT as a prediction tool, this may be used in clinical practice as a predictor of adherence, and as a means of focussing resources and interventions to address non-adherence. PMID- 24797764 TI - ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. AB - AIM OF THE STUDY: Small bowel adenocarcinoma (SBA) is a rare and aggressive tumour with poor outcomes. Because of its low incidence, the number prospective studies remains insufficient leading to poor knowledge and absence of standard of care. Aiming to better understand small bowel carcinogenesis we investigated the frequency of somatic mutations in a large data set of patients in more than 740 mutational hotspots among 46 genes. METHODS: In total, 83 SBA cases were selected from two European databases. The sequencing was performed using the Ion 316 Chip. Additionally we looked into ERBB2 expression and microsatellite instability (MSI) status. RESULTS: The tumours most frequently were duodenal (47%) and stage ?3 (63%). Eight genes were mutated with a frequency >5%: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF and FBXW7. ERBB2 alterations are present in 10 patients (12%) through mutations (7 cases) or amplifications (3 cases). ERBB2 mutations were significantly associated with duodenal tumour location (P=0.04). In this group, there was a positive association with dMMR status (P=0.006) and APC mutation (P=0.02) but negative association with p53 mutations (P=0.038). CONCLUSIONS: This study describes the first large screening of somatic mutations in SBA using next generation sequencing. The ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumour location. In most cases ERBB2 mutation was identical (p.L755S). In clinical practice, this may suggest that more than 10% of the patients with SBA could be treated using an anti-ERBB2-targeted agent. PMID- 24797765 TI - An observational study of patient satisfaction with fesoterodine in the treatment of overactive bladder: effects of additional educational material. AB - AIM: To compare the effects of additional educational material on treatment satisfaction of overactive bladder (OAB) patients treated with a muscarinic receptor antagonist. METHODS: In an observational study of OAB patients being treated by their physician with fesoterodine for 4 months (FAKTEN study), sites were randomised to providing standard treatment or additional educational material including the SAGA tool. Patient satisfaction was assessed by three validated patient-reported outcomes including the Treatment Satisfaction Question. Because of premature discontinuation of the study, descriptive statistical analysis was performed. RESULTS: A total of 431 and 342 patients received standard treatment or additional educational material, respectively. At study end, 76.1% [95% CI = 71.3, 80.4] of patients with standard care and 79.6% [95% CI = 74.4, 84.1] with additional SAGA tool were satisfied with treatment (primary end-point). Comparable outcomes with and without the additional educational material were also found in various patient subgroups, at the 1-month time point, and for the other patient-reported outcomes. A notable exception was the subgroup of treatment-naive patients in which the percentage of satisfied patients was 77.2% vs. 89.5% with standard treatment and additional SAGA tool, respectively (post hoc analysis). DISCUSSION AND CONCLUSIONS: In an observational study, most overactive bladder patients were satisfied with fesoterodine treatment. Because of the small sample size, the study does not support or refute the hypothesis that adding the SAGA tool will improve patient satisfaction with treatment. The potential effect of additional educational material in treatment naive patients warrants further dedicated studies. PMID- 24797766 TI - Evaluation and verification of the nanosphere Verigene RV+ assay for detection of influenza A/B and H1/H3 subtyping. AB - With the emerging risks of drug-resistant viruses and pandemic influenza, rapid and accurate detection of influenza viruses and determination of their subtypes is a crucial component of patient management. This study evaluated the performance of the Verigene respiratory virus plus nucleic acid (Verigene RV+) test for the detection of influenza A/B and subtype determination compared it with conventional molecular methods. Nasopharyngeal swabs were collected from 228 patients with influenza-like illness (influenza A (n = 67), 2009-H1N1 (n = 21), influenza B (n = 80), mixed A & B (n = 3), mixed RSV A and influenza (n = 3), and influenza-negative (n = 54)). Patient samples were analyzed by Influenza A/B one step typing (Seegene, Seoul, Korea), Seeplex RV15 ACE Detection (Seegene), Nanosphere Verigene RV+ assay (Nanosphere, Northbrrook, IL) and virus culture. Out of 228 samples, 109 (47.8%) were positive by culture, and an additional 65 (28.5%) were positive by Seeplex RV15 ACE Detection, Influenza A/B one-step typing or Nanosphere Verigene RV+ assay. In comparison tests with Seeplex RV15 ACE Detection RT-PCR, the sensitivity of the Verigene RV+ kit for detection of the influenza A, 2009-H1N1, influenza B, and mixed A & B was 97.1%, 100%, 100%, and 100%, respectively. The specificity of the Verigene RV+ was 100% for all types. The concordance between Verigene RV+ and Influenza A/B one-step typing for H1, H3, H1/H3 mixed, and 2009-H1N1 was 100% (26/26), 100% (35/35), 100% (4/4), and 100% (21/21), respectively. The Verigene RV+ assay showed acceptable sensitivity and specificity for detection and subtyping of influenza viruses compared with the conventional RT-PCR method. J. Med. Virol. 87: 18-24, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 24797767 TI - Ligation of human Fc receptor like-2 by monoclonal antibodies down-regulates B cell receptor-mediated signalling. AB - B-cell antigen receptor (BCR) signalling and its regulation through negative and positive regulators are critical for balancing B-cell response and function. Human Fc receptor like-2 (FCRL2), a member of the newly identified FCRL family, could influence B-cell signalling due to possession of both immunoreceptor tyrosine-based activation and inhibitory motifs (ITAM and ITIM). Since the natural ligand of FCRL2 has not been identified, we generated FCRL2-specific monoclonal antibodies (mAbs) and employed them to investigate the influence of FCRL2 stimulation on BCR signalling in an FCRL2-expressing B-cell line. Two anti FCRL2 mAb-producing hybridoma clones (5A7-E7 and 3D8-G8) were selected. None of the mAbs displayed any cross-reactivity with the other members of the FCRL family including recombinant FCRL1, -3, -4 and -5, as tested by FACS and ELISA techniques. Engagement of the FCRL2 by these mAbs resulted in significant inhibition of BCR signalling mediators such as calcium mobilization and phosphorylation of the mitogen-activated protein kinases Erk, p38 and Jnk. These findings indicate that the FCRL2 ITIM motifs are functional and the anti-FCRL2 mAbs may mimic the natural ligand of FCRL2 by induction of inhibitory signals in B cells. PMID- 24797768 TI - 'Only connect': the case for public health humanities. AB - Humanities in health has until now been primarily understood to mean humanities in medicine and has generally failed to include public health. I will argue in this paper that the common justifications for the former--including increased empathy among practitioners--are at least as applicable, if not more, to the latter. Growing emphasis on the social determinants of health and cultural competency in public health require public health students and professionals to develop a nuanced understanding of the influence of social context on health behaviour and to empathise with people in difficult circumstances. Literary fiction has been demonstrated to have an impact on skills related to empathy and social intelligence. Further, translating epidemiological evidence into public policy is a core task of public health and there is a growing body of research to indicate that statistical evidence is more persuasive when combined with narrative evidence. In this article I explore similarities and differences between proposed humanities in public health and programmes in humanities in medicine and highlight research gaps and possible implications of a more expansive view of humanities in health. PMID- 24797769 TI - C5-alkynyl-functionalized alpha-L-LNA: synthesis, thermal denaturation experiments and enzymatic stability. AB - Major efforts are currently being devoted to improving the binding affinity, target specificity, and enzymatic stability of oligonucleotides used for nucleic acid targeting applications in molecular biology, biotechnology, and medicinal chemistry. One of the most popular strategies toward this end has been to introduce additional modifications to the sugar ring of affinity-inducing conformationally restricted nucleotide building blocks such as locked nucleic acid (LNA). In the preceding article in this issue, we introduced a different strategy toward this end, i.e., C5-functionalization of LNA uridines. In the present article, we extend this strategy to alpha-L-LNA: i.e., one of the most interesting diastereomers of LNA. alpha-L-LNA uridine monomers that are conjugated to small C5-alkynyl substituents induce significant improvements in target affinity, binding specificity, and enzymatic stability relative to conventional alpha-L-LNA. The results from the back-to-back articles therefore suggest that C5-functionalization of pyrimidines is a general and synthetically straightforward approach to modulate biophysical properties of oligonucleotides modified with LNA or other conformationally restricted monomers. PMID- 24797770 TI - Role of cytolytic impairment of natural killer and natural killer T-cell populations in rheumatoid arthritis. AB - Innate immunity has been widely accepted as one of the major cause for the alteration of immune system and progression of autoimmune diseases. Natural killer (NK) cells and natural killer T (NKT) cells have not been explored in clinical studies for their cytolytic components in association with rheumatoid arthritis (RA). The literature available for these potential candidates is controversial in terms of their protective or pathogenic role in disease severity of RA. Present study explained the role of NK and NKT cell populations and intracellular expression of caspases, perforin, granzymes A and B in the pathogenesis of RA in patients. DAS28 score was measured as the disease severity. Immunochemical parameters were studied by using monoclonal antibodies (mAbs) against different cell types in flow cytometry. Results indicated that that whatsoever is the change in percentage cell populations, ratio of NK and NKT cell populations always remained poised even in the disease state. Reactive oxygen species (ROS) levels were elevated with increased intracellular active caspase-3, perforin and granzyme expression in RA patients. Their elevated expressions were positively correlated with DAS28 suggesting the pathogenic role in RA. The expressions of pro-inflammatory cytokines were enhanced while the anti inflammatory cytokine expressions were diminished in the patients. Present study may point towards futuristic therapeutic targets which can fascinate the pharmaceutical industries to selectively target these molecules in designing the therapeutic strategy of RA patients. PMID- 24797771 TI - An MRI assessment of chronic synovial-based inflammation in gout and its correlation with serum urate levels. AB - It is unclear when the synovial-based inflammatory process of gout begins. The aim of this study was to determine the percentage of patients with inter-critical gout who have chronic synovial-based inflammation as evidenced by synovial pannus on a contrast-enhanced magnetic resonance imaging (MRI) of their most involved joint and determine if the presence and/or severity correlates with their serum urate levels. All patients received a 3 T MRI of their index joint, serum urate level, CRP, and creatinine. The primary endpoint was to determine the prevalence of synovial pannus and the correlation of serum urate levels with the presence and/or severity of the synovial pannus on that same joint. MRI erosions, tophi, swelling, effusion, and osteitis were also documented. Seventy-two of 74 subjects (90% men) completed the protocol. Fifty-three of 72 (74%) index joints were the first metatarsophalangeal joint. Thirty-nine (54.2%) of the patients were on urate-lowering therapy; 15 (20.8%) and 7 (9.7%) were taking colchicine or a NSAID daily, respectively. Of the 72 subjects, 63 (87.5%) had synovial pannus on their MRI with good inter-reader agreement between the two radiologists. The mean serum urate level was 7.93 mg/dL. There was no correlation with the presence (p = 0.33) or severity (p = 0.34) of synovial pannus and serum urate levels. There was also no correlation with the presence or severity of synovial pannus and the secondary endpoints. The majority of patients with inter-critical gout have evidence of chronic synovial-based inflammation. However, the presence and severity of this inflammation do not appear to correlate with serum urate levels. PMID- 24797772 TI - Effects of physical therapy for the management of patients with ankylosing spondylitis in the biological era. AB - Exercise is considered a fundamental tool for the management of ankylosing spondylitis (AS), in combination with pharmacological therapy that with the advent of biological therapy has improved dramatically the control of signs and symptoms of this challenging disease. Current evidence shows that a specific exercise protocol has not been validated yet. The purpose of this review is to update the most recent evidence (July 2010-November 2013) about physiotherapy in AS, analyzing the possible role and synergistic interactions between exercise and biological drugs. From 117 studies initially considered, only 15 were included in the review. The results support a multimodal approach, including educational sessions, conducted in a group setting, supervised by a physiotherapist and followed by a maintaining home-based regimen. Spa exercise and McKenzie, Heckscher, and Pilates methods seem promising in AS rehabilitation, but their effectiveness should be further investigated in future randomized controlled trials (RCTs). When performed in accordance with the American College of Sports Medicine guidelines, cardiovascular training has been proven safe and effective and should be included in AS rehabilitation protocols. Exercise training plays an important role in the biological era, being now applicable to stabilized patients, leading ultimately to a better management of AS by physiatrists and rheumatologists throughout the world. On the basis of the current evidence, further research should aim to determine which exercise protocols should be recommended. PMID- 24797773 TI - Anti-citrullinated peptide/protein antibodies in palindromic rheumatism: comment on the article by Emad Y et al. PMID- 24797774 TI - Prevalence of pes anserine bursitis in symptomatic osteoarthritis patients: an ultrasonographic prospective study. AB - The aim of this prospective study was to determine the prevalence of pes anserine bursitis (PAB) in patients with osteoarthritis. A total of 85 patients with primary knee osteoarthritis diagnosed according to the American College of Rheumatology (ACR) criteria were included in the study. The patients were divided into four groups using the Kellgren-Lawrence staging system. The knee X-rays evaluated according to this system indicated that 15.6% of patients were grade 1, 34.1% grade 2, 37.1% grade 3, and 13.5% grade 4. Ultrasonography (USG) was performed on both knees by a radiologist experienced in musculoskeletal system ultrasonography and unaware of the patients' physical examination or direct X-ray findings. The presence of PAB, longest diameter of bursitis, and area of bursitis were recorded. The average age of the 11 male and 74 female patients included in the study was 58.9 +/- 9.0 years. A total of 170 knees of 85 patients were examined. The incidence of bursitis was significantly higher in females (p = 0.026). The incidence of bursitis on ultrasound was 20% (34/170). There was a statistical difference between the grades for bursitis incidence (p = 0.004). There was a significant positive correlation between both the longest length (p = 0.015, r = 0.187) and area (p = 0.003, r = 0.231) of PAB with osteoarthritis grade. The mean age of bursitis patients was higher than that of those without the condition (p = 0.038). In addition, the osteoarthritis (OA) grade and bursitis prevalence increased as the patients' age increased, and these increases were statistically significant (p < 0.001). PAB is easily evaluated with ultrasonography. Pes anserine bursitis was observed in one out of every five symptomatic OA patients and was more common in female patients and with advanced age. A positive correlation was found between OA grade and PAB size and area. PMID- 24797775 TI - Can Procalcitonin in Cerebrospinal Fluid be a Diagnostic Tool for Meningitis? AB - BACKGROUND: To study the levels of procalcitonin (PCT) in patients with meningitis and control group and compare them with established markers of infection--such as C-reactive protein (CRP), high-sensitivity CRP, and WBC--in cerebrospinal fluid (CSF) and assess the possible discriminative role of PCT in the differential diagnosis of meningitis from other noninfectious diseases. METHODS: We studied CSF samples of patients from Intensive Care Unit, Internal Medicine, Neurology, Hematology, and Pediatric departments. The total number of patients included in the study was 58. The samples were divided into three groups: group 1 with bacterial meningitis (BM) central nervous system (n = 19); group 2 with viral meningitis (VM, n = 11); and group 3, control group, with noninfectious diseases (n = 28). RESULTS: Values of PCT levels >0.5 ng/ml were considered as abnormal. In group 1, mean PCT levels were 4.714 +/- 1.59 ng/ml. In group 2, all patients had PCT <0.5 ng/ml (0.1327 +/- 0.03 ng/ml). In group 3, the mean PCT levels were <0.1 ng/ml. CONCLUSION: PCT values in CSF can be very helpful in distinguishing BM from VM and other noninfectious diseases. PMID- 24797776 TI - [Potential interactions between drugs and dietary supplements]. AB - Purified active plant constituents were isolated and assessed for their pharmacological activities that constitute a basis of modern drug development. The situation with herbal supplements is different because the extract or dried herb or mixture of herbs contains several substances beside the beneficial one(s) that might produce drug interaction with the conventional medicine(s). Most patients are misinformed and believe that anything "natural" must be safe. This article is focusing on plant-based substances referred as dietary supplements (DS). Examples of reported drug interactions and contraindications associated with DS with two case studies are presented. As supplements are typically not prescribed, many doctors seem to have no interest in drug-DS interactions since a typical medical history of the patients does not include any questions about self prescribed remedies of this nature. Rather, patients are left alone when they are tempted to try this or that DS and tend to rely on advice from friends, or on material they read on internet. A better quality control, compliance, public awareness and healthcare professionals vigilance for potential interactions are needed. It is of utmost importance to appreciate the impact of supplements on different stages of pharmacokinetics, especially on drug absorption and metabolism. PMID- 24797777 TI - [Circulating tumor cells and prostate cancer prognosis]. AB - Prostate cancer (PC) is the most common malignant disease in men. Prognosis of patients with metastatic PC is generally unfavourable; however there are significant differences in survival at this stage of the disease. The definition of prognosis is essential for the selection of therapy, respecting an individual risk. In recent years, the association between circulating tumor cells (CTC) detection and response to PC treatment has been widely investigated. Detection of CTC is based on a metastatic process theory and uses well-known tumor-specific antigens on the cell surface. Individual methods assess CTC with different sensitivity and are not yet efficient at the localised PC stage. Only the method of immunomagnetic separation and semi-automatic visualisation (CellSearchTM) has been validated and approved for the use in the PC management. Assessment of the CTC count directly correlates with the prognosis of patients with castration resistant PC. Change in the CTC count during the therapy also considerably improves risk estimation and represents a marker of overall survival. New methods of CTC cultivation and gene profiling may contribute to individualisation of the treatment similarly to breast cancer. The authors present a review article about theory, methods of detection and clinical use of CTC in castration-resistant PC. PMID- 24797778 TI - [Platelets in the pathogenesis of solid tumors]. AB - Cancer cells trigger platelet aggregation. Reciprocally, platelet aggregation promotes tumor growth and metastasis. Within the tumor microenvironment, platelet regulates tumor growth via several mechanisms involving stimulation of angiogenesis, inflammation, coagulation, and stabilizing of vessel wall. In circulation, cancer cells coated by platelets can travel to metastatic site protected from intravascular shear forces and from immune surveillance. Finally, platelets facilitate adhesion of tumor cells and formation of the metastatic niche. Platelet-derived microparticles contain growth factors contributing to tumor angiogenesis. On the other hand, platelets can selectively release anti angiogenic factors in a process connected to tumor dormancy. Therapeutical inhibition of platelet aggregation prevents tumor development in certain tumor types and may contribute to better cancer outcome. PMID- 24797779 TI - Some immunological properties of female saliva and its effect on sperm motility. AB - BACKGROUND: In this study, we investigated pH, levels of IgA, IgG, IgM, lysozyme and spermagglutinating antibodies in human saliva of healthy women, with or without hormonal contraception (HC) and their effect on sperm motility. METHODS AND RESULTS: Saliva was collected immediately after waking up from 59 healthy randomly selected women. We measured pH in sera and in saliva as well as immunoglobulin G, A and M levels in saliva by radial immunodiffusion. Sperm - saliva capillary penetration test in native saliva served for examination of sperm motility, indirect-MAR test for detection of sperm antibodies in sera, and in saliva, both observed by inverted microscope. The average pH values in native saliva according to the menstrual cycles were: from 2-5 days 6.896, from 6-17 days 7.027, and from 18 and more days 7.17. Rapid decrease of sperm motility was registered in acidic saliva in comparison with alkaline. The average concentration of IgA, IgG, IgM and lysozyme slightly differed in women with or without hormonal contraception. Moderate decreasing of sperm motility was found in saliva with higher levels of IgA. No sperm agglutinating antibodies in saliva and in serum were detected in all subjects. CONCLUSIONS: The pH of saliva is influenced by several causes (hormonal, immunological, microbiological factors, by meal and drinks, smoking, etc.). We demonstrated that sperm motility is lower in acidic saliva. pH is markedly changed during various days of menstrual cycles. We proved individual high levels of saliva IgA. Human saliva used as coital lubricant decreases sperm motility, but does not replace a local form of contraception. PMID- 24797780 TI - [Relation of risk factors between metabolic syndrome and nonalcoholic fatty liver disease in children and adolescents]. AB - AIM: In recent years, nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children have increased in line with the increased prevalence of obesity. The aim of this retrospective study was to evaluate a relation between NAFDL and MS in children. METHODS: NAFLD was defined as an elevation of serum transaminase level and hyperechogenic feature of liver on ultrasonography. MS definition was based on the diagnostic criteria of the International Diabetes Federation. The biopsies were done in patients with elevated transaminase levels lasting more than one year. Liver biopsy features were graded according to the NAFLD activity scoring (NAS) and Paediatric NAFLD Histological Score (PNHS). RESULTS: NAFLD was diagnosed in 39 patients and MS was confirmed in 20 patients. The significant differences between patients with MS and without MS were found in the insulin resistance (IR) (P < 0,001), cholesterol levels (P < 0,04) and GGT levels (P < 0,05). Biopsies were done in 20 patients. MS was present in 10 children. No difference was found in the degree of steatosis and NAS in groups with and without MS. No differences were observed in the occurrence of MS diagnostic criteria between patients with and without nonalcoholic steatohepatitis which were evaluated by PNHS. CONCLUSION: Prediction factors for NAFLD are obesity, IR, dyslipidemia. NAFLD is frequently associated with MS. Liver biopsy is necessary for determination of NAFLD histological activity because no non-invasive examination defines the degree of liver pathology. PMID- 24797781 TI - Substrate activity screening with kinases: discovery of small-molecule substrate competitive c-Src inhibitors. AB - Substrate-competitive kinase inhibitors represent a promising class of kinase inhibitors, however, there is no methodology to selectively identify this type of inhibitor. Substrate activity screening was applied to tyrosine kinases. By using this methodology, the first small-molecule substrates for any protein kinase were discovered, as well as the first substrate-competitive inhibitors of c-Src with activity in both biochemical and cellular assays. Characterization of the lead inhibitor demonstrates that substrate-competitive kinase inhibitors possess unique properties, including cellular efficacy that matches biochemical potency and synergy with ATP-competitive inhibitors. PMID- 24797782 TI - Effects of N-adamantyl-4-methylthiazol-2-amine on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats. AB - Thiazole derivatives are attractive candidates for drug development because they can be efficiently synthesized and are active against a number of diseases and conditions, including diabetes. In our present study, we investigated the anti inflammatory and antioxidant properties of N-adamantyl-4-methylthiazol-2-amine (KHG26693), a new thiazole derivative, in a streptozotocin (STZ)-induced model of diabetes mellitus. STZ-induced diabetic rats were intraperitoneally administered KHG26693 (3mg/kg-body weight/day) for 4 weeks. KHG26693 administration significantly decreased blood glucose, triglycerides, and cholesterol and increased insulin. KHG26693 also suppressed several inflammatory responses in STZ induced diabetic rats, as evidenced by decreased levels of serum tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide. Additionally, KHG26693 significantly modulated hepatic lipid peroxidation, catalase and superoxide dismutase activity, and the nonenzymatic antioxidant status (e.g., vitamins C and E), and reduced the glutathione content. These anti-inflammatory/antioxidative actions occurred as a result of the downregulation of inducible nitric oxide synthase and nuclear factor-kappa B. Taken together, our results suggest that KHG26693 successfully reduces the production of oxidative stress in STZ-induced diabetic rats by regulating the oxidation-reduction system, specifically increasing antioxidant capacity. Furthermore, KHG26693 treatment significantly reverted the key enzymes of glucose metabolism, such as glucokinase, glucose-6 phosphatase, glycogen synthase, glycogen phosphorylase, and fructose-1,6 bisphosphatase, to near-normal levels in liver tissues. These results indicate that KHG26693 normalizes disturbed glucose metabolism by enhancing glucose utilization and decreasing liver glucose production via insulin release, suggesting the possibility of future diabetes treatments. PMID- 24797783 TI - ERK1/2 phosphorylation is involved in the antidepressant-like action of 2,5 diphenyl-3-(4-fluorophenylseleno)-selenophene in mice. AB - We investigated the antidepressant-like action of 5 compounds belonging to the selenophene class. The involvement of ERK and CREB activation in this action was also demonstrated. In the experiment 1, time-course and dose-response effect of H DPS, CH3-DPS, Cl-DPS, F-DPS and CF3-DPS were accompanied in the mouse forced swimming test (FST). Firstly, animals received compounds at a dose of 50mg/kg, by intragastric (i.g.) route, at different times (15-240 min) before test. Results showed that the peak of maximum anti-despair behavior induced by Cl-DPS, F-DPS and CF3-DPS was at 30 min; maximum effect of H-DPS and CH3-DPS was found at 60 min, which was maintained until 120 min. Regarding dose-response effect, all compounds reduced immobility time and increased latency for the first episode of immobility at a dose of 50mg/kg. In addition, F-DPS also showed antidepressant like action at a dose of 25mg/kg, whilst H-DPS, CH3-DPS, Cl-DPS and CF3-DPS were not effective at lower doses. Thus, F-DPS was chosen for further investigation of its mechanism of action. Experiment 2 showed that treatment of animals with F-DPS (50 mg/kg, i.g.) significantly increased phosphorylated ERK1/2 levels in the prefrontal cortex and hippocampus; however, pCREB levels were not affected. Additionally, in the experiment 3 anti-immobility effect of F-DPS was completely blocked by pretreatment of animals with PD 98,059, an inhibitor of ERK phosphorylation, suggesting that ERK signalling activation is involved in its antidepressant-like action in mice. Together our data appoint F-DPS as a promising molecule for the development of a new antidepressant therapy. PMID- 24797784 TI - Anti-cancer drug KP1019 induces Hog1 phosphorylation and protein ubiquitylation in Saccharomyces cerevisiae. AB - Ruthenium-based anti-cancer drugs have attracted increasing interest in the last 20 years. KP1019 is one of the ruthenium-containing compounds that has demonstrated anti-tumor activity against various cancers, and has been tested in several clinical trials. Despite its success, the mode of action of KP1019 is not well described. In the present study, we have used budding yeast Saccharomyces cerevisiae to elucidate the action of KP1019. We have found that KP1019 causes dose-dependent cell arrest in the S-phase of cell cycle. Furthermore, we have demonstrated for the first time that the yeast mitogen-activated protein (MAP) kinase Hog1 is essential for the cells in response to KP1019. Hog1 is rapidly phosphorylated upon treatment with KP1019, and the deletion of the HOG1 gene potentiates the growth inhibition effect of KP1019. Moreover, we also observed the up-regulation of glycerol-3-phosphate dehydrogenase 1 (GPD1) mRNA in response to KP1019 treatment, a factor that is essential for the hyperosmotic stress response. Our results also reveal that membrane-bound sensor proteins of high osmolarity glycerol (HOG) pathway are crucial for Hog1 phosphorylation in response to KP1019-induced stress. Furthermore, KP1019 has also been found to increase the accumulation of ubiquitinated proteins and deletion of several members of ubiquitination pathways conferred sensitivity for KP1019. The findings presented here strongly suggest the ability of KP1019 to activate Hog1 MAP kinase and induce protein ubiquitination, which may underlie the therapeutic potential of this compound. In summary, we have disclosed a novel mechanism of KP1019 activity. PMID- 24797785 TI - Idazoxan reduces blood-brain barrier damage during experimental autoimmune encephalomyelitis in mouse. AB - We have previously shown that Idazoxan (IDA), an imidazoline 2 receptor ligand, is neuroprotective against spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE) in mouse, an animal modal of multiple sclerosis (MS). However, the protective mechanism remains unclear. Here, we provided evidence to show that IDA confers neuroprotection through reduction in blood-brain barrier (BBB) damage. EAE was induced by immunizing C57 BL/6 mice with myelin oligodendrocyte glycoprotein35-55 amino acid peptide (MOG35-55). IDA was administrated for 14 days after MOG immunization at 2 mg/kg (i.p., bid). Significant reduction in BBB damage occurred in the IDA-treated group of mice compared with the saline-treated group, as evidenced by the reduction in Evan's blue content in the brain tissue and the reduced BBB tight junction damage viewed under a transmission electron microscope. Moreover, EAE-induced reductions in tight junction proteins (JAM-1, Occludin, Claudin-5 and ZO-1) were also significantly ameliorated in IDA-treated mice, all of which supported the notion that IDA reduced BBB damage. Interestingly, the expression levels of extracellular matrix metalloproteinase-9 (MMP-9) and the ratio of MMP-9 against tissue inhibitor of metalloproteinase-1 (TIMP-1), which is known to be associated with MS-induced BBB damage, were significantly reduced in IDA-treated group, lending further support to the hypothesis that IDA confers brain protection through reducing BBB damage. This study raised a possibility that IDA is a promising pro-drug for development against MS. PMID- 24797786 TI - Cigarette smoke alters non-neuronal cholinergic system components inducing MUC5AC production in the H292 cell line. AB - Cigarette smoke extract (CSE) affects the expression of Choline Acetyl Transferase (ChAT), muscarinic acetylcholine receptors, and mucin production in bronchial epithelial cells. Mucin 5AC (MUC5AC), muscarinic acetylcholine receptor M3, ChAT expression, acetylcholine levels and acetylcholine binding were measured in a human pulmonary mucoepidermoid carcinoma cell line (H292) stimulated with CSE. We performed ChAT/RNA interference experiments in H292 cells stimulated with CSE to study the role of ChAT/acetylcholine in MUC5AC production. The effects of Hemicholinium-3 (HCh-3) (50 MUM) (a potent and selective choline uptake blocker) and Tiotropium bromide (Spiriva((r))) (100 nM), alone or in combination with Salmeterol (SL) and Fluticasone propionate (FP), were tested in this model. MUC5AC, muscarinic acetylcholine receptor M3, ChAT, acetylcholine expression and acetylcholine binding significantly increased in H292 cells stimulated with CSE (5%) compared to untreated cells. HCh-3 reduced acetylcholine binding and MUC5AC production in H292 cells stimulated with CSE. ChAT/RNA interference eliminated the effect of CSE on MUC5AC production. FP reduced ChAT and acetylcholine binding in unstimulated cells, while showing a partial effect in CSE stimulated cells. SL increased the ChAT expression and acetylcholine binding in H292 cells stimulated with or without CSE. Tiotropium, alone or together with FP and SL, reduced acetylcholine binding and MUC5AC production in H292 cells stimulated with CSE. CSE affects the ChAT/acetylcholine expression, increasing MUC5AC production in H292 cells. Pharmacological treatment with anticholinergic drugs reduces the secretion of MUC5AC generated by autocrine acetylcholine activity in airway epithelial cells. PMID- 24797788 TI - Understanding health care delivery as a complex system: achieving best possible health outcomes for individuals and communities by focusing on interdependencies. AB - RATIONALE, AIMS AND OBJECTIVES: The concept of emergence offers a new way of thinking about multimorbidity and chronic disease. RESULTS AND CONCLUSIONS: Multimorbidity and chronic disease are the end results of ongoing perturbations and interconnected activities of simpler substructures that collectively constitute the complex adaptive superstructure known as us, the person or patient. Medical interventions cause perturbations of many different subsystems within the patient, hence they are not limited to the person's bodily function, but also affect his general health perception and his interactions with his external environments. Changes in these domains inevitably have consequences on body function, and close the feedback loop of illness/disease, recovery and regained health. PMID- 24797789 TI - Structured layer of rhenium dye on SiO2 and TiO2 surfaces by Langmuir-Blodgett technique. AB - We demonstrate the Langmuir-Blodgett assembly of two rhenium-bipyridine complexes containing a flexible or an aromatic bridge, and transfer of the monolayer to SiO2 and single crystal TiO2 substrates. Both of the complexes (ReEC and Re2TC) have a hydrophilic carboxylic acid group, which preferentially anchors into the water subphase, and forms stable monolayers at surface pressures up to 40 mN/m. The optimum conditions for the formation of complete monolayers of both ReEC and Re2TC were identified through characterization of the morphology by atomic force microscopy (AFM), the thickness by ellipsometry, and the surface coverage by X ray photoelectron spectroscopy (XPS). X-ray reflectivity measurements (XRR) are consistent with the orientation of the molecules normal to the substrate, and their extension to close to their calculated maximum length. Parameters derived from XRR analysis show that there is a higher packing density for Re2TC monolayers than for ReEC monolayers, attributable to the more rigid bridge in the Re2TC molecule. PMID- 24797787 TI - Development of hepatitis C virus genotype 3a cell culture system. AB - Hepatitis C virus (HCV) genotype 3a infection poses a serious health problem worldwide. A significant association has been reported between HCV genotype 3a infections and hepatic steatosis. Nevertheless, virological characterization of genotype 3a HCV is delayed due to the lack of appropriate virus cell culture systems. In the present study, we established the first infectious genotype 3a HCV system by introducing adaptive mutations into the S310 strain. HCV core proteins had different locations in JFH-1 and S310 virus-infected cells. Furthermore, the lipid content in S310 virus-infected cells was higher than Huh7.5.1 cells and JFH-1 virus-infected cells as determined by the lipid droplet staining area. CONCLUSION: This genotype 3a infectious cell culture system may be a useful experimental model for studying genotype 3a viral life cycles, molecular mechanisms of pathogenesis, and genotype 3a-specific antiviral drug development. PMID- 24797790 TI - [Cost per responder associated with romiplostim and rituximab treatment for adult primary immune thrombocytopenia in France]. AB - PURPOSE OF THE STUDY: This analysis compared the response rates and cost per responder associated with romiplostim and rituximab in adult immune thrombocytopenia from the French National Health System payer perspective. METHODS: A decision analytic model was developed to estimate the cost per patient and per responder of treating adult immune thrombocytopenia patients with romiplostim versus rituximab over 6 months. A systematic literature review identified phase 3 randomized controlled trials. Published response rates were extracted (response definition: >=50*10(9) platelets/liter). Resource utilization was based on French and international treatment guidelines, and clinical expert opinion. Unit costs were derived from literature and French reimbursement lists, and included the costs of routine physician visits, treatment administration, and emergency care. Non-responders incurred bleeding-related event costs. RESULTS: The literature review identified a phase 3 randomized controlled trial for romiplostim with a response rate of 83%. Due to a lack of phase 3 randomized controlled trials for rituximab, a systematic review of studies was selected as the best source, reporting a response rate of 62.5%. Romiplostim and rituximab were associated with similar treatment costs, with an estimated cost per patient for romiplostim of ?17,456 and ?17,068 for rituximab. Rituximab resulted in a 30% higher cost per responder (?27,308 for rituximab versus ?21,031 for romiplostim). Romiplostim use reduced drug administration, intravenous immunoglobulin, and bleeding-related hospitalization costs compared to rituximab. CONCLUSIONS: Due to its high efficacy leading to lower bleeding-related costs, romiplostim represents an efficient use of resources for adult immune thrombocytopenia patients in the French healthcare system. PMID- 24797791 TI - The risk for hepatitis C infection in blood donors in Cluj County, Romania. AB - Blood products safety is based on different criteria including the selection of blood donors. Blood donors referred to Cluj County (Romania) Blood Transfusion Centre in January-March 2012 completed a self-administered questionnaire and were examined by a physician. Data collected from first-time and repeat donors were compared for possible risk factors for hepatitis C infection. In total, 1100 donors were selected. In first-time donors, most frequent factors were age<26 years, female gender and history of health care procedures. Behavioural risk factors (e.g. drug use, sexual promiscuity) may not be properly filtered out in blood donors, suggesting the necessity of improving the health screening process. PMID- 24797792 TI - Using landscape and bioclimatic features to predict the distribution of lions, leopards and spotted hyaenas in Tanzania's Ruaha landscape. AB - Tanzania's Ruaha landscape is an international priority area for large carnivores, supporting over 10% of the world's lions and important populations of leopards and spotted hyaenas. However, lack of ecological data on large carnivore distribution and habitat use hinders the development of effective carnivore conservation strategies in this critical landscape. Therefore, the study aimed to (i) identify the most significant ecogeographical variables influencing the potential distribution of lions, leopards and spotted hyaenas across the Ruaha landscape; (ii) identify zones with highest suitability for harbouring those species; and (iii) use species distribution modelling algorithms (SDMs) to define important areas for conservation of large carnivores. Habitat suitability was calculated based on environmental features from georeferenced presence-only carnivore location data. Potential distribution of large carnivores appeared to be strongly influenced by water availability; highly suitable areas were situated close to rivers and experienced above average annual precipitation. Net primary productivity and tree cover also exerted some influence on habitat suitability. All three species showed relatively narrow niche breadth and low tolerance to changes in habitat characteristics. From 21,050 km2 assessed, 8.1% (1,702 km2) emerged as highly suitable for all three large carnivores collectively. Of that area, 95.4% (1,624 km2) was located within 30 km of the Park-village border, raising concerns about human-carnivore conflict. This was of particular concern for spotted hyaenas, as they were located significantly closer to the Park boundary than lions and leopards. This study provides the first map of potential carnivore distribution across the globally important Ruaha landscape, and demonstrates that SDMs can be effective for understanding large carnivore habitat requirements in poorly sampled areas. This approach could have relevance for many other important wildlife areas that only have limited, haphazard presence-only data, but which urgently require strategic conservation planning. PMID- 24797793 TI - Contribution of phenolics and essential oils to the antioxidant and antimicrobial properties of Disporopsis pernyi (Hua) Diels. AB - This study describes the characterization of essential oil and phenolic compounds in Disporopsis pernyi (Hua) Diels. The essential oil was analyzed by gas chromatography-mass spectroscopy (GC-MS) and twelve volatile bioactive compounds of D. pernyi were identified. Polyphenols were identified by reverse-phase high performance liquid chromatography (RP-HPLC) coupled to electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) and quantified by ultrahigh performance liquid chromatography (UPLC). A total of 4 polyphenolic compounds found in extract were identified as rutin, luteolin, quercetin, and betulinic acid. All obtained extracts and the 4 polyphenolic compounds were evaluated for their antimicrobial and antioxidant properties. The results suggested that the phenolic compounds contributed significantly to the antioxidant and antimicrobial activities of the plant. PMID- 24797794 TI - The evolution of the regulatory framework for antibacterial agents. AB - The rising tide of antibacterial resistance and the lack of a diverse, vibrant pipeline of novel antibacterial agents is a global crisis that impairs our ability to treat life-threatening infections. The recent introduction of a tiered approach to the regulatory framework in this area offers one path to resolving some of the challenges. By drawing heavily on the predictive power of the related sciences of pharmacokinetics and pharmacodynamics, smaller, focused clinical trial programs have become possible for agents that might not otherwise have been possible to progress. There are limitations to these pathways, and they are not easy to implement, but making reliable noninferiority-based approaches available is critical to reinvigorating the global antibiotic pipeline. With the recognition of these ideas by key regulatory authorities in recent guidance, the next challenges in this area will focus on interpretive breakpoints, the extent of data in the prescribing information, ensuring that multiple agents can be progressed, and the challenge of the antibiotic business model. PMID- 24797795 TI - Anticancer effects of anandamide on head and neck squamous cell carcinoma cells via the production of receptor-independent reactive oxygen species. AB - BACKGROUND: The endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2 AG), are considered promising potential anticancer agents. In this study, we examined the anticancer effects of AEA and 2-AG in head and neck squamous cell carcinoma (HNSCC) cell lines. METHODS AND RESULTS: Our results showed that AEA effectively inhibited proliferation of HNSCC cells whereas 2-AG did not. The anticancer effect of AEA seemed to be mediated by a receptor-independent mechanism. Inhibitors of AEA intracellular transportation and transfection of HNSCC cells with fatty acid amide hydrolase, a key enzyme in AEA metabolism, reversed AEA-dependent inhibition of cell proliferation. We found that cyclooxygenase-2 (COX-2) did not mediate the anticancer effects of AEA; instead we observed an increase in reactive oxygen species (ROS) production after AEA treatment. Moreover, antioxidants partially reversed AEA-dependent inhibition of cell proliferation. CONCLUSION: These findings suggest that AEA might have anticancer effects on HNSCC cells by mediating an increase in ROS levels through a receptor-independent mechanism. PMID- 24797796 TI - Hypothermic or normothermic abdominal regional perfusion in high-risk donors with extended warm ischemia times: impact on outcomes? AB - Donation after circulatory determination of death (DCD) has the potential to increase the applicability of transplantation as a treatment for end-stage organ disease; its use is limited, however, by the warm ischemic damage suffered by potential grafts. Abdominal regional perfusion (ARP) has been employed in this setting to not only curtail the deleterious effects of cardiac arrest by re establishing oxygenated flow but also test and even improve the viability of the kidneys and liver prior to transplantation. In the present review article, we discuss experimental and clinical studies that have been published to date on the use of ARP in DCD, differentiating between its application under hypothermic and normothermic conditions. In addition to describing results that have been achieved thus far, we describe the major obstacles limiting the broader implementation of ARP in this context as well as potential means for improving the effectiveness of this modality in the future. PMID- 24797798 TI - Aliphatic phenolic ethers from Trichobotrys effusa. AB - Four novel aliphatic phenolic ethers, namely, trichoethers A-D (1-4), possessing a unique C11-O-C10 skeleton, together with coriloxin, zythiostromic acid A, radicicol, and 3,5-dihydroxytoluene were isolated from the ethyl acetate extracts of the fermented broths of Trichobotrys effusa YMJ1179. The structures of all the compounds were determined based on spectroscopic data analysis. The configurations of 1-4 were established by J values and NOESY and compared with published data. Compounds 1-4 and radicicol exhibited growth-inhibitory activities against the A549 non-small-cell lung cancer cell line with GI50 values of 25.61, 19.32, 16.19, 24.31, and 1.43 MUM, respectively, in comparison with 5 fluorouracil (GI50 = 4.55 MUM). PMID- 24797797 TI - Effects of intermittent training on anaerobic performance and MCT transporters in athletes. AB - This study examined the effects of intermittent hypoxic training (IHT) on skeletal muscle monocarboxylate lactate transporter (MCT) expression and anaerobic performance in trained athletes. Cyclists were assigned to two interventions, either normoxic (N; n = 8; 150 mmHg PIO2) or hypoxic (H; n = 10; ~3000 m, 100 mmHg PIO2) over a three week training (5*1 h-1h30 x week(-1)) period. Prior to and after training, an incremental exercise test to exhaustion (EXT) was performed in normoxia together with a 2 min time trial (TT). Biopsy samples from the vastus lateralis were analyzed for MCT1 and MCT4 using immuno blotting techniques. The peak power output (PPO) increased (p<0.05) after training (7.2% and 6.6% for N and H, respectively), but VO2max showed no significant change. The average power output in the TT improved significantly (7.3% and 6.4% for N and H, respectively). No differences were found in MCT1 and MCT4 protein content, before and after the training in either the N or H group. These results indicate there are no additional benefits of IHT when compared to similar normoxic training. Hence, the addition of the hypoxic stimulus on anaerobic performance or MCT expression after a three-week training period is ineffective. PMID- 24797800 TI - Discrepant amplification results during the development of an assay leads to reclassification of two AIDS reagent repository HIV-2 isolates as HIV-1. AB - The development and verification of HIV-2 assays depends in part on the availability of well-characterized samples, including those from reagent repositories. During the development of an HIV-2 RNA quantification assay, two HIV-2 viral isolates (CDC 301340 and CDC 301342) obtained from the NIAID AIDS Reagent and Reference Repository were not detected leading to an investigation. Two HIV-2 primers/probe sets of known performance in real-time viral RNA quantification assays, targeting different regions of the virus, also failed to generate RT-PCR products for these two isolates. These isolates were tested in the HIV-1 specific COBAS AmpliPrep/COBAS TaqMan HIV-1 Test v2.0 (Roche Molecular Diagnostics) and were quantified at high copy number. Other HIV-2 isolates tested were not amplified in the COBAS HIV-1 TaqMan assay. Furthermore, the discrepant isolates were highly reactive in an HIV-1 p24 antigen test while the other HIV-2 isolates showed very weak, if any, cross-reactivity with the HIV-1 p24 assay. Phylogenetic tree analysis of sequences from the protease-reverse transcriptase regions of the discrepant HIV-2 isolates mapped with HIV-1 Group M, Subtype CRF02_AG confirming these isolates were of HIV-1 origin and had been misclassified as HIV-2. The use of misclassified isolates in the verification of molecular and immunological assays can lead to misinterpretation of test results, misdirection of efforts into assay redesign and increased development costs. The results of this study were shared with the NIAID AIDS Reagent Program, leading to the reclassification of the two discrepant isolates as HIV-1. PMID- 24797801 TI - Cancer detection rates of different prostate biopsy regimens in patients with renal failure. AB - We aimed to evaluate the cancer detection rates of 6-, 10-, 12-core biopsy regimens and the optimal biopsy protocol for prostate cancer diagnosis in patients with renal failure. A total of 122 consecutive patients with renal failure underwent biopsy with age-specific prostate-specific antigen (PSA) levels up to 20 ng/mL. The 12-core biopsy technique (sextant biopsy + lateral base, lateral mid-zone, lateral apex, bilaterally) performed to all patients. Pathology results were examined separately for each sextant, 10-core that exclude parasagittal mid-zones from 12-cores (10a), 10-core that exclude apex zones from 12-cores (10b) and 12-core biopsy regimens. Of 122 patients, 37 (30.3%) were positive for prostate cancer. The cancer detection rates for sextant, 10a, 10b and 12 cores were 17.2%, 29%, 23.7% and 30.7%, respectively. Biopsy techniques of 10a, 10b and 12 cores increased the cancer detection rates by 40%, 27.5% and 43.2% among the sextant technique, respectively. Biopsy techniques of 10a and 12 cores increased the cancer detection rates by 17.1% and 21.6% among 10b biopsy technique, respectively. There were no statistical differences between 12 core and 10a core about cancer detection rate. Adding lateral cores to sextant biopsy improves the cancer detection rates. In our study, 12-core biopsy technique increases the cancer detection rate by 5.4% among 10a core but that was not statistically different. On the other hand, 12-core biopsy technique includes all biopsy regimens. We therefore suggest 12-core biopsy or minimum 10-core strategy incorporating six peripheral biopsies with elevated age- specific PSA levels up to 20 ng/mL in patients with renal failure. PMID- 24797802 TI - Rapid onset of peripheral artery disease in a chronic myeloid leukemia patient without prior arterial disorder: direct relationship with nilotinib exposure and clinical outcome. AB - The second-generation tyrosine kinase inhibitor (TKI) of the BCR-ABL1 oncoprotein nilotinib used in patients with chronic myeloid leukemia is suspected to increase the risk of arterial occlusion, especially in patients with pre-existing cardiovascular risk factors or established cardiovascular diseases. Here, we describe a case of unexpected and rapid onset of symptomatic peripheral artery disease (PAD) associated with silent stenosis of digestive and renal arteries in a nilotinib-treated patient devoid of significant cardiovascular diseases (CVD) risk factor, prior atherosclerotic disease, or other cause of arterial damage. This is the first report to establish a direct relationship between nilotinib exposure and PAD and to reveal that arterial damage is irreversible despite rapid drug withdrawal. However, functional outcome was favorable upon rapid TKI replacement, specific cardiovascular disease management, and development of collateral arterial network. PMID- 24797803 TI - Fabrication of bioinspired composite nanofiber membranes with robust superhydrophobicity for direct contact membrane distillation. AB - The practical application of membrane distillation (MD) for water purification is hindered by the absence of desirable membranes that can fulfill the special requirements of the MD process. Compared to the membranes fabricated by other methods, nanofiber membranes produced by electrospinning are of great interest due to their high porosity, low tortuosity, large surface pore size, and high surface hydrophobicity. However, the stable performance of the nanofiber membranes in the MD process is still unsatisfactory. Inspired by the unique structure of the lotus leaf, this study aimed to develop a strategy to construct superhydrophobic composite nanofiber membranes with robust superhydrophobicity and high porosity suitable for use in MD. The newly developed membrane consists of a superhydrophobic silica-PVDF composite selective skin formed on a polyvinylidene fluoride (PVDF) porous nanofiber scaffold via electrospinning. This fabrication method could be easily scaled up due to its simple preparation procedures. The effects of silica diameter and concentration on membrane contact angle, sliding angle, and MD performance were investigated thoroughly. For the first time, the direct contact membrane distillation (DCMD) tests demonstrate that the newly developed membranes are able to present stable high performance over 50 h of testing time, and the superhydrophobic selective layer exhibits excellent durability in ultrasonic treatment and a continuous DCMD test. It is believed that this novel design strategy has great potential for MD membrane fabrication. PMID- 24797805 TI - The saddle and the horse's tail: cauda equina syndrome. PMID- 24797804 TI - Bead arrays for antibody and complement profiling reveal joint contribution of antibody isotypes to C3 deposition. AB - The development of antigen arrays has provided researchers with great tools to identify reactivities against self or foreign antigens from body fluids. Yet, these approaches mostly do not address antibody isotypes and their effector functions even though these are key points for a more detailed understanding of disease processes. Here, we present a bead array-based assay for a multiplexed determination of antigen-specific antibody levels in parallel with their properties for complement activation. We measured the deposition of C3 fragments from serum samples to reflect the degree of complement activation via all three complement activation pathways. We utilized the assay on a bead array containing native and citrullinated peptide antigens to investigate the levels of IgG, IgM and IgA autoantibodies along with their complement activating properties in serum samples of 41 rheumatoid arthritis patients and 40 controls. Our analysis revealed significantly higher IgG reactivity against the citrullinated fibrinogen beta and filaggrin peptides as well as an IgA reactivity that was exclusive for citrullinated fibrinogen beta peptide and C3 deposition in rheumatoid arthritis patients. In addition, we characterized the humoral immune response against the viral EBNA-1 antigen to demonstrate the applicability of this assay beyond autoimmune conditions. We observed that particular buffer compositions were demanded for separate measurement of antibody reactivity and complement activation, as detection of antigen-antibody complexes appeared to be masked due to C3 deposition. We also found that rheumatoid factors of IgM isotype altered C3 deposition and introduced false-positive reactivities against EBNA-1 antigen. In conclusion, the presented bead-based assay setup can be utilized to profile antibody reactivities and immune-complex induced complement activation in a high throughput manner and could facilitate the understanding and diagnosis of several diseases where complement activation plays role in the pathomechanism. PMID- 24797806 TI - High-level exogenous trans10, cis12 conjugated linoleic acid plays an anti lipogenesis role in bovine mammary epithelial cells. AB - Primary bovine mammary epithelial cells (BMECs) were treated by 0, 37.5, 75, 112.5, 150 MUmol/L trans10, cis12 conjugated linoleic acid (CLA) to evaluate the effects of different level trans10, cis12 CLA on lipogenesis in BMEC. Addition of 75-150 MUmol/L trans10, cis12 CLA reduced significantly the triacylglycerol (TAG) content (P<0.05), but did not have inhibiting action on cell proliferation (P>0.05). Treatment with 150 MUmol/L trans10, cis12 CLA for 48 h resulted in a 17.1% reduction (P<0.0001) of medium chain fatty acids (MCFA, C14=30.0 MUg/L for girls, >=50.0 MUg/L for boys), and the association between serum ferritin and blood cadmium concentrations was assessed after adjustment for various demographic and lifestyle factors. The geometric mean (GM) of blood cadmium was significantly higher among both boys and girls in the low than in the normal ferritin group. After controlling for covariates, multiple regression analysis showed that blood cadmium concentration was inversely correlated with serum ferritin concentration in both boys and girls. In conclusion, iron deficiency is associated with increased blood cadmium concentrations in a representative sample of Korean adolescents, as evaluated in KNHANES. PMID- 24797809 TI - A versatile and efficient markerless gene disruption system for Acidithiobacillus thiooxidans: application for characterizing a copper tolerance related multicopper oxidase gene. AB - The acidophilic bioleaching bacteria can usually survive in high concentrations of copper ions because of their special living environment. However, little is known about the copper homeostatic mechanisms of Acidithiobacillus thiooxidans, an important member of bioleaching bacteria. Here, a putative multicopper oxidase gene (cueO) was detected from the draft genome of A. thiooxidans ATCC 19377. The transcriptional level of cueO in response to 10 mM CuSO4was upregulated 25.01 +/- 2.59 folds. The response of P(cueO) to copper was also detected and might be stimulated by a putative CueR protein. Then, by using the counter-selectable marker lacZ and enhancing the expression of endonuclease I-SceI with tac promoter, a modified markerless gene disruption system was developed and the cueO gene disruption mutant (DeltacueO) of A. thiooxidans was successfully constructed with a markedly improved second homologous recombination frequency of 0.28 +/- 0.048. The DeltacueO mutant was more sensitive to external copper and nearly completely lost the phenoloxidase activity; however, the activity could be restored after complementing the cueO gene. All results suggest the close relation of cueO gene to copper tolerance in A. thiooxidans. In addition, the developed efficient markerless gene knockout method can also be introduced into other Acidithiobacillus strains. PMID- 24797810 TI - Comparison of stability and kinematics of the natural knee versus a PS TKA with a 'third condyle'. AB - PURPOSE: The goal of this study was to compare the kinematics of knees before and after total knee arthroplasty (TKA) that relies on an inter-condylar 'third condyle'. The hypothesis was that the 'third condyle' provides sufficient flexion stability and induces a close to normal femoral rollback, thus granting natural joint kinematics. METHODS: Intra-operative navigation data were collected from 29 consecutive cases that received a cemented TKA (HLS Noetos, Tornier SA, France) designed with an inter-condylar 'third condyle' that engages within the tibial insert beyond 35 degrees flexion. Operations were guided by a non-image-based system (BLU-IGS, Orthokey Italia srl, Italy) that recorded relative femoral and tibial positions in native and implanted knees during: passive range of motion, anterior drawer test at 90 degrees flexion, and varus-valgus stress tests at full extension and at 30 degrees flexion. RESULTS: The total internal tibial rotation during flexion was similar for native (8.2 +/- 4.2 degrees ) and implanted knees (8.0 +/- 5.4 degrees ). The lateral femoral condyle was more posterior in implanted knees (1.2 +/- 9.4 mm) than in native knees (9.5 +/- 3.6 mm) throughout early flexion (p < 0.01), but this difference diminished beyond 100 degrees flexion (n.s.). The implanted knees did not exhibit paradoxical external tibial rotation. Varus-valgus laxity in full extension was lower for implanted knees than for native knees (p = 0.0221), but at 30 degrees flexion was almost identical for both native and implanted knees. Anteroposterior laxity was similar in implanted and native knees. CONCLUSIONS: The 'third condyle' TKA provides similar anteroposterior and mediolateral stability to the natural knee. This feature granted an adequate balance between laxity and constraint to reproduce natural joint kinematics, including smooth femoral rollback, without causing paradoxical external tibial rotation. PMID- 24797811 TI - The lateral femoral notch sign following ACL injury: frequency, morphology and relation to meniscal injury and sports activity. AB - PURPOSE: The purpose of this study was to determine the incidence of the "lateral femoral notch sign" in acute anterior cruciate ligament (ACL) tears and its correlation with lateral meniscal tears. METHODS: Lateral plain radiographs and sagittal magnetic resonance images (each performed within 1 month following injury) of 500 patients with acute and arthroscopically confirmed ACL tears were retrospectively evaluated for depth, length and position of the "lateral femoral notch sign". The accompanying bone bruise was measured, as well. The correlation of the lateral femoral notch sign with high-risk and low-risk pivoting activities as well as with a lateral meniscus tear was evaluated. RESULTS: A total of 26.4 % of the patients had a lateral femoral notch sign deeper than 2.0 mm with a mean depth of 2.8 +/- 0.8 mm SD. All lateral femoral notches were situated near or slightly posterior to Blumensaat's line. ACL injuries sustained during high-risk pivoting sports were more prone to a lateral femoral notch sign than ACL injuries in low-risk pivoting sports (r = 0.107 vs r = -0.107). Of all patients with a lateral femoral notch sign, 40.2 % also had lateral meniscus tears. The correlation between the presence of the lateral femoral notch sign and lateral meniscus tears was statistically significant (p = 0.004). CONCLUSION: In more than one-quarter of patients, plain radiographs may help to establish the diagnosis of an ACL tear. Further, a lateral femoral notch sign greater than 2.0 mm also correlates with lateral meniscus tears. Hence, the lateral femoral notch sign is a useful diagnostic tool in daily clinical practice. LEVEL OF EVIDENCE: IV. PMID- 24797812 TI - Sclerosing injections and ultrasound-guided arthroscopic shaving for patellar tendinopathy: good clinical results and decreased tendon thickness after surgery a medium-term follow-up study. AB - PURPOSE: Treatment of patellar tendinopathy/jumper's knee with ultrasound-guided sclerosing injections or ultrasound-guided arthroscopic shaving has shown good clinical short-term results. Former studies indicate that the tendon thickness and structure stays unaffected after successful treatment. The aim of this study was to evaluate the sonographic findings and clinical outcome 3-5 years after treatment of patellar tendinopathy with ultrasound-guided sclerosing injections or arthroscopic shaving. METHODS: Fifty-seven patellar tendons (43 patients) with chronic patellar tendinopathy were evaluated, with ultrasound, colour Doppler (CD) and visual analogue scale (VAS) for pain and satisfaction with treatment, 3 5 years after treatment. Functional status was evaluated with a single question "Back in full loading activity?" yes or no. RESULTS: At endpoint (mean 46 months), there was a significant decrease in anteroposterior thickness of the proximal patellar tendon in patients treated with ultrasound-guided arthroscopic shaving but not after sclerosing injections. Tendon structure had improved, and CD local blood flow had diminished significantly in both groups. There were good clinical results with a significant decrease in VAS for pain after sclerosing injections (VAS 64 +/- 18 -> 17 +/- 23) with 74 % satisfied patients and also after arthroscopic shaving (VAS 77 +/- 16 -> 13 +/- 23) with 80 % satisfied patients. There were no significant differences in VAS between groups. A significant correlation between low local blood flow and high patient satisfaction was found. CONCLUSIONS: Tendon thickness decreased over time after ultrasound-guided arthroscopic shaving, and tendon structure and local blood flow decreased after both treatments. There were good, and similar, clinical results with both methods. LEVEL OF EVIDENCE: III. PMID- 24797813 TI - Simulating pancreatic neuroplasticity: in vitro dual-neuron plasticity assay. AB - Neuroplasticity is an inherent feature of the enteric nervous system and gastrointestinal (GI) innervation under pathological conditions. However, the pathophysiological role of neuroplasticity in GI disorders remains unknown. Novel experimental models which allow simulation and modulation of GI neuroplasticity may enable enhanced appreciation of the contribution of neuroplasticity in particular GI diseases such as pancreatic cancer (PCa) and chronic pancreatitis (CP). Here, we present a protocol for simulation of pancreatic neuroplasticity under in vitro conditions using newborn rat dorsal root ganglia (DRG) and myenteric plexus (MP) neurons. This dual-neuron approach not only permits monitoring of both organ-intrinsic and -extrinsic neuroplasticity, but also represents a valuable tool to assess neuronal and glial morphology and electrophysiology. Moreover, it allows functional modulation of supplied microenvironmental contents for studying their impact on neuroplasticity. Once established, the present neuroplasticity assay bears the potential of being applicable to the study of neuroplasticity in any GI organ. PMID- 24797814 TI - Redox-responsive drug delivery. AB - The objective of most modern drug delivery strategies is to maximize the effectiveness of drug molecules at diseased tissue and to minimize their effects in healthy ones. This is most often achieved using (bio-)synthetic carrier systems that release the drug at the target location. One emerging strategy to achieve this is to destabilize carriers and release therapeutics using natural redox gradients in the body or associated with disease. The body, however, is composed of numerous microenvironments whose redox homeostasis, as well as its dysregulation due to disease, is complex. The original article and authoritative reviews that constitute this Forum discuss some of the particular redox features associated with diseases and present an overview of how, chemically, redox responsive drug delivery carriers can be designed to respond to these opportunities. PMID- 24797815 TI - Fish with chips: tracking reef fish movements to evaluate size and connectivity of Caribbean marine protected areas. AB - Coral reefs and associated fish populations have experienced rapid decline in the Caribbean region and marine protected areas (MPAs) have been widely implemented to address this decline. The performance of no-take MPAs (i.e., marine reserves) for protecting and rebuilding fish populations is influenced by the movement of animals within and across their boundaries. Very little is known about Caribbean reef fish movements creating a critical knowledge gap that can impede effective MPA design, performance and evaluation. Using miniature implanted acoustic transmitters and a fixed acoustic receiver array, we address three key questions: How far can reef fish move? Does connectivity exist between adjacent MPAs? Does existing MPA size match the spatial scale of reef fish movements? We show that many reef fishes are capable of traveling far greater distances and in shorter duration than was previously known. Across the Puerto Rican Shelf, more than half of our 163 tagged fish (18 species of 10 families) moved distances greater than 1 km with three fish moving more than 10 km in a single day and a quarter spending time outside of MPAs. We provide direct evidence of ecological connectivity across a network of MPAs, including estimated movements of more than 40 km connecting a nearshore MPA with a shelf-edge spawning aggregation. Most tagged fish showed high fidelity to MPAs, but also spent time outside MPAs, potentially contributing to spillover. Three-quarters of our fish were capable of traveling distances that would take them beyond the protection offered by at least 40-64% of the existing eastern Caribbean MPAs. We recommend that key species movement patterns be used to inform and evaluate MPA functionality and design, particularly size and shape. A re-scaling of our perception of Caribbean reef fish mobility and habitat use is imperative, with important implications for ecology and management effectiveness. PMID- 24797817 TI - Carbon Capture Simulation Initiative: a case study in multiscale modeling and new challenges. AB - Advanced multiscale modeling and simulation have the potential to dramatically reduce the time and cost to develop new carbon capture technologies. The Carbon Capture Simulation Initiative is a partnership among national laboratories, industry, and universities that is developing, demonstrating, and deploying a suite of such tools, including basic data submodels, steady-state and dynamic process models, process optimization and uncertainty quantification tools, an advanced dynamic process control framework, high-resolution filtered computational-fluid-dynamics (CFD) submodels, validated high-fidelity device scale CFD models with quantified uncertainty, and a risk-analysis framework. These tools and models enable basic data submodels, including thermodynamics and kinetics, to be used within detailed process models to synthesize and optimize a process. The resulting process informs the development of process control systems and more detailed simulations of potential equipment to improve the design and reduce scale-up risk. Quantification and propagation of uncertainty across scales is an essential part of these tools and models. PMID- 24797816 TI - Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient. AB - BACKGROUND: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC), is metabolized by cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients. METHODS: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs) and adjacent normal hepatic microsomes (NHLMs) of HCC patients (n = 18). Commercial hepatic microsomes (CHLMs) were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting. RESULTS: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax) of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold) than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs. CONCLUSIONS: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9. PMID- 24797818 TI - Toward the directed self-assembly of engineered tissues. AB - Using scaffold-based approaches, tissue engineers have made bold steps toward creating replacement tissues in the laboratory. However, many of these engineered constructs do not fully match the functional properties of their native counterparts. This is partially due to our limited quantitative understanding of the growth and remodeling processes that alter the architecture of engineered tissues, both in culture and after implantation. Here, we consider the mechanisms by which physical cues direct this adaptive response. In particular, we highlight recent experimental and computational studies that characterize quantitatively the mechanics of growth and remodeling in tissue constructs. These advances, from fields as diverse as soft tissue biomechanics and developmental biology, can be used to design new tissue engineering approaches that direct the self-assembly of engineered tissues. PMID- 24797819 TI - The electrical conductivity of thin film donor doped hematite: from insulator to semiconductor by defect modulation. AB - Hematite or alpha-Fe2O3 has emerged as a highly promising photoanode candidate for photoelectrochemical cells. While significant improvements in its performance have recently been achieved, it remains unclear why the maximum photocurrents still remain well below their theoretical predictions. Here, we report, for the first time, a detailed correlation between the electrical conductivity of undoped and 1 atom% Ti doped hematite and the conditions under which it was annealed (20 <= T <= 800 degrees C and 10(-4) <= pO2 <= 1 atm). Hematite thin films grown by pulsed laser deposition onto sapphire single crystals were evaluated by impedance spectroscopy. Hematite's room temperature conductivity can be increased from ~10( 11) S cm(-1) for undoped films by as much as nine orders of magnitude by doping with the Ti donor. Furthermore, by controlling the non-stoichiometry of Ti-doped hematite, one can tune its conductivity by up to five orders of magnitude. Depending on processing conditions, donor dopants in hematite may be compensated largely by electrons or by ionic defects (Fe vacancies). A defect model was derived to explain this phenomenon. In addition, a temperature independent value for the electron mobility of 0.01 cm(2) V(-1) s(-1) for a donor density of 4.0 * 10(20) cm(-3) (1% Ti) was derived. These results highlight the importance of carefully controlling photoanode processing conditions, even when operating within the material's extrinsic dopant regime, and more generally, provide a model for the electronic properties of semiconducting metal oxide photoanodes. PMID- 24797820 TI - Stable cycling of a scalable graphene-encapsulated nanocomposite for lithium sulfur batteries. AB - We report the synthesis of a low-cost carbon/sulfur nanocomposite using Ketjen black (KBC) as the carbon framework, encapsulated by thin graphene sheets using a simple process that relies on binding a functionalized KBC/S nanoparticle surface with graphene oxide (GO), which is reduced in situ. A slight excess of GO is employed to create a second layer of graphene wrapping around the KBC/S. This g KBC/S sulfur cathode exhibits excellent cyclability over 200 cycles where the average stabilized fade rate is only 0.026% or 1.1 mAh g(-1) per cycle. This excellent performance is primarily attributed to the wrapped, internally porous architecture. The large pore volume, small pore diameter, and uniform nanoparticle size of the mesoporous KBC array provides an ideal frame for the fabrication of a homogeneous C/S composite, whereas the graphene/GO sheets serve as an external chemical and physical barrier that inhibits polysulfide diffusion. PMID- 24797821 TI - Molecular tumor board: the University of California-San Diego Moores Cancer Center experience. AB - OBJECTIVE: DNA sequencing tests are enabling physicians to interrogate the molecular profiles of patients' tumors, but most oncologists have not been trained in advanced genomics. We initiated a molecular tumor board to provide expert multidisciplinary input for these patients. MATERIALS AND METHODS: A team that included clinicians, basic scientists, geneticists, and bioinformatics/pathway scientists with expertise in various cancer types attended. Molecular tests were performed in a Clinical Laboratory Improvement Amendments environment. RESULTS: Patients (n = 34, since December 2012) had received a median of three prior therapies. The median time from physician order to receipt of molecular diagnostic test results was 27 days (range: 14-77 days). Patients had a median of 4 molecular abnormalities (range: 1-14 abnormalities) found by next-generation sequencing (182- or 236-gene panels). Seventy-four genes were involved, with 123 distinct abnormalities. Importantly, no two patients had the same aberrations, and 107 distinct abnormalities were seen only once. Among the 11 evaluable patients whose treatment had been informed by molecular diagnostics, 3 achieved partial responses (progression-free survival of 3.4 months, >=6.5 months, and 7.6 months). The most common reasons for being unable to act on the molecular diagnostic results were that patients were ineligible for or could not travel to an appropriately targeted clinical trial and/or that insurance would not cover the cognate agents. CONCLUSION: Genomic sequencing is revealing complex molecular profiles that differ by patient. Multidisciplinary molecular tumor boards may help optimize management. Barriers to personalized therapy include access to appropriately targeted drugs. PMID- 24797822 TI - Costs of allogeneic hematopoietic cell transplantation using reduced intensity conditioning regimens. AB - Reduced intensity conditioning (RIC) regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients and up to 2 years for 311 patients who underwent a RIC HCT at two institutions from January 2008 to December 2010. Multiple linear regression was used to analyze the association between clinical variables, center effect, and costs. Patient and transplant characteristics were comparable between the sites, although differences were seen in pretransplant performance scores. Significant predictors for lower costs for the first 100 days included a diagnosis of lymphoma/myeloma and use of human leukocyte antigen-matched related donors. Grade II-IV acute graft-versus-host disease (GVHD) was associated with higher costs. The overall short-term costs between the two institutions were comparable when adjusted for clinical variables (p = .43). Late costs between 100 days and 2 years after HCT were available for one cohort (n = 311); median costs during this period were $39,000 and accounted for 39% of costs during the first 2 years. Late costs were not associated with any pretransplant variables, but were higher with extensive chronic GVHD and death. After adjustment for clinical characteristics, the overall costs of the RIC transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/alternative donors, transplant for diseases other than lymphoma or myeloma, and acute GVHD were predictors for higher early costs, and extensive chronic GVHD and death were associated with higher late costs. PMID- 24797823 TI - Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of the impact of comprehensive tumor profiling using a targeted next generation sequencing panel. AB - BACKGROUND: Oncogenic genetic alterations "drive" neoplastic cell proliferation. Small molecule inhibitors and antibodies are being developed that target an increasing number of these altered gene products. Next-generation sequencing (NGS) is a powerful tool to identify tumor-specific genetic changes. To determine the clinical impact of extensive genetic analysis, we reviewed our experience using a targeted NGS platform (FoundationOne) in advanced cancer patients. PATIENTS AND METHODS: We retrospectively assessed demographics, NGS results, and therapies received for patients undergoing targeted NGS (exonic sequencing of 236 genes and selective intronic sequencing from 19 genes) between April 2012 and August 2013. Coprimary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage who received genotype-directed therapy. RESULTS: Samples from 103 patients were tested, most frequently breast carcinoma (26%), head and neck cancers (23%), and melanoma (10%). Most patients (83%) were found to harbor potentially actionable genetic alterations, involving cell-cycle regulation (44%), phosphatidylinositol 3-kinase AKT (31%), and mitogen-activated protein kinase (19%) pathways. With median follow-up of 4.1 months, 21% received genotype-directed treatments, most in clinical trials (61%), leading to significant benefit in several cases. The most common reasons for not receiving genotype-directed therapy were selection of standard therapy (35%) and clinical deterioration (13%). CONCLUSION: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of advanced cancer patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients. PMID- 24797824 TI - The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. AB - OBJECTIVES: There are no established tools to identify individuals at risk for developing bipolar disorder. We developed a set of ultra-high-risk criteria for bipolar disorder [bipolar at-risk (BAR)]. The primary aim of the present study was to determine the predictive validity of the BAR criteria. METHODS: This was a 12-month prospective study that was conducted at Orygen Youth Health Clinical Program, a public mental health program for young people aged 15-24 years in metropolitan Melbourne, Australia. At intake, BAR screen-positive individuals and a matched group of individuals who did not meet BAR criteria were observed over a period of 12 months. The BAR criteria include general criteria such as being in the peak age range for the onset of the disorder, as well as sub-threshold mania, depression plus cyclothymic features, and depression plus genetic risk. Conversion to first-episode mania/hypomania was defined by the presence of DSM-IV manic symptoms for more than four days, in line with the DSM-IV definition of hypomania/mania. RESULTS: A total of 559 help-seeking patients were screened. Of the eligible participants, 59 (10.6%) met BAR criteria. Thirty-five participants were included in the BAR group and 35 matched participants were selected to be in the control group. During the follow-up, five BAR patients out of 35 (14.3%) converted to first-episode hypomania/mania as opposed to none in the non-BAR group [chi(2) (1) = 5.38, p = 0.020]. Four out of these five converters had a DSM IV diagnosis of bipolar I or bipolar II disorder. CONCLUSIONS: These findings support the possibility of identification of persons prior to the onset of mania/hypomania. The proposed criteria need further evaluation in larger, prospective studies with longer follow-up periods. PMID- 24797825 TI - The development of outpatient milestones. AB - The Milestones work group sought to establish a baseline of expected competence development across the six core competencies. The subcompetencies and milestones reflect the committee's work with input from ABPN, AADPRT, and AAP. They are intended to serve not only as consistent markers of progress nationwide but also as a basis by which individual programs can build their own milestones that reflect unique qualities of any given learning environment. The Milestones work group anticipates that iterative changes will be made as the milestones are broadly implemented. In anticipating the implementation of outpatient milestones, the committee will be particularly interested to how effectively psychotherapy milestones will be captured through the combination of outpatient evaluations and other data points captured in the program director's semiannual evaluation. PMID- 24797827 TI - Amniotic fluid-derived mesenchymal stem cells prevent fibrosis and preserve renal function in a preclinical porcine model of kidney transplantation. AB - It is well known that ischemia/reperfusion injuries strongly affect the success of human organ transplantation. Development of interstitial fibrosis and tubular atrophy is the main deleterious phenomenon involved. Stem cells are a promising therapeutic tool already validated in various ischemic diseases. Amniotic fluid derived mesenchymal stem cells (af-MSCs), a subpopulation of multipotent cells identified in amniotic fluid, are known to secrete growth factors and anti inflammatory cytokines. In addition, these cells are easy to collect, present higher proliferation and self-renewal rates compared with other adult stem cells (ASCs), and are suitable for banking. Consequently, af-MSCs represent a promising source of stem cells for regenerative therapies in humans. To determine the efficiency and the safety of af-MSC infusion in a preclinical porcine model of renal autotransplantation, we injected autologous af-MSCs in the renal artery 6 days after transplantation. The af-MSC injection improved glomerular and tubular functions, leading to full renal function recovery and abrogated fibrosis development at 3 months. The strong proof of concept generated by this translational porcine model is a first step toward evaluation of af-MSC-based therapies in human kidney transplantation. PMID- 24797826 TI - Wnt-responsive cancer stem cells are located close to distorted blood vessels and not in hypoxic regions in a p53-null mouse model of human breast cancer. AB - Cancer stem cells (CSCs, or tumor-initiating cells) may be responsible for tumor formation in many types of cancer, including breast cancer. Using high-resolution imaging techniques, we analyzed the relationship between a Wnt-responsive, CSC enriched population and the tumor vasculature using p53-null mouse mammary tumors transduced with a lentiviral Wnt signaling reporter. Consistent with their localization in the normal mammary gland, Wnt-responsive cells in tumors were enriched in the basal/myoepithelial population and generally located in close proximity to blood vessels. The Wnt-responsive CSCs did not colocalize with the hypoxia-inducible factor 1alpha-positive cells in these p53-null basal-like tumors. Average vessel diameter and vessel tortuosity were increased in p53-null mouse tumors, as well as in a human tumor xenograft as compared with the normal mammary gland. The combined strategy of monitoring the fluorescently labeled CSCs and vasculature using high-resolution imaging techniques provides a unique opportunity to study the CSC and its surrounding vasculature. PMID- 24797828 TI - Functional outcome after anal sphincter injury and treatment with mesenchymal stem cells. AB - This research demonstrates the regenerative effects of mesenchymal stem cells (MSCs) on the injured anal sphincter by comparing anal sphincter pressures following intramuscular and serial intravascular MSC infusion in a rat model of anal sphincter injury. Fifty rats were divided into injury (n = 35) and no injury (NI; n = 15) groups. Each group was further divided into i.m., serial i.v., or no treatment (n = 5) groups and followed for 5 weeks. The injury consisted of an excision of 25% of the anal sphincter complex. Twenty-four hours after injury, 5 * 10(5) green fluorescent protein-labeled MSCs in 0.2 ml of phosphate-buffered saline (PBS) or PBS alone (sham) were injected into the anal sphincter for i.m. treatment; i.v. and sham i.v. treatments were delivered daily for 6 consecutive days via the tail vein. Anal pressures were recorded before injury and 10 days and 5 weeks after treatment. Ten days after i.m. MSC treatment, resting and peak pressures were significantly increased compared with those in sham i.m. treatment (p < .001). When compared with the NI group, the injury groups had anal pressures that were not significantly different 5 weeks after i.m./i.v. treatment. Both resting and peak pressures were also significantly increased after i.m./i.v. MSC treatment compared with treatment with PBS (p < .001), suggesting recovery. Statistical analysis was done using paired t test with Bonferroni correction. Marked decrease in fibrosis and scar tissue was seen in both MSC-treated groups. Both i.m. and i.v. MSC treatment after injury caused an increase in anal pressures sustained at 5 weeks, although fewer cells were injected i.m. The MSC treated groups showed less scarring than the PBS-treated groups, with the i.v. infusion group showing the least scarring. PMID- 24797830 TI - Effects of soluble and insoluble fractions from bilberries, black currants, and raspberries on short-chain fatty acid formation, anthocyanin excretion, and cholesterol in rats. AB - Dietary fiber and flavonoids, important components in berries, are suggested to improve metabolic health. This study investigates whether soluble and insoluble fractions isolated from bilberry, black currant, and raspberry affect the formation of short-chain fatty acids (SCFAs), uptake and excretion of flavonoids, and levels of cholesterol differently. Cecal SCFA pools were higher in rats fed the soluble than the insoluble fractions (525 vs 166 MUmol, P < 0.001), whereas higher concentrations of butyric acid were found in the distal colon and serum of rats fed the insoluble fractions (5 vs 3 MUmol/g and 58 vs 29 MUmol/L, respectively, P < 0.001). The soluble bilberry fraction gave lower amounts of liver cholesterol (56 mg) than the other berry fractions (87 +/- 5 mg), formed the highest amount of SCFAs (746 vs 266 +/- 21 MUmol), and contributed the highest intake of anthocyanins. Cyanidin-3-glucoside monoglucuronide was detected in the urine of all groups, whereas anthocyanins were found only in groups fed soluble black currant and raspberry. PMID- 24797829 TI - CD99 is upregulated in placenta and astrocytomas with a differential subcellular distribution according to the malignancy stage. AB - In the present study, we searched for genes highly expressed in placenta and that could contribute to the establishment and maintenance of a malignant phenotype in different types of tumours, and in astrocytomas in particular. We employed a strategy based on the integration of in silico data from previously generated massively parallel signature sequencing and public serial analysis of gene expression databases. Among 12 selected genes, CD99 exhibited the highest relative mRNA expression in GBM compared to non-neoplastic brain tissues. In a larger cohort of astrocytic tumours, we further demonstrated increased CD99 expression in all malignant grades, with GBMs showing the highest values. These findings were confirmed at the protein level by Western blotting and immunohistochemistry. Additionally, we demonstrated the CD99 localisation profile in astrocytic tumours. Interestingly, CD99 expression was confined to the cytoplasm or membrane in more malignant astrocytomas, in contrast to non neoplastic brain tissue or non-infiltrative pilocytic astrocytoma, which showed no obvious staining in these structures. Comparison of three GBM cell lines revealed higher CD99 expression at the membrane and higher migratory capacity in the A172 and U87MG lines, but lower CD99 expression and no migratory ability in the T98 line. Knocking down CD99 expression by siRNA decreased significantly the migration of both cell lines. These integrated CD99 gene and protein expression results suggest that CD99 expression in astrocytomas of different malignant grades might contribute to the infiltrative ability and support the importance of CD99 as a potential target to reduce infiltrative astrocytoma capacity in migration and invasion. PMID- 24797831 TI - Progressive cognitive decline in an adult patient with cleidocranial dysplasia. AB - Cleidocranial dysplasia is a skeletal disorder characterized by a defective skull and defective clavicles caused by RUNX2, an activator of osteoblast differentiation. Consistent with the expression pattern of RUNX2, this disorder typically affects the skeletal system, but not the central nervous system. A 56 year-old man with the prototypic skeletal defects of cleidocranial dysplasia and a RUNX2 deletion presented with a progressive cognitive decline after the age of 40 years. After a failed cranioplasty during childhood, he had worn a protective helmet until young adulthood. His current neuroimaging studies revealed extensive cystic encephalomalacia beneath the defective skull, suggesting that his cognitive decline could likely be attributed to repetitive cerebral contusions. Late-onset progressive cognitive decline in the context of a defective skull accompanied by extensive cystic encephalomalacia illustrates the importance of natural calvarial protection against head injury. Since the majority of patients with cleidocranial dysplasia do not wear protective helmets beyond childhood, mainly for cosmetic reasons, a discussion of whether the social disadvantage outweighs the potential risk of brain parenchymal injury may be necessary. PMID- 24797832 TI - Pectoral fin morphology of batoid fishes (Chondrichthyes: Batoidea): explaining phylogenetic variation with geometric morphometrics. AB - The diverse cartilaginous fish lineage, Batoidea (rays, skates, and allies), sister taxon to sharks, comprises a huge range of morphological diversity which to date remains unquantified and unexplained in terms of evolution or locomotor style. A recent molecular phylogeny has enabled us to confidently assess broadscale aspects of morphology across Batoidea. Geometric morphometrics quantifies the major aspects of shape variation, focusing on the enlarged pectoral fins which characterize batoids, to explore relationships between ancestry, locomotion and habitat. A database of 253 specimens, encompassing 60 of the 72 batoid genera, reveals that the majority of morphological variation across Batoidea is attributable to fin aspect-ratio and the chordwise location of fin apexes. Both aspect-ratio and apex location exhibit significant phylogenetic signal. Standardized independent linear contrast analysis reveals that fin aspect ratio can predict locomotor style. This study provides the first evidence that low aspect-ratio fins are correlated with undulatory-style locomotion in batoids, whereas high aspect-ratio fins are correlated with oscillatory locomotion. We also show that it is phylogeny that determines locomotor style. In addition, body and caudal fin-locomotors are shown to exhibit low aspect-ratio fins, whereas a pelagic lifestyle correlates with high aspect-ratio fins. These results emphasize the importance of phylogeny in determining batoid pectoral fin shape, however, interactions with other constraints, most notably locomotor style, are also highlighted as significant. PMID- 24797833 TI - Appraising cardiac dysfunction in liver transplantation: an ongoing challenge. AB - End-stage liver disease (ESLD) is a multisystemic disease that adversely and mutually aggravates other organs such as the heart. Cardiac dysfunction in ESLD encompasses a spectrum of disease that could be aggravated, precipitated or be occurring hand-in-hand with coexisting aetiological factors precipitating cirrhosis. Additionally and more complexly, liver transplantation, the curative modality of ESLD, is responsible for additional intra- and postoperative short- and long-term cardiac morbidity. The phenotypic distinction of the different forms of cardiac dysfunction in ESLD albeit important prognostically and therapeutically is not allowed by the current societal recommendations, due to conceptual, and methodological limitations in the appraisal of cardiac function and structure in ESLD and in designing studies that are based on this appraisal. This review comprehensively discusses the spectrum of cardiac dysfunction in ESLD, discusses the limitations of the current appraisal of cardiac dysfunction in ESLD, and proposes a hypothetical approach for studying cardiac dysfunction in liver transplant candidates. PMID- 24797834 TI - Monoalkoxy BODIPYs--a fluorophore class for bioimaging. AB - Small molecule fluorophores are indispensable tools for modern biomedical imaging techniques. In this report, we present the development of a new class of BODIPY dyes based on an alkoxy-fluoro-boron-dipyrromethene core. These novel fluorescent dyes, which we term MayaFluors, are characterized by good aqueous solubility and favorable in vitro physicochemical properties. MayaFluors are readily accessible in good yields in a one-pot, two-step approach starting from well-established BODIPY dyes, and allow for facile modification with functional groups of relevance to bioconjugate chemistry and bioorthogonal labeling. Biological profiling in living cells demonstrates excellent membrane permeability, low nonspecific binding, and lack of cytotoxicity. PMID- 24797836 TI - Bioethics in China revisited. PMID- 24797835 TI - Pain and depression comorbidity: a preclinical perspective. AB - Pain and depression are two highly prevalent and deleterious disorders with significant socioeconomic impact to society. Clinical observations have long recognized the co-existence and interactions of pain and depression. However, the underlying mechanisms of pain-depression comorbidity and their dynamic interactions remain largely unknown. Preclinical animal studies may provide critical information for the understanding of this important comorbidity. This review analyzed the current preclinical evidence of interactions between pain and depression, which generally supports the causative relationship of the two conditions. In addition, the analysis proposed to apply domain interplay concept in future model development of pain-depression comorbidity and mechanism studies. The application of spectrum-centered animal models will better the understanding of pain-depression dyad and foster the development of more effective therapeutic strategies. PMID- 24797837 TI - MDM2 SNP309 polymorphism is associated with colorectal cancer risk. AB - The human murine double minute 2 (MDM2) is known as an oncoprotein through inhibiting P53 transcriptional activity and mediating P53 ubiquitination. Therefore, the amplification of MDM2 may attenuate the P53 pathway and promote tumorigenesis. The SNP309 T>G polymorphism (rs2279744), which is located in the intronic promoter of MDM2 gene, was reported to contribute to the increased level of MDM2 protein. In this hospital-based case-control study, which consisted of 573 cases and 588 controls, we evaluated the association between MDM2 SNP309 and the risk of colorectal cancer (CRC) in a Chinese population by using the TaqMan method to genotype the polymorphism. We found that the MDM2 SNP309 polymorphism was significantly associated with CRC risk. In addition, in our meta-analysis, we found a significant association between MDM2 SNP309 and CRC risk among Asians, which was consistent with our results. In conclusion, we demonstrated that the MDM2 SNP309 polymorphism increased the susceptibility of CRC in Asian populations. PMID- 24797838 TI - Histological analysis of glucagon-like peptide-1 receptor expression in chicken pancreas. AB - Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrient ingestion inhibits both gastrointestinal emptying and gastric acid secretion and promotes satiety. The main biological effect of GLP-1 is the stimulation of insulin secretion (thereby fulfilling the criterion for an incretin hormone) in order to reduce blood glucose levels in mammalian species. Chicken GLP-1 receptor (cGLP-1R) has also been identified in various tissues by gene expression analysis. Although certain effects of GLP-1 in mammals and birds are consistent, e.g., inhibition of food intake, whether GLP-1 has the same insulinotropic activity in chickens as in mammals is debated. Moreover, the expression of cGLP-1R in chicken pancreatic B cells has not been reported. The localization of cGLP-1R and its mRNA in pancreatic islets is studied by triple immunofluorescence microscopy and in situ hybridization. Triple immunofluorescence microscopy with antisera against cGLP-1R, somatostatin and insulin or glucagon revealed that cGLP-1R protein was exclusively localized in D cells producing somatostatin in chicken pancreatic islets. The D cells were localized in peripheral areas of the pancreatic islets and cGLP-1R mRNA was detected in the same areas, indicating that cGLP-1R mRNA was also expressed in D cells. This is the first report to demonstrate that cGLP-1R is expressed by D cells, not B cells as in mammals. Our study suggests that chicken GLP-1 performs its insulinotropic activity by a different mode of action from that of the mammalian hormone. PMID- 24797839 TI - Expressional changes in growth and inflammatory mediators during Achilles tendon repair in diabetic rats: new insights into a possible basis for compromised healing. AB - Dysregulation of growth and inflammatory mediators might contribute to defective tissue homeostasis and healing, as commonly observed in sedentary lifestyles and in conditions such as diabetes mellitus type-2. The present study aims to assess expression changes in growth and inflammatory mediators in the intact and healing Achilles tendon of type-2 diabetic rats. The study utilized 11 male diabetic Goto Kakizaki (GK) and 10 age- and sex-matched Wistar control rats. The right Achilles tendon was transected in all animals, whereas the left Achilles tendon remained intact. At 2 weeks post-injury, intact and injured tendons were assessed for gene expression for VEGF, Tbeta-4, TGF-beta1, IGF-1, COX-2, iNOS, HIF-1alpha, and IL 1beta by quantitative reverse transcription plus the polymerase chain reaction, and their protein distribution was studied by immunolocalization. In injured tendons of diabetic GK rats, VEGF and Tbeta-4 mRNA and corresponding protein levels were significantly down-regulated compared with those of injured Wistar controls. Compared with intact tendons of diabetic GK rats, TGF-beta1, IGF-1, and COX-2 RNA levels were higher, whereas iNOS mRNA levels were lower in injured tendons of diabetic GK rats. Within Wistar controls, healing at 2 weeks post injury led to significantly down-regulated VEGF and iNOS mRNA levels in injured tendons, whereas TGF-beta1 and HIF-1alpha mRNA levels increased compared with intact tendons. Thus, dysregulation of inflammatory and growth mediators occurs in type-2 diabetes injured tendons. Our data suggest that therapeutic modulation of Tbeta-4 and VEGF represent a new regenerative approach in operated, injured, or degenerative tendon diseases in diabetes. PMID- 24797840 TI - Work-based assessments: do not forget the formative! PMID- 24797841 TI - A proficiency-based skills training curriculum for the SAGES surgical training for endoscopic proficiency (STEP) program. AB - INTRODUCTION: The surgical training for endoscopic proficiency program is a collaborative project between Society of American Gastrointestinal and Endoscopic Surgeons and Olympus America Inc. dedicated to providing flexible endoscopy training to surgery residency programs. Currently it lacks models for proficiency based training. This study developed 2 novel flexible endoscopy simulators, purchased a third, and established face and content validity as well as proficiency metrics for all 3. METHODS: Three simulators were tested-a foam and cardboard upper gastrointestinal tract model, a commercially available colonoscopy model (CM-15, Olympus, Japan), and an endoscopic targeting model created from the Operation Game (Hasbro). Time and errors for the performance of 12 expert surgical endoscopists on each model were used to calculate proficiency scores. Face validity and content validity were established through posttest questionnaires using a 5-point Likert scale. RESULTS: Experts had a mean of 8 years of endoscopic practice (range: 1-24y). Among them, 83% teach residents or fellows using simulation. Most perform more than 50 upper endoscopies (51 to >500) and 100 colonoscopies (101 to >500) per year. The average time for completing the upper gastrointestinal tract model with correct identification of all targets was 133 +/- 56 seconds. Complete navigation of the colonoscopy model averaged 325 +/- 156 seconds. Proper orientation and targeting using the Operation Game model averaged 273 +/- 109 seconds with 3 errors. CONCLUSIONS: This study proves face and content validity for 3 physical flexible endoscopy simulators that can be used to train upper and lower endoscopy as well as instrument targeting. It also establishes expert proficiency metrics that can be used by trainees for structured rehearsal. These relatively inexpensive models will be incorporated into the surgical training for endoscopic proficiency curriculum. PMID- 24797842 TI - A review of the available urology skills training curricula and their validation. AB - BACKGROUND: The transforming field of urological surgery continues to demand development of novel training devices and curricula for its trainees. Contemporary trainees have to balance workplace demands while overcoming the cognitive barriers of acquiring skills in rapidly multiplying and advancing surgical techniques. This article provides a brief review of the process involved in developing a surgical curriculum and the current status of real and simulation based curricula in the 4 subgroups of urological surgical practice: open, laparoscopic, endoscopic, and robotic. METHODS: An informal literature review was conducted to provide a snapshot into the variety of simulation training tools available for technical and nontechnical urological surgical skills within all subgroups of urological surgery using the following keywords: "urology, surgery, training, curriculum, validation, non-technical skills, technical skills, LESS, robotic, laparoscopy, animal models." Validated training tools explored in research were tabulated and summarized. RESULTS AND CONCLUSIONS: A total of 20 studies exploring validated training tools were identified. Huge variation was noticed in the types of validity sought by researchers and suboptimal incorporation of these tools into curricula was noted across the subgroups of urological surgery. The following key recommendations emerge from the review: adoption of simulation-based curricula in training; better integration of dedicated training time in simulated environments within a trainee's working hours; better incentivization for educators and assessors to improvise, research, and deliver teaching using the technologies available; and continued emphasis on developing nontechnical skills in tandem with technical operative skills. PMID- 24797843 TI - A standardized patient model to teach and assess professionalism and communication skills: the effect of personality type on performance. AB - INTRODUCTION: Teaching and assessing professionalism and interpersonal communication skills can be more difficult for surgical residency programs than teaching medical knowledge or patient care, for which many structured educational curricula and assessment tools exist. Residents often learn these skills indirectly, by observing the behavior of their attendings when communicating with patients and colleagues. The purpose of this study was to assess the results of an educational curriculum we created to teach and assess our residents in professionalism and communication. METHODS: We assessed resident and faculty prior education in delivering bad news to patients. Residents then participated in a standardized patient (SP) encounter to deliver bad news to a patient's family regarding a severe burn injury. Residents received feedback from the encounter and participated in an education curriculum on communication skills and professionalism. As a part of this curriculum, residents underwent assessment of communication style using the Myers-Briggs type inventory. The residents then participated in a second SP encounter discussing a severe pulmonary embolus with a patient's family. RESULTS: Resident performance on the SP evaluation correlated with an increased comfort in delivering bad news. Comfort in delivering bad news did not correlate with the amount of prior education on the topic for either residents or attendings. Most of our residents demonstrated an intuitive thinking style (NT) on the Myers-Briggs type inventory, very different from population norms. DISCUSSION: The lack of correlation between comfort in delivering bad news and prior education on the subject may indicate the difficulty in imparting communication and professionalism skills to residents effectively. Understanding communication style differences between our residents and the general population can help us teach professionalism and communication skills more effectively. With the next accreditation system, residency programs would need to demonstrate that residents are acquiring these skills in their training. SP encounters are effective in teaching and assessing these skills. PMID- 24797844 TI - Assessment of virtual reality robotic simulation performance by urology resident trainees. AB - OBJECTIVES: To examine resident performance on the Mimic dV-Trainer (MdVT; Mimic Technologies, Inc., Seattle, WA) for correlation with resident trainee level (postgraduate year [PGY]), console experience (CE), and simulator exposure in their training program to assess for internal bias with the simulator. DESIGN: Residents from programs of the Southeastern Section of the American Urologic Association participated. Each resident was scored on 4 simulator tasks (peg board, camera targeting, energy dissection [ED], and needle targeting) with 3 different outcomes (final score, economy of motion score, and time to complete exercise) measured for each task. These scores were evaluated for association with PGY, CE, and simulator exposure. SETTING: Robotic skills training laboratory. PARTICIPANTS: A total of 27 residents from 14 programs of the Southeastern Section of the American Urologic Association participated. RESULTS: Time to complete the ED exercise was significantly shorter for residents who had logged live robotic console compared with those who had not (p = 0.003). There were no other associations with live robotic console time that approached significance (all p >= 0.21). The only measure that was significantly associated with PGY was time to complete ED exercise (p = 0.009). No associations with previous utilization of a robotic simulator in the resident's home training program were statistically significant. CONCLUSIONS: The ED exercise on the MdVT is most associated with CE and PGY compared with other exercises. Exposure of trainees to the MdVT in training programs does not appear to alter performance scores compared with trainees who do not have the simulator. PMID- 24797845 TI - Communication skills training in surgical residency: a needs assessment and metacognition analysis of a difficult conversation objective structured clinical examination. AB - BACKGROUND: The objective structured clinical examination (OSCE) can be used to evaluate the Accreditation Council for Graduate Medical Education Core Competencies of Professionalism and Interpersonal and Communication Skills. The aim of this study was to describe general surgery resident performance on a "difficult conversation" OSCE. METHODS: In this prospective study, junior and senior residents participated in a 2-station OSCE. Junior stations involved discussing operative risks and benefits and breaking bad news. Senior stations involved discussing goals of care and discussing transition to comfort measures only status. Residents completed post-OSCE checklist and Likert-based self evaluations of experience, comfort, and confidence. Trained standardized patients (SPs) evaluated residents using communication skill-based checklists and Likert based assessments. Pearson correlation coefficients were determined between self assessment and SP assessment. Mann-Whitney U tests were conducted between junior and senior resident variables, using alpha = 0.05. RESULTS: There were 27 junior residents (age 28.1 +/- 1.9 years [29.6% female]) and 27 senior residents (age 32.1 +/- 2.5 years [26.9% female]). The correlation of self-assessment and SP assessment of overall communication skills by junior residents was -0.32 on the risks and benefits case and 0.07 on the breaking bad news case. The correlation of self-assessment and SP assessment of overall communication skills by senior residents was 0.30 on the goals of care case and 0.26 on the comfort measures only case. SP assessments showed that junior residents had higher overall communication skills than senior residents (p = 0.03). Senior residents perceived that having difficult conversations was more level appropriate (p < 0.001), and they were less nervous having difficult conversations (p < 0.01) than junior residents. CONCLUSIONS: We found that residents perform difficult conversations well, that subjective and objective skills are correlated, and that skills-based training is needed across all residency levels. This well-received method may be used to observe, document, and provide resident feedback for these important skills. PMID- 24797846 TI - Construct validation of the key components of Fundamental Skills of Robotic Surgery (FSRS) curriculum--a multi-institution prospective study. AB - BACKGROUND: Recent incorporation of simulation in surgical training necessitates developing validated platforms for training and assessment. A tool should fulfill the fundamental criteria of validation. OBJECTIVE: To report the ability of a simulation-based robotic training curriculum-Fundamental Skills of Robotic Surgery (FSRS)-to assess and distinguish between different performance levels of operator experience (construct validity). MATERIALS AND METHODS: This is a prospective multicenter observational study. Participants were classified as novice (0 robotic cases performed) and experts (>150 robotic cases performed). All participants were required to complete 4 key tasks in a previously validated FSRS curriculum: ball placement, coordinated tool control, fourth arm control, and needle handling and exchange. Using the metrics available in the simulator software, the performances of each group were compared to evaluate construct validation. RESULTS: A convenience cohort of 61 surgeons participated. Novice group (n = 49) consisted of 41 fellows/residents/medical students and 8 trained open/laparoscopic surgeons, whereas expert group consisted of 12 surgeons. The novice group had no previous robotic console experience, whereas the expert group had >150 prior robotic cases experience. An overall significant difference was observed in favor of the expert group in 4 skill sets (p < 0.05). Time to complete all 4 tasks was significantly shorter in the expert group (p < 0.001). The expert group displayed significantly lesser tool collision (p = 0.002) and reduced tissue damage (p < 0.001). In performing most tasks, the expert group's camera (p < 0.001) and clutch usage (p < 0.001) was significantly greater when compared with the novice group. CONCLUSION: The components of the FSRS curriculum showed construct validity. This validation would help in effectively implementing this curriculum for robot-assisted surgical training. PMID- 24797847 TI - Evaluation of a dedicated, surgery-oriented visiting international medical student program. AB - PURPOSE: Programs dedicated to the successful integration of international medical graduates into the U.S. surgical residency training are scarce and foreign students are often unaware of their availability. In 2007, the Department of Surgery at the University of Texas Health Science Center at San Antonio developed the Visiting International Students in San Antonio (VISSA) program designed to bring international senior medical students to rotate at our institution. The program has enrolled 55 students who rotated through various general surgery services. The purpose of this study was to assess prior participants' professional statuses, career selections, and satisfaction with our program. METHODS: A 21-item anonymous online survey was distributed via e-mail. Demographic information, current professional status, residency specialty selection, assessment of satisfaction, and personal experience with the VISSA program were collected. RESULTS: We obtained an 84% (46/55) response rate among participants. Most respondents were men (75.6%) and younger than 25 years of age (82.6%). Students from 14 nations have visited our institution, mostly from Latin America (56.5%) and Asia (36.9%). Before visiting our program, 80.4% considered applying to a residency program in the United States, which increased to 88.9% after rotating at our institution. Of our respondents, 42.1% applied to a residency program in the United States and 17.4% were accepted to a general surgery position (50% categorical and 50% preliminary). Respondents agreed or strongly agreed that being part of the VISSA program helped them obtain a general surgery residency position (90.4%) and considered our program as their first option (77.8%). Independently of their current professional status or residency selection process, 100% of respondents would recommend participation in our program to colleagues at their medical schools. CONCLUSION: A dedicated, surgery oriented visiting foreign medical student program has a positive effect in residency selection, application, and professional development. PMID- 24797848 TI - Evidence-based microsurgical skill-acquisition series part 1: validated microsurgical models--a systematic review. AB - OBJECTIVES: The purpose of this study is to (1) systematically review all the literature pertaining to microsurgical training models and to (2) determine which of these are specific to and validated for microsurgery training. DESIGN: PubMed, MEDLINE (OVID/EBSCO), Google Scholar, and Cochrane Central Register of Controlled Trials were searched using preset terms. The last search date was in July 2012. Articles of all languages, years of publication, sample sizes, and model types pertaining to microsurgery were included. The eligibility criteria included the use of a microsurgical training model on a subject group with statistical analysis and measures of validation. Two assessors independently reviewed the articles and their references. RESULTS: Of the 238 articles reviewed, 9 articles met the criteria. Those excluded were predominantly model descriptions that had not been validated in a set of learners. The 9 models whose performances were assessed in a group of learners included an online curriculum, nonliving prosthetics and biologics, and the live rat femoral artery model. Each model was evaluated for content, construct, face, and criterion (concurrent and predictive) validity, as well as selection and observation/expectant bias. Content, construct, concurrent, and face validities were consistently demonstrated for all 9 models. Selection bias was also reliably well controlled with random allocation of participants to each study group. Observation/expectant bias was controlled in 6 of the 8 papers. Predictive validity, an arguably more difficult factor to measure, was only present in 1 article. CONCLUSIONS: Despite a plethora of papers describing microsurgical learning tools, only 9 were discovered that provided validation of the proposed method of microsurgical skills acquisition. This review depicts the need for basic, yet well-designed studies that substantiate the effectiveness of microsurgical training models by using a subject group and demonstrating a statistical improvement with employment of the model. Ease of access, cost, and assessment tools used also require attention. PMID- 24797849 TI - Face and content validation of the prostatic hyperplasia model and holmium laser surgery simulator. AB - OBJECTIVE: Although a number of simulators have been introduced for prostate surgery, none have undergone validation for holmium laser enucleation of the prostate training. This study was carried out to assess the face and content validities as well as feasibility and acceptability of the new prostatic hyperplasia model and prostate surgery simulator for holmium laser enucleation of the prostate. DESIGN: This is a prospective, observational, and comparative study. Participants were given a 30-minute video tutorial followed by a 45-minute simulation session, with one-to-one mentoring. A survey with qualitative and quantitative fields was used to evaluate their experience. SETTING: This study was carried out in a 2-day modular teaching course hosted by the Holmium User Group at Cambridge University Hospitals, UK, and during the British Association of Urological Surgeons 2013 Annual Meeting. PARTICIPANTS: A total of 36 participants comprising 13 urology trainees and 23 senior urologists of varying levels from all around the globe were recruited. RESULTS: Overall, 87% of the participants believed that holmium laser enucleation of the prostate was an effective method of treatment, simulation-based training, and assessment essential for patient safety and 84% believed a validated simulator would be useful for training. Of the participants, 97% agreed that the simulation should be implemented into training programs and only 31% felt it should be part of accreditation. Participants ranked all components of the simulator greater than 7 of 10 on a global rating scale and believed it was a feasible and acceptable method of training and assessment. CONCLUSIONS: The new simulator for holmium laser enucleation of the prostate has been demonstrated to be useful as a training tool. This study has established face and content validities of the simulator. Senior and trainee urologists believed the simulator was an acceptable tool for training and assessment and its use feasible for novice trainees to acquire skills and knowledge to a predetermined level of proficiency. PMID- 24797850 TI - Factors influencing scholarly impact: does urology fellowship training affect research output? AB - PURPOSE: Residents seek postresidency fellowship training to increase competency with novel surgical techniques and augment their fund of knowledge. Research productivity is a vital component of advancement in academic urology. Our objectives were to use the h-index (an objective and readily available bibliometric that has been repeatedly shown to correlate with scholarly impact, funding procurement, and academic promotion in urology as well as other specialties) to determine whether any relationship exists between fellowship training and scholarly impact among academic urologists. Additional examination was performed to determine whether any differences in scholarly influence are present among practitioners in the major urologic subspecialties. MATERIALS AND METHODS: Overall, 851 faculty members from 101 academic urology departments were organized by academic rank and fellowship completed. Research productivity was calculated using the h-index, calculated from the Scopus database. RESULTS: There was no statistical difference in h-index found between fellowship-trained and nonfellowship-trained academic urologists. The highest h-indices were seen among urologic oncologists (18.1 +/- 0.95) and nonfellowship-trained urologists (14.62 +/- 0.80). Nearly 70% of department chairs included in this analysis were urologic oncologists or general urologists. CONCLUSIONS: No difference in h-index existed between fellowship-trained and nonfellowship-trained urologists, although practitioners in the subspecialty cohorts with the highest research productivity (nonfellowship-trained and urologic oncologists) comprised 70% of department chairpersons. This relationship suggests that a strong research profile is highly valued during selection for academic promotion. Differences existed on further comparison by subspecialty. Fellowship training may represent another potential opportunity to introduce structured research experiences for trainees. PMID- 24797851 TI - High efficacy and students' satisfaction after voluntary vs mandatory use of an e learning program in traumatology and orthopedics--a follow-up study. AB - INTRODUCTION: Within the last decade, e-learning has gained a consistent place in surgical teaching. However, as the use of new programs is often voluntary, more information on the implications of the data regarding user acceptance and knowledge with mandatory use is desirable, especially in the context of the long term developments of courses. MATERIALS: Starting in 2009, the e-learning program Network for Students in Traumatology and Orthopedics was offered in a voluntary blended learning context. Students' satisfaction and increase in knowledge were evaluated using questionnaires and written tests. With proven effectiveness, the program became a mandatory part of the curriculum, and students' attitudes and gain of knowledge were re-evaluated in 2010 and 2011 to detect differences in voluntary vs mandatory use. RESULTS: In the evaluation questionnaires (n = 108 voluntary vs n = 361 mandatory), the overall appreciation regarding the offerings remained high. Significantly more students felt better prepared for clinical situations (p < 0.001) and asked for e-tutoring (p = 0.025) with mandatory use. In written tests, both voluntary (n = 70) and mandatory (n = 147) users showed significantly increased knowledge (p < 0.001). Starting with a lower base level (p < 0.001), mandatory users had a significantly higher absolute increase compared with voluntary users (p = 0.015), leading to a similar final level. DISCUSSION: The presented blended learning concept was an efficient way to teach students orthopedics and traumatology. Data can support the assumption that even if the voluntary evaluation of e-learning offerings might be subject to a selection bias, the results can serve as a representative impression for the students' overall mood and their gain in knowledge. However, as changes would have to be anticipated when shifting to mandatory use, users' perceptions should be constantly evaluated. PMID- 24797852 TI - Identifying areas of weakness in thoracic surgery residency training: a comparison of the perceptions of residents and program directors. AB - OBJECTIVE: To identify core thoracic surgery procedures that require increased emphasis during thoracic surgery residency for residents to achieve operative independence and to compare the perspectives of residents and program directors in this regard. METHODS: A modified Delphi process was used to create a survey that was distributed electronically to all Canadian thoracic surgery residents (12) and program directors (8) addressing the residents' ability to perform 19 core thoracic surgery procedures independently after the completion of residency. Residents were also questioned about the adequacy of their operative exposure to these 19 procedures during their residency training. A descriptive summary including calculations of frequencies and proportions was conducted. The perceptions of the 2 groups were then compared using the Fisher exact test employing a Bonferroni correction. The relationship between residents' operative exposure and their perceived operative ability was explored in the same fashion. RESULTS: The response rate was 100% for residents and program directors. No statistical differences were found between residents' and program directors' perceptions of residents' ability to perform the 19 core procedures independently. Both groups identified lung transplantation, first rib resection, and extrapleural pneumonectomy as procedures for which residents were not adequately prepared to perform independently. Residents' subjective ratings of operative exposure were in good agreement with their reported operative ability for 13 of 19 procedures. CONCLUSION: This study provides new insight into the perceptions of thoracic surgery residents and their program directors regarding operative ability. This study points to good agreement between residents and program directors regarding residents' surgical capabilities. This study provides information regarding potential weaknesses in thoracic surgery training, which may warrant an examination of the curricula of existing programs as well as a reconsideration of what the scope of practice of a general thoracic surgeon should entail. PMID- 24797853 TI - Is current surgical training efficient? A national survey. AB - OBJECTIVES: Evaluation of surgical training in Denmark is competency based with no requirement for a specific number of procedures. This may affect monitoring of surgical progress adversely and cause an underestimation of the time needed to acquire surgical competencies. We investigated the number of common surgical procedures performed by trainees. Trainees' and consultants' expectations from the training program were also investigated. DESIGN AND PARTICIPANTS: A questionnaire was sent to all 115 surgical trainees in Denmark. We asked how many common surgical procedures the trainees had performed during their postgraduate training, whether self-reported procedural confidence was achieved during their training, and whether their training expectations were met. Another questionnaire dealt with the consultants' expectations of the surgical training. RESULTS: The total number of common surgical procedures (Lichtenstein hernia repair, appendectomy, laparoscopic appendectomy, and laparoscopic cholecystectomy) that were performed varied between trainees. One group performed few common procedures during training. A low number in 1 procedure correlated with a similar pattern in other procedures. Approximately one-third did not perform common elective procedures independently until their fifth year. Consultants and trainees viewed training differently. CONCLUSIONS: Our study reveals no common trend in the numbers and types of procedures performed during training. The number of procedures seems to reflect the individual trainee and a local tradition rather than the particular training program. An informal competency-based assessment system with lack of quantitative requirements evidently involves a risk of skewness in training. PMID- 24797854 TI - Is there an association between study materials and scores on the American Board of Orthopaedic Surgeons Part 1 examination? AB - BACKGROUND: Previous studies have shown that certain orthopaedic in-training examination scores can be used to identify which residents may be at risk for failing the American Board of Orthopaedic Surgeons (ABOS) Part 1 examination. However, no studies have examined how study resources may affect residents' ABOS Part 1 scores. The goal of this study is to determine which review sources or review courses, if any, are associated with improved ABOS Part 1 scores. METHODS: A survey was sent to 221 of the 865 examinees who took the ABOS Part 1 examination in 2012. The questions inquired the respondents how well they performed on previous orthopaedic in-training examinations and ABOS Part 1, along with the study sources they most commonly used, review courses they attended, and resources they would recommended if they were to retake ABOS Part 1 examination. RESULTS: Overall, 118 of the 221 (53%) survey recipients completed the survey. Six (5%) of the respondents failed ABOS Part 1 examination. Orthobullets and the American Academy of Orthopaedic Surgeons self-assessment examinations were recommended as the primary study source significantly more (p < 0.01) than most other resources, but there was no significant association between study source and passing ABOS Part 1 or scoring in a certain percentile on ABOS Part 1. Similarly, there were no associations between attending a review course and either passing or scoring in a certain percentile for ABOS Part 1. Half of the respondents who failed ABOS Part 1 attended multiple review courses. CONCLUSIONS: There does not appear to be an association between improved ABOS Part 1 scores and orthopedic study materials or review courses. Further research into the value of certain educational modalities should be conducted to determine the best ways to educate orthopedic residents and determine the value of some of these commonly used orthopedic review modalities. PMID- 24797855 TI - Social media and tomorrow's medical students--how do they fit? AB - OBJECTIVE: The main aim of our study was to establish the prevalence of social networking accounts among a group of second-level students (aged 15-18 years), to determine whether they used privacy settings, and to examine their attitudes to various aspects of social media use in medicine. DESIGN: A descriptive study design was employed. The questionnaire was constructed specifically to address the attitudes of students to social media. No similar suitable validated questionnaire could be identified. The questionnaire consisted of 20 questions with a mixture of open answer, yes/no, and Likert scale response options. PARTICIPANTS: Participation was voluntary and anonymous. Second-level school children interested in studying medicine and aged between 15 and 18 years took part. SETTING: An annual open day organized by the School of Medicine in University College Cork, Ireland, formed the setting. The day comprised a mixture of lectures, demonstrations, and practical sessions designed to give the students insight into life as a medical student. RESULTS: A total of 96 students attended, and all were handed the questionnaires. Of them, 88 students completed the survey. Overall, 90.9% of students had Facebook accounts and 53% had Twitter accounts. Of those with social media accounts, 14.8% reported having no privacy settings. Most respondents felt that unprofessional behavior on social media sites should be a factor considered in admission to medical schools. CONCLUSIONS: Serious consequences can result from lapses in best practice relating to social media behavior. Dedicated reflective learning modules need to be incorporated into undergraduate and postgraduate training programs as a matter of urgency. PMID- 24797857 TI - The refinement of a cultural standardized patient examination for a general surgery residency program. AB - BACKGROUND: Recent articles have documented the importance of cultural competency in surgery. Surgical residency programs have used the Objective Structured Clinical Examinations or cultural standardized patient examinations as a training tool. Past studies evaluating cultural competency have noted the importance of including an observational (control) arm, which would allow for a more objective assessment of a resident's competency in this area. The purpose of our article is to present the results of a follow-up study to a pilot cultural standardized patient examination for surgery residents. METHODS: All first-year surgery residents were required to participate in the videotaped cultural SP examination as part of the general surgery residency curriculum. Two measures were used to assess resident performance. On the day of the examination, the Cross-Cultural Care Survey was administered. The examination was assessed by the residents themselves, faculty observers, and standardized patients, using a written checklist that was developed to evaluate residents on all 6 Accreditation Council for Graduate Medical Education competencies. RESULTS: The current study includes 20 first-year surgery residents from academic years 2011 to 2012 and 2012 to 2013. The examination of pretest differences in groups found that students born outside of the United States had significantly higher scores on attitude (t = 2.68, df = 18, p = 0.02), but no statistically significant differences were found in skillfulness or knowledge or in the overall rating scale. For the overall rating scale, change from pretest to posttest was statistically significant (t = 2.25, df = 18, p = 0.04). Further analysis revealed that students who were born in the United States demonstrated a significant increase in ratings (t = -3.08, df = 10, p = 0.01) whereas students who were not born in the United States showed little change (t = -0.35, df = 7, p = 0.74). These results show that the means in attitude scales changed little for all groups, but both white and US-born students showed greater improvement on skillfulness and knowledge. CONCLUSIONS: Training and measurement of cross-cultural health care skills remains challenging. However, studies like these provide a good starting point from which to build. PMID- 24797856 TI - The positive effect of immediate feedback on medical student education during the surgical clerkship. AB - BACKGROUND AND AIMS: Feedback from faculty to medical students is vital in medical education. The objective of this study was to assess the feasibility and educational benefits of a program that incorporates seeking immediate feedback by students from their faculty during the third-year medical student core surgery clerkship. METHODS: Using a crossover model, students in the intervention group sought daily feedback from their faculty surgeons, whereas those in the nonfeedback comparison group did not seek feedback. These groups crossed over every 2 weeks for the 8 surgical weeks of their 12-week clerkship. Weekly surveys, using 7-point Likert scales, were used by the participating students and surgical faculty to measure outcomes. RESULTS: Among 53 potential students, 33 were enrolled. Students reported significantly more weekly immediate feedback sessions in the experimental group (1.21 vs 0.67, p = 0.002). Additionally, in the experimental group, there were significantly more occasions where faculty surgeons provided specific guidance as to how students could further their education (1.25 vs 0.83, p = 0.02). Although not significant, there were trends toward the experimental group reporting their faculty feedback to be more specific, sufficient, and including both more positive and negative feedback. There were no significant differences in student self-assessments or faculty assessments of knowledge and skills. Student participation was a major impediment to this study. CONCLUSIONS: Despite the challenges, there appear to be real educational gains associated with immediate feedback. The results suggest that an immediate feedback program can be implemented and may enhance the dialog in the student-faculty relationship. Further research could focus on improving student participation and the quality of attending faculty feedback. PMID- 24797858 TI - The relationship between confidence and competence in the development of surgical skills. AB - BACKGROUND: Confidence is a crucial trait of any physician, but its development and relationship to proficiency are still unknown. This study aimed to evaluate the relationship between confidence and competency of medical students undergoing basic surgical skills training. METHODS: Medical students completed confidence surveys before and after participating in an introductory workshop across 2 samples. Performance was assessed via video recordings and compared with pretraining and posttraining confidence levels. RESULTS: Overall, 150 students completed the workshop over 2 years and were evaluated for competency. Most students (88%) reported improved confidence after training. Younger medical students exhibited lower pretraining confidence scores but were just as likely to achieve competence after training. There was no association between pretraining confidence and competence, but confidence was associated with demonstrated competence after training (p < 0.001). CONCLUSIONS: Most students reported improved confidence after a surgical skills workshop. Confidence was associated with competency only after training. Future training should investigate this relationship on nonnovice samples and identify training methods that can capitalize on these findings. PMID- 24797859 TI - "The thyroidectomy story": comic books, graphic novels, and the novel approach to teaching head and neck surgery through the genre of the comic book. AB - As surgical education changes, an instructive need arises to complement the complexity of hands-on manual and visuospatial skills acquired as a result of apprenticing in the operating room (OR) and adjusting to new technologies and robotics. Novel and innovative methods must be employed, not to replace the OR experience but rather to enhance it. Here, we present a fine arts merger with surgical education in the genre of the comic book and graphic novel to address visuospatial skills, motor skills (practice-based learning and improvement), and the narrative, humanistic component (patient care) necessary for a well-rounded surgical education. We examine the important goals of training residents with the development of an "experimental" comic book on the thryoidectomy procedure to enhance textbook and lecture material, where residents and nurses are introduced to technique, narrative, and medical illustration skills (interpersonal communication skills) to assist them in anticipating, reflecting, and potentially facilitating the very proficiency necessary to be successful in the OR while remaining curious and engaged in their craft. PMID- 24797860 TI - Two for one: surgical skills and CanMEDS roles--a combined course for surgical residents. AB - BACKGROUND: The purpose of this study was to develop a surgical skills program for first-year surgical residents by integrating the Canadian Medical Education Direction for Specialists (CanMEDS) roles. METHODS: A 9-week course combining basic surgical skills and CanMEDS roles was developed and provided to 24 residents from the Departments of Surgery and Obstetrics and Gynecology at the University of Calgary. Sessions consisted of a pretest/posttest, teaching the surgical skills, supervised practice, posttest, and teaching CanMEDS roles. RESULTS: The pretest scores indicated the residents' preparation and understanding of the session, which improved as the course progressed. The residents' satisfaction surveys graded on a scale from 1 to 5, syllabus content, syllabus effectiveness, teaching expectations, technical demonstrations, practice sessions, confidence gained, and bench model fidelity indicated a mean of 4.09 (standard deviation = 0.81) satisfaction with the new course. Similarly, preceptors' satisfaction surveys graded on a scale from 1 to 5 demonstrated a mean of 4.16 (standard deviation = 0.69) satisfaction. CONCLUSIONS: Surgical skills and CanMEDS roles of communication, professionalism, collaborator and manager, can be taught simultaneously proving that this new teaching format can be feasible, effective, and logistically convenient, providing a satisfying experience for both residents and preceptors. PMID- 24797861 TI - Virtual reality simulators: valuable surgical skills trainers or video games? AB - BACKGROUND: Virtual reality (VR) and physical model (PM) simulators differ in terms of whether the trainee is manipulating actual 3-dimensional objects (PM) or computer-generated 3-dimensional objects (VR). Much like video games (VG), VR simulators utilize computer-generated graphics. These differences may have profound effects on the utility of VR and PM training platforms. In this study, we aimed to determine whether a relationship exists between VR, PM, and VG platforms. METHODS: VR and PM simulators for laparoscopic camera navigation ([LCN], experiment 1) and flexible endoscopy ([FE] experiment 2) were used in this study. In experiment 1, 20 laparoscopic novices played VG and performed 0 degrees and 30 degrees LCN exercises on VR and PM simulators. In experiment 2, 20 FE novices played VG and performed colonoscopy exercises on VR and PM simulators. RESULTS: In both experiments, VG performance was correlated with VR performance but not with PM performance. Performance on VR simulators did not correlate with performance on respective PM models. CONCLUSIONS: VR environments may be more like VG than previously thought. PMID- 24797863 TI - Surgeons at Ground Zero of the atomic age. PMID- 24797862 TI - Visual control strategies of surgeons: a novel method of establishing the construct validity of a transurethral resection of the prostate surgical simulator. AB - OBJECTIVE: To examine novice and expert differences in visual control strategies while performing a virtual reality transurethral resection of the prostate (TURP) task and to determine if these differences could provide a novel method for assessing construct validity of the simulator. SUBJECTS AND METHODS: A total of 11 novices (no TURP experience) and 7 experts (>200 TURPs) completed a virtual reality prostate resection task on the TURPsim (Simbionix USA Corp, Cleveland, OH) while wearing an eye tracker (ASL, Bedford, MA). Performance parameters and the surgeon's visual control strategy were measured and compared between the 2 groups. RESULTS: Experts resected a greater percentage of prostate than novices (p < 0.01) and had less active diathermy time without tissue contact (p < 0.01). Experts adopted a target-locking visual strategy, employing fewer visual fixations (p < 0.05) with longer mean fixation duration (p < 0.005). With multiple learning trials, novices' performance improved and the adoption of a more expertlike gaze strategy was observed. CONCLUSION: Significant differences between experts and novices in both performance and visual control strategy were observed. The study of visual control strategies may be a useful adjunct, alongside measurements of motor performance, providing a novel method of assessing the construct validity of surgical simulators. PMID- 24797864 TI - Too nice to be a surgeon? PMID- 24797865 TI - Nucleolar persistence during spermatogenesis of the genus Rhodnius (Hemiptera, Triatominae). AB - The Triatominae subfamily is comprised of 18 genera and six tribes. The tribe Rhodniini is comprised of two genera (Rhodnius and Psammolestes). Nucleolar persistence is defined by the presence of the nucleolus or nucleolar corpuscles during the meiotic metaphase. To date, this phenomenon has been described for 13 species of triatomine that are included in the genera Triatoma, Rhodnius, and Panstrongylus. Thus, because the phenomenon of nucleolar persistence has been described in only two species of the genus Rhodnius, we have analyzed the nucleolar behavior during spermatogenesis of eight species of the genus Rhodnius (R. colombiensis, R. montenegrensis, R. nasutus, R. neglectus, R. neivai, R. pictipes, R. prolixus, and R. robustus), with a focus on nucleolar persistence. By means of cytogenetic analysis with silver ions, nucleolar behavior during spermatogenesis is described in the eight species of Rhodnius analyzed. In all of them nucleolar behavior was similar and the phenomenon of nucleolar persistence was often observed. Therefore, we confirm nucleolar persistence as a peculiarity of the genus Rhodnius. However, it is emphasized that new cytogenetic analysis should be performed in the Triatominae subfamily, more specifically among the 15 genera that do not exhibit the nucleolar behavior described, in order to assess whether this phenomenon is truly a synapomorphy of these hematophagous insects. PMID- 24797866 TI - [Endothelin: From discovery to pharmacotherapeutic innovations]. AB - OBJECTIVES: Endothelin (ET) is a major therapeutic target in cardiopulmonary diseases. The purpose of this review is to present the main concepts concerning ET biology, its pathophysiological roles and the major pharmacological and medical advances recently developed around the concept of ET receptor blockade. METHODS: Analysis of PubMed database (keywords: endothelin, endothelin receptor antagonists, pulmonary hypertension, etc.), and of abstract originating from recent international meetings. RESULTS: ET is a peptide produced by vascular endothelial cells as well as by many other tissues. Both its production and its effects are activated in pathological situations associated with endothelial dysfunction. ET is characterized by a strong tropism toward tissues because of its polarized release, the strong tissue receptor density and high affinity of the receptors for the peptide. ET exerts several vascular effects, including vasoconstriction, proliferation and hypertrophy, as well as non-vascular effects, notably stimulation of cardiac hypertrophy, tissue fibrosis and inflammation. Both vascular and non-vascular effects depend on the stimulation of two receptor subtypes, ETA and ETB. ET receptor antagonists (ERA) demonstrated beneficial effects in many different pre-clinical models of cardiovascular and pulmonary diseases, and constitute a first-line treatment of patients with pulmonary arterial hypertension (PAH). Recently, the targeted search for a novel ERA led to the development of macitentan which, compared to existing ERA, show optimized tissue penetration, increased receptor affinity and in vivo pharmacological efficacy in pre-clinical models, associated with a favorable profile, in terms of hepatic safety and drug interactions. The clinical efficacy of macitentan in the treatment of PAH was recently demonstrated in the SERAPHIN trial, which contrasts with previous PAH trials because of its long duration, the high number of patients enrolled, and its primary endpoint evaluating morbidity/mortality. Results show a significant reduction of the primary composite morbidity/mortality endpoint (taking into account both progression of PAH and death) by 30 and 45% with macitentan 3 and 10mg, respectively, compared to placebo, and confirm on the large scale the favorable tolerance profile, especially at the hepatic level. CONCLUSION: The extensive knowledge on the complexity of the ET system allowed the synthesis of a new antagonist optimized, in terms of pharmacological efficacy and safety, which also show promising therapeutic effects in PAH patients, with demonstrated results in a prospective study using a composite primary endpoint of morbidity-mortality. PMID- 24797868 TI - Dehydrated red blood cells in a peripheral blood film: a case of hereditary xerocytosis. PMID- 24797869 TI - Dimensions and attachments of the ankle ligaments: evaluation for ligament reconstruction. AB - For operative reconstruction, precise anatomic information on the dimensions of the ankle ligaments is important and can help to optimize these procedures. The purpose of this study was to investigate the length and width dimensions of the ankle ligaments and to contrast the results with the published literature. Seventeen non-paired adult, formalin-fixed ankle specimen were dissected to expose the capsuloligamentous structures. The following ligaments were investigated: tibiofibular syndesmosis (anterior and posterior tibiofibular ligament/ATiFL and PTiFL), lateral ankle ligaments (anterior and posterior talofibular ligament, calcaneofibular ligament/ATFL, PTFL and CFL), medial ankle ligaments (deltoid ligament, anterior and posterior tibiotalar ligament/ATTL and PTTL). After identification of the ligaments, the dimensions were measured with a ruler and a sliding caliper. Additionally, the attachment area and the center of insertion (COI) were evaluated. The dimensions of the ligaments were recorded. Measurements were calculated and discussed according to the existing literature. The tibial COI of the ATiFL was situated 8.35 +/- 2.05 mm from the inferior articular surface of the tibia and 5.04 +/- 1.32 mm from the fibular notch. Its fibular COI was situated 25.45 +/- 5.84 mm from the tip of the lateral malleolus and 3.12 +/- 1.01 mm from the malleolar articular surface. The calcaneal COI of the CFL was situated 20.63 +/- 3.56 mm anterior and 5.73 +/- 1.89 mm plantar to the superior edge of the calcaneal. Its fibular attachment of the CFL was directly at the tip of the lateral malleolus, dorsal to the fibular attachment of the ATFL. Studies of the therapeutic options in severe ankle ligament injuries have shown better results in anatomical reconstructions compared to other operative treatments. To optimize these procedures, exact anatomical information on the dimensions of the ankle ligaments should be beneficial. PMID- 24797870 TI - Incidence of cervical lesions in Danish women before and after implementation of a national HPV vaccination program. AB - PURPOSE: Approximately 70% of cervical cancers and about 50% of high-grade cervical precursor lesions are caused by human papillomavirus (HPV) types 16 and 18. Denmark introduced the quadrivalent HPV vaccine into the vaccination program for 12-year-old girls in 2009 supplemented by a first catch-up program for 13-15 year-old girls in 2008, and a second program for women up to the age of 27 years in 2012; all with high vaccination coverage. The aim of this study was to evaluate the effectiveness of the vaccine by comparing the incidence trends of cervical lesions before and after its introduction. METHODS: Incident cases of cervical lesions were identified from the nationwide Pathology Data Bank. Age specific incidence rates were estimated for six age groups, and Poisson regression was used to calculate estimated annual percentage change (EAPC). RESULTS: The incidence of atypia or worse (atypia+) and cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased in all age groups in 2000-2010. After introduction of the quadrivalent HPV vaccine into the vaccination program, the incidence of atypia+ decreased significantly in women younger than 18 years (EAPC -33.4%; 95% CI -49.6; -12.0) and in 18-20-year-old women (EAPC -12.6%; 95% CI -19.3; -5.3). The incidence of CIN2+ also decreased significantly in 18-20 year-old women (EAPC -14.8%; 95% CI -21.6; -7.5) in 2010-2013, but no significant decrease was seen in older age groups. CONCLUSION: The incidence of cervical lesions decreased significantly in age groups with high HPV vaccine coverage, indicating an early effect of HPV vaccination. PMID- 24797871 TI - The effect of primary care physician counseling on participation rate and use of sedation in colonoscopy-based colorectal cancer screening program--a randomized controlled study. AB - OBJECTIVES: Physician recommendation is a strong predictor of colorectal cancer (CRC) screening adherence, but there are no sufficient data specific to primary colonoscopy screening programs. The primary objective was to compare the effect of primary care physician's (PCP) counseling with information leaflet about CRC screening on participation rate in opportunistic primary colonoscopy screening program. Secondary objective was to determine the impact of this counseling on a decision to choose unsedated colonoscopy. MATERIAL AND METHODS: Six hundred consecutive subjects 50-65 years of age visiting PCP group practice for routine medical consultation were randomly assigned in a 1:1 ratio either to discuss CRC screening with PCP or to receive an information leaflet on CRC screening only. The outcome measures were the participation rate and the proportion of unsedated colonoscopies assessed on subjects' self-reports collected six months after the intervention. Multivariate logistic regression model with backward selection was used to investigate the association between independent covariates and binary endpoints. RESULTS: Participation rate was 47.0% (141 subjects) in the counseling group and 13.7% (41 patients) in the information leaflet group. The rates of unsedated colonoscopies were 77.0% and 39.0%, respectively. In a multivariate analyses, PCP's counseling was associated with higher participation in CRC screening (adjusted odds ratio [OR] 5.33, 95% confidence intervals [95% CI] 3.55 8.00) and higher rate of unsedated colonoscopies (OR 7.75, 95% CI 2.94-20.45). CONCLUSION: In opportunistic primary colonoscopy screening, PCP's counseling significantly increases participation rate and decreases demand for sedation compared to recruitment with information materials only. NCT01688817. PMID- 24797872 TI - Apolipoprotein B as an independent predictor of arterial stiffness in systemic lupus erythematosus patients. AB - AIM: To determine the relationship of apolipoprotein B (Apo-B) and arterial stiffness determined by brachial-ankle pulse wave velocity (baPWV) in systemic lupus erythematosus (SLE) subjects. METHODS: Eighty-seven Thai SLE subjects with inactive disease activity were studied. Fasting blood was collected for creatinine, glucose, lipid profiles, Apo-B and Apo-A1. Pearson correlation and stepwise-linear regression were used for the analysis. RESULTS: The mean age of the subjects was 36.69 +/- 10.85 years; 6.90% of them had stage 3 or more severe chronic kidney disease, 49.40% took anti-hypertensive drugs and 4.60% had abnormal glucose metabolism. The mean value for baPWV was 1332 +/- 274.12 cm/s. Thirty-six percent of the subjects had increased arterial stiffness with mean Apo B levels of 1.05 +/- 0.31 g/L compared to 0.94 +/- 0.24 in normal arterial stiffness. There were correlations of baPWV with age, systolic blood pressure (BP), diastolic BP and creatinine clearance. Apo-B tended to be associated with baPWV (P = 0.06) whereas low-density lipoprotein cholesterol did not (P = 0.2). By multiple regression analysis, systolic BP, age and Apo-B were the significant predictors of baPWV. CONCLUSION: Apo-B was independently associated with arterial stiffness in SLE subjects. PMID- 24797875 TI - Gold nanoshell/polysaccharide nanofilm for controlled laser-assisted tissue thermal ablation. AB - We report on the fabrication and characterization of a freestanding ultrathin, mucoadhesive gold nanoshell/polysaccharide multilayer nanocomposite (thermonanofilm, TNF), that can be used for controlled photothermal ablation of tissues through irradiation with near-infrared radiation (NIR) laser. The aim of this work is to provide a new strategy to precisely control particle concentration during photothermalization of cancerous lesions, since unpredictable and aspecific biodistributions still remains the central issue of inorganic nanoparticle-assisted photothermal ablation. Gold nanoshell encapsulation in polysaccharide matrix is achieved by drop casting deposition method combined with spin-assisted layer-by-layer (LbL) assembly. Submicrometric thickness of films ensures tissue adhesion. Basic laser-induced heating functionality has been demonstrated by in vitro TNF-mediated thermal ablation of human neuroblastoma cancer cells, evidenced by irreversible damage to cell membranes and nuclei. Ex vivo localized vaporization and carbonization of animal muscular tissue is also demonstrated by applying TNF onto tissue surface. Thermal distribution in the tissue reaches a steady state in a few seconds, with significant increases in temperature (DeltaT > 50) occurring across an 1 mm span, ensuring control of local photothermalization and providing more safety and predictability with respect to traditional laser surgery. A steady-state model of tissue thermalization mediated by TNFs is also introduced, predicting the temperature distribution being known the absorbance of TNFs, the laser power, and the tissue thermal conductivity, thus providing useful guidelines in the development of TNFs. Thermonanofilms can find applications for local photothermal treatment of cancerous lesions and wherever high precision and control of heat treatment is required. PMID- 24797874 TI - Multigeneration reproduction and male developmental toxicity studies on atrazine in rats. AB - BACKGROUND: Reproductive toxicity of Atrazine (ATR) was evaluated in two rat multigenerational studies. Development of male reproductive parameters was evaluated in separate studies after prenatal or postnatal exposure. METHODS: In multigenerational studies, rats received dietary concentrations of 0, 10, 50, 100 or 500 ppm ATR. In separate studies in female rats, ATR was administered by gavage at 0, 1, 5, 25 or 125 mg/kg/day during pregnancy (GD6-21) or lactation (LD2-21). Plasma testosterone concentration, testicular and epididymal weights, and sperm counts were measured in male offspring on PND70 and 170. RESULTS: In the multigenerational studies, parental systemic toxicity occurred at 500 ppm (38.7 mg/kg/day), but reproductive endpoints were unaffected. In the prenatal study, maternal toxicity and embryo-fetal mortality occurred at 125 mg/kg/day. In male offspring, testosterone levels and sperm counts were unaffected, although the percentage of abnormal sperm increased at 125 mg/kg/day (PND 70) and 25 mg/kg/day (PND170). In the postnatal study, maternal toxicity and reduced body weights of male offspring occurred at 125 mg/kg/day. Additionally, reduced testicular (PND70, PND170) and epididymal (PND70) weights and increased numbers of abnormal sperm (PND70, PND170) were seen, but no changes in plasma testosterone or sperm counts. CONCLUSIONS: Dietary administration of ATR did not affect rat reproduction up to a parentally toxic dose of 38.7 mg/kg/day. Some effects on male reproductive system development occurred after high dose, bolus administration to dams, but doses were much higher than expected under normal use conditions. Thus, oral RfDs for ATR would be protective for reproductive effects. PMID- 24797876 TI - Efficient ibuprofen delivery from anhydrous semisolid formulation based on a novel cross-linked silicone polymer network: an in vitro and in vivo study. AB - The use of silicone as a primary polymer in topical semisolid pharmaceutical formulations is infrequent. Recent development of novel silicone materials provides an opportunity to investigate their drug delivery efficiencies. In this study, an anhydrous semisolid formulation was prepared using a novel cross-linked silicone polymer network swollen in isododecane. Similar formulations were prepared using petrolatum, an acrylic, or a cellulose polymer. All formulations contained 5% ibuprofen (IBP). In vitro permeability was evaluated for all formulations and a commercial product using human cadaver epidermis. The silicone formulation delivered IBP more efficiently than all other formulations in terms of flux, cumulative amount, and percent drug release. The silicone formulation showed the maximum flux of 85.9 MUg . cm(-2) . h(-1) and a cumulative IBP release of 261.6 MUg in 8 h, whereas the benchmark showed 20.1 MUg . cm(-2) . h(-1) and 30.9 MUg, respectively. An in vivo study conducted on rats showed calculated blood AUCs of 59.2 and 17.6 MUg . h/g (p < 0.003) for the silicone formulation and the benchmark, respectively. The IBP in excised rat skin was 264 +/- 59 MUg/g for the silicone formulation and 102 +/- 5 MUg/g for the benchmark. The results obtained from the in vitro and in vivo studies demonstrate efficient topical IBP delivery by the silicone formulation. PMID- 24797877 TI - Hepatitis B virus preS1-derived lipopeptide functionalized liposomes for targeting of hepatic cells. AB - To enhance the liver-specific delivery, HBVpreS/2-48(myr) (HBVP), a synthetic HBVpreS-derived lipopeptide endowed with compelling liver tropism, was conjugated to PEGylated liposomes (HBVP-Lip) for hepatic cell-specific delivery. Compared with the non-targeted liposomes, a significantly higher amount of HBVP-Lip were taken up by the primary mice hepatocytes through a receptor-mediated endocytosis mechanism. The endocytosis inhibition assay demonstrated that the endocytosis of HBVP-Lip was mediated mainly by caveolin and clathrin. After systemic administration in mice, HBVP-Lip could be specifically internalized into hepatocytes efficaciously. Furthermore, the hepatoprotective effects of HBVP-Lip loaded with silybin (SLB) on carbon tetrachloride induced acute liver damage were remarkably stronger than the SLB solution and SLB loaded non-targeted liposomes. Preliminary safety results suggested that no acute systemic toxicity or immunotoxicity was observed after intravenous administration with HBVP-Lip. These results indicated that the HBVP-Lip could deliver the payloads to the hepatocytes with high specificity in vitro and in vivo, and raise new possibilities for liver specific drug delivery systems, gene delivery systems, and bio-imaging systems. PMID- 24797879 TI - Quasi-spherical microwells on superhydrophobic substrates for long term culture of multicellular spheroids and high throughput assays. AB - Multicellular tumour spheroids closely recapitulate the physiological environment of tumour tissues. However, their implementation in drug screening assays remains limited due to the technological challenges of forming large numbers of high quality spheroids in platforms compatible with high throughput screening. A simple bench-top microfabrication strategy is demonstrated here based on the principle of ice lithography carried out on superhydrophobic substrates to fabricate quasi-spherical microwells (spheriwells). The microwells shapes and dimensions are directly controlled by the hydrophobicity of the substrate and the volume of the water droplets. The prepared concave microwells enable the formation of dense and homogeneous multicellular tumour spheroids. Spheroids formed within spheriwells are trapped within the microwells, which eliminate loss during media manipulation and facilitate long-term on-chip culture. Morphological and phenotypical changes associated with the growth of MCF-7 adenocarcinoma cells in spheriwells were characterised using imaging flow cytometry and revealed the appearance of heterogeneous populations with loss of E-Cadherin expression. The compatibility of the spheriwells with an on-chip MTT assay is demonstrated. The very unusual shape of the spheriwells, prepared using materials and methods routinely used in most research laboratories, provides a straightforward and scalable platform to prepare high quality multicellular tumour spheroids compatible with high throughput biological screening assays. PMID- 24797880 TI - Multifunctional mesoporous nanoparticles as pH-responsive Fe(2+) reservoirs and artemisinin vehicles for synergistic inhibition of tumor growth. AB - Artemisinin (ART) is an iron-dependent anti-cancer drug. However, simultaneous delivery of hydrophobic ART and Fe(2+) ions into cancer cells remains a major challenge. Herein, we reported Fe3O4@C/Ag@mSiO2 (FCA@mSiO2) multifunctional nanocarriers which can load ART as high as 484 mg/g. Moreover, FCA@mSiO2 nanoparticles demonstrated pH-responsive Fe(2+) release, the concentration of Fe(2+) ions can reach 2.765 nmol/L in HeLa cells cultured with FCA@mSiO2 nanoparticles. The antitumor efficacy of ART-loaded FCA@mSiO2 nanoparticles measured by MTT assay was significantly enhanced compared with free ART. It was suggested that the ART-loaded FCA@mSiO2 nanoparticles are internalized by HeLa cells and located at the acidic compartments of endosomes and lysosomes, releasing Fe(2+) ions to non-enzymatically convert ART to toxic products for killing cancer cells. This result provides a way for using promising natural drugs in anti-cancer therapeutics. PMID- 24797878 TI - Multifunctional polymersomes for cytosolic delivery of gemcitabine and doxorubicin to cancer cells. AB - Although liposomes are widely used as carriers of drugs and imaging agents, they suffer from a lack of stability and the slow release of the encapsulated contents at the targeted site. Polymersomes (vesicles of amphiphilic polymers) are considerably more stable compared to liposomes; however, they also demonstrate a slow release for the encapsulated contents, limiting their efficacy as a drug delivery tool. As a solution, we prepared and characterized echogenic polymersomes, which are programmed to release the encapsulated drugs rapidly when incubated with cytosolic concentrations of glutathione. These vesicles encapsulated air bubbles inside and efficiently reflected diagnostic-frequency ultrasound. Folate-targeted polymersomes showed an enhanced uptake by breast and pancreatic-cancer cells in a monolayer as well as in three-dimensional spheroid cultures. Polymersomes encapsulated with the anticancer drugs gemcitabine and doxorubicin showed significant cytotoxicity to these cells. With further improvements, these vesicles hold the promise to serve as multifunctional nanocarriers, offering a triggered release as well as diagnostic ultrasound imaging. PMID- 24797881 TI - The effect of lipocisplatin on cisplatin efficacy and nephrotoxicity in malignant breast cancer treatment. AB - A lipid-cisplatin conjugate was synthesized for super-molecular assembly with lipids to form a new generation of liposomal cisplatin formulation, lipocisplatin. In vitro, lipocisplatin has higher efficacy in human ovarian cancer A2780 and human breast cancer MCF-7 with the murine breast cancer cell line 4T1 which is currently an established model for stage IV breast cancer as the most sensitive strain. Moreover, lipocisplatin demonstrated a greater MTD value and relatively longer blood circulation as compared to cisplatin. Lipocisplatin preferentially accumulate drugs to the tumor site, resulting in a better tumor inhibition efficacy. Moreover, lipocisplatin exceeds the size cutoff for kidney clearance, hence it bypasses the nephrotoxicity of cisplatin which is a major curse of one of the most efficient anticancer drugs nowadays in clinic. The results here indicated lipocisplatin may be translated into a new generation of liposomal based cisplatin drug in clinic. PMID- 24797882 TI - SiRNA-phospholipid conjugates for gene and drug delivery in cancer treatment. AB - Due to low charge density and stiff backbone structure, small interfering RNA (siRNA) has inherently poor binding ability to cationic polymers and lipid carriers, which results in low siRNA loading efficiency and limits siRNA success in clinical application. Here, siRNA-phospholipids conjugates are developed, which integrate the characteristics of the two phospholipids to self-assemble via hydrophilic siRNA and hydrophobic phospholipid tails to overcome the siRNA's stiff backbone structures and enhance the siRNA loading efficiency. In this study, the thiol-modified sense and antisense siRNA are chemically conjugated with phospholipids to form sense and antisense siRNA-phospholipid, and then these sense or antisense siRNA-phospholipids with equal amounts are annealed to generate siRNA-phospholipids. The siRNA-phospholipids can serve dual functions as agents that can silence gene expression and as a component of nanoparticles to embed hydrophobic anticancer drugs to cure tumor. siRNA-phospholipids together with cationic lipids and DSPE-PEG2000 fuse around PLGA to form siRNA phospholipids enveloped nanoparticles (siRNA-PCNPs), which can deliver siRNAs and hydrophobic anticancer drugs into tumor. In animal models, intravenously injected siRNA-PCNPs embedded DOX (siPlk1-PCNPs/DOX) is highly effective in inhibiting tumor growth. The results indicate that the siRNA-PCNPs can be potentially applied as a safe and efficient gene and anticancer drug delivery carrier. PMID- 24797883 TI - Co-delivery of doxorubicin and RNA using pH-sensitive poly (beta-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer. AB - An appropriate co-delivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of breast cancer by reversing multidrug resistance (MDR). In this work, a new amphiphilic poly (beta-amino ester), poly[(1,4-butanediol)-diacrylate-beta-5-polyethylenimine] block-poly[(1,4-butanediol)-diacrylate-beta-5-hydroxy amylamine] (PDP-PDHA) was synthesized, and the doxorubicin (DOX) and survivin-targeting shRNA (shSur) co loading nanoparticle (PDNs) were prepared. The pH-sensitive poly[(1,4-butanediol) diacrylate-beta-5-hydroxy amylamine] (PDHA) endowed PDNs both pH-triggered drug release characteristics and enhanced endo/lysosomal escape ability, thus improving the cytotoxicity of DOX and the transfection efficiency. PDNs also increased the DOX accumulation, down-regulated 57.7% survivin expression, induced 80.8% cell apoptosis and changed the cell cycle in MCF-7/ADR cells. In the MCF 7/ADR tumor-bearing mice models, after administrated intravenously, PDNs raised the accumulation of DOX and shSur in the tumor tissue by 10.4 and 20.2 folds, respectively, resulting in obvious inhibition of the tumor growth with tumor inhibiting rate of 95.9%. The combination of DOX and RNA interference showed synergistic effect on overcoming MDR. Therefore, PDNs could be a promising co delivery vector for effective therapy of drug resistant breast cancer. PMID- 24797885 TI - Proton therapy in adjuvant treatment of gastric cancer: planning comparison with advanced x-ray therapy and feasibility report. AB - BACKGROUND: Adjuvant chemoradiotherapy improves both overall- and relapse-free survival in patients with resected gastric cancer. However, this comes at the cost of increased treatment-related toxicity. Proton therapy (PT) has distinct dosimetric characteristics that may reduce dose to normal tissues, improving the therapeutic ratio. The purpose of this treatment planning study is to compare PT and intensity-modulated x-ray therapy (IMXT) in gastric cancer with regards to normal tissue sparing. MATERIAL AND METHODS: The patient population consisted of resected gastric cancer patients treated at a single institution between 2008 and 2013. Patients who had undergone 4D CT simulation were replanned to the originally delivered doses (45-54 Gy in 25-30 daily fractions) using six-field photon IMXT and 2-3-field PT (double scattering-uniform scanning techniques). RESULTS: Thirteen patients were eligible for the planning comparison. IMXT provided slightly higher homogeneity indices (median values 0.04 +/- 0.01 vs. 0.07 +/- 0.01, p = 0.03). PT resulted in significantly (p < 0.05) lower intermediate-low doses for all the normal tissues examined (small bowel V15 82 ml vs. 133 ml, liver mean doses Gy 11.9 vs. 14.4 Gy, left/right kidney mean doses 5/0.9 Gy vs. 7.8/3.1 Gy, heart mean doses 7.4 Gy vs. 9.5 Gy). The total energy deposited outside the target volume was significantly lower with PT (median integral dose 90.1 J vs. 129 J). Four patients were treated with PT: treatment was feasible and verifications scans showed that target coverage was robust. CONCLUSION: PT can contribute to normal tissue sparing in the adjuvant treatment of gastric cancer, with a potential benefit in terms of compliance to treatment, acute and late toxicities. PMID- 24797884 TI - Adherence to dual antiplatelet therapy after coronary stenting: a systematic review. AB - BACKGROUND: Adherence to dual antiplatelet therapy (DAPT) is critical after coronary stenting. Although adherence rates are frequently assessed in clinical trials, adherence rates in the unselected population recommended for treatment but beyond clinical trials are largely unknown. Therefore, we performed a systematic review of published observational studies to describe rates of DAPT adherence, trends in DAPT use over time, and patient-level factors associated with nonadherence. HYPOTHESIS: DAPT adherence declines with increasing time after drug-eluting stent implantation. METHODS: PubMed, Cumulative Index to Nursing and Allied Health Literature, Embase, and Web of Knowledge were searched through November 20, 2012 for studies including patients receiving 1 or more drug-eluting stents and reporting the use of aspirin and/or thienopyridines, or assessing factors associated with nonadherence to DAPT after bare metal or drug-eluting stent placement. RESULTS: We included 34 studies in the description of DAPT adherence and 11 studies in the description of factors associated with nonadherence. Adherence to DAPT and thienopyridines was high at 1 month but declined by 12 months. Aspirin adherence was at least 90% throughout. Factors associated with nonadherence included bleeding, lower education level, immigrant status, and lack of education regarding DAPT. CONCLUSIONS: DAPT adherence is suboptimal at 12 months, and interventions to increase adherence should focus on reducing bleeding risk and improving communication between patients and physicians. PMID- 24797886 TI - Small sample GEE estimation of regression parameters for longitudinal data. AB - Longitudinal (clustered) response data arise in many bio-statistical applications which, in general, cannot be assumed to be independent. Generalized estimating equation (GEE) is a widely used method to estimate marginal regression parameters for correlated responses. The advantage of the GEE is that the estimates of the regression parameters are asymptotically unbiased even if the correlation structure is misspecified, although their small sample properties are not known. In this paper, two bias adjusted GEE estimators of the regression parameters in longitudinal data are obtained when the number of subjects is small. One is based on a bias correction, and the other is based on a bias reduction. Simulations show that the performances of both the bias-corrected methods are similar in terms of bias, efficiency, coverage probability, average coverage length, impact of misspecification of correlation structure, and impact of cluster size on bias correction. Both these methods show superior properties over the GEE estimates for small samples. Further, analysis of data involving a small number of subjects also shows improvement in bias, MSE, standard error, and length of the confidence interval of the estimates by the two bias adjusted methods over the GEE estimates. For small to moderate sample sizes (N <=50), either of the bias corrected methods GEEBc and GEEBr can be used. However, the method GEEBc should be preferred over GEEBr, as the former is computationally easier. For large sample sizes, the GEE method can be used. PMID- 24797888 TI - Reply: bilateral pallidal stimulation for Wilson's disease. PMID- 24797889 TI - Novel shikonin derivatives targeting tubulin as anticancer agents. AB - In this study, we report the identification of a new shikonin-phenoxyacetic acid derivative, as an inhibitor of tubulin. A series of compounds were prepared; among them, compound 16 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2 yl)-4-methylpent-3-enyl 2-(4- phenoxyphenyl) acetate] potently inhibited the function of microtubules, inducing cell growth inhibition, apoptosis of cancer cell lines in a concentration and time-dependent manner. Molecular docking involving 16 at the vinblastine binding site of tubulin indicated that a phenoxy moiety interacted with tubulin via hydrogen bonding with asparaginate (Asn) and tyrosine (Tyr). Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density. Cell cycle assay further proved that HepG2 cells were blocked in G2/M phase. Our study provides a new, promising compound for the development of tubulin inhibitors by proposing a new target for the anticancer activity of shikonin. PMID- 24797890 TI - Deciphering ADME genetic data using an automated haplotype approach. AB - OBJECTIVE: To investigate the utility of statistical tools in translating Affymetrix Drug Metabolizing Enzyme and Transporter (DMET) Assay single nucleotide polymorphisms (SNPs) into common consensus star alleles. METHODS: DMET SNP data from clinical trials in different ethnicities were pooled for analyses. Three different statistical methods, PHASE, Bayesian, and expectation maximization (EM), were first assessed by comparing the consistency of calling CYP2D6 alleles among 1108 Asians and 55 Caucasians. Subsequently, the performance of EM in deriving haplotype calls was evaluated against the Affymetrix Translation Table for CYPs 2B6, 2C19, 2C9, and 3A4/5 in 582 Asians, 296 Caucasians, and 369 Africans. Selected DNA samples were sequenced to verify the EM-predicted haplotype calls. RESULTS: PHASE, Bayesian, and EM methods showed a similar CYP2D6 star allele call rate. The EM method, with a 0.99 posterior probability cutoff, was chosen for further evaluation because of its low false positive call rate. Haplotype calls obtained with the EM method were consistent with the Affymetrix Translation Table more than 95% of the time for all five CYPs, except for the CYP2B6 calls in the African descents (83%). In addition, the EM method was superior to the Translation Table-only approach in resolving complex haplotype patterns, identifying novel haplotypes in CYP2B6 and CYP3A5, and determining genotype calls in the presence of missing SNP data. CONCLUSION: A statistical method such as EM could be used to augment the translation of DMET assay SNP data into star alleles, especially for complex genes, to facilitate full utilization and interpretation of clinical pharmacogenetics data. PMID- 24797891 TI - Psychiatric pathology and suicide risk in patients with cancer. AB - The aims of the study were to assess sociodemographic and clinical factors associated with suicidal ideation in patients with cancer who required a psycho oncological support. Among 504 participants, there were 136 (23 men and 113 women) cancer patients who completed psychological assessment when admitted to the Psycho-oncology Outpatient Clinic between 2006 and 2011. Suicidal ideation was assessed by Item 9 of the Brief Symptom Inventory, Hopelessness was assessed by the hopelessness subscale of the Mini-Mental Adjustment to Cancer Scale, and Depression was assessed by the depression subscale of the Hospital and Anxiety Depression Scale. Around 30% of this sample reported affective symptoms and around 20% reported suicidal ideation and hopelessness. Patients who reported suicidal ideation were more hopeless (18.8 +/- 6.7 vs. 15.7 +/- 5.2; t(134) = 2.54; p < 0.05) and reported more depression (11.8 +/- 4.8 vs. 6.8 +/- 4.1; t(134) = 5.30; p < 0.001). It is evident that cancer can result in a strong psychological distress in the patient. It is important, therefore, that cancer patients receive a proper assistance and psychological support and that both the possible presence of depression and suicidal ideation are constantly monitored. PMID- 24797892 TI - Haematological cancer: Down syndrome links to cancer. PMID- 24797893 TI - Effects of ligands for Toll-like receptors 3, 4, and 21 as adjuvants on the immunogenicity of an avian influenza vaccine in chickens. AB - Avian influenza viruses (AIV) are of great concern to the worldwide community as well as the poultry industry. Although existing vaccines are successful in limiting the spread of the virus, these vaccines do not eliminate virus shedding into the environment. As a result, it is of great importance to enhance the efficacy of existing AIV vaccines. Therefore, the objective of the present study was to utilize the immunostimulatory Toll-like receptor ligands poly I:C, lipopolysaccharide (LPS), and CpG DNA motifs, either alone or in combination with each other, as adjuvants to enhance the immunogenicity of an inactivated AIV vaccine. Chickens were vaccinated twice, 14 days apart. Antibody-mediated responses were assessed by collected sera and lacrimal secretions, while cell mediated immunity was assessed by stimulating splenocytes from vaccinated chickens in vitro with the vaccine antigen. The results suggest that CpG alone served as the best single-ligand adjuvant compared to poly I:C or LPS, as it significantly enhanced antibody-mediated responses, as determined by enzyme linked immunosorbant assay. Furthermore, upon combining CpG with poly I:C, a robust antibody-mediated and cell-mediated immune response was elicited, resulting in an enhanced hemagglutination inhibition titer and splenocyte proliferation respectively. Future studies may be aimed at assessing the efficacy of the poly I:C and CpG combination adjuvant in protecting against AIV infection. PMID- 24797894 TI - Adoptive transfer of regulatory T cells promotes intestinal tumorigenesis and is associated with decreased NK cells and IL-22 binding protein. AB - High number of regulatory T cells (Tregs), both circulating and at the tumor site, often indicates a poor prognosis in CRC patient's possibly impairing natural killer (NK) cell function. To determine the role of Tregs in CRC development and their effects on NK cells, we created novel transgenic Rag-Apc mice that lack T cells and develop spontaneous intestinal tumors, and we adoptively transferred Tregs or transiently depleted NK cells during initial stages of tumorigenesis. In 6-weeks old Rag-Apc mice containing microscopic intestinal tumors adoptive transfer of Tregs or transient NK cell depletion dramatically associated with an increase in intestinal tumor multiplicity and tumor size, with significantly decreased survival rates. Importantly, Treg transfer increased small intestinal polyp formation up to 65% (P < 0.0005) and increased colon tumors multiplicities by 84% (P < 0.0001) with a significant decrease in NK cells as compared to control mice. Similarly, in NK depleted mice, colon tumor multiplicities increased up to 40% and small intestinal polyp formation up to 60% (P < 0.0001). Treg transfer or NK cell transient depletion markedly increased interleukin (IL)-22 systemically and the inflammatory signaling molecules P2X7R, and STAT3 in the tumors; and impaired production of the tumor suppressor interferon (IFN)-gamma systemically. Notably, IL-22 binding protein (IL-22 BP) was associated with NKs and a significant decrease was seen at the tumor site in mice adoptively transferred with Tregs or depleted of NK cells. Our results suggest that adoptive transfer of Tregs aggressively promote intestinal tumorigenesis by decreasing NK cell number and activity by modulating IL-22 BP. PMID- 24797895 TI - Prevalence and risk factors for stunting and severe stunting among children under three years old in mid-western rural areas of China. AB - BACKGROUND: Adequate nutrition is needed to ensure optimum growth and development of infants and young children. Although the national economy has developed rapidly during recent decades in China, malnutrition continues to be a major public health problem. The aim of the present study was undertaken to assess the prevalence and risk factors associated with stunting and severe stunting under 3 years old in mid-western rural areas in China. METHODS: A community-based cross sectional survey was carried out in 84 villages in mid-western provinces of China in 2010. A total of 1260 children were selected for nutritional assessment in terms of stunting and severe stunting using the new World Health Organization growth standards. Hierarchical logistic regression was used to examine the risk factors for adverse nutritional status. RESULTS: The prevalence of stunting and severe stunting was 27.0% and 13.2% respectively. Hierarchical logistic regression analysis showed that the risk factors for stunted children were province of residence, caregiver's education, child's gender, low birthweight and duration of exclusive breastfeeding (<6 months). The risk factors for severe stunting in children aged 0-36 months were province of residence, caregiver's education and child's gender. CONCLUSIONS: These results indicate that malnutrition is still a major public health problem among children under 3 years old. The government should implement appropriate nutritional intervention strategies to help reduce the prevalence of malnutrition in children. PMID- 24797896 TI - Anti-neoplastic properties of hydralazine in prostate cancer. AB - Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool. PMID- 24797897 TI - Ramucirumab in metastatic renal cell carcinoma: the sex, race, and age issues. PMID- 24797898 TI - Abstract Annual Meeting BVN-SBN, April 25th 2013, Musee de la Medecine, Brussels, Belgium. PMID- 24797899 TI - A comparison of medication adherence/persistence for asthma and chronic obstructive pulmonary disease in the United Kingdom. AB - AIM: To describe and compare adherence and persistence with maintenance therapies in patients with asthma or chronic obstructive pulmonary disease (COPD) in the United Kingdom (UK). METHODS: A retrospective prescribing database cohort was obtained from 44 general practitioner surgeries in National Health Service Forth Valley Scotland. Patients with physician-diagnosed asthma or COPD who received maintenance therapy between January 2008 and December 2009 were included. Five classes of therapy were assessed: inhaled corticosteroids, long-acting beta agonists, combination therapy inhalers, theophyllines and long-acting muscarinic antagonists. Adherence was calculated using the medication possession ratio (MPR) and persistence was determined using Kaplan-Meier survival analysis for the time to discontinuation (TTD) over 1 year. Two step-wise logistic regressions were performed to assess the contribution of diagnosis to adherence/persistence. RESULTS: A total of 13,322 patients were included in the analysis: 10,521 patients with asthma and 2801 patients with COPD. 25.2% of medication episodes for asthma and 45.6% of medication episodes for COPD were classified as having an adequate medication supply (MPR of 80-120%). The overall median TTD was 92 days (IQR, interquartile range: 50-186 days) for patients with asthma and 116 days (IQR: 58-259 days, comparison p < 0.001) for patients with COPD. Patients with COPD were found to be more likely to achieve an MPR of at least 80% (OR: 1.27, 95% CI: 1.15-1.40), but had a similar likelihood of persistence at 1 year to patients with asthma. CONCLUSION: Adherence and persistence with respiratory therapies in the UK is relatively low. There is suggestion that patients with COPD may display more adherent behaviours than patients with asthma. PMID- 24797901 TI - Cellularized biosynthetic microhydrogel polymers for intravascular liver tissue regeneration therapy. AB - INTRODUCTION: The liver is the natural microenvironment for hepatocytes transplantation but unfortunately engraftment efficiency is low. Cell-laden microhydrogels made of fibrinogen attached to poly(ethylene glycol) (PEG) diacrylate side chains, were used as a cell carrier, for intravascular transplantation. This approach may reduce shear stress and immediate immunological pressure after intravascular transplantation and provide biomatrix for environmental support. AIMS: In vitro assessment of HuH-7 viability and function after polymerization within PEGylated fibrinogen-hydrogel. In vivo assessment of intraportal transplantation of cell-laden microhydrogels with rat adult parenchymal cells. METHODS: (1) In vitro assessment of HuH-7 cell viability and function, after cell-laden hydrogel (hydrogel volume 30 MUL) fabrication, by propidium iodide (PI)/fluorescein diacetate (FDA), and MTT assays, albumin concentration and CYP1A activity. (2) Fabrication of cell-laden microhydrogels and their intraportal transplantion. Engraftment efficiency in vivo was evaluated by real-time qPCR of Y chromosome (SRY gene) and histology. RESULTS: The viability of cells in hydrogels in culture was comparable to viability of not embedded cells during the first 48 h. However, the viability of cells in hydrogels was reduced after 72 h compared with not embedded cells. Activity of CYP1A in hydrogel was comparable to that of not embedded cells (4.33+/-1 pmole/MUg DNA/4 h vs. 5.13+/-1 pmole/MUg DNA/4 h, respectively). Albumin concentration increased at day 3 in hydrogels to 1.4+/-0.6 MUg/10(4)/24 h and was greater to that of free cells, 0.3+/-0.1 MUg/10(4)/24 h. Cell-laden microhydrogels at a size of 150-150-600 MUm (6*10(6) cells/rat) showed better engraftment efficiency at 21 days post-transplantation, compared with isolated cell transplantation (54.6%+/-5% vs. 1.8%+/-1.2%, p<0.001). CONCLUSIONS: The in vitro HuH-7 viability and function after polymerization in PEGylated fibrinogen hydrogel was comparable to cells without the hydrogel. Long-term survival and engraftment efficiency of intravascular transplanted adult hepatocytes is much better in within cell-laden microhydrogels compared with isolated cells. The overall efficiency of the procedure needs to be improved. PMID- 24797902 TI - Structural and functional similarity of amphibian constitutive androstane receptor with mammalian pregnane X receptor. AB - The nuclear receptors and xenosensors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) induce the expression of xenobiotic metabolizing enzymes and transporters, which also affects various endobiotics. While human and mouse CAR feature a high basal activity and low induction upon ligand exposure, we recently identified two constitutive androstane receptors in Xenopus laevis (xlCARa and a) that possess PXR-like characteristics such as low basal activity and activation in response to structurally diverse compounds. Using a set of complementary computational and biochemical approaches we provide evidence for xlCARa being the structural and functional counterpart of mammalian PXR. A three-dimensional model of the xlCARa ligand-binding domain (LBD) reveals a human PXR-like L-shaped ligand binding pocket with a larger volume than the binding pockets in human and murine CAR. The shape and amino acid composition of the ligand-binding pocket of xlCAR suggests PXR-like binding of chemically diverse ligands which was confirmed by biochemical methods. Similarly to PXR, xlCARa possesses a flexible helix 11'. Modest increase in the recruitment of coactivator PGC-1a may contribute to the enhanced basal activity of three gain-of function xlCARa mutants humanizing key LBD amino acid residues. xlCARa and PXR appear to constitute an example of convergent evolution. PMID- 24797904 TI - Occurrence and carcinogenic potential of airborne polycyclic aromatic hydrocarbons in some large-scale enclosed/semi-enclosed vehicle parking areas. AB - Polycyclic aromatic hydrocarbons (PAHs) originating from vehicle exhaust have aroused much attention due to their potential healthy effect. In this study, air samples were collected from three representative parking lots in a metropolitan area, analyzed for PAHs and evaluated for inhalation risk. Atmospheric PAH levels of these parking areas ranged between 1,178-4,793 ng m(-3), one order of magnitude higher than general urban areas. Their benzo[a]pyrene equivalent (BaPeq) values varied in 11.0-98.0 ng m(-3), far exceeding the air quality standard of WHO (1.0 ng m(-3)). Monte Carlo simulation (100,000 trials) results suggest that the potential lifetime inhalation cancer risks of PAHs were 0.27 * 10(-5) to 7.11 * 10(-5) for park employees, which are in the acceptable range acknowledged by US EPA (1.0 * 10(-6) to 1.0 * 10(-4)). Several source diagnostic methods proved that vehicle exhaust was the dominant PAH contributor of these parks with the contribution percentages being >53%; oil combustion and/or coal combustion were other important sources. Logarithms of gas-particle distribution coefficients (Kps) of PAHs in all studied parks were linearly correlated with those of both their sub-cooled vapor pressures (pLs) and octanol-air partition coefficients (KOAs). The correlation coefficients indicated that both adsorption onto black carbon and absorption into organic matter were involved in the partition process, but the latter was dominant. PMID- 24797903 TI - Mammalian TBX1 preferentially binds and regulates downstream targets via a tandem T-site repeat. AB - Haploinsufficiency or mutation of TBX1 is largely responsible for the etiology of physical malformations in individuals with velo-cardio-facial/DiGeorge syndrome (VCFS/DGS/22q11.2 deletion syndrome). TBX1 encodes a transcription factor protein that contains an evolutionarily conserved DNA binding domain termed the T-box that is shared with other family members. All T-box proteins, examined so far, bind to similar but not identical consensus DNA sequences, indicating that they have specific binding preferences. To identify the TBX1 specific consensus sequence, Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was performed. In contrast to other TBX family members recognizing palindrome sequences, we found that TBX1 preferentially binds to a tandem repeat of 5' AGGTGTGAAGGTGTGA-3'. We also identified a second consensus sequence comprised of a tandem repeat with a degenerated downstream site. We show that three known human disease-causing TBX1 missense mutations (F148Y, H194Q and G310S) do not alter nuclear localization, or disrupt binding to the tandem repeat consensus sequences, but they reduce transcriptional activity in cell culture reporter assays. To identify Tbx1-downstream genes, we performed an in silico genome wide analysis of potential cis-acting elements in DNA and found strong enrichment of genes required for developmental processes and transcriptional regulation. We found that TBX1 binds to 19 different loci in vitro, which may correspond to putative cis-acting binding sites. In situ hybridization coupled with luciferase gene reporter assays on three gene loci, Fgf8, Bmper, Otog-MyoD, show that these motifs are directly regulated by TBX1 in vitro. Collectively, the present studies establish new insights into molecular aspects of TBX1 binding to DNA. This work lays the groundwork for future in vivo studies, including chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) to further elucidate the molecular pathogenesis of VCFS/DGS. PMID- 24797905 TI - Minimum ignition energy of nano and micro Ti powder in the presence of inert nano TiO2 powder. AB - The inerting effect of nano-sized TiO2 powder on ignition sensitivity of nano and micro Ti powders was investigated with a Mike 3 apparatus. "A little is not good enough" is also suitable for micro Ti powders mixed with nano-sized solid inertants. MIE of the mixtures did not significantly increase until the TiO2 percentage exceeded 50%. Nano-sized TiO2 powders were ineffective as an inertant when mixed with nano Ti powders, especially at higher dust loadings. Even with 90% nano TiO2 powder, mixtures still showed high ignition sensitivity because the statistic energy was as low as 2.1 mJ. Layer fires induced by ignited but unburned metal particles may occur for micro Ti powders mixed with nano TiO2 powders following a low level dust explosion. Such layer fires could lead to a violent dust explosion after a second dispersion. Thus, additional attention is needed to prevent metallic layer fires even where electric spark potential is low. In the case of nano Ti powder, no layer fires were observed because of less flammable material involved in the mixtures investigated, and faster flame propagation in nanoparticle clouds. PMID- 24797906 TI - Toxicity screening of soils from different mine areas--a contribution to track the sensitivity and variability of Arthrobacter globiformis assay. AB - This study used the Arthrobacter globiformis solid-contact test for assessing the quality of soils collected in areas subjected to past and present mine activities in Europe (uranium mine, Portugal) and North Africa (phosphogypsum pile, Tunisia; iron mine, Morocco). As to discriminate the influence of soils natural variability from the effect of contaminants, toxicity thresholds were derived for this test, based on the dataset of each study area. Furthermore, the test sensitivity and variability was also evaluated. As a result, soils that inhibited A. globiformis dehydrogenase activity above 45% or 50% relatively to the control, were considered to be toxic. Despite the soil metal content determined, the properties of soils seemed to influence dehydrogenase activity. Overall, the contact test provided a coherent outcome comparing to other more time-consuming and effort-demanding ecotoxicological assays. Our results strengthened the feasibility and ecological relevance of this assay, which variability was quite reduced hence suggesting its potential integration within the test battery of tier 1 of soil risk assessment schemes. PMID- 24797907 TI - Emission reduction of NOx, PM, PM-carbon, and PAHs from a generator fuelled by biodieselhols. AB - This investigation examines the particulate matter (PM), particulate carbon, polycyclic aromatic hydrocarbons (PAHs), and nitrogen oxides (NOx) emitted from a generator fueled by petroleum diesel blended with waste-edible-oil-biodiesel and water-containing acetone. Experimental results show that using biodieselhols with water-containing (or pure) acetone as the fuel of generator, in comparison to using petroleum diesel, significantly reduces PM emission; roughly, this reduction increased as percentage of water-containing acetone increased. When the percentages of waste-edible-oil-biodiesel were <= 5 vol%, adding pure or water containing acetone (1-3 vol%) to biodieselhols generated emission reductions of NOx, PM, particle-bound organic carbon (OC), total-PAHs, and total-BaPeq. Consequently, using water-containing acetone biodieselhols as an alternative generator fuel is feasible and helps recycle and reuse waste solvents containing water-containing acetone. PMID- 24797908 TI - Characterization and genotoxicity evaluation of particulate matter collected from industrial atmosphere in Tamil Nadu state, India. AB - Ambient particulate matter (PM) collected in the vicinity of five industries (Cement, Chemical, Thermal power plant, Sponge-iron and Steel) in Tamil Nadu state, India was characterized for size distribution, metals and polycyclic aromatic hydrocarbons (PAHs) content. Genotoxicity of PM and organic matter (OM) extracted from PM was measured in human lung cancer cell-line, A549 and in human liver carcinoma cell-line, HepG2, respectively, using the comet assay. PM values varied from 57.0 MUg/m(3) of air at Cement industry upstream to 561.0 MUg/m(3) of air at Sponge iron industry downstream samples. Their metal content varied from 5.758 MUg/m(3) of air at Chemical industry to 46.144 MUg/m(3) of air at Sponge iron industry and PAH concentration varied from 0.5 ng/m(3) air in upstream Thermal power plant to 3302.4 ng/m(3) air in downstream Sponge iron industry samples. While all PM samples induced DNA strand breaks at higher dose levels, downstream samples of Steel and Sponge iron industries which contained relatively higher concentrations of PAHs and metals and exhibited higher levels of pro oxidant activity as measured by DTT activity induced significantly higher levels of DNA damage in HepG2 and A549 cells. Pretreatment of A549 cells with vitamin C or quercetin significantly reduced PM induced DNA strand breaks. PMID- 24797909 TI - Knockdown of LjALD1, AGD2-like defense response protein 1, influences plant growth and nodulation in Lotus japonicus. AB - The discovery of the enzyme L,L-diaminopimelate aminotransferase (LL-DAP-AT, EC 2.6.1.83) uncovered a unique step in the L-lysine biosynthesis pathway in plants. In Arabidopsis thaliana, LL-DAP-AT has been shown to play a key role in plant pathogen interactions by regulation of the salicylic acid (SA) signaling pathway. Here, a full-length cDNA of LL-DAP-AT named as LjALD1 from Lotus japonicus (Regel) Larsen was isolated. The deduced amino acid sequence shares 67% identity with the Arabidopsis aminotransferase AGD2-LIKE DEFENSE RESPONSE PROTEIN1 (AtALD1) and is predicted to contain the same key elements: a conserved aminotransferase domain and a pyridoxal-5'-phosphate cofactor binding site. Quantitative real-time PCR analysis showed that LjALD1 was expressed in all L. japonicus tissues tested, being strongest in nodules. Expression was induced in roots that had been infected with the symbiotic rhizobium Mesorhizobium loti or treated with SA agonist benzo-(1, 2, 3)-thiadiazole-7-carbothioic acid. LjALD1 Knockdown exhibited a lower SA content, an increased number of infection threads and nodules, and a slight reduction in nodule size. In addition, compared with wild-type, root growth was increased and shoot growth was suppressed in LjALD1 RNAi plant lines. These results indicate that LjALD1 may play important roles in plant development and nodulation via SA signaling in L. japonicus. PMID- 24797910 TI - Evidence for transmission of bluetongue virus serotype 26 through direct contact. AB - The aim of this study was to assess the mechanisms of transmission of bluetongue virus serotype 26 (BTV-26) in goats. A previous study, which investigated the pathogenicity and infection kinetics of BTV-26 in goats, unexpectedly revealed that one control goat may have been infected through a direct contact transmission route. To investigate the transmission mechanisms of BTV-26 in more detail an experimental infection study was carried out in which three goats were infected with BTV-26, three goats were kept uninfected, but were housed in direct contact with the infected goats, and an additional four goats were kept in indirect contact separated from infected goats by metal gates. This barrier allowed the goats to have occasional face-to-face contact in the same airspace, but feeding, watering, sampling and environmental cleaning was carried out separately. The three experimentally infected goats did not show clinical signs of BTV, however high levels of viral RNA were detected and virus was isolated from their blood. At 21 dpi viral RNA was detected in, and virus was isolated from the blood of the three direct contact goats, which also seroconverted. The four indirect barrier contact goats remained uninfected throughout the duration of the experiment. In order to assess replication in a laboratory model species of Culicoides biting midge, more than 300 Culicoides sonorensis were fed a BTV-26 spiked blood meal and incubated for 7 days. The dissemination of BTV-26 in individual C. sonorensis was inferred from the quantity of virus RNA and indicated that none of the insects processed at day 7 possessed transmissible infections. This study shows that BTV-26 is easily transmitted through direct contact transmission between goats, and the strain does not seem to replicate in C. sonorensis midges using standard incubation conditions. PMID- 24797912 TI - Technology and new fluorescence flow cytometry parameters in hematological analyzers. AB - BACKGROUND: Modern hematological analyzers offer a series of new tests in addition to the differential blood cell count. Here, we provide a short overview of the technique and the new tests included in the hematological analyzers manufactured by the company Sysmex (Kobe, Japan). As introduced here, the resulting new extended blood cell count allows for the quantification of DNA- and RNA-rich, activated and/or precursor leukocyte subpopulations. METHODS: To compare the different methods of blood cell counting, repetitive cell counting is carried out by hematological experts using microscopy and using the XE-5000 hematological analyzer. RESULTS: The hematological analyzer delivers more accurate results with respect to normal cells but microscopy is suited better to recognize and count pathological cells. CONCLUSION: With the new hematological analyzers, several new hematological tests are made available as screening tools that were not possible previously using standard cell-counting procedures. PMID- 24797911 TI - Epidemiology of acute respiratory infections in children in Guangzhou: a three year study. AB - Acute Respiratory Infections (ARI) are some of the most common human diseases worldwide. However, they have a complex and diverse etiology, and the characteristics of the pathogens involved in respiratory infections in developing countries are not well understood. In this work, we analyzed the characteristics of 17 common respiratory pathogens in children (<=14 years old) with ARI in Guangzhou, southern China over a 3-year period using real-time polymerase chain reaction. Pathogens were identified in 2361/4242 (55.7%) patients, and the positivity rate varied seasonally. Ten of the 17 pathogens investigated showed positivity rates of more than 5%. The most frequently detected pathogens were respiratory syncytial virus (768/2361, 32.5%), influenza A virus (428/2361, 18.1%), enterovirus (138/2361, 13.3%), Mycoplasma pneumoniae (267/2361, 11.3%) and adenovirus (213/2361, 9.0%). Co-pathogens were common and found in 503 of 2361 (21.3%) positive samples. When ranked according to frequency of occurrence, the pattern of co-pathogens was similar to that of the primary pathogens, with the exception of human bocavirus, human coronavirus and human metapneumovirus. Significant differences were found in age prevalence in 10 of the 17 pathogens (p<=0.009): four basic patterns were observed, A: detection rates increased with age, B: detection rates declined with age, C: the detection rate showed distinct peaks or D: numbers of patients were too low to detect a trend or showed no significant difference among age groups (p>0.05). These data will be useful for planning vaccine research and control strategies and for studies predicting pathogen prevalence. PMID- 24797913 TI - A subtle alternative splicing event gives rise to a widely expressed human RNase k isoform. AB - Subtle alternative splicing leads to the formation of RNA variants lacking or including a small number of nucleotides. To date, the impact of subtle alternative splicing phenomena on protein biosynthesis has been studied in frame preserving incidents. On the contrary, mRNA isoforms derived from frame-shifting events were poorly studied and generally characterized as non-coding. This work provides evidence for a frame-shifting subtle alternative splicing event which results in the production of a novel protein isoform. We applied a combined molecular approach for the cloning and expression analysis of a human RNase kappa transcript (RNase kappa-02) which lacks four consecutive bases compared to the previously isolated RNase kappa isoform. RNase kappa-02 mRNA is expressed in all human cell lines tested end encodes the synthesis of a 134-amino-acid protein by utilizing an alternative initiation codon. The expression of RNase kappa-02 in the cytoplasm of human cells was verified by Western blot and immunofluorescence analysis using a specific polyclonal antibody developed on the basis of the amino acid sequence difference between the two protein isoforms. The results presented here show that subtle changes during mRNA splicing can lead to the expression of significantly altered protein isoforms. PMID- 24797915 TI - Predictive validity and immune cell involvement in the pathogenesis of piroxicam accelerated colitis in interleukin-10 knockout mice. AB - Piroxicam administration is a method for induction of enterocolitis in interleukin-10 knockout (IL-10 k.o.) mice. The piroxicam-accelerated colitis (PAC) IL-10 k.o. model combines a dysregulated immune response against the gut microbiota with a decreased mucosal integrity. The predictive validity and pathogenic mechanisms of the model have not been thoroughly investigated. In this study, IL-10 k.o. mice received piroxicam in the chow, and model qualification was performed by examining the efficacy of prophylactic anti-IL-12/23p40 monoclonal antibody (mAb), anti-TNFalpha mAb, cyclosporine A (CsA) and oral prednisolone treatment. To evaluate cell involvement in the disease pathogenesis, specific cell subsets were depleted by treatment with anti-CD4 mAb, anti-CD8 mAb or clodronate-encapsulated liposomes. T cell receptor co-stimulation was blocked by CTLA4-Ig. Cytokine profiling ELISAs and calprotectin immunohistochemistry were performed on colon tissue. Treatments with anti-IL-12/23p40 mAb and CsA prevented disease in PAC IL-10 k.o. mice and reduced IFNgamma, IL-17A, MPO and calprotectin levels in colon. Anti-TNFalpha mAb treatment caused amelioration of selected clinical parameters. No effect of prednisolone was detected. Depletion of CD8(+) cells tended to increase mortality, whereas treatment with anti-CD4 mAb or CTLA4 Ig had no significant effect on disease development. Clodronate liposome treatment induced a loss of body weight; nevertheless macrophage depletion was associated with a significant reduction in colonic pathology. In conclusion, reference drugs with known efficacy in severe inflammatory bowel disease were efficacious in the PAC IL-10 k.o. model. Our data indicate that in this model macrophages are a main driver of colitis, whereas CD4(+) cells are not. PMID- 24797914 TI - Type IV pilus assembly proficiency and dynamics influence pilin subunit phospho form macro- and microheterogeneity in Neisseria gonorrhoeae. AB - The PilE pilin subunit protein of the gonococcal Type IV pilus (Tfp) colonization factor undergoes multisite, covalent modification with the zwitterionic phospho form modification phosphoethanolamine (PE). In a mutant lacking the pilin-like PilV protein however, PilE is modified with a mixture of PE and phosphocholine (PC). Moreover, intrastrain variation of PilE PC modification levels have been observed in backgrounds that constitutively express PptA (the protein phospho form transferase A) required for both PE and PC modification. The molecular basis underlying phospho-form microheterogeneity in these instances remains poorly defined. Here, we examined the effects of mutations at numerous loci that disrupt or perturb Tfp assembly and observed that these mutants phenocopy the pilV mutant vis a vis phospho-form modification status. Thus, PC modification appears to be directly or indirectly responsive to the efficacy of pilin subunit interactions. Despite the complexity of contributing factors identified here, the data favor a model in which increased retention in the inner membrane may act as a key signal in altering phospho-form modification. These results also provide an alternative explanation for the variation in PilE PC levels observed previously and that has been assumed to be due to phase variation of pptA. Moreover, mass spectrometry revealed evidence for mono- and di-methylated forms of PE attached to PilE in mutants deficient in pilus assembly, directly implicating a methyltransferase based pathway for PC synthesis in N. gonorrhoeae. PMID- 24797916 TI - Flavonols modulate the effector functions of healthy individuals' immune complex stimulated neutrophils: a therapeutic perspective for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) patients usually exhibit immune complex (IC) deposition and increased neutrophil activation in the joint. In this study, we assessed how four flavonols (galangin, kaempferol, quercetin, and myricetin) modulate the effector functions of healthy individuals' and active RA patients' IC-stimulated neutrophils. We measured superoxide anion and total reactive oxygen species production using lucigenin (CL-luc)- and luminol (CL-lum)-enhanced chemiluminescence assays, respectively. Galangin, kaempferol, and quercetin inhibited CL-lum to the same degree (mean IC50=2.5 MUM). At 2.5 MUM, quercetin and galangin suppressed nearly 65% CL-lum of active RA patients' neutrophils. Quercetin inhibited CL-luc the most effectively (IC50=1.71+/-0.36 MUM). The four flavonols diminished myeloperoxidase activity, but they did not decrease NADPH oxidase activity, phagocytosis, microbial killing, or cell viability of neutrophils. The ability of the flavonols to scavenge hypochlorous acid and chloramines, but not H2O2, depended on the hydroxylation degree of the flavonol B ring. Therefore, at physiologically relevant concentrations, the flavonols partially inhibited the oxidative metabolism of IC-stimulated neutrophils without affecting the other investigated effector functions. Using these compounds to modulate IC-mediated neutrophil activation is a promising safe therapeutic strategy to control inflammation in active RA patients. PMID- 24797917 TI - The serotonin transporter gene polymorphism 5-HTTLPR moderates the effects of stress on attention-deficit/hyperactivity disorder. AB - INTRODUCTION: The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to psychosocial stress than L allele homozygotes. This study aimed to investigate whether 5-HTTLPR genotype moderates the effects of stress on ADHD in a multisite prospective ADHD cohort study. METHODS: 5-HTTLPR genotype, as well as the number of stressful life events in the past 5 years and ongoing long-term difficulties, was determined in 671 adolescents and young adults with ADHD, their siblings, and healthy controls (57.4% male, average age 17.3 years). Linear mixed models, accounting for family relatedness, were applied to investigate the effects of genotype, experienced stress, and their interaction on ADHD severity at time point T2, while controlling for ADHD severity at T1 (mean follow-up time 5.9 years) and for comorbid internalizing problems at T2. RESULTS: The interaction between genotype and stress significantly predicted ADHD severity at T2 (p = .006), which was driven by the effect on hyperactivity-impulsivity (p = .004). Probing of the interaction effect made clear that S-allele carriers had a significantly more positive correlation between stress and ADHD severity than L-allele homozygotes. CONCLUSION: The results show that the interaction between 5-HTTLPR and stress is a mechanism involved particularly in the hyperactivity/impulsivity dimension of ADHD, and that this is independent of comorbid internalizing problems. Further research into the neurobiological mechanisms underlying this interaction effect is warranted. PMID- 24797918 TI - Formation of self-assembled triple-layered rotavirus-like particles (tlRLPs) by constitutive co-expression of VP2, VP6, and VP7 in stably transfected high-five insect cell lines. AB - In this study, stable high-five insect cell line constitutively expressing rotavirus (RV) VP2 was co-transfected with VP6 and VP7-recombinant plasmids. The presence of RV proteins in stably transfected high-five cells was verified by molecular and protein analyses. To yield self-assembled triple-layered RV-like particles (tlRLPs), a stable insect high-five cell line was generated to produce RV VP6 and VP7 besides VP2. Self-assembled tlRLPs were observed by transmission electron microscopy (TEM), and enzyme-linked immunosorbent assay (ELISA) was used to assess their antigenicity in vivo. The results suggest that the stable transfected high-five cells are able to generate tlRLPs with the efficient antigenicity. PMID- 24797919 TI - Black TiO2 nanotubes: cocatalyst-free open-circuit hydrogen generation. AB - Here we report that TiO2 nanotube (NT) arrays, converted by a high pressure H2 treatment to anatase-like "black titania", show a high open-circuit photocatalytic hydrogen production rate without the presence of a cocatalyst. Tubes converted to black titania using classic reduction treatments (e.g., atmospheric pressure H2/Ar annealing) do not show this effect. The main difference caused by the high H2 pressure annealing is the resulting room temperature stable, isolated Ti(3+) defect-structure created in the anatase nanotubes, as evident from electron spin resonance (ESR) investigations. This feature, absent for conventional reduction, seems thus to be responsible for activating intrinsic, cocatalytic centers that enable the observed high open circuit hydrogen generation. PMID- 24797920 TI - Residual effect of reductions in red blood cell count and haematocrit and haemoglobin levels after 10-month withdrawal of pioglitazone in patients with Type 2 diabetes. AB - AIM: To investigate the recovery of thiazolidinedione-induced body weight gain and haematopoietic changes after stopping pioglitazone treatment in patients with Type 2 diabetes. METHODS: This retrospective cohort study included 214 patients divided into three groups according to pioglitazone treatment status. The first study arm included patients who received pioglitazone for 38 months then interrupted this for 10 months (pioglitazone-interruption group). The second arm consisted of patients who received pioglitazone throughout the 48 months (pioglitazone-continuous group); the third arm included patients who had never received pioglitazone therapy (control group). RESULTS: Red blood cell count and haematocrit and haemoglobin levels decreased significantly, while body weight increased in the two pioglitazone-treated groups as compared with the control group at 38 months. Multivariate regression analysis showed that the reductions in red blood cell count/haemoglobin levels were associated with pioglitazone use. In the pioglitazone-interruption group, no recoveries of red blood cells, or haematocrit or haemoglobin levels were observed after stopping pioglitazone for 10 months compared with the pioglitazone-continuous group, but body weight gain decreased to a level that was significantly lower than that in the pioglitazone continuous group and did not differ significantly from the control group. CONCLUSION: In this study, we observed a reversal of body weight gain but no recoveries in red blood cells or haematocrit or haemoglobin levels after stopping pioglitazone for 10 months in patients treated with pioglitazone for 38 months. This finding should prompt a reconsideration of the sustained effect of thiazolidinediones on the haematopoietic system in patients with Type 2 diabetes. PMID- 24797921 TI - Contact-force recovery can predict cardiac perforation during radiofrequency ablation. AB - BACKGROUND: During radiofrequency ablation (RFA), the ability to know whether a steam pop has led to cardiac perforation (CP) would be of profound clinical significance. We aimed to determine whether catheter contact-force characteristics can predict whether a steam pop during RFA causes CP. METHODS: We used a 7.5F Thermocool(r) SmarttouchTM force-sensing catheter (Biosense Webster Inc., Diamond Bar, CA, USA) to perform open-chest left atrial RFA under direct visualization in four sheep. We measured the contact force and its direction every 50 ms during RFA. At each steam pop, we noted whether CP occurred. We then analyzed the contact-force signals to determine whether specific features predicted the presence (+) or absence (-) of CP. RESULTS: A total of 24 steam pops occurred; 10 were CP+ and 14 were CP-. At the time of CP+ and CP- events, the contact force was 50 +/- 25 and 40 +/- 15 g, respectively (P = 0.146). All steam-pop events were associated with a rapid drop-off in contact force, but 10 of the 14 CP- events showed an immediate contact-force rebound, whereas none of the CP+ events did. This rebound presumably occurred as the catheter tip resumed contact with the left atrial wall. The average contact-force rebound equaled 80 100% of the contact-force drop-off. CONCLUSIONS: The ability to measure catheter contact force during RFA is a valuable asset, as contact-force recovery may be used to predict CP. Further studies are warranted to validate our findings in the clinical setting. PMID- 24797922 TI - ["The first stages of the human egg" by Auguste d'Eternod published one hundred years ago in the Comptes Rendus de l'Association des Anatomistes]. AB - The development of the embryo and foetus fascinates, but its study in humans is difficult because of both technical and ethical problems. Auguste d'Eternod, Swiss embryologist, published in 1913 an article entitled "The early stages of the human egg" in the Comptes Rendus de l'Association des Anatomistes, the ancestor of the journal Morphologie. This work is focused not only on the early stages of development: fertilization, cleavage of the egg, blastocyst formation, gastrulation, but also on the extra-embryonic processes characteristic of mammals. On the occasion of the centenary of the publication of this work, I propose a critical review by placing the data published in the literature and historical context of the time. Finally, I try to extract from these observations the concepts that are still used today by embryologists. PMID- 24797923 TI - Subpopulation differences in the association between neighborhood urban form and neighborhood-based physical activity. AB - This study investigated whether associations between the neighborhood built environment and neighborhood-based physical activity (PA) varied by sociodemographic and health-related characteristics. A random sample of adults (n=2006) completed telephone- and self-administered questionnaires. Questionnaires captured PA, sociodemographic, and health-related characteristics. Neighborhood-based PA (MET-minutes/week) was compared across low, medium, and high walkable neighborhoods for each sociodemographic (sex, age, dependents, education, income, motor vehicle access, and dog ownership) and health-status (general health and weight status) subpopulation. With few exceptions, subpopulations residing in high walkable neighborhoods undertook more (p<0.05) neighborhood-based PA than their counterparts in less walkable neighborhoods. Improving neighborhood walkability is a potentially effective population health intervention for increasing neighborhood-based PA. PMID- 24797924 TI - Systems biology of monovalent cation homeostasis in yeast: the translucent contribution. AB - Maintenance of monovalent cation homeostasis (mainly K(+) and Na(+)) is vital for cell survival, and cation toxicity is at the basis of a myriad of relevant phenomena, such as salt stress in crops and diverse human diseases. Full understanding of the importance of monovalent cations in the biology of the cell can only be achieved from a systemic perspective. Translucent is a multinational project developed within the context of the SysMO (System Biology of Microorganisms) initiative and focussed in the study of cation homeostasis using the well-known yeast Saccharomyces cerevisiae as a model. The present review summarize how the combination of biochemical, genetic, genomic and computational approaches has boosted our knowledge in this field, providing the basis for a more comprehensive and coherent vision of the role of monovalent cations in the biology of the cell. PMID- 24797925 TI - Towards a systems level understanding of the oxygen response of Escherichia coli. AB - Escherichia coli is a facultatively anaerobic bacterium. With glucose if no external electron acceptors are available, ATP is produced by substrate level phosphorylation. The intracellular redox balance is maintained by mixed-acid fermentation, that is, the production and excretion of several organic acids. When oxygen is available, E. coli switches to aerobic respiration to achieve redox balance and optimal energy conservation by proton translocation linked to electron transfer. The switch between fermentative and aerobic respiratory growth is driven by extensive changes in gene expression and protein synthesis, resulting in global changes in metabolic fluxes and metabolite concentrations. This oxygen response is determined by the interaction of global and local genetic regulatory mechanisms, as well as by enzymatic regulation. The response is affected by basic physical constraints such as diffusion, thermodynamics and the requirement for a balance of carbon, electrons and energy (predominantly the proton motive force and the ATP pool). A comprehensive systems level understanding of the oxygen response of E. coli requires the integrated interpretation of experimental data that are pertinent to the multiple levels of organization that mediate the response. In the pan-European venture, Systems Biology of Microorganisms (SysMO) and specifically within the project Systems Understanding of Microbial Oxygen Metabolism (SUMO), regulator activities, gene expression, metabolite levels and metabolic flux datasets were obtained using a standardized and reproducible chemostat-based experimental system. These different types and qualities of data were integrated using mathematical models. The approach described here has revealed a much more detailed picture of the aerobic-anaerobic response, especially for the environmentally critical microaerobic range that is located between unlimited oxygen availability and anaerobiosis. PMID- 24797927 TI - Preface. PMID- 24797926 TI - The silicon trypanosome: a test case of iterative model extension in systems biology. AB - The African trypanosome, Trypanosoma brucei, is a unicellular parasite causing African Trypanosomiasis (sleeping sickness in humans and nagana in animals). Due to some of its unique properties, it has emerged as a popular model organism in systems biology. A predictive quantitative model of glycolysis in the bloodstream form of the parasite has been constructed and updated several times. The Silicon Trypanosome is a project that brings together modellers and experimentalists to improve and extend this core model with new pathways and additional levels of regulation. These new extensions and analyses use computational methods that explicitly take different levels of uncertainty into account. During this project, numerous tools and techniques have been developed for this purpose, which can now be used for a wide range of different studies in systems biology. PMID- 24797928 TI - Long-term intravital immunofluorescence imaging of tissue matrix components with epifluorescence and two-photon microscopy. AB - Besides being a physical scaffold to maintain tissue morphology, the extracellular matrix (ECM) is actively involved in regulating cell and tissue function during development and organ homeostasis. It does so by acting via biochemical, biomechanical, and biophysical signaling pathways, such as through the release of bioactive ECM protein fragments, regulating tissue tension, and providing pathways for cell migration. The extracellular matrix of the tumor microenvironment undergoes substantial remodeling, characterized by the degradation, deposition and organization of fibrillar and non-fibrillar matrix proteins. Stromal stiffening of the tumor microenvironment can promote tumor growth and invasion, and cause remodeling of blood and lymphatic vessels. Live imaging of matrix proteins, however, to this point is limited to fibrillar collagens that can be detected by second harmonic generation using multi-photon microscopy, leaving the majority of matrix components largely invisible. Here we describe procedures for tumor inoculation in the thin dorsal ear skin, immunolabeling of extracellular matrix proteins and intravital imaging of the exposed tissue in live mice using epifluorescence and two-photon microscopy. Our intravital imaging method allows for the direct detection of both fibrillar and non-fibrillar matrix proteins in the context of a growing dermal tumor. We show examples of vessel remodeling caused by local matrix contraction. We also found that fibrillar matrix of the tumor detected with the second harmonic generation is spatially distinct from newly deposited matrix components such as tenascin C. We also showed long-term (12 hours) imaging of T-cell interaction with tumor cells and tumor cells migration along the collagen IV of basement membrane. Taken together, this method uniquely allows for the simultaneous detection of tumor cells, their physical microenvironment and the endogenous tissue immune response over time, which may provide important insights into the mechanisms underlying tumor progression and ultimate success or resistance to therapy. PMID- 24797930 TI - Nutritional and metabolic requirements for the infection of HeLa cells by Salmonella enterica serovar Typhimurium. AB - Salmonella is the causative agent of a spectrum of human and animal diseases ranging from gastroenteritis to typhoid fever. It is a food--and water--borne pathogen and infects via ingestion followed by invasion of intestinal epithelial cells and phagocytic cells. In this study we employed a mutational approach to define the nutrients and metabolic pathways required by Salmonella enterica serovar Typhimurium during infection of a human epithelial cell line (HeLa). We deleted the key glycolytic genes, pfkA and pfkB to show that S. Typhimurium utilizes glycolysis for replication within HeLa cells; however, glycolysis was not absolutely essential for intracellular replication. Using S. Typhimurium strains deleted for genes encoding components of the phosphotransferase system and glucose transport, we show that glucose is a major substrate required for the intracellular replication of S. Typhimurium in HeLa cells. We also deleted genes encoding enzymes involved in the utilization of gluconeogenic substrates and the glyoxylate shunt and show that neither of these pathways were required for intracellular replication of S. Typhimurium within HeLa cells. PMID- 24797932 TI - Influenza vaccination and humoral alloimmunity in solid organ transplant recipients. AB - Annual influenza vaccination is recommended in solid organ transplant (SOT) recipients. However, concerns have been raised about the impact of vaccination on antigraft alloimmunity. We evaluated the humoral alloimmune responses to influenza vaccination in a cohort of SOT recipients between October 2008 and December 2011. Anti-HLA antibodies were measured before and 4-8 weeks after influenza vaccination using a solid-phase assay. Overall, 169 SOT recipients were included (kidney = 136, lung = 26, liver = 3, and combined = 4). Five (2.9%) of 169 patients developed de novo anti-HLA antibodies after vaccination, including one patient who developed donor-specific antibodies (DSA) 8 months after vaccination. In patients with pre-existing anti-HLA antibodies, median MFI was not significantly different before and after vaccination (P = 0.73 for class I and P = 0.20 for class II anti-HLA antibodies) and no development of de novo DSA was observed. Five episodes of rejection (2.9%) were observed within 12 months after vaccination, and only one patient had de novo anti-HLA antibodies. The incidence of development of anti-HLA antibodies after influenza vaccination in our cohort of SOT recipients was very low. Our findings indicate that influenza vaccination is safe and does not trigger humoral alloimmune responses in SOT recipients. PMID- 24797931 TI - Functional analysis of BcBem1 and its interaction partners in Botrytis cinerea: impact on differentiation and virulence. AB - In phytopathogenic fungi the establishment and maintenance of polarity is not only essential for vegetative growth and differentiation, but also for penetration and colonization of host tissues. We investigated orthologs of members of the yeast polarity complex in the grey mould fungus Botrytis cinerea: the scaffold proteins Bem1 and Far1, the GEF (guanine nucleotide exchange factor) Cdc24, and the formin Bni1 (named Sep1 in B. cinerea). BcBem1 does not play an important role in regular hyphal growth, but has significant impact on spore formation and germination, on the establishment of conidial anastomosis tubes (CATs) and on virulence. As in other fungi, BcBem1 interacts with the GEF BcCdc24 and the formin BcSep1, indicating that in B. cinerea the apical complex has a similar structure as in yeast. A functional analysis of BcCdc24 suggests that it is essential for growth, since it was not possible to obtain homokaryotic deletion mutants. Heterokaryons of Deltacdc24 (supposed to exhibit reduced bccdc24 transcript levels) already show a strong phenotype: an inability to penetrate the host tissue, a significantly reduced growth rate and malformation of conidia, which tend to burst as observed for Deltabcbem1. Also the formin BcSep1 has significant impact on hyphal growth and development, whereas the role of the putative ortholog of the yeast scaffold protein Far1 remains open: Deltabcfar1 mutants have no obvious phenotypes. PMID- 24797933 TI - Understanding alpha,beta-unsaturated imine formation from amine additions to alpha,beta-unsaturated aldehydes and ketones: an analytical and theoretical investigation. AB - A combination of in situ IR spectroscopy (ReactIR) and DFT calculations have been used to understand what factors govern the selectivity in the addition of primary amines to alpha,beta-unsaturated aldehydes and ketones, i.e., 1,2- versus 1,4 addition. It has been found that the 1,2-addition products (alpha,beta unsaturated imines following addition and elimination) usually predominate for most systems. However, exceptions, such as methyl vinyl ketone, selectively give 1,4-addition products. This has been rationalized by DFT calculations that show that major conformational effects are involved, controlled mainly by steric effects of carbonyl substituents, resulting in a model that provides simple and predictable preparation of alpha,beta-unsaturated imines for in situ utilization in synthesis. PMID- 24797934 TI - The Ebert Prize was established in 1873 and it is the oldest pharmacy award in existence in the United States. PMID- 24797937 TI - Antineoplastic effect of calycosin on osteosarcoma through inducing apoptosis showing in vitro and in vivo investigations. AB - Recently, increasing studies have documented that tumorigenesis closely relates to apoptotic processes. Thus, inducing apoptosis is an anti-cancer strategy against osteosarcoma. Here we investigated the anti-proliferative effect of calycosin on human osteosarcoma cell (143B) in vitro. The results showed that calycosin dose-dependently inhibited 143B cell proliferation as reflected in tetrazolium salt (MTT) assay (P<0.01). In addition, calycosin effectively down regulated cellular mRNA expressions of IkappaBalpha, NF-kappaB p65 and cyclin D1 through RT-PCR assay (P<0.01). Next, calycosin-mediated inhibitory effect on 143B tumor-bearing nude mice and the underlying mechanism were evaluated and discussed. As a result, calycosin administration significantly blocked solid tumor growth in 143B-harbored nude mice (P<0.01). Furthermore, intracellular Bcl 2 protein expression was effectively reduced in 143B-harbored tumor tissue through western blotting analysis (P<0.01), while intratumoral Apaf-1 and cleaved Caspase-3 protein levels were up-regulated, respectively (P<0.01). Taken together, calycosin possesses the anti-osteosarcoma potential, in which the mechanism involved was associated with activation of apoptotic, thus inducing apoptosis. PMID- 24797938 TI - No evidence for activated autophagy in left ventricular myocardium at early reperfusion with protection by remote ischemic preconditioning in patients undergoing coronary artery bypass grafting. AB - OBJECTIVE: Remote ischemic preconditioning (RIPC) by repeated brief limb ischemia/reperfusion reduces myocardial injury in patients undergoing coronary artery bypass grafting (CABG). Activation of signal transducer and activator of transcription 5 (STAT5) in left ventricular (LV) myocardium at early reperfusion is associated with such protection. Autophagy, i.e., removal of dysfunctional cellular components through lysosomes, has been proposed as one mechanism of cardioprotection. Therefore, we analyzed whether or not the protection by RIPC is associated with activated autophagy. METHODS: CABG patients were randomized to undergo RIPC (3*5 min blood pressure cuff inflation/5 min deflation) or placebo (cuff deflated) before skin incision (n = 10/10). Transmural myocardial biopsies were taken from the LV before cardioplegia (baseline) and at early (5-10 min) reperfusion. RIPC-induced protection was reflected by decreased serum troponin I concentration area under the curve (194+/-17 versus 709+/-129 ng/ml * 72 h, p = 0.002). Western blotting for beclin-1-phosphorylation and protein expression of autophagy-related gene 5-12 (ATG5-12) complex, light chain 3 (LC3), parkin, and p62 was performed. STAT3-, STAT5- and extracellular signal-regulated protein kinase 1/2 (ERK1/2)-phosphorylation was used as positive control to confirm signal activation by ischemia/reperfusion. RESULTS: Signals of all analyzed autophagy proteins did not differ between baseline and early reperfusion and not between RIPC and placebo. STAT5-phosphorylation was greater at early reperfusion only with RIPC (2.2-fold, p = 0.02). STAT3- and ERK1/2-phosphorylation were greater at early reperfusion with placebo and RIPC (>=2.7-fold versus baseline, p<=0.05). CONCLUSION: Protection through RIPC in patients undergoing CABG surgery does not appear to be associated with enhanced autophagy in LV myocardium at early reperfusion. PMID- 24797939 TI - Performance comparison between mesophilic and thermophilic anaerobic reactors for treatment of palm oil mill effluent. AB - The anaerobic digestion of palm oil mill effluent (POME) was carried out under mesophilic (37 degrees C) and thermophilic (55 degrees C) conditions without long time POME storage in order to compare the performance of each condition in the field of Sumatra Island, Indonesia. The anaerobic treatment system was composed of anaerobic hybrid reactor and anaerobic baffled filter. Raw POME was pretreated by screw decanter to reduce suspended solids and residual oil. The total COD removal rate of 90-95% was achieved in both conditions at the OLR of 15kg[COD]/m(3)/d. The COD removal in thermophilic conditions was slightly better, however the biogas production was much higher than that in the mesophilic one at high OLR. The organic contents in pretreated POME were highly biodegradable in mesophilic under the lower OLRs. The biogas production was 13.5-20.0l/d at the 15kg[COD]/m(3)/d OLR, and the average content of carbon dioxide was 5-35% in both conditions. PMID- 24797940 TI - Reciprocal regulation of reactive oxygen species and phospho-CREB regulates voltage gated calcium channel expression during Mycobacterium tuberculosis infection. AB - Our previous work has demonstrated the roles played by L-type Voltage Gated Calcium Channels (VGCC) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. Here we decipher mechanisms and pathways engaged by the pathogen to regulate VGCC expression in macrophages. We show that M. tb and its antigen Rv3416 use phospho-CREB (pCREB), Reactive Oxygen Species (ROS), Protein Kinase C (PKC) and Mitogen Activated Protein Kinase (MAPK) to modulate VGCC expression in macrophages. siRNA mediated knockdown of MyD88, IRAK1, IRAK2 or TRAF6 significantly inhibited antigen mediated VGCC expression. Inhibiting Protein Kinase C (PKC) or MEK-ERK1/2 further increased VGCC expression. Interestingly, inhibiting intracellular calcium release upregulated antigen mediated VGCC expression, while inhibiting extracellular calcium influx had no significant effect. siRNA mediated knockdown of transcription factors c-Jun, SOX5 and CREB significantly inhibited Rv3416 mediated VGCC expression. A dynamic reciprocal cross-regulation between ROS and pCREB was observed that in turn governed VGCC expression with ROS playing a limiting role in the process. Further dissection of the mechanisms such as the interplay between ROS and pCREB would improve our understanding of the regulation of VGCC expression during M. tb infection. PMID- 24797941 TI - Investigating the effects of probiotics on pneumococcal colonization using an in vitro adherence assay. AB - Adherence of Streptococcus pneumoniae (the pneumococcus) to the epithelial lining of the nasopharynx can result in colonization and is considered a prerequisite for pneumococcal infections such as pneumonia and otitis media. In vitro adherence assays can be used to study the attachment of pneumococci to epithelial cell monolayers and to investigate potential interventions, such as the use of probiotics, to inhibit pneumococcal colonization. The protocol described here is used to investigate the effects of the probiotic Streptococcus salivarius on the adherence of pneumococci to the human epithelial cell line CCL-23 (sometimes referred to as HEp-2 cells). The assay involves three main steps: 1) preparation of epithelial and bacterial cells, 2) addition of bacteria to epithelial cell monolayers, and 3) detection of adherent pneumococci by viable counts (serial dilution and plating) or quantitative real-time PCR (qPCR). This technique is relatively straightforward and does not require specialized equipment other than a tissue culture setup. The assay can be used to test other probiotic species and/or potential inhibitors of pneumococcal colonization and can be easily modified to address other scientific questions regarding pneumococcal adherence and invasion. PMID- 24797943 TI - Determination of rare earth elements in saline matrices using dispersed particle extraction and inductively coupled plasma mass spectrometry. AB - RATIONALE: Rare earth elements play an important role in identifying and indexing the origin of historical and geological samples. In this work, a new approach for the characterization of rare earth elements (REEs) in aqueous sample solutions with high salinity is presented. METHODS: Prior to analysis by inductively coupled plasma mass spectrometry (ICP-MS) the target analytes were separated from interfering matrix constituents by the use of surface-functionalized nanoparticles. Compared with common matrix separation techniques, such as solid phase extraction (SPE), the strength of the method lies in the combination of an advanced extraction procedure with internal standard correction. Thus, known limitations of SPE such as column clogging or incomplete analyte elution could be completely circumvented. Furthermore, time-consuming approaches for signal quantification such as matrix-matched calibration could be avoided since the applied internal standard allows the correction of matrix-induced deviations in sample extraction and ICP-MS analysis. RESULTS: With the developed procedure detection limits <1 ng L(-1) could be achieved for all the investigated elements, with satisfactory relative standard deviations (RSDs) of 3-26% for unspiked samples and <1-2% for spiked samples. Results derived from recovery experiments with spiked oil accumulation water samples confirmed the applicability of the proposed procedure for the determination of REEs in highly saline sample solutions. The procedure was successfully applied to the study of oil accumulation water samples from different oil fields in Lower Austria. CONCLUSIONS: A sample pretreatment procedure with subsequent ICP-MS analysis for the accurate determination of REEs in aqueous sample solutions with high salinity has been developed. PMID- 24797942 TI - The effect of age on complications in women undergoing minimally invasive sacral colpopexy. AB - INTRODUCTION AND HYPOTHESIS: Previous research has demonstrated similar complication rates in older and younger women undergoing abdominal sacral colpopexy via laparotomy. The objective of this study was to compare perioperative complications in older and younger women undergoing minimally invasive sacral colpopexy. METHODS: This was a retrospective study of laparoscopic and robotic sacral colpopexies performed from January 2009 to May 2012 at a large academic center. Patient demographics, surgical data, and perioperative complications were compared in women < 65 and >=65 years of age. Primary outcome was the difference in major complications. RESULTS: A total of 302 women underwent minimally invasive sacral colpopexy during the study period. Mean age was 58.5 +/- 8.8 years and 84 subjects (27.8 %) were >=65 years. Older women were more likely to have had a prior hysterectomy (60.7 vs 39.0 %, p = 0.001) and had more severe preoperative prolapse (86.9 % vs 71.9 % >= POPQ stage III, p = 0.01). There was no significant difference in duration of hospitalization (1.4 vs 1.4 days, p = 0.54). Overall, there were significantly more major complications in women >= 65 years (unadjusted OR 1.84, 95 % CI 1.02 3.35, p = 0.04). After controlling for BMI, route of surgery, estimated blood loss (EBL), and operating room time, age >= 65 remained a significant predictor of complications (adjusted OR 2.28, 95 % CI 1.21-4.29, p = 0.01). CONCLUSIONS: Our findings suggest that older women have a higher rate of major complications following minimally invasive sacral colpopexy, even after controlling for BMI, route of surgery, EBL, and operating room time. This increased risk should be addressed during preoperative counseling and may influence surgical planning. PMID- 24797944 TI - Miniaturization of a planar-electrode linear ion trap mass spectrometer. AB - RATIONALE: We describe the miniaturization of a linear-type ion trap mass spectrometer for possible applications in portable chemical analysis. This work demonstrates the potential and the advantages of using lithographically patterned electrode plates in realizing an ion trap with dimension y0 less than 1 mm. The focus of this work was to demonstrate the viability and flexibility of the patterned electrode approach to trap miniaturization, and also to discover potential obstacles to its use. METHODS: Planar, low-capacitance ceramic substrates were patterned with metal electrodes using photolithography. Plates that were originally used in a linear trap with a half-spacing (y0 ) of 2.19 mm were positioned much closer together such that y0 = 0.95 mm. A capacitive voltage divider provided different radiofrequency (RF) amplitudes to each of 10 electrode elements (5 on each side of the ejection slit), and the capacitor values were adjusted to provide the correct electric field at this closer spacing. The length of the trapping region, 45 mm, is unchanged from the previous device. RESULTS: Electron ionization mass spectra of toluene and dichloromethane demonstrate instrument performance, with better than unit mass resolution for the molecular ion and fragment ion peaks of toluene. Compared with the larger plate spacing, the signal is reduced, corresponding to the reduced trapping capacity of the smaller device. However, the mass resolution of the larger device is retained. CONCLUSIONS: Lithographically patterned substrates are a viable pathway to fabricating highly miniaturized ion traps for mass spectrometry. These results also demonstrate the possibility of significant reduction of the ion trap volume without physical modification of the electrodes. These experiments show promise for further miniaturization using assemblies of patterned ceramic plates. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24797945 TI - Online normal-phase high-performance liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry: effects of different ionization methods on the characterization of highly complex crude oil mixtures. AB - RATIONALE: Characterization of crude oil represents a challenge for researchers due to its complexity. While Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) is the method of choice for such complex matrices the high number of ions present limits the efficiency of the analysis due to charge competition and space charge effects. One way to solve this problem is the direct coupling of FT-ICR MS with high-performance liquid chromatography (HPLC). METHODS: Normal-phase liquid chromatography was applied on a deasphalted crude oil sample by using a polar aminocyano-bonded stationary phase with n-hexane and isopropyl alcohol as a mobile phase. The HPLC system was coupled online to a 12 T ultrahigh-resolution FT-ICR mass spectrometer. Ion chromatograms were obtained with electrospray ionization (ESI), atmospheric pressure photoionization (APPI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure laser ionization (APLI). RESULTS: The chromatographic separation yielded a group separation into two peaks according to the polarity of the components. Each ionization technique was able to uniquely assign components differing in polarity and aromaticity. Additionally, an increase in aromaticity in the course of retention time for nonpolar species in the first peak was observed. Monitoring the ratio between protonated and radical mono-nitrogen species was achieved. CONCLUSIONS: For the analysis of a crude oil sample, online coupling of a normal phase HPLC system to an FT-ICR mass spectrometer was achieved. The results of the different ionization techniques were compared with each other, which enables a detailed characterization of the complex sample. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24797946 TI - 2,5-dihydroxybenzoic acid salts for matrix-assisted laser desorption/ionization time-of-flight mass spectrometric lipid analysis: simplified spectra interpretation and insights into gas-phase fragmentation. AB - RATIONALE: In the last decades the interest in lipids as important components of membranes has considerably increased. Nowadays, lipids are often routinely analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In this regard, many relevant aspects are so far unknown, e.g., gas-phase stabilities, adduct formation and fragmentation. To fill this gap, MALDI matrix salts are presented which allow for simplified lipid analysis and elucidation of the underlying gas-phase fragmentation mechanisms. METHODS: MALDI-TOF MS was used due to its beneficial properties for lipid investigations, e.g., high sensitivity, simple sample preparations, and a high tolerance to contaminants. The lipid hydrolysis, ionization and fragmentation properties of synthesized near neutral Na(+) and NH4 (+) salts of the commonly used MALDI matrix 2,5-dihydroxybenzoic acid were compared to that of DHB free acid itself as well as to base addition to DHB during dried-droplet sample preparation. RESULTS: Many lipid classes such as sterols, triacylglycerols, phosphatidylcholines and -ethanolamines undergo initial protonation with subsequent prompt partial up to quantitative fragmentation when analyzed with classical acidic matrices by MALDI-TOF MS. Neutral matrix salts can prevent initial analyte fragmentation by suppression of analyte protonation. Additionally, intramolecular gas-phase fragmentation reactions can be inhibited due to analyte stabilization by cation chelation. Base addition during sample preparation leads not only to in situ generation of matrix salts but also to analyte hydrolysis. CONCLUSIONS: Neutral DHB salts avoid separation of lipid species into several ionization states when used as matrices in MALDI-TOF MS. This allows for simplified lipid spectra interpretation. Due to the high cationization efficiency of DHB matrix salts, certain lipid classes become detectable which cannot be analyzed easily using standard acidic DHB. PMID- 24797947 TI - Comparison at the peptide level with post-translational modification consideration reveals more differences between two unenriched samples. AB - RATIONALE: In shotgun strategies, peptide sequences are first identified from tandem mass (MS/MS) spectra, and the existence and abundance of the proteins are then inferred from the peptide information. However, the protein inference step can produce errors and a loss of information. To identify the information that is lost using the traditional approaches, this study compared the proteomic data of two leukemia cell lines (Jurkat and K562) at the peptide level with consideration of post-translational modifications (PTMs). METHODS: The raw files from the two cell lines were searched against the decoy IPI-human database version 3.68, which contains forward and reverse sequences. Then the observed modification name in the results was matched with the modification classification on the Unimod website by a manual search. Only the peptides with 'post-translational' modifications were compared between the two cell lines. RESULTS: After searching the database with consideration of PTMs, a total of 44046 non-redundant peptides were identified in both the Jurkat and K562 cell lines. Of these peptides, even without specific PTM enrichment, 11.43% of them (with at least two spectra in one cell line) existed in different PTM forms between the two cell lines, and 1.73% of the peptides were modified in both cell lines, but with different modifications or possibly on different sites. CONCLUSIONS: Comparing proteomic data at the peptide level with consideration of PTMs can reveal more differences between two unenriched samples. PMID- 24797948 TI - Sensitivity of whole wood stable carbon and oxygen isotope values to milling procedures. AB - RATIONALE: Milling of wood samples is a widely applied preparation method for pooling tree-rings from different trees or periods of several years for determination of delta(13)C and delta(18)O values. In this study, whole wood samples were milled using different procedures in order to evaluate potential effects of this preparation method on delta(13)C and delta(18)O values. METHODS: Subsamples of a 5 cm(3) wood piece of a single tree-ring from a lowland white fir were used. The samples were milled with different setups: (i) two and three stainless-steel balls, (ii) 3, 5 and 8 min milling time, and (iii) discontinuous and continuous milling. The delta(13)C values were measured using an elemental analyser connected to an IsoPrime mass spectrometer and delta(18)O values using a Thermo Scientific MAT 253 mass spectrometer and a TC/EA connected by a ConFlo IV. RESULTS: The results show that varying the milling procedure does not alter the delta(13)C and delta(18)O values in comparison to non-milled blank samples. For shorter milling times, an increased variance of delta(18)O values is recorded, probably caused by isotopic gradient between early- and latewood portions of the tree-ring and thereby biasing the insufficiently homogenised samples. No overheating effects on the delta(13)C and delta(18)O values were detected. CONCLUSIONS: Milling of wood samples for carbon and oxygen isotope analyses is an appropriate preparation method. PMID- 24797949 TI - Real-time explosive particle detection using a cyclone particle concentrator. AB - RATIONALE: There is a need for more rapid methods for the detection of explosive particles. We have developed a novel real-time analysis technique for explosive particles that uses a cyclone particle concentrator. This technique can analyze sample surfaces for the presence of particles from explosives such as TNT and RDX within 3 s, which is much faster than is possible by conventional methods. METHODS: Particles are detached from the sample surface with air jet pulses, and then introduced into a cyclone particle concentrator with a high pumping speed of about 80 L/min. A vaporizer placed at the bottom of the cyclone particle concentrator immediately converts the particles into a vapor. The vapor is then ionized in the atmospheric pressure chemical ionization (APCI) source of a linear ion trap mass spectrometer. RESULTS: An online connection between the vaporizer and a mass spectrometer enables high-speed detection within a few seconds, compared with the conventional off-line heating method that takes more than 10 s to raise the temperature of a sample filter unit. Since the configuration enriched the number density of explosive particles by about 80 times compared with that without the concentrator, a sub-ng amount of TNT particles on a surface was detectable. CONCLUSIONS: The detection limit of our technique is comparable with that of an explosives trace detector using ion mobility spectrometry. The technique will be beneficial for trace detection in security applications, because it detects explosive particles on the surface more speedily than conventional methods. PMID- 24797950 TI - Fragmentation reactions of N-benzyltetrahydroquinolines in electrospray ionization mass spectrometry: the roles of ion/neutral complex intermediates. AB - RATIONALE: Electrospray ionization mass spectrometry (ESI-MS) combined with the collision-induced dissociation (CID) technique has assumed increasing importance as an invaluable tool for the structural analysis of organic and biological molecules. However, general rules for elucidating the fragmentation behaviors of charged molecules in the gas phase are still lacking. Therefore, explorations on the mechanistic information are desirable at all times. METHODS: CID experiments of protonated N-benzyltetrahydroquinolines were carried out on ESI ion trap mass spectrometer and accurate mass measurements were performed on a high-resolution ESI quadrupole time-of-flight (Q-TOF) mass spectrometer in positive ion mode. RESULTS: An ion/neutral complex, [RC6H4CH2(+)/tetrahydroquinoline], resulting from cleavage of the C-N bond induced by the positive charge brought in by protonation, was proposed to be the intermediate to elucidate the fragmentation reactions. For all the compounds investigated, benzyl cation transfer, electron transfer and hydride transfer reactions mediated by the complex were observed. Moreover, for the compound substituted by a methyl group at the para-position of the benzylic phenyl ring, proton transfer reaction via the complex also occurs. CONCLUSIONS: This study is a case for better understanding the intriguing roles of ion/neutral complexes in gas-phase fragmentation reactions and enriching the knowledge about the gas-phase chemistry of the benzyl cation. In addition, it provides useful information for researchers working on analysis or structural elucidation of complicated compounds which contain the N benzyltetrahydroquinoline substructure. PMID- 24797951 TI - Metabolite profiling of edible bird's nest using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. AB - RATIONALE: Edible bird's nest (EBN) is a renowned food item in the Chinese community due to the therapeutic effects claimed to be brought about by its consumption. However, very little scientific information has been revealed to support these claims. Thus, metabolite profiling was performed to identify the metabolites and to relate them to the medicinal properties of EBN. The study also aims to further extend the results to determine any possible differences when the EBNs are classified according to their coloration, countries or production sites. METHODS: Extraction of the metabolites was performed via sonication of EBN with methanol and chloroform. Two analytical platforms, namely gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), were utilized to detect the metabolites. This multi-analytical platform would provide a comprehensive coverage of the metabolites in EBN. GC/MS analysis was conducted in scan mode from m/z 50-650. On the other hand, LC/MS analysis was operated in both positive and negative ion mode from m/z 150-1000. RESULTS: Metabolites were identified and their relationships with the medicinal properties of EBN were deduced. Classification with chemometrics illustrates that EBNs could be differentiated according to their coloration, countries and production sites. This differentiation was due to the environment where the EBNs are produced. Furthermore, GC/MS was demonstrated to be more suitable for classification as the processing methods of the EBNs did not cause a significant variation in the metabolites detected by GC/MS. CONCLUSIONS: The overall findings suggest that the novel approach of metabolite profiling offers new insights to understanding EBN and provided evidence to support the medicinal properties of EBN. In addition, the success of classification of EBNs with metabolite profiling combining with chemometrics represents a paradigm shift in the quality control of this food item. PMID- 24797952 TI - A versatile method for simultaneous stable carbon isotope analysis of DNA and RNA nucleotides by liquid chromatography/isotope ratio mass spectrometry. AB - RATIONALE: Liquid chromatography/isotope ratio mass spectrometry (LC/IRMS) is currently the most accurate and precise technique for the measurement of compound specific stable carbon isotope ratios ((13)C/(12)C) in biological metabolites, at their natural abundance. However, until now this technique could not be applied for the analysis of nucleic acids, the building blocks of the carriers of genetic information in living cells and viruses, DNA and RNA. METHODS: Mixed-mode chromatography (MMC) was applied to obtain the complete separation of nine nucleotides (eight originating from DNA/RNA and one nucleotide (inosine monophosphate) that may serve as an internal standard) in a single run using LC/IRMS. We also developed and validated a method for DNA and RNA extraction and an enzymatic hydrolysis protocol for natural samples, which is compatible with LC/IRMS analysis as it minimizes the carbon blank. The method was used to measure the concentration and stable carbon isotope ratio of DNA and RNA nucleotides in marine sediment and in the common marine macro alga (Ulva sp.) at natural abundance levels as well as for (13)C-enriched samples. RESULTS: The detection limit of the LC/IRMS method varied between 1.0 nmol for most nucleotides and 2.0 nmol for late-eluting compounds. The intraday and interday reproducibility of nucleotide concentration measurements was better than, respectively, 4.1% and 8.9% and for delta(13)C measurements better than, respectively, 0.30/00 and 0.50/00. The obtained nucleic acid concentrations and nucleic acid synthesis rates were in good agreement with values reported in the literature. CONCLUSIONS: This new method gives reproducible results for the concentration and delta(13)C values of nine nucleotides. This solvent-free chromatographic method may also be used for other purposes, such as for instance to determine nucleotide concentrations using spectrophotometric detection. This sensitive method offers a new avenue for the study of DNA and RNA biosynthesis that can be applied in various fields of research. PMID- 24797953 TI - Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area. AB - OBJECTIVES: To describe characteristics of visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (HLH) with focus on diagnostic clues and pitfalls, including the frequency of central nervous system (CNS) involvement, and to determine the efficacy of liposomal amphotericin B (L-AmB). STUDY DESIGN: We retrospectively analyzed clinical and laboratory features, diagnostic procedures, and treatment of 13 patients with HLH with imported visceral leishmaniasis, reported to the German HLH reference center (1999-2012). RESULTS: The spectrum of presentations was indistinguishable from patients with hereditary HLH or with acquired HLH because of infections with other pathogens. In 8 patients, disease onset occurred before the age of 2 years, coinciding with the typical age of manifestation of primary HLH. Two patients had mild nonspecific CNS findings. Misleading antiviral IgM (n = 6) and autoantibodies (n = 2) led to inaccurate interpretation of the etiology of HLH, sometimes with inappropriate therapeutic consequences. False negative results for Leishmania were obtained by initial bone marrow microscopy in 6/13, serology in 1/12, bone marrow culture in 2/5, and polymerase chain reaction of peripheral blood in 1/3 patients, and all bone marrow samples tested were Leishmania-positive by polymerase chain reaction (n = 7). L-AmB was administered to 12 patients, 5 of whom had no prior HLH directed immunosuppressive therapy; sodium stibogluconate was administered to 1 patient. Persistent remission was achieved in 11 cases. Two patients required repeated or prolonged L-AmB therapy. CONCLUSIONS: Awareness of diagnostic pitfalls may save patients from unnecessary toxic treatment. CNS involvement is rare. L-AmB shows efficacy in visceral leishmaniasis-associated HLH. PMID- 24797954 TI - The diagnostic yield of rescreening for arteriovenous malformations in children with hereditary hemorrhagic telangiectasia. AB - The diagnostic yield of rescreening children with hereditary hemorrhagic telangiectasia at regular intervals for arteriovenous malformations is unclear. Here, we show that when children with initially negative screening were reassessed after 5 years, no new arteriovenous malformations were detected suggesting that longer intervals between screenings may be adequate. PMID- 24797956 TI - Aluminum manganese oxides with mixed crystal structure: high-energy-density cathodes for rechargeable sodium batteries. AB - We report a new discovery for enhancing the energy density of manganese oxide (Nax MnO2 ) cathode materials for sodium rechargeable batteries by incorporation of aluminum. The Al incorporation results in NaAl(0.1) Mn(0.9) O2 with a mixture of tunnel and layered crystal structures. NaAl(0.1) Mn(0.9) O2 shows a much higher initial discharge capacity and superior cycling performance compared to pristine Na(0.65) MnO2 . We ascribe this enhancement in performance to the formation of a new orthorhombic layered NaMnO2 phase merged with a small amount of tunnel Na(0.44) MnO2 phase in NaAl(0.1) Mn(0.9) O2 , and to improvements in the surface stability of the NaAl(0.1) Mn(0.9) O2 particles caused by the formation of Al-O bonds on their surfaces. Our findings regarding the phase transformation and structure stabilization induced by incorporation of aluminum, closely related to the structural analogy between orthorhombic Na(0.44) MnO2 and NaAl(0.1) Mn(0.9) O2 , suggest a strategy for achieving sodium rechargeable batteries with high energy density and stability. PMID- 24797957 TI - A molecular structural analog of proposed dinuclear active sites in cobalt-based water oxidation catalysts. AB - The compound [Co2(MU-OH)2(OH2)2(DPFN)][NO3]4 is a molecular structural analog of proposed active sites of cobalt phosphate water oxidation catalysts. Computational studies on this system indicate feasible catalytic pathways to oxygen formation, despite the low electrocatalytic activity observed for [Co2(MU OH)2(OH2)2(DPFN)][NO3]4. Electrochemical and reactivity studies implicate the binding of phosphate to the dicobalt core, which may inhibit water oxidation catalysis. PMID- 24797958 TI - Detection of silver nanoparticles inside marine diatom Thalassiosira pseudonana by electron microscopy and focused ion beam. AB - In the following article an electron/ion microscopy study will be presented which investigates the uptake of silver nanoparticles (AgNPs) by the marine diatom Thalassiosira pseudonana, a primary producer aquatic species. This organism has a characteristic silica exoskeleton that may represent a barrier for the uptake of some chemical pollutants, including nanoparticles (NPs), but that presents a technical challenge when attempting to use electron-microscopy (EM) methods to study NP uptake. Here we present a convenient method to detect the NPs interacting with the diatom cell. It is based on a fixation procedure involving critical point drying which, without prior slicing of the cell, allows its inspection using transmission electron microscopy. Employing a combination of electron and ion microscopy techniques to selectively cut the cell where the NPs were detected, we are able to demonstrate and visualize for the first time the presence of AgNPs inside the cell membrane. PMID- 24797959 TI - Extensive hybridization and introgression between Melastoma candidum and M. sanguineum. AB - Natural hybridization can lead to various evolutionary outcomes in plants, including hybrid speciation and interspecific gene transfer. It can also cause taxonomic problems, especially in plant genera containing multiple species. In this study, the hybrid status of Melastoma affine, the most widespread taxon in this genus, and introgression between its putative parental species, M. candidum and M. sanguineum, were assessed on two sites, Hainan and Guangdong, using 13 SSR markers and sequences of a chloroplast intergenic spacer. Bayesian-based STRUCTURE analysis detected two most likely distinct clusters for the three taxa, and 76.0% and 73.9% of the morphologically identified individuals of M. candidum and M. sanguineum were correctly assigned, respectively. 74.5% of the M. affine individuals had a membership coefficient to either parental species between 0.1 and 0.9, suggesting admixture between M. candidum and M. sanguineum. Furthermore, NewHybrids analysis suggested that most individuals of M. affine were F2 hybrids or backcross hybrids to M. candidum, and that there was extensive introgression between M. candidum and M. sanguineum. These SSR data thus provides convincing evidence for hybrid origin of M. affine and extensive introgression between M. candidum and M. sanguineum. Chloroplast DNA results were consistent with this conclusion. Much higher hybrid frequency on the more disturbed Guangdong site suggests that human disturbance might offer suitable habitats for the survival of hybrids, a hypothesis that is in need of further testing. PMID- 24797960 TI - Differences of the anterior segment parameters in children with down syndrome. AB - PURPOSE: The study was undertaken to investigate whether anterior segment findings are different in children with Down syndrome (DS) to normal children and to focus on its clinical significance. METHODS: A cross-sectional case control study was conducted in a total of 38 children with DS and 42 healthy children. This is the first report in the literature stating that. All subjects underwent ophthalmologic examination including slit-lamp biomicroscopy, cycloplegic refraction, intraocular pressure measurement and Scheimpflug imaging measurement. Customized software for Pentacam was used to analyze structural indices of anterior segment parameters. The mean anterior segment values of right eyes were compared between the groups. RESULTS: The mean anterior chamber parameters of patients with DS and controls were measured respectively: Corneal thickness was 502.31 +/- 40.5 and 541.8 +/- 37.42 mm (p < 0.001), corneal volume was 56.63 +/- 4.5 and 61.02 +/- 4.3 mm3 (p < 0.001), corneal radius curvature was 7.41 +/- 0.29 and 7.67 +/- 0.34 mm (p < 0.001), iridocorneal angle was 39.7 +/- 6.2 and 39.5 +/ 6.4 degrees (p = 0.944), anterior chamber volume was 181.65 +/- 27.38 and 185.77 +/- 32.53 m3 (p = 0.528), anterior chamber depth was 3.08 +/- 0.24 and 3.02 +/- 0.31 mm (p = 447), pupil size was 2.95 +/- 0.48 and 3.29 +/- 0.45 mm (p < 0.05). CONCLUSION: The majority of the anterior segment parameters were found to be different in children with Down syndrome. While pupil size, corneal thickness, corneal volume and corneal curvature in DS were less than normal, iridocorneal angle, anterior chamber depth and anterior chamber volume were close to controls. The most important parametric differences in children with DS were seen on the cornea. PMID- 24797961 TI - Barriers to the effective treatment of sepsis: antimicrobial agents, sepsis definitions, and host-directed therapies. AB - Sepsis is a complex clinical syndrome involving both infection and a deleterious host immune response. Antimicrobial agents are key elements of sepsis treatment, yet despite great strides in antimicrobial development in the last decades, sepsis continues to be associated with unacceptably high mortality (~30%). This is the result, on one hand, of the rise of antimicrobial resistant organisms and, on the other hand, of the dearth of effective host-directed immune therapies. A major obstacle to the development of good host-directed therapies is the lack of understanding of the host immune response. The problem is exacerbated by poor nonspecific clinical definitions of disease. Poor definitions have had a profound impact on sepsis research, from epidemiologic studies to the failed clinical trials of host-directed therapies. Therefore, better definitions must be developed to enable advancement in the field. PMID- 24797962 TI - Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. AB - IMPORTANCE: Although cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it are limited. OBJECTIVE: To determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically confirmed Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS: We compared demographic and clinical variables at the earliest visit during life at which participants were found to have cognitive impairment and compared pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and noncarriers of the APOE epsilon4 allele. Data were obtained from the Uniform Data Set, which comprises longitudinal clinical assessments performed in the Alzheimer's Disease Centers funded by the National Institute on Aging. Participants included 193 persons with AD and severe CAA and 232 persons with AD and no CAA. All participants had cognitive impairment and met National Institute on Aging-Reagan Institute neuropathological criteria for AD. MAIN OUTCOMES AND MEASURES: Prevalence of demographic characteristics and the APOE epsilon4 allele and odds ratios (ORs) of clinical variables for the prediction of severe CAA. RESULTS: Persons with severe CAA compared with those without CAA were more likely to carry an APOE epsilon4 allele (64.9% vs 42.8%, respectively; P < .001), to be Hispanic (6.8% vs 1.3%, respectively; P = .003), to have had a transient ischemic attack (12.5% vs 6.1%, respectively; OR = 2.1; 95% CI, 1.0-4.4), and to have lower degrees of diffuse amyloid plaque pathology (mean [SD] Consortium to Establish a Registry for Alzheimer's Disease score, 1.2 [0.5] vs 1.4 [0.8], respectively; P = .01). Those with CAA compared with those without CAA more commonly had intracerebral hemorrhage (9.3% vs 3.5%, respectively; P = .01), cortical microinfarcts (20.7% vs 12.9%, respectively; P = .03), and subcortical leukoencephalopathy (20.5% vs 12.1%, respectively; P = .02). Noncarriers of the APOE epsilon4 allele with severe CAA compared with those without CAA had a higher prevalence of stroke (11.1% vs 3.9%, respectively; OR = 3.8; 95% CI, 1.0-14.6) and hypercholesterolemia (50.0% vs 32.7%, respectively; OR = 2.3; 95% CI, 1.1-4.7). CONCLUSIONS AND RELEVANCE: Being Hispanic and having had a transient ischemic attack-like episode were predictors of CAA in persons with AD. Less diffuse parenchymal amyloid pathology in persons with severe CAA suggests a difference in beta-amyloid trafficking. PMID- 24797964 TI - The effect of cerclage in twin gestations with short cervix: a Bayesian evaluation. AB - OBJECTIVE: Bayesian inference allows the revision of prior clinical estimates of treatment effectiveness based on current data. We apply it to a published dataset evaluating the effect of cerclage upon preterm delivery in twin gestations with a short cervix. STUDY DESIGN: Prior probability distributions for delivery <35 weeks gestation for the control group and the treatment (cerclage) group were constructed under assumptions ranging from treatment having no effect (prior A) to halving early deliveries (prior C). Likelihood functions were calculated based on a published meta-analysis. Posterior probability densities were derived from which risk ratios for early delivery were computed, with 95% credible intervals and the probability of cerclage benefit. RESULTS: Median posterior risk ratios (95% credible intervals) for delivery <35 weeks with cerclage are 1.51 (1.02 2.33) for prior A and 1.11 (0.72-1.77) for prior C. The probability of cerclage benefit ranged from 2.1% for prior A to 31.4% for prior C. By comparison, the conventional risk ratio (95% confidence interval) for early delivery, based on the data alone, is 2.08 (1.18-3.69). CONCLUSIONS: As might be anticipated, those with low expectation of cerclage benefit remain more convinced of the ineffectiveness (or harm) of the procedure than those with higher expectations. PMID- 24797963 TI - Increased human leukocyte antigen-G expression at the maternal-fetal interface is associated with preterm birth. AB - Abstract Objective: The maternal-fetal interface must modulate immune function to allow tolerance of fetal cells while still reacting to pathogens to suppress infection. Human leukocyte antigen-G (HLA-G) is a class Ib major histocompatibility complex protein involved in maternal-fetal tolerance. We posited that alterations in placental HLA-G expression predispose women to preterm birth. The aim of this study was to compare HLA-G expression in the maternal-fetal interface of term versus preterm human placentas. METHODS: We performed a cross-sectional study of specimens from the basal plate of the human placenta from women enrolled in a tissue specimen and clinical data consortium. Immunohistochemistry with digital microscopic analysis was used to quantify HLA-G protein expression in the basal plate from preterm and term placentas. RESULTS: Preterm birth <37 weeks occurred in 29.5% of 149 singleton pregnancies. HLA-G positive cells occupied one-third of the basal plates, and the HLA-G-positive area was increased by 14% in placentas from preterm births than in those from term births (32.1% in term placentas versus 36.6% in preterm placentas). CONCLUSION: Although HLA-G is required for maternal tolerance of the semi allogeneic fetus, higher levels of HLA-G expression at the maternal-fetal interface is associated with preterm birth. PMID- 24797965 TI - Anorexia-cachexia syndrome in pancreatic cancer: recent advances and new pharmacological approach. AB - About 80% of all pancreatic ductal adenocarcinoma patients suffer from a wasting syndrome referred to as the "cancer anorexia-cachexia syndrome" (CACS) characterized by abnormally low weight, weakness and loss of skeletal muscle mass with or without loss of body fat, which directly impacts overall survival, quality of life, and physical activity. The aim of this review was to examine recent findings about CACS' pathophysiology and to describe the current pharmacological approaches. In recent years many efforts were made to improve our knowledge of CACS; currently we know that cachexia arises from a complex and multifactorial interaction between various mechanisms including inflammation, anorexia/malnutrition, alterations of protein and lipid metabolism; consequently its management requires multidisciplinary and multipharmacological approach that should address the different causes underlying this clinical event. On these premises, several drugs have been proposed starting from the first pharmacological treatment based on progestational agents or corticosteroids; most of them are in the preclinical phase, but some have already reached the clinical experimentation stage. In conclusion, to date, there is no standard effective treatment and further studies are needed to unravel the basic mechanisms underlying CACS and to develop newer therapeutic strategies with the hope to improve the quality of life of pancreatic cancer patients. PMID- 24797966 TI - Advances in individualized and regenerative medicine. AB - Molecular and cell biology have resulted in major advances in our understanding of disease pathogenesis as well as in novel strategies for the diagnosis, therapy and prevention of human diseases. Based on modern molecular, genetic and biochemical methodologies it is on the one hand possible to identify for example disease-related point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array and other technologies, it is for example possible to simultaneously analyze thousands of genes or gene products (RNA and proteins), resulting in an individual gene or gene expression profile ('signature'). Such data increasingly allow to define the individual disposition for a given disease and to predict disease prognosis as well as the efficacy of therapeutic strategies in the individual patient ('individualized medicine'). At the same time, the basic discoveries in cell biology, including embryonic and adult stem cells, induced pluripotent stem cells, genetically modified cells and others, have moved regenerative medicine into the center of biomedical research worldwide with a major translational impact on tissue engineering as well as transplantation medicine. All these aspects have greatly contributed to the recent advances in regenerative medicine and the development novel concepts for the treatment of many human diseases, including liver diseases. PMID- 24797967 TI - Outcome prediction in endoscopic surgery for chronic rhinosinusitis - a multidimensional model. AB - PURPOSE: Chronic rhinosinusitis (CRS) is one of the most common diseases in the modern society. In recent years endoscopic sinus surgery (ESS) has become the treatment of choice for patients with CRS refractory to medical therapy. ESS proved to be successful in most, but not all patients with CRS. Currently there is no direct method available to distinguish between patients who are likely to benefit from ESS and those who are not. The aim of this study was to build multidimensional models (artificial neural networks) to predict early outcomes of ESS in individual patients. MATERIAL/METHODS: The study group comprised of 115 patients operated for CRS in the Department of Otolaryngology, Jagiellonian University Collegium Medicum, Cracow. The neural models were created using the Statistica Neural Network computer software package. The models required only information easily achievable for every patient before surgery. Consequently, the models could be readily applicable in everyday clinical practice. To define the results of surgery three different mathematical descriptions were compared. The models' predictions were compared with the actual results of surgery 3-6 months postoperatively. RESULTS: The models were able to predict the early outcome of surgery in 90% of the patients but their quality depended on mathematical representation of the surgery result. The best models were characterized by 93% sensitivity and 86% specificity. CONCLUSIONS: The results of ESS depend on many factors, so reliable outcome prognoses can be produced only by multidimensional models. Artificial neural networks are a promising multidimensional tool facilitating clinical decision making in patients with CRS. PMID- 24797968 TI - Kinetics of C-reactive protein in children with congenital heart diseases in the early period after cardiosurgical treatment with extracorporeal circulation. AB - PURPOSE: The aim of the study was to assess postoperative C-reactive protein (CRP) serum kinetics in children without clinical signs of infection after atrial and ventricular septal defects closure in terms of extracorporeal circulation (ECC). MATERIAL/METHODS: Fifty-two patients met inclusion criteria and were divided into 2 groups: group A (antibiotic prophylaxis with cefazolin given up to 48 h postoperatively) and group B (antibiotic prophylaxis with amoxicillin and clavunic acid given more than 48 h postoperatively). The CRP was measured perioperatively in both groups. The CRP evaluation was the part of routine lab tests during perioperative period, without any modification of the typical perioperative strategy. In the postoperative period CRP was measured after 24h, 48 h, 72 h and 96 h in both groups. RESULTS: There were no differences between CRP levels between both groups of patients. The peak CRP values were observed after 48 h after the operation in ECC in both groups and decreased in the next postoperative days. CONCLUSIONS: In children with congenital heart defects undergoing cardiosurgical treatment with the use of ECC the assessing CRP values in the first postoperative day remains questionable. The maximum peak CRP value after operation with ECC can be much higher than the reference values without infection complications. Single CRP assessment in early postoperative period in these groups of children can lead to over-diagnosis of infections and antibiotics abuse. PMID- 24797969 TI - Quantitative assessment of placental vasculature and placental volume in normal pregnancies with the use of 3D Power Doppler. AB - PURPOSE: The aim of the study was to determine reference values for placental vascular indices and placental volume according to gestational age. MATERIAL/METHODS: The assessment of placental vascular indices and placental volume using 3D Power Doppler and the Virtual Organ Computer-aided Analysis (VOCAL) technique was performed on 100 normal fetuses between 22 and 41 weeks of gestation. In this study the method of the individual setting of the power Doppler gain value was used. Only patients with entirely visualized placenta were included in the study. RESULTS: No statistically relevant difference in the values of placental vascular indices and placental volume between different localizations of the placenta was detected. No statistically significant changes to placental vascular indices depending on gestational age were found. It enabled to determine the 10th, 50th and 90th percentile values for the vascularization index (VI), flow index (FI), vascularization-flow index (VFI), which are independent of gestational age. No correlation was found between placental volume and placental vascular indices. CONCLUSIONS: The values of placental vascular indices are constant between the 22nd and 41st week of a normal pregnancy. Placental volume measured with the use of the VOCAL program increases between 22nd and 41st week of a normal pregnancy. In a normal pregnancy the placental vasculature increases adequately to the increase of its volume. The method of the individual setting of the power Doppler gain value makes it possible to achieve comparable values of placental vascular indices regardless of the distance between the probe and the placenta. PMID- 24797970 TI - Endothelial function, antioxidant status and vascular compliance in newly diagnosed HFE C282Y homozygotes. AB - PURPOSE: This pilot study was aimed to establish techniques for assessing and observing trends in endothelial function, antioxidant status and vascular compliance in newly diagnosed HFE haemochromatosis during the first year of venesection. PATIENTS/METHODS: Untreated newly diagnosed HFE haemochromatosis patients were tested for baseline liver function, iron indices, lipid profile, markers of endothelial function, anti-oxidant status and vascular compliance. Following baseline assessment, subjects attended at 6-weeks and at 3, 6, 9 and 12 months for follow-up studies. RESULTS: Ten patients were recruited (M=8, F=2, mean age=51 years). Venesection significantly increased high density lipoproteins at 12-months (1.25 mmol/L vs. 1.37 mmol/L, p=0.01). However, venesection did not significantly affect lipid hydroperoxides, intracellular and vascular cell adhesion molecules or high sensitivity C-reactive protein (0.57 MUmol/L vs. 0.51 MUmol/L, p=0.45, 427.4 ng/ml vs. 307.22 ng/ml, p=0.54, 517.70 ng/ml vs. 377.50 ng/ml, p=0.51 and 290.75 MUg/dL vs. 224.26 MUg/dL, p=0.25). There was also no significant effect of venesection on anti-oxidant status or pulse wave velocity (9.65 m/s vs. 8.74 m/s, p=0.34). CONCLUSIONS: Venesection significantly reduced high density lipoproteins but was not associated with significant changes in endothelial function, anti-oxidant status or vascular compliance. Larger studies using this established methodology are required to clarify this relationship further. PMID- 24797971 TI - Quality of life in Polish patients with multiple sclerosis. AB - PURPOSE: This study is a pilot evaluation of the quality of life (QoL) in Polish patients with multiple sclerosis (MS). MATERIAL/METHODS: Data from 21 centers in Poland were collected from May 2008 to January 2009. QoL was assessed using the questionnaire Euro Quality of Life (EQ-5D), with Polish population norms. Demographic profile of patients, duration/form/relapsing activity of the disease, disability and comorbidity were also analyzed. RESULTS: Data from 3521 patients (F/M ratio 2.4:1) were collected. The average EQ-5D index was 0.8 +/- 0.27 and the mean score in a visual analog scale (EQ-VAS) was 65.6 +/- 21.5. There was a highly significant positive correlation between both indices (r=0.7334, p<0.0001). The mean patient age was 40.7 years (11.2-92.3 years) and disease duration was 10.3 +/- 8.8 years (0.04-53 years). 74.2% of subjects had relapsing remitting form of MS, while 17.2% were classified as secondary progressive and 8.6% as primary progressive. In the group of relapsing-remitting MS subjects there were 2.5% patients with "benign MS". The average degree of disability on EDSS scale was 3.6 +/- 2.2, while disability >=6 was observed in 20.3% of patients. Most patients did not have other diseases besides MS. CONCLUSIONS: This is the first large study of QoL in patients with MS in Poland (approximately 18% of all patients). Our results confirm a reduction in QoL compared with the general population. Further studies are indicated to identify the modifiable risk factors (e.g. type of treatment) that may affect QoL. PMID- 24797972 TI - High expression of OX40 (CD134) and 4-1BB (CD137) molecules on CD4(+)CD25(high) cells in children with type 1 diabetes. AB - PURPOSE: Despite the rapidly rising incidence of diabetes in children, with the highest rise in children<5 years of age, data on mechanisms that trigger severe beta-cells damage are limited. The aim of the study was to assess the frequency of OX40 (CD134) or 4-1BB (CD137) positive cells in the peripheral blood of children with newly diagnosed type 1 diabetes (T1D) in comparison to healthy controls. MATERIAL/METHODS: The study included 33 children (mean age 7.3 +/- 5.4 years) with newly diagnosed T1D and 39 age-matched healthy controls. Separate analysis was performed in children<5 years. Flow cytometric analysis was performed using the following markers: CD4, CD25, CD137, and CD134. Fasting C peptide level was assessed as well. RESULTS: The frequency of CD4(+)CD25(high)OX40(+) was higher in T1D children than in controls (median value 3.58% vs. 1.1%, respectively; p=0.003). Moreover, T1D children had higher frequency of CD4(+)CD25(high)4-1BB(+) cells than healthy subjects (median value 5.76% vs. 3.74%, respectively; p=0.037). A significant correlation was noted between the age of diabetic children and the C-peptide level (r=0.54, 95% CI [0.19-0.77], p=0.004). In comparison with age-matched controls, children<5 years had higher frequency of CD4(+)CD25(high)OX40(+) (p=0.004) and CD4(+)CD25(high)4 1BB(+) cells (p=0.079). CONCLUSIONS: Our study showed higher frequency of both OX40 and 4-1BB positive cells in T1D children in comparison to controls. It seems that observed differences might be more pronounced in children<5 years of age than in older subjects. Further clinical studies are needed to determine the age related differences in the immune system, in the pathogenesis of T1D. PMID- 24797973 TI - Type II tympanoplasty in chronic cholesteatoma and granulomatous otitis media - distant results of otosurgery. AB - PURPOSE: The objective of this study is to evaluate the impact of changes to the mucous in the middle ear on the outcome of the reconstruction of the ossicular chain exemplified by a type 2 tympanoplasty. MATERIAL/METHODS: A prospective analysis was carried out with regard to patients operated on at the Otolaryngology Department at Collegium Medicum, Jagiellonian University, between 2007 and 2011 due to conditions of the middle ear. The patients who had undergone surgical treatment for the first time because of chronic otitis media were taken into account. The operations involving a type 2 tympanoplasty were earmarked for further analysis. The effectiveness of treatment was measured by the change of the Air-Bone Gap (AGP). RESULTS: The analysis covered 47 patients, whose own modeled incuses were placed on normal stapes. The patients were divided into two groups (with and without cholesteatoma). A statistically significant hearing improvement was observed in the patients with cholesteatoma. In the group without cholesteatoma and with a prevalence of granulomatous lesions, no statistically significant hearing improvement was observed 6 and 12 months following the ear surgery. CONCLUSIONS: In the patients with cholesteatoma and a minor damage to the ossicular chain, a significant hearing improvement is observed after ossiculoplasty. An occurrence of granulomatous lesions is an unfavorable predictor. The Air-Bone Gap measured before the surgery often does not the actual advancement of the pathological process, and hearing improvement after the surgery cannot be prognosticated on the basis of that amount alone. PMID- 24797974 TI - High Fas expression in gastric carcinoma cells as a factor correlating with the occurrence of metastases to regional lymph nodes. AB - PURPOSE: The aim of this study was to evaluate the correlation of the expression of Fas and Fas-L proteins in gastric carcinoma cells on the occurrence of metastases to regional lymph nodes. MATERIAL/METHODS: The study included 89 patients treated surgically for gastric carcinoma. The evaluated clinicomorphological parameters were verified based on both histopathological material collected at surgery and intraoperative image. Fas and Fas-L expression was evaluated immunohistochemically in the neoplastic tissue of the removed gastric tumors. RESULTS: A statistically significant positive correlation between Fas expression in gastric carcinoma cells and the number of regional lymph nodes affected by metastases was observed (p<0.05). No such correlation was noticed with respect to Fas-L. A statistically significant correlation between the depth of neoplastic infiltration of the stomach wall (T feature) and the number of affected lymph nodes was observed (p<0.05). No statistically significant correlations in the other examined clinicomorphological features and the number of metastatic lymph nodes was observed. CONCLUSION: A positive Fas expression correlates with more frequent occurrence of metastases to regional lymph nodes. Determination of this protein expression in cancer cells prior to surgery may be helpful for planning the surgical procedure, especially with respect to the extent of lymph node excision. PMID- 24797975 TI - Procalcitonin and macrophage inflammatory protein-1 beta (MIP-1beta) in serum and peritoneal fluid of patients with decompensated cirrhosis and spontaneous bacterial peritonitis. AB - PURPOSE: Spontaneous bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis causing significant mortality which requires rapid recognition for effective antibiotic therapy, whereas ascitic fluid cultures are frequently negative. The aim of this study was to evaluate the SBP diagnostic efficacy of procalcitonin (PCT) and macrophage inflammatory protein-1 beta (MIP 1beta) measured in serum and peritoneal fluid. MATERIAL/METHODS: Thirty-two participants with liver cirrhosis and ascites were included into the study (11 females and 21 males, mean age 49.5 +/- 11.9 years). The peritoneal fluid and venous blood were collected for routine laboratory examinations and measurements of PCT and MIP-1beta. Patients were divided into two groups according to the ascitic absolute polymorphonuclear leukocytes count (>=250 mm(-3) and <250 mm( 3)). RESULTS: Ascites was sterile in 22 participants and SBP was diagnosed in 10 patients. Serum and ascitic levels of PCT and MIP-1beta did not correlate with clinical and routine laboratory parameters. MIP-1beta in the ascitic fluid was significantly higher in patients with SBP (213 +/- 279 pg/ml vs. 66.3 +/- 49.8 pg/ml; p=0.01). The sensitivity and specificity for diagnosis of SBP with ascitic MIP-1beta were 80% and 72.7%, respectively (cut-off value 69.4 pg/ml) with AUROC 0.77 (95%CI 0.58-0.96). Serum levels of MIP-1beta showed lower diagnostic yield. Serum and ascitic PCT levels were not different in patients with and without SBP. CONCLUSIONS: MIP-1beta concentration in ascitic fluid may distinguish patients with and without SBP with satisfactory sensitivity and specificity. Chemokines should be further explored for diagnostic use. PMID- 24797976 TI - Infectious spondylodiscitis - a case series analysis. AB - PURPOSE: We aimed to describe the clinical and laboratory features as well as diagnostic difficulties in the case series of spondylodiscitis. MATERIALS/METHODS: We retrospectively reviewed 11 cases of spondylodiscitis. The diagnosis of spondylodiscitis was based on clinical, radiological and microbiological evidence and by the response to antimicrobial therapy. RESULTS: There were 7 men and 4 women, and the age ranged from 21 to 74 years. Risk factors of spondylodiscitis were observed in 7 patients. The approximate time from onset of symptoms to diagnosis was from 2 to 7 months (median 45 days). Back pain was the most common symptom. The most frequent location of spondylodiscitis was lumbar spine. Pathogens were isolated in 6 cases and were as follows: Staphylococcus aureus (4 cases), Staphylococcus warneri (1 case) and Escherichia coli (1 case). After therapy, all patients had rapid regression of symptoms and no permanent neurological impairments and recurrence of infection were observed. CONCLUSIONS: Diagnosis of spondylodiscitis is frequently delayed. This disease should be taken into consideration in differential diagnosis in patients with root syndromes accompanied by back pain and usually fever as well as increased values of CRP and ESR. PMID- 24797977 TI - The effect of aging on EEG brain oscillations related to sensory and sensorimotor functions. AB - PURPOSE: The question of the present study is whether the brain as a system with gradually decreasing resources maximizes its performance by reorganizing neural networks for greater efficiency. MATERIAL/METHODS: Auditory event-related low frequency oscillations (delta delta - [2, 4]Hz; theta theta - [4.5, 7]Hz; alpha alpha - [7.5, 12]Hz) were examined during an auditory discrimination motor task (low-frequency tone - right hand movement, high-frequency tone - left hand movement) between two groups with mean age 26.3 and 55 years. RESULTS: The amplitudes of the phase-locked delta, theta and alpha activity were more pronounced with a progressive increase in age during the sensory processing, independent of tone type. The difference between the groups with respect to scalp distribution was tone-independent for delta/theta oscillations, but not for the alpha activity. Age-related and tone-dependent changes in alpha band activity were focused at frontal and sensorimotor areas. Neither functional brain specificity was observed for the amplitudes of the low-frequency (delta, theta, alpha) oscillations during the cognitive processing, which diminished with increasing age. CONCLUSION: The cognitive brain oscillatory specificity diminished with increasing age. PMID- 24797978 TI - Hyperhomocysteinemia, lipid and lipoprotein disturbances in patients with primary hypertension. AB - PURPOSES: The main aim of the study was to answer two questions: what are the concentrations of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apo A-I (apolipoprotein A-I), apo B (apolipoprotein B) and Lp(a) (lipoprotein(a)) in serum of patients with primary hypertension and with hyperhomocysteinemia? Is there any correlation between the concentration of homocysteine in blood serum and investigated lipid and lipoprotein parameters in patients with primary hypertension? MATERIAL/METHODS: We investigated 42 patients with primary hypertension, aged 22-57. The control group consisted of 20 healthy volunteers. The concentration of homocysteine in serum was evaluated using immunochemical method (FPIA - Fluorescence Polarization Immunoassay). The concentration of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides in blood serum were estimated using enzymatic method. Apo A-I, apo B and lipoprotein(a) were assessed using nephelometric method. RESULTS: The analysis of the results revealed statistically significant lower concentrations of HDL-cholesterol and apo A-I in blood serum of patients with primary hypertension and hyperhomocysteinemia than in the population with hypertension and normohomocysteinemia. Negative correlation between homocysteine and HDL cholesterol as well as apo A-I has been revealed. CONCLUSION: Quantitative analysis of the concentration of lipids and lipoproteins in blood serum in patients with primary hypertension and hyperhomocysteinemia may suggest that this type of human population might be more susceptible to atherosclerosis than those with primary hypertension and normal values of homocysteine. PMID- 24797979 TI - Effects on gut properties in exocrine pancreatic insufficient (EPI) pigs, being growth retarded due to pancreatic duct ligation at 7 weeks but not at 16 weeks of age. AB - PURPOSE: Exocrine pancreatic insufficiency (EPI) induced in young pigs by pancreatic duct ligation (PDL) early after weaning result in total growth deprivation while it has little effect in somewhat older pigs. The main objective was to study effects of EPI on gut structure and function in littermate pigs underwent to PDL at different age. MATERIAL/METHODS: Pigs, duct-ligated at either 7 (2 weeks post-weaning, PDL-7) or 16 weeks of age (PDL-16), and euthanized at an age of 21-23 weeks together with un-operated littermates were studied. The intestinal in vitro permeability was studied in separate PDL-pigs and compared to un-operated. RESULTS: Morphometric analysis showed gut mucosal atrophy in the PDL 7 as compared to PDL-16 pigs, while no differences in mucosal disaccharidase activities. The intestinal permeability for different-sized markers was significantly increased in the PDL-pigs compared to the un-operated controls. Analyses of the intestinal digesta showed a total lack of pancreatic enzymes in all PDL-pigs, while instead new, as yet unidentified, enzyme-activities appeared. CONCLUSIONS: All EPI-pigs, independent of age at PDL-operation, displayed adaptive gut changes, however the EPI-pigs operated early after weaning appeared more sensitive, probably related to their gut maturity and possibly explaining the growth arrest seen in these pigs. PMID- 24797980 TI - Serum fetuin A concentration is elevated in children with non-alcoholic fatty liver disease. AB - PURPOSE: To assess the serum fetuin A concentration as a potential marker of subclinical atherosclerosis in obese children with NAFLD. MATERIAL/METHODS: A prospective analysis of 45 obese children initially diagnosed with liver pathology (elevated serum ALT activity and/or ultrasonographic liver brightness and/or hepatomegaly) was conducted. The diagnosis of NAFLD was established in the children with elevated serum ALT activity and liver steatosis on ultrasound examination. Viral hepatitis, autoimmune, metabolic liver diseases (Wilson disease, alpha-1-antitrypsin deficiency, cystic fibrosis) and drug and toxin induced liver injury were excluded in all children. The degree of liver steatosis was graded according to Saverymuttu scale and the total liver lipids concentration was assessed using proton magnetic resonance spectroscopy ((1)H MRS). RESULTS: Serum fetuin A concentration was significantly higher in examined children compared to the control group (n=30) (p=0.00002). Higher serum fetuin A concentration was also observed in children with NAFLD (n=19) in comparison to the controls (p=0.000026). Additionally, higher BMI values, waist circumferences, ALT and GGT activity, intensity of liver steatosis on ultrasound and total concentration of lipids in the liver in (1)H MRS were found in children with NAFLD compared to the rest of the examined obese patients (n=26). There was not found any correlation of the investigated glycoprotein with any other assessed parameters both in children with NAFLD and obese children without NAFLD. CONCLUSION: Higher serum fetuin A concentration found in children with NAFLD compared to the control group support the hypothesis that atherosclerotic processes may develop faster in hepatopatic obese patients. PMID- 24797981 TI - Evaluation of estrogen receptor-beta expression in the epithelium of the oral mucosa in menopausal women under hormone replacement therapy. AB - PURPOSE: We aimed to evaluate the ERbeta expression in the epithelium of the oral mucosa in menopausal women treated with oral, transdermal or local (vaginal) menopausal hormone therapy. MATERIAL/METHODS: In this study, we included 60 women treated with oral, transdermal or vaginal menopausal hormone therapy. The study material was obtained from swabs taken from the buccal mucosa before administering HRT, and after 6 weeks, 3 months, 6 months and 12 months of therapy. We assessed estrogen receptor-beta (ERbeta) expression levels in subsequent swabs by immunohistochemical analysis. RESULTS: The highest increase in the ERbeta expression was observed after 3 months of oral and transdermal hormone therapy. CONCLUSIONS: Oral and transdermal HRT may be an effective method of treatment of oral discomfort in menopausal women. PMID- 24797982 TI - Second stage of Universal Neonatal Hearing Screening - a way for diagnosis and beginning of proper treatment for infants with hearing loss. AB - PURPOSE: To analyze retrospectively the results of hearing testing in infants at the second stage of the Polish Universal Neonatal Hearing Screening Program carried out in the Department of Otolaryngology at the Medical University of Warsaw. MATERIAL/METHODS: A total of 351 infants referred to our Department for the second stage of UNHS were included in the study. There were 39.60% infants referred due to positive result of hearing screening at the first stage of the Program performed in neonatal units, 55.27% with negative screening but risk factors present, and 5.13% without any tests due to equipment failure in the maternity unit. RESULTS: Risk factors were identified in 86.61% of the infants. The most frequent ones were hyperbilirubinemia (71.51%), premature birth (63.25%), and ototoxic medication (62.11%). Otoacoustic emission test showed fail results in 17.66% of the infants, and auditory brainstem responses confirmed hearing loss in 16.81%. Correlation between risk factors and confirmed hearing loss was found for hyperbilirubinemia, low birth weight, intensive therapy for at least 7 days, low Apgar scores, and craniofacial abnormalities. CONCLUSIONS: The early identification of infants with hearing loss is essential for early intervention. Not only infants who fail the initial screening but also the ones with risk factors of hearing impairment should be referred to the centers that are capable of providing the necessary diagnostic services required for the second stage of the UNHSP. Those two steps are needed to both minimize the risk of overlooking a child with hearing loss and properly diagnose hearing impairment. PMID- 24797983 TI - The use of glyburide in the management of gestational diabetes mellitus: a meta analysis. AB - PURPOSE: Glyburide has been used for managing gestational diabetes mellitus (GDM) in a number of countries. It is rather inexpensive. However, its efficacy and safety remain controversial. With this meta-analysis, we evaluated glyburide in comparison with insulin. MATERIAL/METHODS: With a systematic literature search strategy, a total of 93 randomized controlled trials (RCTs) with insulin and glyburide comparison were identified. Based on the revised Consolidated Standards of Reporting Trials (CONSORT) checklist, five of them met the inclusion criteria and were included in this meta-analysis. RESULTS: Six hundred and seventy four subjects were included in these five RCTs. When compared with insulin, glyburide had an increased relative risk (RR) for neonatal hypoglycemia (RR: 1.98; 95% confidence interval [CI]: 1.17, 3.36). Estimation of standard mean differences (SMD) showed that both fetal birth weight and incidence of macrosomia were higher in subjects receiving glyburide than in those receiving insulin (SMD: 0.21; 95% CI: 0.06, 0.36; RR: 2.22; 95% CI: 1.07, 4.61 respectively). There were no significant differences in maternal glucose control, glycated hemoglobin, the rate of Cesarean section, large-for-gestational age, neonatal hypocalcemia, length of stay for neonatal ICU admissions, preterm birth, or congenital anomalies. CONCLUSIONS: Our study suggested that in women with GDM, glyburide is as effective as insulin, but the risks of neonatal hypoglycemia, high fetal birth weight, and macrosomia were higher. PMID- 24797984 TI - Increased expression of the intercellular adhesion molecule-1 (ICAM-1) on peripheral blood neutrophils in acute pancreatitis. AB - PURPOSE: Considering the important role of neutrophils' activation in the pathogenesis of acute pancreatitis (AP), the aim of our study was to evaluate the expression of leukocytes' adhesion molecules in patients with AP. PATIENTS/METHODS: Thirty-five patients (16 women and 19 men; age 32-77 years, median 56 years) with AP were prospectively included into our study. The absolute number of leukocytes was estimated by haematologic analyser. Surface neutrophils antigens (CD) were assayed by the direct fluorescence method for whole blood, using a flow cytometer. RESULTS: At the day 1, significant increase of ICAM-1 expression was found in patients with severe AP (S-AP) (7280 mm(-3) vs 2850 mm( 3) in healthy control; p<0.05). In the days 2, 3 and 5 it sharply decreased and peaked again to 4860 mm(-3) at the day 10. In patients with mild AP (M-AP), not significant elevation of ICAM-1 quickly returned to normal level. In both forms of AP, neutrophil CD62L (L-selectin) expression reached the highest level at the day 1 (8800 mm(-3) and 9020 mm(-3), respectively in M-AP and S-AP, in comparison to 3400 mm(-3) in control; p<0.05). Expression of CD69 (neutrophils' marker of early activation) significantly increased in both M-AP and S-AP. CONCLUSIONS: We have found an early and significant increase of peripheral blood neutrophil CD54/ICAM-1 expression, specific for S-AP but not for M-AP. It may provide a good marker predicting severe course of pancreatitis. PMID- 24797985 TI - Sickle cell anemia: intracranial stenosis and silent cerebral infarcts in children with low risk of stroke. AB - PURPOSE: Children with sickle cell anemia (SCA), who have mean blood flow velocities <170 cm/s in the terminal internal carotid (tICA) or middle cerebral (MCA) arteries on transcranial Doppler ultrasonography (TCD), are considered to be at low risk of stroke. The prevalence of intracranial stenosis, which raises the risk of stroke, is not known in these children. Here, we estimated the prevalence of stenosis and explored its association with silent cerebral infarcts determined based on Magnetic Resonance (MR) scans. PATIENTS/METHODS: We studied prospectively a cohort of 67 children with SCA without prior clinically overt stroke or TIA (median age 8.8 years; range limits 2.3-13.1 years; 33 females) and with TCD mean velocity <170 cm/s. They underwent MR imaging of the brain and MR angiography of intracranial arteries. RESULTS: In 7 children (10.5%, 95% CI: 4.9 20.3%) we found 10 stenoses, including 4 with isolated left tICA stenosis and 3 with multiple stenoses. We found silent infarcts in 26 children (37.7%, 95% CI: 27.2-49.5%). The median number of infarcts in an affected child was 2 (range limits: 1-9), median volume of infarcts was 171 mm(3) (range limits: 7-1060 mm(3)), and median infarct volume in relation to total brain volume was 0.020% (range limits: 0.001-0.101%). The number and volume of infarcts were significantly higher in children with arterial stenosis (both p=0.023). CONCLUSIONS: The prevalence of intracranial arterial stenosis in children with SCA classified as at low risk of stroke by TCD mean velocity <170 cm/s is high. Children with stenosis are at higher risk of brain parenchymal injury as they have more silent cerebral infarcts. PMID- 24797986 TI - BRCA1 gene-related hereditary susceptibility to breast and ovarian cancer in Latvia. AB - PURPOSE: In this report, we summarise data on BRCA1 gene analysis in Latvia to characterise criteria of genetic testing for breast and ovarian cancer susceptibility. MATERIAL/METHODS: Analysis by SSCP/HD, MALDI-TOF mass spectrometry or DNA sequencing was used for mutation detection. Mutations identified were confirmed by direct DNA sequencing. RESULTS: Out of 1068 breast and 231 ovarian cancer patients from different families: 58 carried the c.5266dupC and 43 carried the c.4035delA mutations. Every 4th patient in our study did not report cancer in the family. The breast cancer was diagnosed earlier in carriers of the c.5266dupC than in carriers of the c.4035delA (p=0.003). The incidence of breast or ovarian cancer does not differ among the 2 mutation carriers in our patient group. The nature of the c.5266dupC mutation might be more deleterious. CONCLUSIONS: We recommend the screening of 4 founder BRCA1 mutations in all breast and ovarian cancer patients in Latvia at diagnosis of disease regardless of family history or age. The BRCA1 screening can be carried out efficiently using the MALDI-TOF mass spectrometry mutation detection method developed in the Biomedical Research and Study Centre (Riga, Latvia). PMID- 24797987 TI - Role of left atrial speckle tracking echocardiography in predicting persistent atrial fibrillation electrical cardioversion success and sinus rhythm maintenance at 6 months. AB - PURPOSE: We assessed the value of left atrium speckle tracking imaging (STI) indices, and clinical and other echocardiographic parameters in persistent atrial fibrillation (AF) patients to predict the efficacy of electrical cardioversion (EC) and sinus rhythm (SR) maintenance at 6 months. MATERIAL/METHODS: Eighty persistent AF patients planned to receive EC, underwent echocardiography including STI. After 24h, patients with successful EC were examined to predict SR maintenance. After 6 months patients with no AF recurrence in electrocardiogram (ECG) underwent 7-day ECG to exclude silent AF. Every AF>1 min was a recurrence. RESULTS: SR restored in 61 patients, 19 unsuccessful. Prior use of statins (68.8% vs. 42.1%, p=0.03) was the only factor, determined later by univariate analysis to be a significant EC success predictor (OR=1.09, CL +/- 95% 1.001-1.019, p<0.03). Both groups received similar antiarrhythmics and had similar echocardiographic parameters. After 6 months, SR was maintained in 19 patients (31.1%, Group I); AF recurrences were registered in 42 patients (68.8%, Group II). In Group I, only the mitral valve deceleration time (MVDT) 224.18 +/- 88.13 vs. 181.6 +/- 60.6 in Group II, p=0.04) and the dispersion of time to peak longitudinal strain (dTPLS) (86.0 +/- 68.3 vs. 151.8 +/- 89.6, p=0.03) differed significantly. The univariate analysis revealed dTPLS as a significant predictor of SR maintenance. CONCLUSION: High EC efficacy and frequent AF recurrences were observed. The dispersion of time to the maximal longitudinal strain (LS) of left atrial segments facilitated prediction of SR maintenance. The value of 7-day ECG monitoring for detection of arrhythmia after 6 months was limited. PMID- 24797988 TI - Association between type 1 diabetes and periodontal health. AB - PURPOSE: We assessed periodontal status in patients with type 1 diabetes and healthy individuals in relation to their glycemic control, smoking and inflammatory biomarkers. MATERIAL/METHODS: Periodontal status was examined in 107 patients with diabetes and 40 controls, using Oral Hygiene Index (OHI), Community Periodontal Index (CPI) and tooth number. CPI values of 0-2 and 3-4 were classified as non-periodontitis and periodontitis, respectively. Blood samples were analyzed for glucose, HbA1c, CRP, fibrinogen, interleukin-1 and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Periodontitis was found in 15.0% of the controls and 57.9% of diabetic patients, including 40.0% of these with good metabolic control (GMC) and 59.5% of those with poor metabolic control (PMC). Severe periodontitis was more frequent in the PMC than in the GMC group and in the controls (26.0% vs. 20.0% vs. 5.0%). The PMC patients had lower number of sextants with CPI 0 and higher number of sextants with CPI 3 and CPI 4 as well as lower tooth number in comparison with the controls. The patients with periodontitis had higher TNF-alpha (p<0.001) and OHI (p<0.001) than the patients without periodontitis. The number of sextants with CPI 0 correlated negatively with fibrinogen and TNF-alpha levels, whereas the number of sextants with CPI 3 correlated positively with TNF-alpha and fasting glucose level. CONCLUSIONS: There is good evidence that type 1 diabetes increases the risk of periodontal disease. Our results suggest that poor metabolic control of diabetes together with smoking and inadequate oral hygiene increase the risk of severe periodontal destruction in patients with type 1 diabetes. PMID- 24797989 TI - Intraoperative bleeding during endoscopic sinus surgery and microvascular density of the nasal mucosa. AB - PURPOSE: To evaluate the correlation between quality of the surgical field, intraoperative bleeding during endoscopic sinus surgery (ESS) and the density of microvasculature of the nasal mucosa. MATERIAL/METHODS: Nasal mucosa of 30 patients, operated for chronic rhinosinusitis, was biopsied to assess expression of CD34 antigen on vascular endothelium. Quality of surgical field was evaluated with Fromm-Boezaart scale at mean arterial pressure (MAP) of 70-80 mmHg. If at this MAP surgical field quality was not satisfactory further reduction of hemodynamic parameters was performed until 'bloodless surgical field' (grade 2 or lower) was achieved. The rate of intraoperative bleeding was calculated from the ratio of total blood loss and the operative time. The extent of the disease was assessed according to computed tomography findings using Lund-Mackay staging system. RESULTS: Significant positive correlation (Spearman correlation test; p<0.05) was found between CD34 antigen expression and quality of surgical field at MAP between 70 and 80 mmHg as well as the rate of intraoperative bleeding. More intense reduction of MAP was necessary to achieve 'bloodless surgical field' in patients with high CD34 expression than in those with moderate and low expression. Lund-Mackay score correlated with quality of surgical field but not with the rate of intraoperative bleeding. CONCLUSION: During ESS, it is microvascular density of the nasal mucosa rather than the extent of the disease that contributes to the intensity of intraoperative bleeding, although both factors negatively influence the quality of surgical field. PMID- 24797990 TI - Flavonoids of willow herb (Chamerion angustifolium (L.) Holub) and their radical scavenging activity during vegetation. AB - PURPOSE: Willow herb has been traditionally used in folk medicine and currently it is a potential raw material for production of phytopharmaceuticals. The aim of this work was to determine the highest amount of flavonoids and the highest radical scavenging activity of willow herb, which was collected in different vegetation phases (intensive growing, bud, massive blooming, ripening of fruits (seeds) and the end of vegetation) and in different parts of the plant (blooms, leaves and stems). MATERIAL/METHODS: Raw material was collected at Kaunas Botanical garden of Vytautas Magnus University. Willow herb was extracted using methanol/water mixture (75/25 v/v, %). Methanolic extracts were purified using solid-phase extraction. For determination of the radical scavenging activity of compounds the HPLC system with the on-line post-column DPPH (1,1-diphenyl-2 picrylhydrazyl) radical reaction detection was used. RESULTS: Five flavonoids were identified and their quantitative distribution and radical scavenging activity were evaluated. The highest total amount of flavonoids and radical scavenging activity were determined in willow herb collected during the massive blooming phase (11.12 +/- 0.34 mg/g and 8.71 +/- 0.29 mg/g, respectively). CONCLUSIONS: The highest amount of flavonoids and radical scavenging activity was determined for raw material collected during the massive blooming phase. Evaluation of different parts of the plant during the massive blooming phase revealed that the highest amount of flavonoids and radical scavenging activity are characteristic for blooms of the plant. PMID- 24797991 TI - Gastric cancer patients less than 50 years of age exhibit significant downregulation of E-cadherin and CDX2 compared to older reference populations. AB - PURPOSE: There is an increasing need to identify molecular markers, which can be used to prognosticate patient populations in gastric cancer. Whereas a significant number have been identified, very few have been characterized in the context of their ability to discriminate between young and old age groups in which a survival difference clearly exists. MATERIAL/METHODS: In this study, using immunohistochemistry, we evaluated three markers with proven involvement in gastric cancer. The p53 tumor suppressor, the cell adhesion glycoprotein epithelial cadherin (CDH1) and the caudal-related homeobox transcription factor (CDX2) all of these have important roles in the aetiopathogenesis and/or progression of gastric cancer. RESULTS: After adjustments for TNM stage, tumor grade, histopathological characteristics (Lauren classification), we found significant differences in the expression of these proteins, particularly E cadherin and CDX2 between young and elderly patients. However, these differences did not amount to a significant difference in survival. CONCLUSIONS: This study demonstrates that the protein expression of p53, CDH1 and CDX2 significantly discriminates young patients with gastric cancer who have a better prognostic outlook from older patients, but this difference in expression does not contribute to a survival benefit. PMID- 24797992 TI - Seroprevalence of Helicobacter pylori infection in Polish children and adults depending on socioeconomic status and living conditions. AB - PURPOSE: Helicobacter pylori (H. pylori) is one of the causes of gastritis, peptic ulcer disease, gastric cancer and MALT-lymphoma. The frequency of H. pylori infection is different in various regions of the world and dependent on age, socioeconomic and hygiene status. The objective of this study was to assess seroprevalence and the associated socioeconomic and sociodemographic characteristics influencing H. pylori infection in children and adults in Polish population. MATERIAL/METHODS: In multicenter epidemiological studies, H. pylori infection occurrence was assessed in Poland in the years 2002 and 2003. The seroprevalence of H. pylori infection diagnosis was based on IgG anti-H. pylori antibodies concentration above 24 UI/ml, which was measured using ELISA test. The study included 6565 subjects: 3307 adults (50.37%) and 3258 children (49.63%). RESULTS: Positive result was observed in 3827 subjects (58.29%), i.e. 1043 children (32.01%) and 2784 adults (84.19%). H. pylori infection prevalence was greater in children of poor economic status, who were born in a rural area, lived in crowded houses with no running tap water and with toilet outside the house, and who did not observe hygiene rules. In adults, the factors predisposing to higher probability of being H. pylori infected included: being born in a rural area, having low family income and elementary education, smoking tobacco, drinking high proof alcohols as well as not observing of hygiene rules. CONCLUSIONS: Improvement of socioeconomic status, sanitary and hygienic conditions and the education of the society might decrease H. pylori infection prevalence in children and in adults. PMID- 24797994 TI - Frequency of apnea and respiratory viruses in infants with bronchiolitis. AB - The frequency of apnea in infants <12 months of age admitted with acute bronchiolitis was 5.16% (95% confidence interval: 3.94-6.72). Most commonly detected viruses in the 51 apneic infants were respiratory syncytial virus (33.3%), rhinovirus (13.7%) and viral coinfections (23.5%). Young age and prematurity were the main risk factors for apnea independent of the respiratory syncytial virus status. Non-respiratory syncytial virus infants had a higher rate of prematurity. PMID- 24797993 TI - Influence of age and nutritional status on the performance of the tuberculin skin test and QuantiFERON-TB gold in-tube in young children evaluated for tuberculosis in Southern India. AB - BACKGROUND: Reliable identification of Mycobacterium tuberculosis infection or tuberculosis (TB) disease in young children is vital to assure adequate preventive and curative treatment. The tuberculin skin test (TST) and IFNgamma release assays may supplement the diagnosis of pediatric TB as cases are typically bacteriologically unconfirmed. However, it is unclear to what extent the performance of TST and QuantiFERON-TB Gold In-Tube (QFT; Cellestis' IFNgamma release assay test) depends on the demographic, clinical and nutritional characteristics of children in whom they are tested. METHODS: During a 2-year prospective observational study of 4382 neonates in Southern India, children with suspected TB were investigated and classified by a standard TB diagnostic algorithm. RESULTS: Clinical TB was diagnosed in 13 of 705 children referred for case verification with suspected TB. TST and QFT had a susceptibility for clinical TB of 31% and 23%, respectively, in this group. Children <2 years were more likely to test QFT indeterminate. A height-for-age Z score within the lowest quartile increased the odds ratio (OR) for a positive or indeterminate QFT result [OR 2.46 (1.19-5.06), OR 3.08 (1.10-8.58)], whereas the OR for a positive TST was reduced with a weight-for-height Z score within the lowest quartile [OR 0.17 (0.06-0.47)]. CONCLUSION: The sensitivities of the TST and QFT for clinical TB in children <3 years of age were equally poor in this population. Stunted children were more susceptible to Mycobacterium tuberculosis infection and more prone to indeterminate QFT results. TST was less reliable in children with wasting. PMID- 24797995 TI - Severe blastomycosis in infants. AB - Blastomycosis is a dimorphic fungal infection that can be manifested as pulmonary or extrapulmonary disease. Disease in infants is rare, even in endemic areas. We report a case of severe blastomycosis in a 4-month-old infant, as well as details of 2 other cases from our center and a brief review of infant blastomycosis. PMID- 24797996 TI - Toll-like receptor 6 V327M polymorphism is associated with an increased risk of Klebsiella pneumoniae infection. AB - BACKGROUND: Klebsiella pneumoniae is a common cause of nosocomial pneumonia, especially in children. Toll-like receptors plays an important role in defense against this pathogen. The impact of human TLR6 polymorphisms on susceptibility to K. pneumoniae infection is poorly understood. The aim of the present work was to determine whether single nucleotide polymorphisms in TLR6 are associated with altered immune responses to K. pneumoniae. METHODS: The TLR6 coding region was sequenced in 126 K. pneumoniae culture-positive patients and 142 hospitalized K. pneumoniae culture-negative controls. RESULTS: The frequency of V327M polymorphism was found to be significantly higher in patients than that in controls (16.7% vs. 7.7%). In vitro studies showed that V327M polymorphism did not impair TLR6 expression in transfected HEK 293T cells. Further studies demonstrated that V327M polymorphism was associated with increased IL-8 mRNA expression in transfected HEK 293T cells when stimulated with K. pneumoniae and the specific ligand for TLR2/TLR6 heterodimers known as Pam2CSK4. The present data showed V327M polymorphism to be associated with increased apoptosis of HEK 293T cells when challenged with K. pneumoniae. CONCLUSIONS: Taken together, these data indicated that TLR6 V327M may be involved in mediating deleterious inflammatory responses and modulating host susceptibility to K. pneumoniae. These results provide new insight into the pathophysiologic role of TLR6 V327M in the innate immune response to bacterial infection in human. PMID- 24797997 TI - Associations of host genetic variants on CD4+ lymphocyte count and plasma HIV-1 RNA in antiretroviral naive children. AB - BACKGROUND: CD4 T-lymphocyte (CD4) counts and HIV plasma RNA concentration (RNA) are 2 key HIV disease markers. The complex interplay between virus and host genetics may contribute to differences in viral set point and CD4 status. Determining the effects of host genetic variation on HIV disease markers is often complicated by the use of antiretroviral therapy. In this study, the association between genetic variants and baseline HIV RNA and CD4 counts was examined in a large cohort of antiretroviral naive children. METHODS: Specimens from 1053 HIV infected children were screened for single nucleotide polymorphisms in 78 regions from 17 genes. Linear regression with a robust variance estimator was used to test the association between genetic markers with HIV RNA and CD4 count, controlling for age, race/ethnicity and study. False discovery rate (FDR) controlling was used to adjust for multiple testing. RESULTS: The study population was 60% black, 26% Hispanic and 13% white; median age 2.35 years; 55% female. Baseline median CD4 count was 780/mm; median log10 HIV RNA was 5.17 copies/mL. For analyses of the associations of genetic makers with baseline CD4 count, 6 HLA and 4 additional markers exhibited P < 0.05, but none met the criteria for statistical significance with FDR controlled at 0.05. For baseline HIV RNA, HLA DRB1*15, DRB1*10, B-27/57, B-14, Cw-8, B-57 were statistically significant with FDR controlled at 0.05. CONCLUSIONS: These results provide strong evidence that HLA DRB1*15, DRB1*10, B-27/57, B-14, Cw-8, B-57 are associated with HIV RNA and play a role in HIV pathogenesis in infected children. PMID- 24797998 TI - Integrating social work into palliative care for lung cancer patients and families: a multidimensional approach. AB - Lung cancer patients and their family caregivers face a wide range of potentially distressing symptoms across the four domains of quality of life. A multidimensional approach to addressing these complex concerns with early integration of palliative care has proven beneficial. This article highlights opportunities to integrate social work using a comprehensive quality of life model and a composite patient scenario from a large lung cancer educational intervention National Cancer Institute-funded program project grant. PMID- 24797999 TI - Will next-generation sequencing also take us to the next level of understanding disease mechanisms? PMID- 24798000 TI - Simultaneous pH measurement in endocytic and cytosolic compartments in living cells using confocal microscopy. AB - Intracellular pH is tightly regulated and differences in pH between the cytoplasm and organelles have been reported(1). Regulation of cellular pH is crucial for homeostatic control of physiological processes that include: protein, DNA and RNA synthesis, vesicular trafficking, cell growth and cell division. Alterations in cellular pH homeostasis can lead to detrimental functional changes and promote progression of various diseases(2). Various methods are available for measuring intracellular pH but very few of these allow simultaneous measurement of pH in the cytoplasm and in organelles. Here, we describe in detail a rapid and accurate method for the simultaneous measurement of cytoplasmic and organellar pH by using confocal microscopy on living cells(3). This goal is achieved with the use of two pH-sensing ratiometric dyes that possess selective cellular compartment partitioning. For instance, SNARF-1 is compartmentalized inside the cytoplasm whereas HPTS is compartmentalized inside endosomal/lysosomal organelles. Although HPTS is commonly used as a cytoplasmic pH indicator, this dye can specifically label vesicles along the endosomal-lysosomal pathway after being taken up by pinocytosis(3,4). Using these pH-sensing probes, it is possible to simultaneously measure pH within the endocytic and cytoplasmic compartments. The optimal excitation wavelength of HPTS varies depending on the pH while for SNARF-1, it is the optimal emission wavelength that varies. Following loading with SNARF-1 and HPTS, cells are cultured in different pH-calibrated solutions to construct a pH standard curve for each probe. Cell imaging by confocal microscopy allows elimination of artifacts and background noise. Because of the spectral properties of HPTS, this probe is better suited for measurement of the mildly acidic endosomal compartment or to demonstrate alkalinization of the endosomal/lysosomal organelles. This method simplifies data analysis, improves accuracy of pH measurements and can be used to address fundamental questions related to pH modulation during cell responses to external challenges. PMID- 24798002 TI - Rice CYP703A3, a cytochrome P450 hydroxylase, is essential for development of anther cuticle and pollen exine. AB - Anther cuticle and pollen exine act as protective envelopes for the male gametophyte or pollen grain, but the mechanism underlying the synthesis of these lipidic polymers remains unclear. Previously, a tapetum-expressed CYP703A3, a putative cytochrome P450 fatty acid hydroxylase, was shown to be essential for male fertility in rice (Oryza sativa L.). However, the biochemical and biological roles of CYP703A3 has not been characterized. Here, we observed that cyp703a3-2 caused by one base insertion in CYP703A3 displays defective pollen exine and anther epicuticular layer, which differs from Arabidopsis cyp703a2 in which only defective pollen exine occurs. Consistently, chemical composition assay showed that levels of cutin monomers and wax components were dramatically reduced in cyp703a3-2 anthers. Unlike the wide range of substrates of Arabidopsis CYP703A2, CYP703A3 functions as an in-chain hydroxylase only for a specific substrate, lauric acid, preferably generating 7-hydroxylated lauric acid. Moreover, chromatin immunoprecipitation and expression analyses revealed that the expression of CYP703A3 is directly regulated by Tapetum Degeneration Retardation, a known regulator of tapetum PCD and pollen exine formation. Collectively, our results suggest that CYP703A3 represents a conserved and diversified biochemical pathway for in-chain hydroxylation of lauric acid required for the development of male organ in higher plants. PMID- 24798001 TI - Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. AB - Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). CONCLUSION: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients. PMID- 24798004 TI - Introduction: brief historical overview. AB - Membranes are essential in defining the border and ensuring function of all living cells. As such they are vulnerable and have been a preferred target of attack throughout evolution. The most powerful way of damaging a membrane is through the insertion of pore-forming proteins. Research over the last decades shows that such proteins are produced by bacteria to attack bacterial or eukaryotic cells, vertebrates to kill invading organisms or infected cells, and by eukaryotic cells to "kill" mitochondria and trigger apoptosis. The breadth of effect of these proteins is bringing together, in a very exciting way, research communities that used to be unaware of each other. PMID- 24798003 TI - Hyperglycemia in patients referred for cardiac catheterization is associated with preexisting diabetes rather than a stress-related phenomenon: a prospective cross sectional study. AB - BACKGROUND: An increased serum glucose level in patients with acute coronary syndrome (ACS) is associated with adverse clinical outcome. This hyperglycemia has been attributed, at least in part, to acute stress reaction. Our objective was to determine whether hyperglycemia is a stress-related phenomenon or whether it represents a more sustained and possibly significant background dysglycemia. HYPOTHESIS: Hyperglycemia in patients undergoing coronary angiography is related to background dysglycemia. METHODS: Blood samples were obtained at the time of cardiac catheterization. Patients with hemoglobin A1c >6.5% were excluded to avoid patients with chronic glucose levels above 135 mg/dL. A logistic regression model was created to assess the influence of different variables on hyperglycemia (glucose levels above 140 mg/dL). We also evaluated the effect of glucose levels above 140 mg/dL on major adverse cardiovascular events (MACEs) up to 36 months. RESULTS: There were 2554 consecutive patients prospectively recruited. Serum glucose levels above 140 mg/dL was a strong predictor of MACE (hazard ratio: 2.2, 95% confidence interval [CI]: 1.3-3.6, P = 0.002). Both diabetes mellitus and ACS were associated with hyperglycemia (glucose levels above 140 mg/dL). Nevertheless, the incidence of hyperglycemia was doubled in diabetic patients (odds ratio [OR]: 9.4, 95% CI: 3.9-22.4, P < 0.001) compared with patients with ACS (OR: 4.6, 95% CI: 2.3-9.0, P < 0.001). Combining both conditions was associated with a high likelihood of elevated glucose levels (OR: 15.5, 95% CI: 7.4-32.9, P < 0.001). CONCLUSIONS: Hyperglycemia in patients undergoing cardiac catheterization is a strong predictor of adverse outcome. It is mainly related to background dysglycemia and to a lesser extent to the acute stress accompanying ACS. PMID- 24798005 TI - Distribution of MACPF/CDC proteins. AB - Membrane Attack Complex/Perforin (MACPF) and Cholesterol-Dependent Cytolysins (CDC) form the MACPF/CDC superfamily of important effector proteins widespread in nature. MACPFs and CDCs were discovered separately with no sequence similarity at that stage being apparent between the two protein families such that they were not, until recently, considered evolutionary related. The breakthrough showing they are came with recent structural work that also shed light on the molecular mechanism of action of various MACPF proteins. Similarity in structural properties and conserved functional features indicate that both protein families have the same evolutionary origin. We will describe the distribution of MACPF/CDC proteins in nature and discuss briefly their similarity and functional role in different biological processes. PMID- 24798006 TI - Evolution of the complement system. AB - The mammalian complement system constitutes a highly sophisticated body defense machinery comprising more than 30 components. Research into the evolutionary origin of the complement system has identified a primitive version composed of the central component C3 and two activation proteases Bf and MASP in cnidaria. This suggests that the complement system was established in the common ancestor of eumetazoa more than 500 million years ago. The original activation mechanism of the original complement system is believed to be close to the mammalian lectin and alternative activation pathways, and its main role seems to be opsonization and induction of inflammation. This primitive complement system has been retained by most deuterostomes without major change until the appearance of jawed vertebrates. At this stage, duplication of the C3, Bf and MASP genes as well as recruitment of membrane attack components added the classical and lytic pathways to the primitive complement system, converting it to the modern complement system. In contrast, the complement system was lost multiple times independently in the protostome lineage. PMID- 24798007 TI - Structural features of cholesterol dependent cytolysins and comparison to other MACPF-domain containing proteins. AB - Five different cholesterol-dependent cytolysins (CDCs) have now had their atomic structures solved. Here their structures are compared and shown to vary less in the C-terminal region than they do in their N-terminal MACPF/CDC homology region. The most variable region of the C-terminal domain is the undecapeptide, which is observed in two clusters of conformations, and comparison of this domain with the C2 domain of perforin shows that the two structures have a common ancestor. Structural studies of CDC pre-pore and pore oligomers by cryo-electron microscopy and atomic force microscopy have revealed much about their mechanism of action. Understanding the activity of CDCs has required a combination of structural, biophysical and functional assays but current models of pore formation still require development to account for variable functional pore size. PMID- 24798009 TI - Structural biology of the membrane attack complex. AB - The complement system is an intricate network of serum proteins that mediates humoral innate immunity through an amplification cascade that ultimately leads to recruitment of inflammatory cells or opsonisation or killing of pathogens. One effector arm of this network is the terminal pathway of complement, which leads to the formation of the membrane attack complex (MAC) composed of complement components C5b, C6, C7, C8 and C9. Upon formation of C5 convertases via the classical or alternative pathways of complement activation, C5b is generated from C5 by proteolytic cleavage, nucleating a series of association and polymerisation reactions of the MAC-constituting complement components that culminate in pore formation of pathogenic membranes. Recent structures of MAC components and homologous proteins significantly increased our understanding of oligomerisation, membrane association and integration, shedding light onto the molecular mechanism of this important branch of the innate immune system. PMID- 24798008 TI - Perfringolysin O structure and mechanism of pore formation as a paradigm for cholesterol-dependent cytolysins. AB - Cholesterol-dependent cytolysins (CDCs) constitute a family of pore forming toxins secreted by Gram-positive bacteria. These toxins form transmembrane pores by inserting a large beta-barrel into cholesterol-containing membrane bilayers. Binding of water-soluble CDCs to the membrane triggers the formation of oligomers containing 35-50 monomers. The coordinated insertion of more than seventy beta hairpins into the membrane requires multiple structural conformational changes. Perfringolysin O (PFO), secreted by Clostridium perfringens, has become the prototype for the CDCs. In this chapter, we will describe current knowledge on the mechanism of PFO cytolysis, with special focus on cholesterol recognition, oligomerization, and the conformational changes involved in pore formation. PMID- 24798010 TI - Membrane interactions and cellular effects of MACPF/CDC proteins. AB - The cell membrane is crucial for protection of the cell from its environment. MACPF/CDC proteins are a large superfamily known to be essential for bacterial pathogenesis and proper functioning of the immune system. The three most studied groups of MACPF/CDC proteins are cholesterol-dependent cytolysins from bacteria, the membrane attack complex of complement and human perforin. Their primary function is to form transmembrane pores in target cell membranes. The common mechanism of action comprises water-soluble monomeric proteins binding to the host cell membrane, oligomerization, and formation of a functional pore. This causes a disturbance in gradients of ions and other molecules across the membrane and can lead to cell death. Cells react to this form of attack in a complex manner. Responses can be general, like removing the perforated part of the membrane, or more specific, in many cases depending on binding of proteins to specific receptors to trigger various signalling cascades. PMID- 24798011 TI - The biology of pneumolysin. AB - Cholesterol dependent cytolysins are important in the ability of some bacteria to cause disease in man and animals. Pneumolysin (PLY) plays a key role in the diseases caused by Streptococcus pneumoniae (the pneumococcus). This chapter describes the role of PLY in some of the key process in disease. These include induction of cell death by pore formation and toxin-induced apoptosis as well as more subtle effects on gene expression of host cells including epigenetic effects of the toxin. The use of bacterial mutants that either do not express the toxin or express altered versions in biological systems is described. Use of isolated tissue and whole animal systems to dissect the structure/function relationships of the toxin as well as the role played by different activities in the pathogenesis of infection are described. The role of PLY in meningitis and the associated deafness is discussed as well as the role of the toxin in promoting increased lung permeability and inflammation during pneumococcal pneumonia. Different clinical strains of the pneumococcus produce different forms of PLY and the impact of this on disease caused by these strains is discussed. Finally, the impact of this knowledge on the development of treatment and prevention strategies for pneumococcal disease is discussed. PMID- 24798013 TI - Perforin: a key pore-forming protein for immune control of viruses and cancer. AB - Perforin (PFN) is the key pore-forming molecule in the cytotoxic granules of immune killer cells. Expressed only in killer cells, PFN is the rate-limiting molecule for cytotoxic function, delivering the death-inducing granule serine proteases (granzymes) into target cells marked for immune elimination. In this chapter we describe our current understanding of how PFN accomplishes this task. We discuss where PFN is expressed and how its expression is regulated, the biogenesis and storage of PFN in killer cells and how they are protected from potential damage, how it is released, how it delivers Granzymes into target cells and the consequences of PFN deficiency. PMID- 24798014 TI - Perforin and human diseases. AB - Natural killer (NK) cells and cytotoxic T lymphocytes (CTL) use a highly toxic pore-forming protein perforin (PFN) to destroy cells infected with intracellular pathogens and cells with pre-cancerous transformations. However, mutations of PFN and defects in its expression can cause an abnormal function of the immune system and difficulties in elimination of altered cells. As discussed in this chapter, deficiency of PFN due to the mutations of its gene, PFN1, can be associated with malignancies and severe immune disorders such as familial hemophagocytic lymphohistiocytosis (FHL) and macrophage activation syndrome. On the other hand, overactivity of PFN can turn the immune system against autologous cells resulting in other diseases such as systemic lupus erythematosus, polymyositis, rheumatoid arthritis and cutaneous inflammation. PFN also has a crucial role in the cellular rejection of solid organ allografts and destruction of pancreatic beta-cells resulting in type 1 diabetes. These facts highlight the importance of understanding the biochemical characteristics of PFN. PMID- 24798015 TI - The role of MACPF proteins in the biology of malaria and other apicomplexan parasites. AB - Apicomplexans are eukaryotic parasites of major medical and veterinary importance. They have complex life cycles through frequently more than one host, interact with many cell types in their hosts, and can breach host cell membranes during parasite traversal of, or egress from, host cells. Some of these parasites make a strikingly heavy use of the pore-forming MACPF domain, and encode up to 10 different MACPF domain-containing proteins. In this chapter, we focus on the two most studied and medically important apicomplexans, Plasmodium and Toxoplasma, and describe the known functions of their MACPF polypeptide arsenal. Apicomplexan MACPF proteins appear to be involved in a variety of membrane-damaging events, making them an attractive model to dissect the structure-function relationships of the MACPF domain. PMID- 24798016 TI - Chlamydial MACPF protein CT153. AB - Chlamydiae are obligate intracellular bacterial parasites that infect a wide range of metazoan hosts. Some Chlamydia species are important causes of chronic inflammatory diseases of the ocular, genital and respiratory tracts in humans. Genes located in a variable region of chlamydial genomes termed the plasticity zone are known to be key determinants of pathogenic diversity. The plasticity zone protein CT153, present only in select species, contains a membrane attack complex/perforin (MACPF) domain, which may mediate chlamydial interactions with the host cell. CT153 is present throughout the C. trachomatis developmental cycle and is processed into polypeptides that interact with membranes differently than does the parent protein. Chlamydiae interact extensively with membranes from the time of invasion until they eventually exit host cells, so numerous roles for a MACPF protein in pathogenesis of these pathogens are conceivable. Here, we present an overview of what is known about CT153 and highlight potential roles of a MACPF family protein in a group of pathogens whose intracellular development is marked by a series of interactions with host cell membranes and organelles. Finally, we identify new strategies for identifying CT153 functions made feasible by the recent development of a basic toolset for genetic manipulation of chlamydiae. PMID- 24798012 TI - Multifaceted activity of listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes. AB - The cholesterol-dependent cytolysins (CDCs) are a large family of pore-forming toxins that are produced by numerous Gram-positive bacterial pathogens. These toxins are released in the extracellular environment as water-soluble monomers or dimers that bind to cholesterol-rich membranes and assemble into large pore complexes. Depending upon their concentration, the nature of the host cell and membrane (cytoplasmic or intracellular) they target, the CDCs can elicit many different cellular responses. Among the CDCs, listeriolysin O (LLO), which is a major virulence factor of the facultative intracellular pathogen Listeria monocytogenes, is involved in several stages of the intracellular lifecycle of the bacterium and displays unique characteristics. It has long been known that following L. monocytogenes internalization into host cells, LLO disrupts the internalization vacuole, enabling the bacterium to replicate into the host cell cytosol. LLO is then used by cytosolic bacteria to spread from cell to cell, avoiding bacterial exposure to the extracellular environment. Although LLO is continuously produced during the intracellular lifecycle of L. monocytogenes, several processes limit its toxicity to ensure the survival of infected cells. It was previously thought that LLO activity was limited to mediating vacuolar escape during bacterial entry and cell to cell spreading. This concept has been challenged by compelling evidence suggesting that LLO secreted by extracellular L. monocytogenes perforates the host cell plasma membrane, triggering important host cell responses. This chapter provides an overview of the well-established intracellular activity of LLO and the multiple roles attributed to LLO secreted by extracellular L. monocytogenes. PMID- 24798017 TI - Fungal MACPF-like proteins and aegerolysins: bi-component pore-forming proteins? AB - Proteins with membrane-attack complex/perforin (MACPF) domains are found in almost all kingdoms of life, and they have a variety of biological roles, including defence and attack, organism development, and cell adhesion and signalling. The distribution of these proteins in fungi appears to be restricted to some Pezizomycotina and Basidiomycota species only, in correlation with another group of proteins with unknown biological function, known as aegerolysins. These two protein groups coincide in only a few species, and they might operate in concert as cytolytic bi-component pore-forming agents. Representative proteins here include pleurotolysin B, which has a MACPF domain, and the aegerolysin-like protein pleurotolysin A, and the very similar ostreolysin A, which have been purified from oyster mushroom (Pleurotus ostreatus). These have been shown to act in concert to perforate natural and artificial lipid membranes with high cholesterol and sphingomyelin content. The aegerolysin-like proteins provide the membrane cholesterol/sphingomyelin selectivity and recruit oligomerised pleurotolysin B molecules, to create a membrane-inserted pore complex. The resulting protein structure has been imaged with electron microscopy, and it has a 13-meric rosette-like structure, with a central lumen that is ~4-5 nm in diameter. The opened transmembrane pore is non selectively permeable for ions and smaller neutral solutes, and is a cause of cytolysis of a colloid-osmotic type. The biological significance of these proteins for the fungal life-style is discussed. PMID- 24798018 TI - Fluorescence imaging of MACPF/CDC proteins: new techniques and their application. AB - Structural and biochemical investigations have helped illuminate many of the important details of MACPF/CDC pore formation. However, conventional techniques are limited in their ability to tackle many of the remaining key questions, and new biophysical techniques might provide the means to improve our understanding. Here we attempt to identify the properties of MACPF/CDC proteins that warrant further study, and explore how new developments in fluorescence imaging are able to probe these properties. PMID- 24798019 TI - Acridone alkaloids from Glycosmis chlorosperma as DYRK1A inhibitors. AB - Two new acridone alkaloids, chlorospermines A and B (1 and 2), were isolated from the stem bark of Glycosmis chlorosperma, together with the known atalaphyllidine (3) and acrifoline (4), by means of bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (4) and to a lesser extent chlorospermine B (2) and atalaphyllidine (3) showed significant inhibiting activity on DYRK1A with IC50's of 0.075, 5.7, and 2.2 MUM, respectively. Their selectivity profile was evaluated against a panel of various kinases, and molecular docking calculations provided structural details for the interaction between these compounds and DYRK1A. PMID- 24798020 TI - Broadly defining lasing wavelengths in single bandgap-graded semiconductor nanowires. AB - Designing lasing wavelengths and modes is essential to the practical applications of nanowire (NW) lasers. Here, according to the localized photoluminescence spectra, we first demonstrate the ability to define lasing wavelengths over a wide range (up to 119 nm) based on an individual bandgap-graded CdSSe NW by forward cutting the NW from CdSe to CdS end. Furthermore, free spectral range (FSR) and modes of the obtained lasers could be controlled by backward cutting the NW from CdS to CdSe end step-by-step. Interestingly, single-mode NW laser with predefined lasing wavelength is realized in short NWs because of the strong mode competition and increase in FSR. Finally, the gain properties of the bandgap graded NWs are investigated. The combination of wavelength and mode selectivity in NW lasers may provide a new platform for the next generation of integrated optoelectronic devices. PMID- 24798021 TI - Feasibility and effectiveness of posaconazole prophylaxis in combination with micafungin bridging for patients undergoing allogeneic stem cell transplantation: a 6-yr analysis from the cologne cohort for neutropenic patients. AB - INTRODUCTION: Invasive fungal diseases (IFDs) are an important cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (SCT). METHODS: To compare the effectiveness of two prophylactic antifungal regimens used as standard of care (SOC) in the setting of SCT during the periods of May 2006 - September 2009 (oral posaconazole, POS) and October 2009 - July 2011 (oral posaconazole with intravenous micafungin bridging, POS-MIC), data from the Cologne Cohort of Neutropenic Patients (CoCoNut) study were analyzed after nearest-neighbor matching. Endpoints were occurrence of breakthrough probable/proven IFD under prophylaxis, incidence and duration of persistent febrile neutropenia, incidence of unspecific pneumonic infiltrates, possible IFD, positive galactomannan tests, as well as fungal-free and overall survival. RESULTS: Of 291 patients with 307 SCTs observed during the study period, 212 fulfilled the inclusion criteria and were included into the analysis. Patients receiving POS-MIC were less likely to develop a pneumonic infiltrate (RR 0.71, 95% CI 0.51-1.00) or possible IFD (RR 0.36, 95% 0.15-0.87). They also demonstrated improved fungal-free survival at day 100 (P = 0.009). No significant differences were observed for the incidence of probable or proven IFD, positive galactomannan tests, persistent febrile neutropenia, duration of hospitalization and overall mortality. There was no grade III or IV CTCAE (Common Terminology Criteria for Adverse Events) toxicity related to antifungal prophylaxis. CONCLUSION: Our results suggest that both prophylactic regimens, POS and POS-MIC are feasible, safe and effective. Our data suggest that bridging with intravenous micafungin could indeed improve exposure to antifungal prophylaxis, which may explain the reduced incidence of pneumonia and IFD in the bridging group. PMID- 24798022 TI - The ESX system in Bacillus subtilis mediates protein secretion. AB - Esat-6 protein secretion systems (ESX or Ess) are required for the virulence of several human pathogens, most notably Mycobacterium tuberculosis and Staphylococcus aureus. These secretion systems are defined by a conserved FtsK/SpoIIIE family ATPase and one or more WXG100 family secreted substrates. Gene clusters coding for ESX systems have been identified amongst many organisms including the highly tractable model system, Bacillus subtilis. In this study, we demonstrate that the B. subtilis yuk/yue locus codes for a nonessential ESX secretion system. We develop a functional secretion assay to demonstrate that each of the locus gene products is specifically required for secretion of the WXG100 virulence factor homolog, YukE. We then employ an unbiased approach to search for additional secreted substrates. By quantitative profiling of culture supernatants, we find that YukE may be the sole substrate that depends on the FtsK/SpoIIIE family ATPase for secretion. We discuss potential functional implications for secretion of a unique substrate. PMID- 24798023 TI - MicroRNA-9 regulates neural apoptosis in methylmalonic acidemia via targeting BCL2L11. AB - Methylmalonic acidemia (MMA) is an autosomal-recessive inborn metabolic disorder that results from a deficiency in methylmalonyl-coenzyme A mutase or its cofactor, adenosylcobalamin. Currently, neurological manifestations in MMA are thought to be associated with neural apoptosis. BCL2L11, which is a proapoptotic Bcl-2 family member, is resident in the outer mitochondrial membrane, where this protein acts as a central regulator of the intrinsic apoptotic cascade and mediates excitotoxic apoptosis. MicroRNAs (miRNAs) are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Currently, little is known regarding the role of miRNA in MMA. In our previous study, we preliminarily found that the expression of miR-9 was significantly down-regulated in MMA patient plasma and sensitively changed after VitB12 treatment, which may act as a potential "competitor" of gas chromatography-mass spectrometry for the diagnosis of MMA. In the present study, we first confirmed that miR-9 inhibited BCL2L11 expression by directly targeting its 3'-untranslated region, and the up regulation of miR-9 reduced neural apoptosis induced by methylmalonate via targeting BCL2L11. Taken together, our results suggested that miR-9 might act as a monitor of changes in MMA and might provide new insights into a therapeutic entry point for treating MMA. PMID- 24798024 TI - The apoptotic perspective of autism. AB - Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. The normal brain development during fetal brain development and the first year of life is critical to the behaviors and cognitions in adulthood. Programmed cell death (apoptosis) is an important mechanism that determines the size and shape of the brain and regulates the proper wiring of developing neuronal networks. Pathological activation of apoptotic death pathways under pathological conditions may lead to neuroanatomic abnormalities and possibly to developmental disabilities. It has been demonstrated a possible association between neural cell death and autism. Here, the abnormal apoptosis found in autism from postmortem and animal studies was reviewed and the possible mechanism was discussed. PMID- 24798025 TI - Transfer of blood urea nitrogen to cecal microbes and nitrogen retention in mature rabbits are increased by dietary fructooligosaccharides. AB - To estimate the effect of fructooligosaccharides (FOS) on N utilization, seven mature rabbits were fed a diet containing 5% glucose or FOS for 8 days. During the last 5 days, total feces and urine were collected to measure N levels (Experiment 1). To examine N transfer from the blood to cecal microbes, eight rabbits were fed the same diets as in Experiment 1. After 9 days of feeding, 2 g of glucose or FOS was given orally. Two hours later 20 mg of (15) N-urea was administered via the ear vein, and 1 h later cecal and blood samples were collected (Experiment 2). Urinary N excretion was lowered by FOS feeding (P < 0.05). Total bacterial N and (15) N in the cecum was significantly higher in FOS fed animals (P < 0.05). Urea N in the cecum was lower in FOS-fed rabbits (P < 0.05). Similarly, (15) N atom % excess of cecal urea N was also lower in FOS-fed rabbits than in glucose-fed rabbits. These results suggest that FOS in the diet increases the transfer of blood urea N to the cecum for bacterial synthesis, thereby increasing N utilization. PMID- 24798026 TI - How much information do patients want or need. AB - Based on literature and personal experience, this paper address the question of how much information patients want or need prior to surgery. It underlines the importance of not only answering patients' questions but also making them aware of information available, to help them go through this difficult process. Aspects such as obtaining a second opinion and use of the Internet are also covered. PMID- 24798027 TI - Authors reply to letter to editor: primary hyperparathyroidism: an analysis of failure of parathyroidectomy. PMID- 24798028 TI - Reply to: unplanned extubation and mortality in surgical critically patients: an accidental association or cause? PMID- 24798029 TI - Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? AB - INTRODUCTION: The development of coagulopathy of trauma is multifactorial associated with hypoperfusion and consumption of coagulation factors. Previous studies have compared the role of factor replacement versus FPP for reversal of trauma coagulopathy. The purpose of our study was to determine the time to correction of coagulopathy and blood product requirement in patients who received PCC+FFP compared with patients who received FFP alone. METHODS: We performed a retrospective analysis of a prospectively maintained database of all coagulopathic (INR >= 1.5) trauma patients presenting to our level I trauma center during a 2-years period (2011-2012). Patients were stratified into two groups: patients who received PCC+FFP and patients who received FFP alone. Patients in the two groups were matched in a 1:3 (PCC+FFP:FFP) ratio using propensity score matching for demographics, injury severity, vital parameters, and initial INR. The two groups were then compared for: correction of INR, time to correction of INR, thromboembolic complications, mortality, and cost of therapy. RESULTS: A total of 252 were included in the analysis [PCC+FFP:63; FFP:189]. The mean age was 44 +/- 20 years; 70 % were male, with a median ISS score of 27 [16-38]. PCC use was associated with an accelerated correction of INR (394 vs. 1,050 min; p 0.001), reduction in requirement of pack red blood cell (6.6 vs. 10 units; p 0.001) and FFP (2.8 vs. 3.9 units; p 0.01), and decline in mortality (23 vs. 28%; p 0.04). PCC+FFP use was associated with a higher cost of therapy ($1,470 +/- 845 vs. 1,171 +/- 949; p 0.01) but lower overall cost of transfusion ($7,110 +/- 1,068 vs. 9,571 +/- 1,524; p 0.01) compared with FFP therapy alone. CONCLUSIONS: PCC in conjunction with FFP rapidly corrects INR in a matched cohort of trauma patients not on warfarin therapy compared with FFP therapy alone. The use of PCC as an adjunct to FFP therapy is associated with reduction of blood product requirement and also lowers overall cost. PMID- 24798030 TI - Implementation of a group-based physical activity programme for ageing adults with ID: a process evaluation. AB - RATIONALE, AIM AND OBJECTIVES: This paper describes the results of the process evaluation of a physical activity programme for people with intellectual disabilities (ID), including information about the concepts 'fidelity', 'dose delivered', 'satisfaction' and 'context'. METHODS: Qualitative and quantitative methods among participants and programme leaders were used. RESULTS: The programme was well accepted, feasible and applicable to ageing people with ID. It was successfully implemented in terms of fidelity and dose delivered, although differences between day-activity centres were observed. CONCLUSIONS: The hampering factors that are revealed in this study and the facilitating activities that were part of the implementation plan may be used by care provider services for (ageing) people with ID and other groups of people with cognitive and/or physical deficits, such as frail elderly people or people with dementia when developing and or preparing implementation of health promotion programmes. PMID- 24798031 TI - Identification of thyroid hormone receptor homologs in the fluke Opisthorchis felineus (Platyhelminthes). AB - The liver fluke, Opisthorchis felineus of the Opisthorchiidae family, is a well known causative agent of opisthorchiasis in Russia and Europe. The aim of this work was to identify genes encoding thyroid hormone receptors in O. felineus, and to analyze the expression of possible target genes in response to treatment with exogenous thyroid hormones. We identified two genes encoding thyroid hormone receptors in the O. felineus genome, THRA and THRB. The genes were differentially expressed through the life cycle. The maximal level of mRNA expression of THRA1 and THRB was observed in adult worms. Treatment of the worms with triiodothyronine and thyroxine resulted in an increase in glucose 6-phosphatase mRNA expression and a decrease in malate dehydrogenase mRNA expression, potential gene targets of thyroid hormones. These data indicate that thyroid hormone receptors may perform essential roles in physiological processes in adult O. felineus. PMID- 24798032 TI - Fructose content and composition of commercial HFCS-sweetened carbonated beverages. AB - OBJECTIVE: The obesigenic and related health effects of caloric sweeteners are subjects of much current research. Consumers can properly adjust their diets to conform to nutritional recommendations only if the sugars composition of foods and beverages is accurately measured and reported, a matter of recent concern. We tested the hypothesis that high-fructose corn syrup (HFCS) used in commercial carbonated beverages conforms to commonly assumed fructose percentages and industry technical specifications, and fulfills beverage product label regulations and Food Chemicals Codex-stipulated standards. DESIGN: A high pressure liquid chromatography method was developed and verified for analysis of sugars in carbonated beverages sweetened with HFCS-55. The method was used to measure percent fructose in three carbonated beverage categories. Method verification was demonstrated by acceptable linearity (R(2)>0.99), accuracy (94 104% recovery) and precision (RSD < 2%). RESULT: Fructose comprised 55.58% of total sugars (95% confidence interval 55.51-55.65%), based on 160 total measurements by 2 independent laboratories of 80 randomly selected carbonated beverages sweetened with HFCS-55. The difference in fructose measurements between laboratories was significant but small (0.1%), and lacked relevance. Differences in fructose by product category or by product age were not statistically significant. Total sugars content of carbonated beverages showed close agreement within product categories (95% confidence interval = 0.01-0.54%). CONCLUSIONS: Using verified analytical methodology for HFCS-sweetened carbonated beverages, this study confirmed the hypothesis that fructose as a percentage of total sugars is in close agreement with published specifications in industry technical data sheets, published literature values and governmental standards and requirements. Furthermore, total sugars content of commercial beverages is consistent with common industry practices for canned and bottled products and met the US Federal requirements for nutritional labeling and nutrient claims. Prior concerns about composition were likely owing to use of improper and unverified methodology. PMID- 24798033 TI - The incidence of albuminuria after bariatric surgery and usual care in Swedish Obese Subjects (SOS): a prospective controlled intervention trial. AB - BACKGROUND: Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria. SUBJECTS: The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI ? 34 in men and BMI ? 38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years. RESULTS: During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P < 0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine. CONCLUSIONS: Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care. PMID- 24798034 TI - Supramolecular assemblies of a conjugate of nucleobase, amino acids, and saccharide act as agonists for proliferation of embryonic stem cells and development of zygotes. AB - The synthetic challenges in glycobiology and glycochemistry hamper the development of glycobiomaterials for biomedicine. Here we report the use of molecular self-assembly to sidestep the laborious synthesis of complex glycans for promoting the proliferation of murine embryonic stem (mES) cells. Our study shows that the supramolecular assemblies of a small molecule conjugate of nucleobase, amino acids, and saccharide, as a de novo glycoconjugate, promote the proliferation of mES cells and the development of zygotes into blastocysts of mouse. Molecular engineering confirms that each motif (i.e., adenine, Arg-Gly-Asp (RGD) domain, and glucosamine) is indispensable for the observed activity of the conjugate. As the first example of using assemblies of the molecular conjugates of multiple fundamental biological building blocks to control cell behaviors, this work illustrates an unprecedented approach to use supramolecular assemblies as multifunctional mimics of glycoconjugates. PMID- 24798035 TI - Relationship between nonlinear pressure-induced chemical shift changes and thermodynamic parameters. AB - NMR chemical shift analysis is a powerful method to investigate local changes in the environment of the observed nuclear spin of a polypeptide that are induced by application of high hydrostatic pressure. Usually, in the fast exchange regime, the pressure dependence of chemical shifts is analyzed by a second order Taylor expansion providing the first- and second-order pressure coefficient B1 and B2. The coefficients then are interpreted in a qualitative manner. We show here that in a two-state model, the ratio of B2/B1 is related to thermodynamic parameters, namely the ratio of the difference of compressibility factors Deltabeta' and partial molar volumes DeltaV. The analysis is applied to the random-coil model peptides Ac-Gly-Gly-Xxx-Ala-NH2, with Xxx being one of the 20 proteinogenic amino acids. The analysis gives an average Deltabeta'/DeltaV ratio of 1.6 GPa(-1) provided the condition |DeltaG(0)| ? 2RT holds for the difference of the Gibbs free energies (DeltaG(0)) of the two states at the temperature (T0) and the pressure (p0). The amide proton and nitrogen B2/B1 of a given amino acid Xxx are strongly correlated, indicating that their pressure-dependent chemical shift changes are due to the same thermodynamic process. As a possible physical mechanism providing a two-state model, the hydrogen bonding of water with the corresponding amide protein was simulated for isoleucine in position Xxx. The obtained free energy could satisfy the relation |DeltaG(0)| ? 2RT. The derived relation was applied to the beta-amyloid peptide Abeta and the phosphocarrier protein HPr from S. carnosus. For the transition of state 1 to state 2' of Abeta, the derived relation of B2/B1 to Deltabeta'/DeltaV can be confirmed experimentally. The HPr protein is characterized by substantially higher negative B2/B1 values than those found in the tetrapeptides with an average value of approximately -5.1 GPa(-1) (Deltabeta'/DeltaV of 5.1 GPa(-1) provided |DeltaG(0)| ? 2RT holds). Qualitatively, the B2/B1 ratio can be used to predict regions of the HPr protein involved in the interaction with enzyme I or HPr kinase/phosphatase. PMID- 24798036 TI - Low level tumor necrosis factor-alpha protects cardiomyocytes against high level tumor necrosis factor-alpha: brief insight into a beneficial paradox. AB - Whether tumor necrosis factor-alpha (TNFalpha) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFalpha agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFalpha agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFalpha. To shed light on these mixed findings, we characterized the effects of TNFalpha in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFalpha, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFalpha and then re-challenged with increasing concentrations of TNFalpha and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFalpha increasing approximately 16-fold. TNFalpha preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFalpha receptors [(soluble TNFalpha receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFalpha at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNFalpha" helped cardiomyocyte to withstand toxicity from "high TNFalpha" or other agents. These results also suggested that beneficial or detrimental effects of anti TNFalpha agents might well depend on whether these agents spared or intercepted discrete amounts of TNFalpha that preconditioned cardiomyocytes and made them more resistant to high concentrations of TNFalpha. PMID- 24798039 TI - Awards: what do they mean? PMID- 24798037 TI - The protective effect of apelin against water-immersion and restraint stress induced gastric damage. AB - The aim of the present study was to investigate the gastroprotective effect of apelin on water-immersion and restraint stress (WIRS)-induced gastric lesions. Male Wistar rats were divided into four groups: control, WIRS, F13A + WIRS and F13A. APJ receptor antagonist F13A was administered to rats to determine the influence of apelin on stress-induced gastric injury. WIRS administered for 6 h resulted in the development of gastric mucosal lesions accompanied by a significant increase in plasma corticosterone. WIRS increased the concentration of 4-hydroxynonenol (4-HNE) + malondialdehyde (MDA) and the expression of apelin and hypoxia inducible factor-1alpha (HIF-1alpha) in gastric mucosa. In addition, WIRS reduced the mucosal blood flow and gastric prostaglandin E(2) (PGE(2)) concentration. Plasma corticosterone, which was increased due to stress, was significantly decreased in the F13A + WIRS group. Gastric lesions and the 4-HNE + MDA concentration were also higher in the F13A + WIRS compared to the WIRS group. We conclude that apelin has a gastroprotective effect against stress-induced lesions possibly by reducing lipid peroxidation in gastric mucosa. PMID- 24798040 TI - Cerebral microbleeds as a predictor of macrobleeds: what is the evidence? AB - Cerebral microbleeds on blood-sensitive magnetic resonance imaging sequences have emerged as a common and important marker of small vessel disease. Cerebral microbleeds differ from other imaging manifestations of small vessel disease (e.g. lacunes and leukoaraiosis), as they seem to provide more direct evidence of microvascular leakiness from bleeding-prone arteriopathies, namely hypertensive arteriopathy and cerebral amyloid angiopathy, the two leading causes of spontaneous intracerebral haemorrhage. Thus, cerebral microbleeds in specific sub populations might provide evidence of an ongoing active small vessel arteriopathy with increased future risk of symptomatic intracerebral haemorrhage ('macrobleeding'). If this hypothesis is correct, it raises clinical dilemmas especially regarding the safety of antithrombotic drug use. Although data so far are limited, the relationship of microbleeds to future macrobleeding (and cerebral ischemia) seems to critically depend on the specific patient population and cerebral microbleeds location and burden, which may reflect the nature and severity of the underlying arteriopathies. PMID- 24798038 TI - Definition of cure in childhood acute myeloid leukemia. AB - BACKGROUND: A better understanding of when cure can be declared in childhood acute myeloid leukemia (AML) would reduce anxiety and improve quality of life of AML survivors. The authors determined the likelihood that patients with AML would maintain long-term remission after the completion of therapy. METHODS: The cumulative risk of relapse, the time to relapse, event-free survival, and overall survival were analyzed for 604 patients with AML who were enrolled in 7 successive clinical trials divided into 3 treatment eras (1976-1991, 1991-1997, and 2002-2008). RESULTS: The median time to relapse did not change over time (0.93 years vs 0.76 years vs 0.8 years, respectively, for each consecutive era; P = .22), but the risk of relapse decreased significantly (5-year cumulative incidence of relapse: 52.6% +/- 3.1% vs 31.5% +/- 3.9% vs 22% +/- 3%, respectively, for each consecutive era; P < .001). Among patients who were in remission 4 years from diagnosis, the probabilities of relapse were 1.7%, 2.9%, and 0.9%, respectively, for each consecutive era. In the most recent era, all but 1 of 44 relapses occurred within 4 years of diagnosis. CONCLUSIONS: Children with AML who receive treatment with contemporary therapy and remain in remission 4 years from diagnosis probably are cured. Although late relapses and late deaths from other causes are rare, long-term follow-up of survivors is necessary for the timely management of late adverse effects. PMID- 24798041 TI - Public awareness of stroke symptoms and risk factors and response to acute stroke in Northern Greece. PMID- 24798042 TI - A questionnaire survey of general practitioners in Japan in relation to management of transient ischemic attack. PMID- 24798043 TI - Bilateral medial medullary infarction: the 'heart' reveals the diagnosis. PMID- 24798044 TI - High signal on T1 sequence of magnetic resonance imaging confirmed to be intraplaque haemorrhage by histology in middle cerebral artery. PMID- 24798045 TI - MTHFR C677T polymorphism and its homocysteine-driven effect on blood pressure. PMID- 24798046 TI - Transcriptomic characterization of hepatocellular carcinoma with CTNNB1 mutation. AB - PURPOSE: Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. HCC is a particularly serious threat to the Chinese population. Although many molecular alterations are known to be involved in the tumorigenesis of hepatocytes, no systemic survey has examined the somatic mutations in HCC samples from Chinese patients. Our goal was to elucidate somatic mutations in Chinese HCC patients and investigate the possible molecular mechanisms involved in tumorigenesis. EXPERIMENTAL DESIGN: A total of 110 hepatitis B virus (HBV)-positive HCC samples and 46 HBV-negative HCC samples were genotyped for hot-spot mutations in the CSF1R, CTNNB1, KRAS, BRAF, NRAS, ERBB2, MET, PIK3CA, JAK1, and SMO genes. The transcriptomes of the CTNNB1 mutation-positive HCC samples from the HBV-positive patients (CB+ HCC) were compared to adjacent non-cancerous livers, and significantly altered genes were functionally validated in vitro. RESULTS: CTNNB1 mutations accounted for the majority of the mutations detected in our study. A slightly higher mutation rate was found in the HBV-positive patients than in their negative counterparts. A distinct pattern of CTNNB1 mutation was detected in these two populations, and drastic changes at the transcriptomic level were detected in the CB+ tumors compared to adjacent non-cancerous livers. Potential tumor suppressors (FoxA3 and Onecut1) and oncogenes (MAFG and SSX1) were functionally validated. CONCLUSIONS: Our work is the first systemic characterization of oncogenic mutations in HCC samples from Chinese patients. Targeting the Wnt-beta-catenin pathway may represent a valid treatment option for Chinese HCC patients. Our work also suggests that targeting ONECUT1, FOXA3, SSX1, and MAFG may be a valid treatment option for CTNNB1 mutation positive HCC patients. PMID- 24798047 TI - Generalization of human fear acquisition and extinction within a novel arbitrary stimulus category. AB - Adaptive anxiety relies on a balance between the generalization of fear acquisition and fear extinction. Research on fear (extinction) generalization has focused mostly on perceptual similarity, thereby ignoring the importance of conceptual stimulus relations in humans. The present study used a laboratory procedure to create de novo conceptual categories of arbitrary stimuli and investigated fear and extinction generalization among these stimuli. A matching to-sample task produced two four-member categories of abstract figures. Next, a member from one category was coupled with an aversive electrical stimulation, while a member from the other category was presented alone. As expected, conditioned fear responses generalized to the other members of the first category (skin conductance and online shock-expectancy). Subsequent extinction of the conditioned member also generalized to the other members. However, extinguishing a non-conditioned member failed to reduce fear of the conditioned member itself. We conclude that fears generalize readily across conceptually related stimuli, but that the degree of extinction generalization depends on the stimulus subjected to extinction. PMID- 24798048 TI - Rotation triggers nucleotide-independent conformational transition of the empty beta subunit of F1-ATPase. AB - F1-ATPase (F1) is the catalytic portion of ATP synthase, a rotary motor protein that couples proton gradients to ATP synthesis. Driven by a proton flux, the F1 asymmetric gamma subunit undergoes a stepwise rotation inside the alpha3beta3 headpiece and causes the beta subunits' binding sites to cycle between states of different affinity for nucleotides. These concerted transitions drive the synthesis of ATP from ADP and phosphate. Here, we study the coupling between the mechanical progression of gamma and the conformations of alpha3beta3. Using molecular dynamics simulations, we show that the nucleotide-free beta subunit, initially in the open, low-affinity state, undergoes a spontaneous closing transition to the half-open state in response to the gamma rotation in the synthesis direction. We estimate the kinetics of this spontaneous conformational change and analyze its mechanism and driving forces. By computing free energy profiles, we find that the isolated empty beta subunit preferentially adopts the half-open conformation and that the transition to this conformation from the fully open state is accompanied by well-defined changes in the structure and interactions of the active site region. These results suggest that ADP binding to F1 occurs via conformational selection and is preceded by the transition of the active site to the half-open conformation, driven by the intrinsic elasticity of beta. Our results also indicate that opening of the nucleotide-free beta during hydrolysis is not spontaneous, as previously assumed. Rather, the fully open conformation observed in the F1 X-ray structure is enforced sterically by the gamma subunit whose orientation is stabilized by interactions with the two other beta subunits in the completely closed state. This finding supports the notion that gamma acts by coupling the extreme conformational states of beta subunits within the alpha3beta3 hexamer and therefore is responsible for high efficiency of the coordinated catalysis. PMID- 24798049 TI - The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: The accuracy of noninvasive tools for the diagnosis of severe fibrosis in patients with nonalcoholic fatty liver disease(NAFLD) in clinical practice is still limited. We aimed at assessing the diagnostic performance of combined noninvasive tools in two independent cohorts of Italian NAFLD patients. METHODS: We analysed data from 321 Italian patients(179 Sicilian-training cohort, and 142 northern Italy-validation cohort) with an histological diagnosis of NAFLD. Severe fibrosis was defined as fibrosis >= F3 according to Kleiner classification. The APRI, AST/ALT, BARD, FIB-4, and NFS scores were calculated according to published algorithms. Liver stiffness measurement(LSM) was performed by FibroScan. Cut-off points of LSM, NFS and FIB-4 for rule-in or rule-out F3-F4 fibrosis were calculated by the reported formulas. RESULTS: In the Sicilian cohort AUCs of LSM, NFS, FIB-4, LSM plus NFS, LSM plus FIB-4, and NFS plus FIB-4 were 0.857, 0.803, 0.790, 0.878, 0.888 and 0.807, respectively, while in the northern Italy cohort the corresponding AUCs were 0.848, 0.730, 0.703, 0.844, 0.850, and 0.733 respectively. In the training cohort, the combination of LSM plus NFS was the best performing strategy, providing false positive, false negative and uncertainty area rates of 0%,1.1% and 48% respectively. Similar results were obtained in the validation cohort with false positive, false negative and uncertainty area rates of 0%,7.3% and 40.8%. CONCLUSIONS: The combination of LSM with NFS, two complementary, easy-to-perform, and widely available tools, is able to accurately diagnose or exclude the presence of severe liver fibrosis, also reducing of about 50-60% the number of needed diagnostic liver biopsies. PMID- 24798050 TI - The view from here: The eighth year of RomneyCare. PMID- 24798052 TI - Transcatheter aortic valve replacement: flattening the cost curve. PMID- 24798051 TI - Antioxidants keep the potentially probiotic but highly oxygen-sensitive human gut bacterium Faecalibacterium prausnitzii alive at ambient air. AB - The beneficial human gut microbe Faecalibacterium prausnitzii is a 'probiotic of the future' since it produces high amounts of butyrate and anti-inflammatory compounds. However, this bacterium is highly oxygen-senstive, making it notoriously difficult to cultivate and preserve. This has so far precluded its clinical application in the treatment of patients with inflammatory bowel diseases. The present studies were therefore aimed at developing a strategy to keep F. prausnitzii alive at ambient air. Our previous research showed that F. prausnitzii can survive in moderately oxygenized environments like the gut mucosa by transfer of electrons to oxygen. For this purpose, the bacterium exploits extracellular antioxidants, such as riboflavin and cysteine, that are abundantly present in the gut. We therefore tested to what extent these antioxidants can sustain the viability of F. prausnitzii at ambient air. The present results show that cysteine can facilitate the survival of F. prausnitzii upon exposure to air, and that this effect is significantly enhanced the by addition of riboflavin and the cryoprotectant inulin. The highly oxygen-sensitive gut bacterium F. prausnitzii can be kept alive at ambient air for 24 h when formulated with the antioxidants cysteine and riboflavin plus the cryoprotectant inulin. Improved formulations were obtained by addition of the bulking agents corn starch and wheat bran. Our present findings pave the way towards the biomedical exploitation of F. prausnitzii in redox-based therapeutics for treatment of dysbiosis-related inflammatory disorders of the human gut. PMID- 24798053 TI - Older lesbians and bereavement: experiencing the loss of a partner. AB - There is very little research focused on older bereaved lesbians. This study is a response to the lack of knowledge about the issues for older lesbians who lose a partner. We examined bereavement issues for 55 older lesbians. The study asked participants to describe their concerns and experiences after losing a partner. Qualitative analysis identified several themes that ran throughout, including disenfranchised grief, the loneliness of isolation, and the frustration of relentless battles. These findings indicate the need for social workers to educate themselves and others about the particular needs facing this vulnerable group of older women. PMID- 24798054 TI - Transoral laser microsurgery for laryngeal carcinoma: Survival analysis in a hospital-based population. AB - BACKGROUND: Although already established for treatment for early-stage laryngeal cancers, transoral laser microsurgery indications for more advanced tumors are not unanimous. Additionally, no outcomes concerning the Portuguese population are currently accessible. METHODS: Outcomes of 248 patients presenting laryngeal carcinoma primarily treated by transoral laser microsurgery with curative intention in tertiary referral center were retrospectively evaluated and compared with concerning literature. RESULTS: For supraglottic tumors (23 stage I-II and 20 stage III-IV), 5-year disease-specific survival (DSS) was, respectively, 88.4% and 72.7%, and the total larynx-preservation rate was 90.7%. For glottic cancer (165 stage I-II and 40 stage III-IV), 5-year DSS was, respectively, 96.5% and 90.8% and the larynx preservation rate was 88.3%. CONCLUSION: Transoral laser microsurgery, alone or with neck dissection and adjuvant therapy, is an efficient procedure for treatment of laryngeal cancer in different stages. To the best of our knowledge, this is the first study reporting transoral laser microsurgery outcomes in the Portuguese population. PMID- 24798055 TI - Tuning composition and architecture of biomimetic scaffolds for enhanced matrix synthesis by murine cardiomyocytes. AB - A major onset of heart failure is myocardial infarction, which causes the myocardium to lose cardiomyocytes and transform into a scar tissue. Since mammalian infarcted cardiac tissue has a limited ability to regenerate, alternative strategies including implantation of tissue-engineered scaffolds at the site of damaged myocardium have been explored. The goal is to enable in situ cardiac reconstruction at the injured myocardium site, replace the lost cardiomyocytes, deliver the required biomolecules, and remodel the extracellular matrix (ECM). ECM synthesis and deposition by cardiomyocytes within such scaffolds remains categorically unexplored. Here, we investigated the survival, ECM synthesis and deposition, and matrix metalloproteinases (MMPs) release by cardiomyocytes within three-dimensional (3D) substrates. Rat cardiomyocytes were cultured for three weeks within two structurally different substrates: 3D collagen hydrogels or polycaprolactone (PCL) nanofibrous scaffolds. The concentration and composition of the hydrogels was varied, while PCL nanofibers were surface-modified with various ECM proteins. Results showed that myocyte attachment and survival was higher within collagen hydrogels, while myocyte alignment and beating was noted only within PCL scaffolds. Total protein synthesis by myocytes within PCL scaffolds was significantly higher compared to that within collagen hydrogels, although more protein was deposited as matrix within hydrogels. Significant ECM synthesis and matrix deposition, TIMP-1, and MMP release were noted within modified collagen hydrogels and PCL nanofiber scaffolds. These results were qualitatively confirmed by imaging techniques. Results attest to the prominent role of scaffold composition and architecture in influencing cardiomyocyte phenotype, matrix synthesis and cytokines release, with significant applications in cardiac tissue remodeling strategies. PMID- 24798056 TI - Role of microstructures on the M1-M2 phase transition in epitaxial VO2 thin films. AB - Vanadium dioxide (VO2) with its unique sharp resistivity change at the metal insulator transition (MIT) has been extensively considered for the near-future terahertz/infrared devices and energy harvesting systems. Controlling the epitaxial quality and microstructures of vanadium dioxide thin films and understanding the metal-insulator transition behaviors are therefore critical to novel device development. The metal-insulator transition behaviors of the epitaxial vanadium dioxide thin films deposited on Al2O3 (0001) substrates were systematically studied by characterizing the temperature dependency of both Raman spectrum and Fourier transform infrared spectroscopy. Our findings on the correlation between the nucleation dynamics of intermediate monoclinic (M2) phase with microstructures will open a new avenue for the design and integration of advanced heterostructures with controllable multifunctionalities for sensing and imaging system applications. PMID- 24798057 TI - Cross-linguistic generalization in the treatment of two sequential Spanish English bilingual children with speech sound disorders. AB - PURPOSE: The effect of bilingual service delivery on treatment of speech sound disorders (SSDs) in bilingual children is largely unknown. Bilingual children with SSDs are typically provided intervention in only one language, although research suggests dual-language instruction for language disorders is best practice for bilinguals. This study examined cross-linguistic generalization of bilingual intervention in treatment of two 5-year-old sequential bilingual boys with SSDs (one with Childhood Apraxia of Speech), hypothesizing that selecting and treating targets in both languages would result in significant overall change in their English and Spanish speech systems. METHOD: A multiple baseline across behaviours design was used to measure treatment effectiveness for two targets per child. Children received treatment 2-3 times per week for 8 weeks and in Spanish for at least 2 of every 3 days. Ongoing treatment performance was measured in probes in both languages; overall speech skills were compared pre- and post treatment. RESULT: Both children's speech improved in both languages with similar magnitude; there was improvement in some non-treated errors. CONCLUSION: Treating both languages had an overall positive effect on these bilingual children's speech. Future bilingual intervention research should explore alternating treatments designs, efficiency of monolingual vs bilingual treatment, different language and bilingual backgrounds, and between-group comparisons. PMID- 24798058 TI - Allogeneic tendon-derived stem cells promote tendon healing and suppress immunoreactions in hosts: in vivo model. AB - The medium- to long-term healing effect and infiltration of inflammatory cells, after transplantation of allogeneic tendon-derived stem cell (TDSC) to the rat patellar tendon window wound, were examined. Allogeneic patellar TDSCs derived from a green fluorescent protein rat were used. The outcome of tendon healing and the infiltration of inflammatory cells were examined by histology and immunohistochemistry up to week 16 postinjury. The fate of the transplanted cells was examined by ex vivo fluorescent imaging and immunohistochemistry. Our results showed that the transplantation of allogeneic TDSCs promoted tendon healing with no increased risk of ectopic chondro-ossification up to week 16. A low infiltration of T cells, ED1 macrophages, ED2 macrophages, and mast cells in the window wound was obtained. The transplanted TDSCs were found in the window wound at week 1 and 2, but were absent after week 4 postinjury. In conclusion, allogeneic TDSCs promoted tendon repair in the medium to long term and exhibited weak immunoreactions and anti-inflammatory effects in the hosts after transplantation in a rat model. There was no increased risk of ectopic chondro ossification after TDSC transplantation. The decrease in the number of transplanted cells with time suggested that allogeneic TDSCs did not promote tendon repair through direct differentiation. PMID- 24798059 TI - Reproductive endocrinology: Maternal and fetal insulin levels at birth in women with PCOS. PMID- 24798060 TI - Diabetes: Functional impairment of bone marrow progenitor cells in diabetes mellitus. PMID- 24798061 TI - Reproductive endocrinology: ERRgamma-pre-eclampsia link strengthens. PMID- 24798062 TI - Diabetes: Hypoglycaemia, emergency care and diabetes mellitus. PMID- 24798063 TI - Renal sympathetic denervation - phenomenon or noumenon? PMID- 24798064 TI - Coronary arcade: a rare anomaly of the coronary circulation. AB - Intercoronary communication or 'coronary arcade' is a rare congenital coronary anomaly. We present the case of a 65-year-old man with atypical chest pain for four months. The 12-lead ECG and echocardiogram were normal. Treadmill exercise testing was interrupted at peak exercise due to consecutive salvos of ventricular premature beats, without significant ST-T changes. Coronary angiography showed no significant coronary stenosis, but a connection between the right coronary and circumflex arteries was observed, consistent with coronary arcade. The functional importance of this variant is not clear, but it may cause myocardial ischemia by coronary steal or function as a natural bypass, in which case it may play a protective role in the myocardium if significant atherosclerosis develops. PMID- 24798065 TI - Venturing into kinetics and mechanism of nanoconfined solid-state reactions: trimerization of sodium dicyanamide in nanopores. AB - Research on nanoconfined chemical reactions has the potential of discovering novel means for controlling chemical reactivity which is a task of great fundamental and practical significance. This study is the first attempt to probe the effect of nanoconfinement on the kinetics and mechanism of reactions that occur entirely in the solid state. FTIR, NMR, pXRD, TGA and DSC were employed to analyze the thermally initiated trimerization of sodium dicyanamide in bulk and organically modified nanopores. Nanoconfinement did not cause apparent changes in the net reaction mechanism but decelerated the reaction kinetics dramatically. Kinetic analysis linked the deceleration to a dramatic decrease in the preexponential factor. This is an original effect which is especially noteworthy considering that for nanoconfined liquid state reactions the effect is opposite: significant acceleration due to an increase in the preexponential factor. We propose that the difference arises respectively from disordering of the solid reaction media compared to ordering of the liquid reaction media. PMID- 24798067 TI - Outcomes in renal transplant recipients with lupus nephritis: experience at a single center. AB - BACKGROUND: The long-term prognosis of renal transplant recipients with systemic lupus erythematosus is still controversial. The outcome of these patients depends on the population studied, race/ethnicity, socioeconomic conditions, donor related factors and recurrent lupus nephritis (LN), among other factors. OBJECTIVE: This study was conducted to evaluate kidney transplantation outcomes for adult Brazilian patients with LN at a single center. SUBJECTS AND METHOD: The archival records of all patients with LN who had received a kidney transplant at Santa Casa of Sao Paulo Hospital were reviewed. Kaplan-Meier method was used to determine the survival rate. RESULTS: We identified 18 patients with LN subjected to 22 kidney transplants during the 20-year interval. Two patients received three renal grafts. The majority of the patients were female, with 33.7 +/- 10 years at the time of the transplantation, and half of them were African descendants or mixed. Sixteen transplants were performed from deceased donors and six from living-related donors. The patient survival rate was 90%, and graft survival was 68% at 10 years. Chronic allograft nephropathy was the major cause of graft loss. Two patients developed extra-renal manifestations of lupus. There was no clinical or histological evidence of recurrent LN. CONCLUSION: Renal transplantation is a method which can provide a long-term survival for patients with SLE and end-stage renal disease. PMID- 24798068 TI - Experimental results from RO-PRO: a next generation system for low-energy desalination. AB - A pilot system was designed and constructed to evaluate reverse osmosis (RO) energy reduction that can be achieved using pressure-retarded osmosis (PRO). The RO-PRO experimental system is the first known system to utilize energy from a volume of water transferred from atmospheric pressure to elevated pressure across a semipermeable membrane to prepressurize RO feedwater. In other words, the system demonstrated that pressure could be exchanged between PRO and RO subsystems. Additionally, the first experimental power density data for a RO-PRO system is now available. Average experimental power densities for the RO-PRO system ranged from 1.1 to 2.3 W/m2. This is higher than previous river-to-sea PRO pilot systems (1.5 W/m2) and closer to the goal of 5 W/m2 that would make PRO an economically feasible technology. Furthermore, isolated PRO system testing was performed to evaluate PRO element performance with higher cross-flow velocities and power densities exceeding 8 W/m2 were achieved with a 28 g/L NaCl draw solution. From this empirical data, inferences for future system performance can be drawn that indicate future RO-PRO systems may reduce the specific energy requirements for desalination by ~1 kWh/m3. PMID- 24798066 TI - Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer? AB - Shutter-speed pharmacokinetic analysis of dynamic-contrast-enhanced (DCE)-MRI data allows evaluation of equilibrium inter-compartmental water interchange kinetics. The process measured here - transcytolemmal water exchange - is characterized by the mean intracellular water molecule lifetime (taui). The taui biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE-MRI. We present population-averaged in vivo human breast whole tumor taui changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while K(trans) (measuring mostly contrast agent (CA) extravasation) and kep (CA intravasation rate constant) decrease, taui increases. However, high-resolution, (1 mm)(2), parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms taui value means a trans-membrane water cycling flux of 10(13) H2O molecules s(-1)/cell for a 12 um diameter cell. Analyses of intratumor variations (and therapy-induced changes) of taui in combination with concomitant changes of ve (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, PW, not of cell size. These can be interpreted in light of literature results showing that taui changes are dominated by a PW (active) component that reciprocally reflects the membrane driving P-type ATPase ion pump turnover. For mammalian cells, this is the Na(+), K(+)-ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy. PMID- 24798070 TI - Atrial structure and function 5 years after successful ablation for persistent atrial fibrillation: an MRI study. AB - INTRODUCTION: The atrial outcome after extensive ablation is unknown. We sought to quantify atrial structure and function years after successful ablation for persistent atrial fibrillation (PsAF). METHODS AND RESULTS: We studied after 80 +/- 15 months 26 patients (54 +/- 8 years, 1 woman) with PsAF successfully treated by ablation (2.2 +/- 0.7 stepwise approach procedures, cumulative RF duration 126 +/- 37 minutes). At follow-up atrial scar burden and atrial outflows were quantified using delayed-enhanced and velocity-encoded MRI, respectively. Cine imaging was used to quantify atrial conduit function (CF), active emptying fraction (AEF), expansion index (EI), and the inter-appendage mechanical activation delay. Patients underwent exercise testing at baseline and follow-up. LA and RA scar extent were 29 +/- 6 and 4.3 +/- 2.8%, respectively. LA and RA AEF were 10.0 +/- 5.3 and 30 +/- 8%. Mean inter-appendage delay was 83 +/- 47 ms [42 217]. Complete LAA isolation was found in 3 patients. A wave was absent in 9/26 patients. LA scar extent related to the number of procedures (R = 0.58, P = 0.002) and total RF duration (R = 0.56, P = 0.003). Among follow-up characteristics, LA scar extent related to LAAEF (R = -0.73, P < 0.0001), LAEI (R = -0.64, P = 0.0003), A-wave peak (R = -0.72, P < 0.0001), and inter-appendage mechanical delay (R = 0.47, P = 0.02). At multivariable analysis, LA scar extent was independently related to LAAEF and LAEI. LAAEF and LA scar extent correlated with exercise capacity at follow-up (R = 0.44, P = 0.02, and R = -0.40; P = 0.04). CONCLUSION: LA contractility and compliance are markedly impaired years after successful PsAF ablation. LA dysfunction is closely related to scar burden. PMID- 24798071 TI - The proteolysis adaptor, NblA, initiates protein pigment degradation by interacting with the cyanobacterial light-harvesting complexes. AB - Degradation of the cyanobacterial protein pigment complexes, the phycobilisomes, is a central acclimation response that controls light energy capture. The small protein, NblA, is essential for proteolysis of these large complexes, which may reach a molecular mass of up to 4 MDa. Interactions of NblA in vitro supported the suggestion that NblA is a proteolysis adaptor that labels the pigment proteins for degradation. The mode of operation of NblA in situ, however, remained unresolved. Particularly, it was unclear whether NblA interacts with phycobilisome proteins while part of the large complex, or alternatively interaction with NblA, necessitates dissociation of pigment subunits from the assembly. Fluorescence intensity profiles demonstrated the preferential presence of NblA::GFP (green fluorescent protein) at the photosynthetic membranes, indicating co-localization with phycobilisomes. Furthermore, fluorescence lifetime imaging microscopy provided in situ evidence for interaction of NblA with phycobilisome protein pigments. Additionally, we demonstrated the role of NblA in vivo as a proteolysis tag based on the rapid degradation of the fusion protein NblA::GFP compared with free GFP. Taken together, these observations demonstrated in vivo the role of NblA as a proteolysis adaptor. Additionally, the interaction of NblA with phycobilisomes indicates that the dissociation of protein pigment subunits from the large complex is not a prerequisite for interaction with this adaptor and, furthermore, implicates NblA in the disassembly of the protein pigment complex. Thus, we suggest that, in the case of proteolysis of the phycobilisome, the adaptor serves a dual function: undermining the complex stability and designating the dissociated pigments for degradation. PMID- 24798072 TI - Randomised clinical trial comparing elective single-embryo transfer followed by single-embryo cryotransfer versus double embryo transfer. AB - OBJECTIVE: To analyze the impact of the eSET followed by single-embryo cryotransfer versus double embryo transfer in older women (<38 years) without taking into account embryo quality. STUDY DESIGN: This is a prospective randomised clinical trial performed on 194 couples attempting a first IVF cycle in a Public Hospital in Spain. The women in Group 1 received eSET plus a single embryo cryotransfer, and those in Group 2 received a double embryo transfer (DET). RESULTS: In the intention-to-treat analysis, the cumulative live birth delivery rate in the eSET group was similar to the results obtained for the DET group (45.2% vs. 41.8%; p = 0.60). The rate of multiple gestation was significantly lower in the eSET group than in the DET group (0% vs. 26.4%; p < 0.05). The findings obtained in the per-protocol analysis were similar to those obtained in the intention-to-treat analysis. The per-protocol analysis revealed no significant differences in the rate of implantation (29.8% in eSET vs. 29.7% in DET; p = 0.98), in cumulative pregnancy rates per transfer (49.1% in eSET vs. 46.9% in DET; p = 0.80) or in the cumulative live birth delivery rate (38.6% in eSET vs. 42.2% in DET; p = 0.69). In the cycles with eSET, there were no twin pregnancies (0% in eSET vs. 27.6 in DET; p < 0.05). CONCLUSIONS: For women aged under 38 years with good prognosis, without taking embryo quality as a criterion for inclusion, an eSET policy can be applied, achieving acceptable cumulative clinical pregnancy rates and birth rates. PMID- 24798074 TI - P-glycoprotein makes no contribution to the lower transplacental transfer of digoxin under fetal heart failure, but who should be blamed for? PMID- 24798073 TI - Routine isolation and expansion late mid trimester amniotic fluid derived mesenchymal stem cells in a cohort of fetuses with congenital diaphragmatic hernia. AB - OBJECTIVE: To assess the feasibility of routine isolation and expansion of amniotic fluid derived mesenchymal stem cells (AF-MSC) in fetuses diagnosed with isolated congenital diaphragmatic hernia (CDH). STUDY DESIGN: Redundant AF samples of fetuses with CDH and normal fetuses were obtained. Cell colonies were mechanically selected for each sample. Proliferation capacity was expressed as population doubling time (PDT). Cell lines were further characterized with flow cytometry, differentiation assays and qRT-PCR (OCT4 and NANOG). After cell labeling with LacZ in vivo tracking was performed after fetal tracheal injection in rabbits. RESULTS: Fourteen consecutive CDH samples (median gestational age (GA) of 32.9 weeks; IQR: 27.8-34.3 weeks) and seven control samples (30 weeks; IQR: 28.9-34.4 weeks) were obtained. PDT was similar in both groups (45.4h+/-1.9 vs. 52.3h+/-3.4;NS). AF-MSCs expressed a typical mesenchymal CD marker profile. Clones could be differentiated in osteogenic, adipogenic and chrondrogenic lineages. Expression of multipotency markers was low in all cell lines. We confirmed the presence of injected cells inside the fetal lung three days after intratracheal injection. CONCLUSION: Routine isolation and expansion of AF-MSCs in CDH is feasible and cell lines generated were comparable to those of control samples. AF-MSCs from affected fetuses could potentially be used in future stem cell therapy. PMID- 24798075 TI - Comparative genome analysis of wheat blue dwarf phytoplasma, an obligate pathogen that causes wheat blue dwarf disease in China. AB - Wheat blue dwarf (WBD) disease is an important disease that has caused heavy losses in wheat production in northwestern China. This disease is caused by WBD phytoplasma, which is transmitted by Psammotettix striatus. Until now, no genome information about WBD phytoplasma has been published, seriously restricting research on this obligate pathogen. In this paper, we report a new sequencing and assembling strategy for phytoplasma genome projects. This strategy involves differential centrifugation, pulsed-field gel electrophoresis, whole genome amplification, shotgun sequencing, de novo assembly, screening of contigs from phytoplasma and the connection of phytoplasma contigs. Using this scheme, the WBD phytoplasma draft genome was obtained. It was comprised of six contigs with a total size of 611,462 bp, covering ~94% of the chromosome. Five-hundred-twenty five protein-coding genes, two operons for rRNA genes and 32 tRNA genes were identified. Comparative genome analyses between WBD phytoplasma and other phytoplasmas were subsequently carried out. The results showed that extensive arrangements and inversions existed among the WBD, OY-M and AY-WB phytoplasma genomes. Most protein-coding genes in WBD phytoplasma were found to be homologous to genes from other phytoplasmas; only 22 WBD-specific genes were identified. KEGG pathway analysis indicated that WBD phytoplasma had strongly reduced metabolic capabilities. However, 46 transporters were identified, which were involved with dipeptides/oligopeptides, spermidine/putrescine, cobalt and Mn/Zn transport, and so on. A total of 37 secreted proteins were encoded in the WBD phytoplasma chromosome and plasmids. Of these, three secreted proteins were similar to the reported phytoplasma virulence factors TENGU, SAP11 and SAP54. In addition, WBD phytoplasma possessed several proteins that were predicted to play a role in its adaptation to diverse environments. These results will provide clues for research on the pathogenic mechanisms of WBD phytoplasma and will also provide a perspective about the genome sequencing of other phytoplasmas and obligate organisms. PMID- 24798076 TI - Fungal lysis by a soil bacterium fermenting cellulose. AB - Recycling of plant biomass by a community of bacteria and fungi is fundamental to carbon flow in terrestrial ecosystems. Here we report how the plant fermenting, soil bacterium Clostridium phytofermentans enhances growth on cellulose by simultaneously lysing and consuming model fungi from soil. We investigate the mechanism of fungal lysis to show that among the dozens of different glycoside hydrolases C. phytofermentans secretes on cellulose, the most highly expressed enzymes degrade fungi rather than plant substrates. These enzymes, the GH18 Cphy1799 and Cphy1800, synergize to hydrolyse chitin, a main component of the fungal cell wall. Purified enzymes inhibit fungal growth and mutants lacking either GH18 grow normally on cellulose and other plant substrates, but have a reduced ability to hydrolyse chitinous substrates and fungal hyphae. Thus, C. phytofermentans boosts growth on cellulose by lysing fungi with its most highly expressed hydrolases, highlighting the importance of fungal interactions to the ecology of cellulolytic bacteria. PMID- 24798077 TI - Structure and function of preQ1 riboswitches. AB - PreQ1 riboswitches help regulate the biosynthesis and transport of preQ1 (7 aminomethyl-7-deazaguanine), a precursor of the hypermodified guanine nucleotide queuosine (Q), in a number of Firmicutes, Proteobacteria, and Fusobacteria. Queuosine is almost universally found at the wobble position of the anticodon in asparaginyl, tyrosyl, histidyl and aspartyl tRNAs, where it contributes to translational fidelity. Two classes of preQ1 riboswitches have been identified (preQ1-I and preQ1-II), and structures of examples from both classes have been determined. Both classes form H-type pseudoknots upon preQ1 binding, each of which has distinct unusual features and modes of preQ1 recognition. These features include an unusually long loop 2 in preQ1-I pseudoknots and an embedded hairpin in loop 3 in preQ1-II pseudoknots. PreQ1-I riboswitches are also notable for their unusually small aptamer domain, which has been extensively investigated by NMR, X-ray crystallography, FRET, and other biophysical methods. Here we review the discovery, structural biology, ligand specificity, cation interactions, folding, dynamics, and applications to biotechnology of preQ1 riboswitches. This article is part of a Special Issue entitled: Riboswitches. PMID- 24798078 TI - The K-turn motif in riboswitches and other RNA species. AB - The kink turn is a widespread structure motif that introduces a tight bend into the axis of duplex RNA. This generally functions to mediate tertiary interactions, and to serve as a specific protein binding site. K-turns or closely related structures are found in at least seven different riboswitch structures, where they function as key architectural elements that help generate the ligand binding pocket. This article is part of a Special Issue entitled: Riboswitches. PMID- 24798080 TI - Prediction of gestational diabetes in obese pregnant women from the UK Pregnancies Better Eating and Activity (UPBEAT) pilot trial. AB - AIM: To examine the prediction of gestational diabetes in obese women using routine clinical measures and measurement of biomarkers related to insulin resistance in the early second trimester. METHODS: A total of 117 obese pregnant women participating in a pilot trial of a complex intervention of dietary advice and physical activity were studied. Blood samples were obtained at recruitment (15+0-17+6 weeks' gestation) and demographic, clinical history and anthropometric measures recorded. The biomarkers analysed were plasma lipids (HDL cholesterol, LDL cholesterol, triglycerides), high-sensitivity C-reactive protein, alanine transaminase, aspartate transaminase, ferritin, fructosamine, insulin, adiponectin, tissue plasminogen activator, interleukin-6, visfatin and leptin. Univariate and logistic regression analyses were performed to determine independent predictors and area under the receiver-operating curve was calculated for the model. RESULTS: Of the 106 participants included in the analysis, 29 (27.4%) developed gestational diabetes. Participants with gestational diabetes were older (P = 0.002), more often of parity >= 2, had higher systolic (P = 0.02) and diastolic blood pressure (P = 0.02) and were more likely to be black (P = 0.009). Amongst the blood biomarkers measured, plasma adiponectin alone remained independently associated with gestational diabetes in adjusted models (P = 0.002). The area under the receiver-operating curve for clinical factors alone (0.760) increased significantly (area under the curve 0.834, chi-square statistic (1) = 4.00, P = 0.046) with the addition of adiponectin. CONCLUSIONS: A combination of routinely measured clinical factors and adiponectin measured in the early second trimester in obese women may provide a useful approach to the prediction of gestational diabetes. Validation in a large prospective study is required to determine the usefulness of this algorithm in clinical practice. PMID- 24798081 TI - On the optimal production capacity for influenza vaccine. AB - This paper analyzes the profit maximizing capacity choice of a monopolistic vaccine producer facing the uncertain event of a pandemic in a homogenous population of forward-looking individuals. For any capacity level, the monopolist solves the intertemporal price discrimination problem within the dynamic setting generated by the standard mathematical epidemiological model of infectious diseases. Even though consumers are assumed to be identical, the monopolist will be able to exploit the ex post heterogeneity between infected and susceptible individuals by raising the price of vaccine in response to the increasing hazard rate. The monopolist thus bases its investment decision on the expected profits from the optimal price path given the infection dynamics. It is shown that the monopolist will always choose to invest in a lower production capacity than the social planner. Through numerical simulation, it is demonstrated how the loss to society of having a monopoly producer decreases with the speed of infection transmission. Moreover, it is illustrated how the monopolist's optimal vaccination rate increases as its discount rate rises for cost parameters based on Swedish data. However, the effect of the firm discount rate on its investment decision is sensitive to assumptions regarding the cost of production capacity. PMID- 24798082 TI - Technical simplification of the supermicrosurgical side-to-end lymphaticovenular anastomosis using the parachute technique. AB - BACKGROUND: Supermicrosurgical side-to-end (S-E) lymphaticovenular anastomosis (LVA) is the most favorable anastomotic configuration for the treatment of lymphedema because it creates antegrade and retrograde lymph flow while preserves the native lymph flow. However, it is technically demanding and its successful performance has been limited only to the experienced LVA surgeons. This study aimed to evaluate the applicability of parachute technique in S-E LVA and its potential in decreasing the technical complexity of the procedure. METHODS: Between April 2010 and July 2011, S-E LVAs were performed in 14 patients with bilateral lower limb lymphedema with either the conventional technique or the parachute technique. To exclude interoperator variability of LVAs, only limbs in which S-E LVAs performed by one surgeon were included. Feasibility, anastomotic patency, operative times, and treatment efficacy of both techniques were retrospectively compared. RESULTS: Thirty-seven S-E LVAs were performed by the surgeon; 17 LVAs with parachute technique in seven limbs and 20 LVAs with the conventional technique in seven limbs. Both groups demonstrated 100% anastomotic patency. Time required to perform the S-E anastomosis using the parachute technique was significantly shorter than when the conventional technique was used (8.6 +/- 3.7 vs. 11.3 +/- 3.1 minutes, P = 0.025). Both groups showed similar postoperative reduction in lymphedema indices (19.9 +/- 8.2 vs. 18.9 +/- 10.0, P = 0.841). CONCLUSIONS: The parachute technique simplifies the supermicrosurgical S-E LVA while maintaining efficacy comparable to the conventional technique. PMID- 24798084 TI - Dynamic visual tests to identify and quantify visual damage and repair following demyelination in optic neuritis patients. AB - In order to follow optic neuritis patients and evaluate the effectiveness of their treatment, a handy, accurate and quantifiable tool is required to assess changes in myelination at the central nervous system (CNS). However, standard measurements, including routine visual tests and MRI scans, are not sensitive enough for this purpose. We present two visual tests addressing dynamic monocular and binocular functions which may closely associate with the extent of myelination along visual pathways. These include Object From Motion (OFM) extraction and Time-constrained stereo protocols. In the OFM test, an array of dots compose an object, by moving the dots within the image rightward while moving the dots outside the image leftward or vice versa. The dot pattern generates a camouflaged object that cannot be detected when the dots are stationary or moving as a whole. Importantly, object recognition is critically dependent on motion perception. In the Time-constrained Stereo protocol, spatially disparate images are presented for a limited length of time, challenging binocular 3-dimensional integration in time. Both tests are appropriate for clinical usage and provide a simple, yet powerful, way to identify and quantify processes of demyelination and remyelination along visual pathways. These protocols may be efficient to diagnose and follow optic neuritis and multiple sclerosis patients. In the diagnostic process, these protocols may reveal visual deficits that cannot be identified via current standard visual measurements. Moreover, these protocols sensitively identify the basis of the currently unexplained continued visual complaints of patients following recovery of visual acuity. In the longitudinal follow up course, the protocols can be used as a sensitive marker of demyelinating and remyelinating processes along time. These protocols may therefore be used to evaluate the efficacy of current and evolving therapeutic strategies, targeting myelination of the CNS. PMID- 24798083 TI - IFN-gamma stimulates autophagy-mediated clearance of Burkholderia cenocepacia in human cystic fibrosis macrophages. AB - Burkholderia cenocepacia is a virulent pathogen that causes significant morbidity and mortality in patients with cystic fibrosis (CF), survives intracellularly in macrophages, and uniquely causes systemic infections in CF. Autophagy is a physiologic process that involves engulfing non-functional organelles and proteins and delivering them for lysosomal degradation, but also plays a role in eliminating intracellular pathogens, including B. cenocepacia. Autophagy is defective in CF but can be stimulated in murine CF models leading to increased clearance of B. cenocepacia, but little is known about autophagy stimulation in human CF macrophages. IFN-gamma activates macrophages and increases antigen presentation while also inducing autophagy in macrophages. We therefore, hypothesized that treatment with IFN-gamma would increase autophagy and macrophage activation in patients with CF. Peripheral blood monocyte derived macrophages (MDMs) were obtained from CF and non-CF donors and subsequently infected with B. cenocepacia. Basal serum levels of IFN-gamma were similar between CF and non-CF patients, however after B. cenocepacia infection there is deficient IFN-gamma production in CF MDMs. IFN-gamma treated CF MDMs demonstrate increased co-localization with the autophagy molecule p62, increased autophagosome formation, and increased trafficking to lysosomes compared to untreated CF MDMs. Electron microscopy confirmed IFN-gamma promotes double membrane vacuole formation around bacteria in CF MDMs, while only single membrane vacuoles form in untreated CF cells. Bacterial burden is significantly reduced in autophagy stimulated CF MDMs, comparable to non-CF levels. IL-1beta production is decreased in CF MDMs after IFN-gamma treatment. Together, these results demonstrate that IFN-gamma promotes autophagy-mediated clearance of B. cenocepacia in human CF macrophages. PMID- 24798085 TI - A 13-week repeated-dose oral toxicity and bioaccumulation of aluminum oxide nanoparticles in mice. AB - Because of an increase in the commercial applications of manufactured nanoparticles, the issue of potential adverse health effects of nanoparticles following intended or unintended exposure is rapidly gaining attention. In this study, we evaluated the toxicity of aluminum oxide nanoparticles (AlNPs, rod type, 1.5, 3, and 6 mg/kg) after oral administration to mice for 13 weeks. Compared with the control group, the consumption of diet and drinking water and body weight gain decreased in the group treated with AlNPs. The group treated with 6 mg/kg AlNPs also showed a marked elevation in the count of white blood cells that associated with a significant decrease and increase to the proportion of eosinophils and lymphocytes, respectively. In addition, the secretion of IL-6 and monocyte chemotactic protein-1 increased in a dose-dependent manner in the treated groups. Furthermore, AlNPs showed the highest accumulation in the liver and kidneys compared with the control group, increased the lactate dehydrogenase level in the blood, and induced the development of a pathological lesion in the liver and kidneys. Taken together, we suggest that the target organs of rod-type AlNPs may be the liver, kidneys and the immune system, and the not-observed adverse effect level may be lower than 6 mg/kg. PMID- 24798086 TI - Ceramide/sphingomyelin cycle involvement in gentamicin-induced cochlear hair cell death. AB - Ceramide, a sphingolipid metabolite, regulates diverse cellular processes including apoptosis, cell senescence, the cell cycle, and cellular differentiation. Exogenously administered ceramide reportedly increased cochlear hair cell death due to gentamicin-induced ototoxicity. Ceramide is mainly generated via a ceramide/sphingomyelin cycle by sphingomyelinase and sphingomyelin synthase or via de novo synthesis by serine palmitoyltransferase and ceramide synthase. This study was designed to investigate the possible involvement of neutral sphingomyelinase, sphingomyelin synthase, or serine palmitoyltransferase in hair cell death due to gentamicin. The basal turns of the organ of Corti of Sprague-Dawley rats were dissected on postnatal days 3-5. Cochlear cultures were exposed to media containing 35 MUM gentamicin for 48 h to assess the effects of GW4869 (a neutral sphingomyelinase inhibitor), 2 hydroxyoleic acid (a sphingomyelin synthase activator), and myriocin (a serine palmitoyltransferase inhibitor). Hair cell loss was significantly decreased in the presence of GW4869 or 2-hydroxyoleic acid. Myriocin had no significant effects against gentamicin-induced hair cell loss. In addition, neutral sphingomyelinase was activated by gentamicin exposure. The present findings strongly suggest that the ceramide/sphingomyelin cycle plays an important role in the protection of hair cells against gentamicin-induced ototoxicity. PMID- 24798087 TI - Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA. AB - The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) has been implicated in the etiology of neurodegenerative disease, and recent studies indicate that BMAA can be misincorporated into proteins. BMAA is a developmental neurotoxicant that can induce long-term learning and memory deficits, as well as regionally restricted neuronal degeneration and mineralization in the hippocampal CA1. The aim of the study was to characterize long-term changes (2 weeks to 6 months) further in the brain of adult rats treated neonatally (postnatal days 9 10) with BMAA (460 mg/kg) using immunohistochemistry (IHC), transmission electron microscopy, and laser capture microdissection followed by LC-MS/MS for proteomic analysis. The histological examination demonstrated progressive neurodegenerative changes, astrogliosis, microglial activation, and calcification in the hippocampal CA1 3-6 months after exposure. The IHC showed an increased staining for alpha-synuclein and ubiquitin in the area. The ultrastructural examination revealed intracellular deposition of abundant bundles of closely packed parallel fibrils in neurons, axons, and astrocytes of the CA1. Proteomic analysis of the affected site demonstrated an enrichment of chaperones (e.g., clusterin, GRP-78), cytoskeletal and intermediate filament proteins, and proteins involved in the antioxidant defense system. Several of the most enriched proteins (plectin, glial fibrillar acidic protein, vimentin, Hsp 27, and ubiquitin) are known to form complex astrocytic inclusions, so-called Rosenthal fibers, in the neurodegenerative disorder Alexander disease. In addition, TDP-43 and the negative regulator of autophagy, GLIPR-2, were exclusively detected. The present study demonstrates that neonatal exposure to BMAA may offer a novel model for the study of hippocampal fibril formation in vivo. PMID- 24798088 TI - Mechanisms of acute kidney injury induced by experimental Lonomia obliqua envenomation. AB - Lonomia obliqua caterpillar envenomation causes acute kidney injury (AKI), which can be responsible for its deadly actions. This study evaluates the possible mechanisms involved in the pathogenesis of renal dysfunction. To characterize L. obliqua venom effects, we subcutaneously injected rats and examined renal functional, morphological and biochemical parameters at several time points. We also performed discovery-based proteomic analysis to measure protein expression to identify molecular pathways of renal disease. L. obliqua envenomation causes acute tubular necrosis, which is associated with renal inflammation; formation of hematic casts, resulting from intravascular hemolysis; increase in vascular permeability and fibrosis. The dilation of Bowman's space and glomerular tuft is related to fluid leakage and intra-glomerular fibrin deposition, respectively, since tissue factor procoagulant activity increases in the kidney. Systemic hypotension also contributes to these alterations and to the sudden loss of basic renal functions, including filtration and excretion capacities, urinary concentration and maintenance of fluid homeostasis. In addition, envenomed kidneys increase the expression of proteins involved in cell stress, inflammation, tissue injury, heme-induced oxidative stress, coagulation and complement system activation. Finally, the localization of the venom in renal tissue agrees with morphological and functional alterations, suggesting also a direct nephrotoxic activity. In conclusion, the mechanisms of L. obliqua-induced AKI are complex involving mainly glomerular and tubular functional impairment and vascular alterations. These results are important to understand the mechanisms of renal injury and may suggest more efficient ways to prevent or attenuate the pathology of Lonomia's envenomation. PMID- 24798089 TI - Celecoxib prevents curcumin-induced apoptosis in a hematopoietic cancer cell model. AB - Molecules targeting pro-inflammatory pathways have demonstrated beneficial effects in cancer treatment. More recently, combination of natural and synthetic anti-inflammatory drugs was suggested as an appealing strategy to inhibit tumor growth. Herein, we show that curcumin, a polyphenol from Curcuma longa and celecoxib induce apoptosis in hematopoietic cancer cell lines (Hel, Jurkat, K562, Raji, and U937). Further investigations on the most sensitive cell line, U937, indicated that these effects were tightly associated with an accumulation of the cells in S and G2/M for curcumin and in G0/G1 phase of cell cycle for celecoxib, respectively. The effect of celecoxib on cell cycle is associated with an induction of p27 and the down-regulation of cyclin D1. However, in the case of combination experiments, the pretreatment of U937 cells with celecoxib at non apoptogenic concentrations counteracted curcumin-induced apoptosis. We found that this effect correlated with the prevention of the accumulation in S and G2/M phase of cell cycle induced by curcumin. Similar results have been obtained when celecoxib and curcumin were co-administrated at the same time. Overall our data suggest that this natural and synthetic drug combination is detrimental for cell death induction. PMID- 24798090 TI - Methadone-maintained patients in primary care have higher rates of chronic disease and multimorbidity, and use health services more intensively than matched controls. AB - BACKGROUND: Methadone maintenance treatment in primary care is cost-effective and improves outcomes for opiate-dependent patients. A more developed understanding of the evolving needs of this important cohort will facilitate further improvements in their integrated care within the community. OBJECTIVES: The aim of this study was to compare the burden of chronic disease, multi-morbidity and intensity of health-service use between methadone-maintained patients (MMPs) and matched controls in primary care. METHODS: This is a retrospective matched case control design. Data on chronic disease and health service use was collected in 13 computerized GP surgeries on 414 patients (207 MMPs and 207 controls). Twelve months of records were examined. MMPs were compared with controls matched by gender, age, socio-economic status (SES) and GP surgery. RESULTS: MMPs suffered more chronic disease (OR = 9.1, 95% CI: 5.4-15.1, P < 0.001) and multi-morbidity (OR = 6.6, 95% CI: 4.3-10.2, P < 0.001). They had higher rates of respiratory, psychiatric and infectious disease. MMPs of lower SES had more chronic disease than their peers (OR = 7.2, 95% CI: 2.4-22.0, P < 0.001). MMPs attended the doctor more often with medical problems (OR = 15.4, 95% CI: 8.2-28.7, P < 0.001), with a frequent requirement to have medical issues addressed during methadone management visits. Their care generated more telephone calls (OR = 4.4, 95% CI: 2.8-6.8, P < 0.001), investigations (OR = 1.8, 95% CI: 1.2-2.7, P = 0.003), referrals (2.6, 95% CI: 1.7-4.0, P < 0.001), emergency department visits (2.1, 95% CI: 1.3-3.6, P = 0.004), outpatient attendances (2.3, 95% CI: 1.51-1.43, P < 0.001) and hospital admissions (3.6, 95% CI: 1.6-8.1, P = 0.001). CONCLUSION: Correcting for routine methadone care and drug-related illnesses, MMPs had a higher burden of chronic disease and used both primary and secondary health services more intensively than matched controls. PMID- 24798091 TI - Stroke awareness: take preventive action. PMID- 24798092 TI - Efficacy of voglibose in type 2 diabetes. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is currently at epidemic proportions and the forecast is for a continued sharp increase in global prevalence. An even larger proportion of the population has prediabetes (impaired glucose tolerance [IGT]) underscoring the urgent need for preventive strategies. Even in the presence of adequate glycosylated hemoglobin (HbA1c) levels, postprandial hyperglycemia can occur and is known to have a stronger association with cardiovascular morbidity than fasting glucose. The alpha-glucosidase inhibitor voglibose is widely used in Japan to improve postprandial hyperglycemia. AREAS COVERED: This review examines the literature for the pharmacology, pharmacokinetics, clinical efficacy and safety of voglibose in patients with T2DM. Particular focus is on its efficacy in preventing T2DM in individuals with IGT and its efficacy as add-on therapy or in combination with other oral antidiabetic agents in patients with T2DM. EXPERT OPINION: As the relationship between glucose levels and cardiovascular risk extends below the diabetic threshold, postprandial hyperglycemia is recognized as a key therapeutic target in the treatment of T2DM. Strategies to prevent the progression of IGT to overt T2DM have enormous potential to reduce the individual and societal burden of disease. Voglibose is the first oral antidiabetic agent to gain approval in Japan for this indication. PMID- 24798093 TI - Vinyl dihydropyrans and dihydrooxazines: cyclizations of catalytic ruthenium carbenes derived from alkynals and alkynones. AB - A novel synthesis of 2-vinyldihydropyrans and dihydro-1,4-oxazines (morpholine derivatives) from alkynals and alkynones has been developed. The cyclizations require a mild generation of catalytic ruthenium carbenes from terminal alkynes and (trimethylsilyl)diazomethane followed by trapping with carbonyl nucleophiles. Mechanistic aspects of the new cyclizations are discussed. PMID- 24798095 TI - C9ORF72 repeat expansion and bipolar disorder - is there a link? No mutation detected in a Sardinian cohort of patients with bipolar disorder. PMID- 24798094 TI - Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro. AB - Exposure to ethylene glycol monomethyl ether (EGME), a glycol ether compound found in numerous industrial products, or to its active metabolite, 2 methoxyacetic acid (2-MAA), increases the incidence of developmental defects. Using an in vitro limb bud culture system, we tested the hypothesis that the effects of EGME on limb development are mediated by 2-MAA-induced alterations in acetylation programming. Murine gestation day 12 embryonic forelimbs were exposed to 3, 10, or 30 mM EGME or 2-MAA in culture for 6 days to examine effects on limb morphology; limbs were cultured for 1 to 24 hr to monitor effects on the acetylation of histones (H3K9 and H4K12), a nonhistone protein, p53 (p53K379), and markers for cell cycle arrest (p21) and apoptosis (cleaved caspase-3). EGME had little effect on limb morphology and no significant effects on the acetylation of histones or p53 or on biomarkers for cell cycle arrest or apoptosis. In contrast, 2-MAA exposure resulted in a significant concentration dependent increase in limb abnormalities. 2-MAA induced the hyperacetylation of histones H3K9Ac and H4K12Ac at all concentrations tested (3, 10, and 30 mM). Exposure to 10 or 30 mM 2-MAA significantly increased acetylation of p53 at K379, p21 expression, and caspase-3 cleavage. Thus, 2-MAA, the proximate metabolite of EGME, disrupts limb development in vitro, modifies acetylation programming, and induces biomarkers of cell cycle arrest and apoptosis. PMID- 24798096 TI - A microstrain comparison of passively fitting screw-retained and cemented titanium frameworks. AB - STATEMENT OF PROBLEM: An imprecise fit between frameworks and supporting dental implants in loaded protocols increases the strain transferred to the periimplant bone, which may impair healing or generate microgaps. PURPOSE: The purpose of this study was to investigate the microstrain between premachined 1-piece screw retained frameworks (group STF) and screw-retained frameworks fabricated by cementing titanium cylinders to the prefabricated framework (group CTF). This procedure was developed to correct the misfit between frameworks and loaded implants. MATERIAL AND METHODS: Four internal hexagon cylindrical implants were placed 10 mm apart in a polyurethane block by using the surgical guides of the corresponding implant system. Previously fabricated titanium frameworks (n=10) were divided into 2 groups. In group STF, prefabricated machined frameworks were used (n=5), and, in group CTF, the frameworks were fabricated by using a passive fit procedure, which was developed to correct the misfit between the cast titanium frameworks and supporting dental implants (n=5). Both groups were screw retained under torque control (10 Ncm). Six strain gauges were placed on the upper surface of the polyurethane block, and 3 strain measurements were recorded for each framework. Data were analyzed with the Student t test (alpha=.05). RESULTS: The mean microstrain values between the framework and the implants were significantly higher for group STF (2517 mepsilon) than for group CTF (844 mepsilon) (P<.05). CONCLUSIONS: Complete-arch implant frameworks designed for load application and fabricated by using the passive fit procedure decreased the strain between the frameworks and implants more than 1 piece prefabricated machined frameworks. PMID- 24798097 TI - Surgical management of combat-related upper extremity injuries. AB - This review presents the current surgical management of combat-related upper extremity injuries during the acute phase. The strategy consists of saving the life, saving the limb and retaining function. Surgical tactics are based on damage control orthopaedics techniques of haemorrhage control, wound debridement, and temporary bone stabilization prior to evacuation out of the combat zone. Features of the definitive management of local casualties in battlefield medical facilities are also discussed. In this situation, reconstructive procedures have to take into account the limited resources and operational constraints. PMID- 24798099 TI - Context effects on verb production in specific language impairment (SLI): confrontation naming versus connected speech. AB - A handful of studies have shown that verbs are more vulnerable than nouns to retrieval deficits on picture-based naming tasks for children with specific language impairment (SLI). The aim of this study was to examine if the disproportionate verb as opposed to noun production deficit reported for naming is also found in connected speech. Sixteen children participated in the study: eight children diagnosed with SLI (mean age: 6:3 years) and eight typically language developing (TLD, mean age: 5:9 years) controls. Verb and noun production was measured in connected speech and compared to picture confrontation naming. Both groups of children showed a significant difficulty naming verbs compared to nouns. In contrast, they did not differ on the total number of both verb tokens and verb types produced in connected speech. The findings indicate that the previously reported verb retrieval difficulties in SLI are a product of the confrontation naming task demands rather than a true verb deficit. PMID- 24798098 TI - Synthesis, in vitro antimicrobial and cytotoxic activities of novel pyrimidine benzimidazol combinations. AB - A series of novel 4-substituted-2-{[(1H-benzo[d]imidazol-2-yl)methyl] thio}-6 methylpyrimidine derivatives were designed, synthesized and evaluated for their cytotoxic activities against four human cancer cell lines and inhibitory activities against five type culture strains in vitro. Some of synthetic pyrimidine-benzimidazol combinations showed good inhibitory activities against Stenotrophomonas maltophilia, especially compounds 7b and 7c. Compounds 7a and 7d exhibited enhanced activities against MGC-803 in vitro, when compared to 5-Fu. PMID- 24798100 TI - The nuclear factor kappa B (NF-kappaB) activation is required for phagocytosis of staphylococcus aureus by RAW 264.7 cells. AB - Nuclear factor kappa B (NF-kappaB) is a ubiquitous transcription factor which controls the expression of various genes involved in immune responses. However, it is not clear whether NF-kappaB activation is critical for phagocytosis when Staphylococcus aureus is the pathogen. Using oligonucleotide microarrays, we investigated whether NF-kappaB cascade genes are altered in a mouse leukemic monocyte macrophage cell line (RAW 264.7) when the cells were stimulated to activate a host innate immune response against live S. aureus or heat-inactivated S. aureus (HISA). NF-kappaB cascade genes such as Nfkappab1, Nfkappabiz, Nfkappabie, Rel, Traf1 and Tnfaip3 were up-regulated by all treatments at one hour after incubation. NF-kappaB play an important role in activating phagocytosis in RAW 264.7 cells infected with S. aureus. Inhibition of NF-kappaB significantly blocked phagocytosis of fluorescently labeled S. aureus and decreased the expression of NFkappaB1, IL1alpha, IL1beta and TLR2 in this cell line. Our results demonstrate that S. aureus may activate the NF-kappaB pathway and that NF-kappaB activation is required for phagocytosis of S. aureus by macrophages. PMID- 24798101 TI - Anti-LRP/LR specific antibody IgG1-iS18 impedes adhesion and invasion of liver cancer cells. AB - Two key events, namely adhesion and invasion, are pivotal to the occurrence of metastasis. Importantly, the 37 kDa/67 kDa laminin receptor (LRP/LR) has been implicated in enhancing these two events thus facilitating cancer progression. In the current study, the role of LRP/LR in the adhesion and invasion of liver cancer (HUH-7) and leukaemia (K562) cells was investigated. Flow cytometry revealed that the HUH-7 cells displayed significantly higher cell surface LRP/LR levels compared to the poorly-invasive breast cancer (MCF-7) control cells, whilst the K562 cells displayed significantly lower cell surface LRP/LR levels in comparison to the MCF-7 control cells. However, Western blotting and densitometric analysis revealed that all three tumorigenic cell lines did not differ significantly with regards to total LRP/LR levels. Furthermore, treatment of liver cancer cells with anti-LRP/LR specific antibody IgG1-iS18 (0.2 mg/ml) significantly reduced the adhesive potential of cells to laminin-1 and the invasive potential of cells through the ECM-like Matrigel, whilst leukaemia cells showed no significant differences in both instances. Additionally, Pearson's correlation coefficients suggested direct proportionality between cell surface LRP/LR levels and the adhesive and invasive potential of liver cancer and leukaemia cells. These findings suggest the potential use of anti-LRP/LR specific antibody IgG1-iS18 as an alternative therapeutic tool for metastatic liver cancer through impediment of the LRP/LR- laminin-1 interaction. PMID- 24798102 TI - Short communication: circulating plasma HIV-1 viral protein R in dual HIV 1/tuberculosis infection. AB - Circulating free HIV-1 viral protein R (Vpr) is found in up to one third of subjects with HIV-1 infection. Free Vpr presumably shares some of the immunopathogenic effects of cell-associated Vpr. Here we assessed Vpr in plasma and pleural fluid from HIV/tuberculosis (TB) dually infected subjects with pleural TB and from plasma of patients with pulmonary HIV/TB. Vpr was assessed by western blot analysis. In plasma from HIV/TB subjects with pulmonary TB free Vpr could be detected in 47%. Only one subject, among 26 tested, with HIV monoinfection showed plasma Vpr activity. The majority (87.5%) of patients with pleural HIV/TB demonstrated free Vpr reactivity in their plasma. However, no Vpr activity was found in autologous pleural fluid samples from pleural HIV/TB patients. Standard (s) Vpr reactivity was reduced markedly by the addition of sVpr to pleural fluid from HIV-uninfected subjects. A high incidence of plasma Vpr reactivity in HIV/TB patients implies heightened processing and release of this HIV-1 accessory protein during HIV/TB coinfection. The contribution of free Vpr to HIV-1 immunopathogenesis during HIV/TB needs to be studied. PMID- 24798103 TI - The idea of philosophical sociology. AB - This article introduces the idea of philosophical sociology as an enquiry into the relationships between implicit notions of human nature and explicit conceptualizations of social life within sociology. Philosophical sociology is also an invitation to reflect on the role of the normative in social life by looking at it sociologically and philosophically at the same: normative self reflection is a fundamental aspect of sociology's scientific tasks because key sociological questions are, in the last instance, also philosophical ones. For the normative to emerge, we need to move away from the reductionism of hedonistic, essentialist or cynical conceptions of human nature and be able to grasp the conceptions of the good life, justice, democracy or freedom whose normative contents depend on more or less articulated conceptions of our shared humanity. The idea of philosophical sociology is then sustained on three main pillars and I use them to structure this article: (1) a revalorization of the relationships between sociology and philosophy; (2) a universalistic principle of humanity that works as a major regulative idea of sociological research, and; (3) an argument on the social (immanent) and pre-social (transcendental) sources of the normative in social life. As invitations to embrace posthuman cyborgs, non human actants and material cultures proliferate, philosophical sociology offers the reminder that we still have to understand more fully who are the human beings that populate the social world. PMID- 24798104 TI - Neurolytic sympathectomy in the management of cancer pain-time effect: a prospective, randomized multicenter study. AB - CONTEXT: Sympathectomy is currently used as the fourth step of the modified World Health Organization (WHO) analgesic ladder. Sympathectomy can be performed early, before the second step on the ladder. OBJECTIVES: We hypothesized that early sympathectomy would reduce pain and opioid consumption and improve quality of life. METHODS: One hundred nine patients, with inoperable abdominal or pelvic cancer, reporting visceral pain of 40-70 on a visual analogue scale and taking nonopioid analgesics were allocated randomly into two groups: either blocks were performed before Step 2 of the WHO ladder, then analgesics were managed according to the ladder (Group I) or analgesics were given according to the WHO ladder, and blocks were performed as the fourth step after failure of strong opioids to control pain (Group II). Visual analogue scale scores, responder analysis, daily opioid consumption, related side effects, and quality of life were assessed. RESULTS: Responders were significantly higher in Group I (P < 0.0001), and partial responders and nonresponders significantly increased in Group II (P < 0.0001 and 0.006, respectively). Opioid consumption significantly decreased in Group I (P < 0.0001 during first 12 months and 0.007 at the last assessment time), with concomitant significant reduction in related side effects. The number of patients who had a good analgesic response on tramadol significantly increased in Group I during the first five months (P < 0.05). European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global quality-of-life subscale scores revealed significant improvement until the fifth month in Group I (P < 0.05). CONCLUSION: Sympathectomy before Step 2 on the WHO analgesic ladder seems to lead to better pain control, less opioid consumption, and better quality of life in cancer patients. PMID- 24798106 TI - A phenotype-based classification of NSAIDs hypersensitivity: new patients, new challenges. PMID- 24798105 TI - Recommendations for bowel obstruction with peritoneal carcinomatosis. AB - This article reports on the clinical practice guidelines developed by a multidisciplinary group working on the indications and uses of the various available treatment options for relieving intestinal obstruction or its symptoms in patients with peritoneal carcinomatosis. These guidelines are based on a literature review and expert opinion. The recommended strategy involves a clinical and radiological evaluation, of which CT of the abdomen is a crucial component. The results, together with an analysis of the prognostic criteria, are used to determine whether surgery or stenting is the best option. In most patients, however, neither option is feasible, and the main emphasis, therefore, is on the role and administration of various symptomatic medications such as glucocorticoids, antiemetic agents, analgesics, and antisecretory agents (anticholinergic drugs, somatostatin analogues, and proton-pump inhibitors). Nasogastric tube feeding is no longer used routinely and should instead be discussed on a case-by-case basis. Recent studies have confirmed the efficacy of somatostatin analogues in relieving obstruction-related symptoms such as nausea, vomiting, and pain. However, the absence of a marketing license and the high cost of these drugs limit their use as the first-line treatment, except in highly selected patients (early recurrence). When these medications fail to alleviate the symptoms of obstruction, venting gastrostomy should be considered promptly. Rehydration is needed for virtually every patient. Parenteral nutrition and pain management should be adjusted according to the patient needs and guidelines. PMID- 24798107 TI - Recommendations for the implementation of distress screening programs in cancer centers: report from the American Psychosocial Oncology Society (APOS), Association of Oncology Social Work (AOSW), and Oncology Nursing Society (ONS) joint task force. AB - In 2015, the American College of Surgeons (ACoS) Commission on Cancer will require cancer centers to implement screening programs for psychosocial distress as a new criterion for accreditation. A joint task force from the American Psychosocial Oncology Society, the Association of Oncology Social Work, and the Oncology Nursing Society developed consensus-based recommendations to guide the implementation of this requirement. In this review, the authors provide recommendations regarding each of the 6 components necessary to meet the ACoS standard: 1) inclusion of psychosocial representation on the cancer committee, 2) timing of screening, 3) method/mode of screening, 4) tools for screening, 5) assessment and referral, and 6) documentation. PMID- 24798108 TI - Utilization and preference of nutrition information sources in Australia. AB - BACKGROUND: The prevalence of chronic disease in Australia is rising, and poor nutrition behaviour is a modifiable risk factor for many chronic diseases. The utilization of appropriate nutrition information has been recommended to promote optimal nutrition behaviour. OBJECTIVE: To investigate individuals' utilization and preference of nutrition information sources as well as perceptions of trustworthiness, credibility and effectiveness of sources. DESIGN: Cross sectional online survey. SETTING AND PARTICIPANTS: Ninety-four residents of the Gold Coast, Australia. MAIN OUTCOME MEASURES STUDIED: Respondents' demographic variables, previously utilized and preferred nutrition information sources, perceptions of trustworthiness, credibility and effectiveness of nutrition information sources. RESULTS: Dietitians, nutritionists and GPs were the three most preferred sources and were perceived to be most trustworthy, credible and effective. However, the most utilized nutrition information sources were the Internet (62.9%), friends (59.8%), family (58.8%) and magazines (57.7%). Over 30% of respondents reported time to attend appointments as a barrier to accessing their most preferred nutrition information sources. Between 32 and 60% of respondents reported neutral perceptions of the most frequently utilized nutrition information sources in relation to trustworthiness, credibility and effectiveness. CONCLUSION: Individuals frequently receive nutrition information from sources that are not their most preferred and sources that they do not perceive as trustworthy, credible or effective. Further research is warranted on the impact of these discrepancies on overall nutrition-related health literacy and behaviour. PMID- 24798109 TI - Mechanical properties of a cemented porous implant interface. AB - BACKGROUND: Revision arthroplasty often requires anchoring of prostheses to poor quality or deficient bone stock. Recently, newer porous materials have been introduced onto the market as additional, and perhaps better, treatment options for revision arthroplasty. To date, there is no information on how these porous metals interface with bone cement. This is of clinical importance, since these components may require cementing to other prosthesis components and occasionally to bone. METHODS: We created porous metal and bone cylinders of the same size and geometry and cemented them in a well-established standardized setting. These were then placed under tensile loading and torsional loading until failure was achieved. This permitted comparison of the porous metal/cement interface (group A) with the well-studied bone/cement interface (group B). RESULTS: The group A interface was statistically significantly stronger than the group B interface, despite having significantly reduced depth of cement penetration: it showed a larger maximum tensile force (effect size 2.7), superior maximum tensile strength (effect size 2.6), greater maximum torsional force (effect size 2.2), and higher rotational stiffness (effect size 1.5). INTERPRETATION: The newer porous implants showed good interface properties when cemented using medium-viscosity bone cement. The axial and rotational mechanical strength of a porous metal/cement interface appeared to be greater than the strength of the standard bone/cement interface. These results indicate that cementing of porous implants can provide great stability in situations where it is needed. PMID- 24798110 TI - Retrieved bone-anchored percutaneous amputation prosthesis showing maintained osseointegration after 11 years-a case report. PMID- 24798111 TI - Living in transition - experiences of health and well-being and the needs of adolescents with cerebral palsy. AB - BACKGROUND: Transition to adulthood for adolescents in general is a multifaceted process, and for adolescents with cerebral palsy (CP) it also involves transition from child- to adult-oriented support. CP entails a variety and combination of disabilities, which in association with external factors may make the transition to adult health services difficult. The aim of this study was to gain a deeper understanding of how adolescents with CP experience their own health, well-being and need of support during their transition to adulthood. METHODS: An inductive qualitative approach was used based on interviews with 12 adolescents with CP aged 17-18 years and living in Sweden. Manifest and latent content analysis was used for the analysis of data. RESULTS: The results are described in the main theme 'Living in transition and looking forward to being an adult, but not feeling ready yet and being in need of further support'. Five subthemes highlight the adolescents' experiences of belonging to a family, of the importance of friends and love, of managing daily activities, being surrounded by support and having hopes for the future. CONCLUSIONS: Interviews with adolescents with CP provide valuable information for the planning of transition programmes and for the support of adolescents with disabilities who are in the transition to adult living. According to the adolescents in this study, the support should be flexible and not be fixed to biological age. Personal, individualized information and support was desired by the adolescents in order to be able to manage their own transition. One option to facilitate transition is the stepping-stone of being close to parents or staff members during the first phase, after leaving the parental home. PMID- 24798112 TI - Correlation between macrosomia body indices and maternal fasting blood glucose. AB - To explore the significance of neonatal body indices in identifying pathological macrosomia, we implemented a retrospective study of 254 neonates, including: 100 macrosomia of diabetic pregnancies, 77 macrosomia of healthy pregnancies and 77 normal neonates of healthy pregnancies, using their birth weight, body length, head circumference and chest circumference, to calculate neonatal body indices, multiple regression analysis of the correlation between newborn body indices and maternal fasting blood glucose. The Quetelet Index and Kaup Index of diabetic macrosomia is higher than that of non-diabetic macrosomia; HC:CC (ratio between head circumference and chest circumference) is reversed (p < 0.05). The multiple regression equation of neonatal body indices to maternal fasting blood glucose is BG = 6.959 + 0.031 QI -4.482 * HC:CC. Quetelet index and HC:CC have linear relationship with maternal fasting blood glucose (p < 0.05). Compared with birth weight, Quetelet Index and HC:CC could better reflect the effect of maternal metabolism on the fetus and be of great significance in the prediction of fetal macrosomia. PMID- 24798113 TI - A comparative study on relieving post-episiotomy pain with diclofenac and indomethacin suppositories or placebo. AB - In this study, we compare the prophylactic efficacy of a diclofenac suppository and an indomethacin suppository on decreasing post-episiotomy pain. A total of 90 women with 2nd-degree episiotomy were assigned to receive a single dose of diclofenac suppository (30), indomethacin suppository (30) or placebo (30), according to randomised blocks. The pain was assessed at 1, 2, 4, 6 and 12 hours after receiving analgesia, using the two methods of pain score and visual analogue. This study showed that in the group given diclofenac or indomethacin, at all the assessed hours, the pain measured was considerably less than in the suppository-free group (p < 0.05). Comparing the diclofenac and indomethacin groups, there were only significant differences in the 4 and 12 hour measurements: the diclofenac was more effective than the indomethacin (4th hour), but due to a shorter half-life, the diclofenac group in the 12th hour had more pain (p < 0.05). Diclofenac suppository is recommended at 4-hour intervals for all patients, without internal disorders, to decrease episiotomy pain. PMID- 24798114 TI - Maternal and perinatal outcomes of eclampsia with and without HELLP syndrome in a teaching hospital in western Turkey. AB - In this study, we compared the perinatal and maternal outcomes of women with eclampsia with and without HELLP syndrome. A total of 219 pregnancies complicated by eclampsia with and without HELLP syndrome managed between January 2002 and December 2011, were reviewed. The incidence of eclampsia was 1.7/1,000 deliveries. Among 219 patients with eclampsia, 141 (64.4%) did not develop HELLP syndrome and 78 (35.6%) did develop HELLP syndrome. Maternal age and the rates of nulliparity were similar in both groups. Interval time from eclamptic seizure to delivery was significantly longer in the without-HELLP syndrome group (0.92 +/- 0.29 weeks vs 0.16 +/- 0.12 weeks, p = 0.028). Furthermore, overall perinatal mortality (particularly after gestational week 32) was significantly higher in the with-HELLP syndrome group (20.5% vs 9.9%, p = 0.029). In conclusion, patients with HELLP syndrome had significantly higher perinatal mortality than those with eclampsia without HELLP syndrome and no regular prenatal care. PMID- 24798115 TI - The pioneer physician Euryphon and his method for determination of the female infertility in ancient Greece. PMID- 24798116 TI - The effect of electrical treatment on cyclic fatigue of NiTi instruments. AB - Dentists desire to use NiTi rotary instruments, which do not break inside the root canals of teeth, since the pieces from broken files are difficult to remove. The NiTi rotary instrument breakage is because of cyclic and torsional fatigue. Here the low-voltage (12 V) and high voltage (24 V) electrical treatments were used to enhance the cyclic fatigue of NiTi rotary instruments and increase their durability. In excremental groups, following electrical treatment samples of the NiTi instruments were rotated inside artificial root canals until they broke. Our results showed that electrical treatment with 12-V DC was effective in restoring NiTi instrument's resistance to cyclic fatigue. The scanning electron microscopy images and fractograph of samples exposed to 12-V electrical treatment showed a more regular texture over the surface with less dimpling on fractured site. These patterns can improve the super elasticity of tested devices during rotational movement, and delay the NiTi instruments separation in root canal preparations. PMID- 24798117 TI - Summarizing the fifteen scales of the EORTC QLQ-C30 questionnaire by five aggregate scales with two underlying dimensions: a literature review and an empirical study. AB - The intercorrelations among the 15 scales of the 30-item Core version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire suggest that one may combine (1) the physical functioning and role functioning scales, (2) the emotional functioning and cognitive functioning scales, and (3) the nine symptom scales. Together with the global health/quality of life scale and the social functioning scale, five measures remain. Principal component analysis of those five measures, using data from Japanese and Dutch breast and lung cancer patients, yielded two dimensions: (1) generalized health related quality of life and (2) health-independent psychological well-being. The correlations of these dimensions with the Brief Illness Perception Questionnaire and Karnofsky performance substantiated this interpretation. PMID- 24798118 TI - Depression of focal adhesion kinase induces apoptosis in rat osteosarcoma OSR-6 cells in a caspase-dependent pathway. AB - Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase protein, acts as an early modulator of integrin signaling cascade, regulating basic cellular functions. In transformed cells, unopposed FAK signaling has been considered to promote tumor growth, progression, and metastasis. The aim of this study was to assess the role of FAK in rat osteosarcoma OSR-6 cells. OSR-6 cells were transfected with PGPU6/GFP/shNC (shNC), and PGPU6/GFP/FAK-2434 (shRNA-2434), separately. Expression of FAK was detected by Real-time PCR and Western blots. MTT assay was used to examine changes in cell proliferation. Cell apoptosis was analyzed by flow cytometry. The expression of caspase-3,-7,-9 was measured by Western blots. The expression of FAK in OSR-6 cells significantly decreased in shRNA-2434 group in contrast to the control group (P < 0.01). Cell proliferation was inhibited by shRNA-2434 and shRNA-2434+ cisplatin, and the effects were clearly enhanced when cells were treated with anticancer agents. The level of cell apoptosis in shRNA-2434 and shRNA-2434+ cisplatin group was higher than that in the control group (P < 0.01). The current data support evidence that down regulation of FAK could induce rat osteosarcoma cells (OSR-6) apoptosis through the caspase-dependent cell death pathway. Inhibition of the kinases may be important for therapies designed to enhance the apoptosis in osteosarcoma. PMID- 24798119 TI - Treg/Th17 ratio acts as a novel indicator for acute coronary syndrome. AB - The imbalance of CD4(+)CD25(+) regulatory T (Treg) cells and Th17 cells has shown to be involved in pathogenesis of atherosclerosis and acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)]. The purpose of this study is to explore the significance of Treg/Th17 ratio in early diagnosis for ACS. We detected expression of Treg and Th17 in patients with AMI, UA, stable angina, and subjects with normal coronary arteries at the time of admission. Our results showed that ACS patients have a significant increase of Th17 number, but a marked decline of Treg/Th17 ratio, Treg number, and Treg function. Significant positive correlations in Th17 frequency and negative correlation in Treg frequency, Treg/Th17 ratio were found to levels of oxidized low-density lipoprotein (Ox-LDL), high sensitive C-reactive protein (hsCRP), Lipoprotein (a) [Lp(a)], and Creatine kinase-MB(mass) (CK-MBmass) in serum. Receiver-operating characteristic curves shown that the predictive specificity and sensitivity of Treg/Th17 ratio for ACS and AMI was the highest among all the five markers: Ox-LDL, hsCRP, Lp(a), CK-MBmass, and Treg/Th17 ratio. In conclusion, Treg/Th17 ratio appeared to be a novel indicator for early diagnosis of ACS. PMID- 24798120 TI - Dissociation of explicit and implicit measures of the behavioral inhibition and activation system in borderline personality disorder. AB - Patients with borderline personality disorder (BPD) suffer from various impairments in emotional functioning such as affective instability, inappropriate anger and unstable relationships. These deficits may influence two fundamental motivational systems, the behavioral inhibition system (BIS) and behavioral activation system (BAS). To investigate behavioral intentions and possible impairments in BPD we applied an implicit joystick task to measure implicit behavioral tendencies in response to facial expressions (happiness, sadness, anger, fear and neutral) in 25 patients with BPD and matched 25 healthy controls (HC). Additionally, we evaluated explicit approach and avoidance reactions to these social stimuli, emotion recognition abilities and subjective behavioral ratings. Our data analysis suggests that, although BPD patients accurately identified facial emotional expressions and reacted to them similarly as HC in the joystick task, they had significantly stronger avoidance tendencies in the rating task, especially for happiness and fear. On top of this they exhibited increased BIS sensitivity and decreased BAS sensitivity in the self-report measures. Possible influences are maladaptive cognitive schemas, high negative affect, insecure attachment style and a negative evaluation bias. The observed dysfunctional avoidance ratings may influence the appraisal of socially relevant stimuli and therefore adds further knowledge on social interaction problems in BPD. PMID- 24798121 TI - Nickel-based anode with water storage capability to mitigate carbon deposition for direct ethanol solid oxide fuel cells. AB - The potential to use ethanol as a fuel places solid oxide fuel cells (SOFCs) as a sustainable technology for clean energy delivery because of the renewable features of ethanol versus hydrogen. In this work, we developed a new class of anode catalyst exemplified by Ni+BaZr0.4Ce0.4Y0.2O3 (Ni+BZCY) with a water storage capability to overcome the persistent problem of carbon deposition. Ni+BZCY performed very well in catalytic efficiency, water storage capability and coking resistance tests. A stable and high power output was well maintained with a peak power density of 750 mW cm(-2) at 750 degrees C. The SOFC with the new robust anode performed for seven days without any sign of performance decay, whereas SOFCs with conventional anodes failed in less than 2 h because of significant carbon deposition. Our findings indicate the potential applications of these water storage cermets as catalysts in hydrocarbon reforming and as anodes for SOFCs that operate directly on hydrocarbons. PMID- 24798122 TI - Extramedullary spinal cysts in dogs. AB - OBJECTIVE: To (1) synthesize the terminology used to classify extramedullary spinal cysts in dogs to clarify some of the commonly reported misconceptions, and (2) propose a classification scheme to limit confusion with terminology. STUDY DESIGN: Literature review. METHODS: An online bibliographic search was performed in January 2013 for articles relating to extramedullary spinal cysts in dogs using PubMed (http://www.pubmed.gov/) and Google Scholar (http://scholar.google.com/) databases. Only peer-reviewed clinical literature describing cystic lesions pertaining to the spinal cord and associated structures was included. RESULTS: From 1962 to 2013, 42 articles were identified; 25 (95 dogs) reported meningeal cysts, 10 (24 dogs) described 60 extradural cysts, 3 reports (18 dogs) described discal cysts or acute compressive hydrated nucleus pulposus extrusions (HNPE). Spinal cysts were categorized by location based on cross-sectional imaging as meningeal or extradural non-meningeal. Sub classification was then performed based on surgical findings and pathology. Meningeal cysts included arachnoid diverticulae and Tarlov (perineural) cysts. Extradural non-meningeal cysts included intraspinal cysts of the vertebral joints, ligaments and discs. Discal cysts also fit this category and have been reported extensively in humans but appear rare in dogs. CONCLUSIONS: Extramedullary spinal cysts should be first classified according to location with a sub-classification according to pathologic and surgical findings. Previous canine cases of discal cysts appear to represent a different disease entity and the term acute compressive HNPE is therefore preferred. PMID- 24798123 TI - Feasibility of an automated quantitative computed tomography angiography-derived risk score for risk stratification of patients with suspected coronary artery disease. AB - Coronary computed tomography angiography (CTA) has important prognostic value. Additionally, quantitative CTA (QCT) provides a more detailed accurate assessment of coronary artery disease (CAD) on CTA. Potentially, a risk score incorporating all quantitative stenosis parameters allows accurate risk stratification. Therefore, the purpose of this study was to determine if an automatic quantitative assessment of CAD using QCT combined into a CTA risk score allows risk stratification of patients. In 300 patients, QCT was performed to automatically detect and quantify all lesions in the coronary tree. Using QCT, a novel CTA risk score was calculated based on plaque extent, severity, composition, and location on a segment basis. During follow-up, the composite end point of all-cause mortality, revascularization, and nonfatal infarction was recorded. In total, 10% of patients experienced an event during a median follow up of 2.14 years. The CTA risk score was significantly higher in patients with an event (12.5 [interquartile range 8.6 to 16.4] vs 1.7 [interquartile range 0 to 8.4], p <0.001). In 127 patients with obstructive CAD (>=50% stenosis), 27 events were recorded, all in patients with a high CTA risk score. In conclusion, the present study demonstrated that a fully automatic QCT analysis of CAD is feasible and can be applied for risk stratification of patients with suspected CAD. Furthermore, a novel CTA risk score incorporating location, severity, and composition of coronary lesion was developed. This score may improve risk stratification but needs to be confirmed in larger studies. PMID- 24798125 TI - Large-Scale Purification, Characterization, and Spore Outgrowth Inhibitory Effect of Thurincin H, a Bacteriocin Produced by Bacillus thuringiensis SF361. AB - Large-scale purification of the highly hydrophobic bacteriocin thurincin H was accomplished via a novel and simple two-step method: ammonia sulfate precipitation and C18 solid-phase extraction. The inhibition spectrum and stability of thurincin H as well as its antagonistic activity against Bacillus cereus F4552 spores were further characterized. In the purification method, secreted proteins contained in the supernatant of a 40 h incubated culture of B. thuringiensis SF361 were precipitated by 68 % ammonia sulfate and purified by reverse-phase chromatography, with a yield of 18.53 mg/l of pure thurincin H. Silver-stained SDS-PAGE, high-performance liquid chromatography, and liquid chromatography-mass spectrometry confirmed the high purity of the prepared sample. Thurincin H exhibited a broad antimicrobial activity against 22 tested bacterial strains among six different genera including Bacillus, Carnobacterium, Geobacillus, Enterococcus, Listeria, and Staphylococcus. There was no detectable activity against any of the selected yeast or fungi. The bacteriocin activity was stable for 30 min at 50 degrees C and decreased to undetectable levels within 10 min at temperatures above 80 degrees C. Thurincin H is also stable from pH 2-7 for at least 24 h at room temperature. Thurincin H is germicidal against B. cereus spores in brain heart infusion broth, but not in Tris-NaCl buffer. The efficient purification method enables the large-scale production of pure thurincin H. The broad inhibitory spectrum of this bacteriocin may be of interest as a potential natural biopreservative in the food industry, particularly in post processed and ready-to-eat food. PMID- 24798124 TI - Photosynthetic acclimation to drought stress in Agave salmiana Otto ex Salm-Dyck seedlings is largely dependent on thermal dissipation and enhanced electron flux to photosystem I. AB - Agave salmiana Otto ex Salm-Dyck, a crassulacean acid metabolism plant that is adapted to water-limited environments, has great potential for bioenergy production. However, drought stress decreases the requirement for light energy, and if the amount of incident light exceeds energy consumption, the photosynthetic apparatus can be injured, thereby limiting plant growth. The objective of this study was to evaluate the effects of drought and re-watering on the photosynthetic efficiency of A. salmiana seedlings. The leaf relative water content and leaf water potential decreased to 39.6 % and -1.1 MPa, respectively, over 115 days of water withholding and recovered after re-watering. Drought caused a direct effect on photosystem II (PSII) photochemistry in light acclimated leaves, as indicated by a decrease in the photosynthetic electron transport rate. Additionally, down-regulation of photochemical activity occurred mainly through the inactivation of PSII reaction centres and an increased thermal dissipation capacity of the leaves. Prompt fluorescence kinetics also showed a larger pool of terminal electron acceptors in photosystem I (PSI) as well as an increase in some JIP-test parameters compared to controls, reflecting an enhanced efficiency and specific fluxes for electron transport from the plastoquinone pool to the PSI terminal acceptors. All the above parameters showed similar levels after re-watering. These results suggest that the thermal dissipation of excess energy and the increased energy conservation from photons absorbed by PSII to the reduction of PSI end acceptors may be an important acclimation mechanism to protect the photosynthetic apparatus from over-excitation in Agave plants. PMID- 24798126 TI - Deriving coronary artery calcium scores from CT coronary angiography: a proposed algorithm for evaluating stable chest pain. AB - We validate a method of calcium scoring on CT coronary angiography (CTCA) and propose an algorithm for the assessment of patients with stable chest pain. 503 consecutive patients undergoing coronary artery calcium score (CACS) and CTCA were included. A 0.1 cm2 region of interest was used to determine the mean contrast density on CTCA images either in the left main stem (LM) or right coronary artery. Axial 3 mm CTCA images were scored for calcium using conventional software with a modified threshold: mean LM contrast density (HU) + 2SD. A conversion factor (CF) for predicting CACS from raw CTCA scores (rCTCAS) was determined using a multivariable regression model adjusted for model over optimism (1,000 bootstrap samples). Accuracy of this method was determined using weighted kappa for NICE recommended CACS groupings (0, 1-400, >400) and Bland Altman analysis for absolute score. With the CF applied: CACS = (1.183 * rCTCAS) + (0.002 * rCTCAS * threshold), there was excellent agreement between methods for absolute score (mean difference 5.44 [95% limits of agreement -207.0 to 217.8]). The method discriminated between high (>400) and low risk (<400) calcium scores with a sensitivity and specificity of 85 and 99%, and a PPV and NPV of 92 and 98%, respectively, and led to a significant reduction in radiation exposure (6.9 [5.1-10.2] vs. 5.2 [6.3-8.7] mSv; p < 0.0001). Our proposed method allows a comprehensive assessment of coronary artery pathology through the use of an individualised, semi-automated approach. If incorporated into stable chest pain guidelines the need for further functional testing or invasive angiography could be determined from CTCA alone, supporting a change to the current guidelines. PMID- 24798127 TI - The 90-day prognostic value of copeptin in acute intracerebral hemorrhage. AB - The aim of the study was to assess the 90-day prognostic value of copeptin in a group of Chinese patients with acute intracerebral hemorrhage (ICH). In this study, all consecutive patients with first-ever ICH from 2010 to 2012 were recruited to participate in the study. On admission, plasma copeptin levels were measured by enzyme-linked immunosorbent assay. The Glasgow Coma Scale (GCS) and Hemphill ICH scores were assessed on admission blinded to plasma copeptin levels. For the assessment of functional outcome at 90 days, Modified Rankin Scale was used. During the study period, 271 patients were diagnosed as ICH and were included in the analysis. The median GCS score on admission was 11 points. Patients with an unfavorable outcomes and non-survivors had significantly increased plasma copeptin levels on admission (P < 0.001 for both). Copeptin was an independent prognostic marker of functional outcome and death [odds ratio 3.45 (95 % confidence intervals: 1.85-6.99) and 3.66 (2.42-8.28), respectively, P < 0.001 for both, adjusted for age, the hematoma volume and other predictors] in patients with ICH. In receiver operating characteristic curve analysis, copeptin could improve the Hemphill score in predicting 90-day functional outcome [area under the curve (AUC) of the combined model, 0.83; 95 % CI 0.74-0.90; P < 0.001] and mortality (AUC of the combined model, 0.88; 95 % CI 0.82-0.93; P < 0.001). In conclusion, our study suggests that copeptin levels are a useful tool to predict unfavorable functional outcome and mortality 90 days after ICH and have a potential to assist clinicians. PMID- 24798128 TI - Management of stomal varices with transvenous obliteration utilizing sodium tetradecyl sulfate foam sclerosis. AB - The management of parastomal varices is not established. Transjugular intrahepatic portosystemic shunt (TIPS) creation is the most commonly described treatment; however, the rebleed rate after TIPS is 21-37%. The purpose of the study is to determine the effectiveness of transvenous obliteration using sodium tetradecyl sulfate (STS) and to describe a new simplified technique in obliterating these varices. Four patients are presented who underwent transvenous obliteration using STS. One was obliterated using balloon occlusion from the systemic veins, the second was obliterated without balloon from a transhepatic antegrade approach, and the last two patients were obliterated using the direct antegrade technique. This simplified technique requires only a micropuncture kit (not requiring balloons or coils) and ultrasound transducer compression of the systemic draining veins, relying on high portal pressure to keep the sclerosant confined to the varices. The sclerosant is essentially trapped between the portal pressure and the ultrasound-transducer compression (10-15 min). Technical success was achieved in all four patients without procedural or postprocedural complications and no rebleeding for a mean follow-up of 17 (range 2-33) months. Transvenous obliteration of parastomal varices utilizing STS as a sclerosant is safe and effective. The newly described technique is simple, feasible, and requires minimal equipment (no balloons or coils or catheters). PMID- 24798129 TI - Management of gastric varices in the pediatric population with balloon-occluded retrograde transvenous obliteration (BRTO) utilizing sodium tetradecyl sulfate foam sclerosis with or without partial splenic artery embolization. AB - It is unknown whether spontaneous gastrorenal shunts actually develop in the pediatric population. The minimum age documented in studies from Asia is 32 (range 32-44) years. This study describes three pediatric patients undergoing balloon-occluded retrograde transvenous obliteration (BRTO) for bleeding gastric varices with two of the three patients undergoing combined partial splenic embolization. The first BRTO is a selective-BRTO via a surgical splenorenal shunt (15 years old) and the other two patients underwent conventional-BRTO via a spontaneous gastrorenal shunt (8 and 14 years old). The recurrent significant bleeding that they exhibited before the combined endovascular therapy did not recur for an average of 7.1 (range 1.4-14) months. In the second patient, quantitative digitally subtracted angiography was utilized to evaluate the inline portal venous flow before and after BRTO. PMID- 24798130 TI - Bailout alternative use of re-entry device to achieve a chronically occluded superficial artery recanalization without detectable origin. PMID- 24798131 TI - Three-year results after directional atherectomy of calcified stenotic lesions of the superficial femoral artery. AB - OBJECTIVE: To investigate the 3-year outcome of patients with peripheral arterial disease (PAD) and heavily calcified stenotic lesions of the superficial femoral artery after directional atherectomy. MATERIALS AND METHODS: Fifty-three patients (mean age 67 +/- 10 years; 18 females, 35 males, TASC B and C, mean lesion length 7.9 +/- 3.5 cm) with PAD (Rutherford 2-6) were enrolled into this prospective monocentric study. In total, 59 calcified lesions of the superficial femoral artery were treated with the Silverhawk atherectomy device (Covidien, Plymouth, MN, USA). Patients were followed-up for 36 months with a 6-month interval to perform clinical re-evaluation, including measurement of maximum walking distance and ankle-brachial index (ABI) as well as duplex-sonography. RESULTS: The primary success rate of the procedure was 92 %. In five cases (8 %), additional balloon PTA and/or stent-PTA was necessary. Procedure-related embolization occurred in seven cases (12 %), which were all successfully treated by aspiration. The primary patency rate after 3 years was 55 %. Median Rutherford score decreased significantly from 5 to 0 after 36 months (p < 0.001). At the same time, the ABI increased from 0.65 to 1.12 (not significant). The limb-salvage rate after 3 years was 87 %. CONCLUSION: In this subgroup of patients with POD and calcified stenotic lesions, atherectomy was successfully applied to decrease the plaque burden. Results after 3 years showed a significant decrease of Rutherford score with persistent improvement of ABI and reasonable patency rate. PMID- 24798132 TI - Unusual radiological behaviour after cryoablation of renal cell carcinoma. AB - Cryoablation has evolved into an effective treatment option in patients with renal tumours. The procedure is minimally invasive, and patients are often spared the morbidity and hospital stay that is often associated with open or partial nephrectomy. We present an unusual case of a 62-year-old male patient who underwent cryoablation of a renal cell carcinoma. He subsequently developed apparent exuberant local disease progression, which spontaneously regressed on follow-up CT imaging. PMID- 24798133 TI - Radiation protection methods for the interventionalist's hands: use of an extension tube. AB - PURPOSE: Cumulative radiation exposure to the hands during certain interventional procedures may be high. It is important to decrease the amount of radiation to the operator due to the possibility of deterministic effects. We performed a pilot study to demonstrate a significant decrease in operator dose when using extension tubing (ET) in combination with shielding and collimation during a simulated percutaneous transhepatic cholangiogram (PTC) procedure. METHODS: A whole body, anthropomorphic phantom was used to simulate the patient. A Unfors-Xi Survey detector (to measure scatter) supported by a retort stand and trolley was placed in various positions to simulate the position of hands and eyes/thyroid of an interventionalist. Radiation dose was measured simulating left and right-sided PTC punctures with and without a lead shield, and with and without ET. RESULTS: Regarding the radiation dose to the hands; the use of an ET reduces dose by 54 % in right-sided PTC punctures without a shield and by 91 % if used in combination with a shield. For left-sided PTC punctures, ET reduces hand dose by 75 %. The use of collimation decreases hand dose by approximately 60 %. The use of shielding reduces dose to the eyes/thyroid by 98 %. CONCLUSIONS: The dose to the hands can be significantly reduced with the appropriate use of a shield, ET, and tight collimation. The use of a shield is paramount to reduce dose to the eyes/thyroid. It is important for interventionalists to adhere to radiation protective practice considering the potential deterministic effects during a lifelong career. PMID- 24798134 TI - Successful control of liver metastases from pancreatic solid-pseudopapillary neoplasm (SPN) using hepatic arterial embolization. AB - No systemic agents that are known to be effective for the treatment of solid pseudopapillary neoplasm (SPN) are available. We report the prolonged and sustained control of metastatic pancreatic SPN to the liver using hepatic arterial embolization (HAE), where a total of 13 HAE sessions were performed over a 6-year period. PMID- 24798135 TI - Local control of perivascular malignant liver lesions using percutaneous irreversible electroporation: initial experiences. AB - PURPOSE: This study was designed to assess efficacy and safety in the treatment of perivascular malignant liver lesions using percutaneous, computed tomography (CT)-guided irreversible electroporation (IRE). METHODS: Fourteen patients (mean age 58 +/- 11 years) with 18 malignant liver lesions were consecutively enrolled in this study. IRE was performed in patients not eligible for surgery and lesions abutting large vessels or bile ducts. Follow-up exams were performed using multislice-CT (MS-CT) or MRI. RESULTS: Medium lesion diameter was 20 +/- 5 mm. Ten of 14 (71 %) were successfully treated with no local recurrence to date (mean follow-up 388 +/- 160 days). One case left initial tumor control unclear and additional RFA was performed 4 weeks after IRE. Complications occurred in 4 of 14 (29 %) cases. In one case, intervention was terminated and abdominal bleeding required laparotomy. In two cases, a postinterventional hematothorax required intervention. In another case, abdominal bleeding could be managed conservatively. No complications related to the bile ducts occurred. CONCLUSIONS: Percutaneous IRE seems to be effective in perivascular lesions but is associated with a higher complication rate compared with thermoablative techniques. PMID- 24798136 TI - A newly designed stent for management of malignant distal duodenal stenosis. AB - PURPOSE: To evaluate the clinical effectiveness of a newly designed stent for the treatment of malignant distal duodenal stenosis. METHODS: From March 2011 to May 2013, six patients with malignant duodenal stenosis underwent fluoroscopically guided placement of the new duodenal stent consisting of braided, nested stent wires, and a delivery system with a metallic mesh inner layer. Primary diseases were pancreatic cancer in three patients, gastric cancer in two patients, and endometrial stromal sarcoma in one patient. Duodenal obstructions were located in the horizontal part in two patients, the ascending part in two patients, and the duodenojejunal flexure in two patients. Technical success, defined as the successful stent deployment, clinical symptoms before and after the procedure, and complications were evaluated. RESULTS: Technical success was achieved in all patients. No major complications were observed. Before treatment, two patients could not take any food and the gastric outlet obstruction scoring system (GOOSS) score was 0; the other four patients could take only liquids orally (GOOSS score = 1). After treatment, five patients could take soft food (GOOSS score = 2) and one patient could take a full diet (GOOSS score = 3). The mean duration of primary stent patency was 115.7 days. CONCLUSIONS: The newly designed stent is associated with a high degree of technical success and good clinical outcome and may be clinically effective in the management of malignant distal duodenal obstruction. PMID- 24798137 TI - Radiation exposure of abdominal cone beam computed tomography. AB - PURPOSE: To evaluate patients radiation exposure of abdominal C-arm cone beam computed tomography (CBCT). METHODS: This prospective study was approved by the institutional review board; written, informed consent was waived. Radiation exposure of abdominal CBCT was evaluated in 40 patients who underwent CBCT during endovascular interventions. Dose area product (DAP) of CBCT was documented and effective dose (ED) was estimated based on organ doses using dedicated Monte Carlo simulation software with consideration of X-ray field location and patients' individual body weight and height. Weight-dependent ED per DAP conversion factors were calculated. CBCT radiation dose was compared to radiation dose of procedural fluoroscopy. CBCT dose-related risk for cancer was assessed. RESULTS: Mean ED of abdominal CBCT was 4.3 mSv (95 % confidence interval [CI] 3.9; 4.8 mSv, range 1.1-7.4 mSv). ED was significantly higher in the upper than in the lower abdomen (p = 0.003) and increased with patients' weight (r = 0.55, slope = 0.045 mSv/kg, p < 0.001). Radiation exposure of CBCT corresponded to the radiation exposure of on average 7.2 fluoroscopy minutes (95 % CI 5.5; 8.8 min) in the same region of interest. Lifetime risk of exposure related cancer death was 0.033 % or less depending on age and weight. CONCLUSIONS: Mean ED of abdominal CBCT was 4.3 mSv depending on X-ray field location and body weight. PMID- 24798138 TI - Vertical heterostructures of layered metal chalcogenides by van der Waals epitaxy. AB - We report a facile chemical vapor deposition (CVD) growth of vertical heterostructures of layered metal dichalcogenides (MX2) enabled by van der Waals epitaxy. Few layers of MoS2, WS2, and WSe2 were grown uniformly onto microplates of SnS2 under mild CVD reaction conditions (<500 degrees C) and the heteroepitaxy between them was confirmed using cross-sectional transmission electron microscopy (TEM) and unequivocally characterized by resolving the large area Moire patterns that appeared on the basal planes of microplates in conventional TEM (nonsectioned). Additional photoluminescence peaks were observed in heterostructures of MoS2-SnS2, which can be understood with electronic structure calculations to likely result from electronic coupling and charge separation between MoS2 and SnS2 layers. This work opens up the exploration of large-area heterostructures of diverse MX2 nanomaterials as the material platform for electronic structure engineering of atomically thin two-dimensional (2D) semiconducting heterostructures and device applications. PMID- 24798139 TI - L-Cysteine inhibits root elongation through auxin/PLETHORA and SCR/SHR pathway in Arabidopsis thaliana. AB - L-Cysteine plays a prominent role in sulfur metabolism of plants. However, its role in root development is largely unknown. Here, we report that L-cysteine reduces primary root growth in a dosage-dependent manner. Elevating cellular L cysteine level by exposing Arabidopsis thaliana seedlings to high L-cysteine, buthionine sulphoximine, or O-acetylserine leads to altered auxin maximum in root tips, the expression of quiescent center cell marker as well as the decrease of the auxin carriers PIN1, PIN2, PIN3, and PIN7 of primary roots. We also show that high L-cysteine significantly reduces the protein level of two sets of stem cell specific transcription factors PLETHORA1/2 and SCR/SHR. However, L-cysteine does not downregulate the transcript level of PINs, PLTs, or SCR/SHR, suggesting that an uncharacterized post-transcriptional mechanism may regulate the accumulation of PIN, PLT, and SCR/SHR proteins and auxin transport in the root tips. These results suggest that endogenous L-cysteine level acts to maintain root stem cell niche by regulating basal- and auxin-induced expression of PLT1/2 and SCR/SHR. L Cysteine may serve as a link between sulfate assimilation and auxin in regulating root growth. PMID- 24798140 TI - A diffusion modeling approach to understanding contextual cueing effects in children with ADHD. AB - BACKGROUND: Strong theoretical models suggest implicit learning deficits may exist among children with Attention Deficit Hyperactivity Disorder (ADHD). METHOD: We examine implicit contextual cueing (CC) effects among children with ADHD (n = 72) and non-ADHD Controls (n = 36). RESULTS: Using Ratcliff's drift diffusion model, we found that among Controls, the CC effect is due to improvements in attentional guidance and to reductions in response threshold. Children with ADHD did not show a CC effect; although they were able to use implicitly acquired information to deploy attentional focus, they had more difficulty adjusting their response thresholds. CONCLUSIONS: Improvements in attentional guidance and reductions in response threshold together underlie the CC effect. Results are consistent with neurocognitive models of ADHD that posit subcortical dysfunction but intact spatial attention, and encourage the use of alternative data analytic methods when dealing with reaction time data. PMID- 24798141 TI - A simple risk index and thrombolytic treatment response in acute ischemic stroke. AB - IMPORTANCE: The Stroke Prognostication using Age and the NIH Stroke Scale index, created by combining age in years plus a National Institutes of Health (NIH) Stroke Scale score of 100 or higher (and hereafter referred to as the SPAN-100 index), is a simple risk score for estimating clinical outcomes for patients with acute ischemic stroke (AIS). The association between this index and response to intravenous thrombolysis for AIS has not been properly evaluated. OBJECTIVE: To assess the relationship between SPAN-100 index status and outcome following treatment with intravenous thrombolysis for AIS. DESIGN, SETTING, AND PARTICIPANTS: Using the Virtual International Stroke Trials Archive (VISTA) database, an international repository of clinical trials data, we assessed the SPAN-100 index among 7093 patients with AIS who participated in 4 clinical trials from 2000 to 2006. The SPAN-100 index is considered positive if the sum of the age and the NIH Stroke Scale (a 15-item neurological examination scale with scores ranging from 0 to 42, with higher scores indicating more severe strokes) score is greater than or equal to 100. Multivariable logistic regression analyses were used to determine the independent association between SPAN-100 index status and 90-day outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of severe disability or death measured 90 days after stroke, and the secondary outcomes were death alone and a composite of no disability/modest disability. RESULTS: Of 7093 patients, 743 (10.5%) were SPAN-100 positive, and 2731 (38.5%) received intravenous thrombolysis. Compared with SPAN-100-negative patients, SPAN-100-positive patients were more likely to experience a catastrophic outcome (adjusted odds ratio [AOR], 9.03 [95% CI, 6.68-12.21]) or death alone (AOR, 5.03 [95% CI, 4.06-6.23]) and less likely to experience a favorable outcome (AOR, 0.08 [95% CI, 0.06-0.13]). However, there was an interaction between SPAN-100 index status and thrombolysis treatment (P < .001) revealing a reduction in the likelihood of severe disability/death with thrombolytic treatment for SPAN-100-positive (AOR, 0.46 [95% CI, 0.29-0.71]) but not SPAN-100-negative patients (AOR, 0.96 [95% CI, 0.85-1.07]). Similar interactions between SPAN-100 index status and thrombolysis treatment were observed for the 2 secondary outcomes. CONCLUSION AND RELEVANCE: Compared with the SPAN-100-negative patients with AIS, the SPAN-100-positive patients with AIS seem to have poorer 3-month outcomes but may derive greater benefit when treated with intravenous thrombolysis. The SPAN-100-positive patients are often excluded from AIS clinical trials but should probably not be denied thrombolysis treatment on the basis of such a profile alone. PMID- 24798142 TI - Exploring the catalytic mechanism of alkanesulfonate monooxygenase using molecular dynamics. AB - The complex mechanistic properties of alkanesulfonate monooxygenase (SsuD) provide a particular challenge for identifying catalytically relevant amino acids. In response, a joint computational and experimental study was conducted to further elucidate the SsuD mechanism. Extensive unbiased molecular dynamics (MD) simulations were performed for six SsuD systems: (1) substrate-free, (2) bound with FMNH2, (3) bound with a C4a-peroxyflavin intermediate (FMNOO(-)), (4) bound with octanesulfonate (OCS), (5) co-bound with FMNH2 and OCS, and (6) co-bound with FMNOO(-) and OCS. A previous theoretical study suggested that salt bridges between Arg297 and Glu20 or Asp111 initiated conformational changes critical for catalysis. However, our MD simulations and steady-state kinetic experiments did not corroborate this result. Similar kcat/Km values for both the E20A and D111A SsuD variants to wild-type SsuD suggest that the salt bridges are not critical to the desulfonation mechanism. Instead, the predicted role of Arg297 is to favorably interact with the phosphate group of the reduced flavin. Concomitantly, Arg226 functioned as a "protection" group shielding FMNOO(-) from bulk solvent and was more pronounced when both FMNOO(-) and OCS were bound. The stabilization of FMNOO(-) through electrostatic interactions with Arg226 would properly position the C4a peroxy group for the proposed nucleophilic attack on the sulfur of octanesulfonate. PMID- 24798143 TI - Re: Choi et al. Indoor air 24:158, Indoor air 24:221. PMID- 24798144 TI - Constituents of the roots of Clausena lansium and their potential anti inflammatory activity. AB - Eight new carbazole alkaloids, claulamines C (1), D (2), and E (5) and clausenalines B-F (3, 4, 6-8), four new coumarins, clausemarins A-D (9-12), and 43 known compounds were isolated from the roots of Clausena lansium. The structures of the new compounds were established on the basis of 2D-NMR spectroscopic analysis, and their absolute configurations were established from their ECD spectra. The configuration of wampetin was revised as E using a NOESY experiment. Most of the isolated compounds were evaluated for their potential anti-inflammatory activity. The results showed that compounds 9, 13-18, and 20-22 exhibited strong inhibition of superoxide anion generation with IC50 values ranging from 1.9 to 8.4 MUM, while compounds 18, 19, and 21 inhibited elastase release with IC50 values in the range from 2.0 to 6.9 MUM. PMID- 24798145 TI - Proton transfer induced SOMO-to-HOMO level switching in one-electron oxidized A-T and G-C base pairs: a density functional theory study. AB - In the present study, we show that for one-electron oxidized A-T or G-C base pairs the singly occupied molecular orbital (SOMO) is located on A or G and is lower in energy than the doubly occupied highest-occupied molecular orbital (HOMO) localized to the pyrimidines, T or C. This directs second ionizations to the pyrimidine bases resulting in triplet state diradical dications, (A(*+) T(*+)) and (G(*+)-C(*+)). On interbase proton transfer, the SOMO and HOMO levels switch and the second oxidation is redirected to G and A. For G-C, the doubly oxidized singlet G(-H)(+)-C(H(+)) is more stable than its triplet (G(*+)-C(*+)); however, for A-T, the triplet (A(*+)-T(*+)) lies lowest in energy. The study demonstrates that double ionization of the A-T base pair results in a triplet dication diradical, which is more stable than the proton-transferred triplet or singlet species; whereas, double ionization of the G-C base pair, the proton transferred doubly oxidized singlet, G(-H)(+)-C(H(+)), is more stable and has both oxidations on guanine. In DNA, with both A-T and G-C, multiple oxidations would transfer to the guanine base alone. PMID- 24798146 TI - Soluble Lectin-Like Oxidized LDL Receptor 1 as a Possible Mediator of Endothelial Dysfunction in Patients With Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) defines a well-known cluster of metabolic disturbances associated with an increased risk of cardiovascular disease and diabetes. The aim of this study was to examine the distribution of soluble lectin like oxidized low-density lipoprotein (LDL) receptor-1 (sLOX-1) levels in patients with MetS, possible association of sLOX-1 with oxidized LDL (oxLDL), endothelial nitric oxide synthase (eNOS), nitric oxide (NOx), endothelin-1 (ET 1), paraoxonase 1 (PON1), and arylesterase (ARE) activities, and these parameters compared with healthy controls. METHODS: A total of 55 patients (37 women, 18 men) with MetS and 29 healthy controls (19 women, 10 men) with a body mass index (BMI) less than 25 kg/m(2) were enrolled in the study. RESULTS: sLOX-1, oxLDL, and ET-1 levels were significantly higher in patients with MetS than in control subjects (P = 0.023 P < 0.001, and P < 0.001, respectively). MetS patients have significantly lower eNOS and NOx levels, and PON1 and ARE activities than control subjects (P = 0.017, P < 0.004, P < 0.001, and P = 0.010, respectively). A positive correlation was observed between the sLOX-1 levels and the oxLDL, ET-1, BMI, glucose levels. ET-1 levels also exhibited significant negative correlation with ARE activity. CONCLUSION: sLOX-1 levels are associated with cardiovascular risk factors, such as increased oxLDL, obesity, and diabetes, in patients with MetS. An increased concentration of sLOX-1 could be an early predictor of endothelial damage in MetS. In addition, it appears that oxLDL, ET-1, eNOS, NOx, PON1, and ARE activities may accurately reflect the levels of endothelial dysfunction in MetS patients. PMID- 24798147 TI - Unnatural amino acid mutagenesis reveals dimerization as a negative regulatory mechanism of VHR's phosphatase activity. AB - Vaccinia H1-related (VHR) phosphatase is a dual specificity phosphatase that is required for cell-cycle progression and plays a role in cell growth of certain cancers. Therefore, it represents a potential drug target. VHR is structurally and biochemically well characterized, yet its regulatory principles are still poorly understood. Understanding its regulation is important, not only to comprehend VHR's biological mechanisms and roles but also to determine its potential and druggability as a target in cancer. Here, we investigated the functional role of the unique "variable insert" region in VHR by selectively introducing the photo-cross-linkable amino acid para-benzoylphenylalanine (pBPA) using the amber suppression method. This approach led to the discovery of VHR dimerization, which was further confirmed using traditional chemical cross linkers. Phe68 in VHR was discovered as a residue involved in the dimerization. We demonstrate that VHR can dimerize inside cells, and that VHR catalytic activity is reduced upon dimerization. Our results suggest that dimerization could occlude the active site of VHR, thereby blocking its accessibility to substrates. These findings indicate that the previously unknown transient self association of VHR acts as a means for the negative regulation of its catalytic activity. PMID- 24798148 TI - Construction of upp deletion mutant strains of Lactobacillus casei and Lactococcus lactis based on counterselective system using temperature-sensitive plasmid. AB - Integration plasmids are often used in constructing chromosomal mutations, as it enables the alternation of genes at any location by integration or replacement. Food-grade integration vectors can integrate into the host genome without introducing any selectable markers or residual bases, and the recombination often happens in non-coding region. In this study we used the temperature-sensitive pWV01 replicon to construct 2 chloramphenicol-resistant integration plasmids (pGBHC32-upp) containing the uracil phosphoribosyl transferase (upp) gene as a counterselective marker for Lactobacillus casei (L. casei) ATCC393 and Lactococcus lactis (L. lactis) MG1363. We then ligated the designed homologous arms to the pGBHC32-upp plasmids to allow their integration to the bacterial chromosome, and selected upp deletion mutants of L. casei ATCC393 and L. lactis MG1363 in the presence of 5-fluorouracil (5-FU). Analysis of genetic stability, growth curve, carbon utilization and scanning electronic microscopy showed that, except for 5-FU resistance, there were no significant differences between the wild type and mutant lactic acid bacteria. The integration system and the upp deletion strains could be used in the insertion or deletion of genes at any location of the chromosome of both L. casei ATCC 393 and L. lactis MG1363, and the homologous recombination would not introduce any selectable markers or residual bases. These mutant strains can be further investigated for heterologous protein expression and construction of a live mucosal vaccine carrier. PMID- 24798149 TI - Urologists' personal feelings on PSA screening and prostate cancer treatment. AB - RATIONALE, AIMS AND OBJECTIVE: This study aimed to determine if urologists' feelings on prostate cancer screening with prostate-specific antigen (PSA) and treatment on themselves are consistent with what they recommend to patients. METHODS: A survey regarding prostate cancer screening and treatment was assembled using the SurveyMonkey web site. The link to the survey was then emailed to urologists. Participation was voluntary. RESULTS: The survey was sent to 2672 American urologists and completed by 215 urologists; response rate was 8%. One hundred ninety-eight (92%) were male. Most (56%) urologists recommend PSA screening beginning at age 50 for patients, and this corresponded with the age at which survey responders began their PSA screening. Two urologists did not recommend screening, and 10% were 'not sure' if screening saves lives. Of those that had not had their PSA checked, 34% plan to begin screening at 40-44 with 11% stating they 'never' plan to be screened. One hundred thirty-eight (70%) men completing the survey had their PSA checked. The majority (86%) had it drawn for screening. Nineteen respondents had an elevated PSA with nine men diagnosed with prostate cancer. Eight of these had radical prostatectomy. When faced with the hypothetical diagnosis of an elevated PSA and low-grade prostate cancer, respondents favoured repeat PSA (94%) and surveillance (48%), respectively, than any other option. CONCLUSION: Despite recommendations from the American Urologic Association to screen men for prostate cancer, a significant percentage of urologists do not wish to be screened with PSA. Almost all, however, continue to recommend prostate cancer screening for their patients. Treatment recommendations also varied among the respondents. PMID- 24798150 TI - Development of paediatric biochemistry centile charts as a complement to laboratory reference intervals. AB - Age-specific paediatric reference intervals are used in interpretation of laboratory results. However, interpretation may be problematic when a child just crosses an age bracket and the difference between the original and the subsequent age-specific reference interval is large. Moreover, details about the physiological changes with age may be masked. For the 12 months ending 30 September 2013, results of 16 common clinical biochemistry tests of ambulatory paediatric patients aged 0-19, requested by primary care physicians, were retrospectively collected in a large pathology service, and used to construct smoothed centile charts using a penalised maximum likelihood method. From the developed centile charts, the concentrations of sodium, bicarbonate, creatinine, urate, total protein, and albumin all increased with increasing age of the children. In contrast, the concentrations of potassium, chloride, anion gap, calcium, phosphate and lactate dehydrogenase decreased with increasing age of the children. Changes in the concentrations of urea, alkaline phosphatase, glucose, and total cholesterol varied by age. Generally, the boys and girls shared similar trend patterns until 10-15 years of age, when variations in the age of onset of puberty and development caused the trends of some biochemical measures to differ. The paediatric biochemistry centile charts are intuitive tools to use. They complement age-specific reference intervals in the tracking, interpretation and discussion of laboratory results. They also enhance the understanding of underlying physiological changes in biochemistry in children. PMID- 24798151 TI - Focal nodular hyperplasia and hepatocellular carcinoma: uncommon companions? PMID- 24798152 TI - Angiogenic factor thymidine phosphorylase associates with angiogenesis and lymphangiogenesis in the intestinal-type gastric cancer. AB - As an angiogenic factor, thymidine phosphorylase (TP) expression in primary tumours has been thought to be a risk factor for lymph node (LN) and hepatic metastasis in patients with gastric adenocarcinoma. However, the molecular basis for the induction of metastasis by TP is largely unknown. We aim to elucidate the role of TP expression in gastric cancer neovascularisation and LN metastasis.The angiogenic and lymphangiogenic activity (CD31, D2-40, Ki-67, VEGFC, VEGFR3) and expression status of TP were detected in 103 resected human gastric carcinoma samples by immunohistochemistry. The influence of TP expression on neovascularisation and cancer cell invasion was further comparatively investigated in two groups of nude mice intraperitoneally injected with TP overexpressing MKN-45 cells (MKN-45/TP) and control cells (MKN-45/CV). In gastric cancer tissues, we found that high TP expression and various angiogenic and lymphangiogenic activities were significantly associated with poor prognostic outcomes. In addition, TP expression was also found to be associated with neovascularisation activity of gastric cancer tissues. In vivo, the MKN-45/TP group exhibited significantly increased infiltrating tumour nodules and neovascularisation activity compared to the MKN-45/CV group. TP could strongly influence gastric cancer progression via the dual activities of angiogenesis and lymphangiogenesis. PMID- 24798153 TI - Comparison of two plasma urate assays in patients receiving vitamin C supplementation. AB - The aim of this study was to compare plasma urate (PU) concentrations using two different assays in patients receiving vitamin C supplementation. PU was measured using two routinely available enzymatic uricase methods: (1) uric acid plus method (ascorbate oxidase assay), and (2) uric acid method (non-ascorbate oxidase assay). Twenty patients receiving allopurinol were randomised to an increase in allopurinol dose or commence vitamin C 500 mg/d on a 1:1 ratio. Twenty patients not receiving allopurinol were randomised to start allopurinol or vitamin C 500 mg/d on a 1:1 ratio. Trough fasting samples for plasma ascorbate and urate were measured weekly until week 8. There was no significant difference in the mean PU measured by the two assays. In patients not receiving supplemental vitamin C the mean PU concentrations were identical for both assays. For patients receiving supplemental vitamin C the mean PU concentrations for the ascorbate oxidase assay was 0.525 mmol/L (SE 0.034) and for the non-ascorbate oxidase assay 0.510 mmol/L (SE 0.033), p = 0.079.There is a small non-significant difference in measured PU in patients receiving supplemental vitamin C between the two assays. The assay which does not include ascorbate oxidase results in consistently lower PU concentrations compared to the assay which includes ascorbate oxidase. PMID- 24798154 TI - Transformation of endometrioid carcinoma to carcinoma with trophoblastic differentiation: clinicopathological and whole genomic study. PMID- 24798155 TI - Diagnosis of diabetes in anaemias and haemoglobinopathies: salutary lessons for improved reporting and patient empowerment. PMID- 24798156 TI - Molecular biomarkers for predicting outcomes in urothelial carcinoma of the bladder. AB - Molecular biomarkers are used routinely in the clinical management of several tumours such as prostate, colon, ovarian and pancreatic cancer but management decisions in bladder cancer remain dependent on clinical and pathological criteria, which are limited in their ability to predict outcomes. Molecular markers are urgently needed in detection, surveillance and prognostication of bladder cancer as well as to predict treatment response to intravesical and systemic therapies. Advances in cancer genomics and platforms for biomarker profiling have led to a plethora of biomarkers, which must now be rigorously validated in the clinical setting. Pre-clinical and clinical studies exploring the role of emerging targeted therapies to risk stratify and reduce cancer progression are also needed. PMID- 24798158 TI - High takeoff of the left main coronary artery at autopsy after sudden unexpected death in a male. PMID- 24798157 TI - Development of an internal amplification control system for a real-time PCR assay for detection of Neisseria meningitidis in CSF and EDTA blood. AB - The aim of this study was to assemble and assess a non-competitive internal amplification control (IAC) system targeting the Escherichia coli alanine racemase (alr) gene to include in a real-time polymerase chain reaction (PCR) assay for Neisseria meningitidis. Primers and hybridisation probes specific for the IAC were designed and assessed for specificity. Amplification efficiency and limit of detection for the assembled assay was extrapolated using standard curves constructed with serial dilutions of N. meningitidis in saline, pooled cerebrospinal fluid (CSF) and EDTA blood. The 95% confidence limits (CI) were calculated for IAC crossing-points recorded for assays for N. meningitidis ctrA in saline (negative blank), and N. meningitides-negative samples of CSF and EDTA blood. These limits served as a reference range against which the IAC crossing points recorded for prospective assays are compared to detect sample inhibition. This system was used in testing consecutive EDTA blood samples from two cases of meningococcal disease. The IAC system is specific for Escherichia coli and Shigella species. The amplification efficiency of the assembled assay for N. meningitidis and ability to detect low target DNA levels was not compromised with the inclusion of the IAC system. The IAC crossing-points varied in clinical samples of CSF and EDTA blood. The elucidated reference range for EDTA blood was used to detect sample inhibition in one of the two clinical cases investigated.The IAC system monitors the performance of all processes in the assembled assay for N. meningitidis. Measuring IAC crossing-points serves as an indicator of sample stability and inhibitory properties when testing single or multiple samples from the same patient. Specificity for E. coli and Shigella species enables inclusion in assays of different targets within the same laboratory. Reporting PCR assay results in the context of the IAC crossing-points and reference ranges validates against sample inhibition and suitability for detection of low levels of target DNA in random and multiple samples. PMID- 24798159 TI - Carcinoma cuniculatum of the cervix. PMID- 24798160 TI - BRAFV600E mutation analysis by immunohistochemistry in patients with thoracic metastases from colorectal cancer. AB - The BRAF(V600E) mutation confers worse prognosis to metastatic colorectal cancer (mCRC) patients. In addition, this mutation has a negative predictive value for response to treatment with monoclonal antibodies against EGFR in patients with KRAS wild-type (wt) mCRC. The utility of immunohistochemistry (IHC) as an alternative approach for detection of BRAF(V600E) in the thoracic metastases of sporadic mCRC patients has not been evaluated until now. The purpose of this study was to compare BRAF(V600E) IHC staining with molecular biology methods and to define the diagnostic value of the VE1 antibody for the detection of BRAF(V600E) in this population. BRAF mutations were analysed by two DNA sequencing methods (pyrosequencing and Sanger sequencing) in a Caucasian population of 310 sporadic mCRC with thoracic metastases patients expressing KRAS wt. Detection of the BRAF(V600E) mutation was performed in the corresponding tumours by IHC using the VE1 antibody and compared to results of the DNA-based assays. Thirty-nine out of 310 (13%) of tumours harboured a BRAF mutation, which corresponded to either a BRAF(V600E) in 34 of 310 (11%) cases or a non BRAF(V600E) mutation in 5 of 310 (2%) cases. IHC with VE1 was strongly positive in 32 of 34 (88%) BRAF(V600E) mutated tumours and negative in non-BRAF(V600E) mutated tumours. IHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be either a complementary or an alternative method to molecular testing in mCRC patients. PMID- 24798161 TI - Olmesartan induced enterocolitis. PMID- 24798162 TI - Polyacrylamide hydrogel (Aquamid) filler in vagina. PMID- 24798163 TI - Detection of EGFR mutational profile by direct dideoxy sequencing in cytology and non-cytology biopsy samples. AB - Epidermal growth factor receptor (EGFR) mutational analysis is recommended in the diagnostic work-up of non-small cell lung carcinoma. The first diagnostic biopsy is usually obtained by a minimally invasive procedure, especially in patients with unresectable disease. This paper aims to compare the types of somatic EGFR mutations detected by cytology and non-cytology samples by direct dideoxy sequencing and propose practical guidelines for handling such material. Only samples with sufficient polymerase chain reaction (PCR) product were considered, a total 310 samples (302 patients), of which 168 samples were cytology material and 142 samples were non-cytology biopsy material. All samples were assessed for tumour content and bidirectional direct sequencing was performed on exons 18, 19, 20 and 21. There were 49 cases with EGFR mutation detected (16.2%), without a significant difference in the detection of mutations between either cytology or non-cytology material. EGFR mutation was detected in most sample types including endoscopic ultrasound guided FNA, bronchial washings/brushings and pleural/peritoneal fluid samples. Cytology material can provide an adequate source of material for EGFR mutational analysis, with coordinated effort between clinicians and pathologists critical for best outcome. PMID- 24798164 TI - Cysticercosis in the thyroglossal duct cyst: rare site for a common problem. PMID- 24798165 TI - Asynchronous glands in the endometrium of women with recurrent reproductive failure. AB - Of 969 non-consecutive endometrial biopsies performed for investigation of recurrent reproductive failure, 20 cases (2.1%) showed the striking presence of retarded or asynchronous endometrial glands in otherwise unremarkable mid or late secretory endometrium. These glands were characterised by tall columnar cells with crowded nuclei showing increased reactivity for the proliferative marker MIB 1, occasional mitoses, greatly reduced or absent secretion, and persistent expression of oestrogen receptors and usually progesterone receptors and their isoforms typical of late proliferative phase endometrium. The nearby endometrial stromal cells exhibited no discernibly reduced reactivity for calretinin. These changes were seen in single glands (even portions of glands), or clusters of glands, adjacent to normal late secretory type endometrial glands and set in pseudodecidualised stroma characteristic of late luteal phase. Some examples also displayed adjacent glands with intermediate features and it is speculated that firstly, this is a relatively common phenomenon in women with recurrent miscarriage or implantation failure and with an unknown potential to affect implantation. Secondly, it is an intrinsic defect of the endometrium and can occur in sequential endometrial biopsies in the same patient. Thirdly, it differs from previously described patterns of so-called luteal phase defect or deficient secretory phase in that it occurs in the demonstrated presence of adequate progesterone effect on the endometrium and is associated with persistence rather than exaggerated down-regulation of receptors. Nevertheless, supplementary progesterone therapy (vaginal pessaries) for the first trimester appeared to have a beneficial therapeutic effect on reproductive outcome in these patients. PMID- 24798166 TI - Nationwide prevalence of lymph node metastases in Gleason score 3 + 3 = 6 prostate cancer. AB - Based on revisions of Gleason scoring in 2005, it has been reported that nodal metastases at radical prostatectomy in Gleason 3 + 3 = 6 (GS6) prostate cancer are extremely rare, and that GS6 cancers with nodal metastases are invariably upgraded upon review by academic urological pathologists. We analysed the prevalence and determinants of nodal metastases in a national sample of patients with GS6 cancer.We utilised the SEER database to identify patients diagnosed with GS6 prostate cancer during 2004-2010 who had radical prostatectomy and >=1 lymph node(s) examined. We calculated the prevalence of nodal metastases and constructed a multivariable logistic regression model to identify factors associated with nodal metastases. Among 21,960 patients, the prevalence of nodal metastases was 0.48%. Older age, preoperative PSA >10 ng/mL, and advanced stage were positively associated with nodal metastases. Lymph node metastases in GS6 cancer are more prevalent in a nationwide population compared to academic centres. Revised guidelines for Gleason scoring have made GS6 cancer a more homogeneously indolent disease, which may be relevant in the era of active surveillance. We submit that lymph node metastases in GS6 cancer be used as a proxy for adherence to the 2005 ISUP consensus on Gleason grading. PMID- 24798167 TI - Ascending aortitis: a clinicopathological study of 21 cases in a series of 300 aortic repairs. AB - There are few single-institution clinicopathological series of aortitis. In this study, all ascending aneurysms were prospectively evaluated pathologically with >=6 aortic sections over a 6-year period.Of 300 ascending aortic resections, there were 21 cases of aortitis (7%), in 11 women and 10 men (mean 67, range 41 88 years). There were 19 patients with aneurysms, and two patients with sclerosing periaortitis, clinically suspected to have intramural haematoma. Of the 19 patients with aneurysms (11 women), two had prior temporal arteritis, one ankylosing spondylitis, one IgA nephropathy, one undifferentiated autoimmune disease, one Lyme disease, and one fibromyalgia. In only two patients was aortitis suspected before surgery as the cause of aneurysm. Four patients developed distal aortic aneurysm requiring repeat surgery. Valve replacement or repair was necessary in nine patients, and two patients died after surgery. There were no significant differences between patients with and without autoimmune disease. The histological features were necrotising aortitis in 18 of 19 patients with aneurysmal aortitis, and there was one case of non-necrotising aortitis. One valve showed autoimmune valvulitis, congenitally bicuspid associated with ankylosing spondylitis. Necrotising aortitis was classified as acute (n = 5), healing (n = 9), and healed (n = 4). Acute necrotising aortitis was associated with need for valve replacement (p = 0.01) and younger age (p = 0.01). The healed phase had subtle histological features, sparse medial inflammation, marked medial attenuation, and chronic adventitial inflammation. Two patients with periaortitis demonstrated marked fibroinflammatory thickening of the adventitia with histological features typical of IgG4-related disease; neither had systemic symptoms. Ascending aortitis is histologically diverse, most frequently of the medial necrotising type, and is usually not suspected pre-operatively. Awareness of the histological spectrum is necessary for pathological diagnosis. PMID- 24798168 TI - Epithelioid haemangioendothelioma of the uterine cervix with CAMTA1/WWTR1 translocation. PMID- 24798169 TI - Towards optimising the provision of laboratory services for bone turnover markers. AB - Bone turnover markers (BTMs) are either secreted by osteoblasts during bone formation or released by degradation of the collagen matrix of bone during bone resorption, and may be measured in blood or urine to provide an estimate of the rate of bone remodelling. Increased bone remodelling rate is often associated with bone loss which can result in osteoporosis; however, lack of data preclude the inclusion of BTMs in fracture risk algorithms. The changes in BTMs following therapy for osteoporosis may be useful for monitoring. Serum procollagen type I amino-terminal propeptide (s-PINP) and serum carboxy-terminal cross-linking telopeptide of type I collagen (s-betaCTX) have been designated as reference standard markers of bone formation and resorption respectively in osteoporosis; further research is needed for their routine use in osteoporosis. BTMs are useful in diagnosing and monitoring Paget's disease of bone and other bone diseases associated with abnormal bone formation and/or resorption. Standardised patient preparation is required to mitigate the effect of biological variation, and appropriate sample handling and storage are important to minimise sample degradation. Significant inter-method differences exist for BTMs, and harmonisation of methods for the reference BTMs is being pursued. This will help develop universally accepted decision limits and treatment goals. Australian consensus reference intervals have been developed for some methods for s-PINP and s-betaCTX. PMID- 24798170 TI - The utility of syphilis point of care testing in remote Queensland communities. PMID- 24798171 TI - Pure erythroid leukaemia diagnosed on liver biopsy with concurrent haemophagocytic lymphohistiocytosis. PMID- 24798172 TI - First report of adrenal cortical endothelial (vascular) cyst mimicking phaeochromocytoma (pseudophaeochromocytoma). PMID- 24798173 TI - Comparison of energy metabolism and meat quality among three pig breeds. AB - The objective of this study was to evaluate the effects of muscle-fibre types and hormones on glycolytic potential and meat quality traits and their association with glycolytic-related gene expression in three different altitude pig breeds. The pig breeds studied were the Tibetan pig (TP, high altitude), the Liang-Shan pig (LSP, middle altitude) and the Duroc*(Landrace*Yorkshire) cross (DLY, flatland). The results indicated that TP and LSP had better meat quality than DLY (P<0.01). The glycolytic potential (GP) increased in the order of TP 4) and 44 (72%) of the AS patients were in remission. The median ESR was 14 (34-6) mm/h and 4 (7-2) mm/h (P < 0.001) for the patient and control groups, respectively. The median CRP level was 0.91 (2.72-0.37) mg/dL and 0.15 (0.25-0.07) mg/dL in the patient and control groups, respectively (P < 0.001). Median BASDAI, BASFI and BASMI scores for all AS patients were 3.6 (5.25-2.29), 2.5 (4.22-0.91) and 3 (5 1), respectively. Serum procalcitonin levels were normal (< 0.05 ng/mL) for all patients and controls. CONCLUSION: Serum procalcitonin levels were not high in AS patients and controls, and the levels were independent of disease activity and medications. If bacterial or fungal infection is suspected in an AS patient, serum procalcitonin level may be useful for diagnosis. PMID- 24798192 TI - Stair ambulation biomechanics following total knee arthroplasty: a systematic review. AB - The purpose of this review was to summarize the biomechanical adaptations during stair ambulation that occur after total knee arthroplasty (TKA). Articles were identified by searching PubMed and Web of Science. During stair ascent, knee flexion angle at heel strike and walking velocity were reduced in TKA subjects compared to controls. Results of other variables were not consistent between studies. During stair descent only one study found any differences for knee moments in the sagittal and frontal plane between TKA subjects and controls. Other results during stair descent were not consistent between studies. Differences in methods can partially explain discrepancies between studies in this review. More studies with consistent and improved methods are needed in order to provide better understanding of stair ambulation following TKA. PMID- 24798191 TI - Heat shock protein 27 regulates human prostate cancer cell motility and metastatic progression. AB - Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase human PCa cell invasion and its overexpression is associated with metastatic disease. The role of HSP27 in driving PCa cell movement from the prostate to distant metastatic sites is unknown. Increased HSP27 expression increased metastasis as well as primary tumor mass. In vitro studies further examined the mechanism of HSP27-induced metastatic behavior. HSP27 did not affect cell detachment, adhesion, or migration, but did increase cell invasion. Cell invasion was dependent upon matrix metalloproteinase 2 (MMP-2), whose expression was increased by HSP27. In vivo, HSP27 induced commensurate changes in MMP-2 expression in tumors. These findings demonstrate that HSP27 drives metastatic spread of cancer cells from the prostate to distant sites, does so across a continuum of expression levels, and identifies HSP27-driven increases in MMP-2 expression as functionally relevant. These findings add to prior studies demonstrating that HSP27 increases PCa cell motility, growth and survival. Together, they demonstrate that HSP27 plays an important role in PCa progression. PMID- 24798193 TI - Massive bone defect compromises postoperative cup survivorship of acetabular revision hip arthroplasty with impaction bone grafting. AB - We evaluated 66 acetabular revision arthroplasties using cemented cup with impaction bone grafting (IBG) to detect the extent that bone defect affects the outcome. We defined the maximum acetabular defect distance (MADD), which indicates the greatest depth of the grafted layer. Cup survival analysis with aseptic loosening as the endpoint revealed that the "MADD<=20mm" group showed higher survivorship than the "MADD>20mm" group (95% vs. 74%, P=0.034), and that the simple-wall-defect group (none or one mesh used) showed higher survivorship than the complex-wall-defect group (two meshes used) (96% vs. 73%, P=0.044). A favorable indication for acetabular IBG reconstruction is cases in which those cups can be placed at<=20mm MADD with a simple wall defect. PMID- 24798194 TI - Antibiotic susceptibility in gram-positive chronic joint arthroplasty infections: increased aminoglycoside resistance rate in patients with prior aminoglycoside impregnated cement spacer use. AB - Two-stage revision using aminoglycoside-cement spacers (A-CSs) is widely used to manage chronic periprosthetic joint infection (PJI). However, aminoglycoside resistance in gram-positive cocci (GPC) seems to be increasing. Moreover, the contribution of these A-CSs to select resistant mutants is a matter of concern. We study the antibiotic susceptibility profile of GPC after 113 chronic hip and knee PJIs. Aminoglycoside susceptibility-profiles were compared between cases where A-CSs had previously been used (n: 52), and cases of primary infection (n: 61). 32% of isolates were resistant to gentamicin and 40.6% to tobramycin. Gentamicin resistance after previous A-CS use was significantly higher (49.2% [30/61] vs. 19.3% [16/83]; P: 0.0001) as well as with tobramycin (52.7% [29/55] vs. 30.9% [21/66]; P: 0.014). A high rate of gentamicin-tobramycin resistance exists among the most common bacteria involved in chronic-PJI. The risk of selection for aminoglycoside-resistant mutants in cases of infection relapse is a concern following A-CS use. PMID- 24798195 TI - Comparing attitudinal and situational measures of self-control among felony offenders. AB - BACKGROUND: Hirschi recently revised the measurement of self-control to include the number and salience of costs an individual considers in an offending situation. Evidence is mixed on its predictive utility relative to other self control measures but suffers from different studies operationalising the measure in different ways and mostly examining it with non-offenders. AIMS: This study aimed to investigate Hirschi's reconceptualisation of self-control. Our research question was whether the number and salience of Hirschi's 'costs' are independently related to offending. METHODS: Data on self-perceptions of likelihood of driving while drunk and various self-control and social control measures were collected by researchers during an orientation class for convicted offenders newly received into correctional facilities--one for men and one for women--during January to May 2011. RESULTS: Eight hundred and nineteen men and 194 women completed the ratings. Both attitudinal and situational self-control measures were independently associated with self-rated likelihood of driving while drunk. These findings were confined to the male offenders. CONCLUSIONS: Findings revealed mixed support for Hirschi's conceptualisation of self-control and its relevance. Situational and attitudinal measures of self-control share some common ground but relate differently to offending according to gender. Further research is needed to find out if these results are generalisable to other crime types and whether race/ethnicity could modify the findings. Even among convicted offenders whose crimes are serious and/or frequent enough to result in imprisonment, high self-control may inhibit offending. This has implications for intervention programmes. This is the first study to compare attitudinal and self-control measures in relation to offending among a sample of incarcerated offenders and across gender. PMID- 24798196 TI - Interplay between efficiency and device architecture for small molecule organic solar cells. AB - Small molecule organic solar cells (OSCs) have experienced a resurgence of interest over their polymer solar cell counterparts, owing to their improved batch-to-batch (thus, cell-to-cell) reliability. In this systematic study on OSC device architecture, we investigate five different small molecule OSC structures, including the simple planar heterojunction (PHJ) and bulk heterojunction (BHJ), as well as several planar-mixed structures. The different OSC structures are studied over a wide range of donor:acceptor mixing concentrations to gain a comprehensive understanding of their charge transport behavior. Transient photocurrent decay measurements provide crucial information regarding the interplay between charge sweep-out and charge recombination, and ultimately hint toward space charge effects in planar-mixed structures. Results show that the BHJ/acceptor architecture, comprising a BHJ layer with high C60 acceptor content, generates OSCs with the highest performance by balancing charge generation with charge collection. The performance of other device architectures is largely limited by hole transport, with associated hole accumulation and space charge effects. PMID- 24798197 TI - Spatial interpolation of fine particulate matter concentrations using the shortest wind-field path distance. AB - Effective assessments of air-pollution exposure depend on the ability to accurately predict pollutant concentrations at unmonitored locations, which can be achieved through spatial interpolation. However, most interpolation approaches currently in use are based on the Euclidean distance, which cannot account for the complex nonlinear features displayed by air-pollution distributions in the wind-field. In this study, an interpolation method based on the shortest path distance is developed to characterize the impact of complex urban wind-field on the distribution of the particulate matter concentration. In this method, the wind-field is incorporated by first interpolating the observed wind-field from a meteorological-station network, then using this continuous wind-field to construct a cost surface based on Gaussian dispersion model and calculating the shortest wind-field path distances between locations, and finally replacing the Euclidean distances typically used in Inverse Distance Weighting (IDW) with the shortest wind-field path distances. This proposed methodology is used to generate daily and hourly estimation surfaces for the particulate matter concentration in the urban area of Beijing in May 2013. This study demonstrates that wind-fields can be incorporated into an interpolation framework using the shortest wind-field path distance, which leads to a remarkable improvement in both the prediction accuracy and the visual reproduction of the wind-flow effect, both of which are of great importance for the assessment of the effects of pollutants on human health. PMID- 24798198 TI - Optimal packing of a rotating packed bed for H(2)S removal. AB - The existence of H2S in a system could lead to catalyst deactivation, pipeline corrosion, and environmental pollution. A rotating packed bed (RPB), a novel reactor with high mass transfer efficiency and small dimension, is employed in this study to remove H2S. For RPB, the most significant section for mass transfer is the end-effect zone of packing. A mathematical model for liquid flow in the packing is established to quantify the length of the end-effect zone. A simple and effective visual experimental method is then proposed to investigate the end effect zone in the RPB. A gas-liquid mass transfer experiment is finally employed to confirm the validity of the proposed mathematical model. With the aid of this model, the length of packing of a RPB used for pilot-scale H2S removal is optimized. The optimized RPB removes 99.8% of H2S (15 vol % to 0.03 vol %) from the system. The proposed model can help optimize the design of a RPB reactor. PMID- 24798199 TI - Hepatocellular carcinoma: have we finally found the ultimate staging system for HCC? AB - A staging system capable of addressing the real issues facing patients with hepatocellular carcinoma has long been overdue. The new Hong Kong Liver Cancer staging system might do just that because it deals effectively with the limitations of previous staging systems. PMID- 24798200 TI - Hepatitis B: AASLD guidelines not being followed. PMID- 24798201 TI - Plant-associated bacteria degrade defense chemicals and reduce their adverse effects on an insect defoliator. AB - Phytophagous insects must contend with numerous secondary defense compounds that can adversely affect their growth and development. The gypsy moth (Lymantria dispar) is a polyphagous herbivore that encounters an extensive range of hosts and chemicals. We used this folivore and a primary component of aspen chemical defenses, namely, phenolic glycosides, to investigate if bacteria detoxify phytochemicals and benefit larvae. We conducted insect bioassays using bacteria enriched from environmental samples, analyses of the microbial community in the midguts of bioassay larvae, and in vitro phenolic glycoside metabolism assays. Inoculation with bacteria enhanced larval growth in the presence, but not absence, of phenolic glycosides in the artificial diet. This effect of bacteria on growth was observed only in larvae administered bacteria from aspen foliage. The resulting midgut community composition varied among the bacterial treatments. When phenolic glycosides were included in diet, the composition of midguts in larvae fed aspen bacteria was significantly altered. Phenolic glycosides increased population responses by bacteria that we found able to metabolize these compounds in liquid growth cultures. Several aspects of these results suggest that vectoring or pairwise symbiosis models are inadequate for understanding microbial mediation of plant-herbivore interactions in some systems. First, bacteria that most benefitted larvae were initially foliar residents, suggesting that toxin-degrading abilities of phyllosphere inhabitants indirectly benefit herbivores upon ingestion. Second, assays with single bacteria did not confer the benefits to larvae obtained with consortia, suggesting multi- and inter-microbial interactions are also involved. Our results show that bacteria mediate insect interactions with plant defenses but that these interactions are community specific and highly complex. PMID- 24798202 TI - Conjugated linoleic acids attenuate LPS-induced pro-inflammatory gene expression by inhibiting the NF-kappaB translocation through PPARgamma in buffalo granulosa cells. AB - PROBLEM: In granulosa cells, TLR4-mediated LPS-induced immune response interferes with ovarian granulosa cell function. METHOD OF STUDY: LPS-induced pro inflammatory gene expression was monitored by real-time PCR and NF-kappaB was determined by the immuno-blotting and immuno-staining in granulosa cells in vitro. RESULTS: The LPS (1 MUg/mL) increased pro-inflammatory gene expression which was reverted back by treatment with TLR4 signaling inhibitor. Cotreatment of CLA (10 MUm) with LPS did not show any effect on LPS-induced pro-inflammatory gene expression but granulosa cells pre-treated with CLA for 24 hr, attenuated LPS-induced pro-inflammatory gene expression and nuclear NF-kappaB. GW9662, a PPARgamma-inhibitor, further increased the expression of pro-inflammatory genes. CONCLUSION: The present findings reiterated that pre-treatment with CLA can prevent LPS-induced granulosa cells dysfunction. PMID- 24798203 TI - OsABCB14 functions in auxin transport and iron homeostasis in rice (Oryza sativa L.). AB - Members of the ATP Binding Cassette B/Multidrug-Resistance/P-glyco-protein (ABCB/MDR/PGP) subfamily were shown to function primarily in Oryza sativa (rice) auxin transport; however, none of the rice ABCB transporters have been functionally characterized. Here, we describe that a knock-down of OsABCB14 confers decreased auxin concentrations and polar auxin transport rates, conferring insensitivity to 2,4-dichlorophenoxyacetic acid (2,4-D) and indole-3 acetic acid (IAA). OsABCB14 displays enhanced specific auxin influx activity in yeast and protoplasts prepared from rice knock-down alleles. OsABCB14 is localized at the plasma membrane, pointing to an important directionality under physiological conditions. osabcb14 mutants were surprisingly found to be insensitive to iron deficiency treatment (-Fe). Their Fe concentration is higher and upregulation of Fe deficiency-responsive genes is lower in osabcb14 mutants than in wild-type rice (Nipponbare, NIP). Taken together, our results strongly support the role of OsABCB14 as an auxin influx transporter involved in Fe homeostasis. The functional characterization of OsABCB14 provides insights in monocot auxin transport and its relationship to Fe nutrition. PMID- 24798204 TI - Maternal syntabulin is required for dorsal axis formation and is a germ plasm component in Xenopus. AB - In amphibians and teleosts, early embryonic axial development is driven by maternally deposited mRNAs and proteins, called dorsal determinants, which migrate to the presumptive dorsal side of the embryo in a microtubule-dependent manner after fertilization. Syntabulin is an adapter protein that binds to kinesin KIF5B and to the transmembrane protein Syntaxin1. In zebrafish, a mutation in Syntabulin causes complete embryo ventralization. It is unknown whether Syntabulin plays an analogous role during early development of other species, a question addressed here in Xenopus laevis. in situ hybridization of syntabulin mRNA was carried out at different stages of Xenopus development. In oocytes, syntabulin transcripts were localized to the vegetal cortex of large oocytes and the mitochondrial cloud of very young oocytes. We extended the zebrafish data by finding that during cleavage Xenopus syntabulin mRNA localized to the germ plasm and was later expressed in primordial germ cells (PGCs). This new finding suggested a role for Syntabulin during germ cell differentiation. The functional role of maternal syntabulin mRNA was investigated by knock-down with phosphorothioate DNA antisense oligos followed by oocyte transfer. The results showed that syntabulin mRNA depletion caused the complete loss of dorso-anterior axis formation in frog embryos. Consistent with the ventralized phenotype, syntabulin-depleted embryos displayed severe reduction of dorsal markers and ubiquitous transcription of the ventral marker sizzled. Syntabulin was required for the maternal Wnt/beta-Catenin signal, since ventralization could be completely rescued by injection of beta-catenin (or syntabulin) mRNA. The data suggest an evolutionarily conserved role for Syntabulin, a protein that bridges microtubule motors and membrane vesicles, during dorso-ventral axis formation in the vertebrates. PMID- 24798205 TI - Increasing capacity to deliver diabetes self-management education: results of the DESMOND lay educator non-randomized controlled equivalence trial. AB - AIM: To develop and test a format of delivery of diabetes self-management education by paired professional and lay educators. METHODS: We conducted an equivalence trial with non-randomized participant allocation to a Diabetes Education and Self Management for Ongoing and Newly Diagnosed Type 2 diabetes (DESMOND) course, delivered in the standard format by two trained healthcare professional educators (to the control group) or by one trained lay educator and one professional educator (to the intervention group). A total of 260 people with Type 2 diabetes diagnosed within the previous 12 months were referred for self management education as part of routine care and attended either a control or intervention format DESMOND course. The primary outcome measure was change in illness coherence score (derived from the Diabetes Illness Perception Questionnaire-Revised) between baseline and 4 months after attending education sessions. Secondary outcome measures included change in HbA1c level. The trial was conducted in four primary care organizations across England and Scotland. RESULTS: The 95% CI for the between-group difference in positive change in coherence scores was within the pre-set limits of equivalence (difference = 0.22, 95% CI 1.07 to 1.52). Equivalent changes related to secondary outcome measures were also observed, including equivalent reductions in HbA1c levels. CONCLUSION: Diabetes education delivered jointly by a trained lay person and a healthcare professional educator with the same educator role can provide equivalent patient benefits. This could provide a method that increases capacity, maintains quality and is cost-effective, while increasing access to self-management education. PMID- 24798208 TI - Can interest and enjoyment help to increase use of Internet-delivered interventions? AB - OBJECTIVE: Internet-delivered interventions have proven efficacious in changing people's behaviours and related determinants, but the actual use of these interventions by the target group is often very low. This article investigates whether arousing interest and enjoyment results in increased intervention use in an online context. DESIGN: Invitations to visit a website about Hepatitis A, B and C virus infections (Studies 1 and 3) and the website itself (Studies 2 and 3) were manipulated to arouse interest and enjoyment. MAIN OUTCOME MEASURES: Intention to visit the website (Study 1), clicking on the link to visit the website (Studies 2 and 3) and the number of pages visited on the website (Study 3). RESULTS: Arousing interest through an invitation resulted in a higher intention to visit the website (Study 1) and a higher likelihood of clicking on the link to visit the website in comparison with arousing enjoyment (Study 2). The number of pages visited increased when interest was aroused on the website itself (Study 3). CONCLUSION: Arousing interest is a promising strategy to increase use of Internet-delivered interventions and potentially increase the public health impact of these interventions. PMID- 24798206 TI - Genomes of two new ammonia-oxidizing archaea enriched from deep marine sediments. AB - Ammonia-oxidizing archaea (AOA) are ubiquitous and abundant and contribute significantly to the carbon and nitrogen cycles in the ocean. In this study, we assembled AOA draft genomes from two deep marine sediments from Donghae, South Korea, and Svalbard, Arctic region, by sequencing the enriched metagenomes. Three major microorganism clusters belonging to Thaumarchaeota, Epsilonproteobacteria, and Gammaproteobacteria were deduced from their 16S rRNA genes, GC contents, and oligonucleotide frequencies. Three archaeal genomes were identified, two of which were distinct and were designated Ca. "Nitrosopumilus koreensis" AR1 and "Nitrosopumilus sediminis" AR2. AR1 and AR2 exhibited average nucleotide identities of 85.2% and 79.5% to N. maritimus, respectively. The AR1 and AR2 genomes contained genes pertaining to energy metabolism and carbon fixation as conserved in other AOA, but, conversely, had fewer heme-containing proteins and more copper-containing proteins than other AOA. Most of the distinctive AR1 and AR2 genes were located in genomic islands (GIs) that were not present in other AOA genomes or in a reference water-column metagenome from the Sargasso Sea. A putative gene cluster involved in urea utilization was found in the AR2 genome, but not the AR1 genome, suggesting niche specialization in marine AOA. Co cultured bacterial genome analysis suggested that bacterial sulfur and nitrogen metabolism could be involved in interactions with AOA. Our results provide fundamental information concerning the metabolic potential of deep marine sedimentary AOA. PMID- 24798209 TI - An orthotopic glioblastoma mouse model maintaining brain parenchymal physical constraints and suitable for intravital two-photon microscopy. AB - Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors with no curative treatments available to date. Murine models of this pathology rely on the injection of a suspension of glioma cells into the brain parenchyma following incision of the dura-mater. Whereas the cells have to be injected superficially to be accessible to intravital two-photon microscopy, superficial injections fail to recapitulate the physiopathological conditions. Indeed, escaping through the injection tract most tumor cells reach the extra-dural space where they expand abnormally fast in absence of mechanical constraints from the parenchyma. Our improvements consist not only in focally implanting a glioma spheroid rather than injecting a suspension of glioma cells in the superficial layers of the cerebral cortex but also in clogging the injection site by a cross-linked dextran gel hemi bead that is glued to the surrounding parenchyma and sealed to dura-mater with cyanoacrylate. Altogether these measures enforce the physiological expansion and infiltration of the tumor cells inside the brain parenchyma. Craniotomy was finally closed with a glass window cemented to the skull to allow chronic imaging over weeks in absence of scar tissue development. Taking advantage of fluorescent transgenic animals grafted with fluorescent tumor cells we have shown that the dynamics of interactions occurring between glioma cells, neurons (e.g. Thy1-CFP mice) and vasculature (highlighted by an intravenous injection of a fluorescent dye) can be visualized by intravital two-photon microscopy during the progression of the disease. The possibility to image a tumor at microscopic resolution in a minimally compromised cerebral environment represents an improvement of current GBM animal models which should benefit the field of neuro-oncology and drug testing. PMID- 24798210 TI - Medication monitoring in a nurse-led respiratory outpatient clinic: pragmatic randomised trial of the West Wales Adverse Drug Reaction Profile. AB - OBJECTIVE: To assess the clinical effect of medication monitoring using the West Wales Adverse Drug Reaction (ADR) Profile for Respiratory Medicine. DESIGN: Single-site parallel-arm pragmatic trial using stratified randomisation. SETTING: Nurse-led respiratory outpatient clinic in general hospital in South Wales. PARTICIPANTS: 54 patients with chronic respiratory disease receiving bronchodilators, corticosteroids or leukotriene receptor antagonists. INTERVENTION: Following initial observation of usual nursing care, we allocated participants at random to receive at follow up: either the West Wales ADR Profile for Respiratory Medicine in addition to usual care ('intervention arm' with 26 participants); or usual care alone ('control arm' with 28 participants). MAIN OUTCOME MEASURES: Problems reported and actions taken. RESULTS: We followed up all randomised participants, and analysed data in accordance with treatment allocated. The increase in numbers of problems per participant identified at follow up was significantly higher in the intervention arm, where the median increase was 20.5 [inter-quartile range (IQR) 13-26], while that in the control arm was -1 [-3 to +2] [Mann-Whitney U test: z = 6.28, p<0.001]. The increase in numbers of actions per participant taken at follow up was also significantly higher in the intervention arm, where the median increase was 2.5 [1]-[4] while that in the control arm was 0 [-1.75 to +1] [Mann-Whitney U test: z = 4.40, p<0.001]. CONCLUSION: When added to usual nursing care, the West Wales ADR Profile identified more problems and prompted more nursing actions. Our ADR Profile warrants further investigation as a strategy to optimise medication management. TRIAL REGISTRATION: Controlled-trials.com ISRCTN10386209. PMID- 24798212 TI - Distributional cost-effectiveness analysis of health care programmes--a methodological case study of the UK Bowel Cancer Screening Programme. AB - This paper presents an application of a new methodological framework for undertaking distributional cost-effectiveness analysis to combine the objectives of maximising health and minimising unfair variation in health when evaluating population health interventions. The National Health Service bowel cancer screening programme introduced in 2006 is expected to improve population health on average and to worsen population health inequalities associated with deprivation and ethnicity--a classic case of 'intervention-generated inequality'. We demonstrate the distributional cost-effectiveness analysis framework by examining two redesign options for the bowel cancer screening programme: (i) the introduction of an enhanced targeted reminder aimed at increasing screening uptake in deprived and ethnically diverse neighbourhoods and (ii) the introduction of a basic universal reminder aimed at increasing screening uptake across the whole population. Our analysis indicates that the universal reminder is the strategy that maximises population health, while the targeted reminder is the screening strategy that minimises unfair variation in health. The framework is used to demonstrate how these two objectives can be traded off against each other, and how alternative social value judgements influence the assessment of which strategy is best, including judgements about which dimensions of health variation are considered unfair and judgements about societal levels of inequality aversion. PMID- 24798211 TI - Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. AB - In this review, we focus on the role of oxidative stress in the aetiology of inflammatory bowel diseases (IBD) and colitis-associated colorectal cancer and discuss free radicals and free radical-stimulated pathways as pharmacological targets for anti-IBD drugs. We also suggest novel anti-oxidative agents, which may become effective and less-toxic alternatives in IBD and colitis-associated colorectal cancer treatment. A Medline search was performed to identify relevant bibliography using search terms including: 'free radicals,' 'antioxidants,' 'oxidative stress,' 'colon cancer,' 'ulcerative colitis,' 'Crohn's disease,' 'inflammatory bowel disease.' Several therapeutics commonly used in IBD treatment, among which are immunosuppressants, corticosteroids and anti-TNF-alpha antibodies, could also affect the IBD progression by interfering with cellular oxidative stress and cytokine production. Experimental data shows that these drugs may effectively scavenge free radicals, increase anti-oxidative capacity of cells, influence multiple signalling pathways, e.g. MAPK and NF-kB, and inhibit pro-oxidative enzyme and cytokine concentration. However, their anti-oxidative and anti-inflammatory effectiveness still needs further investigation. A highly specific antioxidative activity may be important for the clinical treatment and relapse of IBD. In the future, a combination of currently used pharmaceutics, together with natural and synthetic anti-oxidative compounds, like lipoic acid or curcumine, could be taken into account in the design of novel anti-IBD therapies. PMID- 24798213 TI - Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer. AB - The purpose was to investigate total cell-free DNA (cfDNA) in colorectal cancer (CRC) patients during treatment with second-line chemotherapy and in healthy controls and patients with different comorbidities. Patient treated with second line irinotecan for metastatic CRC (n = 100), a cohort of healthy controls with and without comorbidity (n = 70 and 100, respectively) were included. cfDNA was quantified by an in-house developed quantitative polymerase chain reaction from plasma samples drawn prior to the first cycle of chemotherapy and at time of progression. cfDNA levels were significantly higher in CRC compared to controls, with a clear capability for discriminating between the groups (receiver operation curve analysis; area under the curve 0.82, p < 0.0001). Patients with high levels had a shorter survival from irinotecan compared to those with lover levels. The cohort independent upper normal limit divided patients into high and low risk groups. The progression-free survival (PFS) was 2.1 months [95% confidence interval (CI) 2.0-3.4] and 6.5 (95% CI 4.2-7.2) months [hazard ratio (HR) 2.53; 95% CI 1.57-4.06, p < 0.0001] and overall survival (OS) 7.4 months (95% CI 4.3 8.7) and 13.8 months (95% CI 11.9-18.9; HR 2.52; 95% CI 1.54-4.13, p < 0.0000), respectively. Cox regression multivariate analysis showed a PFS HR of 1.4 (95% CI 1.1-1.7) for each increase in cfDNA quartile, p = 0.03 and 1.6 (1.3-2.0) for OS, p < 0.0001, respectively. A combined marker analysis with plasma KRAS mutations added further prognostic impact, which was consistent when performed on the samples drawn at time of progression. In conclusion, cfDNA measurement holds important clinical information and could become a useful tool for prediction of outcome from chemotherapy in mCRC. PMID- 24798214 TI - Acute and chronic cadmium exposure promotes E-cadherin degradation in MCF7 breast cancer cells. AB - Cadmium is an environmental carcinogen that usually enters the body at minute concentrations through diet or cigarette smoke and bioaccumulates in soft tissues. In past studies, cadmium has been shown to contribute to the development of more aggressive cancer phenotypes including increased cell migration and invasion. This study aims to determine if cadmium exposure-both acute and chronic contributes to breast cancer progression by interfering with the normal functional relationship between E-cadherin and beta-catenin. An MCF7 breast cancer cell line (MCF7-Cd) chronically exposed to 10(-7) M CdCl2 was previously developed and used as a model system to study chronic exposures, whereas parental MCF7 cells exposed to 10(-6) M CdCl2 for short periods of time were used to study acute exposures. Cadmium exposure of MCF7 cells led to the degradation of the E-cadherin protein via the ubiquitination pathway. This resulted in fewer E cadherin/beta-catenin complexes and the relocation of active beta-catenin to the nucleus, where it interacted with transcription factor TCF-4 to modulate gene expression. Interestingly, only cells chronically exposed to cadmium showed a significant decrease in the localization of beta-catenin to the plasma membrane and an increased distance between cells. Our data suggest that cadmium exposure promotes breast cancer progression by (1) down-regulating E-cadherin, thus decreasing the number of E-cadherin/beta-catenin adhesion complexes, and (2) enhancing the nuclear translocation of beta-catenin to increase expression of cancer-promoting proteins (i.e., c-Jun and cyclin D1). PMID- 24798215 TI - Minor physical anomalies in schizophrenia and bipolar I disorder and the neurodevelopmental continuum of psychosis. AB - OBJECTIVES: Minor physical anomalies (MPAs) have been investigated by numerous studies in patients with schizophrenia in support of the neurodevelopmental hypothesis of the disorder, but have rarely been examined in patients with bipolar disorder or in direct comparisons between the two conditions. The main objective of the present study was to compare the prevalence of MPAs in psychiatrically healthy controls, patients with bipolar I disorder, and patients with schizophrenia. METHODS: A slightly modified version of the Waldrop Physical Anomaly Scale was used to assess MPAs in psychiatrically healthy controls (n = 103), patients with bipolar I disorder (n = 61), and patients with schizophrenia (n = 128). RESULTS: In five out of six topographic regions (mouth, feet, head, eyes, and ears) there was a pattern of lowest regional MPA scores in controls, intermediate in bipolar I disorder, and highest in schizophrenia. The cephalofacial composite score and the total MPA score showed the same pattern, with all between-group differences being statistically significant. Seven individual MPAs in the discriminant analysis model contributed independently to the prediction of the triple-dependent status of 'psychiatrically healthy control, bipolar I disorder patient, schizophrenia patient': high/arched palate, fine electric hair, large gap between first and second toes, third toe >= second toe, epicanthus, malformed ears, and furrowed tongue. CONCLUSIONS: Our findings support the existence of a continuum of neurodevelopmental adversity within the clinical spectrum of psychosis, with bipolar I disorder occupying an intermediate position between psychiatric health and schizophrenia. PMID- 24798216 TI - Robust deep brain stimulation functional MRI procedures in rats and mice using an MR-compatible tungsten microwire electrode. AB - PURPOSE: To develop a series of robust and readily adoptable protocols for the application of deep brain stimulation (DBS)-functional MRI (fMRI) in rodents. METHODS: DBS-fMRI procedures were conducted in rat and mouse under varying anesthetic conditions (isoflurane in rat and mouse, alpha-chloralose in rat). A homemade two-channel tungsten microwire electrode was used to minimize magnetic susceptibility artifacts, and was targeted to the ventral posteromedial (VPM) thalamus for DBS-fMRI scanning procedures. RESULTS: Compared with a commercially available MR-compatible electrode, the tungsten microwire generated greatly reduced magnetic-susceptibility artifacts. In the rat, VPM-DBS using the microwire electrode resulted in robust positive blood-oxygen-level-dependent signal changes in somatosensory cortex that were relatively independent of anesthetic type. In the mouse, VPM-DBS similarly generated large, positive neurovascular responses in somatosensory cortex that were detected using cerebral blood volume measurements. CONCLUSION: Collectively, this work describes reasonable and easily adoptable procedures for conducting DBS-fMRI studies in rodent models. The protocols developed herein may be extended to study DBS effects under numerous experimental conditions and at varying stimulation targets. PMID- 24798217 TI - Pharmacotherapy for tonic-clonic seizures. AB - INTRODUCTION: Occurrence of generalized tonic-clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies. AREAS COVERED: It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used. EXPERT OPINION: Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate. PMID- 24798219 TI - Excessive retinoic acid impaired proliferation and differentiation of human fetal palatal chondrocytes (hFPCs). AB - Chondrocyte proliferation and differentiation is a fundamental process during hard palatogenesis. Excessive retinoic acid (RA), the biologically most active metabolite of vitamin A, has been reported to adversely affect chondrogenesis. The aim of this study was to investigate the mechanisms underlying RA-induced chondrocyte differentiation by using human fetal palatal chondrocytes (hFPCs) aging about 9 weeks of amenorrhea. RA treatment inhibited proliferation and induced apoptosis in hFPCs. Alkaline phosphatase activity assay, quantitative alcian blue staining, and real-time PCR analysis revealed that RA treatment stimulated hFPCs to undergo maturation and terminal differentiation, as demonstrated by decreased chondrogenic markers and increased osteogenic markers. Further studies demonstrated that RA treatment increased Wnt/beta-catenin signaling, as demonstrated by Wnt/beta-catenin target gene expression analysis and a luciferase-based beta-catenin-activated reporter assay. To address the role of Wnt/beta-catenin signaling, we treated hFPCs with Dickkopf-related protein 1, an extracellular inhibitor of Wnt/beta-catenin signaling, and the observed all trans retinoic acid-mediated increases in nuclear accumulation of beta-catenin, alkaline phosphatase activity, and type I collagen mRNA were attenuated, suggesting that RA modulated Wnt signaling at ligand-receptor level. In summary, excessive all-trans retinoic acid inhibited proliferation and promoted ossification of hFPCs by upregulation of Wnt/beta-catenin signaling. PMID- 24798220 TI - Modulation of mouse embryonic stem cell proliferation and neural differentiation by the P2X7 receptor. AB - BACKGROUND: Novel developmental functions have been attributed to the P2X7 receptor (P2X7R) including proliferation stimulation and neural differentiation. Mouse embryonic stem cells (ESC), induced with retinoic acid to neural differentiation, closely assemble processes occurring during neuroectodermal development of the early embryo. PRINCIPAL FINDINGS: P2X7R expression together with the pluripotency marker Oct-4 was highest in undifferentiated ESC. In undifferentiated cells, the P2X7R agonist Bz-ATP accelerated cell cycle entry, which was blocked by the specific P2X7R inhibitor KN-62. ESC induced to neural differentiation with retinoic acid, reduced Oct-4 and P2X7R expression. P2X7R receptor-promoted intracellular calcium fluxes were obtained at lower Bz-ATP ligand concentrations in undifferentiated and in neural-differentiated cells compared to other studies. The presence of KN-62 led to increased number of cells expressing SSEA-1, Dcx and beta3-tubulin, as well as the number of SSEA-1 and beta3-tubulin-double-positive cells confirming that onset of neuroectodermal differentiation and neuronal fate determination depends on suppression of P2X7R activity. Moreover, an increase in the number of Ki-67 positive cells in conditions of P2X7R inhibition indicates rescue of progenitors into the cell cycle, augmenting the number of neuroblasts and consequently neurogenesis. CONCLUSIONS: In embryonic cells, P2X7R expression and activity is upregulated, maintaining proliferation, while upon induction to neural differentiation P2X7 receptor expression and activity needs to be suppressed. PMID- 24798222 TI - Levetiracetam as alternative treatment in Jeavons syndrome. AB - We report on a 25 year old female patient who had a diagnosis of Jeavons syndrome since her childhood. Although valproate led to seizure freedom, she developed persistent reproductive endocrine disorders attributed to this drug. The withdrawal of valproate in parallel with an initiation of levetiracetam monotherapy resulted in a maintenance of clinical remission and a resolution of these abnormalities. This case together with relevant literature data supports the view that the use of levetiracetam might be of benefit for female patients with Jeavons syndrome. PMID- 24798221 TI - Assessment of intramuscular lipid and metabolites of the lower leg using magnetic resonance spectroscopy in boys with Duchenne muscular dystrophy. AB - The purpose of this study was to use proton magnetic resonance spectroscopy to assess intramuscular lipid and metabolites of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) and determine its relationship with strength and functional ability. Spectroscopic measurements were obtained from four muscles of the lower leg in 25 boys with DMD (9.2+/-3.1 years) and 10 healthy boys (10.2+/-2.6 years). Lipid fractions and metabolite concentrations were also determined. Muscle strength, a timed functional test, and the Modified Brooke Lower Extremity Functional Scale were also determined. Lipid fractions were higher (p<0.01) for the DMD group than healthy subjects for all muscles, and lipid fraction was found to be greater in the older DMD boys. The peroneal muscle demonstrated a significant difference in lipid fraction in all DMD age groups. Lipid fractions in all muscles correlated with functional measures (r=0.52-0.70, p<0.001), with smaller inverse correlations with the strength measure (r=-0.36 to -0.56, p<0.05). These findings provide quantifiable information regarding intramuscular lipid and metabolite levels of different muscles across various age groups in boys with DMD and may be used in determining the effect of interventions in future clinical trials. PMID- 24798223 TI - Is acupuncture efficacious therapy in Parkinson's disease? AB - This review aims to assess the evidences from recent clinical studies regarding the efficacy of acupuncture on Parkinson's disease. Relevant literatures were searched from 13 databases under the condition "published between 2000 and 2012" with language restrictions. Eleven studies were indentified including 6 randomized clinical trials (RCTs), 4 uncontrolled open label studies, and 1 crossover trial. The number of trials, and their total sample size were not enough to prove the favorable effects of acupuncture. Five studies failed to report proper diagnostic criteria for enrollment. Two of the 6 RCTs did not include the randomization methods and whether the assessors were blinded. Drop outs were unreported or insufficiently reported in 2 trials. Three RCTs compared the effects of acupuncture with placebo acupuncture. Two of these trials failed to show superiority of acupuncture. One RCT showed beneficial effects of constitutional acupuncture, but not needle acupuncture. Three RCTs that assessed the effects of acupuncture adjunctive to conventional drugs reported beneficial effects of acupuncture. The placebo response to acupuncture was not excluded, because there was no control acupuncture group in these studies. Two uncontrolled studies showed significant positive effects of acupuncture, while other two uncontrolled trials failed. There were no recognized validated acupuncture treatment protocols and a lack of consensus on the location of acupoints. Safety and tolerability were reported only in 5 studies. No study evaluated the long lasting effect of acupuncture following cessation of the treatment. To date, the evidence for the effectiveness of acupuncture for treating Parkinson's disease is not convincing. There are needs for further studies with improved methodological quality. PMID- 24798225 TI - Development of a novel electric field-assisted modified hydrodynamic cavitation system for disintegration of waste activated sludge. AB - In this current study, we present a modified hydrodynamic cavitation device that combines an electric field to substitute for the chemical addition. A modified HC system is basically an orifice plate and crisscross pipe assembly, in which the crisscross pipe imparts some turbulence, which creates collision events. This study shows that for maximizing disintegration, combining HC system, which called electric field-assisted modified orifice plate hydrodynamic cavitation (EFM-HC) in this study, with an electric field is important. Various HC systems were compared in terms of disintegration of WAS, and, among them, the EFM-HC system exhibited the best performance with the highest disintegration efficiency of 47.0+/-2.0% as well as the destruction of WAS morphological characteristics. The experimental results clearly show that a conventional HC system was successfully modified. In addition, electric field has a great potential for efficient disintegration of WAS for as a additional option in a combination treatment. This study suggests continued research in this field may lead to an appropriate design for commercial use. PMID- 24798224 TI - The pattern of brain gray matter impairments in patients with subcortical vascular dementia. AB - Though subcortical ischemic vascular dementia (SIVD) is known to initially affect subcortical regions, numerous brain imaging studies have also documented the widespread cortical alternations. Here we collected brain structural magnetic resonance imaging data from 34 SIVD patients and 35 healthy controls. Voxel-based morphometry (VBM), cortical thickness (and surface area) analysis and deep gray matter volume measurements were performed. VBM analysis showed gray matter volume reduction in lateral and medial temporal lobes, as well as orbitofrontal cortex in SIVD patients. The surface-based analyses revealed more subtle structural differences in the perisylvian area, medial temporal lobe, anterior and posterior cingulate, as well as prefrontal areas. Furthermore, analyses of deep gray matter demonstrated significant atrophy of the hippocampus, amygdala, nucleus accumbens and other nuclei. Finally, we found that thinning in the hippocampus and anterior cingulate cortex, as well as the volume decline in thalamus, caudate nucleus and amygdala was correlated with the cognitive impairment in patients. In conclusion, our study showed the structural abnormalities of the hippocampus and its associated outflow areas, as well as cortices implicated in cholinergic circuits in SIVD. These findings may bring new insights into the dysfunction of brain gray matter in SIVD. PMID- 24798226 TI - Dissolution and reconstitution of casein micelle containing dairy powders by high shear using ultrasonic and physical methods. AB - The effect of shear on the solubilization of a range of dairy powders was investigated. The rate of solubilization of low solubility milk protein concentrate and micellar casein powders was examined during ultrasonication, high pressure homogenization and high-shear rotor-stator mixing and compared to low shear overhead stirring. The high shear techniques were able to greatly accelerate the solubilization of these powders by physically breaking apart the powder agglomerates and accelerating the release of individual casein micelles into solution. This was achieved without affecting the structure of the solubilized proteins. The effect of high shear on the re-establishment of the mineral balance between the casein micelles and the serum was examined by monitoring the pH of the reconstituted skim milk powder after prior exposure to ultrasonication. Only minor differences in the re-equilibration of the pH were observed after sonication for up to 3 min, suggesting that the localized high shear forces exerted by sonication did not significantly affect the mass transfer of minerals from within the casein micelles. PMID- 24798227 TI - Electrochemical investigations of stable cavitation from bubbles generated during reduction of water. AB - Megasonic cleaning is traditionally used for removal of particles from wafer surfaces in semiconductor industry. With the advancement of technology node, the major challenge associated with megasonic cleaning is to be able to achieve high cleaning efficiency without causing damage to fragile features. In this paper, a method based on electrochemistry has been developed that allows controlled formation and growth of a hydrogen bubbles close to a solid surface immersed in an aqueous solution irradiated with ~1 MHz sound field. It has been shown that significant microstreaming from resonating size bubble can be induced by proper choice of transducer duty cycle. This method has the potential to significantly improve the performance of megasonic cleaning technology through generation of local microstreaming, interfacial and pressure gradient forces in close vicinity of conductive surfaces on wafers without affecting the transient cavitation responsible for feature damage. PMID- 24798228 TI - Distribution of electrical energy consumption for the efficient degradation control of THMs mixture in sonophotolytic process. AB - Sonophotolytic degradation of THMs mixture with different electrical energy ratio was carried out for efficient design of process. The total consumed electrical energy was fixed around 50W, and five different energy conditions were applied. The maximum degradation rate showed in conditions of US:UV=1:3 and US:UV=0:4. This is because the photolytic degradation of bromate compounds is dominant degradation mechanism for THMs removal. However, the fastest degradation of total organic carbon was observed in a condition of US:UV=1:3. Because hydrogen peroxide generated by sonication was effectively dissociated to hydroxyl radicals by ultraviolet, the concentration of hydroxyl radical was maintained high. This mechanism provided additional degradation of organics. This result was supported by comparison between the concentration of hydrogen peroxide sole and combined process. Consequently, the optimal energy ratio was US:UV=1:3 for degradation of THMs in sonophotolytic process. PMID- 24798229 TI - Size-selective separation of submicron particles in suspensions with ultrasonic atomization. AB - Aqueous suspensions containing silica or polystyrene latex were ultrasonically atomized for separating particles of a specific size. With the help of a fog involving fine liquid droplets with a narrow size distribution, submicron particles in a limited size-range were successfully separated from suspensions. Performance of the separation was characterized by analyzing the size and the concentration of collected particles with a high resolution method. Irradiation of 2.4MHz ultrasound to sample suspensions allowed the separation of particles of specific size from 90 to 320nm without regarding the type of material. Addition of a small amount of nonionic surfactant, PONPE20 to SiO2 suspensions enhanced the collection of finer particles, and achieved a remarkable increase in the number of collected particles. Degassing of the sample suspension resulted in eliminating the separation performance. Dissolved air in suspensions plays an important role in this separation. PMID- 24798232 TI - Social media in the 2011 Egyptian uprising. AB - This paper uses Gallup poll data to assess two narratives that have crystallized around the 2011 Egyptian uprising: (1) New electronic communications media constituted an important and independent cause of the protests in so far as they enhanced the capacity of demonstrators to extend protest networks, express outrage, organize events, and warn comrades of real-time threats. (2) Net of other factors, new electronic communications media played a relatively minor role in the uprising because they are low-cost, low-risk means of involvement that attract many sympathetic onlookers who are not prepared to engage in high-risk activism. Examining the independent effects of a host of factors associated with high-risk movement activism, the paper concludes that using some new electronic communications media was associated with being a demonstrator. However, grievances, structural availability, and network connections were more important than was the use of new electronic communications media in distinguishing demonstrators from sympathetic onlookers. Thus, although both narratives have some validity, they must both be qualified. PMID- 24798230 TI - Stochastic simulation of notch signaling reveals novel factors that mediate the differentiation of neural stem cells. AB - Notch signaling controls cell fate decisions and regulates multiple biological processes, such as cell proliferation, differentiation, and apoptosis. Computational modeling of the deterministic simulation of Notch signaling has provided important insight into the possible molecular mechanisms that underlie the switch from the undifferentiated stem cell to the differentiated cell. Here, we constructed a stochastic model of a Notch signaling model containing Hes1, Notch1, RBP-Jk, Mash1, Hes6, and Delta. mRNA and protein were represented as a discrete state, and 334 reactions were employed for each biochemical reaction using a graphics processing unit-accelerated Gillespie scheme. We employed the tuning of 40 molecular mechanisms and revealed several potential mediators capable of enabling the switch from cell stemness to differentiation. These effective mediators encompass different aspects of cellular regulations, including the nuclear transport of Hes1, the degradation of mRNA (Hes1 and Notch1) and protein (Notch1), the association between RBP-Jk and Notch intracellular domain (NICD), and the cleavage efficiency of the NICD. These mechanisms overlap with many modifiers that have only recently been discovered to modulate the Notch signaling output, including microRNA action, ubiquitin mediated proteolysis, and the competitive binding of the RBP-Jk-DNA complex. Moreover, we identified the degradation of Hes1 mRNA and nuclear transport of Hes1 as the dominant mechanisms that were capable of abolishing the cell state transition induced by other molecular mechanisms. PMID- 24798233 TI - Mining the genome for lipid genes. AB - Mining of the genome for lipid genes has since the early 1970s helped to shape our understanding of how triglycerides are packaged (in chylomicrons), repackaged (in very low density lipoproteins; VLDL), and hydrolyzed, and also how remnant and low-density lipoproteins (LDL) are cleared from the circulation. Gene discoveries have also provided insights into high-density lipoprotein (HDL) biogenesis and remodeling. Interestingly, at least half of these key molecular genetic studies were initiated with the benefit of prior knowledge of relevant proteins. In addition, multiple important findings originated from studies in mouse, and from other types of non-genetic approaches. Although it appears by now that the main lipid pathways have been uncovered, and that only modulators or adaptor proteins such as those encoded by LDLRAP1, APOA5, ANGPLT3/4, and PCSK9 are currently being discovered, genome wide association studies (GWAS) in particular have implicated many new loci based on statistical analyses; these may prove to have equally large impacts on lipoprotein traits as gene products that are already known. On the other hand, since 2004 - and particularly since 2010 when massively parallel sequencing has become de rigeur - no major new insights into genes governing lipid metabolism have been reported. This is probably because the etiologies of true Mendelian lipid disorders with overt clinical complications have been largely resolved. In the meantime, it has become clear that proving the importance of new candidate genes is challenging. This could be due to very low frequencies of large impact variants in the population. It must further be emphasized that functional genetic studies, while necessary, are often difficult to accomplish, making it hazardous to upgrade a variant that is simply associated to being definitively causative. Also, it is clear that applying a monogenic approach to dissect complex lipid traits that are mostly of polygenic origin is the wrong way to proceed. The hope is that large-scale data acquisition combined with sophisticated computerized analyses will help to prioritize and select the most promising candidate genes for future research. We suggest that at this point in time, investment in sequence technology driven candidate gene discovery could be recalibrated by refocusing efforts on direct functional analysis of the genes that have already been discovered. This article is part of a Special Issue entitled: From Genome to Function. PMID- 24798231 TI - LL-37 concentrations and the relationship to vitamin D, immune status, and inflammation in HIV-infected children and young adults. AB - Antimicrobial peptide LL-37 is produced in response to active vitamin D to exert immunomodulatory effects and inhibits HIV replication in vitro. To date, no studies have investigated LL-37 in HIV-infected patients. This study sought to investigate LL-37 and the relationship to 25-hydroxyvitamin D [25(OH)D] and HIV related variables in this population. HIV-infected subjects and healthy controls ages 1-25 years old were prospectively enrolled in this cross-sectional study. Fasting plasma LL-37 and 25(OH)D concentrations were measured in duplicate with ELISA. HIV(+) subjects (36 antiretroviral therapy (ART)-experienced subjects; 27 ART-naive subjects) and 31 healthy controls were enrolled. Overall, 93% were black and the median age was 20 years. There was no difference in median (interquartile range) LL-37 between the HIV-infected group and controls [58.3 (46.4,69.5) vs. 51.3 (40.8,98.2) ng/ml, respectively; p=0.57]; however, the ART experienced group had higher concentrations than the ART-naive group [66.2 (55.4,77.0) vs. 48.9 (38.9,57.9) ng/ml, respectively; p<0.001]. LL-37 was positively correlated with 25(OH)D in controls, but not in HIV-infected groups, and was positively correlated with current CD4 and DeltaCD4 (current-nadir) in the ART-experienced group. After adjustment for age, race, sex, and HIV duration, the association between LL-37 and CD4 remained significant. These findings suggest that HIV and/or HIV-related variables may alter the expected positive relationship between vitamin D and LL-37 and should be further investigated. PMID- 24798234 TI - Systems genetics: From GWAS to disease pathways. AB - Most common diseases are complex, involving multiple genetic and environmental factors and their interactions. In the past decade, genome-wide association studies (GWAS) have successfully identified thousands of genetic variants underlying susceptibility to complex diseases. However, the results from these studies often do not provide evidence on how the variants affect downstream pathways and lead to the disease. Therefore, in the post-GWAS era the greatest challenge lies in combining GWAS findings with additional molecular data to functionally characterize the associations. The advances in various ~omics techniques have made it possible to investigate the effect of risk variants on intermediate molecular levels, such as gene expression, methylation, protein abundance or metabolite levels. As disease aetiology is complex, no single molecular analysis is expected to fully unravel the disease mechanism. Multiple molecular levels can interact and also show plasticity in different physiological conditions, cell types and disease stages. There is therefore a great need for new integrative approaches that can combine data from different molecular levels and can help construct the causal inference from genotype to phenotype. Systems genetics is such an approach; it is used to study genetic effects within the larger scope of systems biology by integrating genotype information with various ~omics datasets as well as with environmental and physiological variables. In this review, we describe this approach and discuss how it can help us unravel the molecular mechanisms through which genetic variation causes disease. This article is part of a Special Issue entitled: From Genome to Function. PMID- 24798235 TI - Cardiac remodeling associated with protein increase and lipid accumulation in early-stage chronic kidney disease in rats. AB - Chronic kidney disease (CKD) is associated with increased risks of cardiovascular morbidity and mortality. Cardiac remodeling including myocardial fibrosis and hypertrophy is frequently observed in CKD patients. In this study, we investigate the mechanism involved in cardiac hypertrophy associated with CKD using a rat model, by morphological and chemical component changes of the hypertrophic and non-hypertrophic hearts. Sprague-Dawley rats were 4/5 nephrectomized (Nx) at 11 weeks of age and assigned to no treatment and treatment with AST-120, which was reported to affect the cardiac damage, at 18 weeks of age. At 26 weeks of age, the rats were euthanized under anesthesia, and biochemical tests as well as analysis of cardiac condition were performed by histological and spectrophotometric methods. Cardiac hypertrophy and CKD were observed in 4/5 Nx rats even though vascular calcification and myocardial fibrosis were not detected. The increasing myocardial protein was confirmed in hypertrophic hearts by infrared spectroscopy. The absorption of amide I and other protein bands in hypertrophic hearts increased at the same position as in normal cardiac absorption. Infrared spectra also showed that lipid accumulation was also detected in hypertrophic heart. Conversely, the absorptions of protein were obviously reduced in the myocardium of non-hypertrophic heart with CKD compared to that of hypertrophic heart. The lipid associated absorption was also decreased in non-hypertrophic heart. Our results suggest that cardiac remodeling associated with relatively early-stage CKD may be suppressed by reducing increased myocardial protein and ameliorating cardiac lipid load. PMID- 24798236 TI - From genome to function by studying eQTLs. AB - Genome-wide association studies (GWASs) have shown a large number of genetic variants to be associated with complex diseases. The identification of the causal variant within an associated locus can sometimes be difficult because of the linkage disequilibrium between the associated variants and because most GWAS loci contain multiple genes, or no genes at all. Expression quantitative trait locus (eQTL) mapping is a method used to determine the effects of genetic variants on gene expression levels. eQTL mapping studies have enabled the prioritization of genetic variants within GWAS loci, and have shown that trait-associated single nucleotide polymorphisms (SNPs) often function in a tissue- or cell type-specific manner, sometimes having downstream effects on completely different chromosomes. Furthermore, recent RNA-sequencing (RNA-seq) studies have shown that a large repertoire of transcripts is available in cells, which are actively regulated by (trait-associated) variants. Future eQTL mapping studies will focus on broadening the range of available tissues and cell types, in order to determine the key tissues and cell types involved in complex traits. Finally, large meta-analyses will be able to pinpoint the causal variants within the trait-associated loci and determine their downstream effects in greater detail. This article is part of a Special Issue entitled: From Genome to Function. PMID- 24798237 TI - Aberrant methylation and decreased expression of the TGF-beta/Smad target gene FBXO32 in esophageal squamous cell carcinoma. AB - BACKGROUND: F-box protein 32 (FBXO32) (also known as atrogin-1), a member of the F-box protein family, has recently been identified as a transforming growth factor beta (TGF-beta)/Smad target gene involved in regulating cell survival, and it may be transcriptionally silenced by epigenetic mechanisms in some kinds of carcinomas, yet its role in esophageal squamous cell carcinoma (ESCC) has not been defined. METHODS: The role of FBXO32 in ESCC and the correlation of FBXO32 methylation with a series of pathologic parameters were studied in a large cohort of patients with ESCC. RESULTS: Decreased messenger RNA (mRNA) expression and protein expression of FBXO32 were observed in esophageal cancer cell lines, and the silencing of FBXO32 could be reversed by treatment with 5-aza-2' deoxycytidine or trichostatin A in the TE13 cell line. In addition, aberrant methylation of FBXO32 and histone deacetylation was capable of suppressing FBXO32 mRNA and protein expression in TE13 cells. Decreased mRNA and protein expression of FBXO32 was observed in ESCC tumor tissues and was associated with FBXO32 promoter methylation status. A positive correlation between FBXO32 and phosphorylated SMAD family members 2 and 3 expression and Smad4 protein expression also was observed in clinical specimens. FBXO32 methylation status and protein expression were independently associated with survival in patients with ESCC. CONCLUSIONS: FBXO32 may be a functional tumor suppressor. Its inactivation through promoter methylation could play an important role in ESCC carcinogenesis, and reactivation of the FBXO32 gene may have therapeutic potential and might be used as a prognostic marker for patients with ESCC. PMID- 24798238 TI - Molecular mechanisms of ageing and related diseases. AB - Human and other multicellular life species age, and ageing processes become dominant during the late phase of life. Recent studies challenge this dogma, suggesting that ageing does not occur in some animal species. In mammals, cell replicative senescence occurs as early as before birth (i.e. in embryos) under physiological conditions. How the molecular machinery operates and why ageing cells dominate under some circumstances are intriguing questions. Recent studies show that cell ageing involves extensive cellular remodelling, including telomere attrition, heterochromatin formation, endoplasmic reticulum stress, mitochondrial disorders and lysosome processing organelles and chromatins. This article provides an update on the molecular mechanisms underlying the ageing of various cell types, the newly described developmental and programmed replicative senescence and the critical roles of cellular organelles and effectors in Parkinson's disease, diabetes, hypertension and dyskeratosis congenita. PMID- 24798239 TI - Can grey parrots (Psittacus erithacus) succeed on a "complex" foraging task failed by nonhuman primates (Pan troglodytes, Pongo abelii, Sapajus apella) but solved by wrasse fish (Labroides dimidiatus)? AB - Linking specific cognitive abilities of nonhuman species on a laboratory task to their evolutionary history-ecological niche can be a fruitful exercise in comparative psychology. Crucial issues, however, are the choice of task, the specific conditions of the task, and possibly the subjects' understanding or interpretation of the task. Salwiczek et al. (2012) compared cleaner wrasse fish (Labroides dimidaitus) to several nonhuman primate species (capuchins, Sapajus paella; chimpanzees, Pan troglodytes; orangutans, Pongo abelii) on a task purportedly related to the ecological demands of the fish, but not necessarily of the nonhuman primates; fish succeeded whereas almost all of the nonhuman primates that were tested failed. We replicated the two-choice paradigm of the task with three Grey parrots (Psittacus erithacus), whose ecology, evolutionary history, and cortical capacity are arguably more like those of nonhuman primates than fish. Greys succeeded at levels more like fish than all the nonhuman primates, suggesting possible alternative explanations for their success. Fish and nonhuman primate subjects also experienced a reversal of the initial conditions to test for generalization: Greys were similarly tested; they performed more like fish and capuchins (who now succeeded) than the apes (who continued to fail). PMID- 24798240 TI - Preventive care for low-income women in massachusetts post-health reform. AB - BACKGROUND: Before enacting health insurance reform in 2006, Massachusetts provided free breast, cervical cancer, and cardiovascular risk screening for low income uninsured women through a federally subsidized program called the Women's Health Network (WHN). This article examines whether, as women transitioned to insurance to pay for screening tests after health reform legislation was passed, cancer and cardiovascular disease screening changed among WHN participants between 2004 and 2010. METHODS: We examined claims data from the Massachusetts health insurance exchange and chart review data to measure utilization of mammography, Pap smear, and blood pressure screening among WHN participants in five community health centers in greater Boston. We conducted a longitudinal analysis, by insurance type, using generalized estimating equations to examine the likelihood of screening at recommended intervals in the postreform period compared to the prereform period. RESULTS: Pre- and postreform, we found a high prevalence of recommended mammography (86% vs. 88%), Pap smear (88% vs. 89%), and blood pressure screening (87% vs. 91%) that was similar or improved for most women postreform. Screening use differed by insurance type. Recommended mammography screening was statistically significantly increased among women with state-subsidized private insurance (odds ratio [OR] 1.58, p<0.05). Women with unsubsidized private insurance or Medicare had decreased Pap smear use postreform. Although screening prevalence was high, 31% of women required state safety-net funds to pay for screening tests. CONCLUSION: Our results suggest a continued need for safety-net programs to support preventive screening among low income women after implementation of healthcare reform. PMID- 24798241 TI - Sensitive enantioanalysis of beta-blockers via field-amplified sample injection combined with water removal in microemulsion electrokinetic chromatography. AB - In this study, an on-line sample preconcentration technique, field-amplified sample injection combined with water removal by electroosmotic flow (EOF) pump, was applied to realize a highly sensitive chiral analysis of beta-blocker enantiomers by MEEKC. The introduction of a water plug in capillary before the electrokinetic injection provided the effective preconcentration of chiral compounds. And then the water was moving out of the column from the injection end under the effect of the EOF, which avoided dilution of the stacked beta-blocker enantiomers concentration suffering from the presence of water in separation buffer. Moreover, the addition of H3 PO4 and methanol in the sample solution greatly improved the enhancement efficiency further. Under optimized conditions, more than 2700-fold enhancement in sensitivity was obtained for each enantiomer of bupranolol (BU), alprenolol (AL), and propranolol (PRO) via electrokinetic injection. LODs were 0.10, 0.10, 0.12, 0.11, 0.02, and 0.02 ng/mL for S-BU, R-BU, S-AL, R-AL, S-PRO, and R-PRO, respectively. Eventually, the proposed method was successfully applied to the determination of BU, AL, and PRO in serum samples with good recoveries ranging from 93.4 to 98.2%. PMID- 24798242 TI - The comparison of methods for measuring oxidative stress in zebrafish brains. AB - The zebrafish is a versatile model organism with the potential to contribute to our understanding of the molecular pathological mechanisms underlying Alzheimer's disease (AD). An early characteristic of AD brain pathology is lipid peroxidation resulting from oxidative stress. However, changes in lipid peroxidation have not yet been assessed in zebrafish brains, and an earlier attempt to observe changes in F2-isoprostane levels in the brains of zebrafish exposed to hypoxia was unsuccessful. In this article, we examine the utility of various assays of lipid peroxidation and more general assays of intracellular oxidative stress to detect the changes in oxidative stress in the brains of adult zebrafish exposed to hypoxia or explanted into a sodium azide solution for chemical mimicry of hypoxia. Levels of F2-isoprostanes and F4-neuroprostanes were low and variable in zebrafish brains such that statistically significant changes due to hypoxia or chemical mimicry of hypoxia could not be observed. However, measurement of lipid hydroperoxides did reveal significant changes in lipid peroxidation under these conditions, while analyses of catalase gene expression and an assay based on 2',7'-dicholorofluorescein oxidation also revealed changes in oxidative stress levels. PMID- 24798243 TI - New proteomic insights on the role of NPR-A in regulating self-renewal of embryonic stem cells. AB - Embryonic stem cells (ESCs) have the ability to self-renew indefinitely and they can give unlimited source of cells and tissues for cellular therapies. Recently, the natriuretic peptide receptor A (NPR-A) has been recognized as an important regulator for the self-renewal of ESCs. To gain insights into possible novel mechanisms involved in NPR-A pathway that presumably regulates self-renewal and survival of ESCs, we utilized a comprehensive label-free proteomics technology in our study. Targeting of NPR-A gene with small interfering RNA (siRNA) resulted in the inhibition of ESCs self-renewal. Coherently, quantitative label-free shotgun proteomic analysis identified differentially expressed proteins involved in several biological processes, including cell cycle regulation, cell proliferation, cell fate specification, and apoptosis. Interestingly, in addition to Oct4 Nanog, and Sox2, other proteins involved in ESCs self-renewal were down regulated after NPR-A knockdown, such as heterogeneous nuclear ribonucleoprotein A2/B1 (ROA2), non-POU domain-containing octamer-binding protein (Nono), nucleoplasmin (Npm1), histone H2A type 1-B/E (histone H2A.2), SW1/SNF complex (Brg1), polycomb protein Suz12 (Suz12), and cyclin-dependent kinase 4 (Cdk4). Furthermore, several protein candidates involved in early differentiation and cell death were up-regulated or down-regulated as a result of NPR-A knockdown, including importin subunit alpha-4 (Impalpha4), importin-5 (Ipo5), H3 histones, core histone macro-H2A.1 (H2A.y), apurine/apyrimidine endonuclease 1 (Apex1), 78 kDa glucose-regulated protein (Grp78), and programmed cell death 5 (Pdcd5). Overall, these findings depict a comprehensive view to our understanding of the pathways involved in the role of NPR-A in maintaining ESC functions. PMID- 24798244 TI - Multiple sclerosis: the elevated antibody response to Epstein-Barr virus primarily targets, but is not confined to, the glycine-alanine repeat of Epstein Barr nuclear antigen-1. AB - Patients with multiple sclerosis (MS) have elevated antibodies against Epstein Barr virus (EBV), but data on the epitope-resolved specificity of these antibodies are scarce. Using a peptide microarray containing 1465 peptides representing 8 full-length EBV proteins, we identified higher (p<0.001) antibody reactivities to 39 EBV-peptides in MS patients (n=29) compared to healthy controls (n=22). Seventeen of the 39 peptides were from EBNA-1 and 13 located within the glycine-alanine repeat of EBNA-1. Further reactivities were directed against EBNA-3, EBNA-4, EBNA-6, VP26, and LMP1. Thus, antibodies against EBV in MS patients primarily target, but are not confined to, the glycine-alanine repeat of EBNA-1. PMID- 24798245 TI - Two years' outcome of acute mania in bipolar disorder: different effects of age and age of onset. AB - BACKGROUND: Information about differences between younger and older patients with bipolar disorder and between older patients with early and late age of onset of illness during long-term treatment is scarce. OBJECTIVES: This study aimed to investigate the differences in treatment and treatment outcome between older and younger manic bipolar patients and between early-onset bipolar (EOB) and late onset bipolar (LOB) older patients. METHOD: The European Mania in Bipolar Longitudinal Evaluation of Medication study was a 2-year prospective, observational study in 3459 bipolar patients on the treatment and outcome of patients with an acute manic or mixed episode. Patients were assessed at 6, 12, 18, and 24 months post-baseline. We calculated the number of patients with a remission, recovery, relapse, and recurrence and the mean time to achieve this. RESULTS: Older patients did not differ from younger bipolar patients in achieving remission and recovery or suffering a relapse and in the time to achieve this. However, more older patients recurred and in shorter time. Older patients used less atypical antipsychotics and more antidepressants and other concomitant psychiatric medication. Older EOB and LOB patients did not differ in treatment, but more older LOB patients tended to recover than older EOB patients. CONCLUSION: Older bipolar manic patients did not differ from younger bipolar patients in short-term treatment outcome (remission and recovery), but in the long term, this may be more difficult to maintain. Distinguishing age groups in bipolar study populations may be useful when considering treatment and treatment outcome and warrants further study. PMID- 24798246 TI - Relationship education for stepcouples reporting relationship instability- evaluation of the Smart Steps: Embrace the Journey curriculum. AB - Smart Steps: Embrace the Journey is a research-based educational curriculum for stepfamily couples ("stepcouples"). The curriculum is designed to build couple strengths while addressing the unique challenges of repartnering with a child or children from a previous relationship. This study evaluated the effectiveness of this curriculum with 151 individuals in relationally less stable stepcouple relationships who either engaged in the Smart Steps curriculum (n = 97) or were part of the comparison group (n = 54). This study represents methodological and conceptual advances in the study of stepfamily programs with the use of a comparison group, a racially and economically diverse sample, and a relationally at-risk population. Results indicated that those who participated in Smart Steps reported significant increases in individual empowerment, couple quality, family harmony, and parenting efficacy while these measures were unchanged for those who did not receive the program. Implications for future research and for practitioners are provided. PMID- 24798248 TI - Co nanodot arrays grown on a GdAu2 template: substrate/nanodot antiferromagnetic coupling. AB - Controlling anisotropy and exchange coupling in patterned magnetic nanostructures is the key for developing advanced magnetic storage and spintronic devices. We report on the antiferromagnetic interaction between a Co nanodot array and its supporting GdAu2 nanotemplate that induces large anisotropy values in individual Co nanodots. In clear contrast with nonmagnetic Au substrates, GdAu2 triggers an earlier switch from out-of-plane anisotropy in monatomic high dots to in-plane when the dot height becomes biatomic. PMID- 24798249 TI - Trends of isolation of intrinsically resistant to colistin Enterobacteriaceae and association with colistin use in a tertiary hospital. AB - The objective of this investigation was to evaluate the association between colistin consumption and the isolation of intrinsically resistant to colistin Enterobacteriaceae (IRCE) in a university hospital in Crete, Greece. The database of the microbiological laboratory was reviewed retrospectively during 2006-2010. All positive cultures for IRCE were retrieved. We assessed the total consumption of colistin in medical, surgical, and intensive care units (ICUs). A total of 1,304 single-patient IRCE isolates were recorded. Of these, 466 (35.7%) were hospital-acquired, while 838 (64.3%) were community-acquired. Proteus spp. accounted for 72% of them, Serratia spp. for 16.6%, Morganella morganii for 8.4%, and Providencia spp. for 3%. Urine (44.8%), pus (20.4%), and lower respiratory tract specimens (12.8%) accounted for the majority of specimens. IRCE isolated during the first half (2006 to 1st semester of 2008) and second half (2nd semester of 2008 to 2010) of the study period accounted for 5.8% and 7.4% of Gram negative isolates, respectively (p < 0.001). Colistin consumption was not different in the two periods in the hospital, but in the ICU, it was higher in the second half of the study period (p = 0.013). Colistin consumption was associated with the isolation of hospital-acquired IRCE (p = 0.037); a trend was noted between colistin consumption and the isolation of IRCE in the ICU (p = 0.057). In this study, colistin consumption was associated with the isolation of hospital-acquired IRCE. The use of colistin increased in the ICU during the study period. Prudent use of colistin is essential for the prevention of nosocomial outbreaks due to resistant IRCE. PMID- 24798251 TI - Improved pregnancy and birth rates with routine application of nonsurgical embryo transfer. AB - Nonsurgical embryo transfer (NSET) of blastocysts to pseudopregnant female recipients provides many benefits over surgical implantation with less distress for the mice, no anesthesia or analgesia required and a considerable reduction in implantation time per mouse. Although a disposable device to perform NSET is on the market since 2009, it is not generally used in transgenic facilities, most likely because surgical implantation is efficient and inexpensive. Here, we report that with several refinements to the original protocol, the NSET method becomes very attractive and outperforms the traditional surgical transfer on basis of pregnancy rate, birth rate and implantation-related discomfort. Furthermore, repeated use of the same NSET device on several recipient females reduces the costs to a reasonable level. The data presented covers all embryo transfers over the last 5 years at the transgenic facility of the Netherlands Cancer Institute, of which the last 2 years were performed exclusively with NSET. PMID- 24798250 TI - Healthcare workers as vectors of infectious diseases. AB - Nosocomial infections cause considerable morbidity and mortality. Healthcare workers (HCWs) may serve as vectors of many infectious diseases, many of which are not often primarily considered as healthcare-associated. The probability of pathogen transmission to patients depends on several factors, such as the characteristics of a pathogen, HCW and patient. Pathogens with high transmission potential from HCWs to patients include norovirus, respiratory infections, measles and influenza. In contrast, human immunodeficiency virus (HIV) and viral hepatitis are unlikely to be transferred. The prevention of HCW-associated transmission of pathogens include systematic vaccinations towards preventable diseases, continuous education, hand hygiene surveillance, active feedback and adequate staff resources. PMID- 24798252 TI - Faggot cells in a non-promyelocytic acute myeloid leukemia. PMID- 24798253 TI - Volatile gas consumption after introduction of the Drager Zeus(r) anesthesia machine. PMID- 24798254 TI - Brief review: pain management for cancer survivors: challenges and opportunities. AB - PURPOSE: As the number of cancer survivors continues to increase due to advances in medicine, many cancer survivors remain on their same pain management regimen long after their cancer treatment has been completed. Thus, the purpose of this review is to encourage awareness of the challenges and opportunities of pain management in cancer survivorship. It is our expectation that these patients will be referred to pain medicine specialists so their pain management can be optimized during the period of survivorship and ultimately improve their quality of life. PRINCIPAL FINDINGS: Cancer and its treatment can cause significant pain which requires multidrug therapy, including strong analgesics such as opioids. Optimal pain management has been shown to improve the quality of life of cancer patients, and that is also true for cancer survivors. Nevertheless, the appropriate use of pain medications, especially opioids, must be re-evaluated and adjusted during treatment as the patient transitions into survivorship care and thereafter. This may otherwise result in unnecessary opioid use or may even lead to abuse. Fortunately, as cancer treatment is completed and the survivorship period begins, pain improves gradually and the need for pain medication should decrease. Unfortunately, some patients continue to take their potent analgesics during the period of survivorship although it may not be necessary. It is a challenge for pain practitioners who do not see these patients early in their disease or in the recovery period. Nevertheless, this challenge presents an opportunity for pain management providers to educate oncologists to refer cancer survivors to pain centres early during the period of their survivorship. Cancer survivors could then receive optimal care and maintain a better quality of life without having to take unnecessary pain medications. CONCLUSIONS: It is clear that there is a need to improve pain management in cancer patients, particularly in cancer survivors. Pain physicians should play a critical role as part of a multidisciplinary team that cares not only for cancer patients but also for cancer survivors. Optimizing pain management during the cancer survivorship period results in a better quality of life. PMID- 24798255 TI - Intermittent bolus via infraclavicular nerve catheter using a catheter-over needle technique in a pediatric patient. PMID- 24798256 TI - Optimizing the approach to pain, agitation, and delirium in critical care. PMID- 24798257 TI - Iridium-catalysed borylation of sterically hindered C(sp3)-H bonds: remarkable rate acceleration by a catalytic amount of potassium tert-butoxide. AB - The C(sp(3))-H bonds located on the methyl groups of an isopropyl group participate in iridium-catalysed C-H borylation with bis(pinacolato)diboron via a significant rate acceleration caused by a catalytic amount of t-BuOK. PMID- 24798258 TI - Do not add to the stress: is paracetamol prescription well tolerated by children? PMID- 24798259 TI - Anatomical dissections are not obsolete. Cadaver studies can still provide important information for regional anaesthesia. PMID- 24798260 TI - Therapeutic hypothermia after cardiac arrest without return of consciousness: skating on thin ice. PMID- 24798261 TI - Water temperatures influence the marine area use of Salvelinus alpinus and Salmo trutta. AB - The migratory behaviour and spatial area use of sympatric Arctic charr Salvelinus alpinus and brown trout Salmo trutta were investigated during their marine feeding migration. The likelihood of finding individuals of both species in the inner or outer fjord areas was dependent on water temperature in the inner area (especially for S. alpinus), the temperature difference between the inner and outer areas (especially for S. trutta) and fish fork length (both species). The strongest predictor was the water temperature in the inner area, and particularly S. alpinus left this area and moved to the outer areas with increasing temperatures in the inner area. At 8 degrees C in the inner area, the likelihood of finding S. alpinus in the outer areas was >50%. This predictor had a smaller effect on S. trutta, and the likelihood of finding S. trutta in the outer areas only started to increase at around 14 degrees C. The relationships between temperature and area use did not correspond to the species' optimal growth temperatures, but to their previously documented temperature preferences. Individuals of both species used mainly the littoral fjord areas, and to a lesser extent the pelagic areas. In conclusion, temperature differences between the inner and outer marine areas probably resulted in the segregated area use between the species, because water temperatures or factors influenced by temperature affected their migratory behaviour and habitat use differently. The results indicate that increased marine temperatures with global warming may lead to increased spatial overlap between S. trutta and S. alpinus, which again may lead to increased interspecific competition during their marine phase, and with S. alpinus probably being the more negatively affected. PMID- 24798262 TI - Use of botulinum toxin type A in the management of neonatal brachial plexus palsy. AB - OBJECTIVE: To evaluate functional outcomes and the impact on surgical interventions after the use of botulinum neurotoxin type A (BoNT-A) for muscle imbalance, cocontractions, or contractures with neonatal brachial plexus palsy. DESIGN: A retrospective cohort study. SETTING: A brachial plexus center in a tertiary children's hospital. PARTICIPANTS: Fifty-nine patients with neonatal brachial plexus palsy (75 injection procedures, 91 muscles and/or muscle groups) received BoNT-A injections (mean age at injection, 36.2 months; range, 6-123 months; 31 boys; 30 right-sided injuries, 28 left-sided injuries, 1 bilateral injury). METHODS: Data collected retrospectively from medical records, from procedure notes and clinic visits before BoNT-A use, at <=6 months follow-up (BoNT-A active [BA]) and at >=7 months follow-up (BoNT-A not active [BNA]) included demographics, injection indication, side, and site(s), previous surgical history, occupational therapy and/or physical therapy plan, and outcome measurements. MAIN OUTCOME MEASUREMENTS: Outcomes assessed before and after injections included active and passive range of motion, Mallet and Toronto scores, parent comments about arm function, preinjection surgical considerations, and postinjection surgical history. RESULTS: Injection procedures included 51 to shoulder internal rotators, 15 triceps, 15 pronator teres, 9 biceps, and 1 flexor carpi ulnaris. Active and passive shoulder external rotation (SER) range of motion improved after shoulder internal rotator injections (P = .0003 and P = .002, respectively), as did Mallet scores with BA; the latter were sustained with BNA. Surgical intervention was averted, modified, or deferred after BoNT-A in 45% (n = 20) under surgical consideration before BoNT-A. Active elbow flexion improved in 67% (P = .005), sustained BNA (P = .004) after triceps injections; 2 of 7 patients averted surgery. Active supination improved with BA (P = .002), with gains sustained BNA (P = .016). Passive elbow extension improved after biceps injections by an average 17 degrees (P = .004) BA, although not sustained BNA. CONCLUSIONS: BoNT-A is an effective adjunct to therapy and surgery in managing muscle imbalance, cocontractions, and contractures in neonatal brachial plexus palsy. Use of BoNT-A can result in averting, modifying, or deferring surgical interventions in a number of affected children. PMID- 24798263 TI - Activity Limitation Stages empirically derived for Activities of Daily Living (ADL) and Instrumental ADL in the U.S. Adult community-dwelling Medicare population. AB - BACKGROUND: Stages quantify severity like conventional measures but further specify the activities that people are still able to perform without difficulty. OBJECTIVE: To develop Activity Limitation Stages for defining and monitoring groups of adult community-dwelling Medicare beneficiaries. DESIGN: Cross sectional. SETTING: Community. PARTICIPANTS: There were 14,670 respondents to the 2006 Medicare Current Beneficiary Survey. METHODS: Stages were empirically derived for the Activities of Daily Living (ADLs) and the Instrumental Activities of Daily Living (IADLs) by profiling the distribution of performance difficulties as reported by beneficiaries or their proxies. Stage prevalence estimates were determined, and associations with demographic and health variables were examined for all community-dwelling Medicare beneficiaries. MAIN OUTCOME MEASUREMENTS: ADL and IADL stage prevalence. RESULTS: Stages (0-IV) define 5 groups across the separate ADL and IADL domains according to hierarchically organized profiles of retained abilities and difficulties. For example, at ADL-I, people are guaranteed to be able to eat, toilet, dress, and bathe/shower without difficulty, whereas they experience limitations getting in and out of bed or chairs and/or difficulties walking. In 2006, an estimated 6.0, 2.9, 2.2, and 0.5 million beneficiaries had mild (ADL-I), moderate (ADL-II), severe (ADL-III), and complete (ADL-IV) difficulties, respectively, with estimates for IADL stages even higher. ADL and IADL stages showed expected associations with age and health-related concepts, supporting construct validity. Stages showed the strongest associations with conditions that impair cognition. CONCLUSIONS: Stages as aggregate measures reveal the ADLs and IADLs that people are still able to do without difficulty, along with those activities in which they report having difficulty, consequently emphasizing how groups of people with difficulties can still participate in their own lives. Over the coming decades, stages applied to populations served by vertically integrated clinical practices could facilitate large-scale planning, with the goal of maximizing personal autonomy among groups of community-dwelling people with disabilities. PMID- 24798264 TI - Identifying determinants of effective complementary feeding behaviour change interventions in developing countries. AB - As stunting moves to the forefront of the global agenda, there is substantial evidence that behaviour change interventions (BCI) can improve infant feeding practices and growth. However, this evidence has not been translated into improved outcomes on a national level because we do not know enough about what makes these interventions work, for whom, when, why, at what cost and for how long. Our objective was to examine the design and implementation of complementary feeding BCI, from the peer-reviewed literature, to identify generalisable key determinants. We identified 29 studies that evaluated BCI efficacy or effectiveness, were conducted in developing countries, and reported outcomes on infant and young children aged 6-24 months. Two potential determinants emerged: (1) effective studies used formative research to identify cultural barriers and enablers to optimal feeding practices, to shape the intervention strategy, and to formulate appropriate messages and mediums for delivery; (2) effective studies delineated the programme impact pathway to the target behaviour change and assessed intermediary behaviour changes to learn what worked. We found that BCI that used these developmental and implementation processes could be effective despite heterogeneous approaches and design components. Our analysis was constrained, however, by the limited published data on how design and implementation were carried out, perhaps because of publishing space limits. Information on cost-effectiveness, sustainability and scalability was also very limited. We suggest a more comprehensive reporting process and a more strategic research agenda to enable generalisable evidence to accumulate. PMID- 24798265 TI - Dried blood spots allow targeted screening to diagnose mucopolysaccharidosis and mucolipidosis. AB - BACKGROUND: As patients with different types of mucopolysaccharidosis (MPS) and mucolipidosis (ML) may present with overlapping clinical features - including coarse face, hepatosplenomegaly, bone dysplasia and claw-hand deformities, collectively also called 'MPS-like phenotype', enzymatic and/or molecular genetic analyses are indispensable for accurate diagnosis and applying specific therapy. In this prospective study, we screened patients with symptoms compatible with MPS for MPS I, II (males) and VI. METHODS: Dried blood spots/specimens (DBS) were collected from 200 patients with an MPS-like phenotype and analysed for activities of alpha-iduronidase (IDUA), iduronate-2-sulphatase (IDS), and arylsulphatase B (ARSB), the enzymes deficient in mucopolysaccharidosis (MPS) type I, II and VI, respectively. For the samples with pathologic enzyme activity, mutational analysis was carried out using the same DBS. RESULTS: Based on enzymatic analysis of 200 DBS samples, a total of 45 (22.5%) showed low activity; 17 for MPS I (8.5%), 11 for MPS II (5.5%) and 9 for MPS VI (4.5%). Enzyme activities were suggestive for ML II/III in 8 (4.0%) cases. For 41 (91.1%) samples, DNA could be extracted from the filter paper. Mutations were identified in 11 (64.7%), 11 (100%), 9 (100%) and 5 (62.5%) patients putatively diagnosed biochemically with MPS I, II, VI, and ML II/III, respectively. CONCLUSIONS: DBS enzymatic analysis can be used to diagnose MPS/ML. Initial results should be confirmed by a second enzyme assay and/or by molecular genetic testing. Given the advantages of DBS over other sample types in terms of ease of collection, storage and transportation, DBS are particularly useful for screening patients with an MPS-like phenotype in regions lacking specialised laboratories. In order to ascertain the diagnosis in a large number of cases, patients should be assessed in parallel for at least MPS I, II and VI. PMID- 24798266 TI - Carnitine Profile and Effect of Suppletion in Children with Renal Fanconi Syndrome due to Cystinosis. AB - BACKGROUND: Cystinosis is an autosomal recessive disorder marked by intralysosomal cystine accumulation. Patients present with generalized proximal tubular dysfunction called renal Fanconi syndrome. Urinary carnitine loss results in plasma and muscle carnitine deficiency, but no clinical signs of carnitine deficiency have been described. Also, the optimal dose of carnitine supplementation is undefined. This study aimed to determine whether currently recommended carnitine doses result in adequate correction of plasma carnitine. METHODS: Five cystinosis patients with renal Fanconi syndrome, aged 2-18 years, were included. L-carnitine was prescribed 50 mg/kg/day since diagnosis: median 36 (range 18-207) months. Total and free plasma and urine carnitine and carnitine profiles were measured at study onset, after stopping L-carnitine for 3 months and 3 months after reintroducing L-carnitine 50 mg/kg/day. RESULTS: At study onset, plasma free carnitine was normal in all patients, total carnitine (1/5), acetylcarnitine (3/5), and several short- and medium-chain acylcarnitines <=10 carbons (5/5) were increased indicating carnitine over-supplementation. Three months after cessation, carnitine profiles normalized and 3/5 patients showed plasma carnitine deficiency. Three months after reintroduction, plasma free carnitine normalized in all patients, however, carnitine profiles were disturbed in 4/5 patients. Urine free carnitine, acetylcarnitine, and acylcarnitines <=10 carbons were increased in all patients independent of carnitine supplementation. CONCLUSION: Administration of recommended doses L-carnitine (50 mg/kg/day) resulted in over-supplementation. Although the drug is considered to be rather safe, long-term effects of over-supplementation remain unknown warranting cautious use of high doses. Plasma carnitine profile might be used as a monitor, to prevent overdosing. PMID- 24798267 TI - Impact of different antimicrobial therapies on clinical and fiscal outcomes of patients with bacteremia due to vancomycin-resistant enterococci. AB - Vancomycin-resistant enterococci (VRE) are a growing health problem, and uncertainties exist regarding the optimal therapy for bloodstream infection due to VRE. We conducted systematic comparative evaluations of the impact of different antimicrobial therapies on the outcomes of patients with bloodstream infections due to VRE. A retrospective study from January 2008 to October 2010 was conducted at Detroit Medical Center. Unique patients with blood cultures due to VRE were included and reviewed. Three major therapeutic classes were analyzed: daptomycin, linezolid, and beta-lactams. Three multivariate models were conducted for each outcome, matching for a propensity score predicting the likelihood of receipt of one of the therapeutic classes. A total of 225 cases of bacteremia due to VRE were included, including 86 (38.2%) cases of VR Enterococcus faecalis and 139 (61.8%) of VR Enterococcus faecium. Bacteremia due to VR E. faecalis was more frequent among subjects treated with beta-lactams than among those treated with daptomycin or linezolid. The median dose of daptomycin was 6 mg/kg of body weight (range, 6 to 12 mg/kg). After controlling for propensity score and bacteremia due to VR E. faecalis, differences in mortality were nonsignificant among the treatment groups. Therapy with daptomycin was associated with higher median variable direct cost per day than that for linezolid. This large study revealed the three therapeutic classes (daptomycin, linezolid, and beta-lactams) are similarly efficacious in the treatment of bacteremia due to susceptible strains of VRE. PMID- 24798268 TI - Aerosol phage therapy efficacy in Burkholderia cepacia complex respiratory infections. AB - Phage therapy has been suggested as a potential treatment for highly antibiotic resistant bacteria, such as the species of the Burkholderia cepacia complex (BCC). To address this hypothesis, experimental B. cenocepacia respiratory infections were established in mice using a nebulizer and a nose-only inhalation device. Following infection, the mice were treated with one of five B. cenocepacia-specific phages delivered as either an aerosol or intraperitoneal injection. The bacterial and phage titers within the lungs were assayed 2 days after treatment, and mice that received the aerosolized phage therapy demonstrated significant decreases in bacterial loads. Differences in phage activity were observed in vivo. Mice that received phage treatment by intraperitoneal injection did not demonstrate significantly reduced bacterial loads, although phage particles were isolated from their lung tissue. Based on these data, aerosol phage therapy appears to be an effective method for treating highly antibiotic-resistant bacterial respiratory infections, including those caused by BCC bacteria. PMID- 24798269 TI - Pediatric infection and intestinal carriage due to extended-spectrum cephalosporin-resistant Enterobacteriaceae. AB - The objective of this study is to describe the epidemiology of intestinal carriage with extended-spectrum-cephalosporin-resistant Enterobacteriaceae in children with index infections with these organisms. Patients with resistant Escherichia coli or Klebsiella bacteria isolated from the urine or a normally sterile site between January 2006 and December 2010 were included in this study. Available infection and stool isolates underwent phenotypic and molecular characterization. Clinical data relevant to the infections were collected and analyzed. Overall, 105 patients were identified with 106 extended-spectrum cephalosporin-resistant E. coli (n = 92) or Klebsiella (n = 14) strains isolated from urine or a sterile site. Among the 27 patients who also had stool screening for resistant Enterobacteriaceae, 17 (63%) had intestinal carriage lasting a median of 199 days (range, 62 to 1,576). There were no significant differences in demographic, clinical, and microbiological variables between those with and those without intestinal carriage. Eighteen (17%) patients had 37 subsequent resistant Enterobacteriaceae infections identified: 31 urine and 6 blood. In a multivariable analysis, antibiotic intake in the 91 days prior to subsequent urine culture was significantly associated with subsequent urinary tract infection with a resistant organism (hazard ratio, 14.3; 95% confidence interval [CI], 1.6 to 130.6). Intestinal carriage and reinfection were most commonly due to bacterial strains of the same sequence type and with the same resistance determinants as the index extended-spectrum-cephalosporin-resistant Enterobacteriaceae, but carriage and reinfection with different resistant Enterobacteriaceae strains also occurred. PMID- 24798271 TI - In vivo assessment of drug efficacy against Mycobacterium abscessus using the embryonic zebrafish test system. AB - Mycobacterium abscessus is responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of the in vivo therapeutic efficacy of the few potentially active antibiotics against M. abscessus was essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring the in vivo activity of drugs against acute M. abscessus infection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescent M. abscessus-infected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare the in vivo activity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of the in vivo drug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds against M. abscessus. PMID- 24798270 TI - Surveillance of carbapenem-resistant Klebsiella pneumoniae: tracking molecular epidemiology and outcomes through a regional network. AB - Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either blaKPC-2 (48%) or blaKPC-3 (51%). One isolate tested positive for blaNDM-1, a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with blaKPC-3 (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants. PMID- 24798272 TI - Linezolid-induced lactic acidosis in two liver transplant patients with the mitochondrial DNA A2706G polymorphism. AB - Mitochondrial toxicity has been recently suggested to be the underlying mechanism of long-term linezolid-associated toxicity in patients with 16S rRNA genetic polymorphisms. Here, we report for the first time two cases of lactic acidosis due to long-term linezolid exposure in liver transplant recipients who presented an A2706G mitochondrial DNA polymorphism. PMID- 24798273 TI - Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium. AB - Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin resistant (VR) E. faecalis (ATCC 700802), VS Enterococcus faecium (ATCC 6569), and VR E. faecium (ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10(-8) to <10(-9)) for surotomycin at 16 and 32* the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 MUg/ml surotomycin (final MICs of 2 to 8 MUg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 MUg/ml (final MICs of 8 to 32 MUg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 MUg/ml surotomycin (final MICs of 2 to 16 MUg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20* MIC demonstrated equally rapid bactericidal activity (>= 3-log-unit reduction in CFU/ml in <= 8 h) against naive and reduced-susceptibility isolates of C. difficile, VS Enterococcus (VSE), and VR Enterococcus (VRE), except for C. difficile BK (2.6 log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile, E. faecalis, and E. faecium is likely to be rare. PMID- 24798274 TI - Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. AB - Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a >= 10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87 1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility. PMID- 24798275 TI - Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas. AB - New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treatment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains of Mycobacterium tuberculosis. Recently, there has been renewed interest in clofazimine (CFZ). In this study, we utilized the C3HeB/FeJ mouse model, possessing highly organized, hypoxic pulmonary granulomas with caseous necrosis, to evaluate CFZ monotherapy in comparison to results with BALB/c mice, which form only multifocal, coalescing cellular aggregates devoid of caseous necrosis. While CFZ treatment was highly effective in BALB/c mice, its activity was attenuated in the lungs of C3HeB/FeJ mice. This lack of efficacy was directly related to the pathological progression of disease in these mice, since administration of CFZ prior to the formation of hypoxic, necrotic granulomas reconstituted bactericidal activity in this mouse strain. These results support the continued use of mouse models of tuberculosis infection which exhibit a granulomatous response in the lungs that more closely resembles the pathology found in human disease. PMID- 24798276 TI - Sheltering effect and indirect pathogenesis of carbapenem-resistant Acinetobacter baumannii in polymicrobial infection. AB - The role of carbapenem-resistant Acinetobacter baumannii (CRAb) in polymicrobial infection remains elusive. Having observed the ability of CRAb to shelter other susceptible bacteria from carbapenem killing, we sought to determine the factors contributing to this sheltering effect by transforming different recombinant plasmids into recipient A. baumannii cells. The sheltering effects of CRAb were reproduced in recipient A. baumannii cells that highly expressed carbapenem hydrolyzing class D beta-lactamases (CHDLs) through their associated strong promoter. With the use of Western blot analysis and a bioassay, the highly expressed CHDLs were found to be extracellularly released and led to hydrolysis of carbapenem. The level of extracellular CHDLs increased after challenge with a higher concentration of CHDL substrates, such as carbapenem and ticarcillin. This increased CHDL may, in part, be attributed to cell lysis, as indicated by the presence of extracellular gyrase. In the planktonic condition, the sheltering effect for the cocultured susceptible bacteria might represent an indirect and passive effect of the CRAb self-defense mechanism, because coculture with the susceptible pathogen did not augment the amount of the extracellular CHDLs. Polymicrobial infection caused by CRAb and a susceptible counterpart exerted higher pathogenicity than monomicrobial infection caused by either pathogen alone in mice receiving carbapenem therapy. This study demonstrated that CHDL-producing CRAb appears to provide a sheltering effect for carbapenem-susceptible pathogens via the extracellular release of CHDLs and, by this mechanism, can enhance the pathogenesis of polymicrobial infection in the presence of carbapenem therapy. PMID- 24798277 TI - Randomized, double-blind, multicenter safety and efficacy study of rifalazil compared with azithromycin for treatment of uncomplicated genital Chlamydia trachomatis infection in women. AB - A randomized, double-blind study comparing single-dose chlamydia therapies of oral rifalazil (25 mg) and azithromycin (1 g) was conducted in 82 women with uncomplicated genital Chlamydia trachomatis infection. The microbiologic cure rate of C. trachomatis with rifalazil (n = 33) was 84.8% at the visit on day 22 to 26 (test-of-cure visit), versus 92.1% with azithromycin (n = 38), and the number of treatment failures in each group was 5 and 3, respectively. The difference in cure rate was -7.3%, with a lower limit of the 95% confidence interval (95% CI) of -22.5, and thus, noninferiority was not established at the prespecified margin (lower limit of CI of -15%). The overall treatment-emergent adverse event (TEAE) and treatment-related TEAE rates were lower in the rifalazil group (68% and 55%) than in the azithromycin group (71% and 62%), respectively. Subjects classified as treatment failures at day 22 to 26 had a lower mean plasma concentration of rifalazil at the visit on day 8 to 12 than those classified as treatment cures, but this difference was not significant; however, the levels were similar for both groups at the visit on day 22 to 26. A single 25-mg dose of rifalazil was well tolerated and eradicated C. trachomatis in most of these women with uncomplicated genital C. trachomatis infection. (The study was registered at clinicaltrials.gov under registration no. NCT01631201). PMID- 24798278 TI - Penetration of daptomycin into bone and synovial fluid in joint replacement. AB - Daptomycin exhibits clinical activity in the treatment of infections with Gram positive organisms, including infections due to methicillin-resistant Staphylococcus aureus. However, little is known about its penetration into bone and synovial fluid. The aim of our study was to assess the penetration of daptomycin into bone and synovial fluid after a single intravenous administration. This study was conducted in 16 patients who underwent knee or hip replacement and received a single intravenous dose of 8 mg of daptomycin per kg of body weight prior to surgery. Plasma daptomycin concentrations were measured 1 h after the end of daptomycin infusion and when bone fragments were removed. Daptomycin concentrations were also measured on bone fragments and synovial fluid collected at the same time during surgery. All samples were analyzed with a diode array-high-performance liquid chromatography (HPLC) method. After a single-dose intravenous infusion, bone daptomycin concentrations were above the MIC of daptomycin for Staphylococcus aureus in all subjects, and the median bone penetration percentage was 9.0% (interquartile range [IQR], 4.4 to 11.4). These results support the use of daptomycin in the treatment of Staphylococcus aureus bone and joint infections. PMID- 24798279 TI - Intracellular antiviral activity of low-dose ritonavir in boosted protease inhibitor regimens. AB - Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n = 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n = 40), lopinavir-ritonavir 400 and 100 mg twice daily (n = 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n = 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, further in vitro and in vivo studies of the RTV antiviral effect are warranted. PMID- 24798280 TI - Pharmacokinetic comparison to determine the mechanisms underlying the differential efficacies of cationic diamidines against first- and second-stage human African trypanosomiasis. AB - Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first-stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second-stage (meningoencephalitic, or central nervous system [CNS]) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first-stage HAT. However, only DB829 cured animals with second-stage infection. In this study, we aimed to determine the mechanisms underlying the differential efficacies of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. The results showed that DB829, an azadiamidine, had the highest systemic exposure and brain-to plasma ratio, whereas pentamidine and DB75 had the lowest. None of these diamidines was a P-gp substrate, and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacies of these diamidines in mice with second-stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the in vivo efficacies of cationic diamidines against first- and second-stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines. PMID- 24798281 TI - Anti-Candida activity of fluoxetine alone and combined with fluconazole: a synergistic action against fluconazole-resistant strains. AB - The purpose of this work was to determine the antimicrobial activity of fluoxetine, alone and combined with fluconazole, against 29 Candida strains isolated from patients with vulvovaginal candidiasis. MIC and minimum lethal concentration values ranged from 9.8 to 625 MUg/ml for all strains tested. The combination of fluconazole with fluoxetine resulted in synergistic activity against six Candida strains, with fractional inhibitory index (FIX) values between 0.15 and 0.31. An indifferent effect was found for the remaining strains, with FIX values between 0.63 and 1. PMID- 24798282 TI - Inhibition of foamy virus reverse transcriptase by human immunodeficiency virus type 1 RNase H inhibitors. AB - RNase H plays an essential role in the replication of human immunodeficiency virus type 1 (HIV-1). Therefore, it is a promising target for drug development. However, the identification of HIV-1 RNase H inhibitors (RHIs) has been hampered by the open morphology of its active site, the limited number of available RNase H crystal structures in complex with inhibitors, and the fact that, due to the high concentrations of Mg(2+) needed for protein stability, HIV-1 RNase H is not suitable for nuclear magnetic resonance (NMR) inhibitor studies. We recently showed that the RNase H domains of HIV-1 and prototype foamy virus (PFV) reverse transcriptases (RTs) exhibit a high degree of structural similarity. Thus, we examined whether PFV RNase H can serve as an HIV-1 RNase H model for inhibitor interaction studies. Five HIV-1 RHIs inhibited PFV RNase H activity at low micromolar concentrations similar to those of HIV-1 RNase H, suggesting pocket similarity of the RNase H domains. NMR titration experiments with the PFV RNase H domain and the RHI RDS1643 (6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4 dioxo-5-hexenoic acid ethyl ester) were performed to determine its binding site. Based on these results and previous data, in silico docking analysis showed a putative RDS1643 binding region that reaches into the PFV RNase H active site. Structural overlays were performed with HIV-1 and PFV RNase H to propose the RDS1643 binding site in HIV-1 RNase H. Our results suggest that this approach can be used to establish PFV RNase H as a model system for HIV-1 RNase H in order to identify putative inhibitor binding sites in HIV-1 RNase H. PMID- 24798283 TI - Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 1. Ciprofloxacin, moxifloxacin, and grepafloxacin. AB - The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 +/- 5.3 for CIP, 12.6 +/- 7.3 for MXF, and 19.1 +/- 10.5 for GRX (means +/- standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF (VELF), passive diffusion clearance (QELF), and active efflux clearance (CLout) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration. PMID- 24798284 TI - Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 2. Colistin. AB - The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (VELF), a passive diffusion clearance (QELF) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10 fold (0.035 mg kg(-1)). The km was estimated to be 133 MUg ml(-1), and the Vmax, in-to-Km ratio was equal to 2.5 * 10(-3) liter h(-1) kg(-1), which was 37 times higher than the QELF (6.7 * 10(-5) liter h(-1) kg(-1)). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections. PMID- 24798286 TI - In memoriam: Robert C. Moellering, Jr. PMID- 24798285 TI - Targeting methicillin-resistant Staphylococcus aureus with short salt-resistant synthetic peptides. AB - The seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity against Staphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistant Staphylococcus isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), linezolid-resistant S. aureus, and methicillin-resistant Staphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl2. Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms of S. aureus and S. epidermidis compared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4- to 8-fold their antimicrobial concentrations. The potent and salt insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistant S. aureus infections. PMID- 24798287 TI - 4-amino bis-pyridinium derivatives as novel antileishmanial agents. AB - The antileishmanial activity of a series of bis-pyridinium derivatives that are analogues of pentamidine have been investigated, and all compounds assayed were found to display activity against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major, with 50% effective concentrations (EC50s) lower than 1 MUM in most cases. The majority of compounds showed similar behavior in both Leishmania species, being slightly more active against L. major amastigotes. However, compound VGP-106 {1,1'-(biphenyl-4,4'-diylmethylene)bis[4 (4-bromo-N-methylanilino)pyridinium] dibromide} exhibited significantly higher activity against L. donovani amastigotes (EC50, 0.86 +/- 0.46 MUM) with a lower toxicity in THP-1 cells (EC50, 206.54 +/- 9.89 MUM). As such, VGP-106 was chosen as a representative compound to further elucidate the mode of action of this family of inhibitors in promastigote forms of L. donovani. We have determined that uptake of VGP-106 in Leishmania is a temperature-independent process, suggesting that the compound crosses the parasite membrane by diffusion. Transmission electron microscopy analysis showed a severe mitochondrial swelling in parasites treated with compound VGP-106, which induces hyperpolarization of the mitochondrial membrane potential and a significant decrease of intracellular free ATP levels due to the inhibition of ATP synthesis. Additionally, we have confirmed that VGP-106 induces mitochondrial ROS production and an increase in intracellular Ca(2+) levels. All these molecular events can activate the apoptotic process in Leishmania; however, propidium iodide assays gave no indication of DNA fragmentation. These results underline the potency of compound VGP-106, which may represent a new avenue for the development of novel antileishmanial compounds. PMID- 24798288 TI - Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy. AB - Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r(2) of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required. PMID- 24798289 TI - Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compounds active against type VI secretion. AB - The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an alpha-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A1 activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance. PMID- 24798290 TI - Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis. AB - The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (TRZ) in combination with the standard regimen in a well-validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB/c mice to establish human-equivalent doses of TRZ. To determine the bactericidal activity of TRZ against TB in BALB/c mice, three separate studies were performed, including a dose-ranging study of TRZ monotherapy and efficacy studies of human-equivalent doses of TRZ with and without isoniazid (INH) or rifampin (RIF). Therapeutic efficacy was assessed by the change in mycobacterial load in the lung. The human equivalent dose of thioridazine was determined to be 25 mg/kg of body weight, which was well tolerated in mice. TRZ was found to accumulate at high concentrations in lung tissue relative to serum levels. We observed modest synergy during coadministration of TRZ with INH, and the addition of TRZ reduced the emergence of INH-resistant mutants in mouse lungs. In conclusion, this study further illustrates the opportunity to reevaluate the contribution of TRZ to the sterilizing activity of combination regimens to prevent the emergence of drug resistant M. tuberculosis. PMID- 24798291 TI - Structural changes and differentially expressed genes in Pseudomonas aeruginosa exposed to meropenem-ciprofloxacin combination. AB - The effect of a meropenem-ciprofloxacin combination (MCC) on the susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa (MRPA) clinical isolates was determined using checkerboard and time-kill curve techniques. Structural changes and differential gene expression that resulted from the synergistic action of the MCC against one of the P. aeruginosa isolates (1071-MRPA]) were evaluated using electron microscopy and representational difference analysis (RDA), respectively. The differentially expressed, SOS response-associated, and resistance-associated genes in 1071-MRPA exposed to meropenem, ciprofloxacin, and the MCC were monitored by quantitative PCR. The MCC was synergistic against 25% and 40.6% of MDR P. aeruginosa isolates as shown by the checkerboard and time-kill curves, respectively. The morphological and structural changes that resulted from the synergistic action of the MCC against 1071-MRPA were a summation of the effects observed with each antimicrobial alone. One exception included outer membrane vesicles, which were seen in a greater amount upon ciprofloxacin exposure but were significantly inhibited upon MCC exposure. Cell wall- and DNA repair associated genes were differentially expressed in 1071-MRPA exposed to meropenem, ciprofloxacin, and the MCC. However, some of the RDA-detected, resistance associated, and SOS response-associated genes were expressed at significantly lower levels in 1071-MRPA exposed to the MCC. The MCC may be an alternative for the treatment of MDR P. aeruginosa. The effect of this antimicrobial combination may be not only the result of a summation of the effects of meropenem and ciprofloxacin but also a result of differential action that likely inhibits protective mechanisms in the bacteria. PMID- 24798293 TI - A prospective cohort study on the impact of smoking on soft tissue alterations around single implants. AB - OBJECTIVES: To compare smokers to non-smokers in terms of soft tissue alterations following single implant treatment in healed bone. MATERIAL AND METHODS: Non smoking and smoking patients with sufficient bone volume in need of a single implant in the anterior maxilla (15-25) were consecutively recruited in three centres. Conventional single implant surgery was performed and an immediate provisional crown was installed. Eight to 12 weeks later, the latter was replaced by a permanent one (baseline). Papilla regrowth and midfacial recession was registered after 2 years of function. RESULTS: The sample consisted of 39 non smokers (21 females; mean age 42) and 46 smokers (22 females; mean age 45). Smokers had three early failures, whereas all implants integrated successfully in non-smokers. Statistically significant papilla regrowth was observed in non smokers (distal 0.63 mm, mesial 0.76 mm), whereas smokers showed stable papillae (between cohorts: P <= 0.025). Midfacial soft tissue level demonstrated statistically significant regrowth in non-smokers (0.53 mm), whereas it remained stable in smokers (between cohorts: P = 0.004). CONCLUSION: Smokers failed to demonstrate papilla regeneration and showed more midfacial recession following single implant treatment when compared to non-smokers. PMID- 24798292 TI - Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor, and endoplasmic reticulum pathways. AB - Nephrotoxicity is the dose-limiting factor for colistin, but the exact mechanism is unknown. This study aimed to investigate the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in colistin-induced nephrotoxicity. Mice were intravenously administered 7.5 or 15 mg of colistin/kg of body weight/day (via a 3-min infusion and divided into two doses) for 7 days. Renal function, oxidative stress, and apoptosis were measured. Representative biomarkers involved in the mitochondrial, death receptor, and endoplasmic reticulum pathways were investigated, and the key markers involved in apoptosis and autophagy were examined. After 7-day colistin treatment, significant increase was observed with blood urea nitrogen, serum creatinine, and malondialdehyde, while activities of superoxide dismutase (SOD) and catalase decreased in the kidneys. Acute tubular necrosis and mitochondrial dysfunction were detected, and colistin-induced apoptosis was characterized by DNA fragmentation, cleavage of poly(ADP-ribose) polymerase (PARP-1), increase of 8-hydroxydeoxyguanosine (8 OHdG), and activation of caspases (caspase-8, -9, and -3). It was evident that colistin-induced apoptosis involved the mitochondrial pathway (downregulation of Bcl-2 and upregulation of cytochrome C [cytC] and Bax), death receptor pathway (upregulation of Fas, FasL, and Fas-associated death domain [FADD]), and endoplasmic reticulum pathway (upregulation of Grp78/Bip, ATF6, GADD153/CHOP, and caspase-12). In the 15-mg/kg/day colistin group, expression of the cyclin dependent kinase 2 (CDK2) and phosphorylated JNK (p-JNK) significantly increased (P < 0.05), while in the 7.5-mg/kg/day colistin group, a large number of autophagolysosomes and classic autophagy were observed. Western blot results of Beclin-1 and LC3B indicated that autophagy may play a protective role in colistin induced nephrotoxicity. In conclusion, this is the first study to demonstrate that all three major apoptosis pathways and autophagy are involved in colistin induced nephrotoxicity. PMID- 24798294 TI - Atomic picture of ligand migration in toluene 4-monooxygenase. AB - Computational modeling combined with mutational and activity assays was used to underline the substrate migration pathways in toluene 4-monooxygenase, a member of the important family of bacterial multicomponent monooxygenases (BMMs). In all structurally defined BMM hydroxylases, several hydrophobic cavities in the alpha subunit map a preserved path from the protein surface to the diiron active site. Our results confirm the presence of two pathways by which different aromatic molecules can enter/escape the active site. While the substrate is observed to enter from both channels, the more hydrophilic product is withdrawn mainly from the shorter channel ending at residues D285 and E214. The long channel ends in the vicinity of S395, whose variants have been seen to affect activity and specificity. These mutational effects are clearly reproduced and rationalized by the in silico studies. Furthermore, the combined computational and experimental results highlight the importance of residue F269, which is located at the intersection of the two channels. PMID- 24798295 TI - Soluble L-Selectin as an Independent Biomarker of Bronchial Asthma. AB - BACKGROUND: We sought to determine the association of plasma level of soluble L selectin (sL-selectin) and F206L polymorphism of L-selectin with asthma. METHODS: A total of 90 asthmatic patients and 90 sex- and age-matched healthy controls were enrolled. The plasma level of sL-selectin was measured by enzyme-linked immunosorbent assay (ELISA) method. An amplification refractory mutation system polymerase chain reaction was performed to detect F206L polymorphism of L selectin. RESULTS: The mean plasma levels of sL-selectin was significantly higher in the patients with asthma than the controls (2113 +/- 466 vs. 1664 +/- 322 ng/ml, P = 0.001). Logistic regression analysis after adjustment for age, sex, and body mass index demonstrated that plasma levels of sL-selectin are an independent biomarkers for asthma (odds ratio [OR], 1.86; 95% confidence interval [95% CI], 1.42-2.24). The area under the receiver operating characteristic (ROC) curve for sL-selectin was 0.792, 95% CI (0.732-0.862), P = 0.0001. Individuals with the minor homozygote of F206L polymorphism of L-selectin demonstrated a higher level of sL-selectin than the major homozygous (2319 +/- 732 vs. 1917 +/- 453 ng/ml, P = 0.02). No association was found between F206L polymorphism of L selectin with asthma. CONCLUSION: Our study suggests that plasma level of sL selectin is an independent biomarker for asthma. PMID- 24798296 TI - Molecular tailoring approach: a route for ab initio treatment of large clusters. AB - Conspectus Chemistry on the scale of molecular clusters may be dramatically different from that in the macroscopic bulk. Greater understanding of chemistry in this size regime could greatly influence fields such as materials science and atmospheric and environmental chemistry. Recent advances in experimental techniques and computational resources have led to accurate investigations of the energies and spectral properties of weakly bonded molecular clusters. These have enabled researchers to learn how the physicochemical properties evolve from individual molecules to bulk materials and to understand the growth patterns of clusters. Experimental techniques such as infrared, microwave, and photoelectron spectroscopy are the most popular and powerful tools for probing molecular clusters. In general, these experimental techniques do not directly reveal the atomistic details of the clusters but provide data from which the structural details need to be unearthed. Furthermore, the resolution of the spectral properties of energetically close cluster conformers can be prohibitively difficult. Thus, these investigations of molecular aggregates require a combination of experiments and theory. On the theoretical front, researchers have been actively engaged in quantum chemical ab initio calculations as well as simulation-based studies for the last few decades. To obtain reliable results, there is a need to use correlated methods such as Moller-Plesset second order method, coupled cluster theory, or dispersion corrected density functional theory. However, due to nonlinear scaling of these methods, optimizing the geometry of large clusters still remains a formidable quantum chemistry challenge. Fragment-based methods, such as divide-and-conquer, molecular tailoring approach (MTA), fragment molecular orbitals, and generalized energy based fragmentation approach, provide alternatives for overcoming the scaling problem for spatially extended molecular systems. Within MTA, a large system is broken down into two or more subsystems that can be readily treated computationally. Finally, the properties of the large system are obtained by patching the corresponding properties of all the subsystems. Due to these approximations, the resulting MTA-based energies carry some error in comparison with calculations based on the full system. An approach for correcting these errors has been attempted by grafting the error at a lower basis set onto a higher basis set. Furthermore, investigating the growth patterns and nucleation processes in clusters is necessary for understanding the structural transitions and the phenomena of magic numbers in cluster chemistry. Therefore, systematic building-up or the introduction of stochastics for generating molecular assemblies is the most crucial step for studying large clusters. In this Account, we discuss the working principle of MTA for probing molecular clusters at ab initio level followed by a brief summary of an automated and electrostatics guided algorithm for building molecular assemblies. The molecular aggregates presented here as test cases are generated based on either an electrostatic criterion or the basin hopping method. At MP2 level computation, the errors in MTA-based grafted energies are typically reduced to a submillihartree level, reflecting the potential of finding accurate energies of molecular clusters much more quickly. In summary, MTA provides a platform for effectively studying large molecular clusters at ab initio level of theory using minimal computer hardware. PMID- 24798297 TI - Determination and fingerprint analysis of steroidal saponins in roots of Liriope muscari (Decne.) L. H. Bailey by ultra high performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry. AB - Liriope muscari (Decne.) L. H. Bailey is a well-known traditional Chinese medicine used for treating cough and insomnia. There are few reports on the quality evaluation of this herb partly because the major steroid saponins are not readily identified by UV detectors and are not easily isolated due to the existence of many similar isomers. In this study, a qualitative and quantitative method was developed to analyze the major components in L. muscari (Decne.) L. H. Bailey roots. Sixteen components were deduced and identified primarily by the information obtained from ultra high performance liquid chromatography with ion trap time-of-flight mass spectrometry. The method demonstrated the desired specificity, linearity, stability, precision, and accuracy for simultaneous determination of 15 constituents (13 steroidal glycosides, 25(R)-ruscogenin, and pentylbenzoate) in 26 samples from different origins. The fingerprint was established, and the evaluation was achieved using similarity analysis and principal component analysis of 15 fingerprint peaks from 26 samples by ultra high performance liquid chromatography. The results from similarity analysis were consistent with those of principal component analysis. All results suggest that the established method could be applied effectively to the determination of multi ingredients and fingerprint analysis of steroid saponins for quality assessment and control of L. muscari (Decne.) L. H. Bailey. PMID- 24798298 TI - The source of inoculum plays a defining role in the development of MEC microbial consortia fed with acetic and propionic acid mixtures. AB - Microbial electrolysis cells (MECs) can be used as a downstream process to dark fermentation to further capture electron in volatile fatty acids that remain after fermentation, improving this way the viability of the overall process. Acetic and propionic acid are common products of dark fermentation. The main objective of this work was to investigate the effect of different initial concentrations of a mixture of acetic and propionic acids on MECs microbial ecology and hydrogen production performance. To link microbial structure and function, we characterized the anode respiring biofilm communities using pyrosequencing and quantitative-PCR. The best hydrogen production rates (265mL/d/Lreactor) were obtained in the first block of experiments by MEC fed with 1500mg/L acetic acid and 250mg/L propionic acid. This reactor presents in the anode biofilm an even distribution of Proteobacteria, Firmicutes and Bacteroidetes and Arcobacter was the dominant genera. The above fact also correlated to the highest electron load among all the reactors. It was evidenced that although defined acetic and propionic acid concentrations fed affected the structure of the microbial consortia that developed at the anode, the initial inoculum played a major role in the development of MEC microbial consortia. PMID- 24798299 TI - Reactive oxygen species and NLRP3 inflammasome activation. PMID- 24798300 TI - Dietary copper supplementation improves pelt characteristics of female silver fox (Vulpes fulva) during the winter fur-growing season. AB - Copper has an essential role in normal fur pigmentation and fur quality. This study evaluated the effects of cupric citrate (CuCit) supplementation on growth, nutrients metabolism and pelt characteristics of the female silver fox (Vulpes fulva). Fifty age-matched female silver foxes with similar body weights were randomly divided into five dietary groups for 58 days during the winter fur growing season. The basal diet contained 4.92 mg/kg copper. Groups I-V were supplemented with 6, 30, 60, 90 or 150 mg Cu from CuCit per 1 kg dry matter basal diet. Serum alkaline phosphatase activity was significantly higher (P<0.05) in those fed 90 mg/kg Cu than those fed 150 mg/kg Cu. Pelt total thickness was significantly higher (P<0.05) in those fed 30 mg/kg Cu than foxes fed 6 mg/kg Cu supplemented diet, but were similar to the other groups. Length of guard hair was significantly lower (P<0.05) in those fed 90 mg/kg Cu than fed 6 mg/kg Cu and 30 mg/kg Cu, but were similar to the other groups. Length of underhair was significantly higher (P<0.05) in those fed 6 mg/kg Cu than those fed 90 mg/kg Cu, but was similar to the other groups. Considering decreasing environmental contamination and improving pelt performance, supplementing 30 mg/kg Cu from CuCit (actual copper 35 mg/kg dry matter) is appropriate for female silver fox. PMID- 24798301 TI - Medication administration accuracy: using clinical observation and review of patient records to assess safety and guide performance improvement. AB - RATIONALE, AIMS AND OBJECTIVES: Medication-related errors are common and can occur at every step of the medication process. The aim was to explore (1) the extent to which nurses perform fundamental safe practices related to medication administration (MA); (2) the frequency and characteristics of MA errors; and (3) the clinical significance of medication types (classes) subject to error. METHODS: A descriptive, exploratory cross sectional design with point in time sampling was used combining direct observations, conducted by naive observers, and medical record review. A convenience sample of three adult surgical units was drawn from a 1000-bed university hospital. Seventy-two patient-nurse MA encounters were observed including 306 MA doses based on a minimum sample of 100 doses per unit. The Medication Administration Accuracy Assessment developed by the Collaborative Alliance for Nursing Outcomes in the United States was used. RESULTS: Observed adherence to MA safe practices varied between units. Identity control (9%), explaining medication to patient (11%) and medication labelled throughout the process (25%) were found to be safe practices with greatest deviation. 18% of doses involved a MA error (n = 54). Wrong time (9%) was the most common MA error, typically involving analgesics. CONCLUSIONS: Given recent reports suggesting MA safe practices are strongly associated with MA errors, it is timely to strengthen RN awareness of the critical role of safe practices in MA safety. In nursing education, clinical examination using the six safe practices studied herein may enhance medication administration accuracy. PMID- 24798302 TI - Efficient generation human induced pluripotent stem cells from human somatic cells with Sendai-virus. AB - A few years ago, the establishment of human induced pluripotent stem cells (iPSCs) ushered in a new era in biomedicine. Potential uses of human iPSCs include modeling pathogenesis of human genetic diseases, autologous cell therapy after gene correction, and personalized drug screening by providing a source of patient-specific and symptom relevant cells. However, there are several hurdles to overcome, such as eliminating the remaining reprogramming factor transgene expression after human iPSCs production. More importantly, residual transgene expression in undifferentiated human iPSCs could hamper proper differentiations and misguide the interpretation of disease-relevant in vitro phenotypes. With this reason, integration-free and/or transgene-free human iPSCs have been developed using several methods, such as adenovirus, the piggyBac system, minicircle vector, episomal vectors, direct protein delivery and synthesized mRNA. However, efficiency of reprogramming using integration-free methods is quite low in most cases. Here, we present a method to isolate human iPSCs by using Sendai-virus (RNA virus) based reprogramming system. This reprogramming method shows consistent results and high efficiency in cost-effective manner. PMID- 24798304 TI - Dialysis chains and placement on the waiting list for a cadaveric kidney transplant. AB - BACKGROUND: The proliferation of multi-unit for-profit dialysis chains in the ESRD industry has raised concerns for patient quality of care including access to renal transplantation therapy (RTT). The effect of dialysis facility chain status on RTT is unknown. METHODS: Data from the United States Renal Data System were used to identify 4,465 dialysis facilities and 56,714 dialysis patients who started hemodialysis in 2006. Patients were followed from initiation of hemodialysis in 2006 to placement on the renal transplant waiting list or to December 31, 2009. The role of dialysis facility chain status (affiliation, size, and ownership) on placement on the renal transplant waiting list was evaluated by multi-level mixed-effect regression models that account for clustering within facilities. RESULTS: Patients from for-profit chain facilities, compared to nonprofit chain facilities, were 13% (95% CI 0.77-0.98) less likely to be waitlisted. In contrast, among nonchains, facility ownership did not influence likelihood of being waitlisted. There was also a marginally significant difference in waiting list placement by chain size: large chains compared with mid or small chains were 8% (95% CI 0.84-1.00) less likely to place patients on the waiting list. After adjustment for patient and facility characteristics, dialysis facility chain affiliation (chain-affiliated or not) was not found to be independently associated with the likelihood of placement on the transplant waitlist. CONCLUSION: Dialysis chain affiliation expands previously observed ownership-related differences in placement on the waiting list. For-profit ownership of dialysis chain facilities appears to be a significant impediment to access to renal transplants. PMID- 24798303 TI - Modulation of miR-29 expression by alpha-fetoprotein is linked to the hepatocellular carcinoma epigenome. AB - Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P<0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly (P<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P<0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP- HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR-29a expression and induces DNMT3A expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP- HCC cells in nude mice. CONCLUSION: Tumor biology differs considerably between AFP+ HCC and AFP- HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC. PMID- 24798305 TI - A letter to a donor: A medical student's perspective after organ procurement. PMID- 24798306 TI - Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-kappaB inhibitors. AB - BACKGROUND: The instant blood-mediated inflammatory response (IBMIR) has been shown as a major factor that causes damage to transplanted islets. Withaferin A (WA), an inhibitor of nuclear factor (NF) kappaB, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-kappaB inhibitors affected IBMIR using an in vitro human autologous blood islet model. METHODS: Human islets were pretreated with or without NF-kappaB inhibitors WA or CAY10512 before mixing autologous blood in a miniaturized in vitro tube model. Plasma samples were collected at multiple time points and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a panel of proinflammatory cytokines. Infiltration of neutrophils into islets was analyzed using immunohistochemistry. RESULTS: Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blood in the control group, but not in the NF-kappaB inhibitor-treated groups, whereas TAT levels were elevated in all three groups with a peak at 6 hr. Significant elevation of proinflammatory cytokines was observed in the control group after 3 hr, but not in the treatment groups. Significant inhibition of neutrophil infiltration was also observed in the WA group compared with the control (P<0.001) and CAY10512 (P<0.001) groups. CONCLUSIONS: A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-kappaB inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes. PMID- 24798307 TI - Who is the best hematopoietic stem-cell donor for a male patient with acute leukemia? AB - BACKGROUND: Female donors for male recipients worsen the outcome of allogeneic hematopoietic stem-cell transplantation. We wanted to find out whether a male human leukocyte antigen (HLA)-matched unrelated donor (MUD, 8/8, n=2,014) might be an alternative to a female HLA-identical sibling donor (n=2,656) for male patients with acute leukemia. METHODS: This is a retrospective analysis from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. RESULTS: The relative risk (RR) of acute graft-versus-host disease (GVHD) of grades II to IV was increased in the MUD group with acute myeloid leukemia (AML) (RR, 1.47; P<0.001) and acute lymphoblastic leukemia (ALL) (RR, 1.76; P<0.001). There was no difference in incidence of chronic GVHD and nonrelapse mortality between the two groups. Probability of relapse was lower in the MUD group than in the sibling group in patients with ALL (hazards ratio [HR], 0.75; P=0.04) but not in the AML patients (HR, 0.89; P=0.17). Survival was not different between the groups. Leukemia-free survival (LFS) was also similar in the sibling and MUD groups in patients with AML (HR, 1.01; P=0.81) or ALL (HR, 0.93; P=0.45). Factors significantly associated with reduced LFS included active disease, poor cytogenetics, age, year of hematopoietic stem-cell transplantation, reduced-intensity conditioning, and the use of antithymocyte globulin. CONCLUSION: Male patients who received grafts from male MUDs demonstrated an increased incidence of acute GVHD and LFS same as when using HLA-identical female donors. PMID- 24798308 TI - Lack of cross-sensitization between alpha-1,3-galactosyltransferase knockout porcine and allogeneic skin grafts permits serial grafting. AB - BACKGROUND: The current standard of care for burns requiring operative treatment consists of early burn excision and autologous split-thickness skin grafting. However, in large burns, sufficient donor sites may not be available to achieve total coverage, necessitating temporary coverage with allogeneic human cadaver skin grafts or synthetic skin substitutes. A previous study from this laboratory demonstrated that skin grafts from alpha-1,3 galactosyltransferase knockout (GalT KO) miniature swine enjoyed survival comparable to that of allogeneic skin grafts in baboons. METHODS: In the present study, we have evaluated the immune response against sequential GalT-KO and allogeneic skin grafts to determine whether such serial grafts could extend the period of temporary wound coverage before definitive grafting with autologous skin. RESULTS: We report that rejection of primary GalT-KO skin grafts led to an anti-xenogeneic humoral response with no evidence for sensitization to alloantigens nor acceleration of rejection of allogeneic skin grafts. Similarly, presensitization with allogeneic skin did not lead to accelerated rejection of xenogeneic skin. CONCLUSIONS: These data suggest that GalT-KO skin grafts could provide an early first-line treatment in the management of severe burns that would not preclude subsequent use of allografts, and that serial grafting of GalT-KO skin and allogeneic skin could potentially be used to provide an extended period of temporary burn wound coverage. PMID- 24798309 TI - Surveillance of nonmelanoma skin cancer incidence rates in kidney transplant recipients in Ireland. AB - BACKGROUND: The incidence of nonmelanomatous skin cancer (NMSC) is substantially higher among renal transplant recipients (RTRs) than in the general population. With a growing RTR population, a robust method for monitoring skin cancer rates in this population is required. METHODS: A modeling approach was used to estimate the trends in NMSC rates that adjusted for changes in the RTR population (sex and age), calendar time, the duration of posttransplant follow-up, and background population NMSC incidence rates. RTR databases in both Northern Ireland (NI) and the Republic of Ireland (ROI) were linked to their respective cancer registries for diagnosis of NMSC, mainly squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). RESULTS: RTRs in the ROI had three times the incidence (P<0.001) of NMSC compared with NI. There was a decline (P<0.001) in NMSC 10-year cumulative incidence rate in RTRs over the period 1994-2009, which was driven by reductions in both SCC and BCC incidence rates. Nevertheless, there was an increase in the incidence of NMSC with time since transplantation. The observed graft survival was higher in ROI than NI (P<0.05) from 1994-2004. The overall patient survival of RTRs was similar in NI and ROI. CONCLUSION: Appropriate modeling of incidence trends in NMSC among RTRs is a valuable surveillance exercise for assessing the impact of change in clinical practices over time on the incidence rates of skin cancer in RTRs. It can form the basis of further research into unexplained regional variations in NMSC incidence. PMID- 24798310 TI - Comparison of clinicopathologic characteristics of urothelial carcinoma between patients after renal transplantation and on dialysis. AB - BACKGROUND: Urothelial carcinoma (UC) is a common complication after renal replacement therapy (RRT) among Chinese end-stage renal disease (ESRD) patients. It is unclear whether there are any differences in the clinicopathologic characteristics of UC between renal transplantation (RT) and dialysis patients; such differences could impact RRT modality selection. METHODS: We retrospectively reviewed clinicopathologic data for 27 RT patients and 40 dialysis patients who were diagnosed with UC in our center to explore differences in the clinicopathologic characteristics of UC and prognoses between the two groups. RESULTS: The median follow-up period was 92 months (2-137) for the RT group and 71 months (18-155) for the dialysis group. The demographic and baseline data showed no significant differences between the two groups. Upper urinary tract UC (UUC) occurred more frequently in the RT group (22 UUCs in 39 UCs), whereas bladder UC (BUC) predominated in the dialysis group (33 BUCs in 49 UCs) (P=0.025). The pathologic grading in the RT group was significantly higher than that in the dialysis group (P=0.046 for WHO1973 grading, P=0.026 for WHO2004 grading), whereas the difference in tumor stage was not significant (P=0.089). The RT group manifested a higher recurrence rate than the dialysis group (P=0.024). However, the overall and cancer-specific survival rates between the two groups were not significantly different (P=0.239 and P=0.818, respectively). CONCLUSION: Certain traits of UC, including tumor site, pathologic grading, and recurrence-free survival, were notably different between RT and dialysis patients, but the overall and cancer-specific survival rates were similar. PMID- 24798311 TI - Differential effect of bortezomib on HLA class I and class II antibody. AB - BACKGROUND: Bortezomib has been used to reduce HLA antibody in patients either before transplantation or as treatment for antibody-mediated rejection (AMR). Reports on its efficacy show mixed results. The mechanism of action of this agent is via proteasome inhibition. The primary route of synthesis of HLA class I molecules is dependent on peptide generation by the proteasome, whereas that of class II is not. We observed a differential effect of bortezomib on class I versus class II antibody and hypothesized that this was related to a reduced expression of class I HLA antigens. METHODS: The effect of bortezomib on HLA antibody levels was evaluated in 13 patients who were desensitized for incompatible renal transplantation. We calculated the percent difference in HLA antibody level before and after bortezomib treatment and the impact of bortezomib on HLA expression in lymphocytes of healthy control subjects. RESULTS: On average, the level of HLA class I donor-specific antibody (DSA) decreased by 32%, whereas that of class II DSA increased by 29%. In vitro bortezomib treatment of lymphocytes resulted in a mean decrease of 23% in MHC class I expression on B lymphocytes and no change (+1.08%) in MHC class II expression (P=0.0003). The amount of intracellular class I molecules was reduced by a mean of 29% with bortezomib. CONCLUSION: These data indicate that bortezomib reduces HLA class I antibody more effectively than class II antibody. This difference may be due to the reduced expression of class I molecules resulting from treatment with this proteasome inhibitor. PMID- 24798313 TI - On the origin of SCPP genes. PMID- 24798312 TI - HLA monomers as a tool to monitor indirect allorecognition. AB - BACKGROUND: Recognition of donor antigens can occur through two separate pathways: the direct pathway (non-self HLA on donor cells) and the indirect pathway (self-restricted presentation of donor derived peptides on recipient cells). Indirect allorecognition is important in the development of humoral rejection; therefore, there is an increasing interest in the monitoring of indirect alloreactive T-cells. We have used an in vitro model to determine the optimal requirements for indirect presentation and assessed the risk for semidirect presentation in this system. METHODS: HLA-typed monocyte-derived dendritic cells (moDCs) were incubated with cellular fragments or necrotic cells and incubated with either indirect or direct alloreactive T-cell clones. T-cell reactivity was measured through proliferation or cytokine secretion. HLA-typed moDC, monocytes, or PBMCs were incubated with HLA class I monomers, in combination with either direct/indirect T-cell clones. RESULTS: Although both were efficiently taken up, alloreactivity was limited to the semi-direct pathway, as measured by allospecific CD4 (indirect) and CD8 T-cell clones (direct) when cells were used. In contrast, HLA-A2 monomers were not only efficiently taken up but also processed and presented by HLA-typed moDC, monocytes, and PBMCs. Activation was shown by a dose-dependent induction of IFN-gamma production and proliferation by the CD4 T-cell clone. Antigen presentation was most efficient when the monomers were cultured for longer periods (24-48 hr) in the presence of the T-cells. Using this method, no reactivity was observed by the CD8 T-cell clone, confirming no semidirect alloreactivity. CONCLUSION: We have developed a system that could be used to monitor indirect alloreactive T-cells. PMID- 24798314 TI - Comparison of hand-assisted laparoscopy with open total colectomy for slow transit constipation: a retrospective study. AB - OBJECTIVE: To compare the efficacy and safety of hand-assisted laparoscopic colectomy (HALC) and open colectomy (OC) for patients with slow transit constipation (STC). METHODS: Data of patients with STC who underwent total colectomy from January 2008 to December 2012 were retrospectively reviewed after clinical evaluation and an exclusion of secondary causes. These patients were further divided into the HALC and OC groups. Patients' outcomes, including intraoperative and postoperative data on their recovery and complications were compared between the two groups. RESULTS: A total of 68 patients with STC were finally enrolled in the study, including 32 in the HALC group and 36 in the OC group. The baseline characteristics did not significantly differ between the two groups. Compared with the OC group, patients in the HALC group had a shorter length of incision, a longer operative time and less blood loss volume. There was no conversion to OC for patients undergoing HALC and no intraoperative complications in both groups. Furthermore, after operation, patients in HALC group experienced less pain (3.4 +/- 0.7 vs 4.8 +/- 1.0), earlier first passage of flatus (58.3 +/- 6.3 h vs 73.4 +/- 13.0 h), shorter length of postoperative hospital stay (8.8 +/- 1.2 days vs 11.3 +/- 1.7 days) but higher medical cost (RMB 33 979 +/- 3 135 vs RMB 29 828 +/- 3 216). The overall postoperative complications and the satisfaction in defecation were comparable in the two groups. CONCLUSION: HALC is a safe, minimally invasive and effective surgical alternative for treating STC, which is comparable to OC. PMID- 24798316 TI - Rivaroxaban for the Long-term Treatment of Spontaneous Ovarian Vein Thrombosis Caused by Factor V Leiden Homozygosity. AB - OBJECTIVE: To report a case where rivaroxaban was used in the management of an ovarian vein thrombosis and to briefly review the literature, pathophysiology, and clinical implications therein. CASE SUMMARY: A 30-year-old previously healthy woman was diagnosed with acute, spontaneous, left-ovarian vein thrombosis (OVT) with proximal extension into the renal vein. After initial catheter-directed thrombolysis with tPA, angioplasty of the left renal vein, and heparinoid treatment, rivaroxaban was begun for long-term anticoagulation. Three months after her index event she was symptom free, with complete resolution of her thrombosis and no adverse effects or bleeding complications from rivaroxaban. To our knowledge, this is the first report of OVT successfully treated with rivaroxaban. DISCUSSION: OVT is a rare but potentially fatal cause of abdominal pain that may pose diagnostic and therapeutic dilemmas. Factor V Leiden (FVL) homozygosity, an uncommon but severe inherited thrombophilia, increases the risk of thrombosis by approximately 50- to 80-fold. This case report and accompanying literature review highlight important clinical pearls related to the diagnosis and management of OVT and inherited thrombophilias. CONCLUSIONS: This clinical vignette adds to the published literature suggesting that novel oral anticoagulants, such as rivaroxaban, may eventually emerge as an alternative to vitamin K antagonists for the treatment of extra-axial thromboses. Reporting these cases is important because their prevalence is low outside of specialized referral centers, and thus, dissemination of these experiences may help other providers in treating their patients. PMID- 24798315 TI - One-pot two-step radiosynthesis of a new (18)F-labeled thiol reactive prosthetic group and its conjugate for insulinoma imaging. AB - N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-6-fluoronicotinamide ([(18)F]FNEM), a novel prosthetic agent that is thiol-specific, was synthesized using a one-pot two-step strategy: (1) (18)F incorporation by a nucleophilic displacement of trimethylammonium substrate under mild conditions; (2) amidation of the resulting 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester with N-(2-aminoethyl)maleimide trifluoroacetate salt. The radiosynthesis of the maleimide tracer was completed in 75 min from [(18)F]fluoride with 26 +/- 5% decay uncorrected radiochemical yield, and specific activity of 19-88 GBq/MUmol (decay uncorrected). The in vitro cell uptake, in vivo biodistribution, and positron emission tomography (PET) imaging properties of its conjugation product with [Cys(40)]-exendin-4 were described. [(18)F]FNEM-Cys(40)-exendin-4 showed specific targeting of glucagon-like peptide 1 receptor (GLP-1R) positive insulinomas and comparable imaging results to our recently reported [(18)F]FPenM Cys(40)-exendin-4. PMID- 24798317 TI - A Bayesian network model for assessing natural estrogen fate and transport in a swine waste lagoon. AB - Commercial swine waste lagoons are regarded as a major reservoir of natural estrogens, which have the potential to produce adverse physiological effects on exposed aquatic organisms and wildlife. However, there remains limited understanding of the complex mechanisms of physical, chemical, and biological processes that govern the fate and transport of natural estrogens within an anaerobic swine lagoon. To improve lagoon management and ultimately help control the offsite transport of these compounds from swine operations, a probabilistic Bayesian network model was developed to assess natural estrogen fate and budget and then compared against data collected from a commercial swine field site. In general, the model was able to describe the estrogen fate and budget in both the slurry and sludge stores within the swine lagoon. Sensitivity analysis within the model demonstrated that the estrogen input loading from the associated barn facility was the most important factor in controlling estrogen concentrations within the lagoon slurry storage, whereas the settling rate was the most significant factor in the lagoon sludge storage. The degradation reactions were shown to be minor in both stores based on prediction of average total estrogen concentrations. Management scenario evaluations demonstrated that the best possible management options to reduce estrogen levels in the lagoon are either to adjust the estrogen input loading from swine barn facilities or to effectively enhance estrogen bonding with suspended solids through the use of organic polymers or inorganic coagulants. PMID- 24798318 TI - Working with LGBT older adults: an assessment of employee training practices, needs, and preferences of senior service organizations in Minnesota. AB - As the population ages and LGBT older adults become more visible among senior service providers, the need for cultural competency training will grow. Although this training is a relatively new phenomenon, curricula exist. These are generally in person for 2- to 8-hr durations. Training to Serve embarked on a study to investigate preferences in cultural competency format and duration. One hundred and eighty-four Minnesota service providers participated in the online survey. The majority (90%) were interested in participating in LGBT cultural competency training. Results suggest a preference for shorter duration and online formats. Implications for curricula development and future research are included. PMID- 24798319 TI - Validation of a commercially available automated canine-specific immunoturbidimetric method for measuring canine C-reactive protein. AB - BACKGROUND: Measurement of C-reactive protein (CRP) is used for diagnosing and monitoring systemic inflammatory disease in canine patients. An automated human immunoturbidimetric assay has been validated for measuring canine CRP, but cross reactivity with canine CRP is unpredictable. OBJECTIVE: The purpose of the study was to validate a new automated canine-specific immunoturbidimetric CRP method (Gentian cCRP). METHODS: Studies of imprecision, accuracy, prozone effect, interference, limit of quantification, and stability under different storage conditions were performed. The new method was compared with a human CRP assay previously validated for canine CRP determination. Samples from 40 healthy dogs were analyzed to establish a reference interval. RESULTS: Total imprecision was < 2.4% for 4 tested serum pools analyzed twice daily over 10 days. The method was linear under dilution, and no prozone effect was detected at a concentration of 1200 mg/L. Recovery after spiking serum with purified canine CRP at 2 different concentrations was 123% and 116%, respectively. No interference from hemoglobin or triglycerides (10 g/L) was detected. CRP was stable for 14 days at 4 degrees C and 22 degrees C. In the method comparison study, there was good agreement between the validated human CRP assay and the new canine-specific assay. Healthy dogs had CRP concentrations that were less than the limit of quantification of the Gentian cCRP method (6.8 mg/L). CONCLUSIONS: The new canine-specific immunoturbidimetric CRP assay is a reliable and rapid method for measuring canine CRP, suitable for clinical use due to the option for an automated assay. PMID- 24798320 TI - Salvage surgery for recurrent carcinoma of the cervical esophagus postesophagectomy. AB - BACKGROUND: Management of cervical esophageal tumor postesophagectomy is mainly palliative because of inadequate exposure of tumor in the cervicothoracic region. In this study, we propose a means of cure for these patients. METHODS: Between January 2003 and June 2013, 6 patients underwent curative pharyngolaryngectomy and completion cervical esophagectomy via manubrial resection. Operative outcomes were analyzed and compared with a historical cohort who received palliative therapy. RESULTS: One patient required prolonged hospital stay for pneumonia, resulting in a median hospital stay of 30 days (range, 21-55 days). All patients resumed oral feeding at a mean of 15.2 days (range, 14-19 days). Tracheostoma stenosis was noted in 2 patients. One patient developed nodal recurrence, another with distant metastasis, resulting in a median disease-free survival of 13 months (range, 4-20 months). Median overall survival was significantly longer than the cohort group (19.0 vs 3.0 months; p = .013). CONCLUSION: Salvage surgery in patients with carcinoma of the cervical esophagus postesophagectomy is feasible with significantly prolonged survival. PMID- 24798321 TI - The comparative clinical effectiveness and value of simeprevir and sofosbuvir for chronic hepatitis C virus infection. PMID- 24798322 TI - Analytical modelling of the spread of disease in confined and crowded spaces. AB - Since 1927 and until recently, most models describing the spread of disease have been of compartmental type, based on the assumption that populations are homogeneous and well-mixed. Recent models have utilised agent-based models and complex networks to explicitly study heterogeneous interaction patterns, but this leads to an increasing computational complexity. Compartmental models are appealing because of their simplicity, but their parameters, especially the transmission rate, are complex and depend on a number of factors, which makes it hard to predict how a change of a single environmental, demographic, or epidemiological factor will affect the population. Therefore, in this contribution we propose a middle ground, utilising crowd-behaviour research to improve compartmental models in crowded situations. We show how both the rate of infection as well as the walking speed depend on the local crowd density around an infected individual. The combined effect is that the rate of infection at a population scale has an analytically tractable non-linear dependency on crowd density. We model the spread of a hypothetical disease in a corridor and compare our new model with a typical compartmental model, which highlights the regime in which current models may not produce credible results. PMID- 24798323 TI - Bradykinin and histamine-induced cytosolic calcium increase in capillary endothelial cells of bovine adrenal medulla. AB - We have assessed the effect of bradykinin and histamine on the cytosolic free calcium concentration ([Ca(2+)]i ) of bovine adrenal medulla capillary endothelial cells (BAMCECs). To measure [Ca(2+)]i changes in BAMCECs the intracellular fluorescent probe, fluo-3 AM, was used. Bradykinin (3 uM) produced a transient monophasic increase in [Ca(2+)]i , which was depressed by B1650 (0.1 uM), a B2-bradykinin receptor antagonist (D-Arg-[Hyp(3), Thi(5,8) , D-Phe(7)] Bradykinin). Similarly, increase in [Ca(2+)]i induced by histamine was also depressed by tripolidine (0.1 uM), an H1-histamine receptor antagonist. [Ca(2+)]i increase induced by both agonists was unaffected in the absence of extracellular Ca(2+) or presence of antagonists of voltage operated Ca(2+) channels (VOCCs). Thapsigargin (1 uM) did not abolish the increase of [Ca(2+)]i produced by bradykinin, but abolished that of histamine. In contrast, caffeine (100 uM), abolished the [Ca(2+)]i response induced by bradykinin (3 uM), but did not affect the [Ca(2+)]i increase induced by histamine (100 uM). The results indicate the presence of B2 bradykinin- and H1 histamine-receptors in BAMCECs. Liberation of Ca(2+) induced by both agonists occurs through 2 different intracellular mechanisms. While bradykinin activates a sarco(endo) plasmic reticulum (SER) containing a SER Ca(2+) -ATPase (SERCA) thapsigargin-insensitive, histamine activates a SER containing a SERCA thapsigargin-sensitive. We suggest that the increase in [Ca(2+)]i induced by bradykinin and histamine could be of physiological relevance, modulating adrenal gland microcirculation. PMID- 24798324 TI - The UvrD303 hyper-helicase exhibits increased processivity. AB - DNA helicases use energy derived from nucleoside 5'-triphosphate hydrolysis to catalyze the separation of double-stranded DNA into single-stranded intermediates for replication, recombination, and repair. Escherichia coli helicase II (UvrD) functions in methyl-directed mismatch repair, nucleotide excision repair, and homologous recombination. A previously discovered 2-amino acid substitution of residues 403 and 404 (both Asp -> Ala) in the 2B subdomain of UvrD (uvrD303) confers an antimutator and UV-sensitive phenotype on cells expressing this allele. The purified protein exhibits a "hyper-helicase" unwinding activity in vitro. Using rapid quench, pre-steady state kinetic experiments we show the increased helicase activity of UvrD303 is due to an increase in the processivity of the unwinding reaction. We suggest that this mutation in the 2B subdomain results in a weakened interaction with the 1B subdomain, allowing the helicase to adopt a more open conformation. This is consistent with the idea that the 2B subdomain may have an autoregulatory role. The UvrD303 mutation may enable the helicase to unwind DNA via a "strand displacement" mechanism, which is similar to the mechanism used to processively translocate along single-stranded DNA, and the increased unwinding processivity may contribute directly to the antimutator phenotype. PMID- 24798325 TI - Bet v 1 from birch pollen is a lipocalin-like protein acting as allergen only when devoid of iron by promoting Th2 lymphocytes. AB - It is hypothesized that allergens are at the borderline of self and non-self and, through as yet elusive circumstances, mount a Th2 response for allergic sensitization. The major birch pollen allergen Bet v 1 is considered the prototype for the PR-10 protein family causing respiratory allergy. Here, we give structural evidence that Bet v 1 is a lipocalin-like protein with a striking structural resemblance to human lipocalin 2. Lipocalin 2 is highly expressed in the lung where it exerts immunoregulatory functions dependent on being loaded with siderophore-bound iron (holo-form) or not (apo-form). We demonstrate that similar to lipocalin 2, Bet v 1 is capable of binding iron via catechol-based siderophores. Thereby, calculated Kd values of 66 nm surpassed affinities to known ligands nearly by a power of 10. Moreover, we give functional evidence of the immunomodulatory capacity of Bet v 1 being dependent on its iron-loaded state. When incubated to human immune cells, only the apo-form of Bet v 1, but not the holo-form, was able to promote Th2 cells secreting IL13. These results provide for the first time a functional understanding on the allergenicity of Bet v 1 and a basis for future allergen immunotherapies counteracting Th2 immune responses on a molecular basis. PMID- 24798326 TI - The third exon of the budding yeast meiotic recombination gene HOP2 is required for calcium-dependent and recombinase Dmc1-specific stimulation of homologous strand assimilation. AB - During meiosis in Saccharomyces cerevisiae, the HOP2 and MND1 genes are essential for recombination. A previous biochemical study has shown that budding yeast Hop2 Mnd1 stimulates the activity of the meiosis-specific strand exchange protein ScDmc1 only 3-fold, whereas analogous studies using mammalian homologs show >30 fold stimulation. The HOP2 gene was recently discovered to contain a second intron that lies near the 3'-end. We show that both HOP2 introns are efficiently spliced during meiosis, forming a predominant transcript that codes for a protein with a C-terminal sequence different from that of the previously studied version of the protein. Using the newly identified HOP2 open reading frame to direct synthesis of wild type Hop2 protein, we show that the Hop2-Mnd1 heterodimer stimulated Dmc1 D-loop activity up to 30-fold, similar to the activity of mammalian Hop2-Mnd1. ScHop2-Mnd1 stimulated ScDmc1 activity in the presence of physiological (micromolar) concentrations of Ca(2+) ions, as long as Mg(2+) was also present at physiological concentrations, leading us to hypothesize that ScDmc1 protomers bind both cations in the active Dmc1 filament. Co-factor requirements and order-of-addition experiments suggested that Hop2-Mnd1-mediated stimulation of Dmc1 involves a process that follows the formation of functional Dmc1-ssDNA filaments. In dramatic contrast to mammalian orthologs, the stimulatory activity of budding yeast Hop2-Mnd1 appeared to be specific to Dmc1; we observed no Hop2-Mnd1-mediated stimulation of the other budding yeast strand exchange protein Rad51. Together, these results support previous genetic experiments indicating that Hop2-Mnd1 specifically stimulates Dmc1 during meiotic recombination in budding yeast. PMID- 24798327 TI - The splicing factor FUBP1 is required for the efficient splicing of oncogene MDM2 pre-mRNA. AB - Alternative splicing of the oncogene MDM2 is a phenomenon that occurs in cells in response to genotoxic stress and is also a hallmark of several cancer types with important implications in carcinogenesis. However, the mechanisms regulating this splicing event remain unclear. Previously, we uncovered the importance of intron 11 in MDM2 that affects the splicing of a damage-responsive MDM2 minigene. Here, we have identified discrete cis regulatory elements within intron 11 and report the binding of FUBP1 (Far Upstream element-Binding Protein 1) to these elements and the role it plays in MDM2 splicing. Best known for its oncogenic role as a transcription factor in the context of c-MYC, FUBP1 was recently described as a splicing regulator with splicing repressive functions. In the case of MDM2, we describe FUBP1 as a positive splicing regulatory factor. We observed that blocking the function of FUBP1 in in vitro splicing reactions caused a decrease in splicing efficiency of the introns of the MDM2 minigene. Moreover, knockdown of FUBP1 in cells induced the formation of MDM2-ALT1, a stress-induced splice variant of MDM2, even under normal conditions. These results indicate that FUBP1 is also a strong positive splicing regulator that facilitates efficient splicing of the MDM2 pre-mRNA by binding its introns. These findings are the first report describing the regulation of alternative splicing of MDM2 mediated by the oncogenic factor FUBP1. PMID- 24798328 TI - Low density lipoprotein receptor class A repeats are O-glycosylated in linker regions. AB - The low density lipoprotein receptor (LDLR) is crucial for cholesterol homeostasis and deficiency in LDLR functions cause hypercholesterolemia. LDLR is a type I transmembrane protein that requires O-glycosylation for stable expression at the cell surface. It has previously been suggested that LDLR O glycosylation is found N-terminal to the juxtamembrane region. Recently we identified O-glycosylation sites in the linker regions between the characteristic LDLR class A repeats in several LDLR-related receptors using the "SimpleCell" O glycoproteome shotgun strategy. Herein, we have systematically characterized O glycosylation sites on recombinant LDLR shed from HEK293 SimpleCells and CHO wild type cells. We find that the short linker regions between LDLR class A repeats contain an evolutionarily conserved O-glycosylation site at position -1 of the first cysteine residue of most repeats, which in wild-type CHO cells is glycosylated with the typical sialylated core 1 structure. The glycosites in linker regions of LDLR class A repeats are conserved in LDLR from man to Xenopus and found in other homologous receptors. O-Glycosylation is controlled by a large family of polypeptide GalNAc transferases. Probing into which isoform(s) contributed to glycosylation of the linker regions of the LDLR class A repeats by in vitro enzyme assays suggested a major role of GalNAc-T11. This was supported by expression of LDLR in HEK293 cells, where knock-out of the GalNAc-T11 isoform resulted in the loss of glycosylation of three of four linker regions. PMID- 24798329 TI - Mapping topoisomerase sites in mitochondrial DNA with a poisonous mitochondrial topoisomerase I (Top1mt). AB - Mitochondrial topoisomerase I (Top1mt) is a type IB topoisomerase present in vertebrates and exclusively targeted to mitochondria. Top1mt relaxes mitochondrial DNA (mtDNA) supercoiling by introducing transient cleavage complexes wherein the broken DNA strand swivels around the intact strand. Top1mt cleavage complexes (Top1mtcc) can be stabilized in vitro by camptothecin (CPT). However, CPT does not trap Top1mtcc efficiently in cells and is highly cytotoxic due to nuclear Top1 targeting. To map Top1mtcc on mtDNA in vivo and to overcome the limitations of CPT, we designed two substitutions (T546A and N550H) in Top1mt to stabilize Top1mtcc. We refer to the double-mutant enzyme as Top1mt*. Using retroviral transduction and ChIP-on-chip assays with Top1mt* in Top1mt knock-out murine embryonic fibroblasts, we demonstrate that Top1mt* forms high levels of cleavage complexes preferentially in the noncoding regulatory region of mtDNA, accumulating especially at the heavy strand replication origin OH, in the ribosomal genes (12S and 16S) and at the light strand replication origin OL. Expression of Top1mt* also caused rapid mtDNA depletion without affecting mitochondria mass, suggesting the existence of specific mitochondrial pathways for the removal of damaged mtDNA. PMID- 24798331 TI - Expression of the yeast cation diffusion facilitators Mmt1 and Mmt2 affects mitochondrial and cellular iron homeostasis: evidence for mitochondrial iron export. AB - Mmt1 and Mmt2 are highly homologous yeast members of the cation diffusion facilitator transporter family localized to mitochondria. Overexpression of MMT1/2 led to changes in cellular metal homeostasis (increased iron sensitivity, decreased cobalt sensitivity, increased sensitivity to copper), oxidant generation, and increased sensitivity to H2O2. The phenotypes due to overexpression of MMT1&2 were similar to that seen in cells with deletions in MRS3 and MRS4, genes that encode the mitochondrial iron importers. Overexpression of MMT1&2 resulted in induction of the low iron transcriptional response, similar to that seen in Deltamrs3Deltamr4 cells. This low iron transcriptional response was suppressed by deletion of CCC1, the gene that encodes the vacuolar iron importer. Measurement of the activity of the iron-dependent gentisate 1,2 dioxygenase from Pseudaminobacter salicylatoxidans expressed in yeast cytosol, showed that changes in Mmt1/2 levels affected cytosol iron concentration even in the absence of Ccc1. Overexpression of MMT1 resulted in increased cytosolic iron whereas deletion of MMT1/MMT2 led to decreased cytosolic iron. These results support the hypothesis that Mmt1/2 function as mitochondrial iron exporters. PMID- 24798330 TI - Nodal.Gdf1 heterodimers with bound prodomains enable serum-independent nodal signaling and endoderm differentiation. AB - The TGFbeta family member Nodal is central to control pluripotent stem cell fate, but its use as a stem cell differentiation factor is limited by low specific activity. During development, Nodal depends on growth and differentiation factor (Gdf)-1 and on the shared co-receptor Cryptic to specify visceral left-right axis asymmetry. We therefore asked whether the functionality of Nodal can be augmented by Gdf1. Because Nodal and Gdf1 coimmunoprecipitate each other, they were predicted to form heterodimers, possibly to facilitate diffusion or to increase the affinity for signaling receptors. Here, we report that Gdf1 suppresses an unexpected dependence of Nodal on serum proteins and that it is critically required for non-autonomous signaling in cells expressing Cryptic. Nodal, Gdf1, and their cleaved propeptides copurified as a heterodimeric low molecular weight complex that stimulated Activin receptor (Acvr) signaling far more potently than Nodal alone. Although heterodimerization with Gdf1 did not increase binding of Nodal to Fc fusions of co-receptors or Acvr extracellular domains, it was essential for soluble Acvr2 to inhibit Nodal signaling. This implies that Gdf1 potentiates Nodal activity by stabilizing a low molecular weight fraction that is susceptible to neutralization by soluble Acvr2. Finally, in differentiating human ES cells, endodermal markers were more efficiently induced by Nodal.Gdf1 than by Nodal, suggesting that Nodal.Gdf1 is an attractive new reagent to direct stem cell differentiation. PMID- 24798332 TI - Identification of key residues and regions important for porcupine-mediated Wnt acylation. AB - Wnts comprise a family of lipid-modified, secreted signaling proteins that control embryogenesis, as well as tissue homeostasis in adults. Post translational attachment of palmitoleate (C16:1) to a conserved Ser in Wnt proteins is catalyzed by Porcupine (Porcn), a member of the membrane bound O acyltransferase (MBOAT) family, and is required for Wnt secretion and signaling. Moreover, genetic alterations in the PORCN gene lead to focal dermal hypoplasia, an X-linked developmental disorder. Despite its physiological importance, the biochemical mechanism governing Wnt acylation by Porcn is poorly understood. Here, we use a cell-based fatty acylation assay that is a direct readout of Porcn acyltransferase activity to perform structure-function analysis of highly conserved residues in Porcn and Wnt3a. In total, 16-point mutations in Porcn and 13 mutations in Wnt3a were generated and analyzed. We identified key residues within Porcn required for enzymatic activity, stability, and Wnt3a binding and mapped these active site residues to predicted transmembrane domain 9. Analysis of focal dermal hypoplasia-associated mutations in Porcn revealed that loss of enzymatic activity arises from altered stability. A consensus sequence within Wnt3a was identified (CXCHGXSXXCXXKXC) that contains residues that mediate Porcn binding, fatty acid transfer, and Wnt signaling. We also showed that Ser or Thr, but not Cys, can serve as a fatty acylation site in Wnt, establishing Porcn as an O-acyltransferase. This analysis sheds light into the mechanism by which Porcn transfers fatty acids to Wnt proteins and provides insight into the mechanisms of fatty acid transfer by MBOAT family members. PMID- 24798333 TI - N-Glycan-dependent and -independent quality control of human delta opioid receptor N-terminal variants. AB - Quality control (QC) in the endoplasmic reticulum (ER) scrutinizes newly synthesized proteins and directs them either to ER export or ER-associated degradation (ERAD). Here, we demonstrate that the human delta-opioid receptor (hdeltaOR) is subjected to ERQC in both N-glycan-dependent and -independent manners. This was shown by investigating the biosynthesis and trafficking of wild type and non-N-glycosylated F27C variants in metabolic pulse-chase assays coupled with flow cytometry and cell surface biotinylation. Both QC mechanisms distinguished the minute one-amino acid difference between the variants, targeting a large fraction of hdeltaOR-Cys(27) to ERAD. However, the N-glycan independent QC was unable to compensate the N-glycan-dependent pathway, and some incompletely folded non-N-glycosylated hdeltaOR-Cys(27) reached the cell surface in conformation incompatible with ligand binding. The turnover of receptors associating with the molecular chaperone calnexin (CNX) was significantly slower for the hdeltaOR-Cys(27), pointing to an important role of CNX in the hdeltaOR N glycan-dependent QC. This was further supported by the fact that inhibiting the co-translational interaction of hdeltaOR-Cys(27) precursors with CNX led to their ERAD. Opioid receptor pharmacological chaperones released the CNX-bound receptors to ER export and, furthermore, were able to rescue the Cys(27) variant from polyubiquitination and retrotranslocation to the cytosol whether carrying N glycans or not. Taken together, the hdeltaOR appears to rely primarily on the CNX mediated N-glycan-dependent QC that has the capacity to assist in folding, whereas the N-glycan-independent mechanism constitutes an alternative, although less accurate, system for directing misfolded/incompletely folded receptors to ERAD, possibly in altered cellular conditions. PMID- 24798334 TI - UVA light-excited kynurenines oxidize ascorbate and modify lens proteins through the formation of advanced glycation end products: implications for human lens aging and cataract formation. AB - Advanced glycation end products (AGEs) contribute to lens protein pigmentation and cross-linking during aging and cataract formation. In vitro experiments have shown that ascorbate (ASC) oxidation products can form AGEs in proteins. However, the mechanisms of ASC oxidation and AGE formation in the human lens are poorly understood. Kynurenines are tryptophan oxidation products produced from the indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway and are present in the human lens. This study investigated the ability of UVA light-excited kynurenines to photooxidize ASC and to form AGEs in lens proteins. UVA light excited kynurenines in both free and protein-bound forms rapidly oxidized ASC, and such oxidation occurred even in the absence of oxygen. High levels of GSH inhibited but did not completely block ASC oxidation. Upon UVA irradiation, pigmented proteins from human cataractous lenses also oxidized ASC. When exposed to UVA light (320-400 nm, 100 milliwatts/cm(2), 45 min to 2 h), young human lenses (20-36 years), which contain high levels of free kynurenines, lost a significant portion of their ASC content and accumulated AGEs. A similar formation of AGEs was observed in UVA-irradiated lenses from human IDO/human sodium-dependent vitamin C transporter-2 mice, which contain high levels of kynurenines and ASC. Our data suggest that kynurenine-mediated ASC oxidation followed by AGE formation may be an important mechanism for lens aging and the development of senile cataracts in humans. PMID- 24798335 TI - A phosphotyrosine switch for cargo sequestration at clathrin-coated buds. AB - The AP-2 clathrin adaptor complex oversees endocytic cargo selection in two parallel but independent manners. First, by physically engaging peptide-based endocytic sorting signals, a subset of clathrin-dependent transmembrane cargo is directly collected into assembling buds. Synchronously, by interacting with an assortment of clathrin-associated sorting proteins (CLASPs) that independently select different integral membrane cargo for inclusion within the incipient bud, AP-2 handles additional cargo capture indirectly. The distal platform subdomain of the AP-2 beta2 subunit appendage is a privileged CLASP-binding surface that recognizes a cognate, short alpha-helical interaction motif. This signal, found in the CLASPs beta-arrestin and the autosomal recessive hypercholesterolemia (ARH) protein, docks into an elongated groove on the beta2 appendage platform. Tyr-888 is a critical constituent of this spatially confined beta2 appendage contact interface and is phosphorylated in numerous high-throughput proteomic studies. We find that a phosphomimetic Y888E substitution does not interfere with incorporation of expressed beta2-YFP subunit into AP-2 or alter AP-2 deposition at surface clathrin-coated structures. The Y888E mutation does not affect interactions involving the sandwich subdomain of the beta2 appendage, indicating that the mutated appendage is folded and operational. However, the Y888E, but not Y888F, switch selectively uncouples interactions with ARH and beta-arrestin. Phyogenetic conservation of Tyr-888 suggests that this residue can reversibly control occupancy of the beta2 platform-binding site and, hence, cargo sorting. PMID- 24798336 TI - The pyruvate dehydrogenase complexes: structure-based function and regulation. AB - The pyruvate dehydrogenase complexes (PDCs) from all known living organisms comprise three principal catalytic components for their mission: E1 and E2 generate acetyl-coenzyme A, whereas the FAD/NAD(+)-dependent E3 performs redox recycling. Here we compare bacterial (Escherichia coli) and human PDCs, as they represent the two major classes of the superfamily of 2-oxo acid dehydrogenase complexes with different assembly of, and interactions among components. The human PDC is subject to inactivation at E1 by serine phosphorylation by four kinases, an inactivation reversed by the action of two phosphatases. Progress in our understanding of these complexes important in metabolism is reviewed. PMID- 24798337 TI - Human UTY(KDM6C) is a male-specific Nepsilon-methyl lysyl demethylase. AB - The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of N(epsilon)-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyzes demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors. PMID- 24798338 TI - Fibrodysplasia ossificans progressiva-related activated activin-like kinase signaling enhances osteoclast formation during heterotopic ossification in muscle tissues. AB - Fibrodysplasia ossificans progressiva is characterized by extensive ossification within muscle tissues, and its molecular pathogenesis is responsible for the constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2). In this study, we investigated the effects of implanting ALK2 (R206H)-transfected myoblastic C2C12 cells into nude mice on osteoclast formation during heterotopic ossification in muscle and subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells with BMP-2 in nude mice induced robust heterotopic ossification with an increase in the formation of osteoclasts in muscle tissues but not in subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells in muscle induced heterotopic ossification more effectively than that of empty vector transfected cells. A co-culture of ALK2 (R206H)-transfected C2C12 cells as well as the conditioned medium from ALK2 (R206H)-transfected C2C12 cells enhanced osteoclast formation in Raw264.7 cells more effectively than those with empty vector-transfected cells. The transfection of ALK2 (R206H) into C2C12 cells elevated the expression of transforming growth factor (TGF)-beta, whereas the inhibition of TGF-beta signaling suppressed the enhanced formation of osteoclasts in the co-culture with ALK2 (R206H)-transfected C2C12 cells and their conditioned medium. In conclusion, this study demonstrated that the causal mutation transfection of fibrodysplasia ossificans progressiva in myoblasts enhanced the formation of osteoclasts from its precursor through TGF-beta in muscle tissues. PMID- 24798339 TI - Distinct roles for release factor 1 and release factor 2 in translational quality control. AB - In bacteria, stop codons are recognized by two similar class 1 release factors, release factor 1 (RF1) and release factor 2 (RF2). Normally, during termination, the class 2 release factor 3 (RF3), a GTPase, functions downstream of peptide release where it accelerates the dissociation of RF1/RF2 prior to ribosome recycling. In addition to their canonical function in termination, both classes of release factor are also involved in a post peptidyl transfer quality control (post PT QC) mechanism where the termination factors recognize mismatched (i.e. error-containing) ribosome complexes and promote premature termination. Here, using a well defined in vitro system, we explored the role of release factors in canonical termination and post PT QC. As reported previously, during canonical termination, RF1 and RF2 recognize stop codons in a similar manner, and RF3 accelerates their rate of dissociation. During post PT QC, only RF2 (and not RF1) effectively binds to mismatched ribosome complexes; and whereas the addition of RF3 to RF2 increased its rate of release on mismatched complexes, the addition of RF3 to RF1 inhibited its rate of release but increased the rate of peptidyl-tRNA dissociation. Our data strongly suggest that RF2, in addition to its primary role in peptide release, functions as the principle factor for post PT QC. PMID- 24798340 TI - Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation. AB - Despite the number of extensive studies on the immune function and signaling of inflammasomes in various diseases, the activating mechanism of inflammasome, especially the NLRP3 inflammasome, is not fully understood. Nuclear factor E2 related Factor-2 (Nrf2), a key transcription factor that regulates cellular redox homeostasis, has been reported to play both protective and pathogenic roles depending on the disease conditions through undefined mechanism. This study reveals an essential role of Nrf2 in inflammasome activation. LPS stimulation increased Nrf2 protein levels in a Myd88-dependent manner. When compared with wild-type controls, Nrf2-deficient (Nrf2(-/-)) macrophages showed decreased maturation and secretion of caspase-1 and IL-1beta and reduced apoptosis associated speck-like protein containing CARD (ASC) speck formation in response to various NLRP3 and AIM2 inflammasome stimuli. In contrast, NLRC4 inflammasome activation was not controlled by Nrf2. Biochemical analysis revealed that Nrf2 appeared in the ASC-enriched cytosolic compartment after NLRP3 inflammasome activation. Furthermore, mitochondrial reactive oxygen species-induced NLRP3 activation also required Nrf2. Nrf2(-/-) mice showed a dramatic decrease in immune cell recruitment and IL-1beta generation in alum-induced peritonitis, which is a typical IL-1 signaling-dependent inflammation animal model. This work discovered a critical proinflammatory effect of Nrf2 by mediating inflammasome activation. PMID- 24798341 TI - 1-Methyl-tryptophan synergizes with methotrexate to alleviate arthritis in a mouse model of arthritis. AB - Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with no known cure. Current strategies to treat RA, including methotrexate (MTX), target the later inflammatory stage of disease. Recently, we showed that inhibiting indoleamine-2,3-dioxygenase (IDO) with 1-methyl-tryptophan (1MT) targets autoantibodies and cytokines that drive the initiation of the autoimmune response. Therefore, we hypothesized that combining 1MT with MTX would target both the initiation and chronic inflammatory phases of the autoimmune response and be an effective co-therapeutic strategy for arthritis. To test this, we used K/BxN mice, a pre-clinical model of arthritis that develops joint-specific inflammation with many characteristics of human RA. Mice were treated with 1MT, MTX, alone or in combination, and followed for arthritis, autoantibodies, and inflammatory cytokines. Both 1MT and MTX were able to partially inhibit arthritis when used individually; however, combining MTX + 1MT was significantly more effective than either treatment alone at delaying the onset and alleviating the severity of joint inflammation. We went on to show that combination of MTX + 1MT did not lower inflammatory cytokine or autoantibody levels, nor could the synergistic co-therapeutic effect be reversed by the adenosine receptor antagonist theophylline or be mimicked by inhibition of polyamine synthesis. However, supplementation with folinic acid did reverse the synergistic co therapeutic effect, demonstrating that, in the K/BxN model, MTX synergizes with 1MT by blocking folate metabolism. These data suggest that pharmacological inhibition of IDO with 1MT is a potential candidate for use in combination with MTX to increase its efficacy in the treatment of RA. PMID- 24798342 TI - microRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression. AB - Hepatocellular carcinoma (HCC) is classified as a poor prognostic tumor, and becomes frequently aggressive. MicroRNAs emerge as key contributors to tumor progression. This study investigated whether miR-148a dysregulation differentiates poor prognosis of HCC, exploring new targets of miR-148a. miR-148a dysregulation discriminated not only the overall survival and recurrence free survival rates of HCC, but the microvascular invasion. In the human HCC samples, ubiquitin specific protease 4 (USP4) and sphingosine 1-phosphate receptor 1 (S1P1) were up-regulated as the new targets of miR-148a. USP4 and S1P1 were up regulated in mesenchymal-type liver-tumor cells with miR-148a dysregulation, facilitating migration and proliferation of tumor cells. The inverse relationship between miR-148a and the identified targets was verified in a tumor xenograft model. In the analysis of human samples, the expression of USP4, but not S1P1, correlated with the decrease of miR-148a. In a heterotropic patient-derived HCC xenograft model, USP4 was also overexpressed in G1 and G2 tumors when miR-148a was dysregulated, reflecting the closer link between miR-148a and USP4 for a shift in the expansion phase of tumorgraft. In conclusion, miR-148a dysregulation affects the poor prognosis of HCC. Of the identified targets of miR-148a, USP4 overexpression may contribute to HCC progression towards more aggressive feature. PMID- 24798343 TI - Pulse pressure variations to guide fluid therapy in donors: a multicentric echocardiographic observational study. AB - PURPOSE: Preload responsiveness parameters could be useful in the hemodynamic management of septic shock. METHODS: A multicentric prospective echocardiographic observational study was conducted from March 2009 to August 2011. Clinically brain-dead subjects were included. Pulse pressure variations (DeltaPPs) were recorded. Cardiac index, variation of the maximum flow velocity of aortic systolic blood flow, and right ventricular function parameters were evaluated via transthoracic echocardiography. Fluid responsiveness was defined by at least 15% cardiac index increase, 30 minutes after a 500-mL colloid solution infusion. The number of organs harvested was recorded. RESULTS: Twenty-five subjects were included. Pulse pressure variation could not discriminate responders (n=15) from nonresponders (n=10). The best DeltaPP threshold (20%) could discriminate responders with a sensitivity of 100% and a specificity of 40%. Variation of the maximum flow velocity of aortic systolic blood flow, tricuspid annular plane systolic excursion, and right ventricle dilation could not discriminate responders from nonresponders. Eighteen subjects underwent organ harvesting. The number of organs harvested was higher in responders (3.5 [3-5]) than in nonresponders (2.5 [2-3]; P=.03). CONCLUSIONS: A DeltaPP threshold of 13% is insufficient to guide volume expansion in donors. The best threshold is 20%. Fluid responsiveness monitoring could enhance organ harvesting. PMID- 24798344 TI - Immature granulocytes predict microbial infection and its adverse sequelae in the intensive care unit. AB - BACKGROUND: We evaluated the predictive value of immature granulocyte (IG) percentage in comparison with white blood cell counts (WBC) and C-reactive protein (CRP), for infection, its invasiveness, and severity in critically ill patients. METHODS: In 46 consecutive patients, blood samples were collected at the day (0) of a clinical suspicion of microbial infection and at days 1 and 3 thereafter. We defined infections, bloodstream infection, and septic shock within 7 days after enrollment. RESULTS: Of the 46 patients, 31 patients had infection, 15 patients developed bloodstream infection, and 13 patients septic shock. C reactive protein and IG percentage increased with increasing invasiveness and severity of infection, from day 0 onwards. Receiver operating characteristic analysis to predict infection showed an area under the curve of 0.66 (P=.10) for WBC vs 0.74 (P=.01) for CRP and 0.73 (P=.02) for IG percentage on day 0. Comparing WBC and CRP to WBC and IG percentage results in comparable prediction of microbial infection. Comparing WBC and CRP with WBC, CRP, and IG percentage suggests an additional early value of IG percentage, when not elevated, in ruling out infection. CONCLUSION: Immature granulocyte percentage is a useful marker, as CRP, to predict infection, its invasiveness, and severity, in critically ill patients. However, the IG percentage adds to WBC and CRP in the early exclusion of infection and can be obtained routinely without extra blood sampling or costs. PMID- 24798345 TI - Polymyxin B-immobilized fiber column hemoperfusion removes endotoxin throughout a 24-hour treatment period. AB - PURPOSE: The purpose of this study was to evaluate the extent of endotoxin adsorption by polymyxin B-immobilized fiber column hemoperfusion (PMX) performed for a 24-hour treatment period in patients with septic shock. MATERIALS AND METHODS: Nineteen patients with septic shock were retrospectively studied. The plasma endotoxin concentrations of blood drawn from the radial artery and from the outlet circuit of the PMX column were measured by kinetic turbidimetric limulus assay using an MT-358 Toxinometer (Wako Pure Chemical Industries, Ltd, Osaka, Japan) after 24 hours of PMX treatment. The endotoxin removal rate was defined by the following equation: ([radial artery endotoxin concentration - outlet circuit of PMX column endotoxin concentration]/radial artery endotoxin concentration) * 100%. RESULTS: The patients had a median Acute Physiology and Chronic Health Evaluation II score of 29 at intensive care unit admission and a 28-day mortality of 47%. Before the start of the PMX treatment, the median radial arterial plasma endotoxin concentration was 16.48 pg/mL. After 24 hours of PMX treatment, the median radial plasma endotoxin concentration had decreased to 1.857 pg/mL, and the concentration at the outlet circuit of the PMX column was further decreased to 0.779 pg/mL. The median endotoxin removal rate was 74.4%. CONCLUSION: These findings suggest that 24-hour PMX treatment was effective in removing endotoxin continuously throughout the entire treatment period. PMID- 24798346 TI - Procalcitonin, as an early biomarker of colorectal anastomotic leak, facilitates enhanced recovery after surgery. AB - PURPOSE: Procalcitonin (PCT) is a biomarker used to help sepsis diagnosing and monitoring and guide antibiotic therapy. Anastomotic leak (AL) after colorectal surgery is a severe complication associated with relevant short- and long-term sequelae. The aim of our study is to assess the predictive value of PCT levels to early diagnose AL after colorectal surgery. METHODS: Between September 2011 and September 2012, a series of 99 patients underwent colorectal surgery in our institution. In all cases, white blood cell (WBC) count, C-reactive protein (CRP), and PCT levels were measured in first, third, and fifth postoperative day (POD). Anastomotic leaks and all other postoperative complications were recorded. RESULTS: We registered 7 ALs (7.1%). Decreased PCT levels had a significant negative predictive value (NPV) for AL in third and fifth POD (96.7% and 96.7%, respectively), compared with CRP and WBC. The best diagnostic performance was obtained with the combination of PCT and CRP measurements in third and fifth POD (area under the curve, 0.87 and 0.94, respectively). In 5th POD, PCT improves diagnosis, but not in a statistically significant way (area under the curve, 0.86). CONCLUSIONS: Compared with more established biochemical values such as CRP and WBC, PCT is an earlier, more sensitive, and reliable marker of AL. Increased PCT levels in early PODs after colorectal surgery may provide a more effective way to detect AL, before clinical symptoms appear. Moreover, normal PCT values might be also a useful marker to facilitate a safe and early discharge of selected patients after colorectal surgery. PMID- 24798347 TI - Linking annual N2O emission in organic soils to mineral nitrogen input as estimated by heterotrophic respiration and soil C/N ratio. AB - Organic soils are an important source of N2O, but global estimates of these fluxes remain uncertain because measurements are sparse. We tested the hypothesis that N2O fluxes can be predicted from estimates of mineral nitrogen input, calculated from readily-available measurements of CO2 flux and soil C/N ratio. From studies of organic soils throughout the world, we compiled a data set of annual CO2 and N2O fluxes which were measured concurrently. The input of soil mineral nitrogen in these studies was estimated from applied fertilizer nitrogen and organic nitrogen mineralization. The latter was calculated by dividing the rate of soil heterotrophic respiration by soil C/N ratio. This index of mineral nitrogen input explained up to 69% of the overall variability of N2O fluxes, whereas CO2 flux or soil C/N ratio alone explained only 49% and 36% of the variability, respectively. Including water table level in the model, along with mineral nitrogen input, further improved the model with the explanatory proportion of variability in N2O flux increasing to 75%. Unlike grassland or cropland soils, forest soils were evidently nitrogen-limited, so water table level had no significant effect on N2O flux. Our proposed approach, which uses the product of soil-derived CO2 flux and the inverse of soil C/N ratio as a proxy for nitrogen mineralization, shows promise for estimating regional or global N2O fluxes from organic soils, although some further enhancements may be warranted. PMID- 24798349 TI - Synthesis and structural characterization of Al-containing interlayer-expanded MWW zeolite with high catalytic performance. AB - Treatment of the zeolitic layered precursor of Al-MWW, so-called Al-MWW(P), with diethoxydimethylsilane (DEDMS) in acidic media leads to the formation of an aluminosilicate-type interlayer-expanded zeolite MWW (Al-IEZ-MWW) with expanded 12-membered ring (12-MR) micropores. However, the silylation process under acidic conditions simultaneously causes dealumination from the MWW framework, resulting in a decrease in the acid amount. We have developed a method for preparing Al-IEZ MWW without leaching of the Al species. The strategy is to conduct the silylation under weakly acidic conditions; the silylation was conducted in an aqueous solution of an ammonium salt, e.g., NH4Cl, instead of HNO3. Subsequent additional acid treatment led to the formation of Al-IEZ-MWW that shows a high catalytic performance in the acylation of anisole compared to typical Al-MWW as well as Al IEZ-MWW directly prepared under acidic conditions. The change in the state of Al atoms during the preparation process was investigated by high-resolution solid state (27)Al MAS NMR and (27)Al MQMAS NMR techniques. PMID- 24798348 TI - A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma. AB - Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-kappaB signaling. Inhibition of NF-kappaB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-kappaB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-kappaB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-kappaB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-kappaB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL. PMID- 24798350 TI - Good response to infliximab in rheumatoid arthritis following failure of interleukin-1 receptor antagonist. AB - AIM: To evaluate the efficacy of tumor necrosis factor inhibitor infliximab in patients with rheumatoid arthritis (RA) who were disease-resistant to recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS: A total of 104 patients with active RA despite methotrexate (MTX) treatment were enrolled in the open trial. Among them, 27 IL-1Ra nonresponders 'Switchers' and 51 biologic-naive patients 'Naivers' received an infusion of 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy, while the other 26 patients who had never received any biologics 'Controls' continued MTX monotherapy. Clinical outcomes and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks with the American College of Rheumatology (ACR) core set criteria, the Disease Activity Score in 28 joints, and records of adverse events (AEs) and abnormal laboratory findings. RESULTS: At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers, compared with 23% of Controls (P = 0.0013 and 0.0126, respectively). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient's assessment of pain, patient's and physician's global assessment of disease activity, erythrocyte sedimentation rate and C-reactive protein. Switchers even achieved a greater benefit from health assessment questionnaire (HAQ) scores than Naivers. Infliximab was well tolerated, with a similar incidence of AEs across all study groups. CONCLUSION: Switching from IL-1Ra to infliximab is effective in improving disease activity and maintaining joint function. PMID- 24798351 TI - Neurophysiological findings in a newborn with chromosome 10 trisomy. AB - The trisomy of the short arm of chromosome 10 is a rare condition. The phenotypic expression of this genetic aberration is characterised by growth and mental retardation with several neurological signs. We report the neurophysiological findings in a newborn affected by 10p chromosome trisomy who developed seizures. Serial EEGs showed a progressive reduction in burst-suppression activity and a slow rhythmic basal activity. At 1 year of age the recording showed for the first time spikes of high amplitude (up to 800 MUV) in bilateral frontal regions. These findings could be related to an asymmetrical cerebral maturation in the context of perinatal sufferance and brain malformation due to the genetic aberration. PMID- 24798352 TI - Isolated secondary CNS relapse in a case of stage I diffuse large B-cell lymphoma. AB - A 55-year-old woman was admitted to our hospital with a 10-day history of right arm weakness and numbness. The patient's medical history was notable for lobular carcinoma in situ of the right breast in 2008 and stage I diffuse large B-cell lymphoma of the left axilla. The patient had completed treatment with chemotherapy and radiation 2 months prior to presentation. Blood counts, metabolic panel and lumbar puncture were unremarkable. MRI of the brain revealed multiple enhancing masses. The patient was started on dexamethasone, with rapid symptom improvement. A stereotactic brain biopsy revealed CD20 diffuse large B cell lymphoma. The patient was started on high-dose intravenous methotrexate. She has received 11 cycles and has regained near normal function of the right arm. The patient's most recent brain MRI showed near complete resolution of all previously seen abnormal foci of enhancement. PMID- 24798353 TI - Extensive pulmonary involvement with raltegravir-induced DRESS syndrome in a postpartum woman with HIV. AB - An 18-year-old postpartum woman with HIV, on lamivudine-zidovudine, lopinavir ritonavir and raltegravir, presented with a 1-week history of rash and fevers. Initially admitted to obstetrics and gynaecology service for treatment of possible endometritis, she was transferred to the HIV medicine service for high fever, respiratory distress, hypotension and tachycardia. On admission, she was febrile (102 degrees F) with findings of cervical and submandibular lymphadenopathy, diffuse morbilliform rash, generalised pruritus, facial oedema, and oedematous hands and feet. Consultations to various specialty services were initiated to rule out infectious, dermatological, rheumatological and drug induced aetiologies. On the fourth day of hospitalisation, laboratory findings of significant eosinophilia and hepatitis (alanine aminotransferase 147 IU/L and aspartate aminotransferase 124 IU/L), in conjunction with the identification of the timing of medication use, led to a diagnosis of DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome secondary to raltegravir. After discontinuing raltegravir and starting prednisone, her DRESS symptoms completely resolved. PMID- 24798354 TI - Tuberculosis and TNF-inhibitors: history of exposure should outweigh investigations. AB - A 39-year-old Indian man was diagnosed with ulcerative colitis on colonic biopsy and started on mesalazine, prednisolone and azathioprine. However, the colitis remained active and required antitumour necrosis factor (TNF) treatment with infliximab. Prior to starting infliximab, his chest X-ray was normal and QuantiFERON interferon gamma release assay for tuberculosis (TB) was negative. However, his wife had been treated for pulmonary TB 11 years previously when they were cohabiting. On attending for his third dose of infliximab, he was feverish and tachycardic, and was admitted for investigation. Chest X-ray on admission showed changes consistent with miliary TB, and thoracic CT confirmed extensive miliary nodules with supraclavicular and mediastinal lymphadenopathy. Abdominal CT showed multiple mesenteric lymph nodes. Subsequent bronchoalveolar lavage, neck lymph node aspirate and colonic biopsies all cultured Mycobacterium tuberculosis. In retrospect, a clear history of close household TB exposure should have precipitated consideration of TB chemoprophylaxis prior to anti-TNF treatment. PMID- 24798355 TI - Primary gallbladder lymphoma presenting as a polyp. AB - We present an unusual case of a 75-year-old woman, with no significant medical history, presenting with ongoing weight loss and change in bowel habit. Her physical examination and initial blood tests were all normal, and, therefore, radiographic imaging was undertaken. Ultrasound and CT of the abdomen confirmed a gallbladder polyp and a laparoscopic cholecystectomy was subsequently performed. Histological analysis confirmed primary gallbladder lymphoma. This case report is the first to present gallbladder lymphoma presenting as a polyp. The authors discuss the incidence, presentation and management of gallbladder lymphoma. PMID- 24798356 TI - Plate-like osteoma cutis: nothing but skin and bone? AB - Osteoma cutis encompasses a group of cutaneous ossifying disorders, more commonly secondary to trauma, inflammation or neoplasms. Fourteen per cent, however, are primary, and these may be syndromatic (associated to Albright's hereditary osteodystrophy) or occur in isolation. We report a case of a 10-year-old girl who presented with a stone-hard plate on the scalp, with no relevant personal or family history, nor changes in calcium-phosphate metabolism, parathyroid hormone or thyroid function. Skin biopsy confirmed osteoma cutis. Plate-like osteoma cutis is rare, and believed to be a non-progressive form of heterotopic ossification, included in the spectrum of progressive osseus heteroplasia and Albright hereditary osteodystrophy, due to GNAS gene mutations. This recently clarified association should remind us of the possible unfavourable evolution of a seemingly innocent clinical picture, emphasising the need for appropriate evaluation, management and follow-up. PMID- 24798357 TI - Rapidly involuting congenital haemangioma in a term neonate. PMID- 24798358 TI - Infective endocarditis caused by Streptococcus gallolyticus subspecies pasteurianus and colon cancer. AB - A 56-year-old man presented to our department with a 2-month history of fever and chills. He had received a mitral valvuloplasty 3 years ago. He had been administered levofloxacin for 2 months. We discontinued levofloxacin and repeated the blood cultures. Bacterial blood cultures were positive and transoesophageal echocardiography revealed vegetation attached to the posterior mitral leaflet. We started the patient on intravenous antibiotic therapy for infectious endocarditis by Streptococcus gallolyticus subspecies pasteurianus. A colonoscopic screening revealed adenomatoid intracellular carcinoma. Previous studies have reported a weak association between colorectal cancer and Streptococcus bovis biotype II/2, which includes S gallolyticus subspecies pasteurianus; however, the rate is notably higher than the rate of colorectal cancer as indicated by positive faecal occult-blood test results. We conclude that colonoscopies should be routine while scanning for colorectal cancer in all patients with S bovis bacteraemia, regardless of the subspecies. PMID- 24798359 TI - Coronary arteriovenous fistula with coexisting atrial septal defect. PMID- 24798360 TI - Recovery of pituitary function following treatment of an unruptured giant cavernous carotid aneurysm using Surpass flow-diverting stents. AB - Giant aneurysms arising from the cavernous internal carotid artery (ICA) can mimic pituitary adenomas and may cause pituitary dysfunction due to their mass effect on the pituitary gland. We report a case of a 56-year-old man presenting with impotence, fatigue and panhypopituitarism who was found to have a giant unruptured aneurysm arising from the right cavernous ICA with severe mass effect on the pituitary gland. The patient underwent endovascular treatment of the giant aneurysm using two telescoping Surpass flow-diverting stents. At 6-month follow up, repeat cerebral angiography showed Raymond grade II occlusion of the aneurysm with a small neck remnant. At the 10-month follow-up the patient showed full recovery of his pituitary function and clinical resolution of impotence and fatigue. This is the first report of occlusion of a giant cavernous carotid aneurysm using next generation Surpass flow-diverting stents leading to complete recovery of pituitary function. PMID- 24798361 TI - Meconium peritonitis: an interesting entity. PMID- 24798362 TI - Congenital ductus arteriosus aneurysm: an unusual cause of transient neonatal hypertension. AB - Case 1: A term male child was re-admitted on day 10 of life due to acute onset of respiratory distress. Physical examination revealed tachypnoea, tachycardia and blood pressure (BP) above the 95th centile in all four limbs. Cardiovascular examination revealed a short systolic murmur on the sternal border. Abdomen showed hepatomegaly of 3 cm below the costal margin. Chest X-ray showed a cardiothoracic ratio of 0.65 with normal vascularity. Ultrasound and Doppler of the kidneys and brain were normal. The high parasternal view showed a large ductus arteriosus aneurysm (DAA) of 2.0 * 2.5 cm. The baby was managed with inotropes and antihypertensives. CT angiogram showed 1.6 * 0.6 cm thrombosed DAA, which was extending from the posterior descending aorta to the ampulla. With the resolution of aneurysm BPs normalised and antihypertensives were stopped at 6 weeks of age. Case 2: A premature male neonate weighing 1.2 kg was admitted to the neonatal intensive care unit for respiratory distress syndrome. On the 4th day of life during routine measurement of vitals, the BP was consistently above 95th centile in all four limbs. Blood tests revealed thrombocytopenia that persisted inspite of single donor transfusions. The evaluation for sepsis was negative. The ultrasound and Dopplers of the kidneys and brain were all normal. A transthoracic echocardiogram showed a large DAA measuring 5 * 1.8 mm. Hypertension was managed with antihypertensives. Serial transthoracic echocardiogram showed organising DAA. CT angiogram showed 6 mm * 2 mm thrombosed DAA. As the arterial BP normalised, antihypertensives were stopped on day 15 of life. The baby was discharged on day 29 of life and on follow-up BP remained normal. PMID- 24798363 TI - Transverse colon cancer presenting as acute abdominal wall abscess. PMID- 24798364 TI - Priapism in a patient with sickle cell trait using marijuana. AB - A 22-year-old man with a history of multiple episodes of priapism presented to the emergency room with an erection lasting more than 48 h after conservative management failed at home. He had no known family history of sickle cell disease or trait. He was haemodynamically stable. Physical examination revealed an enlarged, tender penis. Laboratory data revealed a positive sickle solubility test. Haemoglobin electrophoresis revealed sickle cell trait and urine drug screen was positive for cannabinoids. Initial management was attempted with intracavernosal phenylephrine without any success. The patient underwent a limited El-Ghorab procedure on the right corpora cavernosa but the priapism did not resolve adequately. Two days later, the patient had to undergo a bilateral El Ghorab procedure and achieved complete resolution of the priapism. PMID- 24798365 TI - Paraesophageal hiatus hernia in an 8-month-old infant with organoaxial volvulus of the stomach. AB - Paraesophageal hiatus hernia is an extremely rare variety of hiatus hernia and it is rarely seen in the paediatric age group. We present an instance of this hernia in which an 8-month-old female infant was admitted with a history of ongoing vomiting and irritability since past 7 days. The subsequent imaging study showed paraesophageal hiatus hernia with twisting of the stomach along its longitudinal axis (organoaxial volvulus). Subsequent surgical repair led to the resolution of symptoms. This kind of volvulus is rare in hiatus hernia and once detected it requires prompt surgical management. Given the asymptomatic presentation of hiatus hernia clinicians need to realise that this can be associated with volvulus of stomach which, if left unrepaired, can lead to severe complications. Thus, prompt consideration is necessary with timely surgical referral to alleviate this rare but important variety of hiatus hernia. PMID- 24798366 TI - Conservative management of bilateral choanal atresia? Bilateral choanal atresia diagnosed in a 5-year-old girl. AB - Choanal atresia (CA) is an obliteration or blockage of the posterior nasal aperture, limiting or obstructing the nasal airway to the nasopharynx. The presentation of unilateral CA commonly occurs at a later age than those children affected by bilateral CA (BCA) and can often persist undiagnosed into adulthood. BCA, on the other hand, typically presents with respiratory obstruction within the first few days of life, or desaturations with or without cyanosis when feeding or during exertion and traditional teaching is that this is a life threatening emergency. We present the case of a 5-year-old girl referred to our department with nasal obstruction, snoring and some mild rhinorrhoea. After investigation she was found to have a mixed bony and membranous BCA and no other craniofacial abnormalities. The BCA was subsequently repaired using urethral dilators and a drill and the child is currently asymptomatic of any restenosis. This case prompts discussion of the various presentations and options in management of CA as well as allowing us an opportunity to discuss the literature on the subject. PMID- 24798367 TI - Uranium in larval shells as a barometer of molluscan ocean acidification exposure. AB - As the ocean undergoes acidification, marine organisms will become increasingly exposed to reduced pH, yet variability in many coastal settings complicates our ability to accurately estimate pH exposure for those organisms that are difficult to track. Here we present shell-based geochemical proxies that reflect pH exposure from laboratory and field settings in larvae of the mussels Mytilus californianus and M. galloprovincialis. Laboratory-based proxies were generated from shells precipitated at pH 7.51 to 8.04. U/Ca, Sr/Ca, and multielemental signatures represented as principal components varied with pH for both species. Of these, U/Ca was the best predictor of pH and did not vary with larval size, with semidiurnal pH fluctuations, or with oxygen concentration. Field applications of U/Ca were tested with mussel larvae reared in situ at both known and unknown pH conditions. Larval shells precipitated in a region of greater upwelling had higher U/Ca, and these U/Ca values corresponded well with the laboratory-derived U/Ca-pH proxy. Retention of the larval shell after settlement in molluscs allows use of this geochemical proxy to assess ocean acidification effects on marine populations. PMID- 24798368 TI - Innate immunity: A COX detox for the immune system? PMID- 24798369 TI - Inflammation: Regulating ROS. PMID- 24798370 TI - Human mesenchymal stem cells resolve airway inflammation, hyperreactivity, and histopathology in a mouse model of occupational asthma. AB - Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL 33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 * 10(6) cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA. PMID- 24798371 TI - Simple and efficient methods for enrichment and isolation of endonuclease modified cells. AB - The advent of Transcription Activator-Like Effector Nucleases (TALENs), and similar technologies such as CRISPR, provide a straightforward and cost effective option for targeted gene knockout (KO). Yet, there is still a need for methods that allow for enrichment and isolation of modified cells for genetic studies and therapeutics based on gene modified human cells. We have developed and validated two methods for simple enrichment and isolation of single or multiplex gene KO's in transformed, immortalized, and human progenitor cells. These methods rely on selection of a phenotypic change such as resistance to a particular drug or ability to grow in a selective environment. The first method, termed co transposition, utilizes integration of a piggyBac transposon vector encoding a drug resistance gene. The second method, termed co-targeting, utilizes TALENs to KO any gene that when lost induces a selectable phenotype. Using these methods we also show removal of entire genes and demonstrate that TALENs function in human CD34+ progenitor cells. Further, co-transposition can be used to generate conditional KO cell lines utilizing an inducible cDNA rescue transposon vector. These methods allow for robust enrichment and isolation of KO cells in a rapid and efficient manner. PMID- 24798372 TI - A survey of veterinary radiation facilities in 2010. AB - A survey of veterinary radiation therapy facilities in the United States, Canada, and Europe was done in 2010, using an online survey tool, to determine the type of equipment available, radiation protocols used, caseload, tumor types irradiated, as well as other details of the practice of veterinary radiation oncology. The results of this survey were compared to a similar survey performed in 2001. A total of 76 facilities were identified including 24 (32%) academic institutions and 52 (68%) private practice external beam radiation therapy facilities. The overall response rate was 51% (39/76 responded). Based on this survey, there is substantial variation among facilities in all aspects ranging from equipment and personnel to radiation protocols and caseloads. American College of Veterinary Radiology boarded radiation oncologists direct 90% of the radiation facilities, which was increased slightly compared to 2001. All facilities surveyed in 2010 had a linear accelerator. More facilities reported having electron capability (79%) compared to the 2001 survey. Eight facilities had a radiation oncology resident, and academic facilities were more likely to have residents. Patient caseload information was available from 28 sites (37% of radiation facilities), and based on the responses 1376 dogs and 352 cats were irradiated in 2010. The most frequently irradiated tumors were soft tissue sarcomas in dogs, and oral squamous cell carcinoma in cats. PMID- 24798373 TI - A platinum(II) complex of liriodenine from traditional Chinese medicine (TCM): Cell cycle arrest, cell apoptosis induction and telomerase inhibition activity via G-quadruplex DNA stabilization. AB - Liriodenine (L), an antitumor active ingredient from the traditional Chinese medicine (TCM), Zanthoxylum nitidum, afforded a platinum(II) complex (1) of L, cis-[PtCl2(L)(DMSO)], which previously reported for its in vitro antitumor activity and intercalative binding with DNA. In this study, complex 1 was further discussed for its antitumor mechanism and structure-activity relationship, comparing with L and cisplatin. Towards the most sensitive BEL-7404 human hepatoma cells, complex 1 significantly induced cell cycle arrest at both G2/M phase and S phase. It suggests that double helix DNA is not the simplex intracellular target for 1. On the other hand, the BEL-7404 cells incubated with 1 and stained by Hoechst 33258 and AO/EB showed typical cell apoptosis in dose dependent manner. The BEL-7404 cells incubated with 1 and stained by JC-1 were also characteristic for cell apoptosis on the loss of mitochondrial membrane potential. Furthermore, the G-quadruplex DNA binding property of complex 1 was also investigated by spectroscopic analyses, fluorescent indicator displacement (FID) assay and fluorescence resonance energy transfer (FRET) assay. The results indicated that 1 stabilized the human telomeric G4-HTG21 DNA better than L. The telomerase inhibition ratio of 1 ((62.50+/-0.03)%), which was examined by telomerase polymerase chain reaction-enzyme-linked immunosorbent assay (PCR ELISA), was much higher than L ((21.77+/-0.01)%). It can be ascribed to the better G4-HTG21 DNA stabilization of 1 than L. The results suggested that the nuclei, mitochondria and telomerase via G-quadruplex DNA stabilization all should be key targets for the antitumor mechanism of 1, in which the central platinum(II) played a key role. PMID- 24798374 TI - The cytotoxicity of the anticancer drug elesclomol is due to oxidative stress indirectly mediated through its complex with Cu(II). AB - Elesclomol is an anticancer drug that is currently undergoing clinical trials. Elesclomol forms a strong 1:1 complex with Cu(II) and may exert its anticancer activity through the induction of oxidative stress and/or its ability to transport copper into the cell. A UV-vis spectrophotometric titration showed that Cu(I) also formed a 1:1 complex with elesclomol. Ascorbic acid, but not glutathione or NADH, potently reduced the Cu(II)-elesclomol complex to produce hydrogen peroxide. Even though hydrogen peroxide mediated reoxidation of the copper(I) produced by ascorbic acid reduction has the potential to lead to hydroxyl radical formation, electron paramagnetic resonance spin trapping experiments, either with or without added hydrogen peroxide, showed that the ascorbic acid-reduced Cu(II)-elesclomol complex could not directly generate damaging hydroxyl radicals. Both Cu(II)-elesclomol and elesclomol potently oxidized dichlorofluorescin in K562 cells. The highly specific copper chelators tetrathiomolybdate and triethylenetetramine were found to greatly reduce the cytotoxicity of both elesclomol and Cu(II)-elesclomol complex towards erythroleukemic K562 cells, consistent with a role for copper in the cytotoxicity of elesclomol. The superoxide dismutating activity of Cu(II)-elesclomol was much lower than that of Cu(II). Depletion of glutathione levels in K562 cells by treatment with buthionine sulfoximine sensitized cells to both elesclomol and Cu(II)-elesclomol. In conclusion, these results showed that elesclomol indirectly inhibited cancer cell growth through Cu(II)-mediated oxidative stress. PMID- 24798375 TI - Cause analysis of the effects of acid-catalyzed steam-exploded corn stover prehydrolyzate on ethanol fermentation by Pichia stipitis CBS 5776. AB - The prehydrolyzate obtained from acid-catalyzed steam-exploded corn stover (ASC) mainly contains xylose and a number of inhibitory compounds that inhibit ethanol fermentation by Pichia stipitis. In this study, the effects of the ASC prehydrolyzate, specifically those of the carbohydrate-degradation products, lignin-degradation products (which were extracted from ASC prehydrolyzate using ethyl acetate), and six major phenolic compounds (added to pure-sugar media individually or in combination), on ethanol fermentation were investigated. Results indicate that the effects of the carbohydrate-degradation products were negligible (10 h delayed) compared with those of pure-sugar fermentation, whereas the effects of the lignin-degradation products were significant (52 h delayed). Meanwhile, the inhibitory effects of the major phenolic compounds were not caused by certain types of inhibitors, but were due to the synergistic effects of various inhibitors. PMID- 24798376 TI - Asymmetric synthesis of duloxetine intermediate (S)-(-)-3-N-methylamino-1-(2 thienyl)-1-propanol using immobilized Saccharomyces cerevisiae in liquid-core sodium alginate/chitosan/sodium alginate microcapsules. AB - Duloxetine intermediate (S)-(-)-3-N-methylamino-1-(2-thienyl)-1-propanol was synthesized using ACA liquid-core immobilized Saccharomyces cerevisiae CGMCC No. 2230. The optimum culture time for ACA liquid-core immobilized cells was found to be 28 h. The optimum ACA liquid-core capsule formation conditions were found to be 90% chitosan deacetylation, 30,000-50,000 chitosan molecular weight, 5.0 g/L chitosan, and pH 6.0 citrate buffer solution. The highest activity was found when reduction conditions were pH 6.0, 30 degrees C and 180 rpm. The ACA-immobilized cells can be reused nine times and only 40% of the activity is retained after nine cycles. Product inhibition of reduction was observed in batch reduction. Continuous reduction in the membrane reactor was found to remove the product inhibition on reduction and improve production capacity. Conversion reached 100% and enantiometric excess of (S)-(-)-3-N-methylamino-1-(2-thienyl)-1-propanol exceeded 99.0% in continuous reduction of 5 g/L 3-N-methylamino-1-(2-thienyl)-1 propanone in the membrane reactor. PMID- 24798377 TI - Distinct and concurrent pathways of Pol II- and Pol IV-dependent siRNA biogenesis at a repetitive trans-silencer locus in Arabidopsis thaliana. AB - Short interfering RNAs (siRNAs) homologous to transcriptional regulatory regions can induce RNA-directed DNA methylation (RdDM) and transcriptional gene silencing (TGS) of target genes. In our system, siRNAs are produced by transcribing an inverted DNA repeat (IR) of enhancer sequences, yielding a hairpin RNA that is processed by several Dicer activities into siRNAs of 21-24 nt. Primarily 24-nt siRNAs trigger RdDM of the target enhancer in trans and TGS of a downstream GFP reporter gene. We analyzed siRNA accumulation from two different structural forms of a trans-silencer locus in which tandem repeats are embedded in the enhancer IR and distinguished distinct RNA polymerase II (Pol II)- and Pol IV-dependent pathways of siRNA biogenesis. At the original silencer locus, Pol-II transcription of the IR from a 35S promoter produces a hairpin RNA that is diced into abundant siRNAs of 21-24 nt. A silencer variant lacking the 35S promoter revealed a normally masked Pol IV-dependent pathway that produces low levels of 24-nt siRNAs from the tandem repeats. Both pathways operate concurrently at the original silencer locus. siRNAs accrue only from specific regions of the enhancer and embedded tandem repeat. Analysis of these sequences and endogenous tandem repeats producing siRNAs revealed the preferential accumulation of siRNAs at GC rich regions containing methylated CG dinucleotides. In addition to supporting a correlation between base composition, DNA methylation and siRNA accumulation, our results highlight the complexity of siRNA biogenesis at repetitive loci and show that Pol II and Pol IV use different promoters to transcribe the same template. PMID- 24798378 TI - Toluene diisocyanate (TDI) disposition and co-localization of immune cells in hair follicles. AB - Diisocyanates (dNCOs) are potent chemical allergens utilized in various industries. It has been proposed that skin exposure to dNCOs produces immune sensitization leading to work-related asthma and allergic disease. We examined dNCOs sensitization by using a dermal murine model of toluene diisocyanate (TDI) exposure to characterize the disposition of TDI in the skin, identify the predominant haptenated proteins, and discern the associated antigen uptake by dendritic cells. Ears of BALB/c mice were dosed once with TDI (0.1% or 4% v/v acetone). Ears and draining lymph nodes (DLNs) were excised at selected time points between 1 h and 15 days post-exposure and were processed for histological, immunohistochemical, and proteomic analyses. Monoclonal antibodies specific for TDI-haptenated protein (TDI-hp) and antibodies to various cell markers were utilized with confocal microscopy to determine co-localization patterns. Histopathological changes were observed following exposure in ear tissue of mice dosed with 4% TDI/acetone. Immunohistochemical staining demonstrated TDI-hp localization in the stratum corneum, hair follicles, and sebaceous glands. TDI-hp were co-localized with CD11b(+) (integrin alphaM/Mac-1), CD207(+) (langerin), and CD103(+) (integrin alphaE) cells in the hair follicles and in sebaceous glands. TDI-hp were also identified in the DLN 1 h post-exposure. Cytoskeletal and cuticular keratins along with mouse serum albumin were identified as major haptenated species in the skin. The results of this study demonstrate that the stratum corneum, hair follicles, and associated sebaceous glands in mice are dendritic cell accessible reservoirs for TDI-hp and thus identify a mechanism for immune recognition following epicutaneous exposure to TDI. PMID- 24798379 TI - Intracerebroventricularly and systemically delivered inhibitor of brain CYP2B (C8 Xanthate), even following chlorpyrifos exposure, reduces chlorpyrifos activation and toxicity in male rats. AB - Chlorpyrifos is a pesticide that is metabolically activated to chlorpyrifos oxon (acetylcholinesterase inhibitor) primarily by the cytochrome P450 2B (CYP2B) enzyme subfamily in the liver and brain. We have previously shown that intracerebroventricular pretreatment with a CYP2B inhibitor, C8-Xanthate, can block chlorpyrifos toxicity. Here, we assessed whether delayed introduction of C8 Xanthate would still reduce toxicity and whether peripheral administration of C8 Xanthate could also inhibit chlorpyrifos activation in the brain and block toxicity. Male rats (N = 4-5/group) were either pretreated with C8-Xanthate (40 MUg intracerebroventricular or 5 mg/kg intraperitoneal), or vehicle (ACSF or saline, respectively), 24 h before chlorpyrifos treatment (125 mg/kg subcutaneous) and then treated daily with inhibitor or vehicle until 7 days post chlorpyrifos treatment. Additional groups received vehicle pretreatment, switching to C8-Xanthate 1, 2, 3, or 4 days after chlorpyrifos and then continuing with daily C8-Xanthate treatment until 7 days post-chlorpyrifos treatment. Neurotoxicity was assessed at baseline (before chlorpyrifos) and then daily after chlorpyrifos, using behavioral assessments (e.g., gait score). Neurochemical assays (e.g., serum and brain chlorpyrifos) were performed at the end of study. Pretreatment with C8-Xanthate completely prevented chlorpyrifos toxicity, and delayed introduction of C8-Xanthate reduced toxicity, even when started up to 4 days after chlorpyrifos treatment. Discontinuation of C8-Xanthate treatment 7 days post-chlorpyrifos treatment did not result in the reappearance of toxicity, tested through 10 days after chlorpyrifos treatment. These findings suggest that CYP2B inhibitor treatment, even days after chlorpyrifos exposure, and using a peripheral delivery route, may be useful as a therapeutic approach to reduce chlorpyrifos toxicity. PMID- 24798380 TI - Dysfunctional lipoproteins from young smokers exacerbate cellular senescence and atherogenesis with smaller particle size and severe oxidation and glycation. AB - Until now, there has been limited information on the effects of smoking on atherogenesis and senescence in the context of lipoprotein parameters, particularly in young smokers who have smoked fewer than 10 cigarettes per day for 3 years. In this study, lipoprotein profiles and functions were compared between smoker (n = 21) and control groups (n = 20). In the smoking group, ferric ion reduction abilities of serum and high-density lipoprotein (HDL) fractions were significantly reduced, and low-density lipoprotein (LDL) was severely oxidized. All lipoprotein particles from the smoker group showed higher advanced glycated end products with more triglyceride (TG) content compared with the control group. Lipoproteins from smokers showed faster agarose gel electromobility as well as greater smear band intensity in SDS-PAGE due to oxidation and glycation. LDL from smokers was more sensitive to oxidation and promoted foam cell forma-tion in macrophages. Gel filtration column chromatography revealed that the protein and cholesterol peaks of VLDL and LDL were elevated in the smoker group, whereas those of HDL were reduced. Human dermal fibroblast cells from the smoker group showed severe senescence following treatment with HDL2 and HDL3. Although HDL from young smokers showed impaired antioxidant ability, smaller particle size, and increased TG content, cholesteryl ester transfer protein activities were greatly enhanced in the serum and HDL fractions of the smoker group. In conclusion, smoking can cause production of dysfunctional lipoproteins having a smaller particle size that exacerbate senescence and atherogenic progress due to oxidation and glycation. PMID- 24798381 TI - Persistence of cisplatin-induced mutagenicity in hematopoietic stem cells: implications for secondary cancer risk following chemotherapy. AB - Cisplatin is a cytostatic agent used in the treatment of many types of cancer, but its use is associated with increased incidences of secondary leukemia. We evaluated cisplatin's in vivo genotoxic potential by analyzing peripheral blood for Pig-a mutant phenotype erythrocytes and for chromosomal damage in the form of micronuclei. Mutant phenotype reticuloyte and erythrocyte frequencies, based on anti-CD59 antibody labeling and flow cytometric analysis, were determined in male Sprague Dawley rats treated for 28 consecutive days (days 1-28) with up to 0.4 mg cisplatin/kg/day, and sampled on days -4, 15, 29, and 56. Vehicle and highest dose groups were evaluated at additional time points post-treatment up to 6 months. Day 4 and 29 blood samples were also analyzed for micronucleated reticulocyte frequency using flow cytometry and anti-CD71-based labeling. Mutant phenotype reticulocytes were significantly elevated at doses >=0.1 mg/kg/day, and mutant phenotype erythrocytes were elevated at doses >=0.05 mg/kg/day. In the 0.4 mg/kg/day group, these effects persisted for the 6 month observation period. Cisplatin also induced a modest but statistically significant increase in micronucleus frequency at the highest dose tested. The prolonged persistence in the production of mutant erythrocytes following cisplatin exposure suggests that this drug mutates hematopoietic stem cells and that this damage may ultimately contribute to the increased incidence of secondary leukemias seen in patients cured of primary malignancies with platinum-based regimens. PMID- 24798382 TI - Developmental treatment with ethinyl estradiol, but not bisphenol A, causes alterations in sexually dimorphic behaviors in male and female Sprague Dawley rats. AB - The developing central nervous system may be particularly sensitive to bisphenol A (BPA)-induced alterations. Here, pregnant Sprague Dawley rats (n = 11-12/group) were gavaged daily with vehicle, 2.5 or 25.0 MUg/kg BPA, or 5.0 or 10.0 MUg/kg ethinyl estradiol (EE2) on gestational days 6-21. The BPA doses were selected to be below the no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day. On postnatal days 1-21, all offspring/litter were orally treated with the same dose. A naive control group was not gavaged. Body weight, pubertal age, estrous cyclicity, and adult serum hormone levels were measured. Adolescent play, running wheel activity, flavored solution intake, female sex behavior, and manually elicited lordosis were assessed. No significant differences existed between the vehicle and naive control groups. Vehicle controls exhibited significant sexual dimorphism for most behaviors, indicating these evaluations were sensitive to sex differences. However, only EE2 treatment caused significant effects. Relative to female controls, EE2-treated females were heavier, exhibited delayed vaginal opening, aberrant estrous cyclicity, increased play behavior, decreased running wheel activity, and increased aggression toward the stimulus male during sexual behavior assessments. Relative to male controls, EE2-treated males were older at testes descent and preputial separation and had lower testosterone levels. These results suggest EE2-induced masculinization/defeminization of females and are consistent with increased volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) at weaning in female siblings of these subjects (He, Z., Paule, M. G. and Ferguson, S. A. (2012) Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. Neurotoxicol. Teratol. 34, 331-337). Although EE2 treatment caused pubertal delays and decreased testosterone levels in males, their behaviors were within the range of control males. Conversely, BPA treatment did not alter any measured endpoint. Similar to our previous reports (Ferguson, S. A., Law, C. D. Jr and Abshire, J. S. (2011) Developmental treatment with bisphenol A or ethinyl estradiol causes few alterations on early preweaning measures. Toxicol. Sci. 124, 149-160; Ferguson, S. A., Law, C. D. and Abshire, J. S. (2012) Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. Neurotoxicol. Teratol. 34, 598 606), the BPA doses and design used here produced few alterations. PMID- 24798383 TI - Chemical tuning enhances both potency toward nrf2 and in vitro therapeutic index of triterpenoids. AB - The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf2. PMID- 24798385 TI - Vascular elastography: a validation study. AB - Vascular elastography techniques are promising tools for mechanical characterization of diseased arteries. These techniques are usually validated with simulations or phantoms or by comparing results with histology or other imaging modalities. In the study described here, vascular elastography was applied to porcine aortas in vitro during inflation testing (n = 10) and results were compared with those of standard bi-axial tensile testing, a technique that directly measures the force applied to the tissue. A neo-Hookean model was fit to the stress-strain data, valid for large deformations. Results indicated good correspondence between the two techniques, with GUS = 110 +/- 11 kPa and GTT = 108 +/- 10 kPa for ultrasound and tensile testing, respectively. Bland-Altman analysis revealed little bias (GUS-GTT = 2 +/- 20 kPa). The next step will be the application of a non-linear material model that is also adaptable for in vivo measurements. PMID- 24798384 TI - A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation. AB - This study was designed to develop and validate a short-term in vivo protocol termed the Fetal Phthalate Screen (FPS) to detect phthalate esters (PEs) and other chemicals that disrupt fetal testosterone synthesis and testis gene expression in rats. We propose that the FPS can be used to screen chemicals that produce adverse developmental outcomes via disruption of the androgen synthesis pathway more rapidly and efficiently, and with fewer animals than a postnatal one generation study. Pregnant rats were dosed from gestational day (GD) 14 to 18 at one dose level with one of 27 chemicals including PEs, PE alternatives, pesticides known to inhibit steroidogenesis, an estrogen and a potent PPARalpha agonist and ex vivo testis testosterone production (T Prod) was measured on GD 18. We also included some chemicals with "unknown" activity including DMEP, DHeP, DHEH, DPHCH, DAP, TOTM, tetrabromo-diethyl hexyl phthalate (BrDEHP), and a relatively potent environmental estrogen BPAF. Dose-response studies also were conducted with this protocol with 11 of the above chemicals to determine their relative potencies. CD-1 mice also were exposed to varying dose levels of DPeP from GD 13 to 17 to determine if DPeP reduced T Prod in this species since there is a discrepancy among the results of in utero studies of PEs in mice. Compared to the known male reproductive effects of the PEs in rats the FPS correctly identified all known "positives" and "negatives" tested. Seven of eight "unknowns" tested were "negatives", they did not reduce T Prod, whereas DAP produced an "equivocal" response. Finally, a dose-response study with DPeP in CD 1 mice revealed that fetal T Prod can be inhibited by exposure to a PE in utero in this species, but at a higher dose level than required in rats.Key words. Phthalate Syndrome, Fetal endocrine biomarkers, Phthalate adverse outcome pathway, testosterone production, fetal rat testis. PMID- 24798386 TI - Synergistic ablation of liver tissue and liver cancer cells with high-intensity focused ultrasound and ethanol. AB - We investigated the combined effect of ethanol and high-intensity focused ultrasound (HIFU), first, on heating and cavitation bubble activity in tissue mimicking phantoms and porcine liver tissues and, second, on the viability of HepG2 liver cancer cells. Phantoms or porcine tissues were injected with ethanol and then subjected to HIFU at acoustic power ranging from 1.2 to 20.5 W (HIFU levels 1-7). Cavitation events and the temperature around the focal zone were measured with a passive cavitation detector and embedded type K thermocouples, respectively. HepG2 cells were subjected to 4% ethanol solution in growth medium (v/v) just before the cells were exposed to HIFU at 2.7, 8.7 or 12.0 W for 30 s. Cell viability was measured 2, 24 and 72 h post-treatment. The results indicate that ethanol and HIFU have a synergistic effect on liver cancer ablation as manifested by greater temperature rise and lesion volume in liver tissues and reduced viability of liver cancer cells. This effect is likely caused by reduction of the cavitation threshold in the presence of ethanol and the increased rate of ethanol diffusion through the cell membrane caused by HIFU induced streaming, sonoporation and heating. PMID- 24798387 TI - Quantification of carotid plaque neovascularization using contrast-enhanced ultrasound with histopathologic validation. AB - We sought to evaluate contrast-enhanced ultrasound (CEUS) imaging for the quantification of carotid plaque neovascularization. Seventeen patients underwent carotid endarterectomy after standard ultrasound and CEUS. Semiquantitative and quantitative analyses of contrast enhancement within the plaque were performed using a visual interpretation scale and quantitative analysis software, respectively. Enhancement intensity (dB) was measured at the plaque (EI(plaque)). Each specimen was stained with CD34 and CD68 to assess for microvessels and macrophages, respectively. Semiquantitative CEUS analyses were correlated with neovascularization at histology (r = 0.70, p = 0.002). Quantitative analysis was also correlated with neovascularization at histology (EI(plaque)r = 0.81, p < 0.001). EI(plaque) (r = 0.64, p = 0.01) was correlated with the degree of enhancement as assessed visually. Semiquantitative and quantitative analyses were not correlated with macrophage infiltration at the plaque. Contrast enhancement in the carotid plaque was correlated with neovascularity at the histopathologic exam. Furthermore, semiquantitative and quantitative measurements were highly correlated with each other, suggesting that either can be used to detect intraplaque neovascularization. PMID- 24798388 TI - Lipid shedding from single oscillating microbubbles. AB - Lipid-coated microbubbles are used clinically as contrast agents for ultrasound imaging and are being developed for a variety of therapeutic applications. The lipid encapsulation and shedding of the lipids by acoustic driving of the microbubble has a crucial role in microbubble stability and in ultrasound triggered drug delivery; however, little is known about the dynamics of lipid shedding under ultrasound excitation. Here we describe a study that optically characterized the lipid shedding behavior of individual microbubbles on a time scale of nanoseconds to microseconds. A single ultrasound burst of 20 to 1000 cycles, with a frequency of 1 MHz and an acoustic pressure varying from 50 to 425 kPa, was applied. In the first step, high-speed fluorescence imaging was performed at 150,000 frames per second to capture the instantaneous dynamics of lipid shedding. Lipid detachment was observed within the first few cycles of ultrasound. Subsequently, the detached lipids were transported by the surrounding flow field, either parallel to the focal plane (in-plane shedding) or in a trajectory perpendicular to the focal plane (out-of-plane shedding). In the second step, the onset of lipid shedding was studied as a function of the acoustic driving parameters, for example, pressure, number of cycles, bubble size and oscillation amplitude. The latter was recorded with an ultrafast framing camera running at 10 million frames per second. A threshold for lipid shedding under ultrasound excitation was found for a relative bubble oscillation amplitude >30%. Lipid shedding was found to be reproducible, indicating that the shedding event can be controlled. PMID- 24798389 TI - A cadaveric and preliminary clinical study of ultrasonographically assisted percutaneous carpal tunnel release. AB - The aim of this study was to assess the effectiveness and safety profile of a new technique for ultrasonographically assisted percutaneous carpal tunnel release. Experiments were performed on 40 hands in 20 cadavers. We first performed a detailed ultrasonographic examination and correlation study that included surgical dissection of the transverse carpal ligament, the related neurovascular structures and the bony landmarks of the radiocarpal, midcarpal and carpometacarpal joints of the right hand. We then used the measurements we made for percutaneous carpal tunnel release of the transverse carpal ligament using intra-operative ultrasonography for guidance and a hook knife on the left-hand side. The completeness of the release and the potential risks of injury to the flexor tendon and neurovascular bundles were examined. Using real-time intra operative ultrasonographic monitoring to clearly delineate these targets, we were able to percutaneously release the transverse carpal ligament completely in 18 (90%) of the 20 hands and partially release it in 2 without injuring any neurovascular bundles. We then performed the procedure on 91 consecutive cases of carpal tunnel syndrome and found that the sensory disturbances disappeared in 100% patients 12 mo post-operatively; only 2 hands were graded as unsatisfactory. There were no intra- or post-operative complications. Based on the results from the cadaveric studies and our successful preliminary clinical outcomes, we conclude that this method is tolerable and that its clinical application can be encouraged. PMID- 24798390 TI - Assessing the imaging capabilities of radial mechanical and electronic echo endoscopes using the resolution integral. AB - Over the past decade there have been significant advances in endoscopic ultrasound (EUS) technology. Although there is an expectation that new technology will deliver improved image quality, there are few methods or phantoms available for assessing the capabilities of mechanical and electronic EUS systems. The aim of this study was to investigate the possibility of assessing the imaging capability of available EUS technologies using measurements of the resolution integral made with an Edinburgh Pipe Phantom. Various radial EUS echo-endoscopes and probes were assessed using an Edinburgh Pipe Phantom. Measurements of the resolution integral (R), depth of field (LR) and characteristic resolution (DR) were made at all operating frequencies. The mean R value for Fuji miniprobes was 16.0. The GF-UM20 and GF-UM2000 mechanical radial scopes had mean R values of 24.0 and 28.5, respectively. The two electronic radial echo-endoscopes had similar mean R values of 34.3 and 34.6 for the Olympus GF-UE260 and Fujinon EG 530 UR scopes, respectively. Despite being older technology, the mechanical GF UM2000 scope had superior characteristic resolution (DR), but could not compare with the depths of field (LR) delivered by the current generation of electronic radial scopes, especially at the standard operating frequencies of 7.5 and 12 MHz. PMID- 24798391 TI - A method to validate quantitative high-frequency power doppler ultrasound with fluorescence in vivo video microscopy. AB - Flow quantification with high-frequency (>20 MHz) power Doppler ultrasound can be performed objectively using the wall-filter selection curve (WFSC) method to select the cutoff velocity that yields a best-estimate color pixel density (CPD). An in vivo video microscopy system (IVVM) is combined with high-frequency power Doppler ultrasound to provide a method for validation of CPD measurements based on WFSCs in mouse testicular vessels. The ultrasound and IVVM systems are instrumented so that the mouse remains on the same imaging platform when switching between the two modalities. In vivo video microscopy provides gold standard measurements of vascular diameter to validate power Doppler CPD estimates. Measurements in four image planes from three mice exhibit wide variation in the optimal cutoff velocity and indicate that a predetermined cutoff velocity setting can introduce significant errors in studies intended to quantify vascularity. Consistent with previously published flow-phantom data, in vivo WFSCs exhibited three characteristic regions and detectable plateaus. Selection of a cutoff velocity at the right end of the plateau yielded a CPD close to the gold-standard vascular volume fraction estimated using IVVM. An investigator can implement the WFSC method to help adapt cutoff velocity to current blood flow conditions and thereby improve the accuracy of power Doppler for quantitative microvascular imaging. PMID- 24798392 TI - Early pregnancy placental bed and fetal vascular volume measurements using 3-D virtual reality. AB - In this study, a new 3-D Virtual Reality (3D VR) technique for examining placental and uterine vasculature was investigated. The validity of placental bed vascular volume (PBVV) and fetal vascular volume (FVV) measurements was assessed and associations of PBVV and FVV with embryonic volume, crown-rump length, fetal birth weight and maternal parity were investigated. One hundred thirty-two patients were included in this study, and measurements were performed in 100 patients. Using V-Scope software, 100 3-D Power Doppler data sets of 100 pregnancies at 12 wk of gestation were analyzed with 3D VR in the I-Space Virtual Reality system. Volume measurements were performed with semi-automatic, pre defined parameters. The inter-observer and intra-observer agreement was excellent with all intra-class correlation coefficients >0.93. PBVVs of multiparous women were significantly larger than the PBVVs of primiparous women (p = 0.008). In this study, no other associations were found. In conclusion, V-Scope offers a reproducible method for measuring PBVV and FVV at 12 wk of gestation, although we are unsure whether the volume measured represents the true volume of the vasculature. Maternal parity influences PBVV. PMID- 24798393 TI - Application of ultrasound in the assessment of plantar fascia in patients with plantar fasciitis: a systematic review. AB - Plantar fasciitis (PFS) is one of the most common causes of heel pain, estimated to affect 10% of the general population during their lifetime. Ultrasound (US) imaging technique is increasingly being used to assess plantar fascia (PF) thickness, monitor the effect of different interventions and guide therapeutic interventions in patients with PFS. The purpose of the present study was to systematically review previously published studies concerning the application of US in the assessment of PF in patients with PFS. A literature search was performed for the period 2000-2012 using the Science Direct, Scopus, PubMed, CINAHL, Medline, Embase and Springer databases. The key words used were: ultrasound, sonography, imaging techniques, ultrasonography, interventional ultrasonography, plantar fascia and plantar fasciitis. The literature search yielded 34 relevant studies. Sixteen studies evaluated the effect of different interventions on PF thickness in patients with PFS using US; 12 studies compared PF thickness between patients with and without PFS using US; 6 studies investigated the application of US as a guide for therapeutic intervention in patients with PFS. There were variations among studies in terms of methodology used. The results indicated that US can be considered a reliable imaging technique for assessing PF thickness, monitoring the effect of different interventions and guiding therapeutic interventions in patients with PFS. PMID- 24798394 TI - Time efficiency and diagnostic agreement of 2-D versus 3-D ultrasound acquisition of the neonatal brain. AB - The purpose of this study was to compare acquisition time efficiency and diagnostic agreement of neonatal brain ultrasound (US) scans obtained with a 3-D volume US acquisition protocol and the conventional 2-D acquisition protocol. Ninety-one consecutive premature neonatal brain ultrasound scans were prospectively performed on 59 neonates with the conventional 2-D acquisition protocol. Immediately after the 2-D study, a coronal 3-D ultrasound volume was acquired and later reconstructed into axial and sagittal planes. All 59 neonates were imaged in the neonatal intensive care unit to rule out intracranial hemorrhage. Total time for 2-D and 3-D acquisition protocols was recorded, and a two-tailed t-test was used to determine if study durations differed significantly. One pediatric neuroradiologist reviewed the reformatted 3-D images, tomographic ultrasound images. Results were compared with the clinical interpretation of the 2-D conventional study. The mean scanning time for the 2-D US acquisition protocol was 10.56 min (standard deviation [SD] = 7.11), and that for the 3-D volume US acquisition protocol was 1.48 min (SD = 0.59) (p <= 0.001). Inter-observer agreement revealed k values of 0.84 for hydrocephalus, 0.80 for germinal matrix hemorrhage/intraventricular hemorrhage, 0.74 for periventricular leukomalacia and 0.91 for subdural collection, hence near-perfect to substantial agreement between imaging protocols. There was a significant decrease in acquisition time for the 3-D volume ultrasound acquisition protocol compared with the conventional 2-D US protocol (p = <0.001), without compromising the diagnostic quality compared with a conventional 2-D US imaging protocol. PMID- 24798396 TI - Inhibitory effects of lysophosphatidic acid receptor-5 on cellular functions of sarcoma cells. AB - Lysophosphatidic acid (LPA) is a bioactive lipid that interacts with G protein coupled LPA receptors (LPA receptor-1 (LPA1) to LPA6). Here, we investigated the effects of LPA signaling via LPA5 on cellular functions of sarcoma cells by generating Lpar5 overexpressing and Lpar5 knockdown cells from rat osteosarcoma and malignant fibrous histiocytoma cells, respectively. The cell motility activity of Lpar5 overexpressing cells was significantly lower, while Lpar5 knockdown cells showed high cell motility, compared with respective controls. Gelatin zymography showed that LPA5 suppressed the activation of matrix metalloproteinase-2. LPA5 also inhibited the cell motility activity of endothelial cells, correlating with the expression levels of vascular endothelial growth factor genes. These results suggest that LPA signaling via LPA5 negatively regulates the cellular functions of rat sarcoma cells. PMID- 24798395 TI - Stability and predictive utility, over 3 years, of the illness beliefs of individuals recently diagnosed with Type 2 diabetes mellitus. AB - AIM: To determine the stability of beliefs of patients with Type 2 diabetes about their diabetes over 3 years, following diagnosis. METHODS: Data were collected as part of a multicentre cluster randomized controlled trial of a 6-h self management programme, across 207 general practices in the UK. Participants in the original trial were eligible for follow-up with biomedical data (HbA1c levels, blood pressure, weight, blood lipid levels) collected at the practice, and questionnaire data collected by postal distribution and return. Psychological outcome measures were depression (Hospital Anxiety and Depression Scale) and diabetes distress (Problem Areas in Diabetes scale). Illness beliefs were assessed using the Illness Perceptions Questionnaire-Revised and the Diabetes Illness Representations Questionnaire scales. RESULTS: At 3-year follow-up, all post-intervention differences in illness beliefs between the intervention and the control group remained significant, with perceptions of the duration of diabetes, seriousness of diabetes and perceived impact of diabetes unchanged over the course of the 3-year follow-up. The control group reported a greater understanding of diabetes during the follow-up, and the intervention group reported decreased responsibility for diabetes outcomes during the follow-up. After controlling for 4-month levels of distress and depression, the perceived impact of diabetes at 4 months remained a significant predictor of distress and depression at 3-year follow-up. CONCLUSIONS: Peoples' beliefs about diabetes are formed quickly after diagnosis, and thereafter seem to be relatively stable over extended follow-up. These early illness beliefs are predictive of later psychological distress, and emphasize the importance of initial context and provision of diabetes care in shaping participants' future well-being. PMID- 24798397 TI - Isolation and functional characterization of human ventricular cardiomyocytes from fresh surgical samples. AB - Cardiomyocytes from diseased hearts are subjected to complex remodeling processes involving changes in cell structure, excitation contraction coupling and membrane ion currents. Those changes are likely to be responsible for the increased arrhythmogenic risk and the contractile alterations leading to systolic and diastolic dysfunction in cardiac patients. However, most information on the alterations of myocyte function in cardiac diseases has come from animal models. Here we describe and validate a protocol to isolate viable myocytes from small surgical samples of ventricular myocardium from patients undergoing cardiac surgery operations. The protocol is described in detail. Electrophysiological and intracellular calcium measurements are reported to demonstrate the feasibility of a number of single cell measurements in human ventricular cardiomyocytes obtained with this method. The protocol reported here can be useful for future investigations of the cellular and molecular basis of functional alterations of the human heart in the presence of different cardiac diseases. Further, this method can be used to identify novel therapeutic targets at cellular level and to test the effectiveness of new compounds on human cardiomyocytes, with direct translational value. PMID- 24798398 TI - Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. AB - Multiple sclerosis (MS) is the most prevalent inflammatory demyelinating disease of the central nervous system. Besides other pathophysiological mechanisms, mitochondrial injury is crucially involved in the development and progression of this disease. Mitochondria have been identified as targets for the peptide hormone melatonin. In the present study, we sought to evaluate the impact of oxidative stress on mitochondrial density and enzyme transcription during experimentally induced demyelination and the protective influence of melatonin. Adult male mice were fed with cuprizone for 5 weeks which caused severe demyelination of the corpus callosum (CC). Animals were simultaneously treated with melatonin by daily intra-peritoneal injections. Melatonin exposure reversed cuprizone-induced demyelination and axon protection. Transmission electron microscopy demonstrated significantly increased mitochondrial numbers and slightly increased mitochondrial size within CC axons after cuprizone exposure. Melatonin antagonized these effects and, in addition, induced the expression of subunits of the respiratory chain complex over normal control values reflecting a mechanism to compensate cuprizone-mediated down-regulation of these genes. Similarly, melatonin modulated gene expression of mitochondrial fusion and fission proteins. Biochemical analysis showed that oxidative stress induced by cuprizone was regulated by melatonin. The data implicate that melatonin abolishes destructive cuprizone effects in the CC by decreasing oxidative stress, restoring mitochondrial respiratory enzyme activity and fusion and fission processes as well as decreasing intra-axonal mitochondria accumulation. PMID- 24798399 TI - X-ray analysis of the effect of the 5-HT3 receptor antagonist granisetron on gastrointestinal motility in rats repeatedly treated with the antitumoral drug cisplatin. AB - Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT3 receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT3 receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin. PMID- 24798400 TI - Vibrotactile masking through the body. AB - Touches on one hand or forearm can affect tactile sensitivity at contralateral locations on the opposite side of the body. These interactions suggest an intimate connection between the two sides of the body. Here, we explore the effect of masking not across the body but through the body by measuring the effect of a masking stimulus on the back on the tactile sensitivity of the corresponding point on the front. Tactile sensitivity was measured on each side of the stomach, while vibrotactile masking stimulation was applied to one side of the front and to points on the back including the point directly behind the test point on the front. Results were compared to sensitivity, while vibrotactile stimulation was applied to a control site on the shoulder. A reduction in sensitivity of about .8 dB was found that required the masking stimulus to be within about 2 cm of the corresponding point on the back. PMID- 24798402 TI - Accounting for Attribute-Level Non-Attendance in a Health Choice Experiment: Does it Matter? AB - An extensive literature has established that it is common for respondents to ignore attributes of the alternatives within choice experiments. In most of the studies on attribute non-attendance, it is assumed that respondents consciously (or unconsciously) ignore one or more attributes of the alternatives, regardless of their levels. In this paper, we present a new line of enquiry and approach for modelling non-attendance in the context of investigating preferences for health service innovations. This approach recognises that non-attendance may not just be associated with attributes but may also apply to the attribute's levels. Our results show that respondents process each level of an attribute differently: while attending to the attribute, they ignore a subset of the attribute's levels. In such cases, the usual approach of assuming that respondents either attend to the attribute or not, irrespective of its levels, is erroneous and could lead to misguided policy recommendations. Our results indicate that allowing for attribute-level non-attendance leads to substantial improvements in the model fit and has an impact on estimated marginal willingness to pay and choice predictions. PMID- 24798401 TI - Structural correlates of motor adaptation deficits in patients with acute focal lesions of the cerebellum. AB - Studies of cerebellar patients employing modern lesion-symptom mapping techniques have provided valuable insights into the contribution of the cerebellum to motor adaptation. In patients with chronic focal lesions of the cerebellum, the process of adapting reaching movements to force field (FF) and visuomotor rotation (VM) perturbations relies on different anatomical structures located primarily within the territory of the superior hand area. By contrast, results within the territory of the inferior hand area are less consistent. Compensatory mechanisms may have masked the contribution of the inferior hand area. To test this hypothesis, reaching adaptation to FF and VM perturbations was investigated in 24 patients with acute and subacute lesions of the cerebellum. High-resolution magnetic resonance images were acquired to perform voxel-based lesion-symptom mapping (VLSM). VLSM confirmed that distinct and only partially overlapping areas located primarily within the territory of the superior hand area were crucial for adaptation to FF and VM. More specifically, current results add to previous findings that lobule V is of particular importance in FF adaptation, whereas lobule VI plays a more important role in VM adaptation. No clear evidence for a contribution of the inferior hand area to either task was found. Reach adaptation appears to depend primarily on the superior hand area within the cerebellum. PMID- 24798403 TI - The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. AB - Tumor cells use activated platelets to promote their proliferation and metastatic potential. Because platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets, we investigated the potential of the reversible P2Y12 inhibitor ticagrelor, a clinical agent used in the prevention of cardiovascular and cerebrovascular events, to inhibit tumor adhesion and metastasis. In B16-F10 melanoma intravenous and intrasplenic metastasis models, mice treated with a clinical dose of ticagrelor (10 mg/kg) exhibited marked reductions in lung (84%) and liver (86%) metastases. Furthermore, ticagrelor treatment improved survival compared to saline-treated animals. A similar effect was observed in a 4T1 breast cancer model, with reductions in lung (55%) and bone marrow (87%) metastases following ticagrelor treatment. In vitro, B16-F10 cells exhibited decreased interaction with platelets from ticagrelor-treated mice compared to saline-treated mice, an effect similar to that observed with blockade of glycoprotein IIbIIIa. Similarly, B16-F10 cells co-incubated with platelets from ticagrelor-treated mice exhibited reduced adhesion to endothelial monolayers compared to those co-incubated with platelets from saline-treated animals, an effect also observed in vivo. Interestingly, pretreatment of endothelial monolayers with ticagrelor did not result in reduced tumor cell adhesion. These findings support a role for P2Y12-mediated platelet activation in promoting metastases, and provide proof-of-concept for the clinical use of ticagrelor in the prevention of tumor metastasis. PMID- 24798404 TI - Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression. AB - Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness. PMID- 24798405 TI - Water-fat separation from a single spatiotemporally encoded echo based on nominal k-space peaking and joint regularized estimation. AB - PURPOSE: To present a new high-resolution single-point water-fat separation algorithm based on the spatiotemporally encoded chemical shift imaging technique. THEORY: Identifying water and fat peaks on the ensemble of the nominal k-space profiles of all spatiotemporally encoded lines enables evaluation of the mean off resonance frequencies of the two components. With utilization of the spatial smoothness and filtering regularizations, the water/fat profiles can be discriminated with twice joint linear least squares estimations line-by-line. METHODS: The effectiveness of the proposed algorithm was assessed by experiments on oil-water phantoms and in vivo in rats at 7T using a spatiotemporally encoded variant of the multishot spin-echo sequence. The results were compared with those obtained from previously proposed 1-point Dixon, 2-point Dixon, and 3-point IDEAL methods. RESULTS: The results demonstrate that the new technique can achieve high quality water-fat separations, comparable in signal-to-noise ratio and contrast to the multipoint methods and is more robust in cases when large areas of low signals or motion artifacts jeopardize the results from the 1-point Dixon method. CONCLUSIONS: The proposed technique is potentially a new viable alternative for single-point water-fat separation. PMID- 24798406 TI - Oligonucleotide delivery: a patent review (2010 - 2013). AB - INTRODUCTION: The use of aptamers, antisense technology and RNA interference has allowed nucleic acids to be considered as promising alternatives to classical drugs. However, nucleic acids face several obstacles in the creation of effective nucleic acid drugs. The development of these approaches has strengthened the pipeline with an increasing number of these therapies in clinical trials. AREAS COVERED: This review covers research and patent literature from the last three years, focusing on the development of safe and effective non-viral drug delivery systems for the treatment of diseases such as cancer or genetic disorders by using oligonucleotides. EXPERT OPINION: The therapeutic applications of oligonucleotides have overcome multiple obstacles, especially in biodistribution and cellular internalization. Cationic lipids are the most used vehicles for the preparation of novel formulations. Combinatorial libraries of these compounds and the use of solid lipid nanoparticles carrying these synthetic cationic lipids (cholesterol and PEG) have enhanced cellular uptake and biocompatibility of nucleic acids. Besides this extensive use, synthesis of oligonucleotides covalently linked to lipids has also emerged as a promising alternative to formulations. The use of peptides alone or in combination with lipids is an expanding field for oligonucleotide delivery. Polymeric platforms are also good candidates as they showed improved cellular uptake, biodegradability, biocompatibility and the possibility of incorporating several components, such as ligands for receptor-mediated endocytosis and molecules, to facilitate endosomal escape. Finally, nanomaterials may also play an important role in the future. The last developments showed improvement in in vivo efficacy, thus gaining a foothold in therapeutics. PMID- 24798407 TI - Total synthesis of (+)-madangamine D. AB - Madangamines are a group of bioactive marine sponge alkaloids, embodying an unprecedented diazapentacyclic skeletal type. The enantioselective total synthesis of madangamine D has been accomplished, and represents the first total synthesis of an alkaloid of the madangamine group. It involves the stereoselective construction of the diazatricyclic ABC core using a phenylglycinol-derived lactam as the starting enantiomeric scaffold and the subsequent assembly of the peripheral macrocyclic rings. The synthesis provides, for the first time, a pure sample of madangamine D and confirms the absolute configuration of this alkaloid family. PMID- 24798408 TI - Different localizations underlying cortical gelastic epilepsy: case series and review of literature. AB - BACKGROUND: Gelastic seizures (GS) are classically observed with hypothalamic hamartomas but they can also be associated with cortical epileptogenic foci. OBJECTIVE: To study the different cortical localizations associated with GS. METHODS: We reviewed the data from all patients with cortical GS investigated in our epilepsy unit from 1974 to 2012 and in the literature from 1956 to 2013. RESULTS: Sixteen cases were identified in our database and 77 in the literature. Investigations provided confident focus localization in 9 and 18, respectively. In our series, the identified foci were located in the mesial temporal structures (2 left, 1 right), lateral temporal cortex (1 right), superior frontal gyrus (1 left), and operculoinsular region [3 right (orbitofrontal or frontal operculum extending into the anterior insula) and 1 left (frontal operculum extending into the anterior insula)]. In the literature, the identified foci (13 right/5 left) were located in the temporal lobe of 4 (1 right inferior, 1 right medial and inferior, 1 right posterior middle, inferior extending posteriorly to the lingual gyrus, and 1 left middle, inferior, and medial), in the frontal lobe of 12 [10 (6 right/4 left) medial (i.e., superior, medial frontal, and/or anterior cingulate gyri), 1 lateral (right anterior inferior frontal gyrus), and 1 right medioposterior orbitofrontal cortex] and in the parietal lobe of 2 (1 left superior parietal lobule and 1 right parietal operculum) patients. CONCLUSION: Ictal laughter is a poorly lateralizing and localizing feature as it may be encountered in patients with a focus in the left or right frontal, temporal, parietal, or insular lobe. PMID- 24798409 TI - The societal integration of individuals with epilepsy: perspectives for the 21st century. AB - Epilepsy is a common neurologic disorder seen throughout the world. Advances in therapy have made it possible for persons with epilepsy (PWEs) to have improved seizure control and a better quality of life. However, it is not entirely clear whether this has resulted in their successful integration into society. This review examines the societal integration of PWEs, identifying both the progress made and the challenges that continue to hamper further advances. In general, PWEs are more integrated in western-oriented cultures. However, there continue to be ongoing difficulties due to poor education and intellectual functioning, poor social and family support, the undertreatment of coexisting psychiatric conditions, transportation and mobility limitations, and problems obtaining employment. This review also discusses the effects of low socioeconomic status on integration and the persisting prejudices that affect certain racial groups. Most importantly, this review underscores the fact that societal stigma towards PWEs is still very much alive. At the beginning of the 21st century, PWEs still encounter difficulties in their quest for full societal integration. Along with medical advances being made to improve seizure control, much still has to be done to bring about the reforms necessary to help PWEs live more meaningful and productive lives. PMID- 24798410 TI - Distinguishing between patients with pure psychogenic nonepileptic seizures and those with comorbid epilepsy by means of clinical data. AB - Patients with psychogenic nonepileptic seizures (PNESs) often have additional epileptic seizures (ESs). Distinguishing between those with ESs and those without ESs is difficult but mandatory. We hypothesize that these two patient groups differ in clinical data, which might be useful for establishing diagnosis. All patients with PNESs (n=114) from the Bethel Epilepsy Centre treated between 1/11/2010 and 1/11/2011 were included. Thirty-six percent had additional epilepsy. In contrast, 84 of the 114 patients with PNESs took antiepileptic drugs (AEDs) (AED treatment: patients with PNESs=44/73, patients with PNESs+ESs=40/41), most of them (65.5%) as polytherapy. Significant differences between both groups were as follows: patients with PNESs were older at disease onset, had a shorter duration from onset to inpatient visit, were less frequently on AEDs, were less frequently on antiepileptic polytherapy, and had a normal EEG compared with patients with PNESs+ESs. Multivariate stepwise logistic regression revealed age at seizure onset, number of AEDs, and difference between number of AEDs and psychiatric drugs as significant predictors of patients with ESs in PNESs (Nagelkerke's r2=0.59). Therefore, clinical data proved to be useful in the diagnostic process. PMID- 24798411 TI - Validation of the generalized anxiety disorder-7 in people with epilepsy: a MEPSY study. AB - The Generalized Anxiety Disorder-7 (GAD-7) is a valuable instrument to screen for anxiety in primary care patients. However, it has not been validated in people with epilepsy (PWE). Therefore, we validated the GAD-7 and examined its differential effect from adverse effects of antiepileptic drugs (AEDs) on the detection of anxiety in Korean PWE. Eligible patients who visited outpatient clinics in 4 tertiary care hospitals and 1 secondary care hospital underwent several instruments including the Mini International Neuropsychiatric Interview Plus Version 5.0.0 (MINI-Plus 5.0.0), the Korean version of the Neurological Disorders Depression Inventory for Epilepsy (K-NDDI-E), the Korean version of the Liverpool Adverse Event Profile (K-LAEP), and the Quality of Life in Epilepsy-10 (QOLIE-10). Two hundred forty-three patients were enrolled in the study, and 51 (21.0%) patients had GAD by the MINI-Plus 5.0.0. Cronbach's alpha coefficient for the GAD-7 was 0.924. At a cutoff score of 6, the GAD-7 had a sensitivity of 92.2%, a specificity of 89.1%, a positive predictive value of 69.1%, and a negative predictive value of 97.7%. The GAD-7 score was well correlated with the K-NDDI-E score, the K-LAEP score, and the QOLIE-10 overall and subscale scores. The impact of adverse effects of AEDs on the GAD-7 was less than that on the K NDDI-E. In conclusion, the GAD-7 is a reliable and valid screening tool for detecting GAD in PWE. PMID- 24798412 TI - Live cell imaging reveals differential modifications to cytoplasmic dynein properties by phospho- and dephosphomimic mutations of the intermediate chain 2C S84. AB - Cytoplasmic dynein is a multisubunit motor protein responsible for intracellular cargo transport toward microtubule minus ends. There are multiple isoforms of the dynein intermediate chain (DYNC1I, IC), which is encoded by two genes. One way to regulate cytoplasmic dynein is by IC phosphorylation. The IC-2C isoform is expressed in all cells, and the functional significance of phosphorylation on IC 2C serine 84 was investigated by using live cell imaging of fluorescent protein tagged IC-2C wild type (WT) and phospho- and dephosphomimic mutant isoforms in axonal transport model systems. Both mutations modulated dynein functional properties. The dephosphomimic mutant IC-2C S84A had greater colocalization with mitochondria than the IC-2C WT or the phosphomimic mutant IC-2C S84D. The dephosphomimic mutant IC-2C S84A was also more likely to be motile than the phosphomimic mutant IC-2C S84D or the IC-2C WT. In contrast, the phosphomimic mutant IC-2C S84D mutant was more likely to move in the retrograde direction than was the IC-2C S84A mutant. The phosphomimic IC-2C S84D was also as likely as the IC-2C WT to colocalize with mitochondria. Both the S84D phospho- and the S84A dephosphomimic mutants were found to be capable of microtubule minus-end-directed (retrograde) movement in axons. They were also observed to be passively transported in the anterograde direction. These data suggest that the IC-2C S84 has a role in modulating dynein properties. PMID- 24798413 TI - Optimization of extraction conditions and fatty acid characterization of Lactobacillus pentosus cell-bound biosurfactant/bioemulsifier. AB - BACKGROUND: There is currently much interest in the use of natural biosurfactants and bioemulsifiers, mainly in the cosmetic, pharmaceutical and food industries. However, there are no studies on the optimization of the extraction conditions of cell-bound biosurfactants. In this work, a biosurfactant with emulsifier properties was extracted from Lactobacillus pentosus cells, under different extraction conditions, and characterized. RESULTS: During extraction, the most influential independent variable, concerning the emulsifying capacity of biosurfactant, was the operation time, followed by temperature and salt concentration. Biosurfactant from L. pentosus was evaluated by Fourier transform infrared spectroscopy and the composition of fatty acids was analyzed by gas chromatography-mass spectrometry. The hydrophobic chain of the biosurfactant from L. pentosus comprises 548 g kg(-1) linoelaidic acid (C18:2), 221 g kg(-1) oleic or elaidic acid (C18:1), 136 g kg(-1) palmitic acid (C16) and 95 g kg(-1) stearic acid (C18). In addition, emulsions of water and rosemary oil were stabilized with a biosurfactant produced by L. pentosus and compared with emulsions stabilized with polysorbate 20. CONCLUSION: The optimum extraction conditions of biosurfactant were achieved at 45 degrees C at 120 min and using 9 g kg(-1) of salt. In all the assays biosurfactant from L. pentosus yielded more stable emulsions and higher emulsion volumes than polysorbate 20. PMID- 24798414 TI - Treadmill exercise induces neutrophil recruitment into muscle tissue in a reactive oxygen species-dependent manner. An intravital microscopy study. AB - Intense exercise is a physiological stress capable of inducing the interaction of neutrophils with muscle endothelial cells and their transmigration into tissue. Mechanisms driving this physiological inflammatory response are not known. Here, we investigate whether production of reactive oxygen species is relevant for neutrophil interaction with endothelial cells and recruitment into the quadriceps muscle in mice subjected to the treadmill fatiguing exercise protocol. Mice exercised until fatigue by running for 56.3+/-6.8 min on an electric treadmill. Skeletal muscle was evaluated by intravital microscopy at different time points after exercise, and then removed to assess local oxidative stress and histopathological analysis. We observed an increase in plasma lactate and creatine kinase (CK) concentrations after exercise. The numbers of monocytes, neutrophils, and lymphocytes in blood increased 12 and 24 hours after the exercise. Numbers of rolling and adherent leukocytes increased 3, 6, 12, and 24 hours post-exercise, as assessed by intravital microscopy. Using LysM-eGFP mice and confocal intravital microscopy technology, we show that the number of transmigrating neutrophils increased 12 hours post-exercise. Mutant gp91phox-/- (non-functional NADPH oxidase) mice and mice treated with apocynin showed diminished neutrophil recruitment. SOD treatment promoted further adhesion and transmigration of leukocytes 12 hours after the exercise. These findings confirm our hypothesis that treadmill exercise increases the recruitment of leukocytes to the postcapillary venules, and NADPH oxidase-induced ROS plays an important role in this process. PMID- 24798416 TI - Statin use is associated with a decreased risk of Barrett's esophagus. AB - BACKGROUND & AIMS: Statins have been associated with a reduced risk of esophageal adenocarcinoma, but little is known about their effect on development of Barrett's esophagus. We evaluated the association between statins and risk of Barrett's esophagus. METHODS: We conducted a case-control study among eligible patients scheduled for elective esophagogastroduodenoscopy and patients eligible for screening colonoscopy, recruited from primary care clinics at a Veterans Affairs center. We compared 303 patients with Barrett's esophagus with 2 separate sex-matched control groups: 606 elective endoscopy controls and 303 primary care controls without Barrett's esophagus. Use of statins and other lipid-lowering medications was ascertained by reviewing filled prescriptions in electronic pharmacy records during a 10-year period before the Barrett's esophagus diagnosis date for patients and study endoscopy date for controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) using conditional multivariable logistic-regression models among 276 patients and 828 controls further matched on age. RESULTS: A smaller proportion of Barrett's esophagus patients filled statin prescriptions (57.4%) than endoscopy controls (64.9%; P = .029) or primary care controls (71.3%; P < .001). Controls had longer durations of statin prescriptions filled than patients (28.6 vs 22.1 months; P = .001). Statin use was associated with a significantly lower risk of Barrett's esophagus (adjusted OR = 0.57; 95% CI: 0.38-0.87) compared with the combined control groups. The risk of Barrett's esophagus was especially lower with statin use among obese patients (OR = 0.26; 95% CI: 0.09-0.71), as was the risk for Barrett's esophagus segments >= 3 cm (OR = 0.13; 95% CI: 0.06-0.30). We found no significant association between Barrett's esophagus and nonstatin lipid-lowering medications (P = .452). CONCLUSIONS: In a case-control study of veterans, statin use was associated with a reduced risk of Barrett's esophagus. The greatest level of risk reduction was observed for obese patients and for long-segment Barrett's esophagus. PMID- 24798418 TI - Risk of hepatitis B infection in pediatric acute lymphoblastic leukemia in a tertiary care center from South India. AB - BACKGROUND: The prevalence of hepatitis B virus (HBV) infection is high in Asian countries. Little is known about outcome of leukemia in HBV infected patients in these regions. Hence, we conducted this study in two cohorts of patients. PROCEDURE: We retrospectively evaluated mortality, reduction in dose intensity and duration of therapy (intensive phase and maintenance phase) in children with acute lymphoblastic leukemia (ALL) who developed HBV infection. Sixty-three patients with ALL were included in the retrospective cohort of the study. These were followed up for a minimum of 5 years. We prospectively investigated the prevalence of anti-HBc antibodies in 105 treatment naive pediatric patients with ALL and negative for HbsAg. RESULTS: Twenty of the 63 patients developed hepatitis, of which 10 were attributed to HBV. All the 10 patients with HBV hepatitis had significantly reduced dose intensity during maintenance therapy with an average delay in completion of therapy of 140 +/- 83 days and also a high mortality (40%). In the prospective cohort of the study, 39% of treatment naive patients who were HBsAg negative were anti-HBc positive at presentation, possibly reflecting occult HBV infection. CONCLUSIONS: HBV infection poses a serious problem in patients with ALL. Hence we propose that in India, in addition to screening for HBsAg, patients with leukemia should also be screened for anti-HBc. Improved hepatitis B vaccine coverage in the community under the universal immunization programme and introduction of HBV nucleic acid test (NAT) for blood donations should also help in addressing the problem. PMID- 24798417 TI - Carbon monoxide, hydrogen sulfide, and nitric oxide as signaling molecules in the gastrointestinal tract. AB - Carbon monoxide (CO) and hydrogen sulfide (H2S) used to be thought of simply as lethal and (for H2S) smelly gaseous molecules; now they are known to have important signaling functions in the gastrointestinal tract. CO and H2S, which are produced in the gastrointestinal tract by different enzymes, regulate smooth muscle membrane potential and tone, transmit signals from enteric nerves, and can regulate the immune system. The pathways that produce nitric oxide, H2S, and CO interact; each can inhibit and potentiate the level and activity of the other. However, there are significant differences between these molecules, such as in half-lives; CO is more stable and therefore able to have effects distal to the site of production, whereas nitric oxide and H2S are short lived and act only close to sites of production. We review their signaling functions in the luminal gastrointestinal tract and discuss how their pathways interact. We also describe other physiological functions of CO and H2S and how they might be used as therapeutic agents. PMID- 24798420 TI - Microstructured fiber@HZSM-5 core-shell catalysts with dramatic selectivity and stability improvement for the methanol-to-propylene process. AB - We report a macroscopic stainless-steel-fiber@HZSM-5 core-shell catalyst by direct growth of 27 wt% HZSM-5 on a 3D microfibrous structure using 20 MUm SS fibers, demonstrating dramatic selectivity and stability improvement in the MTP process. The unprecedented performance is due to the promotion of the olefin methylation/cracking cycle in methanol-to-hydrocarbon catalysis. PMID- 24798419 TI - Effectiveness of a training course for general practice nurses in motivation support in type 2 diabetes care: a cluster-randomised trial. AB - BACKGROUND: Type 2 diabetes is a common metabolic disease with the potential for prevention of complications. The prevention requires a high level of lasting actions from the patients, which may be burdensome. The aim of this trial was to evaluate the effectiveness of a training course for general practice nurses in motivation support at 18 months follow-up in the affiliated type 2 diabetes population. METHODS: Forty general practices with nurse-led diabetes consultations from the area of Aarhus, Denmark were randomised 1?1 to either intervention or usual practice. Intervention practices were offered a 16-hour Self-determination theory-based course including communication training for general practice nurses delivered over 10 months. The affiliated diabetes populations (aged 40-74 years) were identified from registers (intervention n = 2,005; usual n = 2,029). Primary outcomes were register-based glycated haemoglobin (HbA1c) -, total cholesterol levels, and well-being measured by the Problem Areas In Diabetes scale (PAID) and the mental component summary score, SF12 (SF12, mcs). Intention-to-treat analyses were performed. Predefined subgroups analyses were performed. RESULTS: The differences between the intervention- and the control practices' mean HbA1c and total cholesterol at follow-up adjusted for baseline values and clustering were respectively: -0.02% points (95% CI: -0.11 to 0.07; p: 0.67); 0.08 mmol/l (95% CI: 0.01 to 0.15; p: 0.02). Differences in median scores adjusted for clustering were for PAID: 1.25; p = 0.31 and SF12, mcs: 0.99; p = 0.15. Women in intervention practices differed from women in usual practices on mean HbA1c: -0.12%-points (-0.23 to -0.02; p = 0.02) and SF12, mcs: 2.6; p = 0.01. CONCLUSIONS: Offering a training course for general practice nurses in applying the Self-determination theory in current type 2 diabetes care had no effect compared with usual practice measured by HbA1c and total cholesterol levels and the well-being at 18 months of follow-up in a comprehensive register-based diabetes population. Subgroup analyses suggested a possible effect in women, which deserves further attention. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier NCT01187069). PMID- 24798421 TI - Concentration, composition and sources of PAHs in the coastal sediments of the exclusive economic zone (EEZ) of Qatar, Arabian Gulf. AB - Surface sediments were collected from sixteen locations in order to assess levels and sources of polycyclic aromatic hydrocarbons (PAHs) in sediments of Qatar exclusive economic zone (EEZ). Samples were analyzed for 16 parent PAHs, 18 alkyl homologs and for dibenzothiophenes. Total PAHs concentration (?PAHs) ranged from 2.6 ng g(-1) to 1025 ng g(-1). The highest PAHs concentrations were in sediments in and adjacent to harbors. Alkylated PAHs predominated most of the sampling locations reaching up to 80% in offshore locations. Parent PAHs and parent high molecular weight PAHs dominated location adjacent to industrial activities and urban areas. The origin of PAHs sources to the sediments was elucidated using ternary plot, indices, and molecular ratios of specific compounds such as (Ant/Phe+Ant), (Flt/Flt+Pyr). PAHs inputs to most coastal sites consisted of mixture of petroleum and combustion derived sources. However, inputs to the offshore sediments were mainly of petroleum origin. PMID- 24798423 TI - Imbalanced class learning in epigenetics. AB - In machine learning, one of the important criteria for higher classification accuracy is a balanced dataset. Datasets with a large ratio between minority and majority classes face hindrance in learning using any classifier. Datasets having a magnitude difference in number of instances between the target concept result in an imbalanced class distribution. Such datasets can range from biological data, sensor data, medical diagnostics, or any other domain where labeling any instances of the minority class can be time-consuming or costly or the data may not be easily available. The current study investigates a number of imbalanced class algorithms for solving the imbalanced class distribution present in epigenetic datasets. Epigenetic (DNA methylation) datasets inherently come with few differentially DNA methylated regions (DMR) and with a higher number of non DMR sites. For this class imbalance problem, a number of algorithms are compared, including the TAN+AdaBoost algorithm. Experiments performed on four epigenetic datasets and several known datasets show that an imbalanced dataset can have similar accuracy as a regular learner on a balanced dataset. PMID- 24798425 TI - Medical students' achievement on the Bachelor of Medicine, Bachelor of Surgery/Chirurgery Final Part I and II licensing examination: a comparison of students in problem-based learning, community-based education and service, and conventional curricula in Ghana. AB - PURPOSE: Problem-based learning is an established method of teaching and learning in medical education. However, its impact on students' achievement on examinations is varied and inconsistent. We compared the levels of achievement on the Bachelor of Medicine, Bachelor of Surgery/Chirurgery (MB ChB) Part I and II licensing examination of students in problem-based learning, community-based education and service (PBL/COBES), and conventional curricula. METHODS: In 2014, we analyzed the MB ChB Final Part I and II licensing examination results of students in three classes (2004, 2005, and 2006) of the School of Medicine and Health Sciences, University for Development Studies, Tamale, Ghana. Ninety-three students in the 2004 and 2005 cohorts followed a conventional curriculum, and 82 students in the 2006 cohort followed a PBL/COBES curriculum. Using appropriate statistical tools, the analysis compared individual discipline scores and the proportions of students who received distinction/credit/pass grades among the classes. RESULTS: The PBL students had significantly higher mean and median scores than the conventional students in Obstetrics and Gynecology, Internal Medicine, Community Health and Family Medicine, Surgery, and Psychiatry, but not in Child Health and Pediatrics. Also, a significantly (P=0.0010) higher percentage, 95.1% (n=78), of the PBL students passed all the disciplines, compared to 79.6% (n=74) of the conventional students. CONCLUSION: The PBL students significantly performed better in all the disciplines except child health and pediatrics, where the conventional students scored higher. These findings demonstrate that the benefits of the PBL/COBES curriculum are tangible and should be fostered. PMID- 24798424 TI - Burden of invasive pneumococcal disease in children aged 1 month to 12 years living in South Asia: a systematic review. AB - OBJECTIVE: The primary objective was to estimate the burden of invasive pneumococcal disease (IPD) in children aged 1 month to 12 years in South Asian countries. METHODS: We searched three electronic databases (PubMed, Embase and the Cochrane Library) using a comprehensive search strategy, we manually searched published databases (Index Medicus and Current Contents) and we also searched the bibliographies of the included studies and retrieved reviews. The searches were current through June 2013. Eligible studies (community-based and hospital-based) were pooled and a separate analysis for India was also completed. A meta regression analysis and heterogeneity analysis were performed. The protocol was registered with PROSPERO registration number CRD42013004483. RESULTS: A total of 22 studies surveying 36,714 children were included in the systematic review. Hospital-based prospective studies from South Asia showed that 3.57% of children had IPD, and 15% of all bacterial pneumonia cases were due to Streptococcus pneumoniae. Indian studies showed that the incidence of IPD was 10.58% in children admitted to hospitals with suspected invasive bacterial diseases, and 24% of all bacterial pneumonia cases were due to S. pneumonia. Population-based studies from South Asian countries showed that 12.8% of confirmed invasive bacterial diseases were caused by S. pneumonia whereas retrospective hospital based studies showed that 28% of invasive bacterial diseases were due to S. pneumoniae. Meta-regression showed that there was a significant influence of the antigen testing method for diagnosing IPD on IPD prevalence. CONCLUSION: S. pneumoniae is responsible for a substantial bacterial disease burden in children of South Asian countries including India despite the presence of high heterogeneity in this meta-analysis. Treatment guidelines must be formulated, and preventive measures like vaccines must also be considered. PMID- 24798426 TI - Students' perception of the learning environment at Xavier University School of Medicine, Aruba: a follow-up study. AB - Xavier University School of Medicine admits students mainly from the United States and Canada to the undergraduate medical program. A previous study conducted in June 2013 used the Dundee Ready Educational Environment Measure to measure the educational environment and impact of different teaching and learning methods in the program. The present study aims to obtain information about students' perceptions of changes in the educational environment, which underwent modifications in teaching and learning, in January 2014. Information was collected about the participants' semester of study, gender, nationality, and age. Students' perceptions of the educational environment were documented by noting their degree of agreement with a set of 50 statements grouped into five categories. Average scores were compared among different groups. The mean total and category scores were compared to those of the 2013 study. Sixty of the sixty nine students (86.9%) who enrolled in the undergraduate medical program participated in the survey. The majority were male, aged 20-25 years, and of American nationality. The mean+/-SD total score was 151.32+/-18.3. The mean scores for students' perception in the survey categories were perception of teaching/learning (38.45), perception of teachers (33.90), academic self perceptions (22.95), perception of atmosphere (36.32), and social self-perception (19.70). There were no significant differences in these scores among the different groups. All scores except those for academic self-perception were significantly higher in the present study compared to the previous one (P<0.05). The above results will be of particular interest to schools that plan to transition to an integrated curriculum. PMID- 24798427 TI - Assessing study skills among university students: an Iranian survey. AB - PURPOSE: Numerous studies have revealed that study skills have a constructive role on the academic performance of students, in addition to educational quality, student' intelligence, and their affective characteristics. This study aims to examine study skills and the factors influencing them among the health sciences students of Urmia University of Medical Sciences in Iran. METHODS: This was a cross-sectional study carried out from May to November 2013. A total of 340 Urmia health sciences students were selected using a simple sampling method. Data were collected using the Study Skills Assessment Questionnaire of Counseling Center of Houston University and analyzed with descriptive and analytical statistics. RESULTS: The mean and standard deviation of the students' study skills were 172.5+/-23.2, out of a total score of 240. Around 1.2% of the study skills were weak; 86.8%, moderate; and 12%, good. Among the study skills, the scores of time management, and memory and concentration were better than the others. Also, there was a significant positive correlation between study skills scores and the students' family housing status and academic level (P<0.05). CONCLUSION: Although the majority of the participants had moderate study skills, these were not sufficient and far from good. Improving and promoting the study skills of university students require the designing and implementing of education programs for study strategies. Therefore, decision makers and planners in the educational areas of universities should consider the topic described above. PMID- 24798428 TI - Depressive symptoms, HIV medication adherence, and HIV clinical outcomes in Tanzania: a prospective, observational study. AB - Depressive symptoms have been shown to independently affect both antiretroviral therapy (ART) adherence and HIV clinical outcomes in high-income countries. We examined the prospective relationship between depressive symptoms and adherence, virologic failure, and suppressed immune function in people living with HIV/AIDS in Tanzania. Data from 403 study participants who were on stable ART and engaged in HIV clinical care were analyzed. We assessed crude and adjusted associations of depressive symptoms and ART adherence, both at baseline and at 12 months, using logistic regression. We used logistic generalized estimating equations to assess the association and 95% confidence intervals (CI) between depressive symptoms and both virologic failure and suppressed immune function. Ten percent of participants reported moderate or severe depressive symptoms at baseline and 31% of participants experienced virologic failure (>150 copies/ml) over two years. Depressive symptoms were associated with greater odds of reported medication nonadherence at both baseline (Odds Ratio [OR] per 1-unit increase = 1.18, 95% CI [1.12, 1.24]) and 12 months (OR = 1.08, 95% CI [1.03, 1.14]). By contrast, increases in depressive symptom score were inversely related to both virologic failure (OR = 0.93, 95% CI [0.87, 1.00]) and immune system suppression (OR = 0.88, 95% CI [0.79, 0.99]), though the association between depressive symptoms and clinical outcomes was less precise than for the association with nonadherence. Findings indicate a positive association between depressive symptoms and nonadherence, and also an inverse relationship between depressive symptoms and clinical outcomes, possibly due to informative loss to follow-up. PMID- 24798429 TI - The effect of telephone support interventions on coronary artery disease (CAD) patient outcomes during cardiac rehabilitation: a systematic review and meta analysis. AB - BACKGROUND: Cardiac rehabilitation is offered to individuals after cardiac events to aid recovery and reduce the likelihood of further cardiac illness. However, patient participation remains suboptimal and the provision of high quality care to an expanding population of patients with chronic heart conditions is becoming increasingly difficult. A systematic review and meta-analysis was conducted to determine the effect of telephone support interventions compared with standard post-discharge care on coronary artery disease patient outcomes. METHODS: The Cochrane Library, MEDLINE, EMBASE, and CINAHL were searched and randomized controlled trials that directly compared telephone interventions with standard post-discharge care in adults following a myocardial infarction or a revascularization procedure were included. Study selection, data extraction and quality assessment were completed independently by two reviewers. Where appropriate, outcome data were combined and analyzed using a random effects model. For each dichotomous outcome, odds ratios (OR) and 95% confidence intervals (CI) were derived for each outcome. For continuous outcomes, weighted mean differences (WMD) and standardized mean differences (SMD) and 95% CI were calculated. RESULTS: 26 studies met the inclusion criteria. No difference was observed in mortality between the telephone group and the group receiving standard care OR 1.12 (0.71, 1.77). The intervention was significantly associated with fewer hospitalizations than the comparison group OR 0.62 (0.40, 0.97). Significantly more participants in the telephone group stopped smoking OR 1.32 (1.07, 1.62); had lower systolic blood pressure WMD -0.22 (-0.40, -0.04); lower depression scores SMD -0.10 (-0.21, -0.00); and lower anxiety scores SMD -0.14 ( 0.24, -0.04). However, no significant difference was observed for low-density lipoprotein levels WMD -0.10 (-0.23, 0.03). CONCLUSIONS: Compared to standard post-discharge care, regular telephone support interventions may help reduce feelings of anxiety and depression as well as, improve systolic blood pressure control and the likelihood of smoking cessation. PMID- 24798430 TI - Testing the capability of a polynomial-modified gaussian model in the description and simulation of chromatographic peaks of amlodipine and its impurity in ion interaction chromatography. AB - In this paper, the capability of a polynomial-modified Gaussian model to relate the peak shape of basic analytes, amlodipine, and its impurity A, with the change of chromatographic conditions was tested. For the accurate simulation of real chromatographic peaks the authors proposed the three-step procedure based on indirect modeling of peak width at 10% of peak height (W0.1), individual values of left-half width (A) and right-half width (B), number of theoretical plates (N), and tailing factor (Tf). The values of retention factors corresponding to the peak beginning (k(B)), peak apex (k(A)), peak ending (k(E)), and peak heights (H0) of the analytes were directly modeled. Then, the investigated experimental domain was divided to acquire a grid of appropriate density, which allowed the subsequent calculation of W0.1, A, B, N, and Tf. On the basis of the predicted results for Tf and N, as well as the defined criteria for the simulation the following conditions were selected: 33% acetonitrile/67% aqueous phase (55 mM perchloric acid, pH 2.2) at 40 degrees C column temperature. Perfect agreement between predicted and experimental values was obtained confirming the ability of polynomial modified Gaussian model and three-step procedure to successfully simulate the real chromatograms in ion-interaction chromatography. PMID- 24798432 TI - The effect of topical mometasone furoate nasal spray on carriage of Staphylococcus aureus. AB - OBJECTIVES: This study aims to examine the effect of topical mometasone furoate nasal spray on nasal Staphylococcus aureus (S. aureus) colonization in the treatment of allergic rhinitis. PATIENTS AND METHODS: Between January 2012 and February 2013, 53 patients having perennial allergic rhinitis symptoms (37 females, 16 males) and 53 healthy controls (36 females, 17 males) were included in the study. Nasal cultures were obtained and evaluated before and after the treatment in allergic rhinitis patients who were admitted to the ear, nose and throat (ENT) outpatient clinic and receiving a mometasone furoate nasal spray treatment (200 mcg/day) once a day for one-month. In healthy controls, nasal cultures were obtained and evaluated once. RESULTS: In allergic rhinitis patients, five cultures were positive for S. aureus before the treatment while the number of cultures positive for S. aureus was six after the treatment. There was no significant difference in the pre-treatment and post-treatment S. aureus colonization between the patient group and controls (p>0.05). CONCLUSION: Mometasone furoate nasal spray used in the treatment of allergic rhinitis appears to be ineffective for nasal S. aureus colonization. PMID- 24798431 TI - Human papillomavirus 16 oncoprotein E7 stimulates UBF1-mediated rDNA gene transcription, inhibiting a p53-independent activity of p14ARF. AB - High-risk human papillomavirus oncoproteins E6 and E7 play a major role in HPV related cancers. One of the main functions of E7 is the degradation of pRb, while E6 promotes the degradation of p53, inactivating the p14ARF-p53 pathway. pRb and p14ARF can repress ribosomal DNA (rDNA) transcription in part by targeting the Upstream Binding Factor 1 (UBF1), a key factor in the activation of RNA polymerase I machinery. We showed, through ectopic expression and siRNA silencing of p14ARF and/or E7, that E7 stimulates UBF1-mediated rDNA gene transcription, partly because of increased levels of phosphorylated UBF1, preventing the inhibitory function of p14ARF. Unexpectedly, activation of rDNA gene transcription was higher in cells co-expressing p14ARF and E7, compared to cells expressing E7 alone. We did not find a difference in P-UBF1 levels that could explain this data. However, p14ARF expression induced E7 to accumulate into the nucleolus, where rDNA transcription takes place, providing an opportunity for E7 to interact with nucleolar proteins involved in this process. GST-pull down and co-immunoprecipitation assays showed interactions between p14ARF, UBF1 and E7, although p14ARF and E7 are not able to directly interact. Co-expression of a pRb binding-deficient mutant (E7C24G) and p14ARF resulted in EC24G nucleolar accumulation, but not in a significant higher activation of rDNA transcription, suggesting that the inactivation of pRb is involved in this phenomenon. Thus, p14ARF fails to prevent E7-mediated UBF1 phosphorylation, but could facilitate nucleolar pRb inactivation by targeting E7 to the nucleolus. While others have reported that p19ARF, the mouse homologue of p14ARF, inhibits some functions of E7, we showed that E7 inhibits a p53-independent function of p14ARF. These results point to a mutually functional interaction between p14ARF and E7 that might partly explain why the sustained p14ARF expression observed in most cervical pre-malignant lesions and malignancies may be ineffective. PMID- 24798433 TI - [Vascular compression syndromes: our 24 year endoscope-assisted microvascular decompression experiences]. AB - OBJECTIVES: This study aims to report our experience on endoscope-assisted microvascular decompression experiences performed due to vascular compression syndromes such as hemifacial spasm, trigeminal neuralgia, and cochleovestibular nerve compression. PATIENTS AND METHODS: Between March 1999 and June 2013, 55 patients (34 females, 21 males; mean age 44 years; range 24 to 77 years) underwent endoscope-assisted microvascular decompression surgery through a retrosigmoid approach due to vascular compression syndromes in our clinic. The diagnosis was based on history, neurological examination, magnetic resonance imaging findings and audio-vestibular tests. RESULTS: A total of 49 patients (89.1%) had complete relief of the symptoms and two had (3.6%) a partial relief, while four had (7.3%) no relief of the symptoms. Only two patients had (3.6%) cerebrospinal fluid leakages as a perioperative complication. The major offending vessels were anterior and inferior cerebellar arteries in 14 patients. Four patients with essential hypertension became normotensive after decompression of the left medulla oblongata as well. CONCLUSION: Microvascular decompression surgery provides a significant relief of the symptoms in patients with vascular compression syndromes. An angled endoscope as an adjunct to microscope contributes to the diagnosis of the offending vessel in the root entry zone of the cranial nerve. PMID- 24798434 TI - Assessment of tinnitus with tinnitus severity index, tinnitus handicap inventory and distortion product otoacoustic emissions in patients with normal hearing and hearing loss. AB - OBJECTIVES: This study aims to assess ears with tinnitus and without distortion product otoacoustic emissions (DPOAE) in patients with and without hearing loss and to classify the tinnitus symptoms on the basis of tinnitus severity index (TSI) and tinnitus handicap inventory (THI) in both groups. PATIENTS AND METHODS: A total of 102 patients with tinnitus symptoms were included in the study. Of these patients, 48 had (32 males, 16 females; mean age 45+/-8.9 years) normal hearing and 54 patients (42 males, 12 females; mean age 52+/-12.1 years) had hearing loss. Pure tone audiogram, high-frequency audiometer and DPOAE were applied to patients. Tinnitus symptoms of patients were assessed with TSI and THI. RESULTS: Significantly higher tinnitus severity was monitored in group with hearing loss compared with group with normal hearing (p=0.024). There was a significant similarity in the frequencies affected from tinnitus between the groups (p<0.001). The TSI and THI showed significant similar results between two groups (p<0.001). A significant decrease was found in ears with tinnitus in frequencies of 1000 Hz, 2000 Hz, 3000 Hz, 4000 Hz and 6000 Hz with DPOAE compared to the ears without tinnitus in group with normal hearing (p<0.05). CONCLUSION: Our study results show that patients with TSI and THI are affected by tinnitus at the same rate in daily life whether they have hearing loss or not, but those with hearing loss have a higher tinnitus severity. Decreased DPOAE responses can be found in patients with normal hearing, which can be more profound in low frequency tinnitus, particularly. PMID- 24798435 TI - [Postoperative use of antibiotics in septoplasty cases: is it really necessary?]. AB - OBJECTIVES: This study aims to investigate the efficacy of postoperative antibiotic use in the prevention of the surgical site infection. PATIENTS AND METHODS: Eighty patients who underwent septoplasty in our clinic between July 2012 and September 2012 were followed. Forty of them received preoperative antibiotic prophylaxis and postoperative oral antibiotics (group 1). The other 40 received only preoperative antibiotic prophylaxis (group 2). The patients were assessed at the time of removing packings and postoperative first and second week in terms of infection criteria; endoscopic examination was performed and complete blood counting, and C-reactive protein (CRP) levels were studied. Fifteen patients in each group who completed their follow-up were included in the study. RESULTS: Two patients receiving postoperative antibiotics in addition to the prophylaxis developed infection during follow-up. No infection was seen in the prophylaxis group. CONCLUSION: According to the comparison of the two groups, we conclude that there is no need to use postoperative antibiotics to prevent surgical site infections. PMID- 24798436 TI - [An evaluation of the radioprotective effect of vitamin E on the salivary glands of radioactive iodine in rats]. AB - OBJECTIVES: This study aims to examine the acute effect of vitamin E on salivary gland of radioactive iodine (RAI; 131I)-induced rats and to evaluate whether vitamin E have a radioprotective effect. MATERIALS AND METHODS: Sixteen Wistar albino rats were used in the study. The rats were divided into two groups. The first group was administered (131)I orally and 1 ml physiological saline. The second group was administered (131)I and 1 ml vitamin E intraperitoneally. Vitamin E was started two days before the RAI therapy and continued for seven days. On the eighth day, salivary glands were removed and evaluated histopathologically. RESULTS: There was no statistically significant difference between the groups. The changes in the interstitial space of all glands and in acinar epithelial cells of parotid and sublingual glands were observed in a lower number of the rats of vitamin E group, compared to the controls. Except panacinar inflammation, histopathological changes in acinar epithelial cells of the submandibular gland were noticed in a lower number of the rats of vitamin E group. CONCLUSION: Considering the changes in the interstitial space and acinar epithelial cells in a lower number of the rats of vitamin E group, we conclude that vitamin E may have protective effects for interstitial space of all glands and acinar epithelial cells of the parotid and sublingual glands during the acute period. PMID- 24798437 TI - [Evaluation of shrinkage of surgical margins on tongue specimens following formalin fixation]. AB - OBJECTIVES: This study aims to evaluate the alterations in distances to the surgical margins on sheep tongue specimens, through resection, formalin fixation, frozen section, and microscopic examination. MATERIALS AND METHODS: Fifty fresh sheep tongues were used in the study. A metal plate was fixed on the lateral aspect of each tongue to represent tumor tissues. A total of 40 specimens with either 1 cm or 2 cm distances as surgical safety margins of the surrounding plate were prepared using either scalpel or monopolar cautery (10 specimens were prepared for each group). Additional 10 specimens with 1 cm safety margins were prepared using either scalpel or monopolar cautery (5 specimens per group) for frozen section examination. Distances to the metal plates before resection were compared with the ones which were determined after resection, frozen section examination, 24-hour formalin fixation and microscopic examination. RESULTS: Distances to the surgical margins were found to be decreased in all specimens after resection, 10% formalin fixation and microscopic examination. The distances to the surgical margins were observed to be reduced by 6.5-7.5% on average after resection, 10-12% on average after formalin fixation and 30% on average after microscopic examination, compared to the baseline values. The level of shrinkage was reduced by 6.3-10% following microscopic section preparation during frozen section examination. CONCLUSION: Seven to eight-millimeter distance to the surgical margin at minimum should be maintained to achieve a 5 mm in height surgical safety margin during sheep tongue resection. The distance defined by the pathologist may be multiplied with 1.42 to estimate around in-situ distance to the surgical margins. Therefore, 1.42 may be used as a corrective factor for sheep tongue tissues. PMID- 24798438 TI - [Palatal myoclonus]. AB - Palatal myoclonus is an extremely rare disorder. Tinnitus is secondary to rhythmic involuntary movements of the soft palate. Clinical diagnosis is based on the confirmation of the soft palate movements synchronous with an audible clicking noise outside. In this article, we report a 38-year-old female case with a 10 year-history of continuing ear click, who was diagnosed with essential palatal myoclonus. The disease and its differential diagnosis from symptomatic palatal myoclonus were discussed in the light of literature data. PMID- 24798439 TI - Myoepithelial neoplasm of nasal cavity: an uncommon tumor presenting with an unusual clinical presentation. AB - Myoepithelial tumors are rare malignant tumors of salivary glands with uncertain biological behaviors and clinical course. Parotid gland is the common involvement site. In this article, we present a rare case of myoepithelial neoplasm of nasal cavity in an 11-year-old boy in the light of literature data. PMID- 24798440 TI - Hybrid carcinoma of the parotid gland: ductal carcinoma and myoepithelial carcinoma. AB - Hybrid carcinomas are rare neoplasms which are characterized by two different types of tumors localized in a single topographic region of the lesion. Parotid gland is the most common involvement site of hybrid carcinomas among salivary glands. The aggressiveness of the hybrid tumor depends on its high-grade component. In this article, we present a 71-year-old male case with the left parotid gland hybrid carcinoma consisting of salivary duct carcinoma and myoepithelial carcinoma. PMID- 24798441 TI - Submandibular ectopic thyroid with normally located thyroid gland. AB - Ectopic thyroid is a rare developmental anomaly of the thyroid gland which is defined as the presence of thyroid tissue at a site other than the pretracheal area. Nearly 1 to 3% of all ectopic thyroids are located in the lateral neck. Simultaneous submandibular ectopic thyroid tissue presenting with a functional orthotopic thyroid gland is extremely rare. In this article, we report a 37-year old female case admitted to our clinic with a complaint of swollen neck in whom ultrasonography revealed submandibular ectopic thyroid tissue presenting with an orthotopic thyroid gland. PMID- 24798442 TI - [Forestier's syndrome: a rare cause of dysphagia]. AB - Forestier's syndrome (diffuse idiopathic skeletal hyperostosis) is characterized by ossification of the anterolateral aspect of at least four contiguous vertebral bodies. The exact etiology is unclear. Diagnosis is made by radiologic examinations. In this report, we present a case of Forestier's syndrome who admitted with complaints of dysphagia, cervical pain and dyspnea. The diagnosis was based on radiological examinations. Clinic and radiological characteristics of our case were discussed in the light of literature data. PMID- 24798444 TI - A retrospective analysis of incidence and its associated risk factors of upper urinary tract recurrence following radical cystectomy for bladder cancer with transitional cell carcinoma: the significance of local pelvic recurrence and positive lymph node. AB - OBJECTIVE: The aim of this study is to examine the incidence and risk factors of upper urinary tract recurrence (UUTR) following radical cystectomy (RC) in bladder cancer and to evaluate its relationship with neobladder (Neo) or ileal conduit (IC). MATERIALS AND METHODS: All clinicopathologic parameters and perioperative parameters of 311 patients who underwent RC with either Neo or IC by a single surgeon from 1999 to 2012 were retrospectively included in this study. Patients with a history of renal surgery, concomitant UUTR, or a histopathology of non-transitional cell carcinoma were excluded. For statistical analyses of predictive risk factors of UUTR, a multivariate analysis was performed with known risk factors of UUTR, including type of urinary diversion with significance defined as P < 0.05. RESULTS: During the median follow-up period of 53 months, 143 (46.0%) IC and 168 (54.0%) Neo were performed, resulting in 11 (3.5%) cases of UUTR (Neo 7 and IC 4) after RC and all patients then underwent nephroureterectomy. No significant differences in incidence and overall survival in UUTR were observed according different types of urinary diversion (p = 483), and the prognosis for survival of Neo was insignificantly better than that of IC (5-year overall survival 78% vs 74%, respectively, p>0.05). Higher number of positive lymph nodes (HR 9.03) and the presence of pelvic local recurrence (HR 7286.08) were significant predictive factors of UUTR (p<0.05). CONCLUSION: This study reports a UUTR rate of 3.5%, and positive lymph nodes and presence of local recurrence at the pelvis as important risk factors. No significant differences in incidence and survival were observed between Neo and IC. PMID- 24798445 TI - Sensitivity and specificity of in situ proximity ligation for protein interaction analysis in a model of steatohepatitis with Mallory-Denk bodies. AB - The in situ proximity ligation assay (isPLA) is an increasingly used technology for in situ detection of protein interactions, post-translational modifications, and spatial relationships of antigens in cells and tissues, in general. In order to test its performance we compared isPLA with immunofluorescence microscopy by analyzing protein interactions in cytoplasmic protein aggregates, so-called Mallory Denk bodies (MDBs). These structures represent protein inclusions in hepatocytes typically found in human steatohepatitis and they can be generated in mice by feeding of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). We investigated the colocalization of all three key MDB components, namely keratin 8 (K8), keratin 18 (K18), and p62 (sequestosome 1) by isPLA and immunofluorescence microscopy. Sensitivity and specificity of isPLA was assessed by using Krt8-/- and Krt18-/- mice as biological controls, along with a series of technical controls. isPLA signal visualization is a robust technology with excellent sensitivity and specificity. The biological relevance of signals generated critically depends on the performance of antibodies used, which requires careful testing of antibodies like in immunofluorescence microscopy. There is a clear advantage of isPLA in visualizing protein co-localization, particularly when antigens are present at markedly different concentrations. Furthermore, isPLA is superior to confocal microscopy with respect to spatial resolution of colocalizing antigens. Disadvantages compared to immunofluorescence are increased costs and longer duration of the laboratory protocol. PMID- 24798446 TI - A call for humility in the regulation of medical education. PMID- 24798447 TI - Thyroid hormones regulate skeletal muscle regeneration after acute injury. AB - We evaluated the effects of hypo- and hyperthyroid statuses during the initial phase of skeletal muscle regeneration in rats. To induce hypo- or hyperthyroidism, adult male Wistar rats were treated with methimazole (0.03%) or T4 (10 MUg/100 g), respectively, for 10 days. Three days before sacrifice, a crush injury was produced in the solear muscles of one half of the animals, while the other half remained intact. T3, T4, TSH, and leptin serum levels were not affected by the injury. Serum T3 and T4 levels were significantly increased in hyperthyroid and hyper-injury animals. Hypothyroidism was confirmed by the significant increase in serum TSH levels in hypothyroid and hypo-injury animals. Injury increased cell infiltration and macrophage accumulation especially in hyperthyroid animals. Both type 2 and type 3 deiodinases were induced by lesion, and the opposite occurred with the type 1 isoform, at least in the control and hyperthyroid groups. Injury increased both MyoD and myogenin expression in all the studied groups, but only MyoD expression was increased by thyroidal status only at the protein level. We conclude that thyroid hormones modulate skeletal muscle regeneration possibly by regulating the inflammatory process, as well as MyoD and myogenin expression in the injured tissue. PMID- 24798448 TI - Factors associated with glycemic control in adult type 1 diabetes patients treated with insulin pump therapy. AB - Continuous subcutaneous insulin infusion (CSII) by insulin pump seems to improve glycemia and quality of life as compared to conventional insulin therapy in type 1 diabetes (T1DM). However, while many T1DM subjects achieve excellent glycemic control, some others cannot reach recommended goals. In a retrospective analysis, we searched for factors associated with glycemic control in T1DM patients treated with insulin pump therapy. Data from 192 patients (133 women and 59 men) treated with personal insulin pumps at the Department of Metabolic Diseases, University Hospital, Krakow, Poland were analyzed. Sources of information included medical records, memory read-outs from insulin pumps and data from glucose meters. Univariate, multivariate linear and logistic regression analysis for the association with hemoglobin A1c (HbA1c) level were performed. The mean age of the subjects was 28.9 (+/-11.2) years, the mean duration of T1DM-14.6 (+/-7.6) years, mean body mass index-23.5 (+/-3.1) kg/m2. The mean HbA1c level in the entire study group was 7.4% (57 mmol/mol). In the multivariate linear regression analysis, HbA1c correlated with the mean number of daily blood glucose measurements, number of hypoglycemic episodes per 100 blood glucose measurements, age at the examination, and continuous glucose monitoring system use. Multivariate logistic regression analysis for reaching the therapeutic target of HbA1c<7.0% (53 mmol/mol) showed that the independent predictors of achieving this goal included the same four variables. In a large clinical observation, we identified that patient-related and technological factors associated with glycemic control in adult pump-treated T1DM subjects. PMID- 24798449 TI - Impaired growth hormone secretion associated with low glucocorticoid levels: an experimental model for the Giustina effect. PMID- 24798450 TI - Platelet antibody analysis by three different tests. AB - BACKGROUND: Platelet-reactive antibodies lead to thrombocytopenia and bleeding disorders, and diverse assays are used for their detection. In this retrospective analysis, the applicability of three different test systems was compared and antibody specificities were assessed. METHODS: Sera of 1,234 patients were tested with an enzyme-linked immunosorbent assay (ELISA; Lifecodes PAKPLUS((r)) or PAK 12((r)), Gen-Probe) and a solid-phase assay (Capture-P Ready Screen((r)), Immucor Inc.). In cases of suspected anti-HLA class I antibodies, a specific lymphocytotoxicity test (LCT, Bio-Rad((r))) was performed. RESULTS: Platelet antibodies were detected in 366 of 1,234 samples (29.7%). In 70.3% concordant negative but only in 8.4% concordant positive results were obtained with both the methods; 185 of 1,053 in the solid-phase assay negative samples were positive in the ELISA (15.0%). In samples positive in both methods, most antibodies reacted against HLA class I antigens. Glycoprotein (GP) specific platelet antibodies, mainly against GPIIb/IIIa and GPIa/IIa, were more frequently detectable in the ELISA than in the solid-phase assay, whereas weakly positive results have to be interpreted cautiously. CONCLUSION: ELISA, solid-phase assay, and LCT showed highly divergent results. Due to several limitations, the additional analysis by the "monoclonal antibody-specific immobilization of platelet antigen" (MAIPA) assay is highly recommended. PMID- 24798451 TI - Dye-assisted gain of strongly confined surface plasmon polaritons in silver nanowires. AB - Noble metal nanowires are excellent candidates as subwavelength optical components in miniaturized devices due to their ability to support the propagation of surface plasmon polaritons (SPPs). Nanoscale data transfer based on SPP propagation at optical frequencies has the advantage of larger bandwidths but also suffers from larger losses due to strong mode confinement. To overcome losses, SPP gain has been realized, but so far only for weakly confined SPPs in metal films and stripes. Here we report the demonstration of gain for subwavelength SPPs that were strongly confined in chemically prepared silver nanowires (mode area = lambda(2)/40) using a dye-doped polymer film as the optical gain medium. Under continuous wave excitation at 514 nm, we measured a gain coefficient of 270 cm(-1) for SPPs at 633 nm, resulting in partial SPP loss compensation of 14%. This achievement for strongly confined SPPs represents a major step forward toward the realization of nanoscale plasmonic amplifiers and lasers. PMID- 24798452 TI - The omega-3 polyunsaturated fatty acid, eicosapentaenoic acid, attenuates abdominal aortic aneurysm development via suppression of tissue remodeling. AB - Abdominal aortic aneurysm (AAA) is a prevalent vascular disease that can progressively enlarge and rupture with a high rate of mortality. Inflammation and active remodeling of the aortic wall have been suggested to be critical in its pathogenesis. Meanwhile, omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) are known to reduce cardiovascular events, but its role in AAA management remains unclear. Here, we show that EPA can attenuate murine CaCl2-induced AAA formation. Aortas from BALB/c mice fed an EPA-diet appeared less inflamed, were significantly smaller in diameter compared to those from control-diet-fed mice, and had relative preservation of aortic elastic lamina. Interestingly, CT imaging also revealed markedly reduced calcification of the aortas after EPA treatment. Mechanistically, MMP2, MMP9, and TNFSF11 levels in the aortas were reduced after EPA treatment. Consistent with this finding, RAW264.7 macrophages treated with EPA showed attenuated Mmp9 levels after TNF alpha simulation. These results demonstrate a novel role of EPA in attenuating AAA formation via the suppression of critical remodeling pathways in the pathogenesis of AAAs, and raise the possibility of using EPA for AAA prevention in the clinical setting. PMID- 24798453 TI - The link between androgen receptor splice variants and castration-resistant prostate cancer. AB - Resistance to the latest advanced prostate cancer therapies, including abiraterone and enzalutamide, is associated with increased expression of constitutively active androgen receptor splice variants (AR-Vs). The exact mechanism by which these therapies result in AR-Vs is unknown, but may include genomic rearrangement of the androgen receptor gene as well as alternative splicing of the AR pre-messenger RNA (mRNA). An additional complication that hinders further development of effective AR strategies is that the mechanisms by which the directed therapies are bypassed may vary. Finally, the question must be addressed as to whether the androgen receptor remains to be the driver of most castration resistant disease or whether truly AR-independent tumors arise after successful androgen ablation therapy. In this review, we will examine androgen receptor splice variants as an alternative mechanism by which prostate cancer becomes resistant to androgen receptor-directed therapy. PMID- 24798454 TI - Androgen receptor (AR) inhibitor ErbB3-binding protein-1 (Ebp1) is not targeted by the newly identified AR controlling signaling axis heat-shock protein HSP27 and microRNA miR-1 in prostate cancer cells. AB - PURPOSE: Androgen receptor (AR) networks are predominantly involved in prostate cancer (PCa) progression; consequently, factors of AR regulation represent promising targets for PCa therapy. The ErbB3-binding protein 1 (Ebp1) is linked to AR suppression and chemoresistance by so far unknown mechanisms. In this study, an assumed regulation of Ebp1 by the newly identified AR controlling signaling axis heat-shock protein 27 (HSP27)-microRNA-1 (miR-1) was examined. METHODS: Transfection experiments were carried out overexpressing and knockdown HSP27 and miR-1, respectively, in LNCaP and PC-3 cells. Afterward, HSP27- and miR 1-triggered Ebp1 protein expression was monitored by Western blotting. RESULTS: AR-positive LNCaP cells and AR-negative PC-3 cells possessed diverse basal expression levels of Ebp1. However, subsequent studies revealed no differences in cellular Ebp1 concentrations after modulation of HSP27 and miR-1. Furthermore, docetaxel incubation experiments exhibited no effects on Ebp1 protein synthesis. CONCLUSION: In PCa, Ebp1 has been described as a regulator of AR functionality and as an effector of PCa therapy resistance. Our data suggest that Ebp1 functionality is independent from heat-shock-protein-regulated progression networks in PCa. PMID- 24798455 TI - Lower urinary tract symptoms in patients with liver cirrhosis. AB - PURPOSE: To evaluate the prevalence of lower urinary tract symptoms (LUTS) in men with liver cirrhosis. METHODS: In total, 128 men with known liver cirrhosis were prospectively evaluated using the validated German version of the International Prostate Symptom Score (IPSS) questionnaire. In parallel, all men underwent a detailed examination including medical history; physical examination; Child-Pugh liver function score (CPS) assessment; and measurement of blood levels of prostate-specific antigen (PSA), total and free testosterone, sexual hormone binding globulin (SHBG), prolactin, luteotropic hormone (LH), and follicle stimulating hormone (FSH). RESULTS: Mean patient age and mean IPSS was 56 +/- 9 years and 8 +/- 6, respectively. Mild (IPSS: 1-7), moderate (IPSS: 8-19), and severe (IPSS: 20-35) LUTS were present in 60.2 % (77/128), 31.3 % (40/128), and 7.0 % (9/128) of the patients, respectively. Storage symptoms increased with the CPS (p = 0.04). Voiding symptoms and overall IPSS did not differ between the CPS groups (p = 0.93 and p = 0.67). No correlation was found between ascites volume and IPSS, storage symptoms, voiding symptoms, or quality of life (QoL) (p = 0.46, p = 0.26, p = 0.81, p = 0.87). From CPS groups A to C, mean PSA levels (p = 0.04), total and free testosterone levels (p < 0.001 and p < 0.001), and SHBG levels decreased (p = 0.03); however, prolactin levels increased (p = 0.03). LH and FSH levels did not differ between the CPS groups (p = 0.15 and p = 0.35). CONCLUSIONS: Men with liver cirrhosis commonly have LUTS, with a predominance of storage symptoms. Liver cirrhosis may also affect PSA-based prostate cancer risk assessment. Accurate diagnosis and therapy strategies are warranted to improve the QoL of these patients. PMID- 24798456 TI - Glycerol etherification with TBA: high yield to poly-ethers using a membrane assisted batch reactor. AB - In this work, a novel approach to obtain high yield to poly-tert butylglycerolethers by glycerol etherification reaction with tert-butyl alcohol (TBA) is proposed. The limit of this reaction is the production of poly-ethers, which inhibits the formation of poly-ethers potentially usable in the blend with conventional diesel for transportation. The results herein reported demonstrate that the use of a water permselective membrane offers the possibility to shift the equilibrium toward the formation of poly-ethers since the water formed during reaction is continuously and selectively removed from the reaction medium by the recirculation of the gas phase. Using a proper catalyst and optimizing the reaction conditions, in a single experiment, a total glycerol conversion can be reached with a yield to poly-ethers close to 70%, which represents data never before reached using TBA as reactant. The approach here proposed could open up new opportunities for all catalytic reactions affected by water formation. PMID- 24798457 TI - Disgust and the politics of sex: exposure to a disgusting odorant increases politically conservative views on sex and decreases support for gay marriage. AB - Disgust has been implicated as a potential causal agent underlying socio political attitudes and behaviors. Several recent studies have suggested that pathogen disgust may be a causal mechanism underlying social conservatism. However, the specificity of this effect is still in question. The present study tested the effects of disgust on a range of policy preferences to clarify whether disgust is generally implicated in political conservatism across public policy attitudes or is uniquely related to specific content domains. Self-reported socio political attitudes were compared between participants in two experimental conditions: 1) an odorless control condition, and 2) a disgusting odor condition. In keeping with previous research, the present study showed that exposure to a disgusting odor increased endorsement of socially conservative attitudes related to sexuality. In particular, there was a strong and consistent link between induced disgust and less support for gay marriage. PMID- 24798458 TI - The immunosuppressant Protosappanin A diminished recipient T cell migration into allograft via inhibition of IP-10 in rat heart transplant. AB - The immunosuppressant Protosappanin A (PrA), isolated from the medicinal herb, promotes cardiac allograft survival, diminishes inflammatory cell infiltration, and inhibits interferon gamma-induced protein 10 kDa (IP-10) mRNA expression in rats cardiac grafts. Binding of the chemokine IP-10 to its cognate receptor, CXCR3, plays crucial roles in allograft immunity, especially by mediating the recruitment of effector T cells to allografted tissues. In this study, we attempted to determine whether PrA-mediated inhibition of IP-10 contributes to the effect of reduced T cell infiltration into cardiac allograft within a rat model. Administration of PrA (25 mg/kg daily) via oral gavage following heart transplantation significantly reduced the increase of IP-10 mRNA level in allograft and prevented IP-10 secretion by peripheral blood mononuclear cells (PBMC) isolated from recipient rats seven days posttransplantation. Furthermore, in vitro experiments demonstrated that PrA addition to control PBMC prevented IP 10 secretion. Chemotactic migration assays were utilized to evaluate recipient T cell migration towards PBMC supernatant. PrA administration impaired PBMC supernatant-induced T cell migration. Additional in vitro experiments revealed that PrA slightly reduced naive T cell migration towards chemokines. The presence of IP-10 in PBMC supernatant prevented PrA from reducing T cell migration in PrA treated recipients. Neither CXCR3 chemokine ligand Mig nor non-CXCR3 chemokine ligand SDF-1 had any effect on T cell migration in PrA-treated recipients. The addition of anti-CXCR3 antibody restored PrA-mediated inhibition of T cell migration. Immunofluorescence microscopy showed that IP-10 was expressed mainly in CD68 positive infiltrating monocytes. Furthermore, PrA consistently reduced CXCR3+T cell infiltration into cardiac allografts. The reduced intensity of CXCR3 staining in PrA-treated allografts contributed to the previously depressed naive T cell migrating activity induced by PrA. Collectively, these data indicate that PrA inhibition of IP-10 activity reduced recipient T cell migration and infiltration of cardiac allografts, thus partially explaining the immunosuppressive effect of PrA. PMID- 24798459 TI - Expression profiles of perforin, granzyme B and granulysin genes during the estrous cycle and gestation in the bovine endometrium. AB - The conceptus is susceptible to destruction by maternal cytotoxic lymphocytes, which have cytotoxic potential. Therefore, it is expected that mechanisms for regulating cytotoxic lymphocytes exist, but little is known about the expression of cytotoxic genes in the endometrium. In the present study, we examined the spatial and temporal expression patterns of the cytotoxic genes perforin, granzyme B, and granulysin during the estrous cycle and gestation in the bovine endometrium. Endometrial tissues were collected from cows during the estrous cycle and gestation. The gene expression patterns of the three cytotoxic genes were examined using quantitative polymerase chain reaction and in situ hybridization, and cytotoxic lymphocyte subsets were characterized using immunohistochemistry. During mid- to late gestation in the intercaruncular (ICAR), granulysin expression was significantly increased, and a large number of granulysin-expressing cells were localized in the luminal epithelium. Perforin and granzyme B displayed similar expression profiles and were highly expressed in the peri-implantation endometrium, but few cells expressing these genes were found in the endometrial stroma. In conclusion, these findings suggest that in the ICAR epithelium granulysin may play important roles in the establishment and maintenance of gestation during normal pregnancy. PMID- 24798460 TI - The response of newly born mice to odors of murine colostrum and milk: unconditionally attractive, conditionally discriminated. AB - It is a general rule that milk conveys chemosensory cues that are attractive to mammalian neonates. This study investigated whether compositional fluctuations in milk along lactation induce variations in newborn mouse pups' (Mus musculus, strain BALB/c) attraction to milk odor. Pups differing in suckling experience were exposed to the odor of milk sampled from females varying in lactational stage. Immediately after birth, suckling-inexperienced (P0) and suckling experienced (P0suck ) pups were assayed in a series of paired-choice tests contrasting murine milk [of lactation days 0, 3, 15 (abridged L0, L3, L15, respectively)] and a blank (water) to evaluate olfactory detection and attraction of milk odor. Preference tests further paired these milk two-by-two to assess their relative attraction. Results showed first that P0 and P0suck pups detect and positively orient to any milk odor. When L0 is presented against L15 milk, P0 pups orient for a similar duration towards these odor stimuli, whereas P0suck pups spend more time toward the odor of L0 than of L15 milk. Finally, P0suck pups orient similarly to odors of L0 milk collected before/after the first suckling episode (L0 and L0suck , respectively), but the odor of L0 milk was more attractive than that of L3 milk. Thus, mouse pups' positive orientation toward the odors of murine colostrum (assumed to correspond to L0/L0suck milk) and later lactation milk appears unconditional of previous suckling experience, whereas their ability to discriminate or display preference between milk differing in lactation stage appears conditional on postnatal exposure effects. PMID- 24798461 TI - Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures. AB - In patients with genetically heterogeneous disorders such as intellectual disability or epilepsy, exome sequencing is a powerful tool to elucidate the underlying genetic cause. Homozygous and compound heterozygous mutations in C12orf57 have recently been described to cause an autosomal recessive syndromic form of intellectual disability, including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures. Here, we report on two siblings from nonconsanguineous parents harboring two compound heterozygous loss of-function mutations in C12orf57 identified by exome sequencing, including a novel nonsense mutation, and review the patients described in the literature. PMID- 24798462 TI - Antihypertensive and vascular remodelling effects of the imperatorin derivative OW1 in renovascular hypertension rats. AB - OW1 is a novel imperatorin derivative that exhibits vasodilator activity. In the present study, the antihypertensive effect of and inhibition of vascular remodelling by OW1 were investigated in two-kidney, one-clip (2K1C) renovascular hypertensive rats. Rats were subjected to the 2K1C procedure and treated with OW1 (40 or 80 mg/kg per day) for 8 weeks. Blood pressure was measured in conscious rats. Microalbumin (mALB) and total protein (U-TP) concentrations were determined in the urine, as were plasma concentrations of angiotensin (Ang) II, calcitonin gene-related peptide (CGRP) and angiotensin-converting enzyme 1 (ACE). The unclipped kidney was stained with haematoxylin and eosin and Masson trichrome, whereas aortic sections were stained with Masson trichrome. In addition, OW1 induced vasodilatation was evaluated in vitro in rat mesenteric and renal arteries. Immunohistochemical analysis was used to quantify collagen I and III expression. OW1 relaxed rat mesenteric and renal arterial rings in vitro. Treatment of 2K1C hypertensive rats with OW1 (40 and 80 mg/kg per day) for 8 weeks significantly decreased blood pressure. In addition, OW1 reduced plasma AngII and ACE concentrations and increased plasma CGRP concentrations. At 80 mg/kg per day, OW1 decreased blood urea nitrogen, mALB and U-TP levels. Histological analysis revealed that OW1 reduced renal arteriolar thickness and relieved the structural hypertrophic arteries. Moreover, OW1 had an inhibitory effect on vascular remodelling and renal lesions in hypertensive rats. In conclusion, the results suggest that OW1 could potentially be a novel candidate for hypertension intervention. PMID- 24798463 TI - A new genetically encoded single-chain biosensor for Cdc42 based on FRET, useful for live-cell imaging. AB - Cdc42 is critical in a myriad of cellular morphogenic processes, requiring precisely regulated activation dynamics to affect specific cellular events. To facilitate direct observations of Cdc42 activation in live cells, we developed and validated a new biosensor of Cdc42 activation. The biosensor is genetically encoded, of single-chain design and capable of correctly localizing to membrane compartments as well as interacting with its upstream regulators including the guanine nucleotide dissociation inhibitor. We characterized this new biosensor in motile mouse embryonic fibroblasts and observed robust activation dynamics at leading edge protrusions, similar to those previously observed for endogenous Cdc42 using the organic dye-based biosensor system. We then extended our validations and observations of Cdc42 activity to macrophages, and show that this new biosensor is able to detect differential activation patterns during phagocytosis and cytokine stimulation. Furthermore, we observe for the first time, a highly transient and localized activation of Cdc42 during podosome formation in macrophages, which was previously hypothesized but never directly visualized. PMID- 24798464 TI - Routine depression screening and diagnosing strategy for cancer inpatients. AB - BACKGROUND: Clinical practice guidelines frequently recommend systematic screening for depression in cancer patients to improve recognition and prompt appropriate management. We aimed to screen major depressive disorder (MDD) in cancer inpatients using a structured tool and explore its applicability. METHODS: Cancer inpatients were routinely screened by nurses using the Taiwanese Depression Questionnaire (TDQ), and for those screened positive, this was followed by a non-mandated referral to a psychiatrist for clinical evaluation and diagnosis. Patients who completed this two-stage procedure comprised the analysis sample. RESULTS: Routine screening of 8800 patients in a period of 27 months yielded 1087 (26.9%) positive first-time screens. Of them, 298 (27.4%) completed the psychiatric consultation. Depressive disorders were diagnosed in 185 patients (62.1%), mainly adjustment disorder (23.8%) and MDD (21.5%). The estimated prevalence of MDD was 21.5%. Area under the curve was 0.72, a result produced by the receiver operating characteristic curve of the TDQ scores relative to the clinical psychiatric diagnoses of MDD. A TDQ cutoff score of ?26 provided an optimal diagnostic accuracy for MDD. CONCLUSIONS: This two-stage depression screening and diagnosing strategy is practical for improving recognition of MDD and other depressive disorders in cancer patients and could be routinely applied, rather than selectively, in a comprehensive cancer care system. PMID- 24798466 TI - Online resources for culturally and linguistically appropriate services in home healthcare and hospice: resources for Spanish-speaking patients. AB - Home healthcare and hospice clinicians are increasingly working with patients for whom English is not their primary language. Provision of culturally respectful and acceptable patient-centered care includes both an awareness of cultural beliefs that influence the patient's health and also the ability to provide the patient with health information in the language with which he or she is most comfortable. This article identifies resources for understanding the cultural norms of different Spanish-speaking groups as well as materials appropriate for Spanish-speaking patients that healthcare professionals and government agencies from around the world have made available for others to use. PMID- 24798467 TI - Online resources for culturally and linguistically appropriate services in home healthcare and hospice, Part 2: resources for Asian patients. AB - Home care and hospice clinicians are increasingly working with patients for whom English is not their primary language. Provision of culturally respectful and acceptable patient-centered care includes both an awareness of cultural beliefs that influence the patient's health and also the ability to provide the patient with health information in the language with which he or she is most comfortable. This article identifies resources for understanding the cultural norms of Asian born patients and appropriate patient education materials in the many languages spoken by this population. The resources have been made available free on the Web by healthcare professionals and government agencies from around the world. PMID- 24798465 TI - Apamin does not inhibit human cardiac Na+ current, L-type Ca2+ current or other major K+ currents. AB - BACKGROUND: Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear. OBJECTIVE: To test the hypothesis that apamin does not inhibit any major cardiac ion currents. METHODS: We studied human embryonic kidney (HEK) 293 cells that expressed human voltage-gated Na+, K+ and Ca2+ currents and isolated rabbit ventricular myocytes. Whole-cell patch clamp techniques were used to determine ionic current densities before and after apamin administration. RESULTS: Ca2+ currents (CACNA1c+CACNB2b) were not affected by apamin (500 nM) (data are presented as median [25th percentile;75th percentile] (from -16 [-20;-10] to -17 [-19;-13] pA/pF, P = NS), but were reduced by nifedipine to -1.6 [-3.2;-1.3] pA/pF (p = 0.008). Na+ currents (SCN5A) were not affected by apamin (from -261 [ 282;-145] to -268 [-379;-132] pA/pF, P = NS), but were reduced by flecainide to 57 [-70;-47] pA/pF (p = 0.018). None of the major K+ currents (IKs, IKr, IK1 and Ito) were inhibited by 500 nM of apamin (KCNQ1+KCNE1, from 28 [20]; [37] to 23 [18]; [32] pA/pF; KCNH2+KCNE2, from 28 [24]; [30] to 27 [24]; [29] pA/pF; KCNJ2, from -46 [-48;-40] to -46 [-51;-35] pA/pF; KCND3, from 608 [505;748] to 606 [454;684]). Apamin did not inhibit the INa or ICaL in isolated rabbit ventricular myocytes (INa, from -67 [-75;-59] to -68 [-71;-59] pA/pF; ICaL, from -16 [-17; 14] to -14 [-15;-13] pA/pF, P = NS for both). CONCLUSIONS: Apamin does not inhibit human cardiac Na+ currents, L-type Ca2+ currents or other major K+ currents. These findings indicate that apamin is a specific SK current inhibitor in hearts as well as in other organs. PMID- 24798469 TI - Resources for Middle Eastern patients: online resources for culturally and linguistically appropriate services in home healthcare and hospice, Part 3. AB - As the population of patients for whom English is not their primary language grows, home care and hospice clinicians are challenged to provide culturally respectful and acceptable patient-centered care for cultures and languages unfamiliar to them. This article identifies resources for understanding the culture of Middle Eastern-born patients and appropriate patient education materials in most of the languages spoken by this population. The resources have been made available for free on the Web by healthcare professionals, government agencies, and support organizations from around the world. PMID- 24798470 TI - Cultural sensitivity 2014: Home Healthcare Nurse Supplement. PMID- 24798471 TI - Online resources for culturally and linguistically appropriate services in home healthcare and hospice. Part 4: resources for European patients. AB - Provision of culturally and linguistically appropriate care for home care and hospice patients is a national mandate. Finding patient-education materials in languages other than English can be a challenge for clinicians in workplaces lacking affiliation with a hospital that provides multilingual resources to its patients. Many hospitals, government agencies, and foundations have made appropriate resources freely available on the Internet. However, identifying them is time consuming. This article reviews a variety of sources for access to patient-education materials in the multiple languages of Europe. PMID- 24798472 TI - Cultural competence: assessment and education resources for home care and hospice clinicians. AB - Home healthcare and hospice clinicians face many challenges in the complex healthcare system caring for patients and their families in the home environment. One of those challenges is providing culturally competent care for an increasingly diverse population. This article will highlight free, easily accessible, online resources to assist clinicians and organizations to assess organizational and individual cultural competence and provide many resources for cultural competency education programs. PMID- 24798473 TI - Online resources for culturally and linguistically appropriate services for home healthcare and hospice, Part 5: resources for African patients. AB - Providing culturally and linguistically appropriate home healthcare and hospice care to patients who have emigrated from the African continent can be a challenge. This article reviews Web sites that provide introductions to some of the predominant cultures in Africa. Web sites providing patient education material in 13 African languages are also discussed. PMID- 24798476 TI - Ligand-directed active tumor-targeting polymeric nanoparticles for cancer chemotherapy. AB - In recent years, polymeric nanoparticles have appeared as a most viable and versatile delivery system for targeted cancer therapy. Various in vivo studies have demonstrated that virus-sized stealth particles are able to circulate for a prolonged time and preferentially accumulate in the tumor site via the enhanced permeability and retention (EPR) effect (so-called "passive tumor-targeting"). The surface decoration of stealth nanoparticles by a specific tumor-homing ligand, such as antibody, antibody fragment, peptide, aptamer, polysaccharide, saccharide, folic acid, and so on, might further lead to increased retention and accumulation of nanoparticles in the tumor vasculature as well as selective and efficient internalization by target tumor cells (termed as "active tumor targeting"). Notably, these active targeting nanoparticulate drug formulations have shown improved, though to varying degrees, therapeutic performances in different tumor models as compared to their passive targeting counterparts. In addition to type of ligands, several other factors such as in vivo stability of nanoparticles, particle shape and size, and ligand density also play an important role in targeted cancer chemotherapy. In this review, concept and recent development of polymeric nanoparticles conjugated with specific targeting ligands, ranging from proteins (e.g., antibodies, antibody fragments, growth factors, and transferrin), peptides (e.g., cyclic RGD, octreotide, AP peptide, and tLyp-1 peptide), aptamers (e.g., A10 and AS1411), polysaccharides (e.g., hyaluronic acid), to small biomolecules (e.g., folic acid, galactose, bisphosphonates, and biotin), for active tumor-targeting drug delivery in vitro and in vivo are highlighted and discussed. With promise to maximize therapeutic efficacy while minimizing systemic side effects, ligand-mediated active tumor targeting treatment modality has become an emerging and indispensable platform for safe and efficient cancer therapy. PMID- 24798477 TI - Preparation of nanobubbles carrying androgen receptor siRNA and their inhibitory effects on androgen-independent prostate cancer when combined with ultrasonic irradiation. AB - OBJECTIVE: The objective of this study was to investigate nanobubbles carrying androgen receptor (AR) siRNA and their in vitro and in vivo anti-tumor effects, when combined with ultrasonic irradiation, on androgen-independent prostate cancer (AIPC). MATERIALS AND METHODS: Nanobubbles carrying AR siRNA were prepared using poly-L-lysine and electrostatic adsorption methods. Using C4-2 cell activity as a testing index, the optimal irradiation parameters (including the nanobubble number/cell number ratio, mechanical index [MI], and irradiation time) were determined and used for transfection of three human prostate cancer cell lines (C4-2, LNCaP, and PC-3 cells). The AR expression levels were investigated with RT-PCR and Western blot analysis. Additionally, the effects of the nanobubbles and control microbubbles named SonoVue were assessed via imaging in a C4-2 xenograft model. Finally, the growth and AR expression of seven groups of tumor tissues were assessed using the C4-2 xenograft mouse model. RESULTS: The nanobubbles had an average diameter of 609.5+/-15.6 nm and could effectively bind to AR siRNA. Under the optimized conditions of a nanobubble number/cell number ratio of 100?1, an MI of 1.2, and an irradiation time of 2 min, the highest transfection rates in C4-2, LNCaP, and PC-3 cells were 67.4%, 74.0%, and 63.96%, respectively. In the C4-2 and LNCaP cells, treatment with these binding nanobubbles plus ultrasonic irradiation significantly inhibited cell growth and resulted in the suppression of AR mRNA and protein expression. Additionally, contrast-enhanced ultrasound showed that the nanobubbles achieved stronger signals than the SonoVue control in the central hypovascular area of the tumors. Finally, the anti-tumor effect of these nanobubbles plus ultrasonic irradiation was most significant in the xenograft tumor model compared with the other groups. CONCLUSION: Nanobubbles carrying AR siRNA could be potentially used as gene vectors in combination with ultrasonic irradiation for the treatment of AIPC. PMID- 24798479 TI - Bihemispheric gunshot wounds: survival and long-term neuropsychological follow-up of three siblings. AB - PURPOSE: Penetrating gunshot wounds to the head (GSWH) have notoriously poor outcomes with extremely high mortality. Long-term follow-up data of affected children is scant in the medical literature. This report summarizes clinical presentation, management, and long-term outcomes from three children who survived "execution style" frontal, bihemispheric gunshot wounds with no or minimal surgical intervention. METHODS: A retrospective chart review of available medical records and outcomes from standardized, validated psychological instruments was undertaken, summarized, and evaluated. RESULTS: Despite bihemispheric injuries in each patient, no patient required operative intervention. Each child survived without readily evident neurologic impairment; however, the extent of impaired executive function varied widely, and severe disinhibition remains profoundly disabling in one survivor. CONCLUSIONS: Bihemispheric penetrating gunshot injuries are not uniformly fatal and can occasionally be associated with long term favorable survival; however, impaired executive function has significant potential to be profoundly disabling in these injuries. PMID- 24798480 TI - Diffusion tensor imaging studies in late-life depression: systematic review and meta-analysis. AB - OBJECTIVES: Late-life depression (LLD) is the association with more cerebrovascular susceptibilities and white matter damage that can be assessed with diffusion tensor imaging (DTI). To better understand the white matter pathological alterations in LLD, we conducted a systematic review and meta analysis. METHODS: We searched MEDLINE, EMBASE, PsycINFO, PubMed, and Google Scholar databases for DTI studies comparing patients with LLD and healthy controls. For each study, details regarding participants, imaging methods, and results were extracted. Fractional anisotropy, an index of white matter integrity, was the dependent variable for group comparison. Effect sizes indicating the degree of group difference were estimated by random-effects meta analysis. RESULTS: A total of 15 eligible studies were included in the qualitative systematic review, nine of which were suitable for quantitative meta analyses for the dorsolateral prefrontal cortex (DLPFC), corpus callosum, cingulum, and uncinate fasciculus (UF). Compared with the healthy control group, the LLD group showed lower fractional anisotropy in the DLPFC and UF with a large and a medium effect size, respectively, although heterogeneity and publication bias were found in the DLPFC. CONCLUSION: Diffusion tensor imaging studies of LLD consistently showed reduced anisotropy in the DLPFC and UF of patients with LLD. These damaged regions are located with the frontostriatal and limbic networks. Thus, our findings showed that the disruption of frontal and frontal-to-limbic white matter tracts contributes to the pathogenesis of LLD. PMID- 24798481 TI - The impact of modelling rate heterogeneity among sites on phylogenetic estimates of intraspecific evolutionary rates and timescales. AB - Phylogenetic analyses of DNA sequence data can provide estimates of evolutionary rates and timescales. Nearly all phylogenetic methods rely on accurate models of nucleotide substitution. A key feature of molecular evolution is the heterogeneity of substitution rates among sites, which is often modelled using a discrete gamma distribution. A widely used derivative of this is the gamma invariable mixture model, which assumes that a proportion of sites in the sequence are completely resistant to change, while substitution rates at the remaining sites are gamma-distributed. For data sampled at the intraspecific level, however, biological assumptions involved in the invariable-sites model are commonly violated. We examined the use of these models in analyses of five intraspecific data sets. We show that using 6-10 rate categories for the discrete gamma distribution of rates among sites is sufficient to provide a good approximation of the marginal likelihood. Increasing the number of gamma rate categories did not have a substantial effect on estimates of the substitution rate or coalescence time, unless rates varied strongly among sites in a non-gamma distributed manner. The assumption of a proportion of invariable sites provided a better approximation of the asymptotic marginal likelihood when the number of gamma categories was small, but had minimal impact on estimates of rates and coalescence times. However, the estimated proportion of invariable sites was highly susceptible to changes in the number of gamma rate categories. The concurrent use of gamma and invariable-site models for intraspecific data is not biologically meaningful and has been challenged on statistical grounds; here we have found that the assumption of a proportion of invariable sites has no obvious impact on Bayesian estimates of rates and timescales from intraspecific data. PMID- 24798478 TI - Single compartment drug delivery. AB - Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as "privileged," since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective. PMID- 24798482 TI - Antibiofilm properties of interfacially active lipase immobilized porous polycaprolactam prepared by LB technique. AB - Porous biomaterial is the preferred implant due to the interconnectivity of the pores. Chances of infection due to biofilm are also high in these biomaterials because of the presence of pores. Although biofilm in implants contributes to 80% of human infections, there are no commercially available natural therapeutics against it. In the current study, glutaraldehyde cross linked lipase was transferred onto a activated porous polycaprolactam surface using Langmuir Blodgett deposition technique, and its thermostability, slimicidal, antibacterial, biocompatibility and surface properties were studied. There was a 20% increase in the activity of the covalently crosslinked lipase when compared to its free form. This immobilized surface was thermostable and retained activity and stability until 100 degrees C. There was a 2 and 7 times reduction in carbohydrate and 9 and 5 times reduction in biofilm protein of Staphylococcus aureus and Escherichia coli respectively on lipase immobilized polycaprolactam (LIP) when compared to uncoated polycaprolactam (UP). The number of live bacterial colonies on LIP was four times less than on UP. Lipase acted on the cell wall of the bacteria leading to its death, which was confirmed from AFM, fluorescence microscopic images and amount of lactate dehydrogenase released. LIP allowed proliferation of more than 90% of 3T3 cells indicating that it was biocompatible. The fact that LIP exhibits antimicrobial property at the air-water interface to hydrophobic as well as hydrophilic bacteria along with lack of cytotoxicity makes it an ideal biomaterial for biofilm prevention in implants. PMID- 24798483 TI - Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. AB - Distinct from other forms of acute lymphoblastic leukemia (ALL), infant ALL with mixed lineage leukemia (MLL) gene rearrangement, the most common leukemia occurring within the first year of life, might arise without the need for cooperating genetic lesions. Through Ig/TCR rearrangement analysis of MLL-AF4+ infant ALL at diagnosis and xenograft leukemias from mice transplanted with the same diagnostic samples, we established that MLL-AF4+ infant ALL is composed of a branching subclonal architecture already at diagnosis, frequently driven by an Ig/TCR-rearranged founder clone. Some MLL-AF4+ clones appear to be largely quiescent at diagnosis but can reactivate and dominate when serially transplanted into immunodeficient mice, whereas other dominant clones at diagnosis can become more quiescent, suggesting a dynamic competition between actively proliferating and quiescent subclones. Investigation of paired diagnostic and relapse samples suggested that relapses often occur from subclones already present but more quiescent at diagnosis. Copy-number alterations identified at relapse might contribute to the activation and expansion of previously quiescent subclones. Finally, each of the identified subclones is able to contribute to the diverse phenotypic pool of MLL-AF4+ leukemia-propagating cells. Unraveling of the subclonal architecture and dynamics in MLL+ infant ALL may provide possible explanations for the therapy resistance and frequent relapses observed in this group of poor prognosis ALL. PMID- 24798486 TI - Uncertainties around the implementation of a clearing-control policy in a unique catchment in northern Australia: exploring equity issues and balancing competing objectives. AB - Land use change is the most significant driver linked to global species extinctions. In Northern Australia, the landscape is still relatively intact with very low levels of clearing. However, a re-energized political discourse around creating a northern food bowl means that currently intact ecosystems in northern Australia could be under imminent threat from increased land clearing and water extraction. These impacts are likely to be concentrated in a few regions with suitable soils and water supplies. The Daly River Catchment in the Northern Territory is an important catchment for both conservation and development. Land use in the Daly catchment has been subject to clearing guidelines that are largely untested in terms of their eventual implications for the spatial configuration of conservation and development. Given the guidelines are not legislated they might also be removed or revised by subsequent Territory Governments, including the recently-elected one. We examine the uncertainties around the spatial implications of full implementation of the Daly clearing guidelines and their potential effects on equity of opportunity across land tenures and land uses. We also examine how removal of the guidelines could affect conservation in the catchment. We conclude that the guidelines are important in supporting development in the catchment while still achieving conservation goals, and we recommend ways of implementing the guidelines to make best use of available land resources for intensified production. PMID- 24798484 TI - Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. AB - Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naive at sample collection. RESULTS: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months. PMID- 24798485 TI - Understanding the evolution of multimorbidity: evidences from the North West Adelaide Health Longitudinal Study (NWAHS). AB - OBJECTIVE: The aim of this study is to describe the evolution of multimorbidity. STUDY DESIGN AND SETTING: Data from 1854 South Australians who participated in the North West Adelaide longitudinal Health Study (NWAHS) was collected between baseline (2000-2002) and follow-up (2008-2010). Status for eight chronic diseases (CDs) was determined by biomedical measurement or self-report. Chronic disease (CD) mean age of occurrence and order of appearance was investigated. RESULTS: The prevalence of multimorbidity increased from 32% to 64% during the 7.8+/-1.1 years of follow-up. The estimated mean age of onset of a new CD was significantly older for hypertension, cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) and younger for hypercholesterolemia, asthma and other mental problem. Hypercholesterolemia was more likely to develop as a first than as a subsequent CD (39%vs.16%, p<0.0001) while CVD (1%vs.5%, p<0.0001), diabetes (5%vs.11%, p<0.001) and COPD (6%vs.16%, p<0.0001) were less likely. The presence of mood disorders at baseline was associated with an increased risk of developing other mental disorders (36%vs.12%, p<0.0001), diabetes (18%vs.9%, p<0.01) and asthma (30%vs.21%, p<0.05). CONCLUSION: Longitudinal data could be used to study the evolution of multimorbidity and could provide information on CDs mean age of occurrence, order of appearance and impact on the development of future CDs. PMID- 24798487 TI - Electrochemical approach for the development of a simple method for detecting cell apoptosis based on caspase-3 activity. AB - This paper reports a novel approach for the simple detection of cell apoptosis using an electrochemical technique. This method uses caspase-3 activity as an indicator of apoptosis. Caspase-3 activity was detected with differential plus voltammetry (DPV) as an alternative to conventional spectrometry. In this method, p-nitroaniline (pNA) released from Asp-Glu-Val-Asp-pNA by caspase-3 enzyme reaction was measured with DPV by using a glassy carbon electrode. Using this method, we successfully detected cell apoptosis occurring inside living HepG2 cells without the need for a cell lysis step. This method provides an easy assay procedure and, more importantly, allows a live cell apoptosis detection format. This novel electrochemical apoptosis assay using living cells instead of typically used cell lysates will expand the applicable range of the apoptosis assay to include cell activity assays for drug discovery and cell transplantation medicine. PMID- 24798488 TI - Bone-induced c-kit expression in prostate cancer: a driver of intraosseous tumor growth. AB - Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis. PMID- 24798489 TI - FhaC takes a bow to FHA in the two-partner do-si-do. AB - FhaC is an outer membrane transporter from Bordetella pertussis belonging to the two-partner secretion (TPS) pathway with its primary role being the secretion of the virulence factor filamentous haemagglutinin (FHA). FhaC serves as a model transporter of the TPS pathway and significant work has been done to characterize the role of FhaC in FHA secretion. Recent studies characterized interactions between FHA and the POTRA domains of FhaC, suggesting that secretion may involve a successive translocation mechanism mediated by beta-augmentation and/or electrostatic interactions. Moreover, it was also shown that reconstituted FhaC is necessary and sufficient to transport FHA into proteoliposomes. While the crystal structure of FhaC clearly suggests a role in transport, the putative transport pore is plugged by an N-terminal alpha-helix (H1 helix) that occludes access by FHA. Therefore, it has been proposed that the H1 helix must be expelled from the pore in order for secretion of FHA to occur. However, this has yet to be shown experimentally. Guerin et al. (2014) report the first direct experimental evidence to show that the FhaC H1 helix is quite dynamic and exchanges between closed and open states upon interaction with FHA. PMID- 24798491 TI - Thyroid scintigraphy findings in 2096 cats with hyperthyroidism. AB - Thyroid scintigraphy is currently the reference standard for diagnosing and staging cats with hyperthyroidism, but few studies describing the scintigraphic characteristics in a large number of cats have been reported. The objective of this study was to better characterize thyroid scintigraphy findings by evaluating 2096 consecutive cats with hyperthyroidism that were referred over a 3.5-year period. Of these cats, 2068 (98.7%) had a high thyroid-to-salivary ratio (>1.5), whereas 2014 (96.1%) were found to have a high thyroid-to-background ratio (>6.1). When the patterns of the cats' thyroid disease were recorded, 665 (31.7%) had unilateral disease, 1060 (50.6%) had bilateral-asymmetric disease (two thyroid lobes unequal in size), 257 (12.3%) had bilateral-symmetric disease (both lobes similar in size), and 81 (3.9%) had multifocal disease (>=3 areas of increased radionuclide uptake). The number of areas of (99m) TcO(-) 4 uptake in the 2096 cats ranged from 1 to 6 (median, 2), located in the cervical area in 2057 (98.1%), thoracic inlet in 282 (13.5%), and in the thoracic cavity in 115 (5.5%). Ectopic thyroid tissue (e.g. lingual or mediastinal) was diagnosed in 81 (3.9%) cats, whereas thyroid carcinoma was suspected in 35 (1.7%) of the cats. The results of this study support conclusions that most hyperthyroid cats have unilateral or bilateral thyroid nodules, but that multifocal disease will develop in a few cats that have ectopic thyroid disease or thyroid carcinoma. Both ectopic thyroid disease and thyroid carcinoma are relatively uncommon in hyperthyroid cats, with a respective prevalence of ~4% and ~2% in this study. PMID- 24798490 TI - Comparative analysis of P2X1, P2X2, P2X3, and P2X4 receptor subunits in rat nodose ganglion neurons. AB - Nodose ganglion (NG) neurons are visceral primary sensory neurons. The transmission and regulation of visceral sensation is mediated mainly by the P2X purinoceptor (P2X receptor). Although the characteristics of different P2X receptor subunits in the NG have been studied previously, comprehensive analyses have not been performed. In this study, we used immunohistochemistry, immunocytochemistry, and whole cell patch clamp techniques to compare the expression and function of P2X1, P2X2, P2X3, and P2X4 receptor subunits in adult rat NG neurons. Polyclonal antibodies against the four P2X subunits labeled different subpopulations of NG neurons. P2X1 and P2X3 were expressed mainly in small-to-medium sized NG neurons, whereas P2X2 and P2X4 were located mostly in medium- and larger-sized NG neurons. Over 36% of NG neurons were P2X3 positive, which was higher than the other three P2X subunits. In addition, different types of currents were recorded from neurons expressing different P2X subunits. The fast type of ATP current was recorded from neurons containing P2X1-4 subunits, the intermediate type of current was recorded from neurons containing the P2X1, P2X3, and P2X4 subunits, the slow type was recorded from neurons expressing P2X1 3, and/or P2X4 subunits, whereas the very slow type was recorded from neurons containing the P2X2 and P2X3 subunits. These comparative results provide an anatomical verification of the different subunits in NG neurons, and offer direct support for the idea that various functional NG populations have distinct responses to ATP, which might be in part due to the different expression profiles of diverse P2X subunits. PMID- 24798492 TI - Role of platelet-released growth factors in detoxification of reactive oxygen species in osteoblasts. AB - INTRODUCTION: Oxidative stress can impair fracture healing. To protect against oxidative damage, a system of detoxifying and antioxidative enzymes works to reduce the cellular stress. The transcription of these enzymes is regulated by antioxidant response element (ARE). The nuclear factor (erythroid-derived 2) like2 (Nrf2) plays a major role in transcriptional activation of ARE-driven genes. Recently it has been shown that vascular endothelial growth factor (VEGF) prevents oxidative damage via activation of the Nrf2 pathway in vitro. Platelet released growth factor (PRGF) is a mixture of autologous proteins and growth factors, prepared from a determined volume of platelet-rich plasma (PRP). It has already used to enhance fracture healing in vitro. The aim of the present study was to elucidate if platelets can lead to upregulation of VEGF and if platelets can regulate the activity of Nrf2-ARE system in primary human osteoblast (hOB) and in osteoblast-like cell line (SAOS-2). METHODS: Platelets and PRGF were obtained from healthy human donors. HOB and SAOS-2 osteosarcoma cell line were used. The ARE activity was analysed using a dual luciferase reporter assay system. We used Western blot to detect the nuclear accumulation of Nrf2 and the amount of cytosolic antioxidant Thioredoxin Reductase-1 (TXNRD-1), Heme Oxygenase 1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO1). Gene expression analysis was performed by real-time RT PCR. ELISA was used for the quantification of growth factors. RESULTS: The activity of ARE was increased in the presence of PRGF up to 50%. Western blotting demonstrated enhanced nuclear accumulation of Nrf2. This was followed by an increase in the protein expression of the aforementioned downstream targets of Nrf2. Real-time RT PCR data showed an upregulation in the gene expression of the VEGF after PRGF treatment. This was confirmed by ELISA, where the treatment with PRGF induced the protein level of VEGF in both cells. CONCLUSIONS: These results provide a new insight into PRGF's mode of action in osteoblasts. PRGF not only leads to increase the endogenous VEGF, but also it may be involved in preventing oxidative damage through the Nrf2 ARE signalling. Nrf2 activation via PRGF may have great potential as an effective therapeutic drug target in fracture healing. PMID- 24798493 TI - Deletion of core-binding factor beta (Cbfbeta) in mesenchymal progenitor cells provides new insights into Cbfbeta/Runxs complex function in cartilage and bone development. AB - Core-binding factor beta (Cbfbeta) is a subunit of the Cbf family of heterodimeric transcription factors, which plays a critical role in skeletal development through its interaction with the Cbfalpha subunits, also known as Runt-related transcription factors (Runxs). However, the mechanism by which Cbfbeta regulates cartilage and bone development remains unclear. Existing Cbfbeta-deficient mouse models cannot specify the role of Cbfbeta in skeletal cell lineage. Herein, we sought to specifically address the role of Cbfbeta in cartilage and bone development by using a conditional knockout (CKO) approach. A mesenchymal-specific Cbfbeta CKO mouse model was generated by using the Dermo1 Cre mouse line to specifically delete Cbfbeta in mesenchymal stem cells, which give rise to osteoblasts and chondrocytes. Surprisingly, the mutant mice had under-developed larynx and tracheal cartilage, causing alveolus defects that led to death shortly after birth from suffocation. Also, the mutant mice exhibited severe skeletal deformities from defective intramembranous and endochondral ossification, owing to delayed chondrocyte maturation and impaired osteoblast differentiation. Almost all bones of the mutant mice, including the calvariae, vertebrae, tibiae, femurs, ribs, limbs and sternums were defective. Importantly, we showed that Cbfbeta was expressed throughout the skeleton during both embryonic and postnatal development, which explains the multiple-skeletal defects observed in the mutant mice. Consistently, Cbfbeta deficiency impaired both chondrocyte proliferation and hypertrophy zone hypertrophy during growth-plate development in the long bones of mutant mice. Notably, Cbfbeta, Runx1 and Runx2 displayed different expression patterns in the growth plates of the wild-type mice, indicating that Cbfbeta/Runx1 complex and Cbfbeta/Runx2 complex may regulate chondrocyte proliferation and hypertrophy, respectively, in a spatial and temporal manner. Cbfbeta deletion in the mesenchymal progenitors affected bone development by dramatically down-regulating Collagen X (Col X) and Osterix (Osx) but had a dispensable effect on osteoclast development. Collectively, the results demonstrate that Cbfbeta mediates cartilage and bone development by interacting with Runx1 and Runx2 to regulate the expressions of Col X and Osx for chondrocyte and osteoblast development. These findings not only reveal a critical role for Cbfbeta in cartilage and bone development but also facilitate the design of novel therapeutic approaches for skeletal diseases. PMID- 24798494 TI - Growth inhibition effect of HMME-mediated PDT on hepatocellular carcinoma HepG2 cells. AB - Photodynamic therapy (PDT) is considered a promising new strategy for liver cancer treatment. Three elements of PDT--optical output power, irradiation time, and photosensitizer concentration--play important roles in promoting cell death. This research aimed to characterize the effects of hematoporphyrin monomethyl ether (HMME)-based PDT on hepatocellular carcinoma cells HepG2 and thus elucidate the relationship between cell death and the three elements mentioned earlier. Furthermore, in this study, we present a parameter that represents the cumulative effects of these elements. The accumulation of HMME in HepG2 cells was observed by fluorescence microscopy. The absorption spectrum of HMME was detected using fluorescence spectral analysis. The viability of the treated cells was determined using the MTT assay, and cell apoptosis was evaluated using flow cytometry. We found that the fluorescence intensity was positively correlated with the incubation time for up to 2 h. The cell growth inhibition rate was significantly high and gradually increased with increasing concentrations of HMME or increasing light intensity, which was calculated as optical output power * irradiation time. Further analysis revealed an e-exponential decay of the cell survival rate to the product of the HMME concentration and the light intensity. We defined the product as parameter B (B = optical output power * irradiation time * HMME concentration). Similarly, the rate of cell apoptosis showed roughly e exponential growth to parameter B. In conclusion, HMME-mediated PDT can significantly kill HepG2 cells, and the killing effect was related to the cumulative effects of the optical output power, the irradiation time, and the HMME concentration. Therefore, the newly defined parameter B, as a comprehensive physical quantity, may be of great significance for the regulation of light and photosensitizer according to patient-specific conditions in clinical practice. PMID- 24798495 TI - Photochemical degradation of atenolol, carbamazepine, meprobamate, phenytoin and primidone in wastewater effluents. AB - The photochemical degradation of five pharmaceuticals was examined in two secondary wastewater effluents. The compounds, which included atenolol, carbamazepine, meprobamate, phenytoin and primidone, were evaluated for both direct and sensitized photolysis. In the two wastewaters, direct photolysis did not lead to significant compound degradation; however, sensitized photolysis was an important removal pathway for the five pharmaceuticals. Upon solar irradiation, hydroxyl radical (HO) was quantified using the hydroxylation of benzene and singlet oxygen ((1)O2) formation was monitored following the degradation of furfuryl alcohol. Degradation via sensitized photolysis was observed following five-day exposures for atenolol (69-91%), carbamazepine (67 98%), meprobamate (16-52%), phenytoin (44-85%), and primidone (34-88%). Varying removal is likely a result of the differences in reactivity with transient oxidants. Averaged steady state HO concentrations ranged from 1.2 to 4.0*10( 16)M, whereas the concentrations of (1)O2 were 6.0-7.6*10(-14)M. Partial removal due to presence of HO indicates it was not the major sink for most compounds examined. Other transient oxidants, such as (1)O2 and triplet state effluent organic matter, are likely to play important roles in fates of these compounds. PMID- 24798496 TI - Long-term control of viral replication in a Group O, human immunodeficiency virus type 1-infected individual. PMID- 24798497 TI - Endonasal endoscopic surgery for squamous cell carcinoma of the sinonasal cavities and skull base: Oncologic outcomes based on treatment strategy and tumor etiology. AB - BACKGROUND: Oncologic outcomes for sinonasal and skull base squamous cell carcinoma (SCC) treated with an endoscopic endonasal approach (EEA) needs investigation. METHODS: Patients with SCC treated with EEA were stratified by treatment strategy and tumor etiology and reviewed. RESULTS: Thirty-four patients were treated with EEA, or which 27 had definitive resection and 7 had debulking surgery. In the definitive group, 17 had de novo tumors and 10 had tumors arising from inverted papilloma. Definitive resection was associated with better 5-year disease-free survival (DFS) and overall survival (OS) than debulking (62% vs 17%; p = .02; and 78% vs 30%; p = .03). Patients with de novo tumors had similar 5 year DFS and OS to those arising from inverted papilloma (62% vs 62%; p = .75; and 75% vs 86%; p = .24). CONCLUSION: Definitive resection of sinonasal SCC with EEA provides sound oncologic outcomes. SCC arising from inverted papilloma does not have prognostic significance. PMID- 24798498 TI - Rate of force development as a measure of muscle damage. AB - This study tested the hypothesis that rate of force development (RFD) would be a more sensitive indirect marker of muscle damage than maximum voluntary isometric contraction (MVC) peak torque. Ten men performed one concentric cycling and two eccentric cycling (ECC1, ECC2) bouts for 30 min at 60% of maximal concentric power output with 2 weeks between bouts. MVC peak torque, RFD, and vastus lateralis electromyogram amplitude and mean frequency were measured during a knee extensor MVC before, immediately after and 1-2 days after each bout. The magnitude of decrease in MVC peak torque after exercise was greater (P < 0.05) for ECC1 (11-25%) than concentric cycling (2-12%) and ECC2 (0-16%). Peak RFD and RFD from 0-30 ms, 0-50 ms, 0-100 ms, to 0-200 ms decreased (P < 0.05) immediately after all cycling bouts without significant differences between bouts, but RFD at 100-200 ms interval (RFD(100-200)) decreased (P < 0.05) at all time points after ECC1 (24-32%) and immediately after ECC2 (23%), but did not change after CONC. The magnitude of decrease in RFD(100-200) was 7-19% greater than that of MVC peak torque after ECC1 (P < 0.05). It is concluded that RFD(100-200) is a more specific and sensitive indirect marker of eccentric exercise-induced muscle damage than MVC peak torque. PMID- 24798499 TI - Benzyl alcohol attenuates acetaminophen-induced acute liver injury in a Toll-like receptor-4-dependent pattern in mice. AB - Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in industrialized countries. Understanding the mechanisms of APAP-induced liver injury as well as other forms of sterile liver injury is critical to improve the care of patients. Recent studies demonstrate that danger signaling and inflammasome activation play a role in APAP-induced injury. The aim of these investigations was to test the hypothesis that benzyl alcohol (BA) is a therapeutic agent that protects against APAP-induced liver injury by modulation of danger signaling. APAP-induced liver injury was dependent, in part, on Toll like receptor (TLR)9 and receptor for advanced glycation endproducts (RAGE) signaling. BA limited liver injury over a dose range of 135-540 MUg/g body weight or when delivered as a pre-, concurrent, or post-APAP therapeutic. Furthermore, BA abrogated APAP-induced cytokines and chemokines as well as high-mobility group box 1 release. Moreover, BA prevented APAP-induced inflammasome signaling as determined by interleukin (IL)-1beta, IL-18, and caspase-1 cleavage in liver tissues. Interestingly, the protective effects of BA on limiting liver injury and inflammasome activation were dependent on TLR4 signaling, but not TLR2 or CD14. Cell-type-specific knockouts of TLR4 were utilized to further determine the protective mechanisms of BA. These studies found that TLR4 expression specifically in myeloid cells (LyzCre-tlr4-/-) were necessary for the protective effects of BA. CONCLUSION: BA protects against APAP-induced acute liver injury and reduced inflammasome activation in a TLR4-dependent manner. BA may prove to be a useful adjunct in the treatment of APAP and other forms of sterile liver injury. PMID- 24798500 TI - Tuning thin-film electrolyte for lithium battery by grafting cyclic carbonate and combed poly(ethylene oxide) on polysiloxane. AB - A tunable polysiloxane thin-film electrolyte for all-solid-state lithium-ion batteries was developed. The polysiloxane was synthesized by hydrosilylation of polymethylhydrosiloxane with cyclic [(allyloxy)methyl]ethylene ester carbonic acid and vinyl tris(2-methoxyethoxy)silane. (1) H NMR spectroscopy and gel permeation chromatography demonstrated that the bifunctional groups of the cyclic propylene carbonate (PC) and combed poly(ethylene oxide) (PEO) were well grafted on the polysiloxane. At PC/PEO=6:4, the polysiloxane-based electrolyte had an ionic conductivity of 1.55 * 10(-4) and 1.50 * 10(-3) S cm(-1) at 25 and 100 degrees C, respectively. The LiFePO4 /Li batteries fabricated with the thin-film electrolyte presented excellent cycling performance in the temperature range from 25 to 100 degrees C with an initial discharge capacity at a rate of 1 C of 88.2 and 140 mA h g(-1) at 25 and 100 degrees C, respectively. PMID- 24798501 TI - Reconstitution of the peripheral B lymphocyte compartment in patients with ANCA associated vasculitides treated with rituximab for relapsing or refractory disease. AB - While in patients with rheumatoid arthritis B-cell repopulation starts within 9 months after rituximab (RTX) therapy, a delayed B-cell repopulation was reported in some RTX-treated patients with ANCA-associated vasculitides (AAV). To date, the frequency of AAV patients with impaired peripheral B-cell regeneration and the mechanisms leading to the constricted regenerative capacity are unknown. We analyzed the B-cell repopulation kinetic in 37 AAV patients treated with RTX followed by maintenance immunosuppressants. We report on serum concentrations of the B-cell-activating factor BAFF, immunoglobulins and B-cell subpopulations in patients that relapsed after RTX. B-cells were re-detectable in only one patient within 9 months after RTX. In 14 patients (41%), B-cell repopulation started later, after a mean observation time of 21 months. Only seven of these patients had detectable B-cells within the first year after RTX. Twenty patients (59%) had no B-cell reconstitution within the observation period. BAFF was increased in RTX treated AAV patients compared to healthy controls and correlated inversely with peripheral B-cell numbers, IgG- and IgA concentrations. Immunoglobulin concentrations declined significantly after RTX and the IgG concentration correlated with B-cell numbers. Thirteen patients relapsed after RTX. Relapses occurred exclusively either after B-cell reconstitution had started or were accompanied by rising ANCA titres. In relapsed patients, the B-lymphocyte compartment consisted mainly of switched memory B-cells. Our data indicate that RTX treatment can induce secondary immunodeficiency in AAV, with hypogammaglobulinemia and long-lasting B-lymphopenia. Further studies are needed to define the pathophysiology of the impaired B-cell development in RTX-treated AAV patients. PMID- 24798502 TI - Van Hove singularities and excitonic effects in the optical conductivity of twisted bilayer graphene. AB - We report a systematic study of the optical conductivity of twisted bilayer graphene (tBLG) across a large energy range (1.2-5.6 eV) for various twist angles, combined with first-principles calculations. At previously unexplored high energies, our data show signatures of multiple van Hove singularities (vHSs) in the tBLG bands as well as the nonlinearity of the single layer graphene bands and their electron-hole asymmetry. Our data also suggest that excitonic effects play a vital role in the optical spectra of tBLG. Including electron-hole interactions in first-principles calculations is essential to reproduce the shape of the conductivity spectra, and we find evidence of coherent interactions between the states associated with the multiple vHSs in tBLG. PMID- 24798503 TI - Toward consilience in reptile phylogeny: miRNAs support an archosaur, not lepidosaur, affinity for turtles. AB - Understanding the phylogenetic position of crown turtles (Testudines) among amniotes has been a source of particular contention. Recent morphological analyses suggest that turtles are sister to all other reptiles, whereas the vast majority of gene sequence analyses support turtles as being inside Diapsida, and usually as sister to crown Archosauria (birds and crocodilians). Previously, a study using microRNAs (miRNAs) placed turtles inside diapsids, but as sister to lepidosaurs (lizards and Sphenodon) rather than archosaurs. Here, we test this hypothesis with an expanded miRNA presence/absence dataset, and employ more rigorous criteria for miRNA annotation. Significantly, we find no support for a turtle + lepidosaur sister-relationship; instead, we recover strong support for turtles sharing a more recent common ancestor with archosaurs. We further test this result by analyzing a super-alignment of precursor miRNA sequences for every miRNA inferred to have been present in the most recent common ancestor of tetrapods. This analysis yields a topology that is fully congruent with our presence/absence analysis; our results are therefore in accordance with most gene sequence studies, providing strong, consilient molecular evidence from diverse independent datasets regarding the phylogenetic position of turtles. PMID- 24798504 TI - Racial/ethnic socialization and identity development in Black families: the role of parent and youth reports. AB - Racial/ethnic (R/E) socialization is widely practiced in R/E minority families. However, only recently have models been developed to understand how parents' R/E socialization messages influence adolescent development. The primary goal of the present study was to clarify and extend existing work on R/E socialization in African American (Black) families by distinguishing between parent and youth reports of parents' R/E socialization messages and examining the extent to which adolescents and their parents agree about these socialization messages. In addition, we tested a theoretical model in which parent-reported R/E socialization messages have an indirect effect on the development of youth R/E identity through youth reports of their parents' R/E socialization messages. Using a combination of open- and close-ended data from a longitudinal study of self-identified Black adolescents and their parents, we found statistically significant parent-youth agreement about whether parents send both general R/E socialization messages and, for daughters, specific R/E socialization messages. R/E socialization messages focused on promoting cultural pride and history were associated positively with R/E identity development, whereas messages focused on preparing youth for discrimination tended to be unrelated to R/E identity development. The results largely supported the hypothesis that parent reports of parents' R/E socialization messages are related indirectly to the development of adolescent R/E identity via youth reports of parents' R/E socialization messages. PMID- 24798505 TI - Sarcasm and advanced theory of mind understanding in children and adults with prelingual deafness. AB - Two studies addressed key theoretical debates in theory of mind (ToM) development by comparing (a) deaf native signers (n = 18), (b) deaf late signers (n = 59), and (c) age-matched hearing persons (n = 74) in childhood (Study 1: n = 81) and adulthood (Study 2: n = 70) on tests of first- and second-order false belief and conversational sarcasm. Results showed ToM development to be a life span phenomenon for deaf and hearing people alike. Native and late signers were outperformed by hearing peers on advanced ToM in childhood (M = 9 years), but in adulthood (M = 40 years), native signers had caught up, whereas late signers had not. Findings highlight the extended importance of conversational interaction for ToM growth. PMID- 24798506 TI - Cation effects on interfacial water organization of aqueous chloride solutions. I. Monovalent cations: Li+, Na+, K+, and NH4(+). AB - The influence of monovalent cations on the interfacial water organization of alkali (LiCl, NaCl, and KCl) and ammonium chloride (NH4Cl) salt solutions was investigated using surface-sensitive conventional vibrational sum frequency generation (VSFG) and heterodyne-detected (HD-)VSFG spectroscopy. It was found in the conventional VSFG spectra that LiCl and NH4Cl significantly perturb water's hydrogen-bonding network. In contrast, NaCl and KCl had little effect on the interfacial water structure and exhibited weak concentration dependency. The Im chis(2)(omegaIR) spectra from HD-VSFG further revealed that, for all chloride solutions, the net transition dipole moments of hydrogen-bonded water molecules (O -> H) are oriented more toward the vapor phase relative to neat water. This suggests the presence of an interfacial electric field generated from the formation of an ionic double layer in the interfacial region with a distribution of Cl(-) ions located above the countercations, in agreement with predictions from MD simulations. The magnitude of this electric field shows a small but definite cation specificity and follows the order Li(+) ~ Na(+) > NH4(+) > K(+). The observed trend was found to be in good agreement with previously published surface potential data. PMID- 24798507 TI - Specific pathogen-free pig herds also free from Campylobacter? AB - As Specific Pathogen-Free (SPF) pig herds are designed and managed to prevent specific pig diseases, it might be feasible to expand the list of micro-organisms also including zoonotic pathogens such as Campylobacter coli as this agent has its origin in pigs. In a previous survey, 15 of 16 of SPF herds were found free from human pathogenic Yersinia enterocolitica. Accordingly, three nucleus and seven multiplying herds were surveyed for Campylobacter to investigate whether the Norwegian SPF pig pyramid also might be free from this agent. In conclusion, the intervention of Campylobacter at the herd level might be possible as four of 10 SPF herds tested negative in two sets of samples from both autumn 2008 and summer/early autumn 2010. The four negative herds were all located in remote areas several kilometres away from conventional pig farming while the positive SPF farms were all situated in neighbourhoods with conventional pig production. It seems more difficult to control Campylobacter than some specific animal disease agents and another significant zoonotic agent, Y. enterocolitica, in pig herds. PMID- 24798508 TI - Relational Ethics, Depressive Symptoms, and Relationship Satisfaction in Couples in Therapy. AB - The purpose of this study was to examine depressive symptoms and relationship satisfaction as problems related to relational ethics in one's family of origin and current partner relationships in a sample of 68 other-sex couples seeking therapy at a large university clinic. We used the Actor Partner Interdependence Model to analyze dyadic data collected prior to beginning therapy. Specifically, we found significant actor effects between relational ethics in one's family of origin and depressive symptoms, as well as between depressive symptoms and low relationship satisfaction for both male and female partners. We also found significant partner effects for relational ethics in current partner relationship, depressive symptoms, and low relationship satisfaction. Clinical application of contextual therapy theory is discussed. PMID- 24798509 TI - A New Method for Analyzing the Duffy Blood Group Genotype by TaqMan Minor Groove Binding Probes. AB - BACKGROUND: Duffy blood group genotyping is useful to ensure transfusion safety and determine the association of Duffy blood group polymorphism with diseases, and therefore has its clinical significance. In order to improve the existing methods for genotyping of Duffy blood group, which normally require post-PCR manipulation, a new method was developed by using 5'-nuclease assay (NA) with TaqMan minor groove binding (MGB) probes. METHODS: Primers and TaqMan-MGB probes were designed and synthesized to genotype FY*A and FY*B alleles at Duffy blood group locus on a real-time PCR platform. A total of 120 samples were genotyped by using the new 5'-NA and conventional polymerase chain reaction with allele specific primers (PCR-ASP). The results obtained by the two methods were compared. RESULTS: There was a complete concordance of results for all samples genotyped by 5'-NA and PCR-ASP. The retesting results of 5'-NA were consistent with those of the initial testing. The detection limit of 5'-NA was determined as 100 pg per reaction. The FY*A and FY*B allelic frequencies were 93.3% and 6.7% respectively in the Chinese Han population in Dalian. CONCLUSIONS: The 5'-NA for genotyping of Duffy blood group is simple, rapid, reliable, reproducible, sensitive, and high-throughput and is superior to PCR-ASP used in routine genotyping. PMID- 24798510 TI - Bone density and bone turnover marker monitoring after discontinuation of alendronate therapy: an evidence-based decision to do less. PMID- 24798511 TI - Evaluation of two cooling systems under a firefighter coverall. AB - Firemen often suffer from heat strain. This study investigated two chest cooling systems for use under a firefighting suit. In nine male subjects, a vest with water soaked cooling pads and a vest with water perfused tubes were compared to a control condition. Subjects performed 30 min walking and 10 min recovery in hot conditions, while physiological and perceptual parameters were measured. No differences were observed in heart rate and rectal temperature, but scapular skin temperature and fluid loss were lower using the perfused vest. Thermal sensation was cooler for the perfused vest than for the other conditions, while the cool pad vest felt initially cooler than control. However, comfort and RPE scores were similar. We conclude that the cooling effect of both tested systems, mainly providing a (temporally) cooler thermal sensation, was limited and did not meet the expectations. PMID- 24798512 TI - Whole-genome based validation of the adaptive properties of Indian origin probiotic Lactobacillus helveticus MTCC 5463. AB - BACKGROUND: The aim of the study was to mine the Lactobacillus helveticus MTCC 5463 genome for genetic determinants to validate its ability to adapt to gut transit stresses and translate functionality to the host. RESULTS: In silico analysis of the 1 911 350 bp single chromosome of the strain predicted that it had excellent adaptive features like the multisubunit F0F1 ATPase, conjugated bile salt hyrolase, chaperones like hsp33, HtrA, GroEL, GroES, dnaK, grpE, starvation-inducible proteins and heavy-metal transporting ATPases. The genome revealed genes for adhesion and aggregation including exopolysaccharides, capsular polysaccharides sortase, elongation factor Tu, aggregation promoting proteins, fibronectin-binding proteins, S-layer and mucus-binding proteins. We could identify genes conferring physiological benefits like immunostimulation, cholesterol reduction, antibacterial and folate production. Thus, through trait and gene matching, the study established that the strain possessed the genetic arsenal required to adapt to the gut milieu. The predictions of functional genes further validate the experimental evidences of adaptation and probiosis. CONCLUSION: This study provides insight into the feasibility of applying probiogenomics to identify genes that could function as pre-selection criteria for identification of potential probiotic strains. PMID- 24798514 TI - Themes reported by families as important when proceeding with pediatric hematopoietic stem cell transplantation. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an accepted treatment for pediatric malignant and non-malignant conditions. Agreeing to HSCT can be challenging for families. This study explored themes reported by family members as influencing their acceptance of HSCT as a necessary treatment intervention. PROCEDURE: In a four-site study, 107 individuals within 30 families pursuing HSCT for a pediatric malignancy, and 25 individuals within 6 families pursuing HSCT for a pediatric non-malignancy were interviewed pre-HSCT. Semantic content analysis was used in this secondary analysis to identify relevant themes. RESULTS: Fifty-eight parents (and surrogates) 19 patients, 16 donor siblings, and 39 non-donor siblings, half-siblings and cousins, participated. Thirteen themes were identified as influencing the acceptance of HSCT. The most frequently reported were: "recommendation by the child's physician," viewing HSCT as the "best chance for cure," and "desiring a more normal and better quality of life for the patient and family." Seven themes were reported by all categories of family members, though at different frequencies. Two themes ("HSCT being part of the upfront treatment plan": "hearing of HSCT success in others") were only reported by the malignancy group, and one theme ("worrying about disease progression and losing a window of HSCT opportunity") was only reported by the non-malignancy group. CONCLUSION: Parents, patients, and other family members can articulate multiple themes that influence their considerations of HSCT. Understanding these themes may guide discussions between families and healthcare teams. PMID- 24798515 TI - Dynamics of violence. AB - RATIONALE, AIMS AND OBJECTIVES: Three behavioural models suggest different dynamic patterns of intimate partner violence (IPV). However, few studies permit assessment of IPV dynamics. The purpose of this study was to estimate the degree of non-linearity in daily violence between partners over a 3-month period, identify their specific dynamic patterns and determine whether measures of violence severity and dynamics are interrelated. METHODS: From six primary care clinics, we enrolled 200 adult women who experienced violence in the previous month and asked them to complete daily telephone assessments of household environment, marital relationship and violence using Interactive Verbal Response. To assess non-linearity of violence, algorithmic complexity was measured by LZ complexity and lack of regularity was measured by approximate entropy. Lyapunov exponents and correlation dimension saturation were used to approximate dynamic patterns. RESULTS: Of the 9618 daily reports, women reported experiencing abuse on 39% of days, while perpetrating violence themselves on 23% of days. Most (59%) displayed random dynamics, 30% showed chaotic and 12% showed periodic dynamics. All three measures of non-linearity consistently demonstrated non-linear patterns of violence. Using multivariate analysis of variance, neither episode severity for men or women showed significant differences across dynamic types, but chaotic dynamics had the lowest frequencies of violence in men and women while random dynamics had the highest frequencies. Approximate entropy was positively correlated with violence frequency and burden in men and women, but Lyapunov exponent was inversely related to violence. LZ complexity correlated positively with wife-perpetrated violence only. CONCLUSIONS: IPV is rarely a predictable, periodic phenomenon; no behavioural model describes the violence dynamics for all violent relationships. Yet, the measures of non-linearity and specific dynamic patterns correlate with different violent features of these relationships. PMID- 24798513 TI - Acid-sensing hypothalamic neurons controlling arousal. AB - Breathing and vigilance are regulated by pH and CO2 levels in the central nervous system. The hypocretin/orexin (Hcrt/Orx)- and histamine (HA)-containing hypothalamic neurons synergistically control different aspects of the waking state. Acidification inhibits firing of most neurons but these two groups in the caudal hypothalamus are excited by hypercapnia and protons, similar to the chemosensory neurons in the brain stem. Activation of hypothalamic wake-on neurons in response to hypercapnia, seen with the c-Fos assay, is supported by patch-clamp recordings in rodent brain slices: Hcrt/Orx and HA neurons are excited by acidification in the physiological range (pH from 7.4 to 7.0). Multiple molecular mechanisms mediate wake-promoting effects of protons in HA neurons in the tuberomamillary nucleus (TMN): among them are acid-sensing ion channels, Na(+),K(+)-ATPase, group I metabotropic glutamate receptors (mGluRI). HA neurons are remarkably sensitive to the mGluRI agonist DHPG (threshold concentration 0.5 uM) and mGluRI antagonists abolish proton-induced excitation of HA neurons. Hcrt/Orx neurons are excited through block of a potassium conductance and release glutamate with their peptides in TMN. The two hypothalamic nuclei and the serotonergic dorsal raphe cooperate toward CO2/acid-induced arousal. Their interactions and molecular mechanisms of H(+)/CO2-induced activation are relevant for the understanding and treatment of respiratory and metabolic disorders related to sleep-waking such as obstructive sleep apnea and sudden infant death syndrome. PMID- 24798516 TI - Urinary bladder distention evoked visceromotor responses as a model for bladder pain in mice. AB - Approximately 3-8 million people in the United States suffer from interstitial cystitis/bladder pain syndrome (IC/BPS), a debilitating condition characterized by increased urgency and frequency of urination, as well as nocturia and general pelvic pain, especially upon bladder filling or voiding. Despite years of research, the cause of IC/BPS remains elusive and treatment strategies are unable to provide complete relief to patients. In order to study nervous system contributions to the condition, many animal models have been developed to mimic the pain and symptoms associated with IC/BPS. One such murine model is urinary bladder distension (UBD). In this model, compressed air of a specific pressure is delivered to the bladder of a lightly anesthetized animal over a set period of time. Throughout the procedure, wires in the superior oblique abdominal muscles record electrical activity from the muscle. This activity is known as the visceromotor response (VMR) and is a reliable and reproducible measure of nociception. Here, we describe the steps necessary to perform this technique in mice including surgical manipulations, physiological recording, and data analysis. With the use of this model, the coordination between primary sensory neurons, spinal cord secondary afferents, and higher central nervous system areas involved in bladder pain can be unraveled. This basic science knowledge can then be clinically translated to treat patients suffering from IC/BPS. PMID- 24798518 TI - Mutant huntingtin is present in neuronal grafts in Huntington disease patients. AB - OBJECTIVE: Huntington disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin [mHtt]), which is thought to exert its effects in a cell-autonomous manner. Here, we tested the hypothesis that mHtt is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing HD. METHODS: The presence of mHtt aggregates within the grafted tissue was confirmed using 3 different types of microscopy (bright-field, fluorescence, and electron), 2 additional techniques consisting of Western immunoblotting and infrared spectroscopy, and 4 distinct antibodies targeting different epitopes of mHtt aggregates. RESULTS: We describe the presence of mHtt aggregates within intracerebral allografts of striatal tissue in 3 HD patients who received their transplants approximately 1 decade earlier and then died secondary to the progression of their disease. The mHtt(+) aggregates were observed in the extracellular matrix of the transplanted tissue, whereas in the host brain they were seen in neurons, neuropil, extracellular matrix, and blood vessels. INTERPRETATION: This is the first demonstration of the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brain of affected HD patients. These observations raise questions on protein spread in monogenic neurodegenerative disorders of the central nervous system characterized by the formation of mutant protein oligomers/aggregates. PMID- 24798517 TI - Three epilepsy-associated GABRG2 missense mutations at the gamma+/beta- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents. AB - We compared the effects of three missense mutations in the GABAA receptor gamma2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with alpha1, beta2, and wildtype or mutant gamma2 subunits. The mutations R82Q and P83S were identified in families with genetic epilepsy with febrile seizures plus (GEFS+), and N79S was found in a single patient with generalized tonic-clonic seizures (GTCS). Although all three mutations were located in an N-terminal loop that contributes to the gamma+/beta- subunit subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The gamma2(R82Q) and gamma2(P83S) subunits had reduced alpha1beta2gamma2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, gamma2(N79S) subunits were efficiently assembled into GABAA receptors with only minimally altered receptor trafficking, suggesting that N79S was a rare or susceptibility variant rather than an epilepsy mutation. Increased structural variability at assembly motifs was predicted by R82Q and P83S, but not N79S, substitution, suggesting that R82Q and P83S substitutions were less tolerated. Membrane proteins with missense mutations that impair folding and assembly often can be "rescued" by decreased temperatures. We coexpressed wildtype or mutant gamma2 subunits with alpha1 and beta2 subunits and found increased surface and total levels of both wildtype and mutant gamma2 subunits after decreasing the incubation temperature to 30 degrees C for 24h, suggesting that lower temperatures increased GABAA receptor stability. Thus epilepsy-associated mutations N79S, R82Q and P83S disrupted GABAA receptor assembly to different extents, an effect that could be potentially rescued by facilitating protein folding and assembly. PMID- 24798519 TI - Gallotannin is a DNA damaging compound that induces senescence independently of p53 and p21 in human colon cancer cells. AB - The plant secondary metabolite gallotannin (GT) is the simplest hydrolyzable tannin shown to have anti-carcinogenic properties in several cell lines and to inhibit tumor development in different animal models. Here, we determined if GT induces senescence and DNA damage and investigated the involvement of p53 and p21 in this response. Using HCT116 human colon cancer cells wildtype for p53(+/+) /p21(+/+) and null for p53(+/+) /p21(-/-) or p53(-/-) /p21(+/+) , we found that GT induces senescence independently of p21 and p53. GT was found to increase the production of reactive oxygen species (ROS) by altering the redox balance in the cell, mainly by reducing the levels of glutathione and superoxide dismutase (SOD). Using the key antioxidants N-acetyl cysteine, dithiothreitol, SOD, and catalase, we showed that ROS were partially involved in the senescence response. Furthermore, GT-induced cell cycle arrest in S-phase in all HCT116 cell lines. At later time points, we noticed that p53 and p21 null cells escaped complete arrest and re-entered cell cycle provoking higher rates of multinucleation. The senescence induction by GT was irreversible and was accompanied by significant DNA damage as evidenced by p-H2AX staining. Our findings indicate that GT is an interesting anti colon cancer agent which warrants further study. PMID- 24798520 TI - Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. AB - Long non-coding RNAs (lncRNAs) are involved in regulating chromatin modifications, gene transcription, mRNA translation, and protein function. We recently reported a high variation in the basal expression levels of a panel of lncRNAs in HeLa and MCF-7 cells and their differential response to DNA damage induction. Here, we hypothesized that lncRNA molecules with different cellular expression may have a differential abundance in secreted exosomes, and their exosome levels would reflect cellular response to DNA damage. MALAT1, HOTAIR, lincRNA-p21, GAS5, TUG1, CCND1-ncRNA in exosomes secreted from cultured cells were characterized. A different expression pattern of lncRNAs in exosomes was seen compared to cells. RNA molecules with relative low expression levels (lincRNA-p21, HOTAIR, ncRNA-CCND1) were highly enriched in exosomes. TUG1 and GAS5 levels were moderately elevated in exosomes, whereas MALAT1--which was the most abundant molecule in cells--was present at levels comparable to its cellular levels. lincRNA-p21 and ncRNA-CCND1 were the main molecules; exosome levels of them best reflect the change of their cellular levels upon exposure of the cells to bleomycin-induced DNA damage. In conclusion, we provide evidence that lncRNAs have a differential abundance in exosomes, indicating a selective loading. PMID- 24798521 TI - Changes in mortality after Massachusetts health care reform: a quasi-experimental study. AB - BACKGROUND: The Massachusetts 2006 health care reform has been called a model for the Affordable Care Act. The law attained near-universal insurance coverage and increased access to care. Its effect on population health is less clear. OBJECTIVE: To determine whether the Massachusetts reform was associated with changes in all-cause mortality and mortality from causes amenable to health care. DESIGN: Comparison of mortality rates before and after reform in Massachusetts versus a control group with similar demographics and economic conditions. SETTING: Changes in mortality rates for adults in Massachusetts counties from 2001 to 2005 (prereform) and 2007 to 2010 (postreform) were compared with changes in a propensity score-defined control group of counties in other states. PARTICIPANTS: Adults aged 20 to 64 years in Massachusetts and control group counties. MEASUREMENTS: Annual county-level all-cause mortality in age-, sex-, and race-specific cells (n = 146,825) from the Centers for Disease Control and Prevention's Compressed Mortality File. Secondary outcomes were deaths from causes amenable to health care, insurance coverage, access to care, and self reported health. RESULTS: Reform in Massachusetts was associated with a significant decrease in all-cause mortality compared with the control group ( 2.9%; P = 0.003, or an absolute decrease of 8.2 deaths per 100,000 adults). Deaths from causes amenable to health care also significantly decreased (-4.5%; P < 0.001). Changes were larger in counties with lower household incomes and higher prereform uninsured rates. Secondary analyses showed significant gains in coverage, access to care, and self-reported health. The number needed to treat was approximately 830 adults gaining health insurance to prevent 1 death per year. LIMITATIONS: Nonrandomized design subject to unmeasured confounders. Massachusetts results may not generalize to other states. CONCLUSION: Health reform in Massachusetts was associated with significant reductions in all-cause mortality and deaths from causes amenable to health care. PRIMARY FUNDING SOURCE: None. PMID- 24798522 TI - Economic return from the Women's Health Initiative estrogen plus progestin clinical trial: a modeling study. AB - BACKGROUND: The findings of the Women's Health Initiative (WHI) estrogen plus progestin (E+P) trial led to a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States. The economic effect of this shift has not been evaluated relative to the trial's $260 million cost (2012 U.S. dollars). OBJECTIVE: To estimate the economic return from the WHI E+P trial. DESIGN: Decision model to simulate health outcomes for a "WHI scenario" with observed cHT use and a "no-WHI scenario" with cHT use extrapolated from the pretrial period. DATA SOURCES: Primary analyses of WHI outcomes, peer reviewed literature, and government sources. TARGET POPULATION: Postmenopausal women in the United States, aged 50 to 79 years, who did not have a hysterectomy. TIME HORIZON: 2003 to 2012. PERSPECTIVE: Payer. INTERVENTION: Combined hormone therapy. OUTCOME MEASURES: Disease incidence, expenditure, quality-adjusted life years, and net economic return. RESULTS OF BASE-CASE ANALYSIS: The WHI scenario resulted in 4.3 million fewer cHT users, 126,000 fewer breast cancer cases, 76,000 fewer cardiovascular disease cases, 263,000 more fractures, 145,000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100,000 per quality adjusted life-year. RESULTS OF SENSITIVITY ANALYSIS: The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion. LIMITATION: No evaluation of indirect costs or outcomes beyond 2012. CONCLUSION: The WHI E+P trial made high-value use of public funds with a substantial return on investment. These results can contribute to discussions about the role of public funding for large, prospective trials with high potential for public health effects. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute. PMID- 24798524 TI - What can medical education learn from Facebook and Netflix? PMID- 24798523 TI - Comparative effectiveness of cardiac resynchronization therapy with an implantable cardioverter-defibrillator versus defibrillator therapy alone: a cohort study. AB - BACKGROUND: Trials comparing implantable cardioverter-defibrillator (ICD) therapy with cardiac resynchronization therapy with a defibrillator (CRT-D) are limited to selected patients treated at centers with extensive experience. OBJECTIVE: To compare outcomes after CRT-D versus ICD therapy in contemporary practice. DESIGN: Retrospective cohort study using the National Cardiovascular Data Registry's ICD Registry linked with Medicare claims. SETTING: 780 U.S. hospitals implanting both CRT-D and ICD devices. PATIENTS: 7090 propensity-matched patients older than 65 years with reduced left ventricular ejection fraction (<0.35) and prolonged QRS duration on electrocardiography (>=120 ms) having CRT-D or ICD implantation between 1 April 2006 and 31 December 2009. MEASUREMENTS: Risks for death, readmission, and device-related complications over 3 years. RESULTS: Compared with ICD therapy, CRT-D was associated with lower risks for mortality (cumulative incidence, 25.7% vs. 29.8%; adjusted hazard ratio [HR], 0.82 [99% CI, 0.73 to 0.93]), all-cause readmission (cumulative incidence, 68.6% vs. 72.8%; adjusted HR, 0.86 [CI, 0.81 to 0.93]), cardiovascular readmission (cumulative incidence, 45.0% vs. 52.4%; adjusted HR, 0.80 [CI, 0.73 to 0.88]), and heart failure readmission (cumulative incidence, 24.3% vs. 29.4%; adjusted HR, 0.78 [CI, 0.69 to 0.88]). It was also associated with greater risks for device-related infection (cumulative incidence, 1.9% vs. 1.0%; adjusted HR, 1.90 [CI, 1.07 to 3.37]). The lower risks for heart failure readmission associated with CRT-D compared with ICD therapy were most pronounced among patients with left bundle branch block or a QRS duration at least 150 ms and in women. LIMITATIONS: Patients were not randomly assigned to treatment groups, and few patients could be propensity matched. The findings may not extend to younger patients or those outside of fee for-service Medicare. CONCLUSION: In older patients with reduced left ventricular ejection fraction and prolonged QRS duration, CRT-D was associated with lower risks for death and readmission than ICD therapy alone. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 24798525 TI - Patient safety: let's measure what matters. PMID- 24798526 TI - Lessons learned from the Syrian sarin attack: evaluation of a clinical syndrome through social media. AB - On the night of 21 August 2013, sarin was dispersed in the eastern outskirts of Damascus, killing 1400 civilians and severely affecting thousands more. This article aims to delineate the clinical presentation and management of a mass casualty event caused by a nerve agent as shown in the social media. Authors searched YouTube for videos uploaded of this attack and identified 210 videos. Of these, 67 met inclusion criteria and were evaluated in the final analysis.These videos displayed 130 casualties; 119 (91.5%) of which were defined as moderately injured or worse. The most common clinical signs were dyspnea (53.0%), diaphoresis (48.5%), and loss of consciousness (40.7%). Important findings included a severe shortage of supporting measures and lack of antidotal autoinjectors. Decontamination, documented in 25% of the videos, was done in an inefficient manner. Protective gear was not noticed, except for sporadic use of latex gloves and surgical masks.This is believed to be the first time that social media was used to evaluate clinical data and management protocols to better prepare against future possible events. PMID- 24798528 TI - Investing in clinical science: make way for (not-so-uncommon) outliers. PMID- 24798527 TI - Improving health through coverage expansion. PMID- 24798529 TI - A labor of love. PMID- 24798530 TI - Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer. PMID- 24798531 TI - Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer. PMID- 24798532 TI - Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer. PMID- 24798533 TI - Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer. PMID- 24798534 TI - Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer. PMID- 24798535 TI - Goals of palliative care. PMID- 24798536 TI - Goals of palliative care. PMID- 24798537 TI - Severe hypertension related to caffeinated coffee and tranylcypromine: a case report. PMID- 24798544 TI - In the clinic. Screening for colorectal cancer. PMID- 24798545 TI - Effective density and mixing state of aerosol particles in a near-traffic urban environment. AB - In urban environments, airborne particles are continuously emitted, followed by atmospheric aging. Also, particles emitted elsewhere, transported by winds, contribute to the urban aerosol. We studied the effective density (mass-mobility relationship) and mixing state with respect to the density of particles in central Copenhagen, in wintertime. The results are related to particle origin, morphology, and aging. Using a differential mobility analyzer-aerosol particle mass analyzer (DMA-APM), we determined that particles in the diameter range of 50 400 nm were of two groups: porous soot aggregates and more dense particles. Both groups were present at each size in varying proportions. Two types of temporal variability in the relative number fraction of the two groups were found: soot correlated with intense traffic in a diel pattern and dense particles increased during episodes with long-range transport from polluted continental areas. The effective density of each group was relatively stable over time, especially of the soot aggregates, which had effective densities similar to those observed in laboratory studies of fresh diesel exhaust emissions. When heated to 300 degrees C, the soot aggregate volatile mass fraction was ~10%. For the dense particles, the volatile mass fraction varied from ~80% to nearly 100%. PMID- 24798546 TI - GayBy Boomers' social support: exploring the connection between health and emotional and instrumental support in older gay men. AB - We evaluate the association between emotional and instrumental support and perceived health and depression symptoms in a sample of 182 gay/bisexual men age >= 55. Perceived health was positively correlated with number of sources of emotional support and depression was negatively associated with instrumental support and health care providers' knowledge of patients' sexual orientation. Depression mediates the connection between providers' knowledge of patients' sexual orientation and perceived health. Number of sources of emotional support varied negatively with age and ethnic minority status, and positively with living with a partner. Instrumental support seemed to be dependent on living with a partner. PMID- 24798547 TI - [Science fiction becomes reality ]. PMID- 24798548 TI - Intracellular long-chain acyl CoAs activate TRPV1 channels. AB - TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs), another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes. PMID- 24798549 TI - Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan. AB - Reovirus is a double stranded RNA virus, with an intrinsic preference for replication in KRAS mutant cells. As 45% of human colorectal cancers (CRC) harbor KRAS mutations, we sought to investigate its efficacy in KRAS mutant CRC cells, and examine its impact in combination with the topoisimerase-1 inhibitor, irinotecan. Reovirus efficacy was examined in the KRAS mutant HCT116, and the isogenic KRAS WT Hke3 cell line, and in the non-malignant rat intestinal epithelial cell line. Apoptosis was determined by flow cytometry and TUNEL staining. Combination treatment with reovirus and irintoecan was investigated in 15 CRC cell lines, including the HCT116 p21 isogenic cell lines. Reovirus preferentially induced apoptosis in KRAS mutant HCT116 cells compared to its isogenic KRAS WT derivative, and in KRAS mutant IEC cells. Reovirus showed a greater degree of caspase 3 activation with PARP 1 cleavage, and preferential inhibition of p21 protein expression in KRAS mutant cells. Reovirus synergistically induced growth inhibition when combined with irinotecan. This synergy was lost upon p21 gene knock out. Reovirus preferentially induces apoptosis in KRAS mutant colon cancer cells. Reovirus and irinotecan combination therapy is synergistic, p21 mediated, and represents a novel potential treatment for patients with CRC. PMID- 24798550 TI - Fragments of layered manganese oxide are the real water oxidation catalyst after transformation of molecular precursor on clay. AB - A binuclear manganese molecular complex [(OH2)(terpy)Mn(MU-O)2Mn(terpy)(OH2)](3+) (1) is the most prominent structural and functional model of the water-oxidizing Mn complex operating in plants and cyanobacteria. Supported on montmorillonite clay and using Ce(IV) as a chemical oxidant, 1 has been reported to be one of the best Mn-based molecular catalysts toward water oxidation. By X-ray absorption spectroscopy and kinetic analysis of the oxygen evolution reaction, we show that [(OH2)(terpy)Mn(MU-O)2Mn(terpy)(OH2)](3+) is transformed into layered type Mn oxide particles which are the actual water oxidation catalyst. PMID- 24798551 TI - Using membrane-targeted green fluorescent protein to monitor neurotoxic protein dependent degeneration of Drosophila eyes. AB - Age-related neurodegeneration has been studied extensively through the use of model organisms, including the genetically versatile Drosophila melanogaster. Various neurotoxic proteins have been expressed in fly eyes to approximate degeneration occurring in humans, and much has been learned from this heterologous system. Although Drosophila expedites scientific research through rapid generational times and relative inexpensiveness, one factor that can hinder analyses is the examination of milder forms of degeneration caused by some toxic proteins in fly eyes. Whereas several disease proteins cause massive degeneration that is easily observed by examining the external structure of the fly eye, others cause mild degeneration that is difficult to observe externally and requires laborious histological preparation to assess and monitor. Here, we describe a sensitive fluorescence-based method to observe, monitor, and quantify mild Drosophila eye degeneration caused by various proteins, including the polyglutamine disease proteins ataxin-3 (spinocerebellar ataxia type 3) and huntingtin (Huntington's disease), mutant alpha-synuclein (Parkinson's disease), and Abeta42 (Alzheimer's disease). We show that membrane-targeted green fluorescent protein reports degeneration robustly and quantitatively. This simple yet powerful technique, which is amenable to large-scale screens, can help accelerate studies to understand age-related degeneration and to find factors that suppress it for therapeutic purposes. PMID- 24798552 TI - Defining dysbiosis and its influence on host immunity and disease. AB - Mammalian immune system development depends on instruction from resident commensal microorganisms. Diseases associated with abnormal immune responses towards environmental and self antigens have been rapidly increasing over the last 50 years. These diseases include inflammatory bowel disease (IBD), multiple sclerosis (MS), type I diabetes (T1D), allergies and asthma. The observation that people with immune mediated diseases house a different microbial community when compared to healthy individuals suggests that pathogenesis arises from improper training of the immune system by the microbiota. However, with hundreds of different microorganisms on our bodies it is hard to know which of these contribute to health and more importantly how? Microbiologists studying pathogenic organisms have long adhered to Koch's postulates to directly relate a certain disease to a specific microbe, raising the question of whether this might be true of commensal-host relationships as well. Emerging evidence supports that rather than one or two dominant organisms inducing host health, the composition of the entire community of microbial residents influences a balanced immune response. Thus, perturbations to the structure of complex commensal communities (referred to as dysbiosis) can lead to deficient education of the host immune system and subsequent development of immune mediated diseases. Here we will overview the literature that describes the causes of dysbiosis and the mechanisms evolved by the host to prevent these changes to community structure. Building off these studies, we will categorize the different types of dysbiosis and define how collections of microorganisms can influence the host response. This research has broad implications for future therapies that go beyond the introduction of a single organism to induce health. We propose that identifying mechanisms to re establish a healthy complex microbiota after dysbiosis has occurred, a process we will refer to as rebiosis, will be fundamental to treating complex immune diseases. PMID- 24798554 TI - Introduction to the special issue on Stanford Immunology. PMID- 24798555 TI - Prevalence, diagnostic value and clinical characteristics associated with the presence of circulating levels and renal deposits of antibodies against the M type phospholipase A2 receptor in idiopathic membranous nephropathy. AB - The M-type phospholipase A2 receptor (PLA2R) has been identified as one of the target antigens of the autoimmune response in idiopathic membranous nephropathy (MN). The prevalence of anti-PLA2R antibodies in patients with idiopathic MN is around 70% but this varies in accordance with geographic region, and until present, anti-PLA2R has not been shown to be associated with any particular clinical profile of the disease. METHODS: We studied 64 adults with nephrotic syndrome who were diagnosed with MN, confirmed by renal biopsy. Forty-seven patients had idiopathic MN and 17 had secondary MN. We determined the presence of circulating anti-PLA2R antibodies by indirect immunofluorescence (IIF) and their titre by ELISA, and we analysed the presence of anti-PLA2R antibody renal deposits by immunohistochemical techniques. We calculated the sensitivity and specificity of the IIF and ELISA techniques for the identification of patients with renal deposits and for the identification of those with idiopathic MN and we tested whether there were differences in the clinical profile of the disease at the time of diagnosis according to the presence or absence of anti-PLA2R antibodies. RESULTS: We did not observe significant differences in the clinical demographic variables between patients with idiopathic and secondary MN. The prevalence of anti-PLA2R glomerular deposits by IHC was 76.6%. The IIF and ELISA techniques had a similar sensitivity (IIF 94.4% and ELISA 97.2%) and specificity (100%) for the identification of patients with anti-PLA2R renal deposits and the detection of circulating anti-PLA2R antibodies. The determination of anti-PLA2R by IIF identified patients with idiopathic MN with a sensitivity of 72.3% and a specificity of 94.2%. A titre of antibodies >15RU/ml measured by ELISA had a sensitivity of 74.45% and a specificity of 94.2% for the identification of patients with idiopathic MN. Patients with idiopathic MN and anti-PLA2R had significantly higher proteinuria figures (13.25 [P25-P75: 9.05-15.87] compared to 9.43 [P25-P75: 6.30-15] g/day, P:.018). No statistical correlation was observed between the antibody titre measured by ELISA and age, glomerular filtration rate or 24-hour proteinuria or albuminaemia. CONCLUSIONS: The techniques employed to determine anti-PLA2R in patients with MN are highly specific for the diagnosis of idiopathic forms of the glomerular disease. The frequency with which patients with MN and anti-PLA2R were identified is similar to that reported in previous studies. Staining by immunohistochemistry is the most sensitive method for detecting cases of MN associated with the presence of anti-PLA2R antibodies. The IIF and ELISA techniques allow circulating anti-PLA2R antibodies to be detected in most patients with renal deposits, but they may very infrequently have false negative results. The concordance of these tests is high. Patients with idiopathic MN and anti-PLA2R antibody renal deposits have higher proteinuria than patients that are anti-PLA2R negative, but the differences have little clinical importance. PMID- 24798556 TI - Results of the 2012 third survey on Nephrology resident training. AB - The second survey for tutors and the third for residents of the Spanish Society of Nephrology and the Spanish National Commission of Nephrology in 2012 compared with those of 2004 and 2007. 64% of tutors but only 24.6% of resident physicians participated. Tutors: improvement in educational infrastructure. Improvement in teaching organisation and in resident activity reporting. Clear improvement in teaching and in resident assessment. They believe that there should be a five year training period and a compulsory examination at the end of the residency. Resident physicians: improved satisfaction with teaching received with respect to previous surveys, except with regard to renal biopsies and pathological sessions. Improvement in formal training; experience in transplantation (only poor in 7%); experience in peritoneal dialysis (still poor in 21%); level of tutoring (poor in 20%); performance and quality of clinical sessions; scientific activity; quality of training of your service: good/very good in 66% in 2012 versus 26% (2004) and 46% (2007). PMID- 24798557 TI - Diabetes mellitus and kidney disease in the elderly. AB - Management of diabetic elderly patients with chronic kidney disease involves specific characteristics that affect both metabolic control and therapeutic measures. Blood glucose control targets should be individualised based on life expectancy, renal function, hypoglycaemia risk and comorbidity. Metformin may be used alone or in combination with other oral anti-diabetic drugs but must be discontinued when the glomerular filtration rate is less than 30 mL/min. Gliclazide and glipizide are sulfonylureas that do not require dose adjustment in chronic kidney disease but they should be avoided in cases of advanced kidney disease because of the risk of hypoglycaemia. Repaglinide is the only meglitinide recommended in these patients. Alpha-glucosidase inhibitors must be avoided in patients with a glomerular filtration rate of less than 25 mL/min or those undergoing dialysis. Pioglitazone does not require dose adjustment but it has potentially adverse effects in this population. Dipeptidyl peptidase-4 inhibitors are effective and well tolerated. Of the latter, linagliptin does not require dose adjustment. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are not recommended in elderly patients with advanced kidney disease. Lastly, insulin therapy, particularly using the new insulin analogues, allows adequate management of hyperglycaemia in these patients, with different therapeutic regimens that must be individualised in order to avoid hypoglycaemia. PMID- 24798553 TI - Effects of stress on immune function: the good, the bad, and the beautiful. AB - Although the concept of stress has earned a bad reputation, it is important to recognize that the adaptive purpose of a physiological stress response is to promote survival during fight or flight. While long-term stress is generally harmful, short-term stress can be protective as it prepares the organism to deal with challenges. This review discusses the immune effects of biological stress responses that can be induced by psychological, physiological, or physical (including exercise) stressors. We have proposed that short-term stress is one of the nature's fundamental but under-appreciated survival mechanisms that could be clinically harnessed to enhance immunoprotection. Short-term (i.e., lasting for minutes to hours) stress experienced during immune activation enhances innate/primary and adaptive/secondary immune responses. Mechanisms of immuno enhancement include changes in dendritic cell, neutrophil, macrophage, and lymphocyte trafficking, maturation, and function as well as local and systemic production of cytokines. In contrast, long-term stress suppresses or dysregulates innate and adaptive immune responses by altering the Type 1-Type 2 cytokine balance, inducing low-grade chronic inflammation, and suppressing numbers, trafficking, and function of immunoprotective cells. Chronic stress may also increase susceptibility to some types of cancer by suppressing Type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell function. Here, we classify immune responses as being protective, pathological, or regulatory, and discuss "good" versus "bad" effects of stress on health. Thus, short-term stress can enhance the acquisition and/or expression of immunoprotective (wound healing, vaccination, anti-infectious agent, anti-tumor) or immuno-pathological (pro-inflammatory, autoimmune) responses. In contrast, chronic stress can suppress protective immune responses and/or exacerbate pathological immune responses. Studies such as the ones discussed here could provide mechanistic targets and conceptual frameworks for pharmacological and/or biobehavioral interventions designed to enhance the effects of "good" stress, minimize the effects of "bad" stress, and maximally promote health and healing. PMID- 24798558 TI - Prospective study of the complications associated with percutaneous renal biopsy of native kidneys: experience in a centre. AB - BACKGROUND: Percutaneous renal biopsy (PRB) is a key invasive technique in the study of kidney disease and it is associated with considerable morbidity. Retrospective studies have shown minor complications in 10%-20% and major complications in 1.2%-6.6% of cases. However, this aspect has not been studied prospectively. OBJECTIVE: The aim of our study was to prospectively assess complications related to PRB in the native kidney. METHODS: From January 2009 to May 2013, we prospectively analysed PRB performed by nephrologists in native kidneys under ultrasound guidance. We analysed clinical and laboratory variables. We defined minor complications as the decrease in haemoglobin (Hb) of more than 1g/dL and major complications as the need for a transfusion or invasive technique. RESULTS: 241 PRB were performed over this period. The mean patient age was 49 years (+/-17), the majority (56%) were male and 58.1% had high blood pressure. In 51% of cases, we carried out 2 punctures. There were minor complications in 46 patients (19.1%) and major complications in 9 patients (3.7%). In the univariate analysis, pre-PRB Hb was 10.3g/dL (+/-1.3) in patients with major complications and 12.3g/dL (+/-2.2) in the remaining patients (p=.003); in the multivariate analysis: OR 0.51, 95% CI (0.2-0.9), p<.05. CONCLUSIONS: PRB is a procedure that is not without risk, since minor complications occurred in 19.1% and major complications in 3.7% of cases. Pre-PRB Hb is an independent risk factor for the development of major complications. PMID- 24798559 TI - Primary hyperoxaluria. AB - Primary hyperoxaluria (PH) occurs due to an autosomal recessive hereditary disorder of the metabolism of glyoxylate, which causes excessive oxalate production. The most frequent and serious disorder is due to enzyme deficit of alanine-glyoxylate aminotransferase (PH type I) specific to hepatic peroxisome. As oxalate is not metabolised in humans and is excreted through the kidneys, the kidney is the first organ affected, causing recurrent lithiasis, nephrocalcinosis and early renal failure. With advance of renal failure, particularly in patients on haemodialysis (HD), calcium oxalate is massively deposited in tissues, which is known as oxalosis. Diagnosis is based on family history, the presence of urolithiasis and/or nephrocalcinosis, hyperoxaluria, oxalate deposits in tissue forming granulomas, molecular analysis of DNA and enzyme analysis if applicable. High diagnostic suspicion is required; therefore, unfortunately, in many cases it is diagnosed after its recurrence following kidney transplantation. Conservative management of this disease (high liquid intake, pyridoxine and crystallisation inhibitors) needs to be adopted early in order to delay kidney damage. Treatment by dialysis is ineffective in treating excess oxalate. After the kidney transplant, we normally observe a rapid appearance of oxalate deposits in the graft and the results of this technique are discouraging, with very few exceptions. Pre-emptive liver transplantation, or simultaneous liver and kidney transplants when there is already irreversible damage to the kidney, is the treatment of choice to treat the underlying disease and suppress oxalate overproduction. Given its condition as a rare disease and its genetic and clinical heterogeneity, it is not possible to gain evidence through randomised clinical trials. As a result, the recommendations are established by groups of experts based on publications of renowned scientific rigour. In this regard, a group of European experts (OxalEurope) has drawn up recommendations for diagnosis and treatment, which were published in 2012. PMID- 24798560 TI - Economic repercussions of implementing a protocol for urgent surgical repair of thrombosed arteriovenous fistulae. AB - INTRODUCTION: When a patient undergoing haemodialysis suffers from arteriovenous fistula (AVF) thrombosis, (s)he needs an urgent procedure before the next dialysis session. Two different treatment options are available: placing a central venous catheter (CVC) or repairing the AVF. The objective of this study is to assess the possibility of urgent repair of thrombosed AVFs within the emergency care activity of a general surgery department and to determine the possible economic repercussions of implementing this working protocol in an area of healthcare. METHOD: We completed the prospective collection of all the urgent surgical interventions made to repair thrombosed AVFs for the period 2000-2011 at our centre. The clinical results were analysed using two variables: rate of thrombosis (episodes/patient/year) and percentage of recovery. Recovery was deemed effective if after the surgery the patient was able to undergo dialysis of his/her AVF without the need to place a CVC. The "thrombosed AVF" clinical process was defined and implemented, and its economic cost was analysed via a detailed analysis conducted by our centre's Financial Department. This analysis was also conducted for the alternative clinical process (new AVF), using the data published by the Ministry of Health (weight of the Diagnosis-Related Group: vascular accesses for haemodialysis, hospital complexity unit, public cost of outpatient procedures and percentage of economic repercussions of the implementation of this process, comparing the costs of both procedures). RESULTS: During the study period 268 episodes of thrombosis occurred, a rate of 0.1 episodes/patient/year (0.05 on autologous AVFs and 0.43 on grafts). 203 (75%) were treated urgently by the surgery department, of which 168 AVFs (82%) were recovered. The cost of urgently repairing an AVF was estimated at ?999. The average cost of a scheduled AVF intervention, plus the cost of placing and maintaining a CVC, was estimated at ?6,397. The saving made by urgent repair of AVFs in our area of healthcare is ?107,940/year. Extrapolating this to the entire country for a population of 23,000 patients on haemodialysis, the total would be ?9,930,480/year. CONCLUSIONS: It is possible to perform urgent surgical recovery on the majority of AVFs for haemodialysis. Implementing multidisciplinary protocol avoids fitting these patients with catheters, reducing the cost this entails. PMID- 24798561 TI - A lower proportion of circulating active parathyroid hormone in peritoneal dialysis does not allow the pth inter-method adjustment proposed for haemodialysis. AB - INTRODUCTION: Parathyroid hormone (PTH) shows a strong correlation with histomorphometric and biochemical parameters of bone turnover, however its measurement presents limitations due to inter-method variability. Circulating PTH is a mixture of peptides, but only on its whole form (1-84 PTH) is responsible of PTH biological activity. Carboxyl-terminal fragments exhibit antagonist actions and their proportion differs at each stage of chronic kidney disease, as consequence of differences on their renal clearance. The aim of this study is to evaluate possible differences in the proportion of these fragments according to dialysis type: haemodialysis (HD) or peritoneal dialysis (PD). MATERIAL AND METHODS: Serum total (Ca) and ionized calcium (iCa), phosphate (P), carboxyl terminal telopeptides of collagen type I (BCTx) were measured in 73 patients on PD (46 men and 27 women with an age between 22 and 82 years). PTH was quantified by six second generation assays (one isotopic and five chemiluminescence assays) and by one third generation PTH method. RESULTS: Mean serum levels of Ca, iCa, P and BCTx were 9.03, 4.76, 4.73 mg/dl and 1181 pmol/l, respectively. Significant differences were observed in PTH values according to the method used. Adjustment of PTH results to PTH Allegro (Nichols) range of 150-300 nmol/l in PD patients showed higher values than those assessed previously for HD population. The percentage of biologically active 1-84 PTH as the 1-84 PTH/ 7-84 PTH ratio in PD were significantly lower than in HD patients, reflecting the higher proportion of 7-84 PTH circulating fragments for a given intact PTH result in PD. CONCLUSIONS: PD patients have a higher proportion of 7-84 PTH circulating fragments. Consequently, the inter-method adjustment algorithms proposed for HD patients are not useful for PD patients. This study proposes alternative algorithms for PTH inter-method adjustment to be applied in PD. PMID- 24798562 TI - Perioperative renal protection strategies in liver transplantation. AB - Renal failure is one of the most common and major complications in liver transplant recipients. It has been reported to occur at an incidence of 17% to 95%. This complication is associated with prolonged hospital stay in the intensive care unit, the need for postoperative dialysis, infectious complications, acute rejection, and increased mortality. The causes of renal function deterioration differ in the preoperative and postoperative periods. By identifying patients at risk of developing chronic renal failure and by implementing strategies for renal protection at an early stage, it is possible to slow down the progression of renal failure and improve the long-term outcomes in liver transplant recipients. PMID- 24798563 TI - Translational study of the Notch pathway in hypertensive nephropathy. AB - INTRODUCTION: The Notch signalling pathway is activated in a wide variety of human renal diseases. We have recently demonstrated that the activation of this pathway is not involved in experimental renal fibrosis induced by angiotensin II or hypertension. OBJECTIVES: To assess whether the Notch pathway is activated in renal fibrosis related to hypertensive nephrosclerosis. To test the hypothesis, various glomerular diseases characterised by tubulointerstitial fibrosis were analysed. METHOD: Renal biopsies were performed on patients with hypertensive nephrosclerosis, in comparison with diabetic nephropathy and membranous nephropathy at various stages. Gene and protein expression were evaluated by in situ hybridisation and immunohistochemistry respectively. RESULTS: In hypertensive nephrosclerosis low renal expression of notch-related proteins was observed. There was no link between tubulointerstitial fibrosis and the levels of these proteins. By contrast, in the glomerular diseases studied we observed high expression of the transcripts Jagged-1, HES-1 and TGF-beta and the proteins Jagged-1 y Notch-1, localised primarily in tubuloepithelial cells. The levels of expression of the components of the Notch pathway correlate to the degree of tubulointerstitial fibrosis, which confirms the activation of this pathway in progressive nephropathies. CONCLUSIONS: Our data demonstrate that the Notch pathway is not activated in the kidneys of patients with hypertensive nephropathy, which extends the results of experimental models of kidney damage related to hypertension to the realm of human pathology. Our studies provide new information on the complex regulation of the Notch pathway in the kidney. PMID- 24798564 TI - Use of radioactive iodine I-131 and monitoring of radioactivity in patients with chronic kidney disease on haemodialysis. AB - Thyroid carcinoma is a neoplasia with a higher incidence in patients with chronic kidney disease. In recent years advances have been made in diagnostic and therapeutic trials. Dialysis patients are a particular group, their cancer being detected indirectly in the study of secondary hyperparathyroidism and during the study prior to renal transplantation. Thyroidectomy is the definitive treatment, but in patients with risk of recurrence, ablative therapy is required using radioactive iodine I-131, which is predominantly eliminated by renal excretion, therefore its use in patients on dialysis poses a problem in terms of dosage. Two cases are presented of patients on haemodialysis undergoing radioablation with radioactive iodine I-131, which with multidisciplinary treatment had the expected results in the patients. PMID- 24798565 TI - Spanish Society of Nephrology document on KDIGO guidelines for the assessment and treatment of chronic kidney disease. AB - The new Kidney Disease: Improving Global Outcomes (KDIGO) international guidelines on chronic kidney disease (CKD) and the management of blood pressure (BP) in CKD patients are an update of the corresponding 2002 and 2004 KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines. The documents aim to provide updated guidelines on the assessment, management and treatment of patients with CKD. The first guidelines retain the 2002 definition of CKD but present an improved prognosis classification. Furthermore, concepts about prognosis of CKD, recommendations for management of patients, and criteria for referral to the nephrologist have been updated. The second guideline retains the <130/80 mm Hg-goal for management of BP in patients with CKD presenting increased albuminuria or proteinuria (albumin-to-creatinine ratio 30-300 mg/g, and >300 mg/g, respectively) but recommends a less-strict goal of <140/90 mm Hg in patients with normoalbuminuria. The development of the guidelines followed a predetermined process in which the evidence available was reviewed and assessed. Recommendations on management and treatment are based on the systematic review of relevant studies. The GRADE system (Grading of Recommendations Assessment, Development and Evaluation) was used to assess the quality of evidence and issue the grade of recommendation. Areas of uncertainty are also discussed for the different aspects addressed. PMID- 24798566 TI - European renal best practice guideline on the management and evaluation of the kidney donor and recipient. AB - The purpose of this Clinical Practice Guideline is to provide guidance on evaluation of the kidney donor and transplant recipient as well as on the management of the recipient in the perioperative period. It is designed to provide information and aid decision-making. It is not intended to define a standard of care, and should neither be construed as one nor should it be interpreted as prescribing an exclusive course of management. The original version of this guideline was published in Nephrology, Dialysis and Transplantation and this current version is a reduced article aiming to disseminate the guideline into Spanish-speaking countries and transplant communities. PMID- 24798567 TI - Role of monoclonal antibodies in the treatment of immune-mediated glomerular diseases. AB - Non-specific immunosuppressants have represented for decades the only therapies for patients with immune-mediated glomerular diseases. These treatments, however, are associated with high rates of no-response and are burdened by toxicities that frequently offset the benefits of proteinuria reduction. Monoclonal antibodies targeting selective cell populations or mediators implicated in the pathophysiology of glomerular diseases have recently become available. Rituximab, a chimeric monoclonal antibody against the CD20 antigen on B cells, safely reduced proteinuria in patients with nephrotic syndrome secondary to membranous nephropathy, minimal change disease, or focal segmental glomerulosclerosis. Its ability to reduce auto-antibody formation has been instrumental to treat also ANCA-associated vasculitis, lupus nephritis, and mixed cryoglobulinemia. Many reports have also documented the efficacy of the anti-C5 humanized monoclonal antibody Eculizumab to treat atypical hemolytic uremic syndrome, C3 nephropathy, and membranoproliferative glomerulonephritis. Thanks to these encouraging findings, monoclonals are becoming very helpful tools to treat patients with glomerular diseases. Moreover, thanks to their specific mechanism of action, these and other monoclonal antibodies are important in improving our understanding of the pathophysiology of glomerular diseases. Their still high costs, however, might represent a major hurdle for their widespread implementation for all patients in need. PMID- 24798568 TI - Copolymeric micelles for delivery of EGCG and cyclopamine to pancreatic cancer cells. AB - Our objective was to synthesize a copolymer for delivery and protection of (-) epigallocatechin gallate (EGCG). Methoxy poly(ethylene glycol)-b-poly[5-methyl-5 (3, 4, 5-trimethoxybenzoyol)-1, 3-dioxan-2-one-co-lactide] [mPEG-b-P(TM-co-LA)] copolymer was synthesized and characterized. The use of gallate containing monomer resulted in a copolymer that could show enhanced drug loading, stability, and sustained release of EGCG from mPEG-b-P(TM-co-LA) micelles as determined using LC/MS. The combination of EGCG and cyclopamine (CyA) displayed remarkable effects on growth inhibition of Mia PaCa-2 pancreatic cancer cells and induction of apoptosis. Although the expression level of Gli-1 was markedly downregulated by cyclopamine treatment, treatment with EGCG significantly inhibited the phosphorylation of EGFR in Mia PaCa-2 cells. Gallate containing copolymer can be used for micellar delivery of EGCG and CyA and the combination of these drugs can target 2 signaling pathways, thereby providing an effective way to treat pancreatic cancer. PMID- 24798569 TI - The hexadehydro-Diels-Alder reaction: a new chapter in aryne chemistry. PMID- 24798570 TI - Semi-catalytic reduction of secondary amides to imines and aldehydes. AB - Secondary amides can be reduced by silane HSiMe2Ph into imines and aldehydes by a two-stage process involving prior conversion of amides into iminoyl chlorides followed by catalytic reduction mediated by the ruthenium complex [Cp(i Pr3P)Ru(NCCH3)2]PF6 (1). Alkyl and aryl amides bearing halogen, ketone, and ester groups were converted with moderate to good yields under mild reaction conditions to the corresponding imines and aldehydes. This procedure does not work for substrates bearing the nitro-group and fails for heteroaromatic amides. In the case of cyano substituted amides, the cyano group is reduced to imine. PMID- 24798571 TI - Osteoarthritis: Sprifermin shows cartilage-protective effects in knee OA. PMID- 24798572 TI - Connective tissue diseases: TLR4 and fibronectin--persistent fibrogenesis in SSc. PMID- 24798573 TI - Issues in trial design for ANCA-associated and large-vessel vasculitis. AB - Randomized clinical trials (RCTs) have informed the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, although challenges still exist. The evidence base for treating large-vessel vasculitis (LVV) is weaker, but initiatives to standardize diagnostic criteria and outcome measures, and to validate biomarkers in LVV, together with newly initiated RCTs should start to address this need. In this Perspectives, we discuss the prerequisites for RCTs in vasculitis, existing trial evidence, continuing unmet needs, potential therapeutic avenues to explore and considerations in the design of future trials. PMID- 24798575 TI - Breed-specific hematologic reference intervals in healthy adult Dogues de Bordeaux. AB - BACKGROUND: There is an increasing interest for breed-specific reference intervals in veterinary medicine. In a previous study, breed-specific biochemical reference intervals (RIs) have been established for Dogues de Bordeaux (DDBs). This breed is predisposed to familial juvenile glomerulonephropathy and hypothyroidism, and would benefit from hematologic RI. OBJECTIVE: The purpose was de novo establishment of breed-specific hematologic RIs for the DDB in accordance with the International Federation of Clinical Chemistry and Clinical and Laboratory Standards Institute guidelines. METHODS: One hundred and twenty DDBs from France and Belgium were recruited. CBCs were determined with the Sysmex XT 2000iV analyzer within 12 hours of blood collection. RIs were determined using the nonparametric method. Effects of sex, age, and face mask color were studied. RESULTS: RIs were determined in 58 healthy dogs. DDBs had higher RIs for HGB, HCT, MCV, MCHC, and mean platelet volume, and lower RIs for reticulocytes counts, platelets by impedance (PLT-I) and optical count (PLT-O), and plateletcrit when compared with generic canine RIs. Age significantly affected RIs for HGB, HCT, MCHC, WBC, neutrophil, lymphocyte, and monocyte counts. CONCLUSION: The generic canine RIs established in the same laboratory with analogous preanalytical and analytical variations did not differ significantly from breed-specific RIs, and thus have no significant impact on clinical decision making; however, breed specific RIs are advised for some RBC and all platelet-related variables to avoid erroneous suspicion of polycythemia and thrombocytopenia when using general canine RIs for evaluation of DDB. PMID- 24798574 TI - G protein-coupled receptors in rheumatology. AB - G protein-coupled receptors (GPCRs) are transmembrane receptor proteins that allow the transfer of signals across the cell membrane. In addition to their physiological role, GPCRs are involved in many pathophysiological processes including pathways relevant in rheumatoid arthritis (RA), osteoarthritis (OA) and psoriatic arthritis. Two-thirds of all currently available drugs target GPCRs directly or indirectly. However, the detailed mechanism of GPCR signalling is still unclear. Selective modification of GPCR-dependent signalling cascades to inhibit disease progression in rheumatic diseases is now being investigated. One approach is to use antibodies against ligands activating GPCRs. However, several GPCRs are known to be activated by only one ligand. In this case, targeting the receptor itself is a promising approach. So far, more information is available on GPCR action in RA as compared with OA, and even less information is available for other rheumatic diseases. Additional research on the role of GPCRs involved in the pathophysiology of rheumatic diseases is required to develop specific therapeutic approaches. PMID- 24798576 TI - Assembly and validation of versatile transcription activator-like effector libraries. AB - The ability to perturb individual genes in genome-wide experiments has been instrumental in unraveling cellular and disease properties. Here we introduce, describe the assembly, and demonstrate the use of comprehensive and versatile transcription activator-like effector (TALE) libraries. As a proof of principle, we built an 11-mer library that covers all possible combinations of the nucleotides that determine the TALE-DNA binding specificity. We demonstrate the versatility of the methodology by constructing a constraint library, customized to bind to a known p53 motif. To verify the functionality in assays, we applied the 11-mer library in yeast-one-hybrid screens to discover TALEs that activate human SCN9A and miR-34b respectively. Additionally, we performed a genome-wide screen using the complete 11-mer library to confirm known genes that confer cycloheximide resistance in yeast. Considering the highly modular nature of TALEs and the versatility and ease of constructing these libraries we envision broad implications for high-throughput genomic assays. PMID- 24798577 TI - Research and development of anti-Alzheimer's drugs: an analysis based on technology flows measured by patent citations. AB - INTRODUCTION: Alzheimer's disease (AD) is a serious illness with dramatically increasing incidence. Tremendous worldwide efforts have been exerted to find better ways to treat the disease, delay its onset and prevent it from progressing. In order to discover future anti-AD medicines more rationally, it is crucial to understand the evolving process of existing related technologies from the perspective of technology flow. AREAS COVERED: Patent citation has been used broadly as a powerful tool to capture technology flows. This study collects patent data from IMS Health databases on anti-AD drugs, both marketed and in the research and development (R&D) pipeline. In all, 329 US patents from 1978 through 2013 and citations between them are analyzed, in addition to patents related to marketed drugs. EXPERT OPINION: To discover effective agents for AD treatment, one promising strategy is to integrate various technology clusters related to anti-AD drugs in terms of the extremely dispersed patent citation network in this area. In this context, governments should pay more attention to encourage basic research, especially to focus on cross-mechanism anti-AD agents. New theories and targets for AD, such as the tau protein hypothesis, are worthy of researcher note. Drugs targeting beta-amyloid peptide theory show promise for investors. PMID- 24798578 TI - Roads are associated with a blunted stress response in a North American pit viper. AB - Whereas numerous studies have examined roads as anthropogenic stressors in birds and mammals, comparatively few studies have been undertaken on reptiles. We investigated plasma corticosterone (CORT) levels at baseline and following 30min of restraint stress in free-ranging copperhead snakes (Agkistrodon contortrix) captured within the forest interior or while in contact with public roads. There was no difference in baseline CORT levels between snakes in the forest and on roads. Copperheads responded to restraint stress by increasing plasma levels of CORT; however snakes on roads exhibited a lower CORT stress response compared to forest snakes. Additionally, among snakes captured on roads there was a negative association between road traffic and baseline CORT, stressed CORT, and the magnitude of the CORT response. Our results suggest that roads are associated with a blunted stress response in copperheads. Reduced stress responses may be indicative of acclimation, the inhibited ability to mount a stress response in the face of prolonged chronic stress, or that road environments select for individuals with lower CORT responsiveness. Either scenario could result in increased road mortality if snakes do not perceive roads as a potential threat. PMID- 24798579 TI - The use of noninvasive and minimally invasive methods in endocrinology for threatened mammalian species conservation. AB - Endocrinology is an indispensable tool in threatened species research. The study of endocrinology in threatened species not only advances knowledge of endocrine mechanism but also contributes to conservation efforts of studied species. To this end, endocrinology has been traditionally used to understand reproductive and adrenocortical endocrine axes by quantifying excreted steroid metabolites. From these studies a large body of knowledge was created that contributed to the field of endocrinology, aided conservation efforts, and created a template by which to validate and conduct this research for other species. In this regard noninvasive hormone monitoring has become a favored approach to study the basic endocrinology of wildlife species. Due to the increased understanding of endocrine physiology of threatened species, breeding rates of captive population have improved to levels allowing for reintroduction of species to restored natural ecosystems. Although these approaches are still employed, advances in biochemical, molecular, and genomic technologies are providing inroads to describe lesser known endocrine activity in threatened species. These new avenues of research will allow for growth of the field with greater depth and breadth. However, for all approaches to endocrinology, limitations on resources and access to animals will require innovation of current methodologies to permit broad application for use in threatened species research. PMID- 24798580 TI - Metabolic responses to adrenocorticotropic hormone (ACTH) vary with life-history stage in adult male northern elephant seals. AB - Strong individual and life-history variation in serum glucocorticoids has been documented in many wildlife species. Less is known about variation in hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its impact on metabolism. We challenged 18 free-ranging adult male northern elephant seals (NES) with an intramuscular injection of slow-release adrenocorticotropic hormone (ACTH) over 3 sample periods: early in the breeding season, after 70+ days of the breeding fast, and during peak molt. Subjects were blood sampled every 30 min for 2h post-injection. Breeding animals were recaptured and sampled at 48 h. In response to the ACTH injection, cortisol increased 4-6-fold in all groups, and remained elevated at 48 h in early breeding subjects. ACTH was a strong secretagogue for aldosterone, causing a 3-8-fold increase in concentration. Cortisol and aldosterone responses did not vary between groups but were correlated within individuals. The ACTH challenge produced elevations in plasma glucose during late breeding and molting, suppressed testosterone and thyroid hormone at 48 h in early breeding, and increased plasma non-esterified fatty acids and ketoacids during molting. These data suggest that sensitivity of the HPA axis is maintained but the metabolic impacts of cortisol and feedback inhibition of the axis vary with life history stage. Strong impacts on testosterone and thyroid hormone suggest the importance of maintaining low cortisol levels during the breeding fast. These data suggest that metabolic adaptations to extended fasting in NES include alterations in tissue responses to hormones that mitigate deleterious impacts of acute or moderately sustained stress responses. PMID- 24798582 TI - A fully automated rodent conditioning protocol for sensorimotor integration and cognitive control experiments. AB - Rodents have been traditionally used as a standard animal model in laboratory experiments involving a myriad of sensory, cognitive, and motor tasks. Higher cognitive functions that require precise control over sensorimotor responses such as decision-making and attentional modulation, however, are typically assessed in nonhuman primates. Despite the richness of primate behavior that allows multiple variants of these functions to be studied, the rodent model remains an attractive, cost-effective alternative to primate models. Furthermore, the ability to fully automate operant conditioning in rodents adds unique advantages over the labor intensive training of nonhuman primates while studying a broad range of these complex functions. Here, we introduce a protocol for operantly conditioning rats on performing working memory tasks. During critical epochs of the task, the protocol ensures that the animal's overt movement is minimized by requiring the animal to 'fixate' until a Go cue is delivered, akin to nonhuman primate experimental design. A simple two alternative forced choice task is implemented to demonstrate the performance. We discuss the application of this paradigm to other tasks. PMID- 24798581 TI - Measuring fecal testosterone in females and fecal estrogens in males: comparison of RIA and LC/MS/MS methods for wild baboons (Papio cynocephalus). AB - The development of non-invasive methods, particularly fecal determination, has made possible the assessment of hormone concentrations in wild animal populations. However, measuring fecal metabolites needs careful validation for each species and for each sex. We investigated whether radioimmunoassays (RIAs) previously used to measure fecal testosterone (fT) in male baboons and fecal estrogens (fE) in female baboons were well suited to measure these hormones in the opposite sex. We compared fE and fT concentrations determined by RIA to those measured by liquid chromatography combined with triple quadropole mass spectrometry (LC/MS/MS), a highly specific method. Additionally, we conducted a biological validation to assure that the measurements of fecal concentrations reflected physiological levels of the hormone of interest. Several tests produced expected results that led us to conclude that our RIAs can reliably measure fT and fE in both sexes, and that within-sex comparisons of these measures are valid: (i) fTRIA were significantly correlated to fTLC/MS/MS for both sexes; (ii) fTRIA were higher in adult than in immature males; (iii) fTRIA were higher in pregnant than non-pregnant females; (iv) fERIA were correlated with 17beta estradiol (fE2) and with estrone (fE1) determined by LC/MS/MS in pregnant females; (v) fERIA were significantly correlated with fE2 in non-pregnant females and nearly significantly correlated in males; (vi) fERIA were higher in adult males than in immature males. fERIA were higher in females than in males, as predicted, but unexpectedly, fTRIA were higher in females than in males, suggesting a difference in steroid metabolism in the two sexes; consequently, we conclude that while within-sex comparisons are valid, fTRIA should not be used for intersexual comparisons. Our results should open the field to important additional studies, as to date the roles of testosterone in females and estrogens in males have been little investigated. PMID- 24798583 TI - Role of microRNA machinery in kidney fibrosis. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are critical regulators of gene expression at the post-transcriptional level. The miRNAs constitute an abundant class of RNAs conserved from plants to animals and, as such, play key roles in diverse biological processes, including inflammation, development, differentiation and apoptosis. More recently, it has become apparent that changes in miRNA expression contribute to a wide spectrum of human pathologies, including heart and kidney disease, organ developmental abnormalities and neuronal degeneration. Moreover, inflammation and the development of kidney fibrosis is accompanied by changes in miRNA expression. This review summarizes the emerging field deciphering the complex connections between human miRNA biology and different aspects of kidney injury, focusing on kidney fibrosis. The miRNA regulated fibrosis is discussed based on the classification of pivotal mechanisms, notably involving the transforming growth factor-beta1 signalling pathway. In addition, the challenge of miRNA delivery vehicles as mechanisms of cellular transfer are reviewed, as is the use of miRNA as a potential biomarker for disease. PMID- 24798584 TI - 3-D intestinal scaffolds for evaluating the therapeutic potential of probiotics. AB - Biomimetic in vitro intestinal models are becoming useful tools for studying host microbial interactions. In the past, these models have typically been limited to simple cultures on 2-D scaffolds or Transwell inserts, but it is widely understood that epithelial cells cultured in 3-D environments exhibit different phenotypes that are more reflective of native tissue, and that different microbial species will preferentially adhere to select locations along the intestinal villi. We used a synthetic 3-D tissue scaffold with villous features that could support the coculture of epithelial cell types with select bacterial populations. Our end goal was to establish microbial niches along the crypt villus axis in order to mimic the natural microenvironment of the small intestine, which could potentially provide new insights into microbe-induced intestinal disorders, as well as enabling targeted probiotic therapies. We recreated the surface topography of the small intestine by fabricating a biodegradable and biocompatible villous scaffold using poly lactic-glycolic acid to enable the culture of Caco-2 with differentiation along the crypt-villus axis in a similar manner to native intestines. This was then used as a platform to mimic the adhesion and invasion profiles of both Salmonella and Pseudomonas, and assess the therapeutic potential of Lactobacillus and commensal Escherichia coli in a 3-D setting. We found that, in a 3-D environment, Lactobacillus is more successful at displacing pathogens, whereas Nissle is more effective at inhibiting pathogen adhesion. PMID- 24798585 TI - Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia. AB - Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and [(18)F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated. PMID- 24798586 TI - Challenges contributing to disrupted transition from paediatric to adult diabetes care in young adults with type 1 diabetes. AB - AIM: To examine challenges contributing to disruptions in care during the transition from paediatric to adult care among young adults with Type 1 diabetes who are primarily in ethnic minority groups and have low socio-economic status. METHODS: Participants (n = 20) were newly enrolled patients in a transition clinic for young adults with Type 1 diabetes with a history of loss to medical follow-up. Participants completed qualitative semi-structured interviews detailing their transition experiences in addition to demographic, HbA1c and psychosocial measures. Descriptive statistics were completed for quantitative data, and narrative thematic analysis of interviews was used to identify common themes. A mixed-method analysis was used to identify the associations between stressors identified in interviews and clinical and psychosocial variables. RESULTS: Three categories of challenges contributing to loss to follow-up were identified: psychosocial challenges, health provider and health system challenges and developmental challenges. Participants experienced a high degree of stressful life circumstances which were associated with higher HbA1c (r = 0.60, P = 0.005), longer duration of loss to follow-up (r = 0.51, P = 0.02), greater emergency department utilization (r = 0.45, P = 0.05), and lower life satisfaction (r = 0.62, P = 0.003). CONCLUSIONS: A confluence of challenges, including stressful life circumstances, healthcare system barriers and the developmental trajectory of young adulthood, contributes to a high risk of loss to follow-up and poor health in this population of young adults with Type 1 diabetes. An integrated approach to transition addressing medical and psychosocial needs may facilitate improved follow-up and health outcomes in clinical settings. PMID- 24798587 TI - The distribution and frequency of pulmonary neuroendocrine cells in Down syndrome fetal lungs. AB - The pulmonary neuroendocrine cells (PNEC) are located in the epithelial lining of the airways and consist of solitary neuroendocrine cells (NEC) and NEC clusters, the neuroepithelial bodies (NEB). During fetal life, PNEC are the first to differentiate within the primitive airway epithelium, and bombesin expression favors branching of the respiratory tree. We investigated PNEC in Down syndrome (DS), where the lungs often show enlarged and reduced number of alveoli. Immunohistochemistry for bombesin and synaptophysin, PNEC markers, was evaluated in fetal lungs from 15 cases of DS and 11 age-matched controls from the 17th to 23rd week of gestation. Morphometric analysis assessed PNEC in the mucosal lining of each lung, expressed as number/mm. Nonparametric Mann-Whitney U test showed no statistical difference in frequency of PNEC in DS and controls. Our findings suggest that, at least in late second trimester, the distribution and frequency of PNEC in DS fetuses is not altered. PMID- 24798588 TI - Adaptive registration of varying contrast-weighted images for improved tissue characterization (ARCTIC): application to T1 mapping. AB - PURPOSE: To propose and evaluate a novel nonrigid image registration approach for improved myocardial T1 mapping. METHODS: Myocardial motion is estimated as global affine motion refined by a novel local nonrigid motion estimation algorithm. A variational framework is proposed, which simultaneously estimates motion field and intensity variations, and uses an additional regularization term to constrain the deformation field using automatic feature tracking. The method was evaluated in 29 patients by measuring the DICE similarity coefficient and the myocardial boundary error in short axis and four chamber data. Each image series was visually assessed as "no motion" or "with motion." Overall T1 map quality and motion artifacts were assessed in the 85 T1 maps acquired in short axis view using a 4-point scale (1-nondiagnostic/severe motion artifact, 4-excellent/no motion artifact). RESULTS: Increased DICE similarity coefficient (0.78 +/- 0.14 to 0.87 +/- 0.03, P < 0.001), reduced myocardial boundary error (1.29 +/- 0.72 mm to 0.84 +/- 0.20 mm, P < 0.001), improved overall T1 map quality (2.86 +/- 1.04 to 3.49 +/- 0.77, P < 0.001), and reduced T1 map motion artifacts (2.51 +/- 0.84 to 3.61 +/- 0.64, P < 0.001) were obtained after motion correction of "with motion" data (~56% of data). CONCLUSIONS: The proposed nonrigid registration approach reduces the respiratory-induced motion that occurs during breath-hold T1 mapping, and significantly improves T1 map quality. PMID- 24798590 TI - Long-term results of four horizontal rectus muscle recession in nystagmus treatment. AB - PURPOSE: To report the long-term results of four horizontal rectus muscle recessions that were performed for infantile nystagmus syndrome treatment. METHODS: In this case series, patients with infantile nystagmus syndrome who had four horizontal muscle recessions previously were recruited and ophthalmological examination and electronystagmography recordings were performed. Objectively, amplitude and frequency of nystagmus were measured from the recordings and the intensity was calculated. Visual acuity, stereopsis, and alignment were evaluated and compared with the preoperative and postoperative values. RESULTS: The records of the 12 patients who had four horizontal rectus muscle recession surgery were evaluated and six patients (5 male, 1 female) who had regular follow-ups were included in this study. Mean follow-up was 14.17 +/- 0.41 years (minimum 14 years, maximum 15 years) and mean age of patients at the last visit was 22 years (20-28 years). On subjective evaluation, two-thirds (4/6) of the patients were satisfied with the surgical results and had the impression that after surgery, nystagmus decreased in intensity and head posture improved. On objective evaluation, visual acuity was found to be the same, however, stereopsis improved (preoperatively and postoperatively median stereopsis was 600 sec arc vs 200 sec arc final). The decrease in nystagmus amplitude and frequency was still maintained. CONCLUSIONS: Nystagmus surgery on four horizontal rectus muscles has positive effects on binocular function and nystagmus parameters in the long-term follow-up. As we could not treat the primary pathology, the visual acuity was about the same but the decrease in nystagmus amplitude and frequency was still maintained with better stereopsis, and patient satisfaction. PMID- 24798589 TI - Systematic light exposure in the treatment of cancer-related fatigue: a preliminary study. PMID- 24798591 TI - What do we know about the Balkan endemic nephropathy and the uroepithelial tumors? AB - Balkan endemic nephropathy (BEN), a familial chronic tubulo interstitial disease with a slow progression to terminal renal failure, affects people living in the alluvial plains along the tributaries of the Danube River. One of its most peculiar characteristics is a strong association with upper urothelial cancer. An increased incidence of upper urinary tract (UUT) transitional cell cancer (TCC) was discovered among the inhabitants of endemic settlements and in families affected by BEN. In areas where BEN is endemic, the incidence of upper tract TCC is significantly higher, even 100 times, than in non-endemic regions. Until now, several hypotheses have been introduced about the etiopathogenesis of BEN. Only the toxic effect aristolochia clematidis has been confirmed as a factor in the occurrence of the disease. We don't have specific biomarkers for an early diagnosis of BEN and UUT-TCC. With application of modern molecular and genetic methods in investigation of etiopathogenesis and diagnosis of BEN and UUT-TCC we should expect improvement in the study of BEN. PMID- 24798592 TI - Methylation analysis on whole genome level. What did we learn from BEN studies? AB - Recent years have brought the interest of genetic research to the human epigenome. Its unique characteristics--being simultaneously stable and dynamic, present vast opportunities for cell function regulation, maintaining and executing different cell type programmes. Greatest efforts were invested in studying DNA methylation in comparison to histone modifications and miRNA studies. The present review aims to shed some light on the key mechanisms governing the epigenetic characteristics of the human genome and how epigenetic patterns can be analysed on whole genome scale. Here are presented the main advantages and disadvantages of different approaches to methylation analysis. This review presents a link between the methodology and some of its application in BEN research as an example of polygenic disorders. PMID- 24798593 TI - New generation genomic platforms in investigation of complex diseases and BEN. AB - New generation genomic platforms enable us to decipher the complex genetic basis of complex diseases and Balkan Endemic Nephropathy (BEN) at a high-throughput basis. They give valuable information about predisposing Single Nucleotide Polymorphisms (SNPs), Copy Number Variations (CNVs) or Loss of Heterozygosity (LOH) (using SNP-array) and about disease-causing mutations along the whole sequence of candidate-genes (using Next Generation Sequencing). This information could be used for screening of individuals in risk families and moving the main medicine stream to the prevention. They also might have an impact on more effective treatment. Here we discuss these genomic platforms and report some applications of SNP-array technology in a case with familial nephrotic syndrome. PMID- 24798594 TI - Proteomic studies in endemic nephropathy. AB - Endemic nephropathy (EN) is a chronic tubulointerstitial nephropathy with an early insidious and slow development into terminal renal failure. Proteomics is the systematic study of a proteome, which is the total protein content of a cell, organism or body fluids. Application of proteomic technologies in nephrology has enabled more detailed analyses of protein functions and examined their importance in various physiological and pathological states. Biomarkers with high specificity and sensitivity to early diagnosis are needed for a better understanding of the mechanisms of EN development and its consequences. Urine beta2-microglobulin (B2M) was mainly used as a tubular marker of EN but recently alpha1-microglobulin (AMBP) was proposed for the diagnosis of EN. We studied the urine proteins of 360 patients with EN, diabetic nephropathy (DN) and acute kidney injury (AKI) and the healthy population using proteomic tools. Protein maps from the urine of patients with EN showed significant differences in comparison to the healthy subjects and patients with DN and AKI. Our study highlights six proteins in urine that were differentially excreted in the urine of EN patients compared with the other groups and have potential to be markers for EN prediction. In one of our studies, using routine biomarkers, we investigated the potential of urine B2M, AMBP, albumin and total protein as diagnostic markers for EN, in comparison to glomerulonephritis, nephrosclerosis and a healthy state. Modern proteomic technologies are still robust investigation tools, but can access a vast amount of information from one set of experiments in comparison to a classic diagnostic approach. PMID- 24798595 TI - Endemic (Balkan) nephropathy is aristolochic acid nephropathy. AB - Endemic nephropathy is a syndrome that comprises two entities: chronic interstitial nephropathy and urothelial cell cancers predominantly of the upper urinary tract. The etiological agent for the disease is aristolochic acid, a compound found in the plants of Aristolochia spp. The development of urothelial cancers is characterized by the formation of aristolactam DNA adducts leading to mutations, predominantly A: T->T: A transversions. In order to comprehensively understand the gene regulation programs in upper urothelial cancers we performed integrated miRNA and mRNA expression profiling of paired tumours and unaffected urothelium samples. The obtained data will help us to understand the carcinogenesis caused by aristolochic acid and might be the source for the design of a diagnostic biomarker. PMID- 24798596 TI - Evaluation of diagnostic criteria for endemic nephropathy. AB - Diagnosis of endemic nephropathy (EN) is based on the combination of several clinical and laboratory criteria. Despite extensive research no specific diagnostic biomarker for EN has yet been identified. The aim of the study was to evaluate the diagnostic significance of the variables previously proposed as diagnostic criteria, but also new ones. After an extended questionnaire, the clinical and laboratory examination population in EN villages was classified according to the modified WHO criteria. The urinary active form of TGF-beta was measured with a bioassay using a cell line which expresses luciferase activity. In the study we used ROC analysis to examine the predictive value of the tested variables. In the study there was no difference in haemoglobin level between the study subgroups. Leucine aminopeptidase (LAP) in urine and active urinary TGF beta levels were increased in the EN diseased group when compared to other subgroups, but they did not fulfil the statistical criteria needed for differentiating a diseased form from other study subgroups. Both kidney length and parenchima thickness, alfa1-microglobulinuria, and kidney function assessed by MDRD formula were the variables that differentiated the study subgroups well. Based on our results the cut-off value of alfa1-microglobulin for screening should be 23.5 mg/g creatinine instead of 15 mg/g creatinine in the present criteria, and for making a diagnosis of EN 31,5 mg/g creatinine. Persons with a positive family history for EN had a 5.8 times greater risk of developing EN when compared to a negative one. Taken together, the above-mentioned variables should be implemented in new uniform diagnostic criteria for EN. PMID- 24798597 TI - Where are we now in the investigation of rare diseases in the Republic of Macedonia? AB - In Europe Rare Disease (RD) is the one which affects less than 1/2000, in the USA 1/1250, while in Japan RD is the one that affects fewer than 1/50,000 patients. EU estimates that 5-8000 distinct rare diseases affect 6-8% of the Population. The impact of rare diseases in the health systems is impresssive: at least 3 million patients in the UK, 4 million in Germany, and between 27 and 36 million EU citizens. There is not a precise register for rare diseases in the Republic of Macedonia. Rare diseases are becoming increasingly important as possible targets of new forms of treatment, as a valuable source of a novel insight in fundamental lows of biology, and in the specific mechanisms of many diseases. Molecular methods have created a better diagnosis and oftentimes treatment. Rare diseases pose significant problem for the patients, since their problems are often not recognized by the medical community and shunned by the health insurance. The cumulative costs of diagnosis and treatment of rare diseases is significant for any society and oftentimes not acceptable for developing countries. PMID- 24798598 TI - Purine disorders with hypouricemia. AB - Hypouricemia is defined as a serum urate levels less than 2 mg/dL (119 umol/L). Primary hypouricemia is caused by disorders of purine metabolism and transport. This laboratory finding is sometimes overlooked and, following two genetic defects, should be considered in differential diagnosis of unexplained hypouricemia. Hereditary xanthinuria is autosomal recessive and due to mutations in xanthine oxidase, leading to over-production of xanthine and minimal production of urate. Patients have very low serum urate levels and suffer from elevated levels of xanthine in the urine, leading to xanthine stones, haematuria, and sometimes occult chronic kidney failure. Hypouricemia is the key to diagnosis. Hereditary renal hypouricemia is a new genetic defect of renal transport of uric acid. Two types were distinguished: a) renal hypouricemia type 1, caused by the defects in the SLC22A12 gene coding the human urate transporter 1 (hURAT1) and b) renal hypouricemia type 2, caused by the defects in the SLC2A9 gene, which encodes GLUT9 transporter. This disorder predisposes patients to exercise-induced acute renal failure and/or nephrolithiasis. Diagnosis is based on two markers: hypouricemia (<119 umol/L) and increased fractional excretion of uric acid (>10%). Over one hundred cases were identified in Japan and and this number is unique worldwide. Several patients were described in Macedonia. We were able to detect four Czech families with hereditary xanthinuria and eight cases of hereditary renal hypouricemia. In conclusion, hereditary xanthinuria and hereditary renal hypouricemia are still unrecognized conditions. Patients with unexplained hypouricemia need detailed purine metabolic investigations. PMID- 24798599 TI - Wilson's disease. AB - Wilson's disease (WD) is a disorder of copper transport resulting from the defective function of a copper transporting P-type ATPase, ATP7B. The WD incidence is approximately 1/50-10,000 live births worldwide. Clinical manifestations of WD may be of any kind, but usually the symptoms of presentation are hepatic or neuropsychiatric, with a vast range of disturbances for both groups of symptoms. In children, however, clinical symptoms may be absent, making the diagnosis of the disease more difficult than in adults. Hepatic manifestations may range from asymptomatic minor biochemical disturbances, to acute, but mostly chronic, hepatitis, cirrhosis or severe fulminant hepatic failure. The spectrum of neurological manifestations is wide, including tremor, hypersalivation, Dysarthria, coordination defects, dystonia, ataxia. The spectrum of psychiatric manifestations is considerable and may include different disturbances such as altered working performance, anxiety, depression and antisocial behaviour. Kayser-Fleischer rings (KF) are present in 95% of patients with neurological symptoms and somewhat over half of those without neurological symptoms. In children presenting with liver disease, KF rings are usually absent. To obtain a more reliable diagnosis of WD, the Leipzig scoring system was proposed by an international consensus of experts. Wilson's disease copper overload is treated with chelating agents such as penicillamine, trientine and tetrathiomolybdate. Zinc is used mostly for mantainance therapy or the treatment of asymptomatic WD patients. PMID- 24798600 TI - Lysosomal acid lipase deficiency: wolman disease and cholesteryl ester storage disease. AB - Cholesteryl ester storage disease (CESD, OMIM #278000) and Wolman disease (OMIM #278000) are autosomal recessive lysosomal storage disorders caused by a deficient activity of lysosomal acid lipase (cholesteryl ester hydrolase, LAL). Human lysosomal acid lipase is essential for the metabolism of cholesteryl esters and triglycerides. In Wolman disease, LAL activity is usually absent, whereas CESD usually presents some residual LAL activity. In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease. The clinical picture is more variable in CESD. Hepatomegaly and/or elevation of liver transaminases are almost always present. Hepatic steatosis often leads to fibrosis and cirrhosis. Other signs often include splenomegaly, high total cholesterol and LDL-cholesterol, elevated triglycerides, and low HDL-cholesterol. The diagnosis of LAL deficiency requires clinical experience and specialized laboratory tests. The diagnosis is based on finding deficient activity of acid lipase and/or molecular tests. Pilot screening projects using dried blood spot testing in 1) children with atypical fatty liver disease in the absence of overweight, 2) patients with dyslipidaemia and presence of hepatomegaly and/or elevated transaminases, 3) newborns/neonates with hepatomegaly and abdominal distension/failure to thrive/elevated transaminases are currently underway. Early diagnosis is particularly important for the enzyme replacement therapy. Human trials with recombinant LAL are currently ongoing, raising the prospect for specific correction of LAL deficiency in this progressive and often debilitating disorder. PMID- 24798601 TI - Introducing standards of the best medical practice for patients with inherited alpha-1-antitrypsin deficiency in Central Eastern Europe. AB - The Leonardo da Vinci project "Introducing standards of the best medical practice for patients with inherited alpha-1-antitrypsin Deficiency in Central Eastern Europe" belongs to a sub-programme of the European Commission's Lifelong Learning Programme. It started in November 2011 and is conducted in cooperation with eight European partners. The project's main goal is to support development of a Central Eastern European Network (CEE) for alpha-1-antitrypsin Deficiency (AATD) early diagnostics and treatment. Alpha-1-antitrypsin (AAT) is one of the major serine protease inhibitors in the human circulation, and is an acute phase protein produced predominantly by hepatocytes. Severe inherited AATD deficiency occurs in about 1 in 2.500 individuals; most commonly in those of European ancestry. AATD considerably increases the risk of liver disorder in infants, children and adults, while respiratory complications are observed mainly in adults. The average concentration of AAT in plasma in healthy individuals is 1.3 mg/ml. The concentration of AAT during acute phase processes rises 3- to 4-fold above normal. Alpha1-Antitrypsin deficiency (AATD) is a disorder inherited in an autosomal co-dominant fashion. The mutant Z AAT protein differs from the normal M variant by a single amino acid substitution (Glu 342 Lys). Severe ZZ AAT deficiency was first recognized as a hereditary condition predisposing to disease on the basis of 90% lower plasma levels of the protein arising not from the lack of AAT synthesis, but from a defect in its secretion. Most Caucasians of North European descent are homozygous for the normal M variant of AAT, but some carry the Z allele, which is associated with an increased risk of early-onset emphysema and liver disease. The great advantage and main focus of the project is to create a long-lasting European network of cooperation between medical institutions involved in AATD medical care. The network is a response to the needs of CEE countries and at the same time it will help them to participate in the broader frame of the European network of medical centres specializing in AATD. PMID- 24798602 TI - Posterior cerebral artery--variation in the origin and clinical significance. AB - With the introduction of new techniques in diagnostic and interventional radiology and progress in micro-neurosurgery, accurate knowledge of the brain blood vessels is essential in daily clinical work. The aim of this study was to describe the different types of PCA origin, their diameter, and to emphasize their clinical significance. In this study we examined radiographs of 53 patients who had CT angiography undertaken for a variety of clinical reasons, performed as a part of their medical treatment at the University Radiology Clinic in Skopje, R. Macedonia. This study included 24 females and 29 males, ranging in age from 32 to 73 years; mean age 55.3+/-11.5 years. The results showed that the diameter of the posterior cerebral artery was 1.74+/-0.317 mm on the right side and 1.98+/ 0.408 mm on the left side. The adult configuration was present in 37 (69.81%); foetal configuration was present in 12 (22.64%) and transitional configuration was present in 4 (7.54%) of the patients. We found two patients with bilateral foetal type and ten with unilateral foetal type (six on the right side and four on the left side). Despite the limitations of the study, we found that the foetal variant was presented in 22.64% of patients. Thorough knowledge of the anatomy of the intracranial vessels is important to clinicians as well as basic scientists who deal with problems related to intracranial vasculature on a daily basis. PMID- 24798603 TI - Six week follow-up of metabolic effects induced by a high-fat diet and streptozotocin in a rodent model of type 2 diabetes mellitus. AB - This study was initiated to refine and characterize a nongenetic experimental model of type 2 diabetes mellitus and to follow up various metabolic parameters up to six weeks after diabetes induction. Male Wistar rats were divided into 4 groups: CON group--consumed standard rat chow and served as control; HFD group- consumed high-fat diet (45% calories as fat); STZ group-was injected once intraperitoneally with streptozotocin (35 mg/kg) on day 14, and DM-2 group- consumed high-fat diet and was injected with streptozotocin. The metabolic parameters were measured one week after streptozotocin injection (week 3) and at the end of the study (week 9). Our results confirm that HFD-group developed dyslipidaemia, obesity and insulin resistance. All metabolic parameters remained largely unaltered in STZ-group during the study. Only the combination of high-fat diet and streptozotocin (DM-2 group) induced type 2 diabetes that was characterized with moderate hyperglycaemia, insulin resistance, hypertriglyceridaemia, elevated free fatty acids, hypercholesterolaemia and increased plasma glucagon levels at the time of diabetes onset (week 3). The observed changes of the metabolic parameters after six additional weeks demonstrated an aggravated diabetic state, as confirmed from significantly increased fasting plasma glucose values, insufficient insulin secretion, severe hyperlipidaemia, increased glucagon levels, decreased serum adiponectin concentrations and significantly elevated urinary protein excretion. These results indicate that apart from its utility as a model of diabetes aetiology, this model could also be used for elucidating the role of the hormones adiponectin and glucagon in the progression of type 2 diabetes, as well as for investigating the diabetic complications. PMID- 24798604 TI - Splenectomy for haematological disorders. AB - Splenectomy is therapeutic for a large host of conditions. It is a consequence of expanding the list of disorders and liberalizing the indications for splenectomy in many diseases. Red blood cells disorders: autoimmune hemolytic anemia, hereditary spherocytosis, hemoglobinopathies and thalassemia are prone to splenectomy after failure of medical therapy. A variety of thrombocytopenic disorders are improved by splenectomy, and the most common indication for splenectomy is ITP (idiopathic thrombocytopenic purpura). Splenectomy is successful in reversing hypersplenism in a spectrum of disease called myeloproliferative disorders. Relief of symptoms from splenomegaly is also achieved, but it does not affect the inexorable course of the disorder. The role of splenectomy in white blood cells disorders (leukemias and lymphomas) is only palliative and facilitates chemotherapy. Splenectomy in patients with hemathologic disorders imparts a risk of fulminant and life threatening infection "overwhelming postsplenectomy sepsis" that can be obviated by appropriate treatment. Although splenectomy for hemathologic disorders is only therapeutic and not curative, the relief of symptoms and for some disorders facilitation of chemotherapy leads to better quality of life and longer survival. PMID- 24798605 TI - Growth parameters and nutritional status in relation to socioeconomic status of Macedonian adolescents. AB - AIM: To assess the anthropometric parameters of growth and nutritional status in relation to socioeconomic status (SES) of Macedonian adolescents. METHODS: The study included 546 adolescents from urban regions of the Republic of Macedonia, aged 14 to 15 years. Participants were measured with standard equipment and measurement technique according to the International Biological Programme. The following anthropometric indices were calculated: height-for-age (BH), weight-for age (BW) and BMI-for-age (kg/m2). For measuring family wealth, the Family Affluence Scale (FAS) has been used. Adolescents were grouped into three SES groups. RESULTS: Age-specific differences were found for body height and weight in favour of 15-year-old males (p<0.05). There were no significant differences in height and weight among different SES groups. Female participants were more overweight in the high SES group (13.2%) and middle SES group (10.8%), compared to those in the low SES group (6.7%). According to the obtained results in females, the prevalence of obese and underweight females is higher in those with low SES. CONCLUSIONS: Male adolescents were found to be taller and heavier than female adolescents. Both male and female adolescents were taller and heavier in high SES group than those in other SES groups. There were no SES differences in prevalence of underweight, overweight and obesity among Macedonian school adolescents living in urban areas, except among females, those in the low SES group had a significantly higher prevalence of obesity than did those in the MSES and HSES groups. PMID- 24798606 TI - Antigenic phenotype of lung carcinomas: usual spectrum of distribution of thyroid transcription factor-1, cytokeratin 7, cytokeratin 20, and neuron specific enolase--basic immunohistochemical study of 21 cases. AB - Immunohistochemistry (IHC), as such, can be used in routine pathology in order to make correct diagnosis of lung carcinomas. Consequently, more detailed analyses are needed in this field in order to make a wide spectrum of unique combinations for such pulmonary neoplasms. Our aim was to apply an antibody panel, and examine and confirm its utility in the differential diagnosis of lung cancer. Twenty-one cases (both bioptic and surgical material) of diagnosed lung cancer were investigated. An immunohistochemical analysis--(RTU FLEX Immunoperoxidase system) was made using Dako monoclonal antibodies (Cytokeratin 7, CK7; Cytokeratin 20, CK20; Neuron specific enolase, NSE, Thyroid transcription factor-1, TTF1 and Leucocyte common antigen, LCA). LCA expression was not expressed in any of our cases. Most adenocarcinoma were CK7(+)--83.3% and TTF1(+/-)--50%. The CK20(+) expression showed a metastatic pulmonary deposit of adenocarcinoma in the lung. TTF1(+)--100%, NSE(+)--100% and CK7(-)--66.66% expression was found in most cases of SCLC. NSE(+)--100% had the highest expression in carcionoid tumour, while TTF1(+) expression was highest in SCLC. For squamous cell carcinoma (SqCC), immunostaining was negative for this antibody panel, except focal and weak expression of NSE--60%, so we did some extra IHC using CKHMW antibody, which showed the highest expression. The essential antibody panel that we have confirmed and suggest for routine basic differential diagnosis of pulmonary neoplasms is: TTF1, CK7, CK20 and NSE. Due to the high number of co-occurrunces IHC should not be performed alone, but integrated in conjunction with morphological diagnosis. PMID- 24798607 TI - Diagnostic assessment in anterior cruciate ligament (ACL) tears. AB - The aim of this study was to compare findings from clinical examinations, MRI scans and arthroscopy in ACL injury of the knee in order to assess the diagnostic significance of both examination findings. This study was conducted to manage the reliability of clinical diagnosis in ACL tear injuries. All patients attending our clinic with knee pain from 2009 to 2013 underwent systematic and thorough clinical assessment. Of 103 patients with knee problems arthroscopy ACL tears was diagnosed in 73. All these patients underwent therapeutic arthroscopic knee surgery. The clinical diagnosis was evaluated and confirmed during this procedure. The accuracy, sensitivity and specificity were calculated based on these arthroscopic findings. The MRI accuracy of clinical diagnosis in our study was 82.5% for ACL tears. Accuracy for two of three clinical examination tests of clinical diagnosis in our study was 96% and 94% for ACL tears. According to our obtained correlation between clinical examinations, MRI scan and arthroscopy for ACL injuries, we concluded that carefully performed clinical examination can give equal or better diagnosis of ACL injuries in comparison with MRI scan. Our study revealed MRI scan high sensitivity and specificity and not so high accuracy for ACL injuries of the knee joint in comparison with arthroscopy. MRI is an appropriate screening tool for therapeutic arthroscopy, making diagnostic arthroscopy unnecessary in most patients. According to our findings we can conclude that a positive anterior drawer test and a positive Lachman clinical examination test is more accurate for predicting, i.e. diagnosis of ACL tear. On the ither hand, MRI scan findings showed less accuracy for predicting, i.e. diagnosis of ACL tear. According to many studies of clinical examination tests compared (correlated) with arthroscopy, the accuracy of predicting ACL tears depends on the level of the skilled orthopaedic or trauma surgeon's hands. Based on these findings, we feel that MRI, except in certain circumstances, is an expensive and unnecessary diagnostic test in patients with suspected meniscal and ACL pathology. PMID- 24798608 TI - Cross-border reprogenetic services. AB - The purpose of this review is to synthesize the current knowledge on the international movement of patients and biopsied embryo cells for pre-implantation genetic diagnosis and its different applications. Thus far, few attempts have been made to identify the specific nature of this phenomenon called 'cross-border reprogenetic services'. There is scattered evidence, both empirical and speculative, suggesting that these services raise major issues in terms of service provision, risks for patients and the children-to-come, the legal liabilities of physicians, as well as social justice. To compile this evidence, this review uses the narrative overview protocol combined with thematic analysis. Five major themes have emerged from the literature at the conjunction of cross border treatments and reprogenetics: 'scope', 'scale', 'motivations', 'concerns', and 'governance'. Similar themes have already been observed in the case of other medical tourism activities, but this review highlights their singularity with reprogenetic services. It emphasizes the diagnostic and autologous feature of reprogenetics, the constant risk of misdiagnosis, the restriction on certain tests for medically controversial conditions, and the uncertain accessibility of genetic counseling in cross-border settings. PMID- 24798609 TI - Observational gait assessment tools in paediatrics--a systematic review. AB - Instrumented gait analysis (IGA) is an expensive technique used to objectively detect gait abnormalities in children. Observational gait assessment is considered as a cost effective alternate for IGA in regular clinical practice. This article is aimed at systematically reviewing the available paediatric gait analysis tools and examines their reliability and validity compared to IGA. This review also examines the structure of these tools, their clinical use and limitations. Articles were searched from PubMed, CINHL, AMED, BNI, EMBASE, PEDro and Cochrane library from the earliest record on the database to December 2012. Hand searches were carried out in a few journals. Studies that examined children's gait using a structured assessment tool were included and analysed for their quality, reliability and validity. Pre-established criteria were used to judge the quality of methodology and reliability and validity. Five observational gait tools for children with Cerebral Palsy (CP) and one for children with Downs Syndrome were identified. Nine studies related to children with CP were enrolled for this review. None of the tools have accomplished the level of IGA's consistency. Edinburgh Visual Gait Score (EVGS) was found to have better reliability and validity than the other tools. Very limited studies were available for most of the gait assessment tools therefore their clinical use cannot be judged based on the existing evidence. EVGS was found to have better concurrent validity and reliability and it should be considered to assess CP gait in regular practice. Future work to investigate the use of low cost technology to improve observers' accuracy of EVGS is suggested. PMID- 24798610 TI - Frontal plane margin of stability is increased during texting while walking. AB - Injurious falls associated with cell phone use during ambulation are increasingly common. Studies examining texting while walking suggest this task alters the attentional component of walking to the extent that safety may be compromised. Here, we quantified the extent to which frontal plane dynamic stability while walking was affected by the cognitive and physical demands of texting. Twenty experienced texters performed four, 10-min treadmill walking tasks at a self selected velocity in random order: (1) normal walk (control), (2) walking while verbally performing mathematical calculations (cognitive demand), (3) walking while bimanually holding and looking directly at a phone (physical demand), and (4) walking while texting continuous mathematical calculations (cognitive and physical). We quantified the frontal plane minimum margin of stability (MOSmin), a measure that considers the position and normalized velocity of the center of mass with respect to the lateral border of the base of support was calculated over each 10-min walking period. Compared to the normal walking condition, the texting and phone holding conditions resulted in a small but significant (6%) increase in MOSmin (p=0.005 and 0.026, respectively). Compared to normal walking, the effect of performing mathematical calculations on MOSmin was not significant (p=0.80). These results suggest that frontal plane stability of experienced texters during controlled treadmill walking conditions can be affected by the physical, but not the cognitive demand of texting. This may represent a compensatory mechanism by the CNS to ensure stability in the event of an unexpected disturbance. PMID- 24798611 TI - Effect of dual tasking on postural responses to rapid lower limb movement while seated on an exercise ball. AB - Postural adjustments are used by the central nervous system to pre-empt and correct perturbations in balance during voluntary body movements. Alteration in these responses is associated with a number of neuromuscular/musculoskeletal conditions. Attention has been identified as important in this system; performing a concurrent cognitive task has been suggested to reduce the efficacy of this postural control. The aim of this study was to examine the effect of concurrent cognitive tasking on anticipatory postural adjustments while sitting on an exercise ball with a view to help inform future rehabilitation programmes. Bilateral EMG activity was recorded from the external and internal obliques, rectus abdominis, erector spinae and the right rectus femoris of 20 healthy subjects (9 males) with mean (SD) age of 21.88 (0.86) years (range 21-24 years). A rapid hip flexion protocol was carried out under three conditions: no concurrent task, counting out loud up from one and completing a serial sevens task. The addition of the cognitive task delayed and reduced the EMG in the prime mover muscle but had little impact on the responses of the trunk muscles within the time frame of the anticipatory responses; suggestive of a decoupling of voluntary and postural control mechanisms. The results of this study suggest that perhaps the clinical effects of dual task may not be largely due to changes in anticipatory postural adjustments. However, it would be important to compare these results to those seen in older and functionally impaired individuals as this would be more representative of the typical population undertaking such rehabilitation programmes. PMID- 24798612 TI - IRF8 is a transcriptional determinant for microglial motility. AB - Microglia, the resident immune cells of the central nervous system, are constitutively mobile cells that undergo rapid directional movement toward sites of tissue disruption. However, transcriptional regulatory mechanisms of microglial motility remain unknown. In the present study, we show that interferon regulatory factor-8 (IRF8) regulates microglial motility. We found that ATP and complement component, C5a, induced chemotaxis of IRF8 wild-type microglia. However, these responses were markedly suppressed in microglia lacking IRF8 (Irf8 (-/-)). In a consistent manner, phosphorylation of Akt (which plays a crucial role in ATP-induced chemotaxis) was abolished in Irf8 (-/-)microglia. Real-time polymerase chain reaction analysis revealed that motility-related microglial genes such as P2Y12 receptor were significantly suppressed in Irf8 (-/ )microglia. Furthermore, Irf8 (-/-)microglia exhibited a differential expression pattern of nucleotide-degrading enzymes compared with their wild-type counterparts. Overall, our findings suggest that IRF8 may regulate microglial motility via the control of microglial gene expression. PMID- 24798613 TI - The FTO genotype as a useful predictor of body weight maintenance: initial data from a 5-year follow-up study. AB - OBJECTIVE: We examined associations between the fat-mass and obesity-associated (FTO) gene (rs9939609) and any weight change over a 5-year period following a 14 week lifestyle intervention among middle-aged Japanese women. MATERIALS/METHODS: One hundred twenty-eight Japanese women (BMI >25 kg/m2) participated in a 14-week weight loss intervention between 2004 and 2006. Of the participants, 62 consented to the 5-year follow-up measurement session. Of these women, 47 women who achieved a weight loss of at least 10% from their baseline values during the 14 week intervention were included in the analysis. Body weight, body fat, abdominal fat assessed by CT scans, and metabolic risk factors (i.e., blood pressure, lipids, and glucose) were measured at baseline, post-intervention, and at the 5 year follow-up. RESULTS: During the 5-year non-intervention period, increases in body weight, fat mass, total abdominal fat, and subcutaneous abdominal fat were significantly greater in subjects with the homozygous minor allele (AA genotype, n=4; 8.5%) than in those with the homozygous major allele (TT genotype, n=31; 66.0%) or heterozygous allele (TA genotype, n=12; 25.5%). In multiple regression analyses, the variation in rs9939609 was a significant and independent predictor (P<0.001) for regaining weight during the 5-year follow-up. CONCLUSIONS: Our data suggest that Japanese women with the risk allele (AA) of rs9939609 may have more difficulty preventing fat gain from reoccurring after weight loss intervention than women with the other genotypes. PMID- 24798614 TI - Short communication: east meets west: a description of HIV-1 drug resistance mutation patterns of patients failing first line therapy in PEPFAR clinics from Uganda and Nigeria. AB - HIV-1 viral load (VL) monitoring is recommended but seldom performed in resource constrained countries. An evaluation of patients receiving first-line antiretroviral therapy in a multicountry PEPFAR program (RV288) was performed to determine the rates and predictors of virologic suppression. Resistance data from treatment failures are available from Uganda and Nigeria. Each country enrolled 325 subjects into this cross-sectional study. Subjects on first-line therapy were randomly selected for HIV RNA testing (viral load). Regimens included efavirenz or nevirapine with zidovudine/lamivudine or tenofovir/lamivudine. VL was determined from plasma using the Roche COBAS TaqMan HIV-1 Test, High Pure System v1.0 (47 copies/ml). Genotypic resistance testing was performed on samples with VL>1,000 copies/ml. From Uganda, 85% of subjects were undetectable while 7% (23/325) had VL>1,000 copies/ml. The HIV-1 subtype distribution was as follows: A=47.6%, C=14.3%, and D=38.1%. No resistance mutations were found in 14% of subjects. All subjects with resistance had the M184V mutation. Of subjects failing a zidovudine regimen less than 1 year, 88% (7/8) had no thymidine analogue mutations (TAMs), compared to 50% (4/8) failing greater than 1 year. Four subjects (25%) had more than two mutations from the TAM-1 pathway (41L, 210W, 215Y). In Nigeria, 82% were undetectable while 14% (45/325) had VL>1,000 copies/ml. HIV-1 subtype distribution was as follows: 62.8%=CRF02_AG, 34%=pure G, and 2.8%=A. Of the 35 genotyped subjects, 14% (5/35) had no resistance mutations. Of the remainder, 10% (3/30) had no nucleoside analogue mutations while 33% (10/30) had only M184V along with nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. Forty percent (10/25) of subjects on zidovudine failed without TAMs. Another 25% (5/25) of subjects failing on zidovudine had more than two TAM 1 mutations. Individuals failing first-line antiretroviral therapy (ART) may retain sensitivity to one or more nucleoside analogues from the regimen. Knowledge of drug resistance patterns allow for selection of drugs that can be recycled in future regimens. Accumulation of resistance mutations may compromise future treatment options. PMID- 24798616 TI - Biomarkers to assess graft quality during conventional and machine preservation in liver transplantation. AB - A global rising organ shortage necessitates the use of extended criteria donors (ECD) for liver transplantation (LT). However, poor preservation and extensive ischemic injury of ECD grafts have been recognized as important factors associated with primary non-function, early allograft dysfunction, and biliary complications after LT. In order to prevent for these ischemia-related complications, machine perfusion (MP) has gained interest as a technique to optimize preservation of grafts and to provide the opportunity to assess graft quality by screening for extensive ischemic injury. For this purpose, however, objective surrogate biomarkers are required which can be easily determined at time of graft preservation and the various techniques of MP. This review provides an overview and evaluation of biomarkers that have been investigated for the assessment of graft quality and viability testing during different types of MP. Moreover, studies regarding conventional graft preservation by static cold storage (SCS) were screened to identify biomarkers that correlated with either allograft dysfunction or biliary complications after LT and which could potentially be applied as predictive markers during MP. The pros and cons of the different biomaterials that are available for biomarker research during graft preservation are discussed, accompanied with suggestions for future research. Though many studies are currently still in the experimental setting or of low evidence level due to small cohort sizes, the biomarkers presented in this review provide a useful handle to monitor recovery of ECD grafts during clinical MP in the near future. PMID- 24798617 TI - The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment. AB - BACKGROUND & AIMS: We investigated whether the quantification of hepatitis surface antigen (HBsAg) could predict HBsAg loss or hepatitis B virus (HBV) relapse after stopping lamivudine treatment. METHODS: A total of 188 naive chronic hepatitis B patients (83 HBeAg-positive, 105 HBeAg-negative patients), who were previously treated with lamivudine (treatment duration: 89.3 +/- 35.9 weeks, range: 52-243 weeks) but stopped the treatment for at least 12 months were recruited. RESULTS: The cumulative incidence of HBsAg loss and HBV relapse at year 6 after stopping lamivudine treatment was 24% and 65.9% respectively. Cox regression analysis revealed that lower alanine aminotransferase (ALT) at baseline, lower HBsAg levels at the end of treatment, and longer treatment duration were independent predictors for HBsAg loss, and old age, male sex and higher HBsAg levels at the end of treatment were independent predictors for post treatment HBV relapse. At the end of treatment, the HBsAg cut-off value of 300 IU/ml could predict 55.6% (5/9) HBsAg loss in HBeAg-positive patients. In HBeAg negative patients, the HBsAg cut-off values of 120 and 200 IU/ml could predict 79.2% (19/24) HBsAg loss and 93.3% (28/30) post-treatment sustained response respectively. Further HBsAg reduction (>0.22 log IU/ml) at month 6 after stopping treatment was an independent predictor for HBsAg loss after adjusting for HBsAg level at the end of treatment. CONCLUSIONS: Serum HBsAg level at the end of treatment is a useful predictor to guide the timing of stopping lamivudine treatment in chronic hepatitis B patients. PMID- 24798618 TI - Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis. AB - BACKGROUND & AIMS: Presence of hepatic vein tumor thrombosis (HVTT) in patients with hepatocellular carcinoma (HCC) is regarded as signaling an extremely poor prognosis. However, little is known about the prognostic impact of surgical treatment for HVTT. METHODS: Our database of surgical resection for HCC between October 1994 and December 2011 in a tertiary care Japanese hospital was retrospectively analysed. We statistically compared the patient characteristics and surgical outcomes in HCC patients with tumor thrombosis in a peripheral hepatic vein, including microscopic invasion (pHVTT), tumor thrombosis in a major hepatic vein (mHVTT), and tumor thrombosis of the inferior vena cava (IVCTT). Among 1525 hepatic resections, 153 cases of pHVTT, 21 cases of mHVTT, and 13 cases of IVCTT were identified. RESULTS: The median survival time (MST) in the pHVTT and mHVTT groups was 5.27 and 3.95 years, respectively (p=0.77), and the median time to recurrence (TTR) was 1.06 and 0.41 years, respectively (p=0.74). On the other hand, the MST and TTR in the patient group with IVCTT were 1.39 years and 0.25 year respectively; furthermore, the MST of Child-Pugh class B patients was significantly worse (2.39 vs. 0.44 years, p=0.0001). Multivariate analyses revealed IVCTT (risk ratio [RR] 2.54, p=0.024) and R 1/2 resection (RR 2.08, p=0.017) as risk factors for the overall survival. CONCLUSIONS: Hepatic resection provided acceptable outcomes in HCC patients with mHVTT or pHVTT when R0 resection was feasible. Resection of HCC may be attempted even in patients with IVCTT, in the presence of good liver function. PMID- 24798619 TI - Characterization of a novel PXR isoform with potential dominant-negative properties. AB - BACKGROUND & AIMS: The nuclear Pregnane X Receptor (PXR, NR1I2) plays a pivotal role in xenobiotic metabolism. Here, we sought to characterize a new PXR isoform (hereafter called small PXR or sPXR) stemming from alternative transcription starting sites downstream of a CpG Island located near exon 3 of the human PXR gene. METHODS: Quantitative RT-PCR, western blot, methylation-specific PCR, luciferase reporter assays, electro-mobility shift assays, and stable sPXR overexpression were used to examine sPXR expression and function in hepatocellular cell lines, healthy human liver (n=99), hepatocellular adenomas (HCA, n=91) and hepatocellular carcinoma samples (HCC, n=213). RESULTS: Liver sPXR mRNA expression varied importantly among individuals and encodes a 37kDa nuclear protein consisting of the ligand-binding domain of PXR that behaves as a dominant-negative of PXR transactivation properties. In vitro methylation of the sPXR upstream promoter abolished its activity, while the demethylation agent 5 aza-2-deoxycytidine increased sPXR mRNA expression in several cell lines. Finally, we observed that sPXR mRNA expression displayed significant differences related to HCA or HCC biology. CONCLUSIONS: This novel PXR isoform, displaying a dominant-negative activity and regulated by DNA methylation, is associated with outcomes of patients with HCC treated by resection, suggesting that it represents a key modulator of PXR. PMID- 24798620 TI - TGF-beta-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells. AB - BACKGROUND & AIMS: CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) have a profound ability to control immune responses. We have previously shown that the liver is a major source of peripherally induced Tregs. Here, we investigate the liver cell types and molecular mechanisms responsible for hepatic Treg induction. METHODS: To assess the Treg-inducing potential of liver resident antigen presenting cell types, we studied the conversion of Foxp3(-) non-Tregs into Foxp3(+) Tregs induced by liver dendritic cells (DCs), liver sinusoidal endothelial cells (LSECs), or Kupffer cells (KCs). The dependency of Treg induction on TGF-beta was tested in Treg conversion assays using T cells with reduced TGF-beta sensitivity. The suppressive potential of liver cell-induced Tregs was assessed by an in vitro suppression assay and in vivo, in the model of experimental autoimmune encephalomyelitis (EAE). RESULTS: All tested liver cell types were capable of inducing Foxp3(+) Tregs; however, LSECs were most efficient in inducing Tregs. Treg-induction was antigen-specific and depended on TGF-beta. LSECs featured membrane-bound LAP/TGF-beta and the anchor molecule GARP, which is required for tethering LAP/TGF-beta to the cell membrane. LSEC-induced Tregs suppressed proliferation and cytokine secretion of effector T cells in vitro. LSEC-induced Tregs were also functional suppressors in vivo, as neuroantigen specific Tregs induced by LSECs were able to suppress EAE. CONCLUSIONS: We demonstrate that LSECs are the major liver cell type responsible for TGF-beta dependent hepatic Treg induction. The extraordinary capacity of LSECs to induce Tregs was associated with their unique ability to tether TGF-beta to their membrane. PMID- 24798621 TI - Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction. AB - BACKGROUND & AIMS: Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. METHODS: A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. RESULTS: A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). CONCLUSIONS: A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. PMID- 24798622 TI - Reactivation from occult HBV carrier status is characterized by low genetic heterogeneity with the wild-type or G1896A variant prevalence. AB - BACKGROUND & AIMS: Individuals negative for hepatitis B surface antigen (HBsAg) but positive for antibodies to hepatitis B core antigen (anti-HBc) are at risk of hepatitis B virus (HBV) reactivation under immunosuppressive conditions. We investigated clinical features and viral genetics in patients with reactivation from occult HBV infection triggered by chemotherapy or immunosuppressive therapy. METHODS: Clinical courses of 14 individuals originally HBsAg-negative but anti HBc-positive that experienced HBV reactivation were examined. Ultra-deep sequencing analysis of the entire HBV genome in serum was conducted. Prevalence of the G1896A variant in latently infected livers was determined among 44 healthy individuals that were HBsAg-negative but anti-HBc-positive. RESULTS: In 14 cases, HBV reactivation occurred during (n=7) and after (n=7) termination of immunosuppressive therapy. Ultra-deep sequencing revealed that the genetic heterogeneity of reactivated HBV was significantly lower in patients with reactivation from occult HBV carrier status compared with that in patients from HBsAg carrier status. The reactivated viruses in each case were almost exclusively the wild-type G1896 or G1896A variant. The G1896A variant was detected in 42.9% (6/14) of cases, including two cases with fatal liver failure. The G1896A variant was observed in the liver tissue of 11.4% (5/44) of individuals with occult HBV infection. CONCLUSIONS: Reactivation from occult HBV infection is characterized by low genetic heterogeneity, with the wild-type G1896 or G1896A variant prevalent. PMID- 24798623 TI - Von Willebrand factor antigen for detection of hepatopulmonary syndrome in patients with cirrhosis. AB - BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) occurs in 20-30% of patients with liver cirrhosis and is associated with a >2 fold increased mortality. Endothelial dysfunction seems to play a central role in its pathogenesis. von Willebrand factor antigen (vWF-Ag), an established marker of endothelial dysfunction, is significantly elevated in patients with liver cirrhosis, portal hypertension, and in experimental HPS. Aim of the present study was to evaluate the impact of vWF-Ag as a screening marker for presence of HPS in patients with stable cirrhosis. METHODS: 145 patients with stable liver cirrhosis were screened for presence of HPS in this prospective cohort type cross sectional diagnostic study. vWF-Ag and SaO2 levels were assessed at time of screening for HPS. Criteria of HPS were fulfilled in 31 (21%) patients. RESULTS: vWF-Ag levels were significantly higher in patients with HPS compared to patients without HPS (p<0.001). Furthermore, vWF-Ag correlated significantly with gas exchange in HPS positive patients (p<0.05). vWF-Ag is an independent predictor of HPS after correction for sex, age, model for endstage-liver disease (MELD), and hepatic venous pressure gradient (HVPG) (OR per 1% increase of vWF-Ag: 1.02, 95% CI: 1.00 1.04, p<0.05). The best cut-off was 328% at a sensitivity of 100% and specificity of 53.5%; positive predictive value: 36.9%; negative predictive value: 100%. CONCLUSIONS: HPS is associated with elevated vWF-Ag levels. vWF-Ag may be a useful screening tool for early detection of HPS. Further studies investigating vWF-Ag in HPS will be needed to confirm our findings. PMID- 24798624 TI - The role of Kupffer cells in hepatitis B and hepatitis C virus infections. AB - Globally, over 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV). These chronic infections cause liver inflammation, and may result in fibrosis/cirrhosis or hepatocellular carcinoma. Albeit that HBV and HCV differ in various aspects, clearance, persistence, and immunopathology of either infection depends on the interplay between the innate and adaptive responses in the liver. Kupffer cells, the liver-resident macrophages, are abundantly present in the sinusoids of the liver. These cells have been shown to be crucial players to maintain homeostasis, but also contribute to pathology. However, it is important to note that especially during pathology, Kupffer cells are difficult to distinguish from infiltrating monocytes/macrophages and other myeloid cells. In this review we discuss our current understanding of Kupffer cells, and assess their role in the regulation of anti-viral immunity and disease pathogenesis during HBV and HCV infection. PMID- 24798625 TI - Transfer of MHC-class-I molecules among liver sinusoidal cells facilitates hepatic immune surveillance. AB - BACKGROUND & AIMS: In the liver, antigen-presenting cell populations such as Kupffer cells, liver dendritic cells, and liver sinusoidal endothelial cells (LSECs) participate through cross-presentation to CD8 T cells (CTLs) in hepatic immune-regulation and immune-surveillance. The participation of hepatic stellate cells (HSCs) in immune regulation is controversial. Here we studied HSC's contribution to antiviral CTL immunity. METHODS: Flow cytometric analysis of MHC I molecules at the cell surface of liver cells from mice with cell-type restricted MHC-I expression. Mice with HSC-restricted MHC-I expression were infected with a hepatotropic virus and analyzed for development of viral hepatitis after CTL transfer. RESULTS: HSCs transferred MHC-I molecules to LSECs and these molecules were employed for LSEC cross-presentation to CTLs. Such transfer of MHC-I molecules was sufficient to support in vivo LSEC cross presentation of soluble antigens to CTLs. Importantly, this transfer of MHC-I molecules contributed to anti-viral CTL immunity leading to development of immune mediated hepatitis. CONCLUSIONS: Our findings demonstrate transfer of MHC-I molecules among sinusoidal liver cell populations as a potent mechanism to increase anti-viral CTL effector function. The transfer of MHC-I molecules from HSCs supplies LSECs with additional MHC-I molecules for their own cell-intrinsic cross-presentation. Such cross-allocation of MHC-I molecules in liver cell populations is distinct from cross-dressing that occurs among immune cell populations in lymphoid tissues where peptide-loaded MHC-I molecules are transferred. Our findings thus reveal a novel mechanism that increases local cross-presentation and CTL effector function in the liver, which may be instrumental for immune-surveillance during viral infection of antigen-presenting liver cells. PMID- 24798626 TI - Highly selective separation of aminoglycoside antibiotics on a zwitterionic Click TE-Cys column. AB - Hydrophilic interaction liquid chromatography has emerged as a valuable alternative approach to ion-pair chromatography for the separation of aminoglycoside antibiotics in recent years. However, the resolution of structurally related aminoglycosides is a great challenge owing to the limited selectivity. In this work, a cysteine-based zwitterionic stationary phase (named Click TE-Cys) was utilized and compared with five commonly used hydrophilic interaction liquid chromatography columns. Click TE-Cys displayed much better selectivity for structurally similar aminoglycosides. The retention behaviors of aminoglycosides were investigated in detail, revealing that low pH (2.7 or 3.0) and high buffer concentration (>=50 mM) were preferable for achieving good peak shape and selectivity. Effective resolution of ten aminoglycosides including spectinomycin, dihydrostreptomycin, streptomycin, gentamicin C1, gentamicin C2/C2a, gentamicin C1a, kanamycin, paromonycin, tobramycin, and neomycin was realized at optimized conditions. Additionally, spectinomycin and its related impurities were successfully resolved. The results indicated the great potential of the Click TE-Cys column in the separation of aminoglycoside mixtures and related impurities. PMID- 24798628 TI - Outcomes of rectal cancer treatment--influence of age? AB - PURPOSE: To evaluate how age influences the selection to different treatment modalities for rectal cancer and how these differences in approach affect the short- and long-term outcomes. METHODS: A single-center cohort of all 837 rectal cancer patients diagnosed between 1994 and 2006 was analyzed. Patients <75, 75 79, 80-84, and >85 years were compared. RESULTS: Treatment for cure was judged possible for 80.8, 77.9, 74.6, and 65.3 % of the four age groups (p = 0.02), and radiochemotherapy was given to 22.9, 19.3, 10.2, and 2 % of the same groups (p = 0.001). Local resection was performed for 3.7, 14.7, 13.6, and 24.5 % (p < 0.001) and anterior resection for 66.6, 54.1, 56.8, and 49 % (p < 0.001). The 5-year rates of local recurrence were 5.3, 8.3, 12.8, and 22.3 % (p < 0.001), and overall survival was 70, 54, 45.9, and 29.8 % in the four groups treated with curative intent (p < 0.001). Relative survival was 76.4, 72.6, 72.9, and 72.3 % (ns). CONCLUSIONS: Age caused treatment to be modified; there was less surgery for patients over 85 years, less radiochemotherapy over 80 years, and less major radical surgery over 75 years. This strategy resulted in more local recurrences among the elderly, although no certain effect on relative survival was observed. PMID- 24798629 TI - Natural Orifice Transluminal Endoscopic Surgery (NOTES) for colon resections- analysis of the first 139 patients of the German NOTES Registry (GNR). AB - BACKGROUND: The German NOTES registry (GNR) is the largest published database for natural orifice transluminal endoscopic surgery (NOTES) worldwide. Although transvaginal cholecystectomy is the most frequent procedure in the GNR, the number of colorectal resections is increasing. The objective of this study was to analyze the first 139 colonic procedures of the GNR. METHODS: All colonic procedures from the GNR were analyzed regarding patient- and therapy-related parameters. A multivariate analysis was conducted for transvaginal sigmoid resections regarding procedural time, hospital stay, conversion rate, and rate of complications. RESULTS: From October 2008 to January 2013, 139 colon NOTES procedures (12 male, 127 female) were registered. Main diagnoses were sigmoid diverticulitis (85.6 %), colon carcinoma (9.4 %), and ulcerative colitis (3.6 %). Sigmoid resections (87.1 %), proctocolectomies (3.6 %), right-sided resections (2.9 %), left-sided resections (3.6 %), segmental resections (2.2 %), and 1 ileocecal resection (0.7 %) were performed. All procedures were conducted in transvaginal (87.8 %) or transrectal (12.2 %) hybrid technique, with a median of 3 percutaneous trocars. Conversions to laparoscopic technique were necessary in 3.6 % (none to conventional technique). Intraoperative complications were recorded in 2.9 % and postoperative complications in 12.2 %. The institutional case number in transvaginal sigmoid resections correlated negatively with procedural time (p = 0.041) and the number of percutaneous trocars (p = 0.002). CONCLUSION: The analysis of the first 139 colon NOTES operations of the GNR shows the feasibility of co on operations in hybrid technique, especially for transvaginal sigmoid resection as the most frequent procedure. PMID- 24798630 TI - Increased faecal calprotectin predicts recurrence of colonic diverticulitis. AB - BACKGROUND AND AIMS: Colonic diverticulitis shows a high recurrence rate, but the role of faecal markers in predicting recurrence is unknown. The aim of this study was to investigate the role of faecal calprotectin (FC) in predicting recurrence of diverticulitis. PATIENTS/METHODS: A prospective cohort study was performed on 54 patients suffering from acute uncomplicated diverticulitis (AUD) diagnosed by computerized tomography (CT). After remission, patients underwent to clinical follow-up every 2 months. After remission and during the follow-up, FC was analysed. Recurrence of diverticulitis was defined as return to our observation due to left lower-quadrant pain with or without other symptoms (e.g. fever), associated with leucocytosis and/or increased C-reactive protein (CRP). Presence of diverticulitis was confirmed by means of CT. RESULTS/FINDINGS: The mean follow up was 20 months (range 12-24 months). Forty-eight patients were available for the final evaluation, and six patients were lost to follow-up. During follow-up, increased FC was detected in 17 (35.4 %) patients and diverticulitis recurred in eight patients (16.7 %). Diverticulitis recurred in eight (16.7 %) patients: seven (87.5 %) patients showed increased FC during the follow-up, and only one (12.5 %) patient with recurrent diverticulitis did not show increased FC. Diverticulitis recurrence was strictly related to the presence of abnormal FC test during follow-up. CONCLUSIONS: In the present prospective study, increased FC was found to be predictive of diverticulitis recurrence. PMID- 24798631 TI - Impact of D3 lymph node dissection on survival for patients with T3 and T4 colon cancer. AB - PURPOSE: The clinical significance of D3 lymph node dissection for patients with colon cancer remains controversial. This study aims to clarify the impact of D3 lymph node dissection on survival in patients with colon cancer. METHODS: This is a retrospective cohort study from a prospectively registered multi-institutional database of colorectal cancer in Japan. Propensity score matching method was applied to balance potential confounders of the treatment. A cohort of 10,098 patients who underwent radical colectomy for pT3 and pT4 colon cancer between 1985 and 1994 were identified. A total of 3,425 propensity score matched pairs were extracted from the entire cohort. The primary outcome measure was overall survival (OS). RESULTS: In the entire cohort, there was a statistically significant difference in overall survival (OS) between the patients who had D3 and D2 lymph node dissection (p = 0.00003). The estimated hazard ratio (HR) for OS of patients who had D3 versus D2 lymph node dissection was 0.827 (95 % confidence interval, 0.757 to 0.904). In the matched cohort, there was also a significant difference in OS between the two groups (p = 0.0001), and the estimated HR for OS was 0.814 (95 % confidence interval, 0.734 to 0.904). CONCLUSIONS: We found D3 lymph node dissection for pT3 and pT4 colon cancer to be associated with a significant survival advantage in a large-scale database, even after adjusting potential confounders of lymph node dissection. This finding may provide a rationale for D3 lymph node dissection in radical surgery for pT3 and pT4 colon cancer. PMID- 24798632 TI - Routine histological sampling of doughnuts post oncologic anterior resection is not necessary. AB - BACKGROUND: A stapled end-to-end colo-rectal anastomosis is increasingly adopted following a proctectomy for various colorectal conditions. The ensuing doughnuts of colonic tissue created from the stapling device have been routinely sent for histological analysis. However, its efficacy remains debatable. This study aims to determine if there is a role in sending colonic doughnuts for histological examination following a stapled end-to-end colo-rectal anastomosis following proctectomy for colorectal cancers. METHODS: A retrospective review of all histological reports of the doughnuts from patients who underwent a proctectomy followed by a stapled end-to-end colo-rectal anastomosis for colorectal cancer in the National University Hospital, Singapore, from 2004-2010 was performed. RESULTS: A total of 336 patients who underwent a stapled end-to-end anastomosis following proctectomy for colorectal cancer from 2004-2010 had available histological reports. The specimen margins and colonic doughnuts were all negative for malignancy. Clinical decisions were not altered based on doughnut histology results. A total cost of USD$61,017.60 was incurred for the histological processing of these doughnuts. CONCLUSION: There appears to be no additional oncological or cost benefits in sending doughnuts after a stapled end to-end colo-rectal anastomosis following proctectomy for colorectal cancers except in selected clinico-pathological conditions whereby the risk of a positive margin is deemed higher. PMID- 24798633 TI - Birth weight and risk of colorectal cancer: a meta-analysis. PMID- 24798634 TI - The effective diagnostic process may shorten TISD and improve overall survival of young patients with colorectal cancer. PMID- 24798635 TI - Neuropsychiatric symptom clusters targeted for treatment at earlier versus later stages of dementia. AB - OBJECTIVE: To characterize clusters of neuropsychiatric symptoms targeted for tracking the disease course in people with dementia, in relation to stage. METHODS: Baseline symptoms from 2922 subjects from two datasets (one clinic based, one online) were aggregated. Common neuropsychiatric symptoms identified by patients/carers as targets of treatment using a dementia SymptomGuideTM were selected. The Global Deterioration Scale was used for clinic staging, and an artificial neural network algorithm, for staging online subjects. Symptom clusters were detected using multiple correspondence analysis and connectivity graph analysis based on relative risk (RR). In a connectivity graph, each pair of nodes (representing symptoms) is connected if their co-occurrence is statistically significant; direction is indicated as positive if RR > 1 and negative otherwise. RESULTS: Neuropsychiatric symptoms were targeted for treatment in 1072 patients (37%). Agitation (37%) and sleep disturbances (28%) were most common symptoms. One cluster (in people with cognitive impairment, no dementia (CIND) or mild dementia) showed significant co-occurrence of anxiety and restlessness; decreased initiative was chiefly seen in isolation. A second cluster (in moderate/severe dementia) was defined by significant co-occurrence of delusions and hallucinations with sleep disturbances; in these subjects, decreased initiative was related to aggression. CONCLUSIONS: Two analytical methods identified neuropsychiatric symptom clusters targeted to track the disease course. In CIND/mild dementia, a profile of decreased initiative distinct from depression suggests possible executive dysfunction. In moderate/severe dementia, targets more reflected psychotic symptoms. Visual data displays allow the relationships between multiple symptoms to be considered simultaneously, which commonly is how they present in patients. PMID- 24798636 TI - Outcome after discontinuation of TNFalpha-blocking therapy in patients with inflammatory bowel disease in deep remission. AB - BACKGROUND: Few data are available on the disease course in patients with inflammatory bowel disease (IBD) in deep remission after discontinuing tumor necrosis factor alpha (TNFalpha)-blocking therapy. In this prospective multicenter study, we evaluated the relapse rate, predictive factors, and the response to retreatment after discontinuation of TNFalpha-blocking therapy in patients with IBD in deep remission. METHODS: We recruited 52 patients (17 Crohn's disease, 30 ulcerative colitis, and 5 IBD unclassified) in clinical, endoscopic, and fecal calprotectin-based (<100 MUg/g) remission after at least 1 year of TNFalpha-blocking therapy. Clinical and endoscopic remission and relapse were defined according to validated indices. After discontinuation of therapy, the patients were followed up with endoscopic assessment at 4 and 12 months. In the event of a clinical relapse with endoscopically active disease or minor clinical symptoms but severe endoscopic relapse, TNFalpha-blocking therapy was restarted. RESULTS: After a median follow-up time of 13 (range, 12-15) months, 17/51 (33%) patients relapsed (5/17 Crohn's disease, 12/34 ulcerative colitis/IBD unclassified, 1 patient lost to follow-up at 6 mo). Ten experienced clinical and endoscopic relapse, 5 clinical relapse with mild endoscopic activity, and 2 severe endoscopic relapse. No specific predictive factors were associated with the relapse. Retreatment was effective in 94% of patients. CONCLUSIONS: After cessation of TNFalpha-blocking therapy in patients with IBD in deep remission, up to 67% remained in clinical remission during the 12-month follow-up. Importantly, 85% of these patients sustained endoscopic remission. The response to restart of TNFalpha antagonists was effective and well tolerated. PMID- 24798637 TI - Elastic scattering spectroscopy as an optical marker of inflammatory bowel disease activity and subtypes. AB - BACKGROUND: In 10% to 15% of individuals, inflammatory bowel disease (IBD) is difficult to classify as ulcerative colitis (UC) or Crohn's disease (CD). Previous work has demonstrated that probe-based elastic scattering spectroscopy (ESS) can produce spectra, informed by parameters like tissue ultrastructure and hemoglobin content, capable of differentiating pathologies. This study investigates whether ESS is an in vivo optical biomarker for the presence, activity, and type of IBD in the colon. METHODS: Pilot study, a retrospective data analysis. ESS spectra of endoscopically normal and inflamed colon were obtained from 48 patients with IBD and 46 non-IBD controls. Measurements from patients with IBD were categorized as CD or UC based on clinical diagnosis. Spectra were analyzed using high-dimensional methods. Leave-one-patient-out cross validation was used to obtain diagnostic performance estimates. RESULTS: Patients with IBD were distinguishable from non-IBD controls with a sensitivity of 0.93 and specificity of 0.91 based on readings from endoscopically normal mucosa, and 0.94 and 0.93 from inflamed mucosa. In patients with IBD, histologically normal and inflamed colon were distinguishable with per-class accuracies of 0.83 and 0.89, respectively; histologically normal from inactive inflammation with accuracies of 0.73 and 0.89, respectively; and inactive from active colitis with accuracies of 0.87 and 0.84, respectively. The diagnosis of CD versus UC was made with per-class accuracies of 0.92 and 0.87 in normal and 0.87 and 0.85 in inflamed mucosa, respectively. CONCLUSIONS: ESS, a simple, low-cost clinically friendly optical biopsy modality, has the potential to enhance the endoscopic assessment of IBD and its activity in real time and may help to distinguish CD from UC. PMID- 24798638 TI - De novo mutation of the latency-associated peptide domain of TGFB3 in a patient with overgrowth and Loeys-Dietz syndrome features. PMID- 24798640 TI - What do we know about suicidality in autism spectrum disorders? A systematic review. AB - Suicidality is a common and concerning issue across development, and there is a plethora of research on this topic among typically developing children and youth. Very little is known, however, about the nature of suicidality among individuals with autism spectrum disorders (ASDs). The purpose of the current study was to undertake a systematic literature review to assess the current state of the research literature to examine the prevalence of suicidality among individuals with ASD, related demographic and clinical profiles, and associated risk and protective factors. A literature search using key terms related to suicidality and ASD yielded 10 topical studies that were evaluated for the study objectives. Suicidality was present in 10.9-50% of the ASD samples identified in the systematic review. Further, several large-scale studies found that individuals with ASD comprised 7.3-15% of suicidal populations, a substantial subgroup. Risk factors were identified and included peer victimization, behavioral problems, being Black or Hispanic, being male, lower socioeconomic status, and lower level of education. Only one study reported on protective factors, and this is identified as a significant gap in the literature. Several methodological weaknesses were present in the current literature, such as lack of appropriate comparison groups and little to no use of empirically validated measures for ASD diagnosis and suicide assessment. Additional research is necessary to understand better how this unique population experiences and expresses suicidal tendencies. Recommendations for future research are discussed. PMID- 24798639 TI - Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia. AB - Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. Whereas the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a rhesus rotavirus-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker, PROMININ-1 (PROM1), adjacent to ductular reactions within regions of periportal fibrosis. PROM1positive (pos) cells express Collagen-1alpha1. Subsets of PROM1pos cells coexpress progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and alpha-SMOOTH MUSCLE ACTIN (alphaSMA). Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGFbeta) signaling. In vitro cotreatment of PROM1-expressing Mat1a-/- hepatic progenitor cells with recombinant human FGF10 and TGFbeta1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1alpha1, Fibronectin, and alpha-Sma. Infants with BA demonstrate similar expansion of periportal PROM1pos cells with activated Mothers Against Decapentaplegic Homolog 3 (SMAD3) signaling in association with increased hepatic expression of FGF10, FGFR1, and FGFR2 as well as mesenchymal genes SLUG and SNAIL. Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype. CONCLUSION: Expansion of collagen-producing PROM1pos cells within regions of periportal fibrosis is associated with activated FGF and TGFbeta pathways in both experimental and human BA. PROM1pos cells may therefore play an important role in the biliary fibrosis of BA. PMID- 24798641 TI - Physical activity in caregivers: What are the psychological benefits? AB - Previous research demonstrates that physical activity has psychological benefits for people of all ages. However, it is unclear whether people caring for a frail or ill relative would derive similar psychological benefits, considering the potentially stressful caregiver role. This article reviews the current literature describing the effect of physical activity interventions on the psychological status of caregivers. A search from January 1975 to December 2012 identified five intervention studies investigating physical activity and psychological status in caregivers. These focused on female Caucasian caregivers who were older than 60 years. The physical activity interventions improved stress, depression and burden in caregivers, but small sample sizes, short-term follow up and varying results limited the generalizability of the findings. There were few trials investigating male caregivers, and most care-recipients were people with dementia. Studies with caregivers of different ages and gender, with a range of physical activity interventions, are needed to clarify whether physical activity has psychological benefits for caregivers. PMID- 24798642 TI - Do cattle (Bos taurus) retain an association of a visual cue with a food reward for a year? AB - Use of visual cues to locate specific food resources from a distance is a critical ability of animals foraging in a spatially heterogeneous environment. However, relatively little is known about how long animals can retain the learned cue-reward association without reinforcement. We compared feeding behavior of experienced and naive Japanese Black cows (Bos taurus) in discovering food locations in a pasture. Experienced animals had been trained to respond to a visual cue (plastic washtub) for a preferred food (grain-based concentrate) 1 year prior to the experiment, while naive animals had no exposure to the cue. Cows were tested individually in a test arena including tubs filled with the concentrate on three successive days (Days 1-3). Experienced cows located the first tub more quickly and visited more tubs than naive cows on Day 1 (usually P < 0.05), but these differences disappeared on Days 2 and 3. The performance of experienced cows tended to increase from Day 1 to Day 2 and level off thereafter. Our results suggest that Japanese Black cows can associate a visual cue with a food reward within a day and retain the association for 1 year despite a slight decay. PMID- 24798643 TI - An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis in lung adenocarcinoma cancer patients. AB - Leptomeningeal carcinomatosis (LC) is a metastatic cancer invading the central nervous system (CNS). We previously reported a metabolomic diagnostic approach as tested on an animal model and compared with current modalities. Here, we provide a proof of concept by applying it to human LC originating from lung cancer, the most common cause of CNS metastasis. Cerebrospinal fluid from LC (n = 26) and normal groups (n = 41) were obtained, and the diagnosis was established with clinical signs, cytology, MRI and biochemical tests. The cytology on the CSF, the current gold standard, exhibited 69% sensitivity (~100% specificity) from the first round of CSF tapping. In comparison, the nuclear magnetic resonance spectra on the CSF showed a clear difference in the metabolic profile between the LC and normal groups. Multivariate analysis and cross-validation yielded the diagnostic sensitivity of 92%, the specificity of 96% and the area under the curve (AUC) of 0.991. Further spectral and statistical analysis identified myo-inositol (p < 5 * 10(-14)), creatine (p < 7 * 10(-8)), lactate (p < 9 * 10(-4)), alanine (p < 7.9 * 10(-3)) and citrate (p < 3 * 10(-4)) as the most contributory metabolites, whose combination exhibited an receiver-operating characteristic diagnostic AUC of 0.996. In addition, the metabolic profile could be correlated with the grading of radiological leptomeningeal enhancement (R(2) = 0.3881 and p = 6.66 * 10(-4)), suggesting its potential utility in grading LC. Overall, we propose that the metabolomic approach might augment current diagnostic modalities for LC, the accurate diagnosis of which remains a challenge. PMID- 24798644 TI - Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast. AB - Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed experimentally by dedicated experiments. Specifically, our analyses suggest that: (i) arsenic is mainly protein-bound during short-term (acute) exposure, whereas glutathione-conjugated arsenic dominates during long-term (chronic) exposure, (ii) arsenic is not stably retained, but can leave the vacuole via an export mechanism, and (iii) Fps1 is controlled by Hog1-dependent and Hog1-independent mechanisms during arsenite stress. Our results challenge glutathione depletion as a key mechanism for arsenic toxicity and instead suggest that (iv) increased glutathione biosynthesis protects the proteome against the damaging effects of arsenic and that (v) widespread protein inactivation contributes to the toxicity of this metalloid. Our work in yeast may prove useful to elucidate similar mechanisms in higher eukaryotes and have implications for the use of arsenic in medical therapy. PMID- 24798645 TI - Asymmetry of Achilles tendon mechanical and morphological properties between both legs. AB - Although symmetry of Achilles tendon (AT) properties between legs is commonly assumed in research and clinical settings, different loading profiles of both legs in daily life (i.e., foot dominance) may affect the tendon properties in a side-depended manner. Therefore, AT properties were examined with regard to symmetry between legs. Thirty-six male healthy adults (28 +/- 4 years), who were physically active but not involved in sports featuring dissimilar leg load participated. Mechanical and morphological AT properties of the non-dominant and dominant leg were measured by means of ultrasound, magnetic resonance imaging and dynamometry. The AT of the dominant leg featured a significant higher Young's modulus and length (P < 0.05) but a tendency toward lower maximum strain (P = 0.068) compared with the non-dominant leg. The tendon cross-sectional area and stiffness were not significantly different between sides. The absolute asymmetry index of the investigated parameters ranged from 3% to 31% indicating poor AT side symmetry. These findings provide evidence of distinct differences of AT properties between both legs in a population without any sport-specific side depended leg loading. The observed asymmetry may be a result of different loading profiles of both legs during daily activities (i.e., foot dominance) and challenges the general assumption of symmetrical AT properties between legs. PMID- 24798646 TI - BMP and activin membrane-bound inhibitor (BAMBI) inhibits the adipogenesis of porcine preadipocytes through Wnt/beta-catenin signaling pathway. AB - The process of differentiation from preadipocytes to adipocytes contributes to adipose tissue expansion in obesity. Blocking adipogenesis may be conducive to the etiology of obesity-related diseases. BMP and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein, which was identified as a target of beta-catenin in colorectal and hepatocellular tumor cells. However, whether BAMBI affects adipogenesis by Wnt/beta-catenin signaling remains to be explored. In this study, we distinguish BAMBI as an inhibitor of preadipocytes differentiation. We found that BAMBI was downregulated during preadipocytes differentiation. Knockdown of BAMBI increased adipogenesis and blocked Wnt/beta catenin signaling by repressing beta-catenin accumulation. In BAMBI overexpression cells, lipid accumulation was reduced by promoting nuclear translocation of beta-catenin. Lithium chloride (LiCl) is an activator of Wnt/beta-catenin signaling, which is an inhibitor of glycogen synthetase kinase-3 (GSK-3), maintaining the stability of beta-catenin in cytosolic. We showed BAMBI strengthened the anti-adipogenic effects of LiCl. In addition, the results indicated that BAMBI was upregulated by beta-catenin. These observations illuminated that BAMBI inhibits adipogenesis by a feedback loop (BAMBI->beta catenin nuclear translocation->BAMBI), which forms with Wnt/beta-catenin signaling. PMID- 24798647 TI - Use of a physostigmine continuous infusion for the treatment of severe and recurrent antimuscarinic toxicity in a mixed drug overdose. AB - INTRODUCTION: Physostigmine was once a widely used antidote for the treatment of antimuscarinic toxicity. However, reports describing the association of physostigmine with asystole and seizures in severe tricyclic antidepressant poisoning resulted in a decrease in use. Recent literature has demonstrated that physostigmine is a safe and effective antidote for the treatment of antimuscarinic toxicity. There are only two previously published articles regarding the use of physostigmine administered as a continuous intravenous infusion for persistent antimuscarinic toxicity. We present a case of physostigmine continuous infusion for the treatment of antimuscarinic symptoms in a polydrug overdose due to the ingestion of diphenhydramine along with bupropion, citalopram, acetaminophen, and naproxen. CASE PRESENTATION: A 13-year-old female presented with hyperthermia, myoclonus and rigidity, hallucinations, severe agitation, and antimuscarinic toxicity including inability to sweat after a polydrug overdose. Several doses of lorazepam were administered followed by physostigmine which produced resolution of hallucinations and attenuation of the antimuscarinic symptoms including perspiration, temperature improvement, and decreased agitation. After periods of improvement and recurrence of antimuscarinic effects, a continuous infusion of physostigmine was administered at 2 mg/h and continued for almost 8 h to maintain attenuation of symptoms. GABAergic agents including lorazepam and phenobarbital were used later in the hospital course for presumed symptoms of serotonergic and adrenergic toxicity after resolution of antimuscarinic effects. The patient did not experience any adverse effects of physostigmine administration. DISCUSSION: Physostigmine administered as a continuous infusion may be a reasonable treatment option for severe and recurrent symptoms related to antimuscarinic toxicity. PMID- 24798648 TI - Tempest in a tea pot: How did the public conversation on genetically modified crops drift so far from the facts? AB - The debate over genetically modified (GM) crops has raged in Europe since 1996, but had barely risen above a whisper in the USA until recent labeling debates raised public attention. This article will explain GM crops and traits discuss safety assessment provide a view on safety from authoritative organizations discuss selected issues of current debate, and provide the author's perspective as to why the public debate has drifted so far from scientific reality. The economic and environmental benefits of GM crops are beyond scope, but references are provided. GM food and feed undergo comprehensive assessments using recognized approaches to assure they are as safe as the conventional congener. Issues of food safety and nutrition, unrelated to the GM process, may arise when GM foods display novel components or composition. Unanticipated genetic effects in GM crops appear to be limited in contrast to existing variations among conventional varieties resulting from breeding, mutation, and natural mobile genetic elements. Allergenic potential is assessed when selecting genes for introduction into GM crops and remains a theoretical risk to date. Emerging weed and insect resistance is not unique to GM technology and will require the use of integrated pest management/best practices for pest control. Gene flow from GM crops to wild relatives is limited by existing biological barriers but can at time be a relevant consideration in gene selection and planting practices. Insect-resistant GM crops have significantly reduced use of chemical insecticides and appear to have reduced the incidence of pesticide poisoning in areas where small scale farming and hand application are common. Changes in herbicide patterns are more complex and are evolving over time in response to weed resistance management needs. Recent public debate is driven by a combination of unfounded allegations about the technology and purveyors, pseudoscience, and attempts to apply a strict precautionary principle. PMID- 24798649 TI - Biological effect of BMP-2 monitored by PET/CT. PMID- 24798650 TI - HIV-TAT enhances the transdermal delivery of NSAID drugs from liquid crystalline mesophases. AB - Sodium diclofenac (Na-DFC) and celecoxib (CLXB) are common nonsteroidal anti inflammatory (NSAID) drugs which suffer from poor bioavailability and severe side effects when consumed orally, and their transdermal delivery might present important advantages. In this study, the drugs were solubilized in cubic and lamellar mesophases as transdermal delivery vehicles, and a cell-penetrating peptide, HIV-TAT (TAT), was examined as a skin penetration enhancer. SD-NMR, ATR FTIR, and EPR measurements revealed that, in the cubic mesophase (which is rich in water content), TAT populates the aqueous cores and binds water, while in the dense lamellar system (with the lower water content) TAT is bound also to the glycerol monooleate (GMO) and increases the microviscosity and the order degree. TAT secondary structure in the cubic system was found to be a random coil while once it was embedded in the closely packed lamellar system it transforms to a more ordered compact state of beta-turns arranged around the GMO headgroups. TAT remarkably increased the diffusion of Na-DFC and CLXB from the cubic systems by 6 and 9-fold enhancement, respectively. TAT effect on drug diffusion from the lamellar systems was limited to an increase of 1.3- and 1.7-fold, respectively. The dense packing and strong binding in the lamellar phase led to slow diffusion rates and slower drug release in controlled pattern. These effects of the chemical composition and vehicle geometry on drug diffusion are demonstrated with the impacts of TAT which can be specifically utilized for controlling skin delivery of drugs as required. PMID- 24798651 TI - Preventing adolescent drowning: understanding water safety knowledge, attitudes and swimming ability. The effect of a short water safety intervention. AB - Worldwide, epidemiological data indicate that children are a high-risk group for drowning and while progress has been made in understanding toddler drownings, there is a lack of empirical evidence regarding the drowning risk and protective factors inherent for adolescents and young adults. This study used a self-report questionnaire to establish swimming and water safety knowledge and attitudes of young adults and objectively measured their actual swimming ability using formal practical testing procedures. Participants then completed a short, 12-week intervention that encompassed swimming, survival and rescue skills, along with water safety knowledge applicable to a range of aquatic environments. Knowledge, attitudes and swimming ability were then re-measured following the intervention to evaluate its effectiveness. The Wilcoxon matched pairs signed ranks test was performed to detect whether there were significant differences between knowledge, attitude and swim ability scores pre-intervention and post-intervention. A total of 135 participants completed the baseline and follow up questionnaire and all practical testing. Results indicated that these young adults had a very low level of water safety knowledge pre-intervention, although the majority had sound swimming and water safety skills and attitudes. Overall, significant improvements were evident in knowledge (p<0.001) and swim ability (p<0.001) post-intervention, although no changes were observed in attitudes (p=0.079). Previous participation in formal swimming lessons and/or swimming within the school curriculum had no significant impact on water safety knowledge, skills or attitudes of these young adults, and there were few significant gender differences. While it is important to conduct further studies to confirm that these findings are consistent with a more representative sample of young adults, our findings are the first to provide empirical evidence of the value of a comprehensive aquatic education program as a drowning prevention strategy for young adults. PMID- 24798652 TI - Acceptance rate and reasons for rejection of manuscripts submitted to Veterinary Radiology & Ultrasound during 2012. AB - Better understanding of the reasons why manuscripts are rejected, and recognition of the most frequent manuscript flaws identified by reviewers, should help submitting authors to avoid these pitfalls. Of 219 manuscripts submitted to Veterinary Radiology & Ultrasound in 2012, none (0%) was accepted without revision, four (2%) were withdrawn by the authors, 99 (45%) were accepted after revision, and 116 (53%) were rejected. All manuscripts for which minor revision was requested, and 73/86 (85%) manuscripts for which major revision was requested, were ultimately accepted. Acceptance rate was greater for retrospective studies and for manuscripts submitted from countries in which English was the primary language. The prevalences of flaws in manuscripts were poor writing (62%), deficiencies in data (60%), logical or methodological errors (28%), content not suitable for Veterinary Radiology & Ultrasound (26%), and lack of new or useful knowledge (25%). Likelihood of manuscript rejection was greater for lack of new or useful knowledge and content not suitable than for other manuscript flaws. The lower acceptance rate for manuscripts from countries in which English was not the primary language was associated with content not suitable and not poor writing. Submitting authors are encouraged to do more to recognize and address manuscript flaws before submission, for example by internal review. Specifically, submitting authors should express clearly the potential added value of their study in the introduction section of their manuscript, describe completely their methods and results, and consult the Editor-in-Chief if they are uncertain whether their subject matter would be suitable for the journal. PMID- 24798653 TI - Transformation of cellulose and its derived carbohydrates into formic and lactic acids catalyzed by vanadyl cations. AB - The transformation of cellulose or cellulose-derived carbohydrates into platform chemicals is the key to establish biomass-based sustainable chemical processes. The systems able to catalyze the conversion of cellulose into key chemicals in water without the consumption of hydrogen are limited. We report that simple vanadyl (VO(2+)) cations catalyze the conversions of cellulose and its monomer, glucose, into lactic acid and formic acid in water. We have discovered an interesting shift of the major product from formic acid to lactic acid on switching the reaction atmosphere from oxygen to nitrogen. Our studies suggest that VO(2+) catalyzes the isomerization of glucose to fructose, the retro-aldol fragmentation of fructose to two trioses, and the isomerization of trioses, which leads to the formation of lactic acid under anaerobic conditions. The oxidative cleavage of C-C bonds in the intermediates caused by the redox conversion of VO2(+)/VO(2+) under aerobic conditions results in formic acid and CO2. We demonstrate that the addition of an alcohol suppresses the formation of CO2 and enhances the formic acid yield significantly to 70-75 %. PMID- 24798654 TI - Low-dose cytokine-induced neutral ceramidase secretion from INS-1 cells via exosomes and its anti-apoptotic effect. AB - It has been reported that the effect of inflammatory cytokines on beta-cell destruction in type 1 diabetes is concentration-dependent. However, the underlying mechanisms remain unclear. In the present study, we found that a high concentration of cytokines promoted apoptosis in the rat beta-cell line INS-1, whereas a low concentration of cytokines had no effect. We also found that cytokines at a low concentration stimulated neutral ceramidase (NCDase) release via exosomes from INS-1 cells, whereas cytokines at a high concentration inhibited NCDase release. Furthermore, the results showed that the NCDase containing exosomes isolated from the culture medium of INS-1 cells treated with cytokines at a low concentration inhibited apoptosis induced by a high concentration of cytokines. Finally, the results also showed that the protective action of NCDase in the exosomes on apoptosis was mediated by the generation of sphingosine 1-phosphate (S1P) and its interaction with S1P receptor 2. Taken together, these findings revealed a novel NCDase-S1P-phosphate-S1P receptor 2 dependent mechanism by which a low level of inflammatory cytokines protects pancreatic beta-cells from apoptosis induced by a high level of inflammatory cytokines. PMID- 24798655 TI - Evaluation of the utility of serum prolidase as a marker for liver fibrosis. AB - BACKGROUND: Liver dysfunction is common and often unrecognized. Liver biopsy is the gold standard in the assessment of liver fibrosis, but has disadvantages. We assessed the diagnostic accuracy of serum prolidase enzyme activity (SPA) in predicting the presence and degree of liver fibrosis, as compared with liver biopsy. Further, we evaluated the effect of hemolysis on measured SPA levels. METHODS: We undertook a prospective case control study. Thirty eight outpatients without apparent liver illness and 20 patients with liver pathology scheduled to undergo liver biopsy had their SPA levels measured. RESULTS: Patients undergoing liver biopsy had higher SPA levels (361 (268) IU/l [median (interquartile range)]) compared with controls (169 (160) (P < 0.001)). A SPA cutoff value of 200 IU/l yielded a sensitivity of 89%, specificity of 59%, an odds ratio of 11.5, negative predictive value of 92%, and a positive predictive value of 50%. Hemolysis causes an apparent increase in SPA levels. CONCLUSION: Higher SPA levels in patients undergoing liver biopsies compared with controls may reflect the presence of liver fibrosis. SPA levels could not be used to stage the degree of fibrosis. SPA measurement may be useful in the diagnostic workup of suspected liver disease. PMID- 24798656 TI - Retromolar flexible fiber-optic orotracheal intubation: a novel alternative to nasal intubation and tracheostomy in severe trismus. PMID- 24798658 TI - Temporal scales for the coordination of tree carbon and water economies during droughts. PMID- 24798657 TI - Effects of nighttime single-dose administration of vasodilating vs sympatholytic antihypertensive agents on sleep blood pressure in hypertensive patients with sleep apnea syndrome. AB - Obstructive sleep apneas syndrome (OSAS) is associated with nocturnal hypertension with higher sleep blood pressure (BP) and its variability, both of which increase cardiovascular risk. In this crossover design study, the effect of nighttime single-dose administration of vasodilating (nifedipine 40 mg) vs sympatholytic (carvedilol 20 mg) antihypertensive agents on sleep BP in 11 hypertensive OSAS patients was evaluated. The authors recently developed a trigger sleep BP monitor with an oxygen-triggered function that initiates BP measurement when oxygen desaturation falls. The BP-lowering effects of nifedipine on the mean (P<.05) and minimum sleep systolic BPs (SBPs) (P<.01) were stronger than those of carvedilol. Sleep SBP surge (difference between the hypoxia-peak SBP measured by oxygen-triggered function and SBPs within 30 minutes before and after the peak SBP) was only significantly reduced by carvedilol (P<.05). The nighttime dosing of both vasodilating and sympatholytic antihypertensive drugs is effective to reduce sleep BP but with different BP-lowering profiles. PMID- 24798659 TI - Beetroot (Beta vulgaris L.) and naturally fermented beetroot juices from organic and conventional production: metabolomics, antioxidant levels and anticancer activity. AB - BACKGROUND: The aim of the paper was to determine the level of antioxidants and metabolomic fingerprinting in both raw beetroots and naturally fermented beetroot juices from organic (ORG) versus conventional (CONV) production. In addition, the anticancer properties of the fermented beetroot juices were evaluated. RESULTS: The obtained results showed that ORG fresh beetroots contained significantly more dry matter, vitamin C and some individual phenolic compounds than CONV beetroots. The content of total phenolic acids was significantly higher in CONV beetroots compared with the ORG ones. The level of flavonoids was similar in ORG and CONV beetroots. There were only slight differences in the chemical composition of ORG and CONV beetroot juices. Metabolomic analysis provided a possibility to distinguish clearly between ORG and CONV fermented beetroot juices. However, this method was less useful in the case of fresh whole beetroots. It was found that anticancer activity was stronger in the case of ORG fermented juices when compared with CONV ones. CONCLUSION: The obtained results indicate that ORG- and CONV-produced beetroots and fermented beetroot juices have different chemical properties and different impacts on cancer cells. It is necessary to continue research on this topic in order to confirm and understand the achieved results. PMID- 24798660 TI - Ultrafast characterization of phase-change material crystallization properties in the melt-quenched amorphous phase. AB - Phase change materials are widely considered for application in nonvolatile memories because of their ability to achieve phase transformation in the nanosecond time scale. However, the knowledge of fast crystallization dynamics in these materials is limited because of the lack of fast and accurate temperature control methods. In this work, we have developed an experimental methodology that enables ultrafast characterization of phase-change dynamics on a more technologically relevant melt-quenched amorphous phase using practical device structures. We have extracted the crystallization growth velocity (U) in a functional capped phase change memory (PCM) device over 8 orders of magnitude (10(-10) < U < 10(-1) m/s) spanning a wide temperature range (415 < T < 580 K). We also observed direct evidence of non-Arrhenius crystallization behavior in programmed PCM devices at very high heating rates (>10(8) K/s), which reveals the extreme fragility of Ge2Sb2Te5 in its supercooled liquid phase. Furthermore, these crystallization properties were studied as a function of device programming cycles, and the results show degradation in the cell retention properties due to elemental segregation. The above experiments are enabled by the use of an on-chip fast heater and thermometer called as microthermal stage (MTS) integrated with a vertical phase change memory (PCM) cell. The temperature at the PCM layer can be controlled up to 600 K using MTS and with a thermal time constant of 800 ns, leading to heating rates ~10(8) K/s that are close to the typical device operating conditions during PCM programming. The MTS allows us to independently control the electrical and thermal aspects of phase transformation (inseparable in a conventional PCM cell) and extract the temperature dependence of key material properties in real PCM devices. PMID- 24798661 TI - Induction of depressive-like effects by subchronic exposure to cocaine or heroin in laboratory rats. AB - The effect of psychoactive drugs on depression has usually been studied in cases of prolonged drug addiction and/or withdrawal, without much emphasis on the effects of subchronic or recreational drug use. To address this issue, we exposed laboratory rats to subchronic regimens of heroin or cocaine and tested long-term effects on (i) depressive-like behaviors, (ii) brain-derived neurotrophic factor (BDNF) levels in reward-related brain regions, and (iii) depressive-like behavior following an additional chronic mild stress procedure. The long-term effect of subchronic cocaine exposure was a general reduction in locomotor activity whereas heroin exposure induced a more specific increase in immobility during the forced swim test. Both cocaine and heroin exposure induced alterations in BDNF levels that are similar to those observed in several animal models of depression. Finally, both cocaine and heroin exposure significantly enhanced the anhedonic effect of chronic mild stress. These results suggest that subchronic drug exposure induces depressive-like behavior which is accompanied by modifications in BDNF expression and increases the vulnerability to develop depressive-like behavior following chronic stress. Implications for recreational and small-scale drug users are discussed. In the present study, we examined the long-term effects of limited subchronic drug exposure on depressive-like symptoms. Our results demonstrate that short-term, subchronic administration of either cocaine or heroin promotes some depressive-like behaviors, while inducing alterations in BDNF protein levels similar to alterations observed in several animal models of depression. In addition, subchronic cocaine or heroin enhanced the anhedonic effect of chronic stress. PMID- 24798662 TI - Favorable outcomes after whole abdominopelvic radiation therapy for pediatric and young adult sarcoma. AB - BACKGROUND: Current Children's Oncology Group (COG) guidelines recommend 24 Gy whole abdominopelvic radiation therapy (WAP-RT) for pediatric patients with sarcoma with peritoneal dissemination and/or malignant ascites. However, WAP-RT has never been described for pediatric sarcoma excluding desmoplastic small round cell tumor (DSRCT). The objective of this study was to evaluate feasibility, outcomes, and toxicity of WAP-RT in children with sarcoma and peritoneal dissemination. PROCEDURE: Detailed records of all 10 pediatric patients with sarcoma (excluding DSRCT) treated with WAP-RT from 2001 to 2013 were reviewed. RESULTS: Median age was 9.9 years (range, 1.7-33.8). Seven patients had rhabdomyosarcoma, 2 embryonal undifferentiated sarcoma of the liver, and 1 Ewing sarcoma. Patients received a median dose of 24 Gy with intensity-modulated radiation therapy (IMRT) to the whole abdomen and pelvis. Two patients did not complete treatment, one due to transfusion-resistant pancytopenia and one due to moderate acute gastrointestinal toxicity. At a median follow-up of 4.0 years, both relapse-free survival and overall survival were 100%. Acute hematologic toxicities were common, with 40% of patients developing a grade 4 hematologic toxicity. Most acute gastrointestinal toxicities were grade 1 and managed appropriately with anti-diarrheals and anti-emetics. Late effects varied, and half of patients are without long-term sequelae. CONCLUSIONS: All patients remain free of disease, both locally and distantly. Although WAP-RT was associated with acute and late toxicity, treatment was feasible with supportive care. Given the excellent rates of tumor control, we recommend that all providers give WAP-RT with IMRT to patients with pediatric sarcoma and peritoneal dissemination and/or malignant ascites. PMID- 24798663 TI - Editorial: All governments should reinforce their commitment to giving all children a healthy start in life. PMID- 24798664 TI - Twin-twin transfusion syndrome . . . or is it? PMID- 24798665 TI - Dilemmas in therapy. PMID- 24798666 TI - Obstetric risks and outcomes of refugee women at a single centre in Toronto. AB - OBJECTIVES: Women who are refugees during pregnancy may be exposed to homelessness, poor nutrition, and limited access to health care, yet the pregnancy outcomes of this vulnerable population have not been systematically evaluated. We undertook a study to determine the risk of adverse obstetric and perinatal outcomes among refugee women in Toronto. METHODS: Using a retrospective cohort design, we examined pregnancy outcomes for refugee and non-refugee women delivering at St. Michael's Hospital in Toronto, between January 1, 2008, and December 31, 2010. The primary outcome measures were preterm delivery (< 37 weeks' gestational age), low birth weight (< 2500 g), and delivery by Caesarean section. RESULTS: Multiparous refugee women had a significantly higher rate of delivery by Caesarean section (36.4%), and a 1.5-fold increase in rate of low birth weight infants when compared with non-refugee women. In subgroup analysis by region of origin, women from Sub-Saharan Africa had significantly higher rates of low birth weight infants and Caesarean section than non-refugee control subjects. Further, compared with non-refugee control subjects, refugee women had significantly increased rates of prior Caesarean section, HIV-positive status, homelessness, social isolation, and delays in accessing prenatal care. CONCLUSIONS: Refugee women constitute a higher-risk population with increased rates of adverse obstetric and perinatal outcomes. These findings provide preliminary data to guide targeted public health interventions towards meeting the needs for obstetric care of this vulnerable population. Recent changes to the Interim Federal Health Program have highlighted the importance of identifying and diminishing disparities in health outcomes between refugee and non-refugee populations. PMID- 24798667 TI - The urinary protein-to-creatinine ratio in Canadian women at risk of preeclampsia: does the time of day of testing matter? AB - OBJECTIVES: To determine the performance of a protein-to-creatinine ratio threshold of 30 mg/mmol in pregnant women investigated for hypertension according to the time of day of the sample. METHODS: This prospective study included ambulatory pregnant women investigated for hypertensive disorders. A single voided random urine specimen was obtained to determine the protein-to-creatinine ratio, followed immediately by a 24-hour urine collection. Statistical analyses included Spearman correlation, sensitivity, specificity, predictive values, likelihood ratios, and receiver-operator characteristic curves with 95% confidence intervals. A P value < 0.05 was considered statistically significant. RESULTS: Among the 91 specimens analyzed, 47.3% showed significant proteinuria in the 24-hour collection and 33% were first morning samples. The protein-to creatinine ratio and 24-hour urinary protein excretion were highly correlated (r = 0.92, P < 0.001). The diagnostic accuracy of the protein-to-creatinine ratio threshold of 30 mg/mmol was lower in first morning samples than in samples obtained during the rest of the day, with sensitivity 58% and 90%, specificity 93% and 100%, positive predictive value 88% and 100%, negative predictive value 72% and 92%, positive likelihood ratio 8 and not calculable, and negative likelihood ratio 0.45 and 0.1, respectively. The receiver-operator characteristic area under the curve was 0.94 (95% CI 0.86 to 1) for first morning samples and 1.0 (95% CI 0.99 to 1) for other samples. CONCLUSION: A protein-to-creatinine ratio threshold of 30 mg/mmol reliably identifies significant proteinuria, but its reliability is reduced in first morning samples. Consequently, such samples should not be used for this purpose. PMID- 24798668 TI - Prediction of preterm birth in multiple pregnancies: development of a multivariable model including cervical length measurement at 16 to 21 weeks' gestation. AB - OBJECTIVE: To develop a multivariable prognostic model for the risk of preterm delivery in women with multiple pregnancy that includes cervical length measurement at 16 to 21 weeks' gestation and other variables. METHODS: We used data from a previous randomized trial. We assessed the association between maternal and pregnancy characteristics including cervical length measurement at 16 to 21 weeks' gestation and time to delivery using multivariable Cox regression modelling. Performance of the final model was assessed for the outcomes of preterm and very preterm delivery using calibration and discrimination measures. RESULTS: We studied 507 women, of whom 270 (53%) delivered < 37 weeks (preterm) and 66 (13%) < 32 weeks (very preterm). Women with cervical length < 30 mm delivered more often preterm (hazard ratio 1.9; 95% CI 0.7 to 4.8). Other independently contributing predictors were previous preterm delivery, monochorionicity, smoking, educational level, and triplet pregnancy. Prediction models for preterm and very preterm delivery had a c-index of 0.68 (95% CI 0.63 to 0.72) and 0.68 (95% CI 0.62 to 0.75), respectively, and showed good calibration. CONCLUSION: In women with a multiple pregnancy, the risk of preterm delivery can be assessed with a multivariable model incorporating cervical length and other predictors. PMID- 24798669 TI - Use of the Papanicolaou test in women under 25 years of age in Southern Alberta. AB - OBJECTIVES: The introduction of the Papanicolaou (Pap) test in Canada has led to a decline in both the incidence of, and mortality from, cervical cancer. However, cervical cancer in women under the age of 25 is rare, and the updated Canadian Task Force on Preventive Health Care recommendations advise against screening by Pap test in this age group. Screening under the age of 25 can lead to false positive results or to treatment of lesions that may spontaneously regress. The purpose of this observational study was to determine how many Pap tests are performed in women less than 25 years of age despite current guidelines. METHODS: Data were obtained from the Laboratory Information System of Calgary Laboratory Services for women under and over the age of 25 who underwent Pap testing between September and December 2012 and between February and May 2013. RESULTS: Approximately 4% of women aged 15 to 19 and 33% of women aged 20 to 24 had Pap tests after the new guidelines were released. CONCLUSION: Women under the age of 25 continue to undergo unnecessary screening for cervical cancer. This excessive screening may cause physical and psychological harm and may result in unnecessary health care expenditures. PMID- 24798670 TI - Persistent genital arousal in women with pelvic and genital pain. AB - OBJECTIVE: Persistent genital arousal disorder (PGAD) has been identified as a condition of often unprovoked genital arousal associated with a significant level of distress. PGAD is not well understood, and no definitive cause has been determined. The aim of this study was to gain a better understanding of the disorder and to seek commonalities between cases of PGAD encountered in a chronic pain management clinic. METHOD: We reviewed a cohort of 15 women with PGAD who presented to a chronic non-cancer pain clinic in a large urban tertiary teaching hospital that provides pelvic and genital pain management. We conducted a series of interviews to examine medical history, history of presenting illness, and management. Descriptive statistics were used to examine the data. RESULTS: Findings were largely consistent with previous research on PGAD regarding symptomatology and aggravating and alleviating factors. Symptoms of genital pain, depression, and interstitial cystitis were found in over one half of the patients in this cohort. Previous antidepressant use, restless legs syndrome, and pudendal neuralgia were found in a number of cases. Pelvic varices and Tarlov cysts have been previously identified as possible contributors to PGAD, but these were not a common finding in our cohort. CONCLUSION: Further research is needed to build on the current understanding of PGAD. Patients should be asked about persistent arousal as part of a sexual and reproductive history, especially in the case of common comorbidities. PMID- 24798671 TI - Do measurements of uterine septum using three-dimensional ultrasound and magnetic resonance imaging agree? AB - OBJECTIVE: To evaluate the agreement between measurements of uterine septum by 3 D ultrasound (3-D US) and magnetic resonance imaging. METHODS: Fourteen women with a uterine septum underwent both a 3-D US and an MRI followed by hysteroscopic metroplasty in a tertiary care infertility clinic within a university teaching hospital. The agreement between 3-D US and MRI measurements of septum length (SL), septum width (SW) and the distance between fundal serosa and septal tip (SSD) was compared using the Bland Altman limit of agreement analysis. RESULTS: 3-D US correctly identified all women who had a uterine septum identified with MRI. The mean difference in SL was 2.7 mm (upper limit of agreement and lower limit of agreement were 10.3 mm and -4.8 mm, respectively). The mean difference in SW was 2.3 mm (upper limit of agreement and lower limit of agreement of 10.4 mm and -9.2 mm, respectively). The SSD mean difference was 2.8 mm (upper limit of agreement and lower limit of agreement of 10.6 mm and -5 mm, respectively). CONCLUSIONS: Categorical agreement in diagnosis was 100% and agreement between 3-D US and MRI measurements was good with narrow differences. Variations were unlikely to be greater than intra- and inter-observer variations anticipated in MRI readings. 3-D US can replace MRI for diagnosis and measurement of uterine septa. PMID- 24798672 TI - Lymphatic injury at sacrocolpopexy: an unusual complication. AB - BACKGROUND: Lymphorrhea is a rare condition with a paucity of reports in the gynaecologic literature. The most frequent causes are invasive procedures and surgical interventions. CASE: A multiparous woman underwent a total abdominal hysterectomy with prophylactic bilateral salpingectomy and abdominal sacrocolpopexy for pelvic organ prolapse. During retroperitoneal dissection, clear fluid discharge was encountered. Ureteric injury was subsequently ruled out. A sample of the fluid was taken to confirm lymphatic injury. Ligation suture and closing the peritoneum slowed fluid drainage. CONCLUSION: To our knowledge, this is the first reported lymphatic injury in association with a urogynaecologic procedure. Gynaecologists should be aware of this potential complication and should have an approach to diagnosis and management. This case highlights the importance of intraoperative consultation. PMID- 24798673 TI - Should doxylamine-pyridoxine be used for nausea and vomiting of pregnancy? AB - Doxylamine-pyridoxine is the first-line agent for the treatment of nausea and vomiting of pregnancy (NVP) according to Canadian guidelines, and this combination is commonly prescribed to pregnant women. There is limited evidence that doxylamine-pyridoxine is more effective than pyridoxine alone. There is stronger support for the safety of pyridoxine monotherapy than for the combination of doxylamine-pyridoxine during pregnancy, and some conflicting evidence links doxylamine-pyridoxine use to pyloric stenosis and childhood malignancies. The role of doxylamine-pyridoxine as the first-line pharmacological treatment for NVP in Canada should be reconsidered. PMID- 24798674 TI - The use of magnetic resonance imaging in the obstetric patient. AB - OBJECTIVE: To review the biological effects and safety of magnetic resonance imaging (MRI) in the obstetric patient and to review procedural issues, indications, and contraindications for obstetrical MRI. OUTCOMES: This guideline is intended to reassure patients and clinicians of the safety of MRI in pregnancy and to provide a framework for its use. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline in 2013 using controlled vocabulary and key words (e.g., MRI, safety, pregnancy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and in French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to July 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: This article is intended to reassure obstetric care providers that if used in an appropriate manner without the use of contrast agents, MRI in the obstetrical patient is safe for mother and fetus in the second and third trimesters. Because obstetrical MRI is expensive and has limited availability in Canada, this clinical guideline is intended to encourage the judicious use of this resource. SUMMARY STATEMENTS: 1. Fetal magnetic resonance imaging is safe at 3.0 tesla or less during the second and third trimesters. (II 2) 2. It is safe to continue breastfeeding after receiving a gadolinium contrast agent. (III) RECOMMENDATIONS: 1. Use of magnetic resonance imaging during the first trimester of pregnancy should be restricted to maternal indications for which the information is considered clinically imperative. Inadvertent exposure to magnetic resonance imaging during the first trimester has not been associated with any long-term sequelae and should not raise clinical concern. (III-C) 2. Gadolinium contrast may be used in pregnant women when the benefits outweigh the potential risks. (III-C). PMID- 24798675 TI - Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study. AB - IMPORTANCE: Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established. OBJECTIVE: To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years. DESIGN, SETTING, AND PARTICIPANTS: The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years. MAIN OUTCOMES AND MEASURES: Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover. RESULTS: During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95% CI, 1.38-3.41]; total hip DXA relative hazard ratio, 1.87 [95% CI, 1.20-2.92]). CONCLUSIONS AND RELEVANCE: Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with fracture risk and cannot be recommended. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00398931. PMID- 24798677 TI - Examining the time course of young and older adults' mimicry of enjoyment and nonenjoyment smiles. AB - Electromyographic (EMG) research suggests that implicit mimicry of happy facial expressions remains intact with age. However, age-related differences in EMG responses to enjoyment and nonenjoyment smiles have not been explored. The present study assessed younger and older adults' orbicularis oculi (O.oculi; eye) and zygomaticus major (Z.major; cheek) reactions to images of individuals displaying enjoyment and nonenjoyment smiles. Both age groups mimicked displays of enjoyment smiles, and there were no age differences in O.oculi and Z.major activity to these expressions. However, compared with younger participants, older adults showed extended O.oculi activity to nonenjoyment smiles. In an explicit ratings task, older adults were also more likely than younger participants to attribute feelings of happiness to individuals displaying both nonenjoyment and enjoyment smiles. However, participants' ratings of the happiness expressed in images of enjoyment and nonenjoyment smiles were independent of their O.oculi responding to these expressions, suggesting that mimicry and emotion recognition may reflect separate processes. Potential mechanisms underlying these findings, as well as implications for social affiliation in older adulthood, are considered. PMID- 24798676 TI - High expression of S100A4 and endoglin is associated with metastatic disease in head and neck squamous cell carcinoma. AB - The presence of cervical metastasis is responsible for high morbidity and mortality rates in individuals with head and neck squamous cell carcinoma (HNSCC). S100A4, a pleiotropic EF-hand calcium-binding protein, is expressed in various normal and cancer cell types. During cancer progression, molecular disturbances in S100A4 can modulate the activity and expression of pre-metastatic and metastatic genes. In this study, we investigated the association between S100A4 methylation status and protein expression as well as the expression of the S100A4 related-proteins annexin A2 (ANXA2), matrix metallopeptidase-9, and endoglin, for metastasis and other clinicopathological parameters in HNSCC. Formalin-fixed, paraffin-embedded blocks of metastatic and non-metastatic HNSCC and matched cervical lymph node (LN) samples (metastatic LN = mLN, non-metastatic = nmLN, and control LN (lymphadenitis) = cLN) were submitted for methylation specific-polymerase chain reaction and immunohistochemistry. Our results showed that S100A4 methylation status failed to demonstrate association with cervical metastasis and other clinicopathological factors related to HNSCC. HNSCC samples from patients that presented with metastatic disease showed high S100A4 and endoglin expression (p < 0.05). In conclusion, molecular disturbances in S100A4 and endoglin expression might regulate the formation of cervical metastasis in HNSCC. PMID- 24798678 TI - Expectancy bias in anxious samples. AB - Although it is well documented that anxious individuals have negative expectations about the future, it is unclear what cognitive processes give rise to this expectancy bias. Two studies are reported that use the Expectancy Task, which is designed to assess expectancy bias and illuminate its basis. This task presents individuals with valenced scenarios (Positive Valence, Negative Valence, or Conflicting Valence), and then evaluates their tendency to expect subsequent future positive relative to negative events. The Expectancy Task was used with low and high trait anxious (Study 1: n = 32) and anxiety sensitive (Study 2: n = 138) individuals. Results suggest that in the context of physical concerns, both high anxious samples display a less positive expectancy bias. In the context of social concerns, high trait anxious individuals display a negative expectancy bias only when negatively valenced information was previously presented. Overall, this suggests that anxious individuals display a less positive expectancy bias, and that the processes that give rise to this bias may vary by type of situation (e.g., social or physical) or anxiety difficulty. PMID- 24798679 TI - Advances in the discovery of N-acylethanolamine acid amidase inhibitors. AB - N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA has been shown to exert analgesic and anti-inflammatory effects by engaging peroxisome proliferator activated receptor-alpha. Like other fatty acid ethanolamides, PEA is not stored in cells, but produced on demand from cell membrane precursors, and its actions are terminated by intracellular hydrolysis by either fatty acid amide hydrolase or NAAA. Endogenous levels of PEA and OEA have been shown to decrease during inflammation. Modulation of the tissue levels of PEA by inhibition of enzymes responsible for the breakdown of this lipid mediator may represent therefore a new therapeutic strategy for the treatment of pain and inflammation. While a large number of inhibitors of fatty acid amide hydrolase have been discovered, few compounds have been reported to inhibit NAAA activity. Here, we describe the most representative NAAA inhibitors and briefly highlight their pharmacological profile. A recent study has shown that a NAAA inhibitor attenuated heat hyperalgesia and mechanical allodynia caused by local inflammation or nerve damage in animal models of pain and inflammation. This finding encourages further exploration of the pharmacology of NAAA inhibitors. PMID- 24798680 TI - Methods to explore the influence of top-down visual processes on motor behavior. AB - Kinesthetic awareness is important to successfully navigate the environment. When we interact with our daily surroundings, some aspects of movement are deliberately planned, while others spontaneously occur below conscious awareness. The deliberate component of this dichotomy has been studied extensively in several contexts, while the spontaneous component remains largely under-explored. Moreover, how perceptual processes modulate these movement classes is still unclear. In particular, a currently debated issue is whether the visuomotor system is governed by the spatial percept produced by a visual illusion or whether it is not affected by the illusion and is governed instead by the veridical percept. Bistable percepts such as 3D depth inversion illusions (DIIs) provide an excellent context to study such interactions and balance, particularly when used in combination with reach-to-grasp movements. In this study, a methodology is developed that uses a DII to clarify the role of top-down processes on motor action, particularly exploring how reaches toward a target on a DII are affected in both deliberate and spontaneous movement domains. PMID- 24798682 TI - Tumor necrosis factor reduces the amplitude of rat cortical spreading depression in vivo. AB - OBJECTIVE: Brain damage and ischemia often trigger cortical spreading depression (CSD), which aggravates brain damage. The proinflammatory cytokine tumor necrosis factor (TNF) is significantly upregulated during brain damage, but it is unknown whether TNF influences spreading depression in cerebral cortex in vivo. This question is important because TNF not only furthers inflammatory reactions but might also be neuroprotective. Here we tested the hypothesis that TNF affects CSD, and we explored the direction in which CSD is modified by TNF. METHODS: CSD, elicited by pressure microinjection of KCl, was recorded in anesthetized rats and mice. TNF was administered locally into a trough, providing local TNF treatment of a cortical area. For further analysis, antibodies to TNF receptor (TNFR) 1 or 2 were applied, or CSD was monitored in TNFR1 and TNFR2 knockout mice. gamma Aminobutyric acid (GABA)A receptors were blocked by bicuculline. Immunohistochemistry localized the cortical expression of TNFR1 and TNFR2. RESULTS: Local application of TNF to the cortex reduced dose-dependently the amplitude of CSD. This effect was prevented by blockade or knockout of TNFR2 but not by blockade or knockout of TNFR1. TNFR2 was localized at cortical neurons including parvalbumin-positive inhibitory interneurons, and blockade of GABAA receptors by bicuculline prevented the reduction of CSD amplitudes by TNF. INTERPRETATION: We identified a functional link between TNF and CSD. TNF activates TNFR2 in cortical inhibitory interneurons. The resulting release of GABA reduces CSD amplitudes. In this manner, TNF might be neuroprotective in pathological conditions. PMID- 24798683 TI - Assessing neurosurgical non-technical skills: an exploratory study of a new behavioural marker system. AB - RATIONALE, AIMS AND OBJECTIVES: The management of non-technical skills is a major factor affecting teamwork quality and patient safety. This article presents a behavioural marker system for assessing neurosurgical non-technical skills (BMS NNTS). We tested the BMS during deep brain stimulation surgery. METHOD: We developed the BMS in three stages. First, we drew up a provisional assessment tool based on the literature and observation tools developed for other surgical specialties. We then analysed videos made in an operating room (OR) during deep brain stimulation operations in order to ensure there were no significant omissions from the skills list. Finally, we used five videos of operations to identify the behavioural markers of non-technical skills in verbal communications. RESULTS: Analyses of more than six hours of observations revealed 3515 behaviours from which we determined the neurosurgeon's non-technical skills behaviour pattern. The neurosurgeon frequently engaged in explicit coordination, situation awareness and leadership behaviours. In addition, the neurosurgeon's behaviours differed according to the stage of the operation and the OR staff members with whom she was communicating. CONCLUSIONS: Our behavioural marker system provides a structured approach to assessing non-technical skills in the field of neurosurgery. It can also be transferred to other surgical specialties and used in surgeon training curricula. PMID- 24798684 TI - Light-duty vehicle CO2 targets consistent with 450 ppm CO2 stabilization. AB - We present a global analysis of CO2 emission reductions from the light-duty vehicle (LDV) fleet consistent with stabilization of atmospheric CO2 concentration at 450 ppm. The CO2 emission reductions are described by g CO2/km emission targets for average new light-duty vehicles on a tank-to-wheel basis between 2010 and 2050 that we call CO2 glide paths. The analysis accounts for growth of the vehicle fleet, changing patterns in driving distance, regional availability of biofuels, and the changing composition of fossil fuels. New light duty vehicle fuel economy and CO2 regulations in the U.S. through 2025 and in the EU through 2020 are broadly consistent with the CO2 glide paths. The glide path is at the upper end of the discussed 2025 EU range of 68-78 g CO2/km. The proposed China regulation for 2020 is more stringent than the glide path, while the 2017 Brazil regulation is less stringent. Existing regulations through 2025 are broadly consistent with the light-duty vehicle sector contributing to stabilizing CO2 at approximately 450 ppm. The glide paths provide long-term guidance for LDV powertrain/fuel development. PMID- 24798681 TI - Pharmacological and toxicological effects of lithium in zebrafish. AB - Lithium is the paradigmatic treatment for bipolar disorder and has been widely used as a mood stabilizer due to its ability to reduce manic and depressive episodes, efficiency in long-term mood stabilization, and effectiveness in reducing suicide risks. Despite many decades of clinical use, the molecular targets of lithium are not completely understood. However, they are credited at least partially to glycogen synthase kinase 3 (GSK3) inhibition, mimicking and exacerbating Wnt signaling pathway activation. There has been a great effort to characterize lithium cellular and system actions, aiming to improve treatment effectiveness and reduce side effects. There is also a growing concern about lithium's impact as an environmental contaminant and its effects on development. In this scenario, zebrafish is a helpful model organism to gather more information on lithium's effects in different systems and developmental stages. The rapid external development, initial transparency, capacity to easily absorb substances, and little space required for maintenance and experimentation, among other advantages, make zebrafish a suitable model. In addition, zebrafish has been established as an effective model organism in behavioral and neuropharmacological studies, reacting to a wide range of psychoactive drugs, including lithium. So far only a limited number of studies evaluated the toxicological impact of lithium on zebrafish development and demonstrated morphological, physiological, and behavioral effects that may be informative regarding human findings. Further studies dedicated to characterize and evaluate the underlying mechanisms of the toxic effects and the potential impact of exposure on developing and adult individuals are necessary to establish safe clinical management guidelines for women with bipolar disorder of childbearing age and safety disposal guidelines for pharmaceutical neuroactive compounds. PMID- 24798685 TI - Assessment of Silent Neuronal Injury Following Coronary Angiography and Intervention in Patients With Acute Coronary Syndrome. AB - The aim of this study is to evaluate the incidence and predictors of silent neuronal injury (SNI) after coronary angiography (CAG) and intervention by serial measurement of serum neuron-specific enolase (NSE) in patients presented with acute coronary syndrome (ACS). Ninety-eight consecutive patients presented with ACS and underwent CAG and intervention were included in the study. The NSE levels significantly increased after CAG and intervention compared to baseline levels (22.03 +/- 27.70 and 10.08 +/- 3.15 consecutively). Left ventricular ejection fraction in the SNI+ group was significantly lower than that in the SNI- group (43.71% +/- 12.51%, 50.84% +/- 9.34%, P = .002). Maximal creatinine kinase myocardial band, troponin I, and SYNTAX score of the SNI+ group were significantly higher than those of the SNI- group (103.83 +/- 99.22, 51.92 +/- 78.33, P = .006; 50.04 +/- 66.18, 19.18 +/- 30.50, P = .002; 103.83 +/- 99.22, 51.92 +/- 78.33, P = .006; and 50.04 +/- 66.18, 19.18 +/- 30.50, P = .002 successively). SYNTAX score and performing percutaneous coronary intervention were the independent predictors of SNI (P = .009, odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.014-1.107, P = .036, OR = 4.262, 95% CI = 1.097 16.56). Percutaneous coronary intervention and coronary artery lesion complexity may increase the risk of SNI in patients with ACS. PMID- 24798687 TI - Area-level factors associated with electronic health record adoption and meaningful use in the Regional Extension Center Program. AB - OBJECTIVE: To identify area-level correlates of electronic health record (EHR) adoption and meaningful use (MU) among primary care providers (PCPs) enrolled in the Regional Extension Center (REC) Program. MATERIALS AND METHODS: County-level data on 2013 EHR adoption and MU among REC-enrolled PCPs were obtained from the Office of the National Coordinator for Health Information Technology and linked with other county-level data sources including the Area Resource File, American Community Survey, and Federal Communications Commission's broadband availability database. Hierarchical models with random intercepts for RECs were employed to assess associations between a broad set of area-level factors and county-level rates of EHR adoption and MU. RESULTS: Among the 2715 counties examined, the average county-level EHR adoption and MU rates for REC-enrolled PCPs were 87.5% and 54.2%, respectively. Community health center presence and Medicaid enrollment concentration were positively associated with EHR adoption, while metropolitan status and Medicare Advantage enrollment concentration were positively associated with MU. Health professional shortage area status and minority concentration were negatively associated with EHR adoption and MU. DISCUSSION: Increased financial incentives in areas with greater concentrations of Medicaid and Medicare enrollees may be encouraging EHR adoption and MU among REC-enrolled PCPs. Disparities in EHR adoption and MU in some low-resource and underserved areas remain a concern. CONCLUSIONS: Federal efforts to spur EHR adoption and MU have demonstrated some early success; however, some geographic variations in EHR diffusion indicate that greater attention needs to be paid to ensuring equitable uptake and use of EHRs throughout the US. PMID- 24798688 TI - Grape seed proanthocyanidins inhibit cigarette smoke condensate-induced lung cancer cell migration through inhibition of NADPH oxidase and reduction in the binding of p22(phox) and p47(phox) proteins. AB - Cigarette smoking is the major cause of lung cancer. It is therefore important to develop effective strategies that target molecular abnormalities induced by cigarette smoke condensate (CSC). Cigarette smoking increases oxidative stress particularly via activation of NADPH oxidase (NOX), a key source of superoxide anion production. Here, we report that grape seed proanthocyanidins (GSPs) exert an inhibitory effect on the CSC-induced migration of non-small cell lung cancer (NSCLC) cells (A549, H460, and H1299). Using an in vitro invasion assay, we found that treatment of NSCLC cells with CSC increased NSCLC cell migration by enhancing NOX mediated-oxidative stress. Treatment of NSCLC cells with GSPs inhibited the CSC-induced cell migration through reduction in oxidative stress levels and a reduction in the epithelial-to-mesenchymal transition. To identify the molecular targets of GSPs, we examined the effects of GSPs on CSC-induced alterations in the levels of key NOX components, namely p22(phox) and p47(phox) proteins, using A549 cells. We also determined the effect of GSPs on CSC-induced interaction/binding between these proteins, which is a key event in NOX activation. We found that treatment of A549 cells with GSPs not only inhibited the CSC-induced increase in the expression levels of p22(phox) and p47(phox) , but also reduced the binding of p22(phox) to p47(phox) proteins. This new insight into the anti-lung cancer cell migration activity of GSPs could serve as a basis for development of improved chemopreventive or therapeutic strategies for lung cancer. PMID- 24798689 TI - Surfactant-based ionic liquids for extraction of phenolic compounds combined with rapid quantification using capillary electrophoresis. AB - A rapid liquid phase extraction employing a novel hydrophobic surfactant-based room temperature ionic liquid (RTIL), tetrabutylphosphonium dioctyl sulfosuccinate ([4C4 P][AOT]), coupled with capillary electrophoretic-UV (CE-UV) detection is developed for removal and determination of phenolic compounds. The long-carbon-chain RTIL used is sparingly soluble in most solvents and can be used to replace volatile organic solvents. This fact, in combination with functional surfactant-anions, is proposed to reduce the interfacial energy of the two immiscible liquid phases, resulting in highly efficient extraction of analytes. Several parameters that influence the extraction efficiencies, such as extraction time, RTIL type, pH value, and ionic strength of aqueous solutions, were investigated. It was found that, under acidic conditions, most of the investigated phenols were extracted from aqueous solution into the RTIL phase within 12 min. Good linearity was observed over the concentration range of 0.1 80.0 MUg/mL for all phenols investigated. The precision of this method, expressed as RSD, was determined to be within 3.4-5.3% range. The LODs (S/N = 3) of the method were in the range of 0.047-0.257 MUg/mL. The proposed methodology was successfully applied to determination of phenols in real water samples. PMID- 24798686 TI - Outcomes in neurosurgical patients who develop venous thromboembolism: a review of the RIETE registry. AB - OBJECTIVES: Registro Informatizado de Enfermedad TromboEmbolica (RIETE) database was used to investigate whether neurosurgical patients with venous thromboembolism (VTE) were more likely to die of bleeding or VTE and the influence of anticoagulation on these outcomes. METHODS: Clinical characteristics, treatment details, and 3-month outcomes were assessed in those who developed VTE after neurosurgery. RESULTS: Of 40 663 patients enrolled, 392 (0.96%) had VTE in less than 60 days after neurosurgery. Most patients in the cohort (89%) received initial therapy with low-molecular-weight heparin, (33% received subtherapeutic doses). In the first week, 10 (2.6%) patients died (8 with pulmonary embolism [PE], no bleeding deaths; P = .005). After the first week, 20 (5.1%) patients died (2 with fatal bleeding, none from PE). Overall, this cohort was more likely to develop a fatal PE than a fatal bleed (8 vs 2 deaths, P = .058). CONCLUSIONS: Neurosurgical patients developing VTE were more likely to die from PE than from bleeding in the first week, despite anticoagulation. PMID- 24798691 TI - Gender transitions in later life: the significance of time in queer aging. AB - Concepts of time are ubiquitous in studies of aging. This article integrates an existential perspective on time with a notion of queer time based on the experiences of older transgender persons who contemplate or pursue a gender transition in later life. Interviews were conducted with male-to-female identified persons aged 50 years or older (N = 22), along with participant observation at three national transgender conferences (N = 170 hr). Interpretive analyses suggest that an awareness of "time left to live" and a feeling of "time served" play a significant role in later life development and help expand gerontological perspectives on time and queer aging. PMID- 24798693 TI - Hole removal rate limits photodriven H2 generation efficiency in CdS-Pt and CdSe/CdS-Pt semiconductor nanorod-metal tip heterostructures. AB - Semiconductor-metal nanoheterostructures, such as CdSe/CdS dot-in-rod nanorods with a Pt tip at one end (or CdSe/CdS-Pt), are promising materials for solar-to fuel conversion because they allow rational integration of a light absorber, hole acceptor, and electron acceptor or catalyst in an all-inorganic triadic heterostructure as well as systematic control of relative energetics and spatial arrangement of the functional components. To provide design principles of such triadic nanorods, we examined the photocatalytic H2 generation quantum efficiency and the rates of elementary charge separation and recombination steps of CdSe/CdS Pt and CdS-Pt nanorods. We showed that the steady-state H2 generation quantum efficiencies (QEs) depended sensitively on the electron donors and the nanorods. Using ultrafast transient absorption spectroscopy, we determined that the electron transfer efficiencies to the Pt tip were near unity for both CdS and CdSe/CdS nanorods. Hole transfer rates to the electron donor, measured by time resolved fluorescence decay, were positively correlated with the steady-state H2 generation QEs. These results suggest that hole transfer is a key efficiency limiting step. These insights provide possible ways for optimizing the hole transfer step to achieve efficient solar-to-fuel conversion in semiconductor metal nanostructures. PMID- 24798692 TI - Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells. AB - The promise of PARP-inhibitors(PARPis) in the management of epithelial ovarian cancer(EOC) is tempered by the fact that approximately 50% of patients with homologous recombination (HR)-proficient tumors do not respond well to these agents. Combination of PARPis with agents that inhibit HR may represent an effective strategy to enhance their activity in HR-proficient tumors. Using a bioinformatics approach, we identified that heat shock protein 90 inhibitors(HSP90i) may suppress HR and thus revert HR-proficient to HR-deficient tumors. Analysis of publicly available gene expression data showed that exposure of HR-proficient breast cancer cell lines to HSP90i 17-AAG(17-allylamino-17 demethoxygeldanamycin) downregulated HR, ATM and Fanconi Anemia pathways. In HR proficient EOC cells, 17-AAG suppressed HR as assessed using the RAD51 foci formation assay and this was further confirmed using the Direct Repeat-GFP reporter assay. Furthermore, 17-AAG downregulated BRCA1 and/or RAD51 protein levels, and induced significantly more gammaH2AX activation in combination with olaparib compared to olaparib alone. Finally, sublethal concentrations of 17-AAG sensitized HR-proficient EOC lines to olaparib and carboplatin but did not affect sensitivity of the HR-deficient OVCAR8 line arguing that the 17-AAG mediated sensitization is dependent on suppression of HR. These results provide a preclinical rationale for using a combination of olaparib/17-AAG in HR-proficient EOC. PMID- 24798694 TI - CD81 is required for rhoptry discharge during host cell invasion by Plasmodium yoelii sporozoites. AB - Plasmodium sporozoites are transmitted by Anopheles mosquitoes and first infect the liver of their mammalian host, where they develop as liver stages before the onset of erythrocytic infection and malaria symptoms. Sporozoite entry into hepatocytes is an attractive target for anti-malarial prophylactic strategies but remains poorly understood at the molecular level. Apicomplexan parasites invade host cells by forming a parasitophorous vacuole that is essential for parasite development, a process that involves secretion of apical organelles called rhoptries. We previously reported that the host membrane protein CD81 is required for infection by Plasmodium falciparum and Plasmodium yoelii sporozoites. CD81 acts at an early stage of infection, possibly at the entry step, but the mechanisms involved are still unknown. To investigate the role of CD81 during sporozoite entry, we generated transgenic P. yoelii parasites expressing fluorescent versions of three known rhoptry proteins, RON2, RON4 and RAP2/3. We observed that RON2 and RON4 are lost following rhoptry discharge during merozoite and sporozoite entry. In contrast, our data indicate that RAP2/3 is secreted into the parasitophorous vacuole during infection. We further show that sporozoite rhoptry discharge occurs only in the presence of CD81, providing the first direct evidence for a role of CD81 during sporozoite productive invasion. PMID- 24798695 TI - PARK13 regulates PINK1 and subcellular relocation patterns under oxidative stress in neurons. AB - Parkinson's disease (PD) is a progressive and irreversible neurodegenerative disorder coupled to selective degeneration of dopamine-producing neurons in the substantia nigra. The majority of PD incidents are sporadic, but monogenic cases account for 5-10% of cases. Mutations in PINK1 cause autosomal recessive forms of early-onset PD, and PINK1 stimulates Omi/HtrA2/PARK13 protease activity when both proteins act as neuroprotective components in the same stress pathway. Studies on PINK1 and PARK13 have concentrated on phosphorylation-dependent PINK1-mediated activation of PARK13 and mitochondrial functions, because both proteins are classically viewed as mitochondrial. Although PARK13-mediated protective mechanisms are at least in part regulated by PINK1, little is known concerning how these two proteins are regulated in different subcellular compartments or, indeed, the influence of PARK13 on PINK1 characteristics. We show that PARK13 localizes to a variety of subcellular locations in neuronal cells and that PINK1, although more restrictive, also localizes to locations other than those previously reported. We demonstrate that PARK13 accumulation leads to a concomitant accumulation of PINK1 and that the increase in PINK1 levels is compartmental specific, indicating a correlative relationship between the two proteins. Moreover, we show that PARK13 and PINK1 protein levels accumulate in response to H2 O2 and L-DOPA treatments in a subcellular fashion and that both proteins show relocation to the cytoskeleton in response to H2 O2 . This H2 O2 mediated relocation is abolished by PARK13 overexpression. This study shows that PARK13 and PINK1 are subcellular-specific, but dynamic, proteins with a reciprocal molecular relationship providing new insight into the complexity of PD. PMID- 24798696 TI - Subarachnoid hemorrhage prevalence and its association with short-term outcome in pediatric severe traumatic brain injury. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) is an independent prognostic indicator of outcome in adult severe traumatic brain injury (sTBI). There is a paucity of investigations on SAH in pediatric sTBI. The goal of this study was to determine in pediatric sTBI patients SAH prevalence, associated factors, and its relationship to short-term outcome. METHODS: We retrospectively analyzed 171 sTBI patients (pre-sedation GCS <=8 and head MAIS >=4) who underwent CT head imaging within the first 24 h of hospital admission. Data were analyzed with both univariate and multivariate techniques. RESULTS: SAH was found in 42 % of sTBI patients (n = 71/171), and it was more frequently associated with skull fractures, cerebral edema, diffuse axonal injury, contusion, and intraventricular hemorrhage (p < 0.05). Patients with SAH had higher Injury Severity Scores (p = 0.032) and a greater frequency of fixed pupil(s) on admission (p = 0.001). There were no significant differences in etiologies between sTBI patients with and without SAH. Worse disposition occurred in sTBI patients with SAH, including increased mortality (p = 0.009), increased episodes of central diabetes insipidus (p = 0.002), greater infection rates (p = 0.002), and fewer ventilator-free days (p = 0.001). In sTBI survivors, SAH was associated with increased lengths of stay (p < 0.001) and a higher level of care required on discharge (p = 0.004). Despite evidence that SAH is linked to poorer outcomes on univariate analyses, multivariate analysis failed to demonstrate an independent association between SAH and mortality (p = 0.969). CONCLUSION: SAH was present in almost half of pediatric sTBI patients, and it was indicative of TBI severity and a higher level of care on discharge. SAH in pediatric patients was not independently associated with increased risk of mortality. PMID- 24798698 TI - Structural and functional models in molybdenum and tungsten bioinorganic chemistry: description of selected model complexes, present scenario and possible future scopes. AB - A brief description about some selected model complexes in molybdenum and tungsten bioinorganic chemistry is provided. The synthetic strategies involved and their limitations are discussed. Current status of molybdenum and tungsten bioinorganic modeling chemistry is presented briefly and synthetic problems associated therein are analyzed. Possible future directions which may expand the scope of modeling chemistry are suggested. PMID- 24798697 TI - Enantioselective copper-catalyzed carboetherification of unactivated alkenes. AB - Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper catalyzed cyclization of gamma-unsaturated pentenols which terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition-state calculations support a cis-oxycupration stereochemistry determining step. PMID- 24798703 TI - From sparse to dense and from assortative to disassortative in online social networks. AB - Inspired by the analysis of several empirical online social networks, we propose a simple reaction-diffusion-like coevolving model, in which individuals are activated to create links based on their states, influenced by local dynamics and their own intention. It is shown that the model can reproduce the remarkable properties observed in empirical online social networks; in particular, the assortative coefficients are neutral or negative, and the power law exponents gamma are smaller than 2. Moreover, we demonstrate that, under appropriate conditions, the model network naturally makes transition(s) from assortative to disassortative, and from sparse to dense in their characteristics. The model is useful in understanding the formation and evolution of online social networks. PMID- 24798704 TI - Anti-CD44 mAb for the treatment of B-cell chronic lymphocytic leukemia and other hematological malignancies: evaluation of WO2013063498. AB - INTRODUCTION: The CD44 transmembrane glycoprotein family mediates cellular responses to the microenvironment through binding of hyaluronic acid (HA) and other proteins of the extracellular matrix. These interactions start intracellular signaling cascades that foster tumor growth, survival and spread. AREAS COVERED: The patent concerns the use of a humanized anti-CD44 mAb (RG7356) to treat patients with aggressive forms of chronic lymphocytic leukemia (CLL). The RG7356 humanized antibody was designed to bind the constant region of CD44, preventing binding with HA. The interruption of this circuit in vitro is followed by the induction of caspase-dependent apoptosis in leukemic cells. In agreement with a functional association between CD44 and zeta-associated protein of 70 kDa (ZAP-70) in activating intracellular signaling, the strongest effects were observed in ZAP-70(+) CLL cells, generally associated to a poor prognosis. Furthermore, these effects were confirmed using in vivo models, where CLL cells were xenografted in immunocompromised mice. EXPERT OPINION: In summary, these studies suggest that this new humanized mAb may provide additional clinical benefit to CLL patients receiving current standard treatments, specifically to those with a more aggressive disease. PMID- 24798706 TI - Implementation of a reference interferometer for nanodetection. AB - A thermally and mechanically stabilized fiber interferometer suited for examining ultra-high quality factor microcavities is fashioned. After assessing its free spectral range (FSR), the module is put in parallel with a fiber taper microcavity system and then calibrated through isolating and eliminating random shifts in the laser frequency (i.e. laser jitter noise). To realize the taper microcavity junction and to maximize the optical power that is transferred to the resonator, a single-mode optical fiber waveguide is pulled. Solutions containing polystyrene nanobeads are then prepared and flown to the microcavity in order to demonstrate the system's ability to sense binding to the surface of the microcavity. Data is post-processed via adaptive curve fitting, which allows for high-resolution measurements of the quality factor as well as the plotting of time-dependent parameters, such as resonant wavelength and split frequency shifts. By carefully inspecting steps in the time-domain response and shifting in the frequency-domain response, this instrument can quantify discrete binding events. PMID- 24798705 TI - Pregnancy-induced changes in ultradian rhythms persist in circadian arrhythmic Siberian hamsters. AB - The impact of pregnancy and lactation on ultradian rhythms (URs) and circadian rhythms (CRs) of locomotor activity was assessed in circadian rhythmic and arrhythmic Siberian hamsters maintained in a long-day photoperiod (16h light/day). Progressive decrements in CR robustness and amplitude over the course of gestation were accompanied by enhanced URs. Dark-phase UR period and amplitude increased during early gestation and complexity and robustness increased during late gestation. The persistence of pregnancy-associated enhancements of URs in circadian arrhythmic (ARR) hamsters suggests that reproductive modulation of the UR waveform is not dependent on coherent circadian organization. The increased incidence of dark-phase URs appeared more rapidly in ARR dams than entrained (ENTR) dams. Throughout gestation, the percentage of dams with dark-phase URs was significantly greater in the ARR group. Gestational increases in UR complexity and robustness emerged earlier and were greater in ARR than ENTR dams. The attenuation of CRs during lactation is correlated with increased expression of URs. Relaxation of circadian control of the dam's behavior may increase fitness by permitting more efficient interactions with circadian arrhythmic pups. PMID- 24798707 TI - Antihypertensive and anti-inflammatory actions of combined azilsartan and chlorthalidone in Dahl salt-sensitive rats on a high-fat, high-salt diet. AB - Metabolic syndrome (MetS) and chronic kidney disease are global health issues. Metabolic syndrome induces hypertension and commonly results in renal damage. The optimal therapy for hypertension in MetS is unknown. Thiazide diuretics are first line therapy; however, these drugs may have untoward effects. In the present study we investigated the effects of azilsartan (AZL), chlorthalidone (CLTD) and their combination on blood pressure and renal injury in a rodent model with features of MetS. Dahl salt-sensitive rats were fed high-fat (36% fat), high-salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg per day), CLTD (5 mg/kg per day) or AZL + CLTD. Mean arterial pressure was recorded continuously by telemetry. After 26 days, rats were killed humanely and their kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared with vehicle and the combination further reduced blood pressure compared with CLTD alone. All treatments reduced proteinuria and albuminuria. Nephrinuria was prevented only in groups treated with AZL. Nephrinuria was 57% lower and proteinuria was 47% lower with combination therapy compared with AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. Treatment with AZL offers additional protection, as evidenced by lower nephrinuria and plasma monocyte chemoattractant protein-1 levels. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in MetS. PMID- 24798709 TI - Flash visual evoked potentials are not specific enough to identify parieto occipital lobe involvement in term neonates after significant hypoglycaemia. AB - AIM: Hypoglycaemia is a significant problem in high-risk neonates and predominant parieto-occipital lobe involvement has been observed after severe hypoglycaemic insult. We explored the use of flash visual evoked potentials (FVEP) in detecting parieto-occipital lobe involvement after significant hypoglycaemia. METHODS: Full term neonates (n = 15) who underwent FVEP from January 2008 to May 2013 were compared with infants (n = 11) without hypoglycaemia or parietal-occipital lobe injury. Significant hypoglycaemia was defined as being symptomatic or needing steroids, glucagon or a glucose infusion rate of >=12 mg/kg/min. RESULTS: The hypoglycaemia group exhibited delayed latency of the first positive waveform on FVEP. The initial detected time for hypoglycaemia was later in the eight subjects with seizures (median 51-h-old) than those without (median 22-h-old) (P = 0.003). Magnetic resonance imaging showed that 80% of the hypoglycaemia group exhibited occipital-lobe injuries, and they were more likely to exhibit abnormal FVEP morphology (P = 0.007) than the controls. FVEP exhibited 100% sensitivity, but only 25% specificity, for detecting injuries to the parieto-occipital lobes. CONCLUSION: Flash visual evoked potential (FVEP) was sensitive, but not sufficiently specific, in identifying parieto-occipital lobe injuries among term neonates exposed to significant hypoglycaemia. Larger studies exploring the potential role of FVEP in neonatal hypoglycaemia are required. PMID- 24798708 TI - Cell-penetrating, guanidinium-rich molecular transporters for overcoming efflux mediated multidrug resistance. AB - Multidrug resistance (MDR) is a major cause of chemotherapy failure in the clinic. Drugs that were once effective against naive disease subsequently prove ineffective against recurrent disease, which often exhibits an MDR phenotype. MDR can be attributed to many factors; often dominating among these is the ability of a cell to suppress or block drug entry through upregulation of membrane-bound drug efflux pumps. Efflux pumps exhibit polyspecificity, recognizing and exporting many different types of drugs, especially those whose lipophilic nature contributes to residence in the membrane. We have developed a general strategy to overcome efflux-based resistance. This strategy involves conjugating a known drug that succumbs to efflux-mediated resistance to a cell-penetrating molecular transporter, specifically, the cell-penetrating peptide (CPP), d-octaarginine. The resultant conjugates are discrete single entities (not particle mixtures) and highly water-soluble. They rapidly enter cells, are not substrates for efflux pumps, and release the free drug only after cellular entry at a rate controlled by linker design and favored by target cell chemistry. This general strategy can be applied to many classes of drugs and allows for an exceptionally rapid advance to clinical testing, especially of drugs that succumb to resistance. The efficacy of this strategy has been successfully demonstrated with Taxol in cellular and animal models of resistant cancer and with ex vivo samples from patients with ovarian cancer. Next generation efforts in this area will involve the extension of this strategy to other chemotherapeutics and other MDR-susceptible diseases. PMID- 24798710 TI - Safe and effective use of medicines for patients with type 2 diabetes - A randomized controlled trial of two interventions delivered by local pharmacies. AB - BACKGROUND: Poor management of chronic medical treatments may result in severe health consequences for patients as well as costs for society. Non-adherence is common among patients with type 2 diabetes. Interventions by community pharmacists may assist in improving adherence and consequently health outcomes for patients with type 2 diabetes. OBJECTIVES: The study aimed to investigate whether a comprehensive and a brief individually targeted intervention for patients with type 2 diabetes could improve implementation of drug therapy in Danish community pharmacies. The interventions intended to give patients more competence and support to improve adherence and self-management in order to reach treatment goals for diabetes and blood pressure as well as goals for patient perceived outcomes. METHODS: This study was an RCT, comparing two interventions; basic intervention (BI) and extended intervention (EI). The intervention model sought to identify drug-related problems as well as issues experienced by patients in relation to medicines use, and consequently find individually tailored solutions to address the identified problems. RESULTS: The trial included five pharmacies; five pharmacists and five pharmaconomists, and 205 patients; BI (39 patients), EI (41 patients), Control (125 patients). Patient reported systolic blood pressure improved in both groups and significantly in the EI group compared to the control group (P = 0.020). Increase in disease-related knowledge was higher in the EI group compared to the control group (P = 0.006), but not in the BI group (P = 0.139). Except for quality of life, the EI group reported significantly higher improvement in all aspects of beneficial effects from participating in the trial when compared to the control group. No significant differences were detected for changes in hospital admissions or in doctor visits. The two intervention groups reported significantly higher satisfaction with all aspects of patient satisfaction with pharmacy staff in the project than control patients. CONCLUSIONS: The study showed improvement in patient health, well-being, knowledge, and satisfaction as a result of the trial, particularly for the EI group. Thus a program comprising patient narratives, problem and resource identification, and multi-dimensional individually tailored patient medication management solutions seems to be an appropriate intervention to ensure outcome improvement of non-adherent patients. PMID- 24798711 TI - Current situation of the pharmacogenetics of immune recovery in treated HIV infected patients. PMID- 24798712 TI - Role of ALDH5A1 in methadone treatment. PMID- 24798714 TI - Research Highlights: highlights from the latest articles focusing on a new gene set for better drug response prediction of epilepsy patients. PMID- 24798715 TI - Cleveland Clinic's Center for personalized healthcare: setting the stage for value-based care. AB - Cleveland Clinic (OH, USA) launched the Center for Personalized Healthcare in 2011 to establish an evidence-based system for individualizing care by incorporating unique patient characteristics, including but not limited to genetic and family health history information, into the standard medical decision making process. Using MyFamily, a web-based tool integrated into our electronic health record, a patient's family health history is used as a surrogate for genetic, environmental and behavioral risks to identify those with an elevated probability of developing disease. Complementing MyFamily, the Personalized Medication Program was created for the purpose of identifying gene-drug pairs for integration into clinical practice and developing the implementation tools needed to incorporate pharmacogenomics into the clinical workflow. We have successfully implemented the gene-drug pairs HLA-B*57:01-abacavir and TPMT-thiopurines into patient care. Our efforts to establish personalized medical care at Cleveland Clinic may serve as a model for large-scale integration of personalized healthcare. PMID- 24798716 TI - Pharmacogenomics: from cell to clinic (Part 1). AB - The second international European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. The first part of this Conference Scene will focus on the pharmacogenomics and biomarkers used in medical oncology, and in particular solid tumors. In addition, this article covers the two keynote conference introductory lectures by Ann K Daly and Magnus Ingelman-Sundberg. The second part of this article will discuss the clinical implementation of pharmacogenomic tests; the role of transports and pharmacogenomics; how stem cells and other new tools are helping the development of pharmacogenomics and drug discovery; and an update on the clinical translation of pharmacogenomics to personalized medicine. Part two of this Conference Scene will be featured in the next issue of Pharmacogenomics. PMID- 24798717 TI - Future of pharmacogenetics-based therapy for tuberculosis. AB - Personalized medicine uses technology to enable a level of personalization not previously practical. Currently, tuberculosis (TB) therapy is not personalized. Previous reports have shown that a genetic polymorphism of NAT2 is associated with large interindividual and inter-racial differences in the toxicity and efficacy of isoniazid. Herein, we show the safety and efficacy of a pharmacogenetics-based standard TB therapy and also provide a schematic presentation that proposed therapeutic approaches for latent TB infection (LTBI) using NAT2 genotyping. Our data show that the pharmacogenetics-based TB therapy is safer and more efficacious than the standard therapy. Therefore, the therapy using NAT2 genotyping proposed for LTBI herein will be safer and more efficacious than the standard LTBI therapy. Introduction of this therapy with NAT2 genotyping will be one of the cornerstones of personalized medicine. PMID- 24798718 TI - A polymorphism in the promoter is associated with EZH2 expression but not with outcome in advanced pancreatic cancer patients. AB - AIM: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. MATERIALS & METHODS: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). RESULTS: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. CONCLUSION: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC. PMID- 24798719 TI - TNF-alpha SNP rs1800629 and risk of relapse in childhood acute lymphoblastic leukemia: relation to immunophenotype. AB - AIM: In the AIEOP-BFM ALL (Associazione Italiana Ematologia Oncologia Pediatrica Berlin Frankfurt Munster acute lymphoblastic leukemia) 2000 protocol, 70% of relapsed patients had favorable prognostic features and fell within less intensive polychemotherapeutic regimens, suggesting the need for better assessing lower risk stratification. MATERIALS & METHODS: A novel two-phase study design selected 614 children to be genotyped for TNF-alpha SNP rs1800629 (-308G>A). A weighted Cox model was applied to evaluate the SNP effect on hazard of relapse, adjusting for immunophenotype, risk group, age and gender and including interaction terms. RESULTS: Significant interaction was found with immunophenotypes (p = 0.0007, with minor allele genotypes being adverse genetic markers in B-cell acute lymphoblastic leukemia and protective ones in T-cell acute lymphoblastic leukemia), and also with risk protocols (p = 0.0041, with minor allele genotypes as prognostic factor of relapse for standard risk patients [only one T-cell acute lymphoblastic leukemia in the subgroup analyzed]). CONCLUSION: The presence of at least one A allele in TNF-alpha SNP rs1800629 should suggest a closer monitoring in B-cell acute lymphoblastic leukemia standard risk patients. PMID- 24798720 TI - Identification of gene signatures for prednisolone-induced metabolic dysfunction in collagen-induced arthritic mice. AB - BACKGROUND: Prednisolone is a potent anti-inflammatory glucocorticoid (GC) but chronic use is hampered by metabolic side effects. Little is known about the long term effects of GCs on gene-expression in vivo during inflammation. AIM: Identify gene signatures underlying prednisolone-induced metabolic side effects in a complex in vivo inflammatory setting after long-term treatment. MATERIALS & METHODS: We performed whole-genome expression profiling in liver and muscle from arthritic and nonarthritic mice treated with several doses of prednisolone for 3 weeks and used text-mining to link gene signatures to metabolic pathways. RESULTS: Prednisolone-induced gene signatures were highly tissue specific. We identified a short-list of genes significantly affected by both prednisolone and inflammation in liver and involved in glucose and fatty acid metabolism. For several of these genes the association with GCs is novel. CONCLUSION: The identified gene signatures may provide useful starting points for the development of GCs with a better safety profile. PMID- 24798721 TI - Pharmacogenetic landscape of clopidogrel in north Indians suggest distinct interpopulation differences in allele frequencies. AB - AIM: Clopidogrel, a widely used antiplatelet drug, exhibits high interindividual variability; more than 80% of which could be explained by genetic polymorphisms. We built an allele frequency map of variants affecting clopidogrel response in north Indians. MATERIALS & METHODS: We mined a cross-sectional population-scale genome-wide dataset of 2128 Indo-Europeans residing in north India for presence of variants associated with pharmacogenetics of clopidogrel. RESULTS: Our analysis reveals significant differences in population-scale allele frequencies between Indians and the global population. Indians had a higher allele frequency for variants in the CYP2C9*2, CYP2C9*3 and P2RY1 genes whereas lower frequency for the ABCB1, CYP1A2, CYP2C19*2C, CYP3A5 and PON1 genes compared with the global population. Furthermore, from our study we proposed a model to explain the higher prevalence of clopidogrel metabolizers in north Indians. CONCLUSION: This is the largest population-scale genetic epidemiology study that provides a high resolution map of variants associated with clopidogrel response that could be potentially valuable to clinicians to rationally plan appropriate dosage for therapy in resource poor conditions based on population level allele frequencies. PMID- 24798722 TI - How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genotyping. AB - AIM: Drug-drug interactions (DDIs) are a widely recognized major cause of adverse drug reactions, but two other newly described important types of interactions also exist: drug-gene interactions (DGIs) and drug-drug-gene interactions (DDGIs). A drug-gene interaction occurs when a patient's genetic CYP450 type (e.g., CYP2D6 poor metabolizer) affects that patient's ability to clear a drug. A drug-drug-gene interaction occurs when the patient's CYP450 genotype and another drug in the patient's regimen (e.g., a CYP2D6 inhibitor) affect that individual's ability to clear a drug. Their prevalence has not been previously described. This pilot study investigates the frequency of DDIs, DGIs and DDGIs in a sample of CYP450 tested individuals. MATERIALS & METHODS: The investigators conducted a retrospective analysis of 1143 individuals with known CYP2D6, CYP2C19 and CYP2C9 genotypes. Using the individuals' medication lists and YouScript((r)), a software tool to analyze cumulative DDIs and DGIs, the prevalence of DDI, DGI and DDGIs was analyzed. RESULTS: A total of 1053 potential major or substantial interactions were identified in 501 individuals. DDIs accounted for 66.1% of the total interactions. The remaining 33.9% of interactions were DGIs (14.7%) and DDGIs (19.2%). When compared with DDIs alone, DGIs and DDGIs increased the total number of potentially clinically significant interactions by 51.3%. CONCLUSION: In the future, identifying DGIs and DDGIs may lead to a more comprehensive method of identifying individuals who are at risk for adverse drug reactions. PMID- 24798723 TI - MDR1 gene polymorphisms and imatinib response in chronic myeloid leukemia: a meta analysis. AB - BACKGROUND: MDR1 gene polymorphisms were demonstrated to be associated with interindividual variability of imatinib response for chronic myeloid leukemia (CML) patients in several studies; however, the results have been inconclusive. MATERIALS & METHODS: To clarify the effect of common MDR1 variants on clinical response to imatinib, we performed a meta-analysis to quantify the accumulated information from genetic association studies. After a thorough search of the published literature, we undertook a meta-analysis to evaluate the effect of MDR1 C1236T, G2677T and C3435T polymorphisms on imatinib response. RESULTS: Our pooled data showed a significant association between MDR1 C1236T polymorphism and the increasing risk of imatinib resistance in Asian CML patients. However, no significant association was found for the MDR1 G2677T or C3435T polymorphisms in an Asian CML population as well as a Caucasian CML population. CONCLUSION: The synonymous MDR1 C1236T polymorphism might be a risk factor for nonoptimal clinical response to imatinib in Asian CML patients. PMID- 24798725 TI - Towards a personalized treatment in depression: endocannabinoids, inflammation and stress response. AB - The complex nature of depression is mirrored by difficulties in tailoring its treatment. Key underlying mechanisms of this mental disorder include elevated inflammation and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. More recently, the endocannabinoid system has been proposed as another important component in the pathogenesis of depression, and strong evidence suggests that all three systems communicate with each other. A growing number of genetic studies have investigated polymorphisms in depression in each of these systems separately. However, no study to date has looked at these genes in conjunction. In this article we will review the crosstalk between the endocannabinoid system, immune system and HPA axis; and discuss the evidence of gene polymorphisms and their relation to the risk of depression and its treatment. We propose future directions where genes of these three systems are considered from a joint perspective to improve prediction of treatment response, taking into account potentially overlooked genetic variations. PMID- 24798724 TI - Comparative pharmacogenetics of multiple sclerosis: IFN-beta versus glatiramer acetate. AB - Various diseases require the selection of preferable treatment out of available alternatives. Multiple sclerosis (MS), an autoimmune inflammatory/neurodegenerative disease of the CNS, requires long-term medication with either specific disease-modifying therapy (DMT) - IFN-beta or glatiramer acetate (GA) - which remain the only first-line DMTs in all countries. A significant share of MS patients are resistant to treatment with one or the other DMT; therefore, the earliest choice of preferable DMT is of particular importance. A number of conventional pharmacogenetic studies performed up to the present day have identified the treatment-sensitive genetic biomarkers that might be specific for the particular drug; however, the suitable biomarkers for selection of one or another first-line DMT are remained to be found. Comparative pharmacogenetic analysis may allow the identification of the discriminative genetic biomarkers, which may be more informative for an a priori DMT choice than those found in conventional pharmacogenetic studies. The search for discriminative markers of preferable first-line DMT, which differ in carriage between IFN-beta responders and GA responders as well as between IFN-beta nonresponders and GA nonresponders, has been performed in 253 IFN-beta-treated MS patients and 285 GA-treated MS patients. A bioinformatics algorithm for identification of composite biomarkers (allelic sets) was applied on a unified set of immune-response genes, which are relevant for IFN-beta and/or GA modes of action, and identical clinical criteria of treatment response. We found the range of discriminative markers, which include polymorphic variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes, in different combinations. Every allelic set includes the CCR5 genetic variant, which probably suggests its crucial role in the modulation of the DMT response. Special attention should be given to the (CCR5*d+ IFNAR1*G) discriminative combination, which clearly points towards IFN-beta treatment choice for carriers of this combination. As a whole the comparative approach provides an option for the identification of prognostic composite biomarkers for a preferable medication among available alternatives. PMID- 24798726 TI - Epigenetic perspectives on cancer chemotherapy response. AB - Epigenetic programs are now widely recognized as being critical to the biological processes of cancer genesis. However, it has not been comprehensively understood how and to what degree they can influence anticancer drugs responses. The development of drugs targeting epigenetic regulation has generated great enthusiasm, with a growing number in clinical development. We highlight here that epigenetic modifications can be involved in the regulation of genes responsible for the absorption, distribution, metabolism and excretion of drugs and for the pathological progression of cancer, thereby affecting anticancer drug responses. The major epigenetic regulatory mechanisms are reviewed, including DNA methylation, miRNA regulation and histone modification, with the aim of promoting rational use of anticancer drugs in the clinic and epigenetic drug development. PMID- 24798728 TI - Telomere length varies by DNA extraction method: implications for epidemiologic research--response. PMID- 24798729 TI - Telomere length varies by DNA extraction method: implications for epidemiologic research-letter. PMID- 24798730 TI - 31P RINEPT MRSI and VBM reveal alterations in brain aging associated with major depression. AB - PURPOSE: Phosphomono- and diesters, the major components of the choline peak in (1) H magnetic resonance spectroscopy, are associated with membrane anabolic and catabolic mechanisms. With the refocused insensitive nuclei-enhanced polarization transfer technique, these phospholipids are edited and enhanced in the (31) P MR spectrum. In depressed patients, alterations of the choline peak and cerebral volume have been found, indicating a possible relation. Thus, combining MR phosphorous spectroscopy and volumetry in depressed patients seems to be a promising approach to detect underlying pathomechanisms. METHODS: Depressed in patients were either treated with antidepressive medication or with electroconvulsive therapy and compared to matched healthy controls. (31) P magnetic resonance spectroscopy imaging was conducted before and after the treatment phases. A 3D MRI dataset for volumetry was acquired in a dedicated (1) H head coil. RESULTS: Phosphocholine and phosphoethanolamine were increased in depressed patients. Though patients responded to the treatments, phospholipids were not significantly altered. An increased age-related gray matter loss in fronto-limbic regions along with an altered relation of phosphomonoesters/phosphodiesters with age were found in depressed patients. DISCUSSION: The findings of increased phosphomonoesthers and an age*group interaction for gray matter volumes need further research to define the role of phospholipids in major depression and possible associations to gray matter loss. PMID- 24798731 TI - Rab5 and Ndfip1 are involved in Pten ubiquitination and nuclear trafficking. AB - The spatial regulation of Pten is critical for its role as a tumour suppressor with both nuclear and cytoplasmic locations being implicated with distinct functions. In the cytoplasm, Pten plays a central role in opposing PI3K/Akt cell signalling, whereas in the nucleus, Pten is important for maintaining genome stability and enhancing the tumour suppressor activity of APC-CDH1. Despite this diversity in protein function at different subcellular locations, there is limited knowledge on how Pten is able to find different cellular niches. Here, we report that Rab5 GTPase is required for efficient trafficking and ubiquitination of Pten on endosomes inside the cytosol. Using bimolecular fluorescence complementation (BiFC) for imaging protein interactions, we observed that ubiquitinated Pten is localized to peri-nuclear and nuclear regions of the cell. Nuclear trafficking of Pten required both Rab5 as well as the E3 ligase adaptor protein Ndfip1. Rab5 colocalization with Pten was observed on endosomes and expression of a dominant negative form of Rab5 significantly reduced Pten ubiquitination and nuclear trafficking. Genomic deletion of Ndfip1 abrogated nuclear trafficking of ubiquitinated Pten, even in the presence of Rab5. Our findings show that endosomal trafficking and ubiquitination are important mechanisms for the subcellular distribution of Pten. PMID- 24798732 TI - Actin scaffolding by clathrin heavy chain is required for skeletal muscle sarcomere organization. AB - The ubiquitous clathrin heavy chain (CHC), the main component of clathrin-coated vesicles, is well characterized for its role in intracellular membrane traffic and endocytosis from the plasma membrane (PM). Here, we demonstrate that in skeletal muscle CHC regulates the formation and maintenance of PM-sarcomere attachment sites also known as costameres. We show that clathrin forms large coated lattices associated with actin filaments and the muscle-specific isoform of alpha-actinin at the PM of differentiated myotubes. Depletion of CHC in myotubes induced a loss of actin and alpha-actinin sarcomeric organization, whereas CHC depletion in vivo induced a loss of contractile force due to the detachment of sarcomeres from the PM. Our results suggest that CHC contributes to the formation and maintenance of the contractile apparatus through interactions with costameric proteins and highlight an unconventional role for CHC in skeletal muscle that may be relevant to pathophysiology of neuromuscular disorders. PMID- 24798733 TI - Chk2 prevents mitotic exit when the majority of kinetochores are unattached. AB - The spindle checkpoint delays exit from mitosis in cells with spindle defects. In this paper, we show that Chk2 is required to delay anaphase onset when microtubules are completely depolymerized but not in the presence of relatively few unattached kinetochores. Mitotic exit in Chk2-deficient cells correlates with reduced levels of Mps1 protein and increased Cdk1-tyrosine 15 inhibitory phosphorylation. Chk2 localizes to kinetochores and is also required for Aurora B serine 331 phosphorylation in nocodazole or unperturbed early prometaphase. Serine 331 phosphorylation contributed to prometaphase accumulation in nocodazole after partial Mps1 inhibition and was required for spindle checkpoint establishment at the beginning of mitosis. In addition, expression of a phosphomimetic S331E mutant Aurora B rescued chromosome alignment or segregation in Chk2-deficient cells. We propose that Chk2 stabilizes Mps1 and phosphorylates Aurora B-serine 331 to prevent mitotic exit when most kinetochores are unattached. These results highlight mechanisms of an essential function of Chk2 in mitosis. PMID- 24798734 TI - Plasma membrane phosphoinositide balance regulates cell shape during Drosophila embryo morphogenesis. AB - Remodeling of cell shape during morphogenesis is driven by the coordinated expansion and contraction of specific plasma membrane domains. Loss of this coordination results in abnormal cell shape and embryonic lethality. Here, we show that plasma membrane lipid composition plays a key role in coordinating plasma membrane contraction during expansion. We found that an increase in PI(4,5)P2 levels caused premature actomyosin contraction, resulting in the formation of shortened cells. Conversely, acute depletion of PI(4,5)P2 blocked plasma membrane expansion and led to premature actomyosin disassembly. PI(4,5)P2 mediated contractility is counteracted by PI(3,4,5)P3 and the zygotic gene bottleneck, which acts by limiting myosin recruitment during plasma membrane expansion. Collectively, these data support a model in which the ratio of PI(4,5)P2/PI(3,4,5)P3 coordinates actomyosin contractility and plasma membrane expansion during tissue morphogenesis, thus ensuring proper cell shape. PMID- 24798736 TI - Coupling of Hedgehog and Hippo pathways promotes stem cell maintenance by stimulating proliferation. AB - It is essential to define the mechanisms by which external signals regulate adult stem cell numbers, stem cell maintenance, and stem cell proliferation to guide regenerative stem cell therapies and to understand better how cancers originate in stem cells. In this paper, we show that Hedgehog (Hh) signaling in Drosophila melanogaster ovarian follicle stem cells (FSCs) induces the activity of Yorkie (Yki), the transcriptional coactivator of the Hippo pathway, by inducing yki transcription. Moreover, both Hh signaling and Yki positively regulate the rate of FSC proliferation, both are essential for FSC maintenance, and both promote increased FSC longevity and FSC duplication when in excess. We also found that responses to activated Yki depend on Cyclin E induction while responses to excess Hh signaling depend on Yki induction, and excess Yki can compensate for defective Hh signaling. These causal connections provide the most rigorous evidence to date that a niche signal can promote stem cell maintenance principally by stimulating stem cell proliferation. PMID- 24798735 TI - The novel proteins Rng8 and Rng9 regulate the myosin-V Myo51 during fission yeast cytokinesis. AB - The myosin-V family of molecular motors is known to be under sophisticated regulation, but our knowledge of the roles and regulation of myosin-Vs in cytokinesis is limited. Here, we report that the myosin-V Myo51 affects contractile ring assembly and stability during fission yeast cytokinesis, and is regulated by two novel coiled-coil proteins, Rng8 and Rng9. Both rng8Delta and rng9Delta cells display similar defects as myo51Delta in cytokinesis. Rng8 and Rng9 are required for Myo51's localizations to cytoplasmic puncta, actin cables, and the contractile ring. Myo51 puncta contain multiple Myo51 molecules and walk continuously on actin filaments in rng8(+) cells, whereas Myo51 forms speckles containing only one dimer and does not move efficiently on actin tracks in rng8Delta. Consistently, Myo51 transports artificial cargos efficiently in vivo, and this activity is regulated by Rng8. Purified Rng8 and Rng9 form stable higher order complexes. Collectively, we propose that Rng8 and Rng9 form oligomers and cluster multiple Myo51 dimers to regulate Myo51 localization and functions. PMID- 24798738 TI - Membrane-mediated cascade reactions by enzyme-polymer proteinosomes. AB - Proteinosomes comprising a triad of enzyme-polymer amphiphilic building blocks capable of operating together as a multi-step membrane-mediated cascade system are prepared and characterized. PMID- 24798737 TI - Deficiency in perlecan/HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice. AB - Perlecan/HSPG2 (Pln) is a large heparan sulfate proteoglycan abundant in the extracellular matrix of cartilage and the lacunocanalicular space of adult bones. Although Pln function during cartilage development is critical, evidenced by deficiency disorders including Schwartz-Jampel Syndrome and dyssegmental dysplasia Silverman-Handmaker type, little is known about its function in development of bone shape and quality. The purpose of this study was to understand the contribution of Pln to bone geometric and mechanical properties. We used hypomorph mutant mice that secrete negligible amount of Pln into skeletal tissues and analyzed their adult bone properties using micro-computed tomography and three-point-bending tests. Bone shortening and widening in Pln mutants was observed and could be attributed to loss of growth plate organization and accelerated osteogenesis that was reflected by elevated cortical thickness at older ages. This effect was more pronounced in Pln mutant females, indicating a sex-specific effect of Pln deficiency on bone geometry. Additionally, mutant females, and to a lesser extent mutant males, increased their elastic modulus and bone mineral densities to counteract changes in bone shape, but at the expense of increased brittleness. In summary, Pln deficiency alters cartilage matrix patterning and, as we now show, coordinately influences bone formation and calcification. PMID- 24798739 TI - Emotional concerns in follow-up consultations between paediatric oncologists and adolescent survivors: a video-based observational study. AB - OBJECTIVE: The present study aimed to explore (a) to what extent adolescent cancer survivors express emotional concerns during follow-up consultations, (b) the content of these expressions, and (c) the responses to their concerns by the paediatric haemato-oncologists (oncologists). METHODS: Sixty-six follow-up consultations between adolescent patients (aged 12-20 years old; mean = 16) and oncologists (n = 10) were video recorded. Emotional concerns were coded using the Verona coding definitions of emotional sequences (VR-CoDES). The content of the concerns was analysed using thematic analysis. RESULTS: Emotional concerns (n = 115) were identified in 50% of the consultations. Of the concerns, 87% were expressed implicitly as hints to the underlying emotion (cues) rather than explicitly (concerns). The oncologists elicited 66.9% of these expressions. Four main categories of emotional concerns were identified in the thematic analysis: physical (31%), psychological (29%), social (17%), and cancer related (23%). The majority (76.5%) of the oncologists' responses to the cues and/or concerns provided space for further disclosure. The oncologists responded less explicitly to the emotional aspects of physical and cancer-related issues in comparison with the cues or concerns of psychological origin. More cues and concerns were expressed when parents were not present in the consultation. CONCLUSIONS: In this study, almost half of the adolescent patients presented emotional concerns, and a subgroup presented many concerns; these were mainly expressed when initiated by the oncologists. Oncologists should therefore be attentive to hints to underlying emotions to help the adolescent bring forward his or her concerns. PMID- 24798741 TI - Results of bilateral medial rectus recession for comitant esotropia in patients with developmental delay. AB - PURPOSE: There is paucity of literature on surgical outcomes after strabismus surgery in patients with developmental delay. There is no consensus regarding whether standard surgical tables are applicable to these children. The goal of our study was to determine results of strabismus surgery for esotropia among these children. METHODS: Two retrospective cohorts of patients, with developmental delay (excluding Down syndrome) and without developmental delay, who underwent bimedial recession for comitant eso-deviation between January 2005 and January 2011, meeting our criteria, were selected. Amount of surgery performed in these children was compared with standard table. This comparison gave us operated angle of deviation. This operated angle of deviation was expressed as percentage of preoperative angle of deviation to get amount of surgery performed. Response to surgery was defined as percentage of change in angle of deviation after surgery to the operated angle of deviation. Amount of surgery performed, response to surgery, and results were compared between two groups. RESULTS: This study included 25 patients with developmental delay and 53 normal children with comitant esotropia. Age, refractive error, and preoperative angle of deviation were comparable in patients with and without developmental delay. Among patients with developmental delay, on average 72.13%+/-16.08 of angle of deviation was operated; response to surgery gained was 134.06%+/-51.62. In the control group, the average amount of surgery done was 89.08%+/-10.83; response gained was 89.83%+/-22.49. Successful outcome (+/-10 PD of orthophoria) was noted in 60% patients with developmental delay compared to 73.58% in control group. On average 70.67%+/-17.95 angle of deviation was operated in patients with developmental delay with successful outcome. CONCLUSION: Surgical outcome in patients with developmental delay is very unpredictable. An exaggerated response to standard amounts of bimedial recession should be anticipated in these patients. Though there was no statistically significant difference, operating for 70.67%+/-17.95 angle of deviation is more likely to be successful. PMID- 24798740 TI - Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. AB - BACKGROUND: RET/PTC rearrangement, RAS, and BRAF mutations are considered to be mutually exclusive in papillary thyroid carcinoma (PTC). However, although concomitant mutations of RET/PTC, RAS, or BRAF have been reported recently, their significance for tumor progression and survival remains unclear. We sought to examine the prognostic value of concomitant mutations in PTC. METHODS: We investigated 88 PTC for concomitant mutations. Mutation in BRAF exon 15, KRAS, NRAS, and HRAS were studied by polymerase chain reaction (PCR)-sequencing of tumor DNA; RET/PTC rearrangement was determined by reverse transcription (RT)-PCR sequencing of tumor cDNA. RESULTS: BRAF(V600E) was detected in 39 of 82 classic PTC (CPTC) and in all three tall-cell variants (49%, 42/85). KRAS mutation (p.Q61R and p.S65N) was detected in two CPTC (2%, 2/88) and NRAS(Q61R) in one CPTC and two follicular variant PTC (FVPTC; 3%, 3/88). KRAS(S65N) was identified for the first time in thyroid cancer and could activate mitogen-associated protein kinase (MAPK). RET/PTC-1 was detected in nine CPTC, one tall-cell variant, and two FVPTC. Concomitant BRAF(V600E) and KRAS, or BRAF(V600E) and RET/PTC-1 mutations were found in two CPTC, and six CPTC and one tall-cell variant, respectively. In total, 11 concomitant mutations were found in 88 PTC samples (13%), and most of them were in the advanced stage of disease (8/11, 73%; p<0.01). CONCLUSIONS: Our data show that concomitant mutations are a frequent event in advanced PTC and are associated with poor prognosis. The concomitant mutations may represent intratumor heterogeneity and could exert a gene dosage effect to promote disease progression. KRAS(S65N) can constitutively activate the MAPK pathway. PMID- 24798742 TI - Generic imatinib: the real-deal or just a deal? PMID- 24798743 TI - Treatment of aggressive B-cell lymphoma in elderly patients: influence of single nucleotide polymorphisms affecting pharmacodynamics of chemotherapeutics. AB - Clinical and/or biological risk factors are needed to identify elderly patients with aggressive B-cell lymphoma able to receive full-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) treatment. We present a retrospective analysis of 83 patients>=75 years of age (range: 75-97) who were diagnosed with aggressive B cell lymphoma between 2004 and 2011 in our clinic. R CHOP-like therapy was administered in 82% of these patients resulting in a median overall survival of 54 months. A median cumulative dose of 226 mg/m2 doxorubicin and a median of six cycles were applied in these patients. Two genotypes of the CBR3 and MLH1 genes affecting the metabolism of cytostatics identified a subgroup with a favorable prognosis (median overall survival not reached vs. 30 months, p=0.01). A treatment strategy aiming at full-dose R-CHOP was feasible and resulted in an encouraging treatment outcome in patients>=75 years. Pharmacogenetic parameters, if independently validated, may be helpful in elderly patients. PMID- 24798744 TI - Splenic marginal-zone lymphoma: ontogeny and genetics. AB - Splenic marginal-zone lymphoma (SMZL) is a rare tumor that has recently emerged as a prototype for how the interplay between genetics and environment shapes the natural history of lymphomas. Indeed, the recent identification of molecular immunogenetic subgroups within SMZL may prove to be relevant not only for the sub classification of the disease but also for improved understanding of the underlying biology. In contrast to other B-cell lymphomas, SMZL lacks a characteristic genetic lesion, although the majority of cases harbor genomic aberrations, as recently revealed by high-throughput studies that identified recurrent genetic aberrations, several in pathways related to marginal-zone differentiation and B-cell signaling. Here we provide an overview of recent research into the molecular and cellular biology of SMZL and related disorders, with special emphasis on immunogenetics and genomic aberrations, and discuss the value of molecular and cellular markers for the diagnosis and differential diagnosis of these entities. PMID- 24798745 TI - Selective packaging of the influenza A genome and consequences for genetic reassortment. AB - Influenza A viruses package their segmented RNA genome in a selective manner. Electron tomography, biochemical assays, and replication assays of viruses produced by reverse genetics recently unveiled molecular details of this mechanism, whereby different influenza viral strains form different and unique networks of direct intermolecular RNA-RNA interactions. Together with detailed views of the three-dimensional structure of the viral ribonucleoparticles, these recent advances help us understand the rules that govern genome packaging. They also have deep implications for the genetic reassortment processes, which are responsible for devastating pandemics. PMID- 24798746 TI - Influence of individual differences in disease perception on consumer response to direct-to-consumer genomic testing. AB - Individuals who undergo multiplex direct-to-consumer (DTC) genomic testing receive genetic risk results for multiple conditions. To date, research has not investigated the influence of individual differences in disease perceptions among consumers on testing outcomes. A total of 2037 participants received DTC genomic testing and completed baseline and follow-up surveys assessing disease perceptions and health behaviors. Participants were asked to indicate their most feared disease of those tested. Perceived seriousness and controllability of the disease via lifestyle or medical intervention were assessed. Participants most frequently reported heart attack (19.1%) and Alzheimer's disease (18.6%) as their most feared disease. Perceived seriousness and control over the feared disease both influenced response to DTC genomic testing. Greater perceived seriousness and diminished perceived control were associated with higher, but not clinically significant levels of anxiety and distress. In some cases these associations were modified by genetic risk. No significant associations were observed for diet, exercise and screening behaviors. Individual differences in disease perceptions influence psychological outcomes following DTC genomic testing. Higher perceived seriousness may make a consumer more psychologically sensitive to test results and greater perceived control may protect against adverse psychological outcomes. Findings may inform development of educational and counseling services. PMID- 24798748 TI - Second generation imaging of nuclear/cytoplasmic HIV-1 complexes. AB - The ability to visualize fluorescent HIV-1 particles within the nuclei of infected cells represents an attractive tool to study the nuclear biology of the virus. To this aim we recently developed a microscopy-based fluorescent system (HIV-IN-EGFP) that has proven valid to efficiently visualize HIV-1 complexes in the nuclear compartment and to examine the nuclear import efficiency of the virus. The power of this method to investigate viral events occurring between the cytoplasmic and the nuclear compartment is further shown in this study through the analysis of HIV-IN-EGFP in cells expressing the TRIMCyp restriction factor. In these cells the HIV-IN-EGFP complexes are not detected in the nuclear compartment, while treatment with MG132 reveals an accumulation of HIV-1 complexes in the cytoplasm. However, the Vpr-mediated transincorporation strategy used to incorporate IN fused to EGFP (IN-EGFP) impaired viral infectivity. To optimize the infectivity of the HIV-IN-EGFP, we used mutated forms of IN (E11K and K186E) known to stabilize the IN complexes and to partially restore viral infectivity in transcomplementation experiments. The fluorescent particles produced with the modified IN [HIV-IN(K)EGFP_IN(E)] show almost 30% infectivity as compared to wild-type NL4.3. Detailed confocal microscopy analysis revealed that the newly generated viral particles resulted in HIV-1 complexes significantly smaller in size, thus requiring the use of brighter fluorophores for nuclear visualization [HIV-IN(K)sfGFP_IN(E)]. The second-generation visualization system HIV-IN(K)sfGFP_IN(E), in addition to allowing direct visualization of HIV-1 nuclear entry and other viral events related to nuclear import, preserves intact viral properties in terms of nuclear entry and improved infectivity. PMID- 24798747 TI - Oatp1 enhances bioluminescence by acting as a plasma membrane transporter for D luciferin. AB - PURPOSE: Bioluminescence imaging is a powerful tool for studying gene expression and cell migration in intact living organisms. However, production of bioluminescence by cells transfected to express luciferase can be limited by the rate of plasma membrane transport of its substrate D-luciferin. We sought to identify a plasma membrane transporter for D-luciferin that could be expressed alongside luciferase to increase transmembrane flux of its substrate and thereby increase light output. PROCEDURES: Luciferase-expressing cells were transfected with a lentivirus encoding the rat reno-hepatic organic anion transporter protein, Oatp1, which was identified as a potential transporter for D-luciferin. Light output was compared between cells expressing luciferase and those also expressing Oatp1. RESULTS: In two cell lines and in mouse xenografts, co expression of Oatp1 with luciferase increased light output by several fold, following addition of luciferin. CONCLUSIONS: The increase in light output thus obtained will allow more sensitive detection of luciferase-expressing cells in vivo. PMID- 24798749 TI - Synthesis, characterization and anti-breast cancer activity of new 4 aminoantipyrine-based heterocycles. AB - 4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, 1H- and 13C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human tumor breast cancer cell line MCF7, and the results showed that (Z)-4-((3 amino-5-imino-1-phenyl-1H-pyrazol-4(5H)-ylidene)methylamino)-1,5-dimethyl-2 phenyl-1,2-dihydropyrazol-3-one 5, 3-(4-bromophenyl) -1-(1,5-dimethyl-3-oxo-2 phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5 carbonitrile 13, 1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-(4 iodophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 14, 3,3' (4,4'-sulfonylbis(4,1-phenylene))bis(1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro 1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) 16, (Z)-1- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-hydrazono-4 oxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 17, (Z)-1-(1,5-dimethyl 3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-phenyl-2-(2-phenylhydrazono) 1,2,3,4-tetrahydro pyrimidine-5-carbonitrile 18, and (Z)-4-(3-amino-6-hydrazono-7 phenyl-6,7-dihydro pyrazolo[3,4-d]pyrimidin-5-yl)-1,5-dimethyl-2-phenyl-1,2 dihydropyrazol-3-one 19 were the most active compounds with IC50 values ranging from 30.68 to 60.72 uM compared with Doxorubicin as positive control with the IC50 value 71.8 uM. PMID- 24798750 TI - 3D radiation therapy boost improves the outcome of whole brain radiation therapy treated RPA II patients with one or two brain metastases. AB - PURPOSE: to evaluate the role of whole brain radiotherapy (WBRT) and radiation boost (RB) for 208 patients recursive partitioning analysis (RPA) II with 1 or 2 brain metastases (BM) at a single institution. METHODS AND MATERIALS: the dose of WBRT was 30 Gy (10 fractions of 3 Gy). One hundred thirty-two patients (63.5%) benefited from RB of 9 Gy in 3 fractions of 3 Gy at the metastatic site. Patients had 1 or 2 BM in 122 (58.7%) and 86 cases (41.3%), respectively. RESULTS: patients with one or two metastases had similar survival (4.6 and 5.1 months, respectively) (p = 0.4). Median overall survival (OS) for patients treated with WBRT and RB, and with WBRT alone was 5.9 and 3.7 months, respectively (p = 0.03). The 6-, 12- and 24-month OS rates after WBRT and RB were 48.5%, 25% and 10.6%, respectively, while WBRT alone resulted in OS rates of 34%, 22.4% and 3.2%, respectively (p = 0.03). After WBRT and RB, the 6-, 12- and 24-month local control rates were 92%, 82% and 67%, respectively, while they were 81.2%, 75% and 37.5%, respectively, after WBRT alone (p = 0.03). The 6-, 12- and 24-month brain control rates after WBRT and RB were 88.7%, 75.8% and 62%, respectively, and after WBRT alone they were 78.5%, 59% and 37.7%, respectively (p = 0.03). CONCLUSION: additional boost delivered with 3D conformal radiotherapy improves local and brain control rates significantly as well as overall survival for RPA II patients with 1 or 2 unresectable BM. PMID- 24798752 TI - Synthesis and thermotropic studies of two novel series of kinked liquid crystals: 2-(4'-alkoxybiphen-4-yl)-6-methylquinolines and 2-(6-alkoxynaphthalen-2-yl)-6 methylquinolines. AB - Two novel homologous series of kinked (Z-shaped) liquid crystalline compounds were synthesized using a short two-step reaction. Yields of 30%-40% and 51%-57% were obtained for 2-(4'-alkoxybiphen-4-yl)-6-methylquinolines (nO-PPQMe, n = 3-8) and 2-(6-alkoxynaphthalen-2-yl)-6-methylquinolines (iO-NpQMe, i = 3-7), respectively. Spectral analyses agreed with the expected structures. The thermotropic behaviors of these compounds were investigated using polarized optical microscopy and differential scanning calorimetry. An enantiotropic nematic phase appeared to be the main mesophase in these two series of kinked liquid crystalline compounds, and an additional enantiotropic smectic C phase appeared when n = 8. PMID- 24798751 TI - Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC/Stat3 pathway. AB - N-Acetylcysteine (Nac) is an antioxidant administered in both oral and injectable forms. In this study, we used Nac topically to treat burn wounds in vitro and in vivo to investigate mechanisms of action. In vitro, we monitored glutathione levels, cell proliferation, migration, scratch-wound healing activities and the epithelialization-related proteins, matrixmetalloproteinase-1 (MMP-1) and proteins involved in regulating the expression of MMP-1 in CCD-966SK cells treated with Nac. Various Nac concentrations (0.1, 0.5, and 1.0 mM) increased glutathione levels, cell viability, scratch-wound healing activities and migration abilities of CCD-966SK cells in a dose-dependent manner. The MMP-1 expression of CCD-966SK cells treated with 1.0 mM Nac for 24 h was significantly increased. Levels of phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), janus kinase 1 (Jak1), signal transducer and activator of transcription 3 (Stat3), c-Fos and Jun, but not extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), were also significantly increased in a dose-dependent manner compared to the controls. In addition, Nac induced collagenous expression of MMP 1 via the PKC/Stat3 signaling pathway. In vivo, a burn wound healing rat model was applied to assess the stimulation activity and histopathological effects of Nac, with 3.0% Nac-treated wounds being found to show better characteristics on re-epithelialization. Our results demonstrated that Nac can potentially promote wound healing activity, and may be a promising drug to accelerate burn wound healing. PMID- 24798753 TI - LC-MS/MS method for the simultaneous determination of PA-824, moxifloxacin and pyrazinamide in rat plasma and its application to pharmacokinetic study. AB - A simple, sensitive and rapid LC-MS/MS method has been developed and validated for simultaneous determination of PA-824, moxifloxacin, and pyrazinamide in rat plasma using metronidazole as internal standard. Sample preparation involved a simple one-step protein precipitation with methanol, followed by centrifugation and evaporation of the organic solvent. The residue was redissolved in mobile phase and analyzed by LC-MS/MS. An Inertsil((r)) ODS3 C18 column (150mm*4.6mm, 5MUm), a mobile phase composed of methanol-0.03% TEA (triethylamine) in water (85:15, v/v), and a flow rate of 0.5mL/min were employed, and the total run time was 6.0min. The mass spectrometer was run in positive ion ESI-APCI combined mode using multiple reaction monitoring (MRM) to monitor the mass transitions. The method was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification (LLOQ), recovery, and matrix effect. All validation parameters met the acceptance criteria according to regulatory guidelines. The LLOQ was 1.0MUg/mL for pyrazinamide and 0.1MUg/mL for PA-824 and moxifloxacin. The recoveries obtained for PA-824, moxifloxacin and pyrazinamide were >=85%. Intra-day and inter-day coefficients of variation were less than 10%. The method had been successfully applied to a pharmacokinetic study of fixed dose administration of PA-824, moxifloxacin, pyrazinamide and their combination in SD rat. Significant differences of Tmax, Cmax, AUC(0-t) and CLz/F were observed between the single and combined groups after equal dose of PA-824 and moxifloxacin administration, which revealed the possibility of drug-drug interaction (DDI) between the PaMZ combination. PMID- 24798754 TI - Predictors of sexual well-being after endometrial cancer: results of a national self-report survey. AB - PURPOSE: We examined whether sociodemographic, physical, reproductive, psychological and clinical factors at the time of diagnosis were related to women's sexual well-being 3-5 years following treatment for endometrial cancer. METHODS: Of the 1,399 women in the Australian National Endometrial Cancer Study, 644 completed a follow-up questionnaire 3-5 years after diagnosis. Of these, 395 women completed the Sexual-Function Vaginal Changes Questionnaire, which was used to assess sexual well-being. Based on two questions assessing worry and satisfaction with their sexuality, women were classified into lower and higher sexual well-being. Multivariable-adjusted logistic regression models were used to examine sexual well-being 3-5 years following cancer treatment and the factors associated with this at diagnosis and at follow-up. RESULTS: Of the 395 women, 46 % (n = 181) were categorized into the "higher" sexual well-being group. Women who were older (odds ratio [OR] = 1.97; 95 % confidence limit [CI], 1.23-3.17), high school educated (OR = 1.75; 95 % CI, 1.12-2.73), who reported good mental health at the time of diagnosis (OR = 2.29; 95 % CI, 1.32-3.95) and whose cancer was treated with surgery alone (OR = 1.93; 95 % CI, 1.22-3.07) were most likely to report positive sexual well-being. At 3-5 years post-diagnosis, women with few symptoms of anxiety (OR = 2.28; 95 % CI, 1.21-4.29) were also most likely to report positive sexual well-being. CONCLUSIONS: Psychological, sociodemographic and treatment factors are important to positive sexual well-being post-cancer. Care that focuses on maintaining physical and psychosocial aspects of women's lives will be more effective in promoting positive sexual well-being than care that focuses solely on physical function. PMID- 24798755 TI - Magnitude of score change for the palliative prognostic index for survival prediction in patients with poor prognostic terminal cancer. AB - PURPOSE: The use of the palliative prognostic index (PPI) when used only at an initial assessment might be inappropriate as a prognostic tool because it does not reflect the patient's clinical course. The purpose of this study was to assess the utility of PPI score change (?score) between two assessments as a prognostic tool in terminally ill cancer patients categorized as having a poor prognosis. METHODS: A total of 1,035 terminally ill cancer patients categorized as having a poor prognosis (initial PPI score >6) under palliative care between January 2006 and December 2011 at a single medical center in Taiwan were selected. Patients were categorized by magnitude of ?score between the initial PPI and week 1 PPI assessments into five groups (<-20, -20 to 0, 0, 0 to 20, and >20 %) for survival analysis. RESULTS: The median survival was 22 days (range, 8 180 days) in all patients. Median survival duration was 78, 32, 23, 17, and 14 days, and the death rate at the study end was 78.9, 87.1, 96.2, 100, and 100 % in each group, respectively. The c-statistic value for predicting life expectancy less than 30, 60, and 90 days was significantly higher with magnitude of ?score than with the initial PPI score (p < 0.05). CONCLUSIONS: Magnitude of PPI score change within 1-week interval provides a significant difference in survival prediction and is more reliable than initial PPI alone to identify terminally ill cancer patients with better outcome potential in those patients considered to have a poor prognosis. PMID- 24798756 TI - Development of a new stir bar sorptive extraction method for the determination of medium-level volatile thiols in wine. AB - A fast, simple, and reliable analytical method for the determination of medium level volatile thiols in wines is presented. Stir bar sorptive extraction using ethylene glycol-silicone coated stir bars has been used in combination with thermal desorption gas chromatography with mass spectrometry for the analysis of 4-mercapto-4-methylpentan-2-one, 2-furanmethanethiol, 3-mercaptohexyl acetate, and 3-mercaptohexanol in wine. Optimization of the extraction technique was performed using a two-level fractional factorial design. For the extraction step, the optimum conditions were: Ethylene glycol and silicone coated stir bars, pH at 3.5, sample volume of 25 mL, extraction time of 90 min, NaCl content 4.0 g, and stirring speed at 500 rpm. The optimized method achieved good linearity for all studied compounds (r(2) > 0.995) and it provided detection limits of 21.52, 0.36, 0.73, and 2.55 MUg/L for 4-mercapto-4-methylpentan-2-one, 2-furanmethanethiol, 3 mercaptohexyl acetate, and 3-mercaptohexanol, respectively. It was repeatable, with precisions lower than 18% relative standard deviation for both intraday and interday repeatability. The developed procedure is suitable for the determination of these kinds of compounds when they are present at medium concentration levels. It was finally applied to real wine samples with negative aroma derived from the high concentration levels of these compounds. PMID- 24798757 TI - QM/MM studies of the mechanism of unusual bifunctional fructose-1,6-bisphosphate aldolase/phosphatase. AB - Archaeal fructose-1,6-bisphosphate aldolase/phosphatase (FBPA/P) is a newly identified unusual bifunctional enzyme (Nature, 2010, 464, 1077), which contains one single catalytic domain but catalyzes two chemically distinct reactions of gluconeogenesis. It is different from the ordinary enzymes whose active sites are responsible for a specific reaction. To explore the catalytic characteristic of FBPA/P, the aldol condensation mechanism of bifunctional FBPA/P has been investigated using quantum mechanics/molecular mechanics (QM/MM) method. The whole reaction process can be divided into two half-reactions involving seven elementary steps. A Schiff base intermediate is theoretically confirmed, agreeing well with the recently resolved crystal structures (Nature, 2011, 478, 538). The free energy barrier of the rate-limiting step is calculated to be 22.2 kcal mol( 1), which is a concerted process of a nucleophilic attack by the enolic carbon to the ketonic carbon and a proton transfer from Tyr229 to the ketonic oxygen. Lys232 plays an important role in forming a Schiff base intermediate with the substrate (DHAP). Tyr229 functions as a proton shuttle during the catalysis. This is the first theoretical study on the aldol condensation mechanism of FBPA/P, which may provide useful information for understanding bifunctional enzymes. PMID- 24798758 TI - [Shelter from the storm: procedures in patients with electrical storm]. PMID- 24798760 TI - Home food and activity assessment. Development and validation of an instrument for diverse families of young children. AB - The purpose of this study was to refine and psychometrically test an instrument measuring the home food and activity environment of geographically and economically diverse families of preschool aged children. Caregivers of preschool aged children (n = 83) completed a modified self-report questionnaire. Reliably trained researchers conducted independent observations on 25 randomly selected homes. Agreement statistics were conducted at the item level (154 total items) to determine reliability. Frequency counts were calculated to identify item availability. Results showed Kappa statistics were high (.67-1.00) between independent researchers but varied between researchers and parents resulting in 85 items achieving criterion validity (Kappa >.60). Analyses of reliable items revealed the presence in the home of a high frequency of unhealthy snack foods, high fat milk and low frequency of availability of fruits/vegetables and low fat milk. Fifty-two percent of the homes were arranged with a television in the preschool child's bedroom. Physical Activity devices also were found to have high frequency availability. Families reporting lower education reported higher levels of sugar sweetened beverages and less low-fat dairy (p < .05) compared with higher education families. Low-income families (<$27K per year) reported significantly fewer Physical Activity devices (p < .001) compared with higher income families. Hispanic families reported significantly higher numbers of Sedentary Devices (p < .05) compared with non-Hispanic families. There were no significant differences between demographic comparisons on available fruits/vegetables, meats, whole grains, and regular fat dairy. A modified home food and activity instrument was found to reliably identify foods and activity devices with geographically and economically diverse families. PMID- 24798761 TI - Knowledge, perceptions and preferences of elderly regarding protein-enriched functional food. AB - Promoting protein consumption in the elderly population may contribute to improving the quality of their later years in life. Our study aimed to explore knowledge, perceptions and preferences of elderly consumers regarding protein enriched food. We conducted three focus groups with independently living (ID) elderly (N = 24, Mage = 67 years) and three with elderly living in a residential home (RH) (N = 18, Mage = 83 years). Both the ID and RH elderly were predominantly sceptical about functional food in general. Confusion, distrust and a perceived lack of personal relevance were main perceived barriers to purchasing and consuming these products, although a majority of the participants did report occasionally consuming at least one type of functional food. For the ID elderly, medical advice was an important facilitator that could overcome barriers to purchasing and consuming protein-enriched food, indicating the importance of personal relevance for this group. For the RH elderly, in contrast, sensory appeal of protein-enriched foods was a facilitator. Carrier preferences were similar for the two groups; the elderly preferred protein-enriched foods based on healthy products that they consumed frequently. Future studies should explore ways to deal with the confusion and distrust regarding functional food within the heterogeneous population of elderly. PMID- 24798762 TI - Factors associated with low adherence to a Mediterranean diet in healthy children in northern Spain. AB - There is a tendency in Mediterranean countries to abandon the characteristic Mediterranean diet. This is especially apparent within younger populations. This could have negative consequences for health such as, cardiovascular diseases, obesity or metabolic syndrome. The aim of this study was to describe adherence to the Mediterranean diet within a population of school children and to examine the influence of different socio-demographic factors and lifestyle habits. The study was conducted on a representative sample of 321 school children aged 11-12 years from 31 schools in the city of Logrono (La Rioja). Socio-demographic variables, anthropometric variables, blood pressure, level of development, aerobic fitness, lifestyle, physical activity habits and adherence to the Mediterranean diet were recorded. High adherence to the Mediterranean diet was reported by 46.7% of school children, with low adherence being reported by 4.7% of them. Children attending state schools, immigrants and families from low-to-medium socio economic strata reported significantly lower adherence to the Mediterranean diet (p = .039), but the results did not reveal any significant differences in terms of body composition. Correlations were found between adherence to the Mediterranean diet and other lifestyle habits, especially level of physical activity (r = .38) and screen time (r = -.18). Adherence to a Mediterranean diet differs according to the type of school attended by children, and the child's nationality and socio-economic status. Children who attended state schools, immigrants and those from families with a medium-to-low socio-economic status were less likely to follow healthy diets. PMID- 24798763 TI - Food insecurity and CD4% Among HIV+ children in Gaborone, Botswana. AB - We investigated the association between household food insecurity (HFI) and CD4% among 2-6-year old HIV+ outpatients (n = 78) at the Botswana-Baylor Children's Clinical Center of Excellence in Gaborone, Botswana. HFI was assessed by a validated survey. CD4% data were abstracted from the medical record. We used multiple linear regression with CD4% (dependent variable), HFI (independent variable), and controlled for sociodemographic and clinical covariates. Multiple linear regression showed a significant main effect for HFI [beta = -0.6, 95% confidence interval (CI): -1.0 to -0.1] and child gender (beta = 5.6, 95% CI: 1.3 to 9.8). Alleviating food insecurity may improve pediatric HIV outcomes in Botswana and similar Sub-Saharan settings. PMID- 24798764 TI - A prospective cohort study of the effect of depot medroxyprogesterone acetate on detection of plasma and cervical HIV-1 in women initiating and continuing antiretroviral therapy. AB - Depot medroxyprogesterone acetate (DMPA) use among HIV-1-infected women may increase transmission by increasing plasma and genital HIV-1 RNA shedding. We investigated associations between DMPA use and HIV-1 RNA in plasma and cervical secretions. One hundred two women initiated antiretroviral therapy, contributing 925 follow-up visits over a median of 34 months. Compared with visits with no hormonal contraception exposure, DMPA exposure did not increase detection of plasma (adjusted odds ratio: 0.81, 95% confidence interval: 0.47 to 1.39) or cervical HIV-1 RNA (adjusted odds ratio: 1.41, 95% confidence interval: 0.54 to 3.67). Our results suggest that DMPA is unlikely to increase infectivity in HIV positive women who are adherent to effective antiretroviral therapy. PMID- 24798766 TI - On the usefulness of circulating bacterial 16S rDNA as a marker of microbial translocation in HIV-1-infected patients. PMID- 24798765 TI - Delay of antiretroviral therapy initiation is common in East African HIV-infected individuals in serodiscordant partnerships. AB - OBJECTIVE: WHO guidance recommends antiretroviral therapy (ART) initiation for all persons with a known HIV-uninfected partner, as a strategy to prevent HIV transmission. Uptake of ART among HIV-infected partners in serodiscordant partnerships is not known, which we evaluated in African HIV serodiscordant couples. DESIGN: Prospective cohort study. METHODS: Among HIV-infected persons from Kenya and Uganda who had a known heterosexual HIV-uninfected partner, we assessed ART initiation in those who became ART eligible under national guidelines during follow-up. Participants received quarterly clinical and semi annual CD4 monitoring, and active referral for ART upon becoming eligible. RESULTS: Of 1958 HIV-infected ART-eligible partners, 58% were women, and the median age was 34 years. At the first visit when determined to be ART eligible, the median CD4 count was 273 cells per microliter (interquartile range, 221-330), 77% had WHO stage 1 or 2 HIV disease, and 96% were receiving trimethoprim sulfamethoxazole prophylaxis. The cumulative probabilities of initiating ART at 6, 12, and 24 months after eligibility were 49.9%, 70.0%, and 87.6%, respectively. Younger age [<25 years; adjusted hazard ratio (AHR), 1.39; P = 0.001], higher CD4 count (AHR, 1.95; P < 0.001 for >350 compared with <200 cells/uL), higher education (AHR, 1.25; P < 0.001), and lack of income (AHR, 1.15; P = 0.02) were independent predictors for delay in ART initiation. CONCLUSIONS: In the context of close CD4 monitoring, ART counseling, and active linkage to HIV care, a substantial proportion of HIV-infected persons with a known HIV-uninfected partner delayed ART initiation. Strategies to motivate ART initiation are needed, particularly for younger persons with higher CD4 counts. PMID- 24798767 TI - Immunologic effect of zinc supplementation in HIV-infected children receiving highly active antiretroviral therapy: a randomized, double-blind, placebo controlled trial. AB - BACKGROUND: We conducted this study to assess the immunologic effect of daily 20 mg zinc supplementation for 24 weeks in HIV-infected children older than 6 months receiving highly active antiretroviral therapy (ART). METHODS: Fifty-two HIV infected children older than 6 months in whom ART was initiated were randomized to receive either 20 mg of zinc or placebo for a period of 24 weeks. Children underwent clinical examination, anthropometry, and laboratory evaluations: CD4% and count, viral load, and serum zinc level at baseline, 12 weeks, and 24 weeks. The primary outcome evaluated was CD4% value at the end of 12 and 24 weeks of study intervention in the enrolled children. RESULTS: Of 52 children enrolled, 49 completed the study. The median CD4% value rose from 10% to 23% at 12 weeks and to 24.5% at 24 weeks in the zinc group, whereas in the placebo group, the value rose from 11% to 20% at 12 weeks and to 22% at 24 weeks (P = 0.188 for comparison between the zinc and the placebo group at 12 wk and P = 0.3 for comparison at 24 wk). The median (interquartile range) log reductions in the viral load at 12 weeks in the 2 arms were similar at 12 (P = 0.84) and 24 weeks (P = 0.43). CONCLUSIONS: Supplementation of 20 mg zinc daily for 24 weeks did not have any statistically significant effect on the increase in CD4%, decrease in viral load, anthropometric indices, and morbidity profile in HIV-infected children started on ART. PMID- 24798768 TI - Effect of antiretroviral therapy including lopinavir/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in HIV-positive women. AB - OBJECTIVE: Data on the interaction between the etonogestrel (ENG) implant and antiretroviral therapy are lacking. We evaluated the effect of 2 highly active antiretroviral therapy (HAART) regimens (1 including efavirenz and the other ritonavir-boosted lopinavir) on the pharmacokinetic (PK) parameters of an ENG releasing implant in HIV-positive women. DESIGN: Prospective nonrandomized PK study. METHODS: Forty-five HIV-positive women who desired to use ENG implants were included: 15 had received zidovudine/lamivudine + lopinavir/ritonavir for >=3 months (LPV/r-based HAART group), 15 had received zidovudine/lamivudine + efavirenz for >=3 months (EFV-based HAART group), and 15 had not received HAART (non-HAART group). PK parameters were measured using ultra-performance liquid chromatography-mass spectrometry at baseline and 2, 4, 6, 8, 10, 12, 16, 20, and 24 weeks after implant placement. RESULTS: The EFV-based HAART regimen was associated with a reduction in the bioavailability of ENG, which showed decreases of 63.4%, 53.7%, and 70% in the area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of ENG, respectively, compared with the non-HAART group. The LPV/r-based HAART regimen was associated with an increase in ENG bioavailability, which showed 52%, 60.6%, and 33.8% increases in the ENG AUC, Cmax, and Cmin, respectively, compared with the non-HAART group. CONCLUSIONS: The coadministration of EFV decreased the bioavailability of ENG released from the implant, which could impair contraceptive efficacy. However, the coadministration of LPV/r increased the bioavailability of ENG released from the implant, which suggests that this antiretroviral combination does not impair the ENG implant efficacy. PMID- 24798769 TI - Survival after cancer in Italian persons with AIDS, 1986-2005: a population-based estimation. AB - BACKGROUND: Cancer survival in persons with AIDS (PWA) after introduction of antiretroviral therapies remains poorly characterized. The aim is to provide population-based estimates of cancer survival, overall and for the most important cancer types in PWA, and a comparison with persons without AIDS (non-PWA) affected by the same cancer. METHODS: PWA with cancer at AIDS diagnosis or thereafter were individually matched with non-PWA by type of cancer, sex, age, year of diagnosis, area of living, and, for lymphomas, histological subtype. Five year observed survival and hazard ratios (HRs) of death in PWA versus non-PWA with 95% confidence intervals (CIs) were estimated. RESULTS: We included 2262 Italian PWA and 4602 non-PWA with cancer diagnosed during 1986-2005. Between 1986 and 1995, and 1996 and 2005, 5-year survival for all cancers in PWA improved from 12% to 41% and the corresponding HR versus non-PWA decreased from 5.1 (95% CI: 4.3 to 6.1) to 2.9 (95% CI: 2.6 to 3.3). During 1996-2005, HRs were 2.0 (95% CI: 1.4 to 2.9) for Kaposi sarcoma, 3.4 (95% CI: 2.9 to 4.1) for non-Hodgkin lymphoma, and 2.4 (95% CI: 1.4 to 4.0) for cervical cancer. HRs were 2.5 (95% CI: 2.1 to 3.1) for all non-AIDS-defining cancers, 5.9 (95% CI: 3.1 to 11.2) for Hodgkin lymphoma, and 7.3 (95% CI: 2.8 to 19.2) for nonmelanoma skin cancer. A <=3-fold survival difference was found for cancers of the stomach, liver, anus, lung, brain, and the most aggressive lymphoma subtypes. CONCLUSIONS: The persisting, although narrowing, gap in cancer survival between PWA and non-PWA indicates the necessity of enhancing therapeutic approaches, so that PWA can be provided the same chances of survival observed in the general population, and improving cancer prevention and screening. PMID- 24798770 TI - Bioequivalence of a dolutegravir, abacavir, and lamivudine fixed-dose combination tablet and the effect of food. AB - BACKGROUND: The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet. METHODS: Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine. RESULTS: Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. CONCLUSIONS: The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals. PMID- 24798771 TI - Clinical correlates and genetic linkage of social and communication difficulties in families with obsessive-compulsive disorder: Results from the OCD Collaborative Genetics Study. AB - Some individuals with obsessive-compulsive disorder (OCD) have autistic-like traits, including deficits in social and communication behaviors (pragmatics). The objective of this study was to determine if pragmatic impairment aggregates in OCD families and discriminates a clinically and genetically distinct subtype of OCD. We conducted clinical examinations on, and collected DNA samples from, 706 individuals with OCD in 221 multiply affected OCD families. Using the Pragmatic Rating Scale (PRS), we compared the prevalence of pragmatic impairment in OCD-affected relatives of probands with and without pragmatic impairment. We also compared clinical features of OCD-affected individuals in families having at least one, versus no, individual with pragmatic impairment, and assessed for linkage to OCD in the two groups of families. The odds of pragmatic impairment were substantially greater in OCD-affected relatives of probands with pragmatic impairment. Individuals in high-PRS families had greater odds of separation anxiety disorder and social phobia, and a greater number of schizotypal personality traits. In high-PRS families, there was suggestive linkage to OCD on chromosome 12 at marker D12S1064 and on chromosome X at marker DXS7132 whereas, in low-PRS families, there was suggestive linkage to chromosome 3 at marker D3S2398. Pragmatic impairment aggregates in OCD families. Separation anxiety disorder, social phobia, and schizotypal personality traits are part of a clinical spectrum associated with pragmatic impairment in these families. Specific regions of chromosomes 12 and X are linked to OCD in high-PRS families. Thus, pragmatic impairment may distinguish a clinically and genetically homogeneous subtype of OCD. PMID- 24798772 TI - Binge drinking and insomnia in middle-aged and older adults: the Health and Retirement Study. AB - OBJECTIVE: Alcohol use in later life has been linked to poor sleep. However, the association between binge drinking, which is common among middle-aged and older adults, and insomnia has not been previously assessed. METHODS: We studied participants aged 50 years and older (n = 6027) from the 2004 Health and Retirement Study who reported the number of days they had >=4 drinks on one occasion in the prior 3 months. Participants also reported the frequency of four insomnia symptoms. Logistic regression analyses assessed the association between binge drinking frequency and insomnia. RESULTS: Overall, 32.5% of participants had >0 to <=2 binge drinking days/week; and 3.6% had >2 binge drinking days/week. After adjusting for demographic variables, medical conditions, body mass index, and elevated depressive symptoms, participants who binged >2 days/week had a 64% greater odds of insomnia than non-binge drinkers (adjusted odds ratio [aOR] = 1.64, 95% confidence interval [CI] = 1.09-2.47, p = 0.017). Participants reporting >0 to <=2 binge days/week also had a 35% greater odds of insomnia than non-binge drinkers (aOR = 1.35, 95% CI = 1.15-1.59, p = 0.001). When smoking was added to the regression model, these associations fell just below the level of significance. CONCLUSIONS: Results suggest that binge drinking is associated with a greater risk of insomnia among adults aged 50 years and older, although this relationship may be driven in part by current smoking behavior. The relatively high prevalence of both binge drinking and sleep complaints among middle-aged and older populations warrants further investigation into binge drinking as a potential cause of late-life insomnia. PMID- 24798773 TI - Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice. AB - Bile acids (BAs) are signaling molecules that are involved in many physiological functions, such as glucose and energy metabolism. These effects are mediated through activation of the nuclear and membrane receptors, farnesoid X receptor (FXR-alpha) and TGR5 (G-protein-coupled bile acid receptor 1; GPBAR1). Although both receptors are expressed within the testes, the potential effect of BAs on testis physiology and male fertility has not been explored thus far. Here, we demonstrate that mice fed a diet supplemented with cholic acid have reduced fertility subsequent to testicular defects. Initially, germ cell sloughing and rupture of the blood-testis barrier occur and are correlated with decreased protein accumulation of connexin-43 (Cx43) and N-cadherin, whereas at later stages, apoptosis of spermatids is observed. These abnormalities are associated with increased intratesticular BA levels in general and deoxycholic acid, a TGR5 agonist, in particular. We demonstrate here that Tgr5 is expressed within the germ cell lineage, where it represses Cx43 expression through regulation of the transcriptional repressor, T-box transcription factor 2 gene. Consistent with this finding, mice deficient for Tgr5 are protected against the deleterious testicular effects of BA exposure. CONCLUSIONS: These data identify the testis as a new target of BAs and emphasize TGR5 as a critical element in testicular pathophysiology. This work may open new perspectives on the potential effect of BAs on testis physiology during liver dysfunction. PMID- 24798774 TI - Differential mapping of the free barbed and pointed ends of actin filaments in cells. AB - The actin cytoskeleton plays a pivotal role in many cellular processes. Detailed analysis of the architecture of cellular actin networks provides valuable insight into the dynamic self-organization underlying these processes. In particular, since most of the actin turnover occurs at the tips of actin filaments, it is insightful to map the distribution of filament ends. Here we report a method for differentially labeling the pointed and the barbed ends of actin filaments in cellular networks by permeabilizing cells, following a brief fixation, and introducing labeled actin monomers in the presence or absence of capping protein, respectively. This method quantitatively maps the distributions of free barbed ends and free pointed ends in adherent cells, providing information on the polarity of cytoskeletal structures and mapping active sites available for actin assembly or disassembly. We demonstrate the use of this method by mapping the distribution of actin filament ends in motile fish epithelial keratocytes and in several mammalian cell lines, and show that free barbed ends are enriched near the tip of protruding lamellipodia while free pointed ends concentrate toward the rear. PMID- 24798775 TI - A possible explanation for the effects of respiration on heart rate and blood pressure asymmetry. PMID- 24798776 TI - Single left coronary artery with the right coronary artery arising as a continuation from the distal circumflex coronary artery assessed by multislice computed tomography. PMID- 24798777 TI - A new understanding and definition of non-compaction cardiomyopathy using analysis of left ventricular wall mechanics and stresses. PMID- 24798778 TI - Purinergic profile of fainting divers is different from patients with vasovagal syncope. PMID- 24798779 TI - Cardiovascular disease in patients with chronic human immunodeficiency virus infection. AB - In 2012, the United Nations estimated that globally, 34 million people were living with human immunodeficiency virus (HIV) infection at the end of 2011. About 6.5% of AIDS-related mortality is attributable to cardiovascular disease. HIV related cardiovascular disease is diverse. In this review we explore the different disease states associated with HIV such as cardiomyopathy, coronary artery disease, dyslipidemia, electrocardiographic abnormalities, prolonged QT interval and sudden death. The pathophysiology of these numerous diseases is complex and multifactorial. Current management of these patients is challenging due to multiple drug-drug interactions and side effects. However, the approach to prevention is quite familiar, taking on the same rules that apply for any patient to minimize cardiovascular disease risk. The challenges are many, therefore for HIV patients who present after a cardiovascular event, or for prevention of cardiovascular disease, the concept of a heart team is essential, where cardiovascular specialists and the HIV care team work side by side to ensure safety of medications (avoid drug interactions) and to institute a goal directed prevention plan of care. PMID- 24798780 TI - Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting. AB - BACKGROUND: Cardiac autonomic dysfunction reportedly contributes to the AF triggering and maintenance. Heart rate turbulence (HRT) is a promising noninvasive measure of cardiac autonomic function. We investigated whether ambulatory ECG-based HRT measurement could predict in-hospital new-onset atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. METHODS: HRT onset (TO) and slope (TO) were prospectively measured from 24-h Holter recording in 113 consecutive patients prior to CABG. Abnormal HRT was defined as at least one abnormal value in TO (> 0%) and TS (< 2.5 ms/RR). RESULTS: Patients with abnormal HRT (n = 60) showed a significantly higher AF incidence (47% versus 21%, P = 0.005) and AF burden (29 +/- 9 versus 7 +/- 5 h, P = 0.043) than those with normal HRT (n = 53). Abnormal HRT were identified as independent predictors for the new-onset postoperative AF. During the follow-up period (12.0 +/- 10.5 months), the abnormal HRT group showed a worse prognosis versus the normal HRT group regarding the AF recurrence/postoperative stroke (P = 0.018). Additionally, the postoperative AF incidence, in-hospital AF burden, and the rate of AF recurrence/postoperative stroke gradually elevated as the number of abnormal HRT values increased from 0 to 2. CONCLUSIONS: Preoperative abnormal HRT was significantly associated with worse short-term (in-hospital new-onset AF) and long-term outcomes (post-discharge AF recurrence/postoperative stroke) after CABG surgery. Additional studies incorporating preventive interventions depending on the preoperative HRT results might be worthwhile in this patient group. PMID- 24798781 TI - Unusual osteonecrosis of the femur, tibia and fibula in an adult patient with a complex cyanotic congenital heart disease. PMID- 24798782 TI - Increased ventricular wall stress and late gadolinium enhancement in Takotsubo cardiomyopathy. PMID- 24798783 TI - Head-to-head comparison of 2 inflammatory biomarkers for the long-term prediction of left ventricular diastolic dysfunction in type 2 diabetes patients: soluble ST2 versus hs-CRP. PMID- 24798784 TI - Epidemiological profile of Wolff-Parkinson-White syndrome in a general population younger than 50 years of age in an era of radiofrequency catheter ablation. AB - BACKGROUND: The prevalence of Wolff-Parkinson-White (WPW) syndrome varies between 0.68 and 1.7/1000. The epidemiological profile may be modified after the introduction of transcatheter interventions. OBJECTIVES: The aim of this study is to investigate the epidemiological trends of the WPW syndrome in a general population during a period with available and reimbursed transcatheter ablation. METHODS AND RESULTS: Data of WPW patients <50 years old were retrieved from our national database (2000-2010). We identified 6086 (61% male) patients, accounting for an overall prevalence of 0.36/1000 with a peak of 0.61/1000 in ages 20-24 years. The risk of death and sudden death was 0.071% and 0.02% per patient-year, respectively. The 42 deaths occurred at a median age of 29 years. Associated congenial heart disease was noted in 158 (2.6%) patients, including 42 with Ebstein's anomaly that increased the mortality risk (P=0.001, OR=8.5). In those without congenital heart disease, myocardial dysfunction occurred in 115 (1.9%) patients and increased the risk of death (P<0.001, OR=10.6) and sudden death. Radiofrequency catheter ablation was performed in 2527 patients at a median age of 25.7 years (4.54% per patient-year, discharge mortality 0.16%); 11 (0.4%) before the age of 5, and 2231 (88%) after the age of 15. Whereas repeated ablation procedures accounted for 6.0% of the procedures, those in Ebstein's patients were 25%. CONCLUSION: Radiofrequency catheter ablation is already a common treatment for WPW patients, particularly during young adulthood, which accounts for a lower prevalence. Myocardial dysfunction and associated congenital heart disease remain as risks of mortality. PMID- 24798785 TI - A meta-analysis pooling survival curves in randomized controlled trials and propensity-score matched studies of endovascular versus open abdominal aortic aneurysm repair. PMID- 24798786 TI - Associations between N-terminal pro-B-type natriuretic peptide and cardiac function in adults with corrected tetralogy of Fallot. AB - BACKGROUND: Amino-terminal B-type natriuretic peptide (NT-proBNP) may detect early cardiac dysfunction in adults with tetralogy of Fallot (ToF) late after corrective surgery. We aimed to determine the value of NT-proBNP in adults with ToF and establish its relationship with echocardiography and exercise capacity. METHODS AND RESULTS: NT-proBNP measurement, electrocardiography and detailed 2D echocardiography were performed on the same day in 177 consecutive adults with ToF (mean age 34.6 +/- 11.8 years, 58% male, 89% NYHA I, 29.3 +/- 8.5 years after surgical correction). Thirty-eight percent of the patients also underwent a cardiopulmonary-exercise test. Median NT-proBNP was 16 [IQR 6.7-33.6] pmol/L, and was elevated in 55%. NT-proBNP correlated with right ventricular (RV) dilatation (r = 0.271, p < 0.001) and RV systolic dysfunction (r = -0.195, p = 0.022), but more strongly with LV systolic dysfunction (r=-0.367, p<0.001), which was present in 69 patients (39%). Moderate or severe pulmonary regurgitation was not associated with higher NT-proBNP. Tricuspid and pulmonary regurgitation peak velocities correlated with NT-proBNP (r = 0.305, p < 0.001 and r = 0.186, p = 0.045, respectively). LV twist was measured with speckle-tracking echocardiography in 71 patients. An abnormal LV twist (20 patients, 28%) was associated with elevated NT-proBNP (p = 0.030). No relationship between NT-proBNP and exercise capacity was found. CONCLUSIONS: NT-proBNP levels are elevated in more than 50% of adults with corrected ToF, while they are in stable clinical condition. Higher NT-proBNP is most strongly associated with elevated pulmonary pressures, and with LV dysfunction rather than RV dysfunction. NT-proBNP has the potential to become routine examination in patients with ToF to monitor ventricular function and may be used for timely detection of clinical deterioration. PMID- 24798787 TI - Enhancement of tumor uptake and therapeutic efficacy of EGFR-targeted antibody cetuximab and antibody-drug conjugates by cholesterol sequestration. AB - Cetuximab, a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), has been intensively investigated as a promising cancer treatment strategy. The specific mechanism of cetuximab endocytosis and its influence on cetuximab uptake, biodistribution and efficacy still remain elusive. Recently, statins have been reported to synergize with EGFR-targeting agents. Our prior work established that nystatin, a cholesterol-sequestering antifungal drug, facilitates endocytosis via the clathrin-dependent pathway. This study aimed to investigate whether nystatin regulates the uptake and efficacy of cetuximab and cetuximab-based antibody-drug conjugates (cetuximab-ADCs). In vitro and in vivo efficacies of nystatin on the uptake and activity of cetuximab/cetuximab-ADCs were studied in multiple human carcinoma cell lines and xenograft models, respectively. We identified that cholesterol sequestration by nystatin enhanced cetuximab internalization in EGFR-positive carcinoma cells by regulating EGFR trafficking/turnover and facilitating a switch from lipid rafts to clathrin mediated endocytosis. Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues, translating into potentiated antitumor efficacy of cetuximab in vivo (A431 and A549 tumors). Nystatin-enhanced internalization of cetuximab further improved the uptake and potency of cetuximab-doxorubicin and cetuximab-methotrexate conjugates in EGFR positive cetuximab-resistant tumors. Combination therapy with nystatin plus either cetuximab or cetuximab-ADC further prolonged animal survival and significantly suppressed tumor growth, as compared with single-agent cetuximab or cetuximab-ADC. In summary, our results identify a novel mechanism whereby cholesterol sequestration enhances the uptake of EGFR-targeting mAb and ADCs, therefore providing preclinical proof-of-concept that combination with nystatin can potentiate the delivery and efficacy of these EGFR-targeted agents. PMID- 24798788 TI - Evaluation of secretion volume and immunoglobulin A and G concentrations in sow colostrum from anterior to posterior teats. AB - Among domestic animals, teat order is only observed in the pig. In order to achieve the healthy growth and weaning of piglets, it is important to elucidate if volume of colostrum secretion and immunoglobulin A (IgA) and IgG concentrations differ among the teats of a sow. Nine sows were used to evaluate the difference in colostrum secretion volume (CSV) and four of these sows were assessed for IgA and IgG concentrations from each teat. Samples were collected five times during 21 h following parturition. Teats were assigned anatomical locations of teat (1 to 7) from anterior to posterior. The CSV of anterior (locations 1 and 2) and middle teats (locations 3-5) was significantly higher than those of posterior teats (locations 6 and 7) throughout the experiment except for 18 h post-parturition (P < 0.05). The CSV of the teats at location 1 was significantly higher at most collection times than those at locations 6 and 7. A positive correlation of CSV was observed with IgA and IgG concentrations from 12 h and 6 h post-parturition, respectively (P < 0.05). The results suggest that anterior teats secrete greater volumes of colostrum and that these tend to contain higher IgA and IgG than posteriors teats. PMID- 24798789 TI - Alteration in neuromuscular function of the plantar flexors following caffeine ingestion. AB - The aim of this study was to compare the neuromuscular function of the plantar flexors following caffeine or placebo administration. Thirteen subjects (25 +/- 3 years) ingested caffeine or placebo in a randomized, controlled, counterbalanced, double-blind crossover design. Neuromuscular tests were performed before and 1 h after caffeine or placebo intake. During neuromuscular testing, rate of torque development, isometric maximum voluntary torque, and neural drive to the muscles were measured. Triceps surae muscle activation was assessed by normalized root mean square of the EMG signal during the initial phase of contraction (0-100 ms, 100-200 ms) and maximal voluntary contraction (MVC). Furthermore, evoked spinal reflex responses of the soleus muscle (H-reflex evoked at rest and during MVC, V wave) and peak twitch torques were evaluated. The isometric maximum voluntary torque and evoked potentials were not different. However, we found a significant difference between groups for rate of torque development in the time intervals 0 100 ms [41.1 N . m/s (95% CI: 8.3-73.9 N . m/s, P = 0.016)] and 100-200 ms [32.8 N . m/s (95% CI: 2.8-62.8 N . m/s, P = 0.034)]. These changes were accompanied by enhanced neural drive to the plantar flexors. Data suggest that caffeine solely increased explosive voluntary strength of the triceps surae because of enhanced neural activation at the onset of contraction whereas MVC strength was not affected. PMID- 24798790 TI - Pectin modifications: a review. AB - In recent years, the interest in studying modification of pectin has increased. A number of hydroxyl and carboxyl groups distributed along the backbone as well as a certain amount of neutral sugars presented as side chains make pectin capable of preparing a broad spectrum of derivatives. By forming pectin derivatives, their properties may be modified and some other new functional properties may be created. This article attempts to review the information about various methods used for pectin modification, including substitution (alkylation, amidation, quaternization, thiolation, sulfation, oxidation, etc.), chain elongation (cross linking and grafting) and depolymerization (chemical, physical, and enzymatic degradation). Characteristics and applications of some pectin derivatives are also presented. In addition, the safety and regulatory status of pectin and its derivatives were reviewed. PMID- 24798791 TI - Background-free referenced luminescence sensing and imaging of pH using upconverting phosphors and color camera read-out. AB - Fluorescence background and problems with proper signal referencing severely disrupt the read-out of luminescence sensors and images. We present a pH sensor film in combination with a simple read-out technique that overcomes issues of background signals and autofluorescence. It consists of micrometer-sized upconversion phosphors (UCPs) and a pH indicator (Neutral Red) that absorbs their green emission. Both are embedded in a proton permeable hydrogel matrix. The UCPs generate green and red luminescence upon excitation with IR light of 980 nm wavelength. Solely the green light of the UCPs is affected by the pH indicator, while the red emission acts as inert reference signal for ratiometric measurements. The emission peaks of the UCPs match the red and green color channels of standard digital cameras. Thereby, the devised sensor film can be used for referenced ratiometric sensing and 2D imaging of pH using a color camera read-out. The sensor setup using common and hand-held devices is cheap and straightforward and allows for point-of-care measurements. Finally, pH measurements in human serum samples show the potential of this sensor for imaging free of interfering background signals. PMID- 24798792 TI - A role of Anabaena sensory rhodopsin transducer (ASRT) in photosensory transduction. AB - In 2003, Anabaena sensory rhodopsin (ASR), a membrane-bound light sensor protein, was discovered in cyanobacteria. Since then, a large number of functions have been described for ASR, based on protein biochemical and biophysical studies. However, no study has determined the in vivo mechanism of photosensory transduction for ASR and its transducer protein (ASRT). Here, we aimed to determine the role of ASRT in physiological photo-regulation. ASRT is known to be related to photochromism, because it regulates the expression of phycocyanin (cpc gene) and phycoerythrocyanin (pec gene), two major proteins of the phycobilisome in cyanobacteria. By examining wild type and knockout mutant Anabaena cells, we showed that ASRT repressed the expression of these two genes. We also demonstrated physical interactions between ASRT, ASR, and the promoter regions of cpc, pec, kaiABC (circadian clock gene) and the asr operon, both in vitro and in vivo. Binding assays indicated that ASRT had different sites of interaction for binding to ASR and DNA promoter regions. ASRT also influenced the retinal re isomerization rate in dark through a physical interaction with ASR, and it regulated reporter gene expression in vivo. These results suggested that ASRT relayed the photosignal from ASR and directly regulated gene expression. PMID- 24798795 TI - Temperature dependence of the structural relaxation time in equilibrium below the nominal T(g): results from freestanding polymer films. AB - When the thickness is reduced to nanometer scale, freestanding high molecular weight polymer thin films undergo large reduction of degree of cooperativity and coupling parameter n in the Coupling Model (CM). The finite-size effect together with the surfaces with high mobility make the alpha-relaxation time of the polymer in nanoconfinement, tau(alpha)(nano)(T), much shorter than tau(alpha)(bulk)(T) in the bulk. The consequence is avoidance of vitrification at and below the bulk glass transition temperature, T(g)(bulk), on cooling, and the freestanding polymer thin film remains at thermodynamic equilibrium at temperatures below T(g)(bulk). Molecular dynamics simulations have shown that the specific volume of the freestanding film is the same as the bulk glass-former at equilibrium at the same temperatures. Extreme nanoconfinement renders total or almost total removal of cooperativity of the alpha-relaxation, and tau(alpha)(nano)(T) becomes the same or almost the same as the JG beta-relaxation time tau(beta)(bulk)(T) of the bulk glass-former at equilibrium and at temperatures below T(g)(bulk). Taking advantage of being able to obtain tau(beta)(bulk)(T) at equilibrium density below T(g)(bulk) by extreme nanoconfinement of the freestanding films, and using the CM relation between tau(alpha)(bulk)(T) and tau(beta)(bulk)(T), we conclude that the Vogel-Fulcher Tammann-Hesse (VFTH) dependence of tau(alpha)(bulk)(T) cannot hold for glass formers in equilibrium at temperatures significantly below T(g)(bulk). In addition, tau(alpha)(bulk)(T) does not diverge at the Vogel temperature, T0, as suggested by the VFTH-dependence and predicted by some theories of glass transition. Instead, tau(alpha)(bulk)(T) of the glass-former at equilibrium has a much weaker temperature dependence than the VFTH-dependence at temperature below T(g)(bulk) and even below T0. This conclusion from our analysis is consistent with the temperature dependence of tau(alpha)(bulk)(T) found experimentally in polymers aged long enough time to attain the equilibrium state at various temperatures below T(g)(bulk). PMID- 24798794 TI - Influence of mosquito genotype on transcriptional response to dengue virus infection. AB - The mosquito Aedes aegypti is the principal vector that transmits dengue virus (DENV) to humans. The primary factors that trigger a susceptible or refractory interaction of A. aegypti with DENV are not well understood. In this study, our aim is to characterize the influence of vector genotype on differential gene expression of susceptible vs. refractory A. aegypti strains to DENV infection. To accomplish that, we identified differential expression of a set of complementary DNAs (cDNAs; n = 9,504) of the D2S3 (susceptible) and Moyo-D (refractory) strains of A. aegypti to DENV serotype 2 (JAM1409) and compared these results to the differential expression of cDNAs in a different susceptible vector genotype (Moyo S) relative to the same refractory genotype (Moyo-D) identified from our previous study. We observed that, although the number of differentially expressed transcripts (DETs) was similar in both the studies, about ~95% of the DETs were distinct between Moyo-D/D2S3 vs. Moyo-D/Moyo-S. This suggested that A. aegypti response, to infection of a given genotype of dengue, is largely dependent upon the vector genotype. However, we observed a set of common DETs among the vector strains that were associated with predicted functions such as endocytosis, regulation of autophagy, peroxisome, and lipid metabolism that may be relatively universal in conferring mosquito response to DENV infection. PMID- 24798796 TI - Diffusion-weighted magnetic resonance imaging of the normal canine brain. AB - Diffusion-weighted imaging (DWI) MRI has been primarily reported as a method for diagnosing cerebrovascular disease in veterinary patients. In humans, clinical applications for diffusion-weighted MRI have also included epilepsy, Alzheimer's, and Creutzfeld-Jakob disease. Before these applications can be developed in veterinary patients, more data on brain diffusion characteristics are needed. Therefore, the aim of this study was to evaluate the distribution of diffusion in the normal canine brain. Magnetic resonance imaging of the brain was performed in ten, clinically normal, purpose-bred beagle dogs. On apparent diffusion coefficient maps, regions of interest were drawn around the caudate nucleus, thalamus, piriform lobe, hippocampus, semioval center, and cerebral cortex. Statistically significant differences in mean apparent diffusion coefficient were found for the internal capsule, hippocampus, and thalamus. The highest apparent diffusion coefficient (1044.29 +/- 165.21 MUm(2)/s (mean +/- SD (standard deviation)) was detected in the hippocampus. The lowest apparent diffusion coefficient was measured in the semioval center (721.39 +/- 126.28 MUm(2)/s (mean +/- SD)). Significant differences in mean apparent diffusion coefficients of the caudate nucleus, thalamus, and piriform lobe were found by comparing right and left sides. Differences between brain regions may occur due to differences in myelination, neural density, or fiber orientation. The reason for the differences between right and left sides remains unclear. Data from the current study provide background for further studies of diffusion changes in dogs with brain disease. PMID- 24798797 TI - Aqueous batteries based on mixed monovalence metal ions: a new battery family. AB - As existing battery technologies struggle to meet the requirements for widespread use in the field of large-scale energy storage, new concepts are urgently needed to build batteries with high energy density, low cost, and good safety. Here, we demonstrate two new aqueous batteries based on two monovalence metal ions (Li(+) /K(+) and Na(+) /K(+) ) as charge-transfer ions, Ni1 Zn1 HCF/TiP2 O7 and Ni1 Zn1 HCF/NaTi2 (PO4 )3 . These new batteries are unlike the conventional "rocking chair" aqueous metal-ion batteries based on the migration of one type of shuttle ion between cathode and anode. They can deliver specific energy of 46 Wh kg(-1) and 53 Wh kg(-1) based on the total mass of active materials; this is superior to current aqueous battery systems based on sodium-ion and/or potassium-ion technologies. These two new batteries together with the previously developed Li(+) /Na(+) mixed-ion battery not only constitute a new battery family for energy storage, but also greatly broaden our horizons for battery research. PMID- 24798798 TI - Structure of the iron-free true C-terminal half of bovine lactoferrin produced by tryptic digestion and its functional significance in the gut. AB - Bovine lactoferrin, a 76-kDa glycoprotein (Ala1-Arg689) consists of two similar N and C-terminal molecular halves with the ability to bind two Fe(3+) ions. The N terminal half, designated as the N-lobe (Ala1-Arg341) and the C-terminal half designated as the C-lobe (Tyr342-Arg689) have similar iron-binding properties, but the resistant C-lobe prolongs the physiological role of bovine lactoferrin in the digestive tract. Here, we report the crystal structure of true C-lobe, which was produced by limited proteolysis of bovine lactoferrin using trypsin. In the first proteolysis step, two fragments of 21 kDa (Glu86-Lys282) and 45 kDa (Ser283 Arg689) were generated because two lysine residues, Lys85 and Lys282, in the structure of iron-saturated bovine lactoferrin were fully exposed. The 45-kDa fragment was further digested at the newly exposed side chain of Arg341, generating a 38-kDa perfect C-lobe (Tyr342-Arg689). By contrast, the apo lactoferrin was cut by trypsin only at Arg341, which was exposed in the structure of apo-lactoferrin, whereas the other two sites with Lys85 and Lys282 are inaccessible. The purified iron-saturated C-lobe was crystallized at pH 4.0. The structure was determined by the molecular replacement method using coordinates of the C-terminal half (Arg342-Arg689) of intact camel apo-lactoferrin. The structure determination revealed that the iron atom was absent and the iron binding cleft was found in a wide-open conformation, whereas in the previously determined structure of iron-saturated C-lobe of bovine lactoferrin, the iron atom was present and the iron-binding site was in the closed confirmation. PMID- 24798799 TI - Evaluation of the Analytical Performance of the Olympus AU5421 Applied with Parameters Developed by the Toshiba 200FR for Measurement of Blood Ethanol Concentration. AB - BACKGROUND: An accurate determination of blood ethanol concentrations is important. To minimize ethanol degradation in blood samples, sodium fluoride (NaF) collection tubes have been recommended for use. In this study, we attempted to utilize the Olympus AU5421 chemistry analyzer for ethanol analysis based on the parameters established for the Toshiba 200FR. We also evaluated the effect of NaF collection tubes on ethanol concentrations. METHODS: The precision, linearity, accuracy, and carry-over rate of the AU5421 analyzer were evaluated. The results of analysis using the AU5421 and Abbott AxSYM analyzers were also compared. The effects of NaF collection tubes on ethanol concentrations in stored samples were measured. RESULTS: The AU5421 showed a good precision, linearity, accuracy, and carry-over rate. The ethanol concentrations were well correlated with the results obtained using the AxSYM. There was no statistically significant difference in blood ethanol concentrations between the samples collected in tubes with NaF and those collected in tubes without NaF. CONCLUSIONS: Since the AU5421 showed excellent analytical performance, the AU5421 could be used as an alternative to AxSYM for the determination of blood ethanol concentrations. Our analysis also indicated that there is no need to use NaF collection tubes if blood ethanol concentrations are analyzed within 3 h after blood collection. We believe that the results obtained in this study will have important implications for the use of the AU5421 system to measure blood ethanol concentrations. PMID- 24798800 TI - Anthelmintic resistance in cattle nematodes in the US. AB - The first documented case of macrocyclic lactone resistance in gastrointestinal (GI) nematodes of cattle was seen in the US approximately 10 years ago. Since that time the increase incidence of anthelmintic resistance has continued at an alarming rate. Currently parasites of the genera Cooperia and/or Haemonchus resistant to generic or brand-name macrocyclic lactones have be demonstrated in more than half of all operations examined. Both of these parasite genera are capable of causing economic losses by decreasing food intake and subsequently animal productivity. Currently, there are no easy and quick means to detect anthelmintic resistant GI nematodes. Definitive identification requires killing of cattle. The most commonly used field detection method is the fecal egg count reduction test (FECRT). This method can be adapted for use as a screening agent for Veterinarians and producers to identify less than desired clearance of the parasites after anthelmintic treatment. Further studies can then define the reasons for persistence of the egg counts. The appearance of anthelmintic resistance is largely due to the development of very effective nematode control programs that have significantly improved the productivity of the US cattle industry, but at the same time has placed a high level of selective pressure on the parasite genome. The challenges ahead include the development of programs that control the anthelmintic resistant nematodes but at the same time result in more sustainable parasite control. The goal is to maintain high levels of productivity but to exert less selective pressures on the parasites. One of the most effective means to slow the development of drug resistance is through the simultaneous use of multiple classes of anthelmintics, each of which has a different mode of action. Reduction of the selective pressure on the parasites can be attained through a more targeted approach to drug treatments where the producer's needs are met by selective treatment of different classes of animals and not by blanket treatment at a location. The implementation of such programs will vary by the sector of the industry and the individual site. In general, the feedlot will be the easiest sector for developing of programs, while stocker/backgrounder operations will provide the most challenging problems. A major question that must be addressed is whether it is important that parasite control programs to be sustainable over time, or if the pharmaceutical industry develop new control agents at a rate sufficient to render sustainability unimportant. PMID- 24798802 TI - Charting future directions in nursing research: NINR's Innovative Questions Initiative. PMID- 24798801 TI - In vitro study of normoxic epidermal growth factor receptor-induced hypoxia inducible factor-1-alpha, vascular endothelial growth factor, and BNIP3 expression in head and neck squamous cell carcinoma cell lines: Implications for anti-epidermal growth factor receptor therapy. AB - BACKGROUND: We previously showed that activation of epidermal growth factor receptor (EGFR) induces hypoxia inducible factor-1alpha (HIF-1alpha) in head and neck squamous cell carcinoma (HNSCC) cells. In this study, we have furthered this by investigating the mechanism of HIF-1alpha activation by epidermal growth factor (EGF) and its association with the sensitivity to gefitinib. METHODS: EGFR/HIF-1alpha signaling was tested by immunoblot, polymerase chain reaction (PCR), cell proliferation, and apoptosis assays. RESULTS: HIF-1alpha accumulated in cells overexpressing EGF and phosphorylated epidermal growth factor receptor (pEGFR), phosphatidylinositol-3-kinase (pPI3K), and mitogen-activated protein kinase (pMAPK). EGF-induced expression of HIF-1alpha and its targets, vascular endothelial growth factor (VEGF) and BNIP3, were blocked by gefitinib and PI3K inhibitors and MAPK-inhibitors. HIF-1alpha-siRNAs abrogated EGF-induced BNIP3 but not VEGF expression. Gefitinib inhibited cell proliferation and induced apoptosis more strongly in cells with constitutively active EGFR/HIF-1alpha signaling than in cells lacking activation of these pathways. HIF-1alpha-siRNA treatment reduced sensitivity to gefitinib. CONCLUSION: The search for molecular predictors of sensitivity to gefitinib in HNSCC should be extended to the activation status of EGFR-downstream pathways, phosphorylated protein kinase B, pMAPK, and HIF-1alpha. PMID- 24798804 TI - New opportunity for the development of nursing in China. PMID- 24798805 TI - Evaluation of the technological and sensory properties of durum wheat spaghetti enriched with different dietary fibres. AB - The incorporation of fibres, whether insoluble or soluble, in durum wheat pasta negatively impacts desirable end-use properties, especially if incorporated in significant amounts. Fibres can disrupt the starch-protein matrix of the dough during pasta preparation and can also often swell more readily with water than starch, competing with the starch for water during dough development. Similar degrees of substitution with different fibres gave markedly different impacts on firmness, stickiness, cooking loss and sensory attributes, suggesting that results obtained for one fibre cannot readily be generalized to other fibres. The in vitro starch digestibility of the pastas was significantly reduced when resistant starch, beta-glucan-enriched flour, carboxymethyl cellulose or guar gum was incorporated but increased when pollard or inulin was added. In many instances, different sources of the same fibre gave dramatically different impacts on the properties of cooked durum wheat pasta. PMID- 24798806 TI - Structure and thermoelectric properties of spark plasma sintered ultrathin PbTe nanowires. AB - Solution-synthesized thermoelectric nanostructured materials have the potential to have lower cost and higher performance than materials synthesized by solid state methods. Herein we present the synthesis of ultrathin PbTe nanowires, which are compressed by spark plasma sintering at various temperatures in the range of 405-500 degrees C. The resulting discs possess grains with sizes of 5-30 MUm as well as grains with sizes on the order of the original 12 nm diameter PbTe nanowires. This micro- and nanostructure leads to a significantly reduced thermal conductivity compared to bulk PbTe. Careful electron transport analysis shows suppressed electrical conductivity due to increased short-range and ionized defect scatterings, while the Seebeck coefficient remains comparable to the bulk value. The PbTe nanowire samples are found unintentionally p-type doped to hole concentrations of 2.16-2.59 * 10(18) cm(-3). The maximum figure of merit achieved in the unintentionally doped spark plasma sintered PbTe nanowires is 0.33 at 350 K, which is among the highest reported for unintentionally doped PbTe at low temperatures. PMID- 24798807 TI - Diagnostic performance of random urine samples using albumin concentration vs ratio of albumin to creatinine for microalbuminuria screening in patients with diabetes mellitus: a systematic review and meta-analysis. AB - IMPORTANCE: A random urine sample measuring the albumin concentration (UAC) without simultaneously measuring the urinary creatinine is less expensive than measuring the ratio of albumin to creatinine (ACR), but comparisons of their diagnostic performance for microalbuminuria screening among patients with diabetes mellitus (DM) have not been undertaken in previous meta-analyses. OBJECTIVE: To compare the diagnostic performance of the UAC vs the ACR in random urine samples for microalbuminuria screening among patients with DM. DATA SOURCES: Electronic literature searches of PubMed, MEDLINE, and Scopus for English-language publications from the earliest available date of indexing through July 31, 2012. STUDY SELECTION: Clinical studies assessing the UAC or the ACR of random urine samples in detecting the presence of microalbuminuria among patients with DM using a urinary albumin excretion rate of 30 to 300 mg/d in 24 hour timed urine collections as the criterion standard. DATA EXTRACTION AND SYNTHESIS: Bivariate random-effects models for analysis and pooling of the diagnostic performance measures across studies, as well as comparisons between different screening tests. MAIN OUTCOMES AND MEASURES: The primary end point was the diagnostic performance measures of the UAC or the ACR in random urine samples, as well as comparisons between them. RESULTS: We identified 14 studies, with a total of 2078 patients; 9 studies reported on the UAC, and 12 studies reported on the ACR. Meta-analysis showed pooled sensitivities of 0.85 and 0.87 for the UAC and the ACR, respectively, and pooled specificities of 0.88 and 0.88, respectively. No differences in sensitivity (P = .70), specificity (P = .63), or diagnostic odds ratios (P = .59) between the UAC and the ACR were found. The time point of urine collection did not affect the diagnostic performance of either test. CONCLUSIONS AND RELEVANCE: The UAC and the ACR yielded high sensitivity and specificity for the detection of microalbuminuria. Because the diagnostic performance of the UAC is comparable to that of the ACR, our findings indicate that the UAC of random urine samples may become the screening tool of choice for the population with DM, considering the rising incidence of DM and the constrained health care resources in many countries. PMID- 24798808 TI - Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: a comparative study. AB - The multipotent and immunosuppressive capacities of mesenchymal stem cells (MSCs) attract several scientists worldwide towards translational research focusing on treatment of diseases including liver failure. Though MSC's have been isolated from different sources, researchers do not concur on the best source for expansion and clinical translation. In this study, we have compared the isolation, proliferation and expansion of MSCs from umbilical cord blood (UCB), Wharton's Jelly (WJ), bone marrow (BM) and adipose tissue (AT). MSCs were isolated by density gradient separation from UCB, BM and AT and by both enzymatic and explant method for WJ. The MSCs are characterized by their ability to adhere to plastic, expression of positive (CD105, CD73, CD90, CD29, CD44) and negative (CD45, CD14, CD34) markers by flow cytometry and also by their in vitro adipogenic, osteogenic and chondrogenic differentiation. This comprehensive study clearly shows that WJ is better than UCB both in terms of rapidity, yield and ease of procedure. AT and BM are autologous sources for MSC's but the specimen collection involves cumbersome and painful procedures and an invasive approach. However being autologous, they are safe and probable candidates for therapeutic future applications. PMID- 24798809 TI - Amino acid consumption in naive and recombinant CHO cell cultures: producers of a monoclonal antibody. AB - Most commercial media for mammalian cell culture are designed to satisfy the amino acid requirements for cell growth, but not necessarily those for recombinant protein production. In this study, we analyze the amino acid consumption pattern in naive and recombinant Chinese hamster ovary (CHO) cell cultures. The recombinant model we chose was a CHO-S cell line engineered to produce a monoclonal antibody. We report the cell concentration, product concentration, and amino acid concentration profiles in naive and recombinant cell cultures growing in CD OptiCHOTM medium with or without amino acid supplementation with a commercial supplement (CHO CD EfficientFeedTM B). We quantify and discuss the amino acid demands due to cell growth and recombinant protein production during long term fed batch cultivation protocols. We confirmed that a group of five amino acids, constituting the highest mass fraction of the product, shows the highest depletion rates and could become limiting for product expression. In our experiments, alanine, a non-important mass constituent of the product, is in high demand during recombinant protein production. Evaluation of specific amino acid demands could be of great help in the design of feeding/supplementation strategies for recombinant mammalian cell cultures. PMID- 24798810 TI - Hypoxia enhances proliferation and stemness of human adipose-derived mesenchymal stem cells. AB - The aim of the study was to obtain the highest number of multipotent adipose derived mesenchymal stem cells (ADMSCs) by using culture conditions which favour cell expansion without loss of mesenchymal stem cells (MSC)-like properties. Based on the assumption that stem cells reside in niches characterized by hypoxic condition, we investigated if the low oxygen tension may improve the proliferation and stemness of ADMSCs. Intact adipose tissue was resected from eight subjects, and the stromal vascular fraction was obtained by using type II collagenase. The heterogeneity of cellular lineages was confirmed by immunophenotypic analysis that showed the presence of leukocytes (CD45+), endothelial cells (CD34+), and pericytes (CD140+). The immunophenotype of confluent ADMSCs was similar to that of bone marrow-derived MSCs, except for the expression of CD34, which was variable (donor-dependent) and inversely correlated to the CD36 expression. ADMSCs showed a high clonal efficiency (94.5 +/- 1 %) and were able to generate osteoblastic, chondrocytic and adipocytic lineages. ADMSCs were cultured under normoxic (21 % O2) and hypoxic (1 % O2) conditions, and we found that hypoxia significantly favoured ADMSC proliferation and preserved the expression of stemness genes, i.e. Nanog and Sox2. Since hypoxia reflects the microenvironment in which ADMSCs must proliferate and differentiate, the culture in hypoxic condition allows to better understand the biology of these cells and their regenerative potential. Low oxygen concentrations promote cell proliferation and stemness, thus enriching the pool of cells potentially able to differentiate into multi-lineages, and extending the possibility of a long-term expansion. PMID- 24798811 TI - Isolation of serpin-interacting proteins in C. elegans using protein affinity purification. AB - Caenorhabditis elegans is a useful model organism for combining multiple imaging, genetic, and biochemical methodologies to gain more insight into the biological function of specific proteins. Combining both biochemical and genetic analyses can lead to a better understanding of how a given protein may function within the context of a network of other proteins or specific pathway. Here, we describe a protocol for the biochemical isolation of serpin-interacting proteins using affinity purification and proteomic analysis. As the knowledge of in vivo serpin interacting partners in C. elegans has largely been obtained using genetic and in vitro recombinant protein studies, this protocol serves as a complementary approach to provide insight into the biological function and regulation of serpins. PMID- 24798813 TI - Mutual influences in adult romantic attachment, religious coping, and marital adjustment. AB - In this study, we examined associations among romantic attachment anxiety and avoidance, positive and negative religious coping, and marital adjustment in a community sample of 81 heterosexual couples. Multilevel modeling (MLM) for the Actor-Partner Interdependence Model (APIM; Cook & Kenny, 2005) was used to analyze data from both spouses. Romantic attachment avoidance was associated with less positive religious coping, and romantic attachment anxiety was associated with more negative religious coping. Findings are discussed in light of Hall, Fujikawa, Halcrow, Hill, and Delaney's (2009) Implicit Internal Working Model Correspondence framework. We also found support for Sullivan's (2001) compensation model for attachment avoidance but not for attachment anxiety. That is, positive religious coping buffered the deleterious relationship between attachment avoidance and marital adjustment. However, positive religious coping did not attenuate the negative impact of attachment anxiety on marital adjustment and was associated with higher marital adjustment only for those individuals with low attachment anxiety. Surprisingly, negative religious coping reduced the negative impact of the partner's attachment anxiety on respondents' marital adjustment. Results suggest that attachment theory is one useful approach to conceptualizing religious coping, highlight the complexity of these associations, and point to future research directions. Findings also support the consideration of both attachment dimensions and religious coping in research and applied work with adults and couples. PMID- 24798814 TI - A dyadic examination of family-of-origin influence on newlyweds' marital satisfaction. AB - The present study examined the influence of family-of-origin characteristics on current newlywed husbands' and wives' marital satisfaction, as well as possible mediation by current conflict resolution style. Results of a series of structural equation models, based on the Actor-Partner Interdependence Model (APIM), indicated that the family-of-origin characteristics (e.g., parental divorce, interparental conflict) were associated with lower marital satisfaction, especially for wives. Mixed evidence was found to indicate that conflict resolution style may partially mediate this relationship. Current findings provide evidence to support the phenomenon of the intergenerational transmission of marital quality found in the extant literature, but add to this literature by utilizing the APIM, including dyadic data collection and analyses techniques. Interpretations and implications are discussed, and future directions for research are suggested. PMID- 24798812 TI - Investigating spermatogenesis in Drosophila melanogaster. AB - The process of spermatogenesis in Drosophila melanogaster provides a powerful model system to probe a variety of developmental and cell biological questions, such as the characterization of mechanisms that regulate stem cell behavior, cytokinesis, meiosis, and mitochondrial dynamics. Classical genetic approaches, together with binary expression systems, FRT-mediated recombination, and novel imaging systems to capture single cell behavior, are rapidly expanding our knowledge of the molecular mechanisms regulating all aspects of spermatogenesis. This methods chapter provides a detailed description of the system, a review of key questions that have been addressed or remain unanswered thus far, and an introduction to tools and techniques available to probe each stage of spermatogenesis. PMID- 24798815 TI - What difference does a day make? Examining temporal variations in partner maltreatment. AB - Routine activities (RA) theory posits that changes in people's typical daily activities covary with increases or decreases in criminal behaviors, including, but not limited to, partner maltreatment. Using a large clinical database, we examined temporal variations among 24,460 incidents of confirmed partner maltreatment across an 11-year period within the U.S. Air Force (USAF). Specifically, we created regression models that predicted the number of partner maltreatment incidents per day. In addition to several control variables, we coded temporal variables for days of the week, month, year, and several significant days (e.g., holidays, Super Bowl Sunday), which allowed us to examine the independent influence of these variables on partner maltreatment prevalence. While accounting for the influence of all other study variables, we observed significant increases in partner maltreatment for weekend days, New Year's Day, Independence Day, and Super Bowl Sunday. Similar results were found for partner maltreatment incidents involving offender alcohol/drug use. Furthermore, the proportion of incidents involving offender alcohol/drug use increased on New Year's Day and Independence Day. Consistent with RA theory and data from civilian samples, the current results indicate that certain days are associated with increased incidents of partner maltreatment within the USAF. These findings should be used to inform future preventive efforts. PMID- 24798817 TI - Parenting intervention effects on parental depressive symptoms: examining the role of parenting and child behavior. AB - Parental depression is a major risk factor in child development. Growing research suggests parenting programs can positively impact parental depressive symptoms, although the specific mechanisms that explain these effects are unknown. The current study examined parenting mediated effects of a parenting program on mothers' and fathers' depressive symptoms, as well as the role of child behavior in linking parenting to reductions in depressive symptoms. The study samples included 494 mothers and 288 fathers of Mexican origin adolescents who participated in a randomized trial of the Bridges to High School Program/Proyecto Puentes a la Secundaria, a universal prevention and promotion intervention that included parent training but did not directly target parental depressive symptoms. Parenting mediator models tested program effects on parental depressive symptoms through changes in harsh and supportive parenting. Results showed a significant indirect intervention effect on maternal depressive symptoms through changes in mothers' harsh parenting. Next, child behavior models revealed a partial mediation effect of harsh parenting and a full mediation effect of supportive parenting on maternal depressive symptoms through mothers' reports of child externalizing symptoms. Indirect effects of fathers' harsh and supportive parenting on paternal depressive symptoms were also found through fathers' reports of child behavior. PMID- 24798816 TI - Family involvement in the psychological treatment of obsessive-compulsive disorder: a meta-analysis. AB - Psychological treatments for obsessive-compulsive disorder (OCD) are increasingly aimed at improving outcomes by directly incorporating family members to address family disruption, dysfunction, or symptom accommodation. Much remains to be learned about the pooled effects of "family inclusive treatment" (FIT) for OCD and factors that may explain variation in response. Random-effects meta-analytic procedures were conducted to empirically evaluate the overall effect of FITs on OCD, and treatment moderators. Study search criteria yielded 29 studies examining FIT response in 1,366 OCD patients. Outcome variables included OCD symptoms and global functioning. Examined moderators included age group, gender, minority status, treatment length and format, and inclusion of specific family focused treatment elements. FITs for OCD demonstrated a large overall effect on OCD symptoms (pooled d = 1.68, SE = 0.14) and global functioning (pooled d = 0.98, SE = 0.14). Moderator analyses found that individual family treatments (vs. group) and FITs targeting family accommodation of symptoms (vs. those that did not target accommodation) were associated with greater improvements in patient functioning. Results indicate a robust overall response to FITs for OCD and clarify key moderators that inform optimal circumstances for effective treatment. Findings underscore the need for continued momentum in the development, evaluation, and dissemination of FITs for OCD. PMID- 24798818 TI - Single wavelength shadow imaging of Caenorhabditis elegans locomotion including force estimates. AB - This study demonstrates an inexpensive and straightforward technique that allows the measurement of physical properties such as position, velocity, acceleration and forces involved in the locomotory behavior of nematodes suspended in a column of water in response to single wavelengths of light. We demonstrate how to evaluate the locomotion of a microscopic organism using Single Wavelength Shadow Imaging (SWSI) using two different examples. The first example is a systematic and statistically viable study of the average descent of C. elegans in a column of water. For this study, we used living and dead wildtype C. elegans. When we compared the velocity and direction of nematode active movement with the passive descent of dead worms within the gravitational field, this study showed no difference in descent-times. The average descent was 1.5 mm/sec +/- 0.1 mm/sec for both the live and dead worms using 633 nm coherent light. The second example is a case study of select individual C. elegans changing direction during the descent in a vertical water column. Acceleration and force are analyzed in this example. This case study demonstrates the scope of other physical properties that can be evaluated using SWSI while evaluating the behavior using single wavelengths in an environment that is not accessible with traditional microscopes. Using this analysis we estimated an individual nematode is capable of thrusting with a force in excess of 28 nN. Our findings indicate that living nematodes exert 28 nN when turning, or moving against the gravitational field. The findings further suggest that nematodes passively descend in a column of water, but can actively resist the force of gravity primarily by turning direction. PMID- 24798819 TI - A novel class of succinimide-derived negative allosteric modulators of metabotropic glutamate receptor subtype 1 provides insight into a disconnect in activity between the rat and human receptors. AB - Recent progress in the discovery of mGlu1 allosteric modulators has suggested the modulation of mGlu1 could offer possible treatment for a number of central nervous system disorders; however, the available chemotypes are inadequate to fully investigate the therapeutic potential of mGlu1 modulation. To address this issue, we used a fluorescence-based high-throughput screening assay to screen an allosteric modulator-biased library of compounds to generate structurally diverse mGlu1 negative allosteric modulator hits for chemical optimization. Herein, we describe the discovery and characterization of a novel mGlu1 chemotype. This series of succinimide negative allosteric modulators, exemplified by VU0410425, exhibited potent inhibitory activity at rat mGlu1 but was, surprisingly, inactive at human mGlu1. VU0410425 and a set of chemically diverse mGlu1 negative allosteric modulators previously reported in the literature were utilized to examine this species disconnect between rat and human mGlu1 activity. Mutation of the key transmembrane domain residue 757 and functional screening of VU0410425 and the literature compounds suggests that amino acid 757 plays a role in the activity of these compounds, but the contribution of the residue is scaffold specific, ranging from critical to minor. The operational model of allosterism was used to estimate the binding affinities of each compound to compare to functional data. This novel series of mGlu1 negative allosteric modulators provides valuable insight into the pharmacology underlying the disconnect between rat and human mGlu1 activity, an issue that must be understood to progress the therapeutic potential of allosteric modulators of mGlu1. PMID- 24798820 TI - Potent biphalin analogs with u/delta mixed opioid activity: in vivo and in vitro biological evaluation. AB - Biphalin [(Tyr-D-Ala-Gly-Phe-NH-)2 ] is an octapeptide with mixed MU/delta opioid activity. Its structure is based on two identical enkephalin-like portions linked "tail-to-tail" by a hydrazine bridge. This study presents the synthesis and in vitro and in vivo bioassays of two biphalin analogs that do not present the toxicity connected with the presence of the hydrazine moiety and are able to elicit a higher antinociceptive effect than biphalin. PMID- 24798823 TI - Minimal clinically important difference for change in comfortable gait speed of adults with pathology: a systematic review. AB - RATIONALE, AIMS AND OBJECTIVES: Walking speed is an important performance variable, but information on the minimal clinically important difference (MCID) for the measure has not been consolidated. In this review, we aimed to summarize information on the MCID for change in comfortable gait speed measurements for patients with pathology. METHODS: Relevant literature was identified by searches of four databases (PubMed, Web of Knowledge, CINAHL and Scopus), hand searches and consultation with an expert. Inclusion required that articles reported a MCID for comfortable gait speed measurements. Articles were excluded if the MCID was not determined using receiver operating characteristic (ROC) curve analysis. Articles were abstracted for information on participants, interventions, gait speed documentation and the determination of MCID. Quality was assessed using a hybrid 9-item (0-18 point) instrument. RESULTS: Seven articles were selected based on inclusion and exclusion criteria. The populations studied included stroke (n = 3), hip fracture (n = 2), multiple sclerosis (n = 1) and mixed (n = 1). Using 13 different anchors the studies reported MCIDs of 0.08-0.26 m s(-1) . All but three of these MCIDs were between 0.10 and 0.20 m s(-1) . All MCIDs for which the area under the ROC curve exceeded 0.70 were between 0.10 and 0.17 m s( 1) . CONCLUSIONS: Changes in gait speed of 0.10 to 0.20 m s(-1) may be important across multiple patient groups. PMID- 24798824 TI - Boosted activation of right inferior frontoparietal network: a basis for illusory movement awareness. AB - The feeling of illusory movement is considered important in the study of human behavior because it is deeply related to motor consciousness. However, the neural basis underlying the illusion of movement remains to be understood. Following optimal vibratory stimulation of muscle tendon, certain subjects experience illusory movements while others do not. In the present fMRI study, we sought to uncover the neural basis of illusory movement awareness by contrasting a posteriori these two types of subjects. Examining fMRI data using leave-one subject-out general linear models and region of interest analyses, we found that a non-limb-specific associative network, including the opercular part of the right inferior frontal gyrus and the right inferior parietal lobule, was more active in subjects with illusions. On the other hand, levels of activation in other brain areas involved in kinaesthetic processing were rather similar between the two subsamples of subjects. These results suggest that activation of the right inferior frontoparietal areas, once passed a certain threshold, forms the basis of illusory movements. This is consistent with the global neuronal workspace hypothesis that associates conscious processing with surges of frontoparietal activity. PMID- 24798825 TI - Changes in the carbon footprint of Japanese households in an aging society. AB - As the aging and low birthrate trends continue in Japan, and as changes in the working population and consumption patterns occur, new factors are expected to have an impact on consumption-based greenhouse gas (GHG) emissions. We present the impacts of changes in the composition of Japanese households on GHG emission structures using current (2005) consumption-based accounting on the commodity sectors that are expected to require priority efforts for reducing emissions in 2035. This is done using the Global Link Input-Output model (GLIO) and domestic household consumption data and assuming that recent detailed consumption expenditures based on the Social Accounting Matrix (SAM) will continue into the future. The results show that consumption-based GHG emissions derived from Japanese household consumption in 2035 are estimated to be 1061 Mt-CO2eq (4.2% lower than in 2005). This study can be used to reveal more information and as a resource in developing policies to more meticulously and efficiently reduce emissions based on emission and import rates for each domestic and overseas commodity supply chain. PMID- 24798826 TI - Thromboembolism in ultrasound: killing three birds with one stone. PMID- 24798827 TI - Our responsibility for training physicians to understand the effect patient death has on them: the role of the intensivist. PMID- 24798828 TI - The CODEX index: a collection or digest of laws: a code. PMID- 24798830 TI - Point: were industry-sponsored roflumilast trials appropriate? Yes. PMID- 24798831 TI - Counterpoint: were industry-sponsored roflumilast trials appropriate? No. PMID- 24798832 TI - Rebuttal from Drs Suissa and Rabe. PMID- 24798833 TI - Rebuttal from Dr Rho et al. PMID- 24798834 TI - Telemedicine in COPD: time to pause. AB - There is increasing interest in the use of telemedicine to assist in the management of chronic diseases. Telemedicine possibilities for patients with COPD include medical consultations, in-home patient monitoring, and remote rehabilitation. Teleconsultations have been used successfully, saving time and travel costs for patients with only a few subsequently requiring face-to-face visits. Despite many reports, the impact of telemonitoring on the detection of exacerbations, reductions in health-care utilization, and cost savings is equivocal. Given the health-care costs and commitment involved in telemonitoring, well-designed longer-term multicenter studies with appropriate follow-up are required prior to its more widespread application. Emerging evidence from preliminary trials of telerehabilitation for the pulmonary patient is encouraging. It may represent a useful tool for increasing access and building capacity, especially in remote areas. PMID- 24798835 TI - Noncontrast perfusion single-photon emission CT/CT scanning: a new test for the expedited, high-accuracy diagnosis of acute pulmonary embolism. AB - BACKGROUND: Standard ventilation and perfusion (V/Q) scintigraphy uses planar images for the diagnosis of pulmonary embolism (PE). To evaluate whether tomographic imaging improves the diagnostic accuracy of the procedure, we compared noncontrast perfusion single-photon emission CT (Q-SPECT)/CT scans with planar V/Qscans in patients at high risk for PE. METHODS: Between 2006 and 2010, most patients referred for diagnosis of PE underwent both Q-SPECT/CT scan and planar V/Qscintigraphy. All scans were reviewed retrospectively by four observers; planar scans were read with modified Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II and Prospective Investigative Study of Pulmonary Embolism Diagnosis (PISA-PED) criteria. On Q-SPECT/CT scan, any wedge shaped peripheral perfusion defect occupying > 50% of a segment without corresponding pulmonary parenchymal or pleural disease was considered to show PE. The final diagnosis was established with a composite reference standard that included ECG, ultrasound of lower-extremity veins, D-dimer levels, CT pulmonary angiography (when available), and clinical follow-up for at least 3 months. RESULTS: One hundred six patients with cancer and mean Wells score of 4.4 had sufficient follow-up; 22 patients were given a final diagnosis of PE, and 84 patients were given a final diagnosis of no PE. According to PIOPED II, 13 studies were graded as intermediate probability. Sensitivity and specificity for PE were 50% and 98%, respectively, based on PIOPED II criteria; 86% and 93%, respectively, based on PISA-PED criteria; and 91% and 94%, respectively, based on Q-SPECT/CT scan. Seventy-six patients had additional relevant findings on the CT image of the Q-SPECT/CT scan. CONCLUSIONS: Noncontrast Q-SPECT/CT imaging has a higher accuracy than planar V/Qimaging based on PIOPED II criteria in patients with cancer and a high risk for PE. PMID- 24798836 TI - Inflammasomes in respiratory disease: from bench to bedside. AB - The respiratory tract of human subjects is constantly exposed to harmful microbes and air pollutants. The immune system responds to these offenders to protect the host, but an unbalanced inflammatory response itself may promote tissue damage and ultimately lead to acute and chronic respiratory diseases. Deregulated inflammasome activation is emerging as a key modulator of respiratory infections and pathologic airway inflammation in patients with asthma, COPD, and pulmonary fibrosis. Assembly of these intracellular danger sensors in cells of the respiratory mucosa and alveolar compartment triggers a proinflammatory cell death mode termed pyroptosis and leads to secretion of bioactive IL-1beta and IL-18. Here, we summarize and review the inflammasome and its downstream effectors as therapeutic targets for the treatment of respiratory diseases. PMID- 24798837 TI - The changing landscape of adult home noninvasive ventilation technology, use, and reimbursement in the United States. AB - There has been an exponential increase in the use of home noninvasive ventilation (NIV). Despite growing use, there is a paucity of evidence-based guidelines and practice standards in the United States to assist clinicians in the initiation and ongoing management of home NIV. Consequently, home NIV practices are being influenced by complicated local reimbursement policies and coding. This article aims to provide a practice management perspective for clinicians providing home NIV, including Local Coverage Determination reimbursement criteria for respiratory assist devices, Durable Medical Equipment coding, and Current Procedural Terminology coding to optimize clinical care and minimize lost revenue. It highlights the need for further research and development of evidence based clinical practice standards to ensure best practice policies are in place for this rapidly evolving patient population. PMID- 24798838 TI - Symptom relief after large-volume thoracentesis in the absence of lung perfusion. AB - The physiologic basis for relief from dyspnea after therapeutic thoracentesis remains poorly understood. Here, we describe the case of a 46-year-old man with large recurrent pleural effusion with absent perfusion to the affected lung who experienced dramatic dyspnea relief after large-volume thoracentesis. This patient's improvement in breathlessness cannot be attributed to improved gas exchange and suggests the primary physiologic basis for the relief in dyspnea is a change in respiratory system mechanics or work of breathing. PMID- 24798839 TI - Challenges in providing critical care for patients with anti-N-methyl-D-aspartate receptor encephalitis. AB - Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is characterized by a constellation of psychiatric, neurologic, autonomic, and cardiopulmonary manifestations. Although patients typically recover with appropriate treatment, they commonly require weeks to months of inpatient care, including prolonged stays in critical care units. This case series not only advocates for consideration of the disease in the appropriate context but also specifically highlights the distinct challenges intensivists encounter caring for patients with NMDARE. With a greater knowledge of the nuances and sequelae of NMDARE, critical care specialists will be better equipped to anticipate and manage the potentially life-threatening complications of the disease. PMID- 24798840 TI - Nutrition in the ICU: an evidence-based approach. AB - Providing artificial nutrition is an important part of caring for critically ill patients. However, because of a paucity of robust data, the practice has been highly variable and often based more on dogma than evidence. A number of studies have been published investigating many different aspects of critical care nutrition. Although the influx of data has better informed the practice, the results have often been conflicting or counter to prevailing thought, resulting in discordant opinions and different interpretations by experts in the field. In this article, we review and summarize the data from a number of the published studies, including studies investigating enteral vs parenteral nutrition, supplementing enteral with parenteral nutrition, and use of immunonutrition. In addition, published studies informing the practice of how best to provide enteral nutrition will be reviewed, including the use of trophic feedings, gastric residual volumes, and gastric vs postpyloric tube placement. PMID- 24798841 TI - A 50-year-old man with a cough and painful chest wall mass. PMID- 24798842 TI - A 57-year-old woman with persistent cough and pulmonary nodules. PMID- 24798843 TI - A 46-year-old woman with persistent asthma and lung masses. PMID- 24798846 TI - Protein Deposits on the Eyeball! Run for your Lives! PMID- 24798847 TI - Thyroid, typhoid. PMID- 24798848 TI - CODEX index and prognosis of patients with exacerbation of COPD. PMID- 24798849 TI - Response. PMID- 24798850 TI - Comprehensive clinical evidence for pulmonary embolism diagnosis and workup. PMID- 24798851 TI - Drug-eluting stents and noncardiac surgery. PMID- 24798852 TI - Response. PMID- 24798853 TI - Adrenal suppression with mometasone furoate/formoterol. PMID- 24798854 TI - Another rare finding of lymphomatoid granulomatosis on CT scan. PMID- 24798855 TI - Response. PMID- 24798856 TI - Non-vitamin K antagonist oral anticoagulants: an appeal for consensus on terminology. PMID- 24798858 TI - A postoperative patient decompensates during transfer from an outside hospital. PMID- 24798860 TI - Simulations of remote mutants of dihydrofolate reductase reveal the nature of a network of residues coupled to hydride transfer. AB - Recent experimental and theoretical studies have proposed that enzymes involve networks of coupled residues throughout the protein that participate in motions accompanying chemical barrier crossing. Here, we have examined portions of a proposed network in dihydrofolate reductase (DHFR) using quantum mechanics/molecular mechanics simulations. The simulations use a hybrid quantum mechanics-molecular mechanics approach with a recently developed semiempirical AM1-SRP Hamiltonian that provides accurate results for this reaction. The simulations reproduce experimentally determined catalytic rates for the wild type and distant mutants of E. coli DHFR, underscoring the accuracy of the simulation protocol. Additionally, the simulations provide detailed insight into how residues remote from the active site affect the catalyzed chemistry, through changes in the thermally averaged properties along the reaction coordinate. The mutations do not greatly affect the structure of the transition state near the bond activation, but we observe differences somewhat removed from the point of C H cleavage that affect the rate. The mutations have global effects on the thermally averaged structure that propagate throughout the enzyme and the current simulations highlight several interactions that appear to be particularly important. PMID- 24798861 TI - Effects of stress reduction on cardiovascular risk factors in type 2 diabetes patients with early kidney disease - results of a randomized controlled trial (HEIDIS). AB - Current guidelines for the treatment of type 2 diabetes focus on pharmacological treatment of glucose and cardio-vascular risk factors. The aim of this prospective randomized controlled intervention study was to examine the effects of a psychosocial intervention on clinical endpoints and risk factors in patients with type 2 diabetes and early diabetic kidney disease.110 patients were randomized to receive an 8-week mindfulness-based stress reduction (MBSR) training (n = 53) compared to standard care (n = 57). The study was carried out open-labelled and randomization was performed computer-generated in a 1:1 ratio. Primary outcome of the study was the change in urinary albumin excretion (albumin creatinine-ratio, ACR); secondary outcomes were metabolic parameters, intima media thickness (IMT), psychosocial parameters and cardiovascular events.89 patients (42 in control group and 47 in intervention group) were analysed after 3 years of follow-up. After 1 year, the intervention group showed a reduction of ACR from 44 [16/80] to 39 [20/71] mg/g, while controls increased from 47 [16/120] to 59 [19/128] mg/g (p = 0.05). Parallel to the reduction of stress levels after 1 year, the intervention-group additionally showed reduced catecholamine levels (p < 0.05), improved 24 h-mean arterial (p < 0.05) and maximum systolic blood pressure (p < 0.01), as well as a reduction in IMT (p < 0.01). However, these effects were lost after 2 and 3 years of follow-up.This is the first study to show that a psychosocial intervention improves cardiovascular risk factors in high risk type 2 diabetes patients. Trial-Registration: NCT00263419 http://clinicaltrials.gov/ct2/show/NCT00263419 TRIAL REGISTRATION: clinicaltrials.gov-Identifier: NCT00263419. PMID- 24798859 TI - Regulation of p53-targeting microRNAs by polycyclic aromatic hydrocarbons: Implications in the etiology of multiple myeloma. AB - Multiple myeloma (MM) is a common and deadly cancer of blood plasma cells. A unique feature of MM is the extremely low somatic mutation rate of the p53 tumor suppressor gene, in sharp contrast with about half of all human cancers where this gene is frequently mutated. Eleven miRNAs have been reported to repress p53 through direct interaction with the 3' untranslated region. The expression of nine of them is higher in MM plasma cells than in healthy donor counterparts, suggesting that miRNA overexpression is responsible for p53 inactivation in MM. Here, we report that the environmental carcinogen benzo[a]pyrene (BaP) upregulated the expression of seven p53-targeting miRNAs (miR-25, miR-15a, miR 16, miR-92, miR-125b, miR-141, and miR-200a), while 2,3,7,8-tetrachlorodibenzo rho-dioxin (TCDD) upregulated two of them (miR-25 and miR-92) in MM cells. The miR-25 promoter was activated by both BaP and TCDD, and this response was mediated by the aryl hydrocarbon receptor (AhR). We screened 727 compounds that inhibit MM cell survival and down-regulate the expression of p53-targeting miRNAs. We found that (-)-epigallocatechin-3-gallate (EGCG), a constituent of green tea and a major component of the botanical drug Polyphenon(r) E, reduced the expression of four p53-targeting miRNAs, including miR-25, miR-92, miR-141, and miR-200a. Collectively, these data implicate polycyclic aromatic hydrocarbons and AhR in the regulation of p53-targeting miRNAs in MM and identify a potential therapeutic and preventive agent to combat this deadly disease. PMID- 24798862 TI - Importance of exercise in the control of metabolic and inflammatory parameters at the moment of onset in type 1 diabetic subjects. AB - The onset of type 1 diabetes coincides with the final phase of beta-cell destruction. In some cases, this period is characterized by the presence of a functional reserve of beta-cells, favouring an adequate metabolic control (honeymoon phase). Therefore, the extension of this situation could have evident benefits in subsequent diabetes management. We aimed to study the influence of regular physical activity before and after the onset of the disease. We did an observational study of 2 groups of type 1 diabetic patients from onset to a 2 year period. One group (n = 8) exercised regularly (5 or more hours/week) before onset and continued doing so with the same regularity. The second group (n = 11) either did not perform physical activity or did so sporadically. Circulating glycated haemoglobin (HbA1c), C-peptide, protein carbonyls and basal cytokine levels were determined at the beginning and at the end of the 1(st) and 2(nd) year. The more active group debuted with and maintained significantly lower HbA(1c) levels and insulin requirements compared to the more sedentary group. C peptide levels were only significantly higher in the active group at the moment of onset compared to the sedentary group. In addition, determination of basal circulating cytokines revealed a large variability between individuals but no significant differences when comparing the groups. Altogether, the obtained results seem to indicate that physical activity allows a better control at the moment of onset regarding glycaemic control, residual endocrine pancreatic mass and subsequent insulin requirements. PMID- 24798863 TI - Non-invasive screening of diabetes risk by assessing abnormalities of sudomotor function. AB - BACKGROUND: The early detection of diabetes, and subsequent lifestyle intervention, may reduce the burden of diabetes and its complications. Several studies have identified a link between sudomotor dysfunction, insulin resistance, and pre-diabetes. The aim of this study was to evaluate the ability of a new non invasive device EZSCAN evaluating sudomotor function to detect pre-diabetes in a German population at risk for diabetes. METHODS AND FINDINGS: 200 German subjects at risk for diabetes (mean age 56+/-14 years, BMI 28.4+/-5.4 kg/m2) were measured for anthropometric data on inflammatory parameters, including high sensitivity C reactive protein (hs-CRP). The subjects also underwent an oral glucose tolerance test with measurements of plasma glucose, insulin, proinsulin, C-peptide and free fatty acids during 2 h following glucose challenge. Indexes for sensitivity to insulin were calculated: SI using minimal model, HOMA-IR and Matsuda index. Based on the measurement of electrochemical sweat conductance, subjects were classified as no risk, moderate risk or high risk. According to this risk model classification, a significant difference was observed between OGTT-1 h (p=0.004), AUC glucose (p=0.011), AUC C-peptide (p<0.001), HOMA-IR (p=0.009), Matsuda (p=0.002), SI (p<0.001) and hs-CRP (p=0.025) after adjustment for age. Among the 54 subjects with impaired fasting glucose or impaired glucose tolerance according to WHO classification, 37 had a moderate risk and 15 a high risk according to the EZSCAN risk model classification. Among the 12 subjects with newly diagnosed diabetes, 2 had a moderate risk and 10 a high risk according to the risk model classification. No adverse event was reported during or after the study. CONCLUSIONS: These results, in accordance with a previous study performed in India, show that EZSCAN could be developed as a screening tool for diabetes risk, and could help to improve diabetes screening strategies. Results obtained from an at-risk population would have to be confirmed in a larger population. PMID- 24798864 TI - Low sodium but not low fructose improves mtDNA. PMID- 24798866 TI - Superior vena cava flow is a clinically valid measurement in the preterm newborn. PMID- 24798865 TI - Mechanical dyssynchrony after cardiac resynchronization therapy for severely symptomatic heart failure is associated with risk for ventricular arrhythmias. AB - BACKGROUND: Risk factors for ventricular arrhythmias after cardiac resynchronization defibrillator therapy (CRT-D) for severely symptomatic heart failure are of clinical importance but are not clearly defined. The objective of this study was to test the hypothesis that mechanical dyssynchrony after CRT-D is a risk factor for ventricular arrhythmias. METHODS: A total of 266 consecutive CRT-D patients with class III or IV heart failure, QRS duration >=120 msec, and ejection fractions <= 35% were prospectively studied. Dyssynchrony was assessed before and 6 months after CRT-D using speckle-tracking radial strain anteroseptal to-posterior wall delay, predefined as >=130 msec. Ventricular arrhythmias were predefined as appropriate antitachycardia pacing or shock, and the combined end point of ventricular arrhythmias, death, transplantation, or left ventricular assist device implantation was followed over 2 years. RESULTS: Of the initial 266 patients, 11 died, five underwent transplantation, three received left ventricular assist devices before their 6-month echocardiographic examinations, 19 (7%) had inadequate speckle-tracking at 6-month follow-up, and 27 (10%) were lost to follow-up. Accordingly, the study group consisted of 201 patients. Dyssynchrony after CRT-D was observed in 79 (39%) and was associated with a significantly higher ventricular arrhythmic event rate: 21% (P < .001) with persistent dyssynchrony and 35% (P < .001) with new dyssynchrony, compared with 8% with no dyssynchrony after CRT-D. The combined end point of ventricular arrhythmias, death, transplantation, or left ventricular assist device implantation was significantly associated with dyssynchrony after CRT-D (hazard ratio, 2.53; 95% confidence interval, 1.49-4.28; P = .001). Dyssynchrony after CRT-D was associated with ventricular arrhythmias or death in patient subgroups by cardiomyopathy type, QRS width, and morphology (P < .05 for all). CONCLUSIONS: Persistent or new radial dyssynchrony after CRT-D in severely symptomatic patients with heart failure with widened QRS complexes and reduced ejection fractions was associated with an increased rate of ventricular arrhythmias or death and appears to be a marker for a less favorable prognosis. PMID- 24798867 TI - The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway. AB - The activation of apoptotic pathways results in the caspase cleavage of the Lyn tyrosine kinase to generate the N-terminal truncated LynDeltaN. This LynDeltaN fragment has been demonstrated to exert negative feedback on imatinib induced apoptosis in chronic myelogenous leukemia (CML) K562 cells. Our investigations focus on LynDeltaN stability and how reduced stability reduces imatinib resistance. As the proteolytical generated LynDeltaN has a leucine as an N terminal amino acid, we hypothesized that LynDeltaN would be degraded by the N end rule pathway. We demonstrated that LynDeltaN is unstable and that its stability is dependent on the identity of its N-terminus. Additionally we established that LynDeltaN degradation could be inhibited by inhibiting either the proteasome or knocking down the UBR1 and UBR2 ubiquitin E3 ligases. Importantly, we also demonstrate that LynDeltaN degradation by the N-end rule counters the imatinib resistance of K562 cells provided by LynDeltaN expression. Together our data suggest a possible mechanism for the N-end rule pathway having a link to imatinib resistance in CML. With LynDeltaN being an N-end rule substrate, it provides the first example that this pathway can also provide a pro apoptotic function as previous reports have currently only demonstrated anti apoptotic roles for the N-end rule pathway. PMID- 24798868 TI - Inhibition of SIRT1 signaling sensitizes the antitumor activity of silybin against human lung adenocarcinoma cells in vitro and in vivo. AB - Although silybin, a natural flavonolignan, has been shown to exhibit potent antitumor activities against various types of cancers, including lung cancer, the molecular mechanisms behind these activities remain unclear. Silent information regulator 1 (SIRT1) is a conserved NAD(+)-dependent deacetylase that has been implicated in the modulation of transcriptional silencing and cell survival. Furthermore, it plays a key role in carcinogenesis through the deacetylation of important regulatory proteins, including p53. In this study, we investigated the antitumor activity of silybin towards human lung adenocarcinoma cells in vitro and in vivo and explored the role of the SIRT1 signaling pathway in this process. Silybin treatment resulted in a dose- and time-dependent decrease in lung adenocarcinoma A549 cell viability. In addition, silybin exhibited strong antitumor activity illustrated by reductions in tumor cell adhesion, migratory capability, and glutathione levels and by increased apoptotic indices and reactive oxygen species levels. Silybin treatment also downregulated SIRT1 and upregulated p53 acetylation. SIRT1 siRNA (in vitro) or cambinol (a known SIRT1 inhibitor used for in vivo studies) further enhanced the antitumor activity of silybin. In summary, silybin is a potent inhibitor of lung adenocarcinoma cell growth that interferes with SIRT1 signaling, and this inhibition is a novel mechanism of silybin action that may be used for therapeutic intervention in lung adenocarcinoma treatment. PMID- 24798869 TI - Effective ligand passivation of Cu2O nanoparticles through solid-state treatment with mercaptopropionic acid. AB - In colloidal nanoparticle (NPs) devices, trap state densities at their surface exert a profound impact on the rate of charge carrier recombination and, consequently, on the deterioration of the device performance. Here, we report on the successful application of a ligand exchange strategy to effectively passivate the surface of cuprite (Cu2O) NPs. Cu2O NPs were prepared by means of a novel synthetic route based on flame spray pyrolysis. FTIR, XRD, XPS, and HRTEM measurements corroborate the formation of cubic cuprite Cu2O nanocrystals, excluding the possible presence of undesired CuO or Cu phases. Most importantly, steady-state emission and transient absorption assays document that surface passivation results in substantial changes in the intensity of emissive excitonic states--centered at copper and oxygen vacancies--and in the lifetime of excitons near the band edge. To shed light onto ultrafast processes in Cu2O nanocrystals additional pump probe experiments on the femtosecond and nanosecond time scales were carried out. Two discernible species were observed: on one hand, an ultrafast component (~ps) that relates to the excitons; on the other hand, a long lived component (~MUs) that originates from the defects/trap states. PMID- 24798870 TI - CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo controlled study. AB - AIMS: Macrophage recruitment through C-C motif chemokine receptor-2 (CCR2) into adipose tissue is believed to play a role in the development of insulin resistance and type 2 diabetes mellitus (T2DM). The objective of this Phase 2 proof-of-concept study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-41443532, an orally bioavailable CCR2 antagonist, in patients with T2DM. METHODS: This was a 4-week, double-blind, placebo-controlled, randomized, multicenter study. A total of 89 patients were randomized to receive either 250- or 1000-mg of JNJ-41443532 twice daily, 30-mg of pioglitazone once daily (reference arm), or placebo. The primary endpoint was change from baseline in 23-h weighted mean glucose (WMG); secondary endpoints included change from baseline in fasting plasma glucose (FPG), insulin resistance (Homeostatic Model Assessment [HOMA-IR]), insulin secretion (HOMA-%B) and body weight. RESULTS: Absorption of JNJ-41443532 into the systemic circulation occurred at a median tmax of 2 h, and the mean t1/2 was approximately 8 h for both doses; plasma systemic exposures increased slightly more than dose-proportionally. After 4 weeks, reductions in 23-h WMG and FPG were observed in all treatment groups compared with placebo and were significantly lower for 250-mg JNJ-41443532 and pioglitazone. HOMA-IR was lower for all treatment groups, but significantly lower only for pioglitazone. Conversely, HOMA-%B was increased for all groups, but significantly increased only for 250-mg JNJ-41443532. All groups, including placebo, had decreased body weight over time. There were no clinically significant findings during routine safety assessments and the incidence of treatment-emergent adverse events was similar across all groups. CONCLUSIONS: Administration of JNJ-41443532 resulted in modest improvement in glycaemic parameters compared with placebo, and was generally well tolerated in patients with T2DM. PMID- 24798871 TI - Ginsenoside Rd ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice. AB - Multiple sclerosis (MS) is a common disabling autoimmune disease without an effective treatment in young adults. Ginsenoside Rd, extracted from Panax notoginseng, has multiple pharmacological effects and potential therapeutic applications in diseases of the central nervous system. In this study, we explore the efficacy of ginsenoside Rd in experimental autoimmune encephalomyelitis (EAE), an established model of MS. EAE was induced by myelin oligodendrocyte glycoprotein 35-55-amino-acid peptide. Ginsenoside Rd (10-80 mg/kg/day) or vehicle was intraperitoneally administered on the disease onset day, and the therapy persisted throughout the experiments. The dose of 40 mg/kg/day of ginsenoside Rd was selected as optimal. Ginsenoside Rd effectively ameliorated the clinical severity in EAE mice, reduced the permeability of the blood-brain barrier, regulated the secretion of interferon-gamma and interleukin-4, promoted the Th2 shift in vivo (cerebral cortex) and in vitro (splenocytes culture supernatants), and prevented the reduction in expression of brain-derived neurotrophic factor and nerve growth factor in both cerebral cortex and lumbar spinal cord of EAE mice. This study establishes the potency of ginsenoside Rd in inhibiting the clinical course of EAE. These findings suggest that ginsenoside Rd could be a promising agent for amelioration of neuroimmune dysfunction diseases such as MS. PMID- 24798872 TI - Increasing transcriptome response of serpins during the ontogenetic stages in the salmon louse Caligus rogercresseyi (Copepoda: Caligidae). AB - Serine protease inhibitors, or serpins, target serine proteases, and are important regulators of intra- and extracellular proteolysis. For parasite survival, parasite-derived protease inhibitors have been suggested to play essential roles in evading the host's immune system and protecting against exogenous host proteases. The aim of this work was to identify serpins via high throughput transcriptome sequencing and elucidate their potential functions during the lifecycle of the salmon louse Caligus rogercresseyi. Eleven putative, partial serpin sequences in the C. rogercresseyi transcriptome were identified and denoted as Cr-serpins 1 to 11. Comparative analysis of the deduced serpin like amino acid sequences revealed a highly conserved reactive center loop region. Interestingly, P1 residues suggest putative functions involved with the trypsin/subtilisin, elastase, or subtilisin inhibitors, which evidenced increasing gene expression profiles from the copepodid to adult stage in C. rogercresseyi. Concerning this, Cr-serpin 10 was mainly expressed in the copepodid stage, while Cr-serpins 3, 4, 5, and 11 were mostly expressed in chalimus and adult stages. These results suggest that serpins could be involved in evading the immune response of the host fish. The identification of these serpins furthers the understanding of the immune system in this important ectoparasite species. PMID- 24798873 TI - Sequence and comparison of mitochondrial genomes in the genus Nerita (Gastropoda: Neritimorpha: Neritidae) and phylogenetic considerations among gastropods. AB - In the present study, we determined the mitochondrial DNA (mtDNA) sequence of three Neritas, Nerita versicolor, Nerita tessellata, and Nerita fulgurans. We present an analysis of the features of their gene content and genome organization and compare these within the genus Nerita, and among the main gastropod groups. The new sequences were used in a phylogenetic analysis including all available gastropod mitochondrial genomes. Genomic lengths were quite conserved, being 15,866bp for N. versicolor, 15,741bp for N. tessellata and 15,343bp for N. fulgurans. Intergenic regions were generally short; genes are transcribed from both strands and have a nucleotide composition high in A and T. The high similarity in nucleotide content of the different sequences, gene composition, as well as an identical genomic organization among the Nerita species compared in this study, indicates a high degree of conservation within this diverse genus. Values of Ka/Ks of the 13 protein coding genes (PCGs) of Nerita species ranged from 0 to 0.18, and suggested different selection pressures in gene sequences. Bayesian phylogenetic analyses using concatenated DNA sequences of the 13 PCGs and the two rRNAs, and of amino acid sequences strongly supported Neritimorpha and Vetigastropoda as sister groups. PMID- 24798874 TI - Draft genome of formaldehyde-degrading strain, Pseudomonas monteilii IOFA19. AB - The draft genome of Pseudomonas monteilii strain IOFA19 isolated from deep-sea sediment of the Indian Ocean was sequenced to gain insights into its efficient metabolic pathway for degrading formaldehyde. The annotated genome of this strain was subjected to comparative analysis with the genomes of existing sequenced P. monteilii strains QM, SB3101, and SB3078. Differences in the overall genomic content were observed, and relative genes that were hypothetically involved in the formaldehyde-degrading mechanism were identified. PMID- 24798877 TI - Facile one-pot, one-step synthesis of a carbon nanoarchitecture for an advanced multifunctonal electrocatalyst. AB - A one-pot/one-step synthesis strategy was developed for the preparation of a nitrogen-doped carbon nanoarchitecture with graphene-nanosheet growth on the inner surface of carbon nanotubes (CNTs). The N-graphene/CNT hybrids exhibit outstanding electrocatalytic activity for several important electrochemical reactions as a result of their unique morphology and defect structures, such as high but uniform nitrogen doping, graphene insertion into CNTs, considerable surface area, and the presence of iron nanoparticles. The high-yield synthetic process features high efficiency, low-cost, straightforward operation, and simple equipment. PMID- 24798876 TI - Levels of lymphocyte subsets in peripheral blood prior treatment are associated with aggressive breast cancer phenotypes or subtypes. AB - The aim of this study was to assess associations between ER, Ki67, Her-2 phenotypes, molecular subtypes of breast cancer and circulating levels of lymphocyte subsets (CD4+, CD8+, NK, CD19+, CD20+) and the ratio of CD4+ to CD8+ prior to treatment. Cells from peripheral blood were counted by flow cytometry, ER, Her-2, and Ki67 expressions were detected by pathological examination, and Her-2 was also detected by FISH. We conducted a case-case comparison of 494 women with newly diagnosed breast cancer to evaluate association between levels of lymphocyte subsets in peripheral blood and breast cancer phenotypes [ER- vs. ER+; Ki67 >= 14 % vs. Ki67 < 14 %; Her-2+ vs. Her-2-; triple-negative breast cancer (TNBC) vs. luminal A]. Women with the highest levels of CD3+ (OR 0.45, 95 % CI 0.22-0.94), CD4+ (OR 0.22, 95 % CI 0.08-0.59), and the ratio of CD4+/CD8+ (OR 0.17, 95 % CI 0.06-0.47) were least likely to have TNBCs compared with luminal A cancers. The highest tertile of CD8+ (OR 3.67, 95 % CI 1.06-12.72) and NK (OR 2.64, 95 % CI 1.12-6.24) was significantly associated with TNBC compared with luminal A cancer. ER-, Ki67 >= 14 %, Her-2+ were associated with low levels of CD4+ and CD4+/CD8+ compared with ER+, Ki67 < 14 %, Her-2-. Women in the highest level of CD8+ had more likelihood to have ER- and Her-2+ compared with ER+ and Her-2-. High levels of NK cells were associated with increased risk of ER- compared with ER+ cancers. Highest levels of CD19+ and CD20+ were associated with low risk of ER-, compared with ER+ cancers. These findings show that immune function differs among different breast cancer phenotypes or subtypes and is associated with ER-, Her-2+, Ki67 >= 14 %, and TNBC which are likely to be aggressive phenotypes. PMID- 24798875 TI - Long-term influence of chemotherapy on steatosis-associated advanced hepatic fibrosis. AB - To determine whether chemotherapy treatment at least 6 months prior to the detection of hepatic steatosis is associated with advanced hepatic fibrosis. Demographics, comorbid conditions, and laboratory data for cancer patients with hepatic steatosis were reviewed. The primary end point of this study was a low probability of fibrosis as calculated by the AST-to-platelet ratio index (APRI)-a surrogate for the absence of histologic bridging fibrosis and/or cirrhosis. Of 279 patients, 117 (41.9 %) were treated with chemotherapy and 197 (66.3 %) had a low probability of fibrosis by APRI. A smaller proportion of patients treated with chemotherapy had a low probability of hepatic fibrosis compared with untreated patients (64.1 vs. 75.3 %, p = 0.04). On multivariable analysis, chemotherapy treatment was a negative predictive factor for a low probability of fibrosis (OR 0.366 [95 % CI 0.184-0.708], p < 0.01). Among chemotherapy-treated patients, 75 (64.1 %) had a low probability of fibrosis. There were no differences in chemotherapy duration (mean 7.8 vs. 7.5 cycles) and interval from last dose to steatosis diagnosis (24.3 vs. 21.4 months) between patients with and without a low probability of fibrosis. A smaller proportion of patients treated with irinotecan or 5-fluorouracil had a low probability of fibrosis (37.3 vs. 66.7 %, p = 0.04). On multivariable analysis, irinotecan or 5-fluorouracil treatment was a negative predictive factor for low probability of fibrosis (OR 0.277 [95 % CI 0.091-0.779], p = 0.02). Prior chemotherapy treatment, especially with 5-fluorouracil or irinotecan, is a negative predictor for the absence of advanced hepatic fibrosis among patients with steatosis. PMID- 24798878 TI - Reactivity of the uranium(IV) carbene complex [U(BIPM(TMS))(Cl)(MU-Cl)2Li(THF)2] (BIPM(TMS) = {C(PPh2NSiMe3)2}) towards carbonyl and heteroallene substrates: metallo-Wittig, adduct formation, C-F bond activation, and [2 + 2]-cycloaddition reactions. AB - The reactivity of the uranium(IV) carbene complex [U(BIPM(TMS))(Cl)(MU Cl)2Li(THF)2] (1, BIPM(TMS) = {C(PPh2NSiMe3)2}) towards carbonyl and heteroallene substrates is reported. Reaction of 1 with benzophenone proceeds to give the metallo-Wittig terminal alkene product Ph2C=C(PPh2NSiMe3)2 (2); the likely "UOCl2" byproduct could not be isolated. Addition of the bulky ketone PhCOBu(t) to 1 resulted in loss of LiCl, coordination of the ketone, and dimerisation to give [U(BIPM(TMS))(Cl)(MU-Cl){OC(Ph)(Bu(t))}]2 (3). The reaction of 1 with coumarin resulted in ring opening of the cyclic ester and a metallo-Wittig-type reaction to afford [U{BIPM(TMS)[C(O)(CHCHC6H4O-2)]-kappa(3)-N,O,O'}(Cl)2(THF)] (4) where the enolate product remains coordinated to uranium. The reaction of PhCOF with 1 resulted in C-F bond activation and oxidation resulting in isolation of [U(O)2(Cl)2(MU-Cl)2{(MU-LiDME)OC(Ph)=C(PPh2NSiMe3)(PPh2NHSiMe3)}2] (5) along with [U(Cl)2(F)2(py)4] (6). The reactions of 1 with tert-butylisocyanate or dicyclohexylcarbodiimide resulted in the isolation of the [2 + 2]-cycloaddition products [U{BIPM(TMS)[C(NBu(t)){OLi(THF)2(MU-Cl)Li(THF)3}]-kappa(4) C,N,N',N''}(Cl)3] (7) and [U{BIPM(TMS)[C(NCy)2]-kappa(4)-C,N,N',N''}(Cl)(MU Cl)2Li(THF)2] (8). Complexes 2-8 have been variously characterised by single crystal X-ray diffraction, multi-nuclear NMR and FTIR spectroscopies, Evans method solution magnetic moments, variable temperature SQUID magnetometry, and elemental analyses. PMID- 24798880 TI - Targeting CD73 and downstream adenosine receptor signaling in triple-negative breast cancer. AB - INTRODUCTION: Despite significant improvements in diagnosis and therapy over the past 20 years, breast cancer remains a worldwide public health issue. In particular, triple negative breast cancer (TNBC), a subset of very aggressive breast tumors, is associated with a poor prognosis and has very few efficient therapeutic options. The ectonucleotidase CD73 has recently emerged as a promising new target for TNBC in preclinical models. Pharmacological targeting of CD73 and downstream adenosine A2A/A2B receptor signaling is currently an active field of research that could lead to the development of new cancer therapeutics, including options against TNBC. AREAS COVERED: This article reviews the basic structural and molecular features of CD73 and its role in the development of cancer, with a particular focus on CD73's role in the biology of TNBC. EXPERT OPINION: It was recently demonstrated that CD73 expression in TNBC is associated with worse clinical outcomes and increased resistance to anthracycline chemotherapy. Targeted blockade of the CD73/A2A axis has been shown to impair various aspects of tumorigenesis and displays synergism with other anti-cancer treatments in preclinical studies. Hence, we strongly argue for the development of CD73 inhibitors and for the repositioning of A2A antagonists in cancer. PMID- 24798879 TI - Nap1 stimulates homologous recombination by RAD51 and RAD54 in higher-ordered chromatin containing histone H1. AB - Homologous recombination plays essential roles in mitotic DNA double strand break (DSB) repair and meiotic genetic recombination. In eukaryotes, RAD51 promotes the central homologous-pairing step during homologous recombination, but is not sufficient to overcome the reaction barrier imposed by nucleosomes. RAD54, a member of the ATP-dependent nucleosome remodeling factor family, is required to promote the RAD51-mediated homologous pairing in nucleosomal DNA. In higher eukaryotes, most nucleosomes form higher-ordered chromatin containing the linker histone H1. However, the mechanism by which RAD51/RAD54-mediated homologous pairing occurs in higher-ordered chromatin has not been elucidated. In this study, we found that a histone chaperone, Nap1, accumulates on DSB sites in human cells, and DSB repair is substantially decreased in Nap1-knockdown cells. We determined that Nap1 binds to RAD54, enhances the RAD54-mediated nucleosome remodeling by evicting histone H1, and eventually stimulates the RAD51-mediated homologous pairing in higher-ordered chromatin containing histone H1. PMID- 24798882 TI - Systemic injection of neural stem/progenitor cells in mice with chronic EAE. AB - Neural stem/precursor cells (NPCs) are a promising stem cell source for transplantation approaches aiming at brain repair or restoration in regenerative neurology. This directive has arisen from the extensive evidence that brain repair is achieved after focal or systemic NPC transplantation in several preclinical models of neurological diseases. These experimental data have identified the cell delivery route as one of the main hurdles of restorative stem cell therapies for brain diseases that requires urgent assessment. Intraparenchymal stem cell grafting represents a logical approach to those pathologies characterized by isolated and accessible brain lesions such as spinal cord injuries and Parkinson's disease. Unfortunately, this principle is poorly applicable to conditions characterized by a multifocal, inflammatory and disseminated (both in time and space) nature, including multiple sclerosis (MS). As such, brain targeting by systemic NPC delivery has become a low invasive and therapeutically efficacious protocol to deliver cells to the brain and spinal cord of rodents and nonhuman primates affected by experimental chronic inflammatory damage of the central nervous system (CNS). This alternative method of cell delivery relies on the NPC pathotropism, specifically their innate capacity to (i) sense the environment via functional cell adhesion molecules and inflammatory cytokine and chemokine receptors; (ii) cross the leaking anatomical barriers after intravenous (i.v.) or intracerebroventricular (i.c.v.) injection; (iii) accumulate at the level of multiple perivascular site(s) of inflammatory brain and spinal cord damage; and (i.v.) exert remarkable tissue trophic and immune regulatory effects onto different host target cells in vivo. Here we describe the methods that we have developed for the i.v. and i.c.v. delivery of syngeneic NPCs in mice with experimental autoimmune encephalomyelitis (EAE), as model of chronic CNS inflammatory demyelination, and envisage the systemic stem cell delivery as a valuable technique for the selective targeting of the inflamed brain in regenerative neurology. PMID- 24798884 TI - Priming for health: gut microbiota acquired in early life regulates physiology, brain and behaviour. AB - The infant gut microbiome is dynamic, and radical shifts in composition occur during the first 3 years of life. Disruption of these developmental patterns, and the impact of the microbial composition of our gut on brain and behaviour, has attracted much recent attention. Integrating these observations is an important new research frontier. CONCLUSION: Early-life perturbations of the developing gut microbiota can impact on the central nervous system and potentially lead to adverse mental health outcomes. PMID- 24798881 TI - Blocking monocyte transmigration in in vitro system by a human antibody scFv anti CD99. Efficient large scale purification from periplasmic inclusion bodies in E. coli expression system. AB - Migration of leukocytes into site of inflammation involves several steps mediated by various families of adhesion molecules. CD99 play a significant role in transendothelial migration (TEM) of leukocytes. Inhibition of TEM by specific monoclonal antibody (mAb) can provide a potent therapeutic approach to treating inflammatory conditions. However, the therapeutic utilization of whole IgG can lead to an inappropriate activation of Fc receptor-expressing cells, inducing serious adverse side effects due to cytokine release. In this regard, specific recombinant antibody in single chain variable fragments (scFvs) originated by phage library may offer a solution by affecting TEM function in a safe clinical context. However, this consideration requires large scale production of functional scFv antibodies and the absence of toxic reagents utilized for solubilization and refolding step of inclusion bodies that may discourage industrial application of these antibody fragments. In order to apply the scFv anti-CD99 named C7A in a clinical setting, we herein describe an efficient and large scale production of the antibody fragments expressed in E. coli as periplasmic insoluble protein avoiding gel filtration chromatography approach, and laborious refolding step pre- and post-purification. Using differential salt elution which is a simple, reproducible and effective procedure we are able to separate scFv in monomer format from aggregates. The purified scFv antibody C7A exhibits inhibitory activity comparable to an antagonistic conventional mAb, thus providing an excellent agent for blocking CD99 signaling. This protocol can be useful for the successful purification of other monomeric scFvs which are expressed as periplasmic inclusion bodies in bacterial systems. PMID- 24798885 TI - Natriuretic peptide clearance receptor ligand (C-ANP4-23 ) attenuates angiogenesis in a murine sponge implant model. AB - Natriuretic peptide receptor-C activation by the synthetic ligand C-ANP-4-23, a specific agonist for this receptor, has been shown to inhibit key events of the angiogenic cascade, such as migration, proliferation and vascular endothelial growth factor (VEGF) production. In the present study we investigated whether C ANP4-23 could also inhibit angiogenesis in the sponge model in vivo. To this end, we evaluated the effects of C-ANP4-23 on inflammatory and angiogenic components of the fibrovascular tissue induced by polyether polyurethane sponge implants in mice. Measurements of the haemoglobin content (MUg/mg wet tissue) and blood flow (laser Doppler perfusion imaging) of the implants, used as an index of vascularization, revealed that single (200 ng) or multiple (200 ng/day, 5 days) doses of C-ANP4-23 reduced angiogenesis in the implants relative to the phosphate buffered saline-treated group. The peptide exerted an inhibitory effect on nitric oxide production (nitrite levels) and had a dual effect on VEGF levels, depending on the number of doses (i.e. stimulation at 4 days after one dose; inhibition at 7 days after five doses). Histological analysis corroborated the biochemical and functional parameters indicative of inhibition of neovascularization (decreased vessel number) by C-ANP4-23 . The peptide failed to modulate inflammation in our system. The inhibitory effect of C-ANP4-23 on the angiogenic component of the fibrovascular tissue induced by the synthetic matrix extends the range of the its actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases. PMID- 24798887 TI - Topical gels of etofenamate: in vitro and in vivo evaluation. AB - Non-steroid anti-inflammatory drugs (NSAIDs), such as etofenamate, are among the most prescribed drugs used for their analgesic, anti-rheumatic, antipyretic and anti-inflammatory properties. Topical formulations have the main advantage of targeted delivery. However, drugs must overcome the skin due to its role as a physical and chemical barrier against the penetration of chemicals and microorganisms. This barrier must be altered to allow the permeation of drugs at a suitable rate to the desired site of activity. Permeation modulators can intercalate the skin outer layers causing structure disruption, opening an energetically favourable route for the drug to diffuse through. The aim of this work was the development of hydroalcoholic gels containing 5.0% (w/w) of etofenamate for topical administration with anti-inflammatory activity and enhanced drug delivery. The physical and chemical characterization, in vitro release and permeation studies and in vivo anti-inflammatory activity were assessed. The gel with 30% ethanol showed in vivo anti-inflammatory activity with suitable physical chemical and microbiologic characteristics. In vitro release and permeation studies revealed that the different amounts of ethanol used influenced the release profiles of etofenamate. Moreover, it was demonstrated that this formulation is an adequate vehicle for the etofenamate skin permeation. PMID- 24798888 TI - An advanced microencapsulated system: a platform for optimized oral delivery of antidiabetic drug-bile acid formulations. AB - INTRODUCTION: In previous studies, we have shown that a gliclazide-cholic acid derivative (G-CA) mixture resulted in an enhanced ileal permeation of G (ex vivo). When administered orally to diabetic rats, it brought about a significant hypoglycaemic effect. In this study, we aim to create a novel microencapsulated formulation of G-CA with uniform and coherent structure that can be further tested in our rat model of type 1 diabetes (T1D). We also aim to examine the effect of CA addition to G microcapsules in the morphology, structure and excipients' compatibility of the newly designed microcapsules. METHOD: Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) and G-CA-SA (test) at a constant ratio (1:3:30), respectively. Complete characterizations of microcapsules were carried out. RESULTS: The new G-CA-SA formulation is further optimized by the addition of CA exhibiting pseudoplastic-thixotropic rheological characteristics. Bead size remains similar after CA addition, the new microcapsules show no chemical interactions between the excipients and this was supported further by the spectral studies suggesting bead stability. CONCLUSION: The new microencapsulated formulation has good and uniform structural properties and may be suitable for oral delivery of antidiabetic-bile acid formulations. PMID- 24798886 TI - A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. AB - There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus. PMID- 24798889 TI - Correction of gradient nonlinearity artifacts in prospective motion correction for 7T MRI. AB - PURPOSE: To demonstrate the effect of gradient nonlinearity and develop a method for correction of gradient nonlinearity artifacts in prospective motion correction (Mo-Co). METHODS: Nonlinear gradients can induce geometric distortions in magnetic resonance imaging, leading to pixel shifts with errors of up to several millimeters, thereby interfering with precise localization of anatomical structures. Prospective Mo-Co has been extended by conventional gradient warp correction applied to individual phase encoding steps/groups during the reconstruction. The gradient-related displacements are approximated using spherical harmonic functions. In addition, the combination of this method with a retrospective correction of the changes in the coil sensitivity profiles relative to the object (augmented sensitivity encoding (SENSE) reconstruction) was evaluated in simulation and experimental data. RESULTS: Prospective Mo-Co under gradient fields and coils sensitivity inconsistencies results in residual blurring, spatial distortion, and coil sensitivity mismatch artifacts. These errors can be considerably mitigated by the proposed method. High image quality with very little remaining artifacts was achieved after a few iterations. The relative image errors decreased from 25.7% to below 17.3% after 10 iterations. CONCLUSION: The combined correction of gradient nonlinearity and sensitivity map variation leads to a pronounced reduction of residual motion artifacts in prospectively motion-corrected data. PMID- 24798890 TI - "Doing the month": Postpartum practices in Chinese women. AB - This review describes the traditional ancient Chinese postpartum practice of "doing the month" or "zuoyuezi", the evidence for specific practices, maternal adherence to practices, and their effect upon the maternal postpartum physical and psychological health. A comprehensive search yielded 38 English or Chinese publications about common practices, adherence to practices, and their effects upon Chinese women's physical and psychological health. Doing the month involves a series of practices related to the maternal role, physical activity, maintenance of body warmth, and food consumption that are believed to restore maternal postpartum health and prevent future disease. Strengths of these practices include acknowledgment of the woman's societal and familial contribution to childbearing and the provision of consistent family support. There is concern for the effect of some practices upon both maternal physical and psychological health, particularly for postpartum depression. Current evidence about the effects of doing-the-month practices upon maternal health needs to be integrated into the traditional practices of doing the month to improve maternal health. PMID- 24798892 TI - Iron-catalyzed alkylation of alpha-oxo ketene dithioacetals. AB - Iron-catalyzed alkylation of internal olefins, that is, alpha-oxo ketene dithioacetals, was successfully realized by using styrenes as the alkylating reagents. Highly functionalized tetrasubstituted olefins were prepared in moderate to high yields. PMID- 24798891 TI - Adverse drug reactions in an emergency medical dispatching centre. AB - PURPOSE: The purpose of this study is to assess the incidence of adverse drug reactions (ADR) leading to call an emergency medical dispatching centre. METHODS: A prospective, observational, monocentric clinical study performed over a 2-year period (2011-2012) in a French prehospital emergency dispatching centre, the Service d'Aide Medicale Urgente (SAMU) covering 1,156,000 inhabitants. All adult patients (age>=18) who called for any cause were included. We created an electronic trigger 'iatrogenic event' implemented by the dispatching physician for each suspected case of ADR, then we completed the analyses of all the cases with a chief complain represented in more than 1% of the triggered cases. The primary outcome variable was the occurrence of any possible ADR. We then used the French method of causal relationship assessment. RESULTS: The SAMU dispatched 339,915 calls during the study. In total, 1,467 ADRs were identified, representing 0.95% (CI 95% 0.90-1.00%) of cases. ADRs were as serious (SADR) in 51.06% (CI 95% 48.45-53.67%) of cases. The major ADR observed was haemorrhage, (42.81% (CI 95% 40.62-45.00%), n=628) followed by allergy, hypoglycaemia, vomiting, dizziness and drowsiness. The class of drugs most frequently involved was antithrombotic (43.69% (CI 95% 41.45-45.93%), n=641), followed by insulin (17.98% (CI 95%:17.06-18.90%), n=264). CONCLUSIONS: Emergency calls concerning ADRs were estimated as 9/1,000, and one out of two is serious. PMID- 24798893 TI - Pheromone modulates plant odor responses in the antennal lobe of a moth. AB - In nature, male moths are exposed to a complex plant odorant environment when they fly upwind to a sex pheromone source in their search for mates. Plant odors have been shown to affect responses to pheromone at various levels but how does pheromone affects plant odor perception? We recorded responses from neurons within the non-pheromonal "ordinary glome ruli" of the primary olfactory center, the antennal lobe (AL), to single and pulsed stimulations with the plant odorant heptanal, the pheromone, and their mixture in the male moth Agrotis ipsilon. We identified 3 physiological types of neurons according to their activity patterns combining excitatory and inhibitory phases. Both local and projection neurons were identified in each physiological type. Neurons with excitatory responses to heptanal responded also frequently to the pheromone and showed additive responses to the mixture. Moreover, the neuron's ability of resolving successive pulses generally improved with the mixture. Only some neurons with combined excitatory/inhibitory, or purely inhibitory responses to heptanal, also responded to the pheromone. Although individual mixture responses were not significantly different from heptanal responses in these neurons, pulse resolution was improved with the mixture as compared with heptanal alone. These results demonstrate that the pheromone and the general odorant subsystems interact more intensely in the moth AL than previously thought. PMID- 24798895 TI - Expert opinion on best practice guidelines and competency framework for visual screening in children. PMID- 24798894 TI - PAX8/PPARgamma rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma. AB - BACKGROUND: PAX8/PPARgamma rearrangement is a common genetic alteration in follicular thyroid carcinoma (FTC) and has been reported with variable frequency in papillary thyroid carcinoma (PTC). The diagnostic and phenotypic features of thyroid nodules positive for PAX8/PPARgamma on preoperative examination are not well understood. METHODS: The prevalence of PAX8/PPARgamma rearrangement was analyzed in a series of 2015 consecutive thyroid nodules that underwent molecular analysis on cytology specimens and in 446 surgically removed PTCs. For all PAX8/PPARgamma positive cases, cytology and surgical pathology slides were examined and the available clinical records were reviewed. RESULTS: Twenty-two PAX8/PPARgamma rearrangements were identified, including 16 detected preoperatively and 6 postoperatively. The incidence of PAX8/PPARgamma in PTC was 1.1%. Cytologically, most of these nodules were diagnosed as a follicular neoplasm (73%), followed by the diagnosis of atypia of undetermined significance (19%), and none of the cases was diagnosed as cytologically malignant. All nodules with PAX8/PPARgamma detected preoperatively and surgical follow-up available were found to be malignant, among which the most common diagnosis was the encapsulated follicular variant of PTC. Overall, among 20 PAX8/PPARgamma positive tumors that were surgically excised, 17 (85%) were PTC and 3 (15%) were FTC. On follow-up available for 17 patients (mean, 22.4 months), 16 PAX8/PPARgamma-positive cancers showed no evidence of biochemical or structural recurrence, whereas 1 patient with FTC developed bone metastasis. CONCLUSIONS: In this series, PAX8/PPARgamma rearrangement found in thyroid nodules had a 100% predictive value for differentiated thyroid cancer, and was more predictive of PTC than FTC. However, almost all PTC carrying PAX8/PPARgamma were encapsulated follicular-pattern tumors, distinguished from FTC only by nuclear features. Although most tumors carrying this mutation appear to be clinically indolent, at least on short-term follow-up, distant metastasis can develop from FTC positive for PAX8/PPARgamma. PMID- 24798896 TI - The oxidation of tetrabromobisphenol A by potassium monopersulfate with an iron(III)-phthalocyanine-tetrasulfonic acid catalyst in the presence of humic acid. AB - Tetrabromobisphenol A (TBBPA), a type of brominated flame retardant that shows endocrine disruption effects, has been identified in leachates from landfills. Iron(III)-porphyrins that mimic the active site of peroxidases have been shown to be effective in oxidizing halogenated phenols, such as TBBPA. In the present study, TBBPA was subjected to oxidation with potassium monopersulfate (KHSO5) using an iron(III)-phthalocyanine-tetrasulfonic acid (FePcTS), structural analogue of iron(III)-porphyrin, in the presence of humic acid (HA), a major component in landfill leachates. When TBBPA was oxidized using the above system, the levels of degradation and debromination increased with increasing pH in the presence of HA. Because of landfill leachates are weakly alkaline (around pH 8), oxidation products derived from TBBPA were investigated at pH 8. Approximately 48% of the bromine in the degraded TBBPA was incorporated into HA, and hydroxy tribromobisphenol A was determined to be the major brominated intermediate in the HA fraction. In the iron(III)-porphyrin catalytic systems, the brominated intermediate incorporated into HA is mainly TBBPA, and no hydroxy-substituted bromophenols are found. Thus, the catalytic power of FePcTS is higher than that of iron(III)-porphyrin catalysts. PMID- 24798897 TI - Advanced photochemical oxidation of emergent micropollutants: carbamazepine. AB - The combination of UV radiation with hydrogen peroxide has been widely used for the photodegradation of pollutants in aqueous solutions. Statistical design of experiments is a powerful tool to optimize this kind of process. Initial hydrogen peroxide concentration, pH and temperature were considered as the variables for the process optimization. The interactions existing between these three variables were analyzed. Initial concentration of hydrogen peroxide proved to be the most important variable conditioning the removal efficiency, followed by temperature, and pH shows a non-significant positive influence along the whole operation interval. The ANOVA test reported significance for five of the nine involved variables. The Response Surface Methodology technique was used to optimize carbamazepine degradation. Under optimal conditions (hydrogen peroxide concentration = 0.38.10(-3) mol L(-1), pH = 1 and temperature = 35.6 degrees C) total carbamazepine degradation was achieved. PMID- 24798898 TI - Simultaneous removal of nitrate, hydrogen peroxide and phosphate in semiconductor acidic wastewater by zero-valent iron. AB - The zero-valent iron (ZVI) wastewater treatment has been applied to simultaneous removal of nitrate, hydrogen peroxide and phosphate in semiconductor acidic wastewaters. The simultaneous removal occurs by the reactions performed due to the sequential transformation of ZVI under the acidic condition. Fortunately the solution pH of semiconductor acidic wastewaters is low which is effective for the sequential transformation of ZVI. Firstly the reduction of nitrate is taken place by electrons generated by the corrosion of ZVI under acidic conditions. Secondly the ferrous ion generated by the corrosion of ZVI reacts with hydrogen peroxide and generates .OH radical (Fenton reaction). The Fenton reaction consists of the degradation of hydrogen peroxide and the generation of ferric ion. Finally phosphate precipitates out with iron ions. In the simultaneous removal process, 1.6 mM nitrate, 9.0 mM hydrogen peroxide and 1.0 mM phosphate were completely removed by ZVI within 100, 15 and 15 min, respectively. The synergy among the reactions for the removal of nitrate, hydrogen peroxide and phosphate was found. In the individual pollutant removal experiment, the removal of phosphate by ZVI was limited to 80% after 300 min. Its removal rate was considerably improved in the presence of hydrogen peroxide and the complete removal of phosphate was achieved after 15 min. PMID- 24798899 TI - Removal of arsenic, phosphates and ammonia from well water using electrochemical/chemical methods and advanced oxidation: a pilot plant approach. AB - The purpose of this work was to develop a pilot plant purification system and apply it to groundwater used for human consumption, containing high concentrations of arsenic and increased levels of phosphates, ammonia, mercury and color. The groundwater used was obtained from the production well in the Vinkovci County (Eastern Croatia). Due to a complex composition of the treated water, the purification system involved a combined electrochemical treatment, using iron and aluminum electrode plates with simultaneous ozonation, followed by a post-treatment with UV, ozone and hydrogen peroxide. The removal of the contaminant with the waste sludge collected during the electrochemical treatment was also tested. The combined electrochemical and advanced oxidation treatment resulted in the complete removal of arsenic, phosphates, color, turbidity, suspended solids and ammonia, while the removal of other contaminants of interest was up to 96.7%. Comparable removal efficiencies were obtained by using waste sludge as a coagulant. PMID- 24798901 TI - Changes in the expression of epigenetic factors during copper-induced apoptosis in PC12 cells. AB - Despite extensive research on copper toxicity the mechanisms involved are not fully characterized. There have been many recent reports concerning the relationship between epigenetic factors and cell metabolism, but the effects of copper exposure on epigenetic factors have not been investigated. In this study, an in vitro culture system was employed to study the influence of copper on apoptosis and epigenetic factors in PC12 cells. When PC12 cells were exposed to copper, DNA damage was observed as DNA fragmentation. In addition, cytosolic cytochrome c levels were increased by copper treatment. These results suggested that copper induced apoptosis via an oxidative stress pathway. This was consistent with the observation that copper-induced apoptosis was enhanced by further oxidative stress induced by exposing cells to H2O2. In addition, the epigenetic factors were significantly increased in apoptotic cells following exposure to copper and oxidative stress. PMID- 24798900 TI - Sequential ozone advanced oxidation and biological oxidation processes to remove selected pharmaceutical contaminants from an urban wastewater. AB - Sequential treatments consisting in a chemical process followed by a conventional biological treatment, have been applied to remove mixtures of nine contaminants of pharmaceutical type spiked in a primary sedimentation effluent of a municipal wastewater. Combinations of ozone, UVA black light (BL) and Fe(III) or Fe3O4 catalysts constituted the chemical systems. Regardless of the Advanced Oxidation Process (AOP), the removal of pharmaceutical compounds was achieved in 1 h of reaction, while total organic carbon (TOC) only diminished between 3.4 and 6%. Among selected ozonation systems to be implemented before the biological treatment, the application of ozone alone in the pre-treatment stage is recommended due to the increase of the biodegradability observed. The application of ozone followed by the conventional biological treatment leads high TOC and COD removal rates, 60 and 61%, respectively, and allows the subsequent biological treatment works with shorter hydraulic residence time (HRT). Moreover, the influence of the application of AOPs before and after a conventional biological process was compared, concluding that the decision to take depends on the characterization of the initial wastewater with pharmaceutical compounds. PMID- 24798902 TI - Sedimentology, geochemistry, pollution status and ecological risk assessment of some heavy metals in surficial sediments of an Egyptian lagoon connecting to the Mediterranean Sea. AB - Spatial distribution of heavy metals (Co, Cu, Ni, Cr, Mn, Zn and Fe) was studied on Lake Edku's surface sediments in relation to sedimentology and geochemistry characteristics and their contamination status on the ecological system. Lake Edku's sediments were dominated by sandy silt and silty sand textures and were enriched with carbonate content (9.83-58.46%). Iron and manganese were the most abundant heavy metals with ranges of 1.69 to 8.06 mg g(-1) and 0.88 to 3.27 mg g( 1), respectively. Cobalt and nickel showed a harmonic distribution along the studied sediments. The results were interpreted by the statistical means. The heavy metal pollution status and their ecological risk in Lake Edku was evaluated using the sediment quality guidelines and the contamination assessment methods (geoaccumulation, pollution load and potential ecological risk indices, enrichment factor, contamination degree as well as effect range median (ERM) and probable effect level (PEL) quotients). Amongst the determined heavy metals, zinc had the most ecological risk. Overall, the heavy metals in surface sediments showed ecological effect range from moderate to considerable risk, specially, in the stations in front of the seawater and in drain sources that had the highest toxic priority. PMID- 24798903 TI - Geographical information systems and air pollution simulation for Megalopolis' electric power plant in Peloponnese, Greece. AB - The growth and sophistication of geographic information systems (GIS) have propelled us into a new era of environmental analyses. Air pollution is a growing concern in populated areas as many recent studies have associated high levels of pollution with increased illnesses and mortality. The study will focus on the toxicity levels incurred by radioactive lignite-burning Power Generation facilities located in Megalopolis, Greece. An estimate of pollution emissions followed by dispersion simulations for various atmospheric conditions will be given. The exercise will be integrated with a Geographical Information System (GIS) for defining the emission sources and visualizing the dispersion of pollutants over the geographical terrain. Data samples were collected from vegetation in the surrounding areas and analyzed for radioactivity. High energy levels (up to 4-5 times higher than recommended standards, (UNCEAR, 1982) were found in several samples containing (226)Ra, (232)Th, (234)Th, (40)K and (238)U. The study concludes that air quality and vegetation of the neighbouring areas is adversely affected by industrial waste. Greater pollution controls and air quality monitoring should be applied for the benefit and health of its citizens. Radioactivity in food and water and inhaled air become very dangerous for public health thus, the levels of radioactivity should be kept within UNCEAR 1982 limits. PMID- 24798904 TI - The molecular marker-based comparison of Azotobacter spp. populations isolated from industrial soils of Cracow-Nowa Huta steelworks (southern Poland) and the adjacent agricultural soils. AB - The occurrence of Azotobacter spp., which has beneficial effects on plant development, is related to various soil properties, such as pH and fertility. This study evaluated the prevalence of Azotobacter spp. in industrial (H) and agricultural soils (P) in Nowa Huta, Cracow and determined the phenotypic and genetic diversity of these bacteria. The examined bacteria were present in 40% of H and in 50% of P soils. Taxonomic identification of the bacterial isolates indicated the presence of three species--A. salinestris, A. chroococcum and A. vinelandii. The genetic diversity, determined using two fingerprinting methods- Random Analysis of Polymorphic DNA (RAPD) and Rep-PCR (BOX) revealed high level of population diversity. In AMOVA analysis most of diversity was attributed to within-population variation (76-85%), and only 3.78-6.18% was associated with among-group H and P variation. Global test of differences revealed distinct population structure within bacterial strains isolated from H and P areas only for BOX markers (Fst = 0.05732, P = 0.00275). Phenetic analyses: UPGMA and DCA better discriminated H and P groups based on RAPD data. Both BOX and RAPD methods provided an insight into the genetic complexity of Azotobacter spp. variation in soils of different land-use types. PMID- 24798905 TI - Magnetically active biosorbent for chromium species removal from aqueous media. AB - A magnetically active composite as adsorbent was synthesized via a facile in situ one-pot impregnation of magnetic nano-iron oxide (Fe3O4) on the surface of activated carbon (AC) for the formation of AC-Fe3O4. Baker(')s yeast was physically loaded on the resultant adsorbent AC-Fe3O4 to form a novel yeast coated magnetic composite AC-Fe3O4-Yst as biosorbent. The two synthesized adsorbents were characterized by using a scanning electron microscope (SEM) and assessed using Langmuir, the Brunauer-Emmet-Teller (BET) and Dubinin-Radushkevich (D-R) isotherm models. The validity and applicability of these two sorbents in adsorptive removal of chromium species, Cr(VI) and Cr(III), from aqueous solutions under the effect of a magnetic field were studied and evaluated in the presence of various controlling parameters in order to identify the optimal pH, contact time, mass dose and chromium concentrations for such adsorption process. Also, single and multi-stage micro-column techniques were used to study the potential applications of AC-Fe3O4 as magnetically active adsorbents and AC-Fe3O4 Yst as magnetically active biosorbents, for the removal of chromium species from various real water samples. PMID- 24798906 TI - Development of total maximum daily loads for bacteria impaired watershed using the comprehensive hydrology and water quality simulation model. AB - The objective of this study was to develop bacteria total maximum daily loads (TMDLs) for the Hardware River watershed in the Commonwealth of Virginia, USA. The TMDL program is an integrated watershed management approach required by the Clean Water Act. The TMDLs were developed to meet Virginia's water quality standard for bacteria at the time, which stated that the calendar-month geometric mean concentration of Escherichia coli should not exceed 126 cfu/100 mL, and that no single sample should exceed a concentration of 235 cfu/100 mL. The bacteria impairment TMDLs were developed using the Hydrological Simulation Program-FORTRAN (HSPF). The hydrology and water quality components of HSPF were calibrated and validated using data from the Hardware River watershed to ensure that the model adequately simulated runoff and bacteria concentrations. The calibrated and validated HSPF model was used to estimate the contributions from the various bacteria sources in the Hardware River watershed to the in-stream concentration. Bacteria loads were estimated through an extensive source characterization process. Simulation results for existing conditions indicated that the majority of the bacteria came from livestock and wildlife direct deposits and pervious lands. Different source reduction scenarios were evaluated to identify scenarios that meet both the geometric mean and single sample maximum E. coli criteria with zero violations. The resulting scenarios required extreme and impractical reductions from livestock and wildlife sources. Results from studies similar to this across Virginia partially contributed to a reconsideration of the standard's applicability to TMDL development. PMID- 24798907 TI - Y-Stent embolization technique for intracranial bifurcation aneurysms. AB - Wide-necked bifurcation aneurysms often require the use of the technically complex Y-stent technique, which has recently been shown to narrow bifurcation angle in a hemodynamically favorable manner. We sought to evaluate the single center efficacy and safety of Y-stent supported aneurysm coil embolization. All patients undergoing Y-stent supported coiling between September 2006 and December 2012 were identified; records were analyzed for procedural results and complications, with follow-up evaluated for occlusion rate and neurological adverse events. Twenty consecutive patients underwent technically successful Y stent supported coiling, with complete aneurysm occlusion achieved in 19/20 cases (95%). There were no peri-procedural clinically evident neurological complications following Y-stenting. Clinical follow-up was available for a mean of 20.0months and radiographic follow-up was available for a mean of 18.5months. During the follow-up period, three patients (15%) required re-treatment with through-stent coiling for recanalization. At latest follow-up, Raymond grade I occlusion was achieved in 16 patients (80%), Raymond grade II occlusion achieved in four patients (20%) and Raymond grade III occlusion in zero patients. Y stenting for complex intracranial aneurysms appears effective in achieving durable aneurysm occlusion with an acceptable safety profile. Though the procedure is technically more complex than single-stent procedures, the Y-stent configuration should be considered when single-stent supported coiling is not feasible or sufficient. PMID- 24798908 TI - Co-registration of isotope bone scan with CT scan and MRI in the investigation of spinal pathology. AB - Image fusion software enables technetium(99m)-methylene diphosphonate (Tc(99m) MDP) bone scan images to be co-registered with CT scan or MRI, allowing greater anatomical discrimination. We examined the role of bone scan images co-registered with CT scan or MRI in the investigation of patients presenting with axial spinal pain and/or limb pain. One hundred and thirty-nine consecutive patients were examined, and thereafter investigated with CT scan, MRI, and/or dynamic plain films. At this point diagnosis (pathology type and anatomical site) and treatment intention were declared. The co-registered Tc(99m)-MDP bone scan images were then studied, after which diagnosis (pathology type and anatomical site) and treatment intention were re-declared. This data were then analysed to determine whether the addition of co-registered bone scan images resulted in any change in diagnosis or treatment intention. The most significant change in diagnosis was pathology type (10%). Anatomical site changed markedly without overlap of the pre and post isotope fields in 5%, and with overlap in 10%. Treatment intention had a major change in 3.6% and minor change in 8.6%. In the two groups where there was (i) no obvious pathology after full pre-isotope investigation, or (ii) a spinal fusion under suspicion, addition of the bone scan information led to a major change in the pathology and/or anatomical localisation in 18% and 19%, respectively. The addition of co-registered Tc(99m)-MDP bone scan images offers significant diagnostic assistance, particularly in the difficult diagnostic groups where a failed spinal fusion may be the suspected pain generator, or when no pain generator can otherwise be found. PMID- 24798909 TI - Surgical strategies in low-grade gliomas and implications for long-term quality of life. AB - Reports on long-term health related quality of life (HRQL) after surgery for World Health Organization grade II diffuse low-grade gliomas (LGG) are rare. We aimed to compare long-term HRQL in two hospital cohorts with different surgical strategies. Biopsy and watchful waiting was favored in one hospital, while early resections guided with three-dimensional (3D) ultrasound was favored in the other. With a population-based approach 153 patients with histologically verified LGG treated from 1998-2009 were included. Patients still alive were contacted for HRQL assessment (n=91) using generic (EQ-5D; EuroQol Group, Rotterdam, The Netherlands) and disease specific (EORTC QLQ-C30 and BN20; EORTC Quality of Life Department, Brussels, Belgium) questionnaires. Results on HRQL were available in 79 patients (87%), 25 from the hospital that favored biopsy and 54 from the hospital that favored early resection. Among living patients there was no difference in EQ-5D index scores (p=0.426). When imputing scores defined as death (zero) in patients dead at follow-up, a clinically relevant difference in EQ-5D score was observed in favor of early resections (p=0.022, mean difference 0.16, 95% confidence interval 0.02-0.29). In EORTC questionnaires pain, depression and concern about disruption in family life were more common with a strategy of initial biopsy only (p=0.043, p=0.032 and p=0.045 respectively). In long-term survivors an aggressive surgical approach using intraoperative 3D ultrasound image guidance in LGG does not lower HRQL compared to a more conservative surgical approach. This finding further weakens a possible role for watchful waiting in LGG. PMID- 24798910 TI - Are proprioceptive functions affected in Duchenne muscular dystrophy? PMID- 24798911 TI - DNA-polyamine cross-links generated upon one electron oxidation of DNA. AB - The possibility to induce the formation of covalent cross-links between polyamines and guanine following one electron oxidation of double stranded DNA has been evaluated. For such a purpose, a strategy has been developed to chemically synthesize the polyamine-C8-guanine adducts, and efforts have been made to characterize them. Then, an analytical method, based on HPLC separation coupled through electrospray ionization to tandem mass spectrometry, has been setup for their detection and quantification. Using such a sensitive approach, we have demonstrated that polyamine-C8-guanine adducts could be produced with significant yields in double stranded DNA following a one-electron oxidation reaction induced by photosensitization. These adducts, involving either putrescine, spermine, or spermidine, are generated by the nucleophilic addition of primary amino groups of polyamines onto the C8 position of the guanine radical cation. Our data demonstrate that such a nucleophilic addition of polyamines is much more efficient than the addition of a water molecule that leads to 8-oxo-7,8 dihydroguanine formation. PMID- 24798912 TI - Concomitant First and Second Metatarsophalangeal Arthrodesis for Intractable Second Metatarsophalangeal Joint Pain. PMID- 24798913 TI - Arthroscopic Treatment of Posterior Ankle Impingement in the Supine Position Using Coaxial Posterior Portals. PMID- 24798914 TI - Effect of Dorsal Plate Positioning on Dorsiflexion Angle in Arthrodesis of the First Metatarsophalangeal Joint: A Cadaveric Study. AB - BACKGROUND: The relationship between dorsal plate positioning and final dorsiflexion angle after first metatarsophalangeal (MTP) joint fusion has not been well established. The main purpose of this study was to investigate whether changes in dorsal plate positioning along the longitudinal axis affect fusion dorsiflexion angle, as excessive dorsiflexion angles can lead to poor clinical results. METHODS: Ten cadaver foot specimens were randomly assigned to 2 groups for first MTP joint fusion: 1 group used a straight plate, and the other group used a 10-degree precontoured plate. After routine preparation, the plates were placed in an "ideal" position based on clinical and radiological examination. The plates were then moved proximally 3 mm and 6 mm from the initial site, with repeat imaging completed at each position. The radiological dorsiflexion angle was determined for each position, and the results were assessed. RESULTS: Placement of both straight and precontoured plates at positions more proximal from the initial position led to significant increases in dorsiflexion angles (P = .04), although the percentage change was larger in the precontoured plate group (P = .01). While placement of the plate 3 mm proximal from the perceived "ideal" position did increase the dorsiflexion angle, the percentage of specimens with dorsiflexion angles in the suggested optimal range changed minimally. Positioning at 6 mm from the starting point, however, led to significantly increased dorsiflexion angles for both plates (P = .004). CONCLUSION: Positioning the dorsal plate at more proximal locations leads to increasing dorsiflexion angles. Precontoured plates are more likely to lead to excessive dorsiflexion compared with straight plates regardless of plate position. CLINICAL RELEVANCE: Fusion at excessive dorsiflexion angles can be minimized with appropriate selection and proper positioning of the dorsal fusion plate along the longitudinal axis. PMID- 24798915 TI - Combined Posterior and Anterior Ankle Arthroscopy for Posterior and Anterior Ankle Impingement Syndrome in a Switching Position. PMID- 24798916 TI - A Novel Method of Postoperative Wound Care Following Total Ankle Arthroplasty. PMID- 24798918 TI - Iron-loaded mangosteen as a heterogeneous Fenton catalyst for the treatment of landfill leachate. AB - Iron-loaded mangosteen shell powder (Fe-MSP) was found as an effective heterogeneous Fenton catalyst for the treatment of stabilized landfill leachate. Sonolytically produced catalyst has higher efficiency than other catalysts. At the optimal conditions (pH 3, catalyst concentration of 1,750 mg/L and hydrogen peroxide concentration of 0.26 M), 81 % of the chemical oxygen demand (COD) was removed effectively from the landfill leachate. But, the efficiency of Fe-MSP was reduced in the first recycling due to the poisoning of active sites. A metal leaching study indicated that the degradation of the pollutant is mainly due to solid Fe ions present in Fe-MSP rather than the leached ferrous and ferric ions. Hydroxyl radical production in the system was confirmed by the Fenton oxidation of benzoic acid. Compared to the homogeneous Fenton process, the heterogeneous Fenton process using Fe-MSP had higher COD removal efficiency, indicating the practical applicability of the prepared catalyst. PMID- 24798919 TI - A novel low-cost detection method for screening of arsenic in groundwater. AB - In the present work, a novel and simple detection system for As inorganic species contained in groundwater is presented. To reach the required detection limit, the proposed methodology is based on two steps: first is the transport and preconcentration of the inorganic arsenic species using a polymer inclusion membrane (PIM) system and second is the formation of a coloured complex, the absorbance of which is measured. Different parameters related to the membrane composition and the transport kinetics have been studied, and it was found that membranes made of polyvinyl chloride (PVC) as a polymer, and Aliquat 336 as a carrier, ensured efficient arsenic transport when the carrier content was at least 31 % (w/w). The implementation of the designed PIM in a special device that contained only 5 mL of the stripping solution (0.1 M NaCl) allowed As preconcentration from a 100-mL water sample, thus facilitating its detection with the colorimetric method. The new method developed here was validated, and its analytical figures of merit were determined, i.e. limit of detection of 4.5 MUg L(-1) at 820 nm and a relative standard deviation within the range 8-10 %. Finally, the method was successfully applied to the analysis of different water samples from Catalonia region with naturally occurring As. PMID- 24798917 TI - Biological monitoring of environmental exposure to polycyclic aromatic hydrocarbons in subjects living in the area of recycling electronic garbage, in Southern China. AB - The study was undertaken to evaluate the environmental exposure to polycyclic aromatic hydrocarbons in subjects living in the area of recycling electronic garbage in Southern China and research the influence of environment smoke tobacco (EST) to people through active and passive smoking. Urinary concentrations of 2 hydroxynaphthalene, 2-hydoxyfluorene, 9-hydroxyphenanthrene, and 1-hydroxypyrene were determined in 141 randomly selected voluntary residents aged 13 to 81 years in two polycyclic aromatic hydrocarbon (PAH)-exposed groups, two control groups, and an EST research group. The concentrations of 2-hydroxynaphthalene, 2 hydoxyfluorene, 9-hydroxyphenanthrene, and 1-hydroxypyrene in PAH-exposed groups are significantly higher (p<0.05) than those of control groups. Mean value of 1 hydroxypyrene in the residents living in the area of recycling electronic garbage (1.1 MUmol/mol creatinine) is a little higher than those of iron foundry workers, automobile repair workers, and firefighters. Mean value of 2-hydroxynaphthalene (11.3 MUmol/mol creatinine) is much higher than that of shipyard and aircraft maintenance and much lower than some occupational exposure, such as coking batteries, sorting department, and distillation department in coking plant. Some metabolites of PAHs (PAHm) are significantly elevated through active and passive smoking, while the influence of EST to other PAHm is not statistically significant. 2-Hydroxynaphthalene, 2-hydoxyfluorene, 9-hydroxyphenanthrene, and 1 hydroxypyrene in the urine of smokers are, respectively, 3.9, 1.9, 1.4, and 1.9 times to those of nonsmokers. In nonsmokers, passive smokers excreted 1.1, 1.5, 1.9, and 1.5 times of 2-hydroxynaphthalene, 2-hydoxyfluorene, 9 hydroxyphenanthrene, and 1-hydroxypyrene compared to nonpassive smokers. PMID- 24798920 TI - Synthesis and characterization of N-modified titania nanotubes for photocatalytic applications. AB - The modification of titanate nanotubes (TiNT) with nitrogen (NTiNT) was accomplished through impregnation method. TiNT were synthesized via hydrothermal treatment of titania powders in NaOH solution at 130 degrees C for 48 h. The obtained samples were characterized by UV-Vis absorption spectroscopy, Brunauer Emmett-Teller (BET) surface area, XRD, TEM, XPS, and TG analysis. Structure, morphology, composition, and visible light absorption property of nitrogen modified TiO2 nanotubes are found to depend on the nitrogen content and not on the calcination temperature for the range used in this work. The photocatalytic activity of these nanotubes was investigated for the degradation of methylethylketone (MEK) and hydrogen sulfide (H2S) under ultraviolet and solar light radiation. MEK is very resistant to photocatalytic degradation with the prepared materials;, however, the results show that modification of the TiNT with nitrogen in a proportion of 1 to 1 (TiNT to urea weight ratio) and calcination at 400 degrees C lead to materials with high photocatalytic activity under ultraviolet radiation and moderate photocatalytic activity under solar radiation for degradation of H2S. PMID- 24798921 TI - Eutrophic urban ponds suffer from cyanobacterial blooms: Dutch examples. AB - Ponds play an important role in urban areas. However, cyanobacterial blooms counteract the societal need for a good water quality and pose serious health risks for citizens and pets. To provide insight into the extent and possible causes of cyanobacterial problems in urban ponds, we conducted a survey on cyanobacterial blooms and studied three ponds in detail. Among 3,500 urban ponds in the urbanized Dutch province of North Brabant, 125 showed cyanobacterial blooms in the period 2009-2012. This covered 79% of all locations registered for cyanobacterial blooms, despite the fact that urban ponds comprise only 11% of the area of surface water in North Brabant. Dominant bloom-forming genera in urban ponds were Microcystis, Anabaena and Planktothrix. In the three ponds selected for further study, the microcystin concentration of the water peaked at 77 MUg l( 1) and in scums at 64,000 MUg l(-1), which is considered highly toxic. Microcystin-RR and microcystin-LR were the most prevalent variants in these waters and in scums. Cyanobacterial chlorophyll-a peaked in August with concentrations up to 962 MUg l(-1) outside of scums. The ponds were highly eutrophic with mean total phosphorus concentrations between 0.16 and 0.44 mg l( 1), and the sediments were rich in potential releasable phosphorus. High fish stocks dominated by carp lead to bioturbation, which also favours blooms. As urban ponds in North Brabant, and likely in other regions, regularly suffer from cyanobacterial blooms and citizens may easily have contact with the water and may ingest cyanobacterial material during recreational activities, particularly swimming, control of health risk is of importance. Monitoring of cyanobacteria and cyanobacterial toxins in urban ponds is a first step to control health risks. Mitigation strategies should focus on external sources of eutrophication and consider the effect of sediment P release and bioturbation by fish. PMID- 24798923 TI - Mitochondrial dysfunction affecting visual pathways. AB - Mitochondrial dysfunction leads to cellular energetic impairment, which may affect the visual pathways, from the retina to retrochiasmal structures. The most common mitochondrial optic neuropathies include Leber's hereditary optic neuropathy and autosomal dominant optic atrophy, but the optic nerve can be affected in other syndromic conditions, such as Wolfram syndrome and Friedreich's ataxia. These disorders may result from mutations in either the mitochondrial DNA or in the nuclear genes encoding mitochondrial proteins. Despite the inconstant genotype-phenotype correlations, a clinical classification of mitochondrial disorders may be made on the basis of distinct neuro-ophthalmic presentations such as optic neuropathy, pigmentary retinopathy and retrochiasmal visual loss. Although no curative treatments are available at present, recent advances throw new light on the pathophysiology of mitochondrial disorders. Current research raises hopes for novel treatment of hereditary optic neuropathies, particularly through the use of new drugs and mitochondrial gene therapy. PMID- 24798922 TI - Ornamental plants for micropollutant removal in wetland systems. AB - The objective of this paper was to evaluate the efficiency of micropollutant removal, such as Cu, Zn, carbamazepine, and linear alkylbenzene sulfonates (LAS), through the use of a subsurface vertical flow constructed wetland system with ornamental plants. Zantedeschia aethiopica, Canna indica, Carex hirta, Miscanthus sinensis, and Phragmites australis were selected and planted in lysimeters filled up with gravel. The lysimeters were completely saturated with synthetic wastewater (N 280 mg L(-1), P 30 mg L(-1), Cu 3.6 mg L(-1), Zn 9 mg L(-1), carbamazepine 5 MUg L(-1), linear alkylbenzene sulfonates 14 mg L(-1)), and the leaching water was collected for analysis after 15, 30, and 60 days in winter spring and spring-summer periods. Nutrients (N and P) and heavy metals decreased greatly due to both plant activity and adsorption. C. indica and P. australis showed the highest metal content in their tissues and also the greatest carbamazepine and LAS removal. In these plants, the adsorption/degradation processes led to particularly high oxidative stress, as evidenced by the significantly high levels of ascorbate peroxidase activity detected. Conversely, Z. aethiopica was the less efficient plant in metal and organic compound removal and was also less stressed in terms of ascorbate peroxidase activity. PMID- 24798924 TI - Genetics of mitochondrial respiratory chain deficiencies. AB - Oxidative phosphorylation, i.e. ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, and is already fully functioning before birth. This means that, in theory, RC deficiency can give rise to any symptom in any organ or tissue at any age and with any mode of inheritance, due to the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It has long been erroneously believed that RC disorders originate from mutations of mtDNA as, for some time, only mutations or deletions of mtDNA could be identified. However, the number of disease-causing mutations in nuclear genes is now steadily growing. These genes not only encode the various subunits of each complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA metabolism. PMID- 24798926 TI - Natural products from mangrove actinomycetes. AB - Mangroves are woody plants located in tropical and subtropical intertidal coastal regions. The mangrove ecosystem is becoming a hot spot for natural product discovery and bioactivity survey. Diverse mangrove actinomycetes as promising and productive sources are worth being explored and uncovered. At the time of writing, we report 73 novel compounds and 49 known compounds isolated from mangrove actinomycetes including alkaloids, benzene derivatives, cyclopentenone derivatives, dilactones, macrolides, 2-pyranones and sesquiterpenes. Attractive structures such as salinosporamides, xiamycins and novel indolocarbazoles are highlighted. Many exciting compounds have been proven as potential new antibiotics, antitumor and antiviral agents, anti-fibrotic agents and antioxidants. Furthermore, some of their biosynthetic pathways have also been revealed. This review is an attempt to consolidate and summarize the past and the latest studies on mangrove actinomycetes natural product discovery and to draw attention to their immense potential as novel and bioactive compounds for marine drugs discovery. PMID- 24798927 TI - Identification of plakortide E from the Caribbean sponge Plakortis halichondroides as a trypanocidal protease inhibitor using bioactivity-guided fractionation. AB - In this paper, we report new protease inhibitory activity of plakortide E towards cathepsins and cathepsin-like parasitic proteases. We further report on its anti parasitic activity against Trypanosoma brucei with an IC50 value of 5 MUM and without cytotoxic effects against J774.1 macrophages at 100 MUM concentration. Plakortide E was isolated from the sponge Plakortis halichondroides using enzyme assay-guided fractionation and identified by NMR spectroscopy and mass spectrometry. Furthermore, enzyme kinetic studies confirmed plakortide E as a non competitive, slowly-binding, reversible inhibitor of rhodesain. PMID- 24798928 TI - Expert's comment concerning Grand Rounds case entitled "management of the neglected and healed bilateral cervical facet dislocation" (A. Srivastava, R.C. Soh, G.W. Ee, S.B. Tan, B.P. Tow. doi:10.1007/s00586-014-3318-7). PMID- 24798925 TI - Bioactive marine drugs and marine biomaterials for brain diseases. AB - Marine invertebrates produce a plethora of bioactive compounds, which serve as inspiration for marine biotechnology, particularly in drug discovery programs and biomaterials development. This review aims to summarize the potential of drugs derived from marine invertebrates in the field of neuroscience. Therefore, some examples of neuroprotective drugs and neurotoxins will be discussed. Their role in neuroscience research and development of new therapies targeting the central nervous system will be addressed, with particular focus on neuroinflammation and neurodegeneration. In addition, the neuronal growth promoted by marine drugs, as well as the recent advances in neural tissue engineering, will be highlighted. PMID- 24798930 TI - Simultaneous determination of rabeprazole and its two active metabolites in human urine by liquid chromatography with tandem mass spectrometry and its application in a urinary excretion study. AB - A simple and rapid liquid chromatography with tandem mass spectrometry method has been developed and validated for the determination of rabeprazole and its two active metabolites, rabeprazole thioether and desmethyl rabeprazole thioether, in human urine using donepezil as the internal standard. The sample preparation procedure involved a simple dilution of urine sample with methanol (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 C18 column using a mixture of methanol/10 mmol/L ammonium acetate solution (containing 0.05% formic acid; 55:45, v/v) as the mobile phase. The method was validated over the concentration ranges of 0.15-100 ng/mL for rabeprazole, 0.30-400 ng/mL for rabeprazole thioether, and 0.05-100 ng/mL for desmethyl rabeprazole thioether. The established method was highly sensitive with a lower limit of quantification of 0.15 ng/mL for rabeprazole, 0.30 ng/mL for rabeprazole thioether, and 0.05 ng/mL for desmethyl rabeprazole thioether. The intra- and interbatch precision was <4.5% for the low, medium, and high quality control samples of all the analytes. The recovery of the analytes was in the range 95.4-99.0%. The method was successfully applied to a urinary excretion profiles after intravenous infusion administration of 20 mg rabeprazole sodium in healthy volunteers. PMID- 24798931 TI - Polarizability of fullerene [2+2]-dimers: a DFT study. AB - Currently, the exaltation of polarizability of (C60)2 dimers has been predicted with DFT-methods (D. Sh. Sabirov, RSC Adv., 2013, 3(42), 19430). It consists of an increase in the polarizability when two C60 molecules are united, forming a [2+2]-dimer. In the present work, we point attention to the bicage structures of the other fullerenes, which are promising compounds for nano-applications. We have performed the first density-functional theory study on the polarizability of fullerene [2+2]-dimers (Cn)2 (n = 20, 24, 30, 36, 50, and 70) and shown that the exaltation of polarizability is typical for all the members of the fullerenes family. PMID- 24798932 TI - Does minor trauma in pregnancy affect perinatal outcome? AB - PURPOSE: To investigate pregnancy outcome after minor trauma and to identify risk factors at admission that may predict adverse pregnancy outcome. METHODS: A retrospective study held between January-2005 and December-2011. Pregnant women at 23 weeks or more, who were admitted due to minor trauma, were included. A standard protocol was applied: physical examination, lab tests and a fetal heart rate monitoring (FHRM) and tocometer for 1 h. In cases of symptomatic women, abnormal FHRM or presence of uterine contractions, the length of monitoring was extended. All women were admitted for 24 h of observation. The primary outcome was a composite adverse outcome that included at least one of the following: placental abruption, preterm birth and birthweight <2,500 g. To investigate pregnancy outcome and identify risk factors that may predict pregnancy outcome, matched (1:2) non-trauma controls were included. Risk factors examined included maternal obstetric variables, complaints at admission, clinical findings, lab test results, FHRM and tocometer findings. RESULTS: A total of 512 women with minor trauma and 1,024 non-trauma controls were included. Composite outcome occurred in 48 (9.4 %) and 131 (12.9 %) of the study and the control groups, respectively (p = 0.04; OR 0.71; 95 % CI, 0.5-0.99). None of the parameters examined at admission predicted the occurrence of the composite outcome. CONCLUSION: Pregnant women after minor trauma have a favorable pregnancy outcome. None of the parameters examined at admission were predictive of adverse outcome. Extensive evaluation at admission and observation for 24 h are probably unnecessary following minor trauma, particularly for asymptomatic women. PMID- 24798933 TI - Diagnosis of recurrent uterine cervical cancer: PET versus PET/CT: a systematic review and meta-analysis. AB - OBJECTIVE: The aim of this work was to assess and compare the overall value of stand-alone FDG PET and PET/CT in diagnosing recurrent cervical cancer with a meta-analysis. METHODS: All the English published studies which addressed the use of PET whether interpreted with or without the use of CT for the diagnosis of recurrent cervical cancer were collected. Methodological quality of the included studies was evaluated. Pooled sensitivity and specificity were calculated, summary receiver operating characteristics (SROC) curve analysis was used to compare the diagnostic ability of stand-alone PET and PET/CT. RESULT: A total of 18 studies were included in this meta-analysis, with a total of 762 subjects. Pooled sensitivity and specificity of PET and PET/CT were 0.91 (95 % CI 0.87 0.94) and 0.94 (95 % CI 0.89-0.97), and 0.92 (95 % CI 0.91-0.94) and 0.84 (95 % CI 0.74-0.91), respectively. The areas under the SROC curve (AUCs) of PET and PET/CT were 0.9610 and 0.9491, respectively. There was no statistical significance between the AUC of PET and PET/CT (P > 0.05). CONCLUSION: Both PET and PET/CT have good performance in the detection of recurrent cervical cancer. However, interpreted CT images may have limited additional value on PET in detecting recurrent cervical cancer. PMID- 24798934 TI - Can a lymphadenectomy be avoided in early-stage endometrial adenocarcinoma? AB - PURPOSE: Determination of early disease recurrence in patients with early-stage endometrial cancer operated laparoscopically without pelvic or paraaortic lymphadenectomy. METHODS: Retrospective chart review of all patients with endometrial carcinoma operated with laparoscopic-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy between 2004 and 2008. RESULTS: 81 patients were eligible for data analysis. The operation time varied between 32 and 284 min. None of the patients suffered serious intraoperative complications. All patients had endometrial carcinoma of endometrioid type. As adjuvant therapy, patients received no further therapy (n = 30), radiation with brachytherapy with an afterloading technique alone (n = 36) or brachytherapy in combination with percutaneous radiation (n = 15). The observation period varied between 19 and 28 months (median 26 months). No patients were lost to follow-up. During the observation period, none of the patients had recurrence of disease or died. CONCLUSIONS: Laparoscopic-assisted vaginal hysterectomy with bilateral salpingo oophorectomy without pelvic or paraaortic lymphadenectomy combined with stage adapted postoperative irradiation is a safe and efficient treatment option for patients with early-stage endometrial cancer of the endometriod type regarding early disease recurrence. PMID- 24798936 TI - Successful gestation and delivery using clopidogrel for secondary stroke prophylaxis: a case report and literature review. AB - Literature is scarce regarding the use of clopidogrel during pregnancy and the potential hazard to maternal and fetal health. We report a 33-year-old female, who presented to our clinic at 40 weeks gestation with a history of multiple prior ischemic strokes and transient ischemic attacks. The patient was placed on clopidogrel for secondary stroke prophylaxis prior to conception and maintained therapy throughout pregnancy without interruption or complication. Clopidogrel was discontinued 7 days prior to induction of labor, and a healthy baby was vaginally delivered without bleeding complications or congenital anomalies. Clopidogrel was restarted 12 hours postpartum without an incident. To our knowledge, this is the first report of clopidogrel use in pregnancy for secondary stroke prophylaxis. We also provide a current review of the literature of the use of clopidogrel in pregnancy. Based on the limited data available, clopidogrel use in pregnancy has not demonstrated significant toxicity to either the mother or the newborn. However, additional studies are needed to further assess the efficacy and safety of this medication in this patient population. PMID- 24798935 TI - Retrospective comparative study of irinotecan and pegylated liposomal doxorubicin for platinum-resistant or -refractory epithelial ovarian and primary peritoneal carcinoma. AB - PURPOSE: This study was conducted to retrospectively compare the efficacy and safety of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma. METHODS: Nineteen patients who received CPT-11 and eleven patients who received PLD were enrolled. CPT-11 was intravenously administered at a starting dose of 60-100 mg/m(2) on day 1, 8, and 15 every 28 days, and PLD was administered at a starting dose of 40-50 mg/m(2) on day 1 every 28 days. Primary outcomes were overall response rate (complete response [CR] + partial response [PR]), disease control rate (CR + PR + stable disease), and progression-free survival (PFS) in each group. Clinical response was evaluated every two or three cycles using the Response Evaluation Criteria in Solid Tumors criteria; CA125 analysis was not performed. RESULTS: The overall response rate was 21.1 % (PR, four cases) and 0 % (p = 0.10) in the CPT-11 and PLD groups, respectively, and the disease control rate was 73.7 and 45.5 % (p = 0.12), respectively. Median PFS was 25.3 (range 5.4-69.9) weeks and 12.7 (range 4.0 43.1) weeks in the CPT-11 and PLD groups, respectively; however, this difference was not statistically significant (p = 0.064). Major adverse events in the CPT-11 group were neutropenia, nausea, and diarrhea, whereas those in the PLD group included thrombocytopenia, anemia, stomatitis, and hand-foot syndrome. CONCLUSIONS: This retrospective study demonstrated comparable efficacy outcomes for CPT-11 and PLD. The overall response rate, disease control rate, and median PFS were more favorable in the CPT-11 group compared to the PLD group, although the difference was not significant. The adverse event profiles were different between groups. These results suggest that CPT-11 might be a feasible choice as single-agent salvage chemotherapy for platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma beside established regimen like PLD. PMID- 24798938 TI - Mannose binding lectin deposition in skin of lupus erythematosus patients: a case series. AB - INTRODUCTION: Mannose binding lectin (MBL) has been linked to predisposition to systemic lupus erythematosus (SLE) and to disease activity. Some studies found deposits of MBL in glomerular tissue of patients with lupus nephritis. There is no research about the deposition of MBL in skin. MATERIALS AND METHODS: Skin biopsies from lesional and non lesional skin of 4 discoid lupus erythematosus (DLE) and 10 SLE patients were submitted to immunofluorescence staining for IgG, IgA, IgM, C3, C4, C1q, C5b-9 and MBL. Charts were reviewed for demographic, clinical and serological data. Patients with SLE had disease activity measured by SLEDAI. RESULTS: MBL was found only in SLE lesional skin and its presence showed an association trend towards higher disease activity. Deposition of C5b-9 occurred in vessels only in patients with SLE (70%) and in the two patients with kidney involvement. CONCLUSIONS: MBL deposition was found in the lesional skin of SLE patients but not in SLE non lesional skin nor in DLE patients, and it seems to be less frequent and less strong than observed in the kidneys biopsies, suggesting that the complement participation in the pathophysiology of SLE process may not be the same in these two clinical manifestations. PMID- 24798940 TI - Review of musculoskeletal injuries and prevention in the endoscopy practitioner. AB - Practitioners of endoscopy often experience musculoskeletal pain and injury (most often in the back, neck, shoulders, hands, wrists, and thumbs) that are associated with the minute and repetitive strain that is placed on these areas during endoscopic procedures. This review of the current documentation of endoscopy-related pain and injuries among practitioners finds that such problems are widespread and specific in kind as well as strongly correlated with high procedure volume and procedure duration. Research on the nature and impact of cumulative trauma and overuse syndromes in other professions such as dentistry, pianists, production labor, and athletics is brought to bear on the work of the endoscopist. A more thorough understanding of the nature and prevalence of work related pain and injury sustained by endoscopists should inform further development of ergonomic practices and equipment design. This article reviews current recommendations for ergonomic design in the endoscopy procedure space and finds that reported compliance with those recommendations is quite low. Strategies for the management of the risk of musculoskeletal injuries related to the practice of endoscopy include compliance with currently recommended ergonomic practices, education of trainees in ergonomic technique when practicing endoscopy, and research toward the modification and development of more ergonomic endoscopes and procedure spaces. PMID- 24798941 TI - Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with a KRAS mutation assay using allelic discrimination improves the diagnosis of pancreatic cancer. AB - GOALS AND BACKGROUND: Mutation of the KRAS oncogene is present in 75% to 95% of pancreatic cancer tissues. This study aimed to evaluate whether endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), combined with analysis of the KRAS mutation, improves the diagnosis of pancreatic cancer in cases of inconclusive or doubtful cytopathologic analysis. PATIENTS AND METHODS: We prospectively included 186 patients with a pancreatic mass (103 men; mean age: 62 y). Cytopathology and KRAS mutations, using TaqMan MGB allelic discrimination, were performed on EUS-FNA material. A final diagnosis was obtained from EUS-FNA analysis and/or a subsequent biopsy if necessary, and/or surgery, and follow-up: these were pancreatic adenocarcinoma (n=104), other malignant pancreatic tumors (n=22), and benign lesions (n=60, including 35 cases of chronic pancreatitis). RESULTS: Inconclusive or doubtful (low-grade dysplasia or atypia) cytopathology was found in 68 cases. Of these, 29 patients who had adenocarcinoma were subsequently diagnosed, including 19 cases with a former KRAS mutation. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of cytopathology alone to diagnose adenocarcinoma were 73%, 100%, 100%, 75%, and 85%, respectively. When KRAS mutation analysis was combined with pathology, these values reached 88%, 99%, 99%, 89%, and 93%, respectively. The performance of EUS-FNA to diagnose malignancy was similarly improved after the KRAS-mutation assay (negative predictive value increased from 67% to 88%; accuracy increased from 85% to 94%). CONCLUSIONS: EUS-FNA plus KRAS-mutation analysis, using allelic discrimination, is accurate and improves the diagnosis of pancreatic adenocarcinoma when pathology is inconclusive or doubtful. PMID- 24798942 TI - Depression and antidepressant use moderate association between widowhood and Alzheimer's disease. AB - OBJECTIVE: In recent decades, biological evidence has implicated chronic stress in the etiology of Alzheimer's disease (AD). As a result, the relationship between widowhood, one of the most stressful life events, and AD has also received attention. This study extends this literature by investigating whether depression, which may indicate proneness to distress, and antidepressant use, which can protect against hippocampal shrinkage, moderate the relationship between widowhood and increased risk for AD. METHODS: To investigate this, this study utilized data from the Cache County Memory Study, a large population-based epidemiological study of AD, and the Utah Population Database, one of the world's foremost linked genealogical databases, to regress AD on the interaction between widowhood and history of depression and antidepressant use. RESULTS: In Cox regression analyses, history of depression and antidepressant use moderated the association between widowhood and AD (p = 0.007 and p = 0.006, respectively), in that widowhood was associated with 73% and 94% increased hazard of AD among those reporting depression (hazard ratio [HR] = 1.73, 95% confidence interval [CI]: 1.001 to 2.99) and those reporting antidepressant use (HR = 1.94, 95% CI: 1.13 to 3.33). A significant three-way interaction between widowhood, depression, and antidepressant use was also found (p = 0.02), showing depression to moderate the association between widowhood and AD only among those not using antidepressants (p = 0.02). CONCLUSIONS: These findings advance clinical and scientific knowledge concerning the effects of widowhood on risk for AD and underscore the importance of depression and antidepressant use in understanding vulnerability to and protection from these effects. PMID- 24798943 TI - The genetics of functional disability in schizophrenia and bipolar illness: Methods and initial results for VA cooperative study #572. AB - Given the prominence of cognitive impairments and disability associated with schizophrenia and bipolar disorder, substantial interest has arisen in identifying determinants of the diseases and their features. Genetic variation has been linked to skills that underlie disability ("functional capacity" or FC), highlighting need for understanding of these relationships. We describe the design and methods of a large, multisite, observational study focusing on the genetics of functional disability in schizophrenia and bipolar disorder, presenting initial data on recruitment, and characterization of the sample. Known as Veterans Affairs (VA) Cooperative Studies Program (CSP)#572, this study is recruiting, diagnosing, and assessing U.S. Veterans with either schizophrenia or bipolar I disorder. Assessments include neuropsychological (NP) testing, FC, suicidality, and co-morbid conditions such as posttraumatic stress disorder (PTSD). A sample of "psychiatrically healthy" Veterans from another project serves as a comparison group. An interim total of 8,140 participants (42.1% schizophrenia) have been recruited and assessed as of September 30, 2013, with 9 months of enrollment remaining and with a target sample size of 9,500. Veterans with schizophrenia were more likely to never have married, whereas lifetime PTSD and suicidality were more common in the bipolar veterans. Performance on the FC measures and NP tests was consistent with previous results, with mean t-scores of 35 (-1.5 SD) for schizophrenia and 41 (-0.9 SD) for the bipolar Veterans. This large population is representative of previous studies in terms of patient performance and co-morbidities. Subsequent genomic analyses will examine the genomic correlates of performance-based measures. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 24798939 TI - Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine. AB - A significant portion of the world's population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) over a half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A(*)24, HLA-B(*)27, HLA-B(*)53 and HLA-B(*)58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B(*)44 allele. The finding will aid in developing a T cell epitope-based universal herpes vaccine and immunotherapy. PMID- 24798944 TI - Erlotinib might be a double-edged sword in HCC. PMID- 24798945 TI - Using common variants to indicate cancer genes. AB - The catalogue of tumour-specific somatic mutations (SMs) is growing rapidly owing to the advent of next-generation sequencing. Identifying those mutations responsible for the development and progression of the disease, so-called driver mutations, will increase our understanding of carcinogenesis and provide candidates for targeted therapeutics. The phenotypic consequence(s) of driver mutations cause them to be selected for within the tumour environment, such that many approaches aimed at distinguishing drivers are based on finding significantly somatically mutated genes. Currently, these methods are designed to analyse, or be specifically applied to, nonsynonymous mutations: those that alter an encoded protein. However, growing evidence suggests the involvement of noncoding transcripts in carcinogenesis, mutations in which may also be disease driving. We wished to test the hypothesis that common DNA variation rates within humans can be used as a baseline from which to score the rate of SMs, irrespective of coding capacity. We preliminarily tested this by applying it to a dataset of 159,498 SMs and using the results to rank genes. This resulted in significant enrichment of known cancer genes, indicating that the approach has merit. As additional data from cancer sequencing studies are made publicly available, this approach can be refined and applied to specific cancer subtypes. We named this preliminary version of our approach PRISMAD (polymorphism rates indicate somatic mutations as drivers) and have made it publicly accessible, with scripts, via a link at www.precancer.leeds.ac.uk/software-and-datasets. PMID- 24798946 TI - Older adults' perceptions of technologies aimed at falls prevention, detection or monitoring: a systematic review. AB - BACKGROUND: Over recent years a number of Information and Communication Technologies (ICTs) have emerged aiming at falls prevention, falls detection and alarms for use in case of fall. There are also a range of ICT interventions, which have been created or adapted to be pro-active in preventing falls, such as those which provide strength and balance training to older adults in the prevention of falls. However, there are issues related to the adoption and continued use of these technologies by older adults. OBJECTIVES: This review provides an overview of older adults' perceptions of falls technologies. METHODS: We undertook systematic searches of MEDLINE, EMBASE, CINAHL and PsychINFO, COMPENDEX and the Cochrane database. Key search terms included 'older adults', 'seniors', 'preference', 'attitudes' and a wide range of technologies, they also included the key word 'fall*'. We considered all studies that included older adults aged 50 and above. Studies had to include technologies related specifically to falls prevention, detection or monitoring. The Joanna Briggs Institute (JBI) tool and the Quality Assessment Tool for Quantitative Studies by the Effective Public Health Practice Project (EPHPP) were used. RESULTS: We identified 76 potentially relevant papers. Some 21 studies were considered for quality review. Twelve qualitative studies, three quantitative studies and 6 mixed methods studies were included. The literature related to technologies aimed at predicting, monitoring and preventing falls suggest that intrinsic factors related to older adults' attitudes around control, independence and perceived need/requirements for safety are important for their motivation to use and continue using technologies. Extrinsic factors such as usability, feedback gained and costs are important elements which support these attitudes and perceptions. CONCLUSION: Positive messages about the benefits of falls technologies for promoting healthy active ageing and independence are critical, as is ensuring that the technologies are simple, reliable and effective and tailored to individual need. The technologies need to be clearly described in research and older peoples' attitudes towards different sorts of technologies must be clarified if specific recommendations are to be made. PMID- 24798947 TI - Bovine growth hormone gene polymorphism affects stress response in Japanese Black cattle. AB - We investigate the associations between growth hormone (GH) gene polymorphism and behavioral and physiological responses to stressors and learning ability in Japanese Black cattle. Flight distance test was conducted in the first experiment. Steers with haplotype C of GH gene polymorphism avoided human approaches at a significantly greater distance than ones without haplotype C (C: 1.9 +/- 0.9, non-C: 1.0 +/- 0.2 m, P < 0.05). An open-field test was conducted in the second experiment. Behavioral responses did not differ significantly between steers with and without haplotype C. Increases of heart rates to dropping of iron pipes was significantly higher in steers with haplotype C (C:161.7 +/- 21.8, non C:130.7 +/- 31.3%, P < 0.05). Despite basal serum concentrations not being different between steers with and without haplotype C, serum cortisol in blood sampling immediately after severe confinement in a race tended to be higher in steers with haplotype C (P = 0.1). The maze test was conducted as the third experiment. There was no difference in performance in the maze test between steers with and without haplotype C. It is concluded that genetic polymorphism of GH may affect stress responses through GH concentration in steers. PMID- 24798948 TI - Pulmonary hypoplasia presenting with recurrent wheezing in an infant. AB - Pulmonary hypoplasia is characterized by decrease in the number and size of pulmonary airways, alveoli and vessels. In autopsy, pulmonary hypoplasia is a major cause of death in neonates and infants. The disease is usually diagnosed in childhood period. Although it mimics lung parenchymal disease and other vascular abnormalities radiologically, it is easily recognized with computed tomography angiography and magnetic resonance angiography examinations. In 50% of patients, concomitant cardiovascular, neuromuscular, gastrointestinal tract, and urogenital anomalies are also available. There are two types of pulmonary hypoplasia: primary and secondary. Primary unilateral pulmonary hypoplasia may be asymptomatic and the tendency for bronchopulmonary infections is often increased in children. In this case report, a 22-month-old male patient characterized by recurrent infections and recurrent wheezes in infantile period, whose episodes of wheezing regressed after the pulmonectomy, was presented. PMID- 24798949 TI - Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in primary melanocytes. AB - Cutaneous melanoma is a significant cause of morbidity and mortality. Nicotinamide is a safe, widely available vitamin that reduces the immune suppressive effects of UV, enhances DNA repair in keratinocytes and has shown promise in the chemoprevention of non-melanoma skin cancer. Here, we report the effect of nicotinamide on DNA damage and repair in primary human melanocytes. Nicotinamide significantly enhanced the repair of oxidative DNA damage (8-oxo-7,8 dihydro-2'-deoxyguanosine) and cyclobutane pyrimidine dimers induced by UV exposure. It also enhanced the repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine induced by the culture conditions in unirradiated melanocytes. A significant increase in the percentage of melanocytes undergoing unscheduled but not scheduled DNA synthesis was observed, confirming that nicotinamide enhances DNA repair in human melanocytes. In summary, nicotinamide, by enhancing DNA repair in melanocytes, is a potential agent for the chemoprevention of cutaneous melanoma. PMID- 24798950 TI - Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. AB - It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce beta cell dysfunction and subsequent insulin deficiency. Particularly, the pro inflammatory interleukin-1beta is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes. PMID- 24798951 TI - Nanostructured Materials Utilized in Biopolymer-based Plastics for Food Packaging Applications. AB - Most materials currently used for food packaging are nondegradable, generating environmental problems. Several biopolymers have been exploited to develop materials for ecofriendly food packaging. However, the use of biopolymers has been limited because of their usually poor mechanical and barrier properties, which may be improved by adding reinforcing compounds (fillers), forming composites. Most reinforced materials present poor matrix-filler interactions, which tend to improve with decreasing filler dimensions. The use of fillers with at least one nanoscale dimension (nanoparticles) produces nanocomposites. Nanoparticles have proportionally larger surface area than their microscale counterparts, which favors the filler-matrix interactions and the performance of the resulting material. Besides nanoreinforcements, nanoparticles can have other functions when added to a polymer, such as antimicrobial activity, etc. in this review paper, the structure and properties of main kinds of nanostructured materials which have been studied to use as nanofiller in biopolymer matrices are overviewed, as well as their effects and applications. PMID- 24798952 TI - Atmospheric peroxy radical measurements using dual-channel chemical amplification cavity ringdown spectroscopy. AB - Peroxy (HO2 and RO2) radicals are important intermediates in tropospheric oxidation of hydrocarbons, and their accurate atmospheric measurements remain challenging. In this work, the peroxy radical chemical amplification (PERCA) method was combined with cavity ringdown spectroscopy (CRDS) to develop a dual channel instrument for measurements of atmospheric peroxy radicals. In the amplification channel, the peroxy radicals were converted in an excess amount of NO and CO into a higher level of NO2 and measured along with the background NO2, while in the reference channel, only the background NO2 (ambient NO2 and NO2 converted from O3 reaction with NO) was monitored. The NO2 levels from both channels were measured simultaneously at a high time resolution (~1 s) using two identical CRDS systems with one 408.5-nm diode laser, and their difference gave the amplified NO2 from PERCA. The peroxy radical concentration was obtained from the amplified NO2 and the calibrated amplification factor or chain length (CL). The optimized CL was 190 +/- 20 (1sigma) using laboratory-generated HO2 and CH3O2 radical sources. The detection sensitivity was 4 ppt/10 s (3sigma). Ambient measurements in Riverside, CA were carried out. This dual-channel diode-laser PERCA-CRDS instrument was compact and capable of providing real-time, in situ, and sensitive measurements of atmospheric peroxy radicals with fast time response. PMID- 24798953 TI - Postoperative small bowel and colonic anastomotic bleeding. Therapeutic management and complications. AB - INTRODUCTION: Postoperative small bowel or colic anastomotic bleeding (PSCAB) is often a mild complication and is generally treated by a conservative approach. Other therapeutic options are surgery, endoscopic management and angiographic embolization. Our aim is to review our cases of postoperative anastomotic bleeding in patients with small bowel or colic anastomosis, with special attention to their treatment and complications. PATIENTS AND METHODS: Observational retrospective study including patients with PSCAB in the department of General and Digestive Surgery in Vall d'Hebron University Hospital, between 2007 and 2012. Demographic and bleeding characteristics as well as therapeutic management were reviewed, including complications derived from the different therapeutic options. RESULTS: There were 44 cases of bleeding after performing small bowel or colic anastomosis, 25 patients were men (56.8%), with a mean age of 68.2 years (R: 28-92). The mean hematocrit decrease was 8 points (R: 0-17), and hemodynamic instability was detected in 13 patients (29.5%). A conservative management was undertaken in 27 patients (61.3%), surgery in 6 (13.6%), endoscopic treatment in 2 (4.5%) and embolization in 9 (20.5%). 4 patients of cases treated with embolization presented anastomotic leak (44.5%). Mortality was 13.6% (6 patients). A total of 4 of 6 deaths were in the group of patients treated with embolization. CONCLUSIONS: Most patients with PSCAB have a good response to conservative management. When there is failure of this approach, there are different therapeutic options, including angiographic embolization. In our series, we have seen a high incidence of post embolization anastomotic leak; further trials will be necessary to provide valuable evidence of the risk of this therapeutic option. PMID- 24798954 TI - Retroperitoneal neuroblastoma in the adult. An uncommon entity. PMID- 24798955 TI - Leadless endocardial left ventricular resynchronization: is it ready for prime time? PMID- 24798956 TI - Ischaemic stroke prevention in patients with atrial fibrillation and high bleeding risk: opportunities and challenges for percutaneous left atrial appendage occlusion. AB - Patients with atrial fibrillation (AF) are at an increased risk of ischaemic stroke. The efficacy of stroke prevention with vitamin K antagonists in these patients has been well established. However, associated bleeding risks may offset the therapeutic benefits in patients with risk factors for bleeding. Despite improvements achieved by novel oral anticoagulants, bleeding remains a clinically relevant problem, especially gastrointestinal bleeding. Percutaneous occlusion of the left atrial appendage (LAA) may be considered as an alternative stroke prevention therapy in AF patients with a high bleeding risk. This paper explores patient groups in whom oral anticoagulation may be challenging and percutaneous LAA occlusion (LAAO) has a potentially better risk-benefit balance. The current status of LAAO and future directions are reviewed, and particular challenges for LAA occlusion requiring further clinical data are discussed. This article is a summary of the Third Global Summit on LAA occlusion, 15 March 2013, Barcelona, Spain. PMID- 24798957 TI - Contact force and force-time integral in atrial radiofrequency ablation predict transmurality of lesions. AB - AIMS: During radiofrequency (RF) delivery, lesion volume is highly dependent on contact force (CF). It has recently been shown that changes of bipolar electrogram (EGM) predict transmurality. We hypothesized that there is a correlation between CF and EGM criteria of transmural lesion (TL) during RF. METHODS AND RESULTS: We prospectively studied consecutive 512 RF applications from atrial fibrillation ablation procedures. A force-sensing ablation catheter (Tacticath((r)), Endosense) was used to continuously measure CF and force-time integral (FTI) during each RF application. Distal bipolar EGM was analysed before, during, and after each RF application. Depending on initial EGM morphology, transmurality of lesions was defined by: (i) disappearance of the positivity after RF when there was QR morphology, (ii) diminution >75% of the positivity when there was QRS morphology, or (iii) disappearance of the R' positivity when there was RSR' morphology. Electrogram criteria were validated by electrophysiologists blinded to force measurements. Force-time integral was higher in TL than in non-transmural lesions (NTLs): 652 +/- 248 vs. 212 +/- 140 gs (P < 0.001). Mean CF per RF pulse was higher in TL than in NTL: 26.3 +/- 12.5 vs. 11.3 +/- 10.3 g (P < 0.001). The best cut-off to predict TL was an FTI >= 392 gs [sensitivity 0.89, specificity (Sp) 0.93, positive predictive value (PPV) 0.98, and negative predictive value 0.67] and a higher FTI (>700 gs) warrants transmurality of RF atrial lesions (100% Sp and PPV). CONCLUSION: Contact force and FTI during RF are correlated with TL. During RF delivery, a target FTI > 392 gs can be used as an endpoint. PMID- 24798958 TI - Stroke and bleeding risk evaluation in atrial fibrillation: results of the European heart rhythm association survey. AB - The aim of this European Heart Rhythm Association (EHRA) survey was to assess clinical practice in relation to stroke and bleeding risk evaluation in atrial fibrillation, particularly regarding the use of risk evaluation schemes, among members of the EHRA electrophysiology (EP) research network. In this EP Wire survey, we have provided some insights into current practice in Europe for the use of these risk assessment schemes. There were some obvious practice differences. However, reassuring information on current practice in Europe was evident, but more focus on renal function is warranted, especially facing the fact that novel oral anticoagulants are used for antithrombotic therapy. PMID- 24798959 TI - Computational cardiac electrophysiology is moving towards translation medicine. PMID- 24798961 TI - Computational mapping in atrial fibrillation: how the integration of signal derived maps may guide the localization of critical sources. AB - This article discusses the latest development in computational mapping for the identification and localization of critical sources in patients with atrial fibrillation (AF). It focuses on the contribution of electrogram-derived anatomical maps, obtained by applying innovative signal and image processing methodologies, to the investigation of the mechanisms underlying the arrhythmia and to the planning of new target ablation strategies. Reviewed are the experimental studies which allowed to infer the peculiar rate and regularity features of critical sources, the signal processing methods for the quantification of these parameters from atrial electrograms, and the clinical studies mapping rate and organization in AF patients. Finally, we present a novel methodological framework, based on the construction of the logic operation map, designed to merge in a single map the most relevant electrophysiological and anatomical features of the AF process, which may guide the selective identification of critical sources. PMID- 24798960 TI - New insights into defibrillation of the heart from realistic simulation studies. AB - Cardiac defibrillation, as accomplished nowadays by automatic, implantable devices, constitutes the most important means of combating sudden cardiac death. Advancing our understanding towards a full appreciation of the mechanisms by which a shock interacts with the heart, particularly under diseased conditions, is a promising approach to achieve an optimal therapy. The aim of this article is to assess the current state-of-the-art in whole-heart defibrillation modelling, focusing on major insights that have been obtained using defibrillation models, primarily those of realistic heart geometry and disease remodelling. The article showcases the contributions that modelling and simulation have made to our understanding of the defibrillation process. The review thus provides an example of biophysically based computational modelling of the heart (i.e. cardiac defibrillation) that has advanced the understanding of cardiac electrophysiological interaction at the organ level, and has the potential to contribute to the betterment of the clinical practice of defibrillation. PMID- 24798962 TI - Computer-based prediction of the drug proarrhythmic effect: problems, issues, known and suspected challenges. AB - It is likely that computer modelling and simulations will become an element of comprehensive cardiac safety testing. Their role would be primarily the integration and the interpretation of previously gathered data. There are still unanswered questions and issues which we list and describe below. They include sources of data used for the development of the models as well as data utilized as input information, which can come from the in vitro studies and the quantitative structure-activity relationship models. The pharmacokinetics of the drugs in question play a crucial role as their active concentration should be considered, yet the question remains where is the right place to assess it. The pharmacodynamic angle includes complications coming from multiple drugs (i.e. active metabolites) acting in parallel as well as the type of interaction with (potentially) multiple affected channels. Once established, the model and the methodology of its use should be further validated, optimistically against individual data reported at the clinical level as the physiological, anatomical, and genetic parameters play a crucial role in the drug-triggered arrhythmia induction. All the abovementioned issues should be at least considered and hopefully-resolved, to properly utilize the mathematical models for a cardiac safety assessment. PMID- 24798963 TI - Effects of premature anodal stimulations on cardiac transmembrane potential and intracellular calcium distributions computed by anisotropic Bidomain models. AB - AIMS: Cardiac unipolar electrode stimulations induce a particular structure of the transmembrane potential distribution (Vm), called virtual electrode polarization (VEP), which plays an important role in the mechanisms of cardiac excitation, reentry induction, and ventricular defibrillation. Recent experimental studies, based on the optical mapping techniques, have shown that premature stimulations also induce significant changes in the intracellular calcium (Cai) spatial distribution. The aim of this work is to investigate and compare by means of numerical simulations the morphology of the Vm and Cai patterns, generated by applying an S1-S2 stimulation protocol with a premature S2 anodal pulse. METHODS AND RESULTS: We perform parallel finite element simulations of a three-dimensional orthotropic Bidomain model on a block of ventricular tissue by using four membrane models of two species (guinea pig and rabbit), that incorporate the phenomenological or more detailed mechanistic descriptions of the calcium dynamics. During the S2 anodal stimulus, the Cai spatial distribution, computed with all the considered models, presents a configuration similar to the typical VEP pattern of Vm, with a minimum inside the virtual anode and two maxima in the virtual cathodes. After the S2 stimulus turns off, the anode break excitation mechanism yields a Vm pattern exhibiting a clearly propagating wavefront. Differently, the Cai patterns do not show a clear separation between the resting and the activated regions, with the exception of one of the phenomenological models considered, but they show warped dog-bone shaped equi level lines around an elevation in the virtual anode region. CONCLUSION: The VEP pattern of the Cai spatial distribution during the S2 stimulus is in agreement with the previous experimental studies. Moreover, the Cai minimum in the virtual anode can be mainly attributable to the outflow of calcium ions produced by the sodium-calcium (NCX) exchanger, without a significant contribution of the ICaL current. PMID- 24798964 TI - Non-invasive imaging of cardiac electrophysiology in a cardiac resynchronization therapy defibrillator patient with a quadripolar left ventricular lead. AB - AIMS: The present study was aimed to assess epi- and endocardial ventricular electroanatomical activation during cardiac resynchronization therapy (CRT) by means of non-invasive imaging of cardiac electrophysiology (NICE) in a patient with a novel quadripolar LV lead. METHODS AND RESULTS: Non-invasive imaging of cardiac electrophysiology is a novel imaging tool which works by fusing data from high-resolution electrocardiogram (ECG) mapping with a model of the patient's individual cardiothoracic anatomy created from magnetic resonance imaging. This was performed in a cardiac resynchronization therapy defribrillator (CRT-D) patient with a quadripolar left ventricular (LV) lead. Beat-to-beat endocardial and epicardial ventricular activation sequences were computed using NICE during intrinsic conduction as well as during different pacing modes with different LV and biventricular (biV) pacing vectors. The spatial resolution of NICE enabled discrimination of the different pacing vectors during LV and biV pacing. Biventricular pacing resulted in a marked shortening of the total activation duration (TAD) of both ventricles when compared with intrinsic conduction and RV and LV pacing. CONCLUSION: Non-invasive imaging of cardiac electrophysiology facilitates non-invasive imaging of ventricular activation, which may be useful in CRT patients to locate the area of latest ventricular activation as the target area for LV lead placement. Moreover, especially in non-responders to CRT NICE may be further useful to determine the best electrical repositioning option. PMID- 24798965 TI - Electrocardiographic imaging-based recognition of possible induced bundle branch blocks during transcatheter aortic valve implantations. AB - AIMS: Conventional electrocardiogram (ECG)-based diagnosis of left bundle branch block (LBBB) in patients with left ventricular hypertrophy (LVH) is ambiguous. Left ventricular hypertrophy is often seen in patients with severe aortic stenosis in which a transcatheter aortic valve implantation (TAVI) frequently results in a LBBB due to the mechanical interaction of the artificial valve and the conduction system. In this feasibility study, we propose and evaluate the sensitivity of a new electrocardiographic imaging tool; the cardiac isochrone positioning system (CIPS), visualizing the cardiac activation to detect interventricular conduction patterns pre- and post-TAVI. METHODS AND RESULTS: The CIPS translates standard 12-lead ECG into ventricular isochrones, representing the activation sequence. It requires a patient-specific model integrating heart, lungs, and other thoracic structures derived from multi-slice computed tomography. The fastest route-based algorithm was used to estimate the activation isochrones and the results were compared with standard ECG analysis. In 10 patients the CIPS was used to analyse 20 ECGs, 10 pre- and 10 post-TAVI. In 11 cases the CIPS results were in agreement with the ECG-based diagnosis. In two cases there was partial agreement and in seven cases there was disagreement. In four of these cases, the clinical history of the patients favoured interpretation as assessed by CIPS, for the remaining three, it is unknown which method correctly classified the activation. CONCLUSION: This feasibility study applying the CIPS shows promising results to classify conduction disorders originating from the left anterior or posterior ventricular wall, or the septum. The visualization of the activation isochrones as well as ventricular model-derived features might support TAVI procedures and the therapy selection afterwards. PMID- 24798966 TI - Towards computational modelling of the human foetal electrocardiogram: normal sinus rhythm and congenital heart block. AB - AIMS: We aim to engineer a computational model of propagation during normal sinus rhythm in the foetal human heart, by modifying models for adult cardiac tissue to match foetal electrocardiogram (fECG) characteristics. The model will be partially validated by fECG data, and applied to explore possible mechanisms of arrhythmogenesis in the foetal heart. METHODS AND RESULTS: Foetal electrocardiograms have been recorded during pregnancy, with P- and T-waves, and the QRS complex, identified by averaging and signal processing. Intervals of the fECG are extracted and used to modify currently available human adult cardiomyocyte models. RR intervals inform models of the pacemaking cells by constraining their rate, the QT interval and its rate dependence constrain models of ventricular cells, and the width of the P-wave, the QR and PR intervals constrain propagation times, conduction velocities, and intercellular coupling. These cell models are coupled into a one-dimensional (1D) model of propagation during normal sinus rhythm in the human foetal heart. We constructed a modular, heterogeneous 1D model for propagation in the foetal heart, and predicted the effects of reduction in L-type Ca(++) current. These include bradycardia and atrioventricular conduction blocks. These may account quantitatively for congenital heart block produced by positive IgG antibodies. CONCLUSION: The fECG can be interpreted mechanistically and quantitatively by using a simple computational model for propagation. After further validation, by clinical recordings of the fECG and the electrophysiological experiments on foetal cardiac cells and tissues, the model may be used to predict the effects of maternally administered pharmaceuticals on the fECG. PMID- 24798967 TI - Influence of atrial substrate on local capture induced by rapid pacing of atrial fibrillation. AB - AIMS: Preliminary studies showed that the septum area was the only location allowing local capture of both the atria during rapid pacing of atrial fibrillation (AF) from a single site. The present model-based study investigated the influence of atrial substrate on the ability to capture AF when pacing the septum. METHODS AND RESULTS: Three biophysical models of AF with an identical anatomy from human atria but with different AF substrates were used: (i) AF based on multiple wavelets, (ii) AF based on heterogeneities in vagal activation, (iii) AF based on heterogeneities in repolarization. A fourth anatomical model without Bachmann's bundle (BB) was also implemented. Rapid pacing was applied from the septum at pacing cycle lengths in the range of 50-100% of AF cycle length. Local capture was automatically assessed with 24 pairs of electrodes evenly distributed on the atrial surface. The results were averaged over 16 AF simulations. In the homogeneous substrate, AF capture could reach 80% of the atrial surface. Heterogeneities degraded the ability to capture during AF. In the vagal substrate, the capture tended to be more regular and the degradation of the capture was not directly related to the spatial extent of the heterogeneities. In the third substrate, heterogeneities induced wave anchorings and wavebreaks even in areas close to the pacing site, with a more dramatic effect on AF capture. Finally, BB did not significantly affect the ability to capture. CONCLUSION: Atrial fibrillation substrate had a significant effect on rapid pacing outcomes. The response to therapeutic pacing may therefore be specific to each patient. PMID- 24798968 TI - Instantaneous current-voltage relationships during the course of the human cardiac ventricular action potential: new computational insights into repolarization dynamics. AB - AIMS: To adopt a novel three-dimensional (3D) representation of cardiac action potential (AP) to compactly visualize dynamical properties of human cellular ventricular repolarization. METHODS AND RESULTS: We have recently established a novel 3D representation of cardiac AP, which is based on the iterative measurement of instantaneous ion current-voltage profiles during the course of an AP. Such an approach has been originally developed on real patch-clamped ventricular cells, and subsequently improved in silico on several cardiac ventricular AP models of different mammals, and on models of different AP types of the human heart. We apply it here on two different models of human ventricular AP, and show that it compactly provides further insights into repolarization dynamics. The 3D representation of the AP includes equilibrium points during repolarization, and can be screened in terms of what we have shown to be a region, during late repolarization, when membrane conductance becomes negative and repolarization therefore auto-regenerative. We have called this time window auto-regenerative-repolarization-phase (ARRP). CONCLUSION: In addition to previous findings obtained through the same procedure, we show here that 3D current-voltage-time representations of human ventricular AP allow compact visualization of dynamical properties, which are relevant for the physiology and pathology of ventricular repolarization. In particular, we suggest that the volume under the current surface corresponding to the ARRP might be used as a predictor of safety of repolarization, in single cells and during AP conduction in cell pairs. PMID- 24798969 TI - A search for the searchlight - crossmodal interactions in the reticular thalamic nucleus (Commentary on Kimura). PMID- 24798970 TI - CD16+CD56+ cells are a potential culprit for hematuria in IgA nephropathy. AB - BACKGROUND: Hematuria is the first manifestation of urinary abnormality in immunoglobulin A nephropathy (IgAN). Hematuria has recently been reported as a risk factor for deterioration of renal function; however, its cause remains unknown. METHODS: We analyzed the surface marker of peripheral blood mononuclear cells before and immediately after tonsillectomy in IgAN patients and controls (chronic tonsillitis or tonsillar hypertrophy) by flow cytometry and investigated the association with hematuria. To prove our hypothesis that NK cells induce hematuria, we administered IL-12, activator of NK cells, to HIGA mice. In addition, we transferred cultured NK cells to nude rats and transferred the CD16(+)CD56(+) cells, including NK cells, that are derived from the peripheral blood of IgAN patients immediately after tonsillectomy to nude rats to assess the hematuria level and renal histology of the recipients. We also performed cytotoxicity assays against glomerular endothelial cells by NK cells. RESULTS: We found that IgAN patients who showed rapid deterioration of hematuria after tonsillectomy also displayed a significant increase in CD16(+)CD56(+) cells in the peripheral blood immediately after tonsillectomy. Exogenous administration of IL-12 to HIGA mice induced hematuria. Adoptive transfer of either cells of an NK cell line, or of CD16(+)CD56(+) cells derived from IgAN patients, into nude rats induced hematuria in the recipients. In vitro analysis showed that NK cells exert cytotoxic activity toward human glomerular endothelial cells in a dose-dependent manner. CONCLUSIONS: CD16(+)CD56(+) cells seem to be responsible for hematuria in IgAN. PMID- 24798971 TI - Plasma ferritin levels, HFE polymorphisms, and risk of pancreatic cancer among Chinese Han population. AB - The etiology of pancreatic cancer (PC) remains poorly understood. High iron levels can increase the formation of noxious oxygen radicals, which are thought to promote carcinogenesis. The aim of this study was to determine whether iron biomarkers and HFE genotypes, which influence iron regulation, constitute risk factors for PC. A case-control study was conducted to examine plasma ferritin levels (n = 1,000 cases; 1,004 controls), two hemochromatosis gene (HFE) SNPs (n = 1,386 cases; 1,386 controls), and PC risk. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by unconditional logistic regression. We did not observe a significant association between plasma ferritin and PC risk. However, HFE rs1799945 was significantly associated with PC risk, with each additional copy of minor allele T being associated with a 1.21-fold increased risk of PC (OR = 1.21, 95 % CI 1.05-1.39, P = 7.72 * 10(-3)). Overall, high iron levels do not increase the risk of PC. Our observation that HFE rs1799945 increased PC risk warrants replication in additional study populations. PMID- 24798972 TI - Ki-67, TGF-beta1, and elastin content are significantly altered in lip carcinogenesis. AB - Epithelial changes observed in actinic cheilitis (AC) and lower lip squamous cell carcinoma (LLSCC) have been studied using different markers in order to observe diagnostic and prognostic factors for both lesions. The aim of the present study was to analyze Ki-67, TGF-beta1, and elastin content in AC and LLSCC to determine the possible role of these proteins in lip carcinogenesis. Medical records of 29 cases of AC and 53 cases of LLSCC were analyzed. Lesions were classified according histological pattern and submitted to immunostaining for Ki-67, TGF beta1, and elastin. Different percentages of Ki-67-positive cells were found in AC depending on the degree of epithelial dysplasia (p < 0.01). An association was also found between the percentage of Ki-67-positive cells and tumor grade in LLSCC (p < 0.01). An inverse correlation was found between Ki-67 and TGF-beta1 in AC and LLSCC (p < 0.01). Elastosis was thinner and more discontinuous in LLSCC in comparison to AC, and this difference in the elastin immunolabeling pattern was statistically significant between groups (p < 0.01). The present findings indicate that changes in Ki-67 and TGF-beta1 content contribute to lip carcinogenesis. Furthermore, elastin content reflects changes in the extracellular matrix in both AC and LLSCC. PMID- 24798973 TI - Inhibition of macrophage polarization prohibits growth of human osteosarcoma. AB - Osteosarcoma is the most malignant bone tumor characterized by high local aggressiveness and poor therapeutic outcome. Tumor-associated macrophages (TAM) have been shown to participate in the development and progress of many types of cancer cells. However, whether TAM may play a role in the pathogenesis of osteosarcoma is largely unknown. In a mouse model of human osteosarcoma implantation, we showed that the recruited macrophages at the site of the implanted tumor were polarized to an M2 subtype (same as TAM) during the development and growth of the osteosarcoma. In a loss-of-function experiment, we deleted these TAM with a specific macrophage-eliminating liposome, which resulted in decreased tumor growth. Moreover, when the epidermal growth factor receptor (EGFR) in the implanted cancer cells was inhibited by shRNA, the tumor failed to grow in response to the recruited macrophages. Taken together, for the first time, we show that the growth of an osteosarcoma is EGFR signaling-dependent and TAM-mediated. Our data suggest that TAM and EGFR may be good targets for treating human osteosarcoma. PMID- 24798974 TI - Tumor protein D52 (TPD52) and cancer-oncogene understudy or understudied oncogene? AB - The Tumor protein D52 (TPD52) gene was identified nearly 20 years ago through its overexpression in human cancer, and a substantial body of data now strongly supports TPD52 representing a gene amplification target at chromosome 8q21.13. This review updates progress toward understanding the significance of TPD52 overexpression and targeting, both in tumors known to be characterized by TPD52 overexpression/amplification, and those where TPD52 overexpression/amplification has been recently or variably reported. We highlight recent findings supporting microRNA regulation of TPD52 expression in experimental systems and describe progress toward deciphering TPD52's cellular functions, particularly in cancer cells. Finally, we provide an overview of TPD52's potential as a cancer biomarker and immunotherapeutic target. These combined studies highlight the potential value of genes such as TPD52, which are overexpressed in many cancer types, but have been relatively understudied. PMID- 24798975 TI - Retinoic acid receptor-related receptor alpha (RORalpha) is a prognostic marker for hepatocellular carcinoma. AB - Retinoic acid receptor-related receptor alpha (RORalpha) has been proven to play a tumor suppressive role in certain types of solid tumors. However, the clinical characteristic of RORalpha has not been reported by far. This study investigated the expression of RORalpha in hepatocellular carcinoma (HCC) and evaluated its relationship with clinical parameters and prognosis in HCC patients. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot analyses were performed to detect RORalpha expression levels in 20 paired HCC and corresponding adjacent non-cancerous tissues. Immunohistochemistry was performed on 100 archived paraffin-embedded HCC samples. Statistical analyses evaluated the correlations between RORalpha expression and clinicopathological features. qRT PCR showed that RORalpha mRNA expression was significantly down-regulated in tumors compared to the adjacent non-cancerous tissues, and Western blots found that RORalpha protein expression was also reduced in tumor tissues. Immunohistochemical assays revealed that decreased RORalpha expression was present in 65 % of HCC patients. Correlation analyses showed that RORalpha expression was significantly correlated with serum alpha fetoprotein (AFP, p = 0.005), pathology grade (p < 0.001), tumor recurrence (p = 0.008), and vascular invasion (p < 0.001). Kaplan-Meier analysis revealed that patients with low RORalpha expression levels had a shorter overall and disease-free survival than patients with high expression (p < 0.001 and p = 0.002, respectively). Multivariate regression analysis indicated that RORalpha was an independent predictor for overall survival and disease-free survival. In conclusion, the results of our study showed that down-regulated RORalpha expression was associated with poorer prognosis in HCC patients. RORalpha may be a new potential prognostic marker for HCC patients. PMID- 24798976 TI - Rsf-1 overexpression serves as a prognostic marker in human hepatocellular carcinoma. AB - Rsf-1 (HBXAP) was recently reported to be overexpressed in various cancers and associated with the malignant behavior of cancer cells. However, the expression of Rsf-1 and its clinical significance in human hepatocellular carcinoma (HCC) have not been reported. In the present study, we analyzed the expression pattern of Rsf-1 in human HCC tissues and found that Rsf-1 was overexpressed in 41.1 % of HCC specimens. There was a significant association between Rsf-1 overexpression and tumor stage (p = 0.0322), AFP (p = 0.0184), and tumor relapse (p = 0.0112). Furthermore, Rsf-1 overexpression correlated with poor overall survival in HCC patients (p < 0.001). Rsf-1 overexpression could serve as an independent predictor for poor recurrence-free survival (p = 0.0079). Small interfering RNA (siRNA) knockdown in SK-Hep-1 cells with high endogenous Rsf-1 expression inhibited cell proliferation and colony formation, with downregulation of cyclin E protein. In conclusion, Rsf-1 is overexpressed in HCCs and serves as a novel tumor marker. Rsf-1 contributes to hepatocellular carcinoma cell growth through regulation of cell cycle proteins. PMID- 24798977 TI - LOX/COX inhibitors enhance the antineoplastic effects of all-trans retinoic acid in osteosarcoma cell lines. AB - The induced differentiation of tumor cells into mature phenotypes is a promising strategy in cancer therapy. In this study, the effects of combined treatment with all-trans retinoic acid (ATRA) and lipoxygenase/cyclooxygenase inhibitors were examined in two osteosarcoma cell lines, Saos-2 and OSA-01. Caffeic acid and celecoxib were used as inhibitors of 5-lipoxygenase and of cyclooxygenase-2, respectively. Changes in the cell proliferation, matrix mineralization, and occurrence of differentiation markers were evaluated in treated cell populations at intervals. The results confirmed the capability of caffeic acid to enhance the antiproliferative effect of ATRA in both cell lines. In contrast, celecoxib showed the same effect in Saos-2 cells only. Furthermore, the extension of matrix mineralization was observed after combined treatment with ATRA and celecoxib or caffeic acid. The increased expression of osteogenic differentiation markers was observed in both cell lines after the combined application of ATRA and inhibitors. The obtained results clearly demonstrate the capability of lipoxygenase/cyclooxygenase inhibitors to enhance the antiproliferative and differentiating effect of ATRA in osteosarcoma cells, although some of these effects are specific and depend on the biological features of the respective tumor or cell line. PMID- 24798978 TI - Engineering aqueous fiber assembly into silk-elastin-like protein polymers. AB - Self-assembled peptide/protein nanofibers are valuable 1D building blocks for creating complex structures with designed properties and functions. It is reported that the self-assembly of silk-elastin-like protein polymers into nanofibers or globular aggregates in aqueous solutions can be modulated by tuning the temperature of the protein solutions, the size of the silk blocks, and the charge of the elastin blocks. A core-sheath model is proposed for nanofiber formation, with the silk blocks in the cores and the hydrated elastin blocks in the sheaths. The folding of the silk blocks into stable cores--affected by the size of the silk blocks and the charge of the elastin blocks--plays a critical role in the assembly of silk-elastin nanofibers. Furthermore, enhanced hydrophobic interactions between the elastin blocks at elevated temperatures greatly influence the nanoscale features of silk-elastin nanofibers. PMID- 24798979 TI - Comparison of Knoop and Vickers surface microhardness and transverse microradiography for the study of early caries lesion formation in human and bovine enamel. AB - OBJECTIVE: The aims of the present laboratory study were twofold: a) to investigate the suitability of Knoop and Vickers surface microhardness (SMH) in comparison to transverse microradiography (TMR) to investigate early enamel caries lesion formation; b) to compare the kinetics of caries lesion initiation and progression between human and bovine enamel. DESIGN: Specimens (90*bovine and 90*human enamel) were divided into six groups (demineralization times of 8/16/24/32/40/48h) of 15 per enamel type and demineralized using a partially saturated lactic acid solution. SMH was measured before and after demineralization and changes in indentation length (DeltaIL) calculated. Lesions were characterized using TMR. Data were analyzed (two-way ANOVA) and Pearson correlation coefficients calculated. RESULTS: DeltaIL increased with increasing demineralization times but plateaued after 40h, whereas lesion depth (L) and integrated mineral loss (DeltaZ) increased almost linearly throughout. No differences between Knoop and Vickers SMH in their ability to measure enamel demineralization were observed as both correlated strongly. Overall, DeltaIL correlated strongly with DeltaZ and L but only moderately with the degree of surface zone mineralization, whereas DeltaZ and L correlated strongly. Bovine demineralized faster than human enamel (all techniques). CONCLUSIONS: Lesions in bovine formed faster than in human enamel, although the resulting lesions were almost indistinguishable in their mineral distribution characteristics. Early caries lesion demineralization can be sufficiently studied by SMH, but its limitations on the assessment of the mineral status of more demineralized lesions must be considered. Ideally, complementary techniques to assess changes in both physical and chemical lesion characteristics would be employed. PMID- 24798980 TI - Relationships between masticatory rhythmicity, body mass and cephalometrically determined aesthetic and functional variables during development in humans. AB - OBJECTIVE: We studied the relationship between chewing rhythmicity, craniomandibular morphology, and age in humans. DESIGN: Sixty subjects (10M:10F/group*three age groups, viz., 4-8, 10-14, and 17-21 years) participated. Subjects chewed gum for 2min while jaw movements in the frontal plane were videorecorded. Mean and variation in mean chewing cycle duration (TC) were quantified using maximum opening to maximum opening as cycle boundaries. Five "aesthetic" cephalometric variables (e.g., ANB) and seven "functional" variables (e.g., jaw length) were quantified from subjects' lateral cephalographs. Simple linear regression models and several multivariate analyses were used in comparisons. RESULTS: Mean TC increased and variation in TC decreased significantly with age. Body mass correlated with age, height, TC, all seven "functional" variables and only two "aesthetic" variables. Mean TC was correlated significantly with jaw length, distance from condylion to first molar point, distance from gonion to zygomatic arch, and distance from hyoid to menton. CONCLUSIONS: TC appeared to adapt with age. Although TC scaled most significantly with age, it is more likely that TC is mechanistically linked to jaw length or size. The decrease in TC variation with age suggests improved efficiency. TC did not scale with "aesthetic" variables, suggesting that these do not impact chewing rate; however, clinical procedures that impact jaw length may. The negative allometric scaling of TC with "functional" variables may reflect the pedomorphic jaw and face of humans. Further human studies will provide insights into the nature of scaling and adaptation of rhythmic chewing during development. PMID- 24798981 TI - A novel WNT10A mutation causes non-syndromic hypodontia in an Egyptian family. AB - OBJECTIVE: Tooth agenesis is the most common dental anomaly, whose aetiology still remains to be fully elucidated. The aim of this study was to investigate the genetic cause of non-syndromic hypodontia with clinical variability in an Egyptian family. DESIGN: The entire coding regions including exon-intron boundaries of the MSX1, PAX9 and WNT10A genes were investigated by direct sequencing in all affected family members. RESULTS: Novel heterozygous mutation inherited in an autosomal dominant manner was identified in the WNT10A gene. This 21-bp deletion combined with 1-bp insertion, c.-14_7delinsC, eliminates the translation initiation codon leading to either no protein production or translation of alternative open reading frames. None of the control subjects (400 chromosomes) were carriers of this novel WNT10A mutation. No pathogenic mutations were found in the MSX1 and PAX9 genes. CONCLUSIONS: The novel c.-14_7delinsC mutation might be the etiological variant of the WNT10A gene responsible for the permanent tooth agenesis in the Egyptian family. WNT10A is a major candidate gene for non-syndromic hypodontia. PMID- 24798982 TI - Amount of interleukin-1beta and interleukin-1 receptor antagonist in periodontitis and healthy patients. AB - OBJECTIVE: Regulation of interleukin-1beta (IL-1beta) is a critical element of immune responses in health and disease. Additional research is required to determine the levels of interleukin-1 receptor antagonist (IL-1ra) sufficient to inhibit inteleukine-1-induced responses in periodontium. The aim of this study was to compare the levels of IL-1beta, IL-1ra in gingival crevicular fluid samples obtained from periodontitis and healthy patients. DESIGN OF THE STUDY: The periodontitis group consisted of 50 patients (F-31, M-19) with chronic periodontitis. The control group consisted of 30 periodontally healthy subjects (F-19, M-11). Oral hygiene index-simplified, gingival index, pocket depth, clinical attachment level were measured. The concentrations of interleukins in gingival crevicular fluid were measured by the ELISA technique. RESULTS: The total amounts of interleukin-1beta and IL-1ra were significantly higher in periodontitis group than in the control group (P<0.05). The levels of each cytokine were reported also as moles. In the control group there were 800-times more moles/sample of IL-1ra than IL-1beta. In periodontitis group nearly 300 times more moles/sample of IL-1ra was obtained. The significant positive Spearman's rank correlations was identified between both concentrations (R=0.39; P<0.05) and total amounts (R=0.31; P<0.05) of cytokines in the periodontitis group. CONCLUSION: The increased secretion of IL-1ra in periodontitis is not adequate to "curb" the release of IL-1beta. PMID- 24798984 TI - Developing and Evaluating the HRM Technique for Identifying Cytochrome P450 2D6 Polymorphisms. AB - BACKGROUND: Cytochrome P450 2D6 is one of the important enzymes involved in the metabolism of many widely used drugs. Genetic polymorphisms of CYP2D6 can affect its activity. Therefore, an efficient method for identifying CYP2D6 polymorphisms is clinically important. METHODS: We developed a high-resolution melting (HRM) analysis to investigate CYP2D6 polymorphisms. Genomic DNA was extracted from peripheral blood samples from 71 healthy individuals. All nine exons of the CYP2D6 gene were sequenced before screening by HRM analysis. This method can detect the most genotypes (*1, *2, *4, *10, *14, *21 *39, and *41) of CYP2D6 in Chinese. RESULTS: All samples were successfully genotyped. The four most common mutant CYP2D6 alleles (*1, *2, *10, and *41) can be genotyped. The single nucleotides polymorphism (SNP) frequencies of 100C > T (rs1065852), 1039C > T (rs1081003), 1661G > C (rs1058164), 2663G > A (rs28371722), 2850C > T (rs16947), 2988G > A (rs28371725), 3181A > G, and 4180G > C (rs1135840) were 58%, 61%, 73%, 1%, 13%, 3%, 1%, 73%, respectively. We identified 100% of all heterozygotes without any errors. The two homozygous genotypes (1661G > C and 4180G > C) can be distinguished by mixing with a known genotype sample to generate an artificial heterozygote for HRM analysis. Therefore, all samples could be identified using our HRM method, and the results of HRM analysis are identical to those obtained by sequencing. Our method achieved 100% sensitivity, specificity, positive prediction value and negative prediction value. CONCLUSION: HRM analysis is a nongel resolution method that is faster and less expensive than direct sequencing. Our study shows that it is an efficient tool for typing CYP2D6 polymorphisms. PMID- 24798985 TI - Principles and reality of proton therapy treatment allocation. AB - PURPOSE: To present the principles and rationale of the Proton Priority System (PROPS), a priority points framework that assigns higher scores to patients thought to more likely benefit from proton therapy, and the distribution of PROPS scores by patient characteristics METHODS AND MATERIALS: We performed multivariable logistic regression to evaluate the association between PROPS scores and receipt of proton therapy, adjusted for insurance status, gender, race, geography, and the domains that inform the PROPS score. RESULTS: Among 1529 adult patients considered for proton therapy prioritization during our Center's ramp-up phase of treatment availability, PROPS scores varied by age, diagnosis, site, and other PROPS domains. In adjusted analyses, receipt of proton therapy was lower for patients with non-Medicare relative to Medicare health insurance (commercial vs Medicare: adjusted odds ratio [OR] 0.47, 95% confidence interval [CI] 0.34-0.64; managed care vs Medicare: OR 0.40, 95% CI 0.28-0.56; Medicaid vs Medicare: OR 0.24, 95% CI 0.13-0.44). Proton Priority System score and age were not significantly associated with receipt of proton therapy. CONCLUSIONS: The Proton Priority System is a rationally designed and transparent system for allocation of proton therapy slots based on the best available evidence and expert opinion. Because the actual allocation of treatment slots depends mostly on insurance status, payers may consider incorporating PROPS, or its underlying principles, into proton therapy coverage policies. PMID- 24798987 TI - Abstracts from the 2014 World Institute of Pain, May 7-10, 2014, Maastricht, The Netherlands. PMID- 24798986 TI - Facial artery musculomucosal flap in head and neck reconstruction: A systematic review. AB - BACKGROUND: The facial artery musculomucosal (FAMM) flap has emerged as a popular option in head and neck reconstruction in the last decade. The purpose of this study was to conduct a literature review of the FAMM flap. METHODS: We have conducted a search on PubMed using specific key words to identify all articles related to the FAMM flap. We reviewed the modifications of the FAMM flap, its indications, contraindications, complications, and outcomes. RESULTS: Thirty eight articles published from 1992 to 2013 were included for review. A total of 441 FAMM flaps were reported in the literature and the most commonly reconstructed site was the floor of the mouth. Functional and aesthetic outcomes were judged to be excellent. CONCLUSION: The FAMM flap is a versatile reconstructive option for small and medium size defects in the head and neck. Recent studies have explored new applications for this flap, such as in skull base reconstruction. PMID- 24798988 TI - Synthesis and evaluation of novel acyl derivatives from jatropha oil as potential lubricant basestocks. AB - A novel class of jatropha oil-based acylated derivatives from hydroxy alkyl esters of jatropha fatty acids (C1, C3, C4, and C8) and various anhydrides (C2, C3, C4, and C6) were synthesized and their physicochemical and lubricant properties reported. Jatropha fatty acid alkyl esters were dihydroxylated using the in situ performic acid method and further acylated with different anhydrides to produce acylated derivatives. Acylated derivatives of dihydroxy jatropha fatty acid alkyl esters were charaterized by NMR, FTIR, GC, and GC-MS analysis and were evaluated for their viscosity, viscosity index, pour and flash points, and oxidation stability. Most of the derivatives are either in ISO VG 22 or 32 viscosity grade with good viscosity index. It was observed that increase in acyl chain length and branching in the end-chain ester improved the pour point of the diacyl derivatives. All of the hexanoylated esters exhibited better oxidation stability compared to other acylated products, and their pour points are comparable to those of synthetic esters such as TMP trioleates. In general, isoalcohol esters with longer acyl chains showed promise as potential candidates for hydraulic fluids and metal-working fluids in ISO VG 22 and 32 viscosity range. PMID- 24798989 TI - Monitoring galvanic replacement through three-dimensional morphological and chemical mapping. AB - Galvanic replacement reactions on metal nanoparticles are often used for the preparation of hollow nanostructures with tunable porosity and chemical composition, leading to tailored optical and catalytic properties. However, the precise interplay between the three-dimensional (3D) morphology and chemical composition of nanostructures during galvanic replacement is not always well understood as the 3D chemical imaging of nanoscale materials is still challenging. It is especially far from straightforward to obtain detailed information from the inside of hollow nanostructures using electron microscopy techniques such as SEM or TEM. We demonstrate here that a combination of state-of the-art EDX mapping with electron tomography results in the unambiguous determination of both morphology transformation and elemental composition of nanostructures in 3D, during galvanic replacement of Ag nanocubes. This work provides direct and unambiguous experimental evidence toward understanding the galvanic replacement reaction. In addition, the powerful approach presented here can be applied to a wide range of nanoscale transformation processes, which will undoubtedly guide the development of novel nanostructures. PMID- 24798990 TI - Personality predicts obedience in a Milgram paradigm. AB - This study investigates how obedience in a Milgram-like experiment is predicted by interindividual differences. Participants were 35 males and 31 females aged 26 54 from the general population who were contacted by phone 8 months after their participation in a study transposing Milgram's obedience paradigm to the context of a fake television game show. Interviews were presented as opinion polls with no stated ties to the earlier experiment. Personality was assessed by the Big Five Mini-Markers questionnaire (Saucier, 1994). Political orientation and social activism were also measured. Results confirmed hypotheses that Conscientiousness and Agreeableness would be associated with willingness to administer higher intensity electric shocks to a victim. Political orientation and social activism were also related to obedience. Our results provide empirical evidence suggesting that individual differences in personality and political variables matter in the explanation of obedience to authority. PMID- 24798991 TI - Effect of heat treatment on the enzymatic stability of grass carp skin collagen and its ability to form fibrils in vitro. AB - BACKGROUND: The molecular configuration, molecular weight distribution and thermal transition enthalpy (DeltaH) of grass carp skin (GCS) collagens after heat treatment under different conditions were measured using circular dichroism, gel filtration chromatography and differential scanning calorimetry (DSC). The enzymatic stability of collagen was evaluated using different enzymes, while the ability to form fibrils in vitro was assessed by morphological observation of collagen fibrils and turbidity testing. RESULTS: The DeltaH values, in-solution molecular aggregation and the stability to enzymatic hydrolysis of GCS collagen decreased irreversibly and progressively with the duration of heat treatment at 33 degrees C, which was the onset endothermic temperature obtained from the DSC curve. A strong positive linear correlation between the enzymatic sensitivity of collagen and the degree of thermal denaturation was found. A decrease in fibril diameter and D-periodicity length with denaturation could also be observed in the SEM and TEM images. CONCLUSION: The onset endothermic temperature (To ) rather than the denaturation temperature (Td ) is the threshold temperature for configurational stability of GCS collagen in acidic solution, and the biological properties would obviously change if the collagen was heat treated at this temperature. PMID- 24798992 TI - Flow cytometry analyses of phagocytic and respiratory burst activities and cytochemical characterization of leucocytes isolated from wrasse (Labrus bergylta A.). AB - We have isolated leucocytes from peripheral blood (PBL), head kidney (HKL) and spleen (SL) of wrasse (Labrus bergylta A.) and studied the innate immune responses phagocytosis and respiratory burst using flow cytometry. Further, we have characterized the phenotypic properties of the leucocytes by cytochemical staining. We could differentiate between several subsets of leucocytes; lymphocytes, monocytes/macrophages, neutrophils, eosinophils, basophils and small leucocytes that might be precursor or immature cells. One striking observation was the eosinophils which were present among HKL, PBL and SL. The neutrophils had rounded, bean shaped or bi-lobed nuclei and resembled neutrophils in Atlantic cod (Gadus morhua L.) and lumpsucker (Cyclopterus lumpus L.), but were different from the polymorphonucleated neutrophils in Atlantic salmon (Salmo salar L.) and humans. Basophils were observed, but they were rare. Phagocytosis and respiratory burst activities were detected among different cell types. Highest phagocytic activity was observed among monocytes/macrophages and small leucocytes. Several different subtypes had ability to perform an oxygen-dependent degradation of microbes, measured as respiratory burst activity. Knowledge of the basic properties of wrasse's leucocytes and innate immunology can benefit further studies on its adaptive immune responses. PMID- 24798993 TI - Dietary administration of beta-1,3/1,6-glucan and probiotic strain Shewanella putrefaciens, single or combined, on gilthead seabream growth, immune responses and gene expression. AB - It is widely known that beta-glucans and probiotic bacteria are good immunostimulants for fish. In the present work we have evaluated the dietary effect of beta-1,3/1,6-glucan (isolated from Laminarina digitata) and Pdp 11 (Shewanella putrefaciens, probiotic isolated from gilthead seabream skin), single or combined, on growth, humoural (seric level of total IgM antibodies and peroxidase and antiprotease activities) and cellular innate immune response (peroxidase and phagocytic activities of head-kidney leucocytes), as well as the expression of immune-related genes in gilthead seabream (Sparus aurata). Four treatment groups were established: control (non-supplemented diet), Pdp 11 (10(9) cfu g(-1)), beta-1,3/1,6-glucan (0.1%) and beta-1,3/1,6-glucan + Pdp 11 (0.1% and 10(9) cfu g(-1), respectively). Fish were sampled after 1, 2 and 4 weeks of feeding. Interestingly, all supplemented diets produced increments in the seabream growth rates, mainly the Pdp 11-suplemented diet. Overall, Pdp 11 dietary administration resulted in decreased serum IgM levels and peroxidase activity. However, the seric antiprotease activity was increased in fish fed with both supplements together. Furthermore, beta-1,3/1,6-glucan and combined diet increased phagocytic activity after 2 or 4 weeks. At gene level, IL-1beta and INFgamma transcripts were always up-regulated in HK but only the interleukin reached significance after 4 weeks in the group fed with beta-glucan. On the contrary, IgM gene expression tended to be down-regulated being significant after 1 week in seabream specimens fed with beta-glucan or beta-glucan plus Pdp 11. These results suggest that beta-1,3/1,6-glucan and Pdp 11 modulate the immune response and stimulates growth of the gilthead seabream, one of the species with the highest rate of production in Mediterranean aquaculture. PMID- 24798994 TI - Piezo1 is as a novel trefoil factor family 1 binding protein that promotes gastric cancer cell mobility in vitro. AB - BACKGROUND: Trefoil factor family 1 (TFF1) is a member of the TFF-domain peptide family involved in epithelial restitution and cell motility. Recently, we screened Piezo1 as a candidate TFF1-binding protein. AIM: We aimed to confirm Piezo1 as a novel TFF1 binding protein and to assess the role of this interaction in mediating gastric cancer cell mobility. METHODS: This interaction was confirmed by co-immunoprecipitation and co-localisation of TFF1 and Piezo1 in GES 1 cells. We used stable RNA interference to knockdown Piezo1 protein expression and restored the expression of TFF1 in the gastric cancer cell lines SGC-7901 and BGC-823. Cell motility was evaluated using invasion assay and migration assay in vitro. The expression levels of the integrin subunits beta1, beta5, alpha1 as well as the expression of beta-catenin and E-cadherin were detected by Western blot. RESULTS: We demonstrate that TFF1, but not TFF2 or TFF3, bind to and co localize with Piezo1 in the cytoplasm in vitro. TFF1 interacts with the C terminal portion of the Piezo1 protein. Wound healing and trans-well assays demonstrated that the restored expression of TFF1 promoted cell mobility in gastric cancer cells, and this effect was attenuated by the knockdown of Piezo1. Western blots demonstrated the decreased expression of integrin beta1 in Piezo1 knockdown cells. CONCLUSIONS: Our data demonstrate that Piezo1 is a novel TFF1 binding protein that is important for TFF1-mediated cell migration and suggest that this interaction may be a therapeutic target in the invasion and metastasis of gastric cancer. PMID- 24798995 TI - NOD-scidIl2rg (tm1Wjl) and NOD-Rag1 (null) Il2rg (tm1Wjl) : a model for stromal cell-tumor cell interaction for human colon cancer. AB - BACKGROUND/AIMS: Stromal cells and the extracellular environment are vital to human tumors, influencing growth and response to therapy. Human tumor cell lines lack stroma and transplantation into immunodeficient mice does not allow meaningful analyses of the effects of stroma on tumor cell growth. Studies of xenografts of primary human tumor fragments in nude mice and in early scid mouse models were constrained by poor tumor growth accompanied by host-versus-graft reactivity, dramatically altering tumor architecture and tumor microenvironment. In contrast, severely immunodeficient NOD-scid and NOD-Rag1 (null) strains carrying the IL2rg (null) mutation (NSG and NRG) support the growth of many types of human primary tumors. METHODS/RESULTS: We compared the take rate, growth and architectural preservation of 10 clinically distinct primary human colon cancers in NOD-scid, NOD-Rag1 (null) , NSG and NRG mice and determined the contribution of mouse and human cells to the stroma during tumor proliferation and expansion in secondary hosts and tumor response to treatment with 5-fluorouracil (5-FU). NSG and NRG mice more readily support growth of human primary colon tumor fragments than do NOD-scid, NOD-Rag1 (null) mice and maintain tumor architectural integrity in the primary recipient and through subsequent transplant generations. The human colon tumors were responsive to treatment with 5-FU. Human stromal cells in the primary graft were replaced by mouse-derived fibroblasts in a dynamic process during subsequent passages. CONCLUSION: Human colon cancer xenografts propagated in NSG and NRG mice maintain structural fidelity while replacing human stromal cells with murine stromal cells. PMID- 24798996 TI - Alcoholic hepatitis: current management. AB - Alcoholic hepatitis is an acute manifestation of alcoholic liver disease with mortality as high as 40-50% in severe cases. Patients usually have a history of prolonged alcohol abuse with or without a known history of liver disease. Although there is significant range in severity at presentation, patients with severe alcoholic hepatitis typically present with anorexia, fatigue, fever, jaundice, and ascites. The use of either pentoxifylline or corticosteroids in those with severe disease (Maddrey's discriminate function >32) has significant mortality benefit. The addition of N-acetylcysteine to corticosteroids decreases the incidences of hepatorenal syndrome, infection, and short-term mortality, but does not appear to significantly affect 6-month mortality. Nutritional support with high-calorie, high-protein diet is recommended in all patients screening positive for malnutrition. Liver transplantation for a highly selected group of patients with severe alcoholic hepatitis may be an option in the future, but is not currently recommended or available at most transplant institutions. PMID- 24798999 TI - Allopurinol overuse in asymptomatic hyperuricemia: a teachable moment. PMID- 24798997 TI - Somatostatin inhibits the production of interferon-gamma by intestinal epithelial cells during intestinal ischemia-reperfusion in macaques. AB - BACKGROUND: Our previous study found that somatostatin (SST) inhibited the intestinal inflammatory injury in a macaque model of intestinal ischemia reperfusion (IIR); however, the underlying mechanism was unclear. AIMS: The present study was aimed to investigate the effects of SST on IFN-gamma and the systemic inflammatory response after IIR. METHODS: Fifteen macaques were randomly divided into controls, IIR and SST+ IIR groups. ELISA was performed to measure IFN-gamma in ileum tissues, ileac epithelial cells (IECs) and ileal lymphocytes, as well as the systemic levels of IL-6, IL-1beta, TNF-alpha and IFN-gamma in the peripheral circulation and the portal vein. HE staining was performed to evaluate morphological changes in vital organs. Immunohistochemistry was performed to identify the distribution of IFN-gamma, CD4, CD8 and CD57 in the ileum. RESULTS: After IIR, IFN-gamma level was significantly increased in the IECs. IL-6, IL 1beta and TNF-alpha were significantly increased in both the portal vein and the peripheral circulation; in contrast, IFN-gamma level was increased in the portal vein alone. Prophylactic SST reversed the change in IFN-gamma in the IECs and portal vein. SST led to an alleviation of the pathological changes in systemic vital organs. The distribution of CD4(+), CD57(+) and CD8(+) cells was not positively correlated with the secretion of IFN-gamma. CONCLUSION: IECs are the main source of IFN-gamma production after IIR. SST may indirectly lead to mast cell deactivation through the inhibition of IFN-gamma production by IECs. Pretreatment with SST may be beneficial for preventing a massive systemic inflammatory response in vital organs after IIR. PMID- 24798998 TI - Prior capsule endoscopy improves the diagnostic and therapeutic yield of single balloon enteroscopy. AB - BACKGROUND AND AIMS: Although there is substantial literature addressing double balloon enteroscopy, evidence is more limited with regard to the clinical utility of single-balloon enteroscopy (SBE) in evaluating and treating small-bowel diseases. We sought to determine the diagnostic and therapeutic yield of SBE in patients with suspected small-bowel disorders, as well as the impact of preceding capsule endoscopy (CE) on these outcomes. METHODS: We performed a retrospective analysis of a prospectively collected database at a tertiary-care academic medical center between 2011 and 2013 for all patients referred for SBE. RESULTS: A total of 150 patients underwent 170 SBE procedures during the study period. The most frequent indications for SBE included anemia, overt or occult gastrointestinal bleeding, and suspected mass. CE was performed prior to SBE in 113 of 150 patients (75%). The overall diagnostic yield for small-bowel disease by CE was 62%. Therapeutic interventions included hemostasis, polypectomy, and foreign body removal. Total diagnostic and therapeutic yield of SBE was 60 and 28%, respectively. The diagnostic yield of SBE with prior CE was 68 versus 44% for SBE without prior CE (P = 0.002). The therapeutic yield of SBE with prior CE was 35 versus 12% without prior CE (P = 0.001). One endoscopic complication was observed out of 170 procedures, and there were no deaths. CONCLUSIONS: SBE appears to be a safe and effective technique for the diagnosis and treatment of small-bowel disease; however, we recommend performing a CE prior to SBE to improve the diagnostic and therapeutic yield of the procedure. PMID- 24799000 TI - Relations between posttraumatic stress and posttraumatic growth in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. AB - OBJECTIVE: Contemporary models of trauma suggest that posttraumatic stress and growth should be related and that symptoms of stress resulting from a perceived trauma (e.g., childhood cancer) are prerequisite for posttraumatic growth (PTG) to occur. However, empirical data regarding the relationship of posttraumatic stress and growth have been equivocal. The purpose of this study is to examine the relationship between posttraumatic stress symptoms (PTSS) and PTG among adult survivors of childhood cancer. METHODS: Survey methods were used to collect data from 6,162 survivors participating in the Childhood Cancer Survivor Study (CCSS). Nonparametric correlation was examined pairwise between PTG and PTSS using Spearman's correlation coefficient with 95% confidence intervals, with nonlinear canonical correlation analysis being conducted to examine relationships between subscales. A multivariable partial proportional odds model was also fit for PTG total quartiles focusing on associations with PTSS total quartiles while adjusting for sociodemographic and medical variables. RESULTS: Examination of unadjusted PTSS and PTG total scores revealed a Spearman correlation of 0.11 (p < .001), with coefficients ranging from 0.03 to 0.17 between total and subscale scores. The nonlinear canonical correlation analyses resulted in two dimensions with eigenvalues of 0.15 and 0.14, resulting in a fit value of 0.30 and evidence that little variability in the data (15%) was explained by the weighted combinations of the variables. CONCLUSIONS: Although statistically significant, these results do not indicate a robust relationship between PTSS and PTG among adult survivors of childhood cancer. Theories suggesting that PTSS is a prerequisite for PTG should be reconsidered. PMID- 24799001 TI - Maternal depressive symptoms and disease care status in youth with type 1 diabetes. AB - OBJECTIVE: The current study assessed relations among maternal depressive symptoms, poorer youth diabetes adherence, and glycemic control. Specifically, hypothesized mediating links of lowered expectations of parental involvement, less parental monitoring, and more conflict were examined. METHOD: Participants included 225 mothers and their young adolescents, aged 11-14 years (M = 12.73 years, SD = 1.2) diagnosed with T1D. Maternal depressive symptoms and outcome expectancies for maternal involvement were evaluated with self-report questionnaires. Multisource, parent/youth, and multimethod assessment of adherence, parental monitoring, and conflict were evaluated during a baseline assessment from a larger randomized clinical trial. RESULTS: The first hypothesized structural equation model demonstrated a good fit and indicated that more maternal depressive symptoms were directly associated with less parental monitoring and more conflict, which in turn each were associated with poorer adherence and glycemic control. Although higher involvement expectancies were associated with more monitoring and less conflict, they were not associated with other model variables. A second alternative model also fit the data well; poorer youth adherence was associated with more conflict that in turn related to maternal depressive symptoms. CONCLUSIONS: Two models were tested by which maternal depressive symptoms and poorer youth adherence were interrelated via less monitoring and more conflict. Follow-up longitudinal evaluation can best characterize the full extent of these relations. PMID- 24799002 TI - Visualization of endosome dynamics in living nerve terminals with four dimensional fluorescence imaging. AB - Four-dimensional (4D) light imaging has been used to study behavior of small structures within motor nerve terminals of the thin transversus abdominis muscle of the garter snake. Raw data comprises time-lapse sequences of 3D z-stacks. Each stack contains 4-20 images acquired with epifluorescence optics at focal planes separated by 400-1,500 nm. Steps in the acquisition of image stacks, such as adjustment of focus, switching of excitation wavelengths, and operation of the digital camera, are automated as much as possible to maximize image rate and minimize tissue damage from light exposure. After acquisition, a set of image stacks is deconvolved to improve spatial resolution, converted to the desired 3D format, and used to create a 4D "movie" that is suitable for variety of computer based analyses, depending upon the experimental data sought. One application is study of the dynamic behavior of two classes of endosomes found in nerve terminals-macroendosomes (MEs) and acidic endosomes (AEs)-whose sizes (200-800 nm for both types) are at or near the diffraction limit. Access to 3D information at each time point provides several advantages over conventional time-lapse imaging. In particular, size and velocity of movement of structures can be quantified over time without loss of sharp focus. Examples of data from 4D imaging reveal that MEs approach the plasma membrane and disappear, suggesting that they are exocytosed rather than simply moving vertically away from a single plane of focus. Also revealed is putative fusion of MEs and AEs, by visualization of overlap between the two dye-containing structures as viewed in each three orthogonal projections. PMID- 24799003 TI - Online consensus conferences for clinical guidelines development - a survey among participants from the International Guidelines for the Treatment of Actinic Keratosis. AB - RATIONALE, AIMS AND OBJECTIVES: Guideline development requires considerable time and financial resources. New technical devices such as software for online conferences may help to reduce time and financial efforts of guidelines development. The present survey may serve as an explorative pilot for a future study to determine the technical feasibility, acceptability and possible weaknesses of online consensus conferences for clinical guidelines development. METHODS: An anonymous online survey was conducted among participants in the online consensus conference of the International League of Dermatological Societies (ILDS) Guidelines for the Treatment of Actinic Keratosis. RESULTS: The majority of participants reported no technical problems with the participation in the online consensus conference; one participant had substantial technical problems accountable to a regional telephone breakdown. The majority of participants would not have preferred a traditional face-to-face conference, and all participants rated online consensus conferences for international guidelines as absolutely acceptable. Rates of acceptance were particularly high among those participants with prior experience with consensus conferences. Certain aspects, particularly the possibilities of debating, were rated as possibly superior in face-to-face conferences by some participants. CONCLUSIONS: The data from the online survey indicate that online consensus conferences may be an appropriate alternative to traditional face-to-face consensus conferences, especially within the frame of international guidelines that would require high travel costs and time. Further research is necessary to confirm the data from this explorative pilot study. PMID- 24799004 TI - Recent progress on synchrotron-based in-situ soft X-ray spectroscopy for energy materials. AB - Soft X-ray spectroscopy (SXS) techniques such as photoelectron spectroscopy, soft X-ray absorption spectroscopy and X-ray emission spectroscopy are efficient and direct tools to probe electronic structures of materials. Traditionally, these surface sensitive soft X-ray techniques that detect electrons or photons require high vacuum to operate. Many recent in situ instrument developments of these techniques have overcome this vacuum barrier. One can now study many materials and model devices under near ambient, semi-realistic, and operando conditions. Further developments of integrating the realistic sample environments with efficient and high resolution detection methods, particularly at the high brightness synchrotron light sources, are making SXS an important tool for the energy research community. In this progress report, we briefly describe the basic concept of several SXS techniques and discuss recent development of SXS instruments. We then present several recent studies, mostly in situ SXS experiments, on energy materials and devices. Using these studies, we would like to highlight that the integration of SXS and in situ environments can provide in depth insight of material's functionality and help researchers in new energy material developments. The remaining challenges and critical research directions are discussed at the end. PMID- 24799007 TI - Gender income disparities can be explained by alternative factors. PMID- 24799008 TI - Gender income disparities can be explained by alternative factors--reply. PMID- 24799009 TI - Will a policy of refusing reimbursement for health care-associated infections be a sufficient incentive to drive improvements? PMID- 24799010 TI - Conflict of interest disclosures. PMID- 24799011 TI - Will a policy of refusing reimbursement for health care-associated infections be a sufficient incentive to drive improvements?--reply. PMID- 24799012 TI - Identifying livestock-associated methicillin-resistant Staphylococcus aureus in the United States. PMID- 24799013 TI - Intensive glucose control for acute myocardial infarction: an unresolved clinical conundrum. PMID- 24799014 TI - Identifying livestock-associated methicillin-resistant staphylococcus aureus in the United States--reply. PMID- 24799015 TI - Intensive glucose control for acute myocardial infarction--reply. PMID- 24799016 TI - AACE Response to viewpoint of December 9, 2013. PMID- 24799017 TI - AACE Response to viewpoint of December 9, 2013--reply. PMID- 24799019 TI - Tissue oxygen partial pressure in the tibialis anterior muscle in patients with claudication before, during and after a two-stage treadmill stress test. AB - BACKGROUND: The role of the microcirculation in the pathophysiology and symptoms of peripheral arterial obliterative disease (PAOD) has been progressively emphasized during the past decades. Under resting conditions, already, the tissue oxygen partial pressure in the m. tibialis anterior (pO2im) is reduced to about 50% compared to healthy subjects. METHODS: In the framework of this study the pO2im of patients with PAOD stage II according to Fontaine (n=16) in the m. tibialis anterior was measured under resting conditions and during walking on a treadmill in comparison to healthy subjects (n=10). RESULTS: Under resting conditions the pO2im only marginally differed between PAOD patients and healthy subjects. But during exercise the pO2im dropped significantly more severely in PAOD patients and a return to baseline values could only be reached when the treadmill was stopped and the patients stood still. The pO2im minima correlated clearly with the clinical symptom of calf pain. CONCLUSION: The data revealed that the pO2im values were lower in PAOD patients and dropped significantly faster during walking compared to the pO2im values in healthy subjects. The pO2im decrease correlated with the calf pain occurring when the pO2im values approached or fell below 10 mmHg. PMID- 24799020 TI - Influence of parenteral nutrition on blood rheology and platelet aggregation in vitro. AB - BACKGROUND: Parenteral nutrition (PN) is a hyperosmolar solution composed of glucose, amino acids and a lipid emulsion, which is often used despite well-known side effects and complications. OBJECTIVES: In this study the hypothesis was tested that PN could affect hemorheology. METHODS: The influence of increasing plasma concentrations (0, 4, 10 and 25%) of the 3-in-1-mixture of PN on various rheological parameters were studied in vitro. The influence of the individual components was studied with plasma concentrations of 10, 10 and 5%, respectively. Hematological and coagulation tests were performed. Blood viscosity and red blood cell (RBC) aggregation were measured and platelet aggregation in flowing blood was assessed with a PFA-100 instrument. RESULTS: It was found that PN induced RBC shrinkage, which was partially reversible. It reduced RBC aggregation measured by low shear viscosity or RBC sedimentation. Platelet aggregation was strongly inhibited. Coagulation tests were not affected. Investigations with the single components of PN showed that the RBC shrinkage was mainly caused by the amino acid solution and the inhibition of platelet aggregation by all 3 components. The lipid emulsion in higher plasma concentrations led to echinocytosis, indicating that the lipids interact with the outer half of the membrane lipid bilayer. CONCLUSIONS: High concentrations of PN affect blood rheology in several ways. The strongest effect was an inhibition of platelet aggregation, which may have a clinical relevance. Other effects such as RBC shrinkage and decreased RBC aggregation occurred only at high PN concentrations, which are reached in vivo at the infusion site. PMID- 24799021 TI - Modeling the electrostatic potential of asymmetric lipopolysaccharide membranes: the MEMPOT algorithm implemented in DelPhi. AB - Four chemotypes of the rough lipopolysaccharides (LPS) membrane from Pseudomonas aeruginosa were investigated by a combined approach of explicit water molecular dynamics (MD) simulations and Poisson-Boltzmann continuum electrostatics with the goal to deliver the distribution of the electrostatic potential across the membrane. For the purpose of this investigation, a new tool for modeling the electrostatic potential profile along the axis normal to the membrane, MEMbrane POTential (MEMPOT), was developed and implemented in DelPhi. Applying MEMPOT on the snapshots obtained by MD simulations, two observations were made: (a) the average electrostatic potential has a complex profile but is mostly positive inside the membrane due to the presence of Ca(2+) ions, which overcompensate for the negative potential created by lipid phosphate groups; and (b) correct modeling of the electrostatic potential profile across the membrane requires taking into account the water phase, while neglecting it (vacuum calculations) results in dramatic changes including a reversal of the sign of the potential inside the membrane. Furthermore, using DelPhi to assign different dielectric constants for different regions of the LPS membranes, it was investigated whether a single frame structure before MD simulations with appropriate dielectric constants for the lipid tails, inner, and the external leaflet regions, can deliver the same average electrostatic potential distribution as obtained from the MD-generated ensemble of structures. Indeed, this can be attained by using smaller dielectric constant for the tail and inner leaflet regions (mostly hydrophobic) than for the external leaflet region (hydrophilic) and the optimal dielectric constant values are chemotype-specific. PMID- 24799022 TI - Underestimation of thyroid dysfunction risk due to regression dilution bias in a long-term follow-up: Tehran Thyroid Study (TTS). AB - Thyroid dysfunction is linked with mortality and particular diseases. Intra individual variability of measured thyroid function parameters may bias its association with outcomes, the so called "regression dilution" bias. Single measurements of thyroid function parameters result in underestimation of real associations between outcome rates with the "usual life-long levels" of the aforesaid parameters. The aim of this study was to examine the intra-individual variability of FT4 and TSH of study cohorts in the Tehran Thyroid Study (TTS) and to investigate the extent of the risk underestimation during the 4 phases (Ph) of TTS, with median follow-up of 4, 7, and 10 years between the Ph2-Ph1, Ph3-Ph1, and Ph4-Ph1 intervals; respectively. We estimated regression dilution ratios (RDRs) by the Rosner method of linear regression of repeated measures for FT4 and TSH. RDR1, RDR2, and RDR3 were obtained by regressing the repeated measures of the aforesaid parameters of the last 3 TTS follow-ups on the baseline measurements. Calculations showed 0.64 RDR1, 0.58 RDR2, and 0.52 RDR3 for TSH; and 0.62 RDR1, 0.57 RDR2, and 0.55 RDR3 for FT4. A single measurement-based risk estimation in the TTS was underestimated for FT4 about 61.2, 76.5, and 80.4%; and for TSH as 55.8, 73.1 and 93% after 4, 7, and 10 years of follow-up; respectively. In conclusion, using only single measurements of TSH and FT4 the association between thyroid function and outcome rates is considerably underestimated, especially after a long follow-up period. PMID- 24799023 TI - Systemic metabolic signaling in acute and chronic gastrointestinal inflammation of inflammatory bowel diseases. AB - Acute and chronic intestinal inflammation stimulates innate and adaptive immune systems, thereby increasing energy demand of activated immune cells. Energy regulation by systemically released mediators is of critical importance for homeostasis. We wanted to find out how systemic metabolic mediators are affected during intestinal inflammation. A total of 123 patients suffering from Crohn's disease (CD), 76 patients with ulcerative colitis (UC), and 21 healthy controls were recruited. Patients receiving systemic steroids or therapy regimens including biologicals (anti-TNF) were excluded from the study. Serum levels of IL 6, CRP, insulin, glucose, free fatty acid, and RBP-4 were measured by ELISA and RIA. Intestinal inflammation was accompanied by elevated systemic inflammatory para-meters such as IL-6 and CRP in UC and CD and, concomitantly, with elevated insulin levels and increased insulin/glucose ratio in patients with UC. This indicates insulin resistance in liver, muscle, and fat. In addition, intestinal inflammation was associated with elevated levels of circulating free fatty acids in UC and CD, indicating an activation of the organism's appeal for energy-rich substrates (energy appeal reaction). RBP-4 serum levels were also high in acute and chronic intestinal inflammation in UC and CD, which can support insulin resistance. The organism's "energy appeal reaction" in response to acute and chronic inflammation provides free energy in the circulation, which is needed by inflammatory cells. A major mechanism of the redirection program is insulin resistance. New therapeutic strategies might be developed in the future, directly impacting on the storage and utilization of energy-rich fuels. PMID- 24799024 TI - Functional and structural analysis of four novel mutations of CYP21A2 gene in Italian patients with 21-hydroxylase deficiency. AB - Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder mainly caused by defects in the 21-hydroxylase gene (CYP21A2), coding for the enzyme 21 hydroxylase (21-OH). About 95% of the mutations arise from gene conversion between CYP21A2 and the inactive pseudogene CYP21A1P: only 5% are novel CYP21A2 mutations, in which functional analysis of mutant enzymes has been helpful to correlate genotype-phenotype. In the present study, we describe 3 novel point mutations (p.L122P, p.Q481X, and p.E161X) in 3 Italian patients with CAH: the fourth mutation (p.M150R) was found in the carrier state. Molecular modeling suggests a major impact on 21-hydroxylase activity, and functional analysis after expression in COS-7 cells confirms reduced enzymatic activity of the mutant enzymes. Only the p.M150R mutation affected the activity to a minor extent, associated with NC CAH. CYP21A2 genotyping and functional characterization of each disease-causing mutation has relevance both for treatment and genetic counseling to the patients. PMID- 24799025 TI - Male and female hypogonadism are highly prevalent in South Africans with Addison's disease. AB - Hypogonadism may complicate Addison's disease (primary hypoadrenalism), but prevalence and metabolic sequelae of hypogonadism in Addison's disease are poorly described. We recruited patients from the South African Addison's disease national registry who received stable replacement doses of hydrocortisone and had no acute illness. Male biochemical testosterone deficiency was defined as an early morning basal testosterone<9.9 nmol/l and premature ovarian failure (POF) when menopause occurred before 40 years of age. Cardiometabolic risk variables were measured in males only. Male hypogonadism prevalence was 33% (14/42), and 10 patients had newly diagnosed hypogonadism. Two untreated patients had elevated FSH or LH (>10 or 12 IU/l). Testosterone deficiency did not correlate with age, disease duration or hydrocortisone dose. Untreated male hypogonadal subjects had a higher (mean +/- standard deviation) BMI compared to eugonadal subjects 29.2 +/ 4.9 kg/m(2) vs. 24.7 +/- 3.4 kg/m(2) (p=0.01) and a higher median (interquartile range) high-sensitive-CRP 6.4 (2.5-14.0) mg/l vs. 1.45 (0.6-2.8) mg/l (p=0.002). There were no differences between the 2 groups in lipids, lipoproteins and fasting glucose. The median (interquartile range) DHEAS was lower in the hypogonadal 0.31 (0.27-0.37) MUmol/l, compared with the eugonadal group 0.75 (0.50-1.51) MUmol/l (p=0.005). POF was documented in 11% of female patients. Male testosterone deficiency was highly prevalent in this cohort and was primarily due to secondary hypogonadism. Only BMI and hs-CRP were increased in untreated male hypogonadal subjects. Male and female hypogonadism appears to be a common complication of Addison's disease and may contribute to its morbidity. PMID- 24799026 TI - Activation of eIF2alpha signaling cascade is associated with testosterone-induced cell apoptosis in INS-1 cells. AB - Hyperandrogenemia is associated with insulin resistance and type 2 diabetes in women with polycystic ovary syndrome raising the possibility that androgen receptor signaling pathway plays an important role in the development and progression of beta-cell dysfunction. Testosterone is the major circulating androgen in women. In this study, we investigated the effect of testosterone on INS-1 cells to find whether excess androgen could produce endoplasmic reticulum (ER) stress thereby contributing to beta-cell dysfunction. The role of testosterone in INS-1 cell apoptosis was detected by flow cytometry and electron microscopy. Expression of BIP, ATF4, and CHOP were assessed by RT-PCR and Western blot. Testosterone/AR could not only initiate cell apoptosis but also induce the activation of eukaryotic initiation factor 2 alpha (eIF2alpha) cascades in INS-1 cells. Treatment of ER stress inhibitor or flutamide (AR inhibitor) could inhibit testosterone-induced cell apoptosis and CHOP expression. These results suggest that testosterone/AR pathway caused INS-1 cell apoptosis was at least in part through eIF2alpha/CHOP cascades. PMID- 24799027 TI - AKT and AMPK activation after high-fat and high-glucose in vitro treatment of prostate epithelial cells. AB - Considering the increasing consumption of saturated fat and glucose in diets worldwide and its possible association to carcinogenesis, this investigation analysed the proliferation profile of nonmalignant human prostate epithelial cells after exposure to elevated levels of fat and glucose. PNT1A cells were cultured with palmitate (100 or 200 MUM) and/or glucose (450 mg/dl) for 24 or 48 h. Treated cells were evaluated for viability test and cell proliferation (MTS assay). AKT and AMPK phosphorylation status were analysed by Western blotting. After 24 h of high-fat alone or associated with high-glucose treatment, there was an increase in AMPK and AKT activation associated to unchanged MTS-cell proliferation. Following 48 h of high-fat but not high-glucose alone, cells decreased AMPK activation and maintained elevated AKT levels. These data were associated to increased cell proliferation after further high-fat treatment. After longer high-fat exposure, MTS revealed that cells remained proliferating. High-glucose alone or associated to high-fat treatment was not able to increase cell proliferation and AKT activation. A high-fat medium containing 100 MUM of palmitate stimulates proliferation in PNT1A cells by decreasing the activation of AMPK and increasing activation of AKT after longer exposure time. These findings improve the knowledge about the negative effect of high levels of this saturated fatty acid on proliferative disorders of prostate. PMID- 24799028 TI - Reply to letter to the editor by Hind et al. PMID- 24799029 TI - Use of episcleral cyclosporine implants in dogs with keratoconjunctivitis sicca: pilot study. AB - PURPOSE: To describe the use, tolerability, and efficacy of episcleral silicone matrix cyclosporine (ESMC) implants in dogs with keratoconjunctivitis sicca (KCS). METHODS: Retrospective study. ESMC implants (1.9 cm length, 30% wt/wt CsA in silicone; with approximately 12 mg of CsA loaded into them) were used in dogs with KCS responsive to topical CsA (good candidate, GC) or not responsive (poor candidate, PC). Ocular surface inflammation scores, Schirmer tear test (STT) values, and ocular discharge quantity were evaluated and compared. RESULTS: Twenty-seven eyes (15 dogs) received an ESMC implant for KCS; 15 eyes were considered GC, and 12 were considered PC. Both GC eyes and PC eyes showed a significant increase in STT values (increase of 7.7 and 8.5 mm/min; P = 0.023 and P = 0.003, respectively) after placement of ESMC implants (mean follow-up 18 +/- 2 and 10.4 +/- 15 months, respectively). Clinical signs improved significantly in both groups during the same follow-up, with reduction in conjunctival hyperemia (P < 0.001), corneal neovascularization (P = 0.004), corneal opacity (P = 0.003), and ocular discharge (P = 0.002). ESMC implants were well tolerated by all dogs, but two eyes lost the device at 12-months and 1-week follow-up, respectively. CONCLUSIONS: Results from this study suggest that the EMSC implants were well tolerated and efficacious in dogs with KCS responsive to topical CsA as well as dogs with poor response to topical therapy. Further study is needed to determine the duration of efficacy and optimal dose of CsA. PMID- 24799030 TI - Efficient and limiting reactions in aqueous light-induced hydrogen evolution systems using molecular catalysts and quantum dots. AB - Hydrogen produced from water and solar energy holds much promise for decreasing the fossil fuel dependence. It has recently been proven that the use of quantum dots as light harvesters in combination with catalysts is a valuable strategy to obtain photogenerated hydrogen. However, the light to hydrogen conversion efficiency of these systems is reported to be lower than 40%. The low conversion efficiency is mainly due to losses occurring at the different interfacial charge transfer reactions taking place in the multicomponent system during illumination. In this work we have analyzed all the involved reactions in the hydrogen evolution catalysis of a model system composed of CdTe quantum dots, a molecular cobalt catalyst and vitamin C as sacrificial electron donor. The results demonstrate that the electron transfer from the quantum dots to the catalyst occurs fast enough and efficiently (nanosecond time scale), while the back electron transfer and catalysis are much slower (millisecond and microsecond time scales). Further improvements of the photodriven proton reduction should focus on the catalytic rate enhancement, which should be at least in the hundreds of nanoseconds time scale. PMID- 24799031 TI - Is diffusion-weighted imaging a significant indicator of the development of vascularization in hypovascular hepatocellular lesions? AB - OBJECTIVE: The objective was to evaluate the efficacy of diffusion-weighted imaging (DWI) in predicting the development of vascularization in hypovascular hepatocellular lesions (HHLs). MATERIALS AND METHODS: Forty-two HHLs that were diagnosed by computed tomographic (CT) arteriography were evaluated retrospectively. The lesion on DWI was classified as isointense, hypointense, or hyperintense. Follow-up studies that included intravenous dynamic CT or magnetic resonance imaging were performed. RESULTS: The 730-day cumulative developments of vascularization in hypointense, isointense, and hyperintense lesions were 17%, 30%, and 40%, respectively. The differences among these developments were not statistically significant. CONCLUSION: The signal intensity on DWI showed no significant difference in the development of vascularization. PMID- 24799032 TI - Critical neuroprotective roles of heme oxygenase-1 induction against axonal injury-induced retinal ganglion cell death. AB - Although axonal damage induces significant retinal ganglion cell (RGC) death, small numbers of RGCs are able to survive up to 7 days after optic nerve crush (NC) injury. To develop new treatments, we set out to identify patterns of change in the gene expression of axonal damage-resistant RGCs. To compensate for the low density of RGCs in the retina, we performed retrograde labeling of these cells with 4Di-10ASP in adult mice and 7 days after NC purified the RGCs with fluorescence-activated cell sorting. Gene expression in the cells was determined with a microarray, and the expression of Ho-1 was determined with quantitative PCR (qPCR). Changes in protein expression were assessed with immunohistochemistry and immunoblotting. Additionally, the density of Fluoro-gold-labeled RGCs was counted in retinas from mice pretreated with CoPP, a potent HO-1 inducer. The microarray and qPCR analyses showed increased expression of Ho-1 in the post-NC RGCs. Immunohistochemistry also showed that HO-1-positive cells were present in the ganglion cell layer (GCL), and cell counting showed that the proportion of HO 1-positive cells in the GCL rose significantly after NC. Seven days after NC, the number of RGCs in the CoPP-treated mice was significantly higher than in the control mice. Combined pretreatment with SnPP, an HO-1 inhibitor, suppressed the neuroprotective effect of CoPP. These results reflect changes in HO-1 activity to RGCs that are a key part of RGC survival. Upregulation of HO-1 signaling may therefore be a novel therapeutic strategy for glaucoma. PMID- 24799033 TI - Palladium-catalyzed asymmetric amination of allenyl phosphates: enantioselective synthesis of allenes with an additional unsaturated unit. AB - A highly enantioselective Pd-catalyzed amination of allenyl phosphates generating 2,3-allenyl amines with central chirality has been developed. Under the optimized conditions, chiral 2,3-allenyl amines with or without (an) additional C-C double or triple bond(s) have been prepared at 0 degrees C with up to 90% yield and 94% ee by identifying (R)-3,4,5-(MeO)3-MeOBIPHEP as the ligand. PMID- 24799034 TI - An in-fiber integrated optofluidic device based on an optical fiber with an inner core. AB - A new kind of optofluidic in-fiber integrated device based on a specially designed hollow optical fiber with an inner core is designed. The inlets and outlets are built by etching the surface of the optical fiber without damaging the inner core. A reaction region between the end of the fiber and a solid point obtained after melting is constructed. By injecting samples into the fiber, the liquids can form steady microflows and react in the region. Simultaneously, the emission from the chemiluminescence reaction can be detected from the remote end of the optical fiber through evanescent field coupling. The concentration of ascorbic acid (AA or vitamin C, Vc) is determined by the emission intensity of the reaction of Vc, H2O2, luminol, and K3Fe(CN)6 in the optical fiber. A linear sensing range of 0.1-3.0 mmol L(-1) for Vc is obtained. The emission intensity can be determined within 2 s at a total flow rate of 150 MUL min(-1). Significantly, this work presents information for the in-fiber integrated optofluidic devices without spatial optical coupling. PMID- 24799035 TI - Iain D Campbell 1941-2014. PMID- 24799036 TI - JAK-cytokine receptor recognition, unboxed. PMID- 24799037 TI - Let it go: how to deal with a breakup in mitosis. PMID- 24799038 TI - How YidC inserts and folds proteins across a membrane. PMID- 24799039 TI - BioPen: direct writing of functional materials at the point of care. AB - Rapid and precise patterning of functional biomaterials is desirable for point-of care (POC) tissue engineering and diagnostics. However, existing technologies such as dip-pen nanolithography and inkjet printing are currently unsuitable for POC applications due to issues of cost and portability. Here, we report the development of 'BioPen', a portable tool for continuous, defined and scalable deposition of functional materials with micrometer spatial resolution and nanolitre volumetric resolution. BioPen is based upon the ballpoint pen but with multiple "ink sources" (functional material solutions) and with an apparatus that can be optimized for writing living cells, proteins, nucleic acids, etc. We demonstrate POC detection of human immunodeficiency virus type 1 (HIV-1) nucleic acid by writing on paper with BioPen using "ink" consisting of nucleic acid probes and nucleic acid-modified gold nanoparticles. We also demonstrate POC tissue engineering by writing a continuous pattern of living, functional, interconnected cells with a defined extracellular environment. Because it is simple, accurate, inexpensive and portable, BioPen has broad potential for POC detection of diagnostic biomarkers, and for POC engineering of tissues for a range of healing applications. PMID- 24799041 TI - ECM protein nanofibers and nanostructures engineered using surface-initiated assembly. AB - The extracellular matrix (ECM) in tissues is synthesized and assembled by cells to form a 3D fibrillar, protein network with tightly regulated fiber diameter, composition and organization. In addition to providing structural support, the physical and chemical properties of the ECM play an important role in multiple cellular processes including adhesion, differentiation, and apoptosis. In vivo, the ECM is assembled by exposing cryptic self-assembly (fibrillogenesis) sites within proteins. This process varies for different proteins, but fibronectin (FN) fibrillogenesis is well-characterized and serves as a model system for cell mediated ECM assembly. Specifically, cells use integrin receptors on the cell membrane to bind FN dimers and actomyosin-generated contractile forces to unfold and expose binding sites for assembly into insoluble fibers. This receptor mediated process enables cells to assemble and organize the ECM from the cellular to tissue scales. Here, we present a method termed surface-initiated assembly (SIA), which recapitulates cell-mediated matrix assembly using protein-surface interactions to unfold ECM proteins and assemble them into insoluble fibers. First, ECM proteins are adsorbed onto a hydrophobic polydimethylsiloxane (PDMS) surface where they partially denature (unfold) and expose cryptic binding domains. The unfolded proteins are then transferred in well-defined micro- and nanopatterns through microcontact printing onto a thermally responsive poly(N isopropylacrylamide) (PIPAAm) surface. Thermally-triggered dissolution of the PIPAAm leads to final assembly and release of insoluble ECM protein nanofibers and nanostructures with well-defined geometries. Complex architectures are possible by engineering defined patterns on the PDMS stamps used for microcontact printing. In addition to FN, the SIA process can be used with laminin, fibrinogen and collagens type I and IV to create multi-component ECM nanostructures. Thus, SIA can be used to engineer ECM protein-based materials with precise control over the protein composition, fiber geometry and scaffold architecture in order to recapitulate the structure and composition of the ECM in vivo. PMID- 24799043 TI - Shaped Ni nanoparticles with an unconventional hcp crystalline structure. AB - Hourglass-shaped Ni nanoparticles were synthesized with a hexagonal close packed (hcp) structure. The unconventional crystalline structure could be stabilized by intensive utilization of hexadecylamine. The dense organic layer on the surface protected the meta-stable crystalline structure. PMID- 24799042 TI - High-throughput and combinatorial gene expression on a chip for metabolism induced toxicology screening. AB - Differential expression of various drug-metabolizing enzymes (DMEs) in the human liver may cause deviations of pharmacokinetic profiles, resulting in interindividual variability of drug toxicity and/or efficacy. Here, we present the 'Transfected Enzyme and Metabolism Chip' (TeamChip), which predicts potential metabolism-induced drug or drug-candidate toxicity. The TeamChip is prepared by delivering genes into miniaturized three-dimensional cellular microarrays on a micropillar chip using recombinant adenoviruses in a complementary microwell chip. The device enables users to manipulate the expression of individual and multiple human metabolizing-enzyme genes (such as CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2E1 and UGT1A4) in THLE-2 cell microarrays. To identify specific enzymes involved in drug detoxification, we created 84 combinations of metabolic-gene expressions in a combinatorial fashion on a single microarray. Thus, the TeamChip platform can provide critical information necessary for evaluating metabolism induced toxicity in a high-throughput manner. PMID- 24799044 TI - In vivo lung morphometry with accelerated hyperpolarized (3) He diffusion MRI: a preliminary study. AB - PURPOSE: Parallel imaging can be used to reduce imaging time and to increase the spatial coverage in hyperpolarized gas magnetic resonance imaging of the lung. In this proof-of-concept study, we investigate the effects of parallel imaging on the morphometric measurement of lung microstructure using diffusion magnetic resonance imaging with hyperpolarized (3) He. METHODS: Fully sampled and under sampled multi-b diffusion data were acquired from human subjects using an 8 channel (3) He receive coil. A parallel imaging reconstruction technique (generalized autocalibrating partially parallel acquisitions [GRAPPA]) was used to reconstruct under-sampled k-space data. The morphometric results of the generalized autocalibrating partially parallel acquisitions-reconstructed data were compared with the results of fully sampled data for three types of subjects: healthy volunteers, mild, and moderate chronic obstructive pulmonary disease patients. RESULTS: Morphometric measurements varied only slightly at mild acceleration factors. The results were largely well preserved compared to fully sampled data for different lung conditions. CONCLUSION: Parallel imaging, given sufficient signal-to-noise ratio, provides a reliable means to accelerate hyperpolarized-gas magnetic resonance imaging with no significant difference in the measurement of lung morphometry from the fully sampled images. GRAPPA is a promising technique to significantly reduce imaging time and/or to improve the spatial coverage for the morphometric measurement with hyperpolarized gases. PMID- 24799045 TI - The Nordic Five to Fifteen questionnaire could provide the basis for a common neurological disability variable. AB - AIMS: Assessing disabilities in children is essential and Danish parents provide increasingly important feedback on how their child's disability affects daily living. The Nordic Five to Fifteen (FTF) parent questionnaire is widely used in Nordic countries to detect atypical or delayed development in children. Our study evaluated its internal validity and whether it could be used to generate a common disability variable across childhood neurological disorders and severities. METHODS: The 28-statement FTF questionnaire was completed by the parents of children with spina bifida, muscular disorders, spinal atrophy, cerebral palsy, blindness, deafness, mental retardation and disability, who received treatment for brain tumours. Psychometric analysis and Rasch analysis of the five FTF code qualifier level data were carried out. RESULTS: A total of 227 of 332 (68.4%) parents participated. The mean qualifier score was 3.06 (standard deviation 0.89, range 2.31-4.26), and the variances mean was 1.57 (range 0.87-2.38). The corrected code-total correlation was 0.65, and reliability was 0.96. The Rasch analysis demonstrated good fit alignment of codes. CONCLUSION: The FTF questionnaire can be used with children with neurological disabilities, and the Rasch scale analysis results indicate that it could form the analytical basis for developing a common disability variable. PMID- 24799046 TI - Different binding sites for Bacillus thuringiensis Cry1Ba and Cry9Ca proteins in the European corn borer, Ostrinia nubilalis (Hubner). AB - Binding studies using (125)I-Cry9Ca and biotinylated-Cry1Ba proteins showed the occurrence of independent binding sites for these proteins in Ostrinia nubilalis. Our results, along with previously available binding data, indicate that combinations of Cry1A or Cry1Fa proteins with Cry1Ba and/or Cry9Ca could be a good strategy for the resistance management of O. nubilalis. PMID- 24799047 TI - Gross and microscopic pathology of lesions in Pocillopora spp. from the subtropical eastern Pacific. AB - Coral reefs are threatened by a variety of factors including diseases that have caused significant damage in some regions such as in the Caribbean. At present, no data are available on coral diseases in the Mexican Pacific where Pocillopora spp. is a dominant component of coral communities. Here, we describe gross and microscopic morphology of lesions found in pocilloporids at four sites in the Mexican Pacific. Corals were identified and their lesions photographed and quantified in the field. Tissue samples were collected from healthy and affected colonies for histopathology. We recorded seven species of pocilloporids at the study sites with Isla Isabel being the location with the highest coral diversity (H'=1.27). Lesions were present in 42% of the colonies and included discoloration (32%), predation-induced tissue loss (30%), unexplained tissue loss (3%) and overgrowth by sponges or algae (35%). The most affected species, P. damicornis (50%), was also one of the most common in the region. No species was more prone to a particular lesion, but there was a significant association between location and the presence of lesions. Northern Islas Marietas (61%) and Isla Isabel (41%) had the highest prevalence of lesions, followed by Manzanillo (37%) and Bahias de Huatulco (23%). Histological changes included atrophy of the surface body wall with depletion of zooxanthellae (91%) in corals with discoloration (bleaching). Ablation of tissue from mesoglea (18%) was also observed. Colonies with unexplained tissue loss showed atrophy and thinning of the epidermis (89%), characterized by cuboidal instead of pseudocolumnar cells normally found in healthy pseudocolumnar ciliated epithelium. Bacterial aggregates between the mesoglea and gastrodermis (11%) were very conspicuous in healthy and diseased corals. Lesions produced by fish bites and gastropods were associated with tissue atrophy (40%) and, in some cases, algal overgrowth near the lesion (20%). No infectious agents associated with cell pathology were detected microscopically. Bleaching and overgrowth by algae and sponges, as well as unexplained tissue loss, are common in Pocillopora. These lesions and anatomical changes warrant further study since their incidence is potentially indicative of reef degradation. PMID- 24799048 TI - The effects of sublethal levels of 2,4-dichlorophenoxyacetic acid herbicide (2,4 D) on feeding behaviors of the crayfish O. rusticus. AB - The widespread use of herbicides across the globe has increased the probability of synthetic chemicals entering freshwater habitats. On entering aquatic habitats, these chemicals target and disrupt both physiological and behavioral functioning in various aquatic organisms. Herbicides, such as 2,4 dichlorophenoxyacetic acid (2,4-D), can have negative impacts on chemoreception because these receptor cells are in direct contact with water-soluble chemicals in the environment. Studies focusing on lethal concentration (LC50) levels may understate the impact of herbicides within aquatic habitats because damage to the chemoreceptors can result in modified behaviors or lack of appropriate responses to environmental or social cues. The purpose of this experiment was to determine whether exposure to sublethal levels of 2,4-D alters the foraging behaviors of crayfish Orconectes rusticus. We hypothesized that crayfish exposed to greater concentrations of 2,4-D would be less successful in locating food or on locating food would consume smaller amounts possibly due to an inability to recognize the food odors in the contaminated waters. Crayfish were exposed to three sublethal levels of 2,4-D for 96 h and placed into a Y-maze system with a fish gelatin food source placed randomly in the right or left arm. Average walking speed, average time spent in the correct arm, and percent consumption were analyzed. Our data show that crayfish were impaired in their ability to forage effectively. These inabilities to locate and consume adequate amounts of food could result in lower body weights and decreased fitness in populations of crayfish exposed to 2,4-D in natural habitats. PMID- 24799049 TI - The metastatic process: a kaleidoscope of concepts. PMID- 24799050 TI - Investigating the metastatic niche in melanoma: a new therapeutic opportunity? PMID- 24799051 TI - Safety and efficacy of preoperative sorafenib therapy in facilitating cytoreductive surgery in renal cell carcinoma. PMID- 24799052 TI - Targeted therapy in metastatic colon cancer. PMID- 24799053 TI - Pyrosequencing evaluation of low-frequency KRAS mutant alleles for EGF receptor therapy selection in metastatic colorectal carcinoma. AB - AIM: To evaluate whether pyrosequencing (PS) improves the KRAS mutational status predictive value. PATIENTS & METHODS: A retrospective analysis of KRAS mutations by PS and direct sequencing (DS) in 192 metastatic colorectal carcinomas (mCRCs), subgrouped in 51 KRAS mutated at PS and 141 KRAS wild-type at DS. RESULTS: DS failed to detect low-frequency KRAS mutations in four out of 51 mCRCs, whereas PS detected 12 additional low-frequency KRAS mutations in 141 mCRCs KRAS wild-type at DS. After reanalyzing by PS 97 KRAS wild-type tumors treated with anti-EGF receptor (EGFR) antibodies, nine additional mutations were revealed in nonresponders, whereas none of responders exhibited a KRAS-mutated genotype. Of note, KRAS-mutated tumors upon PS showed a worst progression-free survival after EGFR therapy. Finally, PS allowed the detection of additional NRAS, BRAF and exon 20 PIK3CA mutations mostly in KRAS wild-type mCRCs resistant to EGFR therapy. CONCLUSION: PS detection of low-frequency mutations may improve the KRAS predictive value for EGFR therapy selection. PMID- 24799055 TI - The role of gene regulatory networks in promoting cancer progression and metastasis. AB - The majority of deaths owing to cancer are ultimately caused by metastatic disease. However, most research, to date, has focused on the molecular features of cancers at their primary sites rather than on understanding disseminated malignancy in its systemic form. The dynamic nature of metastatic malignancy and its behavior as a co-ordinated systemic disease require a cancer progression paradigm that is integrative and can incorporate both the proximate causes of cancer and the broader ultimate causes in an evolutionary and developmental context. The study of robust cellular attractor states that arise directly from the architectural patterns contained within gene regulatory networks is proposed as a conceptual framework through which many of the other disparate models of cancer metastasis can be more clearly viewed and, ultimately, unified, thus providing a new conceptual framework in which to understand cancer progression and metastasis. PMID- 24799054 TI - Biweekly combination of trastuzumab, docetaxel and gemcitabine for HER2-positive metastatic breast cancer: results of a Phase II GOIM study. AB - AIMS: Clinical activity of chemotherapy plus trastuzumab in HER2 overexpressing advanced breast cancer has been documented. We report the activity and safety results of biweekly combination of trastuzumab, docetaxel and gemcitabine as first-line therapy in HER2-positive advanced breast cancer. PATIENTS & METHODS: Patients were biweekly treated with trastuzumab (4 mg/kg), gemcitabine (1000 mg/m(2)) and docetaxel (50 mg/m(2)). The primary end point was overall response rate, secondary time to progression, clinical benefit rate (partial response plus complete response plus stable disease for >= 24 weeks) and tolerability. RESULTS: A total of 65 patients with HER2-positive advanced breast cancer have been enrolled. In total, 47 patients responded (73%; 95% CI, 60-84), 11 achieved complete response (17%; 95% CI: 8.9-28.7), 36 achieved partial response (56%; 95% CI: 43-68.6). The clinical benefit rate was 87.5% (95% CI: 77-94). Three patients (4.7%) experienced progressive disease. The median time to progression was 14.2 months (95% CI: 10.6-17.8), the median overall survival was 39.3 months and the 36-month survival rate was 55.5% (95% CI: 58-73). The worst toxicities were grade 3 neutropenia (12%), thrombocytopenia (6%) and diarrhea (6%). No cardiac toxicity was reported. CONCLUSION: As first-line therapy, this combination allowed the delivery of polychemotherapy in association to targeted therapy, with clinical activity and mild toxicity. The promising results should be further explored in Phase III randomized clinical trials. PMID- 24799056 TI - CXCL12-CXCR4 contributes to the implication of bone marrow in cancer metastasis. AB - The CXCL12-CXCR4 axis is postulated to be a key pathway in the interaction between (cancer) stem cells and their surrounding supportive cells in the (cancer) stem cell niche. As the bone marrow constitutes a unique microenvironment for cancer cells, the CXCL12-CXCR4 axis assists the bone marrow in regulating cancer progression. This interaction can be disrupted by CXCR4 antagonists, and this concept is being used clinically to harvest hematopoietic stem/progenitor cells from the bone marrow. The functions of CXCL12-CXCR4 axis in cancer cell-tumor microenvironment interaction and angiogenesis have been recently studied. This review focuses on how CXCL12-CXCR4 helps the bone marrow in creating a tumor mircoenvironment that results in the cancer metastasis. It also discusses ongoing research regarding the clinical feasibility of CXCR4 inhibitors. PMID- 24799057 TI - Extracranial oligometastatic renal cell carcinoma: current management and future directions. AB - The term 'oligometastases' was formulated to describe an intermediate state between widespread metastases and locally confined disease. The standard of care in metastatic renal cell carcinoma is systemic therapy; however, in patients with solitary or limited metastases, aggressive local therapies may potentially prolong survival. The literature suggests a survival benefit with surgical metastasectomy, with a reported 5-year survival as high as 45% in those who achieve complete resection. More recently, an expanding body of evidence supports the role of stereotactic ablative body radiation therapy for the treatment of oligometastatic renal cell carcinoma and early results demonstrate comparable local control rates with surgery. There is also increasing interest in the abscopal and immunologic effects of localized radiation. With the proliferation of newer targeted agents and immunomodulatory agents, current work is addressing the optimization of patient selection and avenues towards sequencing and combining the various treatment options. PMID- 24799058 TI - Radiation therapy and the immune system: learning to live together. PMID- 24799059 TI - Breakthrough therapies in melanoma. PMID- 24799061 TI - Orteronel for the treatment of prostate cancer. AB - Orteronel (also known as TAK-700) is a novel hormonal therapy that is currently in testing for the treatment of prostate cancer. Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. Preclinical studies demonstrate that orteronel treatment suppresses androgen levels and causes shrinkage of androgen-dependent organs, such as the prostate gland. Early reports of clinical studies demonstrate that orteronel treatment leads to reduced prostate-specific antigen levels, a marker of prostate cancer tumor burden, and more complete suppression of androgen synthesis than conventional androgen deprivation therapies that act in the testes alone. Treatment with single-agent orteronel has been well tolerated with fatigue as the most common adverse event, while febrile neutropenia was the dose-limiting toxicity in a combination study of orteronel with docetaxel. Recently, the ELM-PC5 Phase III clinical trial in patients with advanced-stage prostate cancer who had received prior docetaxel was unblinded as the overall survival primary end point was not achieved. However, additional Phase III orteronel trials are ongoing in men with earlier stages of prostate cancer. PMID- 24799062 TI - Dacomitinib for the treatment of advanced or metastatic non-small-cell lung cancer. AB - Dacomitinib (PF-00299804) is a second-generation irreversible HER tyrosine kinase inhibitor (TKI). In preclinical studies, dacomitinib has demonstrated anti-tumor activity in lung cancer cell lines with sensitive and resistant EGFR mutations (including the T790 mutation). Safety and well tolerability of dacomitinib were demonstrated in Phase I studies with stomatitis, diarrhea and skin toxicities being the dose-limiting toxicities. The maximum tolerated dose was established to be 45 mg/day. In Phase II and III studies, dacomitinib has shown clinical activity in both HER tyrosine kinase-naive and HER tyrosine kinase failure settings. Further clinical trials are underway to evaluate the efficacy of dacomitinib in non-small-cell lung cancer. PMID- 24799063 TI - Dynamic contrast-enhanced MRI parameters as biomarkers for the effect of vatalanib in patients with non-small-cell lung cancer. AB - AIMS: To assess the utility of dynamic contrast-enhanced MRI parameters in the demonstration of early antiangiogenic effects and as prognostic biomarkers in second-line treatment of advanced-stage non-small-cell lung cancer with vatalanib. PATIENTS & METHODS: The transfer constant (K(trans)) and the initial area under the contrast concentration-time curve at 60 s (AUC60) were assessed in 46 patients. Changes were compared with response evaluation from computed tomography imaging and Response Evaluation Criteria In Solid Tumors guidelines. RESULTS: Statistically significant mean reductions in K(trans) (38.4%; p < 0.0001) and AUC60 (24.9%; p < 0.0001) were found at day 2. After 12 weeks, 16 patients (35%) demonstrated stable disease and 30 (65%) demonstrated progressive disease. No statistically significant differences in day 2 K(trans) and AUC60 reductions between stable disease and progressive disease patients were found. CONCLUSION: Dynamic contrast-enhanced MRI can demonstrate a statistically significant reduction in vascular parameters of non-small-cell lung cancer, but does not predict patient outcome. PMID- 24799064 TI - Hematologic changes during prostate cancer radiation therapy are dependent on the treatment volume. AB - AIM: To assess hematologic changes of modern prostate radiation therapy (RT) comparing different target volumes. PATIENTS & METHODS: Blood samples were evaluated before (T1), during (T2-T4) and 6-8 weeks after (T5) RT in a group of 113 patients. Whole-pelvic RT up to 46 Gy was applied in 27 cases. The total dose to the prostatic fossa (n = 46)/prostate (n = 67) was 66/76 Gy. RESULTS: Erythrocyte, leukocyte and platelet levels decreased significantly relative to baseline levels at T2-T5. Neoadjuvant hormonal therapy had an impact on hemoglobin levels before and during RT. The cumulative incidence of grade 2 leukopenia was 15 versus 2% (p = 0.02) and grade 2 anemia 8 versus 0% (p = 0.03) with versus without whole-pelvic RT, respectively. Lymphocyte decrease was larger at times T2-T5 (36 vs 3% grade 3 toxicity; p < 0.01). CONCLUSION: Prostate RT has a small but significant and longer effect on the blood count. Lower lymphocyte levels need to be considered when larger volumes are treated. PMID- 24799065 TI - Spacer application for prostate cancer radiation therapy. AB - Definitive radiotherapy is a well-recognized treatment option for localized prostate cancer. Rectum toxicity is the dose-limiting toxicity. Dose-volume correlations have been reported in many studies. The application of a spacer to increase the distance between the prostate and anterior rectal wall is an innovative technique, considerably reducing the dose to the rectum. Hyaluronic acid, human collagen, an inflatable balloon or hydrogel are potential materials to create the desired effect. The number of clinical studies is rapidly increasing. Well-tolerated injection or implantation techniques and low rectal treatment-related toxicity have been demonstrated in prospective studies. Long term clinical results and the results of randomized studies are needed to better define the beneficial effect for the patient. PMID- 24799066 TI - PIM kinases: an overview in tumors and recent advances in pancreatic cancer. AB - The PIM kinases represent a family of serine/threonine kinases, which is composed of three different members (PIM1, PIM2 and PIM3). Aberrant expression of PIM kinases is observed in variety of tumors, including pancreatic cancer. The PIM kinases play pivotal roles in the regulation of cell cycle, apoptosis, properties of stem cells, metabolism, autophagy, drug resistance and targeted therapy. The roles of PIM kinases in pancreatic cancer include the regulation of proliferation, apoptosis, cell cycle, formation, angiogenesis and prediction prognosis. Blocking the activities of PIM kinases could prevent pancreatic cancer development. PIM kinases may be a novel target for cancer therapy. PMID- 24799067 TI - Locally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of electrochemotherapy. AB - Electroporation is used to enhance drug diffusion and gene delivery into the cytosol. The combination of electroporation and cytotoxic drugs, electrochemotherapy (ECT), is used to treat metastatic tumor nodules located at the skin and subcutaneous tissue. The objective response rate following a single session of treatment exceeds 80%, with minimal toxicity for the patients. The efficacy of ECT in the bone and visceral metastasis is currently investigated, and Phase II studies have been completed. ECT has been used to treat skin primary tumors, except melanoma, and is under investigation for locally advanced pancreatic cancer. Early evidence suggests that treatment of tumor nodules with ECT recruits components of the immune system and eliciting a systemic immune response against cancer is a challenging clinical perspective. Considering the proven safety in several different clinical applications electroporation should be viewed as a clinical platform technology with wide perspectives for use in ECT, gene therapy and DNA vaccination. PMID- 24799068 TI - Longitudinal and circumferential resection margin in adenocarcinoma of distal esophagus and cardia. AB - Multiple factors are implicated in the long-term survival of patients who have undergone esophagectomy, among these the involvement of longitudinal and circumferential resection margins are well known important prognostic factors. A few studies have assessed the impact of the operative approach on the status of the resection margins, and the data are not well reported, often unclear and, more importantly, there is no scientific evidence or published guideline on what the optimal proximal, distal or circumferential resection margin clearance should be. Owing to the lack of clarity on these points, we undertook a systematic literature review of the impact of longitudinal and circumferential resection margins in patients with operable esophageal cancer, the prognostic significance of margin involvement and the role of neoadjuvant therapy. PMID- 24799069 TI - Determination of colchicine and O-demethylated metabolites in decomposed skeletal tissues by microwave assisted extraction, microplate solid phase extraction and ultra-high performance liquid chromatography (MAE-MPSPE-UHPLC). AB - Microwave assisted extraction (MAE) followed by microplate solid phase extraction (MPSPE) coupled with ultra high performance liquid chromatography (UHPLC) for the semi-quantitative determination of colchicine, 3-demethyl colchicine and 2 demethyl colchicine in postmortem rat bone is described. Rats (n=4) received 50mg/kg colchicine (i.p), and euthanized by CO2 asphyxiation. Remains decomposed to skeleton outdoors and vertebral bones were collected cleaned, and ground to a fine powder. Powdered bone underwent MAE using methanol in a closed microwave system, followed by MPSPE and analysis using UHPLC-PDA. MAE analyte stability was assessed and found to be stable for at least 60 min irradiation time. The majority (>95%) of each analyte was recovered after 15 min. The MPSPE-UHPLC method was linear between 10 and 2,000 ng/mL, with coefficients of variation <20% in triplicate analysis, with a limit of detection of 10 ng/mL for each of the three analytes. Following MAE for 30 min (80 degrees C, 1200W), MPSPE-UHPLC analysis of vertebral bone of colchicine-exposed rats detected colchicine (1.8 4.1 MUg/g), 3-demethyl colchicine (0.77-1.8 MUg/g) and 2-demethyl colchicine (0.43-0.80 MUg/g) in all samples assayed. PMID- 24799071 TI - War on drugs redux: welcome to the war on doping in sports. PMID- 24799070 TI - Asymmetric dimethylarginine does not inhibit arginase activity and is pro proliferative in pulmonary endothelial cells. AB - Asymmetric dimethylarginine (ADMA) is an endogenously produced nitric oxide synthase (NOS) inhibitor. L-Arginine can be metabolised by NOS and arginase, and arginase is the first step in polyamine production necessary for cellular proliferation. We tested the hypothesis that ADMA would inhibit NOS but not arginase activity and that this pattern of inhibition would result in greater L arginine bioavailability to arginase, thereby increasing viable cell number. Bovine arginase was used in in vitro activity assays with various concentrations of substrate (L-arginine, ADMA, N(G) -monomethyl-L-arginine (L-NMMA) and N(G) nitro-L-arginine methyl ester (L-NAME)). Only L-arginine resulted in measurable urea production (Km = 6.9 +/- 0.8 mmol/L; Vmax = 6.6 +/- 0.3 MUmol/mg protein per min). We then incubated bovine arginase with increasing concentrations of ADMA, L NMMA and L-NAME in the presence of 1 mmol/L l-arginine and found no effect of any of the tested compounds on arginase activity. Using bovine pulmonary arterial endothelial cells (bPAEC) we determined the effects of ADMA on nitric oxide (NO) and urea production and found significantly lower NO production and greater urea production (P < 0.003) with ADMA, without changes in arginase protein levels. In addition, ADMA treatment resulted in an approximately 30% greater number of viable cells after 48 h than in control bPAEC. These results demonstrate that ADMA is neither a substrate nor an inhibitor of arginase activity and that in bPAEC ADMA inhibits NO production and enhances urea production, leading to more viable cells. These results may have pathophysiological implications in disorders associated with higher ADMA levels, such as pulmonary hypertension. PMID- 24799072 TI - Brazilian antidoping public policy. AB - Doping, used to improve sports performance, is legally prohibited. This paper describes Brazilian regulations, resolutions, and Federal laws addressing the issue of doping and antidoping which were collected in 2012 from official websites. We conclude that Brazilian laws have constrained doping, and have been updated over the years to conform to worldwide legal guidelines. Study limitations are noted. PMID- 24799073 TI - Homeless drug users and information technology: a qualitative study with potential implications for recovery from drug dependence. AB - BACKGROUND: Having access to information and communication technologies (ICTs) is a prerequisite to meaningful participation in society. OBJECTIVES: This paper seeks to: i. explore the engagement of homeless drug users (HDUs) with ICTs and ii. discuss the findings with reference to recovery from drug dependence. METHODS: The study design was qualitative and longitudinal, involving data collected in 2012-13 via 52 semi-structured interviews with 30 homeless drug users (25 men; five women). Participants were recruited from 17 hostels in two English cities. Interview data were analyzed using Framework. RESULTS: HDUs had access to ICTs, used ICTs, and wanted to engage with them more. Experiences of digital exclusion were a function of participants' inability to afford ICTs, the relatively cheap and poor quality technology available to them, limited knowledge about ICTs, and lack of support in using them. That HDUs were often unable to take full advantage of technology because they had nobody to explain what their devices could do or to show them how they worked was ironic given that using ICTs to (re)establish and maintain relationships were functions of technology that HDUs particularly liked. CONCLUSIONS: The physical, human, cultural, and social capital of HDUs influenced their access to, and use of, ICTs. Equally, ICTs were themselves an important recovery resource. Services and others should endeavor to provide HDUs with easy access to good quality technology, as well as offers of support and education so that all individuals have the knowledge and confidence to make optimum use of the technology that is available to them. PMID- 24799074 TI - Development and in vitro/in vivo evaluation of immediate release perindopril tablets. AB - Perindopril erbumine (PE) is a BCS (Biopharmaceutics Classification System) class 3 drug with high solubility and low permeability. It is an inhibitor of the enzyme that converts angiotensin I (Angiotensin Converting Enzyme, ACE) into angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. The aim of this study was to develop an alternative drug product by using a different salt of perindopril and to evaluate the bioequivalence between PE, not still licensed, and perindopril arginine (PA), licensed in many countries, and to prepare PE tablets by using direct compression method. Many different formulations were prepared, among which F3-coded formulation was only selected due to releasing of 98.03% active substance at 45th minute. Bioequivalence study was planned as a cross-designed, randomized, open labeled, single-dose, single-center study and conducted in 24 male healthy volunteers via peroral route. The results of bioequivalence study were evaluated for Perindopril and Perindoprilat according to Cmax, tmax and AUC criteria. The geometric mean ratios (90% CI) of perindopril and perindoprilat followed test and reference drug were calculated for AUC0-t and Cmax, 105.946% (100.218-112.002%) and 110.437% (102.534-118.948%); 109.542% (98.364-121.992%) and 115.729% (101.031 132.565%), respectively. The 90% confidence intervals of them were found within the standard bioequivalence range (80-125%). PMID- 24799075 TI - Antioxidant activity of idebenone-loaded neutral and cationic solid-lipid nanoparticles. AB - Idebenone (IDE) is a lipophilic benzoquinone electron carrier synthetic analogue of coenzyme Q10, which behaves as an antioxidant and free radical scavenging molecule. Recently, the therapeutic application of IDE in Leber's hereditary optic neuropathy has been discussed. This work was aimed at evaluating the encapsulation of IDE in solid-lipid nanoparticles (SLN). In particular, we tested the possibility of adapting the quasi-emulsion solvent diffusion technique, already proposed to produce polymeric nanoparticles, to prepare positively charged SLN with different compositions. Such a charge, due to the addition of a cationic lipid, would facilitate the interaction with the negatively charged eye surface epithelium, with a consequent longer pre-corneal residence time of the colloidal systems. In a preliminary evaluation of the produced IDE-loaded SLN, the antioxidant activity of the drug was demonstrated using an oxygen radical absorbance capacity assay. Encapsulation of the drug in the nanocarrier systems seems able to protect IDE from degradation and prolong its antioxidant potential. PMID- 24799076 TI - High-efficient nano-carrier gel systems for testosterone propionate skin delivery. AB - The purpose of the current investigation was to evaluate the skin delivery potential of the different nano-carrier gels including liposomal gel, ethosomal gel and microemulsion gel bearing testosterone propionate (TP) as a testosterone deficient therapy. The prepared nano-particles were characterized for their shape, particle size distribution and zeta potential. In vitro skin permeation and in vivo transdermal delivery of nano-carrier gels were studied with the Franz diffusion cells and confocal laser scanning microscopy (CLSM). The results showed that all of nano-particles were almost spherical with low polydispersity and nano metric size range from 40 to 200 nm. TP ethosomal gel also provided an enhanced transdermal flux of 7.64 +/- 1.4 MUg/cm(2)/h and a decreased lag time of 0.69 h across rat skin as compared with the other two formulations. The skin penetration efficiency of TP nano-carrier gels also revealed that TP ethosomal gel would enhanced penetration of rhodamine red (RR)-loaded formulation to the deeper layers of the skin (268 um) than the liposomal gel (192 um) and microemulsion gel (228 um). This study demonstrated TP ethosomal gel is a promising nano-carrier for delivering TP through the skin. PMID- 24799077 TI - A cross-sectional investigation of depressive, anxiety, and stress symptoms and health-behavior participation in Australian university students. AB - Transitioning to university involves a major life change that can have implications for physical and mental health. This study had three objectives: first, assess the mental health and health-behavior participation of Australian university students; second, evaluate clustering of health behaviors; and third, examine how mental health relates to health behaviors. University students (n = 751) enrolled at an Australian regional university completed an online survey containing the Depression, Anxiety, and Stress Scales and a health-behavior questionnaire. Over one-third of students reported mild or higher mental illness symptoms and most reported engaging in multiple unhealthy behaviors. Furthermore, mental health was associated with unhealthy behaviors. For males, depressive symptoms were associated with skipping breakfast and poor sleep quality. For females, depressive symptoms were associated with skipping breakfast, inadequate vigorous physical activity, and short or long sleep hours. Stress symptoms in females were associated with healthy sleep hours, but poor sleep quality. Future research may consider whether an intervention targeting one or two key health behaviors has utility in improving participation in other health behaviors and mental health. PMID- 24799079 TI - No effect of obesity on limb and component alignment after computer-assisted total knee arthroplasty. AB - PURPOSE: This retrospective study aimed to determine if computer navigation provides consistent accuracy for limb and component alignment during TKA irrespective of body mass index (BMI) by comparing limb and component alignment and the outlier rates in obese versus non-obese individuals undergoing computer assisted TKA. METHODS: Six hundred and thirty-five computer assisted total knee arthroplasties (TKAs) performed in non-obese individuals (BMI<30 kg/m(2)) were compared with 520 computer-assisted TKAs in obese individuals (BMI >= 30 kg/m(2)) for postoperative limb and component alignment using full length standing hip-to ankle radiographs. RESULTS: No significant difference in postoperative limb alignment (179.7 degrees +/- 1.7 degrees vs 179.6 degrees +/- 1.8 degrees ), coronal femoral (90.2 degrees +/- 1.6 degrees vs 89.8 degrees +/- 1.9 degrees ) and tibial component (90.2 degrees +/- 1.6 degrees vs 90.3 degrees +/- 1.7 degrees ) alignment and outlier rates (6.2% vs 7.5%) was found between non-obese and obese individuals. Similarly, alignment and the outlier rates were similar when non-obese individuals and a subgroup of morbidly obese individuals (BMI >40 kg/m(2)) were compared. CONCLUSIONS: Computer navigation can achieve excellent limb and component alignment irrespective of a patient's BMI. Although obesity may not be an indication per se for using computer navigation during TKA, it will help achieve consistently accurate limb and component alignment in obese patients. LEVEL OF EVIDENCE: Level II. PMID- 24799080 TI - The inhibitory effect of a Platycodon root extract on ultraviolet B-induced pigmentation due to a decrease in Kit expression. AB - The signaling of stem cell factor (SCF) through its receptor Kit is known to play an important role in regulating cutaneous melanogenesis. In the course of UVB induced pigmentation, the expression of membrane-bound SCF by epidermal keratinocytes is upregulated at an early phase and subsequently activates neighboring melanocytes via their Kit receptors. In order to identify effective skin-lightening materials, we screened botanical extracts to determine their abilities to diminish Kit expression in melanocytes. A Platycodon root extract was consequently found to have a remarkable inhibitory activity on Kit expression. When the extract was applied to three-dimensional human skin substitutes in vitro and to human skin in vivo after UVB irradiation, their pigmentation was significantly reduced, confirming the substantial contribution of the suppression of SCF/Kit signaling to preventing or inhibiting melanin synthesis. These data demonstrate that a Platycodon root extract is a promising material for a skin-lightening product to improve pigmentation-related diseases. PMID- 24799078 TI - Deciphering the metabolism of undecaprenyl-phosphate: the bacterial cell-wall unit carrier at the membrane frontier. AB - During the biogenesis of bacterial cell-wall polysaccharides, such as peptidoglycan, cytoplasmic synthesized precursors should be trafficked across the plasma membrane. This essential process requires a dedicated lipid, undecaprenyl phosphate that is used as a glycan lipid carrier. The sugar is linked to the lipid carrier at the inner face of the membrane and is translocated toward the periplasm, where the glycan moiety is transferred to the growing polymer. Undecaprenyl-phosphate originates from the dephosphorylation of its precursor undecaprenyl-diphosphate, with itself generated by de novo synthesis or by recycling after the final glycan transfer. Undecaprenyl-diphosphate is de novo synthesized by the cytosolic cis-prenyltransferase undecaprenyl-diphosphate synthase, which has been structurally and mechanistically characterized in great detail highlighting the condensation process. In contrast, the next step toward the formation of the lipid carrier, the dephosphorylation step, which has been overlooked for many years, has only started revealing surprising features. In contrast to the previous step, two unrelated families of integral membrane proteins exhibit undecaprenyl-diphosphate phosphatase activity: BacA and members of the phosphatidic acid phosphatase type 2 super-family, raising the question of the significance of this multiplicity. Moreover, these enzymes establish an unexpected link between the synthesis of bacterial cell-wall polymers and other biological processes. In the present review, the current knowledge in the field of the bacterial lipid carrier, its mechanism of action, biogenesis, recycling, regulation, and future perspective works are presented. PMID- 24799081 TI - Inhibitory effect of selected medicinal plants on the release of pro-inflammatory cytokines in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. AB - The inhibitory activities of the methanol extracts from 20 selected medicinal plants on the release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) were evaluated. The major compound from the most active plant extract was also investigated. The inhibitory effect of the methanol extracts on the release of pro-inflammatory cytokines was tested by incubating PBMCs with the sample and then stimulating by lipopolysaccharide at 0.1 MUg/ml. The level of cytokines was determined using enzyme-linked immunosorbent assay. Among the extracts tested, Andrographis paniculata extract demonstrated the strongest inhibition of interleukin (IL)-1beta, IL-1alpha, and IL-6 release, with IC50 values of 1.54, 1.06, and 0.74 MUg/ml, respectively. The IC50 value of A. paniculata extract was significantly higher than that of andrographolide on IL 1alpha, IL-1beta, and IL-6 (p < 0.001) release. The IC50 values of andrographolide for IL-1alpha, IL-1beta, and IL-6 were significantly higher (p < 0.001) than that of dexamethasone. Cymbopogon citratus and Zingiber officinale strongly inhibited the release of IL-1beta, with IC50 values of 3.22 and 3.17 MUg/ml, respectively. To our knowledge, this is the first report that A. paniculata extract and its major compound andrographolide strongly inhibited the release of IL-1alpha, whereas previous studies only showed their inhibitory effect on the release of another IL-1 family member, IL-1beta. The results show that these extracts and this compound have potential effects as anti-inflammatory agents by inhibiting the release of pro-inflammatory cytokines. PMID- 24799082 TI - Effect of revulsive cultivation on the yield and quality of newly formed sclerotia in medicinal Wolfiporia cocos. AB - Wolfiporia cocos is a well-known medicinal mushroom widely used in China, Japan and other Asiatic countries for its various therapeutic effects. 'Revulsive cultivation' is a newly developed method for promoting sclerotia growth in W. cocos field cultivation in China. In this report, we have systematically examined the effects of 'revulsive cultivation' on the yield and quality of newly formed sclerotia. The results showed that the genetic differences between the cultivated strain and the revulsive strain of T1 used in this study did not affect the formation process of new, large sclerotia in which the mycelia of the cultivated strain grew on pine logs directionally assembled on the revulsive strain. Additionally, 'revulsive cultivation', in which the cultivated strain and the revulsive strain used had the same or different genotypes, could remarkably increase the yield, lower the water content, and increase the water-soluble polysaccharide content of the newly formed sclerotia. Moreover, we observed that the changes in the values of the tested economic traits obtained from different genotype combinations through 'revulsive cultivation' were dissimilar. The correlations of these changes with the original sclerotium-forming ability of the cultivated strains and the genetic differences between the cultivated strain and the revulsive strain were not significant. These results will broaden our knowledge regarding the field cultivation of this medical fungus, stimulate new thinking on the study of sclerotium formation in some sclerotium-forming fungi, and promote further studies on the mechanism of sclerotium formation in W. cocos. PMID- 24799083 TI - Reconstruction after proximal gastrectomy for early gastric cancer in the upper third of the stomach: an analysis of our 13-year experience. AB - BACKGROUND: Fundoplication during esophagogastrostomy (EG) after proximal gastrectomy (PG) is a useful procedure to prevent reflux esophagitis, but it is unclear how much of the remnant stomach should be wrapped around the esophagus. METHODS: We analyzed data from 101 patients who underwent PG for upper third early gastric cancer between 1999 and 2011. In all, 64 patients underwent EG, 25 underwent jejunal interposition (JI), and 12 underwent jejunal pouch interposition (JPI). We compared intraoperative details and postoperative outcomes, and investigated the relationships between the degree of the fundoplication during EG and endoscopic findings. RESULTS: The length of the operation was significantly shorter in the EG group than in the other 2 groups (P < .05), and the intraoperative blood loss was significantly less in the EG group (P < .05). The JI and the JPI groups had significantly greater rates of early complications than did the EG group (P = .01). Reflux esophagitis was present in 22% of patients in the EG group, 8% in the JPI group, and none in the JI group. In the EG group, reflux esophagitis was significantly less common in patients with a >180 degrees wrap of the remnant stomach around the esophagus than in patients with a smaller wrap (P = .0008). The rate of body weight loss was significantly less in the EG group compared with the other 2 groups (P < .05). CONCLUSION: Considering the low invasiveness of the procedure and postoperative outcomes, we consider that EG with a >180 degrees wrap as the optimal reconstructive procedure. PMID- 24799084 TI - Cost effective, robust, and reliable coupled separation techniques for the identification and quantification of phospholipids in complex biological matrices: application to insects. AB - The quantification of phospholipid classes and the determination of their molecular structures are crucial in physiological and medical studies. This paper's target analytes are cell membrane phospholipids, which play an important role in the seasonal acclimation processes of poikilothermic organisms. We introduce a set of simple and cost-effective analytical methods that enable efficient characterization and quantification of particular phospholipid classes and the identification and relative distribution of the individual phospholipid species. The analytical approach involves solid-phase extraction and high performance thin-layer chromatography, which facilitate the separation of particular lipid classes. The obtained fractions are further transesterified to fatty acid methyl esters and subjected to gas chromatography coupled to flame ionization detection, which enables the determination of the position of double bonds. Phospholipid species separation is achieved by high-performance liquid chromatography with mass spectrometry, which gives information about the headgroup moiety and attached fatty acids. The total content of each phospholipids class is assessed by phosphorus determination by UV spectrophotometry. The simultaneous analysis of phosphorus, fatty acid residues, and phospholipid species provides detailed information about phospholipid composition. Evaluation of these coupled methods was achieved by application to an insect model, Pyrrhocoris apterus. High correlation was observed between fatty acid compositions as determined by gas chromatography and high-performance liquid chromatography analysis. PMID- 24799085 TI - Is open tracheotomy performed by residents in otorhinolaryngology a safe procedure? A retrospective cohort study. AB - Surgical or percutaneous tracheotomy is one of the commonest operations in the ENT practice and one of the first procedures to be taught to residents. No study exists that demonstrates the safety of this surgical procedure performed by unexperienced surgeons. The purpose was to compare outcomes of tracheotomies performed by supervised residents and surgeons in terms of postoperative complications and mortality, and identify risk factors for the onset of complications. Retrospective cohort study. Otolaryngology-Head and Neck Surgery Department, University of Florence, Italy. We included all patients undergoing tracheotomy from July 2008 to January 2013 and compared tracheotomies performed by supervised residents or surgeons. During the study period, 304 patients were submitted to tracheotomy. Patients operated by surgeons had a significantly higher number of tracheal rings fracture (p = 0.05), subcutaneous emphysema (p = 0.003) and tracheostomy tube displacement (p = 0.003), while supervised residents had a higher number of tracheitis/pneumonia (p = 0.04) as early complications. Patients operated by supervised residents had a significantly higher number of tube obstructions as late complication (p = 0.04). Using multivariate model, risk factors for early postoperative complications were male sex (p = 0.04) and delayed time to substitution with cuffless tube (p = 0.01), while only a trend to statistical significance was observed for urgent tracheotomies concerning the risk for late postoperative complications (p = 0.08). The current practice where residents perform tracheotomies supervised by a surgeon should not be disheartened. Our study demonstrates that it is safe and does not lead to higher risk of complications nor negatively affects the quality of care. PMID- 24799086 TI - Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. AB - Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs. CONCLUSION: These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI. PMID- 24799087 TI - Reevaluation of the Munro dataset to derive more specific TTC thresholds. AB - The threshold of toxicological concern (TTC) concept is a risk assessment tool for substances present at low oral exposure and lacking hazard data. In the past, several thresholds were elaborated by Munro et al. (1996) and Kroes et al. (2004). For these TTC thresholds, the Cramer class III threshold is based on a broad spectrum of substances, including organophosphates. For organophosphates a separate threshold was elaborated by Kroes et al. (2004), however without adjustment of the Cramer class III threshold. Moreover, reference was made by Munro et al. (2008) that for organohalogens a separate threshold also may apply whereas the EFSA (2012) considers that carbamate substances with anti-choline esterase activity can be included in the threshold for organophosphates. In this paper, a reevaluation of the Munro dataset (original TTC database) was performed, focused on the thresholds for organophosphates including carbamates, organohalogens and remaining Cramer class III substances. This way thresholds for each of these groups are elaborated. As a results of the current reevaluation of the Munro dataset, thresholds for life-time exposure are elaborated for the group of organophosphates including carbamates, the group of organohalogens and the remaining Cramer class III substances, being 0.30, 1.5 and 4.0 MUg/kg bodyweight/day, respectively. PMID- 24799088 TI - Big data bioinformatics. AB - Recent technological advances allow for high throughput profiling of biological systems in a cost-efficient manner. The low cost of data generation is leading us to the "big data" era. The availability of big data provides unprecedented opportunities but also raises new challenges for data mining and analysis. In this review, we introduce key concepts in the analysis of big data, including both "machine learning" algorithms as well as "unsupervised" and "supervised" examples of each. We note packages for the R programming language that are available to perform machine learning analyses. In addition to programming based solutions, we review webservers that allow users with limited or no programming background to perform these analyses on large data compendia. PMID- 24799089 TI - Correction of severe pelvic obliquity using maximum-width segmental sacropelvic screw fixation: an analysis of 20 neuromuscular scoliosis patients. AB - STUDY DESIGN: The present study was a retrospective analysis. OBJECTIVE: The purpose of the study was to evaluate the safety and efficacy of the maximum-width (M-W) segmental sacropelvic fixation technique, comprising iliac screws and/or iliosacral pedicle screws, to correct severe pelvic obliquity. Classic spinal fixation using the Luque-Galveston procedure for the correction of neuromuscular scoliosis may be inadequate to manage severe pelvic obliquities. METHODS: A series of 20 consecutive patients with severe neuromuscular spinopelvic deformities was reviewed by an independent observer. Coronal and sagittal Cobb angle, frontal pelvic obliquity, and trunk shift were measured preoperatively, immediately postoperatively and at final follow-up. RESULTS: All 20 patients underwent spinal fusion with instrumentation extending to the pelvis. Fourteen cases had primary operations, and six patients had undergone previous spinal fusion above the pelvis, requiring extension to the pelvis. The mean age of the patients at surgery was 13 years, and the mean duration of the follow-up period was 36 months. The mean preoperative Cobb angle was 84 degrees (range 56 degrees -135 degrees ), which was corrected to a mean of 41 degrees (range 8 degrees -75 degrees ) postoperatively. At the final follow-up, the mean spinal curve remained at 42 degrees (range 10 degrees -75 degrees ). The mean preoperative pelvic obliquity was 42 degrees (range 15 degrees -105 degrees ), which was corrected by 78 % to 9 degrees (range 0 degrees -49 degrees ) postoperatively, with a pelvic obliquity of 10 degrees (range 2 degrees -49 degrees ) at final follow up. Comparing the results of the present study with results in the literature describing the Luque-Galveston or unit rod techniques, despite patients in the present study having a greater mean pelvic obliquity (42 degrees compared with 21 degrees in the literature), a 78 % correction was still achieved, which is similar and, in certain instances, superior to the results of other published case series (78 % compared with 53 %). CONCLUSIONS: Maximum-width (M-W) segmental sacropelvic fixation, comprising iliosacral screws and/or iliac screws, enables a superior correction of severe pelvic obliquity in patients with neuromuscular scoliosis. PMID- 24799091 TI - Exploration of new second-order nonlinear optical materials of the Cs-Hg-Br-I system. AB - A first example of a Cs-Hg-Br-I system, namely Cs2Hg2Br2I4.H2O (1), has been synthesized by reaction in solution. It belongs to the polar monoclinic space group pc with a = 7.460(5) A, b = 13.458(9) A, c = 8.891(6) A, and beta = 92.448(9) degrees . The basic anionic group in the crystal is non-centrosymmetric [Hg2Br2I4](2-), and the groups are aligned in the same direction in the crystal. As a result, 1 exhibits a phase-matchable second harmonic generation (SHG) response as strong as 6 times that of KH2PO4 (KDP). For the purpose of comparison, the known compound Cs2Hg3I8.H2O (2) was also synthesized and its SHG properties were studied for the first time. Band structure and optical property calculations for the two compounds based on DFT methods were also performed. The comprehensive properties of 1 and 2 as well as their analog, Cs2HgCl2I2, have been compared and discussed. PMID- 24799090 TI - Quasi-static image-based immersed boundary-finite element model of left ventricle under diastolic loading. AB - Finite stress and strain analyses of the heart provide insight into the biomechanics of myocardial function and dysfunction. Herein, we describe progress toward dynamic patient-specific models of the left ventricle using an immersed boundary (IB) method with a finite element (FE) structural mechanics model. We use a structure-based hyperelastic strain-energy function to describe the passive mechanics of the ventricular myocardium, a realistic anatomical geometry reconstructed from clinical magnetic resonance images of a healthy human heart, and a rule-based fiber architecture. Numerical predictions of this IB/FE model are compared with results obtained by a commercial FE solver. We demonstrate that the IB/FE model yields results that are in good agreement with those of the conventional FE model under diastolic loading conditions, and the predictions of the LV model using either numerical method are shown to be consistent with previous computational and experimental data. These results are among the first to analyze the stress and strain predictions of IB models of ventricular mechanics, and they serve both to verify the IB/FE simulation framework and to validate the IB/FE model. Moreover, this work represents an important step toward using such models for fully dynamic fluid-structure interaction simulations of the heart. (c) 2014 The Authors. International Journal for Numerical Methods in Engineering published by John Wiley & Sons, Ltd. PMID- 24799093 TI - Micronuclei and other nuclear anomalies in normal human buccal mucosa cells of oral cancer patients undergoing radiotherapy: a field effect. AB - We evaluated micronuclei and other nuclear anomalies in exfoliated epithelial cells of the oral cavity on the side opposite the lesion targeted by radiotherapy and correlated them with radiation doses. Buccal smears were obtained from oral cancer patients undergoing radiotherapy with a cumulative dose of at least 1000 rad for 3 weeks and from controls matched for age, gender and habits. The exfoliated cells from the mucosa were collected using a cytobrush; smears were prepared, fixed in 80% methanol and stained using the Feulgen plus fast green method. The mean number of micronuclei and other nuclear anomalies/1000 cells was significantly greater in patients undergoing radiotherapy treatment, but the differences were not significant compared to radiation doses. It appears that radiotherapy has a potent clastogenic effect on buccal mucosal cells of oral cancer patients. PMID- 24799092 TI - The effects of frozen tissue storage conditions on the integrity of RNA and protein. AB - Unfixed tissue specimens most frequently are stored for long term research uses at either -80 degrees C or in vapor phase liquid nitrogen (VPLN). There is little information concerning the effects such long term storage on tissue RNA or protein available for extraction. Aliquots of 49 specimens were stored for 5-12 years at -80 degrees C or in VPLN. Twelve additional paired specimens were stored for 1 year under identical conditions. RNA was isolated from all tissues and assessed for RNA yield, total RNA integrity and mRNA integrity. Protein stability was analyzed by surface-enhanced or matrix-assisted laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS, MALDI-TOF-MS) and nano liquid chromatography electrospray ionization tandem mass spectrometry (nLC-ESI MS/MS). RNA yield and total RNA integrity showed significantly better results for -80 degrees C storage compared to VPLN storage; the transcripts that were preferentially degraded during VPLN storage were these involved in antigen presentation and processing. No consistent differences were found in the SELDI TOF-MS, MALDI-TOF-MS or nLC-ESI-MS/MS analyses of specimens stored for more than 8 years at -80 degrees C compared to those stored in VPLN. Long term storage of human research tissues at -80 degrees C provides at least the same quality of RNA and protein as storage in VPLN. PMID- 24799094 TI - Efficacy of Ankaferd Blood Stopper on bone healing in diabetic rats: a stereological and histopathological study. AB - We evaluated the effects of Ankaferd Blood Stopper (ABS) and routine antibiotic prophylaxis (AP) on early healing of bone defects in diabetic rats. We used 48 rats in the study. Diabetes was induced in 24 rats using streptozotocin; the remaining 24 healthy untreated rats served as controls. Twelve of the diabetic rats and 12 of the healthy rats were treated with AP for 3 days before surgery. Bilateral bone defects were created in the mandible of all animals. ABS was applied to the defects on the left sides of the mandibles, while nothing was applied to the right sides. Animals were sacrificed on days 7 and 14 after operation and examined for histopathology and by stereology. The volume of newly formed bone was significantly less in the diabetic rats on both days 7 and 14. Local administration of ABS significantly increased the mean volume of newly formed bone in both diabetic and nondiabetic rats at days 7 and 14. No significant difference in new bone formation was found between AP and ABS treatment in diabetic rats. Both AP and local administration of ABS have beneficial effects on bone healing in diabetic animals. PMID- 24799095 TI - Effects of dietary supplementation of lipid-encapsulated zinc oxide on colibacillosis, growth and intestinal morphology in weaned piglets challenged with enterotoxigenic Escherichia coli. AB - This study was aimed to evaluate the effect of dietary supplementation of lipid encapsulated (coated) zinc oxide ZnO on post-weaning diarrhea (colibacillosis) in weaned piglets challenged with enterotoxigenic Escherichia coli (ETEC). Thirty two 35-day-old weaned piglets were orally challenged with 3 * 10(10) colony forming units of ETEC K88 while eight piglets received no challenge (control). Each eight challenged piglets received a diet containing 100 ppm ZnO (low ZnO), 2500 ppm ZnO (high ZnO) or 100 ppm of lipid (10%)-coated ZnO (coated ZnO) for 7 days; control pigs received the low ZnO diet. Daily gain, goblet cell density in the villi of the duodenum, jejunum and ileum, and villus height in the jejunum and ileum, which decreased due to the challenge, were equally greater in the coated ZnO and high ZnO groups versus low ZnO group. Fecal consistency score, serum interleukin-8 concentration, subjective score of fecal E. coli shedding, and digesta pH in the stomach, jejunum and ileum, which increased due to the challenge, were equally low in the coated ZnO and high ZnO groups versus low ZnO. Results suggest that a low level of coated ZnO might well substitute for a pharmacological level of native ZnO in dietary supplementation to alleviate colibacillosis of weaned piglets. PMID- 24799096 TI - Urgent bilateral endoscopic marsupialization for respiratory distress due to bilateral dacryocystitis in a newborn. AB - We describe an infant with respiratory distress due to bilateral dacryocystoceles and dacryocystitis who was successfully treated with urgent bilateral endoscopic marsupialization. A male infant was brought to our outpatient department 7 days after birth, with red, acutely inflamed swellings near the medial canthal area of both eyes. From birth, there had been bluish swelling near the medial canthal area, and redness and swellings developed within 3 days. On physical examination, the child was afebrile but showed respiratory distress with coarse breathing sound. That day, the infant was admitted and treated with intravenous cefotaxime 150 mg. After withholding oral intake for appropriate preoperative fasting, urgent bilateral probing with endoscopy was done. On endoscopy, huge bilateral congenital dacryocystoceles were found. Because of its huge size, the inferior surface of the cyst was touching the nasal floor, which made probe unable to perforate the wall of dacryocystocele. Therefore, an endoscopy-assisted marsupialization of dacryocystoceles and bicanalicular silicone intubation were performed. Both swellings and erythema subsided within 48 hours postoperatively, and the patient was discharged after 72 hours from treatment. PMID- 24799097 TI - Tympanometric changes and eustachian tube function in patients with hypothyroidism. AB - OBJECTIVE: The aim of this study was to investigate the tympanometric changes and eustachian tube function (ETF) in patients with hypothyroidism. METHODS: Automatic ETF tests were performed and tympanometric measurements were evaluated to assess ETF in 40 patients diagnosed with hypothyroidism and a 40-patient euthyroid control group. Levothyroxine sodium tablet treatment was started in patients with hypothyroidism. After achieving a euthyroid state in these patients, the tympanometric measurements and automatic ETF tests were repeated. RESULTS: When the patient groups (hypothyroid and control) were compared in terms of ETF, a statistically significant ET dysfunction was observed in the hypothyroid patient group (P < 0.01).When hypothyroid patients were evaluated in terms of ETF before and after treatment, whereas 61.3% of cases had ET function before treatment, this ratio increased to 78.8% after treatment. Furthermore, according to pressure and compliance measurements, statistically significant increases were found in the after treatment measurements (P < 0.05). CONCLUSIONS: As a result of this study, we have come to the opinion that hypothyroidism can change tympanometric measurements and also cause ET dysfunction. However, more comprehensive and detailed studies researching the effects of hypothyroidism on tympanometric measurements are needed. PMID- 24799098 TI - The utility of the electric mallet. AB - The aim of this study was to evaluate the efficiency of electrical mallet for tooth extraction evaluating the integrity of fresh sockets walls. From July 2009 to February 2012, 427 hopeless teeth were extracted in 156 patients: 96 males and 60 females, with a mean age of 53.2 +/- 26.4 years. Two hundred fifty teeth were extracted from the maxilla and 177 from the mandible. Extractions were performed using an electrical mallet. It pushed blade in a longitudinal movement along central axis, moving up and down toward the periodontal ligament space in a repetitive manner, providing a driving mechanism of longitudinal movements. Intraoral digital radiographic examinations were performed before and immediately after dental extractions to evaluate the lamina dura setting. No fracture or loss of cortical bone plate was observed in fresh sockets of teeth extracted by electrical mallet. All the alveoli revealed full soft tissue secondary healing 2 weeks after complete root extraction. During the healing period, there were no signs of inflamed tissue or exposed bone in any of the cases. As reported in this clinical study, maximum preservation of the alveolar housing and related gingival structures may be achieved following assisted atraumatic tooth extraction by electrical mallet. PMID- 24799099 TI - Does cone beam computed tomography-derived bone density give predictable data about stability changes of immediately loaded implants?: A 1-year resonance frequency follow-up study. AB - The aim of this clinical study was to evaluate whether preoperative bone density value derived from cone-beam computed tomography (CBCT) gives predictable data about primary and secondary stability characteristics of immediately loaded dental implants under different clinical variables. A total of 77 immediately loaded implants placed in 23 patients were included the study. Bone density values of the implant recipient sites were recorded using CBCT. The maximum insertion torque values (ITVs) of the implants were recorded using a digital torque meter during surgery. Resonance frequency measurements were taken using the Osstell Mentor at 4 time points; immediately after surgery (implant stability quotient [ISQ]0) and after 1 (ISQ1), 3 months (ISQ3), and 12 months (ISQ12) of loading. Data were analyzed statistically. The mean bone density and ITVs of all implants were 565 +/- 81 and 36.8 +/- 3.8 N . cm, respectively. The mean ISQ values were 73.6 +/- 5.8 at baseline, 71.1 +/- 6.5 after 1 month, 74.8 +/- 5.6 after 3 months, and 76.6 +/- 5.1 after 12 months of loading. Statistically significant differences were observed between ISQ0 and ISQ1 (P < 0.001), and ISQ0 and ISQ12 (P < 0.001), but not between ISQ0 and ISQ3 (P > 0.05). In regard to stability changes over time, statistically significant correlations were found between bone density values from CBCT and ISQ follow-up measurements, and between ITV and ISQ follow-up measurements in all examination periods. Thus, it is possible to predict primary and secondary stability characteristics of immediately loaded implants by using preoperative CBCT scan and perioperative ITV. PMID- 24799100 TI - A randomized controlled clinical trial to evaluate blood pressure changes in patients undergoing extraction under local anesthesia with vasopressor use. AB - The control of hypertensive patients' blood pressure and heart rate using vasoconstrictors during surgical procedures under anesthesia is still a major concern in everyday surgical practice. This clinical trial aimed to evaluate the variation of blood pressure and heart rate in nonhypertensive and controlled hypertensive voluntary subjects undergoing oral surgery under local anesthesia with lidocaine hydrochloride and epinephrine at 1:100,000 (Alphacaine; DFL, Brazil), performed in the Oral Surgery Department, Dentistry School, Fluminense Federal University. In total, 25 voluntary subjects were divided into 2 groups: nonhypertensive (n = 15) and controlled hypertensives (n = 10). Blood pressure and heart rate were measured at 4 different times: T0, in the waiting room; T1, after placement of the surgical drapes; T2, 10 minutes after anesthesia injection; and T3, at the end of the surgical procedure. A statistically significant difference (P < 0.05) between the groups was found at times T0 and T2 for the systolic pressure but only at time T0 for the diastolic pressure. The assessment of the heart rate of both groups showed a statistically significant difference (P < 0.05) at time T1. An analysis of the employed anesthetic volume indicated no statistically significant difference (P > 0.05) between the amount administered to nonhypertensive and hypertensive subjects. It was concluded that the local anesthetics studied could safely be used in controlled hypertensive and nonhypertensive patients in compliance with the maximum recommended doses. PMID- 24799101 TI - Oropharyngeal branchial cyst in a young child. AB - Second branchial cleft cysts are almost always located in the neck. Their presence in the oropharynx is extremely rare. An oropharyngeal branchial cyst in a 4-year-old child diagnosed by magnetic resonance and histopathology was presented. Anatomic location and pathological findings indicated the second branchial pouch origin. The cyst was excised transorally. Six months' follow-up of the child was uneventful and there was no recurrence. PMID- 24799102 TI - Establishment of an orthotopic transplantation model of tongue carcinoma. AB - OBJECTIVE: This study aims to establish an orthotopic transplantation model of rabbit tongue carcinoma and study its biological characteristics. METHODS: Tongue carcinoma was induced in purebred New Zealand white rabbits by exposure to 7,12 dimethylbenz[alpha]anthracene and mechanical stimulation. Fresh tumor tissues obtained from the induced tongue carcinoma model were then serially transplanted orthotopically into tongues of healthy rabbits. The tumor formation rate, invasion to surrounding tissues, regional lymph node metastases, and distant organ metastases were investigated. Morphological observation by optical and electron microscopy, immunohistochemical examination, and chromosome analysis were performed. RESULTS: An orthotopic transplantation model of rabbit tongue carcinoma, designated as RSCC-2, was established. The tongue cancer was poorly differentiated squamous cell carcinoma. The tumor cell was hypotetraploid with a chromosome mode of 70. Immunohisto chemical examination showed positive staining for keratin. The tongue carcinoma survived in rabbits for 73 rounds of transplantation, using 465 rabbits in total. The average latent period was 12.5 days, and the average rabbit survival period was 37.5 days. The tumor formation rate was 10% to 20% in the first 20 rounds and increased gradually thereafter. After the 45th transplantation, the tumor formation rate and success rate of preservation in liquid nitrogen reached 100%. Regional lymph node metastases (35%) and lung metastases (20%) occurred after 50 rounds. In the advanced stage, tumors invaded the entire tongue. Animals suffered from weight loss and died of cachexia. CONCLUSIONS: RSCC-2 is the first animal model for orthotopical transplantation of primary tongue carcinoma. It successfully simulates the clinical pathological process of primary tongue cancer in human, provides invaluable insights into the pathogenesis and metastasis mechanisms, and can be useful for evaluating new therapeutics for the treatment of tongue cancer. PMID- 24799103 TI - Dynamic mechanical thermal analysis of maxillofacial prosthetic elastomers: the effect of different disinfecting aging procedures. AB - In this study, dynamic mechanical thermal analysis was used to evaluate the changes that occurred in maxillofacial elastomers subjected to different disinfecting regimens. A commercial polydimethyl siloxane (PDMS) and an experimental chlorinated polyethylene (CPE) were treated with different disinfection procedures for a period that simulates 1 year of clinical service: microwave exposure (D1), hypochlorite solution (D2), neutral soap (D3), and a commercial disinfecting solution (D4). A fifth group was kept in dark storage as control. Dynamic mechanical thermal analysis tests operated in a fixed frequency (1 Hz) over a range of temperatures (-130 degrees C to 20 degrees C for PDMS, -60 degrees C to 120 degrees C for CPE). Loss modulus (G"), storage modulus (G'), and loss factor (tandelta) were recorded as a function of temperature. The obtained glass transition temperature (Tg) values were subjected to statistical analysis. Dynamic mechanical thermal analysis revealed changes in Tg values for both materials, which reflect the possible changes in their chemical and physical structure, after different disinfection procedures. The PDMS and CPE samples seem to have less dense structure maybe because of chain scission reaction that probably occurred during the disinfection procedures. According to statistical analysis, Tg values presented significant changes from the control samples among the different materials and disinfecting procedures. Microwave exposure and hypochlorite solution affect CPE significantly, whereas PDMS exhibited significant changes after being treated with a commercial antimicrobial agent, concerning changes that occurred in Tg. In all cases, Tg values were decreased compared with the untreated samples, which were stiffer, presenting higher Tg and G' values. PMID- 24799104 TI - Relative location of foramen ovale, foramen lacerum, and foramen spinosum in Hartel pathway. AB - Trigeminal neuralgia is a common disease in Chinese people. Minimal invasive transforaminal pathway is widely used in treating trigeminal neuralgia. The Hartel pathway is the most commonly used operation route, but it has potential to injure vessels such as arteria meningea media and the internal carotid artery. We measured the location of operation route, foramen spinosum, and foramen lacerum in a three-dimensional pattern. We found that to protect those 2 vessels, the angle and depth of puncture should be well regulated. The horizontal component of the angle between the needle axis and y axis should be more than 22 degrees in women and 20 degrees in men to avoid the injury of arteria meningea media. And for protecting the internal carotid artery, the depth of puncture should be less than 85 mm for women and 93 mm for men, or less than 9 mm after penetrating the meninges. PMID- 24799105 TI - Evaluation of the peri-implant bone around parallel-walled dental implants with a condensing thread macrodesign and a self-tapping apex: a 10-year retrospective histological analysis. AB - The long-term high percentages of survival and success of dental implants reported in the literature are related mainly to new, innovative implant and thread designs, and new implant surfaces that allow to obtain very good primary and secondary stability in most anatomical and clinical situations, even in low quality and quantity of bone, promoting a more rapid osseointegration. The aim of this retrospective study was a histological and histomorphometrical evaluation of the bone response around implants with a parallel-wall configuration, condensing thread macrodesign, and self-tapping apex, retrieved from man for different causes. A total of 10 implants were reported in the present study, and these implants had been retrieved after a loading period comprised between a few weeks to about 8 years. Mineralized newly formed bone was found at the interface of all the implants, in direct contact with the implant surface, with no gaps or connective fibrous tissue. This bone adapted very well to the microirregularities of the implant surface. Areas of bone remodeling were present in some regions of the interface, with many reversal lines. High bone-implant contact percentages were found. In conclusion, both the macrostructure and the microstructure of this specific type of implant could be very helpful in the long-term high survival and success implant percentages. PMID- 24799106 TI - Angular immediate loading: three-dimensional finite element analysis. AB - OBJECTIVE: The aim of the study was to analyze the stress distribution in the bone around implants under 0, 5, 10, and 20 degrees of loading. DESIGN: Four mandible models, embedded with cylindrical implants with immediate-load angle of 0, 5, 10, and 20 degrees, were analyzed using the software ANSYS 10.0. The von Mises stress of the implant-bone interface mainly including the implant neck as well as the middle and apex areas was calculated when the implants were loaded with 200-N forces. RESULTS: Stress is mainly concentrated in the bone interface of the implant neck. With the loading implant inclining by 20 degrees, the stress concentrated in the neck of the distal side bone interface is of statistical significance (P < 0.05) when compared with the other groups; when inclined by 0 and 5 degrees, there is no statistical significance; when inclined by 10 degrees, there is statistical significance. The stress in the mesial side of the implant bone interface is relatively small, and it has no statistical significance in each corresponding site (P > 0.05). CONCLUSIONS: The immediate load of the implant mainly increases the stress in the cortical bone around the neck of the implant. It is necessary to pay attention to the impact of the stress at the angle greater than 20 degrees or above on the implant neck; the stress in change is not obvious in the middle and apex areas of the implant as well as in the middle and apex areas of the implant under a lateral force within 20 degrees. PMID- 24799107 TI - Hezarfen wings: a lower lateral cartilage-based cartilage suspension technique for the adjustment of nasal tip rotation and projection and the correction of supratip deformity. AB - Nasal tip surgery is one of the most important parts of rhinoplasty to achieve an attractive nose. There are numerous techniques focusing on the correction of nasal tip rotation and projection. In this article, a new cartilage support derived from the cephalic border of lower lateral cartilages is used for the adjustment of tip rotation and projection, whereas improving supratip fullness is presented. Bilaterally harvested cartilage extensions are resembled as bird's wings and dedicated to the wings that were created by the world's first scientist who flew from one continent to another: Hezarfen Ahmed Celebi. Thirty-two patients who underwent open-approach rhinoplasty operation including the abovementioned method were evaluated retrospectively. After performing conventional steps of open approach rhinoplasty, a wing is created by making a cephalic incision parallel to the lateral crural axis leaving the medial attachment intact and then undermined. Then, the cartilage is turned over the midline bilaterally as it acts like a curb by pulling or releasing the wings to adjust to the desired tip rotation and projection and sutured to the repaired upper lateral cartilage roof. Other 2 types of using these wings were asymmetric suturing one of the wings to help in the redirection of deviated nasal tip (n = 12) and suturing each other at midline to support the overlying skin like a tent with supratip deficiency (n = 7). The authors presented here both esthetic and functional outcomes of Hezarfen wings' method that was used for both nasal tip adjustments and supratip support. PMID- 24799108 TI - Third-molar extraction with ultrasound bone surgery: a case-control study. AB - PURPOSE: The aim of this case-control study was to evaluate the postoperative period and healing between 2 surgical methods (traditional and ultrasound bone surgery) that are used for mandibular third-molar extraction. PATIENTS AND METHODS: Fifteen patients with impaction of both of the lower third molars and indications for their extractions were used in this study. Bilateral-mandibular third-molar extractions were performed at the same surgical time: traditional surgery with burrs was used on 1 side (control site), and ultrasound surgery was used on the other side (test [T] site). After surgery, the patients were examined at 7 and 14 days and at 1 and 3 months to evaluate tissue healing. The following was assessed at every follow-up: pain, trismus, swelling, and alveolar bone level. RESULTS: The study included 15 patients, and 30 mandibular third-molar extractions were performed. We found only 1 postoperative complication: 1 patient had alveolitis in the control site. Complete recoveries without any complications were reported in all of the patients at the T sites. CONCLUSIONS: Complete recoveries without any complication were reported in all patients at the T sites. The only disadvantage of the piezoelectric technique was the length of operation time, which was increased by approximately 8 minutes; however, this effect was offset by reducing the morbidity. CLINICAL RELEVANCE: Our preliminary study showed that Piezosurgery is an excellent tool for reducing the risk of complications and improving the postoperative period. PMID- 24799109 TI - Evaluation of maxillary growth: is there any difference using relief incision during palatoplasty? AB - INTRODUCTION: Scar retraction due to exposed bone in palatoplasty is the leading cause of constricted maxilla. Modern techniques have focused on minimizing the effects of scarring by reducing the exposure of the bone area. OBJECTIVE: The objective of the study was to compare the palatal mucoperiosteal detachment with minimal lateral incision, followed by their synthesis, with the maintenance of lateral areas for relaxation (similar to the von Langenbeck technique) and evaluate the transversal development of the maxilla. METHODS: A prospective, randomized study was conducted, in which the molding of the dental arch of 14 pigs in 2 stages (at 1 month and 5 months) was performed. The pigs were divided into 3 groups: group 1 underwent lateral incision of the palate for mucoperiosteal detachment and maintenance of bone exposure; group 2 underwent mucoperiosteal palatal detachment with lateral access and no bone exposure; and group 3, the control animals, did not undergo any surgical procedures. Measurements of the dental arches were compared between the groups to assess differences in the development of the maxillary transverse diameter. RESULTS: There were no animals lost during the study. Group 1 showed greater growth restriction of the transverse diameter of the maxilla (36%) when compared with groups 2 (56%) and 3 (59%). Groups 2 and 3 showed similar transverse maxillary development, with no statistical difference. CONCLUSIONS: The technique of mucoperiosteal detachment without lateral relief incision has the advantage of reducing future morbidity of a constricted maxilla. This study demonstrated that the technique described can reduce rates of maxillary underdevelopment, a significant complication inherent in the procedure for palatoplasty. The lateral incisions reduce maxillary growth by approximately 20% as compared with this technique. Level II of evidence. PMID- 24799110 TI - A simple, effective, and cheap method for obtaining a useful metallic condylar head prosthesis. PMID- 24799111 TI - Orbital fracture and eyeball rupture caused by golf-club injury. AB - We report a case of an orbital fracture and an eyeball rupture caused by a golf club injury. A 75-year-old man was struck in his right eye by a golf club while watching behind his son swinging a hybrid-type golf club at his home. A 70-mm muscle-depth laceration was present in the infraorbital area with active bleeding. Computed tomographic imaging of the face revealed a rupture of the right eyeball; fractures in the superior, medial, lateral, and inferior wall of the right orbit; a fracture in the right zygomaticofrontal junction; and a small amount of pneumocephalus in the parafalx region. Under general anesthesia, evisceration of the right eyeball was performed. Not only golfers but also people just watching or passing by can be injured by an errantly struck golf ball or swung golf club. Elderly people as well as children should be instructed in technique and safety and also be supervised when playing golf. Also, the public should be educated about the risk of eye injuries and the benefits of wearing a protective eyewear. PMID- 24799112 TI - A rare cause of unilateral parotid gland swelling: compensatory hypertrophy due to the aplasia of the contralateral parotid gland. AB - In this clinical report, 3 cases, admitted to the ears, nose, throat outpatient clinic with the complaints of unilateral swelling in the parotid region and facial asymmetry, are presented. In the etiology, contralateral parotid gland aplasia with compensatory hypertrophy and sialosis was detected. With this rare condition, clinical and radiological features of this anomaly are discussed. PMID- 24799113 TI - Middle cerebral artery dolichoectasia with radiologic follow-up. AB - Intracranial dolichoectasia is an angiopathy characterized by dilation, elongation, and tortuosity of the cerebral arteries. It most frequently involves the vertebrobasilar arteries and carotid arteries, whereas a more peripheral location involving the anterior and the middle cerebral arteries (MCAs) is less frequent. We present a male patient with MCA dolichoectasia with radiologic follow-up for 3 years, and no ischemia or intracranial bleeding occurred after the antiplatelet therapy. From the reported case series of MCA dolichoectasia, we suggest that surgical procedure should not be adopted unless accompanied by aneurysm located at dolichoectatic MCA. Moreover, anticoagulation or antiplatelet therapy could be a good treatment of option to prevent ischemic events. PMID- 24799114 TI - Surgical treatment of unilateral condylar hyperplasia with piezosurgery. AB - INTRODUCTION: Unilateral condylar hyperplasia (UCH) is a disorder of unknown etiology mainly seen in growing patients, which results in facial asymmetry. High condylectomy alone or in association with orthognathic surgery can improve the occlusion and the facial aesthetics. MATERIALS AND METHODS: Between 2005 and 2012, a total of 5 patients underwent high condylectomy for UCH using a piezoelectric cutting device. All patients were treated postoperatively with functional rehabilitation. RESULTS: The long-term follow-up showed that all patients had a satisfactory temporomandibular joint articular function associated with stable occlusion without any recurrence of further condylar growth. CONCLUSIONS: High condylectomy in the surgical treatment of unilateral UCH seems to be the procedure of choice in growing patients. The use of a piezoelectric cutting device allows a safe and less invasive high condylectomy. PMID- 24799115 TI - Classic Mediterranean type of epiglottic Kaposi sarcoma. AB - Kaposi sarcoma is a malignant, multifocal, vascular, and low-grade tumor that mostly occurs in mucocutaneous sites. Kaposi sarcoma is usually associated with acquired immunodeficiency syndrome and involves lymphatic nodes and visceral organs. In this report, an 81-year-old man with epiglottic Kaposi sarcoma who screened negative for human immunodeficiency virus is presented. PMID- 24799116 TI - gammadelta T cells restrain extrathymic development of Foxp3+-inducible regulatory T cells via IFN-gamma. AB - Inducible Treg (iTreg) cells generated from Ag-stimulated naive CD4(+) T cells in the periphery play an important role in regulating immune responses. TGF-beta is a key cytokine that promotes this conversion process; however, how this process is regulated in vivo remains unclear. Here, we report that gammadelta T cells play a crucial role in controlling iTreg generation and suppressor function. Ag induced iTreg generation was significantly enhanced in C57BL/6 mice in the absence of gammadelta T cells. Inhibition of iTreg conversion was mediated by IFN gamma produced by activated gammadelta T cells but not by activated CD4(+) T cells. BM chimera experiments further confirmed gammadelta-derived IFN-gamma dependent mechanism in regulating iTreg generation in vivo. Lastly, human peripheral blood gammadelta T cells also interfere with iTreg conversion via IFN gamma. Our results suggest a novel function of gammadelta T cells in limiting the generation of iTreg cells, potentially balancing immunity and tolerance. PMID- 24799117 TI - pQuant improves quantitation by keeping out interfering signals and evaluating the accuracy of calculated ratios. AB - In relative protein abundance determination from peptide intensities recorded in full mass scans, a major complication that affects quantitation accuracy is signal interference from coeluting ions of similar m/z values. Here, we present pQuant, a quantitation software tool that solves this problem. pQuant detects interference signals, identifies for each peptide a pair of least interfered isotopic chromatograms: one for the light and one for the heavy isotope-labeled peptide. On the basis of these isotopic pairs, pQuant calculates the relative heavy/light peptide ratios along with their 99.75% confidence intervals (CIs). From the peptides ratios and their CIs, pQuant estimates the protein ratios and associated CIs by kernel density estimation. We tested pQuant, Census and MaxQuant on data sets obtained from mixtures (at varying mixing ratios from 10:1 to 1:10) of light- and heavy-SILAC labeled HeLa cells or (14)N- and (15)N-labeled Escherichia coli cells. pQuant quantitated more peptides with better accuracy than Census and MaxQuant in all 14 data sets. On the SILAC data sets, the nonquantified "NaN" (not a number) ratios generated by Census, MaxQuant, and pQuant accounted for 2.5-10.7%, 1.8-2.7%, and 0.01-0.5% of all ratios, respectively. On the (14)N/(15)N data sets, which cannot be quantified by MaxQuant, Census and pQuant produced 0.9-10.0% and 0.3-2.9% NaN ratios, respectively. Excluding these NaN results, the standard deviations of the numerical ratios calculated by Census or MaxQuant are 30-100% larger than those by pQuant. These results show that pQuant outperforms Census and MaxQuant in SILAC and (15)N-based quantitation. PMID- 24799118 TI - Methods and preliminary findings of a cost-effectiveness study of glass-ionomer based and composite resin sealant materials after 2 yr. AB - The cost-effectiveness of glass-carbomer, conventional high-viscosity glass ionomer cement (HVGIC) [without or with heat (light-emitting diode (LED) thermocuring) application], and composite resin sealants were compared after 2 yr in function. Estimated net costs per sealant were obtained from data on personnel time (measured with activity sampling), transportation, materials, instruments and equipment, and restoration costs for replacing failed sealants from a community trial involving 7- to 9-yr-old Chinese children. Cost data were standardized to reflect the placement of 1,000 sealants per group. Outcomes were the differences in the number of dentine caries lesions that developed between groups. The average sealant application time ranged from 5.40 min (for composite resin) to 8.09 min (for LED thermocured HVGIC), and the average cost per sealant for 1,000 performed per group (simulation sample) ranged from $US3.73 (for composite resin) to $US7.50 (for glass-carbomer). The incremental cost effectiveness of LED thermocured HVGIC to prevent one additional caries lesion per 1,000 sealants performed was $US1,106 compared with composite resin. Sensitivity analyses showed that differences in the cost of materials across groups had minimal impact on the overall cost. Cost and effectiveness data enhance policymakers' ability to address issues of availability, access, and compliance associated with poor oral-health outcomes, particularly when large numbers of children are excluded from care, in economies where oral health services are still developing. PMID- 24799119 TI - Surveillance of patients identified with fungal mold at a public academic medical center. AB - BACKGROUND: This study describes the epidemiology of patients with fungal mold infection or colonization at a large academic medical center during a period of ongoing construction of a new hospital building. METHODS: This is an observational retrospective cohort study performed at a public academic hospital. We performed focused medical record review of all patients with fungal mold isolated on microbiologic culture over a 3-year period from May 2009 through April 2012. We established case definitions by modifying criteria used in previously published studies. We established 4 categories for invasiveness: proven invasive fungal disease (IFD), probable IFD, clinical infection not meeting IFD criteria, or colonization/contamination. We also established 3 categories for association with our health care facilities: health care associated hospital onset (HO), health care-associated community onset (HACO), or community associated (CA). RESULTS: Of the 188 cases included in the study, 15 (7.9%) and 23 (12.2%) met criteria for proven and probable IFD, respectively. Of the cases, 114 (60.6%) represented contamination or colonization, and 36 (19.1%) had clinical infection not meeting IFD criteria. Epidemiologically, 46 (24.5%) cases were HO, 42 (22.3%) cases were HACO, and 100 (53.2%) cases were CA. CONCLUSION: The surveillance methods we established were helpful for characterizing and monitoring fungal mold infections at the study institution. PMID- 24799121 TI - Adherence to and knowledge of best practices and occupational biohazards among manicurists/pedicurists. AB - BACKGROUND: Unsafe behaviors of the professionals working at health and beauty centers are arousing concern among researchers, especially because of the risk of infections related to occupational health. METHODS: This study involved a survey of 153 manicurists/pedicurists working in beauty salons in Belo Horizonte, Brazil between June 2012 and March 2013. The data were analyzed through descriptive statistics, chi(2) tests, and logistic regression. Participants' knowledge of and adherence to best practices were evaluated based on the median results, and serologic markers for hepatitis B and C were identified. RESULTS: Associations (P < .05) were observed between adherence and workload, biosafety training, and hepatitis B surface antibody (anti-HBs) serology, as well as between knowledge and courses in the area and accidents with sharp instruments. Manicurists who participated in a course on biosafety (63.6%) and were positive for anti-HBs reagents (56.8%) achieved better results on issues of adherence. Those who reported taking a specific course on this topic had good scores on issues of knowledge (60%). Reactivity to hepatitis C antibody was identified in 1.3%, and reactivity to anti-HBs was detected in 53%. CONCLUSIONS: Overall, the participants demonstrated poor knowledge of and adherence to good safety practices and exposure to occupational biohazards, such as contact with blood by accidents with sharp instruments and minimal vaccine protection. PMID- 24799120 TI - Trends in racial/ethnic disparities in influenza vaccination coverage among adults during the 2007-08 through 2011-12 seasons. AB - BACKGROUND: Annual influenza vaccination is recommended for all persons aged >=6 months. The objective of this study was to assess trends in racial/ethnic disparities in influenza vaccination coverage among adults in the United States. METHODS: We analyzed data from the 2007-2012 National Health Interview Survey (NHIS) and Behavioral Risk Factor Surveillance System (BRFSS) using Kaplan-Meier survival analysis to assess influenza vaccination coverage by age, presence of medical conditions, and racial/ethnic groups during the 2007-08 through 2011-12 seasons. RESULTS: During the 2011-12 season, influenza vaccination coverage was significantly lower among non-Hispanic blacks and Hispanics compared with non Hispanic whites among most of the adult subgroups, with smaller disparities observed for adults age 18-49 years compared with other age groups. Vaccination coverage for non-Hispanic white, non-Hispanic black, and Hispanic adults increased significantly from the 2007-08 through the 2011-12 season for most of the adult subgroups based on the NHIS (test for trend, P < .05). Coverage gaps between racial/ethnic minorities and non-Hispanic whites persisted at similar levels from the 2007-08 through the 2011-12 seasons, with similar results from the NHIS and BRFSS. CONCLUSIONS: Influenza vaccination coverage among most racial/ethnic groups increased from the 2007-08 through the 2011-12 seasons, but substantial racial and ethnic disparities remained in most age groups. Targeted efforts are needed to improve coverage and reduce these disparities. PMID- 24799122 TI - Clinical value of spleen-preserving distal pancreatectomy: a case-matched analysis with a special emphasis on the postoperative systemic inflammatory response. AB - BACKGROUND: The impact of splenectomy on outcomes after distal pancreatectomy was assessed in the present study, with a special emphasis on the postoperative systemic inflammatory response. METHODS: Thirty-three patients with spleen preserving distal pancreatectomy-Kimura technique (SPDP group) were compared with a group of distal pancreatectomies with splenectomy (DPS group). The two groups were 1:1 matched for age, gender, co-morbidities and pathology. RESULTS: No differences between the groups were observed regarding the overall/severe/infectious morbidity, pancreatic fistulae and postoperative diabetes rates (P-values >= 0.475). An increased blood loss (P = 0.031) and need for intraoperative transfusions (P = 0.004) was observed in the DPS group. Postoperative platelet count and platelet-to-lymphocyte ratio were significantly higher in the DPS group (P < 0.001). CONCLUSION: Spleen removal during DP is not associated with a higher morbidity but with an increased blood loss and need for intraoperative transfusions. Although the postoperative systemic inflammatory response is higher when the splenectomy is performed, the number of postoperative infectious complications is not influenced. Preservation of the spleen during DP for benign and low-grade malignant tumor of the distal pancreas appears to be worthy and should be the first option whenever is technically feasible and it can be safely achieved. PMID- 24799123 TI - Prevalence of adiposity and associated cardiometabolic risk factors in the Samoan genome-wide association study. AB - OBJECTIVE: To describe the prevalence of obesity-related noncommunicable diseases (NCDs) and associated risk factors in a sample of Samoan adults studied in 2010 as part of a genome-wide assocation study (GWAS) for obesity related traits. METHODS: Anthropometric and biochemical data collected from n = 3,475 participants (n = 1,437 male; n = 2,038 female) aged 24.5 to <65 years were used to describe the prevalence of obesity, diabetes, hypertension, and dyslipidemia within the study sample. One way analysis of variance, chi(2) tests, and binary logistic regression were used to identify differences in disease and risk factor prevalence by 10-year age group, gender, or by census region of residence. RESULTS: Obesity was highly prevalent among the study sample; 64.6% of females and 41.2% of males were obese according to Polynesian cutoffs (BMI >= 32 kg/m(2) ). Females were less likely than males to have hypertension (31.7% vs. 36.7%) but equally likely to have diabetes (17.8% vs. 16.4%). With the exception of obesity and low HDL-cholesterol in females only, there were significant differences in the prevalence of all NCDs and associated risk factors by age group, with the oldest age group (55 to <65 years) most affected. In both sexes, residents of the Apia Urban Area were at significantly greater risk of obesity, diabetes, low HDL cholesterol, and high triglycerides than residents of the more rural Savaii region. CONCLUSIONS: The phenotypic characteristics of this sample provide evidence of a continuation of previously reported temporal trends toward obesity and its associated disorders. Attention must be paid to the critical NCD situation in Samoa. PMID- 24799124 TI - Mass-selected site-specific core-fucosylation of ceruloplasmin in alcohol-related hepatocellular carcinoma. AB - A mass spectrometry-based methodology has been developed to study changes in core fucosylation of serum ceruloplasmin that are site-specific between cirrhosis and hepatocellular carcinoma (HCC). The serum samples studied for these changes were from patients affected by cirrhosis or HCC with different etiologies, including alcohol, hepatitis B virus, or hepatitis C virus. The methods involved trypsin digestion of ceruloplasmin into peptides followed by Endo F3 digestion, which removed most of the glycan structure while retaining the innermost N acetylglucosamine (GlcNAc) and/or core-fucose bound to the peptide. This procedure simplified the structures for further analysis by mass spectrometry, where four core-fucosylated sites (sites 138, 358, 397, and 762) were detected in ceruloplasmin. The core-fucosylation ratio of three of these sites increased significantly in alcohol-related HCC samples (sample size = 24) compared to that in alcohol-related cirrhosis samples (sample size = 18), with the highest AUC value of 0.838 at site 138. When combining the core-fucosylation ratio of site 138 in ceruloplasmin and the alpha-fetoprotein (AFP) value, the AUC value increased to 0.954 (ORsite138 = 12.26, p = 0.017; ORAFP = 3.64, p = 0.022), which was markedly improved compared to that of AFP (AUC = 0.867) (LR test p = 0.0002) alone. However, in HBV- or HCV-related liver diseases, no significant site specific change in core-fucosylation of ceruloplasmin was observed between HCC and cirrhosis. PMID- 24799126 TI - In vitro adsorption of aluminum by an edible biopolymer poly(gamma-glutamic acid). AB - Accumulation of aluminum in human has been reported to be associated with dementia, Parkinson's disease, and Alzheimer's disease. The objectives of this study were to evaluate an edible biopolymer poly(gamma-glutamic acid) (gamma-PGA) for aluminum removal efficiency under in vitro conditions as affected by pH, contact time, aluminum concentration, temperature, ionic strength, and essential metals in both aqueous aluminum solution and simulated gastrointestinal fluid (GIF). A low aluminum adsorption occurred at pH 1.5-2.5, followed by a maximum adsorption at pH 3.0-4.0 and precipitating thereafter as aluminum hydroxide at pH > 4. Adsorption was extremely fast with 81-96% of total adsorption being attained within 1 min, reaching equilibrium in 5-10 min. Kinetic data at low (10 mg/L) and high (50 mg/L) concentrations were well described by pseudo-first-order and pseudo-second-order models, respectively. Equilibrium adsorption isotherms at different temperatures were precisely fitted by both Langmuir and Redlich Peterson models with the maximum adsorption capacities at 25, 37, and 50 degrees C being 35.85, 38.68, and 44.23 mg/g, respectively. Thermodynamic calculations suggested endothermic and spontaneous nature of aluminum adsorption by gamma-PGA with increased randomness at the solid/solution interface. Variation in ionic strengths did not alter the adsorption capacity, however, the incorporation of essential metals significantly reduced the aluminum adsorption by following the order copper > iron > zinc > calcium > potassium. Compared to aqueous solution, the aluminum adsorption from simulated GIF was high at all studied pH (1-4) with Langmuir monolayer adsorption capacity being 49.43 mg/g at 37 degrees C and pH 4. The outcome of this study suggests that gamma-PGA could be used as a safe detoxifying agent for aluminum. PMID- 24799125 TI - Non-tuberculous mycobacterial infections at San Francisco General Hospital. AB - BACKGROUND AND AIMS: The epidemiology of non-tuberculous mycobacteria (NTM) infection is not well defined. We evaluated the trends in incidence of NTM infections at San Francisco General Hospital (SFGH), a large metropolitan county hospital. METHODS: We performed a retrospective review of microbiologic and clinical records of all patients with a positive NTM culture reported from 1993 to 2001. NTM infection was defined by the isolation of >1 NTM from any clinical specimen. Patients were stratified by human immunodeficiency virus (HIV) status. Univariate and multivariate logistic regression were used to identify factors that were independently associated with NTM infection. Trends over time were assessed using Poisson test for trend. RESULTS: During the study period, 25 736 samples from 7395 patients were cultured for mycobacteria. Of these samples, 2853 (11.1%) from 1345 patients (18.2%) were culture positive for NTM. Patient characteristics associated with infection included younger age (P < 0.001), male gender (P < 0.001), White ethnicity compared with Asian and Hispanic (P < 0.001 and P = 0.01, respectively), and HIV positivity (P < 0.001). Overall, NTM infection at SFGH decreased significantly from 319 cases in 1993 to 59 in 2001 (P < 0.001). Mycobacterium avium was predominant in both HIV-positive and HIV negative populations (74.5% and 44.6% of isolates, respectively), and Mycobacterium kansasii was the second most common NTM species isolated. The proportion of other NTM species isolated in these groups differed. CONCLUSION: In contrast to other published studies, time-series analyses show that NTM isolation rates decreased during the study period at SFGH, where NTM was most strongly associated with HIV infection. PMID- 24799127 TI - Examining household asthma management behavior through a microeconomic framework. AB - National guidelines on the effective management of pediatric asthma have been promoted for over 20 years, yet asthma-related morbidity among low-income children remains disproportionately high. To date, household and clinical interventions designed to remediate these differences have been informed largely by a health behavior framework. However, these programs have not resulted in consistent sustained improvements in targeted populations. The continued funding and implementation of programs based on the health behavior framework leads us to question if traditional behavioral models are sufficient to understand and promote adaptation of positive health management behaviors. We introduce the application of the microeconomic framework to investigate potential mechanisms that can lead to positive management behaviors to improve asthma-related morbidity. We provide examples from the literature on health production, preferences, trade-offs and time horizons to illustrate how economic constructs can potentially add to understanding of disease management. The economic framework, which can be empirically observed, tested, and quantified, can explicate the engagement in household-level activities that would affect health and well-being. The inclusion of a microeconomic perspective in intervention research may lead to identification of mechanisms that lead to household decisions with regard to asthma management strategies and behavior. The inclusion of the microeconomic framework to understand the production of health may provide a novel theoretical framework to investigate the underlying causal behavioral mechanisms related to asthma management and control. Adaptation of an economic perspective may provide new insight into the design and implementation of interventions to improve asthma-related morbidity in susceptible populations. PMID- 24799128 TI - The impact of the "Village" model on health, well-being, service access, and social engagement of older adults. AB - BACKGROUND: Villages represent an emerging consumer-driven social support model that aims to enhance the social engagement, independence, and well-being of community-dwelling seniors through a combination of social activities, volunteer opportunities, service referral, and direct assistance. This study aimed to assess the perceived impact of Village membership on factors associated with the likelihood of aging in place. Additionally, the research examines the characteristics and service use of members who benefit the most. METHOD: Perceived impacts of Village membership in the areas of social engagement, service access, health and well-being, and self-efficacy for maintaining independence were assessed through a survey of 282 active Village members from five sites in California. Bivariate and multivariate analyses examined associations between member characteristics, volunteerism, service use, and self reported impacts. RESULTS: Villages have the strongest impact in the area of promoting social engagement and facilitating access to services. Three quarters of the participants report that the Village increases their ability to age in place. Positive impacts were associated with level of Village involvement, but less likely among members who had worse self-reported health. CONCLUSION: Villages represent a promising new model designed to support community-dwelling seniors with a number of positive impacts that may reduce social isolation, improve well-being, and increase confidence aging in place. Villages appear to have the greatest benefit for members who are most involved and fewer positive impacts for members in poor health, prompting questions about the long-term effectiveness of the Village model in helping more frail seniors to age in place. PMID- 24799130 TI - The additive damage model: a mathematical model for cellular responses to drug combinations. AB - Mathematical models to describe dose-dependent cellular responses to drug combinations are an essential component of computational simulations for predicting therapeutic responses. Here, a new model, the additive damage model, is introduced and tested in cases where varying concentrations of two drugs are applied with a fixed exposure schedule. In the model, cell survival is determined by whether cellular damage, which depends on the concentrations of the drugs, exceeds a lethal threshold, which varies randomly in the cell population with a prescribed statistical distribution. Cellular damage is assumed to be additive, and is expressed as a sum of separate terms for each drug. Each term has a saturable dependence on drug concentration. The model has appropriate behavior over the entire range of drug concentrations, and is predictive, given single agent dose-response data for each drug. The proposed model is compared with several other models, by testing their ability to fit 24 data sets for platinum taxane combinations and 21 data sets for various other combinations. The Akaike Information Criterion is used to assess goodness of fit, taking into account the number of unknown parameters in each model. Overall, the additive damage model provides a better fit to the data sets than any previous model. The proposed model provides a basis for computational simulations of therapeutic responses. It predicts responses to drug combinations based on data for each drug acting as a single agent, and can be used as an improved null reference model for assessing synergy in the action of drug combinations. PMID- 24799129 TI - The nerve growth factor receptor CD271 is crucial to maintain tumorigenicity and stem-like properties of melanoma cells. AB - BACKGROUND: Large-scale genomic analyses of patient cohorts have revealed extensive heterogeneity between individual tumors, contributing to treatment failure and drug resistance. In malignant melanoma, heterogeneity is thought to arise as a consequence of the differentiation of melanoma-initiating cells that are defined by cell-surface markers like CD271 or CD133. RESULTS: Here we confirmed that the nerve growth factor receptor (CD271) is a crucial determinant of tumorigenicity, stem-like properties, heterogeneity and plasticity in melanoma cells. Stable shRNA mediated knock-down of CD271 in patient-derived melanoma cells abrogated their tumor-initiating and colony-forming capacity. A genome-wide expression profiling and gene-set enrichment analysis revealed novel connections of CD271 with melanoma-associated genes like CD133 and points to a neural crest stem cell (NCSC) signature lost upon CD271 knock-down. In a meta-analysis we have determined a shared set of 271 differentially regulated genes, linking CD271 to SOX10, a marker that specifies the neural crest. To dissect the connection of CD271 and CD133 we have analyzed 10 patient-derived melanoma-cell strains for cell-surface expression of both markers compared to established cell lines MeWo and A375. We found CD271+ cells in the majority of cell strains analyzed as well as in a set of 16 different patient-derived melanoma metastases. Strikingly, only 2/12 cell strains harbored a CD133+ sub-set that in addition comprised a fraction of cells of a CD271+/CD133+ phenotype. Those cells were found in the label retaining fraction and in vitro deduced from CD271+ but not CD271 knock-down cells. CONCLUSIONS: Our present study provides a deeper insight into the regulation of melanoma cell properties and points CD271 out as a regulator of several melanoma-associated genes. Further, our data strongly suggest that CD271 is a crucial determinant of stem-like properties of melanoma cells like colony formation and tumorigenicity. PMID- 24799131 TI - Computer simulations of cellular group selection reveal mechanism for sustaining cooperation. AB - We present a computer simulation of group selection that is inspired by proto cell division. Two types of replicating molecules, cooperators and defectors, reside inside membrane bound compartments. Cooperators pay a cost for other replicators in the cell to receive a benefit. Defectors pay no cost and distribute no benefits. The total population size fluctuates as a consequence of births and deaths of individual replicators. Replication requires activated substrates that are generated at a constant rate. Our model includes mutation between cooperators and defectors and selection on two levels: within proto-cells and between proto-cells. We find surprising similarities and differences between models with and without cell death. In both cases, a necessary requirement for group selection to favor some level of cooperation is the continuous formation of a minimum fraction of pure cooperator groups. Subsequently these groups become undermined by defectors, because of mutation and selection within cells. Cell division mechanisms which generate pure cooperator groups more efficiently are stronger promoters of cooperation. For example, division of a proto-cell into many daughter cells is more powerful in enhancing cooperation than division into two daughter cells. Our model differs from previous studies of group selection in that we explore a variety of different features and relax several restrictive assumptions that would be needed for analytic calculations. PMID- 24799132 TI - Gold-catalyzed allylation of aryl boronic acids: accessing cross-coupling reactivity with gold. AB - A sp(3)-sp(2) C-C cross-coupling reaction catalyzed by gold in the absence of a sacrificial oxidant is described. Vital to the success of this method is the implementation of a bimetallic catalyst bearing a bis(phosphino)amine ligand. A mechanistic hypothesis is presented, and observable transmetalation, C-Br oxidative addition, and C-C reductive elimination in a model gold complex are shown. We expect that this method will serve as a platform for the development of novel transformations involving redox-active gold catalysts. PMID- 24799133 TI - Central nervous system processing of emotions in children with nocturnal enuresis and attention-deficit/hyperactivity disorder. AB - AIM: Nocturnal enuresis (NE) and attention-deficit/hyperactivity disorder (ADHD) are common in childhood. We analysed the central processing of emotions in children with NE, ADHD, NE + ADHD and controls. METHODS: We examined 13 children with NE, 13 with ADHD, 14 with NE + ADHD and 14 controls. Acoustic evoked potentials were recorded using standardised methodology. For the event-related potentials, positive, negative and neutral pictures were presented and time intervals of 250-450, 450-650 and 650-850 msec evaluated. Hypotheses were tested with repeated-measures analyses of variance. RESULTS: In the frontal region, children with NE showed more intense responses to positive and negative pictures than controls measured with event-related potentials. Viewing positive pictures, children with NE + ADHD differed from children with ADHD in the central and parietal and for all types of stimuli in the parietal region. Children with NE + ADHD elicited the strongest responses. Children with ADHD did not differ from controls. There was an unspecific interaction effect of the acoustic evoked potentials in children with NE compared to the controls. CONCLUSION: Children with NE processed emotions differently from children with ADHD and controls. Children with NE + ADHD processed emotions the most intense, displaying interaction effects of the central nervous system that cannot be explained by each disorder alone. PMID- 24799134 TI - Personality influences temporal discounting preferences: behavioral and brain evidence. AB - Personality traits are stable predictors of many life outcomes that are associated with important decisions that involve tradeoffs over time. Therefore, a fundamental question is how tradeoffs over time vary from person to person in relation to stable personality traits. We investigated the influence of personality, as measured by the Five-Factor Model, on time preferences and on neural activity engaged by intertemporal choice. During functional magnetic resonance imaging (fMRI), participants made choices between smaller-sooner and larger-later monetary rewards. For each participant, we estimated a constant sensitivity discount function that dissociates impatience (devaluation of future consequences) from time sensitivity (consistency with rational, exponential discounting). Overall, higher neuroticism was associated with a relatively greater preference for immediate rewards and higher conscientiousness with a relatively greater preference for delayed rewards. Specifically, higher conscientiousness correlated positively with lower short-term impatience and more exponential time preferences, whereas higher neuroticism (lower emotional stability) correlated positively with higher short-term impatience and less exponential time preferences. Cognitive-control and reward brain regions were more activated when higher conscientiousness participants selected a smaller sooner reward and, conversely, when higher neuroticism participants selected a larger-later reward. The greater activations that occurred when choosing rewards that contradicted personality predispositions may reflect the greater recruitment of mental resources needed to override those predispositions. These findings reveal that stable personality traits fundamentally influence how rewards are chosen over time. PMID- 24799136 TI - Large-scale plastic changes of the brain network in an animal model of neuropathic pain. AB - Pain is a multidimensional experience emerging from the flow of information in the brain. It is reasonable therefore to understand pathological pain in terms of plasticity of the distributed brain network. Recently, we demonstrated that multivariate pattern analysis of fluorodeoxyglucose micro-positron emission tomography (FDG micro-PET) imaging can successfully identify neuropathic pain animals at the individual level by capturing the distributed patterns of the resting-state brain activity (Kim et al., 2014). Here, we aimed to reveal the underlying plastic changes of the distributed brain network that enabled successful discrimination of neuropathic pain. We analyzed FDG micro-PET images in awake rats with spinal nerve ligation (SNL) (SNL group, n=13; sham group, n=10) that were acquired in our previous study. In order to investigate the altered functional connectivity pattern of the brain network, first, we developed a node set search algorithm that defines the optimal node set representing the whole brain in given brain images and constructed resting-state brain networks with defined nodes. Graph theoretical analysis revealed that SNL resulted in decreased small-worldness and more fragmented modular structure compared to sham group. Connectivity pattern analyses showed that regions in the brainstem, sensorimotor cortex, and some part of the prefrontal cortex became highly connected following SNL, whereas the cerebellum and some prefrontal regions showed decreased connections. In addition, we found close relationships between characteristics of connectivity and metabolic changes. Our findings suggest that neuropathic pain is associated with connectional plasticity of the resting-state brain. PMID- 24799135 TI - PUNCH: Population Characterization of Heterogeneity. AB - Neuropsychiatric disorders are notoriously heterogeneous in their presentation, which precludes straightforward and objective description of the differences between affected and typical populations that therefore makes finding reliable biomarkers a challenge. This difficulty underlines the need for reliable methods to capture sample characteristics of heterogeneity using a single continuous measure, incorporating the multitude of scores used to describe different aspects of functioning. This study addresses this challenge by proposing a general method of identifying and quantifying the heterogeneity of any clinical population using a severity measure called the PUNCH (Population Characterization of Heterogeneity). PUNCH is a decision level fusion technique to incorporate decisions of various phenotypic scores, while providing interpretable weights for scores. We provide applications of our framework to simulated datasets and to a large sample of youth with Autism Spectrum Disorder (ASD). Next we stratify PUNCH scores in our ASD sample and show how severity moderates findings of group differences in diffusion weighted brain imaging data; more severely affected subgroups of ASD show expanded differences compared to age and gender matched healthy controls. Results demonstrate the ability of our measure in quantifying the underlying heterogeneity of the clinical samples, and suggest its utility in providing researchers with reliable severity assessments incorporating population heterogeneity. PMID- 24799137 TI - Positive effect of acute mild exercise on executive function via arousal-related prefrontal activations: an fNIRS study. AB - Despite the practical implication of mild exercise, little is known about its influence on executive function and its neural substrates. To address these issues, the present study examined the effect of an acute bout of mild exercise on executive function and attempted to identify potential neural substrates using non-invasive functional near-infrared spectroscopy (fNIRS). Twenty-five young individuals performed a color-word matching Stroop task (CWST) and a two dimensional scale to measure changes of psychological mood states both before and after a 10-minute exercise session on a cycle ergometer at light intensity (30% v(.)o2peak) and, for the control session, without exercise. Cortical hemodynamic changes in the prefrontal area were monitored with fNIRS during the CWST in both sessions. The acute bout of mild exercise led to improved Stroop performance, which was positively correlated with increased arousal levels. It also evoked cortical activations regarding Stroop interference on the left dorsolateral prefrontal cortex and frontopolar area. These activations significantly corresponded with both improved cognitive performance and increased arousal levels. Concurrently, this study provides empirical evidence that an acute bout of mild exercise improves executive function mediated by the exercise-induced arousal system, which intensifies cortical activation in task-related prefrontal sub-regions. PMID- 24799138 TI - Helicobacter pylori infection in Omani children. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection is the most common chronic bacterial infection in humans. Its prevalence in Omani adults and children is not known. OBJECTIVE: To report histology-based H. pylori infection prevalence in Omani children. METHODS: A retrospective study of biopsy proven H. pylori infection in children over a 3 year period in a single center. Age, gender, indication for endoscopy, history of recurrent abdominal pain, and anemia were compared between H. pylori-positive and negative children. RESULTS: Of 143 patients who underwent endoscopy, gastric biopsies were available on 112. The overall prevalence of biopsy proven H. pylori infection was 25%. The prevalence in children with recurrent abdominal pain was 30% compared to 22% in children who underwent endoscopy for other indications (p = .382). The prevalence increased from 7% in children aged <5 years, to 33% in those aged between 5 and 10 years (p = .010). There was no significant difference in the prevalence between the 5-10 years age group (33%) and older age group (29%) (p = .814). There was no significant difference in gender or anemia between the two groups. CONCLUSIONS: This study represents the first reported study on the prevalence of biopsy proven H. pylori infection in Omani children. H. pylori infection prevalence is 25%, is lower than regional and many Arab countries. The prevalence appears to increase till age of 5 years. There was no significant association between H. pylori and recurrent abdominal pain, gender, or anemia. PMID- 24799139 TI - Extensor carpi ulnaris subluxation. PMID- 24799140 TI - Radiation-induced osteosarcoma of the hand: case report. AB - Radiation-associated sarcomas represent less than 5% of all sarcomas and can arise from previously irradiated bone or soft tissue. We report a case of radiation-associated osteosarcoma that developed in the hand of a patient who had previously been treated for synovial sarcoma. Despite aggressive, multimodality treatment, the disease progressed rapidly. This case highlights the need for patients and treating physicians to be aware of this potential complication of radiotherapy to the hand. PMID- 24799141 TI - Silicone proximal interphalangeal joint arthroplasty for primary osteoarthritis using a volar approach. AB - PURPOSE: To evaluate the short-term clinical and radiographic outcome of a silicone proximal interphalangeal (PIP) joint implant using a volar approach in patients with primary osteoarthritis. METHODS: We retrospectively reviewed 36 proximal PIP joints that were replaced with Avanta silicone implants in 26 patients. Inclusion criteria were diagnosis of primary osteoarthrtitis of the PIP joint and failure to respond to conservative treatment. Clinical asessment included range of motion, patient satisfaction, and pain scores. The Quick Disabilities of the Arm, Shoulder, and Hand questionnaire was administered at final follow-up. Radiographs were reviewed for alignment and implant fracture. Complications were also recorded. RESULTS: After an average follow-up of 18 months (range, 12-60 mo), pain relief was markedly reduced in all patients, decreasing from a mean score of 7.2 preoperatively to 0.4 postoperatively. The arc of active motion of the PIP joint improved from 33 degrees to 72 degrees . Satisfaction averaged 4.8 on a 5-point Likert scale, and all patients stated they would repeat the surgery. The median final average Quick-Disabilities of the Arm, Shoulder, and Hand score was 7 (range, 4-12). Radiograph review showed 2 implant fractures at 1 and 2 years after surgery, respectively, but without clinical changes. The average deformity in the coronal plane changed from 12 degrees (range, 8 degrees to 18 degrees ) preoperatively to 4 degrees (range, 3 degrees to 8 degrees ) postoperatively, whereas the average flexion contracture changed from 18 degrees (range, 10 degrees to 30 degrees ) to 0 degrees (all patients achieved full active extension). No other complications were observed. No revision surgery has been needed to date. CONCLUSIONS: The volar approach to PIP joint silicone arthroplasty offers the advantages of maintaining the integrity of the extensor mechanism, providing pain relief, and improving postoperative range of motion with minimal complications. However, further research is needed to determine the long-term efficacy of this implant. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24799142 TI - Proximal row carpectomy versus scaphoid excision and intercarpal arthrodesis: intraoperative assessment and procedure selection. AB - PURPOSE: To demonstrate the relative frequency of degenerative changes of the radiolunate and capitolunate joints in osteoarthritis of the wrist as seen by direct visualization, and to demonstrate the disparity between findings on preoperative radiographs and direct visualization. METHODS: We reviewed 18 consecutive patients who underwent either a proximal row carpectomy (PRC) or a scaphoid excision and 4-corner arthrodesis (SEFCA) for symptomatic degenerative arthritis of the wrist. In each case, the articular surfaces of the radiolunate and capitolunate joints were inspected intraoperatively; based on the relative degree of degenerative changes, either a PRC or an SEFCA was performed. We compared preoperative radiographs and the predicted procedure based on them with intraoperative findings and the procedure actually performed. RESULTS: Of 18 wrists, 15 had more severe degenerative changes on the proximal articular surface of the lunate than on the capitate head and underwent a PRC; the remaining 3 had more severe changes on the capitate head than on the proximal surface of the lunate and underwent an SEFCA. In contrast, preoperative radiographs in 13 of the 18 cases revealed degenerative changes at the capitolunate joint and minimal or no changes at the radiolunate joint. An SEFCA was the predicted procedure in all 13, but was performed in 3. The remaining 10 underwent a PRC. CONCLUSIONS: Preoperative radiographs did not correlate well with intraoperative findings in the assessment of degenerative changes at the radiolunate and capitolunate joints, with changes at the radiolunate joint often underestimated. Our findings contradict the widely held contention that the radiolunate joint is consistently spared in osteoarthritis. The lunate fossa of the radius appears to be consistently spared, but not the proximal surface of the lunate. We recommend intraoperative assessment of the articular surfaces, rather than preoperative radiographs, for selection of the surgical procedure. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24799143 TI - Measurement of upper extremity disability using the Patient-Reported Outcomes Measurement Information System. AB - PURPOSE: Current questionnaires used to measure upper extremity-specific disability can be time-consuming and subject to ceiling effects. The National Institutes of Health developed Patient-Reported Outcomes Measurement Information System (PROMIS) measures based on computer adaptive testing (CAT), a technique that is more efficient and less subject to floor and ceiling effects than traditional questionnaires with a fixed number of questions. This study tested the correlation of the Physical Function-Upper Extremity CAT with the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. METHODS: Patients presenting to our orthopedic outpatient clinic were invited to participate in this observational cross-sectional study between August and October 2013. A study sample of 84 patients completed the QuickDASH and PROMIS Physical Function-Upper Extremity CAT, and 3 other PROMIS measures, as well as the 2-question Pain Self-efficacy Questionnaire and the 2-question Patient Health Questionnaire. RESULTS: A strong correlation was found between QuickDASH and PROMIS Physical Function-Upper Extremity CAT, with a significantly shorter completion time for the latter. CONCLUSIONS: We recommend the PROMIS Upper Extremity CAT because it is valid, reliable, and easy to use, and it provides easy reference to population norms (a score of 50 represents the norm in the United States population, and every 10 points represents a standard deviation from the norm). TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic I. PMID- 24799144 TI - Primary flexor tendon repair in zones 1 and 2: early passive mobilization versus controlled active motion. AB - PURPOSE: To compare early passive mobilization (EPM) with controlled active motion (CAM) after flexor tendon surgery in zones 1 and 2. METHODS: We performed a retrospective analysis of collected data of all patients receiving primary flexor tendon repair in zones 1 and 2 from 2006 to 2011, during which time 228 patients were treated, and 191 patients with 231 injured digits were eligible for study. Exclusion criteria were replantation, finger revascularization, age younger than 16 years, rehabilitation by means other than EPM or CAM, and missing information regarding postoperative rehabilitation. This left 132 patients with 159 injured fingers for analysis. The primary endpoint was the comparison of total active motion (TAM) values 4 and 12 weeks after surgery between the EPM and the CAM protocols. The analysis of TAM measurements under the rehabilitation protocols was conducted using t-tests and further linear modeling. We defined rupture rate and the assessment of adhesion/infection as secondary endpoints. RESULTS: There was a statistically significant difference between the TAM values of the EPM and the CAM protocols 4 weeks after surgery. At 12 weeks, however, there was no significant difference between the 2 protocols. Older age and injuries with finger fractures were associated with lower TAM values. Rupture rates were 5% (CAM) and 7% (EPM), which were not statistically different. CONCLUSIONS: This study showed a favorable effect of CAM protocol on TAM 4 weeks after surgery. The percent rupture rate was slightly lower in the patients with CAM than in the patients with EPM regime. Further studies are required to confirm our results and to investigate whether faster recovery of TAM is associated with shorter time out of work. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 24799145 TI - Course of the radial nerve in relation to the center of rotation of the elbow- the need for a rational safe zone for lateral pin placement. AB - PURPOSE: To investigate the course and variability of the radial nerve along the lateral humerus in relation to the center of rotation of the elbow joint in the context of lateral pin placement for hinged external fixation. METHODS: A total of 95 formalin-fixed upper extremities were dissected. The course of the radial nerve along the lateral aspect of the humerus was measured at 3 landmarks with respect to the center of rotation of the elbow. We analyzed the data and the landmark positions correlated with the length of the humerus. RESULTS: The measured positions of 3 landmarks of the radial nerve in the lateral aspect of the humerus ranged from 19% to 43% of the length of the humerus and were located, on average, 6.0, 9.7, and 13.5 cm from the lateral center of rotation. CONCLUSIONS: These data help predict the humeral course of the radial nerve and define a safe zone for pin implantation. However, because of variability in the course of the radial nerve, a safe zone cannot fully ensure prevention of iatrogenic injury to the nerve. The safest method of pin application remains mini open dissection and visual implantation. CLINICAL RELEVANCE: Based on this cadaveric study, it is not possible to define a rational safe zone. The safest method of pin application for dynamic external fixation of the elbow is to perform a mini-open dissection with direct visualization. PMID- 24799146 TI - Ectopic banking of amputated great toe for delayed thumb reconstruction: case report. AB - Ectopic banking of amputated parts is a recognized technique for delayed replantation of an amputated part when the amputation stump will not permit immediate replantation. This is conventionally performed with the intent of transferring the injured part back to its anatomic position when the amputation stump is more appropriate for replantation. Current warfare conditions have led to a commonly encountered military trauma injury pattern of multiple extremity amputations with protected trunk and core structures. This pattern poses many challenges, including the limit or absence of donor sites for immediate or delayed flap reconstructive procedures. We describe a case in which we ectopically banked the great toe of an amputated lower extremity for delayed thumb reconstruction. PMID- 24799147 TI - Second toe metatarsophalangeal joint transfer for sternoclavicular joint reconstruction. AB - PURPOSE: We describe the anatomical basis for microsurgical reconstruction of the sternoclavicular joint using a vascularized, innervated second metatarsophalangeal joint, the surgical technique, and outcomes in 2 patients. METHODS: We harvested the second metatarsophalangeal joint along with the joint capsule, portions of the metatarsal and phalanx, the flexor sheath and flexor tendon, the extensor sheath and tendon, the first metatarsal artery, and the deep peroneal nerve. This composite tissue was used for reconstruction of an excised sternoclavicular joint following infection or chondrosarcoma. The proximal phalanx was dowel-jointed into the manubrium and fixed with 1 or 2 screws; the metatarsal was plated to the remaining clavicle. The joint was oriented to allow maximal elevation and restricted depression, and the normal mediolateral laxity allowed anterior and posterior movement. Vascular anastomoses were performed to branches of the thoracoacromial axis vessels, and digital nerves were connected to a supraclavicular nerve. RESULTS: Two patients had their excised sternoclavicular joints reconstructed using this technique. Both achieved union at the clavicular and sternal junctions. Both obtained restoration of movement of the sternoclavicular joint and upper limb. One patient developed joint subluxation and pain requiring tendon graft reconstruction of the costoclavicular ligament. CONCLUSIONS: In these 2 cases, the vascularized second toe metatarsophalangeal joint satisfactorily reconstructed the widely excised sternoclavicular joint and costoclavicular ligament and restored function. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24799148 TI - Reference Intervals of Serum Sodium, Potassium, and Chlorine in Chinese Han Population and Comparison of Two ISE Methods. AB - BACKGROUND: Currently there are no reference intervals (RIs) of sodium (Na), potassium (K), and chlorine (Cl) on Chinese population. Two kinds of ion selective electrode (ISE) methods were commonly used to determine K, Na, and Cl levels in China, the difference between these two methods needs to be evaluated. METHODS: A total of 4,524 healthy participants (1,916 males and 2,608 females) between 20-79 years old from six cities in China were selected by strict criteria. Serum K, Na, and CL were tested on Roche Modular analyzers in six assigned laboratories. According to EP-9A2, using Roche Modular analyzer (indirect ISE) as comparative method, Olympus AU 5400 analyzer (indirect ISE) and Johnson&Johnson Fusion 5.1 analyzer (direct ISE) were evaluated. RESULTS: In Chinese population, the RIs for K, Na, and CL are 3.6-5.2, 136-146, and 99-110 mmol/l, respectively. Compared to the Roche indirect ISE method, Johnson direct ISE method showed a positive bias; and Olympus indirect ISE method just showed a very slight bias. CONCLUSION: The RIs of K, Na, and Cl of Han Chinese healthy adult population were found to be smaller than those provided by the manufacturer. By a criteria of biological variations for CV, the differences of Na and K between Roche analyzer and Johnson analyzer were not acceptable for clinical application, while the differences of Na, K, and Cl between Roche and Olympus analyzers were acceptable for clinical application. PMID- 24799149 TI - Saving the Baltic Sea, the inland waters of its drainage basin, or both? spatial perspectives on reducing P-loads in eastern Sweden. AB - Nutrient loads from inland sources to the Baltic Sea and adjacent inland waters need to be reduced in order to prevent eutrophication and meet requirements of the European Water Framework Directive (WFD) and the Baltic Sea Action Plan (BSAP). We here investigate the spatial implications of using different possible criteria for reducing water-borne phosphorous (P) loads in the Northern Baltic Sea River Basin District (NBS-RBD) in Sweden. Results show that most catchments that have a high degree of internal eutrophication do not express high export of P from their outlets. Furthermore, due to lake retention, lake catchments with high P-loads per agricultural area (which is potentially of concern for the WFD) did not considerably contribute to the P-loading of the Baltic Sea. Spatially uniform water quality goals may, therefore, not be effective in NBS-RBD, emphasizing more generally the need for regional adaptation of WFD and BSAP related goals. PMID- 24799150 TI - Psychological measurement in Brazil in the 1920s and 1930s. AB - This article deals with the initial applications of psychological tests in Brazil during the 1920s and 1930s, and it is focused on their use in education under the influence of the New School and the Mental Hygiene movements. Thus, the objective is to highlight the implication of psychology as a "social science" (Rose, 1996), a support to the legitimacy of racial theories in force during that period. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24799151 TI - Overgeneral memory in asylum seekers and refugees. AB - BACKGROUND AND OBJECTIVES: Studies in western samples have shown that post traumatic stress disorder (PTSD) and depression are associated with overgeneral autobiographical memory retrieval. This study assesses whether this association extends to asylum seekers and refugees from diverse cultural backgrounds. We discuss implications for those providing testimony of their experiences when seeking asylum. METHOD: 38 asylum seekers and refugees were recruited through clinics and community groups. Clinical interviews assessed PTSD and depression and participants completed a test of autobiographical memory specificity. RESULTS: When accounting for omissions, participants with PTSD and depression recalled a lower proportion of specific memories. Those with PTSD also failed more frequently to report any memory. LIMITATIONS: The sample did not permit separate evaluation of the effects of PTSD and depression on specificity. CONCLUSIONS: Lower memory specificity observed in people experiencing PTSD and depression in western populations extends to asylum seekers and refugees from diverse cultural backgrounds. This study adds to the literature suggesting that being recognised as a refugee fleeing persecution is more difficult for those with post-traumatic symptoms and depression. PMID- 24799152 TI - Implicit affective evaluation of somatosensory sensations in patients with noncardiac chest pain. AB - BACKGROUND AND OBJECTIVES: Etiological models of noncardiac chest pain (NCCP) stress the importance of abnormal implicit affective evaluations of somatosensory sensations, but this has never been studied empirically. The aim was therefore to assess implicit affective evaluations of somatosensory stimuli in NCCP using an experimental design. METHODS: A total of 34 patients with NCCP, 24 patients with cardiac chest pain, and 46 healthy controls, took part in the study. Participants completed a tactile modification of the Affect Misattribution Procedure (tAMP) and answered self-report measures on anxiety sensitivity, somatosensory amplification, and somatic symptom distress. RESULTS: A 3 * 3-ANOVA revealed that most negative judgments were found in the aversive condition, but this effect was not specific to patients with NCCP. Anxiety sensitivity was positively associated with negative implicit evaluations of aversive tactile stimuli in the tAMP. LIMITATIONS: The task seemed to be too difficult for older participants. Also, future studies should apply clinically more relevant, e.g., heart related, stimuli that are more ecologically valid than the electrical stimulation of the finger used as a proxy for aversive somatosensory sensations here. CONCLUSIONS: Against theoretical assumptions, patients with NCCP do not seem to show a stronger implicit negative interpretation bias concerning somatosensory sensations in comparison to patients either with cardiac chest pain, or without chest pain. Nevertheless, anxiety sensitivity seems to contribute significantly to implicit affective interpretations of somatic sensations. Further studies are required investigating the relevance of implicit interpretative processes for the course of NCCP and distressing somatic symptoms in general. PMID- 24799153 TI - Investigation of central nervous system dysfunction in chronic pelvic pain using magnetic resonance spectroscopy and noninvasive brain stimulation. AB - BACKGROUND: Recent studies demonstrate that chronic pelvic pain is associated with altered afferent sensory input resulting in maladaptive changes in the neural circuitry of pain. To better understand the central changes associated with chronic pelvic pain, we investigated the contributions of critical pain related neural circuits using single-voxel proton magnetic resonance spectroscopy (MRS) and transcranial direct current stimulation (tDCS). METHODS: We measured concentrations of neural metabolites in 4 regions of interest (thalamus, anterior cingulate cortex, primary motor, and occipital cortex [control]) at baseline and after 10 days of active or sham tDCS in patients with chronic pelvic pain. We then compared our results to those observed in healthy controls, matched by age and gender. RESULTS: We observed a significant increase in pain thresholds after active tDCS compared with sham conditions. There was a correlation between metabolite concentrations at baseline and quantitative sensory assessments. Chronic pelvic pain patients had significantly lower levels of NAA/Cr in the primary motor cortex compared with healthy patients. CONCLUSIONS: tDCS increases pain thresholds in patients with chronic pelvic pain. Biochemical changes in pain related neural circuits are associated with pain levels as measured by objective pain testing. These findings support the further investigation of targeted cortical neuromodulatory interventions for chronic pelvic pain. PMID- 24799155 TI - The "no reflow" phenomenon following acute myocardial infarction: mechanisms and treatment options. AB - If 'no reflow' is observed within 45min of reperfusion using balloon angioplasty or stent, it is probably related to microthromboemboli, which may also contribute to the extension of the 'no reflow' zone by converting 'low reflow' areas into necrotic ones even when reperfusion is achieved more than 45min after the onset of coronary occlusion. Since 'no reflow' is noted when 45min of coronary occlusion has elapsed even in the absence of a thrombus, 'no reflow' late after reperfusion is predominantly due to tissue necrosis and unlikely to be resolved unless methods to reduce infarct size are used. Attempts at reducing the intracoronary thrombus burden during a coronary procedure for acute myocardial infarction (AMI) have been shown to reduce 'no reflow' and improve clinical outcome, as has the use of potent antithrombotic agents. Drugs that can reduce infarct size, when given intracoronary or intravenous in conjunction with a coronary intervention during AMI can also reduce 'no reflow' and improve outcomes in patients with AMI. The prognostic importance of 'no reflow' post-AMI is related to its close correspondence with infarct size. Although several imaging and non-imaging methods have been used to assess 'no reflow' or 'low reflow' myocardial contrast echocardiography remains the ideal method for its assessment both in and outside the cardiac catheterization laboratory. PMID- 24799154 TI - Circadian rhythms have broad implications for understanding brain and behavior. AB - Circadian rhythms are generated by an endogenously organized timing system that drives daily rhythms in behavior, physiology and metabolism. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock. The SCN is synchronized to environmental changes in the light:dark cycle by direct, monosynaptic innervation via the retino-hypothalamic tract. In turn, the SCN coordinates the rhythmic activities of innumerable subordinate clocks in virtually all bodily tissues and organs. The core molecular clockwork is composed of a transcriptional/post-translational feedback loop in which clock genes and their protein products periodically suppress their own transcription. This primary loop connects to downstream output genes by additional, interlocked transcriptional feedback loops to create tissue-specific 'circadian transcriptomes'. Signals from peripheral tissues inform the SCN of the internal state of the organism and the brain's master clock is modified accordingly. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body. This overview examines landmark studies in the history of the study of circadian timing system, and highlights our current understanding of the operation of circadian clocks with a focus on topics of interest to the neuroscience community. PMID- 24799157 TI - The MOBID-2 pain scale: reliability and responsiveness to pain in patients with dementia. AB - BACKGROUND: Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) pain scale is a staff-administered pain tool for patients with dementia. This study explores MOBID-2's test-retest reliability, measurement error and responsiveness to change. METHODS: Analyses are based upon data from a cluster randomized trial including 352 patients with advanced dementia from 18 Norwegian nursing homes. Test-retest reliability between baseline and week 2 (n = 163), and weeks 2 and 4 (n = 159) was examined in patients not expected to change (controls), using intraclass correlation coefficient (ICC2.1 ), standard error of measurement (SEM) and smallest detectable change (SDC). Responsiveness was examined by testing six priori-formulated hypotheses about the association between change scores on MOBID 2 and other outcome measures. RESULTS: ICCs of the total MOBID-2 scores were 0.81 (0-2 weeks) and 0.85 (2-4 weeks). SEM and SDC were 1.9 and 3.1 (0-2 weeks) and 1.4 and 2.3 (2-4 weeks), respectively. Five out of six hypotheses were confirmed: MOBID-2 discriminated (p < 0.001) between change in patients with and without a stepwise protocol for treatment of pain (SPTP). Moderate association (r = 0.35) was demonstrated with Cohen-Mansfield Agitation Inventory, and no association with Mini-Mental State Examination, Functional Assessment Staging and Activity of Daily Living. Expected associations between change scores of MOBID-2 and Neuropsychiatric Inventory - Nursing Home version were not confirmed. CONCLUSION: The SEM and SDC in connection with the MOBID-2 pain scale indicate that the instrument is responsive to a decrease in pain after a SPTP. Satisfactory test retest reliability across test periods was demonstrated. Change scores >= 3 on total and subscales are clinically relevant and are beyond measurement error. PMID- 24799158 TI - Evaluation of standardized endodontic paper point tear test in New Zealand white rabbits and comparison between corneal sensitivity followed tear tests. AB - OBJECTIVE: To evaluate endodontic paper point tear test (PPTT) in rabbits and compare changes in corneal touch threshold (CTT) induced by Schirmer tear test (STT) and PPTT. Normal corneal sensitivity recovery time after both tear tests was also measured. Also, mean PPTT and STT values were obtained. METHODS: Tear production of 20 eyes, from 10 rabbits, was evaluated using STT and the PPTT. Central corneal touch threshold was measured by a Cochet-Bonnet esthesiometer before any tear test was performed (zero time), immediately after the test (1 min), and consecutively at 6, 11, 16, and 26 min. Tests were conducted on three consecutive days: Day 1 - control condition, no tear tests performed only the CTT; Day 2 - CTT before and after PPTT; and Day 3 - CTT before and after STT. CTT values were compared using repeated measures ANOVA. RESULTS: Corneal touch threshold was significantly increased for at least 16 min after STT, indicating STT causes corneal discomfort. No difference was found between CTT following PPTT and controls, indicating PPTT caused minimal corneal discomfort. The mean (+/-SD) value for STT was 5.2 +/- 1.0 mm/min and for PPTT was 13.8 +/- 1.5 mm/min. DISCUSSION: The aqueous fraction of rabbit's tears can be successfully measured by PPTT. This report established reference values for PPTT in rabbits. Additionally, the absence of a significant difference in CTT after PPTT compared with controls shows that PPTT is well tolerated by rabbits. Considering the improved comfort (compared with STT), accuracy, and low cost, PPTT is a bona fide method of measuring aqueous tear production in rabbits. PMID- 24799156 TI - Distinct effect of impact rise times on immediate and early neuropathology after brain injury in juvenile rats. AB - Traumatic brain injury (TBI) can occur from physical trauma from a wide spectrum of insults ranging from explosions to falls. The biomechanics of the trauma can vary in key features, including the rate and magnitude of the insult. Although the effect of peak injury pressure on neurological outcome has been examined in the fluid percussion injury (FPI) model, it is unknown whether differences in rate of rise of the injury waveform modify cellular and physiological changes after TBI. Using a programmable FPI device, we examined juvenile rats subjected to a constant peak pressure at two rates of injury: a standard FPI rate of rise and a faster rate of rise to the same peak pressure. Immediate postinjury assessment identified fewer seizures and relatively brief loss of consciousness after fast-rise injuries than after standard-rise injuries at similar peak pressures. Compared with rats injured at standard rise, fewer silver-stained injured neuronal profiles and degenerating hilar neurons were observed 4-6 hr after fast-rise FPI. However, 1 week postinjury, both fast- and standard-rise FPI resulted in hilar cell loss and enhanced perforant path-evoked granule cell field excitability compared with sham controls. Notably, the extent of neuronal loss and increase in dentate excitability were not different between rats injured at fast and standard rates of rise to peak pressure. Our data indicate that reduced cellular damage and improved immediate neurological outcome after fast rising primary concussive injuries mask the severity of the subsequent cellular and neurophysiological pathology and may be unreliable as a predictor of prognosis. PMID- 24799159 TI - Chronic postthoracotomy pain and perioperative ketamine infusion. AB - The objectives of this study were to investigate whether continuous intravenous ketamine during the first 72 hours after thoracotomy could reduce the incidence and intensity of chronic postthoracotomy pain (CPTP) and to define the incidence and risk factors of CPTP. Seventy-eight patients receiving thoracotomy for lung tumor (benign or malignant) were randomly divided into two groups: ketamine group (n = 31) and control groups (n = 47). Patients in the ketamine group received intravenous ketamine 1 mg/kg before incision, followed by 2 MUg/kg/minute infusion for 72 hours plus sufentanil patient-controlled intravenous analgesia after thoracotomy. Patients in the control group received intravenous a 0.9% normal saline and infusion plus sufentanil patient-controlled intravenous analgesia. The solutions patients received were blinded. The numerical rating scale (NRS) pain scores and the incidence and risk factors of CPTP were recorded during the first 6 months after surgery. Compared with control group, the incidence of chronic pain in the ketamine group did not decrease at 2 months (chi(2) = 1.599, P = .206) and 6 months (chi(2) = 0.368, P = .544) after surgery. Postoperative pain scores in the ketamine group were not significantly different from those of the control group patients at 2 months (U = 677.5, P = .593) and 6 months (U = 690.5, P = .680). The incidence of CPTP was 78.2% (61/78) at 2 months and 53.8% (42/78) at 6 months after surgery. Retractor used time (OR = 5.811, P = .002), inadequate acute pain control (NRS >= 5) (OR = 5.425, P = .048), and chemotherapy (OR = 3.784, P = .056) were independent risk factors for chronic postthoracotomy pain. The authors conclude that continuous intravenous ketamine (2 MUg/kg/min) during the first 72 hours after thoracotomy was not beneficial to prevent chronic postthoracotomy pain. The independent risk factors for chronic postthoracotomy pain were retractor used time, inadequate acute pain control, and chemotherapy. PMID- 24799161 TI - Effect of methyl jasmonate on the anthocyanin content and antioxidant activity of blueberries during cold storage. AB - BACKGROUND: The effects of postharvest methyl jasmonate (MeJA) fumigation on total soluble solids (TSS), titratable acidity (TA), ascorbic acid, total phenolic content (TPC), total monomeric anthocyanins (TMAs), individual anthocyanins and antioxidant activity of blueberries stored at 1 degrees C for 28 days were evaluated. Prior to storage, the blueberries were fumigated with 0.05 mmol L(-1) MeJA for 12 h. Control blueberries were subjected to the same conditions but were not exposed to MeJA. RESULTS: MeJA treatment had no adverse effect on TSS and TA and inhibited the decrease in ascorbic acid during storage. MeJA treatment induced an enhancement in TPC on day 21; TPC decreased thereafter. Similarly, a significant increase in TMAs and individual anthocyanins was observed 21 days after MeJA treatment. TPC, TMAs and individual anthocyanins increased in control fruits on day 7 and decreased thereafter. Moreover, MeJA treatment maintained higher levels of antioxidant activity during the entire storage period. CONCLUSION: These results suggest that cold storage enhances TPC, TMAs and individual anthocyanin content during short-term storage. However, postharvest application of MeJA to blueberries enhances TPC, TMAs and individual anthocyanin content during long-term storage. PMID- 24799162 TI - In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring. AB - BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used to increase the flexibility of polyvinyl chloride. DEHP and its active metabolite mono-(2 ethylhexyl) phthalate are detected in many biological fluids during fetal and postnatal life. In rodent models, in utero DEHP exposure has been shown to alter sexual organ development, decrease testosterone and aldosterone production, increase body and epididymal adipose tissue weight, and raise serum lipids and glucose levels in male offspring. OBJECTIVES: The objective of this study is to characterize the effects of in utero DEHP exposure on adipose tissue development and function in male offspring. METHODS: Sprague-Dawley pregnant dams were gavaged 1, 20, 50 or 300 mg DEHP per kg per day from gestational day 14 until birth. RESULTS: Global gene expression analyses of postnatal day 60 male offspring that were exposed in utero to 300 mg DEHP per kg per day revealed increased expression of immune response and inflammation markers, and increased expression of differentiation pathway genes in the epididymal whole-adipose tissue and isolated stromal vascular fraction. C-reactive protein and tumor necrosis factor (TNF) serum levels were increased in the 300 mg DEHP in utero exposed offspring. TNF levels in adipose tissue homogenates were increased in the 50 and 300 mg DEHP in utero-exposed offspring. Immunofluorescence studies revealed focal macrophage infiltration in whole-adipose tissue confirmed by increased CD163 tissue content. CONCLUSIONS: In utero DEHP exposure promotes local adipose tissue inflammation and chronic low-grade systemic inflammation. Moreover, evidence is presented, suggesting that DEHP increases the differentiation capacity of the pre-adipocytes of male offspring without affecting total body weight. PMID- 24799164 TI - Stochastic sampling effects in STR typing: Implications for analysis and interpretation. AB - The analysis and interpretation of forensic STR typing results can become more complicated when reduced template amounts are used for PCR amplification due to increased stochastic effects. These effects are typically observed as reduced heterozygous peak-height balance and increased frequency of undetected alleles (allelic "dropout"). To investigate the origins of these effects, a study was performed using the AmpFlSTR((r)) Identifiler Plus((r)) and MiniFiler((r)) kits to amplify replicates from a dilution series of NIST Human DNA Quantitation Standard (SRM((r)) 2372A). The resulting amplicons were resolved and detected on two different genetic analyzer platforms, the Applied Biosystems 3130xL and 3500 analyzers. Results from our study show that the four different STR/genetic analyzer combinations exhibited very similar peak-height ratio statistics when normalized for the amount of template DNA in the PCR. Peak-height ratio statistics were successfully modeled using the Poisson distribution to simulate pre-PCR stochastic sampling of the alleles, confirming earlier explanations that sampling is the primary source for peak-height imbalance in reduced template dilutions. In addition, template-based pre-PCR sampling simulations also successfully predicted allelic dropout frequencies, as modeled by logistic regression methods, for the low-template DNA dilutions. We discuss the possibility that an accurately quantified DNA template might be used to characterize the linear signal response for data collected using different STR kits or genetic analyzer platforms, so as to provide a standardized approach for comparing results obtained from different STR/CE combinations and to aid in validation studies. PMID- 24799163 TI - Can a relatively low-intensity intervention by health professionals prevent weight gain in mid-age women? 12-Month outcomes of the 40-Something randomised controlled trial. AB - BACKGROUND: Weight gain in perimenopausal women results in increased visceral adipose tissue, leading to metabolic syndrome and associated comorbidities. Despite a high prevalence of weight gain at this life stage, interventions to prevent menopausal obesity are lacking. AIM: To test the effectiveness of an intervention delivered by health professionals using a motivational interviewing (MI) counselling style in preventing weight gain in non-obese (body mass index (BMI) 18.5 and 29.9 kg m(-2)) women in late premenopause. METHODS: In a randomised controlled trial, 54 women (mean (s.d.) age 47.3 (1.8) years; BMI 25.1 (2.4) kg m(-2)) who had menstruated within the preceding 3 months were randomly assigned to an MI intervention (n=28) (five health professional MI counselling sessions) or a self-directed intervention (SDI) (print materials only) (n=26). The primary outcome, body weight (kg) and secondary outcomes (blood lipids, glucose, body fat %, lean mass % and waist circumference) were measured at baseline and postintervention (12 months), and intention-to-treat analysis was conducted. RESULTS: Forty women completed all measures and adhered to all protocols. The weight at 12 months for the MI group of 65.6 kg (95% CI: 64.5; 66.8) was significantly different (P=0.034) from the SDI group of 67.4 kg (95% CI: 66.2; 68.6). When stratified by baseline BMI category, the MI group lost significantly more weight (-2.6 kg; 95% CI: -3.9; -1.2) than the SDI group (-0.1 kg; 95% CI: -1.2; 1.0, P=0.002) for the healthy weight women. The overweight women lost weight regardless of the intervention group, with no between-group difference (-3.5 kg; 95% CI: -6.1, -1.0 and -2.3; 95% CI: -4.1, -0.5, P=0.467). CONCLUSION: This relatively low-intensity intervention, incorporating MI into health professional counselling, not only effectively prevented weight gain but also achieved significant weight loss and decreased diastolic blood pressure. Further refinements are required to optimise outcomes for overweight women. PMID- 24799165 TI - Uncertainty in the number of contributors for the European Standard Set of loci. AB - The effect of masking on the assignment of the number of contributors is assessed for the European Standard Set of loci by simulation. The risk that a two person mixture presents as single source is assessed as 2.6*10(-13), a three person mixture presents as a two person 6.7*10(-4) and a four person mixture presents as a three person 0.165. PMID- 24799166 TI - [Special focus: inflammatory diseases of the eye]. PMID- 24799167 TI - [Basic immunology and current therapeutic concepts in ocular allergy]. AB - BACKGROUND: Ocular allergy belongs to the most common ocular diseases globally. Following clinical phenotype and immunopathogenesis different forms of allergy are distinguished, which require different forms of therapeutic approach. This manuscript reviews the basic immunological processes involved in the development of ocular allergies and current and future therapeutic approaches. METHODS: Results of a literature search in PubMed and our own clinical and experimental experience are presented. RESULTS: In the immunopathogenesis of ocular allergy different immune cells such as dendritic cells, B-cells, T-cells, mast cells, eosinophils and regulatory T-cells are involved. Therapeutic approaches focus on either relief of symptoms using antihistamins or mast cell stabilisers or combinations of both. In severe cases steroids or calcineurin inhibitors are used. DISCUSSION: Despite great progress in the investigation of ocular allergy in the past decade several open questions remain, such as the relation of ocular allergy with dry eye disease. Future therapeutic approaches will likely be based on recently identified new aspects such as lymphangiogenesis and will allow better and potentially causal treatment of ocular allergy. PMID- 24799168 TI - [Seasonal and perennial allergic rhinoconjunctivitis]. AB - Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) as well as intermittent and persistent allergic rhinitis are widespread diseases. Because a combined occurrence of ocular and nasal symptoms is very common the summarising term allergic rhinoconjunctivitis is frequently used. SAC and PAC representing the two acute forms of allergic conjunctivitis account for more than 90 % of all cases of allergic conjunctivitis. Compared to the chronic forms of allergic conjunctivitis their course of disease is milder. Nevertheless because of their high prevalence and the proven influence on patients' quality of life they possess clinical and socioeconomic relevance. Allergic rhinoconjunctivitis is caused by a type 1 IgE-mediated hypersensitivity reaction that is provoked by aeroallergens in the majority of cases. The pathognomonic sign is itching. Besides, typical ocular findings are chemosis, conjunctival injection, watery secretion and lid swelling. Otorhinolaryngologists' findings include rhinorrhea, postnasal drip and sneezing. Problems in breathing through the nose resulting from nasal obstruction can cause impaired nighttime sleep and daytime somnolence. In addition to a reduction of allergen exposure by modification of environment and life style factors, in mild forms of SAC and PAC artificial tears are recommended. Topical antihistamines can generate rapid relief from acute symptoms and itching. Topical mast cell stabilisers however provide long-term effects. Dual action drugs that combine antihistamines and mast cell stabilisers show increased patient compliance due to reduced application frequency. Use of topical steroids should be cautious and only temporary. For prolonged treatment periods unpreserved anti-allergic eye-drops should be preferred. Combined topical antihistamines and new-generation topical nasal steroids often used by otorhinolaryngologists demonstrate a good safety profile without systemic side effects. In summary, allergic rhinoconjunctivitis represents a common disease pattern that can be treated effectively. Once it is diagnosed correctly targeted treatment results in improved patients' quality of life quickly. PMID- 24799169 TI - [Vernal keratoconjunctivitis]. AB - Vernal keratoconjunctivitis (VKC) belongs to the group of allergic eye diseases. The incidence varies considerably, depending on the climate zone. In temperate climates VKC occurs only seasonally, while in hot climates it is mostly all year round and rather more severe. Most commonly boys are affected in the first decade of life. Pathophysiological feature is a dense mixed cellular infiltrate with sometimes extremely thickened epithelium. It shows pronounced capillary proliferation, fibrosis and a thickened extracellular matrix. Inflammatory responses can be divided into IgE-mediated and non-IgE mediated inflammation. The clinical picture is characterised by pronounced subjective symptoms and the emergence of giant papillae, mostly on the upper tarsal conjunctiva. Distinction can be made into a limbal form and a palpebral form. Corneal changes are the most threatening complications with development of corneal erosions and shield ulcers. The therapeutic approach uses mainly drugs to block the release of inflammatory mediators such as histamine. These are usually local antihistamines and dual action preparations. Topical steroids or topical calcineurin inhibitors are only used in more severe situations. The same applies for the use of systemic corticosteroids or new biologics e.g., IgE inhibitors. Surgical therapy is predominantly required for the treatment of corneal complications. In general, VKC usually has a self-limiting course. However, during phases of inflammation with the risk of developing vision-threatening complications therapy is always indicated. PMID- 24799170 TI - [Atopic keratoconjunctivitis]. AB - It is useful to define atopic keratoconjunctivitis (AKC) as a non-infectious inflammatory condition of the ocular surface, which is associated with atopy. The pathogenesis of the disorder is not completely understood. The diagnosis is based on the patient's history and the clinical manifestations. Successful management of AKC, which can become a serious condition, requires a multidisciplinary approach that involves prevention, dermatological care and an adequate ophthalmological treatment algorithm. PMID- 24799171 TI - [Giant papillary conjunctivitis]. AB - Giant papillary conjunctivitis is an inflammation of the conjunctiva, which is associated with immunological-allergic disorders, but is difficult to integrate as a defined type of illness. The deposits of contact lenses are responsible in predisposed wearers. They induce a special immune answer to their biochemical ingredients. In addition, roughness of the superficial corneal layers and the conjunctiva, even without any contact lenses after filtrating glaucoma surgery, leads to mechanically induced papillary formations. In former days these symptoms of building giant papillae were seen mostly in wearers of soft hydrogel contact lenses. Nowadays manufacturers have developed contact lens systems with a variety of material components, with an increase of protein and lipid deposits. In combination with the observed non-compliance of wearers regarding lens exchange and contact lens hygiene, GPC is an issue which should be taken into consideration again. PMID- 24799172 TI - [Allergic contact eczema]. AB - Allergic contact eczema due to type IV reactions are more frequent than irritative eczema in facial skin, particularly in the sensitive periorbital region. Concomitant eczema of different locations is pathognomonic and allows a distinction from seborrhoic dermatitis. Avoidance of allergen exposure is mandatory for an effective treatment; therefore allergological examinations have a very high significance. Patch tests with a wide spectrum of potential allergens have to be included in these tests. Therapeutic regimes include a restrictive use of topical steroids. Substances like calcineurin inhibitors are the first-line therapy in facial atopic dermatitis, in spite of therapeutic effects, they have not yet been approved for other forms of periorbital dermatitis. PMID- 24799173 TI - [Treatment of diabetic macular oedema with the VEGF inhibitors ranibizumab and bevacizumab: conclusions from basic in vitro studies]. AB - Diabetic macular oedema (DMO) which may occur at all stages of diabetic retinopathy (DR) is a severe vision-threatening complication. In most cases, laser treatment does not improve visual acuity. Therefore research in ophthalmology focuses on the improvement of the prognosis of DMO patients with a drug-based DMO therapy. Vascular endothelial growth factor (VEGF) is considered the most important therapeutic target because this growth factor also is the most potent permeability factor affecting the inner retinal barrier formed by endothelial cells (ECs). Compared to its angiogenic stimulation of proliferation and migration of ECs, effects of VEGF on permeability have not been studied in all details. In vitro investigations on the behaviour of primary or immortalised retinal endothelial cells confirmed the key role of VEGF in the regulation of the permeability of the inner retinal barrier. Despite the presence of a variety of other factors found to be elevated in DR, a VEGF-disrupted barrier can be completely restored with the VEGF-inhibiting ranibizumab (Lucentis(r)) and bevacizumab (Avastin(r)) when applied at clinically achievable concentrations. The antibody bevacizumab, but not the antibody fragment ranibizumab, accumulates in both retinal EC and pigment epithelial cells during prolonged treatment. This observation might be relevant because patients are often treated for several years and additional long-term side effects may be recognised in the future. PMID- 24799174 TI - [Statement of the German Ophthalmological Society, the Retina Society and the Professional Association of German Ophthalmologists therapy for choroidal neovascularization in myopia ]. PMID- 24799175 TI - Suitability of the molecular subtyping methods intergenic spacer region, direct genome restriction analysis, and pulsed-field gel electrophoresis for clinical and environmental Vibrio parahaemolyticus isolates. AB - Vibrio parahaemolyticus is the leading cause of infectious illness associated with seafood consumption in the United States. Molecular fingerprinting of strains has become a valuable research tool for understanding this pathogen. However, there are many subtyping methods available and little information on how they compare to one another. For this study, a collection of 67 oyster and 77 clinical V. parahaemolyticus isolates were analyzed by three subtyping methods- intergenic spacer region (ISR-1), direct genome restriction analysis (DGREA), and pulsed-field gel electrophoresis (PFGE)--to determine the utility of these methods for discriminatory subtyping. ISR-1 analysis, run as previously described, provided the lowest discrimination of all the methods (discriminatory index [DI]=0.8665). However, using a broader analytical range than previously reported, ISR-1 clustered isolates based on origin (oyster versus clinical) and had a DI=0.9986. DGREA provided a DI=0.9993-0.9995, but did not consistently cluster the isolates by any identifiable characteristics (origin, serotype, or virulence genotype) and ~ 15% of isolates were untypeable by this method. PFGE provided a DI=0.9998 when using the combined pattern analysis of both restriction enzymes, SfiI and NotI. This analysis was more discriminatory than using either enzyme pattern alone and primarily grouped isolates by serotype, regardless of strain origin (clinical or oyster) or presence of currently accepted virulence markers. These results indicate that PFGE and ISR-1 are more reliable methods for subtyping V. parahemolyticus, rather than DGREA. Additionally, ISR-1 may provide an indication of pathogenic potential; however, more detailed studies are needed. These data highlight the diversity within V. parahaemolyticus and the need for appropriate selection of subtyping methods depending on the study objectives. PMID- 24799177 TI - Ambient pressure aerosol-assisted chemical vapour deposition of (CH3NH3)PbBr3, an inorganic-organic perovskite important in photovoltaics. AB - The inorganic-organic perovskite (CH3NH3)PbBr3, which is potentially important in photovoltaics, has been deposited using aerosol-assisted chemical vapour deposition (AACVD). PMID- 24799176 TI - Activation of extracellular signal-regulated kinase1/2 in the medial prefrontal cortex contributes to stress-induced hyperalgesia. AB - Stressful stimuli can exacerbate persistent pain disorder. However, the underlying mechanism is still unknown. Here, to reveal the underlying mechanism for stressful stimuli-induced hyperalgesia in chronic pain, we investigated the effect of extracellular signal-regulated kinase1/2 (ERK1/2) activation on pain hypersensitivity using single-prolonged stress (SPS) model, complete Freund's adjuvant (CFA) model and SPS + CFA model. The experimental results revealed significantly reduced paw withdrawal threshold in the SPS, CFA, and SPS + CFA group compared with the control group. However, the increased phosphorylation of ERK1/2 in the medial prefrontal cortex (mPFC) was observed in the SPS- or SPS + CFA-exposed group but not the CFA group compared with control group. There was also a significant increase in mPFC ERK1/2 phosphorylation and mechanical allodynia after SPS + CFA treatment compared to SPS or CFA treatment alone. Furthermore, inhibiting ERK1/2 phosphorylation by microinjection of U0126, a MAPK kinase (MEK) inhibitor, into the mPFC attenuated SPS + CFA- and SPS- but not CFA induced mechanical allodynia, anxiety-like behavior, and cognitive impairments. These results suggest that the activation of ERK1/2 in the mPFC may contribute to the process of stress-induced cognitive and emotional disorders, leading to an increase in pain sensitivity. PMID- 24799178 TI - Glyceraldehyde-3-phosphate dehydrogenase is regulated by ferredoxin-NADP reductase in the diatom Asterionella formosa. AB - Diatoms are a widespread and ecologically important group of heterokont algae that contribute c. 20% to global productivity. Previous work has shown that regulation of their key Calvin cycle enzymes differs from that of the Plantae, and that in crude extracts, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) can be inhibited by nicotinamide adenine dinucleotide phosphate reduced (NADPH) under oxidizing conditions. The freshwater diatom, Asterionella formosa, was studied using enzyme kinetics, chromatography, surface plasmon resonance, mass spectrometry and sequence analysis to determine the mechanism behind this GAPDH inhibition. GAPDH interacted with ferredoxin-nicotinamide adenine dinucleotide phosphate (NADP) reductase (FNR) from the primary phase of photosynthesis, and the small chloroplast protein, CP12. Sequences of copurified GAPDH and FNR were highly homologous with published sequences. However, the widespread ternary complex among GAPDH, phosphoribulokinase and CP12 was absent. Activity measurements under oxidizing conditions showed that NADPH can inhibit GAPDH-CP12 in the presence of FNR, explaining the earlier observed inhibition within crude extracts. Diatom plastids have a distinctive metabolism, including the lack of the oxidative pentose phosphate pathway, and so cannot produce NADPH in the dark. The observed down-regulation of GAPDH in the dark may allow NADPH to be rerouted towards other reductive processes contributing to their ecological success. PMID- 24799179 TI - Highly efficient alkane oxidation catalyzed by [Mn(V)(N)(CN)4](2-). Evidence for [Mn(VII)(N)(O)(CN)4](2-) as an active intermediate. AB - The oxidation of various alkanes catalyzed by [Mn(V)(N)(CN)4](2-) using various terminal oxidants at room temperature has been investigated. Excellent yields of alcohols and ketones (>95%) are obtained using H2O2 as oxidant and CF3CH2OH as solvent. Good yields (>80%) are also obtained using (NH4)2[Ce(NO3)6] in CF3CH2OH/H2O. Kinetic isotope effects (KIEs) are determined by using an equimolar mixture of cyclohexane (c-C6H12) and cyclohexane-d12 (c-C6D12) as substrate. The KIEs are 3.1 +/- 0.3 and 3.6 +/- 0.2 for oxidation by H2O2 and Ce(IV), respectively. On the other hand, the rate constants for the formation of products using c-C6H12 or c-C6D12 as single substrate are the same. These results are consistent with initial rate-limiting formation of an active intermediate between [Mn(N)(CN)4](2-) and H2O2 or Ce(IV), followed by H-atom abstraction from cyclohexane by the active intermediate. When PhCH2C(CH3)2OOH (MPPH) is used as oxidant for the oxidation of c-C6H12, the major products are c-C6H11OH, c-C6H10O, and PhCH2C(CH3)2OH (MPPOH), suggesting heterolytic cleavage of MPPH to generate a Mn?O intermediate. In the reaction of H2O2 with [Mn(N)(CN)4](2-) in CF3CH2OH, a peak at m/z 628.1 was observed in the electrospray ionization mass spectrometry, which is assigned to the solvated manganese nitrido oxo species, (PPh4)[Mn(N)(O)(CN)4](-).CF3CH2OH. On the basis of the experimental results the proposed mechanism for catalytic alkane oxidation by [Mn(V)(N)(CN)4](2-)/ROOH involves initial rate-limiting O-atom transfer from ROOH to [Mn(N)(CN)4](2-) to generate a manganese(VII) nitrido oxo active species, [Mn(VII)(N)(O)(CN)4](2-), which then oxidizes alkanes (R'H) via a H-atom abstraction/O-rebound mechanism. The proposed mechanism is also supported by density functional theory calculations. PMID- 24799180 TI - A review of the Tabanus semiargenteus-subgroup as part of the Tabanus bovinus species-group (Diptera: Tabanidae) with the description of two new species for science. AB - The semiargenteus-subgroup of the Tabanus bovinus species group is reviewed. The known distribution area of the three previously known species could be significantly increased. T. semiargenteus Olsufjev, 1937 was for the first time recorded from Syria and Iran, T. olsufjevi Hauser, 1960 from Iraq and Iran and T. sarbazensisJezek, 1990 from Lebanon, Syria, Turkey and Iraq. Two new species are described from this region, Tabanus beieri sp. nov. and T. lintzeni sp. nov. The male of T. sarbazensis is described for the first time. Species of the semiargenteus-subgroup are found in arid mountenous areas from the northern Levant (Lebanon, Syria) through south and east Turkey, northern Iraq and Iran towards Nakhichevan and Armenia with records typically from above 1000m, often even above 2000m. Host records are for the first time presented for the subgroup. Females were either collected on or in direct proximity of large ruminants like donkeys, horses and cows, none of the species was observed to attack man. Detailed diagnostic features as well as a key are presented for the females and males of the five species, two colour plates show the habitus as well as the heads in frontal and lateral view. PMID- 24799181 TI - Efficacy and safety of hexaminolevulinate photodynamic therapy in patients with low-grade cervical intraepithelial neoplasia. AB - OBJECTIVE: Non-surgical therapies are needed to reduce the rate of progression of low-grade cervical intraepithelial neoplasia (CIN 1) to high grade CIN (CIN 2/3). The aim of this study was to assess the efficacy and safety of hexaminolevulinate (HAL) photodynamic therapy (PDT) in the treatment of patients with CIN 1. STUDY DESIGN: This phase IIa prospective double-blind study randomized patients with CIN 1 into three groups: HAL vaginal suppository, placebo vaginal suppository or follow-up only. Patients in the first two groups received HAL or placebo suppositories 5 hours before illumination with 50 J/cm(2) red coherent light (633 nm) using a special light catheter. All patients had a follow up including colposcopy, cytology and human papilloma virus (HPV) testing 3 and 6 months and additional biopsy 6 months after PDT. The main outcome measure was efficacy, defined as complete histologic remission 6 months after PDT. Secondary outcomes were histologic remission 3 months and HPV eradication 6 months after first PDT. RESULTS: Seventy patients were randomized: 47 to HAL, 12 to placebo, 11 to follow up only. After 6 months CIN lesions had cleared in 57% of patients in the HAL-PDT group compared to 25% in the combined control group (per protocol population, P = 0.04). Twenty-six patients (37%) reported 44 adverse events (AEs), of which 40 were mild or moderate. Nineteen treatment-related AEs were reported by 15 patients (32%) in the HAL PDT group, one in the placebo PDT group (8%), and none in the follow-up group. The most common adverse events were local discomfort including mild pain/cramping (11) and leucorrhoea (2). CONCLUSION: HAL PDT shows a favorable efficacy and safety profile and represents a promising alternative to observation and surgical procedures in patients with CIN 1. PMID- 24799182 TI - Aspergillus infections in transplant and non-transplant surgical patients. AB - BACKGROUND: Aspergillus infections are associated commonly with immunocompromised states, such as transplantation and hematologic malignant disease. Although Aspergillus infections among patients having surgery occur primarily in transplant recipients, they are found in non-recipients of transplants, and have a mortality rate similar to that seen among transplant recipients. METHODS: We conducted a retrospective analysis of a prospective data base collected from 1996 to 2010, in which we identified patients with Aspergillus infections. We compared demographic data, co-morbidities, and outcomes in non-transplant patients with those in abdominal transplant recipients. Continuous data were evaluated with the Student t-test, and categorical data were evaluated through chi(2) analysis. RESULTS: Twenty-three patients (11 transplant patients and 12 non-transplant patients) were identified as having had Aspergillus infections. The two groups were similar with regard to their demographics and co-morbidities, with the exceptions of their scores on the Acute Physiology and Chronic Health Evaluation II (APACHE II), of 23.6+/-8.1 points for transplant patients vs. 16.8+/-6.1 points for non-transplant patients (p=0.03); Simplified Acute Physiology Score (SAPS) of 16.6+/-8.3 points vs. 9.2+/-4.1 points, respectively (p=0.02); steroid use 91.0% vs. 25.0%, respectively (p=0.003); and percentage of infections acquired in the intensive care unit (ICU) 27.3% vs. 83.3%, respectively (p=0.01). The most common site of infection in both patient groups was the lung. The two groups showed no significant difference in the number of days from admission to treatment, hospital length of stay following treatment, or mortality. CONCLUSIONS: Although Aspergillus infections among surgical patients have been associated historically with solid-organ transplantation, our data suggest that other patients may also be susceptible to such infections, especially those in an ICU who are deemed to be critically ill. This supports the idea that critically ill surgical patients exist in an immunocompromised state. Surgical intensivists should be familiar with the diagnosis and treatment of Aspergillus infections even in the absence of an active transplant program. PMID- 24799183 TI - Meta-analysis of sequencing studies with heterogeneous genetic associations. AB - Recent advances in sequencing technologies have made it possible to explore the influence of rare variants on complex diseases and traits. Meta-analysis is essential to this exploration because large sample sizes are required to detect rare variants. Several methods are available to conduct meta-analysis for rare variants under fixed-effects models, which assume that the genetic effects are the same across all studies. In practice, genetic associations are likely to be heterogeneous among studies because of differences in population composition, environmental factors, phenotype and genotype measurements, or analysis method. We propose random-effects models which allow the genetic effects to vary among studies and develop the corresponding meta-analysis methods for gene-level association tests. Our methods take score statistics, rather than individual participant data, as input and thus can accommodate any study designs and any phenotypes. We produce the random-effects versions of all commonly used gene level association tests, including burden, variable threshold, and variance component tests. We demonstrate through extensive simulation studies that our random-effects tests are substantially more powerful than the fixed-effects tests in the presence of moderate and high between-study heterogeneity and achieve similar power to the latter when the heterogeneity is low. The usefulness of the proposed methods is further illustrated with data from National Heart, Lung, and Blood Institute Exome Sequencing Project (NHLBI ESP). The relevant software is freely available. PMID- 24799184 TI - Impact of pesticides on plant growth promotion of Vigna radiata and non-target microbes: comparison between chemical- and bio-pesticides. AB - To compare the target and non-target effects of two chemical-pesticides (chlorpyrifos and endosulfan) with that of a bio-pesticide (azadirachtin), Vigna radiata (mung bean) was grown in a randomized pot experiment with recommended and higher application rates of pesticides. Colony counts enumerating specific microbial populations, viz. fungi, Pseudomonas, nitrogen-fixing bacteria, and phosphate-solubilizing microorganisms, were performed. In addition, several plant growth parameters such as root and shoot lengths were also monitored. It was observed that the pesticides exerted a suppressive effect on different microbial communities under study in the initial 30 days period. The bacterial and fungal populations in chlorpyrifos treated plants increased thereafter. Endosulfan resulted in enhancement of fungi and nitrogen-fixing bacteria, although phosphate solubilizing microorganisms were suppressed at higher application rates. Azadirachtin, which is gaining popularity owing to its biological origin, did not result in enhancement of any microbial populations; on the other hand, it had a deleterious effect on phosphate-solubilizing bacteria. This study is the first to evaluate the non-target effects of pesticides with a comparison between chemical- and bio-pesticides, and also stresses the importance of critical investigation of bio-pesticides before their wide spread application in agriculture. PMID- 24799186 TI - Effect of sodium selenite and vitamin E on the renal cortex in rats: an ultrastructure study. AB - This study examined the use of vitamin E to alleviate toxic effects of sodium selenite. Adult male albino rats (n=50) was divided into five groups. Group 1 was control, Groups 2 and 4 were treated with sodium selenite (2 mg/kg) for 2 and 4 weeks, respectively, Groups 3 and 5 were treated with sodium selenite (2 mg/kg) and vitamin E (100 mg/kg) for 2 and 4 weeks, respectively. Renal tissues were studied using anti-BCL2 and examined ultrastructurally. Positive Bax immunoreactivity was detected after 2 and more positive after 4 weeks and nearly all groups improved with co-administration of vitamin E. Ultrastructural study revealed lesions in Bowman's capsule and proximal convoluted tubules. The submicroscopic study revealed damage and necrosis of cortical structures after 2 and 4 weeks, respectively. After 4 weeks, cellular changes were seen, such as vacuolation and moderate degeneration of cells, widening of the urinary space scattered through the cortex with loss of cellular details, formation of apical buds, degeneration, and cellular rupture. Present findings disclosed an ameliorative effect of adding vitamin E to sodium selenite-induced changes in cortical tissues. Clinically, it is advised to add vitamin E to avoid selenium overdose hazards. PMID- 24799187 TI - Adhesion to Y-TZP ceramic: study of silica nanofilm coating on the surface of Y TZP. AB - This study evaluated the influence of silica-based film coatings on the surface of yttrium-stabilized tetragonal zirconia polycrystal (Y-TZP), in particular on the durability of the bond strength between the ceramic and resin cement. Eighty Y-TZP (In-Ceram YZ, Vita) blocks (4 * 4 * 3 mm) were obtained and divided into four groups according to the surface treatments (n = 20): tribochemical silica coating (TBS; Cojet, 3M/ESPE), 5 nm SiO2 nanofilm and silanization (F-5), 500 nm SiO2 nanofilm and silanization (F-500), and 500 nm SiO2 nanofilm + hydrofluoric acid-etching + silanization (F-500HF). Specimens of composite resin (3.25 mm in diameter and 3 mm in height) were cemented to Y-TZP blocks using resin cement (Relyx ARC). Half of the specimens from each group were tested 24 h after adhesion (B: baseline condition), and the other half were subjected to aging (A: storage for 90 days and 10,000 thermal cycles). The specimens were subjected to shear testing (SBS) (1 mm/min). After testing, the surfaces were analyzed with a stereomicroscope and scanning electron microscope. Micromorphologic and elemental chemical analyses of the treated Y-TZP surface were made by X-ray energy dispersive spectroscopy. Bond strength data were statistically analyzed by Kruskal-Wallis/Mann-Whitney tests (alpha = 0.05). The surface treatment showed significant differences for B (p = 0.0001) and A (p = 0.0000) conditions. In both storage conditions, TBS and F-5 groups promoted the significantly highest bond strength. Most of the specimens presented adhesive failure. The X-ray energy dispersive spectroscopy analysis depicted the highest peak of silica in the TBS, F-5, and F-500 groups. The adhesion to zirconia can be improved if the surface receives a 5 nm layer of SiO2 nanofilm or is subjected to sandblasting with silica particles, followed by silanization. PMID- 24799188 TI - All-trans retinoic acid improves goat oocyte nuclear maturation and reduces apoptotic cumulus cells during in vitro maturation. AB - All-trans retinoic acid (t-RA) is a natural component and representative physiologically active metabolite of vitamin A, having multiple physiologic functions. The objective of this study was to evaluate the effect of t-RA on goat oocyte maturation and cumulus cell apoptosis during in vitro maturation (IVM). Immature goat cumulus-oocyte complexes (COCs) were matured in vitro in the absence or presence of t-RA at concentrations of 10 nmol/L, 100 nmol/L and 1000 nmol/L. Oocyte maturation and embryo development were assessed by polar body formation and parthenogenetic activation, respectively. Oocyte survival was checked by Trypan blue staining. Apoptosis of cumulus cells was analyzed by terminal deoxynucleotidyl transferase nick end labeling staining and quantitative real-time PCR. In comparison with the control group, 100 nmol/L and 10 nmol/L t RA significantly improved goat nuclear oocyte maturation and survival (P < 0.05). Addition of 1000 nmol/L t-RA improved nuclear maturation (P < 0.05), but had no effect on survival of goat oocytes. t-RA had no positive effect on goat parthenogenetic embryonic cleavage, blastocyst formation or total cell numbers. However, t-RA inhibits the apoptosis of cumulus cells (P < 0.01). t-RA treatment up-regulated the expression of B-cell lymphoma 2 (BCL-2), catalase (CAT) (P < 0.05) and down-regulated the expression of Caspase-8 (P < 0.05). In conclusion, t RA has positive effects on goat oocyte nuclear maturation and reduces apoptotic cumulus cells during IVM. PMID- 24799189 TI - Charge-transfer complexes and their role in exciplex emission and near-infrared photovoltaics. AB - Charge transfer and interactions at organic heterojunctions (OHJs) are known to have critical influences on various properties of organic electronic devices. In this Research News article, a short review is given from the electronic viewpoint on how the local molecular interactions and interfacial energetics at P/N OHJs contribute to the recombination/dissociation of electron-hole pairs. Very often, the P-type materials donate electrons to the N-type materials, giving rise to charge-transfer complexes (CTCs) with a P(delta+) -N(delta-) configuration. A recently observed opposite charge-transfer direction in OHJs is also discussed (i.e., N-type material donates electrons to P-type material to form P(delta-) N(delta+) ). Recent studies on the electronic structures of CTC-forming material pairs are also summarized. The formation of P(delta-) -N(delta+) -type CTCs and their correlations with exciplex emission are examined. Furthermore, the potential applications of CTCs in NIR photovoltaic devices are reviewed. PMID- 24799190 TI - Peptidoglycan remodeling by the coordinated action of multispecific enzymes. AB - The peptidoglycan (PG) cell wall constitutes the main defense barrier of bacteria against environmental insults and acts as communication interface. The biochemistry of this macromolecule has been well characterized throughout the years but recent discoveries have unveiled its chemical plasticity under environmental stresses. Non-canonical D-amino acids (NCDAA) are produced and released to the extracellular media by diverse bacteria. Such molecules govern cell wall adaptation to challenging environments through their incorporation into the polymer, a widespread capability among bacteria that reveals the inherent catalytic plasticity of the enzymes involved in the cell wall metabolism. Here, we analyze the recent structural and biochemical characterization of Bsr, a new family of broad spectrum racemases able to generate a wide range of NCDAA. We also discuss the necessity of a coordinated action of PG multispecific enzymes to generate adequate levels of modification in the murein sacculus. Finally, we also highlight how this catalytic plasticity of NCDAA-incorporating enzymes has allowed the development of new revolutionary methodologies for the study of PG modes of growth and in vivo dynamics. PMID- 24799191 TI - Drosophila blood cell chemotaxis. AB - Drosophila melanogaster contains a population of blood cells called hemocytes that represent the functional equivalent of vertebrate macrophages. These cells undergo directed migrations to disperse during development and reach sites of tissue damage or altered self. These chemotactic behaviors are controlled by the expression of PDGF/Vegf-related ligands in developing embryos and local production of hydrogen peroxide at wounds. Recent work reveals that many molecules important in vertebrate cell motility, including integrins, formins, Ena/VASP proteins and the SCAR/WAVE complex, have a conserved function in these innate immune cells. The use of this model organism has elucidated how damage signals are activated by calcium signaling during inflammation and that the steroid hormone ecdysone activates immune competence at key developmental stages. PMID- 24799192 TI - Impacts of hypersaline acclimation on the acute toxicity of the organophosphate chlorpyrifos to salmonids. AB - Acclimation to hypersaline conditions enhances the acute toxicity of certain thioether organophosphate and carbamate pesticides in some species of euryhaline fish. As the organophosphate chlorpyrifos is commonly detected in salmonid waterways, the impacts of hypersaline conditions on its toxicity were examined. In contrast to other previously examined pesticides, time to death by chlorpyrifos was more rapid in freshwater than in hypersaline water (16ppth). The median lethal time (LT50) after 100MUg/L chlorpyrifos exposure was 49h (95% CI: 31-78) and 120h (95% CI: 89-162) for rainbow trout (Oncorhynchus mykiss) in freshwater and those acclimated to hypersaline conditions, respectively. Previous studies with hypersaline acclimated fish indicated induction of xenobiotic metabolizing enzymes that may detoxify chlorpyrifos. In the current study, chlorpyrifos metabolism was unaltered in liver and gill microsomes of freshwater and hypersaline acclimated fish. Acetylcholinesterase inhibition in brain and bioavailability of chlorpyrifos from the aqueous exposure media were also unchanged. In contrast, mRNA expression of neurological targets: calcium calmodulin dependent protein kinase II delta, chloride intracellular channel 4, and G protein alpha i1 were upregulated in saltwater acclimated fish, consistent with diminished neuronal signaling which may protect animals from cholinergic overload associated with acetylcholinesterase inhibition. These results indicate targets other than acetylcholinesterase may contribute to the altered toxicity of chlorpyrifos in salmonids under hypersaline conditions. PMID- 24799193 TI - Genotoxic potential of several naphthenic acids and a synthetic oil sands process affected water in rainbow trout (Oncorhynchus mykiss). AB - The exploitation of oil sands has raised major environmental concerns, particularly regarding the presence of high concentration in contaminants such as polycyclic aromatic hydrocarbons (PAHs) and naphthenic acids (NAs) in oil sands process-affected water (OSPW). The purpose of this study was, first to evaluate the genotoxic impact of OSPW-related compounds such as NAs and PAHs in a salmonid species and secondly to assess if OSPW exposure leads to genotoxicity. For this purpose, rainbow trout hepatocytes were exposed in vitro to environmentally relevant concentrations of synthetic NAs, naphtalene, benzo(a)pyrene, and extracts of synthetic OSPW (generated by a laboratory bitumen extraction) and of oil sands leaching water (OSLW, mimicking leaching of oil sands in river water). Primary DNA damage was assessed by the formamidopyrimidine-DNA glycolyase (Fpg) modified comet assay. Genotoxicity was observed in hepatocytes exposed to several NAs, mixture of them, OSPW and OSLW extracts. The chemical structure of NAs influences the genotoxicity potential: among the NAs tested, the most cyclic NA was the most genotoxic. It also appears that genotoxicity was more marked for OSPW than for OSLW. Because exposure to OSPW led to oxidative DNA damage, while after exposure to several NAs, these types of DNA damage were limited, the NAs tested in this study could not be qualified as the only major contaminants responsible for OSPW genotoxicity. Notwithstanding, it should be noteworthy that exposure to NAs resulted in genotoxic impact at concentrations lower than those documented by literature for fresh OSPW. Further research is needed to explore the relationships between the chemical structure of NAs and their genotoxicity in the light of the distribution of NAs in fresh OSPW samples as well as in surface waters. PMID- 24799194 TI - Antimicrobial polyurethane thermosets based on undecylenic acid: synthesis and evaluation. AB - In the present study, plant oil-derived surface-modifiable polyurethane thermosets are presented. Polyol synthesis is carried out taking advantage of thiol-yne photopolymerization of undecylenic acid derivatives containing methyl ester or hydroxyl moieties. The prepared methyl ester-containing polyurethanes allow surface modification treatment to enhance their hydrophilicity and impart antimicrobial activity through the following two steps: i) grafting poly(propylene glycol) monoamine (Jeffamine M-600) via aminolysis and ii) Jeffamine M-600 layer complexation with iodine. The antimicrobial activity of the iodine-containing polyurethanes is demonstrated by its capacity to inhibit the growth of Staphylococcus aureus, and Candida albicans in agar media. PMID- 24799195 TI - Prosurvival function of the cellular apoptosis susceptibility/importin-alpha1 transport cycle is repressed by p53 in liver cancer. AB - Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin alpha1 (imp-alpha1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-alpha1 transport cycle by RNAi in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples (r=0.463; P<0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53-/- versus p53+/+) indicated higher protein expression of CAS and imp alpha1 in p53-/- tumors. Consistent with a role of p53 in regulating the CAS/imp alpha1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner. CONCLUSION: The CAS/imp-alpha1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-alpha1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis. PMID- 24799197 TI - Effects of implant neck design on primary stability and overload in a type IV mandibular bone. AB - This study investigates the effect of implant neck design on primary stability and overload using 3D finite element analysis. Four commercial dental implants and mandibular segments are created. Various parameters including the osseointegration condition (non-osseointegration and full osseointegration), force direction (vertical and horizontal), and cortical bone thickness (Tc = 0.3, 0.5, and 1 mm) are considered. The vertical and horizontal forces, 500 N and 250 N, are statically applied at the top of the platform, respectively. Micromotion and von Mises stress are employed to evaluate the risk of osseointegration and bone fatigue before osseointegration condition. After osseointegration, the principal stress is used to analyze the bone overload. Maximal von Mises stress and micromotion of the peri-implant bone decreased as cortical bone thickness increased. Horizontal force induces stress concentration in the bone around the implant neck easier than that of vertical force, and it may result in crestal bone loss. Thinner cortical bone should avoid dental implantation because it causes a noteworthy larger micromotion and stress concentration in cortical bone in particular Tc less than 0.3 mm. PMID- 24799196 TI - Changes in cochlear PMCA2 expression correlate with the maturation of auditory sensitivity. AB - The plasma membrane Ca(2+) ATPase 2 (PMCA2) is necessary for auditory transduction and serves as the primary Ca(2+) extrusion mechanism in auditory stereocilia bundles. To date, studies examining PMCA2 in auditory function using mutant mice have focused on the phenotype of late adolescent and adult mice. Here, we focus on the changes of PMCA2 in the maturation of auditory sensitivity by comparing auditory responses to RNA and protein expression levels in haploinsufficient PMCA2 and wild-type mice from P16 into adulthood. Auditory sensitivity in wild-type mice improves between P16 and 3 weeks of age, when it becomes stable through adolescence. In haploinsufficient mice, there are frequency-dependent loss of sensitivity and subsequent recovery of thresholds between P16 and adulthood. RNA analysis demonstrates that alpha-Atp2b2 transcript levels increase in both wild-type and heterozygous cochleae between P16 and 5 weeks. The increases reported for the alpha-Atp2b2 transcript type during this stage in development support the requisite usage of this transcript for mature auditory transduction. PMCA2 expression also increases in wild-type cochleae between P16 and 5 weeks suggesting that this critical auditory protein may be involved in normal maturation of auditory sensitivity after the onset of hearing. We also characterize expression levels of two long noncoding RNA genes, Gm15082 (lnc82) and Gm15083 (lnc83), which are transcribed on the opposite strand in the 5' region of Atp2b2 and propose that the lnc83 transcript may be involved in regulating alpha-Atp2b2 expression. PMID- 24799198 TI - Betanin attenuates paraquat-induced liver toxicity through a mitochondrial pathway. AB - We attempted to determine whether betanin (from natural pigments) that has anti oxidant properties would be protective against paraquat-induced liver injury in Sprague-Dawley rats. Paraquat was injected intraperitoneally into rats to induce liver toxicity. The rats were randomly divided into four groups: a control group, a paraquat group, and two groups that received betanin at doses of 25 and 100mg/kg/day three days before and two days after they were administered paraquat. We evaluated liver histopathology, serum liver enzymatic activities, oxidative stress, cytochrome P450 (CYP) 3A2 mRNA expression, and mitochondrial damage. The rats that were injected with paraquat incurred liver injury, evidenced by histological changes and elevated serum aspartate aminotransferase and alanine aminotransferase levels; paraquat also led to oxidative stress, an increase of cytochrome P450 3A2 mRNA expression, and mitochondrial damage, indicated by mitochondrial membrane swelling, reduced mitochondrial cytochrome C, and apoptosis-inducing factor protein levels. Pathological damage and all of the above mentioned markers were lesser in the animals treated with betanin than in those who received paraquat alone. Betanin had a protective effect against paraquat-induced liver damage in rats. The mechanism of the protection appears to be the inhibition of CYP 3A2 expression and protection of mitochondria. PMID- 24799199 TI - Protective effect of N-acetylcysteine against DNA damage and S-phase arrest induced by ochratoxin A in human embryonic kidney cells (HEK-293). AB - N-acetylcysteine (NAC) has recently gained particular interest as a beneficial antioxidant. This study investigated the protective effects of NAC against ochratoxin A (OTA)-induced DNA damage and S-phase arrest in human embryonic kidney cells (HEK-293). OTA exposure results in nephrotoxicity, hepatotoxicity as well as immunotoxicity; and, in the present study, the toxicity of OTA toward HEK 293 cells was explored by analyzing the involvement of the oxidative pathway. It was found that OTA treatment led to oxidative damage; meanwhile, OTA treatment induced significant DNA damage and S-phase arrest by down-regulating cyclin A2, cyclin E1, and CDK2 expression. However, NAC pretreatment alleviated OTA-induced ROS overproduction, the loss of mitochondrial membrane potential (DeltaPsim), and the decrease in superoxide dismutase (SOD) activity. NAC pretreatment was also discovered to attenuate OTA-induced DNA damage using the comet assay and by determining the expression of gamma-H2AX. In addition, NAC pretreatment partly ameliorated OTA-induced S-phase arrest by preventing the down-regulation of cyclin A2, cyclin E1 and CDK2 expression in HEK-293 cells. All of these results demonstrated that oxidative damage was involved in OTA-induced DNA damage and cell cycle arrest in HEK-293 cells. Therefore, NAC has the potential to reverse the DNA damage and S-phase arrest induced by OTA. PMID- 24799200 TI - Characterization and antioxidant activities of degraded polysaccharides from two marine Chrysophyta. AB - Water-soluble polysaccharides from Pavlova viridis and Sarcinochrysis marina Geitler (P0 and S0, respectively) and their degradation fragments (P1, P2, S1, S2 and S3) were screened for their antioxidant activity using 1,1-diphenyl-2 picrylhydrazyl (DPPH), hydroxyl-radical (OH) scavenging, lipid peroxidation (LPO) inhibition and the mouse red blood cells (RBCs) hemolysis assay. The physicochemical properties of the polysaccharides were also determined. Chemical analysis showed the presence of sulfate groups and uronic acids. Degradation increased the sulfate group content, but also, in part, damaged the uronic acids. FTIR spectroscopy showed that P0 and S0 had beta-pyranose and alpha-pyranose configurations, respectively. The low molecular weight fragments after degradation exhibited higher antioxidant capacities, of which P2 and S3 showed the strongest antioxidant activity in the given assay system. The half-maximal inhibitory concentration (IC50) values of P2 on DPPH, OH, LPO and RBCs hemolysis assays were 0.45, 0.42, 0.88, and 1.51 mg/ml, respectively, and the corresponding IC50 values of S3 were 0.41, 0.41, 0.79, and 1.04 mg/ml, respectively. All the polysaccharide fragments evoked a significant dose dependent inhibitory effect or scavenging ability. Altogether, these results suggest that the polysaccharide of two marine Chrysophyta could be considered as a potential antioxidant. PMID- 24799201 TI - Glutathione suppresses the enzymatic and non-enzymatic browning in grape juice. AB - Browning tends to occur in grape juice during processing and storage and decreases the commercial value of it. Thus, browning inhibition is an important objective for manufacturers. This study aims to investigate the efficacy of glutathione as a browning inhibitor for use on grape juice. Grape juice browning treated with glutathione was monitored during processing and accelerated browning. 0.04% of glutathione inhibited 99.4% of the polyphenoloxidase activity in the grape juice. Consequently, during processing at room temperature and accelerated browning at 80 degrees C, the browning in the grape juice treated with glutathione was significantly lower than that in the control (p<0.05). The results indicate that glutathione is a promising browning inhibitor used in grape juice. PMID- 24799202 TI - Simultaneous determination of the isomers of Ponceau 4R and Amaranth using an expanded graphite paste electrode. AB - A sensitive and convenient electrochemical method was developed for the simultaneous determination of the isomers of Ponceau 4R and Amaranth by an expanded graphite paste electrode (EGPE). The EGPE was prepared by mixing EG with solid paraffin. Compared with flake graphite paste and carbon paste electrodes, the EGPE showed higher electrocatalytic activity towards the oxidization of Ponceau 4R and Amaranth. Under optimal experimental conditions, the EGPE exhibited wide linear responses to Ponceau 4R and Amaranth ranging from 6*10(-8) to 4*10(-6) mol/L and 8*10(-8) to 4*10(-6)mol/L, respectively, and the detection limits for Ponceau 4R and Amaranth were 2 and 36 nmol/L, respectively, at a signal-to-noise ratio of 3. The EGPE showed good reproducibility, stability and reusability. The proposed method was successfully applied in the detection of Ponceau 4R and Amaranth in grape juice samples. PMID- 24799203 TI - Impact of condensed tannin size as individual and mixed polymers on bovine serum albumin precipitation. AB - Condensed tannins composed of epicatechin from monomer to octamer were isolated from cacao (Theobroma cacao, L.) seeds and added to bovine serum albumin (BSA) individually and combined as mixtures. When added to excess BSA the amount of tannin precipitated increased with tannin size. The amount of tannin required to precipitate BSA varied among the polymers with the trimer requiring the most to precipitate BSA (1000 MUg) and octamer the least (50 MUg). The efficacy of condensed tannins for protein precipitation increased with increased degree of polymerisation (or size) from trimers to octamers (monomers and dimers did not precipitate BSA), while mixtures of two sizes primarily had an additive effect. This study demonstrates that astringent perception is likely to increase with increasing polymer size. Further research to expand our understanding of astringent perception and its correlation with protein precipitation would benefit from sensory analysis of condensed tannins across a range of polymer sizes. PMID- 24799204 TI - The effect of postharvest calcium application in hydro-cooling water on tissue calcium content, biochemical changes, and quality attributes of sweet cherry fruit. AB - To improve storage/shipping quality of sweet cherry (Prunus avium L.), the effect of calcium chloride (CaCl2) added to hydro-cooling water on physiological and biochemical processes related to fruit and pedicel quality was investigated on two major cultivars. The fruit tissue Ca content increased up to 29-85% logarithmically for 'Sweetheart' and 39-188% linearly for 'Lapins' as CaCl2 rate increased from 0.2% to 2.0% at 0 degrees C for 5 min. The increase of fruit tissue Ca content was accompanied by reductions in respiration rate, ascorbic acid degradation, and membrane lipid peroxidation, which enhanced total phenolics content and total antioxidant capacity, and resulted in increases in fruit firmness and pitting resistance and decreases in titratable acidity loss and decay of both cultivars. Pedicel browning was inhibited by CaCl2 at 0.2% and 0.5%, but increased by higher rates at 1.0% and 2.0%, possibly via modifying membrane lipid peroxidation. PMID- 24799205 TI - Phytochemicals, nutritionals and antioxidant properties of two prickly pear cactus cultivars (Opuntia ficus indica Mill.) growing in Taif, KSA. AB - The antioxidant properties, some phytochemicals and nutritionals were characterized in two prickly pear cactus (Opuntia ficus indica Mill.) cultivars; red and yellow; growing in Taif, Kingdom of Saudi Arabia (KSA). The antioxidant properties of red cactus cultivar were higher than the yellow cactus cultivar. Linear correlation appeared between the antioxidant properties and total phenolics. All samples nearly have the same quantity of iron, copper, sodium and potassium. Some phenolic compounds were detected by HPLC-UV analysis. HPLC-RI analysis of all samples revealed the absence of sucrose and the presence of glucose and fructose. According to the above results, this study gave a good indication about the nutritional and pharmaceutical potential of the two cactus cultivars that must be widespread cultivated in arid and semiarid regions as KSA accompanying with establishment of industries beside the cactus farms that used all parts of plants. PMID- 24799206 TI - Characterization of cis- and trans-octadecenoic acid positional isomers in edible fat and oil using gas chromatography-flame ionisation detector equipped with highly polar ionic liquid capillary column. AB - In this study, the characterisation of all cis- and trans-octadecenoic acid (C18:1) positional isomers in partially hydrogenated vegetable oil (PHVO) and milk fat, which contain several cis- and trans-C18:1 positional isomers, was achieved by gas chromatography-flame ionisation detector equipped with a highly polar ionic liquid capillary column (SLB-IL111). Prior to analysis, the cis- and trans-C18:1 fractions in PHVO and milk fat were separated using a silver-ion cartridge. The resolution of all cis-C18:1 positional isomers was successfully accomplished at the optimal isothermal column temperature of 120 degrees C. Similarly, the positional isomers of trans-C18:1, except for trans-6-C18:1 and trans-7-C18:1, were separated at 120 degrees C. The resolution of trans-6-C18:1 and trans-7-C18:1 isomers was made possible by increasing the column temperature to 160 degrees C. This analytical method is suitable for determining the cis- and trans-C18:1 positional isomers in edible fats and oils. PMID- 24799207 TI - Whey microbeads as a matrix for the encapsulation and immobilisation of riboflavin and peptides. AB - Whey microbeads manufactured using a cold-set gelation process, have been used to encapsulate bioactives. In this study whey microbeads were used to encapsulate riboflavin using 2 methods. Riboflavin was added to the microbead forming solution however diffusional losses of riboflavin occurred during the subsequent bead preparation. To overcome riboflavin loss, a second approach to 'load' whey microbeads by soaking in riboflavin was assessed. Significantly (p?0.05) higher concentrations of riboflavin were obtained in 'loaded' microbeads (361 mg/L) compared to riboflavin added to the microbead forming solution (48 mg/L). Riboflavin uptake by the microbeads was shown to be via a partition process. As partitioning is often driven by hydrophobic interactions the uptake of amino acids and peptides of varying hydrophobicities by the microbeads was examined. The % encapsulation increased with increasing molecule hydrophobicity with a maximum of 89% encapsulation. Whey microbeads are well suited to act as sorbents for encapsulation. PMID- 24799208 TI - Copper complexing properties and physico-chemical characterisation of the organic matter in Greek herbal infusions. AB - Complex formation is among the mechanisms affecting metals' bioaccessibility. Evaluating the extent of interactions between trace elements and several constituents of food items is of great interest. This paper examines the release of copper-complexing ligands in herbal infusions of 13 aromatic plants commonly used in Greece. The concentration of ligands (LT) and the copper-binding strength (logKapp) of herbal infusions were determined with Differential Pulse Anodic Stripping Voltammetry (DPASV). All herbal infusions were found to release Cu complexing ligands, at concentrations ranging from 8.8 to 112.5 MUM in rosemary and marjoram, respectively. In all infusions the total copper concentrations were lower than the corresponding LT values, indicating that Cu is fully complexed. Aiming to partially characterise the physico-chemical properties of the released organic material, the surface active substances (SAS), reduced sulphur species (RS) and catalytically active compounds (CAC) were measured, for the first time, in herbal infusions by sensitive electrochemical techniques. PMID- 24799209 TI - Pancreatic lipase selectively hydrolyses DPA over EPA and DHA due to location of double bonds in the fatty acid rather than regioselectivity. AB - The enzymatic hydrolysis of canola, anchovy and seal oils with different types and amounts of polyunsaturated fatty acids was measured using porcine pancreatic lipase (PPL) to establish the fatty acid selectivity of PPL. Substrates were subjected to the same conditions of hydrolysis, with percent hydrolysis monitored using Iatroscan and fatty acid selectivity monitored using gas chromatography (GC). Regardless of their distribution on the glycerol backbone, as monitored by (13)C nuclear magnetic resonance (NMR), alpha-linolenic acid (ALA) and docosapentaenoic acid (DPA) were rapidly cleaved by PPL while eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and stearidonic acid (STA) were hydrolysed more slowly. Results show that PPL preferentially hydrolyses ALA and DPA over EPA, DHA and STA, and this selectivity is due to fatty acid rather than regioselectivity. The primary structural factor associated with resistance to PPL appears to be the distance of the first double bond from the ester linkage being hydrolysed. PMID- 24799210 TI - Nutritional and lipid profiles in marine fish species from Brazil. AB - Centesimal composition and lipid profiles were evaluated in muscle tissue of four species of Brazilian fish using the Kjeldahl and Bligh & Dyer gravimetric methods and gas chromatography, respectively. The moisture, protein, total lipid, and ash values (g/100g) ranged from 71.13 to 78.39; 18.10 to 19.87; 1.05 to 9.03; and 1.03 to 1.73, respectively. Palmitic acid was prevalent among the saturated fatty acids (10.89-20.38%) and oleic acid was the main monounsaturated acid identified (4.26-15.77%). The eicosapentaenoic-EPA (6.41-10.66%) and docosahexaenoic-DHA (9.12-30.20%) acids were the most prevalent polyunsaturated acids. The average values, which are indicative of nutritional quality, were: Polyunsaturated/saturated (P/S) (1.11-1.47), omega6/omega3 (0.08-0.21), hypocholesterolemic/hypercholesterolemic acid ratios (HH) (0.87-2.43), atherogenicity index (IA) (0.26-0.60), and thrombogenicity index (IT) (0.20 0.44). These results demonstrated that the lipid profiles of the studied species are of nutritional quality. PMID- 24799211 TI - Relationship between volatile profile and sensory development of an oat-based biscuit. AB - The shelf-life of plain oatcakes and oatcakes containing a natural antioxidant (rosemary extract) was studied for 28 weeks. The biscuits were evaluated using several chemical analyses to determine oxidation (headspace analysis, free fatty acids profile, peroxide value and anisidine value), in addition to sensory testing. A selection of volatiles, including hexanal, were found to be positively correlated to three sensory parameters (aroma, flavour and aftertaste). These volatiles, responsible for the perception of off-flavour in oat biscuits, were predominantly secondary lipid breakdown products, primarily from the unsaturated fatty acids C18:1 and C18:2. The peroxide value was also found to be a useful tool to assess oxidation in oatcakes. The impact of the antioxidant was insufficient at the concentration tested to be used as a solution to prevent the development of off-flavour; however the antioxidant did appear to slow down the rancidity process. PMID- 24799212 TI - Physicochemical responses and quality changes of red sea bream (Pagrosomus major) to gum arabic coating enriched with ergothioneine treatment during refrigerated storage. AB - The combined effects of gum arabic coating (GA) and ergothioneine (ER) treatment on the sensory and physicochemical characteristics of red sea bream (Pagrosomus major) stored at 4 +/- 1 degrees C for 16 days were investigated. Fish proximate composition, pH value, total volatile basic nitrogen (TVB-N), thiobarbituric acid (TBA), K-value, TCA-soluble peptides, colour, texture profile analyses (TPA), microbiological properties and sensory quality were measured. The results indicate that treatment with gum arabic and ergothioneine (GAER) retarded nucleotide breakdown, lipid oxidation, protein degradation, and reduced microbial growth compare with the control. The efficiency was better than that of GA or ER treatment. Sensory evaluation proved the efficacy of GAER coating by maintaining the overall quality of red sea bream during the storage period. Furthermore, GAER maintained better colour and textural characteristics. Our study suggests that GAER treatment has potential to improve the quality of red sea bream and extend its storage life. PMID- 24799213 TI - Optimization of microwave-assisted extraction of cottonseed oil and evaluation of its oxidative stability and physicochemical properties. AB - Microwave assisted extraction (MAE) is a novel method, which can reduce the extraction time and solvent consumption. This study aimed to evaluate the influence of MAE on oxidative stability and physicochemical properties of cottonseed oil. We found that the optimum extraction conditions were: irradiation time 3.57 min; cottonseed moisture content 14% and cottonseed to solvent ratio 1:4, which resulted in an extraction efficiency of 32.6%, 46 ppm total phenolic content, 0.7% free fatty acids, peroxide value of 0.2 and 11.5 h of Rancimat oxidative stability at 110 degrees C. GC analysis for MAE cottonseed oil determined palmitic acid (23.6%), stearic acid (2.3%), oleic acid (15.6%) and linoleic acid (55.1%), which were not significant different (P>0.05) than conventionally-extracted (control) cottonseed oil. MAE oil samples from whole cottonseed (without dehulling) had the greatest long-term stability, more than oil samples containing BHT. PMID- 24799214 TI - Phytochemicals and antioxidant activities of Rhus tripartitum (Ucria) fruits depending on locality and different stages of maturity. AB - The phytochemical content (total phenolic compounds, total flavonoids, condensed tannins and phenolic composition) and the antioxidant potential of Rhus tripartitum fruits collected from different localities were screened during maturity. Significant variability was detected. HPLC analyses revealed the presence of 24 compounds with notable differences. Flavone and betulinic acid, which have numerous benefits, were the main detected compounds (more than 73%). This work highlights the importance of R. tripartitum fruits as dietary sources of natural antioxidants, and might be appropriate for the development of reliable index to estimate fruit richness with bioactive molecules. PMID- 24799215 TI - Comparative assessment of DNA-based approaches for the quantification of food allergens. AB - Governments all over the world have implemented regulatory frameworks concerning food allergen labelling and established or discussed the implementation of thresholds. Therefore, quantitative methods are needed for their surveillance. DNA-based approaches using a matrix-adapted calibration, an internal standard material and a modified standard addition have been developed. In order to enable a comparative assessment of the available quantification methods, experimental framework conditions and uniform performance criteria were defined. For the evaluation of the experimental results using homogenous sample material, the recovery, repeatability and reproducibility were considered along with the limit of detection and the limit of quantification. In addition, muffin dough and muffins spiked with sesame were analysed to assess the suitability of the methods to quantify sesame in model foods. The modified standard addition emerged from the comparative assessment and the analysis of the model foods to be the most appropriate method to quantify traces of allergens in food. PMID- 24799216 TI - Sample treatment platform using nanoparticles to determine salinomycin in flesh and meat. AB - In this work, we developed a sensitive and selective analytical method of determining salinomycin in flesh and meat using a lab-built laser induced fluorescence microscope (LIFM) with nanoparticles. Two types of nanoparticles, Cy5 doped core-shell silica nanoparticles as a probe and magnetic nanoparticles (MNPs) to extract the target antibiotic from the treated sample, were synthesized and modified for chemical and enzymatic binding. After optimization, the newly developed method was applied to ham, chicken, and meat samples for the quantitative determination of salinomycin. The limits of detection (LODs) obtained from the calibration curve were 48-590 pg/mL, which was about 100-fold lower than that of the ELISA method. PMID- 24799217 TI - 2-Alkenal-scavenging ability of m-diphenols. AB - The reaction between m-diphenols (resorcinol, 2-methylresorcinol, 2,5 dimethylresorcinol, 3-methylphenol, orcinol, and phloroglucinol) and 2-alkenals (2-pentenal and 2-octenal) was studied in an attempt to understand the chemical pathways involved in the scavenging ability of m-diphenols for the 2-alkenals produced as a consequence of lipid oxidation. Phenols reacted chemically with 2 alkenals producing a number of 2H-chromenols, chromandiols, chromanols, and dihydropyrano[3,2-g]chromenes, which were isolated and identified by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). The identification of all these compounds resulted in the construction of a general pathway for these reactions. These results confirm that the 2-alkenal-scavenging ability of m-diphenols is a consequence of their structure. This is a complex reaction in which many different products are formed. The most stable products were the chromandiols. However, the main reaction products were the 2H chromenols. These products were unstable and disappeared as a consequence of polymerisation and browning reactions. PMID- 24799218 TI - Further insights into the role of melanoidins on the antioxidant potential of barley malt. AB - The role of Maillard reaction products isolated from barley malt by gel permeation chromatography and ultrafiltration on the antioxidant potential of pale, melano80 and black malts was evaluated. The roasting process is responsible for the polymerisation of early formed lower molecular weight compounds (<10 kDa) into high molecular weight melanoidins (>300 kDa). Melanoidins showed 3-fold higher capacity to scavenge radicals than the lower molecular weight colorants by the metmyoglobin assay. However, a significant decrease of the capacity of black malt and high molecular weight melanoidins to inhibit Fenton induced hydroxyl degradation of deoxyribose was observed. As the high molecular weight fraction, isolated from the black malt extract, exhibited 4-fold higher reducing power than the lower molecular weight fraction, our results support a pro-oxidant effect due to the catalytic formation of hydroxyl radicals in the presence of ferric ions. PMID- 24799219 TI - Chemical and functional properties of the different by-products of artichoke (Cynara scolymus L.) from industrial canning processing. AB - In this study, the basic chemical composition and functional properties of six by product fractions collected from different steps of artichoke industrial processing were evaluated. Fractions differed in thermal treatment, the bract position in the artichoke head and the cutting size. Contents of moisture, ash, protein, fat, dietary fibre, inulin, total phenolics, total flavonoids, caffeoyl derivatives and flavones were analysed. Antioxidant activity values were also determined. All assessed artichoke by-product fractions contained high-dietary fibre (53.6-67.0%) and low fat (2.5-3.7%). Artichoke by-product fractions contained high levels of inulin, especially in the boiled inner bracts (30%). Total phenolic and flavonoid contents and antioxidant activity (153-729 MUmol gallic acid equivalents, 6.9-19.2 MUmol quercetin equivalents and 85-234 MUmol ascorbic acid equivalents per gram of dry matter, respectively) varied widely with the bract positions in the artichoke head and the thermal treatments. The more interesting fractions for use as functional ingredients were those situated closer to the artichoke heart and thermally treated. PMID- 24799220 TI - Development of a rapid method for the quantitative analysis of four methoxypyrazines in white and red wine using multi-dimensional Gas Chromatography Mass Spectrometry. AB - Alkyl-methoxypyrazines (MPs) are important odour-active constituents of many grape cultivars and their wines. Recently, a new MP - 2,5-dimethyl-3 methoxypyrazine (DMMP) - has been reported as a possible constituent of wine. This study sought to develop a rapid and reliable method for quantifying DMMP, isopropyl methoxypyrazine (IPMP), secbutyl methoxypyrazine (SBMP) and isobutyl methoxypyrazine (IBMP) in wine. The proposed method is able to rapidly and accurately resolve all 4 MPs in a range of wine styles, with limits of detection between 1 and 2 ng L(-1) for IPMP, SBMP and IBMP and 5 ng L(-1) for DMMP. Analysis of a set of 11 commercial wines agrees with previously published values for IPMP, SBMP and IBMP, and shows for the first time that DMMP may be an important and somewhat common odorant in red wines. To our knowledge, this is the first analytical method developed for the quantification of DMMP in wine. PMID- 24799221 TI - Effects of chicken-liver hydrolysates on lipid metabolism in a high-fat diet. AB - The contents of free hydrophobic amino acids, taurine and carnosine/anserine were elevated after hydrolyzing chicken livers by pepsin and compared to dried chicken livers. Chicken-liver-hydrolysates (CLHs) exhibited in vitro inhibitory lipase activity and bile-acid binding ability (p<0.05). Forty-eight male hamsters were assigned randomly to the following groups: (1) chow diet; (2) high-fat diet (HFD); (3) HFD and 100 mg CLH/kg BW; (4) HFD and 200 mg CLH/kg BW; (5) HFD and 400 mg CLH/kg BW; (6) HFD and 200 mg carnosine/kg BW. CLHs alleviated (p<0.05) serum oxidative stress and improved (p<0.05) the serum lipid profile in the high fat dietary groups; meanwhile, improved (p<0.05) antioxidant abilities and decreased (p<0.05) lipid accumulation, oxidative stress and TNF-alpha/IL-1beta levels in the livers. These benefits might result from regulations of lipid homeostasis and increased faecal bile-acid outputs (p<0.05). Hence, lipid homeostasis and antioxidant abilities of CLHs in the high-fat dietary habit were demonstrated and were similar to pure carnosine. PMID- 24799222 TI - Migration of bisphenol A into canned tomatoes produced in Italy: dependence on temperature and storage conditions. AB - A method based on solid-phase extraction followed by liquid chromatography, coupled to UV-visible and fluorescence spectrophotometry, has been developed for determination of bisphenol A (BPA) in canned tomatoes. The limit of quantification (LOQ) of the procedure used is 0.03 MUM (0.26 MUg BPA/kg tomato). For each of three different tomato based products (peeled, cherry and concentrated paste), 16 samples belonging to six commercial brands, retailed in Italian markets, were tested for migration of BPA epoxy-coating cans. All the tomato samples exhibited migration levels below 0.4 MUg/kg, while samples subjected to heating process and/or can's damage by denting, exhibited a significant increase in the migration levels. In any case, no sample contained BPA exceeding the European Union limit for migration, set at 600 MUg/kg of food. By comparing the results for each brand, no relevant difference in BPA concentration was found depending on the kind of tomato products. PMID- 24799223 TI - Comprehensive analysis of Cirsium spinosissimum Scop., a wild alpine food plant. AB - Plants which have been traditionally eaten by alpine populations may provide new opportunities of agricultural development for mountain regions. In this context we investigated the chemical composition of Cirsium spinosissimum (Asteraceae), a perennial thistle. Its receptacles were eaten by shepherds in Valais (Switzerland). Extracts of aerial parts were subjected to a comprehensive metabolite profiling, using a dereplication platform, combining HPLC-PDA-MS and offline microprobe NMR analysis. Twenty compounds, including various phenolic glycosides, a monoterpene lactone, a spermine derivative, and fatty acids, could be identified online, or after targeted isolation. The total phenolic content was determined, and the major flavonoids were quantitatively assessed in fresh receptacles by HPLC-PDA analysis. In addition, substances relevant for nutrition, such as beta-carotene, fatty acids, ascorbic acid, and minerals, were quantified. The ethanolic extract of the receptacles showed no sign of cytotoxicity when tested in Caco-2 cells. PMID- 24799224 TI - Simultaneous determination of mequindox, quinocetone, and their major metabolites in chicken and pork by UPLC-MS/MS. AB - This report presents a UPLC-MS/MS method for determination of mequindox (MEQ), quinocetone (QCT) and their 11 metabolites in chicken and pork samples. Following extraction process with acetonitrile-ethyl acetate, acidulation, and re extraction with ethyl acetate in turn, target analytes were further purified using C18 solid phase extraction (SPE) cartridges for UPLC-MS/MS analysis. Validation was processed with mean recoveries from 69.1% to 113.3% with intra-day relative standard deviation (RSD) <14.7%, inter-day RSD <19.2%, and limit of detection between 0.05 and 1.0 MUg/kg for each analytes. The verified method was successfully applied to the quantitative determination of commercial samples. This developed procedure will help to control food animal products with MEQ and QCT residues, and facilitate further pharmacokinetic and residue studies of similar quinoxaline-1,4-dioxide veterinary drugs. PMID- 24799225 TI - Flavonol glycosides and other phenolic compounds in buds and leaves of different varieties of black currant (Ribes nigrum L.) and changes during growing season. AB - Phenolic compounds in buds and leaves of three varieties of black currant in Finland were identified by HPLC-DAD-ESI-MS/MS. Forty-three phenolic compounds of flavonol glycosides, proanthocyanidins and phenolic acids were found in variety "Mikael" whereas only thirty-five in "Mortti" and "Jaloste n:o 15". Glycosides of quercetin and kaempferol were the major phenolics. Rutin, hyperoside, isoquercitrin, kaempferol-3-O-rutinoise, kaempferol-3-O-glucoside, quercetin-3-O (6"-malonyl)-glucoside and a kaempferol-malonylhexoside were the most abundant flavonol glycosides. The contents of flavonol glycosides ranged from 1 to 7 mg/g fresh weight in leaves showing typically an increasing trend from July to August, reaching the highest values in early October in "Mikael" and the end of August in "Mortti" and "Jaloste n:o 15". This is the first systematic report of the composition and content of phenolic compounds in buds and leaves of black currant. PMID- 24799226 TI - Dramatic solvent effect on the synergy between alpha-tocopherol and BHT antioxidants. AB - During the DPPH scavenging assay carried out in non polar and non protic solvents, such as toluene, BHT regenerates alpha-tocopherol from tocopheryl radical, whereas in polar and protic solvents, like methanol, no regeneration is observed due to a fast electron transfer reaction from the tocopheryl radical to the reactive DPPH radical. Surprisingly, in the presence of a small amount of alcohol, the synergy is exalted and BHT regenerates twice as much alpha tocopherol due to a nucleophilic addition of short alcohols on the BHT oxidation product, giving a new phenolic co-antioxidant. PMID- 24799227 TI - Valorization of pomegranate peel from 12 cultivars: dietary fibre composition, antioxidant capacity and functional properties. AB - The dried powdered fruit peels of pomegranate (Punica granatum L.) (PomP) from 12 cultivars were used to extract and characterise their dietary fibre (DF) and to assess their functional and antioxidant properties. The total DF content varied between 33.10 and 62/100 g. The cellulose, Klason lignin, uronic acid and total neutral sugars (NS) composition of DF was: 16.53-22.71, 20.59-41.86, 13.98-23.31 and 16.88-19.66/100g, respectively. Arabinose and xylose were the most present NS with more than 60% of total NS content. The ratio of insoluble to soluble DF was around 1, reflecting the balanced composition of PomP's DF. Besides, PomP powder showed intermediate values for water- and oil-holding capacities: 2.31-3.53 and 2.80-4.05 mL/g, respectively, and strong retardation effect on the dialysis of glucose, reaching ~60%. Also, it has been shown that most of the antioxidants can be extracted, based on the strong soluble antioxidant activity (2018-2649 MUmol Trolox/g) compared to the insoluble one (13-23 MUmol Trolox/g). PMID- 24799228 TI - Chemical compounds isolated from Talinum triangulare (Portulacaceae). AB - This first phytochemical study of Talinum triangulare Leach (Portulacaceae), also known as 'cariru', which is a commonly consumed food in Northern Brazil, allowed the isolation and structural determination of four new compounds: one acrylamide, 3-N-(acryloyl, N-pentadecanoyl) propanoic acid (5), and three new phaeophytins named (15(1)S, 17R, 18R)-Ficuschlorin D acid (3(1),3(2)-didehydro-7-oxo-17(3)-O phytyl-rhodochlorin-15-acetic acid), (13), Talichorin A (17R, 18R)-phaeophytin b 15(1)-hidroxy, 15(2),15(3)-acetyl-13(1)-carboxilic acid (14), and (15(1)S, 17R, 18R)-phaeophytin b peroxylactone or (15(1)S, 17R, 18R)-hydroperoxy-ficuschlorin D (16), together with twelve known compounds, including four phaeophytins (11,12, 15 and 17). The structures of the compounds were established on the basis of 1D and 2D NMR, IR, HRESI-MS spectra, including GC-MS, and HPLC-UV analysis, as well as comparisons with the literature data. The CD spectra data analysis were used to define the absolute configuration of phaeophytins 12 (13(2)R, 17R, 18R)-13(2) hydroxyphaeophytin a, 13 and 16, 15 (15(1)S, 17R, 18R)-3(1),3(2)-didehydro-15(1) hydroxyrhodochlorin-15-acetic acid delta-lactone-15(2)-methyl-17(3)-phytyl ester and 17 (17R, 18R)-purpurin 18-phytyl ester. PMID- 24799229 TI - Analytical strategies for determination of cadmium in Brazilian vinegar samples using ET AAS. AB - This paper proposes two methods for determination of cadmium in vinegar employing electrothermal atomic absorption spectrometry. The optimization step was performed using two-level full factorial and Box-Behnken designs, being that a new multiple response function was established. Under experimental conditions of pyrolysis temperature of 640 degrees C and atomization temperature of 2000 degrees C, the direct method allows the analysis using the external calibration technique, with limit of quantification of 14 ng L(-1) and characteristic mass of 1.2 pg, having aluminium as chemical modifier. This method was applied in six samples of vinegar acquired from Salvador City, Brazil. The cadmium content varied from 20 to 890 ng L(-1). Other method was also proposed by digestion using nitric acid and hydrogen peroxide in reflux system employing cold finger, being cadmium determined by ETAAS. The results obtained with the complete digestion procedure were in agreement with those found by the direct method proposed herein. PMID- 24799230 TI - Determination of organic milk authenticity using carbon and nitrogen natural isotopes. AB - Natural stable isotopes of carbon and nitrogen ((12)C, (13)C, (14)N, (15)N) have abundances unique to each living creature. Therefore, measurement of the stable isotope ratio of carbon and nitrogen (delta(13)C=(13)C/(12)C, delta(15)N=(15)N/(14)N) in milk provides a reliable method to determine organic milk (OM) authenticity. In the present study, the mean delta(13)C value of OM was higher than that of conventional milk (CM), whereas the mean delta(15)N value of OM was lower than that of CM; nonetheless both delta(13)C and delta(15)N values were statistically different for the OM and CM (P<0.05). Furthermore, the values of delta(13)C and delta(15)N were found to differ statistically with the collection date and the milk brand (P<0.05). The combination of delta(13)C and delta(15)N values was more effective than either value alone in distinguishing between OM and CM. The results of the present study, which is based on preliminary data from a limited sample size and sampling period, could be highly valuable and helpful for consumers, the food industry, and/or government regulatory agencies as it can prevent fraudulent labelling of organic food. Further studies include additional analyses of other milk brands and analyses over longer time periods in order to accurately determine OM authenticity using stable isotopes of carbon and nitrogen. PMID- 24799231 TI - Analysis of the tenderisation of jumbo squid (Dosidicus gigas) meat by ultrasonic treatment using response surface methodology. AB - Due to its unique structure, jumbo squid (Dosidicus gigas) meat is sensitive to heat treatment, which makes the traditional squid products taste tough and hard. This study aimed to tenderise jumbo squid meat through ultrasonic treatment. Response surface methodology (RSM) was used to predict the tenderising effect of various treatment conditions. According to the results of RSM, the optimal conditions appeared to be a power of 186.9 W, a frequency of 25.6 kHz, and a time of 30.8 min, and the predicted values of flexibility and firmness under these optimal conditions were 2.40 mm and 435.1 g, respectively. Protein degradation and a broken muscle fibre structure were observed through histological assay and SDS-PAGE, which suggests a satisfactory tenderisation effect. PMID- 24799232 TI - Quality and antioxidant properties on sweet cherries as affected by preharvest salicylic and acetylsalicylic acids treatments. AB - The effects of salicylic acid (SA) or acetylsalicylic acid (ASA) treatments during on-tree cherry growth and ripening on fruit quality attributes, especially those related with the content on bioactive compounds and antioxidant activity were analysed in this research. For this purpose, two sweet cherry cultivars, 'Sweet Heart' and 'Sweet Late', were used and SA or ASA treatments, at 0.5, 1.0 and 2.0mM concentrations, were applied at three key points of fruit development (pit hardening, initial colour changes and onset of ripening). These treatments increased fruit weight and ameliorated quality attributes at commercial harvest, and led to cherries with higher concentration in total phenolics and in total anthocyanins, as well as higher antioxidant activity, in both hydrophilic and lipophilic fractions. Thus, preharvest treatments with SA or ASA could be promising tools to improve sweet cherry quality and health beneficial effects for consumers. PMID- 24799233 TI - Quality and chemical composition of ten red raspberry (Rubus idaeus L.) genotypes during three harvest seasons. AB - Colour and chemical composition of fruits of 10 red raspberry genotypes grown in Nordic climate during three harvest seasons were studied. The main phenolic compounds in the fruits were ellagitannins and anthocyanins, contributing 57% and 42% to the quantified phenolic compounds, respectively. Cyanidin-3-sophoroside was the most abundant anthocyanin (61%). All quality parameters were significantly affected by genotype. The genotypes could be categorised into three groups. 'Veten' and 'RU984 06038' were characterised by high concentrations of flavonoids, i.e., anthocyanins and quercetin glycosides, and dark red colour. 'Octavia', 'Glen Magna', 'RU004 03067', 'Glen Ample' and 'RU974 07002' were characterised by light colour, high titratable acids and low flavonoid concentrations. 'Malling Hestia', 'RU024 01003' and 'RU004 04095' had high content of dry matter, soluble solids, ascorbic acid and ellagic acid containing compounds, in addition to high hue and chroma values. All quality parameters, except ascorbic acid and lambertianin C, varied significantly between harvest seasons. The lowest seasonal variation in fruit quality was observed in 'RU024 01003' and 'Glen Ample' and the highest 'RU004 03067' and 'Glen Magna'. PMID- 24799234 TI - Effect of atmospheric pressure dielectric barrier discharge plasma on the biological activity of naringin. AB - The biological activity of naringin treated with atmospheric pressure plasma was evaluated to investigate whether exposure to plasma can be used as a method to improve the biological activity of natural materials. Naringin was dissolved in methanol (at 500 ppm) and transferred to a container. A dielectric barrier discharge (DBD) (250 W, 15 kHz, ambient air) was then generated. Treatment with the plasma for 20 min increased the radical-scavenging activity, FRAP value, and the total phenolic compound content of naringin from 1.45% to 38.20%, from 27.78 to 207.78 MUM/g, and from 172.50 to 225.83 ppm, respectively. Moreover, the tyrosinase-inhibition effect of naringin increased from 6.12% to 83.30% upon plasma treatment. Naringin treated with plasma exhibited antimicrobial activity against foodborne pathogens, especially Salmonella Typhimurium; an activity that was absent before plasma treatment. Structural modifications induced in the naringin molecule by plasma might be responsible for improving the biological activity of naringin. PMID- 24799235 TI - Thermal stability of 3-deoxyanthocyanidin pigments. AB - 3-Deoxyanthocyanidins are promising natural colourants due to their unique properties compared to anthocyanins. However, thermal stability of 3 deoxyanthocyanidins is largely unknown. Thermal stability of crude and pure 3 deoxyanthocyanidins was determined at 95 degrees C/2 h and 121 degrees C/30 min, at pH 1-7 using HCl, formic or citric acid as acidulants. The colour retention of crude and pure 3-deoxyanthocyanidins (79-89% after 95 degrees C/2 h and 39-118% after 121 degrees C/30 min) was high compared to literature reports for anthocyanins under similar treatments. pH significantly affected the thermal stability of 3-deoxyanthocyanidins: Colour retention was better at pH 1-2 (70.2 118%) than at pH 3-7 (39.0-86.8%). Chalcones were identified as the major heat degradation products at pH 3-7. Slow rate of chalcone formation and resistance to C-ring fission were identified as the major contributors to thermal stability of 3-deoxyanthocyanidins. Overall, the heat stability of 3-deoxyanthocyanidins indicates good potential for food use. PMID- 24799236 TI - A method to detect diphenylamine contamination of apple fruit and storages using headspace solid phase micro-extraction and gas chromatography/mass spectroscopy. AB - Analysis of headspace concentrations of diphenylamine using solid phase micro extraction (SPME) was examined for its suitability to detect DPA contamination and off-gassing in apple (Malus domestica) fruit, storage rooms and storage materials. Four SPME fibre coatings including polydimethylsiloxane (PDMS, 100 MUm), PDMS/divinylbenzene (PDMS/DVB), Polyacrylate (PA) and PDMS 7 MUm were evaluated. The average limits of detection and of quantification for head space DPA ranged from 0.13 to 0.72 MUg L(-1) and 0.42 to 2.35 MUg L(-1), respectively. Polyacrylate was identified to be the most suitable and compatible fibre for DPA analysis in apple samples, because of its high sensitivity to DPA and low fruit volatile interferences. SPME techniques were further applied to study contamination of DPA in apples, storage rooms and packaging materials. DPA was found in the air of storage rooms containing apples that were not treated with DPA. Wood and plastic bin material, bin liners, and foam insulation all adsorbed and off-gassed DPA and could be potential sources of contamination of untreated apples. PMID- 24799237 TI - The batch adsorption of the epigallocatechin gallate onto apple pomace. AB - The ability of apple pomace for carrying a polyphenol (epigallocatechin-3 gallate, EGCG) was examined. The adsorption characteristics of epigallocatechin gallate onto apple pomace from aqueous solution were determined over a range of concentrations (25-600 mg/L) and temperatures (25, 40 and 55 degrees C). The adsorption of EGCG decreased with increasing temperature. Both the Langmuir and Freundlich models adequately describe the isothermal adsorption of EGCG onto apple pomace. The Gibbs free energy change (DeltaG degrees ) for the adsorption of EGCG onto apple pomace ranged from -15.90 to -22.98 kJ/mol over the temperature range 25-55 degrees C, indicating the adsorption of EGCG onto apple pomace is a spontaneous process, and further that the adsorption process is likely to be dominated by a physisorption mechanism. Our results show that apple pomace has good adsorption characteristics, suggesting that apple pomace may be a useful EGCG carrier for functional food applications. PMID- 24799238 TI - A powerful methodological approach combining headspace solid phase microextraction, mass spectrometry and multivariate analysis for profiling the volatile metabolomic pattern of beer starting raw materials. AB - The volatile metabolomic patterns from different raw materials commonly used in beer production, namely barley, corn and hop-derived products - such as hop pellets, hop essential oil from Saaz variety and tetra-hydro isomerized hop extract (tetra hop), were established using a suitable analytical procedure based on dynamic headspace solid-phase microextraction (HS-SPME) followed by thermal desorption gas chromatography-quadrupole mass spectrometry detection (GC-qMS). Some SPME extraction parameters were optimized. The best results, in terms of maximum signal recorded and number of isolated metabolites, were obtained with a 50/30 MUm DVB/CAR/PDMS coating fiber at 40 degrees C for 30 min. A set of 152 volatile metabolites comprising ketones (27), sesquiterpenes (26), monoterpenes (19), aliphatic esters (19), higher alcohols (15), aldehydes (11), furan compounds (11), aliphatic fatty acids (9), aliphatic hydrocarbons (8), sulphur compounds (5) and nitrogen compounds (2) were positively identified. Each raw material showed a specific volatile metabolomic profile. Monoterpenes in hop essential oil and corn, sesquiterpenes in hop pellets, ketones in tetra hop and aldehydes and sulphur compounds in barley were the predominant chemical families in the targeted beer raw materials. beta-Myrcene was the most dominant volatile metabolite in hop essential oil, hop pellets and corn samples while, in barley, the predominant volatile metabolites were dimethyl sulphide and 3-methylbutanal and, in tetra hop, 6-methyl-2-pentanone and 4-methyl-2-pentanone. Principal component analysis (PCA) showed natural sample grouping among beer raw materials. PMID- 24799239 TI - Effect of trehalose on Lateolabrax japonicus myofibrillar protein during frozen storage. AB - The effect of trehalose on the denaturation of weever (Lateolabrax japonicus) myofibrillar protein during frozen storage at -18 degrees C for 90 d was investigated. Trehalose (2.5-10 g dry weight) was added to 100 g of myofibrillar protein, and changes in the Ca(2+)-adenylpyrophosphatase (ATPase) activity, solubility, sulfhydryl content, and unfrozen water content of myofibrils were examined during frozen storage. Ca(2+)-ATPase activity and myofibrillar protein solubility decreased gradually during frozen storage at -18 degrees C upon addition of trehalose. By contrast, Ca(2+)-ATPase activity and myofibrillar protein solubility in the control group dropped drastically during the first 45 d of storage and then further decreased gradually for up to 90 d of storage, indicating a biphasic denaturation pattern. Trehalose addition significantly increased sulfhydryl and unfrozen water contents in the myofibrillar protein of the treatment groups compared with that of the control group (p<0.05) during frozen storage at -18 degrees C. PMID- 24799240 TI - Nutritional quality and essential oil compositions of Thaumatococcus danielli (Benn.) tissue and seed. AB - Nutritional quality and essential oil compositions of Thaumatococcus danielli (Benn.) tissue and seed were determined. Oil was extracted from the seed using standard methods while the fatty acids of the oil, chemical and anti-nutritional properties of defatted seed flour were determined. Total fat yield of the seed flour was 12.20%. Defatted seed flour had higher crude fibre (36.92%), carbohydrate (40.07%) and ash (8.17%) contents. Major mineral contents were potassium, calcium, sodium and magnesium. The tissue contain appreciable amount of vitamin C (8.10 mg/100 g). Oleic acid (42.59%) was the major fatty acid in the seed oil and the total unsaturated fatty acid was 62.38%. The seed oil had higher acid and saponification values and low iodine value. Oxalate (11.09 mg/100 g) content was the major anti-nutrient in the defatted seed flour. Defatted T. danielli seed flour serves as good source of dietary fibre and energy. PMID- 24799241 TI - Biochemical and antimicrobial activity of phloretin and its glycosilated derivatives present in apple and kumquat. AB - Phloretin and its glycosylated derivatives (phlorizin and phloretin 3',5'-di-C glucoside) are dihydrochalcones that have many interesting biological properties. The results obtained showed that the dihydrochalcones are able to inhibit growth of Gram positive bacteria, in particular Staphylococcus aureus ATCC 6538, Listeria monocytogenes ATCC 13932 and methicillin-resistant S. aureus clinical strains. Moreover, phloretin is active also against the Gram negative bacteria Salmonella typhimurium ATCC 13311. The determination of the enzymatic activity of key metabolic enzymes allowed us to shed some light on the biochemical mechanism of aglycon cell growth inhibition, showing as it remarkably influences the energetic metabolism of S. aureus. In addition, structure/activity determinations highlighted that the presence of a glycosyl moiety bound to the chalcone structure dramatically decreases the antimicrobial activity of phloretin. PMID- 24799242 TI - Antioxidant and free radical-scavenging activity of constituents from two Scorzonera species. AB - The aim of this study was to investigate the secondary metabolites content of Scorzonera papposa DC., an edible plant eaten in the desert region of Jordan and to assess its antioxidant and free radical-scavenging activity. By using this bioassay-oriented approach nine compounds, including the new natural compounds (6 trans-p-coumaroyl)-3-O-beta-D-glucopyranosyl-2-deoxy-D-riburonic acid (1), (6-cis p-coumaroyl)-3-O-beta-D-glucopyranosyl-2-deoxy-D-riburonic acid (2a), (6-trans-p coumaroyl)-3-O-beta-D-glucopyranosyl-2-deoxy-D-riburonic acid methyl ester (3), and (6-trans-p-coumaroyl)-3-O-beta-D-glucopyranosyl-(5-acetyl)-2-deoxy-D riburonic acid (4), having the rare deoxy-D-riburonic acid moiety, were isolated. Their structures were elucidated by UV, MS, (1)H and (13)C NMR and 2D NMR. The antioxidant activity of the S. papposa pure compounds and of related derivatives isolated from another Scorzonera species (S. judaica Eig.) was also tested. The Relative Antioxidant Capacity Index (RACI) was applied as an integrated method to compare the antioxidant activities obtained using different chemical methods. PMID- 24799243 TI - Biochemical characterisation and assessment of fibril-forming ability of collagens extracted from Bester sturgeon Huso huso * Acipenser ruthenus. AB - Collagens purified from Bester sturgeon organs were characterised biochemically, and their fibril-forming abilities and fibril morphologies formed in vitro clarified. Yields of collagens were 2.1%, 11.9%, 0.4%, 18.1%, 0.4%, 0.8% and 0.03% (collagen dry weight/tissue wet weight) from scales, skin, muscle, swim bladder, digestive tract, notochord and snout cartilage, respectively. Using SDS PAGE and amino acid composition analyses, collagens from scales, skin, muscle, the swim bladder and digestive tract were characterised as type I, and collagens from the notochord and snout cartilage as type II. Denaturation temperatures of the collagens, measured using circular dichroism, were 29.6, 26.8, 29.0, 32.9, 31.6 and 36.3 degrees C in scales, skin, muscle, swim bladder, digestive tract, and notochord, respectively. For fibril formation, swim bladder and skin collagen showed a more rapid rate of increase in turbidity, a shorter time to attain the maximum turbidity, and formed thicker fibrils compared with porcine tendon type I collagen. PMID- 24799244 TI - Qualitative screening of 116 veterinary drugs in feed by liquid chromatography high resolution mass spectrometry: potential application to quantitative analysis. AB - Veterinarian and human pharmaceuticals may be intentionally added to animal feed to enhance animal production. Monitoring these substances is necessary for protecting the consumers. In this work, a screening method covering 116 human and veterinary drugs has been developed and validated in five types of animal feed at 0.02 and 0.2 mg kg(-1). After a simple extraction and dilution, the samples were analysed by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Nearly all compounds tested were detected at 0.02 mg kg(-1), based on the presence of the accurate-mass (de)protonated molecule. However, the identification using a second accurate-mass ion was more problematic at this level. Finally, the procedure was applied to 22 feed samples, where trimethoprim, robenidine, or alpha- and beta-nandrolone were detected and identified. The potential applicability of the method to quantitative analysis of the compounds detected in the samples was also evaluated. PMID- 24799245 TI - Single-cultivar extra virgin olive oil classification using a potentiometric electronic tongue. AB - Label authentication of monovarietal extra virgin olive oils is of great importance. A novel approach based on a potentiometric electronic tongue is proposed to classify oils obtained from single olive cultivars (Portuguese cvs. Cobrancosa, Madural, Verdeal Transmontana; Spanish cvs. Arbequina, Hojiblanca, Picual). A meta-heuristic simulated annealing algorithm was applied to select the most informative sets of sensors to establish predictive linear discriminant models. Olive oils were correctly classified according to olive cultivar (sensitivities greater than 97%) and each Spanish olive oil was satisfactorily discriminated from the Portuguese ones with the exception of cv. Arbequina (sensitivities from 61% to 98%). Also, the discriminant ability was related to the polar compounds contents of olive oils and so, indirectly, with organoleptic properties like bitterness, astringency or pungency. Therefore the proposed E tongue can be foreseen as a useful auxiliary tool for trained sensory panels for the classification of monovarietal extra virgin olive oils. PMID- 24799246 TI - Combination of spectra and texture data of hyperspectral imaging for prediction of pH in salted meat. AB - This study was carried out to investigate the feasibility of combining spectral with texture features in order to improve pH prediction for salted pork. Average spectra were extracted from the region of interest (ROI) of hyperspectral images over the wavelength region of 400-1000 nm and 9 characteristic spectral variables were then selected by principal components analysis (PCA). Meanwhile, gray-level gradient cooccurrence matrix (GLGCM) analysis was implemented on the first PC image (accounted for 96% of the total variance) to extract 13 textural feature variables. Partial least-squares regression (PLSR) was developed for predicting pH based on spectral, textural or combined data. Coefficient of determination (R(2)P) of 0.794 for the prediction samples based on data fusion was achieved, which was superior to the results based on spectra (R(2)P=0.783) or texture (R(2)P=0.593) alone. Hence, methods of combining spectral with texture analyses are effective for improving meat quality prediction. PMID- 24799247 TI - In vitro total antioxidant capacity and anti-inflammatory activity of three common oat-derived avenanthramides. AB - To better understand mechanisms underlying the health benefits of oats, the free radical scavenging capacities of oat avenanthramides 2c, 2f, and 2p and their ability to inhibit NF-kappaB activation were evaluated. The antioxidant capacities of 2c, 2f, and 2p against peroxyl radicals, hydroxyl radicals, superoxide anion, singlet oxygen, and peroxynitrite were determined by using ORAC, HORAC, SORAC, SOAC, and NORAC assays, respectively. The total antioxidant capacity of 2c was approximately 1.5-fold those of 2f and 2p. Total antioxidant capacity was primarily attributable to SORAC and ORAC for 2c (>77%, p<0.05), and to ORAC and SOAC for 2f. ORAC accounted for approximately 32% of total antioxidant capacity in 2p. EC50 values for inhibiting TNF-alpha-induced NF kappaB activation in C2C12 cells were 64.3, 29.3, and 9.10 MUM for 2c, 2f, and 2p, respectively. Differences in antioxidant capacities and ability to inhibit NF kappaB among the avenanthramides could be ascribed to structural variations. PMID- 24799248 TI - Effect of fermentation on the antioxidant activity in plant-based foods. AB - This study provides an overview of the factors that influence the effect of fermentation on the antioxidant activity and the mechanisms that augment antioxidative activities in fermented plant-based foods. The ability of fermentation to improve antioxidant activity is primarily due to an increase in the amount of phenolic compounds and flavonoids during fermentation, which is the result of a microbial hydrolysis reaction. Moreover, fermentation induces the structural breakdown of plant cell walls, leading to the liberation or synthesis of various antioxidant compounds. These antioxidant compounds can act as free radical terminators, metal chelators, singlet oxygen quenchers, or hydrogen donors to radicals. The production of protease, alpha-amylase and some other enzymes can be influenced by fermentation that may have metal ion chelation activity. Because the mechanisms that affect antioxidant activity during fermentation are extremely varied, further investigation is needed to establish the precise mechanisms for these processes. PMID- 24799249 TI - Variation of anthocyanins and flavonols in Vaccinium uliginosum berry in Lesser Khingan Mountains and its antioxidant activity. AB - Variation of anthocyanin and flavonol in Vaccinium uliginosum berry from seven locations in the Lesser Khingan Mountains was examined for the first time. A total of 14 anthocyanins and 10 flavonols were identified using HPLC-DAD and HPLC ESI-MS(2) analysis. The composition of anthocyanins and flavonols in berries were the same in all of the locations investigated. Malvidin 3-O-glucoside was the most abundant anthocyanin, and quercetin 3-O-galactoside was the main flavonol compound. The berries from Wuying region had the highest concentrations of both anthocyanins and flavonols. It was found that the concentrations of both anthocyanins and flavonols increased with rising altitude. Furthermore, the concentrations of polyphenols, and especially anthocyanins, in V. uliginosum berry showed significant positive correlation with antioxidant activity as measured by DPPH, ABTS(+) and FRAP assays. This study is valuable for further basic research and applied development of V. uliginosum in the Lesser Khingan Mountains. PMID- 24799250 TI - Military ration chocolate: the effect of simulated tropical storage on sensory quality, structure and bloom formation. AB - A storage trial was conducted to observe the effect of typical northern Australia climatic conditions on a military ration chocolate (RC). The results indicate that sensory quality decreased during storage; after seven days the chocolate was no longer of acceptable appearance. Deterioration in RC sensory quality was strongly correlated with decreases in visual acceptance (appearance) and increases in degree of blooming. Instrumental colour measurements were also strongly correlated with sensory ratings. Visual and microscopic observations provide evidence for movement of fat to and across the surface of the RC, behaviour that may be explained in terms of the phase transition theory of fat blooming. DSC thermographs provide evidence of a shift from predominantly polymorph form V in a fresh RC sample to a greater proportion of form VI in bloomed storage samples. The study provides a baseline against which efforts to improve the quality of RC may be evaluated. PMID- 24799251 TI - Isoflavone extraction from okara using water as extractant. AB - We here report on the use of water as a 'green' extraction solvent for the isolation of isoflavones from okara, a by-product of soymilk production. At a low liquid-to-solid ratio of 20 to 1 and 20 degrees C, 47% of the isoflavones that can be extracted with 70% aqueous ethanol were extracted. The malonyl-glucosides were fully recovered with a ratio of 20 to 1, while beta-glucosides were recovered with an increased liquid-to-solid ratio of 40 to 1. The extraction of aglycones was better at higher ratios, but leveled off before reaching a 100% yield. Temperature hardly affected the total amount of isoflavones. At a 20 to 1 ratio, 20 degrees C, and pH 10, there was no significant difference (p>0.05) between isoflavone extraction in water and in 70% aqueous ethanol. The results suggest that water may be used as a green alternative for separation of isoflavones from okara. PMID- 24799252 TI - Pesticide residues in fruits and vegetables from the Aegean region, Turkey. AB - The purpose of this study was to investigate pesticide residues in fruits and vegetables from the Aegean region of Turkey. A total of 1423 samples of fresh fruit and vegetables were collected from 2010 to 2012. The samples were analysed to determine the concentrations of 186 pesticide residues. The analyses utilized ultrahigh performance liquid chromatography coupled with tandem mass spectrometry (UPLC/MS/MS) and gas chromatography with an electron capture detector (GC-ECD) confirmed by gas chromatography with mass spectrometry (GC-MS) after a multi residue extraction procedure (the QuEChERS method). The results were evaluated according to maximum residue limits (MRLs) for each commodity and pesticide by Turkish Regulation. All pomegranate, cauliflower and cabbage samples were pesticides-free. A total of 754 samples contained detectable residues at or below MRLs, and 48 (8.4%) of the fruit samples and 83 (9.8%) of the vegetable samples contained pesticide residues above MRLs. MRL values were most often exceeded in arugula, cucumber, lemon, and grape commodities. All detected pesticides in apricot, carrot, kiwifruit and leek were below the MRLs. Acetamiprid, chlorpyriphos and carbendazim were the most detected pesticide residues. PMID- 24799253 TI - Nutritional evaluation of microalgae oils rich in omega-3 long chain polyunsaturated fatty acids as an alternative for fish oil. AB - The purpose of this work was to evaluate the nutritional value of the total lipid extract of different omega-3 long chain polyunsaturated fatty acids producing photoautotrophic microalgae in one study. It was shown that microalgae oils from Isochrysis, Nannochloropsis, Phaeodactylum, Pavlova and Thalassiosira contain sufficient omega-3 LC-PUFA to serve as an alternative for fish oil, which was used as the 'golden standard'. In the microalgae oils an important part of the omega-3 long chain polyunsaturated fatty acids are present in the polar lipid fraction, which may be favourable from a bioavailability and stability viewpoint. Consumption of microalgae oil ensures intake of sterols and carotenoids. The intake of sterols, including cholesterol and phytosterols, is probably not relevant. The intake of carotenoids is however definitely significant and could give the microalgae oils a nutritional added value compared to fish oil. PMID- 24799254 TI - Isolation and characterisation of rhizosphere bacteria active against Meloidogyne incognita, Phytophthora nicotianae and the root knot-black shank complex in tobacco. AB - BACKGROUND: The use of dually antagonistic bacteria (DAB) as alternatives to chemicals for biological control of disease complexes has received little attention. In this study targeting the Meloidogyne incognita-Phytophthora nicotianae complex, DAB from the tobacco rhizosphere were identified and screened against the diseases caused by one or both pathogens in tobacco. RESULTS: From 450 soil tobacco rhizosphere samples, 26 DAB were identified and had in vitro nematicidal and antifungal efficacies of 37.2-100% and 32.9-73.4% respectively. These DAB were classified into 19 species of 11 genera. In pot experiments, Streptomyces flavofungini SNA26, Pseudomonas putida SNB53 and Serratia marcescens subsp. sakuensis SNB54 effectively suppressed black shank (control effect 72.0 80.2%), root knot (70.0-81.7) and the disease complex (58.7-68.5%) caused by P. nicotianae, M. incognita and both pathogens in tobacco respectively. CONCLUSION: Nineteen DAB species were demonstrated to be antagonists against the M. incognita P. nicotianae complex. Because S. flavofungini SNA26, P. putida SNB53 and S. marcescens subsp. sakuensis SNB54 significantly suppressed the infection of M. incognita and P. nicotianae in tobacco, these species have potential for development as biocontrol agents against the diseases and complex caused by these two pathogens. PMID- 24799255 TI - Evidence that reduced nitric oxide signal contributes to cutaneous microvascular dysfunction in peripheral arterial disease. AB - Peripheral arterial disease (PAD) is associated with cutaneous microvascular dysfunction and an increased risk of arterial ulceration in the affected lower limb(s). The purpose of this study was to investigate the role of nitric oxide (NO) in cutaneous microvascular dysfunction in patients with PAD. Using laser Doppler flowmetry, we measured skin blood flow (SkBF) in 5 patients with unilateral symptomatic PAD and 10 age-matched healthy controls at baseline and during 40 min of local skin heating to 42 degrees C at 1) untreated lower-leg sites, and 2) lower-leg sites treated with 20 mM N(G)-nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase activity. SkBF was expressed as laser Doppler flux (LDF) and normalized to maximal LDF (%LDF(max)) achieved through localized heating to 44 degrees C and concomitant infusion of 56 mM sodium nitroprusside. Pharmacological agents and control treatments (lactated Ringer's) were administered using intradermal microdialysis. The plateau LDF response to local skin warming at the untreated skin sites was significantly (P<0.05) lower in the diseased limb of the PAD patients (70.3+/-13.6 %max) compared to the non diseased contralateral limb (85.0+/-10.2 %max) and the response observed for the control participants (89.0+/-5.2 %max). The NO contribution to the plateau SkBF response tended to be lower in the diseased limb of the PAD patients (45.1+/ 16.4% versus 56.1+/-10.7% [P=0.12] and 55.4+/-11.5% [P=0.13], respectively). The results suggest that PAD impairs downstream cutaneous microvascular vasodilatory function and that the microvascular dysfunction is probably explained, at least in part, by a reduced NO signal. PMID- 24799256 TI - Development and assessment of brief versions of the Penn State Worry Questionnaire and the Ruminative Response Scale. AB - OBJECTIVES: Worry and depressive rumination have been found to be involved in the onset and maintenance of a range of psychological disorders. The development of brief screening measures for excessive worry and depressive rumination is therefore desirable to facilitate the assessment of worry and rumination in prevention and treatment settings where routine administration of full questionnaires is not practical due to time-related constraints. DESIGN AND METHODS: Using the Penn State Worry Questionnaire (PSWQ) and the Ruminative Response Scale (RRS) as gold standard starting points, brief versions of these measures were developed in a large sample of adolescents (N = 1,952) and results were cross-validated in two independent samples (N = 1,954; N = 457). RESULTS: The brief versions demonstrated acceptable to high internal consistency (brief PSWQ: alpha = .84-.91; brief RRS: alpha = .78-.81) and correlated highly with the full questionnaires (brief PSWQ: r = .91-.94; brief RRS: r = .88-.91). In addition, they showed high sensitivity (brief PSWQ: .90-.92; brief RRS: .90-.93), and high specificity (brief PSWQ: .88-.90; brief RRS: .80-.87) to detect excessive worry and rumination. The validity of the brief measures was further supported by demonstrating that the brief measures showed similar differences in scores between males and females as the full measures as well as substantial relationships to other measures of repetitive negative thinking and symptom measures of anxiety and depression. Finally, the brief measures predicted future symptoms of anxiety and depression. CONCLUSIONS: The brief versions of the PSWQ and RRS are time-efficient and valid instruments for the screening of worry and depressive rumination. Their use in clinical practice is recommended to inform treatment and/or to select individuals at risk for development of psychological disorders who may benefit from preventive interventions. PMID- 24799257 TI - Retinoic acid receptor agonist activity of naturally occurring diterpenes. AB - Recent accumulating evidence indicates that all-trans retinoic acid (ATRA) may be useful for preventing or treating inflammation, allergy, and autoimmune diseases, despite its severe side effects. In this study, screening of 99 crude drugs for retinoic acid receptor (RAR) ligands by luciferase reporter assay demonstrated that the methanol extract of Aralia cordata Rhizoma most effectively activates the transcriptional activity of RARalpha. Pimaradienoic acid (ent-pimara-8(14),15 dien-19-oic acid) was subsequently isolated as the constituent capable of activating RAR. Pimaric acid and abietic acid, which have similar structures to pimaradienoic acid, were also found to be novel RAR agonists, although abietic acid only slightly activated peroxisome proliferator-activated receptor gamma. These three natural RAR agonists with diterpene structures, while structurally different from ATRA, were able to increase the mRNA levels of the constitutive androstane receptor in HepG2 cells, induce F9 cell differentiation followed by Cyp26a1 mRNA expression, and differentiate HL-60 cells via RAR activation in a different manner from ATRA. These results demonstrate that some diterpenes exist as naturally occurring RAR agonists and that the differences in chemical structure between ATRA and these diterpenes may induce distinct gene activation and a specific cellular response. PMID- 24799258 TI - Reversible hyperphagia and obesity in rats with gastric bypass by central MC3/4R blockade. AB - OBJECTIVE: To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food. METHODS: Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery. RESULTS: SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats. Doubling of food intake was entirely due to increased meal frequency, but not meal size. After termination of SHU9119, body weight promptly returned to near preinfusion levels. In sham-operated rats, SHU9119 produced even larger increases in food intake and body weight. CONCLUSIONS: RYGB rats do not settle at a lower level of body weight because they cannot eat more food as they can easily double food intake by increasing meal frequency. The reversible obesity suggests that RYGB rats actively defend the lower body weight. However, because both RYGB and sham-operated rats responded to SHU9119, central melanocortin signaling is not the critical mechanism in RYGB rats responsible for this defense. PMID- 24799259 TI - Autonomous bottom-up fabrication of three-dimensional nano/microcellulose honeycomb structures, directed by bacterial nanobuilder. AB - We investigated the autonomous bottom-up fabrication of three-dimensional honeycomb cellulose structures, using Gluconacetobacter xylinus as a bacterial nanoengine, on cellulose honeycomb templates prepared by casting water-in-oil emulsions on glass substrates (Kasai and Kondo, Macromol. Biosci., 4, 17-21, 2004). The template film had a unique molecular orientation state along the honeycomb frames, but was non-crystalline. When G. xylinus, used as a nanofiber producing bacterium, was incubated on the honeycomb scaffold in a culture medium, it secreted cellulose nanofibers only on the upper surface of the honeycomb frame. The movement was regulated by a selective interaction between the synthesized nanofiber and the surface of the honeycomb frames of the template. The relationship between directed deposition of synthesized nanofibers and ordered fabrication from the nano- to the micro-scale could provide a novel bottom-up methodology, using bacteria, for the design of three-dimensional honeycomb structures as functional materials with nano/micro hierarchical structures, with low energy consumption. PMID- 24799260 TI - High impulsivity as a risk factor for the development of internalizing disorders in detained juvenile offenders. AB - BACKGROUND: Whilst impulsivity is most commonly linked to the development of internalizing disorders, high levels of impulsivity, anxiety, and depression have been found in detained juvenile offenders. We therefore sought to determine whether impulsivity is associated with the development of self-reported anxiety or depression in a sample of detained juvenile offenders. METHODS: 323 male juvenile offenders and 86 typically developing controls, aged 15-17 were assessed. The Schedule for Affective Disorder and Schizophrenia for School-Age Children Present and Lifetime (SADS-PL) was used to assess psychiatric diagnoses, the Barratt Impulsivity Scale (BIS-11) was used to measure impulsivity, and the Screen for Child Anxiety Related Emotional Disorders (SCARED) and the Birleson Depression Self-Rating Scale (DSRS) were used to assess self-reported anxiety and depression respectively. RESULTS: Compared to controls, juvenile offenders had significantly higher scores on the BIS-11 total, as well as on the motor and nonplanning subscales (all p values <0.001), as well as higher DSRS (p<0.001) and SCARED (p<0.05) scores. Within the juvenile offender group, scores on the SCARED correlated positively with BIS-11 total, attention subscale, motor subscale, and total DSRS (all p values <0.01). DSRS scores correlated positively with BIS-11 total, attention subscale, nonplanning subscale, and total SCARED scores (all p values <0.01). Participants were then categorized low, middle or high impulsivity according to scores on the BIS-11. One-way ANOVAs demonstrated a significant difference between these tertiles on DSRS [F(2,320)=4.862, p<0.05] and SCARED total scores [F(2,320)=3.581, p<0.05]. Specifically, post-hoc analyses found that the high impulsivity tertile scored significant higher than the remaining tertiles on both DSRS (16.1 +/- 0.3 vs. 14.0 +/- 0.6, p<0.05) and SCARED (23.3 +/ 0.9 vs. 18.4 +/- 1.4, p<0.05) scores. Using multiple linear regression, BIS-11 attention scores, number of months served in custody, age, and BIS-11 nonplanning scores predicted higher levels of anxiety, whilst only BIS-11 attention and nonplanning scores predicted higher levels of depression. CONCLUSIONS: In detained juvenile offenders, high impulsivity may be an important risk factor not only for the externalizing disorders, but also for anxiety and depression. Results of this study, therefore, suggest that specific facets of impulsivity may represent one mechanism underlying the emergence of anxiety and depression in this population. PMID- 24799261 TI - Neuroticism and impulsivity: their hierarchical organization in the personality characterization of drug-dependent patients from a decision tree learning perspective. AB - OBJECTIVE: Neuroticism and impulsivity are the personality variables most consistently associated with drug-dependent patients. To date, no data mining procedures have been applied to explore the differential role of personality variables in this population. METHODS: The personality profile of 336 drug dependent patients was compared with that of a sample of community participants in the context of a decision tree learning approach using the Alternative Five Factor Model. The resulting discriminant model was cross-validated. RESULTS: Neuroticism and impulsivity were the most relevant variables in the resulting model, but their association appeared to be hierarchically organized. In the personality characterization of these patients, neuroticism became the main discriminant dimension, whereas impulsivity played a differential role, explained by means of an interaction effect. Decision tree learning models appear to be a heuristic theoretical and empirical approximation to the study of relevant variables, such as personality traits, in drug-dependency research. PMID- 24799262 TI - Internet guidance on time out: inaccuracies, omissions, and what to tell parents instead. AB - OBJECTIVE: Pediatricians are frequently asked to address parents' behavioral concerns. Time out (TO) is one of the few discipline strategies with empirical support and is recommended by the American Academy of Pediatrics. However, correctly performed, TO can be a complex procedure requiring training difficult to provide in clinic due to time and cost constraints. The Internet may be a resource for parents to supplement information provided by pediatricians. The present study included evaluation of information on TO contained in websites frequently accessed by parents. It was hypothesized that significant differences exist between the empirically supported parameters of TO and website-based information. METHODS: Predefined search terms were entered into commonly used search engines. The information contained in each webpage (n = 102) was evaluated for completeness and accuracy based on research on TO. Data were also collected on the consistency of information about TO on the Internet. RESULTS: None of the pages reviewed included accurate information about all empirically supported TO parameters. Only 1 parameter was accurately recommended by a majority of webpages. Inconsistent information was found within 29% of the pages. The use of TO to decrease problem behavior was inaccurately portrayed as possibly or wholly ineffective on 30% of webpages. CONCLUSIONS: A parent searching for information about TO on the Internet will find largely incomplete, inaccurate, and inconsistent information. Since nonadherence to any 1 parameter will decrease the efficacy of TO, it is not recommended that pediatricians suggest the Internet as a resource for supplemental information on TO. Alternative recommendations for pediatricians are provided. PMID- 24799263 TI - Intervention for optimal outcome in children and adolescents with a history of autism. AB - OBJECTIVE: Autism spectrum disorders (ASDs) were once considered lifelong disorders, but recent findings indicate that some children with ASDs no longer meet diagnostic criteria for any ASD and reach normal cognitive function. These children are considered to have achieved "optimal outcomes" (OO). The present study aimed to retrospectively examine group differences in the intervention history of children and adolescents with OO and those with high-functioning autism (HFA). METHOD: The current study examined intervention histories in 25 individuals with OO and 34 individuals with HFA (current age, 8-21 years), who did not differ on age, sex, nonverbal intelligence, or family income. Intervention history was collected through detailed parent questionnaires. RESULTS: Children in the OO group had earlier parental concern, received earlier referrals to specialists, and had earlier and more intensive intervention than those in the HFA group. Substantially more children with OO than HFA received applied behavior analysis (ABA) therapy, although for children who received ABA, the intensity did not differ between the groups. Children in the HFA group were more likely to have received medication, especially antipsychotics and antidepressants. There were no group differences in the percent of children receiving special diets or supplements. CONCLUSION: These data suggest that OO individuals generally receive earlier, more intense interventions, and more ABA, whereas HFA individuals receive more pharmacologic treatments. Although the use of retrospective data is a clear limitation to the current study, the substantial differences in the reported provision of early intervention, and ABA in particular, is highly suggestive and should be replicated in prospective studies. PMID- 24799264 TI - Ethnic/Racial differences in peer and parent influence on adolescent prescription drug misuse. AB - PURPOSE: To describe ethnic/racial group differences in prescription drug misuse within a nationally representative sample of US adolescents. Also to identify potential sociocultural influences on this health risk behavior. METHODS: A secondary data analysis was conducted on the public-use data of the 2010 National Survey of Drug Use and Health using the records of 12- to 17-year-old African American, Hispanic, and white participants (N = 18,614). Logistic and Poisson regression analyses focused on examining the predictive role of perceived parental and peer substance use disapproval on adolescents' prescription drug misuse and how these social influences varied by ethnic group. RESULTS: Within this sample, 10.4% of adolescents endorsed misusing 1 or more subtypes of prescription drugs. The results showed significant ethnic group differences in rates of prescription drug misuse such that white adolescents reported the highest rates and African American adolescents reported the lowest rates of prescription drug misuse. Rates of misuse for Hispanic adolescents fell in between. Importantly, perceived parental and peer substance use disapproval decreased the likelihood of prescription drug misuse most significantly among white adolescents compared to Hispanic and African American adolescents. Furthermore, influence of disapproval differed by the type of substance, indicating ethnic group differences in disapproval, such as views of alcohol versus marijuana use. CONCLUSIONS: These findings provide new ethnic group specific information about the role that the attitudes of peers and parents on substance use may play in whether adolescents misuse prescription drugs. Future studies should explore possible parent/peer-related socialization mechanisms, which may account for these ethnic group differences. PMID- 24799265 TI - Outcomes of a weight management clinic for children with special needs. AB - OBJECTIVE: Rates of obesity are elevated among children with special needs (e.g., autism spectrum disorder, Down syndrome, or developmental disabilities). The objective of this study was to evaluate the effectiveness of a multidisciplinary tailored intervention to treat obesity among youth with special needs. METHOD: Seventy-six children aged 2 to 19 years participated in a multidisciplinary weight management clinic adapted for children with special needs. A description of the patients presenting for specialized clinical services is provided, and the impact of the intervention on child body mass index (BMI) and food variety was examined for a subset (n = 30) of children. Descriptive statistics of the patient population at baseline were calculated and a series of t tests, correlations, and analysis of variance models examined change in BMI z-scores (BMIz) and diet variety. Factors related to treatment outcomes were also explored. RESULTS: BMIz decreased significantly by the 6-month follow-up (M = 2.43 to M = 2.36, p < .01). There were significant increases in the variety of fruits, vegetables, and grains that children ate (t(16) = 3.18, p < .01; t(16) = 2.63, p = .02; t(16) = 2.37, p = .03, respectively). CONCLUSION: A multidisciplinary clinic-based intervention was effective in reducing BMIz over a 6-month period and increasing the variety of foods that children were eating. These results have implications for providing tailored weight management interventions for youth with obesity and special needs. PMID- 24799266 TI - Comparison of health care needs of child family members of adults with alcohol or drug dependence versus adults with asthma or diabetes. AB - OBJECTIVE: To compare the health problems, preventive care utilization, and medical costs of child family members (CFMs) of adults diagnosed with alcohol or drug dependence (AODD) to CFMs of adults diagnosed with diabetes or asthma. METHODS: Child family members of adults diagnosed with AODD between 2002 and 2005 and CFMs of matched adults diagnosed with diabetes or asthma were followed up to 7 years after diagnosis of the index adult. Logistic regression was used to determine whether the CFMs of AODD adults were more likely to be diagnosed with medical conditions, or get preventive care, than the CFMs of adults with asthma or diabetes. Children's health services use was compared using multivariate models. RESULTS: In Year 5 after index date, CFMs of adults with AODD were more likely to be diagnosed with depression and AODD than CFMs of adults with asthma or diabetes and were less likely to be diagnosed with asthma, otitis media, and pneumonia than CFMs of adults with asthma. CFMs of AODD adults were less likely than CFMs of adult asthmatic patients to have annual well-child visits. CFMs of AODD adults had similar mean annual total health care costs to CFMs of adults with asthma but higher total costs ($159/yr higher, confidence interval, $56 $253) than CFMs of adult diabetic patients. CFMs of adults with AODD had higher emergency department, higher outpatient alcohol and drug program, higher outpatient psychiatry, and lower primary care costs than CFMs of either adult asthmatic patients or diabetic patients. CONCLUSION: Children in families with an alcohol- or drug-dependent adult have unique patterns of health conditions, and differences in the types of health services used, compared to children in families with an adult asthmatic or diabetic family member. However, overall cost and utilization for health care services is similar or only somewhat higher. This is the first study of its kind, and the results have implications for the reduction of parental alcohol or drug dependence stigma by health care providers, clearly an important issue in this era of health reform. PMID- 24799267 TI - Impact of a family-centered approach on attunement of care and parents' disclosure of concerns: a quasi-experimental study. AB - OBJECTIVE: To assess the importance parents place on family-centered care aspects in Preventive Child Healthcare (PCH) and to evaluate whether a family-centered approach influences the attunement of care to these preferences and the willingness of parents to disclose concerns. METHODS: Parents of infants (mean age = 11.4 weeks) attending Dutch PCH participated in the quasi-experimental study. Parents of infants receiving family-centered care (intervention condition) and parents of infants receiving care-as-usual (control condition) filled in a questionnaire regarding the importance of PCH professionals' attitude, parents' empowerment, and monitoring the broad developmental context. They also assessed their experiences regarding these aspects of care. Furthermore, parents rated their willingness to disclose concerns. We compared the 2 conditions, adjusting for background characteristics, and assessed interactions by socioeconomic status (SES) and the child's social-emotional status. RESULTS: Data were provided by a sample of 2542 parents of infants receiving family-centered care and 2328 parents of infants receiving care-as-usual (return rate of questionnaires 86%). Parents rated the PCH professionals' attitude as most important and monitoring the broad developmental context as least important. Scores were high in both conditions. Compared with care-as-usual, parents receiving family-centered care reported better attunement of care to their preferences (p < .001, effect sizes = 0.10 0.27). Parents' willingness to disclose concerns was similar in both conditions (p = .09). Effects were stable across SES and child's social-emotional status groups. CONCLUSIONS: The family-centered approach improves attunement of care to parents' preferences, but it does not increase their already high willingness to disclose concerns. PMID- 24799269 TI - Malocclusion and quality of life in Brazilian preschoolers. AB - The aim of the present study was to assess the impact of malocclusion on oral health-related quality of life (OHRQoL) among preschool children and their families. This study involved 732 preschoolers. Parents/caregivers filled out the Brazilian version of the Early Childhood Oral Health Impact Scale (B-ECOHIS) and a questionnaire addressing sociodemographic data. Overbite, overjet, and crossbite were recorded during the clinical examination. Bivariate and multiple Poisson regression analyses were performed and prevalence ratio (PR) were calculated (alpha = 5%). The prevalence of negative impact from malocclusion on OHRQoL was 27.6% among the children and 22.3% among the families. Mother's schooling (PR = 1.37; 95% CI: 1.10-1.70), parent's/caregiver's assessment of child's oral health (PR = 2.07; 95% CI: 1.60-2.58), history of toothache (PR = 3.84; 95% CI: 2.34-6.30), and visits to the dentist (PR = 0.59; 95% CI: 0.37 0.94) remained significantly associated with OHRQoL in the final model for the children, whereas parent's/caregiver's assessment of child's oral health (PR = 2.32; 95% CI: 1.71-3.14) and history of toothache (PR = 2.28; 95% CI: 1.69-3.09) remained significantly associated with OHRQoL for the families. Malocclusion was not associated with a negative impact on OHRQoL. In contrast, parents'/caregivers' perceptions regarding the oral health of their children and a history of toothache were predictors of a negative impact on the OHRQoL. PMID- 24799270 TI - PyDBS: an automated image processing workflow for deep brain stimulation surgery. AB - PURPOSE: Deep brain stimulation (DBS) is a surgical procedure for treating motor related neurological disorders. DBS clinical efficacy hinges on precise surgical planning and accurate electrode placement, which in turn call upon several image processing and visualization tasks, such as image registration, image segmentation, image fusion, and 3D visualization. These tasks are often performed by a heterogeneous set of software tools, which adopt differing formats and geometrical conventions and require patient-specific parameterization or interactive tuning. To overcome these issues, we introduce in this article PyDBS, a fully integrated and automated image processing workflow for DBS surgery. METHODS: PyDBS consists of three image processing pipelines and three visualization modules assisting clinicians through the entire DBS surgical workflow, from the preoperative planning of electrode trajectories to the postoperative assessment of electrode placement. The system's robustness, speed, and accuracy were assessed by means of a retrospective validation, based on 92 clinical cases. RESULTS: The complete PyDBS workflow achieved satisfactory results in 92 % of tested cases, with a median processing time of 28 min per patient. CONCLUSION: The results obtained are compatible with the adoption of PyDBS in clinical practice. PMID- 24799271 TI - Precision of volumetric assessment of proximal femur microarchitecture from high resolution 3T MRI. AB - PURPOSE: To evaluate the precision of measures of bone volume and bone volume fraction derived from high-resolution 3T MRI of proximal femur bone microarchitecture using non-uniformity correction. METHODS: This HIPAA compliant, institutional review board approved study was conducted on six volunteers (mean age 56 +/- 13 years), and written informed consent was obtained. All volunteers underwent a 3T FLASH MRI hip scan at three time points: baseline, second scan same day (intra-scans), and third scan one week later (inter-scans). Segmentation of femur images and values for total proximal femur volume (T), bone volume (B), and bone volume fraction (BVF) were calculated using in-house developed software, FireVoxel. Two types of non-uniformity corrections were applied to images (N3 and BiCal). Precision values were calculated using absolute percent error (APE). Statistical analysis was carried out using one-sample one-sided t test to observe the consistency of the precision and paired t test to compare between the various methods and scans. RESULTS: No significant differences in bone volume measurements were observed for intra- and inter-scans. When using non-uniformity correction and assessing all subjects uniformly at the level of the lesser trochanter, precision values overall improved, especially significantly (p < 0.05) when measuring bone volume, B . B values using the combination of N3 or BiCal with CLT had a significant consistent APE values of less than 2.5 %, while BVF values were all consistently and significantly lower than 2.5 % APE. CONCLUSION: Our results demonstrate the precision of high-resolution 3D MRI measures were comparable to that of dual-energy X-ray absorptiometry. Additional corrections to the analysis technique by cropping at the lesser trochanter or using non-uniformity corrections helped to improve precision. The high precision values from these MRI scans provide evidence for MRI of the proximal femur as a promising tool for osteoporosis diagnosis and treatment. PMID- 24799272 TI - Mobile locally operated detachable end-effector manipulator for endoscopic surgery. AB - PURPOSE: Local surgery is safer than remote surgery because emergencies can be more easily addressed. Although many locally operated surgical robots and devices have been developed, none can safely grasp organs and provide traction. A new manipulator with a detachable commercial forceps was developed that can act as a third arm for a surgeon situated in a sterile area near the patient. This mechanism can be disassembled into compact parts that enable mobile use. METHODS: A mobile locally operated detachable end-effector manipulator (LODEM) was developed and tested. This device uses crank-slider and cable-rod mechanisms to achieve 5 degrees of freedom and an acting force of more than 5 N. The total mass is less than 15 kg. The positional accuracy and speed of the prototype device were evaluated while performing simulated in vivo surgery. RESULTS: The accuracy of the mobile LODEM was 0.4 mm, sufficient for handling organs. The manipulator could be assembled and disassembled in 8 min, making it highly mobile. The manipulator could successfully handle the target organs with the required level of dexterity during an in vivo laparoscopic surgical procedure. CONCLUSIONS: A mobile LODEM was designed that allows minimally invasive robotically assisted endoscopic surgery by a surgeon working near the patient. This device is highly promising for robotic surgery applications. PMID- 24799274 TI - Development of a modelled anatomical replica for training young neurosurgeons. AB - INTRODUCTION: The Modelled Anatomical Replica for Training Young Neurosurgeons (MARTYN) is a novel simulation model developed by the Royal College of Surgeons England (RCSEng). This study describes the development of the model and aims to determine its feasibility as a potential future training tool. METHODS AND MATERIALS: Traditional model-making methods were used to develop a prototype. Initial procedural trials tested the feasibility of the model. Eighteen participants, grouped by experience (nine novices, four intermediates and five experienced), completed two tasks: a craniotomy and a burr hole followed by insertion of an external ventricular drain (EVD). Subjective data on confidence, usefulness, realism and preference to other training modalities were collected via a standardised questionnaire and a 5-point Likert scale. RESULTS: Preliminary trials of the model prototype demonstrated feasibility. The novice group had the greatest self-reported benefit from MARTYN training, with significant increases in self-rated confidence in both the craniotomy (p < 0.01) and EVD insertion (p < 0.05) procedures. MARTYN was reported to having good visual and tactile realism overall with the bone component being considered highly realistic. The model was reported to be a useful training tool. When asked to rank preferred training modalities, operative experience was chosen first with cadaveric training and MARTYN consistently scoring a second choice. CONCLUSIONS: MARTYN was developed with the intention to fill the current niche for an inexpensive synthetic model head. This study shows that the use of MARTYN for training is both feasible and realistic. We demonstrate a preliminary face and construct validity of the model in this pilot study. With the reduction in working hours, we believe this model will be a suitable supplement to the current ST 1-3 level cadaveric training and will have a positive impact on patient safety. PMID- 24799273 TI - Priming of microglia in a DNA-repair deficient model of accelerated aging. AB - Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state. PMID- 24799275 TI - Intraorbital and intracanalicular ophthalmic artery aneurysms. Literature review and report of a case. AB - This paper reviews literature about intraorbital ophthalmic artery aneurysms discussing presentation, aetiology and treatment options. In addition we report on a case of intraorbital ophthalmic artery aneurysm with acute onset of headache, visual loss and right eye ophthalmoplegia. PMID- 24799276 TI - Reversible acute bilateral blindness resulting from a frontal brain tumor: a case report. AB - We experienced an unusual case of a 15-year-old girl who suffered acute bilateral blindness caused by a frontal lobe tumour. She underwent emergent operation, after which her vision recovered. This case emphasizes that a brain mass can cause sudden onset blindness and an emergency intervention might save the patient's sight. PMID- 24799277 TI - 5-ALA fluorescence-assisted surgery in pediatric brain tumors: report of three cases and review of the literature. AB - 5-aminolevulinic acid (5-ALA) has been used for the last 5 years to increase the extent of resection in adult brain tumors, mostly glioblastomas, but it is not approved yet as standard adjuvant treatment in the pediatric population. We report three different cases of pediatric brain tumors (two glioblastomas and one medulloblastoma) recently operated using 5-ALA fluorescence guidance, highlighting how useful it is in pediatric high-grade glioma (but not in medulloblastoma) also and confirming the lack of 5-ALA-related side effects. The first glioma was a recurrent GBM, whilst the second was a primary tumor. In all children, 5-ALA was administrated after discussing its use, including pros and cons, with the parents. 5-ALA fluorescence was a very useful tool to better identify tumor tissue and achieve gross-total tumor resection in GBMs, as confirmed by postoperative magnetic resonance imaging (MRI). In the medulloblastoma case no useful 5-ALA fluorescence was identified. No hematological or dermatological complications nor other side effects related to use of 5-ALA were observed. We submit that 5-ALA fluorescence guided surgery can be safe and useful in pediatric high-grade glioma, although its use in children still remains an off-label indication and requires validation through larger studies. PMID- 24799278 TI - Metalloproteinase-9 and neutrophil gelatinase-associated lipocalin plasma and tissue levels evaluation in middle cerebral artery aneurysms. AB - Background. Cerebral aneurysms are relatively common in adults, with a prevalence ranging between 1% and 5%. Subarachnoid hemorrhage, following aneurismal rupture, is a major cause of death and disability in these patients. Matrix Metalloproteinases (MMPs) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) seem to be involved in the pathogenesis and in the clinical course of aneurysms. In this study, we evaluated the relationship between tissue and plasma levels of MMP-9 and NGAL in patient with ruptured and unruptured middle cerebral artery aneurysms. Methods. An open label study was conducted on 7 patients with middle cerebral aneurysms. Three patients had ruptured aneurysms (Group I) and four patients had unruptured aneurysms (Group II). All patients underwent aneurysm clipping. Plasma levels of MMP-9 and NGAL were evaluated through ELISA Test. During the surgery, biopsies of the aneurysmatic arteries were taken and frozen ( 80 degrees C) for Western blot evaluation of MMPs and NGAL expression. Four healthy volunteers (Group III) represented the control group for ELISA testing. Results. Both plasma MMP-9 and NGAL levels were significantly high in aneurysmatic patients respect to those of control patients, and these levels were higher (P < 0.01) in patients with ruptured aneurysms respect to patients with unruptured aneurysms (P < 0.01). The latest findings were similarly evident in tissue evaluation of MMP-9 and NGAL between ruptured and unruptured aneurysms. Conclusion. This study suggests that MMP-9 and NGAL plasma levels may be useful to predict the clinical course of a cerebral aneurysms in order to evaluate the progression of the disease and the tendency of an aneurysm to rupture. PMID- 24799279 TI - Early onset of PRES in a patient with a subarachnoid haemorrhage due to a ruptured intracranial aneurysm. AB - Posterior reversible encephalopathy syndrome (PRES) is rarely associated with subarachnoid haemorrhage (SAH). We present a case involving a patient who developed PRES, prior to induction of hypertensive therapy, 2 days after the onset of a SAH due to a ruptured intracranial aneurysm. PMID- 24799280 TI - Perioperative management for pancreatoduodenectomy following severe acute pancreatitis in patients with periampullary cancer: our experience with six consecutive cases. AB - PURPOSE: We rarely have an opportunity to perform pancreatoduodenectomy (PD) following the onset of severe acute pancreatitis (SAP) for patients with periampullary cancer. The perioperative risks and optimal timing of subsequent PD have, therefore, remained unclear. METHODS: Between January 2006 and December 2012, we performed PD in six patients with SAP. We reviewed these six cases, and compared the perioperative risks of morbidity and mortality with those of 81 concurrent PD patients matched for primary cancer without preoperative SAP. RESULTS: The six patients were classified as having SAP based on the Japanese criteria developed in 2008. The SAP in five patients was caused by ERCP procedures. The median interval from SAP onset to the operation was 111 days. The rate of Grade B/C postoperative pancreatic fistula formation in the SAP patients was significantly higher than that of the 81 control patients (83 vs. 26 %, P < 0.001). In addition, the median postoperative hospital stay was significantly longer in the six SAP patients relative to that of the control patients (40 vs. 30 days, P < 0.001). CONCLUSIONS: An interval of at least 3 months after surgery may be needed to decrease the inflammation of the peripancreas region after SAP. Therefore, unnecessary and low-yield ERCP procedures should be avoided in these patients. PMID- 24799281 TI - Integrating meta-analysis of microarray data and targeted proteomics for biomarker identification: application in breast cancer. AB - The development of signature biomarkers has gained considerable attention in the past decade. Although the most well-known examples of biomarker panels stem from gene expression studies, proteomic panels are becoming more relevant, with the advent of targeted mass spectrometry-based methodologies. At the same time, the development of multigene prognostic classifiers for early stage breast cancer patients has resulted in a wealth of publicly available gene expression data from thousands of breast cancer specimens. In the present study, we integrated transcriptome and proteome-based platforms to identify genes and proteins related to patient survival. Candidate biomarker proteins have been identified in a previously generated breast cancer tissue extract proteome. A mass-spectrometry based assay was then developed for the simultaneous quantification of these 20 proteins in breast cancer tissue extracts. We quantified the relative expression levels of the 20 potential biomarkers in a cohort of 96 tissue samples from patients with early stage breast cancer. We identified two proteins, KPNA2 and CDK1, which showed potential to discriminate between estrogen receptor positive patients of high and low risk of disease recurrence. The role of these proteins in breast cancer prognosis warrants further investigation. PMID- 24799282 TI - The monitoring of microvascular liver blood flow changes during ischemia and reperfusion using laser speckle contrast imaging. AB - OBJECTIVE: The recovery of microvascular liver blood flow (LBF) after ischemia is an important determinant of the degree of hepatocellular injury. Laser speckle contrast imaging (LSCI) was recently suggested to be a suitable instrument for monitoring the LBF. This study was designed to evaluate LSCI in monitoring the LBF changes during liver ischemia and reperfusion (IR). METHODS: A rat model with 120-min ischemia and 60-min reperfusion to 90% of the liver (entire liver except the caudate lobe, which was kept as portal blood bypass) was used. The LBF of the sham operation (SO) group and the IR group was measured with LSCI at the following time points: before ischemia (Baseline), 5 min after the start of ischemia (I-5 min), 5 min before the end of ischemia (I-115 min) and 5 and 60 min after the start of reperfusion (R-5 min and R-60 min). The reproducibility among different rats or repeated measurements, the liver histopathology, the liver biological zero (BZ) and the influence of liver movement on the LSCI measurements were investigated. RESULTS: The entire exposed liver surface after laparotomy was suitable for full-view LSCI imaging. Establishing many circular or oval regions of interest (ROIs) on the LSCI flux image was a simple and convenient method for calculating and comparing the LBF of different ROIs and different liver lobes. There was good-to-moderate intra-individual and inter-individual reproducibility for the LSCI measurements of the LBF in the rats of the SO group. In the IR group, the total blood inflow occlusion resulted in a notable drop of the LBF from the baseline (P<0.05) that remained for the 120 min of ischemia. The LBF decreased further after the reperfusion (P<0.05), reflecting the IR-induced liver microcirculation dysfunction. The histopathological examination revealed severe hepatic sinus congestion and damaged hepatocytes in the IR group. The no flow BZ and liver movement contributed to the LBF values. CONCLUSIONS: LSCI technology is a simple, convenient and accurate method for the real-time monitoring of microvascular LBF changes during ischemia and reperfusion, regardless of the contribution of biological zero and liver movement. This finding suggests the possible application of LSCI for monitoring the microvascular LBF changes intraoperatively. PMID- 24799283 TI - Highly selective allylborations of aldehydes using alpha,alpha-disubstituted allylic pinacol boronic esters. AB - alpha,alpha-Disubstituted allylic pinacol boronic esters undergo highly selective allylborations of aldehydes to give tetrasubstituted homoallylic alcohols with exceptional levels of anti-Z-selectivity (>20:1). The scope of the reaction includes both acyclic and cyclic allylic boronic esters which lead to acyclic and exocyclic tetrasubstituted homoallylic alcohols. The use of beta-borylated allylic boronic esters gave fully substituted alkenes bearing a boronic ester which underwent further cross-coupling enabling a highly modular and stereoselective approach to the synthesis of diaryl tetrasubstituted alkenes. Computational analysis revealed the origin of the remarkable selectivity observed. PMID- 24799284 TI - The association between cardiovascular risk factors and high blood pressure in adolescents: a school-based study. AB - OBJECTIVE: Although previous studies have analyzed the association between cardiovascular risk factors and blood pressure in adolescents, few studies conducted in developing countries analyzed whether the aggregation of risk factors contributes to an increased risk of high blood pressure in adolescents. The objective of this study was to assess the association between cardiovascular risk factors (including general overweight, abdominal obesity, high consumption of foods rich in fats, and insufficient physical activity levels) and high blood pressure in adolescents. METHODS: This study was carried out from 2007 to 2008 with 1021 adolescents (528 girls) from primary schools located in the city of Londrina- Brazil. Blood pressure was assessed using an oscillometric device. General overweight was obtained through body mass index, abdominal obesity was assessed using waist circumference, and the consumption of foods rich in fat and physical activity were assessed using a questionnaire. The sum of these risk factors was determined. RESULTS: Adolescents with three or four aggregated risk factors were more likely to have higher values of systolic and diastolic blood pressure when compared with adolescents who did not have any cardiovascular risk factors (P = 0.001 for both). Logistic regression indicated that groups of adolescents with 2 (OR= 2.46 [1.11-5.42]; P = 0.026), 3 (OR= 4.97 [2.07-11.92]; P = 0.001) or 4 risk factors (OR= 6.79 [2.24-19.9]; P = 0.001) presented an increased likelihood of high blood pressure. CONCLUSIONS: The number of cardiovascular risk factors was found to be related to high blood pressure in adolescents. PMID- 24799286 TI - Predictors of the emergence of apathy after bilateral stimulation of the subthalamic nucleus in patients with Parkinson's disease. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is a valid therapeutic tool that ameliorates motor symptoms in patients with Parkinson's disease (PD). However, apathy is one of the neuropsychiatric complications that may occur after STN-DBS surgery, and this may adversely influence the quality of life of patients despite significant motor improvement. OBJECTIVE: This study aimed to elucidate preoperative predictive factors for the presence of postoperative apathy in patients treated with STN-DBS. METHODS: Twenty-five consecutive PD patients receiving bilateral STN-DBS were recruited. The assessment instruments include modified Hoehn & Yahr stages, Unified Parkinson's Disease Rating Scale motor (part III) and dyskinesia (part IVa) scores, Parkinson's Disease Questionnaire-39 scores, Self-Rating Depression Scale scores, and Apathy Scale scores. Predictive factors for postoperative apathy were assessed. RESULTS: While STN-DBS resulted in a significant improvement in motor symptoms, six patients (24%) developed significant apathy after surgery. In multiple logistic regression analyses, preoperative severity of dyskinesia was found to be an independent predictor for the acute phase of postoperative apathy with STN-DBS (odds ratio = 89.993, p = 0.003). CONCLUSIONS: This study suggests that preoperative dyskinesia may predict postoperative apathy in the acute phase in patients with PD treated with STN-DBS. The pathogenesis of postoperative apathy remains unknown, but in patients with severe dyskinesia before STN-DBS, attention should be given to monitoring for postoperative apathy. PMID- 24799285 TI - Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. AB - Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients' microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low-invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs. PMID- 24799287 TI - Susceptibility artifacts detected on 3T MRI of the knee: frequency, change over time and associations with radiographic findings: data from the joints on glucosamine study. AB - OBJECTIVE: To determine the prevalence of intraarticular susceptibility artifacts and to detect longitudinal changes in the artifacts, on 3T magnetic resonance imaging (MRI) of the knee in a cohort of patients with knee pain, and to assess the association of susceptibility artifacts with radiographic intraarticular calcifications. DESIGN: Three hundred and forty-six knees of 177 subjects aged 35 65 were included. 3T MRI was performed at baseline and at 6 months. Baseline radiographs were assessed for presence/absence of linear/punctate calcifications within the tibiofemoral joint (TFJ) space. Corresponding MRIs were assessed for susceptibility artifacts (i.e., linear/punctate hypointensities) in the TFJ space on coronal dual-echo steady-state (DESS) sequences. Kappa statistics were applied to determine agreement between findings on baseline DESS and radiography. Changes in artifacts over time were recorded. RESULTS: In the medial compartment, 13 (4%) of the knees showed susceptibility artifacts at baseline. Six knees had persistent artifacts and six knees had incident artifacts at follow-up. Agreement between DESS and radiography was kappa = 0.18 (-0.15, 0.51) in the medial compartment. Frequency of artifacts in the lateral compartment was low (2%). CONCLUSION: Susceptibility artifacts detected on knee MRI are not frequent, and likely correspond to vacuum phenomena as they commonly change over time and are not associated with intraarticular calcifications. Radiologists should be aware of these artifacts as they can interfere with cartilage segmentation. PMID- 24799288 TI - Three-year changes in drinking patterns in Spain: a prospective population-based cohort study. AB - BACKGROUND: This study examined changes in alcohol drinking patterns (DP) and associated variables in a Mediterranean country. METHODS: Changes in DP between baseline (2008-2010) and follow-up (2012-2013) were examined on a Spanish population-based cohort of 2254 adults (18-59 years) using multinomial logistic regression. Heavy consumption was defined as >=40 g/day of alcohol in men (>=24 g/day in women) and binge drinking (BD) as the intake of >=80 g of alcohol in men (>=60 g in women) on one occasion in the previous month. Six patterns were defined: (1) non-drinkers; (2) ex-drinkers; (3) moderate drinkers without BD (MNB); (4) moderate drinkers with BD (MB); (5) heavy drinkers without BD (HNB); and (6) heavy drinkers with BD (HB). RESULTS: Overall, 45.2% of participants changed DP during follow-up. Over 24% of non-drinkers and 19.4% of ex-drinkers at baseline qualified as MNB at follow-up. The largest flow was from HNB to MNB (57.1%). Light-drinking patterns experienced the largest gains (ex-drinkers: 37.5% and MNB: 66.7%) by absorbing individuals lost by heavy-drinking patterns (MB: 50.8% and HNB: 48.4%). Men, younger individuals, and current smokers were more likely to report heavy-drinking patterns at one or both assessments. Being married or employed increased the likelihood of reporting light-drinking patterns at both surveys (p<0.05). Improving physical quality of life and exercise were associated with a shift from light- to heavy-drinking pattern during follow-up (p<0.05). CONCLUSIONS: DP in Spain changed over 3 years with a tendency to "regress" toward moderate patterns. Repeated measures of alcohol intake may reduce classification errors and biased results when examining the impact of alcohol on health. PMID- 24799289 TI - Self-reported lifetime marijuana use and interleukin-6 levels in middle-aged African Americans. AB - BACKGROUND: Research examining the relationship between marijuana and cytokine function has been well developed in the biochemical literature. However, scant literature exists regarding this relationship between inflammatory markers and marijuana use in public health or behavioral studies and is virtually nonexistent in non-neurologically compromised African American samples. METHODS: The current study examined the differences in serum interleukin-6 (IL-6), a proinflammatory cytokine, between non-drug users (n=78), marijuana only users (n=46) and marijuana plus other drugs users (n=45) in a community-based sample of middle aged African Americans. Participants included 169 African American adults (50.30% female), with a mean age of 45.68 years (SD=11.72 years) from the Washington, DC metropolitan area. Serum was drawn upon entry into the study and the participants completed a demographic questionnaire, which included questions regarding drug use history. RESULTS: After adjusting for demographic and physiological covariates, analysis of covariance revealed a significant difference between the three groups, F(2,158)=3.08, p=0.04). Post hoc analyses revealed lifetime marijuana only users had significantly lower IL-6 levels (M=2.20 pg/mL, SD=1.93) than their lifetime nonuser counterparts (M=3.73 pg/mL, SD=6.28). No other comparisons among the groups were statistically significantly different. CONCLUSION: The current findings extend previous cellular and biochemical literature, which identifies an inverse association between IL-6 and marijuana use. Examining this relationship in the psychological and behavioral literature could be informative to the development of clinical interventions for inflammatory diseases. PMID- 24799290 TI - Bottom-up and top-down processes in body representation: a study of brain-damaged and amputee patients. AB - OBJECTIVE: Body representation is a complex process involving different sources of top-down and bottom-up information. Processing the position and the relations among different body parts is necessary to build up a specific body representation, that is, the visuospatial body map (or topological map of the body). Here we aimed to investigate how the loss of peripheral or central information affects this representation by testing amputee and brain-damaged patients. METHOD: Thirty-two unilateral brain-damaged patients (i.e., left-brain damaged patients and right-brain-damaged patients who were or were not affected by personal neglect), 18 lower limb amputees and 15 healthy controls took part in the study. The topological body map was assessed by means of the "Frontal body evocation subtest" (Daurat-Hmeljiak, Stambak, & Berges, 1978), in which participants have to put tiles (each representing a body part) on a small wooden board on which a head is depicted. RESULTS: Group statistical analysis showed that in amputee patients the loss of peripheral information about the right lower limb affects the ability to represent relations among different body parts as much as the loss of top-down information in brain-damaged patients with personal neglect. Single case analysis of brain-damaged patients without personal neglect showed that the topological map of the body was deficient in 1 right-brain damaged and 2 left-brain-damaged patients. CONCLUSIONS: Studying amputee and brain-damaged patients together allowed us to highlight the importance of visuospatial information about one's own limbs and the role of both hemispheres (not only the left one) in creating an efficient topological body representation. PMID- 24799292 TI - Heterogeneous ability profiles may be a unique indicator of impending cognitive decline. AB - OBJECTIVE: Prior research has found that within-person standard deviations across different neuropsychological domains are larger in various clinical groups than in healthy control groups, but little is known about the specificity of these measures to clinical conditions. METHOD: Within-person standard deviations were computed across composite scores representing episodic memory, perceptual speed, inductive reasoning, and spatial visualization and compared in older adults differing in the amount of subsequent cognitive change, and as a function of age in a large sample of adults ranging from 18 to 89 years of age. RESULTS: The standard deviations at an initial occasion were significantly greater in older adults who experienced the most negative longitudinal change, but relations of the standard deviations with age were only evident in adults under 65 years of age, and they were negative rather than positive. CONCLUSIONS: These findings suggest that high values of within-person variability may have specificity in predicting late life cognitive decline. PMID- 24799291 TI - Simulating category learning and set shifting deficits in patients weight restored from anorexia nervosa. AB - OBJECTIVE: To examine set shifting in a group of women previously diagnosed with anorexia nervosa who are now weight-restored (AN-WR) and then apply a biologically based computational model (Competition between Verbal and Implicit Systems [COVIS]) to simulate the pattern of category learning and set shifting performances observed. METHOD: Nineteen AN-WR women and 35 control women (CW) were administered an explicit category learning task that required rule acquisition and then a set shift following a rule change. COVIS was first fit to the behavioral results of the controls and then parameters of the model theoretically relevant to AN were altered to mimic the behavioral results. RESULTS: Relative to CW, the AN-WR group displayed steeper learning curves (i.e., hyper learning) before the rule shift, but greater difficulty in learning the new categories after the rule shift (i.e., a deficit in set shifting). Hyper learning and set shifting deficits in the AN-WR group were not associated and differentially correlated with clinical measures. Hyper learning in the AN-WR group was simulated by increasing the model parameter that represents sensitivity to negative feedback (delta parameter), whereas the deficit in set shifting was simulated by altering the parameters that represent changes in rule selection and flexibility (lambda and gamma parameters, respectively). CONCLUSIONS: These simulations suggest that multiple factors can impact category learning and set shifting in AN-WR individuals (e.g., alterations in sensitivity to negative feedback, rule selection deficits, and inflexibility) and provide an important starting point to further investigate this pervasive deficit in adult AN. PMID- 24799293 TI - Reference intervals of several renal and hepatic function parameters for apparently healthy adults from Eastern China. AB - BACKGROUND: Biochemical substances relating to renal and hepatic function are influenced not only by individual factors such as gender, lifestyle, and age but also by ecological factors, such as altitude, climate, and ethnic background. The purpose of the present study was to establish reference intervals for 16 biochemical substances relating to renal and hepatic function in healthy Chinese adults. METHODS: A total of 2,405 apparently healthy individuals (18-77 years of age) were chosen as reference individuals in the present study. The 16 biochemical substances relating to renal and hepatic function were analyzed using a HITACHI RL7600 analyzer. The reference intervals were established using nonparametric methods to estimate the 2.5 and 97.5 percentiles of the distribution as the lower and the upper limits, respectively. RESULTS: Age- and gender-appropriate reference intervals were established for some biochemical substances relating to renal and hepatic function in healthy Chinese adults. CONCLUSION: The reference intervals established in this study can provide a useful clinical tool for the assessment of the kidney and liver damage. In addition, the established reference intervals can be adopted in other clinical laboratories after further validation. PMID- 24799296 TI - Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients. AB - Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation. Forty-four consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS-beta thalassemia) with a median age (interquartile range) of 26 (21-41) years underwent pulmonary function tests, CPET, chest x-ray, and echocardiography to further characterize exercise limitation in SCD. Peak oxygen uptake (V'O2 -peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V'O2 -peak correlated with hemoglobin levels (R = 0.440, P = 0.005), forced vital capacity (FVC) (R = 0.717, P < 0.0001). Cardiothoracic ratio on chest x-ray inversely correlated with FVC (R = -0.637, P < 0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n = 17), cardiovascular dysfunction (n = 2), musculoskeletal function (n = 10), pulmonary ventilatory abnormalities (n = 1), pulmonary vascular exercise limitation (n = 1), and poor effort (n = 3). In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, that is, reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better. PMID- 24799294 TI - Dealing with symptoms and issues of hospitalized patients with cancer in indonesia: the role of families, nurses, and physicians. AB - OBJECTIVE: Patients with cancer often face physical, psychological, social, spiritual, and emotional symptoms. Our aim was to study symptoms and issues of hospitalized patients with cancer in Indonesia, a country with strong family ties, and how family members, nurses, and physicians deal with them. METHODS: In 2011, 150 hospitalized cancer patients in 3 general hospitals in Indonesia were invited to fill in a questionnaire, which was based on the validated Problems and Needs of Palliative Care (short version) questionnaire. Descriptive statistics were performed. RESULTS: Of 119 patients (79%) who completed the questionnaire, 85% stated that their symptoms and issues were addressed. According to these patients, financial (56%), autonomy (36%), and psychosocial (34%) issues were most often addressed by the family alone. Physical symptoms (52%) and spiritual issues (33%) were addressed mainly by a combination of family, nurses, and physicians. CONCLUSIONS: Hospitalized patients with cancer in Indonesia felt that most of their symptoms and issues had been addressed, and the family was highly involved. The strong family ties in Indonesian culture may have contributed to this family role. More research is needed to clarify how this influences patient outcome, quality of care, and quality of life of both the patients and their families, along with the degree of partnership between families and professionals. This information might help answer the question what advantages and disadvantages the family role in caring for a hospitalized patient with cancer generates for the patient, the family, and professional caregivers. PMID- 24799297 TI - Explaining young adults' drinking behaviour within an augmented Theory of Planned Behaviour: temporal stability of drinker prototypes. AB - OBJECTIVES: Prototypes (i.e., social images) predict health-related behaviours and intentions within the context of the Theory of Planned Behaviour (TPB). This study tested the moderating role of temporal stability of drinker prototype perceptions on prototype-intentions and prototype-behaviour relationships, within an augmented TPB. The study examined abstainer, moderate drinker, heavy drinker, tipsy, and drunk prototypes. DESIGN AND METHODS: An online prospective study with 1-month follow-up was conducted among 410 young adults (18-25 years old, Mage = 21.0, SD = 2.14, 21.7% male). Assessed were prototype perceptions (favourability and similarity, T1, T2), stability of prototype perceptions, TPB variables (T1), intentions (T2), and drinking behaviour (T2). Intention analyses were corrected for baseline behaviour; drinking behaviour analyses were corrected for intentions and baseline behaviour. RESULTS: Hierarchical regressions showed that prototype stability moderated the relationships of drunk and abstainer prototype similarity with intentions. Similarity to the abstainer prototype explained intentions to drink sensibly more strongly among individuals with stable perceptions than among those with unstable perceptions. Conversely, intentions were explained stronger among individuals with stable perceptions of dissimilarity to the drunk prototype than among those with unstable perceptions. No moderation effects were found for stability of favourability or for relationships with behaviour. CONCLUSIONS: Stable prototype similarity perceptions were more predictive of intentions than unstable perceptions. These perceptions were most relevant in enhancing the explanation of young adults' intended drinking behaviour. Specifically, young adults' health intentions seem to be guided by the dissociation from the drunk prototype and association with the abstainer prototype. Statement of contribution What is already known on this subject? Prototypes have augmented the Theory of Planned Behaviour in explaining risk behaviour. Temporal stability has been shown to successfully extend the TPB in explaining intentions. Temporal stability of TPB variables can moderate the relationships with behaviour and intentions. What does this study add? Stability of prototype perceptions moderates the prototype intentions relationship. Stability of abstainer and drunk prototype similarity enhances the explanation of (intentional) drinking. Stable prototype perceptions are more explanatory than unstable perceptions. PMID- 24799298 TI - Neuropeptide Y, social function and long-term outcome in schizophrenia. AB - There is a lack of biomarkers in schizophrenia and the mechanisms underlying the observed deficits in social functioning are poorly understood. This cohort study aimed to explore whether neurotransmitter neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from patients with schizophrenia is correlated to social function and clinical variables. A further aim was to determine whether baseline levels of NPY were associated with subsequent 3-year outcome. Fifty-six consecutively admitted patients with schizophrenia were included and underwent lumbar puncture and symptom ratings before antipsychotic treatment. NPY levels in CSF were determined by radioimmunoassay. Social function (Social Competence and Social Interest) was assessed by Nurses' Observation Scale for Inpatient Evaluation while psychiatric symptoms were rated using the Comprehensive Psychopathological Rating Scale. Three-year outcome was assessed with the Strauss-Carpenter Outcome Scale. Cross sectional analysis showed a correlation between level of NPY and Social Competence at index admission (r(s)=0.37, p<0.05). The longitudinal analysis (i.e., at the 3-year follow-up) indicated that, for each standard deviation increase in baseline NPY, there was an increased risk of being unemployed (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.07-3.82), having moderate or severe symptoms (OR 3.09, CI 1.30-7.32) or being hospitalized at least 6 months the previous year (OR 3.24, CI 1.09-9.64). However, NPY was not correlated to Social Interest or clinical variables at index admission. In conclusion, NPY levels in CSF are correlated to Social Competence and seem to predict some aspects of longitudinal outcome in schizophrenia. PMID- 24799299 TI - A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia. AB - The current study explored whether oxytocin can improve social cognition and social skills in individuals with schizophrenia using a six-week, double-blind design. Fourteen participants with schizophrenia were randomized to receive either intranasal oxytocin or a placebo solution and completed a battery of social cognitive, social skills and clinical psychiatric symptom measures. Results showed within group improvements in fear recognition, perspective taking, and a reduction in negative symptoms in the oxytocin group. These preliminary findings indicate oxytocin treatment may help improve certain components of functioning in schizophrenia. Implications for the treatment of social functioning in schizophrenia are discussed. PMID- 24799300 TI - Assessing the immunomodulatory potential of high-molecular-weight extracts from mushrooms; an assay based on THP-1 macrophages. AB - BACKGROUND: Food is a potential source of immunomodulating compounds that may be used to steer immune responses towards a desired status such as reducing inflammatory disorders. However, to identify and characterize such bioactive compounds, biologically relevant and standardized assays are required. Macrophages play an important role in immunomodulation and are suited for developing cell-based assays. An assay was developed based on macrophages, in a homogeneous differentiation state, using the human monocytic cell line THP-1 previously used to assess immunomodulatory properties of low-molecular-weight allergens, hormones, dietary supplements and therapeutic drugs. RESULTS: Zymosan and mushroom polysaccharide extracts lead to a heterogeneous differentiation state of THP-1 monocytes, and these cells secrete low levels of cytokines upon stimulation. Differentiation into macrophages using a low concentration of phorbol 12-myristate 13-acetate improved responsiveness. Elevated levels of cytokines were secreted by cells in a homogenous differentiation state. In addition, it was determined that the assay performs best when using cells at a concentration of (2.5-5) * 10(5) cells mL(-1). CONCLUSION: An assay was developed suitable to distinguish the immunomodulatory properties of food compounds in a reproducible manner. It was evaluated using eight mushroom species by measuring the secretion of relevant cytokines TNF-alpha, IL-1beta, IL-6 and IL-10. PMID- 24799301 TI - Salt stress-induced seedling growth inhibition coincides with differential distribution of serotonin and melatonin in sunflower seedling roots and cotyledons. AB - Indoleamines regulate a variety of physiological functions during the growth, morphogenesis and stress-induced responses in plants. Present investigations report the effect of NaCl stress on endogenous serotonin and melatonin accumulation and their differential spatial distribution in sunflower (Helianthus annuus) seedling roots and cotyledons using HPLC and immunohistochemical techniques, respectively. Exogenous serotonin and melatonin treatments lead to variable effect on hypocotyl elongation and root growth under NaCl stress. NaCl stress for 48 h increases endogenous serotonin and melatonin content in roots and cotyledons, thus indicating their involvement in salt-induced long distance signaling from roots to cotyledons. Salt stress-induced accumulation of serotonin and melatonin exhibits differential distribution in the vascular bundles and cortex in the differentiating zones of the primary roots, suggesting their compartmentalization in the growing region of roots. Serotonin and melatonin accumulation in oil body rich cells of salt-treated seedling cotyledons correlates with longer retention of oil bodies in the cotyledons. Present investigations indicate the possible role of serotonin and melatonin in regulating root growth during salt stress in sunflower. Effect of exogenous serotonin and melatonin treatments (15 MUM) on sunflower seedlings grown in the absence or presence of 120 mM NaCl substantiates their role on seedling growth. Auxin and serotonin biosynthesis are coupled to the common precursor tryptophan. Salt stress-induced root growth inhibition, thus pertains to partial impairment of auxin functions caused by increased serotonin biosynthesis. In seedling cotyledons, NaCl stress modulates the activity of N-acetylserotonin O methyltransferase (HIOMT; EC 2.1.1.4), the enzyme responsible for melatonin biosynthesis from N-acetylserotonin. PMID- 24799303 TI - Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. AB - The presence of circulating autoantibodies, primarily to complement factor H antibodies (CFH-Abs) in plasma characterizes the autoimmune form of atypical hemolytic uremic syndrome (aHUS). This acquired form of aHUS defines a distinct subgroup of aHUS patients, which requires diagnostic and treatment approaches in part different from those of the genetically defined forms. The mechanisms leading to CFH-Ab production and disease onset are not completely understood, but CFH-Ab HUS seems to be secondary to a combination of genetic predisposition and environmental factors. Early diagnosis of this specific aHUS entity is important, as prompt induction of plasma exchange and concomitant immunosuppression leads to a favorable outcome. Nevertheless, information on clinical features and outcome in children is limited. Here, we review the literature on the biological and clinical features of CFH-Ab HUS and discuss therapeutic options. PMID- 24799302 TI - Structures of viral membrane proteins by high-resolution cryoEM. AB - Cryo electron microscopy (cryoEM) has emerged as an excellent tool for resolving high-resolution three-dimensional structures of membrane proteins in a lipid containing environment with interacting partners. The near atomic resolution structures of Venezuelan equine encephalitis virus and dengue virus revealed transmembrane helices in lipid bilayers, receptor-binding glycosylation moieties, and functionally important interactions between their fusion protein and membrane anchored chaperone protein. For pleomorphic enveloped viruses, such as human immunodeficiency virus, glycoprotein complexes can be imaged in isolation to reveal molecular interactions at different states. These high-resolution cryoEM structures have clarified important domains not previously resolved by crystallography and illustrate exciting opportunities to visualize viral membrane proteins in their native and possibly transiently stable functional states, thus uncovering mechanisms of action and informing anti-viral strategies. PMID- 24799304 TI - Role of complement in enterohemorrhagic Escherichia coli-Induced hemolytic uremic syndrome. AB - Hemolytic uremic syndrome (HUS), the most common cause of acute renal failure in childhood, is mainly caused by infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC). Besides its cytotoxic activity, Stx has been shown to interact with the complement system. Complement breakdown products have been found in serum of HUS patients suggesting complement activation and in vitro studies have demonstrated that Stx2 directly activates complement leading to formation of terminal complement complex. Furthermore, Stx2 has been found to bind to factor H (FH) resulting in a reduced cofactor activity on the cell surface. Binding of Stx2 has also been shown for other members of the FH family, namely FH-like protein 1 and FH-related protein 1. Both proteins also compete with FH for Stx binding, so that in the presence of FHR-1 less FH is bound to Stx and therefore more is available for endothelial cell protection. In addition, Stx2 has been demonstrated to downregulate the membrane-bound regulator CD59 on the surface of glomerular endothelial and tubulus epithelial cells on protein and at the mRNA level. In conclusion, Stx modulates complement regulator proteins leading to an impaired control and thus to enhanced complement activation. Its implication in the pathogenesis of EHEC-induced HUS in vivo and whether complement blockage might be a therapeutic option still has to be elucidated. PMID- 24799305 TI - Genetics of atypical hemolytic uremic syndrome (aHUS). AB - Hemolytic uremic syndrome (HUS) is a rare, life-threatening disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The atypical form of HUS (aHUS), representing 5 to 10% of cases, lacks the association with infection by Shiga toxin producing Escherichia coli strains that characterizes the commonest clinical presentation of HUS. In the majority of aHUS cases, the disease results from the complement-mediated damage to the microvascular endothelium because of inherited defects in complement genes or autoantibodies against complement regulatory proteins. Incomplete penetrance of aHUS in carriers of mutations is common to all aHUS-associated complement genes and it is now established that the overall genetic predisposition to aHUS of an individual results from the combination of different inherited factors. Moreover, the patient's genotype influences the clinical evolution, the response to plasma therapies, and the recurrence after transplantation. Here, we describe the genetic component of aHUS, the lessons that we have learned from the functional characterization of the aHUS-associated mutations, and the benefits of a comprehensive genetic analysis of the patients. PMID- 24799306 TI - Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). AB - Dysfunction of the alternative pathway of complement in the fluid phase results in deposition of complement factors in the renal glomeruli. This results in glomerular injury and an ensuing proliferative response. The term "C3 glomerulopathy" is used to define such an entity. It includes both C3 glomerulonephritis and dense deposit disease (DDD). Both C3 glomerulonephritis and DDD are characterized by a proliferative glomerulonephritis and bright glomerular C3 mesangial and capillary wall staining with the absence or scant staining for immunoglobulins (Ig). The two conditions are distinguished based on electron microscopy findings: mesangial and capillary wall deposits are noted in C3 glomerulonephritis, while ribbon-shaped dense osmiophilic intramembranous and mesangial deposits are noted in DDD. On the contrary, uncontrolled activation of the alternative pathway of complement on endothelial cell surface results in endothelial injury with an ensuing thrombotic microangiopathy, termed atypical hemolytic uremic syndrome (aHUS). Kidney biopsy in aHUS is often indistinguishable from other forms of thrombotic microangiopathy including enterohemorrhagic Escherichia coli-induced HUS and thrombotic thrombocytopenic purpura and shows thrombi in glomerular capillaries, mesangiolysis, and endothelial injury as evidenced by swelling and double contour formation along the glomerular capillary walls, with negative immunofluorescence studies for Ig and complement factors and no deposits on electron microscopy. PMID- 24799307 TI - Treatment of C3 glomerulopathy with complement blockers. AB - C3 glomerulopathy (C3G) is a newly defined clinical entity comprising glomerular lesions with predominant C3 staining. Under this definition are now included membranoproliferative glomerulonephritis type II (dense deposit disease) and C3 glomerulonephritis. This group of glomerular diseases with a heterogeneous histological aspect shares a common pathogenesis, that is, a dysregulation of the alternative pathway of complement in the fluid phase leading to C3 deposition in the kidney. Recent advances have expanded our understanding of the underlying mechanisms, leading to the hypothesis that blocking the alternative complement pathway may be an effective treatment for C3Gs, as has been shown in other renal diseases driven by alternative pathway dysregulation, such as atypical hemolytic uremic syndrome. Results of 11 published cases of patients with different forms of C3G treated with eculizumab, an anti-C5 humanized monoclonal antibody, are encouraging. Given the complexity of disease pathogenesis in C3G, a patient tailored approach including a comprehensive workup of complement abnormalities is necessary to evaluate the best treatment options. Clinical trials assessing effectiveness of different complement blockers on the background of the individual complement profile are needed. PMID- 24799308 TI - C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. AB - C3 glomerulopathy (C3G) defines a group of very rare renal diseases in which dysregulation of the alternative and terminal complement pathways plays a pivotal pathogenic role. Dysregulation is driven by genetic and/or acquired defects, with interindividual variability giving rise to two broad subtypes of C3G-dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Patient evaluation should include genetic testing and biomarker profiling of complement activity. There is currently no effective targeted treatment option for C3G and, as a consequence, a variety of supportive measures are used. C3G remains an ideal disease in which new complement therapies can be tested as they become available. Trials must include a comprehensive evaluation of each patient at the genetic and biomarker level so that individual responses to therapy can be predicted and understood in light of the degree of complement dysregulation and underlying pathology. PMID- 24799309 TI - 2014 Eberhard F. Mammen Award announcements: Part I--Most popular articles. PMID- 24799310 TI - Prohibiting consent: what are the costs of denying permanent contraception concurrent with abortion care? AB - OBJECTIVE: Oregon and federal laws prohibit giving informed consent for permanent contraception when presenting for an abortion. The primary objective of this study was to estimate the number of unintended pregnancies associated with this barrier to obtaining concurrent tubal occlusion and abortion, compared with the current policy, which limits women to obtaining interval tubal occlusion after abortion. The secondary objectives were to compare the financial costs, quality adjusted life years, and the cost-effectiveness of these policies. STUDY DESIGN: We designed a decision-analytic model examining a theoretical population of women who requested tubal occlusion at time of abortion. Model inputs came from the literature. We examined the primary and secondary outcomes stratified by maternal age (>30 and <30 years). A Markov model incorporated the possibility of multiple pregnancies. Sensitivity analyses were performed on all variables and a Monte Carlo simulation was conducted. RESULTS: For every 1000 women age <30 years in Oregon who did not receive requested tubal occlusion at the time of abortion, over 5 years there would be 1274 additional unintended pregnancies and an additional $4,152,373 in direct medical costs. Allowing women to receive tubal occlusion at time of abortion was the dominant strategy. It resulted in both lower costs and greater quality-adjusted life years compared to allowing only interval tubal occlusion after abortion. CONCLUSION: Prohibiting tubal occlusion at time of abortion resulted in an increased incidence of unintended pregnancy and increased public costs. PMID- 24799311 TI - Conflicts between the patient's autonomy and cultural sensitivity: what to choose? PMID- 24799312 TI - Drug labeling in the practice of obstetric anesthesia. AB - This commentary outlines the current drug labeling practices that potentially compromise the clinical care of pregnant women and their children. We highlight the need for drug manufacturers and lawmakers to change the status quo and consider practices and regulations that will provide much-needed guidance to clinicians on the safe administration of drugs to certain populations such as pregnant and nursing women. Current practices have de facto contributed to a situation in which evidence is inadequate for individual physicians and patients to weigh the risks and benefits of drug administration and make informed decisions for drug use during pregnancy and lactation. PMID- 24799313 TI - Premenstrual spotting of >=2 days is strongly associated with histologically confirmed endometriosis in women with infertility. AB - OBJECTIVE: The purpose of this study was to assess the prevalence of endometriosis in women with premenstrual spotting and to determine the predictive value of this symptom in the diagnosis of endometriosis. STUDY DESIGN: We conducted a retrospective cohort study of 80 consecutive women who presented to the infertility clinic for evaluation and who subsequently underwent laparoscopic assessment for infertility with or without pelvic pain. Our main outcome measure was the presence or absence of histologically confirmed endometriosis in women with and without premenstrual spotting. RESULTS: Endometriosis was significantly more prevalent in subfertile women who reported premenstrual spotting for >=2 days relative to women without this symptom (89% [34/38 women] vs 26% [11/42 women]; P < .0001). Multinomial logistic regression analysis demonstrated the presence of premenstrual spotting for >=2 days to be associated significantly with the presence of endometriosis (odds ratio, 16; 95% confidence interval, 3.9 65.4; P < .01) and red vesicular lesion type (odds ratio, 52.6; 95% confidence interval, 8.6-323.1; P < .001). CONCLUSION: In this cohort of women with infertility, premenstrual spotting of >=2 days was associated strongly with histologically confirmed endometriosis and a better predictor than dysmenorrhea or dyspareunia of finding endometriosis at laparoscopy. Premenstrual spotting of at least 2 days was also associated strongly with both higher stage disease and the red vesicular peritoneal endometriosis phenotype. PMID- 24799314 TI - Reply: To PMID 24176896. PMID- 24799315 TI - Stepwise synthesis of a Ru4Cd4 coordination cage using inert and labile subcomponents: introduction of redox activity at specific sites. AB - The kinetically inert mononuclear complex [RuL3](PF6)2 (1 : 3 mixture of fac and mer isomers), with three pendant binding sites, reacts with labile Cd(II) ions to complete the assembly of a Ru4Cd4 cubic coordination cage in which reversible redox behaviour has been introduced at the Ru(II) sites. PMID- 24799316 TI - [The respiratory therapist in the intensive care unit team]. AB - Qualified respiratory therapists have been an integral part of the U.S. health care system for over 50 years now and are an indispensable part of the system. Respiratory therapy involves the entire respiratory system and should not to be confused with breathing therapy. The latter includes only certain breathing techniques. Since 2005, the German Respiratory Society also offers nurses and physiotherapists training in respiratory therapy. The core competencies of the numerous intensive care respiratory therapists employed in German intensive care units include, among others, the diagnosis and treatment of acute and chronic respiratory failure, including invasive and non-invasive respiratory therapy, excessive secretion management, including bronchoscopic airway clearance, and inhalation therapy. PMID- 24799317 TI - [Emergency and intensive medical care of status epilepticus]. AB - Convulsive status epilepticus is defined as a general or focal epileptic seizure lasting longer than 5 min or recurrent seizures without regaining consciousness between seizures. Status epilepticus is a life-threatening condition caused by underlying pathologies (e.g., stroke, meningitis, cerebral hypoxia, cerebral edema). In addition, patients are in danger of physical injury and impaired brain stem reflexes. This also applies to nonconvulsive status epilepticus, which is often characterized by an "unclear loss of consciousness". Although it can only be diagnosed by electroencephalography, it is an important differential diagnosis in the prehospital or emergency room situation, which may be decisive for the therapeutic strategy. Benzodiazepines are the first choice treatment for status epilepticus. This article summarizes a guideline-directed therapy with different pharmaceutical substances and ways of application. A pragmatic approach for limited diagnostic and therapeutic possibilities in the emergency situation is presented. PMID- 24799318 TI - Self-Awareness of Executive Functioning Deficits in Adolescents With ADHD. AB - OBJECTIVE: Children with ADHD lack self-awareness of their social and academic deficits, frequently rating themselves more favorably than external sources. The purpose of the current study was to assess whether adolescents with ADHD also hold a positive bias toward their executive functioning (EF). METHOD: Participants include 22 control and 35 ADHD subjects, aged 11 to 16. Participants and their parents completed the Behavior Rating Inventory of Executive Functioning (BRIEF) Self and Parent forms, respectively. Discrepancy scores were calculated for each domain by subtracting the adolescents' T-score from the parents' T-score. RESULTS: Discrepancy scores were significantly higher in the ADHD group than controls within the Inhibit, Shift, Monitor, Emotional Control, Working Memory, and Plan/Organization domains (all p < .05). CONCLUSION: As compared with controls, adolescents with ADHD tend to endorse fewer EF difficulties than what parents report. This is the first study to demonstrate that those with ADHD may overestimate their EF ability. PMID- 24799319 TI - Use of Multiple Informants to Identify Children at High Risk for ADHD in Turkish School-Age Children. AB - OBJECTIVE: To examine the distribution of parent- and teacher-rated ADHD symptoms in a Turkish community sample to identify children at high risk for ADHD and to explore the psychosocial correlates of these high-risk children. METHOD: An 18 item SNAP-IV (Swanson, Nolan, and Pelham) and a three-item impairment scale were completed by parents and teachers on 3,110 children between 7 and 14 years of age from three public schools in Istanbul. RESULTS: Using various case definitions for ADHD, we observed a range of prevalence estimates based on parent (2.7%-9.6%) and teacher (2%-10.1%) reports. Teacher-identified ADHD was associated with low family income and low parental education; parent-identified ADHD was associated with perceived need for mental health treatment. CONCLUSION: Statistically driven threshold on a symptom scale may overestimate the rate of high-risk children. Relying on one informant is likely to miss some children at high risk. As in clinical practice, therefore, data from multiple informants and evidence of impairment are essential for identifying ADHD. PMID- 24799320 TI - Platelet factor 4 inhibits IL-17/Stat3 pathway via upregulation of SOCS3 expression in melanoma. AB - Platelet factor 4 (PF4) was the first discovered CXC chemokine and is found in platelet granules at very high concentration. Now, it is becoming increasingly evident that PF4 actively participates in inflammation and immune response. Recent paper demonstrated that PF4 limits the development and response of the Th17 cells and assisted in regulatory T cell development in transplantation. But, the immunoregulatory role of PF4 in tumor has little known and needs to be further investigated. In our current study, wild-type mice are inoculated with melanoma cell line B16-F10 (1 * 10(6)/mouse) and treated with PF4. PF4 inhibits B16 tumor growth and decreases gammadelta cell infiltration. The expression of interleukin (IL)-17, IL-6, and p-signal transducer and activator of transcription 3 (Stat3) was markedly decreased with treatment of PF4 compared with control in vivo and in vitro. And, the suppressed tumor growth induced by PF4 is abolished by additional treatment of recombinant mouse IL (rmIL)-17. PF4 also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and PF4 fails to suppress expression of p-Stat3, IL-17, and IL-6 in cells transfected with SOCS3 short interfering RNA (siRNA). In conclusion, PF4 inhibits IL-17/Stat3 pathway via upregulation of SOCS3 expression and may contribute to suppressing tumor growth in murine models of melanoma. PMID- 24799321 TI - Serum and salivary matrix metalloproteinases, neutrophil elastase, myeloperoxidase in patients with chronic or aggressive periodontitis. AB - Salivary, serum matrix metalloproteinase-8 (MMP-8), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), neutrophil elastase (NE), and myeloperoxidase (MPO) levels were investigated in generalized chronic periodontitis (GCP), generalized aggressive periodontitis (GAgP), and healthy groups. Whole-mouth clinical periodontal measurements were recorded. Salivary, serum concentrations of MMP-8, MPO, TIMP-1, and NE were determined by immunofluorometric assay or ELISA in 18 patients with GCP, 23 patients with GAgP, 18 individuals with healthy periodontium. Patients in the GAgP group were younger than the other groups (p<0.05). The study groups were similar in gender, smoking status. Plaque index was higher in GCP than GAgP group (p<0.05). Biochemical data were similar in periodontitis groups. Salivary, serum MPO, and salivary NE concentrations were higher; TIMP-1 concentrations were lower in the periodontitis groups than the controls (p<0.05). The present data support a close relationship between salivary, serum protease content and clinical periodontal parameters in patients with generalized periodontitis. PMID- 24799322 TI - High prevalences of hepatitis B and C virus infections among adults living in Binh Thuan province, Vietnam. AB - AIM: Vietnam is one of the countries with the highest mortality from liver cancer, which is mostly attributed to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. For planning preventive strategies against these infections, we investigated prevalences of HBV and HCV infections among adults living in Binh Thuan, Vietnam. METHODS: Our study consisted of a serological survey for HBV and HCV infections and a questionnaire survey on their risk factors. The sample size was calculated based on anticipated rate of hepatitis B surface antigen (HBsAg). Subjects were randomly sampled using a multistage method. Confirmation and family-tree surveys were conducted to examine persistent HBV infection and intrafamilial HBV transmission, respectively. RESULTS: A total of 509 adults, comprised of 230 men (45.2%) and 279 women (54.8%), were enrolled. Prevalences of HBsAg, hepatitis B surface antibody and hepatitis B core antibody were 15.3%, 60.3% and 71.7%, respectively. Most HBV DNA positive sera were classified as genotype B (75.3%) and C (11.7%). Of HBsAg positive subjects, 96.7% were persistently infected and one acutely HBV infected person was identified. Family-tree surveys suggested that horizontal extrafamilial HBV transmission might have been frequent. Prevalences of anti-HCV and HCV RNA were 3.3% and 1.8%, respectively. HCV genotype 6a was prominent (55.6%). CONCLUSION: In Binh Thuan, prevalences of HBV and HCV infections are high, HBV genotype B and HCV genotype 6a are predominant, and horizontal HBV transmission may still occur. Therefore, raising the coverage of a universal HBV vaccination program may be an effective liver cancer control in Vietnam. PMID- 24799323 TI - Poly-omic prediction of complex traits: OmicKriging. AB - High-confidence prediction of complex traits such as disease risk or drug response is an ultimate goal of personalized medicine. Although genome-wide association studies have discovered thousands of well-replicated polymorphisms associated with a broad spectrum of complex traits, the combined predictive power of these associations for any given trait is generally too low to be of clinical relevance. We propose a novel systems approach to complex trait prediction, which leverages and integrates similarity in genetic, transcriptomic, or other omics level data. We translate the omic similarity into phenotypic similarity using a method called Kriging, commonly used in geostatistics and machine learning. Our method called OmicKriging emphasizes the use of a wide variety of systems-level data, such as those increasingly made available by comprehensive surveys of the genome, transcriptome, and epigenome, for complex trait prediction. Furthermore, our OmicKriging framework allows easy integration of prior information on the function of subsets of omics-level data from heterogeneous sources without the sometimes heavy computational burden of Bayesian approaches. Using seven disease datasets from the Wellcome Trust Case Control Consortium (WTCCC), we show that OmicKriging allows simple integration of sparse and highly polygenic components yielding comparable performance at a fraction of the computing time of a recently published Bayesian sparse linear mixed model method. Using a cellular growth phenotype, we show that integrating mRNA and microRNA expression data substantially increases performance over either dataset alone. Using clinical statin response, we show improved prediction over existing methods. We provide an R package to implement OmicKriging (http://www.scandb.org/newinterface/tools/OmicKriging.html). PMID- 24799324 TI - Maternal immunization. AB - Maternal immunization has the potential to protect the pregnant woman, fetus, and infant from vaccine-preventable diseases. Maternal immunoglobulin G is actively transported across the placenta, providing passive immunity to the neonate and infant prior to the infant's ability to respond to vaccines. Currently inactivated influenza, tetanus toxoid, and acellular pertussis vaccines are recommended during pregnancy. Several other vaccines have been studied in pregnancy and found to be safe and immunogenic and to provide antibody to infants. These include pneumococcus, group B Streptococcus, Haemophilus influenzae type b, and meningococcus vaccines. Other vaccines in development for potential maternal immunization include respiratory syncytial virus, herpes simplex virus, and cytomegalovirus vaccines. PMID- 24799325 TI - Editorial Commentary: the trials and tribulations of treating Clostridium difficile infection-one step backward, one step forward, but still progress. PMID- 24799326 TI - Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. AB - BACKGROUND: Clostridium difficile infection (CDI) is a common complication of antibiotic therapy that is treated with antibiotics, contributing to ongoing disruption of the colonic microbiota and CDI recurrence. Two multinational trials were conducted to compare the efficacy of tolevamer, a nonantibiotic, toxin binding polymer, with vancomycin and metronidazole. METHODS: Patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer 9 g (loading dose) followed by 3 g every 8 hours for 14 days, vancomycin 125 mg every 6 hours for 10 days, or metronidazole 375 mg every 6 hours for 10 days. The primary endpoint was clinical success, defined as resolution of diarrhea and absence of severe abdominal discomfort for more than 2 consecutive days including day 10. RESULTS: In a pooled analysis, 563 patients received tolevamer, 289 received metronidazole, and 266 received vancomycin. Clinical success of tolevamer was inferior to both metronidazole and vancomycin (P < .001), and metronidazole was inferior to vancomycin (P = .02; 44.2% [n = 534], 72.7% [n = 278], and 81.1% [n = 259], respectively). Clinical success in patients with severe CDI who received metronidazole was 66.3% compared with vancomycin, which was 78.5%. (P = .059). A post-hoc multivariate analysis that excluded tolevamer found 3 factors that were strongly associated with clinical success: vancomycin treatment, treatment-naive status, and mild or moderate CDI severity. Adverse events were similar among the treatment groups. CONCLUSIONS: Tolevamer was inferior to antibiotic treatment of CDI, and metronidazole was inferior to vancomycin. Trial Registration. clinicaltrials.gov NCT00106509 and NCT00196794. PMID- 24799327 TI - Reply: To PMID 24677197. PMID- 24799328 TI - Plant strengtheners enhance parasitoid attraction to herbivore-damaged cotton via qualitative and quantitative changes in induced volatiles. AB - BACKGROUND: Herbivore-damaged plants release a blend of volatile organic compounds (VOCs) that differs from undamaged plants. These induced changes are known to attract the natural enemies of the herbivores and therefore are expected to be important determinants of the effectiveness of biological control in agriculture. One way of boosting this phenomenon is the application of plant strengtheners, which has been shown to enhance parasitoid attraction in maize. It is unclear whether this is also the case for other important crops. RESULTS: The plant strengtheners BTH [benzo (1,2,3) thiadiazole-7-carbothioic acid S-methyl ester] and laminarin were applied to cotton plants, and the effects on volatile releases and the attraction of three hymenopteran parasitoids, Cotesia marginiventris, Campoletis sonorensis and Microplitis rufiventris, were studied. After treated and untreated plants were induced by real or simulated caterpillar feeding, it was found that BTH treatment increased the attraction of the parasitoids, whereas laminarin had no significant effect. BTH treatment selectively increased the release of two homoterpenes and reduced the emission of indole, the latter of which had been shown to interfere with parasitoid attraction in earlier studies. Canonical variate analyses of the data show that the parasitoid responses were dependent on the quality rather than the quantity of volatile emission in this tritrophic interaction. CONCLUSION: Overall, these results strengthen the emerging paradigm that induction of plant defences with chemical elicitors such as BTH could provide a sustainable and environmentally friendly strategy for biological control of pests by enhancing the attractiveness of cultivated plants to natural enemies of insect herbivores. PMID- 24799329 TI - Wetting-transparent graphene films for hydrophobic water-harvesting surfaces. AB - Wetting-transparent graphene films grown in situ by chemical vapor deposition on hydrophobic (roughened) copper surfaces offer excellent resistance to copper corrosion while maintaining the intrinsic hydrophobicity of the surface, enabling superior performance for water-harvesting applications. PMID- 24799331 TI - Allergen cross-reactivity in allergic rhinitis and oral-allergy syndrome: a bioinformatic protein sequence analysis. AB - BACKGROUND: Clinical allergy cross-reactivity that is seen with related inhalant allergens or between unrelated inhalant allergens and foods in oral allergy syndrome (OAS) remains poorly understood. The goal of this study is to determine whether clinical cross-reactivity can be identified from primary protein sequences in allergy epitopes and food proteins. METHODS: High-throughput analysis was performed by assembling all known allergy epitopes within the Immune Epitope Database (IEDB; http://www.iedb.org) for 5 common species from 5 inhalant allergen subclasses and comparing their protein sequences to each other, as well as to sequences of intact proteins from known cross-reactive foods in the European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL EBI) protein database (http://www.uniprot.org) that have been implicated in OAS. Computational methods were employed to allow for exact matching, gaps, and similar amino acids using multiple algorithms. A phylogenetic tree was created to determine evolutionary relationships between cross-reactive epitopes in OAS. RESULTS: Twenty-three common inhalant allergens had 4429 unique epitopes; the 19 foods implicated in OAS had 9497 protein sequences. The Basic Local Alignment Search Tool (BLAST) algorithm identified interclass and intraclass sequence similarities for the 5 inhalant allergy classes with high similarity for mites, grasses, and trees. Analysis of OAS proteins identified 104 matches to inhalant allergy epitopes that are known to cross-react. The phylogenetic tree displayed relationships that mostly followed organism phylogeny. CONCLUSION: Use of primary protein sequences was successful in explaining clinical allergy cross-reactivity. Clinical correlation is needed for use of these epitopes as diagnostic or therapeutic entities for patients with cross-reactive allergic disease. PMID- 24799330 TI - Contribution of peptidoglycan amidation to beta-lactam and lysozyme resistance in different genetic lineages of Staphylococcus aureus. AB - The enzymes responsible for peptidoglycan amidation in Staphylococcus aureus, MurT and GatD, were recently identified and shown to be required for optimal expression of resistance to beta-lactams, bacterial growth, and resistance to lysozyme. In this study, we analyzed the impact of peptidoglycan amidation in representative strains of the most widespread clones of methicillin resistant S. aureus (MRSA). The inhibition of the expression of murT-gatD operon resulted in different phenotypes of resistance to beta-lactams and lysozyme according to the different genetic backgrounds. Further, clonal lineages CC1 and CC398 (community acquired MRSA [CA-MRSA]) showed a stronger dependency on MurT-GatD for resistance to beta-lactams, when compared to the impact of the impairment of the cell wall step catalyzed by MurF. In the remaining backgrounds similar phenotypes of beta lactam resistance were observed upon the impairment of both cell-wall-related genes. Therefore, for CA-related backgrounds, the predominant beta-lactam resistance mechanism seems to involve genes associated with secondary modifications of peptidoglycan. On the other hand, the lack of glutamic acid amidation had a more substantial impact on lysozyme resistance for cells of CA MRSA backgrounds, than for hospital-acquired MRSA (HA-MRSA). However, no significant differences were found in the resistance level of the respective peptidoglycan structure, suggesting that the lysozyme resistance mechanism involves other factors. Taken together, these results suggested that the different genetic lineages of MRSA were able to develop different molecular strategies to overcome the selective pressures experienced during evolution. PMID- 24799332 TI - Synthesis and properties of a new class of fully conjugated azahexacene analogues. AB - Acenes are a traditional class of polycyclic aromatic hydrocarbons (PAHs) which attracted considerable interest during the last decade because of their outstanding p-channel semiconductor properties. More recently, N-heteroacenes have been prepared. These molecules have been shown to be more stable and can exhibit n-channel semiconductor properties. Inspired by these archetype PAHs, we synthesized a novel class of highly persistent azahexacene analogues 3 a-d. These molecules are composed of a core of four fused five-membered rings derived from their respective diketopyrrolopyrroles. These new pi-conjugated scaffolds show broad and intense absorption in the visible region and possess low-lying HOMO and LUMO levels, leading to much better stability compared to that of acenes and most heteroacenes. PMID- 24799333 TI - Yes, obesity is a serious disease but it must also be taken seriously. PMID- 24799334 TI - BNCT for advanced or recurrent head and neck cancer. AB - The therapeutic effect of surgery and/or combination of conventional chemoradiotherapy is limited in the patients with recurrent squamous cell carcinoma (SCC) and locally advanced non-squamous cell carcinoma without malignant melanoma (non-SCC) of the head and neck. Currently, clinical trials of BNCT for head and neck cancers are being conducted in some institutes to verify its the effectiveness. BNCT was performed in 10 patients with recurrent SCC, 7 patients with recurrent non-SCC and 3 patients with newly diagnosed non-SCC in our university between October 2003 and September 2007. Eleven patients showed complete remission and 7 patients showed partial remission of irradiated site. The effective rate [(CR+PR)/total cases] was 90%. No severe acute or chronic normal-tissue reactions were observed in any patients. BNCT is effective and safe in the patients with recurrent SCC and locally advanced non-SCC. PMID- 24799335 TI - Preventive effect of CuCl2 on behavioral alterations and mercury accumulation in central nervous system induced by HgCl2 in newborn rats. AB - This study investigated the benefits of Cu preexposition on Hg effects on behavioral tests, acetylcholinesterase (AChE) activity and Hg, and essential metal contents in the cerebrum and cerebellum of neonate rats. Wistar rats received (subcutaneous) saline or CuCl2 .2H2O (6.9 mg/kg/day) when they were 3 to 7 days old and saline or HgCl2 (5.0 mg/kg/day) when they were 8 to 12 days old. Mercury exposure reduced the performance of rats in the negative geotaxis (3-13 days) and beaker test (17-20 days), inhibited cerebellum AChE activity (13 days), increased cerebrum and cerebellum Hg (13 days), cerebrum Cu (13 days), and cerebrum and cerebellum Zn levels (33 days). The performance of rats in the tail immersion and rotarod tests as well as Fe and Mg levels were not altered by treatments. Copper prevented all alterations induced by mercury. These results are important to open a new perspective of prevention and/or therapy for mercury exposure. PMID- 24799336 TI - Diagnostic dyspraxia by disrupted fiber connections of the posterior corpus callosum after distal anterior cerebral artery aneurysm rupture. PMID- 24799337 TI - Involvement of organic cation transporter 1 and CYP3A4 in retrorsine-induced toxicity. AB - Retrorsine (RTS) is a hepatotoxic pyrrolizidine alkaloid present in plants of the Senecio genus. The present study is aimed at clarifying the role of organic cation transporters (OCTs) in the liver disposition of RTS, and the coupling of OCT1 and cytochrome P450 (CYP) 3A4 in the hepatotoxicity of RTS. MDCK or LLC-PK1 cells stably expressing liver uptake or efflux transporters were used to investigate the interaction of RTS with these transporters. Primary cultured rat hepatocytes (PCRH) and double-transfected MDCK-hOCT1-CYP3A4 cells were used to determine the contribution of OCT1 and CYP3A4 to the toxicity of RTS. The results showed that RTS inhibited the OCT1-mediated 1-methyl-4-phenylpyridinium (MPP(+)) uptake in MDCK-hOCT1 cells with the IC50 of 2.25+/-0.30MUM. The uptake of RTS in MDCK-hOCT1 cells and PCRH was significantly inhibited by OCT1 inhibitors, while hOCT3, human multidrug and toxin extrusion (hMATE) transporter 1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) showed weak or no obvious interaction with RTS. The toxic effect of RTS on the PCRH was attenuated by OCT1 inhibitors, quinidine and (+)-tetrahydropalmatine ((+)-THP). Compared to mock cells, MDCK-CYP3A4 cells showed a decrease in viability after being treated with RTS. Furthermore, RTS showed a more severe toxicity in the OCT1/CYP3A4 double-transfected cells compared to all other cells. Our data suggests that OCT1 mediates the liver-specific uptake of RTS, and plays an important role in RTS-induced hepatotoxicity together with CYP3A4. Consequently, the OCT1 inhibitors could be applied to protect the liver from the toxicity of RTS. PMID- 24799338 TI - Occurrence of Clostridium difficile PCR-ribotype 027 and it's closely related PCR ribotype 176 in hospitals in Poland in 2008-2010. AB - Since 2003, a rising incidence of Clostridium difficile infection (CDI) in North America and Europe has coincided with outbreaks of C. difficile PCR ribotype 027. This ribotype was not observed in Poland until 2008. In the period 2008-2010, outbreaks of antibiotic-associated diarrhoea occurred in three different hospitals in Poland. Of 30 C. difficile isolates available for microbiological characterisation, 17 (56%) were positive for binary toxin genes and belonged to PCR ribotype 027 (n = 7) and its closely related PCR ribotype 176 (n = 10). All 17 binary toxin-positive C. difficile strains demonstrated high-level resistance to fluoroquinolones (minimum inhibitory concentration (MIC) >= 32 mg/L), including ciprofloxacin, gatifloxacin, and moxifloxacin, as well as erythromycin and clindamycin (MIC >= 256 mg/L for both). Of 14 patients from whom clinical information was available, 50% had a severe form of CDI, defined by fever (>38.5 degrees C), decreased kidney function, and high leucocyte count. We conclude that outbreaks of CDI associated with hypervirulent strains belonging to PCR ribotypes 027 and 176 occurred in hospitals in Poland. Further studies evaluating the clinical impact of type 176 are urgently needed. PMID- 24799339 TI - In vitro effect of antibiotics on biofilm formation by Bacteroides fragilis group strains isolated from intestinal microbiota of dogs and their antimicrobial susceptibility. AB - The Bacteroides fragilis group strains colonize the intestinal tract of dogs as commensal bacteria. Nevertheless, they can be opportunistic pathogens responsible for significant morbidity and mortality rates in dogs, like in oral infections, abscesses and wound infections. The purpose of this study was to evaluate antimicrobial susceptibility in B. fragilis strains isolated from dogs intestinal microbiota and to evaluate the effect of subinhibitory concentrations of some antimicrobials on biofilm formation. A total of 30 B. fragilis group strains were tested for susceptibility to ten antimicrobial agents by broth microdilution method. Thirteen B. fragilis strains were tested for biofilm formation and the biofilm producer strains were chosen to evaluate the effect of subinhibitory concentrations of six antimicrobials on biofilm formation. The isolates were susceptible to amoxicillin-clavulanic acid, metronidazole, imipenem and chloramphenicol. Tetracycline and clindamycin were active against 50% and 33% of the strains, respectively. When biofilm-forming strains were grown in the presence of sub-MICs of imipenem and metronidazole, the inhibition of biofilm formation was observed. In contrast, enrofloxacin at 1/2 MIC caused a significant increase in biofilm formation in two of four strains examined. In conclusion, the B. fragilis group strains isolated were susceptible to most of the antimicrobials tested and the sub-MIC concentrations of imipenem, metronidazole and clindamycin were able to inhibit the biofilm formation. PMID- 24799340 TI - Ordered carbohydrate-derived porous carbons immobilized gold nanoparticles as a new electrode material for electrocatalytical oxidation and determination of nicotinamide adenine dinucleotide. AB - The ordered carbohydrate-derived porous carbons (OC-DPCs) were first functionalized with thiol groups (-SH) and then immobilized with gold nanoparticles (AuNPs). The Au-SH-OC-DPCs were characterized by CHN analysis, transmission electron microscopy (TEM), fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and x-ray diffraction (XRD). The Au-SH-OC-DPCs were applied for the fabrication of a new electrochemical sensor. The electrocatalytic capabilities of the new sensor were tested by the oxidation of nicotinamide adenine dinucleotide (NADH) in a 0.1 M Robinson buffer solution (pH 7.0) using cyclic voltammetry (CV), linear sweep voltammetry (LSV), and differential pulse voltammetry (DPV). The Au-SH-OC-DPCs showed a good voltammetric performance in the electrochemical detection of NADH with a low detection limit (1.0 nM), high sensitivity (4.934 MUA/MUM), and wide linear concentration range (5.0 nM-10 uM). PMID- 24799341 TI - Disturbed default mode network connectivity patterns in Alzheimer's disease associated with visual processing. AB - Changes in connectivity of the posterior node of the default mode network (DMN) were studied when switching from baseline to a cognitive task using functional magnetic resonance imaging. In all, 15 patients with mild to moderate Alzheimer's disease (AD) and 18 age-, gender-, and education-matched healthy controls (HC) participated in the study. Psychophysiological interactions analysis was used to assess the specific alterations in the DMN connectivity (deactivation-based) due to psychological effects from the complex visual scene encoding task. In HC, we observed task-induced connectivity decreases between the posterior cingulate and middle temporal and occipital visual cortices. These findings imply successful involvement of the ventral visual pathway during the visual processing in our HC cohort. In AD, involvement of the areas engaged in the ventral visual pathway was observed only in a small volume of the right middle temporal gyrus. Additional connectivity changes (decreases) in AD were present between the posterior cingulate and superior temporal gyrus when switching from baseline to task condition. These changes are probably related to both disturbed visual processing and the DMN connectivity in AD and reflect deficits and compensatory mechanisms within the large scale brain networks in this patient population. Studying the DMN connectivity using psychophysiological interactions analysis may provide a sensitive tool for exploring early changes in AD and their dynamics during the disease progression. PMID- 24799342 TI - Modifiable lifestyle factors in dementia: a systematic review of longitudinal observational cohort studies. AB - BACKGROUND: Numerous population-based longitudinal studies suggest an association between modifiable lifestyle factors and late-life dementia. A comprehensive description of these factors and their quantification criteria is an important preliminary step toward the elucidation of causes and mechanisms underlying the onset and progression of dementia. OBJECTIVE: To present a systematic review of modifiable lifestyle factors associated with dementia risk in longitudinal observational cohort-studies. METHODS: A systematic review of original articles, published in English until December 2013, listed in four electronic databases (including PubMed, MEDLINE, PsycINFO) was conducted. RESULTS: 75 papers from 33 epidemiologic studies met the inclusion criteria. Included papers focused on dietary habits (n = 26), leisure activities (social, physical, mental) (n = 23), beverages (juice, tea, coffee, alcohol) (n = 15), smoking (n = 13), social network (n = 6), and combined lifestyle factors (n = 2). CONCLUSIONS: Broad consensus emerged on the protective role against dementia of leisure activities. Conflicting results were found for the association between dementia and putative risk factors (smoking) and protective factors (mild-to-moderate alcohol consumption, dietary antioxidants, Mediterranean diet, and living with others). However, studies varied largely in the quantification of lifestyle factors in terms of intensity, frequency and duration of exposure, and in the choice of confounders in statistical analyses. The need for standardized quantification criteria emerges, together with the current limitation in reliably tracking the past history of each patient, from childhood and young adulthood to midlife. PMID- 24799343 TI - Use of autologous hematopoietic cell transplantation as initial therapy in multiple myeloma and the impact of socio-geo-demographic factors in the era of novel agents. AB - Very effective combination chemotherapy using novel agents has become available in multiple myeloma (MM). Its impact on the use of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHCT) as part of initial therapy is unknown. Using the National Cancer Data Base, we studied the rate of upfront AHCT use among 137,409 newly diagnosed MM patients from 1998 to 2010 in the United States and determined whether disparity exists among various sociodemographic as well as geographic subgroups. Overall, 12,378 (9.0%) patients received AHCT as part of initial treatment. The use of upfront AHCT increased steadily from 5.2% in 1998 to 12.1% in 2010 (trend test, P < 0.001), with no sign of plateau. This was seen across all socio-geo-demographic subgroups except among patients treated in the Northeast where the rate fell from 8.7% in 1998 to 6.6% in 2010. In multivariable analysis, patients with the following characteristics were the least likely to receive AHCT (odds ratio): year of diagnosis from 1998 to 2003 before the era of novel agents (0.67), older age (0.35), Black race (0.58), Hispanic ethnicity (0.78), low level of education or annual household income (0.55), residence in a metro area (0.66), no or unknown medical insurance (0.30), treatment at a community cancer center (0.16), and treatment facility located in the Northeast region (0.54). Even after the introduction of novel agents, the rate of upfront AHCT in MM continues to increase annually. Significant disparities exist dependent on demographic, social, and geographic factors. PMID- 24799344 TI - Variation of subfoveal choroidal thickness measurements with spherical equivalent. PMID- 24799345 TI - Psoriasis beyond the skin surface: a pilot study on the ocular involvement. AB - The ocular involvement in psoriasis is not a completely well-known problem. The ophthalmologic involvement occurs in about 10 % of patients, particularly in case of arthropathic or pustular psoriasis. Ocular lesions are more common in males, and they often occur during psoriasis exacerbations. Our study aimed to assess the prevalence and type of ocular involvement in psoriasis, by a comparison between psoriasis and healthy subjects, and if/how a 12-week long systemic immunosuppressive therapy is able to modify them. This study involved thirty-two psoriatic patients and thirty-two healthy subjects. Dermatological evaluation was done using Psoriasis Area and Severity Index, Physician Global Assessment, and Dermatology Life Quality Index (PASI, PGA, and DLQI score). Ophthalmological evaluation included ocular surface involvement (Schirmer, Jones, break-up time- BUT, DR-1 camera), retinal pathologies, and ocular surface disease index. Laboratory investigations including the C-reactive protein (CRP) of all the patients were performed. At baseline, the values of Schirmer, Jones, and BUT tests in the patient group were significantly lower compared to controls; moreover, conjunctival hyperemia was more frequent in psoriatic patients than in healthy subjects. Ocular involvement was more prominent in the subset of psoriatic patients with sebo-psoriasis than in general psoriatic population. A statistically significant correlation was found in sebo-psoriasis between PASI and Schirmer, between PASI and Jones, and between PASI and BUT. On the other hand, the results obtained from DR1 camera showed statistically significant difference between psoriatic and sebo-psoriatic patients at the end of the follow up. After 12 weeks of treatment, the mean values of PASI, PGA, DLQI, CRP, and BUT showed significant changes in psoriatic patients. Our findings suggest a high rate of ocular involvement in psoriatic patients, emphasizing the need of performing periodic ophthalmological examinations in order to avoid underestimating eye diseases and to allow early diagnosis and treatment of patients. PMID- 24799346 TI - A case of epibulbar osseous choristoma with review of literature. AB - Epibulbar osseous choristomas are rare congenital simple choristomas consisting of pure bone on the sclera. It is usually recognized in childhood and most often located in the superotemporal quadrant. A case of 7-year-old male who presented with a history of mass in the left eye was reported in this paper. The mass had been present since birth but had showed slight enlargement during the last 6 months. Examination revealed a 7 * 5 mm reddish, hard, and mobile mass located in the superotemporal quadrant. Excisional biopsy was done. On histopathological examination, excised mass was found to be composed of mature bony trabeculae enclosing osteocytes, and diagnosis of epibulbar osseous choristoma was made. PMID- 24799347 TI - Validation of a hypoxia-inducible factor-1 alpha specimen collection procedure and quantitative enzyme-linked immunosorbent assay in solid tumor tissues. AB - Hypoxia-inducible factor-1 alpha (HIF-1alpha) is an important marker of hypoxia in human tumors and has been implicated in tumor progression. Drugs targeting HIF 1alpha are being developed, but the ability to measure drug-induced changes in HIF-1alpha is limited by the lability of the protein in normoxia. Our goal was to devise methods for specimen collection and processing that preserve HIF-1alpha in solid tumor tissues and to develop and validate a two-site chemiluminescent quantitative enzyme-linked immunosorbent assay (ELISA) for HIF-1alpha. We tested various strategies for HIF-1alpha stabilization in solid tumors, including nitrogen gas-purged lysis buffer, the addition of proteasome inhibitors or the prolyl hydroxylase inhibitor 2-hydroxyglutarate, and bead homogenization. Degassing and the addition of 2-hydroxyglutarate to the collection buffer significantly increased HIF-1alpha recovery, whereas bead homogenization in sealed tubes improved HIF-1alpha recovery and reduced sample variability. Validation of the ELISA demonstrated intra- and inter-assay variability of less than 15% and accuracy of 99.8+/-8.3% as assessed by spike recovery. Inter laboratory reproducibility was also demonstrated (R(2)=0.999). Careful sample handling techniques allow us to quantitatively detect HIF-1alpha in samples as small as 2.5MUg of total protein extract, and this method is currently being applied to analyze tumor biopsy specimens in early-phase clinical trials. PMID- 24799348 TI - Measurement of the temperature of the resting rotor in analytical ultracentrifugation. AB - Accurate measurements of rotor temperature are critical for the interpretation of hydrodynamic parameters in analytical ultracentrifugation. We have recently developed methods for a more accurate determination of the temperature of a spinning rotor using iButton temperature loggers. Here we report that the temperature measured with the iButton on the counterbalance of a resting rotor, following thermal equilibration under high vacuum, closely corresponded to the temperature of the spinning rotor with a precision better than 0.2 degrees C. This strategy offers an inexpensive and straightforward approach to monitor the accuracy of the temperature calibration and determine corrective temperature offsets. PMID- 24799350 TI - Cell proliferation dynamics in regeneration of the operculum head appendage in the annelid Pomatoceros lamarckii. AB - Regeneration of lost or damaged appendages is a widespread and ecologically important ability in the animal kingdom, and also of great significance to developing regenerative medicine. The operculum of serpulid polychaetes is one among the many diverse appendages found in the lophotrochozoan superphylum, a clade hitherto understudied with respect to the mechanisms of appendage regeneration. In this study, we establish the normal time course of opercular regeneration in the serpulid Pomatoceros lamarckii and describe cell proliferation patterns in the regenerating opercular filament. The P. lamarckii operculum regenerates through a rapid and consistent series of morphogenetic events. Based on 5-bromo-2'-deoxyuridine (BrdU) labeling and anti-phosphohistone H3 immunohistochemistry, opercular regeneration appears to be a mixture of an early morphallactic stage, and a later phase characterized by widespread proliferative activity within the opercular filament. Tracking residual pigmentation suggests that the distal part of the stump gives rise to the most distal structures of the operculum via morphallactic remodeling, whereas more proximal structures are derived from the proximal stump. Our work underscores the diversity of regenerative strategies employed by animals and introduces P. lamarckii as an emerging model of appendage regeneration. PMID- 24799349 TI - Treatment of poor placentation and the prevention of associated adverse outcomes- what does the future hold? AB - Poor placentation, which manifests as pre-eclampsia and fetal growth restriction, is a major pregnancy complication. The underlying cause is a deficiency in normal trophoblast invasion of the spiral arteries, associated with placental inflammation, oxidative stress, and an antiangiogenic state. Peripartum therapies, such as prenatal maternal corticosteroids and magnesium sulphate, can prevent some of the adverse neonatal outcomes, but there is currently no treatment for poor placentation itself. Instead, management relies on identifying the consequences of poor placentation in the mother and fetus, with iatrogenic preterm delivery to minimise mortality and morbidity. Several promising therapies are currently under development to treat poor placentation, to improve fetal growth, and to prevent adverse neonatal outcomes. Interventions such as maternal nitric oxide donors, sildenafil citrate, vascular endothelial growth factor gene therapy, hydrogen sulphide donors, and statins address the underlying pathology, while maternal melatonin administration may provide fetal neuroprotection. In the future, these may provide a range of synergistic therapies for pre-eclampsia and fetal growth restriction, depending on the severity and gestation of onset. PMID- 24799351 TI - An evaluation of fish early life stage tests for predicting reproductive and longer-term toxicity from plant protection product active substances. AB - The chronic toxicity of chemicals to fish is routinely assessed by using fish early life stage (ELS) test results. Fish full life cycle (FLC) tests are generally required only when toxicity, bioaccumulation, and persistence triggers are met or when there is a suspicion of potential endocrine-disrupting properties. This regulatory approach is based on a relationship between the results of fish ELS and FLC studies first established more than 35 yrs ago. Recently, this relationship has been challenged by some regulatory authorities, and it has been recommended that more substances should undergo FLC testing. In addition, a project proposal has been submitted to the Organisation for Economic Cooperation and Development (OECD) to develop a fish partial life cycle (PLC) test including a reproductive assessment. Both FLC and PLC tests are animal- and resource-intensive and technically challenging and should therefore be undertaken only if there is clear evidence that they are necessary for coming to a regulatory decision. The present study reports on an analysis of a database of paired fish ELS and FLC endpoints for plant protection product active substances from European Union draft assessment reports and the US Environmental Protection Agency Office of Pesticide Programs Pesticide Ecotoxicity Database. Analysis of this database shows a clear relationship between ELS and FLC responses, with similar median sensitivity across substances when no-observed-effect concentrations (NOECs) are compared. There was also no indication that classification of a substance as a mammalian reproductive toxicant leads to more sensitive effects in fish FLC tests than in ELS tests. Indeed, the response of the ELS tests was generally more sensitive than the most sensitive reproduction NOEC from a FLC test. This analysis indicates that current testing strategies and guidelines are fit for purpose and that there is no need for fish full or partial life cycle tests for most plant protection product active substances. PMID- 24799352 TI - PAX1/SOX1 DNA methylation and cervical neoplasia detection: a Taiwanese Gynecologic Oncology Group (TGOG) study. AB - We aimed to determine whether PAX1/SOX1 methylation could be translated to clinical practice for cervical neoplasia detection when used alone and in combination with current cytology-based Pap screening. We conducted a multicenter case-control study in 11 medical centers in Taiwan from December 2009 to November 2010. Six hundred seventy-six patients were included in the analysis, including 330 in the training set and 346 in the testing set. Multiplex quantitative methylation-specific polymerase chain reaction (PCR) was performed with a TaqMan probe system using a LightCycler 480 Real-Time PCR System (Roche). The level of human papilloma virus (HPV) was analyzed using a Hybrid Capture 2 system (Digene). Receiver operating characteristic curves were generated to obtain the best cutoff values from the training data set. The sensitivities, specificities, and accuracies were validated in the testing set. The sensitivities for methylated ((m)) PAX1(m) and SOX1(m) and HPV testing for detecting CIN3(+) lesions were 0.64, 0.71, and 0.89, and the specificities were 0.91, 0.77, and 0.68, respectively. Combined parallel testing of PAX1(m)/SOX1(m) tests with Pap smearing showed superior specificity (0.84/0.71 vs. 0.66, respectively) and similar sensitivity (0.93/0.96 vs. 0.97) to the combination of Pap smear results and HPV testing. Thus, combined parallel testing using Pap smears and PAX1 or SOX1 methylation tests may provide better performance than a combination of Pap smears with HPV testing in detection for cervical neoplasia. PMID- 24799354 TI - Recruiting Community-Based Dementia Patients and Caregivers in a Nonpharmacologic Randomized Trial: What Works and How Much Does It Cost? AB - OBJECTIVES: The aim of this study was to evaluate the yield and cost of three recruitment strategies-direct mail, newspaper advertisements, and community outreach-for identifying and enrolling dementia caregivers into a randomized trial testing a nonpharmacologic approach to enhancing quality of life of patients and caregivers (dyads). METHOD: Enrollment occurred between 2006 and 2008. The number of recruitment inquiries, number and race of enrollees, and costs for each recruitment strategy were recorded. RESULTS: Of 284 inquiries, 237 (83%) dyads enrolled. Total cost for recruitment across methodologies was US$154 per dyad. Direct mailings resulted in the most enrollees (n = 135, 57%) and was the least costly method (US$63 per dyad) compared with newspaper ads (US$224 per dyad) and community outreach (US$350 per dyad). Although enrollees were predominately White, mailings yielded the highest number of non-Whites (n = 37). DISCUSSION: Direct mailings was the most effective and least costly method for enrolling dyads in a nonpharmacologic dementia trial. PMID- 24799355 TI - Modulator effects of meloxicam against doxorubicin-induced nephrotoxicity in mice. AB - Doxorubicin-induced renal toxicity overshadows its anticancer effectiveness. This study is aimed at assessing the possible modulator effects of meloxicam, a cyclooxigenase-2 inhibitor, on doxorubicin-induced nephrotoxicity in mice and exploring some of the modulator mechanisms. Forty male mice were divided for treatment, for 2 weeks, with saline, meloxicam (daily), doxorubicin (twice/week), or both meloxicam and doxorubicin. Doxorubicin induced a significant increase in relative kidney weight to body weight, kidney lipid perooxidation, plasma levels of interleukin-6 and tumor necrosis factor-alpha, kidney caspase-3 activity, and kidney prostaglandin E2 (PGE2) content. Doxorubicin disturbed kidney histology, abrogated renal function tests (serum creatinine, uric acid, and blood urea nitrogen), induced a significant decrease in antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and catalase) and reduced glutathione (GSH) content. The administration of meloxicam with doxorubicin mitigated all doxorubicin-disturbed parameters. Meloxicam ameliorated doxorubicin induced renal injury via inhibition of inflammatory PGE2, inflammatory cytokines, caspase-3 activity, antioxidant effect, and free radical scavenging activity. PMID- 24799353 TI - Lysosomal adaptation: how the lysosome responds to external cues. AB - Recent evidence indicates that the importance of the lysosome in cell metabolism and organism physiology goes far beyond the simple disposal of cellular garbage. This dynamic organelle is situated at the crossroad of the most important cellular pathways and is involved in sensing, signaling, and transcriptional mechanisms that respond to environmental cues, such as nutrients. Two main mediators of these lysosomal adaptation mechanisms are the mTORC1 kinase complex and the transcription factor EB (TFEB). These two factors are linked in a lysosome-to-nucleus signaling pathway that provides the lysosome with the ability to adapt to extracellular cues and control its own biogenesis. Modulation of lysosomal function by acting on TFEB has a profound impact on cellular clearance and energy metabolism and is a promising therapeutic target for a large variety of disease conditions. PMID- 24799357 TI - Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation. AB - Meta-analysis of randomized studies on the use of low-dose aspirin in women at high risk of preeclampsia (PE) has demonstrated that if treatment is initiated at <=16 weeks' gestation, there is significant reduction in the risk of PE [relative risk (RR) 0.47, 95% confidence interval (CI) 0.36-0.62], fetal growth restriction (RR 0.46, 95% CI 0.33-0.64), preterm birth (RR 0.35, 95% CI 0.22-0.57) and perinatal death (RR 0.41, 95% CI 0.19-0.92), whereas the effect of treatment after 16 weeks is substantially less (RR 0.78, 95% CI 0.61-0.99; RR 0.98, 95% CI 0.88-1.08; RR 0.90, 95% CI 0.83-0.97; and RR 0.93, 95% CI 0.73-1.19, respectively). Moreover, the decrease in the risk of PE from early onset treatment seems to be related to the dose of aspirin, and a dose of >80 mg daily should be considered for optimal benefits. PMID- 24799356 TI - Mild cognitive impairment status and mobility performance: an analysis from the Boston RISE study. AB - BACKGROUND: The prevalence of mild cognitive impairment (MCI) and mobility limitations is high among older adults. The aim of this study was to investigate the association between MCI status and both performance-based and self-report measures of mobility in community-dwelling older adults. METHODS: An analysis was conducted on baseline data from the Boston Rehabilitative Impairment Study in the Elderly study, a cohort study of 430 primary care patients aged 65 or older. Neuropsychological tests identified participants with MCI and further subclassified those with impairment in memory domains (aMCI), nonmemory domains (naMCI), and multiple domains (mdMCI). Linear regression models were used to assess the association between MCI status and mobility performance in the Habitual Gait Speed, Figure of 8 Walk, Short Physical Performance Battery, and self-reported Late Life Function and Disability Instrument's Basic Lower Extremity and Advanced Lower Extremity function scales. RESULTS: Participants had a mean age of 76.6 years, and 42% were characterized with MCI. Participants with MCI performed significantly worse than participants without MCI (No-MCI) on all performance and self-report measures (p < .01). All MCI subtypes performed significantly worse than No-MCI on all mobility measures (p < .05) except for aMCI versus No-MCI on the Figure of 8 Walk (p = .054) and Basic Lower Extremity (p = .11). Moreover, compared with aMCI, mdMCI manifested worse performance on the Figure of 8 Walk and Short Physical Performance Battery, and naMCI manifested worse performance on Short Physical Performance Battery and Basic Lower Extremity. CONCLUSIONS: Among older community-dwelling primary care patients, performance on a broad range of mobility measures was worse among those with MCI, appearing poorest among those with nonmemory MCI. PMID- 24799358 TI - Recent introduction of an allodapine bee into Fiji: A new model system for understanding biological invasions by pollinators. AB - Morphology-based studies have suggested a very depauperate bee fauna for islands in the South West Pacific, and recent genetic studies since have indicated an even smaller endemic fauna with many bee species in this region resulting from human-aided dispersal. These introduced species have the potential to both disrupt native pollinator suites as well as augment crop pollination, but for most species the timings of introduction are unknown. We examined the distribution and nesting biology of the long-tongued bee Braunsapis puangensis that was first recorded from Fiji in 2007. This bee has now become widespread in Fiji and both its local abundance and geographical range are likely to increase dramatically. The impacts of this invasion are potentially enormous for agriculture and native ecosystems, but they also provide opportunities for understanding how social insect species adapt to new environments. We outline the major issues associated with this recent invasion and argue that a long-term monitoring study is needed. PMID- 24799360 TI - Thirty-day mortality risk associated with the postoperative nonresumption of angiotensin-converting enzyme inhibitors: a retrospective study of the Veterans Affairs Healthcare System. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors (ACE-Is) are a widely used class of cardiovascular medication. However, limited data exist on the risks of postoperative nonresumption of an ACE-I. OBJECTIVE: To evaluate the factors and 30-day mortality risks associated with the postoperative nonresumption of an ACE I. DESIGN: A retrospective cohort study. SETTING: Veterans Affairs (VA) Healthcare System. PATIENTS: A total of 294,505 admissions in 240,978 patients with multiple preoperative prescription refills (>3) for an ACE-I who underwent inpatient surgery from calendar years 1999 to 2012. INTERVENTION: None. MEASUREMENTS: We classified surgical admissions based upon the timing of postoperative resumption of an ACE-I prescription from the day of surgery through postoperative days 0 to 14 and 15 to 30, and collected 30-day mortality data. We evaluated the relationship between 30-day mortality and the nonresumption of an ACE-I from postoperative day 0 to 14 using proportional hazard regression models, adjusting for patient- and hospital-level risk factors. Sensitivity analyses were conducted using more homogeneous subpopulations and propensity score models. RESULTS: Twenty-five percent of our cohort did not resume an ACE-I during the 14 days following surgery. Nonresumption of an ACE-I within postoperative day 0 to 14 was independently associated with increased 30-day mortality (hazard ratio: 3.44; 95% confidence interval: 3.30-3.60; P < 0.001) compared to the restart group. Sensitivity analyses maintained this relationship. CONCLUSIONS: Nonresumption of an ACE-I is common after major inpatient surgery in the large VA Health Care System. Restarting of an ACE-I within postoperative day 0 to 14 is, however, associated with decreased 30-day mortality. Careful attention to the issue of timely reinstitution of chronic medications such as an ACE-I is indicated. PMID- 24799359 TI - Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information. AB - Cognitive impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is often considered more detrimental to quality of life than seizures. While it has been previously shown that the encoding of memory during behavior is impaired in the pilocarpine model of TLE in rats, how this information is consolidated during the subsequent sleep period remains unknown. In this study, we first report marked deficits in spatial memory performance and severe cell loss in the CA1 layer of the hippocampus lower spatial coherence of firing in TLE rats. We then present the first evidence that the reactivation of behavior-driven patterns of activity of CA1 place cells in the hippocampus is intact in TLE rats. Using a template-matching method, we discovered that real-time (3-5 s) reactivation structure was intact in TLE rats. Furthermore, we estimated the entropy rate of short time scale (~250 ms) bursting activity using block entropies and found that significant, extended temporal correlations exist in both TLE and control rats. Fitting a first-order Markov Chain model to these bursting time series, we found that long sequences derived from behavior were significantly enriched in the Markov model over corresponding models fit on randomized data confirming the presence of replay in shorter time scales. We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats. PMID- 24799361 TI - The right time and "Pl ACE": optimal management of perioperative angiotensin converting enzyme inhibitors. PMID- 24799362 TI - Renal intraspecific variation along an aridity gradient detected by new renal indices in a desert herbivorous rodent. AB - Mammals that live in arid and semi-arid environments in South America present physiological mechanisms that enable them to conserve water. Body water is lost through the kidneys, lungs, skin, and intestines. Regarding renal adaptation for water conservation, several indices have been used to estimate the capacity of the kidneys to produce a maximum urine concentration. Most studies were conducted at an inter-specific level, with only few performed at the intraspecific level. In this work, we compare renal function and morphology among five populations of Southern mountain cavy, Microcavia australis, present along an aridity gradient. We hypothesized that individuals from drier zones would present morphological and functional renal modifications that imply a greater capability to conserve body water. These features were studied considering the classical indices (RMT, PMT, PMA, and RMA) and three new indices that consider area measurements; the latter showed to be more adequate to reflect intraspecific differences. Our results suggest that the morphological modifications of kidneys, that is, the greater areas of renal inner medulla, would be related to the aridity gradient where populations of Southern mountain cavy occur. PMID- 24799363 TI - Steroid treatment increases the recurrence of radiation-induced organizing pneumonia after breast-conserving therapy. AB - Radiation-induced organizing pneumonia (RIOP) is an important complication of postoperative radiotherapy for breast cancer. Unfortunately, conventional corticosteroid therapy is frequently associated with relapses. The aim of this retrospective study was to evaluate the outcomes of steroid treatment in patients with RIOP. In total, 26 patients diagnosed with RIOP from among 2404 women who received radiotherapy after breast-conserving surgery for breast cancer were included and classified into steroid (n = 7) and nonsteroid (n = 19) groups. Serum, sputum, and bronchoalveolar lavage composition; subjective symptoms (cough, fever, and dyspnea); migratory progression; and RIOP relapse were compared between the groups. Treatment type did not affect the duration of the subjective symptoms, which was 1.6 and 1.7 months for the steroid and nonsteroid groups, respectively. In contrast, RIOP relapse and new pulmonary lesions developed in five patients in the steroid group and only three patients in the nonsteroid group (P = 0.014). By assessing RIOP duration as the time to resolution of symptoms and discontinuation of therapy, the median duration of RIOP was significantly longer in the steroid (17.1 months) than that in the nonsteroid group (2.3 months, P = 0.005), primarily because of frequent relapses. After remission, persistent pulmonary dysfunction did not occur in the nonsteroid group. This single-center retrospective study demonstrates that steroid therapy results in frequent relapses and significantly prolongs RIOP duration. Corticosteroid treatment is considered a critical factor in RIOP recurrence. PMID- 24799365 TI - Caging, but not air deprivation, slows tadpole growth and development in the amphibian Xenopus laevis. AB - Xenopus laevis tadpoles raised in submerged cages in normoxic water develop more slowly than tadpoles raised with access to air. This study distinguishes between the effects of being caged and being deprived access to air on development and growth. Tadpoles were raised in high and low density control tanks and in cages in the same tank that were either completely submerged or with the top exposed to air. Experiments were repeated with the cages in different positions relative to the air stones and with and without the water flow from air stones supplemented with a pump. Whereas caging tadpoles has a large effect on their development and growth, additionally depriving them of air has a small effect and this effect can be removed by optimizing water flow through the cage. The effect of caging, though significant in this study, is small compared to the variation in growth and developmental rates that is commonly encountered within and among controls in lab studies. Caging effects can also be diminished by optimizing rearing conditions and/or having exceptionally vigorous tadpoles. The effects of air deprivation and caging thus pose less of a problem for experimenting on air deprived (AD) and air-restored Xenopus tadpoles than their inherent variability in growth and developmental rates and their susceptibility to growth and developmental arrest. Further, the effect of air deprivation in this air breathing amphibian does not pose a conflict with evolutionary hypotheses for lung loss involving lengthening of the larval period and delay in the onset of air breathing. PMID- 24799366 TI - Lumbar puncture opening pressure is not a reliable measure of intracranial pressure in children. AB - There is very little data correlating lumbar puncture pressures to formal intracranial pressure monitoring despite the widespread use of both procedures. The hypothesis was that lumbar puncture is a single-point measurement and hence it may not be a reliable evaluation of intracranial pressure. The study was therefore carried out to compare lumbar puncture opening pressures with the Camino bolt intracranial pressure monitor in children. Twelve children with a mean age of 8.5 years who had both lumbar puncture and intracranial pressure monitoring were analyzed. The mean lumbar puncture opening pressure was 22.4 mm Hg versus a mean Camino bolt intracranial pressure of 7.8 mm Hg (P < .0001). Lumbar puncture therefore significantly overestimates the intracranial pressure in children. There were no complications from the intracranial pressure monitoring, and the procedure changed the treatment of all 12 children avoiding invasive operative procedures in most of the patients. PMID- 24799364 TI - The proteomics of drusen. AB - The formation of extracellular deposits known as drusen below the macular region of the retina correlates with increased risk of severe visual loss from age related macular degeneration (AMD). Inflammation and complement dysregulation contribute to AMD progression; however, disease mechanisms remain incompletely defined. Multiple genetic and environmental factors influence AMD pathology, and although immune system processes play a central role, multiple molecular mechanisms appear to be involved. Drusen proteomics, including the analyses of constituent proteins, oxidative protein modifications, and pattern recognition receptors, provide a foundation for deciphering mechanisms of drusen biogenesis and AMD pathology. PMID- 24799367 TI - Role of virtual reality for cerebral palsy management. AB - Virtual reality is the use of interactive simulations to present users with opportunities to perform in virtual environments that appear, sound, and less frequently, feel similar to real-world objects and events. Interactive computer play refers to the use of a game where a child interacts and plays with virtual objects in a computer-generated environment. Because of their distinctive attributes that provide ecologically realistic and motivating opportunities for active learning, these technologies have been used in pediatric rehabilitation over the past 15 years. The ability of virtual reality to create opportunities for active repetitive motor/sensory practice adds to their potential for neuroplasticity and learning in individuals with neurologic disorders. The objectives of this article is to provide an overview of how virtual reality and gaming are used clinically, to present the results of several example studies that demonstrate their use in research, and to briefly remark on future developments. PMID- 24799368 TI - Prevalence of Bartonella quintana in patients with fever and head lice from rural areas of Sine-Saloum, Senegal. AB - Trench fever is poorly known by the staff of health facilities that manage febrile patients in Senegal. Bartonella quintana DNA was identified in 5 of 274 (2%) febrile patients from two rural dispensaries and 2 of 71 (3%) head lice specimens collected from the same villages. PMID- 24799370 TI - Ross River virus risk associated with dispersal of Aedes (Ochlerotatus) camptorhynchus (Thomson) from breeding habitat into surrounding residential areas: muddy lakes, Western Australia. AB - Rapid population growth in Western Australia has resulted in increased development of land for residential housing, and new developments are often proposed close to water because of intrinsic aesthetic values. However, this placement may place future residents at risk of mosquito-borne disease, of which Ross River virus (RRV) disease is the most common in Australia. Mosquito dispersal data were combined with a spatial analysis of human RRV cases to show that mosquitoes dispersed readily from larval habitat into surrounding low- and high-density residential areas and that residents living within 2 km of mosquito breeding habitat had a significantly higher rate of RRV disease. This finding highlights the importance of planning authorities in state and local governments to consider the implications of mosquito-borne disease risks when assessing residential development applications. PMID- 24799369 TI - Integrated community case management of childhood illness in Ethiopia: implementation strength and quality of care. AB - Ethiopia has scaled up integrated community case management of childhood illness (iCCM) in most regions. We assessed the strength of iCCM implementation and the quality of care provided by health extension workers (HEWs). Data collectors observed HEWs' consultations with sick children and carried out gold standard re examinations. Nearly all HEWs received training and supervision, and essential commodities were available. HEWs provided correct case management for 64% of children. The proportions of children correctly managed for pneumonia, diarrhea, and malnutrition were 72%, 79%, and 59%, respectively. Only 34% of children with severe illness were correctly managed. Health posts saw an average of 16 sick children in the previous 1 month. These results show that iCCM can be implemented at scale and that community-based HEWs can correctly manage multiple illnesses. However, to increase the chances of impact on child mortality, management of severe illness and use of iCCM services must be improved. PMID- 24799372 TI - A door-to-door survey of bed bug (Cimex lectularius) infestations in row homes in Philadelphia, Pennsylvania. AB - We conducted a door-to-door survey in a residential census tract of Philadelphia to estimate the prevalence and spatial patterns of recent bed bug infestations. We interviewed 596 residents, of whom 66 (11.1%) reported recent bed bug infestations. We confirmed current infestations in a subset of 15 (68.2%) of 22 inspected households. Most residents reported that their infestation began within the past year (2012-2013). We found no correlation between property value and infestation status. Spatial analyses showed significant clustering of bed bug infestations only at fine scales, suggesting limited active dispersal of the insects. Residents used a large variety of treatment methods to eliminate bed bugs, but only 48.1% reported success. Our results provide a prevalence estimate of recent bed bug infestations and highlight the importance of passive rather than active dispersal of bed bugs even among dense urban row homes. PMID- 24799371 TI - Temporal changes in prevalence of molecular markers mediating antimalarial drug resistance in a high malaria transmission setting in Uganda. AB - Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistance-mediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003-2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008-2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time. PMID- 24799373 TI - Hemoglobin concentration and parasitemia on hospital admission predict risk of multiple organ dysfunction syndrome among adults with malaria. AB - Risk factors for progression from acute malaria to multiple organ dysfunction syndrome (MODS) are poorly understood. The MODS is commonly diagnosed with the sequential organ failure assessment (SOFA) scale, but this scale has been understudied in patients with severe malaria. We conducted a cohort study among 426 adult males admitted to hospital with malaria in Bogota, Colombia. We estimated SOFA scores and relative risks (RRs) for MODS during hospitalization according to patients' characteristics on admission. Risk of MODS was 7.3% over a median 6.0 days in hospital. Baseline hemoglobin was strongly, inversely associated with MODS (adjusted RR for hemoglobin <= 8.5 g/dL versus hemoglobin > 11 g/dL = 9.5, 95% confidence interval [CI]: 3.6, 25.3). Plasmodium falciparum malaria and parasitemia were positively associated with MODS. There was a strong interaction between baseline parasitemia and hemoglobin on MODS risk. In conclusion, the use of parasitemia and hemoglobin on admission to identify high risk patients deserves consideration. PMID- 24799374 TI - Epidemiologic patterns of Ross River virus disease in Queensland, Australia, 2001 2011. AB - Ross River virus (RRV) infection is a debilitating disease that has a significant impact on population health, economic productivity, and tourism in Australia. This study examined epidemiologic patterns of RRV disease in Queensland, Australia, during January 2001-December 2011 at a statistical local area level. Spatio-temporal analyses were used to identify the patterns of the disease distribution over time stratified by age, sex, and space. The results show that the mean annual incidence was 54 per 100,000 persons, with a male:female ratio of 1:1.1. Two space-time clusters were identified: the areas adjacent to Townsville, on the eastern coast of Queensland, and the southeast areas. Thus, although public health intervention should be considered across all areas in which RRV occurs, it should specifically focus on high-risk regions, particularly during summer and autumn to reduce the social and economic impacts of RRV infection. PMID- 24799375 TI - Phylogeography and molecular epidemiology of an epidemic strain of dengue virus type 1 in Sri Lanka. AB - In 2009, a severe epidemic of dengue disease occurred in Sri Lanka, with higher mortality and morbidity than any previously recorded epidemic in the country. It corresponded to a shift to dengue virus 1 as the major disease-causing serotype in Sri Lanka. Dengue disease reached epidemic levels in the next 3 years. We report phylogenetic evidence that the 2009 epidemic DENV-1 strain continued to circulate within the population and caused severe disease in the epidemic of 2012. Bayesian phylogeographic analyses suggest that the 2009 Sri Lankan epidemic DENV-1 strain may have traveled directly or indirectly from Thailand through China to Sri Lanka, and after spreading within the Sri Lankan population, it traveled to Pakistan and Singapore. Our findings delineate the dissemination route of a virulent DENV-1 strain in Asia. Understanding such routes will be of particular importance to global control efforts. PMID- 24799376 TI - Role of latent membrane protein 1 in chronic active Epstein-Barr virus infection derived T/NK-cell proliferation. AB - Epstein-Barr virus (EBV) predominantly infects B cells and causes B-cell lymphomas, such as Burkitt lymphoma and Hodgkin lymphoma. However, it also infects other types of cells, including T and natural killer (NK) cells, and causes disorders, such as chronic active EBV infection (CAEBV) and T/NK-cell lymphoma. The CAEBV is a lymphoproliferative disease with poor prognosis, where EBV-positive T or NK cells grow rapidly, although the molecular mechanisms that cause the cell expansion still remain to be elucidated. EBV-encoded latent membrane protein 1 (LMP1) is an oncogene that can transform some cell types, such as B cells and mouse fibroblasts, and thus may stimulate cell proliferation in CAEBV. Here, we examined the effect of LMP1 on EBV-negative cells using the cells conditionally expressing LMP1, and on CAEBV-derived EBV-positive cells by inhibiting the function of LMP1 using a dominant negative form of LMP1. We demonstrated that LMP1 was responsible for the increased cell proliferation in the cell lines derived from CAEBV, while LMP1 did not give any proliferative advantage to the EBV-negative cell line. PMID- 24799377 TI - Detecting O-GlcNAc using in vitro sulfation. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) glycosylation, the covalent attachment of N-acetylglucosamine to serine and threonine residues of proteins, is a post-translational modification that shares many features with protein phosphorylation. O-GlcNAc is essential for cell survival and plays important role in many biological processes (e.g. transcription, translation, cell division) and human diseases (e.g. diabetes, Alzheimer's disease, cancer). However, detection of O-GlcNAc is challenging. Here, a method for O-GlcNAc detection using in vitro sulfation with two N-acetylglucosamine (GlcNAc)-specific sulfotransferases, carbohydrate sulfotransferase 2 and carbohydrate sulfotransferase 4, and the radioisotope (35)S is described. Sulfation on free GlcNAc is first demonstrated, and then on O-GlcNAc residues of peptides as well as nuclear and cytoplasmic proteins. It is also demonstrated that the sulfation on O-GlcNAc is sensitive to OGT and O-beta-N-acetylglucosaminidase treatment. The labeled samples are separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and visualized by autoradiography. Overall, the method is sensitive, specific and convenient. PMID- 24799378 TI - Oligosaccharide G19 inhibits U-87 MG human glioma cells growth in vitro and in vivo by targeting epidermal growth factor (EGF) and activating p53/p21 signaling. AB - G19 is a novel homogeneous sulfated oligosaccharide, prepared from Grateloupia filicina. In the present study, we first reported that oligosaccharide G19 exhibited a dose- and time-dependent anti-proliferation effect against U-87 malignant gliomas (MG) human glioma cells. Further studies indicated that G19 strongly bound to epidermal growth factor (EGF), suppressed EGF receptor phosphorylation and interrupted the phosphatidylinositol-3 kinase/Akt pathway in the cancer cells. Moreover, G19 elevated intracellular reactive oxygen species levels and caused endogenous DNA damage. These actions were associated with activation of ataxia-telangiectasia-mutated/checkpoint kinase 2 pathway. The downregulation of MDM2 with stabilizing p53 and the nuclear location of p21 were induced by G19 to cause cell cycle arrest and apoptosis to some extent. Meanwhile, intrinsic mitochondrial pathway and extrinsic death receptor pathway were involved in G19-mediated apoptosis. Pretreatment with free radical scavenger N-acetyl-l-cysteine nearly completely inversed G19-induced cell growth inhibition, cell cycle arrest and apoptosis in U-87 MG cells. Importantly, G19 could inhibit the growth of U-87 MG tumor cells xenograft in nude mice. The results suggested that G19 could be served as a new targeting drug candidate for human glioma treatment. PMID- 24799379 TI - Editorial: Biochemical and molecular engineering. PMID- 24799381 TI - Knockdown of ribosomal protein L39 by RNA interference inhibits the growth of human pancreatic cancer cells in vitro and in vivo. AB - Pancreatic cancer remains a major unsolved health problem lacking a potent therapeutic option. Our previous studies showed that the ribosomal protein L39 (RPL39) gene was up-regulated after long-term silencing of oncogenic KRAS in pancreatic cancer PANC-1 cells, which indicated that RPL39 may be important for pancreatic cancer development and survival. In the current study, small interfering RNA (siRNA) targeting of the RPL39 gene was performed to determine the effects of the RPL39 gene on growth of pancreatic cancer PANC-1 and BxPC-3 cells in vitro and in vivo. Results from in vitro experiments showed that knockdown of RPL39 expression with RPL39-siRNA suppressed cell proliferation and specifically enhanced cell apoptosis significantly in both PANC-1 and BxPC-3 cells. The increase of caspase-8 activities and the loss of mitochondrial membrane potential after RPL39 silencing indicated that the RPL39 gene may be involved in caspase-8-related mitochondrial apoptosis. Further, treatment with the RPL39-siRNA inhibited the growth of a human pancreatic cancer xenograft in BALB/c nude mice, accompanied by a decreased expression of RPL39. In the xenograft tumors with injection of RPL39-siRNA, the expressions of Ki-67 and CD31 were significantly down-regulated, and apoptosis was markedly induced. Our findings suggested that siRNA against the RPL39 gene may be of value for gene therapy of pancreatic cancer. PMID- 24799385 TI - Unit-based interprofessional leadership models in six US hospitals. AB - The landscape of hospital-based care has shifted to place greater emphasis on improving quality and delivering value. In response, hospitals and healthcare organizations must reassess their strategies to improve care delivery in their facilities and beyond. Although these institutional goals may be defined at the executive level, implementation takes place at local sites of care. To lead these efforts, hospitals need to appoint effective leaders at the frontlines. Hospitalists are well poised to take on the role of the local clinical care improvement leader based on their experiences as direct frontline caregivers and their integral roles in hospital-wide quality and safety initiatives. A unit based leadership model consisting of a medical director paired with a nurse manager has been implemented in several hospitals to function as an effector arm in response to the changing landscape of inpatient care. We provide an overview of this new model of leadership and describe the experiences of 6 hospitals that have implemented it. PMID- 24799386 TI - Tablets: The new prescription? PMID- 24799387 TI - Algae-bacteria association inferred by 16S rDNA similarity in established microalgae cultures. AB - Forty cultivable, visually distinct bacterial cultures were isolated from four Baltic microalgal cultures Chlorella pyrenoidosa, Scenedesmus obliquus, Isochrysis sp., and Nitzschia microcephala, which have been maintained for several years in the laboratory. Bacterial isolates were characterized with respect to morphology, antibiotic susceptibility, and 16S ribosomal DNA sequence. A total of 17 unique bacterial strains, almost all belonging to one of three families, Rhodobacteraceae, Rhizobiaceae, and Erythrobacteraceae, were subsequently isolated. The majority of isolated bacteria belong to Rhodobacteraceae. Literature review revealed that close relatives of the bacteria isolated in this study are not only often found in marine environments associated with algae, but also in lakes, sediments, and soil. Some of them had been shown to interact with organisms in their surroundings. A Basic Local Alignment Search Tool study indicated that especially bacteria isolated from the Isochrysis sp. culture were highly similar to microalgae-associated bacteria. Two of those isolates, I1 and I6, belong to the Cytophaga-Flavobacterium-Bacteroides phylum, members of which are known to occur in close communities with microalgae. An UniFrac analysis revealed that the bacterial community of Isochrysis sp. significantly differs from the other three communities. PMID- 24799388 TI - P(NIPAAM-co-HEMA) thermoresponsive hydrogels: an alternative approach for muscle cell sheet engineering. AB - Loss of skeletal muscle tissue caused by traumatic injury or damage due to myopathies produces a deficit of muscle function for which there is still no clinical treatment. Transplantation of myogenic cells, themselves or combined with materials, has been proposed to increase the regenerative capacity of skeletal muscle but it is hampered by many limitations, such as low cell survival and engraftment or immunological reaction and low biocompatibility of the exogenous materials. Recently, myoblast sheet engineering, obtained with thermoresponsive culture dishes, has attracted attention as a new technique for muscle damage treatment. For this purpose, a series of thermoresponsive hydrogels, constituted by poly(N-isopropylacrylamide-co-2 hydroxyethylmethacrylate) [p(NIPAAM-co-HEMA)] were synthesized by a simple and inexpensive free-radical polymerization of the two co-monomers with a redox initiator. Different ratios of N-isopropylacrylamide (NIPAAm) and 2 hydroxyethylmethacrylate (HEMA) have been examined to evaluate the effects on physicochemical, mechanical and optical hydrogel properties. The murine muscle cell line C2 C12 has been exploited to test the cytotoxicity of the thermoresponsive hydrogels, depending on different synthesis conditions. In this study, we have identified a thermoresponsive hydrogel that allows cell adhesion and viability, together with the detachment of viable sheet of muscle cells, giving the chance to develop further applications for muscle damage and disease. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24799389 TI - New antimicrobial and biocompatible implant coating with synergic silver vancomycin conjugate action. AB - Materials foreign to the body are used ever more frequently, as increasing numbers of patients require implants. As a consequence, the numbers of implant related infections have grown as well, and with increasing resistance. Treatments often fail; thus, new antibacterial coating strategies are being developed by scientists to avoid, or at least strongly reduce, bacterial adhesion to implant surfaces. In this study, we focused on producing a self-protective coating combining silver(I) ions and a vancomycin-derived molecule, intelligent pyridinate vancomycin (IPV), with a synergetic and effective action against bacteria. These Ag(I) -IPV conjugate-coated surfaces are well characterized and exhibit strong bactericidal activity in vitro against Staphylococci strains. Furthermore, the released quantities of both drugs from the coated surfaces do not affect their biocompatibility and soft tissue integration. These newly developed Ag(I) -IPV conjugate coatings thus represent a possible and efficient protection method against bacterial adhesion and biofilm formation during and after implant surgery. PMID- 24799390 TI - Spatiotemporal mapping of matrix remodelling and evidence of in situ elastogenesis in experimental abdominal aortic aneurysms. AB - Spatiotemporal changes in the extracellular matrix (ECM) were studied within abdominal aortic aneurysms (AAAs) generated in rats via elastase infusion. At 7, 14 and 21 days post-induction, AAA tissues were divided into proximal, mid- and distal regions, based on their location relative to the renal arteries and the region of maximal aortic diameter. Wall thicknesses differed significantly between the AAA spatial regions, initially increasing due to positive matrix remodelling and then decreasing due to wall thinning and compaction of matrix as the disease progressed. Histological images analysed using custom segmentation tools indicated significant differences in ECM composition and structure vs healthy tissue, and in the extent and nature of matrix remodelling between the AAA spatial regions. Histology and immunofluorescence (IF) labelling provided evidence of neointimal AAA remodelling, characterized by presence of elastin containing fibres. This remodelling was effected by smooth muscle alpha-actin positive neointimal cells, which transmission electron microscopy (TEM) showed to differ morphologically from medial SMCs. TEM of the neointima further showed the presence of elongated deposits of amorphous elastin and the presence of nascent, but not mature, elastic fibres. These structures appeared to be deficient in at least one microfibrillar component, fibrillin-1, which is critical to mature elastic fibre assembly. The substantial production of elastin and elastic fibre like structures that we observed in the AAA neointima, which was not observed elsewhere within AAA tissues, provides a unique opportunity to capitalize on this autoregenerative phenomenon and direct it from the standpoint of matrix organization towards restoring healthy aortic matrix structure, mechanics and function. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24799391 TI - Cryopreservation of canine semen after cold storage in a Neopor box: effect of extender, centrifugation and storage time. AB - The aim of this work was to assess the combined effect of sperm centrifugation, semen extender and storage time before freezing on post-thaw sperm quality and freezability on chilled stored canine semen in a Neopor box. Sperm parameters evaluated were total and progressive sperm motility by Computer-Assisted Sperm Analysis (CASA) and sperm viability and acrosome integrity using a triple fluorescent stain. Sperm quality and freezability indexes were also studied. First, the effect of centrifugation and two commercial extenders from Minitube (Biladyl A and CaniPRO Freeze A) was evaluated in chilled semen after 24 and 45 hours of cold storage. No significant differences were observed between treatments in almost all the sperm parameters assessed. Secondly, chilled semen was frozen after 24 and 45 hours of cold storage in a Neopor box. The best results were obtained when semen was centrifuged, chilled with CaniPRO Freeze A and then frozen after 24 hours of cold storage, showing no differences in both post-thaw sperm quality and freezability in comparison with semen immediately frozen after collection. In conclusion, dog semen centrifuged after collection and extended with CaniPRO Freeze can be frozen after 24 hours of cold storage in a Neopor box, obtaining similar results to semen immediately frozen after collection. PMID- 24799392 TI - Epicardial fat thickness: threshold values and lifestyle association in male adolescents. AB - BACKGROUND: Obese adolescents with high proportion of visceral fat are at higher risk of developing the metabolic syndrome. OBJECTIVES: The study aims to investigate if echocardiographic epicardial fat thickness (EF) could be predictive of visceral obesity (VO) early in life and to provide EF threshold values specific for male adolescents. Further aim was to investigate the association between EF, lifestyle and metabolic disease familiarity. METHODS: Anthropometric data were collected from 102 normal weight and overweight, healthy male adolescents (mean age: 14.91 +/- 1.98 years); bioelectrical impedance analysis and transthoracic echocardiogram were performed in the same sample. Each participant fulfilled a validated self-administered lifestyle questionnaire. RESULTS: We found higher EF values in sedentary adolescents (P < 0.05), in those who never eat fruit and vegetables (P < 0.05), and in those with overweight mothers (P < 0.05). The strongest independent predictor of EF was waist circumference (P < 0.0001). Using the waist to height ratio as a marker of VO, logistic regression analysis revealed that 1 mm EF gain is responsible for seven times higher VO risk (P < 0.0001). Receiver Operating Characteristic (ROC) analysis showed that the optimal cut-off for EF thickness associated to youth VO is 3.2 mm. CONCLUSION: Ultrasonography EF measurement might be a second-level assessment tool, useful to detect early cardiometabolic damage stage. PMID- 24799393 TI - What did we do before mHealth? PMID- 24799394 TI - Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease. AB - OBJECTIVE: Genome-wide association studies (GWAS) have identified genetic variants within multiple risk loci as predisposing to intestinal inflammatory diseases, including Crohn's disease, ulcerative colitis and coeliac disease. Most risk variants affect regulation of transcription, but a critical challenge is to identify which genes and which cell types these variants affect. We aimed to characterise whole transcriptomes for each common T lymphocyte subset resident within the gut mucosa, and use these to infer biological insights and highlight candidate genes of interest within GWAS risk loci. DESIGN: We isolated the four major intestinal T cell populations from pinch biopsies from healthy subjects and generated transcriptomes for each. We computationally integrated these transcriptomes with GWAS data from immune-related diseases. RESULTS: Robust, high quality transcriptomic data were generated from 1 ng of RNA from precisely sorted cell subsets. Gene expression patterns clearly differentiated intestinal T cells from counterparts in peripheral blood and revealed distinct signalling pathways for each intestinal T cell subset. Intestinal-specific T cell transcripts were enriched in GWAS risk loci for Crohn's disease, ulcerative colitis and coeliac disease, but also specific extraintestinal immune-mediated diseases, allowing prediction of novel candidate genes. CONCLUSIONS: This is the first report of transcriptomes for minimally manipulated intestinal T lymphocyte subsets in humans. We have demonstrated that careful processing of mucosal biopsies allows the generation of transcriptomes from as few as 1000 highly purified cells with minimal interindividual variation. Bioinformatic integration of transcriptomic data with recent GWAS data identified specific candidate genes and cell types for inflammatory pathologies. PMID- 24799395 TI - DNA binding dynamics and energetics of cobalt, nickel, and copper metallopeptides. AB - We present molecular dynamics (MD) and Quantum Theory of Atoms in Molecules (QTAIM) analysis of the DNA binding properties of three metallopeptides to the Drew-Dickerson dodecamer DNA: Co(II) -Gly(1) -Gly(2) -His, Ni(II) -Gly(1) -Gly(2) -His and Cu(II) -Gly(1) -Gly(2) -His. Fairly extensive MD simulations were run on each system until a stable binding mode for each ligand was sampled. Clustering analysis was used in an attempt to find representative structures for the most populated clusters sampled during the MD, and a QTAIM analysis was performed. Additionally, MM-PBSA analysis was performed to obtain approximate binding energies for each complex. The results suggest that stable DNA-metallopeptide complexes are formed with each of the three ligands, and that the most stable interaction is with Co(GGH), then Ni(GGH), and finally Cu(GGH). Bond Critical Points (BCP) information between the minor groove of the DNA and the metallopeptides shows an increase in electronic density between Gly(1) , the His residues, and the oxygen atoms of the thymine nucleotide. Overall, we present a detailed theoretical study of the specific interactions involved and the binding properties of each complex formed. PMID- 24799396 TI - Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. AB - Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to interindividual variability in atorvastatin clearance. However, the importance of the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) in atorvastatin uptake clearance (CLupt) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CLupt in 12 human liver samples. The impact of inhibition on atorvastatin CLupt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by liquid chromatography tandem mass spectrometry. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and interindividual differences in CLupt of each transporter in vivo. Subsequently, hepatic uptake impairment on coadministration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7- to 32-fold among the 12 sample donors. The rank order in expression was OATP1B1 > OATP1B3 ~ NTCP ~ OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 >> OATP2B1 > NTCP, although this rank order varied among individuals. The interindividual differences in transporter expression and CLupt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations. PMID- 24799397 TI - Hepatocellular exposure of troglitazone metabolites in rat sandwich-cultured hepatocytes lacking Bcrp and Mrp2: interplay between formation and excretion. AB - Inhibition of bile acid transport by troglitazone (TGZ) and its major metabolite, TGZ sulfate (TS), may lead to hepatocellular accumulation of toxic bile acids; TS accumulation and hepatotoxicity may be associated with impaired TS biliary excretion. This study evaluated the impact of impaired transport of breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) on the hepatobiliary disposition of generated metabolites, TS and TGZ glucuronide (TG). Sandwich-cultured hepatocytes (SCH) from Mrp2-deficient (TR(-)) rats in combination with Bcrp knockdown using RNA interference were employed. The biliary excretion index (BEI) of generated TS was not significantly altered by impaired Bcrp (20.9 to 21.1%) and/or Mrp2 function (24.4% and 17.5% in WT and TR(-) rat SCH, respectively). Thus, loss-of-function of Mrp2 and/or Bcrp do not appear to be risk factors for increased hepatocellular TS accumulation in rats, potentially because of a compensatory transporter(s) that excretes TS into bile. Further investigations revealed that the compensatory TS biliary transporter was not the bile salt export pump (Bsep) or P-glycoprotein (P-gp). Interestingly, TGZ sulfation was significantly decreased in TR(-) compared with WT rat SCH (total recovery: 2.8 versus 5.0% of TGZ dose), resulting in decreased hepatocellular TS accumulation, even though sulfotransferase activity in TR(-) rat hepatocyte S9 fraction was similar. Hepatocellular TG accumulation was significantly increased in TR(-) compared with WT rat SCH due to increased glucuronidation and negligible TG biliary excretion. These data emphasize that the interplay between metabolite formation and excretion determines hepatocellular exposure to generated metabolites such as TS and TG. PMID- 24799402 TI - First trimester tricuspid regurgitation and fetal abnormalities. AB - BACKGROUND: Tricuspid regurgitation (TR) is a common sonographic finding during the fetal life. It has been reported in 7% of normal fetuses. It may be associated with aneuploidy and with both cardiac and extracardiac defects. OBJECTIVES: In this study, we have looked at the characteristics of fetuses with and without TR at 11+0 to 13+6 weeks' gestation. Groups were compared with respect to the following variables: prevalence of chromosomal defects; other markers of aneuploidy; fetal cardiac; and extracardiac anomalies. METHODS: The study group included women, who underwent an ultrasound examination at 11-13+6 weeks' gestation between 2009 and 2012. The inclusion criteria were singleton pregnancies with crown-rump length measurements of 45-84 mm where the pregnancy outcome was known. RESULTS: Some 1075 patients met our inclusion criteria including 979 fetuses without TR and 96 with TR. There were 72 cases of aneuploidy diagnosed (6.7%). Isolated TR was found in 53 euploid fetuses (5.2%). All of the TR(+) aneuploid fetuses (n=40) had additional ultrasound markers present. Extracardiac anatomy showed a higher prevalence of abnormalities in the group of TR positives (12.5%) vs. TR negatives (1.6%). Abnormal cardiac findings were more frequent in the TR-positive group independently of chromosomal status and were found in 18.8% of fetuses with TR and in 1.9% with a normal tricuspid flow. CONCLUSIONS: TR in combination with other markers is the strongest predictor for aneuploidy. TR, as an isolated parameter, is a poor screening tool both for all and for each individual chromosomal abnormality and congenital cardiac defects. PMID- 24799414 TI - Monofunctional platinum(II) complexes with potent tumor cell growth inhibitory activity: the effect of a hydrogen-bond donor/acceptor N-heterocyclic ligand. AB - In this paper we investigate the possibility of further increase the role of the N-donor aromatic base in antitumor Hollis-type compounds by conferring the possibility to act as a hydrogen-bond donor/acceptor. Therefore, we synthesized the Pt(II) complex cis-[PtCl(NH3 )2 (naph)]NO3 (1) containing the 1,8 naphthyridine (naph) ligand. The naphthyridine ligand is generally monodentate, and the second nitrogen atom can act as H-bond donor/acceptor depending upon its protonation state. The possibility of forming such an H-bond could be crucial in the interaction of the drug with DNA or proteins. Apart from the synthesis of the compound, in this study we evaluated its in vitro antitumor activity in a wide panel of tumor cell lines, also including cells selected for their sensitivity/resistance to oxaliplatin, which was compared with that of previously reported complex 2 ([PtI(2,9-dimethyl-1,10-phenanthroline)(1-methyl-cytosine)]I) and oxaliplatin and cisplatin as reference compounds. The cytotoxicity data were correlated with the cellular uptake and the DNA platination levels. Finally, the reactivity of 1 towards guanosine 5'-monophosphate (5'-GMP) and glutathione was investigated to provide insights into its mechanism of action. PMID- 24799416 TI - Graphene-based electroresponsive scaffolds as polymeric implants for on-demand drug delivery. AB - Stimuli-responsive biomaterials have attracted significant attention in the field of polymeric implants designed as active scaffolds for on-demand drug delivery. Conventional porous scaffolds suffer from drawbacks such as molecular diffusion and material degradation, allowing in most cases only a zero-order drug release profile. The possibility of using external stimulation to trigger drug release is particularly enticing. In this paper, the fabrication of previously unreported graphene hydrogel hybrid electro-active scaffolds capable of controlled small molecule release is presented. Pristine ball-milled graphene sheets are incorporated into a three dimensional macroporous hydrogel matrix to obtain hybrid gels with enhanced mechanical, electrical, and thermal properties. These electroactive scaffolds demonstrate controlled drug release in a pulsatile fashion upon the ON/OFF application of low electrical voltages, at low graphene concentrations (0.2 mg mL(-1) ) and by maintaining their structural integrity. Moreover, the in vivo performance of these electroactive scaffolds to release drug molecules without any "resistive heating" is demonstrated. In this study, an illustration of how the heat dissipating properties of graphene can provide significant and previously unreported advantages in the design of electroresponsive hydrogels, able to maintain optimal functionality by overcoming adverse effects due to unwanted heating, is offered. PMID- 24799415 TI - Metabolic profiles of biological aging in American Indians: the Strong Heart Family Study. AB - Short telomere length, a marker of biological aging, has been associated with age related metabolic disorders. Telomere attrition induces profound metabolic dysfunction in animal models, but no study has examined the metabolome of telomeric aging in human. Here we studied 423 apparently healthy American Indians participating in the Strong Family Heart Study. Leukocyte telomere length (LTL) was measured by qPCR. Metabolites in fasting plasma were detected by untargeted LC/MS. Associations of LTL with each metabolite and their combined effects were examined using generalized estimating equation adjusting for chronological age and other aging-related factors. Multiple testing was corrected using the q-value method (q<0.05). Of the 1,364 distinct m/z features detected, nineteen metabolites in the classes of glycerophosphoethanolamines, glycerophosphocholines, glycerolipids, bile acids, isoprenoids, fatty amides, or L-carnitine ester were significantly associated with LTL, independent of chronological age and other aging-related factors. Participants with longer (top tertile) and shorter (bottom tertile) LTL were clearly separated into distinct groups using a multi-marker score comprising of all these metabolites, suggesting that these newly detected metabolites could be novel metabolic markers of biological aging. This is the first study to interrogate the human metabolome of telomeric aging. Our results provide initial evidence for a metabolic control of LTL and may reveal previously undescribed new roles of various lipids in the aging process. PMID- 24799417 TI - Nano regulation of cisplatin chemotherapeutic behaviors by biomineralization controls. AB - Controllable biomineralization modification of cisplatin can alter the drug biodistribution with extended circulation time in blood. These changes increase passive tumor target and decrease non-specific accumulation significantly, which can improve chemotherapeutic effect with minimum side effects. PMID- 24799418 TI - Oligolysine-conjugated zinc(II) phthalocyanines as efficient photosensitizers for antimicrobial photodynamic therapy. AB - A series of zinc(II) phthalocyanines conjugated with an oligolysine chain (n=2, 4, and 8) were synthesized and characterized by using various spectroscopic methods. As shown by using UV/Vis and fluorescence spectroscopic methods, these compounds were nonaggregated in N,N-dimethylformamide, and gave a weak fluorescence emission and high singlet oxygen quantum yield (Phi(Delta) =0.86 0.89) as a result of their di-alpha-substitution. They became slightly aggregated in water with 0.05 % Cremophor EL, but they could still generate singlet oxygen effectively. The antimicrobial photodynamic activities of these compounds were then examined against various bacterial strains, including the Gram-positive methicillin-sensitive Staphylococcus aureus ATCC 25923 and methicillin-resistant Staphylococcus aureus ATCC BAA-43, and the Gram-negative Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 27853. Generally, the dyes were much more potent toward the Gram-positive bacteria. Only 15 to 90 nM of these photosensitizers was required to induce a 4 log reduction in the cell viability of the strains. For Escherichia coli, the photocytotoxicity increased with the length of the oligolysine chain. The octalysine derivative showed the highest potency with a 4 log reduction concentration of 0.8 MUM. Pseudomonas aeruginosa was most resistant to the photodynamic treatment. The potency of the tetralysine derivative toward a series of clinical strains of Staphylococcus aureus was also examined and found to be comparable with that toward the nonclinical counterparts. Moreover, the efficacy of these compounds in photodynamic inactivation of viruses was also examined. They were highly photocytotoxic against the enveloped viruses influenza A virus (H1N1) and herpes simplex virus type 1 (HSV1), but exhibited no significant cytotoxicity against the nonenveloped viruses adenovirus type 3 (Ad3) or coxsackievirus (Cox B1). The octalysine derivative also showed the highest potency with an IC(50) value of 0.05 nM for the two enveloped viruses. PMID- 24799419 TI - Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate. AB - Evidence from biological and human studies strongly supports a role for MMP and TIMP genes as candidate genes for non-syndromic cleft lip with or without cleft palate (NSCL/P). We previously showed the association of promoter polymorphisms in MMP3 (rs3025058 and rs522616) and TIMP2 (rs8179096) with NSCL/P. In this study, we examined the functional significance of these polymorphisms. A specific DNA-protein complex for MMP3 rs522616 A was detected, and this allele by itself showed greater promoter activity than the G allele. However, the effect of rs522616 was ultimately regulated by the rs3025058 allele on the background. For TIMP2 rs8179096, the T allele showed a 2.5-fold increase in promoter activity when compared with allele C, whereas both C and T alleles were found to bind to nuclear factor kappa B. Our results provide new evidence that promoter polymorphisms in MMP3 and TIMP2 are functional and may affect gene transcription with possible effects on craniofacial development leading to NSCL/P. PMID- 24799420 TI - DPP and DSP are Necessary for Maintaining TGF-beta1 Activity in Dentin. AB - Porcine dentin sialophosphoprotein (DSPP) is the most abundant non-collagenous protein in dentin. It is processed by proteases into 3 independent proteins: dentin sialoprotein (DSP), dentin glycoprotein (DGP), and dentin phosphoprotein (DPP). We fractionated DPP and DSP along with TGF-beta activity by ion exchange (IE) chromatography from developing pig molars and measured their alkaline phosphatase (ALP)-stimulating activity in human periodontal (HPDL) cells with or without TGF-beta receptor inhibitor. We then purified TGF-beta-unbound or -bound DPP and DSP by reverse-phase high-performance liquid chromatography (RP-HPLC) using the ALP-HPDL system. The TGF-beta isoform bound to DPP and DSP was identified as being TGF-beta1 by both ELISA and LC-MS/MS analysis. We incubated carrier-free human recombinant TGF-beta1 (CF-hTGF-beta1) with TGF-beta-unbound DPP or DSP and characterized the binding on IE-HPLC using the ALP-HPDL system. When only CF-hTGF-beta1 was incubated, approximately 3.6% of the ALP-stimulating activity remained. DPP and DSP rescued the loss of TGF-beta1 activity. Approximately 19% and 10% of the ALP stimulating activities were retained by the binding of TGF-beta to DPP and DSP, respectively. The type I collagen infrequently bound to CF-hTGF-beta1. We conclude that both DPP and DSP help retain TGF-beta1 activity in porcine dentin. PMID- 24799421 TI - BET Inhibitor JQ1 Blocks Inflammation and Bone Destruction. AB - BET proteins are a group of epigenetic regulators controlling transcription through reading acetylated histone tails and recruiting transcription complexes. They are considered as potential therapeutic targets in many distinct diseases. A novel synthetic bromodomain and extraterminal domain (BET) inhibitor, JQ1, was proved to suppress oncogene transcription and inflammatory responses. The present study was aimed to investigate the effects of JQ1 on inflammatory response and bone destruction in experimental periodontitis. We found that JQ1 significantly suppressed lipopolysaccharide (LPS)-stimulated inflammatory cytokine transcription, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), as well as receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast markers, such as c-Fos, nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K in vitro. JQ1 also inhibited toll-like receptors 2/4 (TLR2/4) expression and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) phosphorylation and nuclear translocation. Chromatin immunoprecipitation and quantitative polymerase chain reaction (ChIP qPCR) revealed that JQ1 neutralized BRD4 enrichment at several gene promoter regions, including NF-kappaB, TNF-alpha, c-Fos, and NFATc1. In a murine periodontitis model, systemic administration of JQ1 significantly inhibited inflammatory cytokine expression in diseased gingival tissues. Alveolar bone loss was alleviated in JQ1-treated mice because of reduced osteoclasts in periodontal tissues. These unprecedented results suggest the BET inhibitor JQ1 as a prospective new approach for treating periodontitis. PMID- 24799423 TI - From Phenotype to Genotype: Enter Genomics and Transformation of Primary Health Care around the World. AB - The progress in phenotype descriptions, measurements, and analyses has been remarkable in the last 50 years. Biomarkers (proteins, carbohydrates, lipids, hormones, various RNAs and cDNAs, microarrays) have been discovered and correlated with diseases and disorders, as well as physiological responses to disease, injury, stress, within blood, urine, and saliva. Three-dimensional digital imaging advanced how we "see" and utilize phenotypes toward diagnosis, treatment, and prognosis. In each example, scientific discovery led to inform clinical health care. In tandem, genetics evolved from Mendelian inheritance (single gene mutations) to include Complex Human Diseases (multiple gene-gene and gene-environment interactions). In addition, epigenetics blossomed with new insights about gene modifiers (e.g., histone and non-histone chromosomal protein methylation, acetylation, sulfation, phosphorylation). We are now at the beginning of a new era using human and microbial whole-genome sequencing to make significant healthcare decisions as to risk, stratification of patients, diagnosis, treatments, and outcomes. Are we as clinicians, scientists, and educators prepared to expand our scope of practice, knowledge base, integration into primary health care (medicine, pharmacy, nursing, and allied health science professions), and clinical approaches to craniofacial-oral-dental health care? The time is now. PMID- 24799422 TI - Stem Cells and Calcium Phosphate Cement Scaffolds for Bone Regeneration. AB - Calcium phosphate cements (CPCs) have excellent biocompatibility and osteoconductivity for dental, craniofacial, and orthopedic applications. This article reviews recent developments in stem cell delivery via CPC for bone regeneration. This includes: (1) biofunctionalization of the CPC scaffold, (2) co culturing of osteoblasts/endothelial cells and prevascularization of CPC, (3) seeding of CPC with different stem cell species, (4) human umbilical cord mesenchymal stem cell (hUCMSC) and bone marrow MSC (hBMSC) seeding on CPC for bone regeneration, and (5) human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC) seeding with CPC for bone regeneration. Cells exhibited good attachment/proliferation in CPC scaffolds. Stem-cell-CPC constructs generated more new bone and blood vessels in vivo than did the CPC control without cells. hUCMSCs, hESC-MSCs, and hiPSC-MSCs in CPC generated new bone and blood vessels similar to those of hBMSCs; hence, they were viable cell sources for bone engineering. CPC with hESC-MSCs and hiPSC-MSCs generated new bone two- to three-fold that of the CPC control. Therefore, this article demonstrates that: (1) CPC scaffolds are suitable for delivering cells; (2) hUCMSCs, hESCs, and hiPSCs are promising alternatives to hBMSCs, which require invasive procedures to harvest with limited cell quantity; and (3) stem-cell-CPC constructs are highly promising for bone regeneration in dental, craniofacial, and orthopedic applications. PMID- 24799424 TI - Extra-articular ACL Reconstruction and Pivot Shift: In Vivo Dynamic Evaluation With Navigation. AB - BACKGROUND: The pivot-shift test is considered a reliable examination to evaluate the results of anterior cruciate ligament (ACL) reconstruction, as it strongly correlates with patient satisfaction, giving-way episodes, and activity level. The addition of lateral tenodesis (LT) to current techniques of intra-articular reconstruction with a hamstring graft could potentially improve knee laxity in cases of severe rotational instability. PURPOSE: To biomechanically investigate the effect of intra- and extra-articular ACL reconstructions on knee laxity and the pivot-shift phenomenon. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty patients underwent anatomic single-bundle ACL reconstruction with doubled semitendinosus and gracilis tendons with the addition of extra-articular reconstruction. In patients in group A, intra-articular reconstruction was performed first and LT thereafter; in patients in group B, LT was performed first and intra-articular reconstruction thereafter. A navigator equipped with software designed for both static and dynamic evaluations was used to measure maximum anterior tibial translation (ATT) and axial tibial rotation (ATR) at 30 degrees of flexion (static evaluation) and during the pivot-shift test (dynamic evaluation). Measurements were performed before reconstruction, after the first procedure, and after the second procedure. RESULTS: For the static evaluation, in group A, the mean ATT significantly decreased from 14.1 +/- 3.7 mm in the preoperative (ACL-deficient) condition to 6.0 +/- 1.9 mm after ACL reconstruction and to 5.3 +/- 1.6 mm after LT. The mean ATR at 30 degrees of knee flexion significantly decreased from 35.7 degrees +/- 4.8 degrees to 28.9 degrees +/- 4.1 degrees and to 20.9 degrees +/- 4.8 degrees , respectively. In group B, the mean ATT significantly decreased from 13.5 +/- 6.5 mm in the preoperative (ACL deficient) condition to 10.2 +/- 3.2 mm after LT and to 4.0 +/- 1.6 mm after ACL reconstruction. The mean ATR at 30 degrees of knee flexion significantly decreased from 36.7 degrees +/- 4.8 degrees to 26.2 degrees +/- 6.2 degrees and to 23.5 degrees +/- 4.9 degrees , respectively. For the dynamic evaluation (pivot-shift test), in group A, the mean ATT significantly decreased from 15.0 +/ 6.8 mm in the preoperative (ACL-deficient) condition to 9.4 +/- 6.4 mm after ACL reconstruction and to 8.5 +/- 5.4 mm after LT. The mean ATR significantly decreased from 16.9 degrees +/- 4.7 degrees to 11.6 degrees +/- 4.1 degrees and to 6.1 degrees +/- 2.2 degrees , respectively. In group B, the mean ATT significantly decreased from 12.5 +/- 3.3 mm in the preoperative (ACL-deficient) condition to 9.1 +/- 5.9 mm after LT and to 8.1 +/- 5.4 mm after ACL reconstruction. The mean ATR significantly decreased from 16.0 degrees +/- 4.5 degrees to 9.2 degrees +/- 4.3 degrees and to 7.5 degrees +/- 4.0 degrees , respectively. CONCLUSION/CLINICAL RELEVANCE: Extra-articular reconstruction had little effect in reducing the anterior displacement of the tibia at 30 degrees of flexion, but it was more effective than intra-articular reconstruction in reducing ATR. Anatomic ACL reconstruction and LT were synergic in controlling the pivot-shift phenomenon. PMID- 24799425 TI - Structural Properties of the Meniscal Roots. AB - BACKGROUND: Current surgical techniques for meniscal root repair reattach the most prominent, dense portion of the meniscal root and fail to incorporate recently identified peripheral, supplemental attachment fibers. The contribution of supplemental fibers to the biomechanical properties of native meniscal roots is unknown. HYPOTHESIS/PURPOSE: The purpose was to quantify the ultimate failure strengths, stiffness, and attachment areas of the native posterior medial (PM), posterior lateral (PL), anterior medial (AM), and anterior lateral (AL) meniscal roots compared with the most prominent, dense meniscal root attachment after sectioning of supplemental fibers. It was hypothesized that the ultimate failure strength, stiffness, and attachment area of each native root would be significantly higher than those of the respective sectioned root. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve matched pairs of male human cadaveric knees were used. The 4 native meniscal roots were left intact in the native group, whereas the roots in the contralateral knee (sectioned group) were dissected free of all supplemental fibers. A coordinate measuring device quantified the amount of tissue resected in the sectioned group compared with the native group. A dynamic tensile testing machine pulled each root in line with its circumferential fibers. All root attachments were preconditioned from 10 to 50 N at a rate of 0.1 Hz for 10 cycles and subsequently pulled to failure at a rate of 0.5 mm/s. RESULTS: Supplemental fibers composed a significant percentage of the native PM, PL, and AM meniscal root attachment areas. Mean ultimate failure strengths (in newtons) of the native PM, PL, and AM roots were significantly higher than those of the sectioned state, while the ultimate failure strength of the native AL root was indistinguishable from that of the sectioned state. CONCLUSION: Three of the 4 meniscal root attachments (PM, PL, AM) contained supplemental fibers that accounted for a significant percentage of the native root attachment areas, and these fibers significantly contributed to the failure strengths of the native roots. CLINICAL RELEVANCE: These supplemental fibers are not routinely reattached during root repair surgery, suggesting that current techniques fail to reattach the biomechanically relevant attachments of native meniscal roots. PMID- 24799426 TI - Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7-dependent regulatory genes for retinal ganglion cell formation. AB - The bHLH transcription factor ATOH7 (Math5) is essential for establishing retinal ganglion cell (RGC) fate. However, Atoh7-expressing retinal progenitor cells (RPCs) can give rise to all retinal cell types, suggesting that other factors are involved in specifying RGCs. The basis by which a subpopulation of Atoh7 expressing RPCs commits to an RGC fate remains uncertain but is of critical importance to retinal development since RGCs are the earliest cell type to differentiate. To better understand the regulatory mechanisms leading to cell fate specification, a binary genetic system was generated to specifically label Atoh7-expressing cells with green fluorescent protein (GFP). Fluorescence activated cell sorting (FACS)-purified GFP(+) and GFP(-) cells were profiled by RNA-seq. Here, we identify 1497 transcripts that were differentially expressed between the two RPC populations. Pathway analysis revealed diminished growth factor signaling in Atoh7-expressing RPCs, indicating that these cells had exited the cell cycle. In contrast, axon guidance signals were enriched, suggesting that axons of Atoh7-expressing RPCs were already making synaptic connections. Notably, many genes enriched in Atoh7-expressing RPCs encoded transcriptional regulators, and several were direct targets of ATOH7, including, and unexpectedly, Ebf3 and Eya2. We present evidence for a Pax6-Atoh7-Eya2 pathway that acts downstream of Atoh7 but upstream of differentiation factor Pou4f2. EYA2 is a protein phosphatase involved in protein-protein interactions and posttranslational regulation. These properties, along with Eya2 as an early target gene of ATOH7, suggest that EYA2 functions in RGC specification. Our results expand current knowledge of the regulatory networks operating in Atoh7-expressing RPCs and offer new directions for exploring the earliest aspects of retinogenesis. PMID- 24799427 TI - Gold-nanorod-assisted near-infrared stimulation of primary auditory neurons. AB - Infrared stimulation offers an alternative to electrical stimulation of neuronal tissue, with potential for direct, non-contact activation at high spatial resolution. Conventional methods of infrared neural stimulation (INS) rely on transient heating due to the absorption of relatively intense laser beams by water in the tissue. However, the water absorption also limits the depth of penetration of light in tissue. Therefore, the use of a near-infrared laser at 780 nm to stimulate cultured rat primary auditory neurons that are incubated with silica-coated gold nanorods (Au NRs) as an extrinsic absorber is investigated. The laser-induced electrical behavior of the neurons is observed using whole-cell patch clamp electrophysiology. The nanorod-treated auditory neurons (NR-ANs) show a significant increase in electrical activity compared with neurons that are incubated with non-absorbing silica-coated gold nanospheres and control neurons with no gold nanoparticles. The laser-induced heating by the nanorods is confirmed by measuring the transient temperature increase near the surface of the NR-ANs with an open pipette electrode. These findings demonstrate the potential to improve the efficiency and increase the penetration depth of INS by labeling nerves with Au NRs and then exposing them to infrared wavelengths in the water window of tissue. PMID- 24799429 TI - Oxidative stress and antioxidant response in fibroblasts from Werner and atypical Werner syndromes. AB - Werner Syndrome (WS, ICD-10 E34.8, ORPHA902) and Atypical Werner Syndrome (AWS, ICD-10 E34.8, ORPHA79474) are very rare inherited syndromes characterized by premature aging. While approximately 90% of WS individuals have any of a range of mutations in theWRN gene, there exists a clinical subgroup in which the mutation occurs in the LMNA/C gene in heterozygosity. Although both syndromes exhibit an age-related pleiotropic phenotype, AWS manifests the onset of the disease during childhood, while major symptoms in WS appear between the ages of 20 and 30. To study the molecular mechanisms of progeroid diseases provides a useful insight into the normal aging process. Main changes found were the decrease in Cu/Zn and Mn SOD activities in the three cell lines. In AWS, both mRNA SOD and protein levels were also decreased. Catalase and glutathione peroxidases decrease, mainly in AWS. Glutaredoxin (Grx) and thioredoxin (Trx) protein expression was lower in the three progeroid cell lines. Grx and Trx were subjected to post transcriptional regulation, because protein expression was reduced although mRNA levels were not greatly affected in WS. Low antioxidant defense and oxidative stress occur simultaneously in these rare genetic instability disorders at the onset of progeroid disease. PMID- 24799430 TI - Nano-dissection and sequencing of DNA at single sub-nuclear structures. AB - The relative positioning of gene loci within a mammalian nucleus is non-random and plays a role in gene regulation. Some sub-nuclear structures may represent "hubs" that bring specific genetic loci into close proximity where co-regulatory mechanisms can operate. The identification of loci in proximity to a shared sub nuclear structure can provide insights into the function of the associated structure, and reveal relationships between the loci sharing a common association. A technique is introduced based on the nano-dissection of DNA from thin sections of cells by high-precision nano-tools operated inside a scanning electron microscope. The ability to dissect and identify gene loci occupying a shared site at a single sub-nuclear structure is demonstrated here for the first time. The technique is applied to the nano-dissection of DNA in vicinity of a single promyelocytic leukemia nuclear body (PML NB), and reveals novel loci from several chromosomes that are confirmed to associate at PML NBs with statistical significance in a cell population. Furthermore, it is demonstrated that pairs of loci from different chromosomes congregate at the same nuclear body. It is proposed that this technique is the first that allows the de novo determination of gene loci associations with single nuclear sub-structures. PMID- 24799431 TI - PredictProtein--an open resource for online prediction of protein structural and functional features. AB - PredictProtein is a meta-service for sequence analysis that has been predicting structural and functional features of proteins since 1992. Queried with a protein sequence it returns: multiple sequence alignments, predicted aspects of structure (secondary structure, solvent accessibility, transmembrane helices (TMSEG) and strands, coiled-coil regions, disulfide bonds and disordered regions) and function. The service incorporates analysis methods for the identification of functional regions (ConSurf), homology-based inference of Gene Ontology terms (metastudent), comprehensive subcellular localization prediction (LocTree3), protein-protein binding sites (ISIS2), protein-polynucleotide binding sites (SomeNA) and predictions of the effect of point mutations (non-synonymous SNPs) on protein function (SNAP2). Our goal has always been to develop a system optimized to meet the demands of experimentalists not highly experienced in bioinformatics. To this end, the PredictProtein results are presented as both text and a series of intuitive, interactive and visually appealing figures. The web server and sources are available at http://ppopen.rostlab.org. PMID- 24799434 TI - The personal genome browser: visualizing functions of genetic variants. AB - Advances in high-throughput sequencing technologies have brought us into the individual genome era. Projects such as the 1000 Genomes Project have led the individual genome sequencing to become more and more popular. How to visualize, analyse and annotate individual genomes with knowledge bases to support genome studies and personalized healthcare is still a big challenge. The Personal Genome Browser (PGB) is developed to provide comprehensive functional annotation and visualization for individual genomes based on the genetic-molecular-phenotypic model. Investigators can easily view individual genetic variants, such as single nucleotide variants (SNVs), INDELs and structural variations (SVs), as well as genomic features and phenotypes associated to the individual genetic variants. The PGB especially highlights potential functional variants using the PGB built in method or SIFT/PolyPhen2 scores. Moreover, the functional risks of genes could be evaluated by scanning individual genetic variants on the whole genome, a chromosome, or a cytoband based on functional implications of the variants. Investigators can then navigate to high risk genes on the scanned individual genome. The PGB accepts Variant Call Format (VCF) and Genetic Variation Format (GVF) files as the input. The functional annotation of input individual genome variants can be visualized in real time by well-defined symbols and shapes. The PGB is available at http://www.pgbrowser.org/. PMID- 24799432 TI - The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host-parasite interaction. AB - Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5' ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct. PMID- 24799433 TI - Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. AB - Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disorder resulting from expression of RNA containing an expanded CUG repeat (CUG(exp)). The pathogenic RNA is retained in nuclear foci. Poly-(CUG) binding proteins in the Muscleblind-like (MBNL) family are sequestered in foci, causing misregulated alternative splicing of specific pre-mRNAs. Inhibitors of MBNL1-CUG(exp) binding have been shown to restore splicing regulation and correct phenotypes in DM1 models. We therefore conducted a high-throughput screen to identify novel inhibitors of MBNL1-(CUG)12 binding. The most active compound was lomofungin, a natural antimicrobial agent. We found that lomofungin undergoes spontaneous dimerization in DMSO, producing dilomofungin, whose inhibition of MBNL1-(CUG)12 binding was 17-fold more potent than lomofungin itself. However, while dilomofungin displayed the desired binding characteristics in vitro, when applied to cells it produced a large increase of CUG(exp) RNA in nuclear foci, owing to reduced turnover of the CUG(exp) transcript. By comparison, the monomer did not induce CUG(exp) accumulation in cells and was more effective at rescuing a CUG(exp)-induced splicing defect. These results support the feasibility of high throughput screens to identify compounds targeting toxic RNA, but also demonstrate that ligands for repetitive sequences may have unexpected effects on RNA decay. PMID- 24799435 TI - SymD webserver: a platform for detecting internally symmetric protein structures. AB - Internal symmetry of a protein structure is the pseudo-symmetry that a single protein chain sometimes exhibits. This is in contrast to the symmetry with which monomers are arranged in many multimeric protein complexes. SymD is a program that detects proteins with internal symmetry. It proved to be useful for analyzing protein structure, function and modeling. This web-based interactive tool was developed by implementing the SymD algorithm. To the best of our knowledge, SymD webserver is the first tool of its kind with which users can easily study the symmetry of the protein they are interested in by uploading the structure or retrieving it from databases. It uses the Galaxy platform to take advantage of its extensibility and displays the symmetry properties, the symmetry axis and the sequence alignment of the structures before and after the symmetry transformation via an interactive graphical visualization environment in any modern web browser. An Example Run video displays the workflow to help users navigate. SymD webserver is publicly available at http://symd.nci.nih.gov. PMID- 24799436 TI - deepTools: a flexible platform for exploring deep-sequencing data. AB - We present a Galaxy based web server for processing and visualizing deeply sequenced data. The web server's core functionality consists of a suite of newly developed tools, called deepTools, that enable users with little bioinformatic background to explore the results of their sequencing experiments in a standardized setting. Users can upload pre-processed files with continuous data in standard formats and generate heatmaps and summary plots in a straight forward, yet highly customizable manner. In addition, we offer several tools for the analysis of files containing aligned reads and enable efficient and reproducible generation of normalized coverage files. As a modular and open source platform, deepTools can easily be expanded and customized to future demands and developments. The deepTools webserver is freely available at http://deeptools.ie-freiburg.mpg.de and is accompanied by extensive documentation and tutorials aimed at conveying the principles of deep-sequencing data analysis. The web server can be used without registration. deepTools can be installed locally either stand-alone or as part of Galaxy. PMID- 24799437 TI - Staufen1-mediated mRNA decay induces Requiem mRNA decay through binding of Staufen1 to the Requiem 3'UTR. AB - Requiem (REQ/DPF2) was originally identified as an apoptosis-inducing protein in mouse myeloid cells and belongs to the novel Kruppel-type zinc finger d4-protein family of proteins, which includes neuro-d4 (DPF1) and cer-d4 (DPF3). Interestingly, when a portion of the REQ messenger ribonucleic acid (mRNA) 3' untranslated region (3'UTR), referred to as G8, was overexpressed in K562 cells, beta-globin expression was induced, suggesting that the 3'UTR of REQ mRNA plays a physiological role. Here, we present evidence that the REQ mRNA 3'UTR, along with its trans-acting factor, Staufen1 (STAU1), is able to reduce the level of REQ mRNA via STAU1-mediated mRNA decay (SMD). By screening a complementary deoxyribonucleic acid (cDNA) expression library with an RNA-ligand binding assay, we identified STAU1 as an interactor of the REQ mRNA 3'UTR. Specifically, we provide evidence that STAU1 binds to putative 30-nucleotide stem-loop-structured RNA sequences within the G8 region, which we term the protein binding site core; this binding triggers the degradation of REQ mRNA and thus regulates translation. Furthermore, we demonstrate that siRNA-mediated silencing of either STAU1 or UPF1 increases the abundance of cellular REQ mRNA and, consequently, the REQ protein, indicating that REQ mRNA is a target of SMD. PMID- 24799438 TI - Genomic imprinting, methylation and parent-of-origin effects in reciprocal hybrid endosperm of castor bean. AB - Genomic imprinting often results in parent-of-origin specific differential expression of maternally and paternally inherited alleles. In plants, the triploid endosperm is where gene imprinting occurs most often, but aside from studies on Arabidopsis, little is known about gene imprinting in dicotyledons. In this study, we inspected genomic imprinting in castor bean (Ricinus communis) endosperm, which persists throughout seed development. After mapping out the polymorphic SNP loci between accessions ZB306 and ZB107, we generated deep sequencing RNA profiles of F1 hybrid seeds derived from reciprocal crosses. Using polymorphic SNP sites to quantify allele-specific expression levels, we identified 209 genes in reciprocal endosperms with potential parent-of-origin specific expression, including 200 maternally expressed genes and 9 paternally expressed genes. In total, 57 of the imprinted genes were validated via reverse transcriptase-polymerase chain reaction sequencing, and analysis of the genomic DNA methylation distribution between embryo and endosperm tissues showed significant hypomethylation in the endosperm and an enrichment of differentially methylated regions around the identified genes. Curiously, the expression of the imprinted genes was not tightly linked to DNA methylation. These results largely extended gene imprinting information existing in plants, providing potential directions for further research in gene imprinting. PMID- 24799439 TI - Synthesis of oligomeric mannosides and their structure-binding relationship with concanavalin A. AB - Small glycodendrimers with alpha-mannosyl ligands were synthesized by using copper-catalyzed azide-alkyne coupling chemistry and some of these molecules were used as multivalent ligands to study the induction of concanavalin A (Con A) precipitation. The results showed that the monovalent mannose ligand could induce the precipitation of Con A. This unexpected finding initiated a series of studies to characterize the molecular basis of the ligand-lectin interaction. The atypical precipitation is found to be specific to the mannose, fluorescein moiety (FITC), and Con A. Apparently the mannose ligand binds to Con A through hydrogen bonding interactions, whereas the binding of FITC is mediated by hydrophobic forces. PMID- 24799440 TI - Modelling the development and arrangement of the primary vascular structure in plants. AB - BACKGROUND AND AIMS: The process of vascular development in plants results in the formation of a specific array of bundles that run throughout the plant in a characteristic spatial arrangement. Although much is known about the genes involved in the specification of procambium, phloem and xylem, the dynamic processes and interactions that define the development of the radial arrangement of such tissues remain elusive. METHODS: This study presents a spatially explicit reaction-diffusion model defining a set of logical and functional rules to simulate the differentiation of procambium, phloem and xylem and their spatial patterns, starting from a homogeneous group of undifferentiated cells. KEY RESULTS: Simulation results showed that the model is capable of reproducing most vascular patterns observed in plants, from primitive and simple structures made up of a single strand of vascular bundles (protostele), to more complex and evolved structures, with separated vascular bundles arranged in an ordered pattern within the plant section (e.g. eustele). CONCLUSIONS: The results presented demonstrate, as a proof of concept, that a common genetic-molecular machinery can be the basis of different spatial patterns of plant vascular development. Moreover, the model has the potential to become a useful tool to test different hypotheses of genetic and molecular interactions involved in the specification of vascular tissues. PMID- 24799441 TI - Evaluating dissection in the gross anatomy course: Correlation between quality of laboratory dissection and students outcomes. AB - Anatomy learned by active exploration through dissection has many proven benefits including improvement of anatomic knowledge. Decreased laboratory time may affect the quality of dissection and ultimately lower student performance in anatomy translating to lower knowledge acquisition. The aim of this study was to determine whether the quality of students' dissection in teams correlates with their performance in the gross anatomy course. Quality of dissections for each team enrolled in a gross anatomy course at Mayo Medical School was evaluated biweekly using a five-point rubric based on course learning objectives. Assessment of anatomic knowledge was based on sequential laboratory practice practical examination scores, achievements on daily audience response system (ARS) quizzes, and final practical, written, and National Board of Medical Examiners((r)) (NBME((r)) ) Gross Anatomy and Embryology Subject Examinations. Twelve teams comprising 48 students were included in the study. There was a positive correlation between dissection quality and practice practical examination score (R = 0.83) and a negative correlation between dissection quality and ARS quizzes (R = -0.985). Dissection teams with a passing score on their dissection evaluations (>70%) performed better on their final examinations. Based on an end of course survey, students agreed that dissection evaluations should continue to be a part of the course. This study showed that better quality of dissection was associated with higher scores on practice practical examinations, final practical, written, and NBME examinations. The study demonstrated a positive correlation between dissection evaluations, accompanied by formative feedback during the course, and higher scores on final course assessments. PMID- 24799442 TI - A case of congenital central hypoventilation syndrome in a three-generation family with non-polyalanine repeat PHOX2B mutation. AB - We describe a three generation family in whom multiple individuals are variably affected due to a PHOX2B non-polyalanine repeat mutation. This family demonstrates extreme phenotypic variability and autosomal dominant transmission over three generations not previously reported in the wider literature. Novel findings also inclue a history of recurrent second trimester miscarriage. Pediatr Pulmonol. 2014; 49:E140-E143. (c) 2014 Wiley Periodicals, Inc. PMID- 24799443 TI - Aging in iPS cells. PMID- 24799444 TI - Evidence-Based Recommendations for Fertility Preservation Options for Inclusion in Treatment Protocols for Pediatric and Adolescent Patients Diagnosed With Cancer. AB - As survival rates improve for pediatric cancers, increased attention has been paid to late effects of cancer therapy, in particular, infertility. Fertility preservation options are available for pre- and postpubertal cancer patients; however, many providers lack knowledge regarding options. The aim of this article is to provide a comprehensive synthesis of current evidence and recommendations regarding fertility preservation options for children, adolescents, and young adults undergoing cancer treatment. A systematic search was performed to identify fertility preservation evidence. Fifty-three studies and 4 clinical guidelines were used for the review. Final recommendations consisted of 2 strong and 1 weak recommendation for both female and male fertility preservation options. The treatment team should be knowledgeable about fertility preservation so that they can educate patients and families about available fertility preservation options. It is important to consider and discuss all available fertility options with patients at the time of diagnosis. PMID- 24799445 TI - Evidence-Based Practice Recommendations for Hydration in Children and Adolescents With Cancer Receiving Intravenous Cyclophosphamide. AB - Hemorrhagic cystitis is a known complication of cyclophosphamide, an antineoplastic agent used to treat a variety of oncologic diseases in children. Hydration can prevent hemorrhagic cystitis; however, use varies in clinical practice. A team was assembled to develop evidence-based practice recommendations to address the following question: in a population of children with cancer, what is the appropriate pre- and posthydration for the administration of different dose levels of intravenous cyclophosphamide to prevent bladder toxicity? The purpose was to identify the appropriate rate, duration, and route of hydration to prevent bladder toxicity with low, intermediate, and high dose cyclophosphamide. After a systematic search of the literature, 15 pieces of evidence were evaluated and used. There is a moderate level of quality evidence related to hydration for high dose cyclophosphamide and very low quality evidence related to intermediate or low dose cyclophosphamide. Three general recommendations were made for hydration associated with cyclophosphamide. There is a need for further research related to the prevention of bladder toxicity in children with cancer receiving cyclophosphamide. PMID- 24799446 TI - Photodegradable neutral-cationic brush block copolymers for nonviral gene delivery. AB - We report on the fabrication of a photodegradable gene-delivery vector based on PEO-b-P(GMA-g-PDMAEMA) neutral-cationic brush block copolymers that possess cationic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) brushes for DNA compaction, poly(ethylene oxide) (PEO) as a hydrophilic block, and poly(glycidyl methacrylate) (PGMA) as the backbone. The PEO-b-P(GMA-g-PDMAEMA) copolymers were synthesized through the combination of reversible addition-fragmentation transfer (RAFT) polymerization and postmodification. A photocleavable PEO-based macroRAFT agent was first synthesized; next, the PEO-b-PGMA block copolymer was prepared by RAFT polymerization of GMA; this was followed by a click reaction to introduce the RAFT initiators on the side chains of the PGMA block; then, RAFT polymerization of DMAEMA afforded the PEO-b-P(GMA-g-PDMAEMA) copolymer. The obtained neutral-cationic brush block copolymer could effectively complex plasmid DNA (pDNA) into nanoparticles at an N/P ratio (i.e., the number of nitrogen residues per DNA phosphate) of 4. Upon UV irradiation, pDNA could be released owing to cleavage of the pDNA-binding cationic PDMAEMA side chains as well as the nitrobenzyl ester linkages at the diblock junction point. In addition, in vitro gene transfection results demonstrated that the polyplexes could be effectively internalized by cells with good transfection efficiency, and the UV irradiation protocol could considerably enhance the efficiency of gene transfection. PMID- 24799447 TI - Expanding the evidence within evidence-based healthcare: thinking about the context, acceptability and feasibility of interventions. AB - Evidence-based medicine is crucial to contemporary healthcare. It is dependent on systematic review methodology modeled on an arguably inadequate hierarchy of evidence. There has been a significant increase in medical and health research using qualitative and mixed method designs. The perspective taken in this article is that we need to broaden our evidence base if we are to fully take account of issues of context, acceptability and feasibility in the development and implementation of healthcare interventions. One way of doing this is to use a range of methods that better fit the different aspects of intervention development and implementation. Methods for the systematic review of evidence, other than randomised-controlled trials, are available and there is a readiness to incorporate these other types of evidence into good-practice guidance, but we need a clear methodology to translate these advances in research into the world of policy. PMID- 24799448 TI - Team-based learning in the gross anatomy laboratory improves academic performance and students' attitudes toward teamwork. AB - As the healthcare climate shifts toward increased interdisciplinary patient care, it is essential that students become accomplished at group problem solving and develop positive attitudes toward teamwork. Team-based learning (TBL) has become a popular approach to medical education because of its ability to promote active learning, problem-solving skills, communication, and teamwork. However, its documented use in the laboratory setting and physical therapy education is limited. We used TBL as a substitute for one-third of cadaveric dissections in the gross anatomy laboratories at two Doctor of Physical Therapy programs to study its effect on both students' perceptions and academic performance. We surveyed students at the beginning and completion of their anatomy course as well as students who had previously completed a traditional anatomy course to measure the impact of TBL on students' perceptions of teamwork. We found that the inclusion of TBL in the anatomy laboratory improves students' attitudes toward working with peers (P < 0.01). Non-TBL students had significantly lower attitudes toward teamwork (P < 0.01). Comparison of academic performance between TBL and non-TBL students revealed that students who participated in TBL scored significantly higher on their first anatomy practical examination and on their head/neck written examination (P < 0.001). When asked to rate their role in a team, a 10.5% increase in the mean rank score for Problem Solver resulted after the completion of the TBL-based anatomy course. Our data indicate that TBL is an effective supplement to cadaveric dissection in the laboratory portion of gross anatomy, improving both students' grades and perceptions of teamwork. PMID- 24799449 TI - The biotechnological potential of fibrinolytic enzymes in the dissolution of endogenous blood thrombi. AB - Formation of endogenous thrombi in blood vessels is one of the leading causes of death in our modern life. According to data provided by the World Health Organization (WHO) in 2000, heart diseases are responsible for 29% of the total mortality rate in the world. For this, a tremendous amount of research has been done in the area of prevention and treatment of these diseases. The classical therapy of these thrombi relies upon the use of antiplatelets, anticoagulants, or even surgeries. Relatively recently, the fibrinolytic enzymes produced by microorganisms, snakes, earthworms, insects, plants, and other organisms are being successfully used in the treatment of blood clots, especially with regard to the direct dissolving action on fibrin in tandem with less cost and side effects in comparison with the first-generation thrombolytic agents, streptokinase and urokinase. Furthermore, recombinant DNA technology has succeeded in improving and decreasing the undesirable effects of the first generation of enzymes. Recombinant PAs or rt-PAs like alteplase, retelase, saruplase, tenecteplase, lanoteplase, and desmoteplase became available in the drug markets with advantages of less binding loci with PAI-1 to avoid degradation while providing faster and more complete reperfusion in a greater number of patients with less risk of bleeding and intracranial hemorrhage. This review is the first to cover all the natural and recombinant thrombolytic agents used in enzyme therapy. PMID- 24799450 TI - Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. AB - Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living individuals (LLI) (about 100 years old) compared with those from young (about 27 years old) and old (about 75 years old) subjects. We observed that fibroblasts from LLI displayed significantly lower complex I-driven ATP synthesis and higher production of H2O2 in comparison with old subjects. Despite these changes, bioenergetics of these cells appeared to operate normally. This lack of functional consequences was likely due to a compensatory phenomenon at the level of mitochondria, which displayed a maintained supercomplexes organization and an increased mass. This appears to be due to a decreased mitophagy, induced by hyperfused, elongated mitochondria. The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial "hypertrophy". PMID- 24799454 TI - Comparison of survival between the UK and US after surgery for most common pediatric CNS tumors. AB - BACKGROUND: We report a population-based study examining long-term outcomes for common pediatric CNS tumors comparing results from the UK with the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data set and with the literature. No such international study has previously been reported. METHODS: Data between 1996 and 2005 from the UK National Registry of Childhood Tumours (NRCT) and the SEER registry were analyzed. We calculated actuarial survival at each time point from histological diagnosis, with death from any cause as the endpoint. Kaplan-Meier estimation and log-rank testing (Cox proportional hazards regression analysis) were used to calculate survival differences among tumor subtypes, adjusting for age at diagnosis. RESULTS: Population-based outcomes for each tumor type are presented. Overall age-adjusted survival, stratifying for histology (combining pilocytic astrocytoma, anaplastic astrocytoma, glioblastoma, primitive neuroectodermal tumor, medulloblastoma, and ependymoma), is significantly lower for NRCT than SEER (hazard ratio 0.71, P < .001) and at 1, 5, and 10 years. Both NRCT and SEER outcomes are worse than those reported from trials. CONCLUSION: Analyzing data from comprehensive registries minimizes bias associated with trials and institutional studies. The reasons for the poorer outcomes in children treated in the UK are unclear. Likewise, the differences in outcomes between patients in trials and those not in trials need further investigation. We recommend that all children with CNS tumors be recruited into studies-even if these are observational studies. We also suggest that registries be suitably funded to publish independent outcome data (including morbidity) at both a national and an institutional level. PMID- 24799455 TI - Combined modality therapy versus chemotherapy alone as an induction regimen for primary central nervous system lymphoma: a cost-effectiveness analysis. AB - BACKGROUND: In immunocompetent patients with primary central nervous system lymphoma (PCNSL), combined modality therapy (CMT) using high-dose methotrexate and radiotherapy (WBRT) has improved response rates compared with chemotherapy alone. The trade-off is delayed and potentially devastating treatment-related neurotoxicity (NT). METHODS: A cost-effectiveness analysis using a Markov model compared CMT with chemotherapy alone in age-stratified patients with PCNSL. Baseline probabilities were derived from a systematic literature review. Direct and lost productivity costs were collected from a Canadian perspective and presented in Can$ in 2011. Outcomes were life expectancy, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio. RESULTS: The quality adjusted life expectancy was 1.55 QALYs for CMT and 1.53 QALYs for chemotherapy alone. In younger patients (aged <60 years), CMT yielded 2.44 QALYs, compared with 1.89 QALYs for chemotherapy alone, yielding an expected benefit with CMT of 0.55 QALYs or 6.6 quality-adjusted months. The CMT strategy dominated in younger patients, as it was Can$11 951 less expensive than chemotherapy alone. The chemotherapy-alone strategy dominated in older patients, as it was Can$11 244 less expensive than CMT, and there was no difference in QALYs between the strategies. The model was robust in sensitivity analyses of key variables tested through the plausible ranges obtained from costing sources and published literature. CONCLUSION: The preferred induction strategy for younger patients with PCNSL appears to be CMT, which minimized cost while maximizing life expectancy and QALYs. This analysis confirms that the preferred strategy for older patients is chemotherapy alone. PMID- 24799456 TI - Identifying best-fitting inputs in health-economic model calibration: a Pareto frontier approach. AB - BACKGROUND: To identify best-fitting input sets using model calibration, individual calibration target fits are often combined into a single goodness-of fit (GOF) measure using a set of weights. Decisions in the calibration process, such as which weights to use, influence which sets of model inputs are identified as best-fitting, potentially leading to different health economic conclusions. We present an alternative approach to identifying best-fitting input sets based on the concept of Pareto-optimality. A set of model inputs is on the Pareto frontier if no other input set simultaneously fits all calibration targets as well or better. METHODS: We demonstrate the Pareto frontier approach in the calibration of 2 models: a simple, illustrative Markov model and a previously published cost effectiveness model of transcatheter aortic valve replacement (TAVR). For each model, we compare the input sets on the Pareto frontier to an equal number of best-fitting input sets according to 2 possible weighted-sum GOF scoring systems, and we compare the health economic conclusions arising from these different definitions of best-fitting. RESULTS: For the simple model, outcomes evaluated over the best-fitting input sets according to the 2 weighted-sum GOF schemes were virtually nonoverlapping on the cost-effectiveness plane and resulted in very different incremental cost-effectiveness ratios ($79,300 [95% CI 72,500-87,600] v. $139,700 [95% CI 79,900-182,800] per quality-adjusted life-year [QALY] gained). Input sets on the Pareto frontier spanned both regions ($79,000 [95% CI 64,900-156,200] per QALY gained). The TAVR model yielded similar results. CONCLUSIONS: Choices in generating a summary GOF score may result in different health economic conclusions. The Pareto frontier approach eliminates the need to make these choices by using an intuitive and transparent notion of optimality as the basis for identifying best-fitting input sets. PMID- 24799457 TI - Findings from qualitative studies suggest parents of children with disabilities benefit from peer support; whereas findings from quantitative studies are inconclusive. PMID- 24799458 TI - Model-based process development for the purification of a modified human growth hormone using multimodal chromatography. AB - This study demonstrates how the multimodal Capto adhere resin can be used in concert with calcium chloride or arginine hydrochloride as mobile phase modifiers to create a highly selective purification process for a modified human growth hormone. Importantly, these processes are shown to result in significant clearance of product related aggregates and host cell proteins. Furthermore, the steric mass action model is shown to be capable of accurately describing the chromatographic process and the aggregate removal. Finally, justification of the selected operating ranges is evaluated using the model together with Latin hypercube sampling. The results in this article establish the utility of multimodal chromatography when used with appropriate mobile phase modifiers for the downstream bioprocessing of a modified human growth hormone and offer new approaches for bioprocess verification. PMID- 24799459 TI - Cardiac BNP gene delivery prolongs survival in aged spontaneously hypertensive rats with overt hypertensive heart disease. AB - BACKGROUND: Hypertension is a highly prevalent disease associated with cardiovascular morbidity and mortality. Recent studies suggest that patients with hypertension also have a deficiency of certain cardiac peptides. Previously we demonstrated that a single intravenous injection of the myocardium-tropic adeno associated virus (AAV) 9-based vector encoding for proBNP prevented the development of hypertensive heart disease (HHD) in spontaneously hypertensive rats (SHRs). The current study was designed to determine the duration of cardiac transduction after a single AAV9 injection and to determine whether cardiac BNP overexpression can delay the progression of previously established HHD, and improve survival in aged SHRs with overt HHD. METHODS AND RESULTS: To evaluate the duration of cardiac transduction induced by the AAV9 vector, we used four week old SHRs. Effective long-term selective cardiac transduction was determined by luciferase expression. A single intravenous administration of a luciferase expressing AAV9 vector resulted in efficient cardiac gene delivery for up to 18 months. In aged SHRs (9-months of age), echocardiographic studies demonstrated progression of HHD in untreated controls, while AAV9-BNP vector treatment arrested the deterioration of cardiac function at six months post-injection (15 months of age). Aged SHRs with established overt HHD were further monitored to investigate survival. A single intravenous injection of the AAV9-vector encoding rat proBNP was associated with significantly prolonged survival in the treated SHRs (613?38 days, up to 669 days) compared to the untreated rats (480+/-69 days, up to 545 days)(p<0.05). CONCLUSIONS: A single intravenous injection of AAV9 vector elicited prolonged cardiac transduction (up to 18 months post-injection). AAV9 induced cardiac BNP overexpression prevented development of congestive heart failure, and significantly prolonged the survival of aged SHRs with previously established overt HHD. These findings support the beneficial effects of chronic supplementation of BNP in a frequent and highly morbid condition such as HHD. PMID- 24799460 TI - Prognostic significance of human papillomavirus in recurrent or metastatic head and neck cancer: an analysis of Eastern Cooperative Oncology Group trials. AB - BACKGROUND: The purpose of this article was to study the association of human papillomavirus (HPV) with clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Archival baseline tumor specimens were obtained from patients treated on two clinical trials in recurrent or metastatic SCCHN: E1395, a phase III trial of cisplatin and paclitaxel versus cisplatin and 5-fluorouracil, and E3301, a phase II trial of irinotecan and docetaxel. HPV DNA was detected by in situ hybridization (ISH) with a wide-spectrum probe. p16 status was evaluated by immunohistochemistry. Clinical outcomes of interest were objective response, progression-free survival (PFS) and overall survival (OS). RESULTS: We analyzed 64 patients for HPV ISH and 65 for p16. Eleven tumors (17%) were HPV+, 12 (18%) were p16+, whereas 52 (80%) were both HPV- and p16-. The objective response rate was 55% for HPV-positive versus 19% for HPV-negative (P = 0.022), and 50% for p16 positive versus 19% for p16-negative (P = 0.057). The median survival was 12.9 versus 6.7 months for HPV-positive versus HPV-negative patients (P = 0.014), and 11.9 versus 6.7 months for p16-positive versus p16-negative patients (P = 0.027). After adjusting for other covariates, hazard ratio for OS was 2.69 (P = 0.048) and 2.17 (P = 0.10), favoring HPV-positive and p16-positive patients, respectively. The other unfavorable risk factor for OS was loss of >=5% weight in previous 6 months (P = 0.0021 and 0.023 for HPV and p16 models, respectively). CONCLUSION: HPV is a favorable prognostic factor in recurrent or metastatic SCCHN that should be considered in the design of clinical trials in this setting. CLINICAL TRIAL IDENTIFIER: NCT01487733 Clinicaltrials.gov. PMID- 24799461 TI - Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. AB - BACKGROUND: Tumor regression after antiviral therapy (AT) is in favor of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL). PATIENTS AND METHODS: We carried out a cohort study of 704 consecutive HIV negative, HCV-positive patients with indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the Fondazione Italiana Linfomi; 134 patients were managed with AT for lymphoma control. RESULTS: For entire cohort, 5-year overall survival (OS) was 78% [95% confidence interval (CI): 74%-82%] and 5-year progression-free survival (PFS) was 48% (95% CI: 44%-53%). In multivariate analysis, the use of AT during the patients' life had positive impact on OS. Forty-four of the 100 patients treated with first-line AT achieved a complete remission (CR) and 33 a partial response (PR). HCV-RNA clearance was achieved in 80 patients and was related to lymphoma response. At a median follow-up of 3.6 years, 5-year PFS was 63% (95% CI: 50%-73%). CR + PR rate was 85% with AT as second-line treatment. CONCLUSION: AT produces HCV-RNA clearance and consequent tumor regression in most patients with HCV-related indolent NHL. AT used at any time is associated with improved OS. Consequently, AT can be considered an option for patients with indolent lymphomas who do not need immediate cytoreductive treatment. PMID- 24799462 TI - A Golgi-specific protein PAQR3 is closely associated with the progression, metastasis and prognosis of human gastric cancers. AB - BACKGROUND: The aim of this study is to determine whether PAQR3, a protein specifically localized in the Golgi apparatus, is associated with tumor progression, metastasis and survival of human patients with gastric cancer. PATIENTS AND METHODS: PAQR3 expression status was investigated in a large panel of gastric cancer (n = 300) and their corresponding para-cancerous histological normal tissues (PCHNT) at both mRNA and protein levels. The correlation of PAQR3 expression levels with clinical features such as metastasis and prognosis was analyzed. The effect of PAQR3 on the growth and migration of gastric cancer cells was also determined. RESULTS: PAQR3 was frequently down-regulated in gastric cancer samples compared with PCHNT at both mRNA and protein levels (both P < 0.0001). The expression level of PAQR3 was negatively correlated with Helicobacter pylori infection (P < 0.0001), tumor size (P < 0.0001), tumor stage (P < 0.0001), venous and lymphatic invasion (P < 0.0001), distant and nodal metastasis (P < 0.0001), and patient survival (P < 0.0001). Down-regulation of PAQR3 was highly correlated with increased epithelial-mesenchymal transition (EMT) in gastric cancer samples. In addition, PAQR3 overexpression was able to negatively modulate cell proliferation, migration and EMT of gastric cancer cells. CONCLUSION: PAQR3 is markedly down-regulated in human gastric cancers. PAQR3 expression level is closely associated with the progression and metastasis of gastric cancers. PAQR3 is also a new genetic signature that can predict the prognosis of the patients with gastric cancer. PMID- 24799463 TI - Production of recombinant protein in Escherichia coli cultured in extract from waste product alga, Ulva lactuca. AB - This study examined the potential for waste product alga, Ulva lactuca, to serve as a media component for recombinant protein production in Escherichia coli. To facilitate this investigation, U. lactuca harvested from Jamaica Bay was dried, and nutrients acid extracted for use as a growth media. The E. coli cell line BL21(DE3) was used to assess the effects on growth and production of recombinant green fluorescent protein (GFP). This study showed that media composed of acid extracts without further nutrient addition maintained E. coli growth and recombinant protein production. Extracts made from dried algae lots less than six months-old were able to produce two-fold more GFP protein than traditional Lysogeny Broth media. PMID- 24799464 TI - Crosslinked enzyme aggregates of hydroxynitrile lyase partially purified from Prunus dulcis seeds and its application for the synthesis of enantiopure cyanohydrins. AB - Hydroxynitrile lyases are powerful catalysts in the synthesis of enantiopure cyanohydrins which are key synthons in the preparations of a variety of important chemicals. The response surface methodology including three-factor and three level Box-Behnken design was applied to optimize immobilization of hydroxynitrile lyase purified partially from Prunus dulcis seeds as crosslinked enzyme aggregates (PdHNL-CLEAs). The quadratic model was developed for predicting the response and its adequacy was validated with the analysis of variance test. The optimized immobilization parameters were initial glutaraldehyde concentration, ammonium sulfate saturation concentration, and crosslinking time, and the response was relative activity of PdHNL-CLEA. The optimal conditions were determined as initial glutaraldehyde concentration of 25% w/v, ammonium sulfate saturation concentration of 43% w/v, and crosslinking time of 18 h. The preparations of PdHNL-CLEA were examined for the synthesis of (R)-mandelonitrile, (R)-2-chloromandelonitrile, (R)-3,4-dihydroxymandelonitrile, (R)-2-hydroxy-4 phenyl butyronitrile, (R)-4-bromomandelonitrile, (R)-4-fluoromandelonitrile, and (R)-4-nitromandelonitrile from their corresponding aldehydes and hydrocyanic acid. After 96-h reaction time, the yield-enantiomeric excess values (%) were 100 99, 100-21, 100-99, 83-91, 100-99, 100-72, and 100-14%, respectively, for (R) mandelonitrile, (R)-2-chloromandelonitrile, (R)-3,4-dihydroxymandelonitrile, (R) 2-hydroxy-4-phenyl butyronitrile, (R)-4-bromomandelonitrile, (R)-4 fluoromandelonitrile, and (R)-4-nitromandelonitrile. The results show that PdHNL CLEA offers a promising potential for the preparation of enantiopure (R) mandelonitrile, (R)-3,4-dihydroxymandelonitrile, (R)-2-hydroxy-4-phenyl butyronitrile, and (R)-4-bromomandelonitrile with a high yield and enantiopurity. PMID- 24799466 TI - Principles of opioid use in cancer pain. AB - The management of pain is an essential aspect of comprehensive cancer care. Positive outcomes can be achieved in most patients with widely available therapies. There is a broad consensus that opioid-based pharmacotherapy is the first-line strategy for the treatment of moderate or severe chronic pain in populations with active disease, and treatment guidelines have been developed from the known pharmacology of these drugs, extant data, and extensive clinical experience. This article describes the major opioid analgesics available for the treatment of cancer-related pain and reviews the key elements for safe and effective prescribing, including selection of the best drug and route, approaches to titration and long-term administration of baseline and supplemental doses, rotation from one drug to another in poorly responsive patients, and management of opioid risks. PMID- 24799465 TI - Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. AB - PURPOSE: To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS: The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events. RESULTS: A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer. RECOMMENDATIONS: HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2 targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone. PMID- 24799468 TI - Under- or overtreatment of pain in the patient with cancer: how to achieve proper balance. AB - Achieving balance in the appropriate use of opioids for the treatment of cancer pain is complex. The definition of "balance" is continually being modified. Palliative care professionals, pain specialists, and oncologists have long been advocating for the aggressive management of pain for patients with advanced cancer. Some progress has been made in this arena but barriers persist. Fear of addiction by patients, family members, and oncology professionals presents a serious obstacle to the provision of adequate pain control. This is further complicated by societal factors that receive extensive media coverage, such as diversion of prescribed opioids for recreational use and increasing deaths as a result of this inappropriate use of prescription opioids. This growing concern has led to more opioid regulation, which increases obstacles to pain management in this population. Another evolving concern is whether the long-term use of opioids is safe and effective. Data from the chronic nonmalignant pain literature suggest that toxicities may result and misuse has been underestimated, yet little information is available in the cancer population. These issues lead to serious questions regarding how balance might be successfully achieved for patients in an oncology setting. Can pain relief be provided while reducing negative consequences of treatment? Which patient should be prescribed what medications, in what situations, for what kind of pain, and who should be managing the pain? PMID- 24799469 TI - Pain and nociception: mechanisms of cancer-induced bone pain. AB - Cancer pain, especially pain caused by metastasis to bone, is a severe type of pain, and unless the cause and consequences can be resolved, the pain will become chronic. As detection and survival among patients with cancer have improved, pain has become an increasing challenge, because traditional therapies are often only partially effective. Until recently, knowledge of cancer pain mechanisms was poor compared with understanding of neuropathic and inflammatory pain states. We now view cancer-induced bone pain as a complex pain state involving components of both inflammatory and neuropathic pain but also exhibiting elements that seem unique to cancer pain. In addition, the pain state is often unpredictable, and the intensity of the pain is highly variable, making it difficult to manage. The establishment of translational animal models has started to reveal some of the molecular components involved in cancer pain. We present the essential pharmacologic and neurobiologic mechanisms involved in the generation and continuance of cancer-induced bone pain and discuss these in the context of understanding and treating patients. We discuss changes in peripheral signaling in the area of tumor growth, examine spinal cord mechanisms of sensitization, and finally address central processing. Our aim is to provide a mechanistic background for the sensory characteristics of cancer-induced bone pain as a basis for better understanding and treating this condition. PMID- 24799467 TI - Active idiotypic vaccination versus control immunotherapy for follicular lymphoma. AB - PURPOSE: Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM CSF. PATIENTS AND METHODS: Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n=287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. RESULTS: At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n=195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. CONCLUSION: This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study. PMID- 24799470 TI - New opioids. AB - Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is a lack of evidence to support many aspects of current clinical practice. Therefore, there is a significant need for more effective treatment options. New opioids have been marketed in the past years, including hydrocodone and oxymorphone. Moreover, mixed opioids with combined mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral analgesic that possesses a combined mechanism of action: MU-opioid receptor activation with norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been initiated to reduce peripheral opioid-related adverse effects. The rationale is based on the local antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of naloxone, particularly in a prolonged-release formulation. New delivery systems have been developed to provide rapid analgesia with potent opioid drugs such as fentanyl. Despite the upcoming availability of these new drugs and technologies that will add to existing types of opioid medication, their benefits and liabilities will ultimately need to be determined by the individual physician and individual patient experiencing pain. PMID- 24799471 TI - Reply to S. Fuji et al. PMID- 24799473 TI - Predictive value of the international association for the study of lung cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma in tumor recurrence and patient survival. AB - PURPOSE: This study investigated the pattern of recurrence of lung adenocarcinoma and the predictive value of histologic classification in resected lung adenocarcinoma using the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification system. PATIENTS AND METHODS: Histologic classification of 573 patients undergoing resection for lung adenocarcinoma was determined according to the IASLC/ATS/ERS classification system, and the percentage of each histologic component (lepidic, acinar, papillary, micropapillary, and solid) was recorded. The pattern of recurrence of those components and their predictive value were investigated. RESULTS: The predominant histologic pattern was significantly associated with sex (P < .01), invasive tumor size (P < .01), T status (P < .01), N status (P < .01), TNM stage (P < .01), and visceral pleural invasion (P < .01). The percentage of recurrence was significantly higher in micropapillary- and solid-predominant adenocarcinomas (P < .01). Micropapillary- and solid predominant adenocarcinomas had a significantly higher possibility of developing initial extrathoracic-only recurrence than other types (P < .01). The predominant pattern group (micropapillary or solid v lepidic, acinar, or papillary) was a significant prognostic factor in overall survival (OS; P < .01), probability of freedom from recurrence (P < .01), and disease-specific survival (P < .01) in multivariable analysis. For patients receiving adjuvant chemotherapy, solid predominant adenocarcinoma was a significant predictor for poor OS (P = .04). CONCLUSION: In lung adenocarcinoma, the IASLC/ATS/ERS classification system has significant prognostic and predictive value regarding death and recurrence. Solid predominant adenocarcinoma was also a significant predictor in patients undergoing adjuvant chemotherapy. Prognostic and predictive information is important for stratifying patients for aggressive adjuvant chemoradiotherapy. PMID- 24799474 TI - Strategies to help oncologists deliver high-quality care. PMID- 24799472 TI - Role of rehabilitation medicine and physical agents in the treatment of cancer associated pain. AB - PURPOSE: To provide an overview of rehabilitation medicine- and physical modality based approaches to cancer pain management, and to highlight the fact that these approaches are generally used in conjunction and that a majority are focused on minimizing pain during periods of mobility and the performance of activities of daily living. METHODS: We performed a nonsystematic literature review and provide a description of the current standard of care. RESULTS: Rehabilitative and physical modalities used to manage pain can be grouped into four categories: those that modulate nociception, stabilize or unload painful structures, influence physiological processes that indirectly influence nociception, or alleviate pain arising from the overloading of muscles and connective tissues that often occurs after surgery or with sarcopenia in late-stage cancer. Most modalities have been pragmatically refined over the years, and many have an evidence base, although few have been explicitly validated in the oncologic setting. With few exceptions, they are patient controlled and free of adverse effects. CONCLUSION: Physical modalities and rehabilitation medicine offer a range of pain management approaches that may serve as beneficial adjuncts to the conventional systemic and interventional analgesic strategies used to control cancer-related pain. These approaches may be particularly beneficial to patients with movement-associated pain and those who are ambivalent regarding pharmacoanalgesia. PMID- 24799475 TI - Pattern of frequent but nontargeted pharmacologic thromboprophylaxis for hospitalized patients with cancer at academic medical centers: a prospective, cross-sectional, multicenter study. AB - PURPOSE: Hospitalized patients with cancer are considered to be at high risk for venous thromboembolism (VTE). Despite strong recommendations in numerous clinical practice guidelines, retrospective studies have shown that pharmacologic thromboprophylaxis is underutilized in hospitalized patients with cancer. PATIENTS AND METHODS: We conducted a prospective, cross-sectional study of hospitalized patients with cancer at five academic hospitals to determine prescription rates of thromboprophylaxis and factors influencing its use during hospitalization. RESULTS: A total of 775 patients with cancer were enrolled across five academic medical centers. Two hundred forty-seven patients (31.9%) had relative contraindications to pharmacologic prophylaxis. Accounting for contraindications to anticoagulation, the overall rate of pharmacologic thromboprophylaxis was 74.2% (95% CI, 70.4% to 78.0%; 392 of 528 patients). Among the patients with cancer without contraindications for anticoagulation, individuals hospitalized with nonhematologic malignancies were significantly more likely to receive pharmacologic thromboprophylaxis than those with hematologic malignancies (odds ratio [OR], 2.34; 95% CI, 1.43 to 3.82; P=.007). Patients with cancer admitted for cancer therapy were significantly less likely to receive pharmacologic thromboprophylaxis than those admitted for other reasons (OR, 0.37; 95% CI, 0.22 to 0.61; P<.001). Sixty-three percent of patients with cancer classified as low risk, as determined by the Padua Scoring System, received anticoagulant thromboprophylaxis. Among the 136 patients who did not receive anticoagulation, 58.8% were considered to be high risk by the Padua Scoring System. CONCLUSION: We conclude that pharmacologic thromboprophylaxis is frequently administered to hospitalized patients with cancer but that nearly one third of patients are considered to have relative contraindications for prophylactic anticoagulation. Pharmacologic thromboprophylaxis in hospitalized patients with cancer is commonly prescribed without regard to the presence or absence of concomitant risk factors for VTE. PMID- 24799476 TI - Assessment and management of chemical coping in patients with cancer. AB - Chemical coping is a working definition that describes patients' intake of opioids on a scale that spans the range between normal nonaddictive opioid use for pain all the way to opioid addiction. Most patients will fall somewhere between the two extremes in using opioid analgesics to cope with their psychological or spiritual distress. The degree to which patients use their medications in a maladaptive manner will determine their susceptibility to drug toxicity and harm. When there are no obvious cancer-related causes for increased pain intensity, chemical coping and other patient-related factors such as delirium, somatization, and depression should be considered. As part of the initial evaluation of patients with cancer-related pain, a brief screening tool such as the CAGE questionnaire should be used to identify patients who may be at risk for chemical coping. Identifying patients at risk will allow clinicians to avoid unnecessary opioid toxicity, control pain, and improve quality of life. A structured approach for managing opioid use should be adopted, including standardized documentation, opioid treatment agreements, urine drug screens, frequent visits, and restricted quantities of breakthrough opioids. All patients at risk should receive brief motivational interviewing with an objective, nonjudgmental, and empathic style that includes personalized feedback, particularly about markers of risk or harm. For chemical copers approaching the addiction end of the spectrum, with evidence of compulsive use and destructive behavior, referral should be made to substance abuse specialists. PMID- 24799478 TI - T-cell characterization using multicolor flow cytometry after allogeneic hematopoietic stem-cell transplantation. PMID- 24799477 TI - Pain in cancer survivors. AB - Pain is a common problem in cancer survivors, especially in the first few years after treatment. In the longer term, approximately 5% to 10% of survivors have chronic severe pain that interferes with functioning. The prevalence is much higher in certain subpopulations, such as breast cancer survivors. All cancer treatment modalities have the potential to cause pain. Currently, the approach to managing pain in cancer survivors is similar to that for chronic cancer-related pain, pharmacotherapy being the principal treatment modality. Although it may be appropriate to continue strong opioids in survivors with moderate to severe pain, most pain problems in cancer survivors will not require them. Moreover, because more than 40% of cancer survivors now live longer than 10 years, there is growing concern about the long-term adverse effects of opioids and the risks of misuse, abuse, and overdose in the nonpatient population. As with chronic nonmalignant pain, multimodal interventions that incorporate nonpharmacologic therapies should be part of the treatment strategy for pain in cancer survivors, prescribed with the aim of restoring functionality, not just providing comfort. For patients with complex pain issues, multidisciplinary programs should be used, if available. New or worsening pain in a cancer survivor must be evaluated to determine whether the cause is recurrent disease or a second malignancy. This article focuses on patients with a history of cancer who are beyond the acute diagnosis and treatment phase and on common treatment-related pain etiologies. The benefits and harms of the various pharmacologic and nonpharmacologic options for pain management in this setting are reviewed. PMID- 24799479 TI - Management of Posterior Reversible Encephalopathy Syndrome Induced by Carfilzomib in a Patient With Multiple Myeloma. PMID- 24799480 TI - Multicenter randomized controlled trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme: EnROL. AB - PURPOSE: Laparoscopic resection and a multimodal approach known as an enhanced recovery program (ERP) have been major changes in colorectal perioperative care that have improved clinical outcomes for colorectal cancer resection. EnROL (Enhanced Recovery Open Versus Laparoscopic) is a multicenter randomized controlled trial examining whether the benefits of laparoscopy still exist when open surgery is optimized within an ERP. PATIENTS AND METHODS: Adults with colorectal cancer suitable for elective resection were randomly assigned at a ratio of 1:1 to laparoscopic or open surgery within an ERP, stratified by center, cancer site (colon v rectum), and age group (<66 v 66-75 v >75 years) using minimization. The primary outcome was physical fatigue at 1 month postsurgery. Secondary outcomes included hospital stay, complications, other patient-reported outcomes (PROs), and physical function. Patients and outcome assessors were blinded until 7 days postsurgery or discharge if earlier. Central independent and blinded pathologic assessment of surgical quality was undertaken. RESULTS: A total of 204 patients (laparoscopy, n=103; open surgery, n=101) were recruited from 12 UK centers from July 2008 to April 2012. One-month physical fatigue scores were similar in both groups (mean: laparoscopy, 12.28; 95% CI, 11.37 to 13.19 v open surgery, 12.05; 95% CI, 11.14 to 12.96; adjusted mean difference, 0.23; 95% CI, -1.52 to 1.07). Median total hospital stay was significantly shorter after laparoscopic surgery (median: laparoscopy, 5; interquartile range [IQR], 4 to 9 v open surgery, 7; IQR, 5 to 11 days; P=.033). There were no differences in other secondary outcomes or in specimen quality after central pathologic review. CONCLUSION: In patients treated by experienced surgeons within an ERP, physical fatigue and other PROs were similar in both groups, but laparoscopic surgery significantly reduced length of hospital stay. PMID- 24799481 TI - [18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the International Extranodal Lymphoma Study Group IELSG-26 Study. AB - PURPOSE: To assess the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) after rituximab and anthracycline-containing chemoimmunotherapy in patients with primary mediastinal large B-cell lymphoma (PMLBCL). PATIENTS AND METHODS: Among 125 patients prospectively enrolled, 115 were eligible for central review of PET/CT scans at the completion of standard chemoimmunotherapy, by using a five-point scale. Consolidation radiotherapy (RT) was permitted and given to 102 patients. RESULTS: Fifty-four patients (47%) achieved a complete metabolic response (CMR), defined as a completely negative scan or with residual [18F]FDG activity below the mediastinal blood pool (MBP) uptake. In the remaining 61 patients (53%), the residual uptake was higher than MBP uptake but below the liver uptake in 27 (23%), slightly higher than the liver uptake in 24 (21%), and markedly higher in 10 (9%). CMR after chemoimmunotherapy predicted higher 5-year progression-free survival (PFS; 98% v 82%; P=.0044) and overall survival (OS; 100% v 91%; P=.0298). Patients with residual uptake higher than MBP uptake but below liver uptake had equally good outcomes without any recurrence. Using the liver uptake as cutoff for PET positivity (boundary of score, 3 to 4) discriminated most effectively between high or low risk of failure, with 5-year PFS of 99% versus 68% (P<.001) and 5-year OS of 100% versus 83% (P<.001). CONCLUSION: More than 90% of patients are projected to be alive and progression-free at 5 years, despite a low CMR rate (47%) after chemoimmunotherapy. This study provides a basis for using PET/CT to define the role of RT in PMLBCL. PMID- 24799482 TI - Assessment of tumor size reduction improves outcome prediction of positron emission tomography/computed tomography after chemotherapy in advanced-stage Hodgkin lymphoma. AB - PURPOSE: Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT). PATIENTS AND METHODS: The analysis set consisted of 739 patients with residues>=2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkin's disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkin's disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression. RESULTS: In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P=.022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P=.9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%). CONCLUSION: Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse. PMID- 24799483 TI - Nonopioid drugs in the treatment of cancer pain. AB - The WHO analgesic ladder for the treatment of cancer pain provides a three-step sequential approach for analgesic administration based on pain severity that has global applicability. Nonopioids were recommended for mild pain, with the addition of mild opioids for moderate pain and strong opioids for severe pain. Here, we review the evidence for the use of nonopioid analgesic agents in patients with cancer and describe the mode of action of the main drug classes. Evidence supports the use of anti-inflammatory drugs such as acetaminophen/paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) for mild cancer pain. Adding an NSAID to an opioid for stronger cancer pain is efficacious, but the risk of long-term adverse effects has not been quantified. There is limited evidence to support using acetaminophen with stronger opioids. Corticosteroids have a specific role in spinal cord compression and brain metastases, where improved analgesia is a secondary benefit. There is limited evidence for adding corticosteroids to stronger opioids when pain control is the primary objective. Systematic reviews suggest a role for antidepressant and anticonvulsant medications for neuropathic pain, but there are methodologic issues with the available studies. Bisphosphonates improve pain in patients with bony metastases in some tumor types. Denosumab may delay worsening of pain compared with bisphosphonates. Larger studies of longer duration are required to address outstanding questions concerning the use of nonopioid analgesia for stronger cancer pain. PMID- 24799485 TI - Reply to I.E. Haines. PMID- 24799484 TI - Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. AB - PURPOSE: The optimal chemotherapy regimen administered concurrently with preoperative radiation therapy (RT) for patients with rectal cancer is unknown. National Surgical Adjuvant Breast and Bowel Project trial R-04 compared four chemotherapy regimens administered concomitantly with RT. PATIENTS AND METHODS: Patients with clinical stage II or III rectal cancer who were undergoing preoperative RT (45 Gy in 25 fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in three to six daily fractions) were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m(2), 5 days per week), with or without intravenous oxaliplatin (50 mg/m(2) once per week for 5 weeks) or oral capecitabine (825 mg/m(2) twice per day, 5 days per week), with or without oxaliplatin (50 mg/m(2) once per week for 5 weeks). Before random assignment, the surgeon indicated whether the patient was eligible for sphincter-sparing surgery based on clinical staging. The surgical end points were complete pathologic response (pCR), sphincter-sparing surgery, and surgical downstaging (conversion to sphincter-sparing surgery). RESULTS: From September 2004 to August 2010, 1,608 patients were randomly assigned. No significant differences in the rates of pCR, sphincter-sparing surgery, or surgical downstaging were identified between the CVI FU and capecitabine regimens or between the two regimens with or without oxaliplatin. Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < .001). CONCLUSION: Administering capecitabine with preoperative RT achieved similar rates of pCR, sphincter-sparing surgery, and surgical downstaging compared with CVI FU. Adding oxaliplatin did not improve surgical outcomes but added significant toxicity. The definitive analysis of local tumor control, disease-free survival, and overall survival will be performed when the protocol-specified number of events has occurred. PMID- 24799486 TI - Patient education, coaching, and self-management for cancer pain. AB - PURPOSE: Multiple systematic reviews and meta-analyses have identified the effectiveness of patient education in improving cancer pain management. However, the mechanisms by which patient education improves pain outcomes are uncertain, as are the optimal delivery, content, timing, frequency, and duration. This review provides best-bet recommendations based on available evidence to guide service managers and clinicians in developing a patient education program. METHODS: We used patient-centered care, self-management, coaching, and a behavior change wheel as lenses through which to consider the evidence for elements of patient education most likely to be effective within the context of other strategies for overcoming barriers to cancer pain assessment and management. RESULTS: The evidence suggests that optimal strategies include those that are patient-centered and tailored to individual needs, are embedded within health professional-patient communication and therapeutic relationships, empower patients to self-manage and coordinate their care, and are routinely integrated into standard cancer care. An approach that integrates patient education with processes and systems to ensure implementation of key standards for pain assessment and management and education of health professionals has been shown to be most effective. CONCLUSION: Patient education is effective in reducing cancer pain and should be standard practice in all settings. For optimal results, patient education should be integrated with other strategies for implementing evidence-based, person-centered care and overcoming barriers at the levels of patient, provider, and health system. PMID- 24799488 TI - Evidence-based medicine for thromboprophylaxis in hospitalized patients with cancer: why aren't we there yet? PMID- 24799487 TI - Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. AB - PURPOSE: To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS: The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. RESULTS: No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process. RECOMMENDATIONS: Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer. PMID- 24799489 TI - Pain in patients with cancer. PMID- 24799490 TI - Overcoming barriers in cancer pain management. AB - Pain is a devastating symptom of cancer that affects the quality of life of patients, families, and caregivers. It is a multidimensional symptom that includes physical, psychosocial, emotional, and spiritual components. Despite the development of novel analgesics and updated pain guidelines, cancer pain remains undermanaged, and some patients with moderate to severe pain do not receive adequate pain treatment. Inadequate pain management can be attributed to barriers related to health care professionals, patients, and the health care system. Common professional-related barriers include poor pain assessment, lack of knowledge and skill, and the reluctance of physicians to prescribe opioids. Patient-related barriers include cognitive factors, affective factors, and adherence to analgesic regimens. System-related barriers such as limits on access to opioids and the availability of pain and palliative care specialists present additional challenges, particularly in resource-poor regions. Given the multidimensional nature of cancer pain and the multifaceted barriers involved, effective pain control mandates multidisciplinary interventions from interprofessional teams. Educational interventions for patients and health care professionals may improve the success of pain management. PMID- 24799491 TI - Evolving treatment paradigms for primary mediastinal diffuse large B-cell lymphoma. PMID- 24799492 TI - Laying to rest psychostimulants for cancer-related fatigue? PMID- 24799493 TI - Immune responses and outcome in follicular lymphoma. PMID- 24799494 TI - Downstaging of Non-Small-Cell Lung Cancer Through Identification of Reversible Drug Toxicity. PMID- 24799495 TI - A personalized approach to assessing and managing pain in patients with cancer. AB - Pain is one of the most common and distressing symptoms in patients with cancer. In this review, we discuss an evidence-based approach to personalized pain assessment and management. Recent insights into the pain expression pathway have led to a paradigm shift in pain management, allowing clinicians to deliver personalized treatments tailored to the individual's needs. Personalized pain management begins with systematic screening, followed by comprehensive pain assessment. Impeccable characterization of pain informs its etiology and the mechanism to guide treatment choices. Identification of modulators of pain expression such as psychological distress, alcoholism, substance use, and delirium allow clinicians to further tailor treatment recommendations. Documentation of a personalized pain goal provides an individualized response criterion. A multidimensional treatment plan is then formulated targeting the pain mechanism, etiologic factors, and modulators. Finally, longitudinal monitoring customized to the individual's needs allows clinicians to improve adherence and, ultimately, to optimize pain control over time. PMID- 24799496 TI - Opiate pharmacology and relief of pain. AB - Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned. PMID- 24799498 TI - Efficient purification of antiproliferative polysaccharides from Hypsizigus marmoreus with radial flow chromatography. AB - The increasing commercial significance of natural polysaccharides for use in medicinal products is stimulating the development of efficient and easy scale-up techniques for polysaccharide purification. In this research, the crude polysaccharides from submerged cultivation broth of Hypsizigus marmoreus were purified using radial flow chromatography (RFC), and the antiproliferative activity of the purified fractions was evaluated in vitro. DEAE Sepharose CL-6B was selected to be packed in the RFC column based on its good resolution, physical stability, and low cost. Compared with axial flow chromatography (AFC), an efficient chromatographic process with significantly less time and buffer consumption but yielding higher polysaccharide recovery and resolution was established in RFC, which could clearly purify the crude polysaccharides into different fractions. An acceptable linear scale-up effect of RFC from 100 to 500 mL was successfully achieved without loss of resolution and enhancement of time consumption. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in cell cultures indicated that the purified polysaccharide fractions possess moderate antiproliferative activities in three different human cancer cell lines, but have significantly lower cytotoxicity in normal human cell lines in vitro. Among the polysaccharide fractions, the main purified acidic fraction W I could be considered as a novel potential antitumor agent candidate for several tumors, especially for human alveolar epithelial tumors. This research confirmed for the first time that RFC would be a new fast and efficient tool for purification of polysaccharides into different fractions, both at laboratory and commercial scales. PMID- 24799497 TI - Psychological and behavioral approaches to cancer pain management. AB - This review examines evidence for psychological factors that affect pain across the cancer continuum from diagnosis through treatment and long-term survivorship or end of life. Evidence is convincing that emotional distress, depression, anxiety, uncertainty, and hopelessness interact with pain. Unrelieved pain can increase a desire for hastened death. Patients with cancer use many strategies to manage pain, with catastrophizing associated with increased pain and self efficacy associated with lower pain reports. A variety of psychological and cognitive behavioral treatments can reduce pain severity and interference with function, as indicated in multiple meta-analyses and high-quality randomized controlled trials. Effective methods include education (with coping skills training), hypnosis, cognitive behavioral approaches, and relaxation with imagery. Exercise has been tested extensively in patients with cancer and long term survivors, but few exercise studies have evaluated pain outcomes. In survivors post-treatment, yoga and hypnosis as well as exercise show promise for controlling pain. Although some of these treatments effectively reduce pain for patients with advanced disease, few have been tested in patients at the end of life. Given the clear indicators that psychological factors affect cancer pain and that psychological and behavioral treatments are effective in reducing varying types of pain for patients with active disease, these methods need further testing in cancer survivors post-treatment and in patients with end-stage disease. Multidisciplinary teams are essential in oncology settings to integrate analgesic care and expertise in psychological and behavioral interventions in standard care for symptom management, including pain. PMID- 24799499 TI - Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus. AB - Group B Streptococcus (GBS) causes invasive infections in human newborns. We recently showed that the GBS beta-protein attenuates innate immune responses by binding to sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5), an inhibitory receptor on phagocytes. Interestingly, neutrophils and monocytes also express Siglec-14, which has a ligand-binding domain almost identical to Siglec-5 but signals via an activating motif, raising the possibility that these are paired Siglec receptors that balance immune responses to pathogens. Here we show that beta-protein-expressing GBS binds to both Siglec-5 and Siglec-14 on neutrophils and that the latter engagement counteracts pathogen-induced host immune suppression by activating p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways. Siglec-14 is absent from some humans because of a SIGLEC14-null polymorphism, and homozygous SIGLEC14-null neutrophils are more susceptible to GBS immune subversion. Finally, we report an unexpected human specific expression of Siglec-5 and Siglec-14 on amniotic epithelium, the site of initial contact of invading GBS with the fetus. GBS amnion immune activation was likewise influenced by the SIGLEC14-null polymorphism. We provide initial evidence that the polymorphism could influence the risk of prematurity among human fetuses of mothers colonized with GBS. This first functionally proven example of a paired receptor system in the Siglec family has multiple implications for regulation of host immunity. PMID- 24799500 TI - Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells. AB - Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca(-/-) mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation. PMID- 24799501 TI - Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry. AB - There is currently no paradigm in immunology that enables an accurate prediction of how the immune system will respond to any given agent. Here we show that the immunological responses induced by members of a broad class of inorganic crystalline materials are controlled purely by their physicochemical properties in a highly predictable manner. We show that structurally and chemically homogeneous layered double hydroxides (LDHs) can elicit diverse human dendritic cell responses in vitro. Using a systems vaccinology approach, we find that every measured response can be modeled using a subset of just three physical and chemical properties for all compounds tested. This correlation can be reduced to a simple linear equation that enables the immunological responses stimulated by newly synthesized LDHs to be predicted in advance from these three parameters alone. We also show that mouse antigen-specific antibody responses in vivo and human macrophage responses in vitro are controlled by the same properties, suggesting they may control diverse responses at both individual component and global levels of immunity. This study demonstrates that immunity can be determined purely by chemistry and opens the possibility of rational manipulation of immunity for therapeutic purposes. PMID- 24799502 TI - Percutaneous coronary intervention should be guided by fractional flow reserve measurement. PMID- 24799503 TI - Fractional flow reserve-guided percutaneous coronary intervention is not a valid concept. PMID- 24799504 TI - Cardiac resynchronization therapy for pediatric patients with heart failure and congenital heart disease: a reappraisal of results. PMID- 24799505 TI - Contemporary approach to paradoxical embolism. PMID- 24799506 TI - ECG response: May 6, 2014. PMID- 24799507 TI - Perianeurysmal emphysema: clostridium septicum-infected aortic aneurysm. PMID- 24799508 TI - Cause of cardiac disease in a female carrier of Duchenne muscular dystrophy: myocarditis versus genetic cardiomyopathy without skeletal myopathy? PMID- 24799509 TI - Letter by Rai and Bughio regarding article, "subclinical left ventricular dysfunction and silent cerebrovascular disease: the cardiovascular abnormalities and brain lesions (CABL) study". PMID- 24799510 TI - Response to letter regarding article, "subclinical left ventricular dysfunction and silent cerebrovascular disease: the cardiovascular abnormalities and brain lesions (CABL) study". PMID- 24799511 TI - Stakeholder discussion to reduce population-wide sodium intake and decrease sodium in the food supply: a conference report from the American Heart Association Sodium Conference 2013 Planning Group. AB - BACKGROUND: A 2-day interactive forum was convened to discuss the current status and future implications of reducing sodium in the food supply and to identify opportunities for stakeholder collaboration. METHODS AND RESULTS: Participants included 128 stakeholders engaged in food research and development, food manufacturing and retail, restaurant and food service operations, regulatory and legislative activities, public health initiatives, healthcare, academia and scientific research, and data monitoring and surveillance. Presentation topics included scientific evidence for sodium reduction and public health policy recommendations; consumer sodium intakes, attitudes, and behaviors; food technologies and solutions for sodium reduction and sensory implications; experiences of the food and dining industries; and translation and implementation of sodium intake recommendations. Facilitated breakout sessions were conducted to allow for sharing of current practices, insights, and expertise. CONCLUSIONS: A well-established body of scientific research shows that there is a strong relationship between excess sodium intake and high blood pressure and other adverse health outcomes. With Americans getting >75% of their sodium from processed and restaurant food, this evidence creates mounting pressure for less sodium in the food supply. The reduction of sodium in the food supply is a complex issue that involves multiple stakeholders. The success of new technological approaches for reducing sodium will depend on product availability, health effects (both intended and unintended), research and development investments, quality and taste of reformulated foods, supply chain management, operational modifications, consumer acceptance, and cost. The conference facilitated an exchange of ideas and set the stage for potential collaboration opportunities among stakeholders with mutual interest in reducing sodium in the food supply and in Americans' diets. Population-wide sodium reduction remains a critically important component of public health efforts to promote cardiovascular health and prevent cardiovascular disease and will remain a priority for the American Heart Association. PMID- 24799512 TI - Exercise, heart rate variability, and longevity: the cocoon mystery? PMID- 24799514 TI - Heart failure with better ejection fraction: a modern diagnosis. PMID- 24799513 TI - Physical activity and heart rate variability in older adults: the Cardiovascular Health Study. AB - BACKGROUND: Cardiac mortality and electrophysiological dysfunction both increase with age. Heart rate variability (HRV) provides indices of autonomic function and electrophysiology that are associated with cardiac risk. How habitual physical activity among older adults prospectively relates to HRV, including nonlinear indices of erratic sinus patterns, is not established. We hypothesized that increasing the levels of both total leisure-time activity and walking would be prospectively associated with more favorable time-domain, frequency-domain, and nonlinear HRV measures in older adults. METHODS AND RESULTS: We evaluated serial longitudinal measures of both physical activity and 24-hour Holter HRV over 5 years among 985 older US adults in the community-based Cardiovascular Health Study. After multivariable adjustment, greater total leisure-time activity, walking distance, and walking pace were each prospectively associated with specific, more favorable HRV indices, including higher 24-hour standard deviation of all normal-to-normal intervals (Ptrend=0.009, 0.02, 0.06, respectively) and ultralow-frequency power (Ptrend=0.02, 0.008, 0.16, respectively). Greater walking pace was also associated with a higher short-term fractal scaling exponent (Ptrend=0.003) and lower Poincare ratio (Ptrend=0.02), markers of less erratic sinus patterns. CONCLUSIONS: Greater total leisure-time activity, and walking alone, as well, were prospectively associated with more favorable and specific indices of autonomic function in older adults, including several suggestive of more normal circadian fluctuations and less erratic sinoatrial firing. Our results suggest potential mechanisms that might contribute to lower cardiovascular mortality with habitual physical activity later in life. PMID- 24799516 TI - Multiple sclerosis care in Latin America. AB - Before the advent of diagnostic criteria for multiple sclerosis (MS), it was reported that the prevalence of MS in Mexico was "one of the lowest in the world" (1.6/100,000).(1) The notion that MS was a rare neurologic disease among those living in the tropics of the Americas and Southern latitudes was widely accepted. The geopolitical boundaries of the region identified as Latin America (LA) extend from the southern border of United States with Mexico (32 degrees North latitude) to the Argentinian and Chilean Patagonia in South America (56 degrees South latitude). The largest Spanish-speaking island countries in the Caribbean Cuba, Dominican Republic, and Puerto Rico-are also traditionally considered part of LA. The continental mass includes 17 countries with a population of more than 550 million. Due to centuries of racial intermixing, it is a heterogeneous and genetically complex population. The blended cultures of native Amerindians with white Caucasian Europeans and black Africans has resulted in the predominant ethnic Latin American Mestizo. The influence of African genetics is notable in many areas of the subcontinent and the Caribbean. A common observation across LA is the absence of identification of MS in non-mixed Amerindians(2); the reason for this phenomenon is unclear. PMID- 24799515 TI - Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes. AB - BACKGROUND: We hypothesized that patients with heart failure (HF) who recover left ventricular function (HF-Recovered) have a distinct clinical phenotype, biology, and prognosis compared with patients with HF with reduced ejection fraction (HF-REF) and those with HF with preserved ejection fraction (HF-PEF). METHODS AND RESULTS: The Penn Heart Failure Study (PHFS) is a prospective cohort of 1821 chronic HF patients recruited from tertiary HF clinics. Participants were divided into 3 categories based on echocardiograms: HF-REF if EF was <50%, HF-PEF if EF was consistently >=50%, and HF-Recovered if EF on enrollment in PHFS was >=50% but prior EF was <50%. A significant portion of HF-Recovered patients had an abnormal biomarker profile at baseline, including 44% with detectable troponin I, although in comparison, median levels of brain natriuretic factor, soluble fms like tyrosine kinase receptor-1, troponin I, and creatinine were greater in HF REF and HF-PEF patients. In unadjusted Cox models over a maximum follow-up of 8.9 years, the hazard ratio for death, transplantation, or ventricular assist device placement in HF-REF patients was 4.1 (95% confidence interval, 2.4-6.8; P<0.001) and in HF-PEF patients was 2.3 (95% confidence interval, 1.2-4.5; P=0.013) compared with HF-Recovered patients. The unadjusted hazard ratio for cardiac hospitalization in HF-REF patients was 2.0 (95% confidence interval, 1.5-2.7; P<0.001) and in HF-PEF patients was 1.3 (95% confidence interval, 0.90-2.0; P=0.15) compared with HF-Recovered patients. Results were similar in adjusted models. CONCLUSIONS: HF-Recovered is associated with a better biomarker profile and event-free survival than HF-REF and HF-PEF. However, these patients still have abnormalities in biomarkers and experience a significant number of HF hospitalizations, suggesting persistent HF risk. PMID- 24799517 TI - Ramsay Hunt syndrome type II. AB - A 57-year-old man developed 3 days of left facial pain and swelling with left sided hearing loss followed by a painful, unilateral, erythematous, and vesicular rash on the left anterior two-thirds of the tongue, external auditory canal, lip, and face typical of varicella-zoster virus reactivation (figure). Reactivation in the geniculate ganglion or facial nerve is uncommon and typically causes tongue and auricular lesions or facial palsy and was described by Hunt in 1907.(1) The patient received IV acyclovir and oral prednisone with rapid improvement in pain and resolution of lesions and improvement of hearing over 1 month. PMID- 24799518 TI - SET binding factor 1 (SBF1) mutation causes Charcot-Marie-tooth disease type 4B3. PMID- 24799519 TI - Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker study. PMID- 24799520 TI - Journal club: pretreatment EEG in childhood absence epilepsy. AB - Childhood absence epilepsy (CAE) is defined by absence seizures in a normally developing child, with onset between 4 and 10 years of age.(1) Typical absence seizures consist of behavioral arrest with or without automatisms, usually last 30-60 seconds, and demonstrate a characteristic 3-Hz generalized spike-wave (GSW) pattern on EEG, often in response to hyperventilation.(2) Children may have hundreds of episodes daily, many of them subclinical, which can impair sustained attention and memory processing. There is a strong association between CAE and disorders of attention and executive function. This association persists even when seizures are well-controlled. An underlying structural or functional abnormality of the brain has been postulated to explain both observations.(3,4) This article by Dlugos et al.(5) is a post hoc analysis of a randomized, double blinded trial(6) that seeks to characterize the relationship between EEG characteristics prior to treatment, measures of attention, and the outcome of initial antiepileptic treatment. PMID- 24799521 TI - Teaching NeuroImages: brain mass with hilar adenopathy: the importance of histologic diagnosis. AB - A 30-year-old man presented with weeks of progressive headaches, imbalance, and aphasia. Brain MRI revealed an enhancing left frontal mass (figure 1, A and B). Chest imaging revealed mediastinal and hilar adenopathy (figure 1, C and D). Metastatic cancer was initially suspected, but pulmonary lymph node aspiration revealed sarcoidosis (figure 2A). Subsequent brain biopsy revealed glioblastoma (figure 2B). PMID- 24799522 TI - Identification of campath-1 (CD52) as novel drug target in neoplastic stem cells in 5q-patients with MDS and AML. AB - PURPOSE: The CD52-targeted antibody alemtuzumab induces major clinical responses in a group of patients with myelodysplastic syndromes (MDS). The mechanism underlying this drug effect remains unknown. EXPERIMENTAL DESIGN: We asked whether neoplastic stem cells (NSC) in patients with MDS (n = 29) or acute myelogenous leukemia (AML; n = 62) express CD52. RESULTS: As assessed by flow cytometry, CD52 was found to be expressed on NSC-enriched CD34(+)/CD38(-) cells in 8/11 patients with MDS and isolated del(5q). In most other patients with MDS, CD52 was weakly expressed or not detectable on NSC. In AML, CD34(+)/CD38(-) cells displayed CD52 in 23/62 patients, including four with complex karyotype and del(5q) and one with del(5q) and t(1;17;X). In quantitative PCR (qPCR) analyses, purified NSC obtained from del(5q) patients expressed CD52 mRNA. We were also able to show that CD52 mRNA levels correlate with EVI1 expression and that NRAS induces the expression of CD52 in AML cells. The CD52-targeting drug alemtuzumab, was found to induce complement-dependent lysis of CD34(+)/CD38(-)/CD52(+) NSC, but did not induce lysis in CD52(-) NSC. Alemtuzumab also suppressed engraftment of CD52(+) NSC in NSG mice. Finally, CD52 expression on NSC was found to correlate with a poor survival in patients with MDS and AML. CONCLUSIONS: The cell surface target Campath-1 (CD52) is expressed on NSC in a group of patients with MDS and AML. CD52 is a novel prognostic NSC marker and a potential NSC target in a subset of patients with MDS and AML, which may have clinical implications and may explain clinical effects produced by alemtuzumab in these patients. PMID- 24799523 TI - Synergistic anticancer effects of Pam3CSK4 and Ara-C on B-cell lymphoma cells. AB - PURPOSE: The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anticancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test whether Toll-like receptor (TLR) agonists and anticancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic. EXPERIMENTAL DESIGN: We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-beta D-arabinofuranosylcytosine (Ara-C). The effects on the immunogenicity of tumor cells were measured in transfer experiments and in vitro studies. RESULTS: The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells. Cotreatment had no effect on the rate of apoptosis or proliferation of Ara-C-treated cells, but upregulated the expression of several immunomodulatory molecules. Consistent with an increased immunogenicity of Pam3CSK4 and Ara-C-treated B-cell lymphoma cells, rejection of cotreated tumor cells required natural killer cells and T cells. We demonstrate that the upregulation of immunomodulatory molecules in response to Pam3CSK4 and Ara-C depended in part on NF-kappaB. CONCLUSION: TLR agonists can increase the efficacy of conventional cancer therapies by altering the immunogenicity of B-cell lymphoma cells. PMID- 24799525 TI - Enriching mutant sequences by modulating the denaturation time during PCR. PMID- 24799524 TI - Disruption of follicular dendritic cells-follicular lymphoma cross-talk by the pan-PI3K inhibitor BKM120 (Buparlisib). AB - PURPOSE: To uncover the signaling pathways underlying follicular lymphoma follicular dendritic cells (FL-FDC) cross-talk and its validation as new targets for therapy. EXPERIMENTAL DESIGN: FL primary cells and cell lines were cocultured in the presence or absence of FDC. After 24 and 48 hours, RNA was isolated from FL cells and subjected to gene expression profiling (GEP) and data meta-analysis using DAVID and GSEA softwares. Blockade of PI3K pathway by the pan-PI3K inhibitor BKM120 (buparlisib; Novartis Pharmaceutical Corporation) and the effect of PI3K inhibition on FL-FDC cross-talk were analyzed by means of ELISA, RT-PCR, human umbilical vein endothelial cell tube formation, adhesion and migration assays, Western blot, and in vivo studies in mouse FL xenografts. RESULTS: GEP of FL-FDC cocultures yields a marked modulation of FL transcriptome by FDC. Pathway assignment by DAVID and GSEA software uncovered an overrepresentation of genes related to angiogenesis, cell adhesion, migration, and serum-response factors. We demonstrate that the addition of the pan-PI3K inhibitor BKM120 to the cocultures was able to downregulate the expression and secretion of proangiogenic factors derived from FL-FDC cocultures, reducing in vitro and in vivo angiogenesis. Moreover, BKM120 efficiently counteracts FDC-mediated cell adhesion and impedes signaling and migration induced by the chemokine CXCL12. BKM120 inhibits both constitutive PI3K/AKT pathway and FDC- or CXCL12-induced PI3K/AKT pathway, hampers FDC survival signaling, and reduces cell proliferation of FL cells in vitro and in mouse xenografts. CONCLUSIONS: These data support the use of BKM120 in FL therapy to counteract microenvironment-related survival signaling in FL cells. PMID- 24799526 TI - To harmonize and standardize: making measurement results comparable. PMID- 24799527 TI - Quantification of serum IgG subclasses by use of subclass-specific tryptic peptides and liquid chromatography--tandem mass spectrometry. AB - BACKGROUND: Measurement of IgG subclasses is a useful tool for investigation of humoral immune deficiency in the presence of total IgG within reference intervals and IgG4-related disease. Nephelometry has been the method of choice for quantification. We describe an LC-MS/MS method that can multiplex all 4 subclasses along with total IgG by use of either IgG subclass-specific peptide stable isotope-labeled internal standards or a surrogate digest standard for quantification and does not rely on antigen/antibody reactions. METHODS: We combined serum with labeled internal peptide standards and intact purified horse IgG. Samples were denatured, reduced, alkylated, and digested. We analyzed the digested serum by LC-MS/MS for IgG subclasses 1-4 and total IgG. RESULTS: We assayed 112 patient sera by LC-MS/MS and immunonephelometry. The mean of the slopes and R(2) values for IgG1, IgG2, IgG3, IgG4, and IgG were 1.18 and 0.93, respectively. Interassay imprecision for the LC-MS/MS method was <15% for total IgG and subclasses and was slightly improved by use of a calibrator peptide from an exogenous horse IgG. Summed total IgG correlated with the measured total IgG within 10%. Reference intervals and analytical measuring range were all similar to our previous validation data for the immunonephelometry assays. CONCLUSIONS: Total IgG and IgG subclasses 1, 2, 3, and 4 can be quantified by LC-MS/MS with performance comparable to nephelometry. PMID- 24799528 TI - Where are all the new omics-based tests? PMID- 24799529 TI - Programming plasma cell survival. PMID- 24799530 TI - Lymphatics help baby take first breath. PMID- 24799531 TI - B-RAF unlocks axon regeneration. PMID- 24799532 TI - New role identified for LRR-containing proteins in T cell development. PMID- 24799533 TI - IKKbeta links vascular inflammation to obesity and atherosclerosis. AB - IkappaB kinase beta (IKKbeta), a central coordinator of inflammatory responses through activation of NF-kappaB, has been implicated in vascular pathologies, but its role in atherogenesis remains elusive. Here, we demonstrate that IKKbeta functions in smooth muscle cells (SMCs) to regulate vascular inflammatory responses and atherosclerosis development. IKKbeta deficiency in SMCs driven by a SM22Cre-IKKbeta-flox system rendered low density lipoprotein receptor-null mice resistant to vascular inflammation and atherosclerosis induced by high-fat feeding. Unexpectedly, IKKbeta-deficient mice were also resistant to diet-induced obesity and metabolic disorders. Cell lineage analysis revealed that SM22Cre is active in primary adipose stromal vascular cells and deficiency of IKKbeta diminished the ability of these cells to differentiate, leading to accumulation of adipocyte precursor cells in adipose tissue. Mechanistically, reduction of IKKbeta expression or pharmacological inhibition of IKKbeta inhibited proteasome mediated beta-catenin ubiquitination and degradation in murine preadipocytes, resulting in elevated beta-catenin levels and impaired adipocyte differentiation. Further, chronic treatment of mice with a potent IKKbeta inhibitor decreased adipogenesis and ameliorated diet-induced obesity. Our findings demonstrate a pivotal role of IKKbeta in linking vascular inflammation to atherosclerosis and adipose tissue development, and provide evidence for using appropriate IKKbeta inhibitors in the treatment of obesity and metabolic disorders. PMID- 24799536 TI - Portrayal of alcohol consumption in movies and drinking initiation in low-risk adolescents. AB - OBJECTIVES: To investigate the hypothesis that exposure to alcohol consumption in movies affects the likelihood that low-risk adolescents will start to drink alcohol. METHODS: Longitudinal study of 2346 adolescent never drinkers who also reported at baseline intent to not to do so in the next 12 months (mean age 12.9 years, SD = 1.08). Recruitment was carried out in 2009 and 2010 in 112 state funded schools in Germany, Iceland, Italy, Netherlands, Poland, and Scotland. Exposure to movie alcohol consumption was estimated from 250 top-grossing movies in each country in the years 2004 to 2009. Multilevel mixed-effects Poisson regressions assessed the relationship between baseline exposure to movie alcohol consumption and initiation of trying alcohol, and binge drinking (>= 5 consecutive drinks) at follow-up. RESULTS: Overall, 40% of the sample initiated alcohol use and 6% initiated binge drinking by follow-up. Estimated mean exposure to movie alcohol consumption was 3653 (SD = 2448) occurrences. After age, gender, family affluence, school performance, TV screen time, personality characteristics, and drinking behavior of peers, parents, and siblings were controlled for, exposure to each additional 1000 movie alcohol occurrences was significantly associated with increased relative risk for trying alcohol, incidence rate ratio = 1.05 (95% confidence interval, 1.02-1.08; P = .003), and for binge drinking, incidence rate ratio = 1.13 (95% confidence interval, 1.06 1.20; P < .001). CONCLUSIONS: Seeing alcohol depictions in movies is an independent predictor of drinking initiation, particularly for more risky patterns of drinking. This result was shown in a heterogeneous sample of European youths who had a low affinity for drinking alcohol at the time of exposure. PMID- 24799538 TI - Essentials for childhood: promoting healthy outcomes from positive experiences. PMID- 24799537 TI - Attributable cost and length of stay for central line-associated bloodstream infections. AB - BACKGROUND AND OBJECTIVE: Central line-associated bloodstream infections (CLABSI) are common types of hospital-acquired infections associated with high morbidity. Little is known about the attributable cost and length of stay (LOS) of CLABSI in pediatric inpatient settings. We determined the cost and LOS attributable to pediatric CLABSI from 2008 through 2011. METHODS: A propensity score-matched case control study was performed. Children <18 years with inpatient discharges in the Nationwide Inpatient Sample databases from the Healthcare Cost and Utilization Project from 2008 to 2011 were included. Discharges with CLABSI were matched to those without CLABSI by age, year, and high dimensional propensity score (obtained from a logistic regression of CLABSI status on patient characteristics and the presence or absence of 262 individual clinical classification software diagnoses). Our main outcome measures were estimated costs obtained from cost-to charge ratios and LOS for pediatric discharges. RESULTS: The mean attributable cost and LOS between matched CLABSI cases (1339) and non-CLABSI controls (2678) was $55 646 (2011 dollars) and 19 days, respectively. Between 2008 and 2011, the rate of pediatric CLABSI declined from 1.08 to 0.60 per 1000 (P < .001). Estimates of mean costs of treating patients with CLABSI declined from $111 852 to $98 621 (11.8%; P < .001) over this period, but cost of treating matched non CLABSI patients remained constant at ~$48 000. CONCLUSIONS: Despite significant improvement in rates, CLABSI remains a burden on patients, families, and payers. Continued attention to CLABSI-prevention initiatives and lower-cost CLABSI care management strategies to support high-value pediatric care delivery is warranted. PMID- 24799540 TI - Prolonged QTc interval in association with medium-chain acyl-coenzyme A dehydrogenase deficiency. AB - Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial fatty acid oxidation. We report a term male infant who presented at 3 days of age with hypoglycemia, compensated metabolic acidosis, hypocalcemia, and prolonged QTc interval. Pregnancy was complicated by maternal premature atrial contractions and premature ventricular contractions. Prolongation of the QTc interval resolved after correction of metabolic derangements. The newborn screen was suggestive for MCAD deficiency, a diagnosis that was confirmed on genetic analysis that showed homozygosity for the disease associated missense A985G mutation in the ACADM gene. This is the first report of acquired prolonged QTc in a neonate with MCAD deficiency, and it suggests that MCAD deficiency should be considered in the differential diagnoses of acute neonatal illnesses associated with electrocardiographic abnormality. We review the clinical presentation and diagnosis of MCAD deficiency in neonates. PMID- 24799541 TI - Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. AB - BACKGROUND AND OBJECTIVES: Children with Down syndrome (DS) are at significant risk for respiratory syncytial virus (RSV) infection and related hospitalization. We compared hospitalization rates due to respiratory tract infection in children with DS aged <2 years who prospectively received palivizumab during the RSV season with a previously published, similar untreated DS birth cohort. METHODS: A total of 532 children with DS who prospectively received palivizumab were assembled from the prospective Canadian RSV Evaluation Study of Palivizumab registry between 2005 and 2012. The untreated group included 233 children with DS derived from a nationwide Dutch birth cohort from 2003 to 2005. Events during the RSV seasons were counted. Poisson regression analysis was performed to compare incidence rate ratios (95% confidence intervals [CIs]) between groups while controlling for observation length and known risk factors for severe RSV infection. RESULTS: In total, 31 (23 untreated, 8 treated) RSV-related hospitalizations were documented. The adjusted risk of RSV-related hospitalizations was higher in untreated subjects than in palivizumab recipients (incidence rate ratio 3.63; 95% CI, 1.52-8.67). The adjusted risk of hospitalization for all respiratory tract infection (147 events; 73 untreated, 74 treated) was similar (incidence rate ratio untreated versus palivizumab 1.11; 95% CI, 0.80-1.55). CONCLUSIONS: These results suggest that palivizumab is associated with a 3.6-fold reduction in the incidence rate ratio for RSV-related hospitalization in children with DS during the first 2 years of life. A randomized trial is needed to determine the efficacy of RSV immunoprophylaxis in this specific high-risk patient population. PMID- 24799539 TI - Practice-tailored facilitation to improve pediatric preventive care delivery: a randomized trial. AB - OBJECTIVE: Evolving primary care models require methods to help practices achieve quality standards. This study assessed the effectiveness of a Practice-Tailored Facilitation Intervention for improving delivery of 3 pediatric preventive services. METHODS: In this cluster-randomized trial, a practice facilitator implemented practice-tailored rapid-cycle feedback/change strategies for improving obesity screening/counseling, lead screening, and dental fluoride varnish application. Thirty practices were randomized to Early or Late Intervention, and outcomes assessed for 16 419 well-child visits. A multidisciplinary team characterized facilitation processes by using comparative case study methods. RESULTS: Baseline performance was as follows: for Obesity: 3.5% successful performance in Early and 6.3% in Late practices, P = .74; Lead: 62.2% and 77.8% success, respectively, P = .11; and Fluoride: <0.1% success for all practices. Four months after randomization, performance rose in Early practices, to 82.8% for Obesity, 86.3% for Lead, and 89.1% for Fluoride, all P < .001 for improvement compared with Late practices' control time. During the full 6-month intervention, care improved versus baseline in all practices, for Obesity for Early practices to 86.5%, and for Late practices 88.9%; for Lead for Early practices to 87.5% and Late practices 94.5%; and for Fluoride, for Early practices to 78.9% and Late practices 81.9%, all P < .001 compared with baseline. Improvements were sustained 2 months after intervention. Successful facilitation involved multidisciplinary support, rapid-cycle problem solving feedback, and ongoing relationship-building, allowing individualizing facilitation approach and intensity based on 3 levels of practice need. CONCLUSIONS: Practice-tailored Facilitation Intervention can lead to substantial, simultaneous, and sustained improvements in 3 domains, and holds promise as a broad-based method to advance pediatric preventive care. PMID- 24799542 TI - Delayed diagnosis and false relapse due to paternal testosterone use in adrenocortical carcinoma. AB - The prognosis of pediatric adrenocortical carcinoma often depends on prompt diagnosis to begin treatment before metastatic progression. We discuss a girl who presented at 8 months of age with virilization, which was thought to be due to exposure to a topical testosterone preparation being used by her father. Her testosterone level did not decrease promptly after her father discontinued the medication, however, and when she followed up with signs of Cushing syndrome 5 months later, metastatic adrenocortical carcinoma was diagnosed. The patient was successfully treated with surgery and multiagent chemotherapy. Nine months after the end of treatment, her testosterone level was again found to be elevated. Testosterone precursors were now absent, however, and there were no imaging signs of recurrence. Further history showed that her father had restarted topical testosterone, and this time, exogenous exposure was correctly diagnosed. As use of topical testosterone becomes more prevalent, exogenous exposure must be considered in the differential diagnosis of childhood virilization. Any persistent testosterone elevation after exposure ceases or signs of hypercortisolism, however, are inconsistent with this diagnosis. We believe that the risk-benefit ratio favors abdominal ultrasound to rule out malignancy in all children presenting with virilization. PMID- 24799543 TI - Impulsivity, "advergames," and food intake. AB - BACKGROUND AND OBJECTIVES: Previous studies have focused on the effect of food advertisements on the caloric intake of children. However, the role of individual susceptibility in this effect is unclear. The aim of this study was to examine the role of impulsivity in the effect of advergames that promote energy-dense snacks on children's snack intake. METHODS: First, impulsivity scores were assessed with a computer task. Then a randomized between-subject design was conducted with 261 children aged 7 to 10 years who played an advergame promoting either energy-dense snacks or nonfood products. As an extra manipulation, half of the children in each condition were rewarded for refraining from eating, the other half were not. Children could eat freely while playing the game. Food intake was measured. The children then completed questionnaire measures, and were weighed and measured. RESULTS: Overall, playing an advergame containing food cues increased general caloric intake. Furthermore, rewarding children to refrain from eating decreased their caloric intake. Finally, rewarding impulsive children to refrain from eating had no influence when they were playing an advergame promoting energy-dense snacks, whereas it did lead to reduced intake among low impulsive children and children who played nonfood advergames. CONCLUSIONS: Playing an advergame promoting energy-dense snacks contributes to increased caloric intake in children. The advergame promoting energy-dense snacks overruled the inhibition task to refrain from eating among impulsive children, making it more difficult for them to refrain from eating. The findings suggest that impulsivity plays an important role in susceptibility to food advertisements. PMID- 24799544 TI - Factors associated with dental care utilization in early childhood. AB - OBJECTIVES: To identify sociodemographic, dietary, and biological factors associated with families who do not receive dental care in early childhood and to identify risk factors associated with having cavities among children who receive early dental care. METHODS: A cross-sectional study of healthy Canadian children seen for primary health care between September 2011 and January 2013 was conducted through the TARGet Kids! practice-based research network in Toronto, Canada. Adjusted logistic regression was used to determine factors associated with children who were not seen by a dentist in early childhood and to determine risk factors associated with having dental cavities among children who received early dental care. RESULTS: Of the 2505 children included in the analysis, <1% were seen by a dentist by 1 year of age. Older children were less likely to have never been to the dentist (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.87-0.90). Low family income (OR, 2.73; 95% CI, 1.47-5.06), prolonged bottle use (OR, 1.43; 95% CI, 1.03-2.00), and higher intakes of sweetened drinks (OR, 1.20; 95% CI, 1.01-1.42) were associated with increased risk for never having been to the dentist. Among those who had been to the dentist, older children (OR, 1.04; 95% CI, 1.03-1.05), children of low income families (OR, 1.90; 95% CI, 1.17 3.10), and those of East Asian maternal ethnicity (OR, 1.91; 95% CI, 1.10-3.29) were more likely to have dental cavities. CONCLUSIONS: Among healthy urban children seen by a primary care provider, those most susceptible to cavities were least likely to receive early dental care. These findings support the need for publicly funded universal early preventive dental care and underscore the importance for primary care physicians to promote dental care in early childhood. PMID- 24799545 TI - Health care provider-delivered adherence promotion interventions: a meta analysis. AB - BACKGROUND AND OBJECTIVE: Improving medical regimen adherence is essential for maximizing the therapeutic potential of treatments for pediatric chronic illness. Health care providers are uniquely positioned to deliver adherence promotion interventions. However, no studies have summarized the effectiveness of health care provider-delivered adherence interventions. The objective of this study was to describe the effectiveness of health care provider-delivered adherence promotion interventions in improving adherence among children who have chronic illness. Data sources include PubMed, PsycINFO, CINAHL, and Scopus. Studies were included if they were randomized-controlled trials of pediatric interventions aiming to increase adherence to the primary regimen for a chronic illness and at least 1 health care provider delivered the intervention. RESULTS: A total of 35 randomized-controlled studies including 4616 children were included. Greater improvements in adherence were observed immediately after health care provider delivered interventions (d = 0.49; 95% confidence interval, 0.32 to 0.66) than at longer-term follow-up (d = 0.32; 95% confidence interval, 0.10 to 0.54). Treatment effect sizes differed across the adherence behaviors measured. There was significant heterogeneity in treatment effects; however, no moderators of treatment effectiveness were identified. This meta-analysis focused on the published literature. In addition, the majority of studies involved children who had asthma and younger children. CONCLUSIONS: Health care provider-delivered interventions for children who have chronic illness can be effective in improving adherence. Gains in adherence are highest immediately after intervention. Future interventions and studies should include multiple methods of assessing adherence, include active comparators, and address long-term maintenance of adherence gains. PMID- 24799546 TI - Prevention of dental caries in children from birth through age 5 years: US Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2004 US Preventive Services Task Force (USPSTF) recommendation on prevention of dental caries in preschool-aged children. METHODS: The USPSTF reviewed the evidence on prevention of dental caries by primary care clinicians in children 5 years and younger, focusing on screening for caries, assessment of risk for future caries, and the effectiveness of various interventions that have possible benefits in preventing caries. POPULATION: This recommendation applies to children age 5 years and younger. RECOMMENDATION: The USPSTF recommends that primary care clinicians prescribe oral fluoride supplementation starting at age 6 months for children whose water supply is deficient in fluoride. (B recommendation) The USPSTF recommends that primary care clinicians apply fluoride varnish to the primary teeth of all infants and children starting at the age of primary tooth eruption. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine screening examinations for dental caries performed by primary care clinicians in children from birth to age 5 years. (I Statement). PMID- 24799547 TI - The conundrum of early-onset sepsis. PMID- 24799548 TI - Supply and utilization of pediatric subspecialists in the United States. AB - OBJECTIVE: The wide geographic variation in pediatric subspecialty supply in the United States has been a source of concern. Whether children in areas with decreased supply receive less subspecialty care or have worse outcomes has not been adequately evaluated. Among children with special health care needs, we examined the association between pediatric subspecialty supply and subspecialty utilization, need, child disease burden, and family disease burden. METHODS: We measured pediatric subspecialist supply as pediatric subspecialists per capita in each residential county. By using the 2009-2010 National Survey of Children With Special Health Care Needs and controlling for many potential confounders, we examined the association between quintile of pediatric subspecialty supply and parent-reported subspecialty utilization, perceived subspecialty need, and child and family disease burden. RESULTS: County-level pediatric subspecialty supply ranged from a median of 0 (lowest quintile) to 59 (highest quintile) per 100 000 children. In adjusted results, compared with children in the highest quintile, children in the lowest quintile of supply were 4.8% less likely to report ambulatory subspecialty visits (P < .001), 5.3% less likely to perceive subspecialty care needs (P < .001), and 2.3% more likely to report emergency department visits (P = .018). There were no meaningful differences between pediatric subspecialty supply quintiles for other measures of child or family disease burden. CONCLUSIONS: Children living in counties with the lowest supply of pediatric subspecialists had both decreased perceived need for subspecialty care and decreased utilization of subspecialists. However, the differences in supply were not associated with meaningful differences in child or family disease burden. PMID- 24799549 TI - Role of guidelines on length of therapy in chorioamnionitis and neonatal sepsis. AB - BACKGROUND AND OBJECTIVE: Chorioamnionitis (CAM) is a major risk factor for neonatal sepsis. At our institution, neonates exposed to CAM and intrapartum antibiotics are treated with prolonged antimicrobial therapy if laboratory values are abnormal despite a sterile blood culture. Recently, the Committee on the Fetus and Newborn (COFN) recommended a similar strategy for treating neonates exposed to CAM. Our objective was to determine the frequency of abnormal laboratory parameters in term and late-preterm neonates exposed to CAM and evaluate the implication of recent COFN guidelines. METHODS: This retrospective data analysis included late-preterm and term neonates exposed to CAM. Laboratory parameters, clinical symptoms and the number of infants treated with prolonged antibiotics were determined. RESULTS: A total of 554 infants met the inclusion criteria. Eighty-three infants (14.9%) had an abnormal immature to total neutrophil ratio (>0.2) and 121 infants (22%) had an abnormal C-reactive protein level (>1 mg/dL) at 12 hours of age. A total of 153 infants (27.6%) had an abnormal immature to total neutrophil ratio and/or abnormal C-reactive protein level at 12 hours of age. Only 4 (0.7%) of 554 infants had a positive blood culture result. A total of 134 (24.2%) infants were treated with prolonged antibiotics (112 [20.2%] were treated solely based on abnormal laboratory data). Lumbar puncture was performed in 120 (21.6%) infants. CONCLUSIONS: When managed by using a strategy similar to recent COFN guidelines, a large number of term and late-preterm infants exposed to CAM who had sterile blood culture findings were treated with prolonged antibiotic therapy due to abnormal laboratory findings. They were also subjected to additional invasive procedures and had a longer duration of hospitalization. PMID- 24799550 TI - Child passenger deaths involving alcohol-impaired drivers. AB - BACKGROUND AND OBJECTIVE: Approximately 1 in 5 child passenger deaths in the United States involves an alcohol-impaired driver, most commonly the child's own driver. The objective of this study was to document recent trends and state specific rates of these deaths. METHODS: A descriptive analysis of 2001-2010 Fatality Analysis Reporting System data for child passengers aged <15 years killed in alcohol-impaired driving crashes. Driver impairment was defined as a blood alcohol concentration of >=0.08 g/dL. RESULTS: During 2001-2010, 2344 children <15 years were killed in crashes involving at least 1 alcohol-impaired driver. Of these children, 1515 (65%) were riding with an impaired driver. Annual deaths among children riding with an alcohol-impaired driver decreased by 41% over the decade. Among the 37 states included in the state-level analysis, Texas (272) and California (135) had the most children killed while riding with an impaired driver and South Dakota (0.98) and New Mexico (0.86) had the highest annualized child passenger death rates (per 100 000 children). Most (61%) child passengers of impaired drivers were unrestrained at the time of the crash. One third of the impaired drivers did not have a valid driver's license. CONCLUSIONS: Alcohol-impaired driving remains a substantial threat to the safety of child passengers in the United States, and typically involves children being driven by impaired drivers. This risk varies meaningfully among states. To make further progress, states and communities could consider increased use of effective interventions and efforts aimed specifically at protecting child passengers from impaired drivers. PMID- 24799551 TI - About Dr. Darwish. PMID- 24799553 TI - Unused prescription drugs should not be treated like leftovers. PMID- 24799552 TI - Parasomnias. PMID- 24799555 TI - Feds to create surveillance system for drug-resistant bugs. PMID- 24799556 TI - Two-thirds of seniors in long-term care take 10 or more drugs: CIHI. PMID- 24799557 TI - Doctors urge disclosure of sickle cell trait. PMID- 24799558 TI - Irregular menstrual cycles in a young woman. PMID- 24799559 TI - Quebec doctors aim to fill marijuana knowledge gaps. PMID- 24799561 TI - Deconstructing Kranz anatomy to understand C4 evolution. AB - C4 photosynthesis is a complex physiological adaptation that confers greater productivity than the ancestral C3 photosynthetic type in environments where photorespiration is high. It evolved in multiple lineages through the coordination of anatomical and biochemical components, which concentrate CO2 at the active site of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). In most C4 plants, the CO2-concentrating mechanism is achieved via the confinement of Rubisco to bundle-sheath cells, into which CO2 is biochemically pumped from surrounding mesophyll cells. The C4 biochemical pathway relies on a specific suite of leaf functional properties, often referred to as Kranz anatomy. These include the existence of discrete compartments differentially connected to the atmosphere, a close contact between these compartments, and a relatively large compartment to host the Calvin cycle. In this review, we use a quantitative dataset for grasses (Poaceae) and examples from other groups to isolate the changes in anatomical characteristics that generate these functional properties, including changes in the size, number, and distribution of different cell types. These underlying anatomical characteristics vary among C4 origins, as similar functions emerged via different modifications of anatomical characteristics. In addition, the quantitative characteristics of leaves all vary continuously across C3 and C4 taxa, resulting in C4-like values in some C3 taxa. These observations suggest that the evolution of C4-suitable anatomy might require relatively few changes in plant lineages with anatomical predispositions. Furthermore, the distribution of anatomical traits across C3 and C4 taxa has important implications for the functional diversity observed among C4 lineages and for the approaches used to identify genetic determinants of C4 anatomy. PMID- 24799560 TI - Exogenous gamma-aminobutyric acid (GABA) affects pollen tube growth via modulating putative Ca2+-permeable membrane channels and is coupled to negative regulation on glutamate decarboxylase. AB - gamma-Aminobutyric acid (GABA) is implicated in pollen tube growth, but the molecular and cellular mechanisms that it mediates are largely unknown. Here, it is shown that exogenous GABA modulates putative Ca(2+)-permeable channels on the plasma membranes of tobacco pollen grains and pollen tubes. Whole-cell voltage clamp experiments and non-invasive micromeasurement technology (NMT) revealed that the influx of Ca(2+) increases in pollen tubes in response to exogenous GABA. It is also demonstrated that glutamate decarboxylase (GAD), the rate limiting enzyme of GABA biosynthesis, is involved in feedback controls of Ca(2+) permeable channels to fluctuate intracellular GABA levels and thus modulate pollen tube growth. The findings suggest that GAD activity linked with Ca(2+) permeable channels relays an extracellular GABA signal and integrates multiple signal pathways to modulate tobacco pollen tube growth. Thus, the data explain how GABA mediates the communication between the style and the growing pollen tubes. PMID- 24799562 TI - Disruption of the mitochondrial alternative oxidase (AOX) and uncoupling protein (UCP) alters rates of foliar nitrate and carbon assimilation in Arabidopsis thaliana. AB - Under high light, the rates of photosynthetic CO2 assimilation can be influenced by reductant consumed by both foliar nitrate assimilation and mitochondrial alternative electron transport (mAET). Additionally, nitrate assimilation is dependent on reductant and carbon skeletons generated from both the chloroplast and mitochondria. However, it remains unclear how nitrate assimilation and mAET coordinate and contribute to photosynthesis. Here, hydroponically grown Arabidopsis thaliana T-DNA insertional mutants for alternative oxidase (AOX1A) and uncoupling protein (UCP1) fed either NO3 (-) or NH4 (+) were used to determine (i) the response of NO3 (-) uptake and assimilation to the disruption of mAET, and (ii) the interaction of N source (NO3 (-) versus NH4 (+)) and mAET on photosynthetic CO2 assimilation and electron transport. The results showed that foliar NO3 (-) assimilation was enhanced in both aox1a and ucp1 compared with the wild-type, suggesting that foliar NO3 (-) assimilation is probably driven by a decreased capacity of mAET and an increase in reductant within the cytosol. Wild-type plants had also higher rates of net CO2 assimilation (A net) and quantum yield of PSII (phiPSII) under NO3 (-) feeding compared with NH4 (+) feeding. Additionally, under NO3 (-) feeding, A net and phiPSII were decreased in aox1a and ucp1 compared with the wild type; however, under NH4 (+) they were not significantly different between genotypes. This indicates that NO3 (-) assimilation and mAET are both important to maintain optimal rates of photosynthesis, probably in regulating reductant accumulation and over-reduction of the chloroplastic electron transport chain. These results highlight the importance of mAET in partitioning energy between foliar nitrogen and carbon assimilation. PMID- 24799563 TI - Regulation of photosynthesis and stomatal and mesophyll conductance under water stress and recovery in olive trees: correlation with gene expression of carbonic anhydrase and aquaporins. AB - The hypothesis that aquaporins and carbonic anhydrase (CA) are involved in the regulation of stomatal (g s) and mesophyll (g m) conductance to CO2 was tested in a short-term water-stress and recovery experiment in 5-year-old olive plants (Olea europaea) growing outdoors. The evolution of leaf gas exchange, chlorophyll fluorescence, and plant water status, and a quantitative analysis of photosynthesis limitations, were followed during water stress and recovery. These variables were correlated with gene expression of the aquaporins OePIP1.1 and OePIP2.1, and stromal CA. At mild stress and at the beginning of the recovery period, stomatal limitations prevailed, while the decline in g m accounted for up to 60% of photosynthesis limitations under severe water stress. However, g m was restored to control values shortly after rewatering, facilitating the recovery of the photosynthetic rate. CA was downregulated during water stress and upregulated after recovery. The use of structural equation modelling allowed us to conclude that both OePIP1.1 and OePIP2.1 expression could explain most of the variations observed for g s and g m. CA expression also had a small but significant effect on g m in olive under water-stress conditions. PMID- 24799564 TI - Activation of the STING adaptor attenuates experimental autoimmune encephalitis. AB - Cytosolic DNA sensing activates the stimulator of IFN genes (STING) adaptor to induce IFN type I (IFN-alphabeta) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance breakdown, leading to autoimmunity. In this study, we show that systemic treatments with DNA nanoparticles (DNPs) induced potent immune regulatory responses via STING signaling that suppressed experimental autoimmune encephalitis (EAE) when administered to mice after immunization with myelin oligodendrocyte glycoprotein (MOG), at EAE onset, or at peak disease severity. DNP treatments attenuated infiltration of effector T cells into the CNS and suppressed innate and adaptive immune responses to myelin oligodendrocyte glycoprotein immunization in spleen. Therapeutic responses were not observed in mice treated with cargo DNA or cationic polymers alone, indicating that DNP uptake and cargo DNA sensing by cells with regulatory functions was essential for therapeutic responses to manifest. Intact STING and IFN-alphabeta receptor genes, but not IFN-gamma receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on IDO enzyme activity in hematopoietic cells. Thus, DNPs and cyclic diguanylate monophosphate attenuate EAE by inducing dominant T cell regulatory responses via the STING/IFN alphabeta/IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING/IFN-alphabeta pathway in either stimulating or suppressing autoimmunity and identify STING-activating reagents as a novel class of immune modulatory drugs. PMID- 24799565 TI - Cathepsins limit macrophage necroptosis through cleavage of Rip1 kinase. AB - It has recently been shown that programmed necrosis, necroptosis, may play a key role in the development of inflammation. Deciphering the regulation of this pathway within immune cells may therefore have implications in pathology associated with inflammatory diseases. We show that treatment of macrophages with the pan caspase inhibitor (zVAD-FMK) results in both increased phosphorylation and decreased cleavage of receptor interacting protein kinase-1 (Rip1), leading to necroptosis that is dependent on autocrine TNF signaling. Stimulation of cells with TLR agonists such as LPS in the presence of zVAD-FMK also induced Rip1 phosphorylation via a TNFR-independent mechanism. Further examination of Rip1 expression under these stimulatory conditions revealed a regulatory cleavage of Rip1 in macrophages that is not apparently attributable to caspase-8. Instead, we provide novel evidence that cysteine family cathepsins, which are highly abundant in myeloid cells, can also cleave Rip1 kinase. Using small interfering RNA knockdown, specific cathepsin inhibitors, and cell-free cleavage assays, we demonstrate that cysteine cathepsins B and S can directly cleave Rip1. Finally, we demonstrate that only through combined inhibition of cathepsins and caspase-8 could a potent induction of macrophage necroptosis be achieved. These data reveal a novel mechanism of regulation of necroptosis by cathepsins within macrophage cells. PMID- 24799567 TI - An uncertain environment for US hospitals. PMID- 24799568 TI - The payment reform paradox. PMID- 24799566 TI - Simian virus 40 large T antigen induces IFN-stimulated genes through ATR kinase. AB - Polyomaviruses encode a large T Ag (LT), a multifunctional protein essential for the regulation of both viral and host cell gene expression and productive viral infection. Previously, we have shown that stable expression of LT protein results in upregulation of genes involved in the IFN induction and signaling pathway. In this study, we focus on the cellular signaling mechanism that leads to the induction of IFN responses by LT. Our results show that ectopic expression of SV40 LT results in the induction of IFN-stimulated genes (ISGs) in human fibroblasts and confers an antiviral state. We describe a LT-initiated DNA damage response (DDR) that activates IFN regulatory factor 1, causing IFN-beta production and consequent ISG expression in human cells. This IFN-beta and ISG induction is dependent on ataxia-telangiectasia mutated and Rad3-related (ATR) kinase, but independent of ATM. ATR kinase inhibition using a selective kinase inhibitor (ETP-46464) caused a decrease in IFN regulatory factor 1 stabilization and ISG expression. Furthermore, expression of a mutant LT that does not induce DDR also does not induce IFN-beta and ISGs. These results show that, in the absence of viral infection, LT-initiated activation of ATR-dependent DDR is sufficient for the induction of an IFN-beta-mediated innate immune response in human cells. Thus, we have uncovered a novel and critical role for ATR as a mediator of antiviral responses utilizing LT. PMID- 24799569 TI - Hospital financial performance in the recent recession and implications for institutions that remain financially weak. AB - The recent recession had a profound effect on all sectors of the US economy, including health care. We examined how private hospitals fared through the recession and considered how changes in their financial health may affect their ability to respond to future industry challenges. We categorized 2,971 private short-term general medical or surgical hospitals (both nonprofit and for-profit) according to their pre-recession financial health and safety-net status, and we examined their operational status changes and operating and total financial margins during 2006-11. We found that hospitals that were financially weak before the recession remained so during and after the recession. The total margins of nonprofit hospitals (both safety-net and other institutions) declined in 2008 but returned to their pre-recession levels by 2011. The recession did not create additional fiscal pressure on hospitals that were previously financially weak or in safety-net roles. However, both groups continue to have notable financial deficiencies that could limit their abilities to meet the growing demands on the industry. PMID- 24799570 TI - From 'solution shop' model to 'focused factory' in hospital surgery: increasing care value and predictability. AB - The full-service US hospital has been described organizationally as a "solution shop," in which medical problems are assumed to be unstructured and to require expert physicians to determine each course of care. If universally applied, this model contributes to unwarranted variation in care, which leads to lower quality and higher costs. We purposely disrupted the adult cardiac surgical practice that we led at Mayo Clinic, in Rochester, Minnesota, by creating a "focused factory" model (characterized by a uniform approach to delivering a limited set of high quality products) within the practice's solution shop. Key elements of implementing the new model were mapping the care process, segmenting the patient population, using information technology to communicate clearly defined expectations, and empowering nonphysician providers at the bedside. Using a set of criteria, we determined that the focused-factory model was appropriate for 67 percent of cardiac surgical patients. We found that implementation of the model reduced resource use, length-of-stay, and cost. Variation was markedly reduced, and outcomes were improved. Assigning patients to different care models increases care value and the predictability of care process, outcomes, and costs while preserving (in a lesser clinical footprint) the strengths of the solution shop. We conclude that creating a focused-factory model within a solution shop, by applying industrial engineering principles and health information technology tools and changing the model of work, is very effective in both improving quality and reducing costs. PMID- 24799571 TI - Vertical integration: hospital ownership of physician practices is associated with higher prices and spending. AB - We examined the consequences of contractual or ownership relationships between hospitals and physician practices, often described as vertical integration. Such integration can reduce health spending and increase the quality of care by improving communication across care settings, but it can also increase providers' market power and facilitate the payment of what are effectively kickbacks for inappropriate referrals. We investigated the impact of vertical integration on hospital prices, volumes (admissions), and spending for privately insured patients. Using hospital claims from Truven Analytics MarketScan for the nonelderly privately insured in the period 2001-07, we constructed county-level indices of prices, volumes, and spending and adjusted them for enrollees' age and sex. We measured hospital-physician integration using information from the American Hospital Association on the types of relationships hospitals have with physicians. We found that an increase in the market share of hospitals with the tightest vertically integrated relationship with physicians--ownership of physician practices--was associated with higher hospital prices and spending. We found that an increase in contractual integration reduced the frequency of hospital admissions, but this effect was relatively small. Taken together, our results provide a mixed, although somewhat negative, picture of vertical integration from the perspective of the privately insured. PMID- 24799572 TI - Procedures take less time at ambulatory surgery centers, keeping costs down and ability to meet demand up. AB - During the past thirty years outpatient surgery has become an increasingly important part of medical care in the United States. The number of outpatient procedures has risen dramatically since 1981, and the majority of surgeries performed in the United States now take place in outpatient settings. Using data on procedure length, we show that ambulatory surgery centers (ASCs) provide a lower-cost alternative to hospitals as venues for outpatient surgeries. On average, procedures performed in ASCs take 31.8 fewer minutes than those performed in hospitals--a 25 percent difference relative to the mean procedure time. Given the rapid growth in the number of surgeries performed in ASCs in recent years, our findings suggest that ASCs provide an efficient way to meet future growth in demand for outpatient surgeries and can help fulfill the Affordable Care Act's goals of reducing costs while improving the quality of health care delivery. PMID- 24799573 TI - Redesigning care for patients at increased hospitalization risk: the Comprehensive Care Physician model. AB - Patients who have been hospitalized often experience care coordination problems that worsen outcomes and increase costs. One reason is that hospital care and ambulatory care are often provided by different physicians. However, interventions to improve care coordination for hospitalized patients have not consistently improved outcomes and generally have not reduced costs. We describe the rationale for the Comprehensive Care Physician model, in which physicians focus their practice on patients at increased risk of hospitalization so that they can provide both inpatient and outpatient care to their patients. We also describe the design and implementation of a study supported by the Center for Medicare and Medicaid Innovation to assess the model's effects on costs and outcomes. Evidence concerning the effectiveness of the program is expected by 2016. If the program is found to be effective, the next steps will be to assess the durability of its benefits and the model's potential for dissemination; evidence to the contrary will provide insights into how to alter the program to address sources of failure. PMID- 24799574 TI - Socioeconomic status and readmissions: evidence from an urban teaching hospital. AB - The Centers for Medicare and Medicaid Services (CMS) Hospital Readmissions Reduction Program has focused attention on ways to reduce thirty-day readmissions and on factors affecting readmission risk. Using inpatient data from an urban teaching hospital, we examined how elements of individual characteristics and neighborhood socioeconomic status influenced the likelihood of readmission under a single fixed organizational and staffing structure. Patients living in high poverty neighborhoods were 24 percent more likely than others to be readmitted, after demographic characteristics and clinical conditions were adjusted for. Married patients were at significantly reduced risk of readmission, which suggests that they had more social support than unmarried patients. These and previous findings that document socioeconomic disparities in readmission raise the question of whether CMS's readmission measures and associated financial penalties should be adjusted for the effects of factors beyond hospital influence at the individual or neighborhood level, such as poverty and lack of social support. PMID- 24799575 TI - Adding socioeconomic data to hospital readmissions calculations may produce more useful results. AB - To better understand the degree to which risk-standardized thirty-day readmission rates may be influenced by social factors, we compared results for hospitals in Missouri under two types of models. The first type of model is currently used by the Centers for Medicare and Medicaid Services for public reporting of condition specific hospital readmission rates of Medicare patients. The second type of model is an "enriched" version of the first type of model with census tract-level socioeconomic data, such as poverty rate, educational attainment, and housing vacancy rate. We found that the inclusion of these factors had a pronounced effect on calculated hospital readmission rates for patients admitted with acute myocardial infarction, heart failure, and pneumonia. Specifically, the models including socioeconomic data narrowed the range of observed variation in readmission rates for the above conditions, in percentage points, from 6.5 to 1.8, 14.0 to 7.4, and 7.4 to 3.7, respectively. Interestingly, the average readmission rates for the three conditions did not change significantly between the two types of models. The results of our exploratory analysis suggest that further work to characterize and report the effects of socioeconomic factors on standardized readmission measures may assist efforts to improve care quality and deliver more equitable care on the part of hospitals, payers, and other stakeholders. PMID- 24799576 TI - Emergency department profits are likely to continue as the Affordable Care Act expands coverage. AB - To better understand the financial viability of hospital emergency departments (EDs), we created national estimates of the cost to hospitals of providing ED care and the associated hospital revenue using hospital financial reports and patient claims data from 2009. We then estimated the effect the Affordable Care Act (ACA) will have on the future profitability of providing ED care. We estimated that hospital revenue from ED care exceeded costs for that care by $6.1 billion in 2009, representing a profit margin of 7.8 percent (net revenue expressed as a percentage of total revenue). However, this is primarily because hospitals make enough profit on the privately insured ($17 billion) to cover underpayment from all other payer groups, such as Medicare, Medicaid, and unreimbursed care. Assuming current payer reimbursement rates, ACA reforms could result in an additional 4.4-percentage-point increase in profit margins for hospital-based EDs compared to what could be the case without the reforms. PMID- 24799577 TI - In emergency departments, radiologists' access to EHRs may influence interpretations and medical management. AB - The adoption of electronic health records (EHRs) that meet federal meaningful-use standards is a major US national policy priority. Policy makers recognize the potential of electronic communication in delivering high-quality health care, particularly in an environment of expanding remote access to medical care and the ever-increasing need to transmit health care records across institutions. To demonstrate this principle, we sought to estimate the significance of EHR access in emergent neuroradiologic interpretations. Three neuroradiologists conducted a prospective expert-rater analysis of 2,000 consecutive head computed tomography (CT) exams ordered by emergency department (ED) physicians. For each head CT exam, the neuroradiologists compared medical information generated by ED physicians to information generated by the interpreting radiologists who had access to additional EHR-derived patient data. In 6.1 percent of the head CT exams, the neuroradiologists reached consensus--meaning two out of three agreed- that the additional clinical data derived from the EHR was "very likely" to influence radiological interpretations and that the lack of that data would have adversely affected medical management in those patients. Health care providers must recognize the value of implementing EHRs and foster their widespread adoption. PMID- 24799578 TI - An estimated $84.9 billion in uncompensated care was provided in 2013; ACA payment cuts could challenge providers. AB - Millions of uninsured people use health care services every year. We estimated providers' uncompensated care costs in 2013 to be between $74.9 billion and $84.9 billion. We calculated that in the aggregate, at least 65 percent of providers' uncompensated care costs were offset by government payments designed to cover the costs. Medicaid and Medicare were the largest sources of such government payments, providing $13.5 billion and $8.0 billion, respectively. Anticipating fewer uninsured people and lower levels of uncompensated care, the Affordable Care Act reduces certain Medicare and Medicaid payments. Such cuts in government funding of uncompensated care could pose challenges to some providers, particularly in states that have not adopted the Medicaid expansion or where implementation of health care reform is proceeding slowly. PMID- 24799579 TI - US health spending trends by age and gender: selected years 2002-10. AB - This article presents estimates of personal health care spending by age and gender in selected years during the period 2002-10 and an analysis of the variation in spending among children, working-age adults, and the elderly. Our research found that in this period, aggregate spending on children's health care increased at the slowest rate. However, per capita spending for children grew more rapidly than that for working-age adults and the elderly. Per capita spending for the elderly remained about five times higher than spending for children. Overall, females spent more per capita than males, but the gap had decreased by 2010. The implementation of Medicare Part D, the effects of the recent recession, and the aging of the baby boomers affected the spending trends and distributions during the period of this study. PMID- 24799580 TI - Decomposing growth in spending finds annual cost of treatment contributed most to spending growth, 1980-2006. AB - Researchers have disagreed about factors driving up health care spending since the 1980s. One camp, led by Kenneth Thorpe, identifies rising numbers of people being treated for chronic diseases as a major factor. Charles Roehrig and David Rousseau reach the opposite conclusion: that three-quarters of growth in average spending reflects the rising costs of treating given diseases. We reexamined sources of spending growth using data from four nationally representative surveys. We found that rising costs of treatment accounted for 70 percent of growth in real average health care spending from 1980 to 2006. The contribution of shares of the population treated for given diseases increased in 1997-2006, but even then it accounted for only one-third of spending growth. We highlight the fact that Thorpe's inclusion of population growth as part of disease prevalence explains the appreciable difference in results. An important policy implication is that programs to better manage chronic diseases may only modestly reduce average spending growth. PMID- 24799581 TI - Coverage for low-income immigrant children increased 24.5 percent in states that expanded CHIPRA eligibility. AB - The Children's Health Insurance Program Reauthorization Act (CHIPRA) of 2009 provided states with the option of expanding eligibility for federally funded public insurance to low-income immigrant children within their first five years of legal residence in the United States. By 2011 twenty states and the District of Columbia had adopted that option. Using cross-sectional data from the 2003, 2007, and 2011-12 National Survey of Children's Health, we compared trends in coverage and access to care among immigrant children in states that did expand eligibility to children in states that did not. Compared to immigrant children in states that did not expand eligibility, children in states expanding eligibility experienced a 24.5 percent increase in insurance coverage, largely due to greater enrollment in public insurance. Immigrant children in states that expanded eligibility also experienced significant reductions in unmet health care needs, compared to their counterparts in nonexpansion states. Disparities relative to children in nonimmigrant families were substantially reduced in states that expanded eligibility, compared to states that did not. Expanding eligibility for federally funded public insurance to immigrant children within their first five years of legal residence in other states could improve coverage for immigrant children and might also increase access to care. PMID- 24799582 TI - Assessing health care services used by California's undocumented immigrant population in 2010. AB - Undocumented immigrants were excluded from the health benefit Marketplaces created by the Affordable Care Act partly because of claims that they contribute to problems such as high costs and emergency department (ED) crowding. This article examines the likely health care use and costs of undocumented immigrants in California in 2009-10. Using data from the 2009 California Health Interview Survey (CHIS), we developed a model that estimated the state's adult and child undocumented immigrant population, since the survey does not explicitly inquire about undocumented status. The survey also provided information on insurance status, doctor visits, and ED visits in the previous year. We found that undocumented immigrants in California, and the uninsured among them, had fewer or similar numbers of doctor visits, ED visits, and preventive services use compared to US citizens and other immigrant groups. Allowing undocumented immigrants to purchase insurance in the Marketplaces and ensuring receipt of low-cost preventive services can contribute to lower premiums and reduce resource strains on safety-net providers. PMID- 24799583 TI - High incarceration rates among black men enrolled in clinical studies may compromise ability to identify disparities. AB - In 1978 the federal government restricted research on prison and jail inmates in medical studies, the result of decades of unethical research in correctional institutions. We evaluated the impact this policy has had on studies of health outcomes in minority populations, particularly studies involving black men, who are disproportionately incarcerated. Specifically, we explored the effect of incarceration on follow-up rates of fourteen prospective clinical studies funded by the National Heart, Lung, and Blood Institute. We estimated that during the past three decades high rates of incarceration of black men may have accounted for up to 65 percent of the loss to follow-up among black men in these studies. The impact of incarceration was far less among white men, black women, and white women. These estimates suggest that the ability of those studies to examine racial disparities in health outcomes, as well as to understand the experience of this group, could be compromised. We believe that community-recruited subjects who are incarcerated should be allowed to continue participating in observational clinical research that poses minimal risk to participants. PMID- 24799584 TI - The Care Span: Lower Hispanic participation in Medicare Part D may reflect program barriers. AB - Despite the successes of Medicare's Part D prescription drug program, an estimated 12.5 percent of Americans ages sixty-five and older do not have prescription drug coverage. It is possible that some who remain without coverage do so for rational economic reasons. However, barriers to insurance uptake, such as the program's complexity, may exist for certain elderly people. Racial and ethnic minorities may be particularly susceptible to these barriers. To investigate the role that race and ethnicity may play in Medicare Part D participation, we analyzed data from the 2011 National Health and Aging Trends Study. We found that Hispanics were 35 percent less likely than non-Hispanic whites to have coverage, after individual predictors of prescription drug demand were controlled for. There was no statistically significant difference in Part D coverage between non-Hispanic blacks and non-Hispanic whites. Results of a stratified analysis suggest that the difference between Hispanics and non Hispanic whites in Part D coverage may be driven by ethnic disparities among those eligible for the low-income Part D subsidy but not automatically enrolled in it. Further research is needed to identify both the exact mechanisms underlying the observed differential uptake in the rapidly growing elderly Hispanic population and potential policy-based solutions. PMID- 24799585 TI - Eliminating medication copayments reduces disparities in cardiovascular care. AB - Substantial racial and ethnic disparities in cardiovascular care persist in the United States. For example, African Americans and Hispanics with cardiovascular disease are 10-40 percent less likely than whites to receive secondary prevention therapies, such as aspirin and beta-blockers. Lowering copayments for these therapies improves outcomes among all patients who have had a myocardial infarction, but the impact of lower copayments on health disparities is unknown. Using self-reported race and ethnicity for participants in the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) trial, we found that rates of medication adherence were significantly lower and rates of adverse clinical outcomes were significantly higher for nonwhite patients than for white patients. Providing full drug coverage increased medication adherence in both groups. Among nonwhite patients, it also reduced the rates of major vascular events or revascularization by 35 percent and reduced total health care spending by 70 percent. Providing full coverage had no effect on clinical outcomes and costs for white patients. We conclude that lowering copayments for medications after myocardial infarctions may reduce racial and ethnic disparities for cardiovascular disease. PMID- 24799586 TI - Cincinnati Beacon Community Program highlights challenges and opportunities on the path to care transformation. AB - The Cincinnati, Ohio, metropolitan area was one of seventeen US communities to participate in the federal Beacon Community Cooperative Agreement Program to demonstrate how health information technology (IT) could be used to improve health care. Given $13.7 million to spend in thirty-one months, the Cincinnati project involved hundreds of physicians, eighty-seven primary care practices, eighteen major hospital partners, and seven federally qualified health centers and community health centers. The thrust of the program was to build a shared health IT infrastructure to support quality improvement through data exchange, registries, and alerts that notified primary care practices when a patient visited an emergency department or was admitted to a hospital. A special focus of this program was on applying these tools to adult patients with diabetes and pediatric patients with asthma. Despite some setbacks and delays, the basic technology infrastructure was built, the alert system was implemented, nineteen practices focusing on diabetes improvement were recognized as patient-centered medical homes, and many participants agreed that the program had helped transform care. However, the experience also demonstrated that the ability to transfer data was limited in electronic health record systems; that considerable effort was required to adapt technology to support quality improvement; and that the ambitious agenda required more time for planning, training, and implementation than originally thought. PMID- 24799587 TI - 'I don't want Jenny to think i'm abandoning her': views on overtreatment. PMID- 24799588 TI - Foundation support for mental health. PMID- 24799590 TI - Consumer-driven health care. PMID- 24799591 TI - Empowering the patient: the author replies. PMID- 24799592 TI - Value-based insurance design and costs. PMID- 24799593 TI - Value-based insurance design: the authors reply. PMID- 24799594 TI - A new grocery store and obesity rates. PMID- 24799595 TI - Grocery stores and obesity: the authors reply. PMID- 24799596 TI - Older adults and the health care workforce. PMID- 24799597 TI - Linking the community and the emergency department. PMID- 24799599 TI - Decreasing malaria prevalence and its potential consequences for immunity in pregnant women. AB - BACKGROUND: As malaria control is intensified, pregnant women may be less exposed to malaria, thus affecting the acquisition of protective antibody. METHODS: Plasma samples were collected from Malawian and Papua New Guinean (PNG) pregnant women enrolled over 7-year periods, during which malaria prevalence fell by over two thirds. Immunoglobulin G (IgG) levels to schizont extract, merozoite antigens, and VAR2CSA-DBL5epsilon were measured by enzyme-linked immunosorbent assay (ELISA). Levels of IgG to variant surface antigens of infected erythrocytes (IEs) and merozoites and levels of opsonizing IgG to IEs were measured by flow cytometry. RESULTS: In both settings, levels of antibodies in pregnant women to recombinant antigens and to intact IEs but not of opsonizing antibodies decreased over time. After adjustment for coverage with insecticide-treated bed nets (ITNs), these differences disappeared in the Malawian cohort, whereas in the PNG cohort, time was independently associated with a decrease in several antibody responses measured by ELISA. CONCLUSIONS: The impact of falling parasite prevalence on anti-Plasmodium falciparum serological indicators in pregnant women varies by setting. Increased ITN coverage may affect development of antibodies to recombinant antigens, but levels of opsonizing IgG remained stable over time. Opsonizing IgG against placental-binding IEs may persist, thus offering longer lasting protection against malaria during pregnancy. PMID- 24799598 TI - A systematic and functional classification of Streptococcus pyogenes that serves as a new tool for molecular typing and vaccine development. AB - Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate for epidemiological typing is both a virulence factor and a vaccine antigen. Over 220 variants of this protein have been described, making comparisons between proteins difficult, and hindering M protein-based vaccine development. A functional classification based on 48 emm clusters containing closely related M proteins that share binding and structural properties is proposed. The need for a paradigm shift from type-specific immunity against S. pyogenes to emm-cluster based immunity for this bacterium should be further investigated. Implementation of this emm-cluster-based system as a standard typing scheme for S. pyogenes will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development. PMID- 24799600 TI - Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens. AB - Viral culture of urine or saliva has been the gold standard technique for the diagnosis of congenital cytomegalovirus (CMV) infection. Results of rapid culture and polymerase chain reaction (PCR) analysis of urine and saliva specimens from 80 children were compared to determine the clinical utility of a real-time PCR assay for diagnosis of congenital CMV infection. Results of urine PCR were positive in 98.8% of specimens. Three PCR-positive urine samples were culture negative. Results of saliva PCR and culture were concordant in 78 specimens (97.5%). Two PCR-positive saliva samples were culture negative. These findings demonstrate that PCR performs as well as rapid culture of urine or saliva specimens for diagnosing congenital CMV infection and saliva specimens are easier to collect. Because PCR also offers more rapid turnaround, is unlikely to be affected by storage and transport conditions, has lower cost, and may be adapted to high-throughput situations, it is well suited for targeted testing and large scale screening for CMV. PMID- 24799601 TI - Adoptive transfer of Treg cells counters adverse effects of Toxoplasma gondii infection on pregnancy. AB - Acute infection with Toxoplasma gondii (T. gondii) during pregnancy is associated with adverse outcomes. The mechanisms that cause this phenomenon are not clear. Regulatory T cells (Tregs) are involved in maternal tolerance, and here we observed a decrease in the absolute numbers of CTLA-4(+) Tregs and PD-1(+) Tregs in spleen and at the fetal-maternal interface in T. gondii-infected mice. Our results suggest that T. gondii induces apoptosis of Tregs. Additionally, we found that the expression of CTLA-4 and PD-1 on Tregs at fetal-maternal interface were higher than on spleen cells from normal pregnant mice. Therefore, we adoptively transferred Tregs from fetal-maternal interface or from spleens of normal pregnant mice into infected pregnant mice. Pregnancy outcomes were improved when Tregs were transferred from the fetal-maternal interface but not from the spleen. The mechanism appears to be through up-regulation of the number of CTLA-4(+) Tregs and PD-1(+) Tregs and correction of the imbalance between tolerant cytokines (IL-10, TGF-beta) and inflammatory cytokines (IFN-gamma). Our data indicate that Tregs at fetal-maternal interface express high levels of inhibitory molecules that play a vital immuno-protective role during pregnancy. PMID- 24799602 TI - 25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings. AB - BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with increased HIV mortality, but prospective studies assessing treatment outcomes after combination antiretroviral therapy (cART) initiation in resource-limited settings are lacking. METHODS: A case-cohort study (N = 411) was nested within a randomized cART trial of 1571 cART-naive adults in 8 resource-limited settings and the United States. The primary outcome (WHO stage 3/4 disease or death within 96 weeks of cART initiation) was met by 192 cases, and 152 and 29 cases met secondary outcomes of virologic and immunologic failure. We studied prevalence and risk factors for baseline low 25(OH)D (<32 ng/mL) and examined associated outcomes using proportional hazard models. RESULTS: Low 25(OH)D prevalence was 49% and ranged from 27% in Brazil to 78% in Thailand. Low 25(OH)D was associated with high body mass index (BMI), winter/spring season, country-race group, and lower viral load. Baseline low 25(OH)D was associated with increased risk of human immunodeficiency virus (HIV) progression and death (adjusted hazard ratio (aHR) 2.13; 95% confidence interval [CI], 1.09-4.18) and virologic failure (aHR 2.42; 95% CI, 1.33-4.41). CONCLUSIONS: Low 25(OH)D is common in diverse HIV infected populations and is an independent risk factor for clinical and virologic failure. Studies examining the potential benefit of vitamin D supplementation among HIV patients initiating cART are warranted. PMID- 24799603 TI - The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils. AB - The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 MUM), but not histamine (0.1-1 MUM), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 MUM) or JNJ 28610244 (0.1-10 MUM), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 MUM histamine and 10 MUM JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation. PMID- 24799604 TI - Drug analog inhibition of indoleamine 2,3-dioxygenase (IDO) activity modifies pattern recognition receptor expression and proinflammatory cytokine responses early during influenza virus infection. AB - Influenza virus is recognized by PRRs, which are critical in the early response to virus infection and induction of proinflammatory cytokines. IDO is increased in the lung of mice immediately following influenza infection, and the presence of IDO has been shown to mediate immune suppression through depletion of trp and reduction in IL-6 production. To determine the role of IDO activity in the early immune response to influenza infection, IDO activity was inhibited using the synthetic analog, 1MT. The results show that IDO inhibition enhanced proinflammatory cytokine gene and protein expression at 24 and 48 h postinfection, respectively, compared with control-treated mice and affected PRR expression. The enhanced proinflammatory response in the presence of 1MT was attributed to macrophages in the airways, as Raw264.7 and primary AMs showed enhanced production of IFN-beta, IL-1beta, IL-6, and TNF-alpha in the presence of 1MT. These findings provide important knowledge for the role of IDO during initial host response to influenza infection. PMID- 24799605 TI - Immunosuppressive roles of natural killer T (NKT) cells in the skin. AB - The skin is a complex immunological niche providing immunity to invading pathogens while simultaneously maintaining tolerance to innocuous environmental antigens. Consistent with this complex response, the skin is resident to both immunosuppressive and effector cell populations whose activities are tightly regulated. While NKT cells can activate immune responses in the skin, this review will highlight studies on UV-induced photodamage, models of NMSCs, transplantation and allergic inflammation where NKT cells appear to have an immunosuppressive role in the skin. PMID- 24799606 TI - Administration of 131I-Metaiodobenzylguanidine Using the Peristaltic Infusion Pump Method. AB - Syringe pumps are commonly used to administer therapeutic (131)I metaiodobenzylguanidine. Here we describe our recent experience with a peristaltic infusion pump system in a pediatric setting. This method can easily accommodate infusions from several vials simultaneously and is adaptable to various types of peristaltic pump. METHODS: Simple off-the-shelf components are used to vent the vial: a charcoal filter, a 0.22-MUm syringe filter, and a 2.54 cm (1-in) needle. The vial is connected to the primary infusion set using a male/male extension line and a 19-gauge * 8.89-cm (3.5-in) aspirating needle. With aseptic technique, the extension line is attached to the Y connector closest to the primary intravenous line leading from the saline reservoir to the infusion pump. An A-clamp is attached to the primary intravenous line, immediately before the entrance to the pump. Gravity is allowed to clear the air from the extension set and the aspirating needle. After all the air has been purged, the aspirating needle is inserted into the therapy vial using aseptic technique. The pump is programmed with the desired infusion rate and volume to be infused. RESULTS: Twenty-one consecutive infusions have been performed to date using this method. Most of the infusions involved the use of 1 vial. On 7 occasions, 2 or 3 vials connected in series were used to successfully administer the therapy. Overestimation of the volume in the vials or of the total infusion time required can cause air to be pulled into the lines. To prevent this, the volume in the vials is equalized to 30 mL, facilitating calculation of the infusion time. If the infusion is observed over the last 2 or 3 mL and the pump stops when the air fluid mark is about halfway up the extension set, air will be kept out of the primary infusion set. CONCLUSION: This method for infusing one or more vials of therapeutic radiopharmaceuticals is robust and easy to use. During infusion, the radiopharmaceutical remains in a shielded vial. Multiple vials can be connected in series to infuse the entire dose simultaneously. PMID- 24799607 TI - Impact of Time-of-Flight PET/CT with a Large Axial Field of View for Reducing Whole-Body Acquisition Time. AB - The aim of this study was to evaluate the imaging performance of 39- and 52-ring time-of-flight (TOF) PET/CT scanners. We also assessed the potential of reducing the scanning time using a 52-ring TOF PET/CT scanner. METHODS: PET/CT scanners with 39- and 52-ring lutetium oxyorthosilicate detectors were evaluated. The axial fields of view were 16.2 and 21.6 cm, respectively. We used a National Electrical Manufacturers Association International Electrotechnical Commission body phantom filled with an (18)F solution containing background activity of 5.31 and 2.65 kBq/mL for the studies. The sphere-to-background ratio was 4:1. The PET data were acquired for 10 min in 3-dimensional list mode and then reconstructed with both ordered-subsets reconstruction maximization and ordered-subsets reconstruction maximization plus point-spread function plus time-of-flight algorithms. PET images with different acquisition times were reconstructed (from 1 to 10 min). The image quality was physically assessed using the sensitivity, noise-equivalent counting rate, coefficient of variation of background activity, and relative recovery coefficient. RESULTS: The total system sensitivities of the 39- and 52-ring scanners were 5.6 and 9.3 kcps/MBq, respectively. Compared with the 39-ring scanner, the noise-equivalent counting rate of the 52-ring scanner was 60% higher for both the high-activity and the low-activity models. The recovery coefficient was consistent, irrespective of the number of detector rings. The coefficient of variation of the 52-ring scanner using a 3-min acquisition time was equivalent to that of the 39-ring scanner using a 4-min acquisition time. CONCLUSION: The image quality of the 52-ring scanner is superior to that of the 39-ring scanner. The acquisition time per bed position of the 52-ring system can be reduced by about 25% without compromising image quality. In addition, the number of bed positions required is 25% lower for the 52-ring system. Finally, the examination time required for a whole-body PET scan is considered to be reduced by about 40% if the 52-ring scanner is used. PMID- 24799608 TI - Mediterranean diet reduces 24-hour ambulatory blood pressure, blood glucose, and lipids: one-year randomized, clinical trial. AB - The PREvencion con DIeta MEDiterranea (PREDIMED) trial showed that Mediterranean diets (MedDiets) supplemented with either extravirgin olive oil or nuts reduced cardiovascular events, particularly stroke, compared with a control, lower fat diet. The mechanisms of cardiovascular protection remain unclear. We evaluated the 1-year effects of supplemented MedDiets on 24-hour ambulatory blood pressure (BP), blood glucose, and lipids. Randomized, parallel-design, controlled trial was conducted in 2 PREDIMED sites. Diets were ad libitum, and no advice on increasing physical activity or reducing sodium intake was given. Participants were 235 subjects (56.5% women; mean age, 66.5 years) at high cardiovascular risk (85.4% with hypertension). Adjusted changes from baseline in mean systolic BP were -2.3 (95% confidence interval [CI], -4.0 to -0.5) mm Hg and -2.6 (95% CI, 4.3 to -0.9) mm Hg in the MedDiets with olive oil and the MedDiets with nuts, respectively, and 1.7 (95% CI, -0.1 to 3.5) mm Hg in the control group (P<0.001). Respective changes in mean diastolic BP were -1.2 (95% CI, -2.2 to -0.2), -1.2 (95% CI, -2.2 to -0.2), and 0.7 (95% CI, -0.4 to 1.7) mm Hg (P=0.017). Daytime and nighttime BP followed similar patterns. Mean changes from baseline in fasting blood glucose were -6.1, -4.6, and 3.5 mg/dL (P=0.016) in the MedDiets with olive oil, MedDiets with nuts, and control diet, respectively; those of total cholesterol were -11.3, -13.6, and -4.4 mg/dL (P=0.043), respectively. In high risk individuals, most with treated hypertension, MedDiets supplemented with extravirgin olive oil or nuts reduced 24-hour ambulatory BP, total cholesterol, and fasting glucose. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN35739639. PMID- 24799609 TI - Angiotensin-converting enzyme 2 is a critical determinant of angiotensin II induced loss of vascular smooth muscle cells and adverse vascular remodeling. AB - Angiotensin-converting enzyme (ACE) 2 is a key negative regulator of the renin angiotensin system and metabolizes angiotensin II (Ang II) into Ang 1 to 7. Ang II is a vasoactive peptide, which plays an important role in vascular disease. The objective of the present study was to define the role of ACE2 in pathological vascular remodeling. We found upregulation of ACE2 in dilated human aorta with bicuspid aortic valve and in murine aorta in response to Ang II. Ex vivo pressure myography showed increased vascular stiffness in ACE2 knockout (KO) mesenteric arteries in response to Ang II (1.5 mg/kg per day) and with aging. Histological analyses revealed reduced media-to-lumen ratio in ACE2KO mesenteric arteries with loss of vascular smooth muscle cells. Aortic vascular smooth muscle cells from ACE2KO mice showed markedly increased reactive oxygen species and apoptosis in response to Ang II along with increased cleaved caspase-3 and cleaved caspase-8 levels in the ACE2KO aorta. Ang II type 1 receptor blockade and Ang 1 to 7 supplementation prevented the increase in Ang II-induced reactive oxygen species and apoptotic cell death. In the aorta, Ang II resulted in thoracic and abdominal aortic dilation with loss of vascular smooth muscle cell density in ACE2KO aorta as revealed by alpha-smooth muscle actin, calponin staining, and electron microscopy with increased promatrix metalloproteinase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 levels. ACE2 is upregulated in vascular diseases, and ACE2 deficiency exacerbates Ang II-mediated vascular remodeling driven by increased reactive oxygen species and vascular smooth muscle cell apoptosis. In conclusion, the key counter-regulatory role of ACE2 against an activated renin-angiotensin system provides novel insights into the role of ACE2 in vascular diseases. PMID- 24799610 TI - Microsatellite polymorphism in the heme oxygenase-1 promoter is associated with nonsevere and late-onset preeclampsia. AB - Preeclampsia is a serious and phenotypically heterogeneous vascular pregnancy disorder. Heme oxygenase-1 (HO-1) is a stress response enzyme that may protect the maternal endothelium and facilitate adequate metabolic adaptation to pregnancy by its antioxidant and anti-inflammatory functions. HO-1 stress response is modulated by HO-1 gene (HMOX1) polymorphisms. Individuals with the long allele of a guanine-thymine (GTn) microsatellite repeat located in the promoter region of HMOX1 have a higher risk of cardiometabolic diseases compared with those with the short allele. We investigated whether the long GTn allele of HMOX1 is associated with subtypes of preeclampsia. The GTn repeat was genotyped in 759 patients and in 779 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort using DNA fragment analysis. In subtype analyses, the long-long (LL) genotype was associated with nonsevere (additive model: odds ratio [OR], 1.94; 95% confidence interval [CI], 1.13-3.31; recessive model: OR, 1.39; 95% CI, 1.02-1.89) and late-onset (additive model: OR, 1.44; 95% CI, 1.02-2.05; recessive model: OR, 1.28; 95% CI, 1.02-1.59) preeclampsia and with preeclampsia without a small-for-gestational-age infant (recessive model: OR, 1.27; 95% CI, 1.02-1.58). The long allele was associated with nonsevere (OR, 1.35; 95% CI, 1.07 1.70) and late-onset (OR, 1.21; 95% CI, 1.03-1.42) preeclampsia and with preeclampsia without a small-for-gestational-age infant (OR, 1.19; 95% CI, 1.02 1.40). Moreover, both the LL genotype and the long allele were associated with preeclampsia in women who had smoked during pregnancy. In conclusion, the GTn long allele seems to predispose to late-onset, less severe form of preeclampsia. This finding supports the role of HO-1 in the pathogenesis of preeclampsia and suggests that the HO-1 pathway may provide a potential target for the treatment of preeclampsia. PMID- 24799611 TI - Redefined blood pressure variability measure and its association with mortality in elderly primary care patients. AB - Visit-to-visit blood pressure (BP) variability has received considerable attention recently. The objective of our study is to define a variability measure that is independent of change over time and determine the association between longitudinal summary measures of BP measurements and mortality risk. Data for the study came from a prospective cohort of 2906 adults, aged >=60 years, in an urban primary care system with <=15 years of follow-up. Dates of death for deceased participants were retrieved from the National Death Index. Systolic and diastolic BP measurements from outpatient clinic visits were extracted from the Regenstrief Medical Record System. For each patient, the intercept, regression slope, and root mean square error for visit-to-visit variability were derived using linear regression models and used as independent variables in Cox proportional hazards models for both all-cause mortality and mortality attributable to coronary heart disease or stroke. Rate of change was associated with mortality risk in a U shaped relationship and that participants with little or no change in BP had the lowest mortality risk. BP variability was not an independent predictor of mortality risk. By separating change over time from visit-to-visit variability in studies with relatively long follow-up, we demonstrated in this elderly primary care patient population that BP changes over time, not variability, were associated with greater mortality risk. Future research is needed to confirm our findings in other populations. PMID- 24799612 TI - Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension. AB - Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. Although both hemodynamic and tubular effects likely participate, most evidence supports a major role for alpha-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive NaCl cotransporter (NCC) by stimulating beta-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on beta-adrenergic receptors. This effect is not mediated by the activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule to show that distal convoluted tubule cells are especially enriched for beta1 adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. Because the 2 protein kinases, STE20p-related proline- and alanine-rich kinase (encoded by STK39) and oxidative stress-response kinase 1, phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect STE20p related proline- and alanine-rich kinase abundance or its localization in the distal convoluted tubule; instead, we observed a striking activation of oxidative stress-response kinase 1. We confirmed that STE20p-related proline- and alanine rich kinase is not required for NCC activation, using STK39 knockout mice. Together, the data provide strong support for a signaling system involving beta1 receptors in the distal convoluted tubule that activates NCC, at least in part via oxidative stress-response kinase 1. The results have implications about device- and drug-based treatment of hypertension. PMID- 24799613 TI - Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice. AB - Angiotensin II (Ang II) stimulates vascular inflammation, oxidative stress, and formation and rupture of intracranial aneurysms in mice. Because Ang 1-7 acts on Mas receptors and generally counteracts deleterious effects of Ang II, we tested the hypothesis that Ang 1-7 attenuates formation and rupture of intracranial aneurysms. Intracranial aneurysms were induced in wild-type and Mas receptor deficient mice using a combination of Ang II-induced hypertension and intracranial injection of elastase in the basal cistern. Mice received elastase+Ang II alone or a combination of elastase+Ang II+Ang 1-7. Aneurysm formation, prevalence of subarachnoid hemorrhage, mortality, and expression of molecules involved in vascular injury were assessed. Systolic blood pressure was similar in mice receiving elastase+Ang II (mean+/-SE, 148+/-5 mm Hg) or elastase+Ang II+Ang 1-7 (144+/-5 mm Hg). Aneurysm formation was also similar in mice receiving elastase+Ang II (89%) or elastase+Ang II+Ang 1-7 (84%). However, mice that received elastase+Ang II+Ang 1-7 had reduced mortality (from 64% to 36%; P<0.05) and prevalence of subarachnoid hemorrhage (from 75% to 48%; P<0.05). In cerebral arteries, expression of the inflammatory markers, Nox2 and catalase increased similarly in elastase+Ang II or elastase+Ang II+Ang 1-7 groups. Ang 1-7 increased the expression of cyclooxygenase-2 and decreased the expression of matrix metalloproteinase-9 induced by elastase+Ang II (P<0.05). In Mas receptor deficient mice, systolic blood pressure, mortality, and prevalence of subarachnoid hemorrhage were similar (P>0.05) in groups treated with elastase+Ang II or elastase+Ang II+Ang 1-7. The expression of Mas receptor was detected by immunohistochemistry in samples of human intracranial arteries and aneurysms. In conclusion, without attenuating Ang II-induced hypertension, Ang 1-7 decreased mortality and rupture of intracranial aneurysms in mice through a Mas receptor dependent pathway. PMID- 24799614 TI - Arterial stiffness and hypertension: chicken or egg? PMID- 24799615 TI - Go nuts and go extra virgin olive oil! Mediterranean diets reduce blood pressure. PMID- 24799616 TI - Angiotensin (1-7) as a therapy to prevent rupture of intracranial aneurysms? PMID- 24799617 TI - Introduction. PMID- 24799618 TI - Radiation Dosimetry of (18)F-FPEB in Humans. AB - (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB) is a potent and specific radioligand for the metabotropic glutamate receptor subtype 5 (mGluR5). Before undertaking clinical research studies with (18)F-FPEB, we performed studies of human radiation dosimetry. METHODS: Serial whole-body scans were obtained in 9 healthy human subjects (5 men, 4 women) for 190-440 min after the intravenous administration of (18)F-FPEB. Radiation doses were estimated using the OLINDA/EXM software. RESULTS: Peak organ doses were to the urinary bladder wall, 0.258 mGy/MBq (0.955 rad/mCi), and gallbladder wall, 0.193 mGy/MBq (0.716 rad/mCi). The effective dose was 0.025 mSv/MBq (0.0922 rem/mCi). The doses to the red marrow and spleen were 0.00797 mGy/MBq (0.0295 rad/mCi) and 0.00709 mGy/MBq (0.0262 rad/mCi), respectively. Reducing the urinary voiding interval to 60 or 90 min lowered the urinary bladder wall dose to 0.0885 mGy/MBq (0.327 rad/mCi) or 0.128 mGy/MBq (0.473 rad/mCi), respectively, and the effective dose to 0.0149 mSv/MBq (0.0551 rem/mCi) or 0.0171 mSv/MBq (0.0634 rem/mCi), respectively. CONCLUSION: Urinary voiding should be performed during (18)F-FPEB studies to minimize radiation exposure to research subjects. PMID- 24799619 TI - A PET Tracer for Brain alpha2C Adrenoceptors, (11)C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice. AB - We report the development of a PET tracer for alpha2C adrenoceptor imaging and its preliminary preclinical evaluation. alpha2C adrenoceptors in the human brain may be involved in various neuropsychiatric disorders, such as depression, schizophrenia, and neurodegenerative diseases. PET tracers are needed for imaging of this receptor system in vivo. METHODS: High-specific-activity (11)C-ORM-13070 (1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-4-(3-(11)C methoxymethylpyridin-2-yl)-piperazine) was synthesized by (11)C-methylation of O desmethyl-ORM-13070 with (11)C-methyl triflate, which was prepared from cyclotron produced (11)C-methane via (11)C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography. The specificity of (11)C-ORM 13070 binding to alpha2 adrenoceptors was demonstrated in rats pretreated with atipamezole, an alpha2 adrenoceptor antagonist. The alpha2C adrenoceptor selectivity of the tracer was determined by comparing tracer binding in wild-type and alpha2A- and alpha2AC adrenoceptor knockout (KO) mice. (11)C-ORM-13070 and its radioactive metabolites in rat plasma and brain tissue were analyzed with radio-high-performance liquid chromatography and mass spectroscopy. Human radiation dose estimates were extrapolated from rat biodistribution data. RESULTS: The radiochemical yield, calculated from initial cyclotron-produced (11)C-methane, was 9.6% +/- 2.7% (decay-corrected to end of bombardment). The specific activity of the product was 640 +/- 390 GBq/MUmol (decay-corrected to end of synthesis). The radiochemical purity exceeded 99% in all syntheses. The highest levels of tracer binding were observed in the striatum and olfactory tubercle of rats and control and alpha2A KO mice-that is, in the brain regions known to contain the highest densities of alpha2C adrenoceptors. In rats pretreated with atipamezole and in alpha2AC KO mice, (11)C tracer binding in the striatum and olfactory tubercle was low, similar to that of the frontal cortex and thalamus, regions with low densities of alpha2C adrenoceptors. Two radioactive metabolites were found in rat plasma, but only one of them was found in the brain; their identity was not revealed. The estimated effective radiation dose was comparable with the average exposure level in PET studies with (11)C tracers. CONCLUSION: An efficient method for the radiosynthesis of (11)C-ORM 13070 was developed. (11)C-ORM-13070 emerged as a potential novel radiotracer for in vivo imaging of brain alpha2C adrenoceptors. PMID- 24799620 TI - Clinical Role of Subtraction Ictal SPECT Coregistered to MR Imaging and (18)F-FDG PET in Pediatric Epilepsy. AB - A precise assessment of the drug-resistant epileptic pediatric population for surgical candidacy is often challenging, and to date there are no evidence-based guidelines for presurgical identification of the epileptogenic zone. To evaluate the usefulness of radionuclide imaging techniques for presurgical evaluation of epileptic pediatric patients, we compared the results of video electroencephalography (EEG), brain MR imaging, interictal SPECT, ictal SPECT, subtraction ictal SPECT coregistered to MR imaging (SISCOM), and interictal PET with (18)F-FDG. METHODS: Fifty-four children with drug-resistant epilepsy who had undergone video-EEG monitoring, brain MR imaging, interictal and ictal brain perfusion SPECT, SISCOM, and (18)F-FDG PET were included in this study. All abnormal findings revealed by these neuroimaging techniques were compared with the presumed location of the epileptogenic zone (PEZ) as determined by video-EEG and clinical data. The proportion of localizing studies for each technique was statistically compared. In the 18 patients who underwent resective brain surgery, neuroimaging results were compared with histopathology results and surgical outcome. RESULTS: SISCOM and (18)F-FDG PET concordance with the PEZ was significantly higher than MR imaging (P < 0.05). MR imaging showed localizing results in 21 of 54 cases (39%), SISCOM in 36 of 54 cases (67%), and (18)F-FDG PET in 31 of 54 cases (57%). If we consider SISCOM and (18)F-FDG PET results together, nuclear medicine imaging techniques showed coinciding video-EEG results in 76% of patients (41/54). In those cases in which MR imaging failed to identify any epileptogenic lesion (61% [33/54]), SISCOM or (18)F-FDG PET findings matched PEZ in 67% (22/33) of cases. CONCLUSION: SISCOM and (18)F-FDG PET provide complementary presurgical information that matched video-EEG results and clinical data in three fourths of our sample. SISCOM was particularly useful in those cases in which MR imaging findings were abnormal but no epileptogenic lesion was identified. Radionuclide imaging techniques are both useful and reliable, extending the possibility of surgical treatment to patients who may have been discouraged without a nuclear medicine approach. PMID- 24799621 TI - A simple photometric factor in perceived depth order of bistable transparency patterns. AB - Previous studies on perceptual transparency defined the photometric condition in which perceived depth ordering between two surfaces becomes ambiguous. Even under this bistable transparency condition, it is known that depth-order perceptions are often biased toward one specific interpretation (Beck, Prazdny, & Ivry, 1984; Delogu, Fedorov, Belardinelli, & van Leeuwen, 2010; Kitaoka, 2005; Oyama & Nakahara, 1960). In this study, we examined what determines the perceived depth ordering for bistable transparency patterns using stimuli that simulated two partially overlapping disks resulting in four regions: a (background), b (portion of right disk), p (portion of left disk), and q (shared region). In contrast to the previous theory that proposed contributions of contrast against the background region (i.e., contrast at contour b/a and contrast at contour p/a) to perceived depth order in bistable transparency patterns, the present study demonstrated that contrast against the background region has little influence on perceived depth order compared with contrast against the shared region (i.e., contrast at contour b/q and contrast at contour p/q). In addition, we found that the perceived depth ordering is well predicted by a simpler model that takes into consideration only relative size of lightness difference against the shared region. Specifically, the probability that the left disk is perceived as being in front is proportional to (|b - q| - |p - q|) / (|b - q| + |p - q|) calculated based on lightness. PMID- 24799623 TI - Saccadic adaptation induced by a perceptual task. AB - The human motor system and muscles are subject to fluctuations in the short and long term. Motor adaptation is classically thought of as a low-level process that compensates for the error between predicted and executed movements in order to maintain movement accuracy. Contrary to a low-level account, accurate movements might be only a means to support high-level behavioral and perceptual goals. To isolate the influence of high-level goals in adaptation of saccadic eye movements, we manipulated perceptual task requirements in the absence of low level errors. Observers had to discriminate one character within a peripheral array of characters. Between trials, the location of this character within the array was changed. This manipulation led to an immediate strategic change and a slower, gradual adaptation of saccade amplitude and direction. These changes had a similar magnitude to classical saccade adaptation and transferred at least partially to reactive saccades without a perceptual task. These results suggest that a perceptual task can modify oculomotor commands by generating a top-down error signal in saccade maps just like a bottom-up visual position error. Hence saccade adaptation not only maintains saccadic targeting accuracy, but also optimizes gaze behavior for the behavioral goal, showing that perception shapes even low-level oculomotor mechanisms. PMID- 24799622 TI - A double dissociation of the acuity and crowding limits to letter identification, and the promise of improved visual screening. AB - Here, we systematically explore the size and spacing requirements for identifying a letter among other letters. We measure acuity for flanked and unflanked letters, centrally and peripherally, in normals and amblyopes. We find that acuity, overlap masking, and crowding each demand a minimum size or spacing for readable text. Just measuring flanked and unflanked acuity is enough for our proposed model to predict the observer's threshold size and spacing for letters at any eccentricity. We also find that amblyopia in adults retains the character of the childhood condition that caused it. Amblyopia is a developmental neural deficit that can occur as a result of either strabismus or anisometropia in childhood. Peripheral viewing during childhood due to strabismus results in amblyopia that is crowding limited, like peripheral vision. Optical blur of one eye during childhood due to anisometropia without strabismus results in amblyopia that is acuity limited, like blurred vision. Furthermore, we find that the spacing:acuity ratio of flanked and unflanked acuity can distinguish strabismic amblyopia from purely anisometropic amblyopia in nearly perfect agreement with lack of stereopsis. A scatter diagram of threshold spacing versus acuity, one point per patient, for several diagnostic groups, reveals the diagnostic power of flanked acuity testing. These results and two demonstrations indicate that the sensitivity of visual screening tests can be improved by using flankers that are more tightly spaced and letter like. Finally, in concert with Strappini, Pelli, Di Pace, and Martelli (submitted), we jointly report a double dissociation between acuity and crowding. Two clinical conditions-anisometropic amblyopia and apperceptive agnosia-each selectively impair either acuity A or the spacing:acuity ratio S/A, not both. Furthermore, when we specifically estimate crowding, we find a double dissociation between acuity and crowding. Models of human object recognition will need to accommodate this newly discovered independence of acuity and crowding. PMID- 24799624 TI - Bile acids and bicarbonate inversely regulate intracellular cyclic di-GMP in Vibrio cholerae. AB - Vibrio cholerae is a Gram-negative bacterium that persists in aquatic reservoirs and causes the diarrheal disease cholera upon entry into a human host. V. cholerae employs the second messenger molecule 3',5'-cyclic diguanylic acid (c-di GMP) to transition between these two distinct lifestyles. c-di-GMP is synthesized by diguanylate cyclase (DGC) enzymes and hydrolyzed by phosphodiesterase (PDE) enzymes. Bacteria typically encode many different DGCs and PDEs within their genomes. Presumably, each enzyme senses and responds to cognate environmental cues by alteration of enzymatic activity. c-di-GMP represses the expression of virulence factors in V. cholerae, and it is predicted that the intracellular concentration of c-di-GMP is low during infection. Contrary to this model, we found that bile acids, a prevalent constituent of the human proximal small intestine, increase intracellular c-di-GMP in V. cholerae. We identified four c di-GMP turnover enzymes that contribute to increased intracellular c-di-GMP in the presence of bile acids, and deletion of these enzymes eliminates the bile induction of c-di-GMP and biofilm formation. Furthermore, this bile-mediated increase in c-di-GMP is quenched by bicarbonate, the intestinal pH buffer secreted by intestinal epithelial cells. Our results lead us to propose that V. cholerae senses distinct microenvironments within the small intestine using bile and bicarbonate as chemical cues and responds by modulating the intracellular concentration of c-di-GMP. PMID- 24799625 TI - Metal-mediated modulation of streptococcal cysteine protease activity and its biological implications. AB - Streptococcal cysteine protease (SpeB), the major secreted protease produced by group A streptococcus (GAS), cleaves both host and bacterial proteins and contributes importantly to the pathogenesis of invasive GAS infections. Modulation of SpeB expression and/or its activity during invasive GAS infections has been shown to affect bacterial virulence and infection severity. Expression of SpeB is regulated by the GAS CovR-CovS two-component regulatory system, and we demonstrated that bacteria with mutations in the CovR-CovS two-component regulatory system are selected for during localized GAS infections and that these bacteria lack SpeB expression and exhibit a hypervirulent phenotype. Additionally, in a separate study, we showed that expression of SpeB can also be modulated by human transferrin- and/or lactoferrin-mediated iron chelation. Accordingly, the goal of this study was to investigate the possible roles of iron and other metals in modulating SpeB expression and/or activity in a manner that would potentiate bacterial virulence. Here, we report that the divalent metals zinc and copper inhibit SpeB activity at the posttranslational level. Utilizing online metal-binding site prediction servers, we identified two putative metal binding sites in SpeB, one of which involves the catalytic-dyad residues (47)Cys and (195)His. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can modulate the proteolytic activity of SpeB in a manner that preserves the integrity of several other virulence factors essential for bacterial survival and dissemination within the host and thereby may exacerbate the severity of invasive GAS infections. PMID- 24799626 TI - Reciprocal regulation of resistance-nodulation-division efflux systems and the Cpx two-component system in Vibrio cholerae. AB - The Cpx two-component regulatory system has been shown in Escherichia coli to alleviate stress caused by misfolded cell envelope proteins. The Vibrio cholerae Cpx system was previously found to respond to cues distinct from those in the E. coli system, suggesting that this system fulfills a different physiological role in the cholera pathogen. Here, we used microarrays to identify genes that were regulated by the V. cholerae Cpx system. Our observations suggest that the activation of the V. cholerae Cpx system does not induce expression of genes involved in the mitigation of stress generated by misfolded cell envelope proteins but promotes expression of genes involved in antimicrobial resistance. In particular, activation of the Cpx system induced expression of the genes encoding the VexAB and VexGH resistance-nodulation-division (RND) efflux systems and their cognate outer membrane pore protein TolC. The promoters for these loci contained putative CpxR consensus binding sites, and ectopic cpxR expression activated transcription from the promoters for the RND efflux systems. CpxR was not required for intrinsic antimicrobial resistance, but CpxR activation enhanced resistance to antimicrobial substrates of VexAB and VexGH. Mutations that inactivated VexAB or VexGH efflux activity resulted in the activation of the Cpx response, suggesting that vexAB and vexGH and the cpxP-cpxRA system are reciprocally regulated. We speculate that the reciprocal regulation of the V. cholerae RND efflux systems and the Cpx two-component system is mediated by the intracellular accumulation of an endogenously produced metabolic by-product that is normally extruded from the cell by the RND efflux systems. PMID- 24799627 TI - Identification and characterization of a peculiar vtx2-converting phage frequently present in verocytotoxin-producing Escherichia coli O157 isolated from human infections. AB - Certain verocytotoxin-producing Escherichia coli (VTEC) O157 phage types (PTs), such as PT8 and PT2, are associated with severe human infections, while others, such as PT21, seem to be restricted to cattle. In an attempt to delve into the mechanisms underlying such a differential distribution of PTs, we performed microarray comparison of human PT8 and animal PT21 VTEC O157 isolates. The main differences observed were in the vtx2-converting phages, with the PT21 strains bearing a phage identical to that present in the reference strain EDL933, BP933W, and all the PT8 isolates displaying lack of hybridization in some regions of the phage genome. We focused on the region spanning the gam and cII genes and developed a PCR tool to investigate the presence of PT8-like phages in a panel of VTEC O157 strains belonging to different PTs and determined that a vtx2 phage reacting with the primers deployed, which we named Phi8, was more frequent in VTEC O157 strains from human disease than in bovine strains. No differences were observed in the production of the VT2 mRNA when Phi8-positive strains were compared with VTEC O157 possessing BP933W. Nevertheless, we show that the gam-cII region of phage Phi8 might carry genetic determinants downregulating the transcription of the genes encoding the components of the type III secretion system borne on the locus of enterocyte effacement pathogenicity island. PMID- 24799628 TI - Cytadherence of Mycoplasma pneumoniae induces inflammatory responses through autophagy and toll-like receptor 4. AB - Mycoplasma pneumoniae causes pneumonia, tracheobronchitis, pharyngitis, and asthma in humans. The pathogenesis of M. pneumoniae infection is attributed to excessive immune responses. We previously demonstrated that M. pneumoniae lipoproteins induced inflammatory responses through Toll-like receptor 2 (TLR2). In the present study, we demonstrated that M. pneumoniae induced strong inflammatory responses in macrophages derived from TLR2 knockout (KO) mice. Cytokine production in TLR2 KO macrophages was increased compared with that in the macrophages of wild-type (WT) mice. Heat-killed, antibiotic-treated, and overgrown M. pneumoniae failed to induce inflammatory responses in TLR2 KO macrophages. 3-Methyladenine and chloroquine, inhibitors of autophagy, decreased the induction of inflammatory responses in TLR2 KO macrophages. These inflammatory responses were also inhibited in macrophages treated with the TLR4 inhibitor VIPER and those obtained from TLR2 and TLR4 (TLR2/4) double-KO mice. Two mutants that lacked the ability to induce inflammatory responses in TLR2 KO macrophages were obtained by transposon mutagenesis. The transposons were inserted in atpC encoding an ATP synthase F0F1 epsilon subunit and F10_orf750 encoding hypothetical protein MPN333. These mutants showed deficiencies in cytadherence. These results suggest that cytadherence of M. pneumoniae induces inflammatory responses through TLR4 and autophagy. PMID- 24799629 TI - Candida glabrata intra-abdominal candidiasis is characterized by persistence within the peritoneal cavity and abscesses. AB - The pathogenesis of Candida glabrata infections is poorly understood. We studied the pathogenesis of intra-abdominal candidiasis (IAC) in mice that were infected intraperitoneally with C. glabrata and sterile feces. C. glabrata BG2 (5 * 10(8) CFU) caused a 100% mortality rate. Sublethal inocula of BG2 (1 * 10(8) or 1 * 10(7) CFU) caused peritonitis that progressed to abscesses. Three clinical C. glabrata strains (5 * 10(8) CFU) caused 80 to 100% mortality rates, while a fourth (strain 346) caused a 29% mortality rate. Following sublethal inocula (1 * 10(7) CFU), the intra-abscess burdens of virulent strain 356 were ~1 log greater than those of strain 346. A C. glabrata Deltaplb1-2 mutant (phospholipase B genes disrupted) killed mice as well as BG2 did. When sublethal inocula were used, however, the Deltaplb1-2 mutant was associated with more rapid abscess resolution and lower intra-abscess burdens; these findings were reversed by PLB1 and PLB2 reinsertion. The Deltaplb1-2 mutant was also more susceptible than BG2 to killing by human neutrophils in vitro. BG2 and the Deltaplb1-2 mutant were indistinguishable during hematogenously disseminated candidiasis. C. albicans SC5314 was more virulent than C. glabrata BG2 during IAC, causing a 100% mortality rate following a challenge with 5 * 10(7) CFU. In contrast, a sublethal inoculum (1 * 10(7) CFU) of BG2 caused less neutrophil infiltration and greater burdens in peritoneal fluid than SC5314 did and abscesses that persisted longer and contained greater burdens. In conclusion, a mouse model of C. glabrata IAC mimics disease in humans and distinguishes the relative virulence of clinical and gene disruption strains. C. glabrata differed from C. albicans during IAC by being less lethal and eliciting dampened neutrophil responses but resulting in more persistent peritonitis and abscesses. PMID- 24799630 TI - Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection. AB - YopE is a virulence factor that is secreted into host cells infected by Yersinia species. The YopE C-terminal domain has GTPase-activating protein (GAP) activity. The YopE N-terminal domain contains an epitope that is an immunodominant CD8(+) T cell antigen during primary infection of C57BL/6 mice with Yersinia pseudotuberculosis. The characteristics of the CD8(+) T cells generated in response to the epitope, which comprises YopE amino acid residues 69 to 77 (YopE(69-77)), and the features of YopE that are important for antigenicity during primary infection, are unknown. Following intravenous infection of naive C57BL/6 mice with a yopE GAP mutant (the R144A mutant), flow cytometry analysis of splenocytes by tetramer and intracellular cytokine staining over a time course showed that YopE69-77-specific CD8(+) T cells producing gamma interferon (IFN gamma) and tumor necrosis factor alpha (TNF-alpha) were generated by day 7, with a peak at day 14. In addition, ~80% of YopE(69-77)-specific CD8(+) T cells were positive for KLRG1, a memory phenotype marker, at day 21. To determine if residues that regulate YopE activity by ubiquitination or membrane localization affect the antigenicity of YopE(69-77), mice were infected with a yopE ubiquitination or membrane localization mutant (the R62K or L55N I59N L63N mutant, respectively). These mutants elicited YopE(69-77)-specific CD8(+) T cells producing IFN-gamma and TNF-alpha with kinetics and magnitudes similar to those of the parental R144A strain, indicating that primary infection primes effector CD8(+) T cells independently of the ubiquitination or membrane localization of YopE. Additionally, at day 7, there was an unexpected positive correlation between the numbers of YopE(69-77)-specific CD8(+) T cells and CD11b(+) cells, but not between the numbers of YopE(69-77)-specific CD8(+) T cells and bacterial cells, in spleens, suggesting that the innate immune response contributes to the immunodominance of YopE(69-77). PMID- 24799631 TI - Phenotypic differences of Cryptococcus molecular types and their implications for virulence in a Drosophila model of infection. AB - Compared to Cryptococcus neoformans, little is known about the virulence of the molecular types in Cryptococcus gattii. We compared in vitro virulence factor production and survival data using a Drosophila model of infection to further characterize the phenotypic features of different cryptococcal molecular types. Forty-nine different isolates were inoculated into wild-type flies and followed for survival. In vitro, isolates were assessed for growth at 30 and 37 degrees C, melanin production, capsule size, resistance to H(2)O(2), and antifungal susceptibility. A mediator model was used to assess molecular type and virulence characteristics as predictors of survival in the fly model. VGIII was the most virulent molecular type in flies (P < 0.001). At 30 degrees C, VGIII isolates grew most rapidly; at 37 degrees C, VNI isolates grew best. C. gattii capsules were larger than those of C. neoformans (P < 0.001). Mediator model analysis found a strong correlation of Drosophila survival with molecular type and with growth at 30 degrees C. We found molecular-type-specific differences in C. gattii in growth at different temperatures, melanin production, capsule size, ability to resist hydrogen peroxide, and antifungal susceptibility, while growth at 30 degrees C and the VGIII molecular type were strongly associated with virulence in a Drosophila model of infection. PMID- 24799632 TI - Virulence and immunity orchestrated by the global gene regulator sigL in Mycobacterium avium subsp. paratuberculosis. AB - Mycobacterium avium subsp. paratuberculosis causes Johne's disease in ruminants, a chronic enteric disease responsible for severe economic losses in the dairy industry. Global gene regulators, including sigma factors are important in regulating mycobacterial virulence. However, the biological significance of such regulators in M. avium subsp. paratuberculosis rremains elusive. To better decipher the role of sigma factors in M. avium subsp. paratuberculosis pathogenesis, we targeted a key sigma factor gene, sigL, activated in mycobacterium-infected macrophages. We interrogated an M. avium subsp. paratuberculosis DeltasigL mutant against a selected list of stressors that mimic the host microenvironments. Our data showed that sigL was important in maintaining bacterial survival under such stress conditions. Survival levels further reflected the inability of the DeltasigL mutant to persist inside the macrophage microenvironments. Additionally, mouse infection studies suggested a substantial role for sigL in M. avium subsp. paratuberculosis virulence, as indicated by the significant attenuation of the DeltasigL-deficient mutant compared to the parental strain. More importantly, when the sigL mutant was tested for its vaccine potential, protective immunity was generated in a vaccine/challenge model of murine paratuberculosis. Overall, our study highlights critical role of sigL in the pathogenesis and immunity of M. avium subsp. paratuberculosis infection, a potential role that could be shared by similar proteins in other intracellular pathogens. PMID- 24799633 TI - Ractopamine, a livestock feed additive, is a full agonist at trace amine associated receptor 1. AB - Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC's physiological actions begin with its stimulation of beta1- and beta2-adrenergic receptor-mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC's psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse trace amine-associated receptor 1 (mTAAR1), which was completely reversed by the trace amine-associated receptor 1 (TAAR1)-selective antagonist EPPTB [N-(3 ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human beta2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human beta2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug. PMID- 24799634 TI - The genetic variation in monocarboxylic acid transporter 2 (MCT2) has functional and clinical relevance with male infertility. AB - Monocarboxylic acid transporter 2 (MCT2) transports pyruvate and lactate outside and inside of sperms, mainly as energy sources and plays roles in the regulation of spermatogenesis. We investigated the association among genetic variations in the MCT2 gene, male infertility and MCT2 expression levels in sperm. The functional and genetic significance of the intron 2 (+28201A > G, rs10506398) and 3' untranslated region (UTR) single nucleotide polymorphism (SNP) (+2626G > A, rs10506399) of MCT2 variants were investigated. Two MCT2 polymorphisms were associated with male infertility (n = 471, P < 0.05). In particular, the MCT2-3' UTR SNP (+2626 G > A) had a strong association with the oligoasthenoteratozoospermia (OAT) group. The +2626GG type had an almost 2.4-fold higher sperm count than that of the +2626AA type (+2626GG; 66 * 10 6 vs +2626AA; 27 * 10 6 , P < 0.0001). The MCT2-3' UTR SNP may be important for expression, as it is located at the MCT2 3' UTR. The average MCT2 protein amount in sperm of the +2626GG type was about two times higher than that of the +2626AA type. The results suggest that genetic variation in MCT2 has functional and clinical relevance with male infertility. PMID- 24799635 TI - Male accessory gland inflammation prevalence in type 2 diabetic patients with symptoms possibly reflecting autonomic neuropathy. AB - Male accessory gland inflammation or infection (MAGI) is a potentially underdiagnosed complication of type 2 diabetes (DM2); specifically, we reported in a recent study that the frequency of MAGI was 43% among DM2 patients. In previous studies, we have demonstrated that diabetic autonomic neuropathy (DAN) is associated with a peculiar ultrasound characterization of the seminal vesicles (SVs) in DM2 patients. The aim of the present study was to evaluate the frequency of MAGI in two different categories of DM2 patients (i.e. patients with and without symptoms that possibly reflect DAN) and the respective ultrasound characterizations. Sixty DM2 patients with a mean (+/- s.e.m.) age of 42.0 +/- 6.0 years (range: 34-47 years) were classified according to the presence or the absence of symptoms that could possibly reflect DAN (group A: DM2 with symptoms possibly reflecting DAN, n = 28 patients and group B: DM2 without symptoms possibly reflecting DAN, n = 32 patients). The patients in Group A exhibited a significantly higher frequency of MAGI compared with those in group B patients (P < 0.05); moreover, the Group A patients exhibited a significantly higher frequency of ultrasound signs suggestive of vesiculitis (P < 0.05). Finally, the concentrations of lymphocytes but not the concentrations of the leukocytes in the semen were significantly higher (P < 0.05) in group A compared with group B. PMID- 24799636 TI - The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation. AB - It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5 hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10-20, 20-30 and 30-60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys) is significantly lower (22.6 s; 95% CI 18.3-27.8 s) than in male homozygous mutants (Ser/Ser) (40.4 s; 95% CI 20.3-80.4 s) (P = 0.03). It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes. PMID- 24799637 TI - Gene mapping of serotoninergic system polymorphisms provides insight on pathology and treatment of men with lifelong premature ejaculation. PMID- 24799639 TI - Strategies to prevent Clostridium difficile infections in acute care hospitals: 2014 Update. PMID- 24799640 TI - Quality assessment of hospital discharge database for routine surveillance of hip and knee arthroplasty-related infections. AB - OBJECTIVE: Surgical site infection (SSI) surveillance represents a key method of nosocomial infection control programs worldwide. However, most SSI surveillance systems are considered to be poorly cost effective regarding human and economic resources required for data collection and patient follow up. This study aims to assess the efficacy of using hospital discharge databases (HDDs) as a routine surveillance system for detecting hip or knee arthroplasty-related infections (HKAIs). METHODS: A case-control study was conducted among patients hospitalized in the Centre region of France between 2008 and 2010. HKAI cases were extracted from the HDD with various algorithms based on the International Classification of Diseases, Tenth Revision, and procedure codes. The control subjects were patients with hip or knee arthroplasty (HKA) without infection selected at random from the HDD during the study period. The gold standard was medical chart review. Sensitivity (Se), specificity (Spe), positive predictive value (PPV), and negative predictive value (NPV) were calculated to evaluate the efficacy of the surveillance system. RESULTS: Among 18,265 hospital stays for HKA, corresponding to 17,388 patients, medical reports were checked for 1,010 hospital stays (989 patients). We identified 530 cases in total (incidence rate, 1% [95% confidence interval (CI), 0.4%-1.6%), and 333 cases were detected by routine surveillance. As compared with 480 controls, Se was 98%, Spe was 71%, PPV was 63%, and NPV was 99%. Using a more specific case definition, based on a sample of 681 hospital stays, Se was 97%, Spe was 95%, PPV was 87%, and NPV was 98%. CONCLUSIONS: This study demonstrates the potential of HDD as a tool for routine SSI surveillance after low-risk surgery, under conditions of having an appropriate algorithm for selecting infections. PMID- 24799641 TI - The utility of claims data for infection surveillance following anterior cruciate ligament reconstruction. AB - OBJECTIVE: To explore the feasibility of identifying anterior cruciate ligament (ACL) allograft implantations and infections using claims. DESIGN: Retrospective cohort study. METHODS: We identified ACL reconstructions using procedure codes at 6 health plans from 2000 to 2008. We then identified potential infections using claims-based indicators of infection, including diagnoses, procedures, antibiotic dispensings, specialty consultations, emergency department visits, and hospitalizations. Patients' medical records were reviewed to determine graft type, validate infection status, and calculate sensitivity and positive predictive value (PPV) for indicators of ACL allografts and infections. RESULTS: A total of 11,778 patients with codes for ACL reconstruction were identified. After chart review, PPV for ACL reconstruction was 96% (95% confidence interval [CI], 94%-97%). Of the confirmed ACL reconstructions, 39% (95% CI, 35%-42%) used allograft tissues. The deep infection rate after ACL reconstruction was 1.0% (95% CI, 0.7%-1.4%). The odds ratio of infection for allografts versus autografts was 0.41 (95% CI, 0.19-0.78). Sensitivity of individual claims-based indicators for deep infection after ACL reconstruction ranged from 0% to 75% and PPV from 0% to 100%. Claims-based infection indicators could be combined to enhance sensitivity or PPV but not both. CONCLUSIONS: While claims data accurately identify ACL reconstructions, they poorly distinguish between allografts and autografts and identify infections with variable accuracy. Claims data could be useful to monitor infection trends after ACL reconstruction, with different algorithms optimized for different surveillance goals. PMID- 24799642 TI - Factors associated with surgical site infection in colorectal surgery: the Japan nosocomial infections surveillance. AB - OBJECTIVE: Surgical site infection (SSI) is one of the most common healthcare associated infections (HAIs). This study aims to assess factors associated with SSI after colorectal surgery in Japan, using a Japanese national database for HAIs. DESIGN: A retrospective nationwide surveillance-based study. SETTING: Japanese healthcare facilities. METHODS: Data on colon and rectal surgeries performed from 2008 through 2010 were extracted from a national monitoring system for healthcare-associated infections, the Japan Nosocomial Infections Surveillance (JANIS). Factors associated with SSI after colon and rectal surgery were assessed using multivariate logistic regression. RESULTS: The cumulative incidence of SSI for colon and rectal surgery was 15.0% (6,691 of 44,751) and 17.8% (3,230 of 18,187), respectively. Traditional risk factors included in the National Nosocomial Infections Surveillance (NNIS) modified risk index were significant in predicting SSI in the final model for both colon and rectal surgery. Among the additional variables routinely collected in JANIS were factors independently associated with the development of SSI, such as male sex (adjusted odds ratio [aOR], 1.20 [95% confidence interval (CI), 1.14-1.27]), ileostomy or colostomy placement (aOR, 1.13 [95% CI, 1.04-1.21]), emergency operation (aOR, 1.40 [95% CI, 1.29-1.52]), and multiple procedures (aOR, 1.22 [95% CI, 1.13 1.33]) for colon surgery as well as male sex (aOR, 1.43 [95% CI, 1.31-1.55]), ileostomy or colostomy placement (aOR, 1,63 [95% CI, 1.51-1.79]), and emergency operation (aOR, 1.43 [95% CI, 1.20-1.72]) for rectal surgery. CONCLUSIONS: For colorectal operations, inclusion of additional variables routinely collected in JANIS can more accurately predict SSI risk than can the NNIS risk index alone. PMID- 24799643 TI - Real-time polymerase chain reaction detection of asymptomatic Clostridium difficile colonization and rising C. difficile-associated disease rates. AB - OBJECTIVE: To evaluate the accuracy of real-time polymerase chain reaction (PCR) for Clostridium difficile-associated disease (CDAD) detection, after hospital CDAD rates significantly increased following real-time PCR initiation for CDAD diagnosis. DESIGN: Hospital-wide surveillance study following examination of CDAD incidence density rates by interrupted time series design. SETTING: Large university-based hospital. PARTICIPANTS: Hospitalized adult patients. METHODS: CDAD rates were compared before and after real-time PCR implementation in a university hospital and in the absence of physician and infection control practice changes. After real-time PCR introduction, all hospitalized adult patients were screened for C. difficile by testing a fecal specimen by real-time PCR, toxin enzyme-linked immunosorbent assay, and toxigenic culture. RESULTS: CDAD hospital rates significantly increased after changing from cell culture cytotoxicity assay to a real-time PCR assay. One hundred ninety-nine hospitalized subjects were enrolled, and 101 fecal specimens were collected. C. difficile was detected in 18 subjects (18%), including 5 subjects (28%) with either definite or probable CDAD and 13 patients (72%) with asymptomatic C. difficile colonization. CONCLUSIONS: The majority of healthcare-associated diarrhea is not attributable to CDAD, and the prevalence of asymptomatic C. difficile colonization exceeds CDAD rates in healthcare facilities. PCR detection of asymptomatic C. difficile colonization among patients with non-CDAD diarrhea may be contributing to rising CDAD rates and a significant number of CDAD false positives. PCR may be useful for CDAD screening, but further study is needed to guide interpretation of PCR detection of C. difficile and the value of confirmatory tests. A gold standard CDAD diagnostic assay is needed. PMID- 24799644 TI - Assessing the burden of healthcare-associated infections through prevalence studies: what is the best method? AB - OBJECTIVE: To explore differences in the prevalence of healthcare-associated infections (HAIs) according to survey methodology. DESIGN: Repeated point and period prevalence survey strategies. SETTING: University-affiliated primary and tertiary care center. METHODS: Analysis of data collected from 2006 to 2012 from annual HAI prevalence surveys using definitions proposed by the US Centers for Disease Control and Prevention. The study design allowed the analysis of the same data in the format of a point or a period prevalence survey. RESULTS: Pooled point and period HAI prevalence was 7.46% and 9.84% (+32%), respectively. This additional 32% was mainly attributable to infections of the lower respiratory tract (2.42% vs 3.20% [+32%]) and the urinary tract (1.76% vs 2.62% [+49%]). Differences in surgical site infections (1.02% vs 1.20% [+19%]) and bloodstream infections (0.76% vs 0.86% [+13%]) were smaller. HAI prevalence for the point and period methodology in acute and long-term care were 7.47% versus 9.38 (+26%) and 8.37% versus 11.89% (+42%), respectively. Differences were stable over time. Focusing on the 4 major HAIs (respiratory tract, urinary tract, surgical site, and bloodstream infections) misses one-quarter of all HAIs. CONCLUSIONS: More HAIs are identified by the period prevalence method, especially those of shorter duration (lower respiratory and urinary tract), which would make this method more suitable to be used in long-term care. Results of the 2 study methods cannot be benchmarked against each other. PMID- 24799638 TI - Strategies to prevent surgical site infections in acute care hospitals: 2014 update. PMID- 24799645 TI - Accuracy of electronic surveillance of catheter-associated urinary tract infection at an academic medical center. AB - OBJECTIVE: To develop and validate a methodology for electronic surveillance of catheter-associated urinary tract infections (CAUTIs). DESIGN: Diagnostic accuracy study. SETTING: A 425-bed university hospital. SUBJECTS: A total of 1,695 unique inpatient encounters from November 2009 through November 2010 with a high clinical suspicion of CAUTI. METHODS: An algorithm was developed to identify incident CAUTIs from electronic health records (EHRs) on the basis of the Centers for Disease Control and Prevention (CDC) surveillance definition. CAUTIs identified by electronic surveillance were compared with the reference standard of manual surveillance by infection preventionists. To determine diagnostic accuracy, we created 2 * 2 tables, one unadjusted and one adjusted for misclassification using chart review and case adjudication. Unadjusted and adjusted test statistics (percent agreement, sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], and kappa) were calculated. RESULTS: Electronic surveillance identified 64 CAUTIs compared with manual surveillance, which identified 19 CAUTIs for 97% agreement, 79% sensitivity, 97% sensitivity, 23% PPV, 100% NPV, and kappa of .33. Compared with the reference standard adjusted for misclassification, which identified 55 CAUTIs, electronic surveillance had 98% agreement, 80% sensitivity, 99% specificity, 69% PPV, 99% NPV, and kappa of .71. CONCLUSION: The electronic surveillance methodology had a high NPV and a low PPV compared with the reference standard, indicating a role of the electronic algorithm in screening data sets to exclude cases. However, the PPV markedly improved compared with the reference standard adjusted for misclassification, suggesting a future role in surveillance with improvements in EHRs. PMID- 24799646 TI - Development and validation of a simple and easy-to-employ electronic algorithm for identifying clinical methicillin-resistant Staphylococcus aureus infection. AB - BACKGROUND: With growing demands to track and publicly report and compare infection rates, efforts to utilize automated surveillance systems are increasing. We developed and validated a simple algorithm for identifying patients with clinical methicillin-resistant Staphylococcus aureus (MRSA) infection using microbiologic and antimicrobial variables. We also estimated resource savings. METHODS: Patients who had a culture positive for MRSA at any of 5 acute care Veterans Affairs hospitals were eligible. Clinical infection was defined on the basis of manual chart review. The electronic algorithm defined clinical MRSA infection as a positive non-sterile-site culture with receipt of MRSA-active antibiotics during the 5 days prior to or after the culture. RESULTS: In total, 246 unique non-sterile-site cultures were included, of which 168 represented infection. The sensitivity (43.4%-95.8%) and specificity (34.6% 84.6%) of the electronic algorithm varied depending on the combination of antimicrobials included. On multivariable analysis, predictors of algorithm failure were outpatient status (odds ratio, 0.23 [95% confidence interval, 0.10 0.56]) and respiratory culture (odds ratio, 0.29 [95% confidence interval, 0.13 0.65]). The median cost was $2.43 per chart given 4.6 minutes of review time per chart. CONCLUSIONS: Our simple electronic algorithm for detecting clinical MRSA infections has excellent sensitivity and good specificity. Implementation of this electronic system may streamline and standardize surveillance and reporting efforts. PMID- 24799647 TI - Factors associated with healthcare worker acceptance of vaccination: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Healthcare workers experience occupational risk of infection and may transmit infections to patients. Vaccination provides an efficient means of protecting workers and patients, but uptake may be low. We sought to identify factors influencing vaccine acceptance by healthcare workers in order to obtain insights leading to more effective vaccination programs in this population. DESIGN: Systematic review and meta-analysis. METHODS: We searched Medline, Embase, and CINAHL databases to identify studies published up to May 2012. Factors influencing vaccination acceptance were devised a priori. Random-effects meta-analysis was performed to generate summary estimates of effect. Heterogeneity and publication bias were explored using statistical tools. RESULTS: Thirty-seven studies evaluating a variety of vaccines (against influenza, pertussis, smallpox, anthrax, and hepatitis B) were included. Homogeneous effects on vaccine acceptance were identified with desire for self protection (odds ratio [OR], 3.42 [95% confidence interval (CI), 2.42-4.82]) and desire to protect family and friends (OR, 3.28 [95% CI, 1.10-9.75]). Concern that vaccine transmits the illness it was meant to prevent decreased acceptance (OR, 0.42 [95% CI, 0.30-0.58]). Differences in physician and nurse acceptance of immunization were seen between Asian and non-Asian studies. CONCLUSIONS: Consideration of self-protection (rather than absolute disease risk or protection of patients) appears the strongest and most consistent driver of healthcare workers' decisions to accept vaccination, though other factors may also be impactful, and reasons for between-study divergence in effects is an important area for future research. This finding has important implications for the design of programs to enhance healthcare worker vaccine uptake. PMID- 24799648 TI - Impact of mass media on public behavior and physicians: an ecological study of the H1N1 influenza pandemic. AB - BACKGROUND: The mass media plays an important role in public health behavior. PURPOSE: The objective of the present study was to investigate the effect of mass media coverage of the H1N1 pandemic on the number of emergency department (ED) visits and hospital admission rates. METHODS: An ecological study of ED visits to 8 general Israeli hospitals due to influenza-like illness during the period June October 2009 was performed. Data on the number of visits per day for children and adults and daily hospitalization rates were analyzed. Associations with the estimated value of H1N1-related publications and weekly reports from nationwide sentinel clinics were assessed. The analysis was performed in 2012-2013. RESULTS: There were 55,070 ED visits due to influenza-like illness during the study period. The overall number of media reports was 1,812 (14.3% radio broadcasts, 9.8% television broadcasts, 27.5% newspaper articles, and 48.5% major website reports). The overall estimated value of advertising of publications was $16,399,000, excluding the Internet. While H1N1 incidence recorded by Israeli sentinel clinics showed no association with mass media publications, peaks of media reports were followed by an increase in the number of ED visits, usually with a delay of 3 days (P = .005). This association was noted in children (P < .001) but not in adults (P > .1), with a corresponding decrease in hospital admission rates. Publications' framing had no association with ED visits. CONCLUSIONS: During the 2009 H1N1 influenza outbreak in Israel, an increase in mass media coverage was associated with an increase in pediatric ED visits. PMID- 24799649 TI - Randomized crossover study evaluating the effect of a hand sanitizer dispenser on the frequency of hand hygiene among anesthesiology staff in the operating room. AB - Forty anesthesia providers were evaluated with and without hand sanitizer dispensers present on the anesthesia machine. Having a dispenser increased the frequency of hand hygiene only from 0.5 to 0.8 events per hour (P = .01). Other concomitant interventions are needed to further increase hand hygiene frequency among anesthesia providers. PMID- 24799650 TI - Optimum outlier model for potential improvement of environmental cleaning and disinfection. AB - The effectiveness and efficiency of 17 housekeepers in terminal cleaning 292 hospital rooms was evaluated through adenosine triphosphate detection. A subgroup of housekeepers was identified who were significantly more effective and efficient than their coworkers. These optimum outliers may be used in performance improvement to optimize environmental cleaning. PMID- 24799651 TI - Barriers and facilitators of implementation of a mandate for influenza vaccination among healthcare personnel. AB - Mandatory influenza vaccination is associated with improved healthcare personnel vaccination rates, but institutional barriers to implementation and enforcement are reported. We explored barriers and facilitators to mandatory vaccination among a national sample of hospital administrators. Support from employees and administration were cited as key to the success of a mandate. PMID- 24799652 TI - Detection and prevalence of adenoviral conjunctivitis among hospital employees using real-time polymerase chain reaction as an infection prevention tool. AB - Hospital employees with suspected adenoviral conjunctivitis underwent evaluation and testing with real-time polymerase chain reaction. Viral conjunctivitis was suspected in 307 (59%) of 518 employees with eye complaints; adenovirus was detected in 4% (22 of 518). Four employees had genotypes consistent with epidemic keratoconjunctivitis. This algorithm minimizes productivity loss compared with clinical diagnosis. PMID- 24799653 TI - A large epidemic of hepatitis B in Serbia: an integrated model for outbreak investigations in healthcare settings. AB - We report a comprehensive approach for outbreak investigations, including cluster analysis (Bernoulli model), an algorithm to build inferential models, and molecular techniques to confirm cases. Our approach may be an interesting tool to best exploit the large amount of unsystematically collected information available during outbreak investigations in healthcare settings. PMID- 24799654 TI - Survey of preoperative infection prevention for coronary artery bypass graft procedures. PMID- 24799655 TI - Variation in antibiotic prophylaxis selection for coronary artery bypass graft procedures in an era of increasing methicillin-resistant Staphylococcus aureus prevalence. PMID- 24799656 TI - Healthcare worker perception of bare below the elbows: readiness for change? PMID- 24799657 TI - Letter to the editor regarding "healthcare personnel attire in non-operating-room settings" by Bearman et al. PMID- 24799658 TI - Reply to Burden et al. PMID- 24799659 TI - Reply to Burden et al. PMID- 24799660 TI - Achieving zero catheter-associated urinary tract infections in a neurosurgery intensive care unit. PMID- 24799661 TI - Bacteriostatic effect of mixtures of 1% propofol with 4% lidocaine versus 4% lidocaine alone: regards on microbiologic studies in the field of anesthesiology. PMID- 24799662 TI - Implementation of a restricted foods policy at a large academic medical center. PMID- 24799663 TI - Heteroresistance to carbapenems in New Delhi metallo-beta-lactamase-1-producing isolates: a challenge for detection? PMID- 24799664 TI - CAHM, a long non-coding RNA gene hypermethylated in colorectal neoplasia. AB - The CAHM gene (Colorectal Adenocarcinoma HyperMethylated), previously LOC100526820, is located on chromosome 6, hg19 chr6:163 834 097-163 834 982. It lacks introns, encodes a long non-coding RNA (lncRNA) and is located adjacent to the gene QKI, which encodes an RNA binding protein. Deep bisulphite sequencing of ten colorectal cancer (CRC) and matched normal tissues demonstrated frequent hypermethylation within the CAHM gene in cancer. A quantitative methylation specific PCR (qMSP) was used to characterize additional tissue samples. With a threshold of 5% methylation, the CAHM assay was positive in 2/26 normal colorectal tissues (8%), 17/21 adenomas (81%), and 56/79 CRC samples (71%). A reverse transcriptase-qPCR assay showed that CAHM RNA levels correlated negatively with CAHM % methylation, and therefore CAHM gene expression is typically decreased in CRC. The CAHM qMSP assay was applied to DNA isolated from plasma specimens from 220 colonoscopy-examined patients. Using a threshold of 3 pg methylated genomic DNA per mL plasma, methylated CAHM sequences were detected in the plasma DNA of 40/73 (55%) of CRC patients compared with 3/73 (4%) from subjects with adenomas and 5/74 (7%) from subjects without neoplasia. Both the frequency of detection and the amount of methylated CAHM DNA released into plasma increased with increasing cancer stage. Methylated CAHM DNA shows promise as a plasma biomarker for use in screening for CRC. PMID- 24799670 TI - Mitochondrial genome regulates mitotic fidelity by maintaining centrosomal homeostasis. AB - Centrosomes direct spindle morphogenesis to assemble a bipolar mitotic apparatus to enable error-free chromosome segregation and preclude chromosomal instability (CIN). Amplified centrosomes, a hallmark of cancer cells, set the stage for CIN, which underlies malignant transformation and evolution of aggressive phenotypes. Several studies report CIN and a tumorigenic and/or aggressive transformation in mitochondrial DNA (mtDNA)-depleted cells. Although several nuclear-encoded proteins are implicated in centrosome duplication and spindle organization, the involvement of mtDNA encoded proteins in centrosome amplification (CA) remains elusive. Here we show that disruption of mitochondrial function by depletion of mtDNA induces robust CA and mitotic aberrations in osteosarcoma cells. We found that overexpression of Aurora A, Polo-like kinase 4 (PLK4), and Cyclin E was associated with emergence of amplified centrosomes. Supernumerary centrosomes in rho0 (mtDNA-depleted) cells resulted in multipolar mitoses bearing "real" centrosomes with paired centrioles at the multiple poles. This abnormal phenotype was recapitulated by inhibition of respiratory complex I in parental cells, suggesting a role for electron transport chain (ETC) in maintaining numeral centrosomal homeostasis. Furthermore, rho0 cells displayed a decreased proliferative capacity owing to a G 2/M arrest. Downregulation of nuclear-encoded p53 in rho0 cells underscores the importance of mitochondrial and nuclear genome crosstalk and may perhaps underlie the observed mitotic aberrations. By contrast, repletion of wild-type mtDNA in rho0 cells (cybrid) demonstrated a much lesser extent of CA and spindle multipolarity, suggesting partial restoration of centrosomal homeostasis. Our study provides compelling evidence to implicate the role of mitochondria in regulation of centrosome duplication, spindle architecture, and spindle pole integrity. PMID- 24799671 TI - Phosphoglucan-bound structure of starch phosphatase Starch Excess4 reveals the mechanism for C6 specificity. AB - Plants use the insoluble polyglucan starch as their primary glucose storage molecule. Reversible phosphorylation, at the C6 and C3 positions of glucose moieties, is the only known natural modification of starch and is the key regulatory mechanism controlling its diurnal breakdown in plant leaves. The glucan phosphatase Starch Excess4 (SEX4) is a position-specific starch phosphatase that is essential for reversible starch phosphorylation; its absence leads to a dramatic accumulation of starch in Arabidopsis, but the basis for its function is unknown. Here we describe the crystal structure of SEX4 bound to maltoheptaose and phosphate to a resolution of 1.65 A. SEX4 binds maltoheptaose via a continuous binding pocket and active site that spans both the carbohydrate binding module (CBM) and the dual-specificity phosphatase (DSP) domain. This extended interface is composed of aromatic and hydrophilic residues that form a specific glucan-interacting platform. SEX4 contains a uniquely adapted DSP active site that accommodates a glucan polymer and is responsible for positioning maltoheptaose in a C6-specific orientation. We identified two DSP domain residues that are responsible for SEX4 site-specific activity and, using these insights, we engineered a SEX4 double mutant that completely reversed specificity from the C6 to the C3 position. Our data demonstrate that the two domains act in consort, with the CBM primarily responsible for engaging glucan chains, whereas the DSP integrates them in the catalytic site for position-specific dephosphorylation. These data provide important insights into the structural basis of glucan phosphatase site-specific activity and open new avenues for their biotechnological utilization. PMID- 24799672 TI - Location of the unique integration site on an Escherichia coli chromosome by bacteriophage lambda DNA in vivo. AB - The search for specific sequences on long genomes is a key process in many biological contexts. How can specific target sequences be located with high efficiency, within physiologically relevant times? We addressed this question for viral integration, a fundamental mechanism of horizontal gene transfer driving prokaryotic evolution, using the infection of Escherichia coli bacteria with bacteriophage lambda and following the establishment of a lysogenic state. Following the targeting process in individual live E. coli cells in real time revealed that lambda DNA remains confined near the entry point of a cell following infection. The encounter between the 15-bp-long target sequence on the chromosome and the recombination site on the viral genome is facilitated by the directed motion of bacterial DNA generated during chromosome replication, in conjunction with constrained diffusion of phage DNA. Moving the native bacterial integration site to different locations on the genome and measuring the integration frequency in these strains reveals that the frequencies of the native site and a site symmetric to it relative to the origin are similar, whereas both are significantly higher than when the integration site is moved near the terminus, consistent with the replication-driven mechanism we propose. This novel search mechanism is yet another example of the exquisite coevolution of lambda with its host. PMID- 24799665 TI - The other side of the coin: the tumor-suppressive aspect of oncogenes and the oncogenic aspect of tumor-suppressive genes, such as those along the CCND-CDK4/6 RB axis. AB - Although cancer-regulatory genes are dichotomized to oncogenes and tumor suppressor gene s, in reality they can be oncogenic in one situation but tumor suppressive in another. This dual-function nature, which sometimes hampers our understanding of tumor biology, has several manifestations: (1) Most canonically defined genes have multiple mRNAs, regulatory RNAs, protein isoforms, and posttranslational modifications; (2) Genes may interact at different levels, such as by forming chimeric RNAs or by forming different protein complexes; (3) Increased levels of tumor-suppressive genes in normal cells drive proliferation of cancer progenitor cells in the same organ or tissue by imposing compensatory proliferation pressure, which presents the dual-function nature as a cell-cell interaction. All these manifestations of dual functions can find examples in the genes along the CCND-CDK4/6-RB axis. The dual-function nature also underlies the heterogeneity of cancer cells. Gene-targeting chemotherapies, including that targets CDK4, are effective to some cancer cells but in the meantime may promote growth or progression of some others in the same patient. Redefining "gene" by considering each mRNA, regulatory RNA, protein isoform, and posttranslational modification from the same genomic locus as a "gene" may help in better understanding tumor biology and better selecting targets for different sub populations of cancer cells in individual patients for personalized therapy. PMID- 24799673 TI - NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein. AB - To subvert host immunity, influenza A virus (IAV) induces early apoptosis in innate immune cells by disrupting mitochondria membrane potential via its polymerase basic protein 1-frame 2 (PB1-F2) accessory protein. Whether immune cells have mechanisms to counteract PB1-F2-mediated apoptosis is currently unknown. Herein, we define that the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 binds to viral protein PB1-F2, preventing IAV-induced macrophage apoptosis and promoting both macrophage survival and type I IFN signaling. We initially observed that Nlrx1-deficient mice infected with IAV exhibited increased pulmonary viral replication, as well as enhanced inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly enhanced leukocyte recruitment but impaired production of type I IFN in Nlrx1(-/-) mice. Impaired type I IFN production and enhanced viral replication was recapitulated in Nlrx1( /-) macrophages and was associated with increased mitochondrial mediated apoptosis. Through gain- and loss-of-function strategies for protein interaction, we identified that NLRX1 directly bound PB1-F2 in the mitochondria of macrophages. Using a recombinant virus lacking PB1-F2, we confirmed that deletion of PB1-F2 abrogated NLRX1-dependent macrophage type I IFN production and apoptosis. Thus, our results demonstrate that NLRX1 acts as a mitochondrial sentinel protecting macrophages from PB1-F2-induced apoptosis and preserving their antiviral function. We further propose that NLRX1 is critical for macrophage immunity against IAV infection by sensing the extent of viral replication and maintaining a protective balance between antiviral immunity and excessive inflammation within the lungs. PMID- 24799674 TI - Transduction channels' gating can control friction on vibrating hair-cell bundles in the ear. AB - Hearing starts when sound-evoked mechanical vibrations of the hair-cell bundle activate mechanosensitive ion channels, giving birth to an electrical signal. As for any mechanical system, friction impedes movements of the hair bundle and thus constrains the sensitivity and frequency selectivity of auditory transduction. Friction is generally thought to result mainly from viscous drag by the surrounding fluid. We demonstrate here that the opening and closing of the transduction channels produce internal frictional forces that can dominate viscous drag on the micrometer-sized hair bundle. We characterized friction by analyzing hysteresis in the force-displacement relation of single hair-cell bundles in response to periodic triangular stimuli. For bundle velocities high enough to outrun adaptation, we found that frictional forces were maximal within the narrow region of deflections that elicited significant channel gating, plummeted upon application of a channel blocker, and displayed a sublinear growth for increasing bundle velocity. At low velocity, the slope of the relation between the frictional force and velocity was nearly fivefold larger than the hydrodynamic friction coefficient that was measured when the transduction machinery was decoupled from bundle motion by severing tip links. A theoretical analysis reveals that channel friction arises from coupling the dynamics of the conformational change associated with channel gating to tip-link tension. Varying channel properties affects friction, with faster channels producing smaller friction. We propose that this intrinsic source of friction may contribute to the process that sets the hair cell's characteristic frequency of responsiveness. PMID- 24799675 TI - Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. AB - Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple negative breast cancers have increased expression of genes regulated by hypoxia inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs. PMID- 24799676 TI - Transcriptional gene silencing by Arabidopsis microrchidia homologues involves the formation of heteromers. AB - Epigenetic gene silencing is of central importance to maintain genome integrity and is mediated by an elaborate interplay between DNA methylation, histone posttranslational modifications, and chromatin remodeling complexes. DNA methylation and repressive histone marks usually correlate with transcriptionally silent heterochromatin, however there are exceptions to this relationship. In Arabidopsis, mutation of Morpheus Molecule 1 (MOM1) causes transcriptional derepression of heterochromatin independently of changes in DNA methylation. More recently, two Arabidopsis homologues of mouse microrchidia (MORC) genes have also been implicated in gene silencing and heterochromatin condensation without altering genome-wide DNA methylation patterns. In this study, we show that Arabidopsis microrchidia (AtMORC6) physically interacts with AtMORC1 and with its close homologue, AtMORC2, in two mutually exclusive protein complexes. RNA sequencing analyses of high-order mutants indicate that AtMORC1 and AtMORC2 act redundantly to repress a common set of loci. We also examined genetic interactions between AtMORC6 and MOM1 pathways. Although AtMORC6 and MOM1 control the silencing of a very similar set of genomic loci, we observed synergistic transcriptional regulation in the mom1/atmorc6 double mutant, suggesting that these epigenetic regulators act mainly by different silencing mechanisms. PMID- 24799677 TI - Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases. AB - DNA glycosylases are enzymes that perform the initial steps of base excision repair, the principal repair mechanism that identifies and removes endogenous damages that occur in an organism's DNA. We characterized the motion of single molecules of three bacterial glycosylases that recognize oxidized bases, Fpg, Nei, and Nth, as they scan for damages on tightropes of lambda DNA. We find that all three enzymes use a key "wedge residue" to scan for damage because mutation of this residue to an alanine results in faster diffusion. Moreover, all three enzymes bind longer and diffuse more slowly on DNA that contains the damages they recognize and remove. Using a sliding window approach to measure diffusion constants and a simple chemomechanical simulation, we demonstrate that these enzymes diffuse along DNA, pausing momentarily to interrogate random bases, and when a damaged base is recognized, they stop to evert and excise it. PMID- 24799678 TI - Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. AB - A number of pathogens cause host cell death upon infection, and Yersinia pestis, infamous for its role in large pandemics such as the "Black Death" in medieval Europe, induces considerable cytotoxicity. The rapid killing of macrophages induced by Y. pestis, dependent upon type III secretion system effector Yersinia outer protein J (YopJ), is minimally affected by the absence of caspase-1, caspase-11, Fas ligand, and TNF. Caspase-8 is known to mediate apoptotic death in response to infection with several viruses and to regulate programmed necrosis (necroptosis), but its role in bacterially induced cell death is poorly understood. Here we provide genetic evidence for a receptor-interacting protein (RIP) kinase-caspase-8-dependent macrophage apoptotic death pathway after infection with Y. pestis, influenced by Toll-like receptor 4-TIR-domain containing adapter-inducing interferon-beta (TLR4-TRIF). Interestingly, macrophages lacking either RIP1, or caspase-8 and RIP3, also had reduced infection-induced production of IL-1beta, IL-18, TNF, and IL-6; impaired activation of the transcription factor NF-kappaB; and greatly compromised caspase 1 processing. Cleavage of the proform of caspase-1 is associated with triggering inflammasome activity, which leads to the maturation of IL-1beta and IL-18, cytokines important to host responses against Y. pestis and many other infectious agents. Our results identify a RIP1-caspase-8/RIP3-dependent caspase-1 activation pathway after Y. pestis challenge. Mice defective in caspase-8 and RIP3 were also highly susceptible to infection and displayed reduced proinflammatory cytokines and myeloid cell death. We propose that caspase-8 and the RIP kinases are key regulators of macrophage cell death, NF-kappaB and inflammasome activation, and host resistance after Y. pestis infection. PMID- 24799679 TI - Face-selective neurons maintain consistent visual responses across months. AB - Face perception in both humans and monkeys is thought to depend on neurons clustered in discrete, specialized brain regions. Because primates are frequently called upon to recognize and remember new individuals, the neuronal representation of faces in the brain might be expected to change over time. The functional properties of neurons in behaving animals are typically assessed over time periods ranging from minutes to hours, which amounts to a snapshot compared to a lifespan of a neuron. It therefore remains unclear how neuronal properties observed on a given day predict that same neuron's activity months or years later. Here we show that the macaque inferotemporal cortex contains face selective cells that show virtually no change in their patterns of visual responses over time periods as long as one year. Using chronically implanted microwire electrodes guided by functional MRI targeting, we obtained distinct profiles of selectivity for face and nonface stimuli that served as fingerprints for individual neurons in the anterior fundus (AF) face patch within the superior temporal sulcus. Longitudinal tracking over a series of daily recording sessions revealed that face-selective neurons maintain consistent visual response profiles across months-long time spans despite the influence of ongoing daily experience. We propose that neurons in the AF face patch are specialized for aspects of face perception that demand stability as opposed to plasticity. PMID- 24799680 TI - Phyllotreta striolata flea beetles use host plant defense compounds to create their own glucosinolate-myrosinase system. AB - The ability of a specialized herbivore to overcome the chemical defense of a particular plant taxon not only makes it accessible as a food source but may also provide metabolites to be exploited for communication or chemical defense. Phyllotreta flea beetles are adapted to crucifer plants (Brassicales) that are defended by the glucosinolate-myrosinase system, the so-called "mustard-oil bomb." Tissue damage caused by insect feeding brings glucosinolates into contact with the plant enzyme myrosinase, which hydrolyzes them to form toxic compounds, such as isothiocyanates. However, we previously observed that Phyllotreta striolata beetles themselves produce volatile glucosinolate hydrolysis products. Here, we show that P. striolata adults selectively accumulate glucosinolates from their food plants to up to 1.75% of their body weight and express their own myrosinase. By combining proteomics and transcriptomics, a gene responsible for myrosinase activity in P. striolata was identified. The major substrates of the heterologously expressed myrosinase were aliphatic glucosinolates, which were hydrolyzed with at least fourfold higher efficiency than aromatic and indolic glucosinolates, and beta-O-glucosides. The identified beetle myrosinase belongs to the glycoside hydrolase family 1 and has up to 76% sequence similarity to other beta-glucosidases. Phylogenetic analyses suggest species-specific diversification of this gene family in insects and an independent evolution of the beetle myrosinase from other insect beta-glucosidases. PMID- 24799681 TI - Hypochlorite-induced structural modifications enhance the chaperone activity of human alpha2-macroglobulin. AB - Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer's disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human alpha2-macroglobulin (alpha2M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric alpha2M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified alpha2M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid beta-peptide (Abeta1 42). Here, we show that hypochlorite-modified alpha2M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Abeta1-42 neurotoxicity. Our results support the conclusion that alpha2M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity. PMID- 24799683 TI - Noninvasive prenatal diagnosis of common aneuploidies by semiconductor sequencing. AB - Massively parallel sequencing (MPS) of cell-free fetal DNA from maternal plasma has revolutionized our ability to perform noninvasive prenatal diagnosis. This approach avoids the risk of fetal loss associated with more invasive diagnostic procedures. The present study developed an effective method for noninvasive prenatal diagnosis of common chromosomal aneuploidies using a benchtop semiconductor sequencing platform (SSP), which relies on the MPS platform but offers advantages over existing noninvasive screening techniques. A total of 2,275 pregnant subjects was included in the study; of these, 515 subjects who had full karyotyping results were used in a retrospective analysis, and 1,760 subjects without karyotyping were analyzed in a prospective study. In the retrospective study, all 55 fetal trisomy 21 cases were identified using the SSP with a sensitivity and specificity of 99.94% and 99.46%, respectively. The SSP also detected 16 trisomy 18 cases with 100% sensitivity and 99.24% specificity and 3 trisomy 13 cases with 100% sensitivity and 100% specificity. Furthermore, 15 fetuses with sex chromosome aneuploidies (10 45,X, 2 47,XYY, 2 47,XXX, and 1 47,XXY) were detected. In the prospective study, nine fetuses with trisomy 21, three with trisomy 18, three with trisomy 13, and one with 45,X were detected. To our knowledge, this is the first large-scale clinical study to systematically identify chromosomal aneuploidies based on cell-free fetal DNA using the SSP and provides an effective strategy for large-scale noninvasive screening for chromosomal aneuploidies in a clinical setting. PMID- 24799682 TI - Altered global brain signal in schizophrenia. AB - Neuropsychiatric conditions like schizophrenia display a complex neurobiology, which has long been associated with distributed brain dysfunction. However, no investigation has tested whether schizophrenia shows alterations in global brain signal (GS), a signal derived from functional MRI and often discarded as a meaningless baseline in many studies. To evaluate GS alterations associated with schizophrenia, we studied two large chronic patient samples (n = 90, n = 71), comparing them to healthy subjects (n = 220) and patients diagnosed with bipolar disorder (n = 73). We identified and replicated increased cortical power and variance in schizophrenia, an effect predictive of symptoms yet obscured by GS removal. Voxel-wise signal variance was also increased in schizophrenia, independent of GS effects. Both findings were absent in bipolar patients, confirming diagnostic specificity. Biologically informed computational modeling of shared and nonshared signal propagation through the brain suggests that these findings may be explained by altered net strength of overall brain connectivity in schizophrenia. PMID- 24799684 TI - Measuring reversal of HIV-1 latency ex vivo using cells from infected individuals. PMID- 24799685 TI - Projected land-use change impacts on ecosystem services in the United States. AB - Providing food, timber, energy, housing, and other goods and services, while maintaining ecosystem functions and biodiversity that underpin their sustainable supply, is one of the great challenges of our time. Understanding the drivers of land-use change and how policies can alter land-use change will be critical to meeting this challenge. Here we project land-use change in the contiguous United States to 2051 under two plausible baseline trajectories of economic conditions to illustrate how differences in underlying market forces can have large impacts on land-use with cascading effects on ecosystem services and wildlife habitat. We project a large increase in croplands (28.2 million ha) under a scenario with high crop demand mirroring conditions starting in 2007, compared with a loss of cropland (11.2 million ha) mirroring conditions in the 1990s. Projected land-use changes result in increases in carbon storage, timber production, food production from increased yields, and >10% decreases in habitat for 25% of modeled species. We also analyze policy alternatives designed to encourage forest cover and natural landscapes and reduce urban expansion. Although these policy scenarios modify baseline land-use patterns, they do not reverse powerful underlying trends. Policy interventions need to be aggressive to significantly alter underlying land-use change trends and shift the trajectory of ecosystem service provision. PMID- 24799686 TI - Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. AB - Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-alpha, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases. PMID- 24799687 TI - Identification of the 11-cis-specific retinyl-ester synthase in retinal Muller cells as multifunctional O-acyltransferase (MFAT). AB - Absorption of a photon by a rhodopsin or cone-opsin pigment isomerizes its 11-cis retinaldehyde (11-cis-RAL) chromophore to all-trans-retinaldehyde (all-trans RAL), which dissociates after a brief period of activation. Light sensitivity is restored to the resulting apo-opsin when it recombines with another 11-cis-RAL. Conversion of all-trans-RAL to 11-cis-RAL is carried out by an enzyme pathway called the visual cycle in cells of the retinal pigment epithelium. A second visual cycle is present in Muller cells of the retina. The retinol isomerase for this noncanonical pathway is dihydroceramide desaturase (DES1), which catalyzes equilibrium isomerization of retinol. Because 11-cis-retinol (11-cis-ROL) constitutes only a small fraction of total retinols in an equilibrium mixture, a subsequent step involving selective removal of 11-cis-ROL is required to drive synthesis of 11-cis-retinoids for production of visual chromophore. Selective esterification of 11-cis-ROL is one possibility. Crude homogenates of chicken retinas rapidly convert all-trans-ROL to 11-cis-retinyl esters (11-cis-REs) with minimal formation of other retinyl-ester isomers. This enzymatic activity implies the existence of an 11-cis-specific retinyl-ester synthase in Muller cells. Here, we evaluated multifunctional O-acyltransferase (MFAT) as a candidate for this 11 cis-RE-synthase. MFAT exhibited much higher catalytic efficiency as a synthase of 11-cis-REs versus other retinyl-ester isomers. Further, we show that MFAT is expressed in Muller cells. Finally, homogenates of cells coexpressing DES1 and MFAT catalyzed the conversion of all-trans-ROL to 11-cis-RP, similar to what we observed with chicken-retina homogenates. MFAT is therefore an excellent candidate for the retinyl-ester synthase that cooperates with DES1 to drive synthesis of 11-cis-retinoids by mass action. PMID- 24799688 TI - Extraordinary strain hardening by gradient structure. AB - Gradient structures have evolved over millions of years through natural selection and optimization in many biological systems such as bones and plant stems, where the structures change gradually from the surface to interior. The advantage of gradient structures is their maximization of physical and mechanical performance while minimizing material cost. Here we report that the gradient structure in engineering materials such as metals renders a unique extra strain hardening, which leads to high ductility. The grain-size gradient under uniaxial tension induces a macroscopic strain gradient and converts the applied uniaxial stress to multiaxial stresses due to the evolution of incompatible deformation along the gradient depth. Thereby the accumulation and interaction of dislocations are promoted, resulting in an extra strain hardening and an obvious strain hardening rate up-turn. Such extraordinary strain hardening, which is inherent to gradient structures and does not exist in homogeneous materials, provides a hitherto unknown strategy to develop strong and ductile materials by architecting heterogeneous nanostructures. PMID- 24799689 TI - Coevolution can reverse predator-prey cycles. AB - A hallmark of Lotka-Volterra models, and other ecological models of predator-prey interactions, is that in predator-prey cycles, peaks in prey abundance precede peaks in predator abundance. Such models typically assume that species life history traits are fixed over ecologically relevant time scales. However, the coevolution of predator and prey traits has been shown to alter the community dynamics of natural systems, leading to novel dynamics including antiphase and cryptic cycles. Here, using an eco-coevolutionary model, we show that predator prey coevolution can also drive population cycles where the opposite of canonical Lotka-Volterra oscillations occurs: predator peaks precede prey peaks. These reversed cycles arise when selection favors extreme phenotypes, predator offense is costly, and prey defense is effective against low-offense predators. We present multiple datasets from phage-cholera, mink-muskrat, and gyrfalcon-rock ptarmigan systems that exhibit reversed-peak ordering. Our results suggest that such cycles are a potential signature of predator-prey coevolution and reveal unique ways in which predator-prey coevolution can shape, and possibly reverse, community dynamics. PMID- 24799690 TI - Ultrasensitive detection of waste products in water using fluorescence emission cavity-enhanced spectroscopy. AB - Clean water is paramount to human health. In this article, we present a technique for detection of trace amounts of human or animal waste products in water using fluorescence emission cavity-enhanced spectroscopy. The detection of femtomolar concentrations of urobilin, a metabolic byproduct of heme metabolism that is excreted in both human and animal waste in water, was achieved through the use of an integrating cavity. This technique could allow for real-time assessment of water quality without the need for expensive laboratory equipment. PMID- 24799691 TI - The oligonucleotide/oligosaccharide-binding fold motif is a poly(ADP-ribose) binding domain that mediates DNA damage response. AB - Oligonucleotide/oligosaccharide-binding (OB) fold is a ssDNA or RNA binding motif in prokaryotes and eukaryotes. Unexpectedly, we found that the OB fold of human ssDNA-binding protein 1 (hSSB1) is a poly(ADP ribose) (PAR) binding domain. hSSB1 exhibits high-affinity binding to PAR and recognizes iso-ADP ribose (ADPR), the linkage between two ADPR units. This interaction between PAR and hSSB1 mediates the early recruitment of hSSB1 to the sites of DNA damage. Mutations in the OB fold of hSSB1 that disrupt PAR binding abolish the relocation of hSSB1 to the sites of DNA damage. Moreover, PAR-mediated recruitment of hSSB1 is important for early DNA damage repair. We have screened other OB folds and found that several other OB folds also recognize PAR. Taken together, our study reveals a PAR binding domain that mediates DNA damage repair. PMID- 24799692 TI - O-glycosylation regulates polarized secretion by modulating Tango1 stability. AB - Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases. PMID- 24799694 TI - Frizzled3 is required for the development of multiple axon tracts in the mouse central nervous system. AB - Targeted mutation of the Frizzled3 (Fz3) gene in mice has been shown to disrupt the growth and guidance of a subset of peripheral and central axons. Here we used conditional deletion of Fz3 to explore the forebrain territories in which Fz3 action is required for the development of the anterior commissure and the corticothalamic, corticospinal, and thalamocortical tracts. Experiments with region-specific deletion of Fz3 using a variety of Cre lines show that proper routing of corticothalamic and thalamocortical axons in the internal capsule requires Fz3 expression in the ventral telencephalon. The pattern of defects among forebrain axon tracts that are induced by conditional deletion of Fz3 conforms closely to the pattern previously observed with analogous conditional deletion of Celsr3, implying a close mechanistic link between Fz3 and Celsr3 in axon guidance. We further found that several central nervous system axon tracts require Fz3 function as early as embryonic day 11.5, and that Fz3 is required for pathfinding by dopaminergic and serotonergic axons in the brain and by a subset of optic tract axons. In addition, conditional deletion of Fz3 in all tissues caudal to the neck eliminates the spinothalamic tract and the transmission of somatosensory information from the spinal cord to the brain, as determined by neuroanatomic tracing and behavioral testing. PMID- 24799693 TI - Rich-club organization of the newborn human brain. AB - Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a "rich club"--a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich club organization remains intact following premature birth, we reveal significant disruptions in both in cortical-subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants. PMID- 24799695 TI - Antisense-mediated FLC transcriptional repression requires the P-TEFb transcription elongation factor. AB - The functional significance of noncoding transcripts is currently a major question in biology. We have been studying the function of a set of antisense transcripts called COOLAIR that encompass the whole transcription unit of the Arabidopsis floral repressor FLOWERING LOCUS C (FLC). Alternative polyadenylation of COOLAIR transcripts correlates with different FLC sense expression states. Suppressor mutagenesis aimed at understanding the importance of this sense antisense transcriptional circuitry has identified a role for Arabidopsis cyclin dependent kinase C (CDKC;2) in FLC repression. CDKC;2 functions in an Arabidopsis positive transcription elongation factor b (P-TEFb) complex and influences global RNA polymerase II (Pol II) Ser(2) phosphorylation levels. CDKC;2 activity directly promotes COOLAIR transcription but does not affect an FLC transgene missing the COOLAIR promoter. In the endogenous gene context, however, the reduction of COOLAIR transcription by cdkc;2 disrupts a COOLAIR-mediated repression mechanism that increases FLC expression. This disruption then feeds back to indirectly increase COOLAIR expression. This tight interconnection between sense and antisense transcription, together with differential promoter sensitivity to P-TEFb, is central to quantitative regulation of this important floral repressor gene. PMID- 24799696 TI - Governance, agricultural intensification, and land sparing in tropical South America. AB - In this paper we address two topical questions: How do the quality of governance and agricultural intensification impact on spatial expansion of agriculture? Which aspects of governance are more likely to ensure that agricultural intensification allows sparing land for nature? Using data from the Food and Agriculture Organization, the World Bank, the World Database on Protected Areas, and the Yale Center for Environmental Law and Policy, we estimate a panel data model for six South American countries and quantify the effects of major determinants of agricultural land expansion, including various dimensions of governance, over the period 1970-2006. The results indicate that the effect of agricultural intensification on agricultural expansion is conditional on the quality and type of governance. When considering conventional aspects of governance, agricultural intensification leads to an expansion of agricultural area when governance scores are high. When looking specifically at environmental aspects of governance, intensification leads to a spatial contraction of agriculture when governance scores are high, signaling a sustainable intensification process. PMID- 24799698 TI - Bet-hedging during bacterial diauxic shift. AB - When bacteria grow in a medium with two sugars, they first use the preferred sugar and only then start metabolizing the second one. After the first exponential growth phase, a short lag phase of nongrowth is observed, a period called the diauxie lag phase. It is commonly seen as a phase in which the bacteria prepare themselves to use the second sugar. Here we reveal that, in contrast to the established concept of metabolic adaptation in the lag phase, two stable cell types with alternative metabolic strategies emerge and coexist in a culture of the bacterium Lactococcus lactis. Only one of them continues to grow. The fraction of each metabolic phenotype depends on the level of catabolite repression and the metabolic state-dependent induction of stringent response, as well as on epigenetic cues. Furthermore, we show that the production of alternative metabolic phenotypes potentially entails a bet-hedging strategy. This study sheds new light on phenotypic heterogeneity during various lag phases occurring in microbiology and biotechnology and adjusts the generally accepted explanation of enzymatic adaptation proposed by Monod and shared by scientists for more than half a century. PMID- 24799697 TI - Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. AB - Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the key microbial functions influencing host energy metabolism and adiposity remain to be determined. Despite an increased understanding of the genetic content of the gastrointestinal microbiome, functional analyses of common microbial gene sets are required. We established a controlled expression system for the parallel functional analysis of microbial alleles in the murine gut. Using this approach we show that bacterial bile salt hydrolase (BSH) mediates a microbe-host dialogue that functionally regulates host lipid metabolism and plays a profound role in cholesterol metabolism and weight gain in the host. Expression of cloned BSH enzymes in the gastrointestinal tract of gnotobiotic or conventionally raised mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (Ppargamma, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIgamma), and circadian rhythm (Dbp, Per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in a significant reduction in host weight gain, plasma cholesterol, and liver triglycerides, demonstrating the overall impact of elevated BSH activity on host physiology. In addition, BSH activity in vivo varied according to BSH allele group, indicating that subtle differences in activity can have significant effects on the host. In summary, we demonstrate that bacterial BSH activity significantly impacts the systemic metabolic processes and adiposity in the host and represents a key mechanistic target for the control of obesity and hypercholesterolemia. PMID- 24799699 TI - Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection. AB - CD4 T cells are central to orchestrate, sustain, and potentially regenerate antiviral immunity throughout persistent viral infections. Although the evolving immune environment during persistent infection reshapes established CD4 T-cell responses, the fate of naive CD4 T cells primed in the midst of persistent infection is unclear. We demonstrate that, in marked contrast to the onset of infection, virus-specific CD4 T cells primed during an established persistent infection have diminished ability to develop Th1 responses, to efficiently accumulate in peripheral tissues, and almost exclusively differentiate into T follicular helper cells. Consistent with suppressed Th1 and heightened Tfh differentiation, virus-specific CD4 T cells primed during the established persistent infection provide help to B cells, but only limited help to CD8 T cells. The suppression of de novo Th1 generation and tissue distribution was mediated by chronic type I IFN (IFN-I) production and was effectively restored by blocking IFN-I signaling during CD4 T-cell priming. Thus, we establish a suppressive function of chronic IFN-I signaling and mechanism of immunoregulation during an established persistent virus infection. PMID- 24799702 TI - Explaining Asian Americans' academic advantage over whites. AB - The superior academic achievement of Asian Americans is a well-documented phenomenon that lacks a widely accepted explanation. Asian Americans' advantage in this respect has been attributed to three groups of factors: (i) socio demographic characteristics, (ii) cognitive ability, and (iii) academic effort as measured by characteristics such as attentiveness and work ethic. We combine data from two nationally representative cohort longitudinal surveys to compare Asian American and white students in their educational trajectories from kindergarten through high school. We find that the Asian-American educational advantage is attributable mainly to Asian students exerting greater academic effort and not to advantages in tested cognitive abilities or socio-demographics. We test explanations for the Asian-white gap in academic effort and find that the gap can be further attributed to (i) cultural differences in beliefs regarding the connection between effort and achievement and (ii) immigration status. Finally, we highlight the potential psychological and social costs associated with Asian American achievement success. PMID- 24799701 TI - Spatiotemporally different origins of NG2 progenitors produce cortical interneurons versus glia in the mammalian forebrain. AB - The studies on the exact lineage composition of NG2 expressing progenitors in the forebrain have been controversial. A number of studies have revealed the heterogeneous nature of postnatal NG2 cells. However, NG2 cells found in embryonic dates are far less understood. Our study indicates that early NG2 progenitors from a ventral origin (i.e., before embryonic day 16.5) tangentially migrate out of the medial ganglionic eminence and give rise to interneurons in deep layers of the dorsal cerebral cortex. The majority of myelinating oligodendrocytes found in both cortical gray and white matters are, in contrast, derived from NG2 progenitors with a neonatal subventricular zone origin. Our lineage tracing data reflect the heterogeneous nature of NG2 progenitor populations and define the relationship between lineage divergence and spatiotemporal origins. Beyond the typical lineage tracing studies of NG2(+) cells, by costaining with lineage-specific markers, our study addresses the origins of heterogeneity and its implications in the differentiation potentials of NG2(+) progenitors. PMID- 24799700 TI - Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-kappaB and MAPK signaling. AB - Toll-like receptor signaling and subsequent activation of NF-kappaB- and MAPK dependent genes during infection play an important role in antimicrobial host defense. The YopJ protein of pathogenic Yersinia species inhibits NF-kappaB and MAPK signaling, resulting in blockade of NF-kappaB-dependent cytokine production and target cell death. Nevertheless, Yersinia infection induces inflammatory responses in vivo. Moreover, increasing the extent of YopJ-dependent cytotoxicity induced by Yersinia pestis and Yersinia pseudotuberculosis paradoxically leads to decreased virulence in vivo, suggesting that cell death promotes anti-Yersinia host defense. However, the specific pathways responsible for YopJ-induced cell death and how this cell death mediates immune defense against Yersinia remain poorly defined. YopJ activity induces processing of multiple caspases, including caspase-1, independently of inflammasome components or the adaptor protein ASC. Unexpectedly, caspase-1 activation in response to the activity of YopJ required caspase-8, receptor-interacting serine/threonine kinase 1 (RIPK1), and Fas associated death domain (FADD), but not RIPK3. Furthermore, whereas RIPK3 deficiency did not affect YopJ-induced cell death or caspase-1 activation, deficiency of both RIPK3 and caspase-8 or FADD completely abrogated Yersinia induced cell death and caspase-1 activation. Mice lacking RIPK3 and caspase-8 in their hematopoietic compartment showed extreme susceptibility to Yersinia and were deficient in monocyte and neutrophil-derived production of proinflammatory cytokines. Our data demonstrate for the first time to our knowledge that RIPK1, FADD, and caspase-8 are required for YopJ-induced cell death and caspase-1 activation and suggest that caspase-8-mediated cell death overrides blockade of immune signaling by YopJ to promote anti-Yersinia immune defense. PMID- 24799703 TI - A 2,300-year-old architectural and astronomical complex in the Chincha Valley, Peru. AB - Recent archaeological research on the south coast of Peru discovered a Late Paracas (ca. 400-100 BCE) mound and geoglyph complex in the middle Chincha Valley. This complex consists of linear geoglyphs, circular rock features, ceremonial mounds, and settlements spread over a 40-km(2) area. A striking feature of this culturally modified landscape is that the geoglyph lines converge on mounds and habitation sites to form discrete clusters. Likewise, these clusters contain a number of paired line segments and at least two U-shaped structures that marked the setting sun of the June solstice in antiquity. Excavations in three mounds confirm that they were built in Late Paracas times. The Chincha complex therefore predates the better-known Nasca lines to the south by several centuries and provides insight into the development and use of geoglyphs and platform mounds in Paracas society. The data presented here indicate that Paracas peoples engineered a carefully structured, ritualized landscape to demarcate areas and times for key ritual and social activities. PMID- 24799704 TI - Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes. AB - Nonhuman proteins have valuable therapeutic properties, but their efficacy is limited by neutralizing antibodies. Recombinant immunotoxins (RITs) are potent anticancer agents that have produced many complete remissions in leukemia, but immunogenicity limits the number of doses that can be given to patients with normal immune systems. Using human cells, we identified eight helper T-cell epitopes in PE38, a portion of the bacterial protein Pseudomonas exotoxin A which consists of the toxin moiety of the RIT, and used this information to make LMB T18 in which three epitopes were deleted and five others diminished by point mutations in key residues. LMB-T18 has high cytotoxic and antitumor activity and is very resistant to thermal denaturation. The new immunotoxin has a 93% decrease in T-cell epitopes and should have improved efficacy in patients because more treatment cycles can be given. Furthermore, the deimmunized toxin can be used to make RITs targeting other antigens, and the approach we describe can be used to deimmunize other therapeutically useful nonhuman proteins. PMID- 24799706 TI - Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency. AB - Pigs with severe combined immunodeficiency (SCID) may provide useful models for regenerative medicine, xenotransplantation, and tumor development and will aid in developing therapies for human SCID patients. Using a reporter-guided transcription activator-like effector nuclease (TALEN) system, we generated targeted modifications of recombination activating gene (RAG) 2 in somatic cells at high efficiency, including some that affected both alleles. Somatic-cell nuclear transfer performed with the mutated cells produced pigs with RAG2 mutations without integrated exogenous DNA. Biallelically modified pigs either lacked a thymus or had one that was underdeveloped. Their splenic white pulp lacked B and T cells. Under a conventional housing environment, the biallelic RAG2 mutants manifested a "failure to thrive" phenotype, with signs of inflammation and apoptosis in the spleen compared with age-matched wild-type animals by the time they were 4 wk of age. Pigs raised in a clean environment were healthier and, following injection of human induced pluripotent stem cells (iPSCs), quickly developed mature teratomas representing all three germ layers. The pigs also tolerated grafts of allogeneic porcine trophoblast stem cells. These SCID pigs should have a variety of uses in transplantation biology. PMID- 24799707 TI - Intrasperm vertical symbiont transmission. AB - Symbiotic bacteria are commonly associated with cells and tissues of diverse animals and other organisms, which affect hosts' biology in a variety of ways. Most of these symbionts are present in the cytoplasm of host cells and maternally transmitted through host generations. The paucity of paternal symbiont transmission is likely relevant to the extremely streamlined sperm structure: the head consisting of condensed nucleus and the tail made of microtubule bundles, without the symbiont-harboring cytoplasm that is discarded in the process of spermatogenesis. Here, we report a previously unknown mechanism of paternal symbiont transmission via an intrasperm passage. In the leafhopper Nephotettix cincticeps, a facultative Rickettsia symbiont was found not only in the cytoplasm but also in the nucleus of host cells. In male insects, strikingly, most sperm heads contained multiple intranuclear Rickettsia cells. The Rickettsia infection scarcely affected the host fitness including normal sperm functioning. Mating experiments revealed both maternal and paternal transmission of the Rickettsia symbiont through host generations. When cultured with mosquito and silkworm cell lines, the Rickettsia symbiont was preferentially localized within the insect cell nuclei, indicating that the Rickettsia symbiont itself must have a mechanism for targeting nucleus. The mechanisms underlying the sperm head infection without disturbing sperm functioning are, although currently unknown, of both basic and applied interest. PMID- 24799708 TI - Variation in leaf flushing date influences autumnal senescence and next year's flushing date in two temperate tree species. AB - Recent temperature increases have elicited strong phenological shifts in temperate tree species, with subsequent effects on photosynthesis. Here, we assess the impact of advanced leaf flushing in a winter warming experiment on the current year's senescence and next year's leaf flushing dates in two common tree species: Quercus robur L. and Fagus sylvatica L. Results suggest that earlier leaf flushing translated into earlier senescence, thereby partially offsetting the lengthening of the growing season. Moreover, saplings that were warmed in winter-spring 2009-2010 still exhibited earlier leaf flushing in 2011, even though the saplings had been exposed to similar ambient conditions for almost 1 y. Interestingly, for both species similar trends were found in mature trees using a long-term series of phenological records gathered from various locations in Europe. We hypothesize that this long-term legacy effect is related to an advancement of the endormancy phase (chilling phase) in response to the earlier autumnal senescence. Given the importance of phenology in plant and ecosystem functioning, and the prediction of more frequent extremely warm winters, our observations and postulated underlying mechanisms should be tested in other species. PMID- 24799709 TI - Quenched disorder and vestigial nematicity in the pseudogap regime of the cuprates. AB - The cuprate high-temperature superconductors have been the focus of unprecedentedly intense and sustained study not only because of their high superconducting transition temperatures, but also because they represent the most exquisitely investigated examples of highly correlated electronic materials. In particular, the pseudogap regime of the phase diagram exhibits a variety of mysterious emergent behaviors. In the last few years, evidence from NMR and scanning tunneling microscopy (STM) studies, as well as from a new generation of X-ray scattering experiments, has accumulated, indicating that a general tendency to short-range-correlated incommensurate charge density wave (CDW) order is "intertwined" with the superconductivity in this regime. Additionally, transport, STM, neutron-scattering, and optical experiments have produced evidence--not yet entirely understood--of the existence of an associated pattern of long-range ordered point-group symmetry breaking with an electron-nematic character. We have carried out a theoretical analysis of the Landau-Ginzburg-Wilson effective field theory of a classical incommensurate CDW in the presence of weak quenched disorder. Although the possibilities of a sharp phase transition and long-range CDW order are precluded in such systems, we show that any discrete symmetry breaking aspect of the charge order--nematicity in the case of the unidirectional (stripe) CDW we consider explicitly--generically survives up to a nonzero critical disorder strength. Such "vestigial order," which is subject to unambiguous macroscopic detection, can serve as an avatar of what would be CDW order in the ideal, zero disorder limit. Various recent experiments in the pseudogap regime of the hole-doped cuprates are readily interpreted in light of these results. PMID- 24799710 TI - Basal NF-kappaB controls IL-7 responsiveness of quiescent naive T cells. AB - T cells are essential for immune defenses against pathogens, such that viability of naive T cells before antigen encounter is critical to preserve a polyclonal repertoire and prevent immunodeficiencies. The viability of naive T cells before antigen recognition is ensured by IL-7, which drives expression of the prosurvival factor Bcl-2. Quiescent naive T cells have low basal activity of the transcription factor NF-kappaB, which was assumed to have no functional consequences. In contrast to this postulate, our data show that basal nuclear NF kappaB activity plays an important role in the transcription of IL-7 receptor alpha-subunit (CD127), enabling responsiveness of naive T cells to the prosurvival effects of IL-7 and allowing T-cell persistence in vivo. Moreover, we show that this property of basal NF-kappaB activity is shared by mouse and human naive T cells. Thus, NF-kappaB drives a distinct transcriptional program in T cells before antigen encounter by controlling susceptibility to IL-7. Our results reveal an evolutionarily conserved role of NF-kappaB in T cells before antigenic stimulation and identify a novel molecular pathway that controls T-cell homeostasis. PMID- 24799711 TI - Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome. AB - The mammalian mitochondrial ribosomes (mitoribosomes) are responsible for synthesizing 13 membrane proteins that form essential components of the complexes involved in oxidative phosphorylation or ATP generation for the eukaryotic cell. The mammalian 55S mitoribosome contains significantly smaller rRNAs and a large mass of mitochondrial ribosomal proteins (MRPs), including large mito-specific amino acid extensions and insertions in MRPs that are homologous to bacterial ribosomal proteins and an additional 35 mito-specific MRPs. Here we present the cryo-EM structure analysis of the small (28S) subunit (SSU) of the 55S mitoribosome. We find that the mito-specific extensions in homologous MRPs generally are involved in inter-MRP contacts and in contacts with mito-specific MRPs, suggesting a stepwise evolution of the current architecture of the mitoribosome. Although most of the mito-specific MRPs and extensions of homologous MRPs are situated on the peripheral regions, they also contribute significantly to the formation of linings of the mRNA and tRNA paths, suggesting a tailor-made structural organization of the mito-SSU for the recruitment of mito specific mRNAs, most of which do not possess a 5' leader sequence. In addition, docking of previously published coordinates of the large (39S) subunit (LSU) into the cryo-EM map of the 55S mitoribosome reveals that mito-specific MRPs of both the SSU and LSU are involved directly in the formation of six of the 15 intersubunit bridges. PMID- 24799712 TI - Genome-wide high-resolution mapping of chromosome fragile sites in Saccharomyces cerevisiae. AB - In mammalian cells, perturbations in DNA replication result in chromosome breaks in regions termed "fragile sites." Using DNA microarrays, we mapped recombination events and chromosome rearrangements induced by reduced levels of the replicative DNA polymerase-alpha in the yeast Saccharomyces cerevisiae. We found that the recombination events were nonrandomly associated with a number of structural/sequence motifs that correlate with paused DNA replication forks, including replication-termination sites (TER sites) and binding sites for the helicase Rrm3p. The pattern of gene-conversion events associated with cross-overs suggests that most of the DNA lesions that initiate recombination between homologs are double-stranded DNA breaks induced during S or G2 of the cell cycle, in contrast to spontaneous recombination events that are initiated by double stranded DNA breaks formed prior to replication. Low levels of DNA polymerase alpha also induced very high rates of aneuploidy, as well as chromosome deletions and duplications. Most of the deletions and duplications had Ty retrotransposons at their breakpoints. PMID- 24799714 TI - Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism. AB - The dendritic arbors of the larval Drosophila peripheral class IV dendritic arborization neurons degenerate during metamorphosis in an ecdysone-dependent manner. This process-also known as dendrite pruning-depends on the ubiquitin proteasome system (UPS), but the specific processes regulated by the UPS during pruning have been largely elusive. Here, we show that mutation or inhibition of Valosin-Containing Protein (VCP), a ubiquitin-dependent ATPase whose human homolog is linked to neurodegenerative disease, leads to specific defects in mRNA metabolism and that this role of VCP is linked to dendrite pruning. Specifically, we find that VCP inhibition causes an altered splicing pattern of the large pruning gene molecule interacting with CasL and mislocalization of the Drosophila homolog of the human RNA-binding protein TAR-DNA-binding protein of 43 kilo Dalton (TDP-43). Our data suggest that VCP inactivation might lead to specific gain-of-function of TDP-43 and other RNA-binding proteins. A similar combination of defects is also seen in a mutant in the ubiquitin-conjugating enzyme ubcD1 and a mutant in the 19S regulatory particle of the proteasome, but not in a 20S proteasome mutant. Thus, our results highlight a proteolysis-independent function of the UPS during class IV dendritic arborization neuron dendrite pruning and link the UPS to the control of mRNA metabolism. PMID- 24799716 TI - Mutation of mouse Samd4 causes leanness, myopathy, uncoupled mitochondrial respiration, and dysregulated mTORC1 signaling. AB - Sterile alpha motif domain containing protein 4 (Samd4) is an RNA binding protein that mediates translational repression. We identified a Samd4 missense mutation, designated supermodel, that caused leanness and kyphosis associated with myopathy and adipocyte defects in C57BL/6J mice. The supermodel mutation protected homozygous mice from high fat diet-induced obesity, likely by promoting enhanced energy expenditure through uncoupled mitochondrial respiration. Glucose tolerance was impaired due to diminished insulin release in homozygous mutant mice. The defects of metabolism in supermodel mice may be explained by dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling, evidenced by hypophosphorylation of 4E-BP1 and S6 in muscle and adipose tissues of homozygous mice. Samd4 may interface with mTORC1 signaling through an interaction with 14-3 3 proteins and with Akt, which phosphorylates Samd4 in vitro. PMID- 24799718 TI - Marriage of individual pharmacists' achievement on key performance indicators and teaching responsibilities. PMID- 24799715 TI - Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. AB - Circulating cell-free RNA in the blood provides a potential window into the health, phenotype, and developmental programs of a variety of human organs. We used high-throughput methods of RNA analysis such as microarrays and next generation sequencing to characterize the global landscape circulating RNA in a cohort of human subjects. By focusing on genes whose expression is highly specific to certain tissues, we were able to identify the relative contributions of these tissues to circulating RNA and to monitor changes in tissue development and health. As one application of this approach, we performed a longitudinal study on pregnant women and analyzed their combined cell-free RNA transcriptomes across all three trimesters of pregnancy and after delivery. In addition to the analysis of mRNA, we observed and characterized noncoding species such as long noncoding RNA and circular RNA transcripts whose presence had not been previously observed in human plasma. We demonstrate that it is possible to track specific longitudinal phenotypic changes in both the mother and the fetus and that it is possible to directly measure transcripts from a variety of fetal tissues in the maternal blood sample. We also studied the role of neuron-specific transcripts in the blood of healthy adults and those suffering from the neurodegenerative disorder Alzheimer's disease and showed that disease specific neural transcripts are present at increased levels in the blood of affected individuals. Characterization of the cell-free transcriptome in its entirety may thus provide broad insights into human health and development without the need for invasive tissue sampling. PMID- 24799719 TI - Stability of Bortezomib 2.5 mg/mL in Vials and Syringes Stored at 4 degrees C and Room Temperature (23 degrees C). AB - BACKGROUND: Solutions of bortezomib 1.0 mg/mL for IV administration are reportedly stable for up to 42 days. Recent publications have reported that the safety profile of bortezomib is better with subcutaneous administration than with IV administration. OBJECTIVE: To evaluate the stability of higher-concentration bortezomib solutions for subcutaneous administration (i.e., 2.5 mg/mL in 0.9% sodium chloride [normal saline or NS]). METHODS: On study day 0, twelve 3.5-mg vials of powdered bortezomib were each reconstituted with 1.4 mL of NS to prepare solutions with concentration 2.5 mg/mL. Half of the solutions were subsequently stored in the original vials and half were transferred to syringes. Three of each type of container were stored in the refrigerator (4 degrees C) and the other 3 of each type were stored at room temperature (23 degrees C). Concentration analysis and physical inspection were completed on study days 0, 1, 2, 8, 12, 14, 19, and 21. The concentration of bortezomib was determined by a validated liquid chromatographic method with ultraviolet detection. The expiry date was determined according to the time to achieve 90% of the initial concentration, based on the fastest degradation rate calculated from the 95% confidence interval of the observed degradation rate. RESULTS: The analytical method separated degradation products from bortezomib such that the concentration was measured specifically and accurately (with absolute deviations from known concentration averaging 2.99%), with intraday and interday reproducibility averaging 1.51% and 2.51%, respectively. During the study period, all solutions were observed to retain at least 95.26% of the initial concentration in both types of containers at both temperatures. CONCLUSIONS: Bortezomib (3.5 mg in manufacturer's vial) reconstituted with 1.4 mL NS is physically and chemically stable for up to 21 days at 4 degrees C or 23 degrees C when stored in either the manufacturer's original glass vial or a syringe. Subcutaneous injection of bortezomib represents a change in practice, and there is a potential safety concern if a solution of the increased concentration used for subcutaneous administration (2.5 mg/mL) is inadvertently used to prepare a dose intended for IV administration. Therefore, it is recommended that sites switching to subcutaneous administration of bortezomib eliminate 1.0 mg/mL IV solutions altogether or institute substantial barriers to prevent IV administration of the higher concentration of bortezomib. PMID- 24799717 TI - Histone variant H3.3 is an essential maternal factor for oocyte reprogramming. AB - Mature oocyte cytoplasm can reprogram somatic cell nuclei to the pluripotent state through a series of sequential events including protein exchange between the donor nucleus and ooplasm, chromatin remodeling, and pluripotency gene reactivation. Maternal factors that are responsible for this reprogramming process remain largely unidentified. Here, we demonstrate that knockdown of histone variant H3.3 in mouse oocytes results in compromised reprogramming and down-regulation of key pluripotency genes; and this compromised reprogramming for developmental potentials and transcription of pluripotency genes can be rescued by injecting exogenous H3.3 mRNA, but not H3.2 mRNA, into oocytes in somatic cell nuclear transfer embryos. We show that maternal H3.3, and not H3.3 in the donor nucleus, is essential for successful reprogramming of somatic cell nucleus into the pluripotent state. Furthermore, H3.3 is involved in this reprogramming process by remodeling the donor nuclear chromatin through replacement of donor nucleus-derived H3 with de novo synthesized maternal H3.3 protein. Our study shows that H3.3 is a crucial maternal factor for oocyte reprogramming and provides a practical model to directly dissect the oocyte for its reprogramming capacity. PMID- 24799720 TI - Conformity with Optimal Drug-Use Processes: Comparison between the Accreditation Canada Managing Medications Standards and the Hospital Pharmacy in Canada Report. AB - BACKGROUND: A recent symposium on change management highlighted the relatively slow pace of change in the drug-use process. This study was undertaken to determine the degree of concordance between different sources that document levels of conformity with optimal drug-use processes. OBJECTIVE: The primary objective was to compare aggregate national results from the Managing Medications Standards (MMS) of Accreditation Canada and results from the biennial Hospital Pharmacy in Canada survey. The secondary objective was to discuss any significant discrepancies between the 2 sources. METHODS: In this retrospective cross sectional study, attempts were made to pair each Accreditation Canada MMS criterion with specific results from the Hospital Pharmacy in Canada 2009/2010 Report. Average conformity per criterion from the 2010 Accreditation Canada on site surveys was compared with conformity as documented in the Hospital Pharmacy in Canada 2009/2010 Report. A discrepancy ratio was calculated for each criterion, with ratios less than 0.80 or greater than 1.20 being considered significant. RESULTS: Overall, 82 (61%) of 134 MMS criteria could be paired with results from the 2009/2010 Hospital Pharmacy in Canada survey. The average calculated discrepancy ratio (+/- standard deviation) between the 2 sets of results was 0.62 +/- 0.29 (range 0.05 to 1.19). The average discrepancy ratios by domain were as follows: 0.49 for safely administering medications, 0.58 for accurately preparing and dispensing medications, 0.61 for working together to promote medication safety, 0.62 for carefully selecting and procuring medications, 0.69 for monitoring quality and achieving positive results, 0.71 for appropriately ordering medications and transcribing medication orders, and 0.76 for properly labelling and storing medications. For 59 criteria, there was a significant discrepancy between the 2010 MMS on-site surveys and the 2009/2010 Hospital Pharmacy in Canada survey. CONCLUSION: Nearly two-thirds of the MMS criteria could be paired with results from the Hospital Pharmacy in Canada survey, but the average discrepancy ratio of 0.62 indicates substantial discrepancies in the data collected by these 2 methods. Further studies are required to explore the reasons for such discrepancies. PMID- 24799721 TI - Urinary Tract Infections: Leading Initiatives in Selecting Empiric Outpatient Treatment (UTILISE). AB - BACKGROUND: Overuse of fluoroquinolone antibiotics is associated with outbreaks of methicillin-resistant Staphylococcus aureus and of Clostridium difficile associated diarrhea and increasing resistance in gram-negative organisms. Over the past decade, resistance of Escherichia coli to ciprofloxacin has increased in the Regina Qu'Appelle Health Region. In August 2011, an exploratory audit of the Regina General Hospital (RGH) emergency department showed that 20% of new antibiotic orders were for fluoroquinolones, and 60% of these new fluoroquinolone orders were for ciprofloxacin. It was postulated that ciprofloxacin was predominantly prescribed for outpatients with urinary tract infection. OBJECTIVE: To develop, implement, and evaluate a best-practice algorithm for the empiric treatment of uncomplicated urinary tract infection in the RGH emergency department, as part of an educational initiative for emergency physicians. METHODS: A literature review was conducted and local antibiogram data were analyzed to establish a best-practice algorithm for treatment of uncomplicated urinary tract infection in outpatients seen in the emergency department. A chart review was conducted from January to March 2011 to establish a baseline of empiric antibiotic use. An educational strategy targeting emergency physicians described changes in antibiotic resistance patterns in the health region, principles of antimicrobial stewardship, drivers of resistance, and the results of a literature review of best practice for urinary tract infection in outpatients. A post-intervention audit was conducted from January to March 2012 to determine changes in practice. RESULTS: Comparison of results from the post intervention audit with baseline data showed that adherence to best practice increased significantly, from 41% (39/96) before the intervention to 66% (50/76) after the intervention (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.51 5.25; p < 0.001). There was also a significant change in overall antibiotic selection (OR 0.25, 95% CI 0.11-0.58; p < 0.001). Further analysis suggested that this significant change was driven by a decrease in use of ciprofloxacin, from 32% (31/96) to 11% (8/76). CONCLUSION: Creation of a best-practice algorithm and education focused on emergency physicians significantly increased adherence to best practice and optimized antibiotic prescribing for outpatients with uncomplicated urinary tract infection by limiting overuse of fluoroquinolones, primarily ciprofloxacin. PMID- 24799722 TI - Identification of risk factors for nephrotoxicity in patients receiving extended duration, high-trough vancomycin therapy. AB - BACKGROUND: In the past, impurities in vancomycin formulations were thought to contribute to nephrotoxicity. In contrast, when current, purer formulations are dosed at conventional trough levels (i.e., 5-15 mg/L), the incidence of nephrotoxicity is relatively low. Recent guidelines have recommended targeting higher vancomycin trough levels in treatment of complicated methicillin-resistant Staphylococcus aureus infections. Dosing based on these higher trough levels may be associated with nephrotoxicity, so the potential risk factors for vancomycin associated nephrotoxicity require clearer definition. OBJECTIVES: To determine the occurrence of nephrotoxicity in patients receiving more than 7 days of vancomycin therapy with high trough levels (15-20 mg/L) and to identify and evaluate specific risk factors related to development of vancomycin-associated nephrotoxicity (i.e., serum creatinine >= 44.2 MUmol/L or increase >= 50% [i.e., >= 26.2 MUmol/L] from baseline on 2 consecutive days). METHODS: Health care records were reviewed for patients seen at 2 major teaching hospitals between January 2008 and March 2011. Patients who had attained high trough levels of vancomycin were screened for eligibility. Patients with unstable renal function, those undergoing hemodialysis, and those for whom dosage and/or sampling times were unclear were excluded. Univariate and multivariate analyses were performed to identify risk factors associated with nephrotoxicity. Univariate variables with p < 0.1 were included in the logistic regression model. RESULTS: Of the 176 patients with high trough levels included in the analysis, 24 (14%) experienced nephrotoxicity. In univariate analysis, admission to a general medicine unit (the setting of care for 16 [67%] of the 24 patients with nephrotoxicity) and extended duration of vancomycin treatment were identified as risk factors for nephrotoxicity (p < 0.1). Other risk factors included gastrointestinal comorbidity (p = 0.056), malignancy (p = 0.044), and febrile neutropenia (p = 0.032). Multivariate analysis identified treatment on general medicine units and treatment courses longer than 7 days as independent predictors of vancomycin associated nephrotoxicity. CONCLUSION: Patients being treated on general medicine units and those receiving vancomycin for more than 7 days had an increased likelihood of experiencing nephrotoxicity. The increased risk for patients on general medicine units is likely multifactorial. The relationship between treatment duration and risk of nephrotoxicity appeared to be linear. When using extended-duration, high-trough vancomycin therapy, clinicians should be vigilant in monitoring for nephrotoxicity. PMID- 24799723 TI - Ethical issues in pharmacy practice research: an introductory guide. PMID- 24799724 TI - Decentralized automated dispensing devices: systematic review of clinical and economic impacts in hospitals. AB - BACKGROUND: Technologies have been developed over the past 20 years to automate the stages of drug distribution in hospitals, including ordering, dispensing, delivery, and administration of medications, in attempts to decrease medication error rates. Decentralized automated dispensing devices (ADDs) represent one such technology that is being adopted by hospitals across Canada, but the touted benefits, in terms of improved patient safety and cost savings, are increasingly being questioned. OBJECTIVE: To summarize and evaluate the existing literature reporting the clinical and economic impacts of using decentralized ADDs in hospitals. DATA SOURCES: A literature search was conducted in MEDLINE, Embase, and all evidence-based medicine databases for the years 1992 to 2012 to identify English-language articles reporting on the use of ADDs in hospital wards. STUDY SELECTION AND DATA EXTRACTION: All randomized controlled trials, observational studies, before-and-after studies, time series analyses, cost-effectiveness and cost-benefit analyses, and review articles were considered for inclusion. Studies evaluating pharmacy-based ADDs, such as bar code-based medication dispensing carousels, automated dispensing shelves, and combinations of various dispensing modalities, were excluded. DATA SYNTHESIS: Of 175 studies initially identified, 8 were retained for evidence synthesis. It appears that ADDs were effective in reducing medication storage errors and the time that nurses spent taking inventory of narcotics and controlled substances. There was no definitive evidence that using ADDs increased the time that nurses or pharmacists spent with patients, reduced medication errors resulting in patient harm, or reduced costs in Canadian hospitals. However, pharmacy technicians spent more time stocking the machines. CONCLUSION: ADDs have limited potential to decrease medication errors and increase efficiencies, but their impact is highly institution-specific, and use of this technology requires proper integration into an institution's medication distribution process. Before deploying this technology, it is recommended that Canadian hospitals carefully examine their current systems and the benefits they hope to gain with the changes. PMID- 24799725 TI - Use of methadone for opioid weaning in children: prescribing practices and trends. PMID- 24799726 TI - Intermittent intraperitoneal administration of magnesium sulphate in an elderly patient undergoing dialysis. PMID- 24799727 TI - Possible Incompatibility between Amino Acids and Copper in Solutions for Pediatric Parenteral Nutrition. PMID- 24799728 TI - Should key performance indicators be a component of performance assessment for individual clinical pharmacists? PMID- 24799729 TI - [Not Available]. PMID- 24799730 TI - [Not Available]. PMID- 24799731 TI - A vision of pharmacy practice excellence. PMID- 24799732 TI - Editor's Note. PMID- 24799733 TI - Reasons for low quality of life in South Indian cancer patient population: a prospective observational study. AB - Over the last decade, quality of life investigations of cancer patients' have became a critical evaluation parameter in the clinical cancer research and treatment evaluation programs. This study was carried out in a 1200 bed tertiary care teaching hospital, MGM Hospital, located at Warangal, India. Present study assessed the overall quality of life, symptoms of patients affected by breast, head and neck, cervical and stomach cancers by using guidelines and modules of The European Organisation for Research and Treatment of Cancer. The assessment was carried out in two phases, as review I at <=2 cycles and review II at >=5 cycles of treatment. Data were analyzed for 104 individuals with the mean age of 46.1+/-11.2 years. The evaluation was characterised as functional scale and symptom scale. In the functional scale physical, and role functions were significant (P<0.05) in all the 4 types of cancers studied. Additional, future perspective, social and emotional functions were observed to be significant in breast cancer, head and neck cancer and cervical cancer, respectively. Where as in symptom scale pain was observed to be significant for all cancers studied. Individually, breast cancer patient also showed significant parameters like fatigue, arm symptoms, and upset by hair loss. Head and neck cancer patients had insomnia and diarrhoea as additional significant symptom scale parameters. In cervical cancer patients, fatigue, insomnia, menopausal symptoms, and in stomach cancer patients, nausea and vomiting, dysphagia, reflex symptoms and eating restrictions were significantly affected. Most of the findings are similar to past studies in the respective type of cancer patients which shows that, quality of life was mostly influenced by the above mentioned factors and have some interesting implications for management and treatment of cancer. PMID- 24799734 TI - In Silico Analysis to Compare the Effectiveness of Assorted Drugs Prescribed for Swine flu in Diverse Medicine Systems. AB - The genome of the virus H1N1 2009 consists of eight segments but maximum number of mutations occurs at segments 1 and 4, coding for PB2 subunit of hemagglutinin. Comparatively less number of mutations occur at segment 6, coding for neuraminidase. Two antiviral drugs, oseltamivir and zanamivir are commonly prescribed for treating H1N1 infection. Alternate medical systems do compete equally; andrographolide in Siddha and gelsemine in Homeopathy. Recent studies confirm the efficacy of eugenol from Tulsi and vitamins C and E against H1N1. As the protein structures are unavailable, we modeled them using Modeller by identifying suitable templates, 1RUY and 3BEQ, for hemagglutinin and neuraminidase, respectively. Prior to docking simulations using AutoDock, the drug likeness properties of the ligands were screened using in silico techniques. Docking results showed interaction between the proteins individually into selected ligands, except for gelsemine and vitamin E no interactions were shown. The best docking simulation was reported by vitamin C interacting through six hydrogen bonds into proteins hemagglutinin and neuraminidase with binding energies -4.28 and -4.56 kcal/mol, respectively. Furthermore, vitamin C showed hydrophobic interactions with both proteins, two bonds with Arg119, Glu120 of HA, and one bond with Arg74 of NA. In silico docking studies thus recommend vitamin C to be more effective against H1N1. PMID- 24799735 TI - Simultaneous HPLC determination of 22 components of essential oils; method robustness with experimental design. AB - The aim of the present study was the development and validation of a simple, precise and specific reversed phase HPLC method for the simultaneous determination of 22 components present in different essential oils namely cinnamon bark oil, caraway oil and cardamom fruit oil. The chromatographic separation of all the components was achieved on Wakosil-II C18 column with mixture of 30 mM ammonium acetate buffer (pH 4.7), methanol and acetonitrile in different ratio as mobile phase in a ternary linear gradient mode. The calibration graphs plotted with five different concentrations of each component were linear with a regression coefficient R(2) >0.999. The limit of detection and limit of quantitation were estimated for all the components. Effect on analytical responses by small and deliberate variation of critical factors was examined by robustness testing with Design of Experiment employing Central Composite Design and established that this method was robust. The method was then validated for linearity, precision, accuracy, specificity and demonstrated to be applicable to the determination of the ingredients in commercial sample of essential oil. PMID- 24799736 TI - Validated HPLC determination of 4-dimethylaminoantipyrine in different suppository bases. AB - Suppositories are important tools for individual therapy, especially in paediatrics, and an instrumental assay method has become necessary for the quality control of dosage units. The aim of this work was to develop a rapid, effective high-performance liquid chromatography method to assay aminophenazone in extemporaneous suppositories prepared with two different suppository bases, adeps solidus and massa macrogoli. With a novel sample preparation method developed by the authors, 4-dimethylaminoantipyrine was determined in these suppository bases with 95-105% recovery. The measurements were carried out on a Shimadzu Prominence ultra high-performance liquid chromatography system equipped with a 20 MUl sample loop. The separation was achieved on a Hypersil ODS column, with methanol, sodium acetate buffer (pH 5.5+/-0.05, 0.05 M, 60:40, v/v) as the mobile phase at a flow rate of 1.5 ml/min. The chromatograms were acquired at 253 nm. The chromatographic method was fully validated in accordance with current guidelines. The presented data demonstrate the successful development of a rapid, efficient and robust sample preparation and high-performance liquid chromatography method for the routine quality control of the dosage units of suppositories containing 4-dimethylaminoantipyrine. PMID- 24799738 TI - Comparison of Conventional and Microwave-assisted Synthesis of Benzotriazole Derivatives. AB - A green chemistry approach for organic synthesis is described here, which involves microwave exposure of reactants in presence or absence of solvents. A novel and simple method has been developed for the synthesis of some benzotriazole derivatives under microwave irradiation. In addition, these compounds were synthesised also by conventional heating procedures for comparison. All the compounds synthesised were characterised by melting point, TLC, IR and (1)H NMR spectroscopy. Comparison between conventional and microwave assisted synthesis was done by comparing total reaction time and percentage yield. The results suggest that microwave-assisted syntheses lead to higher yields within very short reaction times. On antifungal evaluation by cup plate method, all compounds showed antifungal activity. One compound showed activity similar to and two compounds showed better activity than standard antifungal drug flucanazole. PMID- 24799737 TI - Scientific Insights in the Preparation and Characterisation of a Lead-based Naga Bhasma. AB - Naga bhasma is one of the herbo-metallic preparations used in Ayurveda, a traditional Indian System of Medicine. The preparation of Naga bhasma involves thermal treatment of 'Naga' (metallic lead) in a series of quenching liquids, followed by reaction with realgar and herbal constituents, before calcination to prepare a fine product. We have analysed the intermediates obtained during different stages of preparation to understand the relevance and importance of different steps involved in the preparation. Our results show that 'Sodhana' (purification process) removes heavy metals other than lead, apart from making it soft and amenable for trituration. The use of powders of tamarind bark and peepal bark maintains the oxidation state of lead in Jarita Naga (lead oxide) as Pb(2+). The repeated calcination steps result in the formation of nano-crystalline lead sulphide, the main chemical species present in Naga bhasma. PMID- 24799739 TI - Evaluation of nanodispersion of iron oxides using various polymers. AB - In order to create Fe2O3 and Fe2O3.H2O nanoparticles, various polymers were used as dispersing agents, and the resulting effects on the dispersibility and nanoparticulation of the iron oxides were evaluated. It was revealed that not only the solution viscosity but also the molecular length of the polymers and the surface tension of the particles affected the dispersibility of Fe2O3 and Fe2O3.H2O particles. Using the dispersing agents 7.5% hydroxypropylcellulose-SSL, 6.0% Pharmacoat 603, 5.0% and 6.5% Pharmacoat 904 and 7.0% Metolose SM-4, Fe2O3 nanoparticles were successfully fabricated by wet milling using Ultra Apex Mill. Fe2O3.H2O nanoparticles could also be produced using 5.0% hydroxypropylcellulose SSL and 4.0 and 7.0% Pharmacoat 904. The index for dispersibility developed in this study appears to be an effective indicator of success in fabricating nanoparticles of iron oxides by wet milling using Ultra Apex Mill. PMID- 24799740 TI - Preparation and characterisation of nevirapine oral nanosuspensions. AB - The objective of this study was to prepare and characterise nevirapine nanosuspensions so as to improve the dissolution rate of nevirapine. Nevirapine is a nonnucleoside reverse transcriptase inhibitor of immunodeficiency virus type 1 and it is poorly water-soluble antiretroviral drug. The low solubility of nevirapine can lead to decreased and variable oral bioavailability. Nanosuspension can overcome the oral bioavailability problem of nevirapine. Nevirapine nanosuspensions were prepared using nanoedge method. The suspensions were stabilised using surfactants Lutrol F 127 or Poloxamer 407 and hydroxypropyl methyl cellulose. The nanosuspension was characterised for particle size, polydispersibility index, crystalline state, particle morphology, in vitro drug release and pharmacokinetics in rats after oral administration. The results support the claim for the preparation of nanosuspensions with enhanced solubility and bioavailability. PMID- 24799741 TI - Investigating the Role of Plasma Glucose Concentration as a Phenotypic Marker for CYP2C9 Genetic Variants, in the Diabetic Population of Gujarat. AB - The present study was aimed to investigate the role of plasma glucose concentration as a phenotypic marker and to study the frequency distribution of CYP2C9 genetic variants in Gujarat state diabetic population. One hundred and nine unrelated diabetes mellitus patients treated with sulfonylureas were genotyped for CYP2C9*2 and CYP2C9*3 alleles. Their pre- and posttreatment postprandial blood glucose levels were recorded and mean glucose drop per milligram of drug values were calculated and further used as an index for phenotypic correlation. The frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 alleles in the Gujarat state diabetic population were 0.84, 0.07 and 0.09, respectively. The distribution of CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes were 0.73, 0.08, 0.13, 0.0, 0.06 and 0.0, respectively. Patients with CYP2C9*1/*2 genotype did not show any significant difference in the mean glucose drop per milligram of drug values when compared with wild-type patients in glipizide-treatment group. Patients with CYP2C9*1/*3 genotype showed greater mean glucose drop per milligram of drug values than patients with CYP2C9*1/*1 wild-type genotype for both glipizide and glimepiride while patients with CYP2C9*2/*3 genotype showed greater drop than patients with CYP2C9*1/*1 genotype only in the glipizide-treatment group. The presence of CYP2C9*3 allele significantly affected plasma glucose drop per milligram of drug values in patients taking glipizide and glimepiride, while effects of CYP2C9*2 allele were insignificant. Further studies are needed to confirm the effects of CYP2C9*2 allele on plasma glucose drop per milligram of drug values. However, plasma glucose concentration is a complex physiological marker that cannot be used to establish perfect genotype-phenotype correlation. Hence studies exploring robust phenotypic markers must be initiated. PMID- 24799742 TI - Identification of a Proteinaceous Component in the Leaf of Moringa Oleifera lam. with Effects on High Serum Creatinine. AB - Moringa oleifera Lam. has been an important plant in the history of mankind, both for its nutritional and medicinal uses. Apart from bactericidal effects, the parts of this plant have been effectively used in the treatment of circulatory, respiratory, endocrine, digestive as well as neural disorders. Till date, though, there has been no reported activity of the involvement of any proteinaceous extract from M. oleifera on high levels of serum creatinine. To address this issue, blood samples with high levels of serum creatinine (2 mg/dl and above) were treated with leaf extract from M. oleifera. The crude extract was partially purified initially and eventually purified to completion as well. All these proteinaceous fractions were used to treat samples with high levels of serum creatinine as mentioned above. While the treatment of serum sample having high creatinine with crude extract and partially purified protein fractions showed a decrease of approximately 20% in the levels of serum creatinine over a period of 24 h, the samples treated with purified protein fraction reduced the serum creatinine level by 50%. In light of the fact that increased level of serum creatinine levels have adverse downstream effects on the heart, lungs and other organs, this communication assumes significance because it suggests a way of reducing the level of serum creatinine as an emergency measure. Further, the identification and characterisation of this proteinaceous component and possible in vivo experiments would provide a major tool for the treatment of downstream complications associated with increased serum creatinine via a new sources, albeit a natural one. PMID- 24799743 TI - Pharmacokinetics of vancomycin in oncology egyptian paediatrics: a dosage adjustment trial. AB - The purpose of this study is to determine the pharmacokinetic parameters of vancomycin in Egyptian paediatric oncology patients and to evaluate the factors that influence the variability of the pharmacokinetic parameters in this population. Vancomycin serum concentration at steady state was determined in 51 paediatric cancer patients who were treated with vancomycin multiple intravenous infusions. Also individual vancomycin pharmacokinetic parameters were calculated assuming one compartment model. The mean vancomycin total body clearance and mean vancomycin volume of distribution were significantly higher among the age range of 2 to <12 years as compared with older age. Obese patients showed significant lower values of peak and trough vancomycin concentrations than those of normal and underweight patients. A significant correlation was found between the estimated creatinine clearance (Schwartz formula) and vancomycin total body clearance in the studied patients. Also, a significant direct correlation between vancomycin volume of distribution and ratio between blood urea nitrogen (mg/dl)/weight (kg) was found. As a conclusion, age and obesity were identified as the most important factors influencing vancomycin total body clearance, volume of distribution and serum concentrations in the studied patients. PMID- 24799744 TI - Potential of ozonated sesame oil to augment wound healing in rats. AB - The hypothesis that ozonated oil has wound healing property was investigated in an excision wound model using Sprague Dawley rats. The animals were divided into four groups, which were treated with sesame oil (vehicle), framycetin (standard), or two doses of ozonated sesame oil (peroxide values 500 and 700 mEq/1000 g, respectively). The formulations were topically applied on the excision wounds once daily for 11 consecutive days and the animals were euthanized on the 12(th) day. Wound healing was assessed by measuring the wound contracture, tensile strength, collagen content and superoxide dismutase activity of skin of the excised wound area. On the terminal day, areas of the wounds of the group receiving high dose ozonated oil were significantly smaller than those of the group treated with vehicle. Ozonated oil treated wounds had significantly higher tensile strength, collagen content and superoxide dismutase activity than that of the vehicle treated wounds. Histopathological analysis of skin of the excised wound area treated with ozonated oil revealed better healing activity vis-a-vis vehicle-treated wounds. Thus, it can be concluded that ozonated oil can be of potential therapeutic use for healing wounds. PMID- 24799746 TI - Elevating the quality of disability and rehabilitation research: mandatory use of the reporting guidelines. PMID- 24799745 TI - Nitroimidazooxazoles(#) Part xxiv, Search for Antileishmanial Agents: 2,3-Dihydro 6-nitroimidazo[2,1-b]oxazoles as Potential Antileishmanial Agents. AB - A number of mono and bicyclic nitroimidazoles were screened for in vitro antileishmanial activity. Among these, compounds belonging to the class of nitroimidazo[2,1-b]oxazoles showed moderate to good activity. This class of compounds had been reported previously to have pronounced antitubercular activity, particularly CGI17341 (5a). In the present study (5a) and (5d) and (7) were found to be more potent antileishmanials in vitro than the standard and less toxic in relation to a reference compound. (7) Was earlier formulated to have the phenyl group located on C-2(5b). PMID- 24799747 TI - Physical Therapists' Perceptions of Leadership across the Health Care Continuum: A Brief Report. AB - PURPOSE: To describe and compare Canadian physical therapists' perspectives on the importance of characteristics required for leadership in the workplace and in society and to explore the implications for the profession. METHODS: This quantitative, cross-sectional study used a web-based survey of members of the Canadian Physiotherapy Association (CPA) with a registered email address (n=6156). The perceived importance of leadership characteristics at the workplace level versus the societal level was examined using a Mann-Whitney U test, with the significance set at alpha=0.05. RESULTS: A total of 1,511 respondents completed the questionnaire for a 24.5% response rate; they rated communication, professionalism, and credibility as the most important characteristics. For each of the 15 leadership characteristics, significantly fewer physical therapists chose the rating "extremely important" at the societal level than did so at the workplace level (p<0.001 for all characteristics). CONCLUSIONS: Physical therapists consistently rate leadership characteristics as more important in the workplace than at the societal level. Future research should aim to guide understanding about the reasons for this difference in perceived importance of leadership characteristics across different contexts. PMID- 24799748 TI - Statin-induced rhabdomyolysis: a comprehensive review of case reports. AB - PURPOSE: To identify case reports of statin-induced rhabdomyolysis and summarize common predisposing factors, symptoms, diagnostic findings, functional outcomes, characteristics, treatment, and rehabilitation. METHOD: MEDLINE, CINAHL, SCOPUS, and PEDro databases were searched (1990-2013) for relevant case reports using the search terms "Statins," "Rhabdomyolysis," "Myalgia," "Muscle damage," "Muscle injury," and "Myopathy." Relevance (based on title and abstract) was assessed by one investigator; two investigators independently reviewed the relevant articles to determine inclusion in the review. RESULTS: A total of 112 cases met the inclusion criteria. The majority were in men (70%) and people over 45 years of age (mean 64 [SD 14] years). Simvastatin was the most commonly reported statin (n=55); the majority of cases reported the use of concomitant medications such as fibrates (n=25). Weakness (n=65) and muscle pain (n=64) were the most common symptoms. In 19 cases, the patient was referred to rehabilitation, but the case reports do not include descriptions of the treatment. CONCLUSION: Statin-induced rhabdomyolysis was more commonly reported when statins were used in conjunction with other drugs, which potentiated its effect. Research is needed to identify the role of exercise and rehabilitation following statin-induced rhabdomyoloysis since muscle damage may be severe and may have long-term effects on muscle function. PMID- 24799750 TI - Clinician's Commentary on Vermeltfoort et al.(1.). PMID- 24799749 TI - Attitudes toward Adults with Intellectual Disability: A Survey of Ontario Occupational and Physical Therapy Students. AB - PURPOSE: To examine attitudes of students in Ontario master's degree programmes in occupational therapy (MScOT) and physical therapy (MScPT) toward adults with intellectual disability (ID). METHODS: A quantitative cross-sectional survey study was conducted. An electronic questionnaire was distributed to 1,255 MScOT/PT students at five Ontario universities via email, using a modified Dillman approach. Descriptive statistics were used to describe experiences, attitudes, willingness, and preparedness. RESULTS: Overall response rate was 17.9%. A total of 96.0% of respondents felt "quite" or "very willing" to deliver rehabilitation to adults with ID; however, 50.7% of respondents felt "not at all prepared" or "a little prepared" to interact with this population in a clinical setting. Of those who felt unprepared, 75.4% reported it to be due to inadequate knowledge. In addition, Ontario MScOT/PT students have neutral attitudes toward adults with ID. CONCLUSIONS: While many MScOT/PT students are willing to deliver rehabilitation to adults with ID, a large proportion do not feel adequately prepared to interact with this population in a clinical setting. These findings could inform future research and curricular reform in the rehabilitation professions so that future clinicians are better prepared to provide support for this population. PMID- 24799751 TI - What Do We Know about Knowledge Brokers in Paediatric Rehabilitation? A Systematic Search and Narrative Summary. AB - PURPOSE: To conduct a systematic review of the literature related to the use of knowledge brokers within paediatric rehabilitation, and specifically to determine (1) how knowledge brokers are defined and used in paediatric rehabilitation and (2) whether knowledge brokers in paediatric rehabilitation have demonstrably improved the performance of health care providers or organizations. METHODS: The MEDLINE, CINAHL, EMBASE, and AMED databases were systematically searched to identify studies relating to knowledge brokers or knowledge brokering within paediatric rehabilitation, with no restriction on the study design or primary aim. Following review of titles and abstracts, those studies identified as potentially relevant were assessed based on the inclusion criteria that they: (1) examined some aspect of knowledge brokers/brokering in paediatric rehabilitation; (2) included sufficient descriptive detail on how knowledge brokers/brokering were used; and(3) were peer-reviewed and published in English. RESULTS: Of 1513 articles retrieved, 4 met the inclusion criteria, 3 of which referenced the same knowledge broker initiative. Two papers used mixed methods, one qualitative methodology, and one case presentation. Because of the different methods used in the included studies, the findings are presented in a narrative summary. CONCLUSIONS: This study provides an overview of the limited understanding of knowledge brokers within paediatric rehabilitation. Knowledge broker initiatives introduced within paediatric rehabilitation have been anchored in different theoretical frameworks, and no conclusions can be drawn as to the optimum combination of knowledge brokering activities and methods, nor about optimal duration, for sustained results. PMID- 24799752 TI - Examining interrater reliability and validity of a paediatric cardiopulmonary physiotherapy discharge tool. AB - PURPOSE: To determine the interrater reliability (IRR) of the individual items in the Paediatric Cardiopulmonary Physiotherapy (CPT) Discharge Tool. This tool identifies six critical items that physiotherapists should consider when determining a paediatric patient's readiness for discharge from CPT after upper abdominal, cardiac, or thoracic surgery: oxygen saturation, mobility, secretion retention, discharge planning, auscultation, and signs of respiratory distress. METHODS: A total of 33 paediatric patients (ages 2 to <19 years) who received at least 1 day of CPT following cardiac, thoracic, or upper-abdominal surgery were independently assessed using the Paediatric CPT Discharge Tool by two designated assessors, who assessed each patient within 4 hours of each other. RESULTS: Kappa analysis showed the following levels of interrater agreement for the six items of the Paediatric CPT Discharge Tool: Oxygen Saturation, excellent (kappa=0.80); Mobility, substantial (kappa=0.62); Secretion Clearance, moderate (kappa=0.39); Discharge Planning, fair (kappa=0.37); and Auscultation and Respiratory Distress, poor (kappa=0.24 and kappa=-0.08, respectively). CONCLUSION: Several of the items in the Paediatric CPT Discharge Tool demonstrate good IRR. The discharge tool is ready for further psychometric testing, specifically validity testing. PMID- 24799753 TI - Self-management goal setting: identifying the practice patterns of community based physical therapists. AB - PURPOSE: To describe the collaborative goal-setting practices of community-based physical therapists trained in a self-management (SM) approach who work with clients with chronic conditions and to describe clients' goal-achievement rates. Methods : A retrospective chart review was conducted for 296 randomly selected home-care clients from July 2009 through July 2010 using a chart-abstraction form created to capture demographic data and information related to goal setting and achievement. Data were analyzed using frequencies, percentages, and Pearson's chi square tests. RESULTS: There was no significant relationship between sex, age, or number of chronic conditions and setting SM or non-self-management (NSM) goals or the type of SM goal set. The majority of goals set were "action" as opposed to "verbal" goals. A high proportion (89-100%) of both SM and NSM goals were met. CONCLUSIONS: Clinicians should be aware that it is possible to set SM goals regardless of the client's sex, age, or number of chronic conditions. Other possible influences on goal setting, such as severity of chronic conditions and challenges of the health care system, should be further investigated. PMID- 24799754 TI - Assessing Physical Therapy Students' Performance during Clinical Practice. AB - PURPOSE: To assess the feasibility and acceptability of using the Assessment of Physiotherapy Practice (APP) instrument to assess physiotherapy students' clinical competencies. METHODS: A convenience sample of clinical educators (CEs) and students from the University of British Columbia (UBC) in Vancouver, Canada, completed the instrument currently in use, the Physical Therapist Clinical Performance Instrument (PT-CPI), and the APP. A cross-sectional survey of CEs and physiotherapy students was conducted from 2011 to 2012; the survey included questions worded to elicit opinions about the two instruments when used in the clinical environment with students at different stages of training. Questions addressed various aspects of the instruments, including ease of use, provision of feedback, and completion time. RESULTS: Data were analyzed from 63 CEs from a variety of settings; sufficient data were recorded on 71 student PT-CPI and APP forms. A grading comparison between the PT-CPI and the APP demonstrated equivalence of entry-to-practice standard. Mean completion time was 80 (SD 53) minutes for the PT-CPI and 23 (13) minutes for the APP; mean time difference was 57 (95% CI, 39-75). Students would prefer (82%) that the APP be used to provide feedback and assess their performance on clinical placements. CONCLUSIONS: It is feasible and acceptable to use the APP to assess physiotherapy students' clinical competencies at the University of British Columbia. PMID- 24799755 TI - Clinician's Commentary on Dawes et al.(1.). PMID- 24799756 TI - Identifying balance and fall risk in community-dwelling older women: the effect of executive function on postural control. AB - PURPOSE: The mechanisms linking cognition, balance function, and fall risk among older adults are not fully understood. An evaluation of the effect of cognition on balance tests commonly used in clinical practice to assess community-dwelling older adults could enhance the identification of at-risk individuals. The study aimed to determine (1) the association between cognition and clinical tests of balance and (2) the relationship between executive function (EF) and balance under single- and dual-task testing. METHODS: Participants (24 women, mean age of 76.18 [SD 16.45] years) completed six clinical balance tests, four cognitive tests, and two measures of physical function. RESULTS: Poor balance function was associated with poor performance on cognitive testing of EF. In addition, the association with EF was strongest under the dual-task timed up-and-go (TUG) test and the Fullerton Advanced Balance Scale. Measures of global cognition were associated only with the dual-task performance of the TUG. Postural sway measured with the Standing Balance Test, under single- or dual-task test conditions, was not associated with cognition. CONCLUSIONS: Decreased EF was associated with worse performance on functional measures of balance. The relationship between EF and balance was more pronounced with dual-task testing using a complex cognitive task combined with the TUG. PMID- 24799758 TI - Clinician's Commentary on Li et al.(1.). PMID- 24799757 TI - Stroke-related knowledge, beliefs, and behaviours of chinese and European canadians: implications for physical therapists. AB - PURPOSE: To improve cross-cultural health education on risk-reducing behaviour change by examining the stroke-related knowledge, beliefs, and behaviours of Chinese Canadians (CCs). METHODS: Participants (103 first-generation CCs and 101 European Canadians [ECs] representing the dominant cultural group in Canada) completed a cross-sectional questionnaire about knowledge, health behaviours, and beliefs related to stroke. RESULTS: Compared with ECs, CCs were less aware of risk factors, warning signs, and appropriate responses to stroke in others. Information sources about stroke included mass media, family, and friends. CCs were less likely to smoke and drink alcohol but were also less likely to be physically active or to participate in structured exercise, less likely to have a healthy diet, and more likely to report stress. CONCLUSIONS: Theoretical dimensions of culture may explain variations in stroke-related knowledge, behaviours, and beliefs between CCs and ECs. Awareness of cultural differences can help physical therapists evaluate clients and appropriately tailor lifestyle related health education. PMID- 24799759 TI - Tracking patient outcomes after anterior cruciate ligament reconstruction. AB - Purpose : To model how patients' knee range of motion (ROM), pain, and self reported lower-extremity (LE) functional status change over the first 26 weeks following anterior cruciate ligament (ACL) reconstruction and to estimate the test-retest reliability of these measurements. METHODS: Patients were assessed weekly over 26 weeks following ACL reconstruction. Outcomes were knee ROM, LE functional status measured by the Lower Extremity Functional Scale (LEFS), and pain measured by the 4-item pain intensity measure (P4). A nonlinear model was applied to describe change for each outcome. Intra-class correlation coefficients and standard errors of measurement were applied to estimate test-retest reliability and minimal detectable change. RESULTS: A nonlinear model provided the following model fit values (R(2)): P4=0.71, extension ROM=0.51, flexion ROM=0.99, LEFS=0.97. For pain and ROM, the limit values were reached by approximately 12 weeks after reconstruction; LEFS values continued to increase up to 26 weeks. Test-retest reliability coefficients varied from 0.85 to 0.95. CONCLUSIONS: The greatest improvement occurred in the first 8 weeks after surgery. Recovery was nearly complete by 12 weeks with respect to pain and ROM, although LE functional status continued to improve throughout the study period. Scores on all measures demonstrated reliability, which supports their use with individual patients. PMID- 24799760 TI - Clinician's Commentary on Cupido et al.(1.). PMID- 24799762 TI - Clinician's Commentary on Rodrigues et al.(1.). PMID- 24799761 TI - Ischaemic heart disease-related knowledge, behaviours, and beliefs of indo canadians and euro-canadians: implications for physical therapists. AB - PURPOSE: To examine knowledge, behaviours, and beliefs related to ischaemic heart disease (IHD) of Indo-Canadians (ICs), thereby helping target health education strategies. METHODS: In a cross-sectional descriptive/comparative study, 102 Indian-born Indo-Canadians (ICs) and 102 Canadian-born Euro-Canadians (ECs) completed a standardized questionnaire on IHD knowledge and lifestyle-related behaviours and beliefs. RESULTS: Compared with ECs, ICs were less aware of IHD risk factors. ICs' lifestyle practices and beliefs were consistent with having less perceived control over health than ECs. ICs reported more stress from various sources and resorted less to exercise for stress relief and more to religious/spiritual activities. CONCLUSIONS: In accordance with health belief theory, approaches to educating immigrants from collectivistic cultures such as India to assume responsibility for their personal health may need to be different from those used with ECs, which stress self-management. Such programmes may need to emphasize lifestyle-related health knowledge and beliefs as bases for health behaviour change. PMID- 24799763 TI - What Does the Cochrane Collaboration Say about Preventing and Managing Childhood Obesity? PMID- 24799764 TI - MicroRNA profiling of activated and tolerogenic human dendritic cells. AB - Dendritic cells (DCs) belong to the immune system and are particularly studied for their potential to direct either an activated or tolerogenic immune response. The roles of microRNAs (miRNAs) in posttranscriptional gene expression regulation are being increasingly investigated. This study's aim is to evaluate the miRNAs' expression changes in prepared human immature (iDCs), activated (aDCs), and tolerogenic dendritic cells (tDCs). The dendritic cells were prepared using GM CSF and IL-4 (iDC) and subsequently maturated by adding LPS and IFN-gamma (aDC) or IL-10 and TGF-beta (tDC). Surface markers, cytokine profiles, and miRNA profiles were evaluated in iDC, tDC, and aDC at 6 h and 24 h of maturation. We identified 4 miRNAs (miR-7, miR-9, miR-155 and miR-182), which were consistently overexpressed in aDC after 6 h and 24 h of maturation and 3 miRNAs (miR-17, miR 133b, and miR-203) and miR-23b cluster solely expressed in tDC. We found 5 miRNAs (miR-10a, miR-203, miR-210, miR-30a, and miR-449b) upregulated and 3 miRNAs downregulated (miR-134, miR-145, and miR-149) in both tDC and aDC. These results indicate that miRNAs are specifically modulated in human DC types. This work may contribute to identifying specific modulating miRNAs for aDC and tDC, which could in the future serve as therapeutic targets in the treatment of cancer and autoimmune diseases. PMID- 24799766 TI - Role of fractalkine/CX3CL1 and its receptor in the pathogenesis of inflammatory and malignant diseases with emphasis on B cell malignancies. AB - Fractalkine/CX3CL1, the only member of the CX3C chemokine family, exists as a membrane-anchored molecule as well as in soluble form, each mediating different biological activities. It is constitutively expressed in many hematopoietic and nonhematopoietic tissues such as endothelial and epithelial cells, lymphocytes, neurons, microglial osteoblasts. The biological activities of CX3CL1 are mediated by CX3CR1, that is expressed on different cell types such as NK cells, CD14(+) monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells. The CX3CL1/CX3CR1 axis is involved in the pathogenesis of several inflammatory cancer including various B cell malignancies. In tumors the interaction between cancer cells and cellular microenvironment creates a context that may promote tumor growth, increase tumor survival, and facilitate metastasis. Therefore the role of the CX3CL1/CX3CR1 has attracted interest as to the development of potential therapeutic approaches. Here we review the different effects of the CX3CL1/CX3CR1 axis in several inflammatory and neurodegenerative diseases and in cancer, with emphasis on human B cell lymphomas. PMID- 24799765 TI - Adipokines as potential biomarkers in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by severe joint injury. Recently, research has been focusing on the possible identification of predictor markers of disease onset and/or progression, of joint damage, and of therapeutic response. Recent findings have uncovered the role of white adipose tissue as a pleiotropic organ not only specialized in endocrine functions but also able to control multiple physiopathological processes, including inflammation. Adipokines are a family of soluble mediators secreted by white adipose tissue endowed with a wide spectrum of actions. This review will focus on the recent advances on the role of the adipokine network in the pathogenesis of RA. A particular attention will be devoted to the action of these proteins on RA effector cells, and on the possibility to use circulating levels of adipokines as potential biomarkers of disease activity and therapeutic response. PMID- 24799767 TI - C-reactive protein in human atherogenesis: facts and fiction. AB - The role of C-reactive protein (CRP) in atherosclerosis is controversially discussed. Whereas initial experimental studies suggested a pathogenic role for CRP in atherogenesis, more recent genetic data from Mendelian randomization trials failed to provide evidence for a causative role of CRP in cardiovascular disease. Also, experimental results from laboratories all over the world were indeed contradictory, partly because of species differences in CRP biology and partly because data were not accurately evaluated. Here we summarize the published data from experimental work with mainly human material in order to avoid confusion based on species differences in CRP biology. Experimental work needs to be reevaluated after reconsideration of some traditional rules in research: (1) in order to understand a molecule's role in disease it may be helpful to be aware of its role in physiology; (2) it is necessary to define the disease entity that experimental CRP research deals with; (3) the scientific consensus is as follows: do not try to prove your hypothesis. Specific CRP inhibition followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease. PMID- 24799768 TI - ASD: biochemical mechanisms behind behavioral disorders. PMID- 24799771 TI - Believe in yourself to remove improbable. PMID- 24799770 TI - Genetic and Environmental Influences on Cognition Across Development and Context. AB - Genes account for between approximately 50% and 70% of the variation in cognition at the population level. However, population-level estimates of heritability potentially mask marked subgroup differences. We review the body of empirical evidence indicating that (a) genetic influences on cognition increase from infancy to adulthood, and (b) genetic influences on cognition are maximized in more advantaged socioeconomic contexts (i.e., a Gene * Socioeconomic Status interaction). We discuss potential mechanisms underlying these effects, particularly transactional models of cognitive development. Transactional models predict that people in high-opportunity contexts actively evoke and select positive learning experiences on the basis of their genetic predispositions; these learning experiences, in turn, reciprocally influence cognition. The net result of this transactional process is increasing genetic influence with increasing age and increasing environmental opportunity. PMID- 24799769 TI - Th9/IL-9 profile in human echinococcosis: their involvement in immune response during infection by Echinococcus granulosus. AB - Th9 cells have been reported to contribute to immune responses; however, the role of Th9 cells in Echinococcus granulosus infection is unknown. This study is to determine whether Th9 cells and IL-9 are involved in human Echinococcus granulosus infection. Compared with healthy controls (HC group), the mRNA levels of PU.1, IL-9, and GATA-3 were significantly increased in patients before therapy (CE group), as revealed by qRT-PCR. Flow cytometry analysis showed that the percentages of Th9 and Th2 cells in CE group were significantly higher. The levels of IL-9, IL-4, IL-10, and TGF- beta in CE group were also significantly increased, as detected by CBA assay. The percentages of Th9 and Th2 cells in CE group were positively correlated. After treatments of surgery in combination with albendazole, the PU.1 and GATA-3 mRNA levels were significantly decreased in patients after therapy (PCE group) compared with CE group. The numbers of Th9 and Th2 cells and levels of IL-9, IL-4, IL-10, and TGF- beta were also significantly decreased in PCE group. In conclusion, the ratios of Th9 cells and IL-9 levels were significantly decreased after treatment, suggesting that Th9/IL-9 may be involved in immune response induced by Echinococcus granulosus infection. PMID- 24799772 TI - "Challenges in Writing"-The Writer's Block? PMID- 24799773 TI - A Rare Internal Herniation in Adult: Meckel's Diverticulum. AB - Intestinal obstruction due to Meckel's diverticulum is the most common presentation in adults. There are various mechanisms by which it can cause intestinal obstruction such as volvulus of small intestine around a fibrous band extending from Meckel's diverticulum to umbilicus, intussusception, and Littre's hernia. We report the case of a young adult operated on emergency for acute intestinal obstruction. The CT scan suggested a nonspecific internal herniation. Surgical exploration confirmed a rare type of obstruction due to Meckel's diverticulum. PMID- 24799774 TI - Masson's Hemangioma of Proximal Radial Artery. AB - Tumour like vascular lesions are rare. Here we report a rare case of tumor like vascular lesion from the radial artery. A pulsatile swelling in the forearm is usually diagnosed as a case of Aneurysm, AV fistula or highly vascular tumor. A middle aged man came to us with a painless pulsatile swelling on the lateral aspect of proximal right forearm. The ultrasound scan reported it as case of vascular tumour. Angiogram showed abnormal vascular channels, connected to the aneurysmal dialation of the proximal radial artery. Histopthological examination confirmed it as Masson's hemangioma after excision. This is a benign condition and complete excision is curative. PMID- 24799775 TI - Internal pancreatic stent causing irreversible dilatation of pancreatic duct. AB - A 28-year-old woman underwent a pylorus preserving Whipple procedure for pancreatic serous cystadenoma located on the head of the pancreas. During the operation, an internal stent (7F silastic catheter, 9 cm in length) was placed within the pancreatic duct in the area of pancreaticojejunal end-to-end Dunking type anastomosis to prevent development of fistula. The stent was positioned so that one third of its length would lie into the pancreatic duct, and it was anchored to the periductal pancreatic tissue with only one rapidly absorbable chromic suture. Leakage from the anastomosis was not observed, and she was discharged without any complaint. Early postoperative abdominal CT examination revealed that the stent was retained within the normal caliber pancreatic duct (Fig. 1a). Six months after the operation, she began to complain to epigastric pain triggered by the meals. The laboratory analysis was normal, particularly liver biochemical tests and serum amylase. The internal pancreatic stent within the dilated pancreatic duct was detected by an additional CT examination (Fig. 1b). The stent was removed endoscopically at the third attempt. The pain was resolved after its removal. Control CT examination which was taken at the 18th month after removal of the stent showed dilatation of the pancreatic duct (Fig. 2a). The patient remained free of any complaint, although regressed pancreatic duct dilatation has persisted over 4 years of follow-up (Fig. 2b). PMID- 24799776 TI - High pressure injection injury of the hand. AB - High pressure injection injury of the hand looks rather innocuous but has the potential of affecting the function. The radiological picture is quite alarming and it gives a fair idea about the extent of the damage. The description and the images which follow, emphasize the need for an early and aggressive surgical debridement for a good functional outcome. PMID- 24799777 TI - Jejunal diverticulosis - rare cause of gastrointestinal bleed. AB - Jejunal diverticulosis was first described by Somerling in 1794 and by Sir Astley Cooper in 1807. Jejunal diverticula are rare. Hemorrhage from jejunal diverticula usually presents as gastrointestinal bleeding. Here, we present a case of severe gastrointestinal bleeding presenting as malena due to jejunal diverticulosis. PMID- 24799778 TI - The results of a one-time crystallized phenol application for pilonidal sinus disease. AB - The aim of this study was to investigate the cure rate after a one-time phenol application for pilonidal sinus disease. Forty-eight patients diagnosed with pilonidal sinus from May 2006 to September 2009 were retrospectively reviewed. They were all managed under the same polyclinic conditions in different hospitals by the same surgeon under local anesthesia. Crystallized phenol was applied a total of 97 times on 48 patients. The median follow-up was 22 months (range, six to 38 months). Two patients (4 %) could not participate in the follow-up. One of these patients had 12 sinuses and didn't continue treatment after eight applications of phenol, and the other had nine sinuses and didn't continue treatment after five applications of phenol. The one-time application cure rate was 64.5 %, and the rate of success was 95 % with two or more applications. Recurrence did not occur during this period. A one-time phenol application is an effective treatment for pilonidal sinus disease. Hence, it can be an alternative to surgical treatment. PMID- 24799779 TI - Role of Transrectal Ultrasound in Preoperative Local Staging of Carcinoma Rectum and It's Histopathological Correlation. AB - A precise knowledge of depth of invasion of tumor is essential for the planning of treatment of rectal cancer. TRUS is a new diagnostic modality that has become useful in determining depth of invasion preoperatively and the presence or absence of metastatic lymph nodes. Our aim was to determine Role of Transrectal Ultrasound in Preoperative Local Staging of Carcinoma Rectum and it's Histopathological Correlation. TRUS was used in preoperative local staging of 30 patients with carcinoma rectum. 25patients underwent APR (abdomino-perineal resection) & 5 underwent AR. (anterior resection). Preoperative TRUS staging was compared with pathological staging obtained from biopsy of resected specimen. In staging depth of invasion of rectal wall (T stage) overall accuracy was 83.3 %, over staged 10 %, under staged in 6.67 % sensitivity was 92.5 %, and specificity was 62.5 %. In staging lymph nodes (N stage) overall accuracy was 76.67 %, sensitivity was 79.31 %, specificity was 87.5 %. TRUS is a safe and accurate preoperative local staging method for assessment of both depth of invasion of rectal wall and presence or absence of metastatic lymph nodes. PMID- 24799780 TI - Cytological and morphometric study of urinary epithelial cells with histopathological correlation. AB - This study has been done to asses the utility and accuracy of urinary cytology and morphometric study of exfoliated cells in early detection and follow-up of urothelial neoplasms and thereby help to reduce the disease-related mortality and morbidity. A total 100 patients with urinary symptoms were studied by cytological examination of urine along with morphometric analysis of suspicious epithelial cells. Immunostaining to detect CK-20 expression and p53 over expression was done in smears showing atypical cells. Histopathological confirmation was done in cases which were suspicious on cystoscopy. P value was determined by using unpaired t-test. Statistically significant difference was found between neoplastic and non-neoplastic lesions of the urinary bladder as far as morphometry is concerned. Urinary cytology along with morphometry is an important tool in early detection of urothelial neoplasms. It is also helpful to find out the recurrences during post-operative follow-up period. Overexpression of CK-20 and p53 immunostain in cytology can act as an adjunct to the cytological diagnosis. PMID- 24799781 TI - Criteria for Laparoscopic Advanced Surgery in Semi-Equipped Setup (CLASS): Feasibility Study Based on Institutional Experience. AB - Laparoscopic and Minimally invasive techniques have become a routine practice for various surgical disorders in present times. Though, advanced laparoscopic procedures are feasible they are largely restricted to fewer centers due to lack of advanced instrumentation, finances and expertise at most of them. In this context, we conducted a feasibility study to evolve definite criteria for performing advanced laparoscopic surgeries in resource restricted set-ups. We present our experience with 25 cases of advanced laparoscopic procedures using conventional laparoscopic instruments. We evaluated the clinico-investigative profile and operative details of all the patients. We classified the surgical expertise, laparoscopic instrumentation, surgical set ups and patient factors systematically to evolve the criteria for feasibility of advanced laparoscopicsurgery. Out of the 22 eligible patients for the study, various laparoscopic surgeries performed were - Fundoplication (4), Cystogastrostomy (3), Endoscopic thyroidectomy (7), Thoracoscopic Thyroidectomy (2), Adrenalectomy (5) and Retroperitoneal paraganglioma excision (1). There was no mortality and two morbidities in the form of hypercarbia and a tracheo-cutaneous fistula in 2 cases of endoscopic thyroidectomy. According to the criteria, we propose our surgical set up falls in to Grade 3, for which this criteria fits in. This study demonstrates the feasibility of advanced laparoscopic procedures in semi-equipped set-up, preferably by employing institute specific criteria of CLASS. PMID- 24799782 TI - Quality of life of patients after temporary ileostomy for ileal perforation- a questionnaire based study. AB - In India and some neighboring countries, ileal perforation is a leading indication for an emergent laparotomy, and making a temporary ileostomy is probably the safest practice for these patients with peritonitis. This apparently disfiguring surgery changes body image, and significantly influences physical, mental, emotional, and social life of the stoma patients. Further stress is added by the stoma related complications. The quality of life (QoL) issues of patients with temporary ileostomy for ileal perforations have not been addressed; hence, there is a gap in our existing knowledge about the various factors affecting the quality of life of these patients. This study aimed at assessing the QoL in this particular group of patients with the help of an objective standardized proforma based interview. Despite being limited by its small sample size, the study identifies important associations and provides a platform for further research to improve QoL of these patients. PMID- 24799783 TI - Effects of surgical stress on early nonspecific immune response in children. AB - Surgery alters the body's homeostatic balance and defense mechanisms. In adults transient postoperative cellular and humoral immunosuppression after different degrees of operative stress has been reported. In children the immunologic consequences of operations are not elaborated. This study investigates the effect of minor and major surgery on early nonspecific immune response in terms of neutrophil counts and function. Forty-three children undergoing minor and major elective procedures were studied. Blood samples were collected before, immediately after, and 72 h after surgery. Total white cell count, differential neutrophil count, and neutrophil phagocytic function were studied using nitroblue tetrazolium test. Children were divided into two groups-group 1 underwent minor surgery and group 2 major surgery. In group 1 there was a significant drop in total counts after surgery, but in group 2 total counts were not affected. In both groups, the percentage of neutrophils increased immediately after surgery but fell to near or less than preoperative levels 72 h after surgery. However, the assessment of neutrophil functions by nitroblue tetrazolium test in both unstimulated and stimulated forms revealed it to be unchanged in group 1. In group 2 the unstimulated neutrophil function was elevated 72 h after surgery, whereas stimulated function was elevated immediately after surgery. Minor surgery does not alter the early nonspecific immune response. However, major surgery seems to induce a transient increase in neutrophil phagocytic activity. PMID- 24799784 TI - The effect of preemptive perianal ropivacaine and ropivacaine with dexmedetomidine on pain after hemorrhoidectomy: a prospective, randomized, double blind, placebo-controlled study. AB - The objective of this study was to assess the efficacy of perianal infiltration of ropivacaine and dexmedetomidine added to ropivacainein in the relief of pain after hemorrhoidectomy. Patients in group C(placebo control group, n = 21) received perianal injections of normal saline and those in group RO(ropivacaine injection group, n = 21) received ropivacaine, those in group RD(ropivacaine with dexmedetomidine injection group, n = 19) were administered ropivacaine with dexmedetomidine, prior to the initiation of the operation. Reductions of the VAS score, the frequency with which the PCA button was pushed, and fentanyl consumption were assessed in groups RO and RD as compared to that of group C, and in group RD as compared to that of group RO(p < 0.05). We concluded that the use of perianal ropivacaine injection prior to surgical incision reduced both postoperative pain and fentanyl consumption following hemorrhoidectomy, and the addition of dexmedetomidine to ropivacaine may have an additive effect in postoperative analgesic care. PMID- 24799785 TI - Antesternal colonic interposition for corrosive esophageal stricture. AB - Restoration of swallowing in a patient with dysphagia due to nondilatable corrosive stricture of esophagus remains a surgical challenge. Organs available for replacement are stomach, jejunum, or colon. Jejunum is useful to replace a small segment, whereas stomach and colon are required for a long-segment replacement. In cases where the stomach is also injured, colon remains the only option. The route of colonic interposition has also been a subject of debate over the years. Antesternal, retrosternal, or esophageal bed passage are the routes described. In the present series, the data of antesternal colonic interposition (ACI) performed for nondilatable benign esophageal strictures in 32 patients (1988-2011) have been retrospectively analyzed. The results indicate that ACI for corrosive strictures is a quick and simple procedure. Thoracotomy is avoided and anastomosis is easily performed in the neck, and mortality rate due to anastomotic failure or graft failure is diminished. This retrospective analysis discusses the ease, effectiveness, quality of life, morbidity, and mortality of ACI and compares the pros and cons of ACI with other procedures described in the literature. PMID- 24799786 TI - Stereotactic excision of additional lesions detected with intraoperative ultrasound examination during radiofrequency dissecting sealar (habib(r)) assisted hepatic metastasectomy: report of 4 cases. AB - Intraoperative ultrasound has been using to achieve a proper resection strategy in patients undergoing a hepatic colorectal metastasectomy. This study aims to describe and reveal the place of stereotactic metastasectomy in nonpalpable colorectal liver metastases (CLM). A chart review was initiated for all patients underwent resection for CLM between 2006 and 2011. The data concerning perioperative data and intraoperative strategy were abstracted. Among the 58 patients, who underwent a resection for CLM, 4 (6.9 %) (all men, median age 65.5, range 49-72, years) necessitated a stereotactic metastasectomy. Preoperative evaluations showed 1 (n = 1), 2 (n = 2), or 3 (n = 1) lesions, and intraoperative ultrasound (IUS) found an additional lesion in a case. Stereotactic marking was performed for nonpalpable lesions located in segments IVA, II, and VI and at the junction of segments V and VI. The margins were negative for all lesions both resected with conventional and stereotactic techniques. The examinations of the stereotactic resection materials revealed metastatic adenocarcinoma (patients n = 2), focal nodular hyperplasia (n = 1), and abnormal benign liver histology probably induced by chemotherapy (n = 1). The median (range) operation and hospitalization periods were 217.5 (150-310) minutes and 5.5 (2-9) days. No complications were observed except biliary fistula in a case, which spontaneously disappeared within 2 weeks. A patient died due to systemic disease including hepatic metastases 33 months after the liver surgery. Stereotactic metastasectomy may be feasible for the removal of nonpalpable CLM. Further evaluations are necessitated to understand the accurate place of this novel technique. PMID- 24799787 TI - Harmonic scalpel compared to conventional hemostasis in thyroid surgery. AB - The aim of this study was to determine whether conventional hemostasis (CH) or the harmonic scalpel (HS) results in shorter operative times for thyroidectomy and to evaluate the incidence of postoperative complications with each approach. In this study, 85 consecutive patients undergone open thyroidectomy were randomized into two groups: group CH (conventional hemostasis with classic technique of tying and knots, resorbable ligature, bipolar diathermy) and group HS (harmonic scalpel). Demographics, pathological characteristics, thyroid size, operative time, blood loss, and complications using the Student's t-test and chi (2)-test. The two groups were similar regarding age and sex. There were no intraoperative complications. There was no difference between the two techniques regarding the amount of blood loss for different procedures. No significant differences were found between the two groups concerning mean thyroid weight and mean hospital stay (2.2 days in HS vs. 3.7 in CH; P > 0.05). The mean operative time was significantly shorter in the HS group (47.2 min vs. 79.2 min; P < 0.001). Two (4.7 %) transient recurrent laryngeal nerve palsies were observed in the CH group and no one (0 %) in the HS group. No patient developed permanent palsy. Postoperative transient hypocalcemia occurred more frequently in the CH group (21/43, 48 % vs. 7/42, 16 %). In patients undergoing thyroidectomy, HS is a reliable and safe tool. Comparing with CH techniques, its use reduces operative times, postoperative pain, drainage volume, and transient hypocalcemia. PMID- 24799788 TI - Lower limb pain caused by insufficient muscular microcirculation. AB - Lumbar spinal surgery is a common procedure to treat low back pain. To remark that lower limb perfusion insufficiency may induce the similar syndrome as neuropathic pain, 1,076 cases of postspinal surgery was surveyed within 5 years, in which 51 cases had no obvious improvement 3 months after surgery; 27 cases received second operation because of instability, inadequate decompression, and wrong level; and the other 27 cases including 3 cases after twice spinal surgeries were enrolled. Physical examinations were presented with atypical neuropathic pain and muscle wasting at single lower limbs which deteriorated with long-distance walking. Computed tomography or magnetic resonance imaging scan was studied including the neural structure and lower limb angiography. The report showed degenerative change without definite neural structural compression or vascular occlusion. There was also no significant finding of electrodiagnostic study. The rest radionuclide study of lower limb muscle and myocardium was performed in these 27 cases using Thallium-201. All patients presented 9-24 % (~14%) muscle perfusion difference compared with two legs. Most of peripheral arterial occlusion disease cases presented the symptoms with ischemic pain and vascular claudication. In the study, the patients presented not only ischemic limb but also the bizarre symptoms, such as low back pain with or without radiating root pain and sensory disturbance. Physicians should be aware of the possibility of lower limb pain caused by lower perfusion syndrome. PMID- 24799789 TI - The effect of subareolar isosulfan blue injection on pulse oximeter readings. AB - Besides several side effects including anaphylaxis, blue dyes are also known to cause false pulse oximeter readings. We aimed to examine the effects of subareolar isosulfan blue injection on pulse oximeter (SpO2) readings. The study group included 27 patients undergoing SLNB using both radiocolloid and isosulfan blue. Another group of 27 patients constituted the control group. Pulse oximeter readings were compared. SpO2 decline >=4 % was defined as significant. All but one (96.2 %) of the patients in the study group showed SpO2 declines, compared to only one patient in the control group. Median +/- Interqartile Range (IR) SpO2 decrease was 3.0 +/- 4.0 % in the study and 0.0 +/- 1.0 % in the control group (p < 0.001). There were significant (>=4 %) SpO2 decreases in 13 (48.1 %) patients in the study group. Statistically significant differences were noted between the two groups in all recordings between 15 and 180 min (p < 0.001). Initial time for SpO2 fall and the time to the lowest SpO2 recording were 10.0 +/- 10.0 and 40.0 +/- 30.0 min respectively. Using subareolar injection, the frequency of false readings is comparable with intraparenchymal injections, and is higher than intradermal injections. Time to peak SpO2 fall, and the recovery period, are delayed in the subareolar technique. PMID- 24799790 TI - Crystallized phenol treatment of pilonidal disease improves quality of life. AB - The effects of crystallized phenol treatment of pilonidal sinus on quality of life has not been investigated before. This study aimed to compare the phenol treatment with surgical excision plus primary closure technique in terms of life quality by means of a life quality questionnaire. This is a prospective randomized clinical study. The study was conducted at Training and Teaching Hospital, Kayseri, Turkey. In total, 40 patients with pilonidal disease were randomly assigned into 2 clinically comparable groups between September 2010 and June 2011. Cristallyzed phenol application was done to 20 patients and surgical excision plus primary closure was done to 20 patients for the treatment of pilonidal disease. Data regarding demographic variables were recorded. To evaluate quality of life and patient comfort all patients asked to fill the questionnaire after complete healing occurred. There was no difference between the groups in age, sex and occupation. Two of the 20 patients in the excision and primary closure group had complication of wound dehiscience and needed prolonged wound care. There was significant differences in favor of the phenol group in all terms of life quality except for complete healing time. As a first degree treatment, phenol treatment is better than the other treatment choices of pilonidal disease in terms of time off work perioperative pain, being away from school and social life. Also phenol treatment can be done without any pretreatment laboratory examination. Further studies will be needed about cost effectivity of phenol treatment. PMID- 24799791 TI - The size of external urethral meatus on maximum stretch in Indian adult males. AB - Size of the external urethral meatus in adult Indian males is not yet documented. However, for choosing optimum size of an instrument, it is important to know the maximum stretchable external urethral meatal size in a particular patient. Hence, a prospective study was conducted at our institution to document the maximum stretchable adult male external urethral meatus size. After obtaining consent, 340 adult males who were undergoing urethral instrumentation for reasons other than the diseases of the urethra underwent urethral calibration using a "urethral calibrator" during February 2009 to April 2010. Data were analyzed using the SPSS 17. The average maximum stretchable external urethral meatal size in an Indian adult male was 28.49 Fr. Ours is the only study to document the maximum stretchable adult external urethral meatal size in Indian males which helps us for better instrumentation. PMID- 24799792 TI - Problem-based learning in ophthalmology: A brief review. PMID- 24799793 TI - Optical coherence tomographic assessment of retinal nerve fiber layer thickness changes before and after glaucoma filtration surgery. AB - BACKGROUND: Glaucomatous Optic Neuropathy (GON) is very common in the glaucoma patients, and impaired effect of glaucoma is measured by the Retinal Nerve Fiber Layer (RNFL) thickness. OBJECTIVE: The study was conducted to find out the mean RNFL thickness, RNFL thickness in different quadrants, Intra-Ocular Pressure (IOP) changes, and visual field changes after filtration surgery in different ages and genders using Optical Coherence Tomography (OCT). MATERIALS AND METHODS: The study was an interventional case-series conducted at the Glaucoma Clinic at the Regional Institute of Ophthalmology at Kolkata from March 2009 to August 2010. Fifty-one eyes of 43 open angle glaucoma patients had been selected for clinical and ophthalmologic evaluation. All the eyes of glaucoma patients who fulfilled the inclusion criteria were registered in the study population. The glaucoma filtration surgery was done in these patients. The RNFL thickness, IOP, visual field changes were measured before and after intervention of filtration surgery. Pre-operative OCT images of RNFL were obtained 0 to 120 days before surgery, and post-operative images were obtained from 60 to 120 days after surgery. Data collected in a standard data collection form included schedule. RESULTS: Paired t-test was used. RNFL thickness was (pre-operative: 52.56 +/- 17.40, post-operative: 58.48 +/- 20.20, P < 0.0001) significantly increased after filtration surgery measured by OCT with significant reduction of IOP (r = - 0.38, P = 0.005) irrespective of age and gender. CONCLUSIONS: An increase in RNFL thickness was observed after glaucoma filtration surgery that correlated with IOP reduction. PMID- 24799794 TI - Comparison of relation between visual function index and retinal nerve fiber layer structure by optical coherence tomography among primary open angle glaucoma and primary angle closure glaucoma eyes. AB - PURPOSE: To compare the visual field index (VFI) in primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) eyes, and to study the correlation with disc variables on optical coherence tomography (OCT) in all stages of severity. MATERIALS AND METHODS: Thirty POAG and PACG underwent Humphrey visual field 24-2 along with detailed examination. They also underwent stratus OCT imaging of the optic nerve and retinal nerve fiber layer (RNFL). The correlation of VFI with RNFL thickness was compared in POAG and PACG. RESULTS: The VFI significantly differed between POAG and PACG, with POAG eyes apparently having a better VFI at all severities of glaucoma. There were statistically significant differences in the superior max (Smax) and inferior max (Imax) in early and moderate POAG and PACG eyes. In early and moderate glaucoma, multivariate regression showed that maximum correlation of the VFI was seen with the mean deviation (b = 1.7, P < 0.001), average and superior RNFL thickness (b = 2.1, P < 0.001 and b = 1.8, P = 0.03, respectively), and age (b = 0.7, P = 0.04); while no correlation was seen with intraocular pressure (IOP), axial length, sex, or other clinical variables. VFI did not correlate well with RNFL thickness or other disc variables on OCT in severe glaucoma. CONCLUSION: VFI may not serve as a useful indicator of visual function in severe glaucoma. More useful indicators are required to monitor glaucoma patients with severe damage. PMID- 24799795 TI - Huge congenital teratoma containing tooth in a three-day-old neonate. AB - Congenital teratoma is a rare cause of congenital proptosis. A full term three day-old male child was presented with massive unilateral swelling in the left orbit, which was noted since birth. Diagnosis of orbital teratoma without intracranial extension was made based on clinical examination and imaging. Lid sparing exenteration of the left orbit was done. Histopathological examination confirmed the diagnosis of cystic teratoma. Congenital orbital teratoma with a tooth and mature elements of all the three germ cell layers is reported due to its extreme rarity. PMID- 24799796 TI - Primary conjunctival amyloidosis. AB - A 19-year-old previously healthy male presented with a 4 year history of painless drooping of right upper eyelid. On eversion of the right upper eyelid, a yellowish pink mass was seen in the tarsal region. Rest of the ocular examination was normal in both the eyes. Initial biopsy showed chronic inflammation. Subsequently, the entire mass was excised and histopathological examination showed the presence of amyloid in the subconjunctival stroma. At 3 months follow up, similar lesion was detected in the right lower, left upper, and lower lid, which were treated with cryotherapy, with partial resolution. Patient has been followed up for more than 2 years without any complaints. To our knowledge, this is the first case report of an isolated primary conjunctival amyloidosis with involvement of both the upper and lower palpebral conjunctiva of either eye. It was treated successfully by excision and cryotherapy. PMID- 24799797 TI - Choroidal metastasis from leiomyosarcoma in two cases. AB - Leiomyosarcoma is a malignant tumor of mesenchymal cells and is the most common soft-tissue sarcoma. Leiomyosarcoma is a notably rare tumor in the ophthalmic region and can be of primary, secondary or metastatic origin. To the best of our knowledge, there has only been one published case of leiomyosarcoma metastasis to the choroid. In this case study, we report two cases of primary leiomyosarcoma with metastasis to the choroid of the eye. Both cases displayed systemic metastasis and showed response to high dose plaque radiotherapy. Despite its prevalence as the leading form of sarcoma, leiomyosarcoma rarely metastasizes to the ocular region. PMID- 24799798 TI - Intra-bleb hematoma and hyphema following digital ocular compression. AB - We report successful outcome of a huge post- trabeculectomy intra-bleb hematoma and hyphema that occurred following digital ocular compression. The patient was a 64-year-old lady suffering from bilateral primary angle closure glaucoma and cataract. She was on anti-platelet therapy. She underwent single-site phacoemulsification, intra-ocular lens implantation and trabeculectomy with mitomycin C in the right eye. The trabeculectomy was under-filtering. She was asked to perform digital ocular compression thrice daily. On 15(th) post operative day, she presented with a huge intra-bleb hematoma and hyphema. The hematoma did not respond to conservative measures and was drained to prevent bleb failure. We recommend caution in the consideration of digital ocular compression in patients on prophylactic anti-coagulation. PMID- 24799799 TI - Late post-traumatic flap dislocation and macrostriae after laser in situ keratomileusis. AB - We report an unusual flap-related complication that occurred 4 years after uneventful laser in situ keratomileusis (LASIK) performed in the eye of a 20-year old woman. She developed dislocation with partial infolding of the LASIK flap with macrostriae and epithelial ingrowth in her left eye after trauma by a wooden chip. The flap was refloated, stretched, smoothened, and hydrated on both under and outer surfaces after epithelial debridement. At 1 week, the uncorrected visual acuity was 20/20 with absence of flap striae. The present case highlights that flap adhesions are not very strong even months and years after LASIK. Flap refloatation and stretching with hydration on both sides of the flap are effective in removing flap striae. PMID- 24799800 TI - Manual intrastromal corneal keratotomy: An alternate encouraging approach for refractive error correction. AB - Results of femtosecond based intrastromal astigmatic keratotomy have been reported to be encouraging for correction of Astigmatism. We report a new surgical technique-manual intrastromal corneal keratotomy (MICK) for correction of simple refractive astigmatism (-1.5 DC against the rule). The technique involves the creation of a 100 MUm thickness corneal flap creation using Moria M2 evolution LSK MicroKeratome and 300 MUm depth, 4 mm long manual transverse astigmatic keratotomy on both sides of the steep axis 3 mm from the pupillary center along with four incision peripheral radial keratotomy outside the optic zone (based on the mesopic pupil). The flap was repositioned and routine post operative regimen was followed. Patient achieved 20/20 vision in both eyes post operatively on the first day, which was maintained even at the 1 month follow-up. This simple technique could be useful as an alternative method for correction of refractive errors in patients not suitable for excimer and/or femtosecond laser treatment. PMID- 24799801 TI - Bilateral papilledema: A case of cerebral venous sinus thrombosis. PMID- 24799802 TI - Acute myeloid leukemia presenting as bilateral proptosis and right temporal swelling. PMID- 24799803 TI - Complications of retained intraorbital wooden foreign body. PMID- 24799804 TI - Intraocular glass foreign body-Retained amiss! AB - Open globe injuries with intraocular foreign bodies are important cause of visual morbidity. Timely detection of foreign body is must to improve the visual outcome and to prevent eye from developing complications. It is important to understand the need of meticulous history taking and thorough examination besides other investigations to detect foreign body. Glass foreign bodies are little difficult to visualize because of its transparent nature. The best time to detect foreign body is at the time of primary repair. Until one suspects the presence of foreign body, it is missed most of the time. We chose to report this case as it is unusual to miss big IOFB in anterior chamber impacted in lens matter at the time of primary corneal repair. It is important to remember that an ounce of vigilant vision is worth a pound of care. PMID- 24799805 TI - Cranio-orbital-temporal neurofibromatosis: An uncommon subtype of neurofibromatosis type-1. PMID- 24799806 TI - A rare presentation of bilateral Sturge-Weber syndrome. PMID- 24799807 TI - 3 year old boy with squint and blurred vision in Left Eye. PMID- 24799809 TI - Why patients in pain cannot get "God's own medicine?". PMID- 24799808 TI - Tobacco-alcohol optic neuropathy. Is complete recovery possible? PMID- 24799810 TI - Switch over from intravenous to oral therapy: A concise overview. AB - Majority of the patients admitted to a hospital with severe infections are initially started with intravenous medications. Short intravenous course of therapy for 2-3 days followed by oral medications for the remainder of the course is found to be beneficial to many patients. This switch over from intravenous to oral therapy is widely practiced in the case of antibiotics in many developed countries. Even though intravenous to oral therapy conversion is inappropriate for a patient who is critically ill or who has inability to absorb oral medications, every hospital will have a certain number of patients who are eligible for switch over from intravenous to oral therapy. Among the various routes of administration of medications, oral administration is considered to be the most acceptable and economical method of administration. The main obstacle limiting intravenous to oral conversion is the belief that oral medications do not achieve the same bioavailability as that of intravenous medications and that the same agent must be used both intravenously and orally. The advent of newer, more potent or broad spectrum oral agents that achieve higher and more consistent serum and tissue concentration has paved the way for the popularity of intravenous to oral medication conversion. In this review, the advantages of intravenous to oral switch over therapy, the various methods of intravenous to oral conversion, bioavailability of various oral medications for the switch over program, the patient selection criteria for conversion from parenteral to oral route and application of intravenous to oral switch over through case studies are exemplified. PMID- 24799811 TI - Off-label use of medicine: Perspective of physicians, patients, pharmaceutical companies and regulatory authorities. AB - Off-label prescribing of medicines is prevalent worldwide because it gives freedom to physicians to apply new therapeutic options based on the latest evidence. Although physicians may lawfully prescribe approved drugs for any use consistent with available scientific data and proper medical practice, but unfortunately, usually this is done without adequate scientific data. Often, when the best available therapeutic option fails, patients demand new approach or new treatment which ultimately leads to off-label uses. Major concerns about efficacy and safety have been raised by inappropriate use of off-label drugs because it leads to drug being used without risk-benefit analysis by the regulatory agency. Although the regulatory approval process requires ample proof of efficacy and safety for granting approval for specific indications of prescription drugs but unfortunately, more clarity is required about regulations governing off-label use of medicine. Above all because of the financial aspects involved it is highly impractical to expect that pharmaceutical companies will restrict or stop off label promotion. Off-label use might be compared to double-edged sword which might be very useful for some patients while it can also expose them to unrestricted experimentation, unknown health risks, or ineffective medicine. Hence, there is an urgent need for guidance to encourage proper off-label use of medicine by the distribution of scientifically valid and authentic information from the pharmaceutical companies. In fact, few countries such as the USA and France have taken an initiative and have come up with the regulations about off label use of medicine. PMID- 24799812 TI - Folic acid supplementation on homocysteine levels in children taking antiepileptic drugs: A randomized controlled trial. AB - OBJECTIVES: To assess the level of homocysteine (tHcy) in children taking AEDs and to study whether daily oral supplementation of folic acid for 1 month will reduce the tHcy level. MATERIALS AND METHODS: This was a double-blinded, randomized control trial conducted in Institute of Maternal and Child Health, Kozhikode, India. Totally 60 children were recruited and of them, 48 were enrolled. Of these children, 32 were assigned to the experimental group and 16 to the control group. Baseline data collection and tHcy estimation were done. One mg folic acid tablets were given to the experimental group and placebo tablets to the control group for 30 days. tHcy levels were re-estimated after 1 month follow up. Statistical significance was tested by chi(2) test, and paired and unpaired t tests, as appropriate. Correlation was tested by Pearson correlation test and P value less than 0.05 was taken as the cut-off for statistical significance. RESULTS: Baseline plasma tHcy concentrations in both groups were comparable [11.90 (6.3) and 13.02 (2.4) MUmol/l, respectively]. During the follow-up period, no increase in seizure episodes or no serious adverse reactions were noticed in either group. The reduction of tHcy in the experimental group was 1.92 MUmol/l (P = 0.04) and in the control group, there was an increase of 1.05 MUmol/l (P = 0.16). CONCLUSIONS: In children on AED treatment, folic acid supplementation may reduce tHcy level and thus reduce CVD risk. PMID- 24799813 TI - Identification of risk factors for carbamazepine-induced serious mucocutaneous adverse reactions: A case-control study using data from spontaneous adverse drug reaction reports. AB - OBJECTIVES: To identify risk factors other than genetic for severe carbamazepine induced mucocutaneous reactions, that is, SJS, TEN, and exfoliative dermatitis (ED). MATERIALS AND METHODS: We did a case-control study using data from the Swedish national database of spontaneously reported adverse drug reactions (ADRs). We selected all patients who had been reported from January 1, 1965 to March 31, 2010 as having experienced SJS (n = 78), TEN (n = 6), or ED (n = 8), and assessed as at least possibly related to carbamazepine. We also included diagnoses possibly representative of early signs of these serious conditions, that is, erythema multiforme (EM, n = 34) and scaly rash (n = 13). We compared data on demographics, drug treatment, and clinical features for these patients (cases, n = 139) with those from patients who had experienced any other type of ADR from carbamazepine during the same time period (controls, n = 887). RESULTS: After adjustment for multiple comparisons, alcohol abuse was statistically significantly more common among cases than controls (34.5% vs 8.7%, odds ratio 5.5 [95% confidence interval 3.6-8.4], P = 3.14 * 10(-14) ). The same was seen for SJS and EM individually. CONCLUSION: Alcohol abuse is a possible risk factor for serious carbamazepine-induced mucocutaneous reactions. PMID- 24799814 TI - Assessment of demographics, treatment strategies, and evidence-based medicine use among diabetic and non-diabetic patients with acute coronary syndrome: A cohort study. AB - OBJECTIVES: To evaluate and compare clinical and epidemiological characteristics, treatment strategies, and utilization of evidence-based medicine (EBM) among coronary artery disease (CAD) patients with or without diabetes. MATERIALS AND METHODS: Prospective observational cohort study from a tertiary care hospital in India among patients with CAD (myocardial infarction, unstable angina, or chronic stable angina). Data included demographic information, vital signs, personal particulars, risk factors for CAD, treatment strategies, and discharge medications. We evaluated epidemiologic characteristics and treatment strategies for diabetic and non-diabetic patients. RESULTS: Of 1,073 patients who underwent angiography, 960 patients (30% diabetic) had CAD. Proportion of hypertensive patients was higher among diabetic patients (58 vs 35% non-diabetic, P < 0.001). Similar proportion of patients received medical management in diabetic vs non diabetic CAD patients (35 vs 34%, P = 0.091); in diabetics the use of surgical procedure was higher (22 vs 17%, P = 0.0230) than interventional strategy (percutaneous transluminal coronary angioplasty, 43 vs 49%, P = 0.0445). Key medications (antiplatelet agents, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), beta-blockers, and ahtihyperlipidemic agents) were prescribed in 95, 53/12, 67, and 91% diabetic (n = 252) and 96, 51/8, 67, and 94% non-diabetic (n = 673) patients, respectively on discharge. CONCLUSIONS: Clustering of several risk factors at presentation, typically diabetes and hypertension, is common in CAD patients. Though diabetic patients are managed more conservatively, utilization of EBM for diabetic and non-diabetic patients is consistent with the recommendations. PMID- 24799815 TI - Treatment outcome of standardized regimen in patients with multidrug resistant tuberculosis. AB - OBJECTIVE: To evaluate the treatment outcome of second line drugs used in directly observed treatment, short-course (DOTS)-Plus regimen under Revised National Tuberculosis Control Program (RNTCP). MATERIALS AND METHODS: A prospective, observational study was carried out on multidrug resistant tuberculosis (MDR-TB) patients enrolled for DOTS-Plus regimen at TB and Chest Disease Department from January to December 2009. Demographic details, symptoms, sputum examination and adverse drug reactions were recorded in a case record form. Patients were followed up for 24 months. The data were analysed by Fisher's exact test and paired student's 't' test. RESULTS: Out of 130 patients, 51 (39%) were cured, 7 (5%) completed the treatment, 25 (19%) died, 30 (23%) defaulted and 17 (13%) failure. A significant increase in body weight (P < 0.0001) was observed at the end of the 24 months. Out of 89 patients with sputum culture conversion, majority (73) turned negative within first 3 months. Female gender (P < 0.05), conversion of sputum culture from positive to negative (P < 0.0001), and radiological improvement (P < 0.0001) were found to be positive predictors of a successful treatment outcome. While smoking habit (P < 0.05) and alcohol consumption (P < 0.05) were negative predictors of successful treatment outcome. Thirty five (26%) patients developed ADRs that required withdrawal of causal drug. The most common ADR was joint pain due to pyrazinamide (11) followed by neurological and psychiatric disturbances due to cycloserine (9). CONCLUSION: The treatment outcome of standardized regimen in MDR-TB patients was low. The long duration of treatment and defaulters are major challenges for a successful outcome. PMID- 24799816 TI - Informed consent on camera. PMID- 24799817 TI - Intrahepatic cholestasis in Bruton's agammaglobulinemia receiving mesalamine for co-morbid Crohn's disease. PMID- 24799818 TI - Amniotic fluid volume changes in response to frusemide induced maternal fluid shifts. AB - Frusemide use in pregnancy is generally restricted to patients with cardiac decompensation. In the past, maternal administration of oral frusemide had been tried to identify non-functioning fetal kidneys by utilizing the diuretic effect of frusemide on the fetal kidneys. We report a case of primigravida with severe mitral stenosis presenting in pulmonary edema that received high dose of frusemide. This was associated with the development of transient oligohydramnios. We discuss the clinical significance of this observation and the possible explanations. PMID- 24799819 TI - Alopecia caused by isoniazid. AB - Drug-induced alopecia is a known clinical entity and mainly seen with anti mitotic drug therapy. Alopecia during anti-tuberculosis therapy is very uncommon and previously observed with isoniazid, thiacetazone, and ethionamide. Present communication describes an additional case of isoniazid-induced alopecia in a 10 year-old male child, which was reversible after isoniazid withdrawal. Possible mechanisms of drug-induced alopecia are also briefly discussed. PMID- 24799820 TI - Skin rash during treatment with generic itraconazole. AB - Generic drugs have the same active substance, the same pharmaceutical form, the same therapeutic indications and a similar bioequivalence with the reference medicinal product (branded). Although a similar efficacy is postulated, some cases of clinical inefficacy during treatment with generic formulations have been reported. In this case, we describe a woman with onychomycosis that developed a skin rash during treatment with a generic formulation of itraconazole. Drug administration and its re-challenge confirmed the association between itraconazole and skin rash. Both Naranjo probability scale and World Health Organization causality assessment scale documented a probable association between generic-itraconazole and skin rash. The switch from generic formulation to brand one induced an improvement of symptoms. Since we are unable to evaluate the role of each excipient in the development of skin rash, we cannot rule out their involvement. However, more data are necessary to better define the similarities or differences between branded and generic formulations. PMID- 24799821 TI - Tumor lysis syndrome in multiple myeloma treated with bortezomib. AB - A 65 year old male diagnosed as multiple myeloma was started on bortezomib developed tumor lysis syndrome. Bortezomib induced tumor lysis is rare and suitable precautions should be considered in these patients. PMID- 24799823 TI - Drug utilization pattern and pharmacoeconomic analysis in geriatric medical in patients of a tertiary care hospital of India. PMID- 24799822 TI - A case of tinnitus induced by chlorpromazine in a pediatric patient. AB - Chlorpromazine is a well-known antipsychotic agent that binds with a variety of receptors in the central nervous system. To date, chlorpromazine has never been associated with onset of hearing disorders and tinnitus. We report on an unexpected suspect adverse reaction to chlorpromazine that occurred in a 12-year old boy, affected by severe generalized anxiety disorder. After treatment with chlorpromazine, the patient experienced an enhanced sensitivity to sounds accompanied by perception of noises of the buzzing or ringing type. This clinical case is of great clinical interest as chlorpromazine is not currently included among potentially ototoxic drugs. PMID- 24799824 TI - Author reply. PMID- 24799825 TI - European Heart and Rhythm Association guidelines on new oral anticoagulants: A bold step forward. PMID- 24799826 TI - Author reply. PMID- 24799827 TI - Amikacin, bupivacaine, fentanyl and Kounis syndrome. PMID- 24799828 TI - Author reply. PMID- 24799829 TI - Randomization and online databases for clinical trials. PMID- 24799830 TI - Lorcaserin: A novel antiobesity drug. AB - Obesity is a major co-morbidity with hypertension and diabetes mellitus. There are few drugs for treatment of obesity like orlistat and recentlty approved drug lorcaserin. Lorcaserin has serotonergic properties and acts as an anorectic. It may cause serious side effects, including serotonin syndrome, particularly when taken with certain medicines that increase serotonin levels or activate serotonin receptors. Although, mainstay and first line of approach of treatment will always remain in having low calorie diet and increase in physical activity. Lorcaserin has come as a new hope to achieve success in treating obese patients but still a long road with further extensive research to be undertaken in the treatment of obesity. PMID- 24799831 TI - Aberrant hedgehog signaling and clinical outcome in osteosarcoma. AB - Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration. PMID- 24799832 TI - Novel agents in the management of castration resistant prostate cancer. AB - Prostate cancer (PCa) is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC). Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC. PMID- 24799834 TI - Letter from the editor. PMID- 24799833 TI - Systems oncology: A new paradigm in cancer research. PMID- 24799836 TI - Patterns of acetaminophen use exceeding 4 grams daily in a hospitalized population at a tertiary care center. AB - Unintentional acetaminophen-induced hepatotoxicity has been increasingly recognized as a significant problem, prompting increased scrutiny and restrictions from the US Food and Drug Administration on products combining acetaminophen with narcotics. Patterns of acetaminophen use have not previously been reported in the hospitalized patient population, which may be especially vulnerable to liver injury. We aimed to quantify the frequency at which acetaminophen dosing exceeded the recommended maximum of 4 g/day in hospitalized patients. This was a retrospective, single-center, cohort study at a large tertiary care academic hospital. We queried our inpatient electronic medical record database to identify patients admitted between 2008 and 2010 who were receiving cumulative daily acetaminophen doses exceeding 4 g on at least 1 hospital day. Of 43,761 admissions involving acetaminophen administration, the recommended maximum cumulative daily dose of 4 g was exceeded in 1119 (2.6%) cases. Patients who were administered a larger number of acetaminophen-containing medications were more likely to receive doses in excess of the recommended maximum. Alanine aminotransferase (ALT) levels were checked within 14 days following acetaminophen exposure in excess of 4 g in 35 (3.1%) cases. Excessive acetaminophen dosing of hospitalized patients, who may be at increased risk for acetaminophen-induced hepatotoxicity, occurred in a minority of patients. The use of multiple acetaminophen-containing medication formulations contributed to excessive dosing. ALT level monitoring in this group was infrequent, precluding assessment of biochemical evidence of liver injury. This cohort of patients may represent an ideal population for further prospective study with more intensive and longer-term biochemical monitoring to assess for evidence of liver injury. PMID- 24799837 TI - Ethical considerations for clinical trials in inflammatory bowel disease. AB - Although advancements in the field of inflammatory bowel disease (IBD) include effective therapies for many patients with Crohn's disease and ulcerative colitis, there remains a large unmet need, and there is a large number of investigational agents in the pipeline. Drug development through clinical trials is critical to understanding the safety and efficacy of new therapies in the affected human population, and the need for ethical trial design is of the utmost importance. This paper explores the ethical issues of clinical trials in IBD, focusing on placebo-controlled trials, vulnerable patients, exposure to monoclonal antibodies, globalization of trials, and surgical advances. PMID- 24799838 TI - Fibrosis and cirrhosis in HCV infection. PMID- 24799835 TI - Gastrointestinal motility disorders in children. AB - The most common and challenging gastrointestinal motility disorders in children include gastroesophageal reflux disease (GERD), esophageal achalasia, gastroparesis, chronic intestinal pseudo-obstruction, and constipation. GERD is the most common gastrointestinal motility disorder affecting children and is diagnosed clinically and treated primarily with acid secretion blockade. Esophageal achalasia, a less common disorder in the pediatric patient population, is characterized by dysphagia and treated with pneumatic balloon dilation and/or esophagomyotomy. Gastroparesis and chronic intestinal pseudo-obstruction are poorly characterized in children and are associated with significant morbidity. Constipation is among the most common complaints in children and is associated with significant morbidity as well as poor quality of life. Data on epidemiology and outcomes, clinical trials, and evaluation of new diagnostic techniques are needed to better diagnose and treat gastrointestinal motility disorders in children. We present a review of the conditions and challenges related to these common gastrointestinal motility disorders in children. PMID- 24799839 TI - Difficult endoscopic retrograde cholangiopancreatography. PMID- 24799840 TI - Inflammatory bowel disease and sexual dysfunction. PMID- 24799841 TI - The epidemiology and characteristics of eosinophilic esophagitis. PMID- 24799842 TI - Critical views in gastroenterology & hepatology: aspirin prophylaxis: putting gut bleeds into perspective. PMID- 24799843 TI - Induction and maintenance therapy with vedolizumab, a novel biologic therapy for ulcerative colitis. PMID- 24799844 TI - Commentary: vedolizumab: a new mechanism of action for the treatment of ulcerative colitis. PMID- 24799845 TI - Iron burns: a problem in adults as well as children. AB - Burns from domestic irons are potentially preventable injuries which can result in significant morbidity. Several studies have reported these injuries in children but there are no reports to date in adults. Epidemiology, management and outcome of these injuries is described, and possible preventative strategies are discussed. We present a retrospective case note review of 50 adult and paediatric patients with electric iron burns. Cases were identified from data collected for a national burns database. Information regarding demographics, burn characteristics, treatment and long term outcome was gathered from the medical records. 42 children and 8 adults sustained a burn from an iron during the 4-year study period. The majority of paediatric patients were under 4 years of age. Most burns were small (< 1% TBSA) but despite this 30 (60%) patients were admitted to hospital and 13 (26%) required at least one surgical procedure. In children, most burns occurred at home and were commonly due to pulling the flex or knocking the iron from its surface. In adults, 50% of injuries were associated with epilepsy. Burns from domestic irons are relatively common and cause significant morbidity despite their small size. A bimodal presentation is seen with injuries occurring either before the age of 4 years or during adulthood, when they are typically associated with an underlying medical condition. Education campaigns and design features such as a retractable cord may further reduce the incidence of this type of burn. PMID- 24799846 TI - Neonatal burn injuries: an agony for the newborn as well as the burn care team. AB - This retrospective analysis of neonatal burn injuries was carried out at the Department of Plastic Surgery and Burn Care Centre, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan. A total of 11 neonates who were aged less than 29 days were managed during the 2 year study period. Out of these, 72.7% (8) were male and 27.3% (3) were female. The mean age was 11.18+/-9.67days. The commonest underlying cause of burn insult was accidental direct contact with room heaters in 4 (36.3%) neonates. The TBSA burnt ranged from 3%-55%, with a mean of 18.72+/-17.13%. All the neonates (100%) presented during winter season. Among the body areas affected, the most common was face/head and neck (10). The commonest operative procedure undertaken among the neonates included early wound excision followed by resurfacing with split thickness autografts (5). There were three in hospital mortalities (27.2%) in our series. PMID- 24799847 TI - Selective digestive decontamination (SDD) as a tool in the management of bacterial translocation following major burns. AB - Bacterial translocation after major burns plays an important role in burn sepsis and can be reduced with SDD. 30 patients with burns of 25-50% TBSA were divided into 2 groups. Group I received SDD regimen in the form of amikacin, miconazole, and colistin sulphate. Group II served as a control group. SDD treatment resulted in significant control of infectious episodes and multi-organ dysfunction syndrome (MODS). It also resulted in a reduction of mortality, although this was not statistically significant. Despite the statistical insignificance of the improved mortality rate, SDD treatment seems to be a useful tool in treating this group of highly critical patients. PMID- 24799848 TI - Coexistence of Extended Spectrum Beta-Lactamases, AmpC Beta-Lactamases and Metallo-Beta-Lactamases in Acinetobacter baumannii from burns patients: a report from a tertiary care centre of India. AB - Multidrug-resistant Acinetobacter baumanii is a major pathogen encountered in pyogenic infections, especially from burns patients in hospital settings. Often there is also coexistence of multiple beta-lactamase enzymes responsible for beta lactam resistance in a single isolate, which further complicates treatment options. We conducted a study on burn wound pus samples obtained from the burns unit of our hospital. Phenotypic tests were used to determine the Extended Spectrum Beta-Lactamase, AmpC Beta-Lactamase and Metallo-Beta-Lactamase producing status of the isolates. Almost half of the samples from the burn wounds yielded Acinetobacter baumanii as the predominant pathogen (54.05%). Coexistence of the three resistance mechanisms was seen in 25 of the 100 (25%) isolates of Acinetobacter baumanii. This study emphasizes the need for the detection of isolates that produce these enzymes to avoid therapeutic failures and nosocomial outbreaks. PMID- 24799849 TI - Evaluation of Zataria MultiFlora Boiss and Carum copticum antibacterial activity on IMP-type metallo-beta-lactamase-producing Pseudomonas aeruginosa. AB - Carbapenem resistance due to acquired metallo-beta-lactamases (MBLs) is considered to be more serious than other resistance mechanisms. The aim of this study was to evaluate the antibacterial activity of Zataria multiflora Boiss and Carum copticum plants on IMP-producing P.aeruginosa strains. This experimental study was carried out on hospitalized burn patients during 2011 and 2012. Antibiotics and extracts susceptibility tests were performed by disc diffusion and broth microdilution methods. MBL detection was performed by Combination Disk Diffusion Test (CDDT). The bla(VIM) and bla(IMP) genes were detected by PCR and sequencing methods. Using Combination Disk Diffusion test method, it was found that among 83 imipenem resistant P.aeruginosa strains, 48 (57.9%) were MBL producers. PCR and sequencing methods proved that these isolates were positive for blaIMP-1 genes, whereas none were positive for bla(VIM) genes. The mortality rate of hospitalized patients with MBL-producing Pseudomonas infection was 4/48 (8.3%). It was shown that Zataria multiflora and Carum copticum extracts had a high antibacterial effect on regular and IMP-producing P. aeruginosa strains in 6.25 mg/ml concentration. The incidence of MBL-producing P. aeruginosa in burn patients is very high. In our study, all MBL-producing isolates carry the blaIMP 1 gene. Therefore, detection of MBL-producing isolates is of great importance in identifying drug resistance patterns in P. aeruginosa, and in prevention and control of infections. In this study, it was shown that extracts of Z. multiflora and C. copticum have high antibacterial effects on beta-lactamase producing P. aeruginosa strains. PMID- 24799850 TI - [Not Available]. AB - Marjolin's ulcer refers to the malignant, ulcerous transformation of burn scars or any other wounds. The predominant histological type is squamous cell carcinoma (SCC), and it is characterized by its aggressiveness and increased risk of recurrence and metastases compared to non-SCC scars. The work presented here is a retrospective study of 21 cases of Marjolin's ulcer, collected at the plastic surgery department of the CHU Mohammed VI in Marrakesh, with the aim of addressing the epidemiological, therapeutic and evolutionary aspects of this pathology. Improved prognosis requires not only early diagnosis and treatment, but also a preventive approach which consists of early skin grafts and regular care of any burn scar. PMID- 24799851 TI - Pressure garment therapy (PGT) of burn scars: evidence-based efficacy. AB - Hypertrophic burn scars pose a challenge for burn survivors and providers. In many cases, they can severely limit a burn survivor's level of function, including work and recreational activities. A widespread modality of prevention and treatment of hypertrophic scarring is the utilization of pressure garment therapy (PGT). Despite the magnitude of the problem of hypertrophic scarring and the ubiquitous use of pressure garments as therapy, strong clinical evidence of the efficacy of PGT in the literature is lacking. Some of the challenges facing measurement of efficacy of PGT on hypertrophic scarring are lack of clear definitions for degree of hypertrophic scarring, inability to quantify pressure applied to scars, patient noncompliance to strict PGT time schedules, and inability to conduct randomized controlled trials comparing PGT to no therapy for ethical reasons since PGT is considered a standard of care. In this review, we attempt to summarize and analyze evidence-based literature on PGT and its efficacy in burn hypertrophic scars published in English language in the past 15 years. PMID- 24799852 TI - The role of a dedicated staff psychiatrist in modern burn centers. AB - Psychiatric disorders may be more common in burn-injured subjects than in the general population, and oftentimes contribute to the injury itself. Even in the absence of underlying psychiatric illnesses, burn patients may still benefit from a psychiatric evaluation during and after their hospitalization. In this regard, we included a dedicated psychiatry service in our multidisciplinary burn team. We review herein the course of burn patients that were offered psychiatric evaluation and highlight the benefits of such a program. We conducted an IRB approved retrospective chart review of burn subjects admitted to our institution between June 15, 2009 and April 30, 2010 and identified 83 patients that were examined by our psychiatrist. Indications for consultation, history of psychiatric illness and substance abuse, as well as administered drugs, were recorded. Among the 83 evaluated patients, 48 (57.8%) had a preexisting psychiatric disorder and 36 (43.4%) suffered from substance abuse. The most common indications for consultation were pain (28.1%), alcohol dependence (25.8%), anxiety (24.7%), illicit drug abuse (16.8%), depression (15.7%), post traumatic stress disorder (8.9%), and sleep disturbances (8.9%). Pharmacotherapy was initiated in 75 patients (90.3%). 31 (37.3%) had neither a psychiatric disorder nor a history of substance abuse, although 26 of them (83.9%) still received drugs for psychiatric conditions. The inclusion of a dedicated psychiatrist as part of our burn team has improved our comprehensive burn care. In the overwhelming majority of cases, even in the absence of preexisting psychiatric illnesses, consultation resulted in pharmacologic intervention and enhanced patient care. PMID- 24799853 TI - Suicidal burns in Samarkand burn centers and their consequences. AB - Suicide is a global public health problem, particularly in Asia where few countries with large populations have high suicide rates accounting for the majority of the world's suicides. During a 14-year period, 76 individuals, aged 17 to 66 years, committed suicide from 1995 to 2008 and were included in this report. Data was collected on each patient including, age, sex, place of injury, patient occupation, accommodation, psychiatric illness, suicidal motives, flammable substances used, place of burn, season of the year, and total body surface area (TBSA) burnt. Most suicidal cases (55 out of 76) had a history of depressive episodes and emotional unstable disorders, and 18 of them had a known history of psychiatric illness. In 5 cases alcohol intoxication was present at the moment of suicide, and 3 patients had chronic alcohol dependence together with basic psychiatric disease. It is also evident from this study that the causes of suicide in females are mainly socio-economical and psychological. PMID- 24799854 TI - MBC News. PMID- 24799855 TI - Intrauterine administration of recombinant human chorionic gonadotropin before embryo transfer on outcome of in vitro fertilization/ intracytoplasmic sperm injection: A randomized clinical trial. AB - BACKGROUND: The direct effect of hCG on the human endometrium was studied several times. OBJECTIVE: The objectives of this study were to evaluate the effectiveness of intrauterine injection of recombinant human chorionic gonadotropin (rhCG) before embryo transfer (ET). MATERIALS AND METHODS: In this randomized placebo controlled clinical trial, a total number of 182 infertile patients undergoing their first in vitro fertilization/ intracytoplasmic sperm injection (IVF-ICSI) cycles were randomly assigned to receive 250MUg intrauterine rhCG (n=84) or placebo (n=98) before ET. The implantation and pregnancy rates were compared between groups. RESULTS: Patients who received intrauterine rhCG before ET had significantly higher implantation (36.9% vs. 22.4%; p=0.035), clinical pregnancy rates (34.5% vs. 20.4%; p=0.044) and ongoing pregnancy rate (32.1% vs. 18.4%; p=0.032) when compared to those who received placebo. The abortion (2.4% vs. 2.0%; p=0.929) and ectopic pregnancy rates (1.2% vs. 1.0%; p=0.976) were comparable between groups of rhCG and placebo, respectively. CONCLUSION: Intrauterine injection of 250MUg of rhCG before ET significantly improves the implantation and pregnancy rates in IVF/ICSI cycles. REGISTRATION ID IN IRCT: IRCT2012121711790N1 This article extracted from fellowship course thesis. (Masoumeh Younesi). PMID- 24799856 TI - Comparison effect of physiotherapy with surgery on sexual function in patients with pelvic floor disorder: A randomized clinical trial. AB - BACKGROUND: Female sexual dysfunction is a common problem among general population, especially in urogynecological patient, and can lead to a decrease in quality of life and affect martial relationship. OBJECTIVE: This study was compared the effect of surgical methods versus physiotherapy on sexual function in pelvic floor disorder. MATERIALS AND METHODS: This randomized controlled trial was performed in Urogynecology clinic since August 2007 to December 2009 on 90 patients aged from 25-55 years with previous delivery, positive history of sexual dysfunction with stage <3 of pelvic organ prolapsed and divided in two groups. Group A (n=45) received standard rectocele repair and prineorrhaphy, group B (n=45) received physiotherapy for eight weeks twice a week (electrical stimulation, Kegel exercises). The female sexual function index (FSFI) used to evaluate the sexual function in cases before and after intervention. Frequency of variable scores (libido, orgasm, dysparunia) included without disorder, frequently good, sometimes good, very much and extreme were compared between two groups. RESULTS: Libido and arousal were improved in both groups (p=0.007, p=0.001 respectively). Orgasm and dyspareunia were improved in group B (p=0.001). Dysparunia was more painful in group A. There was significant difference between two groups (improvement of orgasm and dysparunia in group B) (p=0.001). CONCLUSION: It seems that physiotherapy is an appropriate method for treatment of sexual disorder in pelvic floor disorder. REGISTRATION ID IN IRCT: IRCT2013031112790N1. PMID- 24799857 TI - Effect of human T-cell lymphotrophic virus type 1 (HTLV-1) in seropositive infertile women on intracytoplasmic sperm injection (ICSI) outcome. AB - BACKGROUND: Human T-cell Lymphotrophic virus type 1 (HTLV-1) has infected more than 20 million people worldwide. Northeast of Iran, Mashhad, the capital of Razavi Khorasan Province, is endemic for HTLV-1 with a prevalence of 3% among general population. OBJECTIVE: We evaluated the ICSI outcome in our program for (HTLV-1) serodiscordant couples (SDCs) with the female infected in comparison with control group. MATERIALS AND METHODS: This study was performed between 2007 and 2011 in Novin Infertility Treatment Center (Mashhad, Iran). We examined 32 ICSI cycles of HTLV-1 infected women in comparison with an age matched control group (n=62). ICSI outcome was compared regarding fertilization rate (FR), embryo quality parameters, implantation rate (IR), clinical pregnancy rate (PR), and abortion rate (AR). RESULTS: Fertilization (p=0.15), implantation (p=0.33), and pregnancy rate (p=0.12) were similar between the groups. No difference was found regarding the number of transferred embryos (on day 2 or 3) and cryopreserved embryos, multiple pregnancies, or abortion rates between the groups. CONCLUSION: Our results suggest that the embryo quality and ICSI outcome are not affected by HTLV-1 infection in serodiscordant couples. The major finding of this study is that the outcome of ICSI in HIV-I-infected patients and seronegative controls is similar. PMID- 24799858 TI - Association between increased expression of endothelial isoform of nitric oxide synthase in the human fallopian tube and tubal ectopic pregnancy. AB - BACKGROUND: Tubal ectopic pregnancy (tEP) is the most common type of extra uterine pregnancy and the most common cause of maternal mortality. Nitric oxide (NO) is a molecule that incorporates in many physiological processes of female reproductive system. Recent studies have demonstrated the possible role of endothelial isoform of nitric oxide synthase (eNOS) enzyme in the regulation of many reproductive events that occur in the fallopian tube (FT). OBJECTIVE: The aim of this study was to evaluate the expression of eNOS in the FTs of women with tEP. MATERIALS AND METHODS: In this case-control study, a total number of 30FTs samples were obtained from three groups including: 10 FTs of women that bearing an EP, 10 FTs from the non-pregnant women at luteal phase of the menstrual cycle, and 10 FTs of healthy pregnant women (n=10). Samples were fixed in 10% buffered formalin and then were evaluated by immunohistochemistry. RESULTS: Localization of eNOS was seen in secretory and ciliated luminal epithelium and vascular endothelium of all groups. However, we did not observed the expression of eNOS in smooth muscle cells of all groups. Expression of eNOS in luminal epithelium of women with EP compared to non-pregnant women at luteal phase of menstrual cycle and healthy pregnant group showed statistically significant increase (p=0.00). Significant difference in expression of eNOS was not observed in luminal epithelium of FTs of women at luteal phase compared to healthy pregnant groups (p=0.78). CONCLUSION: This study indicates that changes in expression of eNOS in luminal epithelium of FT may lead to development of EP. This article extracted from M.Sc. thesis. (Leyla Fath Bayati). PMID- 24799859 TI - Rabbit antiserum to mouse embryonic stem cells delays compaction of mouse preimplantation embryos. AB - BACKGROUND: Mouse embryonic stem (ES) cells are derived from the inner cell mass (ICM) of the preimplantation blastocysts. So it is suggested that ES and ICM cells should have similar cellular surface molecules and antiserum to ES cells can inhibit ICM development. OBJECTIVE: The objective of this study was to evaluate the effect of rabbit antiserum to ES cells on mouse preimplantation embryo development and chimera production. MATERIALS AND METHODS: Mouse 4-cell embryos were matured in vitro at 37.5(o)C, in humidified 5% CO2 atmosphere for 12 36 h. The embryos were cultured in KSOM medium with or without antiserum for 12 36 h. The ratios of in vitro embryo development of the blastocysts, cell division, attachment potential, alkaline phosphatase activity, post-implantation development, and chimera production were assessed and compared with the control group. P<0.05 was considered as significant. RESULTS: The rabbit antiserum to mouse ES cells showed delay in embryo compaction and induced decompaction at 8 cell stage. The development of 4-cell embryos in the presence of the antiserum for 36h did not lead to a reduced or absent ICM. These embryos still displayed positive alkaline phosphatase activity, normal cell division, embryo attachment, outgrowth formation, implantation and post-implantation development. In addition, decompaction induced by antiserum did not increase production and germline transmission of chimeric mice. CONCLUSION: The results showed that antiserum to ES cells delayed embryo compaction and did not affect post-implantation development and chimera production. PMID- 24799860 TI - Derivation of ES-like cell from neonatal mouse testis cells in autologous sertoli cells co-culture system. AB - BACKGROUND: Spermatogonial stem cell (SSC) is a self-renewing population of male adult stem cell. SSCs have a differentiation potential which are similar to embryonic stem cells. These Embryonic stem like (ES-like) cells can be a potential source for pluripotent cells for stem cell-based therapy. OBJECTIVE: This study presents an economical and simple co-culture system for pluripotent stem cells generation from neonatal mouse testis Materials and Methods: Isolated testicular cells were cultured in DMEM/F12. Characteristics of the isolated cells and obtained ES-like cell were immune-cytochemically confirmed by examining the presence of PLZF, vimentin, Oct4 and Nanog protein. Expression of the pluripotency and germ-cell specific genes was analyzed by qPCR in derived ES-like colony and SSCs respectively. RESULTS: The experiment results indicated that our method of obtaining pluripotent ES-like cells from spermatogonial cells (SCs) is simpler than the described methods. ES-like cells were immunopositive for pluripotency markers. ES-like cell qPCR results indicated significant increase in pluripotency genes expression and significant decrease in germ cell-specific genes expression. CONCLUSION: The results indicated that ES-like cell with pluripotency characteristic were generated from freshly isolated spermatogonial cells. The pluripotent stem cells provide a cellular reservoir usable for regenerative medicine instead of embryonic stem cells. This article extracted from Ph.D. thesis. (Setareh Javanmardi). PMID- 24799861 TI - Prevalence and risk factors associated with preterm birth in Ardabil, Iran. AB - BACKGROUND: Preterm birth is a leading cause of perinatal mortality and long-term morbidity as well as the long-term health consequences and cognitive outcomes. OBJECTIVE: Present study was conducted to determine prevalence and risk factors associated with preterm birth in Ardabil, Iran. MATERIALS AND METHODS: A case control study was conducted between Nov 2010 and July 2011 in all three maternal hospitals in Ardabil. All the live newborns during the study period were investigated. Of 6705 live births during the study period 346 births occurred in <37 weeks were taken as a case and 589 term neonates were taken as a control group. Data were obtained through review of prenatal and hospital delivery records. Univariate and multivariate logistic regression analysis were applied to obtain magnitude of association between independent variables and preterm birth. RESULTS: The prevalence rate of preterm birth was 5.1%. History of previous preterm birth (OR=12.7,CI: 3.9-40.4, p<0.001), hypertension (OR=7.3, CI:2.1-25.4, p=0.002), Oligohydramnios (OR=3.9, CI:1.6-9.5, p=0.002), spouse abuse (OR=3.7, CI:1.1-11.8, p=0.024), preeclampsia (OR=3.6, CI:1.3-10.3, p=0.014), premature rupture of membrane (OR=3.1, CI:1.9-4.9, p=0.000), bleeding or spotting during pregnancy (OR=2.0, CI:1.0-3.8, p=0.037), Hyperemesis Gravid arum (OR=2.0, CI: 1.1 3.8, p=0.015), urinary tract infection in 26-30 weeks , (OR=1. 8 CI:1.0-3.2, p=0.04), diastolic blood pressure <=60 mmg (OR=1.5, CI: 0.99-2.2, p=0.049) were determined as significant risk factors for preterm birth. CONCLUSION: Early detection and treatment of diseases or disorders among pregnant women especially hypertension, Oligohydramnios, preeclampsia, bleeding or spotting, Hyperemesis Gravid arum, urinary tract infection, and low diastolic blood pressure as well as the improving health care quality delivered to pregnant women may reduce preterm prevalence rate. PMID- 24799862 TI - The impact of alpha lipoic acid on developmental competence of mouse vitrified pre-antral follicles in comparison to those isolated from vitrified ovaries. AB - BACKGROUND: Cryopreservation of ovarian tissues and pre-antral follicles is a promising prospect for preservation of women fertility. OBJECTIVE: The aim of this study was to evaluate the in vitro developmental competence of mouse vitrified pre-antral follicles in comparison to isolated pre-antral follicles derived from vitrified ovaries in the presence of alpha lipoic acid (ALA). MATERIALS AND METHODS: Pre-antral follicles derived from fresh, vitrified-warmed ovarian tissues and vitrified-warmed pre-antral follicles were cultured individually with or without ALA, followed by adding hCG to induce ovulation. The follicle growth, oocyte maturation, and embryo development were assessed. RESULTS: The diameter and development of follicles, oocyte maturation and embryo development rates were significantly higher in ALA supplemented groups compared to the respective ALA-free conditions groups. Aforementioned parameters were significantly higher in vitrified-warmed follicles in comparison to follicles derived from vitrified-warmed ovaries. CONCLUSION: These findings support a superior performance of pre-antral follicles when vitrified rather than when isolated from vitrified ovaries with regard to increasing the rates of developmental parameters. Moreover, ALA improves the in vitro maturation of pre antral follicles in vitrified and non-vitrified samples. This article extracted from M.Sc. thesis. (Sahar Hatami). PMID- 24799863 TI - Effect of aqueous and hydro-alcoholic extracts of lettuce (Lactuca sativa) seed on testosterone level and spermatogenesis in NMRI mice. AB - BACKGROUND: One of the considerable uses of lettuce (Lactuca sativa) seed in traditional medicine has been to reduce semen, sperm and sexuality. OBJECTIVE: The aim of this study was to investigate the effects of aqueous and hydro alcoholic extracts of lettuce seed on testosterone level and spermatogenesis. MATERIALS AND METHODS: In this experimental study 24 adult male NMRI mice weighing 20-25gr were purchased. Animals were randomly divided into 4 groups: controls, hydro-alcoholic (200 mg/kg) and aqueous extracts (50, 100mg/kg). The extracts were injected intraperitoneally once a day for 10 consecutive days. 2 weeks after the last injection, the mice were anaesthetized by ether and after laparatomy blood was collected from the heart to determine testosterone by ELISA assay kit. Then testis and cauda epididymis of all animals were removed for analyzing testis morphology and sperm count and viability. RESULTS: Testis weight in hydro-alcoholic and aqueous extracts 100 mg/kg (p=0.001) and aqueous extract 50 mg/kg (p=0.008) groups was increased. Sperm viability in hydro-alcoholic (p=0.001) and aqueous extracts 50 (p=0.026), 100 mg/kg (p=0.045) groups was decreased, Also the results showed a significant decrease in sperm count in hydro alcoholic (p=0.035) and aqueous extracts 50 mg/kg (p=0.006) groups in comparison with control group. Also there was a significant increase in serum level of testosterone in aqueous extract 50 mg/kg group in comparison with control (p=0.002) hydro-alcoholic (p=0.001) and aqueous extracts 100 mg/kg (p=0.003) groups. CONCLUSION: Present results demonstrated that hydro-alcoholic and aqueous 50 mg/kg extracts of lettuce seed have antispermatogenic effects, also aqueous extract 50 mg/kg increased serum level of testosterone in mice. Therefore we can suggest that lettuce seed could be a potential contraceptive agent. This article extracted from M.Sc. student research project. (Ali Akbar Oroojan). PMID- 24799864 TI - Effectiveness of aspirin compare with heparin plus aspirin in recurrent pregnancy loss treatment: A Quasi experimental study. AB - BACKGROUND: Using aspirin, heparin, or both in women with unexplained recurrent miscarriage could be useful, because this problem might be initiated by thrombosis in decidual vessels. OBJECTIVE: To investigate the association between thrombophilia and unexplained recurrent miscarriage and to evaluate the efficacy of anticoagulant treatment. MATERIALS AND METHODS: In this quasi experimental, we enrolled 520 women, who had a history of recurrent miscarriage. Two hundred fifty two women with unexplained recurrent miscarriage were assigned to receive aspirin (80 mg daily) for two month before pregnancy and after confirmation of a viable pregnancy until 36 weeks of gestation or receive aspirin, as the same, plus heparin (5000 unit twice a day) subcutaneously after confirmation of viable pregnancy until 4 weeks after delivery. Type of medication was chosen for each woman according to number of abortion and age. RESULTS: Live-birth rates did not different significantly among the two study groups. The proportions of women who gave birth to a live normal infant were 74.5% in the group receiving aspirin plus heparin (combination-therapy group) and 79.8% in the aspirin group. CONCLUSION: Live-birth rates did not different significantly among the two study groups. So, using aspirin or aspirin plus heparin did not change pregnancy rate in these patients. Using aspirin is easier than injecting heparin which should be chosen case by case. This article extracted from M.Sc. thesis. (Tahereh Jahaninejad) REGISTRATION ID IN IRCT: IRCT2013102315123N1. PMID- 24799865 TI - Propofol or Thiopental sodium in patients undergoing reproductive assisted technologies: Differences in hemodynamic recovery and outcome of oocyte retrieval: A randomized clinical trial. AB - BACKGROUND: Thiopental sodium and Propofol are two widely-used drugs in the induction of anesthesia in assisted reproductive technology (ART). However, the side effects and outcome of recovery from anesthesia of these drugs on ART have not been identified yet. OBJECTIVE: This study aimed at investigating the side effects and hemodynamic effects of using thiopental sodium and propofal as well as effects of these drugs on pregnancy outcome in ART cycles. MATERIALS AND METHODS: In this double blinded) randomized controlled trial, 90 woman candidate for ART were randomly divided into two groups. 47 patients received Propofol (2.5 mg/kg) and 43 patients received thiopental (5mg/kg) for anesthesia induction. The entry hemodynamic parameters of the patients were documented. During the anesthesia process, hemodynamic parameters were checked at five-minute intervals. RESULTS: The results of the study showed a statistically significant difference between two groups in terms of their response to verbal stimulation (p<0.001), the normalization time of the rate and quality of breathing (p<0.001), nausea (p<0.001), and vomiting (p<0.001). Also, in comparison with the other group, all these parameters were better in Propofol group. There was found no significant difference between two groups in terms of other variables. CONCLUSION: Based on the findings of the study, Propofol has fewer known side effects. Vomiting and nausea as two known side effect of anesthesia are significantly lower in patients receiving Propofol than patients who received thiopental. REGISTRATION ID IN IRCT: IRCT201303135393N2 This article extracted from M.D. thesis. (Reza Jouya). PMID- 24799866 TI - Influence of genetic abnormalities on semen quality and male fertility: A four year prospective study. AB - BACKGROUND: Wide range of disorders ranging from genetic disorders to coital difficulties can influence male fertility. In this regard, genetic factors are highlighted as the most frequent, contributed to 10-15%, of male infertility causes. OBJECTIVE: To investigate the influence of genetic abnormalities on semen quality and reproductive hormone levels of infertile men from Northeast China. MATERIALS AND METHODS: 2034 infertile men including 691 patients with abnormal sperm parameters were investigated retrospectively. Semen analysis was performed according to the World Health Organization guidelines. Y chromosome micro deletions were detected by polymerase chain reaction assays. Chromosome analysis was performed using G-banding. RESULTS: The incidence of abnormal chromosomal karyotype in the patients with abnormal sperm parameters was 12.01% (83/691). The most frequent cause was Klinefelter's syndrome 37.35% (31/83). As the same as chromosomal abnormalities group, the volumes of testes (p=0.000 and 0.000, respectively) and the levels of testosterone (T) (p=0.000), and testosterone/ luteinizing hormone (T/LH) (p=0.000) of patients with Y chromosome micro deletions were significantly lower than those of fertile group. In addition, the levels of follicle-stimulating hormone (FSH) (p=0.000), and luteinizing hormone (LH) (p=0.000) were significantly higher in patients with Y chromosome micro deletions than those in the fertile group. Translocation abnormalities displayed slight effect on sperm motility. CONCLUSION: Y chromosome micro deletions and sex chromosome disorders particularly Klinefelter's (47, XXY), have severe adverse influence on normal hormone levels, testicular volume and sperm count, whereas translocation abnormalities may inversely correlate with sperm motility. PMID- 24799867 TI - Effects of ascorbic acid on sperm motility, viability, acrosome reaction and DNA integrity in teratozoospermic samples. AB - BACKGROUND: Oxidative stress in teratozoospermic semen samples caused poor assisted reproductive techniques (ART) outcomes. Among antioxidants, ascorbic acid is a naturally occurring free radical scavenger and as such its presence assists various other mechanisms in decreasing numerous disruptive free radical processes. OBJECTIVE: The main goal of this study was to evaluate potential protective effects of ascorbic acid supplementation during in vitro culture of teratozoospermic specimens. MATERIALS AND METHODS: Teratozoospermic semen samples that collected from 15 volunteers were processed, centrifuged and incubated at 37(o)C until sperm swimmed-up. Supernatant was divided into four groups and incubated at 37(o)C for one hour under different experimental conditions: Control, 10 um A23187, 600um ascorbic acid and 10 um A23187+600 um ascorbic acid. After incubation sperm motility, viability, acrosome reaction, DNA damage and malondialdehyde levels were evaluated. RESULTS: Our results indicated that after one hour incubation, ascorbic acid significantly reduced malondialdehyde level in ascorbic acid group (1.4+/-0.11 nmol/ml) compared to control group (1.58+/-0.13 nmol/ml) (p<0.001). At the end of incubation, progressive motility and viability in ascorbic acid group (64.5+/-8.8% and 80.3+/-6.4%, respectively) were significantly (p<0.05 and p<0.001, respectively) higher than the control group (54.5+/-6.8% and 70.9+/-7.3%, respectively). A23187 significantly (p<0.0001) increased acrosome reaction in A23187 group (37.3+/-5.6%) compared to control group (8.5+/-3.2%) and this effect of A23187 attenuated by ascorbic acid in ascorbic acid+A23187 group (17.2+/-4.4%). DNA fragmentation in ascorbic acid group (20+/-4.1%) was significantly (p<0.001) lower than controls (28.9+/-4.6%). CONCLUSION: In vitro ascorbic acid supplementation during teratozoospermic semen processing for ART could protect teratozoospermic specimens against oxidative stress, and it could improve ART outcome. PMID- 24799868 TI - Results from adding recombinant LH for assisted reproductive technology treatment: A randomized control trial. AB - BACKGROUND: Based on classical two-cell, two-gonadotropin theory, in the follicle, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) put on their main effects on the granulosa and theca cells. LH is essential for androgens production. Androgens are used for estradiol production by granulosa cells. Profound suppression of LH concentrations in some normogonadotropic patients can cause several adverse effects. OBJECTIVE: The main clinical purpose of this study was that normoresponder women treated with controlled ovarian super ovulation for IVF or ICSI may benefit from co-administration of rLH. MATERIALS AND METHODS: 40 patients who were candidates for assisted reproductive technology (ART) were randomly selected. In all patients long luteal protocol was used for ovulation induction. Patients were randomly divided into two groups: Group 1 (n=20) with standard long protocol (GnRH agonist) and r-FSH alone, Group 2 (n=20) with standard long protocol (GnRH agonist) and r-FSH with r-LH. RESULTS were statistically analyzed and compared in two groups. RESULTS: The number of retrieved oocytes, mature oocytes, cleaved embryos, transferred embryos, estradiol levels in Human chorionic gonadotropin (hCG) administration day, implantation rate and clinical pregnancy rate in group 2 were higher but not significantly different. CONCLUSION: Administration of rLH in late follicular phase had no beneficial effect on outcomes in young women with mean age of 31 years. Maybe a greater sample size should be used to see the effects more accurately; also it is possible that rLH will be useful in older patients. Registration ID in IRCT: IRCT201304302575N4. PMID- 24799869 TI - Increasing and decreasing factors of hope in infertile women with failure in infertility treatment: A phenomenology study. AB - BACKGROUND: Assisted reproductive technology (ART) provide the hope of pregnancy for infertile women, but do not always turn this hope into reality. OBJECTIVE: The purpose of this study was to explore the lived experience of infertile women from increasing and decreasing factors of hope in infertile women with failure in infertility treatment. MATERIALS AND METHODS: Using a qualitative research design (Phenomenology study), 23 subjects were selected who had experienced infertility failure visited by gynecologist (Rasekh Infertility center) in 2012. The data were collected through semi structured interviews and analyzed using interpretive research strategies of phenomenology by Collizi's seven-stage method. RESULTS: Totally 96 codes were identified. The data arranged in two categories. The factors decreasing and increasing hope in infertility treatments. Totally 5 themes and 20 sub themes were extracted. The increasing factors which emerged from the data contain "spiritual source", "family interaction and support" and "information through the media", and decreasing factors contain "nature of treatments" and "negatively oriented mind". PMID- 24799870 TI - Prognostic factors of first birth interval using the parametric survival models. AB - BACKGROUND: In recent years, the study of birth intervals has been a main determinant of the levels of fertility in the populations, as it is associated with rates of fertility and population growth. OBJECTIVE: The purpose of this study was to firstly apply survival analysis for modeling of first birth interval and secondly to explore its determinants. MATERIALS AND METHODS: In a cross sectional study, the fertility history of 858 women was collected in rural areas of Shiraz (southern Iran) in 2008. We used the survival analysis such as cox regression and alternative parametric models to evaluate the prognostic factors of first birth interval. RESULTS: Among the explanatory variables of interest, age at marriage, level of women's education, and menstrual status had highly significant effects on the duration of birth interval after marriage (p<0.01). CONCLUSION: It is concluded that the suitable parametric models would be a useful tool for fitting to first birth interval, the fact that has been less paid attention to in researches. PMID- 24799871 TI - The emotional-psychological consequences of infertility among infertile women seeking treatment: Results of a qualitative study. AB - BACKGROUND: Infertility is a major life event that brings about social and psychological problems. The type and rate these problems in the context of socio cultural of different geographical areas and sex of people is different. OBJECTIVE: The aim of this qualitative study was to explain the psychological consequences of infertility in Iranian infertile women seeking treatment. MATERIALS AND METHODS: This qualitative study was done using qualitative content analysis on 25 women affected by primary and secondary infertility with no surviving children in 2012. They were purposefully selected with maximum sample variation from a large Fertility Health Research Center in Tehran, Iran. Data were collected using 32 semi-structured interviews and analyzed by the conventional content analysis method. RESULTS: The findings of this study include four main themes: 1. Cognitive reactions of infertility (mental engagement; psychological turmoil). 2. Cognitive reactions to therapy process (psychological turmoil; being difficult to control in some situations; reduced self-esteem; feelings of failure). 3. Emotional-affective reactions of infertility (fear, anxiety and worry; loneliness and guilt; grief and depression; regret). 4. Emotional-affective reactions to therapy process (fear, anxiety and worry; fatigue and helplessness; grief and depression; hopelessness). CONCLUSION: This study revealed that Iranian infertile women seeking treatment face several psychological-emotional problems with devastating effects on the mental health and well-being of the infertile individuals and couples, while the infertility is often treated as a biomedical issue in Iranian context with less attention on the mental-emotional, social and cultural aspects. This article extracted from Ph.D. thesis. (Seyede Batool Hasanpoor-Azghady). PMID- 24799872 TI - Effects of silver nano-particles on sperm parameters, number of Leydig cells and sex hormones in rats. AB - BACKGROUND: Nano-particles are extensively employed in most industries. Several studies have been started to explore the probable detrimental effects of nano particles on human reproduction. However, there is insufficient and controversially evident of effects of silver nano-particles on sperm parameters and other reproductive indices. OBJECTIVE: Investigation of the effects of silver nano-particles on sperm parameters, sex hormones and Leydig cells in rat as an experimental model. MATERIALS AND METHODS: In this experimental study, 75 male prepubertal Wistar rats were categorized in five groups including control group and 4 experimental groups (n=15 in each group). The rats in the experimental groups were fed silver nano-particles (60 nm in dimension) with concentrations of 25, 50, 100, and 200 mg/kg/day. After 45 days (about one duration of spermatogenesis in rat), samples of blood were taken from the rats for testosterone, leuteinizing hormone (LH), and follicle stimulating hormone (FSH) assessments. Afterwards, the epididymis and the testis of each rat were dissected for analyzing sperm parameters and Leydig cells. RESULTS: The results demonstrated a statistically significant reduction in number of Leydig cells in experimental groups compared to control one. In addition, the data showed a reduction in testosterone and a rise in LH level which was more obvious in high doses (p<0.05); however, FSH level showed a reduction but it was not statistically significant. A significant decrease was also found in sperm motility and normal sperm morphology in the experimental groups compared to the control one. CONCLUSION: Our results demonstrated that silver nano-particles, in addition to interruption in functions of sex hormones, can diminish the number of Leydig cells and sperm parameter indices. It should be noted that the effects of nano-particles on reproductive indices are dose-dependent. PMID- 24799873 TI - Nifedipine compared to magnesium sulfate for treating preterm labor: A randomized clinical trial. AB - BACKGROUND: Preterm labor is the leading cause of infant morbidity and mortality so it may be necessary to administer tocolytics for treatment of it. OBJECTIVE: The aim of this study was to compare the efficacy and safety of magnesium sulfate and nifedipine in the management of preterm labor. MATERIALS AND METHODS: 100 women with documented preterm labor were randomly assigned to receive magnesium sulfate (n=50) and nifedipine (n=50) as tocolytic therapy. Before tocolysis, patient did not receive any sedation. After tocolysis, if patient continued to have contractions, they received other tocolytic agents. The main outcome variables examined were days gain in utero, success rate and side effects of tocolysis. RESULTS: Both drugs were equally effective in prevention of labor and delaying delivery >7 days, 56% vs. 64% in the nifedipine and magnesium sulfate groups, and the days gain in utero was no statistically different in two groups. 6% of nifedipine group and 2% of magnesium sulfate group required drug discontinuation due to severe symptoms. There were also no significant differences in maternal characteristics between two groups. The total success rate and side effects were similar in two groups. CONCLUSION: Oral nifedipine could be a suitable alternative for magnesium sulfate with the same efficacy and side effects in the management of preterm labor. Registration ID in IRCT: IRCT2013090914603N1. PMID- 24799874 TI - Study of cytomegalovirus infection in idiopathic infertility men referred to Shariati hospital, Tehran, Iran. AB - BACKGROUND: Cytomegalovirus (CMV) is a prevalent infection in humans. Recent studies have shown the role of CMV infection in male infertility disorder. AIM: Here we aimed to study the role of CMV infection in men with idiopathic infertility. MATERIALS AND METHODS: We performed a case-control study of CMV serology in 200 patients attending male infertility clinic of a university hospital. There were 154 men diagnosed with infertility and 46 men without infertility. The patients were asked to donate their sperm, blood, and urine. The presence of CMV infection was studied using quantitative polymerase chain reaction. RESULTS: CMV infection was present in 25 of all the studied participants. Controls had a higher sperm count and sperm motility and sperm morphology compared to patients. There were no significant differences in the studied variables between those with and without CMV infection, nor in patients, neither in controls. Sperm morphology was negatively correlated with cigarette smoking (r=-0.15; p<0.03). Even though the prevalence of CMV infection was higher in patients with infertility in control and patient (5/46 vs. 20/154) respectively, this was not statistically significant. CONCLUSION: We did not show a significant role for CMV infection in male infertility. Based on the previous studies, it could be assumed that CMV infection is an important part of the male infertility and its treatment would improve the sperm quality, however this was not confirmed by the present study. PMID- 24799875 TI - Bilateral tubal ectopic pregnancy following intra uterine insemination (IUI): A case report. AB - BACKGROUND: The incidence of ectopic pregnancy varies between 1.5-2% of all pregnancies. Bilateral tubal ectopic pregnancy is rare. It may occur in 1 per 200 000 pregnancies. CASE: This is a case report of 25 year-old woman who underwent intra uterine insemination (IUI), because of tubal factor infertility (unilateral). On the 30(th) day after the IUI she complained from pelvic pain and vaginal bleeding. Pelvic ultrasound showed bilateral tubal ectopic pregnancy with fluid in Douglas Pouch and empty uterine cavity. Exploratory laparotomy, left salpingectomy, and right salpingostomy were performed on the same day of admission. CONCLUSION: The above case suggests that cases presenting with infertility and ectopic pregnancy should be followed very closely with beta-hCG and or Trans Vaginal Sonography (TVS) to exclude double ectopic. So, as in this case, early diagnosis is essential for prevention of maternal morbidity and mortality. PMID- 24799876 TI - Using fertile couples as embryo donors: An ethical dilemma. AB - The use of donated embryos has offered hope for infertile couples who have no other means to have children. In Iran, fertility centers use fertile couples as embryo donors. In this paper, the advantages and disadvantages of this procedure will be discussed. We conclude that embryo-donation should be performed with frozen embryos thus preventing healthy donors from being harmed by fertility drugs. There must be guidelines for choosing the appropriate donor families. In countries where commercial egg donation is acceptable, fertile couples can be procured as embryo donors thus fulfilling the possible shortage of good quality embryos. Using frozen embryos seems to have less ethical, religious and legal problems when compared to the use of fertile embryo donors. PMID- 24799877 TI - A holistic approach to psychological sexual problems in women with diabetic husbands. AB - BACKGROUND: One of negative and influential factor to chronic diseases is creation of sexual problems in the couple's sexual relationship. Sexual health is one of the most important factor in Sexual and marital satisfaction. OBJECTIVE: This study aims to compare the relationship between couple burnout, sexual assertiveness, and sexual dysfunctional beliefs in women with diabetic and non diabetic husbands. MATERIALS AND METHODS: This cross sectional descriptive study was a causal comparative one. The research plan was derived from the master's dissertation for family counseling in Shahid Beheshti University which was done during 2011-2012 in Tehran, Iran. Totally 200 participants were included in this study; 100 participants were women with diabetic husbands and the others were women with non-diabetic husbands. These participants were selected by purposeful sampling method. Data were collected using personality traits and demographic characteristics' questionnaire, couple burnout Measure, Hulbert index of sexual assertiveness and sexual dysfunctional beliefs Questionnaire. RESULTS: RESULTS of the multi-variable analysis of variance indicated that there was a significant difference between couple burnout, sexual assertiveness, and sexual dysfunctional beliefs in women with diabetic and non-diabetic husbands. Women with non-diabetic husbands had a higher mean score in sexual assertiveness factor compared to women with diabetic husbands, whereas in couple burnout and sexual dysfunctional beliefs factors, women with diabetic husbands had a higher mean score. CONCLUSION: It seems that one of the most important factors which influences and increases couple burnout, increases wrong sexual beliefs regarding sexual function, and decreases sexual assertiveness in women is their husbands' sexual dysfunction. In fact, women whose husbands suffer from chronic diseases such as diabetes (which results in sexual dysfunction) have lower sexual assertiveness and higher couple burnout and sexual dysfunctional beliefs compared with other women. This article is extracted from student thesis. (Edalat Asadi). PMID- 24799878 TI - The comparison of anxiety and depression rate between medical staff of infertility centers and obstetrics and gynecology centers of Yazd, Shiraz, Isfahan and Kerman hospitals. AB - BACKGROUND: Regarding the close and continuous interaction of infertility staff with hopeless infertile couples and in the contrary the atmosphere of happiness especially in obstetric wards make a sense that considering anxiety and depression it would be a difference between these two wards. OBJECTIVE: The objective of this study is the comparison of the rate of depression and anxiety between the two wards of infertility and obstetrics and gynecology. MATERIALS AND METHODS: This study is a descriptive-correlation study based on cross-sectional method. 199 individuals who were the staff of infertility and obstetrics and gynecology wards in four provinces enrolled in this study through stratified sampling. Data collection was done by demographic questionnaire, Spiel Berger and Beck depression inventory tests. Data were analyzed by SPSS software using ANOVA test. RESULTS: The result showed the rate of anxiety in obstetrics and gynecology staff of Isfahan center (54.69+/-13.58) and depression rate had increased level in infertility staff of Shiraz center (14.94+/-10.87). Overall, there was significant correlation between anxiety, depression and work place (p=0.047, 0.008 respectively). According to ANOVA test, the mean value of anxiety level was higher in the staff of four obstetrics and gynecology centers and one infertility center Conclusion: As long as we know that infertile couples have little chance for success rate and obstetrics and gynecology wards patients have little risk of failure in treatment, it could be mentioned that the anxiety and depression in the staff are not correlated with the client illness. PMID- 24799879 TI - The relationship between body mass index and sexual function in infertile women: A cross-sectional survey. AB - BACKGROUND: Infertility as the bitterest life experience can affect sexual function. Many studies have shown agitation, depression, marital dissatisfaction, and sexual dysfunction as the psychological outcomes resulting from infertility. Many factors, including body mass index, influence the female sexual function. OBJECTIVE: This study aimed to assess the prevalence of female sexual dysfunction and the relationship between sexual function and body mass index in the Iranian infertile women who had attended the infertility clinic. MATERIALS AND METHODS: This cross-sectional study was conducted on 502 infertile women who had attended Honoree clinic, Jahrom in Iran between April 2012 and December 2012. The infertile cases were classified into three groups according to the body mass index: 20-24.9 (Group I), 25-29.9 (Group II), and >29.9 and above (Group III). In addition, Female sexual function index (FSFI) questionnaire was used in order to assess the sexual problems. Finally, the data were analyzed by descriptive statistics, ANOVA and Student's t-test. RESULTS: The mean age of women was 30.95+/-6.80 years. The results showed that 430 subjects (87.1%) had sexual dysfunction. Furthermore, the rate of sexual dysfunction among the infertile women was reported as 23.30%, 31.47%, and 45.23% in groups I, II, and III, respectively. Considering body mass index, FSFI score was 21.65+/-1.70 in the women with normal weight, 18.08+/-1.52 in overweight women, and 12.21+/-3.62 in obese women and the difference was statistically significant (p<0.001). CONCLUSION: The prevalence of sexual dysfunction was quite high in infertile women, which might be due to the lack of knowledge about marital issues and lack of training in the society. If body mass index is too high, it can have a great effect on fertility. In this study, being overweight and obese based on body mass index had a negative effect on the infertile woman's sexual function. PMID- 24799880 TI - Assessment of ovarian tissues autografted to various body sites followed by IVM in mouse. AB - BACKGROUND: Ovarian tissue transplantation is emerging technologies for fertility preservation. In addition, in vitro maturation (IVM) of oocytes retrieved from ovarian tissues may overcome the fertility defects in certain cases. OBJECTIVE: The aim was to evaluate the best site for ovarian tissue transplantation in mice. Also, feasibility of IVM of oocytes retrieved from auto grafted ovarian tissues was freshly assessed. MATERIALS AND METHODS: Hemi-ovaries from 6 weeks old mice were auto grafted into kidney capsule (K) versus the back muscle (B) and leg muscle (L) in a mouse auto graft model which was stimulated with gonadotrophins. Then ovarian grafts were recovered and processed histologically for follicle assessment compared with control, also the ability of oocytes to mature with IVM was studied 14 days after transplantation. RESULTS: Total follicle count was significantly higher in K-graft (3.5+/-3.17) and the antral follicles were only observed in K-site model. The number of retrieved immature oocytes as well as successful IVM in K-grafts was significantly higher than other groups (p=0.008, p=0.016). CONCLUSION: The kidney capsule is a promising site for ovarian tissue auto graft in mice. This resulted in better follicular survival and IVM outcomes. PMID- 24799881 TI - Comparative expression analysis of Septin 14 in testes of infertile men with normal spermatogenesis and spermatogenic failure. AB - BACKGROUND: Septins are an evolutionary conserved group of GTP-binding and filament-forming proteins that have diverse cellular roles. An increasing body of data implicates the septin family in the pathogenesis of diverse states including cancers, neurodegeneration, and male infertility. OBJECTIVE: The objective of the study was to evaluate the expression pattern of Septin14 in testis tissue of men with and without spermatogenic failure. MATERIALS AND METHODS: The samples retrieved accessible random between infertile men who underwent diagnostic testicular biopsy in Royan institute. 10 infertile men with obstructive azoospermia and normal spermatogenesis and 20 infertile men with non-obstructive azoospermia were recruited for real-time reverse transcription (RT)-PCR analysis of the testicular tissue. Total RNA was extracted with trizol reagent. RESULTS: Comparison of the mRNA level of septin14 revealed that in tissues with partial (n=10) or complete spermatogenesis (n=10), the expression of septin 14 was significantly higher than sertoli cell only tissues. CONCLUSION: The testicular tissues of men with hypospermatogenesis, maturation arrest and sertoli cell only had lower levels of septin 14 transcripts than normal men. These data indicates that Septin 14 expression level is critical for human spermatogenesis. PMID- 24799882 TI - Protective effect of royal jelly on fertility and biochemical parameters in bleomycin-induced male rats. AB - BACKGROUND: Bleomycin (BL) is a glycopeptide antibiotic obtained from the bacterium Streptomyces verticillus which is routinely used for treatment of human cancers. Royal jelly (RJ) is a production from the hypo pharyngeal, mandibular and post cerebral glands of nurse bees. RJ consists of 66% water, 15% sugars, 5% lipids, and 13% proteins, essential amino acids and vitamins. OBJECTIVE: The aim of present study was to evaluate protective effect of royal jelly on sperm parameters and malondialdehyde (MDA) production in rat. MATERIALS AND METHODS: Forty adult male wistar rats (220+/-20gr) were randomly divided into 4 groups (n=10). Control group (CG) received normal saline 10 ml/kg twice a week with Intraperitoneal (I.P) for 48 days (0.3 ml/rat(. Royal Jelly group (RJG) received jelly (100 mg/kg daily) for 48 days orally. Bleomycin group (BLG) received BL (10 mg/kg twice a week) with I.P for 48 days. Royal Jelly+ Bleomycin group (RJ+BLG) received royal Jelly (100 mg/kg /day) orally concomitant with BL administration. Sperm count, motility, and viability were investigated and chromatin quality and DNA integrity were also analyzed. Serum testosterone and MDA concentrations were measured as well. RESULTS: BL caused decline significantly (p<0.05) sperm count, sperm viability, motility as well as testosterone concentration compared to control group while significant (p<0.05) increases in immature sperm, sperm with damaged DNA and MDA concentration were announced in BL in comparison with CG and RJ+BLG. Royal jelly improved Bleomycin-induced toxicity on sperm parameters and testosterone and MDA concentrations. CONCLUSION: The present results support the idea that BL adversely affects sperm parameters and MDA and the RJ with antioxidant properties has positive effects on these parameters. This article extracted from M.Sc. thesis. (Tayebeh amirshahi). PMID- 24799883 TI - New single nucleotide variation in the promoter region of androgen receptor (AR) gene in hypospadic patients. AB - BACKGROUND: Hypospadias is one of the most common congenital abnormalities in the male which is characterized by altered development of urethra, foreskin and ventral surface of the penis. Androgen receptor gene plays a critical role in the development of the male genital system by mediating the androgens effects. OBJECTIVE: In present study, we looked for new variations in androgen receptor promoter and screened its exon 1 for five single nucleotide polymorphisms (SNP) in healthy and hypospadias Iranian men. MATERIALS AND METHODS: In our study, at first DNA was extracted from patients (n=100) and controls (n=100) blood samples. Desired fragments of promoter and exon 1 were amplified using polymerase chain reaction. The promoter region was sequenced for the new variation and exone 1 screened for five SNPs (rs139767835, rs78686797, rs62636528, rs62636529, rs145326748) using restriction fragment length polymorphism technique. RESULTS: The results showed a new single nucleotide variation (C->T) at -480 of two patients' promoter region (2%). None of the mentioned SNPs were detected in patients and controls groups (0%). CONCLUSION: This finding indicates that new single nucleotide polymorphism in androgen receptor promoter may have role in etiology of hypospadias and development of this anomaly. This article extracted from Ph.D. thesis. (Nasim Borhani). PMID- 24799884 TI - Prevalence and clinical significance of antinuclear antibodies in Iranian women with unexplained recurrent miscarriage. AB - BACKGROUND: Antinuclear antibodies (ANAs) in women with recurrent miscarriage have been reported. The presence of moderate to high titers of these antibodies represents an autoimmune condition that can endanger the health of the fetus in pregnant women. OBJECTIVE: In this study, we evaluated the prevalence of ANAs in Iranian women with a history of two or more unexplained abortion. MATERIALS AND METHODS: 560 women with unexplained recurrent miscarriage and 560 healthy controls accounted for this study over a period of 13 months. ANAs were detected by indirect immunofluorescence technique. RESULTS: ANAs were detected in 74 of 560 (13.21%) patient with recurrent miscarriage, and in only 5 of 560 (0.9%) controls (p<0.001). ANA positivity was generally found with low-positive results (1.40-1.80) in about 38% of positive cases, whereas moderate titres (1.160-1.320) and high titres (>1.640) were seen in about 46% and 16% of cases respectively. Finally evaluating of microscopic ANA patterns revealed that about half of positive cases had antibodies against DNA- histone complex, associated with systemic lupus erythematosus disease. CONCLUSION: Antinuclear antibodies are not uncommon in women with unexplained recurrent miscarriage, suggesting the possible role of an autoimmune disorder on abortion, at least in a subgroup of patients. PMID- 24799885 TI - Serum activin A levels and tubal ectopic pregnancy. PMID- 24799886 TI - Effect of chronic valproic Acid treatment on hepatic gene expression profile in wfs1 knockout mouse. AB - Valproic acid (VPA) is a widely used anticonvulsant and mood-stabilizing drug whose use is often associated with drug-induced weight gain. Treatment with VPA has been shown to upregulate Wfs1 expression in vitro. Aim of the present study was to compare the effect of chronic VPA treatment in wild type (WT) and Wfs1 knockout (KO) mice on hepatic gene expression profile. Wild type, Wfs1 heterozygous, and homozygous mice were treated with VPA for three months (300 mg/kg i.p. daily) and gene expression profiles in liver were evaluated using Affymetrix Mouse GeneChip 1.0 ST array. We identified 42 genes affected by Wfs1 genotype, 10 genes regulated by VPA treatment, and 9 genes whose regulation by VPA was dependent on genotype. Among the genes that were regulated differentially by VPA depending on genotype was peroxisome proliferator-activated receptor delta (Ppard), whose expression was upregulated in response to VPA treatment in WT, but not in Wfs1 KO mice. Thus, regulation of Ppard by VPA is dependent on Wfs1 genotype. PMID- 24799887 TI - Effects and Potential Mechanisms of Pioglitazone on Lipid Metabolism in Obese Diabetic KKAy Mice. AB - This study aimed to analyze the effects and potential mechanisms of pioglitazone on triglyceride and cholesterol metabolism in obese diabetic KKAy mice. Pioglitazone was orally administered to KKAy mice over 30 days. Compared to C57BL/6J mice, KKAy mice developed obvious insulin resistance, hepatic steatosis, and hyperlipidemia. Pioglitazone treatment resulted in deteriorated microvesicular steatosis and elevated hepatic triglyceride levels, though plasma triglyceride and free fatty acid levels were reduced by the treatment, compared to nontreated KKAy mice. Plasma alanine aminotransferase activities were also significantly increased. Additionally, pioglitazone increased plasma concentrations of total cholesterol, HDL-cholesterol, and LDL-cholesterol but decreased hepatic cholesterol. Gene expression profiling revealed that pioglitazone stimulated hepatic peroxisome proliferator-activated receptor gamma hyperactivity, and induced the upregulation of adipocyte-specific and lipogenesis related genes but downregulated of genes involved in triglyceride lipolysis and fatty acid beta -oxidation. Pioglitazone also regulated the genes expression of hepatic cholesterol uptake and excretion, such as low density lipoprotein receptor (LDL-R) and scavenger receptor type-BI (SR-BI). These results suggested that pioglitazone could induce excessive hepatic triglyceride accumulation, thus aggravating liver steatosis and lesions in KKAy mice. Furthermore, pioglitazone may suppress the clearance of serum cholesterol from the liver predominantly through inhibition of LDL-R and SR-BI expression, thus increasing the plasma cholesterol. PMID- 24799888 TI - Prediction of human's ability in sound localization based on the statistical properties of spike trains along the brainstem auditory pathway. AB - The minimum audible angle test which is commonly used for evaluating human localization ability depends on interaural time delay, interaural level differences, and spectral information about the acoustic stimulus. These physical properties are estimated at different stages along the brainstem auditory pathway. The interaural time delay is ambiguous at certain frequencies, thus confusion arises as to the source of these frequencies. It is assumed that in a typical minimum audible angle experiment, the brain acts as an unbiased optimal estimator and thus the human performance can be obtained by deriving optimal lower bounds. Two types of lower bounds are tested: the Cramer-Rao and the Barankin. The Cramer-Rao bound only takes into account the approximation of the true direction of the stimulus; the Barankin bound considers other possible directions that arise from the ambiguous phase information. These lower bounds are derived at the output of the auditory nerve and of the superior olivary complex where binaural cues are estimated. An agreement between human experimental data was obtained only when the superior olivary complex was considered and the Barankin lower bound was used. This result suggests that sound localization is estimated by the auditory nuclei using ambiguous binaural information. PMID- 24799889 TI - Overexpression of Testes-Specific Protease 50 (TSP50) Predicts Poor Prognosis in Patients with Gastric Cancer. AB - Purpose. To investigate the expression of TSP50 protein in human gastric cancers and its correlation with clinical/prognostic significance. Methods. Immunohistochemistry (IHC) analysis of TSP50 was performed on a tissue microarray (TMA) containing 334 primary gastric cancers. Western blot was carried out to confirm the expression of TSP50 in gastric cancers. Results. IHC analysis revealed high expression of TSP50 in 57.2% human gastric cancer samples (191 out of 334). However, it was poorly expressed in all of the 20 adjacent nontumor tissues. This was confirmed by western blot, which showed significantly higher levels of TSP50 expression in gastric cancer tissues than adjacent nontumor tissues. A significant association was found between high levels of TSP50 and clinicopathological characteristics including junior age at surgery (P = 0.001), later TNM stage (P = 0.000), and present lymph node metastases (P = 0.003). The survival of gastric cancer patients with high expression of TSP50 was significantly shorter than that of the patients with low levels of TSP50 (P = 0.021). Multivariate Cox regression analysis indicated that TSP50 overexpression was an independent prognostic factor for gastric cancer patients (P = 0.017). Conclusions. Our data demonstrate that elevated TSP50 protein expression could be a potential predictor of poor prognosis in gastric cancer patients. PMID- 24799890 TI - Safety of laparoscopic colorectal surgery in a low-volume setting: review of early and late outcome. AB - Background. There is increasing evidence suggesting that the laparoscopic technique is the treatment of choice for large bowel resection, including for malignancy. The purpose of the study was to assess whether general surgeons, with particular skills in advanced laparoscopy, can adequately provide safe laparoscopic colorectal resections in a low-volume setting. Methods. A retrospective review of prospectively collected case series of all laparoscopic colorectal resections performed under the care of a single general surgeon is presented. The primary endpoint was postoperative clinical outcome in terms of morbidity and mortality. Secondary endpoints were adequacy of surgical margins and number of lymph nodes harvested for colorectal cancer cases. Results. Seventy three patients underwent 75 laparoscopic resections between March, 2003, and May, 2011. There was no elective mortality and the overall 30-day postoperative morbidity was 9.3%. Conversion and anastomotic leakage rates were both 1.3%, respectively. None of the malignant cases had positive margins and the median number of lymph nodes retrieved was 17. Conclusions. Our results support the view that general surgeons with advanced skills in minimally invasive surgery may safely perform laparoscopic colorectal resection in a low-volume setting in carefully selected patient cases. PMID- 24799891 TI - Serum Activins and Follistatin during the Treatment of Chronic Hepatitis C Genotypes 1 and 4 and Their Correlations with Viral Load and Liver Enzymes: A Preliminary Report. AB - Aims. To measure the effect of pegylated interferon- alpha therapy on serum activin-A, activin-B, and follistatin and their correlation with viral load and liver fibrosis in chronic hepatitis C (CHC). Methods. This study was cross sectional and sera were collected from 165 participants classified into 7 groups: 40 healthy negative control, 33 treatment naive patients as positive control, 19 patients at week 4, 22 at week 12, and 19 at week 24 of treatment initiation and 21 responders and 11 nonresponders at the end of 48-week treatment protocol. Serum candidate proteins were measured using ELISA and liver fibrosis was assessed by AST platelet ratio index (APRI). Results. CHC significantly increased activins and decreased follistatin compared to negative control (P < 0.05). Activin-A and follistatin levels returned to the levels of negative control group at weeks 4, 12, and 24 following treatment initiation and were significantly different from positive control (P < 0.05). Both proteins were significantly different between responders and nonresponders. Activin-A correlated positively and significantly with the viral load and APRI. Conclusion. CHC modulates serum activin-A and follistatin and they appear to be influenced by pegylated interferon- alpha therapy. Further studies are needed to explore the role of activins in CHC. PMID- 24799892 TI - Inflammatory bowel disease in australasian children and adolescents. AB - Many reports indicate increasing rates of inflammatory bowel disease, with data also showing changing patterns of this chronic disease in children and adolescents. This review focuses upon the available data of the epidemiology of inflammatory bowel disease in children and adolescents in Australia and New Zealand (collectively termed Australasia). Recent data show high incidence of IBD (especially Crohn disease) in this area and indicate rising rates of IBD in children and adolescents. PMID- 24799893 TI - Association between Faecalibacterium prausnitzii Reduction and Inflammatory Bowel Disease: A Meta-Analysis and Systematic Review of the Literature. AB - Background. Laboratory data suggests a reduction of Faecalibacterium prausnitzii (F. prausnitzii) is confirmed both in fecal samples in inflammatory bowel disease (IBD) patients. Numerous observational studies have suspected dysbiosis, an imbalance between protective and harmful bacteria to be relevant to the etiology and pathogenesis of IBD. Methods. Medline, EMBASE, Pubmed, and others. were searched by 2 independent reviewers. Of 48 abstracts reviewed, 11 studies met our inclusion criteria (subject N = 1180). Meta-analysis was performed with Review Manager 5.2. Results. The bacterial count of F. prausnitzii in IBD patients was significantly lower (6.7888 +/- 1.8875) log10 CFU/g feces than healthy controls (7.5791 +/- 1.5812) log10 CFU/g feces; P < 0.0001. The Standardization Mean Difference of F. prausnitzii in IBD patients was -0.94 (95% confidence interval [CI]: -1.07--0.80). Subgroup analyses revealed a trend toward a greater effect for CD (SMD: -1.13, 95% CI: -1.32--0.94) when compared to UC (SMD: -0.78, 95% CI: -0.97--0.60). Conclusions. The abundance of F. prausnitzii was decreased in IBD patients compared with healthy controls. Furthermore, the reduction of F. prausnitzii and misbalance of the intestinal microbiota are particularly higher in CD patients with ileal involvement. PMID- 24799894 TI - The Role of Virtual Cystoscopy, after Multidetector Computed Tomography Imaging Reconstruction without the Use of Contrast Medium, in the Diagnosis and Evaluations of Bladder Tumors: Preliminary Study. AB - Introduction. Although conventional cystoscopy is considered to be the gold standard for diagnosis and follow-up of bladder tumors, it remains an invasive and costly procedure. With the advent of the multidetector CT (MDCT) scanners supported by specialized software virtual cystoscopy (VC) is possible. We assess the role of VC in diagnosing and evaluating bladder lesions. Materials and Methods. Between September 2010 and October 2011, 25 consecutive patients with cystoscopically confirmed bladder tumor underwent VC. The radiologists involved in this prospective study were blinded to the exact findings. After draining any residual urine with a catheter, the bladder was retrogradely insufflated with 200 600 cc of air. No intravenous or intravesical contrast was used. MDCT scan was performed in supine and prone positions and three-dimensional reconstruction of the urinary bladder was performed. Results. The examination was well tolerated by all patients with no complications. In total, 43 lesions were detected both with conventional cystoscopy and VC. Tumor size measured by CT ranged from 3 to 80 mm in diameter. The pathological report revealed noninvasive transitional cell carcinomas in all cases. Conclusion. VC has promising results in detecting exophytic bladder lesions. In the future it could be part of the diagnostic algorithm for bladder tumors. PMID- 24799895 TI - Web-based depression screening and psychiatric consultation for college students: a feasibility and acceptability study. AB - Background. A steady rise in the prevalence of depression among college students has negatively affected student quality of life. This study investigates the feasibility and acceptability of a Web-based model, including Skype, to screen and provide psychiatric consultation to depressed college students. Methods. Students completed the 9-item Patient Health Questionnaire (PHQ-9) online; those who screened positive (PHQ-9 >= 10) or endorsed any level of suicidal ideation were offered Web-based psychiatric consultation using Skype. After the consultation, students filled out a 7-item satisfaction questionnaire to report on the acceptability of this Web-based method. Results. A total of 972 students consented to the online depression screening and 285 screened positive. Of those, 69 students consented and 17 students successfully completed the psychiatric consultation via Skype. Thirteen (76.4%) students found the interview useful in helping them understand their depression. Fifteen (88.2%) students thought that psychologists and psychiatrists could successfully see patients via videoconferencing. Conclusions. Current online technologies can provide depression screening and psychiatric consultation to college students; those who participated reported a positive experience. Future studies will need to address the low levels of participation among college students and attract students who are underserved, as well as use a videoconferencing platform that adequately protects data confidentiality. PMID- 24799896 TI - Thailand momentum on policy and practice in local legislation on dengue vector control. AB - Over a past decade, an administrative decentralization model, adopted for local administration development in Thailand, is replacing the prior centralized (top down) command system. The change offers challenges to local governmental agencies and other public health agencies at all the ministerial, regional, and provincial levels. A public health regulatory and legislative framework for dengue vector control by local governmental agencies is a national topic of interest because dengue control program has been integrated into healthcare services at the provincial level and also has been given priority in health plans of local governmental agencies. The enabling environments of local administrations are unique, so this critical review focuses on the authority of local governmental agencies responsible for disease prevention and control and on the functioning of local legislation with respect to dengue vector control and practices. PMID- 24799897 TI - Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets. AB - Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes are found in P. falciparum, of which serine proteases are of particular interest due to their involvement in parasite-specific processes of egress and invasion. In P. falciparum, a number of serine proteases belonging to chymotrypsin, subtilisin, and rhomboid clans are found. This review focuses on the potential of P. falciparum serine proteases as antimalarial drug targets. PMID- 24799898 TI - Behavioural outcome in children with congenital adrenal hyperplasia: experience of a single centre. AB - The aim of this study was to determine the behavioral outcome in children with CAH and to identify the risk factors that may influence it. Participants (aged 6 18 years) included 29 girls and 20 boys with CAH and unaffected siblings (25 girls and 17 boys). Psychological adjustment was assessed with parent reports on the Child Behavior Checklist (CBCL). Information about disease characteristics was obtained from medical records. Our study reveals that there was higher incidence of parent-reported problem of anxious/depressed and withdrawn/depressed behaviours, somatic complaints, social, thought, and attention problems, and rule breaking, aggressive, internalizing, and externalizing behaviour among children with CAH compared to controls. The prevalence of internalizing behaviour problems was higher in CAH boys compared with that of controls. Psychosocial adjustment of girls with CAH was found to be similar to unaffected female controls and was within the normal population range. Family income may be associated with behavioral outcome. Glucocorticoid dose may reflect disease severity which may be associated with behavioral outcome. We conclude that internalizing behavioral problem was prevalent among boys with CAH reflecting maladaptive adjustment in coping with chronic illness. This highlighted the importance of psychological and social support for the patients and their families. PMID- 24799899 TI - Pathogenesis and nomenclature of odontogenic carcinomas: revisited. AB - Odontogenic carcinoma is rare group of malignant epithelial odontogenic neoplasms with characteristic clinical behavior and histological features, which requires an aggressive surgical approach. The pathogenesis of this rare group remains still controversial and there have been many varied opinions over the classification of this rare group of lesions. As there have not been many reviews on odontogenic carcinoma, the existing knowledge is mostly derived from the published case reports. This review is discussing the pathogenetic mechanisms and is updating the knowledge on nomenclature system of less explored odontogenic carcinomas. This review might throw light on the pathogenesis and nomenclature system of odontogenic carcinoma and this knowledge may be applied therapeutically. PMID- 24799900 TI - Endoscopic oncology. PMID- 24799901 TI - Epidemic of non-hodgkin lymphoma in new zealand remains unexplained. AB - Background. Non-Hodgkin lymphoma (NHL) incidence rates have increased considerably in New Zealand. Methods. Incidence and mortality rates for NHL from 1981 to 2010 were calculated. Trends in age-specific rates were analysed and age period-cohort models fitted to explore generation-specific changes in incidence and mortality. Results. NHL incidence increased by 67% for men and 74% for women between the 1981-1985 and 2006-2010 time periods in New Zealand. For women born about 1936 and men born about 1946, NHL incidence and mortality have diverged suggesting an improved prognosis for recent generations. Conclusion. The strong generation effects suggest that an exposure before 25 years of age is of major importance in determining the lifetime risk of NHL in New Zealand. NHL incidence rates in New Zealand will continue to increase in the future and probably more in females than males, as generations with increased risk age. Current hypotheses for the cause of NHL do not explain the trends observed. A decline in the prevalence of a protective factor may have also contributed to these trends. Examination of trends for subtypes of NHL and innovative testable hypotheses that may explain these trends are needed. PMID- 24799902 TI - Cancer risks for relatives of children with cancer. AB - We determined the extent and distribution of cancers in relatives of 379 children newly diagnosed with cancer. Family history was collected from 1,337 first-degree and 3,399 second-degree relatives and incidence compared with national age- and gender-specific rates. Overall, 14 children (3.7%) had a relative with a history of childhood cancer and 26 children (6.9%) had a first-degree relative with a history of cancer, with only one of these having an identifiable familial cancer syndrome. There was a higher than expected incidence of childhood cancer among first-degree relatives (parents and siblings) (standardized incidence ratio (SIR) 1.43; 95% CI 0.54-5.08). There was also a higher than expected incidence of adult cancers among first-degree relatives (SIR 1.45; 95% CI 0.93-2.21), particularly in females (SIR 1.82; 95% CI 1.26-3.39). The increased family cancer history in first-degree females was largely attributable to an effect in mothers (SIR 1.78; 95% CI 1.27-3.33). The gender-specific association was reflected in higher than expected incidence rates of breast cancer in both mothers (SIR 1.92; 95% CI 0.72 6.83) and aunts (SIR 1.64; 95% CI 0.98-2.94). These findings support the hypothesis that previously undetected familial cancer syndromes contribute to childhood cancer. PMID- 24799903 TI - A proposed new index for clinical evaluation of interproximal soft tissues: the interdental pressure index. AB - The interdental pressure index (IPI) is introduced to specifically evaluate clinical interproximal-tissue conditions and assess the effect of interproximal hygiene stimulation. This index scores clinical responses of periodontal tissues to the apical pressure of a horizontally placed periodontal probe. It is negative when gingival tissues are firm, bleeding-free, and slightly ischemic by the stimulation; otherwise it is positive. The clinical validation showed high intraoperator agreement (0.92; 95% CI: 0.82-0.96; P = 0.0001) and excellent interoperator agreement (0.76; 95% CI: 0.14-1.38; P = 0.02). High internal consistency with bleeding on probing (kappa = 0.88) and gingival index (Cronbach's alpha = 0.81) was obtained. Histological validation obtained high sensitivity (100%) and specificity (80%) for IPI+ toward inflammatory active form. The same results were recorded for IPI- toward chronic inactive form. IPI results as a simple and noninvasive method with low error probability and good reflection of histological condition that can be applied for oral hygiene motivation. Patient compliance to oral hygiene instructions is essential in periodontal therapy and IPI index can be a practical and intuitive tool to check and reinforce this important aspect. PMID- 24799904 TI - Psychosocial and quality of life outcomes of prosthetic auricular rehabilitation with CAD/CAM technology. AB - Introduction. The psychosocial and quality of life (QoL) of patients with deformed or missing ears are frequently compromised. The aim of this study is to develop innovative techniques using CAD/CAM technology in prosthetic auricular rehabilitation and provide improvement in the treatment outcomes, including their psychology and QoL. Methods. This is a preliminary clinical cohort study. Six patients requesting for auricular reconstruction were recruited and rehabilitated with implant-supported prosthesis using CAD/CAM technology. Different treatment outcomes including QoL and psychological changes were assessed at different time points. Results. A significant reduction in severity of depressive symptoms (P = 0.038) and an improving trend of satisfaction with life were found at 1 year postoperatively when compared with the preoperative findings. The domain scores in ''Body image", ''Family/friends/strangers", and ''Mood" were also significantly higher (P < 0.05) at 1 year postoperatively than 1 week postoperatively. However, only 50% of the patients wear their auricular prosthesis regularly. Conclusion. This preliminary study has confirmed that implant-supported auricular prosthesis could induce improvement in the psychology and QoL with statistically significant differences in the domains of the body image, social interaction, and mood. Our present findings can inform research design and hypotheses generation of future studies. PMID- 24799905 TI - Determination of Acid Dissociation Constants (pK a ) of Bicyclic Thiohydantoin Pyrrolidine Compounds in 20% Ethanol-Water Hydroorganic Solvent. AB - The acid dissociation constants of potential bioactive fused ring thiohydantoin pyrrolidine compounds were determined by potentiometric titration in 20% (v/v) ethanol-water mixed at 25 +/- 0.1 degrees C, at an ionic background of 0.1 mol/L of NaCl using the HYPERQUAD computer program. Proton affinities of potential donor atoms of the ligands were calculated by AM1 and PM3 semiempiric methods. We found, potentiometrically, three different acid dissociation constants for 1a-f. We suggest that these acid dissociation constants are related to the carboxyl, enol, and amino groups. PMID- 24799906 TI - Protein misfolding and neurodegenerative diseases. PMID- 24799907 TI - Therapy with interleukin-22 alleviates hepatic injury and hemostasis dysregulation in rat model of acute liver failure. AB - The therapeutic efficacy of interleukin-22 (IL-22) on liver injury and hematological disturbances was studied in rat model of acute liver failure (ALF) induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS). The following parameters were investigated: (1) survival rate, (2) serum levels of liver function enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)), total bilirubin (TBILI), and total albumen (ALB), (3) blood clotting tests (prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level (FIB)) and white blood cells (WBCs), red blood cells (RBCs), and platelet counts, (4) hepatic levels of tumor necrosis factor- alpha (TNF- alpha ) and cyclooxygenase-2 (COX-2), and (5) liver histopathology. After 48 hours of D-GalN/LPS, the rats exhibited 20% mortality, significant increases in AST, ALT, ALP, TBILI, PT, and aPTT, TNF- alpha , and COX 2 and significant decreases in FIB, WBCs, and RBCs. By contrast, therapy with IL 22 prevented the lethal effect of D-GalN/LPS by 100% and efficiently alleviated all the biochemical and hematological abnormalities that were observed in ALF untreated group. Furthermore, IL-22 treatment decreased the hepatic contents of TNF- alpha and COX-2. The histopathological findings also supported the hepatoprotective effect of IL-22. Taken together, therapy with IL-22 can represent a promising therapeutic tool against liver injury and its associated hemostasis disturbances. PMID- 24799908 TI - Lack of Outer Membrane Protein A Enhances the Release of Outer Membrane Vesicles and Survival of Vibrio cholerae and Suppresses Viability of Acanthamoeba castellanii. AB - Vibrio cholerae, the causative agent of the diarrhoeal disease cholera, survives in aquatic environments. The bacterium has developed a survival strategy to grow and survive inside Acanthamoeba castellanii. It has been shown that V. cholerae expresses outer membrane proteins as virulence factors playing a role in the adherence to interacted host cells. This study examined the role of outer membrane protein A (OmpA) and outer membrane vesicles (OMVs) in survival of V. cholerae alone and during its interaction with A. castellanii. The results showed that an OmpA mutant of V. cholerae survived longer than wild-type V. cholerae when cultivated alone. Cocultivation with A. castellanii enhanced the survival of both bacterial strains and OmpA protein exhibited no effect on attachment, engulfment, and survival inside the amoebae. However, cocultivation of the OmpA mutant of V. cholerae decreased the viability of A. castellanii and this bacterial strain released more OMVs than wild-type V. cholerae. Surprisingly, treatment of amoeba cells with OMVs isolated from the OmpA mutant significantly decreased viable counts of the amoeba cells. In conclusion, the results might highlight a regulating rule for OmpA in survival of V. cholerae and OMVs as a potent virulence factor for this bacterium towards eukaryotes in the environment. PMID- 24799909 TI - Subcutaneous Terbutaline Pump for Maintenance of Tocolysis following Arrest of Acute Preterm Labor. PMID- 24799910 TI - Atrioventricular Dissociation following Blunt Chest Trauma. AB - Blunt chest trauma (BCT) is a common clinical presentation seen in emergency departments. Few cases of cardiac conduction abnormalities due to BCT have been reported in the medical literature. This dysrhythmias may present as permanent conduction defects requiring permanent pacemaker or may have temporary conduction abnormalities requiring temporary pacemaker or supportive care. We present the case of a young woman who suffered from BCT after being kicked by a horse with the development of a significant substernal hematoma. She developed temporary atrioventricular block, which was completely resolved with the decrease in the size of the substernal hematoma suffered. PMID- 24799911 TI - Successful outcome of a corticodependent henoch-schonlein purpura adult with rituximab. AB - Henoch-Schonlein purpura (HSP) is a systemic vasculitis involving small vessels with deposition of immunoglobulin A (IgA) complexes, usually affecting children. Compared with children, HSP in adults is more severe and frequently associated with cancer. We report the case of a 49-year-old woman with medical history of kidney transplantation for segmental glomerular hyalinosis. Eight years after the transplantation, while taking combined immunosuppressive therapy with tacrolimus and azathioprine indicated for the prevention against transplant rejection, she developed a Henoch-Schonlein purpura. Vasculitis involves skin and sciatic peroneal nerve and she received systemic corticosteroid treatment. Because of four relapses and corticosteroid dependence, the patient was treated with rituximab (two intravenous infusions of 1000 mg given two weeks apart). Successful outcome was observed along two years of follow-up. This new case of successful use of rituximab in HSP promotes more investigations of this treatment in clinical trials. PMID- 24799912 TI - A case of secondary leukemia subsequent to myelodysplastic syndromes successfully treated with azacitidine. AB - Elderly patients with secondary acute myeloid leukemia (AML) following myelodysplastic syndrome (MDS) are often medically unfit for or resistant to chemotherapy, and their prognosis is dismal. In the present paper, we reported a case of secondary leukemia following MDS in an 80-year-old male patient who was deemed unfit for chemotherapy owing to his old age and poor physical condition. Despite a high tumor burden, treatment with AZA exerted a remarkable response, leading to an immediate cytoreduction in our case. Our results suggest that AZA can be an attractive therapeutic option for elderly MDS or AML patients, offering adequate efficacy and high tolerability. PMID- 24799913 TI - Late Onset Combined Immunodeficiency Presenting with Recurrent Pneumocystis jiroveci Pneumonia. AB - Late onset combined immunodeficiency (LOCID) is a recently described variant of common variable immunodeficiency (CVID), involving adult patients presenting with opportunistic infections and/or low CD4+ lymphocyte counts. A 36-year-old male with unremarkable past medical history presented with fever, respiratory failure, and lymphocytopenia. He was found to have Pneumocystis jiroveci pneumonia (PJP), subsequently complicated by recurrent hospital-acquired Pseudomonas aeruginosa pneumonia and immune reconstitution phenomena, attributed to restoration of immunoglobulin levels. Clinicians should be aware of LOCID, which could be confused with HIV infection/AIDS or idiopathic CD4 lymphocytopenia. In the English bibliography there is only one case report, where PJP was the initial presentation of CVID (that case would probably be classified as LOCID). Phenomena of immune reconstitution are described in various settings, including primary immunodeficiency, manifesting as temporary clinical and radiologic deterioration and leading to misperceptions of therapeutic failure and/or presence of alternative/additional diagnoses. PMID- 24799914 TI - Oral allergy syndrome in a child provoked by royal jelly. AB - Royal jelly has been demonstrated to have several physiological activities. However, in the literature, different reactions induced by royal jelly are reported. We describe a case of seven-year-old child that was referred to our observation for two episodes of oral allergy syndrome (OAS) that appeared ten minutes after ingestion of royal jelly. Skin prick test with standard panel of inhalant and food allergens, a prick-to-prick test using the royal jelly's extract responsible for patient's reactions, and royal jelly patch test with extemporaneous preparation were performed. The specific IgE by ImmunoCAP System method versus Hymenoptera venom, inhalant allergens, food allergens, and lipid transfer proteins was dosed. According to the positive reactions to royal jelly both by prick-by-prick test and by a first reading patch test, royal jelly immediate hypersensitivity was diagnosed. According to the positive response for almond in both in vivo and in vitro tests we can think of the royal jelly contamination with almond pollen as possible cause of patient's reaction. Moreover, from the results of specific IgE titers versus Compositae pollens, we have argued the possibility that this case of royal jelly allergy could be explained also by the mechanism of cross-reaction with Compositae pollens. PMID- 24799915 TI - Magnetic Nanoparticle Based Nonviral MicroRNA Delivery into Freshly Isolated CD105(+) hMSCs. AB - Genetic modifications of bone marrow derived human mesenchymal stem cells (hMSCs) using microRNAs (miRs) may be used to improve their therapeutic potential and enable innovative strategies in tissue regeneration. However, most of the studies use cultured hMSCs, although these can lose their stem cell characteristics during expansion. Therefore, we aimed to develop a nonviral miR carrier based on polyethylenimine (PEI) bound to magnetic nanoparticles (MNPs) for efficient miR delivery in freshly isolated hMSCs. MNP based transfection is preferable for genetic modifications in vivo due to improved selectivity, safety of delivery, and reduced side effects. Thus, in this study different miR/PEI and miR/PEI/MNP complex formulations were tested in vitro for uptake efficiency and cytotoxicity with respect to the influence of an external magnetic field. Afterwards, optimized magnetic complexes were selected and compared to commercially available magnetic vectors (Magnetofectamine, CombiMag). We found that all tested transfection reagents had high miR uptake rates (yielded over 60%) and no significant cytotoxic effects. Our work may become crucial for virus-free introduction of therapeutic miRs as well as other nucleic acids in vivo. Moreover, in the field of targeted stem cell therapy nucleic acid delivery prior to transplantation may allowfor initial cell modulation in vitro. PMID- 24799916 TI - Incidence of Tuberculosis and Amyloidosis among Sudanese Patients Presented with Enlarged Nodes. AB - Objectives. To determine the incidence of tuberculous lymphadenitis and amyloidosis in enlarged lymph nodes (LN). Methodology. A retrospective study was carried out in the department of pathology at the Faculty of Medicine, University of Kordofan, during one-year period. The study included a group of 103 patients with lymphadenopathy. Results. Of the 103 cases with enlarged neck nodes, 35 (34%) had tuberculous lymphadenitis. Sixteen (46%) cases were males and 19 (54%) cases were females. Out of the 103 patients, amyloidosis was diagnosed in 9/103 (8.7%). Out of the 9 positive cases, 2/9 (22.2%) were males and 7/9 (77.8%) were females. Conclusion. There is high incidence of tuberculous lymphadenitis in patients with enlarged LN in developing countries like North Sudan. Amyloidosis should not be ignored when investigating enlarged LN. PMID- 24799918 TI - Renal denervation - where do we stand in 2014? PMID- 24799917 TI - Molecular and Microscopic-Based Characterization of Plasmodium spp. in Fars and Hormozgan Provinces, South of Iran. AB - Despite malaria control programs in recent years, malaria transmission has not been eliminated in Iran. Molecular techniques including PCR, which has proved more sensitive and specific than microscopic examination methods, help to detect infection in low levels of parasitemia and mixed infections. Main our objectives were setting up nested PCR for detection of malaria and evaluating PCR based on plasmodia DNA from blood smears in Fars province, the comparison of this method with traditional microscopy and also evaluate the data in comparison with its neighboring province, Hormozgan. A total of 149 malaria positive samples including 116, 19, and 14 samples from Shiraz, Jask, and Lengeh ports were utilized in this study, respectively. Blood slides were prepared for microscopic observation. DNA from thin smears was extracted and nested PCR was analyzed using rPLU5 and rPLU6 for genus specification, rFAL1, rFAL2, and rVIV1, rVIV2 for P. falciparum and P. vivax detection, respectively. The results showed that 126 (84.6%), 16 (10.7%), and 7 (4.7%) out of 149 cases were positive for P. vivax, P. falciparum, and mixed infections, respectively, by microscopy. The PCR indicated that 95 (63.7%), 15 (10.1%), and 22 (14.8%) cases were infected with P. vivax, P. falciparum, and mixed mentioned species, respectively, and 17 (11.4%) cases were uninfected. Our results confirmed the considerable sensitivity of nested PCR for detection of the mixed infections. Simultaneous application of PCR even based on microscopy slides can facilitate access to the highest level of confidence in malaria researches. PMID- 24799919 TI - Cardiovascular responses to plyometric exercise are affected by workload in athletes. AB - INTRODUCTION: With regard to blood pressure responses to plyometric exercise and decreasing blood pressure after exercise (post-exercise hypotension), the influence of different workloads of plyometric exercise on blood pressure is not clear. AIM: The purpose of this investigation was to examine the effects of a low, moderate and high workload of plyometric exercise on the post-exercise systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and rate pressure product (RPP) responses in athletes. MATERIAL AND METHODS: TEN MALE ATHLETES (AGE: 22.6 +/-0.5 years; height: 178.2 +/-3.3 cm; and body mass: 75.2 +/ 2.8 kg) underwent PE protocols involving 5 * 10 reps (Low Workload - LW), 10 * 10 reps (Moderate Workload - MW), and 15 * 10 reps (High Workload - HW) depth jump exercise from a 50-cm box in 3 non-consecutive days. After each exercise session, SBP, DBP and HR were measured every 10 min for a period of 70 min. RESULTS: No significant differences were observed among post-exercise SBP and DBP when the protocols (LW, MW and HW) were compared. The MW and HW protocols showed greater increases in HR compared with LW. Also the HW indicated greater increases than LW in RPP at post-exercise (p < 0.05). CONCLUSIONS: All protocols increased SBP, HR and RPP responses at the 10(th) and 20(th) min of post-exercise. With regard to different workloads of plyometric exercise, HW condition indicated greater increases in HR and RPP and strength and conditioning professionals and athletes must keep in their mind that HW of plyometric exercise induces greater cardiovascular responses. PMID- 24799920 TI - Isovolumic contraction acceleration before and after percutaneous closure of atrial septal defects. AB - AIM: To compare systemic right ventricular function by isovolumic myocardial acceleration before and 6 months after the percutaneous closure of atrial septal defects (ASD). MATERIAL AND METHODS: Patients admitted to our tertiary center for the percutaneous closure of atrial septal defects between January 2010 and August 2012 constituted the study group. Right ventricular function of patients was assessed by tissue Doppler echocardiography before and after surgery. Echocardiographic data in patients were compared to age-matched controls without any cardiac pathology and studied in identical fashion mentioned below. RESULTS: A total of 44 patients (24 males, 20 females) and 44 age-matched controls (25 males, 19 females) met the eligibility criteria for the study. Right ventricular end-diastolic and end-systolic volume, right ventricular end-diastolic diameter measurements on echocardiogram, and pulmonary artery pressures in both pre- and post-ASD groups were significantly higher than in controls. Tricuspid annular plane systolic excursion and isovolumic myocardial acceleration measurements significantly increased after the percutaneous closure of the defect; however, post-ASD measurements were still significantly lower than the controls. CONCLUSIONS: Atrial septal defect device closure resulted in a significant increase of isovolumic myocardial acceleration measurements. Tissue Doppler analysis of regional myocardial function offers new insight into myocardial compensatory mechanisms for acute and chronic volume overload of both ventricles. PMID- 24799921 TI - The role of insulin-like growth factor-1 in development of coronary no-reflow and severity of coronary artery disease in patients with acute myocardial infarction. AB - INTRODUCTION: Insulin-like growth factor-1 (IGF-1) has atheroprotective effects via reduction in oxidative stress, cellular apoptosis, pro-inflammatory signaling, and endothelial dysfunction. AIM: We hypothesized that low levels of IGF-1 may be associated with the severity and extent of coronary artery disease and development of the coronary no-reflow phenomenon in patients with acute ST elevation myocardial infarction (STEMI) and investigated the role of the IGF-1 molecule in the coronary no-reflow phenomenon and severity of coronary artery disease (CAD) in patients with acute STEMI in a tertiary hospital. MATERIAL AND METHODS: The study was conducted among 113 patients undergoing primary percutaneous coronary intervention (PPCI) for STEMI, of whom 49 patients developed the no-reflow phenomenon. Coronary no-reflow was defined as Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 or less after intervention. Insulin-like growth factor-1 levels were measured in both groups. The severity and extent of CAD were evaluated according to the Gensini and Syntax scores. RESULTS: Although IGF-1 levels were lower in the no-reflow group, there was not a statistically significant difference between the no-reflow group and the control group (116.65 +/-51.72 vs. 130.82 +/-48.76, p = 0.130). Gensini and Syntax scores were higher in the no-reflow group. There was no association between Gensini and Syntax scores and IGF-1 levels (r = -0.071, r = 0.479, r = 0.158, p = 0.113). CONCLUSIONS: In this study, IGF-1 levels were not statistically different between patients developing the no-reflow phenomenon and controls. There was no association between development of the no-reflow phenomenon and severity of CAD or IGF-1 levels. Nevertheless, large scale studies are needed to verify these results. PMID- 24799922 TI - Noninvasive assessment of cerebral artery stenoses from anatomic computed tomography angiography. AB - Trans-stenotic pressure gradient (TSPG) and fractional flow reserve (FFR) are well-validated hemodynamic indices to assess the ischemic severity of arterial stenoses. However, they have significant restrictions in practice due to invasiveness and high cost. Recently, a noninvasive assessment of FFR from computed tomography (CT) angiography has been well validated in evaluating functional coronary stenoses. We present a case of a 65-year-old woman with cerebral artery stenoses demonstrated by clinical symptoms, transcranial Doppler ultrasound and CT angiography, aiming to transplant the noninvasive functional diagnosis, for the first time, to cerebral artery stenoses and test a computational workflow of noninvasive TSPG and FFR. PMID- 24799923 TI - Transcatheter closure of ventricular septal defects with nitinol wire occluders of type patent ductus arteriosus. AB - Ventricular septal defects closure (VSD) depending on the anatomy and clinical setting can be performed surgically or by a hybrid and transcatheter approach. Two cases of children with VSD will be presented. Patients' defects were closed with various types of occluders made of nitinol wire mesh occluder, patent ductus arteriosus (PDA) type. The first case was a 2.5-year-old boy after cardiosurgical correction of tetralogy of Fallot (TOF). After the procedure, a significant haemodynamic residual VSD was observed, which was not successfully closed during the subsequent reoperation. Despite pharmacological treatment, symptoms of heart failure were observed in this patient. In echocardiographic images the residual VSD was presented as a tunnel-like dissection of the ventricular septum (length 6 mm and diameter 3.4 mm). The defect was closed via arterial access with an Amplatzer Duct Occluder II (ADO II). The procedure was successfully performed without any medical complications. In this child, a significant shunt reduction and a noticeable improvement in the patient's clinical status and diminished symptoms of heart failure were noticed. The second patient was a 4-year-old girl suffering from a multi-perforated perimembranous VSD accompanied by a ventricular septal defect with aneurysm. The defect was closed by a venous approach with a PDA Cardio-O-Fix occluder (very similar to ADO I). No short-term or long-term complications were visible during or after the procedure. Only a mild residual shunt through the VSD was observed 6 months afterwards. Transcatheter VSD closure with a proper morphology, with occluders of type Amplatzer Duct Occluder ADO I or ADO II, constitutes a safe and effective therapeutic alternative. PMID- 24799924 TI - Transcatheter aortic valve implantation complicated by acute pericardial tamponade. AB - Transcatheter aortic valve replacement (TAVR) is now an accepted standard of care for patients with symptomatic severe aortic stenosis who are not candidates for surgery or have high surgical risk. Despite its more widespread adoption as a treatment option and increasing experience of centers, TAVR is still associated with several complications. We therefore report a case of TAVR complicated by acute pericardial tamponade, one of the most severe potential complications of this procedure. We describe the way we approached the problem and we try to give a potential take-home message for others who might encounter such a situation in their own cath lab. PMID- 24799925 TI - Pregnancy after myocardial infarction and coronary artery bypass grafting - is it safe? AB - Pregnancy after myocardial infarction (MI) and coronary artery bypass grafting (CABG), although still rare, is slowly becoming a challenge in everyday clinical practice. In recent decades MI has been observed to occur more frequently in young women. Concurrently an increasing number of women decide to become pregnant at more advanced age. Although pregnancy after MI and CABG may be possible and safe, a multidisciplinary approach involving careful evaluation by the cardiac and obstetric team in each individual is mandatory. Two cases of pregnant women with a history of MI treated with CABG are presented and their management is discussed. PMID- 24799926 TI - Significance of antiplatelet therapy in emergency myocardial infarction treatment. AB - Antiplatelet drugs play a crucial role in the treatment of patients with myocardial infarction, particularly in association with percutaneous coronary intervention. Their main advantage is the reduction of adverse ischemic incidents and the major disadvantage is the increase in the frequency of hemorrhages. Thus, the choice of appropriate drug depends on the right risk assessment of the development of these complications in individual patients. The aim of this article is to provide an update of antiplatelet therapy in emergency myocardial infarction treatment. Currently, the most important role in the process of platelet inhibition is played by ADP P2Y12 blockers: clopidogrel, prasugrel and ticagrelor. Clopidogrel and prasugrel belong to thienopyridines, and ticagrelor, a drug of irreversible action, is an analogue of adenosine triphosphate. By 2011 clopidogrel, alongside aspirin, had the highest recommendations of world cardiology associations for acute coronary syndrome treatment. The position on clopidogrel was changed following the publication of European Society of Cardiology guidelines for STEMI in 2012 which advocate the administration of acetylsalicylic acid (ASA) and ADP receptor blocker (in combination with ASA). It needs to be stressed that prasugrel and ticagrelor received class IB recommendation, while clopidogrel received only IC. However, the most recent studies aimed at introducing a new generation of antiplatelet drugs of high efficacy in prevention of ischemic incidents and of reversible action: cangrelor and elinogrel, which raise hopes for better prognosis for myocardial infarction patients. PMID- 24799927 TI - Beneficial triple-site cardiac resynchronization in a patient supported with an intra-aortic balloon pump for end-stage heart failure. AB - The authors present the case of a 62-year-old male patient with an implantable cardioverter-defibrillator and end-stage heart failure supported with an intra aortic balloon pump. Implantation of a triple-site cardiac resynchronization system and complex heart failure treatment brought a significant improvement, return to home activity and 17-month survival. The patient died due to heart failure aggravation. Within this time he was rehospitalized and successfully treated twice for an electrical storm. PMID- 24799928 TI - Successful transcatheter closure of bilateral multiple coronary arterial fistulae in one session. AB - Coronary artery fistulae represent the most frequent congenital anomalies of the coronary arteries, but multiple bilateral fistulae are a rare condition. Current therapeutic options for symptomatic patients are percutaneous closure and cardiac surgery. Transcatheter closure of fistulae using coils is preferred as an effective and safe alternative to surgery. Here we report the case of a patient with congenital coronary artery fistulae arising from both the left and right coronary arteries draining individually into the right pulmonary artery treated successfully with a transcatheter approach. PMID- 24799929 TI - Transradial approach for carotid artery stenting in a patient with severe peripheral arterial disease. AB - We present a case of a 73-year-old man with critical bilateral internal carotid artery stenosis, recent right-hemisphere stroke and severe peripheral artery disease in whom right internal carotid artery stenting (RICA-CAS) was performed successfully via a right transradial approach. PMID- 24799930 TI - A cockscomb-like aneurysm of the right coronary artery after bare metal stent implantation. AB - Coronary artery aneurysm (CAA) formation is an uncommon but potentially life threatening event after coronary balloon angioplasty or stent implantation. In this report, we present a case of a patient who had a cockscomb-like aneurysm after bare metal stent implantation which was successfully treated with a coronary graft stent. PMID- 24799931 TI - Asymptomatic ST segment elevation in the recovery phase of the exercise stress test due to slow coronary flow. AB - Exercise-induced ST segment elevation without Q wave formation is rarely observed. Frequent causes are significant coronary stenosis, myocardial bridge and coronary vasospasm. Both exercise-induced ST segment elevation due to slow coronary flow and ST segment elevation in the recovery phase of the exercise stress test are very rare. We present a 49-year-old man with asymptomatic inferolateral ST segment elevation in the recovery phase of the exercise stress test due to slow coronary flow, which has not been reported previously. The learning points of the present paper are as follows: a) although significant coronary stenosis, myocardial bridge and coronary vasospasm are frequent causes of exercise-induced ST segment elevation, slow coronary flow might also cause it; b) one should keep in mind that ST segment elevation might also occur in the recovery phase; and c) ST segment elevation might be asymptomatic, as in the present case. PMID- 24799932 TI - Left main aneurysm and what's next? AB - The purpose of the case report is to present a case of a 65-year-old male, referred for coronary angiography because of a typical chest pain. The coronary angiography showed an aneurysm of the left main coronary artery. Despite the absence of obvious ischemic symptoms and because of the potential complications of the aneurysm with a width of 15 mm, the patient underwent surgery. PMID- 24799933 TI - ST-elevation acute coronary syndrome in a patient after heart transplant. AB - The accelerated process of vasculopathy in heart transplant (HTx) recipients is a well-known factor of increased morbidity and mortality among this subset of patients. Heart transplant patients with acute coronary syndrome (ACS) usually do not present with typical symptoms. ST elevation (STE) is a very rare presentation of ACS in HTx recipients. We report a case of a female HTx patient, in whom STE ACS was diagnosed and was subsequently treated with primary percutaneous coronary intervention. PMID- 24799934 TI - Acute inferior myocardial infarction in a patient with a prosthetic aortic valve and high international normalized ratio. AB - ST elevation acute myocardial infarction in patients with a mechanical prosthetic valve is rare and usually due to inadequate anticoagulation. We present a case of acute inferior myocardial infarction in a patient with a prosthetic aortic valve and high international normalized ratio, which has not been reported previously. PMID- 24799935 TI - Endovascular treatment of PA pseudoaneurysm caused by Swan-Ganz catheter. AB - The following case report describes a complication of Swan-Ganz catheterization and its endovascular treatment with a single coil. Application of this particular catheter in the pulmonary artery during cardiac surgery may lead to mechanical perforation and creation of an extravascular sac, which is called a pseudoaneurysm. There are different methods that lead to tamponade or closure of the leakage. Interventional cardiology procedures are nowadays the most appropriate way of treatment of Swan-Ganz catheter induced vascular complications. PMID- 24799936 TI - Essential Oil of Artemisia annua L.: An Extraordinary Component with Numerous Antimicrobial Properties. AB - Artemisia annua L. (Asteraceae) is native to China, now naturalised in many other countries, well known as the source of the unique sesquiterpene endoperoxide lactone artemisinin, and used in the treatment of the chloroquine-resistant and cerebral malaria. The essential oil is rich in mono- and sesquiterpenes and represents a by-product with medicinal properties. Besides significant variations in its percentage and composition have been reported (major constituents can be camphor (up to 48%), germacrene D (up to 18.9%), artemisia ketone (up to 68%), and 1,8 cineole (up to 51.5%)), the oil has been subjected to numerous studies supporting exciting antibacterial and antifungal activities. Both gram-positive bacteria (Enterococcus, Streptococcus, Staphylococcus, Bacillus, and Listeria spp.), and gram-negative bacteria (Escherichia, Shigella, Salmonella, Haemophilus, Klebsiella, and Pseudomonas spp.) and other microorganisms (Candida, Saccharomyces, and Aspergillus spp.) have been investigated. However, the experimental studies performed to date used different methods and diverse microorganisms; as a consequence, a comparative analysis on a quantitative basis is very difficult. The aim of this review is to sum up data on antimicrobial activity of A. annua essential oil and its major components to facilitate future approach of microbiological studies in this field. PMID- 24799937 TI - The Effect of Mushroom Beta-Glucans from Solid Culture of Ganoderma lucidum on Inhibition of the Primary Tumor Metastasis. AB - This study evaluates the effect of mushroom beta-glucans (MBGS) derived from solid culture of Ganoderma lucidum on tumor inhibition by examining size of the primary tumor and rate of metastasis in Lewis lung carcinoma (LLC) bearing mice (C57BL/6), given oral administration of MBGS with radiation therapy. A previous result showed that MBGS enhances NK cell-mediated cytotoxicity in mice without LLC bearing in advance. Furthermore, applications of MBGS in conjunction with radiation therapy were effective in controlling tumor growth, and rate of metastasis, life threatening, and can potentially serve as a protective factor for wounds and hair loss that resulted from the overgrowth of primary tumor in LLC bearing mice. PMID- 24799938 TI - Effect of Eugenol on Cell Surface Hydrophobicity, Adhesion, and Biofilm of Candida tropicalis and Candida dubliniensis Isolated from Oral Cavity of HIV Infected Patients. AB - Most Candida spp. infections are associated with biofilm formation on host surfaces. Cells within these communities display a phenotype resistant to antimicrobials and host defenses, so biofilm-associated infections are difficult to treat, representing a source of reinfections. The present study evaluated the effect of eugenol on the adherence properties and biofilm formation capacity of Candida dubliniensis and Candida tropicalis isolated from the oral cavity of HIV infected patients. All isolates were able to form biofilms on different substrate surfaces. Eugenol showed inhibitory activity against planktonic and sessile cells of Candida spp. No metabolic activity in biofilm was detected after 24 h of treatment. Scanning electron microscopy demonstrated that eugenol drastically reduced the number of sessile cells on denture material surfaces. Most Candida species showed hydrophobic behavior and a significant difference in cell surface hydrophobicity was observed after exposure of planktonic cells to eugenol for 1 h. Eugenol also caused a significant reduction in adhesion of most Candida spp. to HEp-2 cells and to polystyrene. These findings corroborate the effectiveness of eugenol against Candida species other than C. albicans, reinforcing its potential as an antifungal applied to limit both the growth of planktonic cells and biofilm formation on different surfaces. PMID- 24799939 TI - Pleurotus eryngii Ameliorates Lipopolysaccharide-Induced Lung Inflammation in Mice. AB - Pleurotus eryngii (P. eryngii) is consumed as a fresh cultivated mushroom worldwide and demonstrated to have multiple beneficial effects. We investigated the anti-inflammatory effect of P. eryngii in mice with acute lung injury (ALI). Intranasal instillation of lipopolysaccharide (LPS) (10 MU g/site/mouse) induced marked lung inflammation (increase in the number of inflammatory cells, protein leakage, and production of nitric oxide in bronchoalveolar lavage fluid) as well as histopathological damage in the lung, 6 h after treatment. Mice administered heat-treated P. eryngii (0.3-1 g/kg, p.o. (HTPE)) 1 h before LPS challenge showed decreased pulmonary inflammation and ameliorated histopathological damage. These results suggest that HTPE has anti-inflammatory effects against ALI. Thus, P. eryngii itself may also have anti-inflammatory effects and could be a beneficial food for the prevention of ALI induced by bacterial infection. PMID- 24799940 TI - Neuroprotective Effects of Jitai Tablet, a Traditional Chinese Medicine, on the MPTP-Induced Acute Model of Parkinson's Disease: Involvement of the Dopamine System. AB - Jitai tablet (JTT) is a traditional Chinese medicine used to treat neuropsychiatric disorders. We previously demonstrated that JTT treatment led to increased level of dopamine transporter (DAT) in the striatum, thus indicating that JTT might have therapeutic potential for Parkinson's disease (PD), which is characterized by dysregulated dopamine (DA) transmission and decreased striatal DAT expression. The aim of this study was to investigate the neuroprotective effect of JTT on MPTP-induced PD mice. Using locomotor activity test and rotarod test, we evaluated the effects of JTT (0.50, 0.15, or 0.05 g/kg) on MPTP-induced behavioral impairments. Tyrosine hydroxylase TH-positive neurons in the substantia nigra and DAT and dopamine D2 receptor (D2R) levels in the striatum were detected by immunohistochemical staining and/or autoradiography. Levels of DA and its metabolites were determined by HPLC. In MPTP-treated mice, behavioral impairments were alleviated by JTT treatment. Moreover, JTT protected against impairment of TH-positive neurons and attenuated the MPTP-induced decreases in DAT and D2R. Finally, high dose of JTT (0.50 g/kg) inhibited the MPTP-induced increase in DA metabolism rate. Taken together, results from our present study provide evidence that JTT offers neuroprotective effects against the neurotoxicity of MPTP and thus might be a potential treatment for PD. PMID- 24799941 TI - Cryptotanshinone Reverses Reproductive and Metabolic Disturbances in PCOS Model Rats via Regulating the Expression of CYP17 and AR. AB - Objective. To explore the effect of Cryptotanshinone on reversing the reproductive and metabolic disturbances in polycystic ovary syndrome (PCOS) model rats and the possible regulatory mechanisms. Methods. PCOS model rats were induced by subcutaneous injection of dehydroepiandrosterone (DHEA) and verified by histological screening of vaginal exfoliated cells. After Cryptotanshinone intervention, the rats' body weight and ovary morphological were observed; the serum biochemical assessments were analyzed by radioimmunoassay (RIA) and key genes and proteins related with anabolism of androgen and insulin were detected by Real-Time PCR and Immunohistochemical (IHC). Results. The estrous cyclicity of PCOS model rats was significantly recovered by Cryptotanshinone. The body weight, ovarian coefficient, and ovarian morphology had been improved and the serum biochemical indicators including testosterone (T), androstenedione (A2), luteinizing hormone (LH), LH/follicle stimulating hormone (FSH), sexual binding globulin (SHBG), low density cholesterol (LDL-C), fasting insulin (FINS) were reversed after Cryptotanshinone intervention. Specifically, the levels of Cytochrome P450, 17-a hydroxylase/17,20 lyase (CYP17), and androgen receptor (AR) were downregulated significantly. Conclusions. Our data suggest that Cryptotanshinone could rebalance reproductive and metabolic disturbances in PCOS model rats and could be a potential therapeutic agent for the treatment of PCOS. PMID- 24799942 TI - The influence of chlorella and its hot water extract supplementation on quality of life in patients with breast cancer. AB - A self-control, randomized, and open-label clinical trial was performed to test the effects of the unicellular green algae Chlorella and hot water extract supplementation on quality of life (QOL) in patients with breast cancer. Forty five female patients with breast cancer who were living at home and not hospitalized were randomly assigned to 3 groups receiving vitamin mix tablet (control), Chlorella granules (test food-1), or Chlorella extract drink (test food-2) daily for one month. The Functional Assessment of Cancer Therapy-Breast (FACT-B), the Izumo scale for abdominal symptom-specific QOL, and a narrative form questionnaire were used to determine outcomes. Data of thirty-six subjects were included for final analysis. FACT-B scores at presupplementation found no significant group differences in all subscales. Scores on the breast cancer subscale in the Chlorella granule group significantly increased during the supplementation period (P = 0.042). Fifty percent of the Chlorella extract group reported positive effects by the test food such as reduction of fatigue and improvements of dry skin (P < 0.01 versus control group). The findings suggested the beneficial effects of Chlorella on breast cancer-related QOL and of Chlorella extract on vitality status in breast cancer patients. These findings need to be confirmed in a larger study. PMID- 24799944 TI - Efficacy and safety of medicinal plants used in the management of diabetes mellitus. PMID- 24799943 TI - Latest Study on the Relationship between Pathological Process of Inflammatory Injury and the Syndrome of Spleen Deficiency and Fluid Retention in Alzheimer's Disease. AB - Inflammation exists throughout the incidence and progression of Alzheimer's disease (AD). Traditional Chinese medicine (TCM) differentiates the pathogenesis of AD as kidney essence deficiency and qi and blood deficiency as well as blood stasis in syndromes, whose action mechanisms are all associated with the intervention in its inflammatory process. Our preliminary studies both in clinic and in vitro have demonstrated that the syndrome of spleen deficiency and fluid retention has also been an important pathogenesis for the incidence and development of AD. Hence, the paper aims to further illustrate the correlation between inflammatory process in AD and the syndrome of spleen deficiency and fluid retention, laying solid foundation for the application of invigorating the spleen and eliminating the dampness in clinic, and enriching the theoretical connotation for AD prevention and treatment in TCM. PMID- 24799945 TI - Ginsenosides Rb1 and Rg1 Stimulate Melanogenesis in Human Epidermal Melanocytes via PKA/CREB/MITF Signaling. AB - Reduced or defective melanin skin pigmentation may cause many hypopigmentation disorders and increase the risk of damage to the skin triggered by UV irradiation. Ginsenosides Rb1 and Rg1 have many molecular targets including the cAMP-response element-binding protein (CREB), which is involved in melanogenesis. This study aimed to investigate the effects of ginsenosides Rb1 and Rg1 on melanogenesis in human melanocytes and their related mechanisms. The effects of Rb1 and Rg1 on cell viability, tyrosinase activity, cellular melanin content and protein levels of tyrosinase, microphthalmia-associated transcription factor (MITF), and activation of CREB in melanocytes were assessed. Results showed that Rb1 or Rg1 significantly increased cellular melanin content and tyrosinase activity in a dose-dependent manner. By contrast, the cell viability of melanocytes remained unchanged. After exposure to Rb1 or Rg1, the protein levels of tyrosinase, MITF, and phosphorylated CREB were significantly increased. Furthermore, pretreatment with the selective PKA inhibitor H-89 significantly blocked the Rb1- or Rg1-induced increase of melanin content. These findings indicated that Rb1 and Rg1 increased melanogenesis and tyrosinase activity in human melanocytes, which was associated with activation of PKA/CREB/MITF signaling. The effects and mechanisms of Rb1 or Rg1 on skin pigmentation deserve further study. PMID- 24799946 TI - Effects of stingless bee propolis on experimental asthma. AB - Bee products have been used empirically for centuries, especially for the treatment of respiratory diseases. The present study evaluated the effect of treatment with a propolis hydroalcoholic extract (PHE) produced by Scaptotrigona aff. postica stingless bee in a murine asthma model. BALB/c mice were immunized twice with ovalbumin (OVA) subcutaneously. After 14 days, they were intranasally challenged with OVA. Groups P50 and P200 received PHE by gavage at doses of 50 and 200 mg/kg, respectively. The DEXA group was treated with intraperitoneal injection of dexamethasone. The OVA group received only water. The mice were treated daily for two weeks and then they were immunized a second time with intranasal OVA. The treatment with PHE decreased the cell number in the bronchoalveolar fluid (BAL). Histological analysis showed reduced peribronchovascular inflammation after treatment with PHE especially the infiltration of polymorphonuclear cells. In addition, the concentration of interferon- gamma (IFN- gamma ) in the serum was decreased. These results were similar to those obtained with dexamethasone. Treatment with S. aff postica propolis reduced the pathology associated with murine asthma due an inhibition of inflammatory cells migration to the alveolar space and the systemic progression of the allergic inflammation. PMID- 24799947 TI - The effect of the kampo medicine yokukansan on preoperative anxiety and sedation levels. AB - Background. Preoperative anxiety can lead to unfavorable physiological response such as tachycardia and hypertension. Prevention of preoperative anxiety improves surgical outcome and decreases inpatient stay. Yokukansan is one of prescriptions in Kampo, traditional Japanese herbal medicine, and is known to exert anxiolytic effects. The aim of the present study was to compare the effects of diazepam and Yokukansan on preoperative anxiety, salivary amylase activity, and sedation levels. Methods. Seventy American Society of Anesthesiologists physical status I or II patients presenting for hemicolectomy under general anesthesia combined with epidural anesthesia were enrolled. The Diazepam group received diazepam 5 mg orally and the Yokukansan group received Yokukansan 2.5 g orally. Results. Although levels of anxiety and salivary amylase activity were not different between the two groups, the modified Observer's Assessment of Alertness/Sedation Scale of the Yokukansan group was significantly higher compared to that of the Diazepam group. Conclusion. Yokukansan alleviated preoperative anxiety without undesirable sedation, when compared with diazepam. PMID- 24799948 TI - Improving Training Condition Assessment in Endurance Cyclists: Effects of Ganoderma lucidum and Ophiocordyceps sinensis Dietary Supplementation. AB - The main reasons for taking daily dietary supplements are to maintain good health, to improve homeostasis, and to create conditions for reducing the risk of disease. Due to growing market demand, the search for effective, nontoxic, natural compounds with antioxidant and ergogenic properties has increasingly become a matter of interest. This paper describes how a specific combination of fungal supplements can help improve the performance of endurance athletes. We report the effects of a brief 3-month trial of two fungal supplements, Ganoderma lucidum and Cordyceps sinensis (3 capsules of O. sinensis and 2 capsules of G. lucidum per day), in 7 healthy male volunteers, aged between 30 and 40 years, who are all amateur cyclists that participate in "Gran Fondo" cycling races. This trial investigated the effects of fungal supplements on the level of physical fitness of the athletes by monitoring and comparing the following biomarkers just before and after physical exertion: the testosterone/cortisol ratio in the saliva and oxidative stress (DPPH free radical scavenging activity). A decrease of more than 30% in the testosterone/cortisol ratio after race compared to before race was considered as a risk factor for nonfunctional overreaching (NFO) or the overtraining syndrome (OTS). The results show that, after 3 months of supplementation, the testosterone/cortisol ratio changed in a statistically significant manner, thereby protecting the athletes from NFO and OTS. Antioxidant activity was measured by quantifying the scavenging ability of the human serum on the synthetic free radical DPPH. After 3 months of fungal supplementation, the data demonstrate an increased scavenger capacity of free radicals in the athletes' serum after the race, thereby protecting the athletes from oxidative stress. PMID- 24799949 TI - Utility of molecular tests in cytopathology. AB - With the popularity of interventional radiology, diagnostic material obtained can be limited requiring critical decisions on making the best use of it. Molecular testing using nanogram amounts of tissue can add useful diagnostic information by improving sensitivity and/or specificity of the diagnosis. This review examines the use of molecular tests in cervical cytology, "indeterminate" thyroid cytology specimens, pancreatic cyst fluid, urinary tract and pulmonary adenocarcinoma cytologic material. Molecular human papillomavirus (HPV) testing combined with cervical cytology increases sensitivity of detection of high grade lesions. In cytologically negative cases, the HPV negative predictive value endorses longer screening intervals. With the high prevalence of benign thyroid nodules, cytology plays a vital role in screening. However, 10-40% of the specimens obtained are cytologically indeterminate. Molecular analysis of these specimens can predict the malignant risk in these cases. Increased detection of pancreatic cysts has necessitated accurate pre-operative diagnosis delineating non-mucinous from mucinous cysts, which have a potential for progression to adenocarcinoma. Multimodal diagnosis of pancreatic cysts and molecular analysis help to clarify neoplastic risk; and in cases of limited fluid, may be the only available diagnostic information. Urothelial carcinoma (UC) of the bladder, a common cancer with frequent recurrences, requires lifelong surveillance. The UroVysion TM test kit can increase the sensitivity of detection of UC especially in cases of residual/recurrent carcinoma after therapy. Subsets of lung adenocarcinomas are now commonly targeted by therapies based on molecular mutation results of epidermal growth factor receptor, KRAS or echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase re-arrangements. The move toward standardization of reporting of cytology specimens commencing with cervical smears and more recently, thyroid cytology specimens is also changing the practice of cytopathology. Combining the stringent cytology criteria with ancillary molecular testing is expected to yield more discrete and diagnostic categories for research and reporting. The profession is at an exciting point of implementing novel molecular markers to refine diagnostic criteria and create clinically relevant classification systems. PMID- 24799950 TI - Thank you CytoJournal reviewers for your 2012 and 2013 services! PMID- 24799951 TI - The state of cell block variation and satisfaction in the era of molecular diagnostics and personalized medicine. AB - BACKGROUND: In the recent past, algorithms and recommendations to standardize the morphological, immunohistochemical and molecular classification of lung cancers on cytology specimens have been proposed, and several organizations have recommended cell blocks (CBs) as the preferred modality for molecular testing. Based on the literature, there are several different techniques available for CB preparation-suggesting that there is no standard. The aim of this study was to conduct a survey of CB preparation techniques utilized in various practice settings and analyze current issues, if any. MATERIALS AND METHODS: A single E mail with a link to an electronic survey was distributed to members of the American Society of Cytopathology and other pathologists. Questions pertaining to the participants' practice setting and CBs-volume, method, quality and satisfaction-were included. RESULTS: Of 95 respondents, 90/95 (94%) completed the survey and comprise the study group. Most participants practice in a community hospital/private practice (44%) or academic center (41%). On average, 14 CBs (range 0-50; median 10) are prepared by a laboratory daily. Over 10 methods are utilized: Plasma thrombin (33%), HistoGel (27%), Cellient automated cell block system (8%) and others (31%) respectively. Forty of 90 (44%) respondents are either unsatisfied or sometimes satisfied with their CB quality, with low cellular yield being the leading cause of dissatisfaction. There was no statistical significance between the three most common CB preparation methods and satisfaction with quality. DISCUSSION: Many are dissatisfied with their current method of CB preparation, and there is no consistent method to prepare CBs. In today's era of personalized medicine with an increasing array of molecular tests being applied to cytological specimens, there is a need for a standardized protocol for CB optimization to enhance cellularity. PMID- 24799952 TI - Community-based mental health support for orphans and vulnerable children in South Africa: A triangulation study. AB - Community-based care is receiving increasing global attention as a way to support children who are orphaned or vulnerable due to the HIV/AIDS pandemic. Using both qualitative and quantitative methodology, this study assesses community-based responses to the well-being of orphans and vulnerable children (OVC) and compares these responses with the actual mental health of OVC in order to evaluate the South African government's approach of funding community-based organisations (CBOs) that support and care for OVC. The study results show that the activities of CBOs mainly extend government services and address poverty. Although this should not be seen as insignificant, the paper argues that CBOs give very little attention to the mental health of OVC. PMID- 24799953 TI - A semiparametric bivariate probit model for joint modeling of outcomes in STEMI patients. AB - In this work we analyse the relationship among in-hospital mortality and a treatment effectiveness outcome in patients affected by ST-Elevation myocardial infarction. The main idea is to carry out a joint modeling of the two outcomes applying a Semiparametric Bivariate Probit Model to data arising from a clinical registry called STEMI Archive. A realistic quantification of the relationship between outcomes can be problematic for several reasons. First, latent factors associated with hospitals organization can affect the treatment efficacy and/or interact with patient's condition at admission time. Moreover, they can also directly influence the mortality outcome. Such factors can be hardly measurable. Thus, the use of classical estimation methods will clearly result in inconsistent or biased parameter estimates. Secondly, covariate-outcomes relationships can exhibit nonlinear patterns. Provided that proper statistical methods for model fitting in such framework are available, it is possible to employ a simultaneous estimation approach to account for unobservable confounders. Such a framework can also provide flexible covariate structures and model the whole conditional distribution of the response. PMID- 24799954 TI - Aldehyde dehydrogenase1 immunohistochemical staining in primary breast cancer cells independently predicted overall survival but did not correlate with the presence of circulating or disseminated tumors cells. AB - PURPOSE: We hypothesized that aldehyde dehydrogenase 1 (ALDH1) staining in breast cancer tumor cells might be a simple surrogate for the presence of circulating tumor cells (CTCs) or disseminated tumor cells (DTCs). EXPERIMENTAL DESIGN: Whole tissue primary tumor sections from 121 patients enrolled in a clinical trial assessing CTCs and DTCs at the time of surgery were stained for ALDH1 and scored by a dedicated breast pathologist blinded to outcome. Clinical data was extracted and staining was correlated to clinical variables and outcome by Fisher's exact test, the Log rank test and Cox proportional hazards regression analysis respectively. P < 0.05 was considered significant. RESULTS: ALDH1 staining in tumor cells was present in 12% of cases (15/121). In univariate analysis, ALDH1 tumor staining predicted worse overall survival (71% vs. 91% at 5 years P = 0.0074) and was an independent predictor on multivariable analysis of worse overall survival, (HR 4.93) after adjusting for stage, ER, grade, LVI, age and neoadjuvant chemotherapy (P = 0.04). ALDH1 was significantly associated with estrogen receptor (ER) negative (P value = 0.029) primary tumors but not the presence of CTCs or DTCs by multivariate logistic regression. Positive ALDH staining in non-tumor cells of any pattern or morphology was common but did not correlate with CTCs or DTCs, other clinical variables, or outcome. CONCLUSION: ALDH1 tumor staining was associated with ER -negative breast cancer and was an independent predictor of OS. However, it did not correlate to putative cancer stem cell surrogates CTCs and/or DTCs. PMID- 24799956 TI - Carnosine Inhibits the Proliferation of Human Gastric Carcinoma Cells by Retarding Akt/mTOR/p70S6K Signaling. AB - Carnosine (beta-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer. However, its function in human gastric carcinoma remains unclear. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in the cultured human gastric carcinoma cells. The mTOR signaling axis molecules were analyzed in carnosine treated cells. The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin. PMID- 24799955 TI - Safety and efficacy of suicide gene therapy with adenosine deaminase 5 fluorocytosine silmutaneously in in vitro cultures of melanoma and retinal cell lines. AB - Local treatment as a treatment modality is gaining increased general acceptance over time. Novel drugs and methodologies of local administration are being investigated in an effort to achieve disease local control. Suicide gene therapy is a method that has been investigated as a local treatment with simultaneously distant disease control. In our current experiment we purchased HTB-70 (melanoma cell line, derived from metastatic axillary node) and CRL-2302 (human retinal epithelium) were from ATCC LGC Standards and Ancotil((r)), 2.5 g/250 ml (1 g/00ml) (5-Flucytosine) MEDA; Pharmaceuticals Ltd. UK. Adenosine Cytosine Deaminase (Ad.CD) was also used in order to convert the pro-drug 5-Flucytosine to the active 5-Fluoracil. Three different concentrations of 5-Flucytosine (5-FC) were administered (0.2ml, 0.8ml and 1.2ml). At indicated time-points (4h, 8h and 24h) cell viability and apoptosis were measured. Our concept was to investigate whether suicide gene therapy with Ad. CD-5-FC could be used with safety and efficiency as a future local treatment for melanoma located in the eye cavity. Indeed, our results indicated that in every 5-FC administration had mild cytotoxicity for the retinal cells, while increased apoptosis was observed for the melanoma cell line. PMID- 24799957 TI - Highly frequent and enhanced injection site reaction induced by peripheral venous injection of fosaprepitant in anthracycline-treated patients. AB - BACKGROUND: Fosaprepitant-associated injection site reaction (ISR) has been reported in patients treated with cisplatin, an irritant drug. We conducted this retrospective study to clarify the incidence and symptoms of fosaprepitant associated ISR in patients treated with anthracycline. PATIENTS AND METHODS: Fifty six patients receiving 159 injections administering doxorubicin/cyclophosphamide (AC), fluorouracil/epirubicin/cyclophosphamide (FEC), or rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R )CHOP regimen through a peripheral vein at ambulatory treatment centers reviewed for this study from patients' medical records. Incidence of ISR was compared between 24 patients with fosaprepitant injection (fosaprepitant group) and 32 patients without fosaprepitant (control group). Frequency and symptoms of ISR per injection were also compared between 61 injections with fosaprepitant and 98 injections without fosaprepitant. RESULTS: Both the ISR incidence rate per patient and per injection were significantly higher in the fosaprepitant group than in the control group (67% vs. 16%; P=0.0002, 34% vs. 8.2%; P<0.0001, respectively). By multivariate analysis, fosaprepitant injection was found to be a significant independent variable correlated with ISR risk. Symptoms observed in 61 injections of fosaprepitant were pain (n=14, 23%), erythema (n=10, 16%), swelling (n=6, 10%), and delayed drip infusion (n=6, 10%). After the observation period, no ISR occurred when the administration route was changed to central venous injection or oral aprepitant was administered despite the continuation of chemotherapy. CONCLUSION: ISR occurred more frequently and severely when fosaprepitant was injected through the peripheral vein in patients treated with anthracyclines compared to those without fosaprepitant. PMID- 24799958 TI - Quantum entanglement in photoactive prebiotic systems. AB - This paper contains the review of quantum entanglement investigations in living systems, and in the quantum mechanically modelled photoactive prebiotic kernel systems. We define our modelled self-assembled supramolecular photoactive centres, composed of one or more sensitizer molecules, precursors of fatty acids and a number of water molecules, as a photoactive prebiotic kernel systems. We propose that life first emerged in the form of such minimal photoactive prebiotic kernel systems and later in the process of evolution these photoactive prebiotic kernel systems would have produced fatty acids and covered themselves with fatty acid envelopes to become the minimal cells of the Fatty Acid World. Specifically, we model self-assembling of photoactive prebiotic systems with observed quantum entanglement phenomena. We address the idea that quantum entanglement was important in the first stages of origins of life and evolution of the biospheres because simultaneously excite two prebiotic kernels in the system by appearance of two additional quantum entangled excited states, leading to faster growth and self-replication of minimal living cells. The quantum mechanically modelled possibility of synthesizing artificial self-reproducing quantum entangled prebiotic kernel systems and minimal cells also impacts the possibility of the most probable path of emergence of protocells on the Earth or elsewhere. We also examine the quantum entangled logic gates discovered in the modelled systems composed of two prebiotic kernels. Such logic gates may have application in the destruction of cancer cells or becoming building blocks of new forms of artificial cells including magnetically active ones. PMID- 24799959 TI - Analysis of osmoadaptation system in budding yeast suggests that regulated degradation of glycerol synthesis enzyme is key to near-perfect adaptation. AB - In order to maintain its turgor pressure at a desired homeostatic level, budding yeast, Saccharomyces cerevisiae responds to the external variation of the osmotic pressure by varying its internal osmotic pressure through regulation of synthesis and transport of the intracellular glycerol. Hog1PP (dually phosphorylated Hog1), a final effector in the signalling pathway of the hyper osmotic stress, regulates the glycerol synthesis both at transcriptional and non-transcriptional stages. It is known that for a step-change in salt concentration leading to moderate osmotic shock, Hog1PP activity shows a transient response before it returns to the vicinity of pre-stimulus level. It is believed that an integrating process in a negative feedback loop can be a design strategy to yield such an adaptive response. Several negative feedback loops have been identified in the osmoadaptation system in yeast. However, the precise location of the integrating process in the osmoadaptation system which includes signalling, gene regulation, metabolism and biophysical modules is unclear. To address this issue, we developed a reduced model which captures various experimental observations of the osmoadaptation behaviour of wild type and mutant strains. Dynamic simulations and steady state analysis suggested that known information about the osmoadaptation system of budding yeast does not necessarily give a perfect integrating process through the known feedback loops of Hog1PP. On the other hand, regulation of glycerol synthesising enzyme degradation can result in a near integrating process leading to a near-perfect adaptation. PMID- 24799960 TI - Designing synthetic drugs against Plasmodium falciparum: a computational study of histone-lysine N-methyltransferase (PfHKMT). AB - Histone lysine methyltransferase (HKMT) are histone-modifying enzymes that catalyze the transfer of methyl groups to lysine and arginine residues of histone protein. HKMTs have been involved in transcriptional regulation of various proteins in organisms. Malaria parasite also has HKMT, which plays a major role in parasite development and pathogenesis and also in regulation of various biological process and pathways. Our aim is to study fundamental biology of key molecules involved in the survival of Plasmodium falciparum and use these to develop efficient synthetic peptides and chemical compounds. As a first step in this direction, we computationally predicted the three-dimensional structure of HKMT of P. falciparum (PfHKMT) by using iterative threading assembly refinement. The PfHKMT three-dimensional model was validated using PROCHECK and docked with known HKMT inhibitor Bix01294 using Autodock. Our initial results are encouraging and indicate that structural analysis of PfHKMT could be important in developing novel synthetic molecules against malaria. PMID- 24799961 TI - Comment on Masanari Asano et al.: A model of epigenetic evolution based on theory of open quantum systems. PMID- 24799962 TI - Can systems biology approach help in finding more effective treatment for acute myeloid leukemia? AB - Acute myeloid leukemia (AML) is a hematological cancer comprising of cancer stem cells (CSCs) that are responsible for the disease progression, drug resistance and post treatment relapses. Advances in genomic technologies have identified AML as a genetically heterogenous disease with dysregulated gene expression networks. Furthermore, observation of intracellular signaling in individual CSCs by mass cytometry has demonstrated the dysregulation of the mitogen associated protein kinase (MAPK) pathways. It has been envisaged that the future treatment for AML would entail upon formulating individualized treatment plans leading to decreased drug related toxicities for patients. However the emerging role of signaling pathways as dynamic molecular switches influencing the cell cycle process, thereby leading to varying stages of cell differentiation, is making community rethink about the current strategies used for the treatment of AML. This commentary will focus on discovering novel biomarkers and identifying new therapeutic targets, to analyze and treat AML, on a platform enabled by systems biology approach. PMID- 24799963 TI - Identifying pseudogenes from hypothetical proteins for making synthetic proteins. AB - Nature selected certain regions of the genome for encoding proteins. Most of the sequences were used to encode only RNA. What happened to the remaining sections of the genome? It is possible that some sequences were retired and retained as non-functional entities called pseudogenes. Though several evolutionary prospects with functional endpoints exist, we looked at the possibility of hypothetical proteins correlating with the emergence of pseudogenes and potential of such genes to make novel synthetic molecules. In this commentary, we consider two key aspects: (1) does any correlation exist between hypothetical proteins and pseudogenes and (2)-can we make novel and functional proteins from pseudogenes? PMID- 24799964 TI - Evaluation of cervical posture following rapid maxillary expansion: a review of literature. AB - OBJECTIVE: The aim of this article is to elucidate the state of the art about how rapid maxillary expansion (RME) produces changes in natural head position (NHP) in terms of cephalometric angles or inclinometer data during the growth period, according to the available literature. METHODS: Electronic search was done from January 2002 to June 2012 on PubMed, Cochrane and Scopus databases; in addition manual search was conducted as well. According to keywords, eleven papers were eligible for our purpose, but definitely six papers were selected in agreement with the inclusion/exclusion criteria. CONCLUSIONS: The current literature suggests that the potential relationship between RME and NHP is still unclear. In fact, although the change in the position of the head after the rapid palatal expansion is evident clinically, current orthodontic literature does not provide conclusive evidence about the nature of this relationship. PMID- 24799965 TI - Detection of non-cavitated occlusal caries with impedance spectroscopy and laser fluorescence: an in vitro study. AB - OBJECTIVE: To evaluate the performance of an impedance spectroscopy technology for detecting non-cavitated occlusal caries lesions in permanent teeth in vitro. The method was compared with a commonly used laser fluorescence device and validated against histology. MATERIAL AND METHODOLOGY: A non-cavitated sample of 100 extracted posterior teeth was randomly selected and assessed for caries on enamel and dentin level with aid of CarioScan PRO (ACIS) and DIAGNOdent pen (LF pen) by three examiners. After the measurements, the extension of the lesion was histologically determined as gold standard. Sensitivity, specificity, accuracy and receiver-operating curves were calculated. Intra- and inter-examiner reproducibility was expressed by intra class correlation coefficients. RESULTS: The histological caries prevalence was 99% and 41% exhibited dentin caries. The ACIS technique displayed high specificities but almost negligible sensitivities at readings >50. A similar pattern was noted for the LF pen at readings >30. The intra- and inter-examiner reproducibility varied between 0.47 and 0.98 and the values were generally lower for the ACIS technique than for the LF pen. The inter examiner agreement reached excellent levels with both methods. CONCLUSIONS: In vitro,the ACIS technique showed a low ability to disclose occlusal caries lesions in the enamel and/or dentin of non-cavitated permanent molars. However, further in vivo studies of permanent occlusal surfaces are needed to mirror the clinical situation. PMID- 24799966 TI - Pleural cholesterol to the diagnosis of exudative effusion. AB - INTRODUCTION: Diagnostic approaches to patients with a pleural effusion must be precise because many procedures depend on the nature of the fluid in the effusion. To date, no biochemical test is considered an appropriate alternative to Light's criteria. This study compared the absolute pleural cholesterol (PC) level and the pleural cholesterol/serum cholesterol (PC/SC) ratio with Light's criteria to determine exudative pleural effusions. MATERIALS AND METHODOLOGY: This study was a case series of 100 consecutive patients with pleural effusions. The clinical parameters that were used to diagnosis an exudative effusion included the cholesterol level, a pleural cholesterol level >= 50 mg/dL, a pleural/serum ratio >= 0.4, and Light's criteria. The sensitivity, specificity, and positive and negative predictive values of each test for the diagnosis of an exudative effusion were assessed. RESULTS: A total of 79 patients were definitively diagnosed with an exudative effusion and were included in the trial and analyzed. The mean PC level in the exudates was 90.39 mg/dL. The PC levels demonstrated a sensitivity of 97.22%, a specificity of 85.71%, a positive predictive value of 98.59% and a negative predictive value of 75%. The PC/SC ratio demonstrated a sensitivity of 81.48%, a specificity of 57.14%, a positive predictive value of 93.61% and a negative predictive value of 28.57%. CONCLUSION: The pleural cholesterol dosage level and the pleural/serum cholesterol ratio can be utilized as unique biomarkers to identify an exudative effusion and replace Light's criteria. PMID- 24799967 TI - Is Acute Exacerbation of COPD (AECOPD) Related to Viral Infection Associated with Subsequent Mortality or Exacerbation Rate? AB - BACKGROUND: There is a growing interest in better defining risk factors associated with increased susceptibility to exacerbation in patients with COPD. INTRODUCTION: The aim of the study was to determine whether identification of a respiratory virus during a severe acute exacerbation of COPD (AECOPD) increases the risk of subsequent exacerbations and mortality during a one-year followup. METHODS: Secondary analysis of 86 COPD patients admitted for AECOPD between June 2007 and December 2008 at Geneva's University Hospital who were followed up for 1 year. Fifty-one percent of index AECOPD were related to viral infection. Rate of AECOPD, time to next AECOPD, and all-cause mortality were compared between patients with vs without viral index AECOPD. RESULTS: Eighty-one cases were included in this secondary follow-up analysis. Mean exacerbation rate was 1.9 AECOPD per person-year for patients with viral index AECOPD vs 4.0 AECOPD per person year for those with non-viral index AECOPD. Incidence rate ratio (IRR) for subsequent AECOPD during one year follow up was lower for patients with viral index AECOPD (IRR 0.57; [CI 95% 0.39-0.84]), after controlling for previous exacerbations, and was strongly associated with the number of exacerbations in the year preceding the index AECOPD. During the one-year follow-up period, 16 patients (19%) died. In a Cox regression model, patients with a proven viral infection did not have a higher mortality (HR 0.56 [CI 95% 0.20 -1.58]). CONCLUSION: Viral AECOPD was not associated with a higher rate of subsequent exacerbations or mortality during the following year. PMID- 24799968 TI - Both Cyclophilin Inhibitors and Direct-Acting Antivirals Prevent PKR Activation in HCV-Infected Cells. AB - We and others demonstrated that the contact between NS5A and the host factor CypA is critical for HCV replication. CypI, by disrupting NS5A-CypA complexes, block HCV replication both in vitro and in patients. Since NS5A also binds to PKR, a central component of the IFN response, we investigated the possibility of a relationship between CypA, NS5A and PKR in the IFN response to HCV. HCV-infected cells treated with CypI, DAAs or IFN were analyzed for the expression and activation of various components of the innate response. We found that CypI (cyclosporine A, alisporivir, NIM811 and sanglifehrins), drastically prevented the activation/phosphorylation, but not the expression of IFN-induced PKR in HCV infected cells. CypI had no effect on the expression or phosphorylation of other components of the innate response such as eiF2, NF-kB, IRF3, IRF9, STAT1 and STAT2, suggesting a specific effect on PKR. No significant activation of IFN induced PKR was observed in the absence of HCV. Importantly, we found that several classes of DAAs such as NS3/4A protease, NS5B polymerase and NS5A inhibitors also prevented PKR activation. Furthermore, we found that PKR activation by the dsRNA mimic poly I:C cannot be prevented by CypI or DAAs. Our findings suggest that CypI do not have a unique effect on PKR activation, but rather the suppression of HCV replication by any anti-HCV inhibitor, abrogates PKR activation induced by IFN. Moreover, they suggest that the accumulation of dsRNA intermediates allows HCV to exploit the activation of PKR to counteract the IFN response. PMID- 24799969 TI - Absence of anaplastic lymphoma kinase translocations in signet ring cell carcinomas of the upper gastrointestinal tract. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in multiple cancer types. The inversion of echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes on chromosome 2 is present in a subset of patients with non-small-cell lung cancer (NSCLC). ALK rearranged lung cancers demonstrate a significantly higher incidence of signet ring cell histology than do ALK-negative tumors. Based on the histologic similarities of ALK-rearranged NSCLC and signet ring cell carcinomas (SRCCs) of the gastrointestinal tract, we hypothesized that SRCC of the upper gastrointestinal (GI) tract may also harbor ALK translocations. METHODS: Thirty five formalin-fixed, paraffin-embedded (FFPE) diagnostic tissue specimens of SRCC or poorly differentiated adenocarcinoma with greater than 10% signet ring cell features originating from the upper GI tract were obtained and confirmed by a board-certified, GI pathologist. SRCC specimens were analyzed by fluorescence in situ hybridization (FISH) analysis, with an ALK (2p23) break-apart probe. RESULTS: The FISH analysis revealed no evidence of ALK translocation. All 35 (100%) SRCC specimens showed intact ALK FISH signals. CONCLUSIONS: These data indicate that, despite histologic similarities between SRCC of the upper GI tract and ALK-positive NSCLC, ALK translocations are unlikely to be a significant contributor to the molecular etiology of SRCC. Further genomic investigations are ongoing. PMID- 24799970 TI - Overexpression of the HER2/neu Gene: A New Therapeutic Possibility for Patients With Advanced Gallbladder Cancer. AB - BACKGROUND: The HER2/neu gene is a proto-oncogene that can predict the response to treatment with trastuzumab, pertuzumab, and lapatinib. This study was conducted to determine the frequency of HER2/neu overexpression and to identify a subgroup of patients with gallbladder cancer who would benefit from targeted therapy. METHODS: Patients with gallbladder cancer (n = 187; 165 women and 22 men) with a recorded follow-up of at least 5 years were included, along with control subjects (n = 75). An automated immunohistochemical technique was used with an anti-ErbB2 antibody. Scoring was conducted according to the CAP/ASCO (College of American Pathologists/American Society of Clinical Oncology) criteria for breast cancer. RESULTS: Overexpression of HER2/neu was observed in 12.8% of the cases. Of those, 0% were mucosal, 14.3% muscular, 12.8% subserosal, and 10.6% serosal. In 20% of the cases, equivocal staining was observed. Overexpression was more frequent in the advanced cancers and in the better differentiated tumors (13.8% and 17.4%, respectively), but the difference was nonsignificant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%). CONCLUSION: This is the single largest study of HER2/neu expression in gallbladder cancer to use commonly accepted scoring criteria. The results indicate that HER2/neu overexpression occurred in 14% of the advanced gallbladder cancer cases. This subgroup may benefit from inhibitors of the HER2/neu pathway. PMID- 24799971 TI - Prognosis of Patients With Fibrolamellar Hepatocellular Carcinoma Versus Conventional Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. AB - BACKGROUND: Emerging data suggest that the fibrolamellar variant of hepatocellular carcinoma (FL-HCC) differs in clinical course and prognosis from conventional (nonfibrolamellar) HCC (NFL-HCC). Although FL-HCC is believed to have a better prognosis than NFL-HCC, data comparing the prognoses of the two types of HCC remain lacking. The aim of this systematic review was to compare the prognosis of FL- vs. NFL-HCC. METHODS: Two of the authors independently conducted a comprehensive search of the Cochrane Library, PubMed, Scopus, and published proceedings from major hepatology and gastrointestinal meetings from January 1980 to October 2013. Outcomes of interest were mean overall survival (OS) and 5-year survival. The analyses were performed with a fixed- or random-effects model, as appropriate. The Begg's and Egger's tests with visual inspection of the funnel plot were used to assess for population bias. All analyses were performed with RevMan 5.1 (Cochrane IMS). RESULTS: Seventeen studies involving 368 patients with FL-HCC and 9877 patients with NFL-HCC were included in the analysis. There was an overall statistically significant increase in the 5-year survival for the FL-HCC vs. the NFL-HCC patients (RR, 2.09; 95% CI, 1.38-3.16). In a subgroup analysis limited to noncirrhotic patients, there was no significant difference in 5-year survival in the FL-HCC group compared to that in the NFL-HCC group (RR, 1.69; 95% CI, 0.69-4.17). A significant increase in mean OS was reported in patients with FL-HCC compared with the survival time of those with NFL-HCC (84.9 +/- 15.8 vs. 42.9 +/- 6.5 months) undergoing partial hepatectomy, but there was no difference in patients undergoing liver transplantation (51.4 +/- 14.4 vs. 47.5 +/- 5.5 months). CONCLUSION: Patients with FL-HCC treated with hepatic resection had significantly higher 5-year survival rates than did those with NFL-HCC. However, survival was similar for both FL-HCC and conventional HCC in noncirrhotic patients. There seems to be no difference in survival outcomes for FL- and NFL HCC when transplantation is used as the therapeutic option. PMID- 24799972 TI - A 39-year-old female patient with metastatic rectal cancer develops thrombocytopenia. PMID- 24799973 TI - Acute gout episodes during treatment with capecitabine: a case report. PMID- 24799974 TI - Metastatic non-small-cell lung cancer to the liver and pancreas. PMID- 24799975 TI - Littoral cell angioma: gastrointestinal associations. PMID- 24799978 TI - Upcoming articles. PMID- 24799976 TI - Definitive chemoradiation in oligometastatic squamous cell carcinoma of the anal canal. PMID- 24799979 TI - Indices of paraoxonase and oxidative status do not enhance the prediction of subclinical cardiovascular disease in mixed-ancestry South Africans. AB - We evaluated the association of indices of paraoxonase (PON1) and oxidative status with subclinical cardiovascular disease (CVD) in mixed-ancestry South Africans. Participants were 491 adults (126 men) who were stratified by diabetes status and body mass index (BMI). Carotid intima-media thickness (CIMT) was used as a measure of subclinical CVD. Indices of PON1 and oxidative status were determined by measuring levels and activities (paraoxonase and arylesterase) of PON1, antioxidant activity (ferric reducing antioxidant power and trolox equivalent antioxidant capacity), and lipid peroxidation markers (malondialdehyde and oxidized LDL). Diabetic subjects (28.9%) displayed a significant decrease in PON1 status and antioxidant activity as well as increase in oxidized LDL and malondialdehyde. A similar profile was apparent across increasing BMI categories. CIMT was higher in diabetic than nondiabetic subjects (P < 0.0001) but showed no variation across BMI categories. Overall, CIMT correlated negatively with indices of antioxidant activity and positively with measures of lipid oxidation. Sex, age, BMI, and diabetes altogether explained 29.2% of CIMT, with no further improvement from adding PON1 and/or antioxidant status indices. Though indices of PON1 and oxidative status correlate with CIMT, their measurements may not be useful for identifying subjects at high CVD risk in this population. PMID- 24799980 TI - Effects of paracetamol on NOS, COX, and CYP activity and on oxidative stress in healthy male subjects, rat hepatocytes, and recombinant NOS. AB - Paracetamol (acetaminophen) is a widely used analgesic drug. It interacts with various enzyme families including cytochrome P450 (CYP), cyclooxygenase (COX), and nitric oxide synthase (NOS), and this interplay may produce reactive oxygen species (ROS). We investigated the effects of paracetamol on prostacyclin, thromboxane, nitric oxide (NO), and oxidative stress in four male subjects who received a single 3 g oral dose of paracetamol. Thromboxane and prostacyclin synthesis was assessed by measuring their major urinary metabolites 2,3-dinor thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F(1alpha), respectively. Endothelial NO synthesis was assessed by measuring nitrite in plasma. Urinary 15(S)-8-iso-prostaglanding F(2alpha) was measured to assess oxidative stress. Plasma oleic acid oxide (cis-EpOA) was measured as a marker of cytochrome P450 activity. Upon paracetamol administration, prostacyclin synthesis was strongly inhibited, while NO synthesis increased and thromboxane synthesis remained almost unchanged. Paracetamol may shift the COX-dependent vasodilatation/vasoconstriction balance at the cost of vasodilatation. This effect may be antagonized by increasing endothelial NO synthesis. High-dosed paracetamol did not increase oxidative stress. At pharmacologically relevant concentrations, paracetamol did not affect NO synthesis/bioavailability by recombinant human endothelial NOS or inducible NOS in rat hepatocytes. We conclude that paracetamol does not increase oxidative stress in humans. PMID- 24799981 TI - Impaired 8-hydroxyguanine repair activity of MUTYH variant p.Arg109Trp found in a Japanese patient with early-onset colorectal cancer. AB - PURPOSE: The biallelic inactivation of the 8-hydroxyguanine repair gene MUTYH leads to MUTYH-associated polyposis (MAP), which is characterized by colorectal multiple polyps and carcinoma(s). However, only limited information regarding MAP in the Japanese population is presently available. Since early-onset colorectal cancer (CRC) is a characteristic of MAP and might be caused by the inactivation of another 8-hydroxyguanine repair gene, OGG1, we investigated whether germline MUTYH and OGG1 mutations are involved in early-onset CRC in Japanese patients. METHODS: Thirty-four Japanese patients with early-onset CRC were examined for germline MUTYH and OGG1 mutations using sequencing. RESULTS: Biallelic pathogenic mutations were not found in any of the patients; however, a heterozygous p.Arg19* MUTYH variant and a heterozygous p.Arg109Trp MUTYH variant were detected in one patient each. The p.Arg19* and p.Arg109Trp corresponded to p.Arg5* and p.Arg81Trp, respectively, in the type 2 nuclear-form protein. The defective DNA repair activity of p.Arg5* is apparent, while that of p.Arg81Trp has been demonstrated using DNA cleavage and supF forward mutation assays. CONCLUSION: These results suggest that biallelic MUTYH or OGG1 pathogenic mutations are rare in Japanese patients with early-onset CRC; however, the p.Arg19* and p.Arg109Trp MUTYH variants are associated with functional impairments. PMID- 24799982 TI - Resveratrol oligomers for the prevention and treatment of cancers. AB - Resveratrol (3,4',5-trihydroxystilbene) is a naturally derived phytoalexin stilbene isolated from grapes and other plants, playing an important role in human health and is well known for its extensive bioactivities, such as antioxidation, anti-inflammatory, anticancer. In addition to resveratrol, scientists also pay attention to resveratrol oligomers, derivatives of resveratrol, which are characterized by the polymerization of two to eight, or even more resveratrol units, and are the largest group of oligomeric stilbenes. Resveratrol oligomers have multiple beneficial properties, of which some are superior in activity, stability, and selectivity compared with resveratrol. The complicated structures and diverse biological activities are of significant interest for drug research and development and may provide promising prospects as cancer preventive and therapeutical agents. This review presents an overview on preventive or anticancer properties of resveratrol oligomers. PMID- 24799984 TI - Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease. AB - The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease. PMID- 24799983 TI - Global consequences of liver ischemia/reperfusion injury. AB - Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organ's post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with "global" consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion. PMID- 24799985 TI - Lipid lowering effects of iodothyronines: In vivo and in vitro studies on rat liver. AB - Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common liver diseases, leading to the increasing interest for new therapeutic approaches for its treatment. NAFLD primarily depends on a hypercaloric and/or unbalanced diet leading to overweight and obesity. The liver, in fact, plays a central role in lipid metabolism by importing free fatty acids from the blood and synthesizing, storing, oxidizing and exporting lipids. Furthermore, the liver is the target for the thyroid hormones, thyroxine (T4) and 3,3',5-triiodo-L thyronine (T3), that stimulate the basal metabolic rate and lead to body weight loss. In the last decade, other iodothyronines have been shown to possess biological relevance and play some thyromimetic activities; in particular, 3,5 diiodo-L-thyronine (T2) gained large interest. The global effect of iodothyronines on liver lipid metabolism results from the balance between direct and indirect actions on the hepatocyte, leading to stimulation of lipid synthesis, oxidation and autophagy. In this review, the results so far obtained on both in vivo and in vitro models of hepatosteatosis are summarized in order to obtain an updated picture of the lipid-lowering effects of iodothyronines on mammalian liver. PMID- 24799986 TI - Update on inflammatory bowel disease in patients with primary sclerosing cholangitis. AB - Patients with primary sclerosing cholangitis (PSC) complicated by inflammatory bowel disease (IBD) represent a distinct subset of patients with unique characteristics, which have serious clinical implications. The aim of this literature review was to shed light to the obscure clinical and molecular aspects of the two diseases combined utilizing current data available and putting issues of diagnosis and treatment into perspective. The prevalence of IBD, mainly ulcerative colitis in PSC patients is estimated to be 21%-80%, dependent on screening programs and nationality. PSC-associated colitis is likely to be extensive, characterized by rectal sparing, backwash ileitis, and generally mild symptoms. It is also more likely to progress to colorectal malignancy, making it imperative for clinicians to maintain a high level of suspicion when tackling PSC patients. There is no optimal surveillance strategy but current guidelines advocate that colonoscopy is necessary at the time of PSC diagnosis with annual endoscopic follow-up. Random biopsies have been criticized and a shift towards targeted biopsies using chromoendoscopy, laser endomicroscopy and narrow-band imaging has been noted. Techniques directed towards genetic mutations instead of histological abnormalities hold promise for easier, more accurate diagnosis of dysplastic lesions. Chemopreventive measures against colorectal cancer have been sought in these patients. Ursodeoxycholic acid seemed promising at first but subsequent studies yielded conflicting results showing anticarcinogenic effects in low doses (8-15 mg/kg per day) and carcinogenic properties in high doses (15 30 mg/kg per day). PMID- 24799987 TI - Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease. AB - The prevalence of obesity and related conditions like non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and therapeutic options are limited. Alternative treatment options are therefore intensively sought after. An interesting candidate is the natural polyphenol resveratrol (RSV) that activates adenosinmonophosphate-activated protein kinase (AMPK) and silent information regulation-2 homolog 1 (SIRT1). In addition, RSV has known anti-oxidant and anti inflammatory effects. Here, we review the current evidence for RSV-mediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis (NASH) pathogenesis with respect to free fatty acid (FFA) flux from adipose tissue, hepatic de novo lipogenesis, inadequate FFA beta-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits. We review the in vivo evidence from animal studies and clinical trials. The abundance of animal studies reports a decrease in hepatic triglyceride accumulation, liver weight and a general improvement in histological fatty liver changes, along with a reduction in circulating insulin, glucose and lipid levels. Some studies document AMPK or SIRT1 activation, and modulation of relevant markers of hepatic lipogenesis, inflammation and oxidation status. However, AMPK/SIRT1-independent actions are also likely. Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes. Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients. PMID- 24799988 TI - Insulin sensitizers for the treatment of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome, which includes hypertension, central obesity, dyslipidemia and insulin resistance. NAFLD includes a wide spectrum of liver alterations, ranging from simple hepatic steatosis to variable degrees of fibrosis, cirrhosis and even hepatocellular carcinoma. Although the etiology and progression of the disorder remain poorly understood, insulin resistance is considered to play a pivotal role in the pathogenesis. Insulin sensitizers such as biguanides, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years. Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase (ALT/AST) levels in the majority of subjects; however, it has no significant effect on liver histology. TZDs improve insulin sensitivity, serum ALT/AST levels and histology in some cases, but there are some concerns about the safety of long-term therapy. Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are the main points. These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer. The present review provides an overview of insulin sensitizers in the treatment of NAFLD. PMID- 24799989 TI - Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition. AB - Liver injuries are repaired by fibrosis and regeneration. The cause of fibrosis and diminished regeneration, especially in liver cirrhosis, is still unknown. Epithelial-mesenchymal transition (EMT) has been found to be associated with liver fibrosis. The possibility that EMT could contribute to hepatic fibrogenesis reinforced the concept that activated hepatic stellate cells are not the only key players in the hepatic fibrogenic process and that other cell types, either hepatic or bone marrow-derived cells could contribute to this process. Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis, more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders. The debate on the authenticity of EMT or on its contribution to the fibrogenic process has become very animated. The overall result is a general confusion on the meaning and on the definition of several key aspects. The aim of this article is to describe how EMT participates to hepatic fibrosis and discuss the evidence of supporting this possibility in order to reach reasonable and useful conclusions. PMID- 24799991 TI - To treat or not to treat the "immunotolerant phase" of hepatitis B infection: A tunnel of controversy. AB - Hepatitis B virus (HBV) infection is a global public health problem, with an estimated 350 million people worldwide chronically infected and approximately 500000 who die annually from HBV-related liver diseases. Management of chronic HBV is challenging and waves of guidelines emerge every year. One of the hottest topics and a matter of debate is the management of patients in their early immunotolerant phase of infection. With the lack of evidence, dealing with this particular subset of patients creates a great conflict with opposing views. In this review, the author highlights the pros and cons of these views and proposes a reasonable solution to resolve this dilemma. PMID- 24799990 TI - Pediatric non-alcoholic fatty liver disease: New insights and future directions. AB - One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions. PMID- 24799992 TI - Melatonin attenuates cisplatin-induced HepG2 cell death via the regulation of mTOR and ERCC1 expressions. AB - AIM: To elucidate the effects of melatonin on cisplatin-induced hepatocellular carcinoma (HepG2) cell death and to identify potential cross-talk pathways. METHODS: Hepatocellular carcinoma HepG2 cells were treated with melatonin and/or cisplatin for 24 to 48 h. Cell viability and the 50% cytotoxic concentration (CC50) were calculated by MTT assays. The effects and intracellular events induced by the selected concentrations of melatonin (1 mmol/L) and cisplatin (20 MUmol/L) were investigated. Cell death and survival detection were primarily evaluated using a fluorescence microscope to assess 4',6 diamideno-2-phenylindol DNA staining and acridine orange lysosome staining and then further analyzed with immunocytochemistry using an anti-LC3 antibody. The potential molecular responses mediated by melatonin against cisplatin after the combined treatment were investigated by reverse transcription-polymerase chains reaction and Western blot analyses of the genes and proteins associated with cell survival and death. A cell cycle analysis was performed using a flow cytometry assay. RESULTS: Melatonin had a concentration-dependent effect on HepG2 cell viability. At 1 mmol/L, melatonin significantly increased the cell viability percentage and decreased reactive oxygen species production due to cisplatin. Melatonin reduced cisplatin-induced cell death, decreasing phosphorylated p53 apoptotic protein, cleaved caspase 3 and Bax levels but increasing anti-apoptotic Bcl-2 gene and protein expression. When combined with cisplatin, melatonin induced S phase (DNA synthesis) cell cycle arrest and promoted autophagic events in HepG2 cells. Melatonin also had a concentration-dependent effect on Beclin-1 and its autophagic regulator mammalian target of rapamycin (mTOR) as well as the DNA excision repair cross complementary 1 (ERCC1) protein. The expression levels of these proteins were altered in HepG2 cells during cisplatin or melatonin treatment alone. In the combination treatment, melatonin reversed the effects of cisplatin by suppressing the over-expression of mTOR and ERCC 1 and enhancing the expression levels of Beclin-1 and microtubule-associated protein-light chain3-II, leading to intracellular autophagosome progression. CONCLUSION: Melatonin attenuated cisplatin-induced cell death in HepG2 cells via a counter-balance between the roles of apoptotic- and autophagy-related proteins. PMID- 24799993 TI - Murine model to study brain, behavior and immunity during hepatic encephalopathy. AB - AIM: To propose an alternative model of hepatic encephalopathy (HE) in mice, resembling the human features of the disease. METHODS: Mice received two consecutive intraperitoneal injections of thioacetamide (TAA) at low dosage (300 mg/kg). Liver injury was assessed by serum transaminase levels (ALT) and liver histology (hematoxylin and eosin). Neutrophil infiltration was estimated by confocal liver intravital microscopy. Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time. Hemodynamic parameters were measured through tail cuff. Ammonia levels were quantified in serum and brain samples. Electroencephalography (EEG) and psychomotor activity score were performed to show brain function. Brain edema was evaluated using magnetic resonance imaging. RESULTS: Mice submitted to the TAA regime developed massive liver injury, as shown by elevation of serum ALT levels and a high degree of liver necrosis. An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury. This led to mice mortality and weight loss, which was associated with severe coagulopathy. Furthermore, TAA-treated mice presented with increased serum and cerebral levels of ammonia, in parallel with alterations in EEG spectrum and discrete brain edema, as shown by magnetic resonance imaging. In agreement with this, neuropsychomotor abnormalities ensued 36 h after TAA, fulfilling several HE features observed in humans. In this context of liver injury and neurological dysfunction, we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome. CONCLUSION: In summary, we describe a new murine model of hepatic encephalopathy comprising multiple features of the disease in humans, which may provide new insights for treatment. PMID- 24799994 TI - Nuclear medicine dynamic investigations in the diagnosis of Budd-Chiari syndrome. AB - AIM: To investigate the hepatic hemodynamics in the Budd-Chiari syndrome (BCS) using per-rectal portal scintigraphy (PRPS) and liver angioscintigraphy (LAS). METHODS: Fourteen consecutive patients with BCS were evaluated by PRPS between 2003 and 2012. Ten of them underwent LAS and liver scan (LS) with Tc-99m colloid. Eleven patients had clinical manifestations and three were asymptomatic, incidentally diagnosed at PRPS. The control group included 15 healthy subjects. We used new parameters at PRPS, the liver transit time of portal inflow and the blood circulation time between the right heart and liver. PRPS offered information on the hepatic areas missing venous outflow or portal inflow, length and extent of the lesions, open portosystemic shunts (PSS), involvement of the caudate lobe (CL) as an intrahepatic shunt and flow reversal in the splenic vein. LAS was useful in the differential diagnosis between the BCS and portal obstructions, highlighting the hepatic artery buffer response and reversed portal flow. LS offered complementary data, especially on the CL. RESULTS: We described three hemodynamic categories of the BCS with several subtypes and stages, based on the finding that perfusion changes depend on the initial number and succession in time of the hepatic veins (HVs) obstructions. Obstruction of one hepatic vein (HV) did not cause opening of PSS. The BCS debuted by common obstruction of two HVs had different hemodynamic aspects in acute and chronic stages after subsequent obstruction of the third HV. In chronic stages, obstruction of two HVs resulted in opening of PSS. The BCS, determined by thrombosis of the terminal part of the inferior vena cava, presented in the acute stage with open PSS with low speed flow. At least several weeks are required in the obstructions of two or three HVs for the spontaneous opening of dynamically efficient PSS. The CL seems to have only a transient important role of intrahepatic shunt in several types of the BCS. CONCLUSION: Dynamic nuclear medicine investigations assess the extent and length of hepatic venous obstructions, open collaterals, areas without portal inflow, hemodynamic function of the CL and reverse venous flow. PMID- 24799995 TI - Development of novel Vitamin D Receptor-Coactivator Inhibitors. AB - Nuclear receptor coregulators are master regulators of transcription and selectively interact with the vitamin D receptor (VDR) to modulate cell differentiation, cell proliferation and calcium homeostasis. Herein, we report the syntheses and evaluation of highly potent and selective VDR-coactivator inhibitors based on a recently identified 3-indolylmethanamine scaffold. The most active compound, PS121912, selectively inhibited VDR-mediated transcription among eight other nuclear receptors tested. PS121912 is also selectively disrupting the binding between VDR and the third nuclear receptor interaction domain of the coactivator SRC2. Genetic studies revealed that PS121912 behaves like a VDR antagonist by repressing 1,25-(OH)2D3 activated gene transcription. In addition, PS121912 induced apoptosis in HL-60. PMID- 24799996 TI - The University of Queensland study of physical and psychological outcomes for claimants with minor and moderate injuries following a road traffic crash (UQ SuPPORT): design and methods. AB - BACKGROUND: To date research investigating how mental health impacts physical recovery following a road traffic crash (RTC) has focused on cohorts with severe injuries. The UQ SuPPORT study aims to study the physical and psychological outcomes of claimants with minor injuries following an RTC under the Queensland common law compulsory insurance scheme. OBJECTIVES: This paper outlines the protocols of this study as a platform for future publications. METHODS: The 2 year longitudinal cohort study collected interview and survey data from claimants at 6, 12, and 24 months post-RTC. Measures used in the telephone interview included the DSM-IV Composite International Diagnostic Interview for posttraumatic stress disorder, generalized anxiety disorder, major depressive episode, panic attacks, agoraphobia; and self-reported disability (WHO-DAS-II). Quality of life (SF-36v2), alcohol use (AUDIT), social support (MSPSS), quality adjusted life years (EQ-5D), and return to work outcomes were assessed via postal questionnaires. RESULTS: A total of 382 claimants consented to participate at the beginning of the study, and these participants were approached at each wave. Retention was high (65%). The average age of participants at Wave 1 was 48.6 years, with 65% of the sample sustaining minor injuries (Injury Severity Score=1 3). CONCLUSIONS: This study has collected a unique sample of data to investigate recovery patterns of claimants with minor injuries. Future publications will more fully assess the effects of the collected measures on recovery rates 2 years post RTC. PMID- 24799997 TI - Post-plyometric exercise hypotension and heart rate in normotensive individuals: influence of exercise intensity. AB - PURPOSE: The purpose of this study was to compare the effects of high, moderate and low intensity plyometric exercise on the post-exercise systolic and diastolic blood pressure and heart rate responses. METHODS: Ten healthy normotensive men (age, 21.1+/-0.9 years; height, 175.8+/-6 cm; and body mass, 69.1+/-13.6 kg) volunteered to participate in this study and were evaluated for three non consecutive days in depth jump exercise from 20-cm box (low intensity [LI]), 40 cm box (moderate intensity [MI]) and 60-cm box (high intensity [HI]) for 5 sets of 20 repetitions. After each exercise session, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured every 10 min for a period of 90 min. RESULTS: No significant differences were observed among post exercise SBP, DBP and HR when the protocols (LI, MI and HI) were compared. The LI and HI protocols showed greater reduction in SBP at 40(th)-70(th) min of post exercise (~9%), whereas the LI and MI protocols indicated greater reduction in DBP at 10(th)-50(th) min of post exercise (~10%). In addition, the change in the DBP for HI was not significant and the increases in the HR were similar for all intensities. CONCLUSION: It can be concluded that a plyometric exercise (PE) can reduce SBP and DBP post-exercise and therefore we can say that PE has significant effects for reducing BP and HR or post-exercise hypotension. PMID- 24799998 TI - Positive effect of the use of accelerometry on lifestyle awareness of overweight hypertensive patients. AB - PURPOSE: Sedentary habits are strongly associated with increase of cardiovascular risk factors. The present study aimed to verify the role of accelerometry in identifying sedentary behavior, and the possible short term positive effect of this intervention on some anthropometric variables in a group of patients with cardiovascular risks factors. METHODS: To quantify daily Spontaneous Motor Activity (SMA) levels and identify sedentary behavior, an accelerometer was employed, in addition to a simple questionnaire, in a group of overweight, hypertensive subjects. A personalized unsupervised 3 month long physical exercise program was planned. After this time, acceleroometry was again undertaken to analyze the impact of the intervention on some life style parameters, including the number of the steps taken daily, and Physical Activity Level (PAL). In addition, body water balance, weight, and Body Mass Index (BMI) were also evaluated. RESULTS: Assessment of physical activity by accelerometry identifies sedentary behaviors in a larger number of individuals. After three months of regular unsupervised aerobic exercise, PAL improved from 1.56 +/-0.1 to 1.68+/ 0.2 with P<0.005, weight (kg) reduced from 85.13 +/- 20 to 83.10 +/- 19 (P<0.05), BMI from 29.58 to 28.7 (P<0.05). CONCLUSION: Accelerometry allows to objectify PAL, and can be used to monitor improvement of variables strongly related to cardiovascular risk. PMID- 24799999 TI - Naproxen Twice Daily Versus as Needed (PRN) Dosing: Efficacy and Tolerability for Treatment of Acute Ankle Sprain, a Randomized Clinical Trial. AB - PURPOSE: This study was conducted to compare the efficacy and safety of naproxen 500 mg twice daily (BID) versus naproxen 500 mg as needed (PRN) for treatment of ankle sprain. METHODS: In this seven-day, randomized, parallel group trial, 135 patients with ankle sprain occurring less than 48 hours prior to the first dose of study medication were randomized to receive naproxen 500 mg BID (67 patients) and naproxen 500 mg as needed (PRN) (68 patients). The ankle pain was assessed at rest and on full weight bearing using Numeric Rating Scale (NRS) from 0 (no pain) to 10 (the worst imaginable pain). Ankle swelling was assessed as a 4-point scale ranging from 0 (no swelling) to 3 (severe swelling) rated by the investigator. The primary efficacy end point was the patient's assessment of ankle pain via NRS and the degree of swelling on day seven. RESULTS: Results showed a significant decrease in pain on weight bearing, pain at rest and the extent of swelling (P<0.001) in both groups, but there was no substantial difference between the two groups (P>0.05) after seven days. Assessing the safety profile of the two different dosing, 13.3% of the naproxen BID group and 6.7% of the as needed group had adverse events, showing that the as needed regimen was safer (P<0.001). CONCLUSION: Results showed that naproxen as needed may reduce the pain and edema of the sprained ankle with no significant difference compared to the BID regimen, while it possesses better safety profile and lower total drug use. PMID- 24800000 TI - Gender difference of aerobic contribution to surface performances in finswimming: analysis using the critical velocity method. AB - PURPOSE: Finswimming is a speed competition sport practiced on the surface or underwater, by using monofins or two fins. In surface events (SF), competitors should surface within 15 m after the start and any turns. The aim of this study was to investigate the gender differences in the aerobic contribution to SF performances in finswimming, using the critical velocity (CV) concept in the analysis. METHODS: The participants were sixteen monofin swimmers (eight males and eight females; 24+/-6 years). During a two-day period, participants performed maximal effort swimming at five test distances (100 m, 200 m, 400 m, 800 m and 1500 m), and mean swimming velocity (V) of each distance was calculated. CV was calculated as the slope of the regression line between time and distance in the 400 and 800 m SF tests. RESULTS: Although CV was significantly correlated with V800 m and V1500 m for males, it was significantly correlated with V200 m, V400 m, V800 m and V1500 m for females. CONCLUSION: The present results suggest that although the aerobic performance might contribute to SF performance for events from medium distance (i.e. 200m) to long distance (i.e. 1500m) in female participants, it might contribute to the long distance SF performances in male participants. PMID- 24800001 TI - Physiological and Perceived Exertion Responses during International Karate Kumite Competition. AB - PURPOSE: Investigate the physiological responses and rating of perceived exertion (RPE) in elite karate athletes and examine the relationship between a subjective method (Session-RPE) and two objective heart-rate (HR)-based methods to quantify training-load (TL) during international karate competition. METHODS: Eleven karatekas took part in this study, but only data from seven athletes who completed three matches in an international tournament were used (four men and three women). The duration of combat was 3 min for men and 2 min for women, with 33.6+/-7.6 min for the first interval period (match 1-2) and 14.5+/-3.1 min for the second interval period (match 2-3). HR was continuously recorded during each combat. Blood lactate [La(-)] and (RPE) were measured just before the first match and immediately after each match. RESULTS: Means total fights time, HR, %HRmax, [La(-)], and session-RPE were 4.7+/-1.6 min, 182+/-9 bpm, 91+/-3%, 9.02+/-2.12 mmol.L(-1) and 4.2+/-1.2, respectively. No significant differences in %HRmax, [La(-)], and RPE were noticed across combats. Significant correlations were observed between RPE and both resting HR (r=0.60; P=0.004) and mean HR (r=0.64; P=0.02), session-RPE and Banister training-impulse (TRIMP) (r=0.84; P<0.001) and Edwards TL (r=0.77; P<0.01). CONCLUSION: International karate competition elicited near-maximal cardiovascular responses and high [La(-)]. Training should therefore include exercise bouts that sufficiently stimulate the zone between 90 and 100% HRmax. Karate coaches could use the RPE-method to follow competitor's competition loads and consider it in their technical and tactical training. PMID- 24800002 TI - Agreement Analysis among Measures of Thinness and Obesity Assessment in Iranian School Children and Adolescents. AB - PURPOSE: This study investigated the agreement of four anthropometric-based measurements including weight-for-height (WH), body mass index-for-age (BMI), mid upper arm circumference-for-age (MUAC) and triceps skinfold thickness-for-age (TST) to identify underweight and overweight children and adolescents. METHODS: Two data sets were used in this research. The first one was a multistage random sample of 2397 healthy school children in pre-pubertal stage in Shiraz. The second data set consisted of 487 healthy students in pubertal stage and 558 students in post-pubertal stage. The parametric LMS method was used to construct reference centiles curves for each measure. The Kappa statistic was applied to examine the pairwise agreement of the four indices for detecting thinness and obesity. RESULTS: Generally, the pairwise agreement of adiposity measures was higher for identifying obesity than thinness. There was an excellent agreement between WH and BMI for detecting both thin and obese children in almost all subgroups (P<0.001). MUAC had an excellent agreement with BMI in pre-pubertal individuals (P<0.001). However, TST had a weak agreement with the other three indices for detecting thinness and weak to good agreement for classification of obesity. CONCLUSION: The performance of the four anthropometric-based measurements varied by sex and maturity level. MUAC as a simple and low-cost screening tool can also be used as an alternative to BMI for obesity assessment among pre-pubertal groups. PMID- 24800003 TI - Right ventricle chamber of young trained athletes: morphology and function. AB - PURPOSE: The study of the right ventricular (RV) chamber has been recently improved by use of the 3D method. In young asymptomatic trained athletes, RV is not routinely investigated if not in suspected disease. This study is designed to test if the 3D method compared to 2D, adds information to study of RV morphology and function, in the early stages of myocardial remodeling of a group of young athletes. METHODS: The RV chamber function was assessed in 25 young trained athletes (20 soccer and 5 basketball) aged 20+/-3 yrs and compared to 20 sedentary controls by 2D-AC and 3D-RV methods (TomTec), measuring RV diastolic (RVDV) and systolic (RVSV) volumes or ejection fraction (EF). RESULTS: 3D RV volumes were slightly higher in athletes than the 2D volumes in presence of lower EF values, but not significantly higher than in sedentary. Significant differences were conversely found comparing 3D systolic and diastolic RV volumes and 2D-AC volumes within each group with higher values in athletes (RVDV: P=0.001 for athletes and P<0.001 for sedentary, and RVSV: P<0.04 for athletes and P<0.001 for sedentary). CONCLUSION: Although the found EF values were substantially similar, the morphological assessment of the initial modifications of this chamber of the young "athlete's heart", results seem to be more accurate using the 3D method than 2D. The clinical implication of this aspect could be of interest in case of difficulty in drawing a clear diagnosis of any RV chamber disease in young athletes. PMID- 24800004 TI - Evaluation of Relationship between Trunk Muscle Endurance and Static Balance in Male Students. AB - PURPOSE: Fatigue of trunk muscle contributes to spinal instability over strenuous and prolonged physical tasks and therefore may lead to injury, however from a performance perspective, relation between endurance efficient core muscles and optimal balance control has not been well-known. The purpose of this study was to examine the relationship of trunk muscle endurance and static balance. METHODS: Fifty male students inhabitant of Tehran university dormitory (age 23.9+/-2.4, height 173.0+/-4.5 weight 70.7+/-6.3) took part in the study. Trunk muscle endurance was assessed using Sorensen test of trunk extensor endurance, trunk flexor endurance test, side bridge endurance test and static balance was measured using single-limb stance test. A multiple linear regression analysis was applied to test if the trunk muscle endurance measures significantly predicted the static balance. RESULTS: There were positive correlations between static balance level and trunk flexor, extensor and lateral endurance measures (Pearson correlation test, r=0.80 and P<0.001; r=0.71 and P<0.001; r=0.84 and P<0.001, respectively). According to multiple regression analysis for variables predicting static balance, the linear combination of trunk muscle endurance measures was significantly related to the static balance (F (3,46) = 66.60, P<0.001). Endurance of trunk flexor, extensor and lateral muscles were significantly associated with the static balance level. The regression model which included these factors had the sample multiple correlation coefficient of 0.902, indicating that approximately 81% of the variance of the static balance is explained by the model. CONCLUSION: There is a significant relationship between trunk muscle endurance and static balance. PMID- 24800005 TI - Possibility of Delay in the Super-Compensation Phase due to Aging in Jump Practice. AB - PURPOSE: To investigate the possibility of a delay in the super-compensation phase due to aging in jump practice. METHODS: This study evaluated records in three phases (approximately every five years) of a man who had been participating in Masters Athletics for over 20 years. After correcting for air temperature, which would influence the distance on a standing five-step jump using simple regression analysis, the performance curve of the super-compensation phase was calculated at each phase by curvilinear estimation to assess the relationship between the training interval and distance on the standing five-step jump. RESULTS: A peak distance on the standing five-step jump was achieved after a training interval of 60 hours in the first phase; 75 hours in the second phase; and 88 hours in the third phase. That is, the peak distance tended to delay with aging. CONCLUSION: It may be suggested that the super-compensation period would be delayed by aging in jump practice. We would like master athletes to refer this result and improve their performance. PMID- 24800006 TI - Cost-utility analysis of neonatal screening program, shiraz university of medical sciences, shiraz, iran, 2010. AB - OBJECTIVE: The most important cause of infant mortality during the first month of life is related to congenital abnormalities. Nevertheless, timely diagnosis of these diseases can reduce the severity of their effects. The present study aimed to investigate the cost-effectiveness of the neonatal screening program in Fars Province, Iran. METHODS: In this study, costs of executing the screening programs, treatment of the diagnosed cases, treatment of affected, non-screened individuals, quality of life, and incremental cost-effectiveness ratios were measured in two study groups. FINDINGS: Performing the screening programs for phenylketonuria, congenital hypothyroidism, galactosemia, and favism resulted in respectively $3386, $13078, $19641, and $1088 saving per patient. Overall, the study results revealed the cost-effectiveness of execution of the neonatal screening program. CONCLUSION: Neonatal screening program is one of the health interventions which lead to long-term beneficial outcome for the patients, financial saving for the society, and improvement of the patients' quantity as well as quality of life. PMID- 24800007 TI - Alpha 1 antitrypsin deficiency in infants with neonatal cholestasis. AB - OBJECTIVE: Alpha1-antitrypsin deficiency (A1ATD) is the most important indication for liver transplantation in children. The gene frequencies vary in different ethnic groups. In the present study, we attempt to determine the frequencies of the most common defective alleles, Z and S, in Iranian children suffering from idiopathic neonatal cholestasis. Eighty-seven infants were typed for Z and S alleles. METHODS: In a single center study, 87 consecutive liver biopsies from infants with cholestasis were reviewed and patients with neonatal cholestasis enrolled in the study and cases with confirmed biliary tract atresia excluded. Formalin fixed paraffin embedded blocks were used for DNA extraction. AAT genotype was determined by polymerase chain reaction (PCR) assay and amplification of the two most common deficiency variants, S and Z alleles, and then sequencing of PCR products. FINDINGS: There were 48 (55.2%) males and 39 (44.8%) females, with a median age of 60 days. Out of 87 of the study subject, 2 (2.2%) were heterozygous for the S allele, and no ZZ, SS or MZ individual was found in the patients. No other polymorphism was found in the sequencing results. CONCLUSION: In comparison to other populations, AAT deficiency seems not to be an important etiologic factor for neonatal cholestatic liver disease in Iran; however, further studies are recommended to estimate the true mutant gene frequencies. PMID- 24800008 TI - Measuring new born foot length to identify small babies in need of extra care: a cross-sectional hospital based study. AB - OBJECTIVE: The neonatal mortality rate (NMR) continues to remain quite high, one important cause being preterm deliveries. The main obstacle in the pathway towards decreasing NMR is identification of babies in need of extra care. To analyze the utility of newborn foot length as a proxy measure for birth weight and gestational age. METHODS: A cross-sectional study done in a hospital of eastern India with 351 babies during 4 months. Right foot length of each recorded using a plastic, stiff ruler. FINDINGS: 48.1% babies were preterm, 51.8% low birth weight (LBW) and 33.3% very low birth weight (VLBW). Foot length less than 7.75 cm has 92.3% sensitivity and 86.3% specificity for identification of preterm neonates. For identification of LBW babies (<2500 gm) a foot length less than 7.85cm has 100% sensitivity and 95.3% specificity. Foot length less than 6.85 cm has 100% sensitivity and 94.9% specifity for identification of VLBW babies (<1500 gm). CONCLUSION: Foot length may be used in the identification of LBW and preterm babies who are in need of extra care. PMID- 24800009 TI - Cardiovascular involvement in children with osteogenesis imperfecta. AB - OBJECTIVE: Osteogenesis imperfecta is a hereditary disease resulting from mutation in type I procollagen genes. One of the extra skeletal manifestations of this disease is cardiac involvement. The prevalence of cardiac involvement is still unknown in the children with osteogenesis imperfecta. The present study aimed to investigate the prevalence of cardiovascular abnormalities in these patients. METHODS: 24 children with osteogenesis imperfecta and 24 normal children who were matched with the patients regarding sex and age were studied. In both groups, standard echocardiography was performed, and heart valves were investigated. Dimensions of left ventricle, aorta annulus, sinotubular junction, ascending and descending aorta were measured and compared between the two groups. FINDINGS: The results revealed no significant difference between the two groups regarding age, sex, ejection fraction, shortening fraction, mean of aorta annulus, sinotubular junction, ascending and descending aorta, but after correction based on the body surface area, dimensions of aorta annulus, sinotubular junction, ascending and descending aorta in the patients were significantly higher than those in the control group (P<0.05). Two (8.3%) patients had aortic insufficiency and five (20%) patients had tricuspid regurgitation, three of whom had gradient >25 mmHg and one patient had pulmonary insufficiency with indirect evidence of pulmonary hypertension. According to Z scores of aorta annulus, sinotubular junction and ascending aorta, 5, 3, and 1 out of 24 patients had Z scores >2 respectively. CONCLUSION: The prevalence of valvular heart diseases and aortic root dilation was higher in children with osteogenesis imperfecta. In conclusion, cardiovascular investigation is recommended in these children. PMID- 24800010 TI - A novel method for quantification of left ventricular noncompaction using two dimensional echocardiography in children. AB - OBJECTIVE: Although there are several echocardiographic criteria, there is not yet a general consensus about the diagnosis of left ventricular noncompaction. The current criteria are mostly based on the areas with maximal noncompaction in the heart. The echocardiographer may miss this maximal point leading to a misdiagnosis. Accordingly, we suggested a new method to measure the percentage of myocardial noncompaction using two-dimensional echocardiography. METHODS: In this study, the new method was examined on 4 noncompaction and 26 dilated cardiomyopathies, and 25 normal subjects. The percentage of noncompaction was measured at 3 levels (apical, papillary muscle and mitral valve) and averaged. FINDINGS: The mean percentages of myocardial noncompaction were 3.59+/-2.27, 8.86+/-5.52 and 34.7+/-26.1 in the control, dilated cardiomyopathy and noncompaction groups, respectively. A value of 17% or greater could distinguish left ventricular noncompaction from dilated cardiomyopathy with 92% specificity and 100% sensitivity and from normal subjects with 100% specificity and sensitivity. This percentage had a statistically significant association with noncompacted to compacted myocardial thickness ratio (P<0.001). CONCLUSION: This method showed good correlations with the existing echocardiographic and magnetic resonance criteria. However, it is not dependent on finding the area of maximal involvement. Being comparable to magnetic resonance imaging in accuracy, it is easier to perform and more available. PMID- 24800011 TI - Clinical Significance of the Dynamic Changes in Serum Eotaxin, Interleukin 13 and Total IgE in Children with Bronchial Asthma. AB - OBJECTIVE: To determine the serum levels of eotaxin, IL-13 and total IgE (TIgE) in asthmatic children during the acute and clinical remission periods, as well as the changes in pulmonary function to determine their roles, relationships and clinical significance during asthma exacerbation. METHODS: A total of 30 asthmatic children and 22 healthy children were enrolled in the study. The serum eotaxin and IL-13 levels were detected using an enzyme-linked immunosorbent assay and the TIgE level was detected using a fluorescent enzyme-linked immunosorbent assay. The asthmatic children were subjected to pulmonary function tests. FINDINGS: The serum eotaxin, IL-13 and TIgE levels of the asthmatic children during the acute period significantly differed from those during clinical remission. The serum eotaxin, IL-13 and TIgE levels of the asthmatic children during both periods significantly differed from those of healthy children (P<0.001). The serum eotaxin levels during the acute and clinical remission periods were positively correlated with serum IL-13 and with TIgE, and serum IL 13 was correlated with serum TIgE. The pulmonary function indices of asthmatic children during the acute period significantly differed from those during clinical remission (P<0.001). The serum eotaxin and IL-13 levels in the asthmatic children were positively correlated with the forced expiratory volume in 1 second (FEV1) and the peak expiratory flow (PEF) during the acute and clinical remission periods (P<0.05). However, the serum TIgE levels in asthmatic children were not significantly correlated with the FEV1 and PEF during both periods (P>0.05). CONCLUSION: Serum TIgE, IL-13 and eotaxin influence each other during exacerbation of bronchial asthma and influence the corresponding pathophysiologic changes. Serum IL-13 and eotaxin could be used as markers for evaluating the severity of bronchial asthma. PMID- 24800012 TI - Posterior Urethral Valves; A single Center Experience. AB - OBJECTIVE: Posterior urethral valves (PUV) are the most common cause of bladder outlet obstruction in infancy that impair renal and bladder function. This study was planned to evaluate and record the various clinical presentations and management, complications, and surgical management and long-term outcome of PUV. METHODS: In a retrospective study, 98 patients who have been treated for PUV are evaluated in Mofid Children's Hospital from January 2007 to December 2012. Detailed history taken and paraclinical examinations were performed in each patient and diagnosis was confirmed by voiding-cysto-urethrography (VCUG). PUV had been ablated in 62 patients by electric hook, and diversion was performed in 42 (42.85%) cases. Data were analyzed by SPSS software version18. FINDINGS: Totally 98 patients with mean age at diagnosis 62 (+/-13) days were included in this study. Fifty seven cases had been catheterized within one to 6 days of life (mean age one day), PUV was ablated in 62 patients by electric hook, and diversion was performed in 42 cases. The most common symptom in our group was dribbling poor stream 51% and urinary tract infection (UTI) 40.8%. There was vesico-ureteral-reflux (VUR) in 61.2%, and hydronephrosis in 82.6%. Most common associated anomaly was kidney anomalies (multicystic kidney disease and renal agenesis/dysplasia) in 8 (8.2%) patients. Twenty patients had prenatal diagnosis of PUV. Complication occurred in three (3.1%) patients. Mortality occurred in 5 (5.1%) patients. Mean follow-up period was 3.4+/-1.2 years (1.5 months to 5 years). CONCLUSION: Urinary drainage by feeding tube in early days of infancy, followed by valve ablation is the best treatment in PUV, and urinary diversion improves the outcome. VCUG is still the gold-standard imaging modality for documenting PUVs. The factors like renal dysplasia and UTI have their role in final outcome. PMID- 24800013 TI - Migraine and tension-type headache in children and adolescents presenting to neurology clinics. AB - OBJECTIVE: Headache is one of the most common neurologic problems in children and adolescents. Primary headache including migraine and tension-type headache comprises the vast majority of headaches and are associated with marked incidence, prevalence, and individual and social cost. We aimed to assess demographic characteristics and to compare some factors related to primary headaches in children/ adolescents presented to neurology clinics of Tabriz University of Medical Sciences. METHODS: Children from 4 to 15 years of age with the diagnosis of primary headache (migraine or tension-type headaches) who presented to the neurology clinics affiliated to Tabriz University of Medical Sciences, Tabriz, Iran from March 2009 to October 2011 are included in this cross sectional study. Data regarding the type of headache, history of atopy, peripartum asphyxia, and breast feeding, family history of headache and the socioeconomic status of the family were collected. The diagnosis was based on the international headache society diagnostic criteria for the primary headache disorders. FINDINGS: One hundred ninety children (107 females) with primary headache (88 patients with migraine and 102 patients with tension type headache) enrolled in the study. Peripartum asphyxia, history of atopy, family history of headache and low socioeconomic status (SES) were more common in patients with migraine (P-values: 0.007, 0.01, 0.001, 0.003; respectively). CONCLUSION: Physicians need to extent their knowledge regarding the primary headaches. Peripartum asphyxia, history of atopy, headache in parents and low SES have been shown in the present study to be more prevalent in patients with migraine as compared to tension-type headache. PMID- 24800014 TI - Is pneumothorax size on chest x-ray a predictor of neonatal mortality? AB - OBJECTIVE: Pneumothorax in newborns may result in a significant mortality and morbidity. To predict who will survive or die is of great importance in the clinical management. The aim of this study is to address whether assessment of pneumothorax size on chest X-ray may be a predictor of prognosis in newborns presenting with pneumothorax. METHODS: Of 5929 infants admitted to our neonatal intensive care unit (NICU) from January 2007 to April 2011, 60 (1.0%) newborns presenting with pneumothorax were included in the present study. Pneumothorax size was calculated by measuring the widest transverse diameter of pneumothorax area in the posteroanterior view and dividing it by the widest transverse diameter of thoracic cavity above the diaphragm. Clinical data were collected from the patients' records. FINDINGS: Overall mortality rate was 30% (18 patients). Pneumothorax size was significantly higher in nonsurvivors (31.1+/-2.8 vs 16.4+/-1.4, P < 0.001). The cut-off point of pneumothorax size for predicting survival was determined as 20%. The sensitivity was 72% whereas the specificity 83%. Preterm birth, low birth weight, resuscitation at birth, need for mechanical ventilation and chest tube insertion were of great significance in predicting mortality. However, of overall significant parameters, only pneumothorax size was the independent prognostic factor by regression analysis (P = 0.02). CONCLUSION: We conclude that the calculation of pneumothorax size in the newborns is a predictor of prognosis with high sensitivity and specificity. Furthermore newborns with pneumothorax size greater than 20% are likely to have worse prognosis. PMID- 24800015 TI - Mortality risk prediction by application of pediatric risk of mortality scoring system in pediatric intensive care unit. AB - OBJECTIVE: The Pediatric Risk of Mortality (PRISM) score is one of the scores used by many pediatricians for prediction of the mortality risk in the pediatric intensive care unit (PICU). Herein, we intend to evaluate the efficacy of PRISM score in prediction of mortality rate in PICU. METHODS: In this cohort study, 221 children admitted during an 18-month period to PICU, were enrolled. PRISM score and mortality risk were calculated. Follow up was noted as death or discharge. Results were analyzed by Kaplan-Meier curve, ROC curve, Log Rank (Mantel-Cox), Logistic regression model using SPSS 15. FINDINGS: Totally, 57% of the patients were males. Forty seven patients died during the study period. The PRISM score was 0-10 in 71%, 11-20 in 20.4% and 21-30 in 8.6%. PRISM score showed an increase of mortality from 10.2% in 0-10 score patients to 73.8% in 21-30 score ones. The survival time significantly decreased as PRISM score increased (P<=0.001). A 7.2 fold mortality risk was present in patients with score 21-30 compared with score 0-10. ROC curve analysis for mortality according to PRISM score showed an under curve area of 80.3%. CONCLUSION: PRISM score is a good predictor for evaluation of mortality risk in PICU. PMID- 24800017 TI - Effect of oral ondansetron on decreasing the vomiting associated with acute gastroenteritis in Iranian children. AB - OBJECTIVE: The aim of this study was to determine the effect of oral ondansetron in decreasing the vomiting due to acute gastroenteritis in children. METHODS: In a single center, randomized, double blind, controlled trial, the effect of oral ondansetron was compared with placebo on 176 patients between 1 and 10 years old with acute gastroenteritis. 30 minutes after drug administration, oral rehydration therapy (ORT) was initiated. Severity of vomiting was evaluated during emergency department (ED) stay and 48 hours follow up. Data were collected and analyzed by SPSS16. FINDINGS: Fifty two of children (58.5%) were males with the mean age of 3.12 (+/-2.30) years. Ten patients in ondansetron and 14 in placebo group had persistent vomiting during ED stay. After analyzing, there was no significant relation between vomiting in 4 and 48 hours and need for intra venous fluid therapy between the two groups although ondansetron generally decreased ORT failure (P=0.03). CONCLUSION: Although administrayion of oral ondansetron in gastroenteritis could decrease failure of ORT, it seems that further well-conducted clinical studies are needed to determine effects of oral ondansetron precisely. PMID- 24800016 TI - Association between Helicobacter pylori, cagA, and vacA Status and Clinical Presentation in Iranian Children. AB - OBJECTIVE: Seroprevalence of H. pylori infection in Iran exceeds 65% of pediatric population. In this study, we intended to find association between the virulence genes (cagA and vacA) and clinical presentations. METHODS: H. pylori isolates were achieved from the gastric mucosa of children. In each case, the gastric biopsy specimens were cultured and the organisms identified. Detection of different genotypes was carried out by PCR method. FINDINGS: A total of 106 biopsy specimens were cultured and 33 H. pylori isolates obtained. Among these 33 H. pylori strains 24 (73%) were cagA-positive. Genotypes of vacA s1m2, s1m1, s2m2, and s2m1 were 45.5%, 30.3%, 21.2%, and 3%, respectively. Most female patients were infected with genotype s1m2. The vacA-m1 strains were significantly more common in patients with nodular gastritis. There were no statistical differences between the vacA and cagA genotypes and clinical outcomes. CONCLUSION: The frequency of cagA genotype was high. In this study, nodular gastritis was a common finding and was rather significantly associated with m1 allele of vacA. PMID- 24800018 TI - Effectiveness of regular breathing technique (hey-hu) on reduction of intrathecal injection pain in leukemic children: a randomized clinical trial. AB - OBJECTIVE: Children with chronic diseases such as leukemia are subjected to pain during various procedures. Injection pain in children is so important that it is considered as the most stressful aspect of their disease. Distraction is one of the easiest and least costly methods of non-pharmacological pain relief that has not been paid attention to by nurses. In the present study, the effectiveness of regular breathing method (Hey-Hu) in reduction of pain of intrathecal injection in leukemic children was evaluated. METHODS: This study was conducted as a single blind randomized clinical trial among 100 patients coming to a referral hospital related to Shahid Sadoughi University of Medical Sciences, Yazd, Iran. The patients were 6-15 years old children coming to oncology ward suffering from leukemia. They were selected and randomly allocated to either regular breathing group or control group in equal numbers. The pain of children was assessed by Wong pain face scale and also general behaviors of the samples were evaluated by the researcher. In Pain Rating Scale, face 0 is considered happy because there is no hurt and face 5 denotes maximum pain. FINDINGS: Mean pain score in the regular breathing group was significantly lesser than the control group (2.98+/-1.68 and 3.80+/-1.30, respectively; P=0.01). There was no significant difference between the two sexes but in the regular breathing group, mean pain score was significantly lower in children aged above 10 years. CONCLUSION: This study showed that regular breathing can significantly reduce the pain of intrathecal injection in leukemic children, especially in those aged above 10 years. Considering the key role of nurses in a health care team, the researchers hope that the results of this study can help them learn this method and implement it in hospitalized children who undergo painful procedures. PMID- 24800019 TI - The effect of positive family history of autoimmunity in juvenile idiopathic arthritis characteristics; a case control study. AB - OBJECTIVE: To compare Juvenile Idiopathic Arthritis (JIA) patients with and without family history of autoimmune disease with respect to clinical features and laboratory data. METHODS: Sixteen JIA patients with family history of autoimmune disease were identified during study, 32 patients were chosen for comparative group from referred patients to the rheumatology clinic according to the date of referral. Two groups were compared with respect to age of onset, sex, subtype, disease activity, duration of active disease and laboratory variables. FINDINGS: The age of onset was significantly lower in JIA patients with family history of autoimmunity (4.7 years vs. 7.0 years; P=0.02), polyarthicular subtype was more frequent in patients with positive family history (50% vs.25%; P=0.04) most of JIA patients with positive family history were in the active phase at the time of study (64% vs 25%; P=0.02) and had a longer duration of active disease (21.0 months vs 12.3 months; P=0.04). Patients with positive family history had more positive ANA (43.5%% vs 12.5%; P=0.01) and also more positive ADA (75% vs 20.8%; P=0.002). Two groups were similar according to sex, and other laboratory variables. CONCLUSION: JIA patients with family history of autoimmune disease seem to have a more severe disease than patients without such family history, they are younger at the onset, and have mostly poyarthicular subtype. They also have more ANA and ADA positivity. These findings are different from familial JIA case-control studies according to active disease duration, subtype, and ANA positivity. PMID- 24800020 TI - Intrasphincteric botulinum toxin injection in treatment of chronic idiopathic constipation in children. AB - OBJECTIVE: Injection of botulinum toxin into the anal sphincter is a novel and safe new treatment of chronic idiopathic constipation and anal fissure in children. The purpose of this study was to determine the utility of intra sphincteric injection of botox in the treatment of children with refractory constipation. METHODS: All children who suffered from chronic constipation for more than three months, and who had not responded to medical treatment, were referred to pediatrics surgical clinic for surgical intervention by pediatric gastroenterologist. The patients were randomly divided into cases and control group. The control group received no injection and was only treated with stool softeners. The case group received this therapy in addition to injection. After the botox injection, patients were asked about the presence of the signs of constipation including painful defecation, vomiting, stool consistence, soiling and defecation interval. FINDINGS: Defecation of painful stool existed in 88% of patients before botox injection and it was reduced to 15% after botox injection. In the control group, 90% of patients had painful defecation, which reduced to 86% after medical treatment (P=0.0001). Stool was hard in 80% of patients before was reduced to 28% after botox injection. In the control group, it existed in 81% of children and reduced to 78% after medical treatment (P=0.0001). Soiling existed in 62% of patients before and was reduced to 8% after botox injection, but in the control group it reduced from 62% to 42.5% after medical treatment (P=0.0001). In the control group, 98% of the patients had defecation intervals more than 3 days and it was the same after medical treatment. In case group, this index before botox injection was 9.1 days, and after botox injection was reduced to 2.6 days (P=0.0001). CONCLUSION: Our study results showed that injection of botulinum toxin into anal sphincter is an effective and safe new treatment of chronic idiopathic constipation in children. PMID- 24800021 TI - Outcome of very low birth weight infants over 3 years report from an Iranian center. AB - OBJECTIVE: Very low birth weight (VLBW) infants are at high risk for morbidity and mortality. This article determines the frequency of disease, rate od survival, complications and risk factors for morbidity and mortality in VLBW neonates admitted to a level III neonatal intensive care unit (NICU) at Mahdieh Hospital in Tehran. METHODS: This cross-sectional retrospective study was performed from April 2007 to March 2010 on all hospitalized VLBW neonates. Relevant pre- and peri-natal data up to the time of discharge from the hospital or death, including complications during the course of hospitalization, were collected from the case notes, documented on a pre-designed questionnaire and analyzed. FINDINGS: Out of 13197 neonates, 564 (4.3%) were VLBW with 51.4% males. Mean gestational age was 29.6+/-2.5 weeks; mean birth weight 1179+/-257 grams. Mean birth weight, gestational age and Apgar scores were significantly higher in babies who survived than in those who died, (1275+/-189 vs. 944+/-253 grams; 30.5+/-2.2 vs. 27.5+/-2 weeks and 6.9+/-1.7 vs. 5+/-2.1 respectively, P<0.001 in all instances). Overall survival was 70.9%; in extremely low birth weight (ELBW) newborns this figure was 33.3% rising to 84.1% in infants weighing between 1001 1500 grams. Respiratory failure resulting from RDS in ELBW babies was the major factor leading to death. Need for mechanical ventilation, pulmonary hemorrhage and gastro-intestinal bleeding were also significant predictive factors for mortality. CONCLUSION: Birth weight and mechanical ventilation are the major factors predicting VLBW survival. PMID- 24800022 TI - Cholelithiasis in childhood: a cohort study in north of iran. AB - OBJECTIVE: Cholelithiasis rarely occurs in children but the increased use of ultrasonography has led to increased detection of gallstones in patients. The epidemiology and predisposing factors of cholelithiasis vary in different populations. The aim of this study was to describe the clinical presentation, predisposing factors and to evaluate management and outcome of patients referred to Amirkola Children's Hospital jn Babol. METHODS: This cohort study was performed on children with cholelithiasis referred during 2000 to 2011. Cholelithiasis was diagnosed with ultrasonography. The data was obtained based on history, physical exam, clinical and paraclinical investigations and analyzed by SPSS version 18. P-value <0.05 was considered being significant. FINDINGS: From the 66 patients with cholelithiasis, 39 (59.1%) were males. The mean age at diagnosis was 6.6+/-4.5 years. The most common predisposing factor included ceftriaxone therapy (27.3%), hemolytic diseases (13.6%), hepatobiliary diseases (7.5%) and cystic fibrosis (7.5%). In 30.3% of patients, no predisposing factor was detected. The most common complaint was abdominal pain (67%). Among the patients in whom abdominal X-Ray was performed, only 20% had radiopaque gallstones; 6 (9%) patients underwent cholecystectomy. CONCLUSION: According to this study, ceftriaxone therapy and hemolytic diseases were the most common predisposing factors in children with cholelithiasis in our area and cholecystectomy had not been needed in most patients. PMID- 24800023 TI - Correlation between QRS Duration, Pulmonary Insufficiency and Right Ventricle Performance in Totally Corrected Tetralogy of Fallot. AB - OBJECTIVE: Despite progresses in surgical correction of Tetralogy of Fallot, pulmonary insufficiency and progressive dysfunction of the right ventricle impress its long-term prognosis. In this study we examined the correlations between QRS duration, pulmonary insufficiency and right ventricular performance index. METHODS: We enrolled 57 repaired Tetralogy of Fallot patients. QRS duration on electrocardiogram, pulmonary regurgitation index (regurgitation time to diastolic time ratio), and right ventricular myocardial performance index were measured. FINDINGS: There was a strong inverse correlation between QRS duration and pulmonary regurgitation index. However, significant correlation did not exist between QRS duration and right ventricular myocardial performance index. QRS duration >=160 ms predicted severe pulmonary regurgitation with 100% sensitivity and 87% specificity. CONCLUSION: Increased QRS duration can predict severity of pulmonary regurgitation. PMID- 24800024 TI - Tailgut cyst in an infant with imperforate anus: a case report. AB - BACKGROUND: Tailgut cyst (TGC) is a rare congenital lesion that originates from remnants of the embryonic post-anal gut. It presents as a multilocular presacral mass mainly in young women. Microscopically, the cyst lining is composed of different types of epithelium such as stratified squamous, transitional, or glandular. CASE PRESENTATION: We present a term female newborn referred to our hospital for evaluation and management of imperforate anus. During dissection of the presacral space to release the rectum, a multicystic mass adherent to the distal part of rectum was detected and completely excised. Histopathology confirmed the TGC diagnosis. CONCLUSION: TGC is a very rare lesion, but it should be considered in differential diagnosis of any presacral mass, even in infancy. Complete excision is the preferred treatment and can be done more easily neonatally or in infancy. PMID- 24800025 TI - Severe multiple necrotizing fasciitis complicated by abdominal compartment syndrome in an infant. PMID- 24800026 TI - Cytokine Gene Polymorphisms in Childhood Dilated Cardiomyopathy: Interferon- gamma, Tumor Necrosis Factor-alpha and Transforming Growth Factor - beta 1 Genes Are Associated with the Disease in Turkish Patients. PMID- 24800027 TI - Cystic fibrosis: from protein-energy malnutrition to obesity with dyslipidemia. PMID- 24800028 TI - Severe hemolytic disease of the newborn caused by anti-m antibodies. PMID- 24800029 TI - A Novel Missense Mutation in BRAF Caused Cardio-Facio-Cutaneous Syndrome. PMID- 24800030 TI - Validity and reliability of spatio-temporal gait parameters in adolescents. PMID- 24800031 TI - Netherton syndrome, a case report and review of literature. PMID- 24800032 TI - The Effect of GVHD on Long-term Outcomes after Peripheral Blood Allogeneic Stem Cell Transplantation from an HLA-identical Sibling in Adult Acute Lymphocytic Leukemia: A Landmark Analysis Approach in Competing Risks. AB - Allogeneic Hematopoietic stem cell transplantation (HSCT) is the most effective therapy to prevent relapse in acute lymphocytic leukemia (ALL). This benefit is affected by non-relapse mortality (NRM) due to complications such as graft versus host disease (GVHD). A new approach in analyzing time-dependent covariates in competing risks is landmark analysis. So, the aim of this study is to evaluate the effect of acute and chronic GVHD on long-term outcomes, relapse and NRM, after allogeneic HSCT in adult ALL using landmark analysis. This study was conducted on 252 ALL patients who were allogeneic transplanted from an HLA identical sibling with peripheral blood (PB) as the source of stem cell from 2004 to 2012 and were followed-up until 2013. In the first 100 days after transplant, a landmark analysis on days +10, +11, +12, +17, +24, and +31 was applied to assess the effect of acute GVHD on early relapse and NRM. Similarly, for patients alive and event-free at day +100 after transplant, a landmark analysis at time points day +101, months +4, +5, +6, +9, and +12 was applied to evaluate the effect of chronic GVHD on late relapse and NRM. Five-year LFS and OS were 35.0% (95% CI: 29.1, 42.2%) and 37.5% (95% CI: 31.3, 45.0%), respectively. Five-year cumulative incidence of relapse was 44.5% (95% CI: 37.9, 51.0%) while this was 20.4% (95% CI: 15.4, 26.0%) for NRM. The landmark analysis in the first 100 days after transplant showed that the grade III/IV of aGVHD has a lower risk of relapse but higher risk of NRM after adjustment for the EBMT risk score. For patients alive at day +100, cGVHD had no significant effect on relapse. Limited cGVHD had lower risk of NRM and after 6 month post-transplant the risk of NRM decreased and there were not important difference between the groups of cGVHD. Using advanced models enables us to estimate the effects more precisely and ultimately make inference more accurately. PMID- 24800033 TI - The outcomes of esophageal and gastric cancer treatments in a retrospective study, single center experience. AB - INTRODUCTION: Esophageal and gastric cancers are among the most common cancers in Iran. Usually survival of these cases is poor despite of treatment. Here we studied outcome of these cases in our center to have an estimation of general prognosis of patients. METHODS: In this retrospective study, we reviewed the data of patient's files before treatment, including cancer stage at diagnosis, types of treatments and outcomes. We studied 368 patients treated between 1995 and 2011. RESULTS: The study included 368 patients (248 [67.4%] males and 120 [32.6%] females) with a median age of 58 (range: 23 - 94). Sixty nine patients (18.8%) had esophageal cancer with a median age of 58.5 years (range: 33 - 84), and 47.8% (33/69) of whom were male. Sixty five (17.7%) were reported to have gastro esophageal junction (GEJ) with a median age of 62.0 (range: 32 - 94), among them 72.3% (47/65) of whom were male and finally Two hundred thirty four (63.6%) had gastric cancer with a median age of 57.0 (range: 23 - 82), which 71.8% (168/234) of whom were male. The Median follow-up was 10 months. The majority of patients were diagnosed at an advanced stage of disease. Stage III or IV was observed in 65.0% (39/60) of patients with esophageal cancer, 75.0% (33/44) with GEJ cancer and 65.4% (121/185) with gastric cancer. In this study, 58% of patients with esophageal cancer, 50.8% with GEJ and gastric cancers had unresectable disease or metastases at presentation. One-year EFS was 51.8% (95% CI: 39.8 - 67.3%), 32.8% (95% CI: 22.1 - 48.7%), and 56.7% (95% CI: 50.1 - 64.3%) in patients with esophageal, GEJ and gastric cancers, respectively (p = 0.002). The 1-year OS was 54.5% (95% CI: 42.6 - 69.8%), 39.5% (95 CI: 28.1 - 55.5%), and 68.2% (95% CI: 61.8 - 75.3%), respectively (p < 0.001). CONCLUSION: Cancers of the upper gastrointestinal (GI) tract contribute to the high mortality and morbidity rates because they are more likely to be diagnosed at late or advanced stages of disease. Cancer of the GEJ has a poor prognosis compared to esophageal and gastric cancers. Moreover, treatment protocols may need improvement to achieve better results. PMID- 24800034 TI - Emotional/Behavioral problems in children with acute lymphoblastic leukemia: a case-control study. AB - INTRODUCTION: Despite achievements in treating acute lymphoblastic leukemia (ALL) in children, its burden on the psychosocial status of patients is not well defined yet. This study aims to determine the impact of childhood ALL on emotional and behavioral pattern of the patients compared to healthy peers as assessed by the Child Behavior Checklist (CBCL). METHODS: We studied 100 children with ALL (aged 6-12 years) and 100 healthy sex/age peers as control group. All ALL cases were treated by chemotherapy alone. After being informed by a psychologist, parents in both groups were asked to complete the CBCL form. Final results were then compared between the two study groups. RESULTS: There were no significant differences between the groups regarding the general characteristics. Failure in school performance, restricted group activity and less social relations were significantly higher in the ALL cases. Total competence was also significantly disturbed for the ALL cases. Social problems, attention problems, aggressive behavior, externalization, attention deficit/hyperactivity, conduct and oppositional defiant problems were significantly more prevalent in healthy children. Somatic problems were significantly higher in the ALL cases. CONCLUSION: Our findings suggest that except for somatic problems, behavioral problems among the ALL cases are significantly less frequent than the healthy peers, which may stem from better care and support from the families. Our unique findings emphasize the need for more research on the psychosocial status of children with cancer in future. PMID- 24800035 TI - Evaluating the Survival Rate and the Secondary Malignancies after Treating Hodgkin's Lymphoma Patients with Chemotherapy Regimens. AB - In this study we surveyed the average survival time of the treated Hodgkin's lymphoma patients and also the side effects and malignancies occurring secondary to the treatment. This is a retrospective study of patients referring to Ahwaz's Shafa hospital in a period of 10 years diagnosed with Hodgkin's lymphoma without any age restriction. After gathering all their data, we calculated their survival rate and the chance for a relapse and the secondary malignancies. 389 patients were included in the study with an average age of 27.5 years old and they had received only chemotherapy regimens. 87.9% of them had been treated by ABVD and 12.1 % by Stanford V regimen. 23.1% of them experienced a relapse and 13.1% of all patients, passed away during the study. Secondary malignancies were observed in 11 cases. An overall mean survival time of 295.31 months was resulted. The secondary malignancies after treating Hodgkin's lymphoma patients are different between chemotherapy regimens and chemotherapy - radiotherapy. PMID- 24800036 TI - Cut off Determination of Discrimination Indices in Differential Diagnosis between Iron Deficiency Anemia and beta- Thalassemia Minor. AB - OBJECTIVE: The two most frequent hypochromic microcytic anemias are beta- thalassemia minor (BTM) and iron deficiency anemia (IDA). Several discrimination indices have been proposed to quickly discriminate these similar entities via parameters obtained from automated blood count analyzers. The aim of this study to evaluate the diagnostic reliability of ten discrimination indices in the differentiation of Iron deficiency anemia (IDA) from beta Thalassemia Minor (BTM). METHODS: This study was conducted on 100 BTM and 70 cases with IDA in southern Iran. This evaluation was conducted through calculation sensitivity, specificity, positive and negative predictive value, Likelihood ratio positive, likelihood ratio negative and also we recalculated cut-off values for every formulas in our population and determination of Area Under Curve related to receiver operative characteristic (ROC) curves. RESULTS: ROC for each discrimination indices show that, the highest diagnostic value based on the area under the ROC curve are related to the Green & King, England & Frazer and then Sirdah formulas (0.909, 0.907, 0.904, respectively) in South-east of Iran, and relatively different cut-off values for every formula. CONCLUSION: The spectrum beta thalassemia mutations in each population can affect on various RBC indices, therefore, it is suggested to determine cut-off value for every formula in different populations. PMID- 24800037 TI - The prevalence of anemia and hemoglobinopathies in the hematologic clinics of the kermanshah province, Western iran. AB - Hemoglobinopathies are the most common single gene disorders worldwide with a considerable frequency in certain area particularly Mediterranean and Middle Eastern countries. Hemoglobinopathies include structural variants of hemoglobin (Hb S, Hb C, HbE,...) and thalassaemias which are inherited defects in the globin chains synthesis. The present study was conducted to determine the prevalence of hemoglobinopathies in western Iranian patients. A total of 344 patients (151 males and 193 females) with abnormal CBC and/or hemoglobin electrophoresis were enrolled in the present study. Cellulose acetate gel electrophoresis was performed for all patients and abnormal bands were identified by citrate agar gel electrophoresis and PCR based methods. Iron deficiency anemia (IDA) was present in 156 (45.3%) individuals. Thirty four (9.8%) patients had both iron deficiency anemia and alpha-thalassemia trait trait, 41(11.9%) patients were with both iron deficiency anemia and minor beta-thalassemia. There were 31(9%) patients with alpha-thalassemia trait and 5 (2.2%) patients with Hb H disease. Fifty six (16.2%) patients had minor beta-thalassemia. Also, there were 10 (2.9%) individuals homozygous for hemoglobin D-Punjab and one patient with hemoglobin G (0.3%). There was one sample with hemoglobin C. Further, we found 3 patients (0.9%) with sickle cell trait and more 3 patients (0.8%) with S/ beta + thalassemia. Our results indicated that the most frequent cause of hypochromic and/or microcytic anemia in our population was IDA and the minor beta-thalassemia was the second cause that needs to more attention in screening programs. PMID- 24800038 TI - Severe hypercalcemia: a rare and unusual presentation of childhood acute lymphoblastic leukemia. AB - Hypercalcemia in children is a medical emergency and often manifests as nonspecific symptoms such as nausea, vomiting, weight loss, and anorexia. Severe hypercalcemia is a rare complication of malignancy in children, while it can be seen in various types of malignant tumors. It is usually associated with significant morbidity and may be severe enough to threaten life. Incidence of hypercalcemia in hematopoietic malignancies including acute lymphoblastic leukemia (ALL) is very rare and unusual, especially as the initial manifestation of the disease. In this paper a 6-year-old boy who had severe hypercalcemia and gastrointestinal symptoms before the onset of common and usual manifestations of ALL is introduced. PMID- 24800039 TI - Anti-CD20 Antibody is Effective in the Patient with Refractory Amegakaryocytic Thrombocytopenia, 25 Months Follow up. AB - Amegakaryocytic thrombocytopenia (AMT) is a rare cause of acquired thrombocytopenia. The pathogenesis and treatment of AMT is not clearly known. Here we demonstrate a 50-year-old man presented with the clinical manifestations of severe thrombocytopenia (7000 platelets/ul) with a marked decrease to absent of megakaryocytes in the bone marrow. The patient did not respond to intravenous immunoglobulin, cyclosporine or high dose prednisone. After the treatment with anti-CD20 antibody (Rituximab), the patient's clinical symptoms and platelet counts improved. PMID- 24800040 TI - Vitamin D and multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic demyelinating disease and also is one of the most common disabling neurological disorders in young and middle-aged adults. The main pathogenesis of MS has long been thought to be an immune mediated disorder of the central nervous system. The function of the immune system is under the influence of vitamin D which as a modulator of immune response could play a role in autoimmune diseases including MS. Deficiency of vitamin D or variations in DNA sequence (polymorphism) of vitamin D receptor gene diminishes its optimal function on immune system that consequently could lead to increasing risk of MS. However, its role in development and modulating the course of MS is still under investigation. In this review we aimed to discuss the role of vitamin D in body, immune system and consequently altering the risk of MS. PMID- 24800041 TI - Correlations between cytomegalovirus, Epstein-Barr virus, anti-ganglioside antibodies, electrodiagnostic findings and functional status in Guillain-Barre syndrome. AB - BACKGROUND: Due to underlying autoimmune background of Guillain-Barre syndrome (GBS), the possible role of infectious agents cytomegalovirus (CMV) and Epstein Barr virus (EBV) and also due to association of anti-ganglioside antibodies with GBS, the present study aimed to investigate the associations between serum anti ganglioside antibodies (AGA) level, type of infection and electrodiagnostic (ED) findings with the severity and three-month functional outcome of patients with GBS. METHODS: In a prospective study, 30 patients with GBS were selected and before starting the treatment, baseline serum samples of patients were obtained for measuring the serum AGA including the antibodies against GQ1b, GT1b, GD1a, GD1b, GM1, GM2, GM3 and strains of CMV and EBV. All the patients were precisely examined for ED findings. Functional status of patients on admission and three months after admission were recorded according to the modified Rankin scale (mRS). RESULTS: The results of patients' serum assessment revealed that CMV IgM was positive in one patient (3.3%), CMV IgG in 29 patients (96.7%) and EBV IgG in 27 patients (90%). Anti-GM1 was found in 3 patients (10%) and anti-GM3 was found only in one patient (3.3%). However, no statistical significant association was found between the AGA and strain of the disease and ED findings. CONCLUSION: Despite the coexistence of AGA and serum antibodies against CMV and EBV in some GBS patients, there was not clear association in this regard. However, the AGA was positive in patients who suffered from severe phase of the disease. PMID- 24800042 TI - Level of attitude toward complementary and alternative medicine among Iranian patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is an unpredictable neurological disease leading to severe disability in young adults. The majority of MS patients use complementary and alternative medicine (CAM) as adjunct to conventional therapies. This study aimed to investigate the prevalence of CAM utilization among Iranian patients with MS and their attitude toward the CAM usage. METHODS: A cross-sectional study was conducted on 119 definite MS patients referred to Tehran's Imam Khomeini and Sina hospitals. A questionnaire was used to examine the association between participants' health-related factors and usage of CAMs interventions. P value < 0.05 was considered statistically significant. RESULTS: Among the enrolled patients, 60% of the participants agreed with using CAM, 42% experienced the usage of these treatments; out of whom 41% believed its efficiency and 18% reported exacerbation of symptoms. The mean duration of disease diagnosis and mean time from symptoms onset were both longer in users of CAM (P = 0.001). Most socio-demographic factors had no significant effect on the type of used CAM. However, Yoga was significantly more applied in those with higher degree of education (P = 0.002). CONCLUSION: Regarding the widespread use of CAM by Iranian patients with MS, further researches about the safety and efficacy of each treatment on the special outcomes is recommended. PMID- 24800043 TI - Role of C-fibers in pain and morphine induced analgesia/hyperalgesia in rats. AB - BACKGROUND: Usual dosage of morphine (10 mg/kg) induces analgesia and ultra-low dose (ULD) of morphine (1 ug/kg); hyperalgesia, and C-fibers are also bearing u opioid receptors; here the importance of C-fibers on pain and morphine induced analgesia/hyperalgesia is questioned and investigated using pain evaluation methods and infant capsaicin treating for C-fibers lesioning. METHODS: Wistar male rats (200-250 grams) were assigned to three categories i.e. control, sham (receiving neonatal capsaicin vehicle) and c-lesion (receiving neonatal capsaicin), each one with three groups (n=7). They were injected intraperitoneally with single dosage of saline, 10 mg/kg or 1 ug/kg morphine, respectively. Thermal pain threshold was evaluated using the tail flick test before and 30 minutes after the injections. Chemical pain was assessed using the formalin test (FT) 30 minutes after the administrations. RESULTS: Results indicated that thermal (P < 0.001) and chemical pains in both neurogenic and inflammatory phases of FT (P < 0.05) were reduced in C-lesion animals. In the C normal and C-lesion animals, 10 mg/kg morphine exerted analgesia both in thermal (P < 0.001) and two phases of FT (P < 0.01), but it was more potent in C-lesion animals (P < 0.05). Although ULD of morphine in C-normal animals produced hyperalgesic effect in thermal and chemical pains (P < 0.001), in C-lesion animals, it produced analgesia (P < 0.05) at the neurogenic phase of FT. CONCLUSION: Results can raise the C-fibers involvement for a significant portion of nociceptive transmission, because C-lesioning potentiated morphine induced analgesia and eliminated ULD of morphine induced hyperalgesia. Therefore C and Adelta fibers can be involved in morphine analgesia; while, just C-fibers are possibly responsible for only presynaptically hyperalgesic/excitatory action of ULD in morphine. PMID- 24800044 TI - Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients. AB - BACKGROUND: The role of nutrition in the progression of multiple sclerosis (MS) and related complications such as fatigue has been reported by several studies. The aim of this study is the assessment of nutritional status and its relationship with fatigue in multiple sclerosis patients. METHODS: This is a cross-sectional study, in which 101 relapsing-remitting MS patients were enrolled. The fatigue status was determined using the validated Persian version of of the Modified Fatigue Impact Scale (MFIS). Dietary intake was assessed using a 3-day food record questionnaire and compared to dietary reference intake (DRI) values. Association between variables was determined using Pearson Correlation Coefficient. RESULTS: In the preset study, 25 men and 76 women (total = 101) were enrolled. Analysis of dietary intake showed that daily intake of vitamin D, folate, calcium, and magnesium were significantly lower than DRI in all of patients. In men, zinc intake was significantly lower than DRI; while, in women, iron was significantly below the DRI level. After adjusting for energy, MFIS and its physical subscale were highly correlated with intake of folate and magnesium. CONCLUSION: Our findings support that lower magnesium and folate diets are correlated with higher fatigue scores in MS patients. PMID- 24800045 TI - One-shot, low-dosage intratympanic gentamicin for Meniere's disease: Clinical, posturographic and vestibular test findings. AB - BACKGROUND: Meniere's disease has been remained as a difficult therapeutic challenge. The present study aimed to determine the effects of one-shot low dosage intratympanic gentamicin on vertigo control, auditory outcomes and findings of computerized dynamic posturography and vestibular evoked myogenic potentials in patients with unilateral Meniere's disease. METHODS: In a prospective clinical study, 30 patients with unilateral Meniere's disease were treated with one-shot intratympanic injection of 20 milligrams gentamicin. Main outcome measures included clinical, audiometric, postural and vestibular outcomes evaluated 1 and 9 months after the treatment. RESULTS: Mean vertigo attacks frequency, pure tone average threshold and functional level scale significantly decreased after the treatment (P < 0.05). Effective vertigo control (class A and B) obtained in 95.8% of the patients. In total, 75% of patients reported decrease in both aural fullness and tinnitus. Vestibular evoked myogenic potentials became absent in all the patients but four of them. Posturographic scores were improved after the treatment. CONCLUSION: One-shot low-dosage gentamicin was effective in controlling vertigo attacks in Meniere's disease and has useful effects on aural fullness and tinnitus of patients as well. Postural and vestibular tests only have adjunctive role for monitoring therapeutic responses in intratympanic gentamicin-therapy. PMID- 24800046 TI - Thymic pathological examination of non-thymomatous myasthenia gravis patients: A pilot study for prediction of outcome. AB - BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder characterized by weakness and fatigability of skeletal muscles. The aim of this study was to determine if pathological characteristics in non-thymomatous patients of MG would correlate with prognosis in a three year follow up. METHODS: Patients who had had their thymectomy at least three years prior to the study were selected from three hospitals and were followed for 3 years. Prognosis was assessed via a devised prognostic scoring system. A pathological exam of the specimen from the thymus was done using the following immunohistochemical markers: Bcl2, CD 3, CD 4, CD 5, CD 7, CD 10, CD 20cy, CD 23, CD 43, and Ki67. RESULTS: Fifteen patients fulfilled the inclusion criteria and had a complete follow-up. This included 3 males and 12 females with a mean age of 36.6 years at the start of the study. The dominant cell population was T lymphocytes. All T cells expressed CD 3, CD 43, CD 5, and Bcl-2. In 2 patients, CD 10 marker was positive in T cells. B cells were negative for activation marker CD 23, except for germinal center dendritic cells. Due to the limited number of patients in the study, the power of the study would not allow for an analysis to assess correlation between histopathological data and prognosis. CONCLUSION: This pilot study was an attempt to discover any prognostic indices from the histopathological examination of the resected thymic tissue in the patients with myasthenia gravis. PMID- 24800047 TI - Increased carotid intima-media thickness in scuba divers. AB - BACKGROUND: Scuba divers work in high pressure conditions which may cause some changes in physiological status to adapt to this situation. In this study, the carotid intima-media thickness (CIMT) was assessed in divers as a risk factor of cerebrovascular and cardiovascular disorders. METHODS: This historical cohort study was performed on 16 male professional scuba divers as case group and 30 healthy people as controls with age range of 26-66 years. CIMT of both carotids of supine participants was measured by a 10 MHz linear ultrasonic probe quantitatively. Relationship between experience of diving and carotid IMT was evaluated. RESULTS: All the participants were males (mean age 42.9 +/- 10.58. and for the control group was (47.05 +/- 12.31 years). The mean right CIMT in divers and control group was 524.31 +/- 149.40 and 443.66 +/- 59.62 micrometer, respectively. Furthermore, the mean left CIMT in divers and control group was 624.57 +/- 116.15 and 458.44 +/- 49.56 micrometer, respectively. CONCLUSION: The findings demonstrated that long-term occupational diving leads to increased intima-media thickness in scuba divers. PMID- 24800048 TI - Amyloid-based therapies did fail again! It is the right time to change our vision on building block of Alzheimer's disease. PMID- 24800049 TI - Prevalence of Lhermitte's sign in multiple sclerosis versus neuromyelitis optica. PMID- 24800050 TI - Neurotheology: The relationship between brain and religion. AB - "Neurotheology" refers to the multidisciplinary field of scholarship that seeks to understand the relationship between the human brain and religion. In its initial development, neurotheology has been conceived in very broad terms relating to the intersection between religion and brain sciences in general. The author's main objective is to introduce neurotheology in general and provides a basis for more detailed scholarship from experts in theology, as well as in neuroscience and medicine. PMID- 24800051 TI - Graft-free sinus augmentation procedure: a literature review. AB - OBJECTIVES: The restoration of edentulous posterior maxilla with dental implants is challenging due to a deficient posterior alveolar ridge. Over the last decade an advance in the graftless bone augmentation procedures had occurred where the space left beneath the Schneiderian membrane is filled with blood clot in order to produce bone formation. The aim of present article is to review the scientific literature with respect to bone formation in the sinus, after membrane elevation procedure, without using any bone substitutes. MATERIAL AND METHODS: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. The articles were searched from 1993 to 2013. English language articles with minimum one year patient follow-up and radiological and/or histological diagnostics of newly formed bone were included. Articles were excluded, if usage of bone graft or bone substitutes and/or usage of osteotome has been made during sinus lift operation. RESULTS: A total of 19 studies were included: 2 studies were related to the sinus membrane's osteogenic potential, 3 to the histological evidence of bone formation in monkeys and humans, 12 to the radiologic evidence of bone gain, and 2 to the space-maintaining management. 100% of the reviewed articles presented with increased bone formation and high implant survival rates resulting from the graft free technique. CONCLUSIONS: It is clearly shown in the review that the potential of the maxillary sinus to heal and to form new bone without bone grafts or substitutes is of high nature. PMID- 24800052 TI - Comparative Study of Skeletal Stability between Postoperative Skeletal Intermaxillary Fixation and No Skeletal Fixation after Bilateral Sagittal Split Ramus Osteotomy: an 18 Months Retrospective Study. AB - OBJECTIVES: The purpose of the present study was to evaluate skeletal stability after mandibular advancement with bilateral sagittal split osteotomy. MATERIAL AND METHODS: Twenty-six patients underwent single-jaw bilateral sagittal split osteotomy (BSSO) to correct skeletal Class II malocclusion. One group (n = 13) were treated postoperatively with skeletal elastic intermaxillary fixation (IMF) while the other group (n = 13) where threated without skeletal elastic IMF. RESULTS: The mean advancement at B-point and Pog in the skeletal elastic IMF group was 6.44 mm and 7.22 mm, respectively. Relapse at follow-up at B-point was 0.74 mm and -0.29 mm at Pog. The mean advancement at B-point and Pog in the no skeletal elastic IMF group was 6.30 mm and 6.45 mm, respectively. Relapse at follow-up at B-point was -0.97 mm and -0.86 mm at Pog. There was no statistical significant (P > 0.05) difference between the skeletal IMF group and the no skeletal group regarding advancement nor relapse at B-point or Pog. CONCLUSIONS: Bilateral sagittal split osteotomy is characterized as a stable treatment to correct Class II malocclusion. This study demonstrated no difference of relapse between the skeletal intermaxillary fixation group and the no skeletal intermaxillary fixation group. Because of selection-bias and the reduced number of patients it still remains inconclusive whether to recommend skeletal intermaxillary fixation or not in the prevention of relapse after mandibular advancement. PMID- 24800053 TI - Endoplasmic Reticulum Stress-Associated Chaperones, Bip/GRP78 and Calnexin are Overexpressed in Keratocystic Odontogenic Tumours. AB - OBJECTIVES: Odontogenic keratocysts (OKCs) are developmental cysts that have been reclassified according World Health Organization (WHO), to keratocystic odontogenic tumours (KCOTs), a term that better reflects their neoplastic nature. The aim of present study is to evaluate the induction of stress of the endoplasmic reticulum and execution of the resulting unfolded protein response in keratinocystic odontogenic tumours. MATERIAL AND METHODS: We analyzed by immunohistochemistry the expression of the chaperones BiP/GRP78 and calnexin in 24 cases of KCOTs. As controls, we have used 9 cases of periapical or radicular cysts (PACs) and 5 cases of Fibromas (FBs). The PACs and the FBs were included in the analysis, as PACs are the most common type of inflammatory odontogenic cysts of and FBs, as lesions of the connective tissue with unaffected epithelium. RESULTS: Analysis revealed a strong association between both BiP/GRP78 and calnexin expression and KCOTs: 18 out of 24 (75%) KCOTs expressed BiP/GRP78 as opposed to 1 out of 9 (13%) PACs, and none of 5 FBs evaluated (P < 0.001, x(2) test). Calnexin was expressed in 11 out of 24 KCOTs (46%) but only one out of 9 (13%) PACs, and none of the 5 FBs analyzed (P < 0.001, x(2)-test). CONCLUSIONS: Study results imply that induction of endoplasmic reticulum stress maybe of diagnostic value in keratocystic odontogenic tumours characterization. In addition to recent findings suggesting that endoplasmic reticulum stress plays a causative role in keratinization of epithelia, pharmacological interference with the execution of the unfolded protein response should be considered for the management of keratocystic odontogenic tumours. PMID- 24800054 TI - Factors Affecting the Formation, Severity and Location of White Spot Lesions during Orthodontic Treatment with Fixed Appliances. AB - OBJECTIVES: The purpose of the present study was to investigate factors affecting the formation, severity and location of white spot lesions in patients completing fixed appliance therapy. MATERIAL AND METHODS: A total of 45 patients (19 males and 26 females, mean age 15.81 years, standard deviation 2.89 years) attending consecutively Aberdeen Dental Hospital (ADH) between January and June 2013 to have their fixed appliances removed were given a questionnaire to elicit information regarding their dental care and diet. They were then examined clinically as well as their pre-treatment photographs to record treatment data and white spot lesion (WSL) location and severity using a modified version of Universal Visual Scale for Smooth Surfaces (UniViSS Smooth). Absolute risk (AR) and risk ratios (RR) were also calculated. RESULTS: The incidence of at least one WSL observed in patients was 42%, with males displaying a higher incidence than females. The highest incidence of WSLs was recorded on the maxillary canines and lateral incisors, and on the maxillary and mandibular premolars and first molars. The gingival areas of the maxillary and mandibular teeth were the most affected surfaces. Significant (P < 0.05) relationships were found between the presence of WSLs and the following factors: poor oral hygiene (OH), males, increased treatment length, lack of use of fluoride supplements, use of carbonated soft drinks and/or fruit juices and the use of sugary foods. Poor OH posed the highest risk of developing WSL (RR = 8.55). CONCLUSIONS: 42% of patients have developed white spot lesions during fixed appliance therapy. Various contributing risk factors were identified with the greatest risk posed by a poor oral hygiene. PMID- 24800055 TI - Long-Term Symptoms Onset and Heterotopic Bone Formation around a Total Temporomandibular Joint Prosthesis: a Case Report. AB - BACKGROUND: The literature on total alloplastic temporomandibular joint (TMJ) reconstructions is encouraging, and studies on total alloplastic TMJ replacements outcomes showed acceptable improvements in terms of both pain levels and jaw function. Nevertheless, some adverse events, such as heterotopic bone formation around the implanted prosthesis, may occur. In consideration of that, the present manuscript describes a case of heterotopic bone formation around a total temporomandibular joint prosthesis, which occurred several years after the implant. METHODS: The present manuscript describes a case of heterotopic bone formation around a total TMJ prosthesis, which occurred several years after the implant in patients, who previously underwent multiple failed TMJ surgeries. RESULTS: Ten years after the surgical TMJ replacement to solve an ankylotic bone block, the patient came to our attention again referring a progressive limitation in mouth opening. A computerized tomography showed evidence of marked heterotopic bone formation in the medial aspects of the joint, where a new-born ankylotic block occupied most part of the gap created by resecting the coronoid process at the time of the TMJ prosthesis insertion. CONCLUSIONS: Despite this adverse event has been sometimes described in the literature, this is the first case in which its occurrence happened several years after the temporomandibular joint replacement. It can be suggested that an accurate assessment of pre-operative risk factors for re-ankylosis (e.g., patients with multiple failed temporomandibular joint surgeries) and within-intervention prevention (e.g., strategies to keep the bone interfaces around the implant separated) should be better standardized and define in future studies. PMID- 24800056 TI - The role of imaging in patient selection, preoperative planning, and postoperative monitoring in human upper extremity allotransplantation. AB - Objective. To describe the role of imaging in vascular composite allotransplantation based on one institution's experience with upper extremity allotransplant patients. Methods. The institutional review board approved this review of HIPAA-compliant patient data without the need for individual consent. A retrospective review was performed of imaging from 2008 to 2011 on individuals undergoing upper extremity transplantation. This demonstrated that, of the 19 patients initially considered, 5 patients with a mean age of 37 underwent transplantation. Reports were correlated clinically to delineate which preoperative factors lead to patient selection versus disqualification and what concerns dictated postoperative imaging. Findings were subdivided into musculoskeletal and vascular imaging criterion. Results. Within the screening phase, musculoskeletal exclusion criterion included severe shoulder arthropathy, poor native bone integrity, and marked muscular atrophy. Vascular exclusion criterion included loss of sufficient arterial or venous supply and significant distortion of the native vascular architecture. Postoperative imaging was used to document healing and hardware integrity. Postsurgical angiography and ultrasound were used to monitor for endothelial proliferation or thrombosis as signs of rejection and vascular complication. Conclusion. Multimodality imaging is an integral component of vascular composite allotransplantation surgical planning and surveillance to maximize returning form and functionality while minimizing possible complications. PMID- 24800057 TI - Comparative study of modified quantitative buffy coat and two rapid tests in comparison with peripheral blood smear in malaria diagnosis in mumbai, India. AB - In order to identify a quick and reliable technique for accurate diagnosis of malaria, study of the efficiency of the tests such as Parahit total (HRPII & aldolase Ag), Advantage mal card (parasite specific LDH), and modified QBC was done in comparison with conventional blood smear microscopy. One hundred patients infected with P. vivax and 101 infected with P. falciparum were included in this study. The sensitivity of Parahit total, Advantage mal card, and modified QBC for P. falciparum detection was 70.3, 95%, and 98%, and specificity was 98%, 98%, and 96%, respectively. The sensitivity of Parahit total, Advantage mal card, and modified QBC for P. vivax detection was 73%, 97.0%, and 98%, respectively, and specificity of all the tests was 98%. On day 15, in falciparum arm, Advantage mal card and Parahit total showed 8 (7.92%) and 59 (58.41%) false positives. On day 15, in vivax arm, Parahit total revealed 52% false positives. The study indicated that modified QBC could be only used where appropriate facilities are available. Advantage mal card was a better follow-up tool than Parahit total. PMID- 24800058 TI - Schistosoma mansoni Infection and Associated Determinant Factors among School Children in Sanja Town, Northwest Ethiopia. AB - Background. Intestinal schistosomiasis is one of the most widespread parasitic infections in tropical and subtropical countries. Objective. To determine the prevalence of S. mansoni infection and associated determinant factors among school children in Sanja Town, northwest Ethiopia. Methods. A cross-sectional study was conducted from February to March, 2013. 385 school children were selected using stratified proportionate systematic sampling technique. Pretested questionnaire was used to collect sociodemographic data and associated determinant factors. Stool samples were examinedusing formol-ether concentration and Kato-Katz technique. Data were entered and analyzed using SPSS 20.0 statistical software. Multivariate logistic regression was done for assessing associated risk factors and proportions for categorical variables were compared using chi-square test. P values less than 0.05 were taken as statistically significant. Results. The prevalence of S. mansoni infection was 89.9% (n = 346). The overall helminthic infection in this study was 96.6% (n = 372). Swimming in the river, washing clothes and utensil using river water, crossing the river with bare foot, and fishing activities showed significant association with the occurrence of S. mansoni infection. Conclusion. Schistosoma mansoni infection was high in the study area. Therefore, mass deworming at least twice a year and health education for community are needed. PMID- 24800059 TI - Corneal biomechanical assessment using corneal visualization scheimpflug technology in keratoconic and normal eyes. AB - Purpose. To compare the corneal biomechanical properties of keratoconic patients and age-matched controls using corneal visualization Scheimpflug technology (Corvis ST). Methods. Sixty keratoconic eyes from 47 keratoconus patients and 60 normal eyes from 60 controls were enrolled in this prospective study. Tomography and biomechanical parameters of all eyes were obtained with the Pentacam and Corvis ST, respectively. Intraocular pressure was measured using a Goldmann applanation tonometer. Results. The tomography and biomechanical parameters of the keratoconic corneas were significantly different from those of the normal corneas except for the anterior chamber angle, first applanation length, the highest concavity time, and peak distance. The deformation amplitude was the best predictive parameter (area under the curve: 0.882), with a sensitivity of 81.7%, although there was a significant overlap between keratoconic and normal corneas that ranged from 1.0 to 1.4 mm. In both the keratoconus and control groups, the deformation amplitude was negatively correlated with intraocular pressure, central corneal thickness, and corneal volume at 3 and 5 mm. Conclusions. Corvis ST offers an alternative method for measuring corneal biomechanical properties. The possibility of classifying keratoconus based on deformation amplitude deserves clinical attention. PMID- 24800060 TI - The effect of antivascular endothelial growth factor therapy on the development of neovascular glaucoma after central retinal vein occlusion: a retrospective analysis. AB - Purpose. Ischemic central retinal vein occlusion (CRVO) eyes are at high risk of developing neovascular glaucoma (NVG). Our purpose is to investigate the effect of anti-VEGF therapy for macular edema after CRVO on the development of neovascular glaucoma (NVG) in ischemic CRVO eyes. Methods. This is a retrospective case series of 44 eyes from 44 patients with CRVO treated with anti VEGF therapy for macular edema. The primary outcome was the development of NVG. Results. Of the 44 eyes, 14 eyes had ischemic CRVO, and 30 eyes had nonischemic CRVO. Nonischemic eyes received a mean of 8.4 anti-VEGF doses, over mean follow up of 24 months. One nonischemic eye (3.3%) developed NVD but not NVG. The 14 ischemic eyes received a mean of 5.6 anti-VEGF doses, with mean follow-up of 23 months. Of these 14 ischemic eyes, two eyes (14%) developed iris neovascularization and 3 eyes (21%) developed posterior neovascularization. Three of these 5 eyes with neovascularization progressed to NVG, at 19.7 months after symptom onset, on average. Conclusion. Anti-VEGF therapy for macular edema may delay, but does not prevent, the development of ocular NV in ischemic CRVO. Significant risk of NVG still exists for ischemic CRVO eyes. PMID- 24800061 TI - Role of autofluorescence in inflammatory/infective diseases of the retina and choroid. AB - Fundus autofluorescence (FAF) has recently emerged as a novel noninvasive imaging technique that uses the fluorescent properties of innate fluorophores accumulated in the retinal pigment epithelium (RPE) to assess the health and viability of the RPE/photoreceptor complex. Recent case reports suggest FAF as a promising tool for monitoring eyes with posterior uveitis helping to predict final visual outcome. In this paper we review the published literature on FAF in these disorders, specifically patterns in infectious and noninfectious uveitis, and illustrate some of these with short case histories. PMID- 24800063 TI - Esterase Active in Polar Organic Solvents from the Yeast Pseudozyma sp. NII 08165. AB - Esterases/lipases active in water miscible solvents are highly desired in biocatalysis where substrate solubility is limited and also when the solvent is desired as an acyl acceptor in transesterification reactions, as with the case of biodiesel production. We have isolated an esterase from the glycolipid producing yeast-Pseudozyma sp. NII 08165 which in its crude form was alkali active, thermo stable, halo tolerant and also capable of acting in presence of high methanol concentration. The crude enzyme which maintained 90% of its original activity after being treated at 70 degrees C was purified and the properties were characterized. The partially purified esterase preparation had temperature and pH optima of 60 degrees C and 8.0 respectively. The enzyme retained almost complete activity in presence of 25% methanol and 80% activity in the same strength of ethanol. Conditions of enzyme production were optimized, which lead to 9 fold increase in the esterase yield. One of the isoforms of the enzyme LIP1 was purified to homogeneity and characterized. Purified LIP1 had a K m and V max of 0.01 and 1.12, respectively. The purified esterase lost its thermo and halo tolerance but interestingly, retained 97% activity in methanol. PMID- 24800062 TI - The role of epigenetics in the fibrotic processes associated with glaucoma. AB - Glaucoma is an optic neuropathy that affects 60 million people worldwide. The main risk factor for glaucoma is increased intraocular pressure (IOP), this is currently the only target for treatment of glaucoma. However, some patients show disease progression despite well-controlled IOP. Another possible therapeutic target is the extracellular matrix (ECM) changes in glaucoma. There is an accumulation of ECM in the lamina cribrosa (LC) and trabecular meshwork (TM) and upregulation of profibrotic factors such as transforming growth factor beta (TGF beta ), collagen1 alpha 1 (COL1A1), and alpha -smooth muscle actin ( alpha SMA). One method of regulating fibrosis is through epigenetics; the study of heritable changes in gene function caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic mechanisms have been shown to drive renal and pulmonary fibrosis by upregulating profibrotic factors. Hypoxia alters epigenetic mechanisms through regulating the cell's response and there is a hypoxic environment in the LC and TM in glaucoma. This review looks at the role that hypoxia plays in inducing aberrant epigenetic mechanisms and the role these mechanisms play in inducing fibrosis. Evidence suggests that a hypoxic environment in glaucoma may induce aberrant epigenetic mechanisms that contribute to disease fibrosis. These may prove to be relevant therapeutic targets in glaucoma. PMID- 24800064 TI - The influence of gender and self-efficacy on healthy eating in a low-income urban population affected by structural changes to the food environment. AB - Although U.S. obesity prevention efforts have begun to implement a variety of system and environmental change strategies to address the underlying socioecological barriers to healthy eating, factors which can impede or facilitate community acceptance of such interventions are often poorly understood. This is due, in part, to the paucity of subpopulation health data that are available to help guide local planning and decision-making. We contribute to this gap in practice by examining area-specific health data for a population targeted by federally funded nutrition interventions in Los Angeles County. Using data from a local health assessment that collected information on sociodemographics, self-reported health behaviors, and objectively measured height, weight, and blood pressure for a subset of low-income adults (n = 720), we compared health risks and predictors of healthy eating across at-risk groups using multivariable modeling analyses. Our main findings indicate being a woman and having high self-efficacy in reading Nutrition Facts labels were strong predictors of healthy eating (P < 0.05). These findings suggest that intervening with women may help increase the reach of these nutrition interventions, and that improving self-efficacy in healthy eating through public education and/or by other means can help prime at-risk groups to accept and take advantage of these food environment changes. PMID- 24800065 TI - Engagement with Care, Substance Use, and Adherence to Therapy in HIV/AIDS. AB - Engagement with care for those living with HIV is aimed at establishing a strong relationship between patients and their health care provider and is often associated with greater adherence to therapy and treatment (Flickinger, Saha, Moore, and Beach, 2013). Substance use behaviors are linked with lower rates of engagement with care and medication adherence (Horvath, Carrico, Simoni, Boyer, Amico, and Petroli, 2013). This study is a secondary data analysis using a cross sectional design from a larger randomized controlled trial (n = 775) that investigated the efficacy of a self-care symptom management manual for participants living with HIV. Participants were recruited from countries of Africa and the US. This study provides evidence that substance use is linked with lower self-reported engagement with care and adherence to therapy. Data on substance use and engagement are presented. Clinical implications of the study address the importance of utilizing health care system and policy factors to improve engagement with care. PMID- 24800066 TI - Transplacental Transfer of Hepatitis B Neutralizing Antibody during Pregnancy in an Animal Model: Implications for Newborn and Maternal Health. AB - Despite the success of postexposure prophylaxis (PEP) of the newborn in preventing mother-to-child transmission of hepatitis B virus), in non-US clinical trials, administering hepatitis B immune globulin (HBIG) to mothers at the end of pregnancy (in addition to passive-active PEP of the newborn) only partially improved outcomes. That is, a significant percentage of newborns became infected during their first year of life. We used a relevant animal model for human IgG transplacental transfer to study dose, time and subclass dependence of HBV neutralizing antibody (nAb) maternal, and fetal levels at the end of pregnancy. Pregnant guinea pigs received 50 or 100 IU/kg HBIGIV 2-5 days before delivery. Human total IgG, IgG subclasses, and nAb in mothers and their litters were measured. In vitro analyses of guinea pig Fc neonatal receptor binding to HBIGIV, as well as to all human IgG subclasses, were also performed. Our study showed that nAb transferred transplacentally from the pregnant guinea pigs to their litters; no transfer occurred during parturition. The amount of the transferred nAb was dose and time dependent. Thus, selection of an efficacious dose in the clinic is important: microdosing may be underdosing, particularly in cases of high viraemia. PMID- 24800068 TI - Family health conversations: how do they support health? AB - Research shows that living with illness can be a distressing experience for the family and may result in suffering and reduced health. To meet families' needs, family systems intervention models are developed and employed in clinical contexts. For successful refinement and implementation it is important to understand how these models work. The aim of this study was therefore to describe the dialogue process and possible working mechanisms of one systems nursing intervention model, the Family Health Conversation model. A descriptive evaluation design was applied and 15 transcribed conversations with five families were analyzed within a hermeneutic tradition. Two types of interrelated dialogue events were identified: narrating and exploring. There was a flow between these events, a movement that was generated by the interaction between the participants. Our theoretically grounded interpretation showed that narrating, listening, and reconsidering in interaction may be understood as supporting family health by offering the families the opportunity to constitute self identity and identity within the family, increasing the families' understanding of multiple ways of being and acting, to see new possibilities and to develop meaning and hope. Results from this study may hopefully contribute to the successful implementation of family systems interventions in education and clinical praxis. PMID- 24800067 TI - Incisional surgical site infection after elective open surgery for colorectal cancer. AB - BACKGROUND: The purpose of this study was to clarify the incidence and risk factors for incisional surgical site infections (SSI) in patients undergoing elective open surgery for colorectal cancer. METHODS: We conducted prospective surveillance of incisional SSI after elective colorectal resections performed by a single surgeon for a 1-year period. Variables associated with infection, as identified in the literature, were collected and statistically analyzed for their association with incisional SSI development. RESULTS: A total of 224 patients were identified for evaluation. The mean patient age was 67 years, and 120 (55%) were male. Thirty-three (14.7%) patients were diagnosed with incisional SSI. Multivariate analysis suggested that incisional SSI was independently associated with TNM stages III and IV (odds ratio [OR], 2.4) and intraoperative hypotension (OR, 3.4). CONCLUSIONS: The incidence of incisional SSI in our cohort was well within values generally reported in the literature. Our data suggest the importance of the maintenance of intraoperative normotension to reduce the development of incisional SSI. PMID- 24800069 TI - One-stop outpatient management of accessory auricle in children with titanium clip. AB - Introduction. Literature on ideal management of accessory auricles is limited. Traditionally, accessory auricles are managed by paediatricians with suture ligation at the base of the accessory auricle to induce ischaemic necrosis (Mehmi et al, 2007). This method can be associated with complications and poor cosmesis thus leading to the vogue of surgical excision ( Frieden et al, 1995; Sebben, 1989). We present our experience in managing these lesions in children with the application of a titanium clip in a one-stop outpatient setting. Methods. Data was collected retrospectively through review of patient records and telephone questionnaire identifying outcomes from the parents' perspective. Results. Of 42 patients, 24 (57.1%) responded. Eleven (26.2%) underwent surgical excision, 6 (14.3%) had no intervention, and 1 (2.4%) was not contactable. All parents were happy with the outcome and would recommend this management to other parents. Twenty-three (96%) had no complications apart from a tiny residual nubbin, which was considered cosmetically acceptable. One child had a residual nubbin that grew in size requiring surgical excision at later stage. Conclusion. Management of accessory auricles by the application of a titanium clip in one-stop outpatient setting is safe, simple, quick, and well tolerated with no need for admission, anaesthesia, or followup due to the low complication rate. PMID- 24800070 TI - Association between Neck/Shoulder Pain and Trapezius Muscle Tenderness in Office Workers. AB - Background. Neck/shoulder pain is a common musculoskeletal disorder among adults. The pain is often assumed to be related to muscular tenderness rather than serious chronic disease. Aim. To determine the association between neck/shoulder pain intensity and trapezius muscle tenderness in office workers. Methods. 653 employees from two large office workplaces in Copenhagen, Denmark, replied to a questionnaire on health and working conditions (mean: age 43 years, body mass index 24 kg.m(-2), computer use 90% of work time, 73% women). Respondents rated intensity of neck/shoulder pain during the previous three months on a scale of 0 10 and palpable tenderness of the upper trapezius muscle on a scale of "no tenderness," "some tenderness," or "severe tenderness." Odds ratios for tenderness as a function of neck/shoulder pain intensity were determined using cumulative logistic regression controlled for age, gender, and chronic disease. Results. The prevalence of "no," "some," and "severe" tenderness of the trapezius muscle was 18%, 59%, and 23% in women and 51%, 42%, and 7% in men, respectively (chi-square, P < 0.0001). Participants with "no," "some," and "severe" tenderness of the trapezius muscle, respectively, rated their neck/shoulder pain intensity to 1.5 (SD 1.6), 3.8 (SD 2.0), and 5.7 (SD 1.9) for women and 1.4 (SD 1.4), 3.1 (SD 2.2), and 5.1 (SD 1.7) for men. For every unit increase in neck/shoulder pain intensity, the OR for one unit increase in trapezius tenderness was 1.86 (95% confidence interval 1.70 to 2.04). Conclusion. In office workers, a strong association between perceived neck/shoulder pain intensity and trapezius muscle tenderness exists. The present study provides reference values of pain intensity among office workers with no, some, and severe tenderness of the trapezius muscle. PMID- 24800071 TI - Lyophilized Kit for the Preparation of the PET Perfusion Agent [(68)Ga]-MAA. AB - Rapid developments in the field of medical imaging have opened new avenues for the use of positron emitting labeled microparticles. The radioisotope used in our research was (68)Ga, which is easy to obtain from a generator and has good nuclear properties for PET imaging. Methods. Commercially available macroaggregated albumin (MAA) microparticles were suspended in sterile saline, centrifuged to remove the free albumin and stannous chloride, relyophilized, and stored for later labeling with (68)Ga. Labeling was performed at different temperatures and times. (68)Ga purification settings were also tested and optimized. Labeling yield and purity of relyophilized MAA microparticles were compared with those that were not relyophilized. Results. MAA particles kept their original size distribution after relyophilization. Labeling yield was 98% at 75 degrees C when a (68)Ga purification system was used, compared to 80% with unpurified (68)Ga. Radiochemical purity was over 97% up to 4 hours after the labeling. The relyophilized MAA and labeling method eliminate the need for centrifugation purification of the final product and simplify the labeling process. Animal experiments demonstrated the high in vivo stability of the obtained PET agent with more than 95% of the activity remaining in the lungs after 4 hours. PMID- 24800073 TI - Technical Considerations of Phosphorous-32 Bremsstrahlung SPECT Imaging after Radioembolization of Hepatic Tumors: A Clinical Assessment with a Review of Imaging Parameters. AB - Background. Bremsstrahlung (BS) imaging during radioembolization (RE) confirms the deposition of radiotracer in hepatic/extrahepatic tumors. The aim of this study is to demonstrate (32)P images and to optimize the imaging parameters. Materials and Methods. Thirty-nine patients with variable types of hepatic tumors, treated with the intra-arterial injection of (32)P, were included. All patients underwent BS SPECT imaging 24-72 h after tracer administration, using low energy high resolution (LEHR) (18 patients) or medium energy general purpose (MEGP) (21 patients) collimators. A grading scale from 1 to 4 was used to express the compatibility of the (32)P images with those obtained from CT/MRI. Results. Although the image quality obtained with the MEGP collimator was visually and quantitatively better than with the LEHR (76% concordance score versus 71%, resp.), there was no statistically significant difference between them. Conclusion. The MEGP collimator is the first choice for BS SPECT imaging. However, if the collimator change is time consuming (as in a busy center) or an MEGP collimator is not available, the LEHR collimator could be practical with acceptable images, especially in a SPECT study. In addition, BS imaging is a useful method to confirm the proper distribution of radiotherapeutic agents and has good correlation with anatomical findings. PMID- 24800075 TI - The increasing financial impact of chronic kidney disease in australia. AB - The aim of this investigation was to determine and compare current and projected expenditure associated with chronic kidney disease (CKD), renal replacement therapy (RRT), and cardiovascular disease (CVD) in Australia. Data published by Australia and New Zealand Dialysis and Transplant Registry, Australian Institute of Health and Welfare, and World Bank were used to compare CKD-, RRT-, and CVD related expenditure and prevalence rates. Prevalence and expenditure predictions were made using a linear regression model. Direct statistical comparisons of rates of annual increase utilised indicator variables in combined regressions. Statistical significance was set at P < 0.05. Dollar amounts were adjusted for inflation prior to analysis. Between 2012 and 2020, prevalence, per-patient expenditure, and total disease expenditure associated with CKD and RRT are estimated to increase significantly more rapidly than CVD. RRT prevalence is estimated to increase by 29%, compared to 7% in CVD. Average annual RRT per patient expenditure is estimated to increase by 16%, compared to 8% in CVD. Total CKD- and RRT-related expenditure had been estimated to increase by 37%, compared to 14% in CVD. Per-patient, CKD produces a considerably greater financial impact on Australia's healthcare system, compared to CVD. Research focusing on novel preventative/therapeutic interventions is warranted. PMID- 24800074 TI - Prolactin and psychopathology in schizophrenia: a literature review and reappraisal. AB - Secretion of the anterior pituitary hormone prolactin can be significantly increased by antipsychotic drugs, leading to a range of adverse effects in patients with schizophrenia. However, there is evidence from a variety of studies that prolactin may also be related to symptom profile and treatment response in these patients, and recent work has identified variations in prolactin secretion even in drug-free patients. In this paper, a selective review of all relevant studies pertaining to prolactin and schizophrenia, including challenge and provocation studies, is presented. The implications of this work are discussed critically. A tentative model, which synthesizes these findings and argues for a significant role for prolactin in the development of schizophrenia, is outlined. PMID- 24800072 TI - Practical guidelines: lung transplantation in patients with cystic fibrosis. AB - There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation. PMID- 24800076 TI - Impaired Urine Dilution Capability in HIV Stable Patients. AB - Renal disease is a well-recognized complication among patients with HIV infection. Viral infection itself and the use of some antiretroviral drugs contribute to this condition. The thick ascending limb of Henle's loop (TALH) is the tubule segment where free water clearance is generated, determining along with glomerular filtration rate the kidney's ability to dilute urine. Objective. We analyzed the function of the proximal tubule and TALH in patients with HIV infection receiving or not tenofovir-containing antiretroviral treatment in comparison with healthy seronegative controls, by applying a tubular physiological test, hyposaline infusion test (Chaimowitz' test). Material & Methods. Chaimowitz' test was performed on 20 HIV positive volunteers who had normal renal functional parameters. The control group included 10 healthy volunteers. Results. After the test, both HIV groups had a significant reduction of serum sodium and osmolarity compared with the control group. Free water clearance was lower and urine osmolarity was higher in both HIV+ groups. Proximal tubular function was normal in both studied groups. Conclusion. The present study documented that proximal tubule sodium reabsorption was preserved while free water clearance and maximal urine dilution capability were reduced in stable HIV patients treated or not with tenofovir. PMID- 24800077 TI - The evaluation of red cell distribution width in chronic hemodialysis patients. AB - Background. Red cell distribution width (RDW) has been used as a marker of iron deficiency; however, it is accepted as a marker of cardiovascular survival. We aimed to study RDW levels in hemodialysis (HD) patients and the association between RDW and inflammatory, nutritional, and volume markers. Methods. We included 296 HD patients with sufficient iron storage and without anemia or hypervolemia. We grouped patients into four groups according to clinical parameters, albumin, and C-reactive protein (CRP). Results. The lowest RDW levels were found in group 1 (13.2%). Although RDW of group 2 was higher than that of group 1, it was still in normal range (14.7% versus 13.2%, P = 0.028). RDW levels of groups 3 (17.8%) and 4 (18.5%) were significantly higher than those of groups 1 and 2 and above normal range. A positive correlation was detected between RDW and HD duration, interdialytic weight gain (IDWG), serum phosphate, and CRP levels and a negative correlation was detected with serum albumin. HD duration, CRP, IDWG, and serum albumin have been found as independent predictors of RDW elevation. Conclusions. Results of the present study reflect adverse effects of inflammation, malnutrition, and excess IDWG on RDW elevation in an HD study cohort with sufficient iron storage and without anemia and hypervolemia. PMID- 24800078 TI - Oral dalfampridine improves standing balance detected at static posturography in multiple sclerosis. AB - We report a 14-week post-marketing experience on 20 patients with multiple sclerosis (MS) who started prolonged-release (PR) oral dalfampridine 10 mg twice daily according to European Medicine Agency criteria. They underwent serial static posturography assessments and the dizziness handicap inventory (DHI) to investigate whether PR dalfampridine could impact standing balance and self reported perception of balance. The incidence of accidental falls per person per month was also recorded throughout the study. Eight (40%) patients, who had a relevant improvement in walking speed, were defined as treatment responders. They showed a significant improvement of standing balance (with respect to pretreatment assessment) when contrasted with 12 (60%) nonresponders (F [4,15] = 3.959, P = 0.027). No significant changes in DHI score, as well as in its functional, physical, and emotional subscales, were found in both responders and nonresponders at the end of study (all P values are >=0.2). Treatment response did not affect the incidence of accidental falls. Future studies based on larger sample sizes, and with longer followup, are required to confirm the beneficial effect of PR dalfampridine on standing balance. PMID- 24800079 TI - Induced abortion and associated factors in health facilities of Guraghe zone, southern Ethiopia. AB - Unsafe abortion is one of the major medical and public health problems in developing countries including Ethiopia. However, there is a lack of up-to-date and reliable information on induced abortion distribution and its determinant factors in the country. This study was intended to assess induced abortion and associated factors in health facilities of Guraghe zone, Southern Ethiopia. Institution based cross-sectional study was conducted in eight health facilities in Guraghe zone. Client exit interview was conducted on 400 patients using a structured questionnaire. Bivariate and multivariate logistic regression analysis was performed to identify factors associated with induced abortion. Out of 400 women, 75.5% responded that the current pregnancy that ended in abortion is unwanted. However, only 12.3% of the respondents have admitted interference to the current pregnancy. Having more than four pregnancies (AOR = 4.28, CI: (1.24 14.71)), age of 30-34 years (AOR = 0.15, CI: (0.04-0.55)), primary education (AOR = 0.26, CI: (0.13-0.88)), and wanted pregnancy (AOR = 0.44, CI: (0.14-0.65)) were found to have association with induced abortion. The study revealed high level of induced abortion which is underpinned by high magnitude of unwanted pregnancy. There is requirement for widespread expansion of increased access to high quality family planning service and post-abortion care. PMID- 24800080 TI - Which dermatological conditions present to an emergency department in australia? AB - Background/Objectives. There is minimal data available on the types of dermatological conditions which present to tertiary emergency departments (ED). We analysed demographic and clinical features of dermatological presentations to an Australian adult ED. Methods. The St. Vincent's Hospital Melbourne (SVHM) ED database was searched for dermatological presentations between 1 January 2009 and 31 December 2011 by keywords and ICD-10 diagnosis codes. The lists were merged, and the ICD-10 codes were grouped into 55 categories for analysis. Demographic and clinical data for these presentations were then analysed. Results. 123 345 people presented to SVHM ED during the 3-year period. 4817 (3.9%) presented for a primarily dermatological complaint. The most common conditions by ICD-10 diagnosis code were cellulitis (n = 1741, 36.1%), allergy with skin involvement (n = 939, 19.5%), boils/furuncles/pilonidal sinuses (n = 526, 11.1%), eczema/dermatitis (n = 274, 5.7%), and varicella zoster infection (n = 161, 3.3%). Conclusion. The burden of dermatological disease presenting to ED is small but not insignificant. This information may assist in designing dermatological curricula for hospital clinicians and specialty training organisations as well as informing the allocation of dermatological resources to ED. PMID- 24800081 TI - Effect of aerobic exercise training on chinese population with mild to moderate depression in Hong Kong. AB - Background. Exercise has been suggested to be a viable treatment for depression. This study investigates the effect of supervised aerobic exercise training on depressive symptoms and physical performance among Chinese patients with mild to moderate depression in early in-patient phase. Methods. A randomized repeated measure and assessor-blinded study design was used. Subjects in aerobic exercise group received 30 minutes of aerobic training, five days a week for 3 weeks. Depressive symptoms (MADRS and C-BDI) and domains in physical performance were assessed at baseline and program end. Results. Subjects in aerobic exercise group showed a more significant reduction in depressive scores (MADRS) as compared to control (between-group mean difference = 10.08 +/- 9.41; P = 0.026) after 3 weeks training. The exercise group also demonstrated a significant improvement in flexibility (between-group mean difference = 4.4 +/- 6.13; P = 0.02). Limitations. There was lack of longitudinal followup to examine the long-term effect of aerobic exercise on patients with depression. Conclusions. Aerobic exercise in addition to pharmacological intervention can have a synergistic effect in reducing depressive symptoms and increasing flexibility among Chinese population with mild to moderate depression. Early introduction of exercise training in in-patient phase can help to bridge the gap of therapeutic latency of antidepressants during its nonresponse period. PMID- 24800082 TI - Angiogenesis and proliferation index in patients with acute leukemia: a prospective study. AB - Angiogenesis and proliferation as measured by microvessel density (MVD) and proliferation index (PI) are essential correlates of malignancy. The aim of our study was to evaluate difference between these values in AML and ALL and also to study the modulation in these parameters following achievement of remission in acute lymphoblastic leukemia. Differences between adult and adolescent cases of acute leukemia in relation to these values were also studied. We also tried to assess the relationship between angiogenesis and proliferation. Fifty-five patients with acute leukemia were included in the study. Trephine biopsies were immunostained with CD34 and factor VIIIrAg to demonstrate angiogenesis measured as MVD. Immunostaining with PCNA and Ki-67 was done to study proliferation. We found a significant increase in MVD and PI in cases when compared with controls (P < 0.0001). In addition cases with ALL had a significantly higher MVD compared to those with AML (P < 0.01). The patients with ALL who went into remission showed a significant reduction in MVD; PI remained high. The cases which did not achieve remission showed no significant reduction in either MVD or PI. All adolescent cases of ALL were similar to adults with respect to MVD and PI. PMID- 24800083 TI - Prevalence of Dyslipidemia and Management in the Thai Population, National Health Examination Survey IV, 2009. AB - This study determined the prevalence and management of dyslipidemia in Thai adults using data from the Thai National Health Examination Survey IV in 2009. Dyslipidemia was defined based on the Third Adult Treatment Panel guidelines. A total of 19,021 adults aged 20 yr and over were included. Mean (SE) levels of total cholesterol, HDL-C, LDL-C, and triglycerides were 206.4 (1.03), 46.9 (0.34), 128.7 (1.09), and 131.4 (2.20) mg/dL, respectively. Prevalence of high LDL-C, low HDL-C, and high triglycerides were 29.6 %, 47.1 %, and 38.6%, respectively. Compared with individuals in the north and northeast, residents in Bangkok and Central region had significant higher levels of LDL-C but lower level of HDL-C. Triglyceride level was the highest in the northeast residents. Overall, 66.5% of Thais had some forms of dyslipidemia. Awareness and treatment of high LDL-C among those with high LDL-C were 17.8% and 11.7%, respectively. Among individuals aware of high LDL-C, those at highest CHD risk compared with those at low risk had higher percentage of treatment (73.1% versus 51.7%, resp.) but lower percentage of control at goal (32.9% versus 76.4%, resp.). Various forms of dyslipidemia are common in Thai adults, with a low level of awareness and treatment of high LDL-C. PMID- 24800084 TI - Comparison of low-dose rosuvastatin with atorvastatin in lipid-lowering efficacy and safety in a high-risk pakistani cohort: an open-label randomized trial. AB - Background. Treatment of hyperlipidemia is helpful in both primary and secondary prevention of coronary heart disease and stroke. Aim. To compare lipid-lowering efficacy of rosuvastatin with atorvastatin. Methodology. This open-label randomized controlled trial was carried out at 1 Mountain Medical Battalion from September 2012 to August 2013 on patients with type 2 diabetes, hypertension, myocardial infarction, or stroke, meriting treatment with a statin. Those with secondary causes of dyslipidemia were excluded. Blood samples for estimation of serum total cholesterol, triglycerides, HDL-C, and LDL-C were collected after a 12-hour fast. Patients were randomly allocated to receive either atorvastatin 10 mg HS or rosuvastatin 5 mg HS daily. Lipid levels were rechecked after six weeks. Results. Atorvastatin was used in 63 patients and rosuvastatin in 66. There was a greater absolute and percent reduction in serum LDL-C levels with rosuvastatin as compared to atorvastatin (0.96 versus 0.54 mg/dL; P = 0.011 and 24.34 versus 13.66%; P = 0.045), whereas reduction in all other fractions was equal. Myalgias were seen in 5 (7.94%) patients treated with atorvastatin and 8 (12.12%) patients treated with rosuvastatin (P: 0.432). Conclusion. Rosuvastatin produces a greater reduction in serum LDL-C levels and should therefore be preferred over atorvastatin. PMID- 24800085 TI - The Complex Interaction of Matrix Metalloproteinases in the Migration of Cancer Cells through Breast Tissue Stroma. AB - Breast cancer mortality is directly linked to metastatic spread. The metastatic cell must exhibit a complex phenotype that includes the capacity to escape from the primary tumour mass, invade the surrounding normal tissue, and penetrate into the circulation before proliferating in the parenchyma of distant organs to produce a metastasis. In the normal breast, cellular structures change cyclically in response to ovarian hormones leading to regulated cell proliferation and apoptosis. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases. Their primary function is degradation of proteins in the extracellular matrix to allow ductal progression through the basement membrane. A complex balance between matrix metalloproteinases and their inhibitors regulate these changes. These proteinases interact with cytokines, growth factors, and tumour necrosis factors to stimulate branching morphologies in normal breast tissues. In breast cancer this process is disrupted facilitating tumour progression and metastasis and inhibiting apoptosis increasing the life of the metastatic cells. This paper highlights the role of matrix metalloproteinases in cell progression through the breast stroma and reviews the complex relationships between the different proteinases and their inhibitors in relation to breast cancer cells as they metastasise. PMID- 24800086 TI - Manual characterization of sleep spindle index in patients with narcolepsy and idiopathic hypersomnia. AB - This is a retrospective review of PSG data from 8 narcolepsy patients and 8 idiopathic hypersomnia (IH) patients, evaluating electrophysiologic differences between these two central hypersomnias. Spindles were identified according to the AASM Manual for the Scoring of Sleep and Associated Events; and counted per epoch in the first 50 epochs of N2 sleep and the last 50 epochs of N2 sleep in each patient's PSG. Spindle count data (mean +/- standard deviation) per 30 second epoch (spindle index) in the 8 narcolepsy patients was as follows: 0.37 +/- 0.73 for the first 50 epochs of N2; 0.65 +/- 1.09 for the last 50 epochs of N2; and 0.51 +/- 0.93 for all 100 epochs of N2. Spindle index data in the 8 IH patients was as follows: 2.31 +/- 2.23 for the first 50 epochs of N2; 2.84 +/- 2.43 for the last 50 epochs of N2; and 2.57 +/- 2.35 for all 100 epochs of N2. Intergroup differences in spindle count in the first 50 N2 epochs, the last 50 N2 epochs, and all 100 epochs of scored N2 were significant (P < 0.01) as were the intragroup differences between the first 50 N2 epochs and the last 50 N2 epochs. PMID- 24800088 TI - A Rare, Recurrent, De Novo 14q32.2q32.31 Microdeletion of 1.1 Mb in a 20-Year-Old Female Patient with a Maternal UPD(14)-Like Phenotype and Intellectual Disability. AB - We present a 20-year-old female patient from Indonesia with intellectual disability (ID), proportionate short stature, motor delay, feeding problems, microcephaly, facial dysmorphism, and precocious puberty who was previously screened normal for conventional karyotyping, fragile X testing, and subtelomeric MLPA analysis. Subsequent genome wide array analysis was performed on DNA from blood and revealed a 1.1 Mb deletion in 14q32.2q32.31 (chr14:100,388,343 101,506,214; hg19). Subsequent carrier testing in the parents by array showed that the deletion had occurred de novo in the patient and that her paternal 14q32 allele was deleted. The deleted region encompasses the DLK1/GTL2 imprinted gene cluster which is consistent with the maternal UPD(14)-like phenotype of the patient. This rare, recurrent microdeletion was recently shown not to be mediated by low copy repeats, but by expanded TGG repeats, flanking the 14q32.2q32.21 deletion boundaries, a novel mechanism of recurrent genomic rearrangement. This is another example how the application of high resolution genome wide testing provides an accurate genetic diagnosis, thereby improving the care for patients and optimizing the counselling for family. PMID- 24800089 TI - Reactive nodular fibrous pseudotumor: case report and review of the literature. AB - We will describe a case of a patient diagnosed with a rare identity of a benign lesion, "reactive nodular fibrous pseudotumor" (RNFP). It is a tumor which preoperatively can present as a malignant tumor and is only reported in 19 cases. According to the very limited amount of information on this tumor in the literature it is mostly seen after trauma or intraperitoneal inflammation. Our case is the second one of RNFP associated with endometriosis, which is a frequently seen intraperitoneal inflammation process in women. Knowledge that these large pseudotumoral lesions can occur is important to direct the management of these patients. PMID- 24800090 TI - Shortened cervix in the subsequent pregnancy after embolization for postpartum cervical hemorrhage. AB - Introduction. Rupture of a branch of uterine artery during delivery often leads to a massive postpartum hemorrhage that can be successfully treated using uterine artery embolization. Case Report. A 33-year-old woman had a cesarean section at term followed by a secondary postpartum hemorrhage due to a ruptured cervicovaginal branch terminating in a large, partially thrombosed hematoma of the cervix. She was given selective uterine artery embolization, and she was discharged to home in stable condition on the third day after embolization. In the forthcoming pregnancy a shortened cervix was a risk of threatened premature delivery from 26 weeks of gestation onwards. Conclusion. Superselective unilateral embolization of a thrombosed hematoma in the cervix might prevent extensive iatrogenic trauma of the cervix, which allows preservation of reproductive function. PMID- 24800091 TI - Robotic-assisted dissection of bulky lymph nodes in cervical cancer. AB - The resection of bulky lymph node metastases, which may provide a therapeutic benefit, has been proposed in several studies based on laparotomy and laparoscopy. There is no published study in the literature examining the resection of bulky lymph node metastases using a robotic technique. In this report, we presented a patient with cervical cancer who underwent robotic assisted dissection of bulky lymph nodes. The robotic-assisted operation time was 255 minutes, and the mean console time was 215 minutes. The estimated blood loss was 70 mL. The number of lymph nodes retrieved was 28, and the number of the dissected paraaortic lymph nodes was 13. The number of the lymph node metastases was eight. The bulky lymph nodes which are difficult to be eradicated with standard radiation therapy can be resected with robotic-assisted surgery and successful resection of the lymph nodes can improve the treatment strategy. This minimal invasive technique is safe and feasible for bulky lymph node dissection. PMID- 24800092 TI - Missed massive morel-lavallee lesion. AB - A Morel-Lavallee lesion (MLL) involves posttraumatic fluid collection around the greater trochanter. Many cases of MLL are missed at the initial evaluation, and the treatment of MLL is not well established. We present two cases in which MLL was missed at the initial evaluation. Case 1. A 65-year-old man was run over by a parade float. There was subcutaneous hematoma around the left greater trochanter, and no fracture was found. We diagnosed this injury as MLL on the 7th day after the trauma. Although we performed percutaneous drainage, the injured area was infected. Case 2. A 57-year-old man was hit by a train in a factory. There was an iliac wing fracture, but an MLL was not initially recognized. On the 6th day after the trauma, when performing open reduction and internal fixation for the iliac fracture, we recognized the lesion and performed percutaneous drainage simultaneously. This lesion also became infected. In these two cases, the wounds finally healed after a long duration of treatment. We suggest that it is important to keep this injury in mind and debride the lesion early and completely in the treatment course. PMID- 24800093 TI - Impending Carotid Blowout Stabilization Using an LT-D Tube. AB - Adequate stabilization of a patient presenting with a carotid blowout is one of the most challenging issues an on-call ENT surgeon can be confronted with. Reducing the bleeding and securing the airway are essential before more definitive management. We present the case of a 72-year-old patient with head and neck cancer who arrived at the emergency room with a carotid blowout and who was successfully stabilized using a King LT-D ventilation tube. PMID- 24800094 TI - Solitary mastocytoma of the vulva. AB - Solitary mastocytoma of the skin is a rare tumor. Its occurrence in the vulva is extremely rare with only few case reports in the literature. We report a solitary mastocytoma of the vulva in a 10-year-old girl. Her systemic examination was unremarkable. The clinical and histopathological features were consistent with the diagnosis of solitary mastocytoma of the vulva. The follow-up after surgical excision was uneventful. The purpose of this communication is (i) to report a case of solitary mastocytoma occurring in an unusual site, the vulva and to show that (ii) in this case age at presentation is 10 years with infancy as common age of presentation of solitary mastocytoma, and to show that (iii) in appropriate setting this should be included in the differential diagnosis of vulval swelling. PMID- 24800095 TI - Familial mediterranean Fever: diagnosing as early as 3 months of age. AB - Familial Mediterranean Fever is an autosomal recessive disease. Major symptoms of disease are recurrent fever accompanied by serositis attacks. The disease is usually diagnosed before 20 years of age. Symptoms related to FMF are noted when children become more verbal, usually after 2 years of age. In this case report, the youngest patient with the diagnosis of FMF is presented. She was consulted to pediatric rheumatology for the high acute phase response and fever. It was learned that her mother had recurrent swelling of her ankle joints. Mutation analysis was performed and two homozygous mutations (M694V and R202Q) were identified. She was diagnosed as FMF at 3 months of age and colchicine was started. She responded to colchicine. Her uncontrolled acute phase response declined gradually. This case was reported to point out the importance of early remembrance of autoinflammatory diseases even at very early ages especially at endemic countries. PMID- 24800096 TI - Late-Onset Bowel Strangulation due to Reduction En Masse of Inguinal Hernia. AB - Incarcerated inguinal hernia is often encountered by surgeons in daily practice. Although rare, hernial reduction en masse is a potential complication of manual reduction of an incarcerated hernia. Manual reduction was performed in a case of Zollinger classification type VII (combined type) hernia in which the indirect hernia portion included an incarcerated small intestine. This procedure caused hernial reduction en masse, but this went unnoticed, and the remaining portion of the direct hernia in the inguinal region was treated surgically by the anterior approach. Because the incarcerated small bowel that had been reduced en masse was not completely obstructed, the patient's general condition was not greatly affected, and he was able to resume eating. Twenty days after surgery, he developed sudden abdominal pain as a result of gastrointestinal perforation. When performing manual reduction of an incarcerated hernia in cases after self reduction over a long period, the clinician should always be aware of the possibility of reduction en masse. PMID- 24800097 TI - Outcomes after trifocal femoral fractures. AB - Trifocal femur fractures are those of the femoral neck, diaphysis, and distal femur. These high-energy injuries predominantly occur in young people with the potential for long-term complications and disability. We present the cases of two men who were treated with proximal dynamic hip screws and distal periarticular locking plates to effectively manage trifocal femur fractures. Our cases have shown union at 2 years with good functional outcomes without the need for reintervention. We provide evidence for a successful surgical treatment option for these rare and complex injuries. PMID- 24800098 TI - Differential Role of Rapamycin and Torin/KU63794 in Inflammatory Response of 264.7 RAW Macrophages Stimulated by CA-MRSA. AB - Background. Rapamycin suppresses the RAW264.7 macrophage mediated inflammatory response but in lower doses induces it. In the present study, we tested the suppression of the inflammatory response in the presence of mTOR 1 and 2 inhibitors, Torin and KU63794. Methods. RAW264.7 cells were stimulated for 18 hrs with 10(6) to 10(7) CFU/mL inocula of community-acquired- (CA-) MRSA isolate, USA400 strain MW2, in the presence of Vancomycin. Then, in sequential experiments, we added Torin, KU63794, and Rapamycin alone and in various combinations. Supernatants were collected and assayed for TNF, IL-1, IL-6, INF, and NO. Results. Rapamycin induces 10-20% of the inflammatory cascade at dose of 0.1 ng/mL and suppresses it by 60% at dose of 10 ng/mL. The induction is abolished in the presence of Torin KU63794. Torin and KU63794 are consistently suppressing cytokine production 50-60%. Conclusions. There is a differential response between Rapamycin (mTOR-1 inhibitor) and Torin KU63794 (mTOR 1 and 2 inhibitors). Torin and KU63794 exhibit a dose related suppression. Rapamycin exhibits a significant induction-suppression biphasic response. Knowledge of such response may allow manipulation of the septic inflammatory cascade for clinical advantages. PMID- 24800099 TI - The combination therapy with zoledronic Acid and propranolol improves the trabecular microarchitecture and mechanical property in an rat model of postmenopausal osteoporosis. AB - We conducted the present study to investigate the therapeutic effects of propranolol (PRO), alone and in combination with the antiresorptive agent ZOL, in a rat model of postmenopausal osteoporosis. Female Wistar rats were OVX or sham operated at 3 months of age. Twelve weeks after surgery, rats were randomized into six groups: (1) sham + vehicle, (2) OVX + vehicle, (3) OVX + ZOL (100 MU g/kg, i.v. single dose), (4) OVX + ZOL (50 MU g/kg, i.v. single dose), (5) OVX + PRO (0.1 mg/kg, s.c. 5 days per week), and (6) OVX + ZOL (50 MU g/kg, i.v. single dose) + PRO (0.1 mg/kg, s.c. 5 days per week) for 12 weeks. At the end of treatment study, various bone parameters were evaluated. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid shaft, the combination treatment of ZOL and PRO was more effective than each drug administered as a monotherapy. Moreover, combination therapy using ZOL and PRO preserved the trabecular microarchitecture better than single-drug therapy using ZOL or PRO in OVX rats. These data suggest that combination therapy with ZOL plus PRO represents a potentially useful therapeutic option for patients with osteoporosis. PMID- 24800100 TI - Single Ascending Dose Safety and Pharmacokinetics of CDRI-97/78: First-in-Human Study of a Novel Antimalarial Drug. AB - Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T 1/2, MRT, and AUC0-infinity of the active metabolite 97/63 were 11.85 +/- 1.94 h, 13.77 +/- 2.05 h, and 878.74 +/- 133.15 ng.h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials. PMID- 24800101 TI - Minimal clinically important difference in Parkinson's disease as assessed in pivotal trials of pramipexole extended release. AB - Background. The minimal clinically important difference (MCID) is the smallest change in an outcome measure that is meaningful for patients. Objectives. To calculate the MCID for Unified Parkinson's Disease Rating Scale (UPDRS) scores in early Parkinson's disease (EPD) and for UPDRS scores and "OFF" time in advanced Parkinson's disease (APD). Methods. We analyzed data from two pivotal, double blind, parallel-group trials of pramipexole ER that included pramipexole immediate release (IR) as an active comparator. We calculated MCID as the mean change in subjects who received active treatment and rated themselves "a little better" on patient global impression of improvement (PGI-I) minus the mean change in subjects who received placebo and rated themselves unchanged. Results. MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were -1.8 and -2.0, for UPDRS III -6.2 and -6.1, and for UPDRS II + III -8.0 and -8.1. MCIDs in APD for UPDRS II were -1.8 and -2.3, for UPDRS III -5.2 and -6.5, and for UPDRS II + III 7.1 and -8.8. MCID for "OFF" time (pramipexole ER, pramipexole IR) was -1.0 and 1.3 hours. Conclusions. A range of MCIDs is emerging in the PD literature that provides the basis for power calculations and interpretation of clinical trials. PMID- 24800102 TI - Nonmotor symptoms in a malaysian Parkinson's disease population. AB - Background. The nonmotor symptoms are important determinants of health and quality of life in Parkinson's disease but are not well recognized and addressed in clinical practice. This study was conducted to determine the prevalence of nonmotor symptoms and their impact on quality of life in patients with Parkinson's disease. Methods. This was a cross-sectional study among patients with idiopathic Parkinson's disease. Exclusion criteria were a Mini Mental State Examination score of <21/30. Prevalence of nonmotor symptoms was determined using the NMSQuest. The severity of nonmotor symptoms and the quality of life were assessed using validated disease-specific questionnaires (PDQ-39 and NMSS). Results. A total of 113 patients consisting of 60 males and 53 females were recruited. The median duration of illness was 5.0 (2.0-8.0) years. The prevalence rate of nonmotor symptoms in our cohort was 97.3%. The most common reported nonmotor symptom in our cohort was gastrointestinal (76.1%). We found that the severity of the nonmotor symptoms was associated with poorer quality of life scores (r s : 0.727, P < 0.001). Conclusions. Nonmotor symptoms were highly prevalent in our patients with Parkinson's disease and adversely affected the quality of life of our patients. In contrast to western studies, the most common nonmotor symptom is gastrointestinal. The possibility of an Asian diet playing a role in this observation requires further study. PMID- 24800103 TI - Endovascular and Surgical Treatment of Unruptured MCA Aneurysms: Meta-Analysis and Review of the Literature. AB - Introduction. The best treatment for unruptured middle cerebral artery (MCA) aneurysms is unclear. We perform a meta-analysis of recent publications to evaluate the results of unruptured MCA aneurysms treated with surgical clipping and endovascular coiling. Methods. A PubMed search for articles published between January 2004 and November 2013 was performed. The R statistical software package was used to create a random effects model for each desired incidence rate. Cochran's Q test was used to evaluate possible heterogeneity among the rates observed in each study. Results. A total of 1891 unruptured MCA aneurysms, 1052 clipped and 839 coiled, were included for analysis. The complete occlusion rate at 6-9 months mean follow-up was 95.5% in the clipped group and 67.8% in the coiled group (P < 0.05). The periprocedural thromboembolism rate in the clipping group was 1.8% compared with 10.7% in the aneurysms treated by coiling (P < 0.05). The recanalization rate was 0% for clipping and 14.3% for coiling (P = 0.05). Modified Rankin scores of 0-2 were obtained in 98.9% of clipped patients compared to 95.5% of coiled (NS). Conclusions. This review weakly supports clipping as the preferred treatment of unruptured MCA aneurysms. Clinical outcomes did not differ significantly between the two groups. PMID- 24800104 TI - Factors Affecting the Ability of the Stroke Survivor to Drive Their Own Recovery outside of Therapy during Inpatient Stroke Rehabilitation. AB - Aim. To explore factors affecting the ability of the stroke survivor to drive their own recovery outside of therapy during inpatient rehabilitation. Method. One-on-one, in-depth interviews with stroke survivors (n = 7) and their main carer (n = 6), along with two focus groups with clinical staff (n = 20). Data was thematically analysed according to group. Results. Stroke survivors perceived "dealing with loss," whilst concurrently "building motivation and hope" for recovery affected their ability to drive their own recovery outside of therapy. In addition, they reported a "lack of opportunities" outside of therapy, with subsequent time described as "dead and wasted." Main carers perceived stroke survivors felt "out of control ... at everyone's mercy" and lacked knowledge of "what to do and why" outside of therapy. Clinical staff perceived the stroke survivor's ability to drive their own recovery was limited by the lack of "another place to go" and the "passive rehab culture and environment." Discussion. To enable the stroke survivor to drive their own recovery outside of therapy, there is a need to increase opportunities for practice and promote active engagement. Suggested strategies include building the stroke survivor's motivation and knowledge, creating an enriched environment, and developing daily routines to provide structure outside of therapy time. PMID- 24800105 TI - Gross and Morphometric Anatomy of the Male Reproductive System of Bats (Eidolon helvum). AB - The present study aimed at examining the gross and morphometry of the reproductive tract of the male bats (Eidolon helvum). Thirty male bats (adults n = 17 and juveniles n = 13) were captured using net, weighed, aged using relative ossification of the wing bone, and dissected for gross examination. Morphologically, the mean body weight and forearm length in both adults and juveniles were 235.31 +/- 6.30 g, 12.14 +/- 0.19 cm and 69.54 +/- 7.68 g, 7.77 +/ 0.29 cm, respectively. The testicles were completely descended in adults with the penis projected cranially. The epididymides were found at the median border of the testis and continues as vas deferens. No significant differences (P > 0.05) were observed between right and left testicular weights in both adults and juveniles and also in lengths of different parts of the reproductive segments in both age groups assessed, respectively. This work has documented the gross anatomy of the male reproductive tract in bats. Ultrastructure and histochemistry are recommended for further insight into the reproductive biology. PMID- 24800106 TI - Erratum to "Comparative Pharmacokinetics of Levofloxacin in Healthy and Renal Damaged Muscovy Ducks following Intravenous and Oral Administration". PMID- 24800107 TI - A Review of the Antiviral Susceptibility of Human and Avian Influenza Viruses over the Last Decade. AB - Antivirals play an important role in the prevention and treatment of influenza infections, particularly in high-risk or severely ill patients. Two classes of influenza antivirals have been available in many countries over the last decade (2004-2013), the adamantanes and the neuraminidase inhibitors (NAIs). During this period, widespread adamantane resistance has developed in circulating influenza viruses rendering these drugs useless, resulting in the reliance on the most widely available NAI, oseltamivir. However, the emergence of oseltamivir resistant seasonal A(H1N1) viruses in 2008 demonstrated that NAI-resistant viruses could also emerge and spread globally in a similar manner to that seen for adamantane-resistant viruses. Previously, it was believed that NAI-resistant viruses had compromised replication and/or transmission. Fortunately, in 2013, the majority of circulating human influenza viruses remain sensitive to all of the NAIs, but significant work by our laboratory and others is now underway to understand what enables NAI-resistant viruses to retain the capacity to replicate and transmit. In this review, we describe how the susceptibility of circulating human and avian influenza viruses has changed over the last ten years and describe some research studies that aim to understand how NAI-resistant human and avian influenza viruses may emerge in the future. PMID- 24800108 TI - Dichotomous effect of caffeine, curcumin, and naringenin on genomic DNA of normal and diabetic subjects. AB - Nutraceutical compounds show antioxidant and prooxidant properties under stress conditions like cancer, diabetes, and other diseases. The objective of this study is to find the dichotomic behavior of caffeine, curcumin, and naringenin on DNA of diabetic and normal subjects in the presence and absence of copper, hydrogen peroxide, and complex of copper-hydrogen peroxide. Hydrogen peroxide releases hydroxyl free radicals ((*)OH) on oxidation of Cu (I) to Cu (II) through Fenton type reaction to cause DNA damage. In the results, agarose gel electrophoretic pattern speculates the prooxidant effect of caffeine and antioxidant effect of curcumin on DNA in the presence of copper and hydrogen peroxide. UV-Vis spectral analysis shows hyperchromism on addition of DNA to caffeine, hypochromism with curcumin, and subtle changes with naringenin. The chosen nutraceuticals act as inducers and quenchers of oxidative free radicals arising from diabetes. PMID- 24800109 TI - Efficacy of 1.5% dish washing solution and 95% lemon water in substituting perilous xylene as a deparaffinizing agent for routine h and e staining procedure: a short study. AB - Aim. To assess the efficacy of dish washing solution and diluted lemon water in deparaffinizing sections during conventional hematoxylin and eosin staining technique. Objective. The objective is to utilize eco-friendly economical substitute for xylene. Materials and Methods. Using twenty paraffin embedded tissue blocks, three sections each were prepared. One section was stained with conventional H and E method (Group A) and the other two sections with xylene-free (XF) H and E (Groups B and C). Staining characteristics were compared with xylene and scoring was given. Total score of 3-5 was regarded as adequate for diagnosis and less than that inadequate for diagnosis. Statistical Analysis. Chi-square test, Kruskal Wallis ANOVA test, and Mann-Whitney U test were used. Results. Adequacy of nuclear staining, crispness, and staining for diagnosis were greater in both Groups A and C (100%) than Group B (95%). Adequacy of cytoplasmic staining was similar in all the three groups (100%). Group B showed comparatively superior uniform staining and less retention of wax. Conclusion. Dish washing solution or diluted lemon water can be replaced for xylene as deparaffinizing agent in hematoxylin and eosin procedure. PMID- 24800111 TI - Using measurement-based care with patient involvement to improve outcomes in depression. PMID- 24800110 TI - Pilot Study of Implementation of an Internet-Based Depression Prevention Intervention (CATCH-IT) for Adolescents in 12 US Primary Care Practices: Clinical and Management/Organizational Behavioral Perspectives. AB - OBJECTIVE: To explore the implementation of CATCH-IT (Competent Adulthood Transition with Cognitive-behavioral Humanistic and Interpersonal Training), an Internet-based depression intervention program in 12 primary care sites, occurring as part of a randomized clinical trial comparing 2 versions of the intervention (motivational interview + Internet program versus brief advice + Internet program) in 83 adolescents aged 14 to 21 years recruited from February 1, 2007, to November 31, 2007. METHOD: The CATCH-IT intervention model consists of primary care screening to assess risk, a primary care physician interview to encourage participation, and 14 online modules of Internet training to teach adolescents how to reduce behaviors that increase vulnerability to depressive disorders. Specifically, we evaluated this program from both a management/organizational behavioral perspective (provider attitudes and demonstrated competence) and a clinical outcomes perspective (depressed mood scores) using the RE-AIM model (Reach, Efficacy, Adoption, Implementation, and Maintenance of the intervention). RESULTS: While results varied by clinic, overall, clinics demonstrated satisfactory reach, efficacy, adoption, implementation, and maintenance of the CATCH-IT depression prevention program. Measures of program implementation and management predicted clinical outcomes at practices in exploratory analyses. CONCLUSION: Multidisciplinary approaches may be essential to evaluating the impact of complex interventions to prevent depression in community settings. Primary care physicians and nurses can use Internet-based programs to create a feasible and cost-effective model for the prevention of mental disorders in adolescents in primary care settings. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00152529 and NCT00145912. PMID- 24800113 TI - Dealing with the end of life. PMID- 24800112 TI - Helplessness in the helpers: etiology and management. PMID- 24800114 TI - Stimulant-induced psychosis: importance of patient education and compliance. PMID- 24800115 TI - A case of intentional asenapine overdose. PMID- 24800116 TI - A case of acute psychosis secondary to coricidin overdose. PMID- 24800117 TI - Stress-induced cardiomyopathy and possible link to cerebral executive function: a case report. PMID- 24800118 TI - Psychogenic non-epileptic seizures in a second-trimester pregnant woman with a previous child loss. PMID- 24800119 TI - Neurotoxicity with combined use of lithium and haloperidol decanoate. PMID- 24800120 TI - Vaptans are effective in treating hyponatremia in psychotic patients: but we need treatment guidelines. PMID- 24800121 TI - Dr bhardwaj and colleagues reply. PMID- 24800122 TI - "It's Like Being a Well-Loved Child": Reflections From a Collaborative Care Team. AB - OBJECTIVE: The present case study examines how a collaborative care model for the treatment of depression works with a low-income, uninsured adult population in a primary care setting. METHOD: The qualitative interviews were conducted in 2010 at a primary care clinic as part of an evaluation of the Integrated Behavioral Health program, a collaborative care model of identifying and treating mild-to moderate mental disorders in adults in a primary care setting. A single-case study design of an interdisciplinary team was used: the care manager, the primary care physician, the consulting psychiatrist, and the director of social services. Other units of analysis included clinical outcomes and reports that describe the patient demographics, services offered, staff, and other operational descriptions. RESULTS: Multiple themes were identified that shed light on how one primary care practice successfully operationalized a collaborative care model, including the tools they used in novel ways, the role of team members, and perceived barriers to sustainability. CONCLUSIONS: The insights captured by this case study allow physicians, mental health practitioners, and administrators a view into key elements of the model as they consider implementation of a collaborative care model in their own settings. It is important to understand how the model operates on a day-to-day basis, with careful consideration of the more subtle aspects of the program such as team functioning and adapting tools to new processes of care to meet the needs of patients in unique contexts. Attention to barriers that still exist, especially regarding workforce and workload, will continue to be critical to organizations attempting integration. PMID- 24800123 TI - Effects of milnacipran on neurocognition, pain, and fatigue in fibromyalgia: a 13 week, randomized, placebo-controlled, crossover trial. AB - OBJECTIVE: To investigate whether milnacipran is safe and effective in improving cognitive function in patients with fibromyalgia. METHOD: Patients were randomly assigned to receive milnacipran or placebo for 6 weeks, followed by a 1-week washout and then crossover to the other arm for another 6 weeks. The overall trial lasted 13 weeks and was conducted between July 2011 and May 2013. Assessments were performed at each visit. Neurocognition was measured by the Brief Assessment of Cognition (BAC) and MATRICS. Pain was assessed by the visual analog scale (VAS) for pain. Global assessment of fibromyalgia symptoms was measured by the Fibromyalgia Impact Questionnaire (FIQ) and tender point examination. Depression was assessed by the Beck Depression Inventory (BDI). Fatigue was assessed by the Fatigue Severity Scale. Functional outcome was evaluated by the Health Assessment Questionnaire. The Clinical Global Impressions Severity of Illness (CGI-S) and Improvement (CGI-I) scales and the Patients Clinical Global Impression of Change were used to measure the global impression of severity and improvement. RESULTS: 26 subjects were screened, and 20 subjects completed the trial. The change in verbal memory (P = .001) and the composite T score (P = .044) of the BAC and the change in the attention-vigilance domain T score (P = .042) were significantly improved, but there were no differences between the drug and placebo groups. The changes in the CGI-S scores were not significant, but the changes in the Clinical Impression-Improvement (CGI-I) scores showed worsening in the placebo group at week 1 (P = .032), week 2 (P = .024), week 4 (P = .024), and week 6 (P = .60) compared to baseline. The change in FIQ scores was not significant. CONCLUSIONS: Milnacipran may have a potential role in the improvement of pain, disability, and mood. The effect of milnacipran on cognition in fibromyalgia needs further research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01829243. PMID- 24800124 TI - Evaluation of trazodone and quetiapine for insomnia: an observational study in psychiatric inpatients. AB - BACKGROUND: Insomnia is symptomatic of most psychiatric disorders. Non-habit forming agents such as trazodone and quetiapine are commonly used off-label to treat patients with insomnia. The safety and efficacy of trazodone and quetiapine as medications for treatment of insomnia have never been directly contrasted. The objective of this study was to compare the effectiveness of trazodone to quetiapine among inpatient psychiatric patients by measuring the traditional sleep parameters of total sleep time, number of nighttime awakenings, sleep efficiency, sleep latency, length of hospitalization, and patient-reported side effects. METHOD: Participants were recruited from St Helena Hospital Center for Behavioral Health, Vallejo, California. Patient inclusion criteria were age 18 to 65 years, admitted between September 2011 and February 2012, and a physician order for trazodone or quetiapine for insomnia. Exclusion criteria included primary insomnia, pregnancy, concomitant order of trazodone and quetiapine, receiving trazodone or quetiapine up to 2 weeks prior to the study, and inability to coherently communicate. Subjective patient interviews and objective nursing sleep log reviews composed the data set. RESULTS: On average, mean total sleep time hours were longer among patients receiving trazodone versus those receiving quetiapine according to patients' subjective reports (7.80 vs 6.75, respectively, P < .01) and the nursing sleep logs (9.13 vs 8.68, respectively, P = .04). Patients receiving trazodone experienced fewer mean nighttime awakenings versus those receiving quetiapine (0.52 vs 0.75, respectively, P = .04) according to the nursing sleep log report. Patients receiving trazodone reported more side effects of constipation, nausea, and diarrhea than patients receiving quetiapine. CONCLUSIONS: With respect to total sleep time and nighttime awakenings, trazodone was a more effective alternative than quetiapine. However, patients receiving trazodone experienced more gastrointestinal patient-reported side effects. PMID- 24800125 TI - Are antidepressants effective in the treatment of postpartum depression? A systematic review. AB - OBJECTIVE: In spite of the paucity of randomized controlled trials of antidepressants in postpartum depression, these drugs are the most commonly used agents in the pharmacologic treatment of postpartum depression. This article reviews the literature on the efficacy of antidepressants in randomized controlled trials of postpartum depression. DATA SOURCES: Four electronic databases, MEDLINE/PubMed (1966-2013), PsycINFO (1806-2013), EMBASE (1980-2013), and the Cochrane Database of Systematic Reviews, were searched using a combination of the keywords antidepressive agents/therapeutic use, antidepressant drugs, antidepressant agent/drug therapy, depression, postpartum/drug therapy, postpartum depression, and puerperal depression/drug therapy. STUDY SELECTION: The reference lists of articles identified were also searched. All relevant articles published in English were included. A total of 124 articles were identified. The efficacy of antidepressants has been studied in 6 randomized controlled trials, of which 3 were placebo-controlled studies. RESULTS: Placebo controlled randomized data do not support the notion that antidepressants are efficacious in postpartum depression. However, the methodological flaws of studies have to be kept in mind while interpreting the results of these studies. CONCLUSIONS: Due to the paucity of controlled data and methodological limitations of studies, the question about the efficacy of antidepressants in postpartum depression cannot be answered unequivocally. PMID- 24800126 TI - Multiple invasive procedures in a patient with borderline personality: a relationship? PMID- 24800127 TI - The relation between body mass index and substance use: a true can of worms. PMID- 24800128 TI - The Sunshine Act and Transfers of Value: Impact on Non-industry Authorship. AB - The United States Physician Payments Sunshine Act requires pharmaceutical and device manufacturers that participate in United States federal healthcare programs to report certain payments and items of value given to physicians and teaching hospitals. One of these "transfers of value" is the cost of expediting the preparation and publication of industry-sponsored journal articles with the use of outside editorial assistance. This can be problematic for those United Statesbased physician-authors whose home institutions have implemented policies to distance their faculty from pharmaceutical and device manufacturers. Potential strategies include using in-house editorial assistance when available, but transfers of value remain subject to further interpretation, and company policies are not uniform industrywide. PMID- 24800129 TI - The impact of spirituality before and after treatment of major depressive disorder. AB - OBJECTIVE: The authors sought to assess spirituality in depressed patients and evaluate whether the degree of initial depressive symptoms and response to pharmacotherapy treatment has a correlation with degree of spirituality and belief in God. METHODS: Our participants included 84 patients who presented to a depression/anxiety clinic for naturalistic treatment of their depressive illness over the course of two years. All patients met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for major depression, as confirmed by structured interviews using the Structured Clinical Interview for DSM-IV, and were treated with selective serotonin reuptake inhibitors for eight weeks. MEASUREMENTS: Patients were evaluated at baseline and after treatment using the Montgomery Asberg Depression Rating Scale, the Beck Hopelessness Scale, the Dysfunctional Attitude Scale, and the Spiritual Orientation to Life scale. RESULTS: At baseline, patients reporting greater spirituality had significantly lower measures of hopelessness, dysfunctional attitudes, and depressive symptoms. Those who believed in God had a greater mean change score than those who did not on the Montgomery Asberg Depression Rating Scale, the Beck Hopelessness Scale, and the Dysfunctional Attitude Scale, with the Montgomery Asberg Depression Rating Scale showing the greatest mean change score. Significant correlations were detected between the Spiritual Orientation to Life scale score and the Montgomery Asberg Depression Rating Scale, the Beck Hopelessness Scale, and the Dysfunctional Attitude Scale pre-scores, post-scores, and change scores. CONCLUSION: The findings suggest that greater spirituality is associated with less severe depression. Moreover, the degree to which the measures of depressive symptom severity, hopelessness, and cognitive distortions improved over the course of eight weeks was significantly greater for those patients who were more spiritual. PMID- 24800130 TI - Identification and treatment of antidepressant tachyphylaxis. AB - Antidepressant tachyphylaxis describes a condition in which a depressed patient loses a previously effective antidepressant treatment response despite staying on the same drug and dosage for maintenance treatment. It has been suggested that antidepressant tachyphylaxis is a form of relapse related to evolving drug tolerance, but it is also clear that there are other possible reasons for the loss of treatment response unrelated to tolerance, such as medication nonadherence. It has been reported that depressed patients with "true" antidepressant tachyphylaxis may be less responsive to new treatment interventions. Therefore, it is important to identify these patients as part of a comprehensive treatment planning process. PMID- 24800131 TI - Couples Therapy: Treating Selected Personality-disordered Couples Within a Dynamic Therapy Framework. AB - Personality disordered couples present unique challenges for couples therapy. Novice therapists may feel daunted when taking on such a case, especially given the limited literature available to guide them in this specific area of therapy. Much of what is written on couples therapy is embedded in the larger body of literature on family therapy. While family therapy techniques may apply to couples therapy, this jump requires a level of understanding the novice therapist may not yet have. Additionally, the treatment focus within the body of literature on couples therapy tends to be situation-based (how to treat couples dealing with divorce, an affair, illness), neglecting how to treat couples whose dysfunction is not the product of a crisis, but rather a longstanding pattern escalated to the level of crisis. This is exactly the issue in therapy with personality disordered couples, and it is an important topic, as couples with personality pathology often do present for treatment. This article strives to present practical techniques, modeled in case vignettes, that can be applied directly to couples therapy- specifically therapy with personality disordered couples. PMID- 24800132 TI - Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. AB - The serotonin norepinephrine reuptake inhibitors are a family of antidepressants that inhibit the reuptake of both serotonin and norepinephrine. While these drugs are traditionally considered a group of inter-related antidepressants based upon reuptake inhibition, they generally display different chemical structures as well as different pharmacological properties. In this article, we discuss these and other differences among the serotonin norepinephrine reuptake inhibitors, including the year of approval by the United States Food and Drug Administration, generic availability, approved clinical indications, half-lives, metabolism and excretion, presence or not of active metabolites, dosing schedules, proportionate effects on serotonin and norepinephrine, and the timing of serotonin and norepinephrine reuptake (i.e., sequential or simultaneous). Again, while serotonin norepinephrine reuptake inhibitors are grouped as a family of antidepressants, they exhibit a surprising number of differences- differences that may ultimately relate to clinical nuances in patient care. PMID- 24800133 TI - Consent to treatment of minors. PMID- 24800134 TI - Emergency department utilization in the Texas Medicaid emergency waiver following Hurricane Katrina. AB - OBJECTIVE: To estimate the enrollment and emergency department (ED) utilization in TexKat, the Texas Medicaid emergency waiver implemented following Hurricane Katrina. DATA SOURCES: Individual-level enrollment and utilization data from the 2005 Medicaid Analytic Extract. STUDY DESIGN: Descriptive analysis is performed on variables that describe enrollment levels, the demographic characteristics of enrollees, and the most common diagnoses in ED visits. A Poisson regression model is also employed to quantify the factors related to an enrollee's probability of having an ED visit and the average number of ED visits. PRINCIPAL FINDINGS: There were 44,246 individuals enrolled in TexKat in 2005. Roughly 13% of these enrollees had at least one ED visit during the sample period, with one quarter of these individuals having more than one visit. Across all enrollees the most common diagnosis was "other upper respiratory infection," but there were significant differences in diagnosis patterns across racial/ethnic groups. The regression analysis suggests little difference in ED utilization across genders, but significant contrasts across racial/ethnic and age groups. CONCLUSIONS: As very little is known about Medicaid emergency waivers, our analysis may provide important information to policymakers who have to react quickly following a disaster. Our findings may help providers estimate potential increases in ED utilization and prepare for relatively common diagnoses. Furthermore, the analysis across racial/ethnic groups may help government officials identify important areas for outreach among vulnerable populations. PMID- 24800136 TI - Effect of cost-sharing reductions on preventive service use among Medicare fee for-service beneficiaries. AB - BACKGROUND: Section 4104 of the Patient Protection and Affordable Care Act (ACA) waives previous cost-sharing requirements for many Medicare-covered preventive services. In 1997, Congress passed similar legislation waiving the deductible only for mammograms and Pap smears. The purpose of this study is to examine the effect of the deductible waiver on mammogram and Pap smear utilization rates. METHODS: Using 1995-2003 Medicare claims from a sample of female, elderly Medicare fee-for-service beneficiaries, two pre/post analyses were conducted comparing mammogram and Pap smear utilization rates before and after implementation of the deductible waiver. Receipt of screening mammograms and Pap smears served as the outcome measures, and two time measures, representing two post-test observation periods, were used to examine the short- and long-term impacts on utilization. RESULTS: There was a 20 percent short-term and a 25 percent longer term increase in the probability of having had a mammogram in the four years following the 1997 deductible waiver. Beneficiaries were no more likely to receive a Pap smear following the deductible waiver. CONCLUSIONS: Elimination of cost sharing may be an effective strategy for increasing preventive service use, but the impact could depend on the characteristics of the procedure, its cost, and the disease and populations it targets. These historical findings suggest that, with implementation of Section 4104, the greatest increases in utilization will be seen for preventive services that screen for diseases with high incidence or prevalence rates that increase with age, that are expensive, and that are performed on a frequent basis. PMID- 24800135 TI - Methodological issues in using multiple years of the Medicare current beneficiary survey. AB - BACKGROUND: The analysis presented in this paper examines the multi-year capacity of the Medicare Current Beneficiary Survey (MCBS). METHODS: We systematically reviewed the literature for methodological approaches in research using multiple years of the MCBS and categorized the studies by study design, use of survey sampling weights, and variance adjustments. We then replicated the approaches in an empirical demonstration using functional status (activities of daily living (ADL) and 2005-2007 MCBS data. RESULTS: In the systematic review, we identified 22 pooled, 17 repeated cross-sectional, and 17 longitudinal studies. Less than half of these studies explicitly described the weighting approach or variance estimation. In the empirical demonstration, we showed that different study designs and weighting approaches will yield statistically different estimates. CONCLUSION: There is a variety of methodological approaches when using multiple years of the MCBS, and some of them provide biased results. Research needs to improve in describing the methods and preferred approaches for using these complex data. PMID- 24800137 TI - Medicare managed care plan performance: a comparison across hospitalization types. AB - OBJECTIVE: The study evaluates the performance of Medicare managed care (Medicare Advantage [MA]) Plans in comparison to Medicare fee-for-service (FFS) Plans in three states with historically high Medicare managed care penetration (New York, California, Florida), in terms of lowering the risks of preventable or ambulatory care sensitive conditions (ACSC) hospital admissions and providing increased referrals for admissions for specialty procedures. STUDY DESIGN/METHODS: Using 2004 hospital discharge files from the Healthcare Cost and Utilization Project (HCUP-SID) of the Agency for Healthcare Research and Quality, ACSC admissions are compared with 'marker' admissions and 'referral-sensitive' admissions, using a multinomial logistic regression approach. The year 2004 represents a strategic time to test the impact of MA on preventable hospitalizations, because the HMOs dominated the market composition in that time period. FINDINGS: MA enrollees in California experienced 22% lower relative risk (RRR= 0.78, p<0.01), those in Florida experienced 16% lower relative risk (RRR= 0.84, p<0.01), while those in New York experienced 9% lower relative risk (RRR=0.91, p<0.01) of preventable (versus marker) admissions compared to their FFS counterparts. MA enrollees in New York experienced 37% higher relative risk (RRR=1.37, p<0.01) and those in Florida had 41% higher relative risk (RRR=1.41, p<0.01)-while MA enrollees in California had 13% lower relative risk (RRR=0.87, p<0.01)-of referral-sensitive (versus marker) admissions compared to their FFS counterparts. CONCLUSION: While MA plans were associated with reductions in preventable hospitalizations in all three states, the effects on referral-sensitive admissions varied, with California experiencing lower relative risk of referral-sensitive admissions for MA plan enrollees. The lower relative risk of preventable admissions for MA plan enrollees in New York and Florida became more pronounced after accounting for selection bias. PMID- 24800138 TI - Assessing measurement error in Medicare coverage from the National Health Interview Survey. AB - OBJECTIVES: Using linked administrative data, to validate Medicare coverage estimates among adults aged 65 or older from the National Health Interview Survey (NHIS), and to assess the impact of a recently added Medicare probe question on the validity of these estimates. DATA SOURCES: Linked 2005 NHIS and Master Beneficiary Record and Payment History Update System files from the Social Security Administration (SSA). STUDY DESIGN: We compared Medicare coverage reported on NHIS with "benchmark" benefit records from SSA. PRINCIPAL FINDINGS: With the addition of the probe question, more reports of coverage were captured, and the agreement between the NHIS-reported coverage and SSA records increased from 88% to 95%. Few additional overreports were observed. CONCLUSIONS: Increased accuracy of the Medicare coverage status of NHIS participants was achieved with the Medicare probe question. Though some misclassification remains, data users interested in Medicare coverage as an outcome or correlate can use this survey measure with confidence. PMID- 24800139 TI - Cancer outcomes in low-income elders: is there an advantage to being on Medicaid? AB - BACKGROUND: Because of reduced financial barriers, dual Medicare-Medicaid enrollment of low-income Medicare beneficiaries may be associated with receipt of definitive cancer treatment and favorable survival outcomes. METHODS: We used a database developed by linking records from the Ohio Cancer Incidence Surveillance System with Medicare and Medicaid files, death certificates, and U.S. Census data. The study population included community-dwelling Medicare fee-for-service beneficiaries, age 66 years or older, with low incomes, residing in Ohio, and diagnosed with incident loco-regional breast (n=838), colorectal (n=784), or prostate cancer (n=946) in years 1997-2001. We identified as "duals" Medicare beneficiaries who were enrolled in Medicaid at least three months prior to cancer diagnosis. Multivariable logistic regression and survival models were developed to analyze the association between dual status and (1) receipt of definitive treatment; and (2) overall and disease-specific survival, after adjusting for tumor stage and patient covariates. RESULTS: DUAL STATUS WAS ASSOCIATED WITH A SIGNIFICANTLY LOWER LIKELIHOOD TO RECEIVE DEFINITIVE TREATMENT AMONG COLORECTAL CANCER PATIENTS (ADJUSTED ODDS RATIO: 0.60, 95% Confidence Interval, or CI, [0.38, 0.95]), but not among breast or prostate cancer patients. Furthermore, dual status was associated with decreased overall survival among prostate cancer patients (Adjusted Hazard Ratio, or AHR, 1.45, 95% CI [1.05, 2.02]), and decreased disease-specific survival among colorectal cancer patients (AHR: 1.52 [1.05, 2.19]). CONCLUSION: Enrollment of low-income Medicare beneficiaries in Medicaid is not associated with favorable treatment patterns or survival outcomes. Differences in health and functional status between community-dwelling duals and non-duals might help explain the observed disparities. PMID- 24800140 TI - Wisconsin's experience with Medicaid auto-enrollment: lessons for other states. AB - The Patient Protection and Affordable Care Act (ACA) relies heavily on the expansion of Medicaid eligibility to cover uninsured populations. In February 2008, Wisconsin expanded and reformed its Medicaid/CHIP program and, as part of program implementation, automatically enrolled a set of newly eligible parents and children. This process of "auto-enrollment" targeted newly eligible parents and older children whose children/siblings were already enrolled in the state's Medicaid/CHIP program. Auto-enrollment brought over 44,000 individuals into the program, representing more than 60% of all enrollees in the first month of the reformed program. Individuals who were auto-enrolled were modestly more likely to leave the program relative to other individuals who enrolled in February 2008, unless their incomes were high enough to be required to pay premiums; these auto enrollees were much more likely to exit relative to other enrollees subject to premium payments. The higher exit rates exhibited by non-premium paying auto enrollees were likely due to the fact that over 40% of auto-enrollees were covered by a private insurance policy in the month of their enrollment, compared to approximately 30% for regular enrollees. A national simulation of an auto enrollment process similar to Wisconsin's, including the expansion of adult Medicaid eligibility to 133% of the federal poverty level under the ACA, suggests that 2.5 million of the 5.6 million newly eligible parents could be auto enrolled, and approximately 25% of this population would be privately insured. These results suggest that auto-enrollment may be appropriate for other states, especially in their efforts to enroll eligible populations who are not subject to premium requirements. PMID- 24800141 TI - Enhancing Medicare's hospital-acquired conditions policy to encompass readmissions. AB - BACKGROUND: The current Medicare policy of non-payment to hospitals for Hospital Acquired Conditions (HAC) seeks to avoid payment for preventable complications identified within a single admission. The financial impact ($1 million-$50 million/yr) underestimates the true financial impact of HACs when readmissions are taken into account. OBJECTIVE: Define and quantify acute inpatient readmissions arising directly from, or completing the definition of, the current HACs. RESEARCH DESIGN: Observational study. SUBJECTS: All non-federal inpatient admissions to California hospitals, July 2006 to June 2007 with a recorded Social Security number. MEASURES: Readmission to acute care within 1 day for acute complications of poor glycemic control; 7 days for iatrogenic air emboli, incompatible blood transfusions, catheter-associated urinary tract infections and vascular catheter-associated infections; 30 days for deep vein thromboses or pulmonary emboli following hip or knee replacement surgery; and 183 days for foreign objects retained after surgery, mediastinitis following coronary artery bypass grafts, injuries sustained during inpatient care, infections following specific joint or bariatric surgery procedures, and pressure ulcers stages III & IV. RESULTS: An additional estimated $103 million in payments would be withheld if Medicare expands the policy to include non-payment for HAC related readmissions. The majority (90%) of this impact involves mediastinitis, post orthopedic surgery infection, or fall related injury. CONCLUSIONS: Limiting the current HAC policy focus to complications identified during the index admission omits consideration of many complications only identified in a subsequent admission. Non-payment for HAC-related readmissions would enhance incentives for prevention by increasing the frequency with which hospitals are held accountable for HACs. PMID- 24800142 TI - Financial performance of health plans in Medicaid managed care. AB - OBJECTIVE: This study assesses the financial performance of health plans that enroll Medicaid members across the key plan traits, specifically Medicaid dominant, publicly traded, and provider-sponsored. DATA AND METHODS: National Association of Insurance Commissioners (NAIC) financial data, coupled with selected state financial data, were analyzed for 170 Medicaid health plans for 2009. A mean test compared the mean values for medical loss, administrative cost, and operating margin ratios across these plan traits. Medicaid dominant plans are plans with 75 percent of their total enrollment in the Medicaid line of business. FINDINGS: Plans that are Medicaid dominant and publicly traded incurred a lower medical loss ratio and higher administrative cost ratio than multi-product and non-publicly traded plans. Medicaid dominant plans also earned a higher operating profit margin. Plans offering commercial and Medicare products are operating at a loss for their Medicaid line of business. POLICY IMPLICATIONS: Health plans that do not specialize in Medicaid are losing money. Higher medical cost rather than administrative cost is the underlying reason for this financial loss. Since Medicaid enrollees do not account for their primary book of business, these plans may not have invested in the medical management programs to reduce inappropriate emergency room use and avoid costly hospitalization. PMID- 24800143 TI - The national market for Medicare clinical laboratory testing: implications for payment reform. AB - Current Medicare payment policy for outpatient laboratory services is outdated. Future reforms, such as competitive bidding, should consider the characteristics of the laboratory market. To inform payment policy, we analyzed the structure of the national market for Medicare Part B clinical laboratory testing, using a 5 percent sample of 2006 Medicare claims data. The independent laboratory market is dominated by two firms--Quest Diagnostics and Laboratory Corporation of America. The hospital outreach market is not as concentrated as the independent laboratory market. Two subgroups of Medicare beneficiaries, those with end-stage renal disease and those residing in nursing homes, are each served in separate laboratory markets. Despite the concentrated independent laboratory market structure, national competitive bidding for non-patient laboratory tests could result in cost savings for Medicare. PMID- 24800144 TI - Applying the 2003 Beers update to elderly Medicare enrollees in the Part D program. AB - BACKGROUND: Inappropriate prescribing of certain medications known as Beers drugs may be harmful to the elderly, because the potential risk for an adverse outcome outweighs the potential benefit. OBJECTIVES: (1) To assess Beers drug use in dual enrollees compared to non-duals; (2) to explore the association between dual enrollment status and Beers use, controlling for the effects of age, gender, race/ethnicity, census region, and health status; (3) to assess which medication therapeutic category had the highest Beers use. DESIGN: Cross sectional retrospective review of 2007 Centers for Medicare & Medicaid Service Part D data. Potentially inappropriate medication use was assessed, independent of diagnosis, using the 2003 update by Fick et al. FINDINGS: The likelihood of Beers drug use among duals approximates that of non-duals (OR 1.023, 95% CI 1.020-1.026). Characteristics associated with the receipt of a Beers medication include Hispanic origin, younger age, female gender, poor health status, and residence outside of the U.S.' Northeast region. Genitourinary products had the highest Beers use within medication therapeutic categories among both dual and non-dual enrollees (21.1% and 19.9%, respectively). CONCLUSIONS: Part D data can be successfully used to monitor Beers drug use. With adjustments for several important and easily measured demographic, health, and prescription drug use covariates, Beers drug use appears to be as common among non-dual enrollees as it is among dual enrollees in the Part D program. New Part D drug utilization policies that apply to all beneficiaries may need to be enacted to reduce Beers drug use. PMID- 24800145 TI - Evaluating comorbidity scores based on health service expenditures. AB - OBJECTIVE: To describe the performance of Charlson Comorbidity Index (CCI) specifications among Medicare beneficiaries and subgroups. DATA SOURCES: Medicare data for beneficiaries covered by Parts A and B and not Medicare Advantage throughout 2007. STUDY DESIGN: We evaluated several CCI specifications, particularly a model using expenditures related to Charlson categories, to predict 1 year mortality. DATA COLLECTION/EXTRACTION METHODS: Data were obtained from the Chronic Condition Data Warehouse. PRINCIPAL FINDINGS: The use of Charlson related expenditures did not result in improved mortality prediction. CCI models perform less well in population subgroups with higher underlying mortality risks based on age and chronic conditions. CONCLUSIONS: Relatively simple models provide quite adequate discrimination compared to more sophisticated models. Our proposed and more sophisticated model, which added in expenditure information, did not perform as well as much more easily executed methods. PMID- 24800147 TI - Linkages between utilization of prostate surgical pathology services and physician self-referral. AB - OBJECTIVE: Federal law prohibits a physician from referring Medicare patients for procedures or services to health care entities in which the physician has a financial relationship. This law has exceptions which enable physicians to self refer under certain conditions. This study evaluates the effects of self-referral on use rates of surgical pathology services performed in conjunction with prostate biopsies and whether such changes are linked to urologist self-referral arrangements. DATA AND SAMPLE: A targeted market area case study design was employed to identify the sample from Medicare claims data. The sample included male beneficiaries who resided in geographically dispersed counties; were continuously enrolled in Medicare fee-for-service (FFS) during 2005-2007; and who met the criteria to be a potential candidate to undergo a prostate biopsy. OUTCOMES: Prostate biopsy procedures per 1000 male Medicare beneficiaries in each county; counts of surgical pathology specimens (jars) associated with prostate biopsy procedures per 1000 male Medicare beneficiaries in each county. FINDINGS: Regression analysis shows the self-referral share (percentage) of total utilization was associated with significant increases in the use rate of prostate surgical pathology specimens (p<.01). The use rate of prostate surgical pathology specimens (jars) would be 41.5 units higher in a county where the self-referral share of total utilization was 50% compared to a county with no self-referral (share equals 0%). CONCLUSIONS: The findings show that urologist self-referral of prostate surgical pathology services results in increased utilization and higher Medicare spending. The results suggest that exceptions in federal and state self referral prohibitions need to be reevaluated. PMID- 24800146 TI - Volume of home- and community-based services and time to nursing-home placement. AB - OBJECTIVE: The purpose of this study was to determine whether the volume of Home- and Community-Based Services (HCBS) that target Activities of Daily Living disabilities, such as attendant care, homemaking services, and home-delivered meals, increases recipients' risk of transitioning from long-term care provided through HCBS to long-term care provided in a nursing home. DATA SOURCES: Data are from the Indiana Medicaid enrollment, claims, and Insite databases. Insite is the software system that was developed for collecting and reporting data for In-Home Service Programs. STUDY DESIGN: Enrollees in Indiana Medicaid's Aged and Disabled Waiver program were followed forward from time of enrollment to assess the association between the volume of attendant care, homemaking services, home delivered meals, and related covariates, and the risk for nursing-home placement. An extension of the Cox proportional hazard model was computed to determine the cumulative hazard of nursing-home placement in the presence of death as a competing risk. PRINCIPAL FINDINGS: Of the 1354 Medicaid HCBS recipients followed in this study, 17% did not receive any attendant care, homemaking services, or home-delivered meals. Among recipients who survived through 24 months after enrollment, one in five transitioned from HCBS to a nursing-home. Risk for nursing-home placement was significantly lower for each five-hour increment in personal care (HR=0.95, 95% CI=0.92-0.98) and homemaking services (HR=0.87, 95% CI=0.77-0.99). CONCLUSIONS: Future policies and practices that are focused on optimizing long-term care outcomes should consider that a greater volume of HCBS for an individual is associated with reduced risk of nursing-home placement. PMID- 24800148 TI - Service utilization of veterans dually eligible for VA and Medicare fee-for service: 1999-2004. AB - OBJECTIVE: To examine care system choices for Veterans dually-eligible for VA and Medicare FFS following changes in VA eligibility policy, which expanded availability of VA health care services. DATA SOURCES: VA and Medicare FFS enrollment and outpatient utilization databases in 1999 and 2004. STUDY DESIGN: Multinomial logistic regression was used to examine odds of VA-only and Medicare only utilization, relative to dual utilization, in 1999 and 2004. Observational cohort comprising a 5% random sample of dually-eligible Veterans: 73,721 in 1999 and 125,042 in 2004. PRINCIPAL FINDINGS: From 1999 to 2004, persons with the highest HCC risk scores had decreasing odds of exclusive VA reliance (OR=0.26 in 1999 and 0.17 in 2004, p<0.05), but had increasing odds of exclusive Medicare reliance (OR=0.43 in 1999 and 0.56 in 2004, p<0.05).Persons in high VA priority groups had decreasing odds of exclusive VA reliance, as well as decreasing odds of exclusive Medicare reliance, indicating increasing odds of dual use. Newly eligible Veterans with the highest HCC risk scores had higher odds of dual system use, while newly eligible Black Veterans had lower odds of dual system use. CONCLUSIONS: Veterans newly eligible for VA healthcare services, particularly those with the highest risk scores, had higher odds of dual system use compared to earlier eligibles. Providers should ensure coordination of care for Veterans who may be receiving care from multiple sources. Provisions of the Patient Protection and Affordable Care Act may help to ensure care coordination for persons receiving care from multiple systems. PMID- 24800149 TI - The effects of premium changes on ALL Kids, Alabama's CHIP program. AB - OBJECTIVE: Describe the trends in enrollment and renewal in the Alabama Children's Health Insurance Plan (CHIP), ALL Kids, since its creation in 1998, and to estimate the effect that an annual premium increase, along with coincident increases in service copays, had on the decision to renew participation. BACKGROUND: Unlike many other CHIP programs, ALL Kids is a standalone program that provides year long enrollment and contracts with the state's Blue Cross and Blue Shield program for its network of providers and its provider fee structure. In October 2003 premiums for individual coverage were increased by $50 per year and copays by $1 to $3 per visit. POPULATION STUDIED: This study is based upon a sample of 569,650 person-year observations of 230,255 children enrolled in the ALL Kids program between 1999 and 2009. STUDY DESIGN: The study models enrollment as a time series of cross section renewal decisions and specifies a series of linear probability regression models to estimate the effect of changes in the premium shift on the decision to renew. A second analysis includes interaction effects of the premiums shift with demographics, health status, income and previous enrollment to estimate differential response across subgroups. PRINCIPAL FINDINGS: The increases in premiums and copays are estimated to have reduced program renewals by 6.1 to 8.3 percent depending upon how much time one allows for families to renew. Families with a child who has a chronic condition were more likely to renew coverage. However, those with chronic conditions, African Americans and those with lower family incomes were more price-sensitive. CONCLUSIONS: An increase in annual premiums and visit copays had a modest impact on program reenrollment with effects comparable to those found in Florida, New Hampshire, Kansas and Arizona, but smaller than those in Kentucky and Georgia. PMID- 24800150 TI - Medication days' supply, adherence, wastage, and cost among chronic patients in Medicaid. AB - BACKGROUND: In an attempt to contain Medicaid pharmacy costs, nearly all states impose dispensing limits on medication days' supply. Although longer days' supply appears to increase the potential for medication wastage, previous studies suggest that it may also decrease pharmacy expenditures by reducing dispensing fees and drug ingredient costs. This study was conducted to determine whether 90 day refills at community pharmacies could improve adherence, minimize wastage, and control costs. METHODS: This retrospective observational study used California Medicaid claims, from the Walgreens pharmacy chain dated January 2010, to identify 52,898 patients prescribed statin, antihypertensive, selective serotonin reuptake inhibitor (SSRI), or oral hypoglycemic medications. Adherence was measured by medication possession ratio (MPR) and persistency with a 30-day gap. Medication wastage was defined as a switch of drug or drug strength within the same therapeutic class that occurred before the expected refill date. RESULTS: Adherence was 20% higher and persistency was 23% higher for the 90-day group than the 30-day group. This amounted to an average increase of 0.14 MPR and 44 days of continuous therapy. The two groups had comparable proportions of patients with wastage. After subtracting an average wastage cost of $7.34 per person per year (PPPY), all therapeutic classes had PPPY savings: statins ($7.70), antihypertensives ($10.80), SSRIs ($18.52), and oral hypoglycemics ($26.86). CONCLUSION: Across four drug categories and compared to 30-day refills, patients with 90-day refills had greater medication adherence, greater persistency, nominal wastage, and greater savings. PMID- 24800151 TI - CHIP reporting in the CPS. AB - OBJECTIVE: To assess the quality of the Current Population Survey's (CPS) Child Health Insurance Program (CHIP) data. DATA SOURCES: Linked 2000-2004 Medicaid Statistical Information System (MSIS) and the 2001-2004 CPS. DATA COLLECTION METHODS: Centers for Medicare & Medicaid Services provided the Census Bureau with its MSIS file. The Census Bureau linked the MSIS to the CPS data within its secure data analysis facilities. STUDY DESIGN: We compared responses to the CPS health insurance items with Medicaid and CHIP status according to the MSIS. PRINCIPAL FINDINGS: CHIP reporting in the CPS is unreliable. Only 10-30 percent of those with CHIP (but not Medicaid) report this type of coverage in the CPS. Many with CHIP report Medicaid coverage, so the reporting error for a Medicaid CHIP composite is smaller, but still substantial. CONCLUSIONS: The quality of the CPS CHIP information renders it effectively unusable for health policy analysis. Analysts should consider using a Medicaid-CHIP composite for CPS-based analyses. PMID- 24800152 TI - Linking Medicare, Medicaid, and cancer registry data to study the burden of cancers in West Virginia. AB - OBJECTIVE: Develop the WVCR-Linked dataset by combining the West Virginia Cancer Registry (WVCR) with Medicare, Medicaid, and other data sources. Determine health care utilization, costs, and overall burden of four major cancers among the elderly in a rural and medically underserved state population, and to compare them with national estimates. METHOD: We extracted personal identifiers from the West Virginia Cancer Registry (WVCR) data file for individuals >= 65 years of age with an incident diagnosis of any cancer between January 1, 2002 and December 31, 2007. We linked the extracted data with Medicare and Medicaid administrative data using deterministic record linkage procedures. We updated missing vital status information by linking the National Death Index (NDI) data file. The updated WVCR Linked dataset was enriched by links to the U.S. decennial census (2000) file and the Area Resource File. RESULTS: We identified 42,333 individuals, of which 41,574 (98.2%) and 6,031 (14.3%) individuals were matched with Medicare and Medicaid administrative data files, respectively. The NDI data added or updated vital status information for 3,295 (7.8%) individuals in the WVCR-Linked dataset. CONCLUSION: The WVCR-Linked dataset is a comprehensive dataset offering many opportunities to understand factors related to cancer treatment patterns, costs, and outcomes in a rural and medically underserved elderly Appalachian population. Following our example, non-participant states in the Surveillance, Epidemiology and End Results (SEER) program can build a powerful dataset to identify and target cancer disparities, and to improve cancer-related outcomes for their elderly and dual-eligible citizens. PMID- 24800153 TI - The role of data in health care disparities in Medicaid managed care. AB - BACKGROUND: The Affordable Care Act includes provisions to standardize the collection of data on health care quality that can be used to measure disparities. We conducted a qualitative study among leaders of Medicaid managed care plans, that currently have access to standardized quality data stratified by race and ethnicity, to learn how they use it to address disparities. METHODS: We conducted semi-structured interviews with 21 health plan leaders across 9 Medicaid managed care plans in California. We used purposive sampling to maximize heterogeneity in geography and plan type (e.g., non-profit, commercial). We performed a thematic analysis based on iterative coding by two investigators. RESULTS: We found 4 major themes. Improving overall quality was tightly linked to a focus on standardized metrics that are integral to meeting regulatory or financial incentives. However, reducing disparities was not driven by standardized data, but by a mix of factors. Data were frequently only examined by race and ethnicity when overall performance was low. Disparities were attributed to either individual choices or cultural and linguistic factors, with plans focusing interventions on recently immigrated groups. CONCLUSIONS: While plans' efforts to address overall quality were often informed by standardized data, actions to reduce disparities were not, at least partly because there were few regulatory or financial incentives driving meaningful use of data on disparities. Standardized data, as envisaged by the Affordable Care Act, could become more useful for addressing disparities if they are combined with policies and regulations that promote health care equity. PMID- 24800154 TI - Medicare beneficiary knowledge of the Part D program and its relationship with voluntary enrollment. AB - BACKGROUND: The 2003 Medicare Modernization Act established the Part D drug benefit in 2006. Because the benefit involves a voluntary enrollment process with numerous plan options, there has been concern about whether beneficiaries have adequate knowledge of the program, but research on this issue has been limited. OBJECTIVES: To examine Medicare beneficiary knowledge of the Part D program and estimate how knowledge affected voluntary enrollment decisions at the program's outset. METHODS: We linked data from the 2005 Medicare Current Beneficiary Survey with CMS administrative data regarding beneficiary 2006 drug coverage and market characteristics. We estimated a multivariate logistic regression model to explore the relationship between Part D knowledge and beneficiaries' voluntary enrollment in a Part D plan. RESULTS: At the inception of the Medicare Part D benefit, no single knowledge test question was correctly answered by more than three-fourths of beneficiaries. Correct responses to five knowledge test questions were positively associated with enrollment: "everyone has plan choices" (adjusted odds ratio = 1.4); "plans can change costs once per year" (aOR = 1.2); "beneficiaries must use plan pharmacies" (aOR = 1.5); "beneficiaries must pay a penalty if they enroll late" (aOR = 1.3); "assistance is available for low income beneficiaries" (aOR = 1.2). CONCLUSION: Beneficiary understanding of the Part D program in early 2006 was limited. Beneficiary knowledge of Part D program details was associated with enrollment in Medicare Part D. Efforts to educate Medicare beneficiaries about Part D may improve rates of prescription drug coverage. PMID- 24800155 TI - Statistical uncertainty in the Medicare shared savings program. AB - OBJECTIVE: Analyze statistical risks facing CMS and Accountable Care Organizations (ACOs) under the Medicare Shared Savings Program (MSSP). METHODS: We calculate the probability that shared savings formulas lead to inappropriate payment, payment denial, and/or financial penalties, assuming that ACOs generate real savings in Medicare spending ranging from 0-10%. We also calculate expected payments from CMS to ACOs under these scenarios. RESULTS: The probability of an incorrect outcome is heavily dependent on ACO enrollment size. For example, in the MSSP two-sided model, an ACO with 5,000 enrollees that keeps spending constant faces a 0.24 probability of being inappropriately rewarded for savings and a 0.26 probability of paying an undeserved penalty for increased spending. For an ACO with 50,000 enrollees, both of these probabilities of incorrect outcomes are equal to 0.02. The probability of inappropriate payment denial declines as real ACO savings increase. Still, for ACOs with 5,000 patients, the probability of denial is at least 0.15 even when true savings are 5-7%. Depending on ACO size and the real ACO savings rate, expected ACO payments vary from $115,000 to $35.3 million. DISCUSSION: Our analysis indicates there may be greater statistical uncertainty in the MSSP than previously recognized. CMS and ACOs will have to consider this uncertainty in their financial, administrative, and care management planning. We also suggest analytic strategies that can be used to refine ACO payment formulas in the longer term to ensure that the MSSP (and other ACO initiatives that will be influenced by it) work as efficiently as possible. PMID- 24800156 TI - Impact of continued biased disenrollment from the Medicare Advantage Program to fee-for-service. AB - BACKGROUND: Medicare managed care enrollees who disenroll to fee-for-service (FFS) historically have worse health and higher costs than continuing enrollees and beneficiaries remaining in FFS. OBJECTIVE: To examine disenrollment patterns by analyzing Medicare payments following disenrollment from Medicare Advantage (MA) to FFS in 2007. Recent growth in the MA program, introduction of limits on timing of enrollment/disenrollment, and initiation of prescription drug benefits may have substantially changed the dynamics of disenrollment. STUDY DESIGN: The study was based on MA enrollees who disenrolled to FFS in 2007 (N=248,779) and a sample of "FFS stayers" residing in the same counties as the disenrollees (N=551,616). Actual Medicare Part A and Part B payments (excluding hospice payments) in the six months following disenrollment were compared with predicted payments based on claims experience of local FFS stayers, adjusted for CMS Hierarchical Condition Category (CMS-HCC) risk scores. RESULTS: Disenrollees incurred $1,021 per month in Medicare payments, compared with $798 in predicted payments (ratio of actual/predicted=1.28, p < 0.001). Differences between actual and predicted payments were smaller for disenrollees of Preferred Provider Organizations and Private Fee-for-Service plans than of Health Maintenance Organizations. Analysis of 10 individual MA plans revealed variation in the degree of selective disenrollment. CONCLUSIONS: Despite substantial changes in policies and market characteristics of the Medicare managed care program, disenrollment to FFS continues to occur disproportionately among high-cost beneficiaries, raising concerns about care experiences among sicker enrollees and increased costs to Medicare. PMID- 24800157 TI - Reconciling medical expenditure estimates from the MEPS and NHEA, 2007. AB - OBJECTIVE: Provide a comparison of health care expenditure estimates for 2007 from the Medical Expenditure Panel Survey (MEPS) and the National Health Expenditure Accounts (NHEA). Reconciling these estimates serves two important purposes. First, it is an important quality assurance exercise for improving and ensuring the integrity of each source's estimates. Second, the reconciliation provides a consistent baseline of health expenditure data for policy simulations. Our results assist researchers to adjust MEPS to be consistent with the NHEA so that the projected costs as well as budgetary and tax implications of any policy change are consistent with national health spending estimates. DATA SOURCES: The Medical Expenditure Panel Survey produced by the Agency for Healthcare Research and Quality, and the National Health Center for Health Statistics and the National Health Expenditures produced by the Centers for Medicare & Medicaid Service's Office of the Actuary. RESULTS: In this study, we focus on the personal health care (PHC) sector, which includes the goods and services rendered to treat or prevent a specific disease or condition in an individual. The official 2007 NHEA estimate for PHC spending is $1,915 billion and the MEPS estimate is $1,126 billion. Adjusting the NHEA estimates for differences in underlying populations, covered services, and other measurement concepts reduces the NHEA estimate for 2007 to $1,366 billion. As a result, MEPS is $240 billion, or 17.6 percent, less than the adjusted NHEA total. PMID- 24800158 TI - Public reporting and market area exit decisions by home health agencies. AB - OBJECTIVE: To examine whether home health agencies selectively discontinue services to areas with socio-economically disadvantaged people after the introduction of Home Health Compare (HHC), a public reporting program initiated by Medicare in 2003. STUDY DESIGN /METHODS: We focused on agencies' initial responses to HHC and examined selective market-area exits by agencies between 2002 and 2004. We measured HHC effects by the percentage of quality indicators reported in public HHC data in 2003. Socio-economic status was measured by per capita income and percent college-educated at the market-area level. DATA SOURCES: 2002 and 2004 Outcome and Assessment Information Set (OASIS); 2000 US Census file; 2004 Area Resource File; and 2002 Provider of Service File. PRINCIPAL FINDINGS: WE FOUND A SMALL AND WEAK EFFECT OF PUBLIC REPORTING ON SELECTIVE EXITS: a 10-percent increase in reporting (reporting one more indicator) increased the probability of leaving an area with less-educated people by 0.3 percentage points, compared with leaving an area with high education. CONCLUSION: The small level of market-area exits under public reporting is unlikely to be practically meaningful, suggesting that HHC did not lead to a disruption in access to home health care through selective exits during the initial year of the program. PMID- 24800159 TI - The effects of Medicaid policy changes on adults' service use patterns in Kentucky and Idaho. AB - BACKGROUND: In 2006, Idaho and Kentucky became two of the first states to implement changes to their Medicaid programs under authority granted by the 2005 Deficit Reduction Act (DRA). The DRA granted new flexibility in the design of state Medicaid programs, including a state plan amendment (SPA) option for changes that previously would have required a waiver. This paper uses state Medicaid administrative data to analyze the impact of Medicaid policy changes implemented in these states through a series of SPAs in 2006 and 2007. METHODS: Changes in utilization are examined for multiple services, including physician, dental, and ER visits, inpatient stays, and prescriptions, among non-elderly adult Medicaid recipients following changes in cost sharing, reimbursement, service delivery, and covered services. Where possible, enrollees not affected by the changes served as a comparison group. RESULTS: While relatively few adults in Idaho received a wellness exam after such coverage was added, the adoption of managed care for dental services was associated with increased receipt of dental care, including preventive care. The new limits on brand name prescriptions in Kentucky were associated with a reduction in the proportion of enrollees with two or more monthly name brand prescriptions while the small copayments introduced did not appear to have a dramatic impact. CONCLUSIONS: We find that changes in financial incentives on both the supply-side (such as reimbursement increases) and the demand-side (i.e., benefit changes) alone may not be enough to generate the desired levels of preventive care, especially among those with chronic health conditions. PMID- 24800160 TI - Impact of chronic conditions on the cost of cancer care for Medicaid beneficiaries. AB - BACKGROUND: No study has assessed the cost of treating adult Medicaid cancer patients with preexisting chronic conditions. This information is essential for understanding the cost of cancer care to the Medicaid program above that expended for other chronic conditions, given the increasing prevalence of chronic conditions among cancer patients. RESEARCH DESIGN: We used administrative data from 3 state Medicaid programs' linked cancer registry data to estimate cost of care during the first 6 months following cancer diagnosis for beneficiaries with 4 preexisting chronic conditions: cardiac disease, respiratory diseases, diabetes, and mental health disorders. Our base cohort consisted of 6,212 Medicaid cancer patients aged 21 to 64 years (cancer diagnosed during 2001-2003) who were continuously enrolled in fee-for-service Medicaid for 6 months after diagnosis. A subset of these patients who did not die during the 6-month follow up (n=4,628), were matched with 2 non-cancer patients each (n=8,536) to assess incremental cost of care. RESULTS: The average cost of care for cancer patients with the chronic conditions studied was higher than for cancer patients without any of these conditions. The increase in cancer treatment cost associated with the chronic conditions ranged from $4,385 for cardiac disease to $11,009 for mental health disorders. CONCLUSIONS: Chronic conditions, especially the presence of multiple conditions, are associated with a higher cost of care among Medicaid cancer patients, and these increased costs should be reflected in projections of future Medicaid cancer care costs. The implementation of better care-management processes for cancer patients with preexisting chronic conditions may be one way to reduce these costs. PMID- 24800162 TI - Push and release: TLR9 activation plus STAT3 blockade for systemic antitumor immunity. AB - Proper immunostimulation ("push") and immune checkpoint blockade ("release") are both critical for the efficacy of anticancer immunotherapy. We have recently shown that activating Toll-like receptor 9 (TLR9) while specifically blocking signal transducer and activator of transcription 3 (STAT3) in leukemic cells enhances their immunogenicity, allowing for CD8+ T cell-mediated tumor eradication. These findings underscore the therapeutic potential of such a "Push & Release" strategy against hematological malignancies. PMID- 24800161 TI - Measuring prevention more broadly: an empirical assessment of CHIPRA core measures. AB - OBJECTIVE: To assess limitations of using select Children's Health Insurance Program Reauthorization Act (CHIPRA) core claims-based measures in capturing the preventive services that may occur in the clinical setting. METHODS: We use claims data from ALL Kids, the Alabama Children's Health Insurance Program (CHIP), to calculate each of four quality measures under two alternative definitions: (1) the formal claims-based guidelines outlined in the CMS Technical Specifications, and (2) a broader definition of appropriate claims for identifying preventive service use. Additionally, we examine the extent to which these two claims-based approaches to measuring quality differ in assessments of disparities in quality of care across subgroups of children. RESULTS: Statistically significant differences in rates were identified when comparing the two definitions for calculating each quality measure. Measure differences ranged from a 1.9 percentage point change for measure #13 (receiving preventive dental services) to a 25.5 percentage point change for measure #12 (adolescent well-care visit). We were able to identify subgroups based upon family income, rural location, and chronic disease status with differences in quality within the core measures. However, some identified disparities were sensitive to the approach used to calculate the quality measure. CONCLUSIONS: Differences in CHIP design and structure, across states and over time, may limit the usefulness of select claims-based core measures for detecting disparities accurately. Additional guidance and research may be necessary before reporting of the measures becomes mandatory. PMID- 24800163 TI - The immune landscape of human tumors: Implications for cancer immunotherapy. AB - Understanding the spontaneous immune response of cancer patients is critical for the design of efficient anticancer immunotherapies. The power of integrative tumor immunology approaches allowed for a comprehensive view of the immune system evolution in the course of tumor progression and recurrence. We have demonstrated that tumor-infiltrating immune cells are spatiotemporally regulated, a finding that has profound implications for the development of efficient anticancer immunotherapies. PMID- 24800164 TI - Chemotherapy engages multiple pathways leading to IL-1beta production by myeloid leukocytes. AB - Interleukin-1beta (IL-1beta) can limit tumor growth by promoting T cell-mediated antitumor immune responses. Several chemotherapeutic agents can stimulate the production of IL-1beta by tumor-infiltrating leukocytes via the NLRP3 inflammasome. We have recently demonstrated that some chemotherapeutics can also trigger the secretion of IL-1beta by driving the assembly of the caspase-8- and FADD-containing platform known as the ripoptosome. PMID- 24800165 TI - RB1-mediated cell-autonomous and host-dependent oncosuppressor mechanisms in radiation-induced osteosarcoma. AB - The mechanisms by which retinoblastoma 1 (RB1) mediates oncosuppressive functions are still being elucidated. We found that radiation-induced senescence in the bone depends on RB1 and is associated with the secretion of multiple bioactive factors, including interleukin-6 (IL-6), as well as with the infiltration of natural killer T (NKT) cells. Importantly, the inhibition of RB1, IL-6 or NKT cells predisposed mice to radiation-induced osteosarcomas, unveiling a cancer cell-extrinsic mechanisms that underlie the oncosuppressive activity of RB1. PMID- 24800166 TI - The short and sweet of T-cell therapy: Restraining glycolysis enhances the formation of immunological memory and antitumor immune responses. AB - Upon antigenic stimulation, naive CD8+ T cells divert their bioenergetic metabolism from oxidative phosphorylation to aerobic glycolysis. This drives CD8+ T cells to differentiate into short-lived effectors, impairing the establishment of immunological memory. The pharmacological inhibition of glycolysis with 2 deoxyglucose enhances the generation of memory CD8+ T cells and thus improves their immunotherapeutic potential against cancer. PMID- 24800167 TI - Why should we need the gut microbiota to respond to cancer therapies? AB - Cyclophosphamide, one of the most efficient tumoricidal, antiangiogenic, and immunostimulatory drugs employed to date mediates part of its effects through intestinal bacteria, against which the host becomes immunized during treatment. Our recent work suggests that anti-commensal effector pTH17 and memory TH1 CD4+ T cell responses are indispensable for optimal anticancer effects as mediated by cyclophosphamide. PMID- 24800169 TI - Immunosurveillance of senescent cancer cells by natural killer cells. AB - We recently dissected how senescent tumors can trigger complementing signaling pathways that mobilize natural killer (NK) cells to eliminate malignant cells. In addition to cell-intrinsic effects on proliferation, senescence induces the production of chemokine (C-C motif) ligand 2 (CCL2), which recruits NK cells to mediate direct tumoricidal effects. Hence, senescence activates a cancer cell extrinsic oncosuppression program. PMID- 24800168 TI - Implementing combinatorial immunotherapeutic regimens against cancer: The concept of immunological conditioning. AB - Harnessing the host immune system to eradicate cancer has a high therapeutic potential. One paradigm of anticancer immunotherapy is represented by allogeneic stem cell transplantation. In this setting, the host must be conditioned prior to transplantation, allowing for engraftment and subsequent graft-vs.-tumor reactivity. Conditioning may also be a prerequisite for the efficacy of other immunotherapeutic regimens. In particular, tumor debulking followed by conditioning (aimed at blocking endogenous inhibitory stimuli, for instance upon the depletion of regulatory T cells or the inhibition of immune checkpoints) and subsequent immunization (for instance by means of patient-tailored vaccines) based on innovative adjuvants (such as RIG-I ligands) may allow for the elicitation of superior antitumor immune responses. Repetitive boosting might then maintain immunosurveillance. An intense wave of investigation on the optimal timing of immunostimulatory interventions with respect to the administration of immunogenic chemotherapeutics and on the use of small drugs that promote efficient antitumor immune responses will end up in the generation of highly effective immunotherapeutic anticancer regimens. PMID- 24800170 TI - Chemokines and chemokine receptors required for optimal responses to anticancer chemotherapy. AB - Depending on tumor type, stage and immunological contexture, the inhibition of chemokines or their receptors may yield positive or deleterious effects on disease progression. We have recently demonstrated in several murine models of anthracycline-based chemotherapy that the inhibition of chemokine (C-C motif) ligand 2 (CCL2) or chemokine (C-C motif) receptor 2 (CCR2) may impair the elicitation of anticancer immune responses that contribute to therapeutic success. PMID- 24800171 TI - Monocytic myeloid-derived suppressor cells in advanced melanoma patients: Indirect impact on prognosis through inhibition of tumor-specific T-cell responses? AB - The percentage of circulating CD14+CD11b+HLA-DR-/low myeloid-derived suppressor cells (MDSCs) inversely correlates with survival among advanced melanoma patients. High levels of MDSCs are associated with the absence of T lymphocytes specific for melanoma-derived antigens, implying a causal and clinically relevant interaction between these cell subsets. MDSCs might therefore represent prognostic markers as well as targets for the development of novel therapeutic interventions against melanoma. PMID- 24800172 TI - Altering the intratumoral localization of macrophages to inhibit cancer progression. AB - Hypoxia confers to macrophages angiogenic and immunosuppressive properties which promote tumor growth and progression. Preventing the migration of macrophages into hypoxic tumor regions hinders angiogenesis and restores the tumor suppressive properties of these immune cells. We have recently uncovered a neuropilin 1- and semaphorin 3A-dependent signaling pathway that defines the repositioning of macrophages to hypoxic tumor niches, a discovery that generates new options for the development of complementary anticancer treatments. PMID- 24800174 TI - Role of the complement system in NK cell-mediated antitumor T-cell responses. AB - The role of the complement system in oncogenesis and tumor progression remains poorly understood. We have recently demonstrated that the induction of a tumor specific CD8+ T-cell response is improved upon transient inhibition of the complement system, which is coupled to an increased availability of natural killer cells. The complement system may therefore turn out to constitute a promising target for the development of novel anticancer therapeutics. PMID- 24800175 TI - Application of iPS cell-derived macrophages to cancer therapy. AB - We established a method to produce a large quantity of myeloid cells from human inducible pluripotent stem cells (iPSCs). When injected intraperitoneally into mice carrying established peritoneal tumors, iPSC-derived myeloid cells (iPS-MCs) efficiently accumulated within neoplastic lesions. The intraperitoneal injection of iPS-MCs expressing interferon beta significantly inhibited the growth of human gastric and pancreatic cancers implanted in the peritoneal cavity of immunocompromised mice. PMID- 24800173 TI - Trial Watch: Chemotherapy with immunogenic cell death inducers. AB - Accumulating evidence suggests that the clinical efficacy of selected anticancer drugs, including conventional chemotherapeutics as well as targeted anticancer agents, originates (at least in part) from their ability to elicit a novel or reinstate a pre-existing tumor-specific immune response. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). Cancer cells succumbing to ICD are de facto converted into an anticancer vaccine and as such elicit an adaptive immune response. Several common chemotherapeutics share the ability of triggering ICD, as demonstrated in vaccination experiments relying on immunocompetent mice and syngeneic cancer cells. A large number of ongoing clinical trials involve such ICD inducers, often (but not always) as they are part of the gold standard therapeutic approach against specific neoplasms. In this Trial Watch, we summarize the latest advances on the use of cyclophosphamide, doxorubicin, epirubicin, oxaliplatin, and mitoxantrone in cancer patients, discussing high-impact studies that have been published during the last 13 months as well as clinical trials that have been initiated in the same period to assess the antineoplastic profile of these immunogenic drugs as off-label therapeutic interventions. PMID- 24800176 TI - NKp44L: A new tool for fighting cancer. AB - We have recently identified that the ligand of natural cytotoxicity triggering receptor 2 (NCR2, best known as NKp44) is expressed on a large panel of malignant cells. This ligand provides a new tool to investigate how stressed cells are recognized and eliminated by natural killer (NK) cells, and to develop novel immunotherapeutic paradigms against cancer. PMID- 24800177 TI - Is tumor (R)ejection by the immune system the "5th R" of radiobiology? AB - Traditional factors of DNA damage and tumor cell kill, described by the "4 R's" of radiobiology (Reassortment, Reoxygenation, Repair, and Repopulation) fall short in explaining the role of immunity in hosts treated with radiotherapy. We propose a "5th R," (immune-mediated) Rejection, which recognizes the contribution of the immune system to the antineoplastic effects of radiotherapy. PMID- 24800178 TI - Trial Watch: DNA vaccines for cancer therapy. AB - During the past 2 decades, the possibility that preparations capable of eliciting tumor-specific immune responses would mediate robust therapeutic effects in cancer patients has received renovated interest. In this context, several approaches to vaccinate cancer patients against their own malignancies have been conceived, including the administration of DNA constructs coding for one or more tumor-associated antigens (TAAs). Such DNA-based vaccines conceptually differ from other types of gene therapy in that they are not devised to directly kill cancer cells or sensitize them to the cytotoxic activity of a drug, but rather to elicit a tumor-specific immune response. In spite of an intense wave of preclinical development, the introduction of this immunotherapeutic paradigm into the clinical practice is facing difficulties. Indeed, while most DNA-based anticancer vaccines are well tolerated by cancer patients, they often fail to generate therapeutically relevant clinical responses. In this Trial Watch, we discuss the latest advances on the use of DNA-based vaccines in cancer therapy, discussing the literature that has been produced around this topic during the last 13 months as well as clinical studies that have been launched in the same time frame to assess the actual therapeutic potential of this intervention. PMID- 24800181 TI - Formulation development and evaluation of metformin chewing gum with bitter taste masking. AB - BACKGROUND: Medicated gums are intended to be chewed and act either locally, absorbed via the buccal mucosa or swallowed with saliva. We prepared the metformin gum to overcome its side effects including vomiting, diarrhea, and abdomen discomfort. Furthermore, it could be useful for those who have swallowing problems. MATERIALS AND METHODS: Metformin hydrochloride (250 mg) with suitable sweeteners was mixed manually for 5 min. This mixture was spray dried, freeze dried, or directly mixed with chewing gum base. Glycerin, xylitol, and menthol were added and the produced paste was kept in the freezer for 2 h to be stable. As the metformin shows bitter taste, we tried to mask this unpleasant taste with using different methods explained. The releasing pattern was evaluated by using a mechanical chewing machine. The best formulation with the optimized releasing pattern, suitable physicochemical properties and pleasant taste were selected. Content uniformity, releasing percent, and other physicochemical properties were identified as well. Taste, flavor, and appearance characteristics were evaluated by using a self-made questionnaire based on the hedonic test method. RESULTS: The chewing gum dosage content was about 86.2%. The release rate of metformin chewing gum was about 70% after 5 min of mastication. Masking the bitter taste of drug was achieved by using acesulfame-isomalt as sweeteners and prepared it by freeze drying equipment. CONCLUSION: Metfornin chewing gum had suitable appearance and appropriate invitro characteristics that fallow the pharmacopeia suggestions. This chewable gum showed bitterness suppression with a suitable release rate. PMID- 24800180 TI - From mysteries to medicines: drug development for fibrodysplasia ossificans progressive. AB - INTRODUCTION: Fibrodysplasia ossificans progressiva (FOP) is the most disabling disorder of skeletal metamorphosis in humans and leads to the formation of a second skeleton of heterotopic bone. Presently, there is no effective treatment. AREAS COVERED: In this review, the authors discuss heterozygous activating mutations in Activin receptor A, type I/ Activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor that are the genetic cause of FOP and reveal a promising pharmacologic target in the BMP signaling pathway. Despite these germline mutations, episodic disease activation is induced by soft tissue injury and resultant inflammatory triggers that are dependent on responding progenitor cells and a tissue microenvironment that supports heterotopic ossification. EXPERT OPINION: Here we review opportunities and challenges for the development of effective therapeutics for FOP. There are many potential approaches that may eventually be used to harness FOP. The long-term treatment of FOP is likely to involve not one, but several concomitant approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease. PMID- 24800179 TI - The transmembrane channel-like protein family and human papillomaviruses: Insights into epidermodysplasia verruciformis and progression to squamous cell carcinoma. AB - Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs), causing persistent, tinea versicolor-like dermal lesions. In a majority of affected individuals, these macular lesions progress to invasive cutaneous squamous cell carcinoma (CSCC) in sun-exposed areas. While mutations in transmembrane channel-like 6 (TMC6 / EVER1) and 8 (TMC8 / EVER2) have been causally linked to EV, their molecular functions are unclear. It is likely that their protective effects involve regulation of the beta-HPV life cycle, host keratinocyte apoptosis vs. survival balance and/or T-cell interaction with infected host cells. PMID- 24800182 TI - The results of core decompression treatment in patients with avascular necrosis of femoral head in patients at Isfahan City educational hospitals in 2010-2011. AB - BACKGROUND: Avascular necrosis (AVN) of femoral head is one of the multifactorial pathologies, which can disturb hip joint and its range of motion. There have been several therapeutic methods for this pathology, but the results are controversial. Some studies show that core compression prevents the progress of the disease and its symptoms. This study aims to explore this issue. MATERIALS AND METHODS: This clinical trial was conducted on patients who were diagnosed with AVN of femoral head stage I, IIA, at educational hospitals of Isfahan in 2010. The patients who met the inclusion criteria and suffered from AVN of femoral head stage I, IIA for any reason (primary or secondary), entered the study. Six and 12 months after surgery, final assessment in terms of range of motion, return to work, and severity of pain based on vancouver associated score (VAS) was made and recorded. The duration of hospitalization and rate of infection were also recorded. The data were entered into and analyzed by the SPSS software. RESULTS: Mean and standard deviation of pain severity before surgery was 6.82 +/- 1.74 in the participants. After 6 months, pain severity reduced to 4.05 +/- 1.29, and after 12 months, it reached 2.41 +/- 1.82. On the basis of analysis of variance with repeated observation, the severity of pain was significantly reduced in 1 year (P<0.001). CONCLUSION: It can be concluded that core decompression in patients with AVN of femoral head stage I, IIA can improve pain in hip area and increase range of motion. PMID- 24800183 TI - Comparative evaluation of three different methods for HbA1c measurement with High performance liquid chromatography in diabetic patients. AB - BACKGROUND: The global prevalence of diabetes mellitus is increasing rapidly. Measurement of glycated hemoglobin, predominantly HbA1c, is fundamental to the management of patients with diabetes. HbA1c is used to monitor long-term glycemic control, adjust therapy, assess the quality of diabetes care and predict the risk for the development of complications. While HbA1c is the standard method for long term glycemic control in diabetic patients, there are different methods for measurement of HbA1c and all laboratories do not use the reference method (high performance liquid chromatography [HPLC]). The objective of this study is comparison of three different methods with HPLC to find out which method has an acceptable concordance and correlation with the reference method. MATERIALS AND METHODS: Fifty-eight diabetic patients were assessed in this study. The blood sample of each patient was checked with Diazyme (enzymatic assay), Nycocard (boronate-affinity binding) and Biosystem (micro column chromatography). The values of HbA1c of each method were compared with the Knauer-HPLC results. RESULTS: THE MEANS OF THE DIFFERENTIAL VALUES BETWEEN EACH METHOD AND HPLC IN THE ANOVA TEST ARE AS FOLLOWS: M = 1.8, SD = 1.09 for Nycocard-HPLC; M = 1.5, SD = 1.08 for biosystem-HPLC; M = 1.3, SD = 1.2 for Diazyme-HPLC. Pearson's correlation coefficient between HPLC and Nycocard; 0.76, HPLC and Diazyme; 0.75 and between HPLC and Biosystem was 0.68. Linear regression parameters for each method with HPLC were also determined. CONCLUSION: Diazyme had a better performance and showed a greater concordance with HPLC among others, although it was not an ideal alternative for HPLC. PMID- 24800184 TI - Complete incorporation of long diaphyseal sequestrum without surgical intervention in chronic hematogenous osteomyelitis of tibia in an immunocompetent child. AB - Traditionally, the management of chronic osteomyelitis emphasizes the excision of necrotic and infected material (sequestrectomy/debridement) followed by prolonged administration of antibiotics. Most children with chronic osteomyelitis undergo surgery with the inherent risk of damage to their growth plate. Treatment regimen based on findings of imaging with emphasis on antibiotics to potentially reduce the rate of surgical interventions is being increasingly reported. An 8-year-old thin built Indian boy belonging to lower socio-economic group presented to the orthopedic department with the chief complaints of pain in the left upper leg for the last 3 months. Radiograph of the affected limb showed features of chronic osteomyelitis with a large diaphyseal sequestrum on the medial cortex of tibia with incomplete involucrum. No surgery was performed; not even incision and drainage. The sinuses healed completely in 6 weeks time with appropritate antibiotics alone. Gradually, over a period of 8 months, the large tibial diaphyseal sequestrum got fully incorporated into the healthy diaphyseal bone indistinguishable from normal bony architecture with complete clinical remission of sepsis. Our rare case is an example of the evolving notion that antibiotics and supportive care alone may be sufficient enough in the treatment of chronic osteomyelitis even with large diaphyseal sequestrum in paediatric cases where excellent healing potential of the immune-competent child may potentially make surgical intervention redundant. PMID- 24800185 TI - Diagnostic utility of PAX8 in differentiation of mullerian from non-mullerian tumors. AB - BACKGROUND: Considering the high prevalence of female genital tract neoplasms, non-specific nature of the initial symptoms, higher possibility of metastasis by the time of diagnosis, importance of differentiating metastatic Mullerian tumors or metastatic breast cancer in the female genital tract, especially in the ovary, and lack of diagnostic markers with high sensitivity and specificity, the purpose of the current study was to evaluate the utility of Paired box protein8 (PAX8) expression in Mullerian and non-Mullerian neoplasms. MATERIALS AND METHODS: In this descriptive-analytic, cross-sectional study, paraffin-embedded tissues of patients with definitive pathologic diagnosis of Mullerian and non-Mullerian tumors were selected. PAX8 immunohistochemical (IHC) staining was performed for all selected blocks. Immunopositivity of the slides for PAX8 was reviewed. It was defined as the presence of nuclear staining in at least 10% of the tumor cell nuclei. RESULTS: Thirty-seven Mullerian (including 18 ovarian epithelial tumors, 17 endometrial carcinoma and two endocervical adenocarcinoma) and 37 non Mullerian tumors were studied for PAX8 expression. Twenty-nine of 37 (78.4%) and one of 37 (2.7%) of the Mullerian and non-Mullerian tumors were positive for PAX8, respectively. The sensitivity and specificity of PAX8 by IHC for differentiation of Mullerian from non-Mullerian tumors was 78.4% and 97.3%, respectively. CONCLUSION: Our findings indicated that PAX8 could be used as a useful IHC marker for diagnosing Mullerian tumors. It has moderate to high sensitivity, but high specificity, for diagnosing carcinomas of Mullerian origin. PMID- 24800186 TI - Effect of sertraline on proliferation and neurogenic differentiation of human adipose-derived stem cells. AB - BACKGROUND: Antidepressant drugs are commonly employed for anxiety and mood disorders. Sertraline is extensively used as antidepressant in clinic. In addition, adipose tissue represents an abundant and accessible source of adult stem cells with the ability to differentiate in to multiple lineages. Therefore, human adipose-derived stem cells (hADSCs) may be useful for autologous transplantation. MATERIALS AND METHODS: In the present study, we assessed the effect of antidepressant drug Sertraline on the proliferation and neurogenic differentiation of hADSCs using MTT assay and immunofluorescence technique respectively. RESULTS: MTT assay analysis showed that 0.5 MUM Sertraline significantly increased the proliferation rate of hADSCs induced cells (P < 0.05), while immunofluorescent staining indicated that Sertraline treatment during neurogenic differentiation could be decreased the percentage of glial fibrillary acidic protein and Nestin-positive cells, but did not significantly effect on the percentage of MAP2 positive cells. CONCLUSION: Overall, our data show that Sertraline can be promoting proliferation rate during neurogenic differentiation of hADSCs after 6 days post-induction, while Sertraline inhibits gliogenesis of induced hADSCs. PMID- 24800187 TI - The study of mutation in 23S rRNA resistance gene of Helicobacter pylori to clarithromycin in patients with gastrointestinal disorders in Isfahan - Iran. AB - BACKGROUND: Helicobacter pylori antimicrobial resistance is an important factor responsible for treatment failure. The purpose of this study was evaluating the prevalence of point mutations in clarithromycin-resistant clinical isolates of H. pylori in Isfahan city of Iran. MATERIALS AND METHODS: Thirty isolates of H. pylori from 130 biopsy specimens were isolated by culture and confirmed by biochemical and PCR tests. The MIC of clarithromycin antibiotic for 30 clinical isolates of H. pylori was determined by E-test method. The point mutations in the 288 bp of 23S rRNA gene of H. pylori were investigated in four clarithromycin resistant clinical isolates by PCR followed by sequencing. RESULTS: Among 30 isolates of H. pylori, 4 cases were resistant to clarithromycin. One point mutation was found at position T2243C in the 23S rRNA gene in all resistance isolates. CONCLUSIONS: In our study, H. pylori resistance to clarithromycin associated with point mutation at position 2243 (T2243C). PMID- 24800188 TI - Extracorporeal shock wave therapy of gastroc-soleus trigger points in patients with plantar fasciitis: A randomized, placebo-controlled trial. AB - BACKGROUND: Plantar fasciitis is the most common cause of heel pain. Extracorporeal shock wave therapy (ESWT) is an alternative treatment for refractory cases of plantar fasciitis. Studies also demonstrated that ESWT may be an appropriate treatment for myofascial trigger points. This study was designed to evaluate its effectiveness by comparing the ESWT of Gastrocnemius/Soleus (gastroc-soleus) trigger points and heel region with the ESWT of the heel region alone. MATERIALS AND METHODS: The study was carried out among 40 patients with a clinical diagnosis of plantar fasciitis, divided randomly to case (n = 20) and control (n = 20) groups. The case group received ESWT for the heel region and for the gastroc-soleus trigger points. The control group received ESWT just for the heel region. The protocol was the same in both groups and they were treated for three sessions every week. The pain score (100 mm visual analog score [VAS]) and the modified Roles and Maudsley score was evaluated before the first session and eight weeks after the last session. RESULTS: Eight weeks after the last session, although the mean VAS had decreased significantly in both groups, this decrement was more significant in the case group. (P = 0.04). According to the modified Roles and Maudsley score, there was a significant improvement in both the case (P < 0.001) and control (P = 0.01) groups, eight weeks after treatment, but there were significantly better results in the case group. CONCLUSION: The combination of ESWT for both plantar fasciitis and gastroc-soleus trigger points in treating patients with plantar fasciitis is more effective than utilizing it solely for plantar fasciitis. PMID- 24800190 TI - Insights into the effects of tensile and compressive loadings on human femur bone. AB - BACKGROUND: Fragile fractures are most likely manifestations of fatigue damage that develop under repetitive loading conditions. Numerous microcracks disperse throughout the bone with the tensile and compressive loads. In this study, tensile and compressive load tests are performed on specimens of both the genders within 19 to 83 years of age and the failure strength is estimated. MATERIALS AND METHODS: Fifty five human femur cortical samples are tested. They are divided into various age groups ranging from 19-83 years. Mechanical tests are performed on an Instron 3366 universal testing machine, according to American Society for Testing and Materials International (ASTM) standards. RESULTS: The results show that stress induced in the bone tissue depends on age and gender. It is observed that both tensile and compression strengths reduces as age advances. Compressive strength is more than tensile strength in both the genders. CONCLUSION: The compression and tensile strength of human femur cortical bone is estimated for both male and female subjecting in the age group of 19-83 years. The fracture toughness increases till 35 years in male and 30 years in female and reduces there after. Mechanical properties of bone are age and gender dependent. PMID- 24800189 TI - Potent health effects of pomegranate. AB - Accumulating data clearly claimed that Punica granatum L. (pomegranate) has several health benefits. Pomegranates can help prevent or treat various disease risk factors including high blood pressure, high cholesterol, oxidative stress, hyperglycemia, and inflammatory activities. It is demonstrated that certain components of pomegranate such as polyphenols have potential antioxidant, anti inflammatory, and anticarcinogenic effects. The antioxidant potential of pomegranate juice is more than that of red wine and green tea, which is induced through ellagitannins and hydrosable tannins. Pomegranate juice can reduce macrophage oxidative stress, free radicals, and lipid peroxidation. Moreover, pomegranate fruit extract prevents cell growth and induces apoptosis, which can lead to its anticarcinogenic effects. In addition, promoter inhibition of some inflammatory markers and their production are blocked via ellagitannins. In this article, we highlight different studies on the therapeutic effects of pomegranate and their suggested mechanisms of actions. PMID- 24800192 TI - Antifibrinolytics. PMID- 24800191 TI - Prevalence and antimicrobial susceptibility pattern of isolated microorganisms from central venous catheters in ICU patients. AB - BACKGROUND: The abundance of infections associated with intensive care unit (ICU) is increasing due to the increased use of aggressive medical equipments like the central venous catheter (CVC). This study was designed and performed in 2010-2011 at Alzahra hospital, which is a referral center. This study aimed at determining the relative abundance and microbial sensitivity of organisms, which were creating contamination with CVCs in hospitalized patients in the ICUs of Alzahra hospital. MATERIALS AND METHODS: This is a cross-sectional study performed on 71 patients who were hospitalized in the Alzahra hospital ICU and had CVCs during 2010-2011. The data obtained was analyzed by SPSS version 20 software and descriptive statistical approaches and chi-square and t-test trials. RESULTS: In the sample culture obtained from the patients' catheter in 19 cases (26/8%), no microorganism was grown and in 52 cases (73.3%) at least one type of microorganism including bacteria or fungus was grown. In this study, average hospitalization time in patients who got positive results from their catheter culture was significantly more compared with patients who did not grow any kinds of microorganism in their sample cultures. CONCLUSION: In this study, CVCs microbial contamination has a high prevalence, which is a major cause of prolonged patients staying in ICUs, and therefore, it is essential to take precaution and discharge the patient early for decreasing the catheter contamination and preventing the hospital infections incidence in the ICU patients. PMID- 24800193 TI - Inhalation induction with sevoflurane in adult cardiac surgery patients. A case series. AB - INTRODUCTION: Anesthesia induction through volatile agents is a well-established technique in several fields but not in adult patients undergoing cardiac surgery. Successful inhalation induction requires a poorly soluble, reasonably potent and minimally irritant agent, and the benefits associated to this technique include reduced incidence of hypothermia and hypotension and lower costs when compared to some intravenous anesthetics agents. METHODS: Fifty-six patients undergoing coronary artery bypass grafting were observed at the induction of general anesthesia with sevoflurane in oxygen by facial mask. All patients received 2% sevoflurane in 100% oxygen initially for 30 seconds. The inspired concentration of sevoflurane was increased to 7% until loss of consciousness and then reduced back to 2%. Next, intravenous 0.5 ug/kg sufentanil and 0.1 mg/kg pancuronium were administered. Volume-controlled ventilation was started before tracheal intubation. RESULTS: All 56 patients tolerated the inhalational induction. No patient presented signs of airway irritation. Hypotension occurred in 30 patients and was managed with low dose phenylephrine. CONCLUSIONS: This case series showed that inhalation induction is feasible and safe even in adult patients undergoing cardiac surgery. PMID- 24800194 TI - Ultrasound-guided internal jugular vein catheterization: a randomized controlled trial. AB - INTRODUCTION: Even though advantages of ultrasound line placement seem obvious, many countries do not have easy access to such technology. This study aims to compare the degree of difficulty in central venous line placement with or without ultrasound and the incidence of complications, and to establish the effect of the operator's degree of training. METHODS: The study included 257 patients that required central venous catheterization during the study period. Patients were divided into groups according to the operator's experience: expert group (over 70 central accesses performed before the study) (n=152) and in-training or non expert group. Procedures were randomized to "without ultrasound" (n=80 expert and 54 non-expert) and "with ultrasound" (n=72 expert and 51 non-expert). RESULTS: Catheter placements were more successful in the "expert" and in the "with ultrasound" than in the "non-expert" (88% vs 79%; p=0.04) or in the "without ultrasound" groups (91% vs 78%; p=0.005). Incidence of complications was 11.7%, with no significant difference among "with ultrasound" (8.1%) and "without ultrasound" (14.9%) groups. However, the "non-expert" group had fewer complications with the use of ultrasound (7.8% vs 24%). CONCLUSIONS: Ultrasound reduces the incidence of complications when placement is performed by inexperienced operators. Centers with residents should emphasize the necessity of ultrasound for central line catheterization. Training in ultrasound might be of paramount importance in the effectiveness of the technique. PMID- 24800195 TI - Outcomes-based systematic review for management of massive intra-cardiac or pulmonary thrombotic emboli during surgery. AB - INTRODUCTION: The management of massive intra-operative embolism remains controversial. Our hypothesis was that either surgical or medical thrombectomy offers survival benefit in these patients. METHODS: Published case reports were reviewed for intra-operative intra-cardiac or pulmonary embolism and outcomes for the following four intervention groups were evaluated for mortality benefit: surgical embolectomy; thrombolysis; anticoagulation; supportive care alone. We also assessed whether the use of diagnostic modalities prior to each embolism event resulted in a mortality benefit and, separately, whether post-intervention improvement in physiologic parameters resulted in improvement in outcomes. Univariate analyses and logistic regression were performed to assess the impact of the four primary interventions on mortality, the primary outcome. RESULTS: Seventy-eight cases were reviewed and therapeutic interventions resulted in improved survival (70%) compared to supportive care (45%), odds ratio=0.38[0.15 0.98], p=0.04. Univariate analysis of primary interventions with death as a primary outcome resulted in a lack of significantly different outcomes (p=0.08). Mortality rates were 71% in the thrombolytic; 28% in surgical embolectomy; 18% in anticoagulation and 43% in the supportive care groups. The routine pre-event use of trans-esophageal echocardiography was not related with improved outcomes (p=0.36) but the use of pulmonary artery or central venous catheters was (p=0.035). Post-intervention improvements in the physiologic parameters of each diagnostic modality were associated with an improvement in mortality (p<0.05). CONCLUSIONS: Our data present some important trends among the intervention groups, raising significant concerns about the safety for the use of thrombolytics in the management of intra-operative embolism. PMID- 24800196 TI - Sedation with sevoflurane in postoperative cardiac surgery: influence on troponin T and creatinine values. AB - INTRODUCTION: To compare the potential beneficial effects on markers of myocardial injury (troponin T) and renal function between sedation with sevoflurane vs propofol after cardiac surgery using extracorporeal cardiopulmonary bypass. METHODS: A prospective study with sequential selection of patients undergoing coronary or coronary and valve cardiac surgery. Intraoperative anesthesia consisted in sevoflurane and remifentanil, while in the postoperative period patients were divided in two groups to receive sedation with either sevoflurane through the AnaConDa(c) system or propofol. The patients were sedated during a minimum of 120minutes. Markers of myocardial injury and plasmatic creatinine were measured 4, 12, 24, and 48hours after surgery. RESULTS: Data from 129patients, 62sedated with propofol and 67with sevoflurane, were analyzed. The analysis of the troponin T levels showed differences 12 and 48 hours after admission. Mean values at 12hours were 0.89 (standard deviation 0.55) ug.L(-1) in the propofol group and 0.69 (standard deviation 0.40) ug. L(-1)in the sevoflurane group (p = 0.026). TnT levels at 48hours were 0.60 (standard deviation 0.46) ug.L-(1)in the propofol group and 0.37 (standard deviation 0.26) ug.L(-1)in the sevoflurane group (p = 0,007). No differences were found in the groups in the creatinine levels before discharge. CONCLUSIONS: The post-operative sedation with sevoflurane after cardiac surgery with cardiopulmonary bypass is a valid alternative to propofol. It does not increase the number of side effects related to kidney damage in patients with no prior renal disease, leading to reduced troponin T levels 12and 48hours after admission. PMID- 24800197 TI - Practice variations in the conduct of hypothermic circulatory arrest for adult aortic arch repair: focus on an emerging European paradigm. AB - INTRODUCTION: Hypothermic circulatory arrest for adult aortic arch repair is still high-risk. Despite decades of clinical experience, significant practice variations exist around the world. These practice variations in hypothermic circulatory arrest may offer multiple opportunities to improve practice. The hypothesis of this study was that the current conduct of adult hypothermic circulatory arrest in Europe has significant variations that might suggest opportunities for risk reduction. METHODS: An adult hypothermic circulatory arrest questionnaire was developed and then administered at thoracic aortic sessions at international conferences during 2010 in Beijing and Milan. The data was collected, abstracted and analyzed. RESULTS: The majority of the 105 respondents were anesthesiologists based in Europe and China. The typical adult aortic arch repair in Europe was with hypothermic circulatory arrest at moderate hypothermia utilizing bilateral antegrade cerebral perfusion, typically monitored with radial arterial pressure and cerebral oximetry. Brain temperature was frequently measured at distal locations. The preferred neuroprotective agents were steroids, propofol and thiopental. CONCLUSIONS: The opportunities for outcome improvement in this emerging European paradigm of tepid adult aortic arch repair include nasal/tympanic temperature measurement and adoption of unilateral antegrade cerebral perfusion monitored with radial artery pressure and cerebral oximetry. The publication of an evidence-based consensus would enhance these practice-improvement opportunities. PMID- 24800198 TI - General anesthesia soon after dialysis may increase postoperative hypotension - A pilot study. AB - INTRODUCTION: Pilot study associating hemodialysis-to-general-anesthesia time interval and post-operative complications in hemodialysis patients to better define a more optimal pre-anesthetic waiting period. METHODS: Pre-anesthetic and 48-hours post-anesthetic parameters (age, gender, body-mass-index, pre-operative ultrafiltrate, potassium, renal disease etiology, hemodialysis sessions per week, Acute Physiology and Chronic Health Evaluation-II score, Portsmouth-Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity, American Society of Anesthesiologists physical status, Johns Hopkins Surgical Classification System Category, surgical urgency, intra-operative fluids, estimated blood loss, post-operative complications) were collected on chronic hemodialysis patients between 11/2009-12/2010. Continuous data were analyzed by Analysis of Variance or t-test. Bivariate data were analyzed by Fisher's Exact Test. Relative Risks/Confidence Intervals were calculated for statistically significant comparisons (p=0.05). Exclusion criteria were incomplete records, peritoneal dialysis, intra-operative hemodialysis, liver transplant, and cardiopulmonary bypass. RESULTS: Patients were grouped by dialysis to anesthesia time interval: Group 1 >24 hours, Group 2 7-23.9 hours, Group 3 < 7 hours. Among Surgical Category 3-5 patients, hypotension was more common in Group 3 than Group 1 (63.6% vs 9.2%, p<0.0001, relative risk=6.9, confidence interval=3.0-15.7) or Group 2 (63.6% vs 17.3%, p=0.0002, relative risk=3.7, confidence interval=1.9 7.2). Other complications rates were not statistically significant. Disease and surgical severity scores, preoperative ultrafiltrate, and intra-operative fluids were not different. CONCLUSIONS: Post-anesthetic hypotension within 48 hours was more common in those with < 7 hours interval between dialysis and anesthesia. Therefore, if surgical urgency permits, a delay of >=7 hours may limit postoperative hypotension. More precise associations should be obtained through a prospective study. PMID- 24800199 TI - Implantable cardioverter defibrillator during laser transurethral resection of the prostate. AB - Implantable cardioverter defibrillators have been instrumental in the health and safety of patients who are at increased risk of sudden death by ventricular tachycardia or fibrillation. Consensus on the perioperative management of cardiovascular implantable electronic devices has suggested that certain surgical interventions (including transurethral resection of the prostate) may interfere with the sensing capability of the device, thereby resulting in unforeseen adverse outcomes. However, improvements in the implantable cardioverter defibrillators have made it less susceptible to surgical interference. In addition, current guidelines recommend deactivation of the implantable cardioverter defibrillators to an asynchronous mode prior to most surgical interventions. We present the first two case reports in which implantable cardioverter defibrillators were not deactivated prior to GreenLight 180-W XPS laser-guided transurethral resection of the prostate. We left the implantable cardioverter defibrillators activated to allow them to detect and treat lethal arrhythmias by direct rather than extrinsic cardioversion. There was no cardiac arrhythmia incident in these two cases. Laser technology is not a documented source of electromagnetic interference in patients with implantable cardioverter defibrillators. There is no current evidence that links lasers to implantable cardioverter defibrillators malfunction. With increasing numbers of patients with implantable cardioverter defibrillators undergoing many different laser surgical procedures, further studies are warranted to analyze in depth the effects of laser therapy on implantable cardioverter defibrillators function and update in current guidelines. PMID- 24800200 TI - Myopathy should determine the anesthetic management in left ventricular hypertrabeculation/noncompaction. PMID- 24800201 TI - Invited-rejected: the perils of superficiality. PMID- 24800203 TI - Therapy of Helicobacter pylori: present medley and future prospective. AB - The increasing prevalence of antimicrobial resistance has warned clinicians to adopt new strategies for dealing with the H. pylori infection. The success of various therapeutic regimens has recently declined to unacceptable levels. To date, first line therapies (including concomitant therapy and hybrid therapy), second line therapies (including bismuth-containing quadruple therapy and levofloxacin-containing therapy), and third line therapy (culture-guided therapy) had been introduced. In the near future, treatment of H. pylori is entering into a completely new resistance era. In this setting, despite the recent progress, we may only be targeting the patients with problematic H. pylori. Local preference for antibiotic selection should be an inevitable article in each therapeutic regimen worldwide. Meanwhile, improving the patients' compliance protocols and observed side effects in suggested therapeutic regimens should be considered cautiously. The new strategies in treatment should be adopted based upon local resistance patterns, which requires physician's resistance about the recommended guidelines. Designing new therapeutic regimen, which contains most effective available antibiotics with less possible side effects and high patient compliance, represents a challenging task in treatment of H. pylori infections. PMID- 24800205 TI - Diagnostic value of virtual touch tissue quantification for breast lesions with different size. AB - PURPOSE: To evaluate diagnostic value of the virtual touch tissue quantification (VTTQ) for breast lesions with different sizes. MATERIALS AND METHODS: Patients with 206 breast lesions were categorized into three groups according to lesion size (<10 mm, 10-20 mm, and >20 mm). Breast lesions were examined by conventional ultrasound and VTTQ, and shear wave velocity (SWV) of each lesion and adjacent normal breast tissue were measured. Diagnoses were confirmed by pathological examination after surgery. The receiver-operating characteristic curve (ROC) analyses were performed to evaluate the diagnostic value of SWV, and the area under curves (AUC) was compared among groups. RESULTS: SWV of malignant lesions was much higher than that of benign lesions, whereas the difference was not obvious for lesions <10 mm (P = 0.15). There was statistical significant difference of AUC between lesions <10 mm and 10-20 mm (P < 0.05), as well as lesions <10 mm and >20 mm (P < 0.05). The sensitivity of lesions <10 mm was 33.33%, which was relatively low compared to other groups. CONCLUSION: According to our results, VTTQ is a promising method for breast lesions >10 mm, and further studies were warranted to improve sensitivity of VTTQ for breast lesions <10 mm. PMID- 24800202 TI - Bipolar disorder in children. AB - Although bipolar disorder historically was thought to only occur rarely in children and adolescents, there has been a significant increase in children and adolescents who are receiving this diagnosis more recently (Carlson, 2005). Nonetheless, the applicability of the current bipolar disorder diagnostic criteria for children, particularly preschool children, remains unclear, even though much work has been focused on this area. As a result, more work needs to be done to further the understanding of bipolar symptoms in children. It is hoped that this paper can assist psychologists and other health service providers in gleaning a snapshot of the literature in this area so that they can gain an understanding of the diagnostic criteria and other behaviors that may be relevant and be informed about potential approaches for assessment and treatment with children who meet bipolar disorder criteria. First, the history of bipolar symptoms and current diagnostic criteria will be discussed. Next, assessment strategies that may prove helpful for identifying bipolar disorder will be discussed. Then, treatments that may have relevance to children and their families will be discussed. Finally, conclusions regarding work with children who may have a bipolar disorder diagnosis will be offered. PMID- 24800204 TI - msiDBN: a method of identifying critical proteins in dynamic PPI networks. AB - Dynamics of protein-protein interactions (PPIs) reveals the recondite principles of biological processes inside a cell. Shown in a wealth of study, just a small group of proteins, rather than the majority, play more essential roles at crucial points of biological processes. This present work focuses on identifying these critical proteins exhibiting dramatic structural changes in dynamic PPI networks. First, a comprehensive way of modeling the dynamic PPIs is presented which simultaneously analyzes the activity of proteins and assembles the dynamic coregulation correlation between proteins at each time point. Second, a novel method is proposed, named msiDBN, which models a common representation of multiple PPI networks using a deep belief network framework and analyzes the reconstruction errors and the variabilities across the time courses in the biological process. Experiments were implemented on data of yeast cell cycles. We evaluated our network construction method by comparing the functional representations of the derived networks with two other traditional construction methods. The ranking results of critical proteins in msiDBN were compared with the results from the baseline methods. The results of comparison showed that msiDBN had better reconstruction rate and identified more proteins of critical value to yeast cell cycle process. PMID- 24800206 TI - The use of the phrenic nerve communicating branch to the fifth cervical root for nerve transfer to the suprascapular nerve in infants with obstetric brachial plexus palsy. AB - Traditionally, suprascapular nerve reconstruction in obstetric brachial plexus palsy is done using either the proximal C5 root stump or the spinal accessory nerve. This paper introduces another potential donor nerve for neurotizing the suprascapular nerve: the phrenic nerve communicating branch to the C5 root. The prevalence of this communicating branch ranges from 23% to 62% in various anatomical dissections. Over the last two decades, the phrenic communicating branch was used to reconstruct the suprascapular nerve in 15 infants. Another 15 infants in whom the accessory nerve was used to reconstruct the suprascapular nerve were selected to match the former 15 cases with regard to age at the time of surgery, type of palsy, and number of avulsed roots. The results showed that there is no significant difference between the two groups with regard to recovery of external rotation of the shoulder. It was concluded that the phrenic nerve communicating branch may be considered as another option to neurotize the suprascapular nerve. PMID- 24800207 TI - Facing contrast-enhancing gliomas: perfusion MRI in grade III and grade IV gliomas according to tumor area. AB - Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV), calculated with Dynamic Susceptibility Contrast (DSC) Perfusion Weighted Imaging (PWI), allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI) approach in three tumor areas-the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map-in patients affected by contrast enhancing glioma (grades III and IV). Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp.), the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P = 0.036). In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading. PMID- 24800208 TI - An unsupervised approach to predict functional relations between genes based on expression data. AB - This work presents a novel approach to predict functional relations between genes using gene expression data. Genes may have various types of relations between them, for example, regulatory relations, or they may be concerned with the same protein complex or metabolic/signaling pathways and obviously gene expression data should contain some clues to such relations. The present approach first digitizes the log-ratio type gene expression data of S. cerevisiae to a matrix consisting of 1, 0, and -1 indicating highly expressed, no major change, and highly suppressed conditions for genes, respectively. For each gene pair, a probability density mass function table is constructed indicating nine joint probabilities. Then gene pairs were selected based on linear and probabilistic relation between their profiles indicated by the sum of probability density masses in selected points. The selected gene pairs share many Gene Ontology terms. Furthermore a network is constructed by selecting a large number of gene pairs based on FDR analysis and the clustering of the network generates many modules rich with similar function genes. Also, the promoters of the gene sets in many modules are rich with binding sites of known transcription factors indicating the effectiveness of the proposed approach in predicting regulatory relations. PMID- 24800209 TI - Interleukin-6 and vitamin D status during high-intensity resistance training in patients with chronic kidney disease. AB - Background. The aim of this study was to investigate IL-6 and 25-hydroxyvitamin D (25-OH D) associations with muscle size and muscle function in dialysis patients. Methods. Patients were included in a 16-week control period followed by 16 weeks of high-intensity resistance training thrice weekly. IL-6 and 25-OH D were analysed after an over-night fast. Muscle fibre size was analysed in biopsies from m. vastus lateralis. Muscle power was tested using a Leg Extensor Power Rig. Results. Patients (n = 36) with IL-6 >= 6.49 pg/ml (median) were older and had decreased muscle power and a reduced protein intake (P < 0.05) compared with patients with IL-6 < 6.49 pg/ml. IL-6 was not associated with muscle fibre size. Vitamin D deficiency (25-OH D < 50 nmol/l) was present in 51% of the patients and not associated with muscle power. IL-6 remained unchanged during the training period, whilst muscle power increased by 20-23% (P < 0.001). Conclusion. Elevated IL-6 values were associated with decreased muscle power but not with decreased muscle fibre size. Half of the patients were suffering from vitamin D deficiency, which was not associated with muscle power. IL-6 was unchanged by high-intensity resistance training in dialysis patients in this study. PMID- 24800210 TI - Characterization of imidazoline receptors in blood vessels for the development of antihypertensive agents. AB - It has been indicated that activation of peripheral imidazoline I2-receptor (I 2R) may reduce the blood pressure in spontaneously hypertensive rats (SHRs). Also, guanidinium derivatives show the ability to activate imidazoline receptors. Thus, it is of special interest to characterize the I-2R using guanidinium derivatives in blood vessels for development of antihypertensive agent(s). Six guanidinium derivatives including agmatine, amiloride, aminoguanidine, allantoin, canavanine, and metformin were applied in this study. Western blot analysis was used for detecting the expression of imidazoline receptor in tissues of Wistar rats. The isometric tension of aortic rings isolated from male rats was also estimated. The expression of imidazoline receptor on rat aorta was identified. However, guanidinium derivatives for detection of aortic relaxation were not observed except agmatine and amiloride which induced a marked relaxation in isolated aortic rings precontracted with phenylephrine or KCl. Both relaxations induced by agmatine and amiloride were attenuated by glibenclamide at concentration enough to block ATP-sensitive potassium (KATP) channels. Meanwhile, only agmatine-induced relaxation was abolished by BU224, a selective antagonist of imidazoline I2-receptors. Taken together, we suggest that agmatine can induce vascular relaxation through activation of peripheral imidazoline I2-receptor to open KATP channels. Thus, agmatine-like compound has the potential to develop as a new therapeutic agent for hypertension in the future. PMID- 24800211 TI - Effect of ultrasonication on physical properties of mineral trioxide aggregate. AB - AIM: To evaluate the effect on physical properties of Mineral Trioxide Aggregate (MTA) of using direct hand compaction during placement and when using hand compaction with indirect ultrasonic activation with different application times. METHODS: One hundred acrylic canals were obturated in 3 increments with MTA in sample sizes of 10. One group was obturated by hand with an endodontic plugger and the remainder obturated with indirect ultrasonic application, with times ranging from 2 seconds to 18 seconds per increment. Microhardness values, dye penetration depths, and radiographs of the samples were evaluated. RESULTS: As ultrasonic application time per increment increased, microhardness values fell significantly (P < 0.001) while dye penetration values increased (P < 0.001). Microhardness of MTA ultrasonicated for 2 seconds was significantly higher than hand compaction (P = 0.03). Most radiographic voids were visible in the hand compacted group (P < 0.001), which also had higher dye penetration depths than the 2-second ultrasonicated samples. Ultrasonication of MTA for 10-18 seconds resulted in significantly more voids than 2-8 seconds of ultrasonication (P = 0.02). CONCLUSION: The use of ultrasonics with MTA improved the compaction and flow of MTA, but excessive ultrasonication adversely affected MTA properties. A time of 2 seconds of ultrasonication per increment presented the best compromise between microhardness values, dye penetration depths, and lack of radiographic voids. PMID- 24800212 TI - Transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombosis: prognostic factors in a single center study of 188 patients. AB - Transarterial chemoembolization (TACE) could achieve a better survival benefit than conservative treatment for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). In this retrospective study, all HCC patients with Child-Pugh score <7 and PVTT who were consecutively admitted to our center between January 2006 and June 2012 and underwent TACE were enrolled. The efficacy and safety of TACE were analyzed. Prognostic factors were determined by Cox regression analysis. Of the 188 patients included, 89% had hepatitis B virus infection, 100% were at Barcelona Clinic Liver Cancer stage C, and 81% (n = 152) and 19% (n = 36) were at Child-Pugh classes A and B, respectively. The incidence of procedure-related complications was 88%. No procedure-related death was found. The median overall survival was 6.1 months. Type of PVTT (hazard ratio [HR] = 2.806), number of tumor lesions (HR = 2.288), Child-Pugh class (HR = 2.981), and presence of metastasis (HR = 1.909) were the independent predictors of survival. In conclusion, TACE could be selectively used for the treatment of advanced HCC with PVTT. But a high rate of postoperative adverse events should not be undermined in spite of no procedure-related death. Preoperative type of PVTT, number of tumor lesions, Child-Pugh class, and metastasis could predict the prognosis of these patients. PMID- 24800214 TI - A novel feature selection strategy for enhanced biomedical event extraction using the Turku system. AB - Feature selection is of paramount importance for text-mining classifiers with high-dimensional features. The Turku Event Extraction System (TEES) is the best performing tool in the GENIA BioNLP 2009/2011 shared tasks, which relies heavily on high-dimensional features. This paper describes research which, based on an implementation of an accumulated effect evaluation (AEE) algorithm applying the greedy search strategy, analyses the contribution of every single feature class in TEES with a view to identify important features and modify the feature set accordingly. With an updated feature set, a new system is acquired with enhanced performance which achieves an increased F-score of 53.27% up from 51.21% for Task 1 under strict evaluation criteria and 57.24% according to the approximate span and recursive criterion. PMID- 24800213 TI - Oleoylethanolamide: a novel potential pharmacological alternative to cannabinoid antagonists for the control of appetite. AB - The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment. PMID- 24800215 TI - A paradoxical chemoresistance and tumor suppressive role of antioxidant in solid cancer cells: a strange case of Dr. Jekyll and Mr. Hyde. AB - Modulation of intracellular antioxidant concentration is a double-edged sword, with both sides exploited for potential therapeutic benefits. While antioxidants may hamper the efficacy of chemotherapy by scavenging reactive oxygen species and free radicals, it is also possible that antioxidants alleviate unwanted chemotherapy-induced toxicity, thus allowing for increased chemotherapy doses. Under normoxic environment, antioxidants neutralize toxic oxidants, such as reactive oxygen species (ROS), maintaining them within narrow boundaries level. This redox balance is achieved by various scavenging systems such as enzymatic system (e.g., superoxide dismutases, catalase, and peroxiredoxins), nonenzymatic systems (e.g., glutathione, cysteine, and thioredoxin), and metal-binding proteins (e.g., ferritin, metallothionein, and ceruloplasmin) that sequester prooxidant metals inhibiting their participation in redox reactions. On the other hand, therapeutic strategies that promote oxidative stress and eventually tumor cells apoptosis have been explored based on availability of chemotherapy agents that inhibit ROS-scavenging systems. These contradictory assertions suggest that antioxidant supplementation during chemotherapy treatment can have varied outcomes depending on the tumor cellular context. Therefore, understanding the antioxidant-driven molecular pathways might be crucial to design new therapeutic strategies to fight cancer progression. PMID- 24800216 TI - Perfluorocarbon liquid: its application in vitreoretinal surgery and related ocular inflammation. AB - The application of perfluorocarbon liquids has been well acclaimed in vitreoretinal surgery. Its unique physical properties make it an ideal intraoperative tool to improve the efficiency and safety of surgical procedures in complicated cases. The main functions of perfluorocarbon liquids in vitreoretinal surgery include relocating and fixing the detached retina, displacing the subretinal and subchoroidal to fluid anteriorly, revealing proliferative vitreous retinopathy (PVR) for further maneuvers, protecting the macula from exposure to chemicals with potential toxicity, and assisting the removal of foreign body. The related clinical applications include retinal detachment with severe proliferative vitreoretinopathy, giant tear, diabetic retinopathy (DR), retinopathy of prematurity (ROP), and posterior dislocated crystalline and intraocular lenses. The application of perfluorocarbon liquids has been expended over the past fewer years. Several PFCLs related ocular inflammations have been observed in in vitro studies, animal studies, and clinical follow-up. The complete removal of PFCLs is recommended at the end of the surgery in most cases. PMID- 24800217 TI - Engineered tumor cell apoptosis monitoring method based on dynamic laser tweezers. AB - Monitoring the cells' apoptosis progression could provide a valuable insight into the temporal events that initiate cell death as well as the potential for rescue of apoptotic cells. In this paper, we engineered a novel and robust method for monitoring apoptosis of tumor cells based on dynamic laser tweezers, using A549 and HeLa cell line as typical samples. The entire experiment can be completed in a few hours with small amount of fluid sample, presenting great advantages of celerity, microscaled measurement, and label-free explorations without perturbing experimental conditions in combination with other probes. Validity and stability of this method are verified experimentally in terms of physical parameters of the system. The proposed technique has great potential in improving cancer treatment by monitoring the objective efficacy of tumor cell killing. PMID- 24800218 TI - Formetric 4D rasterstereography. PMID- 24800219 TI - Nitrite inhalants use and HIV infection among men who have sex with men in China. AB - OBJECTIVE: This is the first study in China to examine the use of nitrite inhalants and its correlates among men who have sex with men (MSM) in Beijing, China. METHODS: A cross-sectional survey was conducted in 2012. Structured interviews collected data on demographics, sexual and drug use behaviors, and the use of HIV services. Blood specimens were collected and tested for HIV and syphilis. RESULTS: A total of 400 MSM eligible for the study were between 19 and 63 years of age and overall HIV prevalence was 6.0% (9.0% among nitrite inhalant users and 3.3% among nonusers). Nearly half (47.3%) of them reported ever using nitrite inhalants and 42.3% admitted using nitrite inhalants in the past year. Multivariable logistic analysis revealed that ever using nitrite inhalants in the past was independently associated with being aged <=25 years, having higher education attainment, seeking sex via Internet, having casual partners in the past three months, and being HIV positive. CONCLUSION: The use of nitrite inhalants was alarmingly prevalent among MSM in Beijing. The independent association of the nitrite inhalant use with more casual sex partners and HIV infection underscored the need for intervention and prevention of nitrite inhalant use. PMID- 24800220 TI - Outcome and prognostic factors in T4a oropharyngeal carcinoma, including the role of HPV infection. AB - BACKGROUND: The prognosis of patients with advanced oropharyngeal carcinoma (OPSCC) is generally poor. The aim of this study is to investigate the different therapeutic approaches and identify prognostic factors associated with a worse outcome for patients treated for T4a OPSCC, in order to improve treatment selection for the individual. METHODS: A retrospective study was conducted on 426 patients with T4a OPC treated between 1980 and 2010. Eleven prognostic factors including treatment modality, lymph node staging, and p16 status as a surrogate marker for human papillomavirus (HPV) infection were analyzed. RESULTS: Univariate analysis showed a significant difference in DSS between N0 and N+ (57.1% versus 26.9%, P < 0.001), primary surgical and primary nonsurgical treatment (52.7% versus 31.4%, P < 0.001), and perinodal invasion (51.7% versus 19.9%, P = 0.011). P16-negative patients tended towards a worse DSS than p16 positive patients (40.2% versus 64.6%, P = 0.126) but responded better to primary surgery than to nonsurgical treatment (71.4% versus 34.0%, P = 0.113). Multivariate analysis identified the N category as an independent prognostic factor for survival. CONCLUSION: The survival of p16-negative patients was worse than p16-positive patients, although they seem to respond better to primary surgery. The strongest independent prognostic factor for T4a carcinomas proved to be the presence of lymph node metastases. PMID- 24800221 TI - Study of the association between ITPKC genetic polymorphisms and calcium nephrolithiasis. AB - Nephrolithiasis is a multifactorial disease caused by environmental, hormonal, and genetic factors. Genetic polymorphisms of ORAI1, which codes for the main subunit of the store-operated calcium (SOC) channel, were reported to be associated with the risk and recurrence of calcium nephrolithiasis. Inositol 1,4,5-trisphosphate (IP3) 3-kinase C (ITPKC) is a negative regulator of the SOC channel-mediated signaling pathway. We investigated the association between calcium containing nephrolithiasis and genetic variants of ITPKC gene in Taiwanese patients. 365 patients were recruited in this study. Eight tagging single nucleotide polymorphisms of ITPKC were selected for genotyping. ITPKC genotypes were determined by TaqMan assay. ITPKC plasmids were transfected into cells to evaluate the intracellular calcium mobilization. Our results indicated that rs2607420 CC genotype in the intron region of the ITPKC gene is associated with a lower eGFR by both Modification of Diet in Renal Diseases (P = 0.0405) and Cockcroft-Gault (P = 0.0215) equations in patients with calcium nephrolithiasis. Our results identify a novel polymorphism for renal function and highlight the importance of ITPKC as a key molecule to regulate calcium signaling. PMID- 24800222 TI - Computed tomography angiography for detection of middle meningeal artery lesions associated with acute epidural hematomas. AB - BACKGROUND: The natural history of traumatic aneurysms of the middle meningeal artery (MMA) is not well known, but patients with these lesions are more likely to have delayed bleeds. In this paper, we described a series of patients with epidural hematoma who underwent angiotomography (CTA) for MMA vascular lesion diagnosis. METHODS: Eleven patients admitted to our emergency unit with small acute epidural hematoma were prospectively studied. All patients with temporal acute epidural hematomas underwent CTA and cerebral angiogram at our institution for diagnosis of posttraumatic lesions of middle meningeal artery. The findings of angiotomography and digital angiography were reviewed by radiologist and angiographers, respectively, to ensure that the lesions were readily diagnosed without knowing the results of angiotomography and to compare CTA findings with standard angiogram. RESULTS: The causes of head injury were traffic accidents, falls, and aggression. Three of these patients presented traumatic MMA pseudoaneurysm. CT angiography was able to diagnose all of them, with dimensions ranging from 1.5 to 2.8 mm. Conventional angiography confirmed the findings of CT angiography, and the lesions presented with similar dimensions at both methods. CONCLUSIONS: We believe that angiotomography can be a useful technique for diagnosis of vascular lesion associated with small epidural hematoma. PMID- 24800223 TI - Obesity and headache/migraine: the importance of weight reduction through lifestyle modifications. AB - The aim of this study is to determine a possible relationship between prevalence, frequency, and severity of migraine and obesity. All pertinent data from the literature have been critically examined and reviewed in order to assess the possible relationship between obesity and migraine, in particular migraine frequency and disability in children, as well as in adult population studies. Prevalence, frequency, and severity of migraine appear to increase in relation to the body mass index, although this evidence is not supported by all the studies examined. Data from literature suggest that obesity can be linked with migraine prevalence, frequency, and disability both in pediatric and adult subjects. These data have important clinical implications and suggest that clinicians should have a special interest for weight reduction of obese children suffering from migraine, prescribing and supporting intensive lifestyle modifications (dietary, physical activities, and behavioral) for the patient and the entire family. PMID- 24800224 TI - Review of clinical trials on effects of oral antioxidants on basic semen and other parameters in idiopathic oligoasthenoteratozoospermia. AB - Infertility affects 50 to 80 million people worldwide. Male factor is a cause of infertility in almost half of cases, mainly due to oligoasthenoteratozoospermia (OAT). With common diagnostic methods no cause can be found in approximately 30% of cases of male infertility due to OAT and these are considered idiopathic. Reactive oxygen species (ROS) play an important role in male infertility and are proved to be higher in infertile men; antioxidants could oppose their effect. The aim of this paper was to review the literature on clinical trials in the period from year 2000 to year 2013 studying the effects of various types of antioxidant supplements on basic and other sperm parameters and pregnancy rates in subfertile males with idiopathic OAT. The majority of studies were randomized and placebo controlled and confirmed beneficial effect of antioxidants on at least one of the semen parameters; the biggest effect was determined on sperm motility. In many of these trials combinations of more antioxidants were assessed. The optimal dosages of one or more antioxidants were not defined. We concluded that antioxidants play an important role in protecting semen from ROS and can improve basic sperm parameters in case of idiopathic OAT. PMID- 24800225 TI - MicroRNA roles in the NF- kappaB signaling pathway during viral infections. AB - NF- kappa B signaling network is a crucial component of innate immunity. miRNAs are a subtype of small noncoding RNAs, involved in regulation of gene expression at the posttranscriptional level. Increasing evidence has emerged that miRNAs play an important role in regulation of NF- kappa B signaling pathway during viral infections. Both host and viral miRNAs are attributed to modulation of NF- kappa B activity, thus affecting viral infection and clearance. Understandings of the mechanisms of these miRNAs will open a direction for development of novel antivirus drugs. PMID- 24800226 TI - Applied graph-mining algorithms to study biomolecular interaction networks. AB - Protein-protein interaction (PPI) networks carry vital information on the organization of molecular interactions in cellular systems. The identification of functionally relevant modules in PPI networks is one of the most important applications of biological network analysis. Computational analysis is becoming an indispensable tool to understand large-scale biomolecular interaction networks. Several types of computational methods have been developed and employed for the analysis of PPI networks. Of these computational methods, graph comparison and module detection are the two most commonly used strategies. This review summarizes current literature on graph kernel and graph alignment methods for graph comparison strategies, as well as module detection approaches including seed-and-extend, hierarchical clustering, optimization-based, probabilistic, and frequent subgraph methods. Herein, we provide a comprehensive review of the major algorithms employed under each theme, including our recently published frequent subgraph method, for detecting functional modules commonly shared across multiple cancer PPI networks. PMID- 24800227 TI - Minimally invasive video-assisted versus minimally invasive nonendoscopic thyroidectomy. AB - Minimally invasive video-assisted thyroidectomy (MIVAT) and minimally invasive nonendoscopic thyroidectomy (MINET) represent well accepted and reproducible techniques developed with the main goal to improve cosmetic outcome, accelerate healing, and increase patient's comfort following thyroid surgery. Between 2007 and 2011, a prospective nonrandomized study of patients undergoing minimally invasive thyroid surgery was performed to compare advantages and disadvantages of the two different techniques. There were no significant differences in the length of incision to perform surgical procedures. Mean duration of hemithyroidectomy was comparable in both groups, but it was more time consuming to perform total thyroidectomy by MIVAT. There were more patients undergoing MIVAT procedures without active drainage in the postoperative course and we also could see a trend for less pain in the same group. This was paralleled by statistically significant decreased administration of both opiates and nonopiate analgesics. We encountered two cases of recurrent laryngeal nerve palsies in the MIVAT group only. MIVAT and MINET represent safe and feasible alternative to conventional thyroid surgery in selected cases and this prospective study has shown minimal differences between these two techniques. PMID- 24800228 TI - Menopause and metabolic syndrome in tunisian women. AB - OBJECTIVES: This study aimed to evaluate the effect of menopausal status on the risk of metabolic syndrome (MetS) in Tunisian women. METHODS: We analyzed a total of 2680 women aged between 35 and 70 years. Blood pressure, anthropometric indices, fasting glucose, and lipid profile were measured. The MetS was assessed by the modified NCEP-ATPIII definition. RESULTS: The mean values of waist circumference, blood pressure, plasma lipids, and fasting glucose were significantly higher in postmenopausal than in premenopausal women, a difference that was no longer present when adjusting for age. Except for hypertriglyceridaemia, the frequency of central obesity, hyperglycemia, high blood pressure, and high total cholesterol was significantly higher in postmenopausal than in premenopausal women. After adjusting for age, the significance persisted only for hyperglycemia. The overall prevalence of MetS was 35.9%, higher in postmenopausal (45.7% versus 25.6%) than in premenopausal women. A binary logistic regression analysis showed that menopause was independently associated with MetS (OR = 1.41, 95% CI 1.10-1.82) after adjusting for age, residence area, marital status, family history of cardiovascular disease, education level, and occupation. CONCLUSIONS: The present study provides evidence that the MetS is highly prevalent in this group of women. Menopause can be a predictor of MetS independent of age in Tunisian women. PMID- 24800229 TI - Individual subject meta-analysis of parameters for Giardia duodenalis shedding in animal experimental models. AB - Giardia duodenalis is a zoonotic protozoan parasite with public health importance worldwide. While articles about animal model infectivity have been published for G. duodenalis, the studies have used diverse protocols and parameters to evaluate the infectivity of this protozoan parasite. Hence, the objectives of this study were to (1) conduct a meta-analysis of published literature for cyst shedding and diarrhea outcomes in animal models and (2) develop recommendations to help standardize experimental dose response studies. Results showed that, for the outcome of cyst shedding in faeces, the covariates of infective stage (cyst versus trophozoite), Giardia dose, and the interactions between doses and infective stage, as well as dose and species of experimental host, were all significant (P value <= 0.05). This study suggests inoculation of the experimental host with cysts rather than trophozoites and administration of higher doses of Giardia will most likely result in cyst shedding. Based on the results of this meta-analysis, the infective stage (cyst versus trophozoite), parasite dose, and the interactions between dose and infective stage, as well as dose and species of experimental host, should be considered when designing experimental dose response studies that will assist in the study of zoonotic neglected tropical diseases globally. PMID- 24800230 TI - Primary stability recognition of the newly designed cementless femoral stem using digital signal processing. AB - Stress shielding and micromotion are two major issues which determine the success of newly designed cementless femoral stems. The correlation of experimental validation with finite element analysis (FEA) is commonly used to evaluate the stress distribution and fixation stability of the stem within the femoral canal. This paper focused on the applications of feature extraction and pattern recognition using support vector machine (SVM) to determine the primary stability of the implant. We measured strain with triaxial rosette at the metaphyseal region and micromotion with linear variable direct transducer proximally and distally using composite femora. The root mean squares technique is used to feed the classifier which provides maximum likelihood estimation of amplitude, and radial basis function is used as the kernel parameter which mapped the datasets into separable hyperplanes. The results showed 100% pattern recognition accuracy using SVM for both strain and micromotion. This indicates that DSP could be applied in determining the femoral stem primary stability with high pattern recognition accuracy in biomechanical testing. PMID- 24800231 TI - Preliminary in vitro and in vivo evaluation of antidiabetic activity of Ducrosia anethifolia Boiss. and its linear furanocoumarins. AB - Aim. Ducrosia anethifolia is used as flavoring additive. There have been little detailed phytochemical reports on this genus and the antidiabetic activity of this plant is not yet evaluated. Method. Structure of compounds was deduced by spectroscopic analyses. Preliminary in vitro evaluation of the antidiabetic activity of crude extract and its furanocoumarins was carried out ( alpha amylase, alpha -glucosidase, and beta -galactosidase). The in vivo activity was investigated by measuring some oxidative stress markers. Biomarkers of liver injury and kidney were also determined. Results. Eight linear furanocoumarins, psoralen, 5-methoxypsoralen, 8-methoxypsoralen, imperatorin, isooxypeucedanin, pabulenol, oxypeucedanin methanolate, oxypeucedanin hydrate, and 3-O glucopyranosyl- beta -sitosterol, were isolated. All compounds were reported for the first time from the genus Ducrosia except pabulenol. The blood glucose level, liver function enzymes, total protein, lipid, and cholesterol levels were significantly normalized by extract treatment. The antioxidant markers, glucolytic, and gluconeogenic enzymes were significantly ameliorated and the elevated level of kidney biomarkers in the diabetic groups was restored. The compounds showed inhibitory activity in a concentration dependant manner. Imperatorin and 5-methoxypsoralen showed the most potent inhibiting power. Conclusion. D. anethifolia extract showed hypoglycemic, hypolipidemic, and antioxidant effect as well as ameliorating kidney function. This extract and some linear furanocoumarins exhibited carbohydrate metabolizing enzymes inhibitory effect. PMID- 24800232 TI - MicroRNA-24 modulates aflatoxin B1-related hepatocellular carcinoma prognosis and tumorigenesis. AB - MicroRNA-24 (miR-24) may be involved in neoplastic process; however, the role of this microRNA in the hepatocellular carcinoma (HCC) related to aflatoxin B1 (AFB1) has not been well elaborated. Here, we tested miR-24 expression in 207 pathology-diagnosed HCC cases from high AFB1 exposure areas and HCC cells. We found that miR-24 was upregulated in HCC tumor tissues relative to adjacent noncancerous tissue samples, and that the high expression of miR-24 was significantly correlated with larger tumor size, higher microvessel density, and tumor dedifferentiation. Additionally, this microRNA overexpression modified the recurrence-free survival (relative hazard ratio [HR], 4.75; 95% confidence interval [CI], 2.66-8.47) and overall survival (HR = 3.58, 95% CI = 2.34-5.46) of HCC patients. Furthermore, we observed some evidence of joint effects between miR 24 and AFB1 exposure on HCC prognosis. Functionally, miR-24 overexpression progressed tumor cells proliferation, inhibited cell apoptosis, and developed the formation of AFB1-DNA adducts. These results indicate for the first time that miR 24 may modify AFB1-related HCC prognosis and tumorigenesis. PMID- 24800234 TI - Evaluation of two different analytical methods for circulating tumor cell detection in peripheral blood of patients with primary breast cancer. AB - BACKGROUND: Evidence is accumulating that circulating tumor cells (CTC) out of peripheral blood can serve as prognostic marker not only in metastatic but also in early breast cancer (BC). Various methods are available to detect CTC. Comparisons between the different techniques, however, are rare. MATERIAL AND METHODS: We evaluate two different methods for CTC enrichment and detection in primary BC patients: the FDA-approved CellSearch System (CSS; Veridex, Warren, USA) and a manual immunocytochemistry (MICC). The cut-off value for positivity was >=1 CTC. RESULTS: The two different nonoverlapping patient cohorts evaluated with one or the other method were well balanced regarding common clinical parameters. Before adjuvant CHT 21.1% (416 out of 1972) and 20.6% (247 out of 1198) of the patients were CTC-positive, while after CHT 22.5% (359 out of 1598) and 16.6% (177 out of 1066) of the patients were CTC-positive using CSS or MICC, respectively. CTC positivity rate before CHT was thus similar and not significantly different (P = 0.749), while CTC positivity rate immediately after CHT was significantly lower using MICC compared to CSS (P < 0.001). CONCLUSION: Using CSS or MICC for CTC detection, we found comparable prevalence of CTC before but not after adjuvant CHT. PMID- 24800235 TI - Expression profiles of epithelial-mesenchymal transition-associated proteins in epithelial ovarian carcinoma. AB - Epithelial-mesenchymal transition (EMT) has been suggested to contribute to tumor progression and acquisition of therapeutic resistance. To assess the clinical significance of EMT-associated proteins, we evaluated the expression of Snail and Slug, the key regulators of EMT, in the primary ovarian cancer samples (n = 103) by immunohistochemistry. Snail was differentially expressed according to the histologic subtype (P = 0.001) and was predominantly expressed in serous and endometrioid types. In the serous and endometrioid adenocarcinomas, the expression of Snail remained high across the stage and grade, suggesting its role in the early phase of carcinogenesis. However, the expression of Snail and Slug was not related to chemoresistance and poor prognosis and did not serve as independent predictive or prognostic marker. PMID- 24800233 TI - MicroRNAs in hepatocellular carcinoma: carcinogenesis, progression, and therapeutic target. AB - Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer, with dismal outcomes and an increasing incidence worldwide. Hepatocarcinogenesis is a multistep process that progresses from chronic hepatitis through cirrhosis and/or dysplastic nodule to HCC. However, the detailed molecular pathogenesis remains unclear. MicroRNAs (miRNAs), small noncoding RNAs that regulate the translation of many genes, have emerged as key factors involved in several biological processes, including development, differentiation, and cell proliferation. Recent studies have uncovered the contribution of miRNAs to the cancer pathogenesis, as they can behave as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential values in the clinical management of HCC patients as some miRNAs may be used as prognostic or diagnostic markers. In this review, we summarize current knowledge about the roles of miRNAs in carcinogenesis and progression of HCC. We also discuss the potential application of miRNAs as diagnostic biomarkers and their potential roles in the intervention of HCC. PMID- 24800236 TI - The long-term prognostic significance of 6-minute walk test distance in patients with chronic heart failure. AB - BACKGROUND: The 6-minute walk test (6-MWT) is used to assess patients with chronic heart failure (CHF). The prognostic significance of the 6-MWT distance during long-term followup (>5 years) is unclear. METHODS: 1,667 patients (median [inter-quartile range, IQR]) (age 72 [65-77]; 75% males) with heart failure due to left ventricular systolic impairment undertook a 6-MWT as part of their baseline assessment and were followed up for 5 years. RESULTS: At 5 years' followup, those patients who died (n = 959) were older at baseline and had a higher log NT pro-BNP than those who survived to 5 years (n = 708). 6-MWT distance was lower in those who died [163 (153) m versus 269 (160) m; P < 0.0001]. Median 6-MWT distance was 300 (150-376) m, and quartile ranges were <46 m, 46-240 m, 241-360 m, and >360 m. 6-MWT distance was a predictor of all-cause mortality (HR 0.97; 95% CI 0.96-0.97; Chi-square = 184.1; P < 0.0001). Independent predictors of all-cause mortality were decreasing 6-MWT distance, increasing age, increasing NYHA classification, increasing log NT pro-BNP, decreasing diastolic blood pressure, decreasing sodium, and increasing urea. CONCLUSION: The 6-MWT is an important independent predictor of all-cause mortality following long-term followup in patients with CHF. PMID- 24800238 TI - Cytokines, fatigue, and cutaneous erythema in early stage breast cancer patients receiving adjuvant radiation therapy. AB - We investigated the hypothesis that patients developing high-grade erythema of the breast skin during radiation treatment could be more likely to present increased levels of proinflammatory cytokines which may lead, in turn, to associated fatigue. Forty women with early stage breast cancer who received adjuvant radiotherapy were enrolled from 2007 to 2010. Fatigue symptoms, erythema, and cytokine levels (IL-1beta, IL-2, IL6, IL-8, TNF-alpha, and MCP-1) were registered at baseline, during treatment, and after radiotherapy completion. Seven (17.5%) patients presented fatigue without associated depression/anxiety. Grade >=2 erythema was observed in 5 of these 7 patients. IL-1beta, IL-2, IL-6, and TNF-alpha were statistically increased 4 weeks after radiotherapy (P < 0.05). After the Heckman two-step analysis, a statistically significant influence of skin erythema on proinflammatory markers increase (P = 0.00001) was recorded; in the second step, these blood markers showed a significant impact on fatigue (P = 0.026). A seeming increase of fatigue, erythema, and proinflammatory markers was observed between the fourth and the fifth week of treatment followed by a decrease after RT. There were no significant effects of hormone therapy, breast volume, and anemia on fatigue. Our study seems to suggest that fatigue is related to high-grade breast skin erythema during radiotherapy through the increase of cytokines levels. PMID- 24800237 TI - Human pluripotent stem cell-derived cardiomyocytes as research and therapeutic tools. AB - Human pluripotent stem cells (hPSCs), namely, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), with their ability of indefinite self renewal and capability to differentiate into cell types derivatives of all three germ layers, represent a powerful research tool in developmental biology, for drug screening, disease modelling, and potentially cell replacement therapy. Efficient differentiation protocols that would result in the cell type of our interest are needed for maximal exploitation of these cells. In the present work, we aim at focusing on the protocols for differentiation of hPSCs into functional cardiomyocytes in vitro as well as achievements in the heart disease modelling and drug testing on the patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). PMID- 24800239 TI - NMR-based metabolomic profiling of overweight adolescents: an elucidation of the effects of inter-/intraindividual differences, gender, and pubertal development. AB - The plasma and urine metabolome of 192 overweight 12-15-year-old adolescents (BMI of 25.4 +/- 2.3 kg/m(2)) were examined in order to elucidate gender, pubertal development measured as Tanner stage, physical activity measured as number of steps taken daily, and intra-/interindividual differences affecting the metabolome detected by proton NMR spectroscopy. Higher urinary excretion of citrate, creatinine, hippurate, and phenylacetylglutamine and higher plasma level of phosphatidylcholine and unsaturated lipid were found for girls compared with boys. The results suggest that gender differences in the metabolome are being commenced already in childhood. The relationship between Tanner stage and the metabolome showed that pubertal development stage was positively related to urinary creatinine excretion and negatively related to urinary citrate content. No relations between physical activity and the metabolome could be identified. The present study for the first time provides comprehensive information about associations between the metabolome and gender, pubertal development, and physical activity in overweight adolescents, which is an important subject group to approach in the prevention of obesity and life-style related diseases. While this study is preliminary, these results may have the potential to translate into clinical applicability upon further investigations; if biomarkers for Tanner stage can be established, these might be used for identification of individuals susceptible to an early pubertal development. PMID- 24800240 TI - Biomarkers for sepsis. AB - Bloodstream infections are a major concern because of high levels of antibiotic consumption and of the increasing prevalence of antimicrobial resistance. Bacteraemia is identified in a small percentage of patients with signs and symptoms of sepsis. Biomarkers are widely used in clinical practice and they are useful for monitoring the infectious process. Procalcitonin (PCT) and C-reactive protein (CRP) have been most widely used, but even these have limited abilities to distinguish sepsis from other inflammatory conditions or to predict outcome. PCT has been used to guide empirical antibacterial therapy in patients with respiratory infections and help to determine if antibacterial therapy can be stopped. New biomarkers such as those in this review will discuss the major types of biomarkers of bloodstream infections/sepsis, including soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble urokinase-type plasminogen receptor (suPAR), proadrenomedullin (ProADM), and presepsin. PMID- 24800241 TI - Reduced bone and body mass in young male rats exposed to lead. AB - The aim of this study was to see whether there would be differences in whole blood versus tibia lead concentrations over time in growing rats prenatally. Lead was given in the drinking water at 30 mg/L from the time the dams were pregnant until offspring was 28- or 60-day-old. Concentrations of lead were measured in whole blood and in tibia after 28 (28D) and 60 days (60D) in control (C) and in lead-exposed animals (Pb). Lead measurements were made by GF-AAS. There was no significant difference (P > 0.05) in the concentration of whole blood lead between Pb-28D (8.0 +/- 1.1 MUg/dL) and Pb-60D (7.2 +/- 0.89 MUg/dL), while both significantly varied (P < 0.01) from controls (0.2 MUg/dL). Bone lead concentrations significantly varied between the Pb-28D (8.02 +/- 1.12 MUg/g) and the Pb-60D (43.3 +/- 13.26 MUg/g) lead-exposed groups (P < 0.01), while those exposed groups were also significantly higher (P < 0.0001) than the 28D and 60D control groups (Pb < 1 MUg/g). The Pb-60D group showed a 25% decrease in tibia mass as compared to the respective control. The five times higher amount of lead found in the bone of older animals (Pb-60D versus Pb-28D), which reinforces the importance of using bone lead as an exposure biomarker. PMID- 24800242 TI - MicroRNAs 146a and 147b biomarkers for colorectal tumor's localization. AB - The recently identified class of microRNAs (miRs) provided a new insight into cancer research, since abnormalities of members of microRNAs family have been found in various types of cancer. However, the relationship between five miRNAs (miR146a, miR155, miR21, miR135a, and miR147b) and colorectal cancer remains unclear. In the present study, we examined expression of these miRNAs in 25 pair matched colon cancer tissues and normal colon mucosa. The expression levels of miR146a, miR155, miR21, miR135a, and miR147b were quantified by real-time PCR. We found that miR21, miR146a, and miR135a were all expressed at higher levels in colon tumors. On the other hand, miR146a and miR147b expressions are significantly higher in left colon compared to right colon. These two miRs, especially miR146a, seemed to be markers for the left colon tumors. Moreover, significant proportional and inverse correlations were found between miR expressions in tumor and healthy tissue, and the correlations profiles were different depending on cancer localization. Taken together, these results lead us to suggest the presence of different mechanisms regulating miRs expression and consequently their target genes in left and right colon. So the pathway of colorectal carcinogenesis would be different according to the site of the tumor. PMID- 24800243 TI - The double-edged sword in pathogenic trypanosomatids: the pivotal role of mitochondria in oxidative stress and bioenergetics. AB - The pathogenic trypanosomatids Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. are the causative agents of African trypanosomiasis, Chagas disease, and leishmaniasis, respectively. These diseases are considered to be neglected tropical illnesses that persist under conditions of poverty and are concentrated in impoverished populations in the developing world. Novel efficient and nontoxic drugs are urgently needed as substitutes for the currently limited chemotherapy. Trypanosomatids display a single mitochondrion with several peculiar features, such as the presence of different energetic and antioxidant enzymes and a specific arrangement of mitochondrial DNA (kinetoplast DNA). Due to mitochondrial differences between mammals and trypanosomatids, this organelle is an excellent candidate for drug intervention. Additionally, during trypanosomatids' life cycle, the shape and functional plasticity of their single mitochondrion undergo profound alterations, reflecting adaptation to different environments. In an uncoupling situation, the organelle produces high amounts of reactive oxygen species. However, these species role in parasite biology is still controversial, involving parasite death, cell signalling, or even proliferation. Novel perspectives on trypanosomatid-targeting chemotherapy could be developed based on better comprehension of mitochondrial oxidative regulation processes. PMID- 24800244 TI - Comment on "Vitamin D status in migraine patients: a case-control study". PMID- 24800245 TI - Reconciliation of gene and species trees. AB - The first part of the paper briefly overviews the problem of gene and species trees reconciliation with the focus on defining and algorithmic construction of the evolutionary scenario. Basic ideas are discussed for the aspects of mapping definitions, costs of the mapping and evolutionary scenario, imposing time scales on a scenario, incorporating horizontal gene transfers, binarization and reconciliation of polytomous trees, and construction of species trees and scenarios. The review does not intend to cover the vast diversity of literature published on these subjects. Instead, the authors strived to overview the problem of the evolutionary scenario as a central concept in many areas of evolutionary research. The second part provides detailed mathematical proofs for the solutions of two problems: (i) inferring a gene evolution along a species tree accounting for various types of evolutionary events and (ii) trees reconciliation into a single species tree when only gene duplications and losses are allowed. All proposed algorithms have a cubic time complexity and are mathematically proved to find exact solutions. Solving algorithms for problem (ii) can be naturally extended to incorporate horizontal transfers, other evolutionary events, and time scales on the species tree. PMID- 24800246 TI - Identification of simple sequence repeat biomarkers through cross-species comparison in a tag cloud representation. AB - Simple sequence repeats (SSRs) are not only applied as genetic markers in evolutionary studies but they also play an important role in gene regulatory activities. Efficient identification of conserved and exclusive SSRs through cross-species comparison is helpful for understanding the evolutionary mechanisms and associations between specific gene groups and SSR motifs. In this paper, we developed an online cross-species comparative system and integrated it with a tag cloud visualization technique for identifying potential SSR biomarkers within fourteen frequently used model species. Ultraconserved or exclusive SSRs among cross-species orthologous genes could be effectively retrieved and displayed through a friendly interface design. Four different types of testing cases were applied to demonstrate and verify the retrieved SSR biomarker candidates. Through statistical analysis and enhanced tag cloud representation on defined functional related genes and cross-species clusters, the proposed system can correctly represent the patterns, loci, colors, and sizes of identified SSRs in accordance with gene functions, pattern qualities, and conserved characteristics among species. PMID- 24800247 TI - Assessing response using 99mTc-MIBI early after interstitial chemotherapy with carmustine-loaded polymers in glioblastoma multiforme: preliminary results. AB - Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel) are difficult to assess with imaging because of time-related imaging changes. (99m)Tc-sestamibi (MIBI) brain single-photon emission tomography (SPET) has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM). Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients), soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel) was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group (P = 0.0316). The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin (P = 0.0528). Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery. PMID- 24800248 TI - An overview of fotemustine in high-grade gliomas: from single agent to association with bevacizumab. AB - Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas. PMID- 24800249 TI - Meconium indicators of maternal alcohol abuse during pregnancy and association with patient characteristics. AB - AIM: Identification of women with moderate alcohol abuse during pregnancy is difficult. We correlated self-reported alcohol consumption during pregnancy and patient characteristics with objective alcohol indicators measured in fetal meconium. METHODS: A total of 557 women singleton births and available psychological tests, obstetric data and meconium samples were included in statistical analysis. Alcohol metabolites (fatty acid ethyl esters (FAEEs) and ethyl glucuronide (EtG)), were determined from meconium and correlated with patient characteristics. RESULTS: We found that 21.2% of the 557 participants admitted low-to-moderate alcohol consumption during pregnancy. Of the parameters analyzed from meconium, only EtG showed an association with alcohol history (P < 0.01). This association was inverse in cases with EtG value above 120 ng/g. These values indicate women with most severe alcohol consumption, who obviously denied having consumed alcohol during pregnancy. No other associations between socioeconomic or psychological characteristics and the drinking status (via meconium alcohol metabolites) could be found. CONCLUSION: Women who drink higher doses of ethanol during pregnancy, according to metabolite measures in meconium, might be less likely to admit alcohol consumption. No profile of socioeconomic or psychological characteristics of those women positively tested via meconium could be established. PMID- 24800250 TI - First trimester biomarkers in the prediction of later pregnancy complications. AB - Adverse obstetric outcomes, such as preeclampsia, preterm birth, gestational diabetes, and fetal growth restriction, are poorly predicted by maternal history and risk factors alone, especially in nulliparae. The ability to predict these outcomes from the first trimester would allow for the early initiation of prophylactic therapies, institution of an appropriate model and location of care, and recruitment of a truly "high risk" population to clinical trials of interventions to prevent or ameliorate these conditions. To this end, development of adequately sensitive and specific predictive tests for these outcomes has become a significant focus of perinatal research. This paper reviews the biomarkers involved in these multiparametric tests and also outlines the performance of these tests and issues regarding their introduction into clinical practice. PMID- 24800252 TI - IL-6, IL-8, and IL-10 are associated with hyperferritinemia in rapidly progressive interstitial lung disease with polymyositis/dermatomyositis. AB - OBJECTIVE: Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM. METHODS: This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1beta, IL-2, IL 4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-alpha, IFN-alpha, IFN gamma, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. RESULTS: The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF alpha, were significantly correlated with disease activity. In a multivariate analysis, IL-6 (t = 3.6, P = 0.0010), IL-8 (t = 4.8, P < 0.0001), and IL-10 (t = 5.7, P < 0.0001) significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. CONCLUSION: IL-6, IL-8, and IL 10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM. PMID- 24800251 TI - Deregulation of bone forming cells in bone diseases and anabolic effects of strontium-containing agents and biomaterials. AB - Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium effects on bone has led to its expected application in a variety of biomaterial scaffolds used in tissue engineering strategies aiming at bone repairing and regeneration. While summarizing the recent progress in these respects, this review also proposes the new approaches such as systems biology in order to reveal new insights in the pathology of osteoporosis as well as possible discovery of new therapies. PMID- 24800253 TI - Tracking the biogenesis and inheritance of subpellicular microtubule in Trypanosoma brucei with inducible YFP-alpha-tubulin. AB - The microtubule cytoskeleton forms the most prominent structural system in Trypanosoma brucei, undergoing extensive modifications during the cell cycle. Visualization of tyrosinated microtubules leads to a semiconservative mode of inheritance, whereas recent studies employing microtubule plus end tracking proteins have hinted at an asymmetric pattern of cytoskeletal inheritance. To further the knowledge of microtubule synthesis and inheritance during T. brucei cell cycle, the dynamics of the microtubule cytoskeleton was visualized by inducible YFP-alpha-tubulin expression. During new flagellum/flagellum attachment zone (FAZ) biogenesis and cell growth, YFP-alpha-tubulin was incorporated mainly between the old and new flagellum/FAZ complexes. Cytoskeletal modifications at the posterior end of the cells were observed with EB1, a microtubule plus end binding protein, particularly during mitosis. Additionally, the newly formed microtubules segregated asymmetrically, with the daughter cell inheriting the new flagellum/FAZ complex retaining most of the new microtubules. Together, our results suggest an intimate connection between new microtubule formation and new FAZ assembly, consequently leading to asymmetric microtubule inheritance and cell division. PMID- 24800254 TI - Is contrast medium osmolality a causal factor for contrast-induced nephropathy? AB - The exact pathophysiology of contrast-induced nephropathy (CIN) is not fully clarified, yet the osmotic characteristics of contrast media (CM) have been a significant focus in many investigations of CIN. Osmotic effects of CM specific to the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Potentially significant secondary effects include an osmotically induced diuresis with a concomitant dehydrating effect. Clinical experiences that have compared the occurrence of CIN between the various classes of CM based on osmolality have suggested a much less than anticipated advantage, if any, with a lower osmolality. Recent animal experiments actually suggest that induction of a mild osmotic diuresis in association with iso-osmolar agents tends to offset potentially deleterious renal effects of high viscosity-mediated intratubular CM stagnation. PMID- 24800255 TI - Montanoa frutescens and Montanoa grandiflora extracts reduce anxiety-like behavior during the metestrus-diestrus phase of the ovarian cycle in Wistar rats. AB - In previous studies, the anxiolytic-like effects of Montanoa tomentosa and Montanoa frutescens were reported in male rats, but the potential anxiolytic-like effects of Montanoa plants during the different phases of the ovarian cycle in rats remain to be explored. The anxiolytic-like effects of the aqueous crude extracts of M. frutescens (25 and 50 mg/kg) and M. grandiflora (25 and 50 mg/kg) in the elevated plus maze were investigated in Wistar rats during the estrous cycle and compared with 2 mg/kg diazepam as a reference anxiolytic drug. To investigate any motor effect (i.e., hyperactivity, no changes, or hypoactivity) associated with the treatments, the rats were evaluated in the open field test. The M. frutescens (25 and 50 mg/kg) and M. grandiflora (50 mg/kg) extracts exerted anxiolytic-like effects during the metestrus-diestrus phase, similar to diazepam, without disrupting spontaneous motor activity. No significant effects of the extracts were detected in either behavioral test during the proestrus estrus phase, whereas diazepam produced motor hypoactivity in the open field test. These results indicate that the M. frutescens and M. grandiflora extracts possess anxiolytic-like effects that depend on the ovarian cycle phase, supporting the Mexican ancient medicinal use of these plants to ameliorate anxiety disorders. PMID- 24800256 TI - Comparison of the effect of lidocaine adding dexketoprofen and paracetamol in intravenous regional anesthesia. AB - OBJECTIVE: Comparison of dexketoprofen and paracetamol added to the lidocaine in Regional Intravenous Anesthesia in terms of hemodynamic effects, motor and sensorial block onset times, intraoperative VAS values, and analgesia requirements. METHOD: The files of 73 patients between 18 and 65 years old in the ASA I-II risk group who underwent hand and forearm surgery were analyzed and 60 patients were included in the study. Patients were divided into 3 groups: Group D (n = 20), 3 mg/kg 2% lidocaine and 50 mg/2 mL dexketoprofen trometamol; Group P (n = 20), 3 mg/kg 2% lidocaine and 3 mg/kg paracetamol; Group K (n = 20), 3 mg/kg 2% lidocaine. Demographic data, motor and sensorial block times, heart rate, mean blood pressure, VAS values, and intraoperative and postoperative analgesia requirements were recorded. RESULTS: Sensorial and motor block onset durations of Group K were significantly longer than other groups. Motor block termination duration was found to be significantly longer in Group D than in Group K. VAS values of Group K were found higher than other groups. There was no significant difference in VAS values between Group D and Group P. Analgesia requirement was found to be significantly more in Group K than in Group P. There was no significant difference between the groups in terms of heart rates and mean arterial pressures. CONCLUSION: We concluded that the addition of 3 mg/kg paracetamol and 50 mg dexketoprofen to lidocaine as adjuvant in Regional Intravenous Anesthesia applied for hand and/or forearm surgery created a significant difference clinically. PMID- 24800257 TI - Evaluation of virtual touch tissue imaging quantification, a new shear wave velocity imaging method, for breast lesion assessment by ultrasound. AB - OBJECTIVES: To evaluate virtual touch tissue imaging quantification (VTIQ) as a new elastography method concerning its intra- and interexaminer reliability and its ability to differentiate benign from malignant breast lesions in comparison to and in combination with ultrasound (US) B-mode breast imaging reporting and data system (BI-RADS) assessment. MATERIALS AND METHODS: US and VTIQ were performed by two examiners in 103 women with 104 lesions. Intra- and interexaminer reliability of VTIQ was assessed. The area under the receiver operating curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of BIRADS, VTIQ, and combined data were compared. RESULTS: Fifty-four of 104 lesions were malignant. Intraexaminer reliability was consistent, and interexaminer agreement showed a strong positive correlation (r = 0.93). The mean VTIQ values in malignant lesions were significantly higher than those in benign (7.73 m/s +/- 1.02 versus 4.46 m/s +/- 1.87; P < 0.0001). The combination of US-BIRADS with the optimal cut-off for clinical decision making of 5.18 m/s yielded a sensitivity of 98%, specificity of 82%, PPV of 86%, and NPV of 98%. The combination of BIRADS and VTIQ led to improved test validity. CONCLUSION: VTIQ is highly reliable and reproducible. There is a significant difference regarding the mean maximum velocity of benign and malignant lesions. Adding VTIQ to BIRADS assessment improves the specificity. PMID- 24800258 TI - Mental health status among married working women residing in Bhubaneswar city, India: a psychosocial survey. AB - Mental health is a major public health concern worldwide. This study aimed to assess the mental health status and its correlates among married working women residing in Bhubaneswar city of Odisha, India. A cross-sectional study was undertaken in 240 households involving 240 married working women following a multistage cluster random sampling design. Using the predesigned, pretested interview schedule and self-reporting questionnaire, all relevant information was collected. Our study revealed that 32.9% of study respondents had poor mental health and only about 10% of these women had sought any kind of mental health services. Logistic regression analysis showed that 3 predictors such as favourable attitude of colleagues, sharing their own problems with husband, and spending time for yoga/meditation/exercise had significant positive impact on the mental health status of married working women. A preventive program regarding various aspects of mental health for married working women at workplace as well as community level could be a useful strategy in reducing this public health problem. PMID- 24800259 TI - The endothelium, a protagonist in the pathophysiology of critical illness: focus on cellular markers. AB - The endotheliumis key in the pathophysiology of numerous diseases as a result of its precarious function in the regulation of tissue homeostasis. Therefore, its clinical evaluation providing diagnostic and prognostic markers, as well as its role as a therapeutic target, is the focus of intense research in patientswith severe illnesses. In the critically ill with sepsis and acute brain injury, the endothelium has a cardinal function in the development of organ failure and secondary ischemia, respectively. Cellular markers of endothelial function such as endothelial progenitor cells (EPC) and endothelialmicroparticles (EMP) are gaining interest as biomarkers due to their accessibility, although the lack of standardization of EPC and EMP detection remains a drawback for their routine clinical use. In this paper we will review data available on EPC, as a general marker of endothelial repair, and EMP as an equivalent of damage in critical illnesses, in particular sepsis and acute brain injury. Their determination has resulted in new insights into endothelial dysfunction in the critically ill. It remains speculative whether their determination might guide therapy in these devastating acute disorders in the near future. PMID- 24800260 TI - Postsurgical pathologies associated with intradural electrical stimulation in the central nervous system: design implications for a new clinical device. AB - Spinal cord stimulation has been utilized for decades in the treatment of numerous conditions such as failed back surgery and phantom limb syndromes, arachnoiditis, cancer pain, and others. The placement of the stimulating electrode array was originally subdural but, to minimize surgical complexity and reduce the risk of certain postsurgical complications, it became exclusively epidural eventually. Here we review the relevant clinical and experimental pathologic findings, including spinal cord compression, infection, hematoma formation, cerebrospinal fluid leakage, chronic fibrosis, and stimulation-induced neurotoxicity, associated with the early approaches to subdural electrical stimulation of the central nervous system, and the spinal cord in particular. These findings may help optimize the safety and efficacy of a new approach to subdural spinal cord stimulation now under development. PMID- 24800263 TI - Electroluminescence from serpentine carbon nanotube based light-emitting diodes on quartz. AB - A light-emitting diode is fabricated and characterized on a semiconducting serpentine CNT which has many parallel segments with identical chirality. Compared with the individual CNT and CNT-film devices, the device with parallel segments shows improvement of an order of magnitude in current, significantly larger electroluminescent intensity, and narrower emission bands. Serpentine nanotubes are an ideal choice for practical applications of CNT-based light sources. PMID- 24800262 TI - Validation of the STOP-BANG Questionnaire among Patients Referred for Suspected Obstructive Sleep Apnea. AB - BACKGROUND: The STOP-BANG is a simple obstructive sleep apnea (OSA) screening tool, part questionnaire (STOP) and part demographic or physical measures (BANG), developed for use in preoperative surgical clinics. This study assessed sensitivity and specificity of the instrument among patients referred to a sleep disorders laboratory, and also its performance characteristics when BANG physical measures are patient-reported rather than measured. METHODS: Adults referred for diagnostic polysomnography completed the STOP questions and answered four yes/no questions (BANG self-reported) about their body mass index (weight and height), age, neck circumference, and gender, which were also assessed by laboratory technologists (BANG-measured). RESULTS: Among N=219 subjects (mean age 46.3 +/- 13.9 [s.d.] years; 98 [44.8%] males) the sensitivity of the STOP-BANG measured for an apnea/hypopnea index (AHI, events per hour of sleep) >5, >15, and >30 was 82, 93, and 97% respectively. Corresponding negative predictive values were 44, 87, and 96%. Specificities were comparatively low (48, 40, and 33%). The STOP BANG measured and STOP-BANG self-reported scores showed essentially equivalent test characteristics against polysomnography. CONCLUSIONS: The STOP-BANG appears to have limited utility in a referred, sleep laboratory setting. Negative results help to identify some individuals as unlikely to have moderate-to-severe apnea, and may thereby prove useful in identification of patients who would benefit more from laboratory studies than home studies. A STOP-BANG in which all information is self-reported may be as effective as the original version, and has potential to facilitate research or community screening where good negative predictive value is required for an effective screening tool. PMID- 24800261 TI - The dual role of HLA-G in cancer. AB - We here review the current data on the role of HLA-G in cancer based on recent findings of an unexpected antitumor activity of HLA-G in hematological malignancies. For the past decade, HLA-G has been described as a tumor-escape mechanism favoring cancer progression, and blocking strategies have been proposed to counteract it. Aside from these numerous studies on solid tumors, recent data showed that HLA-G inhibits the proliferation of malignant B cells due to the interaction between HLA-G and its receptor ILT2, which mediates negative signaling on B cell proliferation. These results led to the conjecture that, according to the malignant cell type, HLA-G should be blocked or conversely induced to counteract tumor progression. In this context, we will here present (i) the dual role of HLA-G in solid and liquid tumors with special emphasis on (ii) the HLA-G active structures and their related ILT2 and ILT4 receptors and (iii) the current knowledge on regulatory mechanisms of HLA-G expression in tumors. PMID- 24800264 TI - Canine demodicosis: the relationship between response to treatment of generalised disease and markers for inflammation and oxidative status. AB - BACKGROUND: Determination of acute phase proteins and markers of oxidative status may be of value for evaluating the severity of disease and the response to treatment. In canine demodicosis, there is no information available regarding the use of such analytes to discriminate between localized and generalized demodicosis or to monitor the response to treatment. HYPOTHESIS/OBJECTIVES: The aim was to measure analytes related to inflammation and oxidative stress in dogs with localized or generalized demodicosis. In cases of generalized demodicosis, the intention was to study these analytes before and after a period of treatment. ANIMALS: Serum was obtained from three groups: Group 1, healthy dogs; Group 2, dogs with localized demodicosis; and Group 3, dogs with generalized demodicosis. METHODS: Animals from Groups 1 and 2 were sampled at the point of diagnosis. Dogs in Group 3 were treated with oral ivermectin 1% at 0.6 mg/kg once daily, and samples were collected at the point of diagnosis and after 30 days of treatment. C-Reactive protein, haptoglobin, albumin, butyrylcholinesterase, paraoxonase-1 and total antioxidant capacity were measured. RESULTS: Dogs with generalized demodicosis had significantly higher concentrations of C-reactive protein and haptoglobin and lower butyrylcholinesterase activity than dogs in Groups 1 and 2. Dogs in Group 3 also had lower paraoxonase-1 than those in Group 2, The analytes tended to normalize during treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: There was an evident acute phase response and changes in selected oxidative state analytes in generalized demodicosis that do not occur in the localized form. These changes could be used for monitoring the response to treatment. PMID- 24800265 TI - Equine intradermal test threshold concentrations for house dust mite and storage mite allergens and identification of stable acari fauna. AB - BACKGROUND: House dust mite (HDM) and storage mite (SM) stable fauna and their associated equine intradermal test (IDT) threshold concentrations (TCs) for the midwestern region of the USA are unknown. HYPOTHESIS/OBJECTIVES: To determine IDT TCs and serum IgE concentrations for two HDM and three SM species in clinically normal horses over two seasons, and to identify the mite taxa and habitats in a stable. ANIMALS: Thirty-eight clinically normal horses. METHODS: Threshold concentrations for HDMs and SMs were determined using IDT subjective measurements and a statistical model. An enzyme-linked immunosorbent assay was used to quantify serum IgE concentrations for the same mite species. A modified flotation method was used to identify morphologically HDMs and SMs. RESULTS: Subjective IDT TCs were as follows: 1:80,000 w/v for Dermatophagoides farinae in both seasons; 1:80,000 w/v in spring and 1:160,000 w/v in late summer for Dermatophagoides pteronyssinus; 1:40,000 w/v in spring and 1:20,000 w/v in late summer for Acarus siro; 1:20,000 w/v for Lepidoglyphus destructor in both seasons; and 1:20,000 w/v in spring and 1:10,000 w/v in late summer for Tyrophagus putrescentiae. Statistically significant associations for increased serum IgE and a positive IDT reaction were evident for D. farinae in the spring and D. pteronyssinus in both seasons. One mite from all four genera specific to this study was identified; however,two HDM and A. siro species were not detected.Conclusions and clinical importance - This study established HDM and SM IDT dilution concentrations for the horses in this region. Exposure to diverse acaridae fauna may contribute to the pathogenesis of equine allergic disease. PMID- 24800266 TI - On the role of survivin as a stem cell biomarker of canine hair follicle and related tumours. AB - BACKGROUND: Survivin has been identified as one of the most cancer-specific molecules, with a dual function of apoptosis inhibitor and orchestrator of cell division. HYPOTHESIS/OBJECTIVES: Based on our recent results obtained during the study of the role of survivin in epithelial-to-mesenchymal transition, we investigate its potential role in maintenance of stemness in both the normal canine hair follicle and related tumours. METHODS: We performed a simultaneous evaluation, by immunofluorescence, of the expression of survivin and CK15. CK15 was selected as a marker for epidermal and hair follicle stem cells, based on its ability to identify hair follicle stem cells in the normal hair follicle and in canine follicular tumours. In this study, six cases were selected from the cases of hair follicle tumours evaluated in previous studies, based on the highest immunoreactivity for survivin and CK15. Three samples of healthy canine skin were also included as a normal control. RESULTS: A partial co-localization of the molecules was observed in normal hair follicles, as well as in trichoepitheliomas and trichoblastomas. In particular, a different co-expression was observed in relationship to the hair follicle cycle stage. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings suggest that survivin could play an important role in the maintenance of the hair follicle cycle as well as in tumour initiation and maintenance of cancer stem cells. PMID- 24800267 TI - Evaluation of anti-Mullerian hormone in a dog with a Sertoli cell tumour. AB - BACKGROUND: Testicular tumours are common in elderly male dogs, and Sertoli cell tumours (SCTs) are among the most common. An increase in blood estradiol concentration is often seen in canine SCTs, but such measurements do not necessarily correlate with the clinical signs. CASE REPORT: A 6-year-old male Pembroke Welsh corgi was referred for nonpruritic alopecia. Clinical examination revealed cryptorchidism of the right testicle, and blood tests showed an increased estradiol concentration. The cryptorchid testis was removed by laparotomy, and SCT was diagnosed histologically. An enzyme-linked immunosorbent assay kit designed to measure human anti-Mullerian hormone (AMH) revealed a very high preoperative serum AMH concentration, which decreased after surgery. The serum AMH concentrations of two intact healthy control male dogs were lower than that of the dog with the SCT before treatment but higher than thoseof two healthy castrated male dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine serum AMH concentrations, as measured by a human AMH enzyme-linked immunosorbent assay, may be useful as a marker for canine SCT. PMID- 24800268 TI - Hydrodynamic capture of microswimmers into sphere-bound orbits. AB - Self-propelled particles can exhibit surprising non-equilibrium behaviors, and how they interact with obstacles or boundaries remains an important open problem. Here we show that chemically propelled micro-rods can be captured, with little change in their speed, into close orbits around solid spheres resting on or near a horizontal plane. We show that this interaction between sphere and particle is short-range, occurring even for spheres smaller than the particle length, and for a variety of sphere materials. We consider a simple model, based on lubrication theory, of a force- and torque-free swimmer driven by a surface slip (the phoretic propulsion mechanism) and moving near a solid surface. The model demonstrates capture, or movement towards the surface, and yields speeds independent of distance. This study reveals the crucial aspects of activity driven interactions of self-propelled particles with passive objects, and brings into question the use of colloidal tracers as probes of active matter. PMID- 24800269 TI - Selective confinement of oleylamine capped Au nanoparticles in self-assembled PS b-PEO diblock copolymer templates. AB - Amphiphilic polystyrene-block-polyethylene oxide (PS-b-PEO) block copolymers (BCPs) have been demonstrated to be effective in directing organization of colloidal Au nanoparticles (NPs). Au NPs have been incorporated into the polymer and the different chemical affinity between the NP surface and the two blocks of the BCP has been used as a driving force of the assembling procedure. The morphology of the nanocomposites, prepared and fabricated as thin films, has been investigated by means of atomic force and scanning electron microscopies as a function of the NP content and BCP molecular weight. NPs have been effectively dispersed in PS-b-PEO hosts at any investigated content (up to 17 wt%) and a clear effect of the BCP properties on the final nanocomposite morphology has been highlighted. Finally, electrostatic force microscopy has demonstrated the conductive properties of the nanocomposite films, showing that the embedded Au NPs effectively convey their conductive properties to the film. The overall investigation has confirmed the selective confinement of the as-prepared surfactant-coated metal NPs in the PS block of PS-b-PEO, thus proposing a very simple and prompt assembling tool for nanopatterning, potentially suitable for optoelectronic, sensing and catalysis applications. PMID- 24800270 TI - Predictive modeling of post bioprinting structure formation. AB - Cellular particle dynamics (CPD) is an effective computational method to describe the shape evolution and biomechanical relaxation processes in systems composed of micro tissues such as multicellular aggregates. Therefore, CPD is a useful tool to predict the outcome of postprinting structure formation in bioprinting. The predictive power of CPD has been demonstrated for multicellular systems composed of identical volume-conserving spherical and cylindrical bioink units. Experiments and computer simulations were related through an independently developed theoretical formalism based on continuum mechanics. Here we generalize the CPD formalism to (i) include non-identical bioink particles often used in specific bioprinting applications, (ii) describe the more realistic experimental situation in which during the post-printing structure formation via the fusion of spherical bioink units the volume of the system decreases, and (iii) directly connect CPD simulations to the corresponding experiments without the need of the intermediate continuum theory inherently based on simplifying assumptions. PMID- 24800271 TI - Impact of ion valency on the assembly of vimentin studied by quantitative small angle X-ray scattering. AB - The assembly kinetics of intermediate filament (IF) proteins from tetrameric complexes to single filaments and networks depends on the protein concentration, temperature and the ionic composition of their environment. We systematically investigate how changes in the concentration of monovalent potassium and divalent magnesium ions affect the internal organization of the resulting filaments. Small angle X-ray scattering (SAXS) is very sensitive to changes in the filament cross section such as diameter or compactness. Our measurements reveal that filaments formed in the presence of magnesium chloride differ distinctly from filaments formed in the presence of potassium chloride. The principle multi-step assembly mechanism from tetramers via unit-length filaments (ULF) to elongated filaments is not changed by the valency of ions. However, the observed differences indicate that the magnesium ions free the head domains of tetramers from unproductive interactions to allow assembly but at the same time mediate strong inter tetrameric interactions that impede longitudinal annealing of unit-length filaments considerably, thus slowing down filament growth. PMID- 24800272 TI - Sharpening the surface of magnetic paranematic droplets. AB - In a non-uniform magnetic field, the droplets of colloids of nickel nanorods and nanobeads aggregate to form a cusp at the droplet surface not deforming the entire droplet shape. When the field is removed, nanorods diffuse away and the cusp disappears. Spherical particles can form cusps in a similar way, but they stay aggregated after the release of the field; finally, the aggregates settle down to the bottom of the drop. The X-ray phase contrast imaging reveals that nanorods in the cusps stay parallel to each other without visible spatial order of their centers of mass. The formation of cusps can be explained with a model that includes magnetostatic and surface tension forces. The discovered possibility of controlled assembly and quenching of nanorod orientation under the cusped liquid surface offers vast opportunities for alignment of carbon nanotubes, nanowires and nanoscrolls, prior to spinning them into superstrong and multifunctional fibers. Magnetostatic and electrostatic analogies suggest that a similar ideal alignment can be achieved with the rod-like dipoles subject to a strong electric field. PMID- 24800274 TI - Ethical considerations in adolescent drug research. PMID- 24800275 TI - Design of a lens-to-channel waveguide system as a solar concentrator structure. AB - We present a lens-to-channel waveguide solar concentrator, where the lens array and the channel waveguide act as the primary and the secondary concentrator. Sunlight collected by the lens array is coupled into channel waveguides and exits from one end of the tapered waveguide directly onto photovoltaic cells. A 45 degrees coupler is placed at each lens focal point to couple light into the waveguides. This configuration eliminates any inherent decoupling losses. We provide a detailed math model and simulation results using exemplar system parameters, showing that this structure can achieve 800x concentration at 89.1% optical efficiency under +/-0.7 degrees incidence angle. PMID- 24800276 TI - Improving performances of Fresnel CPV systems: Fresnel-RXI Kohler concentrator. AB - The optical design presented here has been done in order to achieve superior optical performance in comparison with the state-of-the-art Fresnel CPV systems. The design consists of a Photovoltaic Concentrator (CPV) comprising a Fresnel lens (F) as a Primary Optical Element (POE) and a dielectric solid RXI as a Secondary Optical Element (SOE), both with free-form surfaces (i.e. neither rotational nor linearly symmetric). It is the first time the RXI-type geometry has been applied to a CPV secondary. This concentrator has ultra-high CAP value ready to accommodate more efficient cells eventually to be developed and used commercially in future. PMID- 24800277 TI - Dish-based high concentration PV system with Kohler optics. AB - We present work at the Steward Observatory Solar Lab on a high concentration photovoltaic system in which sunlight focused by a single large paraboloidal mirror powers many small triple-junction cells. The optical system is of the XRX Kohler type, comprising the primary reflector (X) and a ball lens (R) at the focus that reimages the primary reflector onto an array of small reflectors (X) that apportion the light to the cells. We present a design methodology that provides generous tolerance to mis-pointing, uniform illumination across individual cells, minimal optical loss and even distribution between cells, for efficient series connection. An operational prototype has been constructed with a 3.3m x 3.3m square primary reflector of 2m focal length powering 36 actively cooled triple-junction cells at 1200x concentration (geometric). The measured end to-end system conversion efficiency is 28%, including the parasitic loss of the active cooling system. Efficiency ~32% is projected for the next system. PMID- 24800278 TI - Enhanced photocarrier generation in large-scale photonic nanostructures fabricated from vertically aligned quantum dots. AB - We demonstrate enhanced photocarrier generation using photonic nanostructures fabricated by a wet etching technique with vertically aligned quantum dots (QDs). Using photoluminescence excitation spectroscopy, we found that the photocarrier generation in Ge/Si QDs placed close to the surface is enhanced below the band gap energy of crystalline silicon. The enhancement is explained by light trapping owing to the photonic nanostructures. Electromagnetic wave simulations indicate that the photonic nanostructure with a subwavelength size will be available to light trapping for efficient photocarrier generation by increasing their dip depth. PMID- 24800280 TI - GRIN planar waveguide concentrator used with a single axis tracker. AB - It is generally accepted that small to medium level concentrators could be used as cost-competitive replacements for tracked solar panels. The objective is to design a system that can reach a good level of sun concentration with only one sun-tracking axis and is cheap to fabricate. As the most critical parameter for all concentrator designs, optical efficiency needed improvement to reduce the cost of power produced by our system. By using a graded-index planar waveguide with an index profile similar to SELFOC fiber, the ray's path can be controlled. Also, the concentrator can be fabricated in a single block, which reduces Fresnel reflections. Overall, the optical efficiency can be improved by as much as 33% compared to the same system made with a homogeneous waveguide. Furthermore, the ability to cost-effectively fabricate the concentrator by molding can be preserved, making it possible to reduce the cost of the solar power produced. PMID- 24800279 TI - A two-step design method for high compact rotationally symmetric optical system for LED surface light source. AB - A two-step optimization method is proposed to design a compact single-surface far field illumination system, satisfying the requirements of illuminance uniformity and light control efficiency with h/D less than 3:1. In the first step, the conventional tailored edge-ray design (TED) method is employed to generate prescribed illumination distribution for the rotationally symmetric optical system, and an optimization process is added to reach a balance between illuminance uniformity and light control efficiency. Based on the improved TED method, we can construct an initial optical system more accurate than that obtained by point source assumption. In the second step, an iterative feedback modification process is employed to optimize the initial optical system, so that the degradation of performance due to insufficient control of skew rays is mitigated. Because the initial optical system constructed in the first step is accurate enough, the second-step feedback modification can converge to a satisfactory result within several iterations. As an example, a free-form rotationally symmetric lens with the height of h = 25 mm is designed for a discoidal LED source with the diameter of D = 10 mm. Both high illuminance uniformity of 0.75 and high light control efficiency of 0.86 are obtained simultaneously. The method can be further used to achieve more complex non uniform illumination distributions. The design of an optical system with h/D = 2.5:1 and a circular linear illumination distribution is demonstrated. PMID- 24800281 TI - Light trapping in a polymer solar cell by tailored quantum dot emission. AB - We propose a polymer photovoltaic device with a new scattering mechanism based on photon absorption and re-emission in a quantum dot layer. A matrix of aluminum nanorods with optimized radius and period are used to modify the coupling of light emitted from the quantum dots into the polymer layer. Our analysis shows that this architecture is capable of increasing the absorption of an ordinary polymer photovoltaic device by 28%. PMID- 24800282 TI - Spatio-temporal dynamics behind the shock front from compacted metal nanopowders. AB - Laser ablated shock waves from compacted metal nanoenergetic powders of Aluminum (Al), Nickel coated Aluminum (Ni-Al) was characterized using shadowgraphy technique and compared with that from Boron Potassium Nitrate (BKN), Ammonium Perchlorate (AP) and Potassium Bromide (KBr) powders. Ablation is created by focused second harmonic (532 nm, 7 ns) of Nd:YAG laser. Time resolved shadowgraphs of propagating shock front and contact front revealed dynamics and the precise time of energy release of materials under extreme ablative pressures. Among the different compacted materials studied, Al nanopowders have maximum shock velocity and pressure behind the shock front compared to others. PMID- 24800283 TI - Red-emitting silicon quantum dot phosphors in warm white LEDs with excellent color rendering. AB - We demonstrate red-emitting silicon quantum dot (SiQD) phosphors as a low-cost and environment-friendly alternative to rare-earth element phosphors or CdSe quantum dots. After surface passivation, the SiQD-phosphors achieve high photoluminescence quantum yield = 51% with 365-nm excitation. The phosphors also have a peak photoluminescence wavelength at 630 nm and a full-width-at-half maximum of 145 nm. The relatively broadband red emission is ideal for forming the basis of a warm white spectrum. With 365-nm or 405-nm LED pumping and the addition of green- and/or blue-emitting rare-earth element phosphors, warm white LEDs with color rendering index ~95 have been achieved. PMID- 24800284 TI - Imperfectly geometric shapes of nanograting structures as solar absorbers with superior performance for solar cells. AB - The expectation of perfectly geometric shapes of subwavelength grating (SWG) structures such as smoothness of sidewalls and sharp corners and nonexistence of grating defects is not realistic due to micro/nanofabrication processes. This work numerically investigates optical properties of an optimal solar absorber comprising a single-layered silicon (Si) SWG deposited on a finite Si substrate, with a careful consideration given to effects of various types of its imperfect geometry. The absorptance spectra of the solar absorber with different geometric shapes, namely, the grating with attached nanometer-sized features at the top and bottom of sidewalls and periodic defects within four and ten grating periods are investigated comprehensively. It is found that the grating with attached features at the bottom absorbs more energy than both the one at the top and the perfect grating. In addition, it is shown that the grating with defects in each fourth period exhibits the highest average absorptance (91%) compared with that of the grating having defects in each tenth period (89%), the grating with attached features (89%), and the perfect one (86%). Moreover, the results indicate that the absorptance spectrum of the imperfect structures is insensitive to angles of incidence. Furthermore, the absorptance enhancement is clearly demonstrated by computing magnetic field, energy density, and Poynting vector distributions. The results presented in this study prove that imperfect geometries of the nanograting structure display a higher absorptance than the perfect one, and provide such a practical guideline for nanofabrication capabilities necessary to be considered by structure designers. PMID- 24800285 TI - Compound biomimetic structures for efficiency enhancement of Ga(0.5)In(0.5)P/GaAs/Ge triple-junction solar cells. AB - Biomimetic nanostructures have shown to enhance the optical absorption of Ga(0.5)In(0.5)P/GaAs/Ge triple junction solar cells due to excellent antireflective (AR) properties that, however, are highly dependent on their geometric dimensions. In practice, it is challenging to control fabrication conditions which produce nanostructures in ideal periodic arrangements and with tapered side-wall profiles, leading to sacrificed AR properties and solar cell performance. In this work, we introduce compound biomimetic nanostructures created by depositing a layer of silicon dioxide (SiO(2)) on top of titanium dioxide (TiO(2)) nanostructures for triple junction solar cells. The device exhibits photogenerated current and power conversion efficiency that are enhanced by ~8.9% and ~6.4%, respectively, after deposition due to their improved antireflection characteristics. We further investigate and verify the optical properties of compound structures via a rigorous coupled wave analysis model. The additional SiO(2) layer not only improves the geometric profile, but also serves as a double-layer dielectric coating. It is concluded that the compound biomimetic nanostructures exhibit superior AR properties that are relatively insensitive to fabrication constraints. Therefore, the compound approach can be widely adopted for versatile optoelectronic devices and applications. PMID- 24800286 TI - Aluminum plasmonic nanoparticles enhanced dye sensitized solar cells. AB - We present an investigation on utilizing plasmonic aluminium (Al) nanoparticles (NPs) to enhance the optical absorption of dye-sensitized solar cells (DSCs). The Al NPs exhibit not only the light absorption enhancement in solar cells with localized surface plasmon (LSP) effect but also the chemical stability to iodide/triiodide electrolyte. Besides, the lower work function (~4.06 eV), compared with that of TiO(2) (~4.6 eV), may suppress the quenching processes, such as charge transfer to metal NPs, to reduce the loss. Thus, high concentration of Al NPs could be incorporated into the TiO(2) anodes, and the power conversion efficiency (PCE) of DSCs is improved by nearly 13%. Moreover, electrochemical impedance spectroscopy (EIS) characterization also indicates that the plasmonic DSCs with Al NPs present better electrochemical performance than regular ones, which contributes to the improvement of PCE of the device. PMID- 24800287 TI - Optimization and analysis of 3D nanostructures for power-density enhancement in ultra-thin photovoltaics under oblique illumination. AB - Nanostructures have the potential to significantly increase the output power density of ultra-thin photovoltaic devices by scattering incident sunlight into resonant guided modes. We applied a modified version of the direct-binary-search algorithm to design such nanostructures in order to maximize the output power density under oblique-illumination conditions. We show that with appropriate design of nanostructured cladding layers, it is possible for a 10nm-thick organic absorber to produce an average peak power-density of 4mW/cm(2) with incident polar angle ranging from -90 degrees to 90 degrees and incident azimuthal angle ranging from -23.5 degrees to 23.5 degrees . Using careful modal and spectral analysis, we further show that an optimal trade-off of absorption at lambda~510nm among various angles of incidence is essential to excellent performance under oblique illumination. Finally, we show that the optimized device with no sun tracking can produce on an average 7.23 times more energy per year than that produced by a comparable unpatterned device with an optimal anti-reflection coating. PMID- 24800288 TI - Optical properties of nanopillar AlGaN/GaN MQWs for ultraviolet light-emitting diodes. AB - Nanopillar AlGaN/GaN multiple quantum wells ultraviolet light-emitting diodes (LEDs) were fabricated by nanosphere lithography and dry-etching. The optical properties of the nanopillar LEDs were characterized by both temperature dependent and time-resolved photoluminescence measurements. Compared to an as grown sample, the nanopillar sample has a PL emission peak blue-shift of 7 meV, a 42% enhanced internal quantum efficiency at room temperature and a reduced radiative recombination lifetime from 870 picosecond to 621 picosecond at 7K. These results are directly from the suppressed quantum confined stark effect that is due to the strain relaxation in the nanopillar MQWs, further revealed by micro Raman measurement. Additionally, finite-difference time domain simulation also proves better light extraction efficiency in the nanopillar LEDs. PMID- 24800289 TI - Electrochemically synthesized broadband antireflective and hydrophobic GaOOH nanopillars for III-V InGaP/GaAs/Ge triple-junction solar cell applications. AB - We report the efficiency enhancement of III-V InGaP/GaAs/ Ge triple-junction (TJ) solar cells using a novel structure, i.e., vertically-oriented gallium oxide hydroxide (GaOOH) nanopillars (NPs), as an antireflection coating. The optical reflectance properties of rhombus-shaped GaOOH NPs, which were synthesized by a simple, low-cost, and large-scalable electrochemical deposition method, were investigated, together with a theoretical analysis using the rigorous coupled wave analysis method. For the GaOOH NPs, the solar weighted reflectance of ~8.5% was obtained over a wide wavelength range of 300-1800 nm and their surfaces exhibited a high water contact angle of ~130 degrees (i.e., hydrophobicity). To simply demonstrate the feasibility of device applications, the GaOOH NPs were incorporated into a test-grown InGaP/GaAs/Ge TJ solar cell structure. For the InGaP/GaAs/Ge TJ solar cell with broadband antireflective GaOOH NPs, the conversion efficiency (eta) of ~16.47% was obtained, indicating an increased efficiency by 3.47% compared to the bare solar cell (i.e., eta~13%). PMID- 24800290 TI - Dual-band infrared perfect absorber based on asymmetric T-shaped plasmonic array. AB - An infrared dual-band perfect absorber based on asymmetric T-shaped plasmonic array is designed and numerically investigated. Two distinct absorption peaks are achieved by localized surface plasmon polariton (LSPP) mode over a wide incident angular range. Both the absorption peaks can be finely tuned independently by varying the geometry of the structure. In our proposed structure, the period of the T-shaped structures becomes less and the multiple LSPP peaks are suppressed, which result in the sideband of absorption peaks very low. This dual-band perfect absorber has potential applications such as in infrared imaging devices, thermal bolometers, and wavelength selective radiators. PMID- 24800291 TI - Performance-limiting factors for GaAs-based single nanowire photovoltaics. AB - GaAs nanowires (NWs) offer the possibility of decoupling light absorption from charge transport for high-performance photovoltaic (PV) devices. However, it is still an open question as to whether these devices can exceed the Shockley Queisser efficiency limit for single-junction PV. In this work, single standing GaAs-based nanowire solar cells in both radial and vertical junction configurations is analyzed and compared to a planar thin-film design. By using a self-consistent, electrical-optically coupled 3D simulator, we show the design principles for nanowire and planar solar cells are significantly different; nanowire solar cells are vulnerable to surface and contact recombination, while planar solar cells suffer significant losses due to imperfect backside mirror reflection. Overall, the ultimate efficiency of the GaAs nanowire solar cell with radial and vertical junction is not expected to exceed that of the thin-film design, with both staying below the Shockley-Queisser limit. PMID- 24800292 TI - Type II GaSb quantum ring solar cells under concentrated sunlight. AB - A type II GaSb quantum ring solar cell is fabricated and measured under the concentrated sunlight. The external quantum efficiency confirms the extended absorption from the quantum rings at long wavelength coinciding with the photoluminescence results. The short-circuit current of the quantum ring devices is 5.1% to 9.9% more than the GaAs reference's under various concentrations. While the quantum ring solar cell does not exceed its GaAs counterpart in efficiency under one-sun, the recovery of the open-circuit voltages at higher concentration helps to reverse the situation. A slightly higher efficiency (10.31% vs. 10.29%) is reported for the quantum ring device against the GaAs one. PMID- 24800293 TI - High-efficiency, broad-band and wide-angle optical absorption in ultra-thin organic photovoltaic devices. AB - Metal nanogratings as one of the promising architectures for effective light trapping in organic photovoltaics (OPVs) have been actively studied over the past decade. Here we designed a novel metal nanowall grating with ultra-small period and ultra-high aspect-ratio as the back electrode of the OPV device. Such grating results in the strong hot spot effect in-between the neighboring nanowalls and the localized surface plasmon effect at the corners of nanowalls. These combined effects make the integrated absorption efficiency of light over the wavelength range from 400 to 650 nm in the active layer for the proposed structure, with respect to the equivalent planar structure, increases by 102% at TM polarization and by 36.5% at the TM/TE hybrid polarization, respectively. Moreover, it is noted that the hot spot effect in the proposed structure is more effective for ultra-thin active layers, which is very favorable for the exciton dissociation and charge collection. Therefore such a nanowall grating is expected to improve the overall performance of OPV devices. PMID- 24800294 TI - Side-illuminating LED luminaires with accurate projection in high uniformity and high optical utilization factor for large-area field illumination. AB - A novel light luminaire is proposed and experimentally analyzed, which accurately projects light into a large rectangular area to achieve uniform illumination and a high optical utilization factor at the target. Side-illuminating luminaires for large-scale illuminated area are typically set with an elevated tilt angle to enlarge the illuminated area. However, the light pattern is bent thereby reducing the uniformity and optical utilization factor at the target. In this paper, we propose an efficient and useful approach with a rotationally symmetric projection lens that is trimmed to adjust the bending effect and to form a rectangular illumination light pattern on the ground. The design concept is demonstrated and verified. Several potential applications such as highly uniform illumination with fitting shapes for sport courts are analyzed and discussed. PMID- 24800295 TI - Public relations: For your information. PMID- 24800296 TI - Challenges loom for US health law as new insurance begins. PMID- 24800297 TI - South Africa's battle against HIV/AIDS gains momentum. PMID- 24800298 TI - John St John Long: quackery and manslaughter. PMID- 24800299 TI - John Victor Pickstone. PMID- 24800300 TI - India after polio. PMID- 24800301 TI - Highlights from the 21st CROI. PMID- 24800302 TI - Blastic island in acute myeloid leukemia. PMID- 24800303 TI - Progression of romiplostim myelofibrosis to myeloproliferative neoplasm. PMID- 24800304 TI - Computation of standard errors. AB - OBJECTIVES: We discuss the problem of computing the standard errors of functions involving estimated parameters and provide the relevant computer code for three different computational approaches using two popular computer packages. STUDY DESIGN: We show how to compute the standard errors of several functions of interest: the predicted value of the dependent variable for a particular subject, and the effect of a change in an explanatory variable on the predicted value of the dependent variable for an individual subject and average effect for a sample of subjects. EMPIRICAL APPLICATION: Using a publicly available dataset, we explain three different methods of computing standard errors: the delta method, Krinsky-Robb, and bootstrapping. We provide computer code for Stata 12 and LIMDEP 10/NLOGIT 5. CONCLUSIONS: In most applications, choice of the computational method for standard errors of functions of estimated parameters is a matter of convenience. However, when computing standard errors of the sample average of functions that involve both estimated parameters and nonstochastic explanatory variables, it is important to consider the sources of variation in the function's values. PMID- 24800305 TI - Risk selection into consumer-directed health plans: an analysis of family choices within large employers. AB - OBJECTIVE: To identify the degree of selection into consumer-directed health plans (CDHPs) versus traditional plans over time, and factors that influence choice and temper risk selection. DATA SOURCES/STUDY SETTING: Sixteen large employers offering both CDHP and traditional plans during the 2004-2007 period, more than 200,000 families. STUDY DESIGN: We model CDHP choice with logistic regression; predictors include risk scores, in addition to family, choice setting, and plan characteristics. Additional models stratify by account type or single enrollee versus family. DATA COLLECTION/EXTRACTION METHODS: Risk scores, family characteristics, and enrollment decisions are derived from medical claims and enrollment files. Interviews with human resources executives provide additional data. PRINCIPAL FINDINGS: CDHP risk scores were 74 percent of traditional plan scores in the first year, and this difference declined over time. Employer contributions to accounts and employee premium savings fostered CDHP enrollment and reduced risk selection. Having to make an active choice of plan increased CDHP enrollment but also increased risk selection. Risk selection was greater for singles than families and did not differ between HRA and HSA based CDHPs. CONCLUSIONS: Risk selection was not severe and it was well managed. Employers have effective methods to encourage CDHP enrollment and temper selection against traditional plans. PMID- 24800306 TI - [Effects of postpartum lactation of puerperal women with qi and blood deficiency treated by catgut embedding therapy]. PMID- 24800307 TI - Evidence appraisal of Harman S, Zemek R, Duncan MJ, Ying Y, Petrcich W. Efficacy of pain control with topical lidocaine-epinephrine-tetracaine during laceration repair with tissue adhesive in children: a randomized controlled trial. CMAJ. 2013;185(13):E629-E634. PMID- 24800308 TI - Identifying and eliminating sources of wet packs. PMID- 24800309 TI - Using technology to prevent retained sponges. PMID- 24800310 TI - A multidisciplinary approach to instrument availability. PMID- 24800311 TI - An Army and an AMEDD in transition. PMID- 24800312 TI - Editor's perspectives. PMID- 24800314 TI - Surgical treatment of chronic pancreatitis and its complications. Comparative analysis of results in 91 patients. AB - There is a large variety of proposed conservative, invasive, endoscopic and surgical methods for treatment of chronic pancreatitis and its complications. This study presents a comparative analysis of the results from each group of patients subjected to drainage, resection, denervation and other operative techniques for a total of 91 patients with chronic pancreatitis and its complications. Drainage and resection operative techniques yield comparable results in terms of postoperative pain control 93.1% and 100%, perioperative mortality--3.17% and 5.8%, perioperative morbidity--7.9% and 11.7%, respectively. There is a significant increase in the instances of diabetes in the resection group. Right-side semilunar ganglionectomy is a good method for pain control as an accompanying procedure in the course of another main operative technique. PMID- 24800313 TI - The driving behavior survey as a measure of behavioral stress responses to MVA related PTSD. AB - Numerous treatments are available that address the core symptoms of posttraumatic stress disorder (PTSD). However, there are a number of related behavioral stress responses that are not assessed with PTSD measures, yet these behavioral stress responses affect quality of life. The goal of the current study was to investigate whether a recently developed measure of behavioral stress response, the Driving Behavior Survey (DBS), was sensitive to change associated with treatment among a group of participants diagnosed with PTSD. The DBS indexes anxious driving behavior, which is frequently observed among individuals with motor vehicle accident-related PTSD. Participants (n = 40) were racially diverse adults (M age = 40.78, 63% women) who met diagnostic criteria for motor vehicle accident-related PTSD. Hierarchical linear modeling analyses indicated that participants who were assigned to a brief, exposure-based intervention displayed significant reductions on the DBS subscales relative to participants assigned to the wait-list control condition (r = .41-.43). Moreover, mediational analyses indicated that the observed reductions on the DBS subscales were not better accounted for by reductions in PTSD. Taken together, these findings suggest that the DBS subscales are sensitive to changes associated with PTSD treatment and can be used to augment outcome assessment in PTSD treatment trials. PMID- 24800315 TI - Intraperitoneal perfusion chemotherapy with hyperthermia in some malignant ascites. AB - Intraperitoneal administration of chemotherapeutic drugs with hyperthermia (HIPEC) increases their local effect on malignant peritoneal diseases and reduces systemic cytotoxicity. The most commonly used are cisplatin, doxorubicin, and mitomycin C. A major disadvantage of intraperitoneal chemotherapy is limited penetration of the drug in the tumor lesion depth (1-3 mm). Extended exposure and increased pressure in the abdominal cavity solution increases penetration of the agent into the tumor and hyperthermia has synergy with cytostatic agent on the permeability of cell membranes and metabolism of the drug. Real clinical hyperthermia is achieved at 41 degrees C. Of greatest importance is the concentration of the drug, but crucial for the prognosis is complete cytoreductive surgery. A major disadvantage of the closed technique is the uneven distribution of the perfusion solution in the peritoneal cavity, and the main advantage is better control of the perfusion, keeping of constant hyperthermia of the solution and regular repetition of manipulation, like intravenous chemotherapy. Laparoscopy determines the stage of the tumor process, refines the indications and preoperative selection for HIPEC, monitors the effects of treatment and determines locations for introducing catheters. In the review the results of the inraperitoneal chemotherapy with hyperthermia in gastric, colorectal, ovarian and other cancers are discussed as well as in diffuse malignant peritoneal mesothelioma and others. PMID- 24800316 TI - Intraabdominal hypertention--predisposing factor for visceral alterations and abdominal compartment syndrome. AB - Compartment syndrome (CS) is a condition in which increased pressure in a confined anatomical space adversely affects the function and viability of the tissues therein. AIM: The aim of the following research is to detect the influence of the intraabdominal hypertension (IAH) as an often met condition in visceral surgery on the organs in the abdominal cavity and outside it and on musculus rectus abdominis. METHODS: We used adult Wister rats for creating an experimental model of IAH, using our own experimental method with many advantages. RESULTS: We found expressed alterations in the organs of the group with IAH = 25 mmHg. Morphological changes were found in lung, small intestine, large intestine, stomach, liver, kidneys, spleen and in musculus rectus abdominis In the sham group without IAH we did not find any pathomorphological alterations. CONCLUSIONS. IAH, which is considered as a predictor of ACS and MOF, lasting for only 60 min. and level of = 25 mmHg causes heavy visceral alterations within, and also outside the abdominal cavity, and of the abdominal wall. PMID- 24800317 TI - Studies on the blood group affiliation of patients with liver hemangioma. AB - BACKGROUND: Regardless of the improvement of the imaging methods for diagnosing the focal lesions of the liver, the etiological nature of the processes often remains unspecified. It is known that the blood cells and the vessels both originate from the mesenchyme, which is one of the embryos constituting a part of the mean embryonic layer--the mesoderm. AIM: We set out the goal of establishing, on the basis of our clinical material, whether there is a connection between the blood group affiliation, according to the ABO system, and the liver hemangioma. MATERIALS AND METHODS: The ABO blood group affiliation of patients with liver hemangioma, operated at the Department of General and Liver-pancretatic Surgery, UH "Alexandrovska", in the period from 1995 to April 2013 was as follows: Group 0 - 14 patients (19.4%), Group A - 47 (65.3%), Group B - 6 (8.3%) and Group AB - 5 (6.9%). In the control group of patients: Group 0 - 28 (36.8%), Group A - 25 (32.9%), Group B - 15 (19.7%) and Group AB - 8 (10.5%). Data about the country: Group 0 - 32%, Group A - 44%, Group B - 15% and Group AB - 8%. The patients' blood group affiliation was determined based on the Moc method. RESULTS: We established considerable statistical dependence between Blood Group A, i.e. aglutinogen and patients with liver hemangioma (p < 0.001.). CONCLUSION: The possibility for genetic determination of the liver hemangioma is confirmed, which makes it possible to determine a group of people (with Blood Group A affiliation) with higher risk of developing hemangioma. The conclusion may serve for early diagnostics or as an additional factor for finding a solution to difficult cases in differential-diagnostic terms. PMID- 24800318 TI - Surgical approach in locally advanced colorectal cancer--combined, extended and compound surgery. AB - Cancer of the colon and rectum (colorectal cancer - CRC) is ranked second in prevalence--the men he is after lung cancer, and for women--after breast cancer. There is a steady trend to annual increase in incidence in the country. Definition of locally advanced disease is necessary in order to achieve practical and theoretical clarity regarding not a small percentage of patients with colorectal cancer presenting for treatment to the surgeon. As for the primary and the recurrent locally advanced tumors, postoperative long-term survival is achievable, but only after complete R0-resection. AIM: The objective of the presented literature review is to analyze data from a number of internationally published studies looking multifactorial variety of problems in the primary and recurrent locally advanced colorectal cancer (LAKRK) capable of optimizing behavior in surgical patients with this frequently encountered oncological and social significant pathology. Aim The objective of the presented literature review is to analyze data from a number of internationally published studies looking multifactor variety of problems in the primary and recurrent locally advanced colorectal cancer (LACRC) capable of optimizing behavior in surgical patients with this frequently encountered oncologic and social significant pathology. MATERIAL AND METHODS: A retrospective, critical and comparatively examined published in the world literature review papers, case reports and clinical studies dealing with locally advanced primary and recurrent cancer that goes beyond the colon and rectum involving the surrounding structures and organs with the requirements for individualized "Team" approach of preoperative and intraoperative staging, planning and execution of multivisceral "en-block" resection with typical technical difficulties, complications and results. RESULTS: As "locally advanced" tumors represent 5-22% of all colorectal carcinomas. According to the analyzed data in patients with tumor stage IIB, which extend through the intestinal wall and infiltrated the surrounding structures without lymph node metastases (T4 N0 M0) have a worse chance of survival than those with tumors in stage III, which remain within the intestinal wall, but had spread to the lymph nodes (T1 - 2 N1 - 2). Recent studies confirm that T4 stage is an important independent predictor of disease-free interval and overall survival. Discussed are the terms " combined", "extended" and "compound" surgery. Describe the importance of dissection in lymphnodes in LACRC through related analogue of total mesorectal excision in rectal cancer excision in complete mesocolic excision location in the colon. Discussed are ways of locally advanced primary tumors and recurrences with different types of loco - regional involvement of surrounding structures and organs. Describe in detail the operational- tactical and technical aspects of the block R0- resection in primary and recurrent LAKRK with type and severity of any complications and treatment outcomes. Concerns the importance of an integrated approach with neoadjuvant and adjuvant chemotherapy and radiotherapy. CONCLUSION: Justified the opinion of the adequate, in particular disease, reasonably aggressive pattern to LACRC securing the most favorable long-term survival prognosis. PMID- 24800319 TI - Single-access retroperitoneal adrenalectomy. AB - AIM: To report the first case in our country of a single access--adrenalectomy with lateral retroperitoneal approach by using SILS port and to evaluate the feasibility and safety of this new technique. MATERIALS AND METHODS: A 50-year old man presented with 38 mm right adrenal incidentaloma, functionally nonactive and without radiologic characteristics suggestive of a malignant lesion, discovered on abdominal computed tomography for nephrolithiasis. The single access adrenalectomy was attempted with multichannel SILS port (Covidien), inserted through a 3 cm transverse incision at the tip of rib XII on the right side. RESULTS: The single access retroperitoneal adrenalectomy (SARA) was successfully completed without any intraoperative complications. An additional lateral 5-mm port was needed for retraction of the kidney and for tubular drain in the end stage of the surgery. The operating time was 120 minutes with 40 mL of blood loss. Postoperative recovery was uneventful. The patient was discharged from the hospital on the second postoperative day. Pathologic examination confirmed cortical adenoma of the adrenal grand. No morbidity within one month of follow-up, and excellent cosmetic results. CONCLUSION: This is the first case of a single access retroperitoneal adrenalectomy (SARA) by using SILS port was performed in our country. Based on our primary experience, we believe that SARA is a safe and feasible procedure for selected patients with adrenal tumors and when performed by a surgeon experienced in laparoscopic and adrenal surgery. Although initial technical adjustments are inevitable, simplifying the procedure. However, more surgical experience using this technique is required to confirm our initial impressions. PMID- 24800320 TI - Rethinking dementia. PMID- 24800321 TI - Catheter-associated bladder pain: it's not always infection. AB - This article is a case study examining the diagnosis and management of bladder dysfunction and catheter-associated pain in an older woman with diabetes and a hypotonic bladder. The incidence of diabetes has reached epidemic proportions. Although people with diabetes frequently develop lower urinary tract symptoms and voiding difficulties, this is often an unrecognised problem. As the incidence of diabetes grows, the incidence of diabetes-related bladder dysfunction will also increase. It is important that community nurses are aware of how diabetes affects bladder function and how to enable people with diabetes to manage bladder dysfunction well. PMID- 24800322 TI - Developing a nurse-led integrated 'red legs' service. AB - This project was developed to set up a nurse-led service based on the needs of patients diagnosed with 'red legs'. These patients are often wrongly admitted into hospital for treatment of cellulitis. Representatives from the specialties involved in caring for those individuals with red legs were invited to participate with patients to create a stakeholder group whose purpose was to develop integrated care pathways focused on referral criteria, diagnostics and treatment to inform a new nurse-led service. There was a commitment to utilising a number of facilitation techniques and practice-development methods in the progression of the project with the support of the Foundation of Nursing Studies. Much of the prescribed care can be carried out by the patients at home and only 25% patients have required a follow-up appointment within the new service. The service has now been fully commissioned and a secondment opportunity has been developed to lead the new service. Significant savings have been demonstrated and regular revision of the integrated care pathways with all groups, including the patients, will take place. PMID- 24800323 TI - Supporting behaviour change in older people with type 2 diabetes. AB - This article examines current research on behaviour change in relation to supporting older adults with type 2 diabetes in the community. It outlines the different areas of self-care that older adults with diabetes engage in, argues for the need for behaviour change intervention in adults with the illness and discusses the complexities of diabetes self-care regimens, with particular focus on older adults. A review of current scientific thinking about eliciting behaviour change in areas such as diet, physical activity and medication taking is undertaken. The article concludes with a set of practical recommendations for community health professionals. PMID- 24800324 TI - District nurses' experiences with the free-choice system in Swedish primary care. AB - This article aims to describe the experiences of district nurses regarding their work situation after the free-choice system in primary care in Sweden was implemented. The study comprised a total of 17 semi-structured narratives with district nurses. The narratives were analysed using manifest qualitative content analysis. One category,'being an underused resource', and three subcategories, 'being financially aware','being flexible' and 'being appealing', were identified. A focus on economic benefit can limit the cooperation and exchange of experiences within and between different care units, which could have a negative impact on the quality of care due to competition between different care providers. Underused resources and restrictions in terms of improvement skills have an impact on job satisfaction and the working environment, and affect the quality of care as a result. PMID- 24800325 TI - The role of the community nurse in psoriatic comorbidities interventions. AB - Psoriasis is a chronic disease that affects more than the skin. It has an impact on every facet of an individual's life and is associated with numerous comorbidities, such as obesity, diabetes, cardiovascular disease, psoriatic arthritis, metabolic syndrome, squamous cell carcinoma, lymphoma, depression, anxiety and other immune-related conditions, such as Crohn's disease. Obesity is inextricably linked with type 2 diabetes, hypertension, hyperlipidemia, and cardiovascular disease. Hypertension and cardiovascular disease are precursors for myocardial infarction and stroke. Lifestyle choices, such as smoking, alcohol consumption, inadequate nutrition and physical exercise are behaviours that need to be addressed. With the right education from the community nurse, patients can be informed about the decisions they make and can ultimately choose to live a healthier life. PMID- 24800326 TI - Vulnerable adults and the abolition of powers to remove a person in need of care. AB - The coalition Government is urging parliament to repeal the power of local authorities in England to remove a vulnerable adult who retains decision-making capacity from their home if they are in need of care and attention. The move is justified on the grounds that the power is little used, might contravene the person's human rights and does not reflect the government's person-centred and community-focused reforms of adult social care and support. This article reviews the power to remove a person to a suitable place under the National Assistance Act 1948 and argues that reforming, not repealing, the law is what is required if vulnerable adults are to be protected from abuse and neglect. PMID- 24800327 TI - Palliative care in the community: reflections from 2013. PMID- 24800329 TI - Some action on reflection. PMID- 24800328 TI - Learning from Mandela. PMID- 24800330 TI - Effect of Acacia nilotica leaves extract on hyperglycaemia, lipid profile and platelet aggregation in streptozotocin induced diabetic rats. AB - BACKGROUND: To consider new hypoglycaemic, anti-hyperlipidaemic and anti-platelet aggregation sources, aqueous methanol extract of Acacia Nilotica (AN) leaves was investigated in streptozotocin induced diabetic rats. METHODS: Diabetes mellitus was induced in 90 out of 120 male albino rats by administering 50 mg/Kg bodyweight (bw) streptozotocin intraperitonealy, and was confirmed by measuring fasting blood glucose level > 200 mg/dL on 4th post-induction day. The rats were equally divided into 4 groups, A (normal control), B (diabetic control), C (diabetics rats treated with plant extract) and group D (diabetics rats treated with glyburide). The rats of group C and D were given single dose of 300 mg/Kg bw, AN extract, and 900 microg/Kg bw glyburide respectively for 3 weeks. Blood glucose levels were measured by glucometer, platelet aggregation by DiaMed method, beta-thromboglobulin and insulin by ELISA technique, and lipid components were measured by enzymatic calorimetric method. RESULTS: Significant differences (p < 0.05) were noticed in blood glucose, serum insulin, platelet aggregation and triglyceride levels in diabetic rats treated with AN extract and glyburide as compared to diabetic controlled rats. A significant difference (p < 0.05) in beta thromboglobulin and LDL levels was also noticed in rats treated with glyburide than the diabetic controlled rats. The levels of fasting blood glucose, beta thromboglobulin and platelet aggregation were significantly reduced (p < 0.05) in diabetic rats treated with glyburide than AN extract treated rats. CONCLUSIONS: Administration of AN leaves extract showed hypoglycaemic and anti-platelet aggregation activity in diabetic rats as that of glyburide. PMID- 24800331 TI - Anaemia: the neglected female health problem in developing countries. AB - BACKGROUND: Anaemia is arguably the biggest female health problems in developing countries. The world is still to fully fathom the extent and gravity of the problem. This problem aggravates particularly during and after pregnancies due to increased nutritional demands and inadequate iron supply and is therefore more widespread in parous segments of female population. Objective of this study was to determine prevalence of anaemia in apparently healthy parous female population of Abbottabad and investigate underlying causes. METHODS: This descriptive, cross sectional study was conducted from October 2001 to March 2011 in Abbottabad. Women reporting for various surgical procedures were investigated for anaemia by obtaining history through a structured performa, specifically designed to identify the underlying causes. Sixteen thousand women of childbearing age (20-40 years) were included in the study; 14,800 with history of at least one pregnancy and remaining with no previous pregnancy. Haemoglobin (Hb) was measured using haematology analyser Sysmex (KX21). RESULTS: Of the screened women, 60% were found anaemic (Hb < 12 g/dl) 10% of which were severely anaemic (Hb < 6 g/dl). Anaemia was related to socio-demographic and obstetric history characteristics. The prevalence of anaemia was significantly lower in women who used iron supplements during their pregnancies. Lactating mothers not making up for the iron deficiencies during pregnancies usually carried their anaemia postpartum and beyond. Lower gaps between pregnancies also contributed significantly to the problem. CONCLUSION: Prevalence and severity of anaemia in reproductive age females reporting to surgical units were found to be exceptionally high. Frequency of anaemia in the parous females of relatively affluent city of Abbotabad indicates that anaemia may be on the rise in developing countries. Addressing pregnancy related anaemia and nutritional deficiencies through intake of supplements on regular basis in women before and between pregnancies is essential. PMID- 24800332 TI - Aetiological factors of chronic liver disease in children. AB - BACKGROUND: Chronicity of liver disease is determined either by duration of liver disease or by evidence of either severe liver disease or physical stigmata of chronic liver disease. Chronic liver disease may be caused commonly by persistent viral infections, metabolic diseases, drugs, autoimmune hepatitis, or unknown factors. The objective of this study was to find out the aetiology of chronic liver disease (CLD) in children. METHODOLOGY: It was a descriptive, prospective study which used a structured proforma designed to collect data of cases of CLD from both indoor and outdoor Paediatrics units of Fauji Foundation Hospital, Rawalpindi, and Children Hospital, Pakistan Institute of Medical Sciences, Islamabad. All children under 12 years having either clinical or biochemical evidence of liver disease and/or elevated liver enzymes for more than 3 months were included in this study. RESULTS: Sixty cases of CLD were enrolled from indoor and outdoor units from January 2010 to July 2011. Thirty-nine (65%) cases were male and 21 (35%) were female. Eleven children were less than 1 year, 18 were 1-5 years old and 31 were 5-12 years of age. Viral hepatitis was the most common cause found in 22 (36.7%) cases. Out of these 22 patients with viral aetiology 19 (31.66%) patients had Hepatitis C and 3 (5%) had Hepatitis B. Glycogen storage disease was seen in 8.3% cases, and biliary atresia and Wilson disease in 6.7% each. Other less commonly found cases were autoimmune hepatitis, TORCH infections, hepatoma and drug induced hepatitis (1.7% each). Cause couldn't be established in 35% cases which remained idiopathic. CONCLUSION: Viral hepatitis is the leading cause of chronic liver disease in children, with the highest incidence of chronic Hepatitis C followed by metabolic disorders (glycogen storage disease and Wilson disease) and biliary atresia. Chronic viral hepatitis was most prevalent between 11 months to 12 years of age. Wilson disease was common in 3-7 years age group, and Biliary atresia in 4-7 months age group. Glycogen storage disease was prevalent between 5 months to 3 years. PMID- 24800333 TI - Transnasal endosocpic repair of cerebrospinal fluid rhinorrhoea. AB - BACKGROUND: Cerebrospinal fluid (CSF) leaks can arise as a complication of trauma, hydrocephalus, endoscopic sinus surgery or it may occur spontaneously without any identifiable cause. Surgical repair is recommended in patients who do not respond to the conservative management. In recent years transnasal endoscopic approach has become the preferred method for repairing the CSF leaks and better outcomes have been reported as compared to the intracranial approaches that were previously used. Objective of this study was to analyse the outcome of transnasal endoscopic repair of CSF rhinorrhoea. METHODS: This prospective study was conducted in the Department of Neurosurgery, Ayub Medical College, Abbottabad, from March 2007 to March 2010. Twenty-one patients with CSF rhinorrhoea were included in study that were diagnosed on the basis of clinical evaluation, glucose concentration of nasal discharge, computed tomography (CT) and magnetic resonance imaging (MRI). These patients did not respond to conservative management and were operated transnasally using rigid endoscope. Patients were followed up for a mean duration of 9 months and the outcome was analysed. RESULTS: The patients included in the study ranged in the age group of 12-55 years. Among the patients 13 (57%) were female and 8 (38%) were males. The cause of CSF rhinorrhoea was traumatic in 16 (76.19%), Idiopathic or spontaneous in 4 (19.04%) and 1 (4.7%) case was related to endoscopic surgery for pituitary macroedenoma. In 10 (47.6.8%) patients the site of leak was cribriform plate, 5 (23.8%) had from sphenoid, 4 (19.04%) from frontal sinus and in 2 (9.5%) Ethmoid was affected. Primary surgery was successful in 17 (80.95%) of cases. In 2 (9.5%) cases re-exploration had to be performed. In 1 patient re-exploration had to be done for the third time. Overall success rate was 95%. One patient presented with CSF leak and meningitis 1 month after surgery and unfortunately died. CONCLUSION: Transnasal endoscopic repair of CSF rhinorrhoea is highly successful, safe and less traumatic. PMID- 24800334 TI - Efficacy of zinc as an antibacterial agent against enteric bacterial pathogens. AB - BACKGROUND: Diarrhoea is a serious threat all over the world with great economic implications especially evident in the developing world. This study was aimed at determining in vitro efficacy of Zinc (Zn) against common enteric bacterial pathogens. METHOD: A total of 100 bacterial enteric pathogens: Salmonellae (n = 16), enteropathogenic Escherichia coli (EPEC) (n = 26). Shigellae (n = 28) and Vibrio cholerae (n = 30) were isolated from diarrhoeal stool specimens at Department of Microbiology, Armed Forces Institute of Pathology Rawalpindi during Aapril 2009 to Jan 2010. These isolates were tested against various concentrations of Zn supplemented in Mueller Hinton (MH) agar using a multipoint inoculator. A minimum inhibitory concentration of active Zn in ZnSO4.7H2O ranging from 0.03 mg/ml to 1 mg/ml was used. RESULTS: Zn completely inhibited the growth of all the tested pathogens and most of them were inhibited at a concentration of 0.06 mg/ml to 0.5 mg/ml of Zn. CONCLUSIONS: Zinc has an excellent antibacterial activity against enteric bacterial pathogens common in our setup which may provide basis for treatment of diarrhoea. Clinical study based on these findings is recommended. PMID- 24800335 TI - Role of clean intermittent self catheterisation (CISC) in the prevention of recurrent urethral strictures after internal optical urethrotomy. AB - BACKGROUND: Urethral stricture is one of the oldest diseases Urethral dilatation Internal optical urethrotomy,were the only treatment. Clean Intermittent Self Catheterisation was introduced by Lapides has greatly decreased the recurrence of stricture. Objectives were to determine the role of Clean Intermittent Self Catheterisation (CISC) in the prevention of recurrence of urethral strictures after Internal Optical Urethrotomy and to study the frequency of any postoperative complications and tolerability for the patients associated with this procedure. METHODS: A randomised controlled study conducted in the department of urology and renal transplantation, Institute of Kidney Diseases Hayatabad Medical Complex, Peshawar from June 2007 to June 2010. Total of 60 patients with mean age 48 years (range 20-73) were selected and randomly divided into Treatment Group (30 patients) and Control Group (30 Patients). Eight "drop out" occurred in the treatment group and four "drop out" occurred in the controlled group. All the patients were treated with Internal Optical Urethrotomy using Sachse method followed by indwelling catheter for 5 days. The treatment group was then taught to perform Clean Intermittent Self Catheterisation by inserting a Classic Neleton Catheter (No. 16 or 18) twice a day for 1 week, then once a day for another 4 weeks and then once weekly continued for one year. All the patients were followed up regularly at 1 month intervals during the first 6 months and then every 2 months for the next 6 months. RESULTS: Total of 48 patients completed the study, 22 in the treatment group and 26 in the control group. Within the first year, 4 patients (22%) in the treatment group developed urethral stricture. In the control group, 12 patients (46%) developed urethral stricture within the first year, showing a significant difference (p < 0.01). In the treatment group four patients developed simple UTIs while in the control group three patients developed UTIs, one with concomitant epididymitis. No other complications were noted up to one year follow up. CONCLUSION: Clean Intermittent Self Catheterisation is a simple and effective way of reducing stricture recurrence after Internal Optical Urethrotomy and is associated with less morbidity and is cost effective. CISC is an important modality for maintaining the normal urethral calibre. PMID- 24800336 TI - 'Honey ointment': a natural remedy of skin wound infections. AB - BACKGROUND: Honey is a gift of nature, principally identified and valued to possess antimicrobial and anti-inflammatory activity and has been used as a natural remedy of wounds since ancient times. The objectives of this study were to evaluate the antimicrobial activity of honey against micro-organisms, to formulate a honey ointment and to evaluate the efficacy of such ointment by conducting clinical trials on skin wound infection. METHODS: This experimental study was conducted at Department of Pharmaceutics, Faculty of Pharmacy, University of Karachi and Out-patient Department of Dermatology, Fauji Foundation Hospital, Rawalpindi from November 2009 to October 2010. The antimicrobial activity of Pakistani floral sources (Trachysperm copticum, Acacia nilotica species indica, Zizyphus) honey samples was investigated by disc diffusion method against freshly isolated wound infecting bacteria (Staphylococci aureus, Staphylococci epidermidis, Streptococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Proteus vulgaris and Candida albicans), and Staphylococci aureus ATCC 6538, Pseudomonas aeruginosa ATCC 9022, Escherichia coli ATCC 25922, Candida albican ATCC 15146. An ointment containing 20% active antimicrobial honey was formulated. The efficacy of such ointment was evaluated by passing thought clinical trials. A total number of 27 patients (23 skin wound infection, and 4 diabetic foot ulcer) were involved in the study. Thin layer of newly formulated honey ointment on gauze were applied two to three times per day till complete healing. RESULTS: In microbiological assay the honey samples were found to exhibit a very promising antimicrobial activity against all the micro organisms tested. In clinical trial very significant results (99.15%) healing was observed in skin wound infections cases with mean healing time of 5.86 (2-20) days, and 95% diabetic foot ulcers healed with the mean healing time of 20 (8-40) days. CONCLUSION: Newly formulated ointment containing 20% active antimicrobial honey is very effective and alternative low-cost product for the treatment of wound infections. PMID- 24800337 TI - Impact of multiparity on iron content in multiparous women. AB - BACKGROUND: The effect of multiple pregnancies, a very common pattern in reproductive lifestyle of Pakistani women, needs to be addressed to see if it affects the iron content and hence cause iron deficiency. Recognising this deficiency prior to development of anaemia can prevent disastrous consequences that can complicate the life of the mother and foetus especially in developing countries. The objective of this study was to assess the effect that the stress of multiple pregnancies has on the iron status of the body. METHODS: This comparative study was conducted in a focus group of female population. Two hundred subjects were selected by convenient sampling and grouped depending on their parity status. Data regarding diet, and socioeconomic history was collected on pre-designed questionnaire. Serum Ferritin was used to assess iron deficiency using the Electrochemiluminescence Immunoassay (ECLIA). Data was statistically analysed using SPSS-17. RESULTS: Mean value of serum Ferritin in the nulliparous group was 76.52 +/- 4.92 etag/mL with 16% of nulliparous subjects showing lower than normal values. Thirty-six percent of uniparous subjects showed low serum Ferritin values, mean value-being 45.74 +/- 4.51 etag/mL. Seventy-two percent of the multiparous subjects showed iron deficiency with Ferritin levels of < 20 etag/mL. Mean serum Ferritin in this group was 25.21 +/- 2.75 etag/mL. The differences between the Ferritin levels of the study groups were highly significant (p < 0.01). CONCLUSIONS: Multiparous women had lower serum Ferritin levels than the control group suggesting that the stress of multiple pregnancies takes its toll on the iron content of the body. PMID- 24800338 TI - Assessment of iron deficiency in pregnant women by determining iron status. AB - BACKGROUND: Pregnant women constitute a high risk group for iron deficiency. Maternal iron deficiency and particularly iron deficiency anaemia may be associated with detrimental effects on maternal and infant function and particularly with a higher risk of preterm delivery and delivery of low birth weight neonates. Objective of this study was to assess and compare the iron status of normal healthy non-pregnant women with that of pregnant women of Hazara Division. METHODS: This study was conducted at Faculty of Health Sciences, Hazara University, and Ayub Medical College, Abbottabad from 1st March to 31st August 2006. Altogether 120 women, 90 pregnant at various stages of pregnancy and 30 non pregnant women as control group were included in this study by convenience sampling. Their iron status was assessed by determination of haemoglobin (Hb), Serum ferritin, Serum-iron, Total Iron Binding Capacity (TIBC), Unsaturated Iron Binding Capacity (UIBC), and Percentage saturation of transferrin. Data generated on these variables were subjected to ANOVA and correlation analysis. RESULTS: The salient finding of this study is a significant decrease in Hb, Serum ferritin, Serum iron, percentage saturation of transferrin and a significant increase in values of TIBC and a pronounced increase in UIBC in 2nd and 3rd trimester compared to 1st trimester in iron deficient pregnant women. The mean values of Hb, SF, and Fe/TIBC% were significantly lower in the cases than in the control and significantly higher values of TIBC and UIBC were observed in the cases compared to controls. Significant correlations were observed for TIBC, UIBC and Fe/TIBC% against serum iron in different trimesters of pregnancy. CONCLUSION: A high percentage of the pregnant women are iron deficient due to factors such as high parity, poor dietary habits and socioeconomic status. PMID- 24800339 TI - 'Pap smear' for screening of precancerous conditions of cervix. AB - BACKGROUND: Cervical intra-epithelial neoplasia (CIN) and cervical cancer remain important health problems for women worldwide. It is largely a preventable disease that is characterised by a long lead time. The objective of this study was to determine the frequency of precancerous conditions of cervix (CIN I-III) in women with chronic vaginal discharge by Pap smear screening. METHODS: The study was conducted at the outpatient department of Obstetric and Gynaecology, Nishtar Hospital Multan, and Multan Institute of Nuclear Medicine & Radiotherapy (MINAR) from February 2009 to February 2010. Two hundred and eighty patients with complaint of chronic vaginal discharge were selected. Their detailed history was documented on a Proforma, Pap smear taken at MINAR, and samples sent to pathology department of Nishtar Hospital Multan for cytological examination. All mild dyskaryosis or CIN I cases were advised follow-up with repeat Pap smear in 6-12 months and those with moderate to severe neoplasia (CIN II-III) were further investigated by cervical biopsy and managed accordingly. RESULTS: Of the total, 100 patients were between 25-30 years of age, and 180 between 31-35 years of age. Mean age of patients was 31.6 years, mean age at marriage 21.7 years, and mean parity was 3.6. Most of the patients (67.9%) belonged to low socioeconomic status. The cytological examination of the smears showed no changes (normal) in 100 (35.7%) cases, while 156 (55.7%) cases showed inflammatory changes, 10 (3.6%) showed dysplastic changes, of whom 8 cases had CIN-I (2.8%) and one case was of CIN-II (0.4%). One was having CIN-III/severe dysplasia (0.4%). Inadequate sample was reported in 14 (5%) cases. CONCLUSION: Pap smear should be used as a routine test for all sexually active, young females presented to the gynaecology outpatient department, for early detection of cervical pre cancer (CIN) as it is not uncommon in our set up. PMID- 24800340 TI - Effect of doxorubicin and daunorubicin on the activity of acetylcholinesterase in acute lymphoblastic leukamia. AB - BACKGROUND: Our study was based on the alteration in the Michaelis Mentin parameters Apparent Michaelis Constant (aKm) and Apparent Maximum Velocity (aVm), which reflects activity of actylcholinesterase (AChE). This activity decreases in Acute Lymphoblastic Leukaemia (ALL). This decrease in aKm and aVm values shows bad prognosis. Similarly the anticancer drugs like Daunorubicin and Doxorubicin further decreases the aKm and aVm values which worsen the prognosis. The objective of this study was to determine and compare the extent of inhibition of Acetylecholine Esterase by Daunorubicin and Doxorubicin in ALL. METHODS: Study of 100 patients including both male and female children who's age ranged from 4 to 8 years and were advised doxorubicin and daunorubicin separately were tested by Ellman's method using acetylcholine iodide as substrate and 5,5-dithiobis 2 nitrobenzine as a colour reagent regardless of dose regimen i.e. (once in 3 week, small dose per week or a continuous infusion for 72 to 96 hours. RESULTS: In this study the Michaelis Mentin parameters Apparent Michaelis Constant (aKm) and Apparent Maximum Velocity (aVm) of the enzyme were estimated both in normal individuals and in the patients and also during treatment with daunorubicin and doxorubicin. The value of Michaelis Mentin parameters, aKm, aVm and percentage activity of the enzyme in normal individual are 23, 70, and 100 respectively. The values of aKm, aVm and percentage activity of the enzyme were also estimated in the patients before and after treatment. The values of aKm and aVm in patients of acute lymphoblastic leukaemia and percentage activity of enzyme is decreased. After the treatment with daunorubicin and doxorubicin the values and activity is further decreased. CONCLUSION: We conclude that the drugs under study both decrease the enzyme activity but daunorubicin inhibits the enzyme more than doxorubicin. PMID- 24800341 TI - Gross hepatic changes in developing albino rats exposed to valproic acid. AB - BACKGROUND: Valproid Acid (VPA) is a broad spectrum antiepileptic drug. Its use during pregnancy has been associated with congenital anomalies and hepatotoxicity. This study was designed to assess the effects of VPA on the gross structure of liver in developing albino rats exposed to the drug during various trimesters of pregnancy. METHODS: In this experimental study 40 pregnant rats were divided into 4 equal groups A, B, C and D. Group A received VPA in a dose of 500 mg/Kg/day intraperitonealy (I/P) on days 3, 4 and 5 of gestation. Group B received the drug in a dose of 500 mg/Kg/day I/P on days 8, 9 and 10 of gestation. Group C received VPA in a dose of 500 mg/Kg/day I/P on days 16, 17 and 18 of gestation. Group D received no treatment and was kept as a control group. On day 21, the rats were euthanised by cervical dislocation. The liver of the foetuses were dissected out for the assessment of their gross structure. RESULTS: Foetal liver of the experimental groups showed significant decrease in weight as well as relative tissue weight index (RTWI) as compared to the control group, although the gross appearance of the foetal liver was normal in all the groups. CONCLUSION: The use of VPA during various trimesters of pregnancy produces hepatotoxicity in the developing rats. So, the use of this drug during pregnancy should be carefully decided. PMID- 24800342 TI - Closure of elective abdominal incisions with monofilament, non-absorbable suture material versus polyfilament absorbable suture material. AB - BACKGROUND: Closure of abdominal incisions with different suture materials has been a matter of great controversy. Polypropylene and Polylactide with Polyglycolide are among the commonest suture materials used for closure of abdominal incisions. Objectives of this study were to assess optimal suture material used for closure of elective abdominal incisions and to see complications associated with these suture materials. METHODS: This prospective, comparative, randomised study was conducted at public and private sector hospitals of Nawabshah and Hyderabad from 1st Jan 2005 to 31st October 2009. All patients who underwent abdominal surgery under the investigators' supervision were included in the study. Patients were divided into 2 groups on even or odd numbers. In group-A patients' incision was closed with monofilament, non absorbable Polypropylene (Prolene) No. 1 suture material and in group-B incision was closed with Polyfilament, absorbable, co-polymer of Polylactide with Polyglycolide (Vicryle) No. 1. RESULTS: A total 274 patients were finally analysed for closure of elective abdominal incisions, with 138 (50.4%) patients in Group-A and 136 (49.6%) patients in Group-B. Vicryle was found superior in knot security and suture handling. Superficial wound infection was found in 5.79% patients of Group-A and 6.61% of Group-B. Discharging sinus was found in 3.62% of Group-A vs 0.73% of Group-B. Burst abdomen was seen in 2.17% patients in Group-A and 1.47% in Group-B. Incisional hernia was present in 4.34% of Group-A and 0.73% patients of Group-B. No patient in Group-B developed persistent pain at incisional site while it was found in 8.69% patients of Group-A. CONCLUSION: Polylactide is an optimal suture material in closure of elective abdominal incisions. PMID- 24800343 TI - Effect of ascorbic acid on fatigue of skeletal muscle fibres in long-term cold exposed Sprague Dawley rats. AB - BACKGROUND: On exposure to prolonged cold temperature, the body responds for effective heat production both by shivering and non-shivering thermogenesis. Cold exposure increases the production of reactive oxygen species which influence the sarcoplasmic reticulum Ca++ release from the skeletal muscles and affect their contractile properties. The role of ascorbic acid supplementation on force of contraction during fatigue of cold exposed skeletal muscles was evaluated in this study. METHOD: Ninety healthy, male Sprague Dawley rats were randomly divided into three groups of control (I), cold exposed (II), and cold exposed with ascorbic acid 500 mg/L supplementation mixed in drinking water (III). Group II and III were given cold exposure by keeping their cages in ice-filled tubs for 1 hr/day for one month. After one month, the extensor digitorum longus muscle was dissected out and force of contraction during fatigue in the skeletal muscle fibres was analysed on a computerised data acquisition system. RESULTS: The cold exposed group showed a significant delay in the force of contraction during fatigue of skeletal muscle fibres compared to control group. Group III showed easy fatigability and a better force of contraction than the cold exposed group. CONCLUSIONS: Ascorbic acid increases the force of contraction and decreases resistance to fatigue in the muscles exposed to chronic cold. PMID- 24800344 TI - Frequency of hepatitis C in asymptomatic patients in District Headquarters Hospital Kotli, Azad Kashmir. AB - BACKGROUND: Hepatitis C is a common problem in developing world. It can affect a large number of asymptomatic people in whom it may cause serious complications in long run. Moreover, these asymptomatic infected people pose a serious risk for the transmission of infection to healthy population. Objective of this study was to estimate the frequency of Hepatitis C in asymptomatic adult patients attending medical OPD of District Headquarters Hospital Kotli, Azad Kashmir, and to assess the risk factors associated with its transmission. METHODS: This was a cross sectional study that included asymptomatic patients of both genders, aged 15-80 years, attending medical OPD of District Headquarter Hospital Kotli, Azad Kashmir from January to December, 2008. They attended the OPD for problems other than Hepatitis and most of them presented with vague complaints like generalised body aches, tiredness and dyspeptic symptoms. They were randomly tested for Hepatitis C virus (HCV) antibodies by Immunochromatographic kit method. Positive samples for Hepatitis C antibodies were confirmed by third generation ELISA. Those who were confirmed were assessed for the risk factors associated with HCV transmission. RESULTS: The study included 9,564 patients. Out of them 4,230 (44.22%) were males and 5,334 (55.77%) were females. A total of 611 (6.38%) cases were positive for HCV; 257 (6.08%) were males, and 354 (6.64%) were females. Highest frequency (36%) was found between 21 and 30 years of age, and 60.54% positive patients were 21-40 years old. Blood transfusion was the most common (34.36%) risk factor followed by history of dental procedures (24.54%). In 27.16% no risk factor could be detected. CONCLUSION: Frequency of Hepatitis C is quite high in our population. Rate is higher in young adults. It is needed to adopt organised preventive strategies to overcome this problem. Blood transfusion is still the most significant risk factor followed by dental and surgical procedures. Health related procedures are still not safe in our set up and need to be addressed. PMID- 24800345 TI - Relationship of thyroid-stimulating hormone with metabolic syndrome in a sample of euthyroid Pakistani population. AB - BACKGROUND: Metabolic Syndrome is a group of factors that predispose to cardiovascular diseases. The prevalence of metabolic syndrome is rising rapidly. Recently, a few studies have suggested that lower thyroid function in the reference range may be associated with metabolic syndrome, but the issue remains unsettled. We aimed to elucidate the relationship between thyroid function and components of metabolic syndrome in a sample of euthyroid Pakistani population. METHODS: This analytical, cross-sectional study was conducted at the Department of Physiology, University of Health Sciences, Lahore, Pakistan, and extended over a period of 12 months. It included 100 subjects with metabolic syndrome in the study group and thirty subjects without metabolic syndrome in the control group with age ranging 45-55 years. Both groups had normal thyroid function. After a detailed history and clinical examination, fasting blood was analysed for glucose, triglycerides, high density lipoprotein-cholesterol along with thyroid stimulating hormone (TSH) and free thyroxine. RESULTS: Serum TSH was significantly higher in study group than in control group (p = 0.040). Serum free thyroxine values of study group were slightly but not significantly lower than those of control group. Serum TSH correlated significantly and positively with serum triglycerides in all subjects and with waist circumference and diastolic blood pressure in men. Serum TSH showed a positive and linear relationship with the number of components of metabolic syndrome (p = 0.016) in all subjects. CONCLUSION: High-normal TSH is associated with metabolic syndrome and its components. There may be increased risk of cardiovascular diseases with high normal TSH levels. PMID- 24800346 TI - Childhood strokes: epidemiology, clinical features and risk factors. AB - BACKGROUND: Stroke constitutes a significant health problem in paediatric population. The impact of childhood stroke can easily be realised in terms of economic, social and psychological burden related to disability of the affected children. The objective of study was to outline the epidemiology and clinical features of stroke in a cohort of Pakistani children and also ascertain the causes and potential risk factors in these patients. METHODS: The study was conducted at the Department of Paediatrics, Ayub Teaching Hospital from January 2008 to October 2010. It was a cross sectional study. A total of 46 patients were included in the study who presented with cerebrovascular disease and were assessed clinically using general physical and systemic examination. The salient epidemiological, clinical, neuro-imaging and laboratory data was retrieved in designed protocol. RESULTS: Out of a total of 46 patients, 50% were from either gender. Mean age of presentation was 39 months. Limb weakness was the commonest presenting feature being present in 37 (80.43%) patients. Infectious disorders was the most prevalent risk factor present in 31 (67.39%) patients followed by microcytic hypochromic anaemia in 28 (60.86%) patients. CONCLUSION: A Childhood stroke is a disorder with long term morbidity. Identification of risk factors is important in preventing the disorder by guiding appropriate interventions. PMID- 24800347 TI - Modified acid fast staining: a better diagnostic tool in chronic diarrhoea due to cryptosporidiosis. AB - BACKGROUND: Cryptosporidium parvum is an emerging pathogen responsible for chronic diarrhoea in children and immuno-compromised individuals, especially AIDS patients. Currently, there is no effective therapeutic strategy for treating cryptosporidiosis, therefore control and supportive treatment of cryptosporidiosis depends upon rapid and accurate diagnosis of this infection. METHODOLOGY: A descriptive study was conducted in the Pathology Department of Khyber Medical College and Pathology Laboratory of Khyber Teaching Hospital over a period of one year March 2007-April 2008. A total of 200 stool samples were tested for the presence of C. parvm oocysts from children < 5 years age suffering from diarrhoea for > 5 days. Total and differential leukocyte count was determined to assess immune status of the patients. Modified Ziehl-Neelsen (Z-N) staining, a rapid, sensitive and easy test, was used successfully for the detection of C. parvum oocysts in stool specimen. RESULTS: Cryptosporidium oocysts were found in 18 (9.0%) samples. Out of 18 positive cases, 13 (72.2%) children had lymphopenia hence their immune status was impaired. Infection was common in children between 1-24 months of age. Mean duration of diarrhoea was 11 months. Most of C. parvum infected children were consumers of well water (77.8%). CONCLUSION: Cryptosporidiosis, although a self-limiting disease, rarely investigated routinely, can become chronic and life threatening in immuno compromised individuals. Majority of affected patients are immune-compromised. Modified Z-N is a sensitive and rapid method which can explore the gravity of this infection even further if used routinely and may control morbidity and mortality associated with this infection. PMID- 24800348 TI - Effect of L-arginine therapy on plasma NO2 and NO3 levels, and blood pressure in uremic rabbits. AB - BACKGROUND: Normal kidney function is regulated by Nitric oxide (NO) and Superoxide (O2-) in the body, and consequently controls blood pressure. Nitric Oxide promotes natriuresis and diuresis, and therefore results in reduction of blood pressure. The objective of this study was to determine the effect of L arginine supplementation on blood pressure, urinary protein, nitrite and nitrate in addition to blood urea, serum creatinine and creatinine clearance in uremic rabbits. METHODS: This study was carried out in the Department of Biochemistry Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre, Karachi. A total of 48 rabbits were included in the study. Twenty-four of the rabbits on surgical intervention were prepared as uremic and so became hypertensive as well. Two groups were uremic, one group was given L-arginine and the other was remained untreated. Systolic and diastolic blood pressure was measured on week 0, week 2, week 4, and week 6, while blood and urine was collected on week 0 and week 6. RESULTS: On supplementation with L-arginine to uremic rabbits systolic and diastolic blood pressures were decreased significantly. Nitrite/nitrate and urinary protein were corrected to some extent while blood urea and serum creatinine were unaffected. CONCLUSION: L-arginine has a beneficial role as blood pressure lowering agent in uremic rabbits. It corrects NO2/NO3 plasma level and proteinuria which is indicator of renal failure. PMID- 24800349 TI - In vitro antituberculous activity of thymoquinone, an active principle of Nigella sativa. AB - BACKGROUND: Nigella sativa seed has been used in folk medicine against many ailments including infections. The present study was aimed to investigate activity of thymoquinone, in vitro, against clinical isolates of Mycobacterium tuberculosis. METHODS: Mycobacteria obtained from patients of King Fahd Hospital of University, Alkhobar, Saudi Arabia were subcultured at 37 degrees C in MGIT tubes containing Middlebrook broth and OADC growth supplement and growth detected by BACTEC MicroMGIT fluorometer on day 10. Mycobacteria were then inoculated in MGIT tubes containing thymoquinone 2.5, 5, 10, 20, 40, 80 microg/ml, streptomycin 1.25 microg/ml or controls in Middlebrook broth plus supplement, incubated at 37 degrees C for 14 days and read daily for fluorescence. In addition, isolates were inoculated in culture tubes containing Middlebrook agar (plus supplement) in presence of thymoquinone 2.5, 5, 10, 20, 40, 80 microg/ml, streptomycin 1.25 microg/ml or controls, and incubated at 37 degrees C for 4 weeks. RESULTS: In Middlebrook broth, fluorescence test for tuberculosis was negative with thymoquinone 20, 40 and 80 microg/ml and streptomycin 1.25 microg/ml up to day 14th. With controls, thymoquinone 2.5, 5 and 10 microg/ml fluorescence was detectable from day 10 to 14. In Middlebrook agar, there was no visible growth of tubercle bacillus with thymoquinone 20, 40 and 80 microg/ml and streptomycin 1.25 microg/ml, however, with controls, thymoquinone 2.5 and 5 microg/ml abundant and with 10 microg/ml few colonies were observed. CONCLUSIONS: Thymoquinone possesses activity against M. tuberculosis with MIC of 20 microg/ml and has potential for further investigation. Our study confirms the benefit of N. sativa in native medicine against chest infection. PMID- 24800350 TI - Pancytopenia in two national ethnic groups of Baluchistan. AB - BACKGROUND: Pancytopenia is a recognisable haematological problem with common categorises diagnosis but best possible diagnostic approach is still to be defined. OBJECTIVE: The aim of this study was to determine the frequent causes and clinical presentation of pancytopenia in relation to age and sex in different ethnic groups of two national (Pakistani and Afghan) living in Baluchistan province. METHODS: This is a cross sectional descriptive type of study was carried out on patients (n = 180) for two years (July 2009-June 2011). Cases were successively registered in 2 provincial government hospital and 2 private clinics in Quetta with diagnosis of pancytopenia. RESULTS: The most frequent causes of pancytopenia in both national ethnic groups were malaria (29.44%) fallowed by tuberculosis (17.22%), leukaemia (16.67%), aplastic anaemia (13.33%), hepatitis (12.22%), other diseases (7.22%) and iron deficiency anaemia (3.89%). Overall, 63.89% male subjects were observed pancytopenia as compared to 36.11% female patients. The results also showed that patients with age > 41 years were highly (50%) affected by pancytopenia followed by 21-40 years (30.66%) and < 20 years (19.44%). Moreover, leukaemia cases were observed significantly higher in Afghan subjects (> 41 years). The most common symptom of patients was (71.11%) fever followed by Pallor (42.22%), fatigue (38.33%), weight loss (26.11%) and dizziness (25.56%). Leukaemia and aplastic anaemia were found to be the most serious causes of pancytopenia in Afghan ethnic group. CONCLUSIONS: Malaria, tuberculosis, aplastic anaemia, and leukaemia were the leading causes of pancytopenia in Pakistani and Afghan ethnic groups. Severe pancytopenia has significant relation with the clinical conclusion and can be used as a prognostic marker. PMID- 24800351 TI - Role of tumour necrosis factor in pathogenesis of radicular cyst. AB - BACKGROUND: The radicular cyst is very common odontogenic cyst of the jaws, which is usually associated with a tooth with necrotic pulp. The cyst formation requires proliferation of the epithelial rest cells of Malassez present in the periodontal ligament. Proliferation of epithelial rest cells of Malassez is an essential event in the Pathogenesis of radicular cyst. The wall of the cyst contains epithelial cells, macrophages, fibroblasts and other cells. TNF is one of inflammatory mediators, which is produced by macrophages and monocytes. This study was carried out to investigate the role of tumour necrosis factor in the pathogenesis of radicular cyst, which is by far the commonest cystic lesion of the jaws. METHODS: Explants from 20 radicular cysts were cultured in vitro to grow the epithelial cells. However, the cultures were rapidly contaminated with fibroblasts and it was impossible to grow the epithelial cells separately. Therefore, the proliferative effect of Tumour Necrosis Factor (TNF) was studied on mammalian epithelial cells. RESULTS: TNF at low concentration had a proliferative effect on the epithelial cells, which may play some role in pathogenesis of radicular cyst. CONCLUSION: TNF stimulated the epithelial cell proliferation in low concentration and inhibit the proliferation in higher concentrations. These two effects may have some implications in the pathogenesis of radicular cyst. PMID- 24800352 TI - Crimean Congo hemorrhagic fever in Hazara division. AB - BACKGROUND: Crimean-Congo Hemorrhagic fever (CCHF) is endemic in certain areas of Pakistan with 14 outbreaks in addition to many sporadic cases so far. It is highly fatal zoonotic disease caused by bite of infected tick. The objective of our study is to describe clinical features, treatment and outcome of CCHF positive cases during its outbreak in Hazara division, with the intention to bring focus to this fatal emerging disease. METHODS: This study was conducted in Medical A Unit of Ayub Teaching Hospital, Abbottabad for a period of three months. All patients presenting with fever and platelet count less than 50,000/mm3 were included in the study. Apart from baseline investigations their blood samples were sent for the detection of CCHF virus. All patients were given supportive treatment including fresh frozen plasma and were started on oral Ribavirin. All patients were isolated and barrier personal precautions were observed by health care givers. RESULTS: Eighty-eight patients with fever and thrombocytopenia were included. Among these, 8 were found to be positive for CCHF. Supportive treatment with oral Ribavirin was given to all patients. One patient with CCHF died. One left against advice and six patients recovered completely. CONCLUSIONS: All patients presenting with acute fever and thrombocytopenia should be suspected and evaluated for CCHF. Oral Ribavirin is safe and effective in the treatment of CCHF. PMID- 24800353 TI - Management and maternal outcome in morbidly adherent placenta. AB - BACKGROUND: Morbidly adherent placenta (MAP) with its variants is one of the most feared complications causing high morbidity and mortality in obstetrics. The objective of this study was to analyse different management options and maternal outcome in diagnosed cases of morbidly adherent placenta. METHODS: Descriptive case series was carried out in Obstetrics and Gynaecology Department, Combined Military Hospital, Rawalpindi and one private hospital from Jan 2008 to Dec 2010. During this period all cases of morbidly adherent placenta diagnosed by colour flow Doppler and MRI were analysed. Operative delivery was carried out in all patients. Three different surgical managements namely total abdominal hysterectomy with non separation of placenta, subtotal hysterectomy and trial haemostasis with uterine sparing surgery were carried out on when and where required basis. The outcome like total blood loss, blood transfused, Intensive unit care, postnatal complications including febrile morbidity, hospital stay and prolonged follow ups, were recorded. RESULTS: Total 32 cases of morbidly adherent placenta diagnosed by colour Doppler ultrasound/MRI (magnetic resonance imaging) were identified. In this study the frequency of morbidly adherent placenta found to be 1/274.8 deliveries and 1/122.6 caesarean sections. Initially total caesarean hysterectomy was performed in 16 patients, while subtotal hysterectomy in 9 and Trial haemostasis with uterine sparing in 7 cases out of which two cases underwent total hysterectomy due to massive postpartum haemorrhage same day. One case in subtotal hysterectomy for placenta percreta with bladder invasion had re laparotomy for bladder fistula, while two for severe postpartum haemorrhage. Two needed ventilator support. Maternal morbidity was greater in subtotal hysterectomy and uterine sparing group. One patient died in this study. CONCLUSION: Antenatal diagnosis of morbidly adherent placenta followed by well planned total abdominal hysterectomy with non-separation of placenta adapting multidisciplinary approach is the best surgical option to reduce maternal morbidity/mortality. PMID- 24800354 TI - Perception of academic examination stress: effects on serum leptin, cortisol, appetite and performance. AB - BACKGROUND: Examination stress is a psychological stress that activate hypothalamic-pituitary adrenocortical (HPA) axis to increase circulating levels of glucocorticoids. The fat derived hormone leptin is also released in response to stress-inducing condition. To workout the role of leptin and cortisol in response to perceived levels of examination stress and their effects on academic performance. The present study was designed to monitor the relationship of self reported perceived levels of examination stress on serum levels of cortisol and leptin in female students going to appear in university examination. METHODS: Fifty-six female undergraduate students participated in the study. Examination stress, appetite levels were assessed by a questionnaire and blood samples were collected one hour before appearing in the examination. Performance was evaluated from the marks obtained in that particular examination. RESULTS: Serum cortisol levels increased with an increase in the intensity of perceived examination stress. Serum leptin levels increased only in the group under moderate stress while increases in mild and severe stress group were not significant. Mild to moderate stress enhanced performance but severe stress decreased it. CONCLUSIONS: The present study shows an inverted U-shaped relationship between self reported different levels of perceived examination stress and academic performance. PMID- 24800355 TI - Incidence and visual outcome of acute postoperative endophthalmitis. AB - OBJECTIVES: To assess the incidence and visual outcome of acute post operative endophthalmitis treated by intravitreal antibiotics. METHODS: This Prospective study was conducted at Department of Ophthalmology, Liaquat University Eye Hospital Hyderabad from November 2002 to October 2010. One hundred and nine patients of acute post operative endophthalmitis were treated with intravitreal antibiotics. The inclusion criteria of the patients was the clinical diagnosis of acute post operative endophthalmitis within 14 days of post operative period and visual acuity better than or equal to hand movement close to face. After enrolment, vitreous tap was carried out followed by intravitreal antibiotics injection. The outcome was measured in terms of clinical resolution of endophthalmitis and post resolution best corrected visual acuity. RESULTS: Of the 109 patients 97 meet the criteria and followed completely were included. Sixty patients (61.9%) had extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens implantation while phacoemulsification done in 37 (38.10%) patients. The visual acuity at presentation was 6/60 or worse in 80 (82.5%) patients. Vitreous tap was done in 86 (88.7%) patients. Vitreous biopsy yields an organism in 32 (33%) patients. Coagulase positive were the most common organism. 75 (77.3%) patients received single dose of intravitreal antibiotic. Forty five (46.4%) patients received single antibiotic, cetazidime while two antibiotics given in 52 (53.6%) patients. Twenty five (25.8%) patients also had oral steroids. Ninety one (93.8%) patients responded to intravitreal antibiotics. Seventy five (77.32%) patients achieved final visual outcome better than 6/60 in meantime of 54.08 days. Six (6.2%) patients developed no perception of light and another six patients (6.2%) referred for vitrectomy. CONCLUSION: The final visual outcome of the patients with acute postoperative endophthalmitis is strongly associated with the visual acuity at presentation as well as type of infective organisms. PMID- 24800356 TI - Prognostic significance of serum bilirubin in stroke. AB - BACKGROUND: Oxidative injury is an important cause of the neurologic lesion in stroke. Serum bilirubin is considered a natural antioxidant that may affect the prognosis of stroke. The purpose of this study was to evaluate the prognostic significance of bilirubin in stroke patients. METHODS: A prospective cross sectional study was conducted in Medical Units of Khyber Teaching Hospital, Peshawar. Inpatients admitted with acute attack of stroke were included in this study. Data regarding serum bilirubin and concurrent cerebrovascular risk factors were collected. National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to analyse stroke's severity and functional outcomes, respectively. RESULTS: Hypertension, diabetes mellitus and heart diseases were the most common risk factors. Patients were divided into 3 groups on the basis of serum bilirubin, i.e., < or = 0.6 mg/dl (Group-1), 0.7-0.9 mg/dl (Group-2), and > or = 1.0 mg/dl (Group-3). The mean pre-hospitalisation NIHSS score for Groups 1, 2 and 3 was 5.62, 11.66 and 25.33, respectively; and post hospitalisation score was 0.875, 3.76 and 16.26, respectively. The pre hospitalisation mRS score was 4 for Group-1, 4.52 for Group-2 and 4.93 for Group 3; while post-hospitalisation Mrs Score was 1.50, 2.38 and 4.26, respectively. Average serum bilirubin level was significantly higher in patients with poor outcomes as compared with good outcomes (p < 0.01). CONCLUSIONS: This study suggests that higher serum bilirubin levels were associated with increased stroke severity, longer hospitalisation and poor prognosis. PMID- 24800357 TI - Assessment of left ventricular systolic and diastolic function by tissue Doppler imaging after acute myocardial infarction. AB - OBJECTIVE: To evaluate left ventricular systolic and diastolic function by Tissue Doppler imaging after acute myocardial infarction. METHODS: It was a hospital based, prospective descriptive study, from 1st July 2010 to 31st Dec. 2010. Total of 200 patients having acute myocardial infarction underwent detailed tissue Doppler imaging (TDI) echocardiographic examination for evaluation of left ventricular systolic and diastolic function on day 3, in echocardiographic section of Govt. Lady Reading Hospital, Peshawar. Peak systolic (Sm), peak early diastolic (Em) and peak late diastolic (Am) velocities were recorded at 4 different sites of the mitral annulus. The ejection fraction and pulse wave TDI diastolic parameters were also recorded. Using SPSS version 16 data was analysed, frequencies and Mean +/- SD were determined for categorical and numerical variables, respectively. A p-value < or = 0.05 was considered significant. RESULTS: Total study sample was 200 patients having acute myocardial infarction (MI). The sample was divided into 4 groups, i.e., anterior MI, inferior MI, septal MI, and lateral MI. There were 122 men and 78 women and the mean age was 42 +/- 5 SD. There was a marked reduction in Sm velocity at mitral annulus, especially at the infarction sites. The mean peak systolic velocity from 4 mitral annulus sites was well correlated with ejection fraction (p = 0.0001). Similar to systolic velocities, Em velocity was also reduced, especially at the infarction sites. The mean peak early diastolic velocity from 4 mitral annulus sites was well correlated with ejection fraction (p = 0.0001). The mean Em velocity was correlated well with isovolumic relaxation time (IVRT). There was no correlation between mean Em velocity and deceleration time (DT). CONCLUSION: Tissue Doppler Imaging is a reliable, accurate and easily reproducible modality of echocardiography. The reduced peak systolic velocity and reduced peak early diastolic velocity seems to be an expression of regionally reduced systolic and diastolic functions, respectively. While the reduced mean systolic velocity and reduced mean early diastolic velocity from 4 mitral annulus sites are expressions of globally reduced systolic and diastolic functions, respectively and were correlated well with the ejection fraction. PMID- 24800358 TI - Helicobacter pylori detection in chronic gastritis: a comparison of staining methods. AB - BACKGROUND: Helicobacter pylori is an important cause of chronic gastritis, gastric ulceration and gastric malignancies as gastric carcinoma and MALT lymphoma. Its definitive diagnosis is based on histopathology. Routine H & E stain is not very effective in its detection, immune-stains and fluorescent stains are costly. Need for simple cheap and sensitive stain has always been a topic of hot debate and extensive research. METHOD: paraffin embedded blocks of all adult patients diagnosed as chronic gastritis/gastric ulceration with no accompanying gastric pathology as hypertrophic gastropathys, and neoplasias were taken into study. Three sections of 4 micron were cut and stained with routine H & E, Giemsa, and Cresyl fast violet. RESULTS: Total number of patients was 50. Out of these 37 (74%) were males and 13 (26%) were females. Mean age of the patients was 50.4 years. Thirty-four percent (34%) were positive in normal H & E stain, 68% were positive in Giemsa and 76% were positive in Cresyl fast violet. CONCLUSION: Cresyl fast violet is a good stain for diagnosis ofH. pylori gastritis. PMID- 24800359 TI - Prevalence and risk factors for infantile colic in District Mansehra. AB - OBJECTIVE: Infantile colic is a common problem among infants age 3 days to 3 months. It may affect parental feelings negatively and the parents may undertake all kinds of actions to stop excessive crying. The objective of this study was to assess the incidence of infantile colic and its risk factors in infants born in District Mansehra. METHODS: In this prospective study, all those newborn babies were included who were born at King Abdullah Teaching Hospital Mansehra between January 1st 2008 and March 31, 2008, and those newborn babies who were brought to children OPD for routine check-up and EPI centre for vaccination of this hospital during this time period. For every infant, gender, mode of delivery, gestational age at birth, birth weight, birth order, and mother's reproductive history were collected. These babies were seen at least once in a week up to 12 weeks and history from the mothers about the duration of crying and fussiness behaviour was recorded. At the end of 3 months the infants were again assessed and additional information on infant nutritional source was obtained and any medication used for colic relief was identified. Cases of colic were identified by applying Wessel criteria to recorded data. Chi-square tests were used. RESULTS: From total 512 infants, follow-up was completed for 426 infants. In total, 90 infants (21.77%) satisfied the Wessel criteria for infantile colic. No statistical significance was found between colicky and non-colicky infants according to sex, gestational age at birth, birth weight, type of delivery, and, infant's feeding pattern. However, firstborn infants had higher rate for developing colic (p = 0.03). CONCLUSION: Prevalence of colic was 21.77% in this infant population of District Mansehra. Except for birth order, no other variable was significantly associated with infantile colic. PMID- 24800360 TI - Culture and sensitivity pattern in patients with external ventricular drain infection. AB - BACKGROUND: External ventricular (EVD) is a life saving procedure and involves insertion of a catheter in ventricular space to drain cerebrospinal fluid (CSF). Our objective of this study was to determine the culture and sensitivity (C/S) pattern in patients with EVD infection. METHODS: This cross sectional study was conducted in Department of Neurosurgery, Pakistan Institute of Medical Sciences (PIMS), Islamabad from December 1, 2008 to January 31, 2010. All admitted patients who had acute hydrocephalus, underwent EVD insertion after excluding meningitis and ventriculitis by physical examination and per operative CSF sampling. The EVD was done at right Kocher's point. Prophylactic third generation antibiotic (Ceftriaxone) was started and continued till EVD was in place. C/S was sent to PIMS laboratory on first documented fever and or change of CSF color or when plan was to replace EVD with Ventriculo-peritoneal shunt (VP). Once infection was there CSF was sent for C/S initially and routine examination (R/E) daily. Antibiotics were changed according to C/S report and continued till they were needed. Infection rate was also estimated. RESULTS: Among 76 patients 41 (53.9%) were male and 35 (46.1%) were females. Most were adults and were between 31 to 40 years of age. Mean duration of EVD was 11.41 days. Overall infection rate was 11.8%. Among causative organisms Staphylococcus Aureus (44.4%) was most common followed by Acenitobacter and Enterobacter and commonly used prophylactic antibiotic (Ceftriaxone) had considerable resistance. CONCLUSION: EVD is a simple and life saving procedure. Most common organisms causing infection are Staphylococcus Aureus followed by Acenitobacter. Conventional used antibiotic Ceftriaxone has considerable resistance. PMID- 24800361 TI - Minimal invasive plate osteosynthesis of close fractures of distal tibia. AB - BACKGROUND: The limited soft tissue, subcutaneous location and poor vascularity render the tibial fractures very challenging. Treatment of distal tibial fractures using minimally invasive plate osteosynthesis (MIPO) technique may minimise damage to soft tissues and the vascular integrity of bony fragments, leaving comminuted fragments out of the mechanical construct, preserving soft tissues with limited operative exposure. This descriptive study was conducted to assess the outcome of patients treated with MIPO technique for distal tibial fractures. METHODS: Seventy three cases of multifragmentary fractures of the distal tibia admitted in Bahawal Victoria Hospitals, Bahawalpur between April 2009 and October 2010 were included in this study. Patient's outcome in terms of period of radiologic union of the fractured segments and period of full weight bearing capacity were accessed. RESULTS: There were 66 males and 7 females of mean age 43 years. The mean follow-up period was 13 weeks. (Ranging from 9-16 weeks). All patients were fully weight bearing at 16 weeks (ranging 9-16 weeks) showing radiological union. There were two superficial infections treated successfully using oral antibiotics and no failures of fixation. There were no cases of rotational malalignment. CONCLUSION: MIPO is an effective method of treatment for distal tibial fractures. The use of indirect reduction techniques and small incisions is technically demanding but decreases surgical trauma to soft tissues. PMID- 24800362 TI - Role of alpha-1 blocker in expulsion of stone fragments after extracorporeal shock wave lithotripsy for renal stones. AB - BACKGROUND: Renal stone disease is a significant and worldwide health problem. Recent advances in stone management have allowed kidney stones to be treated using extracorporeal shock wave lithotripsy (ESWL), uretero-renoscopy (URS), and percutaneous nephrostolithotomy (PCNL). Recently, medical expulsion therapy (MET) has been investigated as a supplement to observation in an effort to improve spontaneous stone passage rates. PATIENTS AND METHODS: This study was a randomized, controlled, prospective study to determine whether the administration of Alpha-1-adrenergic receptor antagonists as an adjunctive medical therapy, increases the efficacy of ESWL to treat renal stones. Sixty patients with renal stones of 0.5-1.5 Cm in size (average size 1.2 Cm) were included in this study underwent ESWL followed by administration of Alpha-1-adrenergic receptor antagonists at department of Urology Liaquat National Hospital Karachi from Feb 2008 to Sept 2008. This was a comparative study and patients were divided into two groups. In group A patients received conventional treatment Diclofenac sodium, Anti Spasmodic (Drotverine HCl) as required and Proton Pump inhibitor (Omeprazole 20 mg) once daily after shock wave lithotripsy. In group B patients received alpha-1 blocker, Alfuzosin HCI 5 mg twice daily in addition to conventional treatment. All patients were instructed to drink a minimum of 2 litres water daily. Ultrasound guided Dornier Alpha Impact Lithotripter was utilised for shock wave lithotripsy. RESULTS: Of the 60 patients, 76.7% of those receiving Alfuzosin and 46.7% of controls had achieved clinical success at 1 month (p = 0.01). The mean cumulative diclofenac dose was 485 mg per patient in the Alfuzosin group and 768 mg per patient in the control group (p = 0.002). This difference was statistically significant. CONCLUSION: Alfuzosin therapy as an adjunctive medical therapy after ESWL is more effective than lithotripsy alone for the treatment of patients with large renal stones and is equally safe. It increases the expulsion rates of stones, decreases time to expulsion, and decreases need for analgesia during stone passage. PMID- 24800363 TI - Effect of gender on echocardiographic outcomes of patients presenting with mitral stenosis at a tertiary care hospital. AB - BACKGROUND: To assess the gender-based differences in the echocardiographic outcomes of patients with mitral stenosis presenting at a tertiary care hospital and the clinical implications of such differences. METHODS: A total of 90 echocardiographs of both men and women (aged < or = 15 years) having mitral valve area (MVA) less than 4 cm2 were assessed. In addition to MVA, pressure halftime and left atrial diameter (LAD) of the patients was also recorded. Other co existing valvular lesions were also assessed in addition to mitral stenosis. Statistical analysis was done using SPSS-17. RESULTS: A higher prevalence of mitral stenosis (MS) was found in women than men (76.66% vs 24.44%). Men were having more severe mitral stenosis as compared to women (MVA = 1.19 cm2 vs 1.32 cm2). This also resulted in significantly higher left atrial dilatation in males as compared to women (45.09 vs 41.75, p = 0.0422). Most of the patients had other coexisting valvular lesions and isolated MS was rare. However, men had a predominance of aortic stenosis along with mitral stenosis (27% vs 4%, p = 0.0059) whereas women had a higher prevalence of mitral regurgitation along with mitral stenosis than the men (65% vs 36%, p = 0.0258). CONCLUSION: There were certain significant differences in echocardiographic outcomes of patients based upon their gender. A gender-specific management approach towards the patients with mitral stenosis is essential to have better outcome. PMID- 24800364 TI - Frequency of diabetic retinopathy in hypertensive diabetic patients in a tertiary care hospital of Peshawar, Pakistan. AB - BACKGROUND: Diabetic retinopathy is a common microvascular complication of both type 1 and type 2 diabetes mellitus. If left untreated, it can progress to serious visual disability. Coexistence of hypertension with diabetes has been described as another risk factor adding to the problem. We designed this study to assess the occurrence of diabetic retinopathy in hypertensive diabetic patients of this region and to compare it with normotensive diabetic patients. METHODS: This cross-sectional study was carried out on 200 previously diagnosed diabetic patients. Apart from routine examination and investigations, retinopathy and blood pressure assessment of each patient was done using standard techniques. Hypertensive diabetic subjects (Group-I, n = 107) were compared with non hypertensive diabetics (Group-II, n = 93) for the presence of retinopathy. RESULTS: Retinopathy and hypertension were observed in 51% and 53.5% of the total diabetic patients respectively. Hypertensive diabetic patients had significantly higher percentage of retinopathy compared to non-hypertensive diabetic patients (58 vs 43%; p < 0.05). CONCLUSION: Retinopathy and hypertension are highly prevalent in our diabetic patients. The proportion of retinopathy is significantly more in hypertensive as compared to normotensive diabetics. PMID- 24800365 TI - Changing trend of presentation of acute coronary syndrome in Peshawar over the last sixteen years. AB - BACKGROUND: Once considered as disease of the affluent and developed countries, coronary artery disease is emerging as epidemic in the developing world in general and South Asia in particular. OBJECTIVE: To observe the trend of presentation of acute coronary syndrome in the local population over the last 16 years. MATERIAL AND METHODS: Clinical audit from 1995 to 2010 was carried out in which the data was retrieved from the computerised database of the Department of Cardiology, Lady Reading Hospital Peshawar. The period was divided into four quartiles, and the data of each quartile was analyzed for the total number of admissions, the type of ACS, whether ST-elevated MI or non-ST elevated ACS (comprising unstable angina and non-STEMI), age, gender and mortality. RESULTS: The total admissions into the unit in the first quartile (1995-1998) were 23,827, in the second quartile (1999-2002) 29,005, in the third quartile (2003-2006) 33,206 and in the fourth quartile (2007-2010) were 40,110. Total ACS brunt constituted 8340 (35%), 10,384 (35.8%), 12,180 (36.68%) and 14,920 (37.2%) patients respectively. The mean age of patients was 49.70 +/- 6.4 years, 48.21 +/ 7.2 years, 47.38 +/- 7.1 years and 46.81 +/- 6.2 years respectively. Women were 2356 (28.25% of the total ACS burden) in the first quartile, increasing to 3554 (34.225%), 4817 (39.55%) and 6281 (42.1%) in the following quartiles. STEMI constituted 45.88% (3826) of the total ACS presentations in the first quartile, 47.24% (4905) in the second, 49.55% (6035) in the third and 49.87% (7440) in the last quartile. The mortality rate, however, remained constant throughout (8.4% to 8.8%). CONCLUSION: An increasing trend is seen in the burden of CAD in the local population with increasing presentation as STEMI. It is also evident that CAD is occurring at younger ages and more so in the female population. PMID- 24800366 TI - Craniosynostosis: early recognition prevents fatal complications. AB - BACKGROUND: Craniosynostosis is the premature fusion of cranial vault sutures. The overall incidence is 3-5/10,000 live births. With multiple craniosynostoses, brain growth may be impeded by the unyielding skull. Most cases of single suture involvement can be treated with linear excision of suture. Involvement of multiple sutures or skull has usually required combined efforts of neurosurgeons and craniofacial surgeons. METHODS: On the basis of visible skull deformity all patients were admitted in the Department of Neurosurgery, Liaquat University Hospital, Jamshoro, Pakistan. Patients were examined for signs of raised ICP and other congenital deformities. The records of patients were maintained till follow up. RESULTS: Twenty-seven children were included in this study from 2002 to 2009. Age range was 1-6 years, boys were 18 (66.6%), and girls were 9 (33.3%). The common suture affected was coronal 12 (44.4%). Two children with craniostenosis belonged to same family, and all presented with suture involvement. Three (11.1%) deaths occurred due to hypothermia (1), and blood loss (2). CONCLUSION: Early diagnosis, expert surgical techniques and per- and postoperative care for bleeding and temperature regulation prevent mortality and morbidity. PMID- 24800367 TI - Predictors of mortality after acute stroke a prospective hospital based study. AB - BACKGROUND: The stroke is third leading cause of death in world and 10% of patients with an acute ischemic stroke die within 30 days. Various clinical variables have been implicated as predictors of final outcome of acute stroke. The study was aimed to identify predictors of mortality after an acute stroke. MATERIAL AND METHODS: This prospective study included 149 consecutive patients of acute Hospital Muzaffarabad, Azad Kashmir. The outcome as mortality measures used were Modified Ranking Scale (mRS) and Glasgow Coma Scale (GCS). Examination included clinical, neurological evaluation, laboratory tests, and brain CT. The follow-ups at 14 days were done for all patients. RESULTS: Hospital mortality was 17.4% (26/149) within 14 days. Age and gender had no impact on mortality. Hypertension (p = 0.008), smoking (p = 0.056)), brain infarction (p = < 0.001), hemorrhagic stroke (p = < 0.001), diabetes (p = 0.292), atrial fibrillation (p < 0.001), high mRS (p < 0.001), low GCS score (p < 0.001), on admission were important predictors of mortality. CONCLUSIONS: We report 17.4% mortality at 14 days. Mortality associated with acute stroke needs prevention and control of risk factors. PMID- 24800368 TI - Sampling bacterial biodiversity from a highly contaminated stream flowing through a densely populated urban area in Karachi. AB - BACKGROUND: Few studies have attempted to understand the complexity of microbial populations in Pakistan where infectious diseases are prevalent. This study was undertaken to assess bacterial biodiversity in Nehr-e-Khayyam a heavily polluted stream connected to the Arabian Gulf, which runs through a densely populated urban area in Karachi, Pakistan. METHODS: Employing a universal pair of oligonucleotides capable of amplifying species-specific segments of 16S rRNA gene from all Eubacteria, we generated a library of PCR products using total DNA purified from the collected sample, cloned the amplifers into pGEM-T-Easy and sequenced each recombinant clone. The obtained DNA sequences were subjected to bio-informatic analyses. RESULTS: A total of 71 recombinant clones were obtained from the amplified 16S rDNA products and sequenced. Bioinformatics analyses revealed that 54 (out of 71) were unique sequences from which 42 shared > 97% and 12 shared < 97% homology to their database counterparts. One sequence originated from the plastid DNA of eukaryote Pyramimonas disomata. From the remaining 53 sequences, 45 were Proteo-bacteria and 8 Fermicute in origin. Among 71 sequences, Alpha-, Beta- and Gamma-proteobacteria species constituted -86% of Proteo bacteria identified in the sample while only -13% were Fermicutes. CONCLUSIONS: The microbial niche in Nehr-e-Khayyam is occupied predominantly by heterotrophic Proteo-bacterial and Firmicute strains, some of which are known human pathogens. PMID- 24800369 TI - Health related quality of life after burns: are we really treating burns? AB - BACKGROUND: During the last few decades management of burns has undergone positive revolutionary change. Today, over 50% of all patients with burns involving 80% of their total body-surface area can survive. Although the objective assessment by attending physician can well define a patient's degree of health, the patient's subjective perceptions and expectations that can influence burn survivors experience of their life is much more important. METHODS: Adult burn patients of both sexes admitted to burn unit with major burns either by size or site who required reconstruction for burn injury were the subjects of this study. The health related quality of life was assessed using SF-36v2, questionnaire. RESULTS: The mild to moderate pain complaint by 87 (88%) of all burn survivors, badly impact role physical and general health with resultant decrease in physical component summary. What was more difficult to explain was the decreased mental health which is evident soon after the incidence and persisted throughout the period of follow-up, showing statistically insignificant improvement when compared from basal score (p = 0.008). Longitudinal decline in HRQoL had strong relationship with female sex, involvement of prime area, hospital admissions, hospital stay and sessions of surgery. Sex, occupation, involvement of prime area and hospital admissions, were the important predictors for decrease in physical component summary of burn survivors. Involvement of prime area and hospital admissions were important determinant for decrease in mental component summary. CONCLUSION: The level and quality of multidisciplinary rehabilitation that these victims needs is very low as compared to developed countries. These patients need long-term professional, psychological, and social support. PMID- 24800370 TI - In pursuit of quality by viable quality assurance system: the controllers' perceptions. AB - BACKGROUND: Patients, families and communities expect safe, competent and compassionate nursing care that has always been a core value of nursing. To meet these expectations, a valid and reliable quality assurance (QA) system is crucial to ensure that nurse-graduates are competent, confident and fit to practice. The QA approach is seen to be fundamental for quality improvement, it would be appropriate to consider its influence in the nursing education in Pakistan as the current situation is evident of non-existence of such a system to assure its quality. METHOD: The data is drawn from a qualitative case study conducted in 2004. Among a purposive sample of 71 nurses inclusive of a group of Controllers were interviewed on one-to-one basis. Interviews were audio taped to reduce the risk of any misinterpretation and to facilitate the exact description of data as it was said. The non-directive, semi-structured and open-ended questionnaire was used to collect data. Thematic analysis of verbatim transcripts of the interviews was done. RESULTS: The study findings reveal a unanimous desire of the nurses to gauge quality of nurse education through efficient and effective quality assurance system. CONCLUSION: A crucial need is felt to develop a viable quality assurance system to ensure approved level of quality in nursing education to deliver the right care to the right patient at the right time, every time. The continuous quality assurance and improvement (CQAI) framework based on Deming Quality Cycle (Plan, Do, Check and Act) could facilitate appropriate designing and development of mechanism. PMID- 24800371 TI - PBL wrap up sessions: an approach to enhance generic skills in medical students. AB - BACKGROUND: Problem based learning (PBL) tutorials are being used in various medical schools world wide. Students' active participation is a must for the success of a teaching program. The objective of this study was to evaluate the effectiveness of PBL Wrap-up sessions in an integrated modular medical curriculum in enhancing the generic skills of medical students. METHODOLOGY: This study was conducted on 100 students of 2nd year MBBS who had been taking PBL sessions since 1 1/2 years. Each session concluded with a wrap-up session where students demonstrated their acquired knowledge in the form of PowerPoint presentations, concept maps, skits, models etc. A questionnaire based survey was conducted to find out overall effectiveness of PBL sessions including wrap-up sessions. The questionnaire comprised of 15 questions. Students were asked to rate all those sessions on a likert scale of 1 to 5. RESULTS: Student's responses showed 'Moderate improvement' in 8 out of 15 skills like communication with peers and teachers, presentation skills, self confidence, application of acquired knowledge, using internet and other resources and understanding group dynamics. Improvement in abilities like problem solving, time management, creativity, motivation in studies and self-directed learning was 'Minimal'. In addition students recommended continuation of PBL in the same way for future classes. CONCLUSION: PBL with wrap-up sessions contributed in bringing moderate enhancement of generic learning skills in students which were not properly addressed in the traditional curriculum and are therefore recommended for future implementation. PMID- 24800372 TI - Faculty and students' perception about aptitude of professionalism in admission process of medical college. AB - BACKGROUND: Historically, knowledge and skill were of prime focus in medical education, where as professionalism was perceived as an attribute to be acquired during their MBBS studies. In the past decade, trends have changed and graduating medical students are expected to competently deliver care in a professional manner. The selection of applicants with professional attributes at the time of admission is a stepping stone for the formation of a good doctor. This study was conducted to determine the students' and faculty's perception about aptitude of professionalism in the admission process in our setting. METHODS: In this descriptive cross-sectional study an interactive/scenario-based conversation regarding institutional values, contribute to personal reflection of what will be expected of them in the medical profession and inclusion of such discussion in admission process was made to assess the aptitude of Professionalism of 100 students and 100 faculty members of Avicenna Medical College Lahore. After this conversation the questionnaires were filled by both the groups to record their responses on the aptitude of professionalism. The data was analysed to determine the response patterns of both the groups by using Pearson Chi-Square analysis through crosstabs. All analyses were carried out using SPSS-18. RESULTS: The response of students to professionalism discussion was more positively influenced (91%) compared to the faculty (59%), (p < 0.05). The students agreed that such scenarios do indicate what our institution values in its students and contribute to personal reflection of what will be expected of them in the medical profession. However, faculty agreed more (85%) than the students (67%) for inclusion of such scenarios in admission process, p < 0.05. CONCLUSIONS: Medical Colleges should include some form of assessment regarding aptitude of professionalism in the admission process to identify future medical students' capacity for professional behaviour. Future studies are needed to determine innovative interview strategies for this purpose. PMID- 24800373 TI - Classroom learning environment in Pakistan Institute of Prosthetic and Orthotic Sciences: students' perspective. AB - BACKGROUND: In 2009 the ISPO team conducted an analysis of the student performance at Pakistan Institute of Prosthetic and Orthotic Sciences (PIPOS) and concluded the situation 'unsatisfactory'. This study aims to explore the opinions of the current students regarding the nature of the classroom learning climate at PIPOS. METHODS: This survey was carried out in 2010 at PIPOS, Peshawar. The data was collected on a self adapted questionnaire based on a literature review. It was distributed among the 48 students. The data was considered non-parametric categorical, hence contingency table statistics is applied in descriptive format. The statistics were analysed at 95% CI. RESULTS: The replies reveal that the variables tested were imperative and it was appalling that the majority went for second score 'Fair' while fewer were in grade 'Good'. CONCLUSION: PIPOS stands low in the ISPO 2010 report, with a high student failure rate due to issues related to curriculum and teaching methodology. There is a lot to improve relating the students' level up to the international standards. PMID- 24800374 TI - Distraction osteogenesis of a unilateral hypoplastic mandible. AB - Distraction osteogenesis (DO) is a surgical process in which two bony segments are gradually separated so new soft tissue and bone will form between them by applying tension through a fixation device. There are three phases to this process: latency phase, distraction phase, and consolidation phase. The technique was originally applied to long bones but in recent years the method has been adapted for use in maxillofacial surgery. Distraction osteogenesis is a new variation of more traditional; orthognathic surgical procedures which can be applied for the correction of dento-facial deformities and syndromes of the jaws, treating upper airway obstruction in paediatric patients with mandibualr retrognathia, due to tongue collapse and physical obstruction in the hypopharangeal region. It is an effective and powerful reconstructive surgical technique, which can be performed safely without the need of bone graft or blood transfusion. We present treatment of a child with severe facial asymmetry after unilateral TMJ ankylosis corrected bydistraction osteogenesis. PMID- 24800375 TI - Rehabilitation of a cystic mixed dentition mandible following marsupialization with a multipurpose acrylic splint acting as a space maintainer and an obturator. AB - Radicular cysts are the most common odontogenic cystic lesions of inflammatory origin which can be managed by marsupialisation specially if the cyst is large and is in relation to the vital structures. This article presents a case in which a radicular cyst was present in association with grossly carious deciduous molars and has been treated by marsupialisation. Postoperatively a surgical splint was inserted to maintain the patency of the bone cavity. This obturator splint also acts as a space maintainer to prevent space loss and ensure unimpeded eruption of permanent premolars. PMID- 24800376 TI - Massive leiomyosarcoma of the maxilla. AB - Leiomyosarcoma is a malignant smooth-muscle tumour that is exceedingly rare in the head and neck region. Presenting signs and symptoms of leiomyosarcoma in the orofacial region are generally nonspecific. The tumour is commonly encountered as a slow growing, discreet firm, and non-ulcerated painless mass. We presented a case of massive leiomyosarcoma of the midface which might be the first leiomyosarcoma of midface reported in Pakistan so far to our knowledge. We also discuss the diagnosis and treatment of leiomyosarcoma in this aspect. PMID- 24800377 TI - Renal cell carcinoma in children: a rare entity. AB - We present a 15-years old young child primarily presented to general surgeon for abdominal mass and gross haematuria. His detailed imaging studies and other relevant investigations revealed that it is a case of Paediatric Renal Cell carcinoma (RCC), which was clinically not associated with any of the known malignancies or syndromes. On detailed histo-pathological examination this was reported as a special type of Pediatric RCC not fitting into clear cell, papillary, chromophobic, oncocytoma, or collecting duct RCC. PMID- 24800378 TI - Vaccination against human papillomavirus for prevention of cervix uteri cancer in Pakistan--a public health perspective and debate. PMID- 24800379 TI - In memoriam--Professor Nevin S. Scrimshaw PhD, MD, MPH. PMID- 24800380 TI - The impact of early nutrition on health: key findings from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). AB - INTRODUCTION: The Philippines' Cebu Longitudinal Health and Nutrition Survey (CLHNS) is one of the longest running birth cohort studies in Southeast Asia. This paper illustrates the pathways through which maternal and infant nutrition influence later health outcomes using selected CLHNS findings. METHODS: The CLHNS initially examined the determinants and consequences of low birth weight and early nutrition on child growth and development. It has since expanded to study other health, nutrition, and demographic issues in the life course of the cohort participants such as the consequences of early nutrition on adult health. RESULTS: CLHNS findings have documented important effects of poor maternal nutrition beyond impaired foetal growth (manifested through low birth weight). Mothers who had lower energy intakes and poorer nutritional status during pregnancy had offsprings who were at risk of having higher blood pressure measurements in adolescence. Infants born small at birth were not only more likely to be stunted through adolescence, but were also at greater risk of cardiovascular disease later in life. Among the males, those born thin at birth and have high BMI in adulthood had increased risk of elevated systolic blood pressure. Early infant feeding also had long-term effects on health. Breastfeeding not only protected against morbidity and stunting in childhood, but also lowered the risk of insulin resistance and high triglyceride levels in adulthood among the males. Delayed complementary feeding was associated a with lower risk of overweight in young adulthood. An intergenerational matrilineal effect was also observed among the participants, with maternal birth weight being positively associated with offspring birth weight. CONCLUSION: The CLHNS findings support the WHO recommendations for exclusive breastfeeding until six months, timely introduction of complementary foods, and continued breastfeeding until two years. Since child nutrition begins in utero, programs should focus on improving maternal nutrition during pregnancy to minimise the risk of low birth weight. PMID- 24800381 TI - Lowering dietary glycaemic index through nutrition education among Malaysian women with a history of gestational diabetes mellitus. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) increases risks for type 2 diabetes and cardiovascular diseases. Low glycaemic index (GI) diets improve cardio-metabolic outcomes in insulin-resistant individuals. We examined the feasibility of lowering GI through GI-based-education among Asian post-GDM women. METHODS: A 3-month investigation was carried out on 60 Malaysian women with a mean age of 31.0 +/- 4.5 years and a history of GDM. Subjects were randomised into two groups: LGIE and CHDR. The CHDR group received conventional healthy dietary recommendations only. The LGIE group received GI based-education in addition to conventional healthy dietary recommendations. At baseline and after 3 months, dietary intake of energy and macronutrient intakes including GI diet and glycaemic load was assessed using 3-day food records. Diabetes-Diet and GI concept scores and physical activity levels were assessed using a questionnaire. Adherence to dietary instructions was measured at the end of 3 months. RESULTS: At the end of 3 months, the LGIE group had significant reductions in energy intake (241.7 +/- 522.4Kcal, P = 0.037, ES=0.463), total carbohydrate (48.7 +/- 83.5g, P = 0.010, ES = 0.583), GI (3.9 +/- 7.1, P = 0.017, ES = 0.549) and GL (39.0 +/- 55.3, P = 0.003, ES = 0.705) and significant increases in protein (3.7 +/- 5.4g, 0.003, ES = 0.685) and diet fibre (4.6 +/- 7.3g, P = 0.06). The CHDR group had a significant reduction in fat only (5.7 +/- 9.4g, P = 0.006, ES = 0.606). There was a 30% increase in GI-concept scores in the LGIE group (p < 0.001). Changes in GI-concept scores correlated significantly to the reduction in dietary GI (r = -0.642, P = 0.045). Dietary adherence was comparable in both groups. CONCLUSION: GI-education improves GI-concept knowledge and helps lower dietary glycaemic index among women with a history of GDM. PMID- 24800382 TI - Relationship between family meals away from home and nutritional status of adolescents. AB - INTRODUCTION: Despite the many benefits of family meals, data on association between family meals away from home (FMAFH) and nutritional status of adolescents is limited. This study determined the association between FMAFH with dietary intake and body mass index of adolescents (N = 408). METHODS: Data were obtained through interviewer-administered questionnaire and anthropometric measurements of adolescents. RESULTS: Respondents comprised 53.7% females, 67.6% Chinese with the mean age of sample being 13.7 +/- 0.6 years old. Generally, male adolescents had higher intakes of energy, macronutrients and micronutrients. All nutrients except calcium (51.3%), iron (females--54.7%) and vitamin A (females--86.1%) met the recommended intakes. A higher proportion of male (25.4%) than female (13.6%) adolescents were overweight and obese. About 44% of respondents had family meals > or = 7 times in the previous week with 48.9% reported having family meals at home > or = 7 times weekly. The majority (91.2%) of adolescents had FMAFH at least once a week either at restaurants (53%), fast food outlets (41.6%), food courts in shopping complexes (40%) or food stalls (30.2%). As the frequency of FMAFH increased, there was an increasing trend in energy and energy-adjusted nutrient intakes. However, only energy-adjusted fat intake was significantly high (p < 0.05) in adolescents having FMAFH > 7 times weekly. No significant association was observed for frequency of FMAFH and body mass index. CONCLUSION: With increasing dependence on foods outside the home, FMAFH can be a source of healthy diet for families provided they have the knowledge, skills and motivation to make healthy food choices. PMID- 24800383 TI - A workplace email-linked website intervention for modifying cancer-related dietary and lifestyle risk factors: rationale, design and baseline findings. AB - INTRODUCTION: The use of email and website as channels for workplace health information delivery is not fully explored. This study aims to describe the rationale, design, and baseline findings of an email-linked website intervention to improve modifiable cancer risk factors. METHODS: Employees of a Malaysian public university were recruited by systematic random sampling and randomised into an intervention (n = 174) or control group (n = 165). A website was developed for the intervention and educational modules were uploaded onto the website. The intervention group received ten consecutive weekly emails with hypertext links to the website for downloading the modules and two individual phone calls as motivational support whilst the control group received none. Diet, lifestyle, anthropometric measurements, psychosocial factors and stages of change related to dietary fat, fruit and vegetable intake, and physical activity were assessed. RESULTS: Participants were predominantly female and in non-academic positions. Obesity was prevalent in 15% and 37% were at risk of co-morbidities. Mean intake of fats was 31%, fruit was -1 serving/day and vegetable was < 1 serving/day. Less than 20% smoked and drank alcohol and about 40% were physically inactive. The majority of the participants fell into the Preparation stage for decreasing fat intake, eating more fruit and vegetables, and increasing physical activity. Self-efficacy and perceived benefits were lowest among participants in the Precontemplation/Contemplation stage compared to the Preparation and Action/Maintenance stages. CONCLUSION: Baseline data show that dietary and lifestyle practices among the employees did not meet the international guidelines for cancer prevention. Hence the findings warrant the intervention planned. PMID- 24800384 TI - Stool patterns of Malaysian adults with functional constipation: association with diet and physical activity. AB - INTRODUCTION: Diet and lifestyle modification is commonly used in constipation management. As there is a dearth of studies on this topic in Malaysia, we aim to elucidate the relations between stool patterns, dietary intake and physical activity levels among adults with functional constipation. METHODS: From a database collected via surveys at public events, a convenience sample of 100 adults diagnosed with Rome II-defined functional constipation was enrolled in this cross-sectional study. After severity assessment using the Chinese Constipation Questionnaire, subjects completed 2-week bowel movement diaries to determine stool frequency, consistency and output. Dietary intake and physical activity levels were assessed twice using three-day 24-hour diet recalls and International Physical Activity Questionnaire, respectively. Ninety subjects who completed the study were included in the analysis. RESULTS: Mean weekly stool frequency was 3.9 +/- 1.9 times, consistency score was 2.6 +/- 0.6 (range 1.0 4.0), output was 11.0 +/- 6.3 balls (40 mm diameter) and severity score was 10.3 +/- 3.3 (range 5.0-22.0). Mean daily dietary intakes were: energy 1,719 +/- 427kcal, dietary fibre 15.0 +/- 4.9g and fluid 2.5 +/- 0.8L. The majority of subjects were physically inactive. Stool frequency and output were positively associated with dietary fibre (r(s) = 0.278, P < 0.01; r(s) = 0.226, P < 0.05) and fluid intake (r(s) = 0.257, P < 0.05; OR = 3.571, 95% CI [1.202-10.609]). Constipation severity was associated with higher physical activity levels (OR = 2.467, 95% CI [1.054-5.777]). CONCLUSION: Insufficient intake of dietary fibre and fluid are associated with aggravated constipation symptoms. Further studies are necessary to confirm usefulness of dietary intervention in treatment of constipation as dietary factors alone may not influence overall severity and stool consistency, an integral element of constipation. PMID- 24800385 TI - Malnutrition risk and its association with appetite, functional and psychosocial status among elderly Malays in an agricultural settlement. AB - INTRODUCTION: Malnutrition is a common phenomenon among the elderly and quite often related to psychosocial problems. The objective of this study was to determine malnutrition risk and its association with appetite, functional and psychosocial status among elderly Malays in an agricultural settlement, i.e. FELDA Sungai Tengi, Selangor. METHODS: A cross-sectional study was conducted among 160 subjects (men = 36.2%), with a mean age of 65.0 +/- 3.9 years, who were interviewed to obtain information on malnutrition risk and appetite using Mini Nutritional Assessment Short Form and Simplified Nutritional Appetite Questionnaire, respectively. Functional status was determined using Instrumental Activities of Daily Living (IADL), Elderly Mobility Scale (EMS) and handgrip strength. Mini Mental Status Examination (MMSE), Geriatric Depression Scale and De Jong Gierveld Loneliness Scale were used to identify cognitive impairment, depressive symptoms and loneliness status of subjects respectively. A total of 42.5% of subjects were at risk of malnutrition and 61.2% had poor appetite. The mean scores of IADL and EMS were lower in subjects at risk of malnutrition, compared to those who were not at high risk (p < 0.05 for both parameters). Multiple linear regression showed that 19.8% of malnutrition risk was predicted by poor appetite, decreased functional status (IADL) and depression. CONCLUSION: Malnutrition risk was prevalent and associated with poor appetite, functional status and psychosocial problems among the elderly subjects. The psychosocial aspect should also be incorporated in nutrition intervention programmes in order to improve mental well-being and functional independancy. PMID- 24800386 TI - Prevalence of metabolic syndrome among staff in a Malaysian public university based on Harmonised, International Diabetes Federation and National Cholesterol Education Program Definitions. AB - INTRODUCTION: Metabolic syndrome (MetSyn) as defined by the latest Harmonised definition and the agreement between the Harmonised definition and other definitions is poorly studied among Malaysians. This study was conducted to determine and compare the prevalence of MetSyn according to the Harmonised, International Diabetes Federation (IDF) and National Cholesterol Education Program (NCEP ATPIII) definitions among Malay staff of Universiti Putra Malaysia (UPM). METHODS: Subjects aged between 20 to 65 years were recruited by convenient sampling. Waist circumference, blood pressure, lipid profiles and fasting plasma glucose levels were assessed. The agreement between the Harmonised and other definitions was determined by Kappa statistics. RESULTS: A total of 227 subjects with a mean +/- SD age of 37.9 +/- 9.6 years participated in the study. The overall prevalence of MetSyn was 38.3%, 38.8% and 33.5% according to Harmonised, IDF and NCEP ATP III definitions, respectively. Generally, men had higher prevalence of MetSyn than women. The prevalence increased with age in both genders with a more progressive trend in women. Men in the age group of 20-39 years had a high prevalence of metabolic syndrome. A strong agreement was found between the Harmonised and the IDF definitions (Kappa index = 0.991), and between the Harmonised and the NCEP ATP III definitions (Kappa index = 0.857). CONCLUSION: Regardless of definitions used, the prevalence of metabolic syndrome in the study, especially in young men, was high and warrants further investigation. The Harmonised definition is suitable for diagnosing metabolic syndrome in any population with similar sociodemographic characteristics. PMID- 24800387 TI - The trans fatty acids content of selected foods in Malaysia. AB - INTRODUCTION: There is a lack of information on the trans fatty acid (TFA) content in Malaysian foods. The objective of this study is to determine the TFA content of bakery products, snacks, dairy products, fast foods, cooking oils and semisolid fats, and breakfast cereals and Malaysian fast foods. This study also estimated the quantity of each isomer in the foods assayed. METHODS: The trans fatty acid content of each food sample was assessed in duplicate by separating the fatty acid methyl esters (FAME) in a gas chromatography system equipped with HP-88 column (USA: split ratio 10: 1) for cis/trans separation. Five major TFA isomers, palmitoelaidic acid (16: 1t9), petroselaidic acid (18:1t6), elaidic acid (18:1t9), vaccenic acid (18: 1t11) and linoelaidic acid (18:2t9, 12), were measured using gas chromatography (GC) and the data were expressed in unit values of g/100 g lipid or g/100 g food. RESULTS: The total TFA contents in the studied foods were < 0.001 g-8.77 g/100 g lipid or < 0.001 g-5.79 g/100 g foods. This value falls within the standard and international recommendation level for TFA. The measured range of specific TFA isomers were as follows: palmitoelaidic acid (< 0.001 g-0.26 g/100 g lipid), petroselaidic acid (< 0.001 g - 3.09 g/100 g lipid), elaidic acid (< 0.001 g-0.87 g/100 g lipid), vaccenic acid (< 0.001 g 0.41 g/100 g lipid) and linoelaidic acid (< 0.001 g-6.60 g/100 g lipid). CONCLUSION: These data indicate that most of the tested foods have low TFA contents (< 1 g/100 g lipid). PMID- 24800388 TI - Fibre from pumpkin (Cucurbita pepo L.) seeds and rinds: physico-chemical properties, antioxidant capacity and application as bakery product ingredients. AB - INTRODUCTION: The aims of this study were to determine the proximate composition, functional properties and antioxidant activity of pumpkin seeds and rind. Besides, the effects of dietary fibre in pumpkin seeds and rinds on bread qualities and properties were evaluated. METHODS: Formulations for bread substituted with 0%, 5% and 10% pumpkin seed and rind, respectively were produced. Sensory evaluation of the prepared bread samples for such attributes as appearance, aroma, flavour, texture and overall acceptability was undertaken. The physical properties of the bread samples, including dough expansion, loaf volume, crumb colour and bread texture, were determined. Proximate analysis and determination of antioxidant activity of the bread samples were also conducted. RESULTS: Crude fibre of the pumpkin seeds and pumpkin rinds was high at 31.48% and 14.83%, respectively. The total phenolic compound (TPC) and DPPH radical scavenging activity for the pumpkin rinds were 38.60 mg GAE/100 g dry weight and 69.38%, respectively, which were higher than those of pumpkin seeds. A 5% level of pumpkin rind bread gave the best overall acceptability and sensory attributes, followed by 5% pumpkin seed bread. Total dietary fibre, total phenolic compound and DPPH radical scavenging activity in breads substituted with 5% pumpkin seed and 5% pumpkin rind flour were higher than the values in control bread. CONCLUSION: Pumpkin seeds and rinds can be used as dietary fibre sources in bakery. PMID- 24800389 TI - Effect of storage conditions on quality of prebiotic dark chocolate. AB - INTRODUCTION: A prebiotic such as inulin is a well-known functional plant food ingredient. It is capable of stimulating growth of beneficial bifidobacteria in the intestine thus protecting against intestinal infections, preventing constipation, increasing mineral absorption, reducing the incidence of colon cancer, and producing B vitamins. Inulin added to food therefore has to be stable during food processing especially against heat treatment, low pH and Maillard reaction. METHODS: Newly developed dark chocolate, DC-1, containing inulin (replacing sugar component) as an added value, was stored at 18 degrees C, 60% relative humidity and 25 degrees C, 80% relative humidity (RH) to determine shelf life stability compared to control dark chocolate, DC-0 (with high content of sugar). Sensory evaluation (quantitative descriptive analysis), water activity (a(w)), microbiological content and presence of inulin after storage of the prebiotic chocolate under both conditions were evaluated to determine shelf life. RESULTS: The DC-1 chocolate had at least 12 months of shelf life at 18 degrees C, 60% RH with better acceptance than DC-0; moreover, it did not experience microbiological and inulin content changes. At 25 degrees C, 80% RH, the growth of Aspergillus sp. was observed on the surface of both DC-0 and DC-1 with a(w) > 0.50 after a 2-month storage. CONCLUSION: Shelf life stability of DC-1 is almost similar to DC-0. PMID- 24800390 TI - Formulation of a functional fat spread stabilised by natural antioxidants and emulsifiers. AB - INTRODUCTION: Essential fatty acids (EFAs) play a vital role in the human body and need to be taken through a regular diet. EFAs are susceptible to autoxidation, hence the stability of the EFAs and their products is a matter of concern. METHODS: Margarine containing sunflower oil as a carrier of EFAs was prepared and the effects of water content, incorporation of EFAs, emulsifiers and antioxidants on the physical properties of margarine, that is, slipping point, dropping point and spreadability were studied. The oxidative stability of the formulated margarine was also evaluated after incorporation of EFAs and antioxidants. RESULTS: The incorporation of EFAs in the form of sunflower oil resulted in improved physical properties especially spreadability. The study revealed that up to 45% sunflower oil can be incorporated using glycerol monostearate as an emulsifier with total fat to water ratio of 85:15. Lecithin imparted better spreadability and grainy structure but is known to be susceptible to microbial attack. The capsicum oleoresin showed good activity as an antioxidant. Further addition of kalonji seeds ethanol extract (KEE) as well as curcuminoids resulted in improved spreadability but showed a decrease in oxidation stability. CONCLUSION: A stable and nutritional margarine was developed with the addition of natural antioxidants. Consumers can avail the benefits of both the EFAs and natural antioxidants in the margarine. PMID- 24800391 TI - Proceedings of the 3rd Expert Consultation and Planning Meeting on Infant and Young Child Nutrition--(Part 1). AB - During the 2nd ILSI SEA Region Expert Consultation and Planning Meeting in 2011, the following information gaps were identified: (i) Some Southeast Asian countries did not have data on infant and young child feeding (IYCF) indicators; (ii) There is a need to know the reasons for the disparities in duration of breastfeeding, age of giving complementary foods, and other breastfeeding and complementary feeding practices in Southeast Asian populations; (iii) Optimal complementary feeding practices that are most suitable in the context of Southeast Asia need to be identified. This report presents highlights from a literature review regarding the above topics. Findings from nationwide surveys and small scale studies were compiled to provide a snapshot of the state of infant and young child feeding practices in the region. Results for Cambodia, Indonesia, Philippines, and Vietnam are presented here. PMID- 24800392 TI - Proceedings of the 3rd Expert Consultation and Planning Meeting on Infant and Young Child Nutrition--(Part 2). AB - INTRODUCTION: The Infant and Early Childhood Nutrition Task Force, International Life Sciences Institute Southeast Asia (ILSI SEA) Region, organised the 1st and 2nd Expert Consultation and Planning Meeting on Infant and Early Childhood Nutrition in 2009 and 2011, respectively. The goal of the consultations was "to generate and promote relevant science-based information that will help improve nutritional status, growth and development of infants and young children in Southeast Asia." METHODS: An Expert Panel Core Group was created whose role is to provide advice and recommendations through a review of current scientific knowledge regarding issues related to early childhood growth and nutrition. The Panel is composed of experts representing 7 countries (China, Indonesia, Malaysia, Philippines, Singapore, Thailand, and Vietnam). In July 2012, the Panel convened the 3rd Expert Consultation and Planning Meeting on Infant and Young Child Nutrition in Singapore. This report presents the highlights of the meeting and recommendations made by the Panel on ways to improve infant and young child nutrition in Southeast Asia. RESULTS AND CONCLUSION: The effective use of WHO indicators for assessing infant and young child feeding practices, mitigating the effects of maternal employment on breastfeeding, using behaviour change communication, updating the education of health personnel, and improving maternal health were considered important actions to be taken. Since current feeding practices in Southeast Asia fall short of WHO recommendations, studies are needed to develop strategies which take into consideration the diverse cultural settings that characterise the region. PMID- 24800393 TI - Caffeine and total polyphenol contents of market tea cultivated and processed in Bangladesh. AB - OBJECTIVE: The aim of this study was to determine the contents of caffeine and total polyphenol in six brands of market tea cultivated and processed in Bangladesh. METHODS: Caffeine and polyphenol contents were determined by solvent extraction (AACC) and the International Organisation for Standardisation Method (ISO) 14502-1 respectively. RESULTS: Caffeine contents of the different tea samples ranged between 0.99 +/- 0.17% to 2.08 +/- 0.16% (g/100g materials), while that of total polyphenol was from 36.90 +/- 1.39% to 17.29 +/- 2.30% of gallic acid equivalents (GAE). The order of caffeine concentration in tea samples was found as follows: Organic Black Tea > Taaza Tea > Organic Green Tea > Magnolia Tea > Organic Zinger Tea > Organic Tulsi Tea. The polyphenol concentration in the tea samples was highest in Organic Green Tea followed by Taaza Tea and the rest as follows: Magnolia Tea > Organic Black Tea > Organic Zinger Tea > Organic Tulsi Tea. An indicative difference in amounts of caffeine and polyphenols for different tea brand samples is seen in this study. CONCLUSION: This systematic screening provides information to producers as well as consumers on the quantities of caffeine and polyphenols in commercial tea available in the markets of Bangladesh. PMID- 24800394 TI - Reliable and reproducible method for rapid identification of Nocardia species by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Recently, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been challenged for the identification of Nocardia species. However, the standard ethanol-formic acid extraction alone is insufficient in allowing the membrane proteins of Nocardia species to be ionized by the matrix. We therefore aimed to establish our new extraction method for the MALDI-TOF MS-based identification of Nocardia species isolates. Our modified extraction procedure is through dissociation in 0.5% Tween-20 followed by bacterial heat-inactivation, mechanical breaking of the cell wall by acid-washed glass beads and protein extraction with formic acid and acetonitrile. As reference methods for species identification, full-length 16S rRNA gene sequencing and some phenotypical tests were used. In a first step, we made our own Nocardia database by analyzing 13 strains (13 different species including N. elegans, N. otitidiscaviarum, N. asiatica, N. abscessus, N. brasiliensis, N. thailandica, N. farcinica, N. nova, N. mikamii, N. cyriacigeorgica, N. asteroids, Nocardiopsis alba, and Micromonospora sp.) and registered to the MALDI BioTyper database. Then we established our database. The analysis of 12 challenge strains using the our database gave a 100% correct identification, including 8 strains identified to the species level and 4 strains to the genus level (N. elegans, N. nova, N. farcinica, Micromonospora sp.) according to the manufacture's log score specifications. In the estimation of reproducibility of our method intended for 4 strains, both within-run and between-run reproducibility were excellent. These data indicates that our method for rapid identification of Nocardia species is with reliability, reproducibility and cost effective. PMID- 24800395 TI - [Proposal for the next generation--from a standpoint of physician]. PMID- 24800396 TI - [Overview of the routine examinations for rapid diagnosing of infectious diseases]. PMID- 24800397 TI - [Epidemiological analysis by multivariate statistics of methicillin-resistant Staphylococcus aureus using MALDI biotyper]. PMID- 24800398 TI - CMS gives stage 2 flexibility, may tone down stage 3. PMID- 24800399 TI - Providers embrace new tools and new data sources to make real improvements. PMID- 24800400 TI - Connectathon 2014: aiming for invisibility. PMID- 24800401 TI - Water bearer. PMID- 24800402 TI - Don't ignore the two-midnight rule. It's still in effect. AB - A bill signed into law on April 1 directs the Centers for Medicare & Medicaid Services (CMS) to postpone post-payment audits of the two-midnight rule until after March 31, 2015. In the meantime, CMS has implemented pre-payment "probe and educate" reviews to determine if hospitals are in compliance. The rule is still in effect, and hospitals have to meet its requirements. Legislation pending in Congress would direct CMS to develop criteria for short inpatient stays. Case managers need to make sure documentation is detailed and complete, that all admissions have a signed order by a physician, and that the physician estimates the length of the patient stay and includes a plan for care. PMID- 24800403 TI - Are you ready for ICD-10 implementation? AB - Implementation of ICD-10 has been postponed until Oct. 1, 2015, and all claims submitted after that point must use the new coding system. The biggest change from ICD-9 is the level of detail the new coding system requires. Case managers need to understand basic concepts of ICD-10 and the specificity it requires. They need to work with physicians to make sure that all documentation is complete and detailed. PMID- 24800404 TI - Probe and educate MAC reviews in effect. PMID- 24800405 TI - CMS calls a temporary halt to the RA program. AB - The Recovery Auditors (RA) have been prohibited from issuing new post-payment Additional Document Requests since February but can conduct automated reviews until June 1. CMS is revamping the RA program and will award new contracts to auditors at an undetermined point in the future. Contract changes include fewer records requests for hospitals with low denial rates and postponing RA fees until the second level of appeal. Meanwhile, hospitals still have to comply with records requests issued before February. PMID- 24800406 TI - Case management insider. Patient transitions--it's not just discharge planning anymore. AB - Hand-off communication provides an important link for patients and care providers as patients transition across the continuum of care. make it part of your everyday practice! PMID- 24800407 TI - Program cuts 30-day readmit rate to 10.6%. AB - A readmission reduction program that begins while patients are in the hospital has cut the 30-day readmission rate by 37% at St. Rose Hospital in Hayward, CA. Patient advocates visit patients with diagnoses that put them at risk for readmission on Day 1 and conduct an assessment to determine discharge needs. Advocates collaborate with discharge planners, line up any services needed after discharge, and follow up after discharge and after physician visits. When patients are readmitted, the team drills down to determine the cause and recommends process changes. PMID- 24800408 TI - Providers collaborate to reduce readmissions. AB - By working together and meeting regularly, San Francisco Bay-area hospitals and post-acute partners have prevented an estimated 4,000 readmissions. The program included education for participating hospitals on evidence-based readmission reduction models and other available tools. Hospitals analyzed their readmission data and determined which patients were coming back and why. Representatives of hospitals and post-acute providers meet regularly and collaborate on better patient care. PMID- 24800409 TI - Hospital cuts denials by 63%. PMID- 24800410 TI - Representing colour through hearing and touch in sensory substitution devices. AB - Visual sensory substitution devices (SSDs) allow visually-deprived individuals to navigate and recognise the 'visual world'; SSDs also provide opportunities for psychologists to study modality-independent theories of perception. At present most research has focused on encoding greyscale vision. However at the low spatial resolutions received by SSD users, colour information enhances object ground segmentation, and provides more stable cues for scene and object recognition. Many attempts have been made to encode colour information in tactile or auditory modalities, but many of these studies exist in isolation. This review brings together a wide variety of tactile and auditory approaches to representing colour. We examine how each device constructs 'colour' relative to veridical human colour perception and report previous experiments using these devices. Theoretical approaches to encoding and transferring colour information through sound or touch are discussed for future devices, covering alternative stimulation approaches, perceptually distinct dimensions and intuitive cross-modal correspondences. PMID- 24800411 TI - Auditory coding of human movement kinematics. AB - Although visual perception is dominant on motor perception, control and learning, auditory information can enhance and modulate perceptual as well as motor processes in a multifaceted manner. During last decades new methods of auditory augmentation had been developed with movement sonification as one of the most recent approaches expanding auditory movement information also to usually mute phases of movement. Despite general evidence on the effectiveness of movement sonification in different fields of applied research there is nearly no empirical proof on how sonification of gross motor human movement should be configured to achieve information rich sound sequences. Such lack of empirical proof is given for (a) the selection of suitable movement features as well as for (b) effective kinetic-acoustical mapping patterns and for (c) the number of regarded dimensions of sonification. In this study we explore the informational content of artificial acoustical kinematics in terms of a kinematic movement sonification using an intermodal discrimination paradigm. In a repeated measure design we analysed discrimination rates of six everyday upper limb actions to evaluate the effectiveness of seven different kinds of kinematic-acoustical mappings as well as short-term learning effects. The kinematics of the upper limb actions were calculated based on inertial motion sensor data and transformed into seven different sonifications. Sound sequences were randomly presented to participants and discrimination rates as well as confidence of choice were analysed. Data indicate an instantaneous comprehensibility of the artificial movement acoustics as well as short-term learning effects. No differences between different dimensional encodings became evident thus indicating a high efficiency for intermodal pattern discrimination for the acoustically coded velocity distribution of the actions. Taken together movement information related to continuous kinematic parameters can be transformed into the auditory domain. Additionally, pattern based action discrimination is obviously not restricted to the visual modality. Artificial acoustical kinematics might be used to supplement and/or substitute visual motion perception in sports and motor rehabilitation. PMID- 24800412 TI - Rotational jitter around the observer's line of sight can facilitate visually induced perception of forward self-motion (forward vection). AB - Previous studies have shown that the addition of jittering motion into a visual inducer facilitates vection. A psychophysical experiment with 12 observers found that the expanding visual inducer, which contained rotational jitter around the observer's line of sight, can induce stronger forward vection than a pure radial expansion without any additional jittering component. The results suggested that angular rotational jitter can facilitate vection without the enhancement of motion parallax, which has been considered one of the critical factors in explaining jitter effects. PMID- 24800413 TI - The influence of previous environmental history on audio-visual binding occurs during visual-weighted but not auditory-weighted environments. AB - Although there is substantial evidence for the adjustment of audio-visual binding as a function of the distribution of audio-visual lag, it is not currently clear whether adjustment can take place as a function of task demands. To address this, participants took part in competitive binding paradigms whereby a temporally roving auditory stimulus was assigned to one of two visual anchors (visual weighted; VAV), or, a temporally roving visual stimulus was assigned to one of two auditory anchors (auditory-weighted; AVA). Using a blocked design it was possible to assess the malleability of audiovisual binding as a function of both the repetition and change of paradigm. VAV performance showed sensitivity to preceding contexts, echoing previous 'repulsive' effects shown in recalibration literature. AVA performance showed no sensitivity to preceding contexts. Despite the use of identical equi-probable temporal distributions in both paradigms, data support the contention that visual contexts may be more sensitive than auditory contexts in being influenced by previous environmental history of temporal events. PMID- 24800414 TI - Wearing heavy iron clogs can inhibit vection. AB - Visually induced illusory self-motion perception is termed vection. We measured vection strength in participants wearing either wooden or iron clogs together with or without a weight-jacket (four conditions). We hypothesized that the heavier items would inhibit vection more because they make locomotion difficult. Results partially showed that the iron clogs could inhibit vection. We concluded that cognition of the fact that the heavier iron clogs made locomotion difficult might function as an inhibitor of vection, suggesting that cognition can alter vection strength. PMID- 24800415 TI - Multisensory encoding improves auditory recognition. AB - Recent studies have challenged the long-held belief that recognition is unfailingly degraded by contextual differences between study and test items. In these studies, recognition of pictures presented in silence was better when during study or initial exposure the images were accompanied by a semantically congruent sound rather than silence. In the present study, we sought to examine the generalization of this phenomenon to auditory recognition and found a significant improvement in the recognition of auditory items when coupled with a congruent picture. We discuss these findings within the framework of the redintegration hypothesis of memory retrieval as well as Bayesian inference and learning. PMID- 24800416 TI - Development of a piezoelectric inkjet dopant delivery device for an atmospheric pressure photoionization source with liquid chromatography/mass spectrometry. AB - This paper describes a simple, robust and integrated piezoelectric actuated printhead as a dopant delivery system for atmospheric pressure photoionization with liquid chromatography/mass spectrometry. The newly designed dopant delivery system avoids problems associated with traditional liquid delivery systems such as solvent immiscibility, backpressure and increased post-column dead volume issues. The performance of the new device was tested and evaluated using chlorobenzene as a dopant with a test mixture consisting of 18 different polycyclic aromatic hydrocarbons (PAHs). The results show that the new system works robustly at low dopant consumption level (1.6 uL min(-1)), consuming only approximately 5% of the amount used by conventional sources. The low dopant consumption has resulted in up to a 20-fold reduction in signal intensity of tested PAH molecules, but has led to less presence of background cluster ions and dopant trace contaminant background ions in the source area. Consequently, all tested PAHs were detected with excellent signal-to-noise ratio with at least two- to ten-fold improvements in the limit of detection and quantification compared to those obtained with traditional dopant assistance using a post-column addition method. PMID- 24800417 TI - Influence of electrolytes and a supercharging reagent on charge state distribution and response of neuropeptide ions generated during positive electrospray ionisation mass spectrometry. AB - To aid in the detection of trace quantities of neuropeptides in a biological matrix (as saliva), the influence of different electrolytes and a supercharging reagent on the positive electrospray ionisation mass spectrometry (ESI-MS) response was investigated. Ammonium acetate, sodium chloride and sodium bicarbonate (10(-7) M to 10(-3) M) and the supercharging reagent m-nitrobenzyl alcohol (m-NBA) was added to the mobile phase and the effect on the ESI response and charge-states distribution (CSD) was studied in a group of peptides (molecular weight range 2.2kDa to 3.5kDa; CGRP, VIP, GLP1, CRF and PrRP). As expected, the result indicates that the ESI response is affected by the presence of additives: ammonium acetate shifted the observed charge states ratio whereas the addition of m-NBA resulted in the appearance of higher maximum charge state ions. This increase in higher charge state for all the peptide ions, [M + nH]n+ to [M + (n + 1)H](n+1), was atttributed to protonation of the C-terminal. However, when the composition of MeCN in a mobile phase containing m-NBA was increased, an enhancement of the total ion signal was observed for non-polar peptide samples. This is a very interesting observation as this is not observed in samples without m-NBA and could be a result of how these peptide ions are solubilised and positioned relative to the droplet surface/air interface. PMID- 24800418 TI - H2 unimolecular elimination in electrospray ionization mass spectrometry from erythraline, a spirocyclic alkaloid. AB - Erythrina alkaloids, which contain a spirocyclic structure, are well known due to their important biological activity at the central nervous system. In this study, systematic electrospray ionization tandem mass spectrometry (ESI-MS/MS) and ESI multistage mass spectrometry (MS(n)) analysis of erythraline have shown an unexpected H2 neutral elimination reaction. We have investigated the formation of these ions by accurate-mass ESI-MS/MS with different analyzers and the data suggest a possible unimolecular reaction of H2 loss. PMID- 24800419 TI - Deviant mass shift of hydrated product ions from sodiated beta anilinodidrochalcones using an ion-trap mass spectrometer. AB - The fragmentation reactions of sodiated beta-anilinodidrochalcones have been investigated by electrospray ionization multi-stage mass spectrometry (ESI MS(n)). The fragment ion of sodiated N-benzylidenebenzenamine (P1) easily undergoes ion-molecule reactions with the residual ESI solvent molecules (H2O and CH3OH) in the vacuum system, as verified by MS3 and accurate MS analysis. The formed hydrated ions appear as an unusual leading peak in the profile spectrum, which results in a deviant decreasing mass shift of almost 1 Da. Density functional theory calculations indicate that P1 easily associates with H2O without any energy barrier. Thus, the hydrated P1 exists partially as a loose system of P1 and H2O, which provides a reasonable explanation for the decreasing mass shift of the solvated P1. The above results are important in obtaining structural information from MS(n) spectra and preventing erroneous data interpretation for the analogous adducts. PMID- 24800420 TI - Gas chromatography-mass spectrometric studies of O-alkyl O-2-(N,N-dialkylamino) ethyl alkylphosphonites(phosphonates) for chemical weapons convention verification. AB - The electron ionization (EI) mass spectra of a series of O-alkyl O-2-(N,N dialkylaminolethyl alkylphosphonites(phosphonates), which are precursors of nerve agents, were studied for Chemical Weapons Convention (CWC) verification. General El fragmentation pathways were constructed and discussed. Proposed fragment structures were confirmed through analyzing fragment ions of deuterated analogs and density functional theory (DFT) calculations. The observed fragment ions are due to different fragmentation pathways such as hydrogen and McLafferty+1 rearrangements, alkene, amine and alkoxy elimination by alpha- or beta-cleavage process. Fragment ions distinctly allow unequivocal identification of the interested compounds including those of isomeric compounds. The presence and abundance of fragment ions were found to depend on the size and structure of the alkyl group attached to nitrogen, phosphorus and oxygen atoms. PMID- 24800421 TI - Identificationof potential lung cancer biomarkers by liquid chromatography tandem mass spectrometry-based proteomics analysis of secretomes of two lung cancer cell lines. AB - A label-free nano-liquid chromatography tandem mass spectrometry proteomics analysis on the conditioned media (CM) of two lung cancer cell lines of different histological backgrounds to identify secreted or membrane-bound proteins as novel lung cancer biomarkers was performed. Five hundred and seventy seven proteins were identified and 38% of them were classified as extracellular or membrane bound. For the search of potential biomarkers of lung cancer a series of selection criteria were proposed. We detected known or putative lung cancer markers. In addition, 40 novel proteins were identified, whose role as biomarkers of lung cancer should be explored further. PMID- 24800423 TI - Medicolegal aspects of dermatology. PMID- 24800422 TI - A preliminary study of arecoline and guvacoline presence in the saliva of a "betel-quid" chewer using liquid-chromatography ion trap mass spectrometry. AB - It has been reported that the parasympathomimetic alkaloid arecoline and the nootropic agent guvacoline have been detected in areca nut (Areca catechu L.) during extraction using a basic medium. Here, we have studied the detection of arecoline and guvacoline in vivo in saliva of a "betel-quid" chewer using liquid chromatography ion trap mass spectrometry. In this paper, we provide evidence that guvacoline is absent in the neutral aqueous extract of betel nut, but is present in abundance in the aqueous extract with added time (pH 11.9). In an in vivo experiment, we demonstrated that guvacoline is present in the salivary extracts in the mouth with time (pH 9.5) and without lime (pH5.3). PMID- 24800424 TI - Dermatology and pathology arrangements: navigating the compliance risks. AB - Purchased service arrangements, establishing in-house professional pathology services, conducting technical component histology within a dermatology practice, and electronic medical records technology donations are ways that dermatology practices are responding to the current health care delivery and payment changes. This article will provide a general framework for navigating the compliance risks and structure considerations associated with these relationships between dermatologists and pathologists. PMID- 24800425 TI - Drug safety: implications for the dermatologist and dermatopathologist. AB - The recent decades have seen a plethora of drugs removed from the world-wide market place over safety concerns and reported adverse events. In some cases, drugs with significant reports of adverse drugs events (ADEs) have remained on the market with either a Black Box warning, strict prescribing guidelines, or both. It has been reported that more than 2,000,000 Americans are harmed by ADEs each year. The financial costs associated with ADEs are staggering with over $170 billion spent annually in the United States as a result of ADEs. The implications for the dermatologist and dermatopathologist are daunting for the skin is the organ most frequently affected by ADEs. Many cases of drugs removed from the market are preceded by the filing of one or more product liability lawsuits. This means the dermatologist could be brought under claims of negligence, strict liability, breach of warranty, and consumer protection claims. The potential implications for the dermatologist or dermatopathologist are discussed along with an introduction to the legal process, which comes into play with the filing of the product liability lawsuit. PMID- 24800426 TI - HIPAA, dermatology images, and the law. AB - From smart phones to iPads, the world has grown increasingly reliant on new technology. In this ever-expanding digital age, medicine is at the forefront of these new technologies. In the field of dermatology and general medicine, digital images have become an important tool used in patient management. Today, one can even find physicians who use their cellular phone cameras to take patient images and transmit them to other physicians. However, as digital imaging technology has become more prevalent so too have concerns about the impact of this technology on the electronic medical record, quality of patient care, and medicolegal issues. This article will discuss the advent of digital imaging technology in dermatology and the legal ramifications digital images have on medical care, abiding by HIPAA, the use of digital images as evidence, and the possible abuses digital images can pose in a health care setting. PMID- 24800427 TI - LASERS and the LAW: what the dermatologist needs to know. AB - Dermatologic laser surgery is a continuously evolving field of medicine. According to the American Society for Dermatologic Surgery, over 100 million laser and light source cosmetic procedures were performed by its members in 2003. Procedures, which include hair removal, nonablative treatments, as well as removal of pigmented lesions, tattoos, and unwanted vascular lesions, have revolutionized this field. With an increasing number of physicians and nonphysicians performing these procedures and with the availability of increasingly powerful laser technologies, the potential for problems and their legal consequences continue to increase. This article will address the concept of negligence and the potential for a resultant medical malpractice lawsuit that may arise in such a setting. Inherent in this issue are the associated problems that arise when these procedures are performed by physician extenders. An understanding of the basic principals of a cause of action in medical malpractice will likely protect a physician from losing such a case in a court of law. PMID- 24800428 TI - Medicolegal aspects of prescribing dermatological medications in pregnancy. AB - Medications are commonly used during pregnancy; in fact, female patients take an average of 2.9 medications during pregnancy. Due to this high prevalence, malpractice litigation poses a high legal risk to dermatologists who prescribe medications to female patients who are or may become pregnant. This article introduces the medicolegal risks involved in prescribing dermatological medications to a pregnant patient and discusses ways for a dermatologist to mitigate those risks. International safety classification systems are reviewed, and potential high risk dermatologic medications prescribed in acne, psoriasis, atopic dermatitis, and connective tissue disease are discussed. In addition, the article summarizes resources available to patients as well as the important elements for dermatologists to include when documenting their discussion with the patient in the medical record. PMID- 24800429 TI - Tanning bed legislation and the dermatologist. AB - Indoor ultraviolet (UV) tanning correlates with increased risk of developing melanoma and other skin cancers. Because of the limited scope of individual counseling by physicians and other health care providers, prevention efforts now encompass population-based interventions in the form of legislation to discourage and decrease access to indoor tanning facilities. Legislation increasingly restricts indoor UV tanning at the national, territory, state, or local level and draws attention to the complexities surrounding enforcement and infraction penalties. Further research needs to better define the effect of decreased indoor UV tanning access on skin cancer incidence. PMID- 24800431 TI - Medical malpractice lawsuits and the value of skilled and diverse legal counsel. AB - Medical malpractice claims against dermatologists and dermapathologists arise mostly out of claims for negligence--when a patient claims a provider owed a duty to a patient, breached that duty, and caused damages to the patient. When a health care provider files a claim with his or her insurance company, the insurance company will usually retain and pay an attorney for the health care provider. It is important to understand the role the attorney retained by the insurance company plays to evaluate whether a health care provider should seek the advice of independent or "personal" counsel. PMID- 24800430 TI - Teledermatology, teledermatopathology, interstate dermatopathology and the law. AB - The expansion of telemedicine nationwide has resulted in many states adopting specific telemedicine regulations to avoid the issue of requiring a full medical license to practice telemedicine. How these laws and regulations relate to the practice of telepathology and teledermatology has not been well delineated. It is important to understand these regulations to avoid potential judicial penalties arising from non-compliance. This article aims to outline state-specific telemedicine regulations and penalties. PMID- 24800432 TI - The dermatologist as expert witness-revisited: know the risks before you agree. AB - Legal Standards and requirements exist for dermatologists wishing to serve as expert witnesses. Case law, statutes and licensing/credentialing groups exist to regulate the practice to ensure honesty and integrity. Penalties and sanctions exist for deceptive and fraudulent opinions. However, conversely, private groups must be careful in their efforts to not libel savvy experts or interfere with their legitimate work. PMID- 24800433 TI - Employee contract issues for dermatologists. AB - Employees and employers routinely face negotiating and preparing physician employment contracts. It is important for both sides to know and understand the basic information on what a comprehensive employment contract for a dermatologist should contain. There are various employment contract provisions from both the employee's perspective and the employer's perspective that must be considered when preparing physician employment contracts. This article provides basic advice and recommendations on requirements that should be included in such contracts. It suggests legal pitfalls that can be avoided through various contract clauses. PMID- 24800434 TI - Patent law for the dermatologist. AB - An exciting discovery in the laboratory may translate to a commercial product. How does the patent system fit into the picture? We first discuss the circumstances under which an invention is granted a patent. What is the purpose of a patent and what are the functions of the patent system? Who can apply for a patent? What makes an invention patentable? A patent does not automatically grant a right to make or sell a product. This is because multiple patents can cover a single pharmaceutical product. Understanding the patent landscape covering a product of interest is key to evaluating the risk of infringing another's exclusivity rights. We use a hypothetical example relating to skin cancer to guide a discussion of patent law. PMID- 24800436 TI - The Joint Commission and NQF honor 2013 Eisenberg award recipients. PMID- 24800435 TI - Ten rules for asset protection planning. AB - Asset protection planning is a highly technical area of legal planning. Because of the fraudulent transfer laws, asset protection planning must be done in advance of any claim, be technically sound, not rely upon secrecy, and avoid any number of critical mistakes including keeping personal and business assets separate. Physicians who engage in asset protection planning must avoid critical mistakes, and not count on bankruptcy to provide relief from creditors. General rules and cautions for those who are considering the creation of an asset protection plan for their personal assets. PMID- 24800437 TI - Quality control option changing for clinical laboratories. PMID- 24800438 TI - Standards changes to PCMH certification requirements for ambulatory care. PMID- 24800439 TI - Effective maintenance and testing protects life safety. PMID- 24800440 TI - Top standards compliance issues for 2013. PMID- 24800441 TI - Revised eligibility requirements for ambulatory care. PMID- 24800442 TI - Home health deemed surveys document hand hygiene lapses. PMID- 24800443 TI - Joint Commission Board appoints four new members. PMID- 24800444 TI - Keeping it clean. PMID- 24800445 TI - Edward Joseph Shellard--a phenomenal pharmacognosist: part 2. PMID- 24800446 TI - The relationship between the expeditions of the heroic age of Antarctic exploration and drug companies. PMID- 24800448 TI - Wandsworth's vanishing hospitals. PMID- 24800447 TI - Survivors over six millennia: essential oils. PMID- 24800449 TI - Development and standardization of an assistive technology questionnaire using factor analyses: eight factors consisting of 67 items related to assistive technology practices. AB - The purposes of this study were to identify the factors that underlie assistive technology (AT) and to validate items to be used in an instrument to evaluate AT use. The study consisted of four phases. First, 99 items were developed though a comprehensive literature review. Second, the items were refined through three layers of review. Third, 1,467 respondents rated the results of the reviews. Fourth, exploratory factor analysis, and three confirmatory factor analyses (CFA) were employed to analyze the data. The results of the CFA were statistically significant (root mean square error of approximation [RMSEA] = 0.036, p = 0.00) with a total of 67 items across 8 factors (effectiveness, affordability and dependability, utility, external support, operations, longevity, discomfort, and compatibility). PMID- 24800450 TI - Upper limb contributions to frontal plane balance control in rollator-assisted walking. AB - While assisting with balance is a primary reason for rollator use, few studies have examined how the upper limbs are used for balance. This study examines upper limb contributions to balance control during rollator-assisted walking. We hypothesized that there would be an increased upper limb contribution, measured by mean vertical loading (Fz) and variation in frontal plane center-of-pressure (COPhigh), when walking balance is challenged/impaired. Experiment 1 compared straight-line and beam-walking in young adults (n = 11). As hypothesized, Fz and COPhighincreased in beam-walking compared to baseline (mean Fz: 13.7 vs. 9.1% body weight (BW), p < 0.001, RMS COPhigh: 1.35 vs. 1.07 cm, p < 0.001). Experiment 2 compared older adults who regularly use rollators (RU, n = 10) to older adult controls (CTL, n = 10). The predicted higher upper limb contribution in the RU group was not supported. However, when individuals were grouped by balance impairment, those with the lowest Berg Balance scores (< 45) demonstrated greater speed-adjusted COPhigh than those with higher scores (p = 0.013). Furthermore, greater COPhigh and Fz were correlated to greater reduction in step width, supporting the role of upper limb contributions to frontal plane balance. This work will guide studies assessing reliance on rollators by providing a basis for measurement of upper limb balance contributions. PMID- 24800451 TI - The development of an instrumented wheelchair propulsion testing and training device. AB - Researchers have used several types of testing devices and training surfaces to examine wheelchair propulsion. Testing and training wheelchair users on the actual surface of interest, such as tile floors or ramps, is ideal but difficult. Devices such as treadmills, dynamometers, and ergometers allow for researchers and clinicians to observe wheelchair users in a controlled space. However, these devices often do not have the ability to realistically simulate the environment. This methodological article describes the instrumentation, development and function of a wheelchair dynamometer system, the WheelMill System (WMS), a uniquely adjustable roller system for wheelchairs. Three participants wheeled on the WMS, over a tile surface and up two different graded slopes with the SmartWheel to compare speed and forces. The WMS reasonably simulated propulsion over a tile floor, though the participants' speed was slightly faster on tile, and the peak forces for each propulsion stroke varied more on tile than on the WMS. For the slopes, the speed oscillated over a greater range and was slower, and the measured peak forces were higher than the values measured on the WMS. The WMS may have several applications, though additional studies on a greater and more diverse population are needed. PMID- 24800452 TI - Assessing mouse alternatives to access to computer: a case study of a user with cerebral palsy. AB - The purpose of this study is to describe the process of assessment of three assistive devices to meet the needs of a woman with cerebral palsy (CP) in order to provide her with computer access and use. The user has quadriplegic CP, with anarthria, using a syllabic keyboard. Devices were evaluated through a three-step approach: (a) use of a questionnaire to preselect potential assistive technologies, (b) use of an eTAO tool to determine the effectiveness of each devised, and (c) a conducting semi-structured interview to obtain qualitative data. Touch screen, joystick, and trackball were the preselected devices. The best device that met the user's needs and priorities was joystick. The finding was corroborated by both the eTAO tool and the semi-structured interview. Computers are a basic form of social participation. It is important to consider the special needs and priorities of users and to try different devices when undertaking a device-selection process. Environmental and personal factors have to be considered, as well. This leads to a need to evaluate new tools in order to provide the appropriate support. The eTAO could be a suitable instrument for this purpose. Additional research is also needed to understand how to better match devices with different user populations and how to comprehensively evaluate emerging technologies relative to users with disabilities. PMID- 24800453 TI - Development and validation of Korean version of psychosocial impact of assistive devices scale. AB - This study aimed to develop and assess the reliability of the Korean version of the Psychosocial Impact of Assistive Devices Scale (K-PIADS). Experts and researchers in the field of assistive technology carried out the original PIADS with a rigorous translation process. To this end, comprehensive measures were taken, including preliminary translation, reverse translation, verification, and expert panel review. Forty-eight people who are currently using an assistive technology (AT) device participated in the validation phase of this study. Findings suggested that reliability for a K-PIADS was very high (micro = 0.94). The findings of this study indicated that the result could be applied to psychosocial evaluation related to the quality of life of AT device users with disabilities. Replication studies are warranted to further validate K-PIADS. PMID- 24800454 TI - Evaluation of an augmented virtual reality and haptic control interface for psychomotor training. AB - This study investigated the design of a virtual reality (VR) simulation integrating a haptic control interface for motor skill training. Twenty-four healthy participants were tested and trained in standardized psychomotor control tasks using native and VR forms with their nondominant hands in order to identify VR design features that might serve to accelerate motor learning. The study was also intended to make preliminary observations on the degree of specific motor skill development that can be achieved with a VR-based haptic simulation. Results revealed significant improvements in test performance following training for the VR with augmented haptic features with insignificant findings for the native task and VR with basic haptic features. Although performance during training was consistently better with the native task, a correspondence between the VR training and test task interfaces led to greater improvement in test performance as reported by a difference between baseline and post-test scores. These findings support use of VR-based haptic simulations of standardized psychomotor tests for motor skill training, including visual and haptic enhancements for effective pattern recognition and discrete movement of objects. The results may serve as an applicable guide for design of future haptic VR features. PMID- 24800455 TI - Decoding my HIMSS14 experience. PMID- 24800456 TI - The ripe time to merge? PMID- 24800457 TI - Better put on your running shoes. PMID- 24800458 TI - Facing the music. PMID- 24800459 TI - Witnessing down in the delta: update #1. PMID- 24800460 TI - Transitioning to ICD-10. PMID- 24800461 TI - Why i'm not using an EMR... PMID- 24800462 TI - Integrity--and politics. PMID- 24800464 TI - Clinical question: are non-steroidal anti-inflammatories superior to acetaminophen for sprains/strains? PMID- 24800465 TI - Total patient care is a collaborative effort. PMID- 24800463 TI - Cancer incidence and staging among American Indians in Oklahoma. AB - BACKGROUND: This study describes overall and site specific cancer incidence among AI/ANs compared to whites in Oklahoma and differences in cancer staging. METHODS: Age-adjusted incidence rates obtained from the Oklahoma Central Cancer Registry are presented for all cancer sites combined and for the most common cancer sites among AI/ANs with comparisons to whites. Percentages of late stage cancers for breast, colorectal, and melanoma cancers are also presented. RESULTS: AI/ANs had a significantly higher overall cancer incidence rate compared to whites (629.8/100,000 vs. 503.3/100,000), with a rate ratio of 1.25 (95% CI: 1.22, 1.28). There was a significant disparity in the percentage of late stage melanoma cancers between 2005 and 2009, with 14.0% late stage melanoma for whites and 20.0% for AI/ANs (p-value:0.03). CONCLUSIONS: Overall, there were cancer disparities between AI/ANs and whites in Oklahoma. Incidence rates were higher among AI/ANs for all cancers and many site specific cancers. PMID- 24800466 TI - Metal-based drugs. AB - Metals have been considered for millennia to have medicinal values. With the advent of modern medicine, many metal-based drugs have proven to be highly effective in the clinic. Many different metal ions have shown activity against a range of diseases. The unique electronic structure of transition metals offers great versatility, not always seen in organic drugs, in terms of the ability to tune the properties of a given molecule. This review gives a brief overview of the most established therapeutic metals, and their more common applications, such as platinum-based anticancer drugs. New developments within the field of metallodrugs and novel strategies being employed to improve methods of delivery, are also discussed. PMID- 24800467 TI - Platinum anticancer drugs and photochemotherapeutic agents: recent advances and future developments. AB - Platinum-based chemotherapeutic drugs such as cisplatin, carboplatin and oxaliplatin are widely applied for the treatment of various types of tumours. Over the last few decades, a large variety of Pt(II) and Pt(IV) complexes have been developed to improve the applicability in a wider spectrum of cancers, increase their therapeutic window and reduce the dose-limiting side effects. Photodynamic therapy (PDT), which is the administration of a photosensitiser followed by visible light activation, is a promising route to avoid damage to healthy cells and the surrounding tissue. Transition metal complexes as photochemotherapeutic agents are an attractive option for further development in the field of photoactivated chemotherapy (PACT). These complexes exhibit different numbers and types of excited states which are easily accessible upon light irradiation, subsequently giving rise to the formation of various photoproducts that can enable a distinct mode of action. Platinum-diazido complexes are promising candidates for PACT due to the low cytotoxicity when irradiated with visible light. This review summarises the mode of action of current platinum anticancer drugs with cisplatin as a lead example and the development of non-conventional Pt(II) complexes. Background information regarding PDT the photophysical and photochemical properties of metal complexes is provided, as well as notable examples of photoactivated metal complexes with biological activity. Particular emphasis is placed on recent developments on platinum photoactivated drugs. PMID- 24800468 TI - Nutrimetabonomics: nutritional applications of metabolic profiling. AB - An individual's metabolic phenotype, and ultimately health, is significantly influenced by complex interactions between their genes and the diet. Studying these associations and their downstream biochemical consequences has proven extremely challenging using traditional hypothesis-led strategies. Metabonomics, a systems biology approach, allows the global metabolic response of biological systems to stimuli to be characterised. Through the application of this approach to nutritional-based research, nutrimetabonomics, the biochemical response to dietary inputs is being investigated at greater levels of resolution. This has allowed novel insights to be gained regarding intricate diet-gene interactions and their consequences for health and disease. In this review, we present some of the latest research exploring how nutrimetabonomics can assist in the elucidation of novel biomarkers of dietary behaviour and provide new perspectives on diet health relationships. The use of this approach to study the metabolic interplay between the gut microbiota and the host is also explored. PMID- 24800469 TI - Chemical synthetic biology. AB - Although both the most popular form of synthetic biology (SB) and chemical synthetic biology (CSB) share the biotechnologically useful aim of making new forms of life, SB does so by using genetic manipulation of extant microorganism, while CSB utilises classic chemical procedures in order to obtain biological structures which are non-existent in nature. The main query concerning CSB is the philosophical question: why did nature do this, and not that? The idea then is to synthesise alternative structures in order to understand why nature operated in such a particular way. We briefly present here some various examples of CSB, including those cases of nucleic acids synthesised with pyranose instead of ribose, and proteins with a reduced alphabet of amino acids; also we report the developing research on the "never born proteins" (NBP) and "never born RNA" (NBRNA), up to the minimal cell project, where the issue is the preparation of semi-synthetic cells that can perform the basic functions of biological cells. PMID- 24800470 TI - J. Norman Collie, the inventive chemist. AB - Norman Collie was Professor of Organic Chemistry and Director of Laboratories at University College London between 1902 and 1928. He was a pioneering mountaineer but was also a prolific inventor; this review focuses on that little-known latter aspect of his activities. PMID- 24800471 TI - The Fukushima Daiichi nuclear accident. PMID- 24800472 TI - Recent work on volcanoes. 1913. PMID- 24800473 TI - The physical aspect of the opsonic experiment. 1914. PMID- 24800474 TI - Differences in animal and plant life. 1914. PMID- 24800475 TI - [First Moscow "snapshot" register of acute coronary syndromes: characteristics of patients, management and outcomes during hospitalization]. AB - AIM: To characterize inhospital management of patients (pts) with acute coronary syndromes (ACS) using data from Moscow snapshot registry of hospitalized pts with ACS. METHODS: The registry included data on consecutive pts with ACS hospitalized with label ACS in coronary care units (CCU) or equivalents within 24 hours (h) after onset of symptoms during one week in November 2013. Data was obtained from 32 (17 percutaneous coronary intervention [PCI] capable or "invasive") city hospitals officially treating ACS patients. RESULTS: Total number of pts--584 (mean age 66.4 +/- 13.1 years; > or = 65 years 54.6%; women 44.2%; registered in invasive hospital--42%). Portions of pts labeled ST-elevation (STE) and non ST elevation (NSTE) ACS--27.9 and 72.1%, respectively. Portion of pts hospitalized within 1-st 12 h after symptoms onset--65.2% (68% among STEACS pts). Reperfusion therapy--44.8% of pts with STEACS (54.3% in invasive and 21.3% in noninvasive hospitals, p < 0.0001). Thrombolysis (TI) was performed in 19% of STEACS pts (41.9% prehospital). In hospital median admission to initiation of TI time--0.30 h (quartiles I-III 0.15-0.30 h). Rate of primary (p) PCI in STEACS pts--overall 25.8%, in invasive hospitals--36.2%, in pts admitted within 12 h--31.4 and 40.5%, respectively. Median admission--pPCI initiation time--1.35 h (quartiles I-III 1.00- 2.15 h). PCI rate among NSTEACS pts--6.2 overall and 20.5% in invasive hospitals (14.7% during 1st 72 h). Medication in hospital: aspirin--95.2, clopidogrel--70.7, ticagrelor--4.3%, parenteral anticoagulants--88.9 (1/3 unfractionated heparin [UFH] subcutaneously), ACE inhibitors--83.3, beta-blockers -86.3, statins--58.3%. Mean duration of hospital stay--13.2 +/- 4.4 days. Transferral from noninvasive to invasive hospital for urgent coronary intervention--4.5 and 3.5% of STE and NSTE ACS pts, respectively. Hospital mortality--12.4 and 1.9% among pts registered as STE and NSTEACS, respectively. Cardiac troponins measured--42% (39% among STEACS) pts. CONCLUSION: The following features of inhospital management of pts diagnosed as ACS at CCU (or its equivalent) admission could be object of improvement: low rate of reperfusion therapy and use of PCI, long interval between admission and initiation of PCI, insufficient use of some standard medications, frequent use of subcutaneous UFH, rare transferal of PCI eligible pts from noninvasive to invasive hospitals. However existing management was associated with reported low hospital mortality in patients labeled as NSTEACS. PMID- 24800476 TI - [Comparison of characteristics of atherosclerotic plaques in patients with acute coronary syndrome and stable ischemic heart disease: data of multispiral computed tomography]. AB - AIM: To elucidate possibilities of multispiral computed tomography (MSCT) for assessment of morphology of atherosclerotic plaques in coronary arteries of patients with acute coronary syndrome (ACS) or stable ischemic heart disease (SIHD). MATERIAL AND METHODS: Assessment of internal relief of coronary arteries and composition of atherosclerotic plaques was carried out in 85 patients with ACS and 41 patients with SIHD. MSCT was performed with the use of computed tomograph. Visual assessment included determination of plaque type (calcified, soft, and heterogeneous) and contour (regular, irregular). Quantitative assessment included determination of plaque density and index of remodeling. RESULTS: Among patients with ACS we found 194 plaques (60--soft, 72- heterogeneous, and 62--calcified). Plaques in symptom related compared with non symptom related arteries had higher index of remodeling (1.4 +/- 0.3 and 1.2 +/- 0.2, respectively, p < 0.0001), and more frequently had irregular contour (60.0 and 12.8%, respectively, p < 0.0005). Soft plaques and plaques with irregular contour prevailed in ACS group (68.0%) while calcified plaques were more frequent in SIHD group (66.4%). Plaques with irregular contour were more frequent and index of remodeling was higher in ACS compared with SIHD group (33.5 vs 7.2%, p < 0.0005, and 1.3 +/- 0.2 vs 1.0 +/- 0.2, p < 0.001, respectively). CONCLUSION: According to MSCT data main characteristics of atherosclerotic plaques in patients with ACS were low density and inclusions of microcalcinates. Specific features of plaques in symptom related arteries were irregular contour and positive remodeling index. PMID- 24800477 TI - [Relationship between warfarin dosing and activity of CYP2C9 assessed by the content of losartan and its metabolite E-3174 in the urine of patients with mechanical prosthetic heart valves]. AB - We evaluated effect of activity of cytochrome P450 CYP2C9 on maintenance doses of warfarin in 33 patients with implanted artificial heart valves. Losartan test was used for measurement of concentration of active metabolite E-3174 in urine. Concentration of E-3174 below 2500 ng/ml in patients with genotype CYP2C981/*1 with sensitivity 87% and specificity 66% predicted requirement of low doses (< 5 mg/day) of warfarin in the late postoperative period (odds ratio 14, 95% confidence interval 1.135 to 172.75). PMID- 24800478 TI - [Optimization of pharmacotherapy in patients with essential hypertension with neurohumoral modulators with consideration of data on heart rate variability]. AB - Long-term treatment of patients with essential hypertension (EH) and autonomic dysfunction (sympathicotonia type) with lisinopril in combination with indapamide augmented activity of humoral systems and improved heart rate variability. Addition of a selective beta-blocker bisoprolol to lisinopril/indapamide combination promoted normalization of humoral activity. This gives reason to apply tiered RAAS blockade in order to ensure more effective control of activity of neurohumoral systems in patients with EH ant initial sympathicotonia. PMID- 24800479 TI - [Predictive value of cardiopulmonary exercise testing in various categories of patients with chronic heart value]. AB - AIM: To specify the prognostic value of parameters of cardiopulmonary exercise testing (CPET) in patients with chronic heart value (CHF) on optimal medical treatment depending on gender, age, left ventricular ejection fraction (LVEF), cardiac rhythm and achievement of target respiratory exchange ratio (RER) > or = 1.0. MATERIALS AND METHODS: 111 patients (83 male, mean age 60.6 +/- 12.8 years) with CHF NYHA class I-III on optimal treatment were included in the study. One third had preserved EF, 27.9%--permanent atrial fibrillation (AFib). Average followup was 19.4 +/- 9.6 months. Prognostic value of CPET indices and Heart Failure Survival Score (HFSS) for cardiovascular mortality (CVM) and combined endpoint including CVM or CHF hospitalization were evaluated using logistic regression analysis. RESULTS: CVM amounted 14.4%, combined endpoint was observed in 46.8% of patients. HFSS had the highest predictive value for CVM (in all subgroups of patients) and for combined endpoint (except patients with AFib). In men, patients younger than 65 years, with reduced LVEF and with Afib CVM was also related to ventilatory indices (VE/VCO2, ventilatory class and PetCO2 peak), and combined endpoint was related to VO2peak and its derivativatives. Only HFSS and VE/VCO2 had prognostic value for CVM in patients with AFib. Ventilatory parameters were associated with combined endpoint in all subgroups except Afib. Blood pressure response and heart rate recovery had prognostic significance only in patients with sinus rhythm. Target RER > or = 1.0 was achieved only in 40.5% patients. In patients with RER < 1.0 significant relationship between VO2 peak and combined endpoint was observed. CONCLUSIONS; Heart Failure Survival Score, VE/VCO2, ventilatory class and PetCO peak are the strongest predictors of cardiovascular mortality and heart failure hospitalizations in all subgroups of patients with CHF. CPET has the highest significance for men, age < 65 years, patients with LVEF < 45% and sinus rhythm. In these subgroups VO2 peak and Weber class have predictive value for decompensation of CHF whether RER > or = 1.0 or not. Blood pressure response and heart rate recovery have prognostic significance only in patients with sinus rhythm. PMID- 24800480 TI - [Noncoronary dilated cardiomyopathy after reverse remodeling heart surgery]. AB - We present here analysis of surgical treatment of 24 patients (5 women, 19 men, age 20-75, mean age 50.7 +/- 2.5 years) with dilated cardiomyopathy (DCM) operated during the period from 2008 to 2013. Duration of the disease ranged from 4 months to 12 years (mean 49.4 +/- 7.5 months). According to symptoms and results of 6-minute walk test 3 patients (13%) had heart failure NYHA class III and 21 patients (87%)--NYHA class IV. Average end-diastolic left ventricular size was 7.4 +/- 0.18 cm (6.0-9.2 cm), ejection fraction--26.7 +/- 2.1% (13-47%), mean pulmonary artery pressure 54.9 +/- 2.9 mm Hg (35-80 mmHg). All patients underwent organ-conserving surgery aimed at reverse remodeling of the heart. Surgery was accompanied with implantation of implantable cardioverter defibrillator in 3 patients and/or cardiac resynchronization therapy device in 6 patients. Two patients (8.3%) died during hospitalization of hemodynamically significant ventricular arrhythmias; seven patients (29.2%) died in the late postoperative period. The results of the analysis indicate that reverse-remodeling surgery may be effective in patients with DCM of any age group with preserved reserves of the liver, kidney, and lung function in the absence of active myocarditis. Further observations are needed to determine the place of this operation in the protocol of treatment of patients with DCM. PMID- 24800481 TI - [Novel targets in the treatment of arterial hypertension]. PMID- 24800482 TI - [The problem of cerebrovascular complications in patients with high risk of cardiovascular diseases: focus on diabetes]. PMID- 24800483 TI - [Ambulatory methods of blood pressure measurement in clinical practice]. PMID- 24800484 TI - [Treatment of arteril hypertension in patients with chronic kidney disease: a fixed combination of lercanidipine and enalapril]. AB - The review of literature presents the basic principles of treatment of arteril hypertension in patients with chronic kidney disease. The possibilities of combination therapy with dihydropyridine calcium antagonist lercanidipine and third-generation ACE inhibitor enalapril. Presented studies showing nephroprotective properties of each of the drugs included in the fixed combination in patients with nephropathy. Lercanidipine is highly lipophilic and vazoselektivnost proved its clinical efficacy in patients with proteinuria and decreased kidney function. Given in the literature demonstrating the combination of lercanidipine + enalapril. This combination makes it possible to achieve a more pronounced reduction in blood pressure, including elderly patients, patients with diabetes and obesity. The combination of pharmacological effects of lercanidipine and enalapril, creates additional opportunities for organo and reduce the risk of side effects of therapy. PMID- 24800485 TI - [Modern conceptions of cardiac amyloidosis]. AB - Cardiac amyloidosis is accumulation in the heart of a pathologic fibrillar protein amyloid. It represents a heterogeneous group of states from clinically insignificant amyloid accumulation in isolated atrial amyloidosis to severe involvement of the heart in primary amyloidosis when mean duration of life equals to 6 months. Insufficient awareness of physicians of this pathology leads to erroneous and belated diagnosis of cardiac amyloidosis. This paper contains contemporary data of pathophysiology, clinical manifestation, diagnosis, treatment, and prognosis of various variants of cardiac amyloidosis. PMID- 24800486 TI - [Place of urapidil in the treatment of hypertensive crises from the standpoint of clinical pharmacology and evidence-based medicine]. PMID- 24800487 TI - [European Guidelines on Hypertension in 2013: unchanging, new, unsolved]. PMID- 24800488 TI - [Evaluation of Payne's formula for the correction of calcium: comparison with improved calcium and albumin measurement methods]. AB - The ionized or free fraction of serum calcium is physiologically important for cellular function, but we most often measure total serum calcium. There are a number of correction formulas that can be used to estimate whether low total serum calcium can be attributed simply to low albumin or serum protein. In Japan, Payne's formula has been widely used to correct calcium concentration. However, there are some problems in the measurement methods of total calcium and serum albumin which were used to establish Payne's formula with respect to specificity, calibration curve and stability. Recently, improved measurement methods of calcium and albumin have been adopted at clinical laboratories. Here we evaluated Payne's formula by comparing it with improved measurement methods of total calcium and serum albumin. For the total calcium measurement, o-CPC (o cresolphthaleincomplexone), CPZ(chlorophosphonazo) III, and enzymatic methods were used. For the serum albumin measurement, BCG (bromocresol green) and improved BCP(bromocresol purple) methods were used. The results of this comparison study suggest that the calcium correction equation is not affected by changes in total calcium concentration, but the assay used for albumin may affect the calcium correction equation. Using multiple linear regression, the following equations were derived: BCG between CPZ III [corrected Ca(mg/dL) = total Ca 0.76ALB + 3.2], and improved BCP between CPZ III [corrected Ca = total Ca-0.7ALB + 2.6]. These formulas are simplified respectively as [corrected Ca = total Ca + 0.8(4-ALB], and [corrected Ca = total Ca + 0.7 (4-ALB)]. We conclude that Payne's formula is valid with the BCG method, but with the improved BCP method, our formula is more suitable for correcting calcium. PMID- 24800489 TI - [Verification of complete blood cell count (CBC) data from heparinized blood gas samples]. AB - Complete blood cell count (CBC) data from heparinized blood gas (H-Gas) samples were verified with primary focus on the platelet count (PLT). When a part of H Gas sample was taken to a separation tube from the blood collection syringe and CBC of the sample in the separation tube was repeatedly measured (Procedure 1), the PLT from 5 samples relative to that obtained immediately after the separation was gradually reduced to 72.6-94.2% during serial measurements (every 5 minutes, up to 30 minutes). The change in the scattergram pattern suggested that this PLT decrease was due to the formation of platelet clumps. The white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) values did not significantly change during the repeated measurements. On the other hand, PLT was significantly improved to 96.8-99.8% when the H-Gas sample was kept in the blood collection syringe so as to minimizing the exposure to the air, and the sample for the measurement from H-Gas was taken every time to separation tube from the syringe, followed by CBC measurement without delay (Procedure 2). In addition, while there were significant variations (CV: 11.8-18.2%) in PLT reproducibility among H-Gas samples by Procedure 1, measurements utilizing the Procedure 2 resulted in much smaller variations (CV: 2.2-3.7%). Thus the CBC data obtained from H-Gas samples were equivalent to those from EDTA samples when the Procedure 2 was applied. These data suggest that H-Gas samples can be used for the accurate CBC measurement, including PLT, by applying the Procedure 2. PMID- 24800490 TI - [A discriminant model of mental disorders based on wave form patterns obtained by multi-channel near-infrared spectroscopy]. AB - Multi-channel near-infrared spectroscopy (NIRS) was approved on 2009 as the first advanced medical care modality for use in the field of psychiatry in Japan. We performed NIRS for 185 outpatients in our hospital and 59 healthy subjects to measure hemoglobin concentration changes during verbal fluency tests trying to evaluate the relationships between the wave forms obtained by NIRS and mental disorders. We classified the prefrontal cortex oxy-hemoglobin wave forms obtained from the NIRS into 2 types and sub-classified into 5 wave patterns partly referenced previous papers a) Flat or increasing oxy-Hb form: (1) flat wave pattern, (2) early peak wave pattern, (3) late peak wave pattern during of the task and (4) reascending wave pattern after the task and b) decreasing oxy-Hb form: (5) Decrease wave pattern during the task. Focused on flat or increasing oxy-Hb form, the associations between these 4 wave patterns and psychiatric disorders were confirmed employing the Chi-square test. It was found that the flat wave pattern during the task and depression correlated with a sensitivity of 51.5% and specificity of 90.2%, the late peak wave pattern and bipolar disorder correlated with a sensitivity of 65.9% and specificity of 73.2%, and the re ascending wave pattern after the task and schizophrenia correlated with a sensitivity of 58.9% and specificity of 94.6%. Our findings suggest that the discriminant model based on wave pattern has the potential to provide information supporting a diagnosis of mental disorder in the setting of clinical laboratory testing. PMID- 24800491 TI - [New topics regarding equations for GFR estimation based on serum creatinine and cystatin C]. AB - Japanese GFR equations and CKD-EPI equations based on standardized serum creatinine and standardized cystatin C are recommended in recent Japanese CKD guides and KDIGO guidelines for CKD management, respectively. CKD-EPIcreat overestimates GFR in Japanese subjects, probably due to the difference in muscle mass between Japanese and Caucasians. Unlike CKD-EPIcreat, CKD-EPIcys performs well in Japanese subjects, indicating the advantages of using cystatin C as a GFR marker. KDIGO guidelines suggest measuring eGFRcys in adults with eGFRcreat of 45 59 ml/min/1.73 m2 who do not have markers of kidney damage if confirmation of CKD is required. Creatinine is excreted by glomerular filtration, but also secreted by the tubules. Alteration of the tubular secretion of creatinine may influence the performance of GFR equations based on serum creatinine. Multivariate analysis showed that GFR and serum albumin levels were independent parameters affecting the fractional excretion of creatinine (FE-Cr). Alteration of FE-Cr according to the serum albumin levels may be one of the reasons for the bias of GFR equations based on serum creatinine. Low GFR is a risk factor for all-cause and cardiovascular mortality in a general population. However, the relationship between eGFR and the hazard risk of events is different depending on whether cystatin C or creatinine is used to calculate eGFR. The association between eGFRcys and the hazard risk is much stronger compared with eGFRcreat. Cystatin C may be a useful alternative to creatinine for detecting a high risk of complications in a general population and subjects with CKD. PMID- 24800492 TI - [L-type fatty acid binding protein (L-FABP) and kidney disease]. AB - Liver-type fatty acid binding protein (L-FABP) is expressed in the cytoplasm of human renal proximal tubules. Renal L-FABP expression is up-regulated and urinary excretion of renal L-FABP is increased by various stressors, such as urinary protein, hyperglycemia, tubular ischemia, toxins, and salt-sensitive hypertension, which lead to the progression of kidney disease. Urinary L-FABP levels accurately reflect the degree of tubulointerstitial damage and are strongly correlated with the prognosis of chronic kidney disease (CKD) patients in clinical studies. In patients with type I or type II diabetes, urinary L-FABP levels were reported to be significantly higher in patients with normal levels of urinary albumin than in those with microalbuminuria. Urinary L-FABP may be useful for the early detection of diabetic nephropathy. Furthermore, in a longitudinal study, a higher level of urinary L-FABP was found to be a risk factor for the progression of diabetic nephropathy. With respect to acute kidney disease (AKI), urinary L-FABP facilitates the early detection of AKI before an increase in serum creatinine. Therefore, urinary L-FABP was approved as a new tubular biomarker by the Ministry of Health, Labour and Welfare of Japan. PMID- 24800494 TI - [Epigenetics in kidney diseases]. AB - Increasing evidence has demonstrated that chronic hypoxia in the tubulointerstitium results in irreversible chronic kidney diseases. Hypoxia inducible factor (HIF) is a transcriptional master regulator which takes control of gene expressions under hypoxia. Recently, HIF1 has been reported to organize a cluster of histone-modifying enzymes by binding to their promoter regions in various kinds of cell line. In order to clarify the epigenetic molecular mechanisms by HIF1, we examined the genome-wide analysis of HIF1-binding sites (ChIP-seq) in endothelial cells and HIF1 downstream target genes using DNA microarrays. ChIP-seq results demonstrated that HIF1 binds to the enhancer regions in addition to the promoter regions. We clarified that one of the HIF1 downstream genes, SLC2A3 (solute-carrier family 2A3, also known as glucose transporter 3: GLUT3), is regulated by changing chromosomal conformations under hypoxia via a cooperative combination of HIF1 and KDM3A(lysine(K) specific demethylase 3A), one of the histone demethylases. KDM3A is recruited to the SLC2A3 loci in an HIF1-dependent manner and demethylates histone repressive mark, H3K9me2, up-regulating its expression. In addition, we confirmed the interactions of HIF1 and KDM3A only under hypoxia using co-immunoprecipitation. These experimental results showed novel HIF1-dependent molecular mechanisms from an epigenetic viewpoint. It is important to elucidate the epigenetic mechanisms of chronic hypoxia in order to identify novel therapeutic approaches against chronic kidney disease. PMID- 24800493 TI - [Novel biomarkers for diabetic nephropathy]. AB - Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. An early clinical sign of this complication is an increase of urinary albumin excretion, called microalbuminuria, which is not only a predictor of the progression of nephropathy, but also an independent risk factor for cardiovascular disease. Although microalbuminuria is clinically important to assess the prognosis of diabetic patients, it may be insufficient as an early and specific biomarker of diabetic nephropathy because of a large day-to-day variation and lack of a good correlation of microalbuminuria with renal dysfunction and pathohistological changes. Thus, more sensitive and specific biomarkers are needed to improve the diagnostic capability of identifying patients at high risk. The factors involved in renal tubulo-interstitial damage, the production and degradation of extracellular matrix, microinflammation, etc., are investigated as candidate molecules. Despite numerous efforts so far, the assessment of these biomarkers is still a subject of ongoing investigations. Recently, a variety of omics and quantitative techniques in systems biology are rapidly emerging in the field of biomarker discovery, including proteomics, transcriptomics, and metabolomics, and they have been applied to search for novel putative biomarkers of diabetic nephropathy. Novel biomarkers or their combination with microalbuminuria provide a better diagnostic accuracy than microalbuminuria alone, and may be useful for establishing personal medicine. Furthermore, the identification of novel biomarkers may provide insight into the mechanisms underlying diabetic nephropathy. PMID- 24800495 TI - [Renal disease-related clinical examination in a cohort study]. AB - Various clinical examinations are utilized as variables, surrogate markers, and outcomes in a cohort study. Since the significance of chronic kidney disease as a risk for cardiovascular diseases and premature death was reported, the number of studies including renal disease-related clinical examinations is increasing. Depending on the purpose of the study, renal parameters including the glomerular filtration rate (GFR), proteinuria/albuminuria, hematuria, renal tubular markers, uric acid, bone mineral disorders, and anemia are examined. Among these parameters, GFR and proteinuria/albuminuria are the most frequently used. These parameters are independently associated with the risk of various events, and the combination of these parameters improves the ability to predict the outcomes. Additionally, recent progress in molecular biology has allowed us to include genetic factors as clinical parameters in cohort studies. To investigate the association between the genetic predisposition and outcome, candidate gene analysis and, more recently, genome-wide analysis, are performed. These methodologies are very useful to explore new factors and clarify the underlying mechanisms of the target diseases. Most of the lifestyle-related diseases are multi-factorial, and the association between each factor and the event are sometimes modulated by characters of the examined population. Therefore, careful selection and evaluation of clinical examinations are very important for precise risk evaluation in a cohort study. PMID- 24800496 TI - [Evaluation of cut-off value for autoantibodies against double-stranded DNA complexed nucleosomes based on enzyme linked immunosorbent assay]. AB - The new classification criteria for systemic lupus erythematosus (SLE) by Systemic Lupus International Collaborating Clinics (SLICC) published in 2012 have defined positive level titer of antibody against double stranded (ds) DNA as more than double the reference range if tested by enzyme linked immunosorbent assay (ELISA). The aim of this study was to evaluate optimal cut-off value and diagnostic performance of the anti-dsDNA nucleosome-complexed (anti-dsDNA-NcX) ELISA, which uses salmon testis DNA complexed with purified nucleosomes as antigens, for diagnosis of SLE. Titers of antibodies against dsDNA-complexed nucleosome were measured in sera of 76 patients with SLE, 148 with other connective tissue diseases, and 323 healthy volunteers. Sensitivity, specificity, correlation and concordance rate were compared among anti-dsDNA-NcX, conventional ELISA methods (EIA) and radioimmunoassay (RIA). As a results, concordance rates and Spearman's coefficient of rank correlation (r(s)) of anti-dsDNA-NcX with EIA and RIA were 59.2%, r(s) = 0.40 and 53.9%, r(s) = 0.21, respectively. Receiver operating characteristic curve analysis showed that the titer of 44 IU/mL calculated as 99 percentile of 323 healthy volunteers is a better cut-off value for anti-dsDNA-NcX than the 100 IU/mL recommended by the manufacturer. By setting the cut-off value at 44 IU/mL, anti-dsDNA-NcX showed the highest sensitivity (75.0%) and specificity (90.5%) of the 3 assays. With SLICC criterion, positivity rates of anti-dsDNA-NcX, EIA and RIA for SLE patients were 50.0%, 30.3% and 50.0%, respectively. In conclusion, anti-dsDNA-NcX has a good diagnostic performance for SLE with our proposed cut-off value of 44 IU/mL. PMID- 24800497 TI - [The diagnostic performance of color Doppler ultrasonography for newborn four cases of midgut volvulus accompanied by intestinal malrotation]. AB - Midgut volvulus accompanied by intestinal malrotation is classified as a surgical emergency disease of the newborn, which emerges with the bilious vomiting or melena. This report presents four patients of this disease in our hospital, evaluated by color Doppler ultrasonography before surgical operation. All four patients were presented by bilious vomiting at the onset. By color Doppler ultrasonography method, the whirlpool sign which is the view of intestine and superior mesenteric vein rotated around with the axis of superior mesenteric artery, were shown in all cases. This whirlpool sign led to the diagnosis of midgut volvulus accompanied by intestinal malrotation. Intestinal contrast imaging was tested in three patients for the purpose of confirming the diagnosis. Repair of the volvulus and a ladd operation was performed in all four patients, without the excision of intestine because of no intestinal ischemic change. The clinical courses of four cases were good, and all patients were discharged within 17 days. Early diagnosis and timely surgical operation are essential for decreasing the possibility of occurring intestinal ischemic changes and improving clinical outcome after surgical operation. We propose that color Doppler ultrasonography is the powerful tool for the diagnosis of this disease, especially for the newborn, for whom the available diagnostic tests are limited. PMID- 24800498 TI - [Development of the fingertip blood dilution method for blood cell counting]. AB - For simple examination of blood disorders such as anemia, the results of blood cell counting using a small volume of blood sampled from a finger were evaluated. Because the sampling volume varies, tyramine was added to the blood dilution buffer as an internal standard. When blood is added to a tyramine-containing buffer, tyramine is diluted according to the blood volume regardless of the hematocrit. The degree of blood dilution can be calculated from the difference in the tyramine concentration. The diluted blood was measured for blood cell count items using XE-2100. After cell counting, the diluted blood was centrifuged, and the concentration of the internal standard in the supernatant was measured using the automated biochemical analyzer JCA-BM2250. Correlation coefficients of 0.824 0.995 were obtained in the blood cell counts between fingertip and venous blood samples from 48 volunteers. However, as platelet aggregation was observed by fingertip blood sampling, the correlation coefficient for the platelet count was 0.450. This method is considered to be useful for screening of blood disorders. It may also be applicable to medical care in remote areas and during disasters. PMID- 24800499 TI - [Alpha-Synuclein in blood and cerebrospinal fluid of patients with alpha synucleinopathy]. AB - Alpha-Synuclein protein(alphaS) aggregates from a monomer to assemblies such as oligomers, protofibrils, and mature fibrils. The early intermediate aggregate, that is, the oligomer, has been reported to be the most toxic species. We recently reported that melatonin inhibits alphaS aggregation, including protofibril and oligomer formations. While the alphaS concentration in cerebrospinal fluid was reported to significantly decrease in patients with Parkinson's disease (PD) and dementia with Lewy bodies, there have been reports that the alphaS oligomer concentration was elevated in the cerebrospinal fluid of PD patients. Moreover, it was reported that the alphaS oligomer concentration was also elevated in the blood of PD patients. Further studies may establish alphaS in cerebrospinal fluid and blood as a biomarker of alpha-synucleinopathies, including PD. PMID- 24800500 TI - [Myotonia and cardiac conduction defects in myotonic dystrophy and defect in ion channels]. AB - Myotonic dystrophy (DM), the most common hereditary muscle disease in adults, is caused by the unstable genomic expansion of simple sequence repeats. This disease is characterized by myotonia and various multisystemic complications, most commonly those of the cardiac, endocrine, and central nervous systems. The cardiac abnormalities, especially cardiac conduction defects, significantly contribute to morbidity and mortality in DM patients. Therefore, understanding the pathophysiology of cardiac conduction defects in DM is important. The pathomechanism of DM has been thoroughly investigated. The mutant RNA transcripts containing the expanded repeat give rise to a toxic gain-of-function by perturbing splicing factors in the nucleus, leading to the misregulation of alternative pre-mRNA splicing. In particular, several studies, including ours, have shown that myotonia is caused by alternative splicing of the CLCN1 gene coding the voltage-gated chloride channel in skeletal muscle through an "RNA dominant mechanism". Since the aberrantly spliced isoform does not seem to form a functional channel, the feature of skeletal muscle in DM can be interpreted as a "channelopathy" caused by reduced chloride channel protein. Similarly, we recently identified a misregulation of alternative splicing in an ion channel gene which is known to be responsible for arrhythmic disease showing Mendelian inheritance. Here, we review the cardiac manifestation and RNA-dominant mechanism of DM, and discuss the possible pathophysiology of cardiac conduction defects by referring to hereditary arrhythmic diseases, such as long QT syndrome and Brugada syndrome. PMID- 24800501 TI - [Autoantibodies detected in acetylcholine receptor antibody-negative myasthenia gravis]. AB - Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by pathogenic autoantibodies (Abs) against the acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase (MuSK), and unknown autoantibodies. The seropositivity rates for routine AChR binding Ab and MuSK Ab in MG are 85% and a few % for MG patients in Japan, respectively. The autoimmune target in the remaining patients is unknown. In 2001, Hoch et al. reported that a proportion of AChR-Ab-negative MG patients had serum IgG antibodies against MuSK, shedding new light on the pathogenesis of the disease. This idea has been recently supported by many clinical studies, including neonatal myasthenic syndrome and animal model studies. In 2011, autoantibodies against low-density lipoprotein receptor-related protein 4(Lrp4) were identified in Japanese MG patients and, thereafter, have been reported in Germany and the USA. We developed a simple technique termed Gaussia luciferase immunoprecipitation for detecting antibodies to Lrp4. As a result, nine generalized MG patients out of 300 lacking AChR Ab were found to be positive for Lrp4 antibodies. Thymoma was not observed in any of these patients. These antibodies inhibit the binding of Lrp4 to its ligand and are predominantly of the IgG1 subclass. In other reports of Lrp4 ab, Lrp4 ab-positive sera inhibited the agrin-induced aggregation of AChRs in cultured myotubes, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that Lrp4 is the third autoantigen in patients with MG, and anti-Lrp4 autoantibodies may be pathogenic. Further studies including neuromuscular junction biopsy are needed to clarify the pathomechanism of Lrp4 ab-positive MG. PMID- 24800502 TI - [Biological markers for early diagnosis of Alzheimer's disease]. AB - Dementia is a declined state of cognitive functions which impair daily and social life mainly caused by progressive neurodegenerative disease, such as Alzheimer's disease(AD). The present study showed that about 15% of patients in Japan aged over 65 have dementia. The important point regarding the diagnosis of dementia is to detect it as early as possible. It is critical for the diagnosis to measure the indicators in blood and cerebrospinal fluid (CSF). Blood tests are useful to eliminate other factors that lead to cognitive decline derived from physical causes. CSF markers are significant for monitoring the existence and progression of neuropathologies. We need to accumulate extensive knowledge of the features, types, pathologies, development, and progress of dementia in order to assess patients and/or measured values. PMID- 24800503 TI - [Quantitative analysis of clinical samples using tandem mass spectrometers]. AB - The history of clinical examination in Japan can be divided into 4 periods. The first period was the pioneering years of the 1950s or earlier when medical doctors or technicians performed manual examinations using in-house reagents. The second period involved the propagation of clinical examination in the 1960s 90s, when the development of central laboratory and commercial analytical systems was achieved. The third period (2000s) involved the development of new laboratory services such as blood drawing, infection control, and nutrition support. The fourth period is now, when advanced technologies such as mass spectrometry, high throughput DNA sequencing, and micro/nanotechnologies including MEMS are incorporated in clinical examination. The present period might possibly be called the days of innovation of clinical examination. This symposium will focus on the problems and solutions regarding applying quantitative LC/ESI-MS/MS to clinical examination. PMID- 24800504 TI - [Fundamental knowledge and master of mass spectrometry: important reminder and pitfall in quantitative analysis]. AB - Recently, mass spectrometry has become frequently applied in various areas of research because of the easy handling of instruments. However, its use without an adequate understanding of the characteristics of mass spectrometry and/or with an unreliable analytical method often lead to the misinterpretation of data. Sample pretreatments such as deproteinization, liquid-liquid extraction, and solid-phase extraction are very important to improve detection sensitivity. In addition, during the electrospray ionization process, the components of droplets affect the ionization efficiency of analytes, and, therefore, the elimination of unwanted materials is essential for the development of a reliable analytical method. We experienced marked deviations in measurement values for the sirolimus blood concentration in the same sample. Post-column infusion experiments were very useful for identifying ionization suppression factors in analytical samples, and mass spectrometric analysis was effective for their identification. In consequence, lysophosphatidylcholines suppressed the ionization of sirolimus and an internal standard, ascomycin, and we removed them from analytical samples using a HybridSPE-pretreatment cartridge, which is a solid-phase extraction cartridge for capturing phospholipids from biological samples. The incorporation of this step into the sample pretreatment procedure led to the development of a reliable analytical method for the quantitative determination of sirolimus in human blood using liquid chromatography/electrospray ionization tandem mass spectrometry. In clinical practice, rapid and reliable analytical methods are required for the improvement of medical services, and, therefore, users of mass spectrometers should understand their characteristics. PMID- 24800505 TI - [Differential diagnosis of primary aldosteronism by measurement of hybrid steroids using mass spectrometry]. AB - Primary aldosteronism (PA), characterized by the autonomous hypersecretion of aldosterone, is the most common cause of secondary hypertension. Patients with PA have a higher risk of cardiovascular morbidity than essential hypertension. The two common subtypes of PA, aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA), should be differentiated, because the former is an indication for adrenalectomy, and the latter is treated by medication. 18 Hydroxycortisol and 18-oxocortisol, known as hybrid steroids, have been recognized as markers for the differentiation of aldosterone-producing adenoma and rare glucocorticoid remediable hyperaldosteronism from other subtypes of PA. Hybrid steroids have been measured using immunoassays such as enzyme-linked immunoassays; however, immunoassays for hybrid steroids are not widely used. Recently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) for hybrid steroids was developed. The ability to measure hybrid steroids using LC-MS/MS will be useful for the differential diagnosis of subtypes of PA. PMID- 24800506 TI - [Analyses of lipid hydroperoxides and physiologically active lipids by mass spectrometry]. AB - Numerous studies have been conducted on lipid oxidation in relation to atherosclerosis, inflammation, and various diseases. This review briefly presents the methods of liquid chromatography-electrospray ionization mass spectrometry (LC/MS) for lipid peroxides, and the physiologically active lipid plasmalogen. PMID- 24800507 TI - [Amyloid typing from formalin-fixed paraffin-embedded tissues using LMD-LC-MS/MS system]. AB - Amyloidosis is one of the protein conformational disorders in which normally soluble proteins accumulate insoluble amyloid fibrils, leading to severe organ dysfunction. To date, 30 different amyloidogenic proteins have been reported. Immunohistochemistry (IHC) is usually used to identify the amyloid precursor protein, but the results may be inconclusive owing to a loss of epitopes or small amounts of amyloid deposits, comprising unknown amyloidogenic protein. Recently, laser microdissection (LMD)-liquid chromatography tandem mass spectrometry (LC MS/MS) has been used in a novel method to identify amyloid precursor protein from amyloid-laden formalin-fixed paraffin embedded (FFPE) tissues. We describe the usefulness of the system for amyloid typing in this report. PMID- 24800508 TI - Taxonomic analysis of the Streptomyces sp. 2435 strain, a producer of antimicrobial substances. AB - The study of the taxonomic status of the antimicrobial substances producer strain Streptomyces sp. 2435 was conducted The nucleotide sequence of 16S rRNA gene of the strain was determined and deposited in the Genbank (No JN129837) database. Results of morphological, biochemical and cell wall fatty acids content analyses, evaluation of biosynthesis features of Streptomyces sp 2435, together with the phylogenetic analysis have provided the basis to identify this strain as Streptomyces albus. PMID- 24800509 TI - [Influence of Bradyrhizobium japonicum YKM B-6035 inoculation on the microstructure of soybean rhizosphere cenosis and photosynthetic apparatus]. AB - Development of Bradyrhizobium japonicum YKM B-6035 bacterial cells in suspension culture, aseptic soil and rhizosphere of soybean plants inoculated by nodulate bacteria were investigated. The increase of bacteria number on the surface of main root and rhizosphere was determined in nodulated soybean plants. Photosynthetic apparatus of inoculated plants increased due to morphological characteristics: the leaf blade area and width of mezophyll palisade and spongy layers. Morphological changes in the leaf blade development were confirmed by spectrophotometric measurements of main pigments on the leaf blade. PMID- 24800510 TI - [Hydrolytic activity of microorganisms of the Dead Sea coastal ecosystems]. AB - All strains tested are characterized by proteolytic (caseinolytic) activity, while elastase one was revealed only in two Gracilibacillus strains 6T2 and 7Tl. The activity was high enough (23.1 and 34.7 E/Ml, respectively). These values are at the level of bacterial producers which are described in literature: Bacillus mesentericus 316 M (6 E/Ml), Bacillus thuringiensis IMB B-7324 (50-55 E/Ml). The ability of two strains tested to synthesize enzyme, active against elastine, is important, so far as microbial enzyme may be perspective for using in medicine: elastases are able to dissociation of elastin fibres of connective tissues. These two strains display also fibrinolytic activity, however it was insignificant. Six of eight strains studied manifested alpha-amylase activity (0.01 - 1.173 E/Ml). It was shown that no strains, isolated from the Dead Sea costal ecosystems are able to manifest alpha-L-rhamnosidase activity. PMID- 24800511 TI - Phytopathogenic bacteria in the system of modern agriculture. AB - The stages of studying bacterial diseases of crops and weeds at various farming systems have been characterized, biological properties have been investigated and pathogens identified using traditional and modern molecular genetic methods of research. PMID- 24800512 TI - Whey fermentation by yeast strains Kluyveromyces marxianus UCM Y-2096 and UCM Y 2388. AB - Two Kluyveromyces marxianus strains have been tested for their ability to ferment lactose in the medium containing cheese whey powder (CWP) and lactose at different concentrations. The ethanol production by the selected strains was inhibited by the increase in substrate concentration (100 g/l). The strain K. marxianus UCM Y-2096 was found to yield the higher ethanol formation and to be more resistant to ethanol under microaerophilic conditions. PMID- 24800513 TI - [Features of interaction bacterial strains Micrococcus luteus LBK1 from plants varieties/hybrids cucumber and sweet pepper and with fungus Fusarium oxysporum Scelecht]. AB - The article presents the results of studying the impact of bacterial strain M. luteus LBK1, stimulating the growth and development of plant varieties/hybrids of cucumber and sweet pepper on the intensity of sporulation of the fungus F. oxysporum Scelecht--fusariose rot pathogen. PMID- 24800514 TI - [Growth of microfungi on the external polyethylene anticorrosive coating of oil gas pipes]. AB - The authors have studied the resistance of external anticorrosive polyethylene coat of oil-gas pipes (based on the high-density polyethylene, HDPE) to the action of microfungi, natural contamination, fungistatic and fungicide activity. It was found that the intensity of growth of standard test cultures on the surface of polyethylene coat increases in terms which imitate mineral and organic contaminations, and this results in the decrease of the index of its resistance to the action of microfungi. The microfungi, found in the process of study of natural contamination of polyethylene coat and its components, are presented by six species, Alternaria sp. most frequently occurring among them. The presence of admixtures of nitrogenic and phosphoric organic substances in chemical composition of control standards of adhesive and HDPE, which were not exposed to the influence of microfungi, was established by the method of IR spectroscopy. Changes of the IR spectra were noticed in the surface layer of high density polyethylene pellets under the influence of Penicillium funiculosum 171703 that evidences for the process of its slow oxidation. It is assumed that the damaging of the coating components is due to the presence in their chemical composition of impurities of nitrogen- and phosphorus-containing compounds that are easily absorbed by microscopic fungi. PMID- 24800515 TI - [Influence of bean yellow mosaic virus on metabolism of photosynthetic pigments, proteins and carbohydrates in Glycine soja L]. AB - This paper presents data on BYMV effects on some physiological processes of Glycine soja L. cultivated in the right-bank forest-steppe regions. Pigment content (chlorophyll a, b and carotenoids), soluble proteins and water soluble carbohydrates were estimated and, as has been shown, are subjected to significant changes as compared with control plants, namely: a decrease in the content of chlorophyll a, b and carotenoids was 64%, 53% and 36% compared with the control plants. The significant increase in carbohydrates (56% compared to the control) was observed at the end of the test period. PMID- 24800516 TI - [Saccharomyces cerevisiae as a model organism for studying the carcinogenicity of non-ionizing electromagnetic fields and radiation]. AB - Medical and biological aspects of the effects of non-ionizing electromagnetic (EM) fields and radiation on human health are the important issues that have arisen as a result of anthropogenic impact on the biosphere. Safe use of man-made sources of non-ionizing electromagnetic fields and radiation in a broad range of frequencies--static, radio-frequency and microwave--is a subject of discussions and speculations. The main problem is the lack of understanding of the mechanism(s) of reception of EMFs by living organisms. In this review we have analyzed the existing literature data regarding the effects of the electromagnetic radiation on the model eukaryotic organism--yeast Saccharomyces cerevisiae. An attempt was made to estimate the probability of induction of carcinogenesis in humans under the influence of magnetic fields and electromagnetic radiation of extremely low frequency, radio frequency and microwave ranges. PMID- 24800517 TI - [Cerebrovascular pharmacology of separate and combined vascular pathology of brain and heart]. AB - The effect of nimodipine, mexidol, melatonin, afobazole, 5-hydroxy-adanamtan-2 one, and GABA conjugates with arachidonic acid and docosahexaenoyl dopamine on the cerebral circulation has been studied in intact rats and those with global transient cerebral ischemia, experimental myocardial infarction, and combined vascular pathology of brain and heart. The most pronounced vasodilation activity in rats with global transient cerebral ischemia is exhibited by nimodipine, mexidol, melatonin, afobazole, 5-hydroxy-adanamtan-2-one, and GABA-containing lipid derivatives. This effect of all these drugs (except for nimodipine) is not manifested on the background of GABA receptor blocker bicuculline. In rats with experimental myocardial infarction and combined vascular pathology of brain and heart not all of the compounds mentioned acbove with GABA-ergic mechanism of action stimulate the cerebral blood flow. Thus, both similarity and differences in cerebrovascular effects of these compounds have been found, which depend on the initial state of organism and the vascular pathology of brain and/or heart. The obtained results show good prospects for this direction of research. PMID- 24800518 TI - [Farmacological effect of retabolil on aldosterone level and arterial pressure in rats under the action of vibrations]. AB - The experiments were performed on male rats, which were subjected to single and multiply repeated vibrations (low-frequency, horizontal, high-amplitude) analogous to the action of motor transport vibrations. It is established that the administration of retabolil produces a hypotensive effect and blocks the vibration-induced increase in the level of hypertensive hormone aldosterone. Under conditions of the multiply repeated action of vibrations, both effects were realized via micro-opioid receptors. In the case of a single action, these receptors were only involved in a hypotensive effect but not mediated in aldosterone suppression. Both these effects were absent in the control group of animals (not subjected to vibrations). Therefore, retabolil can be used as a hypotensive and aldosterone-blocking drug for vibration-induced hypertension in animals and, probably, in humans. PMID- 24800519 TI - [Comparative study of the influence of melatonin and diclofenac on some hematologic indices of experimental rheumatoid arthritis in rats]. AB - Pineal hormone melatonin (1 and 5 mg/kg) and diclofenac (8 mg/kg) significantly limited hematologic indices of inflammation and immunologic reactivity in rats with experimental adjuvant arthritis. The effect of melatonin was more pronounced than that of diclofenac. PMID- 24800520 TI - [Calcium-depended mechanism of the antiplatelet activity of benzimidazole derivative RU-891]. AB - We have studied the effect of the new benzimidazole derivative RU-891, known to exhibit antiaggregant activity in vitro and in vivo, on the level of intracellular calcium ions in platelets of laboratory rabbits. Compound RU-891 was found to inhibit the thrombin-induced growth of intracellular calcium ion level in thrombocytes.This effect exceeded t he action o f reference d rugs and was not connected w ith the influence of RU-891 o n the potential-dependent c alci u m channels. PMID- 24800521 TI - [Blood oxygen transport, prooxidant -- antioxidant status, and vasoactive characteristics of vascular endothelium in rats treated with endotoxin and taurine]. AB - Experiments on a group of 74 pregnant rats upon intramuscular introduction of E. coli lipopolysaccharides during pregnancy revealed the correction effect of taurine on the blood oxygen transport function, prooxidant - antioxidant status, and vasoactive characteristics of vascular endothelium. PMID- 24800522 TI - [Effect of byetta on renal osmoregulatory function in patients with diabetes mellitus]. AB - The renal osmoregulatory function was studied in patients with type 2 diabetes mellitus (DM). The renal response to water loading (0.7% b.w.) and simultaneous exenatide (byetta) injection (5 microg) exhibited variation and was dependent on the degree of hyperglycemia. Effective solute-free water excretion was observed in patients with well-controlled DM (HbAlc 6.0 +/- 0.1%), in which CH20 changed from -0.67 +/- 0.2 mL/min to 0.72 +/- 0.2 mL/min. This reaction was absent in patients with poorly controlled DM (HbAlc 8.8 +/- 0.6%) and the process of solute free water reabsorption prevailed: -CH20 = -1.06 +/- 0.1 mL/min in control period vs. -0.99 +/- 0.1 mL/min after treatment. Thus, byetta increases the efficiency of osmoregulation and accelerates the excretion of excess water in patients with compensated carbohydrate metabolism. PMID- 24800523 TI - [Effect of proteflazid on TLRs expression by mononuclear leukocytes of peripheral blood and epithelial cells of mucous membranes and skin in patients with herpes associated erythema multiforme and erythema annulare centrifugum]. AB - The article reports survey data on 23 patients with erythemas, including 19 patients with herpes-associated erythema multiforme (HAEM) and 4 patients with Darier's erythema annulare centrifugum (DEAC). Patients in the initial state (baseline) and after two weeks of therapy with proteflazid were characterized by measuring the levels of Toll-like receptor (TLR) expression in peripheral blood mononuclear cells (PBMC) and in epithelial cells of the throat and the skin. The TLR expression in PBMC and skin was assessed by flow cytometry with monoclonal antibodies (ICA) (Caltag Laboratories, USA; Hycult Biotech, Netherlands) against relevant antigens. In addition, patients were also characterized by the content of subpopulations of lymphocytes expressing surface markers CD3, CD4, CD8, CD16, CD21, CD23, CD72, CD25, and HLA-DR in the peripheral blood, which was measured by flow cytometry. The therapy with proteflazid in patients with both HAEM and DEAC led to normalization of the level of both T-cell and B-cell immunity, which was manifested by an increase in the total number of lymphocytes, CD3+, CD4+, CD21+, and CD72+. Measurements of the dynamics of TLR expression in the course of immunotherapy showed an increase in the number of TLR 2, 3, 4, 7, 8, and 9 in PBMC (which was especially pronounced for TLR2) and in epithelium of the pharyngeal mucosa and skin (increased expression of TLR3, 7, and 9). PMID- 24800524 TI - [Effect of galantamine and testosterone on the arthritic response and dopamine content in rat spleen]. AB - The study was carried out on male Wistar rats with surgically ablated gonads. The rats with gonadectomy and intact rats received galantamine and/or testosterone over 10 days, after which the model arthritis was induced by injection of 200 ml of complete Freund's adjuvant. It was established that gonadectomy reduced arthritic reactions producing ulcer formation at a later time (21 days) as compared to control (rats with arthritis), where they are formed on the local stage of development (day 7). Testosterone replacement therapy completely blocks the development of ulcers on the paws. Galantamine suppresses the arthritic reaction more significantly, reducing paws and ankle-joint edema 1.5 and 1.3 times respectively (n = 12, p <0.05). The appearance of dopamine in the spleen during galantamine treatment may serve as a marker of protective action of the drug under hypoandrogenic conditions. Introduction of galantamine at high level of testosterone does not significantly influence on development of arthritic reaction, which is indicative of a marked imbalance between the hormonal and cholinergic systems and a possibility to modulate arthritic reaction with cholinergic drugs. PMID- 24800525 TI - [Using cycloferon in the complex treatment of herpetic infection in patients with atopic dermatitis]. AB - Clinical efficacy of including cycloferon liniment in combined treatment of herpetic infection in a group of 40 patients with atopic dermatitis has been analyzed. It is concluded that the administration of cycloferon favors dynamic disappearance of general infectious syndrome, reduces timeline of rash as well as length of local inflammation, accelerates epithelization of erosions (on the average 1.2 - 1.4 times, p < 0.05), decreases frequency of recurrent infections, and reduces the level of pro-inflammatory cytokines in the blood of patients. PMID- 24800527 TI - Regulation of spermatogonial stem cell compartment in the mouse testis. AB - Spermatogenesis occurs throughout the adult lifetime of males and is supported by a robust stem cell system. Spermatogonial stem cells (SSCs) are the stem cells of postnatal male germ cells, and not only self-renew but also produce differentiated progeny continuously. Recent report revealed that differentiating spermatogonia could revert into an undifferentiated state, although it was believed that SSCs were homogeneous and that differentiating spermatogonia was not reversible. Although several molecules, which regulate SSC, have been identified so far, molecular mechanisms underlying the maintenance of SSCs as well as the reversible developmental lineage of SSCs remain to be elucidated. In this review, we describe a brief overview of spermatogenesis and summarize the molecular regulation of SSC compartment. PMID- 24800526 TI - [Nephroprotective properties of third-generation beta-adrenoblockers]. AB - Experimental and clinical data on the nephroprotector properties of third generation beta-adrenoblockers nebivolol and carvedilol are reviewed. These properties are related to the antihypertensive effect and ability of drugs to suppress oxidative stress in glomerules, proximal renal tubules, and surrounding interstitial tissue. PMID- 24800528 TI - T-tube drainage and intercostals muscle flap reinforcement for the management of intrathoracic esophago-gastric anastomotic leakage with pyothorax: a case report. AB - We herein report a case of mediastinitis with left pyothorax due to anastomotic leakage after totally laparoscopic proximal gastrectomy (TLPG) successfully managed by T-tube placement and intercostal muscle flap reinforcement. A 51-year old man, who had undergone a TLPG at a referring hospital, was referred for fever, elevated inflammation markers, and pleural effusion on postoperative day 3. A computed tomography (CT) scan revealed mediastinitis with left pyothorax caused by anastomotic leakage. An emergency operation was performed through a left thoracotomy. After an irrigation of the thoracic cavity and a decortication of the pleura, we found a perforation in the left side of the anastomosis. We decided to insert a T-tube through the perforation and performed intercostal muscle flap reinforcement. He got acute respiratory distress syndrome but recovered after treatment in Intensive Care Unit for 24 days. Oral intake was started on day 45 and he was discharged on day 71. A T-tube drainage and wrapping with the intercostal muscle flap is a useful choice of treatment for intrathoracic anastomotic leakage with severe inflammation. PMID- 24800529 TI - Successful treatment of an abdominal aortic aneurysm with a severely angulated and large aortic neck using a modified Zenith. AB - This report presents the case of an abdominal aortic aneurysm (AAA), in which the aortic neck was severely angulated. Furthermore, there was moderate stenosis and a severe angle with calcification of the suprarenal aorta. EVAR was performed with a commercial Zenith stent-graft, with a slight modification, because an open aneurysm repair was risky in general condition. No complications occurred during the follow-up period. PMID- 24800530 TI - Open pelvic ring fracture and multiple fractures of the lower extremities: a case report. AB - A 73-year-old female was hit by a car, and transferred to our hospital. On examination, her consciousness was alert, but her vital signs were unstable. There are three 10-cm open wounds on her right buttock. X-rays showed an unstable pelvic ring fracture, a right femoral shaft, a right proximal tibia and a right tibial plafond fractures. One hour after the injury, transarterial embolization (TAE) followed by external fixation (EF), and retroperitoneal pelvic packing (RPP) was performed. Two days and five days after the injury, thorough debridement of the open wounds was performed. The skin defect on the right buttock and the lower abdomen had enlarged to 40 x 35 cm, therefore, negative pressure wound therapy was applied. On the same day, right femur was fixed using a retrograde intramedullary nailing. 12 days after the injury, the proximal tibial fracture was fixed using a plate, and the tibial plafond fracture was fixed using screws and external fixators. 28 days after the injury, the split thickness skin graft was performed on the right buttock and the lower abdomen. Seven months after the injury, the open wounds were completely healed without infection. She was able to walk smoothly with a T-cane. For the management of open pelvic ring fractures, it is essential to perform TAE, EF and RPP as soon as possible. Providing aggressive management, including thorough debridement, is mandatory to prevent severe infection and sepsis. We achieved a good clinical outcome by using a combination of TAE, EF, RPP and staged surgery, including thorough debridement. PMID- 24800532 TI - [Theory and practice on reconstruction of the ossicular chain with improving of acoustic function]. PMID- 24800531 TI - [A case of surgical treatment for a bilateral pneumothorax that occurred in a patient with severe asbestosis and advanced emphysema]. AB - A 71-year-old male with a history of asbestosis was referred to our department for the treatment of a bilateral pneumothorax. His pulmonary function was severely impaired because of asbestosis and emphysema. Chest computed tomography showed severe emphysema with bilateral multiple bullae. Although chest drainage tubes were placed in the bilateral thorax, the left lung did not completely expand due to a persistent air leak. We performed VATS while retaining the patient's spontaneous respiration under general sedation with regional epidural anesthesia, since one-lung, positive pressure ventilation was considered to be difficult to achieve. After the airway was secured by a laryngeal-mask, the bullae were then thoracoscopically resected. The pneumothorax improved after surgery. PMID- 24800533 TI - [The approach of diagnostic and therapy of subjective idiopathic tinnitus]. PMID- 24800534 TI - [Tinnitus: the mechanism of tinnitus centralization and clinical management]. AB - Tinnitus is the most common disease in Otology, and extremely difficult for treatment in clinic, abnormal events in the cochlea (the abnormal events can result in abnormal neuronal activity in central auditory pathways that can then be finally perceived as tinnitus). Neuroplasticity events at the auditory cortex (AC) have been reported to include hyperactive of cortical neurons and an increase in neuronal synchronization. Our recent studies showed the changes markedly, in the expression of the excitatory glutamate receptor subtype NR2B in mRNA and protein levels, and also some changes in synaptic ultrastructure of neurons in auditory cortex of tinnitus animal. We propose that the mechanisms of tinnitus centralization may arise from abnormal events in the cochlea, and result in abnormal neuronal activity at multiple levels which promote abnormal propagation of neural activity in the central auditory pathway. The plastic change may be positive and adaptive as with learning or memory, or in the compensation after abnormal events in the cochlea that results in new neuronal networks that restore normal function. Alternatively, the neuroplasticity changes might be maladaptive leading perhaps to an imbalance in excitatory and inhibitory events in the brain. Indeed, tinnitus may be the consequence of such maladaptive neuroplasticity brain alterations (synaptic structure) has even gone a step further and described tinnitus as the perceptual manifestation of plastic brain changes that result in abnormal neuronal activity. The neuroplasticity changes may also make tinnitus persists, eventually leading to the existence of tinnitus cochlear-originated in the central pathway. They may also extend to non-sensory areas of the brain giving rise to the attentional and emotional aspects that often accompany the disorder. New pathophysiological insights maybe prompt the development of management approaches to directly target the neuroplasticity processes correlates of tinnitus. PMID- 24800535 TI - [Audiological management for tinnitus: the theoretical framework and clinical applications]. PMID- 24800536 TI - [Effect of negative life events on tinnitus patients quality of life]. AB - OBJECTIVE: To study the relationship between negative life events and quality of life of tinnitus patients, and explore the role of negative life events in psychological counseling and rehabilitation of tinnitus. METHOD: Sixty-one cases of tinnitus patients and 61 normal controls were tested with tinnitus handicap inventory and life event scale, scores were compared and the associated analysis was made. RESULT: Stimulating quantity of negative life events in the tinnitus group, compared with the control group was statistically different (Z = -2.56. P < 0.05). The incidence of negative life events in the tinnitus group compared with the control group was no statistically different (chi2 = 0.05, P > 0.05). The incidence of abnormal scores of negative life events compared with the control group was statistically different (chi2 = 16.68, P < 0.01). Positive correlation in tinnitus group was found between scores of negative life events and scores of tinnitus handicap inventory (r = 0.41, P < 0.01). The higher the score of negative life events, the lower the quality of life with tinnitus patients. CONCLUSION: Severity of negative life events and tinnitus is closely related, and negative life events can reduce the quality of tinnitus patients life. We should pay more attention to negative life events in psychological counseling with tinnitus patients. The intervention in negative life events can improve the quality of life. providing the targeted and individualized theory basis for tinnitus psychological counseling and rehabilitation. PMID- 24800537 TI - [Lexical tone perception and quality of life in nurotron cochlear implant users]. AB - OBJECTIVE: To investigate the lexical tone perception and quality of life of Nurotron cochlear implant users. METHOD: Forty-nine adult cochlear implant users participated in this study. Mandarin tone identification test developed by Beijing Institute of Otolaryngology was used to evaluate the tone perception. Nijmegen cochlear im plantation questionnaire (NCIQ) was administered to quantify the quality of life. RESULT: (1) The average scores of tone perception in quiet was 67.26%. The tone perception rates under quiet condition for all cochlear implant recipients were higher than the opportunity level. (2) The average scores of tone perception under noisy condition was 51.92%. Exc ept for two recipients, the tone perception rates under noise condition for the rest recipients were better than chance. (3) The confusion patterns of tone recognition showed that Tone 3 was the easiest tone to perceive. (4) The postimplant scores for the total , basic sound perception, advanced sound perception, speech pro duction, self esteem, activity and social interactions of NCIQ were 55.4, 72.4, 54.0, 63.4, 50.7, 47.3 and 44.7, respectively. CONCLUSION: The Nurotron cochlear implant users had the ability for lexical tone perception and had an improvement in quality of life after cochlear implantation. PMID- 24800538 TI - [Clinical analysis on 45 cases of urgent tracheotomy]. AB - OBJECTIVE: To investigate the clinical characteristics of urgent tracheotomy patients. METHOD: Forty-five cases of urgent tracheotomy patients were reviewed retrospectively. The clinical characteristics, pre-operative and post-operative clinical manifestation and complication were studied. Most patients for urgent tracheotomy were head and neck tumor, inflammation and head and neck injury. RESULT: Two patients died in operating and two patients died in post-operation. Finding respiratory depression in six patients of long obstruction in post operation. Eleven patients had complication in operating or post-operation. Hemorrhage and pneumoderma and local trauma were the main complications. CONCLUSION: Emergent tracheotomy and elective tracheotomy were different-in the short operation time and body position. Complication incidence rate were higher than normal tracheotomy. Patients of long obstruction after post-operation shouldn't breathe in pure dephlogisticated air to avoidance respiratory depression. PMID- 24800539 TI - [Expression and significance of PTEN, P-ERK and P-AKT in the middle ear cholesteatoma]. AB - OBJECTIVE: Detect the expressions of the protein tyrosine phosphatase gene (PTEN), phosphorylated protein kinase B (P-AKT) and phosphorylated extracellular signal-regulated kinase (P-ERK) in human middle ear cholesteatoma tissue and its correlation to explore their important role in the mechanism of the formation of cholesteatoma. METHOD: Use immunohistochemical SABC method (SABC immunohistochemical method) to detect the expressions and location of PTEN, P-AKT and P-ERK proteins in 40 cases of middle ear cholesteatoma tissue samples and 15 cases of normal ear skin specimens. Use Western blot to detect the expression levels of PTEN, P-AKT, P-ERK proteins and the internal reference GAPDH in 20 cases of cholesteatoma tissue and 10 cases in nor mal ear skin specimens. RESULT: (1) Immunohistochemistry showed coloring of PTEN both in the nucleus and cytoplasm of cholesteatoma and normal skin . Nuclear PTEN positive expression rates in the cholesteatoma was significantly lower than normal skin, and the difference was significant (P < 0.01); cytoplasm PTEN positive expression rates in the cholesteatoma was significantly lower than normal skin, and the difference was significant (P < 0.01); P-AKT mainly expresses in the cytoplasm of cholesteatoma and normal skin. The positive expression rates in the cholesteatoma was significantly higher than normal skin,and the difference was significant (P < 0.01); the P-ERK mainly colors in cholesteatoma and normal skin cell nucleus. the positive expression rates in the cholesteatoma was significantly higher than normal skin, and the difference was significant (P < 0.01). In cholesteatoma specimens, there was a significantly negative relationship (P < 0.01) between PTEN, respectively, and P-AKT, P-ERK protein. (2) Western blot discovered: the expression of PTEN in cholesteatoma was significantly less than the amount of expression in normal skin; P-AKT and P-ERK expression in cholesteatoma was significantly more than the level in normal skin. CONCLUSION: Abnormal expression of PTEN, P-AKT and P-ERK protein in cholesteatoma may be closely related to antiapoptosis and high degree of proliferation in cholesteatoma. Expression of PTEN deletion leads to the weakening of the inhibition. Excessive expression of P AKT gives rise to cholesteatoma epithelial cell apoptosis inhibited; excessive PERK expression result to cholesteatoma epithelial cell proliferation strengthened. PMID- 24800540 TI - [Thirteen cases with tuberculous otitis media and mastoiditis]. AB - OBJECTIVE: To analyze the clinical features and treatment of tuberculous otitis media and mastoiditis. METHOD: Thirteen patients with tuberculous otitis media and mastoiditis were retrospectively analyzed and the related literatures were reviewed. One case was treated by surgery only, and anti-tuberculosis treatment was given to another one patient, and surgical removal of disease lesions in combination with anti-tuberculosis treatment were given to 12 patients. RESULT: One patient received surgery only was found to recur after follow-up for seven months. The patient did not recur after seven months' follow-up after antituberculosis therapy,and other patients did not recur. CONCLUSION: Although the regular anti-tuberculosis chemotherapy treatment was the main treatment for tuberculous otitis and mastoiditis, surgical treatment was helpful to achieved more rapid healing of the ear. PMID- 24800541 TI - [Usefulness of multimodal microscopic-based neuronavigation combined with intraoperative magnetic resonance imaging system in the treatment of lesions of middle skull base]. AB - OBJECTIVE: To evaluate the applicative value of multimodal navigation combined with intraoperative magnetic resonance imaging system in the treatment of complex lesions of middle skull base. METHOD: Nineteen consecutive patients undergoing complex lesions resection using multimodal microscopic navigation combined with iMRI were included. Preoperative radiological images were imported into navigation planning system, based on which approach and microsurgical window were designed. Transcranial approach and extracranial approach(include trans-oral nasal-sphenoidal approach and transsphenoidal approach) were performed in our series. After presumptively total resection were finished, intraoperative magnetic resonance (iMRI)were performed, followed by navigation images updating, and continuing resection if necessary. RESULT: iMRI scan were performed from 1 time to 2 times. In 5 cases with residual seen on iMRI scan, continued resection were carried on in 2 of them. There was no iMRI-associated complications. CONCLUSION: Microscopic-based neuronavigation, in combination with intraoperative magnetic resonance, could provide objective basis for resection, and improve the safety level of tumor resection. PMID- 24800542 TI - [Lingual thyroglossal duct cyst treatment by low temperature coblation on endoscope]. AB - OBJECTIVE: To investigate the treatment for lingual thyroglossal duct cyst by low temperature coblation on endoscope. METHOD: Eleven cases of lingual thyroglossal duct cyst were treated by low temperature coblation on endoscope,to observe the curative effect and complication. RESULT: Eleven cases of lingual thyroglossal duct cyst were satisfied after operation, without serious complication. There were no recurrence during a followed up for 1-3 years after operation. CONCLUSION: The operation for lingual thyroglossal duct cyst by low temperature coblation on endoscope was easy,safe and effective. PMID- 24800543 TI - [The combination of ultrasound and CT evaluate lymph node metastasis of thyroid papillary carcinoma in different compartments]. AB - OBJECTIVE: To evaluate the role of the combination of ultrasound and enhanced CT in analyzing lymph node metastasis in thyroid papillary carcinoma (PTC) patients by compartment. METHOD: Clinical data of 115 cases (141 sides) with PTC were collected. All had undergone ultrasound in neck and enhanced CT both in neck and in mediastinum before surgery. They were divided into ultrasound group. CT group, and the combination of ultrasound and enhanced CT group to evaluate lymph node metastasis. RESULT: For the central compartment, the accuracy of ultrasound was 61.0%. CT was 48.9%, and the combination of ultrasound and CT was 62.4%. For the lateral compartment, ultrasound was 87.9%, CT was 78.7%, the combination of ultrasound and CT was 85.8%. Ultrasound had higher accuracy than CT in the central (P < 0.05) and lateral (P < 0.05) compartment. The combination of ultrasound and CT had higher accuracy than CT in the central compartment (P < 0.05), but there was no significant difference in the lateral compartment (P > 0.05). There was no significant difference in accuracy between ultrasound and the combination of ultrasound and CT neither in central (P > 0.05) nor in lateral (P > 0.05) compartment. Six cases of lymph node metastasis in mediastinum and 1 case in parapharyngeal space detected by CT were pathologically proven. CT found that five patients with pulmonary metastasis. CONCLUSION: The combination of ultrasound and CT or single ultrasound has higher accuracy in preoperative evaluation than single CT for lymph node metastasis in PTC. CT can assess some compartments such as mediastinum which can't be detected by ultrasound, and at the same time to evaluate lung metastasis. To evaluate lymph node metastasis in PTC, the combination of ultrasound and CT is more accurate and considerate than single method. PMID- 24800544 TI - [The expression and clinical significance of OPN and C-met in laryngeal carcinoma]. AB - OBJECTIVE: To investigate the protein expression of OPN and C-met and their relationship with tumorigenesis, invasion and cancer metastasis in laryngeal squamous cell carcinoma (LSCC). METHOD: The expression of OPN and C-met were detected immunohistochemical method(Elivision plus)in 52 laryngeal squamous carcinoma and 30 adjacent tissues, to analyse the relationship between their expression levels and clinical stages, differentiation grades and the metastasis of pelvic lymph nodes. RESULT: The expression of OPN and C-met in laryngeal squamous carcinoma and adjacent tissues were 71.2%, 6.7% and 63.5 %,16.7%, respectively. The positive rate of OPN and C-met with LSCC in stage I-II is 48.1% and 55.6%, and that in 25 cases of stage III-IV is 96.0% and 80.0%, with significant difference among them. The positive rate of OPN is significantly lower in the cases without-metastasis of lymph node (53.6%) than that in the ones with-metastasis of lymph node (91.7%). The positive rate of C-met in the metastasis cases is 83.3%, which is much higher than that in the cases without metastasis (46.4%). The positive rate of OPN and C-met in squamous cell carcinoma with high, medium-grade differentiation is 65.7% and 54.3%, and that in 17 cases of in squamous cell carcinoma with low-grade differentiation is 82.4%. The OPN and C-met positive rate have negative correlations with differentiation grades. CONCLUSION: Expression of OPN and C-met were higher with advance of clinical stages, and it has relation to the metastasis of lymph, but it's difficult to say that there is regular relation between expression of OPN and C-met and differentiation grades. Expression of OPN and C-met have positive correlation in LSCC, and abnormal expression of OPN and C-met have some effect on tumor invasion and metastasis in LSCC patients. PMID- 24800545 TI - [Analysis of epitympanic/antrum cholesteatoma excised by endoscopy and microscope]. AB - OBJECTIVE: Comparison of operation of epitympanic/antrum cholesteatoma excised by endoscopy and microscope. METHOD: Eleven patients with epitympanic/antrum cholesteatoma were analysed, 5 cases were excised by endoscopy and 6 cases were excised under microscope. RESULT: No complication occurred after operation and all patients got dried ear. There were no difference in hearing recovery and closure of perforation of tympanic membrane between two group. The operation time, injury degree, length of stay in hospital and hospitalization expense with endoscopy was superior to that of microscope. CONCLUSION: Considering financial constraints of patients, resection of epitympanic/antrum cholesteatoma cholesteatoma can be adopted by endoscopy. PMID- 24800546 TI - [Gentamicin on inner hair cells ribbon synapses CaV1.3 calcium ion channel protein expression]. AB - OBJECTIVE: To learn the influence the gentamycin on C57BL/6J mice hear and cochlear hair cell ribbon synapses CaV1.3 calcium protein amount. To explore the relationship between hear loss and its dosage correlation change and significance. METHOD: The fixed amino glucoside to C57BL/6J mice was used to make abdominal cavity injection mold every day. The auditory brain-stem response ABR was used to measure the hear of mice in 7th, 14th, 28th after the injection. Immunofluorescence method was used to observe cochlear basement membrane of hair ribbon synapse CaV1.3 calcium channel proteins in the distribution and expression. Inner hair cells synaptic membrane was immune fluorescent tags with CtbP2 and CaV1. 3. RESULT: With the growth of the injected drugs, ABR threshold increased,but all the hair cells and shape had no obvious change. However the amount of hair rib bon synapse CaV1.3 calcium ion channel proteins in the expression had significant differences (P < 0.01). CaV1.3 calcium ion channel proteins increased slightly lower than normal at 7th day, significantly decreased at 14th day, had increased, increased quantity compare with 14th day, but at 28th day after intraperitoneal injection of gentamicin. CONCLUSION: The increasing,decreasing and increasing trend of cochlear hair cells CaV1.3 proteins in the environment of amino glucoside drug toxicity showed that the increase of hair ribbon synapse CaV1.3 proteins may have a compensatory effect on the drug toxicity. With the increase of the drug toxicity effect, this kind of decompensated function could be the listening decline, which may be one of the mechanism of damage to hearing. PMID- 24800547 TI - [RAGE, NF-kappaB, p21 expressions in mouse spiral ganglion cells]. AB - OBJECTIVE: To research advanced glycation end-product receptors (RAGE), NF kappaB, p21 expressions in C57BL/6j mice cochlea spiral ganglion cells(SGC) ,and then to investigate the presbycusis pathogenesis. METHOD: To take C57BL/6J mice:2 month 25,and 10 month 25. Histological sections were observed the SGC. RAGE, NF kappaB, p21 were immunohistochemical in the SGC,with IPP6 to IOD. RESULT: (1) The count SGCs of 10 month-old was obviously decreased comparing to 2 month-old, the count of 2 month SGC is 39 +/- 5, 10 month group is 20 +/- 6, P < 0.01; (2) RAGE, NF-kappaB, p21 expressed in spiral ganglion cell,different place with different age,and the means optical density in the 10 month are higher than the 2 month, respectively. The IOD of RAGE expression in 2 month SGC: 0.179 +/- 0.025, 10 month IOD: 0.308 +/- 0.050; The IOD of NF-kappaB expression in 2 month SGC: 0.181 +/- 0.045, 10 month IOD: 0.335 +/- 0.120; The IOD of p21 expression in 2 month SGC: 0.160 +/- 0.023, 10 month IOD: 0.365 +/- 0.031, compare with 2 group, respectively, P < 0.05, and the difference has statistics sense. CONCLUSION: RAGE,NF-kappaB, p21 expressions are in SGCs and increases with the aging of SGCs, suppose RAGE, NF-kappaB, p21 may participate in the process of presbycusis pathogenesis. PMID- 24800548 TI - [The application of second fixation method in making inner ear cochlea section specimens]. PMID- 24800549 TI - [Four cases of atypical Hunt syndromes involving the vagus nerve]. PMID- 24800550 TI - [Foreign body in parotid gland: a case report]. AB - A 44-year-old male complained recurrent swelling and pain in the left pre auricular mass over 4 years, which aggravated for 4 months. Ultrasonography revealed a mixed mass echo in the left parotid gland. Computed tomography showed an enlarged parotid gland and a 1.5 cm x 0.9 cm low density shadow in the superficial lobe area with strip high-density shadow in the edge. Although the facial nerves of the patient were found adhered to the foreign body during the operation, the foreign body in parotid gland was removed surgically without any injure to them due to facial nerves protection. In conclusion, facial nerves dissection is necessary to avoid the postsurgical facial paralysis in the surgical removal of foreign bodies in parotid gland. PMID- 24800551 TI - [A case of giant cavernous hemangioma of the nasal septum]. AB - To report a case of an adult male with a huge cavernous hemangioma arising from the nasal septum, and the lesion was widely spread to hard palate, sphenoid sinus, ethmoid sinus and right maxillary sinus. After giving embolization, it was completely excised via transnasal endoscopic approach and lateral rhinotomy, histologic examination reported cavernous hemangioma. There was no recurrence at 1 year's follow-up. PMID- 24800552 TI - [Chronic invasive fungal rhinosinusitis complicated with infratemporal fossa fungal infection: 2 cases report]. AB - Two cases of chronic invasive fungal rhinosinusitis were reported. One patient healed while another died with suspicious residual fungal infection. The clinical symptoms of infratemporal fungal infection include maxillofacial pain, with or without fever. Acute or chronic inflammation of soft tissue could be revealed pathologically. Proof of pathogen may not be found in histopathological slice while serological detection may reveal positive evidence. Surgical resection, good drainage and postoperative antifungal therapy could cure or promptly relieve the symptoms of the disease. PMID- 24800553 TI - [A case of malignant melanoma on the left side of the maxillary sinus]. AB - The clinical manifestations of the disease lacked specificity,and the clinical symptoms were nasal obstruction, any blood in snively and slightly swelling pain on face. The neoplasm with unsmooth surface looked taupe and maroon, and was brittle and easy blooding. Paranasal sinus CT:crumbly mass lesion within the shadow filled in the left side of the maxillary sinus,and the sinus stopped up,sinus wall bone was absorpt and thinned, front and rear wall and inner wall bone were boundedness broken off, knuckle partly to the nasal cavity. Direct reinforcement MRI:in addition to the result of paranasal sinus CT,enhance examination found obviously asymmetrical intensify of the focus. The pathological diagnosis of postoperation was malignant melanoma on the left side of the maxillary sinus. PMID- 24800554 TI - [Advances on the anti-tumor and anti-radiation effect of tea polyphenols in nasopharyngeal carcinoma]. AB - NPC is a high incidence of malignant tumors of the head and neck, and is currently used mainly radiotherapy based, supplemented by a comprehensive treatment of chemotherapy, radiotherapy and chemotherapy, which have serious complications and serious impact on the treatment of patients and quality of life. Polyphenols are the main component of tea. Studies have shown that tea polyphenols have a significant anti-tumor effect of im proving the effect of radiotherapy and chemotherapy, reducing radiation damage, reducing conventional chemo therapy drugs IC50 and reducing the complications of chemotherapy. Tea polyphenols in the treatment of nasopharyngeal carcinoma has also made great progress. It has a strong inhibition of nasopharyngeal carcinoma cells, and can greatly reduce the occurrence of xerostomia after radiotherapy, which is of important clinical research value. PMID- 24800555 TI - [Surveillance system after transmission control of schistosomiasis in P.R. China]. AB - Based on the review of status of schistosomiasis transmission and surveillance in P.R. China, this article analyzed the present challenges in the surveillance on schistosomiasis. The focus on schistosomiasis surveillance and the needs for improving surveillance system after the achievement of transmission control of schistosomiasis were explored. PMID- 24800556 TI - [Analysis of schistosomiasis endemic situation in Yunnan Province from 2009 to 2012]. AB - OBJECTIVE: To evaluate the effect of schistosomiasis control in Yunnan Province since achieving the transmission control standards, so as to provide the evidence for formulating the next prevention and control strategy. METHODS: The schistosomiasis epidemic monitoring reports, annual reports, relevant information about Oncomrnelania hupensis snails, and schistosomiasis patient conditions were collected and analyzed for epidemic condition and characteristics of schistosomiasis in Yunnan Province from 2009 to 2012. RESULTS: The various epidemic monitoring indicators all decreased. In 2012, compared with 2009, the prevalence reduced by 33.33% after correction; the number of villages with schistosomiasis patients reduced by 55.56%; the adjusted positive rate of livestock stool tests reduced by 45.45%; the number of villages with infected cow reduced by 42.25%; the actual area with snails reduced by 13.58%; the density of living snails reduced by 25.66%, and no schistosome infected snails were found in 2012. CONCLUSION: There still exist schistosome infections in human and animals in some local areas of Yunnan Province, and it is difficult to achieve the standard of schistosomiasis transmission interrupted in a short period. PMID- 24800557 TI - [Classification and grading of environments with Oncomelania hupensis snails inside embankment of marshland and lake areas]. AB - OBJECTIVE: To classify and grade the environments with Oncomelania hupensis snails inside embankment in marshland and lake areas, so as to improve the work efficiency and realize the systematic management. METHODS: The schistosomiasis endemic area Liaodi and Xiongdi villages in Jiangling County, Hubei Province were selected as the experiment villages, and the environments with snails in the two villages were divided into sections with a length of 500 m, then the snail situation were surveyed by the systematic sampling method with 10 m and 50 m a frame respectively. The environments were classified according to the discovery of infected snails and wild fecal contamination, and the numbers of sites with snails and their areas in different classes were recorded. Meanwhile, the data of sites with infected snails in Jingzhou City during the recent 5 years were collected and graded according to the average density of snails, so as to discuss the correlativity between the grades of environments with snails and the numbers of sites with infected snails and the occurrence rate of frames with snails. RESULTS: There were 1 967 sites with infected snails in Jingzhou City during the recent 5 years, and there was a positive correlation between the grades of environments with snails and the occurrence rate of frames with snails (r(s) = 0.77, P < 0.01), when the grade was 5, the constituent ratio of numbers of sites with infected snails was 3.1%, and when the grade was 2-3, the ratio raised to 56.3%. There were 39 sites with snails in the two villages, the Class 1, 2 and 3 environments included 1, 18 and 20 sites, with the areas of 1080, 51,640 m2 and 41,220 m2, respectively. There were no statistically significant difference between the grades divided by snail survey with 10 m and 50 m a frame ( chi2 = 4.667, P > 0.05), but the time-consuming of the former was 3 times of the latter. CONCLUSIONS: The classification and grading of the environments with snails inside embankment in marshland and lake areas can master the key point of the snail survey. The subsection and setting frames at a suitable distance can save time and manpower, improve work efficiency, as well as understand the distribution of snail status of the environment with snails, which can realize the sort management of the snail environments inside embankment. PMID- 24800558 TI - [Study on shell shape changes of filial generation Oncomelania hupensis snails in Weishan Lake region, Shandong Province]. AB - OBJECTIVE: To explore the shape change characteristics of Oncomelania hupensis snail shell after the snails being passively migrated into Shandong intake area of the South-to-North Water Diversion Project. METHODS: The snails raised on the Dushan island in Weishan Lake region were captured, and 115 the first filial generation snails and 107 the second filial generation ones were selected. The length and width of shells and apertures, and the labial ridge thickness of those snails were measured, the longitudinal rib number of snail spiral was counted, and 107 parental snails were chosen as controls. RESULTS: The labial ridge thickness of the filial generation snail was significantly reduced with the increase of algebras, and the labial ridge thickness among the 3 generations had a significant difference (P < 0.01). Both the length of snail shell and the width of snail apertures were decreased, while the width of snail shell, the length of snail apertures, the multiplication product of snail aperture's length and width and the longitudinal rib number of snail spiral were all increased. CONCLUSION: The body size of Oncomelania snails in Weishan Lake region becomes smaller, and their shells become thinner, which indicates that the environment of the lake region is not suitable for snail breeding, and the snails have natural decay tendency with the extension of time. PMID- 24800559 TI - [Analysis of highly cited schistosomiasis related papers from 2005 to 2012]. AB - OBJECTIVE: To reveal the research focus of schistosomiasis in China through analyzing highly cited schistosomiasis related papers in journals from 2005 to 2012, so as to provide the information for formulating the plan of selecting topics of the editors. METHODS: The published articles related to schistosomiasis in CNKI from 2005 to 2012 were collected, the citation frequency of the papers was calculated according to formula, and the highly cited papers were selected according to the citation frequency. Then the information of highly cited papers including the published time, type, author and author affiliation, citation frequency, journal, grant and research item, research status and development tendency were analyzed. RESULTS: A total of 3 639 published papers related to schistosomiasis were searched and 343 papers (the citation frequency > or = 8) were selected as highly cited papers, and Chinese Journal of Schistosomiasis Control shared 45.19% of them. Among these papers, original articles, reviews and special reports occupied 44.90%, 12.54% and 6.12%, respectively. The first authors of these papers were mainly from centers for disease control and prevention (CDCs) (17.33%), research institutions (22.67%) and colleges/universities (36.00%). Totally 50.44% of the articles received financial supports from research funds/foundations, and most of them were national or provincial funds. The research hotspots focused on epidemiology and prevention, epidemic situation analysis, vaccine, immunologic diagnosis, pharmaceutical research, immunity and infection. CONCLUSIONS: The highly cited papers related to schistosomiasis are mainly from CDCs, institutions and colleges/universities. The research hotspots mainly focus on epidemiology and prevention, vaccine, immunology and pharmaceutical study. The related journals can use this information to chose topic and solicit contributions to improve their influence. PMID- 24800560 TI - [Distribution of univalvia molluscs in area with natural decline of Oncomelania hupensis snails in Eastern Dongting Lake area]. AB - OBJECTIVE: To understand the distribution of univalvia molluscs in Eastern Dongting lake area where the Oncomelania hupensis is extinct, so as to explore the causes of extinction and to provide the evidence for formulating schistosomiasis control strategy. METHODS: The univalvia molluscs of the Qianliang Lake district, Jianxin District and Junshan Park were investigated in August of 2013. All the collected snails were classified and identified. The data were analyzed by using the method of Shapiro-Wilk normality test and non parametric test. The ecological biodiversity differences from each district were compared by the biodiversity indexes. RESULTS: The univalvia molluscs collected were from 6 species in 3 families in Gastropoda class, namely Oncomelania hupensis Gredler in Pomatiopsidae family, Parafossarulus striatulus, Alocinma longicornis, Parafossarulus sineasis, Bithynia fuchsisana in Bithyniidae family, and one genus provisioy nally named Radix in Lymaneidae family. In Junshan Park, a total of 4553 snails were collected, among which 1264 were Oncomelania snails. In Jianxin District, 336 univalvia molluscs were collected, and no Oncomelania snails were found. In Qianliang Lake district, there were only 7 Alocinma longicornis snails, 2 Parafossarulus sinensis snails and 1 Parafossarulus striatulus snail collected. There were significant differences among the distributions of the samples from the three districts (chi2 = 166.225, P < 0.01) .The Simpson's diversity indexes in Qianliang Lake area, Jianxin Dis- trict and Junshan Park were 0.4028, 0.7186 and 0.6788, respectively, and the Shannon-Wiener indexes of the 3 areas were 0.7215, 1.4313 and 1.1999, respectively. CONCLUSIONS: With the extinction of Oncomelania snails, the species and quantities of other snails become rare in Qianliang Lake area. Whether their causes are relevant is worth further studying. PMID- 24800561 TI - [Establishment of malaria early warning system in Jiangsu Province III effect of automatic early warning information system on the response of malaria elimination]. AB - OBJECTIVE: To evaluate the effect of automatic early warning information system on the response of malaria elimination in Jiangsu Province through the operation of the national automatic early warning system of infectious diseases. METHODS: The malaria early warning information was collected from the automatic early warning information subsystem in the national information system for diseases control and prevention. Malaria early warning signals were analyzed from September 1 to December 31, 2012. The statistical analysis was conducted for the completion rates of case investigation within 3 days before and after the application of malaria early warning information system. RESULTS: Jiangsu Province received 85 mobile phone short messages (SMS) of malaria case from early warning system from September 1 to December 31, 2012. After judgments, 23 cases were deleted including 8 repeated cases and 15 cases that were excluded through the microscopy examination and epidemiological investigation by the confirmation of county CDC. From July to December in 2012, the monthly completion rates of case investigation within 3 days were 55.56%, 78.57%, 90.00%, 100%, 100% and 100%, respectively. The completion rates of case investigation within 3 days in July, August, September and October were significantly different by chi2 test ( chi2 = 10.66, P < 0.05). The completion rates of foci investigation and action within 7 days in Jiangsu Province were all 100% from July to December in 2012. CONCLUSIONS: The completion rates of case investigation within 3 days are associated with SMS from the early warning system. The malaria warning system from the national infectious diseases can effectively improve the response to malaria cases for primary CDC. It also plays an important role for the timely confirmation and diagnosis of malaria cases. PMID- 24800562 TI - [Malaria surveillance in Shanghai from 2005 to 2012]. AB - OBJECTIVE: To understand the status of malaria prevalence in Shanghai, so as to provide the evidence for evaluating and promoting malaria elimination. METHODS: The data of population, malaria endemic and monitoring in Shanghai from 2005 to 2012 were collected and analyzed. The malaria positive rates in febrile patients and normal population, the malaria antibody levels of the floating population and location pupils, and the species and density of mosquitoes were investigated and the results were analyzed. RESULTS: The blood examples from 400,177 febrile patients with 0.36% of the total population were examined for malaria, and the annual rates of blood examination varied from 0.15% to 0.83% in the period of 2005 to 2012. Before 2010, the annual blood examination rate was lower than 0.20%, but increased significantly since 2010 because of the implementation of the Action of Malaria Elimination in Shanghai from 2010 to 2020. Totally 604 malaria cases were found and the positive rate of blood examination was 0.15%. During the period of 2006 to 2008, more than 100 malaria cases were found every year, but the number of malaria cases decreased since 2009, and only 26 cases was found in 2012. Since 2011, all the malaria cases have been found infected out of China according to the questionnaire investigation. The malaria positive rate of blood examinations decreased from 0.61% to 0.03% yearly. The proportion of local residents who had the blood examination was 79.02%, but that of the malaria positive in floating population was 83.44%. The active case detection was carried out in 15,759 persons and five cases were found in 2007 and 2008, respectively. The level of malaria antibody was tested in 1 239,440 floating population with the average positive rate of 0.04%. The level of malaria antibody was also tested in 7,065 local pupils but there was no positive for malaria. Only Anopheles sinensis was found in Shanghai suburb, but no other Anopheles mosquitoes were found at the city or towns. The peak of Anopheles den- sity was from the end of July to August. CONCLUSIONS: Malaria surveillance is carried out efficiently in Shanghai, and the result shows Shanghai is in the phase of malaria elimination. The more attention should be paid to persons coming from malaria endemic areas for the malaria blood examination and the general and advanced hospital should maintain the ability of malaria blood examinations simultaneously. PMID- 24800563 TI - [Zoonotic trematode species identified in domestic animals from Huainan area]. AB - OBJECTIVE: To understand the zoonotic trematode species identified in domestic animals from Huainan area, Anhui Province, so as to supply the evidence for the prevention of zoonoses. METHODS: The livestock/definitive hosts were commercially available on category basis, and sacrificed for obtaining the parasitic samples via dissecting the viscera. The specimens were microscopically identified, with reference to the descriptions in the previous literature. RESULTS: By identification, sorting and classification, 41 species of internal trematodes were found so far in the domestic animals fed in Huainan areas, in which 23 species were zoonotic trematodes and 18 were internally parasitic in livestock, belonging to 4 orders, 12 families and 21 genera, and occurred in 9 definitive hosts including chicken, ducks, geese, pigs, cattle, buffaloes, sheep, goats and dogs, respectively. CONCLUSION: The findings suggest that the zoonotic trematodes belong to many kinds and prevalent in the domestic animals in Huainan areas, and such prevalence should call for high attention since it is urgent risk factors for zoonoses in this geographic area. PMID- 24800564 TI - [Establishment of A1E3 and B1C4 monoclonal antibody-based ELISA for detecting circulating antigen of Schistosoma japonicum and its preliminary application]. AB - OBJECTIVE: To establish A1E3 and B1C4 monoclonal antibody-based ELISA for detecting circulating antigen of Schistosoma japonicum and explore its application value in the field. METHODS: The characteristics of A1E3 and B1C4 monoclonal antibodies were analyzed by SDS-PAGE and Western blotting. The SEA based ELISA was used to evaluate the titers of A1E3 and B1C4. The orthogonal test was used to determine the best concentration of coating antibody B1C4 and optimal working concentration of A1E3-HRP. Under the optimal conditions, the serum samples of 20 acute schistosomiasis cases, 46 chronic schistosomiasis cases, and 20 control sera were tested to evaluate its detection sensitivity and specificity. Seventy-two antibody positive serum samples from Jiangling County of Hubei Province were detected and compared to a commercially available ELISA kit, to evaluate the detection effects of this method. RESULTS: The results of SDS PAGE demonstrated that the purified A1E3 and B1C4 contained a clear heavy chain with molecular weight of 88,000 and 52,000 respectively and had the same light chain with molecular weight of 20,000; while Western blotting demonstrated that A1E3 and B1C4 could be recognized by SEA and serum samples of acute schistosomiasis cases. The SEA-based ELISA demonstrated the titers of B1C4 and A1E3 were 1:10(5) and 1:30,000, respectively. The serum samples from all the acute cases and 86.9% of the chronic cases showed a positive reaction. All of the control sera from healthy persons gave a negative response. The positive rates of the double monoclonal antibody ELISA and commercial ELISA for detecting the circulating antigen were 45.8% and 43.1% respectively, and there was no significant difference between the results of the two methods. CONCLUSION: A1E3 and B1C4 monoclonal antibody-based ELISA is established successfully. It exhibits a high sensitivity and specificity in detecting circulating antigen of Schistosoma japonicum. PMID- 24800565 TI - [Construction and identification of pcDNA3-HBsAg-p30-ROP2 expression vector]. AB - OBJECTIVE: To construct a multi-gene recombinant pcDNA3-HBsAg-p30-ROP2 expression vector and identify it preliminarily. METHODS: According to recombinant pcDNA3 p30-ROP2 restriction sites, HBV HBsAg gene sequences of primers were designed and synthesized to amplify target fragment, and then cloned into pcDNA3-HbsAg-p30 ROP2 expression vector. After sequencing, it was identified finally by restriction enzyme digestion and other molecular biology techniques. RESULTS: HBV HBsAg gene segment was amplified by PCR and the multi-gene recombinant pcDNA3 HBsAg-p30-ROP2 expression vector was constructed and identified to be correct as theoretical values. The PCR and restriction enzyme digestion results showed that HBsAg and p30-ROP2 gene in recombinant plasmid were confirmed by DNA sequencing. CONCLUSION: The multi-gene recombinant pcD-NA3-HBsAg-p30-ROP2 expression vector is successfully constructed. PMID- 24800566 TI - [Effect of PvMSP1 on differentiation, maturation and function of dendritic cells]. AB - OBJECTIVE: To investigate the effects of Plasmodium vivax merozoite surface protein 1 (PvMSP1) on differentiation, maturation and function of dendritic cells (DC) and the mechanisms of PvMSP1 on the activation of DC via toll like receptors (TLR). METHODS: DCs were incubated with different doses of PvMSP1 (1.0, 10.0, 100.0 microg/ml) in vitro. The changes of CD83, CD86, and HLA-DR on DC were detected by flow cytometry (FCM); the expressions of cytokine IL-10 and IL-12 of DC were measured by ELISA; the expressions of TLR4 and TLR9 mRNA of DC were measured by RT-PCR; the proliferation induction to autologous lymphocytes of DC was measured by MTT. Meanwhile, the untreated DC and LPS inducing DC were as the negative control and positive control, respectively. All the data were analyzed statistically. RESULTS: Compared with the untreated DC, the proportions of CD83, CD86 and HLA-DR on DC induced by LPS and PvMSP1 increased significantly (all P < 0.05); the expressions of IL-10 and IL-12 of DC induced by LPS increased significantly (P < 0.01), and those induced by PvMSP1 also increased significantly (all P < 0.05). In the LPS inducing group, the TLR4 mRNA production increased (P < 0.05) and the TLR9 mRNA production had no significantly changes (P > 0.05). In the PvMSP1-treated group, the DC TLR4 mRNA production increased (P < 0.01) and the TLR9 mRNA production had no significantly changes (P > 0.05); DC stimulated the proliferation of autologous lymphocytes. CONCLUSION: PvMSP1 enhances DC differentiation and maturation, and the mature DC induced by PvMSPI has the ability of antigen presenting. The route for PvMSP1 inducing DC maturation might be TLR4 pathway rather than TLR9 pathway. PMID- 24800567 TI - [Surveillance of schistosomiasis japonica in potential endemic areas in Hubei Province from 2008 to 2012]. AB - OBJECTIVE: To explore the potential key risk factors of schistosomiasis transmission in potential endemic areas so as to provide the evidence for setting up the prediction and surveillance systems of schistosomiasis outbreak epidemic. METHODS: From 2008 to 2012, fixed and mobile surveillance sites in potential endemic areas of 2 counties in Hubei Province were selected. The immunological assays and stool examinations were carried out to investigate the schistosome infection situation of local people, mobile population and livestock. The distribution of Oncomelania hupensis snails was investigated in risk areas and suspicious areas, and spreading patterns of snails were observed in the rivers that directly connected with the Yangtze River. RESULTS: A total of 6 052 local people aged 6-65 years were screened by IHA immunological tests, and the positive rate of antibody was 1.19% (72/6 052). Totally 72 antibody positives were examined by Kato-Katz technique and there were no positives. A total of 5 004 mobile persons were tested by IHA immunological tests and the positive rate was 1.36% (68/5 004). Totally 68 antibody positives were examined by Kato-Katz technique and there were no positives. Totally 287.07 hm2 potential endemic areas were investigated for Oncomelania snail detection, and no snails were found. The investigation on snail spreading patterns and the surveillance on suspicious circumstances were carried out, with no snails found. CONCLUSIONS: In the schistosomiasis potential endemic areas, some positives of IHA immunological tests are found. Therefore, monitoring is still needed to be strengthened. PMID- 24800568 TI - [Effect of schistosomiasis control projects in Hexi Reservoir on Oncomelania snail control]. AB - OBJECTIVE: To evaluate the effect of schistosomiasis control projects in Hexi Reservoir on Oncomelania hupensis snail control. METHODS: The canal hardening + main water system widening + the overflow dam project, the concrete slope protection, the banking and reclamation + concrete slope protection project, the environment reform project, and the comprehensive treatment were implemented in the tail area, the hydro-fluctuation belt, the rainwater harvesting zoon of the upstream area, the dam area, and the downstream area of the reservoir, respectively. The changes of the snail situation were investigated before and after the construction of the reservoir, and the snail control effects of the schistosomiasis control projects in different parts of the reservoir were analyzed. RESULTS: There were no Oncomelania snails found 3 years in the bottom area, dam area, hydro-fluctuation belt, tail region and downstream of the dam after the construction and storage of the reservoir and the implementation of the schistosomiasis control projects. In the rainwater harvesting zoon of the upstream area, the density of living snails decreased from 0.620 4 snails/0.1 m2 in 2009 to 0.113 2 snails/0.1 m2 in 2013, but the snail area still remained. CONCLUSIONS: The schistosomiasis control projects in Hexi Reservoir have effectively prevented the diffusion of Oncomelania snails from the rainwater harvesting zone of the upstream area to the dam area, and they are effective in the snail control. PMID- 24800569 TI - [Effects of molluscicides at different environments on Oncomelania hupensis snail control in Danyang City]. AB - OBJECTIVE: To evaluate the effects of continuous application of niclosamide ethanolamine salt on Oncomelania hupensis snail control in a marshland, river and channel. METHODS: The Beiwei marshland in Houxiang Town, the Xiaoliang River in Lingkou Town and Laomiao channel in Yunyang Town in Danyang City were selected as study sites, and 4% niclosamide ethanolamine salt and 26% niclosamide powder were used to kill the snails. Based on the historical records and field investigations, the effects of continuous application of niclosamide ethanolamine salt on snail control were evaluated. RESULTS: Compared with the first time of snail repetition, the snail areas decreased by 82.80%, 63.14% and 70.00% in the Beiwei marshland, Xiaoliang River and Laomiao channel, respectively, in 2013. There was a positive correlation between the area and density of snails (r = 0.931, 0.975 and 0.916, respectively; all P values < 0.05). The average densities of living snails decreased significantly by 92.34%, 87.91% and 97.66%, respectively. There was a negative correlation between the corrected mortality of snails and the average density of living snails in the following year, and a negative correlation between the reduction rate of living snail density and the average density of living snails in the following year. CONCLUSION: Molluscicides plays an important role in compressing the snail area, reducing the snail density, and controlling the schistosomiasis transmission. PMID- 24800570 TI - [Correlation between levels of liver fibrosis and liver fibrosis biochemical parameters of advanced schistosomiasis patients]. AB - OBJECTIVE: To explore the correlation between the levels of liver fibrosis and liver fibrosis biochemical parameters of advanced schistosomiasis patients. METHODS: A total of 48 advanced schistosomiasis patients were investigated and they were examined by the liver biopsy and B ultrasound imaging. At the same time, the liver fibrosis biochemical parameters, including glutamine transpeptidase (GGT), alkaline phosphatase (AKP), procollagen III (PC-III), collagen type IV (IV-C), hyaluronic acid (HA) and laminin (LN), were detected. The liver fibrosis levels were classified by the liver biopsy and B ultrasound imaging, respectively, and the correlation between the levels of liver fibrosis and liver fibrosis biochemical parameters were analyzed statistically. RESULTS: There was no correlation between the liver fibrosis levels classified by the liver biopsy and all the liver fibrosis biochemical parameters; there was a weak correlation between the liver fibrosis levels classified by the B ultrasound imaging and GGT, AKP, LN and PC-III, respectively; there was a significant correlation between the liver fibrosis levels classified by the B ultrasound imaging and HA and IV-C, respectively. CONCLUSIONS: B ultrasound examination is a better, noninvasive fibrosis inspection method. Liver fibrosis biochemical parameters combined with the B ultrasound examination may better reflect the overall condition of liver fibrosis. PMID- 24800571 TI - [Experimental observation of toxic effect of Bacillus thuringiensis var. israelensis against Aedes, Culex and Anopheles larvae]. AB - OBJECTIVE: To evaluate the toxic effect of Bacillus thuringiensis var. israelensis (Bti) wettable powder against Aedes, Culex and Anopheles larvae. METHODS: The biological assay was applied to test the lethal concentration of 50% (LC50) of Bti wettable powder against Aedes, Culex and Anopheles larvae. RESULTS: The LC50(s) of Bti wettable powder against Aedes albopictus, Culex pipiens pallens and Anopheles sinensis larvae were 0.104, 0.160 microg/ml and 0.324 microg/ml, respectively; its biological potencies against them were 0.125, 0.192 IU/ml and 0.389 IU/ml, respectively. The LC50(s) of continuous contact of Bti wettable powder with An. sinensis stage III larvae for 1, 2 d and 3 d were 0.324, 0.092 microg/ml and 0.032 microg/ml, respectively, and its biological potencies were 0.389, 0.110 IU/ml and 0.038 IU/ml, respectively. The LC50(s) of the bacteria against An. sinensis stage I , II, III, IV were 0.024, 0.137, 0.324 microg/ml and 0.450 microg/ml, respectively, and the biological potencies were 0.029, 0.164, 0.389 IU/ml and 0.540 IU/ml, respectively. CONCLUSION: Bti wettable powder has a good toxicity to Aedes, Culex and Anopheles larvae, especially for the latter two. It is better to apply the bacteria at the early stage of mosquito larvae. PMID- 24800572 TI - [Evaluation of integrated control measures for soil-transmitted nematodiasis in Jinhu County, Jiangsu Province]. AB - OBJECTIVE: To evaluate the effect of integrated control measures on soil transmitted nematodiasis so as to provide the evidence for formulating the appropriate control strategies and measures in Jinhu County, Jiangsu Province. METHODS: Since 1995, the comprehensive control measures were carried out for soil transmitted nematodiasis, and the measures included deworming, health education, safe water, sanitation and environmental remediation. The effects of the comprehensive control measures were evaluated by the investigations of the prevalence of soil-transmitted nematodiasis, awareness of health knowledge, and behaviors of residents. RESULTS: From 1995 to 2012, 646,437 person--times were administrated in deworming medication with 2.48 times per capita; the benefit rate of safe water was 97.90%; the popularity rate of harmless toilets was 86.89%. The awareness rate of health knowledge increased from 54.05% in 1996 to 95.60% in 2012, the difference between them were statistically significant (chi2 = 230.92, P < 0.01); the rate of correct health behaviors increased from 59.07% in 1996 to 96.40% in 2012, the difference between them had statistical significance (chi2 = 202.69, P < 0.01). The prevalence of soil-transmitted nematodiasis decreased from 62.57% in 1989 to 1.21% in 2012, the difference had statistical significance (chi2 = 1016.92, P < 0.01). The infection rates of Ascaris lumbricodes, hookworm and Trichuris trichiura were 0.58%, 1.12% and 0, respectively in 2012, and compared with the rates of those infections in 1989, the decline rates were 94.96%, 97.28% and 100% respectively, the differences between them were statistically significant (chi2 Ascaris = 129.50, chi2 hookworm = 544.62, chi2 Trichurisch = 254.19, all P < 0.01). CONCLUSION: The comprehensive control strategies and measures are effective and soil-transmitted nematodiasis has been controlled in Jinhu County. PMID- 24800573 TI - [Investigation on awareness status of malaria control knowledge of primary and secondary school students in Shandong Province]. AB - OBJECTIVE: To understand the awareness status of malaria control knowledge of primary and secondary school students in malaria endemic areas of Shandong Province, so as to provide the baseline information for formulating the malaria control strategy. METHODS: A cross-sectional survey was conducted in 5 Type II malaria-endemic counties in Shandong Province. A structured questionnaire survey was administrated to students in primary and secondary schools. RESULTS: A total of 1 884 students were completed with the questionnaires and all were effective. The total awareness rate of malaria control knowledge was 65.9%, and 54.7% of the students knew the transmission route of malaria and only 31.5% of the students were aware of the preventive methods of malaria. There were significant differences of the awareness scores of malaria control knowledge among different malaria endemic areas but there were no significant differences between the awareness rates of male and female students and between two different education levels. CONCLUSIONS: The awareness of malaria control knowledge of primary and secondary school students in Shandong Province is poor; therefore, the health education of malaria control knowledge for primary and secondary school students should be strengthened. PMID- 24800574 TI - [Investigation of prevalence of soil-transmitted nematode infections among Lahu Ethnic residents in Xiaojie Township, Jinghong City, Yunnan Province]. AB - OBJECTIVE: To understand the prevalence of human intestinal parasite infections in Lahu Ethnic residents so as to provide the evidence for effective control. METHODS: The prevalence of soil-transmitted nematode infections in local people was determined by Kato-Katz technique and individual sanitary behaviors and habits were requested by a standardized questionnaire in 3 villages of Xiaojie Township, Jinghong City, Yunnan Province. The relationship between intestinal parasite infections and behavioral characteristics was analyzed. RESULTS: Of 289 subjects, 255 individuals were infected with soil-transmitted nematodes; the prevalence was 88.24%. Among the infected individuals, 210 were found infected with hookworm and the infection rate was 72.66%; 154 subjects were infected with Ascaris lumbricoides and the infection rate was 53.29%; 13 were infected with Trichuris trichura, and the infection rate was 4.50%; 16 were infected with other parasites and the infection rate was 5.54%. The percentages of people with light infection of hookworm, A. lumbricoides and T. trichura were 90.48%, 97.40% and 100%, respectively. CONCLUSIONS: There is high prevalence of soil-transmitted nematode infections in Lahu Ethnic residents in Jinghong City, but the infection intensity was generally low. The control and monitoring of soil-transmitted parasite infections should be strengthened in this area. PMID- 24800575 TI - [Measures of infection source control of schistosomiasis and their effects in four-lake regions of Hubei Province]. AB - OBJECTIVE: To evaluate the effect of a new schistosomiasis control strategy based on the infection source control in four-lake regions of Hubei Province. METHODS: The new strategy based on the infection source control included the safe water supply, feces harmless treatment, replacing cattle with machine, captive livestock, chemotherapy, Oncomelania hupensis snail control in susceptible areas, hardening ditches, etc, and the new control strategy was implemented for 7 years in 9 counties (cities or districts) of the four-lake regions. The schistosomiasis situations were investigated before and after the intervention of the new strategy. RESULTS: The coverage rates of feces harmless toilets (three format toilets), biogas digesters, and safe water supply were 42.00%, 23.16% and 93.76%, respectively. The number of ditch hardening was 1 960; the area of eliminating snails was 1378.42 hm2; the number of persons who received the health education was 3,524,818 accounting for 92.17% of the total population; the number of person time of taking active protection measures was 516,636,963. The average annual decline rates of schistosome infection were 24.42% and 38.38% in residents and cattle, respectively. The endemic villages decreased by 4.77%, the villages with snails decreased by 7.05%, and the villages with snails accounted between 63.19% and 66.21% of the total endemic villages. The area with snails decreased by 90.35%, and the advance schistosomiasis patients decreased by 5.55%, and the fatality rate of advanced schistosomiasis patients decreased by 1.24%. No acute schistosomiasis patients occurred. Type One and Two endemic (heavy endemic) villages decreased to zero; Type Three endemic (moderate endemic) villages decreased by 10.22%; but Type Four endemic (mild endemic) villages increased by 66.38%; and Type Five endemic (no endemic for 5 years) villages decreased by 0.22%. The standards of schistosomiasis transmission controlled have achieved on schedule. CONCLUSION: The implementation of the new schistosomiasis control strategy based on the infection source control in four-lake regions of Hubei Province can effectively control schistosomiasis. PMID- 24800576 TI - [Survey on status of staff for Plasmodium microscopy examinations in Changzhou City]. AB - OBJECTIVE: To understand the current state of staff for Plasmodium microscopy examinations in Changzhou City in the early stage of eliminating malaria action, so as to provide the evidence for achieving the target of malaria elimination. METHODS: The staff for Plasmodium microscopy examinations from medical institutions and centers for disease control and prevention at different levels were investigated by questionnaires and tests of the malaria related theory and microscopic operation. RESULTS: Totally 95 people were investigated, and among them, 40.0% had college degree and 45.3% were university educated. There were 18.9% of them working on Plasmodium microscopy examinations for less than 1 year, 40.0% for 2-5 years, 18.9% for 6-10 years and 22.1% for more than 10 years. The numbers of person-time of provincial and municipal level training, district-level training, and unit-level training in the last year were 0.57, 0.59, and 0.14, respectively. Totally 18.9% of them had the experience of finding Plasmodium at work, and 97.9% of them considered it was necessary or very necessary to do Plasmodium microscopy examinations. However, 57.9% and 8.4% of them considered Plasmodium microscopy examinations increased their work load and work difficulty, respectively. The average correct rates of knowledge tests on malaria before and after training were 72.5% and 91.6% respectively (P < 0.05). The average mark of Plasmodium microscopic tests was 25.3 points (full mark being 50 points), and the passing rate (> or = 30 points) was 58.9%. CONCLUSION: The working experience of staff for Plasmodium microscopy examinations in Changzhou City is relatively poor, and the related training should be enhanced. PMID- 24800577 TI - [Progress of research on parasitic adaptability of schistosome and its application value]. AB - The larval and adult schistosomes can effectively establish the stable parasitic relationship with their final hosts and then maintain the parasitism for a long time, due to the successful adaptation to their parasitic lifestyle. This paper reviews the progress of research on parasitic adaptability of schistosomes in several respects, and demonstrates the application value of schistosomal genes related to parasitic adaptability in schistosomiasis control and exploitation of natural active molecules. PMID- 24800578 TI - [Research progress of molecular genetic analysis in Schistosoma variation]. AB - The development of molecular biology techniques makes important contributions to the researches of heritable variation of Schistosoma. In recent years, the molecular genetic analysis in the Schistosoma variation researches mainly includes the restriction fragment length polymorphism (RFLP), random amplified polymorphism technology (RAPD), microsatellite anchored PCR (SSR-PCR), and polymerase reaction single-strand conformation polymorphism (PCR-SSCP). This article reviews the research progress of molecular genetic analysis in Schistosoma variation in recent years. PMID- 24800579 TI - [Assessment of risk factors of schistosomiasis transmission control in Jingzhou City]. AB - OBJECTIVE: To understand the key risk factors of schistosomiasis transmission in Jingzhou City, so as to provide the evidence for improving the treatment of these risk factors. METHODS: Each village of six counties was investigated and 3 environments were surveyed each village for the distribution of Oncomelania snails and animal stools in the field. The results were analyzed and the risk factors of schistosomiasis transmission were assessed. RESULTS: The density of living snails was 0.43 snails per 0.1 m2, the frequency of the frames with snails was 9.12%, and no schistosome infected snails were found. All of the animal stools collected from the field were from bovines. The schistosome positive rate of animal stools was 37.50% (3/8) among the environments, and the schistosome infection rate of stools was 8.11% (3/37). The schistosome infection rate of animal stools was 0 near the residence living sites, and the positive rates were 12.50% and 8.33% in the ditches and slopes, respectively (chi2 = 0.07, P > 0.05). CONCLUSIONS: Bovine is still the main infectious source of schistosomiasis, i.e. the main risk factor of the disease transmission. Therefore, the strategy of controlling bovine should be strengthened. PMID- 24800580 TI - [Analysis of endemic situation of schistosomiasis in Yugan County of Jiangxi Province in 2012]. AB - OBJECTIVE: To master the epidemic situation and control effect of schistosomiasis in Yugan County, Jiangxi Province. METHODS: The data of the schistosomiasis prevalence in human and cattle as well as Oncomelania hupensis snail status were collected and the change trends were analyzed in Yugan County from 2008 to 2012. RESULTS: The schistosome infection rates of residents in Yugan County have declined every year since 2008, and currently, the prevalence of schistosomiasis was at a low level. No acute schistosomiasis case was found during the past 5 years. In 2012, the infection rate of bovine was above 1% in 88 endemic villages, and the area with schistosome infected snails was 10 hm2. CONCLUSION: In order to achieve the goal of schistosomiasis transmission control in the whole county in 2015, the comprehensive control measures based on infection source control should be strengthened. PMID- 24800581 TI - [A manufacture method of schistosomiasis epidemic maps based on Google Earth]. AB - OBJECTIVE: To make various schistosomiasis epidemic maps based on Google Earth. METHODS: The various elements for schistosomiasis epidemic maps were marked in the Google Earth platform by adding the place mark, path, polygon, overlay and so on. RESULTS: Various schistosomiasis epidemic maps were produced and saved, such as the schistosomiasis epidemic area map of the city, the map of Oncomelania hupensis snail distribution in the town, and the schematic map of snail environments. CONCLUSION: The schistosomiasis epidemic maps based on Google Earth are clear and visual. The production process is very simple and easy to learn. It is suitable for the use in the grass-root schistosomiasis control stations. PMID- 24800582 TI - [Effects of adjusting doses of diuretics at different time in treatment of advanced schistosomiasis ascites]. AB - OBJECTIVE: To investigate the efficacy and safety of adjusting the doses of diuretics of different time in the treatment of advanced schistosomiasis ascites. METHODS: A total of 80 advanced schistosomiasis patients with ascites were randomly divided into an observation group and a control group (40 cases each). The patients in the observation group received spironolactone and furosemide, and the first doses were 100 mg/d and 40 mg/d, respectively. If the efficacy was poor, according to the first doses of the standard increments once every four days, the doses gradually increased to the maximum doses of spironolactone 400 mg/d and furosemide 160 mg/d, respectively. The patients in the control group received spironolactone and furosemide, and the first doses were the same as those of the observation group. If the efficacy was poor, according to the first doses of the standard increments once every seven days, the doses gradually increased to the maximum doses as those of the observation group. Other conventional treatments were the same in both groups. RESULTS: In both groups, the reductions of the total amount of the weight were (5.62 +/- 1.28) kg and (5.42 +/- 1.37) kg respectively; the time of efficacy beginning was (3.84 +/- 2.36) days and (4.65 +/- 2.86) days respectively; the average daily amounts of weight loss were (0.41 +/- 0.16) kg and (0.35 +/- 0.11) kg respectively; the efficient rates were 95% and 92.5% respectively; and there were no significant differences between the two group(all P > 0.05). However, the time of reduction from moderate ascites to mild ascites was (10.70 +/- 3.01) days (6-20 days) in the observation group and the time was (14.75 +/- 5.62) days (7-30 days) in the control group (u = 3.876, P < 0.01). CONCLUSION: The therapy of diuretic doses adjusted by a four-day cycle is more useful for advanced schistosomiasis patients with ascites. PMID- 24800583 TI - [Operation for postoperative re-hemorrhage after splenectomy with periesophagogastric devascularization for advanced schistosomiasis]. AB - OBJECTIVE: To evaluate the efficacy of the operation in the treatment of postoperative re-hemorrhage after splenectomy with periesophagogastric devascularization for advanced schistosomiasis. METHODS: Forty-three re hemorrhage patients, who received varicose ligation combined with pericardial devascularization through left thoracic cavity with esophageal incision from October 2002 to October 2011, after splenectomy with periesophagogastric devascularization due to portal vein hypertension, were investigated retrospectively and followed up for 1 to 9 years. RESULTS: Forty-three re hemorrhage patients operated included 27 cases of selective operation and 16 cases of emergency operation. The mean follow-up time was 6.8 years. The hemostasis rate was 100%. One died after the operation because of engaging in heavy labor, two had melena and were completely relived with the conservative treatment, and all the rest had a good recovery. CONCLUSION: The operation of varicose ligation combined with pericardial devascularization through left thoracic cavity with esophageal incision in the treatment of postoperative re hemorrhage after splenectomy with periesophagogastric devascularization for advanced schistosomiasis has a satisfied efficacy. PMID- 24800584 TI - [Long-term therapeutic effect of Ruangan pills on advanced schistosomiasis patients with ascites]. AB - OBJECTIVE: To evaluate the long-term therapeutic effect of Ruangan pills on advanced schistosomiasis combined with ascites. METHODS: The data of 54 advanced schistosomiasis patients with ascites were collected, and the patients were divided into two groups namely a treatment group and a control group according to whether taking Ruangan pills. The effective rates, improvement status of symptoms and levels of serum albumin (ALB) and hyaluronic acid (HA) of the two groups were compared. RESULTS: The effective rates of the treatment group and control group were 92.59% and 44.44%, respectively, and the difference between them was statistically significant (P < 0.05). After the treatment for 9 and 12 months, the percentages of patients without ascites and patients with symptom improvement in the treatment group were 77.78% and 92.59%, 92.59% and 96.30%, respectively, while those in the control group were 29.63% and 37.00%, 48.15% and 51.85%, respectively, and the differences between the two groups by different time were all statistical significant (all P < 0.05). After the treatment for 9 months, the percentages of patients with the normal levels of ALB and HA were 88.89% and 59.26%, while those in the control group were 40.74% and 14.81%, respectively, and the differences between the two groups were statistically significant (both P < 0.05). CONCLUSION: The long-term treatment of Ruangan pills can not only improve clinical symptoms but also control the ascites recurrence, however, the therapeutic effect and the recurrence rate of ascites in longer-term still need further observation. PMID- 24800585 TI - [Comparison between albendazole and triclabendazole against Fasciola gigantica in human]. AB - OBJECTIVE: To compare the anthelmintic effect of albendazole with that of triclabendazole against Fasciola gigantica. METHODS: Two patients infected with Fasciola gigantica were investigated, and one was administered with albendazole orally (200 mg, twice per day for 5 days) and another was administered with triclabendazole [10 mg/(kg x d) for 2 days]. Their total feces were collected daily during the period of whole therapy, and the eggs of the parasite were collected by using the nylon bag method, and incubated at 28 degrees C. RESULTS: The parasite eggs were detected from the first patient's dejecta on the 1st, 2nd and 5th day after the end of the treatment, and no miracidiums hatched out as well as no eggs developed during the period of 25 days of the incubation. Meanwhile, her body temperature fluctuated between 37.4 degrees C and 38.3 degrees C, and she still complained bellyache. For the other invalid, the eggs were not detected on the 2nd and 5th day after the end of the treatment. However, the eggs before and during the treatment developed the miracidiums of Fasciola gigantica on the 13th day after the incubation, but the eggs collected from the 1st day after the termination of the therapy did not develop and no miracidiums hatched out. At the same time, the signs and symptoms of the patient vanished after the 4th day of the end of the therapy. CONCLUSIONS: Albendazole has no obvious insecticidal activity on adult Fasciola gigantica in the short term, but may affect the development of eggs. Triclabendazole has the anthelmintic effect on the adults as well as eggs of Fasciola gigantica. In addition, triclabendazole has the characteristics of well curative effect, short course of treatment, and no obvious side effects. PMID- 24800586 TI - [Efficiency of three methods for detecting Toxoplasma IgG antibody]. AB - OBJECTIVE: To discuss the test efficiency of three methods for detecting Toxoplasma IgG antibody. METHODS: Totally 304 specimens were detected parallelly for Toxoplasma IgG antibody by using the gold marked method, indirect hemagglutination test (IHA), and enzyme-linked immunosorbent assay (ELISA), and the sensitivity, specificity and Youden index of these methods were compared. RESULTS: The detection sensitivities of gold marked method, IHA, and ELISA for Toxoplasma IgG antibody were 85.5%, 89.8% and 91.9% respectively (chi2 = 4.12, P > 0.05); the specificities were 92.4%, 96.6% and 97.5% respectively (chi2 = 4.06, P > 0.05). The detection efficiency and Youden index of ELISA were 94.1% and 0.89 respectively, being higher than those of IHA and gold marked method. CONCLUSION: The sensitivity and specificity of the ELISA method for Toxoplasma IgG antibody are higher, and in addition, it can be automated. Therefore, it is suitable for large-scale Toxoplasma IgG antibody screening. PMID- 24800587 TI - [Schistosomiasis haematobia misdiagnosed as urinary trace infection: one case report]. AB - This paper reports one case of schistosomiasis haematobia that was misdiagnosed as urinary tract infection. It suggests that epidemiological data should be considered in the diagnosis and treatment of the patients with urinary tract infection symptoms coming back from Africa to avoid misdiagnosis. PMID- 24800588 TI - [Evaluation of Romanian medical journals--where to go?]. PMID- 24800589 TI - [The updated Gold 2014 confirms new combinations]. PMID- 24800590 TI - [Aspects of TB endemia in Romania and the response of the National Programme for Prevention, Surveillance and Control of Tuberculosis]. AB - In Romania, tuberculosis is a major public health problem. Consistent with the remarkable improvement of success rate in bacteriological confirmed cases from 51% in 1995 to 85.8% in 2011, the global incidence of the disease fell from a maximum of 142.2 per hundred thousand in 2002 to 73.3 per hundred thousand in 2013. The endemia attenuation (so far from historically low in 1985) is highlighted also by the incidence in children and mortality rates. In MDR/XDR TB disease, the situation is significantly different. Although, the endemia intensity is low (500 incident cases and 1,500 prevalent cases) the therapeutic impact is minimum, as demonstrated by the analysis of outcomes. The success rate in the range of 20% is unacceptable in a context of significant issues of legislation and procedures deficiency, with an insufficient funding in which a far too large role returns to external programs, unpredictable and limited as objectives and duration. PMID- 24800592 TI - [The Montgomery tracheal prosthesis: actual solution for tracheal stenosis]. AB - Tracheal stenosis is a disorder which is very difficult to diagnose in its early stages. Most cases are reffered to the hospital with an obstruction of at least 50% of the tracheal lumen, when dyspnea is already symptomatic. The cases with obstructive phenomena of over 70% represent immediately endoscopic emergencies, due to the risk of decompensation by adding the obstruction secondary to tracheo bronchial secretions and bleeding. Initial management of a compromised central airway by endoscopic technique allows to obtain optimal conditions for the curative treatment. The main cause is malignancy and the for treatment are used endoscopic techniques with palliative visa. After restoring the permeability of the affected airways, stenting is mandatory to keep them open. Among the first stents invented, there was Montgomery type in 1965. Besides the silicon stent, there are the newest type, metallic or hybrid, which try to compensate disadvantages of silicone type, but with significant financial costs. Though Montgomery stent appeared more than 50 years ago, they are still used with good results, with clear advantages, especially in low incomes public health systems. The paper presents technical data, indications, advantages, disadvantages and techniques for effective placement. It also presents a well-documented clinical case of effective placement of a tracheal stent, with video-documentation of the whole procedure performed by a mix team: endoscopist and surgeon. PMID- 24800591 TI - [New advances in the management and treatment of cystic fibrosis]. AB - Cystic fibrosis represented and continue to represent either for the system and for the practitioner a serious challenge through the severe manifestations of disease, progressive mainly in the lung, through the progres in the management registrated in the last time for fighting lung infections such as Pseudomonas aeruginosa, in understanding of genetic condition, new ways of administration of antibiotics and the problems posed by today transition of these patients from pediatrician to the pulmonologist, infectious disease specialist, rehabilitation specialist etc. There have been noted extensions of survival and improvement of diagnostic rate. Today in France in the Caucasian population, there were 6,000 cases with this common disease, of which half were adults (> 18 years). I'll review a number of novelties reported last year connected to this disease adding recent signals received after the congress organized by the North American Cystic Fibrosis Foundation in October 2013 in North Lake City that maybe in the future will extend the duration of survival of these patients. PMID- 24800593 TI - Alpha-1 antitrypsin deficiency and spontaneous pneumothorax: possible causal relationship. AB - BACKGROUND: An increased incidence of serum alpha-1 antitrypsin deficiency has been reported in patients with chronic obstructive pulmonary disease, but has not been well proven in association with spontaneous pneumothorax. The aim of our study was to evaluate frequency of alpha-1 antitrypsin deficiency in subjects with spontaneous pneumothorax. METHODS: 39 patients with the diagnosis of spontaneous pneumothorax and 100 age- and sex-matched control subjects were included in the study. Alpha-1 antitrypsin concentrations were determined by nephelometry, Serum qualitative Z antitrypsin variant was analyzed using commercial ELISA kits and alpha-1 antitrypsin phenotyping was carried out by means of isoelectric focusing. RESULTS: AAT deficiency phenotypes were detected in 3 (7.7%) patients with spontaneous pneumothorax, and only in 1 (1%) case in the control group. However, the observed differences did not reach statistical significance due to the considerable size disproportion between groups. The mean serum alpha-1 antitrypsin level was significantly higher in patients with spontaneous pneumothorax (1.53 +/- 0.23 g/l) than controls (1.34 +/- 0.37 g/l) (p = 0.03). CONCLUSIONS: Preliminary data confirm the clinical importance of alpha-1 antitrypsin deficiency phenotypes in patients with spontaneous pneumothorax and the need to screen them for alpha1-antitrypsin deficiency. PMID- 24800594 TI - Obstructive sleep apnea syndrome and arterial hypertension--a complicated relationship? The role of controlling blood pressure values in patients with OSAS. AB - BACKGROUND: Arterial hypertension (HT) and obstructive sleep apnea syndrome (OSAS) are associated through cause-effect relationship. We aimed to study the effect of medication controlled hypertension on OSAS patients. METHODS: From 483 followed patients with OSAS, 252 associating HT; 142 patients of them (56.34%) received antihypertensive medication, 59 patients (41.54%) had controlled HT, 83 patients (58.46%) had uncontrolled HT. Demographic and anthropometric data, OSAS symptoms, comorbidities, apnea index (IA), apnea-hypopnea index (IAH), desaturation index, CPAP titration, CPAP failure rate were studiated regarding differences between patients with controlled and uncontrolled HT. RESULTS: Fifty nine patients with controlled HT were: 20 women (33.9%), 39 men (66.1%), with mean age of 56.08 years +/- 11.33, with an average AHI of 53.61 +/- 34.42/hour, an average of CPAP pressure prediction of 10.15 +/- 243 cm H2O. Eighty three patients with uncontrolled HT were: 18 women (21.7%), 65 men (78.3%), with mean age 55 +/- 9.06 years, with an average AHl of 61.91 +/- 43.61/hour, an average of CPAP pressure prediction of 10.47 +/- 2cm H2O. Comparing with the controlled HT group, patients with uncontrolled HT reported morning headaches, morning fatigue and impotency in a higher rate (p = 0.020, 0.018, 0.011 respectively); Epworth Sleepiness Scale was under 10 (cut-off for daytime sleepiness) in patients with controlled HT(p = 0.001) and higher in those with uncontrolled HT. Patients with uncontrolled HT were diagnosed with HT for a longer period (p = 0.006), had higher values of systolic and diastolic blood pressure at the time of the presentation. Statistically significant differences were found only for AHI post CPAP (11.89/h vs. 22.30/h, p = 0.013) and nocturnal desaturation index post-CPAP (6.03/h vs. 16.55/h, p = 0.017), both higher in patients with uncontrolled HT. The hypothesis regarding existing differences related to the cardiovascular comorbidities was not supported. CONCLUSIONS: Controlled blood pressure deletes sleepiness, a defining symptom for OSAS and reduces remaining symptoms (headaches, impotency and morning fatigue). Presence of OSAS symptoms is less common in the controlled HT group, making the OSAS more difficult to suspect. These patients may have a grater benefit from CPAP therapy--they have AHI post CPAP and desaturations post-CPAP significantly lower than patients with uncontrolled HT. PMID- 24800595 TI - Features of severe asthma in young children from Romania. AB - Asthma is the most frequent chronic disease of childhood. In spite of significant improvement of treatment options and diagnostic tools, asthma remains in many patients uncontrolled. The term of "severe asthma" seems to be rather a large umbrella for a heterogeneous group of diseases. This paper is presenting our experience in two respiratory disease clinics that evaluate asthmatic children. Current study was designed to test an algorithm for daily practice in a special group of patients: children with previously diagnosed asthma or recurrent wheezing, evaluated by family physician or pediatrician as severe disease ("Asthma Decalogue in Children"). Out of 313 referrals (during a six months inclusion time) we had 202 children completing study per-protocol. 49 (22.69%) had severe disease, but only 8 had severe asthma (3.7% of total patients and 18.6% of severe patients). They were older, with less male predominance and with more frequent rhino-conjunctivitis and D vitamin deficiency than other asthmatic children with less severe disease. Asthma Decalogue in Children seems to be an efficient tool to differentiate severe asthma from the rest of children with reactive airway diseases. PMID- 24800596 TI - Paradoxical arterial hypoxemia in a left-to-right shunt congenital heart disease. AB - The hepatopulmonary syndrome is a rare complication of different types of chronic hepatic diseases with associated portal venous hypertension, resulting in pulmonary vascular dilatation, predominantly in the lower lung fields, and leading to ventilation-perfusion mismatch, arterial hypoxemia and a poor prognosis. We present the case of 42-year-old male patient with an anomalous drainage of the right superior pulmonary vein into the azygos vein and a portal vein cavernomatosis with associated portal venous hypertension who presented severe oxygen desaturation, during exercise, in the context of a hepatopulmonary syndrome. PMID- 24800597 TI - [Delayed diagnosis in a case of granulomatosis with polyangiitis (Wegener's) with initial predominance of joint involvement]. AB - The authors present the case of a 53-year-old female, initially admitted in a rheumatology department for fever and diffuse arthritis--being diagnosed with sero-positive rheumathoid arthritis. Although the chest X-ray and CT scan of thorax showed several abnormal features (medium lobe atelectasis, pseudo-cyst in the posterior segment of the right upper lobe with satellite milliary nodules, mediastinal lymph node enlargement), the investigations performed in our pneumology department couldn't establish the etiology of radiological abnormalities. With non-steroidal antiinflamatory treatment, the patient got worse, being readmitted in our hospital after 3 months for high fever, diffuse arthralgia with functional impairment, small hemoptysis, loss of hearing and left ear ache and on chest X-ray with bilateral macronodules, some of these with cavitation. The investigations showed a slight alveolar hemorrhagic syndrome, positive cANCA antibodies, negative antiCCP antibodies--the diagnosis of Wegener's granulomatosis with lung and ENT involvement being established. Puls therapy with Solumedrol and i.v. Cyclophosphamide was thereafter initiated with a favorable evolution. This case is special because of the initial misdiagnosis due to the atypical pulmonary manifestations and the non-specific paraclinical findings, in the context of diffuse arthritis with positive rheumatoid factor. PMID- 24800598 TI - [The new directive on tobacco products: "(a Battle) ended, (Battle) is just beginning"!]. AB - As tobacco products are sold in all the 28 member states of the European Union, they are subject of regulation of the internal common market. Thus, the Directive 2001/37/EC lays down rules at Union level concerning the manufacture, presentation and sale of tobacco products. In order to reflect scientific, market and international developments, substantial changes have to be made and the Directive was replaced by a new Directive. The process has begun in 2009 and was finished in December 2013, with a political agreement regarding the new provisions. The final vote in the European Parliament (expected for February 2014) will mark the end of a long and difficult legislative process. The article presents the main changes of the regulation of tobacco products from the point of view of health professionals, closer to their expectations and understandings. The complete text in Romanian and English language of the new directive will be available on: www.stopfumat.eu. PMID- 24800599 TI - [A new conference with international participation--a unique opportunity to discuss the novelties in bronchology. Romania, Cluj-Napoca, November,15-16, 2013]. PMID- 24800600 TI - [The 6th National Conference of the Tabacology Section of the Romanian Society of Pneumology. Pitesti, November 21-23, 2013]. PMID- 24800601 TI - Alarmed by West Virginia's ordeal. PMID- 24800602 TI - High risk on the rig. PMID- 24800603 TI - Make no haste in PPE selection for waste workers. PMID- 24800604 TI - Walking the walk on occupational foot protection. PMID- 24800605 TI - Essential training for childcare workers. PMID- 24800606 TI - Keeping pathogens out of the workplace. PMID- 24800607 TI - Is data the 'king' of your gas detection program? PMID- 24800608 TI - Be prepared: five potential welding safety hazards to avoid. PMID- 24800609 TI - Incorporating rescue into a fall protection plan. PMID- 24800610 TI - To delegate or not to delegate safety? PMID- 24800611 TI - The voyage of the leader-hero. PMID- 24800612 TI - President's message--there is no finish line. PMID- 24800613 TI - Appealing to the next generation of nurses. PMID- 24800614 TI - Candidate profile: Gale Adcock. PMID- 24800615 TI - Candidate profile: Brenda Cleary. PMID- 24800622 TI - Superior Potential of CD34-Positive Cells Compared to Total Mononuclear Cells for Healing of Nonunion Following Bone Fracture. AB - We recently demonstrated that the local transplantation of human peripheral blood (PB) CD34(+) cells, an endothelial/hematopoietic progenitor cell-rich population, contributes to fracture repair via vasculogenesis/angiogenesis and osteogenesis. Human PB mononuclear cells (MNCs) are also considered a potential cell fraction for neovascularization. We have previously shown the feasibility of human PB MNCs to enhance fracture healing. However, there is no report directly comparing the efficacy for fracture repair between CD34(+) cells and MNCs. In addition, an unhealing fracture model, which does not accurately resemble a clinical setting, was used in our previous studies. To overcome these issues, we compared the capacity of human granulocyte colony-stimulating factor-mobilized PB (GM-PB) CD34(+) cells and human GM-PB MNCs in a nonunion model, which more closely resembles a clinical setting. First, the effect of local transplantation of 1 * 10(5) GM-PB CD34(+) cells (CD34(+) group), 1 * 10(7) GM-PB MNCs (containing approximately 1 * 10(5) GM-PB CD34(+) cells) (MNC group), and phosphate-buffered saline (PBS) (PBS group) on nonunion healing was compared. Similar augmentation of blood flow recovery at perinonunion sites was observed in the CD34(+) and MNC groups. Meanwhile, a superior effect on nonunion repair was revealed by radiological, histological, and functional assessment in the CD34(+) group compared with the other groups. Moreover, through in vivo and in vitro experiments, excessive inflammation induced by GM-PB MNCs was confirmed and believed to be one of the mechanisms underlying this potency difference. These results strongly suggest that local transplantation of GM-PB CD34(+) cells is a practical and effective strategy for treatment of nonunion after fracture. PMID- 24800623 TI - Large increase in arthroscopic meniscus surgery in the middle-aged and older population in Denmark from 2000 to 2011. AB - BACKGROUND: Arthroscopic meniscal surgery is the most common orthopedic procedure, and the incidence has increased in Denmark over the last 10 years. Concomitantly, several randomized controlled trials have shown no benefit of arthroscopic procedures including arthroscopic partial meniscectomy in middle aged and older individuals suffering from knee pain with or without knee osteoarthritis. We examined the annual incidence of meniscal procedures together with age, sex, and diagnosis for patients who underwent meniscal procedures in the period 2000-2011 in Denmark. METHODS: Data on age, sex, diagnosis, and surgical procedures were extracted from the Danish National Patient Register for the years 2000-2011, for all records containing meniscal surgery as a primary or secondary procedure. RESULTS: The overall annual incidence of meniscal procedures per 100,000 persons in Denmark doubled from 164 in 2000 to 312 in 2011 (i.e. 8,750 procedures to 17,368 procedures). A 2-fold increase was found for patients aged between 35 and 55, and a 3-fold increase was found for those older than 55. Middle-aged and older patients accounted for 75% of all 151,228 meniscal procedures carried out between 2000 and 2011. INTERPRETATION: The incidence of meniscal procedures performed in Denmark doubled from 2000 to 2011, with the largest increase in middle-aged and older patients. This increase contrasts with the mounting evidence showing no added benefit of arthroscopic partial meniscectomy over non-surgical treatments. Our observations illustrate the long delay in the dissemination, acceptance, and implementation of research evidence into the practice of arthroscopic surgery. PMID- 24800624 TI - Maternal alcohol consumption during pregnancy and the risk of orofacial clefts in infants: a systematic review and meta-analysis. AB - BACKGROUND: The teratogenic effects of maternal alcohol consumption during pregnancy include anomalies of craniofacial structures derived from the cranial neural crest cells. The presence of specific craniofacial anomalies contributes to the diagnosis of fetal alcohol spectrum disorders. Cleft lip and palate [orofacial clefts (OFCs)], also derived from the cranial neural crest cells, are common congenital anomalies, but their relationship with prenatal alcohol consumption is unknown. METHODS: To evaluate the association between maternal consumption of alcohol during pregnancy and the occurrence of OFCs in infants, we conducted a systematic review and meta-analyses of published studies. We examined the associations between any alcohol consumption, binge level drinking, and heavy and moderate levels of consumption vs. no or low levels of consumption. RESULTS: After screening 737 publications, we identified 33 studies (23 case-control and 10 cohort studies). There was considerable heterogeneity in individual study design, quality measures and study results. Findings from random effects meta analyses suggest no relationship between prenatal alcohol consumption and the occurrence of OFCs {pooled odds ratios for any alcohol intake and binge level drinking respectively: cleft lip with or without cleft palate 1.00 [95% confidence interval (CI) 0.86, 1.16] from 18,349 participants in 13 studies, 1.04 [95% CI 0.87, 1.24] [8763 individuals, 4 studies]; cleft palate only 1.05 [95% CI 0.92, 1.21] [21,459 individuals, 17 studies], 0.94 [95% CI 0.74, 1.21] [7730 participants, 4 studies]}. CONCLUSIONS: While we found no association between alcohol consumption during pregnancy and OFCs in infants, the influence of study design, particularly in relation to alcohol exposure measurement and OFC ascertainment cannot be ignored. PMID- 24800625 TI - Special issue of IJMI on the art and science of ICT implementation. PMID- 24800626 TI - Identification of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as novel inhibitors of Chikungunya virus replication. AB - Chikungunya virus (CHIKV) is a re-emerging Alphavirus that is transmitted to humans by Aedes mosquitoes. Currently, there are still no drugs or vaccines available for the treatment or prevention of this disease. Although traditionally restricted to Africa and Asia, the adaptation of the virus to Aedes albopictus, a mosquito species with an almost worldwide distribution, has contributed to the geographical spread of this virus in the past decade. Here, we report on a new family of compounds named [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones that inhibit CHIKV replication in the low micromolar range with no toxicity to the host (Vero) cells. The most potent compound in this series has an EC50 value below 1 MUM with no cytotoxicity detected up to 668 MUM, therefore affording a selectivity index greater than 600. Interestingly, the compounds have little or no antiviral activity on the replication of other members of the Togaviridae family. The exploration and study of this class of selective inhibitors of CHIKV replication will contribute to deeper insights into the CHIKV life cycle and may be a first step toward the development of a clinical drug candidate. PMID- 24800627 TI - Fine neural tuning for orthographic properties of words emerges early in children reading alphabetic script. AB - The left-lateralized N170 component of ERPs for words compared with various control stimuli is considered as an electrophysiological manifestation of visual expertise for written words. To understand the information sensitivity of the effect, researchers distinguish between coarse tuning for words (the N170 amplitude difference between words and symbol strings) and fine tuning for words (the N170 amplitude difference between words and consonant strings). Earlier developmental ERP studies demonstrated that the coarse tuning for words occurred early in children (8 years old), whereas the fine tuning for words emerged much later (10 years old). Given that there are large individual differences in reading ability in young children, these tuning effects may emerge earlier than expected in some children. This study measured N170 responses to words and control stimuli in a large group of 7-year-olds that varied widely in reading ability. In both low and high reading ability groups, we observed the coarse neural tuning for words. More interestingly, we found that a stronger N170 for words than consonant strings emerged in children with high but not low reading ability. Our study demonstrates for the first time that fine neural tuning for orthographic properties of words can be observed in young children with high reading ability, suggesting that the emergent age of this effect is much earlier than previously assumed. The modulation of this effect by reading ability suggests that fine tuning is flexible and highly related to experience. Moreover, we found a correlation between this tuning effect at left occipitotemporal electrodes and children's reading ability, suggesting that the fine tuning might be a biomarker of reading skills at the very beginning of learning to read. PMID- 24800628 TI - Metaphorical sentences are more emotionally engaging than their literal counterparts. AB - Why do people so often use metaphorical expressions when literal paraphrases are readily available? This study focuses on a comparison of metaphorical statements involving the source domain of taste (e.g., "She looked at him sweetly") and their literal paraphrases (e.g., "She looked at him kindly"). Metaphorical and literal sentences differed only in one word and were normed for length, familiarity, imageability, emotional valence, and arousal. Our findings indicate that conventional metaphorical expressions are more emotionally evocative than literal expressions, as the amygdala and the anterior portion of the hippocampus were more active in the metaphorical sentences. They also support the idea that even conventional metaphors can be grounded in sensorimotor and perceptual representations in that primary and secondary gustatory areas (lateral OFC, frontal operculum, anterior insula) were more active as well. A comparison of the individual words that distinguished the metaphorical and literal sentences revealed greater activation in the lateral OFC and the frontal operculum for the taste-related words, supporting the claim that these areas are relevant to taste. PMID- 24800629 TI - Functional reorganization of the visual dorsal stream as probed by 3-D visual coherence in Williams syndrome. AB - Object and depth perception from motion cues involves the recruitment of visual dorsal stream brain areas. In 3-D structure-from-motion (SFM) perception, motion and depth information are first extracted in this visual stream to allow object categorization, which is in turn mediated by the ventral visual stream. Such interplay justifies the use of SFM paradigms to understand dorsal-ventral integration of visual information. The nature of such processing is particularly interesting to be investigated in a neurological model of cognitive dissociation between dorsal (impaired) and ventral stream (relatively preserved) processing, Williams syndrome (WS). In the current fMRI study, we assessed dorsal versus ventral stream processing by using a performance-matched 3-D SFM object categorization task. We found evidence for substantial reorganization of the dorsal stream in WS as assessed by whole-brain ANOVA random effects analysis, with subtle differences in ventral activation. Dorsal reorganization was expressed by larger medial recruitment in WS (cuneus, precuneus, and retrosplenial cortex) in contrast with controls, which showed the expected dorsolateral pattern (caudal intraparietal sulcus and lateral occipital cortex). In summary, we found a substantial reorganization of dorsal stream regions in WS in response to simple visual categories and 3-D SFM perception, with less affected ventral stream. Our results corroborate the existence of a medial dorsal pathway that provides the substrate for information rerouting and reorganization in the presence of lateral dorsal stream vulnerability. This interpretation is consistent with recent findings suggesting parallel routing of information in medial and lateral parts of dorsal stream. PMID- 24800631 TI - Aging affects the interaction between attentional control and source memory: an fMRI study. AB - Age-related source memory impairments may be due, at least in part, to deficits in executive processes mediated by the PFC at both study and test. Behavioral work suggests that providing environmental support at encoding, such as directing attention toward item-source associations, may improve source memory and reduce age-related deficits in the recruitment of these executive processes. The present fMRI study investigated the effects of directed attention and aging on source memory encoding and retrieval. At study, participants were shown pictures of objects. They were either asked to attend to the objects and their color (source) or to their size. At test, participants determined if objects were seen before, and if so, whether they were the same color as previously. Behavioral results showed that direction of attention improved source memory for both groups; however, age-related deficits persisted. fMRI results revealed that, across groups, direction of attention facilitated medial temporal lobe-mediated contextual binding processes during study and attenuated right PFC postretrieval monitoring effects at test. However, persistent age-related source memory deficits may be related to increased recruitment of medial anterior PFC during encoding, indicative of self-referential processing, as well as underrecruitment of lateral anterior PFC-mediated relational processes. Taken together, this study suggests that, even when supported, older adults may fail to selectively encode goal-relevant contextual details supporting source memory performance. PMID- 24800630 TI - Feature diagnosticity affects representations of novel and familiar objects. AB - Many features can describe a concept, but only some features define a concept in that they enable discrimination of items that are instances of a concept from (similar) items that are not. We refer to this property of some features as feature diagnosticity. Previous work has described the behavioral effects of feature diagnosticity, but there has been little work on explaining why and how these effects arise. In this study, we aimed to understand the impact of feature diagnosticity on concept representations across two complementary experiments. In Experiment 1, we manipulated the diagnosticity of one feature, color, for a set of novel objects that human participants learned over the course of 1 week. We report behavioral and neural evidence that diagnostic features are likely to be automatically recruited during remembering. Specifically, individuals activated color-selective regions of ventral temporal cortex (specifically, left fusiform gyrus and left inferior temporal gyrus) when thinking about the novel objects, although color information was never explicitly probed during the task. Moreover, multiple behavioral and neural measures of the effects of feature diagnosticity were correlated across participants. In Experiment 2, we examined relative color association in familiar object categories, which varied in feature diagnosticity (fruits and vegetables, household items). Taken together, these results offer novel insights into the neural mechanisms underlying concept representations by demonstrating that automatic recruitment of diagnostic information gives rise to behavioral effects of feature diagnosticity. PMID- 24800632 TI - The subthalamic nucleus contributes to post-error slowing. AB - pFC is proposed to implement cognitive control via directed "top-down" influence over behavior. But how is this feat achieved? The virtue of such a descriptive model is contingent on a mechanistic understanding of how motor execution is altered in specific circumstances. In this report, we provide evidence that the well-known phenomenon of slowed RTs following mistakes (post-error slowing) is directly influenced by the degree of subthalamic nucleus (STN) activity. The STN is proposed to act as a brake on motor execution following conflict or errors, buying time so a more cautious response can be made on the next trial. STN local field potentials from nine Parkinson disease patients undergoing deep brain stimulation surgery were recorded while they performed a response conflict task. In a 2.5- to 5-Hz frequency range previously associated with conflict and error processing, the degree phase consistency preceding the response was associated with increasingly slower RTs specifically following errors. These findings provide compelling evidence that post-error slowing is in part mediated by a corticosubthalamic "hyperdirect" pathway for increased response caution. PMID- 24800633 TI - Enhanced alpha-oscillations in visual cortex during anticipation of self generated visual stimulation. AB - The perceived intensity of sensory stimuli is reduced when these stimuli are caused by the observer's actions. This phenomenon is traditionally explained by forward models of sensory action-outcome, which arise from motor processing. Although these forward models critically predict anticipatory modulation of sensory neural processing, neurophysiological evidence for anticipatory modulation is sparse and has not been linked to perceptual data showing sensory attenuation. By combining a psychophysical task involving contrast discrimination with source-level time-frequency analysis of MEG data, we demonstrate that the amplitude of alpha-oscillations in visual cortex is enhanced before the onset of a visual stimulus when the identity and onset of the stimulus are controlled by participants' motor actions. Critically, this prestimulus enhancement of alpha amplitude is paralleled by psychophysical judgments of a reduced contrast for this stimulus. We suggest that alpha-oscillations in visual cortex preceding self generated visual stimulation are a likely neurophysiological signature of motor induced sensory anticipation and mediate sensory attenuation. We discuss our results in relation to proposals that attribute generic inhibitory functions to alpha-oscillations in prioritizing and gating sensory information via top-down control. PMID- 24800634 TI - Odorasides A and B, new sphingolipid glucosides from Klienia odora. AB - Two new sphingolipid glucosides, odoraside A (1) and odoraside B (2), have been isolated from chloroform-soluble fraction of the total methanolic extract of Klienia odora, together with five known compounds, beta-sitosterol (3), oleanolic acid (4), betulone (5), 2,3-dihydroxy-12-oleanen-28-oic acid (6), and beta sitosterol 3-O-beta-d-glucopyranoside (7). Their structures were assigned from (1)H and (13)C NMR spectra, DEPT and by 2D COSY, NOESY, HMQC, and HMBC experiments. PMID- 24800635 TI - Highly potential antiplasmodial restricted peptides. AB - Malaria is an infectious disease responsible for approximately one million deaths annually. The antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and P. falciparum have recently been reported. To evaluate antiplasmodial activity, we synthesized five angiotensin II-restricted analogs containing disulfide bridges. To accomplish this, peptides containing two inserted amino acid residues (cysteine) were synthesized by the Fmoc solid-phase method, purified by liquid chromatography, and characterized by mass spectrometry. Conformational studies were performed by circular dichroism. The results indicated that two of the analogs had higher antiplasmodium activity (92% and 98% activity) than angiotensin II (88% activity), measured by fluorescence microscopy. Results showed that the insertion position must be selected, to preserve the hydrophobic interactions between the non-polar residues, as this affects antiplasmodial activity. The circular dichroism studies suggested that the active analogs as well as the native angiotensin II adopt a beta-turn conformation in different solutions. This approach provided insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents. PMID- 24800636 TI - High infection rate of bank voles (Myodes glareolus) with Puumala virus is associated with a winter outbreak of haemorrhagic fever with renal syndrome in Croatia. AB - An outbreak of haemorrhagic fever with renal syndrome (HFRS) started on Medvednica mountain near Zagreb in January 2012. In order to detect the aetiological agent of the disease in small rodents and to make the link with the human outbreak, rodents were trapped at four different altitudes. Using nested RT PCR, Puumala virus (PUUV) RNA was detected in 41/53 (77.4%) bank voles (Myodes glareolus) and Dobrava virus (DOBV) RNA was found in 6/61 (9.8%) yellow-necked mice (Apodemus flavicollis). Sequence analysis of a 341-nucleotide region of the PUUV S segment, obtained from all infected bank voles and five HFRS patients, showed 98.8-100% sequence similarity, indicating that the patients were probably exposed to PUUV on Medvednica mountain. A very large bank-vole population combined with an extremely high infection rate of PUUV was responsible for this unusual winter outbreak of HFRS in Croatia. PMID- 24800638 TI - An iodide-adduct high-resolution time-of-flight chemical-ionization mass spectrometer: application to atmospheric inorganic and organic compounds. AB - A high-resolution time-of-flight chemical-ionization mass spectrometer (HR-ToF CIMS) using Iodide-adducts has been characterized and deployed in several laboratory and field studies to measure a suite of organic and inorganic atmospheric species. The large negative mass defect of Iodide, combined with soft ionization and the high mass-accuracy (<20 ppm) and mass-resolving power (R>5500) of the time-of-flight mass spectrometer, provides an additional degree of separation and allows for the determination of elemental compositions for the vast majority of detected ions. Laboratory characterization reveals Iodide-adduct ionization generally exhibits increasing sensitivity toward more polar or acidic volatile organic compounds. Simultaneous retrieval of a wide range of mass-to charge ratios (m/Q from 25 to 625 Th) at a high frequency (>1 Hz) provides a comprehensive view of atmospheric oxidative chemistry, particularly when sampling rapidly evolving plumes from fast moving platforms like an aircraft. We present the sampling protocol, detection limits and observations from the first aircraft deployment for an instrument of this type, which took place aboard the NOAA WP-3D aircraft during the Southeast Nexus (SENEX) 2013 field campaign. PMID- 24800639 TI - Extending breath analysis to the cellular level: current thoughts on the human microbiome and the expression of organic compounds in the human exposome. PMID- 24800637 TI - New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy. AB - BACKGROUND: Mutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations. METHODS: The diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model. RESULTS: Genetic analysis revealed an m.3472T>C transition in the MT-ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular-genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder. CONCLUSIONS: This mutation expands the spectrum of deleterious changes in mitochondrial DNA encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients. PMID- 24800640 TI - Improvement of doxorubicin efficacy using liposomal anti-polo-like kinase 1 siRNA in human renal cell carcinomas. AB - It is well-known that renal cell carcinomas (RCCs) are resistant to classical cytotoxic anticancer drugs. Therefore, facilitating the impact of anticancer drugs by altering the cell phenotype should be a useful strategy for circumventing this. We developed a multifunctional envelope-type nanodevice (MEND) as an in vivo carrier of siRNA to tumor tissues. We previously reported that a MEND containing YSK05 (YSK-MEND) efficiently delivered siRNA in RCC bearing mice. We herein report on a combination therapy involving the use of siRNA-mediated specific gene knockdown and cytotoxic drug doxorubicin (DOX), and an advantage of YSK-MEND as an investigation tool for in vivo function of a gene. si-PLK1 encapsulated within YSK-MEND was prepared using the tertiary butanol dilution method. The in vitro cellular viability under the exposure of DOX was compared between OS-RC-2 cells with and without si-PLK1 transfection. In an in vivo study, tumor-bearing mice were systemically injected with YSK-MEND and DOX loaded liposomes. The combination of DOX and si-PLK1 drastically reduced tumor growth rate, and apoptotic cells were observed. In an in vitro study, PLK1 knockdown increased G2/M cell population and reduced the expression of cyclin B1 (CCNB1) mRNA. CCNB1 suppression by si-PLK1 encapsulated in YSK-MEND was also observed in the in vivo experiments. A combination of DOX and anti-polo-like kinase 1 siRNA (si-PLK1) resulted in a measurable delay in OS-RC-2 tumor growth. This result suggests that the combination of si-PLK1 delivery and doxorubicin by YSK-MEND holds potential for RCC therapy via cell CCNB1 regulation. PMID- 24800641 TI - Shoulder muscle fatigue development in young and older female adults during a repetitive manual task. AB - Age may modify the association between occupational physical demand and muscle loading, and ultimately increase the risk of musculoskeletal disorders. The goal of this study was to investigate age-related differences in shoulder muscle fatigue development during a repetitive manual task. Twenty participants in two age groups completed an 80-minute simulated low-intensity assembly task. Electromyographic (EMG) manifestation of muscle fatigue was observed in the upper trapezius, deltoid and infraspinatus muscles in both age groups, and coincided with an increase in the subjective ratings of perceived exertions. Compared with the younger group, older group showed a more monotonic decrease in EMG power frequency in the upper trapezius and deltoid muscles. However, the age-related difference in EMG amplitude was less consistent. Relative rest time of the upper trapezius muscle in the older group was less than the young group throughout the task. The observed patterns of EMG measures suggest that older participants may have disadvantages in fatigue resistance in the upper trapezius and posterior deltoid muscles during the simulated repetitive manual task. PMID- 24800642 TI - Interventions to reduce tourniquet-related ischaemic damage in orthopaedic surgery: a qualitative systematic review of randomised trials. AB - Ischaemia of the extremity from the use of a tourniquet and the subsequent reperfusion contribute to the release of reactive oxygen species. This release may result in injury to remote organs. We performed a qualitative systematic review exploring the interventions used to prevent tourniquet-related oxidative damage in adults undergoing orthopaedic surgery, and the possible relationship between biochemical oxidative stress markers and postoperative clinical outcomes. Seventeen randomised controlled studies were included in the qualitative synthesis. Most trials were of low methodological quality and only two studies reported postoperative clinical outcomes. Nine studies tested anaesthetics (propofol, dexmedetomidine, ketamine, and spinal anaesthesia); four studies tested antioxidants (N-acetyl-cysteine, vitamin C, and mannitol); and four studies tested ischaemic pre-conditioning. Fifteen studies showed a significant reduction in biochemical oxidative stress markers. We conclude that propofol and ischaemic pre-conditioning, in particular, appear to show some benefit at reducing oxidative stress following operations under tourniquet; the correlation between a reduction in oxidative stress and postoperative clinical outcomes should be further investigated in the future. PMID- 24800643 TI - Fractal analysis of dendrite morphology using modified box-counting method. AB - The box-counting dimension of a non-stellate neuron changes continuously with its rotation. During preprocessing for box-counting, non-stellate neurons should be arranged so that the major diameters of their dendrite fields are parallel. A non stellate neuronal picture should have the smallest fractal dimension when the angle between the horizontal axis and its major diameter is about 45 degrees . The box-counting method does not consider the position of a picture on the computer screen. Therefore a dispersion of the box dimension values of a neuronal sample is rather large and their mean value is with larger variance. Modified box counting method partly diminishes these findings. To improve a dependence of neuronal rotation on the box-counting dimension of non-stellate neurons, prior to applying box-counting method, non-stellate neurons should be arranged so that the major diameters of their dendrite fields are parallel. PMID- 24800644 TI - Intrahypothalamic injection of cannabidiol increases the extracellular levels of adenosine in nucleus accumbens in rats. AB - Cannabidiol (CBD) is a constituent of Cannabis sativa that promotes wakefulness as well as enhances endogenous levels of wake-related neurotransmitters, including dopamine. However, at this date, the effects of CBD on the sleep inducing molecules, such as adenosine (AD), are unknown. Here, we report that intrahypothalamic injection of CBD (10MUg/1MUL) increases the extracellular levels of AD collected from nucleus accumbens. Furthermore, the pharmacodynamic of this drug shows that effects on the contents of AD last 2h post-injection. These preliminary findings suggest that CBD promotes the endogenous accumulation of AD. PMID- 24800645 TI - Left-right asymmetry is formed in individual cells by intrinsic cell chirality. AB - Many animals show left-right (LR) asymmetric morphology. The mechanisms of LR asymmetric development are evolutionarily divergent, and they remain elusive in invertebrates. Various organs in Drosophila melanogaster show stereotypic LR asymmetry, including the embryonic gut. The Drosophila embryonic hindgut twists 90 degrees left-handedly, thereby generating directional LR asymmetry. We recently revealed that the hindgut epithelial cell is chiral in shape and other properties; this is termed planar cell chirality (PCC). We previously showed by computer modeling that PCC is sufficient to induce the hindgut rotation. In addition, both the PCC and the direction of hindgut twisting are reversed in Myosin31DF (Myo31DF) mutants. Myo31DF encodes Drosophila MyosinID, an actin-based motor protein, whose molecular functions in LR asymmetric development are largely unknown. Here, to understand how PCC directs the asymmetric cell-shape, we analyzed PCC in genetic mosaics composed of cells homozygous for mutant Myo31DF, some of which also overexpressed wild-type Myo31DF. Wild-type cell-shape chirality only formed in the Myo31DF-overexpressing cells, suggesting that cell shape chirality was established in each cell and reflects intrinsic PCC. A computer model recapitulating the development of this genetic mosaic suggested that mechanical interactions between cells are required for the cell-shape behavior seen in vivo. Our mosaic analysis also suggested that during hindgut rotation in vivo, wild-type Myo31DF suppresses the elongation of cell boundaries, supporting the idea that cell-shape chirality is an intrinsic property determined in each cell. However, the amount and distribution of F-actin and Myosin II, which are known to help generate the contraction force on cell boundaries, did not show differences between Myo31DF mutant cells and wild-type cells, suggesting that the static amount and distribution of these proteins are not involved in the suppression of cell-boundary elongation. Taken together, our results suggest that cell-shape chirality is intrinsically formed in each cell, and that mechanical force from intercellular interactions contributes to its formation and/or maintenance. PMID- 24800646 TI - Development and validation of formulae to predict leg length following medial opening-wedge osteotomy of the proximal tibia with hemicallotasis. AB - BACKGROUND: A medial open-wedge osteotomy of the proximal tibia with hemicallotasis (HCO) affects the relative coronal alignment of the femur and tibia with respect to the floor; this also potentially reflects a change in leg length. PURPOSE: The aims of this study are to develop and verify formulae for predicting the postoperative whole leg length (WLL) in HCO. METHODS: We analyzed a training set of 25 HCOs in 25 patients. Formulae for predicting the postoperative leg length were developed using various factors including the length and coronal alignment of the femur and tibia, the length of the proximal or distal fragment from the tibial osteotomy site, the femoro-tibial angle, and the correction angle. The formulae were then verified using the interclass correlation coefficient in an independent consecutive set of 25 HCOs. RESULTS: Significant postoperative increases in tibial bone length and WLL were noted with no postoperative change in femoral bone length. Furthermore, the coronal alignments of femoral and tibial bone axes were significantly abducted. For the formulae for predicting postoperative WLL developed in the training set, the interclass correlation coefficients between the predicted values and the real radiographic measurements in the validation set were more than 0.90, showing great consistency. CONCLUSION: The mathematical models established in this study seemed to predict almost completely the change in leg length after HCO. Our results suggest that these formulae may offer accurate, extremely useful information about the postoperative possibility of leg lengthening for patients planning an HCO. LEVEL OF EVIDENCE: Therapeutic case series; level 4. PMID- 24800647 TI - Evidence for adaptive divergence of thermal responses among Bemisia tabaci populations from tropical Colombia following a recent invasion. AB - There is an increasing evidence that populations of ectotherms can diverge genetically in response to different climatic conditions, both within their native range and (in the case of invasive species) in their new range. Here, we test for such divergence in invasive whitefly Bemisia tabaci populations in tropical Colombia, by considering heritable variation within and between populations in survival and fecundity under temperature stress, and by comparing population differences with patterns established from putatively neutral microsatellite markers. We detected significant differences among populations linked to mean temperature (for survival) and temperature variation (for fecundity) in local environments. A QST - FST analysis indicated that phenotypic divergence was often larger than neutral expectations (QST > FST ). Particularly, for survival after a sublethal heat shock, this divergence remained linked to the local mean temperature after controlling for neutral divergence. These findings point to rapid adaptation in invasive whitefly likely to contribute to its success as a pest species. Ongoing evolutionary divergence also provides challenges in predicting the likely impact of Bemisia in invaded regions. PMID- 24800648 TI - Ugi-based approaches to quinoxaline libraries. AB - An expedient and concise Ugi-based unified approach for the rapid assembly of quinoxaline frameworks has been developed. This convergent and versatile method uses readily available commercial reagents, does not require advanced intermediates, and exhibits excellent bond-forming efficiency, thus exemplifying the operationally simple synthesis of quinoxaline libraries. PMID- 24800649 TI - Skin lesions and inoculation eschars at the tick bite site in spotted fever group rickettsioses: experience from a patient series in eastern crete, Greece. AB - The main clinical signs and symptoms caused by a rickettsial infection typically begin 6-10 days after the bite and are accompanied by nonspecific findings such as fever, headache and muscle pain. The diagnosis is mainly based on serological tests, however antibody presentation may be delayed, at least at the early stages of the disease, while seroconversion is usually detected 10-15 days after disease onset. Culture is difficult, requires optimized facilities and often proves negative. Under this scope, the presence of a characteristic inoculation eschar at the bite site may prove a useful clinical tool towards the early suspicion and diagnosis/differential diagnosis of tick-borne rickettsioses, even before the onset of rash and fever or serological confirmation. We describe herein the presence of skin lesions and/or an inoculation eschar at the tick bite site in 17 patients diagnosed, by molecular means, as suffering from spotted fever group rickettsioses. The detection of the pathogen's DNA in biopsy samples proved to be a useful means for early rickettsiae detection and identification. Moreover, the presence of an infiltrated erythema always seemed to precede the appearance of an eschar by 2-5 days and the initiation of fever by 1-10 days; these two signs might also prove useful in the context of the final diagnosis. PMID- 24800650 TI - Modeling persistence in mesenchymal cell motility using explicit fibers. AB - Cell motility is central to a variety of fundamental processes ranging from cancer metastasis to immune responses, but it is still poorly understood in realistic native environments. Previous theoretical work has tended to focus on intracellular mechanisms or on small pieces of interaction with the environment. In this article, we present a simulation which accounts for mesenchymal movement in a 3D environment with explicit collagen fibers and show that this representation highlights the importance of both the concentration and alignment of fibers. We show good agreement with experimental results regarding cell motility and persistence in 3D environments and predict a specific effect on average instantaneous cell speed and persistence. Importantly, we show that a significant part of persistence in 3D is directly dependent on the physical environment, instead of indirectly dependent on the environment through the biochemical feedback that occurs in cell motility. Thus, new models of motility in three dimensions will need to account for the effects of explicit individual fibers on cells. This model can also be used to analyze cellular persistence in both mesenchymal and nonmesenchymal motility in complex three-dimensional environments to provide insights into mechanisms of cell motion seen in various cancer cell types in vivo. PMID- 24800651 TI - Recombinant factor IX: discrepancies between one-stage clotting and chromogenic assays. AB - New and modified recombinant factor IX (rFIX) products are in development and accurate potency estimation is important to ensure the consistency of production and efficacy of these therapeutics. Collaborative study data obtained during the replacement of the 3rd International Standard (IS) for FIX concentrate suggested that there was a discrepancy between potency estimates for rFIX using clotting and chromogenic methods, when the rFIX candidate was measured against the plasma derived FIX (pdFIX) IS. This study explores potential chromogenic and one-stage clotting method discrepancies in more detail. Five batches each of rFIX and pdFIX were assayed against the 4th IS FIX concentrate (a pdFIX) by activated partial thromboplastin time (APTT) one-stage clotting assay and specific functional chromogenic assay. The potency of rFIX by chromogenic assay was consistently around 70% of the one-stage clotting potency (average 78 and 108 IU mL(-1) respectively). These differences were not observed with pdFIX, which had similar potencies (average 96 IU mL(-1) ) by each assay method. In addition, different APTT reagents yielded different potency estimates for rFIX when assayed against the pdFIX IS, with a variation of up to 23%. In all cases, the differences were largely resolved when a rFIX reference was used as the standard. This study highlights some of the challenges associated with assay of rFIX products in the laboratory and that careful consideration needs to be given to the choice of reference material used. This is especially important with the imminent arrival of new and modified rFIX products. PMID- 24800652 TI - Progranulin in neurodegenerative disease. AB - Loss-of-function mutations in the progranulin gene are a common cause of familial frontotemporal dementia (FTD). The purpose of this review is to summarize the role of progranulin in health and disease, because the field is now poised to begin examining therapeutics that alter endogenous progranulin levels. We first review the clinical and neuropathological phenotype of FTD patients carrying mutations in the progranulin gene, which suggests that progranulin-mediated neurodegeneration is multifactorial and influenced by other genetic and/or environmental factors. We then examine evidence for the role of progranulin in the brain with a focus on mouse model systems. A better understanding of the complexity of progranulin biology in the brain will help guide the development of progranulin-modulating therapies for neurodegenerative disease. PMID- 24800653 TI - When nurses lead. AB - In Fall 2011, the Centers for Medicare and Medicaid Services (CMS) began a major initiative to improve dementia care in nursing homes. The initial goal was to reduce the prevalence of antipsychotic medication use in long-stay nursing home residents with dementia by 15%. Through a new, public-private collaboration, the National Partnership to Improve Dementia Care established coalitions in every state. After 18 months, a 15.1% reduction was achieved nationally. Throughout the initiative, many nurses played key roles in leading the process for change. This article describes the roles of nurse leaders in this national policy work. PMID- 24800654 TI - Protective effect of a laser-induced sub-lethal temperature rise on RPE cells from oxidative stress. AB - Recently introduced new technologies that enable temperature-controlled laser irradiation on the RPE allowed us to investigate temperature-resolved RPE cell responses. In this study we aimed primarily to establish an experimental setup that can realize laser irradiation on RPE cell culture with the similar temperature distribution as in the clinical application, with a precise time/temperature history. With this setup, we conducted investigations to elucidate the temperature-dependent RPE cell biochemical responses and the effect of transient hyperthermia on the responses of RPE cells to the secondary-exposed oxidative stress. Porcine RPE cells cultivated in a culture dish (inner diameter = 30 mm) with culture medium were used, on which laser radiation (lambda = 1940 nm, spot diameter = 30 mm) over 10 s was applied as a heat source. The irradiation provides a radially decreasing temperature profile which is close to a Gaussian shape with the highest temperature in the center. Power setting for irradiation was determined such that the peak temperature (Tmax) in the center of the laser spot at the cells reaches from 40 degrees C to 58 degrees C (40, 43, 46, 50, 58 degrees C). Cell viability was investigated with ethidium homodimer III staining at the time points of 3 and 24 h following laser irradiation. Twenty four hours after laser irradiation the cells were exposed to hydrogen peroxide (H2O2) for 5 h, followed by the measurement of intracellular glutathione, intracellular 4-hydroxynonenal (HNE) protein adducts, and secreted vascular endothelial growth factor (VEGF). The mean temperature threshold for RPE cell death after 3 h was found to be around 52 degrees C, and for 24 h around 50 degrees C with the current irradiation setting. A sub-lethal preconditioning on Tmax = 43 degrees C significantly induced the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, and decreased H2O2-induced increase of intracellular 4 HNE protein adducts. Although sub-lethal hyperthermia (Tmax = 40 degrees C, 43 degrees C, and 46 degrees C) caused a slight increase of VEGF secretion in 6 h directly following irradiation, secondary exposed H2O2-induced VEGF secretion was significantly reduced in the sub-lethally preheated groups, where the largest effect was seen following the irradiation with Tmax = 43 degrees C. In summary, the current results suggest that sub-lethal thermal laser irradiation on the RPE at Tmax = 43 degrees C for 10 s enhances cell defense system against oxidative stress, with increasing the GSH/GSSG ratio. Together with the results that the decreased amount of H2O2-induced 4-HNE in sub-lethally preheated RPE cells was accompanied by the lower secretion of VEGF, it is also strongly suggested that the sub-lethal hyperthermia may modify RPE cell functionality to protect RPE cells from oxidative stress and associated functional decrease, which are considered to play a significant role in the pathogenesis of age-related macular degeneration and other chorioretinal degenerative diseases. PMID- 24800656 TI - Uniform graphitic carbon nitride nanorod for efficient photocatalytic hydrogen evolution and sustained photoenzymatic catalysis. AB - Uniform graphitic carbon nitride nanorods (CNR) were facilely obtained by a morphology-preserving strategy by templating a chiral mesostructured silica nanorod. The hexagonal mesostructured pore structures of one-dimensional silica nanorods can provide nanoconfinement space for carbon nitride condensation to perfect layered structures. CNR demonstrated excellent photocatalytic capability in generating hydrogen from water even with a small specific surface area, compared with its mesoporous counterpart. For further application demonstration, the CNR was used for photocatalytic regeneration of NAD(+) to NADH, the biological form of hydrogen. The in situ NADH regeneration system was further coupled with l-glutamate dehydrogenase for sustainable generation of l-glutamate from alpha-ketoglutarate. The high yield and high efficiency obtained here point a high-throughput and sustainable way for practical enzymatic applications. PMID- 24800655 TI - Reversal of fibrosis by TGF-beta3 in a 3D in vitro model. AB - Corneal scarring following moderate to severe injury is inevitable. Despite significant advancements in the field, current treatments following these types of injuries are limited, and often, the visual recovery is poor. One of the problems and limitations is that corneal wound healing is a complex process, involving corneal cells, extracellular matrix components and growth factors. Therefore, further understanding is required, along with new treatments and techniques to reduce or prevent corneal scarring following injury. Two isoforms of transforming growth factor-beta (TGF-beta), TGF-beta1 and -beta3 (T1 and T3, respectively), are associated with corneal wound healing. T1 has been shown to drive the corneal keratocytes to differentiate into myofibroblasts; whereas, T3 has been found to inhibit fibrotic markers. In the current study, we examined whether the fibrotic characteristics expressed by human corneal fibroblasts (HCF) in our 3-dimensional (3D) construct following T1 stimulation could be reversed by introducing T3 to the in vitro system. To do this, HCF were isolated and cultured in 10% serum, and when they reached confluence, the cells were stimulated with a stable Vitamin C (VitC) derivative for 4 weeks, which allowed them to secrete a self-assembled matrix. Three conditions were tested: (1) CONTROL: 10% serum (S) only, (2) T1: 10%S + T1, or (3) Rescue: 10%S + T1 for two weeks and then switched to 10%S + T3 for another two weeks. At the end of 4 weeks, the constructs were processed for analysis by indirect-immunofluorescence (IF) and transmission electron microscopy (TEM). Different collagens that are normally present in healthy corneas in vivo, such as Type I and V, as well as Type III, which is a fibrotic indicator, were examined. In addition, we examined smooth muscle actin (SMA), a marker of myofibroblasts, and thrombospondin-1 (TSP-1), a multifunctional matrix protein known to activate the latent complex of TGF-beta and appear upon wounding in vivo. Our data showed high expression of collagens type I and V under all conditions throughout the 3D constructs; however, type III and SMA expression were higher in the constructs that were stimulated with T1 and reduced to almost nothing in the Rescue samples. A similar pattern was seen with TSP-1, where TSP-1 expression following "rescue" was decreased considerably. Overall, this data is in agreement with our previous observations that T3 has a significant non-fibrotic effect on HCFs, and presents a novel model for the "rescue" of both cellular and matrix fibrotic components with a single growth factor. PMID- 24800657 TI - Changes in the use of manual vacuum aspiration for postabortion care within the public healthcare service network in Honduras. AB - Honduras is one of the 17 priority countries included in the International Federation of Gynecology and Obstetrics (FIGO) Initiative for the Prevention of Unsafe Abortion and its Consequences. The priority category enables the country to request emergency funding to acquire services or commodities that could contribute toward achieving the objectives laid out in its plan of action. These objectives include improving postabortion care by increasing the use of manual vacuum aspiration (MVA) as an outpatient procedure with minimal human and material resources. Since the Ministry of Health lacked funding, use of the emergency fund was approved for the purchase and distribution of MVA kits nationwide to ensure continuity and the hope of increasing MVA use. Eleven hospitals participating in this initiative provided data for analysis of the outcome. These data show no increase in MVA use; however, as discussed in the article, further investigation provided valuable information on the reasons behind these results. PMID- 24800658 TI - Obstetric competence among primary healthcare workers in Mali. AB - OBJECTIVE: To determine individual and contextual factors associated with emergency obstetric and neonatal care (EmONC) competency among primary healthcare staff in Mali. METHODS: Between November 2011 and April 2012, a competency test was administered to 196 healthcare workers in 65 community health centers in Mali. The test was scored from 0 to 100, and differences among 5 areas of EmONC were assessed. A multilevel linear regression model was used to determine individual and contextual factors associated with score. RESULTS: The mean score was 66.7 (minimum, 15.9; maximum, 97.7). Knowledge was most deficient for postpartum infection and hypertensive complications. Type of health worker, years of experience, number of days absent, and availability of guidelines for management of obstetric complications within the health center were positively associated with test score (P<0.05). Availability of guidelines was associated with higher competency of physicians, health technicians, and obstetric nurses (P<0.001), and seemed to influence the competency of healthcare workers with fewer than 10 years of experience in particular. CONCLUSION: Guidelines must be developed that will facilitate standardization of the management of postpartum infection and other less common complications for which healthcare workers show low competence. Strategies to increase use of these guidelines will be necessary. PMID- 24800659 TI - Obstetric competence among referral healthcare providers in Mali. AB - OBJECTIVE: To determine the factors associated with obstetric competency and clinical practice among obstetric care providers in referral health centers in Mali. METHODS: The present cross-sectional study was conducted between March and May 2012 among 140 obstetric care providers (obstetric nurses, midwives, and physicians) working in referral health centers in Mali. Emergency obstetric care knowledge and skills were evaluated with clinical vignettes developed using national Malian guidelines. The vignettes covered 5 areas of emergency obstetric care, and the results were used to generate a competency score. A backward stepwise random-effects model using a maximum likelihood estimator was applied to evaluate variables independently associated with competency score. RESULTS: Out of 100, the mean+/-SD score was 57.8+/-11.2 for obstetric nurses, 66.4+/-14.7 for midwifes, and 78.6+/-13.4 for physicians (P<0.001). Three variables were significantly associated with a higher competency score: professional qualification, working in an urban setting, and working in a health center with a smaller number of obstetric care providers. CONCLUSION: Increasing the in-service training of both rural staff and lower-level healthcare workers working in larger health centers via facility-based maternal death reviews might help to improve clinical practice and maternal health outcomes. PMID- 24800660 TI - Introduction of misoprostol for the treatment of incomplete abortion beyond 12 weeks of pregnancy in Benin. AB - Improving the care of women who have undergone a spontaneous or induced abortion is an important step in reducing abortion-related morbidity and mortality. Both the International Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization recommend the use of manual vacuum aspiration (MVA) and misoprostol rather than sharp curettage to treat incomplete abortion. MVA was introduced into the public healthcare service in Benin in 2006 and since 2008 misoprostol has been available in 3 large maternity hospitals. The present study opted to use an oral dose of 800 MUg and not to limit to pregnancies of up to 12 weeks, but to include women with second trimester abortions. After 5 years, results show that around three-quarters of the women treated with misoprostol at 13-18 weeks of pregnancy required MVA to complete uterine evacuation and approximately one-quarter had severe bleeding, confirming that the indication of misoprostol for incomplete abortion should be limited to pregnancies of up to 12 weeks. PMID- 24800661 TI - Therapeutic efficacy of three bispecific antibodies on collagen-induced arthritis mouse model. AB - Interleukin-1beta (IL-1beta) and interleukin-17A (IL-17A) are inducible factors and important cytokines in the pathogenesis of rheumatoid arthritis (RA). In the present study, three bispecific and neutralizing antibodies (BsAB-1, BsAB-2 and BsAB-3) against both hIL-1beta and hIL-17A were constructed, their therapeutic efficacy was compared on collagen induced arthritis (CIA) model mice. In vitro assays demonstrated that the three antibodies could simultaneously bind to target both hIL-1beta and hIL-17A. Mice with CIA were subcutaneously administered with one of three antibodies every two days for 29 days, we noticed that, compared with the BsAB-2 and BsAB-3, BsAB-1 antibody therapy resulted in more significant effect on alleviating the severity of arthritis by preventing bone damage and cartilage destruction and substantially decreasing production of CII-specific antibodies. In addition, BsAB-1 antibody was more potent in the inhibition of mRNA expression of IL-2, IL-1beta, IL-17A, TNF-alpha and MMP-3 in the spleen of CIA mice compared to the other two. In summary, BsAB-1 is superior over BsAB-2 and BsAB-3 for the treatment of RA model mice, and may be chosen as an ideal candidate for further development of therapeutic drugs for treatment of RA. PMID- 24800663 TI - Diet quality concept. AB - The term diet quality has recently gained considerable attention in nutritional research. Despite widespread use, it is often poorly defined and remains difficult to measure. Confusion surrounds the term, as there is no consensus on how to define quality of the diet or to pin down a framework for producing a standard indicator. The composite and cut-off selection of most diet quality indices depend on investigator choices in line with research objectives. In addition to the frequently used dietary compliance-based approach, innovative approaches have emerged to construct diet quality indices based on antioxidant and anti-inflammatory profiles of diet. Different viewpoints and overlapping interests may yield different interpretations. Most of the unresolved issues are related directly or indirectly to the multidimensional and open-textured nature of the concept. This review aims to elucidate several debated key points to understand the reasons behind this confusion and address the complexity of how to define and quantify this concept. A standardized and well-defined framework of diet quality is of great importance for both consumers and scientists from different disciplines. PMID- 24800665 TI - Cognitive and motor perturbations in elderly with longstanding diabetes mellitus. AB - Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance; inflammation; oxidative stress; vascular damage; and dysfunction of glucose, protein, and lipid metabolisms. However, comparatively less attention has been paid to neurologic alterations seen in elderly individuals with type 2 diabetes. We review clinical, metabolic, and biochemical aspects of diabetic encephalopathy (DE) and propose that quality of dietary lipids is closely linked to DE. This implies that preventive nutritional interventions may be designed to improve DE. PMID- 24800664 TI - Milk nutritional composition and its role in human health. AB - Dairy and milk consumption are frequently included as important elements in a healthy and balanced diet. It is the first food for mammals and provides all the necessary energy and nutrients to ensure proper growth and development, being crucial in respect to bone mass formation. However, several controversies arise from consumption of dairy and milk products during adulthood, especially because it refers to milk from other species. Despite these controversies, epidemiologic studies confirm the nutritional importance of milk in the human diet and reinforce the possible role of its consumption in preventing several chronic conditions like cardiovascular diseases (CVDs), some forms of cancer, obesity, and diabetes. Lactose malabsorption symptoms and cow milk protein allergy are generally considered to be the adverse reactions to milk consumption. The present article reviews the main aspects of milk nutritional composition and establishes several associations between its nutritious role, health promotion, and disease prevention. PMID- 24800666 TI - Assessing body shape index as a risk predictor for cardiovascular diseases and metabolic syndrome among Iranian adults. AB - OBJECTIVE: Several studies have concluded a positive association between abdominal obesity, general obesity, and chronic diseases. However, the best anthropometric measures to predict the risk for chronic diseases should be clarified in each population. Therefore, the aim of this study was to compare the predictive power of A Body Shape Index (ABSI), body mass index (BMI), and waist to-height ratio and Clinica Universidad de Navarra-Body Adiposity Estimator for metabolic syndrome (MetS) and cardiovascular disease (CVD) risks among Iranians in different age and sex categories. METHODS: This population-based cross sectional study conducted on 9555 individuals, ages >=19 y. Anthropometric measures, blood pressure, and biochemical markers were measured using standard protocols. Hypertension, hyperglycemia, hypercholesterolemia, high low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol levels were considered as the CVD risks. RESULTS: Mean (SD) of age and BMI of participants were 38.7 y (mean 15.5) and 25.7 kg/m(2) (mean 4.6), respectively. ABSI demonstrated the weakest correlations and lowest area under curve (AUC) for various risk factors and MetS. However, the highest odds ratio was observed for ABSI and MetS in different age and sex categories. CONCLUSIONS: Based on the AUC, we concluded that ABSI is a weak predictor for CVD risks and MetS. More studies are needed to determine the best predictor of CVD risk among the Iranian population. PMID- 24800667 TI - Body mass index through self-reported data and body image perception in Spanish adults attending dietary consultation. AB - OBJECTIVES: The aim of this study was to explore, based on sex and age, knowledge regarding weight, height, and the perception of body shape in Spanish adults who attend dietary consultation. We also wanted to determine the participants' desired body shapes and what they considered their best health status. METHODS: The sample consisted of 8100 women and 1220 men from Spain. They were between the ages of 18 and 75 y. Weight (kg) and height (cm) were measured and body mass index (BMI) was calculated. Participants were nutritionally classified following the cutoffs proposed by the World Health Organization. Each individual was asked about his or her weight and height and self-reported BMI was calculated. They also answered a test of body image perception through drawings of human silhouettes that corresponded to an exact BMI. With this, perceived BMI, desired BMI, and BMI considered healthy were estimated. Parametric statistic tests for contrast of mean and percentages were applied. RESULTS: Self-reported and perceived BMI underestimate the BMI obtained through anthropometry. Differences between measured and self-reported BMI are lower in women and increase with age in both sexes. The same result was obtained when comparing measured BMI with perceived BMI through silhouette test. On average, desired BMI and healthy BMI were in the limits of normal weight for all ages and both sexes. However, the difference between them was also lower in women. CONCLUSION: Age and sex influence the perception of excess weight and body image. This could condition the demand of dietary treatment to improve the nutritional status. PMID- 24800668 TI - A 360-degree overview of body composition in healthy people: relationships among anthropometry, ultrasonography, and dual-energy x-ray absorptiometry. AB - OBJECTIVE: The aim of this study was to test the relationship between anthropometry, ultrasonography, and dual-energy x-ray absorptiometry (DXA) for the assessment of body composition in clinical practice. METHODS: The study was carried out in Italian blood donor volunteers belonging to five different age groups (18-70 y old; 25 men and 25 women per group; N = 250 participants; n = 125 men, n = 125 women). A complete history was collected and routine blood analyses were performed to confirm healthy status. All participants were submitted to whole-body DXA (tricompartmental analysis, regional, and total body), ultrasonography (abdominal adiposity evaluation), and anthropometric measurements. DXA was used as gold standard and its biomarkers were taken as reference for fat-lean mass balance, central-peripheral fat distribution, central or visceral fat, and subcutaneous fat. RESULTS: Anthropometric and ultrasound parameters were closely associated with most of DXA parameters. Composite markers representative of central and abdominal visceral fat compartments were significantly correlated with waist circumference, waist-to-hip ratio, and intra abdominal fat thickness by ultrasound, in both men and women (P < 0.025). As expected, subcutaneous depots were significantly correlated with maximum subcutaneous fat thickness measured by ultrasonography (P < 0.025). CONCLUSIONS: Both anthropometry and ultrasonography provide a reliable estimate of visceral adipose tissue in a non-obese population compared with DXA, whereas anthropometry prediction of subcutaneous adiposity is weak. Physicians should be aware of the limits of these techniques for the assessment of body composition. PMID- 24800669 TI - Beverage from Coleus aromaticus reduces leptin levels and improves appetite rating in human volunteers. AB - OBJECTIVE: Coleus aromaticus, commonly called country borage or Indian borage, is a perennial herb grown throughout the Indian subcontinent. Traditionally, the leaves of the plant are used as a cure for cold, cough, and fever as well as to relieve pain from skin irritations. However, the appetite-enhancing potential of the herb was unexplored. Based on the encouraging results of animal studies, this study was taken up to establish the appetite-enhancing potential of Coleus aromaticus in humans by evaluating its ready-to-drink beverage. METHODS: A homogenous and healthy group of volunteers was selected. Ready-to-drink beverages based on the herb karpurvalli (Coleus aromaticus) containing three different concentrations (12% [sensorily optimized level], 18%, and 24%) of the herb juice and a placebo beverage were evaluated with the volunteers. The fasting and postprandial levels of plasma leptin were measured, and the appetite rating on a structured visual analog scale was obtained. RESULTS: The study revealed a significant reduction in leptin levels with 12% juice, whereas a significant increase was seen after consumption of the beverage containing 24%. A similar pattern was obtained with the structured ratings. CONCLUSION: The appetite enhancing effect of the beverage was best when it contained the sensorily optimized level of karpurvalli juice and confirms the results obtained in animal study. To our knowledge, this is the first study validating the appetite enhancing potential of the herb. PMID- 24800670 TI - The immunopotentiating effects of shark-derived protein hydrolysate. AB - OBJECTIVE: Peptides derived from natural sources can act as immunomodulating agents and prevent infections. The aim of this study was to investigate the immunopotentiating and protective effects of a shark-derived protein hydrolysate (SPH) against an enterotoxigenic Escherichia coli H10407 infection in a murine model. METHODS: Mice were fed an aqueous solution of SPH for 7 days before being inoculated with an experimental enterotoxigenic Escherichia coli H10407 infection. After euthanasia, small intestines were removed for histological study and the number of IgA and IgG producing cells was determined by direct immunofluorescence. Cytokines were measured in the serum and the intestinal fluid. RESULTS: The oral administration of SPH enhanced the gut barrier function via up-regulation of immunoglobulin A-producing cells and intestinal cytokines production, including interleukin-6 and tumor necrosis factor-alpha. The increase of transforming growth factor-beta and interleukin-10 contribute to the down regulation of uncontrolled-inflammatory reaction induced by E. coli infection. From these results, the anti-inflammatory properties of SPH may be caused by regulation and priming mechanisms of the immune system. CONCLUSION: Enzymatic protein degradation confers immunomodulating and protective potentials to shark proteins and the resulted peptides could be used as an alternative therapy to reduce the risk of bacterial infections and inflammatory-related diseases. PMID- 24800671 TI - Chemical composition, antioxidant activity and hepatoprotective potential of Rourea induta Planch. (Connaraceae) against CCl4-induced liver injury in female rats. AB - OBJECTIVES: The aim of this study was to evaluate the flavonoid content of an ethanolic leaf extract from the medicinal plant Rourea induta Planch. (RIEE) and to investigate its hepatoprotective potential and in vivo antioxidant effects. METHODS: Using samples from carbon tetrachloride-treated Wistar female rats treated orally with or without RIEE, we evaluated the aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels in plasma; the levels of the hepatic oxidative stress markers catalase, superoxide dismutase, glutathione peroxidase, and reduced glutathione in liver homogenates; and the thiobarbituric acid reactive substance levels. A histopathology study was performed. A quantitative analysis of the RIEE extract was performed using high-performance liquid chromatography to evaluate its flavonoid content. RESULTS: Oral administration of RIEE significantly reduced carbon tetrachloride-induced elevations in the levels of plasma markers of hepatic damage and lipid peroxidation. It also rescued histopathologic alterations observed in the liver and levels of oxidative stress markers. CONCLUSIONS: RIEE exhibits antioxidant and hepatoprotective activities in vivo, which may be attributable to its flavonoids composition [hyperin (2), quercetin-3-O-beta-xyloside (4), quercetin-3 O-alpha-arabinofuranoside (5), and quercetin (6)]. PMID- 24800672 TI - Shark protein improves bone mineral density in ovariectomized rats and inhibits osteoclast differentiation. AB - OBJECTIVES: Fish proteins are potential sources of natural medicines and food additives. There are many studies being performed to develop underutilized fish proteins. Therefore, the aim of this study was to determine how shark protein functions as a dietary supplement for bone health. METHODS: Three groups of ovariectomized (OVX) rats were fed different diets containing 20% casein protein, 20% shark protein, or 20% cod protein for 4 wk. Bone mineral density of the right femur was measured by dual-energy x-ray absorptiometry and quantitative computed tomography. Furthermore, we prepared low-molecular-weight peptides from shark protein using protease for in vitro studies. Calcitriol was added to bone marrow cells and the receptor activator of the nuclear factor-kappaB ligand was added to RAW264 cells. After 7 d, the number of tartrate-resistant acid phosphatase positive cells was counted. RESULTS: In the shark protein-fed group, bone mineral density of the femur epiphysis was higher than that of the casein protein-fed group. In particular, the shark protein-fed group showed an increase in bone mineral density, represented mainly by trabecular bone. Shark protein hydrolysates inhibited osteoclast formation in bone marrow cells and RAW264 cells. CONCLUSIONS: These results suggest that shark protein might suppress the bone loss caused by estrogen deficiency through the suppression of osteoclast formation. PMID- 24800673 TI - Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. AB - OBJECTIVE: The only known treatment of glucose transporter 1 deficiency syndrome (GLUT-1 DS) is a ketogenic diet (KD), which provides the brain with an alternative fuel. Studies in children with intractable epilepsy have shown that a prolonged KD can induce a progressive loss of bone mineral content associated with poor bone health status, probably as a consequence of a chronic acidic environment. The aim of this study is to determine the long-term effects of a KD on body composition and bone mineral status of patients with GLUT-1 DS, is currently unknown. METHODS: In this case series, we report the changes in body composition and bone mineral status observed in three adult patients with GLUT-1 DS who have been treated with a KD for more than 5 y. RESULTS: A long-term KD did not produce appreciable changes in weight and body composition of adults with GLUT-1 DS. Moreover, we found no evidence of potential adverse effects of a KD on bone health. In summary, this case series contributes to a small but growing body of literature that investigated the potential long-term effects of a KD on bone health. CONCLUSIONS: Our data suggest that maintaining a KD for more than 5 y does not pose any major negative effects on body composition, bone mineral content, and bone mineral density in adults with GLUT-1 DS, a finding that is at variance with previous reports focusing on children with intractable epilepsy. Further studies with larger sizes are needed to confirm and expand our findings. PMID- 24800674 TI - Comment on "Body shape index and mortality in hemodialysis patients". PMID- 24800675 TI - Re: Comment on "Body shape index and mortality in hemodialysis patients". PMID- 24800679 TI - An analogue front-end model for developing neural spike sorting systems. AB - In spike sorting systems, front-end electronics is a crucial pre-processing step that not only has a direct impact on detection and sorting accuracy, but also on power and silicon area. In this work, a behavioural front-end model is proposed to assess the impact of the design parameters (including signal-to-noise ratio, filter type/order, bandwidth, converter resolution/rate) on subsequent spike processing. Initial validation of the model is provided by applying a test stimulus to a hardware platform and comparing the measured circuit response to the expected from the behavioural model. Our model is then used to demonstrate the effect of the Analogue Front-End (AFE) on subsequent spike processing by testing established spike detection and sorting methods on a selection of systems reported in the literature. It is revealed that although these designs have a wide variation in design parameters (and thus also circuit complexity), the ultimate impact on spike processing performance is relatively low (10-15%). This can be used to inform the design of future systems to have an efficient AFE whilst also maintaining good processing performance. PMID- 24800677 TI - Dynamics of the presence of israeli acute paralysis virus in honey bee colonies with colony collapse disorder. AB - The determinants of Colony Collapse Disorder (CCD), a particular case of collapse of honey bee colonies, are still unresolved. Viruses including the Israeli acute paralysis virus (IAPV) were associated with CCD. We found an apiary with colonies showing typical CCD characteristics that bore high loads of IAPV, recovered some colonies from collapse and tested the hypothesis if IAPV was actively replicating in them and infectious to healthy bees. We found that IAPV was the dominant pathogen and it replicated actively in the colonies: viral titers decreased from April to September and increased from September to December. IAPV extracted from infected bees was highly infectious to healthy pupae: they showed several-fold amplification of the viral genome and synthesis of the virion protein VP3. The health of recovered colonies was seriously compromised. Interestingly, a rise of IAPV genomic copies in two colonies coincided with their subsequent collapse. Our results do not imply IAPV as the cause of CCD but indicate that once acquired and induced to replication it acts as an infectious factor that affects the health of the colonies and may determine their survival. This is the first follow up outside the US of CCD-colonies bearing IAPV under natural conditions. PMID- 24800676 TI - Viruses and tetraspanins: lessons from single molecule approaches. AB - Tetraspanins are four-span membrane proteins that are widely distributed in multi cellular organisms and involved in several infectious diseases. They have the unique property to form a network of protein-protein interaction within the plasma membrane, due to the lateral associations with one another and with other membrane proteins. Tracking tetraspanins at the single molecule level using fluorescence microscopy has revealed the membrane behavior of the tetraspanins CD9 and CD81 in epithelial cell lines, providing a first dynamic view of this network. Single molecule tracking highlighted that these 2 proteins can freely diffuse within the plasma membrane but can also be trapped, permanently or transiently, in tetraspanin-enriched areas. More recently, a similar strategy has been used to investigate tetraspanin membrane behavior in the context of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infection. In this review we summarize the main results emphasizing the relationship in terms of membrane partitioning between tetraspanins, some of their partners such as Claudin-1 and EWI-2, and viral proteins during infection. These results will be analyzed in the context of other membrane microdomains, stressing the difference between raft and tetraspanin-enriched microdomains, but also in comparison with virus diffusion at the cell surface. New advanced single molecule techniques that could help to further explore tetraspanin assemblies will be also discussed. PMID- 24800680 TI - Development of a novel electrochemical DNA biosensor based on elongated hexagonal pyramid CdS and poly-isonicotinic acid composite film. AB - Three CdS materials with different shapes (i.e., irregular, rod-like, and elongated hexagonal-pyramid) were hydrothermally synthesized through controlling the molar ratio of Cd(2+) to thiourea. Electrochemical experiments showed that the elongated hexagonal-pyramid CdS (eh-CdS) modified on glassy carbon electrode (GCE) had the higher electrical conductivity than the other two forms. Then the eh-CdS modified GCE was further modified with a layer of poly-isonicotinic acid (PIA) through electro-polymerization in IA solution to enhance the stability and functionality of the interface. The layer-by-layer modification process was characterized by atomic force microscopy and electrochemistry. Then 5'-amino functionalized DNA was immobilized on the electrode surface through coupling with the carboxylic groups derived from PIA-eh-CdS composite film. The hybridization performance of the developed biosensor was evaluated using methylene blue as redox indicator, and the results showed that the peak currents of methylene blue varied with target concentrations in a wide linear range from 1.0 * 10(-14)M to 1.0 * 10(-9)M with a low detection limit of 3.9 * 10(-15)M. The biosensor also showed high stability and good discrimination ability to the one-base, three-base mismatched and non-complementary sequence. PMID- 24800681 TI - Colloidal gold-based immunochromatographic strip test compromising optimised combinations of anti-S. suis capsular polysaccharide polyclonal antibodies for detection of Streptococcus suis. AB - A rapid diagnosis kit that detects Streptococcus suis (S. suis) antigens from urine with an immunochromatographic stripe (ICS) test was developed in this study. The ICS test was produced using colloidal gold coated with polyclonal antibodies (pAbs) against S. suis. The pAbs were developed from rabbits immunised with S. suis serotype 2 capsular polysaccharides (CPS). Development of the pAbs was investigated to establish their binding to CPS and to determine the maximum sensitivity of two combination antibodies for the ICS test. The results of the ICS optimisation revealed that the combinations of pAb C-N1 and pAb C-N2 had the highest sensitivity to CPS. The minimum limitation of ICS sensitivity indicated 1.0 * 10(4) colony forming units (CFU) and a CPS concentration of 0.05 ug. The assay time for detection of S. suis antigens is less than 15 min, which is suitable for rapid detection. A cross-reactive test was also conducted, and it detected no other bacteria (Streptococcus pneumoniae, Streptococcus agalactiae, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae). The cross-reactivity of other serotypes in S. suis was also investigated, and tests for serotypes of 1, 1/2, 3, 4, 5, 6, 7, 8, 9, 14, and 16 were positive. This study presents the first report of a development of an ICS that enables the quantitative detection of streptococcal antigens. The S. suis ICS provides several advantages over other methods, including the speed and simplicity of use. PMID- 24800682 TI - Quantitative detection of tumor necrosis factor-alpha by single molecule counting based on a hybridization chain reaction. AB - This work reports a novel and sensitive quantitative method for detection of tumor necrosis factor-alpha (TNF-alpha) based on single molecule counting and hybridization chain reaction (HCR). In the presence of TNF-alpha, sandwich-type immunocomplex was formed on the surface of glass substrate. The streptavidin acted as a bridge bounded to the biotinylated immunocomplex, which provided three sites to fixate the biotinylated initiator strands. The initiator strands triggered the chain reaction of hybridization to form a long double-helix polymer and SYBR Green I, acted as the fluorescence label, intercalated into the grooves of the long dsDNA polymer. Then, the quantitative detection of TNF-alpha was realized by single molecule counting. Under the optimal conditions, HCR-based single molecule counting quantitative method could successfully detect TNF-alpha in the range of 50 fM to 1 pM, and it revealed a reliable result for TNF-alpha detection in real serum. Moreover, the proposed immunosensor exhibited excellent specificity. These results greatly demonstrated that the proposed method possessed the potentiality in clinical application and it was suitable for quantification of biomarker under low concentration. PMID- 24800683 TI - Development of alpha-polyoxometalate-polypyrrole-Au nanoparticles modified sensor applied for detection of folic acid. AB - In this work, electrochemically synthesized gold nanoparticles (AuNPs) and alpha polyoxometalate (alpha-POM) (K7PMO2W9O39 . H2O) were simultaneously doped into electropolymerized polypyrrole (PPy) film using the cyclic voltammetry (CV) technique. Scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and CVs were used to characterize the composite films. The PPy alpha-POM-AuNPs modified gold (Au) electrode was used to determine folic acid (FA) using square-wave voltammetry (SWV). The modified electrode exhibited excellent electrocatalytic ability to the reduction of FA at 0.3 V (vs. SCE) with the electron transfer rate constant (ks) of 1.15 * 10(-19)s(-1). The common coexisting substances showed no interferences on the response of modified electrode to FA. The modified electrode indicated reproducible behavior and a high level stability during the experiments, making it particularly suitable for the analytical purposes. PMID- 24800684 TI - High-temperature acoustic emission sensing tests using a yttrium calcium oxyborate sensor. AB - Piezoelectric materials have been broadly utilized in acoustic emission sensors, but are often hindered by the loss of piezoelectric properties at temperatures in the 500 degrees C to 700 degrees C range or higher. In this paper, a piezoelectric acoustic emission sensor was designed and fabricated using yttrium calcium oxyborate (YCOB) single crystals, followed by Hsu-Nielsen tests for high temperature (>700 degrees C) applications. The sensitivity of the YCOB sensor was found to have minimal degradation with increasing temperature up to 1000 degrees C. During Hsu-Nielsen tests with a steel bar, this YCOB acoustic sensor showed the ability to detect zero-order symmetric and antisymmetric modes at 30 and 120 kHz, respectively, as well as distinguish a first-order antisymmetric mode at 240 kHz at elevated temperatures up to 1000 degrees C. The frequency characteristics of the signal were verified using a finite-element model and wavelet transformation analysis. PMID- 24800685 TI - Local learned dictionaries optimized to edge orientation for inverse halftoning. AB - A method is proposed for fully restoring local image structures of an unknown continuous-tone patch from an input halftoned patch with homogenously distributed dot patterns, based on a locally learned dictionary pair via feature clustering. First, many training sets consisting of paired halftone and continuous-tone patches are collected, and then histogram-of- oriented-gradient (HOG) feature vectors that describe the edge orientations are calculated from every continuous tone patch, to group the training sets. Next, a dictionary learning algorithm is separately conducted on the categorized training sets, to obtain the halftone and continuous-tone dictionary pairs, optimized to edge-oriented patch representation. Finally, an adaptively smoothing filter is applied to the input halftone patch, to predict the HOG feature vector of an unknown continuous-tone patch, and to select one of the previously learned dictionary pairs, based on the Euclidean distance between the HOG mean feature vectors of the grouped training sets and the predicted HOG vector. In addition to using the local dictionary pairs, a patch fusion technique is used to reduce some artifacts, such as color noise and overemphasized edges on smooth regions. Experimental results show that the use of the paired dictionary selected by the local edge orientation and patch fusion technique not only reduced the artifacts in smooth regions, but also provided well expressed fine details and outlines, especially in the areas of textures, lines, and regular patterns. PMID- 24800686 TI - Vagal intimations for catatonia and electroconvulsive therapy. AB - OBJECTIVES: Catatonia is currently viewed as a unique syndrome that consists of specific motor signs responding to benzodiazepines and electroconvulsive therapy (ECT). Advances in catatonia may provide a new window into the mechanism of ECT. Findings on catatonia are updated and related to the mechanism of ECT. METHODS: Selective literature review. RESULTS: There are several putative models and mechanisms of catatonia concerning motor circuitry dysfunction, abnormal neurotransmitters, epilepsy, genetic risk factors, and endocrine and immune dysfunction. Fear and vagal nerve models are presented casting catatonia in an evolutionary-based autonomic neural substrate of social behaviors, engagement, and disengagement according to perceived level of danger. Benzodiazepines and ECT are thought to have autonomic and vagal effects. CONCLUSIONS: Advances in catatonia provide a new window into the mechanism of ECT. Fear and vagal nerve models call for further anatomical, functional, and clinical studies on the vagal nerve and for further studies on the use of anticholinergic medications in catatonia, on vagal function in catatonia, and on the effects of benzodiazepines, ECT, and induced seizures on cholinergic and vagal function. PMID- 24800687 TI - Neuroimaging and electroconvulsive therapy: a review. AB - BACKGROUND: Since the 1970s, a number of neuroimaging studies of electroconvulsive therapy (ECT) have been conducted to elucidate the working action of this highly efficacious treatment modality. The technologies used are single photon emission tomography, positron emission tomography, magnetic resonance imaging, magnetic resonance spectroscopy, and quantitative electroencephalography. METHODS: A PubMed literature search with focus on clinical studies was made from the inception of the database until December 2013 using the search terms electroconvulsive therapy and neuroimaging. RESULTS: Early methods allowing only identification of global changes of cerebral blood flow and cerebral metabolism show considerable ictal increases of these measures, which normalize during the postictal period. Later methodological developments have given access to measurements of minute activity changes in localized cortical and subcortical areas of the brain and have revealed differences in neurophysiology and metabolism between the hyperactive ictal state and the restorative interictal/postictal periods. Recent magnetic resonance imaging studies seem to pave way for new insights into ECT's effects on increased connectivity in the brain during depression. CONCLUSION: The existing data reveal considerable variations among studies and therefore do not yet allow the formulation of a unified hypothesis for the mechanism of ECT. The rapid developments in imaging technology, however, hold promises for further elucidation of the mode of action of ECT. PMID- 24800688 TI - Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia: exploring the evidence for a connection. AB - Preclinical and clinical evidence show that electroconvulsive therapy (ECT) induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues. These changes may impair neuronal functioning and contribute to the mechanisms underlying ECT induced cognitive deficits. Some but not all clinical data on the subject suggest that blood pressure changes during ECT correlate with indices of cognitive impairment. In animal models, pharmacological manipulations of blood pressure during electroconvulsive shocks attenuate electroconvulsive shock-induced amnestic changes; however, the evidence suggests that antihypertensive mechanisms may not necessarily be involved. Clinical studies involving pre-ECT administration of antihypertensive medications do not provide convincing evidence of benefits. It is concluded that there is insufficient support, at present, for the hypothesis that the hypertensive surge during ECT and the resultant blood brain barrier breach contribute meaningfully to ECT-induced cognitive deficits. Future research should address the subset of patients who experience pronounced hypertensive changes during ECT, and clinically relevant outcome measures, such as autobiographical memory impairment, should be examined. PMID- 24800689 TI - Electroconvulsive therapy's mechanism of action: neuroendocrine hypotheses. AB - Despite a range of etiological theories since the introduction of electroconvulsive therapy (ECT) more than 75 years ago, its mechanism of action remains poorly understood. The neuroendocrine hypothesis is based on the seizure related release of hypothalamic hormones into the blood and cerebrospinal fluid and evidence of endocrine dysfunction in many patients with severe mood disorder. The specific effect of ECT was hypothesized to result from the transverse passage of current through the brain with direct stimulation of axial structures including the diencephalon. The prompt release of adrenocorticotropic hormone, cortisol, and prolactin into blood followed ECT with a return to pretreatment baseline levels in several hours. The elevated levels of hormones were absorbed by the cerebrospinal fluid, providing contact with brain cells and central nervous system structures. An apparently specific pattern of ECT-induced hormone changes, limited to prolactin and cortisol, suggested that ECT released a substance with dopaminergic antagonist and antipsychotic properties. As hypothalamic dysfunction is a key finding in endogenomorphic depression and the abnormal endocrine and physiological functions usually normalize with recovery, this led to a search for biological markers that would supplement clinical assessment of diagnosis and treatment response. One of these, the overnight dexamethasone suppression test found that 40% to 50% of melancholic depressed patients had abnormal results, whereas 90% of control patients suppressed normally. This was followed by a period of uncritical overenthusiasm followed by wholesale rejection of the clinical neuroendocrine strategies. Several key methodological issues received inadequate attention, and there have been calls to revisit this topic. PMID- 24800690 TI - A systematic review of men's experiences of their partner's mastectomy: coping with altered bodies. AB - OBJECTIVE: To explore men's experiences of their partner's altered physique and body image as a result of mastectomy and subsequent reconstructive surgeries. DESIGN: A systematic review of qualitative and mixed-methods studies. DATA SOURCES: Ovid, EBSCOhost, Web of Science, SCOPUS and ASSIA ProQuest databases were searched using 1) truncations of breast cancer, hereditary breast cancer and BRCA 2) words relating to partner relationships; spouse, husband, partner, men and couple 3) breast cancer surgeries; mastectomy, prophylactic mastectomy and breast reconstruction and 4) body image. REVIEW METHOD: Methodological rigour was quality assessed. RESULTS: A total of 756 citations were retrieved. Seventeen articles remained following the removal of duplicates, papers unrelated to breast cancer, male breast cancer, papers that excluded men's experiences of their partner's breast cancer and altered body image. Thematic analysis was applied and produced five themes: experiences of the altered body, communication, impact on relationship, information giving and recommendations. CONCLUSION: Men indicated that perceptions of their partner's altered physique and body image, following mastectomy, was secondary to their health. Some men were distressed by their partner's bodily alterations leading to highly complex and emotive coping mechanisms. Men found talking to their partner about physique and body image challenging. Closed communication, however, often led to conflict and poor psychological well-being in both partners. To help prepare for the changes to their partner's body, men desired tailored information. Effective information giving contributes to effective coping strategies helping men to better support their partner affected or at risk from breast cancer, leading to enhanced psychological and emotional well-being in couples. PMID- 24800691 TI - Closing gaps: linking elements that control stomatal movement. AB - Stomata are an attractive experimental system in plant biology, because the responses of guard cells to environmental signals can be directly linked to changes in the aperture of stomatal pores. In this review, the mechanics of stomatal movement are discussed in relation to ion transport in guard cells. Emphasis is placed on the ion pumps, transporters, and channels in the plasma membrane, as well as in the vacuolar membrane. The biophysical properties of transport proteins for H(+), K(+), Ca(2+), and anions are discussed and related to their function in guard cells during stomatal movements. Guard cell signaling pathways for ABA, CO2, ozone, microbe-associated molecular patterns (MAMPs) and blue light are presented. Special attention is given to the regulation of the slow anion channel (SLAC) and SLAC homolog (SLAH)-type anion channels by the ABA signalosome. Over the last decade, several knowledge gaps in the regulation of ion transport in guard cells have been closed. The current state of knowledge is an excellent starting point for tackling important open questions concerning stress tolerance in plants. PMID- 24800692 TI - Complete genome sequencing and comparative analysis of the linezolid-resistant Enterococcus faecalis strain DENG1. AB - Genome level analysis of bacterial strains provides information on genetic composition and resistance mechanisms to clinically relevant antibiotics. To date, whole genome characterization of linezolid-resistant Enterococcus faecalis isolated in the clinic is lacking. In this study, we report the entire genome sequence, genomic characteristics and virulence factors of a pathogenic E. faecalis strain, DENG1. Our results showed considerable differences in genomic characteristics and virulence factors compared with other E. faecalis strains (V583 and OG1RF). The genome of this LZD-resistant E. faecalis strain can be used as a reference to study the mechanism of LZD resistance and the phylogenetic relationship of E. faecalis strains worldwide. PMID- 24800694 TI - A modified method for implantation of pluripotent stem cells under the rodent kidney capsule. AB - Teratoma formation, the standard in vivo pluripotency assay, is also frequently used as a tumorigenicity assay. A common concern in therapeutic stem cell applications is the tumorigenicity potential of a small number of cell impurities in the final product. Estimation of this small number is hampered by the inaccurate methodology of the tumorigenicity assay. Hence, a protocol for tumorigenicity assay that can deliver a defined number of cells, without error introduced by leakage or migration of cells is needed. In this study, we tested our modified transplantation method that allows for transplant of small numbers of pluripotent stem cells (PSCs) under the kidney capsule with minimal cell leakage. A glass capillary with a finely shaped tip and an attached mouth pipette was used to inject PSCs into the rodent kidney capsule. H9 embryonic and induced PSCs were tagged with Fluc and green fluorescence protein reporter genes and divided in different cell doses for transplantation. Bioluminescence imaging (BLI) on the day of surgery showed that the cell signal was confined to the kidney and signal intensity correlated with increasing transplant cell numbers. The overall cell leakage rate was 17% and the rodent survival rate was 96%. Teratoma formation was observed in rodents transplanted with cell numbers between 1 * 10(5)-2 * 10(6). We conclude that this modified procedure for transplanting PSCs under the kidney capsule allows for transplantation of a defined number of PSCs with significant reduction of error associated with cell leakage from the transplant site. PMID- 24800695 TI - On the selection of sampling points for myocardial T1 mapping. AB - PURPOSE: To provide a method for the optimal selection of sampling points for myocardial T1 mapping, and to evaluate how this selection affects the precision. THEORY: The Cramer-Rao lower bound on the variance of the unbiased estimator was derived for the sampling of the longitudinal magnetization curve, as a function of T1 , signal-to-noise ratio, and noise mean. The bound was then minimized numerically over a search space of possible sampling points to find the optimal selection of sampling points. METHODS: Numerical simulations were carried out for a saturation recovery-based T1 mapping sequence, comparing the proposed point selection method to a uniform distribution of sampling points along the recovery curve for various T1 ranges of interest, as well as number of sampling points. Phantom imaging was performed to replicate the scenarios in numerical simulations. In vivo imaging for myocardial T1 mapping was also performed in healthy subjects. RESULTS: Numerical simulations show that the precision can be improved by 13-25% by selecting the sampling points according to the target T1 values of interest. Results of the phantom imaging were not significantly different than the theoretical predictions for different sampling strategies, signal-to-noise ratio and number of sampling points. In vivo imaging showed precision can be improved in myocardial T1 mapping using the proposed point selection method as predicted by theory. CONCLUSION: The framework presented can be used to select the sampling points to improve the precision without penalties on accuracy or scan time. PMID- 24800697 TI - Transforaminal epidural steroid injections followed by mechanical diagnosis and therapy to prevent surgery for lumbar disc herniation. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To report the clinical course of patients with MRI-confirmed lumbar disc herniation-related radicular noncentralizing pain who received transforaminal epidural steroid injections (TESIs) and mechanical diagnosis and therapy (MDT). SUMMARY OF BACKGROUND DATA: Noncentralizing symptoms in patients with lumbar disc herniation are associated with poor outcome. Commonly used treatments for these patients include TESIs and MDT. No study has evaluated the outcome of combining both strategies. METHODS: Consecutive candidates for herniated lumbar disc surgery with noncentralizing chronic pain were eligible. Patients received TESIs followed by MDT. The primary outcomes were pain severity in the leg, disability (Roland-Morris Disability Questionnaire for Sciatica), and global perceived effect (GPE). Outcomes were measured at baseline, discharge, and 12 months. Linear mixed-models and McNemar's tests were used to analyze outcome data. RESULTS: Sixty-nine patients receive TESIs. After TESIs, symptoms were resolved completely in 11 patients (16%). In these patients, symptom resolution was maintained at 12 months. A second subgroup of 32 patients (46%) reported significantly less pain after TESIs and showed centralization with MDT reassessment (significant reductions in leg pain and disability [P < 0.001]) and a satisfaction rate of 90% at 12 months. A third subgroup of 11 patients (16%) reported significantly less pain after TESIs but still showed noncentralization with MDT reassessment (significant reductions in leg pain and disability [P < 0.05] and a satisfaction rate of 50% at 12 months). A fourth subgroup of 15 patients (22%) did not respond on TESIs and received an operative intervention. CONCLUSION: The results indicate that a course of TESIs followed by MDT may be able to avoid surgery in a substantial proportion of candidates for herniated lumbar disc surgery. PMID- 24800696 TI - Immunoexpression of metalloproteinases 2 and 14 and TIMP-2 inhibitor in main types of primary gastric carcinomas and lymph node metastasis. AB - Metalloproteinase-2 (MMP-2) and -14 (MMP-14) and the tissue inhibitor of metalloproteinases type 2 (TIMP-2) participate in epithelial-mesenchymal transition and tumor progression in many cancers. However, the correlation between these enzymes in gastric cancer and the metastatic potential to their respective lymph node needs to be determined. Here, we evaluated the expression of these enzymes in gastric carcinoma and lymph node metastases and their possible involvement in tumor progression. Histological samples from 83 patients with gastric cancer and their respective lymph nodes were used. MMP-2, MMP-14 and TIMP-2 immunoexpression was scored. TIMP-2 expression in tumor-associated macrophages occurred more frequently than in normal mucosa (P = 0.0128). Female tumor samples presented higher MMP-2 expression (P = 0.0248), while TIMP-2 occurred mainly in patients over 50 years old (P = 0.0034). MMP-2 was higher expressed in primary tumor macrophages than in neoplastic cells (P = 0.0118), and was also seen in macrophages from metastatic-affected lymph nodes of intestinal and diffuse histotypes (P = 0.0006). MMP-2, MMP-14 and TIMP-2 expression in mononuclear cells might be correlated with progression of gastric cancer. MMP-14 production by macrophages appears to be more involved in diffuse gastric cancer progression. PMID- 24800698 TI - Cardiomyocyte cytokinesis score: a potential method for cardiomyocyte proliferation. AB - One of the most important indicators of myocardial regeneration is cardiomyocyte proliferation. However, it is difficult to distinguish cardiomyocytes in the regenerating stage from binucleated or multinucleated myocytes by conventional morphometric techniques. As cell cycle progression (CCP) scores have been successfully applied to the evaluation of the proliferation of cancer cells, we sought to establish a multi-gene score to evaluate cardiomyocyte proliferation in this study. Given the disturbances of nuclear division without cell division that occurs in cardiomyocytes, ten cytokinesis-correlated genes (Anln, Aurkb, Cenpa, Kif4, Kif23, Prc1, RhoA, Spin1, TACC2, and CDC42) were chosen to establish the cardiomyocyte cytokinesis score (CC-Score). The expression levels of these genes in H9C2 rat cardiomyoblast cells, the proliferation of which were stimulated or inhibited, were detected using qRT-PCR. To confirm the feasibility of the CC Score system, four conventional methods for evaluating cardiomyocyte proliferation, including the MTT assay, BrdU assay, immunofluorescence, and flow cytometry analysis, were used in each group. The results of the CC-Score in the assessment of the proliferation of H9C2 cells were consistent with those of four commonly used proliferative assay methods. We conclude that the CC-Score can be used to assess the proliferation status of H9C2 cells, and suggest that the CC Score may be a potential method for the assessment of cardiomyocyte proliferation in myocardial regeneration. However, validation studies utilizing primary cultured rat cardiomyocytes and heart tissue are warranted. PMID- 24800700 TI - Platelet-rich plasma: should we wait for the verdict? PMID- 24800699 TI - METelemedicine: a pilot study with rural alcohol users on community supervision. AB - PURPOSE: This pilot study examined a telemedicine-based intervention using motivational enhancement therapy (METelemedicine) to reduce alcohol use among a sample of at-risk, rural alcohol users. METHODS: A total of 127 rural alcohol users were recruited from community supervision offices and engaged in brief intervention sessions using telemedicine. Analysis examined alcohol outcomes at 3 months postbaseline. FINDINGS: Findings indicated that although there were no overall differences between comparison groups on alcohol outcomes, 3+ sessions of METelemedicine significantly reduced the likelihood of any alcohol use by 72% (P < .05). In addition, 3+ sessions of the intervention predicted fewer days of drinking in the follow-up period, fewer drinks per week, and fewer days experiencing alcohol problems. CONCLUSIONS: Findings demonstrate that telemedicine may be a promising approach to deliver interventions with alcohol users who may not utilize formal treatment services. This method has potential to decrease some of the barriers to access and use of evidence-based treatment for populations in need of services. PMID- 24800702 TI - Efinaconazole 10% nail solution: a new topical treatment with broad antifungal activity for onychomycosis monotherapy. AB - BACKGROUND: Topical therapies for onychomycosis are associated with less adverse events than systemic therapies, but poor nail penetration limits their efficacy. Consequently, an efinaconazole 10% nail solution was developed. OBJECTIVE: To review the evidence supporting the usefulness of efinaconazole monotherapy in onychomycosis management. METHODS: PubMed and clinicaltrials.gov databases and abstracts from the 2013 annual meeting of the American Academy of Dermatology were searched in April 2013 using the terms "efinaconazole," "IDP-108," and "KP 103." RESULTS: In vitro, efinaconazole possesses a broad antifungal activity similar or superior to that of other antifungals. Its low affinity for keratin results in good nail penetration. Efinaconazole 10% nail solution administered daily for 36 or 48 weeks to treat mild to moderate toenail onychomycosis caused by dermatophytes results in complete and mycologic cure rates of 15 to 25% and 53 to 87%, respectively. No serious skin reaction is associated with its use. CONCLUSION: Efinaconazole 10% nail solution is a promising new treatment for onychomycosis. PMID- 24800703 TI - Systematic review of interleukin-12, interleukin-17, and interleukin-23 pathway inhibitors for the treatment of moderate-to-severe chronic plaque psoriasis: ustekinumab, briakinumab, tildrakizumab, guselkumab, secukinumab, ixekizumab, and brodalumab. AB - BACKGROUND: Monoclonal antibodies known as biologic agents specifically targeted against interleukin-12 (IL-12), interleukin-17A (IL-17), and interleukin-23 (IL 23) have been the focus of research for moderate-to-severe chronic plaque psoriasis in recent years. OBJECTIVES: To discuss the immune-mediated model of psoriasis and to summarize current knowledge of the clinical efficacy and safety of new biologic agents for moderate-to-severe chronic plaque psoriasis. METHODS: The PubMed database was searched for relevant articles on ustekinumab, briakinumab, tildrakizumab (MK-322), guselkumab, secukinumab, ixekizumab, and brodalumab published between January 2005 and July 2013. RESULTS: Fifty-five articles were identified. These studies suggest that the biologic agents specifically targeting IL-12, IL-17, and IL-23 are efficacious and safe in the treatment of moderate-to-severe psoriasis in adults. CONCLUSION: Current data from clinical trials suggest that biologic agents targeting IL-12, IL-17, and IL 23 are safe and efficacious drugs for use in moderate-to-severe chronic plaque psoriasis. Long-term data still need to be established. PMID- 24800704 TI - Teletriage for provision of dermatologic care: a pilot program in the Department of Veterans Affairs. AB - BACKGROUND: The scarcity of dermatologists has prompted the creation of innovative methods for delivering dermatologic care. METHODS: Teletriage is a method used in teledermatology to efficiently assess skin complaints in patients who do not have prompt access to conventional dermatologic care. Their primary care clinicians are provided with management recommendations, reassured that the lesion of concern is benign, or recommended to send their patient for a face-to face dermatology visit. The Providence VA Medical Center conducted a pilot program testing the utility of teletriage for patients with skin complaints from June 2011 to August 2011. RESULTS: The pilot program revealed that with the teletriage protocol, face-to-face visits were reduced by 38%. This program suggests that teletriage could be a useful tool for providing efficient dermatologic care, and has led to broader implementation. CONCLUSION: Teletriage is a potentially useful approach for efficiently addressing specific dermatologic complaints and improving access to care for those complaints. PMID- 24800705 TI - Burning mouth syndrome: patch test results from a large case series. AB - BACKGROUND: Burning mouth syndrome (BMS) is a burning or sore mouth in the absence of changes in the oral mucosa. It is often difficult to diagnose and treat. Numerous theories of the etiology have been suggested, including contact allergy. OBJECTIVE: To determine the clinical utility of patch testing in patients with BMS. METHODS: We retrospectively reviewed the charts of patients diagnosed with BMS who had patch testing performed between January 1, 2008, and July 31, 2012. RESULTS: Of 142 consecutive patients with BMS, 132 consented to patch testing; 89 (67%) had allergic patch test reactions. Of the patients with positive results, 66 (74%) had results that were deemed to have possible relevance. The most common allergens detected were nickel sulfate 2.5%, dodecyl gallate 0.3%, octyl gallate 0.3%, fragrance mix 8%, benzoyl peroxide 1%, and cinnamic alcohol 1%. CONCLUSIONS: Our findings suggest that contact allergy may be an etiologic factor in some patients with BMS. Patch testing is a useful investigation for BMS patients. PMID- 24800706 TI - Dermatofibrosarcoma protuberans in pediatric patients: a report of 17 cases. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor. In children, there are acquired and congenital presentations. Due to clinical similarities with other conditions, diagnosis may be delayed. OBJECTIVE: To review the clinical characteristics and treatment of DFSP in pediatric patients. METHODS: A retrospective chart review was performed from January 2002 to September 2012. Inclusion criteria were patients under 18 years of age with a histopathologic diagnosis of DFSP. Data on demographics, clinical characteristics, treatments, and outcomes were collected. RESULTS: Information was gathered from 17 patients; 9 (53%) were female. Congenital lesions were reported in 7 patients. The mean delay of diagnosis was 5.7 years; the most common anatomic location was the trunk in 8 of 17 (47%) cases. Treatment options included wide local surgery, Mohs surgery, and imatinib mesylate. CONCLUSION: A detailed medical history and identification of the natural course of common conditions seen in pediatric patients are important to identify less common lesions and to suspect DFSP. PMID- 24800707 TI - Skin conditions in community-living older adults: prevalence and characteristics of medical care service use. AB - BACKGROUND: There are considerable gaps in the knowledge of the global epidemiology of skin conditions in the geriatric population. OBJECTIVE: This study attempted to (1) determine the frequency of skin conditions, (2) evaluate the agreement between two different data sources of information (self-report versus administrative), and (3) document medical care service use for skin conditions in a representative sample of community-dwelling older adults. METHODS: A secondary analysis using data from a longitudinal population-based health survey conducted in Quebec (2005-2008) within a sample of 2,811 community dwelling older adults. RESULTS: Our results highlighted a high prevalence rate of self-reported (13%) and diagnosed skin conditions (21%). Agreement between data sources was low (kappa < 0.20). Most dermatologic-related medical visits were made to dermatologists (almost 60%). CONCLUSION: The epidemiology of skin conditions in the geriatric population is an under researched field, despite its important prevalence and relevance as a source of information for assessing the health care needs of older adults. PMID- 24800708 TI - Systemic corticosteroids are frequently prescribed for psoriasis. AB - BACKGROUND: The use of systemic corticosteroids is discouraged in major psoriasis treatment guidelines. PURPOSE: Our objective was to assess how often systemic corticosteroids are prescribed for psoriasis and trends in their use over time. METHODS: We used National Ambulatory Medical Care Survey (NAMCS) data to determine the systemic medications prescribed for psoriasis from 1989 to 2010. We confirmed the findings by analysis of 2003-2007 MarketScan Medicaid data. RESULTS: Systemic corticosteroids were prescribed at 650,000 (95% CI 380,000 920,000) of 21,000,000 psoriasis visits; 93% of these visits were to dermatologists. Of the top nine systemic medications listed at psoriasis visits, three of them were corticosteroids. Corticosteroids were the second most commonly prescribed systemic medication for psoriasis. No significant change in the use of systemic corticosteroids for psoriasis over time was observed (p = .27). In the MarketScan data, prednisone was prescribed more commonly than either methotrexate or etanercept. LIMITATIONS: Corticosteroid doses and the length of treatment were not recorded in the NAMCS data. CONCLUSIONS: Systemic corticosteroids are among the most common systemic treatments used for psoriasis despite current guidelines. Data are acutely needed on the risks and benefits so that physicians and patients can make evidence-based decisions about their use. PMID- 24800709 TI - Surface anatomy of the lip for the dermatologist. AB - BACKGROUND: Expert treatment of cutaneous facial pathology requires the correct diagnosis and precise anatomic knowledge. Lip surface anatomy is complex. CASE REPORT: This brief report reviews the clinically relevant surface anatomy of the lip. PMID- 24800710 TI - Angiofibroma of the vulva. AB - BACKGROUND: Cellular angiofibroma is a benign and rare tumor. It usually arises in middle-aged women and involves the vulva. Complete local excision of the tumor is the best cure, and, usually, there is no recurrence after surgery. CASE REPORT: We describe a 20-year-old woman with a painless, growing vulvar mass who presented about 3 years ago. Her past medical history was negative for oral contraceptives, tobacco, and alcohol, and there were no similar lesions in her family history. A physical examination revealed two masses on the right and the left labia majora and similar lesions on the left axilla and both breasts. An uncomplicated simple resection of the vulvar masses was done in the operating room. There was no evidence of recurrence 12 months after surgery. Histopathologic examination revealed that the findings were consistent with the diagnosis of the cellular angiofibroma. Based on our knowledge, this patient is the youngest case of vulvar angiofibroma. The lesions were large and symmetrical (on both labia majora), although they differed in size. Extravulvar (breast and axilla) lesions were also noteworthy in this patient. PMID- 24800711 TI - Kerion of the vulva caused by Trichophyton mentagrophytes. AB - BACKGROUND: Deep dermatophytosis of genital skin is a rare clinical manifestation of infection by a common group of pathogens. OBJECTIVE: We emphasize the importance of clinical suspicion and the use of accurate diagnostic methods in the evaluation of deep dermatophytosis. METHODS: We report a single case of tinea pubis, kerion type, caused by Trichophyton mentagrophytes in an immunocompetent host. RESULTS: A 54-year-old female presented with a suppurative infection of the vulva and pubis that was unresponsive to empirical antibiotic therapy. T. mentagrophytes was isolated. Oral itraconazole was initiated on the basis of clinical suspicion and continued for a total of 6 weeks. CONCLUSION: Accurate diagnosis and treatment of deep dermatophytosis of genital skin rests upon proper identification of the pathogen. Prompt initiation of treatment with an oral antifungal agent, such as itraconazole, should be undertaken in order to avoid irreversible scarring alopecia. PMID- 24800712 TI - Ecthyma gangrenosum in a newborn causing external otitis with complete facial nerve palsy. AB - BACKGROUND: Ecthyma gangrenosum (EG) involving the external ear canal is an unusual presentation. OBJECTIVE: To describe a case of EG diagnosed in a 5-day old female who was admitted to our institute with multiple soft-tissue lesions involving the right arm, forearm, back, and perineum and with a complete facial palsy associated with ipsilateral external otitis. RESULTS: The patient presented neonatal sepsis associated with significant leucopenia, thrombocytopenia and alteration of the coagulation profile. Microbiological analysis was performed on the purulent otorrhea and on the exudate material collected at the level of the genital lesion; both of these specimens tested positive for the presence of Pseudomonas aeruginosa. An intravenous antibiotic treatment was administered and a rapid improvement from the infection was observed. CONCLUSION: The rare occurrence of this presentation, combined with the potential for fatal complications from EG if not swiftly diagnosed underline the importance of this case. PMID- 24800713 TI - Scalp trauma: a risk factor for lichen planopilaris? AB - BACKGROUND: Lichen planopilaris is a type of primary scarring alopecia that is characterized by perifollicular lymphocytic inflammation and fibrosis. The cause remains poorly understood, although recent research has begun to unravel some of the molecular mechanisms implicated in the pathogenesis. OBJECTIVE: To present a case of biopsy-proven lichen planopilaris in a patient who had previously suffered serious head injury. Lichen planopilaris developed only in the areas of trauma. CONCLUSION: Our findings highlight the possible association between scalp trauma and the development of lichen planopilaris. Further research is needed to understand the role of scalp trauma in the pathogenesis of scarring alopecia. PMID- 24800715 TI - Motor recovery and cortical plasticity after functional electrical stimulation in a rat model of focal stroke. AB - OBJECTIVE: The aim of this study was to investigate the functional responses and plastic cortical changes in a sample of animals with sequelae of cerebral ischemia that were subjected to a model of functional electrical stimulation (FES). DESIGN: Rats received an ischemic cortical lesion (Rose Bengal method) and were randomized and submitted to an FES stimulation (1-2 mA, 30 Hz, 20-40 mins for 14 days) or sham stimulation. The Foot Fault Test was performed before inducing the cortical lesion and also before and after FES. Brain immunochemistry labeling with microtubule-associated protein-2 and neurofilament-200 markers was performed after FES. RESULTS: The authors found a decreased percentage of errors in the Foot Fault Test (P < 0.001) in the stimulated group compared with the sham group after FES. FES has not altered the lesion size. Spontaneous motor parameters returned to basal values in both groups. The qualitative analysis showed an increased amount of radial microtubule-associated protein-2 immunoreactive fibers in the preserved cortex adjacent to stroke site in the stimulated animals. Regarding the measurements of neurofilament-200 immunostaining, there were no differences between the hemispheres or groups in area or intensity. CONCLUSIONS: Acute and short period of FES led to motor recovery of ankle joint neurodisability. The extent to which compensatory plasticity occurs after stroke or after FES and the extent to which it contributes to functional recovery are yet unclear. The changes induced by the stimulation may improve the ability of the nervous system to undergo spontaneous recovery, which is of substantial interest for neurorehabilitation strategies. PMID- 24800716 TI - Disexecutive functions and depression in patients with Parkinson disease: the impact on rehabilitation outcome. AB - BACKGROUND: Studies relating to patients with Parkinson disease that assess neuropsychologic, psychologic, and clinical aspects are very uncommon. OBJECTIVE: The aim of this study was to analyze the impact of executive functioning (impaired vs. not impaired) or depression (depressed vs. nondepressed) on the outcome of rehabilitation treatment in patients with Parkinson disease without dementia at the medium stage of disease. METHODS: Forty consecutive inpatients affected by Parkinson disease were psychologically and neuropsychologically assessed by means of standardized tests during the first week of admission and at discharge after undergoing an intensive rehabilitation training. RESULTS: At baseline, the patients (mean [SD] age, 70.1 [8.0]; Mini-Mental State Examination [MMSE], >=24) showed impairment in the following executive functions: frontal functions (32.5%), selective and divided attention (55.0% and 41.9%, respectively), and word fluency (17.5%). Depressive symptoms reported using the Geriatric Depression Scale were distributed as follows: mild (n = 13), 32.5%; moderate (n = 4), 10.0%; and severe (n = 5), 12.5%. As for the outcome of the intensive rehabilitation treatment, a general improvement in the Unified Parkinson's Disease Rating Scale, the Berg's scale, the 6-min walking test, and the Timed Up and Go test was observed (P < 0.0001). The improvement was homogeneous for all groupings of the patients for all of the considered variables, indicating that the changes in performance as a result of treatment were unaffected by the presence of executive function deficits or moderate-to severe depression. CONCLUSIONS: The patients' executive function impairment or moderate-to-severe depressive symptoms did not seem to interfere with the outcome of the intensive physical and occupational rehabilitation. Therefore, these aspects in patients without dementia should not be considered a contraindication to an intensive rehabilitation program. Furthermore, despite the presence of impaired executive functions and/or of depressive symptoms, the 4-wk multidisciplinary rehabilitation program resulted to be highly effective. PMID- 24800714 TI - Change and predictors of quality of life in institutionalized older adults with dementia. AB - PURPOSE: This study aims to assess the change in and predictive factors of the quality of life (QoL) of institutionalized older adults with dementia over a 20 month period. METHODS: Information was used from a follow-up study conducted over an average period of 19.61 +/- 1.93 months on a sample of 274 institutionalized older adults aged 60 or over, diagnosed with dementia. Two linear regression models were built to predict change in the EQ-5D index and the quality of life in Alzheimer's disease (QOL-AD) scale, taking as independent variables: sociodemographic characteristics and measures of functional ability (Barthel Index), depression in dementia (Cornell Scale), number of chronic health problems, cognitive level (MEC, the Spanish Mini-Mental State Examination) and severity of dementia (Clinical Dementia Rating) at baseline. RESULTS: The majority of the participants were women (81.75 %) with an average age of 84.70 +/ 6.51 years, single (78.15 %), with severe dementia and moderate functional dependence. There was a significant decrease on the EQ-5D, EQ-VAS and QOL-AD between baseline and follow-up scores. The main predictors of QoL of the institutionalized older adults with dementia were the number of chronic problems and baseline scores of the QoL measures. CONCLUSIONS: A significant decrease in the QoL of institutionalized older adults was observed over a 20-month period. Results suggest that interventions aimed at reducing the number of chronic medical conditions may have a beneficial effect on older adults' QoL. PMID- 24800717 TI - Does activity limitation predict discharge destination for postacute care patients? AB - OBJECTIVE: This study aimed to examine the ability of different domains of activity limitation to predict discharge destination (home vs. nonhome settings) 1 mo after hospital discharge for postacute rehabilitation patients. DESIGN: A secondary analysis was conducted using a data set of 518 adults with neurologic, lower extremity orthopedic, and complex medical conditions followed after discharge from a hospital into postacute care. Variables collected at baseline include activity limitations (basic mobility, daily activity, and applied cognitive function, measured by the Activity Measure for Post-Acute Care), demographics, diagnosis, and cognitive status. The discharge destination was recorded at 1 mo after being discharged from the hospital. RESULTS: Correlational analyses revealed that the 1-mo discharge destination was correlated with two domains of activity (basic mobility and daily activity) and cognitive status. However, multiple logistic regression and receiver operating characteristic curve analyses showed that basic mobility functioning performed the best in discriminating home vs. nonhome living. CONCLUSIONS: This study supported the evidence that basic mobility functioning is a critical determinant of discharge home for postacute rehabilitation patients. The Activity Measure for Post-Acute Care-basic mobility showed good usability in discriminating home vs. nonhome living. The findings shed light on the importance of basic mobility functioning in the discharge planning process. PMID- 24800718 TI - Effect of thermal stimulation on corticomotor excitability in patients with stroke. AB - OBJECTIVE: This study examined the immediate effects of noxious and innocuous thermal stimulation intervention on corticomotor excitability for the paretic arm in patients with stroke. DESIGN: Sixteen patients with stroke for more than 3 mos were randomly assigned into the experimental and control groups. All participants received the thermal stimulation protocol on the affected arm for 30 mins. The experimental group received noxious heat (46 degrees C-47 degrees C) and cold (7 degrees C-8 degrees C) stimuli, and the control group received innocuous heat (40 degrees C-41 degrees C) and cold (20 degrees C-21 degrees C) stimuli. Corticomotor excitability was assessed to measure the motor threshold, size of cortical motor output map, and mean motor evoked potentials for the abductor pollicis brevis by focal transcranial magnetic stimulation before and after 30 mins of thermal stimulation intervention program. RESULTS: The findings of transcranial magnetic stimulation revealed a significant increase in map size of the affected hemisphere and mean motor evoked potentials in the experimental group. Moreover, significant differences in the change values of map size (7.0 [7.9] for the experimental group vs. -1.7 [2.9] for the control group, P = 0.03) and mean (SD) motor evoked potentials (0.4 [8.9] mV for the experimental group vs. -0.1 [0.1] mV for the control group, P = 0.03) were found. CONCLUSIONS: The preliminary results suggest that the noxious 30 mins of thermal stimulation intervention induced neurophysiologic changes in the motor cortex of the lesioned hemisphere. PMID- 24800719 TI - Association between energy availability and physical activity in older adults. AB - OBJECTIVE: Age-related declines in physical activity are commonly observed in human and animal populations, but their physiologic bases are not fully understood. The authors hypothesize that a lack of available energy contributes to low levels of activity in older persons. DESIGN: Cross-sectional analyses of relationships between physical activity level and energy availability were performed in 602 community-dwelling volunteers aged 45-91 yrs from the Baltimore Longitudinal Study of Aging. Energy expenditure was measured at rest and during a maximal 400-m walk for calculation of "available energy." Overall and vigorous physical activity levels were assessed using standardized questionnaires. General linear regression models were used to assess the relationships between available energy and general and vigorous physical activity, and stratified analyses were used to analyze the possible differential association between available energy and physical activity across high and low (peak sustained walking oxygen consumption per unit time, <18.3 ml of oxygen per kilogram per minute) levels of aerobic fitness. RESULTS: Low available energy was associated with low levels of total physical activity (beta = 64.678, P = 0.015) and vigorous activity (beta = 9.123, P < 0.0001). The direct relationship between available energy and physical activity was particularly strong in persons categorized as having low aerobic fitness between available energy and physical activity with both total (beta = 119.783, P = 0.022) and vigorous activity (beta = 10.246, P = 0.015) and was independent of body composition and age. CONCLUSIONS: The findings from this study support the hypothesis that available energy promotes the maintenance of physical activity in older persons. The findings also run counter to the perception that age-related declines in physical activity are primarily societally or behaviorally driven. PMID- 24800721 TI - A microfluidic-based platform for tumour spheroid culture, monitoring and drug screening. AB - The development of novel cellular models that can replace animals in preclinical trials of drug candidates is one of the major goals of cell engineering. Current in vitro screening methods hardly correspond with the in vivo situation, whereas there is a lack of assays for more accurate cell culture models. Therefore, development of automated assays for 3D cell culture models is urgently required. In this work, we present a SpheroChip system: a microfluidic-based platform for long-term 3D cell culture and analysis. The system is compatible with commercially available microplate readers and provides continuous, in situ monitoring of tumour spheroids cultured on a chip. The microfluidic chip consists of cell culture microchambers and hemispherical microwells connected with a concentration gradient generator. HT-29 and Hep-G2 cells were successfully cultured as tumour spheroids in the SpheroChip, and metabolic activity of cells was monitored for up to two weeks by in situ fluorimetric measurements. Cellular response to an anticancer drug was observed using the SpheroChip. The experimental setup provided the unique possibility of observing dynamic changes in metabolic activity of one culture during sequencing days after drug dosage. According to this new approach, unknown phenomena of cellular response to the anticancer drug were observed, such as increase of metabolic activity shortly after drug dosage. Moreover, the influence of a second dose of a drug was evaluated. The SpheroChip system can be used by researchers working on drug screening, evaluation of anticancer procedures and chemoresistance phenomena. PMID- 24800720 TI - Stem cells in the nervous system. AB - Given their capacity to regenerate cells lost through injury or disease, stem cells offer new vistas into possible treatments for degenerative diseases and their underlying causes. As such, stem cell biology is emerging as a driving force behind many studies in regenerative medicine. This review focuses on the current understanding of the applications of stem cells in treating ailments of the human brain, with an emphasis on neurodegenerative diseases. Two types of neural stem cells are discussed: endogenous neural stem cells residing within the adult brain and pluripotent stem cells capable of forming neural cells in culture. Endogenous neural stem cells give rise to neurons throughout life, but they are restricted to specialized regions in the brain. Elucidating the molecular mechanisms regulating these cells is key in determining their therapeutic potential as well as finding mechanisms to activate dormant stem cells outside these specialized microdomains. In parallel, patient-derived stem cells can be used to generate neural cells in culture, providing new tools for disease modeling, drug testing, and cell-based therapies. Turning these technologies into viable treatments will require the integration of basic science with clinical skills in rehabilitation. PMID- 24800722 TI - Platelet reactivity in comatose survivors of cardiac arrest undergoing percutaneous coronary intervention and hypothermia. AB - AIMS: To investigate the effects of clopidogrel and eptifibatide on platelet reactivity in patients resuscitated from cardiac arrest undergoing percutaneous coronary intervention (PCI) and hypothermia. METHODS AND RESULTS: VerifyNow(r) and Multiplate(r) aggregometry were used before, and 4, 12, 22 and 48 hours after 600 mg clopidogrel treatment in 28 post-cardiac arrest hypothermic patients and in 14 normothermic patients with acute coronary syndrome. Basal platelet reactivity after stimulation with iso-thrombin receptor-activating peptide (TRAP) and PAR4-activating peptide (BASE) was significantly lower in the post-cardiac arrest group and persisted up to 48 hours. The antiplatelet effect of clopidogrel measured by VerifyNow and expressed as % inhibition was significantly lower in the post-cardiac arrest group. It was close to zero with an increase to only around 10% after 48 hours. Post-cardiac arrest patients receiving eptifibatide showed profound platelet inhibition measured by both VerifyNow IIb/IIIa and Multiplate TRAP tests for at least 22 hours after administration. CONCLUSIONS: Post-resuscitation syndrome with ongoing hypothermia is associated with decreased platelet reactivity. Clopidogrel loading does not significantly affect platelet function during the first 48 hours. This is in contrast with eptifibatide which produces profound platelet inhibition, and may be used to bridge insufficient inhibition by clopidogrel. PMID- 24800723 TI - Patients with high-risk pregnancies and complicated deliveries have an increased risk of maternal postpartum readmissions. AB - OBJECTIVE: Postpartum readmission after initial hospitalization for delivery can be diminished if better understood. The aim of this study was to determine the risk factors and indications for maternal re-hospitalization after delivery, in order to identify preventable factors. STUDY DESIGN: This was a case control study based on retrospective cohort of patients who delivered at our institution. The patients that were readmitted within 2 weeks of their delivery were included in the study group while the control group was conducted from patients who delivered at the same time but were not re-hospitalized and included twice the number of patients. Demographic characteristics as well as pregnancy, labour and postpartum courses were compared between the two groups. RESULTS: A total of 227 women were re-hospitalized within 14 days after initial discharge. The control group consisted of 450 women. The demographic characteristics were similar among the two groups, so were the rates of obesity, gestational weight gain and smoking. The major indication for readmission was postpartum infections, most of which were not related to immediate postpartum febrile morbidity. Emergency cesarean section was found to be an independent risk factor for readmission. CONCLUSIONS: The rate of patients with high-risk pregnancies and complicated deliveries is higher among postpartum maternal readmissions. These data might suggest more cautious postpartum care for those patients. PMID- 24800724 TI - Up to 40% of premature deaths in US are preventable, says CDC. PMID- 24800725 TI - Pharmacokinetics, pharmacodynamics, and safety of pasireotide LAR in patients with acromegaly: a randomized, multicenter, open-label, phase I study. AB - Pasireotide (SOM230), a multireceptor-targeted somatostatin analogue, has exhibited favorable safety/tolerability in several clinical studies. A long acting-release (LAR) formulation of pasireotide may offer advantages over the subcutaneous formulation. This randomized, open-label, Phase I study evaluated the safety, PK, and PD of pasireotide LAR 20, 40, or 60 mg/month in patients with acromegaly. Safety assessments and blood samples for PK and PD were taken at designated time points. Thirty-five patients were randomized and completed the study. Steady-state pasireotide concentrations were achieved following three monthly injections. Trough pasireotide concentrations (ng/mL) 28 days after each injection were: 2.48, 4.16, and 3.10 (20 mg group); 6.42, 6.62, and 7.12 (40 mg group); and 9.51, 11.7, and 13.0 (60 mg group). At study end, 51% and 57% of patients achieved GH levels <=2.5 MUg/L and IGF-1 levels below ULN, respectively. Compared with baseline, fasting blood glucose and HbA1c levels increased, whereas fasting blood insulin levels decreased. Acromegaly symptoms were generally improved. Adverse events were mostly gastrointestinal and mild/moderate. Pasireotide LAR was generally well tolerated. Steady-state PK was achieved after three monthly doses; exposures were approximately dose proportional. Control of GH, IGF-1, and symptoms improved, suggesting that pasireotide LAR may be an effective treatment for acromegaly. PMID- 24800726 TI - WITHDRAWN: Psychological interventions for overweight or obesity. PMID- 24800727 TI - Femtosecond spectroscopy reveals huge differences in the photoisomerisation dynamics between azobenzenes linked to polymers and azobenzenes in solution. AB - Femtosecond fluorescence up-conversion spectroscopy of two azobenzenes covalently attached to the side chain or linked by covalent bonds at each end into the main chain of polybutylmethacrylate polymer colloids with different cross-linking ratios reveals dramatic differences in the excited-state dynamics compared to the monomer chromophores in solution due to strong mechanical forces in the complex micronetworks. For the azobenzene derivative DR1 in the polymer side chain, the measurements determined an increase of the mean excited-state lifetime after irradiation at lambda = 475 nm to = 5.5 ps from = 0.5 ps for the monomer. For the cross-linked BAAB in the polymer main chain, an increase of was found of more than a factor-of-20. Moreover, with a lifetime of tau = 430 ps, ~12% of the molecules in the tightly (1 : 10) cross-linked polymer were found to remain in the excited state about 100 times longer than observed for the monomer chromophore. These results are of high relevance for applications of photoswitchable polymer materials. PMID- 24800729 TI - The milestones for general psychiatry residency training. PMID- 24800728 TI - Oral cavity contains distinct niches with dynamic microbial communities. AB - Microbes colonize human oral surfaces within hours after delivery. During postnatal development, physiological changes, such as the eruption of primary teeth and replacement of the primary dentition with permanent dentition, greatly alter the microbial habitats, which, in return, may lead to community composition shifts at different phases in people's lives. By profiling saliva, supragingival and mucosal plaque samples from healthy volunteers at different ages and dentition stages, we observed that the oral cavity is a highly heterogeneous ecological system containing distinct niches with significantly different microbial communities. More importantly, the phylogenetic microbial structure varies with ageing. In addition, only a few taxa were present across the whole populations, indicating a core oral microbiome should be defined based on age and oral niches. PMID- 24800730 TI - Suicide prevention and postvention resources: what psychiatry residencies can learn from the Veteran's Administration experience. AB - Suicide risk assessment and coping with the loss of a patient through suicide are two of the more challenging aspects of psychiatry residency. Over the last decade, the Department of Veterans Affairs has focused on a significant effort into the development of a comprehensive suicide prevention. This article aims to describe the initiatives and resources in place at the VHA to help address the issue of suicidal behavior in veterans and how residency programs can use this to enhance teaching of suicide prevention and postvention. PMID- 24800731 TI - Best practices in philanthropy in medical schools. AB - This paper is for academic leaders and administrators who are interested in growing their philanthropic revenue stream. Growing the philanthropic revenue stream will be especially meaningful to leaders and administrators who have seen their other revenue streams decline or stagnate in the last few years. This paper focuses on four best practices for a high-performing development program and gives examples about how to execute on these best practices. PMID- 24800732 TI - Training in integrated mental health-primary care models: a national survey of child psychiatry program directors. AB - OBJECTIVE: The objective of this study was to assess current trainee exposure to integrated mental health/primary care models in US child and adolescent psychiatry fellowship programs. METHODS: In June 2013, an electronic survey was sent to all US child and adolescent psychiatry fellowship program directors (N=123). RESULTS: Fifty-two responses were obtained from the 120 eligible participants (43%). The majority of the program directors who responded (63%) indicated that fellows in their programs regularly participate in clinical care and/or consultation within an outpatient pediatric primary care setting. Program directors identified barriers to increasing training exposure to integrated care delivery as competing clinical demands and challenging financial models for indirect consultation in primary care settings. DISCUSSION: Many child psychiatry fellowship program directors view training in integrated care models as an important part of their teaching and service mission, and are creating novel avenues for exposure. Current funding models, however, may limit the widespread implementation of these opportunities. PMID- 24800734 TI - Waving potential in graphene. AB - Nanoscale materials offer much promise in the pursuit of high-efficient energy conversion technology owing to their exceptional sensitivity to external stimulus. In particular, experiments have demonstrated that flowing water over carbon nanotubes can generate electric voltages. However, the reported flow induced voltages are in wide discrepancy and the proposed mechanisms remain conflictive. Here we find that moving a liquid-gas boundary along a piece of graphene can induce a waving potential of up to 0.1 V. The potential is proportional to the moving velocity and the graphene length inserted into ionic solutions, but sharply decreases with increasing graphene layers and vanishes in other materials. This waving potential arises from charge transfer in graphene driven by a moving boundary of an electric double layer between graphene and ionic solutions. The results reveal a unique electrokinetic phenomenon and open prospects for functional sensors, such as tsunami monitors. PMID- 24800736 TI - Emerging bioinspired polymers: glycopolypeptides. AB - This article highlights the very recent advances in glycopolypeptide synthesis via NCA polymerization and first studies on stimuli-responsive solution behavior and self-assembling structures. Yet glycopolypeptides are almost exclusively considered as smart biofunctional materials for use in biomedical applications, for instance in targeted drug delivery, but also have high potential for usage as structural materials to fabricate bioinspired hierarchical structures. PMID- 24800735 TI - Subscapular system of flaps: An 8-year experience with 105 patients. AB - BACKGROUND: Review patient and defect factors in which this donor site is an optimal choice for reconstruction and to discuss strategies to overcome the perceived drawbacks of this system of flaps. METHODS: A retrospective medical chart review was conducted on all patients who underwent the subscapular system of free flaps for head and neck reconstruction. RESULTS: Ninety-eight reconstructions were performed for mandibular defects, 4 for maxillary defects alone and 3 for combined mandible-maxilla defects. The overall success rate was 98%. CONCLUSION: The subscapular system of free flaps is an excellent option in patients for whom the alternative donor sites are either not usable or lack the associated soft tissue elements required for a successful reconstruction. This flap should also be considered as a first choice for patients with complex/extensive surgical defects requiring multiple, independently mobile, soft tissue components; in patients who will benefit from a large muscle flap placed over the vital structures in the neck; patients of advanced age; and patients in whom early mobilization is critical. PMID- 24800737 TI - Periodic auto-active gels with topologically "polyrotaxane-interlocked" structures. AB - "Polyrotaxane-interlocked" gels which exhibit periodic swelling/deswelling oscillations without "on/off" switching of external stimuli are presented. The mechanical oscillation is driven by the redox oscillation in the BZ reaction and enhanced by the unique topological structure. PMID- 24800738 TI - A 2,4-dichlorophenoxyacetic acid analog screened using a maize coleoptile system potentially inhibits indole-3-acetic acid influx in Arabidopsis thaliana. AB - Studies using inhibitors of indole-3-acetic acid (IAA) transport, not only for efflux but influx carriers, provide many aspects of auxin physiology in plants. 1 Naphtoxyacetic acid (1-NOA), an analog of the synthetic auxin 1-N-naphtalene acetic acid (NAA), inhibits the IAA influx carrier AUX1. However, 1-NOA also shows auxin activity because of its structural similarity to NAA. In this study, we have identified another candidate inhibitor of the IAA influx carrier. The compound, "7-B3; ethyl 2-[(2-chloro-4-nitrophenyl)thio]acetate," is a 2,4 dichlorophenoxyacetic acid (2,4-D) analog. At high concentrations (> 300 uM), 7 B3 slightly reduced IAA transport and tropic curvature of maize coleoptiles, whereas lower concentrations had almost no effect. We have analyzed the effects of 7-B3 on Arabidopsis thaliana seedlings. 7-B3 rescued the 2,4-D-inhibited root elongation, but not the NAA-inhibited root elongation. The effect of 7-B3 was weaker than that of 1-NOA. Both 1-NOA and 7-B3 inhibited DR5::GUS expression induced by IAA and 2,4-D, but not that induced by NAA. At high concentrations, 1 NOA exhibited auxin activity, but 7-B3 did not. Furthermore, 7-B3 inhibited apical hook formation in etiolated seedlings more effectively than did 1-NOA. These results indicate that 7-B3 is a potential inhibitor of IAA influx that has almost no effect on IAA efflux or auxin signaling. PMID- 24800739 TI - TIMI frame count and adverse events in women with no obstructive coronary disease: a pilot study from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). AB - BACKGROUND: TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD. METHODS: TFC was determined in a sample of women with no obstructive CAD enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC). RESULTS: A total of 298 women, with angiograms suitable for TFC analysis and long-term (6-10 year) follow up data, were included in this sub-study. Their age was 55+/-11 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC >35, 15% in women with a cTFC <=35, P<0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality. CONCLUSIONS: In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease. PMID- 24800740 TI - Apurinic/apyrimidinic endonucleases of Mycobacterium tuberculosis protect against DNA damage but are dispensable for the growth of the pathogen in guinea pigs. AB - In host cells, Mycobacterium tuberculosis encounters an array of reactive molecules capable of damaging its genome. Non-bulky DNA lesions are the most common damages produced on the exposure of the pathogen to reactive species and base excision repair (BER) pathway is involved in the repair of such damage. During BER, apurinic/apyrimidinic (AP) endonuclease enzymes repair the abasic sites that are generated after spontaneous DNA base loss or by the action of DNA glycosylases, which if left unrepaired lead to inhibition of replication and transcription. However, the role of AP endonucleases in imparting protection against DNA damage and in the growth and pathogenesis of M.tuberculosis has not yet been elucidated. To demonstrate the biological significance of these enzymes in M.tuberculosis, it would be desirable to disrupt the relevant genes and evaluate the resulting mutants for their ability to grow in the host and cause disease. In this study, we have generated M.tuberculosis mutants of the base excision repair (BER) system, disrupted in either one (MtbDeltaend or MtbDeltaxthA) or both the AP endonucleases (MtbDeltaendDeltaxthA). We demonstrate that these genes are crucial for bacteria to withstand alkylation and oxidative stress in vitro. In addition, the mutant disrupted in both the AP endonucleases (MtbDeltaendDeltaxthA) exhibited a significant reduction in its ability to survive inside human macrophages. However, infection of guinea pigs with either MtbDeltaend or MtbDeltaxthA or MtbDeltaendDeltaxthA resulted in the similar bacillary load and pathological damage in the organs as observed in the case of infection with wild-type M.tuberculosis. The implications of these observations are discussed. PMID- 24800741 TI - Protection of ischemic postconditioning against neuronal apoptosis induced by transient focal ischemia is associated with attenuation of NF-kappaB/p65 activation. AB - BACKGROUND AND PURPOSE: Accumulating evidences have demonstrated that nuclear factor kappaB/p65 plays a protective role in the protection of ischemic preconditioning and detrimental role in lethal ischemia-induced programmed cell death including apoptosis and autophagic death. However, its role in the protection of ischemic postconditioning is still unclear. METHODS: Rat MCAO model was used to produce transient focal ischemia. The procedure of ischemic postconditioning consisted of three cycles of 30 seconds reperfusion/reocclusion of MCA. The volume of cerebral infarction was measured by TTC staining and neuronal apoptosis was detected by TUNEL staining. Western blotting was used to analyze the changes in protein levels of Caspase-3, NF-kappaB/p65, phosphor- NF kappaB/p65, IkappaBalpha, phosphor- IkappaBalpha, Noxa, Bim and Bax between rats treated with and without ischemic postconditioning. Laser scanning confocal microscopy was used to examine the distribution of NF-kappaB/p65 and Noxa. RESULTS: Ischemic postconditioning made transient focal ischemia-induced infarct volume decrease obviously from 38.6% +/- 5.8% to 23.5% +/- 4.3%, and apoptosis rate reduce significantly from 46.5% +/- 6.2 to 29.6% +/- 5.3% at reperfusion 24 h following 2 h focal cerebral ischemia. Western blotting analysis showed that ischemic postconditioning suppressed markedly the reduction of NF-kappaB/p65 in cytoplasm, but elevated its content in nucleus either at reperfusion 6 h or 24 h. Moreover, the decrease of IkappaBalpha and the increase of phosphorylated IkappaBalpha and phosphorylated NF-kappaB/p65 at indicated reperfusion time were reversed by ischemic postconditioning. Correspondingly, proapoptotic proteins Caspase-3, cleaved Caspase-3, Noxa, Bim and Bax were all mitigated significantly by ischemic postconditioning. Confocal microscopy revealed that ischemic postconditioning not only attenuated ischemia-induced translocation of NF kappaB/p65 from neuronal cytoplasm to nucleus, but also inhibited the abnormal expression of proapoptotic protein Noxa within neurons. CONCLUSIONS: We demonstrated in this study that the protection of ischemic postconditioning on neuronal apoptosis caused by transient focal ischemia is associated with attenuation of the activation of NF-kappaB/p65 in neurons. PMID- 24800742 TI - Functional and structural correlates of motor speed in the cerebellar anterior lobe. AB - In athletics, motor performance is determined by different abilities such as technique, endurance, strength and speed. Based on animal studies, motor speed is thought to be encoded in the basal ganglia, sensorimotor cortex and the cerebellum. The question arises whether there is a unique structural feature in the human brain, which allows "power athletes" to perform a simple foot movement significantly faster than "endurance athletes". We acquired structural and functional brain imaging data from 32 track-and-field athletes. The study comprised of 16 "power athletes" requiring high speed foot movements (sprinters, jumpers, throwers) and 16 endurance athletes (distance runners) which in contrast do not require as high speed foot movements. Functional magnetic resonance imaging (fMRI) was used to identify speed specific regions of interest in the brain during fast and slow foot movements. Anatomical MRI scans were performed to assess structural grey matter volume differences between athletes groups (voxel based morphometry). We tested maximum movement velocity of plantarflexion (PF Vmax) and acquired electromyographical activity of the lateral and medial gastrocnemius muscle. Behaviourally, a significant difference between the two groups of athletes was noted in PF-Vmax and fMRI indicates that fast plantarflexions are accompanied by increased activity in the cerebellar anterior lobe. The same region indicates increased grey matter volume for the power athletes compared to the endurance counterparts. Our results suggest that speed specific neuro-functional and -structural differences exist between power and endurance athletes in the peripheral and central nervous system. PMID- 24800743 TI - The RSF1 histone-remodelling factor facilitates DNA double-strand break repair by recruiting centromeric and Fanconi Anaemia proteins. AB - ATM is a central regulator of the cellular responses to DNA double-strand breaks (DSBs). Here we identify a biochemical interaction between ATM and RSF1 and we characterise the role of RSF1 in this response. The ATM-RSF1 interaction is dependent upon both DSBs and ATM kinase activity. Together with SNF2H/SMARCA5, RSF1 forms the RSF chromatin-remodelling complex. Although RSF1 is specific to the RSF complex, SNF2H/SMARCA5 is a catalytic subunit of several other chromatin remodelling complexes. Although not required for checkpoint signalling, RSF1 is required for efficient repair of DSBs via both end-joining and homology-directed repair. Specifically, the ATM-dependent recruitment to sites of DSBs of the histone fold proteins CENPS/MHF1 and CENPX/MHF2, previously identified at centromeres, is RSF1-dependent. In turn these proteins recruit and regulate the mono-ubiquitination of the Fanconi Anaemia proteins FANCD2 and FANCI. We propose that by depositing CENPS/MHF1 and CENPX/MHF2, the RSF complex either directly or indirectly contributes to the reorganisation of chromatin around DSBs that is required for efficient DNA repair. PMID- 24800744 TI - Reduced gamma oscillations in a mouse model of intellectual disability: a role for impaired repetitive neurotransmission? AB - Intellectual disability affects 2-3% of the population; mutations of the X chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals. PMID- 24800745 TI - Evolutionary changes in vertebrate genome signatures with special focus on coelacanth. AB - With a remarkable increase in genomic sequence data of a wide range of species, novel tools are needed for comprehensive analyses of the big sequence data. Self organizing map (SOM) is a powerful tool for clustering high-dimensional data on one plane. For oligonucleotide compositions handled as high-dimensional data, we have previously modified the conventional SOM for genome informatics: BLSOM. In the present study, we constructed BLSOMs for oligonucleotide compositions in fragment sequences (e.g. 100 kb) from a wide range of vertebrates, including coelacanth, and found that the sequences were clustered primarily according to species without species information. As one of the nearest living relatives of tetrapod ancestors, coelacanth is believed to provide access to the phenotypic and genomic transitions leading to the emergence of tetrapods. The characteristic oligonucleotide composition found for coelacanth was connected with the lowest dinucleotide CG occurrence (i.e. the highest CG suppression) among fishes, which was rather equivalent to that of tetrapods. This evident CG suppression in coelacanth should reflect molecular evolutionary processes of epigenetic systems including DNA methylation during vertebrate evolution. Sequence of a de novo DNA methylase (Dntm3a) of coelacanth was found to be more closely related to that of tetrapods than that of other fishes. PMID- 24800746 TI - Obesity and type 2 diabetes in Sub-Sahara Africa. AB - There is a mounting body of evidence regarding the challenge posed by diabetes and obesity on the health systems of many Sub-Sahara African countries. This trend has been linked to the changing demographic profile together with rapid urbanization and changing lifestyles in both rural and urban settings in Africa. Africa is expected to witness the greatest increase in the number of people with diabetes from 19.8 million in 2013 to 41.4 million in 2035 if current trends persist. Excess weight alone currently accounts for at least 2.8 million deaths globally each year through increased risk for type 2 diabetes and cardiovascular complications. This review highlights recent literature on the problem of obesity and type 2 diabetes in Sub-Sahara Africa. It exposes the need for concrete interventions based on the now available wealth of evidence. PMID- 24800748 TI - Systematic analysis of phosphotyrosine antibodies recognizing single phosphorylated EPIYA-motifs in CagA of Western-type Helicobacter pylori strains. AB - The clinical outcome of Helicobacter pylori infections is determined by multiple host-pathogen interactions that may develop to chronic gastritis, and sometimes peptic ulcers or gastric cancer. Highly virulent strains encode a type IV secretion system (T4SS) that delivers the effector protein CagA into gastric epithelial cells. Translocated CagA undergoes tyrosine phosphorylation at EPIYA sequence motifs, called A, B and C in Western-type strains, by members of the oncogenic Src and Abl host kinases. Phosphorylated EPIYA-motifs mediate interactions of CagA with host signaling factors--in particular various SH2 domain containing human proteins--thereby hijacking multiple downstream signaling cascades. Observations of tyrosine-phosphorylated CagA are mainly based on the use of commercial phosphotyrosine antibodies, which originally were selected to detect phosphotyrosines in mammalian proteins. Systematic studies of phosphorylated EPIYA-motif detection by the different antibodies would be very useful, but are not yet available. To address this issue, we synthesized phospho- and non-phosphopeptides representing each predominant Western CagA EPIYA-motif, and determined the recognition patterns of seven different phosphotyrosine antibodies in Western blots, and also performed infection studies with diverse representative Western H. pylori strains. Our results show that a total of 9-11 amino acids containing the phosphorylated EPIYA-motifs are necessary and sufficient for specific detection by these antibodies, but revealed great variability in sequence recognition. Three of the antibodies recognized phosphorylated EPIYA-motifs A, B and C similarly well; whereas preferential binding to phosphorylated motif A and motifs A and C was found with two and one antibodies, respectively, and the seventh anti-phosphotyrosine antibody did not recognize any phosphorylated EPIYA-motif. Controls showed that none of the antibodies recognized the corresponding non-phospho CagA peptides, and that all of them recognized phosphotyrosines in mammalian proteins. These data are valuable in judicious application of commercial anti-phosphotyrosine antibodies and in characterization of CagA phosphorylation during infection and disease development. PMID- 24800749 TI - Inhibiting heat shock factor 1 in human cancer cells with a potent RNA aptamer. AB - Heat shock factor 1 (HSF1) is a master regulator that coordinates chaperone protein expression to enhance cellular survival in the face of heat stress. In cancer cells, HSF1 drives a transcriptional program distinct from heat shock to promote metastasis and cell survival. Its strong association with the malignant phenotype implies that HSF1 antagonists may have general and effective utilities in cancer therapy. For this purpose, we had identified an avid RNA aptamer for HSF1 that is portable among different model organisms. Extending our previous work in yeast and Drosophila, here we report the activity of this aptamer in human cancer cell lines. When delivered into cells using a synthetic gene and strong promoter, this aptamer was able to prevent HSF1 from binding to its DNA regulation elements. At the cellular level, expression of this aptamer induced apoptosis and abolished the colony-forming capability of cancer cells. At the molecular level, it reduced chaperones and attenuated the activation of the MAPK signaling pathway. Collectively, these data demonstrate the advantage of aptamers in drug target validation and support the hypothesis that HSF1 DNA binding activity is a potential target for controlling oncogenic transformation and neoplastic growth. PMID- 24800750 TI - Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism. AB - Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory. PMID- 24800752 TI - Evaluation and automatic correction of metal-implant-induced artifacts in MR based attenuation correction in whole-body PET/MR imaging. AB - The aim of this paper is to describe a new automatic method for compensation of metal-implant-induced segmentation errors in MR-based attenuation maps (MRMaps) and to evaluate the quantitative influence of those artifacts on the reconstructed PET activity concentration. The developed method uses a PET-based delineation of the patient contour to compensate metal-implant-caused signal voids in the MR scan that is segmented for PET attenuation correction. PET emission data of 13 patients with metal implants examined in a Philips Ingenuity PET/MR were reconstructed with the vendor-provided method for attenuation correction (MRMap(orig), PET(orig)) and additionally with a method for attenuation correction (MRMap(cor), PET(cor)) developed by our group. MRMaps produced by both methods were visually inspected for segmentation errors. The segmentation errors in MRMap(orig) were classified into four classes (L1 and L2 artifacts inside the lung and B1 and B2 artifacts inside the remaining body depending on the assigned attenuation coefficients). The average relative SUV differences (epsilon(rel)(av)) between PET(orig) and PET(cor) of all regions showing wrong attenuation coefficients in MRMap(orig) were calculated. Additionally, relative SUV(mean) differences (epsilon(rel)) of tracer accumulations in hot focal structures inside or in the vicinity of these regions were evaluated. MRMap(orig) showed erroneous attenuation coefficients inside the regions affected by metal artifacts and inside the patients' lung in all 13 cases. In MRMap(cor), all regions with metal artifacts, except for the sternum, were filled with the soft-tissue attenuation coefficient and the lung was correctly segmented in all patients. MRMap(cor) only showed small residual segmentation errors in eight patients. epsilon(rel)(av) (mean +/- standard deviation) were: (-56 +/- 3)% for B1, (-43 +/- 4)% for B2, (21 +/- 18)% for L1, (120 +/- 47)% for L2 regions. epsilon(rel) (mean +/- standard deviation) of hot focal structures were: (-52 +/- 12)% in B1, (-45 +/- 13)% in B2, (19 +/- 19)% in L1, (51 +/- 31)% in L2 regions. Consequently, metal-implant-induced artifacts severely disturb MR-based attenuation correction and SUV quantification in PET/MR. The developed algorithm is able to compensate for these artifacts and improves SUV quantification accuracy distinctly. PMID- 24800751 TI - Reversibly Immortalized Mouse Articular Chondrocytes Acquire Long-Term Proliferative Capability While Retaining Chondrogenic Phenotype. AB - Cartilage tissue engineering holds great promise for treating cartilaginous pathologies including degenerative disorders and traumatic injuries. Effective cartilage regeneration requires an optimal combination of biomaterial scaffolds, chondrogenic seed cells, and biofactors. Obtaining sufficient chondrocytes remains a major challenge due to the limited proliferative capability of primary chondrocytes. Here we investigate if reversibly immortalized mouse articular chondrocytes (iMACs) acquire long-term proliferative capability while retaining the chondrogenic phenotype. Primary mouse articular chondrocytes (MACs) can be efficiently immortalized with a retroviral vector-expressing SV40 large T antigen flanked with Cre/loxP sites. iMACs exhibit long-term proliferation in culture, although the immortalization phenotype can be reversed by Cre recombinase. iMACs express the chondrocyte markers Col2a1 and aggrecan and produce chondroid matrix in micromass culture. iMACs form subcutaneous cartilaginous masses in athymic mice. Histologic analysis and chondroid matrix staining demonstrate that iMACs can survive, proliferate, and produce chondroid matrix. The chondrogenic growth factor BMP2 promotes iMACs to produce more mature chondroid matrix resembling mature articular cartilage. Taken together, our results demonstrate that iMACs acquire long-term proliferative capability without losing the intrinsic chondrogenic features of MACs. Thus, iMACs provide a valuable cellular platform to optimize biomaterial scaffolds for cartilage regeneration, to identify biofactors that promote the proliferation and differentiation of chondrogenic progenitors, and to elucidate the molecular mechanisms underlying chondrogenesis. PMID- 24800754 TI - An implantable pressure sensing system with electromechanical interrogation scheme. AB - In this paper, we report on the development of an implantable pressure sensing system that is powered by mechanical vibrations in the audible acoustic frequency range. This technique significantly enhances interrogation range, alleviates the misalignment issues commonly encountered with inductive powering, and simplifies the external receiver circuitry. The interrogation scheme consists of two phases: a mechanical vibration phase and an electrical radiation phase. During the first phase, a piezoelectric cantilever acts as an acoustic receiver and charges a capacitor by converting sound vibration harmonics occurring at its resonant frequency into electrical power. In the subsequent electrical phase, when the cantilever is not vibrating, the stored electric charge is discharged across an LC tank whose inductor is pressure sensitive; hence, when the LC tank oscillates at its natural resonant frequency, it radiates a high-frequency signal that is detectable using an external receiver and its frequency corresponds to the measured pressure. The pressure sensitive inductor consists of a planar coil (single loop of wire) with a ferrite core whose distance to the coil varies with applied pressure. A prototype of the implantable pressure sensor is fabricated and tested, both in vitro and in vivo (swine bladder). A pressure sensitivity of 1 kHz/cm H2O is achieved with minimal misalignment sensitivity (26% drop at 90 degrees misalignment between the implanted device and acoustic source; 60% drop at 90 degrees misalignment between the implanted device and RF receiver coil). PMID- 24800753 TI - Using an FFQ to assess intakes of dietary flavonols and flavones among female adolescents in the Suihua area of northern China. AB - OBJECTIVE: The present study aimed to (i) evaluate the reproducibility and validity of a designed FFQ, (ii) apply the FFQ for estimating the dietary intakes of four flavonols and two flavones in female adolescents and (iii) explain their major dietary sources. DESIGN: The reproducibility between the first and second FFQ administrations (1 year interval) was estimated using the intra-class correlation coefficient. The validity of the first FFQ relative to the average of four three-day 24 h dietary recalls (24-HR) from four seasons was assessed using the Spearman correlation coefficient. Using a flavonoid content database, the individual flavonol and flavone intakes were calculated and the major food sources were estimated. SETTING: Middle school in Suihua area of Heilongjiang Province, northern China. SUBJECTS: Female adolescents (n 887) aged 12-18 years. RESULTS: Better reproducibility and validity were obtained in the present study. The flavonol and flavone intakes were 16.29 and 4.31 mg/d, respectively. Quercetin and kaempferol were the major contributors (26.8 % and 23.7 %, respectively) to the total intake of flavonols and flavones. The main food sources of flavonols and flavones were apples (14.1 %), followed by potatoes (7.5 %), lettuce (7.3 %) and oranges (7.3 %). CONCLUSIONS: The dietary flavonol and flavone intakes among female adolescents in northern China were similar to those reported in several countries, but significant differences were observed in the food sources ascribed to the geographical location and dietary characteristics. PMID- 24800755 TI - Regulation of differentiation and function of helper T cells by lymphocyte derived catecholamines via alpha1- and beta2-adrenoceptors. AB - OBJECTIVE: Recently, we have reported that lymphocyte-derived endogenous catecholamines (CAs) facilitate a shift in the T helper (Th)1/Th2 balance towards Th2. The purpose of this study was to explore the involvement of adrenoreceptors (ARs) in Th differentiation and function modulation by lymphocyte-derived CAs. METHODS: Lymphocytes were separated from the mesenteric lymph nodes of mice, stimulated with concanavalin A (Con A) and treated with pargyline, an inhibitor of CA degradation. RESULTS: Pargyline downregulated the expression of Th1 relative factors, T-bet, interferon (IFN)-gamma and interleukin (IL)-2, but upregulated the expression of Th2-relative factors, GATA-3, IL-4 and IL-10. Pargyline reduced the percentage of IFN-gamma-producing CD4+ cells and the CD4+IFN-gamma+/CD4+IL-4+ cell ratio, although it did not alter the proportion of IL-4-producing CD4+ cells. In addition, the percentage of CD4+CD26+ T cells and the CD4+CD26+/CD4+CD30+ cell ratio were also reduced in the pargyline-treated group. Furthermore, Con A-activated T cells treated with pargyline produced a lower level of IFN-gamma and a higher level of IL-4 than the control group. All these effects were blocked by the alpha1-AR antagonist corynanthine or the beta2 AR antagonist ICI 118551, but not by the alpha2-AR antagonist yohimbine or beta1 AR antagonist atenolol. CONCLUSIONS: These results imply that lymphocyte-derived CAs promote polarization of differentiation and function towards Th2 cells and that this effect is mediated by alpha1-AR and beta2-AR. PMID- 24800756 TI - Two days. PMID- 24800757 TI - A study on the development of public campaign messages for organ donation promotion in Korea. AB - This study aims to find an effective method of expressing a message in public service ads by investigating whether or not a message framing type affects the outcome. Specifically, the study looks into the effects of messaging on organ donation by identifying how the type of message framing (positive vs. negative) and appeal type (rational vs. emotional) affect the attitude and behavioural intention of the consumer. The individual characteristics of each subject such as altruistic mind, level of self-monitoring and issue involvement were selected as intermediate variables that may affect the impact of a message. The study therefore tries to establish a proposition that can be used to generate an effective promotional message on organ donation in a systematic way. PMID- 24800758 TI - Integrating relationship- and research-based approaches in Australian health promotion practice. AB - We examine the perspectives of health promotion practitioners on their approaches to determining health promotion practice, in particular on the role of research and relationships in this process. Using Grounded Theory methods, we analysed 58 semi-structured interviews with 54 health promotion practitioners in New South Wales, Australia. Practitioners differentiated between relationship-based and research-based approaches as two sources of knowledge to guide health promotion practice. We identify several tensions in seeking to combine these approaches in practice and describe the strategies that participants adopted to manage these tensions. The strategies included working in an evidence-informed rather than evidence-based way, creating new evidence about relationship-based processes and outcomes, adopting 'relationship-based' research and evaluation methods, making research and evaluation useful for communities, building research and evaluation skills and improving collaboration between research and evaluation and programme implementation staff. We conclude by highlighting three systemic factors which could further support the integration of research-based and relationship-based health promotion practices: (i) expanding conceptions of health promotion evidence, (ii) developing 'relationship-based' research methods that enable practitioners to measure complex social processes and outcomes and to facilitate community participation and benefit, and (iii) developing organizational capacity. PMID- 24800759 TI - Dual-geometric neighbor embedding for image super resolution with sparse tensor. AB - Neighbors embedding (NE) technology has proved its efficiency in single image super resolution (SISR). However, image patches do not strictly follow the similar structure in the low-resolution and high-resolution spaces, consequently leading to a bias to the image restoration. In this paper, considering that patches are a set of data with multiview characteristics and spatial organization, we advance a dual-geometric neighbor embedding (DGNE) approach for SISR. In DGNE, multiview features and local spatial neighbors of patches are explored to find a feature-spatial manifold embedding for images. We adopt a geometrically motivated assumption that for each patch there exists a small neighborhood in which only the patches that come from the same feature-spatial manifold, will lie approximately in a low-dimensional affine subspace formulated by sparse neighbors. In order to find the sparse neighbors, a tensor-simultaneous orthogonal matching pursuit algorithm is advanced to realize a joint sparse coding of feature-spatial image tensors. Some experiments are performed on realizing a 3X amplification of natural images, and the recovered results prove its efficiency and superiority to its counterparts. PMID- 24800760 TI - Acoustic formulation of elastic guided wave propagation and scattering in curved tubular structures. AB - Recently, the use of guided wave technology in conjunction with tomographic techniques has provided the possibility of obtaining point-by-point maps of corrosion or erosion depth over the entire volume of a pipeline section between two ring arrays of ultrasonic transducers. However, current research has focused on straight pipes and little work has been done on pipe bends and other curved tubular structures which are also the most susceptible to developing damage. Tomography of curved tubes is challenging because of the complexity and computational cost of the 3-D elastic model required to accurately describe guided wave propagation. Based on the definition of travel-time-preserving orthogonal parametric representations of curved tubes, this paper demonstrates that guided wave propagation and scattering can be approximated by an equivalent 2-D acoustic model which is inhomogeneous and elliptically anisotropic. Numerical methods to solve the full wave equation and predict ray paths and travel times are introduced and applied to the case of a bend. Particular emphasis is given to the shortest-path ray tracing method, which is applied to the 2-D model to compute ray paths and predict travel times of the fundamental flexural mode, A0, propagating across a curved pipe. Good agreement is found between predictions and experiments performed on a 220-mm-diameter (8-in-diameter) (D) pipe with 1.5D bend radius. The 2-D model also reveals the existence of an acoustic lensing effect which leads to a focusing phenomenon also confirmed by the experiments. The computational efficiency of the 2-D model makes it ideally suited for tomographic algorithms. PMID- 24800761 TI - The effects of morphine on Parkinson's-related genes PINK1 and PARK2. AB - BACKGROUND: Parkinson's disease (PD) continues to be an important neurological disorder. It is caused by the loss of dopaminergic neurons in the substantia nigra. Dopamine, the neurotransmitter produced from dopaminergic neurons, is a major precursor of endogenous morphine. There are approximately 18 genes associated with PD; their roles have not yet been completely established. PARK2 is a gene that encodes for the protein parkin, and PINK1 is a gene that encodes for PTEN-induced putative kinase 1. MATERIAL AND METHODS: Our objective was to determine if morphine treatment of HTB-11 cells affects the expression of PINK1 and PARK2. HTB-11 cells were treated with 10-7 M morphine for 2 h and a microarray analysis was conducted. To verify the microarray analysis, 3 Q-PCR trials were run using 10-6 M naloxone, morphine (10-7 M), or a naloxone/morphine mix. RESULTS: In both the microarray analysis and the Q-PCR analysis, PARK2 was up-regulated and PINK1 was down-regulated. CONCLUSIONS: Morphine can affect the expression of PD-associated genes. PMID- 24800763 TI - Long-term aircraft noise exposure and body mass index, waist circumference, and type 2 diabetes: a prospective study. AB - BACKGROUND: Long-term aircraft noise exposure may increase the risk of cardiovascular disease, but no study has investigated chronic effects on the metabolic system. OBJECTIVES: The aim of this study was to investigate effects of long-term aircraft noise exposure on body mass index (BMI), waist circumference, and type 2 diabetes. Furthermore, we explored the modifying effects of sleep disturbance. METHODS: This prospective cohort study of residents of Stockholm County, Sweden, followed 5,156 participants with normal baseline oral glucose tolerance tests (OGTT) for up to 10 years. Exposure to aircraft noise was estimated based on residential history. Information on outcomes and confounders was obtained from baseline and follow-up surveys and examinations, and participants who developed prediabetes or type 2 diabetes were identified by self reported physician diagnosis or OGTT at follow-up. Adjusted associations were assessed by linear, logistic, and random-effects models. RESULTS: The mean (+/- SD) increases in BMI and waist circumference during follow-up were 1.09 +/- 1.97 kg/m2 and 4.39 +/- 6.39 cm, respectively. The cumulative incidence of prediabetes and type 2 diabetes was 8% and 3%, respectively. Based on an ordinal noise variable, a 5-dB(A) increase in aircraft noise was associated with a greater increase in waist circumference of 1.51 cm (95% CI: 1.13, 1.89), fully adjusted. This association appeared particularly strong among those who did not change their home address during the study period, which may be a result of lower exposure misclassification. However, no clear associations were found for BMI or type 2 diabetes. Furthermore, sleep disturbances did not appear to modify the associations with aircraft noise. CONCLUSIONS: Long-term aircraft noise exposure may be linked to metabolic outcomes, in particular increased waist circumference. PMID- 24800764 TI - Superelastic organic crystals. AB - Superelastic materials (crystal-to-crystal transformation pseudo elasticity) that consist of organic components have not been observed since superelasticity was discovered in a Au-Cd alloy in 1932. Superelastic materials have been exclusively developed in metallic or inorganic covalent solids, as represented by Ti-Ni alloys. Organosuperelasticity is now revealed in a pure organic crystal of terephthalamide, which precisely produces a large motion with high repetition and high energy storage efficiency. This process is driven by a small shear stress owing to the low density of strain energy related to the low lattice energy. PMID- 24800765 TI - [Sequencing the human genome and society]. PMID- 24800766 TI - [Therapy of anaphylaxis]. PMID- 24800768 TI - [Genomics and personalized medicine]. AB - Personalized medicine has a substantial potential to transform the way diseases will be predicted, prevented and treated. The field will greatly benefit from novel DNA sequencing technologies, in particular commoditization of individual whole genome sequencing. This evolution cannot be stopped, and the medical and scientific community, as well as the society at large, have the responsibility to anticipate the expected benefits from this revolution, but also the potential risks associated with it. Massive investments will be needed for the potential of personalized medicine to be realized, and for the field to come to maturity. In particular, a paradigm change in the way clinical research is done is needed. Switzerland and its Western part pro-actively anticipate these changes. PMID- 24800769 TI - [Ethical and social issues associated with genomic medicine]. AB - Genomic medicine is often presented as a new paradigm for personalized healthcare. Encompassing both a translational approach in research and a vision of future medical practice, genomic medicine may have important impact on the way healthcare professionals diagnostics, treat and prevent diseases. We discuss some ethical and social issues raised by the prospect of genome-based medical practice, namely: changing definitions of disease and identity, assessment of clinical validity and utility of genome screening, mastery of genomic information by healthcare professionals and its communication to patients, and questions related to the costs of genomic medicine for future healthcare. PMID- 24800770 TI - Patient privacy in the genomic era. AB - According to many scientists and clinicians, genomics is taking on a key role in the field of medicine. Impressive advances in genome sequencing have opened the way to a variety of revolutionary applications in modern healthcare. In particular, the increasing understanding of the human genome, and of its relation to diseases and response to treatments brings promise of improvements in better preventive and personalized medicine. However, this progress raises important privacy and ethical concerns that need to be addressed. Indeed, each genome is the ultimate identifier of its owner and, due to its nature, it contains highly personal and privacy-sensitive data. In this article, after summarizing recent advances in genomics, we discuss some important privacy issues associated with human genomic information and methods put in place to address them. PMID- 24800771 TI - [Genomic medicine and infectious diseases]. AB - Relentless progress in our knowledge of the nature and functional consequences of human genetic variation allows for a better understanding of the protracted battle between pathogens and their human hosts. Multiple polymorphisms have been identified that impact our response to infections or to anti-infective drugs, and some of them are already used in the clinic. However, to make personalized medicine a reality in infectious diseases, a sustained effort is needed not only in research but also in genomic education. PMID- 24800772 TI - [Genomics medicine and oncology]. AB - Progress in genomics with, in particular, high throughput next generation sequencing is revolutionizing oncology. The impact of these techniques is seen on the one hand the identification of germline mutations that predispose to a given type of cancer, allowing for a personalized care of patients or healthy carriers and, on the other hand, the characterization of all acquired somatic mutation of the tumor cell, opening the door to personalized treatment targeting the driver oncogenes. In both cases, next generation sequencing techniques allow a global approach whereby the integrality of the genome mutations is analyzed and correlated with the clinical data. The benefits on the quality of care delivered to our patients are extremely impressive. PMID- 24800774 TI - [Not Available]. PMID- 24800775 TI - [Not Available]. PMID- 24800776 TI - [CMW rheumatology 3. Acute swollen knee]. PMID- 24800780 TI - Following the azide-alkyne cycloaddition at the silica/solvent interface with sum frequency generation. AB - The Cu(I) -catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) has arisen as one of the most useful chemical transformations for introducing complexity onto surfaces and materials owing to its functional-group tolerance and high yield. However, methods for monitoring such reactions in situ at the widely used silica/solvent interface are hampered by challenges associated with probing such buried interfaces. Using the surface-specific technique broadband sum frequency generation (SFG), we monitored the reaction of a benzyl azide monolayer in real time at the silica/methanol interface. A strong peak at 2096 cm(-1) assigned to the azides was observed for the first time by SFG. Using a cyano-substituted alkyne, the decrease of the azide peak and the increase of the cyano peak (2234 cm(-1) ) were probed simultaneously. From the kinetic analysis, the reaction order with respect to copper was determined to be 2.1, suggesting that CuAAC on the surface follows a similar mechanism as in solution. PMID- 24800781 TI - Endoscopic classification can predict the infiltrative growth patterns of early stage esophageal cancer: a retrospective study of 133 patients at a single academic tertiary care center. AB - The relationships between two endoscopic classification systems (type I and II) and the infiltrative growth patterns (INF) of early esophageal cancers were evaluated. Among type I carcinomas, the INFs were mainly INFb in the polypoid and mixed types, INFa in the superficial type, and INFc in the excavated type. Among type II carcinomas, INFa was the main pattern in the surface-propagating type, whereas INFb was observed in the intraluminal, bilateral, and mixed types. INFb and INFc were observed in the intramural type. Our results indicate that the superficial and surface-propagating types had the weakest infiltrative potential, whereas the excavated and intramural types had the highest infiltrative potential. PMID- 24800782 TI - An updated meta-analysis of randomized controlled trial assessing the effect of neoadjuvant chemotherapy in advanced gastric cancer. AB - Patients with locally advanced gastric cancer (AGC) have a poor outcome. We performed an updated meta-analysis to assess the effect of neoadjuvant chemotherapy (NAC). By searching electronic databases (PubMed, Embase, Cochrane Library) and ASCO proceedings from 1990 to 2012, all randomized controlled trials (RCTs) which compared the effect of NAC combined surgery versus surgery alone in advanced gastric and gastroesophageal cancer would be included. All calculations and statistical tests were performed. Twelve RCTs with a total of 1,820 patients were included. All patients had resectable gastric or gastroesophageal cancer and received NAC. NAC can slightly improve the survival rate [OR = 1.32, 95% confidence interval (CI): 1.07-1.64, P = 0.01], little, or no significant benefits were suggested in subgroup analyses between different population and regimens either. It can significantly improved the 3-year progression-free survival (PFS) [OR: 1.85 (1.39, 2.46), p < .0001], tumor down-staging rate [OR: 1.71 (1.26, 2.33), p = .0006] and R0 resection rate [OR: 1.38 (1.08, 1.78) p = .01] of patients with AGC. There were no difference between the two arms, in terms of relapse rates [OR: 1.03 (0.60, 1.78), p = 0.92], operative complications [OR: 1.20 (0.90, 1.58), p = 0.21], perioperative mortality [OR: 1.14 (0.64, 2.05), p = 0.65], and grade 3/4 adverse effects. NAC can significantly down-stage the tumor and improve R0 resection rate of patients with gastric and gastroesophageal cancer. It is safe and feasible, and can be tolerated. NAC can slightly improve the survival rate. It needs further prospective multinational multicenter RCTs to define the clinical benefits of NAC and the most effective strategies for gastric and gastroesophageal cancer. PMID- 24800783 TI - ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary. PMID- 24800784 TI - A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala. AB - We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene * environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing. PMID- 24800789 TI - The redox-sensitive chloroplast trehalose-6-phosphate phosphatase AtTPPD regulates salt stress tolerance. AB - AIMS: High salinity stress impairs plant growth and development. Trehalose metabolism has been implicated in sugar signaling, and enhanced trehalose metabolism can positively regulate abiotic stress tolerance. However, the molecular mechanism(s) of the stress-related trehalose pathway and the role of individual trehalose biosynthetic enzymes for stress tolerance remain unclear. RESULTS: Trehalose-6-phosphate phosphatase (TPP) catalyzes the final step of trehalose metabolism. Investigating the subcellular localization of the Arabidopsis thaliana TPP family members, we identified AtTPPD as a chloroplast localized enzyme. Plants deficient in AtTPPD were hypersensitive, whereas plants overexpressing AtTPPD were more tolerant to high salinity stress. Elevated stress tolerance of AtTPPD overexpressors correlated with high starch levels and increased accumulation of soluble sugars, suggesting a role for AtTPPD in regulating sugar metabolism under salinity conditions. Biochemical analyses indicate that AtTPPD is a target of post-translational redox regulation and can be reversibly inactivated by oxidizing conditions. Two cysteine residues were identified as the redox-sensitive sites. Structural and mutation analyses suggest that the formation of an intramolecular disulfide bridge regulates AtTPPD activity. INNOVATION: The activity of different AtTPP isoforms, located in the cytosol, nucleus, and chloroplasts, can be redox regulated, suggesting that the trehalose metabolism might relay the redox status of different cellular compartments to regulate diverse biological processes such as stress responses. CONCLUSION: The evolutionary conservation of the two redox regulatory cysteine residues of TPPs in spermatophytes indicates that redox regulation of TPPs might be a common mechanism enabling plants to rapidly adjust trehalose metabolism to the prevailing environmental and developmental conditions. PMID- 24800790 TI - Campomelic dysplasia. AB - Campomelic dysplasia is a rare hereditary congenital osteochondral dysplasia characterized by abnormal bowing of the lower limbs, sex reversal in males, and other skeletal and extraskeletal abnormalities. It is usually fatal in the neonatal period because of respiratory insufficiency. The diagnosis is usually difficult because of its rare presentation and the prognosis is poor. We present such a case in a 1-month-old child with typical skeletal abnormalities, whose presentation was unusual because of later presentation of respiratory distress and lack of genitourinary abnormalities. PMID- 24800791 TI - New oral anticoagulants in patients with cancer: current state of evidence. AB - Effectiveness of new oral anticoagulants (NOAC) in patients with cancer is not clearly defined. There remain concerns of doubtful benefit and chances of potential harm with newer agents. In this meta-analysis, we evaluated the efficacy and safety of NOAC in patients with cancer. PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through February 28, 2013. Randomized controlled trials reporting efficacy and safety data of NOACs (rivaroxaban, dabigatran, and apixaban) with control (low molecular-weight heparin/vitamin K antagonists/placebo) for patients with cancer were included. Primary efficacy outcome was venous thromboembolism (VTE) or VTE related death, and primary safety outcome was clinically relevant bleeding. We used random-effects models. Six trials randomized 19,832 patients, and 1197 patients had cancer. Risk of VTE or VTE-related death was not significantly different with NOAC versus control [odds ratio (OR), 0.80; 95% confidence interval (CI), 0.39-1.65] in patients with cancer. Separate analysis for individual effects showed similar results for rivaroxaban (OR, 1.08; 95% CI, 0.60 1.94) and dabigatran (OR, 0.91; 95% CI, 0.21-3.91). Clinically relevant bleeding was not higher with NOAC compared with control (OR, 1.49; 95% CI, 0.82-2.71); individual effect of rivaroxaban showed similar results. No statistically significant difference of efficacy and safety with NOAC was found between patients with and without cancer. Rivaroxaban might be equally effective and safe as vitamin K antagonist in patients with cancer. Dabigatran is as effective as comparator; however, safety profile of dabigatran is unknown. Randomized trials of new anticoagulants specific to the cancer population are necessary, and NOAC also need to be evaluated against low-molecular-weight heparin. PMID- 24800792 TI - Statins Prevent Dextrose-Induced Endoplasmic Reticulum Stress and Oxidative Stress in Endothelial and HepG2 Cells. AB - Statins have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. However, antioxidant vitamins, unlike statins, are not as cardioprotective, and this paradox has been explained by failure of vitamin antioxidants to ameliorate endoplasmic reticulum (ER) stress. To determine whether statins prevent dextrose-induced ER stress in addition to their antioxidative effects, human umbilical vein endothelial cells and HepG2 hepatocytes were treated with 27.5 mM dextrose in the presence of simvastatin (lipophilic statin that is a prodrug) and pravastatin (water-soluble active drug), and oxidative stress, ER stress, and cell death were measured. Superoxide generation was measured using 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2 A]pyrazin-3-one hydrochloride. ER stress was measured using the placental alkaline phosphatase assay and Western blot of glucose-regulated protein 75, c jun-N-terminal kinase, phospho-JNK, eukaryotic initiating factor 2alpha and phospho-eIF2alpha, and X-box binding protein 1 mRNA splicing. Cell viability was measured by propidium iodide staining. Superoxide anion production, ER stress, and cell death induced by 27.5 mM dextrose were inhibited by therapeutic concentrations of simvastatin and pravastatin. The salutary effects of statins on endothelial cells in reducing both ER stress and oxidative stress observed with pravastatin and the prodrug simvastatin suggest that the effects may be independent of cholesterol-lowering activity. PMID- 24800793 TI - A new triterpenoid saponin and an oligosaccharide isolated from the fruits of Sapindus mukorossi. AB - A new triterpenoid saponin (1) and a new oligosaccharide (2), together with three known saponins (3-5), have been isolated from n-BuOH extract of the fruits of Sapindus mukorossi Gaertn. The structures were elucidated using detailed analysis of one- and two-dimensional nuclear magnetic resonance spectra along with their mass spectrometric data and the results of acid hydrolysis. Of the isolated compounds 1 and 3-5 displayed cytotoxic effects against human cancer cell lines in A-549 (lung carcinoma), MDA-231 (breast carcinoma) and PC-3 (prostatic carcinoma). PMID- 24800795 TI - Management of obstetric anal sphincter injuries (OASIS) in subsequent pregnancy. AB - Obstetric anal sphincter injuries (OASIS) are common and may greatly affect a patient's quality of life. There is very little information regarding optimum management in future pregnancies. Based upon anecdotal experience, this study describes the recommendations of a cohort of consultant obstetricians in the UK, in this clinical situation. There is limited adherence to the available national guidelines due to the absence of available equipment and expertise to perform endo-anal ultrasound and manometry. Elective episiotomy is still recommended by a small number of obstetricians but the majority of patients are routinely followed up. Caesarean section is only advised for asymptomatic patients with a previous stage 4 tear, and for any symptomatic patient with a previous stage 3 or 4 tear, irrespective of subgrade. A request for elective caesarean section is likely to be granted, irrespective of OASIS grade. The use of postpartum endo-anal ultrasound would help identify those women in whom a further vaginal delivery is unlikely to exacerbate any symptoms of faecal incontinence. PMID- 24800794 TI - Inter-rater reliability of query/probe-based techniques for measuring situation awareness. AB - Query- or probe-based situation awareness (SA) measures sometimes rely on process experts to evaluate operator actions and system states when used in representative settings. This introduces variability of human judgement into the measurements that require inter-rater reliability assessment. However, the literature neglects inter-rater reliability of query/probe-based SA measures. We recruited process experts to provide reference keys to SA queries in trials of a full-scope nuclear power plant simulator experiment to investigate the inter rater reliability of a query-based SA measure. The query-based SA measure demonstrated only 'moderate' inter-rater reliability even though the queries were seemingly direct. The level of agreement was significantly different across pairs of experts who had different levels of exposure to the experiment. The results caution that inter-rater reliability of query/probe-based techniques for measuring SA cannot be assumed in representative settings. Knowledge about the experiment as well as the domain is critical to forming reliable expert judgements. PRACTITIONER SUMMARY: When the responses of domain experts are treated as the correct answers to the queries or probes of SA measures used in representative or industrial settings, practitioners should take caution in assuming (or otherwise assess) inter-rater reliability of the situation awareness measures. PMID- 24800796 TI - [Von Willebrand disease in the Netherlands: the WiN study]. AB - Von Willebrand disease is the most common inherited bleeding disorder and is characterised by mucocutaneous bleeding. Von Willebrand disease is caused by reduced levels or reduced function of von Willebrand factor. Depending on the cause, von Willebrand disease is distinguished into various types with their own characteristics and treatment options. The frequency and severity of bleeding in patients with von Willebrand disease is strongly determined by von Willebrand factor levels, factor VIII levels and the type of von Willebrand disease. Eighty five percent of all adult females with von Willebrand disease reports menorrhagia. A high percentage have postpartum excessive blood loss (37% of all deliveries). The quality of life is reduced in patients with von Willebrand disease. Patients with von Willebrand disease have a reduced risk of arterial thrombosis such as a myocardial or cerebral infarction. PMID- 24800797 TI - [Von Willebrand factor and Von Willebrand disease]. AB - Von Willebrand factor (VWF) is a multimeric adhesive protein that binds platelets to exposed subendothelium and carries factor VIII in the circulation. VWD is classified into three major subtypes, distinguished by a quantitative deficiency of VWF (type 1: partial deficiency; type 3: complete deficiency) or qualitative defects of VWF (type 2A, 2B, 2M and 2N). Its diagnosis is based on both clinical and laboratory criteria. The severity of bleeding varies considerably depending on the level of VWF and the FVIII reduction. Diagnosis is especially difficult in patients with a mild or dubious phenotype (type 1 and 2 VWD). Laboratory strategy includes screening tests: complete blood count, platelet morphology, prothrombin time (PT), activated partial thromboplastin time (aPTT) and platelet function analysis. The next step is measurement of VWF antigen, VWF activity and FVIII activity, and calculating ratios between antigen and activity. Finally, multimers, the affinity of VWF for platelets or FVIII can be analysed. PMID- 24800798 TI - [Acute coronary syndrome after chemotherapy]. AB - Systemic therapy for malignancy may be accompanied by an acute coronary syndrome (ACS), regardless of cardiovascular risk factors. We present three patients with few cardiovascular risk factors and no history of cardiovascular disease, who suffered an ACS within a week of starting systemic treatment of colorectal cancer, non-Hodgkin's lymphoma and breast cancer, respectively. In all three patients, systemic anti-cancer therapy was continued after making individualised adjustments to the treatment regimen. It is important to recognize the possible relationship between chemotherapy - including the oral compound capecitabine - and ACS, and to withhold systemic anti-cancer treatment until the ACS is adequately treated. Subsequently, a decision has to be made regarding the continuation of the systemic anti-cancer treatment. Factors to be included in decision making are the intent of the treatment (curative or palliative), the availability of a regimen with less cardiovascular toxicity but comparable efficacy, the outcome of the ACS and the patient's wishes. PMID- 24800799 TI - [Domestic violence in the accident and emergency department: don't forget the children]. AB - In 2013, the Dutch Government mandated a new policy stating that all healthcare professionals caring for adults in difficult psychosocial situations should always investigate the safety of any children involved. We describe two cases of such 'child checks' in the accident and emergency department (A&E). Patient A, a 10-year-old girl, was referred to the outpatient paediatric department (OPD) after her mother had attended the A&E as a victim of domestic violence (DV). The child had witnessed DV on multiple occasions. The family were referred to voluntary social and psychiatric healthcare. Patient B, a 46 year-old woman, attended the A&E with serious injuries, and said she had tripped over. The A&E physician suspected that the injuries were caused by DV, and the mother and her 9 year-old daughter were referred to the OPD. However, the mother refused to attend, and the family was reported to the Youth Care Office. Because parents' psychosocial problems, such as DV, can seriously affect children, their safety should always be investigated by performing a 'child check'. PMID- 24800800 TI - [Is my patient able to provide informed consent? A practical guideline]. AB - Patient autonomy is a fundamental issue. Sometimes it is unclear whether a patient is capable to consent to a treatment decision. The treating physician judges whether a patient is able to provide informed consent. This judgement is a medical and not a legal decision. Considerations as to whether a patient can provide informed consent should always be systematically and in detail included in the medical records and should be periodically re-evaluated. Even if a patient incapable to consent to a particular medical decision, efforts should be put into finding the optimal treatment (proportional, effective and least substantial). It can be useful to involve a psychiatrist as a second and independent judge of a patient's ability to provide informed consent. A psychiatrist can also judge whether a psychiatric or cognitive disorder influences the ability to consent. PMID- 24800801 TI - [New procedure for review of multicentre studies: procedure improved, implementation variable]. AB - In 2012 the Dutch Central Committee on Research Involving Human Subjects (CCMO) introduced a new procedure to obtain medical ethics committee approval for multicentre studies in the Netherlands. A recent cohort study demonstrated that the 2012 procedure is a more efficient one. Our additional prospective evaluation of two multicentre trials confirmed this finding; the implementation of the 2012 procedure in 16 participating centres shortened the local review procedure by a median of 20 days (from 45 to 25 days). However, 6 of the 16 centres (38%) apparently did not follow the new procedure. Strict procedural adherence has the potential to further streamline the process for obtaining ethical approval for multicentre trials in the Netherlands. PMID- 24800802 TI - Experiential avoidance and well-being: a daily diary analysis. AB - Experiential avoidance (EA) is a regulatory strategy characterised by efforts to control or avoid unpleasant thoughts, feelings and bodily sensations. Most studies of EA have used trait measures without considering the effects of EA on psychological functioning in naturalistic settings. To address this gap, we used daily diary methodology to examine the influence of EA of anxiety on everyday well-being. For two weeks, 89 participants provided daily reports of EA, positive and negative affect, enjoyment of daily events and meaning in life (MIL). Daily EA predicted higher negative affect, lower positive affect, less enjoyment of daily events (exercising, eating food and listening to music) and less MIL. The effect of EA on positive affect was not accounted for by the amount of negative affect experienced. Our daily measure of EA was a stronger predictor of daily well-being than a traditional trait measure (The Acceptance and Action Questionnaire). Taken together, results offer insights into the adverse effects of EA on daily well-being and suggest that EA is a context-specific regulatory strategy that might be best captured using a state-dependent measure. PMID- 24800803 TI - Pulmonary fissure integrity and collateral ventilation in COPD patients. AB - PURPOSE: To investigate whether the integrity (completeness) of pulmonary fissures affects pulmonary function in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: A dataset consisting of 573 CT exams acquired on different subjects was collected from a COPD study. According to the global initiative for chronic obstructive lung disease (GOLD) criteria, these subjects (examinations) were classified into five different subgroups, namely non-COPD (222 subjects), GOLD-I (83 subjects), GOLD-II (141 subjects), GOLD-III (63 subjects), and GOLD-IV (64 subjects), in terms of disease severity. An available computer tool was used to aid in an objective and efficient quantification of fissure integrity. The correlations between fissure integrity, and pulmonary functions (e.g., FEV1, and FEV1/FVC) and COPD severity were assessed using Pearson and Spearman's correlation coefficients, respectively. RESULTS: For the five sub-groups ranging from non-COPD to GOLD-IV, the average integrities of the right oblique fissure (ROF) were 81.8%, 82.4%, 81.8%, 82.8%, and 80.2%, respectively; the average integrities of the right horizontal fissure (RHF) were 62.6%, 61.8%, 62.1%, 62.2%, and 62.3%, respectively; the average integrities of the left oblique fissure (LOF) were 82.0%, 83.2%, 81.7%, 82.0%, and 78.4%, respectively; and the average integrities of all fissures in the entire lung were 78.0%, 78.6%, 78.1%, 78.5%, and 76.4%, respectively. Their Pearson correlation coefficients with FEV1 and FE1/FVC range from 0.027 to 0.248 with p values larger than 0.05. Their Spearman correlation coefficients with COPD severity except GOLD-IV range from -0.013 to -0.073 with p values larger than 0.08. CONCLUSION: There is no significant difference in fissure integrity for patients with different levels of disease severity, suggesting that the development of COPD does not change the completeness of pulmonary fissures and incomplete fissures alone may not contribute to the collateral ventilation. PMID- 24800805 TI - Impact of short-term liquid storage on human CD133(+) stem cells. AB - Stem cell transplantation is a viable strategy for regenerative medicine. However, it is inevitable to have cells undergo storage for several hours or days due to processing and transportation. Therefore, it is crucial to have rigidly controlled conditions ensuring the therapeutic benefit of isolated stem cells. In the present study, we investigated the impact of short-term storage on human CD133(+) cells. CD133(+) cells were isolated from human bone marrow and kept at standardized nonfreezing storage conditions for up to 72 h. Cell viability (apoptosis/necrosis) and expression of CD133 and CXCR4 were analyzed by flow cytometry. Metabolic activity was determined using an MTT assay; colony-forming ability, as well as endothelial-like differentiation, was further evaluated. A qRT-PCR array was employed to investigate the expression of stemness genes. CD133 and CXCR4 expressions were preserved at all time points. After 30 h, cell number and metabolic activity decreased, although no significant changes were detected in cell viability and proliferation as well as endothelial-like differentiation. Cell viability and proliferation decreased significantly only after 72 h of storage. Our results indicate that storage of isolated human CD133(+) bone marrow stem cells in liquid allows for high viability and functionality. However, storage time should be limited in order to avoid cell loss. PMID- 24800806 TI - Prehypertension-associated elevation in circulating lysophosphatidlycholines, Lp PLA2 activity, and oxidative stress. AB - Prehypertension is a risk factor for atherosclerosis. We investigated alterations in plasma metabolites that are associated with prehypertension. A group of 53 individuals was identified who remained within the range of prehypertension during repeated measurements in a 3-year period. This group was compared with the control group of 53 normotensive subjects who were matched for age and gender. Metabolomic profiles were analyzed with UPLC-LTQ-Orbitrap mass spectrometry. The prehypertensive group showed higher levels of lysophosphatidylcholines (lysoPCs) containing C14:0, C16:1, C16:0, C18:2, C18:1, C18:0, C20:5, C20:4, C20:3, and C22:6, higher circulating Lp-PLA2 activity, oxidized LDL (ox-LDL), interleukin 6 (IL-6), urinary 8-epi-PGF2alpha, and higher brachial-ankle pulse wave velocity (ba-PWV), before and after adjusting for BMI, WHR, smoking, alcohol consumption, serum lipid profiles, glucose, and insulin. LysoPC (16:0) was the most important plasma metabolite for evaluating the difference between control and prehypertensive groups, with a variable important in the projection (VIP) value of 17.173, and it showed a positive and independent association with DBP and SBP. In the prehypertensive group, the levels of lysoPC (16:0) positively and significantly correlated with ox-LDL, Lp-PLA2 activity, 8-epi-PGF2alpha, ba-PWV, and IL-6 before and after adjusting for confounding variables. Prehypertension associated elevations in lysoPCs, Lp-PLA2 activity, ox-LDL, urinary 8-epi PGF2alpha, IL-6, and ba-PWV could indicate increased oxidative stress from Lp PLA2-catalyzed PC hydrolysis during increased LDL oxidation, thereby enhancing proinflammation and arterial stiffness. PMID- 24800807 TI - Gastroprotective activity of ethyl-4-[(3,5-di-tert-butyl-2-hydroxybenzylidene) amino]benzoate against ethanol-induced gastric mucosal ulcer in rats. AB - BACKGROUND: The study was carried out to determine the cytotoxic, antioxidant and gastro-protective effect of ethyl-4-[(3,5-di-tert-butyl-2-hydroxybenzylid ene)amino] benzoate (ETHAB) in rats. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of ETHAB was assessed using a MTT cleavage assay on a WRL68 cell line, while its antioxidant activity was evaluated in vitro. In the anti-ulcer study, rats were divided into six groups. Group 1 and group 2 received 10% Tween 20 (vehicle). Group 3 received 20 mg/kg Omeprazole. Groups 4, 5 and 6 received ETHAB at doses of 5, 10, and 20 mg/kg, respectively. After an hour, group 1 received the vehicle. Groups 2-6 received absolute ethanol to induce gastric mucosal lesions. In the WRL68 cell line, an IC50 of more than 100 ug/mL was observed. ETHAB results showed antioxidant activity in the DPPH, FRAP, nitric oxide and metal chelating assays. There was no acute toxicity even at the highest dosage (1000 mg/kg). Microscopy showed that rats pretreated with ETHAB revealed protection of gastric mucosa as ascertained by significant increases in superoxide dismutase (SOD), pH level, mucus secretion, reduced gastric lesions, malondialdehyde (MDA) level and remarkable flattened gastric mucosa. Histologically, pretreatment with ETHAB resulted in comparatively better gastric protection, due to reduction of submucosal edema with leucocyte infiltration. PAS staining showed increased intensity in uptake of Alcian blue. In terms of immunohistochemistry, ETHAB showed down-expression of Bax proteins and over expression of Hsp70 proteins. CONCLUSION/SIGNIFICANCE: The gastroprotective effect of ETHAB may be attributed to antioxidant activity, increased gastric wall mucus, pH level of gastric contents, SOD activity, decrease in MDA level, ulcer area, flattening of gastric mucosa, reduction of edema and leucocyte infiltration of the submucosal layer, increased PAS staining, up-regulation of Hsp70 protein and suppressed expression of Bax. PMID- 24800808 TI - The comparison between robotic and manual ablations in the treatment of atrial fibrillation: a systematic review and meta-analysis. AB - OBJECTIVE: To examine in what aspects and to what extent robotic ablation is superior over manual ablation, we sought to design a meta-analysis to compare clinical outcomes between the two ablations in the treatment of atrial fibrillation. METHODS AND RESULTS: A literature search was conducted of PubMed and EMBASE databases before December 1, 2013. Data were extracted independently and in duplicate from 8 clinical articles and 792 patients. Effect estimates were expressed as weighted mean difference (WMD) or odds ratio (OR) and the accompanied 95% confidence interval (95% CI). Pooling the results of all qualified trials found significant reductions in fluoroscopic time (minutes) (WMD; 95% CI; P: -8.9; -12.54 to -5.26; <0.0005) and dose-area product (Gy*cm2) (WMD; 95% CI; P: -1065.66; -1714.36 to -416.96; 0.001) for robotic ablation relative to manual ablation, with evident heterogeneity (P<0.0005) and a low probability of publication bias. In subgroup analysis, great improvement of fluoroscopic time in patients with robotic ablation was consistently presented in both randomized and nonrandomized clinical trials, particularly in the former (WMD; 95% CI; P: -12.61; -15.13 to -10.09; <0.0005). Success rate of catheter ablation was relatively higher in patients with robotic ablation than with manual ablation (OR; 95% CI; P: 3.45; 0.24 to 49.0; 0.36), the difference yet exhibiting no statistical significance. CONCLUSIONS: This study confirmed and extended previous observations by quantifying great reductions of fluoroscopic time and dose-area product in patients referred for robotic ablation than for manual ablation in the treatment of atrial fibrillation, especially in randomized clinical trials. PMID- 24800809 TI - Lac repressor mediated DNA looping: Monte Carlo simulation of constrained DNA molecules complemented with current experimental results. AB - Tethered particle motion (TPM) experiments can be used to detect time-resolved loop formation in a single DNA molecule by measuring changes in the length of a DNA tether. Interpretation of such experiments is greatly aided by computer simulations of DNA looping which allow one to analyze the structure of the looped DNA and estimate DNA-protein binding constants specific for the loop formation process. We here present a new Monte Carlo scheme for accurate simulation of DNA configurations subject to geometric constraints and apply this method to Lac repressor mediated DNA looping, comparing the simulation results with new experimental data obtained by the TPM technique. Our simulations, taking into account the details of attachment of DNA ends and fluctuations of the looped subsegment of the DNA, reveal the origin of the double-peaked distribution of RMS values observed by TPM experiments by showing that the average RMS value for anti parallel loop types is smaller than that of parallel loop types. The simulations also reveal that the looping probabilities for the anti-parallel loop types are significantly higher than those of the parallel loop types, even for loops of length 600 and 900 base pairs, and that the correct proportion between the heights of the peaks in the distribution can only be attained when loops with flexible Lac repressor conformation are taken into account. Comparison of the in silico and in vitro results yields estimates for the dissociation constants characterizing the binding affinity between O1 and Oid DNA operators and the dimeric arms of the Lac repressor. PMID- 24800810 TI - Lower fetuin-A, retinol binding protein 4 and several metabolites after gastric bypass compared to sleeve gastrectomy in patients with type 2 diabetes. AB - BACKGROUND: Bypass of foregut secreted factors promoting insulin resistance is hypothesized to be one of the mechanisms by which resolution of type 2 diabetes (T2D) follows roux-en-y gastric bypass (GBP) surgery. AIM: To identify insulin resistance-associated proteins and metabolites which decrease more after GBP than after sleeve gastrectomy (SG) prior to diabetes remission. METHODS: Fasting plasma from 15 subjects with T2D undergoing GBP or SG was analyzed by proteomic and metabolomic methods 3 days before and 3 days after surgery. Subjects were matched for age, BMI, metformin therapy and glycemic control. Insulin resistance was calculated using homeostasis model assessment (HOMA-IR). For proteomics, samples were depleted of abundant plasma proteins, digested with trypsin and labeled with iTRAQ isobaric tags prior to liquid chromatography-tandem mass spectrometry analysis. Metabolomic analysis was performed using gas chromatography-mass spectrometry. The effect of the respective bariatric surgery on identified proteins and metabolites was evaluated using two-way analysis of variance and appropriate post-hoc tests. RESULTS: HOMA-IR improved, albeit not significantly, in both groups after surgery. Proteomic analysis yielded seven proteins which decreased significantly after GBP only, including Fetuin-A and Retinol binding protein 4, both previously linked to insulin resistance. Significant decrease in Fetuin-A and Retinol binding protein 4 after GBP was confirmed using ELISA and immunoassay. Metabolomic analysis identified significant decrease of citrate, proline, histidine and decanoic acid specifically after GBP. CONCLUSION: Greater early decrease was seen for Fetuin-A, Retinol binding protein 4, and several metabolites after GBP compared to SG, preceding significant weight loss. This may contribute to enhanced T2D remission observed following foregut bypass procedures. PMID- 24800811 TI - Comparative functional analysis of wheat (Triticum aestivum) zinc finger containing glycine-rich RNA-binding proteins in response to abiotic stresses. AB - Although the functional roles of zinc finger-containing glycine-rich RNA-binding proteins (RZs) have been characterized in several plant species, including Arabidopsis thaliana and rice (Oryza sativa), the physiological functions of RZs in wheat (Triticum aestivum) remain largely unknown. Here, the functional roles of the three wheat RZ family members, named TaRZ1, TaRZ2, and TaRZ3, were investigated using transgenic Arabidopsis plants under various abiotic stress conditions. Expression of TaRZs was markedly regulated by salt, dehydration, or cold stress. The TaRZ1 and TaRZ3 proteins were localized to the nucleus, whereas the TaRZ2 protein was localized to the nucleus, endoplasmic reticulum, and cytoplasm. Germination of all three TaRZ-expressing transgenic Arabidopsis seeds was retarded compared with that of wild-type seeds under salt stress conditions, whereas germination of TaRZ2- or TaRZ3-expressing transgenic Arabidopsis seeds was retarded under dehydration stress conditions. Seedling growth of TaRZ1 expressing transgenic plants was severely inhibited under cold or salt stress conditions, and seedling growth of TaRZ2-expressing plants was inhibited under salt stress conditions. By contrast, expression of TaRZ3 did not affect seedling growth of transgenic plants under any of the stress conditions. In addition, expression of TaRZ2 conferred freeze tolerance in Arabidopsis. Taken together, these results suggest that different TaRZ family members play various roles in seed germination, seedling growth, and freeze tolerance in plants under abiotic stress. PMID- 24800812 TI - Yellow Fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data. AB - BACKGROUND: Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods. METHODS AND FINDINGS: Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone. The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000 380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000-180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%-31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys. CONCLUSIONS: With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns. PMID- 24800813 TI - Cold wall effect eliminating method to determine the contrast recovery coefficient for small animal PET scanners using the NEMA NU-4 image quality phantom. AB - The contrast recovery coefficients (CRC) were evaluated for five different small animal PET scanners: GE Explore Vista, Genisys4, MiniPET-2, nanoScan PC and Siemens Inveon. The NEMA NU-4 2008 performance test with the suggested image quality phantom (NU4IQ) does not allow the determination of the CRC values for the hot regions in the phantom. This drawback of NU4IQ phantom motivated us to develop a new method for this purpose. The method includes special acquisition and reconstruction protocols using the original phantom, and results in an artificially merged image enabling the evaluation of CRC values. An advantageous feature of this method is that it stops the cold wall effect from distorting the CRC calculation. Our suggested protocol results in a set of CRC values contributing to the characterization of small animal PET scanners. GATE simulations were also performed to validate the new method and verify the evaluated CRC values. We also demonstrated that the numerical values of this parameter depend on the actual object contrast of the hot region(s) and this mainly comes from the spillover effect. This effect was also studied while analysing the background activity level around the hot rods. We revealed that the calculated background mean values depended on the target contrast in a scanner specific manner. Performing the artificially merged imaging procedure and additional simulations using the micro hollow sphere (MHS) phantom geometry, we also proved that the inactive wall around the hot spheres can have a remarkable impact on the calculated CRC. In conclusion, we have shown that the proposed artificial merging procedure and the commonly used NU4IQ phantom prescribed by the NEMA NU-4 can easily deliver reliable CRC data otherwise unavailable for the NU4IQ phantom in the conventional protocol or the MHS phantom. PMID- 24800814 TI - Pneumothorax following endobronchial valve therapy and its impact on clinical outcomes in severe emphysema. AB - BACKGROUND: Patients who achieve significant target lobe volume reduction (TLVR) following endobronchial valve (EBV) treatment may experience substantial improvements in clinical outcome measures. However, in cases of rapid TLVR, the risk of pneumothorax increases due to parenchymal rupture of the adjacent untreated lobe. Target lobe collapse may be more likely in EBV-treated patients who have low collateral ventilation. OBJECTIVES: The aim of this study was to evaluate the impact of pneumothorax on outcome following EBV treatment. METHODS: Data from three prospective clinical trials (the US and European cohorts of VENT and the Multicenter Chartis study) were retrieved for the analysis. All patients had undergone chest X-ray within 24 h of EBV implantation to explore the presence of pneumothorax. TLVR was assessed at either 30 (Chartis study) or 180 days (VENT), and clinical outcome measures (forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and 6-min-walk distance (6-MWD)) were assessed 180 days after implantation. RESULTS: The overall rate of pneumothorax following valve therapy was 5.9% (25/421). Among these patients, 68% had a prolonged air leak for >7 days. However, patients who experienced a pneumothorax benefitted from EBV therapy, with a mean TLVR of 65% (n = 20). The mean percent change in FEV1 was 15 +/- 15%, and the mean change in SGRQ was -7 +/ 12 points. CONCLUSIONS: Although pneumothorax is a complication of EBV placement, it does not appear to have a negative impact on clinical outcome in terms of FEV1 and health-related quality of life. PMID- 24800815 TI - Pain assessment in hospitalized older adults with dementia and delirium. AB - Pain can have negative effects leading to prolonged hospital stays. Determining the presence of uncontrolled and untreated pain in patients with cognitive impairments such as delirium, dementia, and delirium superimposed on dementia (DSD) is challenging. One tool commonly suggested for use in assessment of pain in older adults with cognitive impairment is the Pain Assessment In Advanced Dementia (PAINAD) scale. Proper use of the PAINAD scale as part of a comprehensive pain management plan can help reduce the likelihood of a patient experiencing unrecognized and untreated pain. Using an individual example, this article illustrates best practices in pain assessment and management for a woman experiencing DSD during an acute hospitalization. PMID- 24800816 TI - Call to action: promoting domestic and global tobacco control by ratifying the framework convention on tobacco control in the United States. PMID- 24800817 TI - Growth factor independence 1b (gfi1b) is important for the maturation of erythroid cells and the regulation of embryonic globin expression. AB - Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis. Gfi1b-null embryos die at midgestation very likely due to defects in erythro- and megakaryopoiesis. To analyze the full functionality of Gfi1b, we used conditionally deficient mice that harbor floxed Gfi1b alleles and inducible (Mx-Cre, Cre-ERT) or erythroid specific (EpoR-Cre) Cre expressing transgenes. In contrast to the germline knockout, EpoR-Cre mediated erythroid specific ablation of Gfi1b allows full gestation, but causes perinatal lethality with very few mice surviving to adulthood. Both the embryonic deletion of Gfi1b by EpoR-Cre and the deletion in adult mice by Mx-Cre or Cre-ERT leads to reduced numbers of erythroid precursors, perturbed and delayed erythroid maturation, anemia and extramedullary erythropoiesis. Global expression analyses showed that the Hba-x, Hbb-bh1 and Hbb-y embryonic globin genes were upregulated in Gfi1b deficient TER119+ fetal liver cells over the gestation period from day 12.5-17.5 p.c. and an increased level of Hbb-bh1 and Hbb-y embryonic globin gene expression was even maintained in adult Gfi1b deficient mice. While the expression of Bcl11a, a regulator of embryonic globin expression was not affected by Gfi1b deficiency, the expression of Gata1 was reduced and the expression of Sox6, also involved in globin switch, was almost entirely lost when Gfi1b was absent. These findings establish Gfi1b as a regulator of embryonic globin expression and embryonic and adult erythroid maturation. PMID- 24800818 TI - Clinical profiles and outcomes of acute aortic dissection in a predominantly Hispanic population. AB - BACKGROUND: Acute aortic dissection (AAD) is a life-threatening cardiovascular condition with high morbidity and mortality. We sought to assess clinical profiles as well as outcomes of AAD in a predominantly Hispanic population and to explore the relationship between this condition and uncontrolled/untreated hypertension in this community. MATERIAL AND METHODS: This was a single-center, retrospective, cross-sectional study of patients admitted with AAD over a 10 years period. RESULTS: Fifty-nine cases of AAD were included in the analysis. The group of Hispanics with AAD had more females (48.3%, p=0.002), more dyslipidemia and coronary artery disease (p=0.006 and 0.05, respectively), and a tendency to be older and have more hypertension and diabetes compared to non-Hispanics. Although 70.2% of all patients had hypertension, only 52.5% of them were being treated; of those, only 66.7% achieved optimal blood pressure control prior to presentation. Only 47.4% received beta-blockers for blood pressure control in the acute setting. Longer length of in-hospital stay was associated with older age, higher troponin and creatine kinase levels, and presence of hypertension. In hospital death occurred in 10 (17%) patients and mortality was significantly associated with higher serum creatinine (p=0.01). CONCLUSIONS: Hispanic patients with AAD were more likely to be female, of older age, and have more cardiovascular risk factors in comparison to non-Hispanics. In addition, significant under-treatment of hypertension in this population and underutilization of beta-blockers for blood pressure control in the acute settings was evident. Better prevention and timely treatment may improve outcomes for this condition in this population. PMID- 24800819 TI - The contribution of arterial calcification to peripheral arterial disease in pseudoxanthoma elasticum. AB - BACKGROUND AND AIMS: The contribution of arterial calcification (AC) in peripheral arterial disease (PAD) and arterial wall compressibility is a matter of debate. Pseudoxanthoma elasticum (PXE), an inherited metabolic disease due to ABCC6 gene mutations, combines elastic fiber fragmentation and calcification in various soft tissues including the arterial wall. Since AC is associated with PAD, a frequent complication of PXE, we sought to determine the role of AC in PAD and arterial wall compressibility in this group of patients. METHODS AND RESULTS: Arterial compressibility and patency were determined by ankle-brachial pressure index (ABI) in a cohort of 71 PXE patients (mean age 48 +/- SD 14 yrs, 45 women) and compared to 30 controls without PAD. Lower limb arterial calcification (LLAC) was determined by non-contrast enhanced helicoidal CT-scan. A calcification score (Ca-score) was computed for the femoral, popliteal and sub-popliteal artery segments of both legs. Forty patients with PXE had an ABI<0.90 and none had an ABI>1.40. LLAC increased with age, significantly more in PXE subjects than controls. A negative association was found between LLAC and ABI (r = -0.363, p = 0.002). The LLAC was independently associated with PXE and age, and ABI was not linked to cardiovascular risk factors. CONCLUSIONS: The presence of AC was associated with PAD and PXE without affecting arterial compressibility. PAD in PXE patients is probably due to proximal obstructive lesions developing independently from cardiovascular risk factors. PMID- 24800820 TI - Profiling of olfactory receptor gene expression in whole human olfactory mucosa. AB - Olfactory perception is mediated by a large array of olfactory receptor genes. The human genome contains 851 olfactory receptor gene loci. More than 50% of the loci are annotated as nonfunctional due to frame-disrupting mutations. Furthermore haplotypic missense alleles can be nonfunctional resulting from substitution of key amino acids governing protein folding or interactions with signal transduction components. Beyond their role in odor recognition, functional olfactory receptors are also required for a proper targeting of olfactory neuron axons to their corresponding glomeruli in the olfactory bulb. Therefore, we anticipate that profiling of olfactory receptor gene expression in whole human olfactory mucosa and analysis in the human population of their expression should provide an opportunity to select the frequently expressed and potentially functional olfactory receptors in view of a systematic deorphanization. To address this issue, we designed a TaqMan Low Density Array (Applied Biosystems), containing probes for 356 predicted human olfactory receptor loci to investigate their expression in whole human olfactory mucosa tissues from 26 individuals (13 women, 13 men; aged from 39 to 81 years, with an average of 67+/-11 years for women and 63+/-12 years for men). Total RNA isolation, DNase treatment, RNA integrity evaluation and reverse transcription were performed for these 26 samples. Then 384 targeted genes (including endogenous control genes and reference genes specifically expressed in olfactory epithelium for normalization purpose) were analyzed using the same real-time reverse transcription PCR platform. On average, the expression of 273 human olfactory receptor genes was observed in the 26 selected whole human olfactory mucosa analyzed, of which 90 were expressed in all 26 individuals. Most of the olfactory receptors deorphanized to date on the basis of sensitivity to known odorant molecules, which are described in the literature, were found in the expressed olfactory receptors gene set. PMID- 24800821 TI - Influence of artifact removal on rare species recovery in natural complex communities using high-throughput sequencing. AB - Large-scale high-throughput sequencing techniques are rapidly becoming popular methods to profile complex communities and have generated deep insights into community biodiversity. However, several technical problems, especially sequencing artifacts such as nucleotide calling errors, could artificially inflate biodiversity estimates. Sequence filtering for artifact removal is a conventional method for deleting error-prone sequences from high-throughput sequencing data. As rare species represented by low-abundance sequences in datasets may be sensitive to artifact removal process, the influence of artifact removal on rare species recovery has not been well evaluated in natural complex communities. Here we employed both internal (reliable operational taxonomic units selected from communities themselves) and external (indicator species spiked into communities) references to evaluate the influence of artifact removal on rare species recovery using 454 pyrosequencing of complex plankton communities collected from both freshwater and marine habitats. Multiple analyses revealed three clear patterns: 1) rare species were eliminated during sequence filtering process at all tested filtering stringencies, 2) more rare taxa were eliminated as filtering stringencies increased, and 3) elimination of rare species intensified as biomass of a species in a community was reduced. Our results suggest that cautions be applied when processing high-throughput sequencing data, especially for rare taxa detection for conservation of species at risk and for rapid response programs targeting non-indigenous species. Establishment of both internal and external references proposed here provides a practical strategy to evaluate artifact removal process. PMID- 24800822 TI - Comparative genetic analysis of PP2A-Cdc55 regulators in budding yeast. AB - Cdc55, a regulatory B subunit of the protein phosphatase 2A (PP2A) complex, plays various functions during mitosis. Sequestration of Cdc55 from the nucleus by Zds1 and Zds2 is important for robust activation of mitotic Cdk1 and mitotic progression in budding yeast. However, Zds1-family proteins are found only in fungi but not in higher eukaryotes. In animal cells, highly conserved ENSA/ARPP 19 family proteins bind and inhibit PP2A-B55 activity for mitotic entry. In this study, we compared the relative contribution of Zds1/Zds2 and ENSA-family proteins Igo1/Igo2 on Cdc55 functions in budding yeast mitosis. We confirmed that Igo1/Igo2 can inhibit Cdc55 in early mitosis, but their contribution to Cdc55 regulation is relatively minor compared with the role of Zds1/Zds2. In contrast to Zds1, which primarily localized to the sites of cell polarity and in the cytoplasm, Igo1 is localized in the nucleus, suggesting that Igo1/Igo2 inhibit Cdc55 in a manner distinct from Zds1/Zds2. Our analysis confirmed an evolutionarily conserved function of ENSA-family proteins in inhibiting PP2A Cdc55, and we propose that Zds1-dependent sequestration of PP2A-Cdc55 from the nucleus is uniquely evolved to facilitate closed mitosis in fungal species. PMID- 24800823 TI - Designing driver assistance systems with crossmodal signals: multisensory integration rules for saccadic reaction times apply. AB - Modern driver assistance systems make increasing use of auditory and tactile signals in order to reduce the driver's visual information load. This entails potential crossmodal interaction effects that need to be taken into account in designing an optimal system. Here we show that saccadic reaction times to visual targets (cockpit or outside mirror), presented in a driving simulator environment and accompanied by auditory or tactile accessories, follow some well-known spatiotemporal rules of multisensory integration, usually found under confined laboratory conditions. Auditory nontargets speed up reaction time by about 80 ms. The effect tends to be maximal when the nontarget is presented 50 ms before the target and when target and nontarget are spatially coincident. The effect of a tactile nontarget (vibrating steering wheel) was less pronounced and not spatially specific. It is shown that the average reaction times are well described by the stochastic "time window of integration" model for multisensory integration developed by the authors. This two-stage model postulates that crossmodal interaction occurs only if the peripheral processes from the different sensory modalities terminate within a fixed temporal interval, and that the amount of crossmodal interaction manifests itself in an increase or decrease of second stage processing time. A qualitative test is consistent with the model prediction that the probability of interaction, but not the amount of crossmodal interaction, depends on target-nontarget onset asynchrony. A quantitative model fit yields estimates of individual participants' parameters, including the size of the time window. Some consequences for the design of driver assistance systems are discussed. PMID- 24800824 TI - Impaired endoplasmic reticulum stress response in bipolar disorder: cellular evidence of illness progression. AB - Bipolar disorder (BD) is a severe chronic psychiatric disorder that has been associated with cellular dysfunctions related to mitochondria, neurotrophin levels, and oxidative stress. Evidence has shown that endoplasmic reticulum (ER) stress may be a common pathway of the cellular changes described in BD. In the present study we assessed unfolded protein response (UPR) and the effects of this cellular process on lymphocytes from patients with BD. We also evaluated whether the stage of chronicity of BD was associated with changes in UPR parameters. Cultured lymphocytes from 30 patients with BD and 32 age- and sex-matched controls were treated with tunicamycin, an ER stressor, for 12 or 24 h to measure levels of UPR-related proteins (GRP78, eIF2alpha-P, and CHOP) using flow cytometry, and for 48 h to analyse ER stress-induced cell death. In healthy controls but not in patients we found an increase in levels of GRP78, eIF2alpha P, and CHOP after ER stress induction. In addition, tunicamycin-induced cell death was significantly higher in patients compared to controls. More importantly, early-stage patients did not differ from controls while the late stage patients showed an impaired ER stress response. Thus, dysfunction in ER related stress response may be associated with decreased cellular resilience in BD and illness progression. PMID- 24800825 TI - Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. AB - The potential for avian influenza H5N1 outbreaks has increased in recent years. Thus, it is paramount to develop novel strategies to alleviate death rates. Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II. High serum levels of angiotensin II appear to be linked to the severity and lethality of infection, at least in some patients. In experimental mouse models, infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 (ACE2) expression in the lung and increased serum angiotensin II levels. Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice, confirming a role of ACE2 in H5N1-induced lung pathologies. Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice. Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics. PMID- 24800826 TI - Associations of fine particulate matter species with mortality in the United States: a multicity time-series analysis. AB - BACKGROUND: Epidemiological studies have examined the association between PM2.5 and mortality, but uncertainty remains about the seasonal variations in PM2.5 related effects and the relative importance of species. OBJECTIVES: We estimated the effects of PM2.5 species on mortality and how infiltration rates may modify the association. METHODS: Using city-season specific Poisson regression, we estimated PM2.5 effects on approximately 4.5 million deaths for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory diseases in 75 U.S. cities for 2000-2006. We added interaction terms between PM2.5 and monthly average species-to-PM2.5 proportions of individual species to determine the relative toxicity of each species. We combined results across cities using multivariate meta-regression, and controlled for infiltration. RESULTS: We estimated a 1.18% (95% CI: 0.93, 1.44%) increase in all-cause mortality, a 1.03% (95% CI: 0.65, 1.41%) increase in CVD, a 1.22% (95% CI: 0.62, 1.82%) increase in MI, a 1.76% (95% CI: 1.01, 2.52%) increase in stroke, and a 1.71% (95% CI: 1.06, 2.35%) increase in respiratory deaths in association with a 10-MUg/m3 increase in 2-day averaged PM2.5 concentration. The associations were largest in the spring. Silicon, calcium, and sulfur were associated with more all cause mortality, whereas sulfur was related to more respiratory deaths. County level smoking and alcohol were associated with larger estimated PM2.5 effects. CONCLUSIONS: Our study showed an increased risk of mortality associated with PM2.5, which varied with seasons and species. The results suggest that mass alone might not be sufficient to evaluate the health effects of particles. PMID- 24800827 TI - BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. AB - Cardiotoxicity is a dose-limiting side-effect of cancer chemotherapeutics such as anthracyclines. The drug-induced cardiac toxicity is currently monitored with repeated assessments of the left ventricular ejection fraction (LVEF) using multigated equilibrium radionuclide ventriculography (MUGA) or echocardiography. However, the plasma cardiac biomarker B-type natriuretic peptide (BNP) has been suggested for early identification of cardiac dysfunction. The aim of the study was to compare LVEF obtained by MUGA and plasma BNP as predictors of developing congestive heart failure (CHF) or death in a population of anthracycline-treated cancer patients. METHODS: We prospectively followed 333 cancer patients referred to our department for routine monitoring of LVEF with MUGA and measurement of BNP, January-December 2004. Study end points were hospitalization for CHF and death during follow-up 2004-2010. Data were obtained from the Danish National Patient Registry. RESULTS: During follow-up (mean 1,360 days), 21 of the patients were admitted to hospital with a diagnosis of CHF and 194 of the patients died. BNP levels were significantly higher and LVEF lower in the group of patients that developed CHF. Using cut-off points of BNP>100 pg/ml (HR 5.5; CI 1.8-17.2; p = 0.003) and LVEF <50% (HR 7.9; CI 3.0-21.4; p<0.001) both significantly predicted CHF. Using the same cut-off points only BNP (HR 1.9; CI 1.3-2.9; p = 0.002) and not LVEF (HR 1.1; CI 0.7-1.8; p = 0.58) was predictive of overall death. In multivariate Cox analysis both BNP and LVEF were independent predictors of CHF while age remained the only independent predictor of overall death. CONCLUSION: In cancer patients treated with cardiotoxic chemotherapy both BNP and LVEF can significantly predict subsequent hospitalization with CHF. In addition, BNP and not LVEF has a prognostic value in detecting overall death. This prospective study based on the hitherto largest study population supports BNP as a clinical relevant method for monitoring chemotherapy-related cardiac failure and death. PMID- 24800830 TI - Re-estimation of motion and reconstruction for distributed video coding. AB - Transform domain Wyner-Ziv (TDWZ) video coding is an efficient approach to distributed video coding (DVC), which provides low complexity encoding by exploiting the source statistics at the decoder side. The DVC coding efficiency depends mainly on side information and noise modeling. This paper proposes a motion re-estimation technique based on optical flow to improve side information and noise residual frames by taking partially decoded information into account. To improve noise modeling, a noise residual motion re-estimation technique is proposed. Residual motion compensation with motion updating is used to estimate a current residue based on previously decoded frames and correlation between estimated side information frames. In addition, a generalized reconstruction algorithm to optimize a multihypothesis reconstruction is proposed. The proposed techniques using motion and reconstruction re-estimation (MORE) are integrated in the SING TDWZ codec, which uses side information and noise learning. For Wyner Ziv frames using GOP size 2, the MORE codec significantly improves the TDWZ coding efficiency with an average (Bjontegaard) PSNR improvement of 2.5 dB and up to 6 dB improvement compared with DISCOVER. PMID- 24800828 TI - Vibriocidal antibody responses to a bivalent killed whole-cell oral cholera vaccine in a phase III trial in Kolkata, India. AB - BACKGROUND: During the development of a vaccine, identification of the correlates of protection is of paramount importance for establishing an objective criterion for the protective performance of the vaccine. However, the ascertainment of correlates of immunity conferred by any vaccine is a difficult task. METHODS: While conducting a phase three double-blind, cluster-randomized, placebo controlled trial of a bivalent killed whole-cell oral cholera vaccine in Kolkata, we evaluated the immunogenicity of the vaccine in a subset of participants. Randomly chosen participants (recipients of vaccine or placebo) were invited to provide blood samples at baseline, 14 days after the second dose and one year after the first dose. At these time points, serum geometric mean titers (GMT) of vibriocidal antibodies and seroconversion rates for vaccine and placebo arms were calculated and compared across the age strata (1 to 5 years, 5 to 15 years and more than 15 years) as well as for all age groups. RESULTS: Out of 137 subjects included in analysis, 69 were vaccinees and 68 received placebo. There were 5*7 and 5*8 geometric mean fold (GMF) rises in titers to Vibrio cholerae Inaba and Ogawa, respectively at 14 days after the second dose, with 57% and 61% of vaccinees showing a four-fold or greater titer rise, respectively. After one year, the titers to Inaba and Ogawa remained 1*7 and 2*8 fold higher, respectively, compared to baseline. Serum vibriocidal antibody response to V. cholerae O139 was much lower than that to Inaba or Ogawa. No significant differences in the GMF-rises were observed among the age groups. CONCLUSIONS: The reformulated oral cholera vaccine induced a statistically significant anti-O1 Inaba and O1 Ogawa vibriocidal antibody response 14 days after vaccination, which although declined after one year remained significantly higher than baseline. Despite this decline, the vaccine remained protective five years after vaccination. PMID- 24800831 TI - An enantioselective Diels-Alder reaction of 1,2-dihydropyridines with alpha acyloxyacroleins catalyzed by a chiral primary ammonium salt. AB - The first enantioselective Diels-Alder reaction of 1,2-dihydropyridines with alpha-acyloxyacroleins catalyzed by a chiral primary ammonium salt has been developed and it offers more efficient routes to key synthetic intermediates of alkaloids, for which the direct preparations were unavailable before. The asymmetric induction can be understood through the optimized geometry of an iminium salt aqua complex derived from the catalyst and the dienophile. PMID- 24800832 TI - Evolution of rapid development in spadefoot toads is unrelated to arid environments. AB - The extent to which species' life histories evolve to match climatic conditions is a critical question in evolutionary biology and ecology and as human activities rapidly modify global climate. GIS-based climatic data offer new opportunities to rigorously test this question. Superficially, the spadefoot toads of North America (Scaphiopodidae) seem to offer a classic example of adaptive life-history evolution: some species occur in extremely dry deserts and have evolved the shortest aquatic larval periods known among anurans. However, the relationships between the climatic conditions where spadefoots occur and the relevant life-history traits have not been explicitly tested. Here, we analyzed these relationships using GIS-based climatic data, published life-history data, and a time-calibrated phylogeny for pelobatoid frogs. Surprisingly, we find no significant relationships between life-history variables and precipitation or aridity levels where these species occur. Instead, rapid development in pelobatoids is strongly related to their small genome sizes and to phylogeny. PMID- 24800833 TI - Cervical cancer in north-eastern Libya: 2000-2008. AB - Libya is a country with a low population, listed under the EMRO. Using registers and patient records from a major primary oncology clinic, data was gathered from Libyan cervical cancer patients and various parameters were studied across 9 years. Out of 4,090 female cancer cases during the study period, 1.8% were cervical cancer (n = 74). The average age of presentation was 53 years, with most of the cases (60%, n = 44) being premenopausal. Approximately 65% (n = 48) of cervical cancer patients are diagnosed at later stages (i.e. stages III and IV). The majority of these cases are squamous cell carcinoma (83.8%, n = 62), while 16.2% (n = 12) were found to be adenocarcinoma. Patients with squamous cell carcinoma presented at later stages more often than those with adenocarcinoma. Human papilloma virus was strongly implicated in cervical cancer, with 94% (n = 63) of those who were tested being positive for HPV-16 (82.5%, n = 52) and HPV-18 (12.7%, n = 8). Diagnosis was most frequently made through biopsy (97.3%, n = 72) as opposed to Pap smears (2.7%, n = 2). Most Libyan patients were put through chemotherapy (75%, n = 55) and triple therapy (surgery with combined chemotherapy and radiotherapy) was the most common (38%, n = 28) modality of treatment. Comparisons were made between Libya and other nations, either in the developed world or neighbouring countries. The major problem of cervical cancer in Libya is delayed presentation and hence, all the recommendations focus on increased awareness for the populace, implementation of a national cancer control plan and a national screening programme. PMID- 24800834 TI - Impedance Alterations in Healthy and Diseased Mice During Electrically Induced Muscle Contraction. AB - Alterations in the health of muscles can be evaluated through the use of electrical impedance myography (EIM). To date, however, nearly all work in this field has relied upon the measurement of muscle at rest. To provide an insight into the contractile mechanisms of healthy and disease muscle, we evaluated the alterations in the spectroscopic impedance behavior of muscle during the active process of muscle contraction. The gastrocnemii from a total of 13 mice were studied (five wild type, four muscular dystrophy animals, and four amyotrophic lateral sclerosis animals). Muscle contraction was induced via monophasic current pulse stimulation of the sciatic nerve. Simultaneously, multisine EIM (1 kHz to 1 MHz) and force measurements of the muscle were performed. Stimulation was applied at three different rates to produce mild, moderate, and strong contractions. We identified changes in both single and multifrequency data, as assessed by the Cole impedance model parameters. The processes of contraction and relaxation were clearly identified in the impedance spectra and quantified via derivative plots. Reductions in the center frequency fc were observed during the contraction consistent with the increasing muscle fiber diameter. Different EIM stimulation rate-dependencies were also detected across the three groups of animals. PMID- 24800835 TI - Species adaptive strategies and leaf economic relationships across serpentine and non-serpentine habitats on Lesbos, eastern Mediterranean. AB - Shifts in species' traits across contrasting environments have the potential to influence ecosystem functioning. Plant communities on unusually harsh soils may have unique responses to environmental change, through the mediating role of functional plant traits. We conducted a field study comparing eight functional leaf traits of seventeen common species located on both serpentine and non serpentine environments on Lesbos Island, in the eastern Mediterranean. We focused on species' adaptive strategies across the two contrasting environments and investigated the effect of trait variation on the robustness of core 'leaf economic' relationships across local environmental variability. Our results showed that the same species followed a conservative strategy on serpentine substrates and an exploitative strategy on non-serpentine ones, consistent with the leaf economic spectrum predictions. Although considerable species-specific trait variability emerged, the single-trait responses across contrasting environments were generally consistent. However, multivariate-trait responses were diverse. Finally, we found that the strength of relationships between core 'leaf economic' traits altered across local environmental variability. Our results highlight the divergent trait evolution on serpentine and non-serpentine communities and reinforce other findings presenting species-specific responses to environmental variation. PMID- 24800837 TI - Identification of responders to sorafenib in hepatocellular carcinoma: is tumor volume measurement the way forward? AB - OBJECTIVES: Early assessment of hepatocellular carcinoma (HCC) response during sorafenib (SO) treatment is challenging, since tumor necrosis, extension and radiological appearance can be inhomogeneous. We evaluated the predictive value of different imaging criteria - such as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), tumor density and volume variations - in the early follow-up of SO treatment. METHODS: The study included 22 patients. CT images from baseline and 2 months were reviewed to assess response according to RECIST 1.1, mRECIST, EASL, Choi's criteria (decreased tumor density by >=15%) and arterial-enhancing tumor volume ratio; alpha-fetoprotein (AFP) variations were expressed as AFP ratio. RESULTS: The response criteria and volume measurements were reproducible (k > 0.80). The overall disease control rate was 40.9% by EASL and mRECIST, and 27.3% by RECIST 1.1; a >=15% decrease in tumor density was observed in 9 patients (40.9%). The mean volume ratio was 1.73 +/- 2.12, the mean AFP ratio 14 +/- 37. The 1-year survival rate was 65.9%. Volume ratio was the only predictive factor for survival, with 1-year cumulative survival rates of 90% for volume ratios <=1.1 and of 45.4% for volume ratios >1.1 (p = 0.04). CONCLUSIONS: Tumor volume measurements are reproducible and might provide an early predictive marker of response in HCC patients treated with SO. PMID- 24800836 TI - Chronic lymphocytic leukemia cells in a lymph node microenvironment depict molecular signature associated with an aggressive disease. AB - Chronic lymphocytic leukemia (CLL) cells survive longer in vivo than in vitro, suggesting that the tissue microenvironment provides prosurvival signals to tumor cells. Primary and secondary lymphoid tissues are involved in the pathogenesis of CLL, and the role of these tissue microenvironments has not been explored completely. To elucidate host-tumor interactions, we performed gene expression profiling (GEP) of purified CLL cells from peripheral blood (PB; n = 20), bone marrow (BM; n = 18), and lymph node (LN; n = 15) and validated key pathway genes by real-time polymerase chain reaction, immunohistochemistry and/or TCL1 trans genic mice. Gene signatures representing several pathways critical for survival and activation of B cells were altered in CLL cells from different tissue compartments. Molecules associated with the B-cell receptor (BCR), B cell activating factor/a proliferation-inducing ligand (BAFF/APRIL), nuclear factor (NF)-kappaB pathway and immune suppression signature were enriched in LN-CLL, suggesting LNs as the primary site for tumor growth. Immune suppression genes may help LN-CLL cells to modulate antigen-presenting and T-cell behavior to suppress antitumor activity. PB CLL cells overexpressed chemokine receptors, and their cognate ligands were enriched in LN and BM, suggesting that a chemokine gradient instructs B cells to migrate toward LN or BM. Of several chemokine ligands, the expression of CCL3 was associated with poor prognostic factors. The BM gene signature was enriched with antiapoptotic, cytoskeleton and adhesion molecules. Interestingly, PB cells from lymphadenopathy patients shared GEP with LN cells. In EMU-TCL1 transgenic mice (the mouse model of the disease), a high percentage of leukemic cells from the lymphoid compartment express key BCR and NF-kappaB molecules. Together, our findings demonstrate that the lymphoid microenvironment promotes survival, proliferation and progression of CLL cells via chronic activation of BCR, BAFF/APRIL and NF-kappaB activation while suppressing the immune response. PMID- 24800839 TI - Male interference with pollination efficiency in a hermaphroditic orchid. AB - Hermaphroditism can lead to both intra- and intersexual conflict between male and female gender functions. However, the effect that such gender conflicts have on pollination efficiency has seldom been investigated. By artificially reducing the number of available male gametes on an individual, we quantified whether male interference with pollination efficiency occurs in the self-compatible, moth pollinated orchid Satyrium longicauda. We partially emasculated S. longicauda inflorescences and compared pollination success and fecundity in these plants to intact controls. Pollen in both groups of plants was colour-labelled so that its dispersal by pollinators could be tracked directly in the field. Intact flowers on partially emasculated inflorescences exported more pollen and received more cross-pollen and less self-pollen than those on intact inflorescences. Proportion of fruit set per plant was similar between the two treatments; however, fruits on partially emasculated plants had proportionally more viable seeds than those on intact controls. These results provide empirical evidence that male interference with pollination efficiency can occur in a hermaphroditic plant and that such interference can compromise fecundity. The most likely mechanism for such male interference is competition for placement on the proboscis of hawkmoth pollinators. Consequently, male competition for siring success may influence the evolution of sexual systems in hermaphroditic pollinator-dependent plants. PMID- 24800840 TI - Achieving the HIV prevention impact of voluntary medical male circumcision: lessons and challenges for managing programs. AB - Voluntary medical male circumcision (VMMC) is capable of reducing the risk of sexual transmission of HIV from females to males by approximately 60%. In 2007, the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended making VMMC part of a comprehensive HIV prevention package in countries with a generalized HIV epidemic and low rates of male circumcision. Modeling studies undertaken in 2009-2011 estimated that circumcising 80% of adult males in 14 priority countries in Eastern and Southern Africa within five years, and sustaining coverage levels thereafter, could avert 3.4 million HIV infections within 15 years and save US$16.5 billion in treatment costs. In response, WHO/UNAIDS launched the Joint Strategic Action Framework for accelerating the scale-up of VMMC for HIV prevention in Southern and Eastern Africa, calling for 80% coverage of adult male circumcision by 2016. While VMMC programs have grown dramatically since inception, they appear unlikely to reach this goal. This review provides an overview of findings from the PLOS Collection "Voluntary Medical Male Circumcision for HIV Prevention: Improving Quality, Efficiency, Cost Effectiveness, and Demand for Services during an Accelerated Scale-up." The use of devices for VMMC is also explored. We propose emphasizing management solutions to help VMMC programs in the priority countries achieve the desired impact of averting the greatest possible number of HIV infections. Our recommendations include advocating for prioritization and funding of VMMC, increasing strategic targeting to achieve the goal of reducing HIV incidence, focusing on programmatic efficiency, exploring the role of new technologies, rethinking demand creation, strengthening data use for decision-making, improving governments' program management capacity, strategizing for sustainability, and maintaining a flexible scale-up strategy informed by a strong monitoring, learning, and evaluation platform. PMID- 24800841 TI - SDF-1 enhances wound healing of critical-sized calvarial defects beyond self repair capacity. AB - Host blood circulating stem cells are an important cell source that participates in the repair of damaged tissues. The clinical challenge is how to improve the recruitment of circulating stem cells into the local wound area and enhance tissue regeneration. Stromal-derived factor-1 (SDF-1) has been shown to be a potent chemoattractant of blood circulating stem cells into the local wound microenvironment. In order to investigate effects of SDF-1 on bone development and the repair of a large bone defect beyond host self-repair capacity, the BMP induced subcutaneous ectopic bone formation and calvarial critical-sized defect murine models were used in this preclinical study. A dose escalation of SDF-1 were loaded into collagen scaffolds containing BMP, VEGF, or PDGF, and implanted into subcutaneous sites at mouse dorsa or calvarial critical-sized bone defects for 2 and 4 weeks. The harvested biopsies were examined by microCT and histology. The results demonstrated that while SDF-1 had no effect in the ectopic bone model in promoting de novo osteogenesis, however, in the orthotopic bone model of the critical-sized defects, SDF-1 enhanced calvarial critical-sized bone defect healing similar to VEGF, and PDGF. These results suggest that SDF-1 plays a role in the repair of large critical-sized defect where more cells are needed while not impacting de novo bone formation, which may be associated with the functions of SDF-1 on circulating stem cell recruitment and angiogenesis. PMID- 24800849 TI - Analysis of hydrogen bond energies and hydrogen bonded networks in water clusters (H2O)20 and (H2O)25 using the charge-transfer and dispersion terms. AB - The hydrogen bonds and their networks in the water clusters (H2O)20 and (H2O)25 are characterized using the charge-transfer (E(W(a),W(d))(CT)) and dispersion (E(W(a),W(d))(Disp)) terms for every pair of water molecules (Wa, Wd) in the clusters. The terms are evaluated by the perturbation theory based on the ab initio locally projected molecular orbitals (LPMO PT) developed by the present author. The relative binding energies among the isomers evaluated by the LPMO PT agree with those of the high level ab initio wave function based theories. A strong correlation between E(W(a),W(d))(CT) and E(W(a),W(d))(Disp) for the hydrogen bonded pairs is found. The pair-wise interaction energies are characterized by the types of hydrogen-donor (Wd) and hydrogen-acceptor (Wa) water molecules. The strongest pair is that of the D2A1 water molecule as a hydrogen-acceptor and the D1A2 water molecule as a hydrogen-donor, where the DnAm water molecule implies that the water molecule has n hydrogen bonding O-H and m accepting HO. The intra-molecular deformation as well as the O...O distance is also dependent on the types of hydrogen bonded pairs. The ring structures in the cluster are classified by the pattern of alignment of the hydrogen bonds. The lengthening of the hydrogen-bonding OH of Wd is strongly correlated with the charge-transfer (E(W(a),W(d))(CT)) energy. PMID- 24800842 TI - C-reactive protein as a prognostic factor for human osteosarcoma: a meta-analysis and literature review. AB - BACKGROUND: Osteosarcoma is the most common primary bone cancer in growing adolescents and young adults. The prognostic role of C-reactive protein (CRP) in patients with osteosarcoma is not fully investigated. The purpose of this study is to perform a meta-analysis and literature review on the role of CRP in osteosarcoma and to assess the potential role of serum CRP as a prognostic factor for patients with osteosarcoma. METHODS: A detailed literature search was made in Medline for related research publications written in English. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, risk ratio (RR) and corresponding confidence intervals (CIs) were calculated and summarized respectively. RESULTS: Final analysis of 397 patients from 2 eligible studies was performed. Combined RR of CRP expression suggested that the raised serum CRP level had an adverse prognostic effect on overall survival of patients with osteosarcoma (n = 397 in 2 studies; RR = 0.35; 95% CI: 0.18-0.68; p = 0.002). In the uni- and multivariate survival analysis, response rate and CRP levels were the only independent prognostic variables. CONCLUSIONS: The results of this meta-analysis suggest that CRP expression confers a worse prognosis in patients with osteosarcoma. Large prospective studies are necessary to provide solid data to confirm the prognostic significance of CRP. PMID- 24800850 TI - Rapamycin enhances cetuximab cytotoxicity by inhibiting mTOR-mediated drug resistance in mesenchymal hepatoma cells. AB - The synergistic effect of combined drug therapy provides an enhanced treatment for advanced liver cancer. We aimed to investigate the underlying mechanism of cetuximab sensitization by rapamycin in hepatoma cells. Four hepatoma cell lines, HepG2, HuH7, SNU-387, and SNU-449, were treated with cetuximab or cetuximab plus rapamycin and growth inhibition was evaluated by measuring relative cell viability and cell proliferation. The cell phenotype was determined for each hepatoma cell line by western blot analysis of E-cadherin and vimentin expression and mTOR activation status. To identify the role of mTOR signaling in cetuximab sensitization, we used deferoxamine-mediated hypoxia to induce epithelial mesenchymal transition (EMT) in HuH7 and HepG2 cells and measured mTOR activity after rapamycin treatment. Rapamycin significantly increased cetuximab cytotoxicity in hepatoma cell lines with differential sensitivities. Phenotypic differences among hepatoma cell lines, specifically epithelial (HuH7 and HepG2) and mesenchymal (SNU-387 and SNU-449), correlated with the efficacy of rapamycin cotreatment, although rapamycin treatment did not affect cell phenotype. We further showed that rapamycin inhibits mTOR in mesenchymal SNU-387 and SNU-449 cells. In addition, the induction of EMT in HuH7 and HepG2 cells significantly decreased cetuximab cytotoxicity; however, rapamycin treatment significantly restored cetuximab sensitivity and decreased mTOR signaling in these cells. In conclusion, we identified significant differences in rapamycin-induced cetuximab sensitization between epithelial and mesenchymal hepatoma cells. We therefore report that rapamycin cotreatment enhances cetuximab cytotoxicity by inhibiting mTOR signaling in mesenchymal cells. PMID- 24800851 TI - Genkwanin inhibits proinflammatory mediators mainly through the regulation of miR 101/MKP-1/MAPK pathway in LPS-activated macrophages. AB - Genkwanin is one of the major non-glycosylated flavonoids in many herbs with anti inflammatory activities. Although its anti-inflammatory activity in vivo has been reported, the potential molecular mechanisms remain obscure. In this study, by pharmacological and genetic approaches, we explore the anti-inflammatory effects of genkwanin in LPS-activated RAW264.7 macrophages. Genkwanin potently decreases the proinflammatory mediators, such as iNOS, TNF-alpha, IL-1beta and IL-6, at the transcriptional and translational levels without cytotoxicity, indicating the excellent anti-inflammatory potency of genkwanin in vitro. Mechanism study shows that genkwanin significantly suppresses the p38- and JNK-mediated AP-1 signaling pathway and increases the mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression at the posttranscriptional level. We also confirmed that microRNA-101 (miR-101) is a negative regulator of MKP-1 expression. Moreover, regardless of miR-101-deficient cells or miR-101-abundant cells, the suppression effects of genkwanin on supernatant proinflammatory mediators' levels are far less than that in respective negative control cells, suggesting that genkwanin exerts anti-inflammatory effect mainly through reducing miR-101 production. However, genkwanin can't affect the level of phospho-Akt (p-Akt), indicating that the phosphorylation of Akt may be not responsible for the effect of genkwanin on miR-101 production. We conclude that genkwanin exerts its anti-inflammatory effect mainly through the regulation of the miR-101/MKP-1/MAPK pathway. PMID- 24800852 TI - Targeted knockdown of IQGAP1 inhibits the progression of esophageal squamous cell carcinoma in vitro and in vivo. AB - IQGAP1 is a scaffolding protein that can regulate several distinct signaling pathways. The accumulating evidence has demonstrated that IQGAP1 plays an important role in tumorigenesis and tumor progression. However, the function of IQGAP1 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly investigated. In the present study, we showed that IQGAP1 was overexpressed in ESCC tumor tissues, and its overexpression was correlated with the invasion depth of ESCC. Importantly, by using RNA interference (RNAi) technology we successfully silenced IQGAP1 gene in two ESCC cell lines, EC9706 and KYSE150, and for the first time found that suppressing IQGAP1 expression not only obviously reduced the tumor cell growth, migration and invasion in vitro but also markedly inhibited the tumor growth, invasion, lymph node and lung metastasis in xenograft mice. Furthermore, Knockdown of IQGAP1 expression in ESCC cell lines led to a reversion of epithelial to mesenchymal transition (EMT) progress. These results suggest that IQGAP1 plays crucial roles in regulating ESCC occurrence and progression. IQGAP1 silencing may therefore develop into a promising novel anticancer therapy. PMID- 24800858 TI - Monitoring of internet forums to evaluate reactions to the introduction of reformulated OxyContin to deter abuse. AB - BACKGROUND: Reformulating opioid analgesics to deter abuse is one approach toward improving their benefit-risk balance. To assess sentiment and attempts to defeat these products among difficult-to-reach populations of prescription drug abusers, evaluation of posts on Internet forums regarding reformulated products may be useful. A reformulated version of OxyContin (extended-release oxycodone) with physicochemical properties to deter abuse presented an opportunity to evaluate posts about the reformulation in online discussions. OBJECTIVE: The objective of this study was to use messages on Internet forums to evaluate reactions to the introduction of reformulated OxyContin and to identify methods aimed to defeat the abuse-deterrent properties of the product. METHODS: Posts collected from 7 forums between January 1, 2008 and September 30, 2013 were evaluated before and after the introduction of reformulated OxyContin on August 9, 2010. A quantitative evaluation of discussion levels across the study period and a qualitative coding of post content for OxyContin and 2 comparators for the 26 month period before and after OxyContin reformulation were conducted. Product endorsement was estimated for each product before and after reformulation as the ratio of endorsing-to-discouraging posts (ERo). Post-to-preintroduction period changes in ERos (ie, ratio of ERos) for each product were also calculated. Additionally, post content related to recipes for defeating reformulated OxyContin were evaluated from August 9, 2010 through September 2013. RESULTS: Over the study period, 45,936 posts related to OxyContin, 18,685 to Vicodin (hydrocodone), and 23,863 to Dilaudid (hydromorphone) were identified. The proportion of OxyContin-related posts fluctuated between 6.35 and 8.25 posts per 1000 posts before the reformulation, increased to 10.76 in Q3 2010 when reformulated OxyContin was introduced, and decreased from 9.14 in Q4 2010 to 3.46 in Q3 2013 in the period following the reformulation. The sentiment profile for OxyContin changed following reformulation; the post-to-preintroduction change in the ERo indicated reformulated OxyContin was discouraged significantly more than the original formulation (ratio of ERos=0.43, P<.001). A total of 37 recipes for circumventing the abuse-deterrent characteristics of reformulated OxyContin were observed; 32 were deemed feasible (ie, able to abuse). The frequency of posts reporting abuse of reformulated OxyContin via these recipes was low and decreased over time. Among the 5677 posts mentioning reformulated OxyContin, 825 posts discussed recipes and 498 reported abuse of reformulated OxyContin by such recipes (41 reported injecting and 128 reported snorting). CONCLUSIONS: After introduction of physicochemical properties to deter abuse, changes in discussion of OxyContin on forums occurred reflected by a reduction in discussion levels and endorsing content. Despite discussion of recipes, there is a relatively small proportion of reported abuse of reformulated OxyContin via recipes, particularly by injecting or snorting routes. Analysis of Internet discussion is a valuable tool for monitoring the impact of abuse-deterrent formulations. PMID- 24800859 TI - Strain engineering the properties of graphene and other two-dimensional crystals. AB - Graphene has been widely studied for its many extraordinary properties, and other two-dimensional layered materials are now gaining increased interest. These excellent properties make thin layer materials very attractive for integration into a wide variety of technologies, particularly in flexible optoelectronic devices. Therefore, gaining control over these properties will allow for a more focused design and optimisation of these possible technologies. Through the application of mechanical strain it is possible to alter the electronic structures of two-dimensional crystals, such as graphene and transition metal dichalcogenides (e.g. MoS2), and these changes in electronic structure can alter their behaviour. In this perspective we discuss recent advances in the strain engineering of thin layer materials, with a focus on using Raman spectroscopy and electrical transport to investigate the effect of strain as well as the effect of strain on the chemical functionalisation of graphene. PMID- 24800861 TI - Ultrasonic imaging of complex specimens by processing multiple incident angles in full-angle synthetic aperture focusing technique. AB - In the evaluation of large-scale metallic specimens, X-ray CT suffers from limited penetration, which results in artifacts in the reconstructed image. Data fusion of information obtained by different modalities allows correction of those artifacts. In this contribution, an approach is presented to provide complementary data of the inner pattern of the specimen by ultrasonic testing in immersion mode. To process an ultrasonic imaging full-angle synthetic aperture focusing technique, data are acquired along the a priori known contour of the specimen. Substantial discrepancies in speed of sound between the couplant and the material of the specimen lead to refraction effects which are corrected by a virtual source element method. Furthermore, several incident angles at each virtual source are utilized to achieve an enhanced detectability of inner structural edges. However, arising reverberations limit image quality and must be suppressed by predictive deconvolution. Additionally, a subspace analysis and projection method is utilized to remove echoes of the a priori known surface in the reconstructed image which potentially mask information of near-surface structures. In comparison with exclusively perpendicular insonification, resulting images show a significant enhanced possibility of detection for inner structural edges even in adverse orientations for ultrasonic imaging. Furthermore, surface echoes and reverberations are suppressed by the proposed filter methods in a reliable way. PMID- 24800860 TI - Variants of a Thermus aquaticus DNA polymerase with increased selectivity for applications in allele- and methylation-specific amplification. AB - The selectivity of DNA polymerases is crucial for many applications. For example, high discrimination between the extension of matched versus mismatched primer termini is desired for the detection of a single nucleotide variation at a particular locus within the genome. Here we describe the generation of thermostable mutants of the large fragment of Thermus aquaticus DNA polymerase (KlenTaq) with increased mismatch extension selectivity. In contrast to previously reported much less active KlenTaq mutants with mismatch discrimination abilities, many of the herein discovered mutants show conserved wild-type-like high activities. We demonstrate for one mutant containing the single amino acid exchange R660V the suitability for application in allele-specific amplifications directly from whole blood without prior sample purification. Also the suitability of the mutant for methylation specific amplification in the diagnostics of 5 methyl cytosines is demonstrated. Furthermore, the identified mutant supersedes other commercially available enzymes in human leukocyte antigen (HLA) analysis by sequence-specific primed polymerase chain reactions (PCRs). PMID- 24800862 TI - Predicting polycyclic aromatic hydrocarbon concentrations in resident aquatic organisms using passive samplers and partial least-squares calibration. AB - The current work sought to develop predictive models between time-weighted average polycyclic aromatic hydrocarbon (PAH) concentrations in the freely dissolved phase and those present in resident aquatic organisms. We deployed semipermeable membrane passive sampling devices (SPMDs) and collected resident crayfish (Pacifastacus leniusculus) at nine locations within and outside of the Portland Harbor Superfund Mega-site in Portland, OR. Study results show that crayfish and aqueous phase samples collected within the Mega-site had PAH profiles enriched in high molecular weight PAHs and that freely dissolved PAH profiles tended to be more populated by low molecular weight PAHs compared to crayfish tissues. Results also show that of several modeling approaches, a two factor partial least-squares (PLS) calibration model using detection limit substitution provided the best predictive power for estimating PAH concentrations in crayfish, where the model explained >=72% of the variation in the data set and provided predictions within ~3* of measured values. Importantly, PLS calibration provided a means to estimate PAH concentrations in tissues when concentrations were below detection in the freely dissolved phase. The impact of measurements below detection limits is discussed. PMID- 24800863 TI - Entrainment to periodic initiation and transition rates in a computational model for gene translation. AB - Periodic oscillations play an important role in many biomedical systems. Proper functioning of biological systems that respond to periodic signals requires the ability to synchronize with the periodic excitation. For example, the sleep/wake cycle is a manifestation of an internal timing system that synchronizes to the solar day. In the terminology of systems theory, the biological system must entrain or phase-lock to the periodic excitation. Entrainment is also important in synthetic biology. For example, connecting several artificial biological systems that entrain to a common clock may lead to a well-functioning modular system. The cell-cycle is a periodic program that regulates DNA synthesis and cell division. Recent biological studies suggest that cell-cycle related genes entrain to this periodic program at the gene translation level, leading to periodically-varying protein levels of these genes. The ribosome flow model (RFM) is a deterministic model obtained via a mean-field approximation of a stochastic model from statistical physics that has been used to model numerous processes including ribosome flow along the mRNA. Here we analyze the RFM under the assumption that the initiation and/or transition rates vary periodically with a common period T. We show that the ribosome distribution profile in the RFM entrains to this periodic excitation. In particular, the protein synthesis pattern converges to a unique periodic solution with period T. To the best of our knowledge, this is the first proof of entrainment in a mathematical model for translation that encapsulates aspects such as initiation and termination rates, ribosomal movement and interactions, and non-homogeneous elongation speeds along the mRNA. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and may suggest a new approach for re-engineering genetic systems to obtain a desired, periodic, protein synthesis rate. PMID- 24800865 TI - Clinical, microbiologic, and outcome analysis of mycotic aortic aneurysm: the role of endovascular repair. AB - BACKGROUND: Mycotic aortic aneurysm (MAA) is an infrequent but devastating form of vascular disease. METHODS: We conducted a retrospective cohort study at a major medical center to identify independent risk factors for MAA and to provide opinions about treating it. The study population consisted of 43 patients who had had 44 MAAs over a period of 15 y. RESULTS: All of the patients had positive blood cultures, radiologic findings typical of MAA, and clinical signs of infection (leukocytosis, fever, and elevated C-reactive protein). The mean age of the patients was 63.8+/-10.6 y and the mean period of their follow up was 35.7+/ 39.3 mo. Twenty-nine patients with MAAs underwent traditional open surgery, 11 others received endovascular stent grafts, and four MAAs were managed conservatively. The most frequent causative pathogens were Salmonella (36/44 patients [81.8%]), in whom organisms of Salmonella serogroup C (consisting mainly of S. choleraesuis) were identified in 14 patients, organisms of Salmonella serogroup D were identified in 13 patients, and species without serogroup information were identified in nine patients. The overall mortality in the study population was 43.2% (with an aneurysm-related mortality of 18.2%, surgically related mortality of 13.6%, and in-hospital mortality of 22.7%). CONCLUSIONS: Shock is a risk factor for operative mortality. Misdiagnosis and treatment of MAA as low back pain, co-existing connective-tissue disease such as systemic lupus erythematosus and rheumatoid arthritis, and Salmonella serogroup C-associated bacteremia are risk factors for aneurysm-related death. Endovascular repair should be considered as an alternative option to the open repair of MAA. PMID- 24800864 TI - Signaling molecules: hydrogen sulfide and polysulfide. AB - SIGNIFICANCE: Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury. H2S is produced from l-cysteine by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase. RECENT ADVANCES: In addition to these enzymes, we recently identified a novel pathway to produce H2S from d-cysteine, which involves d-amino acid oxidase (DAO) along with 3MST. These enzymes are localized in the cytoplasm, mitochondria, and peroxisomes. However, some enzymes translocate to organelles under specific conditions. Moreover, H2S-derived potential signaling molecules such as polysulfides and HSNO have been identified. CRITICAL ISSUES: The physiological stimulations, which trigger the production of H2S and its derivatives and maintain their local levels, remain unclear. FUTURE DIRECTIONS: Understanding the regulation of the H2S production and H2S-derived signaling molecules and the specific stimuli that induce their release will provide new insights into the biology of H2S and therapeutic development in diseases involving these substances. PMID- 24800867 TI - Effect of the guide strand 3'-end structure on the gene-silencing potency of asymmetric siRNA. AB - siRNAs are short dsRNAs that mediate efficient target gene silencing in a sequence-specific manner. We previously developed a novel siRNA structure, called asiRNA (asymmetric siRNA), which alleviates the off-target effects associated with conventional siRNA structures without decreasing target gene silencing potency. In the present study, we explored the effect of the guide strand 3'-end structure on the gene silencing potency of asiRNA. Interestingly, asiRNAs with a 21 nt guide strand solely composed of RNA resulted in gene silencing that was more than 6-fold more efficient compared with the corresponding asiRNA guide strand harbouring a dTdT (deoxythymidine dinucleotide) at its 3'-end. We demonstrated that the molecular basis of potency of the asiRNA with a 21 nt guide strand composed solely of RNA was due to the enhanced formation of the RISC (RNA induced silencing complex) and increased affinity towards hAgo2 (human Argonaute2). Our observations may assist researchers in designing new asiRNAs with high on-target silencing efficiency with low off-target effects, which is critical for applications in both basic research and therapeutic development. PMID- 24800868 TI - Comparing trace metal bioaccumulation characteristics of three freshwater decapods of the genus Macrobrachium. AB - Potential sources and kinetics of metal bioaccumulation by the three Macrobrachium prawn species M. australiense, M. rosenbergii and M. latidactylus were assessed in laboratory experiments. The prawns were exposed to two scenarios: cadmium in water only; and exposure to metal-rich mine tailings in the same water. The cadmium accumulation from the dissolved exposure during 7 days, followed by depuration in cadmium-free water for 7 days, was compared with predictions from a biokinetic model that had previously been developed for M. australiense. M. australiense and M. latidactylus accumulated significant tissue cadmium during the exposure phase, albeit with different uptake rates. All three species retained >95% of the bioaccumulated cadmium during the depuration phase, indicating very slow efflux rates. Following exposure to tailings, there were significant (p<0.05) differences in tissue arsenic, cadmium, lead and zinc concentrations among species. Cadmium and zinc concentrations were increased relative to controls for all three species but were not different between treatments (direct/indirect contact with tailings), suggesting these metals were primarily accumulated via the dissolved phase. All species bioaccumulated significantly greater arsenic and lead when in direct contact with mine tailings, demonstrating the importance of an ingestion pathway for these metals. Copper was not bioaccumulated above control concentrations for any species. The differences between the metal accumulation of the three prawns indicated that a biokinetic model of cadmium bioaccumulation for M. australiense could potentially be used to describe the metal bioaccumulation of the other two prawn species, albeit with an over-prediction of 3-9 times. Despite these being the same genus of decapod crustacean, the study highlights the issues with using surrogate species, even under controlled laboratory conditions. It is recommended that future studies using surrogate species quantify the metal bioaccumulation characteristics of each species in order to account for any differences between species. PMID- 24800866 TI - Differential expression profiling of spleen microRNAs in response to two distinct type II interferons in Tetraodon nigroviridis. AB - MicroRNAs are endogenous, small non-coding RNAs approximately 18-26 nucleotides in length that regulate target gene expression at the post-transcription level. Interferon-gamma (IFN-gamma) is a Th1 cytokine that is involved in both the innate and adaptive immune responses. We previously identified two IFN-gamma genes in green-spotted puffer fish (Tetraodon nigroviridis). To determine whether miRNAs participate in IFN-gamma-related immune responses, T. nigroviridis spleen cells were treated with recombinant IFN-gamma isoforms, and a Solexa high throughput sequencing method was used to identify miRNAs. In total, 1,556, 1,538 and 1,573 miRNAs were found in the three samples, and differentially expressed miRNAs were determined. In total, 398 miRNAs were differentially expressed after rIFN-gamma1 treatment, and 438 miRNAs were differentially expressed after rIFN gamma2 treatment; additionally, 403 miRNAs were differentially expressed between the treatment groups. Ten differentially expressed miRNAs were chosen for validation using qRT-PCR. Target genes for the differentially expressed miRNAs were predicted, and GO and KEGG analyses were performed. This study provides basic knowledge regarding fish IFN-gamma-induced miRNAs and offers clues for further studies into the mechanisms underlying fish IFN-gamma-mediated immune responses. PMID- 24800869 TI - Gamma rays induce DNA damage and oxidative stress associated with impaired growth and reproduction in the copepod Tigriopus japonicus. AB - Nuclear radioisotope accidents are potentially ecologically devastating due to their impact on marine organisms. To examine the effects of exposure of a marine organism to radioisotopes, we irradiated the intertidal copepod Tigriopus japonicus with several doses of gamma radiation and analyzed the effects on mortality, fecundity, and molting by assessing antioxidant enzyme activities and gene expression patterns. No mortality was observed at 96h, even in response to exposure to a high dose (800Gy) of radiation, but mortality rate was significantly increased 120h (5 days) after exposure to 600 or 800Gy gamma ray radiation. We observed a dose-dependent reduction in fecundity of ovigerous females; even the group irradiated with 50Gy showed a significant reduction in fecundity, suggesting that gamma rays are likely to have a population level effect. In addition, we observed growth retardation, particularly at the nauplius stage, in individuals after gamma irradiation. In fact, nauplii irradiated with more than 200Gy, though able to molt to copepodite stage 1, did not develop into adults. Upon gamma radiation, T. japonicus showed a dose-dependent increase in reactive oxygen species (ROS) levels, the activities of several antioxidant enzymes, and expression of double-stranded DNA break damage genes (e.g. DNA-PK, Ku70, Ku80). At a low level (sub-lethal dose) of gamma irradiation, we found dose dependent upregulation of p53, implying cellular damage in T. japonicus in response to sub-lethal doses of gamma irradiation, suggesting that T. japonicus is not susceptible to sub-lethal doses of gamma irradiation. Additionally, antioxidant genes, phase II enzyme (e.g. GSTs), and cellular chaperone genes (e.g. Hsps) that are involved in cellular defense mechanisms also showed the same expression patterns for sublethal doses of gamma irradiation (50-200Gy). These findings indicate that sublethal doses of gamma radiation can induce oxidative stress-mediated DNA damage and increase the expression of antioxidant enzymes and proteins with chaperone-related functions, thereby significantly affecting life history parameters such as fecundity and molting in the copepod T. japonicus. PMID- 24800870 TI - Assessment of the sensitivity of three North American fish species to disruptors of steroidogenesis using in vitro tissue explants. AB - There is concern regarding exposure of aquatic organisms to chemicals that interfere with the endocrine system. One critical mechanism of endocrine disruption is impairment of steroidogenesis that can lead to altered hormone levels, altered or delayed sexual development, and ultimately reproductive failure. With the current large gap in knowledge and a high degree of uncertainty regarding the sensitivity of fishes native to northern ecosystems to endocrine disrupting chemicals (EDCs), the aim of this study was to develop an in vitro gonadal explant assay enabling the assessment of EDCs on sex-steroid production in wild fish species native to North America. Northern pike (Esox lucius), walleye (Sander vitreus), and white sucker (Catostomus commeroni) were sampled from a reference location in Lake Diefenbaker, Saskatchewan, Canada, at spawn and multiple post-spawn time points. Gonads were excised and immediately exposed for 24h to a model inducer (forskolin) or inhibitor (prochloraz) of steroidogenesis in L-15 supplemented media. Furthermore, seasonal profiles of plasma 11 ketotestosterone (11-KT) and 17-beta estradiol (E2) concentrations were characterized. Enzyme-linked immunosorbent assays were used to quantify hormone concentrations in plasma and media. The seasonal profile of plasma hormones was significantly correlated with basal in vitro hormone production. Gonad tissue exposed to forskolin showed a concentration-dependent increase in E2 and a general increase in 11-KT. Gonad tissue exposed to prochloraz resulted in a decrease of concentrations of 11-KT and E2. These results illustrated that gonadal tissue is undergoing steroidogenesis in an in vitro setting that is comparable to in vivo hormone profiles, and which is responsive to chemical exposure in a concentration-dependent manner. The seasonal time point during which gonad explants were excised and exposed had an impact on the potency and magnitude of responses, resulting in a seasonal effect on sensitivity. Male and female white sucker showed greatest sensitivity to forskolin, while male and female walleye showed greatest sensitivity to prochloraz. Also, gonad explants from these species were found to have greater sensitivity than responses previously reported for in vitro explants of other fish species such as the fathead minnow (Pimephales promelas), and stable cell lines currently used as screening applications to detect chemicals that might disrupt the endocrine system. Therefore, current approaches that use stable cell lines or tissue explants from standardized small bodied laboratory species might not be protective of some wild fish species. Future research is required that investigates whether this in vitro gonadal explant assay is predictive of in vivo effects in wild species of fishes. PMID- 24800872 TI - Haemophilia Experiences, Results and Opportunities (HERO) Study: influence of haemophilia on interpersonal relationships as reported by adults with haemophilia and parents of children with haemophilia. AB - Evidence delineating the effects of haemophilia on interpersonal relationships is sparse and largely outdated, failing to reflect the impact of current treatment strategies. HERO (Haemophilia Experiences, Results and Opportunities) was commenced to garner a more comprehensive understanding of psychosocial issues facing persons with haemophilia (PWH). This article describes the findings of the quantitative HERO survey relating to the influence of haemophilia on interpersonal relationships of adult PWH, and parents/caregivers of children with haemophilia. Separate questionnaires were completed by adult PWH and parents of minor children from 10 countries, including satisfaction with support from partners, family, friends and other social contacts; disclosure of haemophilia and carrier status and family dynamics. A total of 675 PWH and 561 parents completed the survey. Over half of PWH (57%) and parents (84%) were married. Most PWH were satisfied with support from partners (94%), family (90%) and friends (85%), with lower percentages reported among those with inhibitors. Most parents were likewise satisfied with support from partners (88%) and family (83%). Whereas PWH were reticent to disclose their diagnosis beyond family and friends, parents were more likely to share their son's diagnosis, and most were satisfied with the support from their son's peers (74%), teachers (83%) and other adults in supervisory roles (85%). PWH and parents surveyed were satisfied overall with the support they received from partners, family, friends and social contacts. Relationships are affected by haemophilia in various ways, and particularly affected in terms of disease burden, age and social life. PMID- 24800873 TI - Transcatheter aortic valve implantation-induced left bundle branch block: causes and consequences. AB - Transcatheter aortic valve implantation (TAVI) is an alternative treatment option for patients with severe aortic valve stenosis who do not qualify for surgical aortic valve replacement (AVR). Besides its proven clinical benefits, one of the complications of TAVI is the creation of conduction abnormalities, like left bundle branch block (LBBB). New LBBB occurs between 7 and 65% of cases, numbers that differ considerably between devices. In this review, we discuss the possible causes and the clinical significance of TAVI-induced LBBB. Several device- and procedural-related factors seem responsible for the development of LBBB, of which depth of implantation and balloon-annulus diameter ratio are the most important ones. TAVI-induced LBBB negatively affects cardiac function and hospitalization, but its impact on mortality is subject of debate. Future research and registries should implement strict diagnostic criteria for LBBB together with recording of its timing and persistence. PMID- 24800874 TI - The effects of novel, bioresorbable scaffolds on coronary vascular pathophysiology. AB - Percutaneous coronary intervention (PCI) has rapidly evolved over the past 30 years as technology has sought to improve clinical outcomes by addressing pathophysiologic complications arising from the intervention. Stents were designed to resolve the drawbacks of balloon angioplasty by providing radial support to prevent vessel recoil, by sealing coronary dissections, and by preventing abrupt vessel closure. The conceptualization of an ideal drug-eluting fully bioresorbable scaffold (BRS), whether metallic or polymeric, would theoretically address the adverse aspects of permanent metallic stents. In this review of the literature, we will discuss the impact these novel fully BRS platforms have on vascular pathophysiology following PCI. PMID- 24800875 TI - Response to Li and Liu's "Darwin's statements on reversion or atavism". PMID- 24800876 TI - Beliefs about hot flashes drive treatment benefit. PMID- 24800877 TI - Do we need to prescribe exercise differently for premenopausal and postmenopausal women? PMID- 24800878 TI - Examining the relationship between subjective sleep disturbance and menopause: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this study was to conduct a systematic review and meta analysis of the relationship between menopausal stages and sleep disturbance reported using subjective methods. Secondary aims included examining the influence of culture/ethnicity on the relationship between menopausal stages and sleep disturbance. METHODS: Multiple electronic databases were searched from the first available year to November 2013, and a manual search of the reference lists of review articles identified was also conducted. Twenty-four studies with a total of 63,542 midlife women were identified, coded, and analyzed. RESULTS: The crude and adjusted odds of experiencing sleep disturbance were small but statistically significant for perimenopausal and postmenopausal women, using premenopause as the reference group. The ethnicity of the samples influenced effect sizes; Asian and white women both experienced an increased rate of sleep disturbance at the perimenopausal and postmenopausal stages compared with the premenopausal stage, whereas Hispanic women experienced no change in sleep disturbance across the menopausal transition. CONCLUSIONS: The prevalence of sleep disturbance is higher in perimenopausal, postmenopausal, and surgical menopausal women than in premenopausal women. There is an independent relationship between menopausal stages and sleep disturbance beyond the effects of aging and other confounders, although the magnitude of the relationship is small. Culture, ethnicity, or both might affect the levels of sleep disturbance at various menopausal stages. PMID- 24800879 TI - Form and function in the vascular system. PMID- 24800880 TI - Genetic polymorphisms of the glycine N-methyltransferase and prostate cancer risk in the health professionals follow-up study. AB - PURPOSE: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating the ratio of S-adenosylmethionine to S-adenosylhomocysteine, by binding to folate, and by interacting with environmental carcinogens. In Taiwanese men, GNMT was found to be a tumor susceptibility gene for prostate cancer. However, the association of GNMT with prostate cancer risk in other ethnicities has not been studied. It was recently reported that sarcosine, which is regulated by GNMT, increased markedly in metastatic prostate cancer. We hereby explored the association of GNMT polymorphisms with prostate cancer risk in individuals of European descent from the Health Professionals Follow-up Study (HPFS). METHODS: A total of 661 incident prostate cancer cases and 656 controls were identified from HPFS. The GNMT short tandem repeat polymorphism 1 (STRP1), 4 bp insertion/deletion polymorphisms (INS/DEL) and the single nucleotide polymorphism rs10948059 were genotyped to test for their association with prostate cancer risk. RESULTS: The rs10948059 T/T genotype was associated with a 1.62-fold increase in prostate cancer risk (95% confidence interval (CI): 1.18, 2.22) when compared with the C/C genotype. The STRP1 >= 16GAs/>= 16GAs genotype was associated with decreased risk of prostate cancer when compared with the < 16GAs/< 16GAs genotype (odds ratio (OR) = 0.68; 95% CI: 0.46, 1.01). INS/DEL was not associated with prostate cancer risk. Haplotypes containing the rs10948059 T allele were significantly associated with increased prostate cancer risk. CONCLUSION: In men of European descent, the GNMT rs10948059 and STRP1 were associated with prostate cancer risk. Compared to the study conducted in Taiwanese men, the susceptibility GNMT alleles for prostate cancer had a reverse relationship. This study highlights the differences in allelic frequencies and prostate cancer susceptibility in different ethnicities. PMID- 24800881 TI - Hand-assisted laparoscopic radical nephrectomy in pregnancy. AB - PURPOSE: To demonstrate the beneficial results of hand-assisted laparoscopic tumor nephrectomy in pregnancy and to emphasize the proper timing of such surgery for its crucial importance attempting to avoid fatal cancer-related outcomes as a result of late interventions of aggressive tumors. METHODS: A report of a 32-year old woman with a 61 * 41 mm chromophobe renal cell carcinoma (RCC) successfully treated with laparoscopic transperitoneal hand-assisted nephrectomy during the 20th week of gestation is presented. RESULTS: The fetus was stable during the intervention; the postoperative period was uneventful; she had a normal vaginal delivery at term and gave birth to a healthy female child. The patient remained tumor-free at her 34-month follow-up. CONCLUSION: Although the pure laparoscopic interventions have become recognized in the treatment of RCC over the last decade, these methods have their limitations and dangers as well. The hand assistance method makes the procedure faster and safer which is especially important during second or third trimester. Renal biopsy may play a specifically important role in predicting the malignant potential of a renal tumor, whereas postponement of this surgery until after delivery, may lead to the mother's death. To our knowledge, this is the first report on hand-assisted laparoscopic nephrectomy in pregnancy. PMID- 24800882 TI - Insertion technique for prevention of peritoneal dialysis catheter tip migration. PMID- 24800883 TI - Bacterial infection, airway and systemic inflammation and clinical outcomes before and after treatment of AECOPD, a longitudinal and cross-sectional study. AB - Abstract Bacterial infection is a major cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), which are associated with significantly increased airway and systemic inflammation. However, the relationship among bacteriology, the resolution of inflammation and clinical outcomes is largely unknown. In this study, we recruited consecutive patients hospitalized for AECOPD with purulent sputum. We measured the airway and systemic inflammation levels, the COPD assessment test (CAT) score and adverse outcomes between patients with and without potentially pathogenic microorganisms (PPM). Among sputum samples collected from the 135 episodes of AECOPD, 42 (31.1%) were PPM-positive at admission. Compared with those in the PPM-negative group, more patients in the PPM-positive group had >=2 exacerbations in previous year and Anthonisen type I at admission and higher drop in sputum neutrophil, serum hs-CRP and CAT value from exacerbation to the subsequent baseline. No significant differences in the adverse outcomes between the two groups were observed. Among the 38 PPM-positive patients who survived and were discharged from hospital, 19 remained PPM-positive (bacterial persistence group) and 19 PPM-negative (bacterial clearance group). Both inflammation indices and CAT score decreased compared to admission in the two groups, regardless of the bacteriology at discharge. Our data suggest uncultivated bacteria and/or virus might also play important roles in causing inflammation and AECOPD. PMID- 24800884 TI - [Local anesthetic agents. More and more not only sodium channel blockers]. PMID- 24800885 TI - Transarterial infusion with gemcitabine and oxaliplatin for the treatment of unresectable pancreatic cancer. AB - The aim of this study was to evaluate the therapeutic efficacy and the safety of transarterial infusion (TAI) with gemcitabine and oxaliplatin in patients with unresectable pancreatic cancer (PC). After celiac arteriogram and super mesenteric arteriography, 1000 mg/m gemcitabine and 100 mg/m oxaliplatin were infused through 4- or 5-Fr catheters in arteries supplying blood to the tumor. In cases in which the blood-supplying artery could be selectively catheterized, the infusion was performed through a 3-Fr catheter placed in the tumor-supplying artery. Therapeutic courses were repeated every 4 weeks. The tumor response, the overall survival, and adverse effects were monitored. Thirty-two patients with unresectable PC were enrolled in this study, including 20 male and 12 female patients. A total of 105 cycles of TAI (mean=3.3 cycles/patient) were performed. Of 32 patients, partial remission was achieved in eight (25.0%), stable disease in 13 (40.6%), and progressive disease in 11 (34.4%). The overall response rate was 25.0%. The median survival time was 10.0 months (range=4-21 months). Grade III-IV toxicity, vomiting, occurred with a rate of 21.9%. Grade I-II neutropenia, thrombocytopenia, peripheral nerve toxicity, elevated serum transaminases levels, and serum total bilirubin were observed. TAI with gemcitabine and oxaliplatin is well tolerated and highly effective in patients with unresectable PC. PMID- 24800886 TI - Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells. AB - Therapeutic strategies targeting histone deacetylase (HDAC) inhibition have become promising in many human malignancies. Belinostat (PXD101) is a hydroxamate type HDAC inhibitor tested in phase I and II clinical trials in solid tumors and hematological cancers. However, little is known about the use of belinostat for differentiation therapy against acute myelogenous leukemia. Here, we characterize the antileukemia activity of belinostat as a single drug and in combination with all-trans-retinoic acid (RA) in promyelocytic leukemia HL-60 and NB4 cells. Belinostat exerted dose-dependent growth-inhibitory or proapoptotic effects, promoting cell cycle arrest at the G0/G1 or the S transition. Apoptosis was accompanied by activation of caspase 3, degradation of PARP-1, and cell cycle dependent changes in the expression of survivin, cyclin E1, and cyclin A2. Belinostat induced a dose-dependent reduction in the expression of EZH2 and SUZ12, HDAC-1, HDAC-2, and histone acetyltransferase PCAF (p300/CBP-associated factor). Belinostat increased acetylation of histone H4, H3 at K9 and H3 at K16 residues in a dose-dependent manner, but did not reduce trimethylation of H3 at K27 at proapoptotic doses. Combined treatment with belinostat and RA dose dependently accelerated and reinforced granulocytic differentiation, accompanied by changes in the expression of CD11b, C/EBPalpha (CCAAT/enhancer binding protein alpha), and C/EBPepsilon. Our results concluded the usefulness of belinostat, as an epigenetic drug, for antileukemia and differentiation therapy. PMID- 24800887 TI - Statil suppresses cancer cell growth and proliferation by the inhibition of tumor marker AKR1B10. AB - Aldo-keto reductase 1B10 (AKR1B10) is an oncogenic carbonyl reductase that eliminates alpha,beta-unsaturated carbonyl compounds/lipid peroxides and mediates retinoic acid signaling. Targeted inhibition of AKR1B10 activity is a newly emerging strategy for cancer therapy. This study evaluated the inhibitory activity of a small chemical statil towards AKR1B10 and tested its antiproliferative activity in breast (BT-20) and lung (NCI-H460) cancer cells that express AKR1B10. Experimental results showed that statil inhibited AKR1B10 enzyme activity efficiently, with an IC50 at 0.21+/-0.06 umol/l. Exposing BT-20 and NCI-H460 cells to statil and diclofenac, a selective AKR1B10 inhibitor, led to dose-dependent inhibition of cell growth and proliferation and plating efficiency. At higher doses (50 umol/l or higher), statil induced cell death with apoptotic characteristics, such as DNA fragmentation and Annexin-V staining. Furthermore, statil enhanced the susceptibility of cells to acrolein, an active substrate of AKR1B10. Taken together, these data suggest that statil possesses potent antiproliferative activity by inhibiting AKR1B10 activity. PMID- 24800888 TI - 1-Acetylpyrene-salicylic acid: photoresponsive fluorescent organic nanoparticles for the regulated release of a natural antimicrobial compound, salicylic acid. AB - Photoresponsive 1-acetylpyrene-salicylic acid (AcPy-SA) nanoparticles (NPs) were developed for the regulated release of a natural antimicrobial compound, salicylic acid. The strong fluorescent properties of AcPy-SA NPs have been extensively used for potential in vitro cell imaging. The phototrigger capability of our newly prepared AcPy-SA NPs was utilized for the efficient release of an antimicrobial compound, salicylic acid. The photoregulated drug release of AcPy SA NPs has been shown by the subsequent switching off and on of a visible-light source. In vitro biological studies reveal that AcPy-SA NPs of ~68 nm size deliver the antimicrobial drug salicylic acid into the bacteria cells (Pseudomonas aeruginosa) and efficiently kill the cells upon exposure to visible light (>=410 nm). Such photoresponsive fluorescent organic NPs will be highly beneficial for targeted and regulated antimicrobial drug release because of their biocompatible nature, efficient cellular uptake, and light-induced drug release ability. PMID- 24800889 TI - Sustained activation of interferon regulatory factor 3 during infection by paramyxoviruses requires MDA5. AB - Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are the main cytosolic sensors of single-stranded RNA viruses, including paramyxoviruses, and are required to initiate a quick and robust innate antiviral response. Despite different ligand-binding properties, the consensus view is that RIG-I and MDA5 trigger common signal(s) to activate interferon regulatory factor 3 (IRF-3) and NF-kappaB, and downstream antiviral and proinflammatory cytokine expression. Here, we performed a thorough analysis of the temporal involvement of RIG-I and MDA5 in the regulation of IRF-3 during respiratory syncytial virus (RSV) infection. Based on specific RNA interference mediated knockdown of RIG-I and MDA5 in A549 cells, we confirmed that RIG-I is critical for the initiation of IRF-3 phosphorylation, dimerization and downstream gene expression. On the other hand, our experiments yielded the first evidence that knockdown of MDA5 leads to early ubiquitination and proteasomal degradation of active IRF-3. Conversely, ectopic expression of MDA5 prolonged RIG-I-induced IRF-3 activation. Altogether, we provide novel mechanistic insight into the temporal involvement of RIG-I and MDA5 in the innate antiviral response. While RIG-I is essential for initial IRF-3 activation, engagement of induced MDA5 is essential to prevent early degradation of IRF-3, thereby sustaining IRF-3 dependent antiviral gene expression. MDA5 plays a similar role during Sendai virus infection suggesting that this model is not restricted to RSV amongst paramyxoviruses. PMID- 24800890 TI - Septum development in Neurospora crassa: the septal actomyosin tangle. AB - Septum formation in Neurospora crassa was studied by fluorescent tagging of actin, myosin, tropomyosin, formin, fimbrin, BUD-4, and CHS-1. In chronological order, we recognized three septum development stages: 1) septal actomyosin tangle (SAT) assembly, 2) contractile actomyosin ring (CAR) formation, 3) CAR constriction together with plasma membrane ingrowth and cell wall construction. Septation began with the assembly of a conspicuous tangle of cortical actin cables (SAT) in the septation site >5 min before plasma membrane ingrowth. Tropomyosin and myosin were detected as components of the SAT from the outset. The SAT gradually condensed to form a proto-CAR that preceded CAR formation. During septum development, the contractile actomyosin ring remained associated with the advancing edge of the septum. Formin and BUD-4 were recruited during the transition from SAT to CAR and CHS-1 appeared two min before CAR constriction. Actin patches containing fimbrin were observed surrounding the ingrowing septum, an indication of endocytic activity. Although the trigger of SAT assembly remains unclear, the regularity of septation both in space and time gives us reason to believe that the initiation of the septation process is integrated with the mechanisms that control both the cell cycle and the overall growth of hyphae, despite the asynchronous nature of mitosis in N. crassa. PMID- 24800891 TI - Mannitol-1-phosphate dehydrogenases/phosphatases: a family of novel bifunctional enzymes for bacterial adaptation to osmotic stress. AB - The nutritionally versatile soil bacterium Acinetobacter baylyi ADP1 copes with salt stress by the accumulation of compatible solutes, a strategy that is widespread in nature. This bacterium synthesizes the sugar alcohol mannitol de novo in response to osmotic stress. In a previous study, we identified MtlD, a mannitol-1-phosphate dehydrogenase, which is essential for mannitol biosynthesis and which catalyses the first step in mannitol biosynthesis, the reduction of fructose-6-phosphate (F-6-P) to the intermediate mannitol-1-phosphate (Mtl-1-P). Until now, the identity of the second enzyme, the phosphatase that catalyses the dephosphorylation of Mtl-1-P to mannitol, was elusive. Here we show that MtlD has a unique sequence among known mannitol-1-phosphate dehydrogenases with a haloacid dehalogenase (HAD)-like phosphatase domain at the N-terminus. This domain is indeed shown to have a phosphatase activity. Phosphatase activity is strictly Mg(2+) dependent. Nuclear magnetic resonance analysis revealed that purified MtlD catalyses not only reduction of F-6-P but also dephosphorylation of Mtl-1-P. MtlD of A. baylyi is the first bifunctional enzyme of mannitol biosynthesis that combines Mtl-1-P dehydrogenase and phosphatase activities in a single polypeptide chain. Bioinformatic analysis revealed that the bifunctional enzyme is widespread among Acinetobacter strains but only rarely present in other phylogenetic tribes. PMID- 24800892 TI - Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. AB - RATIONALE: Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT2A) receptors. OBJECTIVES: This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects. METHODS: Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter assays in HEK293, Galpha16-CHO, and CHOk1 cells transfected with human receptors. RESULTS: Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT2A, serotonin 1A (5-HT1A), and 5-HT2A beta-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT2A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited beta-arrestin through 5-HT2A activation. CONCLUSIONS: All psychoactive tryptamines are 5-HT2A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines. PMID- 24800893 TI - The effect of quetiapine (SeroquelTM) on conditioned place preference and elevated plus maze tests in rats when administered alone and in combination with (+)-amphetamine. AB - RATIONALE: Recent case reports describe recreational use of quetiapine and drug seeking behaviour to obtain quetiapine, an atypical antipsychotic. OBJECTIVE: We examined the hypothesis that quetiapine (10, 20 or 40 mg/kg) alone or co administered with (+)-amphetamine (0.25, 0.5, 0.75 or 2.0 mg/kg) will affect reward and/or decrease anxiety in rats, as measured by conditioned place preference (CPP) and elevated plus maze (EPM) test, respectively. RESULTS: Quetiapine (20 mg/kg) produced greater open arm time and entries in the EPM test compared to 10 and 40 mg/kg, and quetiapine (10 mg/kg) significantly increased open arm entries and time when co-administered with (+)-amphetamine (0.5 mg/kg) compared to (+)-amphetamine (0.5 mg/kg) alone, suggesting decreased anxiety. Quetiapine (10, 20 or 40 mg/kg) produced no CPP when administered alone; the lowest dose of quetiapine (10 mg/kg) reduced CPP produced by a low dose of (+) amphetamine (0.25 mg/kg), but had no significant effect on CPP produced by a higher dose (0.5 mg/kg). DISCUSSION: The quetiapine-induced anxiolytic effect in the EPM might explain why humans are misusing quetiapine and combining it with (+)-amphetamine. It is possible that humans experience an anxiolytic effect of the combined drugs and relatively unaltered rewarding effects of (+)-amphetamine. The results shed some light on the question of why humans are abusing and misusing quetiapine, despite its dopamine (DA) D2 receptor antagonism; it will be the task of future studies to identify the pharmacological mechanism mediating this behaviour. PMID- 24800894 TI - Inhibition of CaV3.2 T-type calcium channels in peripheral sensory neurons contributes to analgesic properties of epipregnanolone. AB - RATIONALE: T-type calcium channels (T-channels) play an important role in controlling excitability of nociceptors. We have previously shown that a synthetic series of 5beta-reduced steroids induce a voltage-dependent blockade of T-currents in rat dorsal root ganglia (DRG) cells in vitro and induce potent analgesia to thermal stimuli in rats in vivo (Mol Pharmacol 66:1223-1235, 2004). OBJECTIVES: Here, we investigated the effects of the endogenous 5beta-reduced neuroactive steroid molecule, epipregnanolone [(3beta,5beta)-3-hydroxypregnan-20 one], on peripheral nociception. METHODS: We used acutely dissociated DRG cells in vitro from adult rats as well as in vivo pain studies in mice and rats to investigate the effects of epipregnanolone on DRG T-channels. RESULTS: We found that epipregnanolone reversibly blocked DRG T-currents with a half-maximal inhibitory concentration (IC50) of 2 MUM and stabilized the channel in the inactive state. However, sodium, potassium, and gamma-aminobutyric acid (GABA) gated ionic currents were not sensitive to the blocking effects of epipregnanolone even at 10 MUM. In ensuing in vivo studies, we found that intraplantar (i.pl.) injections of epipregnanolone directly into peripheral receptive fields reduced responses to nociceptive heat stimuli in rats in a dose dependent fashion. Furthermore, i.pl. epipregnanolone injections effectively reduced responses to peripheral nociceptive thermal and mechanical stimuli in wild-type mice but had no effect on the responses of CaV3.2 knockout mice. CONCLUSIONS: We conclude that the inhibition of peripheral CaV3.2 T-channels contributes to the potent analgesic effect of the endogenous steroid epipregnanolone. PMID- 24800895 TI - Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice. AB - RATIONALE: Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential. OBJECTIVE: This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at alpha4beta2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2' fluoro-3'-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2' fluorodeschloroepibatidine (RTI-7527-36), and 3'-(3"-dimethylaminophenyl) epibatidine (RTI-7527-76). METHODS: Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature. RESULTS: In the nicotine discrimination assay, the maximum percentage of nicotine appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12 oC. The rank-order potency in the discrimination and hypothermia assays was epibatidine > RTI-7527-36 > nicotine > RTI-7527-102 > varenicline = cytisine = RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI 7527-102, as well as the hypothermic effects of every drug except cytisine. The beta2-subunit selective nAChR antagonist dihydro-beta-erythroidine (DHbetaE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine. CONCLUSIONS: The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing beta2-subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in alpha4beta2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists. PMID- 24800896 TI - Disruption of sensory gating by moderate alcohol doses. AB - RATIONALE: Evidence from a growing body of literature suggests that alcohol, even at moderate-dose levels, disrupts the ability to ignore distractors. However, little work has been done to elucidate the neural processes underlying this deficit. OBJECTIVE: The present study was conducted to determine if low-to moderate alcohol doses affect sensory gating, an electrophysiological phenomenon believed to reflect the pre-attentive filtering of irrelevant sensory information. METHODS: Sixty social drinkers were administered one of three doses intended to produce breath alcohol concentrations of 0.0% (placebo), 0.04% (i.e., low dose), and 0.065% (i.e., moderate dose). A paired-click paradigm consisting of 100 pairs of identical tones (S1 and S2) was used to assess sensory gating. Amplitudes of P50, N100, and P200 auditory evoked potentials (AEPs) were used to calculate gating difference (S1-S2) and ratio (S2/S1) scores. RESULTS: The moderate alcohol dose significantly decreased P50 and N100 gating relative to placebo. Comparisons between the difference and ratio scores helped characterize the gating mechanisms affected at these stages of information processing. Alcohol did not alter P200 sensory gating. CONCLUSIONS: These data suggest that alcohol disrupts pre-attentional sensory-filtering processes at breath alcohol concentrations (BrACs) below the current 0.08% legal limit. Future studies should perform a combined assessment of sensory gating and selective attention to better understand the relationship between these two alcohol-induced deficits. PMID- 24800897 TI - Effects of oxycodone on brain responses to emotional images. AB - RATIONALE: Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans. OBJECTIVE: We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis. METHODS: In a three-session study, healthy adults (N = 17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks. RESULTS: Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces. CONCLUSIONS: Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates. PMID- 24800898 TI - Performance on a strategy set shifting task in rats following adult or adolescent cocaine exposure. AB - RATIONALE: Neuropsychological testing is widespread in adult cocaine abusers, but lacking in teens. Animal models may provide insight into age-related neuropsychological consequences of cocaine exposure. OBJECTIVES: The objective of the present study is to determine whether developmental plasticity protects or hinders behavioral flexibility after cocaine exposure in adolescent vs. adult rats. METHODS: Using a yoked-triad design, one rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling cocaine delivery (1.0 mg/kg) self-administered for 18 sessions (starting P37 or P77), followed by 18 drug-free days. Rats next were tested in a strategy set shifting task, lasting 11-13 sessions. RESULTS: Cocaine self-administration did not differ between age groups. During initial set formation, adolescent-onset groups required more trials to reach criterion and made more errors than adult-onset groups. During the set shift phase, rats with adult-onset cocaine self administration experience had higher proportions of correct trials and fewer perseverative + regressive errors than age-matched yoked-controls or rats with adolescent-onset cocaine self-administration experience. During reversal learning, rats with adult-onset cocaine experience (self-administered or passive) required fewer trials to reach criterion, and the self-administering rats made fewer perseverative + regressive errors than yoked-saline rats. Rats receiving adolescent-onset yoked-cocaine had more trial omissions and longer lever press reaction times than age-matched rats self-administering cocaine or receiving yoked-saline. CONCLUSIONS: Prior cocaine self-administration may impair memory to reduce proactive interference during set shifting and reversal learning in adult onset but not adolescent-onset rats (developmental plasticity protective). Passive cocaine may disrupt aspects of executive function in adolescent-onset but not adult-onset rats (developmental plasticity hinders). PMID- 24800899 TI - The activation of the Akt/PKB signalling pathway in the brains of clozapine exposed rats is linked to hyperinsulinemia and not a direct drug effect. AB - The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy. PMID- 24800900 TI - Laceration injuries and infections among workers in the poultry processing and pork meatpacking industries. AB - BACKGROUND: Workers in poultry processing and pork meatpacking have high rates of acute injuries and chronic disease among. The presence of zoonotic pathogens in these workplaces may interact with injury. METHODS: We investigated incidence of worker injuries, lacerations, and infections reported by 10 companies from 2004 to 2009 and calculated annual incidence rates by industry and company along with temporal trends and job-related risk factors. RESULTS: Average annual mean total injury rates were 6.4 per 100 workers (poultry) and 13.2 per 100 workers (pork). Average annual mean rates for lacerations were 1.8 per 100 workers (poultry) and 1.9 per 100 (pork). Sharp tools and animal products were most frequently reported as sources for lacerations. Animal products were most frequently reported as sources of infected lacerations. CONCLUSIONS: The results indicate that these industries continue to have high injury rates. The results also suggest that zoonotic pathogens may be preventable health and safety risks. PMID- 24800901 TI - Grey leaves in an alpine plant: a cryptic colouration to avoid attack? AB - Cryptic colouration is a common predation-avoidance strategy in animals that is postulated to occur in plants, but few experimental studies have rigorously tested this hypothesis. We investigated the colouration of Corydalis benecincta, an alpine plant with remarkably dimorphic leaf colours (grey and green), based on a cost-benefit analysis. First we tested the premise that herbivores (Parnassius butterflies) cannot distinguish grey leaves from a scree background by spectrographic measurements and by estimating discriminability between leaves and scree using a butterfly colour vision model. Then we estimated the potential costs of inconspicuousness by comparing the photosynthetic performance and visual attractiveness to flower visitors of the two colour morphs. Finally, we examined the potential benefits of inconspicuousness by comparing damage, survivorship and female reproductive success. It is difficult for herbivores to distinguish grey coloured morphs against the background. This grey colour originates in a combination of anthocyanins and chlorophylls. The two colour morphs had similar photosynthetic performance, visual attractiveness and female reproductive success. However, grey morphs had significantly lower herbivore damage and higher survivorship. Grey leaves benefit C. benecincta by reducing herbivory with low investment in anthocyanin synthesis, and little cost on photosynthesis and mating opportunity. This cryptic colouration may have evolved through selection pressure imposed by visually foraging herbivores. PMID- 24800902 TI - Coaptation/elevation role of the middle deltoid muscle fibers: a static biomechanical pilot study using shoulder MRI. AB - PURPOSE: It is generally recognized that the middle deltoid muscle fibers (MDMF) have an elevating effect on the humeral head at small abduction angles. These forces are normally counterbalanced by the coaptation effect of the rotator cuff (RC) muscles to maintain shoulder stability. With RC tears, this balance may be jeopardized leading to shoulder dysfunction. Conversely, not all patients with RC tears develop shoulder dysfunction. The purpose of this study was to investigate the coaptation/elevation forces (CEF) ratio of the MDMF in RC tears subjects and in volunteers, using magnetic resonance imaging (MRI). METHODS: Magnetic resonance imaging images in 10 subjects with RC tears and in five volunteers were used to build a three-dimensional model of the shoulder. The CEF ratio of the MDMF was estimated by representing the glenohumeral joint as a pulley. RESULTS: The CEF ratio increased from the posterior to the anterior fibers of the MDMF.The median and interquartile range (IQR) of the CEF ratios of the posterior-third, middle-third, anterior-third and anterior-surface segments of the deltoid were: 0.16 (IQR = 0.23), 0.61 (IQR = 0.4), 1.42 (IQR = 0.41), 1.94 (IQR = 0.56) in subjects, and 0.06 (IQR = 0.24), 0.45 (IQR = 0.28), 1.32 (IQR = 1.01), 1.49 (IQR = 0.39) in volunteers. In the subjects, the CEF ratio of the anterior-surface segment was greater than all other segments (P <= 0.03). CONCLUSIONS: The CEF ratio of the MDMF increased from its posterior segment to its anterior segment, indicating a greater stabilizing effect of the anterior segment both in RC tears subjects and in volunteers. Strengthening of the anterior fibers of the MDMF could potentially improve shoulder function in subjects with RC tears. PMID- 24800903 TI - Improved non-invasive total haemoglobin measurements after in-vivo adjustment. AB - We hypothesised that an in-vivo adjustment method and/or a newer sensor would increase the accuracy of non-invasive and continuous haemoglobin monitoring (SpHb) measurements. Two sensors, the R1-25 and R2-25a (the newer version), were used with laboratory total haemoglobin concentration (tHb) values simultaneously recorded. In-vivo adjusted SpHb (AdHb) was calculated by a simple formula: AdHb = SpHb - (1(st) SpHb - 1(st) tHb). The correlation coefficients between SpHb (or AdHb) and tHb were compared: SpHb in both sensors correlated strongly with tHb (p < 0.0001). In-vivo adjustment improved the correlation coefficient between SpHb and tHb from 0.86 to 0.95 for the R1-25 and from 0.83 to 0.93 for the R2-25a. There was no difference between the R1-25 and R2-25a sensors. The in vivo adjustment method improved the accuracy of SpHb measurements in both sensors. PMID- 24800904 TI - Effects of meteorological factors on scrub typhus in a temperate region of China. AB - Scrub typhus is emerging and re-emerging in many areas: climate change may affect its spread. To explore the effects of meteorological factors on scrub typhus, monthly cases of scrub typhus from January 2006 to December 2012 in the Laiwu district of temperate northern China were analysed. We examined the correlations between scrub typhus and meteorological factors (and their delayed effects). We built a time-series adjusted negative binomial model to reflect the relationships between climate variables and scrub typhus cases. The key determinants of scrub typhus transmission were temperature, relative humidity and precipitation. Each 1 degrees C increase in monthly average temperature in the previous 3 months, each 1% increase in monthly relative humidity in the previous 2 months and each 1 mm increase in monthly precipitation in the previous 3 months induced 15.4%, 12.6% and 0.7% increases in the monthly number of cases, respectively. In conclusion, scrub typhus is affected by climate change in temperate regions. PMID- 24800905 TI - Is acyclovir effective among critically ill patients with herpes simplex in the respiratory tract? AB - BACKGROUND AND OBJECTIVE: The relevance of the detection of herpes simplex virus type 1 (HSV-1) in the respiratory tract of patients in the intensive care unit (ICU) is unclear. Therefore, it is uncertain whether treatment with an antiviral agent could be beneficial for these patients. STUDY DESIGN: We retrospectively reviewed the records of ICU patients with a positive HSV-1 culture in the respiratory tract or bronchoalveolar lavage (BAL) fluid. We evaluated whether acyclovir treatment (n=106) could have a beneficial effect on mortality as compared with the standard treatment (n=106). RESULTS: Acyclovir treatment was positively linked to in-hospital and ICU-mortality reduction. This favourable influence remained present after correcting for possible confounders and using propensity-adjusted and propensity-matched cohorts: with an odds ratio in the treated group of 3.19 (95% CI 1.79-5.69, p=0.001) for ICU survival and of 3.55 (95% CI 2.16-5.85, p<0.001) for in-hospital survival. The subgroup with HSV-1 detected in the BAL-fluid is the sole contributor to this difference. In the BAL fluid detected group, 48% (n=10) of non-treated patients died in the ICU, versus 21% (n=6) in the acyclovir-treated group (p=0.033), occurring despite an even longer duration of ventilation or ICU stay. CONCLUSIONS: These data highlight the hypothesis that it might be worthwhile to consider treatment of HSV-1 in ICU patients depending on the type of respiratory sample in which the virus is detected. These results warrant a prospective trial to prove causality. PMID- 24800906 TI - Identification of emotional facial expressions among behaviorally inhibited adolescents with lifetime anxiety disorders. AB - The current study examined differences in emotion expression identification between adolescents characterised with behavioural inhibition (BI) in childhood with and without a lifetime history of anxiety disorder. Participants were originally assessed for BI during toddlerhood and for social reticence during childhood. During adolescence, participants returned to the laboratory and completed a facial emotion identification task and a clinical psychiatric interview. Results revealed that behaviorally inhibited adolescents with a lifetime history of anxiety disorder displayed a lower threshold for identifying fear relative to anger emotion expressions compared to non-anxious behaviorally inhibited adolescents and non-inhibited adolescents with or without anxiety. These findings were specific to behaviorally inhibited adolescents with a lifetime history of social anxiety disorder. Thus, adolescents with a history of both BI and anxiety, specifically social anxiety, are more likely to differ from other adolescents in their identification of fearful facial expressions. This offers further evidence that perturbations in the processing of emotional stimuli may underlie the aetiology of anxiety disorders. PMID- 24800907 TI - Vildagliptin in renal impairment. PMID- 24800913 TI - Oligodendrocyte progenitors: adult stem cells of the central nervous system? AB - Oligodendrocyte progenitors (OPs) are a major proliferating cell population within the adult CNS. In response to myelin loss or increasing demand, OPs have the capacity to differentiate into mature, myelinating oligodendrocytes. The name 'oligodendrocyte progenitor' suggests restriction to the oligodendrocyte cell lineage. However, with growing evidence of the lineage plasticity of OPs both in vitro and in vivo, we discuss whether they have potential beyond that expected of dedicated progenitor cells, and hence may justify categorization as adult stem cells. PMID- 24800914 TI - The inflammatory response to sciatic nerve injury in a familial amyloidotic polyneuropathy mouse model. AB - Inflammation is a hallmark of several neurodegenerative disorders including familial amyloidotic polyneuropathy (FAP). FAP is associated with extracellular deposition of mutant transthyretin (TTR), leading to degeneration of cells and tissues, particularly in the peripheral nervous system (PNS). With this work, our goal was to characterize the expression/deposition of TTR and the associated inflammatory immune response, induced by nerve injury, in WT mice and in a mouse model carrying the most common TTR mutation in FAP (V30M). Our results indicate that upon nerve injury TTR is significantly produced by Schwann cells and is dynamically regulated over time in V30M mice, accompanying a peak of inflammation. Strikingly, V30M TTR deposition in nerve tissue occurred, suggesting that inflammation contributes to TTR polymerization. In response to nerve injury, V30M mice display a downregulated innate immune response when compared to WT mice. More specifically, we saw decreased expression of cytokines and chemokines important for the recruitment of immune cells like macrophages and neutrophils, known to be important for the tissue regenerative process which was found impaired in V30M mice. In conclusion, with this work we were able to characterize the biology of TTR both in WT and V30M animals, upon nerve injury, and found that V30M TTR impairs the inflammatory response necessary for nerve regeneration. Taken together, our findings suggest that inflammation is an important target to be considered in therapeutic strategies for FAP. PMID- 24800915 TI - Accuracy of screening mammography in women with a history of lobular carcinoma in situ or atypical hyperplasia of the breast. AB - Women with lobular carcinoma in situ (LCIS), atypical lobular hyperplasia (ALH), atypical ductal hyperplasia (ADH), or atypical hyperplasia (AH) are at increased breast cancer (BC) risk. We investigated the accuracy and outcomes of mammography screening in women with histology-proven LCIS, ALH, ADH, or AH history who had screening through Breast Cancer Surveillance Consortium-affiliated mammography facilities. Screens from two cohorts, defined by LCIS/ALH or ADH/AH history, were compared to two cohorts without such history mammogram-matched for age-group, breast density, family history, screen-year, and mammography registry. Overall 359 BCs (277 invasive BC) occurred within 1 year from screening among 52,380 screens. In the LCIS/ALH cohort [versus comparator screens] cancer incidence rates, cancer detection rates (CDR), and interval cancer rates (ICR) were significantly higher (all P < 0.001); although ICR was 4.4/1,000 screens [versus 0.9/1,000; P < 0.001] the proportion that were interval cancers did not differ between compared cohorts (P = 0.43); screening sensitivity was 76.1 % [versus 82.3 %; P = 0.43], however, specificity was significantly lower at 85.1 % [versus 90.7 %; P < 0.0001]. In the ADH/AH cohort [versus comparator] cancer rates and CDR were significantly higher (P < 0.001); although ICR was 2.6/1,000 screens [versus 0.9/1,000; P = 0.002] the proportion that were interval cancers did not differ between cohorts (P = 0.74); screening sensitivity was 81.0 % [versus 82.6 %; P = 0.74] and specificity was lower at 86.2 % [versus 90.2 %; P < 0.0001]. Mammography screening sensitivity in LCIS/ALH and ADH/AH cohorts did not significantly differ from that of matched screens, however, specificity was lower, and ICRs were higher (reflecting underlying cancer rates). Adjunct screening may be of value in these women if it reduces ICR without substantially reducing specificity. PMID- 24800916 TI - Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. AB - 17 double heterozygous (DH) breast cancer (BC) patients were identified upon the analysis of 5,391 affected women for recurrent Slavic mutations in BRCA1, CHEK2, NBN/NBS1, ATM, and BLM genes. Double heterozygosity was found for BRCA1 and BLM (4 patients), BRCA1 and CHEK2 (4 patients), CHEK2 and NBS1 (3 patients), BRCA1 and ATM (2 patients), CHEK2 and BLM (2 patients), CHEK2 and ATM (1 patient), and NBS1 and BLM (1 patient). DH BC patients were on average not younger than single mutation carriers and did not have an excess of bilateral BC; an additional non breast tumor was documented in two BRCA1/BLM DH patients (ovarian cancer and lymphoplasmacytic lymphoma). Loss-of-heterozygosity (LOH) analysis of involved genes was performed in 5 tumors, and revealed a single instance of somatic loss of the wild-type allele (LOH at CHEK2 locus in BRCA1/CHEK2 double heterozygote). Distribution of mutations in patients and controls favors the hypothesis on multiplicative interaction between at least some of the analyzed genes. Other studies on double heterozygosity for BC-predisposing germ-line mutations are reviewed. PMID- 24800917 TI - Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan. AB - RAD51C plays a key role in homologous recombination-mediated DNA repair and maintenance of genomic stability. Biallelic RAD51C mutations cause Fanconi anemia, and monoallelic mutations predispose women to breast and ovarian cancer. Genetic variability of RAD51C and its impact in Asian populations have been poorly studied. Here, we report the results of comprehensive mutational screening of the RAD51C gene in 348 BRCA1/2-negative breast and/or ovarian cancer patients from Pakistan. Mutation analysis of the complete RAD51C-coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. Three novel protein-truncating mutations, c.204T>A, c.225T>G, and c.701C>G, were identified. c.204T>A was found in one out of 22 (4.5 %) early-onset (<=45 years of age) ovarian cancer patients and c.225T>G in one out of 119 (0.8 %) patients from breast cancer only families. c.701C>G was found in a 60-year-old control with no family history of breast/ovarian cancer. Furthermore, three novel in silico-predicted potentially functional mutations, a missense mutation, c.873T>G, a variant in 5'UTR, c.1 34T>G, and a recurrent intronic variant, c.965+21A>G, were identified. The missense mutation was observed in a patient with bilateral breast cancer from a breast and ovarian cancer family (HBOC), the 5'UTR variant was noted in an early onset breast cancer patient, and the intronic variant in one early-onset breast cancer patient and one ovarian cancer patient from a HBOC family. Five of the six mutations described were not detected in 400 healthy controls. These findings suggest that RAD51C plays a marginal role in breast and ovarian cancer predisposition in Pakistan. Reliable estimation of the clinical implications of carrying a deleterious RAD51C mutation will require identification of additional mutation-positive patients/families. PMID- 24800918 TI - A head impact detection system using SVM classification and proximity sensing in an instrumented mouthguard. AB - Injury from blunt head impacts causes acute neurological deficits and may lead to chronic neurodegeneration. A head impact detection device can serve both as a research tool for studying head injury mechanisms and a clinical tool for real time trauma screening. The simplest approach is an acceleration thresholding algorithm, which may falsely detect high-acceleration spurious events such as manual manipulation of the device. We designed a head impact detection system that distinguishes head impacts from nonimpacts through two subsystems. First, we use infrared proximity sensing to determine if the mouthguard is worn on the teeth to filter out all off-teeth events. Second, on-teeth, nonimpact events are rejected using a support vector machine classifier trained on frequency domain features of linear acceleration and rotational velocity. The remaining events are classified as head impacts. In a controlled laboratory evaluation, the present system performed substantially better than a 10-g acceleration threshold in head impact detection (98% sensitivity, 99.99% specificity, 99% accuracy, and 99.98% precision, compared to 92% sensitivity, 58% specificity, 65% accuracy, and 37% precision). Once adapted for field deployment by training and validation with field data, this system has the potential to effectively detect head trauma in sports, military service, and other high-risk activities. PMID- 24800919 TI - A novel 6-mercaptopurine oral liquid formulation for pediatric acute lymphoblastic leukemia patients - results of a randomized clinical trial. AB - OBJECTIVE: Pediatric patients with acute lymphoblastic leukemia (ALL) are treated with oral 6-mercaptopurine (6MP) for nearly 2 years, but no pediatric formulation has been available. In this study, an oral 6MP liquid suitable for pediatric use was developed and tested in the target population. METHOD: A randomized cross over study was performed in 20 pediatric ALL patients (age 1.9 - 14.6 years), comparing pharmacokinetics and pharmacodynamics of a newly developed 6MP liquid formulation to 6MP capsules, both taken orally for 4 weeks. RESULTS: Based upon trough levels of the principal active metabolite,6-thioguanine nucleotides (6 TGN),a relative bioavailability of the liquid vs. capsules of 1.01 was found (90% CI 0.86 - 1.20), demonstrating bioequivalence. This was supported by the similarly observed 6MP dosages needed for leucocyte depletion, for both formulations (35 mg/day (range 10 - 115 mg)). 75% of the parents/patients (p = 0.005) preferred the oral liquid over the capsules because of the ease of administration. CONCLUSION: We conclude that the novel 6MP liquid is a promising treatment for ALL. PMID- 24800920 TI - Peripheral mononeuropathy associated with valproic acid poisoning in an adult patient. AB - OBJECTIVE: To present the case of axillary nerve neuropathy associated with valproic acid (VPA) poisoning. CASE REPORT: A 26-year-old man was hospitalized because of a suicide attempt with VPA overdose. Toxicology analysis revealed high serum VPA level (2,896 umol/L; therapeutic range: 350 - 690 umol/L). Three days after admission, the patient complained of weakness in his right arm. Neurological examination revealed weakness of flexion and abduction of the right arm and loss of sensation in the skin over the lateral upper right arm. A nerve conduction velocity test was normal in the ulnar, radial, median, musculocutaneous, and suprascapular nerves. Compound muscle action potential showed reduced amplitude and prolonged latencies in the right axillary nerve taken from Erb's point and absent taken from distal stimulation point. Right axillary nerve paresis was diagnosed and the patient underwent a physical therapy program, which resulted in gradual recovery. DISCUSSION: In the presented case, other possible causes of neuropathy were excluded by medical history, laboratory and radiological tests, and clinical course of the disease.The temporal relationship between the VPA poisoning and the occurrence of neuropathy supports the hypothesis of a VPA-caused axillary neuropathy. According to the Naranjo's Adverse Drug Reaction (ADR) Probability Scale, VPA-induced neuropathy was rated "probable". CONCLUSION: VPA-induced neuropathy may be a serious ADR, but it is potentially preventable and reversible. Thus, clinicians should be aware of this rare ADR. PMID- 24800921 TI - Lack of a clinically relevant effect of sugammadex on anti-Xa activity or activated partial thromboplastin time following pretreatment with either unfractionated or low-molecular-weight heparin in healthy subjects. AB - OBJECTIVE: To investigate the potential effect of sugammadex on anti-Xa anticoagulantactivity of enoxaparin and the activated partial thromboplastin time (APTT) of unfractionated heparin (UFH). METHODS: This two-part, randomized, double-blind, placebocontrolled, four-period cross-over study was performed in healthy males (18 - 45 years). In each period, subjects received 40 mg enoxaparin (in part 1), 5,000 units UFH (in part 2), or placebo followed by 4 or 16 mg/kg sugammadex, or placebo. Treatments were separated by >= 4 days. Primary endpoints were anti-Xa activity and APTT both time-averaged from 3 to 30 minutes post-dose. Geometric mean ratios (GMRs) and their two-sided 90% confidence limits were calculated for anticoagulant plus sugammadex (4 or 16 mg/kg) vs. anticoagulant plus placebo. The pre-specified threshold for a potential effect of clinical relevance was a 90% upper confidence limit (UCL) > 1.50. RESULTS: In part 1 (n = 13), the 90% UCLs were 1.07 and 1.08 for GMRs of anti-Xa activity after dosing with 4 and 16 mg/kg sugammadex, respectively. In part 2 (n = 43), the 90% UCLs for GMRs of APTT were 1.06 and 1.15. Neither sugammadex dose produced a treatment effect that met the pre-specified criterion for potential clinical relevance. Treatments were generally well tolerated. CONCLUSIONS: In healthy subjects, treatment with 4 mg/kg and 16 mg/kg sugammadex did not change either anti-Xa activity or APTT to a clinically meaningful extent following pretreatments with enoxaparin or UFH. PMID- 24800922 TI - FOLFIRI and sunitinib as first-line treatment in metastatic colorectal cancer patients with liver metastases--a CESAR phase II study including pharmacokinetic, biomarker, and imaging data. AB - BACKGROUND: The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. METHODS: mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigatora??s decision due to toxicity, or patient withdrawal. RESULTS: 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. CONCLUSIONS: Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC. PMID- 24800923 TI - Podlike N-doped carbon nanotubes encapsulating FeNi alloy nanoparticles: high performance counter electrode materials for dye-sensitized solar cells. AB - Podlike nitrogen-doped carbon nanotubes encapsulating FeNi alloy nanoparticles (Pod(N)-FeNi) were prepared by the direct pyrolysis of organometallic precursors. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and Tafel polarization measurements revealed their excellent electrocatalytic activities in the I(-)/I3(-) redox reaction of dye-sensitized solar cells (DSSCs). This is suggested to arise from the modification of the surface electronic properties of the carbon by the encapsulated metal alloy nanoparticles (NPs). Sequential scanning with EIS and CV further showed the high electrochemical stability of the Pod(N)-FeNi composite. DSSCs with Pod(N)-FeNi as the counter electrode (CE) presented a power conversion efficiency of 8.82%, which is superior to that of the control device with sputtered Pt as the CE. The Pod(N)-FeNi composite thus shows promise as an environmentally friendly, low-cost, and highly efficient CE material for DSSCs. PMID- 24800924 TI - Identification of the specific, shutter-like conformational reorientation in a chiroptical switching polycarbodiimide by VCD spectroscopy. AB - The specific conformational states responsible for the unique, reversible temperature- and solvent-driven chiroptical switching process experienced by poly(N-1-naphthyl-N'-octadecyl-carbodiimide) (PNOC) have been identified using VCD spectroscopy and DFT calculations. The distinct VCD spectra of PNOC corresponding to the two specific conformations were obtained for the polymer dissolved in DCM-d2 (state A) and CDCl3 (predominantly state B). To specifically assign the structures of both conformations, two simplified 7mer models were constructed and optimized using DFT calculations. The theoretical spectra associated with these model conformations show a high level of agreement when compared to the experimental VCD spectra. The two states consist of the naphthyl pendant groups aligned directionally opposing the helical rotation (model A) and aligned with the helicity of the backbone (model B). This pendant reorientation causes very large OR and ECD Cotton effect inversions upon modification to the temperature or solvent composition of dilute (+)-PNOC solutions in specific solvents. In addition, the pendant group equilibrium from state A to B causes a contraction of the helical pitch from the more expanded 5/1 pitch to the more contracted 7/2 pitch resulting in increased disorder of the solvation sphere surrounding the polymer chain. PMID- 24800925 TI - Immunosuppressive activity of daphnetin, one of coumarin derivatives, is mediated through suppression of NF-kappaB and NFAT signaling pathways in mouse T cells. AB - Daphnetin, a plant-derived dihydroxylated derivative of coumarin, is an effective compound extracted from a plant called Daphne Korean Nakai. Coumarin derivates were known for their antithrombotic, anti-inflammatory, and antioxidant activities. The present study was aimed to determine the immunosuppressive effects and the underlying mechanisms of daphnetin on concanavalin A (ConA) induced T lymphocytes in mice. We showed that, in vitro, daphnetin suppressed ConA-induced splenocyte proliferation, influenced production of the cytokines and inhibited cell cycle progression through the G0/G1 transition. The data also revealed that daphnetin could down-regulate activation of ConA induced NF-kappaB and NFAT signal transduction pathways in mouse T lymphocyte. In vivo, daphnetin treatment significantly inhibited the 2, 4- dinitrofluorobenzene (DNFB) -induced delayed type hypersensitivity (DTH) reactions in mice. Collectively, daphnetin had strong immunosuppressive activity both in vitro and in vivo, suggesting a potential role for daphnetin as an immunosuppressive agent, and established the groundwork for further research on daphnetin. PMID- 24800927 TI - Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil. AB - Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract. PMID- 24800928 TI - Comparison and optimization of two MALDI-TOF MS platforms for the identification of medically relevant yeast species. AB - The rapid identification of yeast is essential for the optimization of antifungal therapy. The objective of our study was to evaluate two matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platforms, the bioMerieux VITEK MS (IVD Knowledgebase v.2.0) and Bruker Biotyper (software version 3.1), for the rapid identification of medically relevant yeast. One hundred and seventeen isolates, representing six genera and 18 species, were analyzed using multiple direct smear methods to optimize identification. Sequence analysis was the gold standard for comparison. Isolates were analyzed with VITEK MS using the direct smear method +/- a 25 % formic acid on-plate extraction. For Biotyper, isolates were analyzed using direct smear without formic acid, and with 25 % and 100 % formic acid on-plate extractions. When all methods were included, VITEK MS correctly identified 113 (96.6 %) isolates after 24 h with one misidentification, and Biotyper correctly identified 77 (65.8 %) isolates using a threshold of >=2.0 with no misidentifications. Using a revised threshold of >=1.7, Biotyper correctly identified 103 (88.0 %) isolates, with 3 (2.6 %) misidentifications. For both platforms, the number of identifications was significantly increased using a formic acid overlay (VITEK MS, p < 0.01; Biotyper, p < 0.001), and reducing the Biotyper threshold from >=2.0 to >=1.7 significantly increased the rate of identification (p < 0.001). The data in this study demonstrate that the direct smear method with on-plate formic acid extraction can be used for yeast identification on both MS platforms, and more isolates are identified using the VITEK MS system (p < 0.01). PMID- 24800926 TI - Fecal contamination of drinking-water in low- and middle-income countries: a systematic review and meta-analysis. AB - BACKGROUND: Access to safe drinking-water is a fundamental requirement for good health and is also a human right. Global access to safe drinking-water is monitored by WHO and UNICEF using as an indicator "use of an improved source," which does not account for water quality measurements. Our objectives were to determine whether water from "improved" sources is less likely to contain fecal contamination than "unimproved" sources and to assess the extent to which contamination varies by source type and setting. METHODS AND FINDINGS: Studies in Chinese, English, French, Portuguese, and Spanish were identified from online databases, including PubMed and Web of Science, and grey literature. Studies in low- and middle-income countries published between 1990 and August 2013 that assessed drinking-water for the presence of Escherichia coli or thermotolerant coliforms (TTC) were included provided they associated results with a particular source type. In total 319 studies were included, reporting on 96,737 water samples. The odds of contamination within a given study were considerably lower for "improved" sources than "unimproved" sources (odds ratio [OR] = 0.15 [0.10 0.21], I2 = 80.3% [72.9-85.6]). However over a quarter of samples from improved sources contained fecal contamination in 38% of 191 studies. Water sources in low income countries (OR = 2.37 [1.52-3.71]; p<0.001) and rural areas (OR = 2.37 [1.47-3.81] p<0.001) were more likely to be contaminated. Studies rarely reported stored water quality or sanitary risks and few achieved robust random selection. Safety may be overestimated due to infrequent water sampling and deterioration in quality prior to consumption. CONCLUSION: Access to an "improved source" provides a measure of sanitary protection but does not ensure water is free of fecal contamination nor is it consistent between source types or settings. International estimates therefore greatly overstate use of safe drinking-water and do not fully reflect disparities in access. An enhanced monitoring strategy would combine indicators of sanitary protection with measures of water quality. PMID- 24800929 TI - Pseudomonas aeruginosa in French hospitals between 2001 and 2011: back to susceptibility. AB - The European Antimicrobial Resistance Surveillance Network (EARS-Net) reported an increase in the rates of resistance of Pseudomonas aeruginosa to antimicrobials between 2008 and 2011 in France. This alarming report was based on data collected during the harmonisation of breakpoints by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) committee. However, these data were not supported by the findings of other national surveillance networks. In this study, we assessed the trends in P. aeruginosa antimicrobial drug resistance at six French hospitals over a longer period of time (2001-2011) and with a constant definition of resistance. After the exclusion of incomplete data and duplicates, we sorted 34,065 isolates into the antimicrobial resistance patterns defined by the European Centre for Disease Prevention and Control (ECDC). The proportion of isolates with a resistant pattern (non-susceptible to one or two antimicrobial categories), a multidrug-resistant pattern (non-susceptible to three or four antimicrobial categories) or an extensively drug-resistant pattern (non susceptible to five or six antimicrobial categories) decreased significantly over time. Logically, the proportion of isolates with a wild-type resistance pattern has increased significantly over the same period. No significant changes in the rates of resistance to cephalosporins and penicillins were observed, whereas carbapenem resistance rates increased. By contrast, the proportion of isolates resistant to fluoroquinolones, aminoglycosides and monobactams decreased significantly over time. In conclusion, our data do not confirm the EARS-net data, suggesting instead that antimicrobial drug resistance in P. aeruginosa might not have increased in French hospitals over the last decade. PMID- 24800930 TI - The association between chronic osteomyelitis and increased risk of diabetes mellitus: a population-based cohort study. AB - Chronic inflammation is a well-known risk factor for type 2 diabetes mellitus (T2DM). The influence of chronic osteomyelitis (COM), an inflammatory disease, on the risk of developing T2DM remains unknown. This study investigated the risk of developing T2DM among COM patients. Using a retrospective cohort study, we identified 20,641 patients with COM and 82,564 age- and sex-matched controls for comparison from the Taiwan National Health Insurance Database (NHIRD) from 1997 to 2010. We followed up the COM cohort and the comparison cohort to compare the incidences of diabetes (ICD-9-CM code 250) until the end of 2010 or until the patients were censored because of death or withdrawal from the insurance program. The diabetes risk was analyzed using the Cox proportional hazards regression model. The incidence of T2DM was 1.6-fold higher in the group of COM patients than in the comparison group (29.1 vs. 18.2 per 10,000 person-years). The COM patients exhibited a higher diabetes risk [adjusted hazard ratio (aHR) = 1.64, 95 % confidence interval (CI) = 1.44-1.87] after controlling for the baseline and comorbidities. Younger and higher income patients exhibited a higher COM-to reference incidence rate ratio (IRR) for T2DM compared with that of their counterparts. We also observed an increased risk of T2DM in COM patients with comorbidities (aHR = 1.70, 95 % CI = 1.47-1.96) compared with that of their non COM counterparts. This is the first study to report the association between COM and an increased risk of developing T2DM, particularly among younger and higher income patients. PMID- 24800931 TI - Elevated brain natriuretic peptide level in patients undergoing atrial fibrillation ablation: is it a predictor of failed ablation or a mere function of atrial rhythm and rate at a point in time? AB - BACKGROUND: Pre- and postablation atrial fibrillation (AF) brain natriuretic peptide (BNP) levels were shown to predict increased recurrence of AF following ablation. OBJECTIVE: Our objective was to assess whether elevated BNP levels merely represent the presence of AF at the time of measurement or indeed the true recurrence of AF. METHODS AND RESULTS: In a prospective study of 88 patients undergoing AF ablation, BNP levels were measured immediately before, after, 24 h, and 4-6 months postablation. BNP levels were stratified by presenting rhythm and ventricular rate at the time of measurement. Median BNP level preablation was higher in patients presenting in AF compared to sinus rhythm (SR) (54(44-79) pg/ml vs. 30(18-47) pg/ml, p < 0.001). Postablation restoration of SR in patients presenting in AF reduced median BNP levels from 54(44-79) pg/ml to 40(37-51) pg/ml, (p < 0.001). However, no change was noted in patients who presented in and maintained SR throughout the procedure (30(18-47) pg/ml to 27(16-40) pg/ml, p = 0.270). At 4-6 months, BNP measured in patients in SR was not significantly different from postablation BNP (35(22-53) pg/ml vs. 38(20-52) pg/ml, p = 0.656), although 35% of them had AF recurrence in 1-year follow-up. Median BNP level measured in five patients while in atrial arrhythmia was elevated compared to postablation BNP (464(421-464) pg/ml to 37(36-37) pg/ml, p = 0.043). BNP levels and ventricular rates are positively correlated at all times pre- and postablation. CONCLUSIONS: BNP level rises acutely during AF and with rapid ventricular rates. BNP level seems to be a function of atrial rhythm and ventricular rate rather than short- or long-term predictor of AF ablation success. PMID- 24800932 TI - Lipomatous tumours of the head and neck: a spectrum of biological behaviour. AB - Lipomatous tumours are rare in the head and neck region. Their biological behaviour varies greatly, from absolutely benign to histologically benign but locally infiltrative and, finally, invasive with metastatic potential. Each lipomatous tumour has to be treated accordingly. It is of paramount importance before eventual surgery is planned to perform adequate imaging, diagnostic biopsy and careful assessment. Only in small (<5 cm), superficial soft tissue tumours or when magnetic resonance imaging has demonstrated specific features of lipoma, may diagnostic biopsy be omitted. In these cases, expectant management or simple excision is appropriate. Adequate preoperative diagnosis is important to assure adequate tumour control as well as optimal functional and cosmetic outcome. The major problem in the treatment of lipomatous tumours of the head and neck region is the presence of nearby delicate structures. Especially, wide surgical excision of liposarcomas may be hindered by anatomic constraints and may result in impaired functional and cosmetic outcome. Neoadjuvant radiotherapy and specific systemic chemotherapy may be helpful in the treatment of liposarcoma, especially when unresectable or when primary surgery is expected to result in poor oncological, functional or cosmetic outcome. Greater emphasis placed on the underlying biology of individual sarcoma subtypes, development and evaluation of novel therapies and greater specificity in the selection of chemotherapy agents based on activity in individual histological subtypes are expected to lead to improved efficacy of systemic treatment. PMID- 24800933 TI - The role of maternity care providers in promoting shared decision making regarding birthing positions during the second stage of labor. AB - INTRODUCTION: Through the use of a variety of birthing positions during the second stage of labor, a woman can increase progress, improve outcomes, and have a positive birth experience. The role that a maternity care provider has in determining which position a woman uses during the second stage of labor has not been thoroughly explored. The purpose of this qualitative investigation was to explore how maternity care providers communicate with women during the second stage of labor regarding birthing position. METHODS: A literature-informed framework was developed to conduct a process of deductive content analysis of communication patterns between nulliparous women and their maternity care providers during the second stage of labor. Literature discussing shared decision making, control, and predictors of positive birth experiences were reviewed to develop a coding framework. The framework included the following categories: listening to women, encouragement, information, offering choices, and style of support. Forty-one audiotapes of women and their maternity care providers during the second stage of labor were transcribed verbatim and analyzed. RESULTS: Themes identified in the transcripts included all those in the analytic framework, plus 2 added categories of communication: empathy and interaction. Maternity care providers in this study enabled women to select various birthing positions using a dynamic process that moved between open, informative approaches and more closed, directive approaches, depending on the woman's needs and clinical condition. As clinical conditions unfolded, women became more actively involved in shared decision making regarding birthing positions, and maternity care providers found the right balance between being responsive to the woman's questions or directives. DISCUSSION: Enabling shared decision making during birth is not a linear process using a single approach; it is dynamic process that requires a variety of approaches. Maternity care providers can support a woman to use different birthing positions during the second stage of labor by employing a flexible style that incorporates clinical assessment and the woman's responses. PMID- 24800934 TI - (13) C magnetic resonance spectroscopic imaging of hyperpolarized [1-(13) C, U (2) H5 ] ethanol oxidation can be used to assess aldehyde dehydrogenase activity in vivo. AB - PURPOSE: Aldehyde dehydrogenase (ALDH2) is an emerging drug target for the treatment of heart disease, cocaine and alcohol dependence, and conditions caused by genetic polymorphisms in ALDH2. Noninvasive measurement of ALDH2 activity in vivo could inform the development of these drugs and accelerate their translation to the clinic. METHODS: [1-(13) C, U-(2) H5 ] ethanol was hyperpolarized using dynamic nuclear polarization, injected into mice and its oxidation in the liver monitored using (13) C MR spectroscopy and spectroscopic imaging. RESULTS: Oxidation of [1-(13) C, U-(2) H5 ] ethanol to [1-(13) C] acetate was observed. Saturation of the acetaldehyde resonance, which was below the level of detection in vivo, demonstrated that acetate was produced via acetaldehyde. Irreversible inhibition of ALDH2 activity with disulfiram resulted in a proportional decrease in the amplitude of the acetate resonance. CONCLUSION: (13) C magnetic resonance spectroscopy measurements of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation allow real-time assessment of ALDH2 activity in liver in vivo. PMID- 24800935 TI - Brains in metamorphosis: reprogramming cell identity within the central nervous system. AB - During embryonic development, uncommitted pluripotent cells undergo progressive epigenetic changes that lock them into a final differentiated state. Can mammalian cells change identity within the living organism? Direct lineage reprogramming of cells has attracted attention as a means to achieve organ regeneration. However, it is unclear whether cells in the CNS are endowed with the plasticity to reprogram. Neurons in particular are considered among the most immutable cell types, able to retain their class-specific traits for the lifespan of the organism. Here we focus on two experimental paradigms, glia-to-neuron and neuron-to-neuron conversion, to consider how lineage reprogramming has challenged the notion of CNS immutability, paving the way for the application of reprogramming strategies to reshape neurons and circuits in vivo. PMID- 24800936 TI - Neuronal polarization in vivo: Growing in a complex environment. AB - Neurons are one of the most polarized cell types in the body. During the past three decades, many researchers have attempted to understand the mechanisms of neuronal polarization using cultured neurons. Although these studies have succeeded in discovering the various signal molecules that regulate neuronal polarization, one major question remains unanswered: how do neurons polarize in vivo? PMID- 24800937 TI - Isolation and proteomic characterization of bacterial extracellular membrane vesicles. AB - The secretion of extracellular membrane vesicles (EMVs) is a common phenomenon that occurs in archaea, bacteria, and mammalian cells. EMVs contain biologically active proteins, which have diverse roles in biological processes. The outer membrane vesicles (OMVs) of Gram-negative bacteria and membrane vesicles (MVs) of Gram-positive bacteria have been discovered in various species. The main issues related to bacterial EMVs are their virulence, biogenesis mechanisms, host cell interaction mechanisms, and their potential use as new vaccine candidates. Recently, proteomics has become an essential tool for the characterization of EMVs. Proteomics is useful for the identification, quantification, and protein protein interaction analysis of EMV protein components. This review describes the current understanding of secretory EMVs based on proteomic methods and the characteristics of various bacterial secretory EMVs. Finally, evidence for their potential roles and future applications are discussed. PMID- 24800938 TI - Investigation of the retention behavior of structurally diverse drugs on alpha(1) acid glycoprotein column: insight on the molecular factors involved and correlation with protein binding data. AB - Retention of 49 structurally diverse drugs on alpha1 acid glycoprotein column was investigated under different chromatographic conditions. Acetonitrile and 2 propanol were used as organic modifiers at different percentages and the pH was adjusted at 7.0 using PBS. Analysis of extrapolated and isocratic retention in terms of lipophilicity and electrostatic interactions revealed significant effect of the nature and percentage of organic modifier, which was attributed to the different shielding degree of the charged sites on the stationary phase by the buffer constituents. AGP retention factors were compared to HSA retention factors analyzed previously. Application of LSER analysis, extended to incorporate fractions ionized, demonstrated hydrogen bond acidity, dipolarity/polarizability and excess molar refraction as the most significant parameters for all AGP chromatographic indices, elucidating the differentiation of AGP retention from octanol-water partitioning and HSA retention. An attempt to correlate AGP chromatographic indices to AGP association constants, available in literature, supported the importance of stationary shielding in retention mechanism. Thus, isocratic retention factors logk10(ACN)(AGP) show a moderate but still better performance than lipophilicity in the case of A variant and may be a useful tool for the estimation of relevant association constants. For F1/S binding simulation lower stationary phase shielding is needed to obtain a significant two term regression equation, where logk20(ACN)(AGP) exerts a secondary contribution next to the most important bulk effect expressed by molecular weight. PMID- 24800939 TI - Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors. AB - By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522. PMID- 24800940 TI - Identification of a new selective dopamine D4 receptor ligand. AB - The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4=0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4=3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki <100 nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted. PMID- 24800943 TI - Monte Carlo modeling of proton therapy installations: a global experimental method to validate secondary neutron dose calculations. AB - Monte Carlo calculations are increasingly used to assess stray radiation dose to healthy organs of proton therapy patients and estimate the risk of secondary cancer. Among the secondary particles, neutrons are of primary concern due to their high relative biological effectiveness. The validation of Monte Carlo simulations for out-of-field neutron doses remains however a major challenge to the community. Therefore this work focused on developing a global experimental approach to test the reliability of the MCNPX models of two proton therapy installations operating at 75 and 178 MeV for ocular and intracranial tumor treatments, respectively. The method consists of comparing Monte Carlo calculations against experimental measurements of: (a) neutron spectrometry inside the treatment room, (b) neutron ambient dose equivalent at several points within the treatment room, (c) secondary organ-specific neutron doses inside the Rando-Alderson anthropomorphic phantom. Results have proven that Monte Carlo models correctly reproduce secondary neutrons within the two proton therapy treatment rooms. Sensitive differences between experimental measurements and simulations were nonetheless observed especially with the highest beam energy. The study demonstrated the need for improved measurement tools, especially at the high neutron energy range, and more accurate physical models and cross sections within the Monte Carlo code to correctly assess secondary neutron doses in proton therapy applications. PMID- 24800942 TI - Design, synthesis, and biological evaluation of O-2-modified indenoisoquinolines as dual topoisomerase I-tyrosyl-DNA phosphodiesterase I inhibitors. AB - Tyrosyl-DNA phosphodiesterase I (TDP1) repairs stalled topoisomerase I (Top1)-DNA covalent complexes and has been proposed to be a promising and attractive target for cancer treatment. Inhibitors of TDP1 could conceivably act synergistically with Top1 inhibitors and thereby potentiate the effects of Top1 poisons. This study describes the successful design and synthesis of 2-position-modified indenoisoquinolines as dual Top1-TDP1 inhibitors using a structure-based drug design approach. Enzyme inhibition studies indicate that indenoisoquinolines modified at the 2-position with three-carbon side chains ending with amino substituents show both promising Top1 and TDP1 inhibitory activity. Molecular modeling of selected target compounds bound to Top1 and TDP1 was used to rationalize the enzyme inhibition results and structure-activity relationship analysis. PMID- 24800944 TI - Risk factors of post-traumatic stress disorder (PTSD) after Wenchuan earthquake: a case control study. AB - BACKGROUND: Few clues were found in the literature about the independent risk factors for PTSD among earthquake survivors in Sichuan province three years after the 2008 earthquake. Ours was the first case-control study with matching factors of age and distance from the epicenter among survivors age 16 years or older, three years after the catastrophe. OBJECTIVES: To identify independent risk factors for PTSD among earthquake survivors. METHODS: We performed a population based matched case-control study. The cases were drawn from earthquake areas three years after the Wenchuan earthquake, including 113 cases who met positive criteria for PTSD symptoms according to the PCL-C (PTSD Checklist-Civilian Version) score and 452 controls who did not meet the criteria. Cases and controls were matched individually by birth year (+ three years) and the town they lived in when the earthquake occurred. RESULTS: Independent risk factors for PTSD symptoms included two-week disease prevalence (odds ratio [OR],1.92; 95% confidence interval [CI],1.18-3.13), witnessing someone being killed in the earthquake (OR, 2.04;95%CI, 1.17-3.58), having no regular income after the earthquake (OR, 0.52; 95%CI, 0.28-0.98), receiving mental health support only one time after the earthquake (OR, 2.43; 95%CI, 1.09-5.42) and lower social support (lower PSSS score) (OR, 0.95; 95%CI, 0.93-0.97). CONCLUSION: Earthquake experience, suffering from physical illnesses, lack of stable income, and lower social support were associated with PTSD symptoms. PMID- 24800945 TI - Uptake of compounds that selectively kill multidrug-resistant cells: the copper transporter SLC31A1 (CTR1) increases cellular accumulation of the thiosemicarbazone NSC73306. AB - Acquired drug resistance in cancer continues to be a challenge in cancer therapy, in part due to overexpression of the drug efflux transporter P-glycoprotein (P gp, MDR1, ABCB1). NSC73306 is a thiosemicarbazone compound that displays greater toxicity against cells expressing functional P-gp than against other cells. Here, we investigate the cellular uptake of NSC73306, and examine its interaction with P-gp and copper transporter 1 (CTR1, SLC31A1). Overexpression of P-gp sensitizes LLC-PK1 cells to NSC73306. Cisplatin (IC50 = 77 MUM), cyclosporin A (IC50 = 500 MUM), and verapamil (IC50 = 700 MUM) inhibited cellular accumulation of [(3)H]NSC73306. Cellular hypertoxicity of NSC73306 to P-gp-expressing cells was inhibited by cisplatin in a dose-dependent manner. Cells transiently expressing the cisplatin uptake transporter CTR1 (SLC31A1) showed increased [(3)H]NSC73306 accumulation. In contrast, CTR1 knockdown decreased [(3)H]NSC73306 accumulation. The presence of NSC73306 reduced CTR1 levels, similar to the negative feedback of CTR1 levels by copper or cisplatin. Surprisingly, although cisplatin is a substrate of CTR1, we found that CTR1 protein was overexpressed in high-level cisplatin-resistant KB-CP20 and BEL7404-CP20 cell lines. We confirmed that the CTR1 protein was functional, as uptake of NSC73306 was increased in KB-CP20 cells compared to their drug-sensitive parental cells, and downregulation of CTR1 in KB CP20 cells reduced [(3)H]NSC73306 accumulation. These results suggest that NSC73306 is a transport substrate of CTR1. PMID- 24800947 TI - Sunitinib re-challenge in advanced renal-cell carcinoma. AB - Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal sequences of therapy is therefore the focus of much current research. There is also evidence that treatment 're challenge' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior targeted therapy with sunitinib and/or an alternative tyrosine kinase inhibitor or mammalian target of rapamycin inhibitor. Re challenge with sunitinib appears to be of clinical benefit, thus representing a feasible therapeutic option for patients with advanced RCC who are refractory to other treatments and are able to receive further therapy. These observations support hypotheses that resistance to targeted agents is transient and can be at least partially reversed by re-introduction of the same agent after a treatment break. Median progression-free survival durations appear to be shorter and response rates lower on re-challenge than following initial treatment, although a wider interval between treatments appears to increase response to sunitinib re challenge. PMID- 24800946 TI - Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer. AB - BACKGROUND: Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing. RESULTS: A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients. CONCLUSIONS: Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies. PMID- 24800948 TI - Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study. AB - BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy. PMID- 24800949 TI - Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies. AB - BACKGROUND: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. METHODS: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m( 2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (?6 months). CONCLUSIONS: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance. PMID- 24800957 TI - Polyamines cause elevation of steroid 5alpha-reductase mRNA levels by suppressing mRNA degradation in C6 glioma cells. AB - Polyamines are widely distributed in living organisms, and considered to play a potential role in various cellular processes. The effects of polyamines on gene expression as well as cell proliferation have been suggested to be closely associated with the physiological and pathological functions. However, it seems necessary to investigate their potential roles in the regulation of cellular metabolism and functions. Previously, glial cells have been suggested to be involved in the protection and preservation of neuronal functions, probably through the production of neurotrophic factors in the brain. On the other hand, neuroactive 5alpha-reduced steroids promote glial cell differentiation, resulting in enhancement of their ability to produce brain-derived neurotrophic factor (BDNF). Based on these findings, polyamines are assumed to stimulate the expression of the gene encoding steroid 5alpha-reductase (5alpha-R), which can induce the production of neuroactive 5alpha-reduced steroids in glial cells. The effects of polyamines on 5alpha-R mRNA levels in C6 glioma cells were examined as a model experiment. In consequence, spermine (SPM) and spermidine (SPD), but not putrescine (PUT), have been shown to elevate 5alpha-R mRNA levels without activating the 5alpha-R promoter. Furthermore, SPM increased 5alpha-R mRNA levels under the conditions in which the mRNA biosynthesis was inhibited. Therefore, it can be speculated that polyamines increase 5alpha-R mRNA levels as a consequence of suppressing the degradation of mRNA. PMID- 24800958 TI - The role of BMI1 as a biomarker of cancer stem cells in head and neck cancer: a review. AB - Emerging studies show that BMI1 (B cell-specific Moloney murine leukemia virus integration site 1) has an important function as a biomarker of cancer stem cells (CSCs), i.e. cells with self-renewal characteristics, capable of tumor initiation, progression, invasion, metastasis, tumor recurrence and resistance to chemotherapy and radiotherapy. The failure of current anticancer therapies can be attributed to the relative ineffectiveness of drug and radiation treatments on CSCs, thereby preserving the full capacity of the cells to reproduce tumors. The development of new strategies is currently hindered by the lack of reliable markers for the identification of these CSCs. At present, they have been isolated from solid tumors at various locations using a variety of surface markers, including CD34, CD133, CD24, CD44, CD29 and CD31, in addition to the methods of isolation and cell culture via the Wnt, BMI1, Notch and Hedgehog pathways. The discovery of specific tumor targets for CSCs would constitute a big step in the research for the definitive therapy against cancer. More studies are being conducted that consider the role of CSCs in head and neck cancers with potential for an impact on clinical-surgical outcomes from the knowledge that is being gained. A promising intracellular marker of CSCs in head and neck cancer is the oncoprotein BMI1, with specific data about its prognostic value based on the specific location. PMID- 24800959 TI - Overexpression of sigma factor SigB improves temperature and butanol tolerance of Synechocystis sp. PCC6803. AB - Among phenotypes of interest for an industrial cyanobacteria host are improved tolerance to temperature, salt, and solvent stress. Cellular responses to many stresses are controlled by the network of sensory receptors and downstream regulatory proteins. We applied transcription factor engineering to Synechocystis and tested mutant strains for tolerance to temperature and the biofuel 1-butanol. Histidine kinases (Hik), response regulators (Rre), and an RNA polymerase sigma factor (SigB) were overexpressed or deleted. Overexpression of SigB increased both temperature and butanol tolerance and lowered the intracellular concentration of reactive oxygen species. This report demonstrates that alteration of regulatory proteins in a cyanobacterium can be a useful tool to improve stress tolerance. PMID- 24800960 TI - Enzymatic formation of gold nanoparticles by submerged culture of the basidiomycete Lentinus edodes. AB - We report for the first time that the medicinal basidiomycete Lentinus edodes can reduce Au(III) from chloroauric acid (HAuCl4) to elemental Au [Au(0)], forming nanoparticles. Several methods, including transmission electron microscopy, electron energy loss spectroscopy, X-ray fluorescence, and dynamic light scattering, were used to show that when the fungus was grown submerged, colloidal gold accumulated on the surface of and inside the mycelial hyphae as electron dense particles mostly spherical in shape, with sizes ranging from 5 to 50nm. Homogeneous proteins (the fungal enzymes laccase, tyrosinase, and Mn-peroxidase) were found for the first time to be involved in the reduction of Au(III) to Au(0) from HAuCl4. A possible mechanism forming Au nanoparticles is discussed. PMID- 24800961 TI - Stuck on you: the increasing challenge of morbidly adherent placenta in obstetric practice. PMID- 24800962 TI - Determination of biometric measures to evaluate patient suitability for transoral robotic surgery. AB - BACKGROUND: Transoral robotic surgery (TORS) represents a novel treatment for oropharyngeal cancer and obstructive sleep apnea. Appropriate patient selection is crucial. The purpose of this study was to investigate whether anatomic biometric measures are useful to determine the feasibility of performing TORS. METHODS: Three surgeons independently evaluated feasibility in 51 soft-fix cadavers. Transoral visualization was performed with 2 retractors commonly used in TORS. Seven anthropometric parameters and the degree of mouth opening were recorded. RESULTS: Mandibular body height, hyoid-mental length, and neck circumference demonstrated significant differences between "suboptimal" and "adequate" visualization of base of tongue and epiglottis (p < .05). Limited mouth opening was associated with suboptimal visualization. Neck circumference had the strongest influence on predicting TORS feasibility. CONCLUSION: Mandibular body height, hyoid-mental length, and neck circumference in conjunction with the degree of mouth opening may determine patient suitability for TORS. Clinical evaluation is essential to validate their collective usefulness. PMID- 24800963 TI - Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients. AB - A novel influenza A (H7N9) virus of avian origin emerged in eastern China in the spring of 2013. This virus causes severe disease in humans, including acute and often lethal respiratory failure. As of January 2014, 275 cases of H7N9-infected patients had been reported, highlighting the urgency of identifying biomarkers for predicting disease severity and fatal outcomes. Here, we show that plasma levels of angiotensin II, a major regulatory peptide of the renin-angiotensin system, are markedly elevated in H7N9 patients and are associated with disease progression. Moreover, the sustained high levels of angiotensin II in these patients are strongly correlated with mortality. The predictive value of angiotensin II is higher than that of C-reactive protein and some clinical parameters such as the PaO2/FiO2 ratio (partial pressure of arterial oxygen to the fraction of inspired oxygen). Our findings indicate that angiotensin II is a biomarker for lethality in flu infections. PMID- 24800964 TI - CRF2 receptor-deficiency reduces recognition memory deficits and vulnerability to stress induced by cocaine withdrawal. AB - Psychostimulant drug abuse, dependence and withdrawal are associated with cognitive dysfunction and impact stress-sensitive systems. The corticotropin releasing factor (CRF) system orchestrates stress responses via CRF1 and CRF2 receptors and is implicated in substance use disorders. However, CRF2 role in psychostimulant drug-induced cognitive dysfunction remains to be elucidated. In the present study, wild-type and CRF2-/- mice are injected with cocaine and memory assessed by the novel object recognition (NOR) task throughout relatively long periods of drug withdrawal. Following recovery from the drug-induced memory deficits, the mice are stressed prior to the NOR task and brain gene expression evaluated by in situ hybridization. Cocaine impairs NOR memory in wild-type and CRF2-/- mice. However, following cocaine withdrawal NOR memory deficits last less time in CRF2-/- than in wild-type mice. Furthermore, a relatively mild stressor induces the re-emergence of NOR deficits in long-term cocaine-withdrawn wild-type but not CRF2-/- mice. Cocaine-withdrawn mice show a genotype-independent higher c fos expression in the NOR memory-relevant perirhinal cortex than drug-naive mice. However neither genotype nor drug withdrawal affect the expression of tyrosine hydroxylase in the ventral tegmental area or the locus coeruleus and CRF in the central nucleus of the amygdala or the paraventricular nucleus of the hypothalamus, brain regions implicated in stress and drug responses. These data indicate a new role for the CRF2 receptor in cognitive deficits induced by cocaine withdrawal, both as regards to their duration and their re-induction by stress. Interestingly, prototypical brain stress systems other than CRF do not appear to be involved. PMID- 24800967 TI - WITHDRAWN: Dressings for healing venous leg ulcers. PMID- 24800966 TI - Short-term effects of a web-based guided self-help intervention for employees with depressive symptoms: randomized controlled trial. AB - BACKGROUND: Depressive disorders are highly prevalent in the working population and are associated with excessive costs. The evidence for effective worker directed interventions for employees with depressive symptoms is limited. Treating employees with depressive symptoms before sick leave via the Internet could be beneficial and cost saving. OBJECTIVE: In this study, we developed and tested the effectiveness of a Web-based guided self-help course for employees with depressive symptoms. We report on the posttreatment effectiveness of the intervention. METHODS: This study is a two-arm randomized controlled trial comparing a Web-based guided self-help course to care as usual (CAU). We recruited employees from 6 different companies via the companies' intranet and posters. The main inclusion criterion was elevated depressive symptoms as measured by a score of >=16 on the Center for Epidemiological Studies Depression scale (CES-D). The intervention (Happy@Work) was based on problem-solving treatment and cognitive therapy and consisted of 6 weekly lessons. Participants were asked to submit their weekly assignment via the website after completion. They subsequently received feedback from a coach via the website. Self-report questionnaires on depressive symptoms (CES-D; primary outcome), anxiety measured by the Hospital Anxiety and Depression Scale (HADS), burnout measured by the Maslach Burnout Inventory (MBI), and work performance measured by the Health and Work Performance Questionnaire (HPQ; secondary outcomes) were completed at baseline and at posttreatment. RESULTS: A total of 231 employees were randomized to either the intervention group (n=116) or CAU (n=115).The posttreatment assessment was completed by 171 (74.0%) participants. Both the intervention and the CAU group showed significant improvements in the primary outcome of depressive symptoms, but no differences between the conditions was found (d=0.16, 95% CI -0.10 to 0.41, P=.29). Significant but small effects in favor of the intervention group were found for anxiety symptoms (d=0.16, 95% CI -0.09 to 0.42, P=.04) and exhaustion (d=0.17, 95% CI -0.09 to 0.43, P=.02). CONCLUSIONS: This study showed that a Web-based guided self-help course for employees with depressive symptoms was not more effective in reducing depressive symptoms among employees than CAU. Large improvements in depressive symptoms in the CAU group were unforeseen and potential explanations are discussed. PMID- 24800968 TI - Quantitative determination and confirmatory analysis of N-acetylneuraminic and N glycolylneuraminic acids in serum and urine by solid-phase extraction on-line coupled to liquid chromatography-tandem mass spectrometry. AB - N-acetylneuraminic acid (Neu5Ac) and N-acetylglycolylneuraminic acid (Neu5Gc), two acylated derivatives of 9-C carboxylated monosaccharides, are involved in a number of biological processes as modulators of glycoconjugates. A partially automated method is here presented for determination of these sialic acids in the two most important biofluids for clinical analysis: serum and urine. For this purpose, a solid-phase extraction (SPE) workstation was on-line connected to an LC-MS/MS triple quadrupole mass detector. Hydrolysis to release sialic acids bound to glycoconjugates and derivatization were the two steps implemented as sample preparation prior to SPE-LC-MS/MS analysis. Following thorough optimization of the SPE and LC-MS/MS conditions, the analytical method was validated using the standard addition approach to assess the presence of matrix effects. The proposed method affords detection limits of 0.03ng/mL and 0.04ng/mL for Neu5Ac and Neu5Gc, respectively. The precision (expressed as relative standard deviation) was 1.7 and 4.6% for within-day variability, and 4.8 and 7.2% for between-days variability. Accuracy, estimated using spiked (between 1 and 50ng/mL) and non-spiked samples of both biofluids, ranged from 95.2 to 99.6%. The method was applied to human serum and urine of healthy volunteers, thus showing its suitability for application in both clinical and research laboratories. PMID- 24800969 TI - Magnetic solid phase extraction based on magnetite/reduced graphene oxide nanoparticles for determination of trace isocarbophos residues in different matrices. AB - A simple one-step solvothermal method was applied for the preparation of magnetite/reduced graphene oxide (MRGO), and the synthetic nanocomposites with a magnetic particle size of ~8nm were used as an adsorbent for magnetic solid phase extraction of isocarbophos (ICP) in different sample matrices prior to gas chromatography (GC) detection. The identity of the nanomaterial was confirmed using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy and transmission electron microscopy. It was shown that Fe3O4 nanoparticles with a uniform size were homogeneously anchored on RGO nanosheets. Increased oxidation degrees of graphite oxide, big particle sizes and large loading amounts of Fe3O4 on the surface of RGO led to a decrease of adsorption capacity of MRGO to ICP. The adsorption behavior of this adsorbent was better fitted by the pseudo-second-order kinetic model. Several parameters affecting the extraction efficiency were investigated and optimized, including adsorbent dosage, extraction time, ionic strength and desorption conditions. And then, a rapid and effective method based on MRGO combined with GC was developed for the determination of ICP in aqueous samples. A linear range from 0.05 to 50ngmL(-1) was obtained with a high correlation coefficient (R(2)) of 0.9995, and the limit of detection was found to be 0.0044ngmL(-1). This method was successfully applied to the analysis of ICP in five kinds of samples, including apple, rice, lake water, cowpea and cabbage. The recoveries in different sample matrices were in the range from 81.00% to 108.51% with relative standard deviations less than 9.72%. It can be concluded that the proposed analytical method is highly efficient, sensitive, precise, accurate and practicable. PMID- 24800970 TI - Asymmetrical flow field-flow fractionation for human serum albumin based nanoparticle characterisation and a deeper insight into particle formation processes. AB - Nanoparticles used as drug delivery systems are of growing interest in the pharmaceutical field. Understanding the behaviour and effects of nanosystems in the human body is dependent on comprehensive characterisation of the systems especially with regard to size and size distribution. Asymmetrical flow field flow fractionation (AF4) is a promising method for this challenge as this technique enables chromatographic separation of particles and solute molecules according to their respective size. Within this study AF4 was used for the characterisation of human serum albumin (HSA) based nanoparticles. In a first part, the most important aspects of method development like the choice of cross flow rate, focusing and the increase of sample concentration via outlet stream splitting on the sample separation were evaluated. Sample fractionation was controlled by inline-coupling of a dynamic light scattering detector (DLS, Zetasizer) and was confirmed by DLS batch mode measurements. In a second part the applicability of field-flow fractionation for characterisation of the HSA particle formation process by a desolvation method was evaluated. A time dependent particle formation was observed which was controlled by the amount of desolvating agent. Furthermore, field-flow fractionation in combination with in line dynamic light scattering was used to monitor the increase of particle diameter during PEGylation of the resulting HSA nanoparticles. The separation of nanoparticles from dissolved polyethylene glycol (PEG) could successfully be used for determination of the particles' PEGylation degree. PMID- 24800971 TI - Model-based identification of optimal operating conditions for amino acid simulated moving bed enantioseparation using a macrocyclic glycopeptide stationary phase. AB - Teicoplanin aglycone columns allow efficient separation of amino acid enantiomers in aqueous mobile phases and enable robust and predictable simulated moving bed (SMB) separation of racemic methionine despite a dependency of the adsorption behavior on the column history (memory effect). In this work we systematically investigated the influence of the mobile phase (methanol content) and temperature on SMB performance using a model-based optimization approach that accounts for methionine solubility, adsorption behavior and back pressure. Adsorption isotherms became more favorable with increasing methanol content but methionine solubility was decreased and back pressure increased. Numerical optimization suggested a moderate methanol content (25-35%) for most efficient operation. Higher temperature had a positive effect on specific productivity and desorbent requirement due to higher methionine solubility, lower back pressure and virtually invariant selectivity at high loadings of racemic methionine. However, process robustness (defined as a difference in flow rate ratios) decreased strongly with increasing temperature to the extent that any significant increase in temperature over 32 degrees C will likely result in operating points that cannot be realized technically even with the lab-scale piston pump SMB system employed in this study. PMID- 24800972 TI - Downbeat nystagmus as the presenting symptom of infantile neuroaxonal dystrophy: a case report. AB - Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset and rapid progression of psychomotor regression and hypotonia evolving into spasticity and dementia. Although nystagmus is a well established neurological sign in infantile neuroaxonal dystrophy, it is mainly described as pendular and noticed in later stages of the disease. We report a 13 month-old girl with infantile neuroaxonal dystrophy harboring a compound heterozygous mutation in the PLA2G6 gene with downbeat nystagmus as the only presenting symptom. Our case indicates that downbeat nystagmus can be a rare but very early onset sign of cerebellar involvement in infantile neuroaxonal dystrophy and can anticipate the appearance of psychomotor regression and neuroradiological abnormalities. PMID- 24800973 TI - Vernier assembly: controlling DNA polymerization via length mismatching. AB - Inspired by the principle of the Vernier scale, length mismatching was used to control the lengths of supramolecular DNA polymers. PMID- 24800975 TI - High-dimensional camera shake removal with given depth map. AB - Camera motion blur is drastically nonuniform for large depth-range scenes, and the nonuniformity caused by camera translation is depth dependent but not the case for camera rotations. To restore the blurry images of large-depth-range scenes deteriorated by arbitrary camera motion, we build an image blur model considering 6-degrees of freedom (DoF) of camera motion with a given scene depth map. To make this 6D depth-aware model tractable, we propose a novel parametrization strategy to reduce the number of variables and an effective method to estimate high-dimensional camera motion as well. The number of variables is reduced by temporal sampling motion function, which describes the 6 DoF camera motion by sampling the camera trajectory uniformly in time domain. To effectively estimate the high-dimensional camera motion parameters, we construct the probabilistic motion density function (PMDF) to describe the probability distribution of camera poses during exposure, and apply it as a unified constraint to guide the convergence of the iterative deblurring algorithm. Specifically, PMDF is computed through a back projection from 2D local blur kernels to 6D camera motion parameter space and robust voting. We conduct a series of experiments on both synthetic and real captured data, and validate that our method achieves better performance than existing uniform methods and nonuniform methods on large-depth-range scenes. PMID- 24800976 TI - Fas -670A/G (rs1800682) polymorphism and digestive cancer risk in Asians: a meta analysis. AB - OBJECTIVES: Tumorigenesis is a multistep process that begins with the abrogation of normal controls of apoptosis and cell proliferation, and the Fas receptor ligand system is a key regulator of apoptosis. The Fas -670 A/G single-nucleotide polymorphism (SNP) has been demonstrated to affect the expression of the Fas gene by altering the transcriptional activity in this gene's promoter. However, the association between the Fas -670 A/G polymorphism and digestive cancer risk is still controversial and ambiguous in the Asian population, so we conducted a meta analysis to confirm and clarify the association between the Fas -670 A/G polymorphism and digestive cancer. MATERIALS AND METHODS: A search of PubMed, China National Knowledge Infrastructure (CNKI), and WanFang databases was conducted and encompassed all available articles that had been published up to July 20, 2013. Overall, 15 case-control studies containing 3692 cases and 4895 controls were retrieved based on search criteria for digestive cancer susceptibility related to -670A/G SNP. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. RESULTS: In the overall analysis, the country type and source of control subgroups, no association between the Fas -670 A/G polymorphism and digestive cancer risk was found. However, in the digestive cancer-type subgroups, a significant protective effect was detected between Fas -670 A/G polymorphism and hepatocellular carcinoma in Asians (AG vs. GG: OR=0.89, 95% CI=0.80-0.99; AA+AG vs. GG: OR=0.93, 95% CI=0.87-1.00). CONCLUSIONS: Our investigations demonstrated that the Fas -670 A/G polymorphism might decrease the hepatocellular carcinoma risk in Asian populations. Further studies based on larger sample sizes, other ethnicities, and gene-environment interactions should be conducted to further understand the role of Fas -670 A/G polymorphism in digestive cancer risk. PMID- 24800977 TI - Migrate small, sound big: functional constraints on body size promote tracheal elongation in cranes. AB - Organismal traits often represent the outcome of opposing selection pressures. Although social or sexual selection can cause the evolution of traits that constrain function or survival (e.g. ornamental feathers), it is unclear how the strength and direction of selection respond to ecological shifts that increase the severity of the constraint. For example, reduced body size might evolve by natural selection to enhance flight performance in migratory birds, but social or sexual selection favouring large body size may provide a countervailing force. Tracheal elongation is a potential outcome of these opposing pressures because it allows birds to convey an auditory signal of exaggerated body size. We predicted that the evolution of migration in cranes has coincided with a reduction in body size and a concomitant intensification of social or sexual selection for apparent large body size via tracheal elongation. We used a phylogenetic comparative approach to examine the relationships among migration distance, body mass and trachea length in cranes. As predicted, we found that migration distance correlated negatively with body size and positively with proportional trachea length. This result was consistent with our hypothesis that evolutionary reductions in body size led to intensified selection for trachea length. The most likely ultimate causes of intensified positive selection on trachea length are the direct benefits of conveying a large body size in intraspecific contests for mates and territories. We conclude that the strength of social or sexual selection on crane body size is linked to the degree of functional constraint. PMID- 24800978 TI - Percutaneous complete repair of failed mitral valve prosthesis: simultaneous closure of mitral paravalvular leaks and transcatheter mitral valve implantation single-centre experience. AB - AIMS: Structural deterioration and paravalvular leak (PVL) are complications associated with surgically implanted prosthetic valves, historically requiring reoperation. We present our experience of complete transcatheter repair of a degenerated mitral bioprosthesis. METHODS AND RESULTS: From March 2012 to October 2012, we reviewed consecutive, high-risk surgical patients (n=5) who underwent transcatheter repair of a failed mitral bioprosthesis with severe paravalvular regurgitation (PVR). Manufacturer valve sizes ranged from 27 to 33 mm, regurgitation (n=1), stenosis (n=1), or both (n=3). Percutaneous transapical and transseptal access were achieved with PVL closure performed transapically. An arteriovenous rail was created for transseptal delivery of a Melody valve. All patients had successful PVL closure with no residual PVR. Valve-in-valve (ViV) implantation was successful in four patients. Overall, mean transvalvular mitral gradient was 11.2 mmHg pre-procedure which improved to 5 mmHg post-procedure. Improvement of NYHA Class >=2 was achieved in all patients (19+/-3 months). One patient had controlled Melody valve embolisation which required emergent surgical replacement. Inner valve diameter was 26 mm, too large for Melody valve implantation. CONCLUSIONS: Complete transcatheter repair of a degenerated mitral bioprosthesis with PVR can be performed in the high-risk patient. Accurate measurement is necessary prior to intervention, with concern for embolisation among the larger valve sizes (>31 mm). PMID- 24800980 TI - White phosphorus degradation with a NacNac aluminum carbene analogue: the biradical reaction mechanism. AB - The title compound Al-NacNac is isolobal to the imidazol-2-ylidene (NHC); the latter is considered as a nucleophilic carbene. However, the title compound is different from a typical carbene, as aluminum is a heavier group 13 element with a predominant inert s orbital. Its singlet ground state is a poor Lewis donor (acceptor) toward white phosphorus, but its corresponding lowest energy triplet state forms a strong Al-P bond with (opened) white phosphorus. The reaction of Al NacNac with white phosphorus proceeds in two steps: after the addition of a first carbene analogue, a second one is added, resulting in a transient biradicaloid species. This undergoes facile subsequent rearrangement, and a final ring closure reaction leads to the observed product with a bicyclobutane moiety. It is determined by intramolecular bond formation of two phosphorus centered radicals. Finally, a structure with a large singlet-triplet energy separation is formed. An analogy to the noninnocent ligand character as well as the exciplex view of the monoadduct of white phosphorus with the Al-NacNac system is drawn. PMID- 24800981 TI - Impact of the electrode material and shape on performance of intrinsically tunable ferroelectric FBARs. AB - Experiment-based analysis of losses in tunable ferroelectric xBiFeO3-(1-x)BaTiO3 (BF-BT) film bulk acoustic wave resonators (FBARs) is reported. The Q-factors, effective coupling coefficients, and tunabilities are considered as functions of surface roughness of the ferroelectric film, the acoustic impedance and shape of the electrodes/interconnecting strips, leakage of acoustic waves into the substrate via Bragg reflector, and the relative thicknesses of the electrodes and ferroelectric film. Compared with Al, the high acoustic impedance of Pt electrodes provides higher Q-factor, coupling coefficient, and tunability. However, using Pt in the interconnecting strips results in reduction of the Q factor. PMID- 24800979 TI - Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter. AB - AIMS: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated alpha1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells. RESULTS: alpha1-adrenoceptor (alpha1-AR) signaling translocated activated proline rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that alpha1-AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca2+ overload. INNOVATION: Our data indicate that inhibition of alpha1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present. CONCLUSION: The alpha1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells. PMID- 24800983 TI - Death rates fell significantly after Massachusetts implemented 2006 health reform. PMID- 24800982 TI - Incidence and risk factors for and the effect of a program to reduce the incidence of surgical site infection after cardiac surgery. AB - BACKGROUND: Surgical site infection (SSI) after cardiac surgery (CS) is a serious complication that increases hospital length of stay (LOS), has a substantial financial impact, and increases mortality. The study described here was done to evaluate the effect of a program to reduce SSI after CS. METHODS: In January 2007, a multi-disciplinary CS infection-prevention team developed guidelines and implemented bundled tactics for reducing SSI. Data for all patients who underwent CS from 2006-2008 were used to determine whether there was: 1) A difference in the incidence of SSI in white patients and those belonging to minority groups; 2) a reduction in SSI after intervention; and 3) a statistically significant difference in the incidence of SSI in the third quarter of each year as compared with the other quarters of the year. RESULTS: Of 3,418 patients who underwent CS; 1,125 (32.9%) were members of minority groups and 2,293 (67.1%) were white. Eighty (2.3%) patients developed SSI. There was no significant difference in the incidence of SSI in non-Hispanic white patients and all others (2.1% vs. 2.8%, p=0. 42). The incidence of SSI decreased significantly from 2006 (3.0%) to 2007 (2.5%) and 2008 (1.4%), (p=0.03). Surgical site infection occurred more often in the third quarter of each of the years of the study than in other quarters of each year (3.3 vs. 2.0%, p=0.038). CONCLUSIONS: Implementation of a program to reduce SSI after CS was associated with a lower incidence of SSI across all racial and ethnic groups and over time, but was not associated with a lower incidence of SSI in the third quarter of each year than in the other quarters. PMID- 24800984 TI - Statins in very elderly adults (debate). PMID- 24800985 TI - Genome-wide association study of maternal and inherited loci for conotruncal heart defects. AB - Conotruncal and related heart defects (CTDs) are a group of serious and relatively common birth defects. Although both maternal and inherited genotypes are thought to play a role in the etiology of CTDs, few specific genetic risk factors have been identified. To determine whether common variants acting through the genotype of the mother (e.g. via an in utero effect) or the case are associated with CTDs, we conducted a genome-wide association study of 750 CTD case-parent triads, with follow-up analyses in 358 independent triads. Log-linear analyses were used to assess the association of CTDs with the genotypes of both the mother and case. No association achieved genomewide significance in either the discovery or combined (discovery+follow-up) samples. However, three loci with p-values suggestive of association (p<10-5) in the discovery sample had p-values <0.05 in the follow-up sample and p-values in the combined data that were lower than in the discovery sample. These included suggestive association with an inherited intergenic variant at 20p12.3 (rs6140038, combined p = 1.0 * 10(-5)) and an inherited intronic variant in KCNJ4 at 22q13.1 (rs2267386, combined p = 9.8 * 10(-6)), as well as with a maternal variant in SLC22A24 at 11q12.3 (rs11231379, combined p = 4.2 * 10(-6)). These observations suggest novel candidate loci for CTDs, including loci that appear to be associated with the risk of CTDs via the maternal genotype, but further studies are needed to confirm these associations. PMID- 24800986 TI - Neural mechanisms underlying sexual arousal in connection with sexual hormone levels: a comparative study of the postoperative male-to-female transsexuals and premenopausal and menopausal women. AB - This study compared the brain activation patterns associated with visual sexual arousal in connection with sexual hormone levels in postoperative male-to-female (MTF) transsexuals and normal premenopausal and menopausal women using 3.0 T functional MRI. A total of 30 volunteers including 10 premenopausal women, 10 menopausal women, and 10 postoperative MTF transsexuals who had undergone sex reassignment surgery participated in this study. Brain activity was measured while viewing erotic male and female nude pictures. The free testosterone and estradiol levels of the postoperative MTF transsexuals were not in the normal range seen in normal premenopausal women, but were in range seen in menopausal women. The postoperative MTF transsexuals showed significantly higher activities in the hippocampus, parahippocampal gyrus, amygdala, putamen, globus pallidus, thalamus, and head of caudate nucleus in response to erotic male nude pictures in contrast to female pictures (P<0.005). The predominant activation areas observed in the postoperative MTF transsexuals in contrast to the menopausal women when viewing male nude pictures included the insula, hippocampus, thalamus, and putamen (P<0.005). Similar to the postoperative MTF transsexuals, the premenopausal women showed significantly higher activities than menopausal women in the insula, hippocampus, thalamus, and parahippocampal gyrus (P<0.005). This study revealed that the brain activation patterns associated with visual sexual arousal in postoperative MTF transsexuals are similar to those in premenopausal women, although the sexual hormone levels in the postoperative MTF transsexuals are in the average range of those in menopausal women. PMID- 24800987 TI - Involvement of the insular nitric oxide signaling pathway in the expression of morphine-induced conditioned place preference in rats. AB - Nitric oxide (NO) has been recently reported to play an important role in the rewarding effects of addictive drugs. The regional NO signaling in the brain, however, is not completely clear. Here, we studied the effects of insular NO signaling on the expression of morphine-induced conditioned place preference (CPP). Insular microinjection of the NO inhibitors N-nitro L-arginine methyl ester (L-NAME) and 7-nitroindazole reduced the expression of morphine-induced CPP. The NO donor molsidomine, in contrast, reversed L-NAME-induced reduction of CPP expression. These results suggest that insular NO signaling is involved in the expression of morphine-CPP. PMID- 24800988 TI - Ammonia-driven chirality inversion and enhancement in enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylate mediated by diguanidino-gamma cyclodextrin. AB - In the supramolecular photocyclodimerization of 2-anthracenecarboxylate mediated by 6(A),6(D)-diguanidino-gamma-cyclodextrin (CD), the chiral sense and enantiomeric excess of the photoproduct were dynamic functions of temperature and cosolvent to afford the (M)-anti head-to-head cyclodimer in 64% ee in aqueous methanol at -70 degrees C but the antipodal (P)-isomer in 86% ee in aqueous ammonia at -85 degrees C, while the corresponding diamino-gamma-CD host did not show such unusual photochirogenic behaviors. The ee landscape was very steep against the temperature and sign-inverted against the ammonia content to reveal the opposite temperature dependence at low and high ammonia contents, for which an altered solvent structure and/or guanidinium-carboxylate interaction mode would be responsible. PMID- 24800990 TI - Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies. AB - Comparative genomic hybridization (CGH) arrays have significantly changed the approach to identifying genetic alterations causing intellectual disability and congenital anomalies. Several studies have described the microduplication of Xp22.31, involving the STS gene. In such reports characteristic features and pathogenicity of Xp22.31 duplications remains a subject of debate. Here we present a series of nine previously unreported individuals with Xp22.31 duplications, found through microarray analysis in the course of genetic workup for developmental delay, associated with a combination of talipes anomalies, seizures and/or feeding difficulties. The size of the Xp22.31 duplications ranged from 294 kb to 1.6 Mb. We show a comparison of the breakpoints, inheritance and clinical phenotype, and a review of the literature. This clinically detailed series of Xp22.31 duplication patients provides evidence that the Xp22.31 duplication contributes to a common phenotype. PMID- 24800991 TI - Reliability of cone counts using an adaptive optics retinal camera. AB - BACKGROUND: To assess the reproducibility and repeatability of cone imaging in healthy human eyes, using the RTx-1 Adaptive Optics Retinal Camera and its proprietary cone-counting software. DESIGN: Single-centre, prospective study. PARTICIPANTS: Ten healthy adults. METHODS: Macular cones were imaged. Intrasession repeatability was assessed by comparing 10 consecutive acquisitions obtained by the same operator from each subject. For the intersession study, each subject was imaged five consecutive days. Interoperator reproducibility was also evaluated by comparing the images obtained from 10 different subjects by two independent operators. Finally, intergrader agreement was evaluated by comparing the cone counts measured by two masked graders. MAIN OUTCOME MEASURES: Mean cone density (cells/mm(2) ), spacing between cells (MUm) and percentage of cones with six neighbours calculated on Voronoi diagrams were measured. Correlation coefficients, intraclass correlation coefficients, and coefficients of variation were calculated. RESULTS: Correlation coefficient and intraclass correlation coefficient were respectively 0.81 and 0.96 between operators, and 0.97 and 0.98 between the two graders. The intrasession and intersession coefficients of variation were under 7%. The percentage of cells with six neighbours and the spacing between cones varied in the same proportion (coefficients of variation ranged from 1.66 to 10.05%). CONCLUSIONS: Overall, the test-retest variability of RTx-1 and its software was good in normal human eyes. Further studies in the normal clinical setting are mandatory. PMID- 24800992 TI - Bone microstructure and regional distribution of osteoblast and osteoclast activity in the osteonecrotic femoral head. AB - OBJECTIVE: To detect and compare the bone microstructure and osteoblast and osteoclast activity in different regions of human osteonecrotic femoral heads. METHODS: Osteonecrotic femoral heads were obtained from 10 patients (6 males, 4 females; Ficat IV) undergoing total hip arthroplasty between 2011 and 2013. The samples were divided into subchondral bone, necrotic, sclerotic, and healthy regions based on micro-computed tomography (CT) images. The bone microstructure, micromechanics, and osteoblast and osteoclast activity were assessed using micro CT, pathology, immunohistochemistry, nanoindentation, reverse transcription polymerase chain reaction (RT-PCR), tartrate-resistant acid phosphatase staining and Western blotting. RESULTS: (1) The spatial structure of the bone trabeculae differed markedly in the various regions of the osteonecrotic femoral heads. (2) The elastic modulus and hardness of the bone trabeculae in the healthy and necrotic regions did not differ significantly (P >0.05). (3) The subchondral bone and necrotic region were positive on TRAP staining, while the other regions were negative. (4) On immunohistochemical staining, RANK and RANKL staining intensities were increased significantly in the subchondral bone and necrotic region compared with the healthy region, while RUNX2 and BMP2 staining intensities were increased significantly in the sclerotic region compared with the necrotic region. (5) OPG, RANK, RANKL, RUNX2, BMP2, and BMP7 protein levels were greater in the necrotic and sclerotic region than in subchondral bone and the healthy region. CONCLUSION: The micromechanical properties of bone trabeculae in the necrotic region did not differ significantly from the healthy region. During the progress of osteonecrosis, the bone structure changed markedly. Osteoclast activity increased in subchondral bone and the necrotic region while osteoblast activity increased in the sclerotic region. We speculate that the altered osteoblast and osteoclast activity leads to a reduction in macroscopic mechanical strength. PMID- 24800993 TI - Sexual dysfunction in heart failure patients. AB - Heart failure has a severe impact on different aspects of a patient's life, including sexual function. Sexual problems are common in heart failure (HF) patients, both in men and women, and are not always adequately addressed and treated in the current health care system. Several factors have been described to be related to sexual problems, such as activity intolerance, psychological factors, physiological factors, cardiac medications, recreational habits and co morbidity. The current review summarizes knowledge that can help clinicians treat sexual dysfunction in HF patients. After a good assessment, several steps are advised, including improving HF and co-morbid conditions, discussing psychosocial problems, worries and misunderstandings, managing risk factors and considering PDE-5 inhibitors or other libido enhancing agents. PMID- 24800994 TI - Effects of additional iron doses on hepcidin-25 level in hemodialysis patients without evident iron deficiency. AB - BACKGROUND: Serum hepcidin-25 is not only a marker of iron stores, but also an acute phase reactant, and it could fluctuate in response to erythropoietic activity. STUDY DESIGN: Prospective interventional, 3-months duration, investigating the influence of additional intravenous (IV) iron on hepcidin-25 in hemodialysis (HD) patients without obvious iron deficiency (ID). SETTINGS AND PARTICIPANTS: Single HD unit, 41 patients. MEASUREMENTS: Hepcidin-25 (ELISA method), ferritin, transferrin, transferrin saturation (TSAT), C-reactive protein and serum albumin--at baseline and assessment; hemoglobin, iron and darbepoetin doses--monthly. INTERVENTION: Additional IV iron doses were administered, driven by hemoglobin trend: iron dose increased by 25 % for each 0.5 g/dL hemoglobin drop for baseline ferritin of 200-800 ng/mL. Iron was discontinued for stable hemoglobin or >13 g/dL. Darbepoetin doses were adjusted for 11 g/dL target hemoglobin. RESULTS: At baseline, 21 % of patients had "optimal" iron status; none had "absolute" or "functional" ID, while 15 % had iron "overload." Hepcidin levels were 112.8 (95 % CI 105.3-121.8) ng/mL. Hemoglobin was within the target range. After 75 % augmentation in iron doses, hepcidin-25 decreased by 70 %. Transferrin increased, and TSAT and ferritin decreased. Prevalence of "functional" ID rose to 24 % and of iron "overload" declined to 0 %. Reversal of iron-restricted erythropoiesis was further sustained by unchanging hemoglobin and decrease in darbepoetin doses and darbepoetin resistance index. Reasonable associations between assessment versus baseline ratios for hepcidin-25 and transferrin (inverse), TSAT and ferritin (direct) were found. Despite the increased inflammation, decrease in transferrin and increase in ferritin ratios were independent predictors of hepcidin variability (model of logistic regression r (2) 0.34; p < 0.0001). LIMITATIONS: Low number of participants, less diabetic nephropathy/vascular diseases than general dialyzed population, uncontrolled design, use of hepcidin-25 ELISA assay. CONCLUSIONS: Activation of erythropoiesis by additional IV iron administration overcomes moderate inflammation in suppressing hepcidin-25. Thus, hepcidin-25 could be clinically useful to evaluate iron status in patients with renal anemia. PMID- 24800995 TI - Truncated splice variant PGC-1alpha4 is not associated with exercise-induced human muscle hypertrophy. AB - INTRODUCTION: A truncated PGC-1alpha splice variant (PGC-1alpha4) has been implicated in the regulation of resistance exercise (RE)-induced muscle hypertrophy, and basal expression levels said to be augmented in response to concurrent aerobic (AE) and RE training. AIM: The current study investigated human muscle truncated and non-truncated PGC-1alpha transcripts in response to both acute and chronic RE, and with or without preceding AE (AE+RE). METHODS: Ten men performed 5 weeks of unilateral AE+RE and RE training. Before (untrained) and after (trained) this intervention, PGC-1alpha transcripts were assessed in vastus lateralis muscle biopsies obtained before and 3 h after acute RE, with or without preceding AE. Additionally, samples were collected 72 h after the last exercise bout of the training programme. RESULTS: The truncated splice variant increased (P < 0.05) its expression after acute exercise regardless of mode. However, the expression was greater (P < 0.05) after AE+RE than RE. Other PGC-1alpha transcripts showed similar response. Truncated transcripts originated from both the alternative and proximal promoter, and AE+RE increased PGC-1alpha expression from both promoter sites. RE induced transcripts from the alternative promoter only. PGC-1alpha expressions after acute exercise were comparable across isoforms in both untrained and trained muscle. Steady-state levels of isoforms were unchanged after 5-week training (P > 0.05). Exercise-induced expression of PGC 1alpha variants did not correlate with changes in muscle size or strength (P > 0.05). CONCLUSION: Our results do not support the view that truncated PGC-1alpha coordinates exercise-induced hypertrophy in human skeletal muscle. Rather, all PGC-1alpha isoforms appear to be regulated transiently in response to acute exercise and regardless of mode. PMID- 24800997 TI - Goal conflict and goal facilitation in community-based cardiac rehabilitation: a theory-based interview study. AB - Theories often consider behaviors in isolation of conflicting and facilitating personal goals. We conducted interviews with 13 people in cardiac rehabilitation, investigating whether eliciting physical activity (PA) control beliefs sufficiently captures goal conflict and goal facilitation. We assessed PA, intention, and control beliefs using standard elicitation methods and then assessed goal conflict and goal facilitation. Twelve participants described conflicting, and all described facilitating, personal goals. Most goal facilitation (94%) and conflict (82%) beliefs were identified beyond the control belief elicitation. Goal facilitation and conflict are not captured in a standard control belief elicitation and may supplement single-behavior models to understand PA. PMID- 24800998 TI - Different pharmacokinetic and pharmacodynamic properties of recombinant follicle stimulating hormone (rFSH) derived from a human cell line compared with rFSH from a non-human cell line. AB - Pharmacokinetic and pharmacodynamic properties of a novel recombinant follicle stimulating hormone (rFSH) preparation (FE 999049), expressed by a human cell line (PER.C6), was compared with an rFSH preparation (follitropin alpha) expressed by a Chinese hamster ovary (CHO) cell line in healthy pituitary suppressed women. Following single intravenous administration of 225 IU (Steelman Pohley assay), the clearance was lower, 0.31 versus 0.44 L/h, for FE 999049 than for follitropin alpha. Likewise, the apparent clearance after repeated daily subcutaneous administrations was lower, 0.58 versus 0.99 L/h, and AUC and C(max) higher, 1.7- and 1.6-fold. The absolute bioavailability after a single subcutaneous dose of 450 IU was similar for both preparations, 60-65%. After repeated subcutaneous administration the elimination half-life was approximately 30 and 24 hours for FE 999049 and follitropin alpha. The ovarian responses by number of follicles and serum concentrations of inhibin B and estradiol, were higher with FE 999049 than with follitropin alpha, AUC and C(max) for the two latter being >1.6-fold greater with FE 999049 than with follitropin alpha. These results indicate that administration of equal doses of FE 999049, expressed in a human cell line, and follitropin alpha, expressed in a CHO cell line, display different pharmacokinetic and pharmacodynamic properties in humans. PMID- 24801000 TI - Suburothelial interstitial cells. AB - The suburothelium has received renewed interest because of its role in sensing bladder fullness. Various studies evaluated suburothelial myofibroblasts (MFs), interstitial cells (ICs), interstitial Cajal cells (ICCs) or telocytes (TCs), which resulted in inconsistencies in terminology and difficulties in understanding the suburothelial structure. In order to elucidate these issues, the use of electron microscopy seems to be an ideal choice. It was hypothesized that the cell population of the suburothelial band is heterogeneous in an attempt to clarify the above-mentioned inconsistencies. The suburothelial ICs of the bladder were evaluated by immunohistochemistry (IHC) and transmission electron microscopy (TEM). Bladder samples from 6 Wistar rats were used for IHC and TEM studies and human bladder autopsy samples were used for IHC. Desmin labeled only the detrusor muscle, while all the myoid structures of the bladder wall were positive for alpha-smooth muscle actin (SMA). A distinctive alpha-SMA-positive suburothelial layer was identified. A layered structure of the immediate suburothelial band was detected using TEM: (1) the inner suburothelial layer consisted of fibroblasts equipped for matrix synthesis; (2) the middle suburothelial layer consisted of smooth muscle cells (SMCs) and myoid ICCs, and (3) the outer suburothelial layer consisted of ICs with TC morphology, building a distinctive network. In conclusion, the suburothelial layer consists of distinctive types of ICs but not MFs. The myoid layer, with SMCs and ICCs, which could be considered identical to the alpha-SMA-positive cells in the suburothelial band, seems the best-equipped layer for pacemaking and signaling. Noteworthy, the network of ICs also seems suitable for stromal signaling. PMID- 24801001 TI - Beauty of lotus is more than skin deep: highly buoyant superhydrophobic films. AB - We develop highly buoyant superhydrophobic films that mimic the three-dimensional structure of lotus leaves. The high buoyancy of these structure stems from mechanically robust bubbles that significantly reduce the density of the superhydrophobic films. These highly buoyant superhydrophobic films stay afloat on water surface while carrying a load that is more than 200 times their own weight. In addition to imparting high buoyancy, the incorporation of robust hydrophilic bubbles enables the formation of free-standing structures that mimic the water-collection properties of Namib Desert beetle. We believe the incorporation of robust bubbles is a general method that opens up numerous possibilities in imparting high buoyancy to different structures that needs to stay afloat on water surfaces and can potentially be used for the fabrication of lightweight materials. (Image on the upper left reproduced with permission from Yong, J.; Yang, Q.; Chen, F.; Zhang, D.; Du, G.; Si, J.; Yun, F.; Hou, X. A Bioinspired Planar Superhydrophobic Microboat. J. Micromech. Microeng. 2014, 24, 035006). PMID- 24800999 TI - Who has used internal company documents for biomedical and public health research and where did they find them? AB - OBJECTIVE: To describe the sources of internal company documents used in public health and healthcare research. METHODS: We searched PubMed and Embase for articles using internal company documents to address a research question about a health-related topic. Our primary interest was where authors obtained internal company documents for their research. We also extracted information on type of company, type of research question, type of internal documents, and funding source. RESULTS: Our searches identified 9,305 citations of which 357 were eligible. Scanning of reference lists and consultation with colleagues identified 4 additional articles, resulting in 361 included articles. Most articles examined internal tobacco company documents (325/361; 90%). Articles using documents from pharmaceutical companies (20/361; 6%) were the next most common. Tobacco articles used documents from repositories; pharmaceutical documents were from a range of sources. Most included articles relied upon internal company documents obtained through litigation (350/361; 97%). The research questions posed were primarily about company strategies to promote or position the company and its products (326/361; 90%). Most articles (346/361; 96%) used information from miscellaneous documents such as memos or letters, or from unspecified types of documents. When explicit information about study funding was provided (290/361 articles), the most common source was the US-based National Cancer Institute. We developed an alternative and more sensitive search targeted at identifying additional research articles using internal pharmaceutical company documents, but the search retrieved an impractical number of citations for review. CONCLUSIONS: Internal company documents provide an excellent source of information on health topics (e.g., corporate behavior, study data) exemplified by articles based on tobacco industry documents. Pharmaceutical and other industry documents appear to have been less used for research, indicating a need for funding for this type of research and well-indexed and curated repositories to provide researchers with ready access to the documents. PMID- 24801007 TI - Circulating FGF23 levels in response to acute changes in plasma Ca(2+). AB - The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate homeostasis are closely interrelated, and it is therefore likely that Ca is involved in FGF23 regulation. It has recently been reported that dietary Ca influenced FGF23 levels, with high Ca increasing FGF23. The mechanism remains to be clarified. It remains unknown whether acute changes in plasma Ca influence FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion and hypocalcemia by infusion of ethylene glycol tetraacetic acid (EGTA) in normal and acutely parathyroidectomized rats. Intact plasma FGF23 and intact plasma PTH and plasma Ca(2+) and phosphate were measured. Acute hypercalcemia and hypocalcemia resulted as expected in adequate PTH secretory responses. Plasma FGF23 levels remained stable at all plasma Ca(2+) levels; acute parathyroidectomy did not affect FGF23 secretion. In conclusion, Ca is not a regulator of acute changes in FGF23 secretion. PMID- 24801009 TI - Food-and-beverage environment and procurement policies for healthier work environments. AB - The importance of creating healthier work environments by providing healthy foods and beverages in worksite cafeterias, in on-site vending machines, and at meetings and conferences is drawing increasing attention. Large employers, federal and state governments, and hospital systems are significant purchasers and providers of food and beverages. The American Heart Association, federal government, and other organizations have created procurement standards to guide healthy purchasing by these entities. There is a need to review how procurement standards are currently implemented, to identify important minimum criteria for evaluating health and purchasing outcomes, and to recognize significant barriers and challenges to implementation, along with success stories. The purpose of this policy paper is to describe the role of food-and-beverage environment and procurement policy standards in creating healthier worksite environments; to review recently created national model standards; to identify elements across the standards that are important to consider for incorporation into policies; and to delineate issues to address as standards are implemented across the country. PMID- 24801008 TI - Combinatorial photothermal and immuno cancer therapy using chitosan-coated hollow copper sulfide nanoparticles. AB - Near-infrared light-responsive inorganic nanoparticles have been shown to enhance the efficacy of cancer photothermal ablation therapy. However, current nanoparticle-mediated photothermal ablation is more effective in treating local cancer at the primary site than metastatic cancer. Here, we report the design of a near-infrared light-induced transformative nanoparticle platform that combines photothermal ablation with immunotherapy. The design is based on chitosan-coated hollow CuS nanoparticles that assemble the immunoadjuvants oligodeoxynucleotides containing the cytosine-guanine (CpG) motifs. Interestingly, these structures break down after laser excitation, reassemble, and transform into polymer complexes that improve tumor retention of the immunotherapy. In this "photothermal immunotherapy" approach, photothermal ablation-induced tumor cell death reduces tumor growth and releases tumor antigens into the surrounding milieu, while the immunoadjuvants potentiate host antitumor immunity. Our results indicated that combined photothermal immunotherapy is more effective than either immunotherapy or photothermal therapy alone against primary treated and distant untreated tumors in a mouse breast cancer model. These hollow CuS nanoparticles are biodegradable and can be eliminated from the body after laser excitation. PMID- 24801010 TI - Learning to keep your cool: reducing aggression through the experimental modification of cognitive control. AB - Prior research suggests that recruiting cognitive control resources following exposure to hostile stimuli may allow individuals to more effectively override their aggressive urges. In the current study, a cognitive modification procedure was developed to encourage participants to perform this cognitive operation. It successfully encouraged cognitive control recruitment following hostile primes. More importantly, this procedure allowed individuals prone to hostile attributions to override their aggressive urges. Interestingly, it also led to a slight increase in aggression at low levels of hostile attributions. Discussion focused on theoretical and practical implications of the hypothesised effect, as well as possible explanations for the non-hypothesised effect. PMID- 24801011 TI - Characterization of the NT2-derived neuronal and astrocytic cell lines as alternative in vitro models for primary human neurons and astrocytes. AB - Primary human fetal neurons and astrocytes (HFNs and HFAs, respectively) provide relevant cell types with which to study in vitro the mechanisms involved in various human neurological diseases, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. However, the limited availability of human fetal cells poses a significant problem for the study of these diseases when a human cell model system is required. Thus, generating a readily available alternative cell source with the essential features of human neurons and astrocytes is necessary. The human teratoma-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal and glial cells can be generated. Nevertheless, a direct comparison of NT2 neurons and primary HFNs in terms of their morphology physiological and chemical properties is still missing. This study directly compares NT2-derived neurons and primary HFNs using immunocytochemistry, confocal calcium imaging, high-performance liquid chromatography, and high-content analysis techniques. We investigated the morphological similarities and differences, levels of relevant amino acids, and internal calcium fluctuations in response to certain neurotransmitters/stimuli. We also compared NT2-derived astrocytes and HFAs. In most of the parameters tested, both neuronal and astrocytic cell types exhibited similarities to primary human fetal neurons and astrocytes. NT2-derived neurons and astrocytes are reliable in vitro tools and a renewable cell source that can serve as a valid alternative to HFNs/HFAs for mechanistic studies of neurological diseases. PMID- 24801012 TI - Comparative efficacy and safety of the Ambu((r)) AuraOnce(TM) laryngeal mask airway during general anaesthesia in adults: a systematic review and meta analysis. AB - Previous comparisons between the Ambu((r)) AuraOnce(TM) and other laryngeal mask airways have revealed different results across various clinical studies. We aimed to perform a systematic review with meta-analysis on the efficacy and safety of the AuraOnce compared with other laryngeal mask airways for airway maintenance in adults undergoing general anaesthesia. Our search of PubMed, PubMed Central, Scopus and the Central Register of Clinical Trials of the Cochrane Collaboration yielded nine randomised controlled trials eligible for inclusion. Comparator laryngeal mask airways were the LMA Unique(TM) (four trials), the LMA Classic((r)) (five trials) and the Portex((r)) Soft Seal((r)) (three trials). The AuraOnce provided an oropharyngeal leak pressure higher than the LMA Unique (304 participants, mean (95% CI) difference 3.1 (1.6-4.7) cmH2 O, p < 0.0001) and equivalent to the LMA Classic. The Soft Seal provided a higher leak pressure than the AuraOnce (229 participants, mean (95% CI) difference 3.5 (0.4-6.7) cmH2 O, p = 0.03). Insertion was significantly faster with the AuraOnce than the LMA Unique (304 participants, mean (95% CI) difference 5.4 (2.1-8.71) s, p = 0.001) and Soft Seal (229 participants, mean (95% CI) difference 9.5 (3.0-15.9) s, p = 0.004), but similar to the LMA Classic. The first-insertion success rate of the AuraOnce was equivalent to the LMA Unique, LMA Classic and Soft Seal. We found a higher likelihood of bloodstaining on the cuff with the Soft Seal and a higher incidence of sore throat with the LMA Classic. We conclude that the AuraOnce is an effective alternative to the LMA Classic and LMA Unique, and easier to insert than all three other devices studied. PMID- 24801013 TI - The evolving dynamics of the microbial community in the cystic fibrosis lung. AB - The cystic fibrosis (CF) lung is a niche colonized by a diverse group of organisms, with a more limited number of species including Pseudomonas aeruginosa dominating in adult patients. Whether all members of this microbial community play a direct or indirect role in pulmonary decline has yet to be fully elucidated, but investigations of their interactions with both co-colonizing species and with host cells are beginning to shed light on their virulence potential. It is also emerging that some microbial species within this community adapt as chronic infection is established to survive the hostile environment of the lung, to minimize host clearance and to resist therapeutic intervention. This review highlights the recent developments in CF microbiology focusing on the cooperative, competitive and adaptive interactions of established and emerging pathogens in the lung microbiome. PMID- 24801014 TI - The policy of placing older donors into older recipients: is it worth the risk? AB - BACKGROUND: To expand the donor pool, older donors (>=50 yr) are frequently used in older recipients (>=60 yr). Older recipients and those receiving older donor hearts have independently displayed decreased post-transplant survival. However, outcomes in older patients receiving older donor hearts are contentious. METHODS: Eight hundred and seventy-nine heart transplant patients between 2000 and 2010 were analyzed, excluding patients with donor coronary artery disease. From 380 patients >=60 yr, 327 patients with donors <50 yr old were compared with 53 patients with donors >=50 yr old for: five-yr actuarial survival, freedom from cardiac allograft vasculopathy (CAV: stenosis >=30%), non-fatal major adverse cardiac events (NF-MACE: MI, CHF, stroke, need for pacemaker/ICD), one-yr freedom from any treated rejection. RESULTS: The older vs. younger donor group demonstrated significantly lower five-yr survival (57% vs. 85%, p < 0.001) and freedom from CAV (83% vs. 92%, p = 0.03). No difference was observed in five-yr freedom from NF-MACE and one-yr freedom from any treated rejection. Multivariate analysis found donor age >=50 to be an independent risk factor for death (HR 1.8, CI 1.1-2.9, p = 0.008) and CAV (HR 1.9, CI 1.2-2.9, p = 0.004). CONCLUSIONS: Use of older donors (>=50 yr) in older recipients (>=60 yr) results in lower five-yr survival and freedom from CAV. Caution is required in these cases. Larger studies are warranted to confirm findings. PMID- 24801015 TI - Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. AB - Diagnosis and classification of acute myeloid leukemia (AML) are based on morphology and genetics. An increasing number of gene mutations have been found, and some are used for risk classification in AML patients with normal karyotype (cytogenetically normal (CN)-AML). In this systematic review and meta-analysis, we examined three frequent mutations in CN-AML: mutations of fms-related tyrosine kinase 3 (FLT3-ITD), mutated nucleophosmin (NPM1), and mutations of the CCAAT enhancer-binding protein alpha (CEBPA) gene. A systematic literature search of publications listed in the electronic databases (Embase, Pubmed, Healthstar, BIOSIS, ISI Web of Knowledge and Cochrane) from 2000 up to March 2012 was performed (Fig. 1). Nineteen studies were included and qualitatively analyzed. Two to four studies entered the quantitative meta-analysis incorporating 1,378 to 1,942 patients with CN-AML. Meta-analysis for overall survival (OS) and relapse free survival (RFS) showed FLT3-ITD to predict an unfavorable prognosis, with hazard ratios (HR) of 1.86 and 1.75, respectively. In contrast, meta-analysis of the impact of NPM1 and CEBPA mutations on OS yielded an HR of 0.56 for each mutation, while analysis of impact on RFS produced HRs of 0.37 and 0.42, respectively. This systematic review and meta-analysis aimed to evaluate the prognostic value of mutations in the NPM1, CEBPA, and FLT3 genes. FLT3-ITD was associated with worse prognosis, whereas mutations in NPM1 and CEBPA genes were associated with a favorable prognosis. PMID- 24801016 TI - Different clones of acute leukemia after successful treatment of Hodgkin's disease. PMID- 24801017 TI - Disappearance of fibrosis in secondary myelofibrosis after ruxolitinib treatment: new endpoint to achieve? PMID- 24801019 TI - Acceptability and feasibility of a culturally tailored Internet-delivered intervention to promote blood donation in Blacks. AB - INTRODUCTION: A pilot test of a computer-tailored intervention designed to promote blood donation among Blacks was conducted. METHOD: Intervention content, based on the transtheoretical model, offered participants individually and culturally tailored information on blood donation with emphasis on need specific to race (e.g., sickle-cell disease). Black adults (N = 150) with a diversity of blood donation experience were recruited from a blood center and a survey recruitment website. Posttest assessment included a 14-item evaluation and transtheoretical model questions. RESULTS: Participants rated the program positively (81.3% to 98.7% of participants agreeing or strongly agreeing with evaluation items). For example, 98.7% of respondents reported that the program gave sound advice and that personal feedback was easily understood, and 87.3% felt the program was designed for people like themselves. Ninety-five percent of participants reported that they would recommend the program to others. There were no significant differences in ratings based on demographics. Qualitative responses support program acceptability. Furthermore, pre- and postprogram assessments indicated an increase in intention to donate, t(149) = 3.56, p = .001, d = .29. DISCUSSION: With acceptability and feasibility confirmed, the next steps are to test efficacy and cost-effectiveness for use to increase blood donation, particularly in priority populations. PMID- 24801020 TI - Awareness of media-based antitobacco messages among a community sample of LGBT individuals. AB - PURPOSE: Study objectives were to measure awareness of general antitobacco messages in LGBT-focused and general media outlets among LGBT (lesbian, gay, bisexual, and transgender) individuals and to examine associations between sociodemographic characteristics and awareness levels. METHOD: Data were based on cross-sectional survey data from a racially diverse sample of participants (N = 726). Participants were primarily male (69.3%), with smaller percentages of female (21.8%) and transgender (8.9%). The median age was 31 years. RESULTS: A higher proportion of participants reported awareness of antitobacco messages in general media outlets compared to LGBT-specific media outlets. Awareness of antitobacco messages in general media was positively associated with current smoking and negatively associated with female gender and Latino ethnicity. Awareness of antitobacco messages in LGBT media was positively associated with younger age, current smoking, frequent reading of LGBT newspapers or magazines, and frequent attendance at LGBT bars and negatively associated with Latino ethnicity. CONCLUSIONS: Despite frequent readership, awareness of antitobacco messages in LGBT newspapers/magazines was quite low. We speculate that low awareness is related to the absence of antitobacco messages in LGBT-related media. LGBT-specific media outlets provide an important opportunity for future antitobacco campaigns. PMID- 24801022 TI - [Cancer cells and their environments: friends and foes]. PMID- 24801021 TI - CDR3 analysis of TCR Vbeta repertoire of CD8+ T cells from chickens infected with Eimeria maxima. AB - CD8(+) T cells play a major role in the immune protection of host against the reinfection of Eimeria maxima, the most immunogenic species of eimerian parasites in chickens. To explore the dominant complementarity-determining regions 3 (CDR3) of CD8(+) T cell populations induced by the infection of this parasite, sequence analysis was performed in this study for CDR3 of CD8(+) T cells from E. maxima infected chickens. After 5 days post the third or forth infection, intraepithelial lymphocytes were isolated from the jejunum of bird. CD3(+)CD8(+) T cells were sorted and subjected to total RNA isolation and cDNA preparation. PCR amplification and cloning of the loci between Vbeta1 and Cbeta was conducted for the subsequent sequencing of CDR3 of T cell receptor (TCR). After the forth infection, 2 birds exhibited two same frequent TCR CDR3 sequences, i.e., AKQDWGTGGYSNMI and AGRVLNIQY; while the third bird showed two different frequent TCR CDR3 sequences, AKQGARGHTPLN and AKQDIEVRGPNTPLN. No frequent CDR3 sequence was detected from uninfected birds, though AGRVLNIQY was also found in two uninfected birds. Our result preliminarily demonstrates that frequent CDR3 sequences may exist in E. maxima immunized chickens, encouraging the mining of the immunodominant CD8(+) T cells against E. maxima infection. PMID- 24801023 TI - [Use of RNAi in the treatment of hereditary amyloidosis due to mutation of transthyretin]. PMID- 24801024 TI - [Sex and memory: what yeast can teach us]. PMID- 24801025 TI - [A versatile ubiquitin ligase: guardian of mitochondrial quality and antibacterial immunity?]. PMID- 24801026 TI - [Identification of progenitors of the foetal intestinal epithelium]. PMID- 24801027 TI - [Tumor relapse: what makes you stronger can kill you]. PMID- 24801028 TI - [The tumoral microenvironment: feeding resources, battle field and therapeutic target in cancer]. AB - Tumors grow surrounded by a complex cellular and tissular microenvironment. Its components influence disease outcome, some accelarating growth and invasion and others blocking it. From the very first steps leading a normal tissue to dysplasia, followed by a benign tumor which may become locally invasive and metastatic, interactions between the transformed cells and their microenvironment direct the evolution of this process. Chronic inflammation in a tissue favors tumor first appearance which then accentuate the nutritional and energetic properties of their microenvironment by producing neoangiogenic, immunosuppressive and inflammatory molecules. In contrast a strong memory Th1/cytotoxic reaction can prevent the transition from benign to malignant tumors and control cancer invasivness and metastasis. Knowledge of these multiple phenomena, discussed in the different articles of the present issue has a major clinical impact, since new prognostic tests and efficient novel therapeutic approaches which target the tumor microenvironment are actively developed. PMID- 24801029 TI - [Emerging notions about the microenvironmental control of tumor growth and dissemination]. AB - In spite of a good understanding of the cellular and molecular mechanisms responsible for neoplastic transformation, most cancer therapies remain partially effective and transient. Recent studies established the importance of the tumor microenvironment in tumor growth and dissemination, and in the resistance to antitumor therapies. This review summarizes our current knowledge of the local and systemic effects, sometimes surprising, which result from interactions between neoplastic cancer cells and their microenvironment. PMID- 24801030 TI - [Tumor microenvironment and the pathologist: looking at what we just see]. AB - Owing to the phenomenal advances in molecular technology, the past few years have seen drastic improvements in the knowledge of tumor biology. Whilst efforts are still focused on the cancer cell, it is now clear that analysis of the tumor microenvironment plays a major role in the management of cancer. Known for years as the "stroma reaction", tumor microenvironment was commonly used by pathologists as helpful criteria to establish the diagnostic of histological subtypes. More recently however, research on tumor microenvironment (and immune response in particular) has provided numerous evidences to support a leading role in the assessment of cancer prognosis, and open new avenues in treatment of cancer patients. Prognostic and/or predictive biomarkers issued from this research will have to get through the validation process required by international consensus conferences before any implementation in clinical practice. PMID- 24801031 TI - [The early steps of the metastatic process]. AB - Metastasis is the main cause of cancer-related death. While the development of clinically detectable metastases occurs only at late time points, recent data obtained in mice and humans indicate that cancer cell dissemination is an early event in the progression of several types of cancer. However, disseminated cancer cells can remain dormant for prolonged periods of time. Then, how do cancer cells acquire the ability to disseminate so early? What are the selective pressures driving their dissemination? What are the signals controlling dormancy and why do some cancer cells eventually escape these controls? The present review presents our current understanding on these questions and how this novel paradigm could be translated to the clinic. PMID- 24801032 TI - [The tumoral stroma, a breeding ground for cancer cells]. AB - Carcinomas are constituted by malignant epithelial cells and the tumor microenvironment also called tumoral stroma. The present non-exhaustive review will focus on cellular and molecular key events implicating cancer-associated fibroblasts (CAF) and the extracellular matrix (ECM) in the stroma remodeling processes occuring during tumor invasive steps. We will also discuss the place of the stroma in the cancerology today, the recent progresses done and its usefulness to design new therapies. PMID- 24801033 TI - [Carcinoma-associated fibroblasts in cancer: the great escape]. AB - Cellular and molecular crosstalks between cancer and non-cancer tumor-associated cells result in tumor growth and metastatic spreading. During carcinoma development, tumor cells secrete signaling molecules that influence the surrounding non-cancer cells, which, in return, favor tumor cell growth, survival, migration and metastasis. Carcinoma-associated fibroblasts (CAF) are the most abundant population of non-cancer cells found in tumors, and their presence is often associated with poor clinical prognosis. Here, we summarize the pro-carcinogenic roles of CAF cells during carcinogenesis, with a specific focus on their abilities to drive cancer cell-dependent pro-invasive extracellular matrix remodeling. PMID- 24801034 TI - [Adipose tissue and cancer: a high risk tandem]. AB - Adipose tissue is found in close proximity whith many invasive cancers. In breast cancer, early local tumour invasion results in close interactions of cancer cells with fully differentiated adipocytes. Aside from their energy-storing function, mature adipocytes are also active endocrine cells prone to influence tumour behaviour through heterotypic signaling processes. After a short description of anatomical depots specificities of adipose tissue, we describe the phenotypic changes induced by tumor secretion in tumour-surrounding adipocytes. These cells (that we named CAA for cancer-associated adipocytes) by their ability to secrete pro-inflammatory cytokines, extra-cellular matrix proteins and proteases involved in its remodeling, as well as to release free fatty acid, stimulate tumor proliferation, invasiveness and drug resistance. These results support the concept that adipocytes participate in a deleterious crosstalk with cancer cells to support tumour progression, that might be amplified in obesity conditions and explain the poor prognosis of cancers observed in this subset of patients. PMID- 24801035 TI - [Stromal exosomes allow cancer cell autoactivation]. AB - Exosomes are small vesicles derived from endosomes and carrying several constituants of the cell; if captured by other neighbour cell types, they can trigger novel functions in these cells. We illustrate here (through recently published results) how exosomes released by activated tumor-associated fibroblasts are able to induce in cancer cells a signalling pathway key to the acquisition of motility and hence metastatic property. PMID- 24801036 TI - [Blood vessels in cancer: can't stop whispering]. AB - Tumor initiation and progression is a complex process in which cells acquire aberrant proliferation, survival and migration properties, and the ability to form a dedicated blood vessel network. Recent studies highlighted the existence of an active crosstalk between endothelial cells and the tumor mass. Indeed, cancer stem-like cells have been identified and found in the vicinity of blood vessels, and the latter has been proposed to act as a feeding bed for tumors, especially governing the fate of cancer stem-like cells. Here, we present an overview of the direct interplay between endothelial and cancer cells. We will first introduce the mechanisms involved in tumor angiogenesis. How the microenvironment impacts on endothelial plasticity will next be detailed, focusing on the tumor main secreted factors. Finally, the role of the vascular niche and its angiocrine factors in tumorigenesis will be addressed. PMID- 24801037 TI - [ROS and NADPH oxidase: key regulators of tumor vascularisation]. AB - Oxidative stress is the result of an imbalance between the production of reactive oxygen species (ROS) and antioxidant mechanisms. It is characterized by damage of all cellular components, DNA, proteins, lipids. ROS are nevertheless important for the physiology of an organism, as they are involved in the innate immune defense and several intracellular signaling pathways. They play an important role in tumorigenesis by promoting tumor vasculature, which is essential to their growth and metastatic processes. There are many sources of ROS in the cells, but the NOX enzymes (NADPH oxidase-dependent) are now recognized to have a major role in the oxidative stress process. Indeed, they are present in many tissues where their only function is to produce ROS. This article discusses the NOX in endothelial cells and their role in the tumor angiogenesis. PMID- 24801038 TI - [Tumor hypoxia: a key player in the regulation of stromal and anti-tumor responses]. AB - Hypoxia is a major feature of most solid tumors. Cells adapt to lower oxygen availability by stabilizing HIF transcription factors, which in turn activate the expression of many genes resulting in the survival and maintenance of cellular functions. In tumor cells, exposure to hypoxic stress results in the activation, via the HIF factors, of a series of genes enabling tumor cells to resist to killing by cytotoxic effectors of the immune system. Tissue hypoxia also controls the functions and differentiation of immune cells. This review describes the hypoxia-induced mechanisms of tumor resistance to killing by cytotoxic effectors, and the functional effects of hypoxia on the immune cells. PMID- 24801039 TI - [Tumor microenvironment: regulatory cells and immunosuppressive cytokines]. AB - Immunosuppression is a mechanism developed by cancer cells to help them escape the immune system. Immunosuppression involves expansion of various cell types and production of a variety of cytokines. In this review, we explore the duality of three cancer induced cell populations, regulatory T lymphocytes, Th17 lymphocytes and MDSC, and also the pleiotropic effects of several cytokines induced during cancer development. PMID- 24801040 TI - [The intestinal microbiota: a boost for antitumor treatments]. AB - Two new studies in mice, published in Science, show that the commensal bacteria populations in the gut play a key role in boosting responses to different antitumor regimens. These results argue for a rational use of antibiotics when managing infections in patients undergoing cancer therapies. PMID- 24801041 TI - [Intratumoral immune microenvironment and survival: the immunoscore]. AB - The natural history of cancer involves interactions between the tumor and the host immune system. In humans, clinical and experimental data support the existence of a natural immune response against cancer. We provided evidence that the type, the density and the location of immune cells within the tumor strongly influence the prognosis, independently of the TNM classification. We established a methodology named "immunoscore" to assess in clinical practice the immune infiltrate. An international consortium of expert laboratories is currently testing the immunoscore in routine clinical settings for cancer classification. The availability of the mmunoscore could significantly improve the prognostic assessment of patients and better guide the therapeutic decision. This could result in the implementation of the immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-immune). PMID- 24801042 TI - [Tumor microenvironment and therapeutic resistance process]. AB - Over the last decade, it has become clear that cancer is not just a disease of the genes, and that the tumor microenvironment (TME) plays an important role in cancer progression. Interactions between tumor cells and the TME, made of the extracellular matrix (ECM) and of non-transformed cells (designated here as stromal cells), promote cancer cell survival and drug resistance. Many of the mechanisms involved are known and are either contact-dependent or contact independent. Contact between tumor cells and the ECM or stromal cells as well as the production of soluble factors and microvesicles all contribute. The bone marrow plays a special role in environment-mediated drug resistance as it is not only a sanctuary protecting tumor cells from cytotoxic drugs, but also a source of many stromal cells that colonize primary tumors and contribute to the pre metastatic niche. As our understanding of the mechanisms by which the tumor microenvironment promotes therapeutic resistance progresses, clinical trials testing agents that disrupt the interaction between tumor cells and the stroma have been initiated. This new avenue of therapy is promising. PMID- 24801043 TI - [Chronic myeloid leukemia stem cells: cross-talk with the niche]. AB - The physiological hematopoietic niche located in bone marrow is a pluricellular structure whose components are now well identified. Within this microenvironment, hematopoietic stem cells are in direct contact with mesenchymal stromal cells, osteoblasts and sinusoidal endothelial cells. These close relationships drive specialized cellular functions (proliferation/quiescence, differentiation/self renewal) ensuring an efficient hematopoiesis. Chronic myeloid leukemia (CML) is a major model of leukemic hematopoiesis. The BCR-ABL1 tyrosine kinase, constitutively activated in CML, plays a critical role in the pathogenesis of the disease. An intensive cross-talk between CML progenitors and the components of the hematopoietic niche has recently been demonstrated. Consequently, the occurrence of the so-called leukemic niche promotes both the proliferation of myeloid cells and the maintenance of quiescent leukemic stem cells. This bone marrow niche could also protect CML stem cells from tyrosine kinase inhibitors and probably contribute to their resistance towards targeted therapies. PMID- 24801044 TI - [Rare variants and demographic explosion]. AB - The abundance of rare variants in human DNA is the consequence of tremendous recent expansion of our population. Careful measurement of neutral variants in a European population points to more recent and more rapid expansion than previously believed. PMID- 24801045 TI - First pregnancy events and future breast density: modification by age at first pregnancy and specific VEGF and IGF1R gene variants. AB - PURPOSE: Pregnancy characteristics have been associated with breast cancer risk, but information is limited on their relationship with breast density. Our objective was to examine the relationship between first pregnancy characteristics and later life breast density, and whether the association is modified by genotype. METHODS: The Marin Women's Study was initiated to examine breast cancer in a high-incidence mammography population (Marin County, CA). Reproductive characteristics and pregnancy information including pregnancy-induced hypertension (PIH) were self-reported at the time of mammography. Forty-seven candidate single nucleotide polymorphisms were obtained from saliva samples; seven were assessed in relation to PIH and percent fibroglandular volume (%FGV). Breast density assessed as %FGV was measured on full-field digital mammograms by the San Francisco Mammography Registry. RESULTS: A multivariable regression model including 2,440 parous women showed that PIH during first pregnancy was associated with a statistically significant decrease in %FGV (b = -0.31, 95 % CI 0.52, -0.11), while each month of breast-feeding after first birth was associated with a statistically significant increase in %FGV (b = 0.01, 95% CI 0.003, 0.02). PIH and breast-feeding associations with %FGV were modified by age at first birth. In a subsample of 1,240 women, there was evidence of modification in the association between PIH and %FGV by specific vascular endothelial growth factor (VEGF) (rs3025039) and insulin growth factor receptor-1 (IGFR1) (rs2016347) gene variants. CONCLUSION: These findings suggest that first pregnancy characteristics may exert an influence on extent of breast density later in life and that this influence may vary depending on inherited IGFR1 and VEGF genotypes. PMID- 24801046 TI - Gene-environment interactions between JAZF1 and occupational and household lead exposure in prostate cancer among African American men. AB - PURPOSE: A single nucleotide polymorphism, rs10486567, in JAZF1 has consistently been associated with increased risk of prostate cancer. The physical interaction of zinc finger proteins, such as JAZF1, with heavy metals may play a role in carcinogenesis. This study assessed potential gene-environment statistical interactions (G*E) between rs10486567 and heavy metals in prostate cancer. METHODS: In a case-only study of 228 African American prostate cancer cases, G*E between rs10486567 and sources of cadmium and lead (Pb) were assessed. Unconditional logistic regression was used to estimate interaction odds ratios (IORs), and generalized estimating equations were used for models containing nested data. Case-control validation of IORs was performed, using 82 controls frequency matched to cases on age-race. RESULTS: Among cases, a potential G*E interaction was observed between rs10486567 CC genotype and living in a Census tract with a high proportion of housing built before 1950, a proxy for household Pb exposure, when compared to CT or TT carriers (OR 1.81; 95% CI 1.04-3.16; p = 0.036). A stronger G*E interaction was observed when both housing and occupational Pb exposure were taken into account (OR 2.62; 95% CI 1.03-6.68; p = 0.04). Case-control stratified analyses showed the odds of being a CC carrier were higher in cases compared to controls among men living in areas with older housing (OR 2.03; CI 0.99-4.19; p = 0.05) or having high occupational Pb exposure (OR 2.50; CI 1.01-6.18; p = 0.05). CONCLUSIONS: In African American men, the association between JAZF1 rs10486567 and prostate cancer may be modified by exposure to heavy metals such as Pb. PMID- 24801047 TI - Insulin-like growth factor-1, growth hormone, and daily cycling estrogen are associated with mammographic density in premenopausal women. AB - BACKGROUND: Mammographic density represents epithelial and stromal proliferation, while insulin-like growth factor (IGF)-1, insulin-like growth factor-binding protein-3, growth hormone (GH), and estrogen may influence cellular proliferation. However, whether these growth factors independently, or in combination with estrogen, influence mammographic density in premenopausal women remains unclear. MATERIALS AND METHODS: Growth factors were assessed in 202 ovulating premenopausal women participating in the Energy Balance and Breast Cancer Aspects-I study. Estrogen was assessed in serum, and daily in saliva, throughout a menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms (days 7-12 of the menstrual cycle). Associations between growth factors, estrogen, and mammographic density were studied in regression models. RESULTS: Women with a mean age of 30.7 years had a mean percent mammographic density of 29.8%. Among women in the strata (above median split) of IGF-1 (>25 nmol/l) or GH (>0.80 mlU/l), we observed that an increase in salivary 17beta-estradiol was associated with a higher odds for having higher percent mammographic density (>28.5%). The odds ratios (ORs) per standard deviation increase in 17beta-estradiol were 1.81 [95% confidence interval (CI) 1.08-3.03] in the high IGF-1 stratum and 2.08 (95% CI 1.10-3.94) in the high GH stratum. Furthermore, women in these strata of growth factors (above median) who had an overall average 17beta-estradiol above median (>16.8 pmol/l) had higher ORs for having higher percent mammographic density (>28.5%): IGF-1 4.13 (95 % CI 1.33-12.83) and GH 4.17 (95 % CI 1.41-12.28). CONCLUSION: Growth factors, in combination with cycling estrogen, were associated with percent mammographic density, and may be of potential clinical relevance. PMID- 24801049 TI - High-order statistics of microtexton for HEp-2 staining pattern classification. AB - This study addresses the classification problem of the HEp-2 cell using indirect immunofluorescent (IIF) image analysis, which can indicate the presence of autoimmune diseases by finding antibodies in the patient serum. Generally, the method used for IIF analysis remains subjective, and depends too heavily on the experience and expertise of the physician. Recently, studies have shown that it is possible to identify the cell patterns using IIF image analysis and machine learning techniques. However, it still has large gap in recognition rates to the physical experts' one. This paper explores an approach in which the discriminative features of HEp-2 cell images in IIF are extracted and then, the patterns of the HEp-2 cell are identified using machine learning techniques. Motivated by the progress in the research field of computer vision, as a result of which small local pixel pattern distributions can now be highly discriminative, the proposed strategy employs a parametric probability process to model local image patches (textons: microstructures in the cell image) and extract the higher-order statistics of the model parameters for the image description. The proposed strategy can adaptively characterize the microtexton space of HEp-2 cell images as a generative probability model, and discover the parameters that yield a better fitting of the training space, which would lead to a more discriminant representation for the cell image. The simple linear support vector machine is used for cell pattern identification because of its low computational cost, in particular for large-scale datasets. Experiments using the open HEp-2 cell dataset used in the ICIP2013 contest validate that the proposed strategy can achieve a much better performance than the widely used local binary pattern (LBP) histogram and its extensions, rotation invariant co-occurrence LBP, and pairwise rotation invariant co-occurrence LBP, and that the achieved recognition error rate is even very significantly below the observed intralaboratory variability. PMID- 24801048 TI - Nature and extent of left/right axis defects in T(Wis) /T(Wis) mutant mouse embryos. AB - BACKGROUND: Mutations in the T-box gene Brachyury have well known effects on invagination of the endomesodermal layer during gastrulation, but the gene also plays a role in the determination of left/right axis determination that is less well studied. Previous work has implicated node morphology in this effect. We use the T(Wis) allele of Brachyury to investigate the molecular and morphological effects of the T locus on axis determination in the mouse. RESULTS: Similar to embryos mutant for the T allele, T(Wis) /T(Wis) embryos have a high incidence of ventral and/or reversed heart looping. In addition, heterotaxia between the direction of heart looping and the direction of embryo turning is common. Scanning electron microscopy reveals defects in node morphology including irregularity, smaller size, and a decreased number of cilia, although the cilia appear morphologically normal. Molecular analysis shows a loss of perinodal expression of genes involved in Nodal signaling, namely Cer2, Gdf1, and Nodal itself. There is also loss of Dll1 expression, a key component of the Notch signaling pathway, in the presomitic mesoderm. CONCLUSIONS: Morphological abnormalities of the node as well as disruptions of the molecular cascade of left/right axis determination characterize T(Wis) /T(Wis) mutants. Decreased Notch signaling may account for both the morphological defects and the absence of expression of genes in the Nodal signaling pathway. PMID- 24801050 TI - Dinuclear platinum complexes containing planar aromatic ligands to enhance stacking interactions with proteins. AB - In an approach to design drugs with higher affinity for pi-pi stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2 (L)}2 -MU-{trans-1,4-dach}](NO3 )4 ((A)2 =(NH3 )2 or ethylenediamine (en), L=quinoline (quin) or benzothiazole (bztz), dach=trans-1,4 diaminocyclohexane) were synthesized. The quinoline complex, [{cis-Pt(en)(quin)}2 -MU-(dach)](NO3 )4 (9) was synthesized from the precursor K[PtCl3 (quin)] (1), while the benzothiazole complexes, [{cis-Pt(A)2 (bztz)}2 -MU-(dach)](NO3 )4 ((A)2 =(NH3 )2 (10) and (A)2 =en (11)) were synthesized from the precursors cis-[Pt(A)2 Cl(bztz)] ((A)2 =(NH3 )2 (7) and (A)2 =en (8)). Their interactions with N acetyltryptophan and a model pentapeptide (N-Ac-WLDSW-OH), modeled on the pentapeptide recognition sequence (FSDLW) of p53-mdm2 interaction, were examined by fluorescence spectroscopy. The dinuclear complexes were found to be significantly stronger at quenching the fluorescence of tryptophan than their mononuclear Pt-based analogues indicating stronger binding. Molecular modeling suggests a "sandwich" mode of binding, and the flexibility of the dinuclear motif can allow the design of more selective and stronger-binding complexes. Based on these results a further prototype, [{Pt(en)(9-EtGua)}2 MU-H2 N(CH2 )6 NH2 ](4+) , incorporating the purine 9-ethylguanine (9-EtG) as a stacking moiety, was prepared which showed good cytotoxicity in A2780 and OsACL tumor cell lines. PMID- 24801051 TI - Molecular imaging of cell death in tumors. Increasing annexin A5 size reduces contribution of phosphatidylserine-targeting function to tumor uptake. AB - OBJECTIVE: Annexin A5 is a phosphatidylserine binding protein that binds dying cells in vivo. Annexin A5 is a potential molecular imaging agent to determine efficacy of anti-cancer therapy in patients. Its rapid clearance from circulation limits tumor uptake and, hence, its sensitivity. The aim of this study is to determine if non-invasive imaging of cell death in tumors will benefit from increasing circulation time of annexin A5 by increasing its size. PROCEDURES: Annexin A5 size was increased by complexation of biotinylated annexin A5 with Alexa-Fluor680-labeled streptavidin. The non-binding variant of annexin A5, M1234, was used as negative control. The HT29 colon carcinoma xenograft model in NMRI nude mice was used to measure tumor uptake in vivo. Tumor uptake of fluorescent annexin A5-variants was measured using non-invasive optical imaging. RESULTS: The annexin A5-streptavidin complex (4 ? 1, moles:moles, Mw ~ 200 kDa) binds phosphatidylserine-expressing membranes with a Hill-coefficient of 5.7 +/- 0.5 for Ca2+-binding and an EC50 of 0.9 +/- 0.1 mM Ca2+ (EC50 is the Ca2+ concentration required for half maximal binding)(annexin A5: Hill-coefficient 3.9 +/- 0.2, EC50 1.5 +/- 0.2 mM Ca2+). Circulation half-life of annexin A5 streptavidin is +/- 21 minutes (circulation half-life of annexin A5 is +/- 4 min.). Tumor uptake of annexin A5-streptavidin was higher and persisted longer than annexin A5-uptake but depended less on phosphatidylserine binding. CONCLUSION: Increasing annexin A5 size prolongs circulation times and increases tumor uptake, but decreases contribution of PS-targeting to tumor uptake and abolishes power to report efficacy of therapy. PMID- 24801052 TI - Development and preclinical testing of HNVAC, a cell culture-based H1N1 pandemic influenza vaccine from India. AB - Several limitations of the use of embryonated eggs and the threat of pandemics have highlighted the need for other platforms for the production of influenza vaccines. We report the indigenous development and pre-clinical testing of an MDCK-based H1N1 pandemic influenza vaccine HNVAC from India. The cell bank and virus seed were characterized extensively. The cells were characterized by PCR, electron microscopy, and karyotyping, and found to be of female canine epithelial origin. The virus was confirmed by neutralization, haemagglutination inhibition, neuraminidase inhibition, and PCR and nucleotide sequencing. Adventitious agent testing was performed by both in vitro and in vivo studies. The in vitro studies included culturing, haemadsorption, haemagglutination, PCR and RT-PCR, whereas in vivo studies included passage in embryonated eggs and in laboratory animals. Both cell bank and virus seed were free of adventitious agents. MDCK cell lysates as well as cellular DNA did not produce tumours in newborn or adult laboratory animals. The bioprocess parameters were standardized to recover antigen with minimal levels of process-related impurities. The vaccine bulk was tested for the presence of specific antigen, and quantified by single radial immunodiffusion. Finally, non-adjuvanted and aluminium hydroxide adjuvanted vaccine formulations were found to be safe in preclinical toxicity studies in mice, rats, guinea pigs and rabbits, and immunogenic in mice and rabbits. This is the first and only cell culture-based influenza vaccine platform developed in any developing country. PMID- 24801053 TI - Efficient chromatographic reduction of ovalbumin for egg-based influenza virus purification. AB - Vaccination is the most effective prevention strategy to avoid influenza infection and for protection of large populations. The vast majority of influenza vaccines are still produced with allantoic fluid from fertilized chicken eggs. The presence of ovalbumin, which can constitute over 60% of the total protein content in allantoic fluid, can result in severe allergies. Consequently, efficient reduction of ovalbumin is critical during egg based vaccine manufacturing. Here we present Capto Core 700, a novel core bead chromatographic flow through mode resin for removal of ovalbumin and compare it to sucrose zonal gradient ultracentrifugation, which is the industry standard for egg-based vaccine production. The results demonstrate that core bead chromatography is fully comparable to zonal centrifugation in removing ovalbumin to meet regulatory requirements. Furthermore, the scalability and the shorter process times of this method have the potential to significantly improve the productivity and economy for industrial production compared to zonal centrifugation. PMID- 24801054 TI - Programmable and highly resolved in vitro detection of 5-methylcytosine by TALEs. AB - Gene expression is extensively regulated by specific patterns of genomic 5 methylcytosine (mC), but the ability to directly detect this modification at user defined genomic loci is limited. One reason is the lack of molecules that discriminate between mC and cytosine (C) and at the same time provide inherent, programmable sequence-selectivity. Programmable transcription-activator-like effectors (TALEs) have been observed to exhibit mC-sensitivity in vivo, but to only a limited extent in vitro. We report an mC-detection assay based on TALE control of DNA replication that displays unexpectedly strong mC-discrimination ability in vitro. The status and level of mC modification at single positions in oligonucleotides can be determined unambiguously by this assay, independently of the overall target sequence. Moreover, discrimination is reliably observed for positions bound by N-terminal and central regions of TALEs. This indicates the wide scope and robustness of the approach for highly resolved mC detection and enabled the detection of a single mC in a large, eukaryotic genome. PMID- 24801055 TI - Effect of gamma irradiation on poly(vinyledene difluoride)-lithium bis(oxalato)borate electrolyte. AB - A poly(vinyledene difluoride)-lithium bis(oxalato)borate solid polymer electrolyte prepared by a solvent casting method has been irradiated with different doses of gamma-rays. Differential scanning calorimetry reveals that the polymer electrolyte irradiated with 35 kGy of gamma-rays is the most amorphous sample. This is also supported by the results obtained from X-ray diffraction. The Fourier transform infrared spectrum of each irradiated sample has been deconvoluted in the wavenumber region between 1830 and 1758 cm(-1) in order to predict the percentage of free and contact ions in the samples. The sample exposed to 35 kGy of gamma-rays contains the highest percentage of free ions and the lowest amount of contact ions. This sample also exhibits the highest room temperature conductivity of 3.05 * 10(-4) S cm(-1), which is 15% higher relative to the virgin sample. The number density of free ions is observed to have more control on the conductivity variation with the gamma-radiation dose compared to ionic mobility. This study confirms that gamma-irradiation can be a potential way to obtain highly conductive and mechanically stable polymer electrolytes. PMID- 24801056 TI - Low-level laser therapy to treat fibromyalgia. AB - Several clinical treatments have been proposed to manage symptoms of fibromyalgia. Low-level laser therapy (LLLT) may be a useful tool to treat this dysfunction. The aim of this study was to evaluate the effects of LLLT in patients with fibromyalgia. A placebo-controlled, randomized clinical trial was carried out with 20 patients divided randomly into either an LLLT group (n = 10) or a placebo group (n = 10). The LLLT group was treated with a GaAlAs laser (670 nm, 4 J/cm(2) on 18 tender points) three times a week over 4 weeks. Before and after treatment, patients were evaluated with the Fibromyalgia Impact Questionnaire (FIQ), McGill Pain Questionnaire, and visual analog scale (VAS). Data from the FIQ and McGill questionnaire for the treated and control groups were analyzed by paired t tests, and Wilcoxon tests were used to analyze data from the VAS. After LLLT or sham treatment, the number of tender points was significantly reduced in both groups (LLLT, p < 0.0001; placebo, p = 0.0001). However, all other fibromyalgia symptoms showed significant improvements after LLLT compared to placebo (FIQ, p = 0.0003; McGill, p = 0.0078; and VAS, p = 0.0020). LLLT provided relief from fibromyalgia symptoms in patients and should be further investigated as a therapeutic tool for management in fibromyalgia. PMID- 24801057 TI - Comparative analysis of low-level laser therapy (660 nm) on inflammatory biomarker expression during the skin wound-repair process in young and aged rats. AB - The wound-healing process plays an essential role in the protective response to epidermal injury by tissue regeneration. In the elderly, skin functions deteriorate as a consequence of morphological and structural changes. This study aimed to evaluate and compare the effect of low-level laser therapy (LLLT) in cutaneous wound healing in young and aged rats. A total of 60 male rats comprising 30 young (+/- 30 days) and 30 aged (+/- 500 days) was used. The animals were divided into four experimental groups and underwent skin wound and/or treatment with LLLT (660 nm, 30 mW, 1.07 W/cm(2), 0.028 cm(2), 72 J/cm(2), and 2 J). Analyses were conducted to verify the effects of LLLT in the tissue repair process, in the gene expression, and protein expression of TNF-alpha, IL 1beta, and IL-10, obtained in skin wound model. Results showed that there were significant differences between the young control group and the aged control group and their respective treated groups (LLLT young and LLLT aged). We conclude that LLLT has shown to be effective in the treatment of skin wounds in young and aged animals at different stages of the tissue repair process, which suggests that different LLLT dosimetry should be considered in treatment of subjects of different ages. Further clinical trials are needed to confirm these findings in clinical settings. PMID- 24801058 TI - Positron emission tomography in the evaluation of pulmonary nodules among patients living in a coccidioidal endemic region. AB - BACKGROUND: Within a coccidioidal endemic region, pulmonary nodules due to coccidioidomycosis are common. Uptake of (18)fluorodeoxyglucose ((18)FDG) by positron emission tomography with computed axial tomography (PET/CT) has been used to assess whether pulmonary nodules are malignant but inflammatory lesions can be positive. The purpose of this study was to compare by PET/CT the (18)FDG uptake in pulmonary nodules likely due to coccidioidomycosis to that of nodules shown to be malignant among patients living in a coccidioidal endemic region. METHODS: We retrospectively reviewed patients who underwent a PET/CT at the Southern Arizona Veterans Affairs Health Care System between January 2008 and March 2012 who were subsequently found on biopsy to have pulmonary nodules that were coccidioidal or granulomatous or were due to malignancy. RESULTS: Among 245 diagnostic biopsies where the subject had a previous PET/CT, 15 (6.1 %) were either coccidioidal (n = 12) or granulomatous without an identified organism (n = 3). The median maximum standard unit of uptake (SUV(max)) on PET/CT of coccidioidal or granulomatous lesions was 2.0 compared to 9.8 for malignant lesions (P < 0.001). The maximum diameter of the coccidioidal or granulomatous nodules was 2.1 cm compared to 3.0 cm for the malignant lesions (P = 0.009). On multivariable analysis, an elevated SUV(max) was the only distinguishing feature between the malignant and the granulomatous lesions (OR 1.28, 95 % CI 1.05-1.55; P = 0.013). CONCLUSIONS: Coccidioidal pulmonary nodules take up significantly less (18)FDG than those due to malignancies, but there is considerable overlap between granulomatous and malignant lesions at lower SUV(max). PMID- 24801059 TI - Injury Location and Mechanism for Complex Regional Pain Syndrome: A Nationwide Population-Based Case-Control Study in Taiwan. AB - BACKGROUND: Few studies have investigated the relationship between injury location, mechanism and their association with complex regional pain syndrome (CRPS). We conducted a nationwide database survey to explore this issue. METHODS: This was a population-based case-control study. Five hundred and eighty-nine patients with at least one ambulatory visit or admission with a principal diagnosis of CRPS from 2004 to 2009 were selected. For each CRPS patient, ten age and sex-matched non-CRPS subjects were randomly selected. The odds ratios (PLoS One. 2013;8:e57205) and 95% confidence intervals (95% CIs) of risk factors for CRPS were derived from multivariate logistic regression models. RESULTS: Injury was a risk factor for CRPS (OR, 2.96; 95% CI, 2.18 to 4.02) independent of age and sex. In adjusted models, open wound on the upper limbs (OR 1.25, 95% CI 1.02 to 1.54) conferred higher CRPS risk. Injury mechanisms including nerve and spinal cord injury (OR 2.42, 95% CI 1.44 to 4.08), muscle and joint sprain and strain (OR 1.69, 95% CI 1.40 to 2.03), superficial injury (OR 1.23, 95% CI 1.00 to 1.51), and contusion (OR 1.44, 95% CI 1.20 to 1.74), but not fracture, increased the risk of CRPS. CONCLUSION: Injury in the extremities rather than the trunk is an important risk factor for CRPS. Certain injury mechanisms confer higher risk of CRPS. This nationwide study demonstrated that injury increased CRPS nearly threefold. Open wound, sprain and strain, superficial injury, contusion, and nerve and spinal cord injury are main injury mechanisms. Injury in the extremities confers a higher risk of CRPS. PMID- 24801060 TI - The role of environmental heterogeneity in meta-analysis of gene-environment interactions with quantitative traits. AB - With challenges in data harmonization and environmental heterogeneity across various data sources, meta-analysis of gene-environment interaction studies can often involve subtle statistical issues. In this paper, we study the effect of environmental covariate heterogeneity (within and between cohorts) on two approaches for fixed-effect meta-analysis: the standard inverse-variance weighted meta-analysis and a meta-regression approach. Akin to the results in Simmonds and Higgins (), we obtain analytic efficiency results for both methods under certain assumptions. The relative efficiency of the two methods depends on the ratio of within versus between cohort variability of the environmental covariate. We propose to use an adaptively weighted estimator (AWE), between meta-analysis and meta-regression, for the interaction parameter. The AWE retains full efficiency of the joint analysis using individual level data under certain natural assumptions. Lin and Zeng (2010a, b) showed that a multivariate inverse-variance weighted estimator retains full efficiency as joint analysis using individual level data, if the estimates with full covariance matrices for all the common parameters are pooled across all studies. We show consistency of our work with Lin and Zeng (2010a, b). Without sacrificing much efficiency, the AWE uses only univariate summary statistics from each study, and bypasses issues with sharing individual level data or full covariance matrices across studies. We compare the performance of the methods both analytically and numerically. The methods are illustrated through meta-analysis of interaction between Single Nucleotide Polymorphisms in FTO gene and body mass index on high-density lipoprotein cholesterol data from a set of eight studies of type 2 diabetes. PMID- 24801061 TI - A quicker degradation rate is yielded by a novel kind of transgenic silk fibroin consisting of shortened silk fibroin heavy chains fused with matrix metalloproteinase cleavage sites. AB - Degradation performance of silk fibroin is an important property for its medical applications. Herein we constructed a shortened silk fibroin heavy chain protein fused with a matrix metalloproteinase cleavage site (SSFH-MMP) along with a glutathione S-transferase tag ahead. The digestion assay shows it can be cut by matrix metalloproteinase-2 (MMP-2) at its MMP cleavage site. Furthermore, we introduced the SSFH-MMP into silk fibroin by genetic modification of silkworms in order to increase the degradation rate of the silk fibroin. After acquisition of a race of transgenic silkworms with the coding sequence of the MMP cleavage site in their genomic DNA, we tested some properties of their silk fibroin designated TSF-MMP. The results show that the TSF-MMP has MMP cleavage sites and yields a quicker degradation rate during dilution in MMP-2 enzyme buffer or implantation into tumor tissues compared with that of normal silk fibroin. Moreover, the TSF MMP is in vitro non-toxic to human bone marrow mesenchymal stem cells (hBM-MSCs) indicating that the TSF-MMP may become a biomaterial with a quicker degradation rate for its medical applications. PMID- 24801062 TI - Aligned collagen-GAG matrix as a 3D substrate for Schwann cell migration and dendrimer-based gene delivery. AB - The development of artificial off-the-shelf conduits that facilitate effective nerve regeneration and recovery after repair of traumatic nerve injury gaps is of fundamental importance. Collagen-glycosaminoglycan (GAG) matrix mimicking Schwann cell (SC) basal lamina has been proposed as a suitable and biologically rational substrate for nerve regeneration. In the present study, we have focused on the permissiveness of this matrix type for SC migration and repopulation, as these events play an essential role in nerve remodeling. We have also demonstrated that SCs cultured within collagen-GAG matrix are compatible with non-viral dendrimer based gene delivery, that may allow conditioning of matrix-embedded cells for future gene therapy applications. PMID- 24801063 TI - In vitro bioactivity of titanium-doped bioglass. AB - Previous studies have suggested that incorporating relatively small quantities of titanium dioxide into bioactive glasses may result in an increase in bioactivity and hydroxyapatite formation. The present work therefore investigated the in vitro bioactivity of a titanium doped bioglass and compared the results with 45S5 bioglass. Apatite formation was evaluated for bioglass and Ti-bioglass in the presence and absence of foetal calf serum. Scanning electron microscopy (SEM) images were used to evaluate the surface development and energy dispersive X-ray measurements provided information on the elemental ratios. X-ray diffraction spectra confirmed the presence of apatite formation. Cell viability was assessed for bone marrow stromal cells under direct and indirect contact conditions and cell adhesion was assessed using SEM. PMID- 24801064 TI - Modulation of neural circuits: how stimulus context shapes innate behavior in Drosophila. AB - Remarkable advances have been made in recent years in our understanding of innate behavior and the underlying neural circuits. In particular, a wealth of neuromodulatory mechanisms have been uncovered that can alter the input-output relationship of a hereditary neural circuit. It is now clear that this inbuilt flexibility allows animals to modify their behavioral responses according to environmental cues, metabolic demands and physiological states. Here, we discuss recent insights into how modulation of neural circuits impacts innate behavior, with a special focus on how environmental cues and internal physiological states shape different aspects of feeding behavior in Drosophila. PMID- 24801065 TI - Impact of different tissue-simulating hydrogel compartments on in vitro release and distribution from drug-eluting stents. AB - In vitro drug release testing is an appropriate approach to identify critical parameters helping to predict drug release from drug-eluting stents (DES) prior to studying drug release behavior under in vivo conditions. Drug release and distribution from DES coated with a fluorescent model substance were studied in vitro using the vessel-simulating flow-through cell equipped with different long term stable hydrogel compartments composed of agarose, polyacrylamide or poly(vinyl alcohol). The obtained experimental results were compared with the results of finite-element modeling obtained using experimentally determined diffusion coefficients and partition coefficients. In spite of differences regarding these parameters, experimental and mathematical data yielded only minor differences between the different gels regarding the release and distribution behavior and reasonable agreement between the modeling and the experiment was obtained. In an attempt to further elucidate the dosage form behavior, the diffusion coefficients in the gel as well as in the stent coating were systematically varied in the finite-element model. Changes in the diffusivity in the stent coating mainly impacted on the initial concentrations. Slower diffusion inside the hydrogel yielded a retarded elution from the stent coating and a higher model substance accumulation in the gel compartment at late time points. PMID- 24801066 TI - CT urography: segmentation of urinary bladder using CLASS with local contour refinement. AB - We are developing a computerized system for bladder segmentation on CT urography (CTU), as a critical component for computer-aided detection of bladder cancer. The presence of regions filled with intravenous contrast and without contrast presents a challenge for bladder segmentation. Previously, we proposed a conjoint level set analysis and segmentation system (CLASS). In case the bladder is partially filled with contrast, CLASS segments the non-contrast (NC) region and the contrast-filled (C) region separately and automatically conjoins the NC and C region contours; however, inaccuracies in the NC and C region contours may cause the conjoint contour to exclude portions of the bladder. To alleviate this problem, we implemented a local contour refinement (LCR) method that exploits model-guided refinement (MGR) and energy-driven wavefront propagation (EDWP). MGR propagates the C region contours if the level set propagation in the C region stops prematurely due to substantial non-uniformity of the contrast. EDWP with regularized energies further propagates the conjoint contours to the correct bladder boundary. EDWP uses changes in energies, smoothness criteria of the contour, and previous slice contour to determine when to stop the propagation, following decision rules derived from training. A data set of 173 cases was collected for this study: 81 cases in the training set (42 lesions, 21 wall thickenings, 18 normal bladders) and 92 cases in the test set (43 lesions, 36 wall thickenings, 13 normal bladders). For all cases, 3D hand segmented contours were obtained as reference standard and used for the evaluation of the computerized segmentation accuracy. For CLASS with LCR, the average volume intersection ratio, average volume error, absolute average volume error, average minimum distance and Jaccard index were 84.2 +/- 11.4%, 8.2 +/- 17.4%, 13.0 +/- 14.1%, 3.5 +/- 1.9 mm, 78.8 +/- 11.6%, respectively, for the training set and 78.0 +/- 14.7%, 16.4 +/- 16.9%, 18.2 +/- 15.0%, 3.8 +/- 2.3 mm, 73.8 +/- 13.4% respectively, for the test set. With CLASS only, the corresponding values were 75.1 +/- 13.2%, 18.7 +/- 19.5%, 22.5 +/- 14.9%, 4.3 +/- 2.2 mm, 71.0 +/- 12.6%, respectively, for the training set and 67.3 +/- 14.3%, 29.3 +/- 15.9%, 29.4 +/- 15.6%, 4.9 +/- 2.6 mm, 65.0 +/- 13.3%, respectively, for the test set. The differences between the two methods for all five measures were statistically significant (p < 0.001) for both the training and test sets. The results demonstrate the potential of CLASS with LCR for segmentation of the bladder. PMID- 24801068 TI - Wine and headache. AB - BACKGROUND: The notion of migraine attacks triggered by food and beverages has been posited for centuries. Red wine in particular has been acknowledged as a migraine trigger since antiquity when Celsus (25 B.C.-50 A.D.) described head pain after drinking wine. Since then, references to the relationship between alcohol ingestion and headache attacks are numerous. The most common initiator of these attacks among alcoholic beverages is clearly wine. The aim of this review is to present and discuss the available literature on wine and headache. METHODS: A Medline search with the terms headache, migraine, and wine was performed. Data available on books and written material about wine and medicine as well as abstracts on alcohol, wine, and headache available in the proceedings of major headache meetings in the last 30 years were reviewed. In addition, available technical literature and websites about wine, grapes, and wine making were also evaluated. RESULTS: Full papers specifically on headache and wine are scarce. General literature related to medicine and wine is available, but scientific rigor is typically lacking. The few studies on wine and headache were mostly presented as abstracts despite the common knowledge and patients' complaints about wine ingestion and headache attacks. These studies suggest that red wine, but not white and sparkling wines, do trigger headache and migraine attacks independently of dosage in less than 30% of the subjects. DISCUSSION: Wine, and specifically red wine, is a migraine trigger. Non-migraineurs may have headache attacks with wine ingestion as well. The reasons for that triggering potential are uncertain, but the presence of phenolic flavonoid radicals and the potential for interfering with the central serotonin metabolism are probably the underlying mechanisms of the relationship between wine and headache. Further controlled studies are necessary to enlighten this traditional belief. PMID- 24801069 TI - Toxoplasma gondii 70 kDa heat shock protein: systemic detection is associated with the death of the parasites by the immune response and its increased expression in the brain is associated with parasite replication. AB - The heat shock protein of Toxoplasma gondii (TgHSP70) is a parasite virulence factor that is expressed during T. gondii stage conversion. To verify the effect of dexamethasone (DXM)-induced infection reactivation in the TgHSP70-specific humoral immune response and the presence of the protein in the mouse brain, we produced recombinant TgHSP70 and anti-TgHSP70 IgY antibodies to detect the protein, the specific antibody and levels of immune complexes (ICs) systemically, as well as the protein in the brain of resistant (BALB/c) and susceptible (C57BL/6) mice. It was observed higher TgHSP70-specific antibody titers in serum samples of BALB/c compared with C57BL/6 mice. However, the susceptible mice presented the highest levels of TgHSP70 systemically and no detection of specific ICs. The DXM treatment induced increased parasitism and lower inflammatory changes in the brain of C57BL/6, but did not interfere with the cerebral parasitism in BALB/c mice. Additionally, DXM treatment decreased the serological TgHSP70 concentration in both mouse lineages. C57BL/6 mice presented high expression of TgHSP70 in the brain with the progression of infection and under DXM treatment. Taken together, these data indicate that the TgHSP70 release into the bloodstream depends on the death of the parasites mediated by the host immune response, whereas the increased TgHSP70 expression in the brain depends on the multiplication rate of the parasite. PMID- 24801070 TI - Statistical considerations in economic evaluations: a guide for cardiologists. AB - The author reviews statistical methods commonly applied in economic evaluations that rely on individual patient-level data. The paper includes a review of foundational concepts, unique characteristics of health economic data, and methods developed to address them. The paper then highlights issues that should be considered in the interpretation of findings from economic evaluations. PMID- 24801072 TI - Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes. AB - AIM: Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease. METHODS AND RESULTS: In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-induced mitochondrial translocation of pro-oxidant adaptor p66(Shc) and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reduced NO availability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-kappaB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66(Shc)-dependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1(-/-) mice were protected against mitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F2alpha and plasma levels of adhesion molecules. CONCLUSIONS: Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes. PMID- 24801071 TI - Risk stratification for sudden cardiac death: current status and challenges for the future. AB - Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds. PMID- 24801073 TI - Quality of voluntary medical male circumcision services during scale-up: a comparative process evaluation in Kenya, South Africa, Tanzania and Zimbabwe. AB - BACKGROUND: The rapid expansion of voluntary medical male circumcision (VMMC) has raised concerns whether health systems can deliver and sustain VMMC according to minimum quality criteria. METHODS AND FINDINGS: A comparative process evaluation was used to examine data from SYMMACS, the Systematic Monitoring of the Voluntary Medical Male Circumcision Scale-Up, among health facilities providing VMMC across two years of program scale-up. Site-level assessments examined the availability of guidelines, supplies and equipment, infection control, and continuity of care services. Direct observation of VMMC surgeries were used to assess care quality. Two sample tests of proportions and t-tests were used to examine differences in the percent of facilities meeting requisite preparedness standards and the mean number of directly-observed surgical tasks performed correctly. Results showed that safe, high quality VMMC can be implemented and sustained at-scale, although substantial variability was observed over time. In some settings, facility preparedness and VMMC service quality improved as the number of VMMC facilities increased. Yet, lapses in high performance and expansion of considerably deficient services were also observed. Surgical tasks had the highest quality scores, with lower performance levels in infection control, pre-operative examinations, and post-operative patient monitoring and counseling. The range of scale-up models used across countries additionally underscored the complexity of delivering high quality VMMC. CONCLUSIONS: Greater efforts are needed to integrate VMMC scale-up and quality improvement processes in sub-Saharan African settings. Monitoring of service quality, not just adverse events reporting, will be essential in realizing the full health impact of VMMC for HIV prevention. PMID- 24801074 TI - Stereoselectivity of isoflurane in adhesion molecule leukocyte function associated antigen-1. AB - BACKGROUND: Isoflurane in clinical use is a racemate of S- and R-isoflurane. Previous studies have demonstrated that the effects of S-isoflurane on relevant anesthetic targets might be modestly stronger (less than 2-fold) than R isoflurane. The X-ray crystallographic structure of the immunological target, leukocyte function-associated antigen-1 (LFA-1) with racemic isoflurane suggested that only S-isoflurane bound specifically to this protein. If so, the use of specific isoflurane enantiomers may have advantage in the surgical settings where a wide range of inflammatory responses is expected to occur. Here, we have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies. METHODS: First, binding of isoflurane enantiomers to LFA-1 was studied using 1-aminoanthracene (1-AMA) displacement assays. The binding site of each enantiomer on LFA-1 was studied using the docking program GLIDE. Functional studies employed the flow-cytometry based ICAM binding assay. RESULTS: Both enantiomers decreased 1-AMA fluorescence signal (at 520 nm), indicating that both competed with 1-AMA and bound to the alphaL I domain. The docking simulation demonstrated that both enantiomers bound to the LFA-1 "lovastatin site." ICAM binding assays showed that S-isoflurane inhibited more potently than R-isoflurane, consistent with the result of 1-AMA competition assay. CONCLUSIONS: In contrast with the x-ray crystallography, both enantiomers bound to and inhibited LFA-1. S-isoflurane showed slight preference over R isoflurane. PMID- 24801075 TI - Thoracic impedance as a therapeutic marker of acute decompensated heart failure. PMID- 24801076 TI - Worsening renal function in heart failure: the need for a consensus definition. AB - Acute decompensated heart failure is a common cause of hospitalisation. This is a period of vulnerability both in altered pathophysiology and also the potential for iatrogenesis due to therapeutic interventions. Renal dysfunction is often associated with heart failure and portends adverse outcomes. Identifying heart failure patients at risk of renal dysfunction is important in preventing progression to chronic kidney disease or worsening renal function, informing adjustment to medication management and potentially preventing adverse events. However, there is no working or consensus definition in international heart failure management guidelines for worsening renal function. In addition, there appears to be no concordance or adaptation of chronic kidney disease guidelines by heart failure guideline development groups for the monitoring of chronic kidney disease in heart failure. Our aim is to encourage the debate for an agreed definition given the prognostic impact of worsening renal function in heart failure. We present the case for the uptake of the Acute Kidney Injury Network criteria for acute kidney injury with some minor alterations. This has the potential to inform study design and meta-analysis thereby building the knowledgebase for guideline development. Definition consensus supports data element, clinical registry and electronic algorithm innovation as instruments for quality improvement and clinical research for better patient outcomes. In addition, we recommend all community managed heart failure patients have their baseline renal function classified and routinely monitored in accordance with established renal guidelines to help identify those at increased risk for worsening renal function or progression to chronic kidney disease. PMID- 24801077 TI - Cigarette smoking among patients with chronic diseases. PMID- 24801078 TI - 3D-TEE image artifact of a ventricular septal defect below the tricuspid valve. PMID- 24801079 TI - Kounis syndrome following the performance of skin test to amoxicillin. PMID- 24801080 TI - Socioeconomic inequalities in abdominal obesity among children and adolescents in Shandong, China. PMID- 24801082 TI - Renal sympathetic denervation attenuates the ventricular substrate and electrophysiological remodeling in dogs with pacing-induced heart failure. PMID- 24801081 TI - Successful 13N-ammonia positron emission tomography-guided percutaneous coronary intervention in a patient with single coronary artery ostium suffering acute myocardial infarction. PMID- 24801083 TI - Antigen carbohydrate 125 and creatinine on admission for prediction of renal function response following loop diuretic administration in acute heart failure. AB - BACKGROUND: The use of loop diuretics in acute heart failure (AHF) is largely empirical and has been associated with renal function impairment by reducing renal perfusion but also renal improvement by decreasing renal venous congestion. Antigen carbohydrate 125 (CA125) has emerged as a proxy for fluid overload. We sought to evaluate whether the early changes in creatinine (DeltaCr) induced by intravenous furosemide doses (ivFD) differ among clinical groups defined by overload status (CA125) and creatinine on admission (Cr). METHODS AND RESULTS: We included 526 consecutive patients admitted for AHF. All patients received intravenous furosemide for the first 48 hours. CA125 and Cr were dichotomized at 35 U/ml and 1.4 mg/dl, respectively, and grouped as follows: C1 [Cr <1.4, CA125 <= 35 (n=151)]; C2 [Cr <1.4, CA125 >35 (n=241)]; C3 [Cr >= 1.4, CA125 <= 35 (n=45)]; and C4 [Cr >= 1.4, CA125 >35 (n=89)]. Clinicians in charge of the management of patients were blind to CA125 values. DeltaCr was estimated as the absolute difference in Cr between admission and 48-72 hours. Multivariable linear regression analysis was used for modeling purposes. The adjusted analysis showed a differential effect of ivFD on DeltaCr. Per increase in 20mg/day of ivFD, the mean DeltaCr was 0.010 mg/dl (p=0.464) in C1, 0.002 mg/dl (p=0.831) in C2, 0.045 mg/dl (p=0.032) in C3, and -0.045 mg/dl (p<0.001) in C4 (omnibus p<0.001). A similar pattern of response was observed in a validation cohort. CONCLUSIONS: In patients with AHF, the magnitude and direction of DeltaCr attributable to ivFD were differentially associated with values of CA125 and Cr on admission. PMID- 24801084 TI - Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population. PMID- 24801085 TI - Plasma PCSK9 levels are associated with the severity of coronary stenosis in patients with atherosclerosis. PMID- 24801086 TI - Distinct ECG characteristics of idiopathic ventricular arrhythmias originating from four regions of left coronary veins. PMID- 24801087 TI - Impact of chronic obstructive pulmonary disease on composition of left main coronary artery plaque with intermediate stenosis. PMID- 24801089 TI - Uric acid elevation in atrial fibrillation: is it simply an epiphenomenon or not? PMID- 24801088 TI - Risk of intradialytic hypotension in patients on thrice-weekly versus twice weekly hemodialysis. PMID- 24801090 TI - Factors associated with progression of coronary artery disease measured by intravascular ultrasound: systematic review and meta-analysis. PMID- 24801091 TI - Immunosenescence and inflammation characterize chronic heart failure patients with more advanced disease. AB - BACKGROUND: Chronic heart failure (CHF) is characterized by an inflammatory status with high levels of cytokines such as IL-6. We hypothesized that patients with CHF may develop immunosenescence due to inflammation and that this may be associated with a worse stage of the disease. METHODS AND RESULTS: We compared the immunological features of 58 elderly CHF patients (ECHF), 40 young CHF patients (YCHF), 60 healthy elderly controls (HEC) and 40 healthy young controls (HYC). We characterized leukocyte and lymphocyte subpopulations by flow cytometry, and IL-6 concentration by ELISA. The extent of CHF was classified according to functional and/or morphological criteria: New York Heart Association functional class, AHA/ACC heart failure stages, left ventricular ejection fraction, and left ventricular hypertrophy. CHF patients showed an increased number of leukocytes, neutrophils and monocytes, but a decreased number of lymphocytes. CHF patients had significantly lower levels of B-cells and CD4+ T cells, increased NK-cells in YCHF, and increased CD8+ T-cells only in ECHF. CHF was associated with high differentiation in CD4+ and CD8+ T-lymphocyte subsets. Aging of T-lymphocyte subpopulations and high IL-6 levels were associated with a worse clinical status. IL-6 also correlated positively with the number of highly differentiated T-lymphocytes and with their accelerated aging. CONCLUSIONS: We conclude that CHF patients show a higher degree of immunosenescence than age matched healthy controls. T-lymphocyte differentiation and IL-6 levels are increased in patients with an advanced clinical status and may contribute to disease impairment through a compromised adaptive immune response due to accelerated aging of their immune system. PMID- 24801092 TI - Akhawayni's interventions on treatment and management of stroke. PMID- 24801093 TI - Incidence and prognostic significance of silent atrial fibrillation in acute myocardial infarction. AB - BACKGROUND: Silent atrial fibrillation (AF) has been suggested to be frequent after acute myocardial infarction (MI). Continuous ECG monitoring (CEM) has been shown to improve AF screening in patients at risk of stroke. OBJECTIVES: We aimed to assess the incidence and prognosis of silent AF in patients with acute MI. METHODS: All the consecutive patients with acute MI were prospectively analyzed by CEM >= 48 h after admission. Silent AF was defined as asymptomatic episodes lasting at least 30s. The population was divided into three groups: no-AF, silent AF and symptomatic AF. RESULTS: Among the 849 patients, 135 (16%) developed silent AF and 45 (5%) symptomatic AF. Compared with the no-AF group, patients with silent AF were markedly older (80 vs. 62 y, p<0.001), more frequently women (43% vs. 30%, p=0.006) and less likely to be smokers (20% vs. 36%, p<0.001). They had impaired left ventricular ejection fraction (LVEF) and left atrial (LA) enlargement. By multivariate analysis, age, history of AF, indexed LA area and LVEF were identified as independent predictors of silent AF. In-hospital heart failure and death rates were markedly higher in silent AF group when compared with no-AF patients (41.8% vs 21.0% and 10.4% vs. 1.3%, respectively). CONCLUSION: Our large prospective study showed for the first time that silent AF is more frequent than symptomatic AF after MI. Our work suggests that indexed LA area could help to predict the risk of developing silent AF. Moreover, the onset of silent AF is associated with worse hospital prognosis. PMID- 24801094 TI - Functional health and well-being, arterial stiffness and vascular dysfunction in healthy adults. PMID- 24801095 TI - Coronary dissection at site of recent BRS deployment: a case for the comeback kid? PMID- 24801096 TI - Subcutaneous implantable cardioverter-defibrillator in a young woman. PMID- 24801097 TI - Geoffrey Peter Herzig, MD (1941-2013): transplant pioneer. PMID- 24801100 TI - Delineating cellular interactions between ciliates and fish by co-culturing Tetrahymena thermophila with fish cells. AB - Although several species of Tetrahymena are often described as histophagous and opportunistic pathogens of fish, little is known about ciliate/fish cell interactions, but one approach for studying these is in vitro with cell lines. In this study, T. thermophila, B1975 (wild type) and NP1 (temperature sensitive mutant for phagocytosis) were cultured on monolayers of 3 fish epithelial cell lines, CHSE-214, RTgill-W1, and ZEB2J, and the rabbit kidney epithelial cell line, RK-13. Generally the ciliates flourished, whereas the monolayers died, being completely consumed over several days. The destruction of monolayers required that the ciliates could make contact with the animal cells through swimming, which appeared to dislodge or loosen cells so that they could be phagocytosed. The ciliates internalized into food vacuoles ZEB2J from cell monolayers as well as from cell suspensions. Phagocytosis was essential for monolayer destruction as monolayers remained intact under conditions where phagocytosis was impeded, such as 37 degrees C for NP1 and 4 degrees C for B1975. Monolayers of fish cells supported the proliferation of ciliates. Thus T. thermophila can 'eat' animal cells or be histophagous in vitro, with the potential to be histophagous in vivo. PMID- 24801098 TI - Preemptive DLI without withdrawal of immunosuppression to promote complete donor T-cell chimerism results in favorable outcomes for high-risk older recipients of alemtuzumab-containing reduced-intensity unrelated donor allogeneic transplant: a prospective phase II trial. AB - Although pretransplant alemtuzumab can reduce GVHD following allogeneic transplantation, it may also increase the risk of mixed donor T-cell chimerism and infections. We hypothesized that the early use of DLI without withdrawal of immunosuppressive drugs in patients with mixed T-cell chimerism would lower the risk of relapse without significantly increasing the risk of GVHD post DLI. Thirty-six patients (median age 59 years) were treated in this phase II trial using reduced-intensity conditioning including s.c. alemtuzumab (total dose 43 mg) and a PBSC graft from a matched unrelated donor (UD). DLI without withdrawal of immunosuppressive drugs was administered to all 25 patients with <50% donor T cell chimerism on day +60. The cumulative risks of acute and chronic GVHD were 42% and 59%, respectively. Estimated probabilities of non-relapse mortality (NRM) at day 100 and 1 year were 3% and 14%, respectively. With a median follow up 2.4 years, estimated survivals at day 100, 1 and 2 years were 97%, 71% and 57%, respectively. In multivariate analysis, the occurrence of acute GVHD was associated with an increased risk of mortality, whereas the occurrence of chronic GVHD had a protective effect, associated with decreased relapse and improved disease-free survival. Low-dose alemtuzumab and preemptive DLI provides favorable transplant outcomes including low NRM in an older patient population with high risk malignancies undergoing UD transplantation. PMID- 24801101 TI - Vitamin-E blended and infused highly cross-linked polyethylene for total hip arthroplasty: a comparison of three-dimensional crystalline morphology and strain recovery behavior. AB - Vitamin-E (alpha-tocopherol) is now recognized worldwide as one of the most promising antioxidant agents for highly cross-linked polyethylene (HXLPE) used in total joint replacements. In the contemporary manufacturing processes, two alternative methods are currently accepted to incorporate this antioxidant into polyethylene microstructure: (i) blending vitamin-E before consolidation and radiation crosslinking; (ii) infusing vitamin-E via a homogenizing heat treatment after radiation crosslinking. However, the effects of these technological differences on crystalline morphology and mechanical behavior of polyethylene remains to be fully elucidated. The aim of this paper is to quantitatively evaluate the microstructural differences of commercially available vitamin-E blended and infused HXLPE liner (referred to as Liner BL and IF, respectively). For this purpose, confocal/polarized Raman spectroscopy was used to systematically examine the three-phase percentages (amorphous (alphaa), crystalline (alphac), and intermediate third phase (alphat)), preferential molecular orientation (thetap), and degree of crystalline anisotropy (). Additionally, we compared the time-dependent deformation of Liner BL and IF as obtained by uniaxial stress relaxation tests followed by strain recovery. Distinctive features of the near-surface alphac, thetap, and were clearly observed within the first 35MUm in the two studied liners. Despite the equivalent level of the bulk alphac and , higher restoring force against a uniaxial strain was observed in Liner IF, which reflects a higher crosslink density in its amorphous phase. On the other hands, a higher degree of surface orientational randomness was detected in Liner BL, which is structurally more beneficial for minimizing the in-vivo occurrence of strain softening-assisted wear. PMID- 24801102 TI - A new class of bio-composite materials of unique collagen fibers. AB - A novel collagen-based bio-composite was constructed from micro-crimped long collagen fiber bundles extracted from a soft coral embedded in alginate hydrogel matrix. The mechanical features of this bio-composite were studied for different fiber fractions and in longitudinal and transverse loading modes. The tensile modulus of the alginate hydrogel was 0.60+/-0.35MPa and in longitudinal collagen reinforced construct it increased up to 9.71+/-2.80 for 50% fiber fraction. Ultimate tensile strength was elevated from 0.08+/-0.04MPa in matrix up to 1.21+/ 0.29 for fiber fraction of 30%. The bio-composite demonstrated hyperelastic behavior similar to human native tissues. Additionally, a dedicated constitutive material model was developed to enable the prediction of the longitudinal mechanical behavior of the bio-composite. These findings will allow tailor designed mechanical properties with a quantitatively controlled amount of fibers and their designed spatial arrangement. This unique bio-composite has the potential to be used for a wide range of engineered soft tissues. PMID- 24801103 TI - Preface: differential quantitative structure-activity relationship (DiffQSAR) in the characterization of emerging drug resistance. PMID- 24801104 TI - QSAR models for anti-malarial activity of 4-aminoquinolines. AB - In the present study, predictive quantitative structure - activity relationship (QSAR) models for anti-malarial activity of 4-aminoquinolines have been developed. CORAL, which is freely available on internet (http://www.insilico.eu/coral), has been used as a tool of QSAR analysis to establish statistically robust QSAR model of anti-malarial activity of 4 aminoquinolines. Six random splits into the visible sub-system of the training and invisible subsystem of validation were examined. Statistical qualities for these splits vary, but in all these cases, statistical quality of prediction for anti-malarial activity was quite good. The optimal SMILES-based descriptor was used to derive the single descriptor based QSAR model for a data set of 112 aminoquinolones. All the splits had r(2)> 0.85 and r(2)> 0.78 for subtraining and validation sets, respectively. The three parametric multilinear regression (MLR) QSAR model has Q(2) = 0.83, R(2) = 0.84 and F = 190.39. The anti-malarial activity has strong correlation with presence/absence of nitrogen and oxygen at a topological distance of six. PMID- 24801107 TI - Enhanced photovoltaic performance of perovskite CH3NH3PbI3 solar cells with freestanding TiO2 nanotube array films. AB - Freestanding TiO2 nanotube array films are fabricated and first applied as electrodes in perovskite CH3NH3PbI3 sensitized solar cells. The device demonstrates improved light absorption with more than 90% of light absorbed in the whole visible range and a reduced charge recombination rate, leading to a significant improvement of the photocurrent and efficiency. This study suggests a promising way of improving the conversion efficiency of perovskite solar cells through novel electrodes. PMID- 24801106 TI - Oropharyngeal squamous cell carcinoma in the veteran population: Association with traditional carcinogen exposure and poor clinical outcomes. AB - BACKGROUND: A significant fraction of oropharyngeal squamous cell carcinoma (SCC) cases is associated with traditional carcinogens; in these patients, treatment response and clinical outcomes remain poor. METHODS: We evaluated patient, tumor, and treatment characteristics for 200 veterans with oropharyngeal SCC treated at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) between 2000 and 2012. RESULTS: Most patients (77%) were white and heavy smokers. Twenty-seven patients required tracheostomy and 63 required gastrostomy placement during treatment. Overall survival (OS) at 5 years was 40%. Survival was impacted by T classification, treatment intensity, completion of treatment, and p16 tumor status. Almost 30% of patients were unable to complete a treatment regimen consistent with National Comprehensive Cancer Network (NCCN) guidelines. CONCLUSION: Oropharyngeal SCC in veterans is associated with traditional carcinogens and poor clinical outcomes. Despite heavy smoking exposure, p16 tumor status significantly impacts survival. Careful consideration must be given to improving treatment paradigms for this cohort given their limited tolerance for treatment escalation. PMID- 24801108 TI - Written emotional disclosure for adults with Type 2 diabetes: a primary care feasibility study. AB - AIM: To test the feasibility of written emotional disclosure (WED) for UK primary care patients with Type 2 diabetes. BACKGROUND: WED holds potential to address depressive symptoms in diabetes, yet its feasibility, and potential benefit, for primary care patients has not been established. METHOD: Forty-one adults with Type 2 diabetes were randomised to WED (n=23) or neutral writing (n=18). Principal outcomes were feasibility of recruitment, compliance, acceptability and intervention fidelity. Potential benefit was assessed on between-group differences in depressive symptoms (Centre for Epidemiological Studies Depression scale), diabetes distress (Problem Areas in Diabetes scale), diabetes self management behaviours (Summary of Diabetes Self-care Activities questionnaire) and perceived health status (EQ-5D) at three-month follow-up. FINDINGS: Recruitment was modest (6%), yet an unmet treatment need was identified. Fourteen intervention (61%) and 13(72%) control participants returned their writing, while 12 in each group (89%) then completed all sessions. Intervention fidelity was confirmed. Acceptability to patients was mixed. Exploratory effectiveness analyses suggested that relative to improvement in controls, WED is associated with a potentially clinically important worsening in depressive symptoms (P=0.006) and a non-significant trend for a reduction in healthy dietary behaviour (P=0.057). There was no significant effect on other outcomes. The exploratory nature of the study, however, necessitates that the observed effects are interpreted with caution, and both the feasibility and effectiveness findings may be an artefact of the sample obtained. The evidence for the feasibility of WED in primary care diabetes was hence mixed, and in an unevaluated environment it may cause iatrogenic harm. On balance, WED is apparently not appropriate for use in this context in its current format. At most, further research with a more appropriate sample is required. The feasibility that was demonstrated and the unmet need identified suggest that this may be a worthy endeavour. PMID- 24801105 TI - Developmental ORIgins of Healthy and Unhealthy AgeiNg: the role of maternal obesity--introduction to DORIAN. AB - Europe has the highest proportion of elderly people in the world. Cardiovascular disease, type 2 diabetes, sarcopenia and cognitive decline frequently coexist in the same aged individual, sharing common early risk factors and being mutually reinforcing. Among conditions which may contribute to establish early risk factors, this review focuses on maternal obesity, since the epidemic of obesity involves an ever growing number of women of reproductive age and children, calling for appropriate studies to understand the consequences of maternal obesity on the offspring's health and for developing effective measures and policies to improve people's health before their conception and birth. Though the current knowledge suggests that the long-term impact of maternal obesity on the offspring's health may be substantial, the outcomes of maternal obesity over the lifespan have not been quantified, and the molecular changes induced by maternal obesity remain poorly characterized. We hypothesize that maternal insulin resistance and reduced placental glucocorticoid catabolism, leading to oxidative stress, may damage the DNA, either in its structure (telomere shortening) or in its function (via epigenetic changes), resulting in altered gene expression/repair, disease during life, and pathological ageing. This review illustrates the background to the EU-FP7-HEALTH-DORIAN project. PMID- 24801110 TI - 'Prudent habitat choice': a novel mechanism of size-assortative mating. AB - Assortative mating, an ubiquitous form of nonrandom mating, strongly impacts Darwinian fitness and can drive biological diversification. Despite its ecological and evolutionary importance, the behavioural processes underlying assortative mating are often unknown, and in particular, mechanisms not involving mate choice have been largely ignored so far. Here, we propose that assortative mating can arise from 'prudent habitat choice', a general mechanism that acts under natural selection, and that it can occur despite a complete mixing of phenotypes. We show that in the cichlid Eretmodus cyanostictus size-assortative mating ensues, because individuals of weaker competitive ability ignore high quality but strongly competed habitat patches. Previous studies showed that in E. cyanostictus, size-based mate preferences are absent. By field and laboratory experiments, here we showed that (i) habitat quality and body size are correlated in this species; (ii) territories with more stone cover are preferred by both sexes in the absence of competition; and (iii) smaller fish prudently occupy vacant territories of worse quality than do larger fish. Prudent habitat choice is likely to be a widespread mechanism of assortative mating, as both preferences for and dominance-based access to high-quality habitats are generic phenomena in animals. PMID- 24801109 TI - Characterization of a novel Pseudomonas aeruginosa bacteriophage, KPP25, of the family Podoviridae. AB - Pseudomonas aeruginosa phages belonging to the family Podoviridae are one of the well-characterized phage groups. In this study, a novel P. aeruginosa phage, KPP25, was isolated and characterized. Phage KPP25's morphology was indicative of the family Podoviridae; however, analyses of the whole genome and the virion proteins suggested that it did not belong to any of the known podophage genera. Based on these analyses, phage KPP25 appears to be a novel podophage infecting P. aeruginosa. PMID- 24801111 TI - Penetration force, geometry, and cutting profile of the novel and old Ozurdex needle: the MONO study. AB - PURPOSE: To investigate the geometry, penetration force, and cutting profile of the novel and old needle of the drug delivery system (DDS) for Ozurdex injections in a standardized laboratory setting. METHODS: In this experimental study, the normative geometrical data of the DDS needle were systematically analyzed according to nomenclature DIN 13097 (ISO 7864) and ISO 9626. The force to penetrate a standardized 0.4-mm-thick polyurethane foil was measured by a penetrometer, when the needle was piercing, cutting, and sliding through the foil and plotted as a load-displacement diagram. Magnified images of the consecutive cut were taken after the entire penetration through the foil. RESULTS: In this experimental study, the mean point length was equal to 3.34 mm (3.28-3.36 mm) for the old DDS needle versus 3.33 mm (3.30-3.36 mm) for the new DDS needle. The secondary bevel length was 1.64 mm (1.42-1.73 mm) for the new and 1.66 mm (1.62 1.69 mm) for the old needle. The primary angle was 9.2 degrees (9.0 degrees -9.5 degrees ) for the old and 8.9 degrees (8.5 degrees -9.0 degrees ) for the new needle, respectively. The secondary bevel angle was 117.2 degrees (116 degrees 118 degrees ) for the old and 111.4 degrees (110 degrees -113 degrees ) for the new needle. The mean penetration force of the old DDS needles was significantly higher at all phases of the penetration experiment: The mean piercing force was 0.7 Newton (N) with the old and 0.47 N with the new DDS needle. The mean cutting force was remarkable higher with 1.1 N for the old DDS needle versus 0.78 N for the new DDS needle. The dilatation phase was not statistically significant between 0.94 and 0.99 N in both DDS needles. The friction phase was maintained at significantly higher levels with the old DDS needle of 0.47 N, whereas it returned to the lowest measurements of 0.11 N with the new DDS needle. Both DDS systems induced a characteristic chevron-shaped incision. CONCLUSION: A comparison of the old and new DDS needles demonstrated a reduced penetration force with the modified new DDS needle, which may help to achieve a smooth penetration through the human sclera. PMID- 24801112 TI - Heterogeneity image patch index and its application to consumer video summarization. AB - Automatic video summarization is indispensable for fast browsing and efficient management of large video libraries. In this paper, we introduce an image feature that we refer to as heterogeneity image patch (HIP) index. The proposed HIP index provides a new entropy-based measure of the heterogeneity of patches within any picture. By evaluating this index for every frame in a video sequence, we generate a HIP curve for that sequence. We exploit the HIP curve in solving two categories of video summarization applications: key frame extraction and dynamic video skimming. Under the key frame extraction frame-work, a set of candidate key frames is selected from abundant video frames based on the HIP curve. Then, a proposed patch-based image dissimilarity measure is used to create affinity matrix of these candidates. Finally, a set of key frames is extracted from the affinity matrix using a min-max based algorithm. Under video skimming, we propose a method to measure the distance between a video and its skimmed representation. The video skimming problem is then mapped into an optimization framework and solved by minimizing a HIP-based distance for a set of extracted excerpts. The HIP framework is pixel-based and does not require semantic information or complex camera motion estimation. Our simulation results are based on experiments performed on consumer videos and are compared with state-of-the-art methods. It is shown that the HIP approach outperforms other leading methods, while maintaining low complexity. PMID- 24801113 TI - Preface. Special issue on biosorption. PMID- 24801114 TI - Spider genomes provide insight into composition and evolution of venom and silk. AB - Spiders are ecologically important predators with complex venom and extraordinarily tough silk that enables capture of large prey. Here we present the assembled genome of the social velvet spider and a draft assembly of the tarantula genome that represent two major taxonomic groups of spiders. The spider genomes are large with short exons and long introns, reminiscent of mammalian genomes. Phylogenetic analyses place spiders and ticks as sister groups supporting polyphyly of the Acari. Complex sets of venom and silk genes/proteins are identified. We find that venom genes evolved by sequential duplication, and that the toxic effect of venom is most likely activated by proteases present in the venom. The set of silk genes reveals a highly dynamic gene evolution, new types of silk genes and proteins, and a novel use of aciniform silk. These insights create new opportunities for pharmacological applications of venom and biomaterial applications of silk. PMID- 24801116 TI - No difference in urinary iodine concentrations between Boston-area breastfed and formula-fed infants. AB - BACKGROUND: Thyroid hormone is essential for normal mental and physical development in infancy and childhood and is dependent on adequate iodine intake. During the first few months of life, infants are reliant on breastmilk and/or infant formula as their sole sources of dietary iodine. The iodine status of U.S. infants has not been well studied. METHODS: This was a cross-sectional study of 95 breastfed and/or formula-fed infants less than 3 months of age in the Boston area. We measured iodine content from infants' single spot urine samples and assessed associations with infant feeding type as well as maternal demographic data, salt and multivitamin use, smoking status, and diet. RESULTS: The median infant urine iodine concentration was 197.5 MUg/L (range 40-897.5 MUg/L). Median infant urine iodine concentrations were similar between infants who were exclusively breastfed (n=39, 203.5 MUg/L; range 61.5-395.5 MUg/L), formula-fed (n=44, 182.5 MUg/L; range 40-897.5 MUg/L), and mixed (n=10, 197.8 MUg/L; range 123-592.5) (p=0.88). There were no significant correlations of infant urinary iodine with maternal salt or multivitamin use (regularly or in the past 24 hours), active or secondhand cigarette smoke exposures, infant weight, infant length, or recent maternal ingestion of common iodine-containing foods, although the correlations with iodine-containing foods are difficult to accurately determine due to the small sample sizes of these variables. CONCLUSIONS: Both breastfed and formula-fed infants less than 3 months of age in the Boston area were generally iodine sufficient. Larger studies are needed to confirm these observations among infants nationwide and elucidate other factors that may contribute to infant iodine nutrition. PMID- 24801118 TI - Botulinum toxin for upper oesophageal sphincter dysfunction in neurological swallowing disorders. AB - BACKGROUND: Adequate upper oesophageal sphincter (UOS) opening is critical to safe and efficient swallowing due to the close proximity of the UOS to the airway entrance. Many people with neurological conditions, progressive and non progressive, present with UOS dysfunction. The consequences for the person include difficulty swallowing food with subsequent choking and aspiration (passage of material into the trachea beyond the level of the true vocal cords). Clinical complications include aspiration pneumonia, weight loss, dehydration and malnutrition. Tube feeding is often indicated but is associated with increased mortality. Quality of life is also frequently impacted. A range of interventions exist that aim to improve UOS function and swallowing. These include compensatory strategies, rehabilitation techniques, pharmacological interventions and surgery. Over the last two decades, botulinum toxin has been gaining popularity as an intervention for UOS dysfunction, with some evidence to suggest that it is successful in improving swallow function. Despite a number of studies investigating its efficacy, there is a lack of consensus regarding whether this intervention is effective in improving swallowing for individuals with UOS dysfunction associated with neurological disease. OBJECTIVES: To establish the efficacy and safety of botulinum toxin use aimed at improving UOS dysfunction in people with swallowing difficulties (dysphagia) associated with non-progressive and progressive neurological disease. SEARCH METHODS: We searched the following electronic databases for published trials: the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (1950 to 2013); EMBASE (1980 to 2013); AMED (Allied and Complementary Medicine) (1941 to 2013); CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1937 to 2013). We also searched major clinical trials registers: CCT (http://www.controlled-trials.com); Clinical Trials (http://www.clinicaltrials.gov); Chinese Clinical Trial Register (www.chictr.org); ACTR (http://www.actr.org.au/. We examined the reference lists of all potentially relevant studies to identify further relevant trials. We handsearched published abstracts of conference proceedings from both the Dysphagia Research Society and the European Society of Swallowing Disorders. Digestive Disease Week (published in Gastroenterology) was also handsearched. Additionally, we searched ProQuest Dissertations & Theses for dissertation abstracts. SELECTION CRITERIA: Only randomised controlled trials were sought. DATA COLLECTION AND ANALYSIS: Independent searches were completed by JR, AM, MC and MW. Two review authors (JR and MW) independently inspected titles, abstracts and key words identified from the literature search. MAIN RESULTS: No randomised controlled studies were retrieved. Twenty-nine studies were excluded, mainly on the basis of trial design. AUTHORS' CONCLUSIONS: It was not possible to reach a conclusion on the efficacy and safety of botulinum toxin as an intervention for people with UOS dysfunction and neurological disease. There is insufficient evidence to inform clinical practice. Directions for future research are provided. PMID- 24801119 TI - Randomised study of a bioabsorbable polymer-coated sirolimus-eluting stent: results of the DESSOLVE II trial. AB - AIMS: To compare the efficacy and safety of the MiStent absorbable polymer sirolimus-eluting stent (APSES) with a zotarolimus-eluting stent (ZES). METHODS AND RESULTS: The trial was a 2:1 randomisation at 26 sites of 184 patients implanted with an APSES (n=123) versus a ZES (n=61). Following stent implantation, all patients underwent quantitative coronary angiography at baseline and at nine months of follow-up, while a select subgroup also underwent optical coherence tomography (OCT). The primary efficacy hypothesis was superiority of in-stent late lumen loss (LLL) of APSES compared to ZES. At nine months, the primary endpoint was met, with a mean in-stent LLL of 0.27+/-0.46 mm in 103 APSES patients versus 0.58+/-0.41 mm in 52 ZES patients (p<0.001). The proportion of uncovered stent struts by OCT at nine months was very low in both groups. The mean neointimal thickness of covered struts (p=0.002) and percent net volume obstruction (p<=0.003) were significantly lower in the APSES than in the ZES group. Major adverse cardiac event and stent thrombosis rates were low and comparable between groups. CONCLUSIONS: The DESSOLVE II trial demonstrated superiority in the primary efficacy endpoint of nine-month mean LLL for APSES compared to ZES. Strut coverage by OCT was high with both stents and the clinical safety endpoints including stent thrombosis were equally low in both groups. ClinicalTrials.gov Identifier: NCT01294748. PMID- 24801117 TI - Abnormal Ca(2+) cycling in failing ventricular myocytes: role of NOS1-mediated nitroso-redox balance. AB - SIGNIFICANCE: Heart failure (HF) results from poor heart function and is the leading cause of death in Western society. Abnormalities of Ca(2+) handling at the level of the ventricular myocyte are largely responsible for much of the poor heart function. RECENT ADVANCES: Although studies have unraveled numerous mechanisms for the abnormal Ca(2+) handling, investigations over the past decade have indicated that much of the contractile dysfunction and adverse remodeling that occurs in HF involves oxidative stress. CRITICAL ISSUES: Regrettably, antioxidant therapy has been an immense disappointment in clinical trials. Thus, redox signaling is being reassessed to elucidate why antioxidants failed to treat HF. FUTURE DIRECTIONS: A recently identified aspect of redox signaling (specifically the superoxide anion radical) is its interaction with nitric oxide, known as the nitroso-redox balance. There is a large nitroso-redox imbalance with HF, and we suggest that correcting this imbalance may be able to restore myocyte contraction and improve heart function. PMID- 24801120 TI - Image mapping of untracked free-hand endoscopic views to an ultrasound image constructed 3D placenta model. AB - BACKGROUND: This study presents a tracker-less image-mapping framework for surgical navigation motivated by the clinical need for intuitive visual guidance during minimally invasive fetoscopic surgery. METHODS: A navigation framework mapping 2D endoscopic vision to a 3D ultrasound image model is proposed. This maps an endoscopic image onto a 3D placenta model through a one-time ultrasound image-based localization method followed by a series of concurrent image alignments and texture mapping of the untracked endoscopic video stream. RESULTS: The mean absolute error of our ultrasound image-based localization method was (1.63 mm, 0.93 degrees ). The simulation analysis reveals an upper bound mapping performance with a mean error of 1.53 mm. In a phantom experiment, the overall mapping performance is close to this accuracy and achieves a mean absolute error of 2 mm, thereby supporting the feasibility of this method. CONCLUSION: This novel integration of intraoperative visual guidance has potential contributions to innovative fusions of image guidance techniques for effective navigation in minimally invasive fetoscopic surgery. PMID- 24801121 TI - [Stroke rehabilitation in nursing homes: intensity of and motivation for physiotherapy]. AB - INTRODUCTION: Stroke is a frequent and potential invalidating disease, of which recovery can be improved by rehabilitation. In The Netherlands old and frail stroke patients are rehabilitated in nursing homes. Probably, the intensity of and motivation for physiotherapy are important for successful discharge. The aim was to determine (1) therapy intensity of and motivation for physical therapy of geriatric stroke patients (2) its correlates and (3) the effect on discharge destination. METHODS: Data were obtained from the 'GRAMPS'-study, a longitudinal observational study of stroke rehabilitation in 15 Dutch nursing homes. Direct time spent on physiotherapy was registered during admission. Motivation was measured by the Pittsburgh Rehabilitation Participation Scale (PRPS). Data of 84 patients were analysed using uni- and multivariate regression analysis. RESULTS: Patients received an average 109 min of physiotherapy per week. 69 patients (82%) were good motivated for physiotherapy (had all PRPS scores 4 or higher). Therapy intensity was positively associated with the presence of a partner and good motivation. No significant independent variables of motivation were found. Therapy-intensity was positively related to discharge to prior living situation. CONCLUSION: Intensity of physiotherapy of stroke rehabilitation is an independent variable of successful discharge and is higher when the patient has a partner or is better motivated. These findings stress the importance of high motivation and therapy intensity in geriatric stroke rehabilitation. PMID- 24801122 TI - [Not Available]. PMID- 24801123 TI - Peroxido complexes of vanadium(V) as ligands. Crystal structures of [Cd(NH3)6][{VO(O2)2(OH)}2{MU-Cd(NH3)4}] and [{VO(O2)2(Im)}2{MU-Cu(Im)4}] (Im = Imidazole). AB - Two novel heterometallic complexes [Cd(NH3)6][{VO(O2)2(OH)}2{MU-Cd(NH3)4}] (2) and [{VO(O2)2(Im)}2{MU-Cu(Im)4}] (3) (Im = imidazole) containing peroxidovanadium complexes as metalloligands were prepared and characterized by spectral methods. X-ray single-crystal analysis revealed the presence of unique trinuclear complexes in the crystal structures of 2 and 3. The structure of 2 contains an anionic complex, whose two {VO(O2)2(OH)}(2-) ions are interconnected by a {MU Cd(NH3)4}(2+) group. Compound 3 is a trinuclear neutral complex comprising two {VO(O2)2(Im)}(-) ions and a single bridging {MU-Cu(Im)4}(2+) group. The bonding via an equatorial OH(-) ligand in 2 and via a doubly bonded apical oxygen atom in 3 represents coordination modes previously unobserved for diperoxidovanadium complexes. Compared with complex 2, density functional theory studies reported decreased Cu-MU-O bond orders and increased MU-O-V bond orders in 3, in accordance with the expected Jahn-Teller distortion of the latter complex. PMID- 24801124 TI - A negative-capacitance equivalent circuit model for parallel-plate capacitive-gap transduced micromechanical resonators. AB - A small-signal equivalent circuit for parallel-plate capacitive-gap-transduced micromechanical resonators is introduced that employs negative capacitance to model the dependence of resonance frequency on electrical stiffness in a way that facilitates circuit analysis, that better elucidates the mechanisms behind certain potentially puzzling measured phenomena, and that inspires circuit topologies that maximize performance in specific applications. For this work, a micromechanical disk resonator serves as the vehicle with which to derive the equivalent circuits for both radial-contour and wine-glass modes, which are then used in circuit simulations (via simulation) to match measurements on actual fabricated devices. The new circuit model not only correctly predicts the dependence of electrical stiffness on the impedances loading the input and output electrodes of parallel-plate capacitive- gap-transduced micromechanical device, but does so in a visually intuitive way that identifies current drive as most appropriate for applications that must be stable against environmental perturbations, such as acceleration or power supply variations. Measurements on fabricated devices confirm predictions by the new model of up to 4* improvement in frequency stability against dc-bias voltage variations for contour- mode disk resonators as the resistance loading their ports increases. By enhancing circuit visualization, this circuit model makes more obvious the circuit design procedures and topologies most beneficial for certain mechanical circuits, e.g., filters and oscillators. PMID- 24801125 TI - Catalytic fast pyrolysis of lignocellulosic biomass. AB - Increasing energy demand, especially in the transportation sector, and soaring CO2 emissions necessitate the exploitation of renewable sources of energy. Despite the large variety of new energy carriers, liquid hydrocarbon still appears to be the most attractive and feasible form of transportation fuel taking into account the energy density, stability and existing infrastructure. Biomass is an abundant, renewable source of energy; however, utilizing it in a cost effective way is still a substantial challenge. Lignocellulose is composed of three major biopolymers, namely cellulose, hemicellulose and lignin. Fast pyrolysis of biomass is recognized as an efficient and feasible process to selectively convert lignocellulose into a liquid fuel-bio-oil. However bio-oil from fast pyrolysis contains a large amount of oxygen, distributed in hundreds of oxygenates. These oxygenates are the cause of many negative properties, such as low heating value, high corrosiveness, high viscosity, and instability; they also greatly limit the application of bio-oil particularly as transportation fuel. Hydrocarbons derived from biomass are most attractive because of their high energy density and compatibility with the existing infrastructure. Thus, converting lignocellulose into transportation fuels via catalytic fast pyrolysis has attracted much attention. Many studies related to catalytic fast pyrolysis of biomass have been published. The main challenge of this process is the development of active and stable catalysts that can deal with a large variety of decomposition intermediates from lignocellulose. This review starts with the current understanding of the chemistry in fast pyrolysis of lignocellulose and focuses on the development of catalysts in catalytic fast pyrolysis. Recent progress in the experimental studies on catalytic fast pyrolysis of biomass is also summarized with the emphasis on bio-oil yields and quality. PMID- 24801126 TI - Macrolides are associated with a better survival rate in patients hospitalized with community-acquired but not healthcare-associated pneumonia. AB - BACKGROUND: Macrolide-based treatment has been associated with survival benefit in patients hospitalized with community-acquired pneumonia (CAP). However, the influence of macrolide therapy in all patients hospitalized with pneumonia, including healthcare-associated pneumonia (HCAP), is unclear. METHODS: Analysis of a retrospective single-center cohort. RESULTS: Community-acquired pneumonia was present in 220 (22.5%) of all patients with pneumonia admitted through the emergency department of Barnes-Jewish Hospital, and HCAP was present in 757. Macrolide-based treatment was administered to 411 patients (42.1%). These patients were more likely to have CAP than were patients not receiving macrolide based therapy (35.3% vs. 13.3%; p<0.001) and had lower scores on the CURB-65 tool, a measure of the severity of illness (2.4+/-1.5 vs. 3.1+/-1.3; p<0.001). Patients receiving macrolides also had a lower hospital mortality rate in univariable analysis (12.7% vs. 27.2%; p<0.001). A propensity score analysis showed that macrolide-based treatment was associated with a lower in-hospital mortality rate (adjusted odds ratio [AOR] 0.67; 95% confidence interval [CI] 0.54 0.81; p=0.043). Separate propensity score analyses of patients with CAP (AOR 0.20; 95% CI 0.11-0.34; p=0.003) and HCAP (AOR 0.81; 95% CI 0.65-1.01; p=0.337) produced discordant findings. CONCLUSIONS: Macrolide-based treatment was associated with better survival in patients hospitalized with pneumonia. The survival advantage appeared predominantly among patients with CAP. PMID- 24801128 TI - Proteasome inhibitor carfilzomib interacts synergistically with histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells. AB - In the present study, we investigated the interactions between proteasome inhibitor carfilzomib (CFZ) and histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells. Coexposure of cells to minimally lethal concentrations of CFZ with very low concentration of vorinostat resulted in synergistic antiproliferative effects and enhanced apoptosis in Jurkat T-leukemia cells, accompanied with the sharply increased reactive oxygen species (ROS), the striking decrease in the mitochondrial membrane potential (MMP), the increased release of cytochrome c, the enhanced activation of caspase-9 and -3, and the cleavage of PARP. The combined treatment of Jurkat cells pre-treated with ROS scavengers N-acetylcysteine (NAC) significantly blocked the loss of mitochondrial membrane potential, suggesting that ROS generation was a former event of the loss of mitochondrial membrane potential. Furthermore, NAC also resulted in a marked reduction in apoptotic cells, indicating a critical role for increased ROS generation by combined treatment. In addition, combined treatment arrested the cell cycle in G2-M phase. These results imply that CFZ interacted synergistically with vorinostat in Jurkat T-leukemia cells, which raised the possibility that the combination of carfilzomib with vorinostat may represent a novel strategy in treating T-cell Leukemia. PMID- 24801129 TI - Who pays this doctor? It's time patients knew. PMID- 24801127 TI - Association of pro-inflammatory high-density lipoprotein cholesterol with clinical and laboratory variables in sickle cell disease. AB - Background Although cholesterol levels are known to be decreased in sickle cell disease (SCD), the level of pro-inflammatory high-density lipoprotein cholesterol (proHDL) and its association with clinical complications and laboratory variables has not been evaluated. Design and methods Plasma levels of total cholesterol, high-density lipoprotein cholesterol (HDL), proHDL, and selected clinical and laboratory variables were ascertained in a cohort of SCD patients and healthy African American control subjects in this single-center, cross-sectional study. Results Although total cholesterol was significantly lower in SCD patients compared with control subjects, HDL and proHDL levels were similar in both the SCD and control groups. In univariate analyses, proHDL was correlated with echocardiography-derived tricuspid regurgitant jet velocity. ProHDL was higher in SCD patients with suspected pulmonary hypertension (PHT) compared to patients without suspected PHT. ProHDL was positively correlated with lactate dehydrogenase, total bilirubin, direct bilirubin, indirect bilirubin, prothrombin fragment 1+2, D-dimer, and thrombin-antithrombin complexes. In multivariable analyses, only higher lactate dehydrogenase and direct bilirubin levels were associated with higher levels of proHDL. Conclusions SCD is characterized by hypocholesterolemia. Although proHDL is not increased in SCD patients compared with healthy controls, it is significantly associated with markers of liver disease. In addition, proHDL is associated with tricuspid regurgitant jet velocity and markers of coagulation, although these associations are not significant in multivariable analyses. PMID- 24801130 TI - Aggressive lipid management in very elderly adults: less is more. PMID- 24801131 TI - 18F-FDG-PET/CT in fever of unknown origin: clinical value. AB - OBJECTIVE: Fever of unknown origin continues to be a diagnostic challenge for clinicians. The aim of this study was to confirm whether (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/computed tomography (CT) is a helpful tool in patients suffering from this condition. PATIENTS AND METHODS: Fifty-seven patients with fever of unknown origin were examined with (18)F-FDG-PET/CT as part of their diagnostic workup at the clinicians' discretion. The medical records were read retrospectively to establish the final diagnosis and evaluate the degree to which PET/CT contributed to the diagnosis. RESULTS: The examination was considered helpful if it corresponded to the final diagnosis by showing uptake in an organ considered responsible for the condition, or if it was without focal findings, thereby excluding the patient from having focal infection or malignancy. It was perceived false positive if it pointed towards an organ not regarded by the clinicians as being related to the final diagnosis. It was perceived not helpful if the cause of fever was not visible on (18)F-FDG-PET/CT. We found (18)F-FDG PET/CT helpful in 75% of patients, not helpful in 4%, and false positive in 21% of patients. CONCLUSION: (18)F-FDG-PET/CT is a useful tool in the investigation of fever of unknown origin; it can reduce patient inconvenience and possibly costs to society if used earlier in the diagnostic process. PMID- 24801132 TI - A biocompatible method of controlled retrieval of cell-encapsulating microgels from a culture plate. AB - We report a biocompatible method of selectively retrieving 3-D cell-encapsulating hydrogel microstructures from a culture substrate. First, poly(l lysine)/hyaluronic acid (PLL/HA) polyelectrolyte multilayers (PEMs) with methacrylated chitosan (GMA-Chi) on top were formed on an ITO substrate. Then, a cell-encapsulating hydrogel micropattern was formed; a HepG2 cell-encapsulating heparin-based hydrogel micropattern was fabricated by thiol-ene photopolymerization. The application of an oxidative potential of 2 V resulted in the detachment of the cell-encapsulating hydrogels by the dissolution of PEMs. The time of complete retrieval of the hydrogels was controllable by modulating the number of PEM layers. The applied potential did not affect the viability or the function of the cells in the entire hydrogels. In contrast, when a reductive electrochemical potential (-1.8 V) was applied to a silane-modified ITO to release cell-encapsulating hydrogels by the desorption of silane [Chem. Commun., 2009, 5865], extensive cell death at the bottom of the hydrogel adjacent to the electrode was observed. PMID- 24801133 TI - Refinement of the deletion in 8q22.2-q22.3: the minimum deletion size at 8q22.3 related to intellectual disability and epilepsy. AB - Kuechler et al. [2011] reported five patients with interstitial deletions in 8q22.2-q22.3 who had intellectual disability, epilepsy, and dysmorphic features. We report on a new patient with the smallest overlapping de novo deletion in 8q22.3 and refined the phenotype. The proposita was an 8-year-old girl, who developed seizures at 10 months, and her epileptic seizure became severe and difficult to control with antiepileptic drugs. She also exhibited developmental delay and walked alone at 24 months. She was referred to us for evaluation for developmental delay and epilepsy at the age of 8 years. She had intellectual disability (IQ 37 at 7 years) and autistic behavior, and spoke two word sentences at 8 years. She had mild dysmorphic features, including telecanthus and thick vermilion of the lips. Array comparative genomic hybridization detected a 1.36 Mb deletion in 8q22.3 that encompassed RRM2B and NCALD, which encode the small subunit of p53-inducible ribonucleotide reductase and neurocalcin delta in the neuronal calcium sensor family of calcium-binding proteins, respectively. The minimum overlapping region between the present and previously reported patients is considered to be a critical region for the phenotype of the deletion in 8q22.3. We suggest that the deletion in 8q22.3 may represent a clinically recognizable condition, which is characterized by intellectual disability and epilepsy. PMID- 24801134 TI - Hypercortisolism in obesity-associated hypertension. AB - Obesity is prevalent worldwide and associated with co-morbidities that result in increased cardiovascular risk. Hypertension is the most prevalent obesity comorbidity associated with increased cardiovascular risk. Obesity hypertension is a distinct subtype of essential hypertension. While endogenous Cushing's syndrome is an uncommon cause of both obesity and hypertension, the recent recognition of other hypercortisolemic states has raised the profile of hypercortisolism as an important contributor in obesity hypertension. The high prevalence of exogenous, iatrogenic, pseudo, and subclinical Cushing's syndromes makes hypercortisolism an important diagnostic consideration in the evaluation and management of patients with obesity hypertension who are resistant to conventional management. Available data suggest that the renin-angiotensin aldosterone system modulating antihypertensives have the best efficacy in hypercortisolism-mediated obesity hypertension. Strategies aimed at reducing cortisol production and action also have utility. This review provides a comprehensive overview of the epidemiology, etiopathogenesis and management options available for glucocorticoid-mediated obesity hypertension. PMID- 24801136 TI - Upper limits of intraocular pressure in glaucoma clinical trials. PMID- 24801135 TI - Cardiac target organ damage in hypertension: insights from epidemiology. AB - Hypertension is an important risk factor implicated in the development of multiple common cardiac conditions, including coronary atherosclerosis, heart failure, and atrial fibrillation. Epidemiologic studies have provided insights into the shared pathogenesis of hypertension and subclinical as well as clinically evident cardiac diseases. The mechanistic common ground between chronic blood pressure elevation and cardiac disease likely begins early in life. Understanding these connections will aid ongoing efforts to identify individuals at risk, develop targeted therapeutics, and improve overall outcomes for individuals with elevated blood pressure in the population at large. PMID- 24801137 TI - Process and outcome for international reliability in sleep scoring. AB - OBJECTIVES: The aim was to evaluate the inter-rater reliability in scoring sleep stages in two sleep labs in Berlin Germany and Beijing China. METHODS: The subjects consist of polysomnography (PSGs) from 15 subjects in a German sleep laboratory, with 7 mild to moderate sleep apnea hypopnea syndrome (SAHS) patients and 8 healthy controls, and PSGs from 15 narcolepsy patients in a Chinese sleep laboratory. Five experienced technologists including two Chinese and three Germans without common training scored the PSGs following the 2007 AASM manual except the EEG signals included only two EEG leads (C3/A2 and C4/A1). Differences in inter-scorer agreement were analyzed based on epoch-by-epoch comparison by means of Cohen's kappa, and quantitative sleep parameters by means of intra-class correlation coefficients. RESULTS: Inter-laboratory epoch-by-epoch agreement comparison between scorers from the two countries yielded a moderate agreement with a mean kappa value of 0.57 for controls, 0.58 for SAHS, and 0.54 for narcolepsy. When compared with controls, the inter-scoring agreement is higher for wake and N3 stage scoring in SAHS and N1 and N3 scoring in narcolepsy (p < 0.05). The only sleep stage with lower scoring agreement in both SAHS (kappa 0.69 vs. 0.79, p = 0.034) and narcolepsy (0.66 vs 0.79, p = 0.022) was stage REM. Inter-laboratory comparisons showed that the most common combinations of deviating scorings were N1 and N2, N2 and N3, and N1 and wake. A 6.5 % deviating scoring rate of wake and REM and a 13.4 % deviating scoring rate of N1 and REM indicated that inter-laboratory scoring in narcolepsy was about twice as in SAHS and controls confused. This was further confirmed by agreement analysis of quantitative parameters using intra-class correlation coefficients ICC(2,1) indicating REM sleep scoring agreement was lower in narcolepsy than in controls (p < 0.05). CONCLUSION: Low REM stage scoring agreement exists for narcoleptics and SAHS, indicating the necessity to study sleep stage scoring agreement for a specific sleep disorder. Intensive training is needed for the scoring of sleep in international multiple center studies to improve the scoring agreement. PMID- 24801138 TI - Relationship between sleep, sleep apnea, and neuropsychological function in children with Down syndrome. AB - PURPOSE: To determine whether sleep and sleep disordered breathing (SDB) contribute to the neuropsychological deficits of patients with Down syndrome, and whether treatment of SDB results in improvement in cognitive function. METHODS: In this cohort study, 25 children with Down syndrome underwent overnight polysomnography (PSG), Multiple Sleep Latency Testing (MSLT), and a battery of neuropsychological tests. Patients with SDB underwent a follow up PSG after treatment. All patients repeated the neuropsychological tests 13 months later. RESULTS: At baseline, there was no relationship between SDB and performance on the neuropsychological tests. However, total sleep time and sleep latency were related to tests of cognitive ability (p < 0.05) and comprehension (p < 0.01). The amount of time in slow-wave sleep correlated with tests of achievement (p < 0.01), and adaptive behavior (p < 0.01). Ten patients had SDB confirmed on PSG. Five of these patients were treated successfully with adenotonsillectomy and/or continuous positive airway pressure. The five who did not tolerate treatment were deficient in tests of adaptive behavior (Vineland p < 0.05) visual-motor integration (Beery p < 0.01) and achievement (Woodcock-Johnson p < 0.05) compared to those successfully treated. After treatment the patients improved in ratings of attention (Conners p < 0.05). CONCLUSIONS: Although SDB is common in children with Down syndrome, it is not a major contributor to their cognitive deficits. Cognitive function is related to the amount of sleep and particularly slow wave sleep. Successful treatment of SDB may improve their attention. PMID- 24801139 TI - Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. AB - AIM: Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis. METHODS: Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100 mm) and phenformin (25-500 MUm) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH. RESULTS: Metformin induced respiratory inhibition at complex I in peripheral blood mononuclear cells and platelets (IC50 0.45 mm and 1.2 mm respectively). Phenformin was about 20-fold more potent in complex I inhibition of platelets than metformin. Metformin further demonstrated a dose- and time-dependent respiratory inhibition and augmented lactate release at a concentration of 1 mm and higher. CONCLUSION: Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to complex I, providing a suitable model for probing drug toxicity. Lactate production was increased at concentrations relevant for clinical metformin intoxication, indicating mitochondrial inhibition as a direct causative pathophysiological mechanism. Relative to clinical dosing, phenformin displayed a more potent respiratory inhibition than metformin, possibly explaining the higher incidence of lactic acidosis in phenformin-treated patients. PMID- 24801140 TI - Order of arrival shifts endophyte-pathogen interactions in bean from resistance induction to disease facilitation. AB - Endophytic fungi colonize plants without causing symptoms of disease and can enhance the resistance of their host to pathogens. We cultivated 53 fungal strains from wild lima bean (Phaseolus lunatus) and investigated their effects on pathogens using in vitro assays and experiments in planta. Most strains were annotated as Rhizopus, Fusarium, Penicillium, Cochliobolus, and Artomyces spp. by the sequence of their 18S rRNA gene. In vitro confrontation assays between endophytes and three pathogens (the bacteria Pseudomonas syringae pv. syringae and Enterobacter sp. strain FCB1, and the fungus Colletotrichum lindemuthianum) revealed strong and mainly symmetric reciprocal effects: endophyte and pathogen either mutually inhibited (mainly Enterobacter FCB1 and Colletotrichum) or facilitated (P. syringae) the growth of each other. In planta, the endophytes had a strong inhibitory effect on P. syringae when they colonized the plant before the bacterium, whereas infection was facilitated when P. syringae colonized the plant before the endophyte. Infection with Enterobacter FCB1 was facilitated when the bacterium colonized the plant before or on the same day with the endophyte, but not when the endophyte was present before the bacterium. The order of arrival determines whether fungal endophytes enhance plant resistance to bacterial pathogens or facilitate disease. PMID- 24801141 TI - Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin. AB - The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells. PMID- 24801142 TI - Protective effects of minocycline against short-term ischemia-reperfusion injury in rat brain. AB - The aim of this study was to assess the effects of minocycline on cerebral ischemia-reperfusion (I/R) injury in rats. The study was carried out on 24 male Wistar albino rats, weighing 200-250 g, which were divided into three groups: (i) control (n = 8), (ii) I/R (n = 8) and (iii) I/R + minocycline (n = 8). Minocycline was administrated at a dose of 90 mg/kg p.o. to the I/R group 48, 24 and 1 h before ischemia. Following bilateral exposure of the common carotid arteries by anterior cervical dissection and separation of the vagus nerve, I/R injury was performed by occlusion. Following reperfusion, malondialdehyde (MDA), superoxide dismutase, glutathione peroxidase and catalase levels in the blood and brain tissue, and creatine kinase (CK), CK-BB, lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and protein S100beta levels in the blood were measured and the histopathological changes were monitored. Regarding histopathological evaluation, symptoms of degeneration were significantly improved in the I/R + minocycline group compared to the I/R-only group. Statistical analysis of the biochemical parameters revealed significant differences in MDA (p < 0.001), nitric oxide (p < 0.05), CK (p < 0.05) and CK-MB (p < 0.05) levels between the I/R + minocycline group and the I/R group. According to the literature, the effect of minocycline is firstly assessed by LDH, CK-MB, NSE and S-100beta analysis in addition to antioxidant status and histopathological analysis. PMID- 24801143 TI - Mechanism of graphene oxide as an enzyme inhibitor from molecular dynamics simulations. AB - Graphene and its water-soluble derivative, graphene oxide (GO), have attracted huge attention because of their interesting physical and chemical properties, and they have shown wide applications in various fields including biotechnology and biomedicine. Recently, GO has been shown to be the most efficient inhibitor for alpha-chymotrypsin (ChT) compared with all other artificial inhibitors. However, how GO interacts with bioactive proteins and its potential in enzyme engineering have been rarely explored. In this study, we investigate the interactions between ChT and graphene/GO by using molecular dynamics (MD) simulation. We find that ChT is adsorbed onto the surface of GO or graphene during 100 ns MD simulations. The alpha-helix of ChT plays as an important anchor to interact with GO. The cationic and hydrophobic residues of ChT form strong interactions with GO, which leads to the deformation of the active site of ChT and the inhibition of ChT. In comparison, the active site of ChT is only slightly affected after ChT adsorbed onto the graphene surface. In addition, the secondary structure of ChT is not affected after it is adsorbed onto GO or graphene surface. Our results illustrate the mechanism of the interaction between GO/graphene and enzyme and provide guidelines for designing efficient artificial inhibitors. PMID- 24801144 TI - Agency attribution in infancy: evidence for a negativity bias. AB - Adults tend to attribute agency and intention to the causes of negative outcomes, even if those causes are obviously mechanical. Is this over-attribution of negative agency the result of years of practice with attributing agency to actual conspecifics, or is it a foundational aspect of our agency-detection system, present in the first year of life? Here we present two experiments with 6-month old infants, in which they attribute agency to a mechanical claw that causes a bad outcome, but not to a claw that causes a good outcome. Control experiments suggest that the attribution stems directly from the negativity of the outcome, rather than from physical cues present in the stimuli. Together, these results provide evidence for striking developmental continuity in the attribution of agency to the causes of negative outcomes. PMID- 24801145 TI - Cd hyperfine interactions in DNA bases and DNA of mouse strains infected with Trypanosoma cruzi investigated by perturbed angular correlation spectroscopy and ab initio calculations. AB - In this work, perturbed angular correlation (PAC) spectroscopy is used to study differences in the nuclear quadrupole interactions of Cd probes in DNA molecules of mice infected with the Y-strain of Trypanosoma cruzi. The possibility of investigating the local genetic alterations in DNA, which occur along generations of mice infected with T. cruzi, using hyperfine interactions obtained from PAC measurements and density functional theory (DFT) calculations in DNA bases is discussed. A comparison of DFT calculations with PAC measurements could determine the type of Cd coordination in the studied molecules. To the best of our knowledge, this is the first attempt to use DFT calculations and PAC measurements to investigate the local environment of Cd ions bound to DNA bases in mice infected with Chagas disease. The obtained results also allowed the detection of local changes occurring in the DNA molecules of different generations of mice infected with T. cruzi, opening the possibility of using this technique as a complementary tool in the characterization of complicated biological systems. PMID- 24801146 TI - Antimicrobial susceptibility and molecular epidemiology of Neisseria gonorrhoeae in Germany. AB - Antimicrobial drug resistance in Neisseria gonorrhoeae has become an increasing public health problem. Hence, surveillance of resistance development is of crucial importance to implement adequate treatment guidelines. Data on the spread of antibiotic resistance among gonococcal isolates in Germany, however, is scarce. In a resistance surveillance study conducted by the Paul Ehrlich Society for Chemotherapy between October 2010 and December 2011, 23 laboratories all over Germany were requested to send N. gonorrhoeae isolates to the study laboratory in Frankfurt am Main. Species verification was performed biochemically using ApiNH and with Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS). Antimicrobial susceptibility testing was performed using the Etest method. For molecular epidemiological analysis, N. gonorrhoeae strains were genotyped by means of N. gonorrhoeae multi-antigen sequence typing. A total of 213 consecutive gonococcal isolates were analyzed in this nationwide study. Applying EUCAST breakpoints, high resistance rates were found for ciprofloxacin (74%) and tetracycline (41%). Penicillin non-susceptibility was detected in 80% of isolates. The rate of azithromycin resistance was 6%, while all strains were susceptible to spectinomycin, cefixime, and ceftriaxone. Molecular typing of gonococcal isolates revealed a great heterogeneity of 99 different sequence types (ST), but ST1407 predominated (n=39). This is the first comprehensive German multi-centre surveillance study on antibiotic susceptibility and molecular epidemiology of N. gonorrhoeae with implications for antibiotic choice for treatment of gonorrhoea. The World Health Organization supports the concept that an efficacious treatment of gonorrhoea results in at least 95% of infections being cured. Accordingly, as spectinomycin is not available on the German market, only the third generation cephalosporins cefixime and ceftriaxone are regarded as valuable drugs for empirical treatment of gonorrhoea in Germany. PMID- 24801147 TI - Predisposition to Behcet's disease and VKH syndrome by genetic variants of miR 182. AB - Previous studies have identified miR-182, miR-27a, FoxO1, and IL2RA as regulatory factors for Treg cell development and function. In order to investigate the association of miR-182, miR-27a, FoxO1, and IL2RA gene polymorphisms with Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese Han population, a two-stage association study was performed in 820 BD, 900 VKH patients, and 1,800 controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. In the first stage study, association analysis of 10 single nucleotide polymorphisms (SNPs) was performed in 400 BD, 400 VKH patients, and 600 controls. The results showed significantly decreased frequencies of the miR-182/rs76481776 CC genotype and C allele in BD (P = 3.36 * 10(-4), OR = 0.55; P = 4.74 * 10(-4), OR = 0.59) and VKH patients (P = 1.11 * 10( 4), OR = 0.53; P = 1.26 * 10(-4), OR = 0.56). No significant association of the other nine SNPs with BD or VKH was observed. In the second stage study, association analysis of miR-182/rs76481776 was performed in 420 BD, 500 VKH patients, and 1,200 controls. The second stage and combined studies confirmed the association of miR-182/rs76481776 with BD (CC genotype: P = 3.25 * 10(-7), OR = 0.58; C allele: P = 1.81 * 10(-7), OR = 0.60) and VKH (CC genotype: P = 7.89 * 10(-8), OR = 0.57; C allele: P = 2.52 * 10(-8), OR = 0.59). Real-time PCR analysis showed a significantly increased expression of miR-182 in TT/CT cases compared to CC cases in anti-CD3/CD28 antibodies-stimulated CD4(+) T cells (P = 2.1 * 10(-2)). In conclusion, this study suggests that miR-182, but not miR-27a, FoxO1, and IL2RA, contributes to the genetic susceptibility of BD and VKH. KEY MESSAGE: MiR-182 contributes to genetic susceptibility of BD and VKH. No significant association of miR-27a, FoxO1, and IL2RA with BD or VKH was observed. Significantly increased expression of miR-182 in TT/CT cases compared to CC cases was observed. PMID- 24801148 TI - Prevalence of suboptimal drug treatment in patients with and without multidose drug dispensing--a cross-sectional study. AB - PURPOSE: The aim of this study was to compare the prevalence of suboptimal drug treatment in older patients with and without multidose drug dispensing (MDD). METHODS: In 200 hip fracture patients (>=65 years of age), originally recruited to a randomized controlled study in Sahlgrenska University Hospital in 2009, quality of drug treatment at study entry was compared between patients with and without MDD. Two specialist physicians independently assessed and then agreed on the quality of the drug treatment of each patient. Suboptimal drug treatment was defined as >=1 STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) or >=1 START (Screening Tool to Alert to Right Treatment) outcome assessed as clinically relevant after individual considerations had been made, i.e. over- or undertreatment (>=1 inappropriate and >=1 missing drug, respectively). RESULTS: Patients with MDD (n=100) differed from patients without MDD (n=100) in several ways, for example by being older (87.6 vs. 81.5 years) and using more drugs (8.4 vs. 5.9 drugs). The total number (+/-standard deviation) of inappropriate and/or missing drugs per person was greater in MDD patients compared with patients without MDD (1.92+/-1.52 vs. 1.06+/-1.29, P<0.0001); MDD patients had an additional 0.77 inappropriate drugs and an additional 0.09 missing drugs per person. The prevalence of suboptimal drug treatment was greater in patients with MDD than in those without MDD (86 vs. 55%, P<0.0001). Logistic regression revealed that suboptimal drug treatment was 8.0 times as common in MDD patients, after adjustments for age, sex, number of drugs, cognition, and residence (95% confidence interval 2.4; 26.9). Corresponding figures for over- and undertreatment were 2.9 (1.1; 7.4) and 1.8 (0.8; 4.3), respectively. CONCLUSIONS: Suboptimal drug treatment, including over- and undertreatment, is more common in MDD patients than in patients who receive their drugs via ordinary prescriptions. The findings confirm safety concerns regarding quality of drug treatment in MDD patients. PMID- 24801149 TI - Infections and possible vaccine-drug interactions. PMID- 24801150 TI - Spatial segregation and aggregation of ectomycorrhizal and root-endophytic fungi in the seedlings of two Quercus species. AB - Diverse clades of mycorrhizal and endophytic fungi are potentially involved in competitive or facilitative interactions within host-plant roots. We investigated the potential consequences of these ecological interactions on the assembly process of root-associated fungi by examining the co-occurrence of pairs of fungi in host-plant individuals. Based on massively-parallel pyrosequencing, we analyzed the root-associated fungal community composition for each of the 249 Quercus serrata and 188 Quercus glauca seedlings sampled in a warm-temperate secondary forest in Japan. Pairs of fungi that co-occurred more or less often than expected by chance were identified based on randomization tests. The pyrosequencing analysis revealed that not only ectomycorrhizal fungi but also endophytic fungi were common in the root-associated fungal community. Intriguingly, specific pairs of these ectomycorrhizal and endophytic fungi showed spatially aggregated patterns, suggesting the existence of facilitative interactions between fungi in different functional groups. Due to the large number of fungal pairs examined, many of the observed aggregated/segregated patterns with very low P values (e.g., < 0.005) turned non-significant after the application of a multiple comparison method. However, our overall results imply that the community structures of ectomycorrhizal and endophytic fungi could influence each other through interspecific competitive/facilitative interactions in root. To test the potential of host-plants' control of fungus-fungus ecological interactions in roots, we further examined whether the aggregated/segregated patterns could vary depending on the identity of host plant species. Potentially due to the physiological properties shared between the congeneric host plant species, the sign of hosts' control was not detected in the present study. The pyrosequencing-based randomization analyses shown in this study provide a platform of the high-throughput investigation of fungus-fungus interactions in plant root systems. PMID- 24801151 TI - Cognitive deficits are a matter of emotional context: inflexible strategy use mediates context-specific learning impairments in OCD. AB - The present study examines the interplay between cognitive deficits and emotional context in obsessive-compulsive disorder (OCD) and social phobia (SP). Specifically, this study examines whether the inflexible use of efficient learning strategies in an emotional context underlies impairments in probabilistic classification learning (PCL) in OCD, and whether PCL impairments are specific to OCD. Twenty-three participants with OCD, 30 participants with SP and 30 healthy controls completed a neutral and an OCD-specific PCL task. OCD participants failed to adopt efficient learning strategies and showed fewer beneficial strategy switches than controls only in an OCD-specific context, but not in a neutral context. Additionally, OCD participants did not show any explicit memory impairments. Number of beneficial strategy switches in the OCD specific task mediated the difference in PCL performance between OCD and control participants. Individuals with SP were impaired in both PCL tasks. In contrast to neuropsychological models postulating general cognitive impairments in OCD, the present findings suggest that it is the interaction between cognition and emotion that is impaired in OCD. Specifically, activated disorder-specific fears may impair the flexible adoption of efficient learning strategies and compromise otherwise unimpaired PCL. Impairments in PCL are not specific to OCD. PMID- 24801152 TI - Nonomuraea muscovyensis sp. nov., isolated from soil. AB - A novel actinomycete, strain FMN03(T), was isolated from a soil sample collected from Yuga Zapadnaya South-West Forest Park, Moscow, Russia. The isolate had chemical and morphological properties typical of members of the genus Nonomuraea and formed a distinct 16S rRNA gene subclade with the type strains Nonomuraea roseoviolacea subsp. carminata NBRC 15903(T) and Nonomuraea roseoviolacea subsp. roseoviolacea NBRC 14098(T). The organism formed extensively branched substrate and aerial hyphae, which generated spiral chains of spores with smooth surfaces. The cell wall contained meso-diaminopimelic acid and the whole cell sugars were glucose, galactose and trace amounts of madurose, mannose and xylose. The polar lipids were phosphatidylethanolamine, hydroxyphosphatidylethanolamine, four unidentified phospholipids, four unidentified glycolipids and one unidentified lipid. The predominant menaquinone was MK-9(H4). The major fatty acids were iso C16 : 0 2-OH, C17 : 0 10-methyl, C17 : 1 cis9 and iso-C16 : 0. Analyses of its morphological, physiological and biochemical characteristics, together with DNA DNA relatedness data, confirmed that strain FMN03(T) is a representative of a novel species of the genus Nonomuraea, which is distinct from closely related reference strains. Strain FMN03(T) ( = DSM 45913(T) = KCTC 29233(T)) is proposed as the type strain of a novel species, for which the name Nonomuraea muscovyensis sp. nov. is proposed. PMID- 24801153 TI - Streptococcus cuniculi sp. nov., isolated from the respiratory tract of wild rabbits. AB - Biochemical and molecular genetic studies were performed on four unknown Gram stain-positive, catalase-negative, coccus-shaped organisms isolated from tonsils (n = 3) and nasal samples (n = 1) of four wild rabbits. The micro-organism was identified as a streptococcal species based on its cellular morphological and biochemical tests. Comparative 16S rRNA gene sequencing confirmed its identification as a member of the genus Streptococcus, but the organism did not correspond to any recognized species of this genus. The closest phylogenetic relative of the unknown cocci from wild rabbits was Streptococcus acidominimus NCIMB 702025(T) (97.9% 16S rRNA gene sequence similarity). rpoB and sodA sequence analysis of the novel isolate showed interspecies divergence of 16.2% and 20.3%, respectively, from the type strain of its closest 16S rRNA gene phylogenetic relative, S. acidominimus. The novel bacterial isolate could be distinguished from the type strain of S. acidominimus by several biochemical characteristics, such as the production of esterase C4, acid phosphatase and naphthol-AS-BI phosphohydrolase and acidification of different sugars. Based on both phenotypic and phylogenetic findings, it is proposed that the unknown bacterium be classified as a novel species of the genus Streptococcus, Streptococcus cuniculi sp. nov. The type strain is NED12-00049-6B(T) ( = CECT 8498(T) = CCUG 65085(T)). PMID- 24801154 TI - Nocardioides zeae sp. nov., isolated from the stem of Zea mays. AB - A Gram-stain-positive aerobic organism, isolated from the healthy stem of a Zea mays plant was studied for its taxonomic position. Based on 16S rRNA gene sequence analysis strain JM-1068(T) was most closely related to Nocardioides alkalitolerans (97.2%). The 16S rRNA gene sequence similarity to all other species of the genus Nocardioides was <= 96.1%. The quinone system of strain JM 1068(T) contained the major menaquinone MK-8(H4). The diagnostic diamino acid of the peptidoglycan was LL-diaminopimelic acid. In the polar lipid profile, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and two unidentified phospholipids were predominant. The polyamine pattern contained predominantly spermidine and spermine. The fatty acid profile was composed of iso-C16 : 0 and C18 : 1omega9c in addition to C16 : 0, C17 : 0 and C17 : 1omega8c and low amounts of C16 : 0 2-OH and C17 : 0 2-OH. This supported the allocation of the strain to the genus Nocardioides. In addition, the results of physiological and biochemical tests also allowed phenotypic differentiation of strain JM-1068(T) from N. alkalitolerans. It is concluded that JM-1068(T) represents a novel species of the genus Nocardioides, for which we propose the name Nocardioides zeae sp. nov., with JM-1068(T) ( = CIP 110696(T) = LMG 28079(T)) as the type strain. PMID- 24801155 TI - Pseudogracilibacillus auburnensis gen. nov., sp. nov., isolated from the rhizosphere of Zea mays. AB - A Gram-positive-staining, aerobic, endospore-forming bacterium, strain P-207(T), was isolated from a rhizosphere soil sample in Auburn, AL, USA. On the basis of 16S rRNA gene sequence comparisons, strain P-207(T) was grouped in the vicinity of representatives of the genera Virgibacillus, Ornithinibacillus, Cerasibacillus, Lentibacillus and Oceanobacillus, but could not be assigned clearly to any of these genera. The highest similarity was found to the sequence of Virgibacillus carmonensis LMG 20964(T) (94.4%); however, the 16S rRNA gene sequence similarity to the type strain of the type species of Virgibacillus, Virgibacillus pantothenticus, was only 92.9%. The quinone system of strain P 207(T) consisted predominantly of menaquinone MK-7. The polar lipid profile exhibited the major lipids diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine and moderate to minor amounts of several unidentified phospholipids, glycolipids and phosphoglycolipids, an aminophospholipid and an aminolipid. The diagnostic diamino acid of the peptidoglycan was meso diaminopimelic acid and the polyamine pattern contained predominantly spermidine and spermine. The major fatty acids were anteiso-C15 : 0, anteiso-C17 : 0, iso C16 : 0 and iso-C15 : 0. The G+C content of the genomic DNA was 34 mol%. Because of the low sequence similarity of strain P-207(T) to all representatives of Virgibacillus, Ornithinibacillus, Cerasibacillus, Lentibacillus and Oceanobacillus, which was always <95%, and its unique lipid pattern, we propose that strain P-207(T) represents a novel species in a new genus, for which the name Pseudogracilibacillus auburnensis gen. nov., sp. nov. is proposed. The type strain of Pseudogracilibacillus auburnensis is P-207(T) ( = CCM 8509(T) = LMG 28212(T) = CIP 110797(T)). PMID- 24801156 TI - Bacillus qingshengii sp. nov., a rock-weathering bacterium isolated from weathered rock surface. AB - A novel type of rock-weathering bacterium was isolated from weathered rock (tuff) surface collected from Dongxiang (Jiangxi, eastern China). Cells of strain G19(T) were Gram-reaction-positive, rod-shaped, endospore-forming and non-motile. The strain was aerobic, catalase- and oxidase-positive, and grew optimally at 30 degrees C and pH 7.0. On the basis of 16S rRNA gene sequence analysis, strain G19(T) was shown to belong to the genus Bacillus and the closest phylogenetic relatives were Bacillus aryabhattai B8W22(T) (97.4%) and Bacillus megaterium IAM 13418(T) (97.1%). The DNA G+C content was 36.7 mol% and the predominant respiratory quinone was MK-7. The major fatty acids were iso-C14 : 0, iso-C15 : 0 and anteiso-C15 : 0. The polar lipid profile of strain G19(T) contained phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol and an unidentified lipid. Based on the low level of DNA-DNA relatedness (ranging from 49.4% to 55.0%) to these type strains of species of the genus Bacillus and unique phenotypic characteristics, strain G19(T) represents a novel species of the genus Bacillus, for which the name Bacillus qingshengii sp. nov. is proposed. The type strain is G19(T) ( = CCTCC AB 2013273(T) = JCM 19454(T)). PMID- 24801157 TI - Paludibacterium paludis sp. nov., isolated from a marsh. AB - A bacterial strain, designated KBP-21(T), was isolated from a water sample taken from the Banping Lake Wetland Park in Taiwan and characterized in a taxonomic study using a polyphasic approach. Cells of strain KBP-21(T) were Gram-stain negative, facultatively anaerobic, poly-beta-hydroxybutyrate-accumulating, motile rods that formed yellow colonies. Growth occurred at 15-40 degrees C (optimum, 30 degrees C), at pH 5.0-8.0 (optimum, pH 8.0) and with 0-2% NaCl (optimum, 0%). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain KBP 21(T) belonged to the genus Paludibacterium within the family Neisseriaceae of the class Betaproteobacteria and the closest related neighbour was Paludibacterium yongneupense 5YN8-15(T) with a 16S rRNA gene sequence similarity value of 96.4%. Strain KBP-21(T) contained summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C18 : 1omega7c as the predominant fatty acids. The major respiratory quinone was Q-8. The DNA G+C content of the genomic DNA was 62.1 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one uncharacterized aminophospholipid and several uncharacterized phospholipids. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain KBP-21(T) represents a novel species in the genus Paludibacterium, for which the name Paludibacterium paludis sp. nov. is proposed. The type strain is KBP-21(T) ( = BCRC 80514(T) = LMG 27230(T) = KCTC 32182(T)). PMID- 24801158 TI - Reyranella graminifolii sp. nov., isolated from bamboo (Phyllostachys bambusoides) litter. AB - A novel strain designated Wo-34(T) was isolated from bamboo (Phyllostachys bambusoides) litter. Cells were Gram-stain-negative, non-motile, catalase negative and oxidase-positive rods. The isolate grew aerobically at 15-35 degrees C (optimum 28 degrees C), pH 4.0-9.0 (optimum pH 7.0) and in the presence of 0-1.0% (w/v) NaCl (optimum 0.1% NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain Wo-34(T) belonged to the genus Reyranella with the sequence similarities of 97.9% and 97.3% to the other species of the genus Reyranella, Reyranella massiliensis 521(T) and Reyranella soli KIS14 15(T), respectively. The predominant ubiquinone was Q-10. Major fatty acids were C18 : 1omega7c, C18 : 1 2-OH and C19 : 0 cyclo omega8c. The polar lipids contained phosphatidylmonomethylethanolamine, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unknown aminolipid, unidentified phospholipids and unknown lipids. DNA-DNA relatedness values between strain Wo-34(T) and R. massiliensis DSM 23428(T) and R. soli KACC 13034(T) were 35% and 29%, respectively. On the basis of polyphasic analysis from this study, strain Wo-34(T) represents a novel species of the genus Reyranella for which the name Reyranella graminifolii sp. nov. is proposed. The type strain is Wo-34(T) ( = KACC 17605(T) = NBRC 109813(T)). PMID- 24801159 TI - A combination of four active compounds alleviates cerebral ischemia-reperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/mTOR and JNK pathways. AB - SMXZF is a combination of Rb1, Rg1, schizandrin, and DT-13 (6:9:5:4) derived from Sheng-mai San, a widely used Chinese traditional medicine for the treatment of cardiovascular and cerebral diseases. The present study explores the inhibitory effects and signaling pathways of SMXZF on autophagy induced by cerebral ischemia reperfusion injury. Male C57BL/6 mice were subjected to ischemia-reperfusion insult by right middle cerebral artery occlusion (MCAO) for 1 hr with subsequent 24 hr reperfusion. Three doses of SMXZF (4.5, 9, and 18 mg/kg) were administered intraperitoneally (i.p.) after ischemia for 1 hr. An autophagic inhibitor, 3 methyladenine (3-MA; 300 MUg/kg), was administered i.p. 20 min before ischemia as a positive drug. We found that SMXZF significantly increased cerebral blood flow and reduced the infarct volume, brain water content, and the neurological deficits in a dose-dependent manner. Similar to the positive control, SMXZF at 18 mg/kg also significantly inhibited autophagosome formation. Immunofluorescence staining and Western blotting demonstrated that SMXZF could significantly decrease the expression levels of beclin1 and microtubule-associated protein 1 light chain 3. SMXZF also remarkably inhibited the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) as well as the expression of c-Jun N-terminal kinase (JNK) and its phosphorylation induced by 24 hr reperfusion. Finally, we demonstrated that the optimal administration time of SMXZF was at the early period of reperfusion. This study reveals that SMXZF displays neuroprotective effect against focal ischemia reperfusion injury, possibly associated with autophagy inactivation through AMPK/mTOR and JNK pathways. PMID- 24801160 TI - A national survey of obstetric early warning systems in the United Kingdom: five years on. AB - The Confidential Enquiries into Maternal Deaths in the UK have recommended obstetric early warning systems for early identification of clinical deterioration to reduce maternal morbidity and mortality. This survey explored early warning systems currently used by maternity units in the UK. An electronic questionnaire was sent to all 205 lead obstetric anaesthetists under the auspices of the Obstetric Anaesthetists' Association, generating 130 (63%) responses. All respondents reported use of an obstetric early warning system, compared with 19% in a similar survey in 2007. Respondents agreed that the six most important physiological parameters to record were respiratory rate, heart rate, temperature, systolic and diastolic blood pressure and oxygen saturation. One hundred and eighteen (91%) lead anaesthetists agreed that early warning systems helped to prevent obstetric morbidity. Staffing pressures were perceived as the greatest barrier to their use, and improved audit, education and training for healthcare professionals were identified as priority areas. PMID- 24801162 TI - Urinary biomarkers of acute kidney injury in deceased organ donors--kidney injury molecule-1 as an adjunct to predicting outcome. AB - BACKGROUND: Deceased kidney donors are increasingly "marginal," and many have risk factors for acute kidney injury (AKI) that may impact on subsequent renal transplant outcome. Despite this, determining the presence of AKI at the time of deceased organ donation remains difficult. METHODS: Urine samples from 182 brainstem dead multi-organ donors (all of whom donated hearts that were transplanted) were analyzed for a Luminex(TM) panel of biomarkers linked with AKI. This included KIM-1, NGAL, IFN-gamma, TNF-alpha, cystatin C, Fractalkine and vascular endothelial growth factor. Levels were correlated to early renal transplant outcomes, most specifically delayed graft function. RESULTS: Donor urinary KIM-1 levels were significantly higher in donors whose kidneys displayed aberrant early function (p = 0.011). Fractalkine levels showed a trend toward elevation in such donors but uncorrected this did not attain significance. No correlation occurred with the remaining biomarkers. CONCLUSIONS: KIM-1 appears to show promise as a marker for AKI in deceased cardiac organ donors. The availability of a lateral flow device (Renastick(TM) ) for KIM-1 that also demonstrates higher urinary KIM-1 levels in donors whose kidneys show aberrant initial function (p = 0.03), makes KIM-1 a potential indicator of AKI that may merit further evaluation for its application at the donor bedside. PMID- 24801161 TI - Diuretic exposure in premature infants from 1997 to 2011. AB - OBJECTIVE: Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia. We examined their use and safety in this group. STUDY DESIGN: Retrospective cohort study of infants < 32 weeks gestation and < 1,500 g birth weight exposed to diuretics in 333 neonatal intensive care units from 1997 to 2011. We examined use of acetazolamide, amiloride, bumetanide, chlorothiazide, diazoxide, ethacrynic acid, furosemide, hydrochlorothiazide, mannitol, metolazone, or spironolactone combination. Respiratory support and fraction of inspired oxygen on the first day of each course of diuretic use were identified. RESULTS: About 37% (39,357/107,542) infants were exposed to at least one diuretic; furosemide was the most commonly used (93% with >= 1 recorded dose), followed by spironolactone, chlorothiazide, hydrochlorothiazide, bumetanide, and acetazolamide. About 74% patients were exposed to one diuretic at a time, 19% to two diuretics simultaneously, and 6% to three diuretics simultaneously. The most common combination was furosemide/spironolactone, followed by furosemide/chlorothiazide and chlorothiazide/spironolactone. Many infants were not receiving mechanical ventilation on the first day of each new course of furosemide (47%), spironolactone (69%), chlorothiazide (61%), and hydrochlorothiazide (68%). Any adverse event occurred on 42 per 1,000 infant-days for any diuretic and 35 per 1,000 infant-days for furosemide. Any serious adverse event occurred in 3.8 for any diuretic and 3.2 per 1,000 infant-days for furosemide. The most common laboratory abnormality associated with diuretic exposure was thrombocytopenia. CONCLUSION: Despite no Food and Drug Administration (FDA) indication and little safety data, over one-third of premature infants in our population were exposed to a diuretic, many with minimal respiratory support. PMID- 24801163 TI - Pollen and phytolith evidence for rice cultivation and vegetation change during the mid-late Holocene at the Jiangli site, Suzhou, East China. AB - Pollen and phytolith analyses were undertaken at the Jiangli site in Suzhou, Jiangsu Province, combined with studies on macrofossils by flotation. The concentration of pollen decreased while the percentage of Poaceae pollen in the profile increased from the late phase of the Majiabang Culture to the Songze Culture suggesting that human impact on the local environment intensified gradually. The discovery of rice paddy implies a relatively advanced rice cultivation in this area during the middle-late Holocene. Other than phytoliths, the high percentage of Oryza-type Poaceae pollen (larger than 40 MUm) supplied robust evidence for the existence of rice paddy. Moreover, the fact that the farther from the rice paddy, the lower the concentration and percentage of Poaceae pollen also proves that the dispersal and deposition of pollen is inversely proportional to the distance. PMID- 24801164 TI - Exploring the diversity of arsenic resistance genes from acid mine drainage microorganisms. AB - The microbial communities from the Tinto River, a natural acid mine drainage environment, were explored to search for novel genes involved in arsenic resistance using a functional metagenomic approach. Seven pentavalent arsenate resistance clones were selected and analysed to find the genes responsible for this phenotype. Insights about their possible mechanisms of resistance were obtained from sequence similarities and cellular arsenic concentration. A total of 19 individual open reading frames were analysed, and each one was individually cloned and assayed for its ability to confer arsenic resistance in Escherichia coli cells. A total of 13 functionally active genes involved in arsenic resistance were identified, and they could be classified into different global processes: transport, stress response, DNA damage repair, phospholipids biosynthesis, amino acid biosynthesis and RNA-modifying enzymes. Most genes (11) encode proteins not previously related to heavy metal resistance or hypothetical or unknown proteins. On the other hand, two genes were previously related to heavy metal resistance in microorganisms. In addition, the ClpB chaperone and the RNA-modifying enzymes retrieved in this work were shown to increase the cell survival under different stress conditions (heat shock, acid pH and UV radiation). Thus, these results reveal novel insights about unidentified mechanisms of arsenic resistance. PMID- 24801165 TI - Introduction. Special issue of Gene Expression. PMID- 24801166 TI - Role and regulation of beta-catenin signaling during physiological liver growth. AB - Wnt/beta-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of beta-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. beta-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive beta-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, beta-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of beta catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle, is regulated by beta-catenin-TCF complex. Thus, beta-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of beta-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process will be discussed. In addition, the probability of therapeutically regulating beta-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed. PMID- 24801168 TI - Hepatic fibrosis and the microenvironment: fertile soil for hepatocellular carcinoma development. AB - Hepatocellular carcinoma is an emerging worldwide health threat that has few curative treatment options and poor overall survival. Progressive hepatic fibrosis is a common pathway for all forms of chronic liver disease and is closely linked epidemiologically to hepatocellular carcinoma risk. However, the molecular events that predispose a fibrotic liver to cancer development remain elusive. Nonetheless, a permissive hepatic microenvironment provides fertile soil for transition of damaged hepatocytes into hepatocellular carcinoma. Key predisposing features include alterations in the extracellular matrix, bidirectional signaling pathways between parenchymal and nonparenchymal cells, and immune dysfunction. Emerging research into the contributions of autophagy, tumor-associated fibroblasts, and hepatocellular carcinoma progenitor cells to this dangerous milieu also provides new mechanistic underpinnings to explain the contribution of fibrosis to cancer. As effective antifibrotic therapies are developed, these approaches could attenuate the rising surge of hepatocellular carcinoma associated with chronic liver disease. PMID- 24801167 TI - Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis. AB - Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARalpha-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARalpha activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARalpha, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARalpha, PPARgamma, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARalpha activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic diseases associated with increased energy combustion in liver. PMID- 24801169 TI - Regulation of glucose metabolism in hepatocarcinogenesis by microRNAs. AB - In the past decade, considerable effort has been made in elucidating the mechanism underlying the high level of aerobic glycolysis in cancer cells. While some recent studies have attempted to address this issue, the potential role of microRNAs in this process has not been explored until recently. These studies have demonstrated involvement of just five deregulated miRNAs in glucose metabolism in hepatocarcinogenesis. This review discusses the metabolic significance of these miRNAs in hepatoceullular carcinoma, their targets in glycolysis, gluconeogenesis, and pentose phosphate pathways, and provides an insight into the therapeutic potential of targeting specific miRNAs. PMID- 24801170 TI - Emerging insights into the role of microRNAs in the pathogenesis of cholangiocarcinoma. AB - The microRNAs (miRNAs) are small noncoding RNAs that are potent regulators of gene expression and can regulate several diverse biological functions. This minireview provides an overview of recent studies that have examined the role and involvement of miRNAs in cholangiocarcinomas. These studies provide evidence for deregulated expression of miRNA and are providing new insights into the potential contribution of these in the pathogenesis of cholangiocarcinoma. PMID- 24801171 TI - Pharmacokinetics and exposure-effect relationships of capecitabine in elderly patients with breast or colorectal cancer. AB - PURPOSE: The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure-effect relationship of capecitabine in elderly patients. METHODS: Data collected from 20 elderly patients (75-92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites. RESULTS: The absorption rate constant was found lower in the oldest patient group (>=75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5'-deoxy-5-fluorocytidine, 5'-deoxy-5 fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not. CONCLUSION: This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity. PMID- 24801172 TI - Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent. AB - PURPOSE: SN 28049 is a new DNA-binding topoisomerase II poison identified by its curative activity against the murine colon 38 carcinoma. Previous studies showed activity to be associated with selective drug accumulation and retention in tumour tissue. Retention varied widely among different tumours and was related to antitumour activity. We determined whether differences in the uptake and retention of SN 28049 could be observed in vitro. METHODS: The Co38P and LLTC lines were derived from the murine colon 38 carcinoma and Lewis lung carcinoma (3LL), respectively. The NZM4, NZM10 and NZM52 human melanoma lines, as well as the CCRF/CEM, CEM/VLB100 and CEM/E1000 human leukaemia lines were also utilised. Cell-associated drug was measured by liquid chromatography-mass spectrometry, laser-scanning confocal microscopy and fluorescence microscopy. Data for SN 28049 were compared for four SN 28049 analogues, for the structurally related drug N-[2 (dimethylamino)-ethyl]acridine-4-carboxamide (DACA) and for doxorubicin. RESULTS: Cellular uptake of SN 28049 was rapid and associated with increased fluorescence in cytoplasmic vesicles or bodies. SN 28049 uptake after an incubation time of 1 h varied widely with different cell lines (2-98 pmol/106 cells) and did not correlate with growth inhibitory concentrations (IC50 values), which also varied widely (1.2-19 nM). Changes in the length of the N-linked side chain of SN 28049 had large effects on drug uptake by Co38P cells. SN 28049 uptake by CCRF/CEM cells was only slightly affected by the expression of P-glycoprotein (CEM/VLB100) or MRP1 protein (CEM/E1000). As measured by cytoplasmic fluorescence, SN 28049 was taken up rapidly and retained strongly by Co38P cells, DACA was taken up rapidly and retained poorly, and doxorubicin was taken up slowly and retained moderately. CONCLUSIONS: The results suggest that SN 28049 is actively transported into cytoplasmic vesicles. While vesicle-associated drug is not important for intrinsic cytotoxicity, it may play a key role as a "slow release" form that modifies pharmacokinetics in multicellular structures such as tumours. PMID- 24801174 TI - Determination of early urinary renal injury markers in obese children. AB - BACKGROUND: Obesity is an important health issue, the prevalence of which is increasing in childhood. The aim of this study was to examine urinary renal injury markers in order to determine the renal effect of obesity and its comorbidities in a pediatric population. METHODS: Eighty-four obese children and 64 healthy control subjects were enrolled in the study. We checked their urine using N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and microalbumin as renal injury markers. Associations of renal damage markers with hypertension, an impaired glucose tolerance test, and insulin resistance were assessed. RESULTS: Obese individuals had higher urinary NAG and KIM-1 values compared to those of healthy controls (p = 0.027, p = 0.026). There was no difference in urinary NGAL between obese and lean subjects (p = 0.885). Urinary renal injury markers were not statistically different in the obese group when checked for impaired glucose tolerance, insulin resistance, and hypertension (p > 0.05). CONCLUSIONS: This study shows that urinary NAG and KIM-1 could be used as a screening method for detection of early renal damage in obese children. PMID- 24801173 TI - Making and maintaining lifestyle changes with the support of a lay health advisor: longitudinal qualitative study of health trainer services in northern England. AB - OBJECTIVE: To explore and document the experiences of those receiving support from a lay health trainer, in order to inform the optimisation and evaluation of such interventions. DESIGN: Longitudinal qualitative study with up to four serial interviews conducted over 12 months. Interviews were transcribed and analysed using the constant comparative approach associated with grounded theory. PARTICIPANTS: 13 health trainers, 5 managers and 26 clients. SETTING: Three health trainer services targeting disadvantaged communities in northern England. RESULTS: The final dataset comprised 116 interviews (88 with clients and 28 with staff). Discussions with health trainers and managers revealed a high degree of heterogeneity between the local services in terms of their primary aims and activities. However, these were found to converge over time. There was agreement that health trainer interventions are generally 'person-centred' in terms of being tailored to the needs of individual clients. This led to a range of self reported outcomes, including behaviour changes, physical health improvements and increased social activity. Factors impacting on the maintenance of lifestyle changes included the cost and timing of health-promoting activities, ill-health or low mood. Participants perceived a need for ongoing access to low cost facilities to ensure that any lifestyle changes can be maintained in the longer term. CONCLUSIONS: Health trainers may be successful in terms of supporting people from socio-economically disadvantaged communities to make positive lifestyle changes, as well as achieving other health-related outcomes. This is not a 'one-size-fits-all' approach; commissioners and providers should select the intervention models that best meet the needs of their local populations. By delivering holistic interventions that address multiple lifestyle risks and incorporate relapse prevention strategies, health trainers could potentially have a significant impact on health inequalities. However, rigorous, formal outcome and economic evaluation of the range of health trainer delivery models is needed. PMID- 24801175 TI - Attenuation of unfolded protein response and apoptosis by mReg2 induced GRP78 in mouse insulinoma cells. AB - Murine regenerating (mReg) genes have been implicated in preserving islet cell biology. Expanding on our previous work showing that overexpression of mReg2 protects MIN6 insulinoma cells against streptozotocin-induced apoptosis, we now demonstrate that mReg2 induces glucose-regulated peptide 78 (GRP78) expression via the Akt-mTORC1 axis and protects MIN6 cells against ER stress induced by thapsigargin and glucolipotoxicity. Activation of mTORC1 activity results from both mReg2-induced increased mTOR phosphorylation as well as increased expression of Raptor and GbetaL. Inhibition of Akt and mTORC1 blunted the ability of mReg2 to induce GRP78 and attenuate unfolded protein response (UPR). Knockdown of GRP78 sensitized the cells overexpressing mReg2 to UPR without affecting its ability to activate Akt-mTORC1 signaling. Induced expression of mReg2 may protect insulin producing cells from ER stress in diabetes. PMID- 24801176 TI - Ultrastable atomic force microscopy: improved force and positional stability. AB - Atomic force microscopy (AFM) is an exciting technique for biophysical studies of single molecules, but its usefulness is limited by instrumental drift. We dramatically reduced positional drift by adding two lasers to track and thereby actively stabilize the tip and the surface. These lasers also enabled label-free optical images that were spatially aligned to the tip position. Finally, sub-pN force stability over 100 s was achieved by removing the gold coating from soft cantilevers. These enhancements to AFM instrumentation can immediately benefit research in biophysics and nanoscience. PMID- 24801177 TI - Peroxisomal plant nitric oxide synthase (NOS) protein is imported by peroxisomal targeting signal type 2 (PTS2) in a process that depends on the cytosolic receptor PEX7 and calmodulin. AB - Nitric oxide (NO) production in plant peroxisomes by l-arginine-dependent NO synthase activity has been proven. The PEX5 and PEX7 PTS receptors, which recognize PTS1- and PTS2-containing proteins, are localized in the cytosol. Using AtPex5p and AtPex7p knockdown in Arabidopsis by RNA interference (RNAi) designated as pex5i and pex7i, we found that the l-arginine-dependent protein responsible for NO generation in peroxisomes appears to be imported through an N terminal PTS2. Pharmacological analyzes using a calcium channel blocker and calmodulin (CaM) antagonist show that the import of the peroxisomal NOS protein also depends on calcium and calmodulin. PMID- 24801179 TI - Characterization of the Rx1-dependent transcriptome during early retinal development. AB - BACKGROUND: The transcription factor Rx1, also known as Rax, controls key properties of retinal precursors including migration behavior, proliferation, and maintenance of multipotency. However, Rx1 effector genes are largely unknown. RESULTS: To identify genes controlled by Rx1 in early retinal precursors, we compared the transcriptome of Xenopus embryos overexpressing Rx1 to that of embryos in which Rx1 was knocked-down. In particular, we selected 52 genes coherently regulated, i.e., actived in Rx1 gain of function and repressed in Rx1 loss of function experiments, or vice versa. RT-qPCR and in situ hybridization confirmed the trend of regulation predicted by microarray data for the selected genes. Most of the genes upregulated by Rx1 are coexpressed with this transcription factor, while downregulated genes are either not expressed or expressed at very low levels in the early developing retina. Putative direct Rx1 target genes, activated by GR-Rx1 in the absence of protein synthesis, include Ephrin B1 and Sh2d3c, an interactor of ephrinB1 receptor, which represent candidate novel effectors for the migration promoting activity of Rx1. CONCLUSIONS: This study identifies previously undescribed Rx1 regulated genes mainly involved in transcription regulation, cell migration/adhesion, and cell proliferation that contribute to delineate the molecular mechanisms underlying Rx1 activities. PMID- 24801178 TI - Segmentation of cardiac magnetic resonance cine images of single ventricle: including or excluding the accessorial ventricle? AB - Our aim was to compare two different approaches for segmentation of single ventricle (SV) on cardiac magnetic resonance (CMR) cine images. We retrospectively studied 30 consecutive patients (23 males; aged 27 +/- 10 years) with a treated SV who underwent 1.5-T CMR using ECG-triggered axial true-FISP, HASTE and cine true-FISP sequences. We classified patients for visceroatrial situs, cardiac axis orientation, ventricular loop, morphology of SV and position of great arteries. One experienced reader segmented cine images twice, firstly including only the systemic ventricle, secondly including both systemic and accessorial ventricles. Ejection fraction (EF), indexed end-diastolic volume (EDVI), end-systolic volume (ESVI), and stroke volume (SVI) were calculated. Data were presented as medians and interquartile intervals. Four patients presented dextrocardia and one patient mesocardia. Two had situs ambiguus with asplenia and one situs ambiguus with polisplenia. Four patients showed right morphology of the SV and three levo-ventricle loop. We found 14 levo-trasposition of great arteries (TGA), 4 levo-malposition of great arteries (MGA), four dextro-MGA, two dextro TGA, and one inverted vessel position. When segmenting only the systemic ventricle, EDVI (mL/m2) was 65 (50-91), when segmenting both ventricles 76 (58 110) (P < 0.001); ESVI (mL/m2) was 32 (24-45) and 45 (33-60), respectively (P < 0.001); EF (%) was 49 (43-57) and 33 (24-47), respectively (P = 0.003); SVI (mL/m2) was 34 (17-48) and 33 (24-47) (P = 0.070). The inclusion of the accessorial ventricle in the segmentation of SV produce a biased lower EF showing a very low contribution to the pump function. PMID- 24801180 TI - Salt marshes. AB - Salt marshes are unique ecosystems that are brimming with diversity, and provide crucial shelter to coastal communities. PMID- 24801181 TI - Post-translational modifications of tubulin. AB - Microtubules are the largest filamentous components of the eukaryotic cytoskeleton. In spite of their extraordinary level of structural conservation, microtubules fulfill a vast range of different functions in cells. How this functional diversity is achieved remains an open question; however, recent advances point towards post-translational modifications (PTMs) of tubulin as a potent mechanism to generate microtubule identities. As many microtubule functions have direct implications for development and homeostasis of organisms, understanding the molecular functions of tubulin PTMs could provide a more differentiated view on the role of microtubules in both normal and pathological aspects of organism development. PMID- 24801182 TI - Darwin's finches combat introduced nest parasites with fumigated cotton. AB - Introduced parasites are a threat to biodiversity when naive hosts lack effective defenses against such parasites [1]. Several parasites have recently colonized the Galapagos Islands, threatening native bird populations [2]. For example, the introduced parasitic nest fly Philornis downsi (Diptera: Muscidae) has been implicated in the decline of endangered species of Darwin's finches, such as the mangrove finch (Camarhynchus heliobates) [3]. Here, we show that Darwin's finches can be encouraged to 'self-fumigate' nests with cotton fibers that have been treated with permethrin. Nests with permethrin-treated cotton had significantly fewer P. downsi than control nests, and nests containing at least one gram of cotton were virtually parasite-free. Nests directly fumigated with permethrin had fewer parasites and fledged more offspring than nests treated with water. PMID- 24801183 TI - Leaf mimicry: chameleon-like leaves in a patagonian vine. AB - Mimicry has evolved in plants for a number of traits, both floral and vegetative. The discovery of a vine that mimics the leaf shape of different hosts poses new questions about the function of leaf mimicry, interplant signalling and leaf development. PMID- 24801184 TI - Habitat complexity: coral structural loss leads to fisheries declines. AB - Direct human impacts and global climate change are altering the composition and structure of coral reef habitats. These changes are simplifying size-abundance relationships of reef fish communities, reducing productivity through the system and ultimately threatening fisheries yields. PMID- 24801185 TI - Navigation: many senses make efficient foraging paths. AB - Desert ants have a sequence of optimized behaviours that allow them to forage efficiently. Recent work shows that after using navigational memories to reach previously rewarding areas, ants follow long crosswind sweeps that appear adapted for encountering odour plumes. PMID- 24801186 TI - Evolution: the mystery of imperfect mimicry. AB - Mimicry has long provided some of the most persuasive examples of the power of natural selection. However, some mimics are quite poor. A new study shows that mechanisms by which animals learn might explain how imperfect mimics survive. PMID- 24801187 TI - Hormone crosstalk: directing the flow. AB - Asymmetric distribution of the hormone auxin organizes plant cell fate and drives specification of new organs. Such asymmetries are regulated by polarized auxin transporters called PINs. But what controls PIN polarity? A new study shows that another hormone, cytokinin, degrades PINs on specific membranes to direct auxin flux. PMID- 24801188 TI - Sex: how malaria parasites get turned on. AB - The mechanisms underlying sexual stage switching in Plasmodium spp. have hitherto remained a mystery. However, two recent studies have revealed that an apicomplexan-specific DNA-binding protein is essential for the initiation of this cell fate decision, ultimately providing the malaria community with a novel and important tool in the battle to prevent malaria transmission. PMID- 24801189 TI - Cell biology: ESCRTing trouble out! AB - Calcium entry through a plasma membrane defect leads to the local recruitment of endosomal complex required for transport (ESCRT) proteins. These proteins are hypothesized to drive an outward bending of the affected plasma membrane, forming a small bud that is then shed from the cell, along with the troublesome defect. PMID- 24801190 TI - Invasive species: old foes meet again. AB - Tawny crazy ants are spreading across the southern U.S., replacing one of the most notorious invasive pests, the red imported fire ant. A crucial factor in this process is that tawny crazy ants are able to efficiently detoxify fire ant venom. PMID- 24801191 TI - Programmed cell death: new role in trimming the root tips. AB - How is a rapid cellular turnover of the lateral root cap achieved in plants to control cap size in the growing root tips? Downstream of ANAC033/SOMBRERO, a highly organized and temporally coordinated cell death program involving BFN1 nuclease-mediated rapid corpse clearance eliminates these cells. PMID- 24801192 TI - Pulsatile flow characterization in a vessel phantom with elastic wall using ultrasonic particle image velocimetry technique: the impact of vessel stiffness on flow dynamics. AB - This study aims to experimentally investigate the impact of vessel stiffness on the flow dynamics of pulsatile vascular flow. Vessel phantoms with elastic walls were fabricated using polyvinyl alcohol cryogel to result in stiffness ranging from 60.9 to 310.3 kPa and tested with pulsatile flows using a flow circulation set-up. Two-dimensional instantaneous and time-dependent flow velocity and shear rate vector fields were measured using ultrasonic particle image velocimetry (EchoPIV). The waveforms of peak velocities measured by EchoPIV were compared with the ultrasonic pulse Doppler spectrum, and the measuring accuracy was validated. The cyclic vessel wall motion and flow pressure were obtained as well. The results showed that vessel stiffening influenced the waveforms resulting from vessel wall distension and flow pressure, and the fields of flow velocity and shear rate. The stiffer vessel had smaller inner diameter variation, larger pulse pressure and median pressure. The velocity and shear rate maximized at peak systole for all vessels. The results showed a decrease in wall shear stress for a stiffer vessel, which can initiate the atherosclerotic process. Our study elucidates the impact of vessel stiffness on several flow dynamic parameters, and also demonstrates the EchoPIV technique to be a useful and powerful tool in cardiovascular research. PMID- 24801193 TI - Neonatal blood TSH concentration in Wales (UK): an indicator of iodine sufficiency. AB - OBJECTIVE: Population iodine status can be assessed by urinary iodine concentrations, prevalence of goitre, frequency of newborn thyroid-stimulating hormone (TSH) >5 mU/l and blood thyroglobulin concentrations. The UK population has historically been considered to be iodine sufficient; however, a recent survey of UK schoolgirls has demonstrated median urinary iodine concentrations consistent with mild iodine deficiency. The aim of our study was to assess the prevalence of TSH >5 mU/l in the newborn blood spot screening samples from the eligible population in Wales between 2011 and 2013 to assess iodine sufficiency. MEASUREMENTS: Blood spot TSH data for 104 992 infants during this time period were evaluated. RESULTS: The prevalence of TSH >5 mU/l in samples collected on days 4 and 5 of life were 1.5% and 0.9%, respectively. No increasing trend in blood spot TSH concentration was identified over the 3 years. CONCLUSIONS: The distribution of blood spot TSH data from neonates in Wales has revealed no evidence to support the hypothesis that the population is iodine deficient. However, given that mild iodine deficiency has been reported in a cohort that will be childbearing in the next decade, we recommend that the distribution of neonatal blood spot TSH concentrations is monitored by the UK newborn screening programmes to identify any emerging trends in iodine status. Further studies to correlate maternal urinary iodine and newborn blood spot TSH are required to clarify the TSH cut-off points associated with mild iodine deficiency relevant to the time of blood spot sampling in the UK. PMID- 24801195 TI - Accessing new chemical entities through microfluidic systems. AB - Flow systems have been successfully utilized for a wide variety of applications in chemical research and development, including the miniaturization of (bio)analytical methods and synthetic (bio)organic chemistry. Currently, we are witnessing the growing use of microfluidic technologies for the discovery of new chemical entities. As a consequence, chemical biology and molecular medicine research are being reshaped by this technique. In this Minireview we portray the state-of-the-art, including the most recent advances in the application of microchip reactors as well as the micro- and mesoscale coil reactor-assisted synthesis of bioactive small molecules, and forecast the potential future use of this promising technology. PMID- 24801194 TI - Conjugates of cisplatin and cyclooxygenase inhibitors as potent antitumor agents overcoming cisplatin resistance. AB - Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects with traditional chemotherapeutics. COX-2 is also reported to cause resistance towards antitumor agents, such as cisplatin. Here, the first covalently linked conjugates of cisplatin and COX inhibitors are reported. These conjugates exhibit concerted transport of both drugs into tumor cells and simultaneous action upon intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared with cisplatin and are even able to overcome cisplatin-related resistance of tumor cells. While the results reported show that COX-2 inhibition is not directly responsible for the potent activities of these conjugates, they do represent useful tool compounds for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents. PMID- 24801196 TI - Extension of the diffusion controlled electron transfer theory for intermittent fluorescence of quantum dots: inclusion of biexcitons and the difference of "on" and "off" time distributions. AB - The equations for the diffusion controlled electron transfer (DCET) theory of quantum dot blinking are extended to include biexcitons. In contrast to excitons, which undego resonant light to dark transitions, the biexcitons, having a much larger total energy, undergo a Fermi's Golden rule type transfer (many acceptance states). The latter immediately gives rise to an exponential tail for the light state, and it is explained why the dark state power law behavior is unaffected. Results are given for both continuous and pulsed excitation. The typical -3/2 power law for the light state at low light intensities, and for the dark state at all intensities, as well as dependence of the exponential tail on the square of the light intensity, and a decrease of the power in the power law for the light state from -3/2 to less negative values with increasing light intensity are all consistent with the theory. The desirability of measuring the dependence of the spectral diffusion coefficient on light intensity at room temperature as a test of several aspects of the theory is noted. PMID- 24801197 TI - Long-term quality of life after laparoscopic distal gastrectomy for early gastric cancer: results of a prospective multi-institutional comparative trial. AB - BACKGROUND: The aim of this study was to compare the postoperative health-related quality of life (HRQOL) between open and laparoscopic distal gastrectomy. METHODS: A multi-institutional nonrandomized study was conducted. Patients with clinical T1 gastric cancer were prospectively enrolled and underwent distal gastrectomy by either the open or laparoscopic approach. HRQOL was measured using the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 and the site-specific module for gastric cancer. Questionnaires were completed at baseline and at 1, 3, 6, and 12 months postoperatively. Clinicopathological characteristics and short-term outcome including postoperative morbidity and HRQOL were compared between the approaches. RESULTS: A total of 145 patients (open, n = 72; laparoscopic, n = 73) were enrolled between September 2008 and January 2011 and analyzed. The laparoscopic approach was associated with longer operating time, less blood loss, and a similar incidence of postoperative complications. At each time point, the questionnaires were retrieved from more than 90 % of the patients. The worst scores for most of the scales were observed at 1 month postoperatively and improved thereafter. No statistically significant differences were observed regarding physical functioning, the primary endpoint. On the other hand, role, emotional, cognitive, and social functioning scores were superior in the laparoscopic group at 6 and 12 months postoperatively. Symptom scales including fatigue, pain, eating restriction, taste problems, and anxiety were better in the laparoscopic group before 6 months but not at 12 months. CONCLUSIONS: The study was considered to be negative because no benefit of the laparoscopic approach was observed in terms of physical functioning. However, more favorable scores for some of the symptom scales during the first 6 months and several functioning scales at 12 months after surgery suggest a potential benefit of the laparoscopic approach. PMID- 24801198 TI - Long-term quality-of-life comparison of total gastrectomy and proximal gastrectomy by postgastrectomy syndrome assessment scale (PGSAS-45): a nationwide multi-institutional study. AB - BACKGROUND: Although proximal gastrectomy (PG) is widely accepted as a function preserving operation for early upper-third gastric cancer, postoperative disorders, such as reflux or gastric stasis, have often been pointed out. From the perspective of postoperative disorder, the choice of total gastrectomy (TG) or PG for such cancers is still controversial. By using the newly developed Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, the quality of life after TG and PG was compared. METHODS: The PGSAS-45 consists of 45 items composed of the SF-8 and GSRS scales and 22 new items. The main outcomes are measured by seven subscales (SS) covering symptoms, physical and mental component summary (SF 8), meals (amount and quality), ability to work, dissatisfaction for daily life, and change in body weight. A total of 2,368 eligible questionnaires were acquired from 52 institutions. From these, 393 patients with TG and 193 patients with PG were selected and compared. RESULTS: The PG was better than TG in terms of body weight loss (TG 13.8% vs. PG 10.9%; p = 0.003), necessity for additional meals (2.4 vs. 2.0; p < 0.001), diarrhea SS (2.3 vs. 2.0; p = 0.048), and dumping SS (2.3 vs. 2.0; p = 0.043). There were no differences in the other main outcome measures. CONCLUSIONS: Proximal gastrectomy appears to be valuable as a function preserving procedure for early upper-third gastric cancer. PMID- 24801199 TI - Outcomes of endoscopic submucosal dissection for differentiated-type early gastric cancer with histological heterogeneity. AB - BACKGROUND: Long-term clinical outcomes after endoscopic submucosal dissection (ESD) is unclear for differentiated-type-predominant early gastric cancer (EGC) mixed with undifferentiated component (MUC-EGC). Therefore, the role and appropriate indication of ESD for MUC-EGC remain to be evaluated. METHODS: Between 2007 and 2011, 1,577 differentiated-type EGC lesions [1,408 pure differentiated-type (PuD)-EGCs and 169 MUC-EGCs] in 1,527 consecutive patients were treated by ESD. After ESD, MUC-EGC was managed in the same way as PuD-EGC. The clinicopathological features and long-term outcomes after ESD of MUC-EGC were compared with those of PuD-EGC. RESULTS: En bloc resection and en bloc with R0 resection rates in MUC-EGC cases were 94.1 % and 81.7 %, respectively. MUC-EGC was significantly associated with larger tumor size, more frequent submucosal invasion, and lymphovascular invasion compared to PuD-EGC. Despite these aggressive features of MUC-EGC, no lymph node metastasis or extragastric recurrence occurred during follow-up after ESD if MUC-EGC met the curative endoscopic resection (ER) criteria for tumors of absolute or expanded indications. Four MUC-EGC cases meeting the curative ER criteria underwent additional radical gastrectomy after ESD, and no case showed lymph node metastasis. During a median 48 months of follow-up, overall survival rates for MUC-EGC meeting the curative ER criteria for tumors of absolute or expanded indications (3-year survival rates, 100 % and 100 %) were comparable to those of PuD-EGC. CONCLUSIONS: Long-term outcomes after ESD were favorable for MUC-EGCs meeting the curative ER criteria for tumors of absolute or expanded indications. Therefore, ESD may be used as a promising treatment option for these cases. PMID- 24801200 TI - Monte Carlo derived absorbed fractions for a voxelized model of Oncorhynchus mykiss, a rainbow trout. AB - Simple, ellipsoidal geometries have long been the standard for estimating radiation dose rates in non-human biota (NHB). With the introduction of a regulatory protection standard that emphasizes protection of NHB as its own end point, there has been interest in improved models for the calculation of dose rates in NHB. Here, we describe the creation of a voxelized model for a rainbow trout (Oncorhynchus mykiss), a freshwater aquatic salmonid. Absorbed fractions (AFs) for both photon and electron sources were tabulated at electron energies of 0.1, 0.2, 0.4, 0.5, 0.7, 1.0, 1.5, 2.0, and 4.0 MeV and photon energies of 0.01, 0.015, 0.02, 0.03, 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, and 4.0 MeV. A representative set of the data is made available in this publication; the entire set of absorbed fractions is available as electronic supplementary materials. These results are consistent with previous voxelized models and reinforce the well-understood relationship between the AF and the target's mass and location, as well as the energy of the incident radiation. PMID- 24801201 TI - Probing signal amplification by reversible exchange using an NMR flow system. AB - Hyperpolarization methods are used in NMR to overcome its inherent sensitivity problem. Herein, the biologically relevant target nicotinamide is polarized by the hyperpolarization technique signal amplification by reversible exchange. We illustrate how the polarization transfer field, and the concentrations of parahydrogen, the polarization-transfer-catalyst and substrate can be used to maximize signal amplification by reversible exchange effectiveness by reference to the first-order spin system of this target. The catalyst is shown to be crucial in this process, first by facilitating the transfer of hyperpolarization from parahydrogen to nicotinamide and then by depleting the resulting polarized states through further interaction. The 15 longitudinal one, two, three and four spin order terms produced are rigorously identified and quantified using an automated flow apparatus in conjunction with NMR pulse sequences based on the only parahydrogen spectroscopy protocol. The rates of build-up of these terms were shown to follow the order four~three > two > single spin; this order parallels their rates of relaxation. The result of these competing effects is that the less-efficiently formed single-spin order terms dominate at the point of measurement with the two-spin terms having amplitudes that are an order of magnitude lower. We also complete further measurements to demonstrate that (13)C NMR spectra can be readily collected where the long-lived quaternary (13)C signals appear with significant intensity. These are improved upon by using INEPT. In summary, we dissect the complexity of this method, highlighting its benefits to the NMR community and its applicability for high-sensitivity magnetic resonance imaging detection in the future. PMID- 24801202 TI - The node of Ranvier in multifocal motor neuropathy. AB - Multifocal motor neuropathy affects myelinated motor axons in limb nerves at multifocal sites. It is characterized by weakness and muscle atrophy, motor conduction block, and antibodies against ganglioside GM1 which is expressed on the axolemma of nodes of Ranvier and perinodal Schwann cells. Treatment by regular IVIg courses results in temporary improvement but cannot prevent slowly progressing weakness due to axonal degeneration. This review discusses possible mechanisms of conduction block and the reasons why motor axons are selectively affected in this disorder. PMID- 24801203 TI - Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. AB - The current management of disseminated intravascular coagulation (DIC) is based on aggressive treatment of the underlying condition and resuscitation with appropriate blood products. Anticoagulant therapy has appeared and disappeared in the different guidelines and important documents detailing the treatment of DIC. For example, Surviving Sepsis Campaign (SSC) guidelines, the 'global standard' for the management of severe sepsis, had recombinant activated protein C highly recommended in the original version, but this was withdrawn in the latest version due to the lack of evidence. In contrast, recent international guidance released from the International Society on Thrombosis and Haemostasis has introduced the potential efficacy of other agents. In sepsis-related DIC, the basis for anticoagulant therapy comes from the mounting evidence for the anti-inflammatory effects which these agents possess and can prove beneficial in septic situations. Several studies have clearly shown the important cross-talk between coagulation and inflammation in patients with sepsis. More recently, neutrophil extracellular traps and damage-associated molecular patterns (DAMPs), especially histones, have been demonstrated to play a crucial role in the coagulopathy of sepsis. Once again, the natural anticoagulants have an important function in neutralizing the effects of DAMPs and histones. In this review, in addition to examining the important role of anticoagulants in the septic milieu, the clinical studies examining antithrombin, recombinant thrombomodulin and plasma-derived activated protein C are detailed. However, large-scale randomized controlled trials are yet to be performed, with important consideration of the timing, dosage and duration of treatment. PMID- 24801205 TI - Real-time segmentation of multiple implanted cylindrical liver markers in kilovoltage and megavoltage x-ray images. AB - Gold markers implanted in or near a tumor can be used as x-ray visible landmarks for image based tumor localization. The aim of this study was to develop and demonstrate fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in cone-beam CT (CBCT) projections, for real-time motion management. Thirteen patients treated with conformal stereotactic body radiation therapy in three fractions had 2-3 cylindrical gold markers implanted in the liver prior to treatment. At each fraction, the projection images of a pre-treatment CBCT scan were used for automatic generation of a 3D marker model that consisted of the size, orientation, and estimated 3D trajectory of each marker during the CBCT scan. The 3D marker model was used for real-time template based segmentation in subsequent x-ray images by projecting each marker's 3D shape and likely 3D motion range onto the imager plane. The segmentation was performed in intra-treatment kV images (526 marker traces, 92,097 marker projections) and MV images (88 marker traces, 22,382 marker projections), and in post-treatment CBCT projections (42 CBCT scans, 71,381 marker projections). 227 kV marker traces with low mean contrast-to noise ratio were excluded as markers were not visible due to MV scatter. Online segmentation times measured for a limited dataset were used for estimating real time segmentation times for all images. The percentage of detected markers was 94.8% (kV), 96.1% (MV), and 98.6% (CBCT). For the detected markers, the real-time segmentation was erroneous in 0.2-0.31% of the cases. The mean segmentation time per marker was 5.6 ms [2.1-12 ms] (kV), 5.5 ms [1.6-13 ms] (MV), and 6.5 ms [1.8 15 ms] (CBCT). Fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in CBCT projections was demonstrated for a large dataset. PMID- 24801204 TI - Reduced blood pressure of CFTR-F508del carriers correlates with diminished arterial reactivity rather than circulating blood volume in mice. AB - The F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cause of cystic fibrosis (CF). Both CF patients and F508del carriers have decreased blood pressure. While this has been attributed to salt depletion, recent studies have shown F508del expression interferes with smooth muscle cell calcium mobilization. We tested the hypothesis that carriers of the F508del mutation have lower adult blood pressures and reduced aortic contractility without a reduction in circulating blood volume. By radiotelemetry, F508del heterozygous mice had significantly lower arterial pressures than wild type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg). To replicate the vascular effects of sympathetic arousal, isoproterenol and epinephrine were co-infused, and F508del mice again had significantly reduced arterial pressures. Aortas isolated from F508del heterozygous mice had significantly decreased constriction to noradrenaline (0.9 +/- 0.2 versus 2.9 +/- 0.7 mN). Inhibition of wild-type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR F508del mutation decreases aortic contractility and lowers arterial pressures. As a cAMP-activated chloride channel that facilitates calcium mobilization, we speculate wild-type CFTR co-activation during adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower arterial pressures seen in heterozygote carriers of a CFTR-F508del mutation. PMID- 24801206 TI - Histopathology and biomarkers in prediction of renal function in children after kidney transplantation. AB - BACKGROUND: Early detection of chronic allograft injury is a major challenge after kidney transplantation (RTx) in adults and children. We correlated the expression of four immunohistochemical biomarkers, P-selectin glycoprotein ligand 1 (PSGL-1), vimentin, alpha-smooth muscle actin (alpha-SMA) and collagen IV, to the kidney graft histology and function in pediatric RTx patients. METHODS: We analyzed the histopathology and immunohistochemical stainings of 165 biopsies from 56 patients. Histopathology was scored according to Banff '05 classification and biomarker expression semiquantitatively. Glomerular filtration rate (GFR) was measured annually by (51)Cr-EDTA clearance. RESULTS: In protocol biopsies, the expression of all four biomarkers correlated with the interstitial fibrosis and tubular atrophy (IF/TA) changes, which increased during the first 36months after RTx. At the time of 18month biopsy, we observed the deterioration of GFR in patients with high (>=2) IF/TA score (50 vs. 68ml/min/1.73m(2), p=0.004) or collagen IV expression (45 vs. 65ml/min/1.73m(2), p=0.016). Intense stainings of IF/TA, collagen IV and vimentin are also associated with poor GFR at 36 and 48months, however, the biomarker scores revealed no additional predictive value for concomitant or late GFR compared to IF/TA score. Patients with high and low biomarker expressions showed no significant differences in annual deterioration of GFR, which declined on average 2.2ml/min/1.73m(2)/year over the 7years follow up. CONCLUSIONS: Overall, the results suggest that traditional histopathology is a sufficient predictor for graft function, and the routine use of these histochemical markers as surrogates for graft function deterioration is questioned. PMID- 24801207 TI - Time elapsed after transplantation influences the relationship between the number of regulatory T cells in lung allograft biopsies and subsequent acute rejection episodes. AB - BACKGROUND: Regulatory T lymphocytes (Tregs) play an important role in acute rejection after lung transplantation. However, the importance of the time elapsed after transplantation on the Treg response requires further investigation. We aim to evaluate the change over time in the frequency of Tregs in lung allograft biopsies and to assess how Tregs relate to simultaneous and subsequent acute cellular rejection. MATERIALS AND METHODS: A total of 258 biopsy samples obtained 0.5, 1, 3, 12 and 24 months after transplantation from 58 consecutive lung transplant patients were included. The biopsies were scored for acute rejection according to the ISHLT criteria (A0-A4) and immunohistochemically stained with antibodies against FoxP3. RESULTS: There was a tendency for a decrease in the number of Tregs/mm2 with time. However, the previous levels of Tregs/mm2 did not have any significant effect on future levels of Tregs/mm2. For biopsies taken 0.5 and 1 month after transplantation, a significant correlation between Tregs/mm2 and the degree of acute rejection was found, and logistic regression analysis using updated values for Tregs/mm2 showed a significant relationship between Tregs/mm2 at 2 weeks and an A-score>=2 after 1 and 3 months. At later time points, this correlation disappeared. DISCUSSION AND CONCLUSION: Our data indicate that the time elapsed after transplantation is an important parameter influencing the Treg response after lung transplantation. This observation is in accordance with studies indicating a narrow therapeutic window for induction of tolerance by specifically targeting T-cells. The results also indirectly indicate that Tregs early after transplantation could have an impact on the long-term outcome. PMID- 24801209 TI - Implications of the fast-evolving scale-up of adult voluntary medical male circumcision for quality of services in South Africa. AB - BACKGROUND: The scale-up of voluntary medical male circumcision (VMMC) services in South Africa has been rapid, in an attempt to achieve the national government target of 4.3 million adult male circumcisions for HIV prevention by 2016. This study assesses the effect of the scale-up on the quality of the VMMC program. METHODS AND FINDINGS: This analysis compares the quality of services at 15 sites operational in 2011 to (1) the same 15 sites in 2012 and (2) to a set of 40 sites representing the expanded program in 2012. Trained clinicians scored each site on 29 items measuring readiness to provide quality services (abbreviated version of the WHO Quality Assessment [QA] Guide) and 29 items to assess quality of surgical care provided (pre-op, surgical technique and post-op) based on the observation of VMMC procedures at each site. Declines in quality far outnumbered improvements. The negative effects in terms of readiness to provide quality services were most evident in expanded sites, whereas the declines in provision of quality services tended to affect both repeat sites and expanded sites equally. Areas of notable concern included the monitoring of adverse events, external supervision, post-operative counselling, and some infection control issues. Scores on quality of surgical technique tended to be among the highest across the 58 items observed, and the South Africa program has clearly institutionalized three "best practices" for surgical efficiency. CONCLUSIONS: These findings demonstrate the challenges of rapidly developing large numbers of new VMMC sites with the necessary equipment, supplies, and protocols. The scale up in South Africa has diluted human resources, with negative effects for both the original sites and the expanded program. PMID- 24801208 TI - Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin. AB - BACKGROUND & AIMS: HMG-CoA-reductase-inhibitors (statins) have been shown to interfere with HCV replication in vitro. We investigated the mechanism, requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication. METHODS: HO-1-induction by fluva-, simva-, rosuva-, atorva- or pravastatin was correlated to HCV replication, using non infectious replicon systems as well as the infectious cell culture system. The mechanism of HO-1-induction by statins as well as its relevance for interference with HCV replication was investigated using transient or permanent knockdown cell lines. Polyacrylamide(PAA) gels of different density degrees or the Rho-kinase inhibitor Hydroxyfasudil were used in order to mimic matrix conditions corresponding to normal versus fibrotic liver tissue. RESULTS: All statins used, except pravastatin, decreased HCV replication and induced HO-1 expression, as well as interferon response in vitro. HO-1-induction was mediated by reduction of Bach1 expression and induction of the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) cofactor Krueppel-like factor 2 (KLF2). Knockdown of KLF2 or HO-1 abrogated effects of statins on HCV replication. HO-1-induction and anti-viral effects of statins were more pronounced under cell culture conditions mimicking advanced stages of liver disease. CONCLUSIONS: Statin-mediated effects on HCV replication seem to require HO-1-induction, which is more pronounced in a microenvironment resembling fibrotic liver tissue. This implicates that certain statins might be especially useful to support HCV therapy of patients at advanced stages of liver disease. PMID- 24801211 TI - Prediction of metabolic syndrome by non-alcoholic fatty liver disease in northern urban Han Chinese population: a prospective cohort study. AB - OBJECTIVES: To explore the relationship between non-alcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS), and evaluate the value of NAFLD as a marker for predicting the risk of MetS in a large scale prospective cohort from northern urban Han Chinese population. MATERIALS AND METHODS: A total of 17,920 MetS-free at baseline cohort members was included in the current study between 2005 and 2011. The baseline characteristics of the cohort were compared by NAFLD status at baseline, MetS status after follow-up. Cox proportional hazards models were used to estimate the unadjusted or adjusted hazard ratios (HRs) for NAFLD at baseline predicting the risk of MetS. RESULTS: 2,183 (12.18%) new cases of MetS occurred between 2005 and 2011. In unadjusted model, HRs (95% CIs) for NAFLD predicting MetS was 3.65 (3.35, 3.97). After adjusting the confounding factors of age, gender, the metabolic factors, smoke and exercise, the HRs (95% CIs) was 1.70 (1.55, 1.87). Gender difference was observed, adjusted HRs (95% CIs) of NAFLD for predicting MetS were 2.06(1.72, 2.46) and 1.55(1.39, 1.72) in female and male population, respectively. Moreover, 163 participants developed MetS among participants without any MetS component at baseline, and its adjusted HRs was still significant, 1.87 (1.12, 3.13). CONCLUSION: The present study indicates that NAFLD is an independent risk factor for predicting the risk of MetS in northern urban Han Chinese population, and the people with NAFLD should initiate weight and dietary control to prevent the occurrence of MetS. PMID- 24801212 TI - Chlorella triggers stomatal closure mediated by NADPH oxidase and improves instantaneous water use efficiency in Vicia faba. AB - Stomatal closure induced by live microbes and microbe-associated molecular patterns (MAMPs) has been associated with early defense responses of plants. Chlorella is a unicellular autotrophic microorganism that can synthesize many bioactive substances with positive effects on humans, animals and plants. However, its effects on stomatal movement and instantaneous intrinsic water use efficiency (WUEi) in plants have been not explored yet. Our present work showed that application of Chlorella to isolated epidermal peels of Vicia faba induced stomatal closure in a dose-and time-dependent manner. Pharmacological study revealed that the Chlorella-triggered stomatal closure was mainly mediated by reactive oxygen species (ROS) production via NADPH oxidase. Additionally, exogenous application of optimal concentrations of Chlorella suspension caused an obvious reduction in leaf transpiration rate (E) without a parallel reduction in net photosynthetic rate (Pn), favoring the improvement of WUEi in Vicia faba. The chlorophyll fluorescence and content analysis further indicated that Chlorella had no effects on plant photosynthetic reactions center after short-term foliar application. PMID- 24801214 TI - Geniposide attenuates oligomeric Abeta(1-42)-induced inflammatory response by targeting RAGE-dependent signaling in BV2 cells. AB - The neuroinflammation induced by amyloid-beta (Abeta) is one of the key events in Alzheimer's disease (AD) progress in which microglia are the main cells involved. Receptor for advanced glycation end products (RAGE) mediates and enhances Abeta induced microglial activation and leads to induction of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Geniposide, a pharmacologically active component purified from gardenia fruit, exhibits a broad spectrum anti-inflammatory effect as well as neurotrophic and neuroprotective properties. However, the effects of geniposide on Abeta-mediated microglial pathways have not been fully discovered. Here, we demonstrate that geniposide treatment significantly blocks Abeta-induced RAGE dependent signaling (activation of ERK and NF-kappaB) along with the production of TNF-alpha and IL-1beta in cultured BV2 microglia cells. Notably, based on the data from coimmunoprecipitation assay, we infer that geniposide exerts protective effects on Abeta-induced inflammatroy response through blocking Abeta binding to RAGE and suppressing the RAGE-mediated signaling pathway. Taken together, these findings indicate that geniposide is a potent suppressor of neuroflammation through inhibiting RAGE-dependent signaling pathway. Thus, geniposide may be a potential therapeutic agent for the treatment of neuroinflammation that is involved in neurological diseases such as AD. PMID- 24801215 TI - Cognitive stimulation: the evidence base for its application in neurodegenerative disease. AB - Multiple modalities of cognitive stimulation (CS) have been designed and tested in samples of patients with probable Alzheimer's disease (AD). Despite the substantial inter-study variability, an overall positive impact of CS is reported. This impact has been especially observed in general measures of cognition. The mechanisms by which cognitive exercises would be beneficial for high-order cortical functions are still largely undetermined, however. When CS has been applied to patients with mild cognitive impairment (who are at the prodromal stage of AD) more stringent methodological criteria and designs were used and studies have been of greater clinical and research relevance. At this disease stage, a positive impact of CS has been reported in a range of different cognitive domains, and even at a neuro-computational level by the measurement of test-retest modifications of brain function. The effects of CS in healthy adults have also been studied. This population allows researchers to explore and test specific neural mechanisms possibly underlying the effect of pen-and-paper or computerised exercises. The evidence from these studies and those contributing to a better understanding of the pathophysiology of AD has led to devising forms of CS as preventive and therapeutical measures for neurodegenerative diseases based on novel frameworks of brain structure, function and connectivity. An extensive review of the literature was carried out to clarify whether CS is effective in AD and mild cognitive impairment and, together with the evidence from studies in healthy participants, to identify the relevant mechanisms that might sustain this effectiveness. PMID- 24801216 TI - Early detection of cerebral glucose uptake changes in the 5XFAD mouse. AB - Brain glucose hypometabolism has been observed in Alzheimer's disease (AD) patients, and is detected with (18)F radiolabelled glucose, using positron emission tomography. A pathological hallmark of AD is deposition of brain beta- amyloid plaques that may influence cerebral glucose metabolism. The five times familial AD (5XFAD) mouse is a model of brain amyloidosis exhibiting AD-like phenotypes. This study examines brain beta-amyloid plaque deposition and (18)FDG uptake, to search for an early biomarker distinguishing 5XFAD from wild-type mice. Thus, brain (18)FDG uptake and plaque deposition was studied in these mice at age 2, 5 and 13 months. The 5XFAD mice demonstrated significantly reduced brain (18)FDG uptake at 13 months relative to wild-type controls but not in younger mice, despite substantial beta- amyloid plaque deposition. However, by comparing the ratio of uptake values for glucose in different regions in the same brain, 5XFAD mice could be distinguished from controls at age 2 months. This method of measuring altered glucose metabolism may represent an early biomarker for the progression of amyloid deposition in the brain. We conclude that brain (18)FDG uptake can be a sensitive biomarker for early detection of abnormal metabolism in the 5XFAD mouse when alternative relative uptake values are utilized. PMID- 24801217 TI - Older adults with amnestic mild cognitive impairment exhibit exacerbated gait slowing under dual-task challenges. AB - BACKGROUND: With age, performance of motor tasks becomes more reliant on cognitive resources to compensate for the structural and functional declines in the motor control regions in the brain. We hypothesized that participants with amnestic mild cognitive impairment (aMCI) are more prone to motor dysfunctions than cognitively normal older adults under dual-task conditions where competitive demands challenge cognitive functions while performing a motor task simultaneously. METHODS: Sixteen aMCI participants (females=9, age=64+/-5yrs, clinical dementia rating score=0.5) and 10 age- and education-matched cognitively normal adults (females=5, age=62+/-6yrs) participated. Using a 10-meter-walk test (10MW), gait velocity was recorded at baseline and under 4 different dual-task (DT) conditions designed to challenge working memory, executive function, and episodic memory. Specifically, DT1: verbal fluency; DT2: 5-digit backward span; DT3: serial-7 subtraction; and DT4: 3-item delayed recall. Physical function was measured by Timed Up-and-Go (TUG), simple reaction time (RT) to a free-falling yardstick, and functional reach (FR). RESULTS: No difference was found in physical functions, aerobic fitness, and exercise cardiopulmonary responses between aMCI participants and controls. However, aMCI participants showed more pronounced gait slowing from baseline when compared to the controls (p<0.05; p=0.001; p<0.001; p<0.001, respectively). CONCLUSIONS: Our finding supports the theory of shared resource of motor and cognitive control. Participants with aMCI manifested more gait slowing than cognitively-normal older adults under DT conditions, with the largest differences during tests of working and episodic memory. The outcome of dual-task assessment shows promise as a potential marker for detection of aMCI and early Alzheimer disease. PMID- 24801218 TI - A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF 04447943, in Alzheimer's disease. AB - BACKGROUND: PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3',5' - cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (Abeta) production (Tg2576). OBJECTIVE: This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer's disease (AD). METHODS: Subjects in overall good health with Mini Mental State Examination (MMSE) scores of 14-26 were randomized to 12 weeks treatment with PF-04447943 25 mg q12h (n=91) or placebo (n=100). Concomitant acetylcholinesterase inhibitor or memantine use was excluded. The primary outcome was the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog). The Neuropsychiatric Inventory (NPI), Clinical Global Impression Improvement scale (CGI-I) and standard safety measures were secondary outcomes. RESULTS: Completion rates were similar, 87% PF-04447943 vs 92% placebo. At week 12 the mean (SE) baseline adjusted decrease from baseline in ADAS cog for PF 04447943-treated patients was -1.91 (0.54). Placebo treated patients had a change of -1.60 (0.50). The difference between treatments was -0.31 (90% CI of -1.52, 0.90). Corresponding values for the NPI were -2.86 (0.72) vs -2.70 (0.67) with a treatment difference of -0.16 (90% CI of -1.78, 1.48). Neither these changes nor the distribution of CGI-I scores were statistically significantly different between groups. The incidence of serious adverse events (AEs) was similar between groups with 2 deaths in the placebo group. The PF-04447943 group reported more gastrointestinal AEs including diarrhea (5.5% vs 3%) and nausea (5.5% vs 1%) and had a higher rate of discontinuation due to AEs (6.6% vs 2%). CONCLUSIONS: Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo. PMID- 24801219 TI - The effects of CCRC on cognition and brain activity in aMCI patients: a pilot placebo controlled BOLD fMRI study. AB - OBJECTIVE: To investigate effects and functional mechanism of compound Congrongyizhi Capsule (CCRC), a Chinese medicine, on cognitive functions against amnestic mild cognitive impairment (aMCI) patients with functional magnetic resonance imaging (fMRI) based on n-back task. METHODS: Forty-one aMCI participants from hospital and local communities in Beijing and randomly divided into treatment (16 patients with CCRC capsule treatment), placebo (12 patients with placebo capsules) and control group (13 patients with no treatment). The duration of intervention lasted for 3 months. Neuropsychological tests and fMRI were applied to assess cognitive ability and brain activation changes after three months treatment. RESULTS: Drug group (n=16) presented increased significance in the MMSE (P=0.008) and digit span (P<0.001) tests, while other scores of neuropsychological tests showed no statistical significance. fMRI results showed an increased brain negative activation in drug group during performing the n-back working-memory task in posterior cingulate (PCC), inferior frontal gyrus and lingual gyrus regions after 3 months; placebo and control group did not show the same effect. Meanwhile, there were negative correlations between left PCC activation levels and changed values of MMSE and digit span separately since increased negative activation was associated with better performance on the scores of MMSE and Digit Span tests. CONCLUSIONS: CCRC can increase negative activation degree of PCC under performing working memory tasks while this modulation are associated with better performance on the MMSE and Digit Span. PMID- 24801220 TI - Dimebon attenuates the Abeta-induced mitochondrial permeabilization. AB - The currently available experimental data supports the hypothesis that the neuroprotective effect of dimebon is related to the protection of the brain mitochondria from neurodegeneration. In this study, the influence of dimebon on mitochondria was investigated to gain a better understanding of the neuroprotective effects of this drug. Here, we demonstrate that dimebon enhances the resistance of the isolated rat brain and liver mitochondria to the induction of mitochondrial permeability transition (MPT) by calcium ions even in the presence of atractyloside, a MPT pore (MPTP) opener, but is ineffective against atractyloside-induced mitochondria swelling. Unlike cyclosporine A (CsA), a MPTP inhibitor, Dimebon does not influence the adenine nucleotide translocase (ANT) conformational changes and is not able to prevent the MPT of de-energized mitochondria. Using three different assays, and using amyloid-beta peptide for inducing mitochondrial toxicity, we show that the influence of dimebon on the calcium retention capacity (CRC) of mitochondria depends on the mode of calcium addition. No obvious influence of dimebon on CRC was observed under the conditions of calcium infusion in the pump mode but the increase of CRC of rat brain mitochondria was observed when calcium was added in the bolus mode; the addition of calcium in the single pulse mode led to the increase of the lag period of calcium efflux from mitochondria. From these studies it is shown that dimebon is effective against amyloid-beta (Abeta) potentiated mitochondrial swelling and decrease of calcium retention capacity (CRC) of the brain mitochondria. PMID- 24801221 TI - Food insecurity, a determinant of obesity? - an analysis from a population-based survey in the Paris metropolitan area, 2010. AB - OBJECTIVE: The relationship between food insecurity and obesity is discussed in the literature. The objective of this study was to determine whether food insecurity and obesity were associated in the Paris metropolitan area. METHODS: We used data from third wave of the Health, Inequalities and Social Ruptures (SIRS) cohort study, a longitudinal population-based, representative health and socioepidemiological survey of the general population in the Paris metropolitan area. The participants' BMI (calculated using self-reported height and weight) was analyzed as a continuous variable, and a dichotomous variable (BMI < 30 kg/m(2)/BMI >= 30 kg/m(2)) was constructed. Food insecurity was estimated using the Household Food Security Scale Module (HFSSM) and was treated as a trichotomous variable (food security / low food security / very low food security). Multilevel models were estimated for men and women separately. RESULTS: Obesity (BMI >= 30 kg/m(2)) prevalence was 10.2%. The determinant of obesity differs according to gender. After adjustment for age, income and the sociooccupational group, very low food security was associated with obesity in women (OR = 2.01, 95%CI 1.05-3.82), and women with very low food security had a higher BMI (Coef. = 1.78, 95% CI 0.24-3.31). This association, however, was not significant for men (OR = 1.84, 95%CI 0.64-5.30). CONCLUSION: In times of economic crisis, it is increasingly essential to explore and understand the pathway through which very low food security is linked to obesity. PMID- 24801222 TI - Reward anticipation in the adolescent and aging brain. AB - Processing of reward is the basis of adaptive behavior of the human being. Neural correlates of reward processing seem to be influenced by developmental changes from adolescence to late adulthood. The aim of this study is to uncover these neural correlates during a slot machine gambling task across the lifespan. Therefore, we used functional magnetic resonance imaging to investigate 102 volunteers in three different age groups: 34 adolescents, 34 younger adults, and 34 older adults. We focused on the core reward areas ventral striatum (VS) and ventromedial prefrontal cortex (VMPFC), the valence processing associated areas, anterior cingulate cortex (ACC) and insula, as well as information integration associated areas, dorsolateral prefrontal cortex (DLPFC), and inferior parietal lobule (IPL). Results showed that VS and VMPFC were characterized by a hyperactivation in adolescents compared with younger adults. Furthermore, the ACC and insula were characterized by a U-shape pattern (hypoactivation in younger adults compared with adolescents and older adults), whereas the DLPFC and IPL were characterized by a J-shaped form (hyperactivation in older adults compared with younger groups). Furthermore, a functional connectivity analysis revealed an elevated negative functional coupling between the inhibition-related area rIFG and VS in younger adults compared with adolescents. Results indicate that lifespan-related changes during reward anticipation are characterized by different trajectories in different reward network modules and support the hypothesis of an imbalance in maturation of striatal and prefrontal cortex in adolescents. Furthermore, these results suggest compensatory age-specific effects in fronto-parietal regions. PMID- 24801223 TI - Heterogeneity in the smoking response to health shocks by out-of-pocket spending risk. AB - An existing literature demonstrates that adverse changes to health can lead to improvements in health behaviors. Although the exact explanations for these empirical findings are debated, some posit that individuals learn about their true health risks through health shocks. Updated health risk information can then induce changes in health behaviors. While we follow a learning framework, we argue that past work has neglected the role of health insurance and medically related financial risk within this decision making context. Using longitudinal data from 11 European countries, we investigate the impact of a new cardiovascular (CV) health shock on smoking decisions among older adults and examine whether personal exposure to medical spending risk influences the smoking response. We then explore two potential mechanisms for this link: larger updates to health risk beliefs and higher medical expenditures to incentivize behavior change. We find that CV shocks impact the propensity to smoke, with relatively more impact among individuals with high financial risk exposure to medical spending. We also see larger increases in out-of-pocket expenditures following a shock for this group--consistent with the latter mechanism for behavior change. PMID- 24801224 TI - ATF3 is a novel nuclear marker for migrating ependymal stem cells in the rat spinal cord. AB - The present study identified ATF3 as a novel dynamic marker for ependymal stem/progenitor cells (nestin, vimentin and SOX2 positive) around the central canal of the neonatal or adult rat spinal cord. While quiescent ependymal cells showed cytoplasmic ATF3 expression, during 6-24h in vitro these cells mobilized and acquired intense nuclear ATF3 staining. Their migratory pattern followed a centrifugal pathway toward the dorsal and ventral funiculi, reminiscent of the rostral migratory stream of the brain subventricular stem cells. Thus, the chain cell formation was, by analogy, termed funicular migratory stream (FMS). The FMS process preceded the strong proliferation of ependymal cells occurring only after 24h in vitro. Pharmacological inhibition of MAPK-p38 and JNK/c-Jun (upstream effectors of ATF3 activation) prevented the FMS mobilization of ATF3 nuclear positive cells. Excitotoxicity or ischemia-like conditions, reported to evoke neuronal and glial injury, did not further enhance migration of ependymal cells at 24h, suggesting that, at this early stage of damage, the FMS phenomenon had peaked and that more extensive repair processes are delayed beyond this time point. ATF3 is, therefore, useful to identify activation and migration of endogenous stem cells of the rat spinal cord in vitro. PMID- 24801225 TI - Acupuncture for epilepsy. AB - BACKGROUND: Acupuncture is increasingly used in people with epilepsy. It remains unclear whether existing evidence is rigorous enough to support its use. This is an update of a Cochrane review first published in 2008. OBJECTIVES: To determine the effectiveness and safety of acupuncture in people with epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5), MEDLINE, EMBASE, CINAHL, AMED and other databases (from inception to June 2013). We reviewed reference lists from relevant trials. We did not impose any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing acupuncture with placebo or sham treatment, antiepileptic drugs or no treatment; or comparing acupuncture plus other treatments with the same other treatments, involving people of any age with any type of epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 17 RCTs with 1538 participants that had a wide age range and were suffering mainly from generalized epilepsy. The duration of treatment varied from 7.5 weeks to 1 year. All included trials had a high risk of bias with short follow-up. Compared with Chinese herbs, needle acupuncture plus Chinese herbs was not effective in achieving at least 50% reduction in seizure frequency (80% in control group versus 90% in intervention group, RR 1.13, 95% CI 0.97 to 1.31, 2 trials; assumed risk 500 per 1000, corresponding risk 485 to 655 per 1000). Compared with valproate, needle acupuncture plus valproate was not effective in achieving freedom from seizures (44% in control group versus 42.7% in intervention group, RR 0.97, 95% CI 0.72 to 1.30, 2 trials; assumed risk 136 per 1000, corresponding risk 97 to 177 per 1000) or at least 50% reduction in seizure frequency (69.3% in control group versus 81.3% in intervention group, RR 1.34, 95% CI 0.52 to 3.48, 2 trials; assumed risk 556 per 1000, corresponding risk 289 to 1000 per 1000) but may have achieved better quality of life (QOL) after treatment (QOLIE-31 score (higher score indicated better QOL) mean 170.22 points in the control group versus 180.32 points in the intervention group, MD 10.10 points, 95% CI 2.51 to 17.69 points, 1 trial). Compared with phenytoin, needle acupuncture was not effective in achieving at least 50% reduction in seizure frequency (70% in control group versus 94.4% in intervention group, RR 1.43, 95% CI 0.46 to 4.44, 2 trials; assumed risk 700 per 1000, corresponding risk 322 to 1000 per 1000). Compared with valproate, needle acupuncture was not effective in achieving seizure freedom (14.1% in control group versus 25.2% in intervention group, RR 1.75, 95% CI 0.93 to 3.27, 2 trials; assumed risk 136 per 1000, corresponding risk 126 to 445 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (55.3% in control group versus 73.7% in intervention group, RR 1.32, 95% CI 1.05 to 1.66, 2 trials; assumed risk 556 per 1000, corresponding risk 583 to 923 per 1000) and better QOL after treatment (QOLIE-31 score mean 172.6 points in the control group versus 184.64 points in the intervention group, MD 12.04 points, 95% CI 4.05 to 20.03 points, 1 trial). Compared with antiepileptic drugs, catgut implantation at acupoints plus antiepileptic drugs was not effective in achieving seizure freedom (13% in control group versus 19.6% in intervention group, RR 1.51, 95% CI 0.93 to 2.43, 4 trials; assumed risk 127 per 1000, corresponding risk 118 to 309 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (63.1% in control group versus 82% in intervention group, RR 1.42, 95% CI 1.07 to 1.89, 5 trials; assumed risk 444 per 1000, corresponding risk 475 to 840 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated worse quality of life) mean 53.21 points in the control group versus 45.67 points in the intervention group, MD -7.54 points, 95% CI -14.47 to -0.61 points, 1 trial). Compared with valproate, catgut implantation may be effective in achieving seizure freedom (8% in control group versus 19.7% in intervention group, RR 2.82, 95% CI 1.61 to 4.94, 4 trials; assumed risk 82 per 1000, corresponding risk 132 to 406 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated better quality of life) mean 172.6 points in the control group versus 191.33 points in the intervention group, MD 18.73 points, 95% CI 11.10 to 26.36 points, 1 trial) but not at least 50% reduction in seizure frequency (65.6% in control group versus 91.7% in intervention group, RR 1.31, 95% CI 0.94 to 1.84, 4 trials; assumed risk 721 per 1000, corresponding risk 677 to 1000 per 1000). Acupuncture did not have excess adverse events compared to control treatment in the included trials. AUTHORS' CONCLUSIONS: Available RCTs are small, heterogeneous and have high risk of bias. The current evidence does not support acupuncture for treating epilepsy. PMID- 24801226 TI - A preliminary engineering design of intravascular dual-frequency transducers for contrast-enhanced acoustic angiography and molecular imaging. AB - Current intravascular ultrasound (IVUS) probes are not optimized for contrast detection because of their design for high-frequency fundamental-mode imaging. However, data from transcutaneous contrast imaging suggests the possibility of utilizing contrast ultrasound for molecular imaging or vasa vasorum assessment to further elucidate atherosclerotic plaque deposition. This paper presents the design, fabrication, and characterization of a small-aperture (0.6 * 3 mm) IVUS probe optimized for high-frequency contrast imaging. The design utilizes a dual frequency (6.5 MHz/30 MHz) transducer arrangement for exciting microbubbles at low frequencies (near their resonance) and detecting their broadband harmonics at high frequencies, minimizing detected tissue backscatter. The prototype probe is able to generate nonlinear microbubble response with more than 1.2 MPa of rarefractional pressure (mechanical index: 0.48) at 6.5 MHz, and is also able to detect microbubble response with a broadband receiving element (center frequency: 30 MHz, -6-dB fractional bandwidth: 58.6%). Nonlinear super-harmonics from microbubbles flowing through a 200-MUm-diameter micro-tube were clearly detected with a signal-to-noise ratio higher than 12 dB. Preliminary phantom imaging at the fundamental frequency (30 MHz) and dual-frequency super-harmonic imaging results suggest the promise of small aperture, dual-frequency IVUS transducers for contrast-enhanced IVUS imaging. PMID- 24801227 TI - (99m)Tc-labeled-rhTSH analogue (TR1401) for imaging poorly differentiated metastatic thyroid cancer. AB - BACKGROUND: Differentiated thyroid carcinomas originating from thyroid follicular cells are frequent tumors of the thyroid with relatively good prognosis due to improved surgical techniques and follow-up procedures. Poorly differentiated thyroid cancers, which lose iodine uptake ability, in most cases still express thyrotropin (TSH) receptors (TSHR). Therefore, the aim of this study was to radiolabel a superagonist recombinant human TSH (rhTSH) analogue for imaging poorly differentiated thyroid cancer. METHODS: The TSHR superagonist, TR1401, was labeled with (99m)Tc using an indirect method via succinimidyl-6 hydrazinonicotinate hydrochloride conjugation. In vitro quality controls included SDS-PAGE, cysteine challenge, and cell-binding assay on TSHR positive cell lines (JP09 and ML-1). In vivo studies included tumor targeting experiments in athymic nude CD-1 mice xenografted with several different TSHR positive cells (JP09, K1, and ML-1) and TSHR negative cells (JP02) as control. RESULTS: The superagonist rhTSH analogue TR1401 was labeled with high labeling efficiency (>95%) and high specific activity (9250 MBq/mg). The labeled molecule retained its biologic activity and structural integrity. In tumor targeting experiments, a focal uptake of radiolabeled TR1401 was observed in TSHR positive cells but not in TSHR negative cells. The same observation was made in a dog with spontaneous intraglandular thyroid cancer. CONCLUSIONS: We were able to radiolabel the rhTSH superagonist analogue TR1401 with (99m)Tc efficiently with retention of in vitro and in vivo binding capacity to TSHR. The relative role of such novel radiopharmaceutical versus (131)I scanning of thyroid cancer will require future histopathologic and clinical studies, but it may open new perspectives for presurgical staging of thyroid cancer, and diagnosis of radioiodine negative local relapses and/or distant metastases. PMID- 24801228 TI - Aluminum exposure and toxicity in neonates: a practical guide to halt aluminum overload in the prenatal and perinatal periods. AB - BACKGROUND: During the last years, human newborns have been overexposed to biologically reactive aluminum, with possible relevant consequences on their future health and on their susceptibility to a variety of diseases. Children, newborns and particularly preterm neonates are at an increased risk of aluminum toxicity because of their relative immaturity. DATA SOURCES: Based on recent original publications and classical data of the literatures, we reviewed the aluminum content in mother's food during the intrauterine life as well as in breast milk and infant formula during lactation. We also determined the possible role of aluminum in parenteral nutrition solutions, in adjuvants of vaccines and in pharmaceutical products. A special focus is placed on the relationship between aluminum overexposure and the insurgence of bone diseases. RESULTS: Practical points of management and prevention are suggested. Aluminum sources that infants may receive during the first 6 months of life are presented. In the context of prevention of possible adverse effects of aluminum overload in fetal tissues during development, simple suggestions to pregnant women are described. Finally, practical points of management and prevention are suggested. CONCLUSIONS: Pediatricians and neonatologists must be more concerned about aluminum content in all products our newborns are exposed to, starting from monitoring aluminum concentrations in milk- and soy-based formulas in which, on the basis of recent studies, there is still too much aluminum. PMID- 24801229 TI - Epilepsy in Prader-Willi syndrome: clinical, diagnostic and treatment aspects. AB - BACKGROUND: Epilepsy associated with Prader-Willi syndrome (PWS) represents an early and important complication, often not clearly reported and described in the literature. Consequently, there are controversial data about the clinical characteristics of epilepsy and electroencephalographic (EEG) abnormalities found in these patients. DATA SOURCES: Based on recent original publications, we have reviewed the different types of seizures and EEG findings in PWS patients, the response to antiepileptic treatment, and the prognosis of epilepsy. RESULTS: The frequency of epilepsy in PWS patients ranges from 4% to 26%. The types of seizure include generalized tonic-clonic seizures, complex partial seizures, atypical absence, staring spells, and myoclonic, tonic and hemiclonic seizures, but the most frequent type is focal epilepsy. Status epilepticus has never been reported. EEG abnormalities are not typical but variable in different patients. However, generalized and focal discharges are the most frequently reported findings. There is no evidence of relationship between the course of epilepsy and frequency, morphology and spread of EEG discharges. However, epilepsy in PWS patients is usually responsive to antiepileptic monotherapy with rapid seizure control and a good outcome. CONCLUSIONS: The frequency of epilepsy is higher in PWS patients than in general populations and this complication can be a challenge for the clinicians of these patients. Prospective studies are needed to confirm the good long-term prognosis. PMID- 24801230 TI - Comparative effectiveness of intravenous immunoglobulin from different manufacturing processes on Kawasaki disease. AB - BACKGROUND: The comparative effectiveness of intravenous immunoglobulin (IVIG) for Kawasaki disease was regarded as inconclusive in the international guidelines. However, several new evidences have been published in recent years. DATA SOURCES: A literature search of PubMed was conducted using key words of "Kawasaki disease or mucocutaneous lymph node syndrome" and "immunoglobulin" in combination. Only original articles published after 2004 were selected. A total of 813 papers were found in PubMed. These papers were screened manually by their titles and abstracts. RESULTS: Patients treated with IVIG prepared by betapropiolactonation might have worse outcome (a higher non-responsive rate in one report and a higher rate of coronary aneurysm in two reports). Storage of IVIG in acidic solution might be correlated with a higher rate of coronary aneurysm (two reports). CONCLUSIONS: Different processes of preparation and conditions of preservation of IVIG may have profound effects on its clinical effectiveness. Randomized controlled studies are needed to further elucidate this issue. PMID- 24801231 TI - Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. AB - BACKGROUND: Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase (VLCAD), and which can present as cardiomyopathy in neonates, as hypoketotic hypoglycemia in infancy, and as myopathy in late-onset patients. Although many ACADVL mutations have been described, no prevalent mutations in the ACADVL gene have been associated with VLCADD. Herein, we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD. METHODS: Seven Chinese patients, from newborn to 17 years old, were included in this study. Tandem mass spectrometry was performed to screen for VLCAD deficiency. All exons and flanking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing. Online analysis tools were used to predict the impact of novel mutations. RESULTS: All cases had elevated serum levels of tetradecanoylcarnitine (C14:1) which is the characteristic biomarker for VLCADD. The phenotype of VLCADD is heterogeneous. Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth. Three patients showed hepatomegaly and hypoglycemia in infancy. The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis. Three of the patients died at the age of 6-8 months. Eleven different mutations in the ACADVL gene in the 7 patients were identified, including seven reported mutations (p.S22X, p.W427X, p.A213T, p.G222R, p.R450H, c.296-297delCA, c.1605+1G>T) and four novel mutations (p.S72F, p.Q100X, p.M437T, p.D466Y). The p.R450H and p.D466Y (14.28%, 2/14 alleles) mutations were identified in two alleles respectively. CONCLUSIONS: The clinical manifestations were heterog-eneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients. R450H may be a relatively common mutation in Asian populations. The genotype and phenotype had a certain correlation in our patients. PMID- 24801232 TI - Novel collagen VI mutations identified in Chinese patients with Ullrich congenital muscular dystrophy. AB - BACKGROUND: We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy (UCMD). METHODS: Clinical data of probands were collected and muscle biopsies of patients were analyzed. Exons of COL6A1, COL6A2 and COL6A3 were analyzed by direct sequencing. Mutations in COL6A1, COL6A2 and COL6A3 were identified in 8 patients. RESULTS: Among these mutations, 5 were novel [three in the triple helical domain (THD) and 2 in the second C-terminal (C2) domain]. We also identified five known missense or in-frame deletion mutations in THD and C domains. Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions. CONCLUSIONS: The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI, thereby providing useful information for the genetic counseling of UCMD patients. PMID- 24801234 TI - Sibling composition and child immunization in India and Pakistan, 1990-2007. AB - BACKGROUND: This study aimed to assess trends in gender differentials in child immunization beyond the conventional male-female dichotomy, by considering gender, surviving siblings, birth order and different compositions of older siblings in tandem, during 1990-2007 in India and Pakistan. METHODS: Using different rounds of Demographic and Health Survey datasets, we adopted the World Health Organization guidelines for appraising full immunization among children. Sex composition of surviving older siblings was combined. Cochrane-Armitage and the Chi-square tests were used to test linear and nonlinear trends, respectively. RESULTS: Although child immunization has increased during the period of 1990-2007 in both India and Pakistan, results showed that more than 50% of the eligible children did not receive the recommended immunization. The results also showed that boys and girls with no older surviving siblings and those with only surviving siblings of the opposite sex appeared to have fully immunized proportionally compared with the children with other sibling compositions. CONCLUSION: The findings confirmed that girls and boys were not always treated equally, and that there was a clear pattern of selective neglect in child immunization in both countries during the period of 1990-2007. PMID- 24801233 TI - Decreased concentrating capacity in children with febrile urinary tract infection and normal 99mTc-dimercaptosuccinic acid scan: does medullonephritis exist? AB - BACKGROUND: Although 99mTc-dimercaptosuccinic acid (DMSA) scan is considered the gold standard for the diagnosis of acute pyelonephritis (AP), sometimes it produces false results in children with clinical features of AP. There are no studies on the comparison of the sensitivity of DMSA and concentrating capacity test. METHODS: Eighty-five infants with AP of less than one year old were studied to evaluate whether they had real AP or not. Data were compared between infants with an abnormal (group A, n=64) and those with a normal DMSA scan (group B, n=21) respectively. A DDAVP test was performed for each infant. RESULTS: All the infants in both groups presented a high level of C-reactive protein and fever (>=38 degrees C). There were no differences in clinical and analytical variables except C-reactive protein level in the two groups. Both groups exhibited a low urinary osmolality (87.5% in the group A vs. 85.7% in the group B). The patients with normal DMSA and decreased concentrating capacity have some renal parenchymal damage and not only a lower urinary infection. Of the infants with an abnormal DMSA scan, 33.9% showed renal scars after 6-12 months. No infant with a normal DMSA scan showed scars. The biochemical variables in both groups of infants were not related to vesicoureteral refl ux. CONCLUSION: Infants with AP, normal DMSA scan and low concentrating capacity may be characterized by a localized infection in the medulla (medullonephritis) or by a false negative DMSA scan. PMID- 24801235 TI - Efficacy of tacrolimus in the treatment of children with focal segmental glomerulosclerosis. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the most common glomerular condition leading to end-stage renal disease (ESRD) and the third most common cause of ESRD in pediatric patients. METHODS: This is a retrospective study consisting of 22 pediatric patients with FSGS and heavy proteinuria. After demonstrating steroids resistance, the patients were treated with tacrolimus, targeting a trough level 5-8 ng/mL. The primary outcome is the induction of remission with tacrolimus. RESULTS: Thirteen patients (59%) achieved remission (complete in 31.8% and partial in 27.2%) and 12 patients showed stable or improved renal function over an average follow-up of 2.9 years (range: 0.5-7 years). There was no significant difference in response rate between African American and Caucasian patients. None of the patients had significant side-effect to tacrolimus and none of the repeat biopsies showed an increase in interstitial fibrosis compared to baseline. The best renal outcome was for patients who achieved complete remission. Partially responsive patients had improved renal function compared with resistant patients. CONCLUSION: Tacrolimus is a viable option in the treatment of children with idiopathic steroid resistant FSGS. PMID- 24801236 TI - Effect of maternal lipid profile, C-peptide, insulin, and HBA1c levels during late pregnancy on large-for-gestational age newborns. AB - BACKGROUND: Large-for-gestational age (LGA) newborns can increase the risk of metabolic syndrome. Previous studies have shown that the levels of maternal blood lipids, connecting peptide (C-peptide), insulin and glycosylated hemoglobin (HbA1c) were significantly different between LGA and appropriate-for-gestational age (AGA) newborns. This study aimed to determine the effect of the levels of maternal lipids, C-peptide, insulin, and HbA1c during late pregnancy on LGA newborns. METHODS: This study comprised 2790 non-diabetic women in late pregnancy. Among their newborns, 2236 (80.1%) newborns were AGA, and 554 (19.9%) newborns were LGA. Maternal and neonatal characteristics were obtained from questionnaires and their case records. The levels of maternal fasting serum apolipoprotein A1 (ApoA1), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), C-peptide, insulin and blood HbA1c were measured. The chi-square and Mann Whitney U test were used to analyze categorical variables and continuous variables between the AGA and LGA groups, respectively. Binary logistic regression analysis was made to determine the independent risk factors for LGA newborns. RESULTS: Maternal TG, C-peptide, insulin and HbA1c levels were significantly higher in the LGA group than in the AGA group (P<0.05). The LGA group had significantly lower levels of maternal TC, HDL-C and LDL-C than the AGA group (P<0.05). After adjustment for confounding variables, including maternal age, pre-pregnancy body mass index, education, smoking, annual household income, amniotic fluid volume, gestational hypertension, newborn gender and gestational age at blood collection, high maternal TG levels remained significantly associated with LGA newborns (P<0.05). CONCLUSION: High maternal TG level during late pregnancy is significantly associated with LGA newborns. PMID- 24801237 TI - Premature and neonate modeling of thimerosal exposure and neurodevelopment: additional comments. PMID- 24801238 TI - Author reply: To PMID 24235069. PMID- 24801239 TI - Acid-base chemistry in the formation of Mackay-type icosahedral clusters: MU3 acidity analysis of Sc-rich phases of the Sc-Ir system. AB - The crystal structures of intermetallic phases offer a wealth of geometrical features (helices, multishelled clusters, and host-guest motifs) whose formation has yet to be explained or predicted by chemical theory. A recently developed extension of the acid-base concept to metallic systems, the MU3-acidity model, provides an avenue for developing this understanding for intermetallics formed from transition metals. In this Article, we illustrate how this approach can be used to understand one of the most striking geometrical entities to emerge in intermetallic chemistry, the Mackay cluster of icosahedral quasicrystals. We present MU3-acidity analyses, based on DFT-calibrated Huckel calculations, for a series of Sc-Ir intermetallics: ScIr (CsCl-type), Sc2Ir (Ti2Ni-type), Sc11Ir4, and the Mackay cluster containing phases Sc57Ir13 and Sc44Ir7. We begin by illustrating that a MU3-acidity model correctly predicts that each of these phases is stable relative to disproportionation into their neighboring compounds when a common set of Huckel parameters and d-orbital occupancies is used. Next, we explain these results by developing a relationship between the distance distribution of homoatomic contacts within an atom's coordination sphere and the MU3-neutralization it experiences. For a given average homoatomic distance, the role of heteroatomic contacts is higher when the distribution of homoatomic contacts is narrower. This effect is key to the strength of the acid-base neutralization of the Sc-rich phases, where the Sc atoms find a scarcity of Ir atoms from which to obtain neutralization. Under these circumstances, Sc-Ir contacts should be maximized, whereas the number and distance variations of the Sc-Sc contacts should be minimized. These expectations are borne out by the observed crystal structures. In particular, the Mackay clusters of Sc57Ir13 and Sc44Ir7, in which a central Ir atom is icosahedrally coordinated by a pentagonal dodecahedral array of face-sharing Sc octahedra, represent a natural way of merging the competing needs for enhancing Sc-Ir interactions while diminishing those between the Sc atoms. PMID- 24801241 TI - A distinct reversible colorimetric and fluorescent low pH response on a water stable zirconium-porphyrin metal-organic framework. AB - A water stable zirconium-porphyrin MOF (PCN-222) was synthesized according to the reported method and found to produce a distinct reversible colorimetric and fluorescent "turn-off-turn-on" pH response. The colorimetric response is achieved under acidic conditions starting at pH ~3 and persists under concentrated acidic conditions. To the best of our knowledge, this is the first report of a colorimetric MOF pH sensor. PMID- 24801240 TI - Congenital dyserythropoietic anemia, type II with SEC23B exon 12 c.1385 A -> G mutation, and pseudo-Gaucher cells in two siblings. AB - OBJECTIVE AND IMPORTANCE: Congenital dyserythropoietic anemia (CDA) represents a genotypically and phenotypically heterogeneous group of disorders. CDA type II, the most frequent variant, was recently shown to be caused by mutations in the gene encoding the secretory COPII component SEC23B. We report two siblings hailing from Punjab in northern India with classical CDA type II where this mutation was demonstrated. CLINICAL PRESENTATION: A 7-year-old girl presented with transfusion-dependent anemia, splenomegaly, and progressive growth failure since 1 year of age. Her 5-year-old brother was similarly afflicted, but there was no other family history. Extensive prior work-up for hemolytic anemia, storage and metabolic disorders, and infectious diseases was negative. Hemoglobin was 71 g/l with normal leukocyte, platelet, and corrected reticulocyte counts. Bone marrow examination revealed marked normoblastic erythroid hyperplasia with dyserythropoiesis (36%) and the presence of bi- and multinucleated erythroblasts with equal-sized nuclei. Many pseudo-Gaucher cells were also seen. Iron stores were increased although ring sideroblasts were absent. Hereditary erythrocyte multinuclearity with positive acidified serum (HEMPAS) test revealed lysis of the red cells in four out of five control sera. TECHNIQUE: Genomic DNA sequencing of the SEC23B exon 12 revealed homozygosity for c.1385 A -> G; Y462C mutations in both siblings. CONCLUSION: CDA has traditionally been a difficult diagnosis to establish, since it requires exclusion of other causes of dyserythropoiesis and the performance of complex tests including HEMPAS and electron microscopy for confirmation. The availability of molecular genetic testing for SEC23B promises to streamline and hasten the diagnostic process for this rare and intriguing disease. PMID- 24801242 TI - Graft-appendiceal fistula treated with a rifampicin-silver in-situ graft. AB - BACKGROUND: We report a 52-year-old male presenting with a graft-appendiceal fistula four years after placement of an aorto-bifemoral Dacron prosthesis. CASE REPORT: After appendectomy and total graft removal, the patient was treated with an in-situ repair using a rifampicin-silver graft. This kind of repair has only been reported in an animal study. RESULTS: This infected aortic graft was treated successfully with a rifampicin-silver graft with a follow-up of 15 months without complications. CONCLUSION: In-situ repair of a graft-appendiceal fistula with a rifampicin-silver graft seems a promising strategy. The long-term outcome needs to be studied. PMID- 24801244 TI - Lithium recovery from salt lake brine by H2TiO3. AB - The details of the ion exchange properties of layered H2TiO3, derived from the layered Li2TiO3 precursor upon treatment with HCl solution, with lithium ions in the salt lake brine (collected from Salar de Uyuni, Bolivia) are reported. The lithium adsorption rate is slow, requiring 1 d to attain equilibrium at room temperature. The adsorption of lithium ions by H2TiO3 follows the Langmuir model with an adsorptive capacity of 32.6 mg g(-1) (4.7 mmol g(-1)) at pH 6.5 from the brine containing NaHCO3 (NaHCO3 added to control the pH). The total amount of sodium, potassium, magnesium and calcium adsorbed from the brine was <0.30 mmol g(-1). The H2TiO3 was found capable of efficiently adsorbing lithium ions from the brine containing competitive cations such as sodium, potassium, magnesium and calcium in extremely large excess. The results indicate that the selectivity order Li(+) ? Na(+), K(+), Mg(2+), Ca(2+) originates from a size effect. The H2TiO3 can be regenerated and reused for lithium exchange in the brine with an exchange capacity very similar to the original H2TiO3. PMID- 24801243 TI - Longitudinal study of cognitive and academic outcomes after pediatric liver transplantation. AB - OBJECTIVE: To determine the evolution of cognitive and academic deficits and risk factors in children after liver transplantation. STUDY DESIGN: Patients >=2 years after liver transplantation were recruited through Studies of Pediatric Liver Transplantation. Participants age 5-6 years at Time 1 completed the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wide Range Achievement Test, 4th edition, and Behavior Rating Inventory of Executive Function (BRIEF). Participants were retested at age 7-9 years, Time 2 (T2), by use of the Wechsler Intelligence Scales for Children, 4th edition, Wide Range Achievement Test, 4th edition, and BRIEF. Medical and demographic variables significant at P <= .10 in univariate analysis were fitted to repeated measures modeling predicting Full Scale IQ (FSIQ). RESULTS: Of 144 patients tested at time 1, 93 (65%) completed T2; returning patients did not differ on medical or demographic variables. At T2, more participants than expected had below-average FSIQ, Verbal Comprehension, Working Memory, and Math Computation, as well as increased executive deficits on teacher BRIEF. Processing Speed approached significance. At T2, 29% (14% expected) had FSIQ = 71-85, and 7% (2% expected) had FSIQ <=70 (P = .0001). A total of 42% received special education. Paired comparisons revealed that, over time, cognitive and math deficits persisted; only reading improved. Modeling identified household status (P < .002), parent education (P < .01), weight z score at liver transplantation (P < .03), and transfusion volume during liver transplantation (P < .0001) as predictors of FSIQ. CONCLUSIONS: More young liver transplantation recipients than expected are at increased risk for lasting cognitive and academic deficits. Pretransplant markers of nutritional status and operative complications predicted intellectual outcome. PMID- 24801245 TI - Toxicological effects of nickel chloride on the cytokine mRNA expression and protein levels in intestinal mucosal immunity of broilers. AB - The purpose of this study was to examine the toxicological effects of nickel chloride (NiCl2 ; 300, 600, and 900 mg kg(-1) diet) on the cytokine mRNA expression and protein levels in the intestinal mucosa and cecal tonsil, and on the ileac and cecal tonsil T cells in broilers by the methods of qRT-PCR, flow cytometry and ELISA for 42 days. Results showed that the IL-2, IL-6, IL-10, IL 17, IFN-gamma, and TNF-alpha (LITAF) cytokine mRNA expression and protein levels were lower (P < 0.05 or P < 0.01) and the percentages of T-cell subsets were also lower in the 300, 600, and 900 mg kg(-1) groups than in the control group. It was concluded that dietary NiCl2 in excess of 300 mg kg(-1) could reduce cytokine mRNA expression and protein levels in the intestinal mucosa and cecal tonsil, and the percentages of ileac and cecal tonsil T-cell subsets. Decreasing in cytokine mRNA expression and protein levels of intestinal mucosa and cecal tonsil induced by NiCl2 was closely related to the reduction of T-cell population. Thus, the abnormal expression of these cytokines impacts the intestinal mucosal immune function by the pathways of reducing of lymphocyte population and activation. Also, this study first proved that NiCl2 at higher levels has the toxicological effects on intestinal mucosal immunity. PMID- 24801246 TI - ICH E14-compatible holter bin method and its equivalence to individual heart rate correction in the assessment of drug-induced QT changes. AB - INTRODUCTION: The Holter bin method evaluates QT interval changes in the presence of heart rate changes without correcting the QT interval. However, the method does not allow time-matched comparisons, thus contradicting available guidance and good practice. We report a modification of the methods that allows time matched comparisons without any heart rate correction. METHODS AND RESULTS: The modified Holter bin method (a) finds matching baseline heart rates for each QT reading on treatment and (b) calculates DeltaQT values from the QT intervals on baseline and on treatment that match in heart rates. The difference between DeltaQT values on active treatment and placebo provides the DeltaDeltaQT value. The method was compared with the individual correction method in the data of the mirabegron thorough QT study in which supratherapeutic doses of this beta3 adrenoceptor agonist led to substantial heart rate changes. The modified Holter bin method reproduced closely the results obtained with the individual heart rate correction. At all time points of the mirabegron study, the differences between the mean DeltaDeltaQT values by the Holter bin method and the individual correction method were below 1 millisecond. Compared to the individual correction, the Holter bin method led to slight increases in the standard deviations of DeltaDeltaQT values, but these were on average below 0.25 millisecond. CONCLUSIONS: The Holter bin methodology can be modified to make it compatible with the available guidance and with good practice of clinical investigations. The results obtained with the modified Holter bin method are practically the same as with individualized heart rate corrected QT intervals. The close correspondence between the 2 methods demonstrates that the present possibilities of comparing QT interval duration in the presence of experiment induced heart rate differences are not influenced by methodological artifacts. PMID- 24801247 TI - Robust online multiobject tracking with data association and track management. AB - In this paper, we consider a multiobject tracking problem in complex scenes. Unlike batch tracking systems using detections of the entire sequence, we propose a novel online multiobject tracking system in order to build tracks sequentially using online provided detections. To track objects robustly even under frequent occlusions, the proposed system consists of three main parts: 1) visual tracking with a novel data association with a track existence probability by associating online detections with the corresponding tracks under partial occlusions; 2) track management to associate terminated tracks for linking tracks fragmented by long-term occlusions; and 3) online model learning to generate discriminative appearance models for successful associations in other two parts. Experimental results using challenging public data sets show the obvious performance improvement of the proposed system, compared with other state-of-the-art tracking systems. Furthermore, extensive performance analysis of the three main parts demonstrates effects and usefulness of the each component for multiobject tracking. PMID- 24801249 TI - Nano-chemotherapeutics: maximising lymphatic drug exposure to improve the treatment of lymph-metastatic cancers. AB - Nano-sized drug delivery systems incorporating chemotherapeutic drugs ("nano chemotherapeutics") have been widely employed for the treatment of solid tumours. The dimensions of nanoparticulate drug delivery systems also make them ideal vectors for improving drug exposure to the lymphatic system, potentially enhancing the treatment of lymph-resident metastases. This review examines the physical properties of nanoparticulate drug delivery systems that promote lymphatic exposure and lymph node retention, and discusses methods for improving lymphatic access. Drug delivery systems that have been investigated for the treatment of lymph node metastasis are also reviewed, and recent advances towards active targeting approaches for lymphatic metastases highlighted. PMID- 24801248 TI - Hydrogen sulfide as an oxygen sensor. AB - SIGNIFICANCE: Although oxygen (O2)-sensing cells and tissues have been known for decades, the identity of the O2-sensing mechanism has remained elusive. Evidence is accumulating that O2-dependent metabolism of hydrogen sulfide (H2S) is this enigmatic O2 sensor. RECENT ADVANCES: The elucidation of biochemical pathways involved in H2S synthesis and metabolism have shown that reciprocal H2S/O2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O2 controls H2S inactivation, and the effects of H2S on downstream signaling events are consistent with those activated by hypoxia. H2S-mediated O2 sensing has been demonstrated in a variety of O2-sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. CRITICAL ISSUES: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H2S and its metabolites. FUTURE DIRECTIONS: Development of specific inhibitors of H2S metabolism and effector activation as well as cellular organelle-targeted compounds that release H2S in a time- or environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. PMID- 24801250 TI - Electrical, magnetic, photomechanical and cavitational waves to overcome skin barrier for transdermal drug delivery. AB - Transdermal drug delivery is hindered by the barrier property of the stratum corneum. It limits the route to transport of drugs with a log octanol-water partition coefficient of 1 to 3, molecular weight of less than 500Da and melting point of less than 200 degrees C. Active methods such as iontophoresis, electroporation, sonophoresis, magnetophoresis and laser techniques have been investigated for the past decades on their ability, mechanisms and limitations in modifying the skin microenvironment to promote drug diffusion and partition. Microwave, an electromagnetic wave characterized by frequencies range between 300MHz and 300GHz, has recently been reported as the potential skin permeation enhancer. Microwave has received a widespread application in food, engineering and medical sectors. Its potential use to facilitate transdermal drug transport is still in its infancy stage of evaluation. This review provides an overview and update on active methods utilizing electrical, magnetic, photomechanical and cavitational waves to overcome the skin barrier for transdermal drug administration with insights into mechanisms and future perspectives of the latest microwave technique described. PMID- 24801252 TI - Response by Neil J. Stone, Sunny Intwala, and Dan Katz. PMID- 24801251 TI - Controlled release for local delivery of drugs: barriers and models. AB - Controlled release systems are an effective means for local drug delivery. In local drug delivery, the major goal is to supply therapeutic levels of a drug agent at a physical site in the body for a prolonged period. A second goal is to reduce systemic toxicities, by avoiding the delivery of agents to non-target tissues remote from the site. Understanding the dynamics of drug transport in the vicinity of a local drug delivery device is helpful in achieving both of these goals. Here, we provide an overview of controlled release systems for local delivery and we review mathematical models of drug transport in tissue, which describe the local penetration of drugs into tissue and illustrate the factors - such as diffusion, convection, and elimination - that control drug dispersion and its ultimate fate. This review highlights the important role of controlled release science in development of reliable methods for local delivery, as well as the barriers to accomplishing effective delivery in the brain, blood vessels, mucosal epithelia, and the skin. PMID- 24801253 TI - Altered DNA methylation status of human brain derived neurotrophis factor gene could be useful as biomarker of depression. AB - Brain-derived neurotrophic factor (BDNF) is involved in the survival, development, and synaptic plasticity of neurons. BDNF is believed to be associated with the pathophysiology of psychiatric disorders. Several studies have suggested the relevance of DNA methylation in its promoter region with depression. Here, we report different methylation statuses in groups with different depressive scores or undergoing different levels of job-stress. DNA samples were extracted from the saliva of 774 Japanese workers, and the methylation status was determined using the Illumina HumanMethylation 450 K Microarray. Depressive symptoms were measured using the Kessler's K6 questionnaire. Job-stress scales were assessed via a self-administered questionnaire. Independent DNA pools were formed based on K6 and job-strain scores, and the methylation levels were compared among these pools. The average DNA methylation rate was significantly decreased in the highest K6 score group compared to the lowest group (methylated signals, 14.2% vs. 16.5%, P = 2 . 16 * 10(-198)). This difference remained for the CpG island in the promoter region (10.4% vs. 5.8%, P = 3 . 67 * 10(-133)). Regarding the job-strain score, there was a slight increase in the methylation level of the whole gene in the group with the highest score compared to that with the lowest score; however, these groups showed no difference in the promoter region. Our results revealed significant changes in the DNA methylation status of the complete human BDNF gene in persons with depression compared to normal individuals, especially in the promoter region of exon 1. This indicates that DNA methylation in this gene is a promising biomarker for diagnosing depression. PMID- 24801254 TI - Madden-Julian Oscillation prediction skill of a new-generation global model demonstrated using a supercomputer. AB - Global cloud/cloud system-resolving models are perceived to perform well in the prediction of the Madden-Julian Oscillation (MJO), a huge eastward -propagating atmospheric pulse that dominates intraseasonal variation of the tropics and affects the entire globe. However, owing to model complexity, detailed analysis is limited by computational power. Here we carry out a simulation series using a recently developed supercomputer, which enables the statistical evaluation of the MJO prediction skill of a costly new-generation model in a manner similar to operational forecast models. We estimate the current MJO predictability of the model as 27 days by conducting simulations including all winter MJO cases identified during 2003-2012. The simulated precipitation patterns associated with different MJO phases compare well with observations. An MJO case captured in a recent intensive observation is also well reproduced. Our results reveal that the global cloud-resolving approach is effective in understanding the MJO and in providing month-long tropical forecasts. PMID- 24801255 TI - Unusual presentation of xanthogranuloma on the eyelid of an adult. AB - A 46-year-old man presented with an unusual papillary eyelid lesion in which histopathological study revealed a cutaneous xanthogranuloma. The clinical appearance was distinctively different from juvenile xanthogranuloma. There was no evidence of an infiltrative and orbital process consistent with adult orbital xanthogranulomatous disease. The histopathologic examination of the lesion revealed well-differentiated histiocytes with foamy cytoplasm. Immunohistochemistry stains were positive for CD163 and Factor XIIIa and negative for CD34, CD1A, CD117, and S100. The final histopathologic diagnosis was cutaneous xanthogranuloma. PMID- 24801256 TI - Orbital necrotizing fasciitis and osteomyelitis caused by arcanobacterium haemolyticum: a case report. AB - The facial region is infrequently affected by necrotizing infections. Orbital necrotizing infections are even rarer, seen following trauma, local skin infection, and sinusitis. The authors report a unique case of orbital necrotizing fasciitis and osteomyelitis resulting from Arcanobacterium Haemolyticum ethmoid sinusitis. No prior occurrences of Arcanobacterial species orbital necrotizing fasciitis/osteomyelitis have been reported.A 16-year-old boy presented to the ER with a 3-day history of fever, chills, headache, and sinus pressure. CT scan revealed soft tissue swelling of the right orbit, forehead, and ethmoid sinusitis. Within 24 hours of admission, he suffered rapidly progressive swelling and erythema of the right orbit and forehead with diminished visual acuity, despite broad-spectrum antibiotics. Orbital exploration revealed frankly necrotic fascia and periosteum along the superior aspect. Lateral canthotomy, cantholysis, decompression of the optic nerve, and soft tissue debridement with bone biopsy was performed. Operative specimens isolated Arcanobacterium Haemolyticum. Pathologic examination revealed right orbital osteomyelitis. PMID- 24801257 TI - Unifocal Langerhans cell histiocytosis of the superior oblique muscle. AB - Orbital Langerhans cell histiocytosis (LCH) without bone involvement is rare. Isolated involvement of an extraocular muscle without bone change, to the best of the authors' knowledge, has not been previously reported. They describe a unique case of unifocal LCH of the superior oblique muscle with no bone involvement. A 16-year-old girl presented with a 2-week history of diplopia and headache. CT and MRI showed an enlarged right superior oblique muscle with no associated bone involvement. Biopsy with partial debulking revealed LCH and staging confirmed unifocal disease. The lesion underwent complete radiologic resolution following surgery. There was no recurrence after 16 months follow up. PMID- 24801258 TI - Ectrodactyly ectodermal dysplasia clefting (EEC) syndrome: a rare cause of congenital lacrimal anomalies. AB - A 9-year-old girl with a medical history significant for ectrodactyly ectodermal dysplasia clefting (EEC) syndrome was referred for evaluation of congenital left sided epiphora. The patient had undergone successful right external dacryocystorhinostomy at age 5 to treat congenital right-sided epiphora. On examination, several ocular anomalies were noted, including absence of the upper eyelid puncta, absence of the left inferior punctum, a left lacrimal fistula opening at the left caruncle, increased left tear lake, bilateral hypoplastic meibomian glands, mild conjunctival injection, and thin eyelid cilia and brow hair. Systemic findings included cleft lip and palate status-post repair, ectrodactyly of the hands and feet, adontia and microdontia, a pointed nose, and lightly pigmented, dry hair and skin. The patient underwent examination under anesthesia and left conjunctivodacryocystorhinostomy with insertion of a Jones tube with resolution of lacrimation postoperatively. To the authors' knowledge, this is the second report detailing management of congenital lacrimal anomalies in EEC syndrome, and the first describing management of punctal atresia with conjunctivodacryocystorhinostomy and Jones tube placement. PMID- 24801259 TI - Punctal keratinizing cyst: a clinicopathological correlation of an exceptionally rare lacrimal disorder. AB - Punctal keratinizing cyst is an extremely rare ectasia arising from the most proximal part of the vertical canaliculus just beneath the punctum. To the best of the authors' knowledge, so far only 1 such case has been described in the literature. Typical clinical features and a meticulous histopathological examination aid in the diagnosis. Although rare, it should be kept in the differential diagnosis of punctal and peripunctal lesions. The authors report the second case with a few clinical and pathologic differences. Addition of more such cases to literature will help unravel the etiopathogenesis of this intriguing punctal disorder. PMID- 24801260 TI - Periocular pilomatrixoma: a retrospective analysis of 16 cases. AB - PURPOSE: Pilomatrixoma is a benign tumor of the hair follicle, occurring more frequently in the head and neck. There are relatively few published large case series in the ophthalmic literature. The purpose of this study was to evaluate additional case series of patients with periocular pilomatrixoma, treated in the institute from 1995 to 2011. METHODS: A retrospective analysis of all cases with periocular pilomatrixoma treated during 16 years was made. Data were collected regarding the age at the time of excision, gender, tumor location, tumor dimensions, suspected clinical diagnosis before biopsy, gross appearance, histopathological features, treatment, recurrence, and other syndromes related and family occurrence. RESULTS: Only 16 cases with pilomatrixoma were treated during 16 years. Most of the cases (69%) presented in the first 2 decades of life with female predilection (62.5%). The most common affected site was the upper eyelid (62.5%). All patients were asymptomatic. Various diagnoses were suspected clinically prior to surgical removal and histopathological confirmation of the tumor, and only in 18.75%, pilomatrixoma was suspected. Simple resection was carried out in all cases. No recurrence or malignant transformation was reported. CONCLUSION: Pilomatrixoma is a relatively infrequent periocular tumor, which isn't usually recognized clinically. The findings of the current case series, which is one of the largest published thus far in the ophthalmic literature, are in concordance with the other series of pilomatrixoma, confirming the epidemiologic, clinical, and histopathological features of this tumor in the periocular region. PMID- 24801261 TI - Does total humeral endoprosthetic replacement provide reliable reconstruction with preservation of a useful extremity? AB - BACKGROUND: Controversy exists regarding the ideal method of reconstruction after proximal humeral resection and several reconstructive techniques have been reported. The reconstructive options are very limited when resection of the entire humerus is required. One option is endoprosthetic reconstruction, but there have been few published studies on the outcome of total humeral endoprosthetic reconstruction. QUESTIONS/PURPOSES: The purposes of this study were (1) to assess the longevity of total humerus prostheses in those patients who survived their disease; (2) to review the complications associated with this prosthesis; and (3) to assess the Musculoskeletal Tumor Society functional score in survivors. METHODS: Thirty-four patients (10 males, 24 females) with a mean age of 26 years (range, 7-86 years) were included in this study. Histological diagnosis was osteosarcoma in 15 patients, chondrosarcoma in seven, Ewing's sarcoma in seven, metastatic carcinoma in three, liposarcoma in one, and giant cell tumor of bone in one remaining patient. Twenty-nine patients had their total humeral endoprosthetic replacement for primary reconstruction, whereas the remaining five patients received their implants for failures with other reconstructive techniques. At a minimum followup of 3 months (mean, 8.2 years; range, 3 months to 29 years), 16 patients were alive with no evidence of disease, whereas 13 of the remaining 18 died with metastatic disease. Local recurrence was seen in five patients and all eventually died of disease progression. RESULTS: According to the Kaplan-Meier survival analysis, the cumulative 10-year implant survival rate was 90%. Periprosthetic infection was seen in four patients, postoperative radial nerve palsy in one, and proximal migration of the prosthesis in three, whereas three patients needed a change of the articular elbow bushings at a mean of 16 years after the implant insertion. The mean Musculoskeletal Tumor Society functional score of the 28 patients who survived their disease for more than 12 months after the index procedure and could therefore be functionally assessed was 83% (range, 60%-93%). CONCLUSIONS: From this small, preliminary report, we suggest that total humeral endoprosthetic replacement may be a reasonable option of reconstruction after tumor resection. We have shown that this prosthesis preserves the function of the hand. The local recurrence rate observed suggests that careful selection of patients is crucial. Infection was our most common surgical complication, but we showed that in those who survived their tumor, this prosthesis offers a method to preserve a functional upper extremity in some patients. Further study with more patients is necessary to confirm the value of this reconstruction method. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24801262 TI - Evaluation of the relationship between renal function and renal volume-vascular indices using 3D power Doppler ultrasound. AB - PURPOSE: To investigate the relationship between renal function and total renal volume-vascular indices using 3D power Doppler ultrasound (3DPDUS). MATERIALS AND METHODS: One hundred six patients with hypertensive proteinuric nephropathy (HPN) (49 male, 57 female) and 65 healthy controls (32 male, 33 female) were evaluated prospectively using 3DPDUS. Total renal volume (RV), vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated using Virtual Organ Computer-aided Analysis (VOCAL). The estimated glomerular filtration rates (GFRs) of the patients with HPN and the control group were calculated. The patients with HPN were divided into two groups on the basis of GFR, normal (>=90) or reduced (<90). Differences between groups were compared using ANOVA. Correlations between GFR, renal volume and vascular indices were analyzed using Pearson's correlation analysis. Significance was set at p<0.05. RESULTS: The mean total RV, VI, FI and VFI values in the reduced GFR, normal GFR and control groups were RV (ml): 234.7, 280.7 and 294.6; VI: 17.6, 27.6 and 46.8; FI: 79.1, 88.7 and 93.9 and VFI: 7.1, 12.7 and 23.8. There were statistically significant differences between the groups (p<0.001). Total RVs and vascular indices exhibited significant correlations with estimated GFR (r=0.53-0.59, p<0.001) CONCLUSION: Three-dimensional power Doppler ultrasound is a reliable predictive technique in renal function analysis. PMID- 24801263 TI - Clinical evaluation and surgical decision making for patients with lumbar discogenic pain and facet syndrome. AB - In industrialized countries, more than two thirds of the population suffers from low back pain (LBP) in their lifetime. LBP associated with lumbar disc herniation, stenosis, and instability is a well-known and documented entity. On the other hand, the lumbar discogenic pain and facet syndrome are difficult to be clearly identified, and they are not always detectable by imaging. This article describes the causes of these painful syndromes, which are typically without radicular component, explains the modern diagnostic procedures, and provides guidelines for surgical decision making. PMID- 24801264 TI - Assisted techniques for vertebral cementoplasty: why should we do it? AB - Assisted techniques (AT) for vertebral cementoplasty include multiple mini invasive percutaneous systems in which vertebral augmentation is obtained through mechanical devices with the aim to reach the best vertebral height restoration. As an evolution of the vertebroplasty, the rationale of the AT-treatment is to combine the analgesic and stability effect of cement injection with the restoration of a physiological height for the collapsed vertebral body. Reduction of the vertebral body kyphotic deformity, considering the target of normal spine biomechanics, could improve all systemic potential complications evident in patient with vertebral compression fracture (VCF). Main indications for AT are related to fractures in fragile vertebral osseous matrix and non-osteoporotic vertebral lesions due to spine metastasis or trauma. Many companies developed different systems for AT having the same target but different working cannula, different vertebral height restoration system and costs. Aim of this review is to discuss about vertebral cementoplasty procedures and techniques, considering patient inclusion and exclusion criteria as well as all related minor and/or major interventional complications. PMID- 24801265 TI - Autocatalysis and selective oxidative etching induced synthesis of platinum copper bimetallic alloy nanodendrites electrocatalysts. AB - The controllable synthesis of noble metal alloy nanostructures with highly branched morphology has attracted much attention because of their specific physical and chemical properties. This article reports the synthesis of platinum copper bimetallic alloy nanodendrites (Pt-Cu BANDs) by a facile, one-pot, templateless, and seedless hydrothermal method in the presence of poly(allylamine hydrochloride) (PAH) and formaldehyde (HCHO). The morphology, composition, and structure of Pt-Cu BANDs are fully characterized by various physical techniques, demonstrating Pt-Cu BANDs are highly alloying, porous, and self-supported nanostructures. The formation/growth mechanism of Pt-Cu BANDs is explored and discussed based on the experimental observations. The autocatalytic growth and interdiffusion are responsible for the formation of Pt-Cu alloy whereas selective oxidative etching results in dendritic morphology of Pt-Cu alloy nanostructures. In addition, the electrocatalytic activity and stability of Pt-Cu BANDs for the methanol oxidation reaction (MOR) are investigated by various electrochemical techniques. The synthesized Pt-Cu BANDs show higher electrocatalytic activity and stability than commercially available Pt black. PMID- 24801267 TI - Single cell wound generates electric current circuit and cell membrane potential variations that requires calcium influx. AB - Breaching of the cell membrane is one of the earliest and most common causes of cell injury, tissue damage, and disease. If the compromise in cell membrane is not repaired quickly, irreversible cell damage, cell death and defective organ functions will result. It is therefore fundamentally important to efficiently repair damage to the cell membrane. While the molecular aspects of single cell wound healing are starting to be deciphered, its bio-physical counterpart has been poorly investigated. Using Xenopus laevis oocytes as a model for single cell wound healing, we describe the temporal and spatial dynamics of the wound electric current circuitry and the temporal dynamics of cell membrane potential variation. In addition, we show the role of calcium influx in controlling electric current circuitry and cell membrane potential variations. (i) Upon wounding a single cell: an inward electric current appears at the wound center while an outward electric current is observed at its sides, illustrating the wound electric current circuitry; the cell membrane is depolarized; calcium flows into the cell. (ii) During cell membrane re-sealing: the wound center current density is maintained for a few minutes before decreasing; the cell membrane gradually re-polarizes; calcium flow into the cell drops. (iii) In conclusion, calcium influx is required for the formation and maintenance of the wound electric current circuitry, for cell membrane re-polarization and for wound healing. PMID- 24801268 TI - Loss of heterozygosity in mammary serine protease inhibitor (maspin) and p53 at chromosome 17 and 18 in oral cavity squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the loss of heterozygosity (LOH) in chromosomes 17p13 (p53 gene) and in 18q21 (mammary serine protease inhibitor [maspin] gene), and the expression of both genes in tissues, in patients with oral cavity squamous cell carcinoma (SCC). METHODS: Thirty patients with oral cavity SCC have been evaluated for the presence of LOH in chromosomes 17p13 and 18q21, and the expression of p53 and maspin in tissues. Clinicopathological features and survival in these patients were also analyzed. RESULTS: LOH in 17p13 was more frequently identified in patients with lymph node metastasis and/or high TNM classification. LOH in 18q21 was more frequently identified in high primary T classification patients. Increased expression rate of p53 and/or decreased maspin expression rate were significantly higher in oral cavity SCC than normal tissues. CONCLUSION: LOH on chromosome 17, 18, the expression of p53, and maspin are related to the carcinogenesis of oral cavity SCC. Relationships with clinicopathological factors in oral cavity SCC were also revealed. (c) 2014 Wiley Periodicals, Inc. Head Neck 37: 1239-1245, 2015. PMID- 24801269 TI - Use of home blood pressure monitoring among hypertensive adults in primary care: Minhang community survey. AB - BACKGROUND: Several evidences have supported the benefits of home blood pressure monitoring (HBPM) in improving hypertension awareness and control. However, little was known about the use of HBPM by hypertensive patients in primary care in China. MATERIALS AND METHODS: A cross-sectional questionnaire survey on HBPM use was conducted on 1915 hypertensive patients in Xinzhuang County Hospital in Shanghai, and the factors related to regular use of HBPM were also determined. RESULTS: Overall, 1011 of the 1915 participants engaged in using HBPM, among whom 786 individuals used HBPM more than once a month. Of the 1011 HBPM users, 25.42% chose a mercury sphygmomanometer, 33.55% used wrist-cuff electronic devices, and 46.5% selected arm-cuff electronic devices. In addition, 73% of HBPM users reported HBP readings to their general practitioners. Compared with the less frequent users, patients who used HBPM daily were likely to report their blood pressure (BP) values to the doctors depending on notebook or mechanical memory than on their own memories (P<0.001). Moreover, patients with college education were 2.7 times more likely than those with middle school education or less to engage in frequent HBPM use (odds ratio=2.71, 95% confidence interval=2.03-3.61). CONCLUSION: This local community survey showed that ~40% of hypertension patients used HBPM frequently in primary care in China. However, certain patients chose the improper BP monitoring device or questionable reporting methods. Therefore, the use of arm-cuff electric devices with multiple memory storage or a home BP telemonitoring system should be promoted by health education targeted at hypertensive patients. PMID- 24801270 TI - The combined effect of pasteurization intensity, water activity, pH and incubation temperature on the survival and outgrowth of spores of Bacillus cereus and Bacillus pumilus in artificial media and food products. AB - The objective of the study was to evaluate the combined effects of pasteurization intensity (no heat treatment and 10 min at 70, 80 and 90 degrees C), water activity (aw) (0.960-0.990), pH (5.5-7.0) and storage temperature (7 and 10 degrees C) on the survival and outgrowth of psychrotolerant spores of Bacillus cereus FF119b and Bacillus pumilus FF128a. The experiments were performed in both artificial media and a validation was performed on real food products (cream, bechamel sauce and mixed vegetable soup). It was determined that in general, heat treatments of 10 min at 70 degrees C or 80 degrees C activated the spores of both B. cereus FF119b and B. pumilus FF128a, resulting in faster outgrowth compared to native (non-heat treated) spores. A pasteurization treatment of 10 min at 90 degrees C generally resulted in the longest lag periods before outgrowth of both isolates. Some of the spores were inactivated by this heat treatment, with more inactivation being observed the lower the pH value of the heating medium. Despite this, it was also observed that under some conditions the remaining (surviving) spores were actually activated as their outgrowth took place after a shorter period of time compared to native non-heated spores. While the response of B. cereus FF119b to the pasteurization intensity in cream and bechamel sauce was similar to the trends observed in the artificial media at 10 degrees C, in difference, outgrowth was only observed at 7 degrees C in both products when the spores had been heated for 10 min at 80 degrees C. Moreover, no inactivation was observed in cream or bechamel sauce when the spores were heated for 10 min at 90 degrees C in these two products. This was attributed to the protective effect of fat in the cream and the ingredients in the bechamel sauce. The study provides some insight into the potential microbial (stability and safety) consequences of the current trend towards milder heat treatments which is being pursued in the food industry. PMID- 24801271 TI - Butyric acid released during milk lipolysis triggers biofilm formation of Bacillus species. AB - Bacillus species form biofilms within milking pipelines and on surfaces of equipment in the dairy industry which represent a continuous hygiene problem and can lead to serious economic losses due to food spoilage and equipment impairment. Although much is known about the mechanism by which the model organism Bacillus subtilis forms biofilms in laboratory mediums in vitro, little is known of how these biofilms are formed in natural environments such as milk. Besides, little is known of the signaling pathways leading to biofilm formation in other Bacillus species, such as Bacillus cereus and Bacillus licheniformis, both of which are known to contaminate milk. In this study, we report that milk triggers the formation of biofilm-related structures, termed bundles. We show this to be a conserved phenomenon among all Bacillus members tested. Moreover, we demonstrate that the tasA gene, which encodes a major portion of the matrix which holds the biofilm together, is vital for this process. Furthermore, we show that the free fatty acid (FFA) - butyric acid (BA), which is released during lipolysis of milk fat and demonstrates antimicrobial activity, is the potent trigger for biofilm bundle formation. We finally show that BA-triggered biofilm bundle formation is mediated by the histidine kinase, KinD. Taken together, these observations indicate that BA, which is a major FFA within milk triggers biofilm formation in a conserved mechanism among members of the Bacillus genus. PMID- 24801272 TI - Does direct observation of procedural skills reflect trainee's progress in otolaryngology? AB - BACKGROUND: UK surgical trainees are required to undertake work-based assessments each year in order to progress in their training. Direct Observation of Procedural Skills (DOPS) is one of these assessments. We aim to investigate the validity of DOPS in assessing otolaryngology trainees at all levels. METHODS: A retrospective search of the portfolios of all otolaryngology trainees in North Thames was carried out to identify otolaryngology-specific DOPS. A score (Cs) was calculated for each DOPS based on the percentage of satisfactorily-rated items. The overall performance rating (Ps) was analysed as a separate variable and compared with Cs. The Ps and Cs results were then compared across trainee grades and levels within each grade: Core trainees (CT1-CT2) and specialty trainees (ST3 ST8). RESULTS: Seven hundred and sixty-seven otolaryngology DOPS were completed between August 2008 and September 2013. The tool was found to be reliable and internally consistent. Trainees in ST grade had higher Cs and Ps scores than CT grade (P < 0.001). Pairwise comparison showed that both Cs and Ps increased from CT1 to ST3 (P = 0.005) but not from ST4 onwards (P = 0.198). CONCLUSIONS: Otolaryngology DOPS is a useful tool in assessing otolaryngology trainees especially from CT1-ST3 level. DOPS can also differentiate between junior and senior trainees. However, it was not able to demonstrate progress at levels above ST3, most likely due to the simplicity of the procedures which trainees tend to master in the first few years of training. PMID- 24801273 TI - Plasmodium genome in blood donors at risk for malaria after several years of residence in Italy. AB - BACKGROUND: At present, the main risk of transfusion-transmitted malaria (TTM) in nonendemic countries is chronic, asymptomatic immigrants from malaria-endemic areas. Semi-immune donors may carry undetected parasitemia. This study examines Plasmodium infection in at-risk blood donors in Northern Italy. STUDY DESIGN AND METHODS: Plasma samples from 97 candidate donors and 80 controls were tested for malarial antibodies using a commercial enzyme immunoassay. The conserved 18S rRNA and the mitochondrial genes of Plasmodium were amplified to detect and quantify parasite genomes (copies/mL). Plasmodium species were identified with a species specific nested polymerase chain reaction. Parasitemic samples were further tested by amplification of polymorphic repetitive regions in MSP-1 Block 2, MSP-2 Block 3, and glutamate-rich protein (GLURP) confirmed by sequencing. RESULTS: Three of 83 seropositive (3.6%) and one of 14 seronegative at-risk candidate donors carried Plasmodium genome (4 * 10(3) -8.5 * 10(4) copies/mL): two P. falciparum, one P. malariae (seronegative sample), and one coinfection with P. malariae and P. ovale. Alleles of MSP-1 (MAD20 and K1), MSP-2 (3D7 and FC27), and GLURP were amplified from Sample 261. In Sample 282 only one allele in MSP-2 (FC27) and GLURP was amplified. No alleles were detected in Samples 283 and 331. CONCLUSIONS: Immigrants from endemic countries might carry infectious Plasmodium after 2 to 5 years of continuous residence in Italy. Serologic screening may miss donors carrying P. malariae. Permanent exclusion or screening for both antibodies and genome are needed to prevent TTM. PMID- 24801274 TI - Rapid degradation of Pseudomonas fluorescens 1-aminocyclopropane-1-carboxylic acid deaminase proteins expressed in transgenic Arabidopsis. AB - 1-Aminocyclopropane-1-carboxylate (ACC) deaminase is commonly produced by plant growth-promoting rhizobacteria (PGPR) and has been suggested to facilitate the growth and stress tolerance of hosts via a reduction in levels of ethylene. However, the regulatory mechanism of ACC deaminase (AcdS) protein within host plant cells is largely unknown. Here, we demonstrated beneficial effects and post translational modification of PGPR-originated AcdS proteins in plants. Compared with the wild-type, transgenic Arabidopsis expressing the Pseudomonas fluorescens acdS (PfacdS) gene displayed increased root elongation and reduced sensitivity to 10 MUM exogenous ACC, an ethylene precursor. Arabidopsis expressing PfacdS also showed increased tolerance to high salinity (150 mM NaCl). PfAcdS proteins accumulated in transgenic Arabidopsis were rapidly degraded, which was potentially mediated by the 26S proteasome pathway. The degradation of PfAcdS was alleviated in the presence of exogenous ACC. In conclusion, our data suggest that the plant growth-promoting effects of bacterial AcdS proteins are potentially modulated via protein turnover inside the host plant cells. Such post translational modification plays a physiological role in the mutualistic interactions between microorganisms and plants in the rhizospheric and/or endospheric niche. PMID- 24801275 TI - Does a standardised exercise protocol incorporating a cognitive task provoke postconcussion-like symptoms in healthy individuals? AB - OBJECTIVES: To explore whether an exercise protocol, alone and in combination with two selected cognitive tasks related to working memory, provokes postconcussion-like symptoms in healthy individuals. DESIGN: Prospective single cohort semi-randomised crossover repeated measures (time*condition) design. METHODS: 36 healthy individuals completed three submaximal exercise protocol conditions, namely: exercise alone, exercise with the paced auditory serial addition task, and exercise with Tetris. Self-reported symptoms were measured before exercise and 1-min and 15-min after the cessation of each exercise protocol using the Sports Concussion Assessment Tool 2-Postconcussion symptoms scale. RESULTS: Analysis of variance indicated a significant increase in symptom scores over time (p<0.001), but no effect between conditions (p=0.371) or a significant time*condition interaction (p=0.444). CONCLUSIONS: The combination of working memory tasks and a symptom provoking submaximal exercise protocol did not have an additional effect on the provocation of self-reported symptoms in healthy individuals. Furthermore, the two distinct methods of cognitive load delivery, controlled (paced auditory serial addition task) and pragmatic (Tetris), did not lead to a differential symptom response. These findings provide an initial insight into the scientific foundations for the symptom provocation model that is integral to the currently accepted clinical postconcussion return-to-play protocol. PMID- 24801276 TI - Chemical separation of Mo and W from terrestrial and extraterrestrial samples via anion exchange chromatography. AB - A new two-stage chemical separation method was established using an anion exchange resin, Eichrom 1 * 8, to separate Mo and W from four natural rock samples. First, the distribution coefficients of nine elements (Ti, Fe, Zn, Zr, Nb, Mo, Hf, Ta, and W) under various chemical conditions were determined using HCl, HNO3, and HF. On the basis of the obtained distribution coefficients, a new technique for the two-stage chemical separation of Mo and W, along with the group separation of Ti-Zr-Hf, was developed as follows: 0.4 M HCl-0.5 M HF (major elements), 9 M HCl-0.05 M HF (Ti-Zr-Hf), 9 M HCl-1 M HF (W), and 6 M HNO3-3 M HF (Mo). After the chemical procedure, Nb remaining in the W fraction was separated using 9 M HCl-3 M HF. On the other hand, Nb and Zn remaining in the Mo fraction were removed using 2 M HF and 6 M HCl-0.1 M HF. The performance of this technique was evaluated by separating these elements from two terrestrial and two extraterrestrial samples. The recovery yields for Mo, W, Zr, and Hf were nearly 100% for all of the examined samples. The total contents of the Zr, Hf, W, and Mo in the blanks used for the chemical separation procedure were 582, 9, 29, and 396 pg, respectively. Therefore, our new separation technique can be widely used in various fields of geochemistry, cosmochemistry, and environmental sciences and particularly for multi-isotope analysis of these elements from a single sample with significant internal isotope heterogeneities. PMID- 24801277 TI - Understanding and checking the assumptions of linear regression: a primer for medical researchers. AB - Linear regression (LR) is a powerful statistical model when used correctly. Because the model is an approximation of the long-term sequence of any event, it requires assumptions to be made about the data it represents in order to remain appropriate. However, these assumptions are often misunderstood. We present the basic assumptions used in the LR model and offer a simple methodology for checking if they are satisfied prior to its use. In doing so, we aim to increase the effectiveness and appropriateness of LR in clinical research. PMID- 24801278 TI - Impact of brief and sequential exposure to nystatin on the germ tube formation and cell surface hydrophobicity of oral Candida albicans isolates from human immunodeficiency virus-infected patients. AB - OBJECTIVE: To evaluate the impact of brief and sequential exposure to nystatin on the germ tube formation and cell surface hydrophobicity of oral isolates of Candida albicans obtained from patients infected with human immunodeficiency virus (HIV). MATERIALS AND METHODS: After determining the minimum inhibitory concentration of nystatin, 10 oral isolates of C. albicans from 10 different HIV infected patients were briefly (1 h) and sequentially (10 days) exposed to subtherapeutic concentrations of nystatin. Following a subsequent drug removal, the germ tube formation and cell surface hydrophobicity of these isolates were determined via a germ tube induction assay and an aqueous hydrocarbon assay, respectively. The data obtained from these assays for the control (unexposed to nystatin) and nystatin-exposed isolates were analyzed using Student's t tests. RESULTS: The mean percentage reduction in the germ tube formation and cell surface hydrophobicity of the nystatin-exposed isolates compared to the controls was 30.12 +/- 1.99 (p < 0.001) and 29.65 +/- 2.33 (p < 0.001), respectively. CONCLUSION: These data elucidate the possible pharmacodynamic mechanisms by which nystatin might operate in vivo in the modulation of candidal virulence. PMID- 24801279 TI - Genome stability of adenovirus types 3 and 7 during a simultaneous outbreak in Greater Manchester, UK. AB - A total of 96 isolates of species B adenovirus collected in Greater Manchester, UK and typed previously by serum neutralization were analyzed in five genome regions. Of these, 62 isolates were HAdV-B3 and HAdV-B7 collected during a simultaneous 15 months outbreak. The rest of the isolates were HAdV-B types 3 and 7 and other species B adenovirus types collected in different years following the outbreak. The phylogenetic analysis results of all the isolates in the structural regions hexon L2, penton, and fiber knob were found to be consistent and no mismatches were observed. Most of the isolates in the DNA polymerase and E1A regions had the same clustering patterns as the structural regions. However, one HAdV-B7 and one HAdV-B11 isolate changed their clustering patterns in the DNA polymerase region. In addition, HAdV-B16 isolates changed their clustering patterns in both DNA polymerase and E1A regions. The changes of the clustering patterns of some isolates is more likely related to natural variations rather than recombination which indicate that species B adenovirus genome is stable even when different types are circulating in a limited geographical area simultaneously. PMID- 24801280 TI - Positive affect increases secondary control among causally uncertain individuals. AB - Secondary control (acceptance of and adjustment to negative events) is thought to promote positive affect. We examined the opposite path: could positive affect increase secondary control, particularly among individuals high in causal uncertainty, who stand to benefit from it the most? In two studies, participants completed a causal uncertainty scale, thought about a problem while listening to affect-inducing music or no music, and then completed items that assessed secondary control. In Study 1, the music induced positive or negative affect. In Study 2, the music induced affect that was high or low in activation and positive or negative in valence. In both studies, we found that positive affect-inducing music increased secondary control among high causal uncertainty participants. Furthermore, trait affect did not account for the effects of causal uncertainty, and music did not influence primary control. These findings show that secondary control can fluctuate as a function of state affect. PMID- 24801281 TI - Acute administration of the small-molecule p75(NTR) ligand does not prevent hippocampal neuron loss or development of spontaneous seizures after pilocarpine induced status epilepticus. AB - Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., pro-BDNF) and cleaved to form mature BDNF (mBDNF). After pilocarpine-induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell-signaling pathways, including prosurvival and cell-death machinery in a receptor-specific manner. Pro-BDNF preferentially binds to the p75 neurotrophin receptor (p75(NTR) ), whereas mBDNF is the major ligand of the tropomyosin-related kinase receptor. To elucidate a potential role for p75(NTR) in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A-31, a small-molecule ligand that binds to p75(NTR) to promote survival signaling and inhibit neuronal cell death. Modulation of early p75(NTR) signaling and its effects on electrographic SE, SE induced neurodegeneration, and subsequent spontaneous seizures were examined after LM11A-31 administration. Despite an established neuroprotective effect of LM11A-31 in several animal models of neurodegenerative disorders (e.g., Alzheimer's disease, traumatic brain injury, and spinal cord injury), high-dose LM11A-31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE-induced neuronal cell injury, or inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75(NTR) activation during epileptogenesis and in seizure-induced cell injury in the hippocampus, among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A-31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy. PMID- 24801282 TI - Covalent conjugation of a peptide triazole to HIV-1 gp120 enables intramolecular binding site occupancy. AB - The HIV-1 gp120 glycoprotein is the main viral surface protein responsible for initiation of the entry process and, as such, can be targeted for the development of entry inhibitors. We previously identified a class of broadly active peptide triazole (PT) dual antagonists that inhibit gp120 interactions at both its target receptor and coreceptor binding sites, induce shedding of gp120 from virus particles prior to host-cell encounter, and consequently can prevent viral entry and infection. However, our understanding of the conformational alterations in gp120 by which PT elicits its dual receptor antagonism and virus inactivation functions is limited. Here, we used a recently developed computational model of the PT-gp120 complex as a blueprint to design a covalently conjugated PT-gp120 recombinant protein. Initially, a single-cysteine gp120 mutant, E275CYU-2, was expressed and characterized. This variant retains excellent binding affinity for peptide triazoles, for sCD4 and other CD4 binding site (CD4bs) ligands, and for a CD4-induced (CD4i) ligand that binds the coreceptor recognition site. In parallel, we synthesized a PEGylated and biotinylated peptide triazole variant that retained gp120 binding activity. An N-terminally maleimido variant of this PEGylated PT, denoted AE21, was conjugated to E275C gp120 to produce the AE21 E275C covalent conjugate. Surface plasmon resonance interaction analysis revealed that the PT-gp120 conjugate exhibited suppressed binding of sCD4 and 17b to gp120, signatures of a PT-bound state of envelope protein. Similar to the noncovalent PT-gp120 complex, the covalent conjugate was able to bind the conformationally dependent mAb 2G12. The results argue that the PT-gp120 conjugate is structurally organized, with an intramolecular interaction between the PT and gp120 domains, and that this structured state embodies a conformationally entrapped gp120 with an altered bridging sheet but intact 2G12 epitope. The similarities of the PT-gp120 conjugate to the noncovalent PT-gp120 complex support the orientation of binding of PT to gp120 predicted in the molecular dynamics simulation model of the PT-gp120 noncovalent complex. The conformationally stabilized covalent conjugate can be used to expand the structural definition of the PT-induced "off" state of gp120, for example, by high-resolution structural analysis. Such structures could provide a guide for improving the subsequent structure-based design of inhibitors with the peptide triazole mode of action. PMID- 24801283 TI - Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome. A randomised, prospective, controlled study. AB - INTRODUCTION: Particularly in the setting of acute coronary syndromes, the interplay between vascular and platelet function has been postulated to have direct clinical implications. The present trial is designed to test the effect of clopidogrel, prasugrel and ticagrelor on multiple parameters of vascular function, platelet aggregation, oxidative and inflammatory stress before and up to 4 weeks after coronary artery stenting. METHODS AND ANALYSIS: The study is designed as a three-arm, parallel design, randomised, investigator-blinded study. Patients with unstable angina or non-ST elevation myocardial infarction undergoing coronary intervention with a drug-eluting stent will be randomised to receive 600 mg clopidogrel, 60 mg prasugrel or 180 mg ticagrelor followed by oral therapy with the same drug. The primary endpoint of the trial is the impact of antiplatelet treatments on endothelial function as assessed by flow-mediated dilation at 1 day, 1 week and 1 month in patients who have undergone stenting. Secondary endpoints include the impact of study medications on parameters of macrovascular and microvascular function, platelet reactivity, oxidative and inflammatory stress. The study recruitment is currently ongoing and, after an interim analysis which was performed at 50% of the initially planned population, it is planned to continue until July 2015. ETHICS AND DISSEMINATION: The protocol was approved by the local ethics committee. The trial will provide important pathophysiological insight on the relationship between platelet aggregation and endothelial function, two parameters that have been shown to influence patients' prognosis. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01700322; EudraCT-Nr.: 2011-005305-73. Current V.1.3, from 24 February 2014. PMID- 24801284 TI - Amphipols in G protein-coupled receptor pharmacology: what are they good for? AB - G protein-coupled receptors are at a central node of all cell communications. Investigating their molecular functioning is therefore crucial for both academic purposes and drug design. However, getting the receptors as isolated, stable and purified proteins for such studies still stumbles over their instability out of the membrane environment. Different membrane-mimicking environments have been developed so far to increase the stability of purified receptors. Among them are amphipols. These polymers not only preserve the native fold of receptors purified from membrane fractions but they also allow specific applications such as folding receptors purified from inclusion bodies back to their native state. Of importance, amphipol-trapped G protein-coupled receptors essentially maintain their pharmacological properties so that they are perfectly adapted to further investigate the molecular mechanisms underlying signaling processes. We review here how amphipols have been used to refold and stabilize detergent-solubilized purified receptors and what are the main subsequent molecular pharmacology analyses that were performed using this strategy. PMID- 24801285 TI - Molecular properties affecting the adsorption coefficient of pesticides from various chemical families. AB - Forty pesticides were selected in function of their chemical families and their physico-chemical properties to represent a wide range of pesticide properties. Adsorption of these pesticides was studied on two soils by batch experiments. The two soils differed largely in organic matter and calcite contents. Distribution coefficient Kd was determined for each pesticide on the two soils. Adsorption was higher for the soil having the highest organic matter content and the lowest calcite content. In order to identify pesticide properties governing retention, eight molecular descriptors were determined from three-dimensional (3D) structure of molecules. Class-specific quantitative structure properties relationship (QSPR) soil adsorption models using one and two parameters were developed from experimental Kd. Three properties seemed to influence most retention of pesticides: hydrophobicity, solubility, and polarisability. Models combining these properties were suggested and discussed. PMID- 24801286 TI - Electrochemical removal of synthetic textile dyes from aqueous solutions using Ti/Pt anode: role of dye structure. AB - In this work, the efficiency of electrochemical oxidation (EO) was investigated for removing a dye mixture containing Novacron Yellow (NY) and Remazol Red (RR) in aqueous solutions using platinum supported on titanium (Ti/Pt) as anode. Different current densities (20, 40 and 60 mA cm(-2)) and temperatures (25, 40 and 60 degrees C) were studied during electrochemical treatment. After that, the EO of each of these dyes was separately investigated. The EO of each of these dyes was performed, varying only the current density and keeping the same temperature (25 degrees C). The elimination of colour was monitored by UV visible spectroscopy, and the degradation of organic compounds was analysed by means of chemical oxygen demand (COD). Data obtained from the analysis of the dye mixture showed that the EO process was effective in colour removal, in which more than 90% was removed. In the case of COD removal, the application of a current density greater than 40 mA cm(-2) favoured the oxygen evolution reaction, and no complete oxidation was achieved. Regarding the analysis of individual anodic oxidation dyes, it was appreciated that the data for the NY were very close to the results obtained for the oxidation of the dye mixture while the RR dye achieved higher colour removal but lower COD elimination. These results suggest that the oxidation efficiency is dependent on the nature of the organic molecule, and it was confirmed by the intermediates identified. PMID- 24801287 TI - Fe(III)-EDDS complex in Fenton and photo-Fenton processes: from the radical formation to the degradation of a target compound. AB - The present work compares the efficiency of homogenous Fenton and photo-Fenton processes in the presence of Fe(III)-EDDS complex under different experimental conditions. 4-tert-Butylphenol (4-t-BP), which is one of the endocrine disrupting chemicals, was used as a model pollutant to investigate the Fenton and photo Fenton application. The efficiency of homogenous photo-Fenton process was significantly much higher than homogenous Fenton process, which is due to the rapid formation of Fe(2+) under UV irradiation of the iron complex and the photochemical formation of HO(*) from the photolysis of the complex Fe(III)-EDDS. Through the degradation of 4-t-BP, the effect of Fe(III)-EDDS concentration, H2O2 concentration, pH, and oxygen was investigated in both processes. Such trend was also correlated with pH calculating the polychromatic Fe(2+) quantum yield formation at pH 4.0, 6.0, and 8.6. The results showed that at high Fe(III)-EDDS and H2O2 concentrations, a negative effect was found. By the way, the Fenton process was found to be enhanced at basic pH. These results can be very useful for the use and optimization of such iron complex in water treatment process as function of different physico-chemical conditions. PMID- 24801289 TI - New type of liquid rubber and compositions based on it. AB - The new method for producing the functionalized polymers and oligomers containing carbonyl C=O groups is developed. The method is based on the noncatalytic oxidation of unsaturated rubbers by nitrous oxide (N2O) at 180-230 degrees S. The proposed method allows obtaining the new type of functionalized rubbers liquid unsaturated polyketones with regulated molecular weight and concentration of C=O groups. The influence of the liquid polyketone addition on properties of rubber-based composites is investigated. The study indicates good prospects of using the liquid polyketones for the improvement of properties and operating characteristics of the various types of rubbers and the rubber-cord systems. PMID- 24801288 TI - Contrasting effects of silicates on cadmium uptake by three dicotyledonous crops grown in contaminated soil. AB - The effects of several silicates (talcum powder (TP), calcium silicate (CS), sodium silicate (SS), and potassium silicate (PS)), in comparison with other amendments (quicklime (QL) and potassium dihydrogen phosphate (PDP)) on cadmium (Cd) uptake by three dicotyledonous crops (Amaranthus hypochondriacus L. Cv. 'K112', Amaranthus tricolor L., and Brassica oleracea var. albiflora Kuntze) were investigated in Cd-contaminated soil. The effects of both application methods of amendments (singly and combined) and timing of application were also evaluated. Sodium silicate was the most effective in reducing crop Cd uptake and translocation, which was diminished by 51% in roots, 53% in stems, and 72% in leaves on average. Application of CS amendment showed greater efficiency than PDP amendment in decreasing Cd uptake by crops and resulted in increased biomass. Potassium silicate only slightly decreased shoot Cd concentration. Combination of PDP and SS was able to overcome the inhibitory effect of SS on crop yield while decreasing Cd concentrations in roots, stems and leaves of the tested crops by average rates of 52, 65, and 68% respectively. Applications of SS and PS significantly reduced the root-to-shoot Cd transfer factor. We found that Si accumulation in crops was not associated with lower Cd concentration, indicating that Si in crops may play a major role in alleviating metal stress rather than inhibiting crop Cd accumulation. We suggested that the inhibitive effect of silicates on crops Cd uptake was majorly attributed to the properties of the silicates, those were their specific effects on soil pH and cations, which increased Cd adsorption by soil and suppressed Cd uptake from soil solution by increasing the relative dissolved concentrations of competing cations. PMID- 24801290 TI - Combined effects of DOM and biosurfactant enhanced biodegradation of polycylic armotic hydrocarbons (PAHs) in soil-water systems. AB - This study systematically investigated the interactive effects of dissolved organic matter (DOM) and biosurfactant (rhamnolipid) on the biodegradation of phenanthrene (PHE) and pyrene (PYR) in soil-water systems. The degradations of two polycyclic aromatic hydrocarbons (PAHs) were fitted well with first order kinetic model and the degradation rates were in proportion to the concentration of biosurfactant. In addition, the degradation enhancement of PHE was higher than that of PYR. The addition of soil DOM itself at an environmental level would inhibit the biodegradation of PAHs. However, in the system with co-existence of DOM and biosurfactant, the degradation of PAHs was higher than that in only biosurfactant addition system, which may be attributed to the formation of DOM biosurfactant complex micelles. Furthermore, under the combined conditions, the degradation of PAH increased with the biosurfactant concentration, and the soil DOM added system showed slightly higher degradation than the compost DOM added system, indicating that the chemical structure and composition of DOM would also affect the bioavailability of PAHs. The study result may broaden knowledge of biosurfactant enhanced bioremediation of PAHs contaminated soil and groundwater. PMID- 24801291 TI - Degradation of methylparaben in water by corona plasma coupled with ozonation. AB - The degradation of methylparaben (MeP) in water was investigated using a pulsed corona discharge generated in oxygen, above the liquid. A comparison was made between results obtained in semi-batch corona (SBC) configuration (stationary solution, continuous gas flow) and results obtained in a semi-batch corona with recirculation combined with ozonation (SBCR + O3), where the liquid is continuously circulated between a solution reservoir and the plasma reactor and the effluent gas containing ozone is bubbled through the solution in the reservoir. It was found that MeP was completely degraded after 10-15 min of treatment in both configurations. Oxidation by ozone alone, in the absence of plasma, was a slower process. The energy efficiency for MeP removal (Y MeP) and for mineralization (Y TOC) was significantly higher in the SBCR + O3 configuration (Y MeP = 7.1 g/kWh at 90 % MeP removal and Y TOC = 0.41 g/kWh at 50 % total organic carbon (TOC) removal) than in the SBC configuration (Y MeP = 0.6 g/kWh at 90 % MeP removal and Y TOC = 0.11 g/kWh at 50 % TOC removal). PMID- 24801292 TI - Radionuclides in some edible and medicinal macrofungal species from Tara Mountain, Serbia. AB - Edible and medicinal macrofungi used in human diet represent not only important sources of nutritive elements but toxic substances as well (heavy metals and radionuclides). Radioactivity levels of four radionuclides ((40)K, (137)Cs, (226)Ra, (228)Ra) were determined in the basidiomata (fruiting bodies of a Basidiomycetes) of six lignicolous (Fomitopsis pinicola, Ganoderma applanatum, Hericium clathroides, Megacollybia platyphylla, Pluteus cervinus, Trametes gibbosa) and three mycorrhizal (Boletus luridus, Boletus sp. 1, Boletus sp. 2) species as well as their soil (wood) substrates by gamma spectrometry (high resolution high-purity germanium (HPGe) detector). The aim was to investigate their ability for radionuclide absorption according to transfer factors (from soil and wood), to predict potential bioindicator species as well as species with potential risk for human use. Samples were taken during years 2011 and 2012, at two sites in forest ecosystem of Tara Mountain (Serbia). Observed concentration ranges per dry weight were as follows: 29-3,020 Bq/kg ((40)K), 21.9-735 Bq/kg ((137)Cs), 3-39 Bq/kg ((226)Ra), and 2.0-18 Bq/kg ((228)Ra). Obtained results indicate that the type of basidiome (fleshy/tough), most likely due to a different metabolic rate, has a very important role in radionuclide accumulation. The highest activity concentrations of all analyzed radionuclides were found in species with fleshy basidiomata--P. cervinus, H. clathroides, M. platyphylla, and Boletus species. A species-specific influence on radionuclide uptake was more prominent comparing to habitat differences and the role of fungal trophic mode. No significant variations were observed regarding radionuclide activity among the same fungal species from different sampling sites. PMID- 24801293 TI - Determination of lead(II) sorption capacity of hazelnut shell and activated carbon obtained from hazelnut shell activated with ZnCl2. AB - This study aimed to determine the Pb(+2) adsorption capacities of hazelnut shell and activated carbon obtained from hazelnut shell. It also aimed to determine the effect of ZnCl2 in the activation process. The hazelnut was pyrolyzed at 250 and 700 degrees C. For determining the capture speed of the adsorbents, the pseudo first- and second-order kinetic studies were performed. The Freundlich and Langmuir isotherm models were used to determine adsorption equilibrium. The surface characterization of hazelnut shell and activated carbon was determined by Brunauer-Emmett-Teller (BET) analysis and FTIR spectrum. Pb(+2) adsorption capacity of obtaining activated carbon was determined by ICP-OES analysis. The raw hazelnut shell's BET surface area is 5.92 m(2)/g and the surface area of activated carbons which is pyrolyzed at 250 and 700 degrees C were determined (270.2 and 686.7 m(2)/g, respectively. The surface area of hazelnut shell, which pyrolyzed at 700 degrees C after being activated with ZnCl2, was determined to be 736.49 m(2)/g. Results show that physical adsorption process is dominant for the activated carbon pyrolysis at 700 degrees C but the chemical adsorption is dominant for the activated carbon pyrolysis at lower degrees and for raw hazelnut shell. PMID- 24801294 TI - Spatial variability of bacteria in the rhizosphere of Elsholtzia splendens under Cu contamination. AB - Elsholtzia splendens is a well-known Cu-tolerant plant; yet, the impact of Cu contaminated soil on bacterial community in its rhizosphere is not known. We studied the spatial variability of bacteria in the rhizosphere using Cu contaminated soil with polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and real-time PCR. In the uncontaminated soil, the content of the dissolved organic carbon (DOC) and bacterial diversity gradually increased in the rhizosphere soil along the root growth direction (from the interface zone to the meristematic zone), while for the Cu-contaminated soil, the highest DOC content and the strongest potential bioavailability of Cu were found in the interface zone, which also had the lowest bacteria diversity. Bacteria diversity was positively correlated with DOC in the uncontaminated soil (p < 0.01) but not in the contaminated soil. Compared with uncontaminated soil, some species such as Firmicutes only existed in the rhizosphere of contaminated soil, while the very small amount (if any) of some species exists such as Deinococcus Thermus, indicating that the contaminated environment altered the bacterial composition. Moreover, spatial variation of the bacterial community was found among different soil zones. Real-time PCR confirmed the spatial variation via the gene expression of flagellin (fliC) and chemotaxis gene (cheA). The spatial characteristics of cheA expression were consistent with that of DOC and bacterial diversity. In conclusion, we demonstrated that the spatial variation of the bacterial community in the rhizosphere was present, independent of Cu contamination. DOC and Cu toxicity may affect specific gene expressions such as fliC and cheA, resulting in bacterial spatial variation. PMID- 24801295 TI - Pfizer-sponsored satellite symposium at the European Haemophilia Consortium (EHC) Congress: changing the policy landscape: haemophilia patient involvement in healthcare decision-making. AB - The annual European Haemophilia Consortium (EHC) Conference 2013, held in Bucharest, Romania, 4-5 October, was attended by over 200 patient advocates, policy makers and healthcare professionals from across Europe. Pfizer sponsored a satellite symposium at the conference entitled: 'Changing the policy landscape: haemophilia patient involvement in healthcare decision making', drawing on expertise from a panel specialising in the field of rare disease. The symposium, chaired by Declan Noone (Irish Haemophilia Society) on behalf of Brian O'Mahony (Irish Haemophilia Society), examined the current policy and economic landscape in Europe and how pressures on healthcare budgets are impacting haemophilia care. The symposium also discussed the importance of representing the 'patient voice' in key policy decisions through identification of opportunities for patient advocacy group engagement. Alastair Kent (Genetic Alliance UK) opened the session by highlighting that the downturn in the global economy has refocused decision making in healthcare, moving cost-effectiveness of healthcare interventions higher up the agenda for decision-makers and payers. In light of this, patient engagement is more important than ever, particularly in healthcare technology assessments (HTAs), to ensure that patient and family opinions are represented. Segolene Ayme (Orphanet) built upon this in her session discussing the rare disease policy landscape and regional initiatives taking place in Europe, including the EUROPLAN process, for which the participation of the haemophilia community is critical. Finally, Declan Noone provided an example of how the EHC, through its survey of 35 countries, demonstrated not only the considerable differences in the quality of care available for people with haemophilia across Europe, but also how the data from the survey could be used as a powerful advocacy tool to initiate change in countries with lower gross domestic product (GDP) that face healthcare spending challenges. The meeting closed with a 'call to action' for patient advocacy groups, focusing on avenues by which patients can become involved in the decision-making for policies that will ultimately affect access to, and quality of, haemophilia care in their country. PMID- 24801297 TI - [Faecal calprotectin: less inappropriate endoscopies? - measurement of calprotectin mostly does not replace endoscopy]. PMID- 24801298 TI - [Percutaneous coronary intervention in addition to optimal medical therapy for stabile coronary artery disease - a systematic review and meta-analysis]. AB - OBJECTIVE: We evaluated the effect of percutaneous coronary interventions (PCI) in addition to optimal medical therapy in stable coronary artery disease (CAD). METHODS: A systematic literature search was conducted in the online databases MEDLINE, EMBASE etc. in June 2010, updated in February 2013 in MEDLINE and completed by a hand search. Randomized controlled trials (RCT) and systematic reviews of RCT comparing PCI vs. no PCI in stable CAD were identified and evaluated. Results for death, myocardial infarction and angina pectoris of the RCTs using optimal medical therapy were combined with meta-analysis for relative risk (RR). The strength of the evidence was appraised based on GRADE. RESULTS: After evaluation of 7 systematic reviews and 23 RCT 4 RCTs using optimal medical therapy (Betablockers, ASS, Statins in more than 80% and ACE-Inhibitors in more than 50% of patients the study) were identified. No significant difference was found for the risks of death and of myocardial infarction between the alternatives up to 5 years after beginning the therapy. The PCI reduced the proportion of patients with angina pectoris attacks up to 3 years after beginning the therapy, RR = 0,81 (95 % CI: 0,71 to 0,92). The strength of the evidence was appraised as moderate. CONCLUSION: The use of PCI in addition to optimal medical therapy in stable CAD may reduce the proportion of patients with angina pectoris attacks up to 3 years after beginning the therapy. PMID- 24801299 TI - [Nephrotic syndrome in a woman with tuberous sclerosis]. AB - HISTORY AND CLINICAL FINDINGS: A 50-year-old woman with known tuberous sclerosis complex (TSC) was referred for further work-up of nephrotic syndrome. A left-side nephrectomy due to an anamnestically reported "shrunken kidney" had been performed at the age of 15 years. The patient presented with massive edematous swelling of all extremities and typical cutaneous lesions of TSC. DIAGNOSTIC FINDINGS, TREATMENT AND CLINICAL COURSE: Laboratory analysis revealed nephrotic proteinuria, hypalbuminemia and advanced impairment of kidney function. Computed tomography revealed a massively enlarged remaining kidney with confluent angiomyolipomata. As kidney biopsy was deemed to be too hazardous, a thorough work-up for potentially underlying diseases finally revealed endometrial carcinoma. Hysterectomy resulted in a prompt and sustained decrease of proteinuria and disappearance of edema. CONCLUSION: Although a renal involvement is typical in TSC the occurrence of nephrotic syndrome is not and should give reason for further evaluation. PMID- 24801300 TI - [21-year-old police officer with chest trauma]. PMID- 24801301 TI - [Eosinophilia - inflammation, proliferation, reaction. Part 1: diagnostics]. AB - Eosinophilia presents a challenge to differential diagnostics due to the multitude of possible causes. An initial difficulty is often to distinguish between threatening disease symptoms and relatively harmless secondary reactions. A highly dynamic clinical progression with severe impairment of the vital functions, like breathing, for example, can make swift action necessary. An example of this is known as acute eosinophile pneumonia, which can often only be controlled with the rapid use of high steroid doses. However, a peripheral blood eosinophilia must not lead to an automatic use of steroids before the most important core tests, as this can compromise further diagnostic measures. Furthermore, less dramatic courses require careful handling of an eosinophilia. Various pneumological, infectological, rheumatological or haematological / oncological disease patterns with a prolonged course can develop seriously if they are not recognised in time and treated in a targeted manner. There is no guideline for eosinophile clinical pictures in general. Already the recommendations for a structured diagnosis are scarce and are often concentrated on internist emphases. PMID- 24801302 TI - [Stereotactic radiotherapy with the cyberknife]. PMID- 24801303 TI - [Differential diagnoses of Raynaud's phenomenon]. AB - Raynaud's phenomenon (RP) is characterized by repeated vasospastic attacks of the distal extremities induced by cold, humidity, vibrations or emotional stress. It typically presents a triphasic colour change from white (palor; vasoconstriction) to blue (cyanosis) and red (reactive hyperaemia). The symptoms are based on a primary RP in 90 %. Secondary RP is a symptom of an underlying disease. RP has to be distinguished from other colour changes of the distal extremities like acrocyanosis, erythromelalgia, perniosis and Chilblain-Lupus. Patients history, clinical examination, ANA, ESR/CRP and nailfold capillaroscopy are essential for the early diagnosis of an underlying disease. The initiation of angiologic tests is important in patients with digital ulcers, necrosis or gangrene. Important differential diagnoses in secondary RP are autoimmune rheumatic diseases like systemic sclerosis and systemic lupus erythematodes as well as vascular diseases like arterial occlusions and compression syndromes or concomitant medication (i. e. beta-blocker). PMID- 24801304 TI - A review of echocardiography in anaesthetic and peri-operative practice. Part 2: training and accreditation. AB - Echocardiography has been widely adopted as a diagnostic and monitoring tool in cardiac anaesthesia and critical care. There is considerable interest in how echocardiography could be used to benefit patients in other areas of anaesthesia and peri-operative practice. The first part of review examines the impact and utility of echocardiography, while this second part is concerned with the matter of training and accreditation. There are a number of existing clinical protocols for the use of transthoracic echocardiography with a focused approach. Some of these, such as Focused Intensive Care Echocardiography in the UK, have been developed into structured accreditation processes with embedded supervision. Learning opportunities are now emerging for anaesthetists who wish to acquire echocardiography skills--these encompass clinical, simulation and online resources. Whilst the roll-out of echocardiography for more widespread use in peri-operative management is a long-term project, it is now an appropriate time to consider how this may be achieved. PMID- 24801305 TI - Mid- to late term hypoxia in the mouse alters placental morphology, glucocorticoid regulatory pathways and nutrient transporters in a sex-specific manner. AB - Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus, with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during mid- to late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses, with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults. PMID- 24801306 TI - Rhodopsin in the rod surface membrane regenerates more rapidly than bulk rhodopsin in the disc membranes in vivo. AB - Sustained vertebrate vision requires that opsin chromophores isomerized by light to the all-trans form be replaced with 11-cis retinal to regenerate the visual pigment. We have characterized the early receptor potential (ERP), a component of the electroretinogram arising from photoisomerization-induced charge displacements in plasma membrane visual pigment, and used it to measure pigment bleaching and regeneration in living mice. The mouse ERP was characterized by an outward 'R2' charge displacement with a time constant of 215 MUs that discharged through a membrane with an apparent time constant of ~0.6 ms. After complete bleaching of rhodopsin, the ERP recovered in two phases. The initial, faster phase had a time constant of ~1 min, accounted for ~20% of the total, and was not dependent on the level of expression of the retinal pigment epithelium isomerase, Rpe65. The slower, complementary phase had a time constant of 23 min in wild-type (WT) mice (C57Bl/6) and was substantially slowed in Rpe65(+/-) mice. Comparison of the ERPs of a mouse line expressing 150% of the normal level of cone M-opsin with those of WT mice revealed that M-opsin contributed 26% of the total WT ERP in these experiments, with the remaining 74% arising from rhodopsin. Thus, the fast regenerating fraction (20%) corresponds approximately to the fraction of the total ERP independently estimated to arise from M-opsin. Because both phases of the ERP recover substantially faster than previous measurements of bulk rhodopsin regeneration in living mice, we conclude that delivery of the highly hydrophobic 11-cis retinal to the interior of rod photoreceptors appears to be retarded by transit across the cytoplasmic gap between plasma and disc membranes. PMID- 24801308 TI - Associations of Rhesus and non-Rhesus maternal red blood cell alloimmunization with stillbirth and preterm birth. AB - BACKGROUND: Although the risks of adverse pregnancy outcomes associated with anti D antibodies are well-recognized, much less is known concerning alloimmunization with other red blood cell antibodies detected during routine maternal screening. To date, most reports of adverse pregnancy outcomes associated with non-anti-D antibodies have been from small case studies. The aim of this study was to examine the associations of maternal alloimmunization with specific red blood cell antibodies and the risks of preterm birth and stillbirth in the Swedish population. METHODS: All antibody screening, outcome and covariate data were obtained through linkages of Swedish national health and data registers. Follow up in these population-based registers was available up to 31 December 2002. The final study sample consisted of 1,022,569 singleton births from 668,952 mothers during 1987-2002. RESULTS: In total, 1.3% of the 1,022,569 study pregnancies were alloimmunized. In adjusted logistic regression models, compared with having no antibodies, alloimmunization with anti-D, anti-E, anti-C and anti-c was associated with increased risk of both stillbirth and preterm birth. In addition, anti-Kell was associated with increased risk of preterm birth and anti-Lea with increased risk of stillbirth. Compared with firstborn children, risk of preterm birth associated with alloimmunization was greater in subsequent births CONCLUSIONS: In the largest study to date, alloimmunization with Rhesus, K- and Lea red blood cell antibodies increased the risk of preterm birth and/or stillbirth. The association of anti-Lea with stillbirth was an unexpected finding. Further study of the consequences of non-anti-D alloimmunization is warranted. PMID- 24801307 TI - Response of the human detrusor to stretch is regulated by TREK-1, a two-pore domain (K2P) mechano-gated potassium channel. AB - The mechanisms of mechanosensitivity underlying the response of the human bladder to stretch are poorly understood. Animal data suggest that stretch-activated two pore-domain (K2P) K(+) channels play a critical role in bladder relaxation during the filling phase. The objective of this study was to characterize the expression and function of stretch-activated K2P channels in the human bladder and to clarify their physiological role in bladder mechanosensitivity. Gene and protein analysis of the K2P channels TREK-1, TREK-2 and TRAAK in the human bladder revealed that TREK-1 is the predominantly expressed member of the mechano-gated subfamily of K2P channels. Immunohistochemical labelling of bladder wall identified higher levels of expression of TREK-1 in detrusor smooth muscle cells in comparison to bladder mucosa. Functional characterization and biophysical properties of the predominantly expressed member of the K2P family, the TREK-1 channel, were evaluated by in vitro organ bath studies and the patch-clamp technique. Electrophysiological recordings from single smooth muscle cells confirmed direct activation of TREK-1 channels by mechanical stretch and negative pressure applied to the cell membrane. Inhibition of TREK-1 channels in the human detrusor significantly delayed relaxation of the stretched bladder smooth muscle strips and triggered small-amplitude spontaneous contractions. Application of negative pressure to cell-attached patches (-20 mmHg) caused a 19-fold increase in the open probability (NPo) of human TREK-1 channels. l-Methionine (1 mm), a specific TREK-1 inhibitor, dramatically decreased the NPo of TREK-1 channels from 0.045 +/- 0.003 to 0.008 +/- 0.001 (n = 8, P <= 0.01). Subsequent addition of arachidonic acid (10 MUm), a channel opener, increased the open probability of methionine-inhibited unitary currents up to 0.43 +/- 0.05 at 0 mV (n = 9, P <= 0.05). The results of our study provide direct evidence that the response of the human detrusor to mechanical stretch is regulated by activation of mechano-gated TREK-1 channels. Impaired mechanosensation and mechanotransduction associated with the changes in stretch-activated K2P channels may underlie myogenic bladder dysfunction in humans. PMID- 24801309 TI - What is the 'best' health promotion action to take? PMID- 24801310 TI - A bottom-up art event gave birth to a process of community empowerment in an Italian village. AB - Although community participation is a component of community empowerment, it often remains a theoretical exhortation. Reporting experiences which enable people to take control of their lives, can be useful to suggest practical elements for promoting empowerment. This article describes the experience of a Sardinian village (Ulassai), that developed into a community empowerment. The Laverack's operational domains were used to measure the community empowerment process. The process started in 1979 'almost by chance' with an art performance that was the entry point for community participation. This experience has been the foundation for the community empowerment. Citizens acquired the 'ability of thinking and planning as a community and not mere individuals'. In the following 30 years citizens gave birth to several outcomes rooted in that event. The intermediate outcomes highlight the 'ability of action by a group to mobilize existing resources, and act collectively against opposing forces'. The long-term outcomes demonstrate the 'ability to integrate the cultural experiences that strengthened the community's identification into a sustainable community asset', and the 'ability to cope with global environmental challenges and to collaborate on an equal basis with other stakeholders. The pathways to community empowerment, showed by the community of Ulassai, overlap with the 'operational domains'. The Ulassai experience shows that the empowerment process can start from an event apparently unrelated to health promotion. This community experience illustrates the positive role arts can play in community development. Hence, the call for health promoters to look carefully into those situations that occur naturally in communities. PMID- 24801311 TI - Exercise motivation, self-efficacy, and enjoyment as indicators of adult exercise behavior among the transtheoretical model stages. AB - To better understand the role of motivation in determining exercise participation at the population level, we performed a questionnaire survey of 385 Japanese adults (mean age: 55.0 years, SD: 10.9 years). At baseline, the motivation subscales (intrinsic motivation, identified regulation, and external regulation), self-efficacy, and enjoyment all showed significant differences across the stages of change for exercise. Intrinsic motivation and enjoyment had similar findings, with the highest scores being noted in the maintenance stage. Among the 385 subjects, 183 completed the follow-up questionnaire 3 months later. After 3 months, most of the participants (86.9%) who were in the maintenance stage at baseline remained in the same stage. The number of participants who dropped to a lower stage after 3 months was 23. The changes of exercise stage over the 3-month period differed significantly for identified regulation, introjected regulation, and motivation. There were significant time and group interactions for intrinsic motivation and identified regulation. These findings suggest the importance of intrinsic motivation and identified regulation for performance of regular exercise, as well as the role of introjected regulation for promoting behavioral change among Japanese adults. PMID- 24801312 TI - Becoming a health promoting school: key components of planning. AB - This article looks at the practicalities of implementing the health promoting school (HPS) framework, including conducting a whole school audit, to enable a primary school to successfully adopt the HPS principles. A partnership agreement was signed, between EACH Social and Community Health which is a local Community Health Centre and a primary school in the Eastern suburbs of Melbourne, in Australia. An audit was conducted of the school community with four follow up focus groups of students from grades 3 to 6. Qualitative data was gathered from 20 teachers at the school at a professional development day facilitated by the health promotion staff of the Community Health Centre. The results of the school audit identified that students in grades 3 to 6 and parents valued the outside environment of the school most highly. The staff valued staff attributes most highly. Suggestions from students to improve the school included improving the canteen and outside environment. Staff were most concerned about fitness of both the staff and the students. Parents also identified lack of healthy eating as a concern. The school community sees the value of adopting the HPS framework, however on-going structured support is required if the school is to successfully adopt the HPS approach. The school community needs to understand that the move toward cultural and environmental change is slow. Successful adoption of the HPS model requires time and collaboration. The emphasis needs to be on supporting teachers to change their school from within. Relationships are important. PMID- 24801313 TI - A causal relationship between sense of coherence and psycho-social work environment: from one-year follow-up data among Japanese young adult workers. AB - The aim of this study was to use longitudinal data and investigate by sex the following four hypotheses on the relationship between sense of coherence (SOC) and work environment (WE): (i) a bidirectional cause-effect relationship exists; (ii) WE is the cause and SOC is the effect; (iii) SOC is the cause and WE is the effect; and (iv) no cause-effect relationship exists. Male and female subjects between the ages of 20 and 40 living in Japan were selected as subjects by two stage stratified random sampling, and self-administered questionnaires were sent by mail between January and March 2007 (Time 1). A follow-up was conducted in the same way from January to March of 2008 (Time 2). Responses were obtained from 3,965 individuals (follow-up ratio: 82.6%). This study analyzed 1,291 males and 933 females who were at least 25 years old at Time 1 and who worked the same job in both time periods. The analysis was performed using a cross-lagged model under structural equation modeling. The second hypothesis was selected for both males and females based on the outcome of nested model comparisons. That is, a temporal cause-effect relationship was observed between SOC and WE for both males and females, with WE as the cause and SOC as the effect. PMID- 24801314 TI - Using health promotion competencies for curriculum development in higher education. AB - Health promotion core competencies are used for a variety of reasons. Recently there have been moves to gain international consensus regarding core competencies within health promotion. One of the main reasons put forward for having core competencies is to guide curriculum development within higher education institutions. This article outlines the endeavours of one institution to develop undergraduate and postgraduate curricula around the Australian core competencies for health promotion practitioners. It argues that until core competencies have been agreed upon internationally, basing curricula on these carries a risk associated with change. However, delaying curricula until such risks are ameliorated decreases opportunities to deliver dynamic and current health promotion education within higher institutions. PMID- 24801315 TI - Co-morbid substance use behaviors among youth: any impact of school environment? AB - BACKGROUND: Substance use is common among youth; however, our understanding of co morbid tobacco, alcohol and marijuana use remains limited. The school-environment may play an important role in the likelihood a student engages in high risk substance use behaviors, including co-morbid use. PURPOSE: This study aims to: (i) describe the prevalence of co-morbid substance use behaviors among youth; (ii) identify and compare the characteristics of youth who currently use a single substance, any two substances, and all three substances; (iii) examine if the likelihood of co-morbid use varies by school and; (iv) examine what factors are associated with co-morbid use. METHODS: This study used nationally representative data collected from students in grades 9 to 12 (n = 41,886) as part of the 2006 2007 Canadian Youth Smoking Survey (YSS). Demographic and behavioral data were collected including, current cigarette, alcohol and marijuana use. Results. 6.5% (n = 107,000) reported current use of all three substances and 20.3% (n = 333,000) of any two substances. Multi-level analysis revealed significant between school variability in the odds a student used all three substances and any two substances; accounting for 16.9% and 13.5% of the variability, respectively. Co morbid use was associated with sex, grade, amount of available spending money and perceived academic performance. CONCLUSIONS: Co-morbid substance use is high among youth; however, not all schools share the same prevalence. Knowing the school characteristics that place particular schools at risk for student substance use is important for tailoring drug and alcohol education programs. Interventions that target the prevention of co-morbid substance use are required. PMID- 24801316 TI - Reflections on cultural diversity in oral health promotion and prevention. AB - Dental caries is an extremely debilitating disease with lifelong consequences. In most developed countries significant oral health inequalities exist in disadvantaged communities, including refugee and migrant populations. Addressing these inequalities is becoming increasingly challenging as communities become more culturally diverse. An awareness of traditional oral health practices would enable the dental and broader health professions, to understand these differences and consequently better meet the needs of disadvantaged communities. The use of miswak is a common traditional oral hygiene practice used by a number of culturally diverse groups. Further research is required into the use and effectiveness of traditional oral health practices within developed countries. Such practices need to be understood, respected and incorporated within oral health care, policies and practices in order to reduce significant inequalities experienced in our communities. This commentary describes the current literature on miswak, its effectiveness and the implications for promoting oral health. PMID- 24801319 TI - [The racialization of public health in the United States : the possibility that the concept be allowed to die out]. PMID- 24801322 TI - [Experiences in health promotion and governance in a local area of Mexico : challenges and limitations]. PMID- 24801324 TI - A meta-analysis on the relationship between self-reported presence and anxiety in virtual reality exposure therapy for anxiety disorders. AB - In virtual reality exposure therapy (VRET) for anxiety disorders, sense of presence in the virtual environment is considered the principal mechanism that enables anxiety to be felt. Existing studies on the relation between sense of presence and level of anxiety, however, have yielded mixed results on the correlation between the two. In this meta-analysis, we reviewed publications on VRET for anxiety that included self-reported presence and anxiety. The comprehensive search of the literature identified 33 publications with a total of 1196 participants. The correlation between self-reported sense of presence and anxiety was extracted and meta-analyzed. Potential moderators such as technology characteristics, sample characteristics including age, gender and clinical status, disorder characteristics and study design characteristics such as measurements were also examined. The random effects analysis showed a medium effect size for the correlation between sense of presence and anxiety (r = .28; 95% CI: 0.18-0.38). Moderation analyses revealed that the effect size of the correlation differed across different anxiety disorders, with a large effect size for fear of animals (r = .50; 95% CI: 0.30-0.66) and a no to small effect size for social anxiety disorder (r = .001; 95% CI: -0.19-0.19). Further, the correlation between anxiety and presence was stronger in studies with participants who met criteria for an anxiety disorder than in studies with a non clinical population. Trackers with six degrees of freedom and displays with a larger field of view resulted in higher effect sizes, compared to trackers with three degrees of freedom and displays with a smaller field of view. In addition, no difference in effect size was found for the type of presence measurement and the type of anxiety measurement. This meta-analysis confirms the positive relation between sense of presence and anxiety and demonstrates that this relation can be affected by various moderating factors. PMID- 24801325 TI - Life table parameters and survivorship of Spodoptera exigua (Lepidoptera: Noctuidae) at constant temperatures. AB - Age-specific life table parameters, survivorship, and extra molting of the beet armyworm, Spodoptera exigua (Hubner), were determined at eight constant temperatures of 12, 15, 20, 25, 30, 33, 34, and 36 degrees C with a variation of 0.5 degrees C on sugar beet leaves. No development was observed at 12 and 36 degrees C. The survivorship of overall immature stages was higher at 25 degrees C than the other temperatures. The highest (0.276 d(-1)) and lowest (0.149 d(-1)) value of the intrinsic rate of increase (r) was observed at 30 and 20 degrees C, respectively. Although the highest value of the net reproductive rate was at 25 degrees C (377.7 female offspring at 25 degrees C and 127.4 female offspring at 30 degrees C), the highest value of r was at 30 degrees C, which indicated the importance of shorter development time (16.9 d at 30 degrees C and 27.2 d at 25 degrees C) in enhancing r. The relationship between temperature and r was modeled using the Lactin-2 model. The lower temperature threshold, the upper temperature threshold, and optimal temperature for the r were estimated at 13.1, 32.2, and 34.1 degrees C, respectively. The mean generation time decreased significantly with increasing temperature, with the longest (35.9 d) and shortest (15.1 d) mean generation time was calculated at 20 and 33 degrees C, respectively. PMID- 24801326 TI - Brief report: The protective effects of school engagement for African American adolescent males. AB - This study examined whether school engagement was protective with regard to externalizing behaviors, gang involvement, sexual debut, and unsafe sexual behaviors among African American adolescent males. Self-administered surveys were administered to 219 male students from an urban Chicago high school. Controlling for age and socioeconomic status, higher school engagement levels were associated with lower rates of aggressive behaviors, lower levels of gang involvement, delay of sexual debut, and lower levels of unsafe sexual behaviors. Findings support the development of school-based interventions designed to promote student-teacher bonds, academic performance, and after-school activities for African American youth. PMID- 24801327 TI - 'You have to die first': Exploring the thoughts and feelings on organ donation of British women who have not signed up to be donors. AB - Four White British women who had not signed up to be organ donors were interviewed in depth to investigate their feelings on organ donation. Transcripts were analysed using Interpretative Phenomenological Analysis to reveal how the ability to detach from the body affects the acceptance of organ donation, how organ donation can trigger difficult thoughts and how the family can be used to explain not having signed up. The findings confirm previous empirical evidence but also offer original insight on the discrepancy between attitudes and behaviours, how fears can inhibit action and the importance of communicating organ donation wishes to family. PMID- 24801328 TI - Contextually appropriate emotional word use predicts adaptive health behavior: Emotion context sensitivity and treatment adherence. AB - Emotion context sensitivity is the ability to respond emotionally in a manner that is functionally appropriate for the context in which the emotion arises. This study examined the relationship between emotion context sensitivity and treatment adherence in adults with the chronic illness Thalassemia. Emotional responses were measured by examining the frequency of positive and negative emotional words used to answer two interview questions that created two different emotional contexts. Consistent with previous research on adaptive and contextually appropriate emotions, negative emotion words were related to adherence in the context of the disease itself, while positive emotion words were related to adherence in the context of coping. PMID- 24801329 TI - Psychosocial well-being after kidney transplantation: A matched-pair case-control study. AB - A number of outcome studies showed that kidney transplantation is associated with improvements in health-related quality of life relative to the pre-transplant period, but comparisons with the general population produced mixed results. This study aimed to compare 30 successful (>1 year) kidney transplantation recipients with 30 matched-pair healthy controls on psychosocial well-being. Independent of gender, age and time since transplantation, transplanted patients equalled healthy people in the intrapersonal domains but scored worse in the interpersonal domains of psychosocial well-being. Identifying aspects of life that remain impaired after kidney transplantation may assist the development of interventions targeted at improving patients' adjustment. PMID- 24801330 TI - 'Let's get wasted': A discourse analysis of teenagers' talk about binge drinking. AB - Teenage binge drinking is a significant health issue. To explore teenagers talk about binge drinking, four peer-group interviews were conducted with 20 teenagers, aged 16-18 years, with experience of excessive alcohol use. A discourse analysis showed that a 'drinking is cool' discourse constructed 'getting wasted' as an integral part of social life, while a 'drinking as a social lubricant' discourse described the behavioural functions of alcohol use. Participants also actively resisted an 'alcohol is bad' discourse, which acknowledges the risks of alcohol use. The findings illustrate how teenagers use these resources in sophisticated ways to position the teen drinker positively and negatively. PMID- 24801331 TI - HPV infections among MSM in Shenzhen, China. AB - BACKGROUND: An increasing incidence of anal cancer among men, especially men who have sex with men (MSM) suggests a need to better understand anal human papillomavirus (HPV) infection among this group. METHODS: A cross-sectional study was conducted among MSM in Shenzhen, China. Blood was collected for HIV serological testing and syphilis serological screening, and anal swabs were collected for HPV genotyping. Difference of HPV prevalence between HIV seropositive and HIV seronegative MSM was assessed by chi-square test. Factors associated with anal canal HPV infection were assessed by univariate and multivariate logistic regression. RESULTS: A total of 408 MSM were recruited. HIV and HPV prevalence were 6.9% and 36.4%, respectively. HPV was detected in the anal canal in 71.4% of the HIV-positive MSM and in 33.8% of the HIV-negative MSM (P<0.001). Oncogenic types were seen more often in anal specimens of HIV-positive MSM than in specimens of HIV-negative MSM (P = 0.001). The HPV genotypes detected most frequently were HPV06 (8.2%), HPV16 (7.2%), HPV11 (6.4%), HPV18 (4.7%), HPV58 (4.7%), and HPV52 (4.2%). CONCLUSIONS: In this study, HIV positive MSM had a higher burden of HPV infection, especially oncogenic HPV infection. HPV types 52 and 58 were as popular as those types designed for the currently available vaccine (HPV6, 11, 16, 18). PMID- 24801332 TI - It's how you make them feel! PMID- 24801333 TI - Toxin production and antibiotic resistances in Escherichia coli isolated from bathing areas along the coastline of the Oslo fjord. AB - The presence of enterovirulent and/or antibiotic resistant strains of Escherichia coli in recreational bathing waters would represent a clear health issue. In total, 144 E. coli isolated from 26 beaches along the inner Oslo fjord were examined for virulence determinants and resistance to clinically important antibiotics. No isolates possessed the genetic determinants associated with enterotoxigenic strains and none showed the prototypic sorbitol negative, O157:H7 phenotype. A small number (~1 %) produced alpha-hemolysin. Occurrences and patterns of antibiotic resistances were similar to those of E. coli isolated previously from environmental samples. In total, 6 % of the strains showed one or more clinically relevant resistances and 1.4 % were multi-drug resistant. Microarray analyses suggested that the resistance determinants were generally associated with mobile genetic elements. Resistant strains were not clonally related, and were, furthermore not concentrated at one or a few beach sites. This suggests that these strains are entering the waters at a low rate but in a widespread manner. The study demonstrates that resistant E. coli are present in coastal bathing waters where they can come into contact with bathers, and that the resistance determinants are potentially transferable. Some of the resistances registered in the study are to important antibiotics used in human medicine such as fluoroquinolones. The spread of antibiotic resistant genes, from the clinical setting to the environment, has clear implications with respect to the current management of bacterial infections and the long term value of antimicrobial therapy. The present study is the first of its kind in Norway. PMID- 24801334 TI - Mycobacterium hippocampi sp. nov., a rapidly growing scotochromogenic species isolated from a seahorse with tail rot. AB - A Gram-positive, aerobic, non-motile, non-sporulating, acid-fast, and rod-shaped bacterium (BFLP-6(T)), previously isolated from a seahorse (Hippocampus guttulatus) with tail rot, was studied using a polyphasic taxonomic approach. Growth occurred at 15-35 degrees C (optimum 25 degrees C), at pH 5.0-10.0 (optimum pH 7.0) and at NaCl concentrations between 0 and 6 % (w/v). The G+C content of DNA was 66.7 mol%. The predominant fatty acids were C(18:1) omega9c, C(16:0) and C(16:1) omega6c. A mycolic acid pattern of alpha-mycolates and keto mycolates was detected. Analysis of concatenated sequences (16S rRNA, rpoB, ssrA and tuf genes), and chemotaxonomic and phenotypic features indicated that strain BFLP-6(T) represents a novel species within the genus Mycobacterium, for which the name Mycobacterium hippocampi sp. nov. is proposed. The type strain is BFLP 6(T) (=DSM 45391(T) =LMG 25372(T)). PMID- 24801335 TI - Physiological responses of Pinus sylvestris var. mongolica seedlings to the interaction between Suillus luteus and Trichoderma virens. AB - The effects of the interaction between Suillus luteus (L.) Roussel and Trichoderma virens (J.H. Mill., Giddens & A.A. Foster) Arx on Pinus sylvestris var. mongolica Litv. were studied using plant physiology, mycorrhizal science, forest pathology, and biochemistry. Seedling growth and physiological parameters were determined, including the colonization rate of mycorrhizal fungi, biomass, root activity, photosynthetic pigment content, soluble protein content, antioxidant enzyme activities, rhizosphere soil enzyme activities, and protective enzyme activities. In addition, an optimal resistance system involving T. virens, mycorrhizal fungus (S. luteus), and P. sylvestris var. mongolica seedlings was constructed. Synergies between S. luteus and T. virens were observed, and most of the parameters of P. sylvestris var. mongolica seedlings inoculated with S. luteus 30 days + T. virens were higher than other treatments. After three months, when compared the control, the S. luteus 30 days + T. virens treatment gave increases in height (42.3 %); collar diameter (66.7 %); fresh weight (54 %); dry weight (50 %); soluble protein content (69.86 %); root activity (150 %); chlorophyll a (77.6 %); chlorophyll b (70.5 %); carotenoids (144 %); CAT activity (876.9 %); POD activity (268.3 %); SOD activity (66.18 %); beta-1,3-glucanase activity (125.8 %); chitinase activity (40 %); rhizosphere soil catalase activity (97.8 %); and phosphatase activity (266.7 %). These results indicate that there may be a stimulating factor between S. luteus and T. virens when they are inoculated together (S. luteus 30 days + T. virens). PMID- 24801336 TI - NTBC treatment of the pyomelanogenic Pseudomonas aeruginosa clinical isolate PA1111 inhibits pigment production and increases sensitivity to oxidative stress. AB - Pyomelanin is a brown/black extracellular pigment with antioxidant and iron acquisition properties that is produced by a number of different bacteria. Production of pyomelanin in Pseudomonas aeruginosa contributes to increased resistance to oxidative stress and persistence in chronic infections. We demonstrate that pyomelanin production can be inhibited by 2-[2-nitro-4 (trifluoromethyl) benzoyl]-1,3-cyclohexanedione (NTBC). This treatment increases sensitivity of pyomelanogenic P. aeruginosa strains to oxidative stress, without altering the growth rate or resistance to aminoglycosides. As such, NTBC has potential to function as an anti-virulence factor in treating pyomelanogenic bacterial infections. PMID- 24801337 TI - Antiproliferative, antifungal, and antibacterial activities of endophytic alternaria species from cupressaceae. AB - Recent research has shown the bioprospecting of endophytic fungi from Cupressaceae. Here, we further uncover that the healthy cypress plants such as Cupressus arizonica, Cupressus sempervirens var. cereiformis, and Thuja orientalis host highly bioactive endophytic Alternaria fungal species. Indeed, endophytic Alternaria alternata, Alternaria pellucida, and Alternaria tangelonis were recovered from healthy Cupressaceous trees. Biodiversity and bioactivity of recovered endophytic Alternaria species were a matter of biogeography and host identity. We further extracted such Alternaria's metabolites and highlighted their significant antiproliferative, growth inhibitory, and antibacterial activities against the model target fungus Pyricularia oryzae and the model pathogenic bacteria Bacillus sp., Erwinia amylovora, and Pseudomonas syringae. In vitro assays also indicated that endophytic Alternaria species significantly inhibited the growth of cypress fungal phytopathogens Diplodia seriata, Phaeobotryon cupressi, and Spencermartinsia viticola. In conclusion, since the recovered Alternaria species were originally reported as pathogenic and allergenic fungi, our findings suggest a possible ecological niche for them inside the foliar tissues of Cupressaceous trees. Moreover, in this study, the significant bioactivities of endophytic Alternaria species in association with Cupressaceae plant family are reported. PMID- 24801338 TI - The frozen elephant trunk technique for acute type A aortic dissection: results from 15 years of experience?. AB - OBJECTIVES: We aimed to evaluate the long-term prognosis of prophylactic repair of the descending aorta using the frozen elephant trunk (FET) technique for acute type A aortic dissection (AAAD). METHODS: Between 1997 and 2012, 120 consecutive patients (mean age: 64.4 +/- 10.9 years) underwent total arch replacement with FET for AAAD; 36 patients had an entry at the descending aorta, 68 patients were aged <70 years and 8 patients had Marfan's syndrome. With regard to preoperative morbidity, 23 patients had stroke, 10 had coronary ischaemia and 9 had visceral ischaemia. During intraoperative measurement, the required size and length of the stent graft were determined and inserted under transoesophageal echographic guidance. RESULTS: Seven patients (6%) died in the hospital. Four (3%) cases of stroke and 2 (2%) with spinal cord injuries were noted. Computed tomography prior to discharge indicated complete thrombosis of the false lumen by the stent graft in 113 patients, with a mean diameter of 26.0 +/- 2.5 mm before discharge and 27.5 +/- 2.5 mm at 1 year postoperatively compared with a mean stent graft diameter of 27.8 +/- 1.7 mm. During the long-term follow-up (mean period: 104.6 +/- 51.9 months), 12 patients died of non-aortic events and 5 distal aortic reoperations were required using endovascular stent grafting of the descending aorta, including 1 case with new tear formation. None of the patients had a patent false lumen on the stent graft at the final follow-up. The 10-year survival rate was 75% and the overall 10-year reoperation-free rate on the thoracic aorta was 93%. CONCLUSIONS: The FET technique results in excellent aortic remodelling of the downstream aorta and can improve the long-term outcomes for AAAD. PMID- 24801339 TI - Long-term outcomes of transatrial-transpulmonary repair of tetralogy of Fallot. AB - OBJECTIVES: The surgical approach to repair of tetralogy of Fallot (ToF) has shifted over the years. We aimed to report the long-term follow-up after ToF repair with the transatrial-transpulmonary approach and to determine predictors of long-term outcomes. METHODS: Retrospective analysis of patients operated on in two tertiary referral centres. Primary outcome measures were: death, pulmonary valve replacement (PVR), reintervention for other reasons, internal cardiodefibrillator and/or pacemaker placement. Kaplan-Meier assessment of overall and event-free survival as well as uni- and multivariate analyses of risk factors for outcomes were performed. RESULTS: Four hundred and fifty-three patients were included. Median age at operation was: 0.6 years (range 0-19.6) and median age at the last follow-up was 14.3 years (range 0.1-42.1). Median age at repair decreased from 1.2 years (range 0.6-5.8) (1970-80) to 0.3 years (range 0 4.7) (2000-12). A transannular patch (TP) was used in 65% of all patients. The use of a TP showed a decline from 89% in the initial years of the cohort to 64% in 2000-12. Early mortality was 1.1% (5 patients) for the entire cohort and late mortality 2.4% (11 patients). Overall survival for the entire cohort was 97.3% (95% CI 95.7-98.8) and 91.8% (95% CI 85.9-97.7) at 10 and 25 years, respectively. For patients with a TP (n = 294) vs non-TP (n = 159), this was 97.2% (95% CI 95.2 99.2) vs 97.5% (95% CI 95.1-99.9) at 10-year and 91.0% (95% CI 83.9-98.1) vs 96.3% (95% CI 93.0-99.6) at 25-year follow-up (P = 0.958). Fifty-two patients underwent PVR, and in 5 a pacemaker was inserted. Event-free survival for TP versus non-TP patients was 80.2% (95 CI% 75.5-84.9) vs 81.7% (95% CI 75.2-88.2) at 10-year and 27.9% (95% CI 17.7-38.1) vs 78.5% (95% CI 71.4-85.6) at 25-year follow-up (P = 0.016). In multivariate analysis, both the use of a TP (HR 1.705, 95% CI 1.023-2.842) and the year of surgical repair of tetralogy of Fallot (HR 1.039, 95% CI 1.006-1.073) were associated with a higher probability of an event. CONCLUSIONS: ToF patients corrected with the transatrial-transpulmonary approach have good long-term survival. PVR is a frequent event at longer follow-up, and other events are limited. The use of a TP is a predictor for poorer event-free outcomes, increasing the risk of the composite endpoint 1.7 times. PMID- 24801340 TI - Left ventricular surgical remodelling: is it a matter of shape or volume?. AB - OBJECTIVE: Left ventricular surgical remodelling (LVSR) can be targeted to volume reduction (VR), (independently of the final shape) or to conical shape (CS). The aim of this study was to evaluate the long-term clinical and echocardiographic results of these two surgical strategies. METHODS: From January 1988 to December 2012, 401 patients underwent LVSR: 107 in Group VR (1988-2001) and 294 in Group CS (1998-2012). The latter group of patients had lower ejection fraction (EF) and higher mitral and tricuspid regurgitation grade, with higher incidence of pulmonary hypertension. A propensity score model was built to adjust long-term results for preoperative and operative profiles. RESULTS: Thirty-day mortality was 6.0%. Median follow-up interval time was 100 (3-300) months. Overall 20-year and event-free survival were 36.1 +/- 7.8 and 19.4 +/- 7.2, respectively. No differences were found regarding 10-year survival (Group VR: 55.1 +/- 4.8 vs Group CS: 64.2 +/- 4.2, P = 0.16) and event-free survival (Group VR: 41.1 +/- 4.8 vs Group CS: 50.5 +/- 4.8, P = 0.12). However, Group CS provided better 10-year freedom from cardiac deaths (74.5 +/- 3.7 vs 60.4 +/- 4.8, P = 0.03) and from cardiac events (55.6 +/- 5.0 vs 45.0 +/- 4.9, P = 0.04). After propensity score adjustment, all the main outcomes were significantly better in Group CS. Multivariate Cox analysis confirmed this result; furthermore, to avoid any bias related to improved experience, 30-day mortality being higher in Group VR, we excluded the first month from Cox analysis: left ventricle VR (independently of the final shape) was still confirmed as the wrong approach. At the follow-up, Group CS showed significant improvement in EF (+18 vs +8%), end-systolic volume index (-35 vs -20%) and sphericity index (-6 vs +9%). CONCLUSIONS: LVSR should aim to provide a more physiological shape (conical) rather than simple VR. PMID- 24801341 TI - Control of transposable elements in Arabidopsis thaliana. AB - Arabidopsis thaliana serves as a very good model organism to investigate the control of transposable elements (TEs) by genetic and genomic approaches. As TE movements are potentially deleterious to the hosts, hosts silence TEs by epigenetic mechanisms, such as DNA methylation. DNA methylation is controlled by DNA methyltransferases and other regulators, including histone modifiers and chromatin remodelers. RNAi machinery directs DNA methylation to euchromatic TEs, which is under developmental control. In addition to the epigenetic controls, some TEs are controlled by environmental factors. TEs often affect expression of nearby genes, providing evolutionary sources for epigenetic, developmental, and environmental gene controls, which could even be beneficial for the host. PMID- 24801342 TI - Diversity and evolution of transposable elements in Arabidopsis. AB - Transposable elements are mobile genetic elements that have successfully populated eukaryotic genomes and show diversity in their structure and transposition mechanisms. Although first viewed solely as selfish, transposable elements are now known as important vectors to drive the adaptation and evolution of their host genome. Transposable elements can affect host gene structures, gene copy number, gene expression, and even as a source for novel genes. For example, a number of transposable element sequences have been co-opted to contribute to evolutionary innovation, such as the mammalian placenta and the vertebrate immune system. In plants, the need to adapt rapidly to changing environmental conditions is essential and is reflected, as will be discussed, by genome plasticity and an abundance of diverse, active transposon families. This review focuses on transposable elements in plants, particularly those that have beneficial effects on the host. We also emphasize the importance of having proper tools to annotate and classify transposons to better understand their biology. PMID- 24801343 TI - The plant LINC complex at the nuclear envelope. AB - Significant advances in understanding the plant nuclear envelope have been made over the past few years; indeed, knowledge of the protein network at the nuclear envelope is rapidly growing. One such network, the linker of nucleoskeleton and cytoskeleton (LINC) complex, is known in animals to connect chromatin to the cytoskeleton through the nuclear envelope. The LINC complex is made of Sad1/Unc84 (SUN) and Klarsicht/Anc1/Syne1 homology (KASH) proteins which have been recently characterized in plants. SUN proteins are located within the inner nuclear membrane, while the KASH proteins are included into the outer nuclear membrane. SUN and KASH domains interact and bridge the two nuclear membranes. In Arabidopsis, KASH proteins also interact with the tryptophan-proline-proline (WPP) domain-interacting tail-anchored protein 1 (WIT1), associated with the nuclear pore complex and with myosin XI-i which directly interacts with the actin cytoskeleton. Although evidence for a plant LINC complex connecting the nucleus to the cytoskeleton is growing, its interaction with chromatin is still unknown, but knowledge gained from animal models strongly suggests its existence in plants. Possible functions of the plant LINC complex in cell division, nuclear shape, and chromatin organization are discussed. PMID- 24801344 TI - Genomic variation in Arabidopsis: tools and insights from next-generation sequencing. AB - The release of a reference genome for Arabidopsis thaliana in 2000 has been an enormous boon for the study of plant genetics. Less than a decade later, however, a revolution in sequencing technology had enabled rapid and inexpensive re sequencing of whole A. thaliana genomes. Large-scale efforts to characterize natural genomic variation in A. thaliana have revealed remarkable intra-specific variation in this species, ranging from single-nucleotide differences to large structural rearrangements. The partitioning of this variation by geography and local adaptation has been described using powerful new methods and tools. Simultaneously, an ambitious research agenda has emerged to sequence 1001 A. thaliana lines from around the world, while sequencing of related species is enabling powerful evolutionary genomic analyses. In this review, I summarize recent progress in genomic analysis of natural variation in A. thaliana and its close relatives. This progress has set the stage for the emergence of Arabidopsis as a model genus for evolutionary and functional genomics. PMID- 24801346 TI - Technological preferences of aging cancer patients for delivery services and devices to solve drug-related problems in oncology. AB - AIM: To identify the technological preferences of aging cancer patients with regard to the delivery services and devices for preventing/solving three common drug-related problems (DRPs): medication nonadherence, lack of knowledge in medications, and side effects management. METHODS: A survey was conducted at a cancer center from May to August 2011. Delivery services included in the interviewer-administered questionnaire included voice-activated dispensing, voice reminders, electronic messages, helplines, and mobile phone applications, among others. Three devices were proposed-watches, bracelets, and mobile phones. Descriptive statistics and chi-square tests were performed. RESULTS: A total of 361 surveys were analyzed. Median age of respondents was 61 years. The majority of respondents were female (57.3 %), Chinese (88.9 %), and 65 years and younger (73.4 %). More than half (59.0-63.2 %) were receptive to the use of the delivery services. Patients preferred voice reminder alerts (28.0 %) and electronic messages (17.7 %) to help with their medication nonadherence, and helplines for medications (52.6 %) and side effects management (47.4 %). Higher educated patients were more likely to want delivery services to improve their medication adherence (p = 0.045) and knowledge in medications management (p = 0.050). Middle age patients (age 50-65) were also more likely to want delivery services for the latter DRP (p = 0.009). Among those who wanted delivery services, most preferred mobile phones. CONCLUSION: Middle age and elderly cancer patients are accepting of delivery services to help them with their DRPs. With middle aged patients being more receptive of the delivery services, technology can potentially play an important role in minimizing DRPs. PMID- 24801345 TI - Centromeres and kinetochores of Brassicaceae. AB - The centromere-the primary constriction of monocentric chromosomes-is essential for correct segregation of chromosomes during mitosis and meiosis. Centromeric DNA varies between different organisms in sequence composition and extension. The main components of centromeric and pericentromeric DNA of Brassicaceae species are centromeric satellite repeats. Centromeric DNA initiates assembly of the kinetochore, the large protein complex where the spindle fibers attach during nuclear division to pull sister chromatids apart. Kinetochore assembly is initiated by incorporation of the centromeric histone H3 cenH3 into centromeric nucleosomes. The spindle assembly checkpoint acts during mitosis and meiosis at centromeres and maintains genome stability by preventing chromosome segregation before all kinetochores are correctly attached to microtubules. The function of the spindle assembly checkpoint in plants is still poorly understood. Here, we review recent advances of studies on structure and functional importance of centromeric DNA of Brassicaceae, assembly and function of cenH3 in Arabidopsis thaliana and characterization of core SAC proteins of A. thaliana in comparison with non-plant homologues. PMID- 24801347 TI - Low-level laser therapy for osteonecrotic lesions: effects on osteoblasts treated with zoledronic acid. AB - PURPOSE: Clinical studies have shown that low-level laser therapy (LLLT) can improve local tissue healing of bisphosphonate-induced osteonecrosis of the jaw. However, the effects of laser irradiation on bisphosphonate-treated osteoblasts have not been completely elucidated. METHODS: Human osteoblasts were cultured in plain culture medium (DMEM). After 48 h, plain DMEM was replaced by DMEM with no fetal bovine serum, for a 24-h incubation followed by addition of zoledronic acid (5 MUM) for additional 48 h. Cells were subjected to LLLT (InGaAsP; 780 +/- 3 nm; 0.025 W) at 0.5, 1.5, 3, 5, and 7 J/cm(2), three times every 24 h. Cell viability, total protein production, alkaline phosphatase activity (ALP), mineral nodule formation, gene expression of collagen type I and ALP, and cell morphology were evaluated. RESULTS: LLLT at 0.5 J/cm(2) increased cell viability of cultured osteoblasts. ALP activity and gene expression, in addition to mineral nodule formation and Col-I gene expression, were not increased by LLLT. LLLT applied to ZA-treated cells increased Col-I expression at 0.5, 1.5, and 3 J/cm(2) but did not improve any other cell activity assessed. CONCLUSION: LLLT showed limited effects on bisphosphonate-treated osteoblasts. PMID- 24801348 TI - Mandatory consultation for palliative sedation? Reflections on Koper et al. PMID- 24801349 TI - Interleukin 17-producing gammadeltaT cells promote hepatic regeneration in mice. AB - BACKGROUND & AIMS: Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. gammadeltaT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of gammadeltaT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor delta chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1). METHODS: We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd(-/-), or Clec7a(-/-) mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. gammadeltaT cells were purified by fluorescence-activated cell sorting. RESULTS: In mice, partial hepatectomy up-regulated expression of CCL20 and ligands of Dectin-1, which was associated with recruitment and activation of gammadeltaT cells and their increased production of interleukin (IL)-17 family cytokines. Recruited gammadeltaT cells induced production of IL-6 by antigen presenting cells and suppressed expression of interferon gamma by natural killer T cells, promoting hepatocyte proliferation. Absence of IL-17-producing gammadeltaT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL-17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that gammadeltaT cells are required for inflammatory responses mediated by IL-17 and Dectin-1. CONCLUSIONS: gammadeltaT cells regulate hepatic regeneration by producing IL-22 and IL-17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for gammadeltaT cells to promote hepatic regeneration. PMID- 24801351 TI - Combined study of biphasic and zero-order release formulations with dissolution tests and ATR-FTIR spectroscopic imaging. AB - In this study of multi-layer tablets, the dissolution of biphasic and zero-order release formulations has been studied primarily using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging as well as UV-Vis detection of dissolved drug in the effluent stream and USP dissolution testing. Bilayer tablets, containing the excipients microcrystalline cellulose (MCC) and glucose, were used for biphasic release with nicotinamide and buflomedil as model drugs. ATR-FTIR spectroscopic imaging showed the changing component distributions during dissolution. Further experiments studied monolithic and barrier-layered tablets containing hydroxypropyl methylcellulose, MCC and buflomedil dissolving in a USP I apparatus. These data were compared with UV-Vis dissolution profiles obtained online with the ATR flow-through cell. ATR-FTIR imaging data of the biphasic formulations demonstrated that the drug release was affected by excipient ratios and effects such as interference between tablet sections. Tablets placed in the ATR-FTIR flow-through cell exhibited zero-order UV-Vis dissolution profile data at high flow rates, similar to barrier-layered formulations studied using the USP I apparatus. ATR-FTIR spectroscopic imaging provided information regarding the dissolution mechanisms in multi-layer tablets which could assist formulation development. The ability to relate data from USP dissolution tests with that from the ATR-FTIR flow-through cell could help spectroscopic imaging complement dissolution methods used in the industry. PMID- 24801350 TI - Successful management of benign biliary strictures with fully covered self expanding metal stents. AB - BACKGROUND & AIMS: Fully covered self-expanding metal stents (FCSEMS) are gaining acceptance for the treatment of benign biliary strictures. We performed a large prospective multinational study to study the ability to remove these stents after extended indwell and the frequency and durability of stricture resolution. METHODS: In a nonrandomized study at 13 centers in 11 countries, 187 patients with benign biliary strictures received FCSEMS. Removal was scheduled at 10-12 months for patients with chronic pancreatitis or cholecystectomy and at 4-6 months for patients who received liver transplants. The primary outcome measure was removal success, defined as either scheduled endoscopic removal of the stent with no removal-related serious adverse events or spontaneous stent passage without the need for immediate restenting. RESULTS: Endoscopic removal of FCSEMS was not performed for 10 patients because of death (from unrelated causes), withdrawal of consent, or switch to palliative treatment. For the remaining 177 patients, removal success was accomplished in 74.6% (95% confidence interval [CI], 67.5%-80.8%). Removal success was more frequent in the chronic pancreatitis group (80.5%) than in the liver transplantation (63.4%) or cholecystectomy (61.1%) groups (P = .017). FCSEMS were removed by endoscopy from all patients in whom this procedure was attempted. Stricture resolution without restenting upon FCSEMS removal occurred in 76.3% of patients (95% CI, 69.3%-82.3%). The rate of resolution was lower in patients with FCSEMS migration (odds ratio, 0.22; 95% CI, 0.11-0.46). Over a median follow-up period of 20.3 months (interquartile range, 12.9-24.3 mo), the rate of stricture recurrence was 14.8% (95% CI, 8.2%-20.9%). Stent- or removal-related serious adverse events, most often cholangitis, occurred in 27.3% of patients. There was no stent- or removal-related mortality. CONCLUSIONS: In a large prospective multinational study, removal success of FCSEMS after extended indwell and stricture resolution were achieved for approximately 75% of patients. ClincialTrials.gov number, NCT01014390. PMID- 24801352 TI - Improved subspace estimation for low-rank model-based accelerated cardiac imaging. AB - Sparse sampling methods have emerged as effective tools to accelerate cardiac magnetic resonance imaging (MRI).Low-rank model-based cardiac imaging uses a predetermined temporal subspace for image reconstruction from highly undersampled (k, t)-space data and has been demonstrated effective for high-speed cardiac MRI. The accuracy of the temporal subspace isa key factor in these methods, yet little work has been published on data acquisition strategies to improve subspace estimation. This paper investigates the use of non-Cartesian k-space trajectories to replace the Cartesian trajectories that are omnipresent but are highly sensitive to readout direction. We also propose "self-navigated" pulse sequences that collect both navigator data (for determining the temporal subspace) and imaging data after every RF pulse, allowing for even greater acceleration. We investigate subspace estimation strategies through analysis of phantom images and demonstrate in vivo cardiac imaging in rats and mice without the use of ECG or respiratory gating. The proposed methods achieved 3-D imaging of wall motion, first-pass myocardial perfusion, and late gadolinium enhancement in rats at 74 frames/s,as well as 2-D imaging of wall motion in mice at 97 frames/s. PMID- 24801353 TI - Development and validation of a clinical scoring system for predicting risk of HCC in asymptomatic individuals seropositive for anti-HCV antibodies. AB - BACKGROUND: The development of a risk assessment tool for long-term hepatocellular carcinoma risk would be helpful in identifying high-risk patients and providing information of clinical consultation. METHODS: The model derivation and validation cohorts consisted of 975 and 572 anti-HCV seropositives, respectively. The model included age, alanine aminotransferase (ALT), the ratio of aspirate aminotransferase to ALT, serum HCV RNA levels and cirrhosis status and HCV genotype. Two risk prediction models were developed: one was for all-anti HCV seropositives, and the other was for anti-HCV seropositives with detectable HCV RNA. The Cox's proportional hazards models were utilized to estimate regression coefficients of HCC risk predictors to derive risk scores. The cumulative HCC risks in the validation cohort were estimated by Kaplan-Meier methods. The area under receiver operating curve (AUROC) was used to evaluate the performance of the risk models. RESULTS: All predictors were significantly associated with HCC. The summary risk scores of two models derived from the derivation cohort had predictability of HCC risk in the validation cohort. The summary risk score of the two risk prediction models clearly divided the validation cohort into three groups (p<0.001). The AUROC for predicting 5-year HCC risk in the validation cohort was satisfactory for the two models, with 0.73 and 0.70, respectively. CONCLUSION: Scoring systems for predicting HCC risk of HCV-infected patients had good validity and discrimination capability, which may triage patients for alternative management strategies. PMID- 24801355 TI - Design of weak-donor alkyl-functionalized push-pull pyrene dyes exhibiting enhanced fluorescence quantum yields and unique on/off switching properties. AB - We designed, synthesized, and evaluated environmentally responsive solvatochromic fluorescent dyes by incorporating weak push-pull moieties. The quantum yields of the push (alkyl)-pull (formyl) pyrene dyes were dramatically enhanced by the introduction of alkyl groups into formylpyrene (1-formylpyrene: Phi(F) =0.10; 3,6,8-tri-n-butyl-1-formylpyrene: Phi(F) =0.90; in MeOH). The new dyes exhibited unique sensitivity to solvent polarity and hydrogen-bond donor ability, and specific fluorescence turn-on/off properties (e.g., 3,6,8-tri-n-butyl-1 formylpyrene: Phi(F) =0.004, 0.80, 0.37, and 0.90 in hexane, chloroform, DMSO, and MeOH, respectively). Here, the alkyl groups act as weak donors to suppress intersystem crossing by destabilizing the HOMOs of 1-formylpyrene while maintaining weak intramolecular charge-transfer properties. By using alkyl groups as weak donors, environmentally responsive, and in particular, pH-responsive fluorescent materials may be developed in the future. PMID- 24801354 TI - Usefulness of dynamic MRI enhancement measures for the diagnosis of ACTH producing pituitary adenomas. AB - PURPOSE: The distinction between corticotropin (ACTH)-producing pituitary adenomas and occult ectopic ACTH neoplasms is a challenge and frequently complicated by the detection of nonfunctioning pituitary adenomas on dynamic magnetic resonance imaging (DMRI). Herein, we explored quantitative differences in DMRI measures from ACTH-producing pituitary adenomas. MATERIALS AND METHODS: Fifty-five patients with pathology confirmed ACTH-producing and 44 with nonfunctioning pituitary adenomas were analysed in this retrospective pilot study. The intensities of adenomas and of adjacent pituitary tissue were measured by drawing a region of interest. Time-intensity curves were then constructed, and quantitative analysis included: enhancement time, enhancement peak and prepeak slope (PPS). Multivariable logistic analysis and receiver operating characteristic curves (ROC) were used to evaluate the parameters. RESULTS: Quantitative analysis showed that tumour PPS in ACTH-producing adenomas was markedly lower than that in nonfunctioning adenomas (P = 0.0042) and that the PPS of the adjacent pituitary gland was not different (P = 0.2441). The PPS was >3.0 in 59.1% of nonfunctioning adenomas and <=3.0 in 69.1% of ACTH-producing adenomas (P = 0.0049). Logistic analysis revealed lower tumour PPS levels (P = 0.0123, OR 1.24, 95% CI: 1.05-1.52) were associated with ACTH-producing adenomas. The optimal PPS cut-off determined by ROC analysis was 2.89, with a sensitivity of 69% and specificity of 70%. No significant difference was found between the two groups in enhancement time or enhancement peak. CONCLUSION: Enhancement parameters in DMRI can help distinguishing ACTH producing from nonfunctioning pituitary adenomas, which could be useful in the differential diagnosis between ACTH-producing pituitary adenomas and ectopic ACTH syndrome complicated with nonfunctioning pituitary adenoma. PMID- 24801356 TI - Acidic-pH-activatable fluorescence probes for visualizing exocytosis dynamics. AB - Live imaging of exocytosis dynamics is crucial for a precise spatiotemporal understanding of secretion phenomena, but current approaches have serious limitations. We designed and synthesized small-molecular fluorescent probes that were chemically optimized for sensing acidic intravesicular pH values, and established that they can be used to sensitively and reliably visualize vesicular dynamics following stimulation. This straightforward technique for the visualization of exocytosis as well as endocytosis/reacidification processes with high spatiotemporal precision is expected to be a powerful tool for investigating dynamic cellular phenomena involving changes in the pH value. PMID- 24801357 TI - Crystal plane-dependent gas-sensing properties of zinc oxide nanostructures: experimental and theoretical studies. AB - The sensitivity of a metal oxide gas sensor is strongly dependent on the nature of the crystal surface exposed to the gas species. In this study, two types of zinc oxide (ZnO) nanostructures: nanoplates and nanorods with exposed (0001) and (1010) crystal surfaces, respectively, were synthesized through facile solvothermal methods. The gas-sensing results show that sensitivity of the ZnO nanoplates toward ethanol is two times higher than that of the ZnO nanorods, at an optimum operating temperature of 300 degrees C. This could be attributed to the higher surface area and the exposed (0001) crystal surfaces. DFT (Density Functional Theory) simulations were carried out to study the adsorption of ethanol on the ZnO crystal planes such as (0001), (1010), and (1120) with adsorbed O(-) ions. The results reveal that the exposed (0001) planes of the ZnO nanoplates promote better ethanol adsorption by interacting with the surface oxygen p (O2p) orbitals and stretching the O-H bond to lower the adsorption energy, leading to the sensitivity enhancement of the nanoplates. These findings will be useful for the fabrication of metal oxide nanostructures with specifically exposed crystal surfaces for improved gas-sensing and/or catalytic performance. PMID- 24801358 TI - Ruptured extratesticular epidermal inclusion cyst mimicking polyorchidism with torsion on sonography. AB - The sonographic appearance of epidermal inclusion cysts varies in accordance with the contents of the cyst, ranging from an anechoic lesion to a hyperechoic solid appearing mass. Supernumerary testes are an uncommon congenital abnormality, in which more than two testes are present. We present a rare case of a ruptured scrotal extratesticular epidermal inclusion cyst, which had the sonographic appearance of a supernumerary testicle with torsion. PMID- 24801359 TI - The usefulness of Neisseria gonorrhoeae strain typing by Pulse-Field Gel Electrophoresis (PFGE) and DNA detection as the forensic evidence in child sexual abuse cases: a case series. AB - Diagnosis of alleged child sexual abuse can be made from history in conjunction with physical examination, psychosocial evaluation, and laboratory investigations. Sexually transmitted infection associated with sexual abuse is found in 5 % of the victims, with Neisseria gonorrhoeae being the most common organism. Identification of sexually transmitted disease, particularly N. gonorrhoeae infection, can be useful for the diagnosis of sexual abuse and thus, the initiation of the child protection process. Polymerase Chain Reaction (PCR) is a newer diagnostic assay with a higher sensitivity compared with conventional culture method. In addition, N. gonorrhoeae strain typing can also be used to identify the abuser. In this case series, we present the application of N. gonorrhoeae strain typing (PFGE technique) to identify the abuser, and the confirmation of gonococcal vaginitis by PCR technique. PMID- 24801360 TI - Classifying stages of third molar development: crown length as a predictor for the mature root length. AB - Multiple tooth development staging techniques were reported based on arbitrarily set borderlines between succeeding stages. Anatomic tooth features or predictions of future tooth part dimensions were described to identify the thresholds between the established stages. The need to predict mature tooth dimensions, while the tooth considered is still in development, is a drawback to use this staging technique for dental age estimations. Using the fully mature crown length as a predictor for the future root length could provide a tool for undisputable staging. The aim of this study was first to measure the crown and root length of fully mature third molars and second to investigate whether the crown length could be used as a predictor of the root length, in order to classify the observed root length as a proportion of the future mature root. The crown and root lengths of all present third molars were digitally measured on dental panoramic radiographs of 1,000 subjects. The included subjects were equally distributed in gender, and their age ranged between 22 and 40 years. Two occlusal borders, the cement enamel junction and the root apices, were defined as landmarks for standardized measurements. Regression models with root length as response and crown length as predictor were established and revealed low R (2) and high RMSE values. Due to the small explained variance by the prediction models and the high variation in prediction errors, the observed crown length cannot be used to predict the final root length of a developing third molar. PMID- 24801361 TI - Accuracy of bedside glucometry in critically ill children with peripheral hypoperfusion. AB - The accuracy of glucose test strip in critically care has been questioned. We investigated the accuracy of glucose test strip in critically ill children. Patients, aged from 1 month to 18 years admitted in pediatric intensive care unit. Demographic data, hemodynamic parameters, and perfusion index (PI) were recorded. Glucose test strips were performed from finger stick blood [capillary blood glucose (CBG)] and from whole blood [whole blood glucose (WBG)] along with laboratory plasma blood glucose (PBG) from either arterial or venous blood samples. The accuracy of glucose test strips was defined according to ISO 15197 and Clarke error grid (CEG). One hundred and eighty one blood samplings including 117 arterial blood (CBG, WBGa, PBGa) and 64 venous blood (CBG, WBGv, PBGv) were obtained. The accuracy of WBGa was 98.3 and 95.2% when compared to the accuracy of CBG (88.7 and 83.3%. The accuracy of WBGv was 92.2% and 87.0 when compared to the accuracy of CBG which was 79.7 and 72.9% (ISO 15197: 2003 and 2013, respectively). Bland-Altman plot demonstrated bias and precision of 7.4+/-17.7 mg/dL in acceptable PI group compared to 30.2+/-23.4 mg/dL in low PI group (PI<=0.3). The CBG test strip must be interpreted carefully in critically ill children. A low PI was associated with poor CBG strip accuracy. WBG test strip from arterial blood was more appropriate for glucose monitoring in children with peripheral hypoperfusion. PMID- 24801362 TI - Beta (beta)-antithrombin activity in children and adults: implications for heparin therapy in infants and children. AB - BACKGROUND: Antithrombin, a hemostatic protein and naturally occurring anticoagulant, is a major thrombin inhibitor. The capacity of antithrombin to inhibit thrombin is known to increase a 1000-fold whilst in the presence of unfractionated heparin. beta-antithrombin is an isoform of antithrombin with a high affinity for unfractionated heparin. This study aimed to determine the differences in the anticoagulant activity of the beta-antithrombin isoform in children compared with adults. METHODS: Plasma samples were obtained from 105 healthy individuals from the following age groups: neonates (day 1 and day 3), 28 days to 1 year, 1-5 years, 6-10 years, 11-16 years and adults. The method utilized to measure the activity of beta-antithrombin in plasma is a modified version of the total antithrombin assay routinely used in diagnostic laboratories. The modified version of this assay allows for the specific quantification of the beta-antithrombin glycoform anticoagulant activity alone, as the beta-antithrombin molecule is activated under a high salt concentration, which in turn does not allow activation of other antithrombin isoforms. CONCLUSIONS: This study demonstrated that there are no age-specific differences in the activity of beta-antithrombin. However, considering that the total AT activity is significantly reduced in neonates, our results suggest that in this population beta-antithrombin activity is a major contributor to the overall activity of AT. PMID- 24801363 TI - X-ray phase contrast with injected gas for tumor microangiography. AB - We show that the microvasculature of mouse tumors can be visualized using propagation-based phase-contrast x-ray imaging with gas as the contrast agent. The large density difference over the gas-tissue interface provides high contrast, allowing the imaging of small-diameter blood vessels with relatively short exposure times and low dose using a compact liquid-metal-jet x-ray source. The method investigated is applied to tumors (E1A/Ras-transformed mouse embryonic fibroblasts) grown in mouse ears, demonstrating sub-15-um-diameter imaging of their blood vessels. The exposure time for a 2D projection image is a few seconds and a full tomographic 3D map takes some minutes. The method relies on the strength of the vasculature to withstand the gas pressure. Given that tumor vessels are known to be more fragile than normal vessels, we investigate the tolerance of the vasculature of 12 tumors to gas injection and find that a majority withstand 200 mbar pressures, enough to fill 12-um-diameter vessels with gas. A comparison of the elasticity of tumorous and non-tumorous vessels supports the assumption of tumor vessels being more fragile. Finally, we conclude that the method has the potential to be extended to the imaging of 15 um vessels in thick tissue, including mouse imaging, making it of interest for, e.g., angiogenesis research. PMID- 24801364 TI - Biorefinery concept in a microalgae pilot plant. Culturing, dynamic filtration and steam explosion fractionation. AB - A 53 m(3) microalgae pilot plant with semi-closed photobioreactors has been operated in batch mode at Tarragona, where proper climatic conditions exist. Operations carried-out were microalgae culturing, concentration, cell disruption and lipid extraction. Culturing was performed with and without CO2 fertilization. pH was used to control CO2 dosing. With CO2 fertilization best microalgae concentrations were obtained. Productivities up to 19.9 g/m(2)/day were reached. Although sedimentation and centrifugation was performed, studies focused on dynamic membrane filtration as improved technique compared with conventional one. Significant fouling reduction was obtained by using a vibrational membrane setup. Cell disruption including product pre-extraction was performed by using steam explosion at moderate conditions, as novel technique for this application. Lipid extraction was performed by using conventional techniques with and without exploded material. The amount of lipids obtained from exploded material was higher than with non-exploded material, which shows that steam explosion provides a clear enhancement. PMID- 24801365 TI - Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. AB - Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations. PMID- 24801366 TI - Genetic dissection of drought and heat tolerance in chickpea through genome-wide and candidate gene-based association mapping approaches. AB - To understand the genetic basis of tolerance to drought and heat stresses in chickpea, a comprehensive association mapping approach has been undertaken. Phenotypic data were generated on the reference set (300 accessions, including 211 mini-core collection accessions) for drought tolerance related root traits, heat tolerance, yield and yield component traits from 1-7 seasons and 1-3 locations in India (Patancheru, Kanpur, Bangalore) and three locations in Africa (Nairobi, Egerton in Kenya and Debre Zeit in Ethiopia). Diversity Array Technology (DArT) markers equally distributed across chickpea genome were used to determine population structure and three sub-populations were identified using admixture model in STRUCTURE. The pairwise linkage disequilibrium (LD) estimated using the squared-allele frequency correlations (r2; when r2<0.20) was found to decay rapidly with the genetic distance of 5 cM. For establishing marker-trait associations (MTAs), both genome-wide and candidate gene-sequencing based association mapping approaches were conducted using 1,872 markers (1,072 DArTs, 651 single nucleotide polymorphisms [SNPs], 113 gene-based SNPs and 36 simple sequence repeats [SSRs]) and phenotyping data mentioned above employing mixed linear model (MLM) analysis with optimum compression with P3D method and kinship matrix. As a result, 312 significant MTAs were identified and a maximum number of MTAs (70) was identified for 100-seed weight. A total of 18 SNPs from 5 genes (ERECTA, 11 SNPs; ASR, 4 SNPs; DREB, 1 SNP; CAP2 promoter, 1 SNP and AMDH, 1SNP) were significantly associated with different traits. This study provides significant MTAs for drought and heat tolerance in chickpea that can be used, after validation, in molecular breeding for developing superior varieties with enhanced drought and heat tolerance. PMID- 24801367 TI - A candidate gene approach for identifying differential iron responses in young overweight women to an energy-restricted haem iron-rich diet. AB - Although iron deficiency is common in women especially during dieting, weight management trials rarely examine the longitudinal impact of genetics on iron. This study examined the associations between the TMPRSS6 rs855791 polymorphism and iron indices at baseline and after a 12-month trial comparing two weight loss diets (higher-protein, higher-haem iron (HPHI) vs lower-protein, lower-haem iron (LPLI)). A total of 76 young overweight women (18-25y; BMI?27.5 kg/m(2)) were included at baseline, with 27 (HPHI: n=15; LPLI: n=12) completing the 12-month trial. At baseline, C allele homozygotes exhibited higher serum iron (P=0.047) and lower hepcidin (P=0.023) compared with T allele carriers. After 12 months, no genotypic differences were observed for ferritin and soluble transferrin receptor, although C homozygotes on HPHI showed higher serum iron and transferrin saturation (P<0.05). Results indicate that rs855791 can influence iron metabolism to some extent, but its impact on storage and functional iron status is small relative to dietary protein/iron manipulation. PMID- 24801368 TI - General supplement use, subsequent use and cancer risk in the UK Women's Cohort Study. AB - BACKGROUND/OBJECTIVES: To determine whether general dietary supplement use is associated with cancer risk in UK women and to estimate risks related to use at one and two recording points. SUBJECTS/METHODS: Cox's proportional hazard regression models were used to estimate cancer risks for 32 665 middle-aged women in the UK Women's Cohort Study relating to any current supplement use recorded in a baseline questionnaire. During a median follow-up of 15 years, there were 3936 registered cancer incidences, including 1344 breast, 429 smoking-related and 362 colorectal cancers. Cancer risks for 12 948 of these women, who also completed questionnaires on average 4.4 years later, were estimated in relation to any supplement use at both time points (1527 cancers, including 561 breast, 131 smoking-related and 141 colorectal cancers). Adjustments were made for baseline confounders. RESULTS: Total smoking-related cancers were associated with baseline supplement use (hazard ratio (HR)=1.41, 95% confidence interval (CI): 1.10, 1.81) compared with non-use, but not associated with use at both recording points (HR=1.29; 95% CI: 0.78, 2.13) compared with use at neither. There was no evidence of the associations between total, colorectal or breast cancers and baseline supplement use, or use at both recording points. In sub-analyses, no significant associations with breast cancer were found for premenopausal or postmenopausal baseline users, or similarly for use at both points (HR=1.35, 95% CI: 0.91, 2.01; and HR=0.93, 95% CI: 0.68, 1.26, respectively). CONCLUSIONS: There was evidence that general supplement use was associated with increased smoking-related cancer risk, but there was no evidence of associations with total, colorectal and breast cancers. PMID- 24801370 TI - Nutrition impact symptoms and body composition in patients with COPD. AB - BACKGROUND/OBJECTIVES: Anorexia or lack of appetite is common in chronic obstructive pulmonary disease (COPD) and may be caused or augmented by several symptoms affecting appetite and eating. We aimed to investigate and quantify the extent of nutrition impact symptoms (NIS) in patients with COPD and to explore relationships between NIS and fat-free mass depletion. SUBJECTS/METHODS: The results in this cross-sectional study are based on 169 COPD patients (62% female subjects). Body composition was assessed using bioelectrical impedance spectroscopy and the patients reported NIS by two newly developed questionnaires: the Eating Symptoms Questionnaire (ESQ) and the Disease-Related Appetite Questionnaire (DRAQ). RESULTS: Symptoms with the highest prevalence were dry mouth (71%), stomach ache (39%), pain or aches affecting appetite (36%) and constipation (35%). Problems with diarrhoea and feeling affected by smells were more severe among women compared with men (P<0.05). Thirty-six percent of the patients were depleted (fat-free mass index (FFMI) <15 kg/m2 for women and FFMI<16 kg/m2 for men). Depleted patients had more NIS (P<0.05) and also rated appetite and taste of food as worse compared with non-depleted patients (P<0.05). CONCLUSIONS: NIS are common in patients with COPD, and depleted patients have more severe symptoms. To investigate how these symptoms are best prevented and/or managed and whether NIS prevention/treatment can affect development of malnutrition in patients with COPD is a challenge for the future. PMID- 24801369 TI - Comparative effects of whey and casein proteins on satiety in overweight and obese individuals: a randomized controlled trial. AB - BACKGROUND/OBJECTIVE: Dairy protein seems to reduce appetite by increasing satiety and delaying the return of hunger and subsequently lowering energy intake compared with fat or carbohydrate. The aim of this study was to compare the effect of whey with that of casein proteins on satiety in overweight/obese individuals. METHODS/SUBJECTS: This was a randomized, parallel-design 12-week long study. Seventy subjects with a body mass index between 25 and 40 kg/m(2) and aged 18-65 years were randomized into one of three supplement groups: glucose control (n=25), casein (n=20) or whey (n=25) protein. Before commencing the study, at weeks 6 and 12 of the treatment, a Visual Analogue Scale (VAS) was used to measure subjective sensations of appetite before lunch and before dinner. RESULTS: Rating for VAS (mm) at 6 and 12 weeks showed significantly higher satiety in the whey group compared with the casein (P=0.017 and P=0.025, respectively) or control (P=0.024 and P=0.032, respectively) groups when measured before lunch. Similarly, at 6 and 12 weeks, the score for fullness was also significantly higher in the whey group compared with both casein (P=0.038 and P=0.022, respectively) and control (P=0.020 and P=0.030, respectively) groups. However, these short-term effects on satiety from dairy whey proteins did not have any long-term effects on energy intake or body weight over 12 weeks compared with casein. CONCLUSIONS: Collectively, whey protein supplementation appears to have a positive and acute postprandial effect on satiety and fullness compared with casein and carbohydrate supplementation in overweight and obese individuals. PMID- 24801372 TI - Complete mitochondrial genome of Pareuchiloglanis sinensis (Siluriformes: Sisoridae). AB - The complete mitochondrial genome of Pareuchiloglanis sinensis, an endemic Chinese sisorid fish, was determined by DNA sequencing based on the PCR fragments. The complete mtDNA genome sequence of P. sinensis is 16,593 bp in length, with a gene content of 13 protein-coding, 2 ribosomal RNA, and 22 transfer RNA genes, and a typical gene arrangement identical to many other reported fishes. The overall base composition of the heavy strand was 30.6% A, 24.2% T, 16.0% G and 29.2% C, with a relatively high A + T content (54.8%). This will provide a useful tool for understanding the genetic diversity, population structure and conservation status of P. sinensis in future. PMID- 24801371 TI - Do improvements in dietary behaviour contribute to cardiovascular risk factor reduction over and above cardio-protective medication in newly diagnosed diabetes patients? AB - BACKGROUND/OBJECTIVES: A healthy diet is an integral component of successful diabetes management. However, the comparative importance of adopting a healthy diet for cardiovascular risk factor reduction over and above medication use among newly diagnosed diabetes patients remains unclear. SUBJECTS/METHODS: We computed a dietary score consistent with American Diabetes Association and Diabetes UK recommendations in 574 newly diagnosed diabetes patients by summing standardised values for the intake of total energy, saturated fat, sodium, fibre and plasma vitamin C. In linear regression analyses, stratified by cardio-protective medication use (yes/no), we quantified the comparative longitudinal associations of baseline diet and change in diet over 1 year with change in blood pressure, HbA1c and lipids. RESULTS: Baseline diet was generally not predictive of change in cardiovascular risk factor levels at 1 year. In contrast, dietary change over 1 year among patients prescribed and not prescribed cardio-protective medication after baseline was associated with comparative (p-interaction all ?0.95) reductions in diastolic blood pressure (-2.38 vs -2.93 mm Hg, respectively) and triglycerides (-0.31 vs -0.21 mmol/l, respectively), independent of potential confounding factors and change from baseline to follow-up in physical activity and smoking status. CONCLUSIONS: Modest dietary change over the first year following diagnosis of diabetes was associated with reductions in blood pressure and triglycerides, over and above the effects of cardio-protective medication. Our findings support the notion that dietary change should be viewed as an integral component of successful diabetes self-management, irrespective of medication use. PMID- 24801373 TI - Babinet-inverted optical Yagi-Uda antenna for unidirectional radiation to free space. AB - Nanophotonics capable of directing radiation or enhancing quantum-emitter transition rates rely on plasmonic nanoantennas. We present here a novel Babinet inverted magnetic-dipole-fed multislot optical Yagi-Uda antenna that exhibits highly unidirectional radiation to free space, achieved by engineering the relative phase of the interacting surface plasmon polaritons between the slot elements. The unique features of this nanoantenna can be harnessed for realizing energy transfer from one waveguide to another by working as a future "optical via". PMID- 24801374 TI - Systematic Monitoring of Voluntary Medical Male Circumcision Scale-up: adoption of efficiency elements in Kenya, South Africa, Tanzania, and Zimbabwe. AB - BACKGROUND: SYMMACS, the Systematic Monitoring of the Voluntary Medical Male Circumcision Scale-up, tracked the implementation and adoption of six elements of surgical efficiency-use of multiple surgical beds, pre-bundled kits, task shifting, task sharing, forceps-guided surgical method, and electrocautery--as standards of surgical efficiency in Kenya, South Africa, Tanzania, and Zimbabwe. METHODS AND FINDINGS: This multi-country study used two-staged sampling. The first stage sampled VMMC sites: 73 in 2011, 122 in 2012. The second stage involved sampling providers (358 in 2011, 591 in 2012) and VMMC procedures for observation (594 in 2011, 1034 in 2012). The number of VMMC sites increased significantly between 2011 and 2012; marked seasonal variation occurred in peak periods for VMMC. Countries adopted between three and five of the six elements; forceps-guided surgery was the only element adopted by all countries. Kenya and Tanzania routinely practiced task-shifting. South Africa and Zimbabwe used pre bundled kits with disposable instruments and electrocautery. South Africa, Tanzania, and Zimbabwe routinely employed multiple surgical bays. CONCLUSIONS: SYMMACS is the first study to provide data on the implementation of VMMC programs and adoption of elements of surgical efficiency. Findings have contributed to policy change on task-shifting in Zimbabwe, a review of the monitoring system for adverse events in South Africa, an increased use of commercially bundled VMMC kits in Tanzania, and policy dialogue on improving VMMC service delivery in Kenya. This article serves as an overview for five other articles following this supplement. PMID- 24801375 TI - Successful application of transoral robotic surgery in failures of traditional transoral laser microsurgery: critical considerations. AB - AIMS: To assess the role of transoral robotic surgery (TORS) in managing failures of conventional transoral laser microsurgery (TLM) in cases with difficult laryngeal exposure. METHODS: Retrospective analysis of 3 patients with difficult laryngeal exposure treated with TORS. All 3 cases failed to be managed by conventional TLM after repeated attempts by experienced surgeons. In 2 cases, the initial disease was laryngeal cancer treated by a cricohyoidoepiglottopexy, with an obstructing residual epiglottis. The last case was a bilateral Reinke disease submitted to repeated TLM procedures, producing multiple supraglottic and glottic scars. In all cases, the difficult exposure was produced by a combination of concurrent elements including insufficient mouth opening, short and stiff neck, macroglossia and high-positioned larynx. RESULTS: Two patients were exposed by means of a Davis Meyer mouth gag. The other patient was managed by a Feyh Kastenbauer device. The key of the success was the possibility to work 'around the corner' (30 degrees angle view) where straight alignment of the larynx was impossible. CONCLUSIONS: Where possible, a TORS approach should be considered complementary to TLM in cases of very difficult or even impossible conventional transoral laryngoscopic approach. PMID- 24801376 TI - Finessing the manufacture of mesenchymal stromal cells. PMID- 24801377 TI - Intra-renal arterial injection of autologous bone marrow mesenchymal stromal cells ameliorates cisplatin-induced acute kidney injury in a rhesus Macaque mulatta monkey model. AB - BACKGROUND: Clinically, acute kidney injury (AKI) is a potentially devastating condition for which no specific therapy improves efficacy of the repair process. Bone marrow mesenchymal stromal cells (BM-MSCs) are proven to be beneficial for the renal repair process after AKI in different experimental rodent models, but their efficacy in large animals and humans remains unknown. This study aims to assess the effect of autologous rhesus Macaque mulatta monkey BM-MSC transplantation in cisplatin-induced AKI. METHODS: We chose a model of AKI induced by intravenous administration of 5 mg/kg cisplatin. BM-MSCs were transplanted through intra-arterial injection. The animals were followed for survival, biochemistry analysis and pathology. RESULTS: Transplantation of 5 * 10(6) cells/kg ameliorated renal function during the first week, as shown by significantly lower serum creatinine and urea values and higher urine creatinine and urea clearance without hyponatremia, hyperkalemia, proteinuria and polyuria up to 84 d compared with the vehicle and control groups. The superparamagnetic iron oxide nanoparticle-labeled cells were found in both the glomeruli and tubules. BM-MSCs markedly accelerated Foxp3+ T-regulatory cells in response to cisplatin-induced damage, as revealed by higher numbers of Foxp3+ cells within the tubuli of these monkeys compared with cisplatin-treated monkeys in the control and vehicle groups. CONCLUSIONS: These data demonstrate that BM-MSCs in this unique large-animal model of cisplatin-induced AKI exhibited recovery and protective properties. PMID- 24801378 TI - Group housing during gestation affects the behaviour of sows and the physiological indices of offspring at weaning. AB - To compare the behaviour of sows and the physiological indices of their offspring in stall and group-housing systems, 28 sows were randomly distributed into two systems with 16 sows in stalls, and the other 12 sows were divided into three groups with four sows per pen. The area per sow in stalls and groups was 1.2 and 2.5 m2, respectively. Back fat depth of the sow was measured. Salivary cortisol concentration of the sows, colostrum composition and piglets' serum biochemical indicators were evaluated. The behaviour of the sows, including agonistic behaviour, non-agonistic social behaviour, stereotypical behaviour and other behaviours at weeks 2, 9 and 14 of pregnancy were analysed. The results showed no differences in the back fat depth of sows. Colostrum protein, triglyceride, triiodothyronine, thyroxine and prolactin concentrations in the whey also demonstrated no significant differences between the two housing systems. Salivary cortisol concentration was significantly higher in the sows housed in groups than the sows in stalls. The concentrations of serum total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly higher in the offspring of sows housed in groups (P=0.006 and 0.005, respectively). The GLM procedure for repeated measures analysis showed the frequency of drinking, and non-agonistic social behaviour was significantly higher in the sows housed in groups than the sows in stalls; yet the frequency of agonistic and sham chewing demonstrated the opposite direction. The duration of standing was significantly longer in the sows housed in groups, but the sitting and stereotypical behaviour duration were significantly shorter compared with the sows in stalls. These results indicated that group housing has no obvious influence on the colostrum composition of sows; however, it was better for sows to express their non-agonistic social behaviour and reduce the frequency of agonistic behaviour and stereotypical behaviour. Meanwhile, group housing during gestation significantly increased serum total cholesterol and LDL cholesterol of offspring. PMID- 24801379 TI - Systemic anticancer neural stem cells in combination with a cardiac glycoside for glioblastoma therapy. AB - The tumor-tropic properties of neural stem cells (NSCs) have been shown to serve as a novel strategy to deliver therapeutic genes to tumors. Recently, we have reported that the cardiac glycoside lanatoside C (Lan C) sensitizes glioma cells to the anticancer agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we engineered an FDA-approved human NSC line to synthesize and secrete TRAIL and the Gaussia luciferase (Gluc) blood reporter. We showed that upon systemic injection, these cells selectively migrate toward tumors in the mice brain across the blood-brain barrier, target invasive glioma stem-like cells, and induce tumor regression when combined with Lan C. Gluc blood assay revealed that 30% of NSCs survived 1 day postsystemic injection and around 0.5% of these cells remained viable after 5 weeks in glioma-bearing mice. This study demonstrates the potential of systemic injection of NSCs to deliver anticancer agents, such as TRAIL, which yields glioma regression when combined with Lan C. PMID- 24801381 TI - Does intuition cause cooperation? AB - Recently, researchers claimed that people are intuitively inclined to cooperate with reflection causing them to behave selfishly. Empirical support for this claim came from experiments using a 4-player public goods game with a marginal return of 0.5 showing that people contributed more money to a common project when they had to decide quickly (i.e., a decision based on intuition) than when they were instructed to reflect and decide slowly. This intuitive-cooperation effect is of high scientific and practical importance because it argues against a central assumption of traditional economic and evolutionary models. The first experiment of present study was set up to examine the generality of the intuitive cooperation effect and to further validate the experimental task producing the effect. In Experiment 1, we investigated Amazon Mechanical Turk (AMT) workers' contributions to a 4-player public goods game with a marginal return of 0.5 while we manipulated the knowledge about the other players' contribution to the public goods game (contribution known vs. contribution unknown), the identity of the other players (humans vs. computers randomly generating contributions) and the time constraint (time pressure/intuition vs. forced delay/reflection). However, the results of Experiment 1 failed to reveal an intuitive-cooperation effect. Furthermore, four subsequent direct replications attempts with AMT workers (Experiments 2a, 2b, 2c and Experiment 3, which was conducted with naive/inexperienced participants) also failed to demonstrate intuitive cooperation effects. Taken together, the results of the present study could not corroborate the idea that people are intuitively cooperative, hence suggesting that the theoretical relationship between intuition and cooperation should be further scrutinized. PMID- 24801380 TI - Doxorubicin and 5-fluorouracil induced accumulation and transcriptional activity of p53 are independent of the phosphorylation at serine 15 in MCF-7 breast cancer cells. AB - The chemotherapeutic agents doxorubicin (dox) or 5-fluorouracil (5FU) are used to treat cancer cells as they cause irreparable DNA damage, inducing these aberrant cells to undergo cell death. The mediator of this process is presumed to be in part the tumor suppressor p53 which regulates genes involved in DNA repair and cell death. When MCF-7 breast cancer cells are treated with these drugs, we observed that the level of p53 and the p53 negative regulator, Mdm2, increased, as seen by others. But contrary to some reports, we observed minimal phosphorylation of p53 at serine 15 in MCF-7 cells after drug treatment. Interestingly, we determined that there was differential regulation of the kinases ATM and Chk2 with the drug treatments, likely the cause for the lack of phosphorylation of p53. We found a dramatic drop in p53 DNA binding affinity for p21 and other gene response elements (RE) after drug treatment. To determine if the p53 that accumulated in the drug treated cells was functionally active, we monitored changes in the protein products of two p53-regulated genes following drug treatment with and without the addition of a p53-specific siRNA. In response to 5FU, both p21 and Mdm2 proteins increased and that increase was alleviated if a p53-specific siRNA was added. This effect was not seen with the addition of dox. Thus, the phosphorylation at serine 15 is not necessary for the functional activation of this transcription factor. We propose a new model for the regulation of p53, Mdm2, and MdmX after drug treatment. PMID- 24801383 TI - Design and simulation of coupled-resonator filters using periodically slotted electrodes on FBARs. AB - This paper discusses the use of periodically slotted top electrodes in the film bulk acoustic resonator (FBAR) structure for the realization of wideband coupled resonator filters (CRFs), where evanescent modes in the periodic structure are used for the coupling between adjacent electrodes. First, wave propagation in this structure is investigated. Finite element analysis is performed for the Mo/ZnO/Mo structure. The result suggests that lateral wave propagation is controlled by the Bragg reflection, and that transverse modes can be suppressed when the structure is properly designed. Next, a CRF is designed. It is shown that wideband CRFs are realizable when the period, thickness, and width of slotted electrodes are properly set. PMID- 24801382 TI - Anticoagulants (heparin, low molecular weight heparin and oral anticoagulants) for intermittent claudication. AB - BACKGROUND: Anticoagulant treatment for intermittent claudication might improve functional capacity and prevent acute cardiovascular complications caused by peripheral obstructive arterial disease. This is an update of the review first published in 2001. OBJECTIVES: To assess the effects of anticoagulant drugs (heparin, low molecular weight heparin (LMWH) and oral anticoagulants) in patients with intermittent claudication (Fontaine stage II) in terms of improving walking capacity (pain-free walking distance or absolute walking distance), mortality, cardiovascular events, ankle/brachial pressure index, progression to surgery, amputation-free survival and side effects of these drugs. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013) and CENTRAL (2013, Issue 4). SELECTION CRITERIA: All randomised trials of anticoagulants used to treat patients with intermittent claudication. DATA COLLECTION AND ANALYSIS: Seven studies were included. Only three studies (two evaluating oral anticoagulants, one evaluating heparin) met the high quality methodological inclusion criteria and were included in the primary analysis. Four other studies were included in the sensitivity analysis. The authors extracted the data independently. MAIN RESULTS: No new studies were included for this update. Seven studies with a combined total of 802 participants were included in this review. No significant difference was observed between heparin treatment and control groups for pain-free walking distance or maximum walking distance at the end of treatment. There were no data to indicate that LMWHs benefit walking distance. Revascularisation or amputation-free survival rates were reported in one study only with a five year follow-up. No study reported a significant effect on overall mortality or cardiovascular events and the pooled odds ratios were not significant for these outcomes either. Major and minor bleeding events were significantly more frequent in the group treated with oral anticoagulants compared to control, with a non-significant increase in fatal bleeding events. No major bleeding events were reported in the study evaluating heparin, while a non significant increase in minor bleeding events was reported. AUTHORS' CONCLUSIONS: The benefit of heparin, LMWHs and oral anticoagulants for treatment of intermittent claudication has not been established while an increased risk of major bleeding events has been observed, especially with oral anticoagulants. There is no clear evidence to support the use of anticoagulants for intermittent claudication at this stage. PMID- 24801384 TI - Editorial: insight into the patent reviews and recent studies on nanotechnology and allied technology platforms for biomedical engineering and pharmaceutical drug delivery dosage forms. PMID- 24801385 TI - The sesamoids of the feet in humans: a systematic review and meta-analysis. AB - The prevalence and distribution of the sesamoid bones in the feet has been reported in the literature with a high degree of variability. This systematic review aims to provide a better estimate of the frequency of the sesamoids of the foot and their association with variables such as ancestry, gender, and side. Thirty-seven studies met the inclusion criteria and were submitted for meta analyses, sensitivity analyses and proportion difference tests, whenever possible. At the metatarsophalangeal (MTP) joint of the hallux, sesamoids were nearly always present. At the interphalangeal (IP) joint, the pooled true estimates of large-sampled studies were: (1) an overall prevalence of 22.4 %, (2) a cadaveric rate at 71.6 %, and (3) a radiological rate (based on X-ray images) of 21.1 %. The pooled partition frequencies of the hallucal medial and lateral sesamoids were 10.7 and 1.3 %, respectively. Bipartism was the most frequent partition type (92 %), followed by tripartism (7.5 %) and quadripartism (0.5 %). Middle Eastern ancestry was associated with significantly lower hallucal partition rate (P < 0.0001) and African ancestry with significantly lower prevalence of the IP sesamoid than all other ethnicities (P < 0.001). Feet with a hallux valgus deformity seemed to be associated with significantly higher rate of partition of the medial sesamoid (odds ratio = 3) than that of the normal feet. The respective values of the pooled true prevalence in adults at the MTP joint for the 2nd, 3rd, 4th and 5th toes were 1.9, 0.32, 0.9 and 13 %, respectively. There was a significantly higher prevalence of tibial sesamoids vs lateral sesamoids, with pooled odds ratio of 34.7, 8, 4.8, and 2.27, respectively. Partition was found in around 10 % of the sesamoids of the 5th MTP joint; no partition was noted in the other toes. For most 2nd-5th MTP joints, European ancestry showed the highest frequency whereas African ancestry showed the lowest; Middle Eastern ancestry was in between. No sesamoids were found at the 4th proximal IP joint and at the 4th and 5th distal IP joints. No sesamoids were found at any IP joint in the feet of Middle Eastern and African populations. The pooled rates of the IP sesamoids of the second and third toes in European populations were 1.2 % for the 2nd proximal, 0.33 % for the second distal and 0.6 % for both IP joints of the third toe. This anatomical meta-analysis yielded results that are likely to be more accurate regarding the rates of the sesamoids in the foot, their laterality and partition. It also provided solid evidence for the genetic basis of the frequency distribution among the different populations. PMID- 24801386 TI - A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats. AB - The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic alpha- and beta-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes. PMID- 24801388 TI - Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system? AB - The endocannabinoid system (ECS) regulates numerous cellular and physiological processes through the activation of receptors targeted by endogenously produced ligands called endocannabinoids. Importantly, this signaling system is known to play an important role in modulating energy balance and glucose homeostasis. For example, current evidence indicates that the ECS becomes overactive during obesity whereby its central and peripheral stimulation drives metabolic processes that mimic the metabolic syndrome. Herein, we examine the role of the ECS in modulating the function of mitochondria, which play a pivotal role in maintaining cellular and systemic energy homeostasis, in large part due to their ability to tightly coordinate glucose and lipid utilization. Because of this, mitochondrial dysfunction is often associated with peripheral insulin resistance and glucose intolerance as well as the manifestation of excess lipid accumulation in the obese state. This review aims to highlight the different ways through which the ECS may impact upon mitochondrial abundance and/or oxidative capacity and, where possible, relate these findings to obesity-induced perturbations in metabolic function. Furthermore, we explore the potential implications of these findings in terms of the pathogenesis of metabolic disorders and how these may be used to strategically develop therapies targeting the ECS. PMID- 24801387 TI - mTORC1 and JNK coordinate phosphorylation of the p70S6K1 autoinhibitory domain in skeletal muscle following functional overloading. AB - The present project was designed to investigate phosphorylation of p70S6K1 in an animal model of skeletal muscle overload. Within 24 h of male Sprague-Dawley rats undergoing unilateral tenotomy to induce functional overloading of the plantaris muscle, phosphorylation of the Thr389 and Thr421/Ser424 sites on p70S6K1 was significantly elevated. Since the Thr421/Ser424 sites are purportedly mammalian target of rapamycin complex 1 (mTORC1) independent, we sought to identify the kinase(s) responsible for their phosphorylation. Initially, we used IGF-I treatment of serum-deprived HEK-293E cells as an in vitro model system, because IGF-I promotes phosphorylation of p70S6K1 on both the Thr389 and Thr421/Ser424 sites in skeletal muscle and in cells in culture. We found that, whereas the mTOR inhibitor TORIN2 prevented the IGF-I-induced phosphorylation of the Thr421/Ser424 sites, it surprisingly enhanced phosphorylation of these sites during serum deprivation. JNK inhibition with SP600125 attenuated phosphorylation of the Thr421/Ser424 sites, and in combination with TORIN2 both the effect of IGF-I and the enhanced Thr421/Ser424 phosphorylation during serum deprivation were ablated. In contrast, both JNK activation with anisomycin and knockdown of the mTORC2 subunit rictor specifically stimulated phosphorylation of the Thr421/Ser424 sites, suggesting that mTORC2 represses JNK-mediated phosphorylation of these sites. The role of JNK in mediating p70S6K1 phosphorylation was confirmed in the animal model noted above, where rats treated with SP600125 exhibited attenuated Thr421/Ser424 phosphorylation. Overall, the results provide evidence that the mTORC1 and JNK signaling pathways coordinate the site-specific phosphorylation of p70S6K1. They also identify a novel role for mTORC1 and mTORC2 in the inhibition of JNK. PMID- 24801389 TI - Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner. AB - Glucagon-like peptide-1 (GLP-1) promotes pancreatic beta-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer. PMID- 24801390 TI - Insulin sensitivity is inversely related to cellular energy status, as revealed by biotin deprivation. AB - We have reported an early decrease in glycemia in rats fed a biotin-deficient diet with reduced cellular ATP levels, suggesting increased insulin sensitivity. Here, we show that biotin-deprived rats are more tolerant of glucose, as shown by both oral and intraperitoneal glucose tolerance tests, during which insulin plasma levels were significantly diminished in deficient rats compared with controls. Biotin-deficient rats had lower blood glucose concentrations during intraperitoneal insulin sensitivity tests than controls. Furthermore, more glucose was infused to maintain euglycemia in the biotin-deficient rats during hyperinsulinemic euglycemic clamp studies. These results demonstrate augmented sensitivity to insulin in biotin-deprived rats. They are most likely the consequence of an insulin-independent effect of AMPK activation on GLUT4 membrane translocation with increased glucose uptake. In biotin-deficient cultured L6 muscle cells, there was increased phosphorylation of the energy sensor AMPK. We have now confirmed the augmented AMPK activation in both biotin-deprived in vivo muscle and cultured muscle cells. In these cells, glucose uptake is increased by AMPK activation by AICAR and diminished by its knockdown by the specific siRNAs directed against its alpha1- and alpha2-catalytic subunits, with all of these effects being largely independent of the activity of the insulin-signaling pathway that was inhibited with wortmannin. The enhanced insulin sensitivity in biotin deficiency likely has adaptive value for organisms due to the hormone promotion of uptake and utilization of not only glucose but other nutrients such as branched-chain amino acids, whose deficiency has been reported to increase insulin tolerance. PMID- 24801392 TI - Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function. AB - Diabetes-induced testicular cell death is due predominantly to oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor in controlling the antioxidative system and is inducible by sulforaphane (SFN). To test whether SFN prevents diabetes-induced testicular cell death, an insulin-defective stage of type 2 diabetes (IDS-T2DM) was induced in mice. This was accomplished by feeding them a high-fat diet (HFD) for 3 mo to induce insulin resistance and then giving one intraperitoneal injection of streptozotocin to induce hyperglycemia while age-matched control mice were fed a normal diet (ND). IDS-T2DM and ND-fed control mice were then further subdivided into those with or without 4-mo SFN treatment. IDS-T2DM induced significant increases in testicular cell death presumably through receptor and mitochondrial pathways, shown by increased ratio of Bax/Bcl2 expression and cleavage of caspase-3 and caspase-8 without significant change of endoplasmic reticulum stress. Diabetes also significantly increased testicular oxidative damage and inflammation. All of these diabetic effects were significantly prevented by SFN treatment with upregulated Nrf2 expression. These results suggest that IDS-T2DM induces testicular cell death presumably through caspase-8 activation and mitochondria mediated cell death pathways and also by significantly downregulating testicular Nrf2 expression and function. SFN upregulates testicular Nrf2 expression and its target antioxidant expression, which was associated with significant protection of the testis from IDS-T2DM-induced germ cell death. PMID- 24801391 TI - Identification of a novel phosphorylation site in adipose triglyceride lipase as a regulator of lipid droplet localization. AB - Adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triacylglycerol (TG) hydrolysis, has long been known to be a phosphoprotein. However, the potential phosphorylation events that are involved in the regulation of ATGL function remain incompletely defined. Here, using a combinatorial proteomics approach, we obtained evidence that at least eight different sites of ATGL can be phosphorylated in adipocytes. Among them, Thr372 resides within the hydrophobic region known to mediate lipid droplet (LD) targeting. Although it had no impact on the TG hydrolase activity, substitution of phosphorylation-mimic Asp for Thr372 eliminated LD localization and LD-degrading capacity of ATGL expressed in HeLa cells. In contrast, mutation of Thr372 to Ala gave a protein that bound LDs and functioned the same as the wild-type protein. In nonstimulated adipocytes, the Asp mutation led to decreased LD association and basal lipolytic activity of ATGL, whereas the Ala mutation produced opposite effects. Moreover, the LD translocation of ATGL upon beta-adrenergic stimulation was also compromised by the Asp mutation. In accord with these findings, the Ala mutation promoted and the Asp mutation attenuated the capacity of ATGL to mediate lipolysis in adipocytes under both basal and stimulated conditions. Collectively, these studies identified Thr372 as a novel phosphorylation site that may play a critical role in determining subcellular distribution as well as lipolytic action of ATGL. PMID- 24801393 TI - Acetylcholine-like and trimethylglycine-like PTA (1,3,5-triaza-7 phosphaadamantane) derivatives for the development of innovative Ru- and Pt-based therapeutic agents. AB - The PTA N-alkyl derivatives (PTAC2H4OCOMe)X (1X: 1a, X = Br; 1b, X = I; 1c, X = PF6; 1d, X = BPh4), (PTACH2COOEt)X (2X: 2a, X = Br; 2b, X = Cl; 2c, X = PF6), and (PTACH2CH2COOEt)X (3X: 3a, X = Br; 3c, X = PF6), presenting all the functional groups of the natural cationic compounds acetylcholine or trimethylglycine combined with a P-donor site suitable for metal ion coordination, were prepared and characterized by NMR, ESI-MS, and elemental analysis. The X-ray crystal structures of 1d and 2c were determined. Ligands 1c, 2b, and 3c were coordinated to Pt(II) and Ru(II) to give the cationic complexes cis-[PtCl2(L)2]X2 and [RuCpCl(PPh3)(L)]X (L = 1, 2, 3, X = Cl or PF6) designed with a structure targeted for anticancer activity. The X-ray crystal structure of [CpRu(PPh3)(PTAC2H4OCOMe)Cl]PF6 (1cRu) was determined. The antiproliferative activity of the ligands and the complexes was evaluated on three human cancer cell lines. PMID- 24801394 TI - Is obstructive sleep apnoea syndrome really one of the causes of secondary polycythaemia? AB - BACKGROUND: It is widely believed that sleep apnoea syndrome leads to polycythaemia, but the evidence is largely anecdotal. We believe that polycythaemia is not commonly seen in patients with sleep apnoea syndrome. Therefore, we aimed to determine the relationship between polycythaemia and sleep apnoea syndrome. METHODS: The study included 335 patients diagnosed with obstructive sleep apnoea (OSA) syndrome, all of whom underwent standard nocturnal polysomnography. RESULTS: There were no significant differences in haemoglobin levels or haematocrit (P > 0.05) between the OSA groups in all patients. Of the 335 patients, only 1 male patient with severe OSA (0.3%) had clinically significant polycythaemia. According to regression analysis, there was a weak linear correlation between haemoglobin levels and lowest oxygen saturation levels in female patients (r = -0.242, P = 0.021). CONCLUSION: We think that OSA is very rarely the reason for secondary polycythaemia. PMID- 24801395 TI - An achievement of over 12 percent efficiency in an organic dye-sensitized solar cell. AB - Dye-sensitized solar cells fabricated by using a novel metal-free alkoxysilyl carbazole as a sensitizing dye and a Co(3+/2+)-complex redox electrolyte exhibited light-to-electric energy conversion efficiencies of over 12% with open circuit photovoltages higher than 1 V by applying a hierarchical multi-capping treatment to the photoanode. PMID- 24801396 TI - Outer retinal corrugations in age-related macular degeneration. AB - IMPORTANCE: Optical coherence tomography (OCT) abnormalities of age-related macular degeneration (AMD) have not been fully characterized because of the complex morphology and a lack of correlative histologic studies. Expansion of our ability to interpret increasing attributes brings us closer to the goal of in vivo histologic analysis of the eye by OCT. OBJECTIVE: To describe a new outer retinal finding of AMD using spectral-domain (SD) OCT and suggest histopathologic correlates. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five eyes of 16 patients with AMD with severe atrophy due to either choroidal neovascularization (CNV) or geographic atrophy (GA) and 53 donor eyes of 53 patients with late AMD were included. Imaging studies were conducted at a referral retinal practice and histopathology was done at a university research laboratory. EXPOSURES: Findings in the outer retina were evaluated in SD-OCT images in eyes with atrophy of the retinal pigment epithelium (RPE) and compared with histopathologic findings in eyes with GA or CNV that also showed loss of the RPE. MAIN OUTCOMES AND MEASURES: Spectral-domain OCT and histologic characteristics of the outer retina. RESULTS: The mean (SD) age of the 16 patients was 82.7 (7.9) years. Twenty eyes had CNV and 5 eyes had GA. The mean best-corrected visual acuity was 0.800 logMAR (interquartile range, 0.350-1.000 logMAR), a Snellen equivalent of 20/126. A curvilinear hyperreflective density was identified above the Bruch membrane line within the atrophic area in the SD-OCT images. At the internal border, the material was contiguous with the outer portion of the RPE band. Below the material was a relatively hyporeflective space. The material was thrown into folds in cases with atrophy following CNV or was seen as a sheet with numerous bumps in eyes with GA. Review of histopathologic findings of eyes with advanced GA and CNV revealed a rippled layer of basal laminar deposits in an area of RPE atrophy that was located in the same level as the curvilinear line seen in the OCT images. CONCLUSIONS AND RELEVANCE: We have described a new entity, termed outer retinal corrugations, which may correspond to histological findings of basal laminar deposits, extracellular deposits that persist in eyes with late AMD. Observation of this undulating band does not necessarily mean there is exudation or leakage; as a consequence, these patients do not need treatment based on this solitary finding. PMID- 24801397 TI - Detection of different virus-specific CD8+ T cells after kidney transplantation. AB - BACKGROUND: The early diagnosis of viral reactivation after kidney transplantation (KTX) is an unsolved problem. Survey of virus-specific T-cell responses may identify patients at risk for viral reactivation. We therefore quantified virus-specific CD8+ T-cells to evaluate their potential predictive value for viral reactivation and infection in KTX patients. METHODS: We quantified the virus-specific responses of CD8+ T-cells for CMV, EBV, HPV and HHV in 23 patients undergoing KTX for 6 mo after transplantation. We enumerated T cells for 36 virus-specific binding peptides and five different human leukocyte antigen (HLA) alleles through the binding of Class I iTAg major histocompatibility complex (MHC) tetramers. The patients' pre-operative serologic status for CMV and CMV-specific CD8+ T-cell numbers were correlated with one another (p=0.0046). RESULTS: Three patients had clinical CMV disease and all three remained or became CMV-tetramer-positive for at least one HLA allele during follow-up. Three of the four patients with viral infections caused by or reactivations of viruses other than CMV were initially negative for CMV-specific CD8+ T-cells but became CMV-positive. Most of the patients who were initially CMV tetramer positive also had tetramer-positive T-cells specific for Epstein-Barr virus (EBV); human papillomavirus (HPV)-6b, -11, -16, or -18; or human herpesvirus (HHV)-8. All of the patients who developed viral disease other than that caused by CMV remained or became positive for at least one binding peptide that was specific for a virus not directly related to the clinical features of a viral disease. CONCLUSION: Patients who were positive for any virus had a significantly greater risk of developing complications of viral disease during the 6-mo follow-up period in the study (p=0.026), suggesting a general susceptibility to viral reactivation. The evaluation of virus-specific CD8+ T cells may prospectively help to identify patients at risk for viral reactivation after KTX. PMID- 24801398 TI - Androcin, a novel type of cysteine-rich venom peptide from Androctonus bicolor, induces akinesia and anxiety-like symptoms in mice. AB - A novel type of venom peptide with six disulfide bridges, referred to as Androcin, was identified from the scorpion Androctonus bicolor using a cDNA library strategy. The amino acid sequence of Androncin displays little identity to other known peptides from scorpions. We found that the genomic sequence of Androcin consists of three exons interrupted by two introns that are localized in the signal sequence and mature peptide encoding regions, inserted in phase 2 and phase 0, respectively. This genomic organization is unique among those of the cysteine-rich peptides from scorpions described so far. The primary and secondary structures of Androcin are homologous to those of the N-terminal domains of insulin-like growth factor-binding proteins; this suggests that Androcin may block the normal function of IGFs. Toxicological analysis using the recombinant Androcin peptide revealed that Androcin is able to induce severe akinesia and anxiety-like symptoms in mice. Androcin is a novel mammalian toxin with six disulfide bridges that provides the scorpion with another tool to subdue animals. PMID- 24801399 TI - The Cratylia mollis seed lectin induces membrane permeability transition in isolated rat liver mitochondria and a cyclosporine a-insensitive permeability transition in Trypanosoma cruzi mitochondria. AB - Previous results provided evidence that Cratylia mollis seed lectin (Cramoll 1,4) promotes Trypanosoma cruzi epimastigotes death by necrosis via a mechanism involving plasma membrane permeabilization to Ca(2+) and mitochondrial dysfunction due to matrix Ca(2+) overload. In order to investigate the mechanism of Ca(2+) -induced mitochondrial impairment, experiments were performed analyzing the effects of this lectin on T. cruzi mitochondrial fraction and in isolated rat liver mitochondria (RLM), as a control. Confocal microscopy of T. cruzi whole cell revealed that Cramoll 1,4 binding to the plasma membrane glycoconjugates is followed by its internalization and binding to the mitochondrion. Electrical membrane potential (?Psim ) of T. cruzi mitochondrial fraction suspended in a reaction medium containing 10 MUM Ca(2+) was significantly decreased by 50 MUg/ml Cramoll 1,4 via a mechanism insensitive to cyclosporine A (CsA, membrane permeability transition (MPT) inhibitor), but sensitive to catalase or 125 mM glucose. In RLM suspended in a medium containing 10 MUM Ca(2+) this lectin, at 50 MUg/ml, induced increase in the rate of hydrogen peroxide release, mitochondrial swelling, and ?Psim disruption. All these mitochondrial alterations were sensitive to CsA, catalase, and EGTA. These results indicate that Cramoll 1, 4 leads to inner mitochondrial membrane permeabilization through Ca(2+) dependent mechanisms in both mitochondria. The sensitivity to CsA in RLM characterizes this lectin as a MPT inducer and the lack of CsA effect identifies a CsA-insensitive MPT in T. cruzi mitochondria. PMID- 24801400 TI - Soluble CD93 levels in patients with acute myocardial infarction and its implication on clinical outcome. AB - BACKGROUND: Inflammation plays a key role in the pathogenesis of acute myocardial infarction (MI). However, it is unclear whether marker of immune activation will provide prognostic information in these patients. We hypothesized that circulating levels of soluble CD93 (sCD93), a soluble form of transmembrane glycoprotein CD93, is increased in acute MI patients and its level would be associated with clinical outcomes in patients with acute MI. METHODS: We measured circulating levels of sCD93 in 120 patients with acute MI (63+/-13 yrs, M?F = 85?35) and in 120 age, sex-matched control subjects. In patients with acute MI, clinical characteristics, echocardiographic and laboratory findings were assessed at the time of initial enrollment. The primary outcome was defined as all-cause and cardiovascular death. RESULTS: Circulating sCD93 levels were significantly higher in patients with acute MI than in control subjects (552.1+/-293.7 vs. 429.8+/-114.2 ng/mL, p<0.0001). Upon in vitro inflammatory stimulation, increased CD93 shedding was demonstrated in acute MI patients but not in control subjects. During follow up period (median 208 days, 3-1058 days), the primary outcome occurred in 18 (15%) patients (9 cardiovascular deaths). Circulating levels of sCD93 were associated with all cause (p<0.0001) and cardiovascular (p<0.0001) mortality in patients with acute MI. Multivariate Cox regression analysis revealed that initial sCD93 level was found to be an independent predictor of all cause (p = 0.002) and cardiovascular mortality (p = 0.033) when controlled for age and left ventricular ejection fraction. CONCLUSIONS: Circulating levels of sCD93 are elevated in patients with acute MI and their levels were associated with adverse clinical outcomes. PMID- 24801401 TI - In vivo implantation of porous titanium alloy implants coated with magnesium doped octacalcium phosphate and hydroxyapatite thin films using pulsed laser depostion. AB - The use of porous titanium-based implant materials for bone contact has been gaining ground in recent years. Selective laser melting (SLM) is a rapid prototyping method by which porous implants with highly defined external dimensions and internal architecture can be produced. The coating of porous implants produced by SLM with ceramic layers based on calcium phosphate (CaP) remains relatively unexplored, as does the doping of such coatings with magnesium (Mg) to promote bone formation. In this study, Mg-doped coatings of the CaP types octacalcium phosphate and hydroxyapatite (HA) were deposited on such porous implants using the pulsed laser deposition method. The coated implants were subsequently implanted in a rabbit femoral defect model for 6 months. Uncoated implants served as a reference material. Bone-implant contact and bone volume in the region of interest were evaluated by histopathological techniques using a tri chromatographic Masson-Goldner staining method and by microcomputed tomography (uCT) analysis of the volume of interest in the vicinity of implants. Histopathological analysis revealed that all implant types integrated directly with surrounding bone with ingrowth of newly formed bone into the pores of the implants. Biocompatibility of all implant types was demonstrated by the absence of inflammatory infiltration by mononuclear cells (lymphocytes), neutrophils, and eosinophils. No osteoclastic or foreign body reaction was observed in the vicinity of the implants. uCT analysis revealed a significant increase in bone volume for implants coated with Mg-doped HA compared to uncoated implants. PMID- 24801402 TI - Chaperones are necessary for the expression of catalytically active potato apyrases in prokaryotic cells. AB - NTPDases (nucleoside triphosphate diphosphohydrolases) (also called in plants apyrases) hydrolyze nucleoside 5'-tri- and/or diphosphate bonds producing nucleosides di or monophosphate and inorganic phosphate. For years, studies have been carried out to use both plant and animal enzymes for medicine. Therefore, there is a need to develop an efficient method for the quick production of large amounts of homogeneous proteins with high catalytic activity. Expression of proteins in prokaryotic cells is the most common way for the protein production. The aim of our study was to develop a method of expression of potato apyrase (StAPY4, 5, and 6) genes in bacterial cells under conditions that allowed the production of catalytically active form of these enzymes. Apyrase 4 and 6 were overexpressed in BL21-CodonPlus (DE3) bacteria strain but they were accumulated in inclusion bodies, regardless of the culture conditions and induction method. Co-expression of potato apyrases with molecular chaperones allowed the expression of catalytically active apyrase 5. However, its high nucleotidase activity could be toxic for bacteria and is therefore synthesized in small amounts in cells. Our studies show that each protein requires other conditions for maturation and even small differences in amino acid sequence can essentially affect protein folding regardless of presence of chaperones. PMID- 24801403 TI - Potential xanthine oxidase inhibitory activity of endophytic Lasiodiplodia pseudotheobromae. AB - Xanthine oxidase is considered as a potential target for treatment of hyperuricemia. Hyperuricemia is predisposing factor for gout, chronic heart failure, atherosclerosis, tissue injury, and ischemia. To date, only two inhibitors of xanthine oxidase viz. allopurinol and febuxostat have been clinically approved for used as drugs. In the process of searching for new xanthine oxidase inhibitors, we screened culture filtrates of 42 endophytic fungi using in vitro qualitative and quantitative XO inhibitory assays. The qualitative assay exhibited potential XO inhibition by culture filtrates of four isolates viz. #1048 AMSTITYEL, #2CCSTITD, #6AMLWLS, and #96 CMSTITNEY. The XO inhibitory activity was present only in the chloroform extract of the culture filtrates. Chloroform extract of culture filtrate #1048 AMSTITYEL exhibited the highest inhibition of XO with an IC50 value of 0.61 MUg ml(-1) which was better than allopurinol exhibiting an IC50 of 0.937 MUg ml(-1) while febuxostat exhibited a much lower IC50 of 0.076 MUg ml(-1). Further, molecular phylogenetic tools and morphological studies were used to identify #1048 AMSTITYEL as Lasiodiplodia pseudotheobromae. This is the first report of an endophytic Lasiodiplodia pseudotheobromae from Aegle marmelos exhibiting potential XO Inhibitory activity. PMID- 24801404 TI - Production of xylooligosaccharides by immobilized His-tagged recombinant xylanase from Penicillium occitanis on nickel-chelate Eupergit C. AB - Penicillium occitanis xylanase 2 expressed with a His-tag in Pichia pastoris, termed PoXyn2, was immobilized on nickel-chelate Eupergit C by covalent coupling reaction with a high immobilization yield up to 93.49 %. Characterization of the immobilized PoXyn2 was further evaluated. The optimum pH was not affected by immobilization, but the immobilized PoXyn2 exhibited more acidic and large optimum pH range (pH 2.0-4.0) than that of the free PoXyn2 (pH 3.0). The free PoXyn2 had an optimum temperature of 50 degrees C, whereas that of the immobilized enzyme was shifted to 65 degrees C. Immobilization increased both pH stability and thermostability when compared with the free enzyme. Time courses of the xylooligosaccharides (XOS) produced from corncob xylan indicated that the immobilized enzyme tends to use shorter xylan chains and to produce more xylobiose and xylotriose initially. At the end of 24-h reaction, XOS mixture contained a total of 21.3 and 34.2 % (w/w) of xylobiose and xylotriose with immobilized xylanase and free xylanase, respectively. The resulting XOS could be used as a special nutrient for lactic bacteria. PMID- 24801405 TI - Silver nanoparticles synthesized by pulsed laser ablation: as a potent antibacterial agent for human enteropathogenic gram-positive and gram-negative bacterial strains. AB - Present investigation deals with the study, to quantify the antibacterial property of silver nanoparticles (SNPs), synthesized by pulsed laser ablation (PLA) in aqueous media, on some human enteropathogenic gram-positive and gram negative bacterial strains. Antibacterial property was studied by measuring the zone of inhibition using agar cup double-diffusion method, minimum inhibitory concentration by serial dilution method, and growth curve for 24 h. The results clearly show the potency of antibacterial property of PLA-synthesized SNPs and suggest that it can be used as an effective growth inhibitor against various pathogenic bacterial strains in various medical devices and antibacterial control systems. PMID- 24801406 TI - Purification and characterization of novel halo-acid-alkali-thermo-stable xylanase from Gracilibacillus sp. TSCPVG. AB - An aerobic xylanolytic moderately halophilic and alkali-tolerant bacterium, Gracilibacillus sp. TSCPVG, produces multiple xylanases of unusual halo-acid alkali-thermo-stable nature. The purification of a major xylanase from TSCPVG culture supernatant was achieved by hydrophobic and gel permeation chromatographic methods followed by electroelution from preparatory PAGE. The molecular mass of the purified xylanase was 42 kDa, as analyzed by SDS-PAGE, with a pI value of 6.1. It exhibited maximal activity in 3.5 % NaCl and retained over 75 % of its activity across the broad salinity range of 0-30 % NaCl, indicating a high halo-tolerance. It showed maximal activity at pH 7.5 and had retained 63 % of its activity at pH 5.0 and 73 % at pH 10.5, signifying the tolerance to broad acid to alkaline conditions. With birchwood xylan as a substrate, K m and specific activity values were 21 mg/ml and 1,667 U/mg, respectively. It is an endoxylanase that degrades xylan to xylose and xylobiose and had no activity on p nitrophenyl-beta-D-xylopyranoside, p-nitrophenyl-beta-D-glucopyranoside, p nitrophenyl acetate, carboxymethylcellulose, and filter paper. Since it showed remarkable stability over different salinities, broad pH, and temperature ranges, it is promising for application in many industries. PMID- 24801407 TI - Effect of nickel-cobaltite nanoparticles on production and thermostability of cellulases from newly isolated thermotolerant Aspergillus fumigatus NS (class: Eurotiomycetes). AB - In the present study, effect of nickel-cobaltite (NiCo2O4) nanoparticles (NPs) was investigated on production and thermostability of the cellulase enzyme system using newly isolated thermotolerant Aspergillus fumigatus NS belonging to the class Euratiomycetes. The NiCo2O4 NPs were synthesized via hydrothermal method assisted by post-annealing treatment and characterized through X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. In the absence of NPs in the growth medium, filter paper cellulase (FP) activity of 18 IU/gds was achieved after 96 h, whereas 40 % higher FP activity in 72 h was observed with the addition of 1 mM concentration of NPs in the growth medium. Maximum production of endoglucanase (211 IU/gds), beta-glucosidase (301 IU/gds), and xylanase (803 IU/gds) was achieved after 72 h without NPs (control), while in the presence of 1 mM concentration of NPs, endoglucanase, beta-glucosidase, and xylanase activity increased by about 49, 53, and 19.8 %, respectively, after 48 h of incubation, against control, indicating a substantial increase in cellulase productivity with the addition of NiCo2O4 NPs in the growth medium. Crude enzyme was thermally stable for 7 h at 80 degrees C in presence of NPs, as against 4 h at the same temperature for control samples. Significant increase in the activity and improved thermal stability of cellulases in the presence of the NiCo2O4 NPs holds potential for use of NiCo2O4 NPs during enzyme production as well as hydrolysis. From the standpoint of biofuel production, these results hold enormous significance. PMID- 24801408 TI - Optimization of anaerobic co-digestion of strawberry and fish waste. AB - Anaerobic co-digestion of agri-food waste is a promising management alternative. Its implementation, however, requires evaluating the proportion in which waste should be mixed to optimize their centralized treatment. The combined treatment of strawberry extrudate and fish waste, which are widely generated in Mediterranean areas, was optimized. Strawberry extrudate and fish waste were mixed and treated at different proportions (88:12, 94:6, and 97:3, respectively; wet basis). The proportions selected for the mixture allow the different flows to be absorbed simultaneously. The highest methane production was observed for the ratio 94:6 (0.205 m(3) STP CH4/kg volatile solid) (VS) (STP; 0 degrees C, 1 atm), with a methane production rate in the range of 5 . 10(-3)-9 . 10(-3) m(3) STP/kg VS . d, while the highest organic loading rate was observed for the mixture at a proportion 88:12 (1.9 +/- 0.1 kg VS/m(3) . d). Biodegradability was found to be similar for the 88:12 and 94:6 proportions, with values around 90 % in VS. Nevertheless, the 97:3 ratio was not viable due to a low methane production. An inhibition phenomenon occurred at increasing loads due to the effect of some compounds contained in the fish waste such as chloride or nitrogen. PMID- 24801409 TI - Healthcare costs associated with language difficulties up to 9 years of age: Australian population-based study. AB - PURPOSE: This study aimed to quantify the non-hospital healthcare costs associated with language difficulties within two nationally representative samples of children. METHOD: Data were from three biennial waves (2004-2008) of the Longitudinal Study of Australian Children (B cohort: 0-5 years; K cohort: 4-9 years). Language difficulties were defined as scores <= 1.25 SD below the mean on measures of parent-reported communication (0-3 years) and directly assessed vocabulary (4-9 years). Participant data were linked to administrative data on non-hospital healthcare attendances and prescription medications from the universal Australian Medicare subsidized healthcare scheme. RESULT: It was found that healthcare costs over each 2-year age band were higher for children with than without language difficulties at 0-1, 2-3, and 4-5 years, notably 36% higher (mean difference = $AU206, 95% CI = $90, $321) at 4-5 years (B cohort). The slightly higher 2-year healthcare costs for children with language difficulties at 6-7 and 8-9 years were not statistically different from those without language difficulties. Modelled to the corresponding Australian child population, 2-year government costs ranged from $AU1.2-$AU12.1 million (depending on age examined). Six-year healthcare costs increased with the persistence of language difficulties in the K cohort, with total Medicare costs increasing by $192 (95% CI = $74, $311; p = .002) for each additional wave of language difficulties. CONCLUSION: Language difficulties (whether transient or persistent) were associated with substantial excess population healthcare costs in childhood, which are in addition to the known broader costs incurred through the education system. It is unclear whether healthcare costs were specifically due to the assessment and/or treatment of language difficulties, as opposed to conditions that may be co morbid with or may cause language difficulties. PMID- 24801410 TI - Response by Michael W. Rich. PMID- 24801411 TI - Weight loss strategies: association with consumption of sugary beverages, snacks and values about food purchases. AB - OBJECTIVE: To examine whether weight loss strategies are associated with consumption of sugar-sweetened beverages (SSBs), snacks or food values. METHODS: Cross-sectional analysis of 24-h dietary recall data obtained from the National Health and Nutrition Examination Survey 2007-2010 (N=9440). RESULTS: Adults trying to lose weight consumed roughly 2000 total calories, 250 calories from SSBs, 225 calories from salty snacks, and 350 calories from sweet snacks. Adults not trying to lose weight consumed roughly 2300 total calories, 300 calories from SSBs, 250 calories from salty snacks, and 380 calories from sweet snacks. While overweight and obese adults trying to lose weight consumed fewer calories than those who were not, heavier adults trying to lose weight using dietary strategies or a combination of diet and physical activity consumed more calories than healthy weight adults using that same weight loss strategy (p<0.05). Price (>70%) and nutrition (>50%) were most when making food choices (p<0.05) for all groups. CONCLUSION: Consumption of discretionary calories is high regardless of body weight or weight loss intention. PRACTICE IMPLICATIONS: Promoting reduced SSB and snack consumption in the clinical setting may be important for weight loss, particularly among heavier individuals. Clinicians should consider values related to food purchasing to identify concrete behavioral targets. PMID- 24801412 TI - Challenges of implementing routine health behavior change support in a children's hospital setting. AB - OBJECTIVE: Evidence indicates that health behavior change initiatives are often not implemented successfully. This qualitative study aims to understand the barriers and facilitators to implementation of health behavior change brief advice into routine practice in an acute children's hospital setting. METHODS: Semi-structured interviews were conducted with health professionals working at a UK children's hospital (n=33). Participants were purposively sampled to incorporate a range of specialties, job roles and training. RESULTS: An inductive thematic framework analysis identified two emergent themes. These capture the challenges of implementing routine health behavior change support in a children's hospital setting: (1) 'health professional knowledge, beliefs and behaviors' and (2) 'patient and family related challenges'. CONCLUSION: This study enhances findings from previous research by outlining the challenges pediatric health professionals face in relation to supporting health behavior change. Challenges include failure to assume responsibility, low confidence, prioritization of the health provider relationship with patients and families, health provider and patient knowledge, and low patient and family motivation. PRACTICE IMPLICATIONS: Skills-based behavior change training is needed for pediatric health professionals to effectively support health behavior change. PMID- 24801413 TI - Biliary stricture is the only concern in ABO-incompatible adult living donor liver transplantation in the rituximab era. AB - BACKGROUND & AIMS: With the introduction of rituximab prophylaxis, the survival of ABO-incompatible (ABOi) adult living donor liver transplant (ALDLT) has been strikingly improved due to the decreased incidence of antibody-mediated rejection. However, biliary stricture (BS) related to ABO incompatibility remains an unresolved concern. METHODS: Excluding 105 dual graft ALDLTs, 1102 ALDLT cases including 142 ABOi recipients were included in this study. The desensitization protocol for overcoming the ABO blood group barrier comprised pretransplant plasma exchange, and rituximab (300-375 mg/m(2) BSA). RESULTS: The mean follow-up period was 34.2 +/- 15.4 months. The cumulative graft and patient survival rates were comparable in the two groups. The 1- and 3-year BS-free survival rates of ABOi ALDLT were 81.5 and 79.0%, respectively, lower than those of ABOc ALDLT (87.6 and 85.7%, respectively, p=0.022). In the risk factor analysis, diameter of graft bile duct opening <5mm, antecedent acute cellular rejection, and ABO incompatibility were independent risk factors for BS. Diffuse intrahepatic biliary stricture (DIHBS) exclusively occurred in 12 patients (8.5%) receiving ABOi ALDLT. The deaths of 3 patients and 4 cases of re-transplantation were related to DIHBS. Graft and patient survival rates were significantly reduced in ABOi ALDLT recipients with DIHBS. However, we failed to identify any significant risk factors for DIHBS. CONCLUSIONS: The incidence of BS in ABOi ALDLT is higher than in ABOc, mainly due to the fact of DIHBS which significantly affected survival outcomes. To predict and prevent DIHBS, we need further studies to identify significant risk factors. PMID- 24801414 TI - Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus. AB - BACKGROUND & AIMS: Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice. METHODS: We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7 log IU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared. RESULTS: 120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, with baseline viral load mean 7.8 log IU/ml (+/-0.72) and ALT median 25 U/L (18.75-33). Duration of antiviral theraphy before birth was mean 58 days (+/-19) TDF and 53 (+/-14) lamivudine. Viral load declined by 3.64 log IU/ml (+/-0.9) TDF and 2.81 log IU/ml (+/-1.33) lamivudine. Virologic failure (birth viral load >7 IU/ml) occurred in 3% and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to 2% and 0% in TDF and lamivudine cohorts, compared with 20% in untreated. CONCLUSIONS: TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts. PMID- 24801416 TI - Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications. AB - The emergence and takeover of hepatitis B virus (HBV) variants carrying mutation(s) in the preS/S genomic region is a fairly frequent event that may occur spontaneously or may be the consequence of immunoprophylaxis or antiviral treatments. Selection of preS/S mutants may have relevant pathobiological and clinical implications. Both experimental data and studies in humans show that several specific mutations in the preS/S gene may induce an imbalance in the synthesis of the surface proteins and their consequent retention within the endoplasmic reticulum (ER) of the hepatocytes. The accumulation of mutated surface proteins may cause ER stress with the consequent induction of oxidative DNA damage and genomic instability. Viral mutants with antigenically modified surface antigen may be potentially infectious to immune-prophylaxed patients and may account for cases of occult HBV infection. In addition, preS/S variants were reported to be associated with cases of fulminant hepatitis as well as of fibrosing cholestatic hepatitis, and they are associated with cirrhosis and hepatocellular carcinoma development. PMID- 24801418 TI - Tracheal intubation: variance and adverse events we can do without*. PMID- 24801415 TI - A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy. AB - BACKGROUND & AIMS: NS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited. METHODS: This was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12). RESULTS: The intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p<0.001). Adverse effects were common; 21% of patients experienced hemoglobin <8g/dl and 57% required blood transfusions during the first 16 weeks. Twenty seven percent were hospitalized and 9% died; all were liver-related. CONCLUSIONS: The addition of boceprevir or telaprevir to peginterferon and ribavirin yields SVR12 of 63% in liver transplant recipients with genotype 1 recurrent HCV, despite a high prevalence of advanced fibrosis and prior non-response to peginterferon and ribavirin. Rapid virologic response predicted a high likelihood of SVR. Despite a doubling of SVR rates, poor tolerability and high rates of adverse events were frequent and pose barriers to its widespread application. PMID- 24801417 TI - CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway. AB - BACKGROUND & AIMS: Cancer cells exhibit the reprogrammed metabolism characterized by high level of glycolysis even in the presence of oxygen. Aerobic glycolysis, known as the Warburg effect, supplies cancer cells with the substrates required for biomass generation. To date, several intracellular signaling mediators have been identified in metabolic regulation of cancer cells. However, it remains largely ambiguous how molecules on the cell surface are involved in regulation of cancer metabolism. METHODS: In the current study, we established several HCC cell lines differing in their CD147 (a typical transmembrane glycoprotein) expression status by zinc-finger nuclease and RNAi techniques. Then, we systematically investigated the role of CD147 in the regulation of the Warburg effect in HCC cells and explored the underlying mechanism. RESULTS: We found that CD147 significantly contributed to the reprogramming of glucose metabolism in HCC cells through a p53-dependent way. CD147 facilitated the cell surface expression of MCT1 and lactate export, which led to activation of the PI3K/Akt/MDM2 pathway and thus increased p53 degradation. The gain/loss-of-function studies demonstrated that while CD147 promoted glycolysis, mediated by p53-dependent upregulation of GLUT1 and activation of PFKL, it inhibited mitochondrial biogenesis and functions, mediated by p53-dependent downregulation of PGC1alpha, TFAM, and p53R2. Additionally, proliferation of HCC cells was suppressed by blocking CD147 and/or MCT1, which resulted in down-regulation of glucose metabolism. CONCLUSIONS: We demonstrate that CD147 is a crucial regulator of glucose metabolism. PMID- 24801419 TI - Are early parenteral nutrition and intensive insulin therapy what critically ill children need?*. PMID- 24801420 TI - A desperate need to communicate more effectively with desperate families*. PMID- 24801421 TI - Not off the assembly line but properly tailored: customizing cannulation for extracorporeal life support*. PMID- 24801422 TI - "Out of the blue"-safety and efficacy of pulmonary hypertension treatment in childhood*. PMID- 24801423 TI - Immunocompromised patients and ventilation support: new treatment perspectives and prognosis for applied modes of ventilation*. PMID- 24801424 TI - A beneficial role of central venous oxygen saturation-targeted septic shock management in children: follow the pediatric story, not only the adult story*. PMID- 24801425 TI - Evaluating patient outcomes in medical education research: mission impossible?*. PMID- 24801426 TI - Calfactant: is there a potential role in acute lung injury? PMID- 24801427 TI - The authors reply. PMID- 24801428 TI - Bedside echocardiography for pediatric hemodynamic monitoring: what is the impact in the outcome? PMID- 24801429 TI - The authors reply. PMID- 24801430 TI - Thresholds for cerebral perfusion pressure. PMID- 24801431 TI - The authors reply. PMID- 24801432 TI - Controlled protein embedment onto Au/Ag core-shell nanoparticles for immuno labeling of nanosilver surface. AB - Difficulties in stable conjugation of biomolecules to nanosilver surfaces have severely limited the use of silver nanostructures in biological applications. Here, we report a facile antibody conjugation onto gold/silver (Au/Ag) core-shell nanoparticles by stable and uniform embedment of an antibody binding protein, protein G, in silver nanoshells. A rigid helical peptide linker with a terminal cysteine residue was fused to protein G. A mixture of the peptide-fused protein G and space-filling free peptide was reacted with gold nanoparticles (AuNPs) to form a protein G-linked peptide layer on the particle surface. Uniform silver nanoshells were successfully formed on these protein G-AuNPs, while stably embedding protein G-linked peptide layers. Protein G specifically targets the Fc region of an antibody and thus affords properly orientated antibodies on the particle surface. Compared to Au nanoparticles of similar size with randomly adsorbed antibodies, the present immuno-labeled Au/Ag core-shell nanoparticles offered nearly 10-fold higher sensitivities for naked-eye detection of surface bound antigens. In addition, small dye molecules that were bonded to the peptide layer on Au nanoparticles exhibited highly enhanced surface-enhanced Raman scattering (SERS) signals upon Ag shell formation. The present strategy provides a simple but efficient way to conjugate antibodies to nanosilver surfaces, which will greatly facilitate wider use of the superior optical properties of silver nanostructures in biological applications. PMID- 24801433 TI - Prophylactic pectoralis major muscle flap in prevention of pharyngocutaneous fistula in total laryngectomy after radiotherapy. AB - BACKGROUND: The purpose of this study was to assess the utility of the pectoralis major muscle flap (PMMF) in the prevention of pharyngocutaneous fistula for total laryngectomy after radiotherapy (RT) METHODS: We conducted a retrospective review of 166 patients who underwent a total laryngectomy after RT between 1998 and 2012 at the CHU de Quebec. RESULTS: One hundred fifteen patients underwent a total laryngectomy with primary pharyngeal closure alone and 51 patients received an onlay PMMF. The incidence of pharyngocutaneous fistula in the PMMF group was 14% compared to 36% when only primary closure was done (p = .004). However, the PMMF did not influence the treatment needed for the healing of this complication (p = 1.00). The development of pharyngocutaneous fistula increased the length of stay from 19 to 50 days (p < .0001) and delayed the initiation of oral diet from 15 to 25 days (p = .03). CONCLUSION: Nonirradiated tissue coverage should be routine in total laryngectomy after RT. PMMF is a good adjunct to prevent pharyngocutaneous fistula. PMID- 24801434 TI - XAS and XFM studies of selenium and copper speciation and distribution in the kidneys of selenite-supplemented rats. AB - Dietary selenium has been implicated in the prevention of cancer and other diseases, but its safety and efficacy is dependent on the supplemented form and its metabolites. In this study, X-ray absorption spectroscopy (XAS) and X-ray fluorescence microscopy (XFM) have been used to investigate the speciation and distribution of Se and Cu in vivo. In kidneys isolated from rats fed a diet containing 5 ppm Se as selenite for 3 weeks, Se levels increased 5-fold. XFM revealed a strong correlation between the distribution of Se and the distribution of Cu in the kidney, a phenomenon that has previously been observed in cell culture (Weekley et al., JBIC, J. Biol. Inorg. Chem., 2014, DOI: 10.1007/s00775 014-1113-x). However, X-ray absorption spectra suggest that most of the Se in the kidney is found as Se-Se species, rather than Cu-bound, and that most of the Cu is bound to S and N, presumably to amino acid residues in proteins. Furthermore, SOD1 expression did not change in response to the high Se diet. We cannot rule out the possibility of some Cu-Se bonding in the tissues, but our results suggest mechanisms other than the formation of Cu-Se species and SOD1 upregulation are responsible for the highly correlated distributions of Se and Cu in the kidneys of rats fed high selenite diets. PMID- 24801435 TI - Engineering colloidal quantum dot solids within and beyond the mobility-invariant regime. AB - Colloidal quantum dots are attractive materials for efficient, low-cost and facile implementation of solution-processed optoelectronic devices. Despite impressive mobilities (1-30 cm2 V(-1) s(-1)) reported for new classes of quantum dot solids, it is--surprisingly--the much lower-mobility (10(-3)-10(-2) cm2 V(-1) s(-1)) solids that have produced the best photovoltaic performance. Here we show that it is not mobility, but instead the average spacing among recombination centres that governs the diffusion length of charges in today's quantum dot solids. In this regime, colloidal quantum dot films do not benefit from further improvements in charge carrier mobility. We develop a device model that accurately predicts the thickness dependence and diffusion length dependence of devices. Direct diffusion length measurements suggest the solid-state ligand exchange procedure as a potential origin of the detrimental recombination centres. We then present a novel avenue for in-solution passivation with tightly bound chlorothiols that retain passivation from solution to film, achieving an 8.5% power conversion efficiency. PMID- 24801436 TI - Ambulatory blood pressure monitoring profile in urban African black and European white untreated hypertensive patients matched for age and sex. AB - INTRODUCTION: The aim of this study was to compare the 24-h ambulatory blood pressure (ABP) profile in never-treated black hypertensive patients living in Africa, Mozambique (20-80 years), versus never-treated white hypertensive patients living in Europe. PATIENTS AND METHODS: ABP recordings of untreated black hypertensive patients and white hypertensive patients with 24-h ABP of 130/80 mmHg or more were retrospectively selected from two computerized database records of ABP and matched for age by decades, sex, and BMI. RESULTS: Black hypertensive patients were n=548, 47 +/- 12 years, 52% women, BMI=28.0 +/- 8.2 kg/m(2), 7% smokers, 7% diabetics; white hypertensive patients were n=604, 47 +/- 15 years, 52% women, BMI=27.4 +/- 5.1 kg/m(2), 8.4% diabetics, and 18% smokers (P<0.02). Black hypertensive patients versus white hypertensive patients showed higher casual blood pressure (BP) 160/104 +/- 19/14 versus 149/97 +/- 18/12 mmHg, 24-h ABP 146/92 +/- 16/13 versus 139/85 +/- 11/10 mmHg, daytime ABP 150/95 +/- 16/13 versus 143/88 +/- 13/11 mmHg, night-time BP 139/84 +/- 17/13 versus 130/78 +/- 13/10 mmHg (all P<0.001) and lower night-time BP fall 8.3 +/- 6.9 versus 10.1 +/- 8.7% (P<0.02) and higher BP variability. Differences were still significant in all decades above 30 years of age and when calculations were carried out separately for both men and women. The average 24-h heart rate did not differ between groups. CONCLUSION: Our data suggest that untreated black hypertensive patients systematically present higher clinic and ABP values and a lower night time BP fall than untreated white hypertensive patients for all spectra of age distribution. This might be the reason for the worse cardiovascular prognosis described in black hypertensive patients compared with white hypertensive patients. PMID- 24801437 TI - Single operator endoscopically guided nasogastric tube insertion: Our Experience. PMID- 24801438 TI - Prevention of transfusion-transmitted cytomegalovirus (CMV) infection: Standards of care. PMID- 24801439 TI - Involvement of both PKS and NRPS in antibacterial activity in Lysobacter enzymogenes OH11. AB - Polyketides and nonribosomal peptides represent two large families of natural products (NPs) with diverse structures and important functions. They are synthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS), respectively. Lysobacter enzymogenes is emerging as a novel biocontrol agent against pathogens of crop plants and a new source of bioactive NPs, such as antibacterial antibiotic WAP-8294A2 and antifungal antibiotic HSAF. Genome survey of strain OH11, a Chinese L. enzymogenes isolate, detected four novel PKS, NRPS or hybrid gene clusters, designed as cluster A to D. We further individually mutated five genes (PKS or NRPS) located in these four gene clusters and showed that a PKS gene in cluster A and an NRPS gene in cluster D were involved in the antibacterial activity via a WAP-8294A2 dependent way. The data also showed that none of the five genes was associated with antifungal activity and the regulation of HSAF biosynthesis. Our results reveal the unusual regulatory role of these PKS and NRPS genes that were discovered from genome mining in L. enzymogenes. PMID- 24801444 TI - New developments in inhaled drugs: within and beyond the lungs. PMID- 24801440 TI - Impact of trastuzumab on wound healing in experimental glaucoma surgery. AB - BACKGROUND: To investigate the effects of subconjunctivally administered trastuzumab on wound healing in experimental glaucoma filtration surgery. DESIGN: Comparative, experimental study. SAMPLES: Twenty eight eyes. METHODS: Twenty eight male New Zealand white rabbits were randomly assigned to four groups, each including seven rabbits: The rabbits in the control group were not operated on and did not receive any treatment. The rabbits in the sham group underwent trabeculectomy and had one drop of saline instilled four times a day for 14 days. The rabbits in the mitomycin-C group underwent trabeculectomy, and a sponge soaked in 0.4 mg/mL mitomycin-C was applied intraoperatively to the scleral surgical site for 3 min. The rabbits in the trastuzumab group underwent trabeculectomy and were injected subconjunctivally once with 1.2 mg/0.1 mL of the drug. On day 14 of the experiment, the operated and control eyes were enucleated and immunohistochemically analyzed. MAIN OUTCOME MEASURES: Mean values of fibroblast, mononuclear cell and immunostaining intensities of the transforming growth factor-beta, fibroblast growth factor-beta, and platelet derived growth factor. RESULTS: The mean cell numbers and immunostaining intensities in the sham group were higher than those of the control group (P < 0.01). The mean cell numbers and immunostaining intensities in the mitomycin-C group and trastuzumab group were statistically significantly lower than those of the sham group (P < 0.01) while mean cell numbers and immunostaining intensities in the mitomycin-C group and trastuzumab group were similar (P > 0.05). CONCLUSION: Subconjunctival trastuzumab injection effectively suppressed subconjunctival scarring after experimental glaucoma filtration surgery. PMID- 24801445 TI - From "some butter" to "a butter": an investigation of mass and count representation and processing. AB - This paper investigates the representation of mass and count nouns at the lexical syntactic level, an issue that has not been addressed to date in psycholinguistic theories. A single case study is reported of a man with aphasia, R.A.P., who showed a countability specific deficit that affected processing of mass noun grammar. R.A.P. frequently substituted mass noun determiners (e.g., some, much) with count noun determiners (e.g., a, many). Experimental investigations determined that R.A.P. had a modality-neutral lexical-syntactic impairment. Furthermore, a series of novel experiments revealed that R.A.P.'s processing of mass noun determiners varied depending on how mass nouns were depicted (single vs. multiple depictions) and how congruent these were with the conceptual semantic information of target determiners (e.g., "some" corresponds to multiple but not single concepts). R.A.P.'s determiner difficulties emerged only when mass nouns and determiners were number incongruent. The results of this research clearly indicate that nouns are lexical-syntactically specified for countability, but that the derivation of countability can additionally be influenced by conceptual-semantics. PMID- 24801446 TI - Percutaneous retrieval of an embolised vascular stent. PMID- 24801447 TI - Minimally invasive video-assisted double-valve replacement through right anterolateral Minithoracotomy. AB - OBJECTIVE: This study aimed to investigate feasibility and safety of minimally invasive video-assisted surgery for double-valve (mitral and aortic) replacement through right anterolateral minithoracotomy. METHODS: Between February 2011 and April 2013, 60 patients with combined valvular disease underwent double valve replacement, 26 of them by minimally invasive video-assisted surgery through right anterolateral minithoracotomy (study group) and 34 by median sternotomy (control group). Peripheral cardiopulmonary bypass (CPB) was established through right femoral artery and vein. The incision was made around the right breast approximately 5 cm in length. Pericardiotomy, bicaval occlusion, atriotomy and aortotomy, and double valve replacement were performed with thoracoscope. RESULTS: In the study group, times of CPB and aortic cross-clamp were 146.5 +/- 40.5 min and 91.5 +/- 23.4 min, respectively, which were significantly different from those in the control group, 115.4 +/- 26.5 min and 75.4 +/- 16.5 min (P<0.05). Thoracic drainage in the study group was significantly lower than the control group, 587 +/- 245 ml (study group) versus 756 +/- 267 ml (control group) (P<0.05). Length of ICU and postoperative hospital stay were shorter in the study group, 1.9 +/- 0.8 and 8.7 +/- 4.5 days versus 2.8 +/- 1.3 and 11.2 +/- 5.6 days in the control group (P<0.05), respectively. There was no statistical difference in the postoperative results of TTE (transthoracic echocardiography) (P>0.05). All patients recovered smoothly with follow-up of six months to two years, with no severe complications. CONCLUSIONS: Minimally invasive video-assisted procedure through right anterolateral minithoracotomy is a new promising approach for double valve replacement. Our study suggested that this approach was feasible, safe and had cosmetic effects. PMID- 24801448 TI - Pseudochoreoathetosis in sensory ataxic variant of Guillain-Barre syndrome. PMID- 24801449 TI - Substrate recognition and specificity of double-stranded RNA binding proteins. AB - Recognition of double-stranded (ds) RNA is an important part of many cellular pathways, including RNA silencing, viral recognition, RNA editing, processing, and transport. dsRNA recognition is often achieved by dsRNA binding domains (dsRBDs). We use atomistic molecular dynamics simulations to examine the binding interface of the transactivation response RNA binding protein (TRBP) dsRBDs to dsRNA substrates. Our results explain the exclusive selectivity of dsRBDs toward dsRNA and against DNA-RNA hybrid and dsDNA duplexes. We also provide corresponding experimental evidence. The dsRNA duplex is recognized by dsRBDs through the A-form of three duplex grooves and by the chemical properties of RNA bases, which have 2'-hydroxyl groups on their sugar rings. Our simulations show that TRBP dsRBD discriminates dsRNA- from DNA-containing duplexes primarily through interactions at two duplex grooves. The simulations also reveal that the conformation of the DNA-RNA duplex can be altered by dsRBD proteins, resulting in a weak binding of dsRBDs to DNA-RNA hybrids. Our study reveals the structural and molecular basis of protein-RNA interaction that gives rise to the observed substrate specificity of dsRNA binding proteins. PMID- 24801450 TI - Specificity protein 1 regulates topoisomerase IIbeta expression in SH-SY5Y cells during neuronal differentiation. AB - Topoisomerase IIbeta (top IIbeta) is a nuclear enzyme with an essential role in neural development. The regulation of top IIbeta gene expression during neural differentiation is poorly understood. Functional analysis of top IIbeta gene structure displayed a GC box sequence in its transcription promoter, which binds the nuclear transcription factor specificity protein 1 (Sp1). Sp1 regulates gene expression via multiple mechanisms and is essential for early embryonic development. This study seeks to determine whether Sp1 regulates top IIbeta gene expression during neuronal differentiation. For this purpose, human neuroblastoma SH-SY5Y cells were induced to neuronal differentiation in the presence of all trans retinoic acid (RA) for 5 days. After incubation with 10 MUM RA for 3-5 days, a majority of the cells exited the cell cycle to become postmitotic neurons, characterized by the presence of longer neurite outgrowths and expression of the neuronal marker microtubule-associated protein-2 (MAP2). Elevated Sp1 and top IIbeta mRNA and protein levels were detected and found to be positively correlated with the differentiation stage. Chromatin immunoprecipitation assay demonstrated an increased recruitment of Sp1 to the top IIbeta promoter after RA treatment. Mithramycin A, a compound that interferes with Sp1 binding to GC-rich DNA sequences, downregulated the expression of top IIbeta, resulting in reduced expression of MAP2 and decreased neurite length compared with the control group. Our results indicate that Sp1 regulates top IIbeta expression by binding to the GC box of the gene promoter during neuronal differentiation in SH-SY5Y cells. PMID- 24801451 TI - Computed tomographic angiography criteria in the diagnosis of brain death comparison of sensitivity and interobserver reliability of different evaluation scales. AB - INTRODUCTION: The standardized diagnostic criteria for computed tomographic angiography (CTA) in diagnosis of brain death (BD) are not yet established. The aim of the study was to compare the sensitivity and interobserver agreement of the three previously used scales of CTA for the diagnosis of BD. METHODS: Eighty two clinically brain-dead patients underwent CTA with a delay of 40 s after contrast injection. Catheter angiography was used as the reference standard. CTA results were assessed by two radiologists, and the diagnosis of BD was established according to 10-, 7-, and 4-point scales. RESULTS: Catheter angiography confirmed the diagnosis of BD in all cases. Opacification of certain cerebral vessels as indicator of BD was highly sensitive: cortical segments of the middle cerebral artery (96.3 %), the internal cerebral vein (98.8 %), and the great cerebral vein (98.8 %). Other vessels were less sensitive: the pericallosal artery (74.4 %), cortical segments of the posterior cerebral artery (79.3 %), and the basilar artery (82.9 %). The sensitivities of the 10-, 7-, and 4-point scales were 67.1, 74.4, and 96.3 %, respectively (p<0.001). Percentage interobserver agreement in diagnosis of BD reached 93 % for the 10-point scale, 89 % for the 7 point scale, and 95 % for the 4-point scale (p=0.37). CONCLUSIONS: In the application of CTA to the diagnosis of BD, reducing the assessment of vascular opacification scale from a 10- to a 4-point scale significantly increases the sensitivity and maintains high interobserver reliability. PMID- 24801452 TI - Total arterial compliance estimated by a novel method and all-cause mortality in the elderly: the PROTEGER study. AB - Aortic stiffness, assessed by carotid-to-femoral pulse wave velocity (PWV), often fails to predict cardiovascular (CV) risk and mortality in the very elderly. This may be due to the non-linear association between PWV and compliance or to blood pressure decrease in the frailest subjects. Total arterial compliance (C T) is the most relevant arterial property regarding CV function, compared to local or regional arterial stiffness. A new method for C T estimation, based on PWV, was recently proposed. We aimed to investigate the value of C T to predict all-cause mortality at the elderly. PWV was estimated in 279 elderly subjects (85.5 +/- 7.0 years) who were followed up for a mean period of 12.8 +/- 6.3 months. C T was estimated by the formula C T = k * PWV(-2); coefficient k is body-size dependent based on previous in silico simulations. Herein, k was adjusted for body mass index (BMI) with a 10 % change in BMI corresponding to almost 11 % change in k. For a reference BMI = 26.2 kg/m(2), k = 37. Survivors (n = 185) and non-survivors (n = 94) had similar PWV (14.2 +/- 3.6 versus 14.9 +/- 3.8 m/s, respectively; p = 0.139). In contrast, non-survivors had significantly lower C T than survivors (0.198 +/- 0.128 versus 0.221 +/- 0.1 mL/mmHg; p = 0.018). C T was a significant predictor of mortality (p = 0.022, odds ratio = 0.326), while PWV was not (p = 0.202), even after adjustment for gender, mean pressure and heart rate. Age was an independent determinant of C T (p = 0.016), but not of PWV. C T, estimated by a novel method, can predict all-cause mortality in the elderly. C T may be more sensitive arterial biomarker than PWV regarding CV risk assessment. PMID- 24801453 TI - Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis. AB - BACKGROUND: All aspects of aetiopathogenesis of recurrent aphthous stomatitis (RAS) have not been elucidated. RAS and Behcet's disease (BD) have clinical and immunological characteristics in common. Although T17 cytokines and alpha-enolase have been shown to play effective roles in BD and many other autoinflammatory diseases recently, their roles in RAS have not been studied extensively. In the present study, we investigated levels of several Th1, Th2 and Th17 pathways related cytokines and alpha-enolase to elucidate pathogenesis of RAS and to obtain data about possible treatment alternatives for the condition. METHODS: Serum interleukin-1, interleukin-13, interleukin-17, interleukin-18, interferon gamma and alpha-enolase levels in 24 patients with RAS, 30 patients with BD and 20 healthy controls were measured. RESULTS: Serum interleukin-1, interleukin-13, interleukin-17, interleukin-18, interferon gamma and alpha-enolase levels were higher in patients with RAS and patients with BD than in healthy controls (P < 0.005). CONCLUSION: Like Th1 and Th2 cells, Th17 cells were found to be effective in pathogenesis of RAS. In addition, alpha-enolase, the levels of which were high, may play an important role in etio-pathogenesis of RAS. Further studies to be designed in the light of these findings are required to shed light on pathogenesis and treatment of the condition. PMID- 24801454 TI - [Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options]. AB - In the present paper clinical phenotypes, pathogenetic relationships, and diagnostic algorithms as well as therapeutic concepts of/for systemic mast cell activation disease are reviewed. The reader should be able to recognize and diagnose a systemic mast cell activation disease, as well as to counsel a personalized drug therapy. In the case of chronic multisystem polymorbidity systemic mast cell activation disease should be considered as a differential diagnosis at an early stage. In most cases, specific, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy can be initiated. PMID- 24801455 TI - The minimally invasive MitraClipTM procedure for mitral regurgitation under general anaesthesia: immediate effects on the pulmonary circulation and right ventricular function. AB - A relatively new minimally invasive cardiological procedure, called the MitraClip(TM), does not require sternotomy and may have a number of advantages compared with open mitral valve surgery, but its acute impact on the pulmonary circulation and right ventricular function during general anaesthesia is unclear. We prospectively assessed the effects of the MitraClip procedure in 81 patients with or without pulmonary hypertension (defined as mean pulmonary artery pressure > 25 mmHg), who were anaesthetised using fentanyl (5 MUg.kg(-1)), etomidate (0.2 0.3 mg.kg(-1)), rocuronium (0.5-0.6 mg.kg(-1)) and isoflurane. Placement of the MitraClip led to a 60% increase in mean (SD) right ventricular stroke work index (from 512 (321) to 820 (470) mmHg.ml.m(-2), p < 0.0001), while mean (SD) pulmonary vascular resistance index decreased by 24% (522 (330) to 399 (244) dyn.s.cm(-5), p < 0.0001), and mean (SD) pulmonary artery pressure decreased by 10% (30 (8) to 27 (8) mmHg, p < 0.0001). Patients with pulmonary hypertension experienced a similar decrease in mean pulmonary artery pressure compared with those without, and they also had a slight reduction in mean (SD) pulmonary artery occlusion pressure (22 (6) down to 20 (6) mmHg, p = 0.044). We conclude that successful MitraClip treatment for mitral regurgitation acutely improves right ventricular performance by reducing right ventricular afterload, regardless of whether patients have pre-operative pulmonary hypertension. PMID- 24801456 TI - Major incidents and complications in otherwise healthy patients undergoing elective procedures: results based on 1.37 million anaesthetic procedures. AB - BACKGROUND: Improved anaesthesia safety has made severe anaesthesia-related incidents, complications, and deaths rare events, but concern about morbidity and mortality in anaesthesia continues. This study examines possible severe adverse outcomes or death recorded in a large national surveillance system based on a core data set (CDS). METHODS: Cases from 1999 to 2010 were filtered from the CDS database. Cases were defined as elective patients classified as ASA physical status grades I and II (without relevant risk factors) resulting in death or serious complication. Four experts reviewed the cases to determine anaesthetic involvement. RESULTS: Of 1 374 678 otherwise healthy, ASA I and II patients in the CDS database, 36 met the study inclusion criteria resulting in a death or serious complication rate of 26.2 per million [95% confidence interval (CI), 19.4 34.6] procedures, and for those with possible direct anaesthetic involvement, 7.3 per million cases (95% CI, 3.9-12.3). CONCLUSIONS: This is the first study assessing severe incidents and complications from a national outcome-tracking database. Annual identification and review of cases, perhaps with standardized database queries in the respective departments, might provide more detailed information about the cascades that lead to unfortunate outcomes. PMID- 24801457 TI - High expression of Toll-like receptors 2 and 9 and Th1/Th2 cytokines profile in obese asthmatic children. AB - Asthma is a common pulmonary disease with chronic inflammation of the airways, and obesity is a chronic state of low-grade inflammation. Toll-like receptors (TLRs) are involved in the innate immune response. This study was designed to analyze whether obesity has an effect on the immune response of patients with asthma. We included obese asthmatic, obese, asthmatic, and healthy children. Biochemical and anthropometric analyses were performed. Interleukin (IL)-2, interferon (IFN) gamma, IL-4, IL-10, IL-1beta, and tumor necrosis factor alpha were measured. Peripheral blood mononuclear cells were analyzed by immunostaining with anti-TLR2 and anti-TLR9 antibodies. The data were expressed as means +/- SEM or medians and percentiles. Kruskal-Wallis test and Dunn's multiple comparison test were applied. Asthmatic patients, both obese and nonobese, exhibited a mild asthma phenotype; none had infectious process, exacerbation, or acute symptoms during the 30 days before the inclusion in the study. The IL-2 and IFN-gamma levels in the obese asthmatic group were lower than in the other three groups. IL 4 levels in the obese asthmatic group were almost equal to those of the asthmatic group and more than in the other two groups, without significant difference. There were higher levels of TLR2 and TLR9 in obese asthmatic patients than in the other three groups. There is a decrease in Th1 cytokines in obese asthmatic patients, and we only found a trend to an increased Th2 profile. Patients studied do not appear to fit into any of the endotypes described until now. This is the first study showing the high expression of TLR2 and TLR9 in obese asthmatic patients. It is necessary to study other cytokines in obese asthmatic patients to see if it is possible to fit them into any of the already described endotypes or if it is a distinct endotype. PMID- 24801458 TI - Emergency department visits for acute asthma by adults who ran out of their inhaled medications. AB - This study was designed to determine the percentage of asthma-related emergency department (ED) visits made by patients who recently ran out of their inhaled short-acting beta-agonists or inhaled corticosteroids and to characterize this understudied patient population. A secondary analysis was performed of data from four ED-based multicenter studies of acute asthma during 1996-1998 (n = 64 EDs). In each study, consecutive adult patients, aged 18-54 years, with acute asthma underwent a structured interview that assessed running out of inhaled medications. The analytic cohort comprised 1095 adults. Overall, 324 patients (30%; 95% confidence interval [CI], 27-32%) ran out of either of their inhaled beta-agonists or inhaled corticosteroids during the week before their index ED visit; 311 (28%; 95% CI, 26-31%) ran out of inhaled beta-agonists per se. Among a subset of 518 patients on inhaled corticosteroids, 55 patients (11%; 95% CI, 8 14%) ran out of inhaled corticosteroids. In the multivariable model, predictors of running out of an asthma medication were male sex, non-Hispanic black race, Hispanic ethnicity, no insurance, lower household income, and use of EDs as the preferred source of asthma prescriptions (all p < 0.05). Among patients who ran out of medications, 49% (95% CI, 43-55%) ran out of inhaled beta-agonists and 72% (95% CI, 58-84%) ran out of inhaled corticosteroids, before onset of their acute asthma symptoms. In 1095 adult ED patients with acute asthma, we found that 30% ran out of their inhaled asthma medications before the ED visit. Asthma patients who ran out of medications had sociodemographic characteristics that may help with identification of preventable ED visits. Multifaceted strategies needed to ensure optimal use of inhaled medications are warranted. PMID- 24801459 TI - Airway acidification in childhood asthma exacerbations. AB - Exhaled breath condensate (EBC) is being used increasingly to sample airway lining fluid. In asthmatic patients, the concentration of pH in EBC has been found to be decreased and to be related to airway inflammation. The aim of this study was to determine exhaled pH levels during acute asthma exacerbations in relation to pharmacologic treatment in asthmatic children and compare these with control subjects. Twelve asthmatic children with asthma exacerbation and 27 healthy children were enrolled. Clinical observations and pH in EBC before and after standard treatment for asthma attack, based administration of inhaled beta2 agonist, and corticosteroid, according to international Global Initiative for Asthma guidelines, were compared with those in healthy subjects. All children performed skin-prick tests to aeroallergens. Asthmatic children underwent spirometry. Exhaled pH levels were significantly lower in children with asthma exacerbation before treatment (mean +/- SD = 7.87 +/- 0.66; p = 0.03) but not after treatment (8.11 +/- 0.06; p = 0.40) compared with controls (8.12 + 0.19). Intragroup analyses found that condensate pH levels in asthmatic children before treatment were lower, but not significantly, than those after treatment. No correlation was found between pH values and treatment with systemic corticosteroids or lung function. Asthmatic children were atopic in 75% of cases. Levels of pH are decreased in EBC of asthmatic children with exacerbation before treatment. Larger studies are required to determine whether EBC pH levels may be a useful noninvasive biomarker to guide treatment of asthma exacerbations in childhood. PMID- 24801460 TI - Quality of life issues ranging from the burden of ocular and nasal allergies to the anxiety associated with having to carry self-injectable epinephrine for insect sting allergy. PMID- 24801461 TI - Evaluation and management of a patient with multiple drug allergies. AB - Multiple drug allergy syndrome (MDAS) is a clinical diagnosis made in patients with adverse reactions to two or more structurally unrelated drugs with an underlying immune-mediated mechanism causing the reaction. The evaluation of a patient with MDAS begins with a comprehensive drug allergy history and consideration of the underlying immune mechanism for each reaction. Skin testing is a useful diagnostic tool; however, the only validated immediate hypersensitivity skin testing is for penicillin where the antigenic determinants have been identified. Skin testing to most other drugs, although not validated, can be considered using a nonirritating concentration (NIC). In general, skin test positivity using an NIC suggests that the drug should be avoided, but a negative result does not rule out an IgE-mediated allergy. A test dose, also called a drug provocation test, graded oral challenge, or incremental challenge, should be performed when there is a low likelihood of an IgE-mediated mechanism for the reaction. In patients with a recent IgE-mediated hypersensitivity reaction or positive skin testing with no reasonable alternative treatment options, desensitization protocols can be used to allow the patient to safely receive a necessary drug. The evaluation of patients with MDAS is both challenging and time-consuming for the practicing allergist, who must systematically evaluate each reaction to help determine which drugs can be safely used again in the future. The molecular mechanisms and risk factors for this condition remain poorly understood, but research to further understand this condition is ongoing. PMID- 24801462 TI - The role of Mycoplasma pneumoniae infection in the initial onset and exacerbations of asthma. AB - Asthma is a disease in which airway hyperresponsiveness, increased airway contraction, and airway secretion occur as a result of allergic airway inflammation. Mycoplasma infections are well known to exacerbate asthma pathology as well as to cause the onset of asthma itself. Mechanisms of airway epithelial injury, activation of innate immunity, or increased Th2-dominant immune responses caused by community-acquired distress syndrome toxin (CARDSTx) or diacylated lipoprotein have been reported in exacerbations or the onset of asthma because of Mycoplasma infections. In addition, involvement of cysteinyl leukotriene and transforming growth factor beta has been reported in the increased airway hyperresponsiveness and exacerbation of airway remodeling by Mycoplasma. Recent evidence suggests that treatment with macrolides improves asthma control through an inhibitory action on airway inflammation as well as by eradicating Mycoplasma. PMID- 24801463 TI - Ocular and nasal allergy symptom burden in America: the Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) surveys. AB - Previous nationwide surveys of allergies in the United States have focused on nasal symptoms, but ocular symptoms are also relevant. This study determines the effects of ocular and nasal allergies on patients' lives. Telephone surveys of randomly selected U.S. households (the patient survey) and health care providers (provider survey) were conducted in the United States in 2012. Study participants were 2765 people >=5 years of age who had ever been diagnosed with nasal or ocular allergies and 500 health care providers in seven specialties. Respondents to the patient survey reported a bimodal seasonal distribution of allergy symptoms, with peaks in March to May and September. Nasal congestion was the most common of the symptoms rated as "extremely bothersome" (39% of respondents), followed by red, itchy eyes (34%; p = 0.84 for difference in extreme bothersomeness of nasal and ocular symptoms). Twenty-nine percent of respondents reported that their or their child's daily life was impacted "a lot" when allergy symptoms were at their worst. Workers rated their mean productivity at 29% lower when allergy symptoms were at their worst (p < 0.001 compared with no symptoms). Providers reported that itchy eyes was the symptom causing most patients to seek medical treatment by pediatricians (73%), ophthalmologist/optometrists (72%), and nurse practitioners or physician assistants (62%), whereas nasal congestion was the symptom causing most patients to seek treatment from otolaryngologists (85%), allergist/immunologists (79%), and family medicine practitioners (64%). Ocular and nasal allergy symptoms substantially affected patients' lives and were comparable in their impact. PMID- 24801464 TI - The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: patients' experience with allergen immunotherapy. AB - Allergen immunotherapy (AIT) is used for the treatment of allergic rhinoconjunctivitis as a subcutaneous injection (subcutaneous immunotherapy [SCIT]). Extracts used for SCIT are also used off-label to formulate a liquid delivered as sublingual drops (sublingual immunotherapy [SLIT]). This study was designed to survey patients' experiences and beliefs regarding SCIT and SLIT. People who had ever been diagnosed with nasal and/or ocular allergies were identified in a 2012 telephone survey of U.S. households. Respondents were asked questions about their or their child's use of SCIT and SLIT and their beliefs about AIT. Of 2765 respondents, 46.5% had ever heard of AIT and 22.7% had ever initiated it: 20.9% with SCIT and 1.8% with SLIT (p < 0.0001). The most frequently cited reason for beginning AIT was that symptoms were unresolved with other medications (SCIT, 32.1%; SLIT, 14.0%). Some or full symptom relief was reported by 74.9% of respondents treated with SCIT and 66.0% of those treated with SLIT (p = 0.17 for SCIT versus SLIT). Approximately one-third of respondents who had ever heard of or had been treated with AIT said "don't know" when asked if immunotherapy controls allergy symptoms for years (33.6%), is a very safe treatment (29.3%), or can cure allergy symptoms (27.5%). Effective relief of allergy symptoms was cited most often as the primary benefit of SCIT (37.8%) and convenience was the primary benefit of SLIT (14%). Only one-fifth of respondents had ever been treated with AIT, largely with SCIT. More than one-half of respondents had never heard of AIT and respondents' beliefs indicated a need for educational efforts. PMID- 24801465 TI - The role of zinc, copper, plasma glutathione peroxidase enzyme, and vitamins in the development of allergic diseases in early childhood: The Polish mother and child cohort study. AB - It has been hypothesized that the increase in allergic disorders may, in part, be a consequence of changing diet. The primary aim of this study was to assess the associations between occurrence of atopic dermatitis; food allergy; the incidence of wheeze inhaled glucocorticosteroid use in children during the 1st year of life; and cord blood concentrations of copper, zinc, vitamins (A and E), and glutathione peroxidase activity. We evaluated 240 1-year-old children from the Polish Mother and Child Cohort Study. Women were interviewed during pregnancy to collect demographic and socioeconomic data and medical and reproductive history. Exposure to tobacco constituents was assessed based on questionnaire data. At delivery, umbilical cord blood plasma was sampled. One year after the birth, the child's exposure and health status were examined. In the analyses a multivariable model was used. Higher zinc and copper concentrations in cord blood were associated with increased likelihood of wheezing in 1-year-old children. This effect was seen only among children exposed to tobacco smoke at home. We also showed significantly lower activity of glutathione peroxidase enzyme 3 in umbilical cord blood plasma of children with atopic dermatitis during the 1st year of life. There were no significant associations between vitamin A and E concentrations in plasma and children's health. We showed imbalance in the antioxidant defense system in cord blood, which may lead to development of atopic dermatitis or wheezing in infancy. The association between maternal nutrient status during pregnancy and child's health is complex and interacts with other environmental factors such as tobacco exposure. This study was a part of the clinical trial NCT01861548 registered at ClinicalTrials.gov. PMID- 24801466 TI - Omega-3 fatty acids and asthma in children. AB - The purpose of this study was to summarize and analyze the results of studies supporting the use of omega-3 fatty acids for their therapeutic and preventive value in childhood asthma in light of recent genetic evidence strongly suggesting a pathogenetic role in asthma and to discuss the implications of these findings for future research. Although a considerable number of observational studies have been conducted in children showing a beneficial effect of omega-3 dietary intake in asthma, a fully well-designed, rigorously conducted investigational study is still lacking. Additionally, the few interventional trials with omega-3 supplementation conducted in asthmatic children have often yielded conflicting results. The genetic polymorphism and the gene-nutritional interactions that accompany asthma can be the missing factors and may explain the inconsistent results found in these interventional trials. Therefore, the analyses of key genes variants should be included in future studies to thoroughly investigate the effects of long-chain polyunsaturated fatty acid on asthma. Although a definitive conclusion can not be made supporting a beneficial effect of dietary modification or supplementation with omega-3 for the prevention or modification of asthmatic disease in children, there is sufficient evidence to support this possibility. There is, therefore, a clear need for future research to investigate the feasibility of this dietetic approach to reduce the likely development of asthma and/or the successful treatment of asthmatic disease. From a public health perspective, if a dietetic approach is successfully documented, even if only in a cohort of susceptible individuals, it would offer a far better management tool than currently available, better tolerated, and, in the long run, more cost effective. PMID- 24801467 TI - The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients. AB - Measurement of fractional nitric oxide concentration in exhaled breath (FENO) is a simple, noninvasive method to evaluate eosinophilic airway inflammation. Nitric oxide (NO) arising from peripheral small airways/alveoli (alveolar NO concentration [CalvNO]) can be estimated using multiple flow rates and a two compartment model of the airways and alveoli. Omalizumab, a monoclonal anti-IgE antibody, is approved for the treatment of allergic asthma and also has been shown to decrease FENO levels. This study investigates the effects of omalizumab, when added to an inhaled corticosteroid (ICS) +/- long-acting beta-adrenergic agonist (LABA) treatment, on peripheral small airway/alveolar inflammation reflected by FENO measurements at higher flow rates. We hypothesized that compared with placebo, omalizumab would decrease CalvNO levels in asthmatic patients on ICS +/- LABA. Forty-two patients with moderate-to-severe asthma were randomly assigned 2:1 to either omalizumab (n = 29) or placebo treatment (n = 13) for 16 weeks. Selection criteria included moderate-to-severe asthmatic patients on an ICS +/- LABA, positive skin test to one or more perennial allergen, screening FENO of >13 ppb, and a baseline IgE of 30-700 IU/mL. FENO measured at multiple flow rates was used to calculate CalvNO over the course of 16 weeks. FENO levels decrease with increasing flow rates (p < 0.05 repeated measures ANOVA) but no differences between the placebo and treatment groups in overall CalvNO levels or in the changes of CalvNO with time were found. Omalizumab did not lower the CalvNO, which could have been caused by the initial low CalvNO in this asthmatic population. The model used may not be completely sufficient and/or sensitive enough to detect small changes in CalvNO. PMID- 24801468 TI - Barriers to self-administered therapy for hereditary angioedema. AB - Presently, the movement of care for hereditary angioedema (HAE) is out of the clinic, emergency department, and hospitals and into the home. Much of the transition relies on specialized nurses who teach patients self-administration skills. Our goal was to assess nurses to uncover barriers that they have encountered in an effort to improve self-therapy education and patient care. A survey of 21 questions was sent to 38 HAE home care nurses throughout the United States. Results were collected anonymously and data were analyzed. Nurses feel that there is an increased need for teaching patients self-therapy skills. The majority are very comfortable teaching self-administration and troubleshooting associated problems. Perceived difficulties in providing adequate teaching include distance to patient's home and logistics of coordinating, scheduling, and obtaining supplies. Teaching is preferred when done at home by a visiting nurse with a care partner available and multiple training sessions are needed. Very few patients refused self-administration after initially being taught; reasons cited for refusal include fear of injection or infection, lack of skills, interference of daily activities, and financial restraints. As for nurses, they were most worried about safety, lack of skill retention, and inappropriate use of the drug. Self- administration of HAE treatment is increasingly more accessible and should be offered to patients as a safe and practical option. The barriers to self administration revealed in this study include distance to the patient's home, coordinating care, obtaining medications/equipment, and scheduling training sessions. Moving to self- or home treatment through nursing instruction will improve patient's independence and quality of life, lead to earlier therapy, and reduce costs associated with care. PMID- 24801469 TI - Home treatment of attacks with conestat alfa in hereditary angioedema due to C1 inhibitor deficiency. AB - Conestat alfa, a recombinant human C1 inhibitor (rhC1-INH) is a novel therapeutic option for the acute treatment of hereditary angioedema due to C1-INH (HAE-C1 INH) deficiency. Our aim was to investigate the efficacy and safety profile of conestat alfa in patients with HAE-C1-INH, under real-life conditions. We analyzed 65 edematous episodes requiring acute treatment and occurring in two female HAE-C1-INH patients. The patients were treated at home with rhC1-INH per occasion. They recorded the time of rhC1-INH administration, the time to the onset of improvement, and time to the complete resolution of symptoms, as well as the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Thirty-three HAE attacks occurred in submucosal tissue, 17 in subcutaneous tissue, and 15 had mixed locations. After the administration of rhC1-INH, clinical symptoms improved within 0.50 (0.17-4.50 hours) hours and resolved completely within 9.00 (1.67-58.75 hours) hours. The time between the onset of the attack and the administration of rhC1-INH was correlated with the time when the symptoms stopped worsening (R = 0.3212; p = 0.0096) and the time to complete resolution of the symptoms (R = 0.4774; p < 0.0001). The time to response to the drug differed with attack location. The efficacy and safety of rhC1-INH persisted after repeated use. None of the patients experienced a recurrence of the HAE attack or drug-related systemic adverse events. The mean VAS score of patient satisfaction was 93.14. Home treatment with rhC1-INH was an effective and well-tolerated therapy for all types of HAE attacks. PMID- 24801470 TI - The relationship between insect sting allergy treatment and patient anxiety and depression. AB - Quality of life is affected by history of bee sting allergy. In addition, worry about being stung and also the need to use self-injection of medicine can create or increase anxiety, which can further compromise a patient's ability to enjoy the outdoors and participate in activities. We sought to determine the depression and anxiety in three groups of individuals. We assessed patients with bee sting allergy without epinephrine, bee sting allergy with epinephrine, and bee sting allergy receiving immunotherapy (venom immunotherapy [VIT]). We use two standardized surveys after having Intuitional Review Board approval to determine depression and anxiety in the three cohorts noted previously. We compared the three groups using Wilcoxon rank sum test and statistical significance was considered present for a value of p = 0.05. Overall, the epinephrine group had higher mean anxiety and depression scores compared with the other treatment groups. The VIT group had the lowest mean and median scores for both anxiety and depression. It appears that VIT not only decreases the risk of anaphylaxis and death, but also improves quality of life by reduction of anxiety and depression, especially in female subjects. We found that VIT patients, when compared with nontreated and treated only with epinephrine, had lower anxiety and depression scores. PMID- 24801471 TI - For the patient. PMID- 24801473 TI - Construction of multiple trade-offs to obtain arbitrary singularities of adaptive dynamics. AB - Evolutionary singularities are central to the adaptive dynamics of evolving traits. The evolutionary singularities are strongly affected by the shape of any trade-off functions a model assumes, yet the trade-off functions are often chosen in an ad hoc manner, which may unjustifiably constrain the evolutionary dynamics exhibited by the model. To avoid this problem, critical function analysis has been used to find a trade-off function that yields a certain evolutionary singularity such as an evolutionary branching point. Here I extend this method to multiple trade-offs parameterized with a scalar strategy. I show that the trade off functions can be chosen such that an arbitrary point in the viability domain of the trait space is a singularity of an arbitrary type, provided (next to certain non-degeneracy conditions) that the model has at least two environmental feedback variables and at least as many trade-offs as feedback variables. The proof is constructive, i.e., it provides an algorithm to find trade-off functions that yield the desired singularity. I illustrate the construction of trade-offs with an example where the virulence of a pathogen evolves in a small ecosystem of a host, its pathogen, a predator that attacks the host and an alternative prey of the predator. PMID- 24801474 TI - The impact of abdominal compression on outcome in patients treated with stereotactic body radiotherapy for primary lung cancer. AB - The aim of this study was to evaluate the impact of abdominal compression (AC) on outcome in patients treated with stereotactic body radiotherapy (SBRT) for primary lung cancer. We retrospectively reviewed data for 47 patients with histologically proven non-small cell lung cancer and lung tumour motion >= 8 mm treated with SBRT. Setup error was corrected based on bony structure. The differences in overall survival (OS), local control (LC) and disease-free survival (DFS) were evaluated to compare patients treated with AC (n = 22) and without AC (n = 25). The median follow-up was 42.6 months (range, 1.4-94.6 months). The differences in the 3-year OS, LC and DFS rate between the two groups were not statistically significant (P = 0.909, 0.209 and 0.639, respectively). However, the largest difference was observed in the LC rate, which was 82.5% (95% CI, 54.9-94.0%) for patients treated without AC and 65.4% (95% CI, 40.2-82.0%) for those treated with AC. After stratifying the patients into prognostic groups based on sex and T-stage, the LC difference increased in the group with an unfavourable prognosis. The present study suggests that AC might be associated with a worse LC rate after SBRT using a bony-structure-based set-up. PMID- 24801475 TI - Adjuvant single-fraction radiotherapy is safe and effective for intractable keloids. AB - The aim of this study was to assess the feasibility and efficacy of high-dose, single-fraction electron beam radiotherapy for therapy-resistant keloids. Before 2010, intractable keloids were treated at our institution with post-operative irradiation of 6-15 Gy in 3-5 fractionations. For convenience and cost effectiveness, we have changed our treatment protocol to high-dose single fraction radiotherapy. A total of 12 patients with 16 keloid lesions were treated from January 2010 to January 2013 in our department. A 10-Gy dose of electron irradiation was given within 72 h of the surgical excision. The mean follow-up period was 20 months. Treatments were well tolerated, and there was no recurrence in any of the patients. Severe adverse effects were not observed. Surgical excision of the keloid, followed by immediate, single-fraction, high-dose radiotherapy, is both safe and effective in preventing recurrence of therapy resistant keloids. PMID- 24801476 TI - Marketing coprovided activities. AB - Coproviding is a wonderful way for two or more organizations to work together to provide continuing nursing education. To be transparent to the learners, marketing materials identify the parties involved and prominently note the name of the organization accountable for developing the activity and awarding the contact hours. PMID- 24801477 TI - From violence exposure to development of sexual risk in low-income urban girls: the role of psychopathology. AB - This longitudinal study examined psychopathology as an explanatory mechanism linking childhood violence exposure (CVE) to sexual risk in 177 African American girls recruited from mental health clinics serving low-income communities in Chicago. Beginning at average age 14, girls completed five interviews over 2 years and a sixth assessment including trauma history. CVE reflected sexual, physical, or witnessed violence before age 12. Latent growth modeling accounted for developmental change across the six time points. Externalizing, but not internalizing, symptoms mediated the pathway from CVE to number of partners (indirect effect = .16, 95 % CIBCBS = .04-.29) and inconsistent condom use (indirect effect = .11, CIBCBS = .004-.21). Externalizing problems associated with CVE may help to explain its relationship with sexual risk in low-income, treatment-seeking African American girls. Behavioral interventions addressing aggression, impulsivity, and general risk-taking may be most effective in reducing sexual risk in this population. PMID- 24801478 TI - Pharmacokinetics of sevoflurane elimination from respiratory gas and blood after coronary artery bypass grafting surgery. AB - PURPOSE: Sevoflurane, with a relative low blood-gas partition coefficient, is an ideal anesthetic to achieve rapid offset and recovery from general anesthesia. This study will determine the profiles of four concentration-time curves to characterize the pharmacokinetics of sevoflurane elimination. METHODS: Eight patients (aged 54-76 years) undergoing coronary arterial bypass grafting surgery were enrolled in this study. At the end of surgery, anesthetic gas and blood were sampled 20 min before and after stopping sevoflurane administration, with prior maintenance of a fixed 5% inspired sevoflurane (CIsev) in 6 L/min oxygen flow for 60 min before the cessation of sevoflurane administration for the subsequent 20 min elimination. An infrared analyzer was used to determine both CIsev and end tidal sevoflurane (CEsev). The sevoflurane concentrations in the internal jugular bulb (Jsev), arterial (Asev) and pulmonary arterial blood (PAsev) were analyzed by gas chromatography, and cardiac output was measured using an Opti-Q pulmonary artery catheter. RESULTS: A bi-exponential decay function was the best fit for the CEsev,Jsev, Asev, and PAsev time curves. There were two distinct components, the initial 5-min fast or distribution phase and the subsequent 15-min slow or elimination phase. Before cessation of the sevoflurane supplement, the step-down concentration of sevoflurane was listed in the following order: CIsev > CEsev > Asev ? Jsev > PAsev. During the elimination phase, the fastest decay occurred in CEsev, followed by Jsev, Asev and PAsev. Therefore, a reverse step-down pattern was observed (PAsev > Asev ? Jsev > CEsev) after 20 min. The ratio of Asev to CEsev was 89% at baseline before stopping sevoflurane administration, but the ratio of Asev to CEsev increased to 128% at the twentieth min of the sevoflurane elimination phase. CONCLUSIONS: During elimination, the initial washout of sevoflurane from the functional residual capacity of the lungs was reflected in the fast component of the CEsev, Jsev, Asev, and PAsev time curves. In contrast, the slow component was dominated by the tangible effects of the physiological membrane barriers, such as the alveoli-pulmonary capillary and blood-brain barriers. PMID- 24801479 TI - Development and implementation of a proficiency testing program for Luminex bead based cytokine assays. AB - Luminex bead array assays are widely used for rapid biomarker quantification due to the ability to measure up to 100 unique analytes in a single well of a 96-well plate. There has been, however, no comprehensive analysis of variables impacting assay performance, nor development of a standardized proficiency testing program for laboratories performing these assays. To meet this need, the NIH/NIAID and the Cancer Immunotherapy Consortium of the Cancer Research Institute collaborated to develop and implement a Luminex assay proficiency testing program as part of the NIH/NIAID-sponsored External Quality Assurance Program Oversight Laboratory (EQAPOL) at Duke University. The program currently monitors 25 domestic and international sites with two external proficiency panels per year. Each panel includes a de-identified commercial Luminex assay kit with standards to quantify human IFNgamma, TNFalpha, IL-6, IL-10 and IL-2, and a series of recombinant cytokine-spiked human serum samples. All aspects of panel development, testing and shipping are performed under GCLP by EQAPOL support teams. Following development testing, a comprehensive site proficiency scoring system comprised of timeliness, protocol adherence, accuracy and precision was implemented. The overall mean proficiency score across three rounds of testing has remained stable (EP3: 76%, EP4: 75%, EP5: 77%); however, a more detailed analysis of site reported results indicates a significant improvement of intra- (within) and inter (between) site variation, suggesting that training and remediation for poor performing sites may be having a positive impact on proficiency. Through continued proficiency testing, identification of variables affecting Luminex assay outcomes will strengthen efforts to bring standardization to the field. PMID- 24801480 TI - Enhanced doxorubicin delivery to the brain administered through glutathione PEGylated liposomal doxorubicin (2B3-101) as compared with generic Caelyx,((r))/Doxil((r))--a cerebral open flow microperfusion pilot study. AB - The neuroprotective blood-brain barrier (BBB) keeps many drug candidates below therapeutic levels in the central nervous system. Glutathione PEGylated liposomal doxorubicin (2B3-101) has been developed to safely enhance the delivery of doxorubicin to brain tumors. However, doxorubicin concentration in extracellular brain fluid cannot yet be reliably measured using conventional techniques. Cerebral open flow microperfusion (cOFM), a recently developed sampling technique, allows monitoring of drug concentrations in the brain independent of molecular weight and lipophilicity. In combination with cOFM sampling, sodium fluorescein (NaF) is used as a marker for BBB integrity. Rats received one intravenous dose of 7 mg/kg of either 2B3-101 or PEGylated liposomal doxorubicin (generic Caelyx((r))). Blood and cOFM sampling was performed for 5 h after dose injection. NaF concentration in the brain was monitored and remained low indicating an intact BBB. The brain-to-blood ratio of doxorubicin was 4.8-fold higher after administration of 2B3-101 as compared with generic Caelyx((r)) (p = 0.0016). In conclusion, by using cOFM it was possible to show that 2B3-101 leads to enhanced doxorubicin concentration in the brain without affecting the BBB integrity. PMID- 24801482 TI - A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study. AB - Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419) versus low (n = 183) mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5*10(-5), 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 *10(-6)). In this analysis, one of the SNPs (rs789859) showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115) were nominally significant (lowest p-value 3.278 * 10(-4)). Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64). The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study. PMID- 24801483 TI - A Dynamically Optimized SSVEP Brain-Computer Interface (BCI) Speller. AB - The aim of this study was to design a dynamically optimized steady-state visually evoked potential (SSVEP) brain-computer interface (BCI) system with enhanced performance relative to previous SSVEP BCIs in terms of the number of items selectable on the interface, accuracy, and speed. In this approach, the row/column (RC) paradigm was employed in a SSVEP speller to increase the number of items. The target is detected by subsequently determining the row and column coordinates. To improve spelling accuracy, we added a posterior processing after the canonical correlation analysis (CCA) approach to reduce the interfrequency variation between different subjects and named the new signal processing method CCA-RV, and designed a real-time biofeedback mechanism to increase attention on the visual stimuli. To achieve reasonable online spelling speed, both fixed and dynamic approaches for setting the optimal stimulus duration were implemented and compared. Experimental results for 11 subjects suggest that the CCA-RV method and the real-time biofeedback effectively increased accuracy compared with CCA and the absence of real-time feedback, respectively. In addition, both optimization approaches for setting stimulus duration achieved reasonable online spelling performance. However, the dynamic optimization approach yielded a higher practical information transfer rate (PITR) than the fixed optimization approach. The average online PITR achieved by the proposed adaptive SSVEP speller, including the time required for breaks between selections and error correction, was 41.08 bit/min. These results indicate that our BCI speller is promising for use in SSVEP-based BCI applications. PMID- 24801481 TI - Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1alpha in db/db mice. AB - Peroxisome proliferator-activated receptor (PPAR)-alpha, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARalpha expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha)-estrogen-related receptor (ERR)-1alpha-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL 2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1alpha-ERR-1alpha, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1alpha-ERR-1alpha-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy. PMID- 24801484 TI - Block & replace regime versus titration regime of antithyroid drugs for the treatment of Graves' disease: a retrospective observational study. AB - CONTEXT: Two widely used antithyroid drug (ATD) regimes for Graves' disease (GD) include the 'block & replace' (B&R) regime (a fixed high-dose of ATD combined with levothyroxine) and the 'titration' regime (a titrating dose of ATD). Anecdotally, it is believed that B&R is less prone to fluctuating thyroid function. OBJECTIVE: To study whether, in routine clinical practice, the B&R regime, compared with the titration regime, is associated with more stable thyroid function. METHODS: We retrospectively analysed case-records for 450 patients treated with ATDs for GD at a secondary care hospital. Exclusion criteria included treatment with ATDs for <6 months, thyrotoxicosis due to other causes, treatment with radioiodine or thyroidectomy and pregnancy. RESULTS: Two hundred and twenty three patients were treated with the B&R regime ('B&R group'), 149 with the titration regime ('titration group') and 78 with both regimes. The number of thyroid function tests (TFTs) performed per year (mean(SD): 3.2(1.2) vs 3.4(1.5); adjusted mean difference = -0.4; 95% CI: -0.7 to -0.1; and P = 0.008) and the number of hospital clinic visits per year (mean (SD): 2.9 (1.0) vs 3.2 (1.3); adjusted mean difference = -0.4; 95% CI: -0.7 to -0.2; and P = 0.002) were lower in the B&R group than the titration group. The number of abnormal TFT results per year was similar in the two groups (mean(SD): 1.8(1.3) vs 1.8(1.4); adjusted mean difference = 0.05; 95%CI: -0.3 to 0.4; and P = 0.74). CONCLUSIONS: In this retrospective study, there was little evidence that patients under B&R have more stable thyroid function. Further data from prospective studies, however, are needed to confirm this finding. PMID- 24801485 TI - Assessing the Bronsted basicity of diaminoboryl anions: reactivity toward methylated benzenes and dihydrogen. AB - Treatment of toluene or p-xylene with diaminoboryllithium results in consecutive reactions, involving boryl-anion-mediated deprotonation at the benzylic position followed by nucleophilic substitution at the boron center, producing benzylborane species and LiH. Diaminoboryllithium also cleaves H2 heterolytically affording diaminohydroborane and LiH, while the reaction of lithium diaminoboryl(bromo)cuprate with H2 takes place accompanied by reduction of Cu(I) to give diaminohydroborane, LiH, and Cu(0). PMID- 24801486 TI - Solventless oxidative coupling of amines to imines by using transition-metal-free metal-organic frameworks. AB - A highly efficient, simple, and versatile transition-metal-free metal-organic framework catalytic system is proposed for the oxidative coupling of amines to imines. The catalytic protocol features high activities and selectivities to target products; compatibility with a variety of substrates, including aliphatic amines and secondary amines; and the possibility to efficiently and selectively promote amine cross-coupling reactions. A high stability and recyclability of the catalyst is also observed under the investigated conditions. Insights into the reaction mechanism indicate the formation of a superoxide species able to efficiently promote oxidative couplings. PMID- 24801487 TI - Cytotoxic Effects of a Novel Thialo Benzene Derivative 2,4-Dithiophenoxy-1-iodo-4 bromobenzene (C18H12S2IBr) in L929 Cells. AB - The aim of this study was to compare the cytotoxic effects of a newly synthesized thialo benzene derivative 2,4-dithiophenoxy-1-iodo-4-bromobenzene (C18H12S2IBr) and a well-known antifungal agent, fluconazole, in L929 cells. L929 cells were treated with 250, 500, or 1000 ug/mL of C18H12S2IBr and with the same doses of fluconazole. Cytotoxicity tests including 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT), lactate dehydrogenase (LDH) leakage, and protein content were compared. Glucose and lactate concentrations were measured to determine alterations in metabolic activity. Apoptosis was investigated by TUNEL test and results were supported with survivin enzyme-linked immunosorbent assay. Treatment with C18H12S2IBr resulted in a concentration-dependent cytotoxicity as indicated by MTT, LDH leakage assay, and decreased protein concentration. The loss of cell viability and the increased LDH leakage in 500 ug/mL and 1000 ug/mL C18H12S2IBr and fluconazole groups indicated cell membrane damage and necrotic cell death. In all groups, metabolic activities were altered but apoptosis was not induced. We have previously investigated lower doses of C18H12S2IBr; there was no cytotoxicity in L929 cells. In this study, higher doses caused cytotoxicity and alterations in metabolic activity . When we consider the similar results obtained from fluconazole and especially the lowest dose of C18H12S2IBr, this newly synthesized compound may be a good alternative antifungal agent. PMID- 24801488 TI - A 26-Week Toxicity Assessment of AIR001 (Sodium Nitrite) by Inhalation Exposure in Rats and by Intravenous Administration in Dogs. AB - Historically, nitrogen oxides (NOx) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NOx have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the prospect that inhaled nitrite will lower pulmonary blood pressure (BP) in patients with pulmonary arterial hypertension (PAH), a disease with poor prognosis due to the lack of effective treatment. To characterize potential chronic toxicity associated with inhaled AIR001 (sodium nitrite) for use in the treatment of PAH, 26-week exposures to AIR001 were carried out by inhalation administration in rats and by intravenous infusion in dogs. The studies revealed that methemoglobinemia was the primary adverse effect in both species. Methemoglobin levels less than 40% were well tolerated in both species, while levels greater than 50% methemoglobin caused death in some rats. Additionally, a decrease in systemic BP was also observed with inhaled AIR001 exposure in dogs. These acute secondary and exaggerated pharmacological effects occurred daily throughout the 26-week treatment period. Chronic exposure did not alter the magnitude of either methemoglobinemia or hypotension or result in additional toxicity or compensatory responses. Based on the exposure levels that produced these pharmacodynamic responses in animals, relative to those measured in early clinical studies, it appears that an adequate margin of safety exists to support the continued clinical development of inhaled AIR001. PMID- 24801489 TI - Mustard Gas Inhalation Injury: Therapeutic Strategy. AB - Mustard gas (sulfur mustard [SM], bis-[2-chloroethyl] sulfide) is a vesicating chemical warfare agent and a potential chemical terrorism agent. Exposure of SM causes debilitating skin blisters (vesication) and injury to the eyes and the respiratory tract; of these, the respiratory injury, if severe, may even be fatal. Therefore, developing an effective therapeutic strategy to protect against SM-induced respiratory injury is an urgent priority of not only the US military but also the civilian antiterrorism agencies, for example, the Homeland Security. Toward developing a respiratory medical countermeasure for SM, four different classes of therapeutic compounds have been evaluated in the past: anti inflammatory compounds, antioxidants, protease inhibitors and antiapoptotic compounds. This review examines all of these different options; however, it suggests that preventing cell death by inhibiting apoptosis seems to be a compelling strategy but possibly dependent on adjunct therapies using the other drugs, that is, anti-inflammatory, antioxidant, and protease inhibitor compounds. PMID- 24801490 TI - Comparison of monoclonal gammopathy of undetermined significance-associated neuropathy and chronic inflammatory demyelinating polyneuropathy patients. AB - OBJECTIVES: There are varying reports on whether monoclonal gammopathy of undetermined significance-associated neuropathy (MGUSN) patients are distinguishable from those with chronic inflammatory demyelinating polyneuropathy (CIDP) and whether specific MGUSN subclasses are associated with specific clinical phenotypes. METHODS: We performed a retrospective chart review of MGUSN (n = 56) and CIDP (n = 67) patients. Data extracted included: demographics, neurological examination, and nerve conduction studies (NCS) at baseline and last visit. Clinical status was rated as 0 = worse, 1 = unchanged, 2 = stabilized after a declining course, or 3 = improved. The electrophysiology data were rated as 0 = worse, 1 = stable, or 2 = improved. Statistical analyses were performed using JMP (version 9.0.2 for Macintosh, from SAS). RESULTS: Seventy percent were males, aged 68.1 +/- 12.6 years with neuropathy for 9.8 +/- 6.8 years and follow up of 4.0 +/- 3.2 years. CIDP patients had more severe neuropathy, and were more likely to receive treatment and to respond. The clinical neuropathy status remained unchanged in 52.8 % of the MGUSN and 24.2 % of the CIDP patients, and stabilized in 7.6 % of MGUSN and 30.3 % of CIDP patients. IgM-MGUSN patients did not differ from other immunoglobulin subclasses in response to treatment. The clinical severity and the number of abnormal NCS parameters were greater in the demyelinating MGUSN in comparison to the axonal group. CONCLUSION: MGUSN patients have less severe neuropathy than CIDP patients, but among the MGUSN patients the severity is greater in the demyelinating and the IgM groups. MGUSN patients may do well without treatment and exposure to potential adverse effects. PMID- 24801491 TI - Safety and feasibility of nucleus accumbens stimulation in five patients with epilepsy. AB - In five adult patients with intractable partial epilepsy, safety and feasibility of chronic bilateral electrical stimulation of the nucleus accumbens (NAC) were assessed, also providing initial indications of therapeutic efficacy. Concurrent medication remained unchanged. In this phase 1 trial, clinical outcome parameters of interest were Quality of Life in Epilepsy questionnaire (QOLIE-31-P), Beck Depression Inventory, Mini International Neuropsychiatric Interview, neuropsychological testing, and Liverpool Seizure Severity Scale. Those data were obtained after 6 months of NAC stimulation and compared to the equivalent assessments made directly before implantation of electrodes. Additionally, monthly frequencies of simple partial seizures, complex partial seizures (CPS), and generalised tonic-clonic seizures (GTCS) were assessed during 3 months before electrode implantation and at the end of 6-month NAC stimulation. Proportion of responders, i.e. >=50 % reduction in frequency of disabling seizures (sum of CPS and GTCS), was calculated. Main findings were unchanged psychiatric and neuropsychological assessment and a significant decrease in seizure severity (p = 0.043). QOLIE-31-P total score trended towards improvement (p = 0.068). Two out of five participants were responders. The median reduction in frequency of disabling seizures was 37.5 %. In summary, we provide initial evidence for safety and feasibility of chronic electrical stimulation of the NAC in patients with intractable partial epilepsy, as indicated by largely unchanged neurocognitive function and psychiatric comorbidity. Even though our data are underpowered to reliably assess efficacy, the significant decrease in seizure severity provides an initial indication of antiictal efficacy of NAC stimulation. This calls for larger and at best randomised trials to further elucidate efficacy of NAC stimulation in patients with pharmacologically intractable epilepsy. PMID- 24801492 TI - Personal meaning, social support, and perceived stigma in individuals receiving HIV mental health services. AB - Human immunodeficiency virus (HIV) stigma represents a significant source of stress among individuals living with HIV disease, prompting interest in research to identify factors that may help to ameliorate the stress burden associated with HIV stigma. Consistent with this research line, the current study was conducted as a cross-sectional investigation examining associations between positive global personal meaning, social support, and perceived HIV stigma. Global personal meaning refers to beliefs and aspirations through which one ascribes value and purpose in living. The study sample was comprised of individuals living with HIV disease who presented for an initial visit in a specialty HIV mental health services program. In bivariate analyses, social support was negatively correlated with multidimensional aspects of HIV stigma that included distancing, blaming, and discrimination stigma, whereas personal meaning was negatively associated only with blaming stigma. In further analyses using structural equation modeling, social support significantly mediated the association between personal meaning and both distancing and blaming stigma. Interactions between positive personal meaning and social support may be useful to consider in future research on psychological resource factors and HIV stigma. Understanding these interactions may also inform clinical efforts to address HIV stigma concerns. PMID- 24801493 TI - Psychological support for children with diabetes: are the guidelines being met? AB - The significant role of psychosocial factors in the management of type 1 diabetes in youth has been well documented. The International Society for Pediatric and Adolescent Diabetes (ISPAD) therefore published the Clinical Practice Consensus Guidelines for psychological care of young patients. However, it is unclear if and how these guidelines are being implemented. A questionnaire was created to assess implementation of the guidelines and directed to physicians through the ISPAD listserve via a web-based survey. One hundred fifty-five participants from 47 countries completed the survey. Ninety-six percent of respondents reported that they work in a team with other professionals, and 95 % of teams discuss psychological difficulties associated with diabetes management. Seventy-two percent of respondents reported having "easy access" to a mental health specialist (MHS). In 56 % of practice settings, the MHS is considered to be part of the team; 43 % participate in routine clinic visits and 26 % see all patients. Seventy percent screen for psychological problems and 57 % assess family functioning. Psychosocial or behavioral interventions addressing psychosocial and regimen adherence difficulties are offered by 79 % of teams. Psychological care is available for many children with diabetes worldwide. Yet, nearly 30 % of teams do not have access to a MHS. More training in the recognition of psychosocial problems and counseling skills is warranted. More advocacy is needed to increase availability and utilization of psychological services in routine diabetes care. PMID- 24801494 TI - Magnetometry with nitrogen-vacancy defects in diamond. AB - The isolated electronic spin system of the nitrogen-vacancy (NV) centre in diamond offers unique possibilities to be employed as a nanoscale sensor for detection and imaging of weak magnetic fields. Magnetic imaging with nanometric resolution and field detection capabilities in the nanotesla range are enabled by the atomic-size and exceptionally long spin-coherence times of this naturally occurring defect. The exciting perspectives that ensue from these characteristics have triggered vivid experimental activities in the emerging field of 'NV magnetometry'. It is the purpose of this article to review the recent progress in high-sensitivity nanoscale NV magnetometry, generate an overview of the most pertinent results of the last years and highlight perspectives for future developments. We will present the physical principles that allow for magnetic field detection with NV centres and discuss first applications of NV magnetometers that have been demonstrated in the context of nano magnetism, mesoscopic physics and the life sciences. PMID- 24801495 TI - Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis. AB - OBJECTIVES: In preparation for a pediatric randomized controlled trial on thromboprophylaxis, we determined the frequency of catheter-related thrombosis in children. We also systematically reviewed the pediatric trials on thromboprophylaxis to evaluate its efficacy and to identify possible pitfalls in the conduct of these trials. PATIENTS/METHODS: We searched MEDLINE, EMBASE, Web of Science and the Cochrane Central Register for Controlled Trials for articles published until December 2013. We included cohort studies and trials on patients aged 0-18 years with central venous catheters who underwent active surveillance for thrombosis with radiologic imaging. We estimated the pooled frequency of thrombosis and the pooled risk ratio (RR) with thromboprophylaxis by using a random effects model. RESULTS: From 2651 articles identified, we analyzed 37 articles with 3128 patients. The pooled frequency of thrombosis was 0.20 (95% confidence interval [CI] 0.16-0.24). In 10 trials, we did not find evidence that heparin-bonded catheters (RR 0.34; 95%CI 0.01-7.68), unfractionated heparin (RR 0.93; 95% CI 0.57-1.51), low molecular weight heparin (RR 1.13; 95% CI 0.51 2.50), warfarin (RR 0.85; 95%CI 0.34-2.17), antithrombin concentrate (RR 0.76; 95% CI 0.38-1.55) or nitroglycerin (RR 1.53; 95%CI 0.57-4.10) reduced the risk of thrombosis. Most of the trials were either not powered for thrombosis or were powered to detect large, probably unachievable, reductions in thrombosis. Missing data on thrombosis also limited these trials. CONCLUSIONS: Catheter-related thrombosis is common in children. An adequately powered multicenter trial that can detect a modest, clinically significant reduction in thrombosis is critically needed. Missing outcome data should be minimized in this trial. PMID- 24801496 TI - PaFlexPepDock: parallel ab-initio docking of peptides onto their receptors with full flexibility based on Rosetta. AB - Structural information related to protein-peptide complexes can be very useful for novel drug discovery and design. The computational docking of protein and peptide can supplement the structural information available on protein-peptide interactions explored by experimental ways. Protein-peptide docking of this paper can be described as three processes that occur in parallel: ab-initio peptide folding, peptide docking with its receptor, and refinement of some flexible areas of the receptor as the peptide is approaching. Several existing methods have been used to sample the degrees of freedom in the three processes, which are usually triggered in an organized sequential scheme. In this paper, we proposed a parallel approach that combines all the three processes during the docking of a folding peptide with a flexible receptor. This approach mimics the actual protein peptide docking process in parallel way, and is expected to deliver better performance than sequential approaches. We used 22 unbound protein-peptide docking examples to evaluate our method. Our analysis of the results showed that the explicit refinement of the flexible areas of the receptor facilitated more accurate modeling of the interfaces of the complexes, while combining all of the moves in parallel helped the constructing of energy funnels for predictions. PMID- 24801497 TI - Human dendritic cell maturation and cytokine secretion upon stimulation with Bordetella pertussis filamentous haemagglutinin. AB - In addition to antibodies, Th1-type T cell responses are also important for long lasting protection against pertussis. However, upon immunization with the current acellular vaccines, many children fail to induce Th1-type responses, potentially due to immunomodulatory effects of some vaccine antigens, such as filamentous haemagglutinin (FHA). We therefore analysed the ability of FHA to modulate immune functions of human monocyte-derived dendritic cells (MDDC). FHA was purified from pertussis toxin (PTX)-deficient or from PTX- and adenylate cyclase-deficient Bordetella pertussis strains, and residual endotoxin was neutralized with polymyxin B. FHA from both strains induced phenotypic maturation of human MDDC and cytokine secretion (IL-10, IL-12p40, IL-12p70, IL-23 and IL-6). To identify the FHA domains responsible for MDDC immunomodulation, MDDC were stimulated with FHA containing a Gly->Ala substitution at its RGD site (FHA-RAD) or with an 80 kDa N-terminal moiety of FHA (Fha44), containing its heparin-binding site. Whereas FHA-RAD induced maturation and cytokine production comparable to those of FHA, Fha44 did not induce IL-10 production, but maturated MDDC at least partially. Nevertheless, Fha44 induced the secretion of IL-12p40, IL-12p70, IL-23 and IL-6 by MDDC, albeit at lower levels than FHA. Thus, FHA can modulate MDDC responses in multiple ways, and IL-10 induction can be dissociated from the induction of other cytokines. PMID- 24801498 TI - PCR array analysis of gene expression profiles in chronic active Epstein-Barr virus infection. AB - To determine the host cellular gene expression profiles in chronic active Epstein Barr virus infection (CAEBV), peripheral blood samples were obtained from three patients with CAEBV and investigated using a PCR array analysis that focused on T cell/B-cell activation. We identified six genes with expression levels that were tenfold higher in CAEBV patients compared with those in healthy controls. These results were verified by quantitative reverse transcription-PCR. We identified four highly upregulated genes, i.e., IL-10, IL-2, IFNGR1, and INHBA. These genes may be involved in inflammatory responses and cell proliferation, and they may contribute to the development and progression of CAEBV. PMID- 24801499 TI - Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity. AB - (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6 octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRalpha. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRalpha-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD. PMID- 24801500 TI - Combination radiofrequency ablation and percutaneous osteoplasty for palliative treatment of painful extraspinal bone metastasis: a single-center experience. AB - PURPOSE: To evaluate combined radiofrequency (RF) ablation and percutaneous osteoplasty (POP) in patients with painful extraspinal bone metastases. MATERIALS AND METHODS: In a retrospective study, 38 patients with 54 extraspinal bone metastases (ilium, n = 24; acetabulum, n = 21; femur, n = 7; ischium, n = 1; tibia, n = 1) were treated with RF ablation and POP. All patients had pain refractory to analgesic medication with intensity > 3 on a visual analog scale (VAS). Changes in quality of life were evaluated based on pain relief (VAS score), function on a Karnofsky performance scale, and analgesic dose before and immediately after the procedure and during follow-up. VAS score was the primary outcome, and the others were secondary outcomes. RESULTS: Technical success was achieved in 37 patients (97.4%). Mean VAS score declined significantly from 7.1 +/- 1.5 before treatment to 2.2 +/- 2.0 at 24 hours after treatment (P < .05), 1.6 +/- 1.8 at 3 months after treatment (P < .05), and 1.3 +/- 1.8 at 6 months after treatment (P < .05). Pain relief immediately after the procedure was reported by 35 patients (92.1%); pain regressed completely in 7 (18.4%) patients. After 6 months, narcotic analgesia had been suspended in 32 of 33 patients (97.0%). Pain was controlled by nonsteroidal antiinflammatory drugs in 8 patients (24.2%), and no analgesia was necessary in 24 patients (72.7%). Mean Karnofsky performance scale score after treatment was higher than before treatment (P < .05). The major complication rate was 2.6% (1 of 38 patients), with one case of vasovagal shock. The minor complication rate was 23.7% (9 of 38 patients). CONCLUSIONS: RF ablation with POP is effective for pain relief and functional recovery in patients with painful extraspinal bone metastases and can significantly improve quality of life. PMID- 24801501 TI - Feasibility of percutaneous cementoplasty combined with interventional internal fixation for impending pathologic fracture of the proximal femur. AB - PURPOSE: To evaluate the feasibility of percutaneous cementoplasty and interventional internal fixation for stabilization of impending pathologic fracture of the proximal femur. MATERIALS AND METHODS: From May 2012 to August 2013, six consecutive patients (three men and three women; median age, 58.33 y +/ 21.45; age range, 18-78 y) who underwent percutaneous cementoplasty plus interventional internal fixation for the treatment of metastases to the proximal femur were retrospectively analyzed. The Karnofsky performance status (KPS) and visual analog scale (VAS) score for pain were assessed before and 1 week after the procedure; moreover, the procedure duration, length of hospital stay, risk of fracture at the procedural site, and complications were assessed. RESULTS: The KPS increased from 66.67 +/- 12.11 (range, 60-90) before the procedure to 76.67 +/- 13.66 (range, 60-100) 1 week after the procedure. For symptomatic patients (n = 5), the VAS score decreased from 6.80 +/- 2.39 (range, 3-9) before the procedure to 1.80 +/- 0.84 (range, 1-3) at 1 week after the procedure. The mean procedure duration was 90.00 minutes +/- 10.56 (range, 72-102 min). The average length of hospital stay was 7 days +/- 2 (range, 4-10 d). The only complication noted consisted of thrombophlebitis in one patient, on the operative side, at 15 days after the procedure. No cases of procedural site fracture during follow-up were noted (median, 192 d; range, 30-365 d). CONCLUSIONS: Percutaneous cementoplasty plus interventional internal fixation is a feasible technique for stabilization of impending pathologic fracture of the femur. PMID- 24801502 TI - Current issues in determining dietary protein quality and metabolic utilization. PMID- 24801506 TI - Salivary neoplasms presenting with radiologic venous invasion: an imaging pearl to diagnosing metastatic renal cell carcinoma. AB - We report the case of a 64-year-old otherwise healthy woman who presented with left facial swelling. Imaging of the neck revealed multiple masses in the salivary and thyroid glands. The mass in the left parotid gland was associated with an intravenous extension into the retromandibular, facial and internal jugular veins in the left neck. Based on multiplicity of these masses and the presence of radiologic venous invasion, the diagnosis of metastatic renal cell carcinoma (RCC) was suggested on imaging, which was subsequently confirmed on systemic workup and pathology findings. Although RCC metastasizes to the salivary glands, the primary presentation of RCC with both salivary and thyroid gland masses is extremely rare, with only a few reports. The above feature and its imaging diagnosis based on local venous invasion are the highlights of this report. PMID- 24801505 TI - NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. AB - Androgen receptor (AR) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between AR and forkhead box (FOX) transcription factors, particularly FOXA1. We sought to identity additional FOXA1 binding partners that may mediate prostate-specific gene expression. Here we identify the nuclear factor I (NFI) family of transcription factors as novel FOXA1 binding proteins. All four family members (NFIA, NFIB, NFIC, and NFIX) can interact with FOXA1, and knockdown studies in androgen-dependent LNCaP cells determined that modulating expression of NFI family members results in changes in AR target gene expression. This effect is probably mediated by binding of NFI family members to AR target gene promoters, because chromatin immunoprecipitation (ChIP) studies found that NFIB bound to the prostate-specific antigen enhancer. Forster resonance energy transfer studies revealed that FOXA1 is capable of bringing AR and NFIX into proximity, indicating that FOXA1 facilitates the AR and NFI interaction by bridging the complex. To determine the extent to which NFI family members regulate AR/FOXA1 target genes, motif analysis of publicly available data for ChIP followed by sequencing was undertaken. This analysis revealed that 34.4% of peaks bound by AR and FOXA1 contain NFI binding sites. Validation of 8 of these peaks by ChIP revealed that NFI family members can bind 6 of these predicted genomic elements, and 4 of the 8 associated genes undergo gene expression changes as a result of individual NFI knockdown. These observations suggest that NFI regulation of FOXA1/AR action is a frequent event, with individual family members playing distinct roles in AR target gene expression. PMID- 24801507 TI - RNAdigest: a web-based tool for the analysis and prediction of structure-specific RNAse digestion results. AB - Despite recent developments in analyzing RNA secondary structures, relatively few RNA structures have been determined. To date, many investigators have relied on the traditional method of using structure-specific RNAse enzymes to probe RNA secondary structures. However, if these data were combined with novel computational approaches, investigators would have an informative and valuable tool for RNA structural analysis. To this end, we created the web server "RNAdigest." RNAdigest uses mfold RNA structural models in order to predict the results of RNAse digestion experiments. Furthermore, RNAdigest also utilizes both RNA sequence and the experimental digestion patterns to formulate the constraints for predicting secondary structures of the RNA. Thus, RNAdigest allows for the structural interpretation of RNAse digestion experiments. Overall, RNAdigest simplifies RNAse digestion result analyses while allowing for the identification of unique fragments. These unique fragments can then be used for testing predicted mfold structures and for designing structural-specific DNA/RNA probes. PMID- 24801508 TI - Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. AB - Cardiac stem cells (CSC) from explanted decompensated hearts (E-CSC) are, with respect to those obtained from healthy donors (D-CSC), senescent and functionally impaired. We aimed to identify alterations in signaling pathways that are associated with CSC senescence. Additionally, we investigated if pharmacological modulation of altered pathways can reduce CSC senescence in vitro and enhance their reparative ability in vivo. Measurement of secreted factors showed that E CSC release larger amounts of proinflammatory cytokine IL1beta compared with D CSC. Using blocking antibodies, we verified that IL1beta hampers the paracrine protective action of E-CSC on cardiomyocyte viability. IL1beta acts intracranially inducing IKKbeta signaling, a mechanism that via nuclear factor kappaB upregulates the expression of IL1beta itself. Moreover, E-CSC show reduced levels of AMP protein kinase (AMPK) activating phosphorylation. This latter event, together with enhanced IKKbeta signaling, increases TORC1 activity, thereby impairing the autophagic flux and inhibiting the phosphorylation of Akt and cAMP response element-binding protein. The combined use of rapamycin and resveratrol enhanced AMPK, thereby restoring downstream signaling and reducing IL1beta secretion. These molecular corrections reduced E-CSC senescence, re establishing their protective activity on cardiomyocytes. Moreover ex vivo treatment with rapamycin and resveratrol improved E-CSC capacity to induce cardiac repair upon injection in the mouse infarcted heart, leading to reduced cardiomyocyte senescence and apoptosis and increased abundance of endogenous c Kit(+) CSC in the peri-infarct area. Molecular rejuvenation of patient-derived CSC by short pharmacologic conditioning boosts their in vivo reparative abilities. This approach might prove useful for refinement of CSC-based therapies. PMID- 24801509 TI - Dry-eye screening by using a functional visual acuity measurement system: the Osaka Study. AB - PURPOSE: We determined whether functional visual acuity (VA) parameters and a dry eyes (DEs) symptoms questionnaire could predict DEs in a population of visual terminal display (VDT) users. METHODS: This prospective study included 491 VDT users from the Osaka Study. Subjects with definite DE, diagnosed with the presence of DE symptoms, tear abnormality (Schirmer test <= 5 mm or tear breakup time [TBUT] <= 5 seconds), and conjunctivocorneal epithelial damage (total staining score of >=3 points), or probable DE, diagnosed with the presence of two of them, were assigned to a DE group, and the remainder to a non-DE group. Functional VA was assessed, and DE questionnaires were administered. We assessed whether univariate and discriminant analyses could determine to which group a subject belonged. Sensitivity and specificity were assessed. RESULTS: Of 491 subjects, 320 and 171 were assigned to the DE and non-DE groups, respectively. No significant differences were observed between DE and non-DE groups in Schirmer test value and epithelial damage, but TBUT value (3.1 +/- 1.5 vs. 5.9 +/- 3.0 seconds). The sensitivity and specificity of single test using functional VA parameters were 59% and 49% in functional VA, 60% and 50% in visual maintenance ratio, and 83% and 30% in frequency of blinking, respectively. According to a discriminant analysis using a combination of functional VA parameters and a DE questionnaire, six variables were selected for the discriminant equation, of which area under the curve (AUC) was 0.735. Sensitivity and specificity of diagnoses predicted by the discriminant equation were 85.9% and 45.6%, respectively. CONCLUSIONS: The discriminant equation obtained using functional VA measurement combined with a symptoms questionnaire may suggest the possibility for the first step screening of DE with unstable tear film. Since the questionnaire has an overall poor sensitivity and specificity, further amelioration may be necessary for the actual utilization of this screening tool. PMID- 24801510 TI - Topographic localization of macular retinal ganglion cell loss associated with localized peripapillary retinal nerve fiber layer defect. AB - PURPOSE: To investigate the topographic relationship between ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) defects in open-angle glaucoma patients with localized RNFL defects, using spectral-domain optical coherence tomography (SD-OCT). METHODS: We analyzed 140 eyes of 140 patients showing a localized RNFL defect in one hemifield, the angular width of which was limited to one clock-hour sector. The RNFL and macular GCIPL scans were obtained using SD-OCT. The clock-hour location and width of pRNFL defects on the RNFL deviation map were determined, and their topographic association with corresponding GCIPL defects on the GCIPL deviation map was assessed. RESULTS: A "GCIPL deviation frequency map" demonstrating GCIPL defects corresponding to six different clock-hour locations of pRNFL defects was obtained, and it revealed the following specifics: (1) pRNFL defect at 12, 11, and 10 o'clock corresponded to GCIPL defect in the superior macula, as those at 8, 7, and 6 o'clock did to those in the inferior macula; (2) the overall GCIPL defect had an arcuate shape that appeared as a continuation of the pRNFL defect; (3) the temporal macular region was the frequently damaged site in either hemifield, and was larger in the inferior hemifield than in the superior hemifield. Additionally, an interindividual variability of GCIPL defect was noted for patients with the same clock-hour location of pRNFL defect. CONCLUSIONS: The GCIPL deviation frequency map demonstrating the topographic relationship between pRNFL and GCIPL defects was generated using SD-OCT. Our results indicated the topographic location of retinal ganglion cell death associated with clock-hour location of pRNFL loss in vivo. PMID- 24801511 TI - Comparative analysis of two femtosecond LASIK platforms using iTRAQ quantitative proteomics. AB - PURPOSE: New femtosecond laser platforms may reduce ocular surface interference and LASIK-associated dry eye. This study investigated tear protein profiles in subjects who underwent LASIK using two femtosecond lasers to assess differences in protein expression. METHODS: This was a randomized interventional clinical trial involving 22 patients who underwent femtosecond laser refractive surgery with a contralateral paired eye design. Corneal flaps of 22 subjects were created by either Visumax or Intralase laser. Tear samples were collected preoperatively, and at 1 week and 3 months postoperatively using Schirmer's strips. Tear protein ratios were calculated relative to preoperative protein levels at baseline. The main outcome measures were the levels of a panel of dry eye protein markers analyzed using isobaric tagging for relative and absolute quantitation (iTRAQ) mass spectrometry. RESULTS: A total of 824 unique proteins were quantifiable. Tear protein ratios were differentially regulated between the eyes treated with different lasers. The secretoglobulins Lipophilin A (1.80-fold) and Lipophilin C (1.77) were significantly upregulated (P < 0.05) at 1 week postoperatively in Visumax but not in Intralase-treated eyes. At 1 week, orosomucoid1 was upregulated (1.78) in Intralase but not Visumax-treated eyes. In the same eyes, lysozyme, cathepsin B, and lipo-oxygenase were downregulated at 0.44-, 0.64-, and 0.64-folds, respectively. Transglutaminase-2 was downregulated in both groups of eyes. CONCLUSIONS: Different laser platforms induce distinct biological responses in the cornea and ocular surface, which manifests as different levels of tear proteins. This study has implications for surgical technology and modulation of wound healing responses. (ClinicalTrials.gov number, NCT01252654.). PMID- 24801513 TI - Retinal blood flow and vascular reactivity in chronic smokers. AB - PURPOSE: The aim of this study was to investigate the impact of cigarette smoking in otherwise healthy young individuals on retinal blood flow (RBF) and vascular reactivity (RVR). METHODS: An automated gas flow controller (RespirAct) was used to achieve normoxic hypercapnia in 10 nonsmokers (mean age 28.9; SD 4.6 years) and nine smokers (mean age 27.55; SD 4.7 years). Retinal blood flow measurements were obtained using a prototype Doppler spectral-domain optical coherence tomographer (SD-OCT) and bidirectional laser Doppler velocimetry and simultaneous vessel densitometry during baseline, normoxic hypercapnia, and recovery. Group mean PETCO2 (end-tidal partial pressure of CO2) was increased by 15.9% in the nonsmoking group and by 15.7% in the smoking group, with a concomitant increase in PETO2 (end-tidal partial pressure of O2) by approximately 1.5% to 2% in both groups. RESULTS: In nonsmokers, retinal arteriolar diameter (P < 0.0001), centerline velocity (P = 0.0004), and blood flow (P < 0.0001) significantly increased during normoxic hypercapnia. Similarly, the venous area (P = 0.0418), venous velocity (P = 0.0068), and total venous RBF (P < 0.0001), as measured by the prototype Doppler SD-OCT, significantly increased. In smokers, normoxic hypercapnia resulted in a significant increase in velocity (P = 0.0019), flow (P = 0.0029), and total venous RBF (P = 0.002). Comparing smokers and nonsmokers, the percentage change in arteriolar diameter (P = 0.0379) and blood flow (P = 0.0101) was significantly lower in the smoking group. There was no significant difference in baseline PETCO2 level between smokers and nonsmokers. CONCLUSIONS: Retinal vascular reactivity in response to normoxic hypercapnia is significantly reduced in young, healthy smokers compared with nonsmokers. PMID- 24801512 TI - Expression of the primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 in endothelial and epithelial cell junctions in the eye. AB - PURPOSE: The role of the recently identified primary angle closure glaucoma (PACG) susceptibility gene, pleckstrin homology domain containing, family A member 7 (PLEKHA7), in PACG is unknown. PLEKHA7 associates with apical junctional complexes (AJCs) and is thus implicated in paracellular fluid regulation. We aimed to determine PLEKHA7's localization in the eye and its association with AJCs to elucidate its potential role in PACG. METHODS: Total RNA from ocular tissues was isolated and analyzed by real-time PCR. Frozen and paraffin-embedded human globes were sectioned and used for immunohistochemistry and immunofluorescence analysis. RESULTS: Specific PLEKHA7 expression was found in the muscles, vascular endothelium, and epithelium of the iris, ciliary body and ciliary processes, trabecular meshwork (TM), and choroid. PLEKHA7 expression in musculature and vascular endothelium was confirmed with smooth muscle marker, SMA, and endothelium marker, PECAM-1, respectively. At the above sites, PLEKHA7 colocalization was seen with adherens junction markers (E-cadherin and beta catenin) and tight junction markers (ZO-1). CONCLUSIONS: Specific localization of PLEKHA7 was found within PACG-related structures (iris, ciliary body, and choroid) and blood-aqueous barrier (BAB) structures (posterior iris epithelium, nonpigmented ciliary epithelium, iris and ciliary body microvasculature). The association of PLEKHA7 with AJCs in the eye suggests a potential role for PLEKHA7 in PACG via fluidic regulation. Novel expression of PLEKHA7 was also seen in the ocular smooth muscles and vascular endothelia. PMID- 24801514 TI - siRNA silencing of the mutant keratin 12 allele in corneal limbal epithelial cells grown from patients with Meesmann's epithelial corneal dystrophy. AB - PURPOSE: The aim of this study is to further assess our previously reported keratin 12 (K12)-Leu132Pro specific siRNA in silencing the mutant allele in Meesmann's Epithelial Corneal Dystrophy (MECD) in experimental systems more akin to the in vivo situation through simultaneous expression of both wild-type and mutant alleles. METHODS: Using KRT12 exogenous expression constructs transfected into cells, mutant allele specific knockdown was quantified using pyrosequencing and infrared Western blot analysis, while the silencing mechanism was assessed by a modified rapid amplification of cDNA ends (5'RACE) method. Corneal limbal biopsies taken from patients suffering from MECD were used to establish cultures of MECD corneal limbal epithelial stem cells and the ability of the siRNA to silence the endogenous mutant KRT12 allele was assessed by a combination of pyrosequencing, qPCR, ELISA, and quantitative-fluorescent immunohistochemistry (Q FIHC). RESULTS: The siRNA displayed a potent and specific knockdown of K12 Leu132Pro at both the mRNA and protein levels with exogenous expression constructs. Analysis by the 5'RACE method confirmed siRNA-mediated cleavage. In the MECD cells, an allele-specific knockdown of 63% of the endogenous mutant allele was observed without effect on wild-type allele expression. CONCLUSIONS: Combined with an effective delivery vehicle this siRNA approach represents a viable treatment option for prevention of the MECD pathology observed in K12 Leu132Pro heterozygous individuals. PMID- 24801516 TI - S-sequence spatially-encoded synthetic aperture ultrasound imaging. AB - Synthetic transmit aperture (STA) ultrasound imaging offers near-ideal reconstruction across an entire field of view. This performance comes at the cost of SNR compared with scanning using only dynamic receive focusing. SNR may be enhanced by using spatial encoding using a Hadamard sequence. An encoding based on a Hadamard sequence has two main drawbacks: the array must be capable of transmitting a pulse and an inverted pulse at the same time, and the inverted transmission must be symmetrical with respect to the non-inverted transmission. These are often not the case in practice, and thus Hadamard encoding may require twice as many transmission events and special consideration of the inverted waveform. As an alternative, we propose the use of S-sequences, which are similar to Hadamard sequences, but use half the elements and do not require an inverted pulse. This encoding is implemented on a commercial ultrasound system and compared with STA imaging using single-element emissions and Hadamard encoding in terms of SNR and resolution using a point target. We find that the two encodings perform very similarly despite the increased transmit power and doubling of transmit events in our implementation of Hadamard imaging. Both encodings give up to 19 dB signal improvement over single-element STA imaging, while maintaining resolution. Finally, we show sample in vivo human carotid images with all three methods which illustrate the suitability of S-sequence-encoded STA imaging for a clinical setting. PMID- 24801515 TI - Cost analysis of integrating the PrePex medical device into a voluntary medical male circumcision program in Zimbabwe. AB - BACKGROUND: Fourteen African countries are scaling up voluntary medical male circumcision (VMMC) for HIV prevention. Several devices that might offer alternatives to the three WHO-approved surgical VMMC procedures have been evaluated for use in adults. One such device is PrePex, which was prequalified by the WHO in May 2013. We utilized data from one of the PrePex field studies undertaken in Zimbabwe to identify cost considerations for introducing PrePex into the existing surgical circumcision program. METHODS AND FINDINGS: We evaluated the cost drivers and overall unit cost of VMMC at a site providing surgical VMMC as a routine service ("routine surgery site") and at a site that had added PrePex VMMC procedures to routine surgical VMMC as part of a research study ("mixed study site"). We examined the main cost drivers and modeled hypothetical scenarios with varying ratios of surgical to PrePex circumcisions, different levels of site utilization, and a range of device prices. The unit costs per VMMC for the routine surgery and mixed study sites were $56 and $61, respectively. The two greatest contributors to unit price at both sites were consumables and staff. In the hypothetical scenarios, the unit cost increased as site utilization decreased, as the ratio of PrePex to surgical VMMC increased, and as device price increased. CONCLUSIONS: VMMC unit costs for routine surgery and mixed study sites were similar. Low service utilization was projected to result in the greatest increases in unit price. Countries that wish to incorporate PrePex into their circumcision programs should plan to maximize staff utilization and ensure that sites function at maximum capacity to achieve the lowest unit cost. Further costing studies will be necessary once routine implementation of PrePex-based circumcision is established. PMID- 24801517 TI - An intelligent recovery progress evaluation system for ACL reconstructed subjects using integrated 3-D kinematics and EMG features. AB - An intelligent recovery evaluation system is presented for objective assessment and performance monitoring of anterior cruciate ligament reconstructed (ACL-R) subjects. The system acquires 3-D kinematics of tibiofemoral joint and electromyography (EMG) data from surrounding muscles during various ambulatory and balance testing activities through wireless body-mounted inertial and EMG sensors, respectively. An integrated feature set is generated based on different features extracted from data collected for each activity. The fuzzy clustering and adaptive neuro-fuzzy inference techniques are applied to these integrated feature sets in order to provide different recovery progress assessment indicators (e.g., current stage of recovery, percentage of recovery progress as compared to healthy group, etc.) for ACL-R subjects. The system was trained and tested on data collected from a group of healthy and ACL-R subjects. For recovery stage identification, the average testing accuracy of the system was found above 95% (95-99%) for ambulatory activities and above 80% (80-84%) for balance testing activities. The overall recovery evaluation performed by the proposed system was found consistent with the assessment made by the physiotherapists using standard subjective/objective scores. The validated system can potentially be used as a decision supporting tool by physiatrists, physiotherapists, and clinicians for quantitative rehabilitation analysis of ACL-R subjects in conjunction with the existing recovery monitoring systems. PMID- 24801519 TI - Permissive hypoxaemia versus normoxaemia for mechanically ventilated critically ill patients. AB - BACKGROUND: Permissive hypoxaemia describes a concept in which a lower level of arterial oxygenation (PaO2) than usual is accepted to avoid the detrimental effects of high fractional inspired oxygen and invasive mechanical ventilation. Currently however, no specific threshold is known that defines permissive hypoxaemia, and its use in adults remains formally untested. The importance of this systematic review is thus to determine whether any substantial evidence is available to support the notion that permissive hypoxaemia may improve clinical outcomes in mechanically ventilated critically ill patients. OBJECTIVES: We assessed whether permissive hypoxaemia (accepting a lower PaO2 than is current practice) in mechanically ventilated critically ill patients affects patient morbidity and mortality. We planned to conduct subgroup and sensitivity analyses and to examine the role of bias to determine the level of evidence provided. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 11, part of The Cochrane Library; MEDLINE (1954 to November 2013); EMBASE (1980 to November 2013); CINAHL (1982 to November 2013) and ISI Web of Science (1946 to November 2013). We combined the sensitive search strategies described in the Cochrane Handbook for Systematic Reviews of Interventions to search for randomized controlled trials (RCTs) in MEDLINE and EMBASE. For ongoing trials, we also searched the following databases: MetaRegister of ControlledTrials and the National Research Register. We applied no language restrictions. SELECTION CRITERIA: RCTs and quasi-RCTs that compared outcomes for mechanically ventilated critically ill participants, in which the intervention group was targeted to be hypoxaemic relative to the control group, and the control group was normoxaemic or was mildly hypoxaemic, were eligible for inclusion in this review. Exact values defining 'conventional' and 'permissive hypoxaemia' groupings were purposely not specified, and the manner in which these oxygenation goals were achieved also was not specified. We did state however that the intervention group required a target oxygenation level lower than that of the control group, and that the control group target levels should be in the range of normoxaemia or mild hypoxaemia (not hyperoxaemia). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Using the results of the above searches, two review authors (EG-K and KM) independently screened all titles and abstracts for eligibility and duplication. No discrepancies were encountered, nor was it necessary for review authors to contact the first author of any trial to ask for additional information. MAIN RESULTS: Our search strategy yielded a total of 2419 results. After exclusion of duplications, 1651 candidate studies were identified. Screening of titles and abstracts revealed that no studies met our inclusion criteria. AUTHORS' CONCLUSIONS: This comprehensive review failed to identify any relevant studies evaluating permissive hypoxaemia versus normoxaemia in mechanically ventilated critically ill participants. Therefore we are unable to support or refute the hypothesis that this treatment strategy is of benefit to patients.Given the substantial amount of provocative evidence derived from related clinical contexts (resuscitation, myocardial infarction, stroke), we believe that this review highlights an important unanswered question within critical care. In the presence of two competing harms (hypoxia and hyperoxia), it will be important to carefully evaluate the safety and feasibility of permissive hypoxaemia before proceeding to efficacy and effectiveness trials. PMID- 24801521 TI - Telemedicine in space medicine and extreme terrestrial analogs. PMID- 24801522 TI - Barriers for delivering telehealth in rural australia: a review based on Australian trials and studies. AB - BACKGROUND: Australians in rural and remote areas live with far poorer health outcomes than those in urban areas. Telehealth services have emerged as a promising solution to narrow this health gap, as they improve the level and diversity of health services delivery to rural and remote Australian communities. Although the benefits of telehealth services are well studied and understood, the uptake has been very slow. MATERIALS AND METHODS: To understand the underpinning issues, we conducted a literature review on barriers to telehealth adoption in rural and remote Australian communities, based on the published works of Australian clinical trials and studies. RESULTS: This article presents our findings using a comprehensive barrier matrix. This matrix is composed of four stakeholders (governments, technology developers and providers, health professionals, and patients) and five different categorizations of barriers (regulatory, financial, cultural, technological, and workforce). We explain each cell of the matrix (four stakeholders*five categories) and map the reported work into the matrix. CONCLUSIONS: Several exemplary barrier cases are also described to give more insights into the complexity and dilemma of adopting telehealth services. Finally, we outline recent technological advancements that have a great potential to overcome some of the identified barriers. PMID- 24801525 TI - Usefulness of Genotype MTBDRplus assay in acid-fast bacilli positive smear specimens in Almeria, Spain. AB - INTRODUCTION: The urgent need for operational research evaluating test performance in a real-world setting has been highlighted. The purpose of this study was therefore to evaluate the performance of MTBDRplus assay. MATERIALS: According to the reference method, of the 155 clinical specimens with valid results, 147 were susceptible to rifampicin (RIF) and isoniazid (INH), with 4 being multi-drug resistant (MDR) and 4 with isolated resistance to isoniazid (INH). RESULTS: The results of the MTBDRplus assay were 100% concordant for the MDR and mono-resistant to INH specimens. However, the MTBDRplus assay showed a resistance pattern to RIF in one specimen which was classified as susceptible by the reference method. The majority of the specimens (118/75.6%) were also tested using the MTBDRplus method after culture on Lowenstein-Jensen media, showing 100% agreement with the results of the test directly from the specimens. An MTBDRplus test result was available within an average of 8 days. CONCLUSIONS: Overall, MTBDR results showed excellent results when compared with the reference method and achieved a significant time-reduction. PMID- 24801526 TI - [Shigella sonnei outbreak in a school in Northern Spain]. AB - In October 2012, an outbreak of acute gastroenteritis caused by Shigella sonnei was detected in a nursery and primary school in the north of Spain affecting 112 people: 63.7% were pupils and teachers and 35.7% their co-habitants. The source was a sick child who had travelled to an endemic country, and the key trigger factor was inadequate hygiene in one of the toilets of the school. The enforcement of strict hygiene measures was essential for controlling the outbreak. PMID- 24801520 TI - Autonomic dysfunction in mild cognitive impairment: evidence from power spectral analysis of heart rate variability in a cross-sectional case-control study. AB - BACKGROUND: Mild cognitive impairment (MCI) is set to become a major health problem with the exponential ageing of the world's population. The association between MCI and autonomic dysfunction, supported by indirect evidence and rich with clinical implications in terms of progression to dementia and increased risk of mortality and falls, has never been specifically demonstrated. AIM: To conduct a comprehensive assessment of autonomic function in subjects with MCI by means of power spectral analysis (PSA) of heart rate variability (HRV) at rest and during provocative manoeuvres. METHODS: This cross-sectional study involved 80 older outpatients (aged >= 65) consecutively referred to a geriatric unit and diagnosed with MCI or normal cognition (controls) based on neuropsychological testing. PSA was performed on 5-minute electrocardiographic recordings under three conditions- supine rest with free breathing (baseline), supine rest with paced breathing at 12 breaths/minute (parasympathetic stimulation), and active standing (orthosympathetic stimulation)--with particular focus on the changes from baseline to stimulation of indices of sympathovagal balance: normalized low frequency (LFn) and high frequency (HFn) powers and the LF/HF ratio. Blood pressure (BP) was measured at baseline and during standing. Given its exploratory nature in a clinical population the study included subjects on medications with a potential to affect HRV. RESULTS: There were no significant differences in HRV indices between the two groups at baseline. MCI subjects exhibited smaller physiological changes in all three HRV indices during active standing, consistently with a dysfunction of the orthosympathetic system. Systolic BP after 10 minutes of standing was lower in MCI subjects, suggesting dysautonomia-related orthostatic BP dysregulation. CONCLUSIONS: Our study is novel in providing evidence of autonomic dysfunction in MCI. This is associated with orthostatic BP dysregulation and the ongoing follow-up of the study population will determine its prognostic relevance as a predictor of adverse health outcomes. PMID- 24801527 TI - Aluminum-stabilized low-spin iron(II) hydrido complexes of 1,4,7-trimethyl-1,4,7 triazacyclononane. AB - We investigated herein the reactions of (Me3tacn)FeCln (1a: n = 3, 1b: n = 2) with common aluminum hydride reagents and a bulky dihydridoaluminate {Li(ether)2}{Al(OC6H3-2,6-(t)Bu2)}(MU-H)2, which yielded the diamagnetic hydrido complexes 2-4 containing Fe(II) and Al(III). In particular, the use of divalent 1b afforded excellent isolated yields. The structures of 2-4 were determined using spectroscopic and crystallographic analyses. The crystal structures showed distorted octahedral Fe centers and fairly short Fe-Al distances [2.19-2.24 A]. The structures of cation moiety 2 and neutral complex 4 were further probed using DFT calculations, which indicated a stable low-spin Fe(II) state and strongly electron-donating nature of the (Me3tacn)FeH3 fragment toward the Al(III) center. PMID- 24801528 TI - Measurement of mandibular growth using cone-beam computed tomography: a miniature pig model study. AB - The purpose of this study was to measure the long-term growth of the mandible in miniature pigs using 3D Cone-Beam Computerized Tomography (CBCT). The mandibles of the pigs were scanned monthly over 12 months using CBCT and the 3D mandibular models were reconstructed from the data. Seventeen anatomical landmarks were identified and classified into four groups of line segments, namely anteroposterior, superoinferior, mediolateral and anteroinferior. The inter marker distances, inter-segmental angles, volume, monthly distance changes and percentage of changes were calculated to describe mandibular growth. The total changes of inter-marker distances were normalized to the initial values. All inter-marker distances increased over time, with the greatest mean normalized total changes in the superoinferior and anteroposterior groups (p<0.05). Monthly distance changes were greatest during the first four months and then reduced over time. Percentages of inter-marker distance changes were similar among the groups, reaching half of the overall growth around the 4th month. The mandibular volume growth increased non-linearly with time, accelerating during the first five months and slowing during the remaining months. The growth of the mandible was found to be anisotropic and non-homogeneous within the bone and non-linear over time, with faster growth in the ramus than in the body. These growth patterns appeared to be related to the development of the dentition, providing necessary space for the teeth to grow upward for occlusion and for the posterior teeth to erupt. PMID- 24801529 TI - Ciliates in extreme environments. AB - As eukaryotic microbial life, ciliated protozoan may be found actively growing in some extreme condition where there is a sufficient energy source to sustain it because they are exceedingly adaptable and not notably less adaptable than the prokaryotes. However, a crucial problem in the study of ciliates in extreme environments is the lack of reliable cultivation techniques. To our knowledge, only a tiny fraction of ciliates can be cultured in the laboratory, even for a very limited period, which can partly explain the paucity of our understanding about ciliates diversity in various extremes although the interest in the biodiversity of extremophiles increased significantly during the past three decades. This mini-review aims to compile the knowledge of several groups of free living ciliates that can be microscopically observed in extreme environmental samples, although most habitats have not been sufficiently well explored for sound generalizations. PMID- 24801530 TI - Non-noxious skin stimulation activates the nucleus basalis of Meynert and promotes NGF secretion in the parietal cortex via nicotinic ACh receptors. AB - The effects of non-noxious skin stimulation on nerve growth factor (NGF) secretion in the parietal cortex were examined in anesthetized rats. Innocuous skin stimulation was delivered to the left hindlimb with a soft-hair brush. Extracellular NGF in the right parietal cortex was collected by microdialysis methods using a protein-permeable probe and was measured using an enzyme-linked immune-sorbent assay. Brushing produced a significant increase in extracellular NGF levels. This NGF response was not observed in rats pretreated with a nicotinic ACh receptor (nAChR) antagonist mecamylamine. We further examined whether brushing could activate the basal forebrain nucleus (nucleus basalis of Meynert, NBM), which is the main source of cholinergic fibers in the cerebral cortex, by means of functional MRI. The blood oxygen level-dependent signal in the right NBM was significantly higher during brushing compared to baseline. The results suggest that non-noxious skin stimulation activates NBM and promotes NGF secretion in the parietal cortex via nAChRs. PMID- 24801531 TI - Comparison of two tests of auditory temporal resolution in children with central auditory processing disorder, adults with psychosis, and adult professional musicians. AB - OBJECTIVE: Evaluate auditory temporal resolution threshold outcomes across three different populations. DESIGN: Two commercially available tests of auditory gap detection (Random gap detection (RGDT) test, and Gaps-in-noise (GIN) test) were administered to all participants. STUDY SAMPLE: Adult professional musicians (APM) (N = 11, age range 28-61 years); children with central auditory processing disorder (CAPD) (N = 22, age range 7.5-17 years); and first episode psychosis patients (FEP) (N = 17, age range 18-48 years). RESULTS: It was not possible to calculate a threshold for the RGDT for 13 of 22 children with CAPD and for 7 of 17 adults with FEP due to response inconsistency. Analysis of variance (ANOVA) excluding cases that produced inconsistent RGDT results showed that only RGDT thresholds differed across groups (F = 8.73, p = 0.001). Three t-tests comparing test means within group revealed statistically significant differences between the gap detection thresholds obtained with the RGDT vs. the GIN for each group. No significant correlations were seen between RGDT and GIN. CONCLUSION: Lower/better gap detection thresholds and smaller standard deviations were obtained using the GIN in all three groups. Lack of correlation between the two tests suggests that they may measure different processes. PMID- 24801532 TI - An investigation into the clinical utility of ipsilateral/contralateral asymmetries in bone-conduction auditory steady-state responses. AB - OBJECTIVE: To determine whether ipsilateral/contralateral asymmetries in the bone conduction (BC) ASSR are robust enough in infants to be used clinically to isolate the test ear. DESIGN: Retrospective investigation of three two-channel BC ASSR datasets. SUBJECTS: Forty-eight adults (mean age 26.7 years), 49 infants (mean age 29.6 weeks). METHODS: BC ASSR stimuli were presented as amplitude/frequency modulated sinusoidal tones with carrier frequencies of 500, 1000, 2000, and 4000 Hz (-10 to 45 dB HL). RESULTS: Infants showed greater differences in ipsilateral/contralateral mean amplitudes and phase delays for all experimental conditions compared to adults. Ninety percent of infants had ipsilateral/contralateral asymmetries at 500 and 4000 Hz (20-35 dB HL) using an "amplitude or phase delay" criterion, and at 4000 Hz (20-25 dB HL) using an "amplitude and phase delay" criterion. CONCLUSIONS: As ipsilateral/contralateral asymmetries are not consistently present for 1000- and 2000-Hz BC ASSRs in infants, clinical masking would be needed at these frequencies to isolate the test ear. For 500- and 4000-Hz BC ASSRs, the accuracy of using these asymmetries requires clinical confirmation in a group of infants with hearing loss. PMID- 24801533 TI - Nanocrystals in their prime. PMID- 24801534 TI - Driving change in the battery industry. PMID- 24801536 TI - Two-dimensional crystals: phosphorus joins the family. PMID- 24801537 TI - Chiral mechanical bonds: a move in the right direction. PMID- 24801538 TI - Levitating nanoparticles: on the way to equilibrium. PMID- 24801539 TI - Optical devices: localizing light with electrons. PMID- 24801540 TI - The clinical role of serum concentrations of selected cytokines: IL-1beta, TNF alpha and IL-6 in diagnosis of autoimmune thyroid disease (AITD) in children. AB - Chronic autoimmune thyroiditis (cAIT) leads to hypothyroidism due to T cell mediated cytotoxicity in most cases. By contrast, Graves' disease (GD) with thyrotropin receptor stimulatory autoantibodies cause hyperthyroidism. Cytokines play a crucial role in modulating immune response in both disorders. The aim of study was to evaluate the concentrations of cytokines: IL-1beta, TNF-alpha and IL 6 in these two opposite clinical and hormonal thyroid diseases. The study group consisted of 64 children, 44 newly diagnosed, untreated children with cAIT (n = 22; with hypothyroidism) and GD (n = 22; hyperthyroidism), and the control group of 20 healthy children. Cytokine concentrations were evaluated using the ELISA technique. The studied groups of children did not differ significantly in concentrations of IL-6 (p = 0.48) and TNF-alpha (p = 0.067). In children with hypothyroidism, we found significantly higher concentrations of IL-1beta (median 2.16 pg/ml, IQR 0.87) compared to hyperthyroidism (median 1.39 pg/l, IQR 1.27) (p < 0.01) and the control group (median 1.88 pg/ml, IQR 1.04) (p < 0.05). The results of ROC curve analysis demonstrated the usefulness of IL-1beta (AUC = 0.77, p = 0.003) and TNF-alpha (AUC = 0.691, p = 0.034) as diagnostic parameters in cAIT which enable discrimination of children with autoimmune thyroid disease from healthy individuals. Concentrations of these markers are increased in autoimmune hypothyroidism. We found no significant sex differences in the tested parameters. In conclusion, IL-1beta and TNF-alpha may be considered as markers of hypothyroidism, and could efficiently discriminate between healthy and autoimmune hypothyroid children. Significantly higher concentrations of IL-1beta in children with hypothyroidism may be used to distinguish children with cAIT from GD patients. PMID- 24801542 TI - Primary hyperparathyroidism across the ages: presentation and outcomes. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is a disease process traditionally thought to present during middle age, but can occur at any age. The purpose of this study was to compare PHPT patient characteristics based on patient age at the time of surgical referral. METHODS: A retrospective review of a prospectively managed database of adult patients undergoing parathyroid surgery for PHPT was conducted. Patients with a negative family history, no previous parathyroid surgery, and >=6-mo follow-up were included. Patients were grouped by age for comparison. RESULTS: From 2001-2012, 1372 patients met inclusion criteria. Age groups were as follows: <=50 y, 51-60 y, 61-70 y, and >70 y. Female predominance increased with age (P>0.01). Baseline serum parathyroid hormone levels were higher at the extremes of age (P<0.001). Young patients had the highest serum calcium (P<0.01), urinary calcium (P<0.001), and T-score (P<0.001) measures, and greater incidence of vitamin D deficiency (P=0.03). The use of local anesthesia increased with age, whereas use of outpatient parathyroidectomy decreased with age (both P<0.01). Rates of disease persistence (2.3%-2.9%, P=0.95) and recurrence (2.1%-3.3%, P=0.75) were low, and did not differ. CONCLUSIONS: Patients at the extremes of age are referred with more elevated laboratory indices whereas those in the traditional age range have milder biochemical indices. This may result from differential surgical referral. Individuals with laboratory evidence of abnormal calcium and parathyroid hormone regulation should be evaluated for parathyroidectomy regardless of age because all ages can be successfully treated. PMID- 24801541 TI - Age and sex disparities in discussions about kidney transplantation in adults undergoing dialysis. AB - OBJECTIVES: To explore whether disparities in age and sex in access to kidney transplantation (KT) originate at the time of prereferral discussions about KT. DESIGN: Cross-sectional survey. SETTING: Outpatient dialysis centers in Maryland (n = 26). PARTICIPANTS: Individuals who had recently initiated hemodialysis treatment (N = 416). MEASUREMENTS: Participants reported whether medical professionals (nephrologist, primary medical doctor, dialysis staff) and social group members (significant other, family member, friend) discussed KT with them and, when applicable, rated the tone of discussions. Relative risks were estimated using modified Poisson regression. RESULTS: Participants aged 65 and older were much less likely than those who were younger to have had discussions with medical professionals (44.5% vs 74.8%, P < .001) or social group members (47.3% vs 63.1%, P = .005). Irrespective of sex and independent of race, health related factors, and dialysis-related characteristics, older adults were more likely not to have had discussions with medical professionals (relative risk (RR) = 1.13, 95% confidence interval (CI) = 1.03-1.24, for each 5-year increase in age through 65; RR = 1.28, 95% CI = 1.14-1.42, for each 5-year increase in age beyond 65). Irrespective of age, women were more likely (RR = 1.45, 95% CI = 1.12-1.89) not to have had discussions with medical professionals. For each 5-year increase in age, men (RR = 1.04, 95% CI = 0.99-1.10) and women (RR = 1.17, 95% CI = 1.10 1.24) were more likely not to have discussions with social group members. Of those who had discussions with medical professionals or social group members, older participants described these discussions as less encouraging (all P < .01). CONCLUSION: Older adults and women undergoing hemodialysis are less likely than younger adults and men to have discussions about KT as a treatment option, supporting a need for better clinical guidelines and education for these individuals, their social network, and their providers. PMID- 24801543 TI - Novel anti-adhesive barrier Biobarrier reduces growth of colon cancer cells. AB - BACKGROUND: Postoperative peritoneal carcinomatosis together with adhesion formation are considered as two major clinical complications after resection of malignant abdominal tumors, jeopardizing the beneficial effect of the curative surgery. Biobarrier is a novel anti-adhesive barrier fulfilling the criteria for a good adhesion preventive agent, possessing biochemical properties that may enable it to function as a dual efficient device, reducing both adhesion and tumor development. This study aims to evaluate the effect of novel anti-adhesive device Biobarrier on intra-abdominal tumor progression. MATERIALS AND METHODS: Cells from cancer cell line BN7005H1D2 were treated with Biobarrier to determine the effect of Biobarrier on cell attachment and viability in vitro. For the in vivo experiments, bilateral peritoneal trauma was inflicted in a reproducible syngeneic rat model. To mimic the clinical situation, the animals received an intraperitoneal injection of BN7005H1D2 cancer cells at the end of surgery, resembling perioperative tumor spill after intraperitoneal instillation of Biobarrier. Animals without given anti-adhesive treatment were used as control. RESULTS: Biobarrier applied in vitro hindered cells from attachment to the wells. In vivo treatment with Biobarrier significantly reduced tumor growth at both sites of surgical trauma (P = 0.001 and 0.015) and other non-traumatized intraperitoneal sites (P = 0.021). CONCLUSIONS: Biobarrier maybe effective in reducing intra-abdominal tumor cell implantation with subsequent tumor development in conjunction with peritoneal trauma in a syngeneic rat model. PMID- 24801545 TI - Oxygen sensitivity of atomically passivated CdS nanocrystal films. AB - CdS nanocrystals (NCs) synthesized by colloidal chemistry methods have been intensively studied for various applications. However, little attention has been paid to the interaction between the oxygen molecules present in air and the NC surface, which has a strong influence on the electrical properties of NC films. Here, we discuss the effect of oxygen adsorption at the NC surface on the photoconductivity of CdS NC films that were treated by propyltrichlorosilane, which is known to replace the native ligands at the NC surface with chloride ions. The photocurrent-voltage (PIV) characteristics of NC@Cl films recorded under oxygen atmosphere reveal a significant reduction in the photocurrent, as compared to those recorded under argon or vacuum. We demonstrate that this reduction can be related to adsorbed oxygen ions that effectively passivate the NC surface. This passivation reduces the free electron concentration and thereby reduces the photocurrent. Furthermore, we have investigated the light intensity dependence of the photocurrent dynamics of our devices in argon and in oxygen. These measurements confirm that the adsorption of oxygen is a photo-assisted process. Eventually, the potential of using our devices as oxygen sensors is assessed. A remarkable sensitivity of 35 is obtained at room temperature for 10% (concentration) oxygen flow, which is at least one order of magnitude higher than the results reported in the literature. Our work clarifies the mechanism of the photoconductivity reduction in CdS NC films upon oxygen adsorption and opens up opportunities of exploring such devices for gas sensing applications. PMID- 24801544 TI - Feasibility study of a bio-inspired artificial pancreas in adults with type 1 diabetes. AB - BACKGROUND: This study assesses proof of concept and safety of a novel bio inspired artificial pancreas (BiAP) system in adults with type 1 diabetes during fasting, overnight, and postprandial conditions. In contrast to existing glucose controllers in artificial pancreas systems, the BiAP uses a control algorithm based on a mathematical model of beta-cell physiology. The algorithm is implemented on a miniature silicon microchip within a portable hand-held device that interfaces the components of the artificial pancreas. MATERIALS AND METHODS: In this nonrandomized open-label study each subject attended for a 6-h fasting study followed by a 13-h overnight and post-breakfast study on a separate occasion. During both study sessions the BiAP system was used, and microboluses of insulin were recommended every 5 min by the control algorithm according to subcutaneous sensor glucose levels. The primary outcome was percentage time spent in the glucose target range (3.9-10.0 mmol/L). RESULTS: Twenty subjects (55% male; mean [SD] age, 44 [10] years; duration of diabetes, 22 [12] years; glycosylated hemoglobin, 7.4% [0.7%] [57 (7) mmol/mol]; body mass index, 25 [4] kg/m(2)) participated in the fasting study, and the median (interquartile range) percentage time in target range was 98.0% (90.8-100.0%). Seventeen of these subjects then participated in the overnight/postprandial study, where 70.7% (63.9 77.4%) of time was spent in the target range and, reassuringly, 0.0% (0.0-2.3%) of time was spent in hypoglycemia (<3.9 mmol/L). CONCLUSIONS: The BiAP achieves safe glycemic control during fasting, overnight, and postprandial conditions. PMID- 24801546 TI - Sulfuretin inhibits 6-hydroxydopamine-induced neuronal cell death via reactive oxygen species-dependent mechanisms in human neuroblastoma SH-SY5Y cells. AB - Sulfuretin, a potent anti-oxidant, has been thought to provide health benefits by decreasing the risk of oxidative stress-related diseases. In this study, we investigated the mechanisms of sulfuretin protection of neuronal cells from cell death induced by the Parkinson's disease (PD)-related neurotoxin 6 hydroxydopamine (6-OHDA). We examined whether sulfuretin acts as an anti-oxidant to reduce oxidative stress and mitochondrial-mediated apoptotic cascade events in 6-OHDA-induced neurotoxicity in SH-SY5Y cells. We also investigated whether sulfuretin specifically acts by inhibiting phosphorylation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and glycogen synthase kinase-3beta (GSK-3beta) as well as activation of the nuclear factor kappa B (NF-kappaB) pathway. Sulfuretin significantly inhibited neuronal cell death, neurotoxicity, apoptosis, and reactive oxygen species (ROS) production. Sulfuretin also strikingly attenuated 6-OHDA-induced mitochondrial dysfunction. Moreover, sulfuretin significantly attenuated 6-OHDA-induced phosphorylation of c Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPKs, PI3K/Akt, and GSK-3beta. Eventually, sulfuretin inhibited 6-OHDA induced NF-kappaB translocation to the nucleus induced by 6-OHDA. The results of the current study provide the first evidence that sulfuretin protects SH-SY5Y cells against 6-OHDA-induced neuronal cell death, possibly through inhibition of phosphorylation of MAPK, PI3K/Akt, and GSK-3beta, which leads to mitochondrial protection, NF-kappaB modulations and subsequent suppression of apoptosis via ROS dependent pathways. Thus, we conclude that sulfuretin may have a potential role for neuroprotection and, therefore, may be used as a therapeutic agent for PD. PMID- 24801547 TI - Time delays in presentation and treatment of acute scrotal pain in a provincial hospital. AB - BACKGROUND: Acute scrotal pain is a urological emergency due to the possibility of testicular torsion and subsequent testicular loss if correction is not carried out in a timely manner. METHODS: We conducted a retrospective review of all patients who underwent surgical exploration for acute scrotal pain in a provincial hospital in New Zealand between 1 January 2001 and 31 December 2010. RESULTS: A total of 91 cases were identified. The median delay pre-hospital was 9 h and in-hospital was 2.5 h. Patients who had a non-viable testicular torsion and patients under the age of 14 had longer pre-hospital delays of 24 and 72 h, respectively. In-hospital delays were similar between all pathologies except for non-viable testicular torsions with 7 h and 45 min. Viable testicular torsions had a median in-hospital delay of 2 h and 13 min. CONCLUSION: Delay from the time of testicular pain until surgical exploration is important for the chances of testicular salvage and is made up mostly of pre-hospital delays. Patients under the age of 14 had longer delays pre-hospital. PMID- 24801548 TI - Temperature- and nitrogen source-dependent regulation of GlnR target genes in Listeria monocytogenes. AB - The ubiquitous pathogen Listeria monocytogenes lives either saprophytically in the environment or within cells in a vertebrate host, thus adapting its lifestyle to its ecological niche. Growth experiments at 24 and 37 degrees C (environmental and host temperature) with ammonium or glutamine as nitrogen sources revealed that ammonium is the preferred nitrogen source of L. monocytogenes. Reduced growth on glutamine is more obvious at 24 degrees C. Global transcriptional microarray analyses showed that the most striking difference in temperature-dependent transcription was observed for central nitrogen metabolism genes, glnR (glutamine synthetase repressor GlnR), glnA (glutamine synthetase GlnA), amtB (ammonium transporter AmtB), glnK (PII regulatory protein GlnK), and gdh (glutamate dehydrogenase) when cells were grown on glutamine. When grown on ammonium, both at 24 and 37 degrees C, the transcriptional level of these genes resembles that of cells grown with glutamine at 37 degrees C. Electrophoretic mobility shift assay studies and qPCR analyses in the wild-type L. monocytogenes and the deletion mutant L. monocytogenes ?glnR revealed that the transcriptional regulator GlnR is directly involved in temperature- and nitrogen source-dependent regulation of the respective genes. Glutamine, a metabolite known to influence GlnR activity, seems unlikely to be the (sole) intracellular signal mediating this temperature-and nitrogen source dependent metabolic adaptation. PMID- 24801549 TI - Clinical and economic burden of surgical site infection in hysterectomy. AB - BACKGROUND: Owing to a lack of current understanding of outcomes and costs by type of hysterectomy procedure, we attempt to quantify the incidence and impact of surgical site infection (SSI) in laparoscopic and non-laparoscopic approaches to abdominal and vaginal hysterectomy. METHODS: Patients whose data were contained in the Premier Perspectives Database of 600 hospitals in the United States were selected on the basis of a post-operative diagnosis of SSI and treatment with antibiotics. The incidence of SSI and associated hospital length of stay (LOS) and costs were estimated. The effect of SSI on readmission was also analyzed. RESULTS: Of 210,916 hysterectomies included in the study, 55% were open abdominal procedures. Although the overall incidence of SSI in hysterectomy was low, its incidence was greater in open abdominal hysterectomy than in other approaches to hysterectomy. Patients with an SSI experienced a three- to five fold greater LOS, two-fold greater cost, and three-fold greater risk of hospital readmission than those without an SSI. CONCLUSIONS: This study provides clinical evidence in support of less invasive approaches to hysterectomy. In addition to other documented benefits of such less invasive procedures, the lower incidence of SSIs and lower rates of associated complications and costs with these procedures than with open abdominal hysterectomy should be taken into account when weighing the risks and benefits of a surgical approach for patients whose condition warrants hysterectomy. PMID- 24801550 TI - Multi-material decomposition using statistical image reconstruction for spectral CT. AB - Spectral computed tomography (CT) provides information on material characterization and quantification because of its ability to separate different basis materials. Dual-energy (DE) CT provides two sets of measurements at two different source energies. In principle, two materials can be accurately decomposed from DECT measurements. However, many clinical and industrial applications require three or more material images. For triple-material decomposition, a third constraint, such as volume conservation, mass conservation or both, is required to solve three sets of unknowns from two sets of measurements. The recently proposed flexible image-domain (ID) multi-material decomposition) method assumes each pixel contains at most three materials out of several possible materials and decomposes a mixture pixel by pixel. We propose a penalized-likelihood (PL) method with edge-preserving regularizers for each material to reconstruct multi-material images using a similar constraint from sinogram data. We develop an optimization transfer method with a series of pixel wise separable quadratic surrogate (PWSQS) functions to monotonically decrease the complicated PL cost function. The PWSQS algorithm separates pixels to allow simultaneous update of all pixels, but keeps the basis materials coupled to allow faster convergence rate than our previous proposed material- and pixel-wise SQS algorithms. Comparing with the ID method using 2-D fan-beam simulations, the PL method greatly reduced noise, streak and cross-talk artifacts in the reconstructed basis component images, and achieved much smaller root mean square errors. PMID- 24801552 TI - Paclitaxel-coated balloons and aneurysm formation in peripheral vessels. AB - We report two cases of early aneurysmal vessel dilatation after a paclitaxel coated balloon (PCB) was used for angioplasty of the peripheral vessels. The first case refers to a failing vein bypass with a tight proximal anastomotic stenosis, whereas the second refers to a distal tibial artery occlusion. A PCB was used to treat both patients. Aneurysmal dilatation of the previously treated segment was noted in both patients during subsequent follow-up imaging. In the absence of other causal factors, we attribute both cases to PCB application. The aneurysms that formed had no detrimental effect on the patients' health and required no further treatment; however, it is important to bear in mind this potential risk of presumed paclitaxel toxicity. PMID- 24801551 TI - Mass spectrometry of natural products: current, emerging and future technologies. AB - Although mass spectrometry is a century old technology, we are entering into an exciting time for the analysis of molecular information directly from complex biological systems. In this Highlight, we feature emerging mass spectrometric methods and tools used by the natural product community and give a perspective of future directions where the mass spectrometry field is migrating towards over the next decade. PMID- 24801553 TI - Analysis of multiple genetic polymorphisms in aggressive-growing and slow-growing abdominal aortic aneurysms. AB - BACKGROUND: The natural history of abdominal aortic aneurysms (AAAs) suggests that some remain slow in growth rate whereas many develop a more accelerated growth rate and reach a threshold for intervention. We hypothesized that different mechanisms are responsible for AAAs that remain slow growing and never become actionable vs the aggressive AAAs that require intervention and may be reflected by distinct associations with genetic polymorphisms. METHODS: AAA growth rate was determined from serial imaging data in 168 control and 141 AAA patients with ultrasound or computed tomography imaging studies covering ~5 years. Genetic polymorphisms all previously reported as showing a significant correlation with AAA with functional effects on the expression or function were determined by analysis of the genomic DNA, including angiotensin 1 receptor (rs5186), interleukin-10 (IL-10; rs1800896), methyl-tetrahydrofolate reductase (rs1801133), low-density lipoprotein receptor-related protein 1 (LRP1; rs1466535), angiotensin-converting enzyme (rs1799752), and several matrix metalloproteinase 9 (MMP-9) single nucleotide polymorphisms. RESULTS: Of the AAA patients, 81 were classified as slow AAA growth rate (<3.25 mm/y) vs 60 with aggressive AAA growth rate (>3.25 mm/y, those presenting with a rupture, or those with maximal aortic diameter >5.5 cm [male] or >5.0 cm [female]). Discriminating confounds between the groups were identified by logistic regression. Analyses identified MMP-9 p-2502 single nucleotide polymorphism (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.31-0.94; P = .029) as a significant confound discriminating between control vs slow-growth AAA, MMP-9 D165N (OR, 0.49; 95% CI, 0.26-0.95; P = .035) and LRP1 (OR, 4.99; 95% CI, 1.13-22.1; P = .034) between control vs aggressive-growth AAAs, and methyltetrahydrofolate reductase (OR, 2.99; 95% CI, 1.01-8.86; P = .048), MMP-9 p-2502 (OR, 2.19; 95% CI, 1.05-4.58; P = .037), and LRP1 (OR, 4.96; 95% CI, 1.03-23.9; P = .046) as the statistically significant confounds distinguishing slow-growth AAAs vs aggressive-growth AAAs. CONCLUSIONS: Logistic regression identified different genetic confounds for the slow-growth and aggressive-growth AAAs, indicating a potential for different genetic influences on AAAs of distinct aggressiveness. Future logistic regression studies investigating for potential genetic or clinical confounds for this disease should take into account the growth rate and size of the AAA to better identify confounds likely to be associated with aggressive AAAs likely to require intervention. PMID- 24801554 TI - Observation and surgery are associated with low risk of amputation for blunt brachial artery injury in pediatric patients. AB - BACKGROUND: The ideal treatment for blunt brachial artery (BBA) injury in pediatric patients is controversial. We compared outcomes of surgical and nonsurgical management of BBA injury using the National Trauma Data Bank. METHODS: All patients younger than 18 years who had suffered BBA injury were identified in the pediatric National Trauma Data Bank (2002-2010) by Current Procedural Terminology code. Patients with a penetrating mechanism of injury were excluded. By the International Classification of Diseases, Ninth Revision procedure codes, patients were stratified on the basis of treatment modality: observation vs arterial surgery. Outcomes including upper extremity amputation, mortality, and intensive care unit length of stay were compared between the two groups by two-sample t-test or chi(2) test as appropriate. RESULTS: Among 119 patients with BBA injury, 49 patients (41.2%) underwent arterial surgery and 70 patients (58.8%) were observed. Patients treated with observation were significantly younger, whereas other characteristics including gender and Injury Severity Score were similar. There was no difference in the type of hospital (academic vs nonacademic) or trauma center category between the groups. Two amputations were identified in the database, and both were in the 13- to 17-year age group of the observation cohort (vs arterial surgery; P = .22). There were eight fasciotomies identified; five were in the arterial surgery group (10.2% vs observation, 4.3%; P = .20). No amputation or fasciotomy was required in the 0- to 6-year age group. Length of stay was similar between groups. CONCLUSIONS: Despite slightly lower adverse outcomes, arterial surgery does not appear to confer a significant advantage over nonoperative treatment in pediatric patients with BBA injury. In patients younger than 6 years, both modalities appear to be equality effective. PMID- 24801556 TI - Large eddy simulation of transitional flow in an idealized stenotic blood vessel: evaluation of subgrid scale models. AB - In the present study, we performed large eddy simulation (LES) of axisymmetric, and 75% stenosed, eccentric arterial models with steady inflow conditions at a Reynolds number of 1000. The results obtained are compared with the direct numerical simulation (DNS) data (Varghese et al., 2007, "Direct Numerical Simulation of Stenotic Flows. Part 1. Steady Flow," J. Fluid Mech., 582, pp. 253 280). An inhouse code (WenoHemo) employing high-order numerical methods for spatial and temporal terms, along with a 2nd order accurate ghost point immersed boundary method (IBM) (Mark, and Vanwachem, 2008, "Derivation and Validation of a Novel Implicit Second-Order Accurate Immersed Boundary Method," J. Comput. Phys., 227(13), pp. 6660-6680) for enforcing boundary conditions on curved geometries is used for simulations. Three subgrid scale (SGS) models, namely, the classical Smagorinsky model (Smagorinsky, 1963, "General Circulation Experiments With the Primitive Equations," Mon. Weather Rev., 91(10), pp. 99-164), recently developed Vreman model (Vreman, 2004, "An Eddy-Viscosity Subgrid-Scale Model for Turbulent Shear Flow: Algebraic Theory and Applications," Phys. Fluids, 16(10), pp. 3670 3681), and the Sigma model (Nicoud et al., 2011, "Using Singular Values to Build a Subgrid-Scale Model for Large Eddy Simulations," Phys. Fluids, 23(8), 085106) are evaluated in the present study. Evaluation of SGS models suggests that the classical constant coefficient Smagorinsky model gives best agreement with the DNS data, whereas the Vreman and Sigma models predict an early transition to turbulence in the poststenotic region. Supplementary simulations are performed using Open source field operation and manipulation (OpenFOAM) ("OpenFOAM," http://www.openfoam.org/) solver and the results are inline with those obtained with WenoHemo. PMID- 24801555 TI - Human metabolome associates with dietary intake habits among African Americans in the atherosclerosis risk in communities study. AB - The human metabolome is a measurable outcome of interactions among an individual's inherited genome, microbiome, and dietary intake. We explored the relationship between dietary intake and serum untargeted metabolomic profiles in a subsample of 1,977 African Americans from the Atherosclerosis Risk in Communities (ARIC) Study in 1987-1989. For each metabolite, we conducted linear regression to estimate its relationships with each food group and food category. Potential confounding factors included age, sex, body mass index (weight (kg)/height (m)(2)), energy intake, kidney function, and food groups. We used a modified Bonferroni correction to determine statistical significance. In total, 48 pairs of diet-metabolite associations were identified, including multiple novel associations. The food group "sugar-rich foods and beverages" was inversely associated with 5 metabolites in the 2-hydroxybutyrate-related subpathway and positively associated with 5 gamma-glutamyl dipeptides. The hypothesized mechanism of these associations may be through oxidative stress. "Sugar-rich foods and beverages" were also inversely associated with 7 unsaturated long-chain fatty acids. These findings suggest that the contribution of a sugar-rich dietary pattern to increased cardiovascular disease risk may be partially attributed to oxidative stress and disordered lipid profiles. Metabolomics may reveal novel metabolic biomarkers of dietary intake and provide insight into biochemical pathways underlying nutritional effects on disease development. PMID- 24801557 TI - The relationship between neutrophil gelatinase-associated lipocalin levels and the slow coronary flow phenomenon. AB - OBJECTIVES: There is accumulating evidence that inflammation plays a major role in the development of the slow coronary flow (SCF) phenomenon. In this study, we aimed to study the biomarker neutrophil gelatinase-associated lipocalin (NGAL) as it relates to SCF. MATERIALS AND METHODS: Patients who underwent coronary angiography before and had no significant epicardial coronary disease were included in the study. Patients who had Thrombolysis in Myocardial Infarction frame counts (TFCs) above the normal cutoffs were considered to have SCF and those within normal limits were considered to have normal coronary flow (NCF). The NGAL levels and biochemical profiles of all patients were studied and analyzed with coronary flow parameters. RESULTS: There were 50 patients in the SCF group and 50 patients in the NCF group. The serum NGAL level was higher in those patients in the SCF group versus the NCF group (75.2+/-39.7 vs. 50.6+/ 24.2, P<0.001). There was a significant correlation between the NGAL levels and TFC (r=0.684, P<0.001). Multivariable regression analysis showed that the NGAL levels were an independent predictor of the SCF phenomenon (odds ratio=1.060, 95% confidence interval: 1.008-1.115, P=0.023). CONCLUSION: In this study, we show that patients with SCF have elevated levels of NGAL. We further show a strong correlation between the NGAL levels and coronary blood flow. We conclude that elevated NGAL levels might be a useful tool in predicting SCF in patients who undergo coronary angiography. PMID- 24801558 TI - Correlates of poor outcome among patients with bleeding after coronary interventions. AB - OBJECTIVES: The objective of this study was to identify factors associated with the increased risk of mortality among patients with bleeding complications during percutaneous coronary intervention (PCI). METHODS: The study included 1510 patients with periprocedural bleeding complications of the 14 180 patients undergoing PCI. Bleeding was defined and scaled according to the Bleeding Academic Research Consortium criteria. The main outcome was all-cause mortality at 1 year after PCI. RESULTS: Of the 1510 patients with bleeding within the first 30 days of PCI, 104 patients (6.9%) died during the first year after PCI. One year survival according to the Bleeding Academic Research Consortium classes was as follows: 96.4% (22 deaths) in class 1, 94.7% (12 deaths) in class 2, 91.0% (42 deaths) in class 3a, 85.4% (23 deaths) in class 3b, and 58.3% (five deaths) in class 3c (P<0.001). The Cox proportional hazards model identified bleeding severity [hazard ratio (HR)=1.55, 95% confidence interval 1.25-1.93 for one class increase in bleeding scale, P<0.001], bleeding site [HR=1.79 (1.18-2.71) for nonaccess vs. access site, P=0.006], elevated troponin levels [HR=1.66 (1.09 2.53), P=0.018], multivessel disease [HR=2.15 (1.01-4.56), P=0.047], C-reactive protein [HR=1.04 (1.01-1.06) for 5 mg/l increase, P=0.002], anemia [HR=2.27 (1.39 3.71) for 4 g/dl decrease in hemoglobin, P=0.001], and platelet count [HR=1.11 (1.02-1.21) for 50*10/l increase in platelet count, P=0.013] as independent associates of mortality. Age (P=0.072) and reduced estimated creatinine clearance (P=0.066) were close to reaching statistical significance as associates of mortality. CONCLUSION: Among patients with peri-PCI bleeding, the characteristics of bleeding itself and the cardiovascular risk profile underlie the increased risk for poor outcome after PCI. PMID- 24801559 TI - Cross-linking-based flexibility and proximity relationships between the TM segments of the Escherichia coli YidC. AB - The YidC family members function to insert proteins into membranes in bacteria, chloroplasts, and mitochondria, and they can also act as a platform to fold and assemble proteins into higher-order complexes. Here, we provide information about the proximity relationships and dynamics of the five conserved C-terminal transmembrane (TM) regions within Escherichia coli YidC. By using a YidC construct with tandem thrombin protease sites introduced into the cytoplasmic loop C1, cross-linking between paired-Cys residues located within TM segments or in the membrane border regions was studied using thio-specific homobifunctional cross-linking agents with different spanner lengths or by iodine-catalyzed disulfide formation. These in vivo cross-linking studies that can detect transient interactions and different conformational states of the protein show that TM3, TM4, TM5, and TM6 each have a face oriented toward TM2 of the in vivo expressed YidC. The studies also reveal that YidC is a dynamic protein, as cross linking was observed between cytoplasmic Cys residues with a variety of cross linkers. A large number of conserved proline residues on the cytoplasmic side of the five conserved core TM segments could explain the observed flexibility, and the structural fluctuations of the TM segments could provide an explanation for how YidC is able to recognize a variety of different substrates. PMID- 24801560 TI - Genomics and personalised whole-of-life healthcare. AB - Genome sequencing has the potential for stratified cancer treatment and improved diagnostics for rare disorders. However, sequencing needs to be utilised in risk stratification on a population scale to deepen the impact on the health system by addressing common diseases, where individual genomic variants have variable penetrance and minor impact. As the accuracy of genomic risk predictors is bounded by heritability, environmental factors such as diet, lifestyle, and microbiome have to be considered. Large-scale, longitudinal research programmes need to study the intrinsic properties between both genetics and environment to unravel their risk contribution. During this discovery process, frameworks need to be established to counteract unrealistic expectations. Sufficient scientific evidence is needed to interpret sources of uncertainty and inform decision making for clinical management and personal health. PMID- 24801561 TI - Pilot study assessing the efficacy of a novel treatment for sleep-related breathing disorders in patients undergoing sleep nasendoscopy: Our Experience. PMID- 24801562 TI - Ventilation inhomogeneities in patients with cystic fibrosis: which target lung function parameters offer valuable evaluation? PMID- 24801563 TI - Effect of metformin on the incidence of head and neck cancer in diabetics. AB - BACKGROUND: The purpose of this study was to examine the effect of metformin on head and neck cancer in patients with diabetes. METHODS: We compared 66,600 patients, all with diabetes and all newly diagnosed with head and neck cancer in 2002. Half were being treated with metformin for diabetes (Met(+) ) and half were not (Met(-) : controls). All were matched for comorbidities (obesity, coronary artery disease, hyperlipidemia, and hypertension), sex, and age. The risk of head and neck cancer at the end of 2011 was determined. RESULTS: The incidence of head and neck cancer was 34% lower in the Met(+) cohort than in the Met(-) cohort (adjusted hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.55-0.79). The risks for oropharyngeal cancer (adjusted HR = 0.66; 95% CI = 0.17-0.74) and nasopharyngeal carcinoma (NPC; adjusted HR = 0.50; 95% CI = 0.31-0.80) were significantly lower in the Met(+) cohort than in the Met(-) cohort. CONCLUSION: Metformin is associated with a lower risk of developing head and neck cancer in patients with diabetes. PMID- 24801564 TI - From word superiority to word inferiority: visual processing of letters and words in pure alexia. AB - Visual processing and naming of individual letters and short words were investigated in four patients with pure alexia. To test processing at different levels, the same stimuli were studied across a naming task and a visual perception task. The normal word superiority effect was eliminated in both tasks for all patients, and this pattern was more pronounced in the more severely affected patients. The relationship between performance with single letters and words was, however, not straightforward: One patient performed within the normal range on the letter perception task, while being severely impaired in letter naming and word processing, and performance with letters and words was dissociated in all four patients, with word reading being more severely impaired than letter recognition. This suggests that the word reading deficit in pure alexia may not be reduced to an impairment in single letter perception. PMID- 24801565 TI - [Status quo and potential of health services research: the perspective of Bavarian actors]. AB - In 2011, the Bavarian Parliament decided to advance health services research (HSR) in Bavaria by bundling scientific competencies in a State Working Group and integrating other actors in it. The establishment of such a State Working Group "Health Services Research" -(LAGeV) together with members from science, health care and politics followed in 2012. The objective of this study is to identify the status quo of HSR in Bavaria including its determinants and potential for development based on the actors' perspective.After the inaugural meeting a semi structured questionnaire was sent to all 36 members from 28 organisations. Items comprise information on the respondent's background as well as status quo, future topics and potential for development of HSR in Bavaria.27 members took part in the survey, resulting in a response rate of 75.0%. Satisfaction of actors with the status quo of HSR is rather low, especially regarding the effectiveness of policy advice. Researchers and health care providers are also not much satisfied with the HSR environment. For the future of HSR, respondents prioritise the topics interface and networking research, followed by innovative care concepts, care for patients with multiple or chronic conditions as well as evaluation of innovations, processes and technologies. Potential for development and thus improvement of care is primarily seen in the abolishment of existing constraints by an overall HSR concept (including selective research promotion), networking and cooperation, research funding as well as improving the interface between politics and science. Respondents assess the benefit of an increased networking within the LAGeV as high.Status quo of HSR in Bavaria is not very satisfactory. The survey reveals important constraints as well as promoting factors based on the viewpoints of different groups of actors. It also prioritises future HSR topics and identifies potential for development, which are important for the LAGeV. The findings can be used for advancing HSR in Bavaria and beyond. PMID- 24801566 TI - Morphology of arolia in Auchenorrhyncha (Insecta, Hemiptera). AB - The pretarsal arolium serves as an attachment device in many groups of insects, enabling them to walk efficiently on smooth surfaces, where claws alone do not provide sufficient foothold. The arolia of representatives of all major lineages of Auchenorrhyncha are described and illustrated, mainly using scanning electron microscopy and histology. Glands inside the lumen of the arolia are described for the first time in this group. It is shown that the morphology of arolia within Auchenorrhyncha differs considerably. Some of them are even distinctly bilobed. The cuticle of the contact zone is thickened and formed of branching chitinous rods. In some cases, two layers of rods oriented in different directions were found. An extended definition of "arolium" is proposed. PMID- 24801567 TI - Changes in soleus H-reflex during walking in middle-aged, healthy subjects. AB - INTRODUCTION: To assess the effect of aging on stretch reflex modulation during walking, soleus H-reflexes obtained in 15 middle-aged (mean age 56.4+/-6.9 years) and 15 young (mean age 23.7+/-3.9 years) subjects were compared. METHODS: The H reflex amplitude, muscle activity (EMG) of the soleus and tibialis anterior muscles, and EMG/H-reflex gain were measured during 4-km/h treadmill walking. RESULTS: The normalized H-reflex amplitude was lower in the swing phase for the middle-aged group, and there was no difference in muscle activity. EMG/H-reflex gain did not differ between groups. CONCLUSIONS: H-reflex amplitude during walking was affected by aging, and changes during the swing phase could be seen in the middle-aged subjects. Subdividing the 2 age groups into groups of facilitated or suppressed swing-phase H-reflex revealed that the H-reflex amplitude modulation pattern in the group with facilitated swing-phase H-reflex may be influenced by aging. PMID- 24801568 TI - Female genital mutilation/cutting--towards abandonment of a harmful cultural practice. AB - Globally, the prevalence of, and support for, female genital mutilation/cutting (FGM/C) is declining. However, the entrenched sense of social obligation that propagates the continuation of this practice and the lack of open communication between men and women on this sensitive issue are two important barriers to abandonment. There is limited evidence on the role of men and their experiences in FGM/C. Marriageability of girls is considered to be one of the main driving forces for the continuation of this practice. In some countries, more men than women are advocating to end FGM/C. Moreover, men, as partners to women with FGM/C, also report physical and psychosexual problems. The abandonment process involves expanding a range of successful programs, addressing the human rights priorities of communities and providing power over their own development processes. Anecdotal evidence exists that FGM/C is practised amongst African migrant populations in Australia. The Australian Government supports a taskforce to improve community awareness and education, workforce training and evidence building. Internationally, an African Coordinating Centre for abandonment of FGM/C has been established in Kenya with a major global support group to share research, promote solidarity, advocacy and implement a coordinated and integrated response to abandon FGM/C. PMID- 24801569 TI - Storage of apheresis platelet concentrates after manual replacement of >95% of plasma with PAS 5. AB - BACKGROUND AND OBJECTIVES: Recently, a glucose- and bicarbonate-containing additive solution termed PAS 5 demonstrated acceptable 7-day platelet storage after >95% plasma replacement with PAS on the day of collection (Day 0). In this study, we examined platelet storage in >95% PAS 5 after manual washing of Day 1 apheresis platelets in plasma collected using either the Amicus or Trima plateletpheresis devices. MATERIAL AND METHODS: Triple platelet donations in plasma were obtained from Amicus (n = 10) and Trima (n = 10) plateletpheresis devices and stored overnight before being centrifuged and manually processed into three units with the following storage media: 100% plasma, >95% PAS 5 or 65% PAS 5/35% plasma. Platelet units were sampled on Days 1, 5 and 7 of storage using a range of tests recommended by the UK guidelines. RESULTS: The majority of in vitro assay results for platelets in PAS 5 were similar to results in paired 100% plasma platelets (controls). The pH of PAS 5 stored platelet units was above the UK recommended guidelines of 7.4 by Day 5. PAS 5 platelets were no more activated than controls as evidenced by comparable soluble P-selectin levels and CD62p and CD42b expression. PAS 5 platelets also exhibited adhesion and aggregation profiles higher than (Day 1) or comparable to (Days 5 and 7) controls as measured by Impact R. CONCLUSION: The 7-day in vitro storage parameters investigated were comparable between >95% PAS 5 and 100% plasma platelets derived from both Amicus and Trima plateletpheresis devices, with the exception that lactose dehydrogenase release rate and pH were significantly higher in PAS 5 units. PMID- 24801570 TI - Spatial and temporal variation of lead, cadmium, and zinc in feathers of great tit and blue tit nestlings in Central Poland. AB - In this study, we examined heavy-metal concentrations in feathers of nestling great tits Parus major and blue tits Cyanistes caeruleus at two different sites (urban parkland vs. deciduous forest) located in the Lodz agglomeration in relation to interyear variation. We found that tit species did not differ significantly in lead and cadmium concentrations. Zinc concentration was significantly higher in blue tits. We also found that lead and cadmium levels in blue tit nestlings and the level of lead in great tit nestlings were higher in the parkland site than in the woodland site. We explain habitat variation in heavy-metal concentrations in feathers of nestlings by different levels of contamination at study sites. For both tit species, significant variation in heavy-metal amounts accumulated by nestlings was found between years with the lowest value in a year with the lowest value of rainfall. We suggest that the interyear variation may be accounted for by differences in rainfall, thus influencing quantities of trace elements bioavailable in the environment. PMID- 24801571 TI - Structure of the human P2Y12 receptor in complex with an antithrombotic drug. PMID- 24801572 TI - Systemic sclerosis: comparison of efficacy of oral cyclophosphamide and azathioprine on skin score and pulmonary involvement-a retrospective study. AB - The aim of this study was to evaluate efficacy of azathioprine (AZA) and cyclophosphamide (CYC) as a therapeutic regimen for interstitial lung disease associated with systemic sclerosis (SSc). Thirty-six selected patients included in this retrospective cohort and received one of the two drugs; the first group consists of 15 patients who were treated with AZA (1.5-2 mg/kg/day) and the second group with 21 patients received oral CYC (up to 2 mg/kg/day). Both groups received additional low dose of prednisolone (<=10 mg) for 6 months. Forced vital capacity (FVC), diffusion lung capacity for carbon monoxide (DLCO) and skin score were assessed as outcome measures. Modified Rodnan skin score (mRSS), pulmonary function test and DLCO were evaluated at entry and at the end of study after 12 months. The mean (SD) FVC percentages obtained at baseline and post-treatment in AZA-treated patients were 62.8 +/- 9.8 and 71.1 +/- 20.9 with mean difference of FVC% +7.6 +/- 13.1, p = 0.05, and in CYC-treated patients 59.5 +/- 10.7, 63.1 +/- 16.2 and +2.9 +/- 11.5, respectively, p = 0.19. Baseline and post-treatment DLCO% in AZA-treated patients were 61.4 +/- 25.8 and 76.7 +/- 24.0 with mean difference of +15.0 +/- 14.5, respectively, p = 0.01. In CYC-treated patients, those measures were 67.7 +/- 27.5 and 60.0 +/- 22.9 with mean difference of -8.0 +/- 23.7 (p = 0.12). Following 12 months of treatment in AZA-treated patients, mean difference of changes in mRSS was -2.9 +/- 3.7 and -1.4 +/- 4.5 in CYC-treated patients. Our results indicated that AZA can be effective in ameliorating or stabilizing lung function in selected SSc patient groups. PMID- 24801573 TI - Short-term follow-up of disc cell therapy in a porcine nucleotomy model with an albumin-hyaluronan hydrogel: in vivo and in vitro results of metabolic disc cell activity and implant distribution. AB - PURPOSE: Cell therapy would be favorably performed immediately after nucleotomy, to restore intervertebral disc functionality and to slow down disc degeneration. Promising results were reported from small animal models but remaining problems, especially in larger animals, include loss of vital cells due to annular damage at the injection site and detrimental intradiscal conditions. The aim of the present study was to optimize cell-based disc therapy using a new albumin hyaluronan hydrogel together with bone marrow-derived mesenchymal stem cells in a large porcine disc model. METHODS: Luciferase cell labeling was evaluated to follow-up stem cells metabolically up to 7 days in 3D cell cultures mimicking the harsh disc environment with low oxygen and glucose concentrations. As a pilot in vivo study, the implant was injected into porcine discs after removal of ~10% of nucleus volume and animals were killed immediately after surgery (n = 6) and 3 days later (n = 6). 24 discs were analyzed. Implant persistence and cell activity (luciferase + WST assay) were observed simultaneously. RESULTS: In vitro cell culture with reduction of glucose (20, 5, 0.5, 0 mM) and oxygen (21, 5, 2%) significantly decreased metabolic cell activity and luciferase activity after 3 days, with no recovery and a further decrease after 7 days, establishing luciferase activity as a metabolic sensor. During 3 days of 3D culture with disc like conditions, luciferase activity decreased to 8%. In vivo, initial implant volume shrank to 61% at day 3 with evidence for hydrogel compression. Luciferase activity in vivo at day 3 was 2% without referencing but 23% after referencing to in vitro cell adaptation, and 38% after additional consideration of detected implant volume loss. CONCLUSION: In vitro analysis up to 7 days established for the first time luciferase activity as a metabolic sensor for mesenchymal stem cells used in regenerative disc therapy. Under the present protocol, short-term in vivo analysis after 3 days suggests improved implant retainment inside the disc and persistence of metabolically active cells; however, further studies will have to prove long-term in vivo outcome. PMID- 24801574 TI - Management of the neglected and healed bilateral cervical facet dislocation. AB - INTRODUCTION: There is limited literature on the management of neglected healed (fused) bilateral cervical facet dislocation. The authors report a case of a middle aged male who developed a bilateral facet dislocation but only sought treatment 14 months post injury when he experienced pain and deformity in the cervical spine. CASE REPORT: A 42-year-old male was pushed into a 1.2-m pool by accident and hit his head on the bottom. He immediately felt a sharp pain in his neck but was able to get out of the pool by himself and at the emergency department was found to have no neurological deficit. Standard trauma radiographs were performed and a grade 1 anterolisthesis of C4 on C5 was observed without any facet subluxation or dislocation. An emergent Magnetic Resonance Imaging (MRI) of the cervical spine confirmed X-ray results and in addition demonstrated injury to the posterior ligament complex and a broad-based posterior disc bulge. Computed Tomography (CT) scans revealed no facet dislocation or fractures. Unfortunately, the patient failed to come for his follow-up visits and at 14 months post injury, represented with pain and deformity with impairment of horizontal gaze. Computed tomography and MRI demonstrated a fused (bony) bilateral facet dislocation at C4/5. A cervical spine reconstruction consisting of a posterior-anterior posterior approach was performed to address both the deformity and the pain. At 32-month follow-up, the patient remains well with no neurological symptoms, minimal neck pain and successful fusion. CONCLUSION: Current literature does not offer a clear solution to the management of healed neglected bilateral cervical facet dislocation. The presence of circumferential bony fusion around the deformity necessitates a posterior and anterior release and subsequent stabilization to address this complex problem. We also wish to highlight the order of the reconstructive approach and the need to recognize instability of the cervical spine despite normal CT scans in order to prevent late deformity. PMID- 24801575 TI - The pathological changes in the spinal cord after dural tear with and without autologous fascia repair. AB - PURPOSE: Dural tear is one of the common complications of spinal surgery leading to cerebrospinal fluid leakage followed by serial secondary symptoms. However, little is known about pathological changes of the spinal cord after dural tear. In the present study, we aimed to study the pathological changes in the spinal cord after dural tear with and without autologous fascia repair. METHODS: Sixty Sprague-Dawley rats were used for dural tear and autologous fascia graft repair models. Three days and 1 week after surgery, the pathological changes in the spinal cord were analyzed by immunohistochemistry, Western blot, enzyme-linked immunosorbent assay and spinal somatosensory evoked potentials test. RESULTS: Neuroinflammation was found in the parenchyma of the spinal cord characterized by gliosis, increased expression of inflammatory factors and infiltration of exogenesis immunocells in the rats without repair, which impaired the sensory conduction function of the spinal cord at the early stage of injury. Repairing with autologous fascia could attenuate neuroinflammation and help to maintain normal sensory conduction function of the spinal cord. CONCLUSION: Dural tear could cause a series of inflammatory reactions in the spinal cord and further impair its sensory conduction function at the early stage of injury. Repairing with autologous fascia was a necessary and effective way to prevent the neuroinflammation and to maintain the normal function of the spinal cord. PMID- 24801576 TI - An analysis of thoracic cage deformities and pulmonary function tests in congenital scoliosis. AB - PURPOSE: To determine: (1) the relationship of thoracic cage parameters and preoperative pulmonary function tests (PFTs) in congenital scoliosis (CS) patients. (2) if patients with rib deformity have greater impairment of PFTs than those without rib deformity. METHODS: A total of 218 patients with CS and pulmonary dysfunction (FVC < 80 %) were conducted in one spine center between Jan 2009 and Mar 2013. The demographic distribution, medical records, PFTs and radiographs of all patients were collected. The association of PFTs and thoracic cage deformities was analyzed. RESULTS: In total, 143 patients (65.6 %) had a clinically relevant impairment of pulmonary function. They had smaller BMI, larger thoracic transverse and anteroposterior diameter, more thorax height, scoliotic angle and number of involved vertebra than no clinically impairment. PFTs were negative correlation significantly with scoliotic angle, number of involved vertebra and thoracic sagittal diameter, while thorax height is significant positive. The T1-12 height was significant positive correlation with age, stature, weight, thoracic transverse and sagittal longitudinal diameter, while negative correlation with scoliotic curve, number of involved vertebra, as well as kyphotic angle. PFTs do not correlate with T1-12 height, but significantly associated with the rib anomalies. The FVC and FEV1 were significantly lower in patients with rib anomalies than without rib anomalies. There was no association between the pulmonary function and the location of rib deformities. CONCLUSIONS: PFTs correlate significantly with scoliotic angle, number of involved vertebra, thoracic sagittal diameter, and thorax height. PFTs were significantly lower in patients with rib anomalies, particular to the patients with fused rib. PMID- 24801578 TI - Screening on human hepatoma cell line HepG-2 nucleus and cytoplasm protein after CDK2 silencing by RNAi. AB - The activation of phase-specific cyclin-dependent kinases is associated with ordered cell cycle transitions. Among the mammalian Cdks, Cdk2 is essential for liver cancer cell proliferation. The related cycling protein CDK2 was analyzed by 2D-gel and MALDI-TOF/TOF MS mass assay in liver cancer cells, which CDK2 was silenced. The results showed four significantly different spots in cell ribonucleoprotein (similar to ribosomal protein S12, chaperonin 10-related protein, beta-actin and zinc finger protein 276) and four in plasmosin (aldolase A protein, hCG, anonymous protein and tubulin, gamma complex associated protein 2). In the plasmosin, aldolase A catalyzes the production of tublin and actin. Together they regulate the cell cycle and arrest the cell in the S phage. In the cell ribonucleoprotein, proteins with homology to ribosomal protein S12 and chaperonin 10 play a similar role in cell cycle regulation. PMID- 24801577 TI - Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. AB - The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments. SIGNIFICANCE: Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. PMID- 24801580 TI - DESI-MS as a tool for direct lipid analysis in cultured cells. AB - Desorption electrospray ionization may be used as a fast and convenient method for analysis and identification of lipids in the cell culture. Oxidative stress, which usually involves changes in lipids, was used as a model of pathology to show the utility of this analysis methodology. This paper addresses the surface preparation of cell culture slides, induction of oxidative stress, and cell monolayer culture preparation as well as optimization of the analysis. Advantages and drawbacks of the method were also discussed. PMID- 24801579 TI - Cytotoxicity and genotoxicity of zingiberene on different neuron cell lines in vitro. AB - The main objective of this study is to investigate the cytotoxic, genotoxic and antioxidant properties of zingiberene (ZBN) in an in vitro rat brain cell culture study. The cytotoxic effect was determined against the rat neuron and N2a neuroblastoma (N2a-NB) cell lines using the 3,(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, while the antioxidant activity was assessed using the total antioxidant capacity (TAC) and total oxidative stress (TOS) assays. The effects on DNA damage were also evaluated in this study by the single cell gel electrophoresis assay. The results indicated that ZBN has an anti proliferative activity suppressing the proliferation of N2a-NB cells at concentrations over 50 mg L(-1) and neuron cells at concentrations over 150 mg L( 1). In addition, ZBN treatments at higher doses (<=50 mg L(-1)) led to increases of TOS levels in N2a-NB cell cultures. However 25 mg L(-1) of ZBN treatment caused increases of TAC levels in cultured neuron and N2a-NB cell cultures while ZBN at doses of 10-400 mg L(-1) did not increase the number of total damage score in both cell lines. This study clearly indicates that ZBN has a significant potential to be used as a natural anticancer agent in cultured N2a-NBs. PMID- 24801582 TI - Pediatric obesity screening and prevention strategies. AB - Childhood overweight and obesity is a major health concern in the United States. It is recommended that every well-child examination include body mass index measurements and obesity prevention discussions that encourage healthy eating habits, regular physical exercise, and limited television and computer screen time. Providers can make a difference through strategic intervention. PMID- 24801581 TI - A new spiroplasma isolate from the field cricket (Gryllus bimaculatus) in Taiwan. AB - We briefly described the morphology and transmission pathway of a Spiroplasma sp. isolated from the field cricket, Gryllus bimaculatus in Taiwan, followed by the phylogenetic analysis based on the 16S rRNA gene sequence. The cricket spiroplasma infected the hemolymph, gut, muscle tissues and tracheal cells; therefore we suggest that the pathogen invaded tissues and organs from the hemolymph through the tracheal system and the endoplasmic reticular system. Based on 16S rRNA gene sequences and the phylogeny, this spiroplasma was most closely related to Spiroplasma platyhelix (Identity=95%) isolated from the dragonfly Pachydiplax longipennis and belongs to the Ixodetis clade. PMID- 24801583 TI - The role of payload hydrophobicity in nanotherapeutic pharmacokinetics. AB - Although drug delivery with nanovectors is regarded as one of the paradigm shifting advances in modern medicine, the compatibility and performance of drug vector formulations have not been systematically studied in terms of their physicochemistry and pharmacokinetics (PKs). The drug delivery systems (DDSs), currently available in clinics or trials, were analyzed based on hydrophobicity and anatomical therapeutic chemical (ATC) classification of drug payloads. Four major types of DDSs differentiated based on DDS structure and drug hydrophobicity, where payload hydrophobicity decreased: micelles, serum albumin, liposome membrane, and liposome interior. A strong relationship between the increase in half-life in DDS formulation and drug hydrophobicity was found with up to 200-fold greater increase for hydrophilic drugs. The analysis results seemingly integrated PKs, ATC, and hydrophobicity to reinforce the development or optimization of drug delivery vectors and their formulations. PMID- 24801584 TI - Coherent photoacoustic-ultrasound correlation and imaging. AB - Both photoacoustics and ultrasound have been researched extensively but separately. In this letter, we report an initial study on the coherent correlation between pulsed photoacoustic wave and pulse-echo ultrasound wave. By illuminating an object with a pulsed laser and external ultrasound sequentially, both the endogenous photoacoustic wave and pulse-echo ultrasound wave are received and coherently correlated, demonstrating enhanced signal-to-noise ratio. Image contrast of the proposed coherent photoacoustic-ultrasound imaging is also demonstrated to be improved significantly on vessel-mimicking phantom, due to fusion of the optical absorption and ultrasound reflection contrasts by coherent correlation of either conventional laser-induced photoacoustic imaging or pulse echo ultrasound imaging separately. PMID- 24801585 TI - Management of Klinefelter syndrome during transition. AB - Klinefelter syndrome (KS) is the most common sex chromosomal disorder in males. Key findings in older adolescents and young men are small testes with variable hypo-androgenism, but almost universal azoospermia, most frequently in combination with a history of learning difficulties and behavior problems. Males with KS may come to medical attention through different medical presentations, given its association with several congenital malformations, and psychiatric, endocrine, and metabolic disorders. Preventive care is to be provided from diagnosis, preferentially through a multidisciplinary approach, including that from an endocrinologist, clinical psychologist or psychiatrist, neurologist, urologist, geneticist, sexologist, and a fertility team. Accurate information about the condition and assessment of associated medical conditions should be offered at diagnosis and should be followed by psychological counseling. Medical treatment during transition into adulthood is focused on fertility preservation and testosterone replacement therapy in the case of hypo-androgenism, and alleviation of current or future consequences of testicular fibrosis. However, more research is needed to determine the need for pro-active testosterone treatment in adolescence, as well as the conditions for an optimal testosterone replacement and sperm retrieval in adolescents and young men with KS. Furthermore, screening for associated diseases such as metabolic syndrome, autoimmune diseases, thyroid dysfunction, and malignancies is warranted during this period of life. The practical medical management during transition and, more specifically, the role of the endocrinologist are discussed in this article. PMID- 24801586 TI - Surgical remission of Cushing's syndrome reduces cardiovascular risk. AB - OBJECTIVE: Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls. DESIGN: A retrospective study of 75 patients with CS followed at an academic center. METHODS: Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population. RESULTS: In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001). CONCLUSIONS: Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission. PMID- 24801587 TI - Effect of long-term GH replacement therapy on cardiovascular outcomes in isolated GH deficiency compared with multiple pituitary hormone deficiencies: a sub analysis from the Dutch National Registry of Growth Hormone Treatment in Adults. AB - OBJECTIVE: Isolated GH deficiency (IGHD) could provide a model to investigate the influence of GH deficiency per se and the effect of GH replacement therapy without the influence from other pituitary hormone deficiencies or their treatment. The aim of this study is to address the questions about differences between IGHD and multiple pituitary hormone deficiencies (MPHDs) in clinical presentation and in responsiveness to GH treatment. DESIGN: A nationwide surveillance study was carried out to describe the difference in the clinical presentation and responsiveness to GH treatment of patients with IGHD and MPHDs. METHODS: The Dutch National Registry of GH Treatment in Adults was founded in 1998 to gain more insight into long-term efficacy and safety of GH therapy. Out of 2891 enrolled patients, 266 patients with IGHD at the start of GH treatment were identified and compared with 310 patients with MPHDs. Cardiovascular indices will be investigated at baseline and during long-term follow-up, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity. RESULTS: Patients with IGHD and MPHDs were demonstrated to be different entities at clinical presentation. Metabolically, patients with MPHDs had a larger waist circumference, lower HDL cholesterol level, and higher triglyceride level. The effect of GH treatment was comparable between patient groups. GH seems to protect against rising lipid levels and blood pressure, even after excluding patients using corresponding concomitant medication. The risk for cardiovascular disease or diabetes mellitus during follow-up was not different between patients with IGHD and MPHDs. CONCLUSIONS: Patients with IGHD had a less impaired metabolic profile than patients with MPHDs at baseline. Influence of other pituitary hormone replacement therapies on the effect of GH treatment is not demonstrated. PMID- 24801588 TI - Plasma osteocalcin levels as a predictor of cardiovascular disease in older men and women: a population-based cohort study. AB - OBJECTIVE: The role of osteocalcin (OC) in cardiovascular disease (CVD) is unresolved. We aimed to study the association between plasma OC concentrations and the risk of non-fatal and fatal CVDs. We also aimed to investigate whether such an association, if present, would be mediated by established metabolic risk factors. DESIGN: A population-based longitudinal cohort study. METHODS: In 1995/1996, OC was determined in blood samples drawn from 1319 subjects aged 65-88 years participating in the Longitudinal Aging Study Amsterdam in 1995/1996. The self-reported CVD events were collected every 3 years until 2005/2006, and CVD deaths until 1st January 2007. Cox proportional hazards regression was performed, considering potential confounders (smoking, physical activity, and BMI) and mediators (blood pressure, plasma triglycerides, total and HDL cholesterol, fructosamine, and aortic calcification). RESULTS: During the median 4.1 years follow-up, 709 subjects (53.8%) suffered a CVD event. There was no overall association between OC and CVD: hazard ratio (HR) was 0.97 (95% CI 0.90-1.04) per nmol/l higher plasma OC, adjusted for age and sex. There was a statistical interaction between plasma OC, age, and sex on CVD (P=0.014). In those subjects aged >=75 years, age-adjusted HRs (95% CI) were 0.86 (0.75-0.99) in men and 1.16 (1.03-1.31) in women per nmol/l higher plasma OC. Adjustment for covariates only slightly attenuated the association in older-old men, but did not affect the association in older-old women. CONCLUSION: A higher plasma OC concentration was associated with a reduced risk of CVD in older-old men and with an increased risk of CVD in older-old women. We found no evidence that this was mediated by arterial calcification or metabolic risk factors. PMID- 24801589 TI - Psychological morbidity and impaired quality of life in patients with stable treatment for primary adrenal insufficiency: cross-sectional study and review of the literature. AB - CONTEXT: A high prevalence of psychological morbidity and maladaptive personality as well as impaired quality of life (QoL) is observed in patients with and without hydrocortisone dependency following (cured) Cushing's syndrome. However, it is currently unclear whether a similar pattern is present in patients with chronic glucocorticoid replacement for primary adrenal insufficiency (PAI). OBJECTIVE: To evaluate psychological functioning, personality traits, and QoL in patients with PAI. DESIGN AND SUBJECTS: A cross-sectional study including 54 patients with stable treatment for PAI and 54 healthy matched controls. Both patients and controls completed questionnaires on psychological functioning (Apathy Scale, Irritability Scale, Mood and Anxiety Symptoms Questionnaire short form, and Hospital Anxiety and Depression Scale), personality traits (Dimensional Assessment of Personality Pathology short form), and QoL (Multidimensional Fatigue Inventory, Short Form 36, EuroQoL-5D, Nottingham Health Profile, and Physical Symptom Checklist). RESULTS: Patients with PAI suffered from more psychological morbidity (i.e. irritability and somatic arousal) and QoL impairments compared with controls (all P<0.01). There were no differences regarding maladaptive personality traits between patients and controls. However, there was a strong and consistent positive association between the daily hydrocortisone dose and prevalence of maladaptive personality traits (i.e. identity problems, cognitive distortion, compulsivity, restricted expression, callousness, oppositionality, rejection, conduct problems, social avoidance, narcissism, and insecure attachment, all P<0.05). There was also a strong relation between the mean daily hydrocortisone dose and both psychological morbidity (i.e. depression, P<0.05) and QoL impairments (i.e. general health perception, several measures of physical functioning, and vitality, all P<0.05). CONCLUSION: Patients on stable glucocorticoid replacement therapy for PAI report psychological morbidity and impaired QoL. Psychological morbidity, impaired QoL, and maladaptive personality traits were all associated with higher dosages of hydrocortisone. PMID- 24801590 TI - Associations between thyroid function and mortality: the influence of age. AB - OBJECTIVE: The aim of this study was to investigate the influence of age on the association between thyroid function and mortality. DESIGN: The Nijmegen Biomedical Study is a population-based study, comprising 5816 randomly selected adults of all age groups without previously known thyroid disease. METHODS: TSH, free thyroxine (FT4) and peroxidase antibodies were measured in 2002-2003. The number of deaths were established in 2012 (median follow-up time 9.4 years). RESULTS: Subclinical thyrotoxicosis was associated with mortality in subjects aged <65 years (hazard ratio (HR) 2.5, 95% CI 1.1-5.7), but not in subjects aged >65 years. As for thyroid function within the normal range: in the 493 participants aged 80 years or older, an FT4 level in the high-normal range (18.5 22 pmol/l) was associated with a higher mortality in comparison with FT4 levels in the middle range (11.5-15.0 pmol/l): HR 1.7 (95% CI 1.0-2.9). In these elderly, TSH levels within the high-normal range (3.0-4.0 mIU/l) were also associated with a higher mortality in comparison with TSH levels within the middle range (1.0-2.0 mIU/l): HR 1.8 (95% CI 1.0-3.1). CONCLUSIONS: The relationship between thyroid function and mortality differs according to age. This finding might (partially) explain the discrepant results of previous studies examining the relationship between thyroid function and mortality in different age groups. PMID- 24801591 TI - Impaired health-related quality of life in Addison's disease--impact of replacement therapy, comorbidities and socio-economic factors. AB - OBJECTIVE: Patients with Addison's disease (AD) on conventional replacement therapy have impaired health-related quality of life (HRQoL). It is possible that lower hydrocortisone (HC) doses recommended by current guidelines could restore HRQoL. We compared HRQoL in AD patients treated according to current HC recommendations to that of the age- and gender-standardized general population. SUBJECTS, DESIGN AND MEASUREMENT: We assessed HRQoL in a cross-sectional setting with the 15D instrument in a Finnish AD cohort (n = 107) and compared the results with those of a large sample of general population (n = 5671). We examined possible predictors of HRQoL in AD. Within the patient group, HRQoL was also assessed by SF-36. RESULTS: Mean HC dose was 22 mg/d, corresponding to 12 +/- 4 mg/m2. HRQoL was impaired in AD compared with the general population (15D score; 0.853 vs 0.918, P < 0.001). Within single 15D dimensions, discomfort and symptoms, vitality and sexual activity were most affected. Stepwise regression analysis demonstrated that Patient's Association membership (P = 0.02), female gender (P < 0.01), presence of other autoimmune or inflammatory comorbidity (P < 0.02), lower education (P < 0.02) and longer disease duration (P < 0.05) independently predicted impaired HRQoL, whereas replacement regimens, autoimmune related comorbidities, total number of comorbidities or level of healthcare follow-up did not. In AD, HRQoL was impaired also as assessed by SF-36. CONCLUSIONS: HRQoL is significantly impaired in AD compared with the general population despite use of recommended HC doses. Patient's Association membership was the most significant predictor of impaired HRQoL. This finding should be explored in more detail in the future. PMID- 24801592 TI - Skeleton decoration of NHCs by amino groups and its sequential booster effect on the palladium-catalyzed Buchwald-Hartwig amination. AB - A challenging synthetic modification of PEPPSI-type palladium pre-catalysts consisting of a stepwise incorporation of one and two amino groups onto the NHC skeleton was seen to exert a sequential enhancement of the electronic donor properties. This appears to be positively correlated with the catalytic performances of the corresponding complexes in the Buchwald-Hartwig amination. This is illustrated, for example, by the quantitative amination of 4 chloroanisole by morpholine within 2 h at 25 degrees C with a 2 mol% catalyst/substrate ratio or by a significant reduction of catalytic loading (down to 0.005 mol%) for the coupling of aryl chlorides with anilines (max TON: 19,600). PMID- 24801593 TI - Competing reactions of CO2 with cations and anions in azolide ionic liquids. AB - We show that phosphonium azolide ionic liquids of interest for CO2 capture applications react with CO2 both through the normal anion channel and, at elevated temperatures, through a previously unrecognized cation channel. The reaction is caused by an interaction between the anion and cation that allows proton transfer, and involves a phosphonium ylide intermediate. The cation reaction can be mitigated by using ammonium rather than phosphonium cations. Thus, phosphonium and ammonium cations paired with aprotic heterocyclic anions (AHAs) react with CO2 through different mechanisms at elevated temperatures. This work shows that careful consideration of both physical properties and chemical reactivity of ILs based on AHA anions is needed when designing ionic liquids for CO2 separations. PMID- 24801594 TI - Gene expression profile of Bombyx mori hemocyte under the stress of destruxin A. AB - Destruxin A (DA) is a cyclo-peptidic mycotoxin from the entomopathogenic fungus Metarhizium anisopliae. To uncover potential genes associated with its molecular mechanisms, a digital gene expression (DGE) profiling analysis was used to compare differentially expressed genes in the hemocytes of silkworm larvae treated with DA. Ten DGE libraries were constructed, sequenced, and assembled, and the unigenes with least 2.0-fold difference were further analyzed. The numbers of up-regulated genes were 10, 20, 18, 74 and 8, as well as the numbers of down-regulated genes were 0, 1, 8, 13 and 3 at 1, 4, 8, 12 and 24 h post treatment, respectively. Totally, the expression of 132 genes were significantly changed, among them, 1, 3 and 12 genes were continually up-regulated at 4, 3 and 2 different time points, respectively, while 1 gene was either up or down regulated continually at 2 different time points. Furthermore, 68 genes were assigned to one or multiple gene ontology (GO) terms and 89 genes were assigned to specific Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology. In-depth analysis identified that these genes putatively involved in insecticide resistance, cell apoptosis, and innate immune defense. Finally, twenty differentially expressed genes were randomly chosen and validated by quantitative real-time PCR (qRT-PCR). Our studies provide insights into the toxic effect of this microbial insecticide on silkworm's hemocytes, and are helpful to better understanding of the molecular mechanisms of DA as a biological insecticide. PMID- 24801596 TI - Compatible solute, transporter protein, transcription factor, and hormone-related gene expression provides an indicator of drought stress in Paulownia fortunei. AB - Drought is one of the most devastating effects of global climate change. Leaves contribute significantly to the management of water deficit and plant adaptation to drought stress. In this study, we compared the transcriptomes of leaves of two genotypes of Paulownia fortunei with different drought tolerances. Solexa sequencing and qRT-PCR were used for gene expression analysis and validation. Variations in leaf growth were found between drought-treated and well-watered samples in both genotypes. Drought-treated samples from diploid and autotetraploid P. fortunei cultivars showed inward leaf rolling and smaller blade size compared with the well-watered ones. High throughput transcriptome sequencing generated 266,700,100 high-quality reads representing 110,586 unigenes from the leaves. The drought-treated samples responded to water deficiency by inducing various genes and pathways, such as photosynthesis, carbon fixation in photosynthetic organisms, stress response, plant hormone signal transduction, and flavonoid pathways. Regulatory genes, such as WRKY, and transcription factors, such as NAC, known for leaf development under drought stress, were highly expressed in the drought-treated samples, and so were the genes related to compatible solutes (sugars, sugar alcohols, amino sugars, amino acids, or betaine), hormones, and various transporters. This study illustrates changes in the expression pattern of genes induced in response to drought stress and provides a comprehensive and specific set of drought-responsive genes in P. fortunei. PMID- 24801597 TI - Gap size and wall lesion development next to composite. AB - This in situ study investigated whether there is a relationship between gap size and wall lesion development in dentin next to 2 composite materials, and whether a clinically relevant threshold for the gap size could be established. For 21 days, 14 volunteers wore a modified occlusal splint containing human dentin samples with 5 different interfaces: 4 gaps of 50 um, 100 um, 200 um, or 400 um and 1 non-bonded interface without a gap. Eight times a day, the splint with samples was dipped in a 20% sucrose solution for 10 minutes. Before and after caries development, specimens were imaged with transversal wavelength-independent microradiography (T-WIM), and lesion depth (LD) and mineral loss (ML) were calculated at the 5 different interfaces. After correction for the confounder location (more mesial or distal), a paired t test clustered within volunteers was performed for comparison of gap widths. Results showed no trend for a relationship between the corrected lesion depth and the gap size. None of the differences in lesion depth for the different gap sizes was statistically significant. Also, the composite material (AP-X or Filtek Supreme) gave no statistically significant differences in lesion depth and mineral loss. A minimum gap size could not be established, although, in a non-bonded interface without a measurable gap, wall lesion development was never observed. PMID- 24801598 TI - Geometric morphometrics of nine field isolates of Aedes aegypti with different resistance levels to lambda-cyhalothrin and relative fitness of one artificially selected for resistance. AB - Aedes aegypti, a mosquito closely associated with humans, is the principal vector of dengue virus which currently infects about 400 million people worldwide. Because there is no way to prevent infection, public health policies focus on vector control; but insecticide-resistance threatens them. However, most insecticide-resistant mosquito populations exhibit fitness costs in absence of insecticides, although these costs vary. Research on components of fitness that vary with insecticide-resistance can help to develop policies for effective integrated management and control. We investigated the relationships in wing size, wing shape, and natural resistance levels to lambda-cyhalothrin of nine field isolates. Also we chose one of these isolates to select in lab for resistance to the insecticide. The main life-traits parameters were assessed to investigate the possible fitness cost and its association with wing size and shape. We found that wing shape, more than wing size, was strongly correlated with resistance levels to lambda-cyhalothrin in field isolates, but founder effects of culture in the laboratory seem to change wing shape (and also wing size) more easily than artificial selection for resistance to that insecticide. Moreover, significant fitness costs were observed in response to insecticide resistance as proved by the diminished fecundity and survival of females in the selected line and the reversion to susceptibility in 20 generations of the non selected line. As a practical consequence, we think, mosquito control programs could benefit from this knowledge in implementing efficient strategies to prevent the evolution of resistance. In particular, the knowledge of reversion to susceptibility is important because it can help in planning better strategies of insecticide use to keep useful the few insecticide-molecules currently available. PMID- 24801599 TI - TGFBI, CHST6, and GSN gene analysis in Mexican patients with stromal corneal dystrophies. AB - OBJECTIVES: The purpose of our study was to describe the results of molecular screening of TGFBI, CHST6, and GSN genes in a group of Mexican patients with different stromal corneal dystrophies (CD). MATERIAL AND METHODS: A total of 16 CD Mexican patients pertaining to nine different pedigrees were subjected to a complete ophthalmological investigation. A clinical diagnosis of lattice CD was performed in 10 patients from five pedigrees. Three patients from two pedigrees were diagnosed with granular CD type 2, two patients with unrelated probands had Finnish-type corneal amyloidosis, and one patient had macular CD. Genetic analysis included DNA isolation from blood leukocytes and polymerase chain reaction (PCR) amplification and direct nucleotide sequencing of TGFBI, CHST6, and GSN genes. RESULTS: Seven lattice CD patients from four unrelated families had an identical p.H626R mutation in TGFBI, three patients from a single lattice CD family carried a p.R124C substitution in TGFBI, and a granular type 2 CD pedigree was demonstrated to carry a heterozygous TGFBI p.M619K substitution. A patient having Finnish-type corneal amyloidosis had a p.D187N mutation in GSN. Finally, molecular analysis of CHST6 in a patient with macular CD disclosed the presence of a homozygous p.Y110C change. CONCLUSIONS: This study improves the knowledge of the genetic features of Mexican patients with corneal stromal dystrophies by identifying mutations in the TGFBI, CHST6, and GSN genes. Genetic screening of larger samples of patients from distinct ethnic groups would be of great importance for a better understanding of the mutational spectrum of stromal CD. PMID- 24801600 TI - Membrane rigidification functions upstream of the MEKK1-MKK2-MPK4 cascade during cold acclimation in Arabidopsis thaliana. AB - The MEKK1-MKK2-MPK4 cascade is activated during cold acclimation. However, little is known regarding the perception of low temperature. In this study, we demonstrate that treatment of Arabidopsis with a membrane rigidifier, DMSO, caused MPK4 activation concomitantly with MEKK1 and MKK2 phosphorylation, as well as the cold-inducible gene COR15a expression. These processes are similar to the effects of cold treatment, whereas benzyl alcohol (BA), a membrane fluidizer, prevented such cold-induced events. Moreover, the DMSO-treated seedlings acquired freezing tolerance without cold acclimation. In contrast, the BA-pretreated seedlings did not show freezing tolerance. These results suggest that membrane rigidification activates this MAPK cascade and contributes to the acquisition of freezing tolerance. PMID- 24801601 TI - miR-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells. AB - This study aimed to test the exact functions and potential mechanisms of miR-17 5p in gastric cancer. Using real-time PCR, miR-17-5p was found to be expressed more highly in gastric cancer compared with-normal tissues. Gain- and loss-of function assays demonstrated that miR-17-5p increased the proliferation and growth of gastric cancer cells in vitro and in vivo. Through reporter gene and western blot assays, SOCS6 was shown to be a direct target of miR-17-5p, and proliferative assays confirmed that SOCS6 exerted opposing function to that of miR-17-5p in gastric cancer. In short, miR-17-5p might function as a pro proliferative factor by repressing SOCS6 in gastric cancer. PMID- 24801602 TI - Derivation of point of departure (PoD) estimates in genetic toxicology studies and their potential applications in risk assessment. AB - Genetic toxicology data have traditionally been employed for qualitative, rather than quantitative evaluations of hazard. As a continuation of our earlier report that analyzed ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) dose response data (Gollapudi et al., 2013), here we present analyses of 1-ethyl-1 nitrosourea (ENU) and 1-methyl-1-nitrosourea (MNU) dose-response data and additional approaches for the determination of genetic toxicity point-of departure (PoD) metrics. We previously described methods to determine the no observed-genotoxic-effect-level (NOGEL), the breakpoint-dose (BPD; previously named Td), and the benchmark dose (BMD10 ) for genetic toxicity endpoints. In this study we employed those methods, along with a new approach, to determine the non-linear slope-transition-dose (STD), and alternative methods to determine the BPD and BMD, for the analyses of nine ENU and 22 MNU datasets across a range of in vitro and in vivo endpoints. The NOGEL, BMDL10 and BMDL1SD PoD metrics could be readily calculated for most gene mutation and chromosomal damage studies; however, BPDs and STDs could not always be derived due to data limitations and constraints of the underlying statistical methods. The BMDL10 values were often lower than the other PoDs, and the distribution of BMDL10 values produced the lowest median PoD. Our observations indicate that, among the methods investigated in this study, the BMD approach is the preferred PoD for quantitatively describing genetic toxicology data. Once genetic toxicology PoDs are calculated via this approach, they can be used to derive reference doses and margin of exposure values that may be useful for evaluating human risk and regulatory decision making. PMID- 24801603 TI - Overexpression of miR-483-5p/3p cooperate to inhibit mouse liver fibrosis by suppressing the TGF-beta stimulated HSCs in transgenic mice. AB - The transition from liver fibrosis to hepatocellular carcinoma (HCC) has been suggested to be a continuous and developmental pathological process. MicroRNAs (miRNAs) are recently discovered molecules that regulate the expression of genes involved in liver disease. Many reports demonstrate that miR-483-5p and miR-483 3p, which originate from miR-483, are up-regulated in HCC, and their oncogenic targets have been identified. However, recent studies have suggested that miR-483 5p/3p is partially down-regulated in HCC samples and is down-regulated in rat liver fibrosis. Therefore, the aberrant expression and function of miR-483 in liver fibrosis remains elusive. In this study, we demonstrate that overexpression of miR-483 in vivo inhibits mouse liver fibrosis induced by CCl4 . We demonstrate that miR-483-5p/3p acts together to target two pro-fibrosis factors, platelet derived growth factor-beta and tissue inhibitor of metalloproteinase 2, which suppress the activation of hepatic stellate cells (HSC) LX-2. Our work identifies the pathway that regulates liver fibrosis by inhibiting the activation of HSCs. PMID- 24801604 TI - Physics in ordered and disordered colloidal matter composed of poly(N isopropylacrylamide) microgel particles. AB - This review collects and describes experiments that employ colloidal suspensions to probe physics in ordered and disordered solids and related complex fluids. The unifying feature of this body of work is its clever usage of poly(N isopropylacrylamide) (PNIPAM) microgel particles. These temperature-sensitive colloidal particles provide experimenters with a 'knob' for in situ control of particle size, particle interaction and particle packing fraction that, in turn, influence the structural and dynamical behavior of the complex fluids and solids. A brief summary of PNIPAM particle synthesis and properties is given, followed by a synopsis of current activity in the field. The latter discussion describes a variety of soft matter investigations including those that explore formation and melting of crystals and clusters, and those that probe structure, rearrangement and rheology of disordered (jammed/glassy) and partially ordered matter. The review, therefore, provides a snapshot of a broad range of physics phenomenology which benefits from the unique properties of responsive microgel particles. PMID- 24801605 TI - Proton-induced cross-sections of nuclear reactions on lead up to 37 MeV. AB - Excitation function of proton induced nuclear reactions on lead for production of (206,205,204,203,202,201g)Bi, (203cum,202m,201cum)Pb and (202cum,201cum,200cum,199cum)Tl radionuclides were measured up to 36 MeV by using activation method, stacked foil irradiation technique and gamma-ray spectrometry. The new experimental data were compared with the few earlier experimental results and with the predictions of the EMPIRE3.1, ALICE-IPPE (MENDL2p) and TALYS (TENDL 2012) theoretical reaction codes. PMID- 24801607 TI - The PACE study: a randomized clinical trial of cognitive activity strategy training for older people with mild cognitive impairment. AB - OBJECTIVE: The role of cognition-focused interventions in reducing cognitive decline in older people remains uncertain. This study aimed to clarify whether a group cognitive activity (CA) strategy-training program would decrease the 2-year rate of cognitive decline of people with mild cognitive impairment (MCI). DESIGN: Randomized controlled trial. SETTING: One study site. PARTICIPANTS: 160 older adults with MCI >=65 years of age (mean: 75, SD: 5.8). INTERVENTION: Five-week CA strategy training or a control nonspecific educational program. The primary outcome measure was change from baseline in the total score on the Cambridge Cognitive Examination-Revised (CAMCOG-R). Secondary outcomes of interest included changes in memory, attention, executive functions, mood, and quality of life. Endpoints were collected 10, 52, and 104 weeks post baseline. RESULTS: Intention to treat analysis identified no significant difference in CAMCOG-R scores over time between the two groups (mean difference: -0.36, 95% CI: -1.02,0.29) or across secondary outcome measures. The exceptions were better performance of the CA group on immediate attention (Digit Span Forwards, adjusted mean difference: 0.15, 95% CI: 0.01,0.30) and better quality of life (adjusted mean difference: 0.57, 95% CI: 0.10,1.04) compared with controls. CONCLUSION: The devised program of CA did not improve general cognitive performance of older adults with MCI over a period of 2 years. Although favorable, the beneficial effects of the intervention on attention and quality of life were small, and of uncertain significance. PMID- 24801606 TI - A volatile relationship: profiling an inter-kingdom dialogue between two plant pathogens, Ralstonia Solanacearum and Aspergillus Flavus. AB - Microbes in the rhizosphere have a suite of extracellular compounds, both primary and secondary, that communicate with other organisms in their immediate environment. Here, we describe a two-way volatile interaction between two widespread and economically important soil-borne pathogens of peanut, Aspergillus flavus and Ralstonia solanacearum, a fungus and bacterium, respectively. In response to A. flavus volatiles, R. solanacearum reduced production of the major virulence factor extracellular polysaccharide (EPS). In parallel, A. flavus responded to R. solanacearum volatiles by reducing conidia production, both on plates and on peanut seeds and by increasing aflatoxin production on peanut. Volatile profiling of these organisms using solid-phase micro-extraction gas chromatography mass spectroscopy (SPME-GCMS) provided a first glimpse at the compounds that may drive these interactions. PMID- 24801608 TI - Folk and biological perceptions of dementia among Asian ethnic minorities in Hawaii. AB - OBJECTIVE: To study if Asian ethnic groups in Hawaii today maintain folk-based beliefs about dementia, have inadequate biomedical understanding of dementia, and differ among each other regarding perceptions of dementia. DESIGN: The study adapts and expands a 2004 survey of ethnic groups on perceptions of Alzheimer disease demonstrating that ethnic minority groups hold more folk perceptions and less biomedical perceptions of dementia than Caucasians. This study surveys particular ethnic minority family members of elders admitted to four long-term care and inpatient facilities in Hawaii. Seventy-one family members completed surveys, including 23 Chinese, 18 Filipino, and 30 Japanese participants. Elders may or may not have had the diagnosis of dementia, though an estimated half of elders in all four facilities already held the diagnosis of dementia. RESULTS: Findings indicated that Japanese and Chinese respondents in this study held perceptions about dementia that were more consistent with current biomedical understanding compared with their Filipino counterparts (mean differences/percent correct for Japanese: 57%, Chinese: 56% versus Filipino: 38%; F = 6.39, df = 2,55, p = 0.003). Filipino respondents were less likely than Japanese and Chinese respondents to report that persons with dementia can develop physical and mental problems-97% of Japanese participants and 82% of Chinese participants responded correctly compared with 63% of Filipino participants (Fisher's Exact test p = 0.009). With regard to folk beliefs about dementia, variation occurred with no consistent trend among the groups. CONCLUSION: Low levels of biomedical understanding of dementia were reflected by all three subgroups of Asians living in Hawaii with less prominence of folk beliefs compared with prior studies of ethnic minority perceptions. Education did not predict variability in dementia perceptions among the groups. Lower levels of acculturation, suggested by primary home language other than English, may correlate with a perception of dementia that is less consistent with current biomedical understanding of dementia. Persisting folk beliefs about dementia and the evident lack of biomedical understanding, particularly the belief that dementia is a normal part of aging, emphasizes the need for more culturally tailored strategies in patient education about dementia and the importance of early intervention. PMID- 24801609 TI - Association of depressive symptomatology with receipt of informal caregiving among older American Indians: the native elder care study. AB - OBJECTIVE: Our study objectives were to identify the primary sources of informal caregiving and to examine the association of depressive symptomatology with receipt of informal caregiving among a sample of community-dwelling older American Indians. DESIGN: We conducted a cross-sectional study of older American Indians. PARTICIPANTS: Community-dwelling adults aged 55 years and older who are members of a federally recognized American Indian tribe in the Southeast United States. MEASUREMENTS: We collected information on the participant's primary caregiver, number of informal care hours received in the past week, depressive symptomatology, demographic characteristics, physical health status, and assistance need. RESULTS: Daughters, spouses, and sons were the most common informal primary caregivers with distinct differences by sex of those receiving care. Compared with participants with lower levels, those with a high level of depressive symptomatology received substantially greater hours of informal care (33.4 versus 11.5 hours per week). CONCLUSION: Older American Indians with higher levels of depressive symptomatology received more informal caregiving than those with lower depressive symptomatology. The burden of caregiving of older adults is primarily shouldered by spouses and children with those who care for older adults with depressive symptomatology likely experiencing an even greater burden of care. PMID- 24801610 TI - Discovery of biarylaminoquinazolines as novel tubulin polymerization inhibitors. AB - Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1 3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. Although compounds 1-3 acted as dual inhibitors, the heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. Furthermore, molecular modeling studies allowed the rationalization of the pharmacodynamic properties of the compounds. PMID- 24801611 TI - Dual-aptamer modification generates a unique interface for highly sensitive and specific electrochemical detection of tumor cells. AB - Because circulating tumor cells (CTCs) have been proven to be an important clue of the tumor metastasis, their detection thus plays a pivotal role in the diagnosis and prognosis of cancer. Herein, we fabricate an electrochemical sensor by directly conjugating two cell-specific aptamers, TLS1c and TLS11a, which specifically recognize MEAR cancer cells, to the surface of a glassy carbon electrode (GCE) via the formation of amide bonds. The two aptamers are simultaneously conjugated to the GCE surface via precisely controlled linkers: TLS1c through a flexible linker (a single-stranded DNA T15; ss-TLS1c) and TLS11a through a rigid linker (a double-stranded DNA T15/A15; ds-TLS11a). It is found that such ss-TLS1c/ds-TLS11a dual-modified GCEs show greatly improved sensitivity in comparison with those modified with a single type of aptamer alone or ds TLS1c/ds-TLS11a with both rigid linkers, suggesting that our optimized, rationally designed electrode-aptamer biosensing interface may enable better recognition and thus more sensitive detection of tumor cells. Through the utilization of this dual-aptamer-modified GCE, as few as a single MEAR cell in 10(9) whole blood cells can be successfully detected with a linear range of 1-14 MEAR cells. Our work demonstrates a rather simple yet well-designed and ultrasensitive tumor cell detection method based on the cell-specific aptamer modified GCE, showing a promising potential for further CTC-related clinical applications. PMID- 24801612 TI - Collagen XII: Protecting bone and muscle integrity by organizing collagen fibrils. AB - Collagen XII, largest member of the fibril-associated collagens with interrupted triple helix (FACIT) family, assembles from three identical alpha-chains encoded by the COL12A1 gene. The molecule consists of three threadlike N-terminal noncollagenous NC3 domains, joined by disulfide bonds and a short interrupted collagen triple helix toward the C-terminus. Splice variants differ considerably in size and properties: "small" collagen XIIB (220 kDa subunit) is similar to collagen XIV, whereas collagen XIIA (350 kDa) has a much larger NC3 domain carrying glycosaminoglycan chains. Collagen XII binds to collagen I-containing fibrils via its collagenous domain, whereas its large noncollagenous arms interact with other matrix proteins such as tenascin-X. In dense connective tissues and bone, collagen XII is thought to regulate organization and mechanical properties of collagen fibril bundles. Accordingly, recent findings show that collagen XII mutations cause Ehlers-Danlos/myopathy overlap syndrome associated with skeletal abnormalities and muscle weakness in mice and humans. PMID- 24801613 TI - Round cell sarcomas - biologically important refinements in subclassification. AB - Round cell sarcomas are a heterogeneous group of tumors that often affect children and young adults and, if untreated, often pursue a very aggressive clinical course. Specific subtypes of round cell sarcoma, like Ewing sarcoma or rhabdomyosarcoma, respond to well-defined therapeutic regimens so that proper classification is crucial for appropriate patient management. A subset of round cell sarcomas, however, lack specific clinical, morphologic, and immunophenotypic features and cannot be unequivocally classified based on such features. Systematic application of cytogenetics and molecular genetic techniques has allowed for the identification of an increasing number of genetically defined subgroups within this category of undifferentiated tumors. Although the clinical relevance of these molecular categories is yet to be proven, the systematic identification of lesions that share reproducible biologic, and often morphologic and immunophenotypic features, has great impact in terms of biologic understanding and coherent classification schemes, and will help to guide the potential development of rational new therapies. In this review we discuss the main categories of undifferentiated round cell sarcoma, in relation to Ewing sarcoma and its molecular variants, with particular emphasis on the genetic and biologic features of recently described entities including desmoplastic small round cell tumor and CIC-DUX4 as well as BCOR-CCNB3-associated round cell sarcomas. This article is part of a Directed Issue entitled: Rare Cancers. PMID- 24801614 TI - A tale of two systems: cardiac cephalalgia vs migrainous thoracalgia. AB - The practice of headache medicine is challenging, and excluding secondary causes of headaches is essential for proper diagnosis and treatment. The evaluation of secondary headaches often leads to investigations involving organ systems other than the nervous system. As such, headache, which is typically thought to be neurologic in origin, can be a manifestation of cardiac pathology in the form of cardiac cephalalgia. Conversely, chest pain, which is typically thought to be cardiac in origin, could be a manifestation of a neurologic disease process in the form of atypical migraine aura. In the presented cases, we demonstrate headaches that involve cardiac and neurologic pathology with atypical presentations. PMID- 24801616 TI - What is consumer health informatics? A systematic review of published definitions. AB - BACKGROUND: Consumer health informatics (CHI) is an emerging field that utilizes technology to provide health information to enhance health-care decision making by the public. There is, however, no widely accepted or uniform definition of CHI. A consensus definition would be important for pedagogical reasons, to build capacity and to reduce confusion about what the discipline consists of. AIM: We undertook a systematic review of published definitions of CHI and evaluated them using five quality assessment criteria and measures of similarity. METHODS: Five databases were searched (Embase, Web of Science, MEDLINE, CINAHL and Business Source Complete) resulting in 1101 citations. Twenty-three studies met the inclusion criteria. Definitions were appraised using five criteria (with each scoring out of one): use of published citation, multi-disciplinarity, journal impact, definition comprehensibility, text readability. RESULTS: Most definitions scored low on citation (Mean +/- SD: 0.22 +/- 0.42), multi-disciplinarity (0.15 +/- 0.28) and readability (0.04 +/- 0.21) and somewhat higher on IF (0.35 +/- 0.45) and definition comprehensibility (idea density) (0.87 +/- 0.34) criteria. Overall, the quality of the published definitions was low 1.63 +/- 0.80 (out of five). CONCLUSIONS: The definitions of CHI were variable in terms of the quality assessment criteria. This suggests the need for continued discussion amongst consumer health informaticians to develop a clear consensus definition about CHI. PMID- 24801615 TI - Coevolution of axon guidance molecule Slit and its receptor Robo. AB - Coevolution is important for the maintenance of the interaction between a ligand and its receptor during evolution. The interaction between axon guidance molecule Slit and its receptor Robo is critical for the axon repulsion in neural tissues, which is evolutionarily conserved from planarians to humans. However, the mechanism of coevolution between Slit and Robo remains unclear. In this study, we found that coordinated amino acid changes took place at interacting sites of Slit and Robo by comparing the amino acids at these sites among different organisms. In addition, the high level correlation between evolutionary rate of Slit and Robo was identified in vertebrates. Furthermore, the sites under positive selection of slit and robo were detected in the same lineage such as mosquito and teleost. Overall, our results provide evidence for the coevolution between Slit and Robo. PMID- 24801617 TI - 17beta-Estradiol inhibition of IL-6-Src and Cas and paxillin pathway suppresses human mesenchymal stem cells-mediated gastric cancer cell motility. AB - Epidemiological studies demonstrate that the incidence and mortality of gastric cancer in women are lower than in men worldwide. Many studies have reported the delayed menopause and hormone replacement therapy are associated with a reduced risk for gastric cancer. It has been reported that endogenous estrogen lowers gastric cancer incidence in women, and cancer patients treated with estrogens have a lower subsequent risk of gastric cancer. It has been reported that estrogen decreases the progression of gastric cancer by inhibiting erbB-2 oncogene expression. Overexpression of estrogen receptor might inhibit the proliferation and invasion of MKN28 gastric cancer cells. Accumulating evidence suggests that bone marrow mesenchymal stem cells contribute to the progression of gastric cancer. However, it is unknown if 17beta-estradiol (E2) treatment is sufficient to inhibit human bone marrow mesenchymal stem cells (HBMMSCs)-mediated cell motility in human gastric cancer cells. The results from human cytokine arrays have shown that HBMMSCs notably secrete interleukin 6 (IL-6) protein. Administration of IL-6-specific neutralizing antibody significantly inhibits HBMMSCs-mediated motility activity in human gastric cancer cells. Treatment of recombinant IL-6 soluble protein confirmed the role of IL-6 in mediating HBMMSCs upregulated cell motility. IL-6 mainly upregulates motility activity via activation of Src signaling pathway in human gastric cancer cells. We further observed that E2 treatment inhibits HBMMSCs-induced cellular motility via suppressing the activation of IL-6-Src/Cas/paxillin signaling pathway in human gastric cancer cells. Collectively, these results suggest that E2 treatment significantly inhibits HBMMSCs-induced cellular motility in human gastric cancer cells. PMID- 24801618 TI - Real-time observation of local strain effects on nonvolatile ferroelectric memory storage mechanisms. AB - We use in situ transmission electron microscopy to directly observe, at high temporal and spatial resolution, the interaction of ferroelectric domains and dislocation networks within BiFeO3 thin films. The experimental observations are compared with a phase field model constructed to simulate the dynamics of domains in the presence of dislocations and their resulting strain fields. We demonstrate that a global network of misfit dislocations at the film-substrate interface can act as nucleation sites and slow down domain propagation in the vicinity of the dislocations. Networks of individual threading dislocations emanating from the film-electrode interface play a more dramatic role in pinning domain motion. These dislocations may be responsible for the domain behavior in ferroelectric thin-film devices deviating from conventional Kolmogorov-Avrami-Ishibashi dynamics toward a Nucleation Limited Switching model. PMID- 24801619 TI - Orientation of actin filaments in teleost retinal pigment epithelial cells, and the effect of the lectin, Concanavalin A, on melanosome motility. AB - Retinal pigment epithelial cells of teleosts contain numerous melanosomes (pigment granules) that exhibit light-dependent motility. In light, melanosomes disperse out of the retinal pigment epithelium (RPE) cell body (CB) into long apical projections that interdigitate with rod photoreceptors, thus shielding the photoreceptors from bleaching. In darkness, melanosomes aggregate through the apical projections back into the CB. Previous research has demonstrated that melanosome motility in the RPE CB requires microtubules, but in the RPE apical projections, actin filaments are necessary and sufficient for motility. We used myosin S1 labeling and platinum replica shadowing of dissociated RPE cells to determine actin filament polarity in apical projections. Actin filament bundles within RPE apical projections are uniformly oriented with barbed ends toward the distal tips. Treatment of RPE cells with the tetravalent lectin, Concanavalin A, which has been shown to suppress cortical actin flow by crosslinking of cell surface proteins, inhibited melanosome aggregation and stimulated ectopic filopodia formation but did not block melanosome dispersion. The polarity orientation of F-actin in apical projections suggests that a barbed-end directed myosin motor could effect dispersion of melanosomes from the CB into apical projections. Inhibition of aggregation, but not dispersion, by ConA confirms that different actin-dependent mechanisms control these two processes and suggests that melanosome aggregation is sensitive to treatments previously shown to disrupt actin cortical flow. PMID- 24801620 TI - Variability in mitochondria of zebrafish photoreceptor ellipsoids. AB - Ultrastructural examination of photoreceptor inner segment ellipsoids in larval (4, 8, and 15 days postfertilization; dpf) and adult zebrafish identified morphologically different types of mitochondria. All photoreceptors had mitochondria of different sizes (large and small). At 4 dpf, rods had small, moderately stained electron-dense mitochondria (E-DM), and two cone types could be distinguished: (1) those with electron-lucent mitochondria (E-LM) and (2) those with mitochondria of moderate electron density. These distinctions were also apparent at later ages (8 and 15 dpf). Rods from adult fish had fewer mitochondria than their corresponding cones. The ellipsoids of some fully differentiated single and double cones contained large E-DM with few cristae; these were surrounded by small E-LM with typical internal morphology. The mitochondria within the ellipsoids of other single cones showed similar electron density. Microspectrophotometry of cone ellipsoids from adult fish indicated that the large E-DM had a small absorbance peak (~0.03 OD units) and did not contain cytochrome-c, but crocetin, a carotenoid found in old world monkeys. Crocetin functions to prevent oxidative damage to photoreceptors, suggesting that the ellipsoid mitochondria in adult zebrafish cones protect against apoptosis and function metabolically, rather than as a light filter. PMID- 24801621 TI - S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant. AB - Specific variants of human long-wavelength (L) and middle-wavelength (M) cone opsin genes have recently been associated with a variety of vision disorders caused by cone malfunction, including red-green color vision deficiency, blue cone monochromacy, myopia, and cone dystrophy. Strikingly, unlike disease-causing mutations in rhodopsin, most of the cone opsin alleles that are associated with vision disorders do not have deleterious point mutations. Instead, specific combinations of normal polymorphisms that arose by genetic recombination between the genes encoding L and M opsins appear to cause disease. Knockout/knock-in mice promise to make it possible to study how these deleterious cone opsin variants affect the structure, function, and viability of the cone photoreceptors. Ideally, we would like to evaluate different variants that cause vision disorders in humans against a control pigment that is not associated with vision disorders, and each variant should be expressed as the sole photopigment in each mouse cone, as is the case in humans. To evaluate the feasibility of this approach, we created a line of mice to serve as the control in the analysis of disease-causing mutations by replacing exon 2 through 6 of the mouse M-opsin gene with the corresponding cDNA for a human L-opsin variant that is associated with normal vision. Experiments reported here establish that the resulting pigment, which differs from the endogenous mouse M opsin at 35 amino acid positions, functions normally in mouse cones. This pigment was evaluated in mice with and without coexpression of the mouse short wavelength (S) opsin. Here, the creation and validation of two lines of genetically engineered mice that can be used to study disease-causing variants of human L/M-opsins, in vivo, are described. PMID- 24801622 TI - Effects of mGluR6-deficiency on photoreceptor ribbon synapse formation: comparison of electron microscopic analysis of serial sections with random sections. AB - This study examined the effects of metabotropic glutamate receptor 6 (mGluR6) deficiency on ribbon synapse formation in rod spherules and cone pedicles using serial-section electron microscopy. In a wild-type (WT) mouse, only 3% of spherules had one invaginating bipolar dendrite (1B-type) and 97% of spherules were 2B-type. In contrast, in an mGluR6-knockout (KO) mouse, 29% of spherules were 1B-type and 71% of spherules were 2B-type. Spherules without bipolar invagination were not observed in either genotype. The single invaginating dendrites in 1B-type spherules were larger and the surface areas of synaptic ribbons were 23% smaller in the mGluR6-KO mouse than in the WT mouse. In cones, the number of invaginating bipolar dendrites decreased from 12 in the WT mouse to 9.5 in the mGluR6-KO mouse. This decrease correlated with a decrease in the number of cone synaptic ribbons from 10 in the WT mouse to 8 in the mGluR6-KO mouse. The mGluR6-KO phenotype showed negative effects on ribbon synapse formation. This negativity was similar to those in mGluR6-nob4, Gbeta3-KO, Gbeta5 KO, and RGS-7:RGS-11 double-KO mice, but the detailed manners and degrees of alterations appeared to vary depending on different missing components. Two published morphological assessments of the RGS-7:RGS-11 double-KO phenotype reported conflicting data; therefore, we tested the statistical techniques used in the two analyses. One statistical evaluation measure was effective in identifying a significant difference in structure between the mutant and WT phenotypes, whereas the other measure was ineffective. Conventional random section analysis using the effective measure provided sufficient data for a statistical test of the occurrence of structural changes. However, serial section analysis was required to determine the absolute numbers of ribbons and invaginating dendrites and to estimate structural parameters such as ribbon surface area. PMID- 24801623 TI - Modulation of voltage-gated Ca2+ channels in rat retinal ganglion cells by gabapentin. AB - The alpha2delta auxiliary subunits of voltage-gated Ca2+ channels (VGCCs) are important modulators of VGCC function. Gabapentin interacts with alpha2delta1 and alpha2delta2 subunits and is reported to reduce Ca2+ channel current amplitude (ICa). This study aimed to determine the effects of gabapentin on VGCCs in retinal ganglion cells (RGCs). Whole cell patch clamp was used to record ICa in isolated RGCs, and calcium imaging was used to measure Ca2+ transients from RGCs in situ. Immunohistochemistry was used to detect the presence of alpha2delta1 containing VGCCs in isolated RGCs in the absence and presence of gabapentin pretreatment. Acute administration of gabapentin reduced ICa and Ca2+ transients compared to control conditions. In isolated RGCs, pretreatment with gabapentin (4 18 h) reduced ICa, and cell surface alpha2delta1 staining was reduced compared to nonpretreated cells. Acute administration of gabapentin to isolated RGCs that had been pretreated further reduced ICa. These results show that gabapentin has both short-term and long-term mechanisms to reduce ICa in isolated RGCs. Some Ca2+ channel blockers have been shown to protect RGCs in retinal trauma suggesting that modulation of VGCCs by gabapentin may prevent the deleterious effects of elevated Ca2+ levels in RGCs in trauma and disease. PMID- 24801625 TI - Closed-loop control of grasping with a myoelectric hand prosthesis: which are the relevant feedback variables for force control? AB - In closed-loop control of grasping by hand prostheses, the feedback information sent to the user is usually the actual controlled variable, i.e., the grasp force. Although this choice is intuitive and logical, the force production is only the last step in the process of grasping. Therefore, this study evaluated the performance in controlling grasp strength using a hand prosthesis operated through a complete grasping sequence while varying the feedback variables (e.g., closing velocity, grasping force), which were provided to the user visually or through vibrotactile stimulation. The experiments were conducted on 13 volunteers who controlled the Otto Bock Sensor Hand Speed prosthesis. Results showed that vibrotactile patterns were able to replace the visual feedback. Interestingly, the experiments demonstrated that direct force feedback was not essential for the control of grasping force. The subjects were indeed able to control the grip strength, predictively, by estimating the grasping force from the prosthesis velocity of closing. Therefore, grasping without explicit force feedback is not completely blind, contrary to what is usually assumed. In our study we analyzed grasping with a specific prosthetic device, but the outcomes are also applicable for other devices, with one or more degrees-of-freedom. The necessary condition is that the electromyography (EMG) signal directly and proportionally controls the velocity/grasp force of the hand, which is a common approach among EMG controlled prosthetic devices. The results provide important indications on the design of closed-loop EMG controlled prosthetic systems. PMID- 24801624 TI - A synaptic signature for ON- and OFF-center parasol ganglion cells of the primate retina. AB - In the primate retina, parasol ganglion cells contribute to the primary visual pathway via the magnocellular division of the lateral geniculate nucleus, display ON and OFF concentric receptive field structure, nonlinear spatial summation, and high achromatic temporal-contrast sensitivity. Parasol cells may be homologous to the alpha-Y cells of nonprimate mammals where evidence suggests that N-methyl-D aspartate (NMDA) receptor-mediated synaptic excitation as well as glycinergic disinhibition play critical roles in contrast sensitivity, acting asymmetrically in OFF- but not ON-pathways. Here, light-evoked synaptic currents were recorded in the macaque monkey retina in vitro to examine the circuitry underlying parasol cell receptive field properties. Synaptic excitation in both ON and OFF types was mediated by NMDA as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptors. The NMDA-mediated current-voltage relationship suggested high Mg2+ affinity such that at physiological potentials, NMDA receptors contributed ~20% of the total excitatory conductance evoked by moderate stimulus contrasts and temporal frequencies. Postsynaptic inhibition in both ON and OFF cells was dominated by a large glycinergic "crossover" conductance, with a relatively small contribution from GABAergic feedforward inhibition. However, crossover inhibition was largely rectified, greatly diminished at low stimulus contrasts, and did not contribute, via disinhibition, to contrast sensitivity. In addition, attenuation of GABAergic and glycinergic synaptic inhibition left center-surround and Y-type receptive field structure and high temporal sensitivity fundamentally intact and clearly derived from modulation of excitatory bipolar cell output. Thus, the characteristic spatial and temporal-contrast sensitivity of the primate parasol cell arises presynaptically and is governed primarily by modulation of the large AMPA/kainate receptor-mediated excitatory conductance. Moreover, the negative feedback responsible for the receptive field surround must derive from a nonGABAergic mechanism. PMID- 24801627 TI - The expression of epithelial intercellular junctional proteins in the sinonasal tissue of subjects with chronic rhinosinusitis: a histopathologic study. AB - OBJECTIVE: To evaluate the expression of five epithelial intercellular junctional proteins in the sinonasal tissue of subjects with chronic rhinosinusitis (CRS). METHODS: Forty-one samples of nasal polyp tissue of CRS patients with nasal polyps (wNP), 20 ethmoid sinus mucosa of CRS patients without nasal polyps (sNP) and 19 nasal mucosa of controls were collected and assessed for the expression of zonulae occludens (ZO-1), claudin-1, E-cadherin and desmoglein-1 and -2 (DSG1, DSG2) using immunohistochemical staining. Interleukin (IL)-5, IL-6 and IL-8 concentrations in the tissues were also measured using ELISA. RESULTS: The expression of ZO-1, claudin-1, DSG1 and DSG2 in the CRSwNP patient group and the expression of claudin-1, DSG1 and DSG2 of the CRSsNP patient group was significantly lower compared to that of the control group. Furthermore, the expression of DSG1 in the CRSwNP patient group was also significantly lower than in the CRSsNP patient group. In contrast, the expression of E-cadherin in the CRSwNP and the CRSsNP patient groups was significantly greater compared to the controls. The assessment of associations between the expression of the intercellular junctional proteins and cytokines demonstrated negative correlations between IL-5 and claudin-1, IL-6 and claudin-1, IL-6 and DSG2, IL-8 and DSG1, and IL-8 and DSG2. In contrast, a positive correlation was found between IL-8 and E-cadherin. CONCLUSIONS: Differences in the expression of epithelial intercellular junctional proteins may play an important role in the pathogenesis of CRS. PMID- 24801626 TI - Engineering the human thymic microenvironment to support thymopoiesis in vivo. AB - A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis and to develop potential cell therapies for thymic insufficiency. In this report, we developed an implantable thymic microenvironment composed of two human thymic stroma populations critical for thymopoiesis; thymic epithelial cells (TECs) and thymic mesenchyme (TM). TECs and TM from postnatal human thymi were cultured in specific conditions, allowing cell expansion and manipulation of gene expression, before reaggregation into a functional thymic unit. Human CD34+ hematopoietic stem and progenitor cells (HSPC) differentiated into T cells in the aggregates in vitro and in vivo following inguinal implantation of aggregates in immune deficient mice. Cord blood HSPC previously engrafted into murine bone marrow (BM), migrated to implants, and differentiated into human T cells with a broad T cell receptor repertoire. Furthermore, lentiviral-mediated expression of vascular endothelial growth factor in TM enhanced implant size and function and significantly increased thymocyte production. These results demonstrate an in vivo system for the generation of T cells from human HSPC and represent the first model to allow manipulation of gene expression and cell composition in the microenvironment of the human thymus. PMID- 24801629 TI - SecourHealth: a delay-tolerant security framework for mobile health data collection. AB - Security is one of the most imperative requirements for the success of systems that deal with highly sensitive data, such as medical information. However, many existing mobile health solutions focused on collecting patients' data at their homes that do not include security among their main requirements. Aiming to tackle this issue, this paper presents SecourHealth, a lightweight security framework focused on highly sensitive data collection applications. SecourHealth provides many security services for both stored and in-transit data, displaying interesting features such as tolerance to lack of connectivity (a common issue when promoting health in remote locations) and the ability to protect data even if the device is lost/stolen or shared by different data collection agents. Together with the system's description and analysis, we also show how SecourHealth can be integrated into a real data collection solution currently deployed in the city of Sao Paulo, Brazil. PMID- 24801628 TI - MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden. AB - Infections with Leishmania parasites of the Leishmania Viannia subgenus give rise to both localized cutaneous (CL), and metastatic leishmaniasis. Metastasizing disease forms including disseminated (DCL) and mutocutaneous (MCL) leishmaniasis result from parasitic dissemination and lesion formation at sites distal to infection and have increased inflammatory responses. The presence of Leishmania RNA virus (LRV) in L. guyanensis parasites contributes to the exacerbation of disease and impacts inflammatory responses via activation of TLR3 by the viral dsRNA. In this study we investigated other innate immune response adaptor protein modulators and demonstrated that both MyD88 and TLR9 played a crucial role in the development of Th1-dependent healing responses against L. guyanensis parasites regardless of their LRV status. The absence of MyD88- or TLR9-dependent signaling pathways resulted in increased Th2 associated cytokines (IL-4 and IL-13), which was correlated with low transcript levels of IL-12p40. The reliance of IL-12 was further confirmed in IL12AB-/- mice, which were completely susceptible to infection. Protection to L. guyanensis infection driven by MyD88- and TLR9 dependent immune responses arises independently to those induced due to high LRV burden within the parasites. PMID- 24801630 TI - In-vivo ultrasound and photoacoustic image- guided photothermal cancer therapy using silica-coated gold nanorods. AB - In nanoparticle-augmented photothermal therapy, evaluating the delivery and spatial distribution of nanoparticles, followed by remote temperature mapping and monitoring, is essential to ensure the optimal therapeutic outcome. The utility of ultrasound and photoacoustic imaging to assist photothermal therapy has been previously demonstrated. Here, using a mouse xenograft tumor model, it is demonstrated in vivo that ultrasound-guided photoacoustic imaging can be used to plan the treatment and to guide the therapy. To evaluate nanoparticle delivery and spatial distribution, three-dimensional ultrasound and spectroscopic photoacoustic imaging of a mouse with a tumor was performed before and after intravenous injection of silica-coated gold nanorods. After injection and sufficient circulation of nanoparticles, photothermal therapy was performed for 5 min using an 808-nm continuous-wave laser. During the photothermal therapy, photoacoustic images were acquired continuously and used to measure the temperature changes within tissue. A heterogeneous distribution of temperature, which was spatially correlated with the measured distribution of nanoparticles, indicated that peak temperatures of 53 degrees C were achieved in the tumor. An Arrhenius thermal damage model determined that this thermal deposition would result in significant cell death. The results of this study suggest that ultrasound and photoacoustic imaging can effectively guide photothermal therapy to achieve the desired thermal treatment. PMID- 24801631 TI - Locals, resettlers, and pilgrims: a genetic portrait of three pre-Columbian Andean populations. AB - The common practice of resettlement and the development of administrative and ceremonial systems shaped the population landscape of the Andean region under the Inca rule. The area surrounding Coropuna and Solimana volcanoes, in the Arequipa region (Peru), carried a high-density, multiethnic population. We studied the genetic variation among three pre-Columbian populations from three functionally diverse archaeological sites excavated in this region. By analyzing the genetic composition of a large ceremonial center (Acchaymarca), an isolated pastoral settlement (Tompullo 2), and an agricultural settlement characterized by architectural features rare in the region (Puca), we investigated the patterns of population movements and the distribution of genetic diversity. We obtained mitochondrial DNA sequences for 25 individuals and autosomal microsatellite profiles for 20 individuals from Acchaymarca and Puca sites. These were compared with previously published genetic data for Tompullo 2 and other pre-Columbian populations. We found differences among the genetic portraits of the three populations, congruent with the archaeologically described functions and characteristics of the sites. The Acchaymarca population had the highest genetic diversity and possessed the lowest number of unique mtDNA haplotypes. The Tompullo 2 population exhibited the lowest level of genetic diversity. The Puca population was distinct from the other two populations owing to a high frequency of haplogroup A haplotypes, what potentially explains the non-local character of the burial architecture. Our analyses of microsatellite data suggest that gene flow between sites was mostly mediated by females, which is consistent with ethnohistorical knowledge of the social organization of the pre-Columbian communities. PMID- 24801632 TI - Provider attitudes toward the voluntary medical male circumcision scale-up in Kenya, South Africa, Tanzania and Zimbabwe. AB - BACKGROUND: Countries participating in voluntary medical male circumcision (VMMC) scale-up have adopted most of six elements of surgical efficiency, depending on national policy. However, effective implementation of these elements largely depends on providers' attitudes and subsequent compliance. We explored the concordance between recommended practices and providers' perceptions toward the VMMC efficiency elements, in part to inform review of national policies. METHODS AND FINDINGS: As part of Systematic Monitoring of the VMMC Scale-up (SYMMACS), we conducted a survey of VMMC providers in Kenya, South Africa, Tanzania, and Zimbabwe. SYMMACS assessed providers' attitudes and perceptions toward these elements in 2011 and 2012. A restricted analysis using 2012 data to calculate unadjusted odds ratios and 95% confidence intervals for the country effect on each attitudinal outcome was done using logistic regression. As only two countries allow more than one cadre to perform the surgical procedure, odds ratios looking at country effect were adjusted for cadre effect for these two countries. Qualitative data from open-ended responses were used to triangulate with quantitative analyses. This analysis showed concordance between each country's policies and provider attitudes toward the efficiency elements. One exception was task-shifting, which is not authorized in South Africa or Zimbabwe; providers across all countries approved this practice. CONCLUSIONS: The decision to adopt efficiency elements is often based on national policies. The concordance between the policies of each country and provider attitudes bodes well for compliance and effective implementation. However, study findings suggest that there may be need to consult providers when developing national policies. PMID- 24801633 TI - The impact of early empathy on alliance building, emotional processing, and outcome during experiential treatment of depression. AB - OBJECTIVE: This study examined the relationships among the therapist process of expressed empathy during first sessions, clients' post-session one alliance reports, clients' later working phase emotional processing, and clients' final reductions in depressive symptoms for 30 clients receiving short-term experiential therapy for depression. METHOD: The therapist process of expressed empathy was assessed using a new observer-rated measure: the measure of expressed empathy, which was demonstrated to be valid and reliable. RESULTS: Results indicate that therapist expressed empathy in session one significantly affected the outcome, albeit indirectly. This indirect effect occurred through two direct effects on other important therapy processes that did directly predict client outcomes: (i) Therapist expressed empathy in first sessions directly and positively predicted client reports of first-session alliances; and (ii) therapist expressed empathy directly predicted observer-rated deepened client emotional processing in the working phase of therapy. CONCLUSIONS: Empirical support was provided for the theorized relationships in experiential theory amongst the variables examined. PMID- 24801634 TI - Neonicotinoid binding, toxicity and expression of nicotinic acetylcholine receptor subunits in the aphid Acyrthosiphon pisum. AB - Neonicotinoid insecticides act on nicotinic acetylcholine receptor and are particularly effective against sucking pests. They are widely used in crops protection to fight against aphids, which cause severe damage. In the present study we evaluated the susceptibility of the pea aphid Acyrthosiphon pisum to the commonly used neonicotinoid insecticides imidacloprid (IMI), thiamethoxam (TMX) and clothianidin (CLT). Binding studies on aphid membrane preparations revealed the existence of high and low-affinity binding sites for [3H]-IMI (Kd of 0.16 +/- 0.04 nM and 41.7 +/- 5.9 nM) and for the nicotinic antagonist [125I]-alpha bungarotoxin (Kd of 0.008 +/- 0.002 nM and 1.135 +/- 0.213 nM). Competitive binding experiments demonstrated that TMX displayed a higher affinity than IMI for [125I]-alpha-bungarotoxin binding sites while CLT affinity was similar for both [125I]-alpha-bungarotoxin and [3H]-IMI binding sites. Interestingly, toxicological studies revealed that at 48 h, IMI (LC50 = 0.038 ug/ml) and TMX (LC50 = 0.034 ug/ml) were more toxic than CLT (LC50 = 0.118 ug/ml). The effect of TMX could be associated to its metabolite CLT as demonstrated by HPLC/MS analysis. In addition, we found that aphid larvae treated either with IMI, TMX or CLT showed a strong variation of nAChR subunit expression. Using semi quantitative PCR experiments, we detected for all insecticides an increase of Apisumalpha10 and Apisumbeta1 expressions levels, whereas Apisumbeta2 expression decreased. Moreover, some other receptor subunits seemed to be differently regulated according to the insecticide used. Finally, we also demonstrated that nAChR subunit expression differed during pea aphid development. Altogether these results highlight species specificity that should be taken into account in pest management strategies. PMID- 24801636 TI - Adult-onset Moyamoya disease in a patient with neurofibromatosis type 1. PMID- 24801635 TI - Protracted effects of juvenile stressor exposure are mitigated by access to palatable food. AB - Stressor experiences during the juvenile period may increase vulnerability to anxiety and depressive-like symptoms in adulthood. Stressors may also promote palatable feeding, possibly reflecting a form of self-medication. The current study investigated the short- and long-term consequences of a stressor applied during the juvenile period on anxiety- and depressive-like behavior measured by the elevated plus maze (EPM), social interaction and forced swim test (FST). Furthermore, the effects of stress on caloric intake, preference for a palatable food and indices of metabolic syndrome and obesity were assessed. Male Wistar rats exposed to 3 consecutive days of variable stressors on postnatal days (PD) 27-29, displayed elevated anxiety-like behaviors as adults, which could be attenuated by consumption of a palatable high-fat diet. However, consumption of a palatable food in response to a stressor appeared to contribute to increased adiposity. PMID- 24801637 TI - Symmetry breaking of alpha-[H2W12O40](6-) depends on the transformation of isopolyoxotungstates. AB - Two enantiotopic 1D chain compounds, [Cu3(L1)3(H2O)2(H2W12O40)].4H2O (1a,b; L1 = 2-(4,6-bis(pyridin-2-yl)pyridin-2-yl)pyridine), crystallizing in the chiral space group P212121 were prepared and spontaneously resolved in the absence of any chiral source. Interestingly, compounds 1a,b can be prepared from a [W7O24](6-) aqueous solution, [(n-C4H9)4N]4[W10O32], or Na10[H2W12O42], but when [H2W12O40](6 ) aqueous solution was the starting material, the achiral compound [CuL1]2[H4W12O40].5H2O (2) was obtained. When a terpyridine ligand (L2) having a coordination mode similar to that of L1 was used, the mesomeric dimer [Cu3(L2)3(H2O)(H2W12O40)]2.4H2O (3) was obtained from [W7O24](6-) aqueous solution or Na10[H2W12O42], but from [H2W12O40](6-) aqueous solution only compound [Cu2(L2)2Cl2]2[W10O32] (4) was isolated. It is notable that in compounds 1a,b and 3 the symmetry of the alpha-[H2W12O40](6-) cluster is broken by asymmetric coordination with metal-organic units in a similar mode. As the asymmetric subunit based on a tridecorated [H2W12O40](6-) cluster can be obtained from several isopolyoxotungstate sources except for [H2W12O40](6-), we speculate that the symmetry breaking of alpha-[H2W12O40](6-) depends on the transformation of isopolyoxotungstates. Furthermore, during the transformation a possible reaction intermediate as the precursor for 1a,b, compound [Cu3(L1)3(H2O)3(H4W11O38)] (5), has been presented and characterized by density functional theory (DFT) calculations. PMID- 24801638 TI - Resident and hospitalist perspectives on the "great teaching case": Correlation with actual patient assignment decisions. AB - BACKGROUND: With the advent of limits to resident duty hours and the size of teaching services, many academic institutions have introduced nonteaching services, often triaging perceived better teaching cases to the resident services. OBJECTIVE: To compare resident versus faculty perceptions of ideal cases for teaching services and compare these perceptions with actual triage decisions made by faculty who assigned patients to either teaching or nonteaching services. DESIGN: Residents and hospitalist faculty were surveyed about their perceptions of ideal and actual teaching admissions, first with qualitative, open ended questions and then with quantitative, specific questions generated from responses to the first survey. Characteristics of patients admitted to teaching and nonteaching services were analyzed retrospectively and compared with resident and faculty perceptions. RESULTS: Residents and faculty agreed that rare cases, patients with unique physical findings, and a variety of pathology were ideal for teaching services and that social admissions, benefactors, and patients with chronic or functional pain were not. Residents believed that traditional ("bread and butter") medicine cases were under-represented on the teaching services. Although residents perceived that they received a disproportionate number of older patients, outside transfers, patients with chronic pain, and patients with cancer, the only statistically significant difference was in patient age, with the teaching service actually receiving younger patients (66.7 vs 69.3 years; P=0.008). CONCLUSIONS: Residents and faculty have similar views about ideal teaching cases, but a triage system based on perceived educational merit creates the possibility of resident misperceptions about their case mix, even if patients are distributed relatively equitably. PMID- 24801639 TI - Simultaneous photodynamic and photothermal therapy using photosensitizer functionalized Pd nanosheets by single continuous wave laser. AB - In this work, we prepared chlorin e6 (Ce6)-functionalized Pd nanosheets (Pd-PEI Ce6) for the photodynamic and photothermal combined therapy that use a single laser. To fabricate the Pd-PEI-Ce6 nanocomposite, photosensitizer Ce6 were chemically conjugated to polyethylenimine (PEI) and the formed Ce6-PEI conjugates were then anchored onto Pd nanosheets by electrostatic and coordination interaction. The prepared Pd-PEI-Ce6 nanocomposite were about 4.5 nm in size, exhibited broad, and strong absorption from 450 to 800 nm, good singlet oxygen generation capacity and photothermal conversion efficiency, and excellent biocompability. Significantly greater cell killing was observed when HeLa cells incubated with Pd-PEI-Ce6 were irradiated with the 660 nm laser, attributable to both Pd nanosheets-mediated photothermal ablation and the photodynamic destruction effect of photosensitizer Ce6. The double phototherapy effect was also confirmed in vivo. It was found that the Pd-PEI-Ce6 treated tumor-bearing mice displayed the enhanced therapeutic efficiency compared to that of Pd-PEI, or Ce6-treated mice. Our work highlights the promise of using Pd nanosheets for potential multimode cancer therapies. PMID- 24801640 TI - Axone, an ethnic probiotic containing food, reduces age of sexual maturity and increases poultry production. AB - Axone (Akhuni) is a homemade synbiotic (Nagamese fermented soybean product) served as side dish in North Eastern India. In this study, effects of Axone feeding on growth, weight gain, sexual maturity and egg production on Vanaraja birds (a strain of poultry bird developed at PDP Hyderabad for villages and backyard poultry) were evaluated. Axone incorporation in commercial poultry feed at the rate of 5% (W/W) significantly improved growth rate (weight gain) both in male (p 0.001) and female (p 0.05) chicks, reduced age by 13 days at first egg laying (p 0.01), increased egg production (p <= 0.001) and improved egg weight (p <= 0.01). Microbiological analysis of Axone sample revealed that the major bacteria in Axone samples were Bacillus coagulans, well known for their probiotic value. PMID- 24801641 TI - Photocatalytic reduction of CO2 into hydrocarbon solar fuels over g-C3N4-Pt nanocomposite photocatalysts. AB - Photocatalytic reduction of CO2 into renewable hydrocarbon fuels is an alternative way to develop reproducible energy, which is also a promising way to solve the problem of the greenhouse effect. In this work, graphitic carbon nitride (g-C3N4) was synthesized by directly heating thiourea at 550 degrees C and then a certain amount of Pt was deposited on it to form g-C3N4-Pt nanocomposites used as catalysts for photocatalytic reduction of CO2 under simulated solar irradiation. The main products of photocatalysis were CH4, CH3OH and HCHO. The deposited Pt acted as an effective cocatalyst, which not only influenced the selectivity of the product generation, but also affected the activity of the reaction. The yield of CH4 first increased upon increasing the amount of Pt deposited on the g-C3N4 from 0 to 1 wt%, then decreased at 2 wt% Pt loading. The production rates of CH3OH and HCHO also increased with the content of Pt increasing from 0 to 0.75 wt% and the maximum yield was observed at 0.75 wt%. The Pt nanoparticles (NPs) could facilitate the transfer and enrichment of photogenerated electrons from g-C3N4 to its surface for photocatalytic reduction of CO2. At the same time, Pt was also used a catalyst to promote the oxidation of products. The transient photocurrent response further confirmed the proposed photocatalytic reduction mechanism of CO2. This work indicates that the deposition of Pt is a good strategy to improve the photoactivity and selectivity of g-C3N4 for CO2 reduction. PMID- 24801642 TI - Daptomycin-induced rhabdomyolysis and acute liver injury. AB - Daptomycin use is a known cause of rhabdomyolysis; its role in liver injury is less certain. We report a case of daptomycin-induced rhabdomyolysis with liver injury. This report indicates a role for liver function monitoring while receiving daptomycin, as well as the importance of promptly considering drug toxicities in acute and emergency care settings. PMID- 24801643 TI - Quantitative computer tomography analysis of post-operative subdural fluid volume predicts recurrence of chronic subdural haematoma. AB - BACKGROUND: Post-operative volume of subdural fluid is considered to correlate with recurrence in chronic subdural haematoma (CSDH). Information on the applications of computer-assisted volumetric analysis in patients with CSDHs is lacking. OBJECTIVE: To investigate the relationship between haematoma recurrence and longitudinal changes in subdural fluid volume using CT volumetric analysis. METHODS: Fifty-four patients harbouring 64 CSDHs were studied prospectively. The association between recurrence rate and CT findings were investigated. RESULTS: Eleven patients (20.4%) experienced post-operative recurrence. Higher pre operative (over 120 ml) and/or pre-discharge subdural fluid volumes (over 22 ml) were significantly associated with recurrence; the probability of non-recurrence for values below these thresholds were 92.7% and 95.2%, respectively. CSDHs with larger pre-operative (over 15.1 mm) and/or residual (over 11.7 mm) widths also had significantly increased recurrence rates. Bilateral CSDHs were not found to be more likely to recur in this series. On receiver-operating characteristic curve, the areas under curve for the magnitude of changes in subdural fluid volume were greater than a single time-point measure of either width or volume of the subdural fluid cavity. CONCLUSIONS: Close imaging follow-up is important for CSDH patients for recurrence prediction. Using quantitative CT volumetric analysis, strong evidence was provided that changes in the residual fluid volume during the 'self-resolution' period can be used as significantly radiological predictors of recurrence. PMID- 24801644 TI - Continuous subcutaneous insulin infusion in preschool children: butt or tummy, which is the best infusion set site? AB - BACKGROUND: Choosing the right infusion set site can be an important factor in obtaining good glycemic control, especially in very young children. In an attempt to identify the best infusion site, we performed a crossover study in six preschool children with type 1 diabetes using insulin pump therapy. SUBJECTS AND METHODS: We enrolled six patients 5.2+/-0.7 years old (range, 4-6 years), with type 1 diabetes for more than 1.5 years, using insulin pump therapy for at least 6 months. For each patient, body mass index, glycated hemoglobin, and all data downloaded from the system were evaluated on two occasions: the first with the infusion set placed on the buttock and the second on the abdomen, each for 3 days. The order of infusion set placement was randomized. Mean capillary blood glucose, mean continuous glycemia, mean area under the curve (AUC) using the trapezoidal rule for both >140 mg/dL and <70 mg/dL, insulin daily dose, carbohydrate/insulin ratio, total basal insulin, total bolus insulin, and mean amplitude of glucose excursions (MAGE) were evaluated. RESULTS: Mean glycemic values, mean AUC >140 mg/dL, and MAGE were significantly lower when the infusion set was placed on the buttock versus the abdomen (144.6+/-31.9 mg/dL vs. 166.0+/ 34.8 mg/dL [P=0.000], 28.4+/-18.3% vs. 48.8+/-28.2% [P=0.000], and 32+/-10 vs. 60+/-15 mg/dL [P<0.001], respectively), whereas mean AUC <70 mg/dL was higher (1.47+/-2.77% vs. 0.87+/-1.03% [P<0.001]). CONCLUSIONS: The present findings suggest that preschool children with type 1 diabetes using insulin pump therapy could benefit from inserting the infusion set in the buttock instead of the abdomen. PMID- 24801645 TI - Ciliates and the rare biosphere: a review. AB - Here we provide a brief review of the rare biosphere from the perspective of ciliates and other microbial eukaryotes. We trace research on rarity from its lack of much in-depth focus in morphological and Sanger sequencing projects, to its central importance in analyses using high throughput sequencing strategies. The problem that the rare biosphere is potentially comprised of mostly errors is then discussed in the light of asking community-comparative, novel-diversity, and ecosystem-functioning questions. PMID- 24801646 TI - From the phosphoenolpyruvate phosphotransferase system to selfish metabolism: a story retraced in Pseudomonas putida. AB - Although DNA is the ultimate repository of biological information, deployment of its instructions is constrained by the metabolic and physiological status of the cell. To this end, bacteria have evolved intricate devices that connect exogenous signals (e.g. nutrients, physicochemical conditions) with endogenous conditions (metabolic fluxes, biochemical networks) that coordinately influence expression or performance of a large number of cellular functions. The phosphoenolpyruvate:carbohydrate-phosphotransferase system (PTS) is a bacterial multi-protein phosphorylation chain which computes extracellular (e.g. sugars) and intracellular (e.g. phosphoenolpyruvate, nitrogen) signals and translates them into post-translational regulation of target activities through protein protein interactions. The PTS of Pseudomonas putida KT2440 encompasses one complete sugar (fructose)-related system and the three enzymes that form the so called nitrogen-related PTS (PTS(N) (tr) ), which lacks connection to transport of substrates. These two PTS branches cross-talk to each other, as the product of the fruB gene (a polyprotein EI-HPr-EIIA) can phosphorylate PtsN (EIIA(N) (tr) ) in vivo. This gives rise to a complex actuator device where diverse physiological inputs are ultimately translated into phosphorylation or not of PtsN (EIIA(N) (tr) ) which, in turn, checks the activity of key metabolic and regulatory proteins. Such a control of bacterial physiology highlights the prominence of biochemical homeostasis over genetic ruling -and not vice versa. PMID- 24801647 TI - A novel multiplex pyrosequencing assay for genotyping functionally relevant CTLA 4 polymorphisms: potential applications in autoimmunity and cancer. AB - CTLA-4 expression/function can be affected by single nucleotide polymorphisms (SNPs) of CTLA-4 gene, which have been widely associated with susceptibility or progression to autoimmune diseases and cancer development. In this study, we analyzed six CTLA-4 SNPs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, CT60G>A) in 197 DNA samples from 43 B-lymphoblastoid cell lines (B-LCLs), 40 systemic sclerosis (SSc) patients, 14 pre-analyzed melanoma patients and 100 Italian healthy subjects. Genotyping of -1661A>G, -1577G>A, -658C>T and CT60G>A was performed by newly developed multiplex pyrosequencing (PSQ) assays, whereas 319C>T and +49A>G by T-ARMS PCR and direct sequencing. Genotype/allele frequency were analyzed using chi(2) or Fisher exact test. Our study provides the first multiplex PSQ method that allows simultaneous genotyping of two CTLA-4 SNP pairs (i.e. -1661A>G/-658C>T and -1577G>A/CT60G>A) by two multiplex PSQ reactions. Herein, we show the CTLA-4 genotype distribution in the B-LCLs providing the first and best characterized cell line panel typed for functionally relevant CTLA 4 SNPs. We also report the significant association of the -1661A/G genotype, 1661 & -319 AC-GT diplotype and -319 & CT60 TG haplotype with susceptibility to SSc without Hashimoto's thyroiditis occurrence. Furthermore, we confirmed previous genotyping data referred to melanoma patients and provided new genotyping data for Italian healthy subjects. PMID- 24801649 TI - A Fourier-based approach to the angiographic assessment of flow diverter efficacy in the treatment of cerebral aneurysms. AB - Flow diversion is an emerging endovascular treatment option for cerebral aneurysms. Quantitative assessment of hemodynamic changes induced by flow diversion can aid clinical decision making in the treatment of cerebral aneurysms. In this article, besides summarizing past key research efforts, we propose a novel metric for the angiographic assessment of flow diverter deployments in the treatment of cerebral aneurysms. By analyzing the frequency spectra of signals derived from digital subtraction angiography (DSA) series, the metric aims to quantify the prevalence of frequency components that correspond to the patient-specific heart rate. Indicating the decoupling of aneurysms from healthy blood circulation, our proposed metric could advance clinical guidelines for treatment success prediction. The very promising results of a retrospective feasibility study on 26 DSA series warrant future efforts to study the validity of the proposed metric within a clinical setting. PMID- 24801648 TI - CD40 expression in renal cell carcinoma is associated with tumor apoptosis, CD8(+) T cell frequency and patient survival. AB - The co-stimulatory molecule, CD40, is expressed in renal cell carcinoma (RCC) and a variety of inflammatory diseases in the kidney. We investigated the relationship between tumor-associated CD40 expression, immune milieu of the tumor microenvironment, tumor stage and survival of patients with RCC. The expression of CD40, TUNEL and CD8 in human renal cell carcinomas was analyzed by immunohistochemistry performed on tissue samples obtained at the time of surgery. Computer-assisted quantitation of protein expression was used to analyze results in connection with patient survival and tumor stage. We show for the first time that tumor-associated CD40 expression is associated with prolonged survival in RCC patients. Tumor apoptosis (TUNEL) and CD8 immunostaining were also associated with patient survival. No relation was observed between CD40 expression and tumor stage. Our results suggest CD40 may be a prognostic biomarker indicative of prolonged RCC patient survival. Strategies that up-regulate CD40 expression in some RCC patients may thus improve survival, supporting further studies of agonistic CD40 antibodies in RCC. PMID- 24801650 TI - The Arnold Berliner Award 2014. PMID- 24801651 TI - Profile of intraocular immune mediators in patients with age-related macular degeneration and the effect of intravitreal bevacizumab injection. AB - PURPOSE: To measure intraocular cytokine levels in patients with exudative age related macular degeneration and analyze changes in the cytokine profile 2 days after intravitreal bevacizumab injection. METHODS: This prospective case-control study enrolled 37 patients (37 eyes) with age-related macular degeneration including polypoidal choroidal vasculopathy. Twenty-eight age-matched patients (28 eyes) who underwent cataract surgery were used as controls. Undiluted aqueous humor samples were collected after intravitreal bevacizumab injection. Two days after intravitreal bevacizumab injection, cataract surgery was performed and undiluted aqueous humor samples were collected at the beginning of surgery (10 eyes). Twenty-three cytokines were measured using flow cytometry. P values were corrected in multiple comparisons using the conservative Bonferroni-Holm method. The level of significance was set at 0.0022 (0.05/23). RESULTS: At baseline, aqueous humor levels of vascular endothelial growth factor, angiogenin, interferon gamma-inducible protein (IP)-10, macrophage inflammatory protein (MIP) 1beta, monokine induced by interferon gamma (Mig), and monocyte chemotactic protein (MCP)-1 were significantly higher in the age-related macular degeneration group than in the control group (P < 0.0022). The result of exploratory multivariate analysis showed that elevated angiogenin level was an important factor that discriminates the two groups (P = 0.0004). Two days after intravitreal bevacizumab injection, vascular endothelial growth factor levels tended to be reduced (P = 0.049), whereas interleukin (IL)-6 and IL-8 levels increased significantly (P < 0.0022). CONCLUSION: Vascular endothelial growth factor and also angiogenin, IP-10, MCP-1, MIP-1beta, and Mig may be related to the pathogenesis of age-related macular degeneration. Intravitreal bevacizumab injection increases inflammatory cytokine levels, suggesting the induction of an inflammatory process. PMID- 24801653 TI - Editorial: Mass spectrometry of small molecules and natural products. PMID- 24801652 TI - Endophthalmitis caused by Klebsiella species. AB - PURPOSE: To report the clinical presentation, antibiotic sensitivities, treatment strategies, and visual outcomes associated with endophthalmitis caused by Klebsiella species. METHODS: A noncomparative consecutive case series. Microbiology database records were retrospectively reviewed for all patients with endophthalmitis caused by Klebsiella species from 1990 to 2012 at a large university referral center. The corresponding clinical records were then reviewed to evaluate the endophthalmitis clinical features and treatment outcomes. RESULTS: Seven patients were identified. Clinical settings included endogenous (n = 3), posttraumatic (n = 2), trabeculectomy bleb-associated (n = 1), and postpenetrating keratoplasty (n = 1). Five patients presented with hypopyon. Presenting visual acuity ranged from 20/60 to light perception in nonendogenous cases and 1/200 to light perception in endogenous cases. Klebsiella was sensitive to aminoglycosides, third-generation cephalosporins, and second- and third generation fluoroquinolones in all cases. Initial treatment strategies were vitreous tap and injection (n = 4), pars plana vitrectomy with intravitreal antibiotics (n = 2), and anterior chamber tap and injection (n = 1). All three endogenous cases later underwent enucleation or evisceration. In nonendogenous cases, the final visual acuity was 20/70 or better in all 4 patients. CONCLUSION: Endophthalmitis caused by Klebsiella species is associated with poor visual outcomes. Endogenous cases had high rates of enucleation or evisceration. PMID- 24801654 TI - Biliary microflora in patients undergoing cholecystectomy. AB - BACKGROUND: The management of acute cholecystitis requires a sound knowledge of the biliary microflora. METHODS: Bile samples were taken for culture according to a standard routine during all cholecystectomies performed from April 2007 to February 2009 in the Department of Surgery at Enkoping Hospital. The use of antibiotics within the 3-mo period before surgery, indication for surgery, prophylactic antibiotics, and post-operative complications were recorded prospectively. RESULTS: Altogether, 246 procedures were performed during the study period, of which 149 (62%) were done on women. The mean (+/-SD) age of the study subjects was 49+/-16 y. Bacterial growth was seen in cultures from 34 (14%) of the subjects. The mean age of subjects with positive cultures was 64 y and that of subjects with negative cultures was 47 y (p<0.001). Positive culture was seen in 16 (31%) of the 51 patients who underwent operations for acute cholecystitis, whereas positive cultures were obtained in 18 of 195 patients without acute cholecystitis (9%) (p<0.001). Resistance to ampicillin was recorded in three of 34 (9%) of the cultures with bacterial growth, to co-trimoxazole in one of the 34 (3%) cultures, to fluoroquinolones in one of the 34 (3%) cultures, and to cephalosporins in one of the 34 (3%) cultures. Resistance to piperacillin tazobactam was not observed in any of the cultures. In multivariable logistic regression analysis, a positive culture was the only factor significantly associated with risk for post-operative infectious complications (p<0.05). DISCUSSION: Bacterial growth in the bile is observed more often in patients undergoing surgery for acute cholecystitis. The microflora of the bile is probably important for the outcome of surgery, but further studies are required for assessing the effectiveness of measures for preventing infectious post operative complications. PMID- 24801655 TI - Source of copper may have regressive effects on serum cholesterol and urea nitrogen among male fattening lambs. AB - An experiment was conducted to determine the effect of dietary copper (Cu) on mineral profile, hematological parameters, and lipid metabolism in lambs. Eighteen Zandi male lambs (approximately 3 months of age; 17.53+/-1.6 kg of body weight) were housed in individual pens and were assigned randomly to one of three treatments. Treatments consisted of (1) control (no supplemental Cu), (2) 10 mg Cu/kg dry matter (DM) from copper sulfate (CuS), and (3) 10 mg Cu/kg DM from Cu proteinate (CuP). The Cu concentration was 8.2 mg/kg DM in the basal diet. Blood was sampled from the jugular vein at the beginning of the study (enrollment, before feeding Cu supplement) and at days 25, 50, and 70 of experiment. The amounts of total serum glucose, urea nitrogen, calcium, phosphorus, iron, copper, zinc, and lipids and hematological parameters were measured. Average daily gain and feed efficiency were improved (P<0.05) with Cu supplementation and were better for the lambs fed diet supplemented with CuP. The concentrations of serum Ca, P, and Zn were not affected by source of Cu in the diet. However, Fe concentration was lower (P<0.01) in the Cu-supplemented groups. Experimental treatment had no significant effects on the hematological parameters. The serum glucose concentration was not affected by treatments. However, the urea nitrogen concentrations were significantly affected (P<0.05) by added Cu and was lower for CuP group as compared to the lambs in the CuS and control groups. Addition of Cu had no influence (P>0.05) on the serum triglyceride concentration, but lambs fed with CuP supplement had lower (P<0.05) serum cholesterol than the CuS and control animals. These results indicated that CuP supplemented at 10 mg/kg DM improved gain and enhanced the efficiency of nitrogen in male lambs. PMID- 24801656 TI - Assessment of total and organic mercury levels in blue sharks (Prionace glauca) from the south and southeastern Brazilian coast. AB - Mercury occurrence was evaluated in samples of edible muscle tissue of 27 blue sharks (Prionace glauca) caught in the Atlantic Ocean, adjacent to the south and southeastern Brazilian coast, indicating a slight increase in comparison with previous data obtained for the same studied area and being higher than those fish caught at different sites of the Atlantic Ocean. Total Hg concentrations ranged from 0.46 to 2.40 mg kg(-1) with the organic Hg fraction ranging between 0.44 and 2.37 mg kg(-1). A negative correlation between total Hg concentration in muscle tissue and blue shark size was obtained, and 40% of samples analyzed had Hg concentrations higher than 1.0 mg kg(-1) Hg, the maximum concentration permitted in Brazilian predator fish. Data obtained showed that total Hg can be used as a reliable predictor of organic Hg in blue shark muscle because 95 to 98% of the total Hg measured was found to be organic mercury. The wide range of Hg concentrations obtained for our set of samples can be explained by the heterogeneity of sampled population and the large size of the studied area. Given the adverse toxicological effects of Hg on animals and humans, a regular monitoring program of Hg contamination in Brazilian marine ecosystem can be recommended. PMID- 24801657 TI - Profile and determinants of successful aging in the Ibadan Study of Ageing. AB - OBJECTIVES: To determine the profile and determinants of successful aging in a developing country characterized by low life expectancy and where successful agers may represent a unique group. DESIGN: Community-based cohort study. SETTING: Eight contiguous states in the Yoruba-speaking region of Nigeria. PARTICIPANTS: A multistage clustered sampling of households was used to select a representative sample of individuals (N = 2,149) aged 65 and older at baseline. Nine hundred thirty were successfully followed for an average of 64 months between August 2003 and December 2009. MEASUREMENTS: Lifestyle and behavioral factors were assessed at baseline. Successful aging, defined using each of three models (absence of chronic health conditions, functional independence, and satisfaction with life), was assessed at follow-up. RESULTS: Between 16% and 75% of respondents could be classified as successful agers using one of the three models while 7.5% could be so classified using a combination of all the models. Correlations between the three models were small, ranging from 0.08 to 0.15. Different features predicted their outcomes, suggesting that they represent relatively independent trajectories of aging. Whichever model was used, more men than women tended to be classified as aging successfully. Men who aged successfully, using a combination of all the three models, were more likely never to have smoked (adjusted odds ratio (aOR) = 4.7, 95% confidence interval (CI) = 1.55-14.46) and to report, at baseline, having contacts with friends (aOR = 4.2, 95% CI = 1.0-18.76) or participating in community activities (aOR = 16.0, 95% CI = 1.23-204.40). In women, there was a nonlinear trend for younger age at baseline to predict this outcome. CONCLUSION: Modifiable social and lifestyle factors predicted successful aging in this population, suggesting that health promotion targeting behavior change may lead to tangible benefits for health and well-being in old age. PMID- 24801658 TI - Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review. AB - CONTEXT: If access to effective palliative care is to extend beyond cancer patients, an understanding of the comparative prevalence of palliative care problems among cancer and non-cancer patients is necessary. OBJECTIVES: This systematic review aimed to describe and compare the prevalence of seventeen palliative care-related problems across the four palliative care domains among adults with advanced cancer, acquired immune deficiency syndrome, chronic heart failure, end-stage renal disease (ESRD), chronic obstructive pulmonary disease, multiple sclerosis, motor neuron disease, Parkinson's disease, and dementia. METHODS: Three databases were searched using three groups of keywords. The results of the extraction of the prevalence figures were summarized. RESULTS: The electronic searches yielded 4697 hits after the removal of 1784 duplicates. Of these hits, 143 met the review criteria. The greatest number of studies were found for advanced cancer (n=57) and ESRD patients (n=47), and 75 of the 143 studies used validated scales. Few data were available for people living with multiple sclerosis (n=2) and motor neuron disease (n=3). The problems with a prevalence of 50% or more found across most of the nine studied diagnostic groups were: pain, fatigue, anorexia, dyspnea, and worry. CONCLUSION: There are commonalities in the prevalence of problems across cancer and non-cancer patients, highlighting the need for palliative care to be provided irrespective of diagnosis. The methodological heterogeneity across the studies and the lack of non-cancer studies need to be addressed in future research. PMID- 24801659 TI - Patients' sense of security during palliative care-what are the influencing factors? AB - CONTEXT: Having a sense of security is vitally important to patients who have a limited life expectancy. OBJECTIVES: We sought to identify the factors associated with patients' sense of security during the palliative care period. METHODS: We recruited 174 adult patients (65% of those eligible) from six palliative home care units. The relationship between the patients' sense of security during palliative care and individual factors was evaluated in a stepwise procedure using the generalized linear model (ordinal multinomial distribution and logit link). RESULTS: Respondents' ratings of their sense of security ranged from 1 (never) to 6 (always), with a mean value of 4.6 (SD 1.19). Patients with lower feelings of security experienced higher stress; more worry about personal finances; lower feelings of self-efficacy; a lower sense of security with the palliative care provided (lower ratings on subscales of care interaction); mastery; prevailed own identity; higher symptom intensity (especially depression, anxiety, and lack of well-being); lower health-related quality of life; lower attachment anxiety and avoidance; less support from family, relatives, and friends; lower comfort for those closest to them; and more often had gynecological cancer. Six variables (mastery, nervousness and stress, gynecological cancer, self-efficacy, worrying about personal finances, and avoidance) were selected in building the stepwise model. CONCLUSION: These findings stress the importance of palliative care services in supporting dying patients' sense of security through symptom management with a wide scope and through supporting the patients' sense of mastery, identity, and perception of a secure care interaction and also through attention to the family members' situation. PMID- 24801660 TI - Endoscopic cyst-gastrostomy for pancreatic pseudocysts: refining the indications. AB - BACKGROUND: Pseudocysts are a common consequence of acute pancreatitis and require intervention if symptomatic. Endoscopic management is emerging as a safe and effective alternative to surgery, although its use is not yet widespread. METHODS: We describe our experience of 10 consecutive unselected patients who underwent endoscopic ultrasound-guided cyst-gastrostomy and stent insertion at a tertiary referral centre. Technical aspects of the procedure are detailed with accompanying photographs. RESULTS: Six patients made an uneventful recovery. Four patients developed complications, of which one was successfully salvaged by endoscopy and three required surgery. CONCLUSION: We discuss technical and patient factors which may have contributed to these complications in the context of current literature, and in particular, found that the presence of necrosis was associated with higher morbidity, both in our series and in others. In our experience, endoscopic ultrasound-guided cyst-gastrostomy is best employed in simple, mature pseudocysts without necrotic debris, and we recommend this procedure only after a detailed assessment of the pseudocyst in a specialist hepatobiliary unit. PMID- 24801661 TI - Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse. AB - Moderate social consumption of alcohol is common; however, only a small percentage of individuals transit from social to excessive, uncontrolled alcohol drinking. This suggests the existence of protective mechanisms that prevent the development of alcohol addiction. Here, we tested the hypothesis that the glial cell line-derived neurotrophic factor (GDNF) in the mesolimbic system [e.g. the nucleus accumbens (Acb) and ventral tegmental area (VTA)] is part of such a mechanism. We found that GDNF knockdown, by infecting rat Acb neurons with a small hairpin RNA (shRNA) targeting the GDNF gene, produced a rapid escalation to excessive alcohol consumption and enhanced relapse to alcohol drinking. Conversely, viral-mediated overexpression of the growth factor in the mesolimbic system blocked the escalation from moderate to excessive alcohol drinking. To access the mechanism underlying GDNF's actions, we measured the firing rate of dopaminergic (DAergic) neurons in the VTA after a history of excessive alcohol intake with or without elevating GDNF levels. We found that the spontaneous firing rate of DAergic neurons in the VTA was reduced during alcohol withdrawal and that GDNF reversed this alcohol-induced DA deficiency. Together, our results suggest that endogenous GDNF in the mesolimbic system controls the transition from moderate to excessive alcohol drinking and relapse via reversal of alcohol dependent neuro-adaptations in DAergic VTA neurons. PMID- 24801662 TI - Song recognition by young children with cochlear implants: comparison between unilateral, bilateral, and bimodal users. AB - PURPOSE: To examine song identification by preschoolers with normal hearing (NH) versus preschoolers with cochlear implants (CIs). METHOD: Participants included 45 children ages 3;8-7;3 (years;months): 12 with NH and 33 with CIs, including 10 with unilateral CI, 14 with bilateral CIs, and 9 bimodal users (CI-HA) with unilateral CI and contralateral hearing aid. Preschoolers were asked to identify children's songs presented via 5 versions: (a) full (lyrics sung with piano accompaniment); (b) a cappella (only lyrics); (c) melodic (matching main melodic contour); (d) tonal (only pitch information); and (e) rhythmic (only song's rhythm). RESULTS: The NH group surpassed all CI groups at identifying songs via melodic and tonal versions, but no significant differences emerged between the NH group and any CI group via full, a cappella, or rhythmic versions. Among the CI groups, no significant differences emerged via melodic or rhythmic versions, but bimodal users performed significantly better than bilateral users via the tonal version. Chronological age and duration of CI use correlated significantly with identification via the rhythmic version. CONCLUSION: Bimodal users showed an advantage in identifying songs in the tonal version through use of complementary information. PMID- 24801664 TI - Identification of the recurrent laryngeal nerve at the cricothyroid joint: Our experience of 181 thyroid procedures. PMID- 24801663 TI - Cost-Effectiveness Analysis of Early Reconstruction Versus Rehabilitation and Delayed Reconstruction for Anterior Cruciate Ligament Tears. AB - BACKGROUND: An initial anterior cruciate ligament (ACL) tear can be treated with surgical reconstruction or focused rehabilitation. The KANON (Knee Anterior cruciate ligament, NON-surgical versus surgical treatment) randomized controlled trial compared rehabilitation plus early ACL reconstruction (ACLR) to rehabilitation plus optional delayed ACLR and found no difference at 2 years by an intention-to-treat analysis of total Knee injury and Osteoarthritis Outcome Score (KOOS) results. PURPOSE: To compare the cost-effectiveness of early versus delayed ACLR. STUDY DESIGN: Economic and decision analysis; Level of evidence, 2. METHODS: A Markov decision model was constructed for a cost-utility analysis of early reconstruction (ER) versus rehabilitation plus optional delayed reconstruction (DR). Outcome probabilities and effectiveness were derived from 2 sources: the KANON study and the Multicenter Orthopaedic Outcomes Network (MOON) database. Collectively, these 2 sources provided data from 928 ACL-injured patients. Utilities were measured by the Short Form-6 dimensions (SF-6D). Costs were estimated from a societal perspective in 2012 US dollars. Costs and utilities were discounted in accordance with the United States Panel on Cost Effectiveness in Health and Medicine. Effectiveness was expressed in quality adjusted life-years (QALYs) gained. Principal outcome measures were average incremental costs, incremental effectiveness (as measured by QALYs), and net health benefits. Willingness to pay was set at $50,000, which is the currently accepted standard in the United States. RESULTS: In the base case, the ER group resulted in an incremental gain of 0.28 QALYs over the DR group, with a corresponding lower overall cost to society of $1572. Effectiveness gains were driven by the low utility of an unstable knee and the lower utility for the DR group. The cost of rehabilitation and the rate of additional surgery drove the increased cost of the DR group. The most sensitive variable was the rate of knee instability after initial rehabilitation. When the rate of instability falls to 51.5%, DR is less costly, and when the rate of instability falls below 18.0%, DR becomes the preferred cost-effective strategy. CONCLUSION: An economic analysis of the timing of ACLR using data exclusively from the KANON trial, MOON cohort, and national average reimbursement revealed that early ACLR was more effective (improved QALYs) at a lower cost than rehabilitation plus optional delayed ACLR. Therefore, early ACLR should be the preferred treatment strategy from a societal health system perspective. PMID- 24801665 TI - Imaging in gynaecology. Preface. PMID- 24801666 TI - A novel missense NDP mutation [p.(Cys93Arg)] with a manifesting carrier in an austrian family with Norrie disease. AB - Norrie disease is a rare, X-linked genetic syndrome characterized by combined congenital blindness and progressive hearing impairment. Norrie disease is caused by alterations in the NDP gene encoding the growth factor norrin that plays a key role in vascular development and stabilization of the eye, inner ear and brain. We identified a family with 3 affected deafblind males and a single female carrier presenting with a serous retinal detachment but normal hearing. Genetic analysis revealed a novel c.277T>C missense mutation causing the substitution of a hydrophobic cysteine to a hydrophilic arginine [p.(Cys93Arg)] within the highly conserved cysteine knot domain of the norrin protein. These results should expand the scope for amniocentesis and genetic testing for Norrie disease which is gaining in importance due to novel postnatal therapeutic concepts to alleviate the devastating retinal symptoms of Norrie disease. PMID- 24801667 TI - Osteochondral flaps from the distal femur: expanding applications, harvest sites, and indications. AB - BACKGROUND: The medial and lateral femur provide a source of convex osteochondral vascularized bone. The medial trochlea has been demonstrated to have similar contour to the proximal scaphoid, lunate, and capitate. Other sites of osteochondral harvest such as the posteromedial femur and the lateral trochlea are similar in morphology to the humeral capitellum and medial talus, respectively. These analogous structures offer potential solutions to difficult articular problems. PATIENTS AND METHODS: Patients who underwent osteochondral reconstruction of the extremities were reviewed. These included 16 medial femoral trochlea (MFT) scaphoid nonunion reconstructions, 16 MFT Kienbock lunate reconstructions, 5 MFT capitate reconstructions, 2 lateral femoral trochlea osteochondral reconstructions of medial tarsal avascular necrosis, and 5 posteromedial femoral osteochondral reconstructions of the humeral capitellum for posttraumatic arthritis. RESULTS: Computed tomography (CT) imaging demonstrated 15 of 16 reconstructed scaphoids achieving union. Follow-up wrist motion averaged 46.0 degrees extension and 43.8 degrees flexion, similar to preoperative measurements. CT imaging confirmed healing in 15 of 16 reconstructed lunates. Lichtman staging remained unchanged in 10 patients, improved in 4 patients (3A 2), and worsened in 2 patients (3A-3B). All but one patient experienced improvement in wrist pain. Wrist range of motion at follow-up averaged 50 degrees extension and 38 degrees flexion, similar to preoperative measurements. Capitate, talar, and capitellar reconstructions all resulted in achievement of osseous healing and restoration of joint alignment. CONCLUSIONS: Vascularized osteochondral flaps provide a useful tool in the treatment of difficult articular problems in the extremities. Clinical experience thus far demonstrates a high rate of achieving union with acceptable range of motion and good pain relief. PMID- 24801668 TI - Correlation between Abdominal Perforator Vessels Identified with Preoperative Computed Tomography Angiography and Intraoperative Fluorescent Angiography in the Microsurgical Breast Reconstruction Patient. AB - Background Computed tomography angiography (CTA) has become a reliable method of perforator vessel identification. Indocyanine green laser-assisted fluorescent angiography (ICGLA) produces a real-time image of large and small caliber blood vessels. The aim of this prospective study was to compare ICGLA with CTA to evaluate its reliability of vessel identification and correlation to perforator vessel size and number determined preoperatively by CTA. The effect of both imaging techniques on flap design or intraoperative plan was also evaluated. Methods Over a 1-year period, patients presenting for free-tissue transfer breast reconstruction underwent preoperative CTA mapping of abdominal perforators followed by intraoperative ICGLA. Using visualization software, scaling factors were calculated so that CTA and ICGLA data could be compared. Results A total of 18 patients (24 breast reconstructions) were included. Larger CTA perforator size was associated with larger actual size (p = 0.04). The largest CTA perforator or largest actual perforator was used 78% of the time. Increasing body mass index was not associated with larger CTA perforator size (p = 0.67) or more intense ICGLA blushes (p = 0.13). No significant correlation was found between CTA perforator location and ICGLA skin blush location, size, or intensity. CTA- or ICGLA-guided intraoperative procedure adjustments were done in 72% of the patients. ICGLA identified poor soft tissue perfusion and guided flap resection in 46% of the patients. Conclusions ICGLA skin blush location, size, and intensity does not correlate with CTA-identified perforating vessel location or actual perforating vessel size. Despite this, the ICGLA information was useful for evaluation of soft tissue perfusion and flap design. PMID- 24801670 TI - What ethics integration looks like in neuroscience research. PMID- 24801669 TI - Targeting angiogenesis as a therapeutic means to reinforce osteocyte survival and prevent nonunions in the aftermath of radiotherapy. AB - BACKGROUND: Radiotherapy (XRT) exerts detrimental collateral effects on bone tissue through mechanisms of vascular damage and impediments to osteocytes, ultimately predisposing patients to the debilitating problems of late pathologic fractures and nonunions. We posit that angiogenic therapy will reverse these pathologic effects in a rat model of radiated fracture healing. METHODS: Three groups of rats underwent mandibular osteotomy. Radiated groups received a fractionated 35-Gy dose before surgery. The deferoxamine (DFO) group received local injections postoperatively. A 40-day healing period was allowed before histology. Analysis of variance (ANOVA; p < .05) was used for group comparisons. RESULTS: Radiated fractures revealed a significantly decreased osteocyte count and corresponding increase in empty lacunae when compared to nonradiated fractures (p = .001). With the addition of DFO, these differences were not appreciated. Further, a 42% increase in bony unions was observed after DFO therapy. CONCLUSION: Targeting angiogenesis is a useful means for promoting osteocyte survival and preventing bone pathology after XRT. PMID- 24801671 TI - First trimester markers of preeclampsia in twins: maternal mean arterial pressure and uterine artery Doppler pulsatility index. AB - OBJECTIVE: This study aims to evaluate the distribution of mean arterial pressure (MAP) and uterine artery Doppler pulsatility index (PI) in first trimester twins with and without preeclampsia. METHOD: A total of 147 twins were recruited from a specialist clinic and 110 unaffected singleton pregnancies attending the same institution served as controls. MAP and Doppler PI values were expressed in multiples of the gestation-specific median using published equations. RESULTS: Among the twins, 12 had preeclampsia and two had pregnancy-induced hypertension. Among unaffected pregnancies, there was no significant difference in MAP levels between twins and singletons (P = 0.17, Wilcoxon rank sum test, two-tail). However, the Doppler PI levels were highly statistically significantly lower than in singletons (P < 0.0005). MAP was unrelated to chorionicity (P = 0.46), but there was a statistically significant increase in Doppler PI among monochorionic compared with dichorionic twins (P < 0.01). In twins with preeclampsia, MAP was significantly higher than in unaffected twins (P < 0.02, one-tail), whereas Doppler PI levels were significantly reduced (P < 0.01, two-tail). CONCLUSION: If first trimester screening for preeclampsia is extended to twins, a different normal median Doppler PI equation will be needed. Contrary to expectations, Doppler PI levels may not be raised in affected twins, although this needs confirmation in a larger study. PMID- 24801672 TI - Updates to the guidelines for the diagnosis and management of multiple myeloma. PMID- 24801673 TI - Radiation safety protocol using real-time dose reporting reduces patient exposure in pediatric electrophysiology procedures. AB - Radiation exposure during pediatric catheterization is significant. We sought to describe radiation exposure and the effectiveness of radiation safety protocols in reducing exposure during catheter ablations with electrophysiology studies in children and patients with congenital heart disease. We additionally sought to identify at-risk patients. We retrospectively reviewed all interventional electrophysiology procedures performed from April 2009 to September 2011 (6 months preceding intervention, 12 months following implementation of initial radiation safety protocol, and 8 months following implementation of modified protocol). The protocols consisted of low pulse rate fluoroscopy settings, operator notification of skin entrance dose every 1,000 mGy, adjusting cameras by >5 at every 1,000 mGy, and appropriate collimation. The cohort consisted of 291 patients (70 pre-intervention, 137 after initial protocol implementation, 84 after modified protocol implementation) at a median age of 14.9 years with congenital heart disease present in 11 %. Diagnoses included atrioventricular nodal reentrant tachycardia (25 %), atrioventricular reentrant tachycardia (61 %), atrial tachycardias (12 %), and ventricular tachycardia (2 %). There were no differences between groups based on patient, arrhythmia, and procedural characteristics. Following implementation of the protocols, there were significant reductions in all measures of radiation exposure: fluoroscopy time (17.8 %), dose area product (80.2 %), skin entry dose (81.0 %), and effective dose (76.9 %), p = 0.0001. Independent predictors of increased radiation exposure included larger patient weight, longer fluoroscopy time, and lack of radiation safety protocol. Implementation of a radiation safety protocol for pediatric and congenital catheter ablations can drastically reduce radiation exposure to patients without affecting procedural success. PMID- 24801674 TI - Development and validation of a fetal cardiovascular disease severity scale. AB - Prenatal heart disease spans the spectrum of severity from very mild to severe life-threatening conditions. An accepted scale for grading fetal cardiovascular disease severity would aid in anomaly standardization, counseling, and future research. The Fetal Cardiovascular Disease Severity Scale with seven severity grades ranging from mild (grade 1) to severe (grade 7) disease was developed. Severity grade relates to the cardiovascular condition diagnosed by fetal echocardiography, with factors including postnatal intervention, number of interventions anticipated, likelihood of two-ventricle repair versus single ventricle palliation, and overall prognosis. A survey describing 25 cardiac anomalies was offered to fetal cardiologists at six institutions for validation of scale reliability among practitioners. The study participants graded defects using this scale. A smaller group graded anomalies again more than 2 weeks after the initial survey. The intraclass correlation coefficient (ICC) was used to assess agreement of the respondents. The survey participants were 14 experienced fetal cardiologists: 9 from the Children's Hospital of Philadelphia (CHOP) and 5 from five additional institutions in the United States. The initial survey ICC was high [0.93; 95 % confidence interval (CI) 0.88-0.96]. The subanalysis showed a higher ICC for the participants outside CHOP (0.95; 95 % CI 0.91-0.98 vs. 0.92; 95 % CI 0.86-0.96, respectively). The ICCs were high for all the fetal cardiologists participating in the repeat evaluation, ranging from 0.92 to 0.99 (95 % CI 0.65-1.00). The Fetal Cardiovascular Disease Severity Scale demonstrated good inter- and intrarater reliability among experienced fetal cardiologists and is a valid tool for standardization of prenatal cardiac diagnostic assessment across institutions. The scale has applications for parental counseling and research in fetal cardiovascular disease. PMID- 24801675 TI - Surgical outcomes for patients with Turner syndrome. PMID- 24801677 TI - CaHASE: a Specialist Society Led Academic Collaboration to improve the management of CAH. PMID- 24801676 TI - Function and expression of sulfonylurea, adrenergic, and glucagon-like peptide 1 receptors in isolated porcine islets. AB - The scarcity of human cadaveric pancreata limits large-scale application of islet transplantation for patients with diabetes. Islets isolated from pathogen-free pigs provide an economical and abundant alternative source assuming immunologic barriers are appropriate. Membrane receptors involved in insulin secretion that also have potential as imaging targets were investigated in isolated porcine islets. Quantitative (q)PCR revealed that porcine islets express mRNA transcripts for sulfonylurea receptor 1 (Sur1), inward rectifying potassium channel (Kir6.2, associated with Sur1), glucagon-like peptide 1 receptor (GLP1R), and adrenergic receptor alpha 2A (ADRalpha2A). Receptor function was assessed in static incubations with stimulatory glucose concentrations, and in the presence of receptor agonists. Glibenclamide, an anti-diabetic sulfonylurea, and exendin-4, a GLP-1 mimetic, potentiated glucose-stimulated insulin secretion >2-fold. Conversely, epinephrine maximally reduced insulin secretion 72 +/- 9% (P < 0.05) and had a half maximal inhibitory concentration of 60 nm in porcine islets (95% confidence interval of 45-830 nm). The epinephrine action was inhibited by the ADRalpha2A antagonist yohimbine. Our findings demonstrate that porcine islets express and are responsive to both stimulatory and inhibitory membrane localized receptors, which can be used as imaging targets after transplantation or to modify insulin secretion. PMID- 24801678 TI - Alteration of flower color in Iris germanica L. 'Fire Bride' through ectopic expression of phytoene synthase gene (crtB) from Pantoea agglomerans. AB - KEY MESSAGE: Genetic modulation of the carotenogenesis in I. germanica 'Fire Bride' by ectopic expression of a crtB gene causes several flower parts to develop novel orange and pink colors. Flower color in tall bearded irises (Iris germanica L.) is determined by two distinct biochemical pathways; the carotenoid pathway, which imparts yellow, orange and pink hues and the anthocyanin pathway, which produces blue, violet and maroon flowers. Red-flowered I. germanica do not exist in nature and conventional breeding methods have thus far failed to produce them. With a goal of developing iris cultivars with red flowers, we transformed a pink iris I. germanica, 'Fire Bride', with a bacterial phytoene synthase gene (crtB) from Pantoea agglomerans under the control of the promoter region of a gene for capsanthin-capsorubin synthase from Lilium lancifolium (Llccs). This approach aimed to increase the flux of metabolites into the carotenoid biosynthetic pathway and lead to elevated levels of lycopene and darker pink or red flowers. Iris callus tissue ectopically expressing the crtB gene exhibited a color change from yellow to pink-orange and red, due to accumulation of lycopene. Transgenic iris plants, regenerated from the crtB-transgenic calli, showed prominent color changes in the ovaries (green to orange), flower stalk (green to orange), and anthers (white to pink), while the standards and falls showed no significant differences in color when compared to control plants. HPLC and UHPLC analysis confirmed that the color changes were primarily due to the accumulation of lycopene. In this study, we showed that ectopic expression of a crtB can be used to successfully alter the color of certain flower parts in I. germanica 'Fire Bride' and produce new flower traits. PMID- 24801679 TI - A laminated polymer film formulation for enteric delivery of live vaccine and probiotic bacteria. AB - Live bacterial cells (LBCs) are administered orally as attenuated vaccines to deliver biopharmaceutical agents and as probiotics to improve gastrointestinal (GI) health. However, LBCs present unique formulation challenges and must survive GI antimicrobial defenses including gastric acid after administration. We present a simple new formulation concept, termed polymer film laminate (PFL). LBCs are ambient dried onto cast acid-resistant enteric polymer films that are then laminated together to produce a solid oral dosage form. LBC of a model live bacterial vaccine and a probiotic were dried directly onto a cast film of enteric polymer. The effectiveness at protecting dried cells in a simulated gastric fluid (SGF, pH 2.0) depended on the composition of enteric polymer film used, with a blend of ethylcellulose plus Eudragit L100 55 providing greater protection from acid than Eudragit alone. However, although PFL made from blended polymer films completely released low-molecular-weight dye into intestinal conditions (pH 7.0), they failed to release LBCs. In contrast, PFL made from Eudragit alone successfully protected dried probiotic or vaccine LBC from SGF for 2 h, and subsequently released all viable cells within 60 min of transfer into simulated intestinal fluid. Release kinetics could be controlled by modifying the lamination method. PMID- 24801680 TI - Pedicle subtraction osteotomy in the lumbar spine: indications, technical aspects, results and complications. AB - Pedicle subtraction osteotomy (PSO) consists of creating posteriorly trapezoidal shape of a vertebra, usually L3 or L4, in order to recreate lordosis in the lumbar spine. It is usually indicated to treat rigid kyphotic lumbar spine associated with sagittal imbalance and due to degenerative changes or to iatrogenic flat back. PSO is technically demanding with high rates of complications and should be performed by experienced teams. We presently report our experience about PSO performed in the lumbar spine (below L1) through a series of 25 cases with a special focus on technical aspects and complications associated with the surgical procedure. Mean age was 64 +/- 11 years old. PSO was performed at L4 in the majority of cases. Mean blood loss was 1,070 +/- 470 ml, and mean duration of the surgery was 241 +/- 44 min. VAS decreased from 7.5 +/- 2 preoperatively to 3.2 +/- 2.5 at 1 year, and ODI decreased from 64 +/- 12 preoperatively to 32 +/- 18 at 1 year, p < 0.05. Mean gain of lordosis after PSO varies from 20 degrees to 40 degrees and was measured to 27 degrees +/- 10 degrees on average. Lumbar lordosis (T12-S1) was measured to 21 degrees +/- 10 degrees preoperatively to 50 degrees +/- 11 degrees postoperatively at 1 year, p < 0.05. A total of five major complications (20 %) were observed (two mechanical, one neurological and two infections) necessitating five reoperations. In conclusion, PSO was highly efficient to restore lumbar lordosis and correct sagittal imbalance. It was associated with a non-negligible, but acceptable rate of complications. To limit the risk of mechanical complications, we recommend fusing the adjacent disks whatever the approach (PLIF/TLIF/XLIF). Most complications can be reduced with adequate environment, informed anesthesiologists and experienced surgical team. PMID- 24801681 TI - Developing leaders as systems thinkers-part II. AB - Continued from last month's column in which the demand for nurses as systems thinkers was defined, this month's discussion now focuses on four systems thinking competencies. Having determined the differences between systematic thinking and systems thinking, these competencies will aid professional development educators in advancing systems thinking content and evaluation into programs. PMID- 24801683 TI - Sequential projection pursuit with kernel matrix update and symbolic model selection. AB - This paper proposes a novel way for generating reliable low-dimensional features with improved class separability in a kernel-induced feature space. The feature projections rely on a very efficient sequential projection pursuit method, adapted to support nonlinear projections using a new kernel matrix update scheme. This enables the gradual removal of structure from the space of residual dimensions to allow the recovery of multiple projections. An adaptive kernel function is employed to unfold different types of data characteristics. We follow a holistic model selection procedure that, together with the optimal projections, dimensionality, and kernel parameters, additionally optimizes symbolically the projection index that controls the actual measurement of the data interestingness without user interaction. We tackle the underlying complex bi-level optimization model as a mixture of evolutionary and gradient search. The effectiveness of the proposed algorithm over existing approaches is demonstrated with benchmark evaluations and comparisons. PMID- 24801682 TI - Modeling the electric potential across neuronal membranes: the effect of fixed charges on spinal ganglion neurons and neuroblastoma cells. AB - We present a model for the electric potential profile across the membranes of neuronal cells. We considered the resting and action potential states, and analyzed the influence of fixed charges of the membrane on its electric potential, based on experimental values of membrane properties of the spinal ganglion neuron and the neuroblastoma cell. The spinal ganglion neuron represents a healthy neuron, and the neuroblastoma cell, which is tumorous, represents a pathological neuron. We numerically solved the non-linear Poisson-Boltzmann equation for the regions of the membrane model we have adopted, by considering the densities of charges dissolved in an electrolytic solution and fixed on both glycocalyx and cytoplasmic proteins. Our model predicts that there is a difference in the behavior of the electric potential profiles of the two types of cells, in response to changes in charge concentrations in the membrane. Our results also describe an insensitivity of the neuroblastoma cell membrane, as observed in some biological experiments. This electrical property may be responsible for the low pharmacological response of the neuroblastoma to certain chemotherapeutic treatments. PMID- 24801684 TI - Can endoscopic ultrasound distinguish between mediastinal benign lymph nodes and those involved by sarcoidosis, lymphoma, or metastasis? AB - BACKGROUND: Lymph nodes (LNs) echofeatures on endoscopic ultrasound (EUS) and concurrent fine needle aspiration (FNA) are alternatives to highly invasive approaches for etiologic diagnosis of mediastinal lymphadenopathy (MLAD). AIMS: To evaluate the efficacy of LNs echofeatures and FNA via EUS to distinguish benign LNs from LNs involved by sarcoidosis, lymphoma, and metastasis in non-lung cancer patients. METHODS: A retrospective review of patients who underwent EUS FNA for MLAD was performed. Echofeatures of LNs including echogenicity, margins, shape, and LN size were recorded. Final diagnosis was made based on surgical sampling or clinical diagnosis with long-term follow-up. Only patients diagnosed as benign MLAD, sarcoidosis, lymphoma, and metastasis included. Diagnostic value of echofeatures and FNA was evaluated. RESULTS: Included were 162 patients with final diagnosis of benign (68), sarcoidosis (33), lymphoma (20), and metastasis (41). The median LN along axis in the benign group [20.5 mm (6-76)] was significantly shorter than in the metastasis [28 mm (9-82)] and sarcoidosis [27 mm (17-50)] groups (p < 0.05). The median LN short axis in the benign group [11 mm (2-50)] was significantly shorter than in the metastasis [17 mm (5-44)] and lymphoma [16 mm (7-47)] groups (p < 0.05). No other echofeatures showed a discriminant value among the groups. When performing FNA, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EUS-FNA were 73.7, 100, 100, 72.2, and 84.4 %, respectively. CONCLUSION: Although benign MLAD tend to be smaller than other etiologies, echofeatures of LNs are not reliable etiologic diagnostic approach to MLAD. Therefore, FNA is suggested when feasible. However, due to relatively low sensitivity, LNs with benign FNA results should be subjected to further work-up if they are clinically suspicious. PMID- 24801685 TI - Adiponectin inhibits murine pancreatic cancer growth. AB - BACKGROUND: Adiponectin is an adipose tissue-derived secretory hormone whose plasma concentrations are lower in obese individuals. Obesity is a risk factor for the development and growth of pancreatic cancer, and hypoadiponectinemia was suggested to be involved in the growth of Pan02 murine pancreatic cancer cells that were inoculated into the flanks of congenitally obese mice. AIM: The aim of this study was to clarify the role of adiponectin in the growth of pancreatic cancer cells. METHODS: We examined the effect of adiponectin on the growth of Pan02 cells using recombinant adiponectin and adiponectin knockout mice. RESULTS: The in vitro treatment of Pan02 cells with adiponectin inhibited cellular proliferation that was accompanied by increased apoptosis and caspase-3 and caspase-7 activities. Transplantation of Pan02 cells into the pancreas of knockout mice resulted in a larger tumor volume with fewer terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells compared with wild-type mice. CONCLUSIONS: The results indicate that adiponectin directly suppresses the proliferation of Pan02 cells. PMID- 24801686 TI - Black esophagus: an unexpected complication in an orthotopic liver transplant patient with hemorrhagic shock. PMID- 24801687 TI - Intravenous ilaprazole is more potent than oral ilaprazole against gastric lesions in rats. AB - BACKGROUND AND AIMS: Ilaprazole is a novel proton pump inhibitor that has been marketed as an oral therapy for acid-related diseases in China and Korea. This study aimed to compare the gastroprotective effects of intravenous and enteral ilaprazole in rat models. METHODS: The rats were divided into 7-8 groups receiving vehicle, esomeprazole, and different doses of intravenous and enteral ilaprazole. The rats were then exposed to indomethacin (30 mg/kg, i.g.), or water immersion stress and gastric lesions were examined. The effects of different treatments on histamine (10 MUmol/kg/h)-induced acid secretion were also observed. RESULTS: Intravenous ilaprazole exhibited high antiulcer activity in a dose-dependent manner. Ilaprazole at a dose of 3 mg/kg decreased ulcer number and index to the same extent as 20 mg/kg esomeprazole. Moreover, the potency of intravenous ilaprazole is superior to that of intragastric ilaprazole. In anesthetized rats, the inhibitory effect of intravenous ilaprazole on histamine induced acid secretion is faster and longer-lasting than that of intraduodenal ilaprazole. CONCLUSION: Intravenous ilaprazole is more potent than oral ilaprazole against indomethacin- or stress-induced gastric lesions, with faster and longer inhibition of acid secretion. PMID- 24801689 TI - Crystallography in Switzerland and elsewhere from 1912 to 2013 and beyond. PMID- 24801690 TI - 'Seeing' atoms: the crystallographic revolution. AB - Laue's experiment in 1912 of the diffraction of X-rays by crystals led to one of the most influential discoveries in the history of science: the first determinations of crystal structures, NaCl and diamond in particular, by W. L. Bragg in 1913. For the first time, the visualisation of the structure of matter at the atomic level became possible. X-ray diffraction provided a sort of microscope with atomic resolution, atoms became observable physical objects and their relative positions in space could be seen. All branches of science concerned with matter, solid-state physics, chemistry, materials science, mineralogy and biology, could now be firmly anchored on the spatial arrangement of atoms. During the ensuing 100 years, structure determination by diffraction methods has matured into an indispensable method of chemical analysis. We trace the history of the development of 'small-structure' crystallography (excepting macromolecular structures) in Switzerland. Among the pioneers figure Peter Debye and Paul Scherrer with powder diffraction, and Paul Niggli and his Zurich School with space group symmetry and geometrical crystallography. Diffraction methods were applied early on by chemists at the Universities of Bern and Geneva. By the 1970s, X-ray crystallography was firmly established at most Swiss Universities, directed by full professors. Today, chemical analysis by structure determination is the task of service laboratories. However, the demand of diffraction methods to solve problems in all disciplines of science is still increasing and powerful radiation sources and detectors are being developed in Switzerland and worldwide. PMID- 24801688 TI - TGFbeta activated kinase 1 (TAK1) at the crossroad of B cell receptor and Toll like receptor 9 signaling pathways in human B cells. AB - B cell development and activation are regulated by combined signals mediated by the B cell receptor (BCR), receptors for the B-cell activating factor of the tumor necrosis factor family (BAFF-R) and the innate receptor, Toll-like receptor 9 (TLR9). However, the underlying mechanisms by which these signals cooperate in human B cells remain unclear. Our aim was to elucidate the key signaling molecules at the crossroads of BCR, BAFF-R and TLR9 mediated pathways and to follow the functional consequences of costimulation.Therefore we stimulated purified human B cells by combinations of anti-Ig, B-cell activating factor of the tumor necrosis factor family (BAFF) and the TLR9 agonist, CpG oligodeoxynucleotide. Phosphorylation status of various signaling molecules, B cell proliferation, cytokine secretion, plasma blast generation and the frequency of IgG producing cells were investigated. We have found that BCR induced signals cooperate with BAFF-R- and TLR9-mediated signals at different levels of cell activation. BCR and BAFF- as well as TLR9 and BAFF-mediated signals cooperate at NFkappaB activation, while BCR and TLR9 synergistically costimulate mitogen activated protein kinases (MAPKs), ERK, JNK and p38. We show here for the first time that the MAP3K7 (TGF beta activated kinase, TAK1) is responsible for the synergistic costimulation of B cells by BCR and TLR9, resulting in an enhanced cell proliferation, plasma blast generation, cytokine and antibody production. Specific inhibitor of TAK1 as well as knocking down TAK1 by siRNA abrogates the synergistic signals. We conclude that TAK1 is a key regulator of receptor crosstalk between BCR and TLR9, thus plays a critical role in B cell development and activation. PMID- 24801691 TI - Crystallographic services and technology support for industry. AB - The activities of CSEM's XRD Application Lab are oriented towards the analytical support of technology and product development in the fields of materials sciences, microtechnology, physics, chemistry, nanotechnology and life sciences. Non-destructive X-ray diffraction methods are used for the structural investigation of materials, components and systems. New developments are made with a focus on in situ techniques to 'watch the action' - structural transformations in dependence of applied external fields such as temperature, humidity, magnetic fields or mechanical stresses. PMID- 24801692 TI - Solving the structures of polycrystalline materials: from the Debye-Scherrer camera to SwissFEL. AB - The development of powder diffraction (PD) techniques for structure analysis is traced from its inception almost 100 years ago to the present day, with a brief glimpse of what SwissFEL can contribute in the near future. Although PD data were used in the early days to deduce some simple high-symmetry structures, it was not until computers, instrumentation and synchrotrons arrived on the scene that the true potential of PD data could be realized. In the last 25 years, PD has blossomed into a viable method, not only for structure refinement, but also for structure solution. This means that scientists with polycrystalline materials that cannot be grown as single crystals can still obtain the structural information they need. Historically, structure solution from PD data began with model building, progressed through the application of single-crystal methods to simpler structures and the adaptation of those methods to the special problems posed by PD data, the development of automated model-building algorithms, and most recently to the application of charge flipping. As X-ray sources and detectors continue to develop, the boundary between a powder and a single crystal is narrowing. Laue microdiffraction techniques and the prospects offered by SwissFEL will allow single-crystal data to be collected on some polycrystalline materials. PMID- 24801693 TI - Absolute-structure determination: past, present and future. AB - Single-crystal X-ray crystallography is the major analytical technique in use today for absolute-configuration determination. The origins of absolute-structure determination, starting from Friedel's 1913 proof that the intensities of the opposites hkl and hkl are identical, are traced. The important structural principles derived from the study of chiral, but pseudo-mirror symmetric, methyprylon are described. For the present time, the use of the average and difference intensities of the opposites hkl and hkl are stressed. This leads to the use of Friedif, of 2 AD and selected D plots, of Rmerge and the D-Patterson. The best techniques for absolute-structure determination in the future are described. Some advice to the scientific community concludes the paper. PMID- 24801694 TI - Crystallographic approaches for the investigation of molecular materials: structure property relationships and reverse crystal engineering. AB - This article discusses the connection between crystallography and material science. It sheds light on some of the research opportunities that are currently available and it critically reviews the directions taken by the scientific community in the field of crystal engineering. The focus is on materials formed by the assembly of organic and organometallic molecular building blocks. PMID- 24801695 TI - Complex hydrides - when powder diffraction needs help. AB - 'Real life' energy-related materials such as solid-state hydrogen storage compounds or components of electrochemical cells are usually polycrystalline, poorly crystallized, highly reactive and dynamic systems. Powder diffraction at modern high brilliance X-ray sources is the most useful tool to investigate such systems because it is easy, fast and extremely versatile with respect to measurement conditions as well as in situ setups. However, it is in the nature of these systems that they undergo processes that cannot be investigated by diffraction alone. The central role in hydrogen storage materials is played by hydrogen itself, the worst X-ray scatterer in the periodic system. Gas release, the purpose of a hydrogen storage material, is not detected by diffraction. Amorphous components are badly characterized. We want to show how a complementary approach combining different methods allows to overcome limitations imposed on powder diffraction by the sample nature of 'real' hydrogen storage materials. PMID- 24801696 TI - Quasicrystals - a paradigm shift in crystallography? AB - The discovery of quasicrystals had important consequences for our understanding of long-range order in thermodynamic equilibrium, the definition of the term 'crystal' as well as diffraction theory. Quasicrystals have been observed not only at the atomic scale in binary and ternary intermetallic systems, but also at the mesoscale in self-assembled colloids and block-copolymers, and even at the macroscale in packings of hard polyhedra. How important was the discovery of quasicrystals for crystallography? Did it usher in a scientific revolution and a paradigm shift? These questions are discussed following a short overview of the status of quasicrystal research. PMID- 24801697 TI - Stereochemistry of 2D molecular crystallization. AB - Different stereochemical aspects of molecular recognition in two-dimensional crystallization on metal surfaces are discussed. Scanning tunneling microscopy, a powerful tool with submolecular resolution capabilities, provides detailed insight into the implications of molecular geometry for the two-dimensional crystal lattice. The examples presented here include a homo- to heterochiral phase transition, tiling with pentagonal molecules, chiral restructuring of a metal surface and diastereomeric recognition between enantiomers of different molecular species via polar forces as well as van der Waals interactions. PMID- 24801698 TI - Biocrystallography in Switzerland: achievements and future perspectives. AB - The first protein crystallography group in Switzerland was installed at the Biozentrum of the University of Basel approximately 40 years ago. Since then protein crystallography has grown and matured remarkably and is now established in the molecular biology, biochemistry or biological medicine departments of most major Swiss Universities as well as in the pharmaceutical industry and in biotech startup companies. Swiss X-ray biocrystallography groups have made remarkable contributions from the beginning and have brought Switzerland to the forefront in biostructural research during the last 5 to 10 years. Switzerland has now a leading position in the areas of supramolecular complexes, membrane proteins and structure-based drug design in pharmaceutical and biotech industries. Protein crystallography on the outer membrane protein ompF as well as the development of the lipidic cubic phase crystallization methodology has been pioneered at the Biozentrum. The latter found its somewhat late recognition through the recent explosion in structure determinations of the seven transmembrane helix G-coupled receptors. Highlights from Swiss structural biology groups in the field of supramolecular complexes include the structures of ribosomal particles, of the nucleosome and the pilus assembly complex of uropathogenic E. coli. On the membrane protein side advances in the field of ABC transporters and ion channels are world-recognized achievements of Swiss structural biology. Dedicated laboratories at many academic and industrial institutions, their current research programs, the availability of excellent infrastructure and the continuing efforts to build new facilities such as the SwissFEL indicate an even brighter future for structural biology in Switzerland. PMID- 24801699 TI - Crystallography beyond the Bragg peaks. AB - Diffuse scattering contains information on the real structure of disordered crystals that cannot be deduced from conventional structure analysis based on Bragg reflections. In this article the historical development, current state-of the-art and future perspectives of diffuse scattering are described. The focus is on the last twenty years, in which progress in X-ray instrumentation and computer aided modeling has transformed diffuse scattering research from a qualitative to a quantitative discipline. Examples of cutting edge diffuse scattering experiments and modern real structure modeling techniques are given. PMID- 24801700 TI - Coherent X-ray imaging: bridging the gap between atomic and micro-scale investigations. AB - We present a review of state-of-the art X-ray imaging techniques based on partially coherent synchrotron radiation. Full-field X-ray tomography, X-ray ptychography, scanning small-angle X-ray scattering, and scanning transmission X ray microscopy are imaging techniques that gather structural information at spatial resolution ranging from several microns to a few tens of nanometers in both real- and reciprocal space. These methods exploit contrast mechanisms based on absorption, phase, and spectroscopic signals. We provide examples of how these techniques can be applied to address scientific questions ranging from imaging of biological samples, to foam rheology, and cement composition. PMID- 24801701 TI - Science opportunities at the SwissFEL X-ray Laser. AB - Next-generation X-ray sources, based on the X-ray Free Electron Laser (XFEL) concept, will provide highly coherent, ultrashort pulses of soft and hard X-rays with peak intensity many orders of magnitude higher than that of a synchrotron. These pulses will allow studies of femtosecond dynamics at nanometer resolution and with chemical selectivity. They will produce diffraction images of organic and inorganic nanostructures without deleterious effects of radiation damage. PMID- 24801702 TI - Investigating the antioxidant capacity of coffee! AB - In the 1990s we began to understand that free radical damage is involved in artery-clogging atherosclerosis and health problems like vision loss, cancer or chronic diseases. Studies have shown that the damage especially affects people with a low consumption of antioxidant-rich fruits, vegetables...and coffee. Is this just a fairy tale promoted by the coffee industry? Scientists at the Zurich University of Applied Sciences (ZHAW) in Wadenswil wanted to get to the bottom of the question. PMID- 24801707 TI - Transcriptome from circulating cells suggests dysregulated pathways associated with long-term recurrent events following first-time myocardial infarction. AB - BACKGROUND: Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for high risk cardiovascular diseases. However, the feasibility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome. METHODS AND RESULTS: Whole-genome expression microarray on blood samples from normal cardiac function controls (n=21) and first-time AMI patients (n=31) within 48-hours post MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways. To determine molecular signatures at the time of AMI associated with long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially expressed genes. Bioinformatic analysis of this differential gene-set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of genes involved in the developmental epithelial-to-mesenchymal transition pathway, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome. CONCLUSION: Differentially regulated genes and modulated pathways were identified that were associated with recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients and warrants further study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes. PMID- 24801708 TI - Copper-catalyzed regioselective ortho C-H cyanation of vinylarenes. AB - A copper-based catalytic technique for the regioselective ortho C-H cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper-catalyzed cyanative dearomatization mechanism is proposed to account for the regiochemical course of this reaction. PMID- 24801709 TI - Multimodality multiparametric imaging of early tumor response to a novel antiangiogenic therapy based on anticalins. AB - Anticalins are a novel class of targeted protein therapeutics. The PEGylated Anticalin Angiocal (PRS-050-PEG40) is directed against VEGF-A. The purpose of our study was to compare the performance of diffusion weighted imaging (DWI), dynamic contrast enhanced magnetic resonance imaging (DCE)-MRI and positron emission tomography with the tracer [18F]fluorodeoxyglucose (FDG-PET) for monitoring early response to antiangiogenic therapy with PRS-050-PEG40. 31 mice were implanted subcutaneously with A673 rhabdomyosarcoma xenografts and underwent DWI, DCE-MRI and FDG-PET before and 2 days after i.p. injection of PRS-050-PEG40 (n = 13), Avastin (n = 6) or PBS (n = 12). Tumor size was measured manually with a caliper. Imaging results were correlated with histopathology. In the results, the tumor size was not significantly different in the treatment groups when compared to the control group on day 2 after therapy onset (P = 0.09). In contrast the imaging modalities DWI, DCE-MRI and FDG-PET showed significant differences between the therapeutic compared to the control group as early as 2 days after therapy onset (P<0.001). There was a strong correlation of the early changes in DWI, DCE-MRI and FDG-PET at day 2 after therapy onset and the change in tumor size at the end of therapy (r = -0.58, 0.71 and 0.67 respectively). The imaging results were confirmed by histopathology, showing early necrosis and necroptosis in the tumors. Thus multimodality multiparametric imaging was able to predict therapeutic success of PRS-050-PEG40 and Avastin as early as 2 days after onset of therapy and thus promising for monitoring early response of antiangiogenic therapy. PMID- 24801710 TI - Successful human long-term application of in situ bone tissue engineering. AB - Tissue Engineering (TE) and Regenerative Medicine (RM) have gained much popularity because of the tremendous prospects for the care of patients with tissue and organ defects. To overcome the common problem of donor-site morbidity of standard autologous bone grafts, we successfully combined tissue engineering techniques for the first time with the arteriovenous loop model to generate vascularized large bone grafts. We present two cases of large bone defects after debridement of an osteomyelitis. One of the defects was localized in the radius and one in the tibia. For osseus reconstruction, arteriovenous loops were created as vascular axis, which were placed in the bony defects. In case 1, the bone generation was achieved using cancellous bone from the iliac crest and fibrin glue and in case 2 using a clinically approved beta tricalciumphosphate/hydroxyapatite (HA), fibrin glue and directly auto transplanted bone marrow aspirate from the iliac crest. The following post operative courses were uneventful. The final examinations took place after 36 and 72 months after the initial operations. Computer tomogrphy (CT), membrane resonance imaging (MRI) and doppler ultrasound revealed patent arterio-venous (AV) loops in the bone grafts as well as completely healed bone defects. The patients were pain-free with normal ranges of motion. This is the first study demonstrating successfully axially vascularized in situ tissue engineered bone generation in large bone defects in a clinical scenario using the arteriovenous loop model without creation of a significant donor-site defect utilizing TE and RM techniques in human patients with long-term stability. PMID- 24801712 TI - Bronsted acid ionic liquid as a solvent-conserving catalyst for organic reactions. AB - A sulfonyl-containing ammonium-based Bronsted acid ionic liquid was prepared and used as a liquid heterogeneous catalyst for organic reactions. The unique macroscopic phase heterogeneity of the IL in the reaction system not only ensures an excellent catalytic activity of the IL catalyst but also avoids the use of organic reaction solvents. The catalyst system is applicable for a wide range of reactions. PMID- 24801711 TI - Pathway of programmed cell death and oxidative stress induced by beta hydroxybutyrate in dairy cow abomasum smooth muscle cells and in mouse gastric smooth muscle. AB - The administration of exogenous beta-hydroxybutyrate (beta-HB), as well as fasting and caloric restriction, is a condition associated with beta-HB abundance and decreased appetite in animals. Increased beta-HB and decreased appetite exist simultaneously in some diseases, such as bovine left displaced abomasums (LDA) and human chronic gastritis. However, the effects of beta-HB on stomach injuries have not been explored. To elucidate the possible effects of exogenous beta-HB on the stomach, mice were injected intraperitoneally with beta-HB, and bovine abomasum smooth muscle cells (BSMCs) were treated with different concentrations of beta-HB. We found that beta-HB induced BSMCs endoplasmic reticulum- and mitochondria-mediated apoptotic cell death. beta-HB promoted Bax expression and caspase-12, -9, and -3 activation while blocking Bcl-2 expression. beta-HB also promoted AIF, EndoG release and p53 expression. beta-HB acted on key molecules in the apoptotic cell death pathway and increased p38 and c-June NH2-terminal kinase phosphorylation while inhibiting ERK phosphorylation and PCNA expression. beta-HB upregulated P27 and P21 mRNA levels while downregulating cyclin and CDK mRNA levels, arresting the cell cycle. These results suggest that BSMCs treated with beta-HB can induce oxidative stress, which can be prevented by intracellular calcium chelators BAPTA/AM but not antioxidant NAC. Additionally, these results suggest that beta-HB causes ROS generation through a Ca2+-dependent mechanism and that intracellular Ca2+ levels play a critical role in beta-HB -induced apoptotic cell death. The impact of beta-HB on programmed cell death and oxidative stress in vivo was confirmed in murine experiments. For the first time, we show oxidative stress effects of beta-HB on smooth muscle. We propose that beta-HB is a possible cause of some stomach diseases, including bovine LDA. PMID- 24801713 TI - Platelet-derived growth factor receptor beta: a novel urinary biomarker for recurrence of non-muscle-invasive bladder cancer. AB - Non-muscle-invasive bladder cancer (NMIBC) is one of the most common malignant tumors in the urological system with a high risk of recurrence, and effective non invasive biomarkers for NMIBC relapse are still needed. The human urinary proteome can reflect the status of the microenvironment of the urinary system and is an ideal source for clinical diagnosis of urinary system diseases. Our previous work used proteomics to identify 1643 high-confidence urinary proteins in the urine from a healthy population. Here, we used bioinformatics to construct a cancer-associated protein-protein interaction (PPI) network comprising 16 high abundance urinary proteins based on the urinary proteome database. As a result, platelet-derived growth factor receptor beta (PDGFRB) was selected for further validation as a candidate biomarker for NMIBC diagnosis and prognosis. Although the levels of urinary PDGFRB showed no significant difference between patients pre- and post-surgery (n = 185, P>0.05), over 3 years of follow-up, urinary PDGFRB was shown to be significantly higher in relapsed patients (n = 68) than in relapse-free patients (n = 117, P<0.001). The levels of urinary PDGFRB were significantly correlated with the risk of 3-year recurrence of NMIBC, and these levels improved the accuracy of a NMIBC recurrence risk prediction model that included age, tumor size, and tumor number (area under the curve, 0.862; 95% CI, 0.809 to 0.914) compared to PDGFR alone. Therefore, we surmise that urinary PDGFRB could serve as a non-invasive biomarker for predicting NMIBC recurrence. PMID- 24801715 TI - Settled and unsettled issues in particle settling. AB - Colloid sedimentation has played a seminal role in the development of statistical physics thanks to the celebrated experiments by Perrin, which provided a concrete demonstration of molecular reality and gave strong support to Einstein's theory of Brownian motion. This review, which mostly focuses on settling at low Peclet number, where Brownian fluctuations are dominant, aims to show that a lot more can be learnt both from the sedimentation equilibrium and from the particle settling dynamics of a wide class of systems, ranging from simple colloids to mesogenic suspensions, from soft solids to active particles and living organisms. At the same time, the occurrence of unexpected and surprising effects brings about challenging questions in statistical and fluid mechanics that make sedimentation an exciting field of research. PMID- 24801714 TI - Voluntary medical male circumcision programs can address low HIV testing and counseling usage and ART enrollment among young men: lessons from Lesotho. AB - BACKGROUND: Early diagnosis of HIV and treatment initiation at higher CD4 counts improves outcomes and reduces transmission. However, Lesotho is not realizing the full benefits of ART because of the low proportion of men tested (40%). Public sector VMMC services, which were launched in district hospitals in February 2012 by the Lesotho MOH supported by USAID/MCHIP, include HIV testing with referral to care and treatment. The objective of this study was to better understand the contribution of VMMC services to HIV diagnosis and treatment. METHODS: VMMC clients diagnosed with HIV were traced after 6 months to ascertain whether they: (1) presented to the referral HIV center, (2) had a CD4 count done and (3) were enrolled on ART. Linkages between VMMC and HIV services were assessed by comparing the proportion of HIV-infected males referred from VMMC services with those from other hospital departments. RESULTS: Between March and September 2012, 72 men presenting for VMMC services tested positive for HIV, representing 65% of the total male tests at the hospital; 45 of these men (62.5%) received an immediate CD4 count and went to the HIV referral site; 40 (89%) were eligible for treatment and initiated ART. 27 clients did not have a CD4 count due to stock-out of reagents. Individuals who did not receive a CD4 count on the same day did not return to the HIV center. CONCLUSION: All VMMC clients testing positive for HIV and receiving a CD4 count on the testing day began ART. Providing VMMC services in a district hospital offering the continuum of care could increase diagnoses and treatment uptake among men, but requires an investment in communication between VMMC and ART clinics. In high HIV prevalence settings, investing in PIMA CD4 devices at integrated VMMC clinics is likely to increase male ART enrolment. PMID- 24801716 TI - Friends, Depressive Symptoms, and Life Satisfaction Among Older Korean Americans. AB - This study examined the interactive effects of social network support and depressive symptoms on life satisfaction among older Korean Americans (KAs). Using data from a sample of 200 elders in a large metropolitan area (M age = 72.50, SD = 5.15), hierarchical regression analysis was used to examine the interaction between social network support and depressive symptoms on life satisfaction among older KAs. After controlling for demographic variables, both social network support and depressive symptoms were identified as predictors for life satisfaction. Interaction effects indicated strong associations between higher social network support specifically from friends and lower depressive symptoms with higher levels of life satisfaction. Findings highlight the important role that friends play in terms of social network support for the mental health of older KAs, and the need for geriatric practitioners to monitor and assess the quality of social network support-including friendships-when working with older KAs. PMID- 24801717 TI - Longitudinal Associations Between Immigrant Ethnic Density, Neighborhood Processes, and Latino Immigrant Youth Depression. AB - Depression rates rise in adolescence and the prevalence of depression is higher among Latino adolescents than other race/ethnic groups. Ethnic density among immigrant populations is associated with better health and mental health outcomes among adults, but little is known about its effects among adolescents or its mechanisms. This study examines the pathways by which immigrant density may affect mental health outcomes among Latino youth. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we drew a sample of 2,678 Hispanic youth. Multivariate multilevel logistic regression analyses found that Latino immigrant density predicted lower odds of depression among both male and female immigrant but not non-immigrant Latino adolescents. No mediating effects of neighborhood efficacy, perceived safety or perceived contentment were observed in this study. Results reaffirm the need to further explore the mechanisms through which ethnic density exerts its salubrious effect on immigrant youth mental health. PMID- 24801718 TI - Haploinsufficiency of Def activates p53-dependent TGFbeta signalling and causes scar formation after partial hepatectomy. AB - The metazoan liver exhibits a remarkable capacity to regenerate lost liver mass without leaving a scar following partial hepatectomy (PH). Whilst previous studies have identified components of several different signaling pathways that are essential for activation of hepatocyte proliferation during liver regeneration, the mechanisms that enable such regeneration to occur without accompanying scar formation remain poorly understood. Here we use the adult zebrafish liver, which can regenerate within two weeks following PH, as a new genetic model to address this important question. We focus on the role of Digestive-organ-expansion-factor (Def), a nucleolar protein which has recently been shown to complex with calpain3 (Capn3) to mediate p53 degradation specifically in the nucleolus, in liver regeneration. Firstly, we show that Def expression is up-regulated in the wild-type liver following amputation, and that the defhi429/+ heteroozygous mutant (def+/-) suffers from haploinsufficiency of Def in the liver. We then show that the expression of pro-inflammatory cytokines is up-regulated in the def+/- liver, which leads to distortion of the migration and the clearance of leukocytes after PH. Transforming growth factor beta (TGFbeta) signalling is thus activated in the wound epidermis in def+/- due to a prolonged inflammatory response, which leads to fibrosis at the amputation site. Fibrotic scar formation in def+/- is blocked by the over-expression of Def, by the loss-of-function of p53, and by treatment with anti-inflammation drug dexamethasone or TGFbeta-signalling inhibitor SB431542. We finally show that the Def- p53 pathway suppresses fibrotic scar formation, at least in part, through the regulation of the expression of the pro-inflammatory factor, high-mobility group box 1. We conclude that the novel Def- p53 nucleolar pathway functions specifically to prevent a scar formation at the amputation site in a normal amputated liver. PMID- 24801719 TI - Optic nerve surface temperature during intradural anterior clinoidectomy: a comparison between high-speed diamond burr and ultrasonic bone curette. AB - Ultrasonic bone curettes are increasingly used in cranial base surgery. The heat generated by these devices during anterior clinoidectomy has not been evaluated. The purpose of this study was to compare the optic nerve surface temperature during intradural anterior clinoidectomy using the drill and ultrasonic bone curette. Ten fresh cadaver heads were used. During intradural clinoidectomy and optic nerve unroofing with either a 2-mm diamond burr drill or ultrasonic bone curette, temperature was measured along the medial cisternal and proximal intracanalicular segments of the optic nerve. Additional experiments were performed to determine optimal ultrasonic bone curette settings for anterior clinoidectomy. At the lateral cisternal segment, peak and mean temperature were significantly higher with the ultrasonic bone curette (peak 38.8 vs 29.3 degrees C, p = 0.03, mean 29.5 vs 22.6 degrees C, p = 0.003). At the proximal intracanalicular segment, only peak temperature was significantly higher with the ultrasonic bone curette (peak 32.0 vs 23.5 degrees C, p = 0.02, mean 26.9 vs 22.4 degrees C, p = 0.07). Using standard company settings, room temperature irrigation fluid was heated by the oscillating tip to peak temperature 36.1 degrees C without drilling. In order to maintain emitted irrigation fluid at room temperature, optimal settings were power 70 %, cool irrigation (5 degrees C) at 40 mL/min. Using these settings, the ultrasonic bone curette generated optic nerve surface temperature measurements similar to the drill. Further work is necessary to translate these findings into the operating room. PMID- 24801722 TI - Frontiers in atherosclerosis, heart disease and diabetes. PMID- 24801720 TI - Brainstem cavernoma surgery with the support of pre- and postoperative diffusion tensor imaging: initial experiences and clinical course of 23 patients. AB - The spatial complexity of highly vulnerable structures makes surgical resection of brainstem cavernomas (BSC) a challenging procedure. Diffusion tensor imaging (DTI) allows for the visualization of white matter tracts and enables a better understanding of the anatomical location of corticospinal and sensory tracts before and after surgery.We investigated the feasibility and clinical usefulness of DTI-based fiber tractography in patients with BSC.Pre- and postoperative DTI visualization of corticospinal and sensory tracts were retrospectively analyzed in 23 individuals with BSC. Preoperative and postoperative DTI-fiber accuracy were associated to the neurological findings. Preoperatively, the corticospinal tracts were visualized in 90 % of the cases and the sensory tracts were visualized in 74 % of the cases. Postoperatively, the corticospinal tracts were visualized in 97 % of the cases and the sensory tracts could be visualized in 80 % of the cases. In all cases, the BSC had caused displacement, thinning, or interruption of the fiber tracts to various degrees. Tract visualization was associated with pre- and postoperative neurological findings. Postoperative damage of the corticospinal tracts was observed in two patients. On follow-up, the Patzold Rating (PR) improved in 19 out of 23 patients (83 %, p = 0.0002).This study confirms that DTI tractography allows accurate and detailed white matter tract visualization in the brainstem, even when an intraaxial lesion affects this structure. Furthermore, visualizing the tracts adjacent to the lesion adds to our understanding of the distorted intrinsic brainstem anatomy and it may assists in planning the surgical approach in specific cases. PMID- 24801723 TI - Glucagon-like peptide-1 as a key regulator of lipid and lipoprotein metabolism in fasting and postprandial states. AB - Insulin resistance and the metabolic syndrome are associated with fasting and postprandial dyslipidemia. This involves the hepatic and intestinal overproduction of very low density lipoproteins (VLDL) and chylomicron particles, respectively, which give rise to atherogenic remnants upon lipolysis in the circulation. Recently, the insulin secretagogue glucagon-like peptide-1 (GLP-1) has received attention not only as an anti-diabetic therapy for regulating glycaemia, but also as a regulator of lipid and lipoprotein metabolism. In fact, agents that raise endogenous bioactive levels of GLP-1 (dipeptidyl peptidase 4 inhibitors) and agents that directly stimulate GLP-1 receptors (GLP-1 receptor agonists) have been assessed in both preclinical and clinical trials for their ability to modulate plasma lipid parameters. Here we describe current evidence supporting a role for GLP-1 in preventing elevated intestinal chylomicron output and postprandial hypertriglyceridemia--an independent predictor of cardiovascular risk. Furthermore, we examine a role for GLP-1 in regulating fasting hepatic VLDL production and hindering the development of a potentially devastating comorbidity, hepatic steatosis. Possible mechanisms of action of GLP-1 are discussed including a reduction in intestinal absorption of dietary lipid and enhanced hepatic fatty acid oxidation or autophagy. Finally, we discuss the current controversy over whether these effects could occur via direct receptor stimulation or alternative, indirect pathways. We conclude that GLP- 1-based therapies appear promising in the management of diabetic dyslipidemia, and further studies are warranted to elucidate their mechanisms of action in both the intestine and liver. PMID- 24801724 TI - Effects of diabetic HDL on endothelial cell function. AB - Type 2 diabetes mellitus (T2DM) is accompanied by dysfunctional high-density lipoprotein (HDL) and this is characterized by alterations in its composition and structure compared with HDL from normal subjects (N-HDL). HDL from diabetic subjects (D-HDL) has a diminished endothelial protective capacity including reducted ability to exert antioxidative activity, stimulate endothelial cell (EC) production of nitric oxide (NO) and endothelium-dependent vasomotion, promote endothelial progenitor cell (EPC)-mediated endothelial repair. In addition, D-HDL promotes EC proliferation, migration and adhesion to the matrix. The present review provides an overview of these effects of diabetic HDL on EC function, as well as the possible changes of D-HDL structure and composition which may be responsible for the diminished endothelial protective capacity of D-HDL. PMID- 24801725 TI - Cardiolipin metabolism and the role it plays in heart failure and mitochondrial supercomplex formation. AB - Cardiolipin is a major membrane phospholipid in the mitochondria and is essential for cellular energy metabolism mediated through mitochondrial oxidative phosphorylation. Recent studies indicate that it plays a diverse role in cellular metabolism. Eukaryotic cardiolipin is synthesized de novo from phosphatidic acid via the cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol pathway and is deacylated to monolysocardiolipin in order for it to be remodelled into the form that is observed in mitochondrial membranes. This resynthesis of deacylated cardiolipin from monolysocardiolipin occurs via the Barth Syndrome gene product tafazzin and acyllysocardiolipin acyltransferase-1, monolysocardiolipin acyltransferase-1 and the alpha subunit of trifunctional protein. Heart failure is a disease condition in which the amount and type of cardiolipin is altered. Several animal models have been generated to study the role of altered cardiolipin in heart failure. In many of these models loss of the tetralinoleoyl-cardiolipin species is observed during the development of the heart failure. In the doxycycline inducible short hairpin RNA tafazzin knock down mouse, loss of tetralinoleoyl-cardiolipin is associated with a mitochondrial bioenergetic disruption. Reduction in mitochondrial supercomplex formation and NADH dehydrogenase activity within these supercomplexes is observed. Modulation of CL fatty acyl composition may serve as a therapeutic strategy for the treatment of several pathologies including cardiac dysfunction.We propose that increasing cardiolipin may improve mitochondrial function and potentially serve as a therapy for diseases which exhibit mitochondrial dysfunction involving reduced cardiolipin. PMID- 24801726 TI - Endothelial cell regulation of cardiac metabolism following diabetes. AB - The earliest change that occurs in the diabetic heart is reduced glucose consumption, with a switch to utilization of fatty acids (FA) predominantly as an energy resource. Although this adaptation might be beneficial in the short-term, over a protracted duration, it is potentially catastrophic given the malicious effects produced by high FA in cardiomyocytes. In this review, we describe how the endothelial cell (EC), a "first-responder" to hyperglycemia, communicates with the underlying cardiomyocyte. As this cross-talk is expected to facilitate increased FA delivery to, and utilization by, the cardiomyocyte, understanding this conversationshould assist in devising new therapeutic strategies to prevent or delay diabetic heart disease. PMID- 24801727 TI - Caveolin-1 and ATP binding cassette transporter A1 and G1-mediated cholesterol efflux. AB - Atherosclerosis is one major cause of cardiovascular diseases, the leading cause of death in industrialized countries. Reverse cholesterol transport (RCT) is thought to be one primary pathway to protect against atherosclerosis. The first and rate-limiting step of RCT is ATP-binding cassette transport A1 (ABCA1) and ABCG1-mediated cholesterol efflux from the cells. Recently, caveolin-1 (CAV1), a scaffolding protein that organizes and concentrates certain caveolin-interacting signaling molecules and receptors within caveolae membranes, has been shown to regulate ABCA1 and ABCG1-mediated cholesterol efflux probably via interacting with them. In the present review, we summarize the current knowledge and views on the regulatory role of CAV1 on the cholesterol homeostasis with emphasis on the association of CAV1 with ABCA1 and ABCG1. We conclude that the dominance of the positive regulation by CAV1 on the ABCA1 and ABCG1-mediated cholesterol efflux is depending on the species, cell types, as well as the levels of CAV1 expression. PMID- 24801728 TI - Transcriptional control of collagen I gene expression. AB - Cardiac fibrosis is the pathological remodeling of the extracellular matrix (ECM) in response to stresses such as pressure overload or injury. While initially adaptive, myocardial remodeling and subsequent fibrosis causes increased wall stiffness, arrhythmias, cardiac dysfunction, and eventually heart failure. Though the disease processes and origins may differ, excess deposition of fibrillar collagens type I and III characterizes fibrosis in the heart, lungs, kidneys, liver, and skin. Under normal physiological conditions, high tensile strength collagen fibers maintain cardiac structural integrity, connect individual cardiomyocytes, transmit contractile force, and resist deformation and rupture of the ventricle during systole. Various factors contribute to the development of fibrosis by altering expression of ECM genes, including increased synthesis of pro-inflammatory cytokines, alterations in the levels of circulating hormones, and mechanical strain resulting from ECM degradation. This review focuses on the transcriptional mechanisms governing expression of the major cardiac collagen, type I. Key cis- and trans-acting regulators of collagen I gene expression are discussed. Surprisingly, relatively few transcriptional regulators of collagen synthesis have been identified specifically in cardiac fibroblasts. However, key players have been identified in other tissue and cell types, and are important to consider in elucidating the molecular mechanisms underpinning collagen gene expression in the heart in both health and disease. PMID- 24801729 TI - Histone methylation and transcriptional regulation in cardiovascular disease. AB - Cardiovascular disease (CVD) represents a major health risk to the global population. In disease settings, cells that constitute the vasculature undergo profound changes both morphologically and functionally paralleling alterations in gene expression profile. At the transcriptional level, gene expression is steered by the epigenetic machinery including DNA methyltransferases, histone variants, non-coding regulatory RNAs, chromatin remodeling complexes, and histone modifying enzymes. The N-terminal tails of histones, primarily histones H3 and H4, are post translationally modified creating a unique platform for transcriptional regulation. This review summarizes our current understanding of the role of histone methylation in modulating the vascular transcriptome and its relevance in CVD with an outlook on future directions. PMID- 24801730 TI - Fluorescence ratiometric sensor for trace vapor detection of hydrogen peroxide. AB - Trace vapor detection of hydrogen peroxide (H2O2) represents a practical approach to nondestructive detection of peroxide-based explosives, including liquid mixtures of H2O2 and fuels and energetic peroxide derivatives, such as triacetone triperoxide (TATP), diacetone diperoxide (DADP), and hexamethylene triperoxide diamine (HMTD). Development of a simple chemical sensor system that responds to H2O2 vapor with high reliability and sufficient sensitivity (reactivity) remains a challenge. We report a fluorescence ratiometric sensor molecule, diethyl 2,5 bis((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzyl)oxy)carbonyl)amino)terephthalate (DAT-B), for H2O2 that can be fabricated into an expedient, reliable, and sensitive sensor system suitable for trace vapor detection of H2O2. DAT-B is fluorescent in the blue region, with an emission maximum at 500 nm in the solid state. Upon reaction with H2O2, DAT-B is converted to an electronic "push-pull" structure, diethyl 2,5 diaminoterephthalate (DAT-N), which has an emission peak at a longer wavelength centered at 574 nm. Such H2O2-mediated oxidation of aryl boronates can be accelerated through the addition of an organic base such as tetrabutylammonium hydroxide (TBAH), resulting in a response time of less than 0.5 s under 1 ppm of H2O2 vapor. The strong overlap between the absorption band of DAT-N and the emission band of DAT-B enables efficient Forster resonance energy transfer (FRET), thus allowing further enhancement of the sensing efficiency of H2O2 vapor. The detection limit of a drop-cast DAT-B/TBAH film was projected to be 7.7 ppb. By combining high sensitivity and selectivity, the reported sensor system may find broad application in vapor detection of peroxide-based explosives and relevant chemical reagents through its fabrication into easy-to-use, cost effective kits. PMID- 24801733 TI - Automatic identification and classification of muscle spasms in long-term EMG recordings. AB - Spinal cord injured (SCI) individuals may be afflicted by spasticity, a condition in which involuntary muscle spasms are common. EMG recordings can be analyzed to quantify this symptom of spasticity but manual identification and classification of spasms are time consuming. Here, an algorithm was created to find and classify spasm events automatically within 24-h recordings of EMG. The algorithm used expert rules and time-frequency techniques to classify spasm events as tonic, unit, or clonus spasms. A companion graphical user interface (GUI) program was also built to verify and correct the results of the automatic algorithm or manually defined events. Eight channel EMG recordings were made from seven different SCI subjects. The algorithm was able to correctly identify an average (+/-SD) of 94.5 +/- 3.6% spasm events and correctly classify 91.6 +/- 1.9% of spasm events, with an accuracy of 61.7 +/- 16.2%. The accuracy improved to 85.5 +/- 5.9% and the false positive rate decreased to 7.1 +/- 7.3%, respectively, if noise events between spasms were removed. On average, the algorithm was more than 11 times faster than manual analysis. Use of both the algorithm and the GUI program provide a powerful tool for characterizing muscle spasms in 24-h EMG recordings, information which is important for clinical management of spasticity. PMID- 24801734 TI - Reactive oxygen species (ROS) inducible DNA cross-linking agents and their effect on cancer cells and normal lymphocytes. AB - Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA cross-linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40-80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ~5 MUM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications. PMID- 24801735 TI - Anti-Toll-like receptor 2 and 4 antibodies suppress inflammatory response in mice. AB - Toll-like receptors (TLRs) 2 and 4 recognize different endogenous and exogenous agonists and play a distinct role in infection and inflammation. However, their ultimate effect in a given infectious and inflammatory disease is less understood. We produced polyclonal anti-murine TLR2 and TLR4 antibodies and investigated their effect on cutaneous leishmaniasis and inflammatory arthritis. Administration of these antibodies to susceptible BALB/c mice, infected in the footpad with Leishmania major, reduced footpad swelling but not the parasite load compared with mice treated with control IgG. The antibodies synergistically reduced leishmanial-specific T-cell proliferation, T helper type 1 and type 2 cytokine production, specific IgG1 and IgG2a antibody synthesis, and T-cell receptor and co-stimulatory molecule expression on dendritic cells in infected mice. We then tested the effect of these antibodies on collagen-induced arthritis (CIA) in DBA/1 mice, a classic model of chronic inflammation. Both antibodies markedly suppressed the development of clinical parameters with concomitant reduction of pro-inflammatory cytokine production. These data therefore suggest that anti-TLR2 and 4 antibodies may have a synergistic therapeutic effect on inflammatory disease in vivo. PMID- 24801736 TI - Cost-effective, transfer-free, flexible resistive random access memory using laser-scribed reduced graphene oxide patterning technology. AB - Laser scribing is an attractive reduced graphene oxide (rGO) growth and patterning technology because the process is low-cost, time-efficient, transfer free, and flexible. Various laser-scribed rGO (LSG) components such as capacitors, gas sensors, and strain sensors have been demonstrated. However, obstacles remain toward practical application of the technology where all the components of a system are fabricated using laser scribing. Memory components, if developed, will substantially broaden the application space of low-cost, flexible electronic systems. For the first time, a low-cost approach to fabricate resistive random access memory (ReRAM) using laser-scribed rGO as the bottom electrode is experimentally demonstrated. The one-step laser scribing technology allows transfer-free rGO synthesis directly on flexible substrates or non-flat substrates. Using this time-efficient laser-scribing technology, the patterning of a memory-array area up to 100 cm(2) can be completed in 25 min. Without requiring the photoresist coating for lithography, the surface of patterned rGO remains as clean as its pristine state. Ag/HfOx/LSG ReRAM using laser-scribing technology is fabricated in this work. Comprehensive electrical characteristics are presented including forming-free behavior, stable switching, reasonable reliability performance and potential for 2-bit storage per memory cell. The results suggest that laser-scribing technology can potentially produce more cost effective and time-effective rGO-based circuits and systems for practical applications. PMID- 24801737 TI - Aging and the inhibition of competing hypotheses during visual word identification: evidence from the progressive demasking task. AB - Two experiments used the progressive demasking (PD) task to examine age differences in the ability to inhibit higher frequency competitors during the process of identifying a visually degraded word. In Experiment 1, older adults exhibited a larger inhibitory neighborhood frequency effect (i.e., slower identification of words with many higher frequency competitors) than younger adults, but additional analyses indicated that this difference could be explained by general slowing rather than a deficit in inhibitory abilities. In Experiment 2, a primed version of the PD task was used to promote hypothesis testing by semantically priming the target word (e.g., cry-weep) or a higher frequency competitor of the target (e.g, day-weep) prior to the onset of the demasking sequence. Although older adults were more likely to make identification errors consistent with an inhibitory deficit (e.g., identifying weep as week), these errors were infrequent overall and there was no corresponding evidence of a larger interference effect in the older adults' identification latencies. Taken together, performance in these two tasks provides little evidence of reduced inhibitory functioning in older adults. The implications for the inhibitory deficit hypothesis of cognitive aging and directions for future are discussed. PMID- 24801738 TI - Enhancement of bilateral cortical somatosensory evoked potentials to intact forelimb stimulation following thoracic contusion spinal cord injury in rats. AB - The adult central nervous system is capable of significant reorganization and adaptation following neurotrauma. After a thoracic contusive spinal cord injury (SCI) neuropathways that innervate the cord below the epicenter of injury are damaged, with minimal prospects for functional recovery. In contrast, pathways above the site of injury remain intact and may undergo adaptive changes in response to injury. We used cortical somatosensory evoked potentials (SSEPs) to evaluate changes in intact forelimb pathways. Rats received a midline contusion SCI, unilateral contusion SCI, or laminectomy with no contusion at the T8 level and were monitored for 28 days post-injury. In the midline injury group, SSEPs recorded from the contralateral forelimb region of the primary somatosensory cortex were 59.7% (CI 34.7%, 84.8%; c(2) = 21.9; dof = 1; p = 2.9 *10(-6)) greater than the laminectomy group; SSEPs from the ipsilateral somatosensory cortex were 47.6% (CI 18.3%, 77%; c(2) = 10.1; dof = 1; p = 0.001) greater. Activation of the ipsilateral somatosensory cortex was further supported by BOLD fMRI, which showed increased oxygenation at the ipsilateral hemisphere at day seven post-injury. In the unilateral injury group, ipsilesional side was compared to the contralesional side. SSEPs on day 14 (148%; CI 111%, 185%) and day 21 (137%; CI 110%, 163%) for ipsilesional forelimb stimulation were significantly increased over baseline (100%). SSEPs recorded from the hindlimb sensory cortex upon ipsilesional stimulation were 33.9% (CI 14.3%, 53.4%; c(2) = 11.6; dof = 1; p = 0.0007) greater than contralesional stimulation. Therefore, these results demonstrate the ability of SSEPs to detect significant enhancements in the activation of forelimb sensory pathways following both midline and unilateral contusive SCI at T8. Reorganization of forelimb pathways may occur after thoracic SCI, which SSEPs can monitor to aid the development of future therapies. PMID- 24801740 TI - Thermal and plasma-enhanced atomic layer deposition of TiN using TDMAT and NH3 on particles agitated in a rotary reactor. AB - Titanium nitride (TiN) shows metallic-type electrical behavior and is therefore an interesting material to improve the conductivity of a wide variety of powders. Atomic layer deposition (ALD) is an excellent technique for achieving the desired ultrathin but conformal coatings. To conformally coat large amounts of particles using ALD, agitation of the particles and efficient reactant usage are necessary. Thermal and plasma-enhanced ALD growth of TiN using tetrakis(dimethylamino)titanium (TDMAT) and NH3 as precursors on agitated particles was performed using a rotary reactor to deposit TiN on ZnO submicrometer powder. The NH3 plasma pulse was monitored using in situ mass spectrometry (MS) and optical emission spectroscopy (OES) measurements to gain insight into the reaction mechanism of the plasma-enhanced process. X-ray photoelectron spectroscopy (XPS) and powder resistivity measurements were performed to determine the influence of the deposition process on the composition and conductivity of the deposited TiN layers. PMID- 24801741 TI - A novel variant mutation for congenital dyserythropoietic anemia, type II. PMID- 24801739 TI - Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release. AB - Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease. PMID- 24801742 TI - Lanthanide ion (III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraaminophosphonate for dual biosensing of pH with chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS). AB - Relaxivity-based magnetic resonance of phosphonated ligands chelated with gadolinium (Gd(3+)) shows promise for pH imaging. However instead of monitoring the paramagnetic effect of lanthanide complexes on the relaxivity of water protons, biosensor (or molecular) imaging with magnetic resonance is also possible by detecting either the nonexchangeable or the exchangeable protons on the lanthanide complexes themselves. The nonexchangeable protons (e.g. -CHx, where 3 >= x >= 1) are detected using a three-dimensional chemical shift imaging method called biosensor imaging of redundant deviation in shifts (BIRDS), whereas the exchangeable protons (e.g. -OH or -NHy , where 2 >= y >= 1) are measured with chemical exchange saturation transfer (CEST) contrast. Here we tested the feasibility of BIRDS and CEST for pH imaging of 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraaminophosphonate (DOTA-4AmP(8-)) chelated with thulium (Tm(3+) ) and ytterbium (Yb(3+)). BIRDS and CEST experiments show that both complexes are responsive to pH and temperature changes. Higher pH and temperature sensitivities are obtained with BIRDS for either complex when using the chemical shift difference between two proton resonances vs using the chemical shift of a single proton resonance, thereby eliminating the need to use water resonance as reference. While CEST contrast for both agents is linearly dependent on pH within a relatively large range (i.e. 6.3-7.9), much stronger CEST contrast is obtained with YbDOTA-4AmP(5-) than with TmDOTA-4AmP(5-). In addition, we demonstrate the prospect of using BIRDS to calibrate CEST as new platform for quantitative pH imaging. PMID- 24801744 TI - Ancestral genetic complexity of arachidonic acid metabolism in Metazoa. AB - Eicosanoids play an important role in inducing complex and crucial physiological processes in animals. Eicosanoid biosynthesis in animals is widely reported; however, eicosanoid production in invertebrate tissue is remarkably different to vertebrates and in certain respects remains elusive. We, for the first time, compared the orthologs involved in arachidonic acid (AA) metabolism in 14 species of invertebrates and 3 species of vertebrates. Based on parsimony, a complex AA metabolic system may have existed in the common ancestor of the Metazoa, and then expanded and diversified through invertebrate lineages. A primary vertebrate-like AA-metabolic system via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways was further identified in the basal chordate, amphioxus. The expression profiling of AA-metabolic enzymes and lipidomic analysis of eicosanoid production in the tissues of amphioxus supported our supposition. Thus, we proposed that the ancestral complexity of AA-metabolic network diversified with the different lineages of invertebrates, adapting with the diversity of body plans and ecological opportunity, and arriving at the vertebrate-like pattern in the basal chordate, amphioxus. PMID- 24801746 TI - Being a preceptor-a Nordic qualitative study. AB - BACKGROUND: Positive preceptor experiences enhance learning and even affect the decisions of students to remain in nursing. In light of this, nurse managers have a responsibility, besides maintaining staff competence, to assess whether preceptors live up to their professional obligations. AIM: The aim of this Nordic qualitative study was to gain a deeper understanding of the perceived experiences of preceptorship used to support undergraduate student nurses during their clinical education. METHOD: Data was collected through narrative interviews with 31 preceptors in Finland and Sweden before being analysed using a hermeneutical approach. FINDINGS: Preceptorship is all about teaching in a supportive environment with ethical dimensions uniting theory and praxis. A caring relationship is essential and the basis for student learning and development. CONCLUSION: The preceptors emphasise a caring relationship as the foundation for student learning. Moreover, preceptorship is an ethical issue, a responsibility that should be recognised by all stakeholders. The findings suggest that preceptorship should be examined from a new perspective. The ethical dimension must be recognised and linked to the further education of preceptors. Nurse managers are in a key position to lead for change. PMID- 24801745 TI - Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. AB - Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid beta-glucocerebrosidase (GCase; GBA) gene. The hallmark of GD is the presence of lipid-laden Gaucher macrophages, which infiltrate bone marrow and other organs. These pathological macrophages are believed to be the sources of elevated levels of inflammatory mediators present in the serum of GD patients. The alteration in the immune environment caused by GD is believed to play a role in the increased risk of developing multiple myeloma and other malignancies in GD patients. To determine directly whether Gaucher macrophages are abnormally activated and whether their functional defects can be reversed by pharmacological intervention, we generated GD macrophages by directed differentiation of human induced pluripotent stem cells (hiPSC) derived from patients with types 1, 2, and 3 GD. GD hiPSC-derived macrophages expressed higher levels of tumor necrosis factor alpha, IL-6, and IL-1beta than control cells, and this phenotype was exacerbated by treatment with lipopolysaccharide. In addition, GD hiPSC macrophages exhibited a striking delay in clearance of phagocytosed red blood cells, recapitulating the presence of red blood cell remnants in Gaucher macrophages from bone marrow aspirates. Incubation of GD hiPSC macrophages with recombinant GCase, or with the chaperones isofagomine and ambroxol, corrected the abnormal phenotypes of GD macrophages to an extent that reflected their known clinical efficacies. We conclude that Gaucher macrophages are the likely source of the elevated levels of inflammatory mediators in the serum of GD patients and that GD hiPSC are valuable new tools for studying disease mechanisms and drug discovery. PMID- 24801747 TI - Nursing students at a university - a study about learning style preferences. AB - BACKGROUND: In most adult education, teachers use methods that assume all students learn in the same way. But knowledge of students' learning style preferences highlights the importance of adequate teaching and learning adaptation. OBJECTIVES: The aim of the study was to describe and compare final year nursing students' learning style preferences in two campuses during three semesters. A further aim was to identify differences between learning style preferences and personal characteristics. DESIGN: A descriptive cross-sectional study using the Productivity Environmental Preference Survey (PEPS) questionnaire was conducted at a Swedish rural university. Three semester groups with 263 nursing students participated in 2012-2013. RESULTS: The majority of the students were 'flexible' in their learning style preferences and had none or few strong preferences. Students with strong preferences preferred high structure (75%) and an authority figure present (40%). About a third were highly auditory, tactile and/or kinesthetic while 8% were highly visual. Few significant differences were revealed between the groups of campuses and the groups of semesters or between learning style preferences and upper secondary school and care experience. There were no significant differences between learning style preferences and age and assistant nurse graduation. More women than men were highly motivated, auditory, tactile and kinesthetic and preferred structure and mobility. CONCLUSIONS: The PEPS questionnaire provides nursing students with self-awareness regarding their strengths and shortcomings in learning and teachers with a valuable and practical basis for their selection of adapted individual and group teaching methods. The findings suggest the need for wide variation and interactive teaching approaches, conscious didactic actions between cooperating teachers and conscious learning strategies for nursing students. PMID- 24801748 TI - The commitment of Israeli nursing preceptors to the role of preceptor. AB - BACKGROUND: Despite the professional importance of the preceptorship role and the rise in participation of nurses in training courses for the position, a significant number of nurses are not committed to this role. The reasons for this trend globally, and in Israel in particular, are not clear. OBJECTIVES: The aim of this study is to explore the connections between characteristics of preceptorship, supports, benefits and rewards, and commitment to the preceptor role in Israel. METHODS: The present study is a quantitative correlational study. A questionnaire survey was given to a convenience sample of 200 Israeli registered nurses working as preceptors in hospitals and community settings in the northern part of Israel. RESULTS: Respondents showed a moderate commitment to the role of preceptor. Support within nurses' employment framework, intrinsic benefits and rewards, and to a lesser degree, extrinsic benefits and rewards, were found to be related to nurses' level of commitment to the role of preceptor. No correlation was found between support received from outside the workplace and commitment to the role of preceptor. Additionally, no correlation was found between the characteristics of preceptorship (the number of preceptees during the last six months or the average number of preceptees per session), and commitment to the role of preceptor. The most important factor contributing to commitment was support within the nurses' employment framework CONCLUSIONS: The present study highlights the importance of support from within the nurses' employment framework, and also the role of intrinsic benefits and rewards, in relation to the level of commitment of Israeli preceptors to their role. PMID- 24801749 TI - Regenerative medicine applied to treatment of musculoskeletal diseases. PMID- 24801750 TI - Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder. AB - An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice. Htr2a knock-out mice (Htr2a(-/-)) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a(-/-)mice), were studied in a sample of 485 Caucasian patients with MDD. In response to chronic corticosterone exposure, Htr2a(-/-) mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher "emotionality score" (p<0.01). In patients, the C allele of rs6313 was more frequent in depressed patients (p=0.019) and was also associated with a more severe major depressive episode (p=0.03). This translational and ecological study involving constitutive Htr2a(-/-) knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission. PMID- 24801751 TI - Methylation of BDNF in women with bulimic eating syndromes: associations with childhood abuse and borderline personality disorder. AB - DNA methylation allows for the environmental regulation of gene expression and is believed to link environmental stressors to such mental-illness phenotypes as eating disorders. Numerous studies have shown an association between bulimia nervosa (BN) and variations in brain-derived neurotrophic factor (BDNF). BDNF has also been linked to borderline personality disorder (BPD) and to such traits as reward dependence. We examined the extent to which BDNF methylation corresponded to bulimic or normal-eater status, and also to the presence of comorbid borderline personality disorder (BPD) and childhood abuse. Our sample consisted of 64 women with BN and 32 normal-eater (NE) control women. Participants were assessed for eating-disorder symptoms, comorbid psychopathology, and childhood trauma, and then they were required to provide blood samples for methylation analyses. We observed a significant site*group (BN vs. NE) interaction indicating that women with BN showed increases in methylation at specific regions of the BDNF promoter. Furthermore, examining effects of childhood abuse and BPD, we observed significant site*group interactions such that groups composed of individuals with childhood abuse or BPD had particularly high levels of methylation at selected CpG sites. Our findings suggest that BN, especially when co-occurring with childhood abuse or BPD, is associated with a propensity towards elevated methylation at specific BDNF promoter region sites. These findings imply that hypermethylation of the BDNF gene may be related to eating disorder status, developmental stress exposure, and comorbid psychopathology. PMID- 24801752 TI - Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIalpha as anti-tumor strategy. AB - Our previous studies indicate that phosphatidylinositol 4-kinase IIalpha can promote the growth of multi-malignant tumors via HER-2/PI3K and MAPK pathways. However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIIalpha could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIIalpha knockdown reduced EGFR protein level, and the expression of PI4KIIalpha shows a strong correlation with EGFR in human breast cancer tissues (r = 0.77, P < 0.01). PI4KIIalpha knockdown greatly prolonged the effects and decreased the effective dosage of AG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KIIalpha suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90 mediated the effect of PI4KIIalpha on EGFR. Furthermore, we found that combined inhibition of PI4KIIalpha and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore, we conclude that combined inhibition of PI4KIIalpha and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIalpha presents a novel strategy to combat EGFR-dependent tumors. PMID- 24801753 TI - Effect of silver nanoparticles and silver ions on growth and adaptive response mechanisms of Pseudomonas putida mt-2. AB - The distribution and use of nanoparticles increased rapidly during the last years, while the knowledge about mode of action, ecological tolerance and biodegradability of these chemicals is still insufficient. The effect of silver nanoparticles (AgNP) and free silver ions (Ag(+) , AgNO3 ) on Pseudomonas putida mt-2 as one of the best described bacterial strains for stress response were investigated. The effective concentration (EC50) causing 50% growth inhibition for AgNP was about 250 mg L(-1) , whereas this was only 0.175 mg L(-1) for AgNO3 . However, when calculating the amount of free silver ions released from AgNP both tested compounds showed very similar results. Therefore, the antibacterial activity of AgNP can be explained and reduced, respectively, to the amount of silver ions released from the nanoparticles. Both tested compounds showed a strong activation of the unique membrane adaptive response of Pseudomonas strains, the cis-trans isomerization of unsaturated fatty acids, whereas another important adaptive response of these bacteria, changes in cell surface hydrophobicity, measured as water contact angle, was not activated. These results are important informations for the estimation of environmental tolerance of newly developed, active ingredients like silver nanoparticles. PMID- 24801754 TI - Development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides. AB - Peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule (F11R, aka JAM-A/Junctional adhesion molecule-A), were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. A sequence at the N-terminal of F11R together with another sequence located in the first Ig-loop of this protein, were identified to form a steric active-site operating in the F11R-dependent adhesion between cells that express F11R molecules on their external surface. In silico modeling of the complex between two polypeptide chains with the sequences positioned in the active-site was used to generate peptide-candidates designed to inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-Lys at selective sites, for attaining higher stability to proteolysis in vivo. Using molecular docking experiments we tested different conformational states and the putative binding affinity between two selected D Arg and D-Lys-modified F11R peptides and the proposed binding pocket. The inhibitory effects of the F11R peptide 2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2 on antibody-induced platelet aggregation and on the adhesion of platelets to cytokine-inflammed endothelial cells are reported in detail, and the results point out the significant potential utilization of F11R peptides for the prevention and treatment of atherosclerotic plaques and associated thrombotic events. PMID- 24801755 TI - Anti-galectin-3 therapy: a new chance for multiple myeloma and ovarian cancer? AB - Here we review the role of Galectins in the molecular pathogenesis of multiple myeloma and ovarian cancer, with a special focus on Glectin-3. Multiple myeloma is the second most common hematologic malignancy worldwide. Because the pathogenesis of multiple myeloma is still incompletely understood, there is no ultimately effective cure, and this cancer results fatal. Ovarian cancer is the most lethal gynecologic malignancy worldwide. Due to the lack of screening techniques for early detection, patients are mostly diagnosed with advanced disease, which results ultimately fatal. Multiple myeloma and ovarian cancer have different biologies, but they share a strong dependence on adhesion with extracellular matrix and other cells. Galectin-3 plays a key role in regulating such adhesive abilities of tumor cells. Here we discuss the outcomes and possible mechanism of action of a truncated, dominant negative form of Galectin-3, Galectin-3C, in these malignancies. Overall, we report that Galectin-3C is a promising new compound for effective adjuvant therapies in advanced, refractory multiple myeloma and ovarian cancer. PMID- 24801756 TI - Signaling Pathways and Epigenetic Regulations in the Control of RORgammat Expression in T Helper 17 Cells. AB - T helper 17 (Th17) cells constitute a unique T-cell lineage that plays a crucial role in inflammatory diseases. A decade ago, retinoic acid receptor-related orphan receptor-gammat (RORgammat) was identified as the specific transcription factor required for Th17-cell lineage commitment. However, the underlying mechanisms involved in the regulation of the RORgammat expression remain largely unclear and therefore preclude the accurate identification and manipulation of Th17 cells. In this review, we summarize the recent advances to obtain an understanding of how RORgammat expression is controlled at the molecular level, highlighting the importance of signal transduction pathways and epigenetic regulations in the control of RORgammat expression in Th17 cells. PMID- 24801757 TI - Epigenesis: roles of nanotopography, nanoforces and nanovibration. AB - We consider three biophysical factors operating at the nanoscale which can affect gene expression, and thus, differentiation, in cultured mammalian cells. These factors are nanovibration, nanoforces and the local nanotopography. Work supporting these conclusions is reviewed. It is argued that stirring of the medium close to the cells cannot contribute to the effects. It is suggested that the three factors interact. Possible pathways by which this could occur are outlined. PMID- 24801758 TI - Improving power for robust trans-ethnic meta-analysis of rare and low-frequency variants with a partitioning approach. AB - While genome-wide association studies have discovered numerous bona fide variants that are associated with common diseases and complex traits; these variants tend to be common in the population and explain only a small proportion of the phenotype variance. The search for the missing heritability has thus switched to rare and low-frequency variants, defined as <5% in the population, but which are expected to have a bigger impact on phenotypic outcomes. The rarer nature of these variants coupled with the curse of testing multiple variants across the genome meant that large sample sizes will still be required despite the assumption of bigger effect sizes. Combining data from multiple studies in a meta analysis will continue to be the natural approach in boosting sample sizes. However, the population genetics of rare variants suggests that allelic and effect size heterogeneity across populations of different ancestries is likely to pose a greater challenge to trans-ethnic meta-analysis of rare variants than to similar analyses of common variants. Here, we introduce a novel method to perform trans-ethnic meta-analysis of rare and low-frequency variants. The approach is centered on partitioning the studies into distinct clusters using local inference of genomic similarity between population groups, with the aim to minimize both the number of clusters and between-study heterogeneity in each cluster. Through a series of simulations, we show that our approach either performs similarly to or outperforms conventional and recently introduced meta-analysis strategies, particularly in the presence of allelic heterogeneity. PMID- 24801759 TI - The peopling of Greenland: further insights from the analysis of genetic diversity using autosomal and X-chromosomal markers. AB - The peopling of Greenland has a complex history shaped by population migrations, isolation and genetic drift. The Greenlanders present a genetic heritage with components of European and Inuit groups; previous studies using uniparentally inherited markers in Greenlanders have reported evidence of a sex-biased, admixed genetic background. This work further explores the genetics of the Greenlanders by analysing autosomal and X-chromosomal data to obtain deeper insights into the factors that shaped the genetic diversity in Greenlanders. Fourteen Greenlandic subsamples from multiple geographical settlements were compared to assess the level of genetic substructure in the Greenlandic population. The results showed low levels of genetic diversity in all sets of the genetic markers studied, together with an increased number of X-chromosomal loci in linkage disequilibrium in relation to the Danish population. In the broader context of worldwide populations, Greenlanders are remarkably different from most populations, but they are genetically closer to some Inuit groups from Alaska. Admixture analyses identified an Inuit component in the Greenlandic population of approximately 80%. The sub-populations of Ammassalik and Nanortalik are the least diverse, presenting the lowest levels of European admixture. Isolation-by-distance analyses showed that only 16% of the genetic substructure of Greenlanders is most likely to be explained by geographic barriers. We suggest that genetic drift and a differentiated settlement history around the island explain most of the genetic substructure of the population in Greenland. PMID- 24801761 TI - Dynamic consent: a patient interface for twenty-first century research networks. AB - Biomedical research is being transformed through the application of information technologies that allow ever greater amounts of data to be shared on an unprecedented scale. However, the methods for involving participants have not kept pace with changes in research capability. In an era when information is shared digitally at the global level, mechanisms of informed consent remain static, paper-based and organised around national boundaries and legal frameworks. Dynamic consent (DC) is both a specific project and a wider concept that offers a new approach to consent; one designed to meet the needs of the twenty-first century research landscape. At the heart of DC is a personalised, digital communication interface that connects researchers and participants, placing participants at the heart of decision making. The interface facilitates two-way communication to stimulate a more engaged, informed and scientifically literate participant population where individuals can tailor and manage their own consent preferences. The technical architecture of DC includes components that can securely encrypt sensitive data and allow participant consent preferences to travel with their data and samples when they are shared with third parties. In addition to improving transparency and public trust, this system benefits researchers by streamlining recruitment and enabling more efficient participant recontact. DC has mainly been developed in biobanking contexts, but it also has potential application in other domains for a variety of purposes. PMID- 24801762 TI - Genome-wide UPD screening in patients with intellectual disability. AB - Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. It may occur as isodisomy, heterodisomy or a combination of both and may involve only chromosome segments. UPD can affect each chromosome. The incidence is estimated to be around 1:3500 in live births. Some parts of chromosomes are subject to 'parent-of-origin imprinting' and the phenotypic effect in UPD syndromes is mainly due to functional imbalance of imprinted genes. Isodisomy can result in mutation homozygosity in autosomal-recessive inherited diseases. UPD causes several well-defined imprinting syndromes associated with intellectual disability (ID). Although knowledge on frequency and size of UPDs in patients with unexplained ID remains largely unknown as no efficient genome-wide screening technique was available for detection of both isodisomic and heterodisomic UPDs. SNP microarrays have been proven to be capable to detect UPDs through Mendelian errors. The correct subclassification of UPD requires child parent trio experiments. To further elucidate the role of UPD in patients with unexplained ID, we analyzed a total of 322 child-parent trios. We were not able to detect UPDs (isodisomies and heterodisomies) within our cohort spanning whole chromosomes or chromosomal segments. We conclude that UPD is rare in patients with unexplained ID. PMID- 24801764 TI - MD and QM/MM studies on long-chain L-alpha-hydroxy acid oxidase: substrate binding features and oxidation mechanism. AB - Long-chain L-alpha-hydroxy acid oxidase (LCHAO) is a flavin mononucleotide (FMN) dependent oxidase that dehydrogenates l-alpha-hydroxy acids to keto acids. There were two different mechanisms, named as hydride transfer (HT) mechanism and carbanion (CA) mechanism, respectively, proposed about the catalytic process for the FMN-dependent L-alpha-hydroxy acid oxidases on the basis of biochemical data. However, crystallographic and kinetic studies could not provide enough evidence to prove one of the mechanisms or eliminate the alternative. In the present studies, theoretical computations were carried out to study the molecular mechanism for LCHAO-catalyzed dehydrogenation of L-lactate. Our molecular dynamics (MD) simulations indicated that L-lactate prefers to bind with LCHAO in a hydride transfer mode rather than a carbanion mode. Quantum mechanics/molecular mechanics (QM/MM) calculations were further carried out to obtain the optimized structures of reactants, transition states, and products at the level of ONIOM-EE (B3LYP/6-311++G(d,p)//B3LYP/6-31G(d,p):AMBER). Quantum chemical studies indicated that LCHAO-catalyzed dehydrogenation of L-lactate would be a stepwise catalytic reaction in a hydride transfer mechanism but not a carbanion mechanism. MD simulations, binding free energy calculations, and QM/MM computations were also implemented on the complex between L-lactate and Y129F mutant LCHAO. By comparing the Y129F mutant system with the wild-type system, it was further confirmed that the key residue Tyr129 in the active site of LCHAO would not affect L-lactate's binding to LCHAO but play an important role on the catalytic reaction process through an H-bond interaction. PMID- 24801763 TI - Novel deletions affecting the MEG3-DMR provide further evidence for a hierarchical regulation of imprinting in 14q32. AB - The imprinted region on chromosome 14q32 harbors several maternally or paternally expressed genes as well as two DMRs (differentially methylated regions), the IG DMR and the MEG3-DMR, which both act as imprinting control centers. Genetic aberrations affecting the imprinted gene cluster in 14q32 result in distinct phenotypes, known as maternal or paternal uniparental disomy 14 phenotypes (upd(14)mat, upd(14)pat). In both syndromes, three types of molecular alterations have been reported: uniparental disomy 14, deletions and epimutations. In contrast to uniparental disomy and epimutations, deletions affecting regulatory elements in 14q32 are associated with a high-recurrence risk. Based on two single deletion cases a functional hierarchy of the IG-DMR as a regulator for the methylation of the MEG3-DMR has been proposed. We have identified two novel deletions of maternal origin spanning the MEG3-DMR, but not the IG-DMR in patients with upd(14)pat syndrome, one de novo deletion of 165 kb and another deletion of 5.8 kb in two siblings. The 5.8 kb deletion was inherited from the phenotypically normal mother, who carries the deletion in a mosaic state on her paternal chromosome 14. The methylation at both DMRs was investigated by quantitative next generation bisulfite sequencing and revealed normal methylation patterns at the IG-DMR in all patients with the exception of certain CpG dinucleotides. Thus, we could confirm that deletions of the MEG3-DMR does not generally influence the methylation pattern of the IG-DMR, which strengthens the hypothesis of a hierarchical structure and distinct functional properties of the two DMRs. PMID- 24801765 TI - Understanding the colloidal stability of the mesoporous MIL-100(Fe) nanoparticles in physiological media. AB - The colloidal and chemical stability of nanoparticles of the nontoxic and biodegradable iron(III) trimesate MIL-100(Fe) nanocarrier have been evaluated in the presence of a series of simulated physiological fluids for intravenous and oral administration. MIL-100(Fe) nanoparticles exhibit an appropriate colloidal stability and biodegradability, mainly dependent on both the nature of their physicochemical surface and the media composition, being a priori compatible with their biomedical use. PMID- 24801760 TI - Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP. AB - The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 * 10(-7)). The association was stronger in those with >=10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients. PMID- 24801766 TI - Altered sedative effects of ethanol in mice with alpha1 glycine receptor subunits that are insensitive to Gbetagamma modulation. AB - Alcohol abuse and alcoholism are major health problems and one of the leading preventable causes of death. Before achieving better treatments for alcoholism, it is necessary to understand the critical actions of alcohol on membrane proteins that regulate fundamental functions in the central nervous system. After generating a genetically modified knock-in (KI) mouse having a glycine receptor (GlyR) with phenotypical silent mutations at KK385/386AA, we studied its cellular and in vivo ethanol sensitivity. Analyses with western blotting and immunocytochemistry indicated that the expression of alpha1 GlyRs in nervous tissues and spinal cord neurons (SCNs) were similar between WT and KI mice. The analysis of synaptic currents recorded from KI mice showed that the glycinergic synaptic transmission had normal properties, but the sensitivity to ethanol was significantly reduced. Furthermore, the glycine-evoked current in SCNs from KI was resistant to ethanol and G-protein activation by GTP-gamma-S. In behavioral studies, KI mice did not display the foot-clasping behavior upon lifting by the tail and lacked an enhanced startle reflex response that are characteristic of other glycine KI mouse lines with markedly impaired glycine receptor function. The most notable characteristic of the KI mice was their significant lower sensitivity to ethanol (~40%), expressed by shorter times in loss of righting reflex (LORR) in response to a sedative dose of ethanol (3.5 g/Kg). These data provide the first evidence to link a molecular site in the GlyR with the sedative effects produced by intoxicating doses of ethanol. PMID- 24801767 TI - Influence of aripiprazole, risperidone, and amisulpride on sensory and sensorimotor gating in healthy 'low and high gating' humans and relation to psychometry. AB - Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making. PMID- 24801768 TI - Efficacy and safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful combination therapy of treatment-resistant major depressive disorder. AB - This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to >= 2 different antidepressants for >= 6 weeks within the current MDD episode were acutely treated for 6-8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery Asberg Depression Rating Scale score with Clinical Global Impressions-Severity of Depression score of >= 4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC treated patients. Clinically significant weight gain (>= 7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs. PMID- 24801770 TI - Multichannel-emissive V-shaped boryl-BODIPY dyads: synthesis, structure, and remarkably diverse response toward fluoride. AB - Three new V-shaped boryl-BODIPY dyads (1-3) were synthesized and structurally characterized. Compounds 1-3 are structurally close molecular siblings differing only in the number of methyl substituents on the BODIPY moiety that were found to play a major role in determining their photophysical behavior. The dyads show rare forms of multiple-channel emission characteristics arising from different extents of electronic energy transfer (EET) processes between the two covalently linked fluorescent chromophores (borane and BODIPY units). Insights into the origin and nature of their emission behavior were gained from comparison with closely related model molecular systems and related photophysical investigations. Because of the presence of the Lewis acidic triarylborane moiety, the dyads function as highly selective and sensitive fluoride sensors with vastly different response behaviors. When fluoride binds to the tricoordinate borane center, dyad 1 shows gradual quenching of its BODIPY-dominated emission due to the ceasing of the (borane to BODIPY) EET process. Dyad 2 shows a ratiometric fluorescence response for fluoride ions. Dyad 3 forms fluoride-induced nanoaggregates that result in fast and effective quenching of its fluorescence intensity just for ~0.3 ppm of analyte (i.e., 0.1 equiv = 0.26 ppm of fluoride). The small structural alterations in these three structurally close dyads (1-3) result in exceptionally versatile and unique photophysical behaviors and remarkably diverse responses toward a single analyte, i.e., fluoride ion. PMID- 24801771 TI - Different biomarkers in non-small cell lung cancer in blood vessel invasion. AB - In clinical settings, lung cancer is divided into small cell lung cancer and non small cell lung cancer, and chemotherapy is depended on the difference. Using the same chemotherapy treatment, different effects and prognosis can be seen among squamous-cell carcinoma and adenocarcinoma. These differences indicate that there may be various methods of invasion and immunity between squamous-cell carcinoma and adenocarcinoma. Blood vessel invasion and tumor immune escape play very important roles in the progression and metastasis of cancer, and CD105 and integrins are novel therapeutic targets. We assessed the possible association of CD105 expression and integrins with TNM classification in patients with two types of NSCLC. A total of 72 patients with resected Non-Small Cell Lung Cancer (NSCLC) were reviewed retrospectively. Integrin beta1, beta2, beta3, and alpha5beta1 are assayed by immunofluorescence and integrin alpha5beta1 using immunoblot. Intratumoral microvessel density was determined with an anti-CD34 mAb and an anti CD105 mAb. Invasive ability was assayed with MMP2 and MMP9 using immunofluorescence. The expressions of all integrins, CD105, and CD34 are low in the normal lung tissue and highly expressed in the cancer niche compared to the adjacent tissues. CD105 is highly expressed in the adenocarcinoma niche compared to the squamous-cell carcinoma in NSCLC. The expressions of both MMP2 and MMP9 are low in the normal lung tissue and highly expressed in adjacent tissues. This study shows that blood vessel invasion appears to be an independent negative prognosticator in surgically managed types of NSCLC. However, adequately designed large prospective studies are warranted to confirm the present findings. PMID- 24801769 TI - The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala. AB - We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder. PMID- 24801772 TI - Different long-term outcomes of abdominal aortic aneurysm and intracranial aneurysm models: hemodynamic change may also play an essential role in the initiation and progression of abdominal aortic aneurysm in rabbits. AB - Self-healing phenomenon was found in the periarterial elastase-induced abdominal aortic aneurysm (AAA) in rabbit. This kind of aneurysm model does not progress and heals spontaneously in the long term, which is quite different from the performance of AAA disease in human. In order to better mimic human AAA and overcome this shortcoming of traditional AAA model in rabbit, we studied the pathogenesis of cerebral aneurysm (CA) model in small animal, which shows an excellent long-term patency and progressive enlargement. We found that hemodynamic conditions, such as turbulence flow, high blood flow, and shear stress, play an important role in the formation and progression of CA. So, we hypothesize that hemodynamic change may also play an essential role in the initiation and progression of rabbit AAA, and self-healing will be overcome if hemodynamic condition changes by coarctation of infra-renal aorta after elastase incubation. PMID- 24801773 TI - Biochemical modifications and neuronal damage in brain of young and adult rats after long-term exposure to mobile phone radiations. AB - This study investigated the effect of exposure to mobile phone radiations on oxidative stress and apoptosis in brain of rats. Rats were allocated into six groups (three young and three adult). Groups 1 and 4 were not subjected to the radiation source and served as control groups. In groups 2 and 5, the mobile phones were only connected to the global system for mobile communication, while in groups 3 and 6, the option of calling was in use. Microwaves were generated by a mobile test phone (SAR = 1.13 W/kg) during 60 days (2 h/day). Significant increments in conjugated dienes, protein carbonyls, total oxidant status, and oxidative stress index along with a significant reduction of total antioxidant capacity levels were evident after exposure. Bax/Bcl-2 ratio, caspase-3 activity, and tumor necrosis factor-alpha level were enhanced, whereas no DNA fragmentation was detected. The relative brain weight of young rats was greatly affected, and histopathological examination reinforced the neuronal damage. The study highlights the detrimental effects of mobile phone radiations on brain during young and adult ages. The interaction of these radiations with brain is via dissipating its antioxidant status and/or triggering apoptotic cell death. PMID- 24801774 TI - Ciliates along oxyclines of permanently stratified marine water columns. AB - Studies of microbial communities in areas of the world where permanent marine water column oxyclines exist suggest they are "hotspots" of microbial activity, and that these water features and the anoxic waters below them are inhabited by diverse protist taxa, including ciliates. These communities have minimal taxonomic overlap with those in overlying oxic water columns. Some ciliate taxa have been detected in multiple locations where these stable water column oxyclines exist; however, differences in such factors as hydrochemistry in the habitats that have been studied suggest local selection for distinct communities. We compare published data on ciliate communities from studies of deep marine water column oxyclines in Caricao Basin, Venezuela, and the Black Sea, with data from coastal, shallower oxycline waters in Framvaren and Mariager fjords, and from several deep-sea hypersaline anoxic basins in the Eastern Mediterranean Sea. Putative symbioses between Bacteria, Archaea, and ciliates observed along these oxyclines suggests a strategy of cooperative metabolism for survival that includes chemosynthetic autotrophy and exchanges of metabolic intermediates or end products between hosts and their prokaryotic partners. PMID- 24801775 TI - Uncertainty estimation in diffusion MRI using the nonlocal bootstrap. AB - In this paper, we propose a new bootstrap scheme, called the nonlocal bootstrap (NLB) for uncertainty estimation. In contrast to the residual bootstrap, which relies on a data model, or the repetition bootstrap, which requires repeated signal measurements, NLB is not restricted by the data structure imposed by a data model and obviates the need for time-consuming multiple acquisitions. NLB hinges on the observation that local imaging information recurs in an image. This self-similarity implies that imaging information coming from spatially distant (nonlocal) regions can be exploited for more effective estimation of statistics of interest. Evaluations using in silico data indicate that NLB produces distribution estimates that are in closer agreement with those generated using Monte Carlo simulations, compared with the conventional residual bootstrap. Evaluations using in vivo data demonstrate that NLB produces results that are in agreement with our knowledge on white matter architecture. PMID- 24801777 TI - The Ottawa Charter: a manifesto for 'the protestor'? PMID- 24801776 TI - 17beta-estradiol protects primary macrophages against HIV infection through induction of interferon-alpha. AB - Estrogen has been shown to increase resistance to HIV/SIV transmission by increasing the thickness of the genital epithelium. The immunological role of estrogen in HIV infection of primary target cells is less well characterized. We have found that primary macrophages are a target for anti-HIV activity of 17beta estradiol (E2). E2 did not affect surface expression of CD4 and HIV co-receptors nor HIV attachment to monocyte-derived macrophages (MDMs). In addition, E2 treatment blocked infection by a co-receptor-independent HIV-1VSV-G pseudotyped virus. Quantitative polymerase chain reaction analysis of HIV reverse transcribed DNA products indicated that E2 blocked HIV reverse transcription. E2 upregulated gene expression of interferons (IFNs) in MDMs from multiple donors. However, induction of host restriction factors APOBEC3G, APOBEC3F, or SAMHD1 was not consistent, with exception of APOBEC3A. Anti-HIV activity of E2 was abolished in the presence of IFN-alpha neutralizing antibody, and was absent in bone marrow derived macrophages from IFN-alpha receptor deficient mice. Interestingly, HIV overcame E2-mediated HIV inhibition by suppressing induction of IFNs when MDMs were exposed to HIV before E2 treatment. These results offer a new mechanism of E2 on HIV inhibition. Future studies on the interplay between HIV and E2-mediated innate immune responses will likely provide insights relevant for development of effective strategies for HIV prevention. PMID- 24801778 TI - Reducing alcohol use during pregnancy: listening to women who drink as an intervention starting point. AB - OBJECTIVES: This study assesses factors that contribute to alcohol consumption during pregnancy and identifies potential intervention strategies to reduce consumption. METHODS: The study sample includes 142 pregnant women who attended a public hospital for prenatal health care in Perth, Western Australia. All participants returned a self-completion survey. RESULTS: Women who discontinued drinking during pregnancy were significantly more likely to be engaged in full time home duties and had completed less formal education. Women who continued to drink were more likely to have drunk in previous pregnancies and during the preconception period. Nearly 40% of high risk women reported a negative comment in response to their drinking. One-third of women in the risky group were advised by a health professional not to drink alcohol. Women were most likely to drink in their own home or at the home of a friend. CONCLUSIONS: Participatory research with women who drink while pregnant can assist in identifying potential intervention strategies that have resonance with this group and therefore more potential for creating behaviour change. Implications. The World Health Organization recognises, and has done for over 10 years, that alcohol use during pregnancy which results in Foetal Alcohol Spectrum Disorder is the leading cause of environmental-related birth defects and mental retardation in the Western world. PMID- 24801779 TI - SmartRoads: training Indonesian workers to become road safety ambassadors in industrial and community settings. AB - This paper reports on a programme to improve road safety awareness in an industrial community in the vicinity of Jakarta, in Indonesia. Adapting the model of a successful community and school-based programme in Victoria, in Australia, and using a peer education approach, 16 employees of a major manufacturing company were trained to implement road safety education programmes amongst their peers. Specific target groups for the educators were colleagues, schools and the local community. Over 2 days the employees, from areas as diverse as production, public relations, personnel services, administration and management, learned about road safety facts, causes of traffic casualties, prevention approaches and peer education strategies. They explored and developed strategies to use with their respective target groups and practised health education skills. The newly trained workers received certificates to acknowledge them as 'SmartRoads Ambassadors' and, with follow-up support and development, became road safety educators with a commitment and responsibility to deliver education to their respective work and local communities. This paper argues that the model has potential to provide an effective and locally relevant response to road safety issues in similar communities. PMID- 24801780 TI - Faith communities and their assets for health promotion: the views from health professionals and faith leaders in Dundee, in Scotland. AB - Within the European Union, as well as in Canada and the United States (US), health promoters employ a number of strategies to encourage community-based health improvements. This involves the creation of innovative health promotion partnerships to support and enable people to choose and engage in healthy living practices. Compared to the US, in other Western countries, such as the United Kingdom, faith communities have largely been ignored in health promotion partnerships. This study established existing evidence about health promotion in faith communities in Scotland by examining the perceptions and attitudes concerning health promotion among faith leaders and health promotion professionals. We conducted 33 semi-structured interviews with health promotion professionals (n = 9) and representatives of Christian and non-Christian faith communities (n = 24). The majority of participants expressed an interest in the concept of health promotion in a faith community and could readily envision its application in their area of work. Both groups identified multiple physical assets, as well as social supports within faith communities that could be directed towards healthy living activities. Faith groups and church organisations may constitute potential partners and new settings to increase community capacity for health promotion. Further research and funding for demonstration projects may be particularly helpful to provide evidence of the strengths and limitations of faith-based health promotion in Scotland, which in turn could inform health promotion practice and policy. PMID- 24801781 TI - 'It's just a way of approaching things now': staff perspectives of an anticipatory care programme in Edinburgh. AB - BACKGROUND: Keep Well, an anticipatory care programme aimed at reducing health inequalities in Scotland, commenced in 2006. There is currently little evidence exploring how frontline staff respond to the delivery of anticipatory care. AIM: To understand how staff view changes in practice resulting from the implementation of Keep Well. METHODS: Qualitative interviews were conducted with a purposively selected sample of 12 Keep Well staff. Data were analysed using a thematic analysis approach. RESULTS: Keep Well was viewed positively, especially in terms of increased knowledge and skills for staff and the benefits of a holistic health check to patients. Staff believed that Keep Well has improved their practice beyond the project. Concerns were raised, relating to potential inconveniences for patients, staff turnover, increased workload and procedures. There was a view that anticipatory care should continue to be delivered to deprived communities, provided that there are adequate resources, such as staff and funding, to do so. CONCLUSION: Keep Well staff believe that the project should continue to be offered as a 40-minute holistic health check targeted at patients in deprived areas. PMID- 24801782 TI - Review and recommendations for online physical activity and nutrition programmes targeted at over 40s. AB - ISSUES ADDRESSED: Australia's ageing population is becoming less physically active and increasingly overweight and obese. There is a need to support physical activity and healthy dietary practices to control overweight and obesity and to prevent chronic disease amongst the middle aged and older population (40 years or more). The Internet is emerging as a potentially effective method of delivering health promotion programmes. METHODS: Literature relating to online physical activity and nutrition programmes published from 2000 to 2009 were identified through a search of four databases and by examining reference lists of relevant articles. RESULTS: Eighteen relevant references were identified: 10 online physical activity programmes and eight online physical activity and nutrition programmes. Twelve studies reported significant short-term effects on behaviour change or weight loss, and four studies did not assess behaviour change, but focused on the usefulness of website strategies, attitude changes and/or recruitment methods. Seven studies experienced low retention rates. CONCLUSIONS: Evidence to date suggests that the Internet is no more effective than print materials, face-to-face programmes and other health promotion methods. Several studies found positive short-term effects from using Internet-based programmes, including those aimed at the target group (40 years or more). Therefore the use of the Internet as a method for delivering health promotion programmes is worthy of future consideration. SO WHAT? The Internet provides an opportunity for health promotion professionals to engage vastly more people in health promotion interventions, as well as providing a tool to interact and engage with them. From a population health perspective this is becoming more important as the incidence of lifestyle related diseases increases among middle to older aged people. Although online physical activity and healthy weight programmes vary in degrees of effectiveness, the Internet cannot be ignored as a future medium for health promotion. More research is needed to evaluate the effectiveness of such programmes. PMID- 24801783 TI - From effective partnerships to sulking in the corner: the public health response to multinationals. AB - Multinationals and the for-profit sector evoke a range of responses from public health professionals - from enthusiasm through to distain and anger. Several sessions at the conferences of the International Union for Health Promotion and Education (IUHPE) and of the American Public Health Association (APHA) in 2010 addressed issues related to multinationals, trade and public-private partnerships. However, there was no representation from the for-profit sector at any of these events. This commentary argues that, regardless of whether public health professionals agree or disagree with the actions of multinationals, maintaining a dialogue with them is essential. Recommendations are given for engaging effectively with the for-profit sector. PMID- 24801784 TI - Appropriate health promotion for Australian Aboriginal and Torres Strait Islander communities: crucial for closing the gap. AB - Health promotion for Australian Aboriginal and Torres Strait Islander communities and their people has generally had limited efficacy and poor sustainability. It has largely failed to recognise and appreciate the importance of local cultures and continues to have minimal emphasis on capacity building, community empowerment and local ownership. Culturally Appropriate Health Promotion is a framework of principles developed in 2008 with the World Health Organization and the Global Alliance for Health Promotion. It serves as a guide for community focused health promotion practice to be built on and shaped by the respect for understanding and utilisation of local knowledge and culture. Culturally Appropriate Health Promotion is not about targeting, intervening or responding. Rather, it encourages health programme planners and policymakers to have a greater understanding, respect, a sense of empowerment and collaboration with communities, and their sociocultural environment to improve health. This commentary aims to examine and apply the eight principles of Culturally Appropriate Health Promotion to the Australian Aboriginal and Torres Strait Islander context. It proposes a widespread adoption of the framework for a more respectful, collaborative, locally suitable and therefore appropriate approach to Australian Aboriginal and Torres Strait Islander health promotion. PMID- 24801785 TI - Where are the champions of global health promotion? AB - For many years the World Health Organization (WHO) has provided the global direction and leadership that has helped to shape the way we view health promotion today. The future role of the WHO is now uncertain and the lack of global leadership for health promotion and identification of who will provide the future direction are issues that need to be addressed. The crucial question posed in this commentary is: Where are the individuals and organisations that will provide the global leadership and vision for health promotion in the future? We need named champions for the future leadership of health promotion practice - people and organisations who offer a leadership style that will maintain its global profile, be representative across sectors and have the ability to maintain its political efficacy. The two key health promotion approaches, top-down and bottom-up, do not always share the same goals, and they demand different styles of leadership. This is an important consideration in our goal to find champions who can work with both approaches and understand how to accommodate them as a part of the future direction of health promotion. This commentary raises key questions to stimulate discussion and action towards addressing the lack of global leadership in health promotion. It discusses some of the key players, leadership characteristics and the contradictions in style that are inherent in achieving a goal of charismatic global champions. PMID- 24801790 TI - [Evaluation of the process of the emotional-sexual education programme Neither ogres or princesses]. PMID- 24801791 TI - [Promotion and prevention strategies in the comprehensive health care model: a three-year period 2003-2006, in Tabasco, Mexico]. PMID- 24801793 TI - Proton pump inhibitors and functional decline in older adults discharged from acute care hospitals. AB - OBJECTIVES: To investigate the relationship between use of proton pump inhibitors (PPIs) and incident dependency in older adults discharged from acute care hospitals. DESIGN: Prospective observational study. SETTING: Eleven geriatric and internal medicine acute care wards located throughout Italy. PARTICIPANTS: Individuals (mean age 79.2 +/- 5.5) who were not completely dependent at the time of discharge from participating wards (N = 401). MEASUREMENTS: The outcome of interest was the loss of at least one basic activity of daily living (ADL) from discharge to the end of follow-up (12 months). The relationship between PPI use and functional decline was investigated using logistic regression analysis before and after propensity score matching. RESULTS: Use of PPIs was significantly associated with functional decline before (odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.17-2.60) and after propensity score matching (OR = 2.44; 95% CI = 1.36-4.41). Other predictors of functional decline were hypoalbuminemia (OR = 3.10, 95% CI = 1.36-7.10 before matching, OR = 2.81, 95% CI = 1.09-7.77 after matching) and cognitive impairment (OR = 4.08, 95% CI = 1.63-10.2 before matching, OR = 6.35, 95% CI = 1.70-24.0 after matching). CONCLUSION: Use of PPIs is associated with functional decline during 12 months of follow-up in older adults discharged from acute care hospitals. PMID- 24801794 TI - Creation of nanopores on graphene planes with MgO template for preparing high performance supercapacitor electrodes. AB - Creation of nanopores on graphene planar sheets is of great significance in promoting the kinetic diffusion of electrolyte and enhancing the utilization efficiency of graphene planar sheets. Herein, we developed a facile chemical vapor deposition strategy to prepare highly porous graphene with flake-like MgO as template and ferrocene as the carbon precursor. The graphene layers show a highly porous structure with small mesopores of 4-8 nm, large mesopores of 10-20 nm and additional macropores of 100-200 nm. These nanopores on graphene sheets provide numerous channels for fast ion transport perpendicular to the 2D basal plane, while the good powder conductivity ensures an effective electron propagation within the 2D graphene plane. As a result, a specific capacitance of 303 F g(-1), an areal capacitance up to 17.3 MUF cm(-2) and a nearly tenfold shorter time constant were achieved when compared with those of nonporous and stacked graphene electrodes. The method demonstrated herein would open up an opportunity to prepare porous graphene for a wide applications in energy storage, biosensors, nanoelectronics and catalysis. PMID- 24801795 TI - Ba2B10O17: a new centrosymmetric alkaline-earth metal borate with a deep-UV cut off edge. AB - A new centrosymmetric alkaline-earth metal borate, Ba2B10O17, has been successfully synthesized through high-temperature solid-state reactions. The single-crystal X-ray structural analysis shows that Ba2B10O17 crystallizes in the triclinic space group P1[combining macron]. The parameters of the triclinic unit cell are a = 6.7128(3) A, b = 9.8698(4) A, c = 9.9998(4) A, alpha = 76.860(3) degrees , beta = 83.200(3) degrees , gamma = 73.332(3) degrees , and Z = 2. The title compound features a [B10O17]infinity three-dimensional anionic framework with infinite channels in which the Ba(2+) cations are located. Ba2B10O17 possesses a large experimental band gap of 6.29 eV and a short cut-off edge lower than 180 nm proved by the transmission spectrum on a single crystal sample 0.5 mm in thickness. The calculated band structures and the density of states of Ba2B10O17 suggest that its indirect energy gap is 5.97 eV which agrees with the experimental result. The thermal behavior and the IR spectrum of Ba2B10O17 are also reported in this work. PMID- 24801799 TI - Distribution, sources and potential toxicological significance of polycyclic aromatic hydrocarbons (PAHs) in surface soils of the Yellow River Delta, China. AB - PAH concentrations of 61 surface soil samples collected from the Yellow River Delta (YRD), China were measured to determine occurrence levels, sources, and potential toxicological significance of PAHs. The total concentrations of ?PAHs ranged from 27 to 753 ng/g d.w., with a mean of 118+/-132 ng/g. The highest concentrations was found in the mid-southern part of the YRD (753 ng/g), which was associated with the oil exploration. The ratios indicated that the PAHs throughout the YRD were mostly of pyrogenic origin; while various sites in mid southern part in the region were derived mainly from the petrogenic sources. Multivariate statistical analyses supported that the PAHs in surface soils of the YRD were principally from the coal and biomass combustion, petroleum spills, and/or vehicular emissions. The toxic assessment suggested that the PAHs in soils were at low potential of ecotoxicological contamination level for the YRD. PMID- 24801800 TI - Multiplexed actuation using ultra dielectrophoresis for proteomics applications: a comprehensive electrical and electrothermal design methodology. AB - In this work, we present a methodological approach to analyze an enhanced dielectrophoresis (DEP) system from both a circuit analysis and electrothermal view points. In our developed model, we have taken into account various phenomena and constraints such as voltage degradation (due to the presence of the protecting oxide layer), oxide breakdown, instrumentation limitations, and thermal effects. The results from this analysis are applicable generally to a wide variety of geometries and high voltage microsystems. Here, these design guidelines were applied to develop a robust electronic actuation system to perform a multiplexed bead-based protein assay. To carry out the multiplexed functionality, along a single microfluidic channel, an array of proteins is patterned, where each element is targeting a specific secondary protein coated on micron-sized beads in the subsequently introduced sample solution. Below each element of the array, we have a pair of addressable interdigitated electrodes. By selectively applying voltage at the terminals of each interdigitated electrode pair, the enhanced DEP, or equivalently 'ultra'-DEP (uDEP) force detaches protein bound beads from each element of the array, one by one, without disturbing the bound beads in the neighboring regions. The detached beads can be quantified optically or electrically downstream. For proof of concept, we illustrated 16 plex actuation capability of our device to elute micron-sized beads that are bound to the surface through anti-IgG and IgG interaction which is on the same order of magnitude in strength as typical antibody-antigen interactions. In addition to its application in multiplexed protein analysis, our platform can be potentially utilized to statistically characterize the strength profile of biological bonds, since the multiplexed format allows for high throughput force spectroscopy using the array of uDEP devices, under the same buffer and assay preparation conditions. PMID- 24801802 TI - Sublingual immunotherapy: what we can learn from the European experience. AB - PURPOSE OF REVIEW: To review the recent European studies on sublingual immunotherapy (SLIT). SLIT is currently widely used in Europe and is gaining popularity in the United States. RECENT FINDINGS: Longer treatment with SLIT compared with subcutaneous immunotherapy (SCIT) is needed to reduce the rhinitis symptoms in house dust mite (HDM) allergic children. SLIT appears to be well tolerated and effective for treating rhinitis and asthma in children, adults, and the elderly. Studies on HDM, grass, and ragweed have demonstrated posttreatment efficacy in both monosensitized and polysensitized patients. SUMMARY: SLIT has been shown to be an effective treatment for airway allergies, and recent studies give support for the use of SLIT as the first choice for allergy treatment compared with medication and SCIT. The use of SLIT may potentially improve the compliance of allergen immunotherapy and may make allergy treatment more accessible and well tolerated. PMID- 24801801 TI - Bacterial species-specific hospital mortality rate for intra-abdominal infections. AB - BACKGROUND: Intra-abdominal infections (IAIs) are a major cause of morbidity and death. We hypothesized that the involvement of specific organisms would predict death independently. PATIENTS AND METHODS: All patients with IAIs treated at an academic tertiary-care facility over eight years (June 1999-June 2007) were included. The data collected were demographics, co-morbidities, source of infection, intra-abdominal culture results, type of infection (community-acquired vs. nosocomial), type of intervention (operative vs. percutaneous drainage), and outcome. The Charlson Comorbidity Index and multiple organ dysfunction score (MODS) were used in the analysis. RESULTS: A total of 389 patients were admitted for 452 infection episodes (IEs) during the study period. None of the 129 patients with appendiceal-related infections died, and these patients were excluded from further analysis. Thus, 323 non-appendiceal IEs were evaluated. The overall mortality rate was 8.7%. The mean age of the patients was 54 y, and 50% of them were male. Intra-abdominal cultures were obtained from 303 IEs (93.8%). The most common cause of IAI was post-operative infection (44%). There were 49 distinct species isolated. The most common were Enterococcus (105), Escherichia coli (75), Streptococcus (62), Staphylococcus (51), and Bacteroides (46). Bivariable analysis revealed multiple risk factors associated with death. Logistic regression demonstrated that independent risk factors for death were age >=65 years (odds ratio [OR] 3.92), cardiac event (OR=8.17), catheter-related blood stream infection (OR=6.16), and growth of Clostridium (OR=13.03). The growth of Streptococcus was predictive of survival. The C statistic was 0.89. CONCLUSIONS: In addition to age and intrinsic patient factors, the presence of specific bacterial organisms independently predicts death in patients with non appendiceal IAI. PMID- 24801803 TI - The relationship between allergic rhinitis and viral infections. AB - PURPOSE OF REVIEW: Viral airway inflammation is one of the most common respiratory conditions. The clinical symptoms of viral rhinitis, especially watery rhinorrhea and nasal congestion, may be similar to the symptoms of allergic rhinitis. Both conditions affect considerable numbers of patients and can lead to many upper airway consequences, especially secondary bacterial infection. Viral infection can also lead to lower respiratory traction conditions such as bronchitis, bronchiolitis, pneumonia and, especially, asthma. This article will review the existing scientific literature examining the linkage and relationship between viral infection and allergic airway disease. RECENT FINDINGS: The relationship between viral and allergic airway inflammation can be discussed in terms of the influence of pathogenesis from one condition to the other. Recently, many studies show how early infection can decrease the chance of allergic development. However, there is some evidence demonstrating that viral infection can deteriorate the clinical symptoms of airway allergy. SUMMARY: Viral infection can affect the immune system and allergy as both 'enhancing effect' and 'protective effect'. The influential factors depend on the virulence of the viral strain, the innate immune system and the environmental conditions. PMID- 24801804 TI - How to do a composite mesh repair for the recurrent ventral abdominal hernia. PMID- 24801805 TI - Bilateral abducens nerve palsy associated with subarachnoid hemorrhage. AB - OBJECTIVE: Isolated abducens nerve palsies associated with intracranial aneurysms have rarely been reported. The purpose of the study was to study the patients with bilateral abducens nerve palsy in association with subarachnoid hemorrhage (SAH). METHODS: All patients admitted and managed at our center with a diagnosis of SAH and had bilateral abducens nerve palsy were included in the study. The demographic and clinical details, radiological findings, treatment data, and outcome of these patients were retrieved from the computerized database of our hospital. RESULTS: Nine patients, with a mean age of 49.4 years, met the inclusion criteria. Male to female ratio of 1.25:1). Average duration of symptoms before presentation was 2.6 days (ranging from 1 to 4 days). Third nerve palsy in addition to bilateral abducens nerve palsy was present in 4 patients (44%). DSA demonstrated aneurysms in 7 patients; 4 had posterior circulation aneurysms and 3 had aneurysms of anterior circulation. Two patients had angionegative SAH. The abnormality resolved in all but one patient over a time period of 4-9 weeks, and one patient died due to unrelated cause. CONCLUSIONS: Bilateral abducens nerve palsy in association with SAH is rarely described. Proposed mechanisms include direct compression of the bilateral abducens nerves, vasospasm of the pontine branches of the basilar artery and hydrocephalous. Most of the patients in our series showed resolution of the symptoms over a period of 4-9 weeks. PMID- 24801806 TI - Cervical synovial cyst. AB - Synovial cysts of the cervical spine are extremely rare. They can therefore pose a diagnostic challenge. We present an unusual case of acute symptomatology secondary to spontaneous haemorrhage into a cervical facet joint cyst. PMID- 24801807 TI - Influences of semantic and prosodic cues on word repetition and categorization in autism. AB - PURPOSE: To investigate sensitivity to prosodic and semantic cues to emotion in individuals with high-functioning autism (HFA). METHOD: Emotional prosody and semantics were independently manipulated to assess the relative influence of prosody versus semantics on speech processing. A sample of 10-year-old typically developing children (n = 10) and children with HFA (n = 10) were asked to repeat words that were either emotionally congruent or incongruent in form and content (Experiment 1A). In a second task (Experiment 1B), the same participants were asked to classify stimuli on the basis of emotional prosody. A final experiment (Experiment 2) focused on sensitivity to congruence in a non-emotional source of variation: talker gender. RESULTS: The results revealed a selective impairment in spontaneous integration of prosodic and semantic cues to emotion in HFA; however, the same participants were able to categorize emotions on the basis of prosody under reduced task demands. Individuals with HFA were highly sensitive to another surface characteristic in speech: talker gender. CONCLUSIONS: The study reveals impairment in the spontaneous integration of prosodic and semantic cues to emotion in HFA; however, insensitivity to surface detail, such as prosody, in HFA appears to be highly task dependent and selective to the domain of emotion. PMID- 24801808 TI - Reduction-responsive cholesterol-based block copolymer vesicles for drug delivery. AB - We developed a new robust reduction-responsive polymersome based on the amphiphilic block copolymer PEG-SS-PAChol. The stability and robustness were achieved by the smectic physical cross-linking of cholesterol-containing liquid crystal polymer PAChol in the hydrophobic layer. The reduction-sensitivity was introduced by the disulfide bridge (-S-S-) that links the hydrophilic PEG block and the hydrophobic PAChol block. We used a versatile synthetic strategy based on atom transfer radical polymerization (ATRP) to synthesize the reduction responsive amphiphilic block copolymers. The reductive cleavage of the disulfide bridge in the block copolymers was first evidenced in organic solution. The partial destruction of PEG-SS-PAChol polymersomes in the presence of a reducing agent was then demonstrated by cryo-electron microscopy. Finally, the calcein release from PEG-SS-PAChol polymersomes triggered by glutathione (GSH) was observed both in PBS suspension and in vitro inside the macrophage cells. High GSH concentrations (>=35 mM in PBS or artificially enhanced in macrophage cells by GSH-OEt pretreatment) and long incubation time (in the order of hours) were, however, necessary to get significant calcein release. These polymersomes could be used as drug carriers with very long circulation profiles and slow release kinetics. PMID- 24801809 TI - Improving cancer patient care with combined medication error reviews and morbidity and mortality conferences. AB - BACKGROUND: To reduce the occurrence of medication errors, a systemic approach was developed combining anti-neoplastic medication error reviews and morbidity and mortality conferences (M&MCs). We report the first experience of implementing this strategy in oncology. METHODS: The case reports submitted to combined reviews were prepared by physicians and pharmacists, and medication error(s) were described and chronological and root-cause analyses were performed. RESULTS: Ten combined reviews were conducted, which involved the departments of haematology, medical oncology, pneumology, gastroenterology and clinical oncology pharmacy. A total of 91 errors were analysed, of which 3 had reached the patient. Thirty-four corrective actions were proposed; 53% consisted of changes in practice, 35% in procedural reminders and 12% in on-ward education sessions. CONCLUSIONS: The combination of medication error reviews and M&MCs appears to be an efficient means of improving cancer patient safety and personnel proficiency. This multidisciplinary work is indispensable to improve future patient management through the critical analysis of past medical errors. PMID- 24801810 TI - Clinical staging in laryngeal cancer: accuracy of the 0- and 30-degree Hopkins rod-lens endoscope in measuring tumour extent: an experimental study with 23 volunteers: Our Experience. PMID- 24801811 TI - Comparison of assessments of fitness to drive for people with dementia. AB - Cognitive tests are used to inform recommendations about the fitness to drive of people with dementia. The Rookwood Driving Battery (RDB) and Dementia Drivers' Screening Assessment (DDSA) are neuropsychological batteries designed to assist in this process. The aim was to assess the concordance between the classifications (pass/fail) of the RDB and DDSA in individuals with dementia, and to compare any discordant classifications against on-road driving ability. Participants were identified by community mental health teams and psychiatrists. Twenty four participants were recruited. The mean age was 74.1 (SD 8.9) years and 18 (75%) were men. Each participant was assessed on the RDB and DDSA in an order determined by random allocation. Those with discrepant results also had an on road assessment. The agreement between the tests was 54% using a cut-off of > 6 on the RDB, and 75% using the cut-off to > 10 on the RDB. Three participants with discrepant results agreed to be assessed on the road and all were found to be safe to drive. The findings suggested that there was poor concurrent validity between the RDB and DDSA. This raises questions about the choice of assessments in making clinical recommendations about fitness to drive in people with dementia. PMID- 24801812 TI - Prognostic value of 18F-fludeoxyglucose uptake in 287 patients with head and neck squamous cell carcinoma. AB - BACKGROUND: The prognostic value of 18F-Fludeoxyglucose (FDG) uptake could be due to its association with already known clinical risk factors. METHODS: Correlation between FDG uptake metrics and other known risk factors from 287 patients were analyzed. Time to any failure was analyzed using Cox proportional hazards model stratified by tumor subsite. The resulting multivariate prognostic model was used to generate a table of 2-year freedom from failure estimates with confidence intervals (CIs). RESULTS: Increasing values of standardized uptake value maximum (SUVmax) correlated with other known risk factors. The reduced Cox model included SUVmax (hazard ratio [HR] = 1.34), cisplatin (HR = 0.37), smoking status (HR = 1.49), and gross target volume (GTV; HR = 1.74) as significant prognostic factors. Including SUVmax in the model changed the 2-year failure estimate by more than 10% for a quarter of the patients (23%). CONCLUSION: FDG uptake retains statistical significance in a multivariate analysis and has clinically relevant prognostic impact. We developed a prognostic model for risk stratification of patients in a clinical setting. PMID- 24801813 TI - Some pyrazole and pyrazolo[3,4-d]pyrimidine derivatives: synthesis and anticancer evaluation. AB - 5-Amino-1-p-tolyl-1H-pyrazole-4-carbonitrile (1) was used for the preparation of some novel pyrazoles and pyrazolo[3,4-d]pyrimidines 2-10. Moreover, the cytotoxicity and in vitro anticancer activities of the prepared compounds were also assessed against the MCF-7 breast cancer, HepG2 liver cancer, and A549 lung carcinoma cell lines, along with investigation of the effect of the synthesized compounds on the expression of urokinase plasminogen activator (uPA). The tested compounds exhibited remarkable cytotoxic activity against MCF-7 and HepG2 cells. Among the tested compounds, 2 and 9 revealed promising anticancer activity compared to the activity of the commonly used anticancer drug, doxorubicin, by inhibiting the expression of uPA. PMID- 24801814 TI - QF-PCR rapid aneuploidy screen and aCGH analysis of cell free fetal (cff) DNA in supernatant of compromised amniotic fluids (AF). AB - OBJECTIVE: The aim of this study was to determine whether cell free fetal (cff) DNA in residual amniotic fluid (AF) supernatant obtained from bloody, low-volume and late gestation samples can be used for prenatal diagnosis by quantitative fluorescence polymerase chain reaction (QF-PCR) and array comparative genomic hybridization (aCGH). METHOD: A total of 49 compromised AFs were analyzed in this case-control, double-blinded study. The samples were processed through: a conventional cytogenetic approach utilizing Fluorescence in situ Hybridization and/or karyotype (Approach I); QF-PCR analysis to establish the presence of maternal cell contamination (MCC) (Approach II) and a newly proposed approach using AF supernatant cff DNA (Approach III). Data on clinical impact and turn around-time was collected. RESULTS: Evidence of MCC was not detected in any of the cff DNA samples, and informative results were provided for all cases, including nine aneuploidies. In contrast, the conventional approach (I) failed to provide results either due to MCC or culture failure in a significant proportion of cases. An adequate amount of quality cff DNA was obtained for successful aCGH testing. CONCLUSION: We have shown that it is feasible to isolate pure cff DNA from routinely discarded AF supernatant to perform QF-PCR and microarray analyses, providing timely and informative results even for problematic grossly bloody and otherwise compromised AF samples or culture failures. PMID- 24801816 TI - Abdominal tuberculosis with periportal lymph node involvement mimicking pancreatic malignancy in an immunocompetent adolescent. AB - Abdominal tuberculosis manifesting as isolated lymphadenopathy is rare, particularly in children. Tuberculous involvement of the pancreatic head and peripancreatic area can simulate a neoplasm of the pancreatic head. To our knowledge, obstructive jaundice caused by tuberculous lymphadenopathy has not been reported in children or adolescents. Here we present radiologic findings in a case of tuberculous lymphadenopathy that mimicked malignancy of the pancreatic head and caused obstructive jaundice in an immunocompetent adolescent. PMID- 24801815 TI - Reduced MIR130A is involved in primary immune thrombocytopenia via targeting TGFB1 and IL18. AB - MicroRNAs (miRNAs) play a vital role in the regulation of immunological functions and prevention of autoimmune disease. The abnormal expressions of several miRNAs in patients with the acquired autoimmune disease, immune thrombocytopenia (ITP), have been reported. However, the exact mechanism of miRNAs in the pathogenesis of ITP is currently not well understood. This study examined the miRNA expression profile of peripheral blood mononuclear cells (PBMCs) in ITP patients by miRNA array and TaqMan real-time polymerase chain reaction. MIR130A expression was found to be significantly decreased in PBMCs from patients with active chronic ITP compared with that of normal controls. Subsequently, dual-luciferase reporter gene analysis was used to validate that MIR130A targeted the transforming growth factor-beta1 (TGFB1) and interleukin 18 (IL18) genes. In addition, we also monitored the dynamic expression of MIR130A and its targeted genes pre- and post treatment of ITP patients and determined that the expression of MIR130A and TGFB1 was up-regulated, whereas IL18 expression was down-regulated after effective treatment. In conclusion, this study suggests that reduced MIR130A is involved in ITP via targeting of TGFB1 and IL18 expression. PMID- 24801817 TI - Intraosseous pseudotumor in a child with hypofibrinogenemia. AB - Intraosseous pseudotumor (i.e. chronic, encapsulated, hemorrhagic fluid collection that can be seen in any portion of the tubular bones) is an uncommon complication of severe hemophilia; however, it can occur with other rare bleeding disorders. We present the case of an 11-year-old girl with hypofibrinogenemia who had multiple intramedullary lesions that were consistent with intramedullary pseudotumor associated with this rare bleeding disorder. Percutaneous biopsy of a pseudotumor is contraindicated due to the high prevalence of complications, including life-threatening bleeding. Therefore, radiologists should make the diagnosis with characteristic MR imaging findings in a patient with a severe coagulation disorder. PMID- 24801818 TI - A randomized controlled trial: child life services in pediatric imaging. AB - BACKGROUND: Children undergoing procedures in pediatric health care facilities and their families have been shown to benefit from psychosocial services and interventions such as those provided by a Certified Child Life Specialist (CCLS). The comprehensive impact of a CCLS in a pediatric imaging department is well recognized anecdotally but has not been examined in a prospective or randomized controlled fashion. OBJECTIVE: We prospectively assessed the impact of a CCLS on parent satisfaction, staff satisfaction, child satisfaction, and parent and staff perceptions of child pain and distress in a pediatric imaging department. MATERIALS AND METHODS: Eligible children between 1 and 12 years of age (n = 137) presenting to the pediatric imaging department for an imaging procedure were randomly assigned to an intervention or control arm. Those assigned to the intervention received the comprehensive services of a CCLS. The control group received standard of care, which did not include any child life services. Quantitative measures of satisfaction and perception of child pain and distress were assessed by parents and staff using a written 5-point Likert scale questionnaire after the imaging procedure. Children 4 and older were asked to answer 3 questions on a 3-point scale. RESULTS: Statistically significant differences between the intervention and control groups were found in 19 out of 24 measures. Parents in the intervention group indicated higher satisfaction and a lower perception of their child's pain and distress. Staff in the intervention group indicated greater child cooperation and a lower perception of the child's pain and distress. Children in the intervention group indicated a better overall experience and less fear than those in the control group. CONCLUSION: Child life specialists have a quantifiably positive impact on the care of children in imaging departments. Measures of parent satisfaction, staff satisfaction, child satisfaction, child pain and child distress are shown to be positively impacted by the services of a CCLS. These results have significant implications for hospitals striving to increase satisfaction, decrease costs and improve quality of care. In a health care landscape that is changing quickly and increasingly focused on the cost of care, future research should assess whether the core tenants of the child life profession support and contribute quantifiably to high quality, cost-effective practices in health care. PMID- 24801819 TI - PENDISC: a simple method for constructing a mathematical model from time-series data of metabolite concentrations. AB - The availability of large-scale datasets has led to more effort being made to understand characteristics of metabolic reaction networks. However, because the large-scale data are semi-quantitative, and may contain biological variations and/or analytical errors, it remains a challenge to construct a mathematical model with precise parameters using only these data. The present work proposes a simple method, referred to as PENDISC (Parameter Estimation in a N on- DImensionalized S-system with Constraints), to assist the complex process of parameter estimation in the construction of a mathematical model for a given metabolic reaction system. The PENDISC method was evaluated using two simple mathematical models: a linear metabolic pathway model with inhibition and a branched metabolic pathway model with inhibition and activation. The results indicate that a smaller number of data points and rate constant parameters enhances the agreement between calculated values and time-series data of metabolite concentrations, and leads to faster convergence when the same initial estimates are used for the fitting. This method is also shown to be applicable to noisy time-series data and to unmeasurable metabolite concentrations in a network, and to have a potential to handle metabolome data of a relatively large scale metabolic reaction system. Furthermore, it was applied to aspartate-derived amino acid biosynthesis in Arabidopsis thaliana plant. The result provides confirmation that the mathematical model constructed satisfactorily agrees with the time-series datasets of seven metabolite concentrations. PMID- 24801820 TI - Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. AB - BACKGROUND: Xenotransplantation using pig cells, tissues, or organs may be associated with the transmission of porcine microorganisms and the development of zoonoses. Among all porcine microorganisms porcine endogenous retroviruses (PERVs) represent a special risk because they are integrated in the genome of all pigs and able to infect human cells. In previous preclinical and retrospective clinical trials of xenotransplantation, no transmission of PERV was observed. The first clinical trial of (alginate-encapsulated) porcine islet cell transplantation in New Zealand, which was approved by the New Zealand Government as an open-label phase I/IIa safety/efficacy trial, offers the possibility to analyze microbiological safety in a prospective clinical study. METHODS: Before the trial started, a multilevel testing strategy was used to screen for 26 microorganisms in donor pigs of the Auckland Island strain and the islet cell preparations used for treatment. Donor testing was performed using molecular methods including multiplex real-time PCR. Blood samples from 14 pig islet cell recipients were also investigated by molecular biological methods at weeks 1, 4, 8, 12, 24, and 52 post-transplant for the transmission of porcine microorganisms. Sera were also monitored at these time points for antibodies against PERVs. RESULTS: Beginning in 2009, fourteen patients with severe unaware hypoglycemia were treated with one of four different dosages of alginate-encapsulated porcine islets ranging from 5000-20,000 islet equivalents delivered in a single dose. No transmission of either PERVs or other porcine microorganisms was detected by PCR and immunological methods. CONCLUSION: These findings support previous results and strongly indicate the safety of xenotransplantation as performed here. PMID- 24801821 TI - Incidence and risk factors of postoperative headache after endovascular coil embolization of unruptured intracranial aneurysms. AB - BACKGROUND: Endovascular coil embolization for unruptured intracranial aneurysms (UIAs) has gained popularity because of its low morbidity and mortality in a short-term context. However, Headache is sometimes brought about or worsened after endovascular treatment, and this complaint may lead to perplexing situations, albeit infrequently. The aim of this study is to estimate the practical incidence and risk factors of postoperative headache in patients with endovascular embolization of UIAs. METHOD: One hundred and thirty patients who underwent endovascular treatment of UIAs between March 2006 and May 2012 were enrolled according to inclusion criteria. From a retrospective chart review, the patients who had worsening or newly developed headache from postoperative day 1 to in-hospital stay were investigated for analyzing risk factors of post embolization headache. Factors based on patients' demographics, anatomical and radiological features of the lesions, treatment, utilized devices and outcome were investigated, and statistically verified. RESULTS: Headache occurred or was exacerbated in 32 patients (24.6 %). Of these, 30 patients showed improvement within days, but two patients with previous migraine history complained of intermittent headache over 3 months after the embolization. Univariate comparison between the headache group and the non-headache group showed that internal carotid artery (ICA) segment aneurysm, stent-assisted coiling, and no history of hypertension were associated with post-embolization headache (p < 0.05). However, stent-assisted coiling and no history of hypertension were significantly associated with post-embolization headache in logistic regression analysis (p < 0.05). CONCLUSIONS: In the current study, stent-assisted coiling and no history of hypertension were important risk factors for headache in patients undergoing endovascular coil embolization for UIAs. Further investigations are still necessary to confirm the correlation of other factors which did not reach statistical significance in post-embolization headache in this limited study. PMID- 24801823 TI - A health policy resource guide for nurses. AB - This column helps nurses and advanced practice nurses learn why it is essential to engage in health policy. It also supports readers in their efforts to discover new understanding and take action. PMID- 24801822 TI - Loss of ERbeta expression in papillary thyroid carcinoma is associated with recurrence in young female. AB - OBJECTIVES: We investigated the expression of oestrogen receptors (ERs) in papillary thyroid cancers (PTCs) and evaluated their prognostic role. METHODS: We enrolled 81 female patients who underwent thyroid surgery and had a confirmed diagnosis of PTC between 01 January 1995 and 31 December 1996. Data on clinicopathologic parameters were obtained from patients' medical records. Tissue paraffin blocks of these 81 patients were collected for immunohistochemistry for ERalpha and ERbeta. RESULTS: ERalpha expression was observed in only eight patients (9.9%). In contrast, ERbeta expression was positive in 36 (44.4%) patients. Total thyroidectomy (84.4% vs 61.1%, P = 0.017) and cervical lymph node metastasis (62.2% vs 22.2%, P = 0.000) were more frequent in the ERbeta-negative group than in the ERbeta-positive group. Among younger female patients (<45 years), the ERbeta-negative group showed a tendency towards more frequent recurrent or persistent disease than the ERbeta-positive group (42.3% vs 13.6%, P = 0.029). In contrast, the ERalpha-positive group showed more recurrent or persistent disease than the ERalpha-negative group in older female patients (100% vs 24.1%, P = 0.024). In multivariate analysis, ERbeta negativity, extrathyroidal invasion and radioactive iodine treatment were risk factors for recurrence in young female patients. CONCLUSION: Loss of ERbeta expression was associated with recurrence in young female PTC patients. This finding suggests that oestrogen might play a protective role in the progression of PTC via ERbeta, especially in young female patients. PMID- 24801824 TI - SEPAR year of the chronic patient and domiciliary respiratory care. Points for reflection. PMID- 24801825 TI - Systematic review of evidence and consensus on diverticulitis: an analysis of national and international guidelines. AB - AIM: The study aimed to analyse the currently available national and international guidelines for areas of consensus and contrasting recommendations in the treatment of diverticulitis and thereby to design questions for future research. METHOD: MEDLINE, EMBASE and PubMed were systematically searched for guidelines on diverticular disease and diverticulitis. Inclusion was confined to papers in English and those < 10 years old. The included topics were classified as consensus or controversy between guidelines, and the highest level of evidence was scored as sufficient (Oxford Centre of Evidence-Based Medicine Level of Evidence of 3a or higher) or insufficient. RESULTS: Six guidelines were included and all topics with recommendations were compared. Overall, in 13 topics consensus was reached and 10 topics were regarded as controversial. In five topics, consensus was reached without sufficient evidence and in three topics there was no evidence and no consensus. Clinical staging, the need for intraluminal imaging, dietary restriction, duration of antibiotic treatment, the protocol for abscess treatment, the need for elective surgery in subgroups of patients, the need for surgery after abscess treatment and the level of the proximal resection margin all lack consensus or evidence. CONCLUSION: Evidence on the diagnosis and treatment of diverticular disease and diverticulitis ranged from nonexistent to strong, regardless of consensus. The most relevant research questions were identified and proposed as topics for future research. PMID- 24801826 TI - Effect of different "states" of sorbed water on amorphous celecoxib. AB - Glass transition temperature (Tg) of an amorphous drug is a vital physical phenomenon that influences its visco-elastic properties, physical, and chemical stability. Water acts as a plasticizer for amorphous drugs thus increasing their recrystallization kinetics. This reduces the solubility advantage of an amorphous drug. Hence, there is an interest in understanding the relationship between water content and Tg of amorphous drug. We have studied the effect of "state" of sorbed water on Tg of amorphous celecoxib (ACLB). ACLB was allowed to sorb water at relative humidity of 33%, 53%, 75%, and 93%. ALCB showed biphasic sorption of water designated as "bound" and "solvent-like" state of water associated with ACLB. Molecular modeling studies provided deeper insights into the interaction of water with ACLB. A distinct co-relationship between the state of water and its plasticization capacity was observed. Bound state of water had a very profound effect on the fall in experimentally observed Tg (T(g-exp)) value. Solvent-like state of water had little impact on T(g-exp) value. Tg of ACLB-water mixture was predicted by Gordon-Taylor equation (T(g-pre)). The deviations in T(g-exp) and Tg pre were correlated to volume non-additivity and non-ideal mixing. This study has implications on the development of formulations based on amorphous forms. PMID- 24801831 TI - Optimal object association in theDempster-Shafer framework. AB - Object association is a crucial step in target tracking and data fusion applications. This task can be formalized as the search for a relation between two sets (e.g., a sets of tracks and a set of observations) in such a way that each object in one set is matched with at most one object in the other set. In this paper, this problem is tackled using the formalism of belief functions. Evidence about the possible association of each object pair, usually obtained by comparing the values of some attributes, is modeled by a Dempster-Shafer mass function defined in the frame of all possible relations. These mass functions are combined using Dempster's rule, and the relation with maximal plausibility is found by solving an integer linear programming problem. This problem is shown to be equivalent to a linear assignment problem, which can be solved in polynomial time using, for example, the Hungarian algorithm. This method is demonstrated using simulated and real data. The 3-D extension of this problem (with three object sets) is also formalized and is shown to be NP-Hard. PMID- 24801832 TI - Directed transport of polymer drops on vibrating superhydrophobic substrates: a molecular dynamics study. AB - Using molecular dynamics simulations of a coarse-grained polymer liquid we investigate the transport of droplets on asymmetrically structured (saw-tooth shaped), vibrating substrates. Due to a continuous supply of power by substrate vibrations and the asymmetry of its topography, the droplets are driven in a preferred direction. We study this directed motion as a function of the size of the droplets, the linear dimensions of the substrate corrugation, and the period of vibrations. Two mechanisms of driven transport are identified: (i) one that relies on the droplet's contact lines and (ii) in a range of vibration periods, the entire contact area contributes to the driving. In this latter regime, the set-up may be used in experiments for sorting droplets according to their size. Additionally, we show that the linear dimension of the substrate corrugation affects the flux inside the droplet. While on a substrate with a fine corrugation droplets mostly slide, on a more coarsely corrugated substrate the flux may exhibit an additional rotation pattern. PMID- 24801833 TI - Improved measurement of intersession latency in mfVEPs. AB - PURPOSE: The purpose of the study is to present a method (Selfcorr) by which to measure intersession latency differences between multifocal VEP (mfVEP) signals. METHODS: The authors compared the intersession latency difference obtained using a correlation method (Selfcorr) against that obtained using a Template method. While the Template method cross-correlates the subject's signals with a reference database, the Selfcorr method cross-correlates traces across subsequent recordings taken from the same subject. RESULTS: The variation in latency between intersession signals was 0.8 +/- 13.6 and 0.5 +/- 5.0 ms for the Template and Selfcorr methods, respectively, with a coefficient of variability CV_TEMPLATE = 15.83 and CV_SELFCORR = 5.68 (n = 18, p = 0.0002, Wilcoxon). The number of analyzable sectors with the Template and Selfcorr methods was 36.7 +/- 8.5 and 45.3 +/- 8.7, respectively (p = 0.0001, paired t test, two tailed). CONCLUSIONS: The Selfcorr method produces smaller intersession mfVEP delays and variability over time than the Template method. PMID- 24801834 TI - Whole-body irradiation increases the magnitude and persistence of adoptively transferred T cells associated with tumor regression in a mouse model of prostate cancer. AB - Adoptive immunotherapy has demonstrated efficacy in a subset of clinical and preclinical studies, but the T cells used for therapy often are rendered rapidly nonfunctional in tumor-bearing hosts. Recent evidence indicates that prostate cancer can be susceptible to immunotherapy, but most studies using autochthonous tumor models demonstrate only short-lived T-cell responses in the tolerogenic prostate microenvironment. Here, we assessed the efficacy of sublethal whole-body irradiation (WBI) to enhance the magnitude and duration of adoptively transferred CD8(+) T cells in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We demonstrate that WBI promoted high-level accumulation of granzyme B (GzB, Gzmb)-expressing donor T cells both in lymphoid organs and in the prostate of TRAMP mice. Donor T cells remained responsive to vaccination in irradiated recipients, but a single round of WBI-enhanced adoptive immunotherapy failed to affect significantly the existing disease. Addition of a second round of immunotherapy promoted regression of established disease in half of the treated mice, with no progression observed. Regression was associated with long-term persistence of effector/memory phenotype CD8(+) donor cells. Administration of the second round of adoptive immunotherapy led to reacquisition of GzB expression by persistent T cells from the first transfer. These results indicate that WBI conditioning amplifies tumor-specific T cells in the TRAMP prostate and lymphoid tissue, and suggest that the initial treatment alters the tolerogenic microenvironment to increase antitumor activity by a second wave of donor cells. PMID- 24801835 TI - Restoration of miR17/20a in solid tumor cells enhances the natural killer cell antitumor activity by targeting Mekk2. AB - Aberrant microRNA (miRNA) expression has been identified in various human solid cancers. However, whether the levels of miRNA expression in tumor cells have any effect on tumor progression has not been determined. In this proof-of-concept study, the restoration of high-level expression of the miR17-92 cluster of miRNAs reveals its function as a tumor suppressor in murine solid cancer cells. Specifically, genetically engineered expression of higher levels of miR17/20a in the miR17-92 cluster in both murine breast cancer and colon cancer cells triggered natural killer (NK)-cell recognition by inhibiting the expression of MHC class I (H-2D) through the Mekk2-Mek5-Erk5 pathway. Results from the mouse tumor studies were recapitulated using samples of human solid tumors. Together, these data indicate that miR17/20a miRNAs function as tumor suppressors by reprogramming tumor cells for NK cell-mediated cytotoxicity. PMID- 24801836 TI - Therapeutic in situ autovaccination against solid cancers with intratumoral poly ICLC: case report, hypothesis, and clinical trial. AB - Pathogen-associated molecular patterns (PAMP) are stand-alone innate and adaptive immunomodulators and critical vaccine components. We present a strategy of sequential intratumoral (i.t.) and intramuscular (i.m.) injections of the stabilized dsRNA viral mimic and PAMP, polyinosinic-polycytidylic acid-polylysine carboxymethylcellulose (poly-ICLC, Hiltonol; Oncovir). We report the first treated patient, a young man with an exceptionally advanced facial embryonal rhabdomyosarcoma with extension to the brain. After treatment, the patient showed tumor inflammation consistent with immunotherapy, followed by gradual, marked tumor regression, with extended survival. Sequential i.t. and i.m. poly-ICLC injections mimicking a viral infection can induce an effective, in situ, personalized systemic therapeutic "autovaccination" against tumor antigens of a patient. We postulate a three-step immunomodulatory process: (i) innate-immune local tumor killing induced by i.t. poly-ICLC; (ii) activation of dendritic cells with Th1 cell- and CTL-weighted priming against the released tumor antigens; and (iii) i.m. poly-ICLC maintenance of the systemic antitumor immune response via chemokine induction, facilitation of CTL killing through the induction of costimulators such as OX40, inflammasome activation, and increase in the T effector/Treg ratio. These results support the use of certain simple and inexpensive i.t. PAMPs to favorably stimulate effective immunity against solid cancers. A phase II clinical trial testing the hypothesis presented has begun accrual (clinicaltrials.gov, NCT01984892). PMID- 24801838 TI - Editorial. PMID- 24801837 TI - The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. AB - Myeloid cells play important regulatory roles within the tumor environment by directly promoting tumor progression and modulating the function of tumor infiltrating lymphocytes, and as such, they represent a potential therapeutic target for the treatment of cancer. Although distinct subsets of tumor-associated myeloid cells have been identified, a broader analysis of the complete myeloid cell landscape within individual tumors and also across different tumor types has been lacking. By establishing the developmental and transcriptomic signatures of infiltrating myeloid cells from multiple primary tumors, we found that tumor associated macrophages (TAM) and tumor-associated neutrophils (TAN), while present within all tumors analyzed, exhibited strikingly different frequencies, gene expression profiles, and functions across cancer types. We also evaluated the impact of anatomic location and circulating factors on the myeloid cell composition of tumors. The makeup of the myeloid compartment was determined by the tumor microenvironment rather than the anatomic location of tumor development or tumor-derived circulating factors. Protumorigenic and hypoxia-associated genes were enriched in TAMs and TANs compared with splenic myeloid-derived suppressor cells. Although all TANs had an altered expression pattern of secretory effector molecules, in each tumor type they exhibited a unique cytokine, chemokine, and associated receptor expression profile. One such molecule, haptoglobin, was uniquely expressed by 4T1 TANs and identified as a possible diagnostic biomarker for tumors characterized by the accumulation of myeloid cells. Thus, we have identified considerable cancer-specific diversity in the lineage, gene expression, and function of tumor-infiltrating myeloid cells. PMID- 24801839 TI - Element analysis of small and even smaller objects by ICPMS and LA-ICPMS. AB - Inductively coupled plasma mass spectrometry is increasingly used for non traditional applications such as the analysis of solids at high spatial resolution when combined with laser ablation or the analysis of engineered nanoparticles. This report highlights recent projects and discusses the potentials and limitations these techniques offer. High-resolution laser ablation instrumentation allows element imaging at the MUm-scale and can, therefore, be applied to, e.g., the mapping of metal isotope-labeled antibodies in biological tissues. Despite these advancements, the quantitative analysis of laser-produced aerosols is still a major concern. Here, the accuracy of analysis was found to strongly depend on particle size distribution but also on the morphology and composition of particles. In order to achieve a controlled supply of nanoparticles for analysis by inductively coupled plasma mass spectrometry, a dedicated microdroplet injection system was developed and characterized. This system allows a reproducible injection of single nanoparticles together with internal standards to determine their mass and composition. PMID- 24801840 TI - Mass spectrometry research at the Laboratory for Organic Chemistry, ETH Zurich. AB - This contribution covers the most important activities of the Zenobi research group at the Organic Chemistry Laboratory, ETH Zurich. We work in a number of interrelated areas that encompass fundamental/mechanistic research, instrument and methods development, and applications. This is illustrated with examples from the mass spectrometric study of noncovalent interactions, using both native ESI and MALDI for ionization, the investigation of the gas-phase conformation of ionized bio-macromolecules, the use of ambient mass spectrometry for rapid, on line analyses of, for example, exhaled breath, and the use of MALDI and microarray technologies for studying metabolites with extreme sensitivity, sufficient to probe the metabolites from single cells. PMID- 24801841 TI - Mass spectrometry in Earth sciences: the precise and accurate measurement of time. AB - Precise determinations of the isotopic compositions of a variety of elements is a widely applied tool in Earth sciences. Isotope ratios are used to quantify rates of geological processes that occurred during the previous 4.5 billion years, and also at the present time. An outstanding application is geochronology, which utilizes the production of radiogenic daughter isotopes by the radioactive decay of parent isotopes. Geochronological tools, involving isotopic analysis of selected elements from smallest volumes of minerals by thermal ionization mass spectrometry, provide precise and accurate measurements of time throughout the geological history of our planet over nine orders of magnitude, from the accretion of the proto-planetary disk, to the timing of the last glaciation. This article summarizes the recent efforts of the Isotope Geochemistry, Geochronology and Thermochronology research group at the University of Geneva to advance the U Pb geochronological tool to achieve unprecedented precision and accuracy, and presents two examples of its application to two significant open questions in Earth sciences: what are the triggers and timescales of volcanic supereruptions, and what were the causes of mass extinctions in the geological past, driven by global climatic and environmental deterioration? PMID- 24801842 TI - Vitamin E and vitamin E acetate absorption from self-assembly systems under pancreas insufficiency conditions. AB - We determined the bioavailability of vitamin E from self-assembly structures in patients with diagnosed chronic pancreas insufficiency. Vitamin E solubilized in dispersed inverted bicontinuous cubic phase and in micellar formulation was delivered directly to the small intestine by tube-feeding. A cross-over study with randomization of 6 subjects and 2 treatments including a combined dose of 18 mg (27 IU) of vitamin E (RRR-[5,7-methyl-((2)H6)]-alpha-tocopherol) and 27 mg (27 IU) vitamin E acetate (RRR-[5-methyl-(2)H3]-alpha-tocopheryl acetate) was applied over a time period of 1 h. Plasma samples were collected for 56 h and analyzed by liquid chromatography-mass spectrometry. Appearance of labeled tocopherols originating from the treatment started at 25 h and reached Cmax (0.6-4.6 MUM depending on subject) in the 7-9 h window. From the Tmax onwards, both forms of tocopherols diminished slowly to 30-50% of their maxima within 56 h. Strong inter individual variation was observed in the plasma appearance curves (relative standard deviation varied between 38-45%). No significant discrimination was found between the absorption of free or acetylated forms of deuterated alpha tocopherol confirming that application of acetylated alpha-tocopherol provides the same bioavailability as free alpha-tocopherol. This observation is valid in both dispersed inverted bicontinuous cubic phase and micellar formulations. Furthermore, since the area-under-the-curve values from cubic phase and from micellar formulations are similar, the cubic phase formulation could represent an alternative delivery system for lipophilic micronutrients in conditions or studies where polysorbate-based micelles cannot be generated. PMID- 24801843 TI - Comparison of UHPLC-ESI-MS and Hadamard transform atmospheric pressure ion mobility-ESI-MS for rapid profiling of isomeric flavonoids. AB - Hadamard transform atmospheric pressure ion mobility-MS and rapid UHPLC-MS methods were investigated for analysis of closely related isomeric flavonoids and their glycosides using a test set of seven standards. On a time scale of a few minutes, the flavonoid aglycones were all separated by ion mobility, but not by UHPLC. The glycosides were better resolved by IMS but not completely separated by both methods. The results suggest that IMS provides sufficient resolution for separation of isomeric polyphenols such as flavonoids in high-throughput metabolomics studies. PMID- 24801844 TI - Mass spectrometry in environmental toxicology. AB - In environmental toxicology, mass spectrometry can be applied to evaluate both exposure to chemicals as well as their effects in organisms. Various ultra-trace techniques are employed today to measure pollutants in different environmental compartments. Increasingly, effect-directed analysis is being applied to focus chemical monitoring on sites of ecotoxicological concern. Mass spectrometry is also very instrumental for studying the interactions of chemicals with organisms on the molecular and cellular level, providing new insights into mechanisms of toxicity. In the future, diverse mass spectrometry-based techniques are expected to become even more widely used in this field, contributing to the refinement of currently used environmental risk assessment strategies. PMID- 24801845 TI - iMatrixSpray: a free and open source sample preparation device for mass spectrometric imaging. AB - A device was built for matrix deposition in mass spectrometric imaging. This spray-type instrument requires no user interaction other than providing the spray solution and selecting the pre-defined or custom-built method. Robustness was achieved by utilizing a delta-robotics design in combination with a simple liquid system. All the information describing the systems is provided as open source and hardware and the design is therefore suitable for wide distribution and adaption by the scientific community. PMID- 24801846 TI - Liquid extraction surface analysis (LESA) of hydrophobic TLC plates coupled to chip-based nanoelectrospray high-resolution mass spectrometry. AB - Direct identification and structural characterization of analyte spots on TLC plates have always been of great interest and the development of interfaces that allow TLC to be combined with MS is making steady progress. The recently introduced liquid extraction surface analysis (LESA) approach has the potential to hyphenate TLC with MS. A mixture of lipid standards was separated on HPTLC RP 18 glass plates using chloroform:methanol :acetonitrile 2:1:1 (v:v:v) as mobile phase. After visualization with primuline dye (0.02% in acetone:water 8:2 (v:v)), LESA was performed, followed by a chip-based nanoflow infusion in combination with FTICRMS. The optimized extraction solvent composition was methanol:chloroform:water:formic acid 52:24:24:0.2 (v:v:v:v). A nanoelectrospray voltage of 1.6 kV and a gas pressure of 0.2 psi were applied in all experiments. All phospholipids were extracted successfully and detected unambiguously using the optimized TLC-LESA-FTICRMS procedure. Sampling the tricaprylin spot gave the most intense signals and also tricaprin was detected. Three other triacylglycerols of higher molecular mass have logP values between 15.5 and 21.6, which are the highest among all investigated compounds and are not detected from their corresponding spots, due to the fact that the solubility of very apolar lipids is not high enough in the extraction solvent. It was demonstrated that TLC can be elegantly combined with mass spectrometry based on the LESA approach. In general, apart from the analysis of lipids, TLC-LESA-MS has a high potential for medium-polar compounds separated on reversed-phase TLC plates, but limitations are present when very apolar compounds have to be extracted. PMID- 24801847 TI - Conquering the outdoors with on-site mass spectrometry. AB - In recent years, mass spectrometers with a membrane inlet separating gases from water for final analysis have been used successfully for the on-site quantification of dissolved gases in surface waters. In 'classical' membrane inlet mass spectrometers (MIMS), the membrane directly separates the water from the high-vacuum environment of the mass spectrometer. The gas equilibrium MIMS (GE-MIMS) that is described in this review, however, makes use of an intermediate pressure reduction stage after the membrane inlet. Hence, the gas concentrations after the membrane are at steady state, near solubility equilibrium with the water to be analyzed. This setup has several advantages over classical MIMS, which enable autonomous and continuous in-field operation. The GE-MIMS can be used to acquire noble gas concentration time series (NGTS). Noble gases are useful tracers for physical gas exchange and transport in groundwater and other aqueous systems. Hence NGTS enable the temporal dynamics of physical gas exchange and transport in groundwater and other aqueous systems to be investigated. To determine the O2 turnover that has occurred in groundwater since recharge, both the O2 concentration in situ and the total input of O2 to the groundwater since recharge is needed. Determination of the latter is only possible if the relevant physical exchange and transport mechanisms can be quantified. In particular, gas exchange between soil air and groundwater often significantly affects groundwater O2 concentrations. Determination of O2 turnover in groundwater therefore requires a combined analysis of O2 and noble gas concentrations. PMID- 24801848 TI - 50 years of mass spectrometry at Firmenich: a continuing love story. AB - Mass spectrometry (MS) has been intensively used in the field of flavor and fragrance since its beginning in the 1950s, and it remains an essential technique for current and future research in this field. After a short historical section on the introduction and development of MS at Firmenich, this work reviews the main applications of MS-based techniques published by Firmenich researchers over the past 5 years. It exemplifies the use of gas chromatography (GC)-MS for the discovery of new odorant - hence volatile - molecules in a broad range of natural products, such as fruits, meats, and vegetables. Non-volatile compounds play a major role in taste attributes and are also possible precursors of odorant molecules. Their identification by liquid chromatography (LC)-MS in the context of malodor generation from sweat is a typical example of such a relationship. With their high selectivity and sensitivity, GC-MS and LC-MS instruments are used in the fields of flavor and fragrance not only for identification, but also as unique tools for the accurate quantitation of compounds in complex matrices. This is particularly important for regulatory analyses such as dosage of potential allergens in perfumes and for the development of delivery systems. Finally, because of the rapid response time of MS, the kinetics of processes such as the release of flavors in the mouth during food consumption can be monitored by direct sampling into the mass spectrometer. PMID- 24801849 TI - Elucidation of nucleic acid-drug interactions by tandem mass spectrometry. AB - In continuation of the long tradition of mass spectrometric research at the University of Bern, our group focuses on the characterization of nucleic acids as therapeutic agents and as drug targets. This article provides a short overview of our recent work on platinated single-stranded and higher-order nucleic acids. Nearly three decades ago the development of soft ionization techniques opened a whole new chapter in the mass spectrometric analysis of not only nucleic acids themselves, but also their interactions with potential drug candidates. In contrast to modern next generation sequencing approaches, though, the goal of the tandem mass spectrometric investigation of nucleic acids is by no means the complete sequencing of genetic DNA, but rather the characterization of short therapeutic and regulatory oligonucleotides and the elucidation of nucleic acid drug interactions. The influence of cisplatin binding on the gas-phase dissociation of nucleic acids was studied by the means of electrospray ionization tandem mass spectrometry. Experiments on native and modified DNA and RNA oligomers confirmed guanine base pairs as the preferred platination site and laid the basis for the formulation of a gas-phase fragmentation mechanism of platinated oligonucleotides. The study was extended to double-stranded DNA and DNA quadruplexes. While duplexes are believed to be the main target of cisplatin in vivo, the recently discovered DNA quadruplexes constitute another promising target for anti-tumor drugs owing to their regulatory functions in the cell cycle. PMID- 24801850 TI - From high- to super-resolution mass spectrometry. AB - High-resolution mass spectrometry (MS) is indispensable for the molecular-level analysis of biological and environmental samples with great intra- and inter molecular complexity. Here, we summarize developments in Fourier transform mass spectrometry (FTMS), the flagship of high-resolution MS techniques, accomplished in our laboratory. Particularly, we describe the recent and envisioned progress in structural analysis of: i) isolated large proteins and their simple mixtures, with a focus on monoclonal antibodies, via top-down, middle-down, and extended bottom-up mass spectrometry; ii) complex protein mixtures and proteomes via extended bottom-up proteomics; and iii) crude oil fractions and similar complex molecular mixtures. Despite the unequivocal success in molecular structural analysis, the demonstrated results clearly indicate that the compromise between MS acquisition speed (throughput) and achievable resolution level inhibits further advances of MS applications in the areas related to life, environmental, and material sciences. To further advance beyond state-of-the-art FTMS capabilities in these areas, we present the technique of super-resolution mass spectrometry that has been pioneered by our laboratory. PMID- 24801852 TI - Appraising Alfred Werner's groundbreaking ideas. AB - The Chemical Institutes of the University of Zurich celebrate the 100(th) anniversary of the Nobel prize award to Alfred Werner in 1913. PMID- 24801853 TI - Freshness indices of roasted coffee: monitoring the loss of freshness for single serve capsules and roasted whole beans in different packaging. AB - With the growing demand for high-quality coffee, it is becoming increasingly important to establish quantitative measures of the freshness of coffee, or the loss thereof, over time. Indeed, freshness has become a critical quality criterion in the specialty coffee scene, where the aim is to deliver the most pleasant flavor in the cup, from highest quality beans. A series of intensity ratios of selected volatile organic compounds (VOC) in the headspace of coffee (by gas chromatography-mass spectrometry) were revisited, with the aim to establish robust indicators of freshness of coffee - called freshness indices. Roasted whole beans in four different packaging materials and four commercial capsule systems from the Swiss market were investigated over a period of up to one year of storage time. These measurements revealed three types of insight. First, a clear link between barrier properties of the packaging material and the evolution of selected freshness indices was observed. Packaging materials that contain an aluminum layer offer better protection. Second, processing steps prior to packaging are reflected in the absolute values of freshness indices. Third, differences in the standard deviations of freshness-indices for single serve coffee capsule systems are indicative of differences in the consistency among systems, consistency being an important quality attribute of capsules. PMID- 24801857 TI - Photocaging of carboxylic acids: a modular approach. AB - Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support. PMID- 24801858 TI - A comparison of six methods for stabilizing population dynamics. AB - Over the last two decades, several methods have been proposed for stabilizing the dynamics of biological populations. However, these methods have typically been evaluated using different population dynamics models and in the context of very different concepts of stability, which makes it difficult to compare their relative efficiencies. Moreover, since the dynamics of populations are dependent on the life-history of the species and its environment, it is conceivable that the stabilizing effects of control methods would also be affected by such factors, a complication that has typically not been investigated. In this study, we compare six different control methods with respect to their efficiency at inducing a common level of enhancement (defined as 50% increase) for two kinds of stability (constancy and persistence) under four different life history/environment combinations. Since these methods have been analytically studied elsewhere, we concentrate on an intuitive understanding of realistic simulations incorporating noise, extinction probability and lattice effect. We show that for these six methods, even when the magnitude of stabilization attained is the same, other aspects of the dynamics like population size distribution can be very different. Consequently, correlated aspects of stability, like the amount of persistence for a given degree of constancy stability (and vice versa) or the corresponding effective population size (a measure of resistance to genetic drift) vary widely among the methods. Moreover, the number of organisms needed to be added or removed to attain similar levels of stabilization also varies for these methods, a fact that has economic implications. Finally, we compare the relative efficiencies of these methods through a composite index of various stability related measures. Our results suggest that Lower Limiter Control (LLC) seems to be the optimal method under most conditions, with the recently proposed Adaptive Limiter Control (ALC) being a close second. PMID- 24801859 TI - An in-silico study of the regulation of CHO cells glycolysis. AB - In this work, a kinetic-metabolic model previously developed for CHO cells is used to study glycolysis regulation. The model is assessed for its biological relevance by analyzing its ability to simulate metabolic events induced following a hypoxic perturbation. Feedback and feedforward regulatory mechanisms known to occur to either inhibit or activate fluxes of glycolysis, are implemented in various combined scenarios and their effects on the metabolic response were analyzed. This study aims at characterizing the role of intermediates of glycolysis and of the cell energetic state, described as the AMP-to-ATP ratio, as inhibitors and activators of glycolysis pathway. In addition to the glycolysis pathway, we here describe the transient metabolic response of pathways that are connected to glycolysis, such as the pentose phosphate pathway, TCA cycle, cell bioenergetics system, glutamine and amino acids metabolisms. Taken individually, each regulatory mechanism leads to an oscillatory behavior in response to a hypoxic perturbation, while their combination clearly damps oscillations. However, only the addition of the cell energetic state to the regulatory mechanisms results in a non-oscillating response leading to metabolic flux rate rearrangement corresponding to the anaerobic metabolism expected to prevail under hypoxic conditions. We thus demonstrate in this work, from model simulations, that the robustness of a cell energetic metabolism can be described from a combination of feedback and feedforward inhibition and activation regulatory mechanisms of glycolysis fluxes, involving intermediates of glycolysis and the cell energetic state itself. PMID- 24801862 TI - Recurrence of hepatocellular carcinoma: importance of mRECIST response to chemoembolization and tumor size. AB - Determining risk for recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) is an important clinical need. We assessed consecutive patients who underwent LT for HCC following sequential transarterial chemoembolization (TACE). Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Cox proportional hazard models were used to predict HCC recurrence. One hundred seventy-three patients underwent TACE and imaging to assess response prior to LT. TACE responses were: CR = 23.7%, PR = 24.3%, SD = 27.7% and PD = 24.3%. Five-year HCC recurrence rate was 5.3% in patients responding to TACE (CR/PR), versus 17.6%, among patients who did not respond (SD/PD, p = 0.014). In multivariate analysis, independent pre-LT predictors of recurrence were response to TACE and largest radiologic size of tumor (>3 cm vs. <=3 cm). HCC recurrence rate for patients with tumor size >3 cm and no response to TACE was 35.8%, compared with 1.9% for patients with tumor size <=3 cm and response to TACE (p = 0.0007). We conclude that mRECIST criteria and tumor size differentiate patients with high or low likelihood of HCC recurrence after LT. These findings raise the possibility of incorporating response to TACE and largest tumor size to identify patients at highest risk for HCC recurrence. PMID- 24801863 TI - Total transverse rupture of the duodenum after blunt abdominal trauma. AB - AIM: Complete transverse rupture of the duodenum as an isolated lesion in blunt trauma can be considered as exceptional. The aim of this report is to discuss diagnostic procedures and surgical options in such an infrequent presentation. CASE EXPERIENCE: We report on a 37 year old man who had a total transverse rupture of the duodenum after blunt abdominal trauma. Diagnosis was suspected after contrast enhanced CT scan and confirmed at laparotomy; duodenal rupture was repaired by an end to end duodenal-duodenal anastomosis, after Kocher maneuver. The patient had fast and complete recovery. DISCUSSION: A high index of suspicion is necessary for timely diagnosis. Multi detector contrast enhanced CT scan is the gold standard for that aim. Surgical management must be tailored on an individual basis, since many techniques are available for both reconstruction and duodenum decompression. Kocher maneuver is essential for complete inspection of the pancreatic duodenal block and for appropriate reconstruction. CONCLUSIONS: Management of isolated duodenal rupture can be difficult. Contrast enhanced TC scans is essential for timely diagnosis. Primary repair can be achieved by an end to end duodenum anastomosis after Kocher maneuver, although alternative techniques are available for tailored solutions. Complex duodenum decompression techniques are not mandatory. PMID- 24801860 TI - Comparing dengue and chikungunya emergence and endemic transmission in A. aegypti and A. albopictus. AB - Chikungunya and dengue are re-emerging mosquito-borne infectious diseases that are of increasing concern as human travel and expanding mosquito ranges increase the risk of spread. We seek to understand the differences in transient and endemic behavior of chikungunya and dengue; risk of emergence for different virus vector assemblages; and the role that virus evolution plays in disease dynamics and risk. To address these questions, we adapt a mathematical mosquito-borne disease model to chikungunya and dengue in Aedes aegypti and Aedes albopictus mosquitoes. We derive analytical threshold conditions and important dimensionless parameters for virus transmission; perform sensitivity analysis on quantities of interest such as the basic reproduction number, endemic equilibrium, and first epidemic peak; and compute distributions for the quantities of interest across parameter ranges. We found that chikungunya and dengue exhibit different transient dynamics and long-term endemic levels. While the order of most sensitive parameters is preserved across vector-virus combinations, the magnitude of sensitivity is different across scenarios, indicating that risk of invasion or an outbreak can change with vector-virus assemblages. We found that the dengue - A. aegypti and new Reunion strain of chikungunya - A. albopictus systems represent the highest risk across the range of parameters considered. These results inform future experimental and field research efforts and point toward effective mitigation strategies adapted to each disease. PMID- 24801864 TI - Evaluation of bias, precision, robustness and runtime for estimation methods in NONMEM 7. AB - NONMEM is the most widely used software for population pharmacokinetic (PK) pharmacodynamic (PD) analyses. The latest version, NONMEM 7 (NM7), includes several sampling-based estimation methods in addition to the classical methods. In this study, performance of the estimation methods available in NM7 was investigated with respect to bias, precision, robustness and runtime for a diverse set of PD models. Simulations of 500 data sets from each PD model were reanalyzed with the available estimation methods to investigate bias and precision. Simulations of 100 data sets were used to investigate robustness by comparing final estimates obtained after estimations starting from the true parameter values and initial estimates randomly generated using the CHAIN feature in NM7. Average estimation time for each algorithm and each model was calculated from the runtimes reported by NM7. The method giving the lowest bias and highest precision across models was importance sampling, closely followed by FOCE/LAPLACE and stochastic approximation expectation-maximization. The methods relative robustness differed between models and no method showed clear superior performance. FOCE/LAPLACE was the method with the shortest runtime for all models, followed by iterative two-stage. The Bayesian Markov Chain Monte Carlo method, used in this study for point estimation, performed worst in all tested metrics. PMID- 24801871 TI - Impaired insulin signaling affects renal organic anion transporter 3 (Oat3) function in streptozotocin-induced diabetic rats. AB - Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCzeta) inhibitors inhibited insulin stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCzeta in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCzeta/Akt/PKB signaling pathway. PMID- 24801873 TI - Formation of breath figure arrays in methanol vapor assisted by surface active agents. AB - Breath figure (BF) process is a promising technique for fabricating honeycomb polymer films. It is usually conducted in water vapor. While, in organic vapors only unique polymer can be used to prepare BF arrays as reported in our previous article (Breath Figure in Nonaqueous Vapor. Soft Matter, 2013, 506-514), although new structure features are induced in the film. In this paper, a universal modified BF processing is devised for preparing porous films in methanol vapor with conventional polymers, by adding a small amount of surface active agent into the casting solution, such as siloxane- and fluorine-containing block copolymers. The pores in the PS films prepared with this method are of cylindrical shape with large depth-diameter aspect ratio, and the diameter and depth of pores can be well controlled by the experiment conditions. Based on these results, the formation mechanism of honeycomb structure in methanol vapor is discussed. PMID- 24801874 TI - Dependence of V2 illusory contour response on V1 cell properties and topographic organization. AB - An illusory contour is an image that is perceived as a contour in the absence of typical contour characteristics, such as a change in luminance or chromaticity across the stimulus. In cats and primates, cells that respond to illusory contours are sparse in cortical area V1, but are found in greater numbers in cortical area V2. We propose a model capable of illusory contour detection that is based on a realistic topographic organization of V1 cells, which reproduces the responses of individual cell types measured experimentally. The model allows us to explain several experimentally observed properties of V2 cells including variability in orientation tuning and inducer spacing preference. As a practical application, the model can be used to estimate the relationship between the severity of a cortical injury in the primary visual cortex and the deterioration of V2 cell responses to real and illusory contours. PMID- 24801872 TI - Serum YKL-40 level is associated with the chemotherapy response and prognosis of patients with small cell lung cancer. AB - This study was to explore the association between the serum YKL-40 level and the clinical characteristics, the response to chemotherapy and prognosis in small cell lung cancer (SCLC). Serum YKL-40 levels were detected and compared in 120 patients with SCLC pre- and post-chemotherapy, and in 40 healthy controls. Receiver operating characteristics (ROC) curves were adopted for diagnosis and calculation of area under ROC curve in SCLC. The Kaplan-Meier method, univariate and multivariate Cox regression analysis were used to analyze the correlation between pre-chemotherapy serum YKL-40 levels and progression-free survival (PFS) and overall survival (OS). The pre-chemotherapy serum YKL-40 levels were significantly higher than those of the controls (p<0.001). The post-chemotherapy serum YKL-40 levels in the SCLC cases were lower than pre-chemotherapy serum YKL 40 levels in these cases (p = 0.026). The patients with high serum YKL-40 showed a poorer response to chemotherapy than those patients with low serumYKL-40 (p = 0.031). Univariate analysis revealed that SCLC patients with high serum YKL-40 had a shorter PFS and OS than those with low serum YKL-40 (HR of 1.74, p = 0.033; HR of 1.33, p = 0.001). Cox multivariate analysis indicated that YKL-40 was an independent prognostic indicator of PFS and OS (HR of 1.12, p = 0.029; HR of 1.84, p = 0.025). Kaplan-Meier survival curves further confirmed that patients with low serum YKL-40 have longer PFS and OS (p = 0.016 and p = 0.041, respectively). These results suggest that YKL-40 is a potential prognostic marker of chemotherapy response in SCLC. PMID- 24801875 TI - Volumetric fibular transfer planning with shape-based indicators in mandibular reconstruction. AB - In preoperative planning for mandibular reconstructive surgery, it is necessary to determine the osteotomy lines for fibular shaping and the proper placement of fibular segments in the mandible. Although virtual surgical planning has been utilized in preoperative decision making, current software designs require manual operation and a trial-and-error process to refine the reconstruction plan. We have developed volumetric fibular transfer simulation software that can quickly design a preoperative plan based on direct volume manipulation and quantitative comparison with the patient's original mandible. We propose three quantitative shape indicators-volume ratio, contour error, and maximum projection-for symmetrical lesions of the mandible, and have implemented a parallel computation algorithm for the semiautomatic placement of fibular segments. Using this virtual planning software, we conducted a retrospective study of the computed tomography data from nine patients. We found that combining direct volume manipulation with real-time local search of placement improved the applicability of the planning system to optimize mandibular reconstruction. PMID- 24801876 TI - The kinematics of cytotoxic lymphocytes influence their ability to kill target cells. AB - Cytotoxic lymphocytes (CTL) have been reported to show a range of motility patterns from rapid long-range tracking to complete arrest, but how and whether these kinematics affect their ability to kill target cells is not known. Many in vitro killing assays utilize cell lines and tumour-derived cells as targets, which may be of limited relevance to the kinetics of CTL-mediated killing of somatic cells. Here, live-cell microscopy is used to examine the interactions of CTL and primary murine skin cells presenting antigens. We developed a qualitative and quantitative killing assay using extended-duration fluorescence time-lapse microscopy coupled with large-volume objective software-based data analysis to obtain population data of cell-to-cell interactions, motility and apoptosis. In vivo and ex vivo activated antigen-specific cytotoxic lymphocytes were added to primary keratinocyte targets in culture with fluorometric detection of caspase-3 activation in targets as an objective determinant of apoptosis. We found that activated CTL achieved contact-dependent apoptosis of non-tumour targets after a period of prolonged attachment - on average 21 hours - which was determined by target cell type, amount of antigen, and activation status of CTL. Activation of CTL even without engagement of the T cell receptor was sufficient to mobilise cells significantly above baseline, while the addition of cognate antigen further enhanced their motility. Highly activated CTL showed markedly increased vector displacement, and velocity, and lead to increased antigen-specific target cell death. These data show that the inherent kinematics of CTL correlate directly with their ability to kill non-tumour cells presenting cognate antigen. PMID- 24801877 TI - New Ianthelliformisamine derivatives as antibiotic enhancers against resistant Gram-negative bacteria. AB - A series consisting of ianthelliformisamimes A, B, and C as well as its synthetic analogues was prepared in high chemical yield, from 27 to 91%, using peptide coupling as the key step, and the compounds were evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria and clinical isolates. The mechanism of action of one of these derivatives against Pseudomonas aeruginosa when combined with doxycycline was precisely evaluated utilizing bioluminescence to measure ATP efflux and fluorescence to evaluate membrane depolarization. PMID- 24801879 TI - Franck-Condon blockade in a single-molecule transistor. AB - We investigate vibron-assisted electron transport in single-molecule transistors containing an individual Fe4 Single-Molecule Magnet. We observe a strong suppression of the tunneling current at low bias in combination with vibron assisted excitations. The observed features are explained by a strong electron vibron coupling in the framework of the Franck-Condon model supported by density functional theory. PMID- 24801878 TI - Induction of protective effector immunity to prevent pathogenesis caused by the respiratory syncytial virus. Implications on therapy and vaccine design. AB - Human respiratory syncytial virus (hRSV) is the leading cause of respiratory illness in infants and young children around the globe. This pathogen, which was discovered in 1956, continues to cause a huge number of hospitalizations due to respiratory disease and it is considered a health and economic burden worldwide, especially in developing countries. The immune response elicited by hRSV infection leads to lung and systemic inflammation, which results in lung damage but is not efficient at preventing viral replication. Indeed, natural hRSV infection induces a poor immune memory that allows recurrent infections. Here, we review the most recent knowledge about the lifecycle of hRSV, the immune response elicited by this virus and the subsequent pathology induced in response to infection in the airways. Novel findings about the alterations that this virus causes in the central nervous system and potential therapies and vaccines designed to treat or prevent hRSV infection are discussed. PMID- 24801880 TI - Genetic structure and molecular variability of Cucumber mosaic virus isolates in the United States. AB - Cucumber mosaic virus (CMV) has a worldwide distribution and the widest host range of any known plant virus. From 2000 to 2012, epidemics of CMV severely affected the production of snap bean (Phaseulos vulgaris L.) in the Midwest and Northeastern United States. Virus diversity leading to emergence of new strains is often considered a significant factor in virus epidemics. In addition to epidemics, new disease phenotypes arising from genetic exchanges or mutation can compromise effectiveness of plant disease management strategies. Here, we captured a snapshot of genetic variation of 32 CMV isolates collected from different regions of the U.S including new field as well as historic isolates. Nucleotide diversity (pi) was low for U.S. CMV isolates. Sequence and phylogenetic analyses revealed that CMV subgroup I is predominant in the US and further showed that the CMV population is a mixture of subgroups IA and IB. Furthermore, phylogenetic analysis suggests likely reassortment between subgroups IA and IB within five CMV isolates. Based on phylogenetic and computational analysis, recombination between subgroups I and II as well as IA and IB in RNA 3 was detected. This is the first report of recombination between CMV subgroups I and II. Neutrality tests illustrated that negative selection was the major force operating upon the CMV genome, although some positively selected sites were detected for all encoded proteins. Together, these data suggest that different regions of the CMV genome are under different evolutionary constraints. These results also delineate composition of the CMV population in the US, and further suggest that recombination and reassortment among strain subgroups does occur but at a low frequency, and point towards CMV genomic regions that differ in types of selection pressure. PMID- 24801881 TI - Preconditioning with glutamine protects against ischemia/reperfusion-induced hepatic injury in rats with obstructive jaundice. AB - OBJECTIVE: To ascertain whether glutamine (Gln) pretreatment protects rats with obstructive jaundice from hepatic ischemia/reperfusion (I/R) injury and to determine the underlying molecular mechanisms. METHODS: An obstructive jaundice rat model was developed by bile duct ligation. On the first day after the operation, all rats were randomized into two groups and received oral Gln or normal saline (NS) daily for 7 days. Then both groups underwent a 15-min liver ischemia via the Pringle maneuver. Blood samples as well as liver and intestinal tissues were harvested and measured after 1, 6 and 24 h of reperfusion. RESULTS: The results showed that the histological morphology of the liver and intestinal tissues significantly improved in the Gln group after I/R injury compared with the NS group. Serum proteins and enzymes associated with hepatic function also significantly improved in the Gln group. The level of glutathione increased and the levels of malondialdehyde and myeloperoxidase decreased in the Gln group. The levels of interleukin-1beta and tumor necrosis factor-alpha decreased in the Gln group. Moreover, bcl-2 protein expression was upregulated and intercellular adhesion molecule 1 and bax protein expression downregulated in the Gln group; the caspase 3 mRNA level significantly increased in the Gln group. CONCLUSIONS: The study demonstrates that preconditioning with Gln significantly improves hepatic structure and function after I/R injury in rats with obstructive jaundice. The protective effect of Gln was mediated by the inhibition of reactive oxygen species and inflammation as well as a reduction in hepatocyte apoptosis. PMID- 24801882 TI - Voluntary medical male circumcision (VMMC) in Tanzania and Zimbabwe: service delivery intensity and modality and their influence on the age of clients. AB - BACKGROUND: Scaling up voluntary medical male circumcision (VMMC) to 80% of men aged 15-49 within five years could avert 3.4 million new HIV infections in Eastern and Southern Africa by 2025. Since 2009, Tanzania and Zimbabwe have rapidly expanded VMMC services through different delivery (fixed, outreach or mobile) and intensity (routine services, campaign) models. This review describes the modality and intensity of VMMC services and its influence on the number and age of clients. METHODS AND FINDINGS: Program reviews were conducted using data from implementing partners in Tanzania (MCHIP) and Zimbabwe (PSI). Key informant interviews (N = 13 Tanzania; N = 8 Zimbabwe) were conducted; transcripts were analyzed using Nvivo. Routine VMMC service data for May 2009-December 2012 were analyzed and presented in frequency tables. A descriptive analysis and association was performed using the z-ratio for the significance of the difference. Key informants in both Tanzania and Zimbabwe believe VMMC scale-up can be achieved by using a mix of service delivery modality and intensity approaches. In Tanzania, the majority of clients served during campaigns (59%) were aged 10-14 years while the majority during routine service delivery (64%) were above 15 (p<0.0001). In Zimbabwe, significantly more VMMCs were done during campaigns (64%) than during routine service delivery (36%) (p<0.00001); the difference in the age of clients accessing services in campaign versus non campaign settings was significant for age groups 10-24 (p<0.05), but not for older groups. CONCLUSIONS: In Tanzania and Zimbabwe, service delivery modalities and intensities affect client profiles in conjunction with other contextual factors such as implementing campaigns during school holidays in Zimbabwe and cultural preference for circumcision at a young age in Tanzania. Formative research needs to be an integral part of VMMC programs to guide the design of service delivery modalities in the face of, or lack of, strong social norms. PMID- 24801883 TI - Pregnancy complications and neuropsychological outcomes: A review. AB - Pregnancy complications elevate risk of associated adverse medical, socioenvironmental, and behavioral outcomes in children. These are likely to have a substantial impact on neuropsychological functioning and mental health across the child's lifespan. Thus, an understanding of the complex relationships between pregnancy complications and neuropsychological outcomes is critical for both practitioners and researchers. This review summarizes prevalent pregnancy complications and the associated psychological and neuropsychological findings, highlighting methodological challenges that have restricted investigations of these outcomes and identifying opportune areas for future study. PMID- 24801884 TI - A better resolution for integrating methods for monitoring Plasmodium falciparum resistance to antimalarial drugs. AB - Effective chemotherapy is the mainstay of malaria control. However, resistance of falciparum malaria to antimalarial drugs compromised the efforts to eliminate the disease and led to the resurgence of malaria epidemics. Three main approaches are used to monitor antimalarial drug efficacy and drug resistance; namely, in vivo trials, in vitro/ex vivo assays and molecular markers of drug resistance. Each approach has its implications of use as well as its advantages and drawbacks. Therefore, there is a need to use an integrated approach that would give the utmost effect to detect resistance as early as its emergence and to track it once spread. Such integration becomes increasingly needed in the era of artemisinin based combination therapy as a forward action to deter resistance. The existence of regional and global networks for the standardization of methodology, provision of high quality reagents for the assessment of antimalarial drug resistance and dissemination of open-access data would help in approaching an integrated resistance surveillance system on a global scale. PMID- 24801885 TI - Evaluation of three recombinant Leishmania infantum antigens in human and canine visceral leishmaniasis diagnosis. AB - Visceral leishmaniasis (VL) is a neglected disease and is fatal if untreated. Dogs serve as reservoirs for Leishmania infantum (syn. L. chagasi) due to their susceptibility to infection and high skin parasitism. Therefore, VL control in Brazil involves the elimination of seropositive dogs, among other actions. However, the most frequently used serological tests have limitations regarding sensitivity and specificity. In this study, we have selected three Leishmania antigens (C1, C8 and C9) and have produced them as recombinant proteins using pET 28a-TEV vector and Escherichia coli BL-21 as expression system. When tested in ELISA with human samples, the C9 antigen was the one showing the most promising results, with 68% sensitivity and 78% specificity. When testing canine samples, the C1, C8 and C9 antigens showed a sensitivity range from 70% to 80% and specificity range from 60% to 90%. The C1 antigen presented higher sensitivity (80%) and the C8 antigen presented higher specificity (90%). Due to it, we decided to mix and test C1 and C8 antigens together, resulting in the C18 antigen. The mix also yielded high percentages of detected symptomatic and asymptomatic dogs however it did not improve the performance of the diagnostic. Comparison of our tests with the tests recommended by the Brazilian Ministry of Health revealed that our antigens' sensitivities and the percentage of detected asymptomatic dogs were much higher. Our results suggest that the C1, C8, C18 and C9 recombinant proteins are good antigens to diagnose canine visceral leishmaniasis and could potentially be used in screening tests. To diagnose human visceral leishmaniasis, the C9 antigen presented reasonable results, but more optimization must be performed for this antigen to provide better performance. PMID- 24801887 TI - Spatiotemporal sparse Bayesian learning with applications to compressed sensing of multichannel physiological signals. AB - Energy consumption is an important issue in continuous wireless telemonitoring of physiological signals. Compressed sensing (CS) is a promising framework to address it, due to its energy-efficient data compression procedure. However, most CS algorithms have difficulty in data recovery due to nonsparsity characteristic of many physiological signals. Block sparse Bayesian learning (BSBL) is an effective approach to recover such signals with satisfactory recovery quality. However, it is time-consuming in recovering multichannel signals, since its computational load almost linearly increases with the number of channels. This work proposes a spatiotemporal sparse Bayesian learning algorithm to recover multichannel signals simultaneously. It not only exploits temporal correlation within each channel signal, but also exploits inter-channel correlation among different channel signals. Furthermore, its computational load is not significantly affected by the number of channels. The proposed algorithm was applied to brain computer interface (BCI) and EEG-based driver's drowsiness estimation. Results showed that the algorithm had both better recovery performance and much higher speed than BSBL. Particularly, the proposed algorithm ensured that the BCI classification and the drowsiness estimation had little degradation even when data were compressed by 80%, making it very suitable for continuous wireless telemonitoring of multichannel signals. PMID- 24801886 TI - Hsc70 contributes to cancer cell survival by preventing Rab1A degradation under stress conditions. AB - Heat shock cognate protein 70 (Hsc70) acts as a molecular chaperone for the maintenance of intracellular proteins, which allows cancer cells to survive under proteotoxic stress. We attempted to use Hsc70 to identify key molecules in cancer cell survival. Here, we performed mass-spectrometry-based proteomics analysis utilizing affinity purification with anti-Hsc70 antibodies; as a result, 83 differentially expressed proteins were identified under stress conditions. This result implies that there was a change in the proteins with which Hsc70 interacted in response to stress. Among the proteins identified under both serum depleted and 5-fluorouracil-treated conditions, Rab1A was identified as an essential molecule for cancer cell survival. Hsc70 interacted with Rab1A in a chaperone-dependent manner. In addition, Hsc70 knockdown decreased the level of Rab1A and increased the level of its ubiquitination under stress conditions, suggesting that Hsc70 prevented the degradation of Rab1A denatured by stress exposure. We also found that Rab1A knockdown induced cell death by inhibition of autophagosome formation. Rab1A may therefore contribute to overcoming proteotoxic insults, which allows cancer cells to survive under stress conditions. Analysis of Hsc70 interactors provided insight into changes of intracellular status. We expect further study of the Hsc70 interactome to provide a more comprehensive understanding of cancer cell physiology. PMID- 24801888 TI - High positive affect shortly after missile attacks and the heightened risk of posttraumatic stress disorder among Israeli adolescents. AB - Previous research has demonstrated that positive emotions help build psychological resources and facilitate adaptation to stress, yet few studies have considered the possible negative effects of positive emotions on stress. This study examined the relationship between high arousal, positive and negative affect, and posttraumatic stress disorder (PTSD) symptoms among 503 Israeli adolescents following a period of escalated missile attacks on their city. Our findings revealed that not only negative affect, but also positive affect at very high levels exhibited 2 weeks following missile attacks were independently associated with PTSD symptoms 21/2 months later (eta(2) = .09, eta(2) = .02, respectively). Although the literature recognizes the risk factor of negative affect on the development of PTSD, we suggest that also positive affect at high levels immediately after such experiences may be a case of emotion context insensitivity and thus a maladaptive response to trauma. Further research should examine the mechanisms associated with positive emotions and PTSD. PMID- 24801889 TI - Objective assessment of fall risk in Parkinson's disease using a body-fixed sensor worn for 3 days. AB - BACKGROUND: Patients with Parkinson's disease (PD) suffer from a high fall risk. Previous approaches for evaluating fall risk are based on self-report or testing at a given time point and may, therefore, be insufficient to optimally capture fall risk. We tested, for the first time, whether metrics derived from 3 day continuous recordings are associated with fall risk in PD. METHODS AND MATERIALS: 107 patients (Hoehn & Yahr Stage: 2.6+/-0.7) wore a small, body-fixed sensor (3D accelerometer) on lower back for 3 days. Walking quantity (e.g., steps per 3 days) and quality (e.g., frequency-derived measures of gait variability) were determined. Subjects were classified as fallers or non-fallers based on fall history. Subjects were also followed for one year to evaluate predictors of the transition from non-faller to faller. RESULTS: The 3 day acceleration derived measures were significantly different in fallers and non-fallers and were significantly correlated with previously validated measures of fall risk. Walking quantity was similar in the two groups. In contrast, the fallers walked with higher step-to-step variability, e.g., anterior-posterior width of the dominant frequency was larger (p = 0.012) in the fallers (0.78 +/- 0.17 Hz) compared to the non-fallers (0.71 +/- 0.07 Hz). Among subjects who reported no falls in the year prior to testing, sensor-derived measures predicted the time to first fall (p = 0.0034), whereas many traditional measures did not. Cox regression analysis showed that anterior-posterior width was significantly (p = 0.0039) associated with time to fall during the follow-up period, even after adjusting for traditional measures. CONCLUSIONS/SIGNIFICANCE: These findings indicate that a body-fixed sensor worn continuously can evaluate fall risk in PD. This sensor based approach was able to identify transition from non-faller to faller, whereas many traditional metrics were not successful. This approach may facilitate earlier detection of fall risk and may in the future, help reduce high costs associated with falls. PMID- 24801890 TI - Loss of Notch1-dependent p21(Waf1/Cip1) expression influences the Notch1 outcome in tumorigenesis. AB - Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor-suppressor and oncogenic components. In this study we investigated the effects of reactive oxygen species (ROS) on Notch1 signaling outcome in keratinocyte biology. We demonstrate that Notch1 function contributes to the arsenic-induced keratinocyte transformation. We found that acute exposure to arsenite increases oxidative stress and inhibits proliferation of keratinocyte cells by upregulation of p21(waf1/Cip1). The necessity of p21(waf1/Cip1) for arsenite-induced cell death was demonstrated by targeted downregulation of p21(waf1/Cip1) by using RNA interference. We further demonstrated that on acute exposure to arsenite, p21(waf1/Cip1) is upregulated and Notch1 downmodulated, whereas on chronic exposure to arsenite, malignant progression of arsenite treated keratinocytes cells was accompanied by regained expression and activity of Notch1. Notch1 activity in arsenite-transformed keratinocytes inhibits arsenite-induced upregulation of p21(waf1/Cip1) by sustaining c-myc expression. We further demonstrated that c-myc collaborates with Nrf2, a key regulator for the maintenance of redox homeostasis, to promote metabolic activities that support cell proliferation and cytoprotection. Therefore, Notch1-mediated repression of p21(waf1/Cip1) expression results in the inhibition of cell death and keratinocytes transformation. Our results not only demonstrate that sustained Notch1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect, but also may provide mechanistic insights into the molecular aspects that determine whether Notch signaling will be either oncogenic or tumor suppressive. PMID- 24801892 TI - Gallium(III) complexes of NOTA-bis (phosphonate) conjugates as PET radiotracers for bone imaging. AB - Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4 diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 degrees C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 +/- 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 +/- 0.38 and SUV of 4.87 +/- 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 +/- 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT. PMID- 24801893 TI - Supercritical fluid extraction and separation of uranium from other actinides. AB - The feasibility of separating U from nitric acid solutions of mixed actinides using tri-n-butylphosphate (TBP)-modified supercritical fluid carbon dioxide (sc CO2) was investigated. The actinides U, Np, Pu, and Am were extracted into sc-CO2 modified with TBP from a range of nitric acid concentrations, in the absence of, or in the presence of, a number of traditional reducing and/or complexing agents to demonstrate the separation of these metals from U under sc-CO2 conditions. The separation of U from Pu using sc-CO2 was successful at nitric acid concentrations of less than 3M in the presence of acetohydroxamic acid (AHA) or oxalic acid (OA) to mitigate Pu extraction, and the separation of U from Np was successful at nitric acid concentrations of less than 1M in the presence of AHA, OA, or sodium nitrite to mitigate Np extraction. Americium was not well extracted under any condition studied. PMID- 24801891 TI - Differentiating asthma phenotypes in young adults through polyclonal cytokine profiles. AB - BACKGROUND: Recent research has emphasized the need to better discriminate asthma phenotypes and consider underlying mechanistic endotypes in epidemiologic and clinical studies. Although allergic asthma and nonallergic asthma are frequently combined into 1 disease category in observational research and clinical trials, few studies have investigated the extent to which these 2 separate phenotypes are associated with distinct cytokine immunologic profiles in a representative young adult population. OBJECTIVE: To investigate the cytokine production-based endotypes underlying the clinical phenotypes of allergic and nonallergic asthma in a population-based birth cohort evaluated as young adults. METHODS: Participants included 18- to 21-year-old members (n = 540) of a suburban Detroit birth cohort study, the Childhood Allergy Study. Phorbol myristate acetate stimulated whole blood interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, IL-17A, IL 17F, IL-22, and interferon-gamma secretory responses were analyzed for associations comparing participants with allergic vs nonallergic asthma phenotypes with those without asthma. RESULTS: T-helper cell type (TH) 2 polarized responses, measured as higher mean IL-5 and IL-13 secretions and lower ratios of interferon-gamma and IL-12 to 3 TH2 cytokines (IL-4, IL-5, or IL-13), were observed only in participants with allergic asthma. Nonallergic asthma was associated with TH1-polarized responses, including higher adjusted interferon gamma secretion compared with participants with allergic asthma and, surprisingly, those without asthma (odds ratio 2.5, confidence interval 1.2-5.1, P < .01). CONCLUSION: As expected, young adults with a history of an allergic asthma phenotype exhibited a TH2-polarized cytokine response after polyclonal stimulation. However, TH1 polarization was observed in patients with a history of nonallergic asthma. Allergic and nonallergic asthma are associated with etiologically distinct immune endotypes, underscoring the importance of discriminating these endotypes in research analyses and clinical management. PMID- 24801894 TI - Evaluation of simultaneous biodegradation of methane and toluene in landfill covers. AB - The biodegradation of CH4 and toluene in landfill cover soil (LCS) and waste biocover soil (WBS) was investigated with a serial toluene concentration in the headspace of landfill cover microcosms in this study. Compared with the LCS sample, the higher CH4 oxidation activity and toluene-degrading capacity occurred in the WBS sample. The co-existence of toluene in landfill gas would positively or negatively affect CH4 oxidation, mainly depending on the toluene concentrations and exposure time. The nearly complete inhibition of toluene on CH4 oxidation was observed in the WBS sample at the toluene concentration of ~ 80,000 mg m(-3), which was about 10 times higher than that in the LCS sample. The toluene degradation rates in both landfill covers fitted well with the Michaelis Menten model. These findings showed that WBS was a good alternative landfill cover material to simultaneously mitigate emissions of CH4 and toluene from landfills to the atmosphere. PMID- 24801895 TI - Mechanisms and reaction pathways for simultaneous oxidation of NOx and SO2 by ozone determined by in situ IR measurements. AB - Ozone (O3) oxidation combined with wet scrubbing is a promising method for the simultaneous removal of SO2 and NOx in flue gas. In this study, the O3 oxidation processes of NO and SO2, as well as their coexistence, were investigated using an in situ IR spectrometer. Experimental results showed that the O3 concentration and the reaction temperature played critical roles in the O3 oxidation process of NO. Around 80 degrees C, when inlet molar ratio of O3/NO was less than 1, NO was mainly oxidized to NO2, while when the ratio was greater than 1, NO would be further oxidized to NO3, N2O5, and HNO3. NO3 was the key intermediate product for the formation of N2O5 and HNO3. However, the subsequent reactions of NO3 were temperature dependence. With the increase of reaction temperature above 100 degrees C, the concentration of NO2 increased whereas the concentrations of N2O5 and HNO3 decreased. The oxidation of SO2 by O3 was negligible and SO2 had little influence on the oxidation of NO in the simultaneous oxidation of NO and SO2. Finally, based on the in situ IR results, the oxidation mechanism is discussed and the reaction pathways are proposed. PMID- 24801896 TI - Methionine oxidation in albumin by fine haze particulate matter: an in vitro and in vivo study. AB - The potential effects of inhaled fine particulate matter (PM2.5), found in haze episodes, on the oxidation of the proteins in the lungs are not well understood. We investigated the effects of PM2.5 from haze episodes on protein oxidation. PM2.5 was collected from the air pollution in Beijing (BJ), Xian (XA), Xiamen (XM) and Hong Kong (HK) during a period of intensive haze episodes. The chemical characteristics of these samples and their effects on albumin oxidation were investigated. The levels of PM2.5 in BJ and XA were 4-6 times higher than in XM and HK. The concentrations of the polycyclic aromatic hydrocarbons (PAHs) components of the PM2.5 from BJ and XA were 10 times higher than those found in XM and HK. The haze PM2.5 increased oxidative stress. Addition of PM2.5 samples collected from haze episodes to albumin in vitro resulted in oxidation of methionine moieties; nasal instillation of PM2.5 suspensions in mice resulted in oxidation of methionine in the albumin in the bronchoalveolar lavage fluid. The methionine moieties participate in peptide chain crosslinking, and methionine oxidation in the albumin could be attributed to the PAH compounds. Our findings may be helpful in explaining the potential respiratory effects during haze episodes. PMID- 24801897 TI - Response of soil bacterial community to metal nanoparticles in biosolids. AB - The increasing use of engineered nanoparticles (NPs) in industrial and household applications will very likely lead to the increased release of such materials into the public sewer systems. During the wastewater treatment process, some fraction of NPs would always be concentrated in the biosolids. When biosolids is applied on the agricultural land, NPs are introduced into the soil matrix. In the current study we investigate the influence of five different metal nanoparticles present in biosolids on soil microbial community as a function of time. Results indicate that ZnO and Zero Valent Cu NPs were not toxic to soil bacterial community. Biosolids mixed with Ag NPs and TiO2 (both anatase and rutile phase) in contrast changed the bacterial richness and composition in wavering pattern as a function of time. Based on the observations made in the study, we suggest caution when interpreting the toxicity of NPs based on single time point study. PMID- 24801898 TI - Control and impact of the nanoscale distribution of supported cobalt particles used in Fischer-Tropsch catalysis. AB - The proximity of nanoparticles may affect the performance, in particular the stability, of supported metal catalysts. Short interparticle distances often arise during catalyst preparation by formation of aggregates. The cause of aggregation of cobalt nanoparticles during the synthesis of highly loaded silica supported catalysts was found to originate from the drying process after impregnation of the silica grains with an aqueous cobalt nitrate precursor. Maximal spacing of the Co3O4 nanoparticles was obtained by fluid-bed drying at 100 degrees C in a N2 flow. Below this temperature, redistribution of liquid occurred before and during precipitation of a solid phase, leading to aggregation of the cobalt particles. At higher temperatures, nucleation and growth of Co3O4 occurred during the drying process also giving rise to aggregation. Fischer Tropsch catalysis performed under industrially relevant conditions for unpromoted and Pt-promoted cobalt catalysts revealed that the size of aggregates (13-80 nm) of Co particles (size ~9 nm) had little effect on activity. Large aggregates exhibited higher selectivities to long chain alkanes, possibly related to higher olefin formation with subsequent readsorption and secondary chain growth. Most importantly, larger aggregates of Co particles gave rise to extensive migration of cobalt (up to 75%) to the external surface of the macroscopic catalyst grains (38-75 MUm). Although particle size did not increase inside the silica support grains, migration of cobalt to the external surface partly led to particle growth, thus causing a loss of activity. This cobalt migration over macroscopic length scales was suppressed by maximizing the distance between nanoparticles over the support. Clearly, the nanoscale distribution of particles is an important design parameter of supported catalysts in particular and functional nanomaterials in general. PMID- 24801899 TI - Novel active fixation mechanism permits precise placement of a left ventricular lead: early results from a multicenter clinical study. AB - BACKGROUND: Left ventricular (LV) lead implantation for cardiac resynchronization therapy (CRT) is associated with lead dislodgement rates ranging from 3% to 10%, and some implant approaches to prevent dislodgement may contribute to suboptimal CRT response. We report our early human experience with an LV lead with a side helix for active fixation to the coronary vein wall. OBJECTIVES: To assess the feasibility and safety of the Model 20066 LV lead and to evaluate the implant procedure. METHODS: The Model 20066 is a 4-F bipolar steroid eluting lead that has a small exposed side helix and can be delivered using a guidewire or stylet. At the desired vein location, the lead body is rotated clockwise until the helix is fixated. This study was a single-arm, prospective, nonrandomized trial that enrolled 40 patients from 4 centers who met standard indications for CRT. RESULTS: The lead was successfully implanted in 39 of 40 (98%) patients. In 38 of 40 (95%) patients, the implanters were successful at implanting at a predetermined target site. There were no Model 20066 LV lead dislodgements reported within 12 months of follow-up. The electrical performance of the tip and ring electrodes was stable through the 12-month follow-up visit and similar to other LV leads. Overall lead handling was rated as acceptable for all implants. CONCLUSION: This new LV lead specifically designed with an active fixation mechanism for stability and precise placement was successfully and safely deployed in the coronary vasculature. PMID- 24801900 TI - Gender disparity in response to CRT: here's the skinny. PMID- 24801901 TI - NFI-C regulates osteoblast differentiation via control of osterix expression. AB - In bone marrow, bone marrow stromal cells (BMSCs) have the capacity to differentiate into osteoblasts and adipocytes. Age-related osteoporosis is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow. In this study, we demonstrate that disruption of nuclear factor I-C (NFI-C) impairs osteoblast differentiation and bone formation, and increases bone marrow adipocytes. Interestingly, NFI-C controls postnatal bone formation but does not influence prenatal bone development. We also found decreased NFI-C expression in osteogenic cells from human osteoporotic patients. Notably, transplantation of Nfic-overexpressing BMSCs stimulates osteoblast differentiation and new bone formation, but inhibits adipocyte differentiation by suppressing peroxisome proliferator-activated receptor gamma expression in Nfic( /-) mice showing an age-related osteoporosis-like phenotype. Finally, NFI-C directly regulates Osterix expression but acts downstream of the bone morphogenetic protein-2-Runx2 pathway. These results suggest that NFI-C acts as a transcriptional switch in cell fate determination between osteoblast and adipocyte differentiation in BMSCs. Therefore, regulation of NFI-C expression in BMSCs could be a novel therapeutic approach for treating age-related osteoporosis. PMID- 24801902 TI - Activation of the ubiquitin-proteasome system against arsenic trioxide cardiotoxicity involves ubiquitin ligase Parkin for mitochondrial homeostasis. AB - Parkin is an E3 ubiquitin ligase involved in the elimination of damaged mitochondria. Ubiquitination of mitochondrial substrates by Parkin results in proteasomal as well as lysosomal degradation of mitochondria, the latter of which is executed by the autophagy machinery and is called as mitophagy (mitochondrial autophagy). The aim of this study is to examine the possible role of Parkin against cardiotoxicity elicited by arsenic trioxide (ATO) exposure in HL-1 mouse atrial cardiomyocytes. HL-1 cells were administered 1-10MUM ATO for up to 24h, and the involvements of apoptosis, and the ubiquitin-proteasome and autophagy lysosome systems (UPS and ALS) were examined. ATO dose-dependently reduced mitochondrial membrane potentials (DeltaPsim) in HL-1 cells, indicating that ATO works as a mitochondrial toxin in these cells. Apoptosis was evident in cells exposed to more than 6MUM ATO for 24h. Levels of Parkin in mitochondria-rich fractions were increased, suggesting the recruitment of Parkin to mitochondria. Ubiquitination of the voltage-dependent anion channel1 (VDAC1), a substrate of Parkin, was also proved by immunoprecipitation. Accumulation of ubiquitinated proteins including both K48- and K63-lineages was observed in HL-1 cells after ATO exposure, implying an increased demand for proteasomal as well as lysosomal degradation of cellular proteins. Although UPS was activated by ATO as proved by increased proteasomal activity, only slight activation of the ALS marker LC3 was observed, suggesting differential reactions of UPS and ALS to ATO toxicity. The abrogation of UPS by the proteasome inhibitor bortezomib significantly sensitized HL-1 cells to ATO toxicity, showing the contribution of UPS to the maintenance of cellular homeostasis during ATO exposure. Taken together, our results reveal the activation of Parkin as well as UPS during ATO exposure in HL-1 cardiomyocytes, which contributes to the maintenance of mitochondrial as well as cellular homeostasis. PMID- 24801903 TI - A review on the molecular mechanisms involved in insulin resistance induced by organophosphorus pesticides. AB - There is increasing evidence reporting that organophosphorus pesticides (OPs) impair glucose homeostasis and cause insulin resistance and type 2 diabetes. Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Formation of advanced glycation end products, accumulation of lipid metabolites, activation of inflammatory pathways and oxidative stress have all been implicated in the pathogenesis of insulin resistance. Ultimately, these molecular processes activate a series of stress pathways involving a family of serine kinases, which in turn have a negative effect on insulin signaling. Experimental and clinical data suggest an association between these molecular mechanisms and OPs compounds. It was first reported that OPs induce hyperglycemia. Then a concomitant increase of blood glucose and insulin was pointed out. For some years only, we have begun to understand that OPs promote insulin resistance and increase the risk of type 2 diabetes. Overall, this review outlines various mechanisms that lead to the development of insulin resistance by OPs exposure. PMID- 24801904 TI - The expression of beta-catenin in different subtypes of breast cancer and its clinical significance. AB - The Wnt/beta-catenin signaling pathway is implicated in mammary oncogenesis. Reports of beta-catenin expression and its association with outcome in breast cancer are controversial. This study was performed to address the distribution of beta-catenin expression in invasive breast cancer and the correlation between beta-catenin expression and survival of breast cancer patients, and to determine whether beta-catenin was specifically activated in any molecular subtypes. Immunohistochemistry was performed on a tissue microarray containing 169 invasive breast cancers to detect expression of beta-catenin. One hundred thirty one of the 169 patients were followed up. Correlation between beta-catenin expression and different molecular subtypes was determined using chi-square analysis. Overall survival (OS) was analyzed by Kaplan-Meier method with log-rank test. The invasive breast cancer displayed the different patterns of beta-catenin expression from normal tissues with significantly increased cytoplasmic and nuclear staining of beta-catenin. Aberrant beta-catenin expression was observed in 109 in the 169 cases (64.50 %), and there was no difference in beta-catenin expression in the four molecular subtypes. Furthermore, aberrant beta-catenin expression was significantly associated with adverse outcome not only in the entire cohort but also in each of the different molecular subtypes. beta-catenin activation is preferentially found and is associated with a poor clinical outcome in invasive breast cancer independent of molecular subtype. PMID- 24801905 TI - Eg5 inhibitor, a novel potent targeted therapy, induces cell apoptosis in renal cell carcinoma. AB - Eg5 is critical for mitosis and overexpressed in various malignant tumors, which has now been identified as a promising target in cancer therapy. However, the anti-cancer activity of Eg5 inhibitor in renal cell carcinoma (RCC) remains an open issue. In this paper, we evaluated, for the first time, the therapeutic benefit of blocking Eg5 by S-(methoxytrityl)-L-cysteine (S(MeO)TLC) in RCC both in vitro and vivo. The expression of Eg5 was examined in clinical tissue samples and various kidney cell lines, including 293T, 786-0, and OS-RC-2. The anti proliferative activity of Eg5 inhibitors, (S)-trityl-L-cysteine (STLC) and S(MeO)TLC, was evaluated by a cell viability assay. An apoptosis assay with Hoechst nuclear staining and flow cytometry was applied to investigate the efficacy of the S(MeO)TLC, which is more potent than STLC. Immunofluorescence was used to research the possible mechanism. Furthermore, in vivo studies were performed by using subcutaneous xenograft models, which were used to confirm its role as a potential anti-neoplastic drug. The Eg5 expression was detected in kidney cell lines and RCC tissues, which was low in normal kidney samples. STLC and S(MeO)TLC exhibited their optimal anti-proliferative activity in 72 h, and cells treated with S(MeO)TLC presented characteristic monoastral spindle phenotype in 24 h and apoptotic cells in 48 h. In vivo, S(MeO)TLC effectively suppressed tumor growth in subcutaneous xenograft models. Inhibition of Eg5 represses the proliferation of RCC in vitro and in vivo. All these findings collectively demonstrate that S(MeO)TLC, a potent Eg5 inhibitor, is a promising anti-cancer agent for the treatment of RCC. PMID- 24801906 TI - Prognostic value of CYP2W1 expression in patients with human hepatocellular carcinoma. AB - CYP2W1 overexpression has been reported in a variety of human cancers. However, the role of CYP2W1 in hepatocellular carcinoma (HCC) remains unclear. This study was designed to evaluate the expression and prognostic significance of CYP2W1 in human HCC. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was conducted to detect CYP2W1 messenger RNA (mRNA) expression in 41 pairs of fresh-frozen HCC tissues and adjacent noncancerous tissues. In addition, CYP2W1 expression was analyzed by immunohistochemistry in 133 clinicopathologically characterized HCC cases. The relationship between CYP2W1 expression and clinicopathological features was analyzed by appropriate statistics. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between CYP2W1 expression and prognosis of HCC patients. The relative mRNA expression of CYP2W1 was significantly higher in HCC tissues than in adjacent noncancerous tissues (P < 0.001). In addition, CYP2W1 expression was significantly correlated with tumor size (P = 0.023), histological differentiation (P = 0.04), and tumor stage (P = 0.014). The Kaplan Meier survival curves indicated that patients with high expression of CYP2W1 had shorter overall survival than those with low expression (P < 0.001). Furthermore, Cox regression analyses showed that CYP2W1 expression was an independent predictor of overall survival. Our data suggest that CYP2W1 could play an important role in HCC and might serve as a valuable prognostic marker and potential target for gene therapy in the treatment of HCC. PMID- 24801907 TI - Overexpression of SPAG9 correlates with poor prognosis and tumor progression in hepatocellular carcinoma. AB - Sperm-associated antigen 9 (SPAG9) was reported as a novel biomarker for several cancers and associated with the malignant behavior of cancer cells. However, its expression pattern and biological role in human hepatocellular carcinoma (HCC) have not been reported. In the present study, we analyzed SPAG9 expression in human HCC tissues by immunohistochemistry and found that SPAG9 overexpression is correlated with tumor stage (p < 0.001), tumor multiplicity (p = 0.019), tumor size (p = 0.034), AFP levels (p = 0.006), and tumor relapse (p = 0.0017). Furthermore, SPAG9 overexpression is correlated with poor overall survival (p < 0.001) and relapse-free survival (p = 0.002). Transfection of SPAG9 small interfering RNA (siRNA) was performed in Bel-7402 cell line. Colony formation and MTT showed that SPAG9 siRNA knockdown inhibited HCC cell proliferation. We also found that SPAG9 depletion could increase cell apoptosis. In addition, the level of cyclin D1 and cyclin E protein expression was downregulated after siRNA treatment. In conclusion, SPAG9 is overexpressed in human HCC and serves as a prognostic marker. SPAG9 contributes to cancer cell growth through regulation of cyclin proteins. PMID- 24801908 TI - MiR-145 inhibits osteosarcoma cells proliferation and invasion by targeting ROCK1. AB - MicroRNAs (miRNAs) contribute to the development and progression of various types of human cancers. The aim of this study was to study the role of miR-145 and to identify its functional target gene in osteosarcoma (OS) cells. We found that miR 145 was reduced in OS tissues and cell lines. Enforced expression of miR-145 inhibited cell proliferation, migration, and invasion abilities of MG-63 cells. Furthermore, we revealed that Rho-associated protein kinase 1 (ROCK1) was a target of miR-145 in OS. Finally, we found that silencing of ROCK1 performed similar effects with miR-145 in MG-63 cells, and ROCK1 was inversely correlated with miR-145 in OS tissues. Collectively, these data indicate that miR-145 may act as a tumor suppressor and contributes to the progression of OS through targeting ROCK1. PMID- 24801909 TI - WIP1 regulates the proliferation and invasion of nasopharyngeal carcinoma in vitro. AB - Wild-type p53-induced phosphatase (WIP1) is overexpressed and functionally altered in multiple human malignancies. The present study investigated its abnormal expression and dysfunctions in nasopharyngeal carcinoma (NPC) in vitro. Here, analysis of WIP1 mRNA and protein in human NPC tissues revealed that both WIP1 messenger RNA (mRNA) and protein were elevated and were correlated with NPC clinical stage and metastasis in patients. In vitro experiments further showed that WIP1 inhibition led to a decrease in the proliferative ability of NPC CNE-2 and 5-8F cells accompanied by cell cycle arrest and increased apoptosis. In addition, WIP1 knockdown inhibited the invasiveness of CNE-2 and 5-8F cells and was associated with the down-regulation of the expression of matrix metallopeptidase 9 (MMP-9) mRNA and protein. Taken together, our data demonstrate that WIP1 regulates the proliferation and invasiveness of NPC cells in vitro, and this may be correlated with its modulation of MMP-9 expression, cell cycle progression and apoptosis. WIP1 functioned as a potential therapeutic target in NPC management. PMID- 24801910 TI - The role of anti-VEGF agents in the treatment of advanced gastric cancer: a meta analysis of randomized controlled trials. AB - Inhibition of vascular epithelial growth factor (VEGF) signaling pathways has proven to be an effective strategy for the treatment of several common solid tumors, but its role in the management of advanced gastric cancer (AGC) is yet to be defined. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of anti-VEGF agents in the treatment of AGC. Several databases were searched, including PubMed, Embase, and Cochrane databases. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 adverse events (AEs). The pooled hazard ratio (HR) or relative risk (RR) and 95 % confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. Seven RCTs which involved 2,340 patients were ultimately identified. The pooled analysis demonstrated that anti-VEGF therapy significantly improved OS (HR 0.74, 95 % CI 0.61-0.91, p = 0.003), PFS (HR 0.59, 95 % CI 0.44-0.78, p < 0.001), and ORR (RR 1.43, 95 % CI 1.14-1.79, p = 0.002) when compared to non-anti-VEGF therapy. Sensitivity analysis further confirmed this association. Additionally, more incidences of grade 3 or 4 thrombocytopenia, diarrhea, and hypertension were observed in anti-VEGF therapy. The anti-VEGF therapy offers a significant survival benefit in patients with AGC, especially for those previously treated patients, when compared to non-anti-VEGF therapy. With the present available data from randomized clinical trials, we could not clearly set the role of specific anti-VEGF agents in the treatment of AGC. Further studies are recommended to identify patients who could derive greater benefits from specific anti-VEGF agents. PMID- 24801911 TI - Essential role of amino acid position 226 in oligosaccharide elongation by amylosucrase from Neisseria polysaccharea. AB - Amylosucrase from Neisseria polysaccharea is a remarkable transglucosylase that synthesizes an insoluble amylose-like polymer from sole substrate sucrose. One particular amino acid, Arg226, was proposed from molecular modeling studies to play an important role in the formation of the active site topology and in the accessibility of ligands to the catalytic site. The systematic mutation of this Arg residue by all 19 other possible amino acids revealed that all single-mutants had a higher activity on sucrose compared to the wild-type enzyme. An extensive kinetic investigation showed that catalytic efficiencies are greatly impacted by the presence of natural acceptors in the reaction media, their chain length and the nature of the amino acid at position 226. Compared to the wild-type enzyme, the R226N mutant showed a 10-fold enhancement in the catalytic efficiency and a nearly twofold higher production of an insoluble amylose-like polymer that can be of interest for biotechnological applications. PMID- 24801912 TI - Physicochemical characterization of nebulized superparamagnetic iron oxide nanoparticles (SPIONs). AB - BACKGROUND: Aerosol-mediated delivery of nano-based therapeutics to the lung has emerged as a promising alternative for treatment and prevention of lung diseases. Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted significant attention for such applications due to their biocompatibility and magnetic properties. However, information is lacking about the characteristics of nebulized SPIONs for use as a therapeutic aerosol. To address this need, we conducted a physicochemical characterization of nebulized Rienso, a SPION-based formulation for intravenous treatment of anemia. METHODS: Four different concentrations of SPION suspensions were nebulized with a one-jet nebulizer. Particle size was measured in suspension by transmission electron microscopy (TEM), photon correlation spectroscopy (PCS), and nanoparticle tracking analysis (NTA), and in the aerosol by a scanning mobility particle sizer (SMPS). RESULTS: The average particle size in suspension as measured by TEM, PCS, and NTA was 9+/ 2 nm, 27+/-7 nm, and 56+/-10 nm, respectively. The particle size in suspension remained the same before and after the nebulization process. However, after aerosol collection in an impinger, the suspended particle size increased to 159+/ 46 nm as measured by NTA. The aerosol particle concentration increased linearly with increasing suspension concentration, and the aerodynamic diameter remained relatively stable at around 75 nm as measured by SMPS. CONCLUSIONS: We demonstrated that the total number and particle size in the aerosol were modulated as a function of the initial concentration in the nebulizer. The data obtained mark the first known independent characterization of nebulized Rienso and, as such, provide critical information on the behavior of Rienso nanoparticles in an aerosol. The data obtained in this study add new knowledge to the existing body of literature on potential applications of SPION suspensions as inhaled aerosol therapeutics. PMID- 24801913 TI - Trias of keratosis pilaris, ulerythema ophryogenes and 18p monosomy: Zouboulis syndrome. AB - Keratosis pilaris and ulerythema ophryogenes (keratosis pilaris atrophicans faciei) are part of a group of hereditary disorders of hair follicle keratinization involving follicular inflammation and subsequent atrophy. Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18. This trias was first described in a patient by Zouboulis et al. (1994) and has been reported by different authors in four additional patients since then. We have reviewed the five almost identical cases that have been reported in 20 years and we suggest the existence of a new rare syndrome characterized by the trias keratosis pilaris, ulerythema ophryogenes and monosomy 18p. Recognition of the syndrome could assist in early diagnosis of monosomy 18p in these patients. PMID- 24801914 TI - Three cases of reconstruction with a simply designed bilobed flap after excision of squamous cell carcinomas of the lateral eyebrow areas. AB - Squamous cell carcinoma is frequently observed on the lateral eyebrow, one of the most difficult sites for one-stage reconstruction because of its location close to the eyelids. The reconstruction of defects by the single-stage flap is advantageous for elderly patients because of its good functional and aesthetic outcome. We surgically treated three cases of squamous cell carcinoma on this area and performed reconstruction with a simply designed bilobed flap, all of which resulted in favorable outcomes. We therefore report on the usefulness of this reconstructive method for the lateral eyebrow defects. PMID- 24801915 TI - Infantile generalized pustular psoriasis: successful disease control with intermittent etretinate. AB - Infantile generalized pustular psoriasis is a rare form of psoriasis and the best treatment is controversial. We experienced a 2-year-old female with erythema on her neck and axilla starting at 3 months of age. She presented with recurrent annular and geographic scaly erythema with a few pustules on the neck, precordium and axilla, but no fever. The histopathology revealed subcorneal neutrophilic infiltration and microabscesses without Kogoj's spongiform pustules. The initial diagnosis was subcorneal pustular dermatosis. However, she developed widespread geographic erythema and numerous pustules over her entire body with a fever when she got a cold. A second skin biopsy revealed monolocular pustules and Kogoj's spongiform pustules in the subcorneal layer. Etretinate was administrated after a diagnosis of pustular psoriasis was made and her condition improved gradually. The choice of treatment depends on patient age, general condition and the disease severity. PMID- 24801916 TI - Case of disseminated cutaneous Mycobacterium chelonae infection mimicking cutaneous vasculitis. AB - Mycobacterium chelonae is a non-tuberculous, rapidly growing mycobacteria and is widely distributed in the natural environment. In the immunocompetent status, localized cutaneous infections such as cellulitis and subcutaneous abscesses commonly occur after traumatic injury. However, disseminated cutaneous infections occur on a background of immunosuppression. Cutaneous M. chelonae infection presents with a variety of skin eruptions. We report a case of disseminated M. chelonae infection mimicking cutaneous vasculitis. The patient was treated with long-term oral corticosteroids and injected etanercept for the treatment of rheumatoid arthritis and asthma. Because the skin eruptions were preceded by asthma and rheumatoid arthritis and the pathological findings showed fibrinoid necrosis around the vascular of dermis, cutaneous vasculitis was first suspected. The culture from the pus revealed the bacterium which grew within 5 days on Ogawa's culture medium suggesting a rapidly growing mycobacteria. This bacterium was identified as M. chelonae by the DNA-DNA hybridization method. We chose 800 mg/day clarithromycin and 500 mg/day levofloxacin as a result of the drug sensitivity test. After 6 months of the treatment, infection symptoms disappeared. Rapidly growing mycobacteria should be considered in the differential diagnosis of infections in patients under immunosuppression caused by diseases or drugs such as corticosteroids and biologic agents. Repeated bacterial examinations are important and required for the diagnosis of rapidly growing mycobacteria. PMID- 24801917 TI - Successful experience of rituximab therapy for systemic sclerosis-associated interstitial lung disease with concomitant systemic lupus erythematosus. AB - Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti-CD20 antibody, for SSc-associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti-topoisomerase I antibody levels. In addition, our detailed time-course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease-modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications. PMID- 24801918 TI - Histological studies of facial acne and atrophic acne scars treated with a bipolar fractional radiofrequency system. AB - Various fractional radiofrequency (FRF) treatments have demonstrated significant beneficial effects and minor side-effects on atrophic acne scars and acne vulgaris by creating micro-thermal injuries in the skins. However, histological studies to identify the precise mechanism responsible for the success of bipolar FRF treatments are lacking. In this study, six human subjects with these diseases were histologically analyzed after treatment with a bipolar FRF system (eMatrix; Syneron, Yokneam, Israel) and the effects of multiple passes were compared. Histopathological results showed that two-pass FRF treatment created deeper dermal thermal injury zones compared to one-pass treatment. Periadnexal collagen was coagulated, as well as that in the sebaceous glands, as evaluated in all cases with two-pass FRF treatment. No severe side-effects were observed after treatment. Our experience suggests that the level of dermal thermal injury is directly related to the number of passes, and that a large benefit of this treatment for these diseases is the preservation of adnexal structures. PMID- 24801919 TI - CD8(+) aggressive lymphoma in a human T-cell leukaemia virus type-1 carrier. PMID- 24801920 TI - Two cases of acquired idiopathic generalized anhidrosis successfully treated by steroid pulse therapy. PMID- 24801921 TI - Case of erlotinib-induced photosensitivity. PMID- 24801922 TI - Unilateral linear punctate palmar keratoderma. PMID- 24801923 TI - Late-onset self-healing Langerhans cell histiocytosis in a patient with atopic dermatitis. PMID- 24801924 TI - Case of pigmented epithelioid melanocytoma with lymph node metastases. PMID- 24801925 TI - Novel G144D mutation of the GLA gene in a Chinese patient with Fabry disease. PMID- 24801926 TI - Necrobiosis lipoidica with infiltration of Th17 cells into vascular lesions. PMID- 24801927 TI - Three cases of psoriasis vulgaris associated with myasthenia gravis. PMID- 24801928 TI - Annular erythema of Sjogren's syndrome treated successfully with low-dose cyclosporine. PMID- 24801929 TI - Pyoderma gangrenosum with corneal perforation by Mooren's ulcer. PMID- 24801930 TI - Temperature and pressure based NMR studies of detergent micelle phase equilibria. AB - Bulk thermodynamic and volumetric parameters (DeltaGmic degrees , DeltaHmic degrees , DeltaSmic degrees , DeltaCp,mic degrees , DeltaVmic degrees , and Deltakappamic degrees ) associated with the monomer-micelle equilibrium, were directly determined for a variety of common detergents [sodium n-dodecyl sulfate (SDS), n-dodecyl phosphocholine (DPC), n-dodecyl-beta-d-maltoside (DDM), and 7 cyclohexyl-1-heptyl phosphocholine (CyF)] via 1H NMR spectroscopy. For each temperature and pressure point, the critical micelle concentration (cmc) was obtained from a single 1H NMR spectrum at a single intermediate concentration by referencing the observed chemical shift to those of pure monomer and pure micellar phases. This permitted rapid measurements of the cmc over a range of temperatures and pressures. In all cases, micelle formation was strongly entropically favored, while enthalpy changes were all positive, with the exception of SDS, which exhibited a modestly negative enthalpy of micellization. Heat capacity changes were also characteristically negative, while partial molar volume changes were uniformly positive, as expected for an aggregation process dictated by hydrophobic effects. Isothermal compressibility changes were found to be consistent with previous measurements using other techniques. Thermodynamic measurements were also related to spectroscopic studies of topology and micelle structure. For example, paramagnetic effects resulting from the addition of dioxygen provided microscopic topological details concerning the hydrophobicity gradient along the detergent chains within their respective micelles as detected by 1H NMR. In a second example, combined 13C and 1H NMR chemical shift changes arising from application of high pressure, or upon micellization, of CyF provided site-specific details regarding micelle topology. In this fashion, bulk thermodynamics could be related to microscopic topological details within the detergent micelle. PMID- 24801931 TI - Self-assembly of rod-coil diblock copolymers within a rod-selective slit: a dissipative particle dynamics simulation study. AB - Dissipative particle dynamics simulations are performed to investigate the self assembly of rod-coil diblock copolymers R(N(R))C(N-N(R)) within a rod-selective slit. The self-assembled structure of the confined system is sensitively dependent on the rigidity ktheta and the fraction fR of the rod block and the slit height H. From the phase diagram of structures with respect to ktheta and fR for N = 12 and H = 6, we observe four main structures including disordered cylinder (DC) structure, hexagonally packed cylinders (HPC) perpendicular to the slit surfaces, and lamellar structures parallel (L?) and perpendicular (L?) to surfaces. And structure transitions can be achieved by tuning ktheta. The effect of the slit height on the self-assembled structure is also studied for R6C6 and R7C5 copolymers with large ktheta. For R6C6, different structures near surfaces and in the interior of slit are observed in relatively wide slits. Whereas for R7C5, L? structure, whose lamellar domain spacing decays exponentially with H, is generally generated. Our results suggest an effective way to control the ordering of rod-coil diblock copolymers under nanoscale confinement. PMID- 24801934 TI - Construction of the tetrahedral trifluorophosphine platinum cluster Pt4(PF3)8 from smaller building blocks. AB - The experimentally known but structurally uncharacterized Pt4(PF3)8 is predicted to have an S4 structure with a central distorted Pt4 tetrahedron having four short Pt?Pt distances, two long Pt-Pt distances, and all terminal PF3 groups. The structures of the lower nuclearity species Pt(PF3)n (n = 4, 3, 2), Pt2(PF3)n (n = 7, 6, 5, 4), and Pt3(PF3)6 were investigated by density functional theory to assess their possible roles as intermediates in the formation of Pt4(PF3)8 by the pyrolysis of Pt(PF3)4. The expected tetrahedral, trigonal planar, and linear structures are found for Pt(PF3)4, Pt(PF3)3, and Pt(PF3)2, respectively. However, the dicoordinate Pt(PF3)2 structure is bent from the ideal 180 degrees linear structure to approximately 160 degrees . Most of the low-energy binuclear Pt2(PF3)n (n = 7, 6, 5) structures can be derived from the mononuclear Pt(PF3)n (n = 4, 3, 2) structures by replacing one of the PF3 groups by a Pt(PF3)4 or Pt(PF3)3 ligand. In some of these binuclear structures one of the PF3 groups on the Pt(PF3)n ligand becomes a bridging group. The low-energy binuclear structures also include symmetrical [Pt(PF3)n]2 dimers (n = 2, 3) of the coordinately unsaturated Pt(PF3)n (n = 3, 2). The four low-energy structures for the trinuclear Pt3(PF3)6 include two structures with central equilateral Pt3 triangles and two structures with isosceles Pt3 triangles and various arrangements of terminal and bridging PF3 groups. Among these four structures the lowest-energy Pt3(PF3)6 structure has an unprecedented four-electron donor eta(2) MU3-PF3 group bridging the central Pt3 triangle through three Pt-P bonds and one Pt-F bond. Thermochemical studies on the aggregation of these Pt-PF3 complexes suggest the tetramerization of Pt(PF3)2 to Pt4(PF3)8 to be highly exothermic regardless of the mechanistic details. PMID- 24801935 TI - TB or not TB? Genomic portraits provide answers. PMID- 24801939 TI - Bacterial genetics: Amplified origins of antibiotic resistance. PMID- 24801941 TI - A re-evaluation of the archaeal membrane lipid biosynthetic pathway. AB - Archaea produce unique membrane lipids in which isoprenoid alkyl chains are bound to glycerol moieties via ether linkages. As cultured representatives of the Archaea have become increasingly available throughout the past decade, archaeal genomic and membrane lipid-composition data have also become available. In this Analysis article, we compare the amino acid sequences of the key enzymes of the archaeal ether-lipid biosynthesis pathway and critically evaluate past studies on the biochemical functions of these enzymes. We propose an alternative archaeal lipid biosynthetic pathway that is based on a 'multiple-key, multiple-lock' mechanism. PMID- 24801936 TI - Exploitation of the host ubiquitin system by human bacterial pathogens. AB - Ubiquitylation is a crucial post-translational protein modification that regulates several cellular processes in eukaryotes, including inflammatory responses, endocytic trafficking and the cell cycle. Importantly, ubiquitylation also has a central role in modulating eukaryotic defence systems; however, accumulating evidence shows that many bacterial pathogens exploit host ubiquitin systems for their own benefit. In this Review, we highlight the ways in which human bacterial pathogens target ubiquitylation to subvert and manipulate host defence systems, with a focus on the role of molecular mimicry and secreted bacterial effector proteins. These strategies enable bacterial pathogens to maximize effector function and obtain nutrients, thereby promoting bacterial proliferation. PMID- 24801943 TI - New studies on molecular chirality in the gas phase: enantiomer differentiation and determination of enantiomeric excess. AB - Chirality plays a fundamental role in the activity of biological molecules and broad classes of chemical reactions. The chemistry of life is built almost exclusively on left-handed amino acids and right-handed sugars, a phenomenon known as "homochirality of life". Furthermore, most drugs developed in the last decade are of specified chirality. Thus, fast and reliable methods that can differentiate molecules of different handedness, determine the enantiomeric excess of even molecular mixtures, and allow for an unambiguous determination of molecular handedness are of great interest, in particular with respect to complex mixtures. In this perspective article, we discuss the recent developments, with an emphasis on modern spectroscopic methods using gas-phase samples, such as photoelectron circular dichroism, Coulomb explosion imaging, and microwave three wave mixing. PMID- 24801942 TI - In-depth characterisation of Retinal Pigment Epithelium (RPE) cells derived from human induced pluripotent stem cells (hiPSC). AB - Induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) has widely been appreciated as a promising tool to model human ocular disease emanating from primary RPE pathology. Here, we describe the successful reprogramming of adult human dermal fibroblasts to iPSCs and their differentiation to pure expandable RPE cells with structural and functional features characteristic for native RPE. Fibroblast cultures were established from skin biopsy material and subsequently reprogrammed following polycistronic lentiviral transduction with OCT4, SOX2, KLF4 and L-Myc. Fibroblast-derived iPSCs showed typical morphology, chromosomal integrity and a distinctive stem cell marker profile. Subsequent differentiation resulted in expandable pigmented hexagonal RPE cells. The cells revealed stable RNA expression of mature RPE markers RPE65, RLBP and BEST1. Immunolabelling verified localisation of BEST1 at the basolateral plasma membrane, and scanning electron microscopy showed typical microvilli at the apical side of iPSC-derived RPE cells. Transepithelial resistance was maintained at high levels during cell culture indicating functional formation of tight junctions. Secretion capacity was demonstrated for VEGF-A. Feeding of porcine photoreceptor outer segments revealed the proper ability of these cells for phagocytosis. IPSC-derived RPE cells largely maintained these properties after cryopreservation. Together, our study underlines that adult dermal fibroblasts can serve as a valuable resource for iPSC-derived RPE with characteristics highly reminiscent of true RPE cells. This will allow its broad application to establish cellular models for RPE-related human diseases. PMID- 24801944 TI - Ciliates and the rare biosphere-community ecology and population dynamics. AB - Application of deep sequencing technologies to environmental samples and some detailed morphological studies suggest that there is a vast, yet unexplored rare ciliate biosphere, tentatively defined in terms of operational taxonomic units. However, very few studies complemented molecular and phylogenetic data with morphological and ecological descriptions of the species inventory. This is mainly because the sampling effort increases strongly with decreasing species abundance. In spite of this limited knowledge, it is clear that species that are rare under certain environmental conditions (temporal rare biosphere) may become abundant when the physical, chemical, and biological variables of their habitat change. Furthermore, some species may always be present in low numbers if their dispersal rates are exceedingly high (accidental rare biosphere). An intriguing question is whether there are some species that are always rare, i.e., in every suitable environment. This permanent rare biosphere is conceptually different from the temporal rare biosphere. This review characterizes typical aquatic habitats of the rare ciliate biosphere, portrays different scenarios under which some or even many species may be permanently rare (background fauna), and identifies some fundamental questions that need to be addressed to achieve a better understanding of the population dynamics of the rare ciliate biosphere. PMID- 24801945 TI - Iterative method for predistortion of MRI gradient waveforms. AB - The purpose of this work is to correct for transient gradient waveform errors in magnetic resonance imaging (MRI), whether from eddy currents, group delay, or gradient amplifier nonlinearities, which are known to affect image quality. An iterative method is proposed to minimize error between desired and measured gradient waveforms, whose success does not depend on accurate knowledge of the gradient system impulse response. The method was applied to half-pulse excitation for 2-D ultra-short echo time (UTE) imaging on a small animal MRI system and to spiral 2-D excitation on a human 7T MRI system. Predistorted gradient waveforms reduced temporal signal variation caused by excitation gradient trajectory errors in 2-D UTE, and improved the quality of excitation patterns produced by spiral excitation pulses. Iterative gradient predistortion is useful for minimizing transient gradient errors without requiring accurate characterization of the gradient system impulse response. PMID- 24801946 TI - Differential induction of cytokines by human neonatal, adult, and elderly monocyte/macrophages infected with dengue virus. AB - Immunosuppressive status against infections in monocytes from neonates and elderly subjects has been reported. The interaction between dengue virus and monocytes/macrophages plays an important role during dengue disease. The aim of this study was to determine the cytokine response of monocytes from individuals with different ages after infection with dengue virus. Monocyte/macrophage cultures from neonatal, adult, and elderly subjects (n=10 each group) were incubated with all four dengue virus types (DENV-1 to -4). After 1 and 3 days of culture, cytokine concentrations (TNF-alpha, IL-6, and IL-1beta) were determined in culture supernatants by enzyme-linked immunosorbant assay. Increased production of all studied cytokines was induced by the different viral types in monocyte/macrophage cultures regardless of their source. However, lower cytokine concentrations were found in neonatal and elderly monocytes. The relative monocyte/macrophage immunosuppressive status observed in neonates and the elderly could be relevant during dengue infection in those age groups and important in innate and adaptive immunity responses against this virus. PMID- 24801947 TI - Geriatric syndromes in individuals admitted to vascular and urology surgical units. AB - OBJECTIVES: To document the incidence of geriatric syndromes (delirium, functional decline, falls, and pressure ulcers) in two surgical units and to determine the association between the occurrence of geriatric syndromes and admission type (elective vs nonelective), severity of surgery, and surgical subspecialty unit. DESIGN: Retrospective cohort study. SETTING: One vascular surgical unit and one urology surgical unit in an Australian tertiary teaching hospital. PARTICIPANTS: Individuals aged 65 and older admitted to a study unit for 3 days or more (N = 112). MEASUREMENTS: Delirium was identified using a validated chart extraction tool. Functional decline from admission to discharge was identified from nursing documentation. Falls were identified according to documentation in the medical record cross-checked with the hospital incident reporting system. Pressure ulcers were identified according to documentation in the medical record. RESULTS: Geriatric syndromes were present in 32% of participants. Delirium was identified in 21%, functional decline in 14%, falls in 8%, and pressure ulcers in 5%. Individuals admitted directly from the emergency or outpatient department and interhospital transfers (nonelective) were significantly more likely to develop any geriatric syndrome than those on an elective surgery list before admission to the hospital (41% vs 18%, P = .01). In multivariable analysis, nonelective admission (odds ratio (OR) = 3.3, 95% confidence interval (CI) = 1.6-4.7, P = .005), major surgery (OR = 3.1, 95% CI = 1.7-3.7, P = .004) and preexisting impairment in activities of daily living (OR 2.9, 95% CI 1.5-3.6, P = .007) increased the likelihood of geriatric syndromes. CONCLUSION: Geriatric syndromes are common in older adults undergoing surgery, and nonelective admission and major surgery increase the likelihood of geriatric syndromes occurring during hospitalization. Baseline dependency in ADLs is an important risk factor for the occurrence of these conditions. PMID- 24801948 TI - Fluorine-functionalized and simultaneously reduced graphene oxide as a novel hole transporting layer for highly efficient and stable organic photovoltaic cells. AB - A one-step reduction and functionalization of graphene oxide (FrGO) was easily achieved using a novel phenylhydrazine-based reductant containing fluorine atoms, which can induce p-type doping due to its high electronegativity. The FrGO-based OPV exhibited a high power conversion efficiency of ~6.71% and a superior OPV stability to commercial PEDOT:PSS. PMID- 24801949 TI - Investigation of the interaction between quercetin and human serum albumin by multiple spectra, electrochemical impedance spectra and molecular modeling. AB - Quercetin (Qu), a flavonoid compound, exists widely in the human diet and exhibits a variety of pharmacological activities. This work is aimed at studying the effect of Qu on the bioactive protein, human serum albumin (HSA) under simulated biophysical conditions. Multiple spectroscopic methods (including fluorescence and circular dichroism), electrochemical impedance spectra (EIS) and molecular modeling were employed to investigate the interaction between Qu and HSA. The fluorescence quenching and EIS experimental results showed that the fluorescence quenching of HSA was caused by formation of a Qu-HSA complex in the ground state, which belonged to the static quenching mechanism. Based on the calculated thermodynamic parameters, it concluded that the interaction was a spontaneous process and hydrogen bonds combined with van der Waal's forces played a major role in stabilizing the Qu-HSA complex. Molecular modeling results demonstrated that several amino acids participated in the binding process and the formed Qu-HSA complex was stabilized by H-bonding network at site I in sub-domain IIA, which was further confirmed by the site marker competitive experiments. The evidence from circular dichroism (CD) indicated that the secondary structure and microenvironment of HSA were changed. Alterations in the conformation of HSA were observed with a reduction in the amount of alpha helix from 59.9% (free HSA) to 56% (Qu-HSA complex), indicating a slight unfolding of the protein polypeptides. PMID- 24801955 TI - The future of the journal. PMID- 24801958 TI - Guideline implementation powered by feedback and education improves manual hyperinflation performance. AB - AIM: To determine whether a literature-based guideline, powered by educational meetings and individual feedback, improves manual hyperinflation (MH) performance by intensive care unit (ICU) nurses. BACKGROUND: MH is frequently applied in intubated and mechanically ventilated ICU patients. MH is a complex intervention, and large variation in its performance has been found. MATERIALS AND METHODS: First, a literature-based guideline on MH was developed. The intervention consisted of education of this guideline and individual feedback. Before and 3 months after the intervention, ICU nurses performed MH maneuvers in a skills laboratory. Data collected included applied volumes, peak inspiratory flows (PIF) and peak expiratory flows (PEF), and the use of inspiratory holds. RESULTS: Eighty nurses participated. Decrease of PIF was not statistically significant. PEF increased from 52 +/- 7 to 83 +/- 23 L/min (P < 0.01). PIF to PEF ratio decreased from 1.4 [1.1-1.7] to 0.8 [0.6-1.1] (P < 0.01). Peak inspiratory pressures decreased from 40 +/- 14 to 19 +/- 6 cm H2 O (P < 0.01). The proportion of nurses applying inspiratory holds increased from 14% to 58%; use of rapid release of the resuscitation bag, considered mandatory, increased from 4% to 61%. CONCLUSION: Implementation of a literature-based guideline on MH, powered by educational meetings and individual feedback, improves MH performance by ICU nurses. RELEVANCE TO CLINICAL PRACTICE: If it is decided to practice MH in the care of the intubated and mechanical ventilated patient, a standardized, uniform performed MH procedure is a prerequisite. PMID- 24801959 TI - Substituent and Solvent Effects on the Absorption Spectra of Cation-pi Complexes of Benzene and Borazine: A Theoretical Study. AB - Time-dependent density functional theory (TDDFT) has been used to predict the absorption spectra of cation-pi complexes of benzene and borazine. Both polarized continuum model (PCM) and discrete solvation model (DSM) and a combined effect of PCM and DSM on the absorption spectra have been elucidated. With decrease in size of the cation, the pi -> pi* transitions of benzene and borazine are found to undergo blue and red shift, respectively. A number of different substituents (both electron-withdrawing and electron-donating) and a range of solvents (nonpolar to polar) have been considered to understand the effect of substituent and solvents on the absorption spectra of the cation-pi complexes of benzene and borazine. Red shift in the absorption spectra of benzene cation-pi complexes are observed with both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs). The same trend has not been observed in the case of substituted borazine cation-pi complexes. The wavelength of the electronic transitions corresponding to cation-pi complexes correlates well with the Hammet constants (sigmap and sigmam). This correlation indicates that the shifting of spectral lines of the cation-pi complexes on substitution is due to both resonance and inductive effect. On incorporation of solvent phases, significant red or blue shifting in the absorption spectra of the complexes has been observed. Kamlet Taft multiparametric equation has been used to explain the effect of solvent on the absorption spectra of complexes. Polarity and polarizability are observed to play an important role in the solvatochromism of the cation-pi complexes. PMID- 24801960 TI - Predictive properties of the video head impulse test: measures of caloric symmetry and self-report dizziness handicap. AB - OBJECTIVES: The purpose of this investigation was to determine whether a predictable relationship existed between self-reported dizziness handicap and video Head Impulse Test (vHIT) results in a large sample of patients reporting to a dizziness clinic. Secondary objectives included describing the characteristics of the vHIT ipsilesional and contralesional vestibulo-ocular reflex slow-phase velocity in patients with varying levels of canal paresis. Finally, the authors calculated the sensitivity and specificity of the vHIT for detecting horizontal semicircular canal impairment using the caloric test as the "gold standard." DESIGN: Participants were 115 adults presenting to a tertiary medical care center with symptoms of dizziness. Participants were administered a measure of self report dizziness handicap (i.e., Dizziness Handicap Inventory) and underwent caloric testing and vHIT at the same appointment. RESULTS: Results showed that (1) there were no significant group differences (i.e., vHIT normal versus vHIT abnormal) in the Dizziness Handicap Inventory total score, (2) both ipsilesional and contralateral velocity gain decreased with increases in caloric paresis, and (3) a caloric asymmetry of 39.5% was determined to be the cutoff that maximized discrimination of vHIT outcome. CONCLUSIONS: The level of self-reported dizziness handicap is not predicted by the outcome of the vHIT, which is consistent with the majority of published reports describing the poor relationship between quantitative tests of vestibular function and dizziness handicap. Further, the study findings have demonstrated that vHIT and caloric data are not redundant, and each test provides unique information regarding the functional integrity of the horizontal semicircular canal at different points on the frequency spectrum. The vHIT does offer some advantages over caloric testing, but at the expense of sensitivity. The vHIT can be completed in less time, is not noxious to the patient, and requires very little laboratory space. However, the study data show that a caloric asymmetry of 39.5% is required to optimize discrimination between an abnormal and normal vHIT. It is the authors' contention that the vHIT is a complementary test to the balance function examination and should viewed as such rather than as a replacement for caloric testing. PMID- 24801961 TI - Spontaneous haemoperitoneum due to segmental arterial mediolysis and rupture of the left colic artery. PMID- 24801962 TI - Talker identification across source mechanisms: experiments with laryngeal and electrolarynx speech. AB - PURPOSE: The purpose of this study was to determine listeners' ability to learn talker identity from speech produced with an electrolarynx, explore source and filter differentiation in talker identification, and describe acoustic-phonetic changes associated with electrolarynx use. METHOD: Healthy adult control listeners learned to identify talkers from speech recordings produced using talkers' normal laryngeal vocal source or an electrolarynx. Listeners' abilities to identify talkers from the trained vocal source (Experiment 1) and generalize this knowledge to the untrained source (Experiment 2) were assessed. Acoustic phonetic measurements of spectral differences between source mechanisms were performed. Additional listeners attempted to match recordings from different source mechanisms to a single talker (Experiment 3). RESULTS: Listeners successfully learned talker identity from electrolarynx speech but less accurately than from laryngeal speech. Listeners were unable to generalize talker identity to the untrained source mechanism. Electrolarynx use resulted in vowels with higher F1 frequencies compared with laryngeal speech. Listeners matched recordings from different sources to a single talker better than chance. CONCLUSIONS: Electrolarynx speech, although lacking individual differences in voice quality, nevertheless conveys sufficient indexical information related to the vocal filter and articulation for listeners to identify individual talkers. Psychologically, perception of talker identity arises from a "gestalt" of the vocal source and filter. PMID- 24801963 TI - Clinical severity of rhinovirus/enterovirus compared to other respiratory viruses in children. AB - BACKGROUND: Human rhinovirus/enterovirus (HRV/ENT) infections are commonly identified in children with acute respiratory infections (ARIs), but data on their clinical severity remain limited. OBJECTIVES: We compared the clinical severity of HRV/ENT to respiratory syncytial virus (RSV), influenza A/B (FLU), and other common respiratory viruses in children. PATIENTS/METHODS: Retrospective study of children with ARIs and confirmed single positive viral infections on mid turbinate swabs by molecular assays. Outcome measures included hospital admission and, for inpatients, a composite endpoint consisting of intensive care admission, hospitalization >5 days, oxygen requirements or death. RESULTS: A total of 116 HRV/ENT, 102 RSV, 99 FLU, and 64 other common respiratory viruses were identified. Children with single HRV/ENT infections presented with significantly higher rates of underlying immunosuppressive conditions compared to those with RSV (37.9% versus 13.6%; P < 0.001), FLU (37.9% versus 22%; P = 0.018) or any other single viral infection (37.9% versus 22.5%; P = 0.024). In multivariable analysis adjusted for underlying conditions and age, children with HRV/ENT infections had increased odds of hospitalization compared to children with RSV infections (OR 2.6; 95% CI 1.4, 4.8; P < 0.003) or FLU infections (OR 3.0; 95% CI 1.6, 5.8; <0.001) and increased odds of severe clinical disease among inpatients (OR 3.0; 95% CI 1.6,5.6; P = 0.001) when compared to those with FLU infections. CONCLUSIONS: Children with HRV/ENT had a more severe clinical course than those with RSV and FLUA/B infections and often had significant comorbidities. These findings emphasize the importance of considering HRV/ENT infection in children presenting with severe acute respiratory tract infections. PMID- 24801964 TI - Burkholderia sp. induces functional nodules on the South African invasive legume Dipogon lignosus (Phaseoleae) in New Zealand soils. AB - The South African invasive legume Dipogon lignosus (Phaseoleae) produces nodules with both determinate and indeterminate characteristics in New Zealand (NZ) soils. Ten bacterial isolates produced functional nodules on D. lignosus. The 16S ribosomal RNA (rRNA) gene sequences identified one isolate as Bradyrhizobium sp., one isolate as Rhizobium sp. and eight isolates as Burkholderia sp. The Bradyrhizobium sp. and Rhizobium sp. 16S rRNA sequences were identical to those of strains previously isolated from crop plants and may have originated from inocula used on crops. Both 16S rRNA and DNA recombinase A (recA) gene sequences placed the eight Burkholderia isolates separate from previously described Burkholderia rhizobial species. However, the isolates showed a very close relationship to Burkholderia rhizobial strains isolated from South African plants with respect to their nitrogenase iron protein (nifH), N-acyltransferase nodulation protein A (nodA) and N-acetylglucosaminyl transferase nodulation protein C (nodC) gene sequences. Gene sequences and enterobacterial repetitive intergenic consensus (ERIC) PCR and repetitive element palindromic PCR (rep-PCR) banding patterns indicated that the eight Burkholderia isolates separated into five clones of one strain and three of another. One strain was tested and shown to produce functional nodules on a range of South African plants previously reported to be nodulated by Burkholderia tuberum STM678(T) which was isolated from the Cape Region. Thus, evidence is strong that the Burkholderia strains isolated here originated in South Africa and were somehow transported with the plants from their native habitat to NZ. It is possible that the strains are of a new species capable of nodulating legumes. PMID- 24801965 TI - Environmental heterogeneity and microbial inheritance influence sponge-associated bacterial composition of Spongia lamella. AB - Sponges are important components of marine benthic communities. High microbial abundance sponges host a large diversity of associated microbial assemblages. However, the dynamics of such assemblages are still poorly known. In this study, we investigated whether bacterial assemblages present in Spongia lamella remained constant or changed as a function of the environment and life cycle. Sponges were collected in multiple locations and at different times of the year in the western Mediterranean Sea and in nearby Atlantic Ocean to cover heterogeneous environmental variability. Co-occurring adult sponges and offsprings were compared at two of the sites. To explore the composition and abundance of the main bacteria present in the sponge mesohyl, embryos, and larvae, we applied both 16S rRNA gene-denaturing gradient gel electrophoresis (DGGE) and sequencing of excised DGGE bands and quantitative polymerase chain reactions (qPCR). On average, the overall core bacterial assemblage showed over 60 % similarity. The associated bacterial assemblage fingerprints varied both within and between sponge populations, and the abundance of specific bacterial taxa assessed by qPCR significantly differed among sponge populations and between adult sponge and offsprings (higher proportions of Actinobacteria in the latter). Sequences showed between 92 and 100 % identity to sequences previously reported in GenBank, and all were affiliated with uncultured invertebrate bacterial symbionts (mainly sponges). Sequences were mainly related to Chloroflexi and Acidobacteria and a few to Actinobacteria and Bacteroidetes. Additional populations may have been present under detection limits. Overall, these results support that both ecological and biological sponge features may shape the composition of endobiont bacterial communities in S. lamella. PMID- 24801966 TI - Protein S-100 and neuron-specific enolase serum levels remain unaffected by electroconvulsive therapy in patients with depression. AB - The mechanism of the reversible cognitive deficits that might occur within an electroconvulsive therapy (ECT) treatment has not been clarified in a substantial way yet. Although the data available so far do not point towards a cause due to any structural or diffuse damage, further clarification, especially of the role of S-100 seems to be necessary before robust conclusions can be drawn. Serum levels of protein S-100 and neuron-specific enolase (NSE) were analysed in 19 patients with depression, who received ECT. The sampling was adjusted for the short half-life of protein S-100. Several outcome parameters such as Hamilton Depression Rating Scale and Mini-mental state examination before and after the ECT, response and remission to the treatment were recorded. S-100 and NSE levels at baseline, 30 and 60 min after the third session and after the end of the ECT remained stable. S-100 and NSE levels were neither associated with antidepressant response or remission nor with alterations in the cognitive performance. Although aiming for detecting potential rise in these established brain damage markers, an increase due to ECT was not observed, which is in line with the previous studies concerning the safety of ECT on a cellular basis. PMID- 24801967 TI - Tactile sensor using acoustic reflection for lump detection in laparoscopic surgery. AB - PURPOSE: Laparoscopic surgery limits a surgeon's tactile sense. A tactile sensor could allow real-time tumor detection in laparoscopic surgery through lump inspection. This study was aimed at developing a simple and biocompatible tactile sensor for laparoscopic surgery. The proposed tactile sensor has a forceps-like shape, has no electrical elements in the tissue contact area, and can be sterilized and cleaned. METHODS: We developed a tactile sensor using acoustic reflection. It is composed of a handle with a speaker and a microphone, an aluminum tube, and a sensor tip with a deformable elastic cavity. The acoustic wave in the tube is the superposition of the input wave and two waves reflected at the closed edge and the projection generated by deformation due to contact with an object. By measuring the acoustic wave in the tube, information of the deformation is derived. RESULTS: The sensor is modeled, and the output is analyzed to determine design parameters of the sensor. Then, a prototype of the sensor is assembled. Fundamental experiments show that the sensor output increases with increasing normal deformation. Moreover, experiments using a phantom of the stomach wall with a 0-IIc type tumor (most common early stage gastric cancer) show that large sensor output is obtained for the lump when the sensor is moved across the back surface of the tumor. CONCLUSIONS: The theoretical and experimental results show that the sensor is sensitive to the deformation due to contact with an object and has the potential to detect a lump in laparoscopic surgery. PMID- 24801969 TI - [A plea for a functional basic model of psychiatric care]. PMID- 24801970 TI - [Integrated health care managed by community psychiatric services - pro]. PMID- 24801971 TI - [Integrated health care managed by community psychiatric services - contra]. PMID- 24801972 TI - [Reports from the Federal Directors Conference]. PMID- 24801973 TI - Pain and treatment from a human primate perspective. AB - Human animals have evolved with the primary missions of survival and reproduction and these natural drives may impact behavior whether humans are aware of them or not. The author offers evidence in support of the idea that injury and resulting acute or chronic pain may trigger the unconscious human primate brain to believe there is a threat to survival. This perceived threat may be exacerbated or mitigated by the pain manager, both of which may impact health outcomes in a negative or positive way, respectively. The commentary argues the patient-health care provider relationship is of paramount importance for those with chronic pain and illness and should be nurtured for the best possible outcomes. PMID- 24801974 TI - Subacute pain after total knee arthroplasty. AB - Acute pain during and immediately after total knee arthroplasty (TKA) can be well controlled by spinal anesthesia, local infiltration analgesia, and peripheral nerve blocks; this enables early or fast-track rehabilitation. However, about half of patients have clinically significant pain in the following weeks. Active movements and rehabilitation of joint function, muscle strength, and ability to maintain balance and prevent falls all become more difficult when the joint is painful on movement. Intensive analgesic and antihyperalgesic treatment during the first few weeks after TKA surgery may reduce the risk of chronic pain after this operation, which is itself intended to remove the patient's chronic osteoarthritis pain. Spinal cord stimulation may be an effective option for patients with mainly neuropathic pain after TKA surgery. PMID- 24801975 TI - A case of severe low back pain after surgery. AB - The etiology of chronic back pain is often unknown but can include failed spinal surgery. Pain can often be of mixed type and it is important to evaluate pain mechanisms. Comorbid factors often contribute to pain chronicity. Multimodal treatment, including opioid rotation where indicated, may offer a successful management approach. Other rehabilitative procedures such as physiotherapy, exercise therapy, and good sleep hygiene may have a profound impact on patient quality of life. Spinal cord stimulation may be an effective option for some patients with failed spinal surgery syndrome. A case of severe low back pain after surgery in a 45-year-old man is presented to illustrate this. PMID- 24801976 TI - Pain management discussion forum: serious interaction among frequently used drugs for chronic pain. AB - A query and response regarding a patient who was taking high-dose tramadol and duloxetine is presented. The patient developed serotonin syndrome. Risks for this clinically important drug interaction and management of the syndrome are discussed. PMID- 24801977 TI - Pain and other symptoms in cancer survivors. AB - Pain is common in cancer survivors. Long-term pain, often of neuropathic origin, is common after operations, radiotherapy, and chemotherapy. Pain and other concomitant symptoms and side effects should be assessed with validated and reliable scales and questionnaires. Cancer survivors with severe pain should be seen by a pain specialist. Multidisciplinary rehabilitation and individualized pain management may improve quality of life in cancer survivors. Four case reports are presented to illustrate this. PMID- 24801978 TI - Impact of contrast injection and stent-graft implantation on reproducibility of volume measurements in semiautomated segmentation of abdominal aortic aneurysm on computed tomography. AB - PURPOSE: To assess the impact of contrast injection and stent-graft implantation on feasibility, accuracy, and reproducibility of abdominal aortic aneurysm (AAA) volume and maximal diameter (D-max) measurements using segmentation software. MATERIALS AND METHODS: CT images of 80 subjects presenting AAA were divided into four equal groups: with or without contrast enhancement, and with or without stent-graft implantation. Semiautomated software was used to segment the aortic wall, once by an expert and twice by three readers. Volume and D-max reproducibility was estimated by intraclass correlation coefficients (ICC), and accuracy was estimated between the expert and the readers by mean relative errors. RESULTS: All segmentations were technically successful. The mean AAA volume was 167.0 +/- 82.8 mL and the mean D-max 55.0 +/- 10.6 mm. Inter- and intraobserver ICCs for volume and D-max measurements were greater than 0.99. Mean relative errors between readers varied between -1.8 +/- 4.6 and 0.0 +/- 3.6 mL. Mean relative errors in volume and D-max measurements between readers showed no significant difference between the four groups (P >= 0.2). CONCLUSION: The feasibility, accuracy, and reproducibility of AAA volume and D-max measurements using segmentation software were not affected by the absence of contrast injection or the presence of stent-graft. KEY POINTS: * AAA volumetry by semiautomated segmentation is accurate on CT following endovascular repair. * AAA volumetry by semiautomated segmentation is accurate on unenhanced CT. * Standardization of the segmentation technique maximizes the reproducibility of volume measurements. PMID- 24801979 TI - Investigation into the possibility of vertical transmission of avian bornavirus in free-ranging Canada geese (Branta canadensis). AB - To investigate the possibility of in ovo infection with avian bornavirus (ABV) in wild Canada geese (Branta canadensis), 53 eggs were opportunistically collected at various stages of embryonic development from 16 free-ranging goose nests at a large urban zoo site where ABV infection is known to be present in this species. ABV RNA was detected in the yolk of one of three unembryonated eggs using real time reverse transcription polymerase chain reaction. ABV RNA was not identified in the brains from 23 newly hatched goslings or 19 embryos, nor from three early whole embryos. Antibodies against ABV were not detected in the plasma of any of the hatched goslings using an enzyme-linked immunosorbent assay. Possible reasons for the failure to detect ABV RNA in hatchlings or embryos include low sample size, eggs deriving from parents not actively infected with ABV, the testing of only brain tissue, and failure of the virus to replicate in Canada goose embryos. In conclusion, this preliminary investigation demonstrating the presence of ABV RNA in the yolk of a Canada goose egg provides the first evidence for the potential for vertical transmission of ABV in waterfowl. PMID- 24801980 TI - Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal. AB - Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nalpha-acetyllysine (AcLys) and determined the structure of the cross link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross link formation is likely to involve an Amadori rearrangement. PMID- 24801981 TI - Distinct phenotypes of human prostate cancer cells associate with different adaptation to hypoxia and pro-inflammatory gene expression. AB - Hypoxia and inflammation are strictly interconnected both concurring to prostate cancer progression. Numerous reports highlight the role of tumor cells in the synthesis of pro-inflammatory molecules and show that hypoxia can modulate a number of these genes contributing substantially to the increase of cancer aggressiveness. However, little is known about the importance of the tumor phenotype in this process. The present study explores how different features, including differentiation and aggressiveness, of prostate tumor cell lines impact on the hypoxic remodeling of pro-inflammatory gene expression and malignancy. We performed our studies on three cell lines with increasing metastatic potential: the well differentiated androgen-dependent LNCaP and the less differentiated and androgen-independent DU145 and PC3. We analyzed the effect that hypoxic treatment has on modulating pro-inflammatory gene expression and evaluated the role HIF isoforms and NF-kB play in sustaining this process. DU145 and PC3 cells evidenced a higher normoxic expression and a more complete hypoxic induction of pro inflammatory molecules compared to the well differentiated LNCaP cell line. The role of HIF1alpha and NF-kB, the master regulators of hypoxia and inflammation respectively, in sustaining the hypoxic pro-inflammatory phenotype was different according to cell type. NF-kB was observed to play a main role in DU145 and PC3 cells in which treatment with the NF-kB inhibitor parthenolide was able to counteract both the hypoxic pro-inflammatory shift and HIF1alpha activation but not in LNCaP cells. Our data highlight that tumor prostate cell phenotype contributes at a different degree and with different mechanisms to the hypoxic pro-inflammatory gene expression related to tumor progression. PMID- 24801982 TI - Brain-derived neurotrophic factor (BDNF)-induced tropomyosin-related kinase B (Trk B) signaling is a potential therapeutic target for peritoneal carcinomatosis arising from colorectal cancer. AB - Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal metastatic nodules was found to be reduced, as compared with control mice. BDNF/TrkB signaling may thus be a potential target for treating peritoneal carcinomatosis arising from colorectal cancer. PMID- 24801983 TI - Factors associated with prospective leptin concentrations throughout pregnancy in pregestational normal weight, overweight and obese women. AB - BACKGROUND: Leptin concentrations increase throughout pregnancy but little is known about factors that influence this physiological change and whether they differ according to pregestational body mass index (BMI). OBJECTIVE: To assess whether longitudinal trends of leptin in pregnancy are influenced by biochemical, anthropometric and lifestyle factors in women with normal weight (NW), overweight (OW) or obese (OB) pregestational BMI. DESIGN AND METHODS: Prospective cohort of 232 pregnant women followed at 5-13th, 20-26th and 30-36th gestational weeks. The effect of selected variables on longitudinal behaviour of plasma leptin concentrations, stratifying for NW (18.5-24.9 kg/m(2) ), OW (25-29.9 kg/m(2) ) and OB (>=30.0 kg/m(2) ) pregestational BMI was assessed through longitudinal linear mixed-effects models. RESULTS: The multiple regression model for women with NW revealed associations of maternal body weight (beta = 0.714, CI = 0.491 to 0.937), serum HDL-cholesterol (beta = 0.239, CI =0.089 to 0.388) and C reactive protein (CRP) (beta = -0.138, CI = -0.272 to -0.004) with plasma leptin concentrations. Maternal body weight (beta = -0.871, CI = 0.475 to 1.267) and serum HDL-cholesterol concentrations (beta = 0.315, CI = -0.022 to 0.651) were also associated with leptin in OW women. In OB women, serum HDL-cholesterol (beta = 0.722, CI = 0.219 to 1.226), maternal body weight (beta = 0.666, CI = 0.187 to 1.145), triglycerides concentrations (beta = -0.130, CI = -0.241 to -0.020) and dietary carbohydrate (beta = 0.075, CI = 0.023 to 0.126) were significantly associated with plasma leptin. CONCLUSION: Maternal body weight and serum concentrations of HDL-cholesterol were associated with leptin changes independent of pregestational BMI. Serum CRP concentrations were associated with leptin only in NW women and serum triglycerides concentrations and dietary carbohydrate only in OB. These results indicate that factors that influence leptin concentrations differ according to pregestational BMI. PMID- 24801984 TI - Vesical preservation in patients with late bladder exstrophy referral: histological insights into functional outcome. AB - PURPOSE: We evaluated bladder growth after combined bladder and epispadias repair in children 5 years or older, and correlated the histological findings with final surgical outcomes. MATERIALS AND METHODS: We prospectively evaluated 8 late bladder exstrophy referrals from a series of 26 patients treated during a 5-year period. Evaluated outcome measures were bladder capacity (expressed as percentage of expected bladder capacity for age), upper tracts status, continence and histological findings (collagen-to-smooth muscle ratio and type III-to-total collagen ratio). Data were analyzed using nonparametric Spearman rank correlation coefficient and Mann-Whitney U test. RESULTS: Mean age at combined bladder and epispadias repair was 8.9 years. Volitional voiding with a mean +/- SD bladder capacity of 90 +/- 7.48 ml was achieved in all patients except 1 with a suprapubic fistula. However, mean +/- SD bladder capacity was 33.1% +/- 7.47% of expected bladder capacity, and was inversely proportional to age at surgery. Mean +/- SD compliance and pressure specific bladder volume less than 20 cm H2O were 13.86 +/- 4.97 ml/cm H2O and 69.29 +/- 18.07 ml, respectively. Two patients had nonobstructive hydroureteronephrosis with bilateral polar scarring. Mean +/- SD collagen-to-smooth muscle and type III-to-total collagen ratios were 2.96 +/- 1.062 and 0.4 +/- 0.106, respectively. The latter showed a significant negative correlation to bladder compliance (p = 0.025). CONCLUSIONS: Successful anatomical closure stimulates bladder growth, even in cases of late referral. However, due to histological alterations, these bladders are poorly distensible and noncompliant. Thus, to have an acceptable functional outcome with preserved upper tracts, augmentation cystoplasty is needed in cases of late referral. PMID- 24801985 TI - Deletion of the MGMT gene in familial melanoma. AB - The DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) is important for maintaining normal cell physiology and genomic stability. Alterations in MGMT play a critical role in the development of several types of cancer, including glioblastoma, lung cancer, and colorectal cancer. The purpose of this study was to explore the function of genetic alterations in MGMT and their connection with familial melanoma (FM). Using multiplex ligation-dependent probe amplification, we identified a deletion that included the MGMT gene in one of 64 families with a melanoma predisposition living in western Sweden. The mutation segregated with the disease as a heterozygous deletion in blood-derived DNA, but a homozygous deletion including the promoter region and exon 1 was seen in tumor tissue based on Affymetrix 500K and 6.0 arrays. By sequence analysis of the MGMT gene in the other 63 families with FM from western Sweden, we identified four common polymorphisms, nonfunctional, as predominantly described in previous studies. We conclude that inherited alterations in the MGMT gene might be a rare cause of FM, and we suggest that MGMT contributes to melanoma predisposition. PMID- 24801986 TI - Transanal total mesorectal excision with a side-to-end stapled anastomosis - a video vignette. PMID- 24801988 TI - Using THz time-scale infrared spectroscopy to examine the role of collective, thermal fluctuations in the formation of myoglobin allosteric communication pathways and ligand specificity. AB - In this investigation we use THz time-scale spectroscopy to conduct an initial set of studies on myoglobin with the aim of providing further insight into the global, collective thermal fluctuations in the protein that have been hypothesized to play a prominent role in the dynamic formation of transient ligand channels as well as in shaping the molecular level basis for ligand discrimination. Using the two ligands O2 and CO, we have determined that the perturbation from the heme-ligand complex has a strong influence on the characteristics of the myoglobin collective dynamics that are excited upon binding. Further, the differences detected in the collective protein motions in Mb-O2 compared with those in Mb-CO appear to be intimately tied with the pathways of long-range allosteric communication in the protein, which ultimately determine the trajectories selected by the respective ligands on the path to and from the heme-binding cavity. PMID- 24801987 TI - Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenstrom macroglobulinaemia. AB - In Waldenstrom macroglobulinaemia (WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells (LPC). Ectopic expression of SPIB in healthy donor CD19(+) cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF4 and XBP1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM1, XBP1 spliced form, IRF4 and ID2. Knock-down of SPIB also led to decreased BCL2 expression. Given that SPIB is a direct target of POU2AF1 (OBF1) in complex with POU2F2 or POU2F1, we next examined their expression in WM LPC. POU2F2 transcription, as well as POU2F2 and POU2AF1 protein expression was higher in WM LPC. Ectopic expression of POU2F2 in healthy donor CD19(+) cells induced transcription of SPIB and suppressed transcription of PRDM1 and IRF4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2AF1 in SPIB and ID2 promoters. These findings establish a molecular hierarchy among POU2F2, SPIB and ID2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM. PMID- 24801989 TI - Sesquiterpenes inhibiting the microglial activation from Laurus nobilis. AB - The inhibitory reagents to inhibit the activation of microglial cells may be potentially useful for the treatment of neurodegenerative diseases. The leaves of the plant Laurus nobilis belonging to the family Lauraceae, namely, bay leaves, have been used as a popular spice, and their extract showed moderate inhibition on microglial activation. A further phytochemical investigation of the leaves led to the isolation of two new (1, 2) and eight known (3-10) sesquiterpenes. Their structures were elucidated on the basis of extensive 1D and 2D NMR (HMQC, HMBC, (1)H-(1)H COSY, and NOESY) spectroscopic data analyses and Chem3D modeling. The following biological studies disclosed that these isolated compounds showed inhibitory activities on LPS-induced microglial activation. The results of our phytochemical investigation, including two new sesquiterpenes (1 and 2) and the first report of two compounds (3 and 4) from this species, further revealed the chemical composition of bay leaves as a popular spice, and the biological studies implied that bay leaves, containing bioactive substances with the inhibition of microglial activation, were potentially beneficial to human health. PMID- 24801995 TI - Highly sensitive LC-MS/MS method for determination of galantamine in rat plasma: application to pharmacokinetic studies in rats. AB - A rapid and highly sensitive assay method has been developed and validated for the estimation of galantamine (GLM) in rat plasma using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive ion mode. The assay procedure involves a simple liquid-liquid extraction of GLM and phenacetin (internal standard, IS) from rat plasma using acetonitrile. Chromatographic separation was achieved with 0.2% formic acid:acetonitrile (50:50, v/v) at a flow rate of 0.60 mL/min on an Atlantis dC18 column with a total run time 2.5 min. The MS/MS ion transitions monitored were 288.10 -> 213.10 for GLM and 180.10 -> 110.10 for IS. Method validation was performed as per United States Food and Drug Administration guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 0.12 ng/mL and linearity was observed from 0.12 to 525 ng/mL. The intra- and inter-day precision were in the ranges of 4.73-11.7 and 5.83-8.64%, respectively. This novel method has been applied to a pharmacokinetic study in rats. PMID- 24801996 TI - Cold adaptation: structural and functional characterizations of psychrophilic and mesophilic acetate kinase. AB - Acetate kinase catalyzes the reversible magnesium-dependent phosphoryl transfer from ATP to acetate to form acetyl phosphate and ADP. Here, we report functional and some structural properties of cold-adapted psychrotrophic enzyme; acetate kinase with those from mesophilic counterpart in Escherichia coli K-12. Recombinant acetate kinase from Shewanella sp. AS-11 (SAK) and E. coli K-12 (EAK) were purified to homogeneity following affinity chromatography and followed by Super Q column chromatography as reported before [44]. Both purified enzymes are shared some of the common properties such as (similar molecular mass, amino acid sequence and similar optimum pH), but characterized shift in the apparent optimum temperature of specific activity to lower temperature as well as by a lower thermal stability compared with EAK. The functional comparisons reveal that SAK is a cold adapted enzyme, having a higher affinity to acetate than EAK. In the acetyl phosphate and ADP-forming direction, the catalytic efficiency (k(cat)/K(m)) for acetate was 8.0 times higher for SAK than EAK at 10 degrees C. The activity ratio of SAK to EAK was increased with decreasing temperature in both of the forward and backward reactions. Furthermore, the activation energy, enthalpy and entropy in both reaction directions that catalyzed by SAK were lower than those catalyzed by EAK. The model structure of SAK showed the significantly reduced numbers of salt bridges and cation-pi interactions as compared with EAK. These results suggest that weakening of intramolecular electrostatic interactions of SAK is involved in a more flexible structure which is likely to be responsible for its cold adaptation. PMID- 24801997 TI - Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. AB - Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine based inhibitor series to explore the effects of fluorine on affinity and species selectivity. We show that increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding sites. Key hydrogen-bond and stacking interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding, suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species-selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases. PMID- 24801998 TI - 3D 15N/15N/1H chemical shift correlation experiment utilizing an RFDR-based 1H/1H mixing period at 100 kHz MAS. AB - Homonuclear correlation NMR experiments are commonly used in the high-resolution structural studies of proteins. While (13)C/(13)C chemical shift correlation experiments utilizing dipolar recoupling techniques are fully utilized under MAS, correlation of the chemical shifts of (15)N nuclei in proteins has been a challenge. Previous studies have shown that the negligible (15)N-(15)N dipolar coupling in peptides or proteins necessitates the use of a very long mixing time (typically several seconds) for effective spin diffusion to occur and considerably slows down a (15)N/(15)N correlation experiment. In this study, we show that the use of mixing proton magnetization, instead of (15)N, via the recoupled (1)H-(1)H dipolar couplings enable faster (15)N/(15)N correlation. In addition, the use of proton-detection under ultrafast MAS overcomes the sensitivity loss due to multiple magnetization transfer (between (1)H and (15)N nuclei) steps. In fact, less than 300 nL (~1.1 micromole quantity) sample is sufficient to acquire the 3D spectrum within 5 h. Our results also demonstrate that a 3D (15)N/(15)N/(1)H experiment can render higher resolution spectra that will be useful in the structural studies of proteins at ultrafast MAS frequencies. 3D (15)N/(15)N/(1)H and 2D radio frequency-driven dipolar recoupling (RFDR)-based (1)H/(1)H experimental results obtained from a powder sample of N acetyla-L-(15)N-valyl-L-(15)N-leucine at 70 and 100kHz MAS frequencies are presented. PMID- 24801999 TI - Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells. AB - Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 . 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR 26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings. PMID- 24802002 TI - Injury-related emergency department visits by children and adolescents: United States, 2009-2010. AB - KEY FINDINGS: Key findings Data from the National Hospital Ambulatory Medical Care Survey, 2009-2010 In 2009-2010, an annual average of 11.9 million injury related emergency department (ED) visits were made by children and adolescents aged 18 years and under in the United States. The injury-related ED visit rate was 151 per 1,000 persons aged 18 years and under, and rates were higher for males than for females for all age groups (0-4 years, 5-12 years, and 13-18 years). The injury-related ED visit rates among persons aged 5-12 years and 13-18 years were higher for non-Hispanic black persons than for other race and ethnicity groups. Leading causes of injury-related ED visits among both males and females included falls and striking against or being struck unintentionally by objects or persons. Visit rates were higher for males than for females for both of these causes. Injury is the leading cause of death and a major source of morbidity among children and adolescents in the United States (1,2). The emergency department (ED) plays an important role in the care of injuries, and these visits often represent the initial contact with a provider for the injury (3). This report examines nationally representative data on injury-related ED visits by children and adolescents aged 18 years and under in the United States during 2009-2010. Injury-related ED visit rates were also compared for the age groups 0-4, 5-12, and 13-18 years, as these correspond to the preschool, school age, and teen life periods respectively. PMID- 24802000 TI - Medial temporal lobe roles in human path integration. AB - Path integration is a process in which observers derive their location by integrating self-motion signals along their locomotion trajectory. Although the medial temporal lobe (MTL) is thought to take part in path integration, the scope of its role for path integration remains unclear. To address this issue, we administered a variety of tasks involving path integration and other related processes to a group of neurosurgical patients whose MTL was unilaterally resected as therapy for epilepsy. These patients were unimpaired relative to neurologically intact controls in many tasks that required integration of various kinds of sensory self-motion information. However, the same patients (especially those who had lesions in the right hemisphere) walked farther than the controls when attempting to walk without vision to a previewed target. Importantly, this task was unique in our test battery in that it allowed participants to form a mental representation of the target location and anticipate their upcoming walking trajectory before they began moving. Thus, these results put forth a new idea that the role of MTL structures for human path integration may stem from their participation in predicting the consequences of one's locomotor actions. The strengths of this new theoretical viewpoint are discussed. PMID- 24802004 TI - Electrochemical switching with 3D DNA tetrahedral nanostructures self-assembled at gold electrodes. AB - Nanomechanical switching of functional three-dimensional (3D) DNA nanostructures is crucial for nanobiotechnological applications such as nanorobotics or self regulating sensor and actuator devices. Here, DNA tetrahedral nanostructures self assembled onto gold electrodes were shown to undergo the electronically addressable nanoswitching due to their mechanical reconfiguration upon external chemical stimuli. That enables construction of robust surface-tethered electronic nanodevices based on 3D DNA tetrahedra. One edge of the tetrahedron contained a partially self-complementary region with a stem-loop hairpin structure, reconfigurable upon hybridization to a complementary DNA (stimulus DNA) sequence. A non-intercalative ferrocene (Fc) redox label was attached to the reconfigurable tetrahedron edge in such a way that reconfiguration of this edge changed the distance between the electrode and Fc. PMID- 24802005 TI - The Development of a Measure of Confidence in Delivering Therapy to People with Intellectual Disabilities. AB - Current policy in UK health services emphasizes that, where possible, people with intellectual disabilities should access the same services as people without intellectual disabilities. One of the barriers to this is the confidence of clinicians and therapists. In this paper, we report on the development of a scale to describe the confidence of therapists in working with people with intellectual disabilities (the Therapy Confidence Scale-Intellectual Disabilities [TCS-ID]). One-hundred and eighty-one therapists who provided talking therapies but who did not work primarily with people with intellectual disabilities completed the scale; 43 people completed the scale twice for test-retest reliability purposes. One-hundred and seven people also completed a scale of general therapy self efficacy. The TCS-ID has a single factor structure accounting for 62% of the variance, Cronbach's alpha for the scale is 0.93 and test-retest reliability is 0.83. There are significant differences in confidence based upon participants experience in working with people with intellectual disabilities and their therapeutic orientation, and there is a significant association between the TCS ID and the General Therapy Self-efficacy Scale. Sixty clinicians working in mainstream mental health services received training on adapting their therapeutic approaches to meet the needs of people with intellectual disabilities. The TCS-ID was used pre-training and post-training and demonstrated a significant increase in confidence for all group. We suggest that the scale has good psychometric properties and can be used to develop an understanding of the impact of training for mainstream therapist in working with people with intellectual disabilities. KEY PRACTITIONER MESSAGE: There is increasing emphasis on people with intellectual disabilities receiving services from mainstream mental health services. There is no research describing the experiences and outcomes of people with intellectual disabilities receiving mainstream talking therapy services. The confidence that clinicians have in working with people with intellectual disabilities may be a barrier to them receiving mainstream services. The Therapy Confidence Scale-Intellectual Disabilities is a psychometrically sound scale for measuring the confidence of therapists in working with people with intellectual disabilities and is a useful outcome measure for training clinicians to work with people with intellectual disabilities. PMID- 24802006 TI - Genetic variation in immunoglobulin G receptor affects survival after lung transplantation. AB - Chronic rejection remains the most important complication after lung transplantation (LTx). There is mounting evidence that both rheumatoid arthritis and chronic rejection share similar inflammatory mechanisms. As genetic variants in the FCGR2A gene that encodes the immunoglobulin gamma receptor (IgGR) have been identified in rheumatoid arthritis, we investigated the relationship between a genetic variant in the IgGR gene and chronic rejection and mortality after LTx. Recipient DNA from blood or explant lung tissue of 418 LTx recipients was evaluated for the IgGR (rs12746613) polymorphism. Multivariate analysis was carried out, correcting for several co-variants. In total, 216 patients had the CC-genotype (52%), 137 had the CT-genotype (33%) and 65 had the TT-genotype (15%). Univariate analysis demonstrated higher mortality in the TT-genotype compared with both other genotypes (p < 0.0001). Multivariate analysis showed that the TT-genotype had worse survival compared with the CC-genotype (hazard ratio [HR] = 2.26, p = 0.0002) but no significance was observed in the CT genotype (HR = 1.32, p = 0.18). No difference was seen for chronic rejection. The TT-genotype demonstrated more respiratory infections (total, p = 0.037; per patient, p = 0.0022) compared with the other genotypes. A genetic variant in the IgGR is associated with higher mortality and more respiratory infections, although not with increased prevalence of chronic rejection, after LTx. PMID- 24802001 TI - Integrating omics technologies to study pulmonary physiology and pathology at the systems level. AB - Assimilation and integration of "omics" technologies, including genomics, epigenomics, proteomics, and metabolomics has readily altered the landscape of medical research in the last decade. The vast and complex nature of omics data can only be interpreted by linking molecular information at the organismic level, forming the foundation of systems biology. Research in pulmonary biology/medicine has necessitated integration of omics, network, systems and computational biology data to differentially diagnose, interpret, and prognosticate pulmonary diseases, facilitating improvement in therapy and treatment modalities. This review describes how to leverage this emerging technology in understanding pulmonary diseases at the systems level -called a "systomic" approach. Considering the operational wholeness of cellular and organ systems, diseased genome, proteome, and the metabolome needs to be conceptualized at the systems level to understand disease pathogenesis and progression. Currently available omics technology and resources require a certain degree of training and proficiency in addition to dedicated hardware and applications, making them relatively less user friendly for the pulmonary biologist and clinicians. Herein, we discuss the various strategies, computational tools and approaches required to study pulmonary diseases at the systems level for biomedical scientists and clinical researchers. PMID- 24802007 TI - Postural responses of young adults to collision in virtual world combined with horizontal translation of haptic floor. AB - Balance and postural response strategies change when subjects are exposed to horizontal translations of the floor or virtual reality or both. This may impact the balance training strategy and balance capabilities assessment in the future telerehabilitation. In the study 15 neurologically intact volunteers participated. Balance standing frame with virtual reality tasks and our novel haptic floor able to generate horizontal translations were used. The postural responses were measured with center of gravity and muscle electromyography of plantar-dorsiflexors, quadriceps, hamstrings, hip and spine muscles in three scenarios. The results demonstrated that center of gravity and electromyographic activity were comparable; with low latency at translation only, longer latency at combination with virtual reality and long latency when only virtual reality was applied. Soleus and semimembranousis demonstrated lower latency at back-right horizontal translations when virtual reality was present. The outcomes suggests that the postural strategy changes from ankle to ankle-hip strategy with availability of additional sensory systems which may be an important issue for objective balance evaluation in the clinical environment and remote telerehabilitation. PMID- 24802008 TI - George Zografi and the science of solids and surfaces. PMID- 24802017 TI - Monolayer assembly of ferrimagnetic Co(x)Fe(3-x)O4 nanocubes for magnetic recording. AB - We report a facile synthesis of monodisperse ferrimagnetic Co(x)Fe(3-x)O4 nanocubes (NCs) through thermal decomposition of Fe(acac)3 and Co(acac)2 (acac = acetylacetonate) in the presence of oleic acid and sodium oleate. The sizes of the NCs are tuned from 10 to 60 nm, and their composition is optimized at x = 0.6 to show strong ferrimagnetism with the 20 nm Co0.6Fe2.4O4 NCs showing a room temperature Hc of 1930 Oe. The ferrimagnetic NCs are self-assembled at the water air interface into a large-area (in square centimeter) monolayer array with a high packing density and (100) texture. The 20 nm NC array can be recorded at linear densities ranging from 254 to 31 kfci (thousand flux changes per inch). The work demonstrates the great potential of solution-phase synthesis and self assembly of magnetic array for magnetic recording applications. PMID- 24802016 TI - Modeling genome-wide dynamic regulatory network in mouse lungs with influenza infection using high-dimensional ordinary differential equations. AB - The immune response to viral infection is regulated by an intricate network of many genes and their products. The reverse engineering of gene regulatory networks (GRNs) using mathematical models from time course gene expression data collected after influenza infection is key to our understanding of the mechanisms involved in controlling influenza infection within a host. A five-step pipeline: detection of temporally differentially expressed genes, clustering genes into co expressed modules, identification of network structure, parameter estimate refinement, and functional enrichment analysis, is developed for reconstructing high-dimensional dynamic GRNs from genome-wide time course gene expression data. Applying the pipeline to the time course gene expression data from influenza infected mouse lungs, we have identified 20 distinct temporal expression patterns in the differentially expressed genes and constructed a module-based dynamic network using a linear ODE model. Both intra-module and inter-module annotations and regulatory relationships of our inferred network show some interesting findings and are highly consistent with existing knowledge about the immune response in mice after influenza infection. The proposed method is a computationally efficient, data-driven pipeline bridging experimental data, mathematical modeling, and statistical analysis. The application to the influenza infection data elucidates the potentials of our pipeline in providing valuable insights into systematic modeling of complicated biological processes. PMID- 24802018 TI - A clustering-based graph Laplacian framework for value function approximation in reinforcement learning. AB - In order to deal with the sequential decision problems with large or continuous state spaces, feature representation and function approximation have been a major research topic in reinforcement learning (RL). In this paper, a clustering-based graph Laplacian framework is presented for feature representation and value function approximation (VFA) in RL. By making use of clustering-based techniques, that is, K-means clustering or fuzzy C-means clustering, a graph Laplacian is constructed by subsampling in Markov decision processes (MDPs) with continuous state spaces. The basis functions for VFA can be automatically generated from spectral analysis of the graph Laplacian. The clustering-based graph Laplacian is integrated with a class of approximation policy iteration algorithms called representation policy iteration (RPI) for RL in MDPs with continuous state spaces. Simulation and experimental results show that, compared with previous RPI methods, the proposed approach needs fewer sample points to compute an efficient set of basis functions and the learning control performance can be improved for a variety of parameter settings. PMID- 24802020 TI - Fish consumption and acute coronary syndrome: a meta-analysis. AB - BACKGROUND: Findings on the association between fish consumption and acute coronary syndrome are inconsistent. We assessed the role of fish consumption in acute coronary syndrome by conducting a dose-response meta-analysis. METHODS: We conducted a literature search of MEDLINE and Embase databases from 1966 to June 2013 for prospective cohort and case-control studies that evaluated the association between fish consumption and acute coronary syndrome among general populations without cardiovascular disease history. Additional studies were identified via hand search of references of relevant articles. Estimates of relative risk (RR) were pooled using random-effects model. Sex and age effects were also evaluated. RESULTS: Our search retrieved 11 prospective cohort and 8 case-control studies, totaling 408,305 participants. Among prospective cohort studies, the highest category of fish consumption (ie, >=4 times per week) was associated with the greatest risk reduction in acute coronary syndrome (RR 0.79; 95% confidence interval [CI], 0.70-0.89). In dose-response analysis, each additional 100-g serving of fish per week was associated with a 5% reduced risk (RR per serving 0.95; 95% CI, 0.92-0.97). Subgroup analysis and meta-regression suggested that the risk reduction did not differ across sex or age groups. No heterogeneity was observed among prospective cohort (P = .73) and case-control (P = .29) studies. There was no evidence of publication bias. CONCLUSION: Our meta analysis demonstrated that there is an inverse association between fish consumption and the risk of acute coronary syndrome. Fish consumption appears beneficial in the primary prevention of acute coronary syndrome, and higher consumption is associated with greater protection. PMID- 24802019 TI - Pharmacokinetics of single- and multiple-dose emtricitabine in healthy male Chinese volunteers. AB - Emtricitabine (FTC) is used for the treatment of HIV infection and pre-exposure chemoprophylaxis. It is often used in combination with tenofovir disoproxil fumarate (TDF). This study was designed to evaluate FTC pharmacokinetics in healthy male Chinese volunteers. Sixty subjects were recruited into this single centre, randomised, open-label study and randomly received single (groups A, B and C) or multiple oral doses (once daily for 6 days; groups D, E and F) of 200 mg FTC capsules alone (A and D), or combined with 300-mg TDF tablets (B and E), or 200 mg of FTC plus 300 mg of TDF with a high-fat diet (C and F), respectively. FTC was well-tolerated in all groups. After a single dose, there were no differences in the mean AUC0-infinity values; however, there were significant differences in the mean Tmax values (1.05, 1.40 and 2.10 h for groups A, B and C, respectively; p < 0.05). In the multiple-dose study, our results were significantly different from published t1/2 values following single-dose FTC. PMID- 24802021 TI - Exploring entrustment: housestaff autonomy and patient readmission. PMID- 24802022 TI - Costs and impacts of scaling up voluntary medical male circumcision in Tanzania. AB - BACKGROUND: Given the proven effectiveness of voluntary medical male circumcision (VMMC) in preventing the spread of HIV, Tanzania is scaling up VMMC as an HIV prevention strategy. This study will inform policymakers about the potential costs and benefits of scaling up VMMC services in Tanzania. METHODOLOGY: The analysis first assessed the unit costs of delivering VMMC at the facility level in three regions-Iringa, Kagera, and Mbeya-via three currently used VMMC service delivery models (routine, campaign, and mobile/island outreach). Subsequently, using these unit cost data estimates, the study used the Decision Makers' Program Planning Tool (DMPPT) to estimate the costs and impact of a scaled-up VMMC program. RESULTS: Increasing VMMC could substantially reduce HIV infection. Scaling up adult VMMC to reach 87.9% coverage by 2015 would avert nearly 23,000 new adult HIV infections through 2015 and an additional 167,500 from 2016 through 2025-at an additional cost of US$253.7 million through 2015 and US$302.3 million from 2016 through 2025. Average cost per HIV infection averted would be US$11,300 during 2010-2015 and US$3,200 during 2010-2025. Scaling up VMMC in Tanzania will yield significant net benefits (benefits of treatment costs averted minus the cost of performing circumcisions) in the long run-around US$4,200 in net benefits for each infection averted. CONCLUSION: VMMC could have an immediate impact on HIV transmission, but the full impact on prevalence and deaths will only be apparent in the longer term because VMMC averts infections some years into the future among people who have been circumcised. Given the health and economic benefits of investing in VMMC, the scale-up of services should continue to be a central component of the national HIV prevention strategy in Tanzania. PMID- 24802023 TI - Current controversies in screening mammography. PMID- 24802024 TI - Correlation between severity of growth hormone deficiency and thyroid metabolism and effects of long-term growth hormone treatment on thyroid function in children with idiopathic growth hormone deficiency. AB - BACKGROUND/AIM: The significance of changes in thyroid function in children during growth hormone (GH) treatment remains uncertain. We aimed to evaluate the impact of GH replacement on thyroid status in children with idiopathic GH deficiency (GHD). METHODS: Data of 105 GHD children (82 M, 23 F; aged 11.13 years) during a 36-month follow-up were analyzed. At diagnosis the areas under the curve of GH (AUCGH) were calculated during a GH-releasing hormone + arginine (GHRH-Arg) and insulin tolerance test. RESULTS: A significant DeltafT3 (p < 0.001) was documented at 12 months, without any further change at 24 and 36 months and without fT4 and TSH modifications. Grouping patients according to DeltafT3 at 12 months into those with lower (n = 80, 76%) or greater values than the 75th percentile (n = 25, 24%), the latter showed lower AUCGH and GH peak during a GHRH-Arg (p = 0.018 and 0.014, respectively) and insulin tolerance test (p = 0.023 and 0.020, respectively) at diagnosis. In addition, children with lower GH at diagnosis showed a greater DeltafT3 at 12 months (p = 0.030). CONCLUSIONS: In GHD children, GH treatment is associated with a significant increase in fT3 in the first 12 months, more pronounced in patients with more severe GHD, highlighting the strong correlation between severity of GHD and thyroid metabolism. PMID- 24802025 TI - Analysis of xylene in aqueous media using needle-trap microextraction with a carbon nanotube sorbent. AB - This paper describes a new extraction technique with needles and a sorbent based on carbon nanotubes to analyze trace amounts of three isomers of xylenes in aqueous samples. In this research, results have been compared with one commercial sorbent. The synthesized sorbent was prepared using sol-gel technology and was packed into 20 gauge needles, and the same size needle was used for packing the commercial sorbent. In the extraction process, a purge and trap sampling methodology is developed, so purging and trapping cycles were performed by a sampling pump. Optimized conditions for standard xylene samples have been obtained, and eight urine samples from workers that were exposed to xylene in the workplace were collected and analyzed. Experimental parameters such as limits of detection and quantification were investigated, and these two parameters were <1 MUg/L. PMID- 24802027 TI - Towards high-performance Lewis acid organocatalysis. AB - The combination of Lewis acid organocatalysis and internal hydrogen-bond assistance was used to develop a new type of highly active disulfonimide catalyst. The increased Lewis acidity was documented by activity comparisons as well as theoretical investigations. Finally, the potential of the hydrogen-bond assisted disulfonimide catalyst was demonstrated by its application in an enantioselective transformation. PMID- 24802026 TI - Loading into nanoparticles improves quercetin's efficacy in preventing neuroinflammation induced by oxysterols. AB - Chronic inflammatory events appear to play a fundamental role in Alzheimer's disease (AD)-related neuropathological changes, and to result in neuronal dysfunction and death. The inflammatory responses observed in the AD brain include activation and proliferation of glial cells, together with up-regulation of inflammatory mediators and of free radicals. Along with glial cells, neurons themselves can also react and contribute to neuroinflammatory changes in the AD brain, by serving as sources of inflammatory mediators. Because excess cholesterol cannot be degraded in the brain, it must be excreted from that organ as cholesterol oxidation products (oxysterols), in order to prevent its accumulation. Among risk factors for this neurodegenerative disease, a mechanistic link between altered cholesterol metabolism and AD has been suggested; oxysterols appear to be the missing linkers between the two, because of their neurotoxic effects. This study shows that 24-hydroxycholesterol, 27 hydroxycholesterol, and 7beta-hydroxycholesterol, the three oxysterols potentially implicated in AD pathogenesis, induce some pro-inflammatory mediator expression in human neuroblastoma SH-SY5Y cells, via Toll-like receptor 4/cyclooxygenase-2/membrane bound prostaglandin E synthase (TLR4/COX-2/mPGES-1); this clearly indicates that oxysterols may promote neuroinflammatory changes in AD. To confirm this evidence, cells were incubated with the anti-inflammatory flavonoid quercetin; remarkably, its anti-inflammatory effects in SH-SY5Y cells were enhanced when it was loaded into beta-cyclodextrin-dodecylcarbonate nanoparticles, versus cells pretreated with free quercetin. The goal of loading quercetin into nanoparticles was to improve its permeation across the blood-brain barrier into the brain, and its bioavailability to reach target cells. The findings show that this drug delivery system might be a new therapeutic strategy for preventing or reducing AD progression. PMID- 24802028 TI - Screening of endocrine disruption activity in sediments from the Uruguay River. AB - Sediment constitutes an important sink of endocrine disruptor compounds; however, the potential of sediments to act as a source of endocrine disruptors should be more extensively investigated. The main objective of this study was to determine whether exposure of immature common carp to Uruguay River sediments undergo physiological and endocrine alterations. The lower Uruguay River watershed supports intensive agricultural and forest production, receives municipal sewage discharge and industrial effluent, and a new large pulp mill was constructed in 2006. A 30-day semi-static assay was performed using sediments from four sites along the Uruguay River and compared with an unexposed group in dechlorinated water as a negative control. We focused on two upstream and two downstream sites of a new elemental chlorine free pulp mill. The results showed that plasma vitellogenin levels increased in fish along the river and significant differences were found between the exposed and unexposed groups. Condition factor and gonadosomatic index were not different; however, a significant difference in hepatosomatic index was observed in fish exposed to sediment from an industrial site. A significant reduction in primary spermatocyte accumulation was observed in the exposed group compared with that in the control group, and some individuals exposed to sediments from industrial sites presented with testis-ova. Our results suggest that Uruguay River sediments act as an important source of estrogenic compounds that could be responsible for the alterations observed. Future studies are needed to identify the causal agents and determine exposure routes. PMID- 24802029 TI - Effects of atomic geometry and electronic structure of platinum surfaces on molecular adsorbates studied by gap-mode SERS. AB - Surface enhanced Raman scattering (SERS) spectra of organic monolayers were measured on various types of polycrystalline and single crystalline Pt substrates with nanometric or atomic surface features, including heteroepitaxial Pt monolayers, using sphere-plane type nanogap structures. Although atomic geometry and electronic structures of a metal surface significantly influence metal molecule interactions, such effects are often hindered in conventional SERS measured on a roughened surface because of the spectral information averaging at various adsorption sites. In this study, the use of atomically defined Pt surfaces revealed detailed surface effects; the observed preferential adsorption geometry on each surface was well explained by atomic surface arrangements. The peak shift of the intramolecular vibration in the anchor group was in good agreement with the variation of the d-band center of Pt substrates. Moreover, in electrochemical SERS study the Stark shift of an extramolecular vibrational mode at around 400 cm(-1), which is not accessible in infrared absorption spectroscopy, was monitored on an atomically defined heteroepitaxial Pt monolayer electrode. PMID- 24802031 TI - Contrast-enhanced ultrasound appearances of enhancement patterns of intrahepatic cholangiocarcinoma: correlation with pathological findings. AB - The aim of this study was to investigate the correlation between enhancement patterns of intrahepatic cholangiocarcinoma (ICC) on contrast-enhanced ultrasound (CEUS) and pathological findings. The CEUS enhancement patterns of 40 pathologically proven ICC lesions were retrospectively analysed. Pathologically, the degree of tumour cell and fibrosis distribution in the lesion was semi quantitatively evaluated. Four enhancement patterns were observed in the arterial phase for 32 mass-forming ICCs: peripheral rim-like hyperenhancement (n = 19); heterogeneous hyperenhancement (n = 6); homogeneous hyperenhancement (n = 3); and heterogeneous hypo-enhancement (n = 4). Among the four enhancement patterns, the differences in tumour cell distribution were statistically significant (p < 0.05). The hyperenhancing area on CEUS corresponded to more tumour cells for mass forming ICCs. Heterogeneous hyperenhancement (n = 2) and heterogeneous hypo enhancement (n = 2) were observed in the arterial phase for four periductal infiltrating ICCs. In this subtype, fibrosis was more commonly found in the lesions. Heterogeneous hyperenhancement (n = 1) and homogeneous hyperenhancement (n = 3) were observed in the arterial phase for four intraductal-growing ICCs. This subtype tended to have abundant tumour cells. The CEUS findings of ICC relate to the degree of carcinoma cell proliferation at pathological examination. Hyperenhancing areas in the tumour always indicated increased density of cancer cells. PMID- 24802032 TI - Recent advances in engineering proteins for biocatalysis. AB - Protein engineers are increasingly able to rely on structure-function insights, computational methods, and deeper understanding of natural biosynthesis processes, to streamline the design and applications of enzymes. This review highlights recent successes in applying new or improved protein engineering strategies toward the design of improved enzymes and enzymes with new activities. We focus on three approaches: structure-guided protein design, computational design, and the use of novel scaffolding and compartmentalization techniques to improve performance of multienzyme systems. Examples described address problems relating to enzyme specificity, stability, and/or activity, or aim to balance sequential reactions and route intermediates by co-localizing multiple enzymes. Specific applications include improving production of biofuels using enzymes with altered cofactor specificity, production of high-value chiral compounds by enzymes with tailored substrate specificities, and accelerated cellulose degradation via multi-enzyme scaffold assemblies. Collectively, these studies demonstrate a growing variety of computational and molecular biology tools. Continued advances on these fronts coupled with better mindfulness of how to apply proteins in unique ways offer exciting prospects for future protein engineering and biocatalysis research. PMID- 24802030 TI - Liver as a source for thymidine phosphorylase replacement in mitochondrial neurogastrointestinal encephalomyopathy. AB - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive mitochondrial disease associated with mutations in the nuclear TYMP gene. As a result, the thymidine phosphorylase (TP) enzyme activity is markedly reduced leading to toxic accumulation of thymidine and therefore altered mitochondrial DNA. MNGIE is characterized by severe gastrointestinal dysmotility, neurological impairment, reduced life expectancy and poor quality of life. There are limited therapeutic options for MNGIE. In the attempt to restore TP activity, allogenic hematopoietic stem cell transplantation has been used as cellular source of TP. The results of this approach on ~ 20 MNGIE patients showed gastrointestinal and neurological improvement, although the 5-year mortality rate is about 70%. In this study we tested whether the liver may serve as an alternative source of TP. We investigated 11 patients (7M; 35-55 years) who underwent hepatic resection for focal disorders. Margins of normal liver tissue were processed to identify, quantify and localize the TP protein by Western Blot, ELISA, and immunohistochemistry, and to evaluate TYMP mRNA expression by qPCR. Western Blot identified TP in liver with a TP/GAPDH ratio of 0.9 +/- 0.5. ELISA estimated TP content as 0.5 +/- 0.07 ng/MUg of total protein. TP was identified in both nuclei and cytoplasm of hepatocytes and sinusoidal lining cells. Finally, TYMP mRNA was expressed in the liver. Overall, our study demonstrates that the liver is an important source of TP. Orthotopic liver transplantation may be considered as a therapeutic alternative for MNGIE patients. PMID- 24802034 TI - Influence of dry matter intake, dry matter digestibility, and feeding behavior on body weight gain of beef steers. AB - This study was conducted to determine the relative contribution of feeding behavior, DMI, apparent DM digestibility (DMD), and passage rate on variation in BW gain. One hundred forty-three crossbred steers were used in this study to determine the factors that contribute to variation in BW gain. Steers were 304 +/ 1 d of age and had an initial BW of 338 +/- 3 kg. Steers had ad libitum access to feed, and fresh feed was offered twice daily at 0800 and 1500 h. Individual feed intake and BW gains were determined for 106 d. Titanium dioxide was used as an external marker to estimate apparent DMD and passage rate. A multiple regression analysis was used to determine the relative contribution of initial BW, feed intake, feeding behaviors, digestibility, and passage rate to variance in BW gain, and a path analysis was conducted to determine direct and indirect relationships of the variables. In the regression analysis, initial BW and DMI accounted for 33% of the variation in BW gain. Substituting meal events and meal size for DMI did not increase the amount of variance in BW gain (27%) accounted for by the regression model. There was a slight increase in the variance in BW gain (35%) when apparent DMD was added to initial BW and DMI. When meal events and meal size were substituted for DMI, there was a decrease (30%) in variance accounted for in BW gain. The regression coefficient for the passage rate did not differ from zero (P = 0.63) when the passage rate was substituted for apparent DMD in the regression model that also included initial BW and DMI, nor did it differ from zero (P = 0.39) in the model that substitutes meal events and meal size for DMI. Three models were used in the path analysis. For all 3 models there was a positive correlation (P < 0.001) between DMI and BW gain but not between apparent DMD and BW gain. In all 3 models there was a significant correlation between meal size, meal events, and initial BW on DMI (P < 0.001). Results of both the regression and path analyses suggest that both apparent DMD and passage rate accounted for small proportions of the variance, suggesting that they are minor contributors toward variance in BW gain among cattle fed the same concentrate diet. PMID- 24802033 TI - Selection via pluripotency-related transcriptional screen minimizes the influence of somatic origin on iPSC differentiation propensity. AB - The value of induced pluripotent stem cells (iPSCs) within regenerative medicine is contingent on predictable and consistent iPSC differentiation. However, residual influence of the somatic origin or reprogramming technique may variegate differentiation propensity and confound comparative genotype/phenotype analyses. The objective of this study was to define quality control measures to select iPSC clones that minimize the influence of somatic origin on differentiation propensity independent of the reprogramming strategy. More than 60 murine iPSC lines were derived from different fibroblast origins (embryonic, cardiac, and tail tip) via lentiviral integration and doxycycline-induced transgene expression. Despite apparent equivalency according to established iPSC histologic and cytomorphologic criteria, clustering of clonal variability in pluripotency related gene expression identified transcriptional outliers that highlighted cell lines with unpredictable cardiogenic propensity. Following selection according to a standardized gene expression profile calibrated by embryonic stem cells, the influence of somatic origin on iPSC methylation and transcriptional patterns was negated. Furthermore, doxycycline-induced iPSCs consistently demonstrated earlier differentiation than lentiviral-reprogrammed lines using contractile cardiac tissue as a measure of functional differentiation. Moreover, delayed cardiac differentiation was predominately associated with upregulation in pluripotency related gene expression upon differentiation. Starting from a standardized pool of iPSCs, relative expression levels of two pluripotency genes, Oct4 and Zfp42, statistically correlated with enhanced cardiogenicity independent of somatic origin or reprogramming strategy (R(2) = 0.85). These studies demonstrate that predictable iPSC differentiation is independent of somatic origin with standardized gene expression selection criteria, while the residual impact of reprogramming strategy greatly influences predictable output of tissue specification required for comparative genotype/phenotype analyses. PMID- 24802035 TI - U. S. consumer perceptions of U. S. and Canadian beef quality grades. AB - A U.S. consumer (n = 642) study (Baltimore, MD; Phoenix, AZ; and Lubbock, TX) was conducted to compare consumer sensory scores of U.S. beef (83 USDA Choice [Choice] and 96 USDA Select [Select]) and Canadian beef (77 AAA and 82 AA) strip loins. Strip loins (n = 338) were obtained from beef processors in Canada and the United States and were wet aged until 21 d postmortem at 2 degrees C. Marbling scores were assigned at 21 d and loins were paired according to quality grades and marbling score. Strip loins were fabricated into 2.54-cm thick steaks; steaks were vacuum packaged and frozen until further evaluations. Proximate analysis was performed to compare fat, moisture, and protein. Choice and Canadian AAA had similar marbling scores and intramuscular fat. Both Choice and Canadian AAA had greater (P < 0.05) marbling scores and intramuscular fat than Canadian AA, but Select strip loins had intermediate values that were not different from any of the other grades (P > 0.05). Consumers' opinions did not differ when comparing equivalent grades (Choice with Canadian AAA and Select with Canadian AA), but they rated Choice and Canadian AAA more palatable than Select and Canadian AA for all sensory attributes (P < 0.05). Regarding percentage of acceptability and likelihood to buy score, consumers indicated a preference and greater probability to buy (P = 0.001 and P = 0.004, respectively) strip loin steaks from higher quality grade carcasses (Choice and Canadian AAA) than lower quality grade carcasses (Select and Canada AA). Additionally, consumers gave their opinion of Canadian beef, where its quality and safety were rated as "good" to "excellent" for both attributes (76.72% and 88.36%, respectively; P < 0.05), feeling confident in beef that is imported from Canada. In the same way, consumers indicated that country-of-origin labeling was a minimal factor influencing their beef steak purchasing decisions. Results from this consumer study indicated U.S. consumers could not differentiate between U.S. and Canadian beef within comparable quality grades; however, strip loin steaks from higher quality grades were more palatable than lower quality grades according to consumer scores for eating quality traits. PMID- 24802036 TI - Colostrum yield and piglet growth during lactation are related to gilt metabolic and hepatic status prepartum. AB - It was hypothesized that colostrum production could be influenced by sow peripartum endocrine, metabolic, and hepatic status. The plant extract silymarin was shown to influence endocrine and hepatic status in several species. The aims of the present study were to investigate the effects of silymarin intake during late pregnancy on sow hormonal and hepatic status and to determine whether relations exist between sow hepatic and metabolic status during the peripartum period and colostrum yield and piglet performances during lactation. From d 107 of pregnancy until farrowing, nulliparous sows were either fed 12 g/d of silymarin (SIL; n = 15) or no treatment (Control; n = 12). Piglet BW was recorded directly after birth, 24 h after birth of the first piglet, and at 7, 14, and 21 d of lactation. Blood samples were collected from sows on d 107 and 109 of pregnancy, daily from d 111 of pregnancy until d 2 of lactation, and on d 7 and 21 of lactation. They were assayed for endocrine, metabolic, and hepatic variables. Colostrum yield was estimated during 24 h starting at the onset of farrowing. Silymarin did not influence colostrum yield (3.7 +/- 0.3 kg) or gross composition (P > 0.10), nor did it affect serum prolactin concentrations or plasma concentrations of progesterone, estradiol-17beta, or cortisol (P > 0.10). Mean litter BW gain was lower (P < 0.05) during the first week and tended (P < 0.10) to be lower during the second week of lactation in litters from SIL sows. Silymarin had no effect on plasma concentrations of aspartate transaminase, alanine transaminase, gamma-glutamyl transferase (gamma-GT), alkaline phosphatase, or total cholesterol (P > 0.10). Colostrum yield was positively correlated with urea (r = 0.50; P = 0.01) and creatinine (r = 0.43; P = 0.03) concentrations in sows on the day before farrowing. Mean litter BW gain over 2 wk was negatively correlated with concentrations of beta-hydroxybutyric acid (r = 0.50; P = 0.01) and gamma-GT (r = -0.42; P = 0.03) on the day before farrowing and was positively correlated with urea concentrations on the day before farrowing (r = 0.54; P = 0.01). In conclusion, at the dose of 12 g/d, silymarin did not influence prolactin concentrations or the hepatic status of sows, had no impact on colostrum production, and decreased litter BW gain in early lactation. Colostrum yield and litter performance during lactation were correlated with some markers of sow metabolic and hepatic status measured during the prepartum period. PMID- 24802037 TI - The USDA quality grades may mislead consumers. AB - This study was designed to explore consumers' perceptions about and knowledge of USDA beef quality grades. Data were collected from over 1,000 consumers in online surveys in November and December 2013, and estimates were weighted to force the sample to mirror the U.S. population in terms of age, gender, education, and region of residence. When asked to rank Prime, Choice, and Select grades in terms of leanness, only 14.4% provided the correct ranking with 57.1% of respondents incorrectly indicating steaks grading Prime were the leanest. Despite perceptions that the Prime name indicated the leanest product, in a subsequent question, 55.6% of respondents thought Prime grade to be the juiciest of the 3 grades. In addition to inquiring about perceptions of the grade names, respondents also indicated perceptions of pictures of steaks. Only 14.5% of respondents correctly matched the steak pictures with their corresponding USDA quality grade name, an outcome that is statistically worse than would have occurred through pure random matching (P = 0.03). When asked to match pictures of steaks with expected prices, 54.8% of respondents incorrectly matched the picture of the Prime steak with the lowest price level. More highly educated consumers with greater preferences for steak consumption were more likely to provide correct answers. Results reveal substantial confusion over quality grading nomenclature and suggest the need for more education or for a transition toward more descriptive terminology at the retail level. PMID- 24802038 TI - Estimation of the net energy requirements for maintenance in growing and finishing pigs. AB - The objective of this experiment was to determine the net energy requirements for maintenance of growing and finishing pigs using regression models. Thirty-six growing (27.38 +/- 2.24 kg) and 36 finishing (70.25 +/- 2.61 kg) barrows were used and within each phase. Pigs received a corn-soybean meal diet fed at 6 levels of feed intake, which were calculated as 0, 20, 40, 60, 80, or 100% of the estimated ad libitum ME intake (2,400 kJ ME/kg BW(0.6).d(-1)) of the pigs. Measurements were conducted on 6 pigs per feeding level and per stage of growth. After a 5-d adjustment period, barrows in the fasted treatment were kept in respiration chambers for 2 d to measure the fasting heat production. Barrows in the other treatments were kept individually in respiration chambers for a 5-d balance trial followed by a 2-d fasting period. Heat production (HP) in the fed state was measured and feces and urine were collected in the balance trial. The total HP increased (P < 0.01) with increasing feeding levels. Fasting HP increased (P < 0.01) as previous feeding level increased and was less (P = 0.012) in finishing pigs than growing pigs if calculated per kilogram BW(0.6) per day. When using an exponential regression analysis, ME requirements for maintenance were estimated at 973 and 921 kJ/kg BW(0.6).d(-1) and NE requirements for maintenance were estimated at 758 and 732 kJ/kg BW(0.6).d(-1) for growing and finishing pigs, respectively. The efficiencies of using ME for growth and for maintenance were estimated at 66 and 78.7% for growing and finishing pigs, respectively. It is concluded that exponential regression between HP and a wide range of ME intake may be used as a new method to determine the NE requirement for maintenance. PMID- 24802039 TI - Genetic parameters for lamb birth weight, survival and death risk traits. AB - This paper reports genetic parameters for lamb survival and mortality traits on sheep farms in New Zealand. Lamb survival and mortality records were obtained from 38 flocks (103,357 lambs) from 5 yr of lambing data (2007 to 2011) and include many breeds and their crosses (predominantly Romney, Perendale, Coopworth, and Texel). A number of models were tested, all including environmental weather effects and investigating the random environmental effect of dam and litter (dam/year) as well as logit transformation for binary traits. Total heritability (direct + maternal) estimates were low for lamb viability at birth (0.01), lamb death risk to dystocia (0.01), and lamb death risk to starvation exposure (0.01) from birth to 3 d of age in an analysis accounting for direct and maternal genetic effects and the maternal environmental effects. Lamb survival heritabilities reported are very low (total heritabilities range from 0.02 to 0.06). The total heritabilities for the lamb death risk traits are lower than reported estimates of survival to 3 d of age or to weaning suggesting selection for the postmortem traits are not warranted at this time within these flocks. The total heritability for lamb birth weight was moderate (0.38) and the genetic correlations with the lamb death risk traits suggested that directional selection on lamb birth weight would have an effect on survival, although it is likely to have a nonlinear effect and therefore an optimum birth weight at which survival is maximized. This study has also shown that the total heritabilities may be overestimated when not accounting for maternal genetic and environment effects and in particular not accounting for the random environmental effect of litter (dam/year). PMID- 24802040 TI - Comparison of three CIDR-based fixed-time AI protocols in beef heifers. AB - Several effective fixed-time AI (FTAI) protocols have been developed to facilitate AI in beef heifers that circumvent the need for estrus detection. Among these are the 5-d CO-Synch + controlled intravaginal progesterone insert (CIDR) protocol (5dCO), PGF2alpha (PG) 6-d CIDR protocol (PG-6dCIDR), and 14-d CIDR-PG protocol (14dCIDR-PG). Although each of these protocols varies in duration and approach to synchronizing estrus and ovulation, each has been reported as an effective method to facilitate FTAI in beef heifers. Therefore, the objective of this study was to compare FTAI pregnancy rates in beef heifers synchronized with these 3 CIDR-based protocols. Virgin beef heifers (n = 801) at 4 locations were synchronized with 1 of 3 protocols: 1) 5dCO, an injection of GnRH (100 MUg) and insertion of a CIDR on d -5, PG (25 mg) and CIDR removal on d 0 with a second injection of PG (>4 h after CIDR removal) on d 0 and FTAI at 72 h after CIDR removal, 2) PG-6dCIDR, PG (25 mg) on d -9, GnRH (100 MUg) and insertion of a CIDR on d -6, PG and CIDR removal on d 0, and FTAI at 66 h after CIDR removal, or 3) 14dCIDR-PG, a 14-d CIDR insert from d -30 to -16, PG (25 mg) on d 0, and FTAI at 66 h after PG. All heifers received an injection of GnRH (100 MUg) concurrent with FTAI. Timing of treatment initiation was offset to allow all heifers to receive FTAI concomitantly and at random. Pregnancy success was determined between 35 and 40 d after FTAI by transrectal ultrasonography. Blood samples were collected before the beginning of each protocol and at the initiation of each protocol to determine estrous cycling status (77%). Data were analyzed using the GLIMMIX procedures of SAS. As expected, because of the duration of protocols, fewer heifers in the 14dCIDR-PG treatment were pubertal at initiation of synchronization than in the 5dCO (P < 0.05) and PG-6dCIDR (P = 0.10) treatments. Fixed-time AI pregnancy success did not differ between treatments (P = 0.14; 62.6%, 56.9%, and 53.3% for 5dCO, PG-6dCIDR, and 14dCIDR PG, respectively). However, heifers that had reached puberty by initiation of synchronization had greater (P < 0.01) pregnancy success compared to heifers that were prepubertal (60.7% and 47.3%, respectively). In summary, all 3 protocols had similar FTAI pregnancy success, and puberty status had the greatest impact on pregnancy success. PMID- 24802041 TI - Methods to create thermally oxidized lipids and comparison of analytical procedures to characterize peroxidation. AB - The objective of this experiment was to evaluate peroxidation in 4 lipids, each with 3 levels of peroxidation. Lipid sources were corn oil (CN), canola oil (CA), poultry fat, and tallow. Peroxidation levels were original lipids (OL), slow oxidized lipids (SO), and rapid-oxidized lipids (RO). To produce peroxidized lipids, OL were either heated at 95 degrees C for 72 h to produce SO or heated at 185 degrees C for 7 h to produce RO. Five indicative measurements (peroxide value [PV], p-anisidine value [AnV], thiobarbituric acid reactive substances [TBARS] concentration, hexanal concentration, 4-hydroxynonenal [HNE] concentration, and 2,4-decadienal [DDE]) and 2 predictive tests (active oxygen method [AOM] stability and oxidative stability index [OSI]) were performed to quantify the level of oxidation of the subsequent 12 lipids with varying levels of peroxidation. Analysis showed that a high PV accurately indicated the high level of lipid peroxidation, but a moderate or low PV may be misleading due to the unstable characteristics of hydroperoxides as indicated by the unchanged PV of rapidly oxidized CN and CA compared to their original state (OL). However, additional tests, which measure secondary peroxidation products such as AnV, TBARS, hexanal, HNE, and DDE, may provide a better indication of lipid peroxidation than PV for lipids subjected to a high level of peroxidation. Similar to PV analysis, these tests may also not provide irrefutable information regarding the extent of peroxidation because of the volatile characteristics of secondary peroxidation products and the changing stage of lipid peroxidation. For the predictive tests, AOM accurately reflected the increased lipid peroxidation caused by SO and RO as indicated by the increased AOM value in CN and CA but not in poultry fat and tallow, which indicated a potential disadvantage of the AOM test. Oxidative stability index successfully showed the increased lipid peroxidation caused by SO and RO in all lipids, but it too may have disadvantages similar to AnV, TBARS, hexanal, DDE, and HNE because OSI directly depends on quantification of the volatile secondary peroxidation products. To accurately analyze the peroxidation damage in lipids, measurements should be determined at appropriate time intervals by more than 1 test and include different levels of peroxidation products simultaneously. PMID- 24802042 TI - Reliability of molecular breeding values for Warner-Bratzler shear force and carcass traits of beef cattle - an independent validation study. AB - Interest in genetic improvement of carcass and tenderness traits of beef cattle using genome-based selection (GS) and marker-assisted management programs is increasing. The success of such a program depends on the presence of linkage disequilibrium between the observed markers and the underlying QTL as well as on the relationship between the discovery, validation, and target populations. For molecular breeding values (MBV) predicted for a target population using SNP markers, reliabilities of these MBV can be obtained from validation analyses conducted in an independent population distinct from the discovery set. The objective of this study was to test MBV predicted for carcass and tenderness traits of beef cattle in a Canadian-based validation population that is largely independent of a United States-based discovery set. The discovery data set comprised of genotypes and phenotypes from >2,900 multibreed beef cattle while the validation population consisted of 802 crossbred feeder heifers and steers. A bivariate animal model that fitted actual phenotype and MBV was used for validation analyses. The reliability of MBV was defined as square of the genetic correlation (R(2) g) that represents the proportion of the additive genetic variance explained by the SNP markers. Several scenarios involving different starting marker panels (384, 3K, 7K, and 50K) and different sets of SNP selected to compute MBV (50, 100, 200, 375, 400, 600, and 800) were investigated. Validation results showed that the most reliable MBV (R(2) g) were 0.34 for HCW, 0.36 for back fat thickness, 0.28 for rib eye area, 0.30 for marbling score, 0.25 for yield grade, and 0.38 for Warner-Bratzler shear force across the different scenarios explored. The results indicate that smaller SNP panels can be developed for use in genetic improvement of beef carcass and tenderness traits to exploit GS benefits. PMID- 24802044 TI - Lupus pernio--a patient case study. AB - An 80 year old female patient was seen in the Otolaryngology department with a skin manifestation of her sarcoidosis, known as lupus pernio. Around 25% of patients with sarcoidosis have skin disease and the presence of lupus pernio may suggest a more aggressive form of the disease. Photography of this relatively rare presentation not only helped us diagnose her underlying medical condition but also served as a baseline during treatment. PMID- 24802045 TI - The establishment of a 3D breast photography service in medical illustration. AB - This paper aims to describe the development of a 3D breast photography service managed by the Medical Illustration Department, in the Belfast Health and Social Care Trust, Northern Ireland. Dedicated 3D breast photography equipment was installed in Medical Illustration for 18 months. Women were referred for a variety of indications including pre- and post-surgical assessment. A dedicated 3D breast photography protocol was developed locally and this requires further refinement to allow reproducibility in other centres. There are image/data artefacts associated with this technology and special techniques are required to reduce these. Specialist software is necessary for clinicians and scientists to use 3D breast photography data in surgical planning and measurement of surgical outcome. PMID- 24802046 TI - Vedolizumab for the treatment of ulcerative colitis. AB - Ulcerative colitis is a chronic inflammatory disease of the large intestine that often develops in the young. A few new treatment options have become available in the past decade, but management of a large proportion of patients still remains challenging because of side effects, unresponsiveness and cost. A novel strategy targeting trafficking of immune cells to the sites of inflammation involves reducing expression or binding of adhesion molecules to integrins. Natalizumab was the first therapeutic antibody blocking infiltration of leukocytes, but because of lack of selectivity to the gut and associated risk of progressive multifocal leukoencephalopathy, it will probably never be tested in ulcerative colitis. In this article we discuss molecules that block leukocyte trafficking to inflamed bowel that have been tested in ulcerative colitis. Because of favourable efficacy and safety data, we will review the development, pharmacology and clinical data of vedolizumab, a gut-selective alpha4beta7 antibody, in depth. PMID- 24802047 TI - Postresuscitation hemodynamics during therapeutic hypothermia after out-of hospital cardiac arrest with ventricular fibrillation: a retrospective study. AB - AIMS OF THE STUDY: To evaluate the incidence of postresuscitation myocardial depression (PRMD) and hemodynamical parameters associated with PRMD in patients treated with therapeutic hypothermia (TH) after out-of-hospital cardiac arrest with ventricular fibrillation (OHCA-VF). METHODS: Analysis of hemodynamical data from computerized clinical databases of two academic ICUs during two year period. We analyzed hemodynamical data from a subgroup of patients with pulmonary artery catheter (PAC). We defined PRMD as a cardiac index (CI) less than 1.5l/(minm(2)) any time during the first 12h and compared clinical variables and hemodynamical parameters in patients with or without PRMD. RESULTS: Of 120 included patients PAC monitoring was used in 47 (39%). Of 47, 31 (66%, 95% CI 52% to 80%) developed PRMD. There was no difference in urinary output, lactate, mean arterial or central venous pressures or mixed venous saturation between patients with or without PRMD. Low CI was reversed with dobutamine infusion. Presence or absence PRMD was not associated with 6-month neurological outcome. CONCLUSION: Two-thirds of the OHCA-VF patients develops transient postresuscitation myocardial depression not easily detected without monitoring of CI during therapeutic hypothermia. Further controlled studies are warranted to evaluate the value of different hemodynamic targets and monitoring after cardiac arrest in terms of outcome. PMID- 24802049 TI - The effects of nitroglycerin, norepinephrine and aminophylline on intrapulmonary arteriovenous anastomoses in healthy humans at rest. AB - We have investigated the effects of the intravenous infusion of nitroglycerin (NTG), norepinephrine (NE) and aminophylline (AMP) on the opening and recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) in healthy humans at rest. In ten volunteers saline contrast echocardiography was performed during administration of two doses of the NTG (3MUgkg(-1)min(-1) and 6MUgkg(-1)min(-1)) and NE (0.1MUgkg(-1)min(-1) and 0.25MUgkg(-1)min(-1)) as well as 30min following the administration of AMP at rate of 6mgkg(-1). Echocardiography was used to assign bubble scores (0-5) based on the number and spatial distribution of bubbles in the left ventricle. Doppler ultrasound was used to estimate pulmonary artery systolic pressure. Using a Finometer the following hemodynamic parameters were assessed: heart rate, stroke volume, cardiac output, total peripheral resistance as well as systolic, diastolic and mean arterial pressure. The most important finding from the current study was that nitroglycerin, norepinephrine and aminophylline in the applied doses were not found to promote IPAVA opening in healthy humans at rest. PMID- 24802048 TI - Characterization and screening of IgG binding to the neonatal Fc receptor. AB - The neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from degradation and increases the serum half-life of IgG, thereby contributing to a higher concentration of IgG in the serum. Because altered FcRn binding may result in a reduced or prolonged half-life of IgG molecules, it is advisable to characterize Fc receptor binding of therapeutic antibody lead candidates prior to the start of pre-clinical and clinical studies. In this study, we characterized the interactions between FcRn of different species (human, cynomolgus monkey, mouse and rat) and nine IgG molecules from different species and isotypes with common variable heavy (VH) and variable light chain (VL) domains. Binding was analyzed at acidic and neutral pH using surface plasmon resonance (SPR) and biolayer interferometry (BLI). Furthermore, we transferred the well-accepted, but low throughput SPR-based method for FcRn binding characterization to the BLI-based Octet platform to enable a higher sample throughput allowing the characterization of FcRn binding already during early drug discovery phase. We showed that the BLI based approach is fit-for-purpose and capable of discriminating between IgG molecules with significant differences in FcRn binding affinities. Using this high-throughput approach we investigated FcRn binding of 36 IgG molecules that represented all VH/VL region combinations available in the fully human, recombinant antibody library Ylanthia(r). Our results clearly showed normal FcRn binding profiles for all samples. Hence, the variations among the framework parts, complementarity-determining region (CDR) 1 and CDR2 of the fragment antigen binding (Fab) domain did not significantly change FcRn binding. PMID- 24802050 TI - Musculotendon translational stiffness and muscle activity are modified by shear forces. AB - BACKGROUND: In this study we investigate whether the nervous system is responsive to anterior-posterior shearing forces applied to the knee. Specifically, we examine whether the nervous system will increase musculotendon stiffness along the anterior-posterior degree-of-freedom via relative changes in muscle activation. METHODS: While seated on a Biodex, 12 male participants performed knee extensor moments against a cuff at three different distances (265mm, 310mm, and 355mm) from the knee joint. This was done for each combination of knee angle (20 degrees , 45 degrees , 70 degrees ), moment (25%, 75% of maximum), and angular velocity (0 degrees /s, 10 degrees /s). By altering cuff position, the magnitude of the shear force could be changed while holding moment constant. We then calculated the 6-degree-of-freedom, musculotendon stiffness matrix of the knee and interpreted the eigenvalues and eigenvectors of this matrix using stiffness ellipses. FINDINGS: Anterior-Posterior knee stiffness significantly increased with an increase in shear force at 20 degrees and 45 degrees of knee flexion. This coincided with significant increases in semitendinosus and vastus medialis activity. INTERPRETATION: We found that the nervous system can significantly increase stiffness along a translational degree-of-freedom in response to translational loading, and did so by activating muscles geometrically oriented to provide stiffness along the anterior-posterior degree-of-freedom. PMID- 24802052 TI - Rotational diffusion of organic solutes in 1-methyl-3-octylimidazolium tetrafluoroborate-diethylene glycol mixtures: influence of organic solvent on the organized structure of the ionic liquid. AB - Rotational diffusion of two structurally similar organic solutes, 9 phenylanthracene (9-PA) and rhodamine 110 (R110), has been investigated in 1 methyl-3-octylimidazolium tetrafluoroborate-diethylene glycol ([MOIM][BF4]-DEG) mixtures to understand the influence of organic solvent on the organized structure of the ionic liquid. The reorientation times (tau(r)) of nonpolar and charged solutes have been measured as a function of viscosity (eta) by changing the temperature (T) as well as the composition of the ionic liquid-organic solvent mixture. These results when analyzed using the Stokes-Einstein-Debye (SED) hydrodynamic theory follow the relationship tau(r) = A(eta/T)(n), where A is the ratio of hydrodynamic volume of the solute to Boltzmann constant. However, in neat [MOIM][BF4] and up to 0.4 mole fraction of DEG (x(DEG)), significant deviations from the SED hydrodynamic theory have been noticed with n being much less than unity. As x(DEG) is increased further, the parameters A and n increase considerably for both solutes, and their rotational diffusion follows the predictions of the SED hydrodynamic theory. It has also been observed that the trends in the variation of tau(r) with eta/T for 9-PA and R110 are not similar. These observations have been rationalized by taking into consideration the organized structure of the ionic liquid, which gradually becomes homogeneous at the microscopic level with the addition of the organic solvent. PMID- 24802053 TI - Yielding behavior in colloidal glasses: comparison between "hard cage" and "soft cage". AB - Rheological measurements are utilized to examine the yielding behavior of a polystyrene (PS) core and poly(N-isopropylacrylamide) (PNIPAM) shell microgel system with varying shell/core ratio. For a shell/core ratio of 0.15 at high concentrations, the suspensions show a typical hard sphere (HS) yielding response where the loss modulus (G") exhibits a single peak due to cage breaking. As a result of tighter cages and less cage distortion prior to yielding, the peak location of G" decreases with volume fraction. For a shell/core ratio of 1.10, which behaves like a soft jammed glass at high concentration, the suspensions exhibit a one-step yielding behavior similar to that of HS glass. However, the location of the peak in G" increases with volume fraction, demonstrating the important role of particle deformation in the breakage of cages. For an intermediate shell/core ratio of 0.34, the system displays a two-step yielding behavior, as observed in previous reports for attractive glasses. By increasing the volume fraction, the strain of the first peak increases while the second one decreases. In addition, as the effective volume fraction increases to 112%, the two peaks merge into one broad peak. It is demonstrated that the first peak of G" is due to deformation of the shell, and the second peak of G" is attributed to cage breaking as a result of the cores colliding with each other. Combining these results, a yielding state diagram from typical HS to soft jammed glass is demonstrated. PMID- 24802051 TI - Applied equine genetics. AB - Genome sequencing of the domestic horse and subsequent advancements in the field of equine genomics have led to an explosion in the development of tools for mapping traits and diseases and evaluating gene expression. The objective of this review is to discuss the current progress in the field of equine genomics, with specific emphasis on assembly and analysis of the reference sequence and subsequent sequencing of a Quarter Horse mare; the genomic tools currently available to researchers and their implications in genomic investigations in the horse; the genomics of Mendelian and non-Mendelian traits; the genomics of performance traits and considerations regarding genetic testing in the horse. The whole-genome sequencing of a Quarter Horse mare has provided additional variants within the equine genome that extend past single nucleotide polymorphisms to include insertions/deletions and copy number variants. Equine single nucleotide polymorphism arrays have allowed for the investigation of both simple and complex genetic traits while DNA microarrays have provided a tool for examining gene expression across various tissues and with certain disease conditions. Recently, next-generation sequencing has become more affordable and both whole-genome DNA sequencing and transcriptome-wide RNA sequencing are methodologies that are being applied to equine genomic research. Research in the field of equine genomics continues to expand rapidly as the cost of genotyping and sequencing decreases, resulting in a need for quality bioinformatics software and expertise to appropriately handle both the size and complexity of these data. PMID- 24802054 TI - The written language performance of children with Attention Deficit Hyperactivity Disorder in Taiwan. AB - Poor writing is common in children with Attention Deficit Hyperactivity Disorder (ADHD). However, the writing performance of children with ADHD has been rarely formally explored in Taiwan, so the purpose of this study was to investigate writing features of children with ADHD in Taiwan. There were 25 children with ADHD and 25 normal children involved in a standardization writing assessment - Written Language Test for Children, to assess their performance at the dictation, sentence combination, adding/deducting redical, cloze and sentence making subtests. The results showed that except for the score of the sentence combining subtest, the score of children with ADHD was lower than the normal student in the rest of the subtests. Almost 60% of ADHD children's scores were below the 25th percentile numbers, but only 20% for normal children. Thus, writing problems were common for children with ADHD in Taiwan, too. First, children with ADHD performed worse than normal children on the dictation and cloze subtests, showing the weaker abilities of retrieving correct characters from their mental lexicon. Second, children with ADHD performed worse on the adding/deducting redical subtest than normal children did. Finally, at the language level, the score of children with ADHD on the sentence combination subtest was not lower than normal children, implicating their normal grammatic competence. It is worth mentioning that Taiwanese children with ADHD ignore the details of characters when they are writing, a finding that is common across languages. PMID- 24802055 TI - Disruption of the myostatin gene in porcine primary fibroblasts and embryos using zinc-finger nucleases. AB - Myostatin represses muscle growth by negatively regulating the number and size of muscle fibers. Myostatin lossof- function can result in the double-muscling phenotype and increased muscle mass. Thus, knockout of myostatin gene could improve the quality of meat from mammals. In the present study, zinc finger nucleases, a useful tool for generating gene knockout animals, were designed to target exon 1 of the myostatin gene. The designed ZFNs were introduced into porcine primary fibroblasts and early implantation embryos via electroporation and microinjection, respectively. Mutations around the ZFNs target site were detected in both primary fibroblasts and blastocysts. The proportion of mutant fibroblast cells and blastocyst was 4.81% and 5.31%, respectively. Thus, ZFNs can be used to knockout myostatin in porcine primary fibroblasts and early implantation embryos. PMID- 24802056 TI - Inhibition of cell proliferation and migration by miR-509-3p that targets CDK2, Rac1, and PIK3C2A. AB - CDK2 is a key regulator of cell cycle progression. In this study, we screened for miRNAs targeting CDK2 using a luciferase-3'-untranslated region reporter assay. Among 11 hit miRNAs, miR-509-3p reduced CDK2 protein levels and significantly inhibited cancer cell growth. Microarray, Western blotting, and luciferase reporter analyses revealed additional targets of miR-509-3p, including Rac1 and PIK3C2A. Overexpression of miR-509-3p induced G1 cell-cycle arrest and inhibited colony formation and migration. RNAi experiments indicated that the growth inhibitory effects of miR-509-3p may occur through down-regulation of CDK2, Rac1, and PIK3C2A. Targeting of multiple growth regulatory genes by miR-509-3p may contribute to effective anti-cancer therapy. PMID- 24802057 TI - Astrogliosis is a possible player in preventing delayed neuronal death. AB - Mitigating secondary delayed neuronal injury has been a therapeutic strategy for minimizing neurological symptoms after several types of brain injury. Interestingly, secondary neuronal loss appeared to be closely related to functional loss and/or death of astrocytes. In the brain damage induced by agonists of two glutamate receptors, N-ethyl-D-aspartic acid (NMDA) and kainic acid (KA), NMDA induced neuronal death within 3 h, but did not increase further thereafter. However, in the KA-injected brain, neuronal death was not obviously detectable even at injection sites at 3 h, but extensively increased to encompass the entire hemisphere at 7 days. Brain inflammation, a possible cause of secondary neuronal damage, showed little differences between the two models. Importantly, however, astrocyte behavior was completely different. In the NMDA injected cortex, the loss of glial fibrillary acidic protein-expressing (GFAP+) astrocytes was confined to the injection site until 7 days after the injection, and astrocytes around the damage sites showed extensive gliosis and appeared to isolate the damage sites. In contrast, in the KA-injected brain, GFAP+ astrocytes, like neurons, slowly, but progressively, disappeared across the entire hemisphere. Other markers of astrocytes, including S100beta, glutamate transporter EAAT2, the potassium channel Kir4.1 and glutamine synthase, showed patterns similar to that of GFAP in both NMDA- and KA-injected cortexes. More importantly, astrocyte disappearance and/or functional loss preceded neuronal death in the KA-injected brain. Taken together, these results suggest that loss of astrocyte support to neurons may be a critical cause of delayed neuronal death in the injured brain. PMID- 24802058 TI - Muscle-bone and fat-bone interactions in regulating bone mass: do PTH and PTHrP play any role? AB - Metabolic bone disease occurs when there is a net loss in bone density. Osteoporosis, the most common metabolic bone disease, is a devastating problem and an increasingly major public health issue. A substantial body of evidence in the elderly population indicates that a relationship exists between the components of body weight and various measures of bone/mass, density, and function. Both muscle and fat contribute to the body's total weight and the intimate associations of muscle, fat, and bone are known. But the close functional interactions between muscle and bone or fat and bone are largely unidentified and have drawn much attention in recent years. Each of these tissues not only responds to afferent signals from traditional hormone systems and the central nervous systems but also secretes factors with important endocrine functions. Studies suggest that during growth, development, and aging, the relationship of muscle and fat with the skeleton possibly governs bone homeostasis and turnover. A better understanding of the endocrine function and the cellular and molecular mechanisms and pathways linking muscle or adipose tissues with bone anabolism and catabolism is a new avenue for novel pathways for anabolic drug discovery. These in turn will likely lead to more rational therapy toward increasingly prevalent disorders like osteoporosis. In this review, some of the recent works on the interaction of bone with muscle and fat are highlighted, and in so doing the role of parathyroid hormone (PTH), and PTH related peptide (PTHrP) is surveyed. PMID- 24802059 TI - Glucose variability inversely associates with endothelial progenitor cells in type 1 diabetes. PMID- 24802064 TI - Imaging: Stepping towards real-time assessment of donor organs. PMID- 24802062 TI - Therapeutic approaches to diabetic nephropathy--beyond the RAS. AB - Despite improvements in glycaemic and blood pressure control, and the efficacy of renin-angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway-further research into the potential nephroprotective effects of novel glucose-lowering agents is required. PMID- 24802067 TI - Transplantation: The relevance of the FAVORIT blood pressure associations. PMID- 24802066 TI - Hyperosmolarity drives hypertension and CKD--water and salt revisited. AB - An epidemic of chronic kidney disease (CKD) in Mesoamerica is providing new insights into the mechanisms by which salt and water might drive hypertension and CKD. Increasingly, evidence suggests that recurrent dehydration and salt loss might be a mechanism that causes CKD, and experimental studies suggest a key role for increased plasma osmolarity in activating both intrarenal (polyol fructokinase) and extrarenal (vasopressin) pathways that drive renal injury. Thus, we propose that water and salt might influence blood pressure and kidney disease through the timing and combination of their intake, which affect plasma osmolarity as well as intrarenal and extrarenal mechanisms of renal injury. The type of fluid intake might also be important, as fluids containing fructose can trigger activation of these pathways. Future studies should investigate the effects of salt, sugar and fluid intake on plasma osmolarity as a potential pathogenetic mechanism in renal injury and high blood pressure. PMID- 24802069 TI - Classification of dynamic contrast enhanced MR images of cervical cancers using texture analysis and support vector machines. AB - Dynamic contrast enhanced MRI (DCE-MRI) provides insight into the vascular properties of tissue. Pharmacokinetic models may be fitted to DCE-MRI uptake patterns, enabling biologically relevant interpretations. The aim of our study was to determine whether treatment outcome for 81 patients with locally advanced cervical cancer could be predicted from parameters of the Brix pharmacokinetic model derived from pre-chemoradiotherapy DCE-MRI. First-order statistical features of the Brix parameters were used. In addition, texture analysis of Brix parameter maps was done by constructing gray level co-occurrence matrices (GLCM) from the maps. Clinical factors and first- and second-order features were used as explanatory variables for support vector machine (SVM) classification, with treatment outcome as response. Classification models were validated using leave one-out cross-model validation. A random value permutation test was used to evaluate model significance. Features derived from first-order statistics could not discriminate between cured and relapsed patients (specificity 0%-20%, p values close to unity). However, second-order GLCM features could significantly predict treatment outcome with accuracies (~70%) similar to the clinical factors tumor volume and stage (69%). The results indicate that the spatial relations within the tumor, quantified by texture features, were more suitable for outcome prediction than first-order features. PMID- 24802070 TI - Adsorption of linear aliphatic alpha,omega-dithiols on plasmonic metal nanoparticles: a structural study based on surface-enhanced Raman spectra. AB - The adsorption mechanism of linear aliphatic alpha,omega-dithiols with chain lengths of 6, 8 and 10 carbon atoms on silver and gold nanoparticles has been studied by surface-enhanced Raman scattering (SERS) spectroscopy. SERS spectra provided the structural marker bands of these compounds and they were employed to obtain information about the adsorption and coordination mechanism, the orientation, conformational order, and packing of the aliphatic chains of dithiols on the metal nanoparticle surface. The effect of the type of metal (silver or gold) and the extent of surface coverage on all the above mentioned properties is discussed. It was found that the adsorption of dithiols on Au nanoparticles leads to a more disordered structure of the aliphatic chains of dithiols in comparison with the adsorption on Ag nanoparticles. The interaction through both thiol groups makes the adsorption of dithiols on metal surfaces substantially different from that of monothiols; in particular, the orientation of dithiols is perpendicular, while monothiols adopt a tilted orientation. Dithiols may act as linkers between metal nanoparticles and induce the formation of nanogaps with a controllable interparticle distance. The nanogaps thus formed are able to produce hot spots exhibiting a large intensification of electromagnetic field in these points which has been proved by the observation of intense SERS spectra of dithiols until a concentration of 10(-8) M, corresponding to a large Raman enhancement factor of 5 * 10(6). PMID- 24802071 TI - Structurally diverse copper complexes bearing NNO-tridentate Schiff-base derivatives as efficient catalysts for copolymerization of carbon dioxide and cyclohexene oxide. AB - Structurally diverse copper acetate complexes based on NNO-tridentate Schiff-base ligands were synthesized and characterized as mono-, di-, and trinuclear complexes with respect to varied ancillary ligands. Treatment of the ligand precursors (L(1)-H = 2-(1-((2-(dimethylamino)ethyl)imino)ethyl)-4-methylphenol, L(2)-H = 4-chloro-2-(1-((2-(dimethylamino)ethyl)imino)ethyl)phenol, and L(3)-H = 2-(1-((2-(dimethylamino)ethyl)imino)ethyl)-5-methylphenol) with Cu(OAc)2.H2O (1 equiv) in refluxing ethanol afforded five-coordinate mono- or bimetallic copper complexes ([(L(1))Cu(OAc)(H2O)] (1); [(L(2))Cu(OAc)(H2O)] (2); [(L(3))2Cu2(OAc)2] (3)) in high yields. Dinuclear copper acetate analogue [(L(1))2Cu2(OAc)2] (4) resulted from treatment of L(1)-H as the ligand precursor in refluxing anhydrous MeOH with equimolar proportions of metal acetate salt under a dry nitrogen atmosphere. However, a trinuclear complex, [(L(4))2Cu3(OAc)4] (5), was obtained on utilizing 2-(1-((2-(dimethylamino)ethyl)imino)ethyl)-5-methoxyphenol (L(4)-H) as the proligand under the same synthetic route of 1-3; this complex was also synthesized in the reaction of L(4)-H and copper(II) acetate monohydrate in the ratio of 2:3, giving a quantitative yield. All complexes are active catalysts for copolymerization of cyclohexene oxide (CHO) and CO2 without cocatalysts. In particular, dinuclear Cu complex 3 performed satisfactorily to produce polycarbonates with controllable molecular weights and high carbonate linkages. These copper complexes are the first examples that are effective for both CO2/CHO copolymerization and formation of polymers in a controlled fashion. PMID- 24802072 TI - Probabilistic assessment of environmental exposure to the polycyclic musk, HHCB and associated risks in wastewater treatment plant mixing zones and sludge amended soils in the United States. AB - The objective of this work was to conduct an environmental risk assessment for the consumer use of the polycyclic musk, HHCB (CAS No. 1222-05-5) in the U.S. focusing on mixing zones downstream from municipal wastewater treatment plants (WWTPs) and sludge amended soils. A probabilistic exposure approach was utilized combining statistical distributions of effluent and sludge concentrations for the U.S. WWTPs with distributions of mixing zone dilution factors and sludge loading rates to soil to estimate HHCB concentrations in surface waters and sediments below WWTPs and sludge amended soils. These concentrations were then compared to various toxicity values. Measured concentrations of HHCB in effluent and sludge from a monitoring program of 40 WWTPs across the U.S. formed the basis for estimating environmental loadings. Based upon a Monte Carlo analysis, the probability of HHCB concentrations being below the PNEC (predicted no effect concentration) for pelagic freshwater organisms was greater than or equal to 99.87% under both mean and low flow regimes. Similarly, the probability of HHCB concentrations being less than the PNEC for freshwater sediment organisms was greater than or equal to 99.98%. Concentrations of HHCB in sludge amended soils were estimated for single and repeated annual sludge applications with tilling of the sludge into the soil, surface application without tilling and a combination reflecting current practice. The probability of soil HHCB concentrations being below the PNEC for soil organisms after repeated sludge applications was 94.35% with current sludge practice. Probabilistic estimates of HHCB exposures in surface waters, sediments and sludge amended soils are consistent with the published values for the U.S. In addition, the results of these analyses indicate that HHCB entering the environment in WWTP effluent and sludge poses negligible risk to aquatic and terrestrial organisms in nearly all exposure scenarios. PMID- 24802073 TI - Estimation of physicochemical properties of 52 non-PBDE brominated flame retardants and evaluation of their overall persistence and long-range transport potential. AB - Non-PBDE (polybromodiphenyl ether) brominated flame retardants (BFRs) used as alternatives to PBDEs should be evaluated in terms of their environmental contamination potential. We first used two well-known estimation tools, EPI Suite and SPARC, to estimate the physicochemical properties of 52 non-PBDE BFRs. We assessed the dependence of the properties on the molecular weight and chemical structure of the compounds. The accuracy of the estimates was evaluated by comparing results with previous experimental data. In the case of EPI Suite, we have recommended an appropriate calculation method for the air-water partition coefficient. Half-lives in each environmental medium were also estimated with EPI Suite. Based on the estimated properties and half-lives, the overall persistence (Pov) and long-range transport potential (LRTP) of the BFRs were calculated using the Organization for Economic Cooperation and Development Pov and LRTP Screening Tool. We selected some POP-like chemicals from among the non-PBDE BFRs on the basis of their Pov and LRTP. From a Monte Carlo analysis of the calculated results for the selected BFRs, we suggest physicochemical properties to be measured in the future. PMID- 24802075 TI - Reduced embodied simulation in psychopathy. AB - OBJECTIVES: Psychopathy is characterized by severe deficits in emotion processing and empathy. These emotional deficits might not only affect the feeling of own emotions, but also the understanding of others' emotional and mental states. The present study aims on identifying the neurobiological correlates of social cognitive related alterations in psychopathy. METHODS: We applied a social cognitive paradigm for the investigation of face processing, emotion recognition, and affective Theory of Mind (ToM) to 11 imprisoned psychopaths and 18 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation. RESULTS: While showing no overall behavioural deficit, psychopathy was associated with altered brain activation. Psychopaths had reduced fusiform activation related to face processing. Related to affective ToM, psychopaths had hypoactivation in amygdala, inferior prefrontal gyrus and superior temporal sulcus, areas associated with embodied simulation of emotions and intentions. Furthermore, psychopaths lacked connectivity between superior temporal sulcus and amygdala during affective ToM. CONCLUSIONS: These results replicate findings of alterations in basal face processing in psychopathy. In addition, they provide evidence for reduced embodied simulation in psychopathy in concert with a lack of communication between motor areas and amygdala which might provide the neural substrate of reduced feeling with others during social cognition. PMID- 24802074 TI - A truncated FatB resulting from a single nucleotide insertion is responsible for reducing saturated fatty acids in maize seed oil. AB - KEY MESSAGE: We identified a G-nucleotide insertion in a maize FatB responsible for reducing saturated fatty acids through QTL mapping and map-based cloning and developed an allele-specific DNA marker for molecular breeding. Vegetable oils with reduced saturated fatty acids have signficant health benefits. SRS72NE, a Dow AgroSciences proprietory maize inbred line, was found to contain signficantly reduced levels of palmitic acid and total saturated fatty acids in seed oil when compared to other common inbreds. Using F2 and F3 populations derived from a cross between SRS72NE and a normal inbred SLN74, we have demonstrated that the reduced saturated fatty acid phenotype in SRS72NE is controlled by a single QTL on chromosome 9 that explains 79.1 % of palmitic acid and 79.6 % total saturated fatty acid variations. The QTL was mapped to an interval of 105 kb that contains one single gene, a type B fatty acyl-ACP thioesterase (ZmFatB; GRMZM5G829544). ZmFatB alleles from SRS72NE and common inbreds were cloned and sequenced. SRS72NE fatb allele contains a single nucleotide (G) insertion in the 6th exon, which creates a premature stop codon 22 base pairs down stream. As a result, ZmFatB protein from SRS72NE is predicted to contain eight altered and 90 deleted amino acids at its C-terminus. Because the affected region is part of the conserved acyl-ACP thioesterase catalytic domain, the truncated ZmFatB in SRS72NE is likely non-functional. We also show that fatb RNA level in SRS72NE is reduced by 4.4 fold when compared to the normal allele SNL74. A high throughput DNA assay capable of differentiating the normal and reduced saturate fatty acid alleles has been developed and can be used for accelerated molecular breeding. PMID- 24802076 TI - The D(+) + H2 reaction: differential and integral cross sections at low energy and rate constants at low temperature. AB - The D(+) + H2 reaction is investigated by means of a time independent quantum mechanical (TIQM) and statistical quantum mechanical (SQM) methods. Differential cross sections and product rotational distributions obtained with these two theoretical approaches for collision energies between 1 meV and 0.1 eV are compared to analyze the dynamics of the process. The agreement observed between the TIQM differential cross sections and the SQM predictions as the energy increases revealed the role played by the complex-forming mechanism. The importance of a good description of the asymptotic regions is also investigated by calculating rate constants for the title reaction at low temperature. PMID- 24802077 TI - Non-invasive transmission electron microscopy of vacancy defects in graphene produced by ion irradiation. AB - Irradiation with high-energy ions has been widely suggested as a tool to engineer properties of graphene. Experiments show that it indeed has a strong effect on graphene's transport, magnetic and mechanical characteristics. However, to use ion irradiation as an engineering tool requires understanding of the type and detailed characteristics of the produced defects which is still lacking, as the use of high-resolution transmission microscopy (HRTEM)--the only technique allowing direct imaging of atomic-scale defects--often modifies or even creates defects during imaging, thus making it impossible to determine the intrinsic atomic structure. Here we show that encapsulating the studied graphene sample between two other (protective) graphene sheets allows non-invasive HRTEM imaging and reliable identification of atomic-scale defects. Using this simple technique, we demonstrate that proton irradiation of graphene produces reconstructed monovacancies, which explains the profound effect that such defects have on graphene's magnetic and transport properties. This finding resolves the existing uncertainty with regard to the effect of ion irradiation on the electronic structure of graphene. PMID- 24802078 TI - Time providing care outside visits in a home-based primary care program. AB - OBJECTIVES: To assess how much time physicians in a large home-based primary care (HBPC) program spend providing care outside of home visits. Unreimbursed time and patient and provider-related factors that may contribute to that time were considered. DESIGN: Mount Sinai Visiting Doctors (MSVD) providers filled out research forms for every interaction involving care provision outside of home visits. Data collected included length of interaction, mode, nature, and with whom the interaction was for 3 weeks. SETTING: MSVD, an academic home-visit program in Manhattan, New York. PARTICIPANTS: All primary care physicians (PCPs) in MSVD (n = 14) agreed to participate. MEASUREMENTS: Time data were analyzed using a comprehensive estimate and conservative estimates to quantify unbillable time. RESULTS: Data on 1,151 interactions for 537 patients were collected. An average 8.2 h/wk was spent providing nonhome visit care for a full-time provider. Using the most conservative estimates, 3.6 h/wk was estimated to be unreimbursed per full-time provider. No significant differences in interaction times were found between patients with and without dementia, new and established patients, and primary-panel and covered patients. CONCLUSION: Home-based primary care providers spend substantial time providing care outside home visits, much of which goes unrecognized in the current reimbursement system. These findings may help guide practice development and creation of new payment systems for HBPC and similar models of care. PMID- 24802079 TI - Ionic liquid and deep eutectic solvent-activated CelA2 variants generated by directed evolution. AB - Chemoenzymatic cellulose degradation is one of the key steps for the production of biomass-based fuels under mild conditions. An effective cellulose degradation process requires diverse physico-chemical dissolution of the biomass prior to enzymatic degradation. In recent years, "green" solvents, such as ionic liquids and, more recently, deep eutectic liquids, have been proposed as suitable alternatives for biomass dissolution by homogenous catalysis. In this manuscript, a directed evolution campaign of an ionic liquid tolerant beta-1,4-endoglucanase (CelA2) was performed in order to increase its performance in the presence of choline chloride/glycerol (ChCl:Gly) or 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), as a first step to identify residues which govern ionic strength resistance and obtaining insights for employing cellulases on the long run in homogenous catalysis of lignocellulose degradation. After mutant library screening, variant M4 (His288Phe, Ser300Arg) was identified, showing a dramatically reduced activity in potassium phosphate buffer and an increased activity in the presence of ChCl:Gly or [BMIM]Cl. Further characterization showed that the CelA2 variant M4 is activated in the presence of these solvents, representing a first report of an engineered enzyme with an ionic strength activity switch. Structural analysis revealed that Arg300 could be a key residue for the ionic strength activation through a salt bridge with the neighboring Asp287. Experimental and computational results suggest that the salt bridge Asp287-Arg300 generates a nearly inactive CelA2 variant and activity is regained when ChCl:Gly or [BMIM]Cl are supplemented (~5-fold increase from 0.64 to 3.37 MUM 4-MU/h with the addition ChCl:Gly and ~23-fold increase from 3.84 to 89.21 MUM 4-pNP/h with the addition of [BMIM]Cl). Molecular dynamic simulations further suggest that the salt bridge between Asp287 and Arg300 in variant M4 (His288Phe, Ser300Arg) modulates the observed salt activation. PMID- 24802081 TI - HIP-55/DBNL-dependent regulation of adrenergic receptor mediates the ERK1/2 proliferative pathway. AB - The activation of beta-adrenergic receptors (beta-ARs) plays a key role in regulating cardiac function. However, the detailed regulatory mechanisms of beta AR-induced fibrosis are still unclear. We used a proteomics approach to analyze the changes in protein expression patterns in cardiac fibrosis with beta-AR stimulation. HIP-55 (also called debrin-like; DBNL) was revealed as a novel regulator in the signaling regulatory network with beta-AR activation. Further studies of both HIP-55-overexpressed and -deficient cardiac fibroblasts indicated that HIP-55 negatively regulated beta-AR-activated cardiac fibroblast proliferation and the proliferative signaling pathway may be associated with the extracellular signal-regulated protein kinase (ERK) activation. Our data provide a new mechanistic insight into the role of HIP-55 in beta-AR-induced cardiac fibroblast proliferation and suggest a new treatment strategy for proliferative disorders. PMID- 24802082 TI - Fatty acid binding protein 4 deficiency protects against oxygen-induced retinopathy in mice. AB - Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide due to increasing survival rates of premature infants. Initial suppression, followed by increased production of the retinal vascular endothelial growth factor-A (VEGF) expression are key events that trigger the pathological neovascularization in ROP. Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone that is induced by VEGF in a subset of endothelial cells. FABP4 exhibits a pro-angiogenic function in cultured endothelial cells and in airway microvasculature, but whether it plays a role in modulation of retinal angiogenesis is not known. We hypothesized that FABP4 deficiency could ameliorate pathological retinal vascularization and investigated this hypothesis using a well-characterized mouse model of oxygen-induced retinopathy (OIR). We found that FABP4 was not expressed in retinal vessels, but was present in resident macrophages/microglial cells and endothelial cells of the hyaloid vasculature in the immature retina. While FABP4 expression was not required for normal development of retinal vessels, FABP4 expression was upregulated and localized to neovascular tufts in OIR. FABP4-/- mice demonstrated a significant decrease in neovessel formation as well as a significant improvement in physiological revascularization of the avascular retinal tissues. These alterations in retinal vasculature were accompanied by reduced endothelial cell proliferation, but no effect on apoptosis or macrophage/microglia recruitment. FABP4-/- OIR samples demonstrated decreased expression of genes involved in angiogenesis, such as Placental Growth Factor, and angiopoietin 2. Collectively, our findings suggest FABP4 as a potential target of pathologic retinal angiogenesis in proliferative retinopathies. PMID- 24802083 TI - Human infants' preference for left-to-right oriented increasing numerical sequences. AB - While associations between number and space, in the form of a spatially oriented numerical representation, have been extensively reported in human adults, the origins of this phenomenon are still poorly understood. The commonly accepted view is that this number-space association is a product of human invention, with accounts proposing that culture, symbolic knowledge, and mathematics education are at the roots of this phenomenon. Here we show that preverbal infants aged 7 months, who lack symbolic knowledge and mathematics education, show a preference for increasing magnitude displayed in a left-to-right spatial orientation. Infants habituated to left-to-right oriented increasing or decreasing numerical sequences showed an overall higher looking time to new left-to-right oriented increasing numerical sequences at test (Experiment 1). This pattern did not hold when infants were presented with the same ordinal numerical information displayed from right to left (Experiment 2). The different pattern of results was congruent with the presence of a malleable, context-dependent baseline preference for increasing, left-to-right oriented, numerosities (Experiment 3). These findings are suggestive of an early predisposition in humans to link numerical order with a left-to-right spatial orientation, which precedes the acquisition of symbolic abilities, mathematics education, and the acquisition of reading and writing skills. PMID- 24802084 TI - Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. AB - Thrombotic thrombocytopenic purpura (TTP) is a clearly defined entity of thrombotic microangiopathies (TMAs), a heterogeneous group of disorders characterized by microangiopathic hemolytic anemia with red cell fragmentation, thrombocytopenia, and organ dysfunction due to disturbed microcirculation. TTP is characterized by a severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme responsible for physiological cleavage of von Willebrand factor (VWF). Organ dysfunction can be severe and life threatening, and immediate start of appropriate therapy is necessary to avoid permanent damage or death. The therapeutic options, however, are often limited to symptomatic measures, and are not standardized or based on high scientific evidence. During the last years, not only considerable progress has been made in better diagnosis of TTP, but also new therapeutic strategies have been established. Initial treatment still is based on plasma exchange and symptomatic measures to protect organ function, but new concepts (immunosuppression, targeted anti-VWF or anticomplement therapy, and replacement with recombinant enzymes) are currently under development. PMID- 24802085 TI - Treatment of enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome (eHUS). AB - Treatment of enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome (eHUS) still mostly relies on supportive intensive care regimens. Antibiotic treatment, as administered to eHUS patients during the 2011 O104:H4 outbreak, may reduce the shedding period, but this may apply only to this particular strain. In any case, there is no evidence for a beneficial use in the diarrheal phase and earlier warnings that antibiotic therapy at this stage may actually increase the likelihood of HUS remain unrefuted. Plasma exchange, a frequently chosen therapy in acute atypical HUS, was not beneficial for the outbreak patients and a prospective study of 274 pediatric eHUS patients even indicates a poorer long term outcome. As eHUS is a disease where complement plays a pathophysiological role and individual beneficial treatments had been published, eculizumab was broadly administered during the outbreak, in particular to severely ill patients. The equally good outcome of treated versus untreated patients obviously does not allow a clear-cut statement, but rather points toward an advantageous use, at least for the severe cases. Although the role of complement should not be overestimated, the use of a complement blocker--not necessarily being a therapeutic option for uncomplicated eHUS--in severe disease may actually make the difference between favorable or detrimental outcome. PMID- 24802086 TI - Comment on "E-cigarettes and cardiovascular risk: beyond science and mysticism". PMID- 24802087 TI - Response to "Comment on 'E-cigarettes and cardiovascular risk: beyond science and mysticism'". PMID- 24802088 TI - Short-term neuroplastic effects of brain-controlled and muscle-controlled electrical stimulation. AB - OBJECTIVES: Functional electrical stimulation (FES) has been shown to facilitate the recovery of grasping function in individuals with incomplete spinal cord injury. Neurophysiological theory suggests that this benefit may be further enhanced by a more consistent pairing of the voluntary commands sent from the user's brain down their spinal cord with the electrical stimuli applied to the user's periphery. The objective of the study was to compare brain-machine interfaces (BMIs)-controlled and electromyogram (EMG)-controlled FES therapy to three more well-researched therapies, namely, push button-controlled FES therapy, voluntary grasping (VOL), and BMI-guided voluntary grasping. MATERIALS AND METHODS: Ten able-bodied participants underwent one hour of each of five grasping training modalities, including BMI-controlled FES (BMI-FES), EMG-controlled FES (EMG-FES), conventional push button-controlled FES, VOL, and BMI-guided voluntary grasping. Assessments, including motor-evoked potential, grip force, and maximum voluntary contraction, were conducted immediately before and after each training period. RESULTS: Motor-evoked potential-based outcome measures were more upregulated following BMI-FES and especially EMG-FES than they were following VOL or FES. No significant changes were found in the more functional outcome measures. CONCLUSIONS: These results provide preliminary evidence suggesting the potential of BMI-FES and EMG-FES to induce greater neuroplastic changes than conventional therapies, although the precise mechanism behind these changes remains speculative. Further investigation will be required to elucidate the underlying mechanisms and to conclusively determine whether these effects can translate into better long-term functional outcomes and quality of life for individuals with spinal cord injury. PMID- 24802089 TI - An efficient system for secretory production of fibrinogen using a hepatocellular carcinoma cell line. AB - AIM: Despite an increasing demand, blood products are not always safe because most are derived from blood donations. One possible solution is the development and commercialization of recombinant fibrinogen, but this process remains poorly developed. This study aimed to develop an effective production system for producing risk-free fibrinogen using human hepatocellular cell lines and serum free media. METHODS: Three human liver cancer cell lines (HepG2, FLC-4 and FLC-7) were cultivated in a serum-supplemented medium or two serum-free media (ASF104N and IS-RPMI) to compare their fibrinogen secretion abilities. Fibrinogen subunit gene expression was estimated by quantitative polymerase chain reaction. Massive fibrinogen production was induced using a 5-mL radial flow bioreactor (RFB) while monitoring glucose metabolism. Subsequently, fibrinogen's biochemical characteristics derived from these cells were analyzed. RESULTS: FLC-7 cell culture combined with IS-RPMI resulted in significantly better fibrinogen production (21.6 MUg/10(7) cells per day). ASF104N had more positive effects on cell growth compared with IS-RPMI, whereas fibrinogen production was more efficient with IS-RPMI than with ASF104N. Changing the medium from ASF104N to IS RPMI led to significantly increased fibrinogen gene expression and glucose consumption. In the RFB culture, the fibrinogen secretion rate of FLC-7 cells reached 0.73 MUg/mL per day during a 42-day cultivation period. The subunit composition and clot formation activity of FLC-7 cell-derived fibrinogen corresponded to those of plasma fibrinogen. CONCLUSION: The FLC-7 cell culture system is suitable for large-scale fibrinogen preparation production. PMID- 24802090 TI - A transactional model of spoken vocabulary variation in toddlers with intellectual disabilities. AB - PURPOSE: The authors examined (a) whether dose frequency of milieu communication teaching (MCT) affects children's canonical syllabic communication and (b) whether the relation between early canonical syllabic communication and later spoken vocabulary is mediated by parental linguistic mapping in children with intellectual disabilities (ID). METHOD: The authors drew on extant data from a recent differential treatment intensity study in which 63 toddlers with ID were randomly assigned to receive either five 1-hr MCT sessions per week (i.e., daily treatment) or one 1-hr MCT session per week (i.e., weekly treatment) for 9 months. Children's early canonical syllabic communication was measured after 3 months of treatment, and later spoken vocabulary was measured at posttreatment. Midpoint parental linguistic mapping was measured after 6 months of treatment. RESULTS: A moderate-sized effect in favor of daily treatment was observed on canonical syllabic communication. The significant relation between canonical syllabic communication and spoken vocabulary was partially mediated by linguistic mapping. CONCLUSIONS: These results suggest that canonical syllabic communication may elicit parental linguistic mapping, which may in turn support spoken vocabulary development in children with ID. More frequent early intervention boosted canonical syllabic communication, which may jump-start this transactional language-learning mechanism. Implications for theory, research, and practice are discussed. PMID- 24802091 TI - Characterization of the invasiveness of monophasic and aphasic Salmonella Typhimurium strains in 1-day-old and point-of-lay chickens. AB - Egg-related outbreaks of salmonellosis are a significant health concern. Although Salmonella Enteritidis (SE) is the major egg-associated serotype, Salmonella Typhimurium (ST) can also infect the hen's reproductive tract and contaminate eggs. Recently, monophasic and aphasic variants of ST have been reported with increased frequency in Europe, and the isolation of these variants from laying flocks triggers the same legislative restrictions associated with biphasic ST strains. However, little is known about the colonization, invasiveness and persistence of monophasic and aphasic ST strains in laying hens. In this study, seven groups of 1-day-old and point-of-lay commercial Hy-line chicken layers were separately challenged with four different strains of monophasic ST, one aphasic ST, one biphasic ST and one egg-invasive SE strain. Tissue samples and cloacal swabs (point-of-lay chickens only) were collected at regular intervals post challenge in order to recover the Salmonella challenge strains. In 1-day-old chicks, only the aphasic ST strain and the SE strain were recovered after direct plating, suggesting that the number of salmonellas colonizing the tissues of the chicks infected with the other strains was likely to be low. Interestingly, all of the strains colonized well in the point-of-lay chickens, and there was no statistical difference in the overall number of positive samples or Salmonella counts between the seven strains. Salmonella was recovered from the point-of-lay birds to the end of the study (20 days after challenge). Monophasic and aphasic ST strains colonized point-of-lay birds as efficiently as biphasic ST and SE strains. Further studies are necessary to estimate the invasiveness of these strains in naturally-infected vaccinated laying hens, and to assess the impact of natural infection on egg contamination. PMID- 24802092 TI - A 1,2-propylene oxide sensor utilizing cataluminescence on CeO2 nanoparticles. AB - A simple and sensitive gas sensor was proposed for the determination of 1,2 propylene oxide (PO) based on its cataluminescence (CTL) by oxidation in the air on the surface of CeO2 nanoparticles. The luminescence characteristics and optimal conditions were investigated in detail. Under optimized conditions, the linear range of the CTL intensity versus the concentration of PO was 10-150 ppm, with a correlation coefficient (r) of 0.9974 and a limit of detection (S/N = 3) of 0.9 ppm. The relative standard deviation for 40 ppm PO was 1.2% (n = 7). There was no or only weak response to common foreign substances including acetone, formaldehyde, ethyl acetate, acetic acid, chloroform, propanol, carbon tetrachloride, ether and methanol. There was no significant change in the catalytic activity of the sensor for 100 h. The proposed method was simple and sensitive, with a potential of detecting PO in the environment and industry. PMID- 24802093 TI - Revision IPAA: strategies for success. AB - The history of ileal pouch-anal anastomosis (IPAA) is one of success with durable surgical and functional results. However, pouch failure, due to infection, mechanical, or functional disability, represents a challenge to both surgeon and patient. Practicing surgeons who deal with the revision pouch face a variety of challenges. Success requires a strategy, which includes critical planning, preparation, and surgical techniques in order that surgeons continue to provide solutions and hope to patients. PMID- 24802094 TI - The hMTH1 paradox: antioxidants recommended in cancer? PMID- 24802095 TI - Mesenchymal stem cells from different murine tissues have differential capacity to metabolize extracellular nucleotides. AB - Mesenchymal stem cells (MSCs) have shown a great potential for cell-based therapy and many different therapeutic purposes. Despite the recent advances in the knowledge of MSCs biology, their biochemical and molecular properties are still poorly defined. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'-nucleotidase (eNT/CD73) are widely expressed enzymes that hydrolyze extracellular nucleotides, generating an important cellular signaling cascade. Currently, studies have evidenced the relationship between the purinergic system and the development, maintenance, and differentiation of stem cells. The objective of this study is to identify the NTPDases and eNT/CD73 and compare the levels of nucleotide hydrolysis on MSCs isolated from different murine tissues (bone marrow, lung, vena cava, kidney, pancreas, spleen, skin, and adipose tissue). MSCs from all tissues investigated expressed the ectoenzymes at different levels. In MSCs from pancreas and adipose tissue, the hydrolysis of triphosphonucleosides was significantly higher when compared to the other cells. The diphosphonucleosides were hydrolyzed at a higher rate by MSC from pancreas when compared to MSC from other tissues. The differential nucleotide hydrolysis activity and enzyme expression in these cells suggests that MSCs play different roles in regulating the purinergic system in these tissues. Overall MSCs are an attractive adult-derived cell population for therapies, however, the fact that ecto-nucleotide metabolism can affect the microenvironment, modulating important events, such as immune response, makes the assessment of this metabolism an important part of the characterization of MSCs to be applied therapeutically. PMID- 24802096 TI - Stereotactic body radiation therapy for primary lung cancers clinically diagnosed without pathological confirmation: a single-institution experience. AB - BACKGROUND: Pathological diagnosis of small lung lesions is sometimes difficult in medically inoperable patients. The purpose of this study was to evaluate the adverse events and the outcomes of stereotactic body radiation therapy (SBRT) for lung lesions which were clinically diagnosed as primary lung cancer without pathological confirmation. METHODS: Between April 2003 and April 2011, 88 patients with small lung lesions which were clinically diagnosed as primary lung cancer were treated with SBRT. The median tumor size was 19 mm (range 8-40 mm). The radiation dose was 48 Gy in four fractions in all patients. The median follow up was 23 months (range 6-91 months). RESULTS: Recurrence was observed in 13 patients. The local control rate, progression-free survival rate, and overall survival rate at 3 years were 90, 67, and 80 %, respectively. Two patients (2.3 %) had Grade 2 radiation pneumonitis, and six patients (6.8 %) had Grade 2 rib fractures. There were no adverse events of Grade 3 or greater. CONCLUSIONS: SBRT appears to be a safe and effective treatment option for small lung lesions that are clinically diagnosed as primary lung cancer without pathological confirmation. PMID- 24802097 TI - Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: a shorter drug-free interval leads to more efficient antitumor effects. AB - BACKGROUND: A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate day administration of S-1/LV in in vivo xenograft tumor models. METHODS: Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis. RESULTS: Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP. CONCLUSION: Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients. PMID- 24802099 TI - HIV/hepatitis C virus coinfection management: changing guidelines and changing paradigms. AB - OBJECTIVES: The aim of the study was to consider the impact of new direct-acting antiviral (DAA) regimens on hepatitis C virus (HCV) treatment in HIV/HCV coinfection. METHODS: Current coinfection guidelines were reviewed and the impact of recent DAA publications evaluating HIV-coinfected individuals was considered. RESULTS: Current coinfection guidelines recommend HIV antiretroviral therapy initiation prior to HCV antiviral therapy. New all-oral, combination antiviral therapy composed of one or more DAAs with or without ribavirin will change this paradigm. As these regimens are better tolerated, it will be possible to offer nearly all HCV-infected patients antiviral therapy, including those with HIV infection. All-oral regimens may impact the incidence of HCV infection by providing a treatment option that can be safely and broadly utilized in high-risk populations with the benefits of curing individual patients and addressing broader public health concerns related to HCV. CONCLUSIONS: HCV infection treatment should no longer be a secondary consideration restricted to the minority of HIV/HCV-coinfected patients. PMID- 24802100 TI - Living in supportive housing for people with serious mental illness: a paradoxical everyday life. AB - Since the closure of large psychiatric institutions, various types of community based supportive housing for people with serious mental illness (SMI) have been developed. There is currently limited knowledge about users' experiences of living in supportive housing. The aim of the present study was to describe user experiences of living in supportive housing for people with SMI. Twenty-nine people living in such facilities participated in open, qualitative interviews. Data were subjected to latent content analysis. Three main themes emerged from this analysis: (i) having a nest, which included the subthemes of a place to rest and having someone to attach to; (ii) being part of a group, with the subthemes of being brought together and a community spirit; and (iii) leading an oppressive life, including the subthemes of questioning one's identity, sense of inequality, and a life of gloom. It could be concluded that user experiences of living in supportive housing are complex and paradoxical. In order to provide supportive housing, staff need to recognize and work within social group processes, and perform continual and structural evaluations of users' social and emotional needs. PMID- 24802098 TI - Modeling progressive non-alcoholic fatty liver disease in the laboratory mouse. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world and its prevalence is rising. In the absence of disease progression, fatty liver poses minimal risk of detrimental health outcomes. However, advancement to non-alcoholic steatohepatitis (NASH) confers a markedly increased likelihood of developing severe liver pathologies, including fibrosis, cirrhosis, organ failure, and cancer. Although a substantial percentage of NAFLD patients develop NASH, the genetic and molecular mechanisms driving this progression are poorly understood, making it difficult to predict which patients will ultimately develop advanced liver disease. Deficiencies in mechanistic understanding preclude the identification of beneficial prognostic indicators and the development of effective therapies. Mouse models of progressive NAFLD serve as a complementary approach to the direct analysis of human patients. By providing an easily manipulated experimental system that can be rigorously controlled, they facilitate an improved understanding of disease development and progression. In this review, we discuss genetically- and chemically-induced models of NAFLD that progress to NASH, fibrosis, and liver cancer in the context of the major signaling pathways whose disruption has been implicated as a driving force for their development. Additionally, an overview of nutritional models of progressive NAFLD is provided. PMID- 24802101 TI - A vaccine of L2 epitope repeats fused with a modified IgG1 Fc induced cross neutralizing antibodies and protective immunity against divergent human papillomavirus types. AB - Current human papillomavirus (HPV) major capsid protein L1 virus-like particles (VLPs)-based vaccines in clinic induce strong HPV type-specific neutralizing antibody responses. To develop pan-HPV vaccines, here, we show that the fusion protein E3R4 consisting of three repeats of HPV16 L2 aa 17-36 epitope (E3) and a modified human IgG1 Fc scaffold (R4) induces cross-neutralizing antibodies and protective immunity against divergent HPV types. E3R4 was expressed as a secreted protein in baculovirus expression system and could be simply purified by one step Protein A affinity chromatography with the purity above 90%. Vaccination of E3R4 formulated with Freunds adjuvant not only induced cross-neutralizing antibodies against HPV pseudovirus types 16, 18, 45, 52, 58, 6, 11 and 5 in mice, but also protected mice against vaginal challenges with HPV pseudovirus types 16, 45, 52, 58, 11 and 5 for at least eleven months after the first immunization. Moreover, vaccination of E3R4 formulated with FDA approved adjuvant alum plus monophosphoryl lipid A also induced cross-neutralizing antibodies against HPV types 16, 18 and 6 in rabbits. Thus, our results demonstrate that delivery of L2 antigen as a modified Fc-fusion protein may facilitate pan-HPV vaccine development. PMID- 24802102 TI - Size-dependent effects of gold nanoparticles uptake on maturation and antitumor functions of human dendritic cells in vitro. AB - Gold nanoparticles (GNPs) are claimed as outstanding biomedical tools for cancer diagnostics and photo-thermal therapy, but without enough evidence on their potentially adverse immunological effects. Using a model of human dendritic cells (DCs), we showed that 10 nm- and 50 nm-sized GNPs (GNP10 and GNP50, respectively) were internalized predominantly via dynamin-dependent mechanisms, and they both impaired LPS-induced maturation and allostimulatory capacity of DCs, although the effect of GNP10 was more prominent. However, GNP10 inhibited LPS-induced production of IL-12p70 by DCs, and potentiated their Th2 polarization capacity, while GNP50 promoted Th17 polarization. Such effects of GNP10 correlated with a stronger inhibition of LPS-induced changes in Ca2+ oscillations, their higher number per DC, and more frequent extra-endosomal localization, as judged by live cell imaging, proton, and electron microscopy, respectively. Even when released from heat-killed necrotic HEp-2 cells, GNP10 inhibited the necrotic tumor cell induced maturation and functions of DCs, potentiated their Th2/Th17 polarization capacity, and thus, impaired the DCs' capacity to induce T cell-mediated anti tumor cytotoxicity in vitro. Therefore, GNP10 could potentially induce more adverse DC-mediated immunological effects, compared to GNP50. PMID- 24802104 TI - Learning profiles for noninvasive transcutaneous Doppler ultrasound. AB - OBJECTIVE: This study aimed to establish learning profiles for noninvasive transcutaneous Doppler ultrasound. MATERIALS AND METHODS: Four trainees attended a 2-h lecture, followed by a 15-min demonstration on a volunteer and a 30-min hands-on workshop in a small group setting. Then, they underwent hands-on practice on 50 participants without supervision. The skill acquisitions in terms of signal magnitude, signal quality, and measurement time of the trainees were evaluated through 50 assessments, and were compared with that of a trainer with extensive experience on the use of an ultrasonic cardiac output monitor acting as a 'gold standard'. The learning profile for each individual trainee was analyzed using the cumulative sum graphical method. RESULTS: Four trainees performed ultrasonic cardiac output monitor on 50 participants. All trainees attained proficiency after 18-36 assessments to achieve aortic signal magnitude and quality comparable with the trainer. It requires a minimum of nine assessments to obtain three aortic scans within 5 min with 95% success rates. Only half of the trainees achieved competence in pulmonary scans and the minimum number of assessments required was 36. A minimum of 22 assessments were required for three pulmonary scans within 10 min with 95% success rates. CONCLUSION: A substantial period of learning needs to be undertaken to achieve proficiency on the use of noninvasive transcutaneous Doppler ultrasound. Cumulative sum analysis is a useful tool for ongoing quality assessment during medical education and training in practical procedures on an individual basis. PMID- 24802103 TI - Spontaneous abortion is associated with elevated systemic C5a and reduced mRNA of complement inhibitory proteins in placenta. AB - Spontaneous abortion in early pregnancy due to unknown reasons is a common problem. The excess complement activation and consequent placental inflammation and anti-angiogenic milieu is emerging as an important associated factor in many pregnancy-related complications. In the present study we sought to examine the expression of complement inhibitory proteins at the feto-maternal interface and levels of complement split products in the circulation to understand their role in spontaneous abortion. Consenting pregnant women who either underwent elective abortion due to non-clinical reasons (n = 13) or suffered miscarriage (n = 14) were recruited for the study. Systemic levels of complement factors C3a and C5a were measured by enzyme-linked immunosorbent assay (ELISA). Plasma C5 and C3 protein levels were examined by Western blot. Expressions of complement regulatory proteins such as CD46 and CD55 in the decidua were investigated by quantitative polymerase chain reaction (PCR) and Western blot. The median of plasma C3a level was 82.83 ng/ml and 66.17 ng/ml in elective and spontaneous abortion patients, respectively. Medians of plasma C5a levels in elective and spontaneous abortion patients were 0.96 ng/ml and 1.14 ng/ml, respectively. Only plasma C5a levels but not C3a levels showed significant elevation in spontaneous abortion patients compared to elective abortion patients. Further, there was a threefold decrease in the mRNA expressions of complement inhibitory proteins CD46 and CD55 in the decidua obtained from spontaneous abortion patients compared to that of elective abortion patients. These data suggested that dysregulated complement cascade may be associated with spontaneous abortion. PMID- 24802106 TI - Management of the Toddler's fracture with and without initial radiological evidence. AB - Toddler's fracture (TF) occurs in young children after minor trauma. Clinical diagnosis can be challenging and initial radiological evidence may be lacking. The aim of this study was to compare the management and outcomes of clinically diagnosed TF patients with and without initial radiological evidence. A retrospective cohort study of patients aged between 9 and 36 months treated for TF in a Scottish Paediatric Emergency Department was conducted. Patients with a radiologically confirmed TF were more likely to be placed in a cast than those with a presumptive clinical TF diagnosis (92 vs. 47%; P<0.02). Overall cast duration and duration from follow-up to discharge from clinic were similar in both groups. There were no complications with management in or out of cast. The initial presumptive clinical diagnosis of TF may be as significant as that with radiological confirmation. Follow-up imaging is unlikely to affect management if the diagnosis remains clinically clear. PMID- 24802105 TI - Results of a simple intervention to improve documentation quality in major trauma. AB - OBJECTIVES: Accurate and thorough documentation is an important part of medical care, providing a legally binding historical record of events and means of communication. Trauma is a complex multidisciplinary environment, in which documentation is particularly important, but can be poor as a result. We investigate the effect of introducing a proforma documentation booklet, acting as a physical prompt to ensure full patient assessment, as well as full documentation, on documentation quality. METHODS: A case note review of all major trauma patients admitted over 12 months at a district hospital was performed by clinicians with case note review experience 6 months before and after introduction of a trauma booklet. Documentation quality was assessed, as was the presence of complete trauma teams. RESULTS: A total of 297 consecutive trauma patients over 12 months were reviewed: 136 patients preintervention and 161 patients after implementation of the trauma booklet. Use of a trauma booklet significantly increased the rate of primary survey documentation [82.8% (114/136) vs. 98.8% (159/161), chi P<0.001]. Similar results were seen for documented completion of secondary surveys [39% (53/136) vs. 66.5% (107/161), P<0.001]. Following implementation of a trauma booklet, a significant increase in full trauma team presence was observed (43.4 vs. 67.1%, P<0.001). CONCLUSION: This study has demonstrated the potential of the introduction of a structured proforma to significantly improve documentation quality in major trauma. In the future, all hospitals accepting trauma patients could benefit from the introduction of similar proformas. PMID- 24802107 TI - One-step prepared fluorescent copper nanoclusters for reversible pH-sensing. AB - A one-step synthesis of water soluble and pH-responsive trypsin-stabilized fluorescent copper nanoclusters (CuNCs) was reported without using additional protective or reducing agents, and the as-prepared CuNCs exhibited highly stable properties including oxidation resistance, thermal stability and photostability. PMID- 24802108 TI - Periplasmic multilamellar membranous structures in Nicotiana tabacum L. pollen grains treated with Ni2+ or Cu2+. AB - Essential trace elements Ni(2+) and Cu(2+) can block pollen germination without causing cell death. Mechanisms of this effect remain unclear. Using TEM, we studied the effects of Ni(2+) or Cu(2+) treatment on the ultrastructure of the aperture regions in tobacco pollen preparing to germinate in vitro, since in these zones, the main fluxes of water, ions, and metabolites cross the plasmalemma. Neither Ni(2+) nor Cu(2+) altered the cytoplasm ultrastructure, but both affected the reorganization of apertural periplasm during pollen activation. Numerous multilamellar membranous structures continuous with the plasma membrane could be seen in hydrated but not yet activated pollen. When the normal activation was completed, the structures disappeared and the plasmalemma became smooth. In the presence of 1 mM Ni(2+) or 100 MUM Cu(2+), these structures preserved its original appearance. It is assumed to be the storage form for the membrane material, which is to provide an initial phase of the pollen tube growth. Ni(2+) and Cu(2+) affect the utilization of these membranes, thereby, blocking the pollen germination. PMID- 24802109 TI - Ultrastructure of Cosmarium strains (Zygnematophyceae, Streptophyta) collected from various geographic locations shows species-specific differences both at optimal and stress temperatures. AB - Plant species collected from various climatic zones and stressed in vitro at various temperatures reveal changes in cellular ultrastructure which are in accordance with the climate at their sampling sites. This observation initiated the investigation to establish if stress at different temperatures may cause diverse extents of changes in the ultrastructure of microalgal strains originating from different geographic zones. The study revealed that the six Cosmarium strains demonstrated ultrastructural characteristics that were consistent with their source location under optimal, low and high temperature conditions, pointing to their preference to specific climatic niches. Interestingly, chloroplasts of all of the Cosmarium strains correspond to a sun adapted type, which is concomitant with earlier statements that these strains are rendered as high-light adapted algae. The Cosmarium strains developed multiple ultrastructural responses which enabled them to cope with excessive temperatures, occasionally occurring in desmid natural habitats. The appearance of cubic membranes and increased number of plastoglobules may represent the first line in protection against high-temperature stress, which is accompanied by the alteration of protein synthesis and the appearance of stress granules in order to preserve cell homeostasis. However, the prolonged warm- or cold-temperature stress obviously initiated the programmed cell death, as concluded from the appearance of several ultrastructural features observed in all of the Cosmarium strains. The fair acclimation possibilities and the ability to undergo programmed cell death in order to save the population, certainly favor the cosmopolitan distribution of the genus Cosmarium. PMID- 24802110 TI - The role of dissolved cations in coffee extraction. AB - The flavorsome compounds in coffee beans exist in the form of aprotic charge neutral species, as well as a collection of acids and conjugate salts. The dissolution and extraction of these organic molecules is a process dependent on the dissolved mineral content of the water. It is known that different rates and compositions of coffee extraction are achieved through the control of the water "impurities", Na(+), Mg(2+), and Ca(2+), which coordinate to nucleophilic motifs in coffee. Using density functional theory, we quantify the thermodynamic binding energies of five familiar coffee-contained acids, caffeine, and a representative flavor component, eugenol. From this, we provide insight into the mechanism and ideal mineral composition of water for extraction of flavorsome compounds in coffee. PMID- 24802111 TI - Influenza A viral nucleoprotein interacts with cytoskeleton scaffolding protein alpha-actinin-4 for viral replication. AB - Influenza A virus (IAV), similar to other viruses, exploits the machinery of human host cells for its survival and replication. We identified alpha-actinin-4, a host cytoskeletal protein, as an interacting partner of IAV nucleoprotein (NP). We confirmed this interaction using co-immunoprecipitation studies, first in a coupled in vitro transcription-translation assay and then in cells either transiently co-expressing the two proteins or infected with whole IAV. Importantly, the NP-actinin-4 interaction was observed in several IAV subtypes, including the 2009 H1N1 pandemic virus. Moreover, immunofluorescence studies revealed that both NP and actinin-4 co-localized largely around the nucleus and also in the cytoplasmic region of virus-infected A549 cells. Silencing of actinin 4 expression resulted in not only a significant decrease in NP, M2 and NS1 viral protein expression, but also a reduction of both NP mRNA and viral RNA levels, as well as viral titers, 24 h post-infection with IAV, suggesting that actinin-4 was critical for viral replication. Furthermore, actinin-4 depletion reduced the amount of NP localized in the nucleus. Treatment of infected cells with wortmannin, a known inhibitor of actinin-4, led to a decrease in NP mRNA levels and also caused the nuclear retention of NP, further strengthening our previous observations. Taken together, the results of the present study indicate that actinin-4, a novel interacting partner of IAV NP, plays a crucial role in viral replication and this interaction may participate in nuclear localization of NP and/or viral ribonucleoproteins. PMID- 24802112 TI - Attitudes, perceptions and potential uptake of male circumcision among older men in Turkana County, Kenya using qualitative methods. AB - BACKGROUND: In many communities, older men (i.e., over 25 years of age) have not come forward for Voluntary Medical Male Circumcision (VMMC) services. Reasons for low demand among this group of men are not well understood, and may vary across geographic and cultural contexts. This paper examines the facilitators and barriers to VMMC demand in Turkana County, Kenya, with a focus on older men. This is one of the regions targeted by the VMMC program in Kenya because the Turkana ethnic group does not traditionally circumcise, and the rates of HIV and STD transmission are high. METHODS AND FINDINGS: Twenty focus group discussions and 69 in-depth interviews were conducted with circumcised and uncircumcised men and their partners to elicit their attitudes and perceptions toward male circumcision. The interviews were conducted in urban, peri-urban, and rural communities across Turkana. Our results show that barriers to circumcision include stigma associated with VMMC, the perception of low risk for HIV for older men and their "protection by marriage," cultural norms, and a lack of health infrastructure. Facilitators include stigma against not being circumcised (since circumcision is associated with modernity), protection against disease including HIV, and cleanliness. It was also noted that older men should adopt the practice to serve as role models to younger men. CONCLUSIONS: Both men and women were generally supportive of VMMC, but overcoming barriers with appropriate communication messages and high quality services will be challenging. The justification of circumcision being a biomedical procedure for protection against HIV will be the most important message for any communication strategy. PMID- 24802114 TI - A double pruning scheme for boosting ensembles. AB - Ensemble learning consists of generating a collection of classifiers whose predictions are then combined to yield a single unified decision. Ensembles of complementary classifiers provide accurate and robust predictions, which are often better than the predictions of the individual classifiers in the ensemble. Nevertheless, ensembles also have some drawbacks: typically, all classifiers are queried to compute the final ensemble prediction. Therefore, all the classifiers need to be accessible to address potential queries. This entails larger storage requirements and slower predictions than a single classifier. Ensemble pruning techniques are useful to alleviate these drawbacks. Static pruning techniques reduce the ensemble size by selecting a sub-ensemble of classifiers from the original ensemble. In dynamic pruning, the querying process is halted when the partial ensemble prediction is sufficient to reach a stable final decision with a reasonable amount of confidence. In this paper, we present the results of a comprehensive analysis of static and dynamic pruning techniques applied to Adaboost ensembles. These ensemble pruning techniques are evaluated on a wide range of classification problems. From this analysis, one concludes that the combination of static and dynamic pruning techniques provides a notable reduction in the memory requirements and an improvement in the classification time without a significant loss of prediction accuracy. PMID- 24802113 TI - Type AB thymoma is not a mixed tumor of type A and type B thymomas, but a distinct type of thymoma. AB - Type AB thymoma is generally regarded to be a mixture of type A and type B thymomas, but has not been studied extensively. In this study, we precisely investigated the characteristics of type AB thymoma immunohistochemically and compared it with other types of thymoma, including type A, metaplastic, and type B1 thymoma. In type A thymoma, the tumor cells were composed solely of pan cytokeratin (CK-AE1/AE3)(+) claudin-1(+) vimentin(-) epithelial membrane antigen (EMA)(-) short spindle cells. Metaplastic thymoma exhibited biphasic architecture of epithelial islands of short spindle cells, which were phenotypically almost identical to the tumor cells in type A thymoma, and anastomosing bundles of CK AE1/AE3(-) claudin-1(-) vimentin(+) EMA(+) fibroblast-like long spindle-shaped epithelial cells. Interestingly, we found that there were two distinctive subtypes of cell in type AB thymoma: the conventional subtype and the metaplastic subtype. The conventional subtype is characterized by type A-like components resembling type A thymoma. The metaplastic subtype is characterized by type A like components extensively resembling the anastomosing bundles of fibroblast like long spindle epithelial cells. Interestingly, the metaplastic subtype was a major subtype (14/19 cases), while the conventional subtype was a minor one (5/19 cases). In contrast to the rarity of metaplastic thymoma, the metaplastic subtype of type AB thymoma appears to be a major subtype of type AB thymoma. PMID- 24802115 TI - Characteristics and anticancer properties of bacterial cellulose films containing ethanolic extract of mangosteen peel. AB - Bacterial cellulose (BC) films containing an ethanolic extract of mangosteen peel were prepared and their physical, chemical, and anticancer properties were characterized. The cumulative absorption and release profiles of bioactive compounds in the films were determined based on total phenolic and alpha mangostin content. The BC films were filled with total phenolic compounds expressed as gallic acid equivalent varying from 4.72 to 275.91 mg/cm3 dried film, and alpha-mangostin varying from 2.06 to 248.20 mg/cm3 dried film. A Fourier transform infrared spectroscopy evaluation showed that there were weak interactions between the functional groups of the extract and the BC. Decreases in the water absorption capacity and water vapor transmission rate of the modified films were detected. Release studies were performed using Franz diffusion cells. In a non-transdermal system, the release of bioactive compounds from the films depended on concentration, immersion time, and the pH of the dissolution medium. A transdermal diffusion study showed that 59-62% of total phenolic compounds that were initially loaded were released from the films and more than 95% of bioactive compounds released from the films were adsorbed into pig skin. Only very small amount of the bioactive compounds penetrated through pig skin and into phosphate and acetate buffers. In studies of anticancer abilities, the release of 2.0 MUg/ml alpha-mangostin from the BC films could suppress the growth of B16F10 melanoma (approximately 31% survival). With the release of alpha-mangostin at greater than 17.4-18.4 MUg/ml, less than 15 and 5% survival of B16F10 melanoma and MCF-7 breast cancer cells, respectively, was observed. PMID- 24802116 TI - Functional characterization of GhAKT1, a novel Shaker-like K+ channel gene involved in K+ uptake from cotton (Gossypium hirsutum). AB - Shaker-like potassium (K(+)) channels in plants play an important role in K(+) absorption and transport. In this study, we characterized a Shaker-like K(+) channel gene GhAKT1 from the roots of Gossypium hirsutum cv. Liaomian17. Phylogenetic analysis showed that the GhAKT1 belongs to the AKT1-subfamily in the Shaker-like K(+) channel family. Confocal imaging of a GhAKT1-green fluorescent fusion protein (GFP) in transgenic Arabidopsis plants indicated that GhAKT1 is localized in the plasma membrane. Transcript analysis located GhAKT1 predominantly in cotton leaves with low abundance in roots, stem and shoot apex. Similarly, beta-glucuronidase (GUS) activity was detected in both leaves and roots of PGhAKT1::GUS transgenic Arabidopsis plants. In roots, the GUS signals appeared in the epidermis, cortex and endodermis and root hairs, suggesting the contribution of GhAKT1 to K(+) uptake. In leaves, GhAKT1 was expressed in differentiated leaf primordial as well as mesophyll cells and veins of expanded leaves, pointing to its involvement in cell elongation and K(+) transport and distribution in leaves. Severe K(+) deficiency did not affect the expression of GhAKT1 gene. GhAKT1-overexpression in either the Arabidopsis wild-type or akt1 mutant enhanced the growth of transgenic seedlings under low K(+) deficiency and raised the net K(+) influx in roots at 100MUM external K(+) concentration, within the range of operation of the high-affinity K(+) uptake system. The application of 2mM BaCl2 resulted in net K(+) efflux in roots, and eliminated the differences between GhAKT1-overexpression lines and their acceptors indicating that the K(+) uptake mediated by GhAKT1 is also as Ba(2+)-sensitive as AtAKT1. PMID- 24802117 TI - Identification, characterization and nutritional regulation of two isoforms of acyl-coenzyme A oxidase 1 gene in Nile tilapia (Oreochromis niloticus). AB - In peroxisome, acyl-coenzyme A oxidase 1 (ACOX1) is the first rate-limiting enzyme of the fatty acid beta-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs. Two isoforms of acyl-coenzyme A oxidase 1 were firstly identified in Nile tilapia (Oreochromis niloticus) in this study. ACOX1 isoform1 (ACOX1i1) and ACOX1 isoform2 (ACOX1i2) were encoded by the single gene with 661 amino acids in length. The coding region of both isoforms consisted of 14 exons. The residues from 89 to 193 in ACOX1i1 were encoded by exon 3b, while in ACOX1i2 they were encoded by exon 3a. Homologous alignment analysis indicated that the varied region (the residues from 89 to 193) of ACOX1i1 was more conserved than ACOX1i2 in vertebrates (Mammalia, Aves, Amphibia and Pisces). The mRNA expression level of ACOX1i1 and ACOX1i2 was detected separately in eleven tissues and the results indicated that ACOXi1 expression was the highest in liver followed by kidney and brain, while the expression of ACOXi2 was the highest in kidney followed by liver. The normalized levels of both transcript variants were comparable in most tissues, however the level of ACOX1i2 was significantly higher than that of ACOX1i1 in white muscle and kidney (5.1 fold and 3.1 fold), and ACOX1i1 was significantly higher than ACOX1i2 in gill and brain (4.8 fold and 1.9 fold). In different nutritional states, the expression levels of both isoforms in liver were comparable between fasting and most of post feeding time points, except that the expression at 3h post-feeding was significantly lower than others. The expression of ACOX1i1 in the kidney also showed the similar pattern, indicating the lowest expression at 8h post-feeding, however, no significant change was seen in ACOX2i2 among all nutritional states. These results suggested that ACOX1i1 and i2 may play different roles in tissues, and their expression levels were differently modulated by nutritional stage. PMID- 24802118 TI - Effects of growth phase and nitrogen starvation on expression of fatty acid desaturases and fatty acid composition of Isochrysis aff. galbana (TISO). AB - Very long-chain polyunsaturated fatty acids (VLC-PUFAs) are important dietary requirements for maintaining human health. Many marine microalgae are naturally high in omega-3 VLC-PUFAs, however, the molecular mechanisms underpinning fatty acid (FA) desaturation and elongation in algae are poorly understood. An advanced molecular understanding would facilitate improvements of this nascent industry. We aimed to investigate expression responses of four front-end fatty acid desaturase genes and downstream effects on FA profiles to nitrogen limitation and cultivation growth stage in Isochrysis aff. galbana (TISO). Cultures were grown in nitrogen-replete and -deplete medium; samples were harvested during logarithmic, late logarithmic and stationary growth phases to analyse FA content/composition and gene expression of ?(6)-, ?(8)-, ?(5)- and ?(4) desaturases (d6FAD (putative), d8FAD, d5FAD and d4FAD, respectively). d6FAD (putative) exhibited no differential expression, while d8FAD, d5FAD and d4FAD were significantly upregulated during logarithmic growth of nutrient-replete cultures, coinciding with rapid cell division. In conclusion, it is demonstrated that expression of some FADs in I. aff. galbana varies with culture age and nitrogen status which has downstream consequences on FA desaturation levels. This has implications for the commercial production of VLC-PUFAs where a trade-off between total lipid yield and VLC-PUFAs has to be made. PMID- 24802119 TI - Rapid differentiation of Listeria monocytogenes epidemic clones III and IV and their intact compared with heat-killed populations using Fourier transform infrared spectroscopy and chemometrics. AB - The objectives of this study were to determine if Fourier transform infrared (FT IR) spectroscopy and multivariate statistical analysis (chemometrics) could be used to rapidly differentiate epidemic clones (ECs) of Listeria monocytogenes, as well as their intact compared with heat-killed populations. FT-IR spectra were collected from dried thin smears on infrared slides prepared from aliquots of 10 MUL of each L. monocytogenes ECs (ECIII: J1-101 and R2-499; ECIV: J1-129 and J1 220), and also from intact and heat-killed cell populations of each EC strain using 250 scans at a resolution of 4 cm(-1) in the mid-infrared region in a reflectance mode. Chemometric analysis of spectra involved the application of the multivariate discriminant method for canonical variate analysis (CVA) and linear discriminant analysis (LDA). CVA of the spectra in the wavelength region 4000 to 600 cm(-1) separated the EC strains while LDA resulted in a 100% accurate classification of all spectra in the data set. Further, CVA separated intact and heat-killed cells of each EC strain and there was 100% accuracy in the classification of all spectra when LDA was applied. FT-IR spectral wavenumbers 1650 to 1390 cm(-1) were used to separate heat-killed and intact populations of L. monocytogenes. The FT-IR spectroscopy method allowed discrimination between strains that belong to the same EC. FT-IR is a highly discriminatory and reproducible method that can be used for the rapid subtyping of L. monocytogenes, as well as for the detection of live compared with dead populations of the organism. PRACTICAL APPLICATION: Fourier transform infrared (FT-IR) spectroscopy and multivariate statistical analysis can be used for L. monocytogenes source tracking and for clinical case isolate comparison during epidemiological investigations since the method is capable of differentiating epidemic clones and it uses a library of well-characterized strains. The FT-IR method is potentially less expensive and more rapid compared to genetic subtyping methods, and can be used for L. monocytogenes strain typing by food industries and public health agencies to enable faster response and intervention to listeriosis outbreaks. FT IR can also be applied for routine monitoring of the pathogen in food processing plants and for investigating postprocessing contamination because it is capable of differentiating heat-killed and viable L. monocytogenes populations. PMID- 24802120 TI - Smoking and weight among patients using clozapine. AB - BACKGROUND: Both obesity and smoking are common in schizophrenia patients taking clozapine, causing cardiovascular disease and premature deaths. METHODS: Two hundred and thirty-seven patients with schizophrenia or related psychoses treated with clozapine completed the Liverpool University Neuroleptic Assessment Scale (LUNSERS) and a questionnaire including current height, weight, changes therein and smoking status. AIMS: The aim of this study was to analyze weight and weight change in smoking and non-smoking patients taking clozapine. A possible interaction between obesity and smoking was explored. RESULTS: No association was found between weight change and smoking status during clozapine treatment. There was no significant difference in body mass index (BMI) between non-smokers and smokers. In the analysis of covariance (ANCOVA) with BMI as the dependent variable, the best fitting model comprised age, sex, intensity of sedation, and reported amount of smoking as explanatory variables (etap(2)= 0.116; P = 0.029; power = 0.750). None of the explanatory proportions of any single factor was significant. CONCLUSIONS: Estimated according to reported weight gain and BMI, no difference was found between smoking and non-smoking clozapine-treated patients. Number of cigarettes smoked explained BMI if age and sex were taken into account. This result is in line with the findings of some general population studies, where heavy smoking has been associated with a greater risk of obesity. PMID- 24802121 TI - Adolescent loneliness and psychiatric morbidity in the general population: Identifying "at risk" groups using latent class analysis. AB - BACKGROUND: Previous research has shown that loneliness is strongly associated with both physical and psychological ill health, particularly among adolescents. Factor analytic research has also shown that loneliness is a multi-dimensional construct, characterized by e.g. feelings of isolation, and relational and collective connectedness. While factor analytic representations of the phenomenon effectively illustrate the structure and form of the loneliness construct, they may not adequately capture its expression in the population within, among and across individuals. METHOD: The current study modelled the expression of loneliness among a population sample of Northern Irish adolescents using latent class analysis. Data from the Young Life and Times Survey (2011) was used to identify the fewest groups of adolescents in the population characterized by discrete and shared loneliness profiles based on their responses to the UCLA Loneliness Scale (UCLA-LS). Individual "at risk" status for psychiatric morbidity was then assessed on the basis of LCA-group membership. RESULTS: Four groups of adolescents were identified: 1) high loneliness, characterized predominantly by feelings of isolation, 2) intermediate loneliness (two groups), and a baseline group with low levels of loneliness. While all groups were more likely to screen positive for psychiatric morbidity compared with the baseline group, notable risk, however, was attributable to specific isolation experiences or disconnectedness, that characterized both the profiles of the high loneliness group and the similar, but less severe, intermediate loneliness group. CONCLUSIONS: Loneliness is distributed throughout the adolescent population; however, among a significant minority, loneliness is predominantly characterized by feelings of isolation and is strongly indicative of psychological ill health. PMID- 24802122 TI - Mortality among forensic psychiatric patients in Finland. AB - BACKGROUND: Both mental illness and criminality are associated with higher risk of early death, yet the mortality among forensic psychiatric patients who are affected by both mental illness and criminal behaviour has scarcely been studied. AIMS: To analyse the mortality among all patients who were committed to a compulsory forensic psychiatric hospital treatment in Finland between 1980 and 2009. Mortality was analysed according to the age when the patient was committed to forensic treatment. RESULTS: A total of 1253 patients were included, of which 153 were females and 1100 were males. The mean follow-up time in this study was 15.1 years, and 351 (28%) had died during the follow-up period. The standardized mortality rate (SMR) for the whole study group was 2.97 (95% CI 2.67-3.29). Among females the SMR was 3.62 (95% CI 2.57-5.09), and among males 2.91 (95% CI 2.61 3.25). The SMRs were higher when patients were committed to forensic treatment before the age of 40 years. CONCLUSION: This study showed an increased mortality among forensic psychiatric patients compared with the general population and the mortality was inversely proportional to the age when the treatment had begun. In contrast to the earlier studies, the mortality in this study was lower indicating that prolonged treatment may have an overall protective effect on forensic psychiatric patients. PMID- 24802123 TI - Behaviour problems and cortisol levels in very-low-birth-weight children. AB - Abstract Background. There are still diverging results concerning the behaviour of children with very-low-birth-weight (VLBW) and they have been questioned to display different levels of stress hormone than normal-birth-weight (NBW) children. Aims. This study examined behaviour and the stress hormone cortisol in children with VLBW at the ages of 7 and 9 years compared with children with NBW. Results. Fifty-one VLBW and 50 NBW children were studied with the Child Behavior Checklist. Cortisol rhythm was measured through saliva samples three times a day for 2 days. VLBW children displayed more behavioural problems than NBW children, specifically social and attention problems, although still within normal ranges. They showed lower cortisol levels both at 7 and 9 years of age. No strong association between behaviour and cortisol levels was shown. Conclusion. VLBW children display more behaviour problems compared with NBW children but both groups score are within the normal range. Down-regulation of their hypothalamic pituitary-adrenal (HPA) function in terms of lower cortisol levels is also noted. PMID- 24802124 TI - NF-kappaB-mediated integrin-linked kinase regulation in angiotensin II-induced pro-fibrotic process in cardiac fibroblasts. AB - AIMS: Cardiac fibrosis is a final outcome of many clinical conditions that lead to cardiac failure and is characterized by a progressive substitution of cellular elements by extracellular-matrix proteins, such as collagen type I, collagen type II, connective tissue growth factor (CTGF), etc. The aim of this study was to identify the mechanisms responsible for angiotensin II (Ang II)-stimulated cardiac fibrosis using rat neonatal cardiac fibroblasts. MAIN METHODS: Neonatal fibroblasts were transfected with IkappaBalpha mutant, constitutively active (ca) integrin-linked kinase (ILK), dominant negative of ILK and small interfering RNA (siRNA) of ILK in the presence and absence of Ang-II stimulation. The pro fibrotic gene expression and protein levels were determined by quantitative real time PCR and western blotting using their specific probes and antibodies. NF kappaB translocation was determined by immunocytochemistry and confocal microscopy images were analyzed. KEY FINDINGS: Our results indicate that overexpression of ILK promotes a pro-fibrotic process by upregulating collagen type I and CTGF genes via activation of nuclear factor-kappaB (NF-kappaB) in cardiac fibroblasts. Inactivation of either NF-kappaB by the super-repressor IkappaBalpha or ILK by siRNA significantly attenuates the pro-fibrotic process. Moreover, ILK overexpression triggers NF-kappaB-p65 translocation to the nucleus, and ILK inhibition prevents the translocation in cardiac fibroblasts stimulated with Ang II. SIGNIFICANCE: Our data suggest that the Ang II-stimulated pro fibrotic process is regulated by a complex mechanism involving crosstalk between ILK and NF-kappaB activation. This dual mechanism may play a critical role in the progression of cardiac fibrosis. PMID- 24802125 TI - Compound K protects pancreatic islet cells against apoptosis through inhibition of the AMPK/JNK pathway in type 2 diabetic mice and in MIN6 beta-cells. AB - AIMS: Compound K (CK) is known to possess anti-diabetic activities but the mechanism for this action is unknown. The present study observed the protective effect of CK on islet cell apoptosis through the AMP-activated protein kinase (AMPK) mediated C-Jun N-terminal kinase (JNK) pathway. MAIN METHODS: Treatment effect of CK on type 2 diabetic (T2D) mice and palmitate-induced MIN6 beta-cells injury was observed. Fasting plasma glucose, triacylglycerol, total cholesterol, insulin levels and glucose tolerance test were evaluated. The expression of AMPK and JNK was detected in islet and MIN6 cells. KEY FINDINGS: CK treatment (30 mg/kg) decreased fasting plasma glucose, triacylglycerol, total cholesterol, elevated plasma insulin levels and improved glucose tolerance in T2D mice. CK treatment attenuated islet cell apoptosis and caspase-3 activity accompanied by a decrease in AMPK and JNK activation. Meanwhile, CK treatment attenuated the palmitate-induced reduction in MIN6 beta-cell viability, apoptosis and caspase-3 activity and activation of AMPK and JNK. The AMPK activator AICAR attenuated the CK-mediated inhibition of palmitate-induced apoptosis. SIGNIFICANCE: These data suggest that CK treatment provides a beneficial anti-diabetic effect in mice with T2D and this protective effect may be mediated through prevention of beta-cell apoptosis via inhibition of the AMPK-JNK pathway. PMID- 24802127 TI - Monosodium glutamate, a food additive, induces depressive-like and anxiogenic like behaviors in young rats. AB - Monosodium glutamate (MSG) has been the target of research due to its toxicological effects. AIMS: We investigated the depressive- and anxiogenic-like behaviors in rats exposed to neonatal subcutaneous injection of MSG. The involvement of the serotonergic system, by measuring [(3)H] serotonin (5-HT) uptake in cerebral cortices, and the hypothalamic pituitary adrenal (HPA) axis, by determining serum adrenocorticotropic hormone (ACTH) and corticosterone levels, was also examined. MATERIALS AND METHODS: Male and female newborn Wistar rats were divided into control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 5th postnatal day. The behavioral tests [spontaneous locomotor activity, contextual fear conditioning, and forced swimming test (FST)] were performed from the 60th to 64th postnatal day. MSG-treated animals showed alteration in the spontaneous locomotor activity, an increase in the number of fecal pellets and the number of animal's vocalizations and urine occurrence, and a decrease in the grooming time. KEY FINDINGS: The MSG exposure increased the immobility time in the FST and the freezing reaction in the contextual fear conditioning. Additionally, MSG treatment increased the [(3)H]5-HT uptake in the cerebral cortices of rats and induced a deregulation of HPA axis function (by increasing serum ACTH and corticosterone levels). SIGNIFICANCE: In conclusion MSG-treated rats are more susceptible to develop anxiogenic- and depressive-like behaviors, which could be related to a dysfunction in the serotonergic system. PMID- 24802128 TI - Distribution study of tryptanthrin in rat tissues by HPLC and its relationship with meridian tropism of indigo naturalis in traditional Chinese medicine. AB - The aim of the present study is to characterize the distribution of tryptanthrin (TRYP) in rat tissues following oral administration at a dose of 100 mg/kg and its relationship with meridian tropism (MT) of indigo naturalis (IN) in traditional Chinese medicine (TCM). For quantitative analysis in biological samples, a sensitive, inexpensive and accurate high-performance liquid chromatographic method was developed and validated with 2-hydroxy acetophenone as internal standard, a Shimadzu C18 column and water-acetonitrile (55:45, v/v) as mobile phase. Acceptable intra-day and inter-day precision at high, medium and low concentration was acquired with RSD ranging from 0.87 to 5.22% and from 1.25 to 6.47%, respectively. Good assay and extraction recoveries were obtained with a single and relatively fast step to precipitate protein. The extraction recovery of TRYP ranged from 87.5 to 94.5 %. TRYP concentration was highest in the liver and remained for a much longer time than in other tissues. It could also be detected in kidney, lung, heart and spleen, but not in brain under the experimental conditions. The results confirmed the traditional knowledge of TCM that MT of IN belongs to the liver meridians and demonstrated that TRYP is one of the active constituents of the MT of IN. PMID- 24802126 TI - Effects of thiol antioxidant beta-mercaptoethanol on diet-induced obese mice. AB - AIMS: Obesity and insulin resistance are associated with increased oxidant stress. However, treatments of obese subjects with different types of antioxidants often give mixed outcomes. In this work, we sought to determine if long-term supplementation of a thiol antioxidant, beta-mercaptoethanol, to diet induced obese mice may improve their health conditions. MAIN METHODS: Middle-age mice with pre-existing diet-induced obesity were provided with low concentration beta-mercaptoethanol (BME) in drinking water for six months. Animals were assessed for body composition, gripping strength, spontaneous physical and metabolic activities, as well as insulin and pyruvate tolerance tests. Markers of inflammation were assessed in plasma, fat tissue, and liver. KEY FINDINGS: BME treated mice gained less fat mass and more lean mass than the control animals. They also showed increased nocturnal locomotion and respiration, as well as greater gripping strength. BME reduced plasma lipid peroxidation, decreased abdominal fat tissue inflammation, reduced fat infiltration into muscle and liver, and reduced liver and plasma C-reactive protein. However, BME was found to desensitize insulin signaling in vivo, an effect also confirmed by in vitro experiments. SIGNIFICANCE: Long-term supplementation of low dose thiol antioxidant BME improved functional outcomes in animals with pre-existing obesity. Additional studies are needed to address the treatment impact on insulin sensitivity if a therapeutic value is to be explored. PMID- 24802129 TI - Determination of sulfotransferase forms involved in the metabolic activation of the genotoxicant 1-hydroxymethylpyrene using bacterially expressed enzymes and genetically modified mouse models. AB - 1-Methylpyrene, a carcinogenic polycyclic aromatic hydrocarbon, forms benzylic DNA adducts, in particular N2-(1-methylpyrenyl)-2'-deoxyguanosine, in mice and rats. It is bioactivated via 1-hydroxymethylpyrene (1-HMP) to electrophilic 1 sulfooxymethylpyrene (1-SMP). In this study, we explored the role of individual mouse sulfotransferase (SULT) forms in this activation. First, we showed that all nine mouse SULTs tested were able to activate 1-HMP to a mutagen in the his- Salmonella typhimurium reversion test. Some activation was even observed with Sult2a3 and Sult5a1, orphan forms for which no substrates were identified hitherto. Subsequently, we used cytosolic preparations from tissues of four mouse lines (wild-type, Sult1a1-, Sult1d1-, and transgenic for human SULT1A1/2) for the activation of 1-HMP in the mutagenicity assay. The most prominent impacts of the genetic SULT status were 96% decrease in hepatic activation by Sult1a1 knockout, 99% decrease in renal activation by Sult1d1 knockout, and 100-fold increase in pulmonary activation by transgenic human SULT1A1/2. Finally, we treated the various mouse lines with 1-HMP (19.3 mg/kg, intraperitoneally), and then determined 1-SMP levels in plasma and DNA adducts in tissues. Transgenic human SULT1A1/2 strongly enhanced 1-SMP plasma levels and DNA adduct formation in the liver, lung, heart, and kidney but not in the colon. Sult1a1 and Sult1d1 knockout reduced plasma 1-SMP levels as well as DNA adduct formation in some tissues (strongest effects: 97% decrease in 1-SMP and 89% decrease in hepatic adducts in Sult1a1- mice). The adduct levels detected in various tissues did not accurately reflect the activation capacity of these tissues determined in vitro, probably due to the distribution of the reactive metabolite 1-SMP via the circulation. In conclusion, we demonstrated that many mouse SULT forms are able to activate 1 HMP. In vivo, we verified a prominent role of Sult1a1 in hepatic and renal adduct formation and a smaller but unambiguous role of Sult1d1, and demonstrated the strong impact of transgenic human SULT1A1/2. PMID- 24802130 TI - Nitrogen-doped porous carbon/Co3O4 nanocomposites as anode materials for lithium ion batteries. AB - A simple and industrially scalable approach to prepare porous carbon (PC) with high surface areas as well as abundant nitrogen element as anode supporting materials for lithium-ion batteries (LIBs) was developed. Herein, the N-doped PC was prepared by carbonizing crawfish shell, which is a kind of food waste with abundant marine chitin as well as a naturally porous structure. The porous structure can be kept to form the N-doped PC in the pyrolysis process. The N doped PC-Co3O4 nanocomposites were synthesized by loading Co3O4 on the N-doped PC as anode materials for LIBs. The resulting N-doped PC-Co3O4 nanocomposites release an initial discharge of 1223 mA h g(-1) at a current density of 100 mA g( 1) and still maintain a high reversible capacity of 1060 mA h g(-1) after 100 cycles, which is higher than that of individual N-doped PC or Co3O4. Particularly, the N-doped PC-Co3O4 nanocomposites can be prepared in a large yield with a low cost because the N-doped PC is derived from abundant natural waste resources, which makes it a promising anode material for LIBs. PMID- 24802131 TI - Sequential therapy with belimumab followed by rituximab in Sjogren's syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. AB - OBJECTIVES: The overexpression of B-cell activating factor (BAFF) in mucosa associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sjogren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated. METHODS: We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids, as well as with cyclophosphamide, azathioprine, plasma exchange, hyperbaric therapy, VAC therapy, prostacyclin, mycophenolate mofetil and surgery, had previously failed. Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab. RESULTS: This sequential belimumab rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years. CONCLUSIONS: Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS. PMID- 24802132 TI - Efficacy and potential microRNA mechanism for computed tomography-guided percutaneous radiofrequency ablation of primary lung cancer and lung metastasis from liver cancer. AB - BACKGROUND: The aim of this study was to evaluate comparatively the effectiveness of computed tomography-guided percutaneous radiofrequency ablation (CT-PRFA) for primary non-small cell lung cancer (NSCLC) and lung metastases from hepatocellular carcinoma (HCC) and to explore the potential miRNA mechanisms for the efficacy of CT-PRFA. METHODS: 14 patients pathologically diagnosed with NSCLC and 12 patients with lung metastases from HCC were enrolled in the study and underwent CT-PRFA. Clinical outcomes were compiled on the basis of review of medical records, imaging follow-up reports, and any biopsy-proved residual or recurrent disease. Real-time RT-PCR was used to quantify the selected miRNAs known to be play key roles in lung cancer. RESULTS: A total of 21 tumors were treated with umbrella-tip electrodes and spiral-tip electrodes were used for the remaining 8 tumors. The median follow-up was 13.5 months (range, 3-30 months) and no patient was lost to follow-up. The rate of technique efficacy for primary tumors was ~93% (13 of 14). Treatment was successful in 11 out of 12 (91.7%) lung metastases patients. Overall survival rate was 80.8% at 2 years, and cancer specific survival rate was 100% at 2 years. The tumor-free survival was 69.2% at 1 year and 26.9% at 2 years. Before PRFA, tumor suppressor let-7a and miR-34a were downregulated whereas oncomiR miR-21 was upregulated in primary tumors, and let-7a and miR-126 levels were downregulated whereas oncomiRs miR-21, miR-155 and miR-17-5p/miR-20b levels were upregulated in secondary tumors. This abnormal expression was normalized by CT-PRFA. Most notably, CT-PRFA failed to normalize the deregulated miRNAs in the non-survivors. CONCLUSIONS: CT-PRFA is a effective treatment for primary NSCLCs and secondary lung tumors from HCC and the efficacy may be related to its ability to normalize deregulated expression of miRNAs: upregulating tumor suppressor miRNAs and downregulating oncomiRs. PMID- 24802133 TI - Prickly poppies can get pricklier: ontogenetic patterns in the induction of physical defense traits. AB - Plant ontogeny is a common source of variation in defense and herbivory. Yet, few studies have investigated how the induction of physical defense traits changes across plant ontogeny. Physical defense traits are costly to produce, and thus, it was predicted that induction as a cost-saving strategy would be particularly favorable for seedlings, leading to ontogenetic declines in the inducibility of these traits. We tested for induction of three different physical defense traits (prickles, latex and leaf toughness) in response to mechanical defoliation and jasmonic acid application using prickly poppies (Argemone glauca and A. mexicana, Papaveraceae) as a model system. Genetic variation in the induction of physical defenses was tested using maternal sib-ships sampled from multiple populations. Both species induced higher densities of laminar prickles, although the magnitude of induction was much higher in the endemic Hawaiian prickly poppy, A. glauca, than in the cosmopolitan A. mexicana. The magnitude of prickle induction was also higher in young compared to older juvenile plant stages in A. glauca, demonstrating a strong role of ontogeny. Neither latex exudation nor leaf toughness was induced in either species. Although significant genetic variation was detected within and among populations for constitutive expression of physical defense traits in Argemone, there was no evidence for genetic variation in the induction of these traits. This study provides the first evidence for the induction of physical defenses in prickly poppies, emphasizing how an ontogenetically explicit framework can reveal new insights into plant defense. Moreover, this study illustrates how sister species comparisons between island vs. continental plants can provide new insights into plant functional and evolutionary ecology, highlighting a fruitful area for future research on more species pairs. PMID- 24802134 TI - Predicting peroxidase subcellular location by hybridizing different descriptors of Chou' pseudo amino acid patterns. AB - Peroxidases as universal enzymes are essential for the regulation of reactive oxygen species levels and play major roles in both disease prevention and human pathologies. Automated prediction of functional protein localization is rarely reported and also is important for designing new drugs and drug targets. In this study, we first propose a support vector machine (SVM)-based method to predict peroxidase subcellular localization. Various Chou' pseudo amino acid descriptors and gene ontology (GO)-homology patterns were selected as input features to multiclass SVM. Prediction results showed that the smoothed PSSM encoding pattern performed better than the other approaches. The best overall prediction accuracy was 87.0% in a jackknife test using a PSSM profile of pattern with width=5. We also demonstrate that the present GO annotation is far from complete or deep enough for annotating proteins with a specific function. PMID- 24802135 TI - A novel oncogenic role of inositol phosphatase SHIP2 in ER-negative breast cancer stem cells: involvement of JNK/vimentin activation. AB - Overexpression of SH2-containing-5'-inositol phosphatase-2 (SHIP2) correlates with poor survival in breast cancer. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here, we showed that the percentage of SHIP2(+) cells was positively correlated with that of CD24(-) CD44(+) cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24(-) CD44(+) subpopulation than the remaining subpopulation. Data mining of microarray analysis of 295 breast tumors showed a significant correlation of higher SHIP2 expression with distant metastasis. Examination of patient-derived mouse xenografts revealed that SHIP2 protein and its tyrosine 1135 phosphorylation were significantly higher in BCSCs, identified as CD24(-) CD44(+) or aldehyde dehydrogenase (ALDH(+)), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere forming efficiency, ALDH(+) subpopulation in vitro and tumorigenicity of BCSCs in vivo. Overexpression of SHIP2 enhanced the expression of epithelial-mesenchymal transition markers including vimentin (VIM), which was mainly expressed in ER negative breast cancer cells with higher level in mammospheres than monolayer culture. Ablation of c-Jun N-terminal kinase 1 (JNK1), JNK2, or VIM diminished the increased ALDH(+) population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than non-BCSCs and silencing of JNK suppressed SHIP2-mediated upregulation of VIM. Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2-induced phospho-JNK/VIM upregulation. In conclusion, SHIP2 plays a key role in BCSCs of ER-negative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs. PMID- 24802137 TI - Digital artery intravascular myopericytoma--a rare cause of a painful finger. PMID- 24802136 TI - Rumination and perceived impairment associated with depressive symptoms in a verbal adolescent-adult ASD sample. AB - The aim of this study was to examine the association between depressive symptoms and several psychosocial constructs (insight into autism symptoms, rumination, desire for social interaction, and satisfaction with social support) that may play a role in the development or maintenance of depression in verbally fluent adolescents and adults with ASD. Participants included 50 individuals with ASD and verbal IQ >= 70, aged 16-35 (sample size varied by measure). Elevated depressive symptoms on the Beck Depression Inventory, 2nd edition (BDI-II), were associated with greater self-perceived, autism-related impairments (n = 48), greater rumination (n = 21), and lower perceived social support (n = 37). Rumination tended to moderate the association between self-perceived autism symptoms and BDI-II scores (n = 21), and was significantly associated with ASD related insistence on sameness behaviors (n = 18). An unexpected relationship between depressive features and social participation and motivation will need to be clarified by longitudinal research. These and similar findings contribute to our understanding of the phenomenology of depression in ASD, which is critical to the development of practical prevention and treatment. PMID- 24802138 TI - L-dopa is a potent stimulator of cortisol in short children. AB - AIMS: In this study, we evaluated the diagnostic usefulness of oral L-dopa as a stimulatory agent for cortisol. METHODS: In 27 short children that were evaluated for possible growth hormone deficiency (GHD), the levels of serum GH and cortisol were determined after oral L-dopa administration and after i.m. glucagon administration. We defined cortisol concentrations >18 MUg/dl (496 nmol/l) as adequate response. Peak GH concentration <10 ng/ml in both tests defined GHD. RESULTS: Twenty-five out of the 27 children (93%) studied showed a normal cortisol response, i.e. a peak serum cortisol >18 MUg/dl in the L-dopa test, whereas 19 children (70%) had a normal cortisol response after stimulation with glucagon. In the children with normal cortisol response in both tests, the mean peak serum cortisol concentration was 28.7 (SD 1.59) after L-dopa and 26.65 (SD 1.26) MUg/dl after glucagon administration. There was no statistically significant difference in peak serum cortisol response to L-dopa between GH deficient and GH-sufficient children [25.90 (SD 4.9) vs. 29.87 (SD 9.9) MUg/dl, respectively]. CONCLUSIONS: These results clearly suggest that L-dopa administration is a potent stimulus for cortisol secretion at least in short children. PMID- 24802139 TI - Lower arm electromyography (EMG) activity detection using local binary patterns. AB - This paper presents a new electromyography activity detection technique in which 1-D local binary pattern histograms are used to distinguish between periods of activity and inactivity in myoelectric signals. The algorithm is tested on forearm surface myoelectric signals occurring due to hand gestures. The novel features of the presented method are that: 1) activity detection is performed across multiple channels using few parameters and without the need for majority vote mechanisms, 2) there are no per-channel thresholds to be tuned, which makes the process of activity detection easier and simpler to implement and less prone to errors, 3) it is not necessary to measure the properties of the signal during a quiescent period before using the algorithm. The algorithm is compared to other offline single- and double-threshold activity detection methods and, for the data sets tested, it is shown to have a better overall performance with greater tolerance to the noise in the real data set used. PMID- 24802140 TI - Bistetracene: an air-stable, high-mobility organic semiconductor with extended conjugation. AB - We report the synthesis and characterization of "bistetracene", an unconventional, linearly extended conjugated core with eight fused rings. The annellation mode of the system allows for increased stability of the conjugated system relative to linear analogues due to the increased number of Clar aromatic sextets. By attaching the appropriate solubilizing substituents, efficient molecular packing with large transfer integrals can be obtained. The electronic structure calculations suggest these large polycyclic aromatic hydrocarbons (PAHs) exhibit excellent intrinsic charge transport properties. Charge carrier mobilities as large as 6.1 cm(2) V(-1) s(-1) and current on/off ratios of 10(7) were determined experimentally for one of our compounds. Our study provides valuable insight into the design of unconventional semiconductor compounds based on higher PAHs for use in high-performance devices. PMID- 24802142 TI - Thermal body patterns for healthy Brazilian adults (male and female). AB - The aim of this study was to establish the skin temperature (Tsk) thermal profile for the Brazilian population and to compare the differences between female and male Brazilian adults. A total of 117 female and 103 male were examined with a thermographic camera. The Tsk of 24 body regions of interest (ROI) were recorded and analyzed. Male Tsk results were compared to female and 10 ROI were evaluated with respect to the opposite side of the body (right vs. left) to identify the existence of significant contralateral Tsk differences (DeltaTsk). When compared right to left, the largest contralateral DeltaTsk was 0.3 degrees C. The female vs. male analysis yielded significant differences (p<0.05) in 13 of the 24 ROI. Thigh regions, both ventral and dorsal, had the highest DeltaTsk by sex (~1.0 degrees C). Tsk percentile below P5 or P10 and over P90 or P95 may be used to characterize hypothermia and hyperthermia states, respectively. Thermal patterns and Tsk tables were established for Brazilian adult men and women for each ROI. There is a low Tsk variation between sides of the body and gender differences were only significant for some ROIs. PMID- 24802143 TI - Effects of temperature and modified atmospheres on diapausing 5th instar codling moth metabolism. AB - The oxygen and capacity limitation of thermal tolerance (OCLTT) has been established in aquatic insect larvae, but OCLTT has not been shown to generally apply to terrestrial insects. Previous research indicates that heat treatments in combination with high concentrations of carbon dioxide and low concentrations of oxygen may be effective for controlling diapausing codling moth, a quarantine pest in walnuts, but treatment requires long times and the killing mechanism is unknown. In this study, the effects of temperature and modified atmospheres on metabolism in diapausing 5th instar codling moth (Cydia pomonella) was investigated with multi-channel differential scanning calorimeters, one equipped with an oxygen sensor. O2 consumption and metabolic heat rates in air were measured simultaneously at isothermal temperatures from 5 to 50 degrees C at 5 degrees C intervals. Both rates increased with increasing temperatures from 5 to 40 degrees C. The ratio of metabolic heat rate to O2 consumption rate at temperatures <=40 degrees C shows that a portion of the metabolic heat is from normal anabolic reactions of metabolism. At 45 and 50 degrees C in air, O2 consumption and metabolic heat rates dropped to near zero. These results indicate that treatment of walnuts in air at >45 degrees C for a short period of time (minutes) is effective in killing diapausing 5th instar codling moth larvae. Continuous heating scans at 0.4 degrees C/min were used to measure metabolic heat rates from 10 to 50 degrees C with air and modified atmospheres with lowered oxygen and high carbon dioxide. A rapid increase was observed in heat rates above 40 degrees C in scans with O2>=11%. Taken together with the isothermal results showing no metabolic heat production or oxygen uptake at 45 and 50 degrees C, these results demonstrate that thermal damage to cell membranes and loss of control of oxidation reactions is the lethal mechanism at high temperature when O2>=11%. The data from scans with O2<=2% and high CO2 show the effects of oxygen limitation as postulated by the OCLTT. However, CO2 anesthesia appears to protect larvae from oxygen limitation at high temperature. These results show that treatment of walnuts in air at temperatures >45 degrees C will rapidly kill diapausing 5th instar codling moths. PMID- 24802144 TI - Breaking the temperature-size rule: thermal effects on growth, development and fecundity of a crustacean from temporary waters. AB - The temperature-size rule (TSR) is a well-established phenomenon to describe the growth response of ectotherms to temperature by which individuals maintained at low temperatures grow more slowly, but attain a larger size upon maturity. Although there are adaptive and non-adaptive theories about the plasticity of body size in response to temperature, these cannot be applied to all ectotherms, and little is known about the changes in growth and development rates through ontogeny. The ostracod species Heterocypris bosniaca, an inhabitant of freshwater temporary ponds, was used to examine the growth and development rates of its nine growth stages and female fecundity at four different temperatures (15 degrees C, 20 degrees C, 25 degrees C and 30 degrees C). The development rate of this species accelerates with increasing temperature, reaching a maximum value at 25 degrees C. The growth factor has a reverse-TSR in younger instars, and the typical TSR is followed only in the last two moults, resulting in non-monotonic response of adult size to temperature. Fecundity (total offspring per female) was not directly related to adult size and was generally higher at lower temperatures. Our results agree with recent research showing that the TSR may vary during ontogeny, and may not be a general trend in ostracod species from temporary waters. Indeed, adult carapace size seems to follow the pattern of a thermal reaction norm, probably influenced by the reduction of oxygen bioavailability at low temperature and the drastic increase in metabolic demand at the upper extreme of the thermal gradient. PMID- 24802141 TI - New tags for recombinant protein detection and O-glycosylation reporters. AB - Monoclonal antibodies (mAbs), because of their unique specificity, are irreplaceable tools for scientific research. Precise mapping of the antigenic determinants allows the development of epitope tagging approaches to be used with recombinant proteins for several purposes. Here we describe a new family of tags derived from the epitope recognized by a single highly specific mAb (anti-roTag mAb), which was obtained from a pool of mAbs reacting with the rotavirus nonstructural protein 5 (NSP5). The variable regions of the anti-roTag mAb were identified and their binding capacity verified upon expression as a single chain/miniAb. The minimal epitope, termed roTag, was identified as a 10 amino acid sequence (SISSSIFKNE). The affinity of the anti-roTag/roTag interaction was found to be comparable to that of the anti-SV5/SV5 tag interaction. roTag was successfully used for detection of several recombinant cytosolic, secretory and membrane proteins. Two additional variants of roTag of 10 and 13 amino acids containing O-glycosylation susceptible sites (termed OG-tag and roTagO) were constructed and characterised. These tags were useful to detect proteins passing through the Golgi apparatus, the site of O-glycosylation. PMID- 24802145 TI - The effects of fasting on swimming performance in juvenile qingbo (Spinibarbus sinensis) at two temperatures. AB - We measured the following variables to investigate the effects of fasting and temperature on swimming performance in juvenile qingbo (Spinibarbus sinensis): the critical swimming speed (Ucrit), resting metabolic rate (MO2rest) and active metabolic rate (MO2active) of fish fasting for 0 (control), 1, 2 and 4 weeks at low and high acclimation temperatures (15 and 25 degrees C). Both fasting treatment and temperature acclimation had significant effects on all parameters measured (P<0.05). Fasting at the higher temperature had a negative effect on all measured parameters after 1 week (P<0.05). However, when acclimated to the lower temperature, fasting had a negative effect on Ucrit until week 2 and on (MO2rest), (MO2active) and metabolic scope (MS, (MO2active)-(MO2rest)) until week 4 (P<0.05). The values of all parameters at the lower temperature were significantly lower than those at the higher temperature in the identical fasting period groups except for (MO2rest) of the fish that fasted for 2 weeks. The relationship between fasting time (T) and Ucrit was described as Ucrit(15)= 0.302T(2)-0.800T+35.877 (r=0.781, n=32, P<0.001) and Ucrit(25)=0.471T(2) 3.781T+50.097 (r=0.766, n=32, P<0.001) at 15 and 25 degrees C, respectively. The swimming performance showed less decrease in the early stage of fasting but more decrease in the later stage at the low temperature compared to the high temperature, which might be related to thermal acclimation time, resting metabolism, respiratory capacity, energy stores, enzyme activity in muscle tissue and energy substrate utilization changes with fasting between low and high temperatures. The divergent response of the swimming performance to fasting in qingbo at different temperatures might be an adaptive strategy to seasonal temperature and food resource variation in their habitat. PMID- 24802146 TI - Phenotypic plasticity in thermal tolerance in the Glanville fritillary butterfly. AB - Ambient temperature is an ubiquitous environmental factor affecting all organisms. Global climate change increases temperature variation and the frequency of extreme temperatures, which may pose challenges to ectotherms. Here, we examine phenotypic plasticity to temperature and genotypic effects on thermal tolerance in the Glanville fritillary butterfly (Melitaea cinxia). We found no significant difference in heat or cold tolerance in populations originating from a continental climate in China and from Finland with moderate temperature variation. Acclimation to large-amplitude temperature variation increased heat tolerance in both populations, but decreased cold tolerance and increased hsp70-2 expression in the Chinese population only. The latter result indicates a genotypic effect in the response to temperature variation. In the Finnish population, a non-synonymous SNP in the phosphoglucose isomerase (Pgi) gene was associated with heat knock-down time. PMID- 24802147 TI - Unusual change in activity pattern at cool temperature in a reptile (Sphenodon punctatus). AB - Animals that can be active both during day and night offer unique opportunities to identify factors that influence activity pattern. By experimental manipulations of temperatures under constant photoperiod, we aimed to determine if emergence, activity and thermoregulatory behaviour of juvenile tuatara (Sphenodon punctatus) varied at different temperatures (20 degrees C, 12 degrees C and 5 degrees C). To help clarify its activity pattern, we compared tuatara with two lizard species endemic of the South Island of New Zealand for which activity pattern is known and clearly defined: the nocturnal common gecko Woodworthia "Otago/Southland" and the diurnal McCann's skink Oligosoma maccanni. Tuatara showed similar responses to both species of lizards. Similar to the diurnal skinks, tuatara emerged quickly at 20 degrees C and 12 degrees C while nocturnal geckos took more time to emerge. Like nocturnal geckos, tuatara continued to be active at 5 degrees C, but only during the day. Interestingly, tuatara shifted from diurno-nocturnal activity at 20 degrees C and 12 degrees C to being strictly diurnal at 5 degrees C. We suggest that this temperature dependent strategy maximises their survival during cold periods. PMID- 24802148 TI - Ways to measure body temperature in the field. AB - Body temperature (Tb) represents one of the key parameters in ecophysiological studies with focus on energy saving strategies. In this study we therefore comparatively evaluated the usefulness of two types of temperature-sensitive passive transponders (LifeChips and IPTT-300) and one data logger (iButton, DS1922L) mounted onto a collar to measure Tb in the field. First we tested the accuracy of all three devices in a water bath with water temperature ranging from 0 to 40 degrees C. Second, we evaluated the usefulness of the LifeChips and the modified iButtons for measuring Tb of small heterothermic mammals under field conditions. For this work we subcutaneously implanted 14 male edible dormice (Glis glis) with transponders, and equipped another 14 males with data loggers to simultaneously record Tb and oxygen consumption with a portable oxygen analyzer (Oxbox). In one individual we recorded Tb with both devices and analyzed recorded Tb patterns. LifeChips are able to measure temperature within the smallest range from 25 to 40 degrees C with an accuracy of 0.07+/-0.12 degrees C. IPTT-300 transponders measured temperature between 10 and 40 degrees C, but accuracy decreased considerably at values below 30 degrees C, with maximal deviations of nearly 7 degrees C. An individual calibration of each transponder is therefore needed, before using it at low Tbs. The accuracy of the data logger was comparatively good (0.12+/-0.25 degrees C) and stable over the whole temperature range tested (0-40 degrees C). In all three devices, the repeatability of measurements was high. LifeChip transponders as well as modified iButtons measured Tb reliably under field conditions. Simultaneous Tb-recordings in one edible dormouse with an implanted LifeChip and a collar-mounted iButton revealed that values of both measurements were closely correlated. Taken together, we conclude that implanted temperature-sensitive transponders represent an appropriate and largely non-invasive method to measure Tb also under field conditions. PMID- 24802149 TI - Effects of whole-body cryotherapy duration on thermal and cardio-vascular response. AB - Whole-body cryotherapy (WBC) is the exposure of minimally dressed participants to very cold air, either in a specially designed chamber (cryo-chamber) or cabin (cryo-cabin), for a short period of time. Practitioners are vague when it comes to recommendations on the duration of a single session. Recommended exposure for cryo-chamber is 150s, but no empirically based recommendations are available for a cryo-cabin. Therefore the aim of this study was to examine thermal and cardio vascular responses after 90, 120, 150 and 180s of WBC in a cryo-cabin. Our hypothesis was that skin temperature would be significantly lower after longer exposers. Twelve male participants (age 23.9+/-4.2 years) completed four WBC of different durations (90, 120, 150 and 180s) in a cryo-cabin. Thermal response, heart rate and blood pressure were measured prior, immediately after, 5min after and 30min after the session. Skin temperature differed significantly among different durations, except between 150 and 180s. There was no significant difference in heart rate and blood pressure. Thermal discomfort during a single session displayed a linear increase throughout the whole session. Our results indicate that practitioners and clinicians using cryo-cabin for WBC do not need to perform sessions longer than 150s. We have shown that longer sessions do not substantially affect thermal and cardio-vascular response, but do increase thermal discomfort. PMID- 24802150 TI - NMR- and MS-based metabolomics: various organ responses following naphthalene intervention. AB - Naphthalene, a polycyclic aromatic hydrocarbon, is a ubiquitous environmental pollutant capable of causing illness. In this study, we deconvoluted the metabolites related to naphthalene intervention in various organs by using nuclear magnetic resonance (NMR) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Male ICR mice were intraperitoneally dosed with olive oil (vehicle), and a low dose and a high dose (100 and 200 mg kg(-1) body wt, respectively) of naphthalene. After 48 h, the lungs, liver, and kidneys were collected for analysing the metabolic responses. The metabolites were extracted and non-targeted profiled using NMR. Low NMR resolution limited the identification of the hydrophobic metabolites. Therefore, LC-MS/MS-based focus lipidomics was applied to profile phosphorylcholine-containing lipids and sphingolipids. Chemometric analysis revealed that succinate and lactate were significantly increased in the lungs, suggesting that energy metabolisms and antioxidation were increased following naphthalene treatment. In the liver, anti oxidative stress-related metabolites increased, enabling the oxidative stress during naphthalene biotransformation and detoxification to be overcome. The elevation of glutathione protected kidneys from reactive-naphthalene-metabolite induced injury. Significant alteration of hydrophobic metabolites (membrane constituents) revealed lung and liver were the target organs of naphthalene treatment. MS data demonstrated that phosphatidylcholine (PC) and ceramide species were significantly altered in the lungs and liver, whereas only PC was observed in the kidneys. Elevated numbers of unsaturated bonds and fatty acyl chains in both ceramides and PCs were determined to reduce cellular membrane rigidity and facilitating the trafficking of recovery elements into the cell for rejuvenation. To conclude, the complementary results of NMR- and MS-based metabolomics enabled the characterization of naphthalene-induced changes in various organs. PMID- 24802151 TI - Mono-6A-(4-methoxybutylamino)-6A-beta-cyclodextrin as a chiral selector for enantiomeric separation. AB - A new member of the family of methoxylalkylamino monosubstituted beta cyclodextrins, mono-6(A)-(4-methoxybutylamino)-6(A)-beta-cyclodextrin, has been developed as a chiral selector for enantioseparation in capillary electrophoresis. This amino cyclodextrin exhibited good enantioselectivities for 16 model acidic racemates including three dansyl amino acids at an optimum pH of 6.0. Excellent chiral resolutions over six were obtained for alpha-hydroxy acids and 2-phenoxypropionic acids with 3.0 mM chiral selector. The good chiral recognition for alpha-hydroxyl acids was attributed to inclusion complexation, electrostatic interactions, and hydrogen bonding. The hydrogen-bonding-enhanced chiral recognition was revealed by NMR spectroscopy. The chiral separation of acidic racemates was further improved with the addition of methanol (<=10 vol%) as an organic additive. PMID- 24802152 TI - Reliability of nerve function assessments for people with peripheral neuropathy. AB - Examining degenerative sensory and reflexive activity among people with peripheral neuropathy (PN) is important for clinical examinations and understanding relevant neural impairments. However, other than the test of presynaptic inhibition, the reliability of other related tests is largely unknown. The purpose of this project was to examine the test-retest reliability of lower extremity sensory and reflexive measures in people with PN. Twelve participants (8 women, 4 men, age = 72.5 +/- 9.2 years) diagnosed with PN were assessed on two occasions at least 7 d apart. Plantar sensitivity, H-reflex and active and passive ankle proprioception (AAP and PAP) were tested. Paired student's t-test and Intraclass correlation coefficients (ICC) were used for statistical analysis. Significant difference was observed in AAP at 0o position (p = 0.04). No other significant differences were observed. Moderate to high reliability was observed at measures of Plantar sensitivity (0.92), peak to peak H (0.71) and M (0.84) waves, latency between H and M (0.78), H-Index (0.85), AAP (0.62) and PAP index (0.60). Low reliability was observed of other parameters. The measures of Hmax, Mmax, latency, H-Index, plantar sensitivity and AAP & PAP indices of proprioception tests can be measured reliably for further study in this population. PMID- 24802153 TI - Smoke signals: evidence grows in tobacco's effects on cancer patients. PMID- 24802154 TI - Women who adhere to cancer prevention guidelines face lower risk. PMID- 24802155 TI - Diabetes drug may activate molecule that triggers cancer growth. PMID- 24802156 TI - Acute hypercortisolism: what can the surgeon offer? AB - Rapid onset or acute hypercortisolism is a rare critical illness requiring emergency management. The majority of patients will have underlying malignancy with surgery an obvious choice in the minority with resectable disease. For those with unresectable disease, medical management alone has been the traditional approach. However, this often proves inadequate raising interest in the role of surgery as palliation in this setting. Patient selection, timing of surgery and optimal surgical technique are areas of current controversy with little literature available to provide answers. Decisions regarding management of patients with acute hypercortisolism are complex, and these patients are best managed in a subspecialized setting. PMID- 24802157 TI - Urine specimen detection of zolpidem use in patients with pain. AB - This study examined zolpidem and concurrent opioid, benzodiazepine, other central nervous system (CNS) depressants, and alcohol use. Urine specimens were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Specimens were tested for zolpidem (n = 71,919) and separated into a provider-reported medication list documenting (n = 5,257) or not documenting zolpidem use (n = 66,662). Zolpidem positive specimens were further separated into reported and unreported use cohorts. The total number of zolpidem-positive specimens in the reported and unreported use cohorts was 3,391 and 3,190, respectively. Non-informed prescribers were 4.4% (3,190/71,919) among the general population and 48.5% (3,190/6,581) when only zolpidem users were considered. In the zolpidem user population, the most common concurrent opioids in both cohorts were hydrocodone and oxycodone. Alprazolam and clonazepam were higher in the unreported use cohort (P <= 0.05). The unreported use cohort also had a higher detection of zolpidem plus a benzodiazepine (49.7 vs. 46%; P <= 0.05), zolpidem plus an opioid and a benzodiazepine (40.8% vs. 37.4%; P <= 0.05) and zolpidem plus an opioid, a benzodiazepine, and an other CNS depressant (12.9 vs. 10.9%; P <= 0.05). Concurrent use of zolpidem, an opioid, a benzodiazepine and an other CNS depressant is prevalent in a pain patient population. PMID- 24802158 TI - Quantitative mass barcode-like image of nicotine in single longitudinally sliced hair sections from long-term smokers by matrix-assisted laser desorption time-of flight mass spectrometry imaging. AB - The matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometric technique (IMS) offered a new breakthrough perspective in the analysis of drug abuse in forensic science; however, it only produced barcode like images, semi-quantitative analysis. In order to develop intermittent monitoring by this IMS for forensic and medical sciences, it is important to quantitatively measure the contents of longitudinally sliced hair sections. We developed quantitative imaging mass spectrometry (QIMS) of nicotine (NC) in longitudinally sliced hairs by MALDI-IMS with the selected reaction monitoring mode using a labeled NC ((13)C3-NC) standard for the serially chronological monitoring and traceability of NC intake in heavy smokers. The calibration curve of NC/(13)C3-NC was virtually a linear equation at ranges from 1 to 50 ng/mL, the slope was 0.020, and the intercept was almost 0.023 and the R(2) was 0.9965. The limit of quantitation of NC was calculated as 1.6 ng/mg hair (an average weight of the hair would be assumed 0.06 mg/cm) by QIMS. Moreover, NC concentrations in two separate heavy smokers (n = 3) were 8.5 +/- 1.2 and 34.5 +/- 2.8 ng/mg hair, respectively, and covariations were ~10% using a single hair. Quantitative mass barcode-like image of sliced section of hair allowed for the quantitative assessment of NC concentrations in long-term smokers similar to drugs and medicines during drug histories. PMID- 24802159 TI - Improved buprenorphine immunoassay performance after urine treatment with beta glucuronidase. AB - Buprenorphine (BUP), a semi-synthetic opioid analgesic, is increasingly prescribed for the treatment of chronic pain and opioid dependence. Urine immunoassay screening methods are available for monitoring BUP compliance and misuse; however, these screens may have poor sensitivity or specificity. We evaluated whether the pretreatment of urine with beta-glucuronidase (BG) improves the sensitivity and overall accuracy of three BUP enzyme immunoassays when compared with liquid chromatography-tandem mass spectrometry (LC-MS-MS). Urine samples sent to our laboratories for BUP testing (n = 114) were analyzed before and after BG pretreatment by cloned enzyme donor immunoassay (CEDIA), enzyme immunoassay (EIA) and homogenous EIA (HEIA) immunoassays using a common 5 ng/mL cutoff. Total BUP and norbuprenorphine (NBUP) concentrations were measured by LC MS-MS as the reference method. Urine BG pretreatment improved EIA, HEIA and CEDIA sensitivities from 70, 82 and 94%, respectively, to 97% for each of the three methods, when compared with LC-MS-MS. While the specificity of the EIA and HEIA remained 100% after BG pretreatment, the specificity of the CEDIA decreased from 74 to 67%. Urine pretreatment with BG is recommended to improve sensitivity of the EIA and HEIA BUP screening methods. PMID- 24802160 TI - High-performance multipanel biosensors based on a selective integration of nanographite petals. AB - We report the first selective growth of nanographite petals and various carbon nanomaterials onto a multipanel electrochemical platform. Different types of nanomaterials can be obtained by fine-tuning the growth parameters of the chemical vapor deposition (CVD) process. First, absolute novelty is the catalytic CVD selective growth of different carbon nanomaterials only on the working electrodes of the platform. A second novelty is the growth obtained at complementary metal-oxide-semiconductor compatible temperatures. These novel electrodes have been incorporated in sensors in which performance characteristics improve with the content of nanostructures. Unprecedented sensing parameters with respect to both direct and enzyme-mediated electrochemical biodetection have been obtained. PMID- 24802161 TI - Improved cyclopropanation activity of histidine-ligated cytochrome P450 enables the enantioselective formal synthesis of levomilnacipran. AB - Engineering enzymes capable of modes of activation unprecedented in nature will increase the range of industrially important molecules that can be synthesized through biocatalysis. However, low activity for a new function is often a limitation in adopting enzymes for preparative-scale synthesis, reaction with demanding substrates, or when a natural substrate is also present. By mutating the proximal ligand and other key active-site residues of the cytochrome P450 enzyme from Bacillus megaterium (P450-BM3), a highly active His-ligated variant of P450-BM3 that can be employed for the enantioselective synthesis of the levomilnacipran core was engineered. This enzyme, BM3-Hstar, catalyzes the cyclopropanation of N,N-diethyl-2-phenylacrylamide with an estimated initial rate of over 1000 turnovers per minute and can be used under aerobic conditions. Cyclopropanation activity is highly dependent on the electronic properties of the P450 proximal ligand, which can be used to tune this non-natural enzyme activity. PMID- 24802162 TI - More than charged base loss--revisiting the fragmentation of highly charged oligonucleotides. AB - Tandem mass spectrometry is a well-established analytical tool for rapid and reliable characterization of oligonucleotides (ONs) and their gas-phase dissociation channels. The fragmentation mechanisms of native and modified nucleic acids upon different mass spectrometric activation techniques have been studied extensively, resulting in a comprehensive catalogue of backbone fragments. In this study, the fragmentation behavior of highly charged oligodeoxynucleotides (ODNs) comprising up to 15 nucleobases was investigated. It was found that ODNs exhibiting a charge level (ratio of the actual to the total possible charge) of 100% follow significantly altered dissociation pathways compared with low or medium charge levels if a terminal pyrimidine base (3' or 5') is present. The corresponding product ion spectra gave evidence for the extensive loss of a cyanate anion (NCO(-)), which frequently coincided with the abstraction of water from the 3'- and 5'-end in the presence of a 3'- and 5' terminal pyrimidine nucleobase, respectively. Subsequent fragmentation of the M NCO(-) ion by MS(3) revealed a so far unreported consecutive excision of a metaphosphate (PO3 (-))-ion for the investigated sequences. Introduction of a phosphorothioate group allowed pinpointing of PO3 (-) loss to the ultimate phosphate group. Several dissociation mechanisms for the release of NCO(-) and a metaphosphate ion were proposed and the validity of each mechanism was evaluated by the analysis of backbone- or sugar-modified ONs. PMID- 24802163 TI - Modality effects in paced serial addition task: differential responses to auditory and visual stimuli. AB - Paced Auditory Serial-Addition Task (PASAT) is a complex task commonly used to examine patients with diffuse brain damage. A visual version of the neuropsychological test (Paced Visual Serial-Addition Task, PVSAT) has also been introduced to clinical practice, and both versions were adapted to be used in neuroimaging, namely functional magnetic resonance imaging (fMRI). The aim of our work was direct comparison of auditory and visual versions of the paced serial addition test (PASAT/PVSAT) in a within-subject and within-session study and description of the commonalities and differences in both activated and deactivated brain regions. Twenty young adult right-handed healthy volunteers participated in the study and underwent whole-brain fMRI examination during PASAT and PVSAT performance. Higher-level statistical analysis was performed to generate group mean activation and deactivation maps for both tasks, their conjunctions and differences across modalities. In PASAT/PVSAT activation conjunction analysis, we confirmed the existence of a modality-independent neural network similar to working memory tasks and to previous PASAT or PVSAT studies. In PASAT/PVSAT deactivation conjunction analysis, we observed a rather symmetrical extensive pattern of deactivated regions, overlapping the default mode network. Significant differences between PASAT and PVSAT were found in the right frontal eye field (FEF) and bilaterally in the striate and extrastriate cortices. Activation in one task and deactivation in the other jointly contributed to significant differences in all occipital and occipitotemporal regions. Both tasks activated right FEF, but activation during PASAT was significantly stronger than during PVSAT. Between-modality differences should be considered when preparing and interpreting neuroimaging experiments. PMID- 24802164 TI - Enhanced immobilization of gold nanoclusters on graphite. AB - The immobilization of individual biological molecules by metal nanoparticles requires that the particles themselves be immobilized. We introduce a new technique for immobilization of gold clusters based on their binding to small tunnels in a graphite support, themselves created by the implantation of small clusters. These tunnels are shown to perform as more effective cluster immobilization sites than point defects on the surface of graphite. The method is tested with atomic force microscopy (AFM) (both contact and noncontact mode) scanning. Size-selected clusters with 923, 561, 309, and 147 atoms have been immobilized and imaged with high-resolution, noncontact AFM. PMID- 24802165 TI - Identifying risk of readmission in hospitalized elderly adults through inpatient medication exposure. AB - OBJECTIVE: To use electronic health record (EHR) data to examine the association between inpatient medication exposure and risk of hospital readmission. DESIGN: Retrospective, observational study. SETTING: Tertiary and quaternary care academic health system in Durham, North Carolina. PARTICIPANTS: All individuals aged 60 and older who were residents of Durham County, North Carolina and were hospitalized and discharged alive from Duke University Hospital between 2007 and 2009 (N = 4,627). MEASUREMENTS: Independent variables were inpatient exposure to individual medication classes. Primary outcome was readmission to a Duke Health System hospital within 30 days. RESULTS: Readmission rate was 21% (n = 955). In adjusted models, exposure to anticonvulsants (odds ratio OR 1.26, 95% confidence interval (CI) = 1.08-1.48), benzodiazepines (OR = 1.23, 95% CI = 1.04-1.44), corticosteroids (OR = 1.26, 95% CI = 1.07-1.50), and opioids (OR = 1.25, 95% CI = 1.06-1.47) was associated with greater likelihood of readmission. Exposure to antidepressants (OR = 1.85, 95% CI = 1.16-2.96) and opioids on the cardiology service (OR = 1.76, 95% CI = 1.01-3.07) and exposure to opioids on the medicine service (OR = 1.94, 95% CI = 1.17-3.22) were associated with greater odds of readmission than for individuals on the surgery service. CONCLUSION: Exposure of hospitalized elderly adults to certain medication classes was associated with greater likelihood of readmission. Incorporating medication data from EHRs may improve the performance of hospital readmission prediction models. PMID- 24802166 TI - Suppressor of cytokine signaling (SOCS) 2 attenuates renal lesions in rats with diabetic nephropathy. AB - Diabetic nephropathy (DN) involves damage to the kidney caused by diabetes. It is characterized by renal hypertrophy, tubular atrophy/dilation and glomerular hyperfiltration. Suppressor of cytokine signaling (SOCS) 2 has recently been indicated to be involved in the pathogenesis of DN, however, the exact regulatory mechanisms remain unclear. This study was conducted to explore the role of SOCS2 in the development and progress of DN in a rat model of streptozocin (STZ) induced diabetes. Recombinant adenoviruses expressing SOCS2 were used to upregulate the expression of SOCS2 in the kidneys of diabetic rats. Our results demonstrated that intrarenal injection of SOCS2 adenoviruses reduced STZ-induced renal lesions, including renal/glomerular hypertrophy, glomerular hyperfiltration, aberrant inflammation and fibrosis. Increased expression levels of proinflammatory proteins (monocyte chemoattractant protein-1, tumor necrotic factor-alpha and interleukin-6) and profibrotic proteins (transforming growth factor-beta, collagen IV and fibronectin) in the diabetic kidneys were decreased after SOCS2 gene delivery. Additionally, adenovirus-mediated upregulation of renal SOCS2 markedly inhibited STZ-induced phosphorylation increases of Janus kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, STAT5 and extracellular receptor-activated kinase (ERK) 1/2. In summary, the present research demonstrates that SOCS2 reduces renal lesions associated with diabetes in rats. PMID- 24802167 TI - Proximal ADMM for multi-channel image reconstruction in spectral X-ray CT. AB - The development of spectral X-ray computed tomography (CT) using binned photon counting detectors has received great attention in recent years and has enabled selective imaging of contrast agents loaded with K-edge materials. A practical issue in implementing this technique is the mitigation of the high-noise levels often present in material-decomposed sinogram data. In this work, the spectral X ray CT reconstruction problem is formulated within a multi-channel (MC) framework in which statistical correlations between the decomposed material sinograms can be exploited to improve image quality. Specifically, a MC penalized weighted least squares (PWLS) estimator is formulated in which the data fidelity term is weighted by the MC covariance matrix and sparsity-promoting penalties are employed. This allows the use of any number of basis materials and is therefore applicable to photon-counting systems and K-edge imaging. To overcome numerical challenges associated with use of the full covariance matrix as a data fidelity weight, a proximal variant of the alternating direction method of multipliers is employed to minimize the MC PWLS objective function. Computer-simulation and experimental phantom studies are conducted to quantitatively evaluate the proposed reconstruction method. PMID- 24802168 TI - Highly ordered molecular films on Au(111): the N-heteroacene approach. AB - This study presents an innovative synthesis of dihydrotetraazapentacene (DHTAP) and the scanning tunneling microscopy (STM) investigation of the initial stages of its growth on Au(111). We were able to demonstrate that, up to the fourth monolayer, the DHTAP films show a high structural order and growths in perfect epitaxy. This behavior can be unequivocally attributed to the stabilizing effect of intralayer hydrogen bonding interactions. PMID- 24802169 TI - Interaction of Quillaja bark saponins with food-relevant proteins. AB - The surface activity and aggregation behaviour of two Quillaja bark saponins (QBS) are compared using surface tension, conductometry and light scattering. Despite formally of the same origin (bark of the Quillaja saponaria Molina tree), the two QBS show markedly different ionic characters and critical micelle concentrations (7.7.10(-6) mol.dm(-3) and 1.2.10(-4) mol.dm(-3)). The new interpretation of the surface tension isotherms for both QBS allowed us to propose an explanation for the previous discrepancy concerning the orientation of the saponin molecules in the adsorbed layer. The effect of three food-related proteins (hen egg lysozyme, bovine beta-lactoglobulin and beta-casein) on surface tension of the saponins is also described. Dynamic surface tension was measured at fixed protein concentrations and QBS concentrations varying in the range 5.10( 7)-1.10(-3) mol.dm(-3). Both dynamic and extrapolated equilibrium surface tensions of the protein/QBS mixtures depend not only on the protein, but also on the QBS source. In general, the surface tension for mixtures of the QBS with lower CMC and less ionic character shows less pronounced synergistic effects. This is especially well visible for beta-casein/QBS mixtures, where a characteristic maximum in the surface tension isotherm around the molar ratio of one can be noticed for one saponin product, but not for the other. PMID- 24802170 TI - Presentations and outcomes of patients with acute decompensated heart failure admitted in the winter season. AB - BACKGROUND: Seasonal variations in cardiovascular disease is well recognized. However, little is known about the presentations and outcomes of Japanese heart failure (HF) patients in the winter season. METHODS AND RESULTS: We used a single hospital-based cohort from the Shinken Database 2004-2012, comprising all new patients (n=19,994) who visited the Cardiovascular Institute Hospital. A total of 375 patients who were admitted owing to acute decompensated HF were included in the analysis. Of these patients, 136 (36%) were admitted in winter. Winter was defined as the period between December and February. The HF patients admitted in winter were older, and had a higher prevalence of hypertension and diabetes mellitus than the patients admitted in other seasons. Patients with conditions categorized as clinical scenario 1 tended to be admitted more commonly in winter. HF with preserved left ventricular ejection fraction (LVEF) was more common in HF patients admitted in winter than in those admitted in other seasons. Beta-blocker use at hospital discharge was more common in the patients admitted in other seasons. Kaplan-Meier curves and log-rank test results indicated that the incidences of all-cause death, cardiovascular death, and HF admission were comparable between the patients admitted in winter and those admitted in other seasons. CONCLUSIONS: HF admission was frequently observed in the winter season and HF patients admitted in the winter season were older, and had higher prevalence of hypertension and diabetes mellitus, and preserved LVEF suggesting that we might need to pay more attention for elderly patients with hypertension, diabetes mellitus, and HF with preserved LVEF to decrease HF admissions in the winter season. PMID- 24802171 TI - Cardiovascular and bleeding risk of non-cardiac surgery in patients on antiplatelet therapy. AB - BACKGROUND: The perioperative risk of non-cardiac surgery (NCS) in the patients on antiplatelet therapy after percutaneous coronary intervention (PCI) remains unclear. METHODS: This study was a retrospective and single center study. Between January 2008 and December 2011, 198 patients who had already received PCI underwent NCS in our hospital. Among them, 63 patients underwent surgery on dual antiplatelet therapy (DAPT group) and 88 patients on single antiplatelet therapy (SAPT group). We compared bleeding events and cardiovascular events during perioperative period between the two groups. RESULTS: There was no stent thrombosis in either group. The bleeding events in the DAPT group were significantly higher than that in the SAPT group (9.5% vs 2.3%, p=0.049). There was no difference in events between with or without heparin-bridge in the SAPT group. CONCLUSIONS: The frequency of bleeding events was higher in the DAPT group. Both bleeding and cardiovascular events with aspirin alone were low in our study. It may be safe to undergo NCS with SAPT after PCI. PMID- 24802172 TI - Factors responsible for elevated plasma B-type natriuretic peptide levels in severe aortic stenosis: comparison between elderly and younger patients. AB - BACKGROUND: Elevated plasma B-type natriuretic peptide (BNP) is a predictor of outcome and helpful for risk stratification in aortic stenosis (AS). However, left ventricular (LV) diastolic dysfunction progresses with aging and may also influence plasma BNP levels in elderly patients. We hypothesized that plasma BNP levels may be influenced by age in severe AS, and that factors that affect the elevation of plasma BNP levels may be different between elderly and younger patients with AS. METHODS: We performed echocardiography in 341 patients with severe AS [aortic valve area (AVA)<1.0cm(2)] and classified them into two groups by age (elderly >=75 years old, n=201; younger patients <75 years old, n=140). We used multivariate linear regression analysis to assess the factors that determine plasma BNP levels in both groups. RESULTS: Age was found to be one of the independent determinants of plasma BNP levels in all patients (beta=0.135, p=0.005). Although AVA was similar in the two groups, plasma BNP levels and E/e' were significantly higher in elderly than younger patients [133.0 (IQR, 73.3 329.7)pg/dl vs 92.8 (IQR, 40.6-171.8)pg/dl, p<0.01; 20+/-8 vs 16+/-6, p<0.01, respectively). In multivariate stepwise linear regression analysis, AVA index, LV ejection fraction, mass index, E/e', estimated systolic pulmonary artery pressure (eSPAS), and the presence of atrial fibrillation were independent determinants of plasma BNP levels in younger patients. In contrast, the independent determinants of plasma BNP levels in elderly patients were LV ejection fraction, mass index, E/e', eSPAS, the presence of atrial fibrillation, age, and hemoglobin levels, but not AVA index. CONCLUSIONS: There may be differences in the factors that influence plasma BNP levels between elderly and younger patients with severe AS. In elderly patients, plasma BNP levels may be influenced more by these factors than AS severity compared with younger patients. PMID- 24802173 TI - Ketoconazole as an adrenal steroidogenesis inhibitor: effectiveness and risks in the treatment of Cushing's disease. PMID- 24802174 TI - Advances in understanding autoimmune pituitary disease: standardized methods for autoantibody detection. PMID- 24802179 TI - Bariatric surgery and adolescents. PMID- 24802180 TI - According to the CPLL proteome sheriffs, not all aperitifs are created equal! AB - Combinatorial peptide ligand libraries (CPLLs) have been adopted for investigating the proteome of a popular aperitif in Northern Italy, called "Amaro Branzi", stated to be an infusion of a secret herbal mixture, of which some ingredients are declared on the label, namely Angelica officinalis, Gentiana lutea and orange peel, sweetened by a final addition of honey. In order to assess the genuineness of this commercial liqueur, we have prepared extracts of the three vegetable ingredients, assessed their proteomes, and compared them to the one found in the aperitif. The amaro's proteome was identified via prior capture with CPLLs at two different pH values (2.2 and 4.8). Via mass spectrometry analysis of the recovered fractions, after elution of the captured populations in 4% boiling SDS, we could confirm the presence of the following: six proteins originating from honey, 11 from orange peels, 29 from G. lutea and 46 from A. officinalis (including shared species), plus 33 species which could not be attributed to the other secret ingredients, due to paucity of genomic data on plant proteins, for a total of 93 unique gene products (merging shared proteins). This fully confirmed the genuineness of the product. Considering that most of these species could be present in trace amounts, undetectable by conventional techniques, the CPLL methodology, due to its ability to enhance the signal of trace components up to 3 to 4 orders of magnitude, could represent a powerful tool for investigating the genuineness and natural origin of commercial beverages in order to protect consumers from adulterated products. PMID- 24802181 TI - Point mutations in firefly luciferase C-domain demonstrate its significance in green color of bioluminescence. AB - Firefly luciferase is a two-domain enzyme that catalyzes the bioluminescent reaction of firefly luciferin oxidation. Color of the emitted light depends on the structure of the enzyme, yet the exact color-tuning mechanism remains unknown by now, and the role of the C-domain in it is rarely discussed, because a very few color-shifting mutations in the C-domain were described. Recently we reported a strong red-shifting mutation E457K in the C-domain; the bioluminescence spectra of this enzyme were independent of temperature or pH. In the present study we investigated the role of the residue E457 in the enzyme using the Luciola mingrelica luciferase with a thermostabilized N-domain as a parent enzyme for site-directed mutagenesis. We obtained a set of mutants and studied their catalytic properties, thermal stability and bioluminescence spectra. Experimental spectra were represented as a sum of two components (bioluminescence spectra of putative "red" and "green" emitters); lambdamax of these components were constant for all the mutants, but the ratio of these emitters was defined by temperature and mutations in the C-domain. We suggest that each emitter is stabilized by a specific conformation of the active site; thus, enzymes with two forms of the active site coexist in the reactive media. The rigid structure of the C-domain is crucial for maintaining the conformation corresponding to the "green" emitter. We presume that the emitters are the keto- and enol forms of oxyluciferin. PMID- 24802182 TI - Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. AB - Obesity is characterized by dysfunctional white adipose tissue (WAT) that ultimately may lead to metabolic diseases. Calorie restriction (CR) reduces the risk for age and obesity-associated complications. The impact of CR on obesity has been examined with human intervention studies, which showed alterations in circulating adipokines. However, a direct effect of CR on the human adipocyte secretome remains elusive. Therefore, the effect of a 96h low glucose CR on the secretion profile of in vitro cultured mature human SGBS adipocytes was investigated by using proteomics technology. Low-glucose CR decreased the adipocyte triglyceride contents and resulted in an altered secretion profile. Changes in the secretome indicated an improved inflammatory phenotype. In addition, several adipocyte-secreted proteins related to insulin resistance showed a reversed expression after low-glucose CR. Furthermore, 6 novel CR regulated adipocyte-secreted proteins were identified. Since resveratrol (RSV) mimics CR we compared results from this study with data from our previous RSV study on the SGBS adipocyte secretome. The CR and RSV adipocyte secretomes partly differed from each other, although both treatment strategies lead to secretome changes indicating a less inflammatory phenotype. Furthermore, both treatments induced SIRT1 expression and resulted in a reversed expression of detrimental adipokines associated with metabolic complications. PMID- 24802183 TI - Infection control and biosecurity in equine disease control. AB - Infectious diseases are an important cause of morbidity and mortality in horses, along with economic costs and broader impacts associated with the loss of members of a species that generates income, acts as a working animal and is a companion. Endemic diseases continue to challenge, emerging diseases are an ever-present threat and outbreaks can be both destructive and disruptive. While infectious diseases can never be completely prevented, measures can be introduced to restrict the entry of pathogens into a population or limit the implications of the presence of a pathogen. Objective research regarding infection control and biosecurity in horses is limited, yet a variety of practical infection prevention and control measures can be used. Unfortunately, infection control can be challenging, because of the nature of the equine industry (e.g. frequent horse movement) and endemic pathogens, but also because of lack of understanding or motivation to try to improve practices. Recognition of the basic concepts of infection control and biosecurity, and indeed the need for measures to control infectious diseases, is the foundation for successful infection prevention and control. PMID- 24802184 TI - Accurate description of calcium solvation in concentrated aqueous solutions. AB - Calcium is one of the biologically most important ions; however, its accurate description by classical molecular dynamics simulations is complicated by strong electrostatic and polarization interactions with surroundings due to its divalent nature. Here, we explore the recently suggested approach for effectively accounting for polarization effects via ionic charge rescaling and develop a new and accurate parametrization of the calcium dication. Comparison to neutron scattering and viscosity measurements demonstrates that our model allows for an accurate description of concentrated aqueous calcium chloride solutions. The present model should find broad use in efficient and accurate modeling of calcium in aqueous environments, such as those encountered in biological and technological applications. PMID- 24802185 TI - Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of beta-N acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4 trideoxy-1,4-iminopentitols. AB - The enantiomers of XYLNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminoxylitol) are prepared from the enantiomers of glucuronolactone; the synthesis of the enantiomers of LYXNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminolyxitol) from an L arabinono-delta-lactone and a D-ribono-delta-lactone is reported. A comparison is made of the inhibition of beta-N-acetylhexosaminidases (HexNAcases) and alpha-N acetylgalactosaminidase (alpha-GalNAcase) by 8 stereoisomeric 2-N-acetylamino 1,2,4-trideoxy-1,4-iminopentitols; their N-benzyl derivatives are better inhibitors than the parent compounds. Both XYLNAc and LABNAc are potent inhibitors against HexNAcases. None of the compounds show any inhibition of alpha GalNAcase. PMID- 24802186 TI - Avoiding CT angiography radiation in management of post-partum hemorrhage. PMID- 24802187 TI - Finding the most accurate method to measure head circumference for fetal weight estimation. AB - OBJECTIVE: Accurate measurement of fetal head biometry is important for fetal weight estimation (FWE) and is therefore an important prognostic parameter for neonatal morbidity and mortality and a valuable tool for determining the further obstetric management. Measurement of the head circumference (HC) in particular is employed in many commonly used weight equations. The aim of the present study was to find the most accurate method to measure head circumference for fetal weight estimation. STUDY DESIGN: This prospective study included 481 term pregnancies. Inclusion criteria were a singleton pregnancy and ultrasound examination with complete fetal biometric parameters within 3 days of delivery, and an absence of structural or chromosomal malformations. Different methods were used for ultrasound measurement of the HC (ellipse-traced, ellipse-calculated, and circle calculated). As a reference method, HC was also determined using a measuring tape immediately after birth. FWE was carried out with Hadlock formulas, including either HC or biparietal diameter (BPD), and differences were compared using percentage error (PE), absolute percentage error (APE), limits of agreement (LOA), and cumulative distribution. RESULTS: The ellipse-traced method showed the best results for FWE among all of the ultrasound methods assessed. It had the lowest median APE and the narrowest LOA. With regard to the cumulative distribution, it included the largest number of cases at a discrepancy level of +/-10%. The accuracy of BPD was similar to that of the ellipse-traced method when it was used instead of HC for weight estimation. CONCLUSION: Differences between the three techniques for calculating HC were small but significant. For clinical use, the ellipse-traced method should be recommended. However, when BPD is used instead of HC for FWE, the accuracy is similar to that of the ellipse-traced method. The BPD might therefore be a good alternative to head measurements in estimating fetal weight. PMID- 24802188 TI - Transurethral injection of polyacrylamide hydrogel (Bulkamid((r))) for the treatment of female stress or mixed urinary incontinence. AB - OBJECTIVE: The aim of this study was to evaluate the cure effect of a transurethral injection (TUI) of Bulkamid((r)) for female urodynamic stress (USI) and stress-predominant mixed urinary incontinence. The hypothesis was that the cure effect of Bulkamid((r)) is positive in patients who have undergone previous unsuccessful anti-incontinence surgery and in patients with ISD (Intrinsic Sphincter Deficiency). STUDY DESIGN: This retrospective clinical study was performed on 52 patients for whom previous anti-incontinence surgery had failed (n=40) and on patients with ISD. Five patients had a reinjection of Bulkamid((r)). The efficacy of TUI was evaluated an average of 22 months (minimum - 6 months, maximum - 50 months) after the procedure. Subjective assessment of the leakage of urine was based on the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-UI SF). Objective assessment of leakage of urine was assessed by the cough test. The cure effect of procedures was evaluated by VAS (Visual Analog Scale: VAS score 0-100; 100 - without leakage of urine, dry) and by using the five-point Likert scale. The statistics were calculated using the software STATISTICA 10-StatSoft. Inc software (Tulsa, USA). RESULTS: A retrospective study was performed on 52 women with urinary incontinence (stress 43, mixed 9), and 51 patients completed the study. One patient with SUI died during the study. Their mean age was 70 years, mean body mass index (BMI) was 28.65, and mean parity was 1.76. Objective assessment by cough test showed that 19.6% of patients had negative results for this test 22 months after the operation. Subjective assessment by the ICIQ-UI SF questionnaire showed that 15.7% of patients were completely dry, while 45.1% of patients were dry or improved. The mean VAS score was 51.3, and on the Likert scale the cure effect was evaluated as 5 or 4 ("cured" or "improved") in 54.9% of patients. CONCLUSIONS: The hypothesis that the cure effect of Bulkamid((r)) is positive in patients who have undergone previous unsuccessful anti-incontinence surgery, and in patients with ISD, was confirmed. The procedure is an option for failed anti incontinence surgery or for patients with ISD. PMID- 24802189 TI - Monoclonal antibody targeting of the cell surface molecule TM4SF5 inhibits the growth of hepatocellular carcinoma. AB - The cell surface transmembrane receptor TM4SF5 has been implicated in hepatocellular carcinoma (HCC), but its candidacy as a therapeutic target has not been evaluated. Building on findings that immunization with a peptide vaccine targeting human TM4SF5 can exert prophylactic and therapeutic effects in a murine model of HCC, we developed a monoclonal antibody to characterize expression of TM4SF5 in HCC and to target its function there as an anticancer strategy. We found that the antibody modulated cell signaling in HCC cells in vitro, reducing cell motility, modulating E-cadherin expression, altering p27(kip1) localization, and increasing RhoA activity. Using a mouse xenograft model of human HCC, we documented the in vivo efficacy of the antibody, which suppressed tumor growth in either tumor prevention or treatment designs. Our work offers a preclinical proof of concept for TM4SF5 as a promising target for antibody therapeutics to treat HCC. Cancer Res; 74(14); 3844-56. (c)2014 AACR. PMID- 24802190 TI - Loss of Cdk2 and cyclin A2 impairs cell proliferation and tumorigenesis. AB - Cell-cycle inhibition has yet to offer a generally effective approach to cancer treatment, but a full evaluation of different combinations of cell-cycle inhibitors has not been evaluated. Cyclin A2, a core component of the cell cycle, is often aberrantly expressed in cancer where it may impact cell proliferation. In this study, we investigated the role of cyclin A2 in tumorigenesis using a conditional genetic knockout mouse model. Cyclin A2 deletion in oncogene transformed mouse embryonic fibroblasts (MEF) suppressed tumor formation in immunocompromised mice. These findings were confirmed in mice with cyclin A2 deficient hepatocytes, where a delay in liver tumor formation was observed. Because cyclin A2 acts in complex with Cdk2 in the cell cycle, we explored a hypothesized role for Cdk2 dysregulation in this effect through conditional deletions of both genes. In oncogene-transformed MEFs lacking both genes, tumor formation was strongly suppressed in a manner associated with decreased proliferation, premature senescence, and error-prone recovery from serum deprivation after immortalization. Whereas loss of cyclin A2 led to a compensatory increase in Cdk1 activity, this did not occur with loss of both Cdk2 and cyclin A2. Our work offers a rationale to explore combinations of Cdk1 and Cdk2 inhibitors as a general approach in cancer therapy. PMID- 24802191 TI - Ly49 family receptors are required for cancer immunosurveillance mediated by natural killer cells. AB - According to the missing-self hypothesis, natural killer (NK) cells survey for target cells that lack MHC-I molecules. The Ly49 receptor family recognizes loss of MHC-I and is critical for educating NK cells, conferring the ability to eliminate transformed or infected cells. In this study, we evaluated their requirement in innate immune surveillance of cancer cells using genetically manipulated mice with attenuated expression of Ly49 receptors (NKC(KD)) in several models of carcinoma and metastasis. We found that NKC(KD) mice exhibited uncontrolled tumor growth and metastases. Expression of two MHC-I alleles, H 2K(b) and H-2D(b), was decreased in tumors from NKC(KD) mice in support of the likelihood of NK-mediated tumor immunoediting. These tumor cells exhibited directed alterations to their cell surface expression in response to the genetically altered immune environment to evade host recognition. Immunoediting in NKC(KD) mice was restricted to MHC-I molecules, which are ligands for Ly49 receptors, while expression of Rae-1 and Mult1, ligands for another NK cell receptor, NKG2D, were unaffected. Restoring NK cell education in NKC(KD) mice with a transgene for the inhibitory self-MHC-I receptor Ly49I restored suppression of cancer onset and growth. Interestingly, immune surveillance mediated by activating Ly49 receptors remained intact in NKC(KD) mice, as demonstrated by the ability to stimulate the NKG2D receptor with tumor cells or splenocytes expressing Rae-1. Together, our results genetically establish the integral role of Ly49 in NK cell-mediated control of carcinogenesis through MHC-I dependent missing-self recognition. PMID- 24802192 TI - Reactions of metallocarbenes derived from N-sulfonyl-1,2,3-triazoles. AB - Metal-stabilized carbenes derived from diazo compounds have become broadly useful reactive intermediates for organic synthesis. This tutorial review will describe the recent advances in using N-sulfonyl-1,2,3-triazoles as precursors for the formation of metal-bound imino carbene intermediates. These intermediates undergo a variety of synthetically useful transformations, which include transannulation reactions to generate new heterocycles, cyclopropanation and subsequent ring expansions, ylide formation with subsequent rearrangements, and C-H functionalization. Furthermore, many of these transformations can be conducted with high levels of enantioselectivity by use of chiral rhodium(II) catalysts. PMID- 24802193 TI - Role of 18F-FDG PET/CT in the diagnosis of infective endocarditis in patients with an implanted cardiac device: a prospective study. AB - PURPOSE: Infective endocarditis (IE) is widely underdiagnosed or diagnosed after a major delay. The diagnosis is currently based on the modified DUKE criteria, where the only validated imaging technique is echocardiography, and remains challenging especially in patients with an implantable cardiac device. The aim of this study was to assess the incremental diagnostic role of (18)F-FDG PET/CT in patients with an implanted cardiac device and suspected IE. METHODS: We prospectively analysed 27 consecutive patients with an implantable device evaluated for suspected device-related IE between January 2011 and June 2013. The diagnostic probability of IE was defined at presentation according to the modified DUKE criteria. PET/CT was performed as soon as possible following the clinical suspicion of IE. Patients then underwent medical or surgical treatment based on the overall clinical evaluation. During follow-up, we considered: lead cultures in patients who underwent extraction, direct inspection and lead cultures in those who underwent surgery, and a clinical/instrumental reevaluation after at least 6 months in patients who received antimicrobial treatment or had an alternative diagnosis and were not treated for IE. After the follow-up period, the diagnosis was systematically reviewed by the multidisciplinary team using the modified DUKE criteria and considering the new findings. RESULTS: Among the ten patients with a positive PET/CT scan, seven received a final diagnosis of "definite IE", one of "possible IE" and two of "IE rejected". Among the 17 patients with a negative PET/CT scan, four were false-negative and received a final diagnosis of definite IE. These patients underwent PET/CT after having started antibiotic therapy (>=48 h) or had a technically suboptimal examination. CONCLUSION: In patients with a cardiac device, PET/CT increases the diagnostic accuracy of the modified Duke criteria for IE, particularly in the subset of patients with possible IE in whom it may help the clinician manage a challenging situation. PMID- 24802194 TI - Comment on Aksoy et al.: FDG and FDG-labelled leucocyte PET/CT in the imaging of prosthetic joint infection. PMID- 24802195 TI - FDG and FDG-labelled leucocyte PET/CT in the imaging of prosthetic joint infection: response to Lazzeri et al. PMID- 24802196 TI - Incidence of urinary tract tumours in a two-year period (2010-2011) at the Institute of Pathology, Faculty of Medicine, Skopje, Macedonia. AB - We performed a retrospective analysis of tumours of the kidneys and the lower urinary tract diagnosed at the Institute of Pathology, Faculty of Medicine, Ss. Cyril and Methodius University, Skopje, Macedonia, in a two-year period (2010 2011), with the aim of highlighting the main morphological characteristics and to present the statistical features of these tumours. All the cases were diagnosed on paraffin sections from surgical specimens routinely stained with H&E, and immunohistochemically with a panel of monoclonal antibodies. The analysis revealed a total of 755 cases, of which 166 (14%) were located in the kidney including the renal pelvis, and 649 (86%) were tumours of the urinary bladder. Twelve of the renal tumours (11.3%) were benign, and the rest were malignant tumours. Most of them were adenocarcinomas (n=77; 72.6%) and 17 cases (16%) were transitional cell carcinomas originating from the renal pelvis. The analysis of the lower urinary tract tumours showed a strong prevalence of malignant urothelial tumours (96%), with a male to female ratio of almost 4:1. Low grade morphology was a predominant feature (71.7%) and 51 cases (22.9%) were of high grade. The percentage of urothelial tumours of the kidney in our series is higher than in most of the reported series, which should lead to an expanded analysis. PMID- 24802198 TI - Autism--genetics, electrophysiology and clinical syndromes. AB - Autism is a severe and the most heritable developmental disorder, whose pathogenesis is still largely unknown. The rising incidence of autism in the last decade has increased the scientific interest and research. More than a thousand papers concerned with information about the etiology of this "static disorder of the immature brain" can be found on Pub Med. The aim of this paper is to give a review of published genetic chromosomal anomalies associated with autistic spectrum disorders, as well as to discuss common syndromes associated with autistic traits. In addition, some of our own findings in genetics, as well as in quantitative electroencephalography and neurofeedback training in autistic children, will be presented and discussed. Generally, the subsequent analyses indicate that the causes of autism include fewer common single-gene mutations and chromosomal abnormalities, as well as multiple interacting genes of weak effect. Genome-wide linkage analysis has identified several susceptibility loci and positional and functional candidate genes which appear to represent possible risks of the autistic spectrum. Electrophysiological findings showed high delta/theta activity in frontal-central regions, while in 25% high beta activity was detected as a result of anxiety. Neurofeedback is a promising therapy for symptom mitigation. PMID- 24802197 TI - Mutational analysis of TAC and TACR3 in idiopathic central precocious puberty. AB - BACKGROUND: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood, and is thought to arise from the effect of multiple genes. Familial ICPP have been reported suggesting the existence of monogenic causes of ICPP. The neurokinin B (NKB) system has recently been implicated in the regulation of the human reproductive axis. In humans, NKB and its receptor are encoded by the TAC3 and TACR3 genes, respectively. Mutations in these genes have been suggested to be causative for ICPP. METHODS: ICPP was defined by pubertal onset before 8 yrs of age in girls, and a pubertal LH response to GnRH testing. Twenty eight girls with ICPP were included in the study (age at diagnosis was 5.72+/-2.59; bone age, 6.12+/-2.81, height at the start of treatment, 0.90+/-1.48 SD). LHRH test was performed and was pubertal in all subjects (LH 20.35+/-32.37 mIU/ml; FSH 23.32+/-15.72 mIU/ml). The coding regions of TAC and TACR3 were sequenced. RESULTS: No rare variants were detected in TAC and TACR3 in the 28 subjects with ICPP. CONCLUSIONS: We confirmed that mutations in TAC and TACR3 are not a common cause for ICPP. PMID- 24802199 TI - The role of the special educator and rehabilitator with a child with a rare disease. AB - In the case of a child with a rare disease the role of the special educator and rehabilitator is important if in addition to the primary disease the child is affected by motor, sensory, mental or emotional deficiency. The special educator and rehabilitator participates in the discovery on their first visit to the health institution. For each child the special educator and rehabilitator prepares a file with all the relevant data, takes anamnestic data, or complements it, to get a complete picture of the problem, and inputs data from the observation. S/he collaborates with members of the professional team. S/he provides advice, assists and works with the parents. S/he assesses the psycho motor abilities of the person and how the person functions in the environment. The special educator and rehabilitator performs the following assessments: assessment of dominant lateralization; assessment of psycho-motor abilities of the upper extremities; assessment of psycho-motor abilities of the lower extremities; differentiation of the motor abilities of the fingers; assessment of the possibilities for maintaining the equilibrium of the body; assessment of coordination of the upper and lower extremities in rhythm. The special educator and rehabilitator assesses and examines the praxical organization, specifically melokinetic, ideomotory, ideatory and constructive praxis. This includes assessment of the graphomotoric as a practical activity through testing for quality of lineation, graphomotoric array through analysis of the maturity of the manuscript and the disgraphy of the manuscript. Gnostic organization is examined through assessment of knowledge of body parts, assessment of knowledge of lateralization on themselves and others, assessment of experience and orientation in space and time. Practognostic organization is examined with tests for imitation of movements. Evaluation of the organization of speech through the test of articulation on voices, semantic test and evaluation of lexical abilities and dyslexic reading. Assessment of the organization of cognitive functions where thought operation is expressed, and the special educator investigates the level of comprehension of: serialization, classification, correspondence and conservation. At the end, the child's behaviour is examined. Based on the data obtained, a plan and a strategy for further treatment is developed. After a certain period of time the child is re-examined (evaluation) and we check whether are there any advances in education and rehabilitation. The special educator and rehabilitator is in constant contact with the parents for certain problems that the children have with social adaptation, and they build strategies for future activities. PMID- 24802200 TI - Prevalence of low bone mass and vitamin D deficiency in pediatric and adult patients with cystic fibrosis in Republic of Macedonia. AB - Bone disease in cystic fibrosis (CF) has become a topic of widespread interest and impact in the CF community. Recently, some biochemical markers have been proposed to provide information about the dynamics of bone turnover. Only limited information is available for young patients. Imbalance between bone formation and degradation in CF especially in puberty has become an important issue for developing osteopenia. Influence of vitamin D receptor alleles on BMD suggests that these polymorphisms have a greater influence on BMD in childhood. The aim of our study was to assess prevalence of vitamin D deficiency and osteopenia in pediatric and adult CF patients. METHODS: The study included 77 clinically stable CF patients (range 5-36 y), who regularly attended CF center at the Pediatric Clinic in Skopje, Macedonia. Serum osteocalcin (OC), betacrosslaps, 25OHD and PTH were determined by electrohemiluminiscent method. BMD was measured via dual energy-ray absorptiometry (DXA) scans with spinal scores recorded. RESULTS: 50% of the CF patients with PI had serum vitamin D>20 ng (range 10-44 ng/ml) with no difference of age. Osteopenia was determined in 35% of patients. High plasma betacrosslaps values reflect raised osteoclast activity in 50% of patients with osteopenia. We found one CF patient homozygote for Taq1 and Bsm1, one for Taq1 and one for Fok1. These patients have vitamin D deficiency and osteopenia. CONCLUSIONS: Bone remodeling in CF patients is impaired. Further investigations are needed to find underlying pathogenesis of low bone mass and vitamin D deficiency. PMID- 24802201 TI - Posttraumatic soft tissue impingement of the ankle: arthroscopic findings and surgical outcomes. AB - Painful conditions and limited dorsal flexion of the ankle, which are the result of the friction of joint tissues and also the cause and the effect of altered joint biomechanics, are called ankle impingement syndromes. Post-traumatic ankle injures, like an ankle sprains or ankle fractures, are the main causes of impingement lesions, which result in chronic ankle pain. PURPOSE: To evaluate the results for patients treated arthroscopically for anterolateral soft tissue impingement after ankle injury. METHODS: Twelve patients underwent operative arthroscopy for anterolateral impingement between 2010 and 2012, A retrospective study with a mean follow up of 1 year. There were 7 females and 5 males, average age 44.1 years. RESULTS: Preoperative American ankle and foot score was average, 68 (63-71) points and after the operation 92 (87-95) points. CONCLUSION: Soft tissue impingement of the talocrural joint shows painful and limited dorsal flexion and plantar extension, effusion and joint line tenderness especially in the anterolateral gutter. Arthrofibrosis following ankle fractures causes an unfavorable surgical outcome, and arthroscopic debridement of fibrous tissue is an effective means of improving articular function. PMID- 24802202 TI - Uterus preserving vaginal surgery versus vaginal hysterectomy for correction of female pelvic organ prolapse. AB - AIM: The objective of this study is to evaluate uterus preserving vaginal procedure of cervical amputation with uterosacral ligament plication (modified Manchester operation) and compare it to vaginal hysterectomy regard recurrence rate, duration of surgery, blood loses, intra and post-operative complications, duration of hospital stay. METHODS: Consecutive women with pelvic organ prolapse who underwent either vaginal hyste-rectomy or a modified Manchester procedure were included. Assessments were made preoperatively and at 1-year follow-up, including physical examination with pelvic organ prolapse quantification standardized questionnaires. RESULTS: 66 patients were included in the study with a one year follow-up. We found no significant difference in: recurrence of POP and reintervention (recurrence with required treatment n (%): 3(10) vs. 5(15), p=0.28) and hospital stay (mean+/-SD days: 5+/-2 vs. 7+/-2, p=0.97). Significant less blood loses (250+/-210 ml. vs. 360+/-230 ml.) and shorter operation time (67+/-20 min. vs 102+/-22 min.) in modified Manchester group, but significant more urinary retention (cases: 8 vs 6) in modified Manchester group. The overall functional outcome was acceptable for both procedures. CONCLUSIONS: We found an excellent performance of both procedures regarding recurrences and intra and post operative complications. A high degree of acceptance-satisfaction shows the modified Manchester operation and is good option for the treatment of uterine prolapse in younger women who wish to keep their uterus and in all cases of genital prolapse with elongation of uterine cervix (when there is not other uterine pathology). Shorter operation time and lower blood lose are another factors for stronger recommendation of the modified Manchester operation for patients with concomitant diseases and/or older age patients with elevated risk from anesthesia and/or surgery. PMID- 24802203 TI - Removable dentures with eclipse-repairing and relining. AB - While utilizing removable dentures, regardless of whether the dentures are acrylic or fabricated of eclipse resin, the need for their filling-relining or their repair frequently arises. The purpose of this study is to display the technicalities of the procedure for rebasing and relining of removable light curing eclipse denture resin. MATERIAL AND METHODS: This study presents cases of relining and repairing of removable dentures fabricated from light curing ECLIPSE resin on patients at the Department for Removable Prosthodontics at the University Dental Clinic Centre in Skopje. CONCLUSION: One of the most significant features of this method of fabrication of removable eclipse dentures and their relining and repairing is the shortened duration of work in the dental laboratory. The displayed mode of rebasing also allows us to maintain one of the advantages of this type of dentures--the absence of allergy stomatitis symptoms. PMID- 24802204 TI - An assessment of career satisfaction among Macedonian dentists. AB - AIM: The aim of this study was to assess the level of overall career satisfaction in relation to various personal and work-related factors among the dentists in the Republic of Macedonia. MATERIALS AND METHODS: The sample comprised 118 registered dentists, working in different conditions (34 public practice dentists, 32 completely private, 42 private dentists who work with a health insurance fund and 10 concessioners). All of them filled in a questionnaire which contained 16 items, divided into five groups. The different clusters of questions were related to various working conditions and personal factors. The first four groups of questions were answered with a--point Likert format with a score range from 1 (very dissatisfied) to 4 (very satisfied). In the fifth group, dentists chose one of four offered answers. The statistical analyses were made by one-way ANOVA and chi-square tests. RESULTS: Significant differences related to working conditions were found between public practitioners (moderately dissatisfied) and private practitioners (very satisfied) (F=41.41 (df=3); p<0.01). A high prevalence of dentists (89.83%) had felt stressed on their work place and 61.8% of public dental health practitioners had felt stressed at work "very often". The main sources of job-related stress for public dental practitioners were their supervisors (50%) and patients (26. 47%), while private practitioners were mostly stressed by inspectors (76.19%) and patients (21.87%) (chi2=44.5 (df=9); p<0.01). CONCLUSION: The findings in our study showed overall low levels of career satisfaction among the dentists (public and private) in the Republic of Macedonia. The finding that high percentages of dentists feel stress at their work place very often requires further exploration. PMID- 24802205 TI - Chronic periapical lesions: correlations with clinical finding. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between periapical lesions with and without clinical symptoms. MATERIAL AND METHOD: This study was performed on cases with chronic periapical lesion diagnosis. During oral surgery procedures, 80 tissue samples were obtained. Anamnesis data were taken from each subject included in the study. Periapical tissue samples were processed for laboratory procedures including: histological and pathological examination of lesions by light microscopy analysis and microbiological status assessment by qualitative and semi-quantitative analysis of bacteriological findings. RESULTS AND CONCLUSION: The results obtained illustrate that symptomatic apical periodontitis was more frequent with teeth without previous endodontic therapy. Even though a pathological type of periapical inflammation is significantly associated with the presence or absence of clinical symptoms (p=0.0002), they do not have an effect on making a clinical diagnosis. Statistical analysis showed no significant difference (p>0.05). Comparative analysis of symptom persistence and infection severity was performed. It was found that positive symptoms were in relation to the quantity of the bacterial growth only in the group previous endodontically treated and these two factors do show relation with an accuracy of 95%. The growth of a mixture of several, mainly anaerobic, bacterial species is closely related to the presence of clinical symptoms. PMID- 24802206 TI - Intensified insulin treatment is associated with improvement in skin microcirculation and ischaemic foot ulcer in patients with type 1 diabetes mellitus: a long-term follow-up study. AB - AIMS/HYPOTHESIS: We investigated skin microcirculation and its association with HbA1c and the incidence of ischaemic foot ulcer in patients with type 1 diabetes formerly randomised (1982-1984) to intensified conventional treatment (ICT) or standard treatment (ST) with insulin for a mean of 7.5 years. METHODS: We re determined the skin microcirculation of 72 patients (ICT 35 vs ST 37) from the original Stockholm Diabetes Intervention Study with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine (ACh) (endothelial dependent vasodilatation), sodium nitroprusside (SNP) (endothelial-independent vasodilatation), and capsaicin (C-nociceptive-dependent vasodilatation). HbA1c levels (mean of 14 values/patient) were prospectively collected between 1990 and 1995 and tested for association with skin microcirculation. The patients were followed until first hospitalisation for an ischaemic foot ulcer or until 2011. RESULTS: During the median 28 years of follow-up, three patients developed ischaemic foot ulcers in the ICT group compared with ten in the ST group (logrank, p = 0.035). At the time of iontophoresis, HbA1c was lower in the ICT group (median 57 mmol/mol [minimum-maximum 40-79 mmol/mol]) compared with the ST group (68 mmol/mol [41-96 mmol/mol], p < 0.01) (DCCT: ICT 7.4% [5.8-9.4%] vs ST 8.4% [5.9-10.9%]). Stimulated blood flow was higher in the ICT vs ST group with significantly increased perfusion units (PU) for: ACh (8.1 PU [4.6-24.7 PU] vs 5.3 PU [1.7-21.4 PU], p < 0.01); SNP (8.1 PU [2.2-20.1 PU] vs 5.6 PU [2.3-19.2 PU], p = 0.03); and capsaicin (5.0 PU [1.7-22.9 PU] vs 3.4 PU [1.5-8.4 PU], p < 0.01). HbA1c was associated with vasodilatation induced by ACh (b = -0.02, p < 0.01) and capsaicin (b = -0.02, p = 0.03). HbA1c was independently associated with ACh (b = -1.48, p < 0.01) and capsaicin-induced vasodilatation (b = -1.45, p < 0.01). CONCLUSIONS/INTERPRETATION: Improved glycaemic control in patients with type 1 diabetes is associated with an improvement in skin microcirculation and with a lower incidence of ischaemic foot ulcers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01957930. PMID- 24802208 TI - Terretonin G, a new sesterterpenoid antibiotic from marine-derived Aspergillus sp. OPMF00272. PMID- 24802207 TI - Site-specific promoter caging enables optochemical gene activation in cells and animals. AB - In cell and molecular biology, double-stranded circular DNA constructs, known as plasmids, are extensively used to express a gene of interest. These gene expression systems rely on a specific promoter region to drive the transcription of genes either constitutively (i.e., in a continually "ON" state) or conditionally (i.e., in response to a specific transcription initiator). However, controlling plasmid-based expression with high spatial and temporal resolution in cellular environments and in multicellular organisms remains challenging. To overcome this limitation, we have site-specifically installed nucleobase-caging groups within a plasmid promoter region to enable optochemical control of transcription and, thus, gene expression, via photolysis of the caging groups. Through the light-responsive modification of plasmid-based gene expression systems, we have demonstrated optochemical activation of an exogenous fluorescent reporter gene in both tissue culture and a live animal model, as well as light induced overexpression of an endogenous signaling protein. PMID- 24802209 TI - Investigating specific bacterial resistance to AMPs by using a magainin I resistant Escherichia coli model. AB - Antimicrobial peptides (AMPs) are multifunctional compounds that may show antimicrobial and immunomodulatory activities. With the rapid increase in the incidence of multidrug-resistant bacteria, there is an enormous interest in AMPs as templates for the production of new antibiotics. However, there are concerns that the therapeutic administration of AMPs can select resistant strains. In order to distinguish between resistant and non-resistant strains and verify resistance specificity to AMPs, in this study a magainin I-resistant Escherichia coli model was used. First, the identity of all strains was confirmed by matrix assisted laser desorption ionization-time of flight (MALDI-TOF)-MS, VITEK 2 and MicroScan, and the susceptible and magainin-resistant strains were successfully differentiated by MALDI-TOF-MS analysis. Furthermore, cross-resistances to a broad spectrum of antibiotics were evaluated, showing that all E. coli strains are susceptible to the drugs tested, suggesting that the resistance seems to be specific to AMPs. Finally, the specific resistance to magainin I compared with other AMPs was checked by microdilution. This experiment showed that the magainin MICs were 62 and 104 MUM for susceptible and resistant strains, respectively. The other AMPs MICs were 3.4 MUM to proline-arginine-rich 39-amino-acid peptide, 43 MUM to porcine myeloid antimicrobial 23-amino-acid peptide-23 and 1.2 MUM to cecropin P1 for all strains, demonstrating any additional resistance to peptides here evaluated, confirming that the resistance seems to be essentially specific to magainin I. In summary, the data reported here reinforce the proposal that magainin I seems not to be merely a membrane disruptor, probably showing additional molecular targets in pathogenic bacteria. PMID- 24802210 TI - Erinacene D, a new aromatic compound from Hericium erinaceum. PMID- 24802211 TI - Cytotoxic anthrasteroid glycosides, malsterosides A-C, from Malbranchea filamentosa. PMID- 24802212 TI - Determination of the presence and pharmacokinetic profile of ciprofloxacin by TLC and HPLC method respectively in broiler chicken after single oral administration. AB - The objective of this study was to determine the presence of ciprofloxacin and pharmacokinetics of ciprofloxacin in blood plasma of broiler chicken after single oral administration at feeding state. Ciprofloxacin was administered orally at 10 mg kg(-1) to each of the 10 broiler chickens at feeding state. Presence of ciprofloxacin was determined by TLC method and pharmacokinetics by HPLC method. Peak plasma concentration (Cmax) of ciprofloxacin, 0.26+/-0.03 mg l(-1) was achieved at 4.40+/-0.1 h (Tmax). Biological half-life of ciprofloxacin was 5.25+/ 0.02 h. Area under the curve (AUC) was 13.397+/-0.13 mg ml(-1) h, elimination rate constant was 0.13+/-0.02 h(-1), volume of distribution was 0.194+/-0.04 l kg(-1) and bioavailability was 49+/-0.48%. On the basis of the results of the present study, we conclude that, feeding state may have a vital effect on the pharmacokinetic profile of ciprofloxacin in broiler blood plasma. PMID- 24802213 TI - Angiolactone, a new butyrolactone isolated from the terrestrial myxobacterium, Angiococcus sp. PMID- 24802214 TI - Free solar lanterns to below poverty line girls in India: a step toward achieving millennium development goals. AB - Development sectors like health cannot function in isolation. Intersectoral coordination between various departments helps in bringing a positive change in the health-seeking behavior of society in the long run. The decision by the Government of India to provide free solar lanterns (lamps) to the school-going girls of below poverty line families is a welcome step in this context. This initiative would help in reducing the number of school dropout girls and thus help in improving the health indicators that are directly related to women's education. Thus it is an initiative that will help in attainment of Millennium Development Goals through women's education and empowerment. Along with that, the environment-friendly approach will definitely have an impact on health of the girls by switching from kerosene/wood stoves to solar lantern light. Also this initiative would pave the path of real "intersectoral coordination" in the health sector in India that is marred with watertight functioning of various departments. There is an urgent need to popularize the scheme and involve different stakeholders like corporate houses, media, nongovernment organizations, multinational welfare agencies, and local governing bodies for ensuring the availability and utilization of solar lanterns in India. PMID- 24802215 TI - Child sexual abuse prevention policy: an analysis of Erin's law. AB - Child sexual abuse affects thousands of children in the United States and is vastly underreported. Tertiary prevention policies, primarily in the form of sex offender registries and community notification programs, have received the most attention and funding. Few policies have focused on school-based prevention. One recently passed law in Illinois mandates all K-5 public schools to implement sexual abuse prevention programs. The law was championed by a young social worker, Erin Merryn. Through the multiple streams framework, this article examines the unique set of political circumstances, united with Merryn's advocacy, which created the opportunity for the law to pass. PMID- 24802216 TI - Racial disparity: substance dependency and psychological health problems among welfare recipients. AB - This study explored the racial disparity of substance dependency and psychological health among White, African American, and Hispanic Temporary Assistance to Needy Families (TANF) recipients as well as the relationship between substance dependency and psychological health. It analyzed 1,286 TANF recipients from the 2006 National Survey on Drug Use and Health data. Analysis of variance indicated that Whites were experiencing more nicotine and alcohol dependency and psychological distress than others, but African Americans and Hispanics were experiencing more cocaine dependency than Whites. Ordinary least squares regression revealed that nicotine dependency is significantly related to the psychological distress of Whites. Alcohol dependency is significantly associated with the psychological distress of three groups. Culturally competent programs are suggested. PMID- 24802217 TI - Diabetes in homeless persons: barriers and enablers to health as perceived by patients, medical, and social service providers. AB - The ways homelessness and diabetes affect each other is not well known. The authors sought to understand barriers and enablers to health for homeless people with diabetes as perceived by homeless persons and providers. The authors performed semistructured interviews with a sample of participants (seven homeless persons, six social service providers, and five medical providers) in an urban Midwest community. Data analysis was performed with the qualitative editing method. Participants described external factors (chaotic lifestyle, diet/food availability, access to care, and medications) and internal factors (competing demands, substance abuse, stress) that directly affect health. Social service providers were seen as peripheral to diabetes care, although all saw their primary functions as valuable. These factors and relationships are appropriately modeled in a complex adaptive chronic care model, where the framework is bottom up and stresses adaptability, self-organization, and empowerment. Adapting the care of homeless persons with diabetes to include involvement of patients and medical and social service providers must be emergent and responsive to changing needs. PMID- 24802218 TI - The role of cultural proverbs and myths in shaping sexual worldviews of adolescents in Botswana: evidence from an HIV/STD prevention research study. AB - The literature has shown that adolescents are exposed to socio-cultural activities that put them at risk of HIV and other sexually transmitted infections. To develop effective intervention strategies and programs, it is imperative to understand how the cultural proverbs and myths create sexual norms and shape the worldview of adolescents. The findings indicate that some cultural proverbs and myths negatively influence adolescents hence expose them to risky sexual behaviors. PMID- 24802220 TI - Effective doctor-patient communication: an updated examination. AB - This article examines, in detail, the quality of doctor-patient interaction. Doctor-patient communication is such a powerful indicator of health care quality that it can determine patients' self-management behavior and health outcomes. The medical visit (i.e., the medical encounter) plays a pivotal role in the health care process. In fact, doctor-patient communication is one of the most essential dynamics in health care, affecting the course of patient care and patient compliance with recommendations for care. Unlike many other analyses (that often look at only one or two specific aspects of doctor-patient relationships), this analysis is more encompassing; it looks at doctor-patient communication from multiple perspectives. PMID- 24802219 TI - An exploration of women offenders' health literacy. AB - In the past decade the sentencing of women in Canada to correctional detention has increased. Compared to the general population, women in conflict with the law tend to have higher rates of mortality and morbidity. This exploratory research investigated health promotion and health-literacy issues for women offenders. Semistructured interviews of 12 women serving probation orders were analyzed. Data analysis highlighted three overarching themes: (a) health information access, (b) networks of support, and (c) tailoring the health system. These findings have relevancy for health promotion practice with women offenders, and implications for correctional services community reintegration programs and community health sectors. PMID- 24802221 TI - Ryan White CARE Act Part D: matches and gaps in political commitment and local implementation. AB - This article demonstrates the opportunities for and challenges of the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act Part D to implementing its mandate for comprehensive family-centered systems of care for women, infants, children, and youth with HIV/AIDS. Part D legislation should promote practices addressing families with models for basic security, judiciously embrace those universal public health policies aiming to improve children's overall welfare, and consistently repudiate those policies infringing on human rights of women infected with HIV, or ignoring their children's basic needs. The proposed revisions to Part D implementation may renew its political commitment to serving the needs of families who are HIV affected. PMID- 24802222 TI - Complex lives: resiliency of African American Women with HIV/AIDS serving as informal kinship care providers. AB - Using the resiliency model as a framework, this qualitative description study was designed to elicit the experiences of African American women living with HIV/AIDS serving as informal kinship care providers. Themes emerging from the interviews included (a) strengths of informal social supports, (b) benefits of living with HIV as opposed to women who are not HIV positive, and (c) negative experiences of child welfare services. Findings suggest a plethora of resources women accessed through community-based agencies because of their HIV/AIDS status, as opposed to child welfare agencies. PMID- 24802225 TI - Hypertriglyceridemia influences the degree of postprandial lipemic response in patients with metabolic syndrome and coronary artery disease: from the CORDIOPREV study. AB - OBJECTIVE: To determine whether metabolic syndrome traits influence the postprandial lipemia response of coronary patients, and whether this influence depends on the number of MetS criteria. MATERIALS AND METHODS: 1002 coronary artery disease patients from the CORDIOPREV study were submitted to an oral fat load test meal with 0.7 g fat/kg body weight (12% saturated fatty acids, 10% polyunsaturated fatty acids, 43% monounsaturated fatty acids), 10% protein and 25% carbohydrates. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Total and incremental area under the curves of the different postprandial parameters were calculated following the trapezoid rule to assess the magnitude of change during the postprandial state. RESULTS: Postprandial lipemia response was directly related to the presence of metabolic syndrome. We found a positive association between the number of metabolic syndrome criteria and the response of postprandial plasma triglycerides (p<0.001), area under the curve of triglycerides (p<0.001) and incremental area under the curve of triglycerides (p<0.001). However, the influence of them on postprandial triglycerides remained statistically significant only in those patients without basal hypertriglyceridemia. Interestingly, in stepwise multiple linear regression analysis with the AUC of triglycerides as the dependent variable, only fasting triglycerides, fasting glucose and waist circumference appeared as significant independent (P<0.05) contributors. The multiple lineal regression (R) was 0.77, and fasting triglycerides showed the greatest effect on AUC of triglycerides with a standardized coefficient of 0.75. CONCLUSIONS: Fasting triglycerides are the major contributors to the postprandial triglycerides levels. MetS influences the postprandial response of lipids in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients. PMID- 24802227 TI - Xanthogranulomatous inflammation of gallbladder and bile duct causing obstructive jaundice masquerades gallbladder cancer: a formidable diagnostic challenge continues. PMID- 24802226 TI - Practical aspects of risk assessment in gastrointestinal stromal tumors. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract, which are characterized in the majority of cases by activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors has revolutionized the management of patients with metastatic GIST. However, complete surgical resection remains the mainstay of management for those with localized disease. Recently, three large trials have confirmed the benefit of adjuvant imatinib therapy in patients who were at high risk of recurrence following complete resection. In this setting, it is critical that oncologists understand the various GIST risk assessment criteria and be able to apply these methods to accurately assess the risk of recurrence and the need for adjuvant imatinib therapy. PURPOSE: The aim of this review is to outline the risk stratification systems currently available to oncologists who are treating patients with GIST, so they can be optimally applied for clinical decision-making. PMID- 24802228 TI - Attending to affective domain learning: essential to prepare the kind of graduates the public needs. PMID- 24802229 TI - MALDI-TOF mass spectrometry confirms difficulties in separating species of the Avibacterium genus. AB - In the present study a well-characterized strain collection (n = 33) of Avibacterium species was investigated by matrix-assisted laser desorption ionization-time-of flight mass spectrometry (MALDI-TOF MS). The robustness of the currently available reference database (Bruker Biotyper 3.0) was tested to determine the degree of identification of these strains. Reproducible signal patterns were obtained from all strains. However, identification of most strains was only possible at genus level. Furthermore, two strains could not be identified by this method. Based on their protein spectra profiles, a MALDI main spectra dendrogram was created to determine their relationship. Most strains were closely related-for example, 26 strains formed cluster 1 including the type strains of Avibacterium volantium, Avibacterium gallinarum, Avibacterium endocarditidis and Avibacterium avium-while Avibacterium paragallinarum biovars 1 and 2 formed cluster 2 and, finally, strain 55000 remained on its own. The present MALDI-TOF MS results confirm recent findings that only certain isolates of Av. paragallinarum represent a well-defined species within the genus Avibacterium, making a taxonomic revision essential. To improve identification of Avibacterium at species level by MALDI-TOF MS, relevant reference strains were included in the newly created database and results are presented. In conclusion, Av. paragallinarum can be identified by MALDI/Biotyper and not the other species of the genus. PMID- 24802231 TI - Real-time transrectal ultrasonography-guided hands-free technique for focal cryoablation of the prostate. AB - OBJECTIVES: To describe, step-by-step, our hands-free technique for focal cryoablation of prostate cancer. MATERIALS AND METHODS: After detailed discussion of its limitations and benefits, consent was obtained to perform focal cryoablation in patients with biopsy-proven unilateral low- to intermediate-risk prostate cancer. The procedure was performed transperineally, using a hands-free technique (without an external grid template) under real-time bi-plane transrectal ultrasonography (TRUS) guidance, using an argon/helium-gas-based third generation cryoablation system. Follow-up consisted of validated questionnaires, physical examination, PSA measures, multiparametric TRUS and/or magnetic resonance imaging (MRI) and mandatory biopsy. RESULTS: The important steps for achieving safety, satisfactory oncological and functional outcomes included: patient selection, including TRUS/MRI fusion target biopsy; thermocouple and cryoprobe placement with a hands-free technique, allowing delivery in unrestricted angulations according to the prostatic contour, the course of the neurovascular bundle and the rectal wall angle; and hands-free bi plane TRUS probe manipulation to facilitate real-time monitoring of anatomical landmarks at the ideal angle of the image plane. To achieve a lethal temperature in the known cancer area, while preserving the urinary sphincter, neurovascular bundle, urethra and rectal wall, continuous intraoperative control of the thermocouple temperatures was necessary, as were real-time TRUS monitoring of ice ball size, control of the energy delivered and the use of a warming urethral catheter. CONCLUSION: We have described step-by-step the focal cryoablation of prostate cancer using a hands-free technique. This technique facilitates the effective delivery of cryoprobes and the intra-operative real-time quick manipulation of the TRUS probe. PMID- 24802232 TI - Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: A propensity score analysis. AB - AIM: Patients with hepatocellular carcinoma (HCC) who receive an initial full dose of sorafenib (800 mg/day) often require a decreased dose (400 mg/day) or discontinuation of therapy because of severe adverse events. We conducted a retrospective analysis of patients with HCC to compare the safety and efficacy of full- to half-dose sorafenib. METHODS: We reviewed the medical records of 218 consecutive patients with intermediate or advanced stage HCC who received half (n = 73) or full-dose sorafenib (n = 145) between 2009 and 2012 at four institutions. A propensity score-matching analysis was used to adjust for potential bias. RESULTS: Multivariate logistic regression analysis showed that increased age was an independent factor for the selection of initial half-dose sorafenib (odds ratio, 1.10; 95% confidence interval, 1.05-1.15; P < 0.001). Fifty-eight patients each in the half-dose and full-dose groups were selected for propensity score matching. The incidence of grade 3-4 severe adverse effects was lower in the half-dose group (47.4% vs 66.7%, P = 0.037). In contrast, the median progression-free survival (PFS) and overall survival (OS) rates were not significantly different (half-dose group, 3.8 and 10.2 months; full-dose group, 2.5 and 8.8 months; P = 0.143 and 0.911, respectively). CONCLUSION: Propensity score-matched analyses indicate that initial half-dose sorafenib treatment led to fewer severe adverse effects and a comparable survival benefit compared with a full dose in select patients with HCC, particularly for those of advanced age. PMID- 24802230 TI - Impact of treatment response metrics on photodynamic therapy planning and outcomes in a three-dimensional model of ovarian cancer. AB - Common methods to characterize treatment efficacy based on morphological imaging may misrepresent outcomes and exclude effective therapies. Using a three dimensional model of ovarian cancer, two functional treatment response metrics are used to evaluate photodynamic therapy (PDT) efficacy: total volume, calculated from viable and nonviable cells, and live volume, calculated from viable cells. The utility of these volume-based metrics is corroborated using independent reporters of photodynamic activity: viability, a common fluorescence based ratiometric analysis, and photosensitizer photobleaching, which is characterized by a loss of fluorescence due in part to the production of reactive species during PDT. Live volume correlated with both photobleaching and viability, suggesting that it was a better reporter of PDT efficacy than total volume, which did not correlate with either metric. Based on these findings, live volume and viability are used to probe the susceptibilities of tumor populations to a range of PDT dose parameters administered using 0.25, 1, and 10 MUM benzoporphyrin derivative (BPD). PDT with 0.25 MUM BPD produces the most significant reduction in live volume and viability and mediates a substantial shift toward small nodules. Increasingly sophisticated bioengineered models may complement current treatment planning approaches and provide unique opportunities to critically evaluate key parameters including metrics of therapeutic response. PMID- 24802233 TI - Factor analysis of treatment outcomes from a UK specialist addiction service: relationship between the Leeds Dependence Questionnaire, Social Satisfaction Questionnaire and 10-item Clinical Outcomes in Routine Evaluation. AB - INTRODUCTION AND AIMS: To examine the relationship between three outcome measures used by a specialist addiction service (UK): the Leeds Dependence Questionnaire (LDQ), the Social Satisfaction Questionnaire (SSQ) and the 10-item Clinical Outcomes in Routine Evaluation (CORE-10). DESIGN AND METHOD: A clinical sample of 715 service user records was extracted from a specialist addiction service (2011) database. The LDQ (dependence), SSQ (social satisfaction) and CORE-10 (psychological distress) were routinely administered at the start of treatment and again between 3 and 12 months post-treatment. A mixed pre/post-treatment dataset of 526 service users was subjected to exploratory factor analysis. Parallel Analysis and the Hull method were used to suggest the most parsimonious factor solution. RESULTS: Exploratory factor analysis with three factors accounted for 66.2% of the total variance but Parallel Analysis supported two factors as sufficient to account for observed correlations among items. In the two-factor solution, LDQ items and nine of the 10 CORE-10 items loaded on the first factor >0.41, and the SSQ items on factor 2 with loadings >0.63. A two dimensional summary appears sufficient and clinically meaningful. DISCUSSION AND CONCLUSIONS: Among specialist addiction service users, social satisfaction appears to be a unique construct of addiction and is not the same as variation due to psychological distress or dependence. Our interpretation of the findings is that dependence is best thought of as a specific psychological condition subsumed under the construct psychological distress. PMID- 24802234 TI - Effects of acupuncture on progesterone and prolactin in rats of embryo implantation dysfunction. AB - OBJECTIVE: To investigate the effect of acupuncture on progesterone (P4) and prolactin (PRL) in rats of embryo implantation dysfunction (EID). METHODS: On the first day of pregnancy, 72 female Wistar rats were randomly allocated into the normal group, the EID model group, the acupuncture group and the P4 group (18 in each group). The normal group was injected sesame oil, while the other three groups were given mifepristone to establish the EID model. The acupuncture group and the P4 group were given treatment of acupuncture and P4 injection, respectively. The serum of P4 and PRL were detected by radioimmunoassay, and the mRNA and protein expressions of P4 receptor (PR) and PRL receptor (PRLR) were detected using real-time polymerase chain reaction and immunohistochemical method, respectively. RESULTS: Compared with the normal group, the serum levels of P4 and PRL as well as the mRNA and protein expression levels of PR and PRLR in the EID model group were significantly lowered (P<0.01 or P<0.05). The above indices in the acupuncture group and the P4 group were significantly elevated compared with the EID model group (P<0.01 or P<0.05). CONCLUSION: Acupuncture can promote embryo implantation effectively, which might be related to the effects of acupuncture on upregulating the P4 and PRL levels in serum and the PR and PRLR expression levels in rats. PMID- 24802235 TI - Xihuang Pill () induces mesenchymal-epithelial transition and inhibits loss of apical-basal polarity in colorectal cancer cell through regulating ZEB1-SCRIB loop. AB - OBJECTIVE: To investigate the antiproliferative and anti-metastasis effect of Xihuang Pill (, XP) on human colorectal cancer cell and to explore the molecular mechanism by which it produces the effects. METHODS: Highly metastatic human colorectal cancer cell line LoVo was treated with low-, medium-, and highdose XP containing serum (XP-L, XP-M, XP-H) groups for 48 h, cells intervened with no drug rat serum and PD98059 [extracellular signal-regulated kinase (ERK) inhibitor] as negative and positive controls (NC and PC) groups. Cell proliferation assay was made using cell counting kit-8 (CCK8). The 8 MUm pore size transwell chamber and 4', 6-diamidino-2-phenylindole (DAPI) staining were applied to examine the ability of invasion and migration of the cells. The protein expression of ERK1/2, zinc fifi nger E-box-binding homeobox 1 (ZEB1), Scrib and lethal giant larvae homolog 2 (Lgl2) was detected by Western blotting while the relative mRNA quantity of E-cadherin, N-cadherin, Occludin and junctional adhesion molecule-1 (JAM1) was measured by realtime fluorescent quantitative polymerase chain reaction (RT-qPCR). RESULTS: XP induced a dose dependent suppression on the proliferation of LoVo cells (P <0.05 or P<0.01), with the inhibition rates varied from 27.30% to 31.08%. Transwell assay showed that when preprocessed with PD98059 and XP-containing serum, the number of cells that passed the filter decreased significantly compared with that of NC group (P <0.05 or P<0.01). Moreover, XP inhibited the protein expression of ERK1/2 and ZEB1 (P <0.05); and up-regulated the protein expression of Scrib and Lgl2 (P <0.05). The mRNA levels of E-cadherin, Occludin and JAM1 of the XP intervened groups and PC group markedly ascended (P <0.05) while that of N-cadherin showed a descending tendency (P>0.05). CONCLUSION: XP intervention suppressed the ability of proliferation, invasion and migration of the LoVo cells. Regulating ZEB1-SCRIB Loop so as to recover epithelial phenotype and apical junctional complex might be one of the mechanisms by which XP produces the anti-metastasis effect. PMID- 24802236 TI - MicroRNA expression profile of dexamethasone-induced human bone marrow-derived mesenchymal stem cells during osteogenic differentiation. AB - MiRNAs have been identified in various plants and animals where they function in post-transcriptional regulation. Although studies revealed that dexamethasone play a pivotal role in the osteogenic differentiation of human bone marrow derived mesenchymal stem cells (hBMSCs), the identification of specific miRNAs and their regulatory roles in this process remain poorly defined. In this study, microarrays were used to analyze the miRNA expression profile of dexamethasone induced hBMSCs derived from three donors, and RT-PCRs were used to confirm the microarray results. Nine upregulated miRNAs and seven downregulated miRNAs were identified. The putative target genes of these miRNAs were predicted using bioinformatics analysis. Subsequently, we focused our attention on the functional analysis of an upregulated miRNA, miR-23a. Overexpression of miR-23a inhibited osteogenic differentiation of hBMSCs at the cellular, mRNA, and protein levels. The results of our study provide an experimental basis for further research on miRNAs functions during osteogenic differentiation of dexamethasone-induced hBMSCs. PMID- 24802237 TI - International neuromodulation society critical assessment: guideline review of implantable neurostimulation devices. AB - INTRODUCTION: Spinal cord stimulation (SCS) is well accepted for the treatment of chronic pain since its beginning in 1967. As its use continues to enter into the chronic pain treatment algorithm earlier, conscience patient selection and durability of the therapy are clearly clinically relevant. To improve treatment efficacy, consensus statements and guidelines were developed. OBJECTIVE: The purpose of this work is to review the relevant guideline statements for implantable neurostimulation therapies to treat chronic pain and to identify guideline gaps and future directions for recommendation platforms. MATERIALS AND METHODS: A systematic literature search through EMBASE, Medline, Cochrane data base, as well as peer-reviewed, nonindexed journals and materials presented at national and international meetings was performed to chronologically identify consensus statements or guideline statements for use of neurostimulation therapies to treat chronic neuropathic pain limited to the English language. RESULTS: From 1998 to 2013, 22 guideline statements were identified. Thirteen of the 22 guidelines were society-sponsored guideline statements from ten societies. Two guideline statements were from research foundations, two were government supported, and one statement was published as a position statement. CONCLUSIONS: The current available guideline statements have clear deficiencies in either scope of coverage, evidence synthesis, or lack of transparency of funding. Improved evidence and best practice/guideline assessment may improve patient outcomes and accessibility to these important modalities. Further prospective comparator randomized data are required to not only provide data of clinical and cost-effectiveness in other indications but also to better describe the position of neurostimulation application within the disease management pathway. Therein cases where there appears to be sufficient evidence and consensus, every effort should be made to secure access to these effective therapies. Importantly, each guideline only has a useful clinical half-life, if not updated. This should be acknowledged by both clinicians and third-party payers. Based on these deficiencies, the International Neuromodulation Society recommended the creation of a consensus conference to examine the appropriate use of neurostimulation for pain and ischemic disease. PMID- 24802238 TI - Flow injection determination of diclofenac sodium based on its sensitizing effect on the chemiluminescent reaction of acidic potassium permanganate-formaldehyde. AB - A sensitive and simple chemiluminescent (CL) method for the determination of diclofenac sodium has been developed by combining the flow injection technique and its sensitizing effect on the weak CL reaction between formaldehyde and acidic potassium permanganate. A calibration curve is constructed for diclofenac sodium under optimized experimental parameters over the range 0.040-5.0 ug/mL and the limit of detection is 0.020 ug/mL (3sigma). The inter-assay relative standard deviation for 0.040 ug/mL diclofenac sodium (n = 11) is 2.0%. This method is rapid, sensitive, simple, and shows good selectivity and reproducibility. The proposed method has been successfully applied to the determination of the studied diclofenac sodium in pharmaceutical preparations with satisfactory results. Furthermore, the possible mechanism for the CL reaction has been discussed in detail on the basis of UV and CL spectra. PMID- 24802241 TI - An SPE-assisted BODIPY fluorometric paper sensor for the highly selective and sensitive determination of Cd2+ in complex sample: rice. AB - By using sensing technology, the individual component analysis at trace level in complex samples remains problematic simply because of various interfering species. For example, the determination of Cd(2+) in rice is difficult due to the co-existing interfering metal cations at thousands or even millions of times higher concentrations. In this study, a heavy-metal ion sensitive BODIPY (4,4 difluoro-4-bora-3a,4a-diaza-s-indacene)-based fluorometric paper sensor with assistance of solid phase extraction (SPE) was developed for the highly selective and sensitive determination of trace Cd(2+) in rice. SPE column packed with prepared sulfonated PS-DVB microspheres was employed to enrich trace Cd(2+) and meanwhile remove most interfering heavy-metal ions in simulated complex rice sample with oxalic acid as eluent, which was theoretically selected on the basis of f values. Mn(2+), as a major coexistent heavy-metal ion, could not be easily removed by SPE, but showed little fluorescent response for BODIPY fluorometric paper sensor even in excess amounts. Combining the separation and enrichment capability of SPE column with the selectivity of BODIPY-based fluorometric paper sensor, we were able to detect trace Cd(2+) in complex samples. The response of fluorometric paper sensor was linearly related with Cd(2+) concentrations in the range of 0.5-4 MUM, with a detection limit of 0.5 MUM. Twelve real rice samples spiked with Cd(2+) were analysed using this method and the results are in good agreement with ICP-MS measurements. PMID- 24802240 TI - Economic valuation and determinants of informal care to people with Alzheimer's disease. AB - OBJECTIVE: To estimate the monetary value of informal care to people with Alzheimer's disease (AD) in Spain and to identify the main determinants of the time of informal care. DATA AND METHODS: We used the Survey on Disabilities, Autonomy and Dependency carried out in Spain in 2008 to obtain information on disabled individuals with Alzheimer and their informal caregivers. Assessment of informal care time was performed using three different approaches: the proxy good method, the opportunity cost method and the contingent valuation method. A statistical multivariate analysis--an ordered probit model--was performed to study the determinants of informal care provided. RESULTS: The average number of required informal hours per year was 4,151. The cost per caregiver ranged from 31,839 to 52,760 euros under the proxy good method; it was estimated at 20,053 euros under the opportunity cost method; and it ranged between 18,680 and 29,057 euros under the contingent valuation method. The degree of dependency and the formal care services were the main variables that explained the variability of the informal time provided. When a person presents a very high level of dependency, the probability of receiving more than 100 h of informal care per week is 25.8% higher than a non-dependent person with AD. Formal in-home care complements informal caregiving, while formal care outside the home replaces it. CONCLUSIONS: Informal care represents a high social cost in people with AD, regardless of the estimation method considered. A higher level of dependence is associated with more hours of informal care provided. PMID- 24802239 TI - Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone. AB - Lymphocytic choriomeningitis virus (LCMV) can be transmitted through congenital infection, leading to persistent infection of numerous organ systems including the central nervous system (CNS). Adult mice persistently infected with LCMV (LCMV-cgPi mice) exhibit learning deficits, such as poor performance in spatial discrimination tests. Given that deficits in spatial learning have been linked to defects in adult neurogenesis, we investigated the impact of congenital LCMV infection on generation of neuroblasts from neural progenitor cells within neurogenic zones of adult mice. In LCMV-cgPi mice, QPCR and immunohistochemistry detected presence of LCMV glycoprotein-coding RNA and nucleoprotein in the hippocampal dentate gyrus and subventricular zone (SVZ), sites of neurogenesis that harbor populations of neuroblasts. Numbers of neuroblasts were reduced in LCMV-cgPi mice, as determined by IHC quantification, and analysis of BrdU incorporation by flow cytometry revealed lower numbers of BrdU-labeled neuroblasts. Additionally, TUNEL assays performed in situ showed increased numbers of apoptotic cells in the two neurogenic regions. Next, neurosphere cultures were infected in vitro with LCMV and differentiated to create a population of cells that consisted of both transit amplifying cells and neuroblasts. Immunocytochemical and TUNEL assays revealed increased numbers of TUNEL-positive cells that express nestin, suggesting that the drop in numbers of neuroblasts was due to a combination of impaired proliferation and apoptosis of progenitor cells. LCMV-cgPi mice exhibited transcriptional up-regulation several cytokines and chemokines, including gamma-interferon inducible chemokines CXCL9 and CXCL10. Chronic up-regulation of these chemokines can facilitate a pro inflammatory niche that may contribute to defects in neurogenesis. PMID- 24802243 TI - Enhanced ethanol production from pomelo peel waste by integrated hydrothermal treatment, multienzyme formulation, and fed-batch operation. AB - Pomelo peel is an abundant pectin-rich biomass waste in China and has the potential to serve as a source of fuels and chemicals. This study reports a promising way to deal with pomelo peel waste and to utilize it as raw material for ethanol production via simultaneous saccharification and fermentation (SSF). An integrated strategy, incorporating hydrothermal treatment, multienzyme formulation, and fed-batch operation, was further developed to enhance the ethanol production. The results show that hydrothermal treatment (120 degrees C, 15 min) could significantly reduce the use of cellulase (from 7 to 3.8 FPU g(-1)) and pectinase (from 20 to 10 U g(-1)). A multienzyme complex, which consists of cellulase, pectinase, beta-glucosidase, and xylanase, was also proven to be effective to improve the hydrolysis of pretreated pomelo peel, leading to higher concentrations of fermentative sugars (36 vs 14 g L(-1)) and galacturonic acid (23 vs 9 g L(-1)) than those with the use of a single enzyme. Furthermore, to increase the final ethanol concentration, fed-batch operation by adding fresh substrate was employed in the SSF process. A final solid loading of 25% (w/v), which is achieved by adding 15% fresh substrate to the SSF system at an initial solid loading of 10%, produced 36 g L(-1) ethanol product in good yield (73.5%). The ethanol concentration is about 1.73-fold that at the maximum solid loading of 14% for batch operation, whereas both of them have a closed ethanol yield. The results indicate that the use of the fed-batch mode could alleviate the decrease in ethanol yield at high solid loading, which is caused by significant mass transfer limitation and increased inhibition of toxic compounds in the SSF process. The integrated strategy demonstrated in this work could open a new avenue for dealing with pectin-rich biomass wastes and utilization of the wastes to produce ethanol. PMID- 24802242 TI - Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201). AB - OBJECTIVES: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. METHODS: Thirty four participants with virologic suppression >= 48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell associated markers (HLA-DR, CD's 38/69/94/95/158/279). RESULTS: Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) >50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL >50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92-55.3). Simplification was associated with transient increases in naive and CD25+ CD4+ T-cells, and had no impact on IA levels. CONCLUSIONS: Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. TRIAL REGISTRATION: ClinicalTrials.gov NCT00084019. PMID- 24802244 TI - Polymerization kinetics of resin cements after light activation through fibre posts: an in vitro study. AB - AIM: To measure the polymerization of light-cured (Variolink Veneer, VLV) and dual-cured (Variolink II, VLII) resin luting cements after light activation through different lengths of fibre post ex vivo. METHODOLOGY: Degree of conversion after prolonged direct light activation (PLA) [12 min after LED light activation for 3 min] was determined using ATR-FTIR. Models were then produced to allow samples of VLV and VLII (n = 5 each group) to be light-activated through 3, 6 and 9 mm lengths of fibre post (Fiber Lux). Degree of conversion was assessed by ATR-FTIR and expressed as a percentage of the degree of conversion achieved after PLA. Data were analysed using anova and Tukey's test (P < 0.05). RESULTS: Mean [SD] degree of conversion for VLV and VLII after PLA was 57.97% [1.51] and 54.71% [3.77], respectively. Light activation of VLV through a 3 mm post produced 81.62% of the PLA value, compared with 71.03% for the 6 mm and 46.04% for the 9 mm post. Conversion after activation through 9 mm posts was significantly less than through 3 mm and 6 mm posts (P < 0.05). For VLII, activation through a 3 mm post produced 66.51% of the PLA value, compared with 54.38% for the 6 mm and 41.56% for the 9 mm post. A significant decrease in degree of conversion was noted for VLII as post length increased (P < 0.05). CONCLUSIONS: The degree of conversion for VLV reduced after light activation through 9 mm posts when compared to 3 mm and 6 mm posts, whilst the degree of conversion for VLII decreased with every increase in post length. PMID- 24802246 TI - Trifluoromethyl-modified dipeptides by ZrCl4-promoted aza-Henry reactions. AB - Chiral (R)-1-phenylethylamine was successfully employed in a tandem aza-Henry addition-reduction reaction to give chiral beta-nitro alpha-trifluoromethyl amines. A subsequent coupling reaction with N-Boc-protected amino acids leads to obtain optically pure CF3-modified dipeptides carrying two different N-protecting groups. These peptidomimetic units are characterized by the presence of the [CH(CF3)NH] group as mimetic of the natural [CONH] peptidic bond and can be used for the synthesis of more complex CF3-modified peptides after selective deprotection of one of the two amine functions. 2D NMR spectral analyses were employed to determine the absolute configurations of all newly synthesized chiral compounds. PMID- 24802247 TI - Synthesis and preliminary biological evaluation of O-2((2 [(18)F]fluoroethyl)methylamino)ethyltyrosine ([(18)F]FEMAET) as a potential cationic amino acid PET tracer for tumor imaging. AB - Amino acid transport is an attractive target for oncologic imaging. Despite a high demand of cancer cells for cationic amino acids, their potential as PET probes remains unexplored. Arginine, in particular, is involved in a number of biosynthetic pathways that significantly influence carcinogenesis and tumor biology. Cationic amino acids are transported by several cationic transport systems including, ATB(0,+) (SLC6A14), which is upregulated in certain human cancers including cervical, colorectal and estrogen receptor-positive breast cancer. In this work, we report the synthesis and preliminary biological evaluation of a new cationic analog of the clinically used PET tumor imaging agent O-(2-[(18)F]fluroethyl)-L-tyrosine ([(18)F]FET), namely O-2((2 [(18)F]fluoroethyl)methylamino)ethyltyrosine ([(18)F]FEMAET). Reference compound and precursor were prepared by multi-step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [(18)F]fluorination in 16-20% decay-corrected yields with radiochemical purity >99%. The new tracer showed good stability in vitro and in vivo. Cell uptake assays demonstrated that FEMAET and [(18)F]FEMAET accumulate in prostate cancer (PC-3) and small cell lung cancer cells (NCI-H69), with an energy-dependent mechanism. Small animal PET imaging with NCI-H69 xenograft-bearing mice revealed good tumor visualization comparable to [(18)F]FET and low brain uptake, indicating negligible transport across the blood-brain barrier. In conclusion, the non-natural cationic amino acid PET probe [(18)F]FEMAET accumulates in cancer cells in vitro and in vivo with possible involvement of ATB(0,+). PMID- 24802245 TI - Emerging role of leptin in rheumatoid arthritis. AB - Numerous studies have suggested the importance of leptin against autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and psoriasis. To summarize our current understanding of the role of leptin in inflammatory responses and rheumatoid arthritis (RA), a systematic review was conducted to assess the discrepancy of leptin in RA and its effect on immunity according to different studies. Recently, emerging data have indicated that leptin is involved in the pathological function of RA, which is common in autoimmune disorders. This review discusses the possible consequences of leptin levels in RA. Blocking the key signal pathways of leptin and inhibiting the leptin activity-like leptin antagonist may be a promising way for potential therapeutic treatment of RA at risk of detrimental effects. However, leptin was increased in patients with RA and may also regulate joint damage. Thus, more understanding of the mechanism of leptin in RA would be advantageous in the future. PMID- 24802249 TI - Further studies on control synthesis of discrete-time T-S fuzzy systems via augmented multi-indexed matrix approach. AB - This paper is concerned with further studies on control synthesis of discrete time Takagi-Sugeno (T-S) fuzzy systems. To do this, a novel slack variable technique, which is homogenous polynomially parameter-dependent on both the current-time normalized fuzzy weighting functions and the past-time normalized fuzzy weighting functions with arbitrary degrees, is presented by developing an efficient augmented multi-indexed matrix approach. Under the framework of homogenous matrix polynomials, the algebraic properties of both the current-time normalized fuzzy weighting functions and the past-time normalized fuzzy weighting functions are collected into sets of augmented multi-indexed matrices. Thus, more information about the underlying normalized fuzzy weighting functions is involved into control synthesis. Consequently, the relaxation quality of control synthesis of discrete-time T-S fuzzy systems is improved significantly. Finally, a numerical example is provided to illustrate the effectiveness of the proposed method. PMID- 24802248 TI - The hydrophobic contacts between the center of the betaI domain and the alpha1/alpha7 helices are crucial for the low-affinity state of integrin alpha4 beta7. AB - Integrin alpha4 beta7 mediates both rolling and firm adhesion of lymphocytes by modulating its affinity to the ligand: mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Integrin activation is associated with allosteric reshaping in the beta subunit I (betaI) domain. A prominently conformational change comprises displacement of the alpha1 and alpha7 helices in the betaI domain, suggesting that the location of these helices is important for the change in integrin affinity. In the present study, we report that the hydrophobic contacts between the center of the beta7 I domain and the alpha1/alpha7 helices play critical roles in keeping alpha4 beta7 in a low-affinity state. Using molecular dynamics simulation, we identified nine hydrophobic residues that might be involved in the critical hydrophobic contacts maintaining integrin in a low-affinity state. Integrin beta7 I domain exhibited a lower binding free energy for ligand after disrupting these hydrophobic contacts by substituting the hydrophobic residues with Ala. Moreover, these alpha4 beta7 mutants not only showed high-affinity binding to soluble MAdCAM-1, but also demonstrated firm cell adhesion to immobilized MAdCAM-1 in shear flow and enhanced the strength of the alpha4 beta7 MAdCAM-1 interaction. Disruption of the hydrophobic contacts also induced the active conformation of alpha4 beta7 . Thus, the findings obtained in the present study reveal an important structural basis for the low-affinity state of integrin. PMID- 24802250 TI - Management of rectal cancer in France in a well-defined population. AB - OBJECTIVE: The aim of this study was to draw a picture of diagnostic assessment and patterns of care for rectal cancer in France using population-based registries data. METHODS: The study included a random sample of 669 cases of rectal cancers diagnosed in 2005. RESULTS: Diagnostic assessment was performed by colonoscopy in 91.4% of the cases. An abdominal computed tomography was performed in 59.4% of the cases and chest computed tomography in 47.8%. An R0 resection was performed in 65.8% of cases and an R1/R2 resection in 16.1%. A rectal endosocography was performed in 40.4% and MRI in 10.4%. The sphincter was preserved in 73.6% of patients aged younger than 75 years of age and in 62.5% of those older than 75 years of age (P=0.002). In cases of R0 resection, neoadjuvant radiotherapy was performed in 47.8% of patients younger than 75 years of age and in 34.1% of older patients (P=0.007). Postoperative chemotherapy was administered in 23.9% of stage II and 67.8% of stage III resected patients. CONCLUSION: The management of rectal cancers can be improved. Preoperative staging has not reached its full development; very few patients received neoadjuvant treatment, whereas adjuvant chemotherapy was often performed, although its benefit is still unclear. The management of elderly patients was less optimal than that of younger patients. PMID- 24802251 TI - Measurement of mass-based carbon nanotube penetration through filtering facepiece respirator filtering media. AB - Recent studies suggest that a wide range of human health effects could result from exposure to carbon nanotubes (CNTs). A National Institute for Occupational Safety and Health survey of the carbonaceous nanomaterial industry found that 77% of the companies used respiratory protection, such as filtering facepiece respirators (FFRs). Despite CNT studies in some occupational settings being reported, the literature for mass-based penetration of CNTs through FFRs is lacking. The aim of this study was to conduct a quantitative study of single walled CNT (SWCNT) and multiwalled CNT (MWCNT) penetration through FFRs. A CNT aerosol respirator testing system was used to generate charge-neutralized airborne SWCNTs and MWCNTs for this study. The size distribution was 20-10000 nm, with 99% of the particles between 25 and 2840 nm. Mass median diameters were 598 and 634 nm with geometric standard deviations of 1.34 and 1.48 for SWCNTs and MWCNTs, respectively. Upstream and downstream CNTs were collected simultaneously using closed-face 3.7-cm-diameter filter cassettes. These samples were subsequently analyzed for organic carbon and elemental carbon (EC), with EC as a measure of mass-based CNTs. The mass-based penetration of SWCNTs and MWCNTs through six FFR models at constant flow rates of 30 l min(-1) (LPM) was determined. Generally, the penetrations of SWCNTs and MWCNTs at 30 LPM had a similar trend and were highest for the N95 FFRs, followed by N99 and P100 FFRs. The mass-based penetration of MWCNTs through six FFR models at two constant flow rates of 30 and 85 LPM was also determined. The penetration of MWCNTs at 85 LPM was greater compared with the values of MWCNTs at 30 LPM. PMID- 24802252 TI - Airborne exposures to monoethanolamine, glycol ethers, and benzyl alcohol during professional cleaning: a pilot study. AB - A growing body of epidemiologic evidence suggests an association between exposure to cleaning products and respiratory dysfunction. Due to the lack of quantitative assessments of respiratory exposures to airborne irritants and sensitizers among professional cleaners, the culpable substances have yet to be identified. PURPOSE: Focusing on previously identified irritants, our aims were to determine (i) airborne concentrations of monoethanolamine (MEA), glycol ethers, and benzyl alcohol (BA) during different cleaning tasks performed by professional cleaning workers and assess their determinants; and (ii) air concentrations of formaldehyde, a known indoor air contaminant. METHODS: Personal air samples were collected in 12 cleaning companies, and analyzed by conventional methods. RESULTS: Nearly all air concentrations [MEA (n = 68), glycol ethers (n = 79), BA (n = 15), and formaldehyde (n = 45)] were far below (<1/10) of the corresponding Swiss occupational exposure limits (OEL), except for ethylene glycol mono-n-butyl ether (EGBE). For butoxypropanol and BA, no OELs exist. Although only detected once, EGBE air concentrations (n = 4) were high (49.48-58.72mg m(-3)), and close to the Swiss OEL (49mg m(-3)). When substances were not noted as present in safety data sheets of cleaning products used but were measured, air concentrations showed no presence of MEA, while the glycol ethers were often present, and formaldehyde was universally detected. Exposure to MEA was affected by its amount used (P = 0.036), and spraying (P = 0.000) and exposure to butoxypropanol was affected by spraying (P = 0.007) and cross-ventilation (P = 0.000). CONCLUSIONS: Professional cleaners were found to be exposed to multiple airborne irritants at low concentrations, thus these substances should be considered in investigations of respiratory dysfunctions in the cleaning industry; especially in specialized cleaning tasks such as intensive floor cleaning. PMID- 24802254 TI - Nonlinear optical microscopy with vibrational contrast. AB - Nonlinear optical techniques which provide vibrational contrast have gained increasing attention in microscopy during the last two decades. After outlining the potential of these techniques, we give a brief introduction to coherent anti Stokes Raman scattering, stimulated Raman scattering and sum frequency generation and discuss their suitability for contrast generation in optical microscopy. The rapid developments in these fields during the last decade have resulted in many different applications. Three exemplary application areas will therefore be presented in the last part of this manuscript. PMID- 24802253 TI - Brainstem neurons survive the identical ischemic stress that kills higher neurons: insight to the persistent vegetative state. AB - Global ischemia caused by heart attack, pulmonary failure, near-drowning or traumatic brain injury often damages the higher brain but not the brainstem, leading to a 'persistent vegetative state' where the patient is awake but not aware. Approximately 30,000 U.S. patients are held captive in this condition but not a single research study has addressed how the lower brain is preferentially protected in these people. In the higher brain, ischemia elicits a profound anoxic depolarization (AD) causing neuronal dysfunction and vasoconstriction within minutes. Might brainstem nuclei generate less damaging AD and so be more resilient? Here we compared resistance to acute injury induced from simulated ischemia by 'higher' hippocampal and striatal neurons versus brainstem neurons in live slices from rat and mouse. Light transmittance (LT) imaging in response to 10 minutes of oxygen/glucose deprivation (OGD) revealed immediate and acutely damaging AD propagating through gray matter of neocortex, hippocampus, striatum, thalamus and cerebellar cortex. In adjacent brainstem nuclei, OGD-evoked AD caused little tissue injury. Whole-cell patch recordings from hippocampal and striatal neurons under OGD revealed sudden membrane potential loss that did not recover. In contrast brainstem neurons from locus ceruleus and mesencephalic nucleus as well as from sensory and motor nuclei only slowly depolarized and then repolarized post-OGD. Two-photon microscopy confirmed non-recoverable swelling and dendritic beading of hippocampal neurons during OGD, while mesencephalic neurons in midbrain appeared uninjured. All of the above responses were mimicked by bath exposure to 100 uM ouabain which inhibits the Na+/K+ pump or to 1-10 nM palytoxin which converts the pump into an open cationic channel. Therefore during ischemia the Na+/K+ pump of higher neurons fails quickly and extensively compared to naturally resilient hypothalamic and brainstem neurons. The selective survival of lower brain regions that maintain vital functions will support the persistent vegetative state. PMID- 24802255 TI - You and your kin: Neural signatures of family-based group perception in the subgenual cortex. AB - Attachment to one's kin as an in-group emerges from a fundamental human motivation and is vital for human survival. Despite important recent advances in the field of social neuroscience, the neural mechanisms underlying family-related in-group perception remain obscure. To examine the neural basis of perceiving family-related in-group boundaries in response to written kinship scenarios, we used functional magnetic resonance imaging in 27 healthy adults and obtained self report ratings of family-related entitativity, which measures to what degree participants perceive their family as a coherent and distinct group in society. We expected that activity in the subgenual cingulate cortex and septo hypothalamic region would track individual differences in entitativity. Perceiving one's family as a distinct and cohesive group (high entitativity) was associated with increased subgenual cortex response to kinship scenarios. The subgenual cingulate cortex may represent a key link between kin-related emotional attachment and group perception, providing a neurobiological basis for group belongingness. PMID- 24802256 TI - Arachidonic acid induces brain endothelial cell apoptosis via p38-MAPK and intracellular calcium signaling. AB - Arachidonic acid (AA), a bioactive fatty acid whose levels increase during neuroinflammation, contributes to cerebral vascular damage and dysfunction. However, the mode of injury and underlying signaling mechanisms remain unknown. Challenge of primary human brain endothelial cells (HBECs) with AA activated a stress response resulting in caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and disruption of monolayer integrity. AA also induced loss of mitochondrial membrane potential and cytochrome c release consistent with activation of intrinsic apoptosis. HBEC stimulation with AA resulted in sustained p38-MAPK activation and subsequent phosphorylation of mitogen-activated protein kinase activated protein-2 (MAPKAP-2) kinase and heat shock protein-27 (Hsp27). Conversely, other unsaturated and saturated fatty acids had no effect. Pharmacological and RNA interference-mediated p38alpha or p38beta suppression abrogated AA signaling to caspase-3 and Hsp27, suggesting involvement of both p38 isoforms in AA-induced HBEC apoptosis. Hsp27 silencing also blocked caspase-3 activation. AA stimulated intracellular calcium release, which was attenuated by inositol 1,4,5-trisphosphate (IP3) receptor antagonists. Blockade of intracellular calcium release decreased caspase-3 activation, but had no effect on AA-induced p38-MAPK activation. However, inhibition of p38-MAPK or blockade of intracellular calcium mobilization abrogated AA-induced cytochrome c release. AA induced caspase-3 activation was abrogated by pharmacological inhibition of lipooxygenases. These findings support a previously unrecognized signaling cooperation between p38-MAPK/MAPKAP-2/Hsp27 and intracellular calcium release in AA-induced HBEC apoptosis and suggest its relevance to neurological disorders associated with vascular inflammation. PMID- 24802257 TI - Liquid chromatography-tandem mass spectrometric assay for the determination of vaccarin in rat plasma: application to a pharmacokinetic study. AB - Vaccarin, a flavonoid glycoside, is considered one of the major active constituents of Vaccaria segetalis. A simple and specific liquid chromatography tandem mass spectrometric method was developed and validated for quantifying vaccarin in rat plasma following intravenous dosing. Plasma samples were precipitated with methanol and separated on a Venusil-C18 analytical column (2.1 * 50 mm, 5 um particles) with gradient elution consisting of methanol and 0.1% (v/v) formic acid as the mobile phase. The detection was performed on an Agilent Triple Quad LC/MS with electrospray ionization inlet in the positive multiple reaction monitoring mode. Good linearity was achieved over the concentration range of 12.5-25,000 ng/mL (r(2) > 0.99). Intra- and inter-day precisions were <9.1%, and accuracy ranged from -2.8 to 8.7%. The lower limit of quantification for vaccarin was 12.5 ng/mL, and the analyte was stable under various storage conditions. This validated method was successfully applied to the preliminary pharmacokinetic studies of vaccarin following intravenous administrations of 1.21, 2.41, and 4.82 mg/kg vaccarin in rats. PMID- 24802258 TI - Planar chiral dialkoxysilane: introduction of inherent chirality and high reactivity in conventional achiral alkene. AB - A simple eight-membered dialkoxysilane (E)-1 prepared from 2-pentene-1,5-diol, showed remarkably stable planar chirality along with high reactivity toward epoxidation, Diels-Alder reaction, and cycloaddition reaction with azide. PMID- 24802259 TI - Hierarchical nanohybrids with porous CNT-networks decorated crumpled graphene balls for supercapacitors. AB - One of the most challenging issues in developing supercapacitor technology is the rational design and synthesis of active electrode materials, at the nanoscale, with favorable morphologies, reasonable porous structure, and excellent conductivity. By transforming a two-dimensional (2D) graphene sheet into a crumpled ball shape, a novel three-dimensional (3D) graphene structure with a large surface area and aggregation-resistant properties has been proposed as an active material in supercapacitors to address the issues associated with the restacking of 2D graphene sheets. To further improve the mass transport/electron transfer and address the issue of limited contact spots between the crumpled graphene balls (CGBs) or between the CGBs and the current collector, we report here a unique hierarchical nanohybrid with porous carbon nanotube (CNT)-networks decorated CGBs (p-CNTn/CGBs), which not only greatly improves the affinity for bridging the active material and the current collector but also maintains favorable features for supercapacitor applications, such as a large surface area, 3D hierarchical nanostructure, excellent electrical conductivity, and outstanding aggregation-resistance. The performance established on the p-CNTn/CGBs far exceeded the bare CGB and reduced graphene oxide (RGO) counterparts in terms of specific capacitance and rate capabilities. PMID- 24802260 TI - Work experience, job-fulfillment and burnout among VMMC providers in Kenya, South Africa, Tanzania and Zimbabwe. AB - BACKGROUND: Human resource capacity is vital to the scale-up of voluntary medical male circumcision (VMMC) services. VMMC providers are at risk of "burnout" from performing a single task repeatedly in a high volume work environment that produces long work hours and intense work effort. METHODS AND FINDINGS: The Systematic Monitoring of the Voluntary Medical Male Circumcision Scale-up (SYMMACS) surveyed VMMC providers in Kenya, South Africa, Tanzania, and Zimbabwe in 2011 (n = 357) and 2012 (n = 591). Providers self-reported on their training, work experience, levels of job-fulfillment and work fatigue/burnout. Data analysis included a descriptive analysis of VMMC provider characteristics, and both bivariate and multivariate analyses of factors associated with provider work fatigue/burnout. In 2012, Kenyan providers had worked in VMMC for a median of 31 months compared to South Africa (10 months), Tanzania (15 months), and Zimbabwe (11 months). More than three-quarters (78 - 99%) of providers in all countries in 2012 reported that VMMC is a personally fulfilling job. However, 67% of Kenyan providers reported starting to experience work fatigue/burnout compared to South Africa (33%), Zimbabwe (17%), and Tanzania (15%). Despite the high level of work fatigue/burnout in Kenya, none of the measured factors (i.e., gender, age, full time versus part-time status, length of service, number of operations performed, or cadre) were significantly associated with work fatigue/burnout in 2011. In 2012, logistic regression found increases in age (p<.05) and number of months working in VMMC (p<.01) were associated with an increased likelihood of experiencing work fatigue/burnout, while higher career total VMMCs decreased the likelihood of experiencing burnout. CONCLUSION: Given cross-country differences, further elucidation of cultural and other contextual factors that may influence provider burnout is required. Continuing to emphasize the contribution that providers make in the fight against HIV/AIDS is important. PMID- 24802261 TI - Examining continuity of care for Medicaid-enrolled children receiving oral health services in medical offices. AB - Children living in poverty encounter barriers to dentist visits and disproportionally experience dental caries. To improve access, most state Medicaid programs reimburse pediatric primary care providers for delivering preventive oral health services. To understand continuity of oral health services for children utilizing the North Carolina (NC) Into the Mouths of Babes (IMB) preventive oral health program, we examined the time to a dentist visit after a child's third birthday. This retrospective cohort study used NC Medicaid claims from 2000 to 2006 for 95,578 Medicaid-enrolled children who received oral health services before age 3. We compared children having only dentist visits before age 3 to those with: (1) only IMB visits and (2) both IMB and dentist visits. Cox proportional hazards regression was used to estimate the time to a dentist visit following a child's third birthday. Propensity scores with inverse-probability-of treatment-weights were used to address confounding. Children with only IMB visits compared to only dentist visits before age 3 had lower rates of dentist visits after their third birthday [adjusted hazard ratio (AHR) = 0.41, 95 % confidence interval (CI) 0.39-0.43]. No difference was observed for children having both IMB and dentist visits and only dentist visits (AHR = 0.99, 95 % CI 0.96-1.03). Barriers to dental care remain as children age, hindering continuity of care for children receiving oral health services in medical offices. PMID- 24802262 TI - Prevalence of serious psychological distress and mental health treatment in a national sample of pregnant and postpartum women. AB - This study examines the prevalence and correlates of past month serious psychological distress (SPD) and past year mental health treatment (MHT) across pregnancy and the postpartum. Data are from the 2008 to 2012 National Surveys on Drug Use and Health. Prevalence estimates of SPD as well as MHT among women with SPD were generated for each trimester and across the postpartum period. Correlates of SPD and MHT were examined among pregnant and postpartum women. The prevalence of past month SPD was 6.4 % in first trimester women and 3.9 % in third trimester women. In postpartum women, SPD prevalence ranged from 4.6 % (0-2 months) to 6.9 % (3-5 months). Correlates of SPD among pregnant and postpartum women included being younger; non-Hispanic black; unmarried; making under $20,000 annually; having past month cigarette use; or having a past year alcohol or illicit drug use disorder. Only 38.5 % of pregnant and 49.5 % of postpartum women with past month SPD reported past year MHT. Those who received MHT were more likely to be white; widowed, divorced, or separated; have insurance; and have a history of depression or anxiety than their counterparts with no MHT. Pregnant women with SPD were less likely to report past year MHT than postpartum women, even after adjusting for potential confounders. Over half of pregnant and postpartum women with past month SPD are not receiving MHT. Increased contact with health care professionals during this time may be an opportunity for screening, identification, and referral to MHT. PMID- 24802264 TI - Protective effects of total extracts of Averrhoa carambola L. (Oxalidaceae) roots on streptozotocin-induced diabetic mice. AB - BACKGROUND: In Chinese culture, the roots of Averrhoa carambola L. have long been used for medical purposes due to their potent pharmaceutical activities, such as improving digestive function and treating diabetes. METHODS: Recently, we prepared extracts of Averrhoa carambola L. root (EACR), which were isolated from Averrhoa carambola L. roots using ethanol or water. This study was designed to investigate the potential effects of EACR on streptozotocin (STZ) diabetic mice and to explore the underlying mechanism of these effects. Male mice were injected with STZ through the tail vein (120 mg/kg body weight) and were identified as a diabetic mouse model when the level of blood glucose was >=11.1 mmol/L. Subsequently, the mice were administered EACR (150, 300, 600, 1200 mg/kg body weight/d) and metformin (320 mg/kg body weight/d) via intragastric gavage for three weeks. RESULTS: The results indicated that EACR significantly decreased the serum levels of blood glucose, total cholesterol (TC), triglycerides (TGs) and free fatty acids (FFAs), whereas the content of serum insulin was elevated. In addition, the expressions of apoptosis-related regulators (including caspase-3, caspase-8 and caspase-9) and the apoptosis-induced protein Bax were markedly down regulated by EACR, whereas the expression of the anti-apoptotic Bcl-2 protein was notably increased. Furthermore, EACR could protect the diabetic mice against the STZ-induced apoptosis of pancreatic beta cells. CONCLUSION: Taken together, these findings indicate that EACR plays an effective hyperglycemic role that is associated with ameliorating metabolic functions and with inhibiting apoptosis in pancreas tissue. PMID- 24802263 TI - Knowledge and satisfaction of pharmacists attending an educational workshop on evidence-based management of low back pain. AB - Pharmacists are well positioned to provide quality care to people with low back pain (LBP). Education and training can equip pharmacists with the knowledge to optimally manage LBP in primary care. The aim of this study was to investigate the knowledge and satisfaction of pharmacists who attended a 2-h educational workshop on the evidence-based management of LBP. Case-based learning, underpinned by key adult learning principles, was one teaching method used to deliver important educational messages. Knowledge was assessed using a questionnaire consisting of multiple-choice, true/false questions and a written vignette based on a real-life clinical case scenario. Written feedback from pharmacists was used to gauge the success and limitations of the intervention. One hundred and ninety-three pharmacists completed the in-house assessment. Pharmacists demonstrated an accurate understanding of evidence-based pharmacological management of LBP, with all identifying paracetamol as the first line drug choice for non-specific LBP. Ninety-nine per cent of pharmacists identified the symptoms presented in the vignette as a syndrome representing a significant clinical red flag requiring urgent referral. This educational intervention has delivered key messages on LBP management to pharmacists. There is a continued need for educational interventions addressing common conditions. PMID- 24802265 TI - Assembly of heterobimetallic Ni(II)-Ln(III) (Ln(III) = Dy(III), Tb(III), Gd(III), Ho(III), Er(III), Y(III)) complexes using a ferrocene ligand: slow relaxation of the magnetization in Dy(III), Tb(III) and Ho(III) analogues. AB - A family of dinuclear 3d-4f heterobimetallic complexes [LNi(H2O)(MU OAc)Ln(NO3)2].CH3CN; {Ln = Dy(III) (1), Tb(III) (2), Ho(III) (3), Gd(III) (4), Er(III) (5), Y(III) (6)} have been synthesized by utilizing a ferrocene-based, dual compartmental ligand H2L. 1-6 are isostructural and crystallize in the triclinic (P1) space group. In these complexes Ni(II) is present in the inner coordination sphere of the dianionic [L](2-) ligand; Ln(III) is encapsulated in the outer coordination pocket. Ni(II) shows a 2N, 4O coordination environment in a distorted octahedral geometry, while the Ln(III) ion possesses a 9O coordination environment in a distorted tricapped trigonal prismatic geometry. ESI-MS studies suggest that the structural integrity of 1-6 is retained in solution. Electrochemical studies reveal that these complexes show a reversible one-electron response typical of the ferrocene motif along with an irreversible one-electron oxidation involving the Ni(II)/Ni(III) couple. Magnetic studies revealed the presence of ferromagnetic exchange coupling between Ni(II) and Ln(III) centers as shown by the increase of chiMT value upon cooling below 50 K for compounds 1, 2, 4 and 5. Further, dynamic magnetic susceptibility measurements (1-3) confirm the absence of an out-of-phase (chi'') signal at zero dc fields. However, when these measurements were carried out at 1000 Oe dc field the chi'' signal was observed, although maxima could not be detected up to 2 K. PMID- 24802266 TI - Expression levels of insulin-like growth factors 1 and 2 in head and neck squamous cell carcinoma. AB - Insulin-like growth factors (IGF) 1 and 2 are known as potential mitogens for normal and neoplastic cells. IGF2 is a main fetal growth factor while IGF1 is activated through growth hormone action during postnatal growth and development. However, there is strong evidence that activation of IGF2 by its E2F transcription factor 3 (E2F3) is present in different types of cancer. Also high levels of IGF1 strongly correlate with cancer development due to anti-apoptotic properties and enhancement of cancer cell differentiation, which can be attenuated by IGFBP3. Head and neck cancer is known as one of the six most common human cancers. The main risk factor for head and neck cancer is consumption of tobacco and alcohol as well as viral infection and bacterial infection by stimulation of chronic local inflammation. There is also a genetic basis for this form of cancer; however, the genetic markers are not yet established. In this study we investigated the levels of the expression of IGF2, IGF1, E2F3 and IGFBP3 in human cancers and healthy tissues surrounding the tumor obtained from each of 41 patients. Our study indicated that there is no alteration of the levels of expression of IGF2, E2F3 and IGF1 in head and neck squamous cell carcinoma (HNSCC) cases studied in selected experimental population, but there was evidence for upregulation of pro-apoptotic IGFBP3 in cancer when comparing to healthy tissue. These important findings indicate that insulin-growth factors are not directly associated with HNSCC showing some variability between patients and location of tumor. However, elevated level of IGFBP3 suggests possible regulatory role of IGF signal by its binding protein in this type of tumor. PMID- 24802267 TI - Influence of the rehabilitation of injured loggerhead turtles (Caretta caretta) on their blood levels of environmental organic pollutants and elements. AB - We monitored the levels of 57 organic pollutants and 11 elements in the blood of 61 live stranded loggerhead sea turtles at the beginning and end of the rehabilitation period with the goal of evaluating whether recuperation of normal physiological conditions has an influence on the circulating levels of these pollutants from the blood. According to our results, several pollutants (OCPs, PCBs and toxic elements) are mobilized from storage tissues to the blood in sick turtles, and this is more evident in the subgroup of cachectic animals. We observed a significant decrease in the concentrations of some contaminants at the end of the rehabilitation period, probably due to redistribution processes. In contrast, an increase in the levels of the essential elements selenium and zinc was observed after a period of correct feeding and supplementation during hospitalization. PMID- 24802268 TI - A tiered approach to distinguish sources of gasoline and diesel spills. AB - Approximately 11% and 25% of annual Canadian oil spill accidents are gasoline and diesel spills, respectively. Gasoline and diesel spills are a challenge to conventional environmental forensic techniques because refinery processes remove most of the higher molecular weight biomarkers. This study presents a tiered environmental forensics strategy that includes such information as site operational history, geology/hydrogeology, GC/FID pre-screening, volatile GC/MS, semi-volatile GC/MS, and GC/MS selected ion monitoring (SIM) chromatograms for fingerprinting of gasoline and diesel spills. GC/FID pre-screening analysis identified the presence of two individual gasoline and diesel plumes at a fuel service station (study site). The gasoline plume is present between the upgradient fuel underground storage tanks (USTs) and the downgradient diesel plume, suggesting that the diesel impacts to groundwater may not be originated from the current UST leakage. Similar distribution of C3-alkylbenzenes (the most stable chemicals in gasoline) and the consistent diagnostic ratios of the analyte pairs with similar solubility indicate that the source for the dissolved gasoline constituents in the gasoline impacted zone likely originated from a gasoline leakage from the current USTs on the study site. In the diesel impacted zone, the distinct distribution and diagnostic ratios of sesquiterpanes (biomarkers for diesel) and alkylated PAHs confirm that the diesel plume originate from different crude oil sources than the current USTs. PMID- 24802269 TI - Coastal sediments in the Gulf of Bothnia as a source of dissolved PCDD/Fs and PCBs to water and fish. AB - High levels of PCDD/Fs and PCBs in Baltic Sea biota have been a matter of great concern during the last decades. We measured the freely dissolved concentrations of PCDD/Fs and PCBs in sediment pore water and bottom water in eight areas along the Swedish coast of the Gulf of Bothnia, by using state-of-the-art passive samplers. Chemical activity ratios (calculated from freely dissolved concentrations in pore water and bottom water based on chemical activity ratios) for PCDD/Fs were higher than 1 at all stations (PCDD/Fs average 27; stdev 22). High activity ratios suggest that the sediments have a potential to act as a source of dissolved PCDD/Fs to the water column. Activity ratios for PCBs varied between 0.3 and 17 (average 2; stdev 4). The concentrations of PCDD/Fs and PCBs in bottom water were significantly correlated with concentrations in sediment pore water (p<0.00001 to p=0.03) as well as with concentrations in juvenile perch caught in the same areas (p<0.00001 to p=0.02). To our knowledge, this is the first study demonstrating a correlation between in-situ measured freely dissolved PCDD/F concentrations and lipid-normalized contents in stationary fish. Our results confirm that freely dissolved concentrations should be used as chemical predictors of bioaccumulation. The results from this study imply that continued efforts to reduce levels of PCDD/Fs and PCBs in coastal sediments will have positive effects on concentrations of these contaminants in lower trophic levels of Baltic Sea ecosystems. PMID- 24802270 TI - Predicting PCB concentrations in cow milk: validation of a fugacity model in high mountain pasture conditions. AB - A fugacity model reported in the literature was applied to a high-altitude pasture in the Italian Alps. The model takes into account three compartments (digestive tract, blood and fat tissues) in unsteady-state conditions using food as the contamination source. Disregarding biotransformation inside cow tissues, the predicted concentrations of 14 polychlorinated biphenyls (PCBs) in milk were in good agreement with the observed data, especially for congeners known for their resistance to biotransformation (e.g., CB-138 and 153). In contrast, the predicted concentrations were clearly overestimated for congeners with high biotransformation susceptibilities. Therefore data measured in milk and faeces were used to calculate the first-order-biotransformation rate constants in dairy cows. The PCB absorption efficiency observed for pasture conditions was lower than that observed in the cowshed. The final version of the model included biotransformation and observed PCB absorption and was able to predict PCB concentrations in cow milk with mean differences between the predicted and measured data below +/- 20% for most congeners. PMID- 24802271 TI - Multi-year persistence of beach habitat degradation from nourishment using coarse shelly sediments. AB - Beach nourishment is increasingly used to protect public beach amenity and coastal property from erosion and storm damage. Where beach nourishment uses fill sediments that differ in sedimentology from native beach sands, press disturbances to sandy beach invertebrates and their ecosystem services can occur. How long impacts persist is, however, unclear because monitoring after nourishment typically only extends for several months. Here, monitoring was extended for 3-4 years following each of two spatially separated, replicate nourishment projects using unnaturally coarse sediments. Following both fill events, the contribution to beach sediments of gravel-sized particles and shell fragments was enhanced, and although diminishing through time, remained elevated as compared to control sites at the end of 3-4 years of monitoring, including in the low intertidal and swash zones, where benthic macroinvertebrates concentrate. Consequently, two infaunal invertebrates, haustoriid amphipods and Donax spp., exhibited suppressed densities over the entire post-nourishment period of 3-4 years. Emerita talpoida, by contrast, exhibited lower densities on nourished than control beaches only in the early summer of the first and second years and polychaetes exhibited little response to nourishment. The overall impact to invertebrates of nourishment was matched by multi-year reductions in abundances of their predators. Ghost crab abundances were suppressed on nourished beaches with impacts disappearing only by the fourth summer. Counts of foraging shorebirds were depressed for 4 years after the first project and 2 years after the second project. Our results challenge the view that beach nourishment is environmentally benign by demonstrating that application of unnaturally coarse and shelly sediments can serve as a press disturbance to degrade the beach habitat and its trophic services to shorebirds for 2-4 years. Recognizing that recovery following nourishment can be slow, studies that monitor impacts for only several months are inadequate. PMID- 24802272 TI - Airborne particulate matter (PM2.5) and the prevalence of allergic conjunctivitis in Japan. AB - OBJECTIVE: Exposure to particulate matter less than 2.5 MUm in diameter (PM2.5) is associated with asthma and respiratory symptoms, but little is known about the influence of PM2.5 on allergic conjunctivitis. The purpose of this study was to examine the association of PM2.5 with outpatient attendance for allergic conjunctivitis. METHODS: We conducted a time-series analysis of the association between outpatient attendance for allergic conjunctivitis and PM2.5 levels from May to July (non-pollen season) and from August to October (the autumnal pollen season) in 2012. Air pollution data (including the levels of PM2.5, oxidants, nitric oxide, nitrogen dioxide, nitrogen oxide, carbon monoxide, methane, non methane hydrocarbons, and total hydrocarbons) and data on the daily weather conditions (temperature, wind speed, and humidity) were collected at a centrally located monitoring station in Tokyo. We calculated weekly average values for the daily number of outpatient visits, as well as the air pollution and weather data, and used the weekly average values for analysis. RESULTS: There was a significant association between the number of outpatient visits for allergic conjunctivitis and the PM2.5 level (r=0.62, p=0.0177) from May to July, while no correlation was found between the number of outpatient visits and any variable assessed from August to November. Multivariate analysis also showed that PM2.5 was a significant predictor of the number of outpatient visits from May to July (odds ratio=9.05, p=0.0463), while there were no significant predictors of the number of outpatient visits from August to October. From May to July, PM2.5 showed a negative correlation with humidity (r=-0.53, p=0.0499). CONCLUSIONS: These findings suggest a possible role of PM2.5 in the development of allergic conjunctivitis during the non-pollen season. This association between PM2.5 and allergic conjunctivitis may have broad public health implications in relation to allergic diseases. PMID- 24802274 TI - Lipid binding specificity of bovine alpha-lactalbumin: a multidimensional approach. AB - Many soluble proteins are known to interact with membranes in partially disordered states, and the mechanism and relevance of such interactions in cellular processes are beginning to be understood. Bovine alpha-lactalbumin (BLA) represents an excellent prototype for monitoring membrane interaction due to its conformational plasticity. In this work, we comprehensively monitored the interaction of apo-BLA with zwitterionic and negatively charged membranes utilizing a variety of approaches. We show that BLA preferentially binds to negatively charged membranes at acidic pH with higher binding affinity. This is supported by spectral changes observed with a potential-sensitive membrane probe and fluorescence anisotropy measurements of a hydrophobic probe. Our results show that BLA exhibits a molten globule conformation when bound to negatively charged membranes. We further show, using the parallax approach, that BLA penetrates the interior of negatively charged membranes, and tryptophan residues are localized at the membrane interface. Red edge excitation shift (REES) measurements reveal that the immediate environment of tryptophans in membrane-bound BLA is restricted, and the restriction is dependent on membrane lipid composition. We envision that understanding the mechanism of BLA-membrane interaction would help in bioengineering of alpha-lactalbumin, and to address the mechanism of tumoricidal and antimicrobial activities of BLA-oleic acid complex. PMID- 24802275 TI - Sphingosine induces the aggregation of imine-containing peroxidized vesicles. AB - Lipid peroxidation plays a central role in the pathogenesis of many diseases like atherosclerosis and multiple sclerosis. We have analyzed the interaction of sphingosine with peroxidized bilayers in model membranes. Cu(2+) induced peroxidation was checked following UV absorbance at 245nm, and also using the novel Avanti snoopers(r). Mass spectrometry confirms the oxidation of phospholipid unsaturated chains. Our results show that sphingosine causes aggregation of Cu(2+)-peroxidized vesicles. We observed that aggregation is facilitated by the presence of negatively-charged phospholipids in the membrane, and inhibited by anti-oxidants e.g. BHT. Interestingly, long-chain alkylamines (C18, C16) but not their short-chain analogues (C10, C6, C1) can substitute sphingosine as promoters of vesicle aggregation. Furthermore, sphinganine but not sphingosine-1-phosphate can mimic this effect. Formation of imines in the membrane upon peroxidation was detected by (1)H-NMR and it appeared to be necessary for the aggregation effect. (31)P-NMR spectroscopy reveals that sphingosine facilitates formation of non-lamellar phase in parallel with vesicle aggregation. The data might suggest a role for sphingosine in the pathogenesis of atherosclerosis. PMID- 24802273 TI - Tualang honey improves human corneal epithelial progenitor cell migration and cellular resistance to oxidative stress in vitro. AB - Stem cells with enhanced resistance to oxidative stress after in vitro expansion have been shown to have improved engraftment and regenerative capacities. Such cells can be generated by preconditioning them with exposure to an antioxidant. In this study we evaluated the effects of Tualang honey (TH), an antioxidant containing honey, on human corneal epithelial progenitor (HCEP) cells in culture. Cytotoxicity, gene expression, migration, and cellular resistance to oxidative stress were evaluated. Immunofluorescence staining revealed that HCEP cells were holoclonal and expressed epithelial stem cell marker p63 without corneal cytokeratin 3. Cell viability remained unchanged after cells were cultured with 0.004, 0.04, and 0.4% TH in the medium, but it was significantly reduced when the concentration was increased to 3.33%. Cell migration, tested using scratch migration assay, was significantly enhanced when cells were cultured with TH at 0.04% and 0.4%. We also found that TH has hydrogen peroxide (H2O2) scavenging ability, although a trace level of H2O2 was detected in the honey in its native form. Preconditioning HCEP cells with 0.4% TH for 48 h showed better survival following H2O2-induced oxidative stress at 50 uM than untreated group, with a significantly lower number of dead cells (15.3 +/- 0.4%) were observed compared to the untreated population (20.5 +/- 0.9%, p<0.01). Both TH and ascorbic acid improved HCEP viability following induction of 100 uM H2O2, but the benefit was greater with TH treatment than with ascorbic acid. However, no significant advantage was demonstrated using 5-hydroxymethyl-2-furancarboxaldehyde, a compound that was found abundant in TH using GC/MS analysis. This suggests that the cellular anti-oxidative capacity in HCEP cells was augmented by native TH and was attributed to its antioxidant properties. In conclusion, TH possesses antioxidant properties and can improve cell migration and cellular resistance to oxidative stress in HCEP cells in vitro. PMID- 24802276 TI - Patient survival after surgical treatment of rectal cancer: impact of surgeon and hospital characteristics. AB - BACKGROUND: Surgeon and hospital factors are associated with the survival of patients treated for rectal cancer. The relative contribution of each of these factors toward determining outcomes is poorly understood. METHODS: We used data from the Surveillance, Epidemiology, and End Results-Medicare database to analyze the outcomes of patients aged 65 years and older undergoing operative treatment for nonmetastatic rectal cancer, diagnosed in the United States between 1998 and 2007. These data were linked to a registry to identify whether the treating surgeon was a board-certified colorectal surgeon versus a noncolorectal surgeon. Hospital volume and hospital certification as a National Cancer Institute designated Comprehensive Cancer Centers were also analyzed. The primary outcome of interest was long-term survival. RESULTS: Our data source yielded 6432 patients. Initial analysis demonstrated improved long-term survival in patients treated by higher-volume colorectal surgeons, higher-volume hospitals, teaching hospitals, and National Cancer Institute (NCI)-designated Comprehensive Cancer Centers. Based on an iterative approach to modeling the interactions between these various factors, we found a robust effect of surgeon subspecialty status, hospital volume, and NCI designation. Surgeon volume was not distinctly associated with long-term survival. CONCLUSIONS: Patients treated for rectal cancer by board-certified colorectal surgeons in centers that are higher volume and/or NCI-designated Comprehensive Cancer Centers experience better overall survival. These differences persist after adjustment for a broad range of patient and contextual risk factors, including surgeon volume. Patients and payers can use these results to identify surgeons and hospitals where outcomes are most favorable. PMID- 24802277 TI - Metal-organic framework threaded with aminated polymer formed in situ for fast and reversible ion exchange. AB - A porous metal-organic framework composite with flexible anion-exchange polymers threaded within the host cavity demonstrates very fast and reversible ion exchange activity. Polyvinyl benzyl trimethylammonium hydroxide (PVBTAH) caged in ZIF-8 is synthesized in steps of chloro-monomer impregnation, in situ polymerization, amination, and alkaline ion exchange. The synthesized non-cross linked PVBTAH~ZIF-8 material exhibits superior ion-exchange kinetics compared to conventional ion-exchange resins. PMID- 24802278 TI - Management of bone metastases in patients with castration-resistant prostate cancer. AB - Bone metastases are a very common problem in prostate cancer. They are associated with considerable morbidity, adversely affect quality of life and frequently lead to advanced bone events (so-called skeletal-related events, SREs); SREs include fractures, spinal cord compression and the requirement for bone surgery or bone radiation. The aim of this paper was to evaluate currently available treatment options in the prevention and management of SREs and bone metastases in men with castration-resistant prostate cancer and to outline the importance of interdisciplinary management strategies. It also discusses the diagnostic workup of osseous metastases and practical considerations for the utilization of bone targeted therapies in accordance with current guidelines to provide a consensus for special and/or difficult clinical situations. PMID- 24802279 TI - Clinical and imaging features in different inner border-zone infarct patterns. AB - BACKGROUND AND PURPOSE: The clinical and imaging features of different inner border-zone infarct patterns, corona radiata (CR) and centrum semiovale (CSO), is not quiet clear. Both are mostly reported together in previous studies. We intended to observe their clinical and imaging features. METHOD: We observed 83 patients-47 cases with CR infarct lesion pattern and 36 cases with CSO. The lesion patterns were determined by diffusion-weighted imaging. Basic, clinical and radiologic features were compared between the patients with CR and CSO infarct lesion patterns. RESULTS: There was no significant difference between CR and CSO infarct patterns in terms of risk factors. However, patients with CR infarct had a higher initial National Institutes of Health Stroke Scale (NIHSS) score at admission (5.2 +/- 2.3) than with CSO (3.9 +/- 2.0, p = 0.009). Early clinical deterioration (OR, 2.42; 95% CI, 1.12-5.21; p = 0.024) and middle cerebral artery (MCA) stenosis (OR, 10.31; 95% CI, 3.30-32.19; p < 0.0001) were independently associated with the CR infarct lesion pattern. Partial infarct lesion shape (OR, 5.95; 95% CI, 1.40-25.33; p = 0.016) and internal carotid artery (ICA) stenosis (OR, 5.28; 95% CI, 1.92-14.51; p = 0.001) were independently correlated with the CSO infarct lesion pattern. CONCLUSIONS: Although CR and CSO infarct patterns might share common etiology and mechanisms, their clinical and imaging features are different. PMID- 24802281 TI - Structure and stability of phenoxide and fluorophenoxide anions investigated with infrared multiple-photon dissociation and detachment spectroscopy and tandem mass spectrometry. AB - The gas-phase infrared multiple-photon dissociation and detachment (IRMPD) vibrational action spectra of the unsubstituted phenoxide anion and a series of fluorine- and trifluoromethyl-substituted phenoxide anions in the spectral region between 600 and 1800 cm(-1) are presented along with density functional theory (DFT) harmonic vibrational frequency calculations to establish the characteristic vibrations of the phenoxide functionality. The fluorophenoxide anions studied include the conjugate bases of o-, m-, and p-fluorophenol (C6H4FO(-)) as well as o-, m-, and p-alpha,alpha,alpha-trifluorocresol (CF3C6H4O(-)). The influence of the substituent on the characteristic vibrational frequencies is interpreted in terms of inductive and resonance shifts. In addition to the dissociation induced by infrared multiple-photon excitation, the electron detachment is also shown to play an important role in the decomposition of the unsubstituted phenoxide. It is demonstrated that the amount of electron detachment relative to dissociation is strongly mitigated by fluorination, and interpretations aided by DFT energy calculations suggest this is primarily due to the increased availability of low energy dissociation pathways in the substituted phenoxides. Collision-induced dissociation (CID) mass spectrometry of the parent ions is used to estimate relative energies of the dissociation processes, and particular fragmentation motifs are elucidated. In particular, overall HF and CO losses provide facile decomposition pathways, yielding interesting fragment ions such as C6H(-) or C3H2FO(-) from the CF3C6H4O(-) parent anions. PMID- 24802280 TI - Importance of cell-cell contact in the therapeutic benefits of cardiosphere derived cells. AB - Cardiosphere-derived cells (CDCs) effect therapeutic regeneration after myocardial infarction (MI) both in animal models and in humans. Here, we test the hypothesis that cell-cell contact plays a role in mediating the observed therapeutic benefits of CDCs, above and beyond conventional paracrine effects. Human CDCs or vehicle were injected into immunodeficient (SCID) mouse hearts during acute MI. CDC transplantation augmented the proportion of cycling (Ki67(+) ) cardiomyocytes and improved ventricular function. CDC-conditioned media only modestly augmented the percentage of Ki67(+) cardiomyocytes (>control but = 3 mm) in the lower incisors were enrolled. Twenty five patients were randomly assigned to the control group and the other 25 patients to the test group. All defects were treated with the coronally advanced flap + connective tissue graft (CAF + CTG) and in the test group the labial submucosal tissue (LST) was removed. Post-operative morbidity was evaluated at 1 week. Clinical and aesthetic evaluations were made at 1 year. RESULTS: Statistically greater recession reduction, probability of CRC (adjusted OR 7.94 95% CI = 1.88-33.50, p = 0.0024) and greater increase in GT were observed in the test group. Greater graft exposure and increase in KTH were demonstrated in the control group. Better aesthetics outcomes were observed in the test group. No statistically significant between groups differences were demonstrated in patient analgesic assumption and post-operative discomfort and bleeding. CONCLUSIONS: LST removal during CAF + CTG surgery is indicated to provide better root coverage and aesthetic outcomes in the treatment of gingival recessions affecting the lower incisors. PMID- 24802284 TI - Trihapto ligation of a borirene to a single metal atom: a heterocyclic analogue of the eta3-cyclopropenyl ligand. AB - The first example of a complex containing an eta(3)-coordinated borirene ligand bound to a single metal atom was prepared by photolytic transfer of an arylborylene ligand to diphenylacetylene and loss of three CO ligands from the precursor. The eta(3)-borirene complex possesses a chromium(0) atom which is also bound to one phenyl group in an eta(6) fashion. The complex was isolated in 15% yield along with the corresponding metal-free borirene, which was isolated in 62% yield. The bonding between the chromium center and the borirene ring was studied computationally by DFT methods. PMID- 24802285 TI - Fluticasone propionate/formoterol fumarate in fixed-dose combination for the treatment of asthma. AB - A new combination inhaler containing fluticasone, a potent inhaled corticosteroid (ICS), and formoterol, a long-acting beta-agonist (LABA) with rapid onset and sustained bronchodilator effect, has been approved for treatment of persistent asthma in patients >=12 years of age requiring combination ICS-LABA therapy. The fluticasone/formoterol combination, delivered via pressurized metered-dose inhaler and available in three dose strengths, has demonstrated a good safety and tolerability profile in trials of up to 1 year. The efficacy of fluticasone/formoterol is greater than that of fluticasone or formoterol alone and noninferior to that of fluticasone/salmeterol and budesonide/formoterol in tightly controlled 8-12-week clinical trials. Advantages of the fluticasone/formoterol combination aerosol include rapid onset of bronchodilation, an attribute preferred by patients, and emission of a high fine particle fraction that is consistent at different flow rates, which may aid consistency of delivery (given patient variability in inhalation maneuvers) and provide real-life benefits. PMID- 24802286 TI - Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high resolution mass spectrometry. AB - New types of synthetic cannabinoid designer drugs are constantly introduced to the illicit drug market to circumvent legislation. Recently, N-(1-Adamantyl)-1-(5 fluoropentyl)-1H-indazole-3-carboxamide (5F-AKB-48), also known as 5F-APINACA, was identified as an adulterant in herbal products. This compound deviates from earlier JHW-type synthetic cannabinoids by having an indazole ring connected to an adamantyl group via a carboxamide linkage. Synthetic cannabinoids are completely metabolized, and identification of the metabolites is thus crucial when using urine as the sample matrix. Using an authentic urine sample and high resolution accurate-mass Fourier transform Orbitrap mass spectrometry, we identified 16 phase-I metabolites of 5F-AKB-48. The modifications included mono-, di-, and trihydroxylation on the adamantyl ring alone or in combination with hydroxylation on the N-fluoropentylindazole moiety, dealkylation of the N fluoropentyl side chain, and oxidative loss of fluorine as well as combinations thereof. The results were compared to human liver microsomal (HLM) incubations, which predominantly showed time-dependent formation of mono-, di-, and trihydroxylated metabolites having the hydroxyl groups on the adamantyl ring. The results presented here may be used to select metabolites specific of 5F-AKB-48 for use in clinical and forensic screening. PMID- 24802287 TI - The European Parliament proposal for the new EU General Data Protection Regulation may severely restrict European epidemiological research. PMID- 24802289 TI - Supramolecular polymorphism: tunable electronic interactions within pi-conjugated peptide nanostructures dictated by primary amino acid sequence. AB - We present a systematic study of the photophysical properties of one-dimensional electronically delocalized nanostructures assembled from pi-conjugated subunits embedded within oligopeptide backbones. The nature of the excited states within these nanostructures is studied as a function of primary amino acid sequence utilizing steady-state and time-resolved spectroscopies, and their atomistic structure is probed by molecular simulation. Variations introduced into the amino acid side chains at specific residue locations along the molecular peptide backbone lead to pronounced changes in the observed photophysical behavior of the fibrillar structures (spanning H-like excitonic coupling and disordered excimeric coupling) that arise from subtle changes in the pi-stacking within them. These results indicate that residue modification-in terms of relative size, solvation properties, and with respect to the distance from the central pi-electron core enables the ability to tune chromophore packing and the resulting photophysics of supramolecular assemblies of pi-conjugated bioelectronic materials in a rational and systematic manner. PMID- 24802288 TI - Palmoplantar erythrodysesthesia-like skin symptoms in patients under various chemotherapeutics: preventive and therapeutic options. AB - BACKGROUND/AIMS: The palmoplantar erythrodysaesthesia (PPE) is an inflammatory cutaneous side effect in patients under chemotherapy with pegylated liposomal doxorubicin (PLD), with indications that also other chemotherapeutics induce similar side effects. Recently, it has been demonstrated that PLD escapes with the sweat onto the skin inducing radical-forming processes that damage the skin. The topical application of antioxidants with a high radical protection factor has proven to be a very efficient prevention strategy for PLD-treated patients. METHODS: 68 patients, who had been treated with 12 different chemotherapeutics and experienced side effects similar to PPE, were treated with a meanwhile commercially available ointment. RESULTS: At the beginning of the therapy, 46 patients suffered from a PPE of severity grade III, while in 22 patients a PPE of severity grade II was diagnosed. The application of the ointment resulted in a significant improvement of the clinical symptoms and the skin status in all these patients; their chemotherapies could be continued. CONCLUSION: The obtained results suggest that radical-forming processes play an essential role in a great number of chemotherapeutics which induce dermal side effects. The topical application of the antioxidant-containing ointment proved to be a good therapeutic option which needs further evaluation. PMID- 24802290 TI - Reviews of individual patient data (IPD) are useful for geriatrics: an overview of available IPD reviews. AB - OBJECTIVES: To determine how many individual patient data (IPD) reviews that included older people were available in MEDLINE and whether the effectiveness of treatments differed between older and younger individuals. DESIGN: Overview of IPD reviews. SETTING: A MEDLINE search was conducted for IPD reviews of randomized controlled trials published before July 2012. PARTICIPANTS: IPD reviews that presented a regression model that included age as a factor or a subgroup analysis of individuals aged 70 and older or in which all participants were aged 70 and older. MEASUREMENTS: Whether the IPD reviews reported similar conclusions for the younger and older populations was evaluated. RESULTS: Twenty six IPD reviews with a subgroup of older individuals and eight reviews with only older individuals were included (median N = 3,351). The most important reason for choosing an IPD review was the ability to perform a subgroup analysis in the older population. Fourteen IPD reviews suggested that older people should receive different treatments from younger people because of differences in effectiveness, six of which indicated that the investigated treatment(s) should be avoided in older adults. CONCLUSION: IPD review is a valuable approach for generating evidence in older adults. Treatment effects frequently differed between older and younger individuals. Still, IPD results should be applied to older adults cautiously, because they are often excluded from primary trials. The collaborative sharing of raw data should be promoted to improve evidence-based decisions for this group. PMID- 24802291 TI - Variation in mating systems of salamanders: mate guarding or territoriality? AB - Two of the most common mating tactics in vertebrates are mate guarding and territoriality, yet much of the research on these strategies has focused on mating systems in birds, despite novel insights gained from studying less traditional systems. North American stream salamanders that comprise the Eurycea bislineata complex represent an excellent nontraditional system for comparing mating strategies because these species exhibit a continuum of male morphologies, diverse habitat associations, and various potential mating strategies. We studied two species within this complex that exhibit the extremes of this continuum, Eurycea aquatica (robust morph) and Eurycea cirrigera (slender morph). The larger head in males of E. aquatica is due to larger musculature around the jaw and may be associated with aggressive behavior. Therefore, we hypothesized that the robust morphology exhibited by males of E. aquatica provides benefits during either territorial defense or mate defense and that males of E. cirrigera would not exhibit aggression in either scenario. We found that neither species exhibited aggressive behavior to defend a territory. However, in the presence of a female, males of E. aquatica were significantly more aggressive toward intruding males than were males of E. cirrigera. Therefore, mate-guarding behavior occurs in E. aquatica, and the enlarged head of males likely aids in deterring rivals. This is the first demonstration of mate-guarding behavior in a plethodontid, the most speciose family of salamanders. PMID- 24802292 TI - The concise synthesis of spiro-cyclopropane compounds via the dearomatization of indole derivatives. AB - A concise synthesis of spiro-cyclopropane compounds from indole derivatives and sulfur ylides has been developed via a dearomatization strategy. Moreover, the spiro-cyclopropane compounds could be conveniently transformed to rearomatized indole derivatives in the presence of acids. PMID- 24802293 TI - A quick, easy, cheap, effective, rugged, and safe sample pretreatment and liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of 33 mycotoxins in Lentinula edodes. AB - Lentinula edodes, one of the most cultivated edible fungi in the world, are usually neglected for mycotoxins contamination due to the initial thinking of its resistance to mycotoxingenic molds. In the present study, a sensitive and reliable liquid chromatography with tandem mass spectrometry method was developed for the simultaneous quantification of 33 mycotoxins in L. edodes. Targeted mycotoxins were extracted using a quick, easy, cheap, effective, rugged, and safe procedure without any further clean-up step, and analyzed by liquid chromatography with tandem mass spectrometry on an Agilent Poroshell 120 EC-C18 column (100 * 3 mm, 2.7 MUm) with a linear gradient elution program using water containing 5 mM ammonium acetate and methanol as the mobile phase. After validation by determining linearity (R(2) > 0.99), sensitivity (LOQ <= 20 ng/kg), recovery (73.6-117.9%), and precision (0.8-19.5%), the established method has been successfully applied to reveal the contamination states of various mycotoxins in L. edodes. Among the 30 tested samples, 22 were contaminated by various mycotoxins with the concentration levels ranging from 3.3-28,850.7 MUg/kg, predicting that the edible fungus could be infected by the mycotoxins producing fungi. To the best of our knowledge, this is the first report about real mycotoxins contamination in L. edodes. PMID- 24802294 TI - Dynamic MR image reconstruction-separation from undersampled (k,t)-space via low rank plus sparse prior. AB - Dynamic magnetic resonance imaging (MRI) is used in multiple clinical applications, but can still benefit from higher spatial or temporal resolution. A dynamic MR image reconstruction method from partial (k, t)-space measurements is introduced that recovers and inherently separates the information in the dynamic scene. The reconstruction model is based on a low-rank plus sparse decomposition prior, which is related to robust principal component analysis. An algorithm is proposed to solve the convex optimization problem based on an alternating direction method of multipliers. The method is validated with numerical phantom simulations and cardiac MRI data against state of the art dynamic MRI reconstruction methods. Results suggest that using the proposed approach as a means of regularizing the inverse problem remains competitive with state of the art reconstruction techniques. Additionally, the decomposition induced by the reconstruction is shown to help in the context of motion estimation in dynamic contrast enhanced MRI. PMID- 24802295 TI - Elucidating the origin of spurious modes in aluminum nitride microresonators using a 2-D finite-element model. AB - In this work, an approach has been developed to predict the location of large spurious modes in the resonant response of aluminum nitride (AlN) microelectromechanical systems (MEMS) resonators over a wide range of desired operating frequencies. This addresses significant challenges in the design of more complex AlN devices, namely the prediction and elimination of spurious modes in the resonance response. Using the finite element method (FEM), the dispersion curves at wavelengths ranging from 8 to 20 MUm were computed. It was determined that the velocities of symmetric Lamb (S0) and high-order antisymmetric (A) modes overlap at specific wavelengths. A 2-D FEM analysis showed that both the S0 and higher order A modes are mutually excited at a common operating wavelength. From this analysis, the coupling-of-modes (COM) parameters were extracted and used to compute the P-matrix and S-parameters using a 6-port transmission matrix. The P matrix simulation was able to predict the electrical response of the S0 and nearby spurious modes. This work identified specific wavelength regions where COM has limited accuracy because of mode conversion. In these regions, the reflection (kappa(p)) and transduction (zeta(p)) parameters change rapidly. PMID- 24802296 TI - Utility of different seizure induction protocols in psychogenic nonepileptic seizures. AB - Psychogenic non epileptic seizure (PNES) can be induced by several induction tests but their relative usefulness has not been evaluated. In this study, we report the sensitivity and specificity of various induction tests in the diagnosis of PNES and assess their discomfort level. The induction tests were: (a) compression of temple region (CTR), (b) verbal suggestion (VS), (c) tuning fork application (TFA), (d) moist swab application (MSA), (e) torch light stimulation (TLS) and (f) saline injection (SI). Up to 3 trials were done for each test except for normal saline injection which was given once. For comparison of these tests, patients with epileptic seizures were included as controls. The time to precipitate PNES was recorded and patients' discomfort levels were noted on a 0-10 scale. Video EEG was recorded in the PNES patients. 140 patients with PNES and 50 controls with epileptic seizures were included. The diagnostic yield of CTR was 65.7%, TFA 61.4%, MSA 60.7%, SI 55.6%, VS 54.3% and TLS 40.7%. These tests did not induce seizures in the controls. All these tests had 100% specificity and 100% positive predictive value in the diagnosis of PNES. The maximum discomfort was reported with SI and minimum with MSA. The similarity of efficacy and discomfort with CTR and TFA appear to be the most optimal induction techniques when compared with VS, AMS, TLS, and SI. PMID- 24802297 TI - Impact of albuminuria on the incidence of periprocedural myocardial injury in patients undergoing elective coronary stent implantation. AB - Albuminuria has traditionally been associated with an elevated risk of cardiovascular events. However, few studies have examined the potential relation between albuminuria and periprocedural risk in percutaneous coronary intervention (PCI). The aim of this study was to evaluate the impact of albuminuria on the incidence of periprocedural myocardial injury (PMI) in patients who underwent PCI. The study included 252 consecutive patients who underwent PCI. The incidence of PMI was significantly higher in patients with albuminuria than in those with normoalbuminuria (31.9% vs 43.3%, respectively, p = 0.014). Even after adjustment for confounders, the presence of albuminuria predicted PMI (odds ratio 2.07, 95% confidence interval 1.08 to 3.97, p = 0.029). Furthermore, patients with albuminuria and preserved estimated glomerular filtration rate had a 4.2-fold higher risk for PMI than did patients with normoalbuminuria and preserved estimated glomerular filtration rate. In conclusion, albuminuria was a strong predictor of PMI in patients who underwent PCI. PMID- 24802299 TI - Aesthetic earlobe remodeling: my personal experience with an LBO laser at 532 nm. AB - Since 1960, when Maiman built the first laser equipment, this technology has gone through a continuous development and an increasing utilization in several fields. Nowadays many pathologies find a less traumatic solution in laser technology. Laser can be either used to treat lesions with a high bleeding risk such as hemangioma and lymphangioma or in patients with coagulation diseases or hypertension, taking advantage of its capability to coagulate. Moreover healing and scarring are improved by the laser's effect of biostimulation and inhibition of bacterial growth, this leading to a greater comfort for the patient. The tissue vaporization and the dimension of the damaged area depend on several factors, those related to the laser used, such as wavelength, power, emission mode (continued or pulsed mode) and the power density, and those concerning to the treated tissue, like color and consistency. In this Study, we used an Lithium Borate, (LBO), laser, instead of scalpel for earlobe reduction in a 35-year-old male patient with pending lobule. LBO laser works through a solid active medium emitting a visible green light. A diode laser, with a wavelength of 810 nm, stimulates a crystal of Nd:YAG, which has a wavelength of 1064 nm. Then a crystal of LBO doubles the vibration frequency of the photons, leading to a final wavelength of 532 nm. PMID- 24802298 TI - Upregulation of gelatinases and epithelial-mesenchymal transition in small airway remodeling associated with chronic exposure to wood smoke. AB - BACKGROUND: Peribronchiolar fibrosis is an important feature of small airway remodeling (SAR) in cigarette smoke-induced COPD. The aim of this study was to investigate the role of gelatinases (MMP9, MMP2) and epithelial-mesenchymal transition (EMT) in SAR related to wood smoke (WS) exposure in a rat model. METHODS: Forty-eight female Sprague-Dawley rats were randomly divided into the WS group, the cigarette smoke (CS) group and the clean air control group. After 4 to 7 months of smoke exposure, lung tissues were examined with morphometric measurements, immunohistochemistry and Western blotting. Serum MMP9 and TIMP1 concentrations were detected by ELISA. In vitro, primary rat tracheal epithelial cells were stimulated with wood smoke condensate for 7 days. RESULTS: The COPD like pathological alterations in rats exposed chronically to WS were similar to those exposed to CS; the area of collagen deposition was significantly increased in the small airway walls of those exposed to WS or CS for 7 months. The expression of gelatinases in rats induced by WS or CS exposure was markedly increased in whole lung tissue, and immunohistochemistry showed that MMP9, MMP2 and TIMP1 were primarily expressed in the airway epithelium. The serum levels of MMP9 and TIMP1 were significantly higher in rats secondary to WS or CS exposure. Few cells that double immunostained for E-cadherin and vimentin were observed in the airway subepithelium of rats exposed to WS for 7 months (only 3 of these 8 rats). In vitro, the expression of MMP9 and MMP2 proteins was upregulated in primary rat tracheal epithelial cells following exposure to wood smoke condensate for 7 days by Western blotting; positive immunofluorescent staining for vimentin and type I collagen was also observed. CONCLUSIONS: These findings suggest that the upregulation of gelatinases and EMT might play a role in SAR in COPD associated with chronic exposure to wood smoke. PMID- 24802300 TI - Fabrication and characterization of bioactive and antibacterial composites for dental applications. AB - There is an increasing clinical need to design novel dental materials that combine regenerative and antibacterial properties. In this work the characterization of a recently developed sol-gel-derived bioactive glass ceramic containing silver ions (Ag-BG) is presented. The microstructural characteristics, ion release profile, zeta potential value and changes in weight loss and pH value as a function of the immersion time of Ag-BG in Tris buffer are evaluated. Ag-BG is also incorporated into natural extracellular matrix (ECM) hydrogel to further enhance its regenerative properties. Then, the micro and macro architectures of these new composites (ECM/Ag-BG) are characterized. In addition, the antibacterial properties of these new composites are tested against Escherichia coli and Enterococcus faecalis, a bacterium commonly implicated in the pathogenesis of dental pulp infections. Cell-material interaction is also monitored in a primary culture of dental pulp cells. Our study highlights the benefits of the successful incorporation of Ag in the bioactive glass, resulting in a stable antibacterial material with long-lasting bactericidal activity. Furthermore, this work presents for the first time the fabrication of new Ag doped composite materials, with inductive pulp-cell proliferation and antibacterial properties (ECM/Ag-BG). This advanced composite made of Ag-BG incorporated into natural ECM possesses improved properties that may facilitate potential applications in tooth regeneration approaches. PMID- 24802301 TI - Resisting protein adsorption on biodegradable polyester brushes. AB - The protein adsorption and degradation behaviors of poly(lactic acid), poly(glycolic acid) (PGA) and poly(epsilon-caprolactone) (PCL) brushes and their co-polymer brushes with oligo(ethylene glycol) (OEG) were studied. Both brush structure and relative amount of OEG and polyester were found to be important to the protein resistance of the brushes. A protein-resisting surface can be fabricated either by using OEG as the top layer of a copolymer brush or by increasing the amount of OEG relative to polyester when using a hydroxyl terminated OEG (OEG-OH) and a methoxy terminated OEG (OEG-OMe) mixture as the substrate layer. The degradation of single polyester brushes and their co-polymer brushes using OEG-OH as a substrate layer or using OEG as a top layer was hindered. This phenomenon was rationalized by the inhibition of the proposed back biting process as the hydroxy end groups of polyester were blocked by OEG molecules. Among these brushes tested, PGA co-polymer brushes using the methoxy/hydroxyl OEG mixture as the substrate layer proved to be both protein resistant and degradable due to the relatively large amount of OEG moieties and the good biodegradability of PGA. PMID- 24802302 TI - Theoretical study on two-step mechanisms of peptide release in the ribosome. AB - A quantum mechanical study of different two-step mechanisms of peptide release in the ribosome has been carried out using the M06-2X density functional. Reoptimization with MP2 has also been carried out for the stationary points of some selected mechanisms. The uncatalyzed processes in solution have been treated with the SMD solvation model. From the results obtained in this paper for the peptide release process we can conclude that the energy barriers for the two-step mechanisms are lower than the ones for the concerted process, that the 2'OH plays also an important role in the catalytic process and that the side chain does not only accommodate a nucleophilic water molecule in the PTC, but it also contributes to activate this molecule through electron transfer to the water oxygen. We have also found that the second step is the rate-determining one, and that the two most favorable mechanisms, in which a water or a formamide molecule is added, follow a quite different strategy to catalyze the reaction. The main conclusion of our work is that the two-step mechanisms cannot be disregarded, since they can contribute to clarify the complex and yet unsolved problem of the mechanism of the peptide release process. PMID- 24802303 TI - Epidemiology of shivering (shivers) in horses. AB - REASONS FOR PERFOMING STUDY: Investigating the epidemiology of shivering in horses. OBJECTIVES: The purpose of this study was to characterise the signalment, clinical signs and management factors associated with shivering (also known as shivers), a relatively rare, poorly defined movement disorder in horses. STUDY DESIGN: Web-based case series survey and case-control study. METHODS: A Web-based survey was used to obtain information from owners, worldwide, who suspected that their horse had shivering. Survey respondents were asked to answer standardised questions and to provide a video of the horse. Authors reviewed the surveys and videos, and horses were diagnosed with shivering if they displayed normal forward walking, with difficulty during manual lifting of the hoof and backward walking due to hyperflexion or hyperextension of the pelvic limbs. Cases confirmed by video were designated 'confirmed shivering', while those with compatible clinical signs but lacking video confirmation were designated 'suspected shivering'. Owners of confirmed shivering horses were asked to provide information on 2 horses without signs of shivering (control group). RESULTS: Three hundred and five surveys and 70 videos were received; 27 horses were confirmed shivering (50 controls), 67 were suspected shivering and the rest had a variety of other movement disorders. Suspected shivering horses resembled confirmed shivering cases, except that the suspected shivering group contained fewer draught breeds and fewer horses with exercise intolerance. Confirmed shivering signs often began at <5 years of age and progressed in 74% of cases. Owner-reported additional clinical signs in confirmed cases included muscle twitching (85%), muscle atrophy (44%), reduced strength (33%) and exercise intolerance (33%). Shivering horses were significantly taller (confirmed shivering, mean ~173 cm; control horses, ~163 cm) with a higher male:female ratio (confirmed shivering, 3.2:1 vs. control, 1.7:1). No potential triggering factors or effective treatments were reported. CONCLUSIONS: Shivering is a chronic, often gradually progressive movement disorder that usually begins before 7 years of age and has a higher prevalence in tall male horses. PMID- 24802304 TI - Preparation of functionalized heteroaromatics using an intramolecular Wittig reaction. AB - The development of efficient methods for the synthesis of heteroaromatic compounds is always of great importance for chemists. In this 'Perspective', we describe a general approach for the synthesis of functionalized heteroaromatics via intramolecular Wittig reactions. In all cases, the reaction proceeds via in situ generated phosphorus ylides. We especially emphasize the importance of chemoselective intramolecular Wittig reactions using designed Michael acceptors and suitable acyl chloride as trapping reagents, which allows formation of two different classes of heteroaromatics from the same substrates. This metal-free approach is quite general and works in a number of examples, furnishing the corresponding products in moderate to good yields under relatively mild reaction conditions. PMID- 24802305 TI - Ex vivo and in vivo assessment of the non-linearity of elasticity properties of breast tissues for quantitative strain elastography. AB - The aim of this study was to reveal the background to the image variations in strain elastography (strain imaging [SI]) depending on the manner of manipulation (compression magnitude) during elasticity image (EI) acquisition. Thirty patients with 33 breast lesions who had undergone surgery followed by SI assessment in vivo were analyzed. An analytical approach to tissue elasticity based on the stress-elastic modulus (Young's modulus) relationship was adopted. Young's moduli were directly measured ex vivo in surgical specimens ranging from 2.60 kPa (fat) to 16.08 kPa (invasive carcinoma) under the weak-stress condition (<0.2-0.4 kPa, which corresponds to the appropriate "light touch" technique in SI investigation. The contrast (ratio) of lesion to fat in elasticity ex vivo gradually decreased as the stress applied increased (around 1.0 kPa) on the background of significant non-linearity of the breast tissue. Our results indicate that the differences in non-linearity in elasticity between the different tissues within the breast under minimal stress conditions are closely related to the variation in EI quality. The significance of the "pre-load compression" concept in tissue elasticity evaluation is recognized. Non-linearity of elasticity is an essential attribute of living subjects and could provide useful information having a considerable impact on clinical diagnosis in quantitative ultrasound elastography. PMID- 24802308 TI - Challenges in reduction of dinitrogen by proton and electron transfer. AB - Ammonia is an important nutrient for the growth of plants. In industry, ammonia is produced by the energy expensive Haber-Bosch process where dihydrogen and dinitrogen form ammonia at a very high pressure and temperature. In principle one could also reduce dinitrogen upon addition of protons and electrons similar to the mechanism of ammonia production by nitrogenases. Recently, major breakthroughs have taken place in our understanding of biological fixation of dinitrogen, of molecular model systems that can reduce dinitrogen, and in the electrochemical reduction of dinitrogen at heterogeneous surfaces. Yet for efficient reduction of dinitrogen with protons and electrons major hurdles still have to be overcome. In this tutorial review we give an overview of the different catalytic systems, highlight the recent breakthroughs, pinpoint common grounds and discuss the bottlenecks and challenges in catalytic reduction of dinitrogen. PMID- 24802306 TI - Network inefficiencies in autism spectrum disorder at 24 months. AB - Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral symptoms that emerge during the first years of life. Associated with these symptoms are differences in the structure of a wide array of brain regions, and in the connectivity between these regions. However, the use of cohorts with large age variability and participants past the generally recognized age of onset of the defining behaviors means that many of the reported abnormalities may be a result of cascade effects of developmentally earlier deviations. This study assessed differences in connectivity in ASD at the age at which the defining behaviors first become clear. There were 113 24-month-old participants at high risk for ASD, 31 of whom were classified as ASD, and 23 typically developing 24 month-old participants at low risk for ASD. Utilizing diffusion data to obtain measures of the length and strength of connections between anatomical regions, we performed an analysis of network efficiency. Our results showed significantly decreased local and global efficiency over temporal, parietal and occipital lobes in high-risk infants classified as ASD, relative to both low- and high-risk infants not classified as ASD. The frontal lobes showed only a reduction in global efficiency in Broca's area. In addition, these same regions showed an inverse relation between efficiency and symptom severity across the high-risk infants. The results suggest delay or deficits in infants with ASD in the optimization of both local and global aspects of network structure in regions involved in processing auditory and visual stimuli, language and nonlinguistic social stimuli. PMID- 24802307 TI - Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. AB - Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB-TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB-TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses. PMID- 24802309 TI - The assessment of arterial stiffness in endemic (Balkan) nephropathy patients undergoing haemodialysis. AB - Cardiovascular (CV) complications are the most important cause of morbidity and mortality in patients with advanced chronic kidney disease (CKD). Arterial stiffness (AS) has been recognized as a strong and independent predictor for CV events in CKD. Our aim was to assess indices of AS in a group of Endemic (Balkan) Nephropathy (EN) patients undergoing haemodialysis (HD). Hypertenison was not considered an importnat feauture in earlier stages of the disease, and therefore we presumed that those patients would have lower AS. Interestingly, we found AS to be even higher in this group of EN patients. This result should be confirmed in a larger cohort of EN patients. PMID- 24802310 TI - Endemic nephropathy and upper urothelial carcinoma--new insights in molecular biology. AB - Upper Tract Urothelial Carcinoma (UTUC) is an uncommon disease which occurs more frequently in some regions of Balkan countries than in other areas in the world. Investigation of UTUC in the South Morava River basin and its tributaries where BEN is endemic revealed increased frequency not only of tumour of the renal pelvis and ureter but also of urinary bladder tumours. A comparative morphological and immunohistochemical study of UTUC in the BEN region and control rural and city populations free of BEN, identify growth pattern as the best morphological characteristic which differentiated BEN and control tumours, i.e. solid growth for BEN tumours and papillary for control tumours. Overexpression of tumour suppressor p53 as well as decreased expression of E-CD was detected in BEN tumours. Other cells cycle related molecular markers--Cyclin D1, p16, and HER-2 showed no difference in expression between groups, as well as the proliferative marker Ki-67. Investigation of apoptosis-related markers identifies Bax as a specific marker of BEN-associated UTUC. Decrease of the pro-apoptotic protein Bax together with alteration of Survivin may be indicative of specific disturbances of an intrinsic apoptotic pathway in UTUC arising in endemic areas. PMID- 24802311 TI - A historical overview of Balkan Endemic Nephropathy (BEN) in relation to published hypotheses. AB - Balkan Endemic Nephropathy occurs with a high rate of prevalence in Serbia, Bulgaria, Romania, Bosnia and Herzegovina, and Croatia. The first cases described in Bulgaria, Serbia and Romania date to the late 1950s and early 1960s. BEN has been characterized to date as a chronic, slowly progressive familial tubular interstitial renal disease of unknown aetiology. The disease is characterized by its endemic nature, long incubation period, the familial clustering of the disease, and a exceptionally high incidence of upper urothelial tumour associated with BEN. To date several hypotheses have presented some findings that could be relevant to the etiology of BEN, but only one of them, chronic poisoning with Aristolochic acids, has provided convincing evidence related to BEN etiology and its clinical characteristics. PMID- 24802312 TI - Update on the role of the complement system in the pathogenesis of thrombotic microangiopathies. AB - In thrombotic microangiopathies (TMA) pathological changes of the small vessels are present, which lead to ischaemia of the affected tissues, low platelet-count and intravascular haemolytic anaemia with fragmentocytes. Two main clinical syndromes belong to the group of TMAs: the haemolytic uraemic syndrome (HUS) with kidney failure, mainly affecting children, and the thrombotic thrombocytopenic purpura (TTP), starting primarily in adulthood. HUS can be clinically classified into two forms: typical and atypical HUS, the latter being caused by defective regulation of the complement system. However, acccording to recent studies, complement activation is also present in other TMAs. Complement activation products (C3a, C5a, MAC) are able to activate endothelial cells, which results in loss of their antiinflammatory and antithrombotic potential. Activation of the complement system can also lead to direct activation of platelets and granulocytes. The consequent endothelial damage and thrombosis forms the pathological basis of the TMAs. Exploring the exact pathogenetic role of the complement system in these diseases makes the development of new therapeutic methods possible. PMID- 24802313 TI - New insights into septo-optic dysplasia. AB - Septo-Optic Dysplasia (SOD) is a rare disorder with postulated genetic and environmental etiology. Whilst initially considered as a very rare disease (defined as incidence of approx. 1 in 50,000 births) recent data gave a reported incidence of 1 in 10,000, with equal sex distribution. The diagnosis of SOD is predominantly a clinical one, and made with the presence of two or more features of the classic triad: 1) hypopituitarism, 2) optic nerve hypoplasia, and 3) midline brain defects, typically absence or hypoplasia of the septum pellucidum and/or corpus callosum. Hypopituitarism ranges from isolated to multiple hormone deficits, with diabetes insipidus in a minority. The condition is heterogeneous and may also manifest additional brain defects. Although homozygous mutations in the homeobox gene HESX1 have been identified in SOD, these are uncommon and genetic diagnosis can be made in only <1% of patients with autosomal recessive inheritance. Autosomal dominant inheritance has also been reported. SOX2, SOX3 and OTX2 mutations have also been identified in some forms of SOD. The aetiology of SOD is uncertain but viral infections, environmental teratogens and vascular or degenerative damage have been postulated to account for its sporadic occurrence. Other factors (endogenous or exogenous) include parental age, parity, smoking, alcohol and substance abuse, antenatal bleeding, and ethnicity. Cocaine abuse during pregnancy, which is a potent vasoconstrictor has recently been identified as a potential external cause. The phenotype of SOD is highly variable; the clinical picture may include visual impairment, short stature, obesity and sleep-wake inversion. Approximately 75-80% of patients exhibit optic nerve hypoplasia, which may be the first presenting feature. Pituitary insufficiency may evolve over time, and children with possible SOD must be kept under careful endocrine follow-up. Untreated hormonal abnormalities will further jeopardize neurodevelopment of children with SOD and could also lead to life threatening adrenal crises. The attention should be focussed on early diagnosis and treatment and education of paediatricians how to recognize this complex disorder. PMID- 24802314 TI - Tissue expansion in limbs vs other body regions. AB - INTRODUCTION: The development of tissue expansion technique as an important routine procedure in plastic and reconstructive surgery in the past two decades reflects the tendency of getting quality skin that would replace the defect. The aim of this study was to present our experience in the application of tissue expanders in the limbs, and to compare the complications of this procedure in limb and non-limb sites. MATERIAL AND METHODS: This retrospective study included 16 expanders in 14 patients. Indications for tissue expansion were post burn scarring and contractures, post mastectomy reconstruction and before excision of giant nevus. The expanders were placed in the following sites: scalp, breast, abdomen, leg and arm. RESULTS: Despite the fact that there were complications in 3 out of the 16 expanders used, failure occurred in 1 expander, which was removed. The remaining complications were managed either by immediate delivery whenever expansion approached full size or by salvage of the expander by exteriorizing the buried part in cases of infection. PMID- 24802315 TI - Open reduction and internal fixation versus external fixation and/or kirschner wires for distal radius fractures. A systematic review. AB - The aim of this study was to compare open reduction and plate fixation in the treatment of distal radius fractures with percutaneous fixation methods (external fixation and/or K-wires) regarding the outcome, using self-reported questionnaires (PRWE--Patient rated wrist evaluation, DASH--Disabilities of the Arm, Shoulder and Hand) as a primary aim, and grip strength and radiological parameters as a secondary aim. DATA SOURCE: We performed a systematic review of available evidence through a search of the electronic Medline PubMed database. STUDY SELECTION: Randomized clinical trials were included, as well as nonrandomized retrospective studies if they directly compared percutaneous fixation with ORIF, in the last ten years. DATA EXTRACTION: Functional (PRWE, DASH), objective (grip strength), as well as radiographic outcomes were extracted and reported. DATA SYNTHESIS: Ten studies were analysed, a total of 647 distal radius fractures (DRF) were included in the meta-analysis, 140 fractures treated with external fixation, 179 with K-wires (total 319 percutaneous fixation), and 328 fractures treated with ORIF. The meta-analysis showed no statistically significant differences between the results for the DRF treatment with ORIF or percutaneous methods at 3, 6 and 12 months regarding PRWE scores and grip strength, as well as final radiological outcome (volar tilt, radial length, radial tilt, ulnar variance). At 3 and 6 months there was a significant difference in the DASH score favouring open reduction and plate fixation, but at 12 months the meta-analysis showed no significant difference between the two methods compared. CONCLUSIONS: The results of this meta-analysis for the operative treatment of distal radius fractures did not clearly demonstrate a relevant advantage of any of the fixation methods. PMID- 24802316 TI - Depression among physicians working in public healthcare in Belo Horizonte, Brazil. AB - PURPOSE: Prevalence of depressive disorders has been reported among physicians in a number of different settings. The aim of the present study is to assess the prevalence of self-reported depression and its associated factors among physicians working in the public healthcare system of Belo Horizonte, Minas Gerais state, Brazil. METHODS: A cross-sectional survey was carried out in 2009 to investigate individual and occupational dimensions of depressive disorders in a group of physicians working at several municipal healthcare units. The percentage of physicians that self-reported a confirmed diagnosis of depression by another physician was used as the prevalence proportion; the Poisson regression univariate and multivariate models were applied to study factors associated with depression. RESULTS: The response rate was 81.2 %, of which 12.0 % reported depression confirmed by another physician. Reports of RSI/WMSD (p < 0.001) and passive work (p < 0.05) were positively and independently associated with the outcome. CONCLUSIONS: Our data bring valuable information that may help guide interventions and health-promoting activities for physicians by indicating concrete measures to change working conditions that affect mental health. PMID- 24802317 TI - Professional care seeking for mental health problems among women and men in Europe: the role of socioeconomic, family-related and mental health status factors in explaining gender differences. AB - PURPOSE: This comparative study examines cross-national variation in gender differences in primary and specialized mental health care use in Europe. We investigate to what extent socioeconomic, family-related, and mental health factors explain the gender difference, and how the impact of these groups of determinants on gender differences in mental health care use varies between countries. METHODS: Data from the Eurobarometer 248 (2005-2006) for 29 European countries is used and country-specific logistic regression analyses are performed. RESULTS: Gender differences in professional care seeking are largely need based. In almost one-third of the countries examined, the gender difference is mainly attributable to women's poorer mental health status. However, in some countries, family and socioeconomic characteristics also have an independent contribution to the gender difference in mental health care use. Women's higher likelihood of a lower socioeconomic position, might partly explain their higher primary care use, while in some countries, it restricts their specialized care use. In addition, some social conditions, as having children and being widowed, seem to function in a few countries as suppressors of women's care use. CONCLUSIONS: Our study has shown that the gender difference in mental health care use, with women having a higher care use, is not a consistent European phenomenon and is dependent on the type of care provider, with greater gender inequity in the use of primary health care. The social roles adopted by men and women have in some countries on top of the mental health status a relevant influence on the greater tendency among women to contact a care provider. How the socioeconomic and family characteristics moderate the relation between gender and mental health care use is not straightforward and country dependent. PMID- 24802328 TI - MiR-34c inhibits osteosarcoma metastasis and chemoresistance. AB - Studies have shown that miR-34c is associated with metastasis and the chemoresponse of several cancers, but its role in osteosarcoma (OS) is unclear. Here, we investigated the role and mechanism of miR-34c in OS metastasis and chemoresponse. In this study, we found that the expression of miR-34c was significantly decreased in specimens from OS patients with a poor chemoresponse or metastasis compared to those with a good chemoresponse and no metastasis. The inhibition of miR-34c significantly stimulated OS cell invasion and chemoresistance in vitro. In contrast, restoring miR-34c significantly inhibited OS cell invasion and chemoresistance. Furthermore, we identified Notch1 and lymphoid enhancer-binding factor 1 (LEF1) as target genes of miR-34c in OS cells and demonstrated that Notch1 and LEF1 have a major role in the effects of miR-34c on OS cell chemosensitivity and metastasis. Taken together, our data indicate that miR-34c suppresses OS metastasis and chemoresistance by targeting Notch1 and LEF1. Restoring miR-34c may have important implications for the development of strategies for inhibiting metastasis and overcoming OS cell resistance to chemotherapy. PMID- 24802329 TI - High-dose idarubicin plus busulfan as conditioning regimen to autologous stem cell transplantation: promising post-remission therapy for acute myeloid leukemia in first complete remission? AB - The optimal post-remission therapy (PRT) for acute myeloid leukemia (AML) remains uncertain. We reported 32 AML patients in first complete remission (CR1) undergoing autologous hematopoietic stem cell transplantation (ASCT) with a characteristic conditioning regimen, termed I-Bu, based on high-dose idarubicin plus busulfan, which considerably strengthened antileukemic activity. Most patients were in better or intermediate-risk group except that cytogenetic or molecular risk information was missing for 18.7 % of the patients. Unpurged peripheral blood stem cells were used in all the cases. The adverse effects were mild and reversible. Only one case of transplant-related mortality was observed. All the patients in this study acquired hematopoietic reconstitution after ASCT. After a median follow-up of 30 (6-119) months, 24 patients (75.0 %) were alive in which 20 (62.5 %) patients were in continuous CR. There were 11 (34.4 %) patients who relapsed after HSCT. Cumulative relapse probability was about 40 % after 24 months. Median OS and DFS have not been reached. Patients in the better and intermediate-risk group had different clinical outcomes, but the differences were not statistically significant. ASCT with I-Bu regimen is possibly promising PRT for better and intermediate-risk AML patients in CR1. PMID- 24802330 TI - TNF-alpha-mediated caspase-8 activation induces ROS production and TRPM2 activation in adult ventricular myocytes. AB - AIMS: TRPM2 is a Ca(2+)-permeable cationic channel of the transient receptor potential (TRP) superfamily that is linked to apoptotic signalling. Its involvement in cardiac pathophysiology is unknown. The aim of this study was to determine whether the pro-apoptotic cytokine tumour necrosis factor-alpha (TNF alpha) induces a TRPM2-like current in murine ventricular cardiomyocytes. METHODS AND RESULTS: Adult isolated cardiomyocytes from C57BL/6 mice were exposed to TNF alpha (10 ng/mL). Western blotting showed TRPM2 expression, which was not changed after TNF-alpha incubation. Using patch clamp in whole-cell configuration, a non specific cation current was recorded after exposure to TNF-alpha (ITNF), which reached maximal steady-state amplitude after 3 h incubation. ITNF was inhibited by the caspase-8 inhibitor z-IETD-fmk, the antioxidant N-acetylcysteine, and the TRPM2 inhibitors clotrimazole, N-(P-amylcinnamoyl) anthranilic acid and flufenamic acid (FFA). TRPM2 has previously been shown to be activated by ADP ribose, which is produced by poly(ADP-ribose) polymerase 1 (PARP-1). TNF-alpha exposure resulted in increased poly-ADP-ribosylation of proteins and the PARP-1 inhibitor 3-aminobenzamide inhibited ITNF. TNF-alpha exposure increased the mitochondrial production of reactive oxygen species (ROS; measured with the fluorescent indicator MitoSOX Red), and this increase was blocked by the caspase 8 inhibitor z-IETD-fmk. Clotrimazole and TRPM2 inhibitory antibody decreased TNF alpha-induced cardiomyocyte death. CONCLUSION: These results demonstrate that TNF alpha induces a TRPM2 current in adult ventricular cardiomyocytes. TNF-alpha induces caspase-8 activation leading to ROS production, PARP-1 activation, and ADP-ribose production. TNF-induced TRPM2 activation may contribute to cardiomyocyte cell death. PMID- 24802333 TI - Reprogramming sertoli cells into pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) have potential applications in the restoration of fertility, regenerative medicine, and animal biotechnology. In this study, we present the induction of iPSCs from mouse Sertoli cells (SCs) by introducing four factors--Oct4, Sox2, Klf4, and c-Myc. As early as day 3 after induction, expression of these factors was detected and typical embryonic stem like cells began to form. On day 18, these exogenous genes were silenced and colonies were selected according to morphological characteristics. The iPSCs induced from SCs, termed SCiPSCs, strongly expressed pluripotent markers, showed a normal karyotype, and had proliferation and differentiation characteristics similar to those of embryonic stem cells (ESCs), both in vitro and in vivo. Furthermore, exposure of SCiPSCs to nitric oxide (NO) allowed them to maintain pluripotency through the activation of the pluripotent genes Oct4 and Sox2 and upregulation of Nanog expression. Moreover, NO prevented SCiPSCs from undergoing apoptosis by activating the antiapoptotic genes Bcl2 and Bcl2lll, downregulating the proapoptotic genes Bak1 and Casp7, and blocking the activation of the proapoptotic gene Bac. These effects were reversed by exposure to l-NG monomethylarginine (l-NMMA), a NO inhibitor. These data demonstrate that iPSCs can be generated from SCs and that the self-renewal and pluripotency of SCiPS cells can be maintained in the presence of NO. PMID- 24802331 TI - Meta-analysis of molecular imaging of serotonin transporters in major depression. AB - The success of serotonin-selective reuptake inhibitors has lent support to the monoamine theory of major depressive disorder (MDD). This issue has been addressed in a number of molecular imaging studies by positron emission tomography or single-photon emission computed tomography of serotonin reuptake sites (5-HTT) in the brain of patients with MDD, with strikingly disparate conclusions. Our meta-analysis of the 18 such studies, totaling 364 MDD patients free from significant comorbidities or medication and 372 control subjects, revealed reductions in midbrain 5-HTT (Hedges' g=-0.49; 95% CI: (-0.84, -0.14)) and amygdala (Hedges' g=-0.50; 95% CI: (-0.78, -0.22)), which no individual study possessed sufficient power to detect. Only small effect sizes were found in other regions with high binding (thalamus: g=-0.24, striatum: g=-0.32, and brainstem g= 0.22), and no difference in the frontal or cingulate cortex. Age emerged as an important moderator of 5-HTT availability in MDD, with more severe reductions in striatal 5-HTT evident with greater age of the study populations (P<0.01). There was a strong relationship between severity of depression and 5-HTT reductions in the amygdala (P=0.01). Thus, molecular imaging findings indeed reveal widespread reductions of ~10% in 5-HTT availability in MDD, which may predict altered spatial-temporal dynamics of serotonergic neurotransmission. PMID- 24802334 TI - Adolescent health topic app design assignment. PMID- 24802332 TI - Role of microRNA29b in blood-brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism. AB - Although blood-brain barrier (BBB) integrity is maintained by the cross-talk of endothelial cells, junction proteins, and neurogliovascular network, the epigenetic mechanisms behind BBB permeability are largely unknown. We are reporting for the first time miR29b-mediated regulation of BBB, which is a novel mechanism underlying BBB integrity. We hypothesize that miR29b regulates BBB dysfunction by regulating DNMT3b, which consequently regulates the levels of metalloproteinases, that can eat up the membrane and junction proteins leading to leaky vasculature. In addition, 5'-azacytidine (5'-aza) was used to test its efficacy on BBB permeability. Blood-brain barrier disruption model was created by using homocysteine, and in the models miR29b was identified to be most affected, by using microRNA RT(2)-qPCR array. MiR29b mimics and inhibitors also confirmed that miR29b regulates the levels DNMT3b and MMP9. In hyperhomocysteinemic cystathionine-beta-synthase deficient (CBS(+/-)) mice with high brain vessel permeability, miR29b levels were also high as compared with wild-type (WT) mice. Interestingly, 5'-aza improved BBB permeability by decreasing the expression of miR29b. In conclusion, our data suggested miR29b-mediated regulation of BBB dysfunction through DNMT3b and MMP9. It also potentiates the use of microRNAs as candidates for future epigenetic therapies in the improvement of BBB integrity. PMID- 24802335 TI - Preferences in the management of high-risk prostate cancer among urologists in Europe: results of a web-based survey. AB - OBJECTIVE: To explore preferences in the management of patients with newly diagnosed high-risk prostate cancer (PCa) among urologists in Europe through a web-based survey. MATERIALS AND METHODS: A web-based survey was conducted between 15 August and 15 September 2013 by members of the Prostate Cancer Working Group of the Young Academic Urologists Working Party of the European Association of Urology (EAU). A specific, 29-item multiple-choice questionnaire covering the whole spectrum of diagnosis, staging and treatment of high-risk PCa was e-mailed to all urologists included in the mailing list of EAU members. Europe was divided into four geographical regions: Central-Eastern Europe (CEE), Northern Europe (NE), Southern Europe (SE) and Western Europe (WE). Descriptive statistics were used. Differences among sample segments were obtained from a z-test compared with the total sample. RESULTS: Of the 12,850 invited EAU members, 585 urologists practising in Europe completed the survey. High-risk PCa was defined as serum PSA >=20 ng/mL or clinical stage >= T3 or biopsy Gleason score >= 8 by 67% of responders, without significant geographical variations. The preferred single imaging examinations for staging were bone scan (74%, 81% in WE and 70% in SE; P = 0.02 for both), magnetic resonance imaging (53%, 72% in WE and 40% in SE; P = 0.02 and P = 0.01, respectively) and computed tomography (45%, 60% in SE and 23% in WE; P = 0.01 for both). Pre-treatment predictive tools were routinely used by 62% of the urologists, without significant geographical variations. The preferred treatment was radical prostatectomy as the initial step of a multiple-treatment approach (60%, 40% in NE and 70% in CEE; P = 0.02 and P < 0.01, respectively), followed by external beam radiation therapy with androgen deprivation therapy (29%, 45% in NE and 20% in CEE; P = 0.01 and P = 0.02, respectively), and radical prostatectomy as monotherapy (4%, 7% in WE; P = 0.04). When surgery was performed, the open retropubic approach was the most popular (58%, 74% in CEE, 37% in NE; P < 0.01 for both). Pelvic lymph node dissection was performed by 96% of urologists, equally split between a standard and extended template. There was no consensus on the definition of disease recurrence after primary treatment, and much heterogeneity in the administration of adjuvant and salvage treatments. CONCLUSION: With the limitation of a low response rate, the present study is the first survey evaluating preferences in the management of high-risk PCa among urologists in Europe. Although the definition of high-risk PCa was fairly uniform, wide variations in patterns of primary and adjuvant/salvage treatments were observed. These differences might translate into variations in quality of care with a possible impact on ultimate oncological outcome. PMID- 24802336 TI - The immunologic and antioxidant effects of L-phenylalanine on the uterine implantation of mice embryos during early pregnancy. AB - L-phenylalanine (L-PHE) is a synthetic precursor of catecholamines. Because it cannot be synthesised by an organism, it must be absorbed from the environment. Despite the wide use of L-PHE, whether L-PHE has a negative impact on embryo implantation and development is poorly understood. This study attempted to determine the roles of L-PHE in embryo implantation and development and in the immune response and antioxidant status of the uterus in early pregnancy mice injected intraperitoneally with 320 mg/kg L-PHE. The embryo number of treated mice decreased by 57.6%, and the size of their embryos was reduced by 2.8% (P?0.05) along the long diameter and 11.9% (P?0.05) along the short diameter at E9 compared with control mice. In addition, L-PHE significantly suppressed B lymphocyte proliferation. L-PHE increased IL-2 secretion but decreased the IL-4 concentration, thereby up-regulating the ratio of IL-2/IL-4 to 1.37-8.45. An analysis of the oxidant and antioxidant status showed that, compared with the control mice, the level of superoxide dismutase activity decreased by 21.54 39.94% and the glutathione peroxidase activity decreased by 15.27-18.96% among the L-PHE-treated mice at E1-E9. However, the malonaldehyde content increased by 14.29%-90.11% among the L-PHE-treated mice. Therefore, L-PHE impaired embryo implantation by disrupting cytokine-based immunity and oxidative stress in the uterus. PMID- 24802337 TI - Teen donors, adult problems? Evaluating the long-term risks of living kidney donation from adolescents. PMID- 24802338 TI - Vascular anastomosis for pediatric renal transplantation--a potential new strategy in low-weight children? PMID- 24802339 TI - The use of everolimus in pediatric kidney transplantation. PMID- 24802340 TI - Is it time to consider early discharge for pediatric patients after hematopoietic stem cell transplant? PMID- 24802341 TI - Best practices in the pediatric pretransplant psychosocial evaluation. AB - Assessment of psychosocial functioning is an often-included component of the pretransplant evaluation process. This study reviews several domains of assessment that have been related to post-transplant outcomes across solid organ transplant populations. These include evaluation of patient and family past adherence, knowledge about the transplantation process, and their neurocognitive, psychological, and family functioning. To date, few comprehensive pretransplant evaluation measures have been standardized for use with children; however, several assessment measures used to evaluate the aforementioned domains are reviewed throughout the study. Additionally, this article discusses some developmental, illness-specific, and cultural considerations in conducting the psychosocial evaluation. We also discuss ethical issues specific to the pediatric psychosocial evaluation. Recommendations are advanced to promote a comprehensive evaluation that identifies family strengths and risk factors as they begin the transplant journey. PMID- 24802342 TI - Three-yr safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. AB - The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty-seven children (9.1 +/- 5 yr old) received basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5-3 MUg/mL), and prednisone. Three wk later everolimus was started (C0:5-10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three-yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post-transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post-transplant was 105.5 +/- 31 and 110.7 +/- 27 mL/min/1.73 m(2), respectively. A growth velocity of 7.7 +/- 6.7 cm/yr was achieved with positive catch-up growth. No malignancy or post-transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low-dose cyclosporine, and low-dose prednisone leads to good long-term efficacy in de novo pediatric KT recipients. PMID- 24802343 TI - Recurrence of idiopathic focal segmental glomerulosclerosis after kidney transplantation: experience of a Korean tertiary center. AB - FSGS is the second most common cause of idiopathic NS in children. It often progresses to ESRD and commonly recurs after KT. To investigate the risk factors and the prognosis of recurrence in pediatric idiopathic FSGS in Korea, retrospective review of 43 KT in 38 children with idiopathic FSGS of last two decades was conducted. The patients presented at the median age of 5.1 yr (range 1.1-13.8 yr) and received KT 5.7 yr later (range 1.3-17.6 yr). FSGS recurred in 20 allografts immediately after transplantation, only in those who presented with NS but not in those who presented with AUA. The risk factors for recurrence were age of onset >5 yr and progression to ESRD within six yr but not sooner than 18 months. CR was achieved in 13 patients with FSGS recurrence and sustained in nine without subsequent relapse over a median of six and a half yr (0.6-20.7 yr). Pediatric idiopathic FSGS presenting with NS recurred in more than half of patients after transplantation. Interestingly, more rapid progression within less than 18 months did not predict recurrence. To identify high-risk patients of recurrence, an international cooperative study would be necessary. PMID- 24802344 TI - Outcome of liver re-transplantation in children--impact and special analysis of early re-transplantation. AB - In case of graft failure, re-LTX is the only life-saving option but it has been associated with inferior results. This study analyzes the outcome following pediatric re-LTX with a main focus on the timely relation between initial transplant and re-LTX. All pediatric LTX at our institution between 2000 and 2010 divided into patients with primary LTX and patients undergoing re-LTX early (<=30 days) or late (>30 days) after previous LTX were analyzed. Two hundred and ninety eight primary LTX(79%), 33 early (9%), and 46 late (12%) re-LTX were performed. Patient/graft survival was significantly worse for children undergoing early re LTX compared to primary LTX and late re-LTX (p = 0.024/0.001 and p = 0.015/0.03). One-/five-yr graft survival rates were 66%/49% for early re-LTX compared to 86%/76% for late re-LTX and 90%/74% for primary LTX. The inferior results in children undergoing early re-LTX were due to events occurring in the first six months with similar survival thereafter. No difference in outcome was evident after adjustment of the groups for high-urgency status. Outcome was excellent for primary LTX and late re-LTX, supporting late re-LTX in children. Early re-LTX takes an elevated risk of early graft loss and patient death; however, beyond the early postoperative period, the outcome was comparable. PMID- 24802345 TI - Hemorrhage requiring surgical intervention among children on pulsatile ventricular assist device support. AB - Bleeding complications are a source of morbidity after Berlin EXCOR VAD implantation yet remain poorly characterized. We evaluated our experience to describe the bleeding complications among pediatric VAD recipients. We hypothesized that those with bleeding requiring exploration had abnormal coagulation profile compared with those without bleeding. The retrospective study included 43 consecutive patients with end-stage heart failure supported on pediatric mechanical cardiac support as a bridge to transplantation. Day-/event based analysis on factors below associated with (i) bleeding and (ii) bleeding in next 48 h. Cases with bleeding were compared with day-matched patients without bleeding complications. Among 43 subjects bleeding occurred in 47% of cases, which necessitated exploration or chest tube placement. Twenty of 34 interventions for bleeding occurred in the first seven post-operative days. No differences in coagulation parameters or use of antiplatelet agents were noted among those who had bleeding vs. those who did not. Our results indicate that (i) re-bleeding requiring re-exploration was common, (ii) most of the bleeding occurred early post-implantation, (iii) there were no differences in coagulation parameters or the use of antiplatelet agents within 48 h of bleeding compared with those who did not bleed on each successive post-operative day. PMID- 24802346 TI - Antifungal prophylaxis in pediatric lung transplantation: an international multicenter survey. AB - Fungal infections create a significant risk to pediatric lung transplant recipients. However, no international consensus guidelines exist for fungal infection prevention strategies. It was the aim to describe the current strategies of antifungal prophylaxis in pediatric lung transplant centers. A self administered, web-based survey on current practices to prevent fungal infection was circulated to centers within the IPLTC. Twenty-one (88%) IPLTC centers participated, predominantly from Europe and the US. More than 50% of respondents perform adult and pediatric lung transplant operations. Twenty-four percent use universal prophylaxis, 28% give prophylaxis to all patients but stratify the antifungal coverage based on pretransplant risk, and 48% target prophylaxis to only the children with CF or pretransplantation fungal colonization. Commonly, centers aim to target Aspergillus and Candida infection. Monotherapy with either voriconazole or inhaled amphotericin B is used in the majority of centers. Institutions utilize prophylactic therapy for variable time periods (40% 3-6 months; 30% >=12 months). Alternative drugs were prescribed for lack of tolerance, toxicity, or positive surveillance culture. TDM (itraconazole/voriconazole) was used in 86% of centers. The survey revealed a wide range of antifungal prophylaxis strategies as current international practice in pediatric lung transplant recipients. PMID- 24802347 TI - Home care during neutropenia after allogeneic hematopoietic stem cell transplantation in children and adolescents is safe and may be more advantageous than isolation in hospital. AB - After ASCT, children are isolated in hospital to prevent neutropenic infections. Patients living within two-h drive from the hospital were given the option of treatment at home after ASCT. Daily visits by an experienced nurse and phone calls from a physician from the unit were included in the protocol. We compared 29 children and adolescents treated at home with 58 matched hospital controls. The children spent a median time of 13 days at home (range 2-24 days) and 6 (0 35) days in hospital. The cumulative incidence of acute GVHD grades II-IV was 21% in the home-care children and 39% in the controls (p = 0.1). Chronic GVHD and probability of relapse were similar in the two groups. TRM at five yr was 11% in the home-care patients and 18% in the controls. Overall survival at three yr was 77% and 62%, respectively (p = 0.33). None of the patients died at home. Median costs were 38,748 euros in the home-care patients and 49,282 euros in those treated in the hospital (p = 0.2). We conclude that it is safe for children and adolescents to be treated at home during the pancytopenic phase after ASCT. PMID- 24802348 TI - Neurological complications after allogeneic hematopoietic stem cell transplantation in children, a single center experience. AB - In this study, we retrospectively examined the data of children who underwent allo-HSCT from HLA-matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow-up of neurologic complications. BU-based conditioning regimens were used in most of the cases (n = 62). The median duration of follow-up for the 89 patients was 20 months (range 1-41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range -6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3-17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%). PMID- 24802349 TI - Gross hematuria as a sign of acute rejection. AB - In the contemporary era of potent immunosuppressive regimens, previously encountered signs of renal allograft rejection such as fever and hematuria are rarely encountered. We report a teenager with severe recurrent acute humoral and cellular rejection whose presenting feature was gross hematuria with the presence of blood clots in the urine. We want to highlight that severe rejection even in the setting of modern immunosuppressive drugs can present as gross hematuria. Contrary to conventional wisdom that gross hematuria with the presence of blood clots in the urine is indicative of pathology in the renal collecting system, a parenchymal disease process should also be considered in renal transplant recipients. PMID- 24802350 TI - Soil organic carbon redistribution by water erosion--the role of CO2 emissions for the carbon budget. AB - A better process understanding of how water erosion influences the redistribution of soil organic carbon (SOC) is sorely needed to unravel the role of soil erosion for the carbon (C) budget from local to global scales. The main objective of this study was to determine SOC redistribution and the complete C budget of a loess soil affected by water erosion. We measured fluxes of SOC, dissolved organic C (DOC) and CO2 in a pseudo-replicated rainfall-simulation experiment. We characterized different C fractions in soils and redistributed sediments using density fractionation and determined C enrichment ratios (CER) in the transported sediments. Erosion, transport and subsequent deposition resulted in significantly higher CER of the sediments exported ranging between 1.3 and 4.0. In the exported sediments, C contents (mg per g soil) of particulate organic C (POC, C not bound to soil minerals) and mineral-associated organic C (MOC) were both significantly higher than those of non-eroded soils indicating that water erosion resulted in losses of C-enriched material both in forms of POC and MOC. The averaged SOC fluxes as particles (4.7 g C m(-2) yr(-1)) were 18 times larger than DOC fluxes. Cumulative emission of soil CO2 slightly decreased at the erosion zone while increased by 56% and 27% at the transport and depositional zone, respectively, in comparison to non-eroded soil. Overall, CO2 emission is the predominant form of C loss contributing to about 90.5% of total erosion-induced C losses in our 4-month experiment, which were equal to 18 g C m(-2). Nevertheless, only 1.5% of the total redistributed C was mineralized to CO2 indicating a large stabilization after deposition. Our study also underlines the importance of C losses by particles and as DOC for understanding the effects of water erosion on the C balance at the interface of terrestrial and aquatic ecosystems. PMID- 24802351 TI - Novel compound heterozygous mutations identified in ADAMTSL4 gene in a Chinese family with isolated ectopia lentis. PMID- 24802352 TI - Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase. AB - Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti aquaporin-4-positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice. PMID- 24802353 TI - Fannin-Lubbock-I [alpha2beta2119(GLY>ASP)], a rare mutation in the beta-globin gene, has been detected for the first time in a Hindu Brahmin family in West Bengal, India. AB - This study aims to describe the hemoglobin Fannin-Lubbock-I, which has a rare mutation substituting the amino acid glycine with aspartic acid at codon 119 of the beta-globin chain. A Bengalee Hindu Brahmin family from Kolkata in West Bengal was the focus of this study. Molecular analysis using ARMS-PCR and direct DNA sequencing revealed the presence of a GGC > GAC mutation in codon 119 of the beta-globin gene in a heterozygote state in three women of the same family. This is the first report of the hemoglobin Fannin-Lubbock-I from India. Our results will help to identify this mutation, which is relatively infrequent in our population. PMID- 24802354 TI - When yesterday's consumption strikes back: deviation from usual consumption inversely predicts amounts consumed the next weekend evening. AB - INTRODUCTION AND AIMS: Young adults' weekend alcohol consumption is characterised by heavy episodic drinking (HED) with low alcohol use in between. This study investigates whether consuming a lower or higher number of drinks than usual on a given evening predicts consumption the following evening. DESIGN AND METHODS: In French-speaking Switzerland, 115 young adults (57% female, mean age = 23.2) answered questionnaires on their cellphones six times every Thursday, Friday and Saturday evening over five consecutive weeks. Multilevel models with group-mean centering were used to analyse 462 evening pairs. RESULTS: Although the sample average number of drinks consumed tended to increase from Thursday [Mmen (SD) = 3.6 (5.0); Mwomen (SD) = 2.9(4.2)] to Saturday [Mmen (SD) = 7.4( 7.1); Mwomen (SD) = 5.2(5.6)], substantial day-to-day variations were observed within individuals. Variations from the usual consumption (i.e. higher or lower number of drinks than usual) on the first day had a significant inverse impact on amounts consumed the following day (unstandardised regression coefficient (B) = 0.27, P < 0.01). This effect was more marked for evening pairs including HED (B = -0.44, P < 0.001). Men and heavy drinkers were less subject to day-to-day variations than women and usually moderate drinkers. DISCUSSION AND CONCLUSIONS: The inverse relationship might result from adverse consequences experienced after HED or an intentional reduction in alcohol consumption in anticipation of a heavy drinking session the next day. Event-specific prevention is needed for women and usually light or moderate drinkers as their more distinct consumption peaks put them at greater risk, particularly of accidents and injuries. PMID- 24802355 TI - James Edmund Reeves (1829-1896) and the contentious 19th century battle for medical professionalism in the United States. AB - During his life, Dr James E Reeves was a national figure in the US. His work included multiple professional publications, civic and professional leadership positions, and the drafting of a landmark law that confirmed the right of states to regulate the medical profession. While much of Reeves' work supported the successful struggle of 19th century regular physicians to gain control of the practice of medicine, he challenged his colleagues when their self-interests conflicted with his perception of the public good. He was frequently lauded for this work by physicians and the public but he also made professional enemies. Perhaps for this reason, his considerable accomplishments were forgotten after his death. His story reminds us of the difficult contradiction that exists within the regulation of medicine, guarding the public's welfare while protecting the interests of medical professionals. It also reminds us that history may temporarily overlook those who fight our difficult battles. PMID- 24802356 TI - Norman Barrett (1903-1979): Unorthodox pioneer of thoracic and oesophageal surgery. AB - It is an interesting quirk of medical history that the legacy of Norman Barrett most ostensibly lies in the name of a disease the he was quite emphatically wrong about, at least when he first described it. Indeed, there are those who argue to remove the eponym in favour of the title 'Columnar Lined Epithelium', in part because of what little Barrett actually had to do with the correct initial characterisation of this disease. Yet the sum of Norman Barrett's contributions to modern medicine is much more than a mistaken characterisation of a pathological process. Barrett was truly a pioneer of chest surgery in the UK - a speciality in its embryonic stages when he first qualified. He was also renowned as a teacher and academic of the highest calibre. In tracing the story of his life we can see how his natural attributes, life experiences and keen appreciation of the arts (especially history) facilitated personal success and such sharp insight into the vagaries of modern academic medicine. PMID- 24802357 TI - Prevalence of sexual victimization and correlates of forced sex in Japanese men who have sex with men. AB - Studies of men who have sex with men (MSM) in diverse geographic and cultural contexts have identified health challenges affecting this population. MSM might be particularly vulnerable to sexual victimization and forced sex. The aim of this research study was to examine prevalence of sexual victimization and correlates of forced sex among Japanese MSM. We recruited a sample of 5,731 Japanese MSM who completed an internet-administered survey. Participants reported on history of different types of sexual victimization, unprotected anal sex, other health risk behaviors, exposure to gay-related teasing and bullying, depression, and suicidality. Over one-fifth of the sample (21.4%) reported experiencing at least one form of sexual victimization, and 8.7% reported a history of forced sex. MSM who had ever experienced forced sex were significantly more likely to report experiencing psychological risks (depression OR = 1.55, 95% CI = 1.28-1.89; attempted suicide OR = 2.25, 95% CI = 1.81-2.81; other forms of bullying OR = 1.38, 95% CI = 1.13-1.68) and other behavioral risks (unprotected anal sex OR = 1.56, 95% CI = 1.29-1.90; sex venue attendance OR = 1.27, 95% CI = 1.04-1.54; methamphetamine use OR = 1.57, 95% CI = 1.05-1.36), compared to MSM who had not experienced forced sex. Efforts to develop holistic and integrated health services for Japanese MSM are warranted, particularly related to psychosocial determinants of HIV prevention. However, due to cultural factors that emphasize familial and social relations and that stigmatize same-sex behavior, Japanese MSM might experience challenges to seeking social support and health services. Interventions must be provided in safe and non-judgmental settings where Japanese MSM feel comfortable disclosing their health and social support needs. PMID- 24802358 TI - Applications of micelle enhancement in luminescence-based analysis. AB - Micelles are self-assembled aggregates that arrange themselves into spheres in aqueous media. When the surfactant concentration reaches the critical micelle concentration, extensive aggregation of the surfactant monomers occurs to form micelles. A micelle has both a hydrophilic and a hydrophobic part. This allows them to form a spherical shape and for their glycolipid and phospholipid components to form lipid bilayers. The importance of micelles is increasing because of their wide analytical applications. Recently, colloidal carrier systems have received much attention in the field of analytical chemistry, especially in luminescence enhancement applications. PMID- 24802359 TI - Stress-associated cardiovascular reaction masks heart rate dependence on physical load in mice. AB - When tested on the treadmill mice do not display a graded increase of heart rate (HR), but rather a sharp shift of cardiovascular indices to high levels at the onset of locomotion. We hypothesized that under test conditions cardiovascular reaction to physical load in mice is masked with stress-associated HR increase. To test this hypothesis we monitored mean arterial pressure (MAP) and heart rate in C57BL/6 mice after exposure to stressful stimuli, during spontaneous locomotion in the open-field test, treadmill running or running in a wheel installed in the home cage. Mice were treated with beta1-adrenoblocker atenolol (2mg/kg ip, A), cholinolytic ipratropium bromide (2mg/kg ip, I), combination of blockers (A+I), anxiolytic diazepam (5mg/kg ip, D) or saline (control trials, SAL). MAP and HR in mice increased sharply after handling, despite 3weeks of habituation to the procedure. Under stressful conditions of open field test cardiovascular parameters in mice were elevated and did not depend on movement speed. HR values did not differ in I and SAL groups and were reduced with A or A+I. HR was lower at rest in D pretreated mice. In the treadmill test HR increase over speeds of 6, 12 and 18m/min was roughly 1/7-1/10 of HR increase observed after placing the mice on the treadmill. HR could not be increased with cholinolytic (I), but was reduced after sympatholytic (A) or A+I treatment. Anxiolytic (D) reduced heart rate at lower speeds of movement and its overall effect was to unmask the dependency of HR on running speed. During voluntary running in non-stressful conditions of the home cage HR in mice linearly increased with increasing running speeds. We conclude that in test situations cardiovascular reactions in mice are governed predominantly by stress-associated sympathetic activation, rendering efforts to evaluate HR and MAP reactions to workload unreliable. PMID- 24802360 TI - High dietary fat intake influences the activation of specific hindbrain and hypothalamic nuclei by the satiety factor oleoylethanolamide. AB - Chronic exposure to a diet rich in fats changes the gastrointestinal milieu and alters responses to several signals involved in the control of food intake. Oleoylethanolamide (OEA) is a gut-derived satiety signal released from enterocytes upon the ingestion of dietary fats. The anorexigenic effect of OEA, which requires intestinal PPAR-alpha receptors and is supposedly mediated by vagal afferents, is associated with the induction of c-fos in several brain areas involved in the control of food intake, such as the nucleus of the solitary tract (NST) and the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). In the present study we investigated whether the exposure to a high fat diet (HFD) alters the hindbrain and hypothalamic responses to OEA. To this purpose we evaluated the effects of OEA at a dose that reliably inhibits eating (10mg/kg i.p.) on the induction of c-fos in the NST, area postrema (AP), PVN and SON in rats maintained either on standard chow or a HFD. We performed a detailed analysis of the different NST subnuclei activated by i.p. OEA and found that peripheral OEA strongly activates c-fos expression in the AP, NST and in the hypothalamus of both chow and HFD fed rats. The extent of c-fos expression was, however, markedly different between the two groups of rats, with a weaker activation of selected NST subnuclei and stronger activation of the PVN in HFD fed than in chow-fed rats. HFD-fed rats were also more sensitive to the immediate hypophagic action of OEA than chow-fed rats. These effects may be due to a decreased sensitivity of vagal afferent fibers that might mediate OEA's actions on the brain and/or an altered sensitivity of brain structures to OEA. PMID- 24802361 TI - Interacting effects of discharge and channel morphology on transport of semibuoyant fish eggs in large, altered river systems. AB - Habitat fragmentation and flow regulation are significant factors related to the decline and extinction of freshwater biota. Pelagic-broadcast spawning cyprinids require moving water and some length of unfragmented stream to complete their life cycle. However, it is unknown how discharge and habitat features interact at multiple spatial scales to alter the transport of semi-buoyant fish eggs. Our objective was to assess the relationship between downstream drift of semi-buoyant egg surrogates (gellan beads) and discharge and habitat complexity. We quantified transport time of a known quantity of beads using 2-3 sampling devices at each of seven locations on the North Canadian and Canadian rivers. Transport time was assessed based on median capture time (time at which 50% of beads were captured) and sampling period (time period when 2.5% and 97.5% of beads were captured). Habitat complexity was assessed by calculating width?depth ratios at each site, and several habitat metrics determined using analyses of aerial photographs. Median time of egg capture was negatively correlated to site discharge. The temporal extent of the sampling period at each site was negatively correlated to both site discharge and habitat-patch dispersion. Our results highlight the role of discharge in driving transport times, but also indicate that higher dispersion of habitat patches relates to increased retention of beads within the river. These results could be used to target restoration activities or prioritize water use to create and maintain habitat complexity within large, fragmented river systems. PMID- 24802363 TI - A national survey of renal replacement therapy prescribing practice for acute kidney injury in Malaysian intensive care units. AB - OBJECTIVES: To describe renal replacement therapy (RRT) prescribing practices in Malaysian intensive care units (ICU), and compare this with previously published data from other regions. METHOD: A survey was sent to physicians responsible for prescribing RRT in major ICU throughout Malaysia. The questionnaire sought information on the physicians' background, and detailed information regarding RRT settings. RESULTS: Nineteen physicians from 24 sites throughout Malaysia responded to the survey (response rate 79.2%). Sixteen respondents were intensivists (84%), 2 were anaesthetists (11%) and one was a nephrologist (5%). The majority (58%) used continuous venovenous haemofiltration (CVVH) as the treatment of choice for acute kidney injury (AKI) in critically ill patients. RRT prescription was predominantly practitioner-dependent (63%), while 37% reported use of a dedicated protocol. The mean blood flow rate and effluent flow rate used for continuous RRT (CRRT) were 188.9 +/- 28.9 mL/min and 30.6 +/- 4.7 mL/kg/h respectively. Replacement fluid solutions containing both lactate and bicarbonate were commonly used during CRRT, applied both pre- and post-dilution. CONCLUSION: CRRT was the first-choice modality used to treat AKI in critically ill patients. CVVH was the most common CRRT technique used, while other RRT modalities were used less frequently. Overall, RRT practices were similar to those observed in other regions, although the modality and settings used were slightly different, likely due to local availability. PMID- 24802364 TI - Medium-sized heterocycle synthesis by the use of synergistic effects of Ni-NHC and gamma-coordination in cycloisomerization. AB - This paper describes a new approach in transition-metal-catalyzed unsymmetric cycloisomerization for medium-sized heterocycles. The steric and electronic effects of an NHC-NiH catalyst and gamma-heteroatom chelation were used together as a basis for 1,n-diene termini differentiation and for n(gamma)-exo-trig (head to-tail) product selectivity. Heterocycles bearing an exocyclic methylene such as oxepines, thiepines, siloxepines, and oxocanes were synthesized from the corresponding 1,n-dienes by a fine-tuning of the NHC properties. The implication of the underlying hypothesis was further demonstrated in a competition experiment in which strained oxepines were formed preferentially over other competing oxa /carbocycles. Under more forcing physical conditions and the use of a suitable NHC ligand, the exocyclic methylene products were isomerized further into endocyclic olefin products regioselectively in one pot. PMID- 24802362 TI - Phosphokinase antibody arrays on dendron-coated surface. AB - Monitoring protein phosphorylation at the cellular level is important to understand the intracellular signaling. Among the phosphoproteomics methods, phosphokinase antibody arrays have emerged as preferred tools to measure well characterized phosphorylation in the intracellular signaling. Here, we present a dendron-coated phosphokinase antibody array (DPA) in which the antibodies are immobilized on a dendron-coated glass slide. Self-assembly of conically shaped dendrons well-controlled in size and structure resulted in precisely controlled lateral spacing between the immobilized phosphosite-specific antibodies, leading to minimized steric hindrance and improved antigen-antibody binding kinetics. These features increased sensitivity, selectivity, and reproducibility in measured amounts of protein phosphorylation. To demonstrate the utility of the DPA, we generated the phosphorylation profiles of brain tissue samples obtained from Alzheimer's disease (AD) model mice. The analysis of the profiles revealed signaling pathways deregulated during the course of AD progression. PMID- 24802365 TI - Arsenic and lung disease mortality in Bangladeshi adults. AB - BACKGROUND: Chronic arsenic exposure through drinking water is a public health problem affecting millions of people worldwide, including at least 30 million in Bangladesh. We prospectively investigated the associations of arsenic exposure and arsenical skin lesion status with lung disease mortality in Bangladeshi adults. METHODS: Data were collected from a population-based sample of 26,043 adults, with an average of 8.5 years of follow-up (220,157 total person-years). There were 156 nonmalignant lung disease deaths and 90 lung cancer deaths ascertained through October 2013. We used Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals (CIs) for lung disease mortality. RESULTS: Creatinine-adjusted urinary total arsenic was associated with nonmalignant lung disease mortality, with persons in the highest tertile of exposure having a 75% increased risk for mortality (95% CI = 1.15 2.66) compared with those in the lowest tertile of exposure. Persons with arsenical skin lesions were at increased risk of lung cancer mortality (hazard ratio = 4.53 [95% CI = 2.82-7.29]) compared with those without skin lesions. CONCLUSIONS: This prospective investigation of lung disease mortality, using individual-level arsenic measures and skin lesion status, confirms a deleterious effect of ingested arsenic on mortality from lung disease. Further investigations should evaluate effects on the incidence of specific lung diseases, more fully characterize dose-response, and evaluate screening and biomedical interventions to prevent premature death among arsenic-exposed populations, particularly among those who may be most susceptible to arsenic toxicity. PMID- 24802366 TI - Heat and mortality in New York City since the beginning of the 20th century. AB - BACKGROUND: Heat is recognized as one of the deadliest weather-related phenomena. Although the impact of high temperatures on mortality has been a subject of extensive research, few previous studies have assessed the impact of population adaptation to heat. METHODS: We examined adaptation patterns by analyzing daily temperature and mortality data spanning more than a century in New York City. Using a distributed-lag nonlinear model, we analyzed the heat-mortality relation in adults age 15 years or older in New York City during 2 periods: 1900-1948 and 1973-2006, to quantify population adaptation to high temperatures over time. RESULTS: During the first half of the century, the decade-specific relative risk of mortality at 29 degrees C vs. 22 degrees C ranged from 1.30 (95% confidence interval [CI]= 1.25-1.36) in the 1910s to 1.43 (1.37-1.49) in the 1900s. Since the 1970s, however, there was a gradual and substantial decline in the relative risk, from 1.26 (1.22-1.29) in the 1970s to 1.09 (1.05-1.12) in the 2000s. Age specific analyses indicated a greater risk for people age 65 years and older in the first part of the century, but there was less evidence for enhanced risk among this older age group in more recent decades. CONCLUSION: The excess mortality with high temperatures observed between 1900 and 1948 was substantially reduced between 1973 and 2006, indicating population adaption to heat in recent decades. These findings may have implications for projecting future impacts of climate change on mortality. PMID- 24802367 TI - Additive effect of in-hospital TIMI bleeding and chronic kidney disease on 1-year cardiovascular events in patients with acute coronary syndrome: Data from Taiwan Acute Coronary Syndrome Full Spectrum Registry. AB - In-hospital bleeding (IHB) is associated with the risk of subsequent cardiovascular events (CVE) in acute coronary syndrome (ACS). We investigated whether increased risk of CVE by IHB is influenced by chronic kidney disease (CKD) or both have detrimental effects on CVE. In a Taiwan national-wide registry, 2819 ACS patients were enrolled. CKD is defined as an estimated glomerular filtration rate of <60 ml/min per 1.73 m2. The primary end point is the composite of death, non-fatal myocardial infarction and non-fatal stroke at 12 months. 53 (1.88%) and 949 (33.7%) patients suffered from IHB and CKD, respectively. Both IHB and CKD are independently associated with increased risk of the primary end point (HR 2.04, 95% CI 1.05-3.99, p = 0.037 and HR 2.17, 95% CI 1.63-2.87, p < 0.01, respectively). The Kaplan-Meier curves show significantly higher event rates among those with IHB and CKD in the whole, ST-elevation and non-ST elevation populations (all p < 0.01). Patients with IHB+ / CKD-, IHB- / CKD+ and IHB+ / CKD+ have 1.88-, 2.13- and 2.98-fold risk to suffer from the primary end point compared with those without IHB and CKD (p = 0.23, <0.01 and <0.01, respectively). IHB or CKD is independently associated with poor cardiovascular outcome and patients with both IHB and CKD have the worst outcome in ACS. PMID- 24802368 TI - Comparative cell attachment, cytotoxicity and antibacterial activity of radiopaque dicalcium silicate cement and white-coloured mineral trioxide aggregate. AB - AIM: To comparatively examine the cell attachment, cytotoxicity, and antibacterial activity of radiopaque dicalcium silicate cement (RDSC) and ProRoot white-coloured mineral trioxide aggregate (WMTA). METHODOLOGY: AlamarBlue was used for real-time and repeated monitoring of MG63 cell attachment on freshly mixed and set cements. The pH changes in the growth medium at different time points were also measured. Cytotoxicity evaluation was performed according to ISO 10993-5 specifications. The antibacterial activity of the cement specimens was evaluated using Enterococcus faecalis. RESULTS: There were no significant differences (P > 0.05) between the two cements for cell attachment either in the fresh groups or in the set groups at all culture times. Neither freshly mixed group nor set groups had significant pH differences. In the case of cytotoxicity, RDSC was significantly (P < 0.05) superior to WMTA at 12 and 24 h of incubation. RDSC and WMTA possessed similar antimicrobial activity, substantiated by the formation of growth inhibition zones and bacteriostasis ratio in E. faecalis strains. CONCLUSIONS: The cell attachment, cytotoxicity and antibacterial efficacy of RDSC were comparable to those reported for ProRoot WMTA. The results of the current study suggest that this RDSC could be used as a root-end filling material and root sealer. PMID- 24802369 TI - Size-fitting effect for hybridization of DNA/mercaptohexanol mixed monolayers on gold. AB - In this article we proposed a simple hexagonal model for exploring the hybridization of thiol-modified probe DNA self-assembled monolayers (SAMs) on gold with target DNA molecules in solution. The size-fitting coefficient d(c)/d(t) from the model was used to discuss the principle for DNA optimal hybridization, where d(c) was the channel diameter among three adjacent probe DNA molecules on gold and dt was the gyration diameter of the target DNA molecules in solution. Experimentally we investigated the hybridization effect (hybridization efficiency H(E) and hybridization density H(D)) of thiol-modified probe DNA (DNA base amount m = 15, 25 or 35)/mercaptohexanol (MCH) mixed SAMs on gold in 1 M electrolyte solution by chronocoulometry (CC) and electrochemical impedance spectroscopy (EIS). The surface coverage Gamma(m) of the probe DNA on gold was adjusted by changing the mixed concentration ratio of probe DNA with MCH (C(DNA)/C(MCH)) in the assembly solution. Results indicated that with the increase of C(DNA)/C(MCH), H(E) decreased gradually; H(D) first increased and then decreased, which arrived at the biggest at C(DNA)/C(MCH) = 1 for all the probe DNA/MCH mixed SAMs (m = 15, 25, 35). The optimal Gamma(m) for achieving the biggest H(D) in DNA hybridization decreased with the increase of m from 15 to 35. The experimental conclusions obtained by CC and EIS measurements verified each other. Combining the simple model with our experimental results, we ascertained that d(c)/d(t) decreased with the increase of m, which showed a good linear relationship. These conclusions provided an important reference and guidance for controllably constructing DNA sensors with optimal performance. PMID- 24802370 TI - Three-dimensional cellular distribution in polymeric scaffolds for bone regeneration: a microCT analysis compared to SEM, CLSM and DNA content. AB - In orthopaedic surgery the tissues damaged by injury or disease could be replaced using constructs based on biocompatible materials, cells and growth factors. Scaffold design, porosity and early colonization are key components for the implant success. From biological point of view, attention may be also given to the number, type and size of seeded cells, as well as the seeding technique and cell morphological and volumetric alterations. This paper describes the use of the microCT approach (to date used principally for mineralized matrix quantification) to observe construct colonization in terms of cell localization, and make a direct comparison of the microtomographic sections with scanning electron microscopy images and confocal laser scanning microscope analysis. Briefly, polycaprolactone scaffolds were seeded at different cell densities with MG63 osteoblastic-like cells. Two different endpoints, 1 and 2 weeks, were selected for the three-dimensional colonization and proliferation analysis of the cells. By observing all images obtained, in addition to a more extensive distribution of cells on scaffolds surfaces than in the deeper layers, cell volume increased at 2 weeks compared to 1 week after seeding. Combining the cell number quantification by deoxyribonucleic acid analysis and the single cell volume changes by confocal laser scanning microscope, we validated the microCT segmentation method by finding no statistical differences in the evaluation of the cell volume fraction of the scaffold. Furthermore, the morphological results of this study suggest that an effective scaffold colonization requires a precise balance between different factors, such as number, type and size of seeded cells in addition to scaffold porosity. PMID- 24802371 TI - Simplifying electronic data capture in clinical trials: workflow embedded image and biosignal file integration and analysis via web services. AB - To improve data quality and save cost, clinical trials are nowadays performed using electronic data capture systems (EDCS) providing electronic case report forms (eCRF) instead of paper-based CRFs. However, such EDCS are insufficiently integrated into the medical workflow and lack in interfacing with other study related systems. In addition, most EDCS are unable to handle image and biosignal data, although electrocardiography (EGC, as example for one-dimensional (1D) data), ultrasound (2D data), or magnetic resonance imaging (3D data) have been established as surrogate endpoints in clinical trials. In this paper, an integrated workflow based on OpenClinica, one of the world's largest EDCS, is presented. Our approach consists of three components for (i) sharing of study metadata, (ii) integration of large volume data into eCRFs, and (iii) automatic image and biosignal analysis. In all components, metadata is transferred between systems using web services and JavaScript, and binary large objects (BLOBs) are sent via the secure file transfer protocol and hypertext transfer protocol. We applied the close-looped workflow in a multicenter study, where long term (7 days/24 h) Holter ECG monitoring is acquired on subjects with diabetes. Study metadata is automatically transferred into OpenClinica, the 4 GB BLOBs are seamlessly integrated into the eCRF, automatically processed, and the results of signal analysis are written back into the eCRF immediately. PMID- 24802372 TI - Evaluation of low-cost telemammography screening configurations: a comparison with film-screen readings in vulnerable areas. AB - The aim of this study was to evaluate the diagnostic accuracy for detecting breast cancer using different telemammography configurations, including combinations of both low-cost capture devices and consumer-grade color displays. At the same time, we compared each of these configurations to film-screen readings. This study used a treatment-by-reader-by-case factorial design. The sample included 70 mammograms with 34 malignant cases. The readers consisted of four radiologists who classified all of the cases according to the categories defined by the Breast Imaging Reporting and Data System (BI-RADS). The evaluated capture devices included a specialized film digitizer and a digital camera, and the evaluated displays included liquid crystal display (LCD) and light-emitting diode (LED) consumer-grade color displays. Receiver operating characteristic curves, diagnostic accuracy (measured as the area under these curves), accuracy of the composition classification, sensitivity, specificity, and the degree of agreement between readers in the detection of malignant cases were also evaluated. Comparisons of diagnostic accuracy between film-screen and the different combinations of digital configurations showed no significant differences for nodules, calcifications, and asymmetries. In addition, no differences were observed in terms of sensibility or specificity when the degree of malignancy using the film-screen method was compared to that provided with digital configurations. Similar results were observed for the classification of breast composition. Furthermore, all observed reader agreements of malignant detection between film-screen and digital configurations were substantial. These findings indicate that the evaluated digital devices showed comparable diagnostic accuracy to the reference treatment (film-screen). PMID- 24802373 TI - Biological inorganic chemists pay tribute to Ivano Bertini. PMID- 24802375 TI - Atom environment kernels on molecules. AB - The measurement of molecular similarity is an essential part of various machine learning tasks in chemical informatics. Graph kernels provide good similarity measures between molecules. Conventional graph kernels are based on counting common subgraphs of specific types in the molecular graphs. This approach has two primary limitations: (i) only exact subgraph matching is considered in the counting operation, and (ii) most of the subgraphs will be less relevant to a given task. In order to address the above-mentioned limitations, we propose a new graph kernel as an extension of the subtree kernel initially proposed by Ramon and Gartner (2003). The proposed kernel tolerates an inexact match between subgraphs by allowing matching between atoms with similar local environments. In addition, the proposed kernel provides a method to assign an importance weight to each subgraph according to the relevance to the task, which is predetermined by a statistical test. These extensions are evaluated for classification and regression tasks of predicting a wide range of pharmaceutical properties from molecular structures, with promising results. PMID- 24802376 TI - A physiological approach to motor development within and across domains. PMID- 24802377 TI - Chiral phosphoric-acid-catalyzed transfer hydrogenation of ethyl ketimine derivatives by using benzothiazoline. AB - Chiral phosphoric acid catalyzed transfer hydrogenation of ketimines derived from propiophenone derivatives and reductive amination of alkyl ethyl ketone derivatives were extensively examined in the presence of two representative hydrogen donors. The excellent enantioselective transfer hydrogenation was achieved by use of benzothiazoline as a hydrogen donor. The theoretical studies elucidated that the unsymmetrical structure of benzothiazoline plays an important role in high enantioselective hydrogenation. PMID- 24802378 TI - Differential evolution enhanced with multiobjective sorting-based mutation operators. AB - Differential evolution (DE) is a simple and powerful population-based evolutionary algorithm. The salient feature of DE lies in its mutation mechanism. Generally, the parents in the mutation operator of DE are randomly selected from the population. Hence, all vectors are equally likely to be selected as parents without selective pressure at all. Additionally, the diversity information is always ignored. In order to fully exploit the fitness and diversity information of the population, this paper presents a DE framework with multiobjective sorting based mutation operator. In the proposed mutation operator, individuals in the current population are firstly sorted according to their fitness and diversity contribution by nondominated sorting. Then parents in the mutation operators are proportionally selected according to their rankings based on fitness and diversity, thus, the promising individuals with better fitness and diversity have more opportunity to be selected as parents. Since fitness and diversity information is simultaneously considered for parent selection, a good balance between exploration and exploitation can be achieved. The proposed operator is applied to original DE algorithms, as well as several advanced DE variants. Experimental results on 48 benchmark functions and 12 real-world application problems show that the proposed operator is an effective approach to enhance the performance of most DE algorithms studied. PMID- 24802379 TI - Interfering with the neural activity of mirror-related frontal areas impairs mentalistic inferences. AB - According to recently proposed interactive dual-process theories, mentalizing abilities emerge from the coherent interaction between two physically distinct neural systems: (1) the mirror network, coding for the low-level embodied representations involved in pre-reflective sociocognitive processes and (2) the mentalizing network per se, which codes for higher level representations subtending the reflective attribution of psychological states. However, although the latest studies have shown that the core areas forming these two neurocognitive systems do indeed maintain effective connectivity during mentalizing, it is unclear whether an intact mirror system (and, more specifically, its anterior node, namely the posterior inferior frontal cortex) is a prerequisite for accurate mentalistic inferences. Intraoperative brain mapping via direct electrical stimulation offers a unique opportunity to address this issue. Electrical stimulation of the brain creates a "virtual" lesion, which provides functional information on well-defined parts of the cerebral cortex. In the present study, five patients were mapped in real time while they performed a mentalizing task. We found six responsive sites: four in the lateral part of the right pars opercularis and two in the dorsal part of the right pars triangularis. On the subcortical level, two additional sites were located within the white matter connectivity of the pars opercularis. Taken as a whole, our results suggest that the right inferior frontal cortex and its underlying axonal connectivity have a key role in mentalizing. Specifically, our findings support the hypothesis whereby transient, functional disruption of the mirror network influences higher order mentalistic inferences. PMID- 24802381 TI - Shared vs. specific brain activation changes in dyslexia after training of phonology, attention, or reading. AB - Whereas the neurobiological basis of developmental dyslexia has received substantial attention, only little is known about the processes in the brain during remediation. This holds in particular in light of recent findings on cognitive subtypes of dyslexia which suggest interactions between individual profiles, training methods, and also the task in the scanner. Therefore, we trained three groups of German dyslexic primary school children in the domains of phonology, attention, or visual word recognition. We compared neurofunctional changes after 4 weeks of training in these groups to those in untrained normal readers in a reading task and in a task of visual attention. The overall reading improvement in the dyslexic children was comparable over groups. It was accompanied by substantial increase of the activation level in the visual word form area (VWFA) during a reading task inside the scanner. Moreover, there were activation increases that were unique for each training group in the reading task. In contrast, when children performed the visual attention task, shared training effects were found in the left inferior frontal sulcus and gyrus, which varied in amplitude between the groups. Overall, the data reveal that different remediation programmes matched to individual profiles of dyslexia may improve reading ability and commonly affect the VWFA in dyslexia as a shared part of otherwise distinct networks. PMID- 24802380 TI - Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity. AB - Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area. PMID- 24802383 TI - Highly transparent and efficient counter electrode using SiO2/PEDOT-PSS composite for bifacial dye-sensitized solar cells. AB - A highly transparent and efficient counter electrode was facilely fabricated using SiO2/poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) inorganic/organic composite and used in bifacial dye-sensitized solar cells (DSCs). The optical properties of SiO2/PEDOT-PSS electrode can be tailored by the blending amount of SiO2 and film thickness, and the incorporation of SiO2 in PEDOT-PSS provides better transmission in the long wavelength range. Meanwhile, the SiO2/PEDOT-PSS counter electrode shows a better electrochemical catalytic activity than PEDOT-PSS electrode for triiodide reduction, and the role of SiO2 in the catalytic process is investigated. The bifacial DSC with SiO2/PEDOT-PSS counter electrode achieves a high power conversion efficiency (PCE) of 4.61% under rear-side irradiation, which is about 83% of that obtained under front-side irradiation. Furthermore, the PCE of bifacial DSC can be significantly increased by adding a reflector to achieve bifacial irradiation, which is 39% higher than that under conventional front-side irradiation. PMID- 24802382 TI - Ciprofloxacin as a potential radio-sensitizer to tumor cells and a radio protectant for normal cells: differential effects on gamma-H2AX formation, p53 phosphorylation, Bcl-2 production, and cell death. AB - Ionizing radiation increases cell mortality in a dose-dependent manner. Increases in DNA double strand breaks, gamma-H2AX, p53 phophorylation, and protein levels of p53 and Bax also occur. We investigated the ability of ciprofloxacin (CIP), a widely prescribed antibiotic, to inhibit DNA damage induced by ionizing radiation. Human tumor TK6, NH32 (p53 (-/-) of TK6) cells, and human normal peripheral blood mononuclear cells (PBMCs) were exposed to 2-8 Gy (60)Co-gamma photon radiation. gamma-H2AX (an indicator of DNA strand breaks), phosphorylated p53 (responsible for cell-cycle arrest), Bcl-2 (an apoptotic protein, and cell death were measured. Ionizing irradiation increased gamma-H2AX amounts in TK6 cells (p53(+/+)) within 1 h in a radiation dose-dependent manner. CIP pretreatment and posttreatment effectively inhibited the increase in gamma-H2AX. CIP pretreatment reduced Bcl-2 production but promoted p53 phosphorylation, caspase-3 activation and cell death. In NH32 cells, CIP failed to significantly inhibit the radiation-induced gamma-H2AX increase, suggesting that CIP inhibition involves in p53-dependent mechanisms. In normal healthy human PBMCs, CIP failed to block the radiation-induced gamma-H2AX increase but effectively increased Bcl 2 production, but blocked the phospho-p53 increase and subsequent cell death. CIP increased Gadd45alpha, and enhanced p21 protein 24 h postirradiation. Results suggest that CIP exerts its effect in TK6 cells by promoting p53 phosphorylation and inhibiting Bcl-2 production and in PBMCs by inhibiting p53 phosphorylation and increasing Bcl-2 production. Our data are the first to support the view that CIP may be effective to protect normal tissue cells from radiation injury, while enhancing cancer cell death in radiation therapy. PMID- 24802384 TI - Measuring causes of adult mortality in rural northern Malawi over a decade of change. AB - BACKGROUND: Verbal autopsy could be more widely used if interpretation by computer algorithm could be relied on. We assessed how InterVA-4 results compared with clinician review in diagnosing HIV/AIDS-related deaths over the period of antiretroviral (ART) roll-out. DESIGN: In the Karonga Prevention Study demographic surveillance site in northern Malawi, all deaths are followed by verbal autopsy using a semi-structured questionnaire. Cause of death is assigned by two clinicians with a third as a tie-breaker. The clinician review diagnosis was compared with the InterVA diagnosis using the same questionnaire data, including all adult deaths from late 2002 to 2012. For both methods data on HIV status were used. ART was first available in the district from 2005, and within the demographic surveillance area from 2006. RESULTS: There were 1,637 adult deaths, with verbal autopsy data for 1,615. Adult mortality and the proportion of deaths attributable to HIV/AIDS fell dramatically following ART introduction, but for each year the proportion attributed to HIV/AIDS by InterVA was lower than that attributed by clinician review. This was partly explained by the handling of TB cases. Using clinician review as the best available 'gold standard', for those aged 15-59, the sensitivity of InterVA for HIV/AIDS deaths was 59% and specificity 88%. Grouping HIV/AIDS/TB sensitivity was 78% and specificity 83%. Sensitivity was lower after widespread ART use. CONCLUSIONS: InterVA underestimates the proportion of deaths due to HIV/AIDS. Accepting that it is unrealistic to try and differentiate TB and AIDS deaths would improve the estimates. Caution is needed in interpreting trends in causes of death as ART use may affect the performance of the algorithm. PMID- 24802385 TI - Indigenous health and environmental risk factors: an Australian problem with global analogues? AB - Indigenous people experience poorer health than non-Indigenous people, and this well-described inequality has been observed in many countries. The contribution of different risk factors to the health 'gap' has understandably focussed on those factors for which there are sufficient data. However, this has precluded environmental risk factors - those present in air, water, food, and soil - due to a lack of data describing exposures and outcomes. These risk factors are demonstrably important at the global scale, as highlighted by the 2010 Global Burden of Disease study. Here, we describe how a greater focus on environmental risk factors is required in order to define their role in the Indigenous health gap. We use the Australian context as a case study of an issue we feel has global analogues and relevance. Suggestions for how and why this situation should be remedied are presented and discussed. PMID- 24802386 TI - Experiences and perceptions about cause and prevention of cardiovascular disease among people with cardiometabolic conditions: findings of in-depth interviews from a peri-urban Nepalese community. AB - BACKGROUND: Nepal currently faces an increasing burden of cardiovascular disease (CVD). Earlier studies on health literacy and the behavior dimension of cardiovascular health reported a substantial gap between knowledge and practice. OBJECTIVE: This qualitative study aimed to deepen understanding of the community perspective on cardiovascular health from the patients' viewpoint. DESIGN: We conducted in-depth interviews (IDIs) with 13 individuals with confirmed heart disease, hypertension, or diabetes mellitus. All participants provided verbal consent. We used an IDI guide to ask respondents about their perception and experiences with CVD, particularly regarding causation and preventability. We manually applied qualitative content analysis to evaluate the data and grouped similar content into categories and subcategories. RESULTS: Respondents perceived dietary factors, particularly consumption of salty, fatty, and oily food, as the main determinants of CVD. Similarly, our respondents unanimously linked smoking, alcohol intake, and high blood pressure with cardiac ailments but reported mixed opinion regarding the causal role of body weight and physical inactivity. Although depressed and stressed at the time of diagnosis, respondents learned to handle their situation better over time. Despite good family support for health care, the financial burden of disease was a major issue. All respondents understood the importance of lifestyle modification and relied upon health professionals for information and motivation. Respondents remarked that community awareness of CVD was inadequate and that medical doctors or trained local people should help increase awareness. CONCLUSIONS: This study provided insight into the perceptions of patients regarding CVD. Respondents embraced the importance of lifestyle modification only after receiving their diagnosis. Although better health care is important in terms of aiding patients to better understand and cope with their disease, interventions should be tailored to improve the community's cardiovascular health literacy and preventive practices. PMID- 24802387 TI - The electrostatic interactions of relaxin-3 with receptor RXFP4 and the influence of its B-chain C-terminal conformation. AB - Relaxin-3 (also known as insulin-like peptide 7) is an insulin/relaxin superfamily peptide hormone that can bind and activate three relaxin-family peptide receptors: RXFP3, RXFP4, and RXFP1. Recently, we identified key electrostatic interactions between relaxin-3 and its cognate receptor RXFP3 by using a charge-exchange mutagenesis approach. In the present study, the electrostatic interactions between relaxin-3 and RXFP4 were investigated with the same approach. Mutagenesis of the negatively charged extracellular residues of human RXFP4 identified a conserved EXXXD(100-104) motif that is essential for RXFP4 activation by relaxin-3. Mutagenesis of the conserved positively charged Arg residues of relaxin-3 demonstrated that B12Arg, B16Arg and B26Arg were all involved in the binding and activation of RXFP4, especially B26Arg. The activity complementation between the mutant ligands and the mutant receptors suggested two probable electrostatic interaction pairs: Glu100 of RXFP4 versus B26Arg of relaxin-3, and Asp104 of RXFP4 versus both B12Arg and B16Arg of relaxin-3. For interaction with the essential EXXXD motifs of both RXFP3 and RXFP4, a folding back conformation of the relaxin-3 B-chain C-terminus seems to be critical, because it brings B26Arg sufficiently close to B12Arg and B16Arg. To test this hypothesis, we replaced the conserved B23Gly-B24Gly dipeptide of relaxin-3 with an Ala-Ser dipeptide that occupied the corresponding position of insulin-like peptide 5 and resulted in an extended helical conformation. The mutant relaxin-3 showed a significant decrease in receptor-activation potency towards both RXFP3 and RXFP4, suggesting that a folding-back conformation of the B-chain C-terminus was important for relaxin-3 to efficiently interact with the EXXXD motifs of both receptors. PMID- 24802388 TI - Sex differences in white matter abnormalities after mild traumatic brain injury: localization and correlation with outcome. AB - PURPOSE: To evaluate sex differences in diffusion-tensor imaging (DTI) white matter abnormalities after mild traumatic brain injury (mTBI) using tract-based spatial statistics (TBSS) and to compare associated clinical outcomes. MATERIALS AND METHODS: The institutional review board approved this study, with waiver of informed consent. DTI in 69 patients with mTBI (47 male and 22 female patients) and 21 control subjects (10 male and 11 female subjects) with normal conventional magnetic resonance (MR) images were retrospectively reviewed. Fractional anisotropy (FA) maps were generated as a measure of white matter integrity. Patients with mTBI underwent serial neurocognitive testing with Immediate Post Concussion Assessment and Cognitive Testing (ImPACT). Correlation between sex, white matter FA values, ImPACT scores, and time to symptom resolution (TSR) were analyzed with multivariate analysis and TBSS. RESULTS: No significant difference in age was seen between males and females (control subjects, P = .3; patients with mTBI, P = .34). No significant difference was seen in initial ImPACT symptom scores (P = .33) between male and female patients with mTBI. Male patients with mTBI had significantly decreased FA values in the uncinate fasciculus (UF) bilaterally (mean FA, 0.425; 95% confidence interval: 0.375, 0.476) compared with female patients with mTBI and control subjects (P < .05), with a significantly longer TSR (P = .04). Multivariate analysis showed sex and UF FA values independently correlated with TSR longer than 3 months (adjusted odds ratios, 2.27 and 2.38; P = .04 and P < .001, respectively), but initial symptom severity did not (adjusted odds ratio, 1.15; P = .35). CONCLUSION: Relative sparing of the UF is seen in female compared with male patients after mTBI, with sex and UF FA values as stronger predictors of TSR than initial symptom severity. PMID- 24802389 TI - Ultra-high-performance liquid chromatography tandem mass spectrometry method for the determination of gambogenic acid in dog plasma and its application to a pharmacokinetic study. AB - A highly sensitive and rapid ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of gambogenic acid in dog plasma. Gambogic acid was used as an internal standard (IS). After a simple liquid-liquid extraction by ethyl acetate, the analyte and internal standard were separated on an Acquity BEH C18 (100 * 2.1 mm, 1.7 um; Waters ) column at a flow rate of 0.2 mL/min, using 0.1% formic acid-methanol (10:90, v/v) as mobile phase. Electrospray ionization source was applied and operated in the positive ion mode. Multiple reaction monitoring mode with the transitions m/z 631.3 -> 507.3 and m/z 629.1 -> 573.2 was used to quantify gambogenic acid and the internal standard, respectively. The calibration curves were linear in the range of 5-1000 ng/mL, with a coefficient of determination (r) of 0.999 and good calculated accuracy and precision. The low limit of quantification was 5 ng/mL. The intra-and inter-day precisions (relative standard deviations) were <15%. The methodology recoveries were more than 66.63%. This validated method was successfully applied to a pharmacokinetic study after intravenous injection administration of gambogenic acid in dogs at a dose of 1 mg/kg. PMID- 24802390 TI - Resveratrol reduces the proinflammatory effects and lipopolysaccharide- induced expression of HMGB1 and TLR4 in RAW264.7 cells. AB - BACKGROUND: Resveratrol (Res) is a polyphenol anti-inflammatory agent. We have studied the link between the anti-inflammatory effects of Res and the high mobility group box 1(HMGB1) signaling pathway. METHODS: Murine macrophage-like RAW264.7 cells (RAW264.7 cells) were either untreated (control) or treated with Res, LPS, or LPS + Res. Levels of IL-6, NO, and TNF-alpha were measured by ELISA and colorimetric assays. Expression of HMGB1 was detected by qRT-PCR, western blot, and immunofluorescence assays. Protein and mRNA expression levels of TLR4 were also examined. RESULTS: Res significantly reduced the levels of IL-6, NO, and TNF-alpha in RAW264.7 cells exposed to LPS. Expression levels of HMGB1 (mRNA and protein) and of TLR4 in the LPS + Res-treated cells were lower than in cells treated with LPS alone. CONCLUSIONS: Res can block the inflammatory effects induced by LPS in RAW264.7 cells. Down-regulation of HMGB expression may be one of the mechanisms of action of Res. Res may also influence TLR4 expression in the HMGB1-TLR4 signaling pathway. PMID- 24802391 TI - Symmetry analysis of talus bone: A Geometric morphometric approach. AB - OBJECTIVE: The main object of this study was to use a geometric morphometric approach to quantify the left-right symmetry of talus bones. METHODS: Analysis was carried out using CT scan images of 11 pairs of intact tali. Two important geometric parameters, volume and surface area, were quantified for left and right talus bones. The geometric shape variations between the right and left talus bones were also measured using deviation analysis. Furthermore, location of asymmetry in the geometric shapes were identified. RESULTS: Numerical results showed that talus bones are bilaterally symmetrical in nature, and the difference between the surface area of the left and right talus bones was less than 7.5%. Similarly, the difference in the volume of both bones was less than 7.5%. Results of the three-dimensional (3D) deviation analyses demonstrated the mean deviation between left and right talus bones were in the range of -0.74 mm to 0.62 mm. It was observed that in eight of 11 subjects, the deviation in symmetry occurred in regions that are clinically less important during talus surgery. CONCLUSIONS: We conclude that left and right talus bones of intact human ankle joints show a strong degree of symmetry. The results of this study may have significance with respect to talus surgery, and in investigating traumatic talus injury where the geometric shape of the contralateral talus can be used as control. Cite this article: Bone Joint Res 2014;3:139-45. PMID- 24802392 TI - A screening pattern recognition method finds new and divergent targets for drugs and natural products. AB - Computational target prediction methods using chemical descriptors have been applied exhaustively in drug discovery to elucidate the mechanisms-of-action (MOAs) of small molecules. To predict truly novel and unexpected small molecule target interactions, compounds must be compared by means other than their chemical structure alone. Here we investigated predictions made by a method, HTS fingerprints (HTSFPs), that matches patterns of activities in experimental screens. Over 1,400 drugs and 1,300 natural products (NPs) were screened in more than 200 diverse assays, creating encodable activity patterns. The comparison of these activity patterns to an MOA-annotated reference panel led to the prediction of 5,281 and 2,798 previously unknown targets for the NP and drug sets, respectively. Intriguingly, there was limited overlap among the targets predicted; the drugs were more biased toward membrane receptors and the NPs toward soluble enzymes, consistent with the idea that they represent unexplored pharmacologies. Importantly, HTSFPs inferred targets that were beyond the prediction capabilities of standard chemical descriptors, especially for NPs but also for the more explored drug set. Of 65 drug-target predictions that we tested in vitro, 48 (73.8%) were confirmed with AC50 values ranging from 38 nM to 29 MUM. Among these interactions was the inhibition of cyclooxygenases 1 and 2 by the HIV protease inhibitor Tipranavir. These newly discovered targets that are phylogenetically and phylochemically distant to the primary target provide an explanation for spontaneous bleeding events observed for patients treated with this drug, a physiological effect that was previously difficult to reconcile with the drug's known MOA. PMID- 24802393 TI - Identification of a functional nuclear localization signal within the human USP22 protein. AB - Ubiquitin-specific processing enzyme 22 (USP22), a member of the deubiquitinase family, is over-expressed in most human cancers and has been implicated in tumorigenesis. Because it is an enzymatic subunit of the human SAGA transcriptional cofactor, USP22 deubiquitylates histone H2A and H2B in the nucleus, thus participating in gene regulation and cell-cycle progression. However, the mechanisms regulating its nuclear translocation have not yet been elucidated. It was here demonstrated that USP22 is imported into the nucleus through a mechanism mediated by nuclear localization signal (NLS). The bipartite NLS sequence KRELELLKHNPKRRKIT (aa152-168), was identified as the functional NLS for its nuclear localization. Furthermore, a short cluster of basic amino acid residues KRRK within this bipartite NLS plays the primary role in nuclear localization and is evolutionarily conserved in USP22 homologues. In the present study, a functional NLS and the minimal sequences required for the active targeting of USP22 to the nucleus were identified. These findings may provide a molecular basis for the mechanism underlying USP22 nuclear trafficking and function. PMID- 24802394 TI - JNK and AKT/GSK3beta signaling pathways converge to regulate periodontal ligament cell survival involving XIAP. AB - Periodontal ligament cells (PDLCs) were incubated with H2O2 and the levels of XIAP protein, protein kinase B (AKT), phosphorylated forms of AKT (pAKT), c-Jun N terminal kinase (JNK), and glycogen synthase kinase-3beta (GSK3beta) were determined by western immunoblotting or immunocytochemistry. After overexpression and knockdown of XIAP, the AKT, pAKT, JNK and GSK3beta levels were determined in PDLCs exposed to H2O2. We demonstrated that 72 h of 250 MUM H2O2 exposure resulted in an increase in apoptosis. Meanwhile, XIAP levels were decreased with 72 h of 250 MUM H2O2 exposure, while there were also a decrease of JNK2, AKT, pAKT, and GSK3beta levels. Such reductions induced by 72 h of 250 MUM H2O2 treatment were partially recovered in PDLCs overexpressing XIAP. Interestingly, these reductions (except for pAKT) were mimicked by RNA interference of XIAP. These results suggest that, after 72 h of 250 MUM H2O2 exposure, Akt, JNK, and GSK3beta intracellular kinase signaling pathways converge to regulate PDLC survival involving XIAP. PMID- 24802395 TI - Modulation of mitochondrial function by stem cell-derived cellular components. AB - Huntington's disease (HD) is the most common hereditary neurodegenerative diseases, in which the loss of striatal neuron caused by the aggregation of mutant huntingtin protein (mHtt) is the main pathological feature. Our previous studies have demonstrated that human adipose stem cells (hASC) and its extracts can slow down the progression of HD in vitro and in vivo. hASC are readily accessible adult stem cells, and the cytosolic extracts contain a number of neurotrophic factors. Here, we further explored the role of the hASC extracts in neuronal death and mitochondrial function in HD. Our results showed that the hASC extracts prevent mHtt-induced cell toxicity and cell apoptosis. Moreover, the hASC extracts recovered mHtt-induced mitochondrial oxidative stress and reduced mitochondrial membrane potential. The hASC extracts blocked the interaction between p53 and mHtt, and decreased the endogenous p53 levels at both transcriptional and post-translational levels, resulting in the instability of p53 and increased neuronal survival. Taken together, these findings implicate protective roles of hASC extracts in mHtt-induced mitochondrial apoptosis, providing insights into the molecular mechanism of the hASC in the therapeutic strategy of HD. PMID- 24802396 TI - Glutathione peroxidase-1 is required for self-renewal of murine embryonic stem cells. AB - Embryonic stem (ES) cells are pluripotent cells that are capable of giving rise to any type of cells in the body and possess unlimited self-renewal potential. However, the exact regulatory mechanisms that govern the self-renewal ability of ES cells remain elusive. To understand the immediate early events during ES cell differentiation, we performed a proteomics study and analyzed the proteomic difference in murine ES cells before and after a 6-h spontaneous differentiation. We found that the expression level of glutathione peroxidase-1 (GPx-1), an antioxidant enzyme, is dramatically decreased upon the differentiation. Both knockdown of GPx-1 expression with shRNA and inhibiting GPx-1 activity by inhibitor led to the differentiation of ES cells. Furthermore, we showed that during early differentiation, the quick degradation of GPx-1 was mediated by proteasome. Thus, our data indicated that GPx-1 is a key regulator of self renewal of murine embryonic stem cells. PMID- 24802397 TI - Characterization of essential genes by topological properties in the perturbation sensitivity network. AB - Genes that are indispensable for survival are called essential genes. In recent years, the analysis of essential genes has become extremely important for understanding the way a cell functions. With the advent of large-scale gene expression profiling technologies, it is now possible to profile transcriptional changes in the entire genome of Saccharomyces cerevisiae. Notwithstanding the accumulation of gene expression profiling in recent years, only a few studies have used these data to construct the network for S. cerevisiae. In this paper, based on the transcriptional profiling of the S. cerevisiae genome in hundreds of different gene disruptions, the perturbation sensitivity (PS) network is constructed. A scale-free topology with node degree following a power-law distribution is shown in the PS network. Twelve topological properties are used to investigate the characteristics of essential and non-essential genes in the PS network. Most of the properties are found to be statistically discriminative between essential and non-essential genes. In addition, the F-score is used to estimate the essentiality of each property, and the core number demonstrates the highest F-score among all properties. PMID- 24802398 TI - The PDZ-binding motif of the avian NS1 protein affects transmission of the 2009 influenza A(H1N1) virus. AB - By nature of their segmented RNA genome, influenza A viruses (IAVs) have the potential to generate variants through a reassortment process. The influenza nonstructural (NS) gene is critical for a virus to counteract the antiviral responses of the host. Therefore, a newly acquired NS segment potentially determines the replication efficiency of the reassortant virus in a range of different hosts. In addition, the C-terminal PDZ-binding motif (PBM) has been suggested as a pathogenic determinant of IAVs. To gauge the pandemic potential from human and avian IAV reassortment, we assessed the replication properties of NS-reassorted viruses in cultured cells and in the lungs of mice and determined their transmissibility in guinea pigs. Compared with the recombinant A/Korea/01/2009 virus (rK09; 2009 pandemic H1N1 strain), the rK09/VN:NS virus, in which the NS gene was adopted from the A/Vietnam/1203/2004 virus (a human isolate of the highly pathogenic avian influenza H5N1 virus strains), exhibited attenuated virulence and reduced transmissibility. However, the rK09/VN:NS-PBM virus, harboring the PBM in the C-terminus of the NS1 protein, recovered the attenuated virulence of the rK09/VN:NS virus. In a guinea pig model, the rK09/VN:NS-PBM virus showed even greater transmission efficiency than the rK/09 virus. These results suggest that the PBM in the NS1 protein may determine viral persistence in the human and avian IAV interface. PMID- 24802399 TI - Functional artificial luciferases as an optical readout for bioassays. AB - This study elucidates functional artificial luciferases (ALucs) wholly synthesized for bioassays and molecular imaging. The ALucs bearing epitopes were newly created by amending the sequences of our previously reported ALucs in light of a multi-sequence alignment and hydrophobicity search. The synthesized ALucs are survived in live cells and stable in culture media for 25 days after secretion. The epitopes in ALucs are exposed during the secretion process and indeed valid for column purification and immunological assays. The ALucs exerted a 9400-times stronger optical intensity with a coelenterazine derivative (CTZ i), when compared with Renilla reniformis luciferase 8.6-535. A supersecondary structure of ALuc30 was predicted with respect to the X-ray crystallographic information of the coelenterazine-binding protein (CBP). The structure revealed that ALuc30 has a room for accommodating the iodide of CTZ i. This study guides on how to create functional artificial luciferases and predicts the structural details with the current bioinformatics technologies. PMID- 24802400 TI - Phospholipase D1 decreases type I collagen levels in hepatic stellate cells via induction of autophagy. AB - Hepatic stellate cells (HSCs) are major players in liver fibrogenesis. Accumulating evidence shows that suppression of autophagy plays an important role in the development and progression of liver disease. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to yield phosphatidic acid (PA) and choline, was recently shown to modulate autophagy. However, little is known about the effects of PLD1 on the production of type I collagen that characterizes liver fibrosis. Here, we examined whether PLD1 regulates type I collagen levels in HSCs through induction of autophagy. Adenovirus-mediated overexpression of PLD-1 (Ad-PLD1) reduced type I collagen levels in the activated human HSC lines, hTERT and LX2. Overexpression of PLD1 in HSCs led to induction of autophagy as demonstrated by increased LC3-II conversion and formation of LC3 puncta, and decreased p62 abundance. Moreover, inhibiting the induction of autophagy by treating cells with bafilomycin or a small interfering (si)RNA for ATG7 rescued Ad-PLD1-induced suppression of type I collagen accumulation in HSCs. The effects of PLD on type I collagen levels were not related to TGF-beta/Smad signaling. Furthermore, treatment of cells with PA induced autophagy and inhibited type I collagen accumulation. The present study indicates that PLD1 plays a role in regulating type I collagen accumulation through induction of autophagy. PMID- 24802401 TI - Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion. AB - The increased glycolysis and proton secretion in tumors is proposed to contribute to the proliferation and invasion of cancer cells during the process of tumorigenesis and metastasis. Here, treatment of human breast cancer cells with proton pump inhibitor (PPI) lansoprazole (LPZ) induces cell apoptosis in a dose dependent manner. In the implantation of the MDA-MB-231 xenografts in nude mice, administration of LPZ significantly inhibits tumorigenesis and induces large scale apopotosis of tumor cells. LPZ markedly inhibits intracellular proton extrusion, induces an increase in intracellular ATP level, lysosomal alkalinization and accumulation of reactive oxygen species (ROS) in breast cancer cells. The ROS scavenger N-acetyl-l-cysteine (NAC) and diphenyleneiodonium (DPI), a specific pharmacological inhibitor of NADPH oxidases (NOX), significantly abolish LPZ-induced ROS accumulation in breast cancer cells. Our results suggested that LPZ may be used as a new therapeutic drug for breast tumor. PMID- 24802402 TI - A dual functional fluorescent probe for glioma imaging mediated by blood-brain barrier penetration and glioma cell targeting. AB - Glioma is a huge threat for human being because it was hard to be completely removed owing to both the infiltrating growth of glioma cells and integrity of blood brain barrier. Thus effectively imaging the glioma cells may pave a way for surgical removing of glioma. In this study, a fluorescent probe, Cy3, was anchored onto the terminal of AS1411, a glioma cell targeting aptamer, and then TGN, a BBB targeting peptide, was conjugated with Cy3-AS1411 through a PEG linker. The production, named AsT, was characterized by gel electrophoresis, (1)H NMR and FTIR. In vitro cellular uptake and glioma spheroid uptake demonstrated the AsT could not only be uptaken by both glioma and endothelial cells, but also penetrate through endothelial cell monolayer and uptake by glioma spheroids. In vivo, AsT could effectively target to glioma with high intensity. In conclusion, AsT could be used as an effective glioma imaging probe. PMID- 24802403 TI - Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. AB - Cognitive impairment, the most common and severe comorbidity of epilepsy, greatly diminishes the quality of life. However, current therapeutic interventions for epilepsy can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both seizures and cognition deficits. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits, and antioxidants have a putative antiepileptic potential. Metformin, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of metformin on seizures, cognitive impairment and brain oxidative stress markers observed in pentylenetetrazole-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of pentylenetetrazole (37 mg/kg, i.p.) every other day for 14 injections. Metformin was injected intraperitoneally in dose of 200mg/kg along with alternate-day PTZ. We found that metformin suppressed the progression of kindling, ameliorated the cognitive impairment and decreased brain oxidative stress. Thus the present study concluded that metformin may be a potential agent for the treatment of epilepsy as well as a protective medicine against cognitive impairment induced by seizures. PMID- 24802404 TI - MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells. AB - Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC), in subsets of patients, radioresistance is still a major problem in the treatment. In this study, we demonstrated that irradiation induced MET overexpression and activation, and the aberrant MET signal mediated by hepatocyte growth factor (HGF) induced radioresistance. We also found that MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. Further investigation indicated that PHA-665752 suppressed the phosphorylation of the Akt, ERK1/2, and STAT3 proteins in a dose dependent manner. Our data indicated that the combination of IR with a MET inhibitor, such as PHA-665752, might be a promising therapeutic strategy for NPC. PMID- 24802405 TI - Type I collagen prevents amyloid aggregation of hen egg white lysozyme. AB - Both collagen and amyloidogenic proteins have an inherent ability to undergo a self-assembly process leading to formation of supramolecular structures. Though our understanding of collagen-amyloid link is very poor, a few experimental evidences have indicated the protective nature of collagen against amyloid fibril formation. To further our understanding of collagen-amyloid relationship, we have explored the role of type I collagen on amyloid-aggregation of lysozyme. Thioflavin-T assay data indicated strong inhibition of both spontaneous and seeded aggregation of lysozyme by collagen. Both chemical and thermal denaturation experiments have showed increased lysozyme stability in the presence of collagen. However, the presence of collagen did not alter lysozyme activity. These findings confirm that type I collagen is capable of blocking or interfering with the amyloid aggregation of lysozyme, and the results may have significant implications for the design of collagen based therapeutics against aggregation of disease linked amyloidogenic proteins. PMID- 24802406 TI - The histone acetyltransferase MOF overexpression blunts cardiac hypertrophy by targeting ROS in mice. AB - Imbalance between histone acetylation/deacetylation critically participates in the expression of hypertrophic fetal genes and development of cardiac hypertrophy. While histone deacetylases play dual roles in hypertrophy, current evidence reveals that histone acetyltransferase such as p300 and PCAF act as pro hypertrophic factors. However, it remains elusive whether some histone acetyltransferases can prevent the development of hypertrophy. Males absent on the first (MOF) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. Here in this study, we reported that MOF expression was down-regulated in failing human hearts and hypertrophic murine hearts at protein and mRNA levels. To evaluate the roles of MOF in cardiac hypertrophy, we generated cardiac-specific MOF transgenic mice. MOF transgenic mice did not show any differences from their wide-type littermates at baseline. However, cardiac-specific MOF overexpression protected mice from transverse aortic constriction (TAC)-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observed lower expression of hypertrophic fetal genes in TAC-challenged MOF transgenic mice compared with that of wide-type mice. Mechanically, MOF overexpression increased the expression of Catalase and MnSOD, which blocked TAC induced ROS and ROS downstream c-Raf-MEK-ERK pathway that promotes hypertrophy. Taken together, our findings identify a novel anti-hypertrophic role of MOF, and MOF is the first reported anti-hypertrophic histone acetyltransferase. PMID- 24802407 TI - miR-214 promotes the proliferation and invasion of osteosarcoma cells through direct suppression of LZTS1. AB - Previous studies have shown that miR-214 functions either as an oncogene or a tumor suppressor in various human cancer types. The role of this microRNA in osteosarcoma (OS) is presently unclear. Here, we demonstrated that miR-214 is frequently upregulated in OS specimens, compared with noncancerous bone tissues. Bioinformatics analysis further revealed leucine zipper, putative tumor suppressor 1 (LZTS1) as a potential target of miR-214. Expression patterns of miR 214 were inversely correlated with those of LZTS1 mRNA and protein in OS tissues. Data from reporter assays showed that miR-214 directly binds to the 3' untranslated region (3'-UTR) of LZTS1 mRNA and suppresses expression at both transcriptional and translational levels. In functional assays, miR-214 promoted OS cell proliferation, invasion and tumor growth in nude mice, which could be reversed by overexpression of LZTS1. Taken together, our data provide compelling evidence that miR-214 functions as an onco-miRNA in OS, and its oncogenic effects are mediated chiefly through downregulation of LZTS1. PMID- 24802408 TI - JMJD2A predicts prognosis and regulates cell growth in human gastric cancer. AB - A number of JmjC domain-containing histone demethylases have been identified and biochemically characterized in mammalian. JMJD2A is a transcriptional cofactor and enzyme that catalyzes demethylation of histone H3 lysines 9 and 36. Here in this study, we aim to explore the role of JMJD2A in human gastric cancer. Quantitative real-time PCR, Western blot and immunohistochemistry analyses reveal higher expression of JMJD2A in clinical gastric cancer tissues than that in normal gastric mucosa. JMJD2A expression is associated with tumor stage and nodal status, and high level of JMJD2A predicts poor overall and disease-free survival. Univariate and multivariate survival analyses demonstrate that JMJD2A could serve as an independent prognostic factor. Furthermore, we show that inhibition the expression of JMJD2A attenuates the growth and transformation of three lines of gastric cancer cells. Mechanically, JMJD2A knockdown induces apoptosis of gastric cancer cells by up-regulating the expression of pro-apoptotic proteins and by down-regulating anti-apoptotic protein. Finally, we show that JMJD2A level is correlated with the level of the pro-apoptotic microRNA miR-34a in gastric cancer tissues and JMJD2A represses the expression of miR-34a by decreasing its promoter activity. Those findings demonstrate that JMJD2A regulates gastric cancer growth and serves as an independent prognostic factor, and implicate that JMJD2A may be a promising target for intervention. PMID- 24802409 TI - Human CTP:phosphoethanolamine cytidylyltransferase: enzymatic properties and unequal catalytic roles of CTP-binding motifs in two cytidylyltransferase domains. AB - CTP:phosphoethanolamine cytidylyltransferase (ECT) is a key enzyme in the CDP ethanolamine branch of the Kennedy pathway, which is the primary pathway of phosphatidylethanolamine (PE) synthesis in mammalian cells. Here, the enzymatic properties of recombinant human ECT (hECT) were characterized. The catalytic reaction of hECT obeyed Michaelis-Menten kinetics with respect to both CTP and phosphoethanolamine. hECT is composed of two tandem cytidylyltransferase (CT) domains as ECTs of other organisms. The histidines, especially the first histidine, in the CTP-binding motif HxGH in the N-terminal CT domain were critical for its catalytic activity in vitro, while those in the C-terminal CT domain were not. Overexpression of the wild-type hECT and hECT mutants containing amino acid substitutions in the HxGH motif in the C-terminal CT domain suppressed the growth defect of the Saccharomyces cerevisiae mutant of ECT1 encoding ECT in the absence of a PE supply via the decarboxylation of phosphatidylserine, but overexpression of hECT mutants of the N-terminal CT domain did not. These results suggest that the N-terminal CT domain of hECT contributes to its catalytic reaction, but C-terminal CT domain does not. PMID- 24802410 TI - Automated quantification of FISH signals in urinary cells enables the assessment of chromosomal aberration patterns characteristic for bladder cancer. AB - Targeting the centromeres of chromosomes 3, 7, 17 (CEP3, 7, 17) and the 9p21 locus (LSI9p21) for diagnosing bladder cancer (BC) is time- and cost-intensive and requires a manual investigation of the sample by a well-trained investigator thus overall limiting its use in clinical diagnostics and large-scaled epidemiological studies. Here we introduce a new computer-assisted FISH spot analysis tool enabling an automated, objective and quantitative assessment of FISH patterns in the urinary sediment. Utilizing a controllable microscope workstation, the microscope software Scan^R was programmed to allow automatic batch-scanning of up to 32 samples and identifying quadruple FISH signals in DAPI scanned nuclei of urinary sediments. The assay allowed a time- and cost efficient, automated and objective assessment of CEP3, 7 and 17 FISH signals and facilitated the quantification of nuclei harboring specific FISH patterns in all cells of the urinary sediment. To explore the diagnostic capability of the developed tool, we analyzed the abundance of 51 different FISH patterns in a pilot set of urine specimens from 14 patients with BC and 21 population controls (PC). Herein, the results of the fully automated approach yielded a high degree of conformity when compared to those obtained by an expert-guided re-evaluation of archived scans. The best cancer-identifying pattern was characterized by a concurrent gain of CEP3, 7 and 17. Overall, our automated analysis refines current FISH protocols and encourages its use to establish reliable diagnostic cutoffs in future large-scale studies with well-characterized specimens collectives. PMID- 24802411 TI - Cancer cells recovering from damage exhibit mitochondrial restructuring and increased aerobic glycolysis. AB - Instead of relying on mitochondrial oxidative phosphorylation, most cancer cells rely heavily on aerobic glycolysis, a phenomenon termed as "the Warburg effect". We considered that this effect is a direct consequence of damage which persists in cancer cells that recover from damage. To this end, we studied glycolysis and rate of cell proliferation in cancer cells that recovered from severe damage. We show that in vitro Damage-Recovered (DR) cells exhibit mitochondrial structural remodeling, display Warburg effect, and show increased in vitro and in vivo proliferation and tolerance to damage. To test whether cancer cells derived from tumor microenvironment can show similar properties, we isolated Damage-Recovered (T(DR)) cells from tumors. We demonstrate that T(DR) cells also show increased aerobic glycolysis and a high proliferation rate. These findings show that Warburg effect and its consequences are induced in cancer cells that survive severe damage. PMID- 24802412 TI - Surgical efficiencies and quality in the performance of voluntary medical male circumcision (VMMC) procedures in Kenya, South Africa, Tanzania, and Zimbabwe. AB - INTRODUCTION: This analysis explores the association between elements of surgical efficiency in voluntary medical male circumcision (VMMC), quality of surgical technique, and the amount of time required to conduct VMMC procedures in actual field settings. Efficiency outcomes are defined in terms of the primary provider's time with the client (PPTC) and total elapsed operating time (TEOT). METHODS: Two serial cross-sectional surveys of VMMC sites were conducted in Kenya, Republic of South Africa, Tanzania and Zimbabwe in 2011 and 2012. Trained clinicians observed quality of surgical technique and timed 9 steps in the VMMC procedure. Four elements of efficiency (task-shifting, task-sharing [of suturing], rotation among multiple surgical beds, and use of electrocautery) and quality of surgical technique were assessed as explanatory variables. Mann Whitney and Kruskal Wallis tests were used in the bivariate analysis and linear regression models for the multivariate analyses to test the relationship between these five explanatory variables and two outcomes: PPTC and TEOT. The VMMC procedure TEOT and PPTC averaged 23-25 minutes and 6-15 minutes, respectively, across the four countries and two years. The data showed time savings from task sharing in suturing and use of electrocautery in South Africa and Zimbabwe (where task-shifting is not authorized). After adjusting for confounders, results demonstrated that having a secondary provider complete suturing and use of electrocautery reduced PPTC. Factors related to TEOT varied by country and year, but task-sharing of suturing and/or electrocautery were significant in two countries. Quality of surgical technique was not significantly related to PPTC or TEOT, except for South Africa in 2012 where higher quality was associated with lower TEOT. CONCLUSIONS: SYMMACS data confirm the efficiency benefits of task sharing of suturing and use of electrocautery for decreasing TEOT. Reduced TEOT and PPTC in high volume setting did not result in decreased quality of surgical care. PMID- 24802414 TI - Lighting up individual DNA damage sites by in vitro repair synthesis. AB - DNA damage and repair are linked to fundamental biological processes such as metabolism, disease, and aging. Single-strand lesions are the most abundant form of DNA damage; however, methods for characterizing these damage lesions are lacking. To avoid double-strand breaks and genomic instability, DNA damage is constantly repaired by efficient enzymatic machinery. We take advantage of this natural process and harness the repair capacity of a bacterial enzymatic cocktail to repair damaged DNA in vitro and incorporate fluorescent nucleotides into damage sites as part of the repair process. We use single-molecule imaging to detect individual damage sites in genomic DNA samples. When the labeled DNA is extended on a microscope slide, damage sites are visualized as fluorescent spots along the DNA contour, and the extent of damage is easily quantified. We demonstrate the ability to quantitatively follow the damage dose response to different damaging agents as well as repair dynamics in response to UV irradiation in several cell types. Finally, we show the modularity of this single molecule approach by labeling DNA damage in conjunction with 5 hydroxymethylcytosine in genomic DNA extracted from mouse brain tissue. PMID- 24802413 TI - Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy. AB - BACKGROUND: Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor-positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment-related toxicities like musculoskeletal pain. Although pain-related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation. METHODS: Postmenopausal women initiating AI therapy who were enrolled in a prospective clinical trial completed questionnaires at baseline to assess sleep, fatigue, mood, and pain. Reasons for treatment discontinuation during the first year of treatment were recorded. Associations between baseline patient-reported symptoms and treatment discontinuation because of toxicity were identified using logistic regression. RESULTS: Four hundred forty-nine patients were evaluable. The odds of treatment discontinuation were higher in patients who reported a greater number of symptoms before AI initiation. Baseline poor sleep quality was associated with early treatment discontinuation, with an odds ratio (OR) of 1.91 (95% confidence interval [CI], 1.26-2.89; P = .002). Baseline presence of tired feeling and forgetfulness had similar ORs for discontinuation (tired feeling: OR, 1.76; 95% CI, 1.15-2.67; P = .009; forgetfulness: OR, 1.66; 95% CI, 1.11-2.48; P = .015). An increasing total number of baseline symptoms was associated with an increased likelihood of treatment discontinuation, with an OR of 1.89 (95% CI, 1.20-2.96; P = .006) for 3 to 5 symptoms versus 0 to 2 symptoms. CONCLUSIONS: Symptom clusters in breast cancer survivors that are present before the initiation of adjuvant AI therapy may have a negative impact on a patient's persistence with therapy. Interventions to manage these symptoms may improve breast cancer outcomes and quality of life. PMID- 24802415 TI - Protective effects of bexarotene against amyloid-beta25-35-induced dysfunction in hippocampal neurons through the insulin signaling pathway. AB - BACKGROUND: Bexarotene, a retinoid X receptor agonist, has been shown to reverse neurodegeneration in mouse models of Alzheimer's disease (AD), accompanied by a decreased level of amyloid-beta (Abeta), which is a hallmark of AD. However, the mechanism underlying this therapeutic effect may involve enhancing the sensitivity to insulin. OBJECTIVE: This study was to test the hypothesis that bexarotene would protect against Abeta25-35-induced dysfunction through the insulin signaling pathway. METHODS: Using a whole-cell patch clamp technique, the excitability and voltage-gated potassium currents of hippocampal neurons were examined in four groups of cells (control, Abeta, Abeta+bexarotene and bexarotene). RESULTS: It was found that insulin increased the excitability of neurons. Bexarotene could enhance this effect and reverse the Abeta25-35-induced decrease in the firing rate of the action potential (AP). In addition, the properties of the single AP (sAP) and voltage-gated outward K+ currents were recorded, which finally showed similar changes to those in the firing frequency. CONCLUSION: The effects of bexarotene on Abeta-impaired excitability and sAP duration were mainly associated with K+ channels through insulin signaling pathway, which may be an additional mechanism underlying the protective effect of bexarotene on AD. PMID- 24802417 TI - Set-shifting and its relation to clinical and personality variables in full recovery of anorexia nervosa. AB - OBJECTIVE: First, this study aimed to explore whether set-shifting is inefficient after full recovery of anorexia nervosa (recAN). Second, this study wanted to explore the relation of set-shifting to clinical and personality variables. METHOD: A total of 100 recAN women were compared with 100 healthy women. Set shifting was assessed with Berg's Card Sorting Test. Expert interviews yielded assessments for the inclusion/exclusion criteria, self-ratings for clinical and personality variables. RESULTS: Compared with the healthy control group, the recAN participants achieved fewer categories, showed more perseverations and spent less time for shifting set. Perfectionism is correlated with set-shifting but in converse directions in the two groups. DISCUSSION: Our study supports the findings of inefficiencies in set-shifting after full recovery from AN. Higher perfectionism in the recAN group is associated with better set-shifting ability, whereas higher perfectionism in the healthy control group is related to worse set shifting ability. PMID- 24802416 TI - IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. AB - In anatomic pathology, immunohistochemistry (IHC) serves as a diagnostic and prognostic method for identification of disease markers in tissue samples that directly influences classification and grading the disease, influencing patient management. However, till today over most of the world, pathological analysis of tissue samples remained a time-consuming and subjective procedure, wherein the intensity of antibody staining is manually judged and thus scoring decision is directly influenced by visual bias. This instigated us to design a simple method of automated digital IHC image analysis algorithm for an unbiased, quantitative assessment of antibody staining intensity in tissue sections. As a first step, we adopted the spectral deconvolution method of DAB/hematoxylin color spectra by using optimized optical density vectors of the color deconvolution plugin for proper separation of the DAB color spectra. Then the DAB stained image is displayed in a new window wherein it undergoes pixel-by-pixel analysis, and displays the full profile along with its scoring decision. Based on the mathematical formula conceptualized, the algorithm is thoroughly tested by analyzing scores assigned to thousands (n = 1703) of DAB stained IHC images including sample images taken from human protein atlas web resource. The IHC Profiler plugin developed is compatible with the open resource digital image analysis software, ImageJ, which creates a pixel-by-pixel analysis profile of a digital IHC image and further assigns a score in a four tier system. A comparison study between manual pathological analysis and IHC Profiler resolved in a match of 88.6% (P<0.0001, CI = 95%). This new tool developed for clinical histopathological sample analysis can be adopted globally for scoring most protein targets where the marker protein expression is of cytoplasmic and/or nuclear type. We foresee that this method will minimize the problem of inter observer variations across labs and further help in worldwide patient stratification potentially benefitting various multinational clinical trial initiatives. PMID- 24802418 TI - Resist the call to install cameras in care homes. AB - Last week's BBC Panorama documentary depicting the abuse of older people in a south London care home reignited the debate about whether CCTV should be installed in such settings. Those in favour argue that abuse would be prevented if the perpetrators feared being caught on camera. However, there is a long list of reasons why the introduction of such surveillance systems on a routine basis should be resisted. PMID- 24802419 TI - RAF nurse awarded L500k compensation. AB - A high-ranking Royal Air Force nurse has been awarded more than half a million pounds against the Ministry of Defence after accusing it of favouring men instead of women over promotion. PMID- 24802421 TI - Unison considers members' ballot over payroll deficits. AB - A health union has raised the prospect of industrial action after a payroll glitch left thousands of nurses out of pocket. PMID- 24802420 TI - Care home surveillance could be a 'bridge too far' says whistleblower. AB - One of the UK's largest care home companies is consulting on whether to install surveillance cameras in residents' rooms to root out poor care. PMID- 24802422 TI - Mid Staffs whistleblower honoured. AB - The nurse who blew the whistle on poor care at Stafford Hospital collected her OBE last week. PMID- 24802423 TI - NMC fee increase to be debated in parliament. AB - The Nursing and Midwifery Council's proposed registration fee increase to L120 is likely be debated in parliament after a petition against the rise reached 100,000 signatures. PMID- 24802424 TI - Understaffed NHS trust faces special measures. AB - England's chief inspector of hospitals Sir Mike Richards has recommended that a trust with unsafe staffing levels should be placed in special measures. PMID- 24802425 TI - Your chance to take pay action. AB - RCN members have their final opportunity to say whether they would consider industrial action on the government's decision to deny the majority of nurses in England a pay rise. PMID- 24802426 TI - Healthcare support worker scheme aims to boost status and standards. AB - Patients could be asked their views on whether healthcare support workers are fit to work unsupervised as part of a care certificate being launched this summer. PMID- 24802428 TI - Complacency in asthma must end. AB - Healthcare professionals should be better educated to recognise the factors that increase the risk of asthma attacks and deaths, a UK-wide study has found. PMID- 24802429 TI - Race is on to meet health visitor target by 2015. AB - An extra 2,333 health visitors will need to be appointed in under a year to meet the government's target to boost their numbers in England by 4,200. PMID- 24802430 TI - Vital role of specialist MS nurses recognised in proposed guideline. AB - Specialist multiple sclerosis nurses should form part of a co-ordinated, multidisciplinary approach to the care of patients together with neurologists, GPs and physiotherapists, according to draft guidance. PMID- 24802431 TI - Become a future literary winner. AB - Nurses hoping to follow in the footsteps of award-winning nurse novelist Nathan Filer can enrol on a new creative writing course for healthcare workers. PMID- 24802432 TI - 'Shocking' learning disability revelations. AB - Almost two thirds of inpatients with learning disabilities are given tranquilisers regularly, an England-wide census of learning disability services has revealed. PMID- 24802433 TI - Nurse of the year's fundraising China trek. AB - Nursing Standard's nurse of the year 2013 Matthew Hodson has completed the challenge of a lifetime by trekking along the Great Wall of China. PMID- 24802435 TI - Improving the health of the world. AB - The hard work, dedication and professionalism of nurses will be marked worldwide on International Nurses' Day, with many events highlighting principles and values that go back to the days of Florence Nightingale. PMID- 24802441 TI - Asthma. AB - Essential facts In the UK, 5.4 million people are estimated to have asthma--the third highest prevalence in the world--and 1.1 million of these are children. The National Institute for Health and Care Excellence (NICE) says that asthma is the most common long-term medical condition, and 1 in 11 children have it. PMID- 24802443 TI - Hidden toll of FGM. PMID- 24802442 TI - Reach out to children. PMID- 24802444 TI - 'Safe staffing may cost diddly-squat'. PMID- 24802459 TI - Support our campaign for better treatment for people with MS. AB - Two new medicines for people with multiple sclerosis (MS) have recently been approved for use on the NHS, and two more will hopefully follow within the next year, taking the total to 11. It is an exciting, unprecedented time, but people with MS continue to face significant difficulties accessing the treatments they need, the information to decide what is right for them, and the MS specialists who can help. PMID- 24802460 TI - Government tinkering with AfC will not resolve NHS pay crisis. AB - Your readers panel (reflections April 30) was asked whether nurses should sacrifice incremental payments to give every NHS nurse in England a 1 per cent rise. PMID- 24802461 TI - Is morale among nurses so low that we have lost our voice? AB - I was happy to respond to the call to sign Nursing Standard's e-petition (tinyurl.com/pay-petition) urging the government to reconsider its decision to withhold the 1 per cent annual pay rise next year to nurses who are due to receive incremental pay rises (News April 9, 23 and 30). PMID- 24802462 TI - We must stand in solidarity and fight for our rights to get a better pay deal. AB - Following health secretary Jeremy Hunt's rejection of the NHS Pay Review Body's recommendations to give all nurses a 1 per cent pay rise in 2014/15, nearly 330,000 nurses will miss out on the pay award (News April 30). It will be given only to nurses at the top of their pay bands. PMID- 24802464 TI - Debrisoft is a wound debridement product, not a wound dressing. AB - In your April 2 edition (News) you highlighted the recent publication of NICE guidance on the Debrisoft monofilament debridement pad, which has the potential to save the NHS about L15 million a year. PMID- 24802466 TI - Searching for information on Francis Cyril Mason (1907-99). AB - I am researching my family tree and would appreciate some help. I am looking to find more information about my uncle, Francis Cyril Mason, who was a nurse. PMID- 24802468 TI - Male and female reproductive systems and associated conditions. AB - Sexual reproduction is the process in which a male sperm unites with a female ovum to permit fertilisation. Each fertilised cell contains a set of chromosomes from each parent, therefore both the male and female gametes contribute equally to the process of reproduction. This article provides an overview of the normal anatomy and physiology of the male and female reproductive systems. Common disorders of these systems are also discussed. PMID- 24802469 TI - Maintaining best practice in record-keeping and documentation. AB - This article considers best practice in record-keeping and documentation in the light of recent public inquiries and reports, renewed national interest in record keeping standards, and the challenge of moving from paper to electronic healthcare documentation and digital storage of data. The nature of the nurse patient relationship is also changing, and should be reflected in nurses' record keeping practices. Collaborative approaches to the planning and evaluation of care, and more emphasis on patients having a greater sense of ownership of information held about them should be reflected in nurses' and other healthcare professionals' attitudes and approaches to this aspect of practice. PMID- 24802470 TI - Whooping cough. AB - The CPD article was relevant to my practice because most upper respiratory tract infections exhibit similar symptoms initially. It is essential to be able to diagnose whooping cough because it is an acute and highly contagious disease. PMID- 24802471 TI - The community team. AB - The first patient I went to visit during my time working with the respiratory team was a man who had chronic obstructive pulmonary disease (COPD). He was frightened of his breathlessness, felt that clinicians had 'given up on him' and thought nothing could be done to help. PMID- 24802472 TI - My life as a military nurse. AB - With a strong family history of military service, I knew from a young age that I was destined to join the army. PMID- 24802476 TI - Role model in community. AB - Di Waddington's nominator gave her such a good press that her boss worried she might be head-hunted and lost to the Avon Valley Community Care Team at Southern Health NHS Foundation Trust. PMID- 24802475 TI - Building a better future. AB - The world we live in is constantly evolving and the boundaries between populations continue to change. We have become increasingly aware of the inequities in health care, and of what the response might be. This inspires some of us to take action in an attempt to bring about change. PMID- 24802477 TI - Personal delivery to home. AB - Every autumn, a team of bank nurses--the Torbay Council Flu's-ease Team--is retained for ten weeks to deliver the influenza and pneumococcal vaccines to people living in residential settings and those who are confined to their home. PMID- 24802478 TI - Tailored e-learning. AB - Children with complex needs have many carers supporting them: nurses, family members, school staff and care assistants. The South Warwickshire NHS Foundation Trust children's community nursing team, led by nurse consultant David Widdas, could see this led to inconsistencies in standards. PMID- 24802479 TI - To help the children. AB - Advantage Healthcare agency nurse Paul Watson developed a pocket-sized, collapsible spacer device that children can use with standard asthma metered dose inhalers. Spacers are generally large, unwieldy gadgets that children can be reluctant to carry around and use. PMID- 24802480 TI - Go-to pain expert. AB - Headley Court Defence Medical Rehabilitation Centre in Surrey cares for military patients returning from Iraq and Afghanistan with multiple and complex injuries. PMID- 24802481 TI - Ready for the front line. AB - Tristan Griffin, officer commanding for the British Army's field mental health team, introduced a programme of mindfulness--a form of meditation--for nurses and medical reservists preparing for deployment to Camp Bastion in Afghanistan, site of the largest military hospital in the world. PMID- 24802482 TI - Linked in and up to speed. AB - NeuroResponse is a nurse-led service for people with multiple sclerosis (MS) and long-term neurological conditions. PMID- 24802483 TI - The power of social media. AB - A weekly Twitter chat aimed principally at nurses takes place every Thursday at 8pm using #WeNurses. Co-ordinator Teresa Chinn first decided to use Twitter to discuss professional issues when she felt isolated as an agency nurse. PMID- 24802484 TI - Empowered to succeed. AB - At a time of low nurse staffing levels and high patient turnover at the Defence Medical Rehabilitation Centre at Headley Court in Surrey, healthcare assistant Sergeant Letso Rapoo suggested establishing a ward led and staffed by healthcare assistants (HCAs) for patients requiring a lower level of supervision or preparing for their discharge. PMID- 24802485 TI - Mental health gets physical. AB - The physical health of people with severe mental illness is often neglected. Patients are more likely to smoke and have a poor diet, while psychiatric medication is known to affect physical health adversely. Yet these patients are less likely to be offered a physical health check. PMID- 24802486 TI - Treating the complexities. AB - Anxiety and depression are common yet under-treated in respiratory care, says Karen Heslop-Marshall, nurse consultant in the Respiratory Cognitive Behavioural Therapy (CBT) Team at Newcastle upon Tyne Hospitals NHS Foundation Trust. PMID- 24802487 TI - Support from the clinic. AB - At around seven cases per 100,000 people, prevalence of fibrotic or interstitial lung disease (ILD) is relatively high. 'This represents a 35 per cent increase in the eight years to 2008, roughly 5,000 new cases each year,' reported Anne-Marie Russell, a National Institute of Health Research fellow at the Royal Brompton and Harefield NHS Foundation Trust. PMID- 24802488 TI - Raising public awareness. AB - Upper gastrointestinal (GI) cancer nurse specialist Claire Sedgwick from Newcastle upon Tyne Hospitals NHS Foundation Trust was concerned to find poor awareness of the symptoms of upper gastrointestinal and oesophageal cancers. PMID- 24802489 TI - Quality and equality. AB - The Purple Star quality kite mark was developed by Hertfordshire County Council's Health Liaison Nursing Team for services committed to providing equal care for people with a learning disability. PMID- 24802490 TI - In case of emergency. AB - Mental health professionals are largely untutored in the management of medical problems, so clinical skills adviser Gary Jordan from Health Education Yorkshire and the Humber devised a day course on recognising and assessing medical conditions in psychiatric settings (RAMPPS), using simulation. PMID- 24802491 TI - Preparing for civvy street. AB - Veterans First at North Essex Partnership NHS Foundation Trust is a specialist mental health team for veterans and military personnel who are being discharged or leaving the military for medical reasons. PMID- 24802492 TI - A boon to the community. AB - A consummate professional and a very special practitioner is how patient David Heywood describes community nurse Suren Beebakhy of Stockport NHS Foundation Trust. PMID- 24802493 TI - Someone to rely on. AB - When Yvonne Pywell was admitted to the Welland Centre at St Mary's Hospital in Kettering over Christmas with severe depression, 'calm, caring, compassionate and capable' healthcare assistant Paula Lawrence of Northamptonshire Healthcare NHS Foundation Trust became her refuge. PMID- 24802494 TI - Ready to go the extra mile. AB - Amanda Jacobs' husband Richard, known to everyone as Jake, was a patient on Ward 21, the oncology ward at the Royal Shrewsbury Hospital. PMID- 24802495 TI - Dedicated and passionate. AB - Claire Marsden met midwife Ann Tasker, formerly employed at Airedale NHS Foundation Trust, when she supported her through labour when her son Harry was born at Airedale General Hospital in Keighley in 2009. PMID- 24802496 TI - Enabling early intervention. AB - The Hospital Alcohol Liaison Service (HALS) at Lancashire Teaching Hospitals NHS Foundation Trust was set up in 2013 following concern about the rising number of admissions for alcohol-related liver disease. Nurse specialists Kerry Anderson, Keighley Allan, Angela Platt and Emma Dermody take referrals seven days a week across two hospital sites. PMID- 24802497 TI - Nurse-led day care detox. AB - Alcohol detoxification nurse Anya Farmbrough and nurse consultant for homelessness and health inequality Pamela Campbell are central to the Alcohol Day Detoxification Service in Solent NHS Trust. PMID- 24802498 TI - Asthma action plan. AB - When an audit of asthma care in schools revealed some worrying findings, specialist community public health and school nurse Kirsten Ellmore and the Shropshire School Nursing Team from Shropshire Community Health NHS Trust decided to act. PMID- 24802499 TI - Every school day counts. AB - The Think Twice, Every Day Counts project was devised to address a rise in absence days in Portsmouth's schools, of which just over half were attributable to health reasons. PMID- 24802500 TI - Support for fellow students. AB - Third-year mental health student nurse Julie Sheen from the University of Chester was completing a practice placement on an adult psychiatric ward, when a young student was admitted. PMID- 24802501 TI - Signs of communication. AB - When third-year mental health nursing students Simon Nielson and Samantha Stonehouse from Liverpool John Moores University came to care for a deaf patient, communication turned out to be problematic. PMID- 24802502 TI - 'It's been mind-expanding'. AB - For the eight judges of the Nursing Standard Nurse Awards, judging the record 700 entries addressing the many problems faced by patients and nurses could be seen as a challenge. PMID- 24802503 TI - A cocktail of synthetic stimulants found in a dietary supplement associated with serious adverse events. AB - Food supplements are regularly found to contain pharmacologically active substances. Recently, the food supplement Dexaprine was removed from the Dutch market because it was associated with severe adverse events. Reports to the Dutch Poisons Information Center (DPIC) showed that ingestion of as little as half a tablet caused several cases of nausea, agitation, tachycardia, and palpitations and even one case of cardiac arrest. The remaining tablets of four patients were sent in by different healthcare professionals. Analysis by ultra-performance liquid chromatography quadrupole time of flight mass-spectrometry (UPLC-QTOF-MS) confirmed the presence of synephrine, oxilofrine, deterenol, yohimbine, caffeine, and theophylline. Two more compounds were found which were tentatively identified as beta-methyl-beta-phenylethylamines. This incident is only the next in a series of similar incidents involving dietary supplements with (undeclared) active substances that are either unsafe or have no known safety profile. PMID- 24802504 TI - Controlled morphology modulation of anodic TiO2 nanotubes via changing the composition of organic electrolytes. AB - Titanium dioxide (TiO2) nanotubes are prepared by electrochemical anodization using Ti metal foils under a DC bias of 30 V for 20 h. The electrolyte is a mixture of formamide (FA) and ethylene glycol (EG), which contains NH4F (0.3 wt%) and H2O (2.0 v%). The diameter and wall thickness of the nanotubes decrease with the increase of EG content, while the length first decreases with the increase of EG content and then increases again. An O-ring-like pattern is formed on the outer surface of TiO2 nanotubes upon the introduction of FA into the EG electrolyte, upon which the surface becomes rougher and rougher with increasing FA content. This is caused by the breaking and re-establishment of a double layer at the interface. All of the observed phenomena are closely related to the conductivity and viscosity of the electrolyte as well as the formation of hydrogen bond in the system. The proposed mechanism is confirmed by introducing hydroxyl ions into the pure EG electrolyte. PMID- 24802508 TI - Recombinant expression and characterization of the cytoplasmic rice beta glucosidase Os1BGlu4. AB - The Os1BGlu4 beta-glucosidase is the only glycoside hydrolase family 1 member in rice that is predicted to be localized in the cytoplasm. To characterize the biochemical function of rice Os1BGlu4, the Os1bglu4 cDNA was cloned and used to express a thioredoxin fusion protein in Escherichia coli. After removal of the tag, the purified recombinant Os1BGlu4 (rOs1BGlu4) exhibited an optimum pH of 6.5, which is consistent with Os1BGlu4's cytoplasmic localization. Fluorescence microscopy of maize protoplasts and tobacco leaf cells expressing green fluorescent protein-tagged Os1BGlu4 confirmed the cytoplasmic localization. Purified rOs1BGlu4 can hydrolyze p-nitrophenyl (pNP)-beta-D-glucoside (pNPGlc) efficiently (kcat/Km = 17.9 mM(-1) . s(-1)), and hydrolyzes pNP-beta-D fucopyranoside with about 50% the efficiency of the pNPGlc. Among natural substrates tested, rOs1BGlu4 efficiently hydrolyzed beta-(1,3)-linked oligosaccharides of degree of polymerization (DP) 2-3, and beta-(1,4)-linked oligosaccharide of DP 3-4, and hydrolysis of salicin, esculin and p-coumaryl alcohol was also detected. Analysis of the hydrolysis of pNP-beta-cellobioside showed that the initial hydrolysis was between the two glucose molecules, and suggested rOs1BGlu4 transglucosylates this substrate. At 10 mM pNPGlc concentration, rOs1BGlu4 can transfer the glucosyl group of pNPGlc to ethanol and pNPGlc. This transglycosylation activity suggests the potential use of Os1BGlu4 for pNP-oligosaccharide and alkyl glycosides synthesis. PMID- 24802509 TI - Spectral and Kinetic Properties of Radical Cations Derived from Oxoisoaporphines: Relevance to Electron-Transfer Processes Involving Phytoalexins. AB - The thermally induced intermolecular electron transfer reaction in acetonitrile between the tetracyanoethylene (TCNE), a pi-electron acceptor with a large electron affinity, and six oxoisoaporphines (2,3-dihydro-7H-dibenzo[de,h]quinolin 7-one, 5-methoxy-2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one, 1 azabenzo[de]anthracen-7-one, 5-methoxy-1-azabenzo[de]anthracen-7-one, 7H benzo[e]perimidin-7-one, and 2-methyl-7h-benzo[e]perimidin-7-one) is reported. Spectral and kinetic characteristics are presented for radical cations derived from these six oxoisoaporphines either generated by a thermal reaction or generated radiolytically in argon-saturated 1,2-dichloroethane, oxygen-saturated acetone, and acetonitrile. The radical cations of oxoisoaporphines are insensitive to oxygen and are mostly characterized by absorption maxima of their most intense bands located at lambdamax = 400-410 nm, except of the radical cations derived from 2,3-dihydrooxoisoaporphines. For the latter compounds, the absorption maxima of the most intense absorption bands are located at lambdamax = 290-295 nm. Their locations are independent of the presence of functional groups and the solvents used. They are formed in bimolecular processes with pseudo-first order rate constants ranging from 2.1 * 105 to 1.5 * 106 s-1 (in solutions containing 10-4 M of the substrate), depending on the derivative and the solvent used. They are stable either when formed via the electron-transfer reaction with TCNE or when generated in isolation in pulse radiolysis of Ar-saturated 1,2 dichloroethane. In acetone and acetonitrile they decay predominantly by first order kinetics with the first-order rate constants ranging from 2.3 * 104 to 5.1 * 104 s-1. Formation of dimeric radical cations for all of the oxoisoaporphines studied was observed in acetonitrile solutions, and for azaoxoisoaporphines also in acetone solutions. The experimental spectra show a reasonably good agreement with the ZINDO/S semiempirical quantum mechanical calculations of radical cation absorptions. PMID- 24802511 TI - Use of pressurized metered dose inhalers in patients with chronic obstructive pulmonary disease: review of evidence. AB - The inhaled route is considered to be the best route to administer drugs for treating respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), for both safety and efficacy. Inhalation devices are classified into four types - pressuriszed metered dose inhalers (pMDIs), dry powder inhalers, breath actuated inhalers and nebulizers. pMDIs are portable, convenient, multi-dose devices and these advantages have made them very popular with patients. They were introduced in the 1950s as the first portable, multi dose delivery system for bronchodilators. Even though pMDIs are the most widely used devices for inhalation therapy in asthma and COPD, studies establishing their use and providing clinical data with bronchodilators and combination therapies in patients with COPD are limited. A summary of the use of pMDI with spacers in patients with COPD in terms of lung deposition and impact on lung function are presented in this review article. A review of use of the pMDI device in patients with COPD with different available and prescribed medications (bronchodilators-beta2-agonists and anticholinergics, and their combination with inhaled corticosteroids) is discussed. PMID- 24802510 TI - De novo transcriptome sequencing and analysis of the cereal cyst nematode, Heterodera avenae. AB - The cereal cyst nematode (CCN, Heterodera avenae) is a major pest of wheat (Triticum spp) that reduces crop yields in many countries. Cyst nematodes are obligate sedentary endoparasites that reproduce by amphimixis. Here, we report the first transcriptome analysis of two stages of H. avenae. After sequencing extracted RNA from pre parasitic infective juvenile and adult stages of the life cycle, 131 million Illumina high quality paired end reads were obtained which generated 27,765 contigs with N50 of 1,028 base pairs, of which 10,452 were annotated. Comparative analyses were undertaken to evaluate H. avenae sequences with those of other plant, animal and free living nematodes to identify differences in expressed genes. There were 4,431 transcripts common to H. avenae and the free living nematode Caenorhabditis elegans, and 9,462 in common with more closely related potato cyst nematode, Globodera pallida. Annotation of H. avenae carbohydrate active enzymes (CAZy) revealed fewer glycoside hydrolases (GHs) but more glycosyl transferases (GTs) and carbohydrate esterases (CEs) when compared to M. incognita. 1,280 transcripts were found to have secretory signature, presence of signal peptide and absence of transmembrane. In a comparison of genes expressed in the pre-parasitic juvenile and feeding female stages, expression levels of 30 genes with high RPKM (reads per base per kilo million) value, were analysed by qRT-PCR which confirmed the observed differences in their levels of expression levels. In addition, we have also developed a user friendly resource, Heterodera transcriptome database (HATdb) for public access of the data generated in this study. The new data provided on the transcriptome of H. avenae adds to the genetic resources available to study plant parasitic nematodes and provides an opportunity to seek new effectors that are specifically involved in the H. avenae-cereal host interaction. PMID- 24802512 TI - Short-term effects of particulate matter on stroke attack: meta-regression and meta-analyses. AB - BACKGROUND AND PURPOSE: Currently there are more and more studies on the association between short-term effects of exposure to particulate matter (PM) and the morbidity of stroke attack, but few have focused on stroke subtypes. The objective of this study is to assess the relationship between PM and stroke subtypes attack, which is uncertain now. METHODS: Meta-analyses, meta-regression and subgroup analyses were conducted to investigate the association between short term effects of exposure to PM and the morbidity of different stroke subtypes from a number of epidemiologic studies (from 1997 to 2012). RESULTS: Nineteen articles were identified. Odds ratio (OR) of stroke attack associated with particular matter ("thoracic particles" [PM10]<10 um in aerodynamic diameter, "fine particles" [PM2.5]<2.5 um in aerodynamic diameter) increment of 10 ug/m3 was as effect size. PM10 exposure was related to an increase in risk of stroke attack (OR per 10 ug/m3 = 1.004, 95%CI: 1.001 ~ 1.008) and PM2.5 exposure was not significantly associated with stroke attack (OR per 10 ug/m3 = 0.999, 95%CI: 0.994 ~ 1.003). But when focused on stroke subtypes, PM2.5 (OR per 10 ug/m3 = 1.025; 95%CI, 1.001~1.049) and PM10 (OR per 10 ug/m3 = 1.013; 95%CI, 1.001 ~ 1.025) exposure were statistically significantly associated with an increased risk of ischemic stroke attack, while PM2.5 (all the studies showed no significant association) and PM10 (OR per 10 ug/m3 = 1.007; 95%CI, 0.992 ~ 1.022) exposure were not associated with an increased risk of hemorrhagic stroke attack. Meta-regression found study design and area were two effective covariates. CONCLUSION: PM2.5 and PM10 had different effects on different stroke subtypes. In the future, it's worthwhile to study the effects of PM to ischemic stroke and hemorrhagic stroke, respectively. PMID- 24802513 TI - Epigenetic variation in monozygotic twins: a genome-wide analysis of DNA methylation in buccal cells. AB - DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ) twins offers a unique experimental design to examine the extent to which such variation is related to individual-specific environmental influences and stochastic events or to familial factors (DNA sequence and shared environment). We measured genome-wide DNA methylation in buccal samples from ten MZ pairs (age 8-19) using the Illumina 450k array and examined twin correlations for methylation level at 420,921 CpGs after QC. After selecting CpGs showing the most variation in the methylation level between subjects, the mean genome-wide correlation (rho) was 0.54. The correlation was higher, on average, for CpGs within CpG islands (CGIs), compared to CGI shores, shelves and non-CGI regions, particularly at hypomethylated CpGs. This finding suggests that individual specific environmental and stochastic influences account for more variation in DNA methylation in CpG-poor regions. Our findings also indicate that it is worthwhile to examine heritable and shared environmental influences on buccal DNA methylation in larger studies that also include dizygotic twins. PMID- 24802514 TI - Seasonal and geographical variation in diapause and cold hardiness of the Asian corn borer, Ostrinia furnacalis. AB - Asian corn borer, Ostrinia furnacalis (Guenee), is a key corn pest in the Asian Western Pacific countries. It overwinters as full-grown larvae in plant stalks or in a spun-silk covering located in the plant debris in the temperate regions of China. Supercooling point (SCP) and survival rate after low sub-zero temperature treatment were assessed for field-collected populations in the laboratory using a cool bath with a 1 degrees C/min cooling rate until -40 degrees C. Mean SCPs were varied among geographical populations, with a significant decline from -22.7 degrees C of Haikou, the multivoltine tropical population in the south, to -28.5 degrees C of Gongzhuling, the univoltine temperate population in the northeast of China. In addition, there was more than 1 degrees C difference in SCP between Gongzhuling univoltine and bivoltine populations that were from the same geographic origin. Mean SCPs of the Guangzhou population fluctuated over the year, with significantly lower SCPs in winter than in other seasons, which correlated with a significantly higher proportion of diapausing larvae in winter than in other seasons. Over 41% of overwintering larvae from the northeast population could withstand to be supercooled for a few minutes to the low sub zero temperature of -40 degrees C, but only 6.7% of their southern counterparts did so. The findings from this study suggest that O. furnacalis mostly takes advantage of freeze avoidance as diapausing larvae for overwintering in the southern region, whereas it exhibits freeze tolerance in diapause in the northeastern region. PMID- 24802515 TI - Pathological mechanism for delayed hyperenhancement of chronic scarred myocardium in contrast agent enhanced magnetic resonance imaging. AB - OBJECTIVES: To evaluate possible mechanism for delayed hyperenhancement of scarred myocardium by investigating the relationship of contrast agent (CA) first pass and delayed enhancement patterns with histopathological changes. MATERIALS AND METHODS: Eighteen pigs underwent 4 weeks ligation of 1 or 2 diagonal coronary arteries to induce chronic infarction. The hearts were then removed and perfused in a Langendorff apparatus. The hearts firstly experienced phosphorus 31 MR spectroscopy. The hearts in group I (n = 9) and II (n = 9) then received the bolus injection of Gadolinium diethylenetriamine pentaacetic acid (0.05 mmol/kg) and gadolinium-based macromolecular agent (P792, 15 umol/kg), respectively. First pass T2* MRI was acquired using a gradient echo sequence. Delayed enhanced T1 MRI was acquired with an inversion recovery sequence. Masson's trichrome and anti- von Willebrand Factor (vWF) staining were performed for infarct characterization. RESULTS: Wash-in of both kinds of CA caused the sharp and dramatic T2* signal decrease of scarred myocardium similar to that of normal myocardium. Myocardial blood flow and microvessel density were significantly recovered in 4-week-old scar tissue. Steady state distribution volume (DeltaR1 relaxation rate) of Gd DTPA was markedly higher in scarred myocardium than in normal myocardium, whereas DeltaR1 relaxation rate of P792 did not differ significantly between scarred and normal myocardium. The ratio of extracellular volume to the total water volume was significantly greater in scarred myocardium than in normal myocardium. Scarred myocardium contained massive residual capillaries and dilated vessels. Histological stains indicated the extensively discrete matrix deposition and lack of cellular structure in scarred myocardium. CONCLUSIONS: Collateral circulation formation and residual vessel effectively delivered CA into scarred myocardium. However, residual vessel without abnormal hyperpermeability allowed Gd-DTPA rather than P792 to penetrate into extravascular compartment. Discrete collagen fiber meshwork and loss of cellularity enlarged extracellular space accessible to Gd-DTPA, resulting in the delayed hyper-enhanced scar. PMID- 24802516 TI - Identification and validation of quantitative trait loci (QTL) for canine hip dysplasia (CHD) in German Shepherd Dogs. AB - Canine hip dysplasia (CHD) is the most common hereditary skeletal disorder in dogs. To identify common alleles associated with CHD, we genotyped 96 German Shepherd Dogs affected by mild, moderate and severe CHD and 96 breed, sex, age and birth year matched controls using the Affymetrix canine high density SNP chip. A mixed linear model analysis identified five SNPs associated with CHD scores on dog chromosomes (CFA) 19, 24, 26 and 34. These five SNPs were validated in a by sex, age, birth year and coancestry stratified sample of 843 German Shepherd Dogs including 277 unaffected dogs and 566 CHD-affected dogs. Mean coancestry coefficients among and within cases and controls were <0.1%. Genotype effects of these SNPs explained 20-32% of the phenotypic variance of CHD in German Shepherd Dogs employed for validation. Genome-wide significance in the validation data set could be shown for each one CHD-associated SNP on CFA24, 26 and 34. These SNPs are located within or in close proximity of genes involved in bone formation and related through a joint network. The present study validated positional candidate genes within two previously known quantitative trait loci (QTL) and a novel QTL for CHD in German Shepherd Dogs. PMID- 24802517 TI - Relationships of obesity and diabetes mellitus to other primary cancers in surgically treated gastric cancer patients. AB - BACKGROUND: Other primary cancers (OPC) have been reported in gastric cancer (GC) patients. Recent studies have shown relationships of obesity and diabetes mellitus to cancer development in several organs. The purpose of this study was to investigate the relationships of obesity and diabetes mellitus (DM) to the prevalence of OPC in GC patients. METHODS: We reviewed 435 GC patients who were treated surgically and followed their outcomes after surgery. Patients with body mass index (BMI) >= 25 kg/m(2) were defined as obese. Fasting plasma glucose (FPG) and HbA1c levels were examined before surgery. RESULTS: OPC was observed in 109 GC patients (25.1%): 40 (9.2%) with synchronous OPC and 76 (18.2%) with metachronous OPC. The most common OPC was colorectal cancer (22.8%). OPC was frequently observed in patients with DM (p = 0.0022), and DM was an independent risk factor for the occurrence of OPC (odds ratio, 2.215; 95% confidence interval, 1.2007-4.0850; p = 0.011). Synchronous OPC was frequently observed in patients with obesity (p = 0.025), and obesity was an independent risk factor for the occurrence of synchronous OPC (odds ratio, 2.354; 95% confidence interval, 1.1246-4.9279; p = 0.023). Metachronous OPC was frequently observed in patients with DM (p = 0.0071), and DM was an independent risk factor for the occurrence of OPC (odds ratio, 2.680; 95% confidence interval, 1.0291-6.9780; p = 0.044). CONCLUSION: There is a need to be aware of the possibility of OPC in GC patients with DM/obesity. They should undergo intensive screening for OPC before and after gastrectomy. PMID- 24802518 TI - Minimally invasive in the treatment of clavicle middle part fractures with locking reconstruction plate. AB - PURPOSE: We aimed to assess the possibility and feasibilities in the treatment of clavicle midpiece fracture by minimally invasive with percutaneous locking reconstitution plate. METHODS: Total 29 cases of patients with clavicle midpiece fractures were reviewed including 13 males and 16 females. All the patients were treated by minimally invasive with locking reconstitution plates. RESULTS: All the patients showed satisfaction of the appearance of incision and union of all the fractures. One case suffered fixation device failure and 3 cases suffered skin irritation responses. CONCLUSION: The minimally invasive with locking reconstruction plate is a good option for clavicle midpiece fractures treatment with good fracture healing. PMID- 24802519 TI - The impact of primary tumor resection on overall survival in patients with colorectal carcinoma and unresectable distant metastases: a prospective cohort study. AB - BACKGROUND: To compare the patients with primary colorectal carcinoma (CRC) and non-resectable distant metastases with or without primary colorectal tumor resection as a primary treatment in terms of postoperative mortality and overall survival (OS). PATIENTS AND METHODS: The clinicopathological data of 188 CRC patients with non-resectable distant metastases was analyzed. All patient data were collected prospectively. Colorectal tumor was resected in 121 patients (64.3%). Kaplan-Meier method was used for calculation and plotting of the OS curves of the patient groups, and log-rank test was used for the comparison of the survival curves. The relative importance of the prognostic features was investigated using the Cox proportional hazards model. RESULTS: In the whole series and in the patient group undergoing emergency surgical intervention, mortality rate was lower in patients having colorectal tumor resection compared with non-resected patients, with differences approaching the significance level (p = 0.072 and p = 0.076, respectively). Median OS time was significantly longer in resection group (11.0 months), compared with non-resection group (5.5 months) (p < 0.001); in the multivariate Cox analysis colorectal tumor resection had independent prognostic significance (p < 0.001). CONCLUSION: Resection of colorectal tumor in primary CRC patients with non-resectable distant metastasis gives significant survival advantage without increasing postoperative mortality compared with non-resection. PMID- 24802520 TI - Complete pathological response after neoadjuvant treatment in locally advanced esophageal cancer predicts long term survival: a retrospective cohort study. AB - BACKGROUND AND OBJECTIVES: Esophageal cancer incidence is gradually increasing worldwide. Studies have looked at the pathological stage rather than clinical stage as predictor of survival. We looked at patients with complete pathological response to compare their survival outcomes to those who had residual disease after neoadjuvant treatment. MATERIALS AND METHODS: All patients with esophageal cancer who underwent neoadjuvant treatment followed by resection at our institute were retrospectively reviewed. Overall survival and disease free survival were calculated for patients with complete pathological response and compared to those with residual disease using log rank test. RESULTS: Mean age of our patients was 51.08 years with standard deviation of 10.17 years. 39% belong to stage IIa while 5% belong to Stage IIb. 56% were Stage III. Final histopathological stage was recorded and both disease free and overall survival were calculated. 45% of our patients had complete pathological response. Patients with complete pathological response had mean survival of 62.73 months +/- 17.02 compared to 41.42 months for patients who had residual disease. 5 year disease free survival was 58%. CONCLUSION: Complete Pathological response significantly improves overall and disease free survival. It is also the predictor of long term survival. PMID- 24802521 TI - Dynamic mechanical analysis of high pressure polymerized urethane dimethacrylate. AB - OBJECTIVES: The aim of this study was to compare the viscoelastic properties of high pressure (HP) polymerized urethane dimethacrylate (UDMA) with those of control, ambient pressure thermo-polymerized and photo-polymerized, UDMA and to assess the effect of varying polymerization parameters (protocol, temperature, and initiator) on the viscoelastic properties of HP polymerized UDMA. METHODS: The viscoelastic properties of the two control polymers, polymerized under atmospheric pressure, and four experimental polymers, polymerized under HP, were determined via dynamic mechanical analysis (DMA), in three point bending configuration. Atomic force microscopy (AFM) was used to characterize fractured polymer surface morphologies. RESULTS: The results showed that: HP-polymerization lead to a polymer with significantly higher Tg and E'rub, indicative of a higher crosslink density; modifying the polymerization protocol resulted in a significant increase in tandelta; increasing the polymerization temperature lead to a significant decrease in E'rub and Tg; and that the polymer with no initiator had the lowest E', E", Tg, and E'rub and the highest tandelta, suggesting that under this conditions a polymer with significantly reduced crosslink density had been obtained. A characteristic nodular appearance was seen for the two control polymers under AFM, while a modified surface morphology was present in the case of HP polymerized materials. SIGNIFICANCE: The DMA results suggest that polymerization under HP resulted in polymers with an increased crosslink density and that the higher polymerization temperature or the lack of initiator was detrimental to the viscoelastic properties determined. Changes in polymer network morphology were identified by AFM characterization. PMID- 24802522 TI - Tuning the self-assembly of rectangular amphiphilic cruciforms. AB - The self-assembly of a series of nonionic amphiphilic cruciforms based on the 1,2,4,5-tetrakis(phenylethynyl)benzene (TPEB) skeleton, in which the peripheral substituents have been modified to modulate the morphology of the supramolecular structures, is reported. The presence of linear paraffinic and hydrophilic chains in TPEBs 1 and 2 gives rise to two-dimensional structures of high aspect ratio. In contrast, the incorporation of dendronized hydrophilic chains results in the formation of twisted ribbons in amphiphile 3 and impedes the organized self assembly of TPEB 4. Theoretical calculations show that the self-assembly of these amphiphiles might be initiated with the formation of pi-stacked dimeric units. Compound 2, which self-assembles into different morphologies depending on the solvent, interacts by pi-stacking and also by the interdigitation of the peripheral decyl tails to generate bidimensional supramolecular structures. The steric demand exerted by the dendronized polar wedges in 3 and 4 strongly conditions their supramolecular organization. This steric demand together with the interdigitation of the decyl chains results in the self-assembly of cruciform 3 into helical aggregates. However, the lack of the paraffinic chains in 4 impedes this helical organization, and the formation of amorphous material is visualized. The joint experimental and theoretical study presented herein provides relevant guidelines for the modulated self-assembly of nonionic amphiphilic molecules. PMID- 24802523 TI - Teaching about vulnerable populations: nursing students' experience in a homeless center. PMID- 24802524 TI - Changes in 5-hydroxytryptamine and cortisol plasma levels in menopausal women after inhalation of clary sage oil. AB - The purpose of this study was to examine the antidepressant-like effects of clary sage oil on human beings by comparing the neurotransmitter level change in plasma. The voluntary participants were 22 menopausal women in 50's. Subjects were classified into normal and depression tendency groups using each of Korean version of Beck Depression Inventory-I (KBDI-I), KBDI-II, and Korean version of Self-rating Depression Scale. Then, the changes in neurotransmitter concentrations were compared between two groups. After inhalation of clary sage oil, cortisol levels were significantly decreased while 5-hydroxytryptamine (5 HT) concentration was significantly increased. Thyroid stimulating hormone was also reduced in all groups but not statistically significantly. The different change rate of 5-HT concentration between normal and depression tendency groups was variable according to the depression measurement inventory. When using KBDI-I and KBDI-II, 5-HT increased by 341% and 828% for the normal group and 484% and 257% for the depression tendency group, respectively. The change rate of cortisol was greater in depression tendency groups compared with normal groups, and this difference was statistically significant when using KBDI-II (31% vs. 16% reduction) and Self-rating Depression Scale inventory (36% vs. 8.3% reduction). Among three inventories, only KBDI-II differentiated normal and depression tendency groups with significantly different cortisol level. Finally, clary sage oil has antidepressant-like effect, and KBDI-II inventory may be the most sensitive and valid tool in screening for depression status or severity. PMID- 24802525 TI - Optogenetic brain interfaces. AB - The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light. For this purpose, the cell-types of interest are genetically targeted to produce light-sensitive proteins. Once these proteins are expressed, neural activity can be controlled by exposing the cells to light of appropriate wavelengths. Optogenetics provides a unique combination of features, including multimodal control over neural function and genetic targeting of specific cell-types. Together, these versatile features combine to a powerful experimental approach, suitable for the study of the circuitry of psychiatric and neurological disorders. The advent of optogenetics was followed by extensive research aimed to produce new lines of light-sensitive proteins and to develop new technologies: for example, to control the distribution of light inside the brain tissue or to combine optogenetics with other modalities including electrophysiology, electrocorticography, nonlinear microscopy, and functional magnetic resonance imaging. In this paper, the authors review some of the recent advances in the field of optogenetics and related technologies and provide their vision for the future of the field. PMID- 24802526 TI - Antioxidant biomarker survey ensuing long-term selenium withdrawal in Acipenser baeri fed Se-cysteine diets. AB - Two selenium withdrawal periods, 30 and 90 days, were considered for sturgeon fed 90 days three Se-cysteine diets (1.25, 5, 20 mgkg(-1)). Subsequently Acipenser baeri was fed the previous control diet (0.32 mgSekg(-1)) for 90 days. Levels of superoxide dismutase, catalase, glutathione peroxidases, glutathione reductase, glyoxalase-II and malondialdehyde were determined in liver and kidney. Chemical analyses were carried out for the same tissues and for muscle. A reduction of Se levels in all tissues was recorded and the metalloid concentration decreased more quickly in liver than in kidney and muscle. At the end of the withdrawal Se concentration in muscle remained high in specimens previously fed 20 mgSekg(-1) diet, and disturbance of key antioxidant enzymes was recorded in liver and kidney. Moreover, alterations in glutathione peroxidases, and glyoxalase-II activities persisted even after 90 withdrawal days and were indicative of oxidative stress induced by Se-cysteine concentrations. PMID- 24802527 TI - Protective effect of curcumin against cytomegalovirus infection in Balb/c mice. AB - Curcumin has been found to suppress the activity of human cytomegalovirus (HCMV) in vitro, whereas its protective effects against HCMV infection in vivo remain unclear. In this study, we aimed to investigate the protective effects of curcumin against HCMV infection in Balb/c mice. Mice were randomly divided into the control, model, model+ganciclovir (positive control), and model+high-dose, model+middle-dose, and model+low-dose curcumin groups. In the model groups, each mouse was given HCMV by tail injection intravenously. Positive control animals were given ganciclovir. Animals in the curcumin treatment groups were given different concentrations of curcumin. The anti-HCMV activities of ganciclovir and curcumin were assessed by serological examination and pathology. Ganciclovir and curcumin treatment reduced the HCMV IgM level and HCMV DNA load; decreased the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), and lactate dehydrogenase (LDH) as well as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) generation in infected mice. These treatments also suppressed malondialdehyde (MDA) content and upregulated superoxide dismutase (SOD) and glutathione (GSH) levels. In addition, both treatments prevented pathological changes of the lung, kidney, liver, and heart tissues in infected mice. Our findings indicate that curcumin protected Balb/c mice against HCMV infection possibly by its anti-inflammatory and antioxidant effects. PMID- 24802528 TI - Multiatlas segmentation as nonparametric regression. AB - This paper proposes a novel theoretical framework to model and analyze the statistical characteristics of a wide range of segmentation methods that incorporate a database of label maps or atlases; such methods are termed as label fusion or multiatlas segmentation. We model these multiatlas segmentation problems as nonparametric regression problems in the high-dimensional space of image patches. We analyze the nonparametric estimator's convergence behavior that characterizes expected segmentation error as a function of the size of the multiatlas database. We show that this error has an analytic form involving several parameters that are fundamental to the specific segmentation problem (determined by the chosen anatomical structure, imaging modality, registration algorithm, and label-fusion algorithm). We describe how to estimate these parameters and show that several human anatomical structures exhibit the trends modeled analytically. We use these parameter estimates to optimize the regression estimator. We show that the expected error for large database sizes is well predicted by models learned on small databases. Thus, a few expert segmentations can help predict the database sizes required to keep the expected error below a specified tolerance level. Such cost-benefit analysis is crucial for deploying clinical multiatlas segmentation systems. PMID- 24802529 TI - Arylalkene synthesis via decarboxylative cross-coupling of alkenyl halides. AB - A bimetallic catalyst system generated from readily available palladium(II) and copper(I) salts, 1,10-phenanthroline and tri-1-naphthylphosphine was found to efficiently mediate the decarboxylative cross-coupling of alkenyl bromides and chlorides with aromatic carboxylates. It allows the regiospecific synthesis of a broad range of aryl- and heteroarylalkenes in high yields. PMID- 24802530 TI - A randomized controlled trial of combination treatment with ketoconazole 2% cream and adapalene 0.1% gel in pityriasis versicolor. AB - BACKGROUND: Ketoconazole cream and adapalene gel are effective drugs against pityriasis versicolor. However, there are no reports on combination treatment with both compounds in pityriasis versicolor. OBJECTIVE: To evaluate the efficacy and safety of combination therapy with adapalene 0.1% gel and ketoconazole 2% cream against pityriasis versicolor. METHODS: Participants with pityriasis versicolor were randomly assigned to two groups: the combination group was treated with adapalene 0.1% gel and ketoconazole 2% cream once daily, and the monotherapy group received ketoconazole 2% cream twice daily. The treatment lasted 2 weeks in both groups. Outcomes were assessed at baseline and 1, 2 and 4 weeks after the initiation of treatment. RESULTS: We noted clinically significant differences in total improvement rates between groups Weeks 1 and 2. A statistically significant difference was obtained Week 4. The treatment was well tolerated by all participants. CONCLUSIONS: The combination of adapalene 0.1% gel and ketoconazole 2% cream is effective and safe in the treatment of pityriasis versicolor. This therapeutic regimen was rapid, providing a valuable option for patients with pityriasis versicolor. PMID- 24802542 TI - Four subtypes of self-neglect in older adults: results of a latent class analysis. AB - OBJECTIVES: To determine whether there are subtypes of elder self-neglect (SN) with different risk factors that can be targeted using medical and social interventions. DESIGN: Cohort study using archived data of Adult Protective Services (APS) substantiated cases of elder SN between January 1, 2004, and December 31, 2008. SETTING: Houston, Harris County, Texas. PARTICIPANTS: Adults aged 65 and older with APS region VI substantiated SN between January 1, 2004, and December 31, 2008 (N = 5,686). MEASUREMENTS: Adult Protective Services caseworkers used the Client Assessment and Risk Evaluation (CARE) tool during home investigations, assessing risk of harm in the domains of living conditions, financial status, physical and medical status, mental health, and social connectedness. Latent class analysis was used to identify unique subtypes of elder SN. RESULTS: Four unique subtypes of elder SN were identified, with approximately 50% of individuals manifesting physical and medical neglect problems. Other subtypes included environmental neglect (22%), global neglect (21%), and financial neglect (9%). Older age, Caucasian descent, and mental status problems were more strongly associated with global neglect behaviors. African Americans were more likely to experience financial and environmental neglect than Caucasians and non-white Hispanics. CONCLUSION: Elder SN consists of unique subtypes that may be amenable to customized multidisciplinary interventions. Future studies are needed to determine whether these subtypes impose differential mortality risks and whether multidisciplinary tailored interventions can reduce SN and prevent early mortality. PMID- 24802543 TI - Heterobimetallic catechol-phosphine complexes with palladium and a group-13 element: structural flexibility and dynamics. AB - Group-13 metal acetylacetonates [M(acac)3] (M = Al, Ga, In) or Al(OiPr)3 react with a complex [Pd(catphosH)2] that may act as chelating ligand towards a second metal, or with a mixture of catechol phosphine (catphosH2) and [PdCl2(cod)], to give heterometallic complexes featuring either dinuclear M(catphos)2Pd or trinuclear M{(catphos)2Pd}2 motifs. Characterisation of the products by crystallographic and solution NMR studies gives insight into the structural diversity and flexibility of the coordination environments of the group-13 elements and their impact on the stability of the multinuclear complexes. The results indicate that gallium and indium are the most suitable elements for the stabilisation of di- and trinuclear assemblies, respectively. Dynamic NMR spectroscopy allowed to follow the dynamic averaging of the coordination environments of the four distinguishable catechol phosphines in the indium complex [M{(catphos)2Pd}2]H. The results revealed that the isomerisation follows a complicated pathway involving several distinguishable proton transfer steps, and allowed to propose a mechanistic explanation for the observed isomerisation. PMID- 24802544 TI - Support for the stability of the Alberta Infant Motor Scale after 'back-to sleep'. PMID- 24802545 TI - A comparison of techniques for myelomeningocele defect closure in the neonatal period. AB - PURPOSE: Numerous techniques have been described for repair of myelomeningoceles, but outcome data is scarce. PATIENTS AND METHODS: A retrospective review was performed in 32 consecutive patients who underwent neonatal myelomeningocele repair and extra-dural closure to determine the influence of repair type on outcome. All procedures for myelomeningocele closure were classified into one of three groups, which included primary closure, myocutaneous flaps, and fasciocutaneous flaps. RESULTS: Defect size ranged from 1 to 48 cm(2). Primary skin closure was performed in 3 patients, fasciocutaneous flaps in 13 patients, and myocutaneous flaps in 16 patients. The overall complication rate was 18%. No difference in the complication rates among the primary closure, myocutaneous, and fasciocutaneous flap groups was observed in our analysis. While not statistically significant, our data documents an association of fasciocutaneous flaps with postoperative complications that were not evident with primary skin closure or myocutaneous flaps (odds ratio 3.8; p = 0.15). The occurrence of one or more complications was associated with a longer hospital stay. CONCLUSIONS: Myocutaneous flaps provide a secure repair and should be considered for smaller myelomeningocele defects in addition to the larger defects where they are more traditionally used. We propose a tissue-based classification of closure techniques strictly for multi-institution outcome comparison that may ultimately inform clinical decision-making. PMID- 24802546 TI - Trajectories of productivity loss over a 20-year period: an analysis of the National Longitudinal Survey of Youth. AB - OBJECTIVES: We investigated multiple trajectories of the probability of reporting health-related productivity loss over a 20-year period among adults aged 25-44 years and explored differences among the trajectories in demographic and personal characteristics and employment outcomes in midlife. METHODS: A latent class growth analysis of health-related productivity loss was estimated on 12 waves of data from the National Longitudinal Survey of Youth (NLSY79) (N=5699), an ongoing nationally representative longitudinal survey of Americans. Waves 1-5 were collected annually at ages 25-29 years. Waves 6-12 were collected biennially at ages 30-44 years. Productivity loss was measured as "health fully preventing a person from working" or "health limiting the amount of kind of work a person could do". Differences among trajectories were assessed using analyses of variance (ANOVA) and Chi-square tests. RESULTS: A five-group trajectory model for productivity loss was identified: (i) no risk, (ii) low risk, (iii) high risk, (iv) increasing risk at early ages, and (v) increasing risk at later ages. At the first wave, after the waves used for the trajectory model in which respondents were approximately age 45 years, the no- and low-risk groups worked the most weeks and hours per week and had the highest percentages of participants employed >= 10 weeks compared to the high-risk and early-/late-onset increasing-risk groups, all of which had the lowest levels of mastery, self-esteem, education, and socioeconomic status. CONCLUSIONS: There are several developmental patterns of productivity loss, with some trajectories being associated with lower work participation in midlife. These high risk patterns may be indicative of individuals needing intervention to prevent premature work withdrawal. PMID- 24802547 TI - CT enterography at 100 kVp with iterative reconstruction compared to 120 kVp filtered back projection: evaluation of image quality and radiation dose in the same patients. AB - PURPOSE: To perform qualitative and quantitative comparison of images in same patients undergoing CT enterography (CTE) with 100 kVp iterative reconstruction and 120 kVp filtered back projection. METHODS: In this retrospective study, 50 consecutive patients who underwent imaging with 100 kVp and iterative reconstruction (100-IR) and had prior imaging with 120 kVp filtered back projection (120-FBP) were included. Subjective image quality parameters were evaluated by two independent and blinded readers, with higher score implying better image quality. We developed a quantitative measure of image sharpness by measuring edge-width of the psoas-fat interface. Image noise was measured as a standard deviation of attenuation measurement in the homogeneous region of the subcutaneous fat. Image sharpness and noise were measured and compared between 100-IR and 120-FBP acquisitions. RESULTS: There was approximately 33% lower radiation dose as estimated by CTDIvol with 100-IR compared to 120-FBP (9.95 vs. 15.0; p < 0.0001). There were no significant differences in overall image quality, bowel wall sharpness, and subjective assessment of noise and artifact between 100-IR and 120-FBP for both readers. Mesenteric vessel clarity score was significantly higher with 100-IR for 1 reader (4.34 vs. 4.04; p = 0.008), but not for the second reader. There was higher image sharpness (1.62 vs. 1.89; p < 0.0001) and higher image noise (14.4 vs. 13.2; p = 0.020) with 100-IR compared to 120-FBP acquisition. CONCLUSIONS: CTE performed at 100 kVp with iterative reconstruction demonstrates dose reduction without significant impact on various measures of image quality when compared to conventional 120 kVp FBP. PMID- 24802548 TI - CT findings of acute pelvic inflammatory disease. AB - PURPOSE: To determine the computed tomographic (CT) findings of acute pelvic inflammatory disease (PID). METHODS: This retrospective, single-institution case control study was approved by our institutional review board, and the informed consent was waived owing to the retrospective nature of the study. CT images of 32 women with clinically proven acute PID and 32 control subjects with other conditions of similar presentation were retrospectively reviewed. Analysis of CT findings included hepatic capsular enhancement, pelvic fat haziness, complicated ascites, uterine serosal enhancement, tubal thickening, endometritis, and oophoritis. Comparison of CT findings was performed with the Chi square test or the Fisher exact test and logistic regression analysis was used to determine significant CT findings in predicting PID. RESULTS: The CT findings that showed a statistically significant difference were hepatic capsular enhancement on late arterial phase (p = 0.003), pelvic fat haziness (p = 0.045), and tubal thickening (p = 0.001). Subsequent multivariate logistic regression analysis revealed that the presence of hepatic capsular enhancement on late arterial phase and tubal thickening were significant predictors of PID (hepatic capsular enhancement on late arterial phase, p = 0.015, odds ratio [OR] = 4.8; tubal thickening, p = 0.005, OR = 10.5). CONCLUSION: Diagnostic morphological CT findings in women with clinically proven PID and acute abdominal pain include hepatic capsular enhancement on late arterial phase and tubal thickening. PMID- 24802550 TI - Quantitative analysis of conductivity and viscosity of ionic liquids in terms of their relaxation times. AB - The frequency-dependent viscosity and conductivity of various ionic liquids were measured experimentally, and their mean relaxation times were determined. The relaxation times of the viscosity and conductivity were approximately correlated with their respective zero-frequency limiting values. The Walden products, however, appeared to have no correlation with the ratio of the relaxation time of viscosity to that of conductivity in general. When the alkyl chain of the cation is as short as butyl, more viscous ionic liquids tend to show larger difference between two relaxation times and larger Walden products. Lengthening the alkyl chain of the cation decreases the Walden product while slightly increasing the relaxation time ratio, which was elucidated in terms of the decrease in the high frequency shear modulus. In addition, the contribution of the mesoscopic structure to viscosity was suggested in the case of the ionic liquid with the longest alkyl chain studied in this work, 1-dodecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide. PMID- 24802549 TI - Circulating anti-retinal antibodies in response to anti-angiogenic therapy in exudative age-related macular degeneration. AB - PURPOSE: To determine changes in anti-retinal antibodies (ARAs) during anti-VEGF therapy in patients with exudative age-related macular degeneration (AMD) and to assess the correlations between ARAs and disease activity. METHODS: The study comprised 98 patients treated with intravitreal bevacizumab. The ophthalmic examination included best corrected visual acuity (BCVA), slit lamp biomicroscopy, fundoscopy, fluorescein angiography (FA), and optical coherence tomography (OCT). Serum ARAs levels were assessed by indirect immunofluorescence (IIF) on normal monkey retina substrate. These studies were repeated at 4 week intervals within 8 months of a follow-up. The sera of 50 sex- and age-matched healthy subjects were used as controls. RESULTS: At baseline examination, 94 (95.5%) of the 98 patients were positive for ARAs. The ARAs titres were significantly higher (p = 0.0000) than in controls. A positive correlation was found between titres of ARAs and the diameter of choroidal neovascularization (CNV) as measured by FA (p = 0.0000), and central retinal thickness (CRT) assessed by OCT (p = 0.0000). A positive correlation was also found between the diameter of CNV, CRT and the complexity of circulating ARAs. Following treatment all patients demonstrated significant decrease in ARAs levels as well as improvement of BCVA, reduction of subretinal fluid on OCT and decreased leakage on FA. CONCLUSION: Changes in serum ARAs levels occurred in parallel with clinical outcomes of anti-VEGF therapy. Treatment reduced serum levels of ARAs, with the greatest reduction occurring during the 'loading' phase. This study demonstrated that ARAs may act as a serum biomarker of the efficacy of anti-VEGF therapy. PMID- 24802551 TI - Enzyme-catalyzed oxidation of 5-hydroxymethylfurfural to furan-2,5-dicarboxylic acid. AB - Furan-2,5-dicarboxylic acid (FDCA) is a biobased platform chemical for the production of polymers. In the past few years, numerous multistep chemical routes have been reported on the synthesis of FDCA by oxidation of 5 hydroxymethylfurfural (HMF). Recently we identified an FAD-dependent enzyme which is active towards HMF and related compounds. This oxidase has the remarkable capability of oxidizing [5-(hydroxymethyl)furan-2-yl]methanol to FDCA, a reaction involving four consecutive oxidations. The oxidase can produce FDCA from HMF with high yield at ambient temperature and pressure. Examination of the underlying mechanism shows that the oxidase acts on alcohol groups only and depends on the hydration of aldehydes for the oxidation reaction required to form FDCA. PMID- 24802552 TI - Synthesis of new asymmetric xanthene dyes via catalyst-free S(N)Ar with sulfur nucleophiles. AB - Addition of a single functional handle to the tricyclic moiety of fluorescein results in asymmetric xanthene dyes. Our synthesis of a new class of asymmetric xanthenes proceeds via an unusual SNAr with sulfur nucleophiles on electron rich aromatic xanthenes scaffolds in the absence of a metal catalyst. The resulting 3' thioethers exhibit high photostability and are conveniently converted into reactive dyes for macromolecule labelling. PMID- 24802553 TI - Residential indoor and personal PM10 exposures of ambient origin based on chemical components. AB - Many studies have focused on the relationships of particulate matter between indoor, outdoor and personal exposure; however, considerable uncertainties remain regarding the portion of indoor particles and personal exposure of ambient origin. As part of the Particle Exposure Assessment for Community Elderly (PEACE) study in Tianjin, China, we have further interpreted the relationships between personal, residential indoor, outdoor and community PM10 (particulate matter with aerodynamic diameters of less than 10 MUm). Comparisons of the chemical compositions of PM10 samples were performed using the coefficient of divergence (COD). A robust regression method, least-trimmed squared (LTS) regression, was used to estimate the infiltration factors of PM10 from residential outdoor to indoor environments based on the particulate component concentrations. Personal exposures of ambient origin were also estimated. A relatively good correlation was found between the personal and indoor PM10 samples with respect to chemical composition. The infiltration factors (Finf) of the residential indoor-outdoor PM10 were 0.74+/-0.31 (mean+/-SD) in summer and 0.44+/-0.22 in winter, with medians of 0.98 and 0.48, respectively. The residential outdoor contributions to the indoor environments were 87+/-55 MUg/m(3) in summer and 80+/-54 MUg/m(3) in winter, with medians of 75 MUg/m(3) and 61 MUg/m(3), respectively. The personal exposures of ambient origin were 92+/-44 MUg/m(3) in summer and 89+/-47 MUg/m(3) in winter, with medians of 81 MUg/m(3) and 80 MUg/m(3), respectively. This study indicated that the infiltrations in an urbanized area in North China exhibited a seasonal difference: the residential outdoor contributions to residential indoor environments were larger in summer due to the higher use of natural ventilation. The personal exposures of ambient origin were comparable during the different seasons, whereas those of non-ambient origin were higher in summer than in winter. PMID- 24802554 TI - Persistent organic pollutants (POPs) and fibroids: results from the ENDO study. AB - To evaluate the association between persistent organic pollutants (POPs) and uterine fibroids, we used previously collected data from a cohort of women aged 18-44 years undergoing laparoscopy or laparotomy at 14 participating hospital surgical centers (n=473). POP concentrations were measured in omental fat and serum. Presence of fibroids was defined on the basis of a postoperative diagnosis (n=99). Odds ratios (OR) and 95% confidence interval (CI) for each POP by biologic medium were estimated using unconditional logistic regression adjusted for identified covariates. Concentrations were higher in omental fat than in serum for all POPs. Serum p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) was the only POP associated with fibroids (per 1-SD increase in log-transformed p,p' DDE OR (95% CI): 1.37 (1.05-1.80)). In analyses excluding women diagnosed with endometriosis, a number of polychlorinated biphenyls (PCBs) measured in omental fat were associated with fibroids (PCB 99: 1.64 (1.08, 2.49); PCB 138: 1.64 (1.03, 2.59); PCB 146: 1.54 (1.01, 2.37); PCB 153: 1.88 (1.12, 3.13); PCB 196: 1.60 (1.02, 2.51); PCB 206: 1.52 (1.01, 2.29)). Although exploratory, our study suggests that PCBs may be associated with fibroids in the absence of other gynecologic disorders such as endometriosis, but the associations varied by biologic media with more POPs emerging when quantified in fat. PMID- 24802555 TI - Improved exposure characterization with robotic (PIPER) sampling and association with children's respiratory symptoms, asthma and eczema. AB - Particulate matter (PM) and its constituents are recognized risk factors for the development of respiratory symptoms and illness in children. Most measurements of exposure have relied upon stationary indoor monitors (SIMs), overlooking the role of resuspended PM. To improve exposure characterization to resuspended aerosol PM, a recently developed methodology has been employed. The goal of this study was to characterize the resuspendable fraction of house dust and early childhood exposures to PM and its constituents in the child's home and compare conventional SIM and the Pre-toddler Inhalable Particulate Environmental Robotic (PIPER), an innovative mobile sampler. The study seeks to demonstrate that PIPER provides a more relevant estimate of exposure from inhalable particulate matter through improved correlation with respiratory symptoms in young children. Seventy-five households with children between 3 and 59 months of age were recruited from clinics in central New Jersey. Demographic information, and responses to a health questionnaire based upon that used by the International Study of Allergies and Asthma in Childhood (ISAAC), and household data were collected. Household exposures to inhalable PM (PM100) and endotoxin were determined with simultaneous SIM and mobile (PIPER) sampling. Univariate and multivariate analyses were carried out. History of wheeze ("recent" (<1 year) and "ever"), cough, asthma and eczema was evaluated. Multivariate analysis models included PM100 and endotoxin levels by tertiles of exposure. Risk of asthma for the highest tertile of PM100, as measured by PIPER (odds ratio=4.2; 95% confidence interval 0.7-24.0), was compared with measurements by SIM (odds ratio=0.7; 95% confidence interval 0.2 2.6). Measurements of PM and its constituents with PIPER are more strongly associated with asthma, eczema and wheeze compared with measurements using SIMs. Application of this methodology may provide useful insights into early childhood exposures related to the etiology of childhood illnesses associated with inhalation exposures. PMID- 24802556 TI - A side-by-side comparison of three allergen sampling methods in settled house dust. AB - Understanding allergen exposure and potential relationships with asthma requires allergen sampling methods, but methods have yet to be standardized. We compared allergen measurements from dust collected from 200 households with asthmatics and conducted a side-by-side vacuum sampling of settled dust in each home's kitchen, living room and subject's bedroom by three methods (EMM, HVS4 and AIHA). Each sample was analyzed for dust mite, cockroach, mouse, rat, cat and dog allergens. The number of samples with sufficient dust mass for allergen analysis was significantly higher for Eureka Mighty Mite (EMM) and high volume small surface sampler (HVS4) compared with American Industrial Hygiene Association (AIHA) in all rooms and surfaces tested (all P<0.05). The allergen concentration (weight of allergen divided by total weight of dust sampled) measured by the EMM and HVS4 methods was higher than that measured by the AIHA. Allergen loadings (weight of allergen divided by surface area sampled) were significantly higher for HVS4 than for AIHA and EMM. Cockroach and rat allergens were rarely detected via any method. The EMM method is most likely to collect sufficient dust from surfaces in the home and is relatively practical and easy. The AIHA and HVS4 methods suffer from insufficient dust collection and/or difficulty in use. PMID- 24802557 TI - Applying parallel factor analysis and Tucker-3 methods on sensory and instrumental data to establish preference maps: case study on sweet corn varieties. AB - BACKGROUND: Traditional internal and external preference mapping methods are based on principal component analysis (PCA). However, parallel factor analysis (PARAFAC) and Tucker-3 methods could be a better choice. To evaluate the methods, preference maps of sweet corn varieties will be introduced. RESULTS: A preference map of eight sweet corn varieties was established using PARAFAC and Tucker-3 methods. Instrumental data were also integrated into the maps. The triplot created by the PARAFAC model explains better how odour is separated from texture or appearance, and how some varieties are separated from others. CONCLUSION: Internal and external preference maps were created using parallel factor analysis (PARAFAC) and Tucker-3 models employing both sensory (trained panel and consumers) and instrumental parameters simultaneously. Triplots of the applied three-way models have a competitive advantage compared to the traditional biplots of the PCA-based external preference maps. The solution of PARAFAC and Tucker-3 is very similar regarding the interpretation of the first and third factors. The main difference is due to the second factor as it differentiated the attributes better. Consumers who prefer 'super sweet' varieties (they place great emphasis especially on taste) are much younger and have significantly higher incomes, and buy sweet corn products rarely (once a month). Consumers who consume sweet corn products mainly because of their texture and appearance are significantly older and include a higher ratio of men. PMID- 24802559 TI - Multi-mass-spring model and energy transmission of one-dimensional periodic structures. AB - This paper deals with a classical problem on a linear elastic lattice. A multi mass-spring model is proposed to build the unit cell. Based on this multi-mass spring model, a detailed investigation on the band of frequency gaps of one dimensional periodic structures is conducted. A unified formulation to study the band structures of one-dimensional periodic structures is obtained. To determine the bound frequencies of the bands of frequency gaps, a very simple method without investigating the dispersion curves is proposed based on the modal analytical method. The method presented in this paper is applicable to general cases and is much more convenient than that proposed by other related investigations. In addition, the dynamic property of a finite periodic structure is investigated from the view of energy input, energy distribution, and interactions between the external excitation and the finite periodic structure, from which the energy flow pattern is illustrated clearly. PMID- 24802558 TI - Population pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children. AB - AIM: The aim of the study was to investigate the pharmacokinetics and pharmacodynamics of norepinephrine in hypotensive critically ill children, including associated variability factors. METHODS: This was a prospective study in an 18-bed neonatal and paediatric intensive care unit. All children were aged less than 18 years, weighed more than 1500 g and required norepinephrine for systemic arterial hypotension. The pharmacokinetics and haemodynamic effects were described using the non-linear mixed effect modelling software MONOLIX. RESULTS: Norepinephrine dosing infusions ranging from 0.05 to 2 MUg kg(-1) min(-1) were administered to 38 children whose weight ranged from 2 to 85 kg. A one compartment open model with linear elimination adequately described the norepinephrine concentration-time courses. Bodyweight (BW) was the main covariate influencing norepinephrine clearance (CL) and endogenous norepinephrine production rate (q0) via an allometric relationship: CL(BWi) = thetaCL * (BWi)(3/4) and q0(BWi) = thetaq0 * (BWi)(3/4) . The increase in mean arterial pressure (MAP) as a function of norepinephrine concentration was well described using an Emax model. The effects of post-conceptional age (PCA) and number of organ dysfunctions were significant on basal MAP level (MAP0i = MAP0 * PCA/9i (0.166) ) and on the maximal increase in MAP (32 mmHg and 12 mmHg for a number of organ dysfunctions <=3 and >=4, respectively). CONCLUSION: The pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children highlight the between-subject variability which is related to the substantial role of age, BW and severity of illness. Taking into account these individual characteristics may help clinicians in determining an appropriate initial a priori dosing regimen. PMID- 24802560 TI - Electrochemiluminescent pH sensor measured by the emission potential of TiO2 nanocrystals and its biosensing application. AB - This work reports for the first time a potential-based nano electrochemiluminescent (ECL) pH sensor, using anatase TiO2 nanocrystals (NCs) as the ECL probe. The first ECL peak potential of the TiO2 NCs shifted negatively with increasing pH, showing a linear range from -0.47 V (vs Ag/AgCl) at pH 3 to 1.06 V at pH 10. This phenomenon was attributed to the absorption of 'potential determining ions' of OH(-) on the surface of TiO2 NCs, leading to larger impedance of the electron injection. Other common 'potential-determining ions', such as phosphate, induced a slight potential shift of 0.03 V at a concentration of 0.1 M. Using urease as an enzyme model, a urea biosensor was developed by the simultaneous modification of urease and TiO2 NCs on indium-tin oxide (ITO) electrodes. The biosensor, measured on the basis of the pH increase caused by the enzyme catalysis reaction, had a linear range of 0.01-2.0 mM, with a potential shift of 0.175 V. The as-prepared pH sensor, which has simple construction procedures and acceptable sensitivity and selectivity, may provide new avenues for the construction of ECL bioanalytical methodologies. PMID- 24802562 TI - Impact of immigration on HIV-1 molecular epidemiology in West Africa, Maghreb and Southern Europe. AB - There is global concern about the relation between international migration and the course of the AIDS epidemic. Maghreb is a North African region, which lies between sub-Saharan Africa and Europe. It has been turned recently into a region of immigration, since there are more and more flows of West African migrants hoping to reach European countries. Here we provide an overview on HIV-1 molecular epidemiology particularly in West African countries, Maghreb (Morocco, Algeria, Tunisia) and southern European countries (Spain, France, and Italy). The studies conducted in several countries of the region revealed different features of HIV-1 molecular epidemiology, especially for the distribution of viral subtypes and for transmitted drug resistance profiles. Furthermore, migration from West Africa to Europe seems to be a potential source of non-B subtype mobility to Maghreb and eventually to southern Europe, where HIV-1 non-B variants significantly increased in the last 10 to 15 years. As genetic differences between subtypes might impact the drug resistance pathways, it is important to provide continuous surveillance programs for the early detection of new variants spreading in the population before they become more prevalent, and to identify resistance profiles in different infected populations, especially migrants. PMID- 24802561 TI - Considerations for preparing a randomized population health intervention trial: lessons from a South African-Canadian partnership to improve the health of health workers. AB - BACKGROUND: Community-based cluster-randomized controlled trials (RCTs) are increasingly being conducted to address pressing global health concerns. Preparations for clinical trials are well-described, as are the steps for multi component health service trials. However, guidance is lacking for addressing the ethical and logistic challenges in (cluster) RCTs of population health interventions in low- and middle-income countries. OBJECTIVE: We aimed to identify the factors that population health researchers must explicitly consider when planning RCTs within North-South partnerships. DESIGN: We reviewed our experiences and identified key ethical and logistic issues encountered during the pre-trial phase of a recently implemented RCT. This trial aimed to improve tuberculosis (TB) and Human Immunodeficiency Virus (HIV) prevention and care for health workers by enhancing workplace assessment capability, addressing concerns about confidentiality and stigma, and providing onsite counseling, testing, and treatment. An iterative framework was used to synthesize this analysis with lessons taken from other studies. RESULTS: The checklist of critical factors was grouped into eight categories: 1) Building trust and shared ownership; 2) Conducting feasibility studies throughout the process; 3) Building capacity; 4) Creating an appropriate information system; 5) Conducting pilot studies; 6) Securing stakeholder support, with a view to scale-up; 7) Continuously refining methodological rigor; and 8) Explicitly addressing all ethical issues both at the start and continuously as they arise. CONCLUSION: Researchers should allow for the significant investment of time and resources required for successful implementation of population health RCTs within North-South collaborations, recognize the iterative nature of the process, and be prepared to revise protocols as challenges emerge. PMID- 24802563 TI - Upconversion nanoparticles for ratiometric fluorescence detection of nitrite. AB - We have developed a selective upconversion switching method for the ratiometric fluorescence detection of nitrite using upconversion nanoparticles (UCNPs) and an efficient nitrite reaction. The green emission (lambda(em) = 539 nm) of NaYF4:Yb(3+),Er(3+) nanoparticles can be selectively quenched by the neutral red (NR) dye due to the spectral overlap between the emission at 539 nm and the absorption of NR, while its red emission (lambda(em) = 654 nm) remains unchanged. Nitrite reacts specifically and strongly with NR to form diazonium salt and lose the diazonium group, which sharply decreases the absorption of NR. Thus, the green emission of NaYF4:Yb(3+),Er(3+) can be recovered by increasing the amount of nitrite, leading to visible color changes from red to orange-yellow and finally green under excitation at 980 nm. The increase in the ratio of emission intensities (I539/I654) is quantitatively correlated to the concentration of nitrite ions. Moreover, the developed method has been successfully applied to nitrite detection in real samples such as drinking water, natural water and meat foods. In particular, the upconversion sensors can efficiently avoid background optical interference and thus show potential for the detection of nitrite salts in complex samples. PMID- 24802587 TI - Spatial and temporal variation of surface ozone, NO and NO2 at urban, suburban, rural and industrial sites in the southwest of the Iberian Peninsula. AB - Surface ozone is one of the most important photochemical pollutants in the low atmosphere, causing damage to human health, vegetation, materials and climate. The weather (high temperatures and high solar radiation), orography (presence of the Guadalquivir valley) and anthropogenic (the cities of Cadiz, Cordoba, Huelva and Seville and two important industrial complexes) characteristics of the southwestern Iberian Peninsula make this region ideal for the formation and accumulation of ozone. To increase the knowledge of ozone behaviour in this area, the monthly, daily and weekly variations of ozone and its precursors, nitrogen oxides (NO(x) = NO + NO2), were analysed over a 4-year period (2003 to 2006). Using the k-means cluster technique, 12 representative stations of five different areas with different ozone behaviour were selected from a total of 29 monitoring sites. This is the first time that the analysis of these atmospheric pollutants has been carried out for the whole area, allowing therefore a complete understanding of the dynamics and the relationships of these compounds in this region. The results showed an opposite behaviour among ozone and NO and NO2 concentrations in urban and suburban zones, marked by maximums of ozone (minimums NO(x)) in spring and summer and minimums (maximums) in autumn and winter. A seasonal behaviour, with lower amplitude, was also observed in rural and industrial areas for ozone concentrations, with the NO and NO2 concentrations remaining at low and similar values during the year in rural zones due to the absence of emission sources in their surroundings. The daily cycles of ozone in urban, suburban and industrial sites registered a maximum value in the early afternoon (14:00-17:00 UTC) while for NOx two peaks were observed, at 7:00-10:00 UTC and 20:00-22:00. In the case of rural stations, no hourly peak of ozone or NO(x) was registered. The weekend effect was studied by using a statistical contrast tests (Student's t). The results indicated that only areas influenced by important traffic emissions presented a weekend effect for NO and NO2, whereas an ozone weekend effect was not detected in any case. PMID- 24802588 TI - Estimating impacts of land use on groundwater quality using trilinear analysis. AB - Groundwater is connected to the landscape above and is thus affected by the overlaying land uses. This study evaluated the impacts of land uses upon groundwater quality using trilinear analysis. Trilinear analysis is a display of experimental data in a triangular graph. Groundwater quality data collected from agricultural, septic tank, forest, and wastewater land uses for a 6-year period were used for the analysis. Results showed that among the three nitrogen species (i.e., nitrate and nitrite (NO(x)), dissolved organic nitrogen (DON), and total organic nitrogen (TON)), NO(x) had a high percentage and was a dominant species in the groundwater beneath the septic tank lands, whereas TON was a major species in groundwater beneath the forest lands. Among the three phosphorus species, namely the particulate phosphorus (PP), dissolved ortho phosphorus (PO4(3-)) and dissolved organic phosphorus (DOP), there was a high percentage of PP in the groundwater beneath the septic tank, forest, and agricultural lands. In general, Ca was a dominant cation in the groundwater beneath the septic tank lands, whereas Na was a dominant cation in the groundwater beneath the forest lands. For the three major anions (i.e., F(-), Cl(-), and SO4(2-)), F(-) accounted for <1% of the total anions in the groundwater beneath the forest, wastewater, and agricultural lands. Impacts of land uses on groundwater Cd and Cr distributions were not profound. This study suggests that trilinear analysis is a useful technique to characterize the relationship between land use and groundwater quality. PMID- 24802589 TI - Heavy metal in water and aquatic organisms from different intertidal ecosystems, Persian Gulf. AB - Intertidal ecosystems are being damaged by anthropogenic activities, particularly in the developing countries. In this study, the load of heavy metals was determined in water, fish, shrimp, and crab collected from four intertidal ecosystems, including coral reef, rocky shore, mangrove forest, and muddy habitat along the Persian Gulf coasts. Generally, the sequence of metal accumulation in the water of coral reef and mangrove forest was Ni > Pb > V > Cd > As > Hg, whereas in muddy habitats and rocky shores, the sequence was Ni > Pb > V > Cd > Hg > As and Ni > V > Pb > As > Hg > Cd, respectively. Water of the coral reef had the highest level of Ni (97.44 MUg l(-1)), Pb (3.92 MUg l(-1)), V (10.42 MUg l( 1)), Cd (3.92 MUg l(-1)), As (1.87 MUg l(-1)), and Hg (0.74 MUg l(-1)). For the most part, the highest concentrations of the studied metals were found in the liver and the gills of Johnius belangerii and the hepatopancreas of Portunus pelagicus and Metapenaus affinis collected from the coral reef ecosystem. PMID- 24802591 TI - Convenient three-dimensional cell culture in supermolecular hydrogels. AB - A convenient three-dimensional cell culture was developed by employing high swelling property of hybrid hydrogels coassembled from C2-phenyl-based supermolecular gelators and sodium hyaluronate. Imaging and spectroscopic analysis by scanning electron microscopy (SEM), atomic force microscopy (AFM), transform infrared (FT-IR) spectra confirm that the hybrid gelators can self assemble into nanofibrous hydrogel. The high swelling property of dried gel ensures cell migration and proliferation inside bulk of the hydrogels, which provides a facial method to study disease models, the effect of drug dosages, and tissue culture in vitro. PMID- 24802590 TI - Pre-morbid fertility in psychosis: findings from the AESOP first episode study. AB - Individuals with psychotic illnesses are known to have a reduced fertility. It is unclear whether this is due to biological or social factors. Most fertility studies have been conducted in chronic schizophrenia, where confounders like medication and hospitalisation make this difficult to elicit. A less severe reduction of fertility has been observed in some ethnic minorities, but results are inconsistent. We sought to investigate pre-morbid fertility in an ethnically diverse sample of individuals with first-onset psychosis. Data were derived from 515 people with a first psychotic episode (FEP) and 383 controls. We made case control comparisons of differences in the proportion of those with children (fertility rates) and mean number of children (MNC). Analyses were then stratified by diagnosis, gender and ethnicity, and adjusted for potential confounders. We found that FEP showed a reduced fertility rate (age-adjusted OR of having children 0.47 [95% CI=0.39, 0.56]), irrespective of diagnosis, and there was little evidence of confounding by gender, ethnicity, religious background, education level, or history of past relationships (fully adjusted OR=0.55, 95% CI=0.37, 0.80). Women had a somewhat greater reduction in fertility rates than men (Men: age-adjusted OR 0.61 [95% CI 0.42, 0.89]; Women: age adjusted OR 0.46 [95% CI 0.31, 0.69]) and we could not find any evidence of ethnic differences in the degree of fertility reduction. FEP who had previously experienced a stable relationship had an MNC that was comparable to that of the general population and had a later onset of illness. This is the largest case control study to date to investigate fertility in first-onset psychosis. Our data suggests that fertility is affected, even prior to the onset of a psychotic illness, and there are likely to be biological and environmental factors involved, but the former seem to have a stronger influence. PMID- 24802592 TI - Cardiac shock wave therapy attenuates H9c2 myoblast apoptosis by activating the AKT signal pathway. AB - BACKGROUND: Previous studies have demonstrated that Cardiac Shock Wave Therapy (CSWT) improves myocardial perfusion and cardiac function in a porcine model of chronic myocardial ischemia and also ameliorates myocardial ischemia in patients with severe coronary artery disease (CAD). Apoptosis plays a key role in ischemic myocardial pathogenesis. However, it remains unclear whether CSWT is beneficial for ischemia/hypoxia (I/H)-induced myocardial cell apoptosis and by which mechanism CSWT could improve heart function. We put forward the hypothesis that CSWT might protect heart function during ischemia/hypoxia by decreasing apoptosis. METHODS: We generated ischemia/hypoxia (I/H)-induced apoptosis in the H9c2 myoblast cell line to examine the CSWT function and possible mechanisms. H9c2 cells were treated under hypoxic serum-starved conditions for 24 h and then treated with or without CSWT (500 shots, 0.06, 0.09, 0.12mJ/mm(2)). The apoptotic cell rate was determined by flow cytometry assay, cell viability was examined by the MTT assay, nuclear fragmentation was detected by Hoechst 33342 staining, and the mitochondrial-mediated intrinsic pathway of apoptosis was assessed by the expression of Bax and Bcl-2 protein and Caspase3 activation. RESULTS: First, apoptosis could be induced by ischemia/hypoxia in H9c2 cells. Second, CSWT attenuates the cell death and decreases the H9c2 cell apoptosis rate induced by ischemia and hypoxia. Third, CSWT suppresses the expression of apoptosis molecules that regulate the intrinsic pathway of apoptosis in H9c2 cells. Fourth, CSWT increases the phosphorylation of AKT, which indicates the activation of the PI3K-AKT pathway. CONCLUSIONS: These results indicate that CSWT exerts a protective effect against I/H-induced cell death, potentially by preventing the activation of components of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that the PI3K-Akt pathway may be involved in the CSWT effects on apoptosis. PMID- 24802593 TI - Cost drivers for voluntary medical male circumcision using primary source data from sub-Saharan Africa. AB - BACKGROUND: As voluntary medical male circumcision (VMMC) programs scale up, there is a pressing need for information about the important cost drivers, and potential efficiency gains. We examine those cost drivers here, and estimate the potential efficiency gains through an econometric model. METHODS AND FINDINGS: We examined the main cost drivers (i.e., personnel and consumables) associated with providing VMMC in sub-Saharan Africa along a number of dimensions, including facility type and service provider. Primary source facility level data from Kenya, Namibia, South Africa, Tanzania, Uganda, and Zambia were utilized throughout. We estimated the efficiency gains by econometrically estimating a cost function in order to calculate the impact of scale and other relevant factors. Personnel and consumables were estimated at 36% and 28%, respectively, of total costs across countries. Economies of scale (EOS) is estimated to be eight at the median volume of VMMCs performed, and EOS falls from 23 at the 25th percentile volume of VMMCs performed to 5.1 at the 75th percentile. CONCLUSIONS: The analysis suggests that there is significant room for efficiency improvement as indicated by declining EOS as VMMC volume increases. The scale of the fall in EOS as VMMC volume increases suggests that we are still at the ascension phase of the scale-up of VMMC, where continuing to add new sites results in additional start-up costs as well. A key aspect of improving efficiency is task sharing VMMC procedures, due to the large percentage of overall costs associated with personnel costs. In addition, efficiency improvements in consumables are likely to occur over time as prices and distribution costs decrease. PMID- 24802594 TI - Monocular and binocular edges enhance the perception of stereoscopic slant. AB - Gradients of absolute binocular disparity across a slanted surface are often considered the basis for stereoscopic slant perception. However, perceived stereo slant around a vertical axis is usually slow and significantly under-estimated for isolated surfaces. Perceived slant is enhanced when surrounding surfaces provide a relative disparity gradient or depth step at the edges of the slanted surface, and also in the presence of monocular occlusion regions (sidebands). Here we investigate how different kinds of depth information at surface edges enhance stereo slant about a vertical axis. In Experiment 1, perceived slant decreased with increasing surface width, suggesting that the relative disparity between the left and right edges was used to judge slant. Adding monocular sidebands increased perceived slant for all surface widths. In Experiment 2, observers matched the slant of surfaces that were isolated or had a context of either monocular or binocular sidebands in the frontal plane. Both types of sidebands significantly increased perceived slant, but the effect was greater with binocular sidebands. These results were replicated in a second paradigm in which observers matched the depth of two probe dots positioned in front of slanted surfaces (Experiment 3). A large bias occurred for the surface without sidebands, yet this bias was reduced when monocular sidebands were present, and was nearly eliminated with binocular sidebands. Our results provide evidence for the importance of edges in stereo slant perception, and show that depth from monocular occlusion geometry and binocular disparity may interact to resolve complex 3D scenes. PMID- 24802595 TI - Response times across the visual field: empirical observations and application to threshold determination. AB - This study aimed to determine if response times gathered during perimetry can be exploited within a thresholding algorithm to improve the speed and accuracy of the test. Frequency of seeing (FoS) curves were measured at 24 locations across the central 30 degrees of the visual field of 10 subjects using a Method of Constant Stimuli, with response times recorded for each presentation. Spatial locations were interleaved, and built up over multiple 5-min blocks, in order to mimic the attentional conditions of clinical perimetry. FoS curves were fitted to each participant's data for each location, and response times derived as a function of distance-from-threshold normalised to the slope of each FoS curve. This data was then used to derive a function for the probability of observing response times given the distance-from-threshold, and to seed simulations of a new test procedure (BURTO) that exploited the probability function for stimulus placement. Test time and error were then simulated for patients with various false response rates. When compared with a ZEST algorithm, simulations revealed that BURTO was about one presentation per location faster than ZEST, on average, while sacrificing less precision and bias in threshold estimates than simply terminating the ZEST earlier. Despite response times varying considerably for a given individual and their thresholds, response times can be exploited to reduce the number of presentations required in a visual field test without loss of accuracy. PMID- 24802596 TI - Celebrating nurses. PMID- 24802598 TI - Pain assessment and management strategies for elderly patients. AB - Home healthcare nurses play a critical role in pain assessment and management in elderly patients. People 65 years of age and older are the largest consumers of prescription and nonprescription pain medications in the United States and are at increased risk for adverse reactions and inadequate pain management. This article seeks to explore strategies to assist hospice and home healthcare nurses in assessing and managing elderly patients' pain. The goal is to provide tools to assist nurses in streamlining elderly patient care and improving quality of life while decreasing mortality and morbidity for this patient population. PMID- 24802599 TI - Patient education in home care: strategies for success. AB - This article describes principles for patient education, beginning with assessment of learning needs through evaluation. Strategies for effective teaching in the home care setting are presented, including use of educational resources. PMID- 24802600 TI - The ARTT model: painting a better picture for the vulnerable among us. AB - A low-socioeconomic housing development serves as a clinical site for senior nursing students in their community health rotation. The students learn to conceptualize the art and science of nursing through application of a model assessment, referral, teaching, and therapeutic use of self (called ARTT) developed by the author. PMID- 24802601 TI - Decreasing informal caregiver burden with social media. AB - In 2008, there were 44 million informal family caregivers and the number is expected to rise in the next decade. Hospice clinicians need to explore ways to decrease the burden of care for these informal caregivers. The use of electronic technology and social media may be a key component in improving support at end of life in the home setting. PMID- 24802602 TI - Care transitions: best practices and evidence-based programs. AB - The Center for Healthcare Research & Transformation (CHRT) sponsors research and public information to promote evidence-based care delivery, improve population health, and expand access to care. Housed at the University of Michigan, CHRT is a nonprofit partnership between U-M and Blue Cross Blue Shield of Michigan to test the best ideas for improving the effectiveness and efficiency of the health care system. PMID- 24802603 TI - Prediabetes. PMID- 24802604 TI - Benefit for caregivers of veterans. PMID- 24802605 TI - Home oxygen. PMID- 24802606 TI - Hospice crisis management: during short lengths of stay. PMID- 24802607 TI - A kid at heart. PMID- 24802608 TI - The relative odds of lifetime health conditions and infectious diseases among men who have sex with men compared with a matched general population sample. AB - To address the understudy of health conditions and infectious diseases that are not strictly related to sexual transmission among men who have sex with men (MSM), this study examined the relative odds of 10 health conditions and two infectious diseases in a sample of MSM compared with a matched general population sample. MSM (N = 653) living mainly in Chicago were sampled through successive administrations of an Internet-based survey (2008-2010) that assessed physical and mental health, substance use, and HIV status. Propensity score matching was used to obtain a demographically comparable sample of men (N = 653) from aggregated administrations (2008-2012) of the National Survey on Drug Use and Health. Multivariate Firth logistic regressions compared the odds of ever having been diagnosed with each condition or disease, controlling for demographics, substance use, psychological distress, and HIV/AIDS status. MSM were more likely (p < .01) to have experienced: ulcers (odds ratio [OR] = 2.3), hypertension (OR = 2.1), liver disease (OR = 5.7), and sexually transmitted infections other than HIV/AIDS (OR = 8.9). Two other conditions, pneumonia and pancreatitis, as well as tuberculosis, were significant at p < .05 but below the statistical threshold used to reduce alpha error. The findings suggest that relative to non-sexual minority men, MSM are more likely to experience a range of health conditions not specifically attributable to HIV/AIDS, sexual behavior, psychological distress, or substance use. The implications for research on the health status and provision of health care to MSM in light of the study findings are considered. PMID- 24802609 TI - Meta-analysis reveals a lack of association between UGT2B17 deletion polymorphism and tumor susceptibility. AB - PURPOSE: UGT2B17 is a vital member of the UGT2 family and functions as a detoxification enzyme which catalyzes the glucuronidation of lipophilic compounds. Accumulating evidences implicates that it may contribute to the susceptibility of tumor risk. Identification of a UGT2B17 deletion polymorphism has attracted studies to evaluate the association between the UGT2B17 deletion polymorphism and tumor risk in diverse populations. However, the available results are conflicting. METHODS: A meta-analysis based on 14 studies from 10 publications including 5,732 cases and 5,112 controls was performed. Published literature from PubMed, EMBASE and Web of Science was pooled and the crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the associations. RESULTS: Conclusively, our results indicate that individuals with a UGT2B17 deletion polymorphism were associated with tumor risks (OR = 1.29, 95% CI = 1.03-1.63, P<0.001) in a recessive model. However, after excluding two studies for their heterogeneity, the result then demonstrated that the UGT2B17 deletion polymorphism was not associated with tumor risks (OR = 1.118, 95% CI = 0.938-1.332, P>0.1). A subgroup analysis based on tumor type, sex or race did not show significant results. CONCLUSION: These results suggest that the UGT2B17 deletion polymorphism is not associated with tumor risks. PMID- 24802610 TI - Cell therapy for bone repair: narrowing the gap between vision and practice. AB - This position paper summarises a vision of how cell-based therapies can be applied clinically to regenerate bone, as well as the steps needed to narrow the gap between that vision and clinical reality. It is a result of the presentations and discussion of the "Cell Therapy for Bone Repair" breakout session at the AO Foundation Symposium "Where Science Meets Clinics" in Davos, Switzerland from September 5-7, 2013. Participants included leaders from science, medicine, and industry from around the world. The session included clinical and scientific presentations, as well as an extended discussion among participants. Bone tissue has an innate regenerative capacity that in most cases allows functional healing at damage sites. However, there are a number of serious conditions in which bone does not fully heal and the result is significant morbidity. The clinical need for new therapies is clear, and the breakout session participants were enthusiastic about the potential impact on cell-based therapies for bone repair in the clinic. However, they also recognised the significant challenges that face the development of commercially viable cell therapy products. This paper outlines a vision in which patient selection is based on expected therapeutic outcome to create a consistently successful, cost-effective, cell-based therapy for bone repair. The need for a more complete understanding of bone repair, a better infrastructure for preclinical studies, and the need for collaboration among stakeholders is discussed. PMID- 24802611 TI - Cell therapy for intervertebral disc repair: advancing cell therapy from bench to clinics. AB - Intervertebral disc (IVD) degeneration is a major cause of pain and disability; yet therapeutic options are limited and treatment often remains unsatisfactory. In recent years, research activities have intensified in tissue engineering and regenerative medicine, and pre-clinical studies have demonstrated encouraging results. Nonetheless, the translation of new biological therapies into clinical practice faces substantial barriers. During the symposium "Where Science meets Clinics", sponsored by the AO Foundation and held in Davos, Switzerland, from September 5-7, 2013, hurdles for translation were outlined, and ways to overcome them were discussed. With respect to cell therapy for IVD repair, it is obvious that regenerative treatment is indicated at early stages of disc degeneration, before structural changes have occurred. It is envisaged that in the near future, screening techniques and non-invasive imaging methods will be available to detect early degenerative changes. The promises of cell therapy include a sustained effect on matrix synthesis, inflammation control, and prevention of angio- and neuro-genesis. Discogenic pain, originating from "black discs" or annular injury, prevention of adjacent segment disease, and prevention of post-discectomy syndrome were identified as prospective indications for cell therapy. Before such therapy can safely and effectively be introduced into clinics, the identification of the patient population and proper standardisation of diagnostic parameters and outcome measurements are indispensable. Furthermore, open questions regarding the optimal cell type and delivery method need to be resolved in order to overcome the safety concerns implied with certain procedures. Finally, appropriate large animal models and well-designed clinical studies will be required, particularly addressing safety aspects. PMID- 24802612 TI - A vision on the future of articular cartilage repair. AB - An AO Foundation (Davos, Switzerland) sponsored workshop "Cell Therapy in Cartilage Repair" from the Symposium "Where Science meets Clinics" (September 5 7, 2013, Davos) gathered leaders from medicine, science, industry, and regulatory organisations to debate the vision of cell therapy in articular cartilage repair and the measures that could be taken to narrow the gap between vision and current practice. Cell-based therapy is already in clinical use to enhance the repair of cartilage lesions, with procedures such as microfracture and articular chondrocyte implantation. However, even though long term follow up is good from a clinical perspective and some of the most rigorous randomised controlled trials in the regenerative medicine/orthopaedics field show beneficial effect, none of these options have proved successful in restoring the original articular cartilage structure and functionality in patients so far. With the remarkable recent advances in experimental research in cell biology (new sources for chondrocytes, stem cells), molecular biology (growth factors, genes), biomaterials, biomechanics, and translational science, a combined effort between scientists and clinicians with broad expertise may allow development of an improved cell therapy for cartilage repair. This position paper describes the current state of the art in the field to help define a procedure adapted to the clinical situation for upcoming translation in the patient. PMID- 24802613 TI - Barriers and strategies for the clinical translation of advanced orthopaedic tissue engineering protocols. AB - Research in orthopaedic tissue engineering has intensified over the last decade and new protocols continue to emerge. The clinical translation of these new applications, however, remains associated with a number of obstacles. This report highlights the major issues that impede the clinical translation of advanced tissue engineering concepts, discusses strategies to overcome these barriers, and examines the need to increase incentives for translational strategies. The statements are based on presentations and discussions held at the AO Foundation sponsored symposium "Where Science meets Clinics 2013" held at the Congress Center in Davos, Switzerland, in September, 2013. The event organisers convened a diverse group of over one hundred stakeholders involved in clinical translation of orthopaedic tissue engineering, including scientists, clinicians, healthcare industry professionals and regulatory agency representatives. A major point that emerged from the discussions was that there continues to be a critical need for early trans-disciplinary communication and collaboration in the development and execution of research approaches. Equally importantly was the need to address the shortage of sustained funding programs for multidisciplinary teams conducting translational research. Such detailed discussions between experts contribute towards the development of a roadmap to more successfully advance the clinical translation of novel tissue engineering concepts and ultimately improve patient care in orthopaedic and trauma surgery. PMID- 24802614 TI - COX-2 inhibitors arrest prostate cancer cell cycle progression by down-regulation of kinetochore/centromere proteins. AB - BACKGROUND: Previous studies have shown that COX-2 inhibitors inhibit cancer cell proliferation. However, the molecular mechanism remains elusive. METHODS: Prostate cancer LNCaP, 22Rv1, and PC3 cells were cultured and treated with the COX-2 inhibitors celecoxib and CAY10404. Knockdown of COX-2 in LNCaP cells was carried out using lentiviral vector-loaded COX-2 shRNA. Cell cycle progression and cell proliferation were analyzed by flow cytometry, microscopy, cell counting, and the MTT assay. The antagonists of EP1, EP2, EP3, and EP4 were used to examine the effects of the PGE2 signaling. The effect of COX-2 inhibitors and COX-2 knockdown on expression of the kinetochore/centromere genes and proteins was determined by RT-PCR and immunoblotting. RESULTS: Treatment with the COX-2 inhibitors celecoxib and CAY10404 or knockdown of COX-2 significantly inhibited prostate cancer cell proliferation. Flow-cytometric analysis and immunofluorescent staining confirmed the cell cycle arrested at the G2/M phase. Biochemical analysis showed that inhibition of COX-2 or suppression of COX-2 expression induced a dramatic down-regulation of key proteins in the kinetochore/centromere assembly, such as ZWINT, Cdc20, Ndc80, CENP-A, Bub1, and Plk1. Furthermore, the EP1 receptor antagonist SC51322, but not the EP2, EP3, and EP4 receptor antagonists, produced similar effects to the COX-2 inhibitors on cell proliferation and down-regulation of kinetochore/centromere proteins, suggesting that the effect of the COX-2 inhibition is through inactivation of the EP1 receptor signaling. CONCLUSIONS: Our studies indicate that inhibition of COX 2 can arrest prostate cancer cell cycle progression through inactivation of the EP1 receptor signaling and down-regulation of kinetochore/centromere proteins. PMID- 24802616 TI - Cyclic adenosine 5'-diphosphoribose (cADPR) cyclic guanosine 3',5'-monophosphate positively function in Ca(2+) elevation in methyl jasmonate-induced stomatal closure, cADPR is required for methyl jasmonate-induced ROS accumulation NO production in guard cells. AB - Methyl jasmonate (MeJA) signalling shares several signal components with abscisic acid (ABA) signalling in guard cells. Cyclic adenosine 5'-diphosphoribose (cADPR) and cyclic guanosine 3',5'-monophosphate (cGMP) are second messengers in ABA induced stomatal closure. In order to clarify involvement of cADPR and cGMP in MeJA-induced stomatal closure in Arabidopsis thaliana (Col-0), we investigated effects of an inhibitor of cADPR synthesis, nicotinamide (NA), and an inhibitor of cGMP synthesis, LY83583 (LY, 6-anilino-5,8-quinolinedione), on MeJA-induced stomatal closure. Treatment with NA and LY inhibited MeJA-induced stomatal closure. NA inhibited MeJA-induced reactive oxygen species (ROS) accumulation and nitric oxide (NO) production in guard cells. NA and LY suppressed transient elevations elicited by MeJA in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in guard cells. These results suggest that cADPR and cGMP positively function in [Ca(2+)]cyt elevation in MeJA-induced stomatal closure, are signalling components shared with ABA-induced stomatal closure in Arabidopsis, and that cADPR is required for MeJA-induced ROS accumulation and NO production in Arabidopsis guard cells. PMID- 24802619 TI - Laparoscopic radical prostatectomy for high-risk prostate cancer. AB - OBJECTIVE: To investigate the results of performing laparoscopic radical prostatectomy (LRP) in patients with high-risk prostate cancer (HRPC): PSA level of >=20 ng/mL +/- biopsy Gleason >=8 +/- clinical T stage >=2c. PATIENTS AND METHODS: Of a total of 1975 patients having LRP during a 159-month period from 2000 to 2013, 446 (22.6%) had HRPC; all patients were staged by preoperative magnetic resonance imaging or computed tomography and isotope bone scanning. The median (range) patient age was 64.0 (36-79) years; body mass index 27.0 (18-43) kg/m(2) ; PSA level 8.1 (0.1-93) ng/mL and biopsy Gleason 8 (6-10). All patients had a pelvic lymphadenectomy, which was done using an extended template after April 2008 (53.3%). Neurovascular bundle (NVB) preservation was done in 41.5% (bilateral 26.3%; unilateral 15.2%) of patients; an incremental or partial nerve sparing technique was used in 99 of the 302 (32.8%) NVBs preserved. RESULTS: The median (range) gland weight was 58.5 (20-161) g; operating time 180 (92-330) min; blood loss 200 (10-1400) mL; postoperative hospitalisation 3.0 (2-7) nights; catheterisation time 14 (2-35) days; complication rate 7.6%; lymph node (LN) count 16 (2-51); LN positivity 16.2%; LN involvement 2 (1-8); positive surgical margin (PSM) rate 26.0%; up-grading 2.5%; down-grading 4.3%; up-staging from T1/2 to T3, 24.7%; down-staging from T3 to T1/2, 6.1%. No cases were converted to open surgery and three patients were transfused (0.7%) after surgery. At a mean (range) follow-up of 24.9 (3-120) months, 79.2% of patients were free of biochemical recurrence, 91.8% were continent and 64.4% of previously potent non diabetic men aged <70 years were potent after bilateral nerve preservation. CONCLUSION: The low morbidity, 55.4% specimen-confinement rate, 26.0% PSM rate, 79.2% biochemical disease-free survival, 91.8% continence rate and 64.4% potency rate, at 35.2 months in the present study serve as evidence firstly that surgery is an effective treatment for patients with HRPC, curing many and representing the first step of multi-modal treatment for others, and that LRP for HRPC appears to be as effective as open RP in this context. PMID- 24802617 TI - Fibrin-mediated delivery of an ovarian follicle pool in a mouse model of infertility. AB - The cryopreservation and autotransplantation of ovarian tissue is emerging as a powerful approach for preserving fertility. However, for cancer patients, it may not be possible to transplant ovarian tissue due to the risk of re-seeding disease. We investigated strategies for transplantation of individually isolated follicles to minimize the risk of re-introducing cancer cells present within the vasculature of ovarian stroma. Procedures for large-scale isolation of early stage follicles and their encapsulation into fibrin hydrogels were developed. For in vivo validation studies, mice were ovariectomized and transplanted with encapsulated follicles into the ovarian bursa. A substantial increase in the number of secondary follicles was observed in the graft at 9 days after transplantation, and antral follicles by day 21, demonstrating primordial follicle recruitment into the growing pool. Initially, elevated follicle stimulating hormone levels declined substantially by day 21, indicating feedback from the graft; presence of corpora lutea showed the graft's capability of restoring hormone cyclicity. Taken together, the transplanted follicles were able to engraft, mature, and restore ovarian function in an infertile mouse. This biomaterial may, thus, provide a platform for follicle transplantation with a low risk of cancer contamination and for developing strategies that preserve fertility for women facing a cancer diagnosis. PMID- 24802620 TI - Fast and accurate localization of multiple RF markers for tracking in MRI-guided interventions. AB - OBJECT: A new method for 3D localization of N fiducial markers from 1D projections is presented and analysed. It applies to semi-active markers and active markers using a single receiver channel. MATERIALS AND METHODS: The novel algorithm computes candidate points using peaks in three optimally selected projections and removes fictitious points by verifying detected peaks in additional projections. Computational complexity was significantly reduced by avoiding cluster analysis, while higher accuracy was achieved by using optimal projections and by applying Gaussian interpolation in peak detection. Computational time, accuracy and robustness were analysed through Monte Carlo simulations and experiments. The method was employed in a prototype MRI guided prostate biopsy system and used in preclinical experiments. RESULTS: The computational time for 6 markers was better than 2 ms, an improvement of up to 100 times, compared to the method by Flask et al. (J Magn Reson Imaging 14(5):617 627, 2001). Experimental maximum localization error was lower than 0.3 mm; standard deviation was 0.06 mm. Targeting error was about 1 mm. Tracking update rate was about 10 Hz. CONCLUSION: The proposed method is particularly suitable in systems requiring any of the following: high frame rate, tracking of three or more markers, data filtering or interleaving. PMID- 24802621 TI - Retransformation of marker-free potato for enhanced resistance against fungal pathogens by pyramiding chitinase and wasabi defensin genes. AB - Multi-auto-transformation vector system has been one of the strategies to produce marker-free transgenic plants without using selective chemicals and plant growth regulators and thus facilitating transgene stacking. In the study reported here, retransformation was carried out in marker-free transgenic potato CV. May Queen containing ChiC gene (isolated from Streptomyces griseus strain HUT 6037) with wasabi defensin (WD) gene (isolated from Wasabia japonica) to pyramid the two disease resistant genes. Molecular analyses of the developed shoots confirmed the existence of both the genes of interest (ChiC and WD) in transgenic plants. Co expression of the genes was confirmed by RT-PCR, northern blot, and western blot analyses. Disease resistance assay of in vitro plants showed that the transgenic lines co-expressing both the ChiC and WD genes had higher resistance against the fungal pathogens, Fusarium oxysporum (Fusarium wilt) and Alternaria solani (early blight) compared to the non-transformed control and the transgenic lines expressing either of the ChiC or WD genes. The disease resistance potential of the transgenic plants could be increased by transgene stacking or multiple transformations. PMID- 24802623 TI - Automatic programming via iterated local search for dynamic job shop scheduling. AB - Dispatching rules have been commonly used in practice for making sequencing and scheduling decisions. Due to specific characteristics of each manufacturing system, there is no universal dispatching rule that can dominate in all situations. Therefore, it is important to design specialized dispatching rules to enhance the scheduling performance for each manufacturing environment. Evolutionary computation approaches such as tree-based genetic programming (TGP) and gene expression programming (GEP) have been proposed to facilitate the design task through automatic design of dispatching rules. However, these methods are still limited by their high computational cost and low exploitation ability. To overcome this problem, we develop a new approach to automatic programming via iterated local search (APRILS) for dynamic job shop scheduling. The key idea of APRILS is to perform multiple local searches started with programs modified from the best obtained programs so far. The experiments show that APRILS outperforms TGP and GEP in most simulation scenarios in terms of effectiveness and efficiency. The analysis also shows that programs generated by APRILS are more compact than those obtained by genetic programming. An investigation of the behavior of APRILS suggests that the good performance of APRILS comes from the balance between exploration and exploitation in its search mechanism. PMID- 24802624 TI - The effects of bilateral bipolar sacral neurostimulation on urinary bladder activity during filling before and after irritation in a rat model. AB - AIMS: To design an optimal rat model for studying sacral neurostimulation (SNS), and examine the effect of SNS on myogenic non-voiding contractions (NVC) during filling before and after intraluminal irritation. METHODS: Bilateral paired bipolar SNS was performed in 10 female urethane anesthetized Sprague-Dawley rats at the L6-S1 trunks at 10 Hz, 0.1 msec pulse duration and 0.15-0.80 mA (below motor threshold). Transvesical cystometry was performed before and during SNS under conditions of control (saline, N = 10) and irritation [0.25% acetic acid (AA), N = 5]. RESULTS: Functional bladder capacity (FBC) and NVC count were significantly increased during SNS under both control and irritation conditions (P < 0.01 for all). In six instances (four in control, two in irritation), micturition reflexes were completely inhibited by SNS resulting in overflow incontinence. Filling compliance, NVC period and NVC maximum amplitude were not affected by SNS (P > 0.05 for all). Non-parametric two-way analysis of variance for repeated measures revealed increased FBC and NVC count during SNS under both control and irritation conditions (P = 0.004 for both, N = 5 rats). Linear regression analysis of NVC count versus FBC revealed a slope significantly different than zero, independent of control or irritation conditions (slope 33.10 +/- 2.43, R(2) = 0.81, P < 0.001). CONCLUSIONS: This model achieved reliable, reversible and robust increases in bladder capacity up to overflow incontinence at stimulations below somatic motor threshold. SNS dramatically increased FBC and reversed AA-induced changes without affecting the character of normal NVC associated with bladder filling. Increased number of NVC is simply a consequence of increased fill time. PMID- 24802626 TI - Randomized controlled trial of perioperative ICD management: magnet application versus reprogramming. AB - BACKGROUND: There are insufficient data to guide perioperative implantable cardioverter-defibrillator (ICD) management for patients undergoing surgical procedures using electrocautery. METHODS: We conducted a multicenter randomized controlled trial of patients with ICDs undergoing surgery with monopolar electrocautery. Subjects were randomized to an "Off" group (ICD therapy programmed off, then postoperatively programmed on) or a "Magnet" group (ICD therapy suspended with a magnet and no immediate postoperative ICD interrogation). Also, a registry was maintained of ICD patients with procedures within 6 inches of the ICD (all programmed off). The primary endpoint was ICD off time with secondary endpoints being caregiver handoffs and incidence of electromagnetic interference (EMI). RESULTS: All patients (n = 80) had pectoral ICDs. Subject demographics were well matched in each group, and duration of electrocautery was similar (80 minutes vs 64 minutes, P = 0.58). The mean "excess" ICD off time (ICD off time - electrocautery time) was significantly higher in the Off group than the Magnet group (115 minutes vs 28 minutes, P < 0.001). Mean number of caregiver handoffs were higher in the Off group (6.6 vs 5.5, P < 0.001). There was no EMI in any lower abdominal or lower extremity procedures. Neither group had arrhythmic events or device reset. CONCLUSION: A magnet protocol simplifies perioperative ICD management for procedures using electrocautery more than 6 inches from the ICD. This protocol results in significantly shorter time with ICD therapy off, fewer provider handoffs, no risk of inadvertently discharging patients home with ICD therapies off, and no device reset. PMID- 24802625 TI - Prenatal origins of temperament: fetal growth, brain structure, and inhibitory control in adolescence. AB - OBJECTIVE: Individual differences in the temperamental dimension of effortful control are constitutionally based and have been associated with an adverse prenatal developmental environment, with structural brain alterations presenting a potential mechanism. We investigated this hypothesis for anatomically defined brain regions implicated in cognitive and inhibitory motor control. METHODS: Twenty-seven 15-16 year old participants with low, medium, or high fetal growth were selected from a longitudinal birth cohort to maximize variation and represent the full normal spectrum of fetal growth. Outcome measures were parent ratings of attention and inhibitory control, thickness and surface area of the orbitofrontal cortex (lateral (LOFC) and medial (MOFC)) and right inferior frontal gyrus (rIFG), and volumetric measures of the striatum and amygdala. RESULTS: Lower birth weight was associated with lower inhibitory control, smaller surface area of LOFC, MOFC and rIFG, lower caudate volume, and thicker MOFC. A mediation model found a significant indirect effect of birth weight on inhibitory control via caudate volume. CONCLUSIONS: Our findings support a neuroanatomical mechanism underlying potential long-term consequences of an adverse fetal developmental environment for behavioral inhibitory control in adolescence and have implications for understanding putative prenatal developmental origins of externalizing behavioral problems and self-control. PMID- 24802627 TI - Effect of growth factors on antimicrobial peptides and pro-inflammatory mediators during wound healing. AB - BACKGROUND: Antimicrobial peptides (AMPs), such as human beta-defensin-2 (hBD-2) and the CC-chemokine ligand 20 (CCL20), exhibit direct microbicidal effects and mediator-like activity. It was hypothesized that wounding induces the expression of AMPs and pro-inflammatory mediators and that endogenous mediators, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-alpha (TGF alpha), modulate this induced expression. MATERIAL AND METHODS: Monolayers of gingival epithelial cells (GECs) and gingival fibroblast (HGFs) from three different donors were wounded using the scratch assay (in vitro wounding) in the presence (test group) or absence (control group) of IGF-1 and TGF-alpha. In vitro wound closure was monitored over time (0, 6, 24, 48, 72 h), and wound areas were microscopically analyzed (Axio-Vision(r) Software, Zeiss). Gene expression analysis of the GAPDH, hBD-2, CCL20, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) was performed by qPCR. RESULTS: In comparison to control cells, IGF-1 and TGF-alpha significantly enhanced in vitro wound closure (P < 0.05). In GECs, IGF-1 induced the gene expression of IL-1 beta and IL-8 when compared to control cells (P < 0.05). In HGFs, wounding per se induced the messenger RNA of hBD-2, CCL20, and IL-1 beta, whereas IGF-1 and TGF-alpha reversed this effect (P < 0.05). CONCLUSION: In gingival cells, the gene expression of AMPs was altered by injury, and endogenous growth factors further influenced the expression profiles, but with high interindividual differences. PMID- 24802628 TI - Fractal analysis for the assessment of trabecular peri-implant alveolar bone using panoramic radiographs. AB - OBJECTIVES: There is no consensus on the relationship between fractal dimension and trabecular bone complexity. Our aims were to examine the changes in fractal dimension (FD) from peri-implant alveolar bone on digital panoramic radiographs 6 and 12 months after prosthodontic loading and to compare these with baseline values calculated just after loading. MATERIAL AND METHODS: Three panoramic radiographs taken from 76 implant patients taken (1) after prosthodontic loading (3 months +/- 2 weeks after insertion = baseline), (2) 6 months +/- 2 weeks after loading, and (3) 12 months +/-2 weeks after loading were considered for the study. Panoramic images were obtained using storage phosphor plates of the Digora PCT system and saved into a computer. Three regions of interest from mesial, distal, and apical areas were selected for each implant on three consecutive panoramic images. Statistical analysis of the data was performed using two-way repeated measures ANOVA, independent t test and paired t test, and pairwise comparisons (P < 0.05). RESULTS: Mean FD values at baseline were 1.202, 1.224, and 1.199 for apical, mesial, and distal areas. The FD values were calculated as 1.121, 1.113, and 1.128 at the 6th month. The differences between values calculated at baseline and the 6th month were statistically significant for all aspects, indicating a significant decrease in FD 6 months after prosthodontic loading (P < 0.05). FD values calculated at the 12th month were 1.121, 1.110, and 1.121 for apical, mesial, and distal aspects, respectively, with no significant differences from corresponding values obtained at the 6th month (P > 0.05). CONCLUSIONS: FD values of trabecular bone around implants 6 months after prosthodontic loading are significantly lower than the baseline values. However, no significant decrease or increase was observed at 12 months, which revealed comparable results with peri-implant alveolar bone at 6 months. CLINICAL RELEVANCE: Trabecular bone around successful dental implants exhibits lower fractal dimension values 6 months after prosthodontic loading and displays stable bony microstructure at 12 months of follow-up. PMID- 24802629 TI - Comparative evaluation of thickness of jaw-closing muscles in patients with long standing bilateral temporomandibular joint ankylosis: a retrospective case controlled study. AB - OBJECTIVES: The aim of the study was to compare the thickness and cross-sectional area (CSA) of masseter and medial pterygoid muscles in young patients with long standing bilateral temporomandibular joint ankylosis (bTMJA) in relation to controls. METHODS: Axial sections of computed tomography scans of patients with bTMJA from two tertiary care university hospitals were reviewed from 1995 to 2010 and compared to age- and sex-matched controls. The outlines of masseter and medial pterygoid muscles corresponding to a predefined reference plane were traced onto acetate paper. The thickness and CSA of the muscles were calculated using an image-analyzing software and calibrated according to the scale provided in the CT scan slides. RESULTS: Out of a total of 167 cases of temporomandibular joint ankylosis (TMJA), 15 fulfilled the inclusion criteria. The mean thickness and CSA of masseter and medial pterygoid muscles in cases of bTMJA were 19.4 mm (SD 2.3), 734.9 mm(2) (SD 156.7), 11.53 mm (SD 1.35), and 267.4 mm(2) (SD 65.35), respectively. For the control group, respective values were 10.5 mm (SD 1.8), 430.1 mm(2) (SD 66.8), 9.2 mm (SD 1.2), and 254.6 mm(2) (SD 45.7). There was a statistically significant increased thickness and CSA of the muscles in cases of bTMJA as compared to control as evaluated by Mann-Whitney U test. CONCLUSIONS: The results show that thickness and CSA of masseter and medial pterygoid muscles in patients with bTMJA were larger as compared to controls. This may suggest that, muscular hyperactivity, may be a cofactor in the pathogenesis of TMJA. CLINICAL SIGNIFICANCE: Although temporomandibular joint ankylosis is one of the most restrictive musculoskeletal disorder in the maxillofacial region, there is little information on the form and function of jaw muscles in this condition. This study evaluates thickness and cross-sectional areas of jaw elevator muscles and indicates that muscle hyperactivity might be associated with ankylosis, thereby providing a probable hypothesis on the etiopathogenesis of this condition. PMID- 24802630 TI - Masticatory rehabilitation following upper and lower jaw reconstruction using vascularised free fibula flap and enossal implants-19 years of experience with a comprehensive concept. AB - OBJECTIVES: Conventional prosthesis is generally inapplicable following reconstruction with free fibula flaps (FFF) due to impaired bone and soft tissue conditions, and rehabilitation via enossal implants in FFF is relatively novel. This retrospective study aimed to document the surgical aspects of this option and to describe related supplementary procedures that can help optimise the definitive outcome. MATERIAL AND METHODS: One hundred nineteen implants were inserted within FFFs in 37 patients (mean age 51.8 +/- 10.6 years), who underwent ablative surgery of the maxilla (3) and mandible (34). In a cross-sectional study design with a follow-up period of 3-172 months, we analysed types and configurations of graft design, patterns of implant insertion and methods for prosthetic rehabilitation as well as primary stability and survival rate. RESULTS: Most patients underwent jaw reconstruction using a mono-barrel FFF (14 osseous and 18 osteocutaneous/osteomyocutaneous); three patients received double barrel reconstruction of the mandible. Three patients with maxillary defects were reconstructed using mono-barrel grafts (one osteocutaneous and two prefabricated grafts). Pre-prosthetic procedures were required in 23 patients to optimise conditions in the peri-implant soft tissue. Iliac bone onlay graft was used in six patients to achieve appropriate vertical height in mono-barrel grafts. A total of 10 implants in eight patients (five irradiated) could not be loaded. All other implants showed stable osseous integration and satisfactory peri-implant soft tissue conditions. CONCLUSION: Masticatory rehabilitation can be achieved using enossal implants inserted in FFF. Special requirements can be met through selection of an appropriate graft configuration and optimal implant positioning. Supplementary pre-prosthetic procedures are usually required as they improve long term survival. CLINICAL RELEVANCE: This overview provides a reliable and comprehensive algorithm for standard implant-borne rehabilitation of patients with fibula grafts. PMID- 24802631 TI - Epstein-Barr virus associated peri-implantitis: a split-mouth study. AB - OBJECTIVES: Herpesviral-bacterial synergism may play a potential role in periodontitis and peri-implantitis (PI) etiopathogenesis. PI lesions can worsen depending on specific microbial challenge and host susceptibility. This cross sectional split-mouth study aimed to substantiate herpesviral-bacterial co infection in PI patients and assess associations with periodontopathogen salivary contamination. METHODS: PCR-based identification was performed on 23 patients presenting PI and contralateral healthy implants, and compared to unstimulated whole saliva. Clinical evaluation included probing depths, bleeding on probing, and suppuration. Radiographs were assessed for the presence of lamina dura and bone loss. Three sample sites per patient were tested: PI lesions, healthy implant sulci, and saliva. Quantitative PCR evaluated Epstein-Barr virus (EBV) and cytomegalovirus (CMV) copy counts. Significance of group comparisons for binary-dependent variables, within-subjects designs, was determined by McNemar's chi-square test. Risk analysis was evaluated through odds ratios (OR). RESULTS: PI lesions were 14.2 (P = 0.001; 95 % confidence interval [CI], 1.6-124.1) and 3 times (P = 0.03; 95 % CI, 0.7-11.9) more likely to harbor EBV than healthy implants and saliva, respectively. EBV positive predictive value was 90 %. PI was associated with absence of lamina dura and higher periodontopathogen proportions. Saliva sampling showed high agreement with PI bacterial detection (89-100 % rate) but not with EBV (44.4 %). The OR of PI lesions harboring Treponema denticola or Tannerella forsythia was 6.79 (P = 0.007; 95 % CI, 1.8-25.0) and 3.3 (P < 0.0001; 95 % CI, 0.3-34.3) times higher than healthy implants, respectively. Saliva of patients with PI was 5.6 times more likely to be contaminated with Prevotella nigrescens than healthy peri-implant sulci (P = 0.002). PI lesions were 1.92 times more likely to harbor Prevotella nigrescens than healthy implants (P = 0.04). CONCLUSIONS: EBV is a potential candidate in peri-implantitis etiopathogenesis. Saliva PCR analysis is useful in predicting peri-implantitis specific bacterial infection but not EBV or CMV. CLINICAL SIGNIFICANCE: Herpesviral-bacterial synergism may favor ongoing microbial challenge in peri implant disease and exacerbate its progression. EBV infection may explain non responsive to treatment PI. Peri-implantitis individuals may benefit from antiviral therapy. PMID- 24802632 TI - Detection of herpesviruses and human papillomavirus in acute apical abscesses by real-time PCR. AB - OBJECTIVE: The recent use of polymerase chain reaction (PCR)-based molecular methods to detect herpesviruses in periradicular lesions has suggested that some herpesviruses, especially human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) can participate in the pathogenesis of the periradicular lesions. Based on the applicability of molecular techniques for virus identification, the aim of the study was to investigate the presence of HCMV, EBV, and human papillomavirus (HPV) in samples from acute apical abscesses. To the best of our knowledge, this is the first study in Turkish population to survey apical abscess samples for the presence of herpesviruses and HPV. MATERIAL AND METHODS: Microbial samples were collected from 27 apical abscess specimens and 6 control samples. DNA was extracted from clinical samples by using spin column-based nucleic acid purification method, and viral loads were evaluated using real-time PCR methods following the kit protocols recommended by the manufacturers. RESULTS: HCMV DNA was found alone in five (18.5 %) samples, EBV DNA alone in two (7.4 %), HPV DNA alone in two (7.4 %), and in one, both HCMV and EBV (4 %). As for the healthy pulps used as noninflamed controls, no control specimens contained HCMV, EBV, or HPV DNA. CONCLUSION: The present PCR-based findings have identified HCMV, EBV, and HPV as an inhabitant of acute apical abscesses. Additional studies using in vitro or animal model systems are required to elucidate the role of HCMV, EBV, and HPV in the pathogenesis of periapical pathosis. CLINICAL RELEVANCE: The present viral findings may have future therapeutic relevance for periapical abscesses and other periapical pathosis. PMID- 24802633 TI - Optically active chiral CuO "nanoflowers". AB - Helical symmetry can be found in most flowers with a rotation of contort petal aestivation. For micro- and nanoscale analogies, flower mimicking structures have been reproduced; however, the conceptual chirality of "nanoflowers" has not yet been defined. Here, the chirality of the "flower" was defined by its nanosized chiral structure and consequent optical activity (OA), opening new horizons for the physical theory and chiral materials. We report the surfactant-mediated hydrothermal synthesis of chiral CuO nanoflowers using sodium dodecyl sulfate (SDS) as a structure-directing agent, an amino alcohol as a symmetry-breaking agent, and cupric salt as the inorganic source. Two levels of hierarchical chirality exist for a CuO nanoflower including primary helically arranged "nanoflakes" and secondary helical "subnanopetals" that form "nanopetals". The nanoflowers exhibited a prominent optical response to circularly polarized light (CPL) at the absorption bands characteristic of CuO. PMID- 24802634 TI - MOF positioning technology and device fabrication. AB - Metal organic frameworks (MOFs) offer the highest surface areas per gram of any known material. As such, they epitomise resource productivity in uses where specific surface area is critical, such as adsorption, storage, filtration and catalysis. However, the ability to control the position of MOFs is also crucial for their use in devices for applications such as sensing, delivery, sequestration, molecular transport, electronics, energy production, optics, bioreactors and catalysis. In this review we present the current technologies that enable the precise positioning of MOFs onto different platforms. Methods for permanent localisation, dynamic localisation, and spatial control of functional materials within MOF crystals are described. Finally, examples of devices in which the control of MOF position and functionalisation will play a major technological role are presented. PMID- 24802636 TI - [Urea cycle disorders in primary care]. PMID- 24802635 TI - Prediction of substrates for glutathione transferases by covalent docking. AB - Enzymes in the glutathione transferase (GST) superfamily catalyze the conjugation of glutathione (GSH) to electrophilic substrates. As a consequence they are involved in a number of key biological processes, including protection of cells against chemical damage, steroid and prostaglandin biosynthesis, tyrosine catabolism, and cell apoptosis. Although virtual screening has been used widely to discover substrates by docking potential noncovalent ligands into active site clefts of enzymes, docking has been rarely constrained by a covalent bond between the enzyme and ligand. In this study, we investigate the accuracy of docking poses and substrate discovery in the GST superfamily, by docking 6738 potential ligands from the KEGG and MetaCyc compound libraries into 14 representative GST enzymes with known structures and substrates using the PLOP program [ Jacobson Proteins 2004 , 55 , 351 ]. For X-ray structures as receptors, one of the top 3 ranked models is within 3 A all-atom root mean square deviation (RMSD) of the native complex in 11 of the 14 cases; the enrichment LogAUC value is better than random in all cases, and better than 25 in 7 of 11 cases. For comparative models as receptors, near-native ligand-enzyme configurations are often sampled but difficult to rank highly. For models based on templates with the highest sequence identity, the enrichment LogAUC is better than 25 in 5 of 11 cases, not significantly different from the crystal structures. In conclusion, we show that covalent docking can be a useful tool for substrate discovery and point out specific challenges for future method improvement. PMID- 24802637 TI - [Tricuspid valve endocarditis secondary to cellulitis]. PMID- 24802638 TI - [Incidence of childhood obesity in the United States]. PMID- 24802639 TI - Automated genome mining of ribosomal peptide natural products. AB - Ribosomally synthesized and posttranslationally modified peptides (RiPPs), especially from microbial sources, are a large group of bioactive natural products that are a promising source of new (bio)chemistry and bioactivity.1 In light of exponentially increasing microbial genome databases and improved mass spectrometry (MS)-based metabolomic platforms, there is a need for computational tools that connect natural product genotypes predicted from microbial genome sequences with their corresponding chemotypes from metabolomic data sets. Here, we introduce RiPPquest, a tandem mass spectrometry database search tool for identification of microbial RiPPs, and apply it to lanthipeptide discovery. RiPPquest uses genomics to limit search space to the vicinity of RiPP biosynthetic genes and proteomics to analyze extensive peptide modifications and compute p-values of peptide-spectrum matches (PSMs). We highlight RiPPquest by connecting multiple RiPPs from extracts of Streptomyces to their gene clusters and by the discovery of a new class III lanthipeptide, informatipeptin, from Streptomyces viridochromogenes DSM 40736 to reflect that it is a natural product that was discovered by mass spectrometry based genome mining using algorithmic tools rather than manual inspection of mass spectrometry data and genetic information. The presented tool is available at cyclo.ucsd.edu. PMID- 24802640 TI - Otoconia-deficient mice show selective spatial deficits. AB - The vestibular system contributes to the performance of various spatial memory tasks, but few studies have attempted to disambiguate the roles of the semicircular canals and otolith organs in this performance. This study tested the otolithic contribution to spatial working and reference memory by evaluating the performance of otoconia-deficient tilted mice on a radial arm maze and a Barnes maze. One radial arm maze task provided both intramaze and extramaze cues, whereas the other task provided only extramaze cues. The Barnes maze task provided only extramaze cues. On the radial arm maze, tilted mice performed similar to control mice when intramaze cues were available, but committed more working and reference memory errors than control mice when only extramaze cues were available. On the Barnes maze task, control and tilted mice showed similar latency, distance, and errors during acquisition training. On the subsequent probe trial, both groups spent the greatest percentage of time in the goal quadrant, indicating they were able to use extramaze cues to guide their search. Overall, these results suggest signals originating in the otolith organs contribute to spatial memory, but are not necessary for all aspects of spatial performance. PMID- 24802641 TI - Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity. AB - We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in gamma-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of gamma GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2--generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium. PMID- 24802642 TI - Nine years of irrigation cause vegetation and fine root shifts in a water-limited pine forest. AB - Scots pines (Pinus sylvestris L.) in the inner-Alpine dry valleys of Switzerland have suffered from increased mortality during the past decades, which has been caused by longer and more frequent dry periods. In addition, a proceeding replacement of Scots pines by pubescent oaks (Quercus pubescens Willd.) has been observed. In 2003, an irrigation experiment was performed to track changes by reducing drought pressure on the natural pine forest. After nine years of irrigation, we observed major adaptations in the vegetation and shifts in Scots pine fine root abundance and structure. Irrigation permitted new plant species to assemble and promote canopy closure with a subsequent loss of herb and moss coverage. Fine root dry weight increased under irrigation and fine roots had a tendency to elongate. Structural composition of fine roots remained unaffected by irrigation, expressing preserved proportions of cellulose, lignin and phenolic substances. A shift to a more negative delta13C signal in the fine root C indicates an increased photosynthetic activity in irrigated pine trees. Using radiocarbon (14C) measurement, a reduced mean age of the fine roots in irrigated plots was revealed. The reason for this is either an increase in newly produced fine roots, supported by the increase in fine root biomass, or a reduced lifespan of fine roots which corresponds to an enhanced turnover rate. Overall, the responses belowground to irrigation are less conspicuous than the more rapid adaptations aboveground. Lagged and conservative adaptations of tree roots with decadal lifespans are challenging to detect, hence demanding for long-term surveys. Investigations concerning fine root turnover rate and degradation processes under a changing climate are crucial for a complete understanding of C cycling. PMID- 24802644 TI - Dynamic biological changes in fibroblasts during hypertrophic scar formation and regression. AB - The human hypertrophic scar undergoes hyperplasia and regression during progression. This study aimed to investigate whether fibroblasts in scar tissue undergo biological changes during the formation and regression of human hypertrophic scar. Using 32 scar samples, we measured collagen production by Masson's staining and the expression levels of transforming growth factor (TGF) beta1 and vascular endothelial growth factor (VEGF) by immunohistochemistry. In addition, fibroblasts from scar tissue were isolated and cultured, and total RNA was extracted for measurement of TGF-beta1, VEGF and collagen transcript levels by reverse transcription-polymerase chain reaction (RT-PCR). Masson's staining showed that the number of fibroblasts and microvessels increased gradually in early and proliferative scars but decreased in regressive scars. Immunohistochemistry revealed that the expression of TGF-beta1 and VEGF increased in early scars, peaked in proliferative scars and decreased in regressive scars. Moreover, the expression of TGF-beta1, VEGF, collagen I and collagen III mRNAs also increased in early and proliferative scars and decreased significantly in regressive scars. Dynamic changes in fibroblast biology correlated with the formation and progression of hypertrophic scar. PMID- 24802643 TI - Inhibition of Polo kinase by BI2536 affects centriole separation during Drosophila male meiosis. AB - Pharmacological inhibition of Drosophila Polo kinase with BI2536 has allowed us to re-examine the requirements for Polo during Drosophila male gametogenesis. BI2536-treated spermatocytes persisted in a pro-metaphase state without dividing and had condensed chromosomes that did not separate. Centrosomes failed to recruit gamma-tubulin and centrosomin (Cnn) and were not associated with microtubule arrays that were abnormal and did not form proper bipolar spindles. Centrioles, which usually separate during the anaphase of the first meiosis, remained held together in a V-shaped configuration suggesting that Polo kinase regulates the proteolysis that breaks centriole linkage to ensure their disengagement. Despite these defects spermatid differentiation proceeds, leading to axoneme formation. PMID- 24802645 TI - Teaching medical ethics to meet the realities of a changing health care system. AB - The changing context of medical practice--bureaucratic, political, or economic- demands that doctors have the knowledge and skills to face these new realities. Such changes impose obstacles on doctors delivering ethical care to vulnerable patient populations. Modern medical ethics education requires a focus upon the knowledge and skills necessary to close the gap between the theory and practice of ethical care. Physicians and doctors-in-training must learn to be morally sensitive to ethical dilemmas on the wards, learn how to make professionally grounded decisions with their patients and other medical providers, and develop the leadership, dedication, and courage to fulfill ethical values in the face of disincentives and bureaucratic challenges. A new core focus of medical ethics education must turn to learning how to put ethics into practice by teaching physicians to realistically negotiate the new institutional maze of 21st-century medicine. PMID- 24802646 TI - Spinoza, Styron, and the ethics of healing. AB - In this essay I discuss a passage from William Styron's memoir of his long struggle with chronic severe depression, from the standpoint of a Spinozian understanding of agency and self-worth. In this passage Styron relates how in hearing a piece of music he was abruptly struck by a recollection of "all the joys [his] house had known" and how this brought a realization that it would be wrong for him to kill himself: wrong because it would be an abandonment of those who had shared in those joys and a "desecration" of himself. He tells how this realization led him to admit himself to hospital for treatment and thereby to a slow and difficult recovery. This, I propose, illustrates the Spinozian idea that the value of an individual life is properly understood in terms of that individual's participation in the actualization of a shared value and that individual agency is empowered by the knowledge of such value. PMID- 24802647 TI - Special communication: Biotechnology from the perspective of Iranian law. PMID- 24802649 TI - Influence of allograft weight to recipient bodyweight ratio on outcome of cadaveric renal transplantation. AB - AIM: One of the factors that may affect survival and function of kidney graft is its functional mass. METHODS: In a prospective study, we investigated the impact of the ratio between donor kidney weight in grams and recipient bodyweight in kilograms (DKW/RBW) on creatinine clearance, inulin clearance, and proteinuria: 154 kidneys from deceased donors were weighed and the mean kidney weight was 227 +/- 59 g, the bodyweight of the recipients was 64 +/- 19 kg. RESULTS: This study showed significant lower values of modification of diet in renal disease (MDRD) in patients with DKW/RBW ratio 2.5 g/kg and between 2.5 and 4.5 g/kg compared with those with DKW/RBW ratio >4.5 g/kg as well as in patients with DKW/RBW ratio <3 g/kg and between 3 and 4 g/kg compared with those with DKW/RBW ratio >4 g/kg; moreover a random coefficient model showed a different time evolution in creatinine clearance values in patients with DKW/RBW <= 3 g/kg when compared with patients with DKW/RBW ratio >4 g/kg. There were significant lower values of inulin clearance in patients with DKW/RBW ratio between 2.5 and 4.5 g/kg compared with those with DKW/RBW ratio >4.5 g/kg at 12 post-transplant months and a significantly greater occurrence and earlier appearance of proteinuria in the recipients with DKW/RBW ratio <2.5 g/kg. DKW/RBW ratio did not influence DGF incidence and graft survival. Donor and recipient gender, number of acute rejection episodes and donor age also significantly influenced MDRD values. CONCLUSIONS: Measurements of graft weight as well as donor kidney and recipient body matching should be recommended as influencing renal function. PMID- 24802650 TI - Asymmetric flow field-flow fractionation in the field of nanomedicine. AB - Asymmetric flow field-flow fractionation (AF4) is a widely used and versatile technique in the family of field-flow fractionations, indicated by a rapidly increasing number of publications. It represents a gentle separation and characterization method, where nonspecific interactions are reduced to a minimum, allows a broad separation range from several nano- up to micrometers and enables a superior characterization of homo- and heterogenic systems. In particular, coupling to multiangle light scattering provides detailed access to sample properties. Information about molar mass, polydispersity, size, shape/conformation, or density can be obtained nearly independent of the used material. In this Perspective, the application and progress of AF4 for (bio)macromolecules and colloids, relevant for "nano" medical and pharmaceutical issues, will be presented. The characterization of different nanosized drug or gene delivery systems, e.g., polymers, nanoparticles, micelles, dendrimers, liposomes, polyplexes, and virus-like-particles (VLP), as well as therapeutic relevant proteins, antibodies, and nanoparticles for diagnostic usage will be discussed. Thereby, the variety of obtained information, the advantages and pitfalls of this emerging technique will be highlighted. Additionally, the influence of different fractionation parameters in the separation process is discussed in detail. Moreover, a comprehensive overview is given, concerning the investigated samples, fractionation parameters as membrane types and buffers used as well as the chosen detectors and the corresponding references. The perspective ends up with an outlook to the future. PMID- 24802651 TI - Pregnancy incidence and correlates in a clinical trial preparedness study, North West Province South Africa. AB - INTRODUCTION: Women in HIV prevention trials often must typically agree to avoid pregnancy. Regardless, some become pregnant. Screening tools predicting pregnancy risk could maximize trial safety and efficiency. OBJECTIVES: We assessed incidence and correlates of pregnancy among women at high HIV risk. METHODS: We enrolled sexually-active, HIV-negative women into an observational cohort (2008 2011). At enrollment demographic, contraceptive, reproductive, pregnancy intention and behavioural data were collected. Women reported if one or both partners wanted or intended for the couple to become pregnant. We measured gender role beliefs using a locally validated eight-point index. We tested HIV and pregnancy, and inquired about sexually transmitted infection symptoms (STIs) at enrollment and monthly. HIV testing included behavioural counselling and condom provision, but did not specifically counsel women to avoid pregnancy. Cox proportional hazard modelling evaluated the associations with pregnancy. The multivariate model included the following variables "Recent pregnancy attempts", "Gender Roles Beliefs", "Self-reported STIs" and "Age". RESULTS: We screened 1068 women and excluded (24.6%, 263/1068) who did not report risk behaviour. Non pregnant, non-sterilized women aged 18-35 (median = 21 years) enrolled (n = 438). Most women reported one partner (74.7%) and a prior live birth (84.6%). Median follow-up time was 6 months (range 0.7-15.5). Pregnancy incidence was 25.1 per 100 women-years (n = 57 pregnancies). Conservative beliefs on gender roles (Adjusted Hazard Ratio (aHR) 1.8; 95% confidence interval [CI] 1.1-2.9), recent pregnancy attempts (aHR 1.9; 95% CI 1.1-3.4) and baseline self-reported STI (aHR 2.5; 95% CI 1.4-4.4) were associated with increased incident pregnancy. Report of no pregnancy intention was associated with lowered pregnancy risk (aHR 0.3; 95% CI 0.1-0.7). CONCLUSIONS: We identified new and confirmed existing factors that can facilitate screening for pregnancy risk. PMID- 24802652 TI - High b value (2,000 s/mm2) diffusion-weighted magnetic resonance imaging in prostate cancer at 3 Tesla: comparison with 1,000 s/mm2 for tumor conspicuity and discrimination of aggressiveness. AB - OBJECTIVE: The objective of our study was to investigate tumor conspicuity and the discrimination potential for tumor aggressiveness on diffusion-weighted magnetic resonance imaging (DW-MRI) with high b value at 3-T. MATERIALS AND METHODS: The institutional review board approved this study and waived the requirement for informed consent. A total of 50 patients with prostate cancer (69 cancer foci; 48 in the PZ, 20 in the TZ, and one in whole prostate) who underwent multiparametric prostate MRI including DW-MRI (b values: 0, 1000 s/mm2 and 0, 2000 s/mm2) on a 3-T system were included. Lesion conspicuity score (LCS) using visual assessment (1 = invisible for surrounding normal site; 2 = slightly high intensity; 3 = moderately high; and 4 = very high) and tumor-normal signal intensity ratio (TNR) were assessed, and apparent diffusion coefficient (ADC, *10 3 mm2/s) of the tumor regions and normal regions were measured. RESULTS: Mean LCS and TNR at 0, 2000 s/mm2 was significantly higher than those at 0, 1000 s/mm2 (p<0.001 for both). In addition, ADC at both 0, 1000 and 0, 2000 s/mm2 was found to distinguish intermediate or high risk cancer with Gleason score >=7 from low risk cancer with Gleason score <=6 (p<0.001 for both). Furthermore, ADC of tumor regions correlated with Gleason score at both 0, 1000 s/mm2 (rho = -0.602; p<0.001) and 0, 2000 s/mm2 (rho = -0.645; p<0.001). CONCLUSIONS: For tumor conspicuity and characterization of prostate cancer on DW-MRI of 3-T MRI, b = 0, 2000 s/mm2 is more useful than b = 0, 1000 s/mm2. PMID- 24802653 TI - Systems pharmacology strategies for anticancer drug discovery based on natural products. AB - Cancer is a complex disease, known medically as malignant neoplasm. Natural products (NPs) play a very important role in anticancer drug discovery and a large number of NPs have been proven to have potential anticancer effects. Compared with newly synthesized chemical compounds, NPs show a favorable profile in terms of their absorption and metabolism in the body with low toxicity. Searching for multi-target natural drugs can be regarded as a solution to improve therapeutic efficacy and safety. In this work, we collected 104 cancer-associated target proteins from the Protein Data Bank. Based on the Universal Natural Products Database, all of the NPs were docked to 104 cancer-associated target proteins. Then we explored the potential of NPs and several herbs in anticancer drug discovery by using a network-based multi-target computational approach. The NPs with the most potential for anticancer drug discovery and their indications were predicted based on a docking score-weighted prediction model. We also explored the interactions between NPs and cancer target proteins to find the pathological networks, potential drug candidates and new indications. PMID- 24802655 TI - Emulating facial biomechanics using multivariate partial least squares surrogate models. AB - A detailed biomechanical model of the human face driven by a network of muscles is a useful tool in relating the muscle activities to facial deformations. However, lengthy computational times often hinder its applications in practical settings. The objective of this study is to replace precise but computationally demanding biomechanical model by a much faster multivariate meta-model (surrogate model), such that a significant speedup (to real-time interactive speed) can be achieved. Using a multilevel fractional factorial design, the parameter space of the biomechanical system was probed from a set of sample points chosen to satisfy maximal rank optimality and volume filling. The input-output relationship at these sampled points was then statistically emulated using linear and nonlinear, cross-validated, partial least squares regression models. It was demonstrated that these surrogate models can mimic facial biomechanics efficiently and reliably in real-time. PMID- 24802654 TI - A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. AB - BACKGROUND: Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. METHODS: Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to event endpoints. RESULTS: Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. CONCLUSIONS: GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes. PMID- 24802657 TI - Tolerability and pharmacokinetics of lobeglitazone, a novel peroxisome proliferator-activated receptor-gamma agonist, after a single oral administration in healthy female subjects. AB - BACKGROUND AND OBJECTIVES: Lobeglitazone is a recently approved peroxisome proliferator-activated receptor-gamma agonist for the treatment of type 2 diabetes mellitus in Korea. The purpose of this study was to investigate the pharmaco kinetic properties of lobeglitazone in healthy females and to compare these with historical data in healthy males. METHODS: This study was designed as a block-randomized, double-blind, placebo-controlled, parallel-group study. A single 2 or 4 mg oral dose of lobeglitazone or a placebo was randomly administered to 22 female subjects, and pharmacokinetic blood samples were obtained after dosing. Pharmacokinetic parameters were calculated by a non compartmental method, and the results were compared with those previously obtained from male subjects. Tolerability was assessed by clinical and laboratory parameters. RESULTS: During the study, a total of 28 adverse events (AEs) were observed in the lobeglitazone group (n = 16) and nine AEs in the placebo group (n = 6). Serious AEs or significant clinical changes were not observed. After oral administration, lobeglitazone was rapidly absorbed with the time to maximum plasma concentration (t(max)) ranging from 0.5 to 4.0 h. The mean (standard deviation) maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) for the 2 mg dose were 214.8 (56.4) ug/L and 2,251.3 (721.2) ug.h/L, respectively, and the corresponding values for the 4 mg dose were 310.0 (47.8) ug/L and 6,942.6 (1,778.9) ug.h/L, respectively. The ratios (95 % CIs) for the geometric means (female/male) of the C(max) and AUCinfinity were 1.23 (0.89-1.69) and 1.11 (0.73 1.68), respectively (2 mg), and 1.28 (1.01-1.63) and 2.36 (1.60-3.47), respectively (4 mg). CONCLUSION: Lobeglitazone was well-tolerated in healthy females. There was no sex difference for systemic lobeglitazone exposure at a 2 mg dose; however, female subjects showed greater systemic exposure than males after the administration of 4 mg of lobeglitazone. In spite of the pharmacokinetic difference, dose adjustment based on sex alone is not needed in clinical use because therapy should be individualized for each patient to achieve glycemic control. PMID- 24802656 TI - Recent advances in COPD disease management with fixed-dose long-acting combination therapies. AB - Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting beta2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD. PMID- 24802658 TI - Mechanisms and models of spinal cord stimulation for the treatment of neuropathic pain. AB - Spinal cord stimulation (SCS) is an established and cost-effective therapy for treating severe chronic pain. However, despite over 40 years of clinical practice and the development of novel electrode designs and treatment protocols, increases in clinical success, defined as the proportion of patients that experience 50% or greater self-reported pain relief, have stalled. An incomplete knowledge of the neural circuits and systems underlying chronic pain and the interaction of SCS with these circuits may underlie this plateau in clinical efficacy. This review summarizes prior work and identifies gaps in our knowledge regarding the neural circuits related to pain and SCS in the dorsal horn, supraspinal structures, and the Pain Matrix. In addition, this review discusses and critiques current experimental and computational models used to investigate and optimize SCS. Further research into the interactions between SCS and pain pathways in the nervous system using animal and computational models is a fruitful approach to improve this promising therapy. PMID- 24802659 TI - Force frequency structure below 1 Hz in chronic stroke: paretic arm control. AB - This study investigated force variability and frequency structure below 1 Hz to determine whether coupled bilateral training and neuromuscular stimulation facilitated force control in paretic arms. Fifteen chronic stroke participants received 9h of coupled bilateral movement training. Unilateral and bilateral force control tasks were administered before and after rehabilitation. Repeated measures ANOVAs were performed on the: (a) coefficient of variation and (b) absolute and relative power below 1 Hz in the paretic hand. Further, a multiple linear regression analysis determined the relationship between the coefficient of variation and frequency power. Three significant rehabilitation findings indicated: (a) reduced force variability across unilateral and bilateral force control conditions, (b) decreased absolute power in 0.09-0.41 Hz and 0.59-1.08 Hz whereas increased relative power in 0.59-1.08 Hz during unilateral force control, and (c) reduced absolute and relative power in 0.09-0.41 Hz that were associated with decreased variability during both unilateral and bilateral force control. Improved force variability in controlling unilateral paretic arms after training was attributed to less power below 0.41 Hz. Reorganization of the force frequency structure appears as a prominent component in force control improvements in paretic arms. PMID- 24802660 TI - A study on the photophysics of 9-amino-10-cyanoanthracene: probing its dual absorption and emission behavior. AB - The photophysics of a donor-acceptor substituted chromophore, 9-amino-10 cyanoanthracene (ACAN), has been investigated in polar and nonpolar solvents to understand its intriguing dual absorption and emission behavior. Steady-state and time-resolved fluorescence studies clearly indicate that the short wavelength emission band of ACAN arises from the higher excited singlet state, S2, while the longer wavelength emission band arises from the intramolecular charge transfer (ICT) state, S1. Interestingly, both these states can be populated by direct excitation from the ground state. Temperature dependent studies reveal a pronounced activation controlled nonradiative decay channel for the ICT state of ACAN. It is proposed that this activation controlled nonradiative de-excitation arises because of a large relative displacement and a cross-over of the potential energy (PE) surfaces of ACAN in the ground and the ICT states, as a result of different twist angles of the amino group in these two states. Qualitative PE diagrams have accordingly been presented to correlate and rationalize the observed results. The present study also brings to light the interesting excited state prototropic behavior of ACAN and the consequent modulation of the ICT emission that has not been reported in the literature so far. PMID- 24802661 TI - Structural and functional analysis of hypothetical and conserved proteins of Clostridium tetani. AB - The progress in biological technologies has led to rapid accumulation of microbial genomic sequences with a vast number of uncharacterized genes. Proteins encoded by these genes are usually uncharacterized, hypothetical, and/or conserved. In Clostridium tetani (C. tetani), these proteins constitute up to 50% of the expressed proteins. In this regard, understanding the functions and the structures of these proteins is crucially important, particularly in C. tetani, which is a medically important pathogen. Here, we used a variety of bioinformatics tools and databases to analyze 10 hypothetical and conserved proteins in C. tetani. We were able to provide a detailed overview of the functional contributions of some of these proteins in several cellular functions, including (1) evolving antibiotic resistance, (2) interaction with enzymes pathways, and (3) involvement in drug transportation. Among these candidates, we postulated the involvement of one of these hypothetical proteins in the pathogenic activity of tetanus. The structural and functional prediction of these proteins should serve in uncovering and better understanding the function of C. tetani cells to ultimately discover new possible drug targets. PMID- 24802663 TI - Ammonia photodissociation promoted by Si(100). AB - Using in situ X-ray photoelectron spectroscopy measurements after reaction, we show that hydrogen-terminated Si(100) perturbs the bonding of physisorbed NH3 enabling a photochemical decomposition pathway at wavelengths different from those characteristic of either the molecule in the gas phase or the semiconductor bandgap. UV illumination only of gas phase NH3 at partial pressures from 0.1 to 100 Torr produced a maximum at 10 Torr in the N surface coverage. This is in good agreement with a model of the radical production rate showing that at this pressure the gas density balances the flux of photons at the surface with energies sufficient to dissociate NH3. UV illumination of both the gas phase and the surface produced a monotonic increase in the N coverage with pressure as well as coverages that were 3-10 times higher than when only the gas phase was illuminated. The amine saturation coverage scaled with the UV fluence at 10 Torr and 75 degrees C, reaching 6.9 * 10(14) atoms/cm(2) (~1 N atom per Si surface atom) at 19 mW/cm(2) and 12 * 10(14) atoms/cm(2) (~1.8 N per Si) at 35 mW/cm(2). Monochromatic illumination showed that the wavelengths driving deposition were not correlated with the Si bandgap, but instead were roughly the same as gas phase photodissociation (lambda < 220 nm). The primary driving force to replace the hydrogen termination with amine groups was direct photodissociation of NH3 molecules whose electronic structure was perturbed by interaction with the surface. Amine groups enhanced the surface reaction of water present as a contaminant in the source gas. These results show that molecules in weakly bound surface states can have a dramatic impact on the photochemistry. PMID- 24802662 TI - Evidence for aldosterone-dependent growth of renal cell carcinoma. AB - The aim if this study was to investigate the hypothesis that K-RAS 4A is upregulated in a mineralocorticoid-dependent manner in renal cell carcinoma and that this supports the proliferation and survival of some renal cancers. Expression of the K-RAS in renal tumour tissues and cell lines was examined by real-time PCR and Western blot and mineralocorticoid receptor, and its gatekeeper enzyme 11beta-hydroxysteroid dehydrogenase-2 was examined by immunocytochemistry on a tissue microarray of 27 cases of renal cell carcinoma. Renal cancer cells lines 04A018 (RCC4 plus VHL) and 04A019 (RCC4 plus vector alone) were examined for the expression of K-RAS4A and for the effect on K-RAS expression of spironolactone blockade of the mineralocorticoid receptor. K-RAS4A was suppressed by siRNA, and the effect on cell survival, proliferation and activation of the Akt and Raf signalling pathways was investigated in vitro. K-RAS4A was expressed in RCC tissue and in the renal cancer cell lines but K-RAS was downregulated by spironolactone and upregulated by aldosterone. Spironolactone treatment and K-RAS suppression both led to a reduction in cell number in vitro. Both Akt and Raf pathways showed activation which was dependent on K-RAS expression. K-RAS expression in renal cell carcinoma is at least partially induced by aldosterone. Aldosterone supports the survival and proliferation of RCC cells by upregulation of K-RAS acting through the Akt and Raf pathways. PMID- 24802664 TI - Practical synthesis of natural plant-growth regulator 2-azahypoxanthine, its derivatives, and biotin-labeled probes. AB - We describe a practical, large-scale synthesis of the "fairy-ring" plant-growth regulator 2-azahypoxanthine (AHX), and its biologically active hydroxyl metabolite (AOH) and riboside derivative (AHXr). AHXr, a biosynthetic intermediate, was synthesized from inosine via a biomimetic route. Biotinylated derivatives of AHX and AHXr were also synthesized as probes for mechanistic studies. PMID- 24802665 TI - Comment on Kalfon et al.: Tight computerized versus conventional glucose control in the ICU: a randomized controlled trial. PMID- 24802666 TI - Enabling speech in ICU patients during mechanical ventilation. PMID- 24802667 TI - Pediatric ophthalmoscopy by video laryngoscope. PMID- 24802668 TI - Solubilization of n-alkylbenzenes into gemini surfactant micelles in aqueous medium. AB - Solubilization of benzene, toluene, ethylbenzene, n-propylbenzene, n butylbenzene, and n-pentylbenzene into micelles of decanediyl-1-10 bis(dimethyltetradecylammonium bromide) (14-10-14,2Br(-)) has been investigated in the temperature range from 288.2 to 308.2 K. The equilibrium concentrations of all the solubilizates are determined spectrophotometrically. The concentration of the solubilizates remains constant below the critical micelle concentration (cmc) and increases linearly with an increase in 14-10-14,2Br(-) concentration above the cmc. Compared to the mother micelle, the solubilized micelles indicate much larger hydrodynamic diameters, which are determined by dynamic light scattering. Therefore, the Gibbs energy change for the solubilization of n-alkylbenzenes has been evaluated by the partitioning of the solubilizates between the aqueous and micellar phases. Furthermore, the enthalpy and entropy changes for the solubilization could be calculated from temperature dependence of the Gibbs energy change. From the thermodynamic parameters, it is found that the solubilization for the present system is entropy-driven and that the location of the solubilizates moves into the inner core of the micelle with an elongation of their alkyl chains. The movement on the location is also supported by the results of absorption spectra, Fourier transform infrared (FTIR) spectra, and two dimensional nuclear Overhauser effect spectroscopy (2-D NOESY). PMID- 24802669 TI - Severe metabolic acidosis in adult patients with Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) leads to progressive paresis, respiratory failure and premature death. Long-term positive pressure ventilation can improve quality of life and survival, but previously unrecognized complications may arise. We analyzed the characteristics of severe metabolic acidosis occurring in 8 of 55 DMD patients, of 20-36 years of age, observed over a 5-year period. All patients were on positive pressure ventilation and were being treated for chronic constipation. Before admission, they had had a reduced intake of fluids and food. Upon examination, they were severely ill, dyspneic and suffering from abdominal discomfort. Metabolic acidosis with a high anion gap was noted in 5 of the 8 patients and with a normal anion gap in the other 3. They all recovered after the administration of fluids and nutrition, the regulation of bowel movements and treatment with antibiotics, as appropriate. Metabolic acidosis is a life threatening, potentially preventable complication in older DMD patients. Early recognition, subsequent administration of fluids, nutrition and antibiotics and regulation of bowel movements seem to be essential. PMID- 24802671 TI - Ab initio molecular dynamics simulations of structural changes associated with the incorporation of fluorine in bioactive phosphate glasses. AB - Phosphate-based bioactive glasses containing fluoride ions offer the potential of a biomaterial which combines the bioactive properties of the phosphate glass and the protection from dental caries by fluoride. We conduct accurate first principles molecular dynamics simulations of two compositions of fluorinated phosphate-based glass to assess its suitability as a biomaterial. There is a substantial amount of F-P bonding and as a result the glass network will be structurally homogeneous on medium-range length scales, without the inhomogeneities which reduce the bioactivity of other fluorinated bioactive glasses. We observe a decrease in the network connectivity with increasing F content, caused by the replacement of bridging oxygen atoms by non-bridging fluorine atoms, but this decrease is small and can be opposed by an increase in the phosphate content. We conclude that the structural changes caused by the incorporation of fluoride into phosphate-based glasses will not adversely affect their bioactivity, suggesting that fluorinated phosphate glasses offer a superior alternative to their silicate-based counterparts. PMID- 24802672 TI - Neutral sulfur nucleophiles: synthesis of thioethers and thioesters by substitution reactions of N-heterocyclic carbene boryl sulfides and thioamides. AB - Newly discovered boryl sulfides and N-borylthioamides are shown to serve as neutral sources of sulfur nucleophiles in substitutions reactions. For example, heating of diMe-Imd-BH(SPh)2 with benzyl bromides, primary bromides, or acid chlorides provides the corresponding thioethers or thioesters in high yields. Likewise, N-phenyltetrazole thioethers/esters are made from a readily available N borylthionotetrazole. The formation of the boryl sulfide and its onward nucleophilic substitution can be telescoped down to a one-pot reaction whose components are an NHC-borane (NHC-BH3), a disulfide, and an electrophile. PMID- 24802670 TI - MiR-135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF-beta/BMP signaling. AB - Several transcription factors (TFs) have been implicated in neuroectoderm (NE) development, and recently, the TF PAX6 was shown to be critical for human NE specification. However, microRNA networks regulating human NE development have been poorly documented. We hypothesized that microRNAs activated by PAX6 should promote NE development. Using a genomics approach, we identified PAX6 binding sites and active enhancers genome-wide in an in vitro model of human NE development that was based on neural differentiation of human embryonic stem cells (hESC). PAX6 binding to active enhancers was found in the proximity of several microRNAs, including hsa-miR-135b. MiR-135b was activated during NE development, and ectopic expression of miR-135b in hESC promoted differentiation toward NE. MiR-135b promotes neural conversion by targeting components of the TGF beta and BMP signaling pathways, thereby inhibiting differentiation into alternate developmental lineages. Our results demonstrate a novel TF-miRNA module that is activated during human neuroectoderm development and promotes the irreversible fate specification of human pluripotent cells toward the neural lineage. PMID- 24802674 TI - Morning glory disc anomaly with Chiari type I malformation. AB - Morning glory disc anomaly is a rare optic nerve dysplasia associated with various neovascular abnormalities. Due to these associations, children with morning glory disc anomaly have brain imaging and angiography to detect other congenital defects. The authors report the case of an infant with morning glory disc anomaly and coexisting Chiari type I malformation. PMID- 24802673 TI - A new class of protein cancer biomarker candidates: differentially expressed splice variants of ERBB2 (HER2/neu) and ERBB1 (EGFR) in breast cancer cell lines. AB - Combined RNA-Seq and proteomics analyses reveal striking differential expression of splice isoforms of key proteins in important cancer pathways and networks. Even between primary tumor cell lines from histologically similar inflammatory breast cancers, we find striking differences in hormone receptor-negative cell lines that are ERBB2 (Her2/neu)-amplified versus ERBB1 (EGFR) over-expressed with low ERBB2 activity. We have related these findings to protein-protein interaction networks, signaling and metabolic pathways, and methods for predicting functional variants among multiple alternative isoforms. Understanding the upstream ligands and regulators and the downstream pathways and interaction networks for ERBB receptors is certain to be important for explanation and prediction of the variable levels of expression and therapeutic responses of ERBB+tumors in the breast and in other organ sites. Alternative splicing is a remarkable evolutionary development that increases protein diversity from multi-exonic genes without requiring expansion of the genome. It is no longer sufficient to report the up- or down-expression of genes and proteins without dissecting the complexity due to alternative splicing. This article is part of a Special Issue entitled: 20Years of Proteomics in memory of Viatliano Pallini. Guest Editors: Luca Bini , Juan J. Calvete, Natacha Turck, Denis Hochstrasser and Jean-Charles Sanchez. PMID- 24802676 TI - Pertussis - an old disease, new challenges. PMID- 24802675 TI - Sub-urothelial polyp enucleation resection and urothelial auto-augmentation cystoplasty: a simple method for bladder exstrophy-epispadias complex reconstruction in bladder plate polyposis. AB - OBJECTIVES: To report the results of a novel technique of sub-urothelial polyp enucleation resection (SUPER) and urothelial auto-augmentation cystoplasty (UAAC) in patients with bladder exstrophy and polyposis plate. METHODS: Twenty-eight patients with bladder exstrophy covered by plate polyposis were referred for further management. From these, 12 patients had undergone SUPER, UAAC technique, and subsequent bladder closure. In this technique, the urothelium covering the polyps was utilized as tissue for auto-augmentation cystoplasty. Sixteen patients had been operated by simple polyps' excision and bladder closure. Biopsies of polyps were obtained in both groups at the time of closure for pathological evaluations. The bladder plate was measured pre-and post-bladder plate augmentation. The patients were evaluated every 3 months for 1 year and biannually thereafter for urinary continence and social dryness. Dry period of >3 h during the day with or without nocturnal incontinence was defined as social dryness. RESULTS: All patients experienced an uneventful postoperative period. No sign of metaplasia or dysplasia was observed in the histological and cystoscopy evaluations. These findings suggest that neither polyp recurrence nor bladder tumor development has occurred in any of the groups. The urinary continence improved significantly in the polyp's urothelial coverage augmentation cystoplasty technique (66.7%), while 31.3% of patients in simple closure technique achieved continence. Significantly higher mean bladder capacity was obtained in the augmentation group (190 +/- 38 ml) and (119 +/- 21 ml), respectively. Postoperative mild hydronephrosis and vesicoureteral reflux were significantly lower in auto-augmentation technique. CONCLUSION: The final clinical outcome of children with bladder exstrophy polyposis is promising. The combined SUPER and UAAC technique is feasible, safe and reproducible option for bladder exstrophy-epispadias complex (BEEC) patients with bladder plate polyposis. However, it will add one supplementary operation to the single or staged bladder reconstruction. These patients may warrant further surveillance with histopathological evaluations during the adult life. PMID- 24802678 TI - A combined computational and experimental study of the [Co(bpy)3](2+/3+) complexes as one-electron outer-sphere redox couples in dye-sensitized solar cell electrolyte media. AB - A combined experimental and computational investigation conducted to understand the nature of the interactions between cobalt II/III redox mediators ([Co(bpy)3](2+/3+)) and their impact on the performance of the corresponding dye sensitized solar cells (DSCs) is reported. The fully optimized equilibrium structures of cobalt(II/III)-tris-bipyridine complexes in the gas phase and acetonitrile solvent are obtained by the density functional B3LYP method using LanL2DZ and 6-31G(d,p) basis sets. The harmonic vibrational frequencies, infrared intensities and Raman scattering activities of the complexes are also calculated. The scaled computational vibrational wavenumbers show very good agreement with the experimental values. Calculations of the electronic properties of the complexes are also performed at the TD-B3LYP/6-31G(p,d)[LanL2DZ] level of theory. Detailed interpretations of the infrared and Raman spectra of the complexes in different phases are reported. Detailed atomic orbital coefficients of the frontier molecular orbitals and their major contributions to electronic excitations of the complexes are also reported. These results are in good agreement with the experimental electrochemical values. Marcus diagram is derived for the electron transfer reaction Co(II) + D35(+)-> Co(III) + D35 using the Co-N bond length as a reaction coordinate. PMID- 24802677 TI - The impact of parental knowledge and tanning attitudes on sun protection practice for young children in Germany. AB - Public health campaigns have improved knowledge on UVR-associated skin cancer risk and increased sun protection awareness. However, tanned skin is still a common beauty ideal. The relationship between knowledge, attitudes and protective behavior is not fully understood yet. A population-based survey was thus performed in the district of Erlangen involving 2,619 parents of 3- to 6-year old children. By means of a self-administered standardized questionnaire parental knowledge about risk factors for skin cancer, their attitudes towards tanning and details of protective measures taken for their children were assessed. The study analyzed specifically the impact of parental tanning attitudes on sun-protective measures for their children while controlling for parental knowledge about skin cancer risk factors. While parental knowledge was significantly (inversely) associated with agreement to the statement "Tanned skin is healthy skin", this was not the case for "Tanning makes me look better". Overall, tanning affirmative attitudes were inversely associated with protective measures taken for the children, whereas parental knowledge had a positive impact on sun protection at the beach only. Multivariable analyses provided evidence for an effect of parental attitude on protective behavior independent of parental knowledge. Tanning attitudes and tanned skin as the misguided ideal of beauty need to be addressed in future public health campaigns to enhance the effectiveness of preventive activities in changing sun protective behavior. PMID- 24802679 TI - Introduction. PMID- 24802680 TI - Writing life. AB - SUMMARY In her 1994 essay "Writing Life," Beth Brant discusses the role of writing in her life, the circumstances that surrounded her writing and editing endeavours, and her relationships with loved ones. Issues of racism, homophobia, and class oppression are explored through writing. PMID- 24802681 TI - A state of mind in the garden. AB - SUMMARY Nicole Brossard reflects on the writing process in relation to self, narrative voice, language, translation, lesbian desire and sexuality, genre blurring, memory, and the cultural milieu. She explores her resistant negotiations of traditional autobiographical modes of writing. PMID- 24802682 TI - Voices in the outer room. AB - SUMMARY An argument (in the form of a demonstration) for the development of a queer aesthetic, the essay asks whether it is our charge as lesbian writers to hold a mirror up to our experience, to "self-disclose" (so often such narratives change nothing but succeed in flattening our lives), or to find the form that will answer to queer habits of being, radical sensibilities and ideologies. The essay takes three different liminal spaces as its ground-a sickroom, a conversation on an airplane, and a Catholic confessional-to explore my own aesthetic process, the role played by randomness and interruption in that process, the complex presence of external and internalized (dis)embodied voices in my self-writing, and the desire through my work to create what I call "disruptive beauty." PMID- 24802683 TI - k/not theory. AB - SUMMARY This paper discusses the role of the personal experience in the writing process. Using a personal/journal writing style the author charts the journey of a recent play Skin into Rainbows from first draft to production. The author plays with the constructs of writing and juxtapositions these against a form of Knot Theory to measure their value, playing with math and language techniques in a search for truth. PMID- 24802684 TI - To Grandmother's House I Go. AB - SUMMARY Within the mode of "biomythography" that owes its identification as a genre to Audre Lorde's ZAMI,Jewelle Gomez examines her own writing processes. Her explorations revolve around her work-in-process about her great grandmother's life. Issues of truth, memory, history, race, and community are considered. The author also discusses the embodied nature of writing. PMID- 24802685 TI - Karla jay. AB - SUMMARY Karla Jay discusses Tales of the Lavender Menace: A Memoir of Liberation (published in 1999). She engages the connections between the personal and the political in her memoir. The reception by readers, family relations, the history of the feminist movement, racism, and homophobia are also deliberated in relation to the writing "process" and the motivations to write. PMID- 24802686 TI - Memories in flesh and marble. AB - SUMMARY This piece is about writing and having children and the places they occupy in my life. It describes a sense of isolation, of being cut off from others like me and my efforts to recreate connections, in fiction and in flesh. I explain how I came to be the mother of twins and recount some of the battles fought with doctors, midwives and strangers, as well as between my lover and myself. Lesbian motherhood may no longer be an oxymoron, but it is an awkward, uneasy category open to endless, hostile questioning from outsiders. Better to write our own stories, around lived contradictions, than accept our inscription under erasure on doctors' forms and birth certificates. PMID- 24802687 TI - Writing my-self-body. AB - SUMMARY The author traces her changes in attitude toward her body, sexuality, and public disclosure of her lesbianism through reflections upon her writings as the years pass. She addresses the connections between the body and writing, and celebrates the community of lesbian writers who push outward the boundaries of language to assert that there are no boundaries. PMID- 24802688 TI - A.d., a memoir. AB - SUMMARY These excerpts are reprinted from Kate Millett's A.D., A Memoir,a book in which Millett reflects upon her early life and her lifelong deep love for her Aunt Dorothy. Aunt Dorothy was the benefactor who financed Millett's Oxford education; she died in 1984 without ever accepting Millett's choice of lifestyle. As well as deliberating the devastating effects of homophobia, Millett contemplates several of her books and discusses the writing process, the circumstances surrounding the writing, and the reception of her books by her Aunt Dorothy. PMID- 24802689 TI - Shani mootoo. AB - SUMMARY Shani Mootoo discusses her creative process, with a particular focus on her novel Cereus Blooms at Night. She elaborates on the writing process in relation to other forms of art, and explores the relationship of her characters in Cereus Blooms to her own life experiences. PMID- 24802690 TI - The truth about writing/writing about the truth. AB - SUMMARY The essay examines how one writer turns her life experience into fiction, and explores the question so often asked of fiction writers, "Is that story really true?" Author Leslea Newman uses her own work to show how the experience of losing her good friend, the poet Gerard Rizza, to AIDS, translated into a short story, a children's book and a novel told in fifty poems. Each form tells a different sort of truth about the experience the author went through in her process of assimilating her grief into her life and her work. PMID- 24802692 TI - Mozart's Laugh. PMID- 24802691 TI - Striving to be selfish. AB - SUMMARY In "Striving to Be Selfish," Ruthann Robson explores the different kinds of selfishness it takes to be a writer and a dyke, especially the necessary focus on the higher self. Distinguishing the writer from the author (and the dyke from the lesbian), she argues that there is an almost spiritual dimension to the practices of writing and sex. PMID- 24802693 TI - A truth of being. AB - SUMMARY In an exploration of what it means to write from a lesbian perspective, Vanessa Scrivens examines the process and the power of self-writing. She states that writing gives one the strength to give birth to the inner conscience and the courage to look it in the eye. A short piece of autobio/fictional writing that follows this discussion will hopefully give an example of the true potential that self-writing has. PMID- 24802694 TI - The unfinished moon. AB - SUMMARY The author explores several questions. She asks: What does it mean to exist as a lesbian writer given that we have no lesbian homeland or ancestral tongue, little presence in the external narrative matrix, a scarcity of close friendships among ourselves, a lack of contact with younger lesbian writers, and an erasure of our lesbianism due to heterosexuals relating to us as "single" women in the literary community? If the intense individuation processes of establishing our lesbian identities are what we share more than our diverse lifestyles as lesbians-how do we enable a feminist-lesbian literary community and tradition to flourish? PMID- 24802695 TI - Why writers make lousy lovers. AB - SUMMARY Jess Wells takes a light-hearted look at the pit-falls of being in love with a writer, describing the difficulties with time and reality. Wells then encourages lesbian authors to develop diversity among their art forms,Income and inspiration sources. She wraps up with a call for lesbian writers to cultivate discipline and gratitude. PMID- 24802696 TI - Nobody ever asked me if I had an agent. AB - SUMMARY There are many ways to write about/think about how I became an author. I like to think I chose this way because I had a 'hidden talent' that was brought forth by being in another country. This story could also be the story of a divorce, a yearning for adventure, the love of a genre, the quest for identity. I like to tell the story in this way because I like the idea that we all have hidden talents that are revealed by circumstance. And I like to urge people to do radical things. PMID- 24802697 TI - Pyroglutamylated amyloid-beta peptide reverses cross beta-sheets by a prion-like mechanism. AB - The amyloid hypothesis causatively relates the fibrillar deposits of amyloid beta peptide (Abeta) to Alzheimer's disease (AD). More recent data, however, identify the soluble oligomers as the major cytotoxic entities. Pyroglutamylated Abeta (pE Abeta) is present in AD brains and exerts augmented neurotoxicity, which is believed to result from its higher beta-sheet propensity and faster fibrillization. While this concept is based on a set of experimental results, others have reported similar beta-sheet contents in unmodified and pyroglutamylated Abeta, and slower aggregation of pE-Abeta as compared to unmodified Abeta, leaving the issue unresolved. Here, we assess the structural differences between Abeta and pE-Abeta peptides that may underlie their distinct cytotoxicities. Transmission electron microscopy identifies a larger number of prefibrillar aggregates of pE-Abeta at early stages of aggregation and suggests that pE-Abeta affects the fibrillogenesis even at low molar fractions. Circular dichroism and FTIR data indicate that while the unmodified Abeta readily forms beta-sheet fibrils in aqueous media, pE-Abeta displays increased alpha-helical and decreased beta-sheet propensity. Moreover, isotope-edited FTIR spectroscopy shows that pE-Abeta reverses beta-sheet formation and hence fibrillogenesis of the unmodified Abeta peptide via a prion-like mechanism. These data provide a novel structural mechanism for pE-Abeta hypertoxicity; pE-Abeta undergoes faster formation of prefibrillar aggregates due to its increased hydrophobicity, thus shifting the initial stages of fibrillogenesis toward smaller, hypertoxic oligomers of partial alpha-helical structure. PMID- 24802700 TI - Noninvasive brain-computer interfaces for augmentative and alternative communication. AB - Brain-computer interfaces (BCIs) promise to provide a novel access channel for assistive technologies, including augmentative and alternative communication (AAC) systems, to people with severe speech and physical impairments (SSPI). Research on the subject has been accelerating significantly in the last decade and the research community took great strides toward making BCI-AAC a practical reality to individuals with SSPI. Nevertheless, the end goal has still not been reached and there is much work to be done to produce real-world-worthy systems that can be comfortably, conveniently, and reliably used by individuals with SSPI with help from their families and care givers who will need to maintain, setup, and debug the systems at home. This paper reviews reports in the BCI field that aim at AAC as the application domain with a consideration on both technical and clinical aspects. PMID- 24802701 TI - Selecting protein families for environmental features based on manifold regularization. AB - Recently, statistics and machine learning have been developed to identify functional or taxonomic features of environmental features or physiological status. Important proteins (or other functional and taxonomic entities) to environmental features can be potentially used as biosensors. A major challenge is how the distribution of protein and gene functions embodies the adaption of microbial communities across environments and host habitats. In this paper, we propose a novel regularization method for linear regression to adapt the challenge. The approach is inspired by local linear embedding (LLE) and we call it a manifold-constrained regularization for linear regression (McRe). The novel regularization procedure also has potential to be used in solving other linear systems. We demonstrate the efficiency and the performance of the approach in both simulation and real data. PMID- 24802699 TI - Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures. AB - Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence-based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in gamma-aminobutyric acid (GABA)ergic neurotransmission between the immature and mature brain, and trauma-induced alterations in the function of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform-specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24802703 TI - Population attributable risk from obesity to arthritis in the Canadian Population Health Longitudinal Survey 1994-2006. AB - OBJECTIVES: To examine the relationship, potential associations, and determine the population attributable risk percent (PAR%) between obesity and arthritis in Canadians aged 40 to 79 from 1994 to 2006. METHODS: Our study population were the 17 276 respondents in the Canadian National Population Longitudinal Health Survey data, from 1994/1995 to 2006/2007. RESULTS: Respondents who were overweight and obese increased over time, with arthritis increasing from 20% to 30% over the study period. Women reported a 10% higher prevalence of arthritis than men. Men aged 70-79 and women aged 60-69 were most likely to report arthritis. PAR% calculations indicated that 3.8% of arthritis in 1994 and 7.5% in 2006 in the overall population could be attributed to overweight, while the proportion of arthritis attributable to obesity increased from 7.0% in 1994 to 10.2% in 2006. CONCLUSIONS: Increasing overweight/obesity of the population was positively associated with arthritis in Canada for both sexes. In addition to the many other beneficial health effects, reducing levels of excess weight may result in either less arthritis or fewer manifestations of symptoms of arthritis or both. PMID- 24802704 TI - Bitter tastants alter gastric-phase postprandial haemodynamics. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Since Greco-Roman times bitter tastants have been used in Europe to treat digestive disorders, yet no pharmacological mechanism has been identified which can account for this practice. This study investigates whether the bitter tastants, gentian root (Gentian lutea L.) and wormwood herb (Artemisia absinthium L.), stimulate cephalic and/or gut receptors to alter postprandial haemodynamics during the gastric-phase of digestion. MATERIALS AND METHODS: Normal participants ingested (1) 100 mL water plus capsules containing either cellulose (placebo-control) or 1000 mg of each tastant (n=14); or (2) 100mL of water flavoured with 500 or 1500 mg of each tastant (a) gentian (n=12) and (b) wormwood (n=12). A single beat-to-beat cardiovascular recording was obtained for the entire session. Pre/post-ingestion contrasts with the control were analysed for (1) the encapsulated tastants, in the "10 to 15" minute post ingestion period, and (2) the flavoured water in the "5 to 10" minute post ingestion period. RESULTS: Water, the placebo-control, increased cardiac contraction force and blood pressure notwithstanding heart rate decreases. Encapsulated tastants did not further alter postprandial haemodynamics. In contrast gentian (500 and 1500 mg) and wormwood (1500 mg) flavoured water elicited increased peripheral vascular resistance and decreased cardiac output, primarily by reducing stroke volume rather than heart rate. CONCLUSIONS: Drinking 100mL water elicits a pressor effect during the gastric-phase of digestion due to increased cardiac contraction force. The addition of bitter tastants to water elicits an additional and parallel pressor effect due to increased peripheral vascular resistance; yet the extent of the post-prandial blood pressure increases are unchanged, presumably due to baroreflex buffering. The vascular response elicited by bitter tastants can be categorised as a sympathetically-mediated cephalic-phase response. A possible mechanism by which bitter tastants could positively influence digestion is altering gastric-phase postprandial haemodynamics and supporting postprandial hyperaemia. PMID- 24802705 TI - Student-run clinics in Canada: an innovative method of delivering interprofessional education. AB - The age of siloed healthcare delivery is coming to an end. Research demonstrates that interprofessional collaboration (IPC), the provision of comprehensive services to patients by multiple health providers who collaborate within and across settings, improves the efficiency of the healthcare system, work environments, and patient outcomes. However, developing IPC skills requires training, often referred to as interprofessional education (IPE). This report aims to describe an innovation in IPE: student-run clinics (SRCs). SRCs are organizations composed of students from various disciplines who collaboratively plan and deliver healthcare and health promotion. Recent trends in Canadian SRCs are contrasted with those in the United States. The literature supporting SRCs as a method of delivering IPE, as well as the benefits conferred to patients, students, and communities at large is explored. It is clear that SRCs in Canada are an evolving approach to IPE and are filling a previously undiscovered healthcare niche. PMID- 24802706 TI - The courage to be a geriatrician. AB - Nursing homes can be grim, frightening places to many who encounter them for the first time. Part of this reaction may come from the way nursing homes remind us of our own frailty, the limits of our hopes of never-ending independence and self determination. This essay details one physician's struggle to find value in the lives of his nursing home residents, working against a cultural insistence that life's meaning and value depend upon one's actions and achievements. Searching for and finding meaning that transcends the accomplishments and failures of life, that out-survives a failing mind and body is what allowed this physician to find the courage to resist his prejudices against the elderly and infirm. This courage to insist that life is of sufficient value as is, regardless of human ability, is what theologian Paul Tillich calls "the courage to be." PMID- 24802707 TI - [CpRu]-catalyzed carbene insertions into epoxides: 1,4-dioxene synthesis through S(N)1-like chemistry with retention of configuration. AB - Rather than lead to the usual deoxygenation pathway, metal carbenes derived from alpha-diazo-beta-ketoesters undergo three-atom insertions into epoxides using a combination of 1,10-phenanthroline and [CpRu(CH3CN)3][BAr(F)] as the catalyst. Original 1,4-dioxene motifs are obtained as single regio- and stereoisomers. A perfect syn stereochemistry (retention, e.r. up to 97:3) is observed for the ring opening, which behaves as an S(N)1-like transformation. PMID- 24802708 TI - miR-129-3p, as a diagnostic and prognostic biomarker for renal cell carcinoma, attenuates cell migration and invasion via downregulating multiple metastasis related genes. AB - PURPOSE: Downregulation of miRNA expression has been identified as a novel feature of renal cell carcinoma (RCC). Recently, miR-129-2 is well known to be frequently reduced by DNA methylation and has anti-tumor effects in various tumors but so far not in RCC. The aim of this study was to investigate the clinical significance and the role of it in RCC. METHODS: The expression levels of miR-129-3p and miR-129-5p, two mature products of miR-129-2, were determined by real-time quantitative reverse transcription PCR in 69 cases of paired different kidney tumors and normal tissues and clear cell RCC (ccRCC) cell lines. The roles of them in RCC cells were assessed by functional analyses. Protein expression was detected by Western blot. RESULTS: miR-129-3p, but not miR-129-5p, was widely attenuated in human ccRCC, and chromophobe RCC. miR-129-3p could yield 73.5 % accuracy in discriminating ccRCCs from normal tissues. The relative miR 129-3p expression significantly differed between malignant and benign kidney tumors. Importantly, low miR-129-3p levels were associated with short disease free and overall survival. Ectopic expression of miR-129-3p robustly impaired RCC cell migratory and invasive properties, but had no impact on cell viability and cell cycle distribution. Finally, miR-129-3p decreased multiple metastasis related genes in RCC cells, including SOX4, phosphorylation of focal adhesion kinase and MMP-2/9 expression. CONCLUSIONS: miR-129-3p may act as a promising diagnostic biomarker for discriminating ccRCC from benign tumors and normal tissues and an independent prognostic biomarker in ccRCC. miR-129-3p may exert its anti-metastatic function through modulating multiple targets. PMID- 24802709 TI - A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns. AB - The MLH1 c.2252_2253delAA mutation was found in 11 unrelated families from a restricted area south-west of Turin among 140 families with mutations in the mismatch repair genes. The mutation is located in the highly conserved C-terminal region, responsible for dimerization with the PMS2 protein. Twenty-five tumour tissues from 61 individuals with the c.2252_2253delAA mutation were tested for microsatellite instability (MSI) and protein expression. We compared the clinical features of these families versus the rest of our cohort and screened for a founder effect. All but one tumours showed the MSI-high mutator phenotype. Normal, focal and lack of MLH1 staining were observed in 16, 36 and 48 % of tumours, respectively. PMS2 expression was always lost. The mutation co segregated with Lynch syndrome-related cancers in all informative families. All families but one fulfilled Amsterdam criteria, a frequency higher than in other MLH1 mutants. This was even more evident for AC II (72.7 vs. 57.5 %). Moreover, all families had at least one colon cancer diagnosed before 50 years and one case with multiple Lynch syndrome-related tumours. Interestingly, a statistically significant (p = 0.0057) higher frequency of pancreatic tumours was observed compared to families with other MLH1 mutations: 8.2 % of affected individuals versus 1.6 %. Haplotype analysis demonstrated a common ancestral origin of the mutation, which originated about 1,550 years ago. The mutation is currently classified as having an uncertain clinical significance. Clinical features, tissue analysis and co-segregation with disease strongly support the hypothesis that the MLH1 c.2252_2253delAA mutation has a pathogenic effect. PMID- 24802710 TI - Regulation of keratinocyte differentiation by O-GlcNAcylation. AB - BACKGROUND: O-linked beta-N-acetylglucosamine (O-GlcNAc) modification is one of the posttranslational modification, emerging as an important regulatory mechanism in various cellular events. OBJECTIVE: We attempted to investigate whether O GlcNAcylation is involved in keratinocyte differentiation. METHODS: Immunohistochemistry and Western blot were performed to demonstrate O GlcNAcylation in keratinocyte differentiation. RESULTS: During calcium-induced keratinocyte differentiation, overall O-GlcNAcylation was decreased in a temporal manner. We focused our attention on transcription factor Sp-1, which is implicated in keratinocyte differentiation. Total Sp-1 level did not change during keratinocyte differentiation. However, O-GlcNAcylated Sp-1 was decreased in a keratinocyte differentiation-dependent manner. Interestingly, transcriptional activity of Sp-1, in terms of involucrin and loricrin promoter activities, was markedly increased by overexpression of O-GlcNAcase (OGA). In addition, membrane permeable non-O-GlcNAcylated Sp-1 did show transcriptional activity, while membrane permeable O-GlcNAcylated Sp-1 did not, suggesting O GlcNAcylated Sp-1 is an inactive form in keratinocyte differentiation. CONCLUSION: Our results reveal that O-GlcNAcylation is a dynamic regulatory mechanism for keratinocyte differentiation. PMID- 24802711 TI - EGb-761 prevents ultraviolet B-induced photoaging via inactivation of mitogen activated protein kinases and proinflammatory cytokine expression. AB - BACKGROUND: EGb-761 is an antioxidant and anticarcinogen; however, its role as a photoprotector remains unknown. OBJECTIVE: To determine whether EGb-761 photoprotects human dermal fibroblasts and BALB/c mice skin against ultraviolet B (UVB) light irradiation. METHODS: To simulate chronic photodamage, shaved BALB/c mice were exposed to UVB irradiation (90mJ/cm(2)) thrice weekly for 3 months. EGb 761 (2mg/cm(2)) was topically applied 1h before irradiation to evaluate its effect. The mechanisms by which EGb-761 protects the skin from photodamage were evaluated by immunohistochemical analysis, enzyme-linked immunosorbent assay (ELISA), and Western blotting. RESULTS: In BALB/c mice, the signs of photoaging or photodamage, such as coarse wrinkle formation, epidermal hyperplasia, and elastic fiber degeneration, markedly reduced with the topical application of EGb 761. Western blot and ELISA revealed that the activation of MMP-1 in cultured fibroblasts markedly diminished after pretreatment with EGb-761. In addition, EGb 761 inhibited UVB-induced overexpression by the fibroblasts of the proinflammatory cytokines, such as interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha. The phosphorylation of the mitogen-activated protein kinase (MAPK) signal transduction pathway components, including extracellular signal-regulated kinase, C-Jun N-terminal kinase, and p38, which are induced by UV irradiation, was significantly inhibited in vivo and in vitro. EGb-761 also diminished the generation of UVB-induced reactive oxygen species (ROS). CONCLUSIONS: EGb-761 photoprotects mice and cultured fibroblasts, inhibits the UVB-induced phosphorylation of MAPK pathway components, and reduces the expression of the proinflammatory cytokines by suppressing ROS generation. Thus, topically applied EGb-761 may be a promising photoprotective agent. PMID- 24802712 TI - Induction of cytotoxic T cells as a novel independent survival factor in malignant melanoma with percutaneous peptide immunization. AB - BACKGROUND: Malignant melanoma (MM) often shows multiple chemo-resistance, leading to poor prognosis of the patients. Therapeutic anti-cancer vaccination may be a feasible way to prolong the survival of patients. We have demonstrated that application of antigenic peptides via the tape-stripped, horny layer-removed skin, known as percutaneous peptide immunization (PPI), induces tumor cell specific cytotoxic T lymphocytes (CTLs) in rodents and humans. OBJECTIVE: To evaluate clinical significance of PPI in advanced MM patients. METHODS: We performed PPI in 59 patients undergoing advanced MM with Melan-A, tyrosinase, MAGE-2, MAGE-3 and gp-100 peptides based on HLA typing in individuals. The induction of CTLs was assessed by the tetramer or pentamer flow cytometry in 35 patients. Patients showing positive CTL responses to all antigens were defined as complete responder (n=18), and those showing negative responses to at least one applied antigen were classified as incomplete responder (n=17). The primary endpoint of the study was overall survival (OS). For statistical analysis, log rank test, univariate and multivariate Cox proportional hazard model were used. RESULTS: OS of the complete responders was longer than that of the incomplete responders (median survival time: 55.8 vs 20.3 months, log rank P=0.089). A hazard ratio for the complete responders relative to the incomplete responders was 0.23 (95% confidence interval: 0.06-0.93, P=0.039) in a multivariate Cox proportional hazard model. CONCLUSION: The induction of CTLs was a novel independent survival factor, and the induction of peptide-specific CTLs by PPI contributes to the prolonged survival and represents an impact on therapeutic approaches in MM. Unique trial number: UMIN000005706. PMID- 24802713 TI - Vasoconstriction and anti-inflammatory properties of the selective alpha adrenergic receptor agonist brimonidine. AB - BACKGROUND: The facial erythema of rosacea is recognized as the most prevalent and most difficult manifestation of rosacea to treat. A recent approach in patients with rosacea has been to reduce this erythema through vasoconstriction of cutaneous blood vessels by selectively targeting alpha2-adrenergic receptors with brimonidine. OBJECTIVE: To further investigate the pharmacodynamic profile of brimonidine, its vasoconstrictive effects and its anti-inflammatory properties. METHODS: The potency for the alpha1A, alpha1B, alpha2A, alpha2B and alpha2C receptors of brimonidine was measured, as well as performing a large target profiling study in order to determine the target selectivity profile of brimonidine. The vasoconstrictive effects of brimonidine were measured using ex vivo wire myography and human skin biopsy neuroinflammation models. The anti inflammatory properties of brimonidine were measured using two in vivo mice ear inflammation models. RESULTS: Brimonidine was found to be highly selective for the alpha2A adrenoreceptor (EC50 0.45nM) over the other alpha-adrenoreceptors. Additionally, the large target profiling study demonstrated the high selectivity of brimonidine with minimal off-target effects. The ex vivo wire myography model showed that brimonidine is a potent vasoconstrictor of human subcutaneous vessels with a diameter of less than 200MUm (EC50 0.4nM). The ex vivo human skin biopsy neuroinflammation model demonstrated that brimonidine completely inhibited vasodilation induced by capsaicin. Both in vivo mouse ear inflammation models highlighted that brimonidine inhibited ear edema (up to 76%) when compared to vehicle. CONCLUSION: The selectivity, vasoconstrictive and anti-inflammatory properties of brimonidine that have been described in these studies are in agreement with the benefits observed with this compound in the treatment of facial erythema in rosacea. PMID- 24802714 TI - Characterization of serum microRNAs profile of PCOS and identification of novel non-invasive biomarkers. AB - BACKGROUND: Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women of reproductive age, is characterized by polycystic ovaries, chronic anovulation, hyperandrogenism and insulin resistance. Despite the high prevalence of hyperandrogenemia, a definitive endocrine marker for PCOS has so far not been identified. Circulating miRNAs have recently been shown to serve as diagnostic/prognostic biomarkers in patients with cancers. Our current study focused on the altered expression of serum miRNAs and their correlation with PCOS. METHOD AND RESULTS: We systematically used the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to identify and validate the expression of serum miRNAs of PCOS patients. The expression levels of three miRNAs (miR-222, miR-146a and miR-30c) were significantly increased in PCOS patients with respect to the controls in our discovery evaluation and followed validation. The area under the receiver operating characteristic (ROC) curve (AUC) is 0.799, 0.706, and 0.688, respectively. The combination of the three miRNAs using multiple logistic regression analysis showed a larger AUC (0.852) that was more efficient for the diagnosis of PCOS. In addition, logistic binary regression analyses show miR-222 is positively associated with serum insulin, while miR-146a is negatively associated with serum testosterone. Furthermore, bioinformatics analysis indicated that the predicted targets function of the three miRNAs mainly involved in the metastasis, cell cycle, apoptosis and endocrine. CONCLUSION: Serum miRNAs are differentially expressed between PCOS patients and controls. We identified and validated a class of three serum miRNAs that could act as novel non-invasive biomarkers for diagnosis of PCOS. These miRNAs may be involved in the pathogenesis of PCOS. PMID- 24802715 TI - A unified classification of alien species based on the magnitude of their environmental impacts. AB - Species moved by human activities beyond the limits of their native geographic ranges into areas in which they do not naturally occur (termed aliens) can cause a broad range of significant changes to recipient ecosystems; however, their impacts vary greatly across species and the ecosystems into which they are introduced. There is therefore a critical need for a standardised method to evaluate, compare, and eventually predict the magnitudes of these different impacts. Here, we propose a straightforward system for classifying alien species according to the magnitude of their environmental impacts, based on the mechanisms of impact used to code species in the International Union for Conservation of Nature (IUCN) Global Invasive Species Database, which are presented here for the first time. The classification system uses five semi quantitative scenarios describing impacts under each mechanism to assign species to different levels of impact-ranging from Minimal to Massive-with assignment corresponding to the highest level of deleterious impact associated with any of the mechanisms. The scheme also includes categories for species that are Not Evaluated, have No Alien Population, or are Data Deficient, and a method for assigning uncertainty to all the classifications. We show how this classification system is applicable at different levels of ecological complexity and different spatial and temporal scales, and embraces existing impact metrics. In fact, the scheme is analogous to the already widely adopted and accepted Red List approach to categorising extinction risk, and so could conceivably be readily integrated with existing practices and policies in many regions. PMID- 24802716 TI - Is endemic political corruption hampering provision of ART and PMTCT in developing countries? AB - INTRODUCTION: Leadership is a key factor in the success of HIV prevention and treatment. Positive HIV-related outcomes are also affected by funding levels for HIV, health sector resources, disease burden and the socio-economic environment. Leadership on HIV as well as these other factors are affected by the quality of political governance of the country, which may be an overarching factor that influences the making of effective responses to the HIV epidemic. AIM: The aim of the study was to investigate the association between quality of political governance, on one hand, and coverage of antiretroviral therapy (ART) and prevention of mother-to-child transmission (PMTCT), on the other, in low- to middle-income countries. METHODS: This investigation was carried out through a global review, online data sourcing and statistical analyses. We collected data on health burden and resources, the socio-economic environment, HIV prevalence, ART and PMTCT coverage and indicators of political governance. Outcome variables were coverage of ART (from 2004) and PMTCT (from 2007) to 2009 as a percentage of persons needing it. Potential predictors of treatment coverage were fitted with a baseline multilevel model for univariable and multivariable analyses. RESULTS: Countries with higher levels of political voice and accountability, more political stability and better control of corruption have higher levels of ART coverage but not PMTCT coverage. Control of corruption (in standard deviation units) had a strong association with ART (AOR=1.82, p=0.002) and PMTCT (AOR=1.97, p=0.01) coverage. Indicators of economic development were not significant when control of corruption was included in the multivariable regression model. Many countries in all income groups had high ART but not PMTCT coverage (e.g. Mexico, Brazil and Romania in the upper-middle-income group; Papua New Guinea and Philippines in the lower-middle-income group; and Cambodia, Laos and Comoros in the low-income group). Very few low-income countries (notably, Haiti and Kenya) had high PMTCT coverage. CONCLUSIONS: Our research found a significant relationship between quality of political governance and treatment coverage. Measures and policies for improving the quality of political governance should be considered as a part of HIV programme implementation to more effectively improve the welfare of people living with HIV, particularly mothers living with HIV and their babies. PMID- 24802718 TI - Spectroscopic and molecular docking studies on the charge transfer complex of bovine serum albumin with quinone in aqueous medium and its influence on the ligand binding property of the protein. AB - The spectral techniques such as UV-Vis, (1)H NMR and fluorescence and electrochemical experiments have been employed to investigate the interaction between 2-methoxy-3,5,6-trichloro-1,4-benzoquinone (MQ; a water soluble quinone) and bovine serum albumin (BSA) in aqueous medium. The fluorescence of BSA was quenched by MQ via formation of a 1:1 BSA-MQ charge transfer adduct with a formation constant of 3.3*10(8) L mol(-1). Based on the Forster's theory the binding distance between them is calculated as 2.65 nm indicating high probability of binding. For the first time, influence of quinone on the binding property of various types of ligands such as aspirin, ascorbic acid, nicotinimide and sodium stearate has also been investigated. The results indicated that the strong and spontaneous binding existing between BSA and MQ, decreased the intensity of binding of these ligands with BSA. Since Tryptophan (Trp) is the basic residue present in BSA, a comparison between binding property of Trp-MQ adduct with that of BSA-MQ with these ligands has also been attempted. 1H NMR titration study indicated that the Trp forms a charge transfer complex with MQ, which reduces the interaction of Trp with the ligands. Molecular docking study supported the fact that the quinone interacts with the Trp212 unit of the BSA and the free energy change of binding (DeltaG) for the BSA-MQ complex was found to be -46 kJ mol(-1), which is comparable to our experimental free energy of binding ( 49 kJ mol(-1)) obtained from fluorescence study. PMID- 24802717 TI - Matrix effects in biological mass spectrometry imaging: identification and compensation. AB - Matrix effects in mass spectrometry imaging (MSI) may affect the observed molecular distribution in chemical and biological systems. In this study, we use mouse brain tissue of a middle cerebral artery occlusion (MCAO) stroke model to examine matrix effects in nanospray desorption electrospray ionization MSI (nano DESI MSI). This is achieved by normalizing the intensity of the sodium and potassium adducts of endogenous phosphatidylcholine (PC) species to the intensity of the corresponding adduct of the PC standard supplied at a constant rate with the nano-DESI solvent. The use of MCAO model with an ischemic region localized to one hemisphere of the brain enables immediate comparison of matrix effects within one ion image. Furthermore, significant differences in sodium and potassium concentrations in the ischemic region in comparison with the healthy tissue allowed us to distinguish between two types of matrix effects. Specifically, we discuss matrix effects originating from variations in alkali metal concentrations and matrix effects originating from variations in the molecular composition of the tissue. Compensation for both types of matrix effects was achieved by normalizing the signals corresponding to endogenous PC to the signals of the standards. This approach, which does not introduce any complexity in sample preparation, efficiently compensates for signal variations resulting from differences in the local concentrations of sodium and potassium in tissue sections and from the complexity of the extracted analyte mixture derived from local variations in molecular composition. PMID- 24802719 TI - Extracellular bio-production and characterization of small monodispersed CdSe quantum dot nanocrystallites. AB - Engineered nanoparticles of diverse forms are being profoundly used for various applications and demand ecologically benign synthesis processes. Conventional chemical methods employed for the syntheses of nanoparticles are environmentally unfriendly and energy intensive. Biologically inspired biofabrication approaches that utilize naturally existing microorganisms or plant extracts or biomaterials might overcome these issues. The present investigation for the first time shows the synthesis of small and monodispersed cadmium selenide nanoparticles utilizing the plant pathogenic fungus, Helminthosporum solani upon incubating with an aqueous solution of CdCl2 and SeCl4 under ambient conditions. Multiple physical characterizations involving ultraviolet-visible and photoluminescence spectroscopy, transmission electron microscopy, selected area electron diffraction and X-ray photoelectron spectroscopy confirmed the production, purity, optical and surface characteristics, crystalline nature, size and shape distributions, and elemental composition of the nanoparticles. Pluralities of the particles are monodisperse spheres with a mean diameter of 5.5+/-2 nm, are hydrophilic, highly stable with a broad photoluminescence and 1% quantum yield. This approach provides an alternative facile route for the biofabrication of quantum dot that is reliable, environmentally friendly, and lends itself directly for the creation of fluorescent biological labels. PMID- 24802720 TI - Linear support vector regression and partial least squares chemometric models for determination of Hydrochlorothiazide and Benazepril hydrochloride in presence of related impurities: a comparative study. AB - Partial least squares regression (PLSR) and support vector regression (SVR) are two popular chemometric models that are being subjected to a comparative study in the presented work. The comparison shows their characteristics via applying them to analyze Hydrochlorothiazide (HCZ) and Benazepril hydrochloride (BZ) in presence of HCZ impurities; Chlorothiazide (CT) and Salamide (DSA) as a case study. The analysis results prove to be valid for analysis of the two active ingredients in raw materials and pharmaceutical dosage form through handling UV spectral data in range (220-350 nm). For proper analysis a 4 factor 4 level experimental design was established resulting in a training set consisting of 16 mixtures containing different ratios of interfering species. An independent test set consisting of 8 mixtures was used to validate the prediction ability of the suggested models. The results presented indicate the ability of mentioned multivariate calibration models to analyze HCZ and BZ in presence of HCZ impurities CT and DSA with high selectivity and accuracy of mean percentage recoveries of (101.01+/-0.80) and (100.01+/-0.87) for HCZ and BZ respectively using PLSR model and of (99.78+/-0.80) and (99.85+/-1.08) for HCZ and BZ respectively using SVR model. The analysis results of the dosage form were statistically compared to the reference HPLC method with no significant differences regarding accuracy and precision. SVR model gives more accurate results compared to PLSR model and show high generalization ability, however, PLSR still keeps the advantage of being fast to optimize and implement. PMID- 24802721 TI - Bipolar resistance switching in transparent ITO/LaAlO3/SrTiO3 memristors. AB - We report reversible bipolar resistance switching behaviors in transparent indium tin oxide (ITO)/LaAlO3/SrTiO3 memristors at room temperature. The memristors exhibit high optical transparency, long retention, and excellent antifatigue characteristics. The high performances are promising for employing ITO/LaAlO3/SrTiO3 memristors in nonvolatile transparent memory and logic devices. The nonvolatile resistance switching behaviors could be attributed to the migration of positively charged oxygen vacancies from the SrTiO3 substrate to the LaAlO3 film, resulting in Poole-Frenkel emission for the low resistance state and thermionic emission for the high resistance state. PMID- 24802723 TI - Detection of weak frequency jumps for GNSS onboard clocks. AB - In this paper, a weak frequency jump detection method is developed for onboard clocks in global navigation satellite systems (GNSS). A Kalman filter is employed to facilitate the onboard real-time processing of atomic clock measurements, whose N-step prediction residuals are used to construct the weak frequency jump detector. Numerical simulations show that the method can successfully detect weak frequency jumps. The detection method proposed in this paper is helpful for autonomous integrity monitoring of GNSS satellite clocks, and can also be applied to other frequency anomalies with an appropriately modified detector. PMID- 24802722 TI - The central nervous system effects of the partial GABA-Aalpha2,3 -selective receptor modulator AZD7325 in comparison with lorazepam in healthy males. AB - AIMS: AZD7325 is a novel alpha2,3 -subtype-selective partial GABA-A-receptor modulator. This study investigated the pharmacodynamics of single oral doses of AZD7325 2 mg and 10 mg on the central nervous system (CNS) compared with placebo and lorazepam 2 mg. METHODS: This double-blind, randomized, four way crossover study enrolled 16 healthy males and administered two validated CNS test batteries to measure drug effects on cognitive, neurophysiologic and psychomotor function and subjective feelings. The pharmacological selectivity of AZD7325 was compared with lorazepam by plotting saccadic peak velocity change from baseline (DeltaSPV) against body sway (DeltaSway) and visual analogue scale for alertness(DeltaVASalertness ). This analysis has previously been used to identify alpha2,3 -subtype-selectivity. RESULTS: In contrast with the robust impairment caused by lorazepam (all P < 0.05 vs. placebo), neither dose of AZD7325 induced statistically significant effects on any pharmacodynamic measurements. Lorazepam induced SPV-reduction was linearly related to changes in other neurophysiologic biomarkers. In contrast, the slopes of the regression lines were flatter for AZD7325, particularly for the Deltalog(Sway) -DeltaSPV relation (estimate slope, AZD7325 10 mg vs. lorazepam, difference [95% confidence interval], P value 0.00036 vs. -0.00206, 0.001704 [0.000639, 0.002768], P = 0.0018) and the DeltaVASalertness -DeltaSPV relationship (0.01855 vs. 0.08216, -0.06360 [-0.1046, -0.02257], P = 0.0024). AZD7325 10 mg and lorazepam induced different response patterns on VAS 'feeling high' and electro-encephalography. CONCLUSION: The characteristic DeltaSPV-relative effect profiles of AZD7325 vs. lorazepam suggest anxio-selectivity related to alpha2,3 -selective GABAA agonism. However, exploration of higher doses may be warranted. The paucity of effects on most CNS PD parameters also indicates a mitigated side effect pattern, with potentially lower cognitive and neurophysiological side effect burden than non-selective benzodiazepines. PMID- 24802724 TI - Ectopic over-expression of miR-429 induces mesenchymal-to-epithelial transition (MET) and increased drug sensitivity in metastasizing ovarian cancer cells. AB - OBJECTIVE: We recently determined that the ectopic over-expression of miR-429 and other members of the miR-200 family of microRNAs in ovarian cancer (OC) mesenchymal-like cell lines induces mesenchymal-to-epithelial transition (MET) with a concomitant increase in sensitivity to platinum drugs. We sought to determine if metastasizing OC cells isolated from an OC patient could also be induced by miR-429 to undergo MET and become sensitized to established first-line platinum-based therapies. METHODS: We established and characterized a new primary cell line (OCI-984) from free-floating OC cells isolated from the ascites fluid of an advanced stage OC patient. miR-429 was ectopically over-expressed in these cells. RESULTS: The over-expression of miR-429 in OCI-984 cells induced morphological, functional and molecular changes consistent with MET and a concomitant significant increase in the sensitivity of the converted cells to cisplatin. CONCLUSIONS: Our findings indicate that the miR-200 family of microRNAs, and miR-429 in particular, play a critical role in the functioning of OC metastasizing cells and that targeted delivery of miR-429, and perhaps other miR-200 family members, in combination with platinum-based chemotherapies may be an effective strategy in reducing OC metastasis and tumor recurrence. PMID- 24802725 TI - NRAS mutations are more prevalent than KIT mutations in melanoma of the female urogenital tract--a study of 24 cases from the Netherlands. AB - OBJECTIVE: The aim of this study was to evaluate a series of primary melanomas of the female urogenital tract for oncogenic mutations in KIT, NRAS and BRAF in order to identify patients who may be amenable to targeted therapy. METHODS: We reviewed twenty-four cases of female urogenital tract melanomas and used Sanger sequencing analysis for the detection of oncogenic mutations in exons 9, 11, 13, and 17 of KIT; exons 2 and 3 of NRAS; and exon 15 of BRAF. RESULTS: Twenty-four patients were included: fourteen vaginal melanomas, four cervical melanomas, five urethral melanomas and one vulvar melanoma. NRAS mutations (4/24, 21%) were more prevalent than KIT mutations (1/24, 4%), while BRAF mutations were absent. Three of four NRAS mutations were present in vaginal melanomas (21%), mainly affecting codon 61 (3/4). They were mutually exclusive with the KIT mutation. The KIT mutation was present in a vaginal melanoma and affected exon 17. CONCLUSIONS: Melanomas of the female urogenital tract relatively commonly harbor mutations in NRAS; this makes NRAS an interesting therapeutic target for these patients in the advanced setting. KIT mutations were rare in our study in contrast to some previous reports. We cannot exclude that anatomical site-related differences and/or population related differences in KIT mutation frequency exist within urogenital tract melanomas. PMID- 24802726 TI - Levetiracetam-induced psychosis in a pregnant woman with prior substance abuse. PMID- 24802727 TI - Focused opportunities for resident education on today's inpatient psychiatric units. AB - The functions and nature of inpatient psychiatric units have changed dramatically over recent decades, as has the role of psychiatric residents on these units. Nonetheless, clinical rotations on inpatient psychiatry remain as core clinical experiences in psychiatric residency. This column reviews the key changes in the residents' inpatient experience and articulates appropriate educational goals for current inpatient rotations in the areas of the psychiatric interview, diagnosis and formulation, treatment planning, working as a member of a multidisciplinary team, and working with acutely ill and involuntary patients. PMID- 24802728 TI - Mallard duck (Anas platyrhynchos)-mediated dispersal of Lemnaceae: a contributing factor in the spread of invasive Lemna minuta? AB - Our ability to predict and manage the spread of alien, invasive plants is limited by a lack of understanding of dispersal potential. Invasive Lemna minuta has spread within a few decennia throughout Europe. However, the mechanism by which the species continues to spread remains a matter of speculation. In this study, hypothesised epizoochorous transport of L. minuta propagules by mallard ducks was investigated. Landolt (Biosystematic investigations in the family of duckweeds (Lemnaceae) (Vol. 2), The family of Lemnaceae - a monographic study (Vol. 1), 1986, Veroffentlichungen des Geobotanischen Institutes Der Eidg. Techniasche Hochschule, Stiftung Rubel, Zurich, Switzerland) referred to desiccation as the key limitation of the "colonization capability" of Lemnaceae. Therefore, we analysed retention of viability in L. minuta kept outside the liquid growth medium. Our data show prolonged viability of L. minuta fronds inserted between the feathers of a mallard duck. Consistently, the relative humidity between feathers ranged between 65% and 90%. Taking together evidence of entanglement and retention of L. minuta between the feathers of live ducks, with retention of viability, we consider it likely that mallards contribute to L. minuta dispersal. These data have implications for the management strategy of this invasive species. PMID- 24802729 TI - Is there an impact of treatment with DPP-4 inhibitors on lymphocyte subpopulations in type 2 diabetic patients? AB - INTRODUCTION: Dipeptidil peptidase 4 inhibitors (DPP-4) are a group of antihyperglycemic agents. DPP-4 is an enzyme expressed on lymphocyte surface as co-stimulatory molecule in activation processes. The aim was to assess lymphocyte subpopulations initially and after 14 days of treatment with DPP-4 inhibitors sitagliptin, saxagliptin and vildagliptin. MATERIAL AND METHODS: The study was conducted in three groups 10 subjects each, of type 2 diabetic patients. In subjects studied an initial tests followed by repeated ones after 14 days of treatment with sitagliptin, saxagliptin, and vildagliptin in therapeutic doses were performed. Baseline test as well as lymphocyte subpopulations (total T cells, and T-cell subsets CD4+, CD8+, CD26+, CD45RA+, CD45RO+, CD4+/CD25+) using 7-colour flow cytometry method were performed. RESULTS: In patients receiving sitagliptin no significant increase in lymphocyte subpopulations were observed. In patients who received vildagliptin significant increase of total T-cells (p < 0.05); in patients treated with saxagliptin significant (p < 0.05) though mild increased percentage of total T-cells and CD4+, CD26+, CD45RO+ subsets were found. CONCLUSIONS: The study showed mild but significant increase of several T cell subsets after treatment with saxagliptin and vildagliptin with non significant elevation after treatment with sitagliptin. It seems that changes are not expressed enough to have a clinical impact. PMID- 24802730 TI - Metabolic control and its variability are major risk factors for microalbuminuria in children with type 1 diabetes. AB - INTRODUCTION: To assess in a prospective study the course and the predictors of microalbuminuria in children and adolescents with type 1 diabetes. MATERIAL AND METHODS: 438 children and adolescents who developed diabetes in the years 1985 2004 were followed for 9.2 +/- 3.4 years from the diagnosis. Microalbuminuria was assessed on the basis of timed overnight urine collections performed once per year. Variability of glycated haemoglobin was expressed as a coefficient of variation (%) calculated by dividing standard deviation (adjusted for the number of measurements) by mean of HbA1c. RESULTS: Microalbuminuria was noted in 99 patients (22.6%) after 8.27 +/- 3.3 years of diabetes. In 29 individuals (6.6%), microalbuminuria was persistent. The prevalence of microalbuminuria was not dependent on the period of diabetes diagnosis. During followup, 17 (58.6%) patients with persistent MA reverted to normoalbuminuria. Children without any episodes of microalbuminuria had significantly lower HbA1c variability (8.44%; 95% CI 7.81-9.08%) than those with one (10.28% 95% CI 9.10-11.47%; p = 0.007). The difference of HbA1c variability between patients with and without microalbuminuria persisted after correction by mean HbA1c (p = 0.04). Risk factors for ever developing microalbuminuria during the observation period in multivariate analysis included: mean HbA1c (HR [95% CI]: 1.17 [1.00-1.37; p = 0.05]) and its variability (1.04 [1.00-1.07]; p = 0.05), insulin dose (HR per 0.1 unit*kg- 1*day-1: 0.87 [0.79-0.96]; p = 0.005), presence of arterial hypertension (1.63 [1.07-2.49]; p = 0.02), and age at onset of diabetes (1.15 [1.08-1.21]; p < 0.0001). CONCLUSIONS: Children who develop microalbuminuria are characterised by poorer and more variable metabolic control, hinting at the importance of interventions aimed at both improvement and stabilisation of HbA1c levels. PMID- 24802731 TI - The effect of calpain-10 gene polymorphism on the development of type 2 diabetes mellitus in a Turkish population. AB - INTRODUCTION: The variations in the Calpain-10 gene have been suggested to be related to susceptibility to type 2 diabetes mellitus (T2DM) in different populations. In this study, we investigated the relationship between single nucleotide polymorphism (SNP)-19, -44 and -63 in the Calpain-10 gene and the development of T2DM in a Turkish population. MATERIAL AND METHODS: A total of 211 subjects were recruited: 118 patients with a diagnosis of T2DM and 93 unrelated healthy subjects. RESULTS: There were no significant differences in the genotype and allele distribution of SNPs studied between the patients with T2DM and controls (p > 0.05), whereas the frequencies of 121 haplotype and 122/121 haplotype combination were found to be higher in patients with T2DM than in controls (p < 0.05). No association was observed between the variations in the Calpain-10 gene and glycaemic control and lipid parameters (p > 0.05). The SNP-19 insertion/insertion was significantly related to increased body mass index (BMI) in male diabetic patients (p < 0.05). CONCLUSIONS: The present study indicates that 121 haplotype and 122/121 haplotype combination of SNP-19, -44 and -63 in the Calpain-10 gene are associated with the development of T2DM in Turkish patients. PMID- 24802732 TI - Zoledronic acid increases bone mineral density and improves health-related quality of life over two years of treatment in Chinese women with postmenopausal osteoporosis. AB - INTRODUCTION: Osteoporosis is characterised by decreased bone mass and weakened bones, with an increased risk of fractures. Osteoporotic fracture, the most serious complication of osteoporosis, is related not only to lower bone mineral density (BMD), but also falls. Osteoporosis and fractures are associated with a decreased health-related quality of life (HRQL). Zoledronic acid (ZOL) is an intravenous once-yearly bisphosphonate that has been shown to be effective and safe in improving BMD and reducing fracture risk in controlled clinical trials. MATERIAL AND METHODS: In this self-controlled, prospective trial, 220 postmenopausal women with osteoporosis (mean age 67 years) received a single infusion of ZOL 5 mg at baseline and month 12. BMD, HRQL and Fall Index (FI) were measured at baseline, and months 12 and 24 (before each use of ZOL). The main outcome measures were the changes in lumbar spine and hip BMD and the changes in HRQL, the Short Form-36 questionnaire (SF-36). Additional comparisons were based on the FI. LSD multiple comparisons were used in the comparisons of BMD, SF-36 domain scores and FI. RESULTS: The patients had significantly higher L1-4, total hip, femoral neck and trochanter BMD (P < 0.05) with improved HRQL (P < 0.05) over two years of treatment of once-yearly ZOL 5mg. FI was reduced (P < 0.05) with oral daily elemental calcium and vitamin D in the treatment course. CONCLUSIONS: ZOL improves BMD and HRQL, especially in the physical aspects, over two years of treatment in women with postmenopausal osteoporosis, and can help improve balance ability. PMID- 24802733 TI - Vitamin D deficiency during winter months among an adult, predominantly urban, population in Northern Poland. AB - INTRODUCTION: Vitamin D is vital in the regulation of the calcium-phosphate metabolism, has a direct impact on the musculoskeletal system, and also affects numerous other systems. Widespread vitamin D deficiency and its detrimental effect on health have been reported globally. Data concerning vitamin D status in Polish adult population is scarce. MATERIAL AND METHODS: Ambulatory patients of an outpatient clinic in Gdansk were included in the study. Serum concentrations of 25(OH) D, parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium and phosphorus were determined. In a questionnaire declared UVB exposure, dietary vitamin D and calcium intake, and health status of the subjects were assessed. Non- and parametric tests, logistic regression and population attributable risk were applied in data analysis. RESULTS: 448 adults were examined from February to mid-April 2012, 305 women and 143 men, aged 19 to 86 (mean 46.3 +/- 14.9 years). Mean 25-hydroxyvitamin D concentration was 14.3 +/- 6.6 ng/mL. 84.4% of subjects were vitamin D deficient (25(OH)D < 20 ng/mL); 13.2% presented insufficient (20 30 ng/mL), and 2.5% (or 11 subjects) sufficient 25(OH)D concentrations. Significantly higher 25(OH)D concentrations were found in subjects who reported more UVB exposure, supplemented vitamin D orally and those who declared more physical activity. 21% of subjects had elevated serum PTH concentration (i.e. > 62 pg/mL); mean parathormone was 48.6 +/- 25.2 pg/mL. A linear correlation was found between the logarithm of PTH and logarithm of 25(OH)D concentrations (r = 0.21, p < 0.001). CONCLUSIONS: Results obtained here demonstrate the necessity of implementing a monitoring and prophylaxis programme of vitamin D deficiency in Poland. PMID- 24802734 TI - How to select nodules for fine-needle aspiration biopsy in multinodular goitre. Role of conventional ultrasonography and shear wave elastography - a preliminary study. AB - INTRODUCTION: The wide prevalence and relatively low malignancy ratio of thyroid nodular disease (TND) make the selection of suspicious lesions for fine-needle aspiration biopsy (FNAB) a vital problem in endocrinology. Apart from the decision as to whether FNAB is necessary, there is often a second problem - which nodule or nodules to choose in a case of multinodular goitre (MNG), when the number of lesions may be high. The aim of this study was to compare the usefulness of conventional ultrasonography (US) to that of a novel method of tissue stiffness assessment - shear wave elastography (SWE) - in differentiating between malignant and benign nodules and in selecting the most suspicious lesions in MNG. MATERIAL AND METHODS: Patients with MNG, referred for thyroidectomy irrespectively of indications for surgery, underwent thyroid US and SWE examination before surgery, between August and December 2010. Results of these examinations were correlated with the histopathological outcomes. RESULTS: 80 patients with 339 thyroid nodules were included. Ten thyroid cancers (TCs) in ten patients were diagnosed in histopathology. All ten cancers were the least elastic lesions in MNG (using quantitative data on maximal tissue stiffness). Four cancers appeared as the biggest lesions in MNG, while one was equally the biggest in a particular goitre (there were other lesions of the same size) taking into account maximal diameter. Three of ten cancers possessed the highest number of suspicious features in MNG, a further four had the highest number equally, with at least one other lesion in the same goitre. CONCLUSIONS: On the basis of our results, the relatively high stiffness of a lesion compared to other nodules from the same MNG should be considered as a strong argument for choosing that particular one for FNAB. PMID- 24802735 TI - Shear wave elastography of adrenal masses is feasible and may help to differentiate between solid and cystic lesions - an initial report. AB - INTRODUCTION: The aim of this study was to evaluate the feasibility and usefulness of supersonic shear wave elastography (SSWE) in the diagnosis of nonmalignant adrenal masses. MATERIAL AND METHODS: 13 patients with a total number of 16 adrenal masses were enrolled in the study. In each case, both conventional ultrasound imaging and SSWE for stiffness assessment were performed. The final diagnosis was based on CT, MRI, biochemical studies, surgery or more than one year of follow up. RESULTS: The final diagnosis: nodular hyperplasia in six masses, six adenomas, three cysts, and one myelolipoma. All solid adrenal masses presented the elastography signal in contrast to cystic lesions that were devoid of it, as shear waves do not propagate through fluids. CONCLUSIONS: SSWE is a feasible technique that can be applied during ultrasound of the abdomen and retroperitoneum. SSWE presents potential for the differentiation of solid and cystic adrenal lesions. Further large scale studies evaluating the possibility of differentiation of adrenal and other retroperitoneal masses with SSWE are warranted. PMID- 24802736 TI - Forskolin-stimulated vasopressin and oxytocin release from the rat hypothalamo neurohypophysial system in vitro is inhibited by melatonin. AB - INTRODUCTION: Previous in vivo and in vitro studies have shown that melatonin changes vasopressin (AVP) and oxytocin (OT) secretion from the rat neurohypophysis. Additionally, melatonin is known to inhibit the forskolin induced (forskolin is a strong adenylyl cyclase - AC activator) increase in cAMP accumulation in the rat pituitary. To determine whether the possible response of vasopressinergic and/or oxytocinergic neurones to melatonin could be mediated through a cAMP-dependent mechanism, the effect of different concentrations of melatonin (i.e. 10-11, 10-9, 10-7, 10-5 and 10-3 M) on forskolin-stimulated AVP and OT release from the rat hypothalamo-neurohypophysial (H-NH) system was studied in vitro. MATERIAL AND METHODS: Male rats served as donors of the H-NH explants, which were placed in 1 mLof normal Krebs-Ringer fluid (nKRF), heated to 37oC and constantly gassed with carbogen (95% O2 and 5% CO2). The H-NH explants were incubated successively in nKRF {fluid B1} and incubation fluid as B1 enriched with an appropriate concentration of melatonin, i.e. 10-11 - 10-3 M and/or forskolin (at a concentration of 10-5 M) or their vehicles (0.1% ethanol or DMSO) {fluid B2}. After 20 min incubation in fluid B1 and next B2, the media were collected and immediately frozen before AVP and OT estimation by the RIA. The AVP and OT secretion was determined by using B2/B1 ratio for each H-NH explant. RESULTS: We have demonstrated that the highly effective AC activator - forskolin significantly stimulated both AVP and OT release from isolated rat H-NH system. Such an effect of forskolin was reduced by melatonin at concentrations of 10-9, 10-7 and 10-5 M. The strongest effect was exerted by this hormone at a concentration of 10-7 M, which inhibited not only forskolin-stimulated, but also basal, AVP and OT release. On the contrary, the highest studied concentration (i.e. 10-3 M) of melatonin stimulated both AVP and OT basal release, but when forskolin was present in the medium melatonin at such a concentration remained inactive in modifying these hormones release from the H-NH system in vitro. CONCLUSIONS: Our present results demonstrate that in the male rat: 1. The influence of melatonin on the vasopressinergic and oxytocinergic neurones activity is mediated partly through a cAMP-dependent mechanism. 2. The effect of melatonin in this respect depends on its concentration. PMID- 24802737 TI - The relationship between adipose tissue-derived hormones and gestational diabetes mellitus (GDM). AB - Gestational diabetes mellitus (GDM) is defined as a glucose intolerance of varying severity with onset or first recognition during pregnancy. The prevalence of GDM is growing rapidly worldwide, resulting in numerous and serious complications for both mother and foetus. Two major metabolic disorders, insulin resistance and beta cells dysfunction, are currently linked to the pathogenesis of GDM, although the cellular mechanisms involved in the development of GDM are not yet completely understood. Increasing evidence from clinical and experimental studies indicates that adipose tissue dysfunction, characterised by abnormal production of adipokines, is an essential factor linked to insulin resistance and GDM. To date, several adipose tissue-derived hormones have been identified, including leptin, adiponectin, resistin, visfatin, apelin, retinol-binding protein 4 (RBP-4), vaspin, and omentin. The relationship of leptin and adiponectin to insulin resistance in GDM is relatively well documented, but the molecular mechanisms by which these hormones affect insulin resistance are not yet fully known. The other aforementioned adipokines appear to be also important players in the pathophysiology of GDM, although their precise function in this complex process remains to be established. The aim of this article is to review the literature concerning the relationship between the above-mentioned adipokines and GDM, and to clarify their role in the pathophysiology of GDM. PMID- 24802738 TI - Interesting coincidence of atypical TSH-secreting pituitary adenoma and chronic lymphocytic leukemia. AB - Thyrotropin-secreting adenomas (TSH-oma) are very rare pituitary tumours. They are macroadenomas usually presenting with signs and symptoms of hyperthyroidism, and mass effects. They can co-secrete other hormones such as growth hormone or prolactin. Different malignancies, including haematological ones, are reported in patients with pituitary diseases. Chronic lymphocytic leukemia (CLL) occurs mostly in older patients, more often in males. CLL is associated with increased risk of second malignancies such as other blood neoplasms, skin and solid tumours. We present a successful neurosurgical outcome in a patient with an interesting coincidence of atypical TSH-oma and asymptomatic CLL. PMID- 24802739 TI - The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease (AITD). AB - Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder. AITD development occurs due to loss of immune tolerance and reactivity to thyroid autoantigens: thyroid peroxidase (TPO), thyroglobulin (TG) and thyroid stimulating hormone receptor (TSHR). This leads to infiltration of the gland by T cells and B cells that produce antibodies specific for clinical manifestations of hyperthyroidism in Graves' disease (GD) and chronic autoimmune thyroiditis (cAIT). In addition, T cells in Hashimoto's thyroiditis induce apoptosis in thyroid follicular cells, leading ultimately to the destruction of the gland. Cytokines are involved in the pathogenesis of thyroid diseases working in both the immune system and directly targeting the thyroid follicular cells. They are involved in the induction and effector phase of the immune response and inflammation, playing a key role in the pathogenesis of autoimmune thyroid disease. The presence of multiple cytokines has been demonstrated: IL-1alpha, IL 1b, IL-2, IL-4 , IL-6, IL-8, IL-10, IL-12, IL-13, IL-14, TNF-alpha and IFN-gamma within the inflammatory cells and thyroid follicular cells. Finally, cytokines derived from T cells can directly damage thyroid cells, leading to functional disorders and may also stimulate the production of nitric oxide (NO) and prostaglandin (PG), thus increasing the inflammatory response in AITD. Immunological mechanisms involved in the pathogenesis of AITD are strongly related to each other, but differences in the image of cAIT and GD phenotype are possibly due to a different type of immune response observed in these two counteracting clinical thyroid diseases. This article describes the potential role of cytokines and immune mechanisms in the pathogenesis of AITD. PMID- 24802740 TI - The applicability of the international classification of functioning, disability, and health to study lifestyle and quality of life of colorectal cancer survivors. AB - BACKGROUND: Well-designed studies on lifestyle and health-related quality of life (HRQoL) in colorectal cancer survivors based on a biopsychosocial instead of a traditional biomedical approach are warranted. We report on the applicability of the International Classification of Functioning, Disability, and Health (ICF) as useful biopsychosocial framework to improve research on how lifestyle influences colorectal cancer survivors' HRQoL, using the Energy for life after ColoRectal cancer (EnCoRe) study as an example. METHODS: The ICF was used to develop a conceptual model for studying lifestyle and colorectal cancer survivors' HRQoL, by identifying relevant factors from literature and mapping them within the ICF. Subsequently, this model was used for selection of measurement instruments and biomarkers. By linking meaningful concepts within selected measures to the ICF, we could assess the ICF coverage of our developed conceptual model. RESULTS: Within selected measures, 450 meaningful concepts were identified, of which 88% were linked to the ICF. The linking process resulted in 132 distinctive ICF categories assigned (38% within "Body Functions," 2% within "Body Structures," 46% within "Activities and Participation," and 14% within "Environmental Factors"). CONCLUSIONS: The selected EnCoRe study measures broadly cover ICF domains relevant to colorectal cancer survivors, stressing the relevance of using a biopsychosocial approach for studying this population's HRQoL. IMPACT: The developed conceptual model will guide data analyses and interpretation, and facilitate early transfer of results for development, evaluation, and implementation of personalized multidisciplinary lifestyle interventions. We recommend the ICF as an invaluable framework for improving the quality and scope of HRQoL studies. PMID- 24802741 TI - Reducing prostate cancer racial disparity: evidence for aggressive early prostate cancer PSA testing of African American men. AB - BACKGROUND: There is continuing controversy about prostate cancer testing and the recent American Urological Association guidelines. We hypothesize that the reduction and elimination of racial survival disparity among African American men (AAM; high-risk group) compared with European American men (EAM; intermediate risk group) during the PSA testing era compared with the pre-PSA era strongly supports the use of PSA testing in AAM. METHODS: We used Surveillance, Epidemiology, and End Results (SEER) data to investigate relative survival disparities between AAM and EAM. To evaluate pre-PSA testing era, we selected malignant first primary prostate cancer in AAM and EAM, all stages, diagnosed during 1973-1994. To evaluate relative survival disparities in the current PSA testing era, we selected malignant first primary local, regional, and distant stage prostate cancers diagnosed during 1998-2005 to calculate 5-year relative survival rates. RESULTS: Age-adjusted 5-year relative survival of prostate cancer diagnosed during 1973-1994 in the national SEER data revealed significantly shorter survival for AAM compared with EAM (P < 0.0001). The SEER-based survival analysis from 1995 to 2005 indicated no statistical difference in relative survival rates between AAM and EAM by year of diagnosis of local, regional, or distant stage prostate cancer. CONCLUSION: We conclude that the elimination of prostate cancer racial disparity of local, regional, and metastatic prostate cancer relative survival in the current PSA testing era compared with pre-PSA era as an endpoint to test PSA efficacy as a marker for prostate cancer diagnosis is evidence for aggressive testing of AAM. IMPACT: Evidence for screening AAM. PMID- 24802743 TI - Co-occurrence of estrogenic and antiestrogenic activities in wastewater: quantitative evaluation of balance by in vitro ERalpha reporter gene assay and chemical analysis. AB - Endocrine-disrupting chemicals are exogenous substances that alter the function of the endocrine system, with adverse health effects on organisms or their progeny. In vitro estrogen receptor (ER) reporter gene assays have long been used to measure estrogenic activity in wastewater. Nevertheless, there is still uncertainty about their usefulness in environmental monitoring on account of a discrepancy between the estrogenic response of the in vitro assay and concentrations of estrogenic compounds determined by chemical analysis. Here, we measured estrogenic and antiestrogenic activities in wastewater by ERalpha reporter gene assay. All samples were simultaneously analyzed for estrone, 17beta estradiol, estriol, and 17alpha-ethynylestradiol, and the concentrations were used to predict estrogenic activity. All samples in which measured estrogenic activity was significantly lower than predicted showed strong antiestrogenic activity. In addition, we confirmed that the fraction that did not have antiestrogenic activity showed stronger estrogenic activity than the unfractionated wastewater extract. These results indicate that antiestrogenic compounds in wastewater suppress the activity of natural estrogens, and the reporter gene assay represents the net activity. PMID- 24802742 TI - Serum fucosylated haptoglobin as a novel prognostic biomarker predicting high Gleason prostate cancer. AB - BACKGROUND: Fucosylation is an oligosaccharide modification associated with cancer and inflammation, which is catalyzed by fucosyltransferases. Fucosylated haptoglobin (Fuc-Hpt) has been identified as a novel biomarker for pancreatic cancer. In this study, we evaluated serum Fuc-Hpt as a biomarker for prostate cancer, and investigated the expression of fucosyltransferases and haptoglobin in prostate cancer cell lines. METHODS: We measured the preoperative serum Fuc-Hpt levels in 98 patients who underwent radical prostatectomy (RP) using an established lectin-antibody ELISA. Fucosyltransferase and haptoglobin mRNA and protein expressions in prostate cancer cell lines were determined using quantitative PCR and Western blotting. RESULTS: Serum Fuc-Hpt levels were significantly associated with Gleason score (GS), but not prostate-specific antigen (PSA) levels. The area under the receiver-operator characteristics curve (AUC) for the prediction of GS >=7 in prostatectomy specimens by Fuc-Hpt was 0.753, in contrast to the PSA AUC of 0.561 and the PSAD AUC of 0.558. The Fuc-Hpt AUC for the prediction of GS upgrade from GS 6 at biopsy to GS >=7 after RP was 0.689, in contrast to the PSA AUC of 0.588 and PSAD AUC of 0.557. Multivariable analysis revealed that Fuc-Hpt levels were significantly associated with biochemical recurrence after prostatectomy. A high expression of alpha-(1-6) fucosyltransferase (FUT8) and haptoglobin was observed in prostate cancer cell line, suggesting that certain kinds of prostate cancer cells produce Fuc-Hpt. CONCLUSION: Elevated serum Fuc-Hpt level could be a novel cancer biomarker for predicting the prognosis of patients with prostate cancer, particularly those with high GSs. PMID- 24802744 TI - Modified transurethral resection of the prostate (TURP) for men with moderate lower urinary tract symptoms (LUTS) before brachytherapy is safe and feasible. AB - OBJECTIVE: To report the urinary toxicity outcomes for patients at greater risk of voiding symptoms and retention who received a modified limited transurethral resection of the prostate (TURP) before low-dose rate (LDR) brachytherapy. PATIENTS AND METHOD: Data were analysed from patients receiving the above procedures between 2006 to present, taken from the prospective brachytherapy database of 2000 patients at the St. Luke's Cancer Centre. The limited TURP (TURP(BXT) ) was performed at a median (range) of 64 (25-205) days before seed implantation with a median resection weight of 1.15 g. Selection criteria were based on patients with moderate lower urinary tract symptoms, poor flow or post void residual urine volume (PVR), or a prominent middle lobe or high bladder neck on transrectal ultrasonography. Baseline prostate cancer characteristics, uroflowmetry, International Prostate Symptom Score (IPSS) and quality-of-life QoL scores were collected and compared with follow-up IPSS and QoL scores. RESULTS: Data for 112 patients was gathered from the database. The TURP(BXT) resulted in statistically significant improvements before LDR brachytherapy in maximum urinary flow rate (Qmax ) and PVR, IPSS and QoL scores (the mean Qmax before vs after the TURP(BXT) was 11.3 vs 16.7 mL/s). The IPSS and QoL scores at 6 months after seed implantation were increased compared with baseline values before the TURP(BXT) (mean IPSS at 6 months 11.7 vs 9.2 before TURP(BXT) ), but no difference at 1 year (mean IPSS 9), and improved scores at 2, 3, 4 and 5 years follow-up (mean IPSS of 7.9, 5.6, 5.3 and 7.4, respectively). CONCLUSION: The present study suggests patients at increased risk of deteriorating voiding symptoms, including urinary retention, are no longer contraindicated against LDR brachytherapy if they receive a modified TURP before seed implantation. This procedure does not appear to carry the risk of urinary incontinence thought to be associated with a conventional TURP before LDR brachytherapy. PMID- 24802745 TI - Aqueous humour levels of ghrelin in exfoliation syndrome and exfoliation glaucoma patients. AB - PURPOSE: To investigate levels of ghrelin in the aqueous humour (AqH) of patients with exfoliation syndrome and exfoliation glaucoma and compare them to levels of ghrelin in control subjects. METHODS: This cross-sectional study involved 15 patients with exfoliation syndrome, 8 with exfoliation glaucoma and 12 control subjects for whom cataract surgery was indicated. The AqH was aspirated from the anterior chamber with a 27-G needle under sterile conditions prior to tissue manipulation. Ghrelin levels were quantified using radioimmunassay kits. RESULTS: Levels of ghrelin in the AqH were 187.87 +/- 80.1 pg/mL in the eyes exhibiting exfoliation syndrome, 98.53 +/- 50.9 pg/mL in the eyes exhibiting exfoliation glaucoma and 111.40 +/- 77.5 pg/mL in the controls. Ghrelin level of patients with exfoliation syndrome were significantly higher than those of patients with exfoliation glaucoma and the controls (P < 0.05). Ghrelin levels of patients with exfoliation glaucoma were lower than those of the controls but were not reach statistically significant (P > 0.05). Age, gender and IOP did not have a significant effect on ghrelin levels in patients with exfoliation syndrome and exfoliation glaucoma. CONCLUSION: This study is the first to report elevated levels of ghrelin in the AqH in eyes exhibiting exfoliation syndrome. Findings suggest ghrelin might play role in the etiopathogenesis of exfoliation syndrome to exfoliation glaucoma. PMID- 24802746 TI - Barriers and motivators to voluntary medical male circumcision uptake among different age groups of men in Zimbabwe: results from a mixed methods study. AB - BACKGROUND: We conducted quantitative and qualitative studies to explore barriers and motivating factors to VMMC for HIV prevention, and to assess utilization of existing VMMC communication channels. METHODS AND FINDINGS: A population-based survey was conducted with 2350 respondents aged 15-49. Analysis consisted of descriptive statistics and bivariate analysis between circumcision and selected demographics. Logistic regression was used to determine predictors of male circumcision uptake compared to intention to circumcise. Focus group discussions (FGDs) were held with men purposively selected to represent a range of ethnicities. 68% and 53% of female/male respondents, respectively, had heard about VMMC for HIV prevention, mostly through the radio (71%). Among male respondents, 11.3% reported being circumcised and 49% reported willingness to undergo VMMC. Factors which men reported motivated them to undergo VMMC included HIV/STI prevention (44%), improved hygiene (26%), enhanced sexual performance (6%) and cervical cancer prevention for partner (6%). Factors that deterred men from undergoing VMMC included fear of pain (40%), not believing that they were at risk of HIV (18%), lack of partner support (6%). Additionally, there were differences in motivators and barriers by age. FGDs suggested additional barriers including fear of HIV testing, partner refusal, reluctance to abstain from sex and myths and misconceptions. CONCLUSIONS: VMMC demand-creation messages need to be specifically tailored for different ages and should emphasize non-HIV prevention benefits, such as improved hygiene and sexual appeal, and need to address men's fear of pain. Promoting VMMC among women is crucial as they appear to have considerable influence over men's decision to get circumcised. PMID- 24802748 TI - The quest for significance model of radicalization: implications for the management of terrorist detainees. AB - Radicalization and its culmination in terrorism represent a grave threat to the security and stability of the world. A related challenge is effective management of extremists who are detained in prison facilities. The major aim of this article is to review the significance quest model of radicalization and its implications for management of terrorist detainees. First, we review the significance quest model, which elaborates on the roles of motivation, ideology, and social processes in radicalization. Secondly, we explore the implications of the model in relation to the risks of prison radicalization. Finally, we analyze the model's implications for deradicalization strategies and review preliminary evidence for the effectiveness of a rehabilitation program targeting components of the significance quest. Based on this evidence, we argue that the psychology of radicalization provides compelling reason for the inclusion of deradicalization efforts as an essential component of the management of terrorist detainees. PMID- 24802749 TI - Cardiorespiratory Changes and Pain Response of Lift Laparoscopy Compared to Capnoperitoneum Laparoscopy in Dogs. AB - OBJECTIVE: To compare intraoperative physiologic variables and post-operative pain associated with lift laparoscopy and conventional capnoperitoneum laparoscopy. STUDY DESIGN: Prospective randomized case controlled study. ANIMALS: Healthy dogs (n = 30). METHODS: Dogs having laparoscopic ovariohysterectomy were randomly assigned to lift laparoscopy (n = 14) or capnoperitoneum (16) laparoscopy. Physiologic variables measured intraoperatively were documented. Postoperatively, pain response was assessed in a blinded fashion using the short Glasgow pain scale and von Frey filament aesthesiometry. RESULTS: Lift laparoscopy was associated with less frequency of hypercapnia, required less anesthetic gas, and was not more time-consuming or painful than capnoperitoneum laparoscopy. CONCLUSIONS: Lift laparoscopy is a feasible alternative to capnoperitoneum laparoscopy, especially in dogs where pressurized capnoperitoneum is not desired. PMID- 24802751 TI - From seconds to femtoseconds: solar hydrogen production and transient absorption of chalcogenorhodamine dyes. AB - A series of chalcogenorhodamine dyes with oxygen, sulfur, and selenium atoms in the xanthylium core was synthesized and used as chromophores for solar hydrogen production with a platinized TiO2 catalyst. Solutions containing the selenorhodamine dye generate more hydrogen [181 turnover numbers (TONs) with respect to chromophore] than its sulfur (30 TONs) and oxygen (20 TONs) counterparts. This differs from previous work incorporating these dyes into dye sensitized solar cells (DSSCs), where the oxygen- and selenium-containing species perform similarly. Ultrafast transient absorption spectroscopy revealed an ultrafast electron transfer under conditions for dye-sensitized solar cells and a slower electron transfer under conditions for hydrogen production, making the chromophore's triplet yield an important parameter. The selenium-containing species is the only dye for which triplet state population is significant, which explains its superior activity in hydrogen evolution. The discrepancy in rates of electron transfer appears to be caused by the presence or absence of aggregation in the system, altering the coupling between the dye and TiO2. This finding demonstrates the importance of understanding the differences between, as well as the effects of the conditions for DSSCs and solar hydrogen production. PMID- 24802750 TI - The role of H1 linker histone subtypes in preserving the fidelity of elaboration of mesendodermal and neuroectodermal lineages during embryonic development. AB - H1 linker histone proteins are essential for the structural and functional integrity of chromatin and for the fidelity of additional epigenetic modifications. Deletion of H1c, H1d and H1e in mice leads to embryonic lethality by mid-gestation with a broad spectrum of developmental alterations. To elucidate the cellular and molecular mechanisms underlying H1 linker histone developmental functions, we analyzed embryonic stem cells (ESCs) depleted of H1c, H1d and H1e subtypes (H1-KO ESCs) by utilizing established ESC differentiation paradigms. Our study revealed that although H1-KO ESCs continued to express core pluripotency genes and the embryonic stem cell markers, alkaline phosphatase and SSEA1, they exhibited enhanced cell death during embryoid body formation and during specification of mesendoderm and neuroectoderm. In addition, we demonstrated deregulation in the developmental programs of cardiomyocyte, hepatic and pancreatic lineage elaboration. Moreover, ectopic neurogenesis and cardiomyogenesis occurred during endoderm-derived pancreatic but not hepatic differentiation. Furthermore, neural differentiation paradigms revealed selective impairments in the specification and maturation of glutamatergic and dopaminergic neurons with accelerated maturation of glial lineages. These impairments were associated with deregulation in the expression profiles of pro-neural genes in dorsal and ventral forebrain-derived neural stem cell species. Taken together, these experimental observations suggest that H1 linker histone proteins are critical for the specification, maturation and fidelity of organ-specific cellular lineages derived from the three cardinal germ layers. PMID- 24802752 TI - The amino acid exchange R28E in ciliary neurotrophic factor (CNTF) abrogates interleukin-6 receptor-dependent but retains CNTF receptor-dependent signaling via glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR). AB - Ciliary neurotrophic factor (CNTF) is a neurotrophic factor with therapeutic potential for neurodegenerative diseases. Moreover, therapeutic application of CNTF reduced body weight in mice and humans. CNTF binds to high or low affinity receptor complexes consisting of CNTFR.gp130.LIFR or IL-6R.gp130.LIFR, respectively. Clinical studies of the CNTF derivative Axokine revealed intolerance at higher concentrations, which may rely on the low-affinity binding of CNTF to the IL-6R. Here, we aimed to generate a CNTFR-selective CNTF variant (CV). CV-1 contained the single amino acid exchange R28E. Arg(28) is in close proximity to the CNTFR binding site. Using molecular modeling, we hypothesized that Arg(28) might contribute to IL-6R/CNTFR plasticity of CNTF. CV-2 to CV-5 were generated by transferring parts of the CNTFR-binding site from cardiotrophin like cytokine to CNTF. Cardiotrophin-like cytokine selectively signals via the CNTFR.gp130.LIFR complex, albeit with a much lower affinity compared with CNTF. As shown by immunoprecipitation, all CNTF variants retained the ability to bind to CNTFR. CV-1, CV-2, and CV-5, however, lost the ability to bind to IL-6R. Although all variants induced cytokine-dependent cellular proliferation and STAT3 phosphorylation via CNTFR.gp130.LIFR, only CV-3 induced STAT3 phosphorylation via IL-6R.gp130.LIFR. Quantification of CNTF-dependent proliferation of CNTFR.gp130.LIFR expressing cells indicated that only CV-1 was as biologically active as CNTF. Thus, the CNTFR-selective CV-1 will allow discriminating between CNTFR- and IL-6R-mediated effects in vivo. PMID- 24802753 TI - Rpb4 subunit functions mainly in mRNA synthesis by RNA polymerase II. AB - RNA polymerase II (Pol II) is the central enzyme that carries out eukaryotic mRNA transcription and consists of a 10-subunit catalytic core and a subcomplex of subunits Rpb4 and Rpb7 (Rpb4/7). Rpb4/7 has been proposed to dissociate from Pol II, enter the cytoplasm, and function there in mRNA translation and degradation. Here we provide evidence that Rpb4 mainly functions in nuclear mRNA synthesis by Pol II, as well as evidence arguing against an important cytoplasmic role in mRNA degradation. We used metabolic RNA labeling and comparative Dynamic Transcriptome Analysis to show that Rpb4 deletion in Saccharomyces cerevisiae causes a drastic defect in mRNA synthesis that is compensated by down-regulation of mRNA degradation, resulting in mRNA level buffering. Deletion of Rpb4 can be rescued by covalent fusion of Rpb4 to the Pol II core subunit Rpb2, which largely restores mRNA synthesis and degradation defects caused by Rpb4 deletion. Thus, Rpb4 is a bona fide Pol II core subunit that functions mainly in mRNA synthesis. PMID- 24802754 TI - Prostaglandin E2 inhibits alpha-smooth muscle actin transcription during myofibroblast differentiation via distinct mechanisms of modulation of serum response factor and myocardin-related transcription factor-A. AB - Differentiation of lung fibroblasts into contractile protein-expressing myofibroblasts by transforming growth factor-beta1 (TGF-beta1) is a critical event in the pathogenesis of pulmonary fibrosis. Transcription of the contractile protein alpha-smooth muscle actin (alpha-SMA) is mediated by the transcription factor serum-response factor (SRF) along with its co-activator, myocardin-related transcription factor-A (MRTF-A). The endogenous lipid mediator prostaglandin E2 (PGE2) exerts anti-fibrotic effects, including the inhibition of myofibroblast differentiation. However, the mechanism by which PGE2 inhibits alpha-SMA expression is incompletely understood. Here, we show in normal lung fibroblasts that PGE2 reduced the nuclear accumulation of MRTF-A.SRF complexes and consequently inhibited alpha-SMA promoter activation. It did so both by independently inhibiting SRF gene expression and nuclear import of MRTF-A. We identified that p38 MAPK is critical for TGF-beta1-induced SRF gene expression and that PGE2 inhibition of SRF expression is associated with its ability to inhibit p38 activation. Its inhibition of MRTF-A import occurs via activation of cofilin 1 and inactivation of vasodilator-stimulated phosphoprotein. Similar effects of PGE2 on SRF gene expression were observed in fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis. Thus, PGE2 is the first substance described to prevent myofibroblast differentiation by disrupting, via distinct mechanisms, the actions of both SRF and MRTF-A. PMID- 24802755 TI - Eosinophil granule proteins: form and function. AB - Experimental and clinical data strongly support a role for the eosinophil in the pathogenesis of asthma, allergic and parasitic diseases, and hypereosinophilic syndromes, in addition to more recently identified immunomodulatory roles in shaping innate host defense, adaptive immunity, tissue repair/remodeling, and maintenance of normal tissue homeostasis. A seminal finding was the dependence of allergic airway inflammation on eosinophil-induced recruitment of Th2-polarized effector T-cells to the lung, providing a missing link between these innate immune effectors (eosinophils) and adaptive T-cell responses. Eosinophils come equipped with preformed enzymatic and nonenzymatic cationic proteins, stored in and selectively secreted from their large secondary (specific) granules. These proteins contribute to the functions of the eosinophil in airway inflammation, tissue damage, and remodeling in the asthmatic diathesis. Studies using eosinophil-deficient mouse models, including eosinophil-derived granule protein double knock-out mice (major basic protein-1/eosinophil peroxidase dual gene deletion) show that eosinophils are required for all major hallmarks of asthma pathophysiology: airway epithelial damage and hyperreactivity, and airway remodeling including smooth muscle hyperplasia and subepithelial fibrosis. Here we review key molecular aspects of these eosinophil-derived granule proteins in terms of structure-function relationships to advance understanding of their roles in eosinophil cell biology, molecular biology, and immunobiology in health and disease. PMID- 24802756 TI - Deciphering the transcriptional regulation of cholesterol catabolic pathway in mycobacteria: identification of the inducer of KstR repressor. AB - Cholesterol degradation plays a prominent role in Mycobacterium tuberculosis infection; therefore, to develop new tools to combat this disease, we need to decipher the components comprising and regulating the corresponding pathway. A TetR-like repressor (KstR) regulates the upper part of this complex catabolic pathway, but the induction mechanism remains unknown. Using a biophysical approach, we have discovered that the inducer molecule of KstR in M. smegmatis mc(2)155 is not cholesterol but 3-oxo-4-cholestenoic acid, one of the first metabolic intermediates. Binding this compound induces dramatic conformational changes in KstR that promote the KstR-DNA interaction to be released from the operator, retaining its dimeric state. Our findings suggest a regulatory model common to all cholesterol degrading bacteria in which the first steps of the pathway are critical to its mineralization and explain the high redundancy of the enzymes involved in these initial steps. PMID- 24802757 TI - The peptide-binding cavity is essential for Als3-mediated adhesion of Candida albicans to human cells. AB - The adhesive phenotype of Candida albicans contributes to its ability to colonize the host and cause disease. Als proteins are one of the most widely studied C. albicans virulence attributes; deletion of ALS3 produces the greatest reduction in adhesive function. Although adhesive activity is thought to reside within the N-terminal domain of Als proteins (NT-Als), the molecular mechanism of adhesion remains unclear. We designed mutations in NT-Als3 that test the contribution of the peptide-binding cavity (PBC) to C. albicans adhesion and assessed the adhesive properties of other NT-Als3 features in the absence of a functional PBC. Structural analysis of purified loss-of-PBC-function mutant proteins showed that the mutations did not alter the overall structure or surface properties of NT Als3. The mutations were incorporated into full-length ALS3 and integrated into the ALS3 locus of a deletion mutant, under control of the native ALS3 promoter. The PBC mutant phenotype was evaluated in assays using monolayers of human pharyngeal epithelial and umbilical vein endothelial cells, and freshly collected human buccal epithelial cells in suspension. Loss of PBC function resulted in an adhesion phenotype that was indistinguishable from the Deltaals3/Deltaals3 strain. The adhesive contribution of the Als3 amyloid-forming-region (AFR) was also tested using these methods. C. albicans strains producing cell surface Als3 in which the amyloidogenic potential was destroyed showed little contribution of the AFR to adhesion, instead suggesting an aggregative function for the AFR. Collectively, these results demonstrate the essential and principal role of the PBC in Als3 adhesion. PMID- 24802758 TI - A cryptic polyreactive antibody recognizes distinct clades of HIV-1 glycoprotein 120 by an identical binding mechanism. AB - Polyreactive antibodies play an important role for neutralization of human immunodeficiency virus (HIV). In addition to intrinsic polyreactive antibodies, the immune system of healthy individuals contains antibodies with cryptic polyreactivity. These antibodies acquire promiscuous antigen binding potential post-translationally, after exposure to various redox-active substances such as reactive oxygen species, iron ions, and heme. Here, we characterized the interaction of a prototypic human antibody that acquires binding potential to glycoprotein (gp) 120 after exposure to heme. The kinetic and thermodynamic analyses of interaction of the polyreactive antibody with distinct clades of gp120 demonstrated that the antigen-binding promiscuity of the antibody compensates for the molecular heterogeneity of the target antigen. Thus, the polyreactive antibody recognized divergent gp120 clades with similar values of the binding kinetics and quantitatively identical changes in the activation thermodynamic parameters. Moreover, this antibody utilized the same type of noncovalent forces for formation of complexes with gp120. In contrast, HIV-1 neutralizing antibodies isolated from HIV-1-infected individuals, F425 B4a1 and b12, demonstrated different binding behavior upon interaction with distinct variants of gp120. This study contributes to a better understanding of the physiological role and binding mechanism of antibodies with cryptic polyreactivity. Moreover, this study might be of relevance for understanding the basic aspects of HIV-1 interaction with human antibodies. PMID- 24802759 TI - Histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) controls mammary gland development by regulating key developmental and lineage specification genes. AB - The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b(-/-) mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b(-/-) strains, the majority of these Jarid1b(-/-) mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b(-/-) mice exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor alpha. Mechanistically, JARID1B was required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms. PMID- 24802760 TI - Nonverbal intelligence in young children with dysregulation: the Generation R Study. AB - Children meeting the Child Behavior Checklist Dysregulation Profile (CBCL-DP) suffer from high levels of co-occurring internalizing and externalizing problems. Little is known about the cognitive abilities of these children with CBCL-DP. We examined the relationship between CBCL-DP and nonverbal intelligence. Parents of 6,131 children from a population-based birth cohort, aged 5 through 7 years, reported problem behavior on the CBCL/1.5-5. The CBCL-DP was derived using latent profile analysis on the CBCL/1.5-5 syndrome scales. Nonverbal intelligence was assessed using the Snijders Oomen Nonverbal Intelligence Test 2.5-7-Revised. We examined the relationship between CBCL-DP and nonverbal intelligence using linear regression. Analyses were adjusted for parental intelligence, parental psychiatric symptoms, socio-economic status, and perinatal factors. In a subsample with diagnostic interview data, we tested if the results were independent of the presence of attention deficit hyperactivity disorder (ADHD) or autism spectrum disorders (ASD). The results showed that children meeting the CBCL-DP (n = 110, 1.8%) had a 11.0 point lower nonverbal intelligence level than children without problems and 7.2-7.3 points lower nonverbal intelligence level than children meeting other profiles of problem behavior (all p values <0.001). After adjustment for covariates, children with CBCL-DP scored 8.3 points lower than children without problems (p < 0.001). The presence of ADHD or ASD did not account for the lower nonverbal intelligence in children with CBCL-DP. In conclusion, we found that children with CBCL-DP have a considerable lower nonverbal intelligence score. The CBCL-DP and nonverbal intelligence may share a common neurodevelopmental etiology. PMID- 24802761 TI - Tumor necrosis factor-alpha regulates matrix metalloproteinase-2 expression and cell migration via ERK pathway in rat glomerular mesangial cells. AB - Mesangial cells (MCs), vascular smooth muscle-derived cells, contribute to glomerular injury by generating a number of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Matrix metalloproteinases (MMPs), regulated by various stimuli, are important in remodeling of glomerular ECM, which leads to a number of renal diseases. We investigated whether TNF-alpha participated in the regulation of MMPs and explored signal pathways involved in TNF-alpha-induced MMPs expression in rat glomerular MCs. Western blot and RT-qPCR results showed that treatment with TNF-alpha significantly increased the expression of MMP-2, but not MMP-9 at both protein and mRNA levels in rat glomerular MCs. The extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-kappaB) signal pathways were activated by TNF-alpha. Moreover, the activation of NF kappaB pathway in rat MCs was effectively inhibited by PD98059, specific inhibitor of ERK, suggesting a role for ERK in regulating NF-kappaB function. PD98059 or NF-kappaB signal pathway selective inhibitor Bay 11-7082 effectively blocked TNF-alpha-induced expression of MMP-2 in rat MCs, as determined by gene and protein expression. C-jun N-terminal kinase (JNK) signal pathway had no effect on TNF-alpha-induced expression of MMP-2, even though it was also activated by TNF-alpha in rat MCs. Furthermore, TNF-alpha could induce the cell migration of rat MCs, whereas ERK signal pathway specific inhibitor PD98059 compromised the cell migration triggered by TNF-alpha. Thus, TNF-alpha upregulates the expression of MMP-2 via activation of ERK-dependent NF-kappaB pathway in rat MCs, which may contribute to the cell migration of rat MCs. PMID- 24802762 TI - Optimization of molecular representativeness. AB - Representative subsets selected from within larger data sets are useful in many chemoinformatics applications including the design of information-rich compound libraries, the selection of compounds for biological evaluation, and the development of reliable quantitative structure-activity relationship (QSAR) models. Such subsets can overcome many of the problems typical of diverse subsets, most notably the tendency of the latter to focus on outliers. Yet only a few algorithms for the selection of representative subsets have been reported in the literature. Here we report on the development of two algorithms for the selection of representative subsets from within parent data sets based on the optimization of a newly devised representativeness function either alone or simultaneously with the MaxMin function. The performances of the new algorithms were evaluated using several measures representing their ability to produce (1) subsets which are, on average, close to data set compounds; (2) subsets which, on average, span the same space as spanned by the entire data set; (3) subsets mirroring the distribution of biological indications in a parent data set; and (4) test sets which are well predicted by qualitative QSAR models built on data set compounds. We demonstrate that for three data sets (containing biological indication data, logBBB permeation data, and Plasmodium falciparum inhibition data), subsets obtained using the new algorithms are more representative than subsets obtained by hierarchical clustering, k-means clustering, or the MaxMin optimization at least in three of these measures. PMID- 24802763 TI - MOF-based electronic and opto-electronic devices. AB - Metal-organic frameworks (MOFs) are a class of hybrid materials with unique optical and electronic properties arising from rational self-assembly of the organic linkers and metal ions/clusters, yielding myriads of possible structural motifs. The combination of order and chemical tunability, coupled with good environmental stability of MOFs, are prompting many research groups to explore the possibility of incorporating these materials as active components in devices such as solar cells, photodetectors, radiation detectors, and chemical sensors. Although this field is only in its incipiency, many new fundamental insights relevant to integrating MOFs with such devices have already been gained. In this review, we focus our attention on the basic requirements and structural elements needed to fabricate MOF-based devices and summarize the current state of MOF research in the area of electronic, opto-electronic and sensor devices. We summarize various approaches to designing active MOFs, creation of hybrid material systems combining MOFs with other materials, and assembly and integration of MOFs with device hardware. Critical directions of future research are identified, with emphasis on achieving the desired MOF functionality in a device and establishing the structure-property relationships to identify and rationalize the factors that impact device performance. PMID- 24802764 TI - Insights on the design and electron-acceptor properties of conjugated organophosphorus materials. AB - The development of conjugated organic materials has become a rapidly evolving field of research, particularly with a view toward practical applications in so called organic electronics that encompass a variety of device types, such as OLEDs, OPVs, and OFETs. Almost all of these devices minimally require the presence of electron-donor and -acceptor components that act as p- and n-type semiconductors, respectively. Research over the past two decades has shown that while there is an abundant resource of organic p-type materials, suitable n-type species are few and far between. To overcome this severe bottleneck for the further development of organic electronics, researchers have identified organo main-group avenues as valuable alternatives toward organic electron-acceptor materials that may ultimately be used as n-type components in practical devices. One particular element of interest in this context is phosphorus, which at first glance may not necessarily suggest such properties. In this Account, I provide detailed insights on the origin of the electron-acceptor properties of organophosphorus-based conjugated materials and include an overview of important molecular species that have been developed by my group and others. To this end, I explain that the electron-acceptor properties of conjugated organophosphorus materials originate from an interaction known as negative hyperconjugation. While this particular interaction creates a simply inductively withdrawing phosphoryl substituent for pi-conjugated scaffolds, incorporation of a phosphorus atom as an integral part of a cyclic substructure within a pi-conjugated system provides a much more complex, versatile, and consequently highly valuable tool for the tuning of the electron-acceptor properties of the materials. Notably, the degree of negative hyperconjugation can effectively be tailored in various ways via simple substitution at the phosphorus center. This is now well established for phosphole-based molecular materials, in which the electron-acceptor properties are also mirrored by the degree of antiaromaticity of the system. Particularly, fused and pi-extended phosphole materials show appreciable electron-acceptor properties, evident in low reduction potentials and corresponding LUMO levels. But these features do not always translate into powerful n-type materials. My group and others have thus recently been focusing on molecular organophosphorus scaffolds that also involve incorporation of imino or carbonyl groups, next to the incorporation of low coordinate phosphorus centers, to achieve superior electron-acceptor features. This state-of-the-art research has confirmed the great potential of the organophosphorus route toward powerful electron-acceptor materials, but further work is required to also establish these species as functional n-type materials. PMID- 24802765 TI - Impact of the pneumococcal conjugate vaccine on serotype distribution and susceptibility trends of pediatric non-invasive Streptococcus pneumoniae isolates in Tokai, Japan over a 5-year period. AB - Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in February 2010 markedly reduced the burden of invasive pneumococcal disease (IPD) and changed serotype distribution in Japan. We investigated the serotype distribution and susceptibility trends of non-invasive Streptococcus pneumoniae isolates collected from pediatric patients. A total of 564 pneumococcal isolates were collected over a 5-year period between 2008 and 2012. The coverage of PCV7 significantly decreased throughout the study period, from 49.3% in period 1 (between June 2008 and April 2009) to 23.4% in period 4 (between October 2011 and March 2012). This change was mainly due to a large decrease in the frequency of 19F (from 20.6% to 9.9%) and 6B (from 10.3% to 2.7%) and an increase in serotype 3 (from 5.1% to 13.5%) and serogroup 15 (from 4.4% to 9.0%). According to serotype replacement, the susceptible ratios of S. pneumoniae to beta-lactams increased slightly while macrolide resistance remained high. The high frequency of macrolide-resistant pneumococcal isolates may continue because of the high frequency of erm(B) in replace serotypes such as serotype 3 and serogroup 15. The continuous surveillance study is essential following the introduction of a second generation 13-valent pneumococcal conjugate vaccine (PCV13). PMID- 24802766 TI - Seroepidemiology of tetanus in Korean adults and adolescents in 2012. AB - This seroepidemiologic study was performed to evaluate the immune status against tetanus in Korean adolescents and adults and to provide evidence to develop strategies for tetanus prevention. Between July 2012 and December 2012, serum samples were collected from adults and adolescents 11 years of age and older, and serum anti-tetanus IgG titers were determined using a commercial ELISA kit. Subjects were divided into six age groups: 11-20 years, 21-30 years, 31-40 years, 41-50 years, 51-60 years, and >=61 years. The mean anti-tetanus IgG titers and tetanus seroprevalence of the age groups were compared. A total of 1193 adults and adolescents were enrolled. Mean anti-tetanus IgG titer and tetanus seroprevalence of all subjects were 1.20 +/- 3.58 IU/mL and 56.4%, respectively. The mean anti-tetanus IgG titer decreased with an increase in age (p < 0.001). Tetanus seroprevalence increased from 92.0% in the 11-20 year age group to 95.7% in the 21-30 year age group, and then decreased with a further increase in age (p < 0.001). These results reflected an appropriate Td booster vaccine coverage at 11-12 years of age. However, the tetanus seroprevalence of adults older than 41 years was as low as the levels in previous studies: therefore, adults should be more encouraged to acquire decennial Td booster vaccinations recommended by the National Immunization Program. PMID- 24802767 TI - A Sequence of events model of episodic memory shows parallels in rats and humans. AB - A critical feature of episodic memory is the ability to remember the order of events as they occurred in time, a capacity shared across species including humans, nonhuman primates, and rodents. Accumulating evidence suggests that this capacity depends on a network of structures including the hippocampus and the prefrontal cortex, but their respective contributions remain poorly understood. As addressing this important issue will require converging evidence from complementary investigative techniques, we developed a cross-species, nonspatial sequence memory task suitable for behavioral and neurophysiological studies in rodents and in humans. The task involves the repeated presentation of sequences of items (odors in rats and images in humans) and requires subjects to make a judgment as to whether each item is presented "in sequence" or "out of sequence." To shed light on the cognitive processes and sequence representations supporting performance, different types of "out of sequence" probe trials were used including: (i) repeating an item from earlier in the sequence (Repeats; e.g., ABAD), (ii) skipping ahead in the sequence (Skips; e.g., ABD), and (iii) inserting an item from a different sequence into the same ordinal position (Ordinal Transfers; e.g., A2CD). We found a remarkable similarity in the performance of rats and humans, particularly in the pattern of results across probe trial types. Thus, the results suggest that rats and humans not only remember the sequences of events, but also use similar underlying cognitive processes and mnemonic representations. This strong cross-species correspondence validates this task for use in future basic and clinical interdisciplinary studies aimed at examining the neural mechanisms underlying episodic memory. PMID- 24802768 TI - Functional DNA methylation in a transcript specific 3'UTR region of TrkB associates with suicide. AB - Previous studies indicate that a subgroup of suicide completers has low cortical brain expression levels of TrkB-T1, a TrkB gene transcript that is highly expressed in astrocytes. Epigenetic modifications, including methylation changes in the TrkB promoter, partially explain TrkB-T1 low expression levels in brain tissue from suicide completers. The aim of this study was to investigate whether methylation changes in other regions of the TrkB gene could also contribute to the significant downregulation of the TrkB-T1 transcript observed in the brain of suicide completers. Methylation levels were assessed on BA8/9 from suicide completers expressing low TrkB-T1 transcript levels and controls, using custom made Agilent arrays tiling the whole TrkB gene. After statistical correction for multiple testing, five probes located in the TrkB-T1 3'UTR region were found hypermethylated in the frontal cortex of suicide completers. These results were validated for four CpGs spanning a 150 bp sequence by cloning and Sanger sequencing bisulfite treated DNA. We found a significant correlation between the methylation level at these four CpGs and TrkB-T1 expression in BA8/9. Site specific hypermethylation on this 3'UTR sequence induced decreased luciferase activity in reporter gene cell assays. Site-specific differential methylation in the TrkB-T1 3'UTR region associates with functional changes in TrkB-T1 expression and may play a significant role in the important decrease of cortical TrkB-T1 expression observed among suicide completers. PMID- 24802769 TI - Adaptive compression therapy for venous leg ulcers: a clinically effective, patient-centred approach. AB - A prospective, randomised, 12-week study was performed to evaluate the efficacy and tolerability of two compression methods for venous leg ulcers (VLUs); a new adaptive compression therapy (ACT) system, combining intermittent and sustained pneumatic compression (n = 38) and a conventional four-layer bandage system (n = 52). Primary outcomes were ulcer healing and safety. Secondary outcomes were comfort, compliance, ulcer pain, patient-perceived product performance and quality of life. Ulcer healing rate was similar (31.6% versus 42.3%, respectively, P = 0.30) between the treatments. Adverse events and patient-rated comfort were also similar. Average daily usage for the dual system was 10.5 and 1.8 hours in the sustained and intermittent modes, respectively, representing its use during 71% of waking hours. Predicted final ulcer pain was also similar (P = 0.68). Performance was subjectively better for adaptive compression and significantly higher for exudate management (P = 0.04), skin protection (P < 0.001), removal ease (P = 0.0007), bathing (P < 0.0001) and sleep comfort (P = 0.0405). The adjusted final quality-of-life score was 0.1025 higher for adaptive compression (P = 0.0375). Subjects with healed ulcers attained higher final scores than unhealed subjects (P = 0.0004). This study provides evidence that ACT is comparably efficacious to successfully heal VLUs compared with four-layer bandage management but is better accepted and achieves higher patient-reported quality-of-life scores in these challenging patients. PMID- 24802770 TI - Gender and racial/ethnic background predict weight loss after Roux-en-Y gastric bypass independent of health and lifestyle behaviors. AB - Our study investigated how demographic, health, and behavioral factors interacted to affect weight outcomes in bariatric patients. Roux-en-Y gastric bypass (RYGB) patients who were non-Hispanic black, Hispanic, or non-Hispanic white race/ethnicity, had no revisions to their RYGB during 2004-2009, and had at least 1 year of follow-up data for body weight after surgery (n = 860) were surveyed by phone about their health and behaviors. The main outcomes of interest were percent excess weight loss and percent of initial weight lost. Participants were 47 +/- 11 years old, 54 % non-Hispanic white, 25 % Hispanic, and 21 % non Hispanic black, 82 % female, 60 % married, 82 % had some college education, and 47 % had an annual income between $35,000 and $80,000. At the time of surgery, patients had lost 50 +/- 29 % of their excess weight and had achieved 24 +/- 15 % initial weight lost after an average of 54 months of follow-up. After accounting for weight at the time of surgery, demographics, and self-reported health and behavior, non-Hispanic black men had significantly greater weight loss compared to non-Hispanic white men (p < .05). There were no differences between racial/ethnic groups of women in weight outcomes. Percent excess weight loss was related to greater diet soda intake, and percent initial weight lost was related to greater water intake. Independent of health status and lifestyle behaviors, age, and weight at the time of surgery, race/ethnicity, gender, and diet soda and water intake were the strongest predictors of weight outcomes after RYGB surgery. PMID- 24802771 TI - Conflicts of interest in psychiatry: strategies to cultivate literacy in daily practice. AB - The relationship between psychiatry and pharmaceutical companies has come under scrutiny during the past decade. Concerns are growing that financial ties of psychiatrists to the pharmaceutical industry may unduly influence professional judgments involving the primary interests of patients. Such conflicts of interest threaten the public trust in psychiatry. The goal of conflict of interest policies is to protect the integrity of professional judgment and to preserve public trust. The disclosure of individual and institutional financial relationships is a critical but limited first step in the process of identifying and responding to conflicts of interest. Conflict of interest policies and procedures can be strengthened by engaged psychiatrists, researchers, institutions, and professional associations in developing policies and consensus standards. Research on conflicts of interest can provide a stronger evidence base for policy design and implementation. Society has traditionally granted the medical profession considerable autonomy and may be willing to continue do so in the case of conflicts of interest. Nevertheless, concern is growing that stronger measures are needed. To avoid undue regulatory burdens, psychiatrists can play a vital role in designing responsible and reasonable conflict of interest policies that reduce the risks of bias and the loss of trust. Psychiatrists and the institutions that carry out research, education, clinical care, and practice guideline development must recognize public concerns about conflicts of interest and take effective measures soon to maintain public trust with a cultural change in the practice of psychiatry, from reactive treatment-seeking for mental illness to proactive advocacy for patients. PMID- 24802772 TI - A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis. AB - The histone methyltransferase EZH2 is frequently mutated in germinal center derived diffuse large B-cell lymphoma and follicular lymphoma. To further characterize these EZH2 mutations in lymphomagenesis, we generated a mouse line where EZH2(Y641F) is expressed from a lymphocyte-specific promoter. Spleen cells isolated from the transgenic mice displayed a global increase in trimethylated H3K27, but the mice did not show an increased tendency to develop lymphoma. As EZH2 mutations often coincide with other mutations in lymphoma, we combined the expression of EZH2(Y641F) by crossing these transgenic mice with Eu-Myc transgenic mice. We observed a dramatic acceleration of lymphoma development in this combination model of Myc and EZH2(Y641F). The lymphomas show histologic features of high-grade disease with a shift toward a more mature B-cell phenotype, increased cycling and gene expression, and epigenetic changes involving important pathways in B-cell regulation and function. Furthermore, they initiate disease in secondary recipients. In summary, EZH2(Y641F) can collaborate with Myc to accelerate lymphomagenesis demonstrating a cooperative role of EZH2 mutations in oncogenesis. This murine lymphoma model provides a new tool to study global changes in the epigenome caused by this frequent mutation and a promising model system for testing novel treatments. PMID- 24802773 TI - Eltrombopag and high-dose dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. AB - Immune thrombocytopenia (ITP) results from platelet destruction and production suppression. Eltrombopag belongs to a new class of thrombopoietin-mimetic drugs that raise platelet counts in ITP patients. We performed a single-arm study to assess the response to a single course of dexamethasone (40 mg by mouth, days 1 4) in combination with eltrombopag (50 mg, days 5-32) in 12 adults with newly diagnosed ITP in an outpatient setting. Median follow-up was 12.5 months. After therapy (day 33), 100% of patients achieved at least >=30 * 10(9)/L platelets. Four patients relapsed. Complete response at 6 months (platelets >=100 * 10(9)/L) was achieved in 50% of patients and response at 6 months (platelets >=30 <100 * 10(9)/L) was achieved in another 25%; relapse-free survival was 66.7% at 12 months (median response duration of 8.3 months). In conclusion, eltrombopag/dexamethasone is a feasible frontline therapy for ITP. This trial is registered at www.clinicaltrials.gov as NCT01652599. PMID- 24802774 TI - Mapping hematopoiesis in a fully regenerative vertebrate: the axolotl. AB - Hematopoietic stem cell (HSC)-derived cells are involved in wound healing responses throughout the body. Unfortunately for mammals, wound repair typically results in scarring and nonfunctional reparation. Among vertebrates, none display such an extensive ability for adult regeneration as urodele amphibians, including 1 of the more popular models: the axolotl. However, a lack of knowledge of axolotl hematopoiesis hinders the use of this animal for the study of hematopoietic cells in scar-free wound healing and tissue regeneration. We used white and cytomegalovirus:green fluorescent protein(+) transgenic white axolotl strains to map sites of hematopoiesis and develop hematopoietic cell transplant methodology. We also established a fluorescence-activated cell sorter enrichment technique for major blood lineages and colony-forming unit assays for hematopoietic progenitors. The liver and spleen are both active sites of hematopoiesis in adult axolotls and contain transplantable HSCs capable of long term multilineage blood reconstitution. As in zebrafish, use of the white axolotl mutant allows direct visualization of homing, engraftment, and hematopoiesis in real time. Donor-derived hematopoiesis occurred for >2 years in recipients generating stable hematopoietic chimeras. Organ segregation, made possible by embryonic microsurgeries wherein halves of 2 differently colored embryos were joined, indicate that the spleen is the definitive site of adult hematopoiesis. PMID- 24802776 TI - Five-column chromatography separation for simultaneous determination of hard-to detect radionuclides in water and swipe samples. AB - There is a growing demand for the rapid determination of hard-to-detect radionuclides in environmental and biological samples for environmental monitoring, radiological protection, and nuclear forensic reasons. A new method using five-column chromatography separation has been developed for the simultaneous determination of Pu, Np, Th, U, Am, Cm, Pm, Y, and Sr isotopes, as well as iron-55, by inductively coupled mass spectrometry (ICPMS), alpha spectrometry, Cerenkov and liquid scintillation (LS) counting. Spiked swipe and water samples as well as proficient testing water standards were analyzed to validate the separation procedure, and the results are in good agreement with the expected values. The method provides quick sample turnaround time and high analysis throughput with low analysis cost. The flexibility of the method also allows for its easy adaptation to various emergency and routine radioassays. PMID- 24802775 TI - A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. AB - Stimulation of platelet production by thrombopoietin-receptor agonists (TPO-RAs) is an effective second-line treatment in immune thrombocytopenia (ITP). This 28 day phase 2 study assigned subjects with ITP of >=3 months to once-daily oral avatrombopag (2.5, 5, 10, or 20 mg), an investigational nonpeptide TPO-RA active in humans, or placebo; subjects completing randomized treatment could enroll in a 24-week extension study. Of 64 randomized subjects, 13% (avatrombopag 2.5 mg), 53% (5 mg), 50% (10 mg), and 80% (20 mg), vs 0% for placebo, achieved a platelet count (PC) response of >=50 * 10(9)/L with >=20 * 10(9)/L increase above baseline at day 28. Fifty-three subjects (83%) entered the extension: 52% and 76% had a durable (PC response at >=75% of their platelet assessments over the last 14 weeks) and overall (stable response or response at any >=2 consecutive visits) response, respectively. All subjects experienced >=1 adverse event (AE) (most commonly fatigue, headache, and epistaxis); 19% (n = 12) reported >=1 serious AE; 10 (16%) withdrew due to an AE (5 due to increased PC). Avatrombopag was active and generally well tolerated, with PC response rates and AE incidence comparable with other TPO-RAs. These studies were registered at www.clinicaltrials.gov as #NCT00441090 and #NCT00625443. PMID- 24802777 TI - Qualitative approach to attempted suicide by adolescents and young adults: the (neglected) role of revenge. AB - BACKGROUND: Suicide by adolescents and young adults is a major public health concern, and repetition of self-harm is an important risk factor for future suicide attempts. OBJECTIVE: Our purpose is to explore the perspective of adolescents directly involved in suicidal acts. METHODS: Qualitative study involving 16 purposively selected adolescents (sex ratio1 ? 1) from 3 different centers. Half had been involved in repeated suicidal acts, and the other half only one. Data were gathered through semistructured interviews and analyzed according to Interpretative Phenomenological Analysis. RESULTS: We found five main themes, organized in two superordinate themes. The first theme (individual dimensions of the suicide attempt) describes the issues and explanations that the adolescents saw as related to themselves; it includes the subthemes: (1) negative emotions toward the self and individual impasse, and (2) the need for some control over their lives. The second main theme (relational dimensions of attempted suicide) describes issues that adolescents mentioned that were related to others and includes three subthemes: (3) perceived impasse in interpersonal relationships, (4) communication, and (5) revenge. CONCLUSIONS: Adolescents involved in suicidal behavior are stuck in both an individual and a relational impasse from which there is no exit and no apparent way to reach the other. Revenge can bridge this gap and thus transforms personal distress into a relational matter. This powerful emotion has been neglected by both clinicians and researchers. PMID- 24802778 TI - Professionalising health promotion? PMID- 24802779 TI - 21st century determinants of health and wellbeing: a new challenge for health promotion. PMID- 24802780 TI - Does health promotion need a Code of Ethics? Results from an IUHPE mixed method survey. AB - BACKGROUND: Health promotion is an ethically challenging field involving constant reflection of values across multiple cultures of what is regarded as good and bad health promotion practice. While many disciplines are guided by a Code of Ethics (CoE) no such guide is available to health promoters. The International Union for Health Promotion and Education (IUHPE) has been nominated as a suitable candidate for developing such a code. It is within this context that the IUHPE Student and Early Career Network (ISECN), through its Ethics Working Group, has taken up the challenge of preparing the foundations for a CoE for health promotion. METHODS: An online survey comprising open and closed-answer questions was used to gather the opinions of IUHPE members regarding the need for a CoE for health promotion. The quantitative data were calculated with descriptive analyses. A thematic analysis approach was used to analyze and interpret the qualitative data. RESULTS: IUHPE members (n = 236) from all global regions responded to the survey. The majority (52%) of the respondents had 11 years' experience or more in the field of health promotion. Ethical dilemmas were commonly encountered. The need for a CoE for health promotion was expressed by 83% of respondents. Respondents also offered their views of possibilities, ideas and challenges regarding the development of a CoE for health promotion. CONCLUSIONS: Considering that health promoters encounter ethical dilemmas frequently in their practice, this study reinforces the need to develop a CoE for the field. The recommendations from the survey provide a good basis for future work to develop such a code. PMID- 24802781 TI - An exploration of the connection between two meaning perspectives: an evidence based approach to health information delivery to vulnerable groups of Arabic- and Somali-speaking asylum seekers in a Swedish context. AB - The right to health care is significant for asylum seekers, particularly as many of them have experienced traumatic life events in their home country, during flight or in their host country. Post-migration living conditions have more impact than pre-migration conditions on ill health among asylum seekers, which underscores the importance of health care-related refugee reception policies. The purpose of this article is to explore the perceived meaning of comprehensive health information provided by a nurse to Arabic- and Somali-speaking adult asylum seekers, in a Swedish context, during its introduction at the Migration Board. In our study, the endpoint was whether asylum seekers found such health information relevant, understandable and respectful. Following an oral presentation, participants filled in a questionnaire consisting of three close ended questions. A total of 39 groups of presentation attendees included 626 asylum seekers (415 Arabic- and 211 Somali-speaking). Data were analysed with descriptive statistics. Comments underwent content analysis. We also present some socio-demographic data on these asylum seekers. Independently of gender and language, the participants expressed their gratitude for and the meaningfulness of receiving professional, fact-based information, as well as being treated with concern and respect. They indicated a great need for this and felt relieved by being listened to. They liked the pedagogic group method, the opportunity for dialogue and to practice exercising their rights. These promising results indicate that exercising the asylum-seekers' right to receive such health information would improve future reception policies not only in Sweden, but throughout the EU. A renewed focus on communication and pedagogic skills, instead of just cultural training, should be considered for health care professionals assisting asylum seekers. PMID- 24802782 TI - The mental health of adolescent school children: a comparison among Japan, Korea, and China. AB - This study compared the mental health of adolescents in three countries in northeast Asia: Japan, South Korea, and China. The study sample included a total of 1,399 third graders at junior high schools: 632 from Yonago City and Tottori City in Japan, 377 from Wonju City in Korea, and 390 from Changchun City in China. Mental health was measured by the Ochanomizu University Health Examination, which includes mental health scales composed of somatic symptoms, eating disorders, depression, interpersonal relationships, powerlessness, and impulsiveness; self-resilience; familial relationships; friendships; a feeling of gloom during the previous month; current well-being; and counseling. The results of this study were as follows: first, Japanese students experienced more difficulties in interpersonal relationships and experienced more feelings of powerlessness than Korean and Chinese students. Korean students were vulnerable to somatic symptoms and impulsiveness, whereas Chinese students experienced more depression than Korean and Japanese students. Second, more female students were in the poor mental health group than male students. Third, Japanese female students ranked the lowest of all groups for the Resilience Index scores. Fourth, when in need of counseling, students solicited advice from teachers (classroom teachers, health teachers or club teachers) about their study-related problems, and asked for advice from friends regarding problems or worries about peer and family relations. However, a number of students received no counseling for their troubles. The study concluded that it is necessary to promote a healthy environment for students, with easy access to counseling from mental health care professionals. PMID- 24802783 TI - Introducing home based skin-to-skin care for low birth weight newborns: a pilot approach to education and counseling in Ghana. AB - Skin-to-skin contact (STSC) for low birth weight newborns in community settings may greatly improve survival, especially where access to health facilities is limited. Community STSC has been implemented in large-scale trials in Asia and is recommended by WHO and UNICEF. In countries where the practice is entirely new, such as Ghana, STSC may need special educational approaches. OBJECTIVE: The dual aims of this study were to understand the acceptance and barriers to STSC in an African community setting and to use in-depth formative research to contribute to the success of a behavior-based health intervention. DESIGN: A rapid qualitative study with an intentionally small sample. SETTING: Kintampo, Ghana, a predominately rural, agrarian area in the center of the country with diverse ethnic groups in a forest-savannah transition zone. METHOD: Key informants were consulted through in-depth interviews and focus group discussions to develop the pilot. Five mothers participated in pilot instruction (four refused), which included counseling and used a trials-of-improved-practices methodology; data from group discussion with traditional birth attendants were also included. RESULTS: It was difficult to overcome barriers to the practice (post partum pain, fear of harming the umbilicus), and less intractable barriers (traditional carrying practices, fear of causing harm, lack of back support, time constraints, breast feeding issues) were reported. CONCLUSION: Some study participants tried STSC but none did it continuously. As promotion of STSC could be vital for improving newborn survival in low resource settings, tackling perceived barriers may be an important way to increase acceptability of this practice. PMID- 24802784 TI - The International Union for Health Promotion and Education (IUHPE) Student and Early Career Network (ISECN): a case illustrating three strategies for maximizing synergy in professional collaboration. AB - The International Union for Health Promotion and Education (IUHPE) Student and Early Career Network (ISECN) was constructed upon a foundation of research, using the Bergen Model of Collaborative Functioning (BMCF) as a blueprint to inform its leadership, communication, structure, and culture. The BMCF consists of inputs (partners, mission, and financial resources), throughputs (operational processes), and outputs (synergy and antagony). In this commentary, we use the BMCF to describe the ISECN work, highlighting opportunities, successes, and challenges. We also put forward three strategies derived from the BMCF that have been purposefully employed by ISECN to maximize its production of synergy from the voluntary contributions of its members. PMID- 24802785 TI - Educating the Canadian public about the social determinants of health: the time for local public health action is now! AB - Despite Canada's history of developing health promotion and population health concepts, Canada falls behind other wealthy nations in having these ideas implemented in the form of public policy that strengthens the social determinants of health (SDH). Much of this has to do with the lack of awareness by Canadians about the SDH that stems from the lack of media reporting on the determinants of health and the unwillingness of most local public health units across Canada to raise these issues in a consistent manner. Canada is not unique in this situation. If the public health community in Canada is to live up to its self professed mission of improving the health of Canadians it must undertake to educate the public about the SDH as effectively as it took on the task of educating the public of the importance of not smoking, of exercising and adopting a healthy diet. PMID- 24802789 TI - [Temporal perspectives: understanding them to take them into account for our health promotion interventions]. PMID- 24802790 TI - [Continuity of hospital care and foreign doctors: regularization of a system and its limitations in France]. PMID- 24802794 TI - [Unhealthy eating, physical inactivity and childhood obesity in Colombia: an urgent call for the state and civil society to undertake effective action]. PMID- 24802796 TI - DNA barcode ITS2 coupled with high resolution melting (HRM) analysis for taxonomic identification of Sideritis species growing in Greece. AB - Identification of genotypes in Sideritis is complicated owing to the morphological similarity and common occurrence of natural hybridisation within Sideritis species. Species- and genotype-specific DNA markers are very useful for plant identification, breeding and preservation programs. Herein, a real-time polymerase chain reaction (PCR) of ITS2 barcode region coupled with high resolution melting-curve (HRM) analysis was evaluated for an accurate, rapid and sensitive tool for species identification focusing on seven Sideritis species growing in Greece. The HRM assay developed in this study is a rapid and straightforward method for the identification and discrimination of the investigated Sideritis species. This assay is simple compared to other genotyping methods as it does not require DNA sequencing or post-PCR processing. Therefore, this method offers a new alternative for rapid detection of Sideritis species. PMID- 24802797 TI - Biochemical characterization and growth patterns of new yeast isolates. AB - African sorghum opaque beers play a vital role in the diet of millions of consumers. In the current study we investigated the growth profiles of yeast strains isolated from kpete-kpete, a traditional starter used to produce tchoukoutou, an opaque sorghum beer in Benin. 10 yeast strains were isolated from sorghum beer starters and cultivated under both liquid and solid media for phenotypic growth characterization. All yeast isolates were able to grow both on solid and liquid media. Based on their growth profiles, the isolates were clustered into three groups: (i) the aggressive growth pattern (30%), (ii) the moderate growth pattern (50%), and (iii) the slow growth pattern (20%). Based on gene expression pattern, absorbance (A(600 nm)) and diameter of growth in both liquid and solid media respectively, yeast strains YK34, YK15 and YK48 were clustered in the first group, and referred to as the most aggressive growth strains, followed by group 2 (YK24, YK5, YK12, YK20, YK2) and group 3 (YK37, YK41). This growth pattern was confirmed by Invertase gene expression profiling of the yeasts showing group 1 with high level of Invertase gene expression followed by group 2 and group 3 respectively. Our results suggest that YK34, YK15 and YK48 and YK2 yeast strains constitute the best candidates in fermentation of sorghum beer production based on growth rate and assimilation of carbon and nitrogen sources. PMID- 24802798 TI - Adsorption of indium(III) ions from aqueous solution using chitosan-coated bentonite beads. AB - Batch adsorption study was utilized in evaluating the potential suitability of chitosan-coated bentonite (CCB) as an adsorbent in the removal of indium ions from aqueous solution. The percentage (%) removal and adsorption capacity of indium(III) were examined as a function of solution pH, initial concentration, adsorbent dosage and temperature. The experimental data were fitted with several isotherm models, where the equilibrium data was best described by Langmuir isotherm. The mean energy (E) value was found in the range of 1-8kJ/mol, indicating that the governing type of adsorption of indium(III) onto CCB is essentially physical. Thermodynamic parameters, including Gibbs free energy, enthalpy, and entropy indicated that the indium(III) ions adsorption onto CCB was feasible, spontaneous and endothermic in the temperature range of 278-318K. The kinetics was evaluated utilizing the pseudo-first order and pseudo-second order model. The adsorption kinetics of indium(III) best fits the pseudo-second order (R(2)>0.99), which implies that chemical sorption as the rate-limiting step. PMID- 24802799 TI - Parenting behaviors and vagal tone at six months predict attachment disorganization at twelve months. AB - The authors investigated the relationships among parenting behaviors, infant vagal tone, and subsequent attachment classification. Vagal tone was assessed among 6-month olds (n = 95) during the still-face paradigm (SFP) via respiratory sinus arrhythmia (RSA), while attachment security and disorganization were measured at 12 months during the strange situation procedure (SSP). Infants demonstrating higher levels of RSA during the normal interaction and reunion episodes of the SFP whose mothers were also rated as negative-intrusive exhibited higher levels of attachment disorganization at 12 months, while infants with lower RSA and mothers who were negative-intrusive did not exhibit higher levels of disorganization. These results suggest that high levels of RSA may not be adaptive within the context of negative-intrusive parenting. PMID- 24802801 TI - Detachably assembled microfluidic device for perfusion culture and post-culture analysis of a spheroid array. AB - Microfluidic devices permit perfusion culture of three-dimensional (3D) tissue, mimicking the flow of blood in vascularized 3D tissue in our body. Here, we report a microfluidic device composed of a two-part microfluidic chamber chip and multi-microwell array chip able to be disassembled at the culture endpoint. Within the microfluidic chamber, an array of 3D tissue aggregates (spheroids) can be formed and cultured under perfusion. Subsequently, detailed post-culture analysis of the spheroids collected from the disassembled device can be performed. This device facilitates uniform spheroid formation, growth analysis in a high-throughput format, controlled proliferation via perfusion flow rate, and post-culture analysis of spheroids. We used the device to culture spheroids of human hepatocellular carcinoma (HepG2) cells under two controlled perfusion flow rates. HepG2 spheroids exhibited greater cell growth at higher perfusion flow rates than at lower perfusion flow rates, and exhibited different metabolic activity and mRNA and protein expression under the different flow rate conditions. These results show the potential of perfusion culture to precisely control the culture environment in microfluidic devices. The construction of spheroid array chambers allows multiple culture conditions to be tested simultaneously, with potential applications in toxicity and drug screening. PMID- 24802800 TI - Predicting pneumonia mortality using CURB-65, PSI, and patient characteristics in patients presenting to the emergency department of a comprehensive cancer center. AB - The prognostic accuracy of the CURB-65 criteria and pneumonia severity index (PSI) in immunocompromised cancer patients with pneumonia is unknown. We sought to determine whether CURB-65 and PSI predict 28-day mortality in cancer patients with pneumonia, and identify other factors that predispose cancer patients with pneumonia to a high mortality risk. We assessed sensitivities, specificities, predictive values, and areas under the receiver operating curve area under the curve (AUC) of the CURB-65 and PSI in predicting the 28-day mortality of cancer patients presenting to our institution's emergency department with pneumonia. We used the DeLong and Clarke-Pearson approach to determine whether the addition of other risk factors improved the scales' performances. The overall and pneumonia related 28-day mortality rates were 20.2% (n = 44) and 17.4% (n = 38), respectively. In predicting 28-day mortality, the CURB-65 score had sensitivity of 45% and specificity of 81%, and the PSI score had sensitivity of 82% and specificity of 34%. The CURB-65 and PSI discriminated poorly between fatal and nonfatal pneumonia cases (AUCs, 0.664 and 0.658, respectively; 95% confidence interval [CI], 0.57-0.75 for each). The addition of radiation therapy (RT) within 4 weeks and stem cell transplant (SCT) significantly improved the AUCs of the CURB-65 (0.75; 95% CI, 0.67-0.83) and PSI (0.73; 95% CI, 0.65-0.82). Inadequate performances of CURB-65 and PSI demonstrate that a tool for predicting pneumonia related mortality in cancer patients and other immunocompromised populations is needed. Pneumonia patients who have undergone recent RT or (SCT) are at a high risk of dying from pneumonia and require special consideration when assessing pneumonia-related mortality risk. PMID- 24802802 TI - A reciprocal effects model of the temporal ordering of motivation and burnout among youth table tennis players in intensive training settings. AB - Using self-determination theory (SDT) (Deci, E.L., & Ryan, R.M. (1985). Intrinsic motivation and self-determination in human behavior. New York, NY: Plenum) as the theoretical framework, we conducted a longitudinal investigation of the temporal ordering between motivation and burnout among youth athletes in intensive training setting. Data were collected from 145 table tennis players in intensive training centres at three time points during a 2-month period characterised by a simultaneous increase in social, physical and psychological demands for these athletes. Structural equation modelling of cross-lagged panel models was used to test the hypotheses. Results showed significant paths leading from athlete burnout - especially sport devaluation and reduced sense of accomplishment - at time 1 to amotivation, intrinsic and extrinsic motivations at times 2 and 3. Only two significant paths leading from motivation (introjected regulation at time 1) to burnout (emotional/physical exhaustion at time 2 and reduced sense of accomplishment at time 3) were identified. Overall, our results suggest that athlete burnout predicts motivation over time but motivation did not predict athlete burnout over time. Results are discussed in terms of current research findings on SDT. PMID- 24802803 TI - Long-term outcomes and complications of trabeculectomy for secondary glaucoma in patients with familial amyloidotic polyneuropathy. AB - OBJECTIVE: Secondary glaucoma is a serious complication in patients with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP). We assessed the long-term outcomes and complications of trabeculectomy with mitomycin C (MMC) for secondary glaucoma associated with FAP. METHODS: Medical case records of Kumamoto University Hospital were retrospectively reviewed. Twenty-one eyes of 13 patients (10 with FAP ATTR Val30Met; 3 with FAP ATTR Tyr114Cys) underwent trabeculectomy with MMC and follow-up of at least 2 years. The primary outcome measure was Kaplan-Meier survival, with failure of this treatment being defined as an intraocular pressure (IOP) of <=5 mm Hg or >=22 mm Hg on two consecutive visits or as additional operations needed to reduce IOP. Secondary outcome measures included complications, bleb characteristics, and additional postoperative interventions required. RESULTS: The mean postoperative follow-up period was 5.7 years (range, 2.2-12.7 years). Kaplan-Meier analysis indicated probabilities of success of 0.76, 0.67, and 0.53 at 1, 2, and 3 years after operation, respectively. Significant complications included ocular decompression retinopathy in 7 eyes (33%) and bleb encapsulation in 10 eyes (48%). Twelve eyes (57%) needed additional surgery, such as bleb revision or trabeculectomy with MMC, to reduce IOP. CONCLUSIONS: Trabeculectomy with MMC may not be optimal for patients with FAP-related glaucoma and may have several significant complications. PMID- 24802804 TI - Helicobacter pylori and the molecular pathogenesis of intestinal-type gastric carcinoma. AB - Gastric carcinoma is an inflammation-related cancer caused by long-term infection with the human bacterial pathogen, Helicobacter pylori. The pattern of acute-on chronic inflammation causes progressive mucosal damage which may result in atrophy with metaplastic epithelia and eventually gastric cancer. Recently, it has been recognized that H. pylori can also cause genetic instability such as double-stranded DNA breaks and can produce gene activation and silencing via epigenetic pathways. As genetic instability is the hallmark of cancer, we highlight recent progress in understanding the gastric carcinogenesis in relation to H. pylori-related inflammation, H. pylori-induced double-stranded DNA breakage and aberrant gene expression as well as the mechanisms and role of H. pylori associated epigenetic change in gene expression. PMID- 24802805 TI - Diabetes Attitude Scale: validation in type-2 diabetes patients in multiple centers in China. AB - OBJECTIVE: The aim of the paper is to report the development and psychometric testing of Diabetes Attitude Scale. METHOD: A prospective study was performed. The cultural equivalency and content validity of the Diabetes Attitude Scale were determined by panels of endocrinologists, physiologists, nurses and dieticians. An accurate and usable translation was obtained for each of five subscales examining attitudes on need for special training, the seriousness of type-2 diabetes, the need for controlling the condition, its psychosocial impact and the degree of autonomy given to patients in decision making. The validation was derived from 5961 patients with type-2 diabetes, recruited from 50 centers in 29 provinces throughout China between March 1st and September 30th, 2010. RESULTS: The modified Diabetes Attitude Scale showed an acceptable level of internal consistency. The strength of the inter-correlations among the domains of five subscales suggests that the instrument measures related but separate domains of patients' attitudes toward diabetes. Moreover, the test-retest intraclass correlation coefficients were high enough to support the stability of the Chinese version of the third version of the scale. CONCLUSIONS: The psychometric properties of the Chinese version of Diabetes Attitude Scale demonstrated satisfactory validity and reliability and appeared to effectively evaluate attitudes toward diabetes in patients with type-2 diabetes. PMID- 24802806 TI - Serotonergic therapies for cognitive symptoms in Alzheimer's disease: rationale and current status. AB - Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Research focused on identifying compounds that restore cognition and memory in AD patients is a very active investigational pursuit. Cholinesterase inhibitors for the symptomatic treatment of cognitive decline in AD have been in use for more than a decade but provide only modest benefits in most patients. Preclinical research is constantly providing new information on AD. The involvement of the serotonergic system in higher cognitive processes such as memory and learning has been widely described and extensive serotonergic denervation has been reported in AD. This review aims to explain the rationale behind testing serotonergic therapies for AD in terms of current knowledge about the pathophysiology of the disease. Based on preclinical studies, certain serotonin (5-HT) receptor ligands have been suggested to have the ability to modify or improve memory/cognition, specifically 5-HT receptors acting at 5-HT1A, 5-HT4 and 5-HT6 receptors. This article summarizes the pharmacology, efficacy, safety and tolerability data for the various serotonergic agents currently in clinical development for AD. PMID- 24802807 TI - Yeast frataxin is stabilized by low salt concentrations: cold denaturation disentangles ionic strength effects from specific interactions. AB - Frataxins are a family of metal binding proteins associated with the human Friedreich's ataxia disease. Here, we have addressed the effect of non specifically binding salts on the stability of the yeast ortholog Yfh1. This protein is a sensitive model since its stability is strongly dependent on the environment, in particular on ionic strength. Yfh1 also offers the unique advantage that its cold denaturation can be observed above the freezing point of water, thus allowing the facile construction of the whole protein stability curve and hence the measurement of accurate thermodynamic parameters for unfolding. We systematically measured the effect of several cations and, as a control, of different anions. We show that, while strongly susceptible to ionic strength, as it would be in the cellular environment, Yfh1 stability is sensitive not only to divalent cations, which bind specifically, but also to monovalent cations. We pinpoint the structural bases of the stability and hypothesize that the destabilization induced by an unusual cluster of negatively charged residues favours the entrance of water molecules into the hydrophobic core, consistent with the generally accepted mechanism of cold denaturation. PMID- 24802809 TI - TAP study of toluene total oxidation over a Co3O4/La-CeO2 catalyst with an application as a washcoat of cordierite honeycomb monoliths. AB - The total oxidation of toluene was studied over a Co3O4/La-CeO2 catalyst in a Temporal Analysis of Products (TAP) set-up in the temperature range 713 K to 873 K in the presence and absence of dioxygen. It has been demonstrated that the reaction proceeds via a Mars-van Krevelen mechanism. The reaction rate increased 8.4 times if both toluene and dioxygen were present in the feed. The partial reaction order with respect to O2 diminished from 0.9 to 0.6 with an increase in temperature from 763 to 873 K. Adsorbed oxygen species with a lifetime of ~8 s have been found on a catalyst fully oxidized by dioxygen. Catalysis of isotopically labeled (18)O2/(12)C6H5(13)CH3 results in the formation of products containing (18)O, which indicates that both lattice and adsorbed oxygen are involved in the total oxidation of toluene. The role of adsorbed oxygen is activation of the C-H bond in toluene. The reaction network of the catalytic total oxidation of toluene consists of the following sequence: adsorption of toluene on the catalyst surface; activation of toluene by dehydrogenation with adsorbed oxygen; oxidation of activated toluene mainly by the lattice oxygen and re-oxidation of the reduced catalyst by dioxygen. PMID- 24802808 TI - Advantages of repeated low dose against single high dose of kainate in C57BL/6J mouse model of status epilepticus: behavioral and electroencephalographic studies. AB - A refined kainate (KA) C57BL/6J mouse model of status epilepticus (SE) using a repeated low dose (RLD) of KA (5 mg/kg, intraperitoneal; at 30 min intervals) was compared with the established single high dose (SHD) of KA (20 mg/kg, intraperitoneal) model. In the RLD group, increased duration of convulsive motor seizures (CMS, Racine scale stage >=3) with a significant reduction in mortality from 21% to 6% and decreased variability in seizure severity between animals/batches were observed when compared to the SHD group. There was a significant increase in the percentage of animals that reached stage-5 seizures (65% versus 96%) in the RLD group. Integrated real-time video-EEG analysis of both groups, using NeuroScore software, revealed stage-specific spikes and power spectral density characteristics. When the seizures progressed from non convulsive seizures (NCS, stage 1-2) to CMS (stage 3-5), the delta power decreased which was followed by an increase in gamma and beta power. A transient increase in alpha and sigma power marked the transition from NCS to CMS with characteristic 'high frequency trigger' spikes on the EEG, which had no behavioral expression. During SE the spike rate was higher in the RLD group than in the SHD group. Overall these results confirm that RLD of KA is a more robust and consistent mouse model of SE than the SHD of KA mouse model. PMID- 24802810 TI - Ursolic acid induces autophagy in U87MG cells via ROS-dependent endoplasmic reticulum stress. AB - Malignant gliomas are the most common primary brain tumors, and novel ways of treating gliomas are urgently needed. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported to exhibit promising antitumor activity. Here, we evaluated the effects of UA on U87MG cells and explored the underlying molecular mechanisms. The results demonstrated that both G1-phase arrest and autophagy were induced by UA in U87MG cells. Evidence of UA-induced autophagy included the formation of acidic vesicular organelles, increase of autophagolysosomes and LC3 II accumulation. UA was also found to induce ER stress and an increase in intracellular calcium accompanied by ROS production. The increase in free cytosolic calcium induced by UA activated the CaMKK-AMPK-mTOR kinase signaling cascade, which ultimately triggered autophagy. Western blot analysis showed that UA promoted the phosphorylation of PERK and eIF2alpha; this was followed by the upregulation of the downstream protein CHOP, implying the involvement of the ER stress-mediated PERK/eIF2alpha/CHOP pathway in glioma cells. Meanwhile, UA activated IRE1alpha and subsequently increased the levels of phosphorylated JNK and Bcl-2, resulting in the dissociation of Beclin1 from Bcl-2. Furthermore, TUDCA and the silencing of either PERK or IRE1alpha partially blocked the UA induced accumulation of LC3-II, suggesting that ER stress precedes the process of autophagy. Additionally, NAC attenuated the UA-induced elevation in cytosolic calcium, ER stress markers and autophagy-related proteins, indicating that UA triggered ER stress and autophagy via a ROS-dependent pathway. Collectively, our findings revealed a novel cellular mechanism triggered by UA and provide a molecular basis for developing UA into a drug candidate. PMID- 24802811 TI - Acanthoic acid, a diterpene in Acanthopanax koreanum, ameliorates the development of liver fibrosis via LXRs signals. AB - Liver X receptors (LXRs)-mediated signals in acanthoic acid (AA) ameliorating liver fibrosis were examined in carbon tetrachloride (CCl4)-induced mice and TGF beta stimulated hepatic stellate cells (HSCs). AA was isolated from the root of Acanthopanax koreanum Nakai (Araliaceae). CCl4-treated mice were intraperitoneally injected with 10% CCl4 in olive oil (2 mL/kg for 8 weeks). In AA treated groups, mice were intragastrically administrated with AA (20 mg/kg or 50 mg/kg) 3 times per week for 8 weeks. Administration of AA reduced serum aminotransferase and tissue necrosis factor-alpha (TNF-alpha) levels evoked by CCl4, and the reverse of liver damage was further confirmed by histopathological staining. Administration of AA reduced the expression of fibrosis markers and regulated the ratio of MMP-13/TIMP-1, further reversed the development of liver fibrosis. TGF-beta (5 ng/ml) was added to activate HSC-T6 cells for 2 h, and then treated with AA (1, 3, or 10 MUmol/l) for 24 h before analysis. Cells were collected and proteins were extracted to detect the expressions of LXRs. AA could inhibit the expression of alpha-SMA stimulated by TGF-beta and increase the expression of LXRbeta. In vivo and in vitro experiments, AA could modulate liver fibrosis induced by CCl4-treatment via activation of LXRalpha and LXRbeta, while inhibit HSCs activation only via activation of LXRbeta. Acanthoic acid might ameliorate liver fibrosis induced by CCl4 via LXRs signals. PMID- 24802812 TI - Genital evolution: why are females still understudied? AB - The diversity, variability, and apparent rapid evolution of animal genitalia are a vivid focus of research in evolutionary biology, and studies exploring genitalia have dramatically increased over the past decade. These studies, however, exhibit a strong male bias, which has worsened since 2000, despite the fact that this bias has been explicitly pointed out in the past. Early critics argued that previous investigators too often considered only males and their genitalia, while overlooking female genitalia or physiology. Our analysis of the literature shows that overall this male bias has worsened with time. The degree of bias is not consistent between subdisciplines: studies of the lock-and-key hypothesis have been the most male focused, while studies of cryptic female choice usually consider both sexes. The degree of bias also differed across taxonomic groups, but did not associate with the ease of study of male and female genital characteristics. We argue that the persisting male bias in this field cannot solely be explained by anatomical sex differences influencing accessibility. Rather the bias reflects enduring assumptions about the dominant role of males in sex, and invariant female genitalia. New research highlights how rapidly female genital traits can evolve, and how complex coevolutionary dynamics between males and females can shape genital structures. We argue that understanding genital evolution is hampered by an outdated single-sex bias. PMID- 24802813 TI - Rapid and extensive alteration of phosphorus speciation during oxic storage of wet sediment samples. AB - The chemical forms of phosphorus (P) in sediments are routinely measured in studies of P in modern and ancient marine environments. However, samples for such analyses are often exposed to atmospheric oxygen during storage and handling. Recent work suggests that long-term exposure of pyrite-bearing sediments can lead to a decline in apatite P and an increase in ferric Fe-bound P. Here, we report on alterations in P speciation in reducing modern Baltic Sea sediments that we deliberately exposed to atmospheric oxygen for a period of either one week or one year. During oxidation of the sediment, extensive changes occurred in all measured P reservoirs. Exchangeable P all but disappeared during the first week of exposure, likely reflecting adsorption of porewater PO4 by Fe(III) (oxyhydr)oxides (i.e. ferric Fe-bound P formation). Detrital and organic P were also rapidly affected: decreases in both reservoirs were already observed after the first week of exposure to atmospheric oxygen. This was likely because of acidic dissolution of detrital apatite and oxidation of organic matter, respectively. These processes produced dissolved PO4 that was then scavenged by Fe(III) (oxyhydr)oxides. Interestingly, P in authigenic calcium phosphates (i.e. apatite: authigenic Ca-P) remained unaffected after the first week of exposure, which we attributed to the shielding effect of microfossils in which authigenic Ca-P occurs in Baltic Sea sediments. This effect was transient; a marked decrease in the authigenic Ca-P pool was observed in the sediments after one year of exposure to oxygen. In summary, we show that handling and storage of wet sediments under oxic conditions can lead to rapid and extensive alteration of the original sediment P speciation. PMID- 24802814 TI - Major increase in admission- and incidence rates of acute colonic diverticulitis. AB - PURPOSE: Hospitalization for acute colonic diverticulitis has become more and more frequent. We studied the changes in the rate of admission and incidence of the disease during the last 25 years. METHODS: We performed a retrospective analysis of all cases treated for acute diverticulitis during 1988-2012 at one hospital serving a defined population in Mid-Norway. The study made a distinction between admission rates and incidence rates. The admission rates defined the total number of cases admitted, while the incidence rates defined the number of new patients hospitalized for acute diverticulitis (first admission). Poisson regression was used to analyse factors associated with diverticulitis incidence rates. RESULTS: A total of 851 admissions in 650 different patients were identified, with an overall admission rate of 38.5 (CI 35.9 to 41.1) per 100,000 person-years. The admission rate increased from 17.9 (CI 14.1 to 22.3)/100,000 during 1988-1992 to 51.1 (CI 44.8 to 58.0)/100,000 during 2008-2012. Poisson regression analysis showed a significant increase in admission rates with a factor of 2.8 (C.I. 2.2 to 3.5) during 25 years. The overall incidence rate (IRR) of new patients was 29.4 (CI 27.1 to 31.7)/100,000 person-years. IRR increased significantly with a factor of 2.6 (CI 1.96 to 3.34) during 25 years, while IRR for perforations increased even more, by a factor of 3.3 (CI 1.24 to 8.58). CONCLUSION: The hospital admission rates as well as incidence rates for acute colonic diverticulitis increased significantly during the 25-year time span. PMID- 24802815 TI - Do smoking and obesity really do not have any negative influence on wound healing after surgery of pilonidal disease? PMID- 24802816 TI - Pd(II)-catalyzed ligand controlled synthesis of methyl 1-benzyl-1H-indole-3 carboxylates and bis(1-benzyl-1H-indol-3-yl)methanones. AB - A simple change of ligand and solvent allows controlled, effective switching between cyclization-carbonylation and cyclization-carbonylation-cyclization coupling (CCC-coupling) reactions of 2-alkynylanilines catalyzed by palladium(II). The use of a [Pd(tfa)2(box)] catalyst in iPrOH afforded symmetrical ketones bearing two indoles in good yields; replacing the catalyst and solvent with Pd(tfa)2 and DMSO-MeOH led to the formation of methyl 1-benzyl 1H-indole-3-carboxylates in good yields. PMID- 24802818 TI - Contra la corriente (against the current). AB - ABSTRACT The experiences of a Latina Lesbian behavioral scientist at the National Institutes of Health, the largest biomedical research facility in the world, are chronicled. She broke ground in directing the first federally funded major clinical study focused on Lesbian sexuality and health. PMID- 24802819 TI - Ordinary insurrections. AB - ABSTRACT Lesbian cartoonist Alison Bechdel published her first Dykes to Watch Out For comic strip almost twenty years ago. During a phone interview with Marny Hall, Bechdel describes the ways in which her politics and her art have intersected and evolved over the years. Bechdel also discusses the harsh realities of subcultural economics, as well as the strategies she has relied upon to support herself and her art. PMID- 24802817 TI - Climate change and Southern Ocean ecosystems I: how changes in physical habitats directly affect marine biota. AB - Antarctic and Southern Ocean (ASO) marine ecosystems have been changing for at least the last 30 years, including in response to increasing ocean temperatures and changes in the extent and seasonality of sea ice; the magnitude and direction of these changes differ between regions around Antarctica that could see populations of the same species changing differently in different regions. This article reviews current and expected changes in ASO physical habitats in response to climate change. It then reviews how these changes may impact the autecology of marine biota of this polar region: microbes, zooplankton, salps, Antarctic krill, fish, cephalopods, marine mammals, seabirds, and benthos. The general prognosis for ASO marine habitats is for an overall warming and freshening, strengthening of westerly winds, with a potential pole-ward movement of those winds and the frontal systems, and an increase in ocean eddy activity. Many habitat parameters will have regionally specific changes, particularly relating to sea ice characteristics and seasonal dynamics. Lower trophic levels are expected to move south as the ocean conditions in which they are currently found move pole-ward. For Antarctic krill and finfish, the latitudinal breadth of their range will depend on their tolerance of warming oceans and changes to productivity. Ocean acidification is a concern not only for calcifying organisms but also for crustaceans such as Antarctic krill; it is also likely to be the most important change in benthic habitats over the coming century. For marine mammals and birds, the expected changes primarily relate to their flexibility in moving to alternative locations for food and the energetic cost of longer or more complex foraging trips for those that are bound to breeding colonies. Few species are sufficiently well studied to make comprehensive species-specific vulnerability assessments possible. Priorities for future work are discussed. PMID- 24802820 TI - JEB (Joan E. Biren). AB - ABSTRACT This article is based on a telephone interview between Joan E. Biren and Gayle Pitman. During the interview, Joan, a lesbian-feminist photographer and video producer, talked about the effect the women's movement had on her career choice, the barriers and oppression she endures as a result of working for social change, and the personal characteristics and coping strategies she utilizes as she attempts to overcome these barriers. Joan's story offers an inspiring portrait of a woman who, in the face of adversity, stays true to her feminist politics and integrates lesbianism, feminism, and activism in her everyday life. PMID- 24802821 TI - Advocacy meets the scientific method. AB - ABSTRACT Dr. Judith Bradford is a social science researcher who has been a key figure in the evolution of lesbian health research. With Caitlin Ryan, Judy was instrumental in creating the National Lesbian Health Care Survey (NLHCS) in the mid-1980s. After assuming the Directorship of the Survey and Evaluation Research Lab (SERL) at the Virginia Commonwealth University (VCU), she became involved in the recent Institute of Medicine (IOM) Committee process, which resulted in increased attention to lesbian health at the national level. The IOM Committee recommendations have been instrumental in lobbying efforts by Judy and others for inclusion of LBGT issues in Healthy People 2010, the United States Public Health Service blueprint used by PHS agencies nationwide. Judy's current activities include helping to develop the Lesbian Health Research Institute and serving as the part-time Director of Lesbian Health Research at Fenway Community Health in Boston. PMID- 24802822 TI - How lesbian artists support their art. AB - ABSTRACT This essay examines how lesbian artists from Great Britain, Belgium, Australia, New Zealand, Canada, and the USA have supported their work through a variety of jobs from waitressing to college teaching. Social security, unemployment compensation, family-of-ori-gin assistance, and independent incomes are discussed along with photography as an income-producing skill. Some women felt more comfortable discussing blue-collar jobs than family assistance. The closet remains a necessity for artists who have reached the greatest mainstream success. Although lesbian periodicals have seldom offered money, they have been significant in building audiences for les-bian-themed art and self-esteem in lesbian artists. Finally, the making of art is discussed as a supportive and healing activity. PMID- 24802823 TI - Changing the world. AB - ABSTRACT The author explores the contradictions in using/needing/having capital to end the institutions of capitalism. The essay also examines what a cultural worker is, the ways we value our own labor, the importance of putting our resources into our communities, how we can sustain activism over time, and how we are inspired and inspire others to change the world. Michelle Cliff's conceptualization of the application of thesis + antithesis = synthesis is used as a framework. PMID- 24802824 TI - Lesbian Giving-and Getting. AB - ABSTRACT Lesbian philanthropy is rooted in a tradition of radical giving. Without the inspiration and vision of the small, community-based "alternative" foundations of the late 1960s and 1970s, with their commitment to "change, not charity" and to funding grassroots groups dedicated to social justice, today's profusion of queer organizations would not have been possible. Lesbians and bisexual women-both as donors and as activists-have been central to both movements. Today, contributions from individuals are responsible for the vast majority of the 1999 increase in overall giving-an increase of $15.80 billion over 1998, to a record $190.16 billion. (Since 1997, giving has increased by more than $15 billion annually.) But the questions that inspired a groundbreaking re evaluation of traditional philanthropy thirty years ago still remain: who is giving, and to which groups? Now more than ever, it is vitally important for lesbians to recognize that the intersection between the radical philanthropic movement-which seeks to disrupt the power relations of traditional charitable giving-and the lesbian/gay/bi-sexual/transgender movements-which seek at least to dispel homophobia and at best to disrupt heteronormativity-is where both can become more inclusive, representative, and revolutionary. PMID- 24802825 TI - Shoestring science. AB - ABSTRACT Nanette K. Gartrell, MD, is a psychiatrist, teacher and researcher who has served on the faculties of Harvard Medical School and the University of California, San Francisco. For the past thirty years, without relying on major grants, she has been gathering data to depathologize lesbianism. Her earliest investigations contributed to the effort to remove "homosexuality" from the list of mental disorders. More recently, Dr. Gartrell has been conducting a national, longitudinal study of lesbian families. In this overview of her research career, Dr. Gartrell discusses the strategies that she has used successfully for pursuing scientific investigations on a shoestring budget. PMID- 24802826 TI - The jewelle gomez stories as told to amanda kovattana. AB - ABSTRACT Fiction and the performing arts are powerful tools for cultural activism. As Jewelle Gomez tells the story of how her black lesbian vampire novel, The Gilda Stories, was brought to the stage, it becomes clear that many people who would not otherwise seek out such stories are exposed to the stories of minorities via plays. Part of this retelling illustrates how arts funding is controlled by politics. Jewelle Gomez also demonstrates her activism by teaching lesbians how their money can be used in powerful ways to encourage the changes they would like to see in the world. PMID- 24802827 TI - A burning love for lesbian literature. AB - ABSTRACT Barbara Grier's enjoyment of and commitment to lesbian literature have been guiding forces in her life. While working non-professional jobs for little pay, she managed to find money to buy the books she loved. Her enthusiasm led her to devote considerable time and energy to The Ladder while simultaneously working a full-time job. When The Ladder was no longer financially viable, she founded Naiad Press, and, for the first nine years of its existence, continued to hold a full-time job. In 1982, she became the first paid employee of Naiad, which enabled her to focus exclusively on her passions: writing, editing, and publishing lesbian literature. PMID- 24802828 TI - Funding the national center for lesbian rights. AB - ABSTRACT The Executive Director and Development Director of the National Center for Lesbian Rights (NCLR) describe NCLR's growth over the past 23 years in the context of lesbian feminist activism and increasing philanthropy among lesbians. NCLR's activist lawyering on family, youth, immigration and elder law issues is radical work that is transforming the lives of ordinary lesbians, and which depends on the financial support of lesbians. The organization's earliest financial supporters were lawyers, who remain a core group of donors today. NCLR has grown as increasing numbers of lesbians grasp the personal connection between the organization's legal victories and the effect of discrimination in their own lives. NCLR has also built a professional fundraising infrastructure and major gifts program, which are key to its long-term institutional growth. In recent years the feminist philanthropy movement and NCLR's own donor activists have helped lesbians express their activism by giving back to their community through charitable contributions to lesbian organizations,Including NCLR. NCLR will continue to advance lesbian civil rights by maintaining strong relationships with current donors and finding creative ways to meet its greatest fundraising challenge: how to reach the vast majority of lesbians who are quietly living their lives and are not part of any organization. PMID- 24802829 TI - Lesbian activism in silicon valley. AB - ABSTRACT Kathy Levinsonis aJewish lesbian mother who advocates for social justice. Her activism arose out of experiences in childhood and her years as a college athlete at Stanford. As a senior executive at Charles Schwab & Co., Inc. and most recently the President and Chief Operating Officer of E*TRADE Group,Inc., she forged a successful career in business and technology. A well known and visible figure in gay, lesbian, bisexual and transgender, women's and Jewish philanthropy and activism nationwide, Kathy's greatest aspiration is to change the world one person at a time, one conversation at a time, one dollar at a time. PMID- 24802830 TI - Daughters of Bilitis and the Ladder that Teetered. AB - ABSTRACT This article traces the economic history of the Daughters of Bilitis, the first national Lesbian organization, and its periodical The Ladder. Besides membership, subscriptions and fundraisers were monetary donations and in-kind "gifts" from businesses. Staff labor was volunteer. Compensation for authors was DOB's guarantee of full rights to their own work. Funding was precarious until an anonymous donor came to the rescue. Funds were funneled through a member/friend who singularly decided what project to back. Officers of the organization were not privy to an overall plan, nor any accounting of how the funds were spent. In the end, secrecy was the undoing of DOB as a national organization and the demise of The Ladder as well. PMID- 24802831 TI - Changing hearts, changing minds. AB - ABSTRACT This article is comprised of excerpts from an interview with Dee Mosbacher, MD, PhD, a psychiatric consultant and lesbian ac tivist who has expressed her visions of social change through documentary films. Dee describes the beginnings of her political activism in the social change and women's health movements of the 1960s and 1970s and her evolution as an activist filmmaker over the past two decades. She explores the process of fundraising, the importance of working collabor-atively, her experience balancing activism with her work as a psychiatrist, and the rewards of making films that have an impact on people's lives. She also discusses her visions for the future and provides recommendations for young lesbian activists. PMID- 24802832 TI - Time is more valuable than money. AB - ABSTRACT Marcia Munson, a feminist, gay rights, and environmental activist for the last thirty years, has chosen to reserve a significant portion of her life for doing volunteer work by living simply and working part time at the IRS (Internal Revenue Service). While choosing to retain the simple lifestyle of the "70s in order to pursue her activist dreams, the author recognizes that the "70s model of self-funded activism no longer works today. During the 1970s, volunteers were often able to support their projects with funds from their own pockets, or could scrape by on small salaries provided by CETA grants and work-study money. In the 1980s, fundraising events to raise money gained popularity. By the 1990s, many non-profit organizations operated primarily with paid staff, and the main volunteer activity had become raising money. Looking back at "70s activism, Munson points out that the services of a skilled, experienced volunteer can be as valuable as money to an organization. PMID- 24802833 TI - Rainbow philanthropy. AB - ABSTRACT Martina Navratilova was the first professional athlete to proclaim her lesbianism. After retiring from a stunning tennis career, Martina Navratilova has emerged as a prominent author, television commentator, and public speaker. She is an influential advocate of lesbigay causes, and a major contributor to the lesbigay community. This article describes Martina's "passion [and] #1 cause"-the Rainbow Endowment. PMID- 24802834 TI - My roots as an activist. AB - ABSTRACT Caitlin Ryan describes her early activist experiences, highlighting her work coordinating the 2nd National Gay Health Conference in 1979, publishing the first national lesbian and gay health directory, organizing the National Lesbian and Gay Health Foundation, and initiating and serving as co-investigator of the National Lesbian Health Care Survey. She describes the challenges of funding these and other projects, and of integrating lesbian activism into her life. An early AIDS activist, Ryan was the first director of AID Atlanta, a member of the Federation of AIDS Related Organizations, a founder of the National Association of People with AIDS, and a convener of the minority AIDS working group that became the National Minority AIDS Council. Drawing on her extensive experience, Ryan discusses the challenges facing lesbian research today. She believes that research and training infrastructure are sorely needed, particularly funding for policy and applied research to address longstanding gaps in understanding our rapidly evolving communities. Noting that our diversity and our evolving needs require more varied funding approaches that do not fit the narrow scope or "disease model" focus of government agencies, she urges lesbian activists to advocate for these issues. PMID- 24802835 TI - Enhancing and inspiring lesbian philanthropy. AB - ABSTRACT Diane Sabin has a long history of Lesbian activism and philanthropy while supporting herself in full-time non-activist jobs. In 1997, Diane joined with her friend, Andrea Gillespie, who had envisioned a unique organization entitled 100 Lesbians and our Friends. Its goal is to enhance and inspire Lesbian philanthropy for social change and cultural memory. 100 Lesbians and our Friends is a grassroots initiative developed by San Francisco Bay Area Lesbians who share information about and a passion for Lesbian projects, organizations, and individuals in need of funding. 100 Lesbians and our Friends is the vehicle through which Diane encourages Lesbians to live examined lives, to stretch our generosity, and to develop our strength as individuals and as a community. PMID- 24802836 TI - The sound of activism. AB - ABSTRACT A longtime advocate for female empowerment and equality, Boden Sandstrom has worked for political change in many arenas. In the 1960s, she began a career as a librarian, but soon made activism her full-time job, working for feminist, leftist and socialist causes. In the 1970s, she found a way to turn her lifelong passion for music into a career as a sound engineer. Once established in that profession, she began donating her services to political events, marches, demonstrations, and rallies. After thirteen years of running her own company, called Woman Sound,Inc. (later City Sound Productions,Inc.), she turned to the study of ethnomusicology. She is now Program Manager and Lecturer for the Ethnomusicology Program at the University of Maryland, where she is also working on her doctorate in that subject. She continues to freelance as a sound engineer and serve as a technical producer for major events. PMID- 24802837 TI - Caring deeply, changing the world. AB - ABSTRACT Sherry Thomas's history of activism and fundraising in the lesbian feminist community, told in her own words, offers us a point of view of periods of our evolving culture and knowledge that will both inspire and teach. From the rural reaches of Northern California and the nascent consciousness raising and country women's movement, to the burgeoning publishing and women's bookstore culture, Sherry was on the frontlines. Then in the larger lesbigay community, first for San Francisco's Main Library fundraising campaign and currently for Lambda Legal Defense, Sherry teaches us how inextricably related organizing and funding are. PMID- 24802838 TI - Out about class. AB - ABSTRACT Lesbian activist Leonie Walker traces the evolution of her involvement in social change philanthropy and her work to bring together activists of diverse class and racial backgrounds. She shows how she was trained as an activist, discusses conscious and socially responsible ways to steward wealth, and gives voice to the seldom-heard experiences of LGBT people with inherited wealth. The co-founder of the Women Managing Wealth program at the Ms. Foundation and a board member of Astraea Lesbian Action Foundation, she has also developed and facilitated numerous Dismantling Classism workshops. In this article, she discusses the importance of, and ways of implementing, cross-class, cross-race dialogue that can further understanding among activists of different backgrounds. PMID- 24802839 TI - Familial clusters of HTLV-1-associated myelopathy/tropical spastic paraparesis. AB - OBJECTIVE: HTLV-1 proviral loads (PVLs) and some genetic factors are reported to be associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, there are very few reports on HAM/TSP having family history. We aimed to define the clinical features and laboratory indications associated with HAM/TSP having family history. METHODS: Records of 784 HAM/TSP patients who were hospitalized in Kagoshima University Hospital and related hospitals from 1987 to 2012 were reviewed. Using an unmatched case control design, 40 patients of HAM/TSP having family history (f-HAM/TSP) were compared with 124 patients suffering from sporadic HAM/TSP, who were admitted in series over the last 10 years for associated clinical features. RESULTS: Of the 784 patients, 40 (5.1%) were f-HAM/TSP cases. Compared with sporadic cases, the age of onset was earlier (41.3 vs. 51.6 years, p<0.001), motor disability grades were lower (4.0 vs. 4.9, p = 0.043) despite longer duration of illness (14.3 vs. 10.2 years, p = 0.026), time elapsed between onset and wheelchair use in daily life was longer (18.3 vs. 10.0 years, p = 0.025), cases with rapid disease progression were fewer (10.0% vs. 28.2%, p = 0.019), and protein levels in cerebrospinal fluid (CSF) were significantly lower in f-HAM/TSP cases (29.9 vs. 42.5 mg, p<0.001). There was no difference in HTLV-1 PVLs, anti-HTLV-1 antibody titers in serum and CSF, or cell number and neopterin levels in CSF. Furthermore, HTLV-1 PVLs were lower in cases with rapid disease progression than in those with slow progression in sporadic cases [corrected] CONCLUSIONS: We demonstrated that HAM/TSP aggregates in the family, with a younger age of onset and a slow rate of progression in f-HAM/TSP cases compared with sporadic cases. These data also suggested that factors other than HTLV-1 PVLs contribute to the disease course of HAM/TSP. PMID- 24802840 TI - Craniovertebral junction instability in adult patients with Down syndrome. PMID- 24802841 TI - Perfusion computed tomography: an imaging biomarker for brain tumors' grading. PMID- 24802842 TI - Pay attention to the diagnosis and management of bow hunter's syndrome. PMID- 24802843 TI - Extracranial-intracranial bypass and the versatile vertebral artery. PMID- 24802844 TI - Gross total resection plays a leading role in survival of patients with glioblastoma multiforme. PMID- 24802845 TI - Image-guided maximal resection of intrinsic tumors. PMID- 24802846 TI - Don't lose the lungs for the brain: pulmonary complications after subarachnoid hemorrhage. PMID- 24802847 TI - High cervical instability in adult patients with Down syndrome. PMID- 24802850 TI - Astragaloside IV inhibits the up-regulation of Wnt/beta-catenin signaling in rats with unilateral ureteral obstruction. AB - OBJECTIVE: To investigate the effect of Astragaloside IV (AS-IV) on the regulation of the Wnt/beta-catenin signaling pathway in rats with unilateral ureteral obstruction (UUO). METHODS: Rat renal interstitial fibrosis models were prepared using unilateral ureteral ligation. Rats were randomly divided into sham group, sham group with AS-IV (33mg/kg), unilateral ureteral obstruction group, and unilateral ureteral obstruction group receiving varied doses of AS-IV (3.3, 10, and 33 mg/kg). Immunohistochemical analysis, real-time fluorescence quantitative PCR (FQ-PCR), and western blot were used to detect the expression of genes and proteins associated with the Wnt/beta-catenin signaling pathway in renal tissues. RESULTS: Levels of Wnt3, Wnt4, and Frizzled gene expression increased significantly in the UUO model; AS-IV was associated with the downregulation of the expression of Wnt3, Wnt4, Frizzled4, p-LRP5, p-LRP6, disheveled, beta-catenin, LEF-1, TCF-1, Snail, Jagged 1, Twist, MMP2, and MMP7 proteins in a concentration-dependent manner, while the expression of APC, CK1, and E-cadherin was increased. CONCLUSIONS: AS-IV effectively inhibits the up regulation of proteins in the Wnt/beta-catenin signaling pathway in UUO-model rats, indicating its possible inhibitory effects on renal interstitial fibrosis. PMID- 24802851 TI - Prognostic impact of definitive local therapy of the primary tumor in men with metastatic prostate cancer at diagnosis: A population-based, propensity score analysis. AB - BACKGROUND: This study investigated whether definitive local therapy [radical prostatectomy (RP) or brachytherapy (BT)] of the primary tumor improves survival in men with metastatic prostate cancer (PrCA) at diagnosis. METHODS: Data on newly diagnosed metastatic PrCA cases (stage IV, N=7858) were obtained from the Surveillance Epidemiology and End Results (SEER) program. Conventional multivariable survival analysis and propensity score analysis were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (95% CI) comparing men who underwent definitive local therapy of the primary tumor to those who did not. RESULTS: After adjusting for sociodemographic and tumor attributes, having RP after diagnosis with metastatic PrCA was associated with 73% (HR=0.27, 95% CI: 0.20-0.38) lower risk of all-cause mortality and 72% (HR=0.28, 95% CI: 0.20-0.39) reduced risk of death from PrCA. Having BT also was associated with 57% (HR=0.43, 95% CI: 0.31-0.59) and 54% (HR=0.46, 95% CI: 0.33 0.64) lower risk of all-cause and PrCA-specific mortality. Similar results were observed in propensity score-adjusted analysis as well as when stratified by age and extent of tumor metastasis. CONCLUSIONS: These findings suggest that definitive local therapy improves survival in men with metastatic PrCA at diagnosis. Future work should consider comorbidities, diet, physical activity and smoking status. PMID- 24802849 TI - Fas/Fas ligand mediates keratinocyte death in sunitinib-induced hand-foot skin reaction. AB - Sunitinib, a multitargeted receptor Y kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among the 29 biomarkers examined, soluble FasL (sFasL) showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with those of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg kg(-1) per day) for 4 weeks to mice caused the maximally affected skin area with an erosion-to-ulceration response to tape-stripping. The skin biopsies of mice administered sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR. PMID- 24802852 TI - Cancer risks in children with congenital malformations in the nervous and circulatory system-A population based cohort study. AB - AIM: We estimated the age and organ-specific cancer risk for children with a congenital malformation (CM) in the nervous or in the circulatory system. METHODS: We identified 1,709,456 live born singletons in Denmark between 1 January 1977 and 31 December 2007 and excluded children with chromosomal birth defects. Information on CMs was obtained from the Danish National Hospital Register. Information on cancer occurrence was obtained from the Danish Cancer Registry. We applied Cox proportional hazards regression model to estimate hazard ratios (HR) for cancer. Children entered into the CM cohort on the day of birth regardless of when the CM was diagnosed or on the day of CM diagnosis in an alternative analysis. RESULTS: Overall, 4484 (0.26%) and 24,643 (1.44%) children were diagnosed with a CM in the nervous and in the circulatory system, respectively. Compared with children without any CM, children with a CM in the nervous system had a 5.97 fold (95%CI [confidence interval]: 4.66-7.64) higher risk of cancer, including cancer in the central nervous system (HR=18.84, 95%CI: 12.67-28.01), in the mesothelial and soft tissue (HR=15.64, 95%CI: 7.99-30.60), in the skin (HR=4.91, 95%CI: 2.19-11.0). The associations were stronger early in life. Children with a CM in the circulatory system had a 2.64 fold (95%CI: 2.21 3.16) higher risk of cancer, including cancer in the lymphatic and haematopoietic tissues (HR=3.22, 95%CI: 2.43-4.27) and cancer in the CNS (HR=2.40, 95%CI: 1.43 4.02). Some of these associations were weaker in the alternative analysis. Children with subtypes of CM in the two systems showed a higher cancer risk. CONCLUSIONS: Children who were diagnosed with a CM in the nervous system had a substantially higher cancer risk especially early in life. Children diagnosed with a CM in the circulatory system had a moderately higher cancer risk. PMID- 24802853 TI - A highly efficient Cu-catalyzed S-transfer reaction: from amine to sulfide. AB - A highly efficient Cu-catalyzed dual C-S bonds formation reaction, proceeding in alcohol and water under air, is reported, in which inodorous stable Na2S2O3 is used as a sulfurating reagent. This powerful strategy provides a practical and efficient approach to construct thioethers, using readily available aromatic amines and alkyl halides as starting materials. Sensitive and synthetic useful functional groups could be tolerated. Furthermore, pharmaceuticals, glucose, an amino acid, and a chiral ligand are successfully furnished by this late-stage sulfuration strategy. PMID- 24802854 TI - Effects of hemicellulose pre-extraction and cellulose nanofiber on the properties of rice straw pulp. AB - The aim of this study was to evaluate the influence of mild alkaline pre extraction on the hemicelluloses removal of rice straw. In addition, the performance of cellulose nanofibers (CNFs) addition on some physico-mechanical properties obtained from extracted and un-extracted (control) samples were investigated. An optimum compromise was found as operating conditions (10% soda, 50 degrees C, and 90min) that provided moderate hemicelluloses removal (48.1%). The residual extracted rice straw particles were subjected to soda-anthraquinone pulping at 160 degrees C for 30-60min with 6 to 18% active alkali charge. Compared with the control samples, the screened yield and Kappa number for extracted pulps decreased slightly. Extracted samples showed better air resistance compared with the un-extracted (control) pulps. However, pre extraction was found to negatively impact on some mechanical properties such as decrease in burst and tensile indices while addition of CNFs and refining of fibers could improve the strength properties considerably. In general, the addition of CNFs in any concentrations considerably enhanced tensile and burst indices of the sheets in extracted and un-extracted conditions, compared with the unfilled ones. The improvement in mechanical properties was considered one of the key benefits brought by CNFs reinforcement. On the other hand, the stretch properties of the beaten pulps are higher than those of control samples. SEM observations showed that CNFs were deposited on the voids between the rice straw fibers. PMID- 24802855 TI - Impact of non-storing biomass on PHA production: an enrichment culture on acetate and methanol. AB - The use of enrichment cultures for polyhydroxyalkanoate (PHA) production from substrate mixtures such as wastewater inevitably results in the establishment of a non-PHA-storing population besides the PHA-producing bacteria. This reduces the maximum PHA content that can be established, and increases downstream-processing costs. The aim of this study was to investigate the impact of non-storing biomass on the PHA production process. A microbial culture was enriched in a sequencing batch reactor fed with acetate and methanol. Methanol served as model substrate for compounds unsuitable for PHA production. The enrichment was dominated by Plasticicumulans acidivorans, a known PHA producer, and Methylobacillus flagellatus, an obligate methylotroph that cannot store PHA. As expected, the presence of the non-storing population lowered the maximum PHA content of the culture, from more than 80 to 66wt.%. To mimic a nitrogen-rich waste stream, additional accumulation experiments were performed with continuous supply of carbon and ammonium. In these experiments P. acidivorans still accumulated large amounts of PHA, but unrestricted growth of the non-storing, methylotrophic population reduced the maximum overall PHA content to 52wt.%. Besides ammonium limitation, other strategies to restrict the fraction of non-storing biomass should be developed. The mixture of acetate and methanol is a useful model substrate for the development of such strategies. PMID- 24802856 TI - Control and prediction of degradation of biopolymer based hydrogels with poly(E caprolactone) subunits. AB - Complex hydrogels consisting of natural and synthetic polymers, stabilized by combining different physical and chemical cross-linking methods, were assessed by in vitro degradation tests performed at 37 degrees C in phosphate buffer solution. Four biopolymer-based hydrogel series were comparatively evaluated as sponge or dense films as regards mass loss, morphology changes and thermal behavior over the fixed incubation period, considering as main factors of influence the composition, the adopted stabilization mode and the microstructure of the 3D construct. To facilitate the selection of the appropriate material for envisaged applications, matching the specific needs, the obtained data were used to generate an artificial neural network (ANN) model, able to establish correlations of the examined formulations and preparation parameters with mass loss. The comparison of experimental and calculated data showed that the developed ANN shows reasonable predictive performance (rtraining/validation(2)=0.99). PMID- 24802857 TI - A multi-level geographical study of Italian political elections from Twitter data. AB - In this paper we present an analysis of the behavior of Italian Twitter users during national political elections. We monitor the volumes of the tweets related to the leaders of the various political parties and we compare them to the elections results. Furthermore, we study the topics that are associated with the co-occurrence of two politicians in the same tweet. We cannot conclude, from a simple statistical analysis of tweet volume and their time evolution, that it is possible to precisely predict the election outcome (or at least not in our case of study that was characterized by a "too-close-to-call" scenario). On the other hand, we found that the volume of tweets and their change in time provide a very good proxy of the final results. We present this analysis both at a national level and at smaller levels, ranging from the regions composing the country to macro-areas (North, Center, South). PMID- 24802858 TI - Cross-talk in mechanomyographic signals from the forearm muscles during sub maximal to maximal isometric grip force. AB - PURPOSE: This study aimed: i) to examine the relationship between the magnitude of cross-talk in mechanomyographic (MMG) signals generated by the extensor digitorum (ED), extensor carpi ulnaris (ECU), and flexor carpi ulnaris (FCU) muscles with the sub-maximal to maximal isometric grip force, and with the anthropometric parameters of the forearm, and ii) to quantify the distribution of the cross-talk in the MMG signal to determine if it appears due to the signal component of intramuscular pressure waves produced by the muscle fibers geometrical changes or due to the limb tremor. METHODS: Twenty, right-handed healthy men (mean +/- SD: age = 26.7+/-3.83 y; height = 174.47+/-6.3 cm; mass = 72.79+/-14.36 kg) performed isometric muscle actions in 20% increment from 20% to 100% of the maximum voluntary isometric contraction (MVIC). During each muscle action, MMG signals generated by each muscle were detected using three separate accelerometers. The peak cross-correlations were used to quantify the cross-talk between two muscles. RESULTS: The magnitude of cross-talk in the MMG signals among the muscle groups ranged from, R2(x, y) = 2.45-62.28%. Linear regression analysis showed that the magnitude of cross-talk increased linearly (r2 = 0.857 0.90) with the levels of grip force for all the muscle groups. The amount of cross-talk showed weak positive and negative correlations (r2 = 0.016-0.216) with the circumference and length of the forearm respectively, between the muscles at 100% MVIC. The cross-talk values significantly differed among the MMG signals due to: limb tremor (MMGTF), slow firing motor unit fibers (MMGSF) and fast firing motor unit fibers (MMGFF) between the muscles at 100% MVIC (p<0.05, eta2 = 0.47 0.80). SIGNIFICANCE: The results of this study may be used to improve our understanding of the mechanics of the forearm muscles during different levels of the grip force. PMID- 24802859 TI - A quantitative assessment method for Ascaris eggs on hands. AB - The importance of hands in the transmission of soil transmitted helminths, especially Ascaris and Trichuris infections, is under-researched. This is partly because of the absence of a reliable method to quantify the number of eggs on hands. Therefore, the aim of this study was to develop a method to assess the number of Ascaris eggs on hands and determine the egg recovery rate of the method. Under laboratory conditions, hands were seeded with a known number of Ascaris eggs, air dried and washed in a plastic bag retaining the washing water, in order to determine recovery rates of eggs for four different detergents (cationic [benzethonium chloride 0.1% and cetylpyridinium chloride CPC 0.1%], anionic [7X 1% - quadrafos, glycol ether, and dioctyl sulfoccinate sodium salt] and non-ionic [Tween80 0.1% -polyethylene glycol sorbitan monooleate]) and two egg detection methods (McMaster technique and FLOTAC). A modified concentration McMaster technique showed the highest egg recovery rate from bags. Two of the four diluted detergents (benzethonium chloride 0.1% and 7X 1%) also showed a higher egg recovery rate and were then compared with de-ionized water for recovery of helminth eggs from hands. The highest recovery rate (95.6%) was achieved with a hand rinse performed with 7X 1%. Washing hands with de-ionized water resulted in an egg recovery rate of 82.7%. This washing method performed with a low concentration of detergent offers potential for quantitative investigation of contamination of hands with Ascaris eggs and of their role in human infection. Follow-up studies are needed that validate the hand washing method under field conditions, e.g. including people of different age, lower levels of contamination and various levels of hand cleanliness. PMID- 24802860 TI - Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study. AB - BACKGROUND: Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full length human PTH 1-84 (rhPTH[1-84]) is being developed for the treatment of hypoparathyroidism. OBJECTIVE: The goal of this study was to investigate the pharmacokinetics and pharmacodynamics of a single subcutaneous injection of rhPTH(1-84) in patients with hypoparathyroidism. METHODS: This was an open-label, dose-escalating study of single subcutaneous administration of 50 ug and then 100 ug of rhPTH(1-84). Enrolled patients (age range, 25-85 years) had >=12 months of diagnosed hypoparathyroidism defined according to biochemical evidence of hypocalcemia with concomitant low-serum intact PTH and were taking doses >=1000 mg/d of oral calcium and >=0.25 ug/d of active vitamin D (oral calcitriol). The patient's prescribed dose of calcitriol was taken the day preceding but not on the day of or during the 24 hours after rhPTH(1-84) administration. Each patient received a single 50-ug rhPTH(1-84) dose, had at least a 7-day washout interval, and then received a single 100-ug rhPTH(1-84) dose. The following parameters were assessed: plasma PTH; serum and urine total calcium, magnesium, phosphate, and creatinine; and urine cyclic adenosine monophosphate. RESULTS: After administration of rhPTH(1-84) 50 ug (n = 6) and 100 ug (n = 7), the approximate t1/2 was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at ~12 hours. The median AUC was similar with calcitriol and rhPTH(1-84) for serum 1,25-dihydroxyvitamin D (calcitriol, 123-227 pg . h/mL; rhPTH[1-84], 101-276 pg . h/mL), calcium (calcitriol, 3.3-3.7 mg . h/dL; rhPTH[1-84], 3.3-7.6 mg . h/dL), and magnesium (calcitriol, 0.7-0.9 mg . h/dL; rhPTH[1-84], 1.3-2.8 mg . h/dL). In contrast, the median AUC for phosphate was strongly negative with rhPTH(1-84) (calcitriol, -1.0 to 0.8 mg . h/dL; rhPTH[1-84], -21.3 to -26.5 mg . h/dL). Compared with calcitriol, rhPTH(1-84) 50 ug reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1-84) 100 ug reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1-84) 50 ug increased urinary phosphate excretion and phosphate-to creatinine ratios by 53% and 54%, respectively, and rhPTH(1-84) 100 ug increased them by 45% and 42%. Urine cyclic adenosine monophosphate-to-creatinine ratio increased with rhPTH(1-84) by 2.3-fold (50 ug) and 4.4-fold (100 ug) compared with calcitriol. CONCLUSIONS: PTH replacement therapy with rhPTH(1-84) regulated mineral homeostasis of calcium, magnesium, phosphate, and vitamin D metabolism toward normal in these study patients with hypoparathyroidism. PMID- 24802861 TI - Mitochondrial calcium uniporter activity is dispensable for MDA-MB-231 breast carcinoma cell survival. AB - Calcium uptake through the mitochondrial Ca2+ uniporter (MCU) is thought to be essential in regulating cellular signaling events, energy status, and survival. Functional dissection of the uniporter is now possible through the recent identification of the genes encoding for MCU protein complex subunits. Cancer cells exhibit many aspects of mitochondrial dysfunction associated with altered mitochondrial Ca2+ levels including resistance to apoptosis, increased reactive oxygen species production and decreased oxidative metabolism. We used a publically available database to determine that breast cancer patient outcomes negatively correlated with increased MCU Ca2+ conducting pore subunit expression and decreased MICU1 regulatory subunit expression. We hypothesized breast cancer cells may therefore be sensitive to MCU channel manipulation. We used the widely studied MDA-MB-231 breast cancer cell line to investigate whether disruption or increased activation of mitochondrial Ca2+ uptake with specific siRNAs and adenoviral overexpression constructs would sensitize these cells to therapy related stress. MDA-MB-231 cells were found to contain functional MCU channels that readily respond to cellular stimulation and elicit robust AMPK phosphorylation responses to nutrient withdrawal. Surprisingly, knockdown of MCU or MICU1 did not affect reactive oxygen species production or cause significant effects on clonogenic cell survival of MDA-MB-231 cells exposed to irradiation, chemotherapeutic agents, or nutrient deprivation. Overexpression of wild type or a dominant negative mutant MCU did not affect basal cloning efficiency or ceramide-induced cell killing. In contrast, non-cancerous breast epithelial HMEC cells showed reduced survival after MCU or MICU1 knockdown. These results support the conclusion that MDA-MB-231 breast cancer cells do not rely on MCU or MICU1 activity for survival in contrast to previous findings in cells derived from cervical, colon, and prostate cancers and suggest that not all carcinomas will be sensitive to therapies targeting mitochondrial Ca2+ uptake mechanisms. PMID- 24802862 TI - Up-regulation of SUMO E3 ligases during lung schistosomula and adult worm stages. AB - Small ubiquitin-like modifier (SUMO) conjugation of proteins occurs through a concert action of enzymes using a similar ubiquitination mechanism. After a C terminal peptide is cleaved from the SUMO precursor by a protease to reveal a di glycine motif, SUMO is activated by an E1 enzyme (Aos1/Uba2) and conjugated to target proteins by the sole E2 enzyme (Ubc9) guided to the appropriate substrates by the SUMO E3 ligase. Previous reports from our group showed that Schistosoma mansoni has two paralogs of SUMO: one E2 conjugation Ubc9 and two SUMO-specific proteases (SENPs). The differential gene expression profile observed for SUMO pathway genes throughout the S. mansoni life cycle attests for the distinct patterns of SUMO conjugates observed during parasite development particularly during the cercariae to schistosomula transition. To continue this investigation, we here analysed the repertoire of SUMO E3 ligases and their expression profiles during cercariae/schistosomula transition. In silico analysis through S. mansoni databases showed two conserved SUMO E3 ligases: protein inhibitor of activated STAT (PIAS) and Ran-binding protein 2 (RanBP2). Furthermore, expression levels of the SUMO E3 ligases were measured by qRT-PCR using total RNA from cercariae, adult worms and mechanically transformed schistosomula. Our data showed an up regulation of expression in lung schistosomula and adult worm stages. In conclusion, the differential expression of SmPIAS and SmRanBP2 during schistosomula development was similar to the expression levels of all genes related to SUMO conjugation, thereby suggesting that the control of protein activity, localisation or stability during cercariae to schistosomula transition is SUMO-dependent. PMID- 24802863 TI - The morphological and molecular characterization of Myxobolus khaliji n. sp. (Myxozoa: Myxosporea) from the double bar seabream Acanthopagrus bifasciatus (Forsskal, 1775) in the Arabian Gulf, Saudi Arabia. AB - Myxobolus khaliji n. sp., a new myxosporean, is described from the intestinal wall of the double bar seabream Acanthopagrus bifasciatus, collected from the Arabian Gulf off the coast of Saudi Arabia. It is characterized by the presence of ellipsoidal or round plasmodia of 2-4 mm in diameter. Mature spores were subspherical to elliptical in the frontal view, with a slightly pointed anterior end and a bluntly rounded posterior end, and measured 8.1 +/- 0.4 (7.2-9.5) MUm long, 6.3 +/- 0.6 (5.1-7.4) MUm wide, and 9.2 +/- 0.7 (8.3-10.2) thick. Spore valves are relatively thin, sometimes with a prominent thick caudal appendage. Two equal elliptical polar capsules were situated in the plane of the suture line at the anterior end of the spores and occupied above half of the spore length. Polar capsules measured 5.5 +/- 0.7 (4.1-6.1) MUm long and 3.2 +/- 0.2 (2.1-4.2) MUm wide. Polar filaments, wound in three to four coils, were situated perpendicularly to the longitudinal axis of the polar capsules. Combining the morphological characteristics, host specificity and geographical distribution, tissue tropism, and the molecular analysis of the partial sequence of the SSU ribosomal DNA gene, it was concluded that M. khaliji n. sp. was distinct from all previously described Myxobolus species. Phylogenetic analysis placed the present Myxobolus species in a marine Henneguya clade, which is a sister group of marine Myxobolus species. This is the first Myxobolus species with Henneguya-like spores from the marine environment to be found in the Saudi Arabian coasts of the Arabian Gulf. PMID- 24802864 TI - Anthelmintic activity of Artemisia annua L. extracts in vitro and the effect of an aqueous extract and artemisinin in sheep naturally infected with gastrointestinal nematodes. AB - There is no effective natural alternative control for gastrointestinal nematodes (GIN) of small ruminants, with Haemonchus contortus being the most economically important GIN. Despite frequent reports of multidrug-resistant GIN, there is no new commercial anthelmintic to substitute failing ones. Although trematocidal activity of artemisinin analogs has been reported in sheep, neither artemisinin nor its plant source (Artemisia annua) has been evaluated for anthelmintic activity in ruminants. This study evaluated the anthelmintic activity of A. annua crude extracts in vitro and compared the most effective extract with artemisinin in sheep naturally infected with H. contortus. A. annua leaves extracted with water, aqueous 0.1% sodium bicarbonate, dichloromethane, and ethanol were evaluated in vitro by the egg hatch test (EHT) and with the bicarbonate extract only for the larval development test (LDT) using H. contortus. The A. annua water, sodium bicarbonate (SBE), ethanol, and dichloromethane extracts tested in vitro contained 0.3, 0.6, 4.4, and 9.8% of artemisinin, respectively. The sodium bicarbonate extract resulted in the lowest LC99 in the EHT (1.27 MUg/mL) and in a LC99 of 23.8 MUg/mL in the LDT. Following in vitro results, the SBE (2 g/kg body weight (BW)) and artemisinin (100 mg/kg BW) were evaluated as a single oral dose in naturally infected Santa Ines sheep. Speciation from stool cultures established that 84-91% of GIN were H. contortus, 8.4-15.6 % were Trichostrongylus sp., and 0.3-0.7% were Oesophagostomum sp. Packed-cell volume and eggs per gram (EPG) of feces were used to test treatment efficacy. The SBE tested in vivo contained no artemisinin, but had a high antioxidant capacity of 2,295 MUmol of Trolox equivalents/g. Sheep dosed with artemisinin had maximum feces concentrations 24 h after treatment (126.5 MUg/g artemisinin), which sharply decreased at 36 h. By day 15, only levamisole-treated sheep had a significant decrease of 97% in EPG. Artemisinin-treated and SBE-treated sheep had nonsignificant EPG reductions of 28 and 19%, respectively, while sheep in infected/untreated group had an average EPG increase of 95%. Sheep treated with artemisinin and A. annua SBE maintained blood hematocrits throughout the experiment, while untreated/infected controls had a significant reduction in hematocrit. This is the first time oral dose of artemisinin and an aqueous extract of A. annua are evaluated as anthelmintic in sheep. Although oral dose of artemisinin and SBE, at single doses, were ineffective natural anthelmintics, artemisinin analogs with better bioavailability than artemisinin should be tested in vivo, through different routes and in multiple doses. The maintenance of hematocrit provided by artemisinin and A. annua extract and the high antioxidant capacity of the latter suggest that they could be combined with commercial anthelmintics to improve the well-being of infected animals and to evaluate potential synergism. PMID- 24802865 TI - No detection of Besnoitia besnoiti DNA in the semen of chronically infected bulls. AB - Bovine besnoitiosis is a chronic and debilitating disease observed in many European countries that may cause important economic losses in cattle. The recent widespread of the parasite in Europe had led the European Food Safety Authority to declare bovine besnoitiosis as a re-emerging disease in Europe. Many aspects of the epidemiology of bovine besnoitiosis such as the main routes of transmission are still unclear and need to be further studied. Among the different hypotheses, a sexual transmission has not yet been investigated. Therefore, the aim of this study was to evaluate the presence of Besnoitia besnoiti DNA in the semen of naturally infected bulls by using a highly sensitive method (real-time qPCR). Both pre-sperm and sperm fractions of 40 bulls, including seronegative (n = 11), seropositive subclinically (n = 17), and seropositive clinically (n = 12) infected animals, were collected by electroejaculation and analyzed by real-time qPCR. No B. besnoiti DNA was detected in 27 pre-sperm and 28 sperm fractions of the 40 examined bulls, suggesting that the transmission of B. besnoiti infection by the semen of chronically infected bulls is very unlikely. PMID- 24802866 TI - Chemical composition and larvicidal activity of plant extracts from Clausena dentata (Willd) (Rutaceae) against dengue, malaria, and filariasis vectors. AB - Mosquitoes in the larval stage are attractive targets for pesticides because mosquitoes breed in water, and thus, it is easy to deal with them in this habitat. The use of conventional pesticides in the water sources, however, introduces many risks to people and/or the environment. Natural pesticides, especially those derived from plants, are more promising in this aspect. Aromatic plants and their essential oils are very important sources of many compounds that are used in different respects. Insecticides of botanical origin may serve as suitable alternative to chemical insecticides. Acetone, chloroform, ethyl acetate, methanol, and petroleum benzine leaf extracts of Clausena dentata were tested against the fourth instar larvae of Anopheles stephensi, Culex quinquefasciatus, and Aedes aegypti (Diptera: Culicidae). Larval mortality was observed after 24 h of exposure. The highest larval mortality was found in acetone leaf extract, C. quinquefasciatus (LC50 = 0.150278 mg/ml; LC90 = 7.302613 mg/ml), A. aegypti (LC50 = 0.169495 mg/ml; LC90 = 1.10034 mg/ml), and A. stephensi (LC50 = 0.045684 mg/ml; LC90 = 0.045684 mg/ml). GC-MS analysis of plant extracts of acetone solvent revealed 16 compounds, of which the major compounds were benzene,1,2,3-trimethoxy-5-(2-propenyl) (14.97%), Z,Z-6,28 heptatriactontadien-2-one (6.81%), 2-allyl-4-methylphenol (28.14%), 2-allyl-4 methylphenol (17.34%), and 2,6,10,14,18,22-tetracosahexaene, 2,6,10,15,19,23 hexamethyl (10.35%). Our result shows acetone leaf extracts of C. dentata have the potential to be used as an ideal eco-friendly approach for mosquito control. PMID- 24802867 TI - Human oestriasis acquired in Florence and review on human myiasis in Italy. AB - Myiases-causing flies are widely observed in tropical countries, whereas in Italy, a temperate country, their epidemiology and clinical presentation are poorly known. We report three cases of human conjunctival myiasis recently observed at our hospital, and the results of a review of the literature on human myiasis in Italy. In August 2012, a case of Oestrus ovis conjunctival myiasis acquired in the city centre of Florence, Italy was diagnosed at our hospital. In the early fall of 2013, two additional cases, acquired in the neighbouring areas, occurred. The review of literature showed that, up to the middle of 1990s, myiasis in Italy was mainly an occupational disease of shepherds, caused by O. ovis. Recently, cases of travel acquired furuncular myiasis emerged, together with "opportunistic" autochthonous cases of wound myiasis in patients with underlying health conditions. Considering the causative agents of human of myiasis in Italy, among the 703 autochthonous cases reported, 98.1% were caused by O. ovis, while among the 42 imported cases described, 59.5% were due to Cordylobia spp. and 40.5% to Dermatobia hominis. Our findings suggest that O. ovis conjunctival myiasis may still be observed in urban setting in Italy. Health care providers should know and implement the basic rules of entomoprophylaxis for myiasis in the facilities where they are working and use these indications to educate patients and care givers in both pretravel care and geriatric outpatient settings. PMID- 24802868 TI - First report of an Acanthamoeba genotype T13 isolate as etiological agent of a keratitis in humans. AB - Several strains of free-living amoebae (FLA) belonging to the genus Acanthamoeba are able to cause a painful sight-threatening disease of the cornea designated as Acanthamoeba keratitis (AK). In this case report, a 22-year-old woman, wearer of soft contact lenses, was treated after the initial examination, and follow-up laboratory results led to the diagnosis of Acanthamoeba keratitis. The patient recovered under the targeted therapy, demonstrating that the acanthamoebae were the etiological agents of the keratitis in this case. The acanthamoebae belonged morphologically to group II. Genotyping of the causative Acanthamoeba strain based on sequences of the PCR amplimer ASA.S1 amplified from 18S ribosomal DNA by using the genus-specific primers JDP1 and JDP2 followed. The phylogenetic comparison of ASA.S1 confirmed that the isolated Acanthamoeba strain is closely related to genotype T13 supported by pairwise sequence identities of 97.1-98.0% and bootstrap support of 980 replicates with reference sequences of genotype T13. These results regarding the Acanthamoeba keratitis-causing isolate KaBo expands the number of known pathogenic genotypes to 12. To our knowledge, this is the first report of a T13 Acanthamoeba genotype being associated with keratitis in humans. PMID- 24802869 TI - Hepatozoon canis in German red foxes (Vulpes vulpes) and their ticks: molecular characterization and the phylogenetic relationship to other Hepatozoon spp. AB - In this study, the prevalence of Hepatozoon spp. in red foxes (Vulpes vulpes) and their ticks from Germany, as well as molecular characterizations and phylogenetic relationship to other Hepatozoon spp. were investigated. DNA extracts of 261 spleen samples and 1,953 ticks were examined for the presence of Hepatozoon spp. by a conventional polymerase chain reaction (PCR) targeting the 18S rRNA gene. The ticks included four tick species: Ixodes ricinus, Ixodes canisuga, Ixodes hexagonus and Dermacentor reticulatus. A total of 118/261 foxes (45.2%) and 148/1,953 ticks (7.5%) were Hepatozoon PCR-positive. Amplicons from 36 positive foxes and 41 positive ticks were sequenced. All sequences obtained from foxes and 39/41 from ticks had a 99% similarity to Hepatozoon canis, whereas two ticks' sequences had a 99% identity to Hepatozoon sp. The obtained Hepatozoon sequences in this study were phylogenetically related to other Hepatozoon sequences detected in other countries, which may represent strain variants. The high prevalence of H. canis DNA in red foxes in this study supports the suggested role of those animals in distribution of this parasite. Furthermore, detection of DNA of H. canis in foxes and all examined tick species collected from those foxes allows speculating about previously undescribed potential vectors for H. canis and suggests a potential role of the red fox in its natural endemic cycles. PMID- 24802870 TI - New insights into the life cycle of Platynosomum (Trematoda: Dicrocoeliidae). AB - The platynosomiasis, a worldwide parasitic disease with importance for domestic cat, has an etiological agent species of trematodes of the genus Platynosomum, whose complete life cycles are not yet known. The real role of lizards in the transmission of this dicrocoeliid parasite (as obligatory intermediate or paratenic host) still needs to be defined. In the present study, oval-shaped encysted metacercariae obtained from terrestrial isopods (Oniscidea sp. and Nagurus nanus) and elongated excysted metacercariae found in biliary ducts and gallbladder of lizards (Hemidactylus mabouia) in Brazil were used for morphological characterization and experimental infection of mice. Adult parasites recovered from bile ducts and liver of mice inoculated orally with metacercariae from both hosts (isopods and lizards) were identified as Platynosomum illiciens (=Platynosomum fastosum), showing that lizards are paratenic (not obligatory) hosts involved in the life cycle of this parasite. Moreover, Subulina octona is reported as the first intermediate host of P. illiciens in South America, and terrestrial isopods are presented here as new natural second intermediate hosts of the parasite. Finally, it is pointed out that high prevalence and intensity of infection of intermediate and paratenic hosts were observed. These findings on the life cycle of P. illiciens are relevant considering that they may indicate possible control measures of platynosomiasis. PMID- 24802871 TI - Serological survey for antibody to Encephalitozoon cuniculi in horses in the USA. AB - Encephalitozoon cuniculi is an obligate intracellular microsporidian parasite that can result in clinical and subclinical infection in many species. In the present study, a serological survey was conducted using samples from 105 horses in the state of New Jersey; 49 of the samples were obtained from clinically abnormal animals. Five or 4.8% of 105 serum samples were found to demonstrate reactivity by ELISA with titers of 1:64 to 1:1,024. One of the samples was obtained from a clinically normal horse. Clinical signs and diagnoses from the other animals included lameness, colic, osteochondritis dissecans, and fever. All clinical issues were resolved with hospitalization and treatment without the institution of E. cuniculi-focused therapy. This is the first report on the detection of E. cuniculi antibodies in horses in the USA. PMID- 24802872 TI - Rabconnectin-3a regulates vesicle endocytosis and canonical Wnt signaling in zebrafish neural crest migration. AB - Cell migration requires dynamic regulation of cell-cell signaling and cell adhesion. Both of these processes involve endocytosis, lysosomal degradation, and recycling of ligand-receptor complexes and cell adhesion molecules from the plasma membrane. Neural crest (NC) cells in vertebrates are highly migratory cells, which undergo an epithelial-mesenchymal transition (EMT) to leave the neural epithelium and migrate throughout the body to give rise to many different derivatives. Here we show that the v-ATPase interacting protein, Rabconnectin-3a (Rbc3a), controls intracellular trafficking events and Wnt signaling during NC migration. In zebrafish embryos deficient in Rbc3a, or its associated v-ATPase subunit Atp6v0a1, many NC cells fail to migrate and misregulate expression of cadherins. Surprisingly, endosomes in Rbc3a- and Atp6v0a1-deficient NC cells remain immature but still acidify. Rbc3a loss-of-function initially downregulates several canonical Wnt targets involved in EMT, but later Frizzled-7 accumulates at NC cell membranes, and nuclear B-catenin levels increase. Presumably due to this later Wnt signaling increase, Rbc3a-deficient NC cells that fail to migrate become pigment progenitors. We propose that Rbc3a and Atp6v0a1 promote endosomal maturation to coordinate Wnt signaling and intracellular trafficking of Wnt receptors and cadherins required for NC migration and cell fate determination. Our results suggest that different v-ATPases and associated proteins may play cell-type-specific functions in intracellular trafficking in many contexts. PMID- 24802873 TI - Delivering of proteins to the plant vacuole--an update. AB - Trafficking of soluble cargo to the vacuole is far from being a closed issue as it can occur by different routes and involve different intermediates. The textbook view of proteins being sorted at the post-Golgi level to the lytic vacuole via the pre-vacuole or to the protein storage vacuole mediated by dense vesicles is now challenged as novel routes are being disclosed and vacuoles with intermediate characteristics described. The identification of Vacuolar Sorting Determinants is a key signature to understand protein trafficking to the vacuole. Despite the long established vacuolar signals, some others have been described in the last few years, with different properties that can be specific for some cells or some types of vacuoles. There are also reports of proteins having two different vacuolar signals and their significance is questionable: a way to increase the efficiency of the sorting or different sorting depending on the protein roles in a specific context? Along came the idea of differential vacuolar sorting, suggesting a possible specialization of the trafficking pathways according to the type of cell and specific needs. In this review, we show the recent advances in the field and focus on different aspects of protein trafficking to the vacuoles. PMID- 24802874 TI - Degradation of organelles or specific organelle components via selective autophagy in plant cells. AB - Macroautophagy (hereafter referred to as autophagy) is a cellular mechanism dedicated to the degradation and recycling of unnecessary cytosolic components by their removal to the lytic compartment of the cell (the vacuole in plants). Autophagy is generally induced by stresses causing energy deprivation and its operation occurs by special vesicles, termed autophagosomes. Autophagy also operates in a selective manner, recycling specific components, such as organelles, protein aggregates or even specific proteins, and selective autophagy is implicated in both cellular housekeeping and response to stresses. In plants, selective autophagy has recently been shown to degrade mitochondria, plastids and peroxisomes, or organelle components such as the endoplasmic-reticulum (ER) membrane and chloroplast-derived proteins such as Rubisco. This ability places selective-autophagy as a major factor in cellular steady-state maintenance, both under stress and favorable environmental conditions. Here we review the recent advances documented in plants for this cellular process and further discuss its impact on plant physiology. PMID- 24802875 TI - Importance of Kupffer cells in the development of acute liver injuries in mice. AB - Kupffer cells reside within the liver sinusoid and serve as gatekeepers. They produce pro- and anti-inflammatory cytokines and other biologically important molecules upon the engagement of pattern recognition receptors such as Toll-like receptors. Kupffer cell-ablated mice established by in vivo treatment with clodronate liposomes have revealed many important features of Kupffer cells. In this paper, we review the importance of Kupffer cells in murine acute liver injuries and focus on the following two models: lipopolysaccharide (LPS)-induced liver injury, which is induced by priming with Propionibacterium acnes and subsequent challenge with LPS, and hypercoagulability-mediated acute liver failure such as that in concanavalin A (Con A)-induced hepatitis. Kupffer cells are required for LPS sensitization induced by P. acnes and are a major cellular source of interleukin-18, which induces acute liver injury following LPS challenge. Kupffer cells contribute to Con A-induced acute liver failure by initiating pathogenic, intrasinusoidal thrombosis in collaboration with sinusoidal endothelial cells. The mechanisms underlying these models may shed light on human liver injuries induced by various etiologies such as viral infection and/or abnormal metabolism. PMID- 24802876 TI - Development of drug delivery systems based on layered hydroxides for nanomedicine. AB - Layered hydroxides (LHs) have recently fascinated researchers due to their wide application in various fields. These inorganic nanoparticles, with excellent features as nanocarriers in drug delivery systems, have the potential to play an important role in healthcare. Owing to their outstanding ion-exchange capacity, many organic pharmaceutical drugs have been intercalated into the interlayer galleries of LHs and, consequently, novel nanodrugs or smart drugs may revolutionize in the treatment of diseases. Layered hydroxides, as green nanoreservoirs with sustained drug release and cell targeting properties hold great promise of improving health and prolonging life. PMID- 24802878 TI - Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and 15N NMR labeling experiments. AB - Imidazole-1-sulfonyl azide hydrogen sulfate is presented as an efficient reagent for the synthesis of sulfonyl azides from primary sulfonamides. The described method is experimentally simple and high-yielding and does not require the addition of Cu salts. Furthermore, (15)N NMR mechanistic studies show the reaction proceeds via a diazo transfer mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable advantage over existing diazo transfer reagents in terms of impact stability, cost, and ease of use. PMID- 24802879 TI - The normal appendix on CT: does size matter? AB - PURPOSE: (1) To evaluate the frequency of visualisation and measurements of the normal appendix. (2) To correlate Body Mass Index (BMI) and gender with visualisation of the normal appendix. (3) To correlate age, gender and body length with appendiceal length. MATERIALS AND METHODS: A retrospective review of 186 patients undergoing abdominal CT without suspicion of acute appendicitis was done. Frequency of visualisation and measurements (including maximal outer diameter, wall thickness, length, content, location of base and tip) of normal appendices were recorded. RESULTS: Prevalence of appendectomy was 34.4%. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of visualisation of the normal appendix were 76%, 94%, 96%, 67%, and 82% respectively. The mean maximal diameter of the appendix was 8.19 mm+/-1.6 (SD) (range, 4.2-12.8 mm). The mean length of the appendix was 81.11 mm+/-28.44 (SD) (range, 7.2-158.8 mm). The mean wall thickness of the appendix was 2.22 mm+/ 0.56 (SD) (range, 1.15-3.85 mm). The most common location of the appendiceal tip was pelvic in 66% appendices. The most common location of the appendiceal base was inferior, medial, and posterior in 37%. The normal appendix contained high density material in 2.2%. There was a significant correlation between gender and appendiceal length, with men having longer appendices than women. CONCLUSION: Most normal appendices are seen at multislice CT using i.v. contrast. The maximal outer diameter of the normal appendix overlaps with values currently used to diagnose appendicitis on CT. PMID- 24802881 TI - Intra-abdominal leiomyoma with right atrial extension. PMID- 24802880 TI - Prognostic implication of physical signs of congestion in acute heart failure patients and its association with steady-state biomarker levels. AB - BACKGROUND: Congestive physical findings such as pulmonary rales and third heart sound (S3) are hallmarks of acute heart failure (AHF). However, their role in outcome prediction remains unclear. We sought to investigate the association between congestive physical findings upon admission, steady-state biomarkers at the time of discharge, and long-term outcomes in AHF patients. METHODS: We analyzed the data of 133 consecutive AHF patients with an established diagnosis of ischemic or non-ischemic (dilated or hypertrophic) cardiomyopathy, admitted to a single-center university hospital between 2006 and 2010. The treating physician prospectively recorded major symptoms and congestive physical findings of AHF: paroxysmal nocturnal dyspnea, orthopnea, pulmonary rales, jugular venous distension (JVD), S3, and edema. The primary endpoint was defined as rehospitalization for HF. RESULTS: Majority (63.9%) of the patients had non ischemic etiology and, at the time of admission, S3 was seen in 69.9% of the patients, JVD in 54.1%, and pulmonary rales in 43.6%. The mean follow-up period was 726 +/- 31 days. Patients with pulmonary rales (p < 0.001) and S3 (p = 0.011) had worse readmission rates than those without these findings; the presence of these findings was also associated with elevated troponin T (TnT) levels at the time of discharge (odds ratio [OR] 2.8; p = 0.02 and OR 2.6; p = 0.05, respectively). CONCLUSION: Pulmonary rales and S3 were associated with inferior readmission rates and elevated TnT levels on discharge. The worsening of the readmission rate owing to congestive physical findings may be a consequence of on-going myocardial injury. PMID- 24802877 TI - Association of dioxin and other persistent organic pollutants (POPs) with diabetes: epidemiological evidence and new mechanisms of beta cell dysfunction. AB - The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet. For this reason, it has been recently proposed that other "nontraditional" risk factors could contribute to the diabetes epidemics. In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis. In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed. PMID- 24802882 TI - Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. AB - BACKGROUND: Melatonin is a hormone that regulates circadian rhythm, and its levels decline with age. As melatonin levels decrease, older adults are prone to develop disorders related to an altered circadian rhythm. The effective dose of melatonin supplementation in these disorders remains unclear. OBJECTIVES: Our objective was to define the optimal dosage of exogenous melatonin administration in disorders related to altered melatonin levels in older adults aged 55 years and above by determining the dose-response effect of exogenous administered melatonin on endogenous levels. METHODS: We conducted a systematic review through PubMed/MEDLINE and Embase, both from 1980 until November 2013. Included articles studied the effect of exogenous melatonin administration on endogenous melatonin levels in either serum, urine, or saliva in humans aged 55 years and above. RESULTS: We included 16 articles, nine of which were randomized controlled trials (RCTs). The mean age varied from 55.3 to 77.6 years. Melatonin dosage varied from 0.1 mg to 50 mg/kg and was administered orally in all studies. Pre- and post intervention levels revealed a significant elevation of the post-intervention melatonin levels in a dose-dependent fashion. The maximum concentrations measured in serum and urine were all elevated compared with placebo, and a higher elevation in older adults than in younger adults was demonstrated. Even though there were no differences between times to reach maximum concentration in serum and urine, melatonin levels with higher doses were maintained longer above a certain threshold than were lower doses. CONCLUSION: In older adults, we advise the use of the lowest possible dose of immediate-release formulation melatonin to best mimic the normal physiological circadian rhythm of melatonin and to avoid prolonged, supra-physiological blood levels. PMID- 24802884 TI - Ferrocenylpyrazolyl palladium complexes as catalysts for the polymerisation of 1 heptene and 1-octene to highly branched polyolefins. AB - Reactions of [PdCl2(NCMe)2] with the ferrocenylpyrazolyl compounds: 3-ferrocenyl 1H-pyrazole-5-carboxylate (L1), ethyl-1-(2-bromoethyl)-3-ferrocenyl-1H-pyrazole-5 carboxylate (L2a), ethyl-1-(2-bromoethyl)-5-ferrocenyl-1H-pyrazole-3-carboxylate (L2b), 3-ferrocenylpyrazolyl-methylenepyridine (L3) and 3-ferrocenyl-5 methylpyrazolyl-methylenepyridine (L4) at room temperature afforded [PdCl2(L1)] (1), [PdCl2(L2a)] (2a), [PdCl2(L2b)] (2b), [PdCl2(L3)] (3) and [PdCl2(L4)] (4) respectively. Compounds L1-L4 and their palladium complexes were obtained in moderate to high (50-90%) yield and characterized by NMR spectroscopy, elemental analysis, and in selected cases by single crystal X-ray crystallography. Complexes 1-4 were used as pre-catalysts for the reactions of 1-heptene and 1 octene with EtAlCl2 as a co-catalyst. The activities of 1, 2a and 3b were relatively low (10 083-18 250 g molPd(-1) h(-1)) with 1-heptene being a better monomer for these complexes. However, pre-catalysts 3 and 4 showed moderate activities (123 000-448 000 g molPd(-1) h(-1)) 1-octene being the better monomer. The polyolefins obtained were characterized by both (1)H and (13)C{(1)H} NMR to be highly branched polyolefins with degree of branching up to 270 branches per 1000 carbon atoms. However, low molecular weights between 888 and 1198 were recorded with narrow PDI between 1.02 and 1.44. PMID- 24802883 TI - Design and high-resolution structure of a beta3-peptide bundle catalyst. AB - Despite the widespread exploration of alpha-peptides as catalysts, there are few examples of beta-peptides that alter the course of a chemical transformation. Our previous work demonstrated that a special class of beta(3)-peptides spontaneously self-assembles in water into discrete protein-like bundles possessing unique quaternary structures and exceptional thermodynamic stability. Here we describe a series of beta(3)-peptide bundles capable of both substrate binding and chemical catalysis--ester hydrolysis. A combination of kinetic and high-resolution structural analysis suggests an active site triad composed of residues from at least two strands of the octameric bundle structure. PMID- 24802885 TI - Efficacy of azithromycin for treatment of acute exacerbation of chronic fibrosing interstitial pneumonia: a prospective, open-label study with historical controls. AB - BACKGROUND: Acute exacerbation of chronic fibrosing interstitial pneumonia (AE CFIP) is an often fatal condition with no established treatment. Recently, macrolides were found to be beneficial in cases of acute lung injury. OBJECTIVES: To examine the clinical effectiveness and safety of intravenous azithromycin in patients hospitalized for AE-CFIP. METHODS: A prospective, open-label study with historical controls was conducted. Twenty consecutive patients with AE-CFIP received azithromycin. They were compared with a historical cohort treated with fluoroquinolone (n = 56). All patients received high-dose steroid pulse therapy. The primary end point was mortality at 60 days. The secondary end point was safety of intravenous azithromycin in patients with AE-CFIP. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to investigate the relationship between azithromycin use and survival time. RESULTS: Mortality was significantly lower in the patients treated with azithromycin than in those treated with fluoroquinolone (mortality rate at 60 days: 20 vs. 69.6%, p < 0.001; median survival time: not reached vs. 29.5 days, p < 0.001). The IPTW adjusted hazard of mortality at 60 days in patients receiving azithromycin was 0.17 (95% CI 0.05-0.61). No serious adverse events were observed. CONCLUSIONS: Azithromycin was associated with improved outcomes in patients with AE-CFIP. Further studies are needed to verify this finding (Clinical trial JMA-IIA00095). PMID- 24802886 TI - Muscle strength and physical performance as predictors of mortality, hospitalization, and disability in the oldest old. AB - OBJECTIVES: To evaluate the predictive value of muscle strength and physical performance in the oldest old for all-cause mortality; hospitalization; and the onset of disability, defined as a decline in activities of daily living (ADLs), independent of muscle mass, inflammatory markers, and comorbidities. DESIGN: A prospective, observational, population-based follow-up study. SETTING: Three well circumscribed areas of Belgium. PARTICIPANTS: Five hundred sixty participants aged 80 and older were followed for 33.5 months (interquartile range 31.1-35.6 months). MEASUREMENTS: Grip strength, Short Physical Performance Battery (SPPB) score, and muscle mass were measured at baseline; ADLs at baseline and after 20 months; and all-cause mortality and time to first hospitalization from inclusion onward. Kaplan-Meier curves and Cox proportional hazards models were calculated for all-cause mortality and hospitalization. Logistic regression analysis was used to determine predictors of decline in ADLs. RESULTS: Kaplan-Meier curves showed significantly higher all-cause mortality and hospitalization in subjects in the lowest tertile of grip strength and SPPB score. The adjusted Cox proportional hazards model showed that participants with high grip strength or a high SPPB score had a lower risk of mortality and hospitalization, independent of muscle mass, inflammatory markers, and comorbidity. A relationship was found between SPPB score and decline in ADLs, independent of muscle mass, inflammation, and comorbidity. CONCLUSION: In people aged 80 and older, physical performance is a strong predictor of mortality, hospitalization, and disability, and muscle strength is a strong predictor of mortality and hospitalization. All of these relationships were independent of muscle mass, inflammatory markers, and comorbidity. PMID- 24802888 TI - Molecular structures of C- and N-terminus cysteine modified cecropin P1 chemically immobilized onto maleimide-terminated self-assembled monolayers investigated by molecular dynamics simulation. AB - Biosensors using peptides or proteins chemically immobilized on surfaces have many advantages such as better sensitivity, improved stability, and longer shelf life compared to those prepared using physically adsorbed biomolecules. Chemical immobilization can better control the interfacial conformation and orientation of peptides and proteins, leading to better activity of these biomolecules. In this research, molecular dynamics (MD) simulations were employed to systematically investigate the structure and dynamics of surface-tethered antimicrobial peptide cecropin P1 (CP1) modified with a cysteine residue at the C- (CP1c) or N-terminus (cCP1). Such CP1c and cCP1 molecules were chemically immobilized onto a silane EG4-maleimide self-assembled monolayer (SAM) surface by forming a thio-ether bond between the cysteine group in CP1c or cCP1 and the surface maleimide group. The simulation results showed that the immobilized cCP1 (via the N-terminus) tends to bend and gradually lie down onto the SAM surface, due to the large structural fluctuation of the C-terminus induced by unfavorable interactions between the hydrophobic C-terminal residues and water. Differently, the tethered CP1c (via the C-terminus) more or less stands up on the surface, only tilting slightly even after 60 ns. The simulation results can be well correlated to the recent experimental results obtained from sum frequency generation (SFG) vibrational spectroscopic study. The current simulation data provide more atomic level details on how the hydrophobicity difference in the C-terminus and N-terminus of the amphiphilic peptide can lead to different structures of the same peptide tethered to the surface via different termini. This knowledge can be used to rationally design chemically immobilized peptides to achieve desired structure and functionality. PMID- 24802887 TI - Shaping the microenvironment: evidence for the influence of a host galaxin on symbiont acquisition and maintenance in the squid-Vibrio symbiosis. AB - Most bacterial species make transitions between habitats, such as switching from free living to symbiotic niches. We provide evidence that a galaxin protein, EsGal1, of the squid Euprymna scolopes participates in both: (i) selection of the specific partner Vibrio fischeri from the bacterioplankton during symbiosis onset and, (ii) modulation of V. fischeri growth in symbiotic maintenance. We identified two galaxins in transcriptomic databases and showed by quantitative reverse-transcriptase polymerase chain reaction that one (esgal1) was dominant in the light organ. Further, esgal1 expression was upregulated by symbiosis, a response that was partially achieved with exposure to symbiont cell-envelope molecules. Confocal immunocytochemistry of juvenile animals localized EsGal1 to the apical surfaces of light-organ epithelia and surrounding mucus, the environment in which V. fischeri cells aggregate before migration into the organ. Growth assays revealed that one repeat of EsGal1 arrested growth of Gram-positive bacterial cells, which represent the cell type first 'winnowed' during initial selection of the symbiont. The EsGal1-derived peptide also significantly decreased the growth rate of V. fischeri in culture. Further, when animals were exposed to an anti-EsGal1 antibody, symbiont population growth was significantly increased. These data provide a window into how hosts select symbionts from a rich environment and govern their growth in symbiosis. PMID- 24802889 TI - Modeling a crowdsourced definition of molecular complexity. AB - This paper brings together the concepts of molecular complexity and crowdsourcing. An exercise was done at Merck where 386 chemists voted on the molecular complexity (on a scale of 1-5) of 2681 molecules taken from various sources: public, licensed, and in-house. The meanComplexity of a molecule is the average over all votes for that molecule. As long as enough votes are cast per molecule, we find meanComplexity is quite easy to model with QSAR methods using only a handful of physical descriptors (e.g., number of chiral centers, number of unique topological torsions, a Wiener index, etc.). The high level of self consistency of the model (cross-validated R(2) ~0.88) is remarkable given that our chemists do not agree with each other strongly about the complexity of any given molecule. Thus, the power of crowdsourcing is clearly demonstrated in this case. The meanComplexity appears to be correlated with at least one metric of synthetic complexity from the literature derived in a different way and is correlated with values of process mass intensity (PMI) from the literature and from in-house studies. Complexity can be used to differentiate between in-house programs and to follow a program over time. PMID- 24802890 TI - Effects of anti-inflammatory vagus nerve stimulation in endotoxemic rats on blood and spleen lymphocyte subsets. AB - BACKGROUND: Anti-inflammatory cytokine effects of vagus nerve stimulation in sepsis syndromes are well established. Effects on immune cells are less clear. Therefore, we studied changes in peripheral and spleen leukocyte subsets in an endotoxic rat sepsis model. METHODS: Ventilated and sedated adult male SD rats received 5 mg/kg b.w. lipopolysaccharide intravenously to induce endotoxic sepsis. Controls and a group with both-sided vagotomy were compared to animals with both sided vagotomy and left distal vagus nerve stimulation. 4.5 h after sepsis induction immune cell counts and types in the peripheral blood and spleen were determined [T-lymphocytes (CD3+), T-helper cells (CD3+ CD4+), activated T helper cells (CD3+ CD4+ CD134+), cytotoxic T-cells (CD3+ CD8+), activated cytotoxic T-cells (CD3+ CD8+ CD134+), B-lymphocytes (CD45R+ CD11cneg-dim), dendritic cells (CD11c+ OX-62 +), natural killer cells (CD161+ CD3neg) and granulocytes (His48 +)] together with cytokine and chemokine plasma levels (IL10; IFN-g, TNF-a, Cxcl5, Ccl5). RESULTS: Blood cell counts declined in all LPS groups. However, vagus nerve stimulation but not vagotomy activated cytotoxic T cells. Vagotomy also depleted natural killer cells. In the spleen, vagotomy resulted in a strong decline of all cell types which was not present in the other septic groups where only granulocyte numbers declined. CONCLUSION: Vagotomy strongly declines immune cell counts in the septic spleen. This could not be explained by an evasion or apoptosis of cells. A marginalisation of spleen immune cells into the peripheral microcirculation might be therefore most likely. Further studies are warranted to clear this issue. PMID- 24802891 TI - A new look at a poorly immunogenic neutralization epitope on cytomegalovirus glycoprotein B. Is there cause for antigen redesign? AB - The immune response is able to control cytomegalovirus infection in most subjects. However, in some patient groups the virus is not well contained resulting in disease and severe morbidity. The development of efficacious vaccines is therefore a high priority. Antibodies may contribute to protection against disease caused by CMV but the most efficient targets for protective humoral immunity are not precisely known. Glycoprotein B (gB) is a protein that is targeted by virus-neutralizing antibodies. One epitope on gB, AD-2, is poorly immunogenic following natural infection and vaccination. It is consequently not effectively exploited as a target for antibodies by the immune system. However, antibodies specific for this epitope, when they develop, display important functional activities that may play a role in protection against infection. In this study critical features of human antibody recognition of this epitope are re assessed based on structural and immunochemical data. The analysis suggests that the immune system may only be able to develop an AD-2 specific antibody response through rare, very specific rearrangement events that by chance create a naive B cell that can be recruited into an AD-2 specific immune response. These results reinvigorate the notion that if we are to be able to effectively exploit AD-2 specific humoral immunity we need to readdress the nature of the antigen incorporated into vaccines so as to more effectively recruit B cells into the response against this epitope. PMID- 24802892 TI - Mechanisms of eukaryotic transcription: a meeting report August 27-31, 2013, CSHL, Cold Spring Harbor, New York. AB - The "Mechanisms of Eukaryotic Transcription" meeting at Cold Spring Harbor Laboratory, organized by Stephen Buratowski (Harvard Medical School), Katherine Jones (The Salk Institute for Biological Studies) and John Lis (Cornell University), counted with 364 registered attendees, 64 speakers and 215 posters. Top-notch researchers in a very dynamic and collegial atmosphere chaired eight sessions. Here, I discuss selected presentations of each session from an impressive list of speakers. I apologize in advance to speakers whose work I did not discuss due to space constraints. PMID- 24802903 TI - Reply to comment on Li et al.: Noncontinuous versus continuous wound drainage after total knee arthroplasty: a meta-analysis. PMID- 24802904 TI - Sleep alterations in children with refractory epileptic encephalopathies: a polysomnographic study. AB - Data on the relationship between sleep disturbances and refractory epileptic encephalopathies (EEs) are scarce. Our aim was to assess, by means of nocturnal polysomnography, if children with EEs present with objective alterations in sleep organization. Twenty-three children with EEs (12 males; mean age: 8.7+/-1.4years) and 40 healthy controls (22 males; mean age: 8.8+/-1.1years) underwent an overnight full polysomnography (PSG). Relative to controls, children with EEs showed a significant reduction in all PSG parameters related to sleep duration time in bed (TIB-min p<0.001), total sleep time (TST-min p<0.001), and sleep percentage (SPT-min p<0.001), as well as significantly higher REM latency (FRL min p<0.001), rate in stage shifting (p=0.005), and number of awakenings/hour (p=0.002). Relative to controls, children with EEs also showed significant differences in respiratory parameters (AHI/h p<0.001, ODI/h p<0.001, SpO2% p<0.001, SpO2 nadir% p<0.001) and a higher rate of periodic limb movements (PLMs% p<0.001). Our findings suggest that sleep evaluation could be considered mandatory in children with refractory epileptic encephalopathy in order to improve the clinical management and the therapeutic strategies. PMID- 24802902 TI - Monitoring vigabatrin in head injury patients by cerebral microdialysis: obtaining pharmacokinetic measurements in a neurocritical care setting. AB - AIMS: The aims were to determine blood-brain barrier penetration and brain extracellular pharmacokinetics for the anticonvulsant vigabatrin (VGB; gamma vinyl-gamma-aminobutyric acid) in brain extracellular fluid and plasma from severe traumatic brain injury (TBI) patients, and to measure the response of gamma-aminobutyric acid (GABA) concentration in brain extracellular fluid. METHODS: Severe TBI patients (n = 10) received VGB (0.5 g enterally, every 12 h). Each patient had a cerebral microdialysis catheter; two patients had a second catheter in a different region of the brain. Plasma samples were collected 0.5 h before and 2, 4 and 11.5 h after the first VGB dose. Cerebral microdialysis commenced before the first VGB dose and continued through at least three doses of VGB. Controls were seven severe TBI patients with microdialysis, without VGB. RESULTS: After the first VGB dose, the maximum concentration of VGB (Cmax ) was 31.7 (26.9-42.6) MUmol l(-1) (median and interquartile range for eight patients) in plasma and 2.41 (2.03-5.94) MUmol l(-1) in brain microdialysates (nine patients, 11 catheters), without significant plasma-brain correlation. After three doses, median Cmax in microdialysates increased to 5.22 (4.24-7.14) MUmol l(-1) (eight patients, 10 catheters). Microdialysate VGB concentrations were higher close to focal lesions than in distant sites. Microdialysate GABA concentrations increased modestly in some of the patients after VGB administration. CONCLUSIONS: Vigabatrin, given enterally to severe TBI patients, crosses the blood-brain barrier into the brain extracellular fluid, where it accumulates with multiple dosing. Pharmacokinetics suggest delayed uptake from the blood. PMID- 24802905 TI - Methods for nuclei detection, segmentation, and classification in digital histopathology: a review-current status and future potential. AB - Digital pathology represents one of the major evolutions in modern medicine. Pathological examinations constitute the gold standard in many medical protocols, and also play a critical and legal role in the diagnosis process. In the conventional cancer diagnosis, pathologists analyze biopsies to make diagnostic and prognostic assessments, mainly based on the cell morphology and architecture distribution. Recently, computerized methods have been rapidly evolving in the area of digital pathology, with growing applications related to nuclei detection, segmentation, and classification. In cancer research, these approaches have played, and will continue to play a key (often bottleneck) role in minimizing human intervention, consolidating pertinent second opinions, and providing traceable clinical information. Pathological studies have been conducted for numerous cancer detection and grading applications, including brain, breast, cervix, lung, and prostate cancer grading. Our study presents, discusses, and extracts the major trends from an exhaustive overview of various nuclei detection, segmentation, feature computation, and classification techniques used in histopathology imagery, specifically in hematoxylin-eosin and immunohistochemical staining protocols. This study also enables us to measure the challenges that remain, in order to reach robust analysis of whole slide images, essential high content imaging with diagnostic biomarkers and prognosis support in digital pathology. PMID- 24802906 TI - Paenibacterin, a novel broad-spectrum lipopeptide antibiotic, neutralises endotoxins and promotes survival in a murine model of Pseudomonas aeruginosa induced sepsis. AB - Paenibacterin, produced by Paenibacillus thiaminolyticus OSY-SE, is active both against Gram-negative and Gram-positive pathogens, including antibiotic-resistant strains of Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus aureus and Enterococcus faecalis. Paenibacterin showed relatively low cytotoxicity against a human kidney cell line (ATCC CRL-2190), with a 50% inhibitory concentration (IC50)>=109MUg/mL. The cationic paenibacterin molecule binds to the negatively charged Gram-negative endotoxins in vitro, suggesting that paenibacterin can neutralise lipopolysaccharides. In a murine septic shock model, two 500MUg doses of paenibacterin significantly increased the survival of mice challenged with a lethal level of P. aeruginosa. Considering that paenibacterin is effective against many strains of antibiotic-resistant pathogens, this study suggests that this antimicrobial agent is a promising candidate as a new drug. PMID- 24802907 TI - Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease. AB - BACKGROUND: Several reports in the literature suggest a difference in outcome between melanoma patients with macroscopic (clinically palpable) nodal disease from an unknown primary (MUP) and a known primary (MKP). The purpose of this study was to compare the outcomes for MUP and MKP patients after therapeutic lymph node dissection (TLND) for macroscopic nodal disease. METHODS: From a large, prospective, single-institution database, the details of melanoma patients who first presented with macroscopic nodal disease and underwent TLND between 1971 and 2010 were extracted and analyzed. RESULTS: There were 287 MUP patients and 264 MKP patients who fulfilled the study selection criteria. MUP patients had better disease-free, distant metastasis-free, and melanoma-specific survival after their TLND than MKP patients (all p < 0.001). Extranodal melanoma extension, >3 positive lymph nodes, and administration of adjuvant radiotherapy were all independent predictors of reduced disease-free and melanoma-specific survival (all p < 0.05). MUP patients also had a better prognosis than MKP patients whose primary melanoma had regression (p = 0.001). CONCLUSIONS: The occurrence and improved outcome of MUP patients may be due to immune-induced total regression of the primary tumor and better immunologic prevention or control of distant metastatic disease. Alternatively, in some MUP patients, melanoma may not be metastatic but may originate de novo from nevus cells in lymph nodes, with the more favorable prognosis attributable to their primary nodal origin and complete surgical resection. PMID- 24802908 TI - Prognostic factors and outcome of spermatic cord sarcoma. AB - PURPOSE: To evaluate management and outcome in a large series of patients with spermatic cord sarcomas (SCS), a rare malignancy. METHODS: Eighty-two patients with localized SCS treated at two dedicated sarcoma units between 1992 and 2013 were included. Disease-specific survival (DSS) and crude cumulative incidence of local recurrence and distant metastases (DM) were estimated by Kaplan-Meier plots and log rank tests. RESULTS: Median follow-up was 33 months (interquartile range 13-72 months). Sixty-one patients presented with primary disease. Liposarcoma was the most common histotype, but surprisingly, 37 % of tumors were of high grade. Seventeen patients (21 %) received radiotherapy and 12 patients (15 %) chemotherapy. Five-year DSS for the whole series was 92 % [95 % confidence interval (CI) 83-97]. Five-year rates of local recurrence and DM were 26 % (95 % CI 15-42) and 24 % (95 % CI 15-38), respectively. Tumor grade was found to be a significant predictor of both DSS and DM (both p < 0.001). Quality of surgical margins was proved to affect the local outcome (p = 0.025), while the rates of distant metastases were found to differ significantly by histology (p = 0.010). Exclusively in the liposarcoma subgroup, quality of surgical margins was also directly associated with DSS (p = 0.043). CONCLUSIONS: Wide excision of the tumor is critical for cure, especially in the liposarcoma subgroup. The role of radiotherapy and chemotherapy is not established. PMID- 24802909 TI - Systematic review of FDG-PET prediction of complete pathological response and survival in rectal cancer. AB - BACKGROUND: Advances in the management of rectal cancer have resulted in an increased application of multimodal therapy with the aim of tailoring therapy to individual patients. Complete pathological response (pCR) is associated with improved survival and may be potentially managed without radical surgical resection. Over the last decade, there has been increasing interest in the ability of functional imaging to predict complete response to treatment. The aim of this review was to assess the role of (18)F-flurordeoxyglucose positron emission tomography (FDG-PET) in prediction of pCR and prognosis in resectable locally advanced rectal cancer. METHODS: A search of the MEDLINE and Embase databases was conducted, and a systematic review of the literature investigating positron emission tomography (PET) in the prediction of pCR and survival in rectal cancer was performed. RESULTS: Seventeen series assessing PET prediction of pCR were included in the review. Seven series assessed postchemoradiation SUVmax, which was significantly different between response groups in all six studies that assessed this. Nine series assessed the response index (RI) for SUVmax, which was significantly different between response groups in seven series. Thirteen studies investigated PET response for prediction of survival. Metabolic complete response assessed by SUV2max or visual response and RISUVmax showed strong associations with disease-free survival (DFS) and overall survival (OS). CONCLUSION: SUV2max and RISUVmax appear to be useful FDG-PET markers for prediction of pCR and these parameters also show strong associations with DFS and OS. FDG-PET may have a role in outcome prediction in patients with advanced rectal cancer. PMID- 24802910 TI - Nomogram predicting severe adverse events after musculoskeletal tumor surgery: analysis of a national administrative database. AB - BACKGROUND: There have been no nationwide surveys of postoperative adverse events (AEs) after musculoskeletal tumor surgery focusing on their severity. Therefore, we developed a nomogram to predict severe AEs after musculoskeletal tumor surgery. METHODS: We identified patients in the Diagnosis Procedure Combination database who underwent musculoskeletal tumor surgery during 2007-2012, and defined severe AEs as follows: (i) in-hospital mortality; (ii) postoperative medications including massive transfusion (>=1,400 mL), catecholamines, gamma globulin products, protease inhibitors, and medications for disseminated intravascular coagulation; and (iii) postoperative interventions consisting of mechanical ventilation, dialysis support, and cardiac support. Logistic regression models were used to address the occurrence of severe AEs. RESULTS: Of 5,716 patients identified, 613 patients (10.7 %) had severe AEs. Multivariate analyses showed an inverse relationship between body mass index (BMI) and severe AEs (odds ratio 1.80 for BMI <18.50; p < 0.001) after adjustment for other significant factors, including sex, age, tumor location, Charlson comorbidity index, type of surgery, and duration of anesthesia. A nomogram and a calibration plot based on these results were well-fitted to predict the probability of severe AEs after musculoskeletal tumor surgery (concordance index 0.781). CONCLUSIONS: We developed a nomogram predicting the probability of severe AEs after musculoskeletal tumor surgery. In addition, we clarified that underweight, but not overweight or obese, status was significantly associated with increased severe AEs after adjusting for patient background characteristics. PMID- 24802912 TI - Safety and simulation. PMID- 24802911 TI - Rates of dinosaur body mass evolution indicate 170 million years of sustained ecological innovation on the avian stem lineage. AB - Large-scale adaptive radiations might explain the runaway success of a minority of extant vertebrate clades. This hypothesis predicts, among other things, rapid rates of morphological evolution during the early history of major groups, as lineages invade disparate ecological niches. However, few studies of adaptive radiation have included deep time data, so the links between extant diversity and major extinct radiations are unclear. The intensively studied Mesozoic dinosaur record provides a model system for such investigation, representing an ecologically diverse group that dominated terrestrial ecosystems for 170 million years. Furthermore, with 10,000 species, extant dinosaurs (birds) are the most speciose living tetrapod clade. We assembled composite trees of 614-622 Mesozoic dinosaurs/birds, and a comprehensive body mass dataset using the scaling relationship of limb bone robustness. Maximum-likelihood modelling and the node height test reveal rapid evolutionary rates and a predominance of rapid shifts among size classes in early (Triassic) dinosaurs. This indicates an early burst niche-filling pattern and contrasts with previous studies that favoured gradualistic rates. Subsequently, rates declined in most lineages, which rarely exploited new ecological niches. However, feathered maniraptoran dinosaurs (including Mesozoic birds) sustained rapid evolution from at least the Middle Jurassic, suggesting that these taxa evaded the effects of niche saturation. This indicates that a long evolutionary history of continuing ecological innovation paved the way for a second great radiation of dinosaurs, in birds. We therefore demonstrate links between the predominantly extinct deep time adaptive radiation of non-avian dinosaurs and the phenomenal diversification of birds, via continuing rapid rates of evolution along the phylogenetic stem lineage. This raises the possibility that the uneven distribution of biodiversity results not just from large-scale extrapolation of the process of adaptive radiation in a few extant clades, but also from the maintenance of evolvability on vast time scales across the history of life, in key lineages. PMID- 24802913 TI - Moment-specific compliance with hand hygiene. AB - BACKGROUND: Hand hygiene is an important component of patient-safety education. The World Health Organization recommends the use of hand hygiene measures at five clinical moments. While previous studies have treated hand hygiene as a single entity, we investigated whether and how the compliance of students may vary across the five clinical moments. We also studied their reasons for non compliance with a view to inform teaching. METHOD: A voluntary self-administered questionnaire survey was conducted on a convenient sample of 339 medical and nursing students. The five clinical moments studied were: before touching a patient (moment 1); before a clean/aseptic procedure (moment 2); after body fluid exposure risk (moment 3); after touching a patient (moment 4); and after touching the patient's surroundings (moment 5). RESULTS: The overall reported compliance rate was 83.0 per cent. The compliance rates were significantly lower at moments 1 and 5. Nursing students reported better overall compliance (p = 0.01), and at moments 2 (p = 0.0001) and 3 (p = 0.0001), than medical students. Medical students fared better at moment 4 (p = 0.009). The most common reason reported for non-compliance was 'forgetfulness'. DISCUSSION: We identified differences in compliance rates across the five clinical moments of hand hygiene. Education programmes should not treat the hand hygiene process as a single entity, but should adopt a moment-specific approach to promote recall, with particular emphases on moments 1 and 5. Nursing and medical students may require different education strategies. Future studies on hand hygiene may also adopt a moment specific approach. PMID- 24802914 TI - Human-factors training for surgical trainees. AB - BACKGROUND: Shortcomings in non-technical skills have frequently been shown to play a role in adverse events during surgery. Human-factors training has an increasing role to play in enhancing patient safety and reducing medical errors. Programmes in non-technical skills are promoted by the surgical Royal Colleges in the UK and Ireland, and are currently aimed at consultants, senior trainees and theatre teams. Since 2009, the Severn Postgraduate Deanery School of Surgery in the UK has developed a 1-day human-factors training course specifically designed for junior surgical trainees. METHODS: Analysis of post-course feedback on self assessed confidence in the use of non-technical skills was undertaken for all junior surgical trainees undertaking the course in 2012/13. RESULTS: Thirty-three junior surgical trainees attended the 1-day human-factors training course. In all, 91 per cent of trainees reported that the course would change their practice. There was a statistically significant difference between the self assessed confidence of trainees in the use of all four categories of non technical skills (p <= 0.001) before and after the course. DISCUSSION: The Severn Deanery offers a compulsory human-factors training course for surgeons at the start of their career. Given the importance of reducing human error, maintaining patient safety and the introduction of competency-based training with an emphasis on simulation, human-factors training has a vital place in surgical training, and is highly recommended to others involved in training junior surgical trainees. PMID- 24802915 TI - Defining insight: a challenge that matters. AB - BACKGROUND: Insight is a fundamental consideration in the maintenance and improvement of performance. What is required is a definition that can be used consistently along with an understanding of the dynamic nature of insight, and therefore its potential for improvement. CONTEXT: The work presented is a review of contemporary literature about insight, self-awareness and emotional intelligence, and experience from the National Clinical Assessment Service (NCAS) in the assessment of 300 doctors with performance problems. SUMMARY OF RESULTS: This work has led to the construction of a working definition of insight that incorporates reflection, emotional intelligence, self-awareness and motivation. The validity and utility of this definition was tested using data from NCAS's growing experience. CONCLUSIONS: The assessment of insight in NCAS performance assessments has involved the use of information from a variety of sources, including psychometric profiling, multisource feedback and self-assessment. This has been corroborated with findings from clinical performance assessment and the outcomes of remediation plans. IMPLICATIONS: A definition of insight is offered that is greater than just self-awareness, and that involves emotional intelligence and motivation. The use of this broad definition is of fundamental importance in the production of educational and development programmes at all levels. PMID- 24802916 TI - Anxiety and self-awareness in video feedback. AB - BACKGROUND: Doctor-patient communication is an integral part of good medical practice and medical education throughout the UK. Innovative methods of clinical communication training make use of technology, including video feedback, within undergraduate learning; however, medical students may encounter barriers such as social anxiety and self-awareness that could prevent them from fully benefiting from training sessions. This study investigated the extent to which medical student anxiety and self-awareness impacted on their learning experience in video feedback workshops. METHODS: Written reflections on the experience of using video feedback were gathered from third-year medical students (n = 47). Reflections were thematically analysed to identify key themes relating to anxiety and self awareness perceptions. RESULTS: Students reported a high level of anxiety at the prospect of being video-recorded while interacting with a simulated patient. Levels of public self-awareness were high and students were concerned at being judged as inadequate by their peers. The peer feedback sessions were used to readjust students' perceptions of their own abilities by comparing their own performance with that of their peers. DISCUSSION: Clinical communication trainers should be aware of the anxiety and high public self-awareness that students may experience prior to video feedback sessions, and should aim to reduce this by informing students as much as possible about the process and by shifting their focus away from the peer appraisal of performance. Students appear to find the opportunity to improve the accuracy of their self-perception of their own skills as the main benefit of clinical communication video feedback training, and this area could be investigated further to determine how to derive maximum benefit. PMID- 24802917 TI - Surgical skills training: time to start early. AB - BACKGROUND: Changes in undergraduate medical curricula, combined with reforms in postgraduate education, have training implications for surgical skills acquisition in a climate of reduced clinical exposure. Confidence and prior experience influences the educational impact of learning. Currently there are limited formal basic surgical skills programmes integrated into UK undergraduate curricula. CONTEXT: Early skills targeting is valuable for students entering surgical, related allied specialties and even traditionally non-surgical specialties, such as General Practice. Such experience can make students more confident and subsequently competent future junior doctors and trainees. INNOVATION: The integration of skills training through the use of simple low fidelity training models can bridge the gap between undergraduate skills education and postgraduate training, whereas approaches involving more recent advances in simulation may prepare students further by making available more contextualised and scenario-based learning environments. IMPLICATIONS: We suggest that it is an ideal time for the introduction of dedicated basic surgical skills programmes into UK undergraduate medical curricula. Training will benefit all students. Importantly, training can inspire confidence, clinical interest, and can also provide a solid foundation of skills that can support and enable junior doctors' further postgraduate training. PMID- 24802918 TI - Ensuring standards for the extended role of optometry. AB - BACKGROUND: In optometry, as in other health professions, such as pharmacy and nursing, there has been an expansion in the role of the optometrist in primary eye care, taking on aspects of care such as prescribing, which was traditionally undertaken by general practitioners. In optometry, this extended role involves monitoring eye conditions that do not require treatment or monitoring in secondary care, roles that were traditionally referred on. However, any extended role requires educational support. The development of a national educational programme can prevent any duplication of effort and provide a system of disseminating support to practitioners, who often work in isolation. CONTEXT: The National Education Programme was developed and supported by the National Health Service (NHS) Education for Scotland (NES). This a national body responsible for supporting NHS services in Scotland, by developing and delivering education and training for those who work in NHS Scotland. INNOVATION: Optometrists were given educational support in three main stages: simulation of component skills; safe learning in a simulated health care context; and support for the transfer of those skills to practice, including the use of mentoring via e-mail. The evaluation of this three-stage process has been positive. IMPLICATIONS: To further develop any expanded role in health care practice, safe guidelines for practice are required. Simulation can provide support at the start of this process in setting standards. However, mentorship in the practice area, as reported in this study, was required to embed newly acquired skills. PMID- 24802919 TI - Can new doctors be prepared for practice? A review. AB - BACKGROUND: The transition from medical student to junior doctor is an important period of change. Research shows junior doctors often experience high levels of stress, and consequently burnout. Understanding how to prepare for the transition may allow individuals who are likely to struggle to be identified and assisted. The aim of this paper is to systematically review the literature on preparedness for practice in newly qualified junior doctors. METHODS: This was a systematic review of literature concerning the transition from student to junior doctor, published in the last 10 years, and that measured or explored one or more factors affecting preparedness. RESULTS: Nine papers were included in this review. These varied in design and methodological quality. Most used survey methodology (n = 7). Six found knowledge and skills, particularly deficiencies in prescribing and practical procedures, relevant in terms of preparedness. Five looked at personal traits, with high levels of neuroticism and low confidence deemed to be important. Medical school and workplace factors, including early clinical experience and shadowing, positively affected preparedness. A lack of senior support proved detrimental. The influence of demographics was inconclusive. DISCUSSION: The studies reviewed indicate that both personal and organisational factors are pertinent to managing the transition from student to junior doctor. Further prospective studies, both qualitative and quantitative, drawing on theories of change, are required to identify what precise factors would make a difference to this transition. PMID- 24802920 TI - Effective foundation trainee local inductions: room for improvement? AB - BACKGROUND: We aimed to evaluate whether UK foundation trainees receive local unit inductions, and their timing, content and value. METHODS: We used published literature and guidelines from the UK's General Medical Council (GMC) and National Health Service Litigation Authority (NHSLA) to identify key topics to be covered at the induction. We surveyed all foundation doctors in the North Western Foundation School and used questionnaires to assess inductions for the posts starting in December 2011. RESULTS: The total response rate was 45 per cent, but this covered 100 per cent of the programmes and departments in the school: 22 per cent received an induction before their post; 10 per cent received no induction whatsoever. There was a large difference between how useful trainees find most topics and how often they were provided. Some departments use more interactive formats in induction, such as e-learning and practical workshops. Overall, trainees expressed very positive views about the potential value of inductions, and 88 per cent felt that inductions should be standardised. Trust monitoring of inductions often appears to be unreliable. DISCUSSION: Timely, good-quality inductions can potentially reduce service delays and improve patient safety. Inductions currently appear not to be prioritised in the trusts studied, and they are not focused on the needs of trainees. Local inductions are currently suffering from a lack of guidelines into their implementation. From this study we have drawn up a set of guidelines for local induction and a template for an induction booklet. We recommend inductions should contain a minimum set of essential topics, be multidisciplinary, include more trainee input and be monitored more effectively. PMID- 24802921 TI - Clinical teaching: widening the definition. AB - BACKGROUND: In all medical specialities, trainees are increasingly encouraged to develop teaching skills alongside their clinical professional development. However, there have been few empirical UK-based studies that have examined trainees' attitudes and understanding of their own engagement with educational activities. This study therefore aimed to explore this in the context of general practitioner (GP) training using a qualitative approach. METHODS: Twenty GP registrars from the North Western Deanery were recruited to four focus groups. The data obtained using a semi-structured topic guide were analysed for thematic content, and the rigour of this methodology was increased by peer checking of the coding. Participation was voluntary and ethical approval was obtained. RESULTS: The majority of registrars interviewed initially presumed that teaching role development was only in relation to educating those junior to them, and thus followed a vertical hierarchical structure; however, during focus group discussions, the registrars started to recognise a range of other teaching modalities that they had not previously noted. These included peer-to-peer teaching sessions, examination preparation groups and, indeed, the everyday education of patients during consultations. DISCUSSION: Although this study has been conducted in the context of GP training, it is plausible to suggest that skewed perceptions from trainees as to what constitutes teaching may indeed exist in other speciality training schemes. There is therefore a need to shift current thinking around teaching engagement away from the traditional senior-junior relationship, and instead widen the definition of what it means to be involved in teaching activities. PMID- 24802922 TI - What do medical students expect in a teacher? AB - BACKGROUND: Medical students prefer some teachers over others within the same medical school or department. The objective of our study was to find out what qualities may allow all teachers to be nearly on a par in terms of student preference. METHODS: A single-centre cross-sectional study was conducted among first- to fifth-year medical students. All students were surveyed with a questionnaire to identify the qualities that they would like to see in their medical teachers. Three rounds of survey were conducted using the Modified Delphi technique in order to obtain the consensus of the students. If more than 85 per cent of the students agreed on a quality, it was considered final. In the final round students were asked to rate the chosen qualities in order of importance. The data were analysed using the statistical software spss 17. RESULTS: A total of 181 students responded to the survey. The qualities identified by medical students were grouped into four major and 11 minor categories. All qualities were ranked according to importance, as determined by the students. Teaching (158; 88%) and interpersonal (157; 87%) skills were ranked as the most important skills required of a medical teacher, followed by personal (150; 83%) and professional (140; 77%) skills. Administrative skills were deemed the least essential (112; 62%) of the skills sought in a medical educator. CONCLUSION: Medical students' preference for one teacher over another is directly correlated with a teacher's ability to teach, his or her interpersonal skills, as well as personal and professional qualities. PMID- 24802923 TI - The role of the assessor: exploring the clinical supervisor's skill set. AB - BACKGROUND: Clinical supervisors have several different responsibilities. Although their responsibilities as an assessor are important, little is known about what skill set should be acquired for this role and how to foster their development. Documenting assessor skills to study their acquisition and development is critical. METHODS: A web survey based on the principles of Appreciative Inquiry was distributed to faculty members and residents from a Department of Medicine at a Canadian University. Participants were asked to list five and then to identify five (from a list of 10) characteristics or skills demonstrated by clinical supervisors recognised for their excellent assessment skills. RESULTS: Seventeen per cent of faculty members and 23 per cent of residents completed the survey. Fairness is perceived as a key characteristic of an excellent assessor. Faculty members consider that appropriate medical knowledge and skills are important. Residents expressed the importance of appropriate feedback. Both groups indicated the importance of direct observation as a basis for assessment. DISCUSSION: This study offers preliminary insights into the characteristics of excellent assessors. Given the importance of assessment in the daily activities of clinical supervisors, research efforts should strive to better characterise this role in the hopes of increasing the quality and accuracy of assessment. PMID- 24802924 TI - The benefits of a peer-assisted mock OSCE. AB - BACKGROUND: Objective structured clinical examinations (OSCEs) are associated with high stress and anxiety levels, which could have a negative impact on student performance. Students frequently have no opportunity to practise OSCEs other than in the high-stakes examination itself. This study describes the design and implementation of a peer-run mock OSCE exam for medical students, and the feasibility, acceptability and perceived impact of this educational initiative. METHODS: An OSCE training programme was designed by four fourth-year students. It involved the recruitment of 103 fourth-year tutors to facilitate the running and feedback of OSCE stations to 245 third-year medical students prior to their summative end-of-year exam. Tutees and tutors completed a questionnaire to assess the quality and perceptions of the benefits of this educational intervention. RESULTS: A total of 245 (85% of the year-3 group) tutee and 65 tutor surveys were completed over three evenings: 100 per cent of respondents classified the quality of the OSCE stations and resuscitation session as 'fantastic' or 'good'. The main themes from the tutee comments were: improved confidence and valued feedback. The main themes from the tutor comments were: motivation to continue with peer assisted learning (PAL) projects and improved teaching skills. CONCLUSIONS: The peer-assisted mock OSCE improved tutee confidence and reduced the anxieties associated with OSCEs. Tutors gain valuable teaching skills. This PAL model is an acceptable, feasible and beneficial method of preparing students for this challenging style of health care examination. PMID- 24802925 TI - The medical exhibition seminar. AB - BACKGROUND: Our aim was to develop, introduce and evaluate a new clinical interdisciplinary teaching and learning activity (TLA) using modern pedagogical principles. METHOD: All fourth-year students at the clinical course in basic surgery at Karolinska University Hospital in Huddinge participated. Fifteen urological and 15 colorectal pictures were presented. All pictures had a correlating statement on a sheet. The assignment was to correlate each picture with the best possible statement. Peer as well as teacher discussions were permitted. A facilitated discussion about the pictures followed. Evaluation was performed by questionnaire. The final examination results of the course were analysed. RESULTS: Over 80 per cent of the medical students evaluated the seminar (n = 199). The general opinion of the TLA was 8.79 on a 10-point graded visual digital scale (1, bad; 10, excellent). The student self-assessed level of enjoyment and of the activity was 9.0 and 8.5, respectively. Nine out of 10 students rated the Medical Exhibition Seminar 'as good as' (24%) or 'better than' (64%) traditional lecturing, and 73 and 63 per cent, respectively, rated it 'as good as' or 'better than' case method teaching (case) and problem-based learning (PBL). The method did not change the final examination results. CONCLUSION: Medical Exhibition Seminar teaching is a learner-centred and problem-based teaching method that should be included in our pedagogical toolbox. It is designed to be an effective, efficient and modern pedagogical tool suitable for our modern health care system. PMID- 24802926 TI - The mentor-protege relationship in medicine. PMID- 24802927 TI - The medical school rumour mill: a repeating cycle of misinformation. PMID- 24802928 TI - Is there evidence of power in my teaching? PMID- 24802929 TI - Do we need to be taught how to care? PMID- 24802933 TI - Does tandem clerking improve training? PMID- 24802934 TI - Response to 'Does tandem clerking improve training?'. PMID- 24802935 TI - Harnessing social media for medical education. PMID- 24802936 TI - Movement patterns in a partial migrant: a multi-event capture-recapture approach. AB - Partial migration is a pervasive albeit poorly studied phenomenon by which some individuals of a population migrate while others are residents. It has tremendous consequences on seasonal variations of population size/structure and therefore management. Using a multi-event capture-mark-recapture/recovery (CMR) approach, we assessed seasonal site occupancy, survival and site fidelity of a partially migratory diving duck, the Common pochard (Aythya ferina), in an area potentially including both local breeders and winter visitors. The modelling exercise indeed discriminated two different categories of individuals. First, locally breeding females which had a probability of being present in our study area during winter of 0.41. Females of this category were found to be more faithful to their breeding site than males (breeding site fidelity probabilities of 1 and 0.11, respectively). The second category of birds were winter visitors, which included adults of both sexes, whose probability of being present in the study area during the breeding season was nil, and young of both sexes with a 0.11 probability of being present in the area during the breeding season. All wintering individuals, among which there was virtually no locally breeding male, displayed a high fidelity to our study area from one winter to the next (0.41-0.43). Estimated annual survival rates differed according to age (adults 0.69, young 0.56). For both age classes mortality was higher during late winter/early spring than during summer/early winter. Our study is among the first to show how and under which conditions the multi-event approach can be employed for investigating complex movement patterns encountered in partial migrants, providing a convenient tool for overcoming state uncertainty. It also shows why studying patterns of probability of individual presence/movements in partial migrants is a key towards understanding seasonal variations in numbers. PMID- 24802937 TI - Catalytic asymmetric synthesis of 3,3'-diaryloxindoles as triarylmethanes with a chiral all-carbon quaternary center: phase-transfer-catalyzed S(N)Ar reaction. AB - Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S(N)Ar reaction of 3-aryloxindoles under phase-transfer conditions. The presence of a urea moiety in the chiral phase transfer catalyst was important for obtaining high enantioselectivity in this reaction. PMID- 24802938 TI - Novel bacteria associated with Arctic seashore lichens have potential roles in nutrient scavenging. AB - While generally described as a bipartite mutualistic association between fungi and algae or cyanobacteria, lichens also host diverse and heretofore little explored communities of nonphototrophic endolichenic bacteria. The composition and possible roles of these bacterial communities in the lichen symbiotic association constitute an emerging field of research. Saxicolous (rock-dwelling) seashore lichens present an unusual environment, characterized by rapid fluctuations in temperature, salinity, exposure to solar radiation, etc. The present study focuses on the bacterial biota associated with 4 species of crustose, halophilic, saxicolous seashore lichens found in northern Iceland. A denaturing gradient gel electrophoresis based characterization of the composition of the lichen-associated microbiotas indicated that they are markedly lichen species-specific and clearly distinguishable from the environmental microbiota represented by control sampling. A collection of bacterial strains was investigated and partially identified by 16S rDNA sequencing. The strains were found to belong to 7 classes: Alphaproteobacteria, Bacilli, Actinobacteria, Flavobacteria, Cytophagia, Sphingobacteria, and Gammaproteobacteria. Several isolates display only a modest level of similarity to their nearest relatives found in GenBank, suggesting that they comprise previously undescribed taxa. Selected strains were tested for inorganic phosphate solubilization and biodegradation of several biopolymers, such as barley beta-glucan, xylan, chitosan, and lignin. The results support a nutrient-scavenging role of the associate microbiota in the seashore lichen symbiotic association. PMID- 24802940 TI - Increased ultraviolet radiation sensitivity of Escherichia coli grown at low temperature. AB - The repair of DNA damage caused by ultraviolet radiation (UVR) is well understood in both lower and higher organisms. Genetic studies carried out at optimum temperature for growth, 37 degrees C in Escherichia coli, have revealed the major pathways of DNA repair. We show that E. coli cells grown at 20 degrees C are more sensitive to UVR than cells grown at 37 degrees C. The analysis of knockout mutants demonstrates that cells impaired in recombinational DNA repair pathways show increased UV sensitivity at 20 degrees C. Cells with mutations in the nucleotide excision repair (NER) pathway genes are highly sensitive to UVR when grown at 37 degrees C and retain that sensitivity when grown at 20 degrees C, whereas wild-type cells are not sensitive when grown at 37 degrees C but become more sensitive to UVR when grown at low temperatures. Our results taken along with reports from the literature suggest that the UVR sensitivity of E. coli cells at low temperature could be due to impaired NER function. PMID- 24802939 TI - Impacts of different salinities on bacterial biofilm communities in fresh water. AB - Natural and anthropogenic salinization continuously impacts inland aquatic ecosystems. Associated bacterial biofilms respond rapidly to environmental conditions and are potential bioindicators for changes in water quality. This study evaluates the effects of different salinity concentrations (0.30/00-100/00) on bacterial biofilms communities grown in fresh water from Lake Bosten. Bacterial communities associated with biofilms were analyzed using terminal restriction fragment length polymorphism and clone library analyses of 16S rRNA genes. Results indicated that the attached bacterial community composition (ABCC) changed over several weeks of biofilm growth, but all followed similar bacterial successional trends in the different salinity groups. Detailed analysis showed the following. (i) ABCC did not differ (P > 0.05) in the low-salinity groups (0.30/00-3.50/00), which may be related to the lower osmotic pressure and the shorter time scale (weeks) of their present habitats. (ii) There were significant differences between the oligosaline (3.50/00) and saline (100/00) groups (P < 0.05). In particular, genus Flavobacterium became dominant in attached bacterial communities in the saline groups. The higher abundance of genus Flavobacterium was possibly due to the biological and metabolic characteristics of the bacteria. (iii) Some bacterial taxa can maintain the higher abundance within attached bacteria in the entire process of biofilms growth, such as the genera Hydrogenophaga and Methyloversatilis in Betaproteobacteria and the family Sphingomonadaceae in Alphaproteobacteria. These data suggested that the bacterial successional trends within biofilms seem almost unaffected by salinity (0.30/00 100/00), but ABCC in saline groups (100/00) are notably changed. PMID- 24802941 TI - Botryosphaeriales fungi produce extracellular enzymes with biotechnological potential. AB - Phytopathogenic fungi are known for producing an arsenal of extracellular enzymes whose involvement in the infection mechanism has been suggested. However, these enzymes are largely unknown and their biotechnological potential also remains poorly understood. In this study, the production and thermostability of extracellular enzymes produced by phytopathogenic Botryosphaeriaceae was investigated. Hydrolytic and oxidative activities were detected and quantified at different temperatures. Most strains (70%; 37/53) were able to produce simultaneously cellulases, laccases, xylanases, pectinases, pectin lyases, amylases, lipases, and proteases. Surprisingly for mesophilic filamentous fungi, several enzymes proved to be thermostable: cellulases from Neofusicoccum mediterraneum CAA 001 and from Dothiorella prunicola CBS 124723, lipases from Diplodia pinea (CAA 015 and CBS 109726), and proteases from Melanops tulasnei CBS 116806 were more active at 70 degrees C than at any of the other temperatures tested. In addition, lipases produced by Diplodia pinea were found to be significantly more active than any other known lipase from Botryosphaeriales. The thermal activity profile and the wide array of activities secreted by these fungi make them optimal producers of biotechnologically relevant enzymes that may be applied in the food and the health industries (proteases), the pulp-and-paper and biofuel industries (cellulases), or even in the detergent industry (lipases, proteases, amylases, and cellulases). PMID- 24802943 TI - Automatic identification and removal of ocular artifacts in EEG--improved adaptive predictor filtering for portable applications. AB - Electroencephalogram (EEG) signals have a long history of use as a noninvasive approach to measure brain function. An essential component in EEG-based applications is the removal of Ocular Artifacts (OA) from the EEG signals. In this paper we propose a hybrid de-noising method combining Discrete Wavelet Transformation (DWT) and an Adaptive Predictor Filter (APF). A particularly novel feature of the proposed method is the use of the APF based on an adaptive autoregressive model for prediction of the waveform of signals in the ocular artifact zones. In our test, based on simulated data, the accuracy of noise removal in the proposed model was significantly increased when compared to existing methods including: Wavelet Packet Transform (WPT) and Independent Component Analysis (ICA), Discrete Wavelet Transform (DWT) and Adaptive Noise Cancellation (ANC). The results demonstrate that the proposed method achieved a lower mean square error and higher correlation between the original and corrected EEG. The proposed method has also been evaluated using data from calibration trials for the Online Predictive Tools for Intervention in Mental Illness (OPTIMI) project. The results of this evaluation indicate an improvement in performance in terms of the recovery of true EEG signals with EEG tracking and computational speed in the analysis. The proposed method is well suited to applications in portable environments where the constraints with respect to acceptable wearable sensor attachments usually dictate single channel devices. PMID- 24802944 TI - Hydrogen ordering and new polymorph of layered perovskite oxyhydrides: Sr2VO(4 x)H(x). AB - Compositionally tunable vanadium oxyhydrides Sr2VO(4-x)H(x) (0 <= x <= 1.01) without considerable anion vacancy were synthesized by high-pressure solid-state reaction. The crystal structures and their properties were characterized by powder neutron diffraction, synchrotron X-ray diffraction, thermal desorption spectroscopy, and first-principles density functional theory (DFT) calculations. The hydrogen anions selectively replaced equatorial oxygen sites in the VO6 layers via statistical substitution of hydrogen in the low x region (x < 0.2). A new orthorhombic phase (Immm) with an almost entirely hydrogen-ordered structure formed from the K2NiF4-type tetragonal phase with x > 0.7. Based on the DFT calculations, the degree of oxygen/hydrogen anion ordering is strongly correlated with the bonding interaction between vanadium and the ligands. PMID- 24802945 TI - Cdk5/p35 is required for motor coordination and cerebellar plasticity. AB - Previous studies have implicated the role of Purkinje cells in motor learning and the underlying mechanisms have also been identified in great detail during the last decades. Here we report that cyclin-dependent kinase 5 (Cdk5)/p35 in Purkinje cell also contributes to synaptic plasticity. We previously showed that p35(-/-) (p35 KO) mice exhibited a subtle abnormality in brain structure and impaired spatial learning and memory. Further behavioral analysis showed that p35 KO mice had a motor coordination defect, suggesting that p35, one of the activators of Cdk5, together with Cdk5 may play an important role in cerebellar motor learning. Therefore, we created Purkinje cell-specific conditional Cdk5/p35 knockout (L7-p35 cKO) mice, analyzed the cerebellar histology and Purkinje cell morphology of these mice, evaluated their performance with balance beam and rota rod test, and performed electrophysiological recordings to assess long-term synaptic plasticity. Our analyses showed that Purkinje cell-specific deletion of Cdk5/p35 resulted in no changes in Purkinje cell morphology but severely impaired motor coordination. Furthermore, disrupted cerebellar long-term synaptic plasticity was observed at the parallel fiber-Purkinje cell synapse in L7-p35 cKO mice. These results indicate that Cdk5/p35 is required for motor learning and involved in long-term synaptic plasticity. PMID- 24802942 TI - Association between the XPG Asp1104His and XPF Arg415Gln polymorphisms and risk of cancer: a meta-analysis. AB - BACKGROUND: The XPG (xeroderma pigmentosum type G) Asp1104His and XPF (xeroderma pigmentosum type F) Arg415Gln polymorphisms had been implicated in cancer susceptibility. The previous published data on the association between XPG Asp1104His and XPF Arg415Gln polymorphisms and cancer risk remained controversial. METHODOLOGY/PRINCIPAL FINDINGS: To derive a more precise estimation of the association between the XPG Asp1104His and XPF Arg415Gln polymorphisms and overall cancer risk, we performed a meta-analysis to investigate the association between cancer susceptibility and XPG Asp1104His (32,162 cases and 39,858 controls from 66 studies) and XPF Arg415Gln polymorphisms (17,864 cases and 20,578 controls from 32 studies) in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly elevated cancer risk was found when all studies were pooled into the meta-analysis of XPG Asp1104His (dominant model: OR = 1.05, 95% CI = 1.00-1.10; Asp/His vs. Asp/Asp: OR = 1.06, 95% CI = 1.01-1.11). In the further stratified and sensitivity analyses, significantly decreased lung cancer risk was found for XPF Arg415Gln (dominant model: OR = 0.82, 95% CI = 0.71-0.96; Arg/Gln versus Arg/Arg: OR = 0.83, 95% CI = 0.71-0.97; additive model: OR = 0.83, 95% CI = 0.72-0.95) and significantly increased other cancer risk was found among hospital-based studies for XPG Asp1104His (dominant model: OR = 1.23, 95% CI = 1.02-1.49). CONCLUSIONS/SIGNIFICANCE: In summary, this meta-analysis suggests that XPF Arg415Gln polymorphism may be associated with decreased lung cancer risk and XPG Asp1104His may be a low-penetrant risk factor in some cancers development. And larger scale primary studies are required to further evaluate the interaction of XPG Asp1104His and XPF Arg415Gln polymorphisms and cancer risk in specific populations. PMID- 24802946 TI - Enhancing the performance of lateral shear strain estimation by using 2-D strain imaging. AB - Radio-frequency (RF) ultrasound can be used to estimate deformation of biological tissue. Decorrelation of sequentially acquired ultrasound signals resulting from the deformation imposes a limitation on the precision (elastographic signal-to noise ratio; SNRe) of estimating these deformations; this is presented as the lateral shear strain filter. In this paper, we explore the effect of a 2-D-window based strain estimation approach on the lateral shear strain filter and propose an extension of the 1-D theoretical lateral shear strain filter to 2-D. We compared the performance of the 2-D approach in simulated ultrasound data and a tissue-mimicking phantom with that of the 2-D lateral shear strain filter. In simulations, the 2-D-window-based approach shows an effect in the axial direction similar to the 2-D prediction. In simulations and experiments, increasing the window size in the lateral direction shows an increase in the maximum SNRe of the lateral shear strain filter. Increasing the lateral overlap has no effect on the estimation of lateral shear strain. These results were confirmed in the tissue mimicking phantom experiments. When compared with the 2-D lateral shear strain filter, the results obtained with the 2-D-window-based approach showed an enhanced performance by incorporating the lateral window size in the lateral shear strain estimation, which was consistent with the proposed theory. PMID- 24802948 TI - Reversibility and stability of ZnO-Sb2Te3 nanocomposite films for phase change memory applications. AB - (ZnO)x(Sb2Te3)1-x materials with different ZnO contents have been systemically studied with an aim of finding the most suitable composition for phase change memory applications. It was found that ZnO-doping could improve thermal stability and electrical behavior of Sb2Te3 film. Sb2Te3-rich nanocrystals, surrounded by ZnO-rich amorphous phases, were observed in annealed ZnO-doped Sb2Te3 composite films, and the segregated domains exhibited a relatively uniform distribution. The ZnO-doped Sb2Te3 composite films, especially with 5.2 at% ZnO concentration were found to have higher crystallization temperature, higher crystalline resistance, and faster crystallization speed in comparison with Ge2Sb2Te5. A reversible repetitive optical switching behavior can be observed in (ZnO)5.2(Sb2Te3)94.8, confirming that the ZnO doping is responsible for a fast switching and the compound is stable with cycling. Therefore, it is promising for the applications in phase change memory devices. PMID- 24802947 TI - Enzymatically cross-linked bovine lactoferrin as injectable hydrogel for cell delivery. AB - Lactoferrin (LF), a 78 kDa glycoprotein, has recently been recognized as an effector molecule in the skeleton due to its ability to decrease osteoclastogenesis and increase osteoblast proliferation, survival, and differentiation. The objective of the study is to investigate the feasibility of developing an injectable hydrogel from bovine lactoferrin (bLF) as a cell delivery vehicle. The study demonstrated the feasibility of cross-linking tyramine substituted bLF in the presence of horse radish peroxidase and hydrogen peroxide (H2O2). The gel presented a mild environment to maintain mouse bone marrow-derived stromal cell (mBMSC) viability and proliferation. Stromal cells derived from multiple gene reporter transgenic mouse (Ibsp-Topaz/Dmp1-mCherry) line showed the ability of the cells to undergo osteogenic differentiation in the hydrogel when cultured in mineralization media. The cross-linked gel supported protein phosphorylation/de-phosphorylation in the encapsulated MC3T3-E1 cells. bLF and bLF gel also showed the ability to modulate growth factor production in mBMSCs. PMID- 24802949 TI - A serum-free medium developed for in vitro expansion of murine intestinal stem cells. AB - Intestinal stem cells (ISCs) are located at the base of the intestinal crypts and have the ability to self-renew as well as to differentiate into mature epithelial cells. Recently, ISCs have received much attention for the treatment of many intestinal diseases. However, many challenges face those studying ISCs because insufficient ISCs are available. Therefore, the development of a culture medium for ISC expansion is an important necessity for basic research and clinical application. In this study, we described the technique used to develop a serum free medium for expanding ISCs in vitro. Furthermore, five serum substitutes were selected and optimized in order to maintain the long-term proliferation and enteroid-forming ability of ISCs: (i) ethanolamine; (ii) ascorbic acid phosphate; (iii) transferrin; (iv) glutathione; and (v) sodium selenite. Analysis of gene expression of Lgr5, Bmi1, Msi1 and PTEN demonstrated that our serum-free medium sustained the expression of genes involved in ISC-related functions in the expanded ISCs. Additionally, the expression intensity of surface markers, including Lgr5, CD24 and CD44, on serum-free expanded cells in crypts was greatly increased. Taken together, our results demonstrate that the number of ISCs can be expanded and their functionality maintained in our serum-free medium, indicating the suitability of this serum-free expansion medium for increasing the numbers of ICSs available for basic research and clinical applications in the future. PMID- 24802950 TI - From dinosaurs to modern bird diversity: extending the time scale of adaptive radiation. AB - What explains why some groups of organisms, like birds, are so species rich? And what explains their extraordinary ecological diversity, ranging from large, flightless birds to small migratory species that fly thousand of kilometers every year? These and similar questions have spurred great interest in adaptive radiation, the diversification of ecological traits in a rapidly speciating group of organisms. Although the initial formulation of modern concepts of adaptive radiation arose from consideration of the fossil record, rigorous attempts to identify adaptive radiation in the fossil record are still uncommon. Moreover, most studies of adaptive radiation concern groups that are less than 50 million years old. Thus, it is unclear how important adaptive radiation is over temporal scales that span much larger portions of the history of life. In this issue, Benson et al. test the idea of a "deep-time" adaptive radiation in dinosaurs, compiling and using one of the most comprehensive phylogenetic and body-size datasets for fossils. Using recent phylogenetic statistical methods, they find that in most clades of dinosaurs there is a strong signal of an "early burst" in body-size evolution, a predicted pattern of adaptive radiation in which rapid trait evolution happens early in a group's history and then slows down. They also find that body-size evolution did not slow down in the lineage leading to birds, hinting at why birds survived to the present day and diversified. This paper represents one of the most convincing attempts at understanding deep-time adaptive radiations. PMID- 24802951 TI - Vitamin C supplementation does not influence plasma and blood mononuclear cell IL 6 and IL-10 levels after exercise. AB - The aim of this study was to determine whether the highest vitamin C supplementation associated with complete bioavailability influences the plasma and blood mononuclear cell IL-6 and IL-10 response to exercise. A double-blinded study of supplementation with vitamin C was performed. After 15 days of supplementation with vitamin C (500 mg . day(-1), n = 16) or a placebo (n = 15), participants in the study completed a 15-km run competition. Blood samples were taken before and after competition. Oxidative stress markers, antioxidants, cortisol, IL-6 and IL-10 were determined in plasma or serum. IL-6 and IL-10 protein and mRNA levels were measured in blood mononuclear cells. Although higher plasma and blood mononuclear cell vitamin C levels were observed in the supplemented group when compared with the placebo one, the two groups showed identical exercise-induced changes in all the measured parameters. Exercise induced increased IL-6 and IL-10 levels in plasma and blood mononuclear cells. IL 6 and IL-10 mRNA levels in blood mononuclear cells increased after the competition. After recovery, IL-6 mRNA returned to basal levels and IL-10 mRNA levels remained elevated. In conclusion, exercise induced increased IL-6 and IL 10 production in blood mononuclear cells. However, vitamin C supplementation did not influence IL-6 and IL-10 response to exercise. PMID- 24802952 TI - Mechanism of AuCl3-catalyzed cyclization of 1-(indol-2-yl)-3-alkyn-1-ols: a DFT study. AB - A computational study with the B3LYP functional was carried out to elucidate the mechanisms of AuCl3- and AgOTf-catalyzed cyclization of 1-(indol-2-yl)-3-alkyn-1 ols. The theoretical studies suggested that the two main processes, cycloaddition and hydrogen-transfer, are included in all possible reaction pathways. Calculations revealed that AuCl3 is more effective in catalytic ability than AgOTf to catalyze the cyclization of 1-(indol-2-yl)-3-alkyn-1-ols into carbazole derivatives. More importantly, we found that the ligands of catalysts, Cl- and OTf-, are critical in a stepwise proton-transport process involved in intramolecular nucleophilic addition because they act as a proton shuttle to lower the activation free energy barrier of the rate-determining step. The theoretical discovery of the role of ligands of catalysts in hydrogen shift process suggests that AuCl3- and AgOTf-catalyzed cyclization of 1-(indol-2-yl)-3 alkyn-1-ols can be accelerated when ligands with the property of nucleophile are used. Our theoretical calculations reproduced the experimental results very well. The present study is expected to help understand other transition metal-catalyzed reactions and to give guidance for future design of new catalysts. PMID- 24802953 TI - Electrochemical activation of diamond microelectrodes: implications for the in vitro measurement of serotonin in the bowel. AB - The electrochemical pretreatment of diamond microelectrodes was investigated for the purpose of learning how an anodic, cathodic or a combined anodic + cathodic polarization affects the charge-transfer kinetics for two surface-sensitive redox systems: ferri/ferrocyanide and serotonin (5-hydroxytryptamine, 5-HT). The pretreatments were performed in 0.5 mol L(-1) H2SO4. The anodic pretreatment was performed galvanically for 30 s at 250 mA cm(-2). The cathodic pretreatment was performed for 180 s at -250 mA cm(-2). The combined pretreatment involved application of the anodic step first followed by the cathodic step. The results clearly demonstrate that the best performance for both redox systems is obtained after the cathodic polarization, which presumably activates the electrode by cleaning the surface and removing site-blocking surface carbon-oxygen functionalities. The cathodic pretreatment was found to be effective at activating a fouled microelectrode in situ. This observation has important implication for the measurement of 5-HT in the bowel. PMID- 24802954 TI - Fermentation of glycerol into ethanol in a microbial electrolysis cell driven by a customized consortium. AB - The in situ generation of ethanol from glycerol-containing wastewater shows promise to improve the economics of the biodiesel industry. Consequently, we developed a microbial electrolysis cell (MEC) driven by the synergistic metabolisms of the exoelectrogen Geobacter sulfurreducens and the bacterium Clostridium cellobioparum, which fermented glycerol into ethanol in high yields (90%) and produced fermentative byproducts that served as electron donors for G. sulfurreducens. Syntrophic cooperation stimulated glycerol consumption, ethanol production, and the conversion of fermentation byproducts into cathodic H2 in the MEC. The platform was further improved by adaptively evolving glycerol-tolerant strains with robust growth at glycerol loadings typical of biodiesel wastewater and by increasing the buffering capacity of the anode medium. This resulted in additional increases in glycerol consumption (up to 50 g/L) and ethanol production (up to 10 g/L) at rates that greatly exceeded the capacity of the anode biofilms to concomitantly remove the fermentation byproducts. As a result, 1,3-propanediol was generated as a metabolic sink for electrons not converted into electricity syntrophically. The results highlight the potential of consortia to process glycerol in MECs and provide insights into genetic engineering and system design approaches that can be implemented to further improve MEC performance to satisfy industrial needs. PMID- 24802955 TI - Usefulness of the tri-axial accelerometer for assessing balance function in children. AB - BACKGROUND: The aim of this study was to verify whether the tri-axial accelerometer can be used for quantitatively evaluating balance function in children. METHODS: In total, 198 participants, including 172 healthy children aged 3-11 years (87 boys, 85 girls) and 26 young adults aged 21-24 years (seven men, 19 women), were enrolled in this study. The participants undertook three types of balance tasks: quiet standing with eyes open and closed, one-leg standing on the dominant leg and non-dominant leg, and walking on the floor and a balance beam. We derived the root mean square from participants' accelerations measured by the tri-axial accelerometer. RESULTS: We found that for quiet standing, one-leg standing, and walking tasks, postural sway decreased with age. Girls controlled their posture better than boys of the same age on all tasks. There was a significant sex difference in quiet standing for children aged 8-9 years. Furthermore, sex differences existed in one-leg standing for children aged 5-11 years. A mild positive correlation was observed between static and dynamic balance. CONCLUSIONS: The tri-axial accelerometer is a useful quantitative tool for evaluating both static and dynamic balance function in children. Thus, it has the potential to be used clinically for diagnosis and rehabilitation. PMID- 24802956 TI - Closer to the native state. Critical evaluation of cryo-techniques for Transmission Electron Microscopy: preparation of biological samples. AB - Over the years Transmission Electron Microscopy (TEM) has evolved into a powerful technique for the structural analysis of cells and tissues at various levels of resolution. However, optimal sample preservation is required to achieve results consistent with reality. During the last few decades, conventional preparation methods have provided most of the knowledge about the ultrastructure of organelles, cells and tissues. Nevertheless, some artefacts can be introduced at all stagesofstandard electron microscopy preparation technique. Instead, rapid freezing techniques preserve biological specimens as close as possible to the native state. Our review focuses on different cryo-preparation approaches, starting from vitrification methods dependent on sample size. Afterwards, we discuss Cryo-Electron Microscopy Of VItreous Sections (CEMOVIS) and the main difficulties associated with this technique. Cryo-Focused Ion Beam (cryo-FIB) is described as a potential alternative for CEMOVIS. Another post-processing route for vitrified samples is freeze substitution and embedding in resin for structural analysis or immunolocalization analysis. Cryo-sectioning according to Tokuyasu is a technique dedicated to high efficiency immunogold labelling. Finally, we introduce hybrid techniques, which combine advantages of primary techniques originally dedicated to different approaches. Hybrid approaches permit to perform the study of difficult-to-fix samples and antigens or help optimize the sample preparation protocol for the integrated Laser and Electron Microscopy (iLEM) technique. PMID- 24802957 TI - Dendritic cells in autoimmune disorders and cancer of the thyroid. AB - Dendritic cells (DCs), considered as one of the crucial immune regulatory populations, are implicated in the immune pathology of various disorders. Also in the thyroid gland, DCs were shown to be involved in early and chronic phases of various types of autoimmunity - including Hashimoto's thyroiditis and Graves' disease. In thyroid malignant processes, DCs are suggested as an important element of both tumour defence and tumour immune evasion mechanisms. Recent findings emphasize a crucial role of interactions between particular DC subsets and other regulatory cell populations (e.g. FoxP3+ regulatory T cells) in thyroid pathology. Additionally, an increasing attention has been paid to the control of DC function by thyrometabolic conditions. PMID- 24802958 TI - A novel approach for preventing esophageal stricture formation: olmesartan prevented apoptosis. AB - Accidentally ingested corrosive substances can cause functional and structural damage to the esophageal tissue resulting in stricture formation. It has been reported that the administration of olmesartan (OLM) can have anti-inflammatory, antifibrotic and antiapoptotic effects on injured tissue. The aim of our study was to check if OLM could prevent formation of scars in the corrosive esophageal burn model. Fifty-one Wistar Albino rats were divided into six groups: Control, Sham, OLM, Sham + OLM, Burn, and Burn + OLM. Olmesartan (5 mg/kg) was given by gavage once per day for 21 consecutive days after injury. The morphology of the esophagus was assessed after Masson trichrome staining, and apoptosis was evaluated using the terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL) method. The serum nucleosomes (as an indicator of apoptosis), serum p53 protein, and esophageal tissue p53 protein levels of each group were measured by immunoassays. Muscularis mucosa damage, submucosal collagen deposition, and tunica muscularis injury in the Burn + OLM group decreased significantly compared with the Burn group (p < 0.05). Similarly, the number of apoptotic cells in the Burn + OLM group decreased compared with the Burn group (p < 0.05). Serum levels of nucleosomes and p53 and tissue of p53 protein did not differ between the groups. Exogenously administered OLM can effectively prevent the occurrence of esophageal strictures caused by corrosive esophageal burns. PMID- 24802959 TI - Influence of infliximab pretreatment on ischemia/reperfusion injury in rat intestine. AB - The Pringle maneuver is used in hepatic surgery to prevent blood loss but is associated with ischemia- reperfusion injury. To investigate the effect of infliximab on inflammation and apoptosis in rat intestinal mucosa during ischemia reperfusion (IR) injury. A total of 30 male Wistar albino rats were equally divided into three groups to be subjected to (i) sham operation (sham), (ii) IR injury via Pringle maneuver (pringle) or (iii) infliximab (IFX) group (IFX was given at a dose 3 mg/kg for 3 days before IR injury). Following reperfusion period of 60 min., intestinal tissue and blood samples were taken and processed by standard histological methods. The Pringle maneuver and following reperfusion caused significant histopathological changes, increased serum transaminases' activity and the levels of oxidative stress markers and decreased glutathione peroxidase activity. IFX pretreatment partially prevented these changes. Infliximab pretreatment may protect intestinal mucosa against ischemia reperfusion injury. Further studies are needed to investigate mechanism and evaluate safety and optimal dosing of IFX in humans exposed to the possible tissue damage by ischemia-reperfusion. PMID- 24802960 TI - A histological and immunohistochemical study of beta cells in streptozotocin diabetic rats treated with caffeine. AB - In this study, the histological, immunohistochemical, morphometric, and biochemical changes to pancreatic beta-cells in STZ-induced diabetes were evaluated in rats treated with different doses of caffeine. Fifty adult male Wistar albino rats were divided into five groups: the nondiabetic control group, the diabetic untreated group, and three diabetic groups treated with different doses of caffeine (10, 50, and 100 mg/kg/day). Blood glucose and serum insulin levels were measured. The pancreata were collected and processed into paraffin sections. They were stained using hematoxylin and eosin (H&E) and Masson trichrome stains. The insulin expression in beta-cells was assessed using immunohistochemistry. Morphometrically, the percentage area of anti-insulin antibody reaction, the percentage of beta-cells per total islet cell number, and the average area of the islets were determined. STZ-induced degenerative changes in beta-cells led to decreases in the number of functioning beta-cells and insulin immunoreactivity and to increases in the number of collagen fibers in the islets. In STZ-treated rats, caffeine significantly decreased blood glucose concentration while increasing blood insulin levels at the highest applied dose. It also induced a significant increase in the number of immunoreactive beta cells. In conclusion, caffeine may have a protective role in the biochemical and microscopic changes in pancreatic beta-cells in diabetes induced in rats through STZ administration. PMID- 24802961 TI - Effect of apelin on mitosis, apoptosis and DNA repair enzyme OGG 1/2 expression in intestinal cell lines IEC-6 and Caco-2. AB - Apelin is a regulatory peptide, identified as an endogenous ligand of the Apelin receptor (APJ). Both the apelin and the APJ were detected in brain, lung, heart, mammary gland, kidney, placenta, adipose tissues and the gastrointestinal tract. Apelin is considered an important regulatory gut peptide with a potential physiological role in gastrointestinal cytoprotection, regulation of food intake and drinking behaviour. The aim of the present study was to assess the effect of the apelin on mitosis, apoptosis and the expression of DNA repair enzyme (OGG 1/2), and APJ receptor in intestinal cell lines: rat crypt (IEC-6) and human enterocyte model (Caco-2). The cell cultures were incubated with the apelin-12 (10-8 M) for 4, 6, 12, 24 and 48 h and the apoptosis (caspase 3), mitosis (Ki-67) and DNA repair enzyme (OGG1/2) markers were studied by Real-Time qRT-PCR and immunofluorescent methods. The results of Real-Time qRT-PCR and immunocytochemical analysis showed that the levels of mRNAs were inversely related to the expression level of corresponding proteins. Immunofluorescent studies revealed inhibitory effect of apelin-12 on apoptosis, mitosis and the expression of OGG1/2 in the intestinal crypt cell line IEC-6. However, in the enterocyte model Caco-2 cells apelin stimulated apoptosis and mitosis, and reduced OGG1/2 expression. These findings suggest that apelin may be involved in the control of epithelial cell turnover in the gastrointestinal tract. PMID- 24802962 TI - Tobacco smoking alters the number of oral epithelial cells with apoptotic features. AB - Tobacco smoking is a global problem associated with the occurrence of many systemic diseases and tumors. Oral cavity tumors are common tobacco-related cancers, and of all the anatomical structures that are exposed to the effects of smoking, the oral cavity remains the least-explored area. Changes that occur in the biology of oral epithelial keratinocytes under the influence of the components of tobacco smoke often go unnoticed, if they are asymptomatic. The proper functioning of the oral epithelium is determined by the proliferation and differentiation of the cells in keratinization - the process of programmed cell death, which extends through to the mechanisms of apoptosis. Due to incomplete knowledge of the impact of tobacco smoke on the biology of keratinocytes, an evaluation of the cell cycle was conducted and the apoptosis of oral epithelial keratinocytes was analyzed. The study involved 77 patients divided into four groups according to their intensity of smoking, ranging from 0 to 27 pack-years. There were no differences in the cell count between nonsmokers and smokers in the proper cell-cycle phases. The percentage of proliferating cells in the oral epithelium is about 11%. A reduction in the number of early-apoptotic cells (caspase positive/propidium iodide negative) and an increase in the number of late-apoptotic cells (caspase positive/annexin V positive/propidium iodide positive) were observed to occur with increasing pack-years. The present study demonstrates that smoking does not affect the oral keratinocyte cell cycle, but does modify the number of cells with early and late apoptotic features. An intensification of the impact of tobacco smoke components on the biology of the oral keratinocytes is clearly noticeable at approximately 6 pack-years. This indicates that the biology of the first organ exposed to tobacco smoke - the oral epithelium - is altered by tobacco smoking. PMID- 24802963 TI - Treatment of Graves' disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes. AB - Almost all cases of hyperthyroidism in children result from Graves' disease (GD). Recent studies have confirmed a significant role of T regulatory cells (Tregs) in the development of autoimmune diseases. However, the interactions between T cell responses and Treg proliferation in GD are still poorly understood. The aim of this study was to assess the proliferation of Treg cells (Tregs) and CD3+ T lymphocytes isolated from 50 children with GD before and after treatment with the thyreostatic drug methimazole (MMI). The proliferation rates, measured by methyl 3H-thymidyne incorporation, of CD3+ cells and Tregs stimulated with mitogen phorbol 12-myristate 13-acetate (PMA) were compared with those of unstimulated cells. The proliferation rates of both PMA-stimulated and unstimulated CD3+ cells prior to treatment with MMI were significantly higher than after treatment. Simultaneously, the proliferation rates of both PMA-stimulated and unstimulated Tregs were significantly lower before MMI treatment. Moreover, we observed higher cell proliferation rates of unstimulated and PMA-stimulated Tregs before the initiation of MMI therapy and after treatment in patients who had no relapse of hyperthyroidism. There was a positive correlation between the CD3+ cells proliferation rate before MMI treatment and fT3, as well as fT4 concentration in peripheral blood. The proliferation rates of CD3+ T cells before and after MMI treatment positively correlated with the TSI index. Thus, children suffering from Graves' disease presented lower Tregs proliferative potential compared with CD3+ T cells. Cocultures of CD3+ T cells and Tregs showed that Tregs were not capable of efficiently inhibiting the proliferation of CD3+ T cells in GD patients. Conclusions. MMI treatment reduced the proliferative activity of CD3+ T cells in pediatric GD patients and increased the proliferation rate of Tregs. We suggest that Treg cells that are partly dysfunctional in GD disease are probably suppressed by CD3+ T cells and that methimazole exerts some immunomodulatory effects. PMID- 24802964 TI - Enhanced protein adsorption and patterning on nanostructured latex-coated paper. AB - Specific interactions of extracellular matrix proteins with cells and their adhesion to the substrate are important for cell growth. A nanopatterned latex coated paper substrate previously shown to be an excellent substrate for cell adhesion and 2D growth was studied for directed immobilization of proteins. The nanostructured latex surface was formed by short-wavelength IR irradiation of a two-component latex coating consisting of a hydrophilic film-forming styrene butadiene acrylonitrile copolymer and hydrophobic polystyrene particles. The hydrophobic regions of the IR-treated latex coating showed strong adhesion of bovine serum albumin (cell repelling protein), fibronectin (cell adhesive protein) and streptavidin. Opposite to the IR-treated surface, fibronectin and streptavidin had a poor affinity toward the untreated pristine latex coating. Detailed characterization of the physicochemical surface properties of the latex coated substrates revealed that the observed differences in protein affinity were mainly due to the presence or absence of the protein repelling polar and charged surface groups. The protein adsorption was assisted by hydrophobic (dehydration) interactions. PMID- 24802965 TI - Size controlled hydroxyapatite and calcium carbonate particles: synthesis and their application as templates for SERS platform. AB - An elegant route for hydroxyapatite (HA) particle synthesis via ionic exchange reaction is reported. Calcium carbonate particles (CaCO3) were recrystallized into HA beads in water solution with phosphate ions. The size of initial CaCO3 particles was controlled upon the synthesis by varying the amount of ethylene glycol (EG) in aqueous solution. The average size of HA beads ranged from 0.6+/ 0.1 to 4.3+/-1.1MUm. Silver nanoparticles were deposited on the surface of HA and CaCO3 particles via silver mirror reaction. Surface enhanced Raman scattering of silver functionalized beads was demonstrated by detecting Rhodamine B. CaCO3 and HA particles have a great potential for design of carrier which can provide diagnostic and therapeutic functions. PMID- 24802966 TI - Quantifying the bioadhesive properties of surface-modified polyurethane-urea nanoparticles in the vascular network. AB - Nanomedicine research is currently requiring new standard methods to quantify the biocompatibility and bioadhesivity of emerging biomaterials designed to be used in contact with blood or soft tissues. In this study, we used biotinylated polyurethane-urea nanoparticles as a model to examine the applicabitility of an adapted hemagglutination assay to quantify the bioadhesive potential of these nanoparticles to red blood cells and, in turn, to extrapolate this data to vascular endothelial cells. We demonstrated that biotinylated nanoparticles adsorb to human erythrocytes and preferentially gather in erythrocyte contact areas. Moreover, these nanoparticles promoted a higher percentage of pig and human erythrocyte agglutination than naked polyurethane-urea nanoparticles in a biotin concentration-dependent manner. Conversely, pegylated nanoparticles were used as a negative control of the technique thus showing decreasing hemagglutination values as compared to naked nanoparticles until a minimum threshold. Furthermore, hemagglutination assay demonstrated an excellent positive correlation with bioadhesion quantification in human endothelial cells and the endothelial layer of pig aorta thus validating the hemagglutination assay described here as a useful method for predicting nanoparticle bioadhesivity to vascular endothelium. Therefore, the methodology described here is a versatile and straightforward method that allows evaluating the bioadhesive features of surface-modified polyurethane-urea nanoparticles in contact with blood and the vascular network and appears as a powerful tool to better design any drug delivery systems or implantable devices for biomedical applications. PMID- 24802967 TI - Comparative study of directional differentiation of human and mouse embryonic stem cells into cardiomyocytes. AB - This comparative study investigates the method, efficiency, and anti-hypoxic ability of cardiomyocytes, directionally induced from human (h) and mouse (m) embryonic stem cells (ESCs). hESCs were induced into cardiomyocytes by suspension culture, without inducers, or adherent culture using the inducers activin A and BMP4. mESCs were induced into cardiomyocytes by hanging-drop method, without inducers or induced with vitamin C. All four methods successfully induced ESCs to differentiate into cardiomyocytes. There was a significant difference between groups with and without inducers. A significant difference was found between mESC and hESC groups with inducers. The average beating frequency of cardiomyocytes differentiated from hESC was lower than cardiomyocytes differentiated from mESC, while the average beating frequency of cardiomyocytes differentiated from the same cell line, despite different culture methods, did not differ. Beating cardiomyocytes of each group were positive for cTnT staining. Spontaneous action potentials of beating cardiomyocytes were detected by patch-clamp experiments in each group. Different apoptotic ratios were detected in beating cardiomyocytes in each group and the difference between cardiomyocytes induced from mESCs and hESCs was statistically significant. The differentiation efficiencies in the groups without inducers were significantly higher than those without inducers. The induction of mESCs was more simple and efficient compared with hESCs. Without the presence of other protective factors, the anti-hypoxic ability of cardiomyocytes induced from hESCs was stronger and the beating times were longer in vitro compared with mESCs. PMID- 24802968 TI - Sex-specific disruptions in spatial memory and anhedonia in a "two hit" rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling. AB - Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors. PMID- 24802969 TI - Thalamic structural connectivity in medial temporal lobe epilepsy. AB - The thalamus has been implicated in various stages of medial temporal lobe epilepsy (MTLE) seizure evolution. The relative density and functional significance (in epileptogenesis) of thalamic projections to MTL subregions, however, remains to be determined. This study used structural and diffusion magnetic resonance imaging (MRI) to evaluate thalamic connection density with distinct MTL subregions in terms of location and volume. Nineteen MTLE patients with unilateral hippocampal sclerosis (HS; 12 right; 10 female) were compared to 19 age-matched controls. Five regions of interest (ROIs) per hemisphere were created in native space: thalamus, amygdala, entorhinal cortex, hippocampus, and parahippocampus. Separate probabilistic tractography analyses were performed between the thalamus and each ipsilateral MTL subregion (four per hemisphere). Individual connectivity profiles and regional volumes were assessed. The medial pulvinar consistently showed the highest connection density with the hippocampus in healthy controls and in MTLE patients. Decreased thalamic connected volume was observed for thalamohippocampal pathways in patients with MTLE, and indicates pathway-specific deafferentation. Regional hippocampal and thalamic atrophy was also observed, indicating gray and white matter loss in the thalamohippocampal pathway. Consistent localization of dense medial pulvinar (PuM) connectivity with the hippocampus suggests chronic PuM stimulation could modulate the MTLE seizure network. Decreased thalamic connected volume is a promising biomarker for epileptogenesis that merits longitudinal validation. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24802971 TI - Rediscovering medicinal plants' potential with OMICS: microsatellite survey in expressed sequence tags of eleven traditional plants with potent antidiabetic properties. AB - Herbal medicines and traditionally used medicinal plants present an untapped potential for novel molecular target discovery using systems science and OMICS biotechnology driven strategies. Since up to 40% of the world's poor people have no access to government health services, traditional and folk medicines are often the only therapeutics available to them. In this vein, North East (NE) India is recognized for its rich bioresources. As part of the Indo-Burma hotspot, it is regarded as an epicenter of biodiversity for several plants having myriad traditional uses, including medicinal use. However, the improvement of these valuable bioresources through molecular breeding strategies, for example, using genic microsatellites or Simple Sequence Repeats (SSRs) or Expressed Sequence Tags (ESTs)-derived SSRs has not been fully utilized in large scale to date. In this study, we identified a total of 47,700 microsatellites from 109,609 ESTs of 11 medicinal plants (pineapple, papaya, noyontara, bitter orange, bermuda brass, ratalu, barbados nut, mango, mulberry, lotus, and guduchi) having proven antidiabetic properties. A total of 58,159 primer pairs were designed for the non redundant 8060 SSR-positive ESTs and putative functions were assigned to 4483 unique contigs. Among the identified microsatellites, excluding mononucleotide repeats, di-/trinucleotides are predominant, among which repeat motifs of AG/CT and AAG/CTT were most abundant. Similarity search of SSR containing ESTs and antidiabetic gene sequences revealed 11 microsatellites linked to antidiabetic genes in five plants. GO term enrichment analysis revealed a total of 80 enriched GO terms widely distributed in 53 biological processes, 17 molecular functions, and 10 cellular components associated with the 11 markers. The present study therefore provides concrete insights into the frequency and distribution of SSRs in important medicinal resources. The microsatellite markers reported here markedly add to the genetic stock for cross transferability in these plants and the literature on biomarkers and novel drug discovery for common chronic diseases such as diabetes. PMID- 24802972 TI - Location, dynamics and solvent relaxation of a Nile Red-based phase-sensitive fluorescent membrane probe. AB - Fluorescent membrane probes offer the advantage of high sensitivity, suitable time resolution, and multiplicity of measurable parameters, and provide useful information on model and cell membranes. In this paper, we have explored the location, dynamics, and solvent relaxation characteristics of a novel Nile Red based phase-sensitive probe (NR12S). Unlike Nile Red, NR12S enjoys unique orientation and location in the membrane, and is localized exclusively in the outer leaflet of the membrane bilayer. By analysis of membrane depth using the parallax approach, we show that the fluorescent group in NR12S is localized at the membrane interface, a region characterized by slow solvent relaxation. Our results show that NR12S exhibits REES (red edge excitation shift), consistent with its interfacial localization. More interestingly, REES of NR12S displays sensitivity to the membrane phase. In addition, fluorescence emission maximum, anisotropy, and lifetime of NR12S are dependent on the membrane phase. We envision that NR12S may prove to be a useful probe in future studies of complex natural membranes. PMID- 24802970 TI - High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures. AB - Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49f(hi) /CD90(lo) cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49f(hi) /CD90(lo) cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. PMID- 24802973 TI - Elevated sensitivity of macrosteatotic hepatocytes to hypoxia/reoxygenation stress is reversed by a novel defatting protocol. AB - Macrosteatotic livers exhibit elevated intrahepatic triglyceride (TG) levels in the form of large lipid droplets (LDs), reduced adenosine triphosphate (ATP) levels, and elevated reactive oxygen species (ROS) levels, and this contributes to their elevated sensitivity to ischemia/reperfusion injury during transplantation. Reducing macrosteatosis in living donors through dieting has been shown to improve transplant outcomes. Accomplishing the same feat for deceased donor grafts would require ex vivo exposure to potent defatting agents. Here we used a rat hepatocyte culture system exhibiting a macrosteatotic LD morphology, elevated TG levels, and an elevated sensitivity to hypoxia/reoxygenation (H/R) to test for such agents and ameliorate H/R sensitivity. Macrosteatotic hepatocyte preconditioning for 48 hours with a defatting cocktail that was previously developed to promote TG catabolism reduced the number of macrosteatotic LDs and intracellular TG levels by 82% and 27%, respectively, but it did not ameliorate sensitivity to H/R. Supplementation of this cocktail with l-carnitine, together with hyperoxic exposure, yielded a similar reduction in the number of macrosteatotic LDs and a 57% reduction in intrahepatic TG storage, likely by increasing the supply of acetyl coenzyme A to mitochondria, as indicated by a 70% increase in ketone body secretion. Furthermore, this treatment reduced ROS levels by 32%, increased ATP levels by 27% (to levels near those of lean controls), and completely abolished H/R sensitivity as indicated by approximately 85% viability after H/R and the reduction of cytosolic lactate dehydrogenase release to levels seen in lean controls. Cultures maintained for 48 hours after H/R were approximately 83% viable and exhibited superior urea secretion and bile canalicular transport in comparison with untreated macrosteatotic cultures. In conclusion, these findings show that the elevated sensitivity of macrosteatotic hepatocytes to H/R can be overcome by defatting agents, and they suggest a possible route for the recovery of discarded macrosteatotic grafts. PMID- 24802974 TI - Effects of 20 mg oral Delta(9) -tetrahydrocannabinol on the olfactory function of healthy volunteers. AB - AIMS: Olfactory loss impairs the patient's quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Delta(9) tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment. METHODS: The effects of 20 mg oral THC on olfaction were assessed in a placebo controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration. RESULTS: Delta(9) -Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 +/- 4.2 to 32.2 +/- 5.6, 95% confidence interval for differences THC vs. placebo, -7.8 to -2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function. CONCLUSIONS: Considering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies. PMID- 24802975 TI - Impact of a premature menopause on cognitive function in later life. AB - OBJECTIVE: To determine whether premature menopause (<=40 years) can have long lasting effects on later-life cognition and investigate whether this association varies depending on the type of menopause and use of hormone treatment (HT). DESIGN: Population-based cohort study. SETTING: The French Three-City Study. POPULATION: Four thousand eight hundred and sixty-eight women aged at least 65 years. METHODS: Multivariable-adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later-life cognitive function. MAIN OUTCOME MEASURES: Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis. RESULTS: Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non-surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12-1.87, P=0.004) and visual memory (OR 1.39, 95%CI 1.09-1.77, P=0.007) in later life. HT at the time of premature menopause appeared beneficial for later-life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years. CONCLUSION: Both premature surgical menopause and premature ovarian failure were associated with long-term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long-term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women. PMID- 24802976 TI - Four weeks of functional electrical stimulated cycling after spinal cord injury: a clinical cohort study. AB - The aim of this study was to determine the efficacy and the effects of functional electrical stimulated cycling (FES cycling) in patients with spinal cord injury during their rehabilitation in a special acute care unit. Thirty patients [10 with American Spinal Injury Association Impairment Scale (AIS) grade A, three with AIS grade B, 15 with AIS grade C, two with AIS grade D] aged 44+/-15.5 years and 2 (median) (interquartile range, 1.0-4.25) months after spinal cord injury were included in the study. The patients participated in a 20-min FES-cycling program 2 days per week for 4 weeks during their acute inpatient rehabilitation. The influence on muscle cross-section, muscle and leg circumference, spasticity, and the walking ability parameter (distance, time, aids) was measured. Muscle stimulation intensity and output parameters (pedalling time and distance) were also recorded. Spasticity decreased during hip abduction and adduction (70 and 98.1%, respectively). Spasticity during knee flexion and knee extension decreased by 66.8 and 76.6%, and a decrease was found during dorsal foot extension (67.8%; for all, P<0.05). Presession-postsession comparisons showed that after 4 weeks of FES cycling, an increase in the circumference of the cross-sectional area of 15.3% on the left and of 17% on the right m. rectus femoris could be observed in group AIS A+B. In the AIS C+D group, the circumference of the left m. rectus femoris increased by 25% and that of the right m. rectus femoris by 21% (for all, P<0.05). The results of the study show that FES cycling in combination with function-oriented physiotherapy and occupational therapy can have a positive influence on spasticity, walking ability, and muscular reactivation. It seems to support circulatory processes within the rehabilitation of paraplegics already after a 4-week intervention. PMID- 24802977 TI - Differences between rehabilitation team, rehabilitants, and significant others in opinions on functioning of subacute stroke survivors: Turku ICF study. AB - To assess quantitative differences between rehabilitation team, rehabilitants, and significant others in opinions on functioning of subacute stroke survivors. During inpatient interdisciplinary neurorehabilitation, the interdisciplinary team, nurses, rehabilitants, and significant others reported their opinions on the functioning of consecutive 62 rehabilitants. Data were gathered using the structured form based on the International Classification of Functioning, Disability and Health (ICF) Brief Core Set for Stroke. Agreement between observers on the presence and severity of restrictions in functioning was analyzed. The strongest agreement between different observers on all studied ICF categories was achieved between the interdisciplinary team and nurses (weighted squared kappa=0.7-0.9). The weakest agreement was detected between the team and rehabilitants (weighted squared kappa=0.1-0.6). Support by family was found to be an important facilitating factor of functioning by all observers. Limitations in cognitive activity were identified less frequently than other restrictions. Opinions on restrictions in functioning may differ between the interdisciplinary team, rehabilitants, and significant others. These differences can be assessed quantitatively and documented using the ICF Core Set for Stroke. This potential observer-dependent discrepancy should be taken into account during the process of neurorehabilitation. PMID- 24802978 TI - Disability in Italian neurosurgical patients: validity of the 12-item World Health Organization Disability Assessment Schedule. AB - The aim of the study was to assess factor structure, internal consistency and validity of the Italian version of the World Health Organization Disability Assessment Schedule 12-item version (WHODAS-12) in patients scheduled for neurosurgical procedures for brain tumours, cerebrovascular or spinal diseases. Disability was assessed with the WHODAS-12, quality of life with the eight-item European Health Interview Survey-Quality of Life, well-being with the Psychological General Well-Being Index-Short and general health with the Karnofsky Performance Status (KPS) scales. Factor analysis was used to confirm WHODAS-12 one-factor structure; root mean square error of approximation (RMSEA) and chi2/d.f. ratio were used to test the model fit. Internal consistency was assessed with Cronbach's alpha coefficient, item-total correlation and interitem correlation; convergent validity was assessed with Pearson's coefficient and discriminative validity was assessed with the t-test, dividing patients between those with KPS greater than 90 and KPS of 90 or less. The one-factor structure was confirmed (RMSEA=0.079; chi2/d.f.=2.16) and internal consistency was adequate. Correlations between the three outcome measures were significant, negative and moderate; the t-test showed disability scores to be statistically significantly higher in patients with KPS of 90 or less. Our results confirm factor structure and validity of WHODAS-12 in Italian neurosurgical inpatients; we therefore support its use in neurosurgery departments. PMID- 24802979 TI - Building on Cram's legacy: stimulated gating in hemicarcerands. AB - CONSPECTUS: Donald Cram's pioneering Nobel Prize-winning work on host-guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host-guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating. The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a "chair" to a "boat" structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating. We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account. PMID- 24802980 TI - Maternal plasma and amniotic fluid cytokines in monochorionic, diamniotic twin pregnancies complicated by twin-to-twin transfusion syndrome. AB - INTRODUCTION: Cytokine imbalance has been implicated in placental-related pathologies, i.e. recurrent miscarriage and pre-eclampsia. Such conditions are more prevalent in multiple pregnancies. Twin-to-twin transfusion syndrome (TTTS) is associated with asymmetric placental blood flow and intra-cardiac pressures. We hypothesised that cytokine expression may be aberrant in this condition and that fetoscopic laser ablation (FLA) may cause local cytokine release. MATERIAL AND METHODS: A prospective cohort of monochorionic, diamniotic twins with TTTS (n = 23) was studied. Circulating T helper cell type 1 (TH1)/TH2 maternal cytokines and cytokine-related and angiogenic factors were measured in plasma and amniotic fluid before and after FLA by human FASTQuant or ELISA. Basal comparisons were made with uncomplicated monochorionic and dichorionic (DC) twins. RESULTS: Median maternal plasma platelet-derived growth factor-BB was highest in uncomplicated DC twins (p = 0.049), whereas tissue inhibitor of metalloproteinases (TIMP)-1 was highest in TTTS twins (p = 0.003). In TTTS amniotic fluid, interleukin (IL)-6, IL 1beta, tumour necrosis factor-alpha, IL-10, IL-4, IL-8, interferon-gamma, TIMP-1 and intercellular adhesion molecule-1 were significantly higher than maternal plasma concentrations. There were no significant differences in plasma or amniotic fluid cytokines after FLA, with the exception of amniotic fluid keratinocyte growth factor, which was significantly reduced. DISCUSSION: TTTS is associated with minimal changes in cytokine levels when compared to uncomplicated twins, although the majority of cytokine levels were higher in amniotic fluid than maternal blood. It does not appear that FLA evokes a significant change in cytokines. PMID- 24802981 TI - Nanoparticle catalysts for proton exchange membrane fuel cells: can surfactant effects be beneficial for electrocatalysis? AB - Platinum (Pt) nanoparticles were prepared in aqueous dispersion using the non ionic surfactant nonylphenolethoxylate (NP9) and the cationic surfactant tetradecyltrimethylammonium bromide (TTAB). The surfactants were added to give colloidal stability. Such species are generally considered to block electrochemical active sites and to be undesirable for the oxygen reduction reaction (ORR). However, the procedures used to remove them are likely to cause particle aggregation. The purpose of this work was to investigate the effect of surfactants on Pt ORR performance. The nanoparticles prepared using NP9 showed good oxygen reduction performance when compared with the commercial Pt/C catalyst TKK, without removing the surfactant. In contrast, Pt nanoparticles prepared using the cationic surfactant TTAB showed very poor ORR performance, exemplifying the importance of careful surfactant selection in catalyst synthesis. PMID- 24802982 TI - Aromatic interactions modulate the 5'-base selectivity of the DNA-binding autoantibody ED-10. AB - We present detailed computational analyses of the binding of four dinucleotides to a highly sequence-selective single-stranded DNA (ssDNA) binding antibody (ED 10) and selected point mutants. Anti-DNA antibodies are central to the pathogenesis of systemic lupus erythematosus (SLE), and a more complete understanding of the mode of binding of DNA and other ligands will be necessary to elucidate the role of anti-DNA antibodies in the kidney inflammation associated with SLE. Classical molecular mechanics based molecular dynamics simulations and density functional theory (DFT) computations were applied to pinpoint the origin of selectivity for the 5'-nucleotide. In particular, the strength of interactions between each nucleotide and the surrounding residues were computed using MMGBSA as well as DFT applied to a cluster model of the binding site. The results agree qualitatively with experimental binding free energies, and indicate that pi-stacking, CH/pi, NH/pi, and hydrogen-bonding interactions all contribute to 5'-base selectivity in ED-10. Most importantly, the selectivity for dTdC over dAdC arises primarily from differences in the strength of pi-stacking and XH/pi interactions with the surrounding aromatic residues; hydrogen bonds play little role. These data suggest that a key Tyr residue, which is not present in other anti-DNA antibodies, plays a key role in the 5'-base selectivity, while we predict that the mutation of a single Trp residue can tune the selectivity for dTdC over dAdC. PMID- 24802983 TI - Leishmanicidal evaluation of tetrahydroprotoberberine and spirocyclic erythrina alkaloids. AB - Leishmaniasis is one of the World's most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and seven alkaloids 3-9, were obtained from Erythrina verna. The structures of the compounds were confirmed by mass spectrometry and 1D- and 2D-NMR spectroscopy. The leishmanicidal activity of compounds 1-9 against Leishmania amazonensis was tested on promastigote forms and cytotoxicity against J774 (macrophage cell line) was assessed in vitro. Compound 1 showed potent activity (IC50 = 0.18 ug/mL), compared with the standard amphotericin B (IC50 = 0.20 ug/mL). The spirocyclic erythrina-alkaloids showed lower leishmanicidal activity than dibenzoquinolizine type alkaloids. PMID- 24802984 TI - The role of microRNA in head and neck cancer: current knowledge and perspectives. AB - Head and neck cancer is one of the most commonly diagnosed malignancies worldwide. Patients with advanced disease stages frequently develop recurrences or distant metastasis, which results a five-year survival rates of less than 60% despite considerable advances in multimodality therapy. A better understanding of molecular basis of tumorigenesis is required to improve clinical outcomes and to develop new anti-cancer drugs. microRNAs (miRNAs) are a class of small, non coding, RNA molecules that modulate gene expression post-transcriptionally. They are important regulator in normal biological process; however miRNAs deregulation has been observed in many different tumors and is involved in tumorigenesis. miRNAs may act as tumor suppressors or as oncogenes. Several studies on head and neck cancer demonstrated how aberrant expression of miRNAs is involved in proliferation, metastasis, chemoresistence, and radioresistance. In addition, miRNAs are excellent biomarker targets because they circulate stable in human body fluids and can be obtained with non-invasive methods. Moreover, miRNAs up and down regulation has been correlated with specific cancer phenotype (poor prognosis, aggressiveness and resistance to treatment), playing a role as prognostic biomarkers. This review summarizes current finding on miRNAs in head and neck cancer and their potential role as target for next drug therapy. PMID- 24802985 TI - Anti-ulcer activity of essential oil constituents. AB - Essential oils have attracted considerable worldwide attention over the last few decades. These natural products have wide-ranging pharmacological activities and biotechnological applications. Faced with the need to find new anti-ulcer agents and the great effort on the development of drugs for the treatment of ulcers, in this review, the anti-ulcer activities of 21 bioactive compounds found in essential oils are discussed. PMID- 24802986 TI - In vitro inhibitory effects of scutellarin on six human/rat cytochrome P450 enzymes and P-glycoprotein. AB - Inhibition of cytochrome P450 (CYP) and P-glycoprotein (P-gp) are regarded as the most frequent and clinically important pharmacokinetic causes among the various possible factors for drug-drug interactions. Scutellarin is a flavonoid which is widely used for the treatment of cardiovascular diseases. In this study, the in vitro inhibitory effects of scutellarin on six major human CYPs (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and six rat CYPs (CYP1A2, CYP2C7, CYP2C11, CYP2C79, CYP2D4, and CYP3A2) activities were examined by using liquid chromatography-tandem mass spectrometry. Meanwhile, the inhibitory effects of scutellarin on P-gp activity were examined on a human metastatic malignant melanoma cell line WM-266-4 by calcein-AM fluorometry screening assay. Results demonstrated that scutellarin showed negligible inhibitory effects on the six major CYP isoenzymes in human/rat liver microsomes with almost all of the IC50 values exceeding 100 MUM, whereas it showed values of 63.8 MUM for CYP2C19 in human liver microsomes, and 63.1 and 85.6 MUM for CYP2C7 and CYP2C79 in rat liver microsomes, respectively. Scutellarin also showed weak inhibitory effect on P-gp. In conclusion, this study demonstrates that scutellarin is unlikely to cause any clinically significant herb-drug interactions in humans when co-administered with substrates of the six CYPs (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and P-gp. PMID- 24802987 TI - Antiparasitic activity of natural and semi-synthetic tirucallane triterpenoids from Schinus terebinthifolius (Anacardiaceae): structure/activity relationships. AB - Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 ug/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 ug/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees. PMID- 24802988 TI - Exploiting Illumina sequencing for the development of 95 novel polymorphic EST SSR markers in common vetch (Vicia sativa subsp. sativa). AB - The common vetch (Vicia sativa subsp. sativa), a self-pollinating and diploid species, is one of the most important annual legumes in the world due to its short growth period, high nutritional value, and multiple usages as hay, grain, silage, and green manure. The available simple sequence repeat (SSR) markers for common vetch, however, are insufficient to meet the developing demand for genetic and molecular research on this important species. Here, we aimed to develop and characterise several polymorphic EST-SSR markers from the vetch Illumina transcriptome. A total number of 1,071 potential EST-SSR markers were identified from 1025 unigenes whose lengths were greater than 1,000 bp, and 450 primer pairs were then designed and synthesized. Finally, 95 polymorphic primer pairs were developed for the 10 common vetch accessions, which included 50 individuals. Among the 95 EST-SSR markers, the number of alleles ranged from three to 13, and the polymorphism information content values ranged from 0.09 to 0.98. The observed heterozygosity values ranged from 0.00 to 1.00, and the expected heterozygosity values ranged from 0.11 to 0.98. These 95 EST-SSR markers developed from the vetch Illumina transcriptome could greatly promote the development of genetic and molecular breeding studies pertaining to in this species. PMID- 24802989 TI - Age-related activation of MKK/p38/NF-kappaB signaling pathway in lung: from mouse to human. AB - We and others previously reported that the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6 significantly accumulate with age in mouse lung. This is accompanied by elevated phosphorylation of p38. Here, we further investigate whether aging affects activation of p38 signaling and the inflammatory reaction after exposure to lipopolysaccharide (LPS) in the lungs of mice in vivo and humans ex vivo. The data showed that activation of p38 peaked at 0.5h and then rapidly declined in young (2-month-old) mouse lung, after intranasal inhalation challenge with LPS. In contract, activation of p38 peaked at 24h and was sustained longer in aged (20 month-old) mice. As well as altered p38, activations of its upstream activator MKK and downstream substrate NF-kappaB were also changed in the lungs of aged mice, which corresponded with the absence in the early phase but delayed increases in concentrations of TNF-alpha, IL-1beta and IL-6. Consistent with the above observations in mice, similar patterns of p38 signaling also occurred in human lungs. Compared with younger lungs from adult-middle aged subjects, the activation of p38, MKK and NF-kappaB, as well as the production of pro inflammatory cytokines were significantly increased in the lungs of older subjects ex vivo. Exposure of human lung cells to LPS induced rapid activation of p38, MKK and NF-kappaB in these cells from adult-middle aged subjects, but not older subjects, with increases in the production of the pro-inflammatory cytokines. The LPS-induced rapid activation in the lung cells from adult-middle aged subjects occurred as early as 0.25h after exposure, and then declined. Compared with adult-middle aged subjects, the LPS exposure did not induce marked changes in the early phase, either in the activation of p38, MKK and NF-kappaB, or in the production of TNF-alpha, IL-1beta or IL-6 in the lung cells from older subjects. In contrast, these changes occurred relatively late, peaked at 16h and were sustained longer in the lungs of older subjects. These data support the hypothesis that the sustained activation of the p38 signaling pathway at baseline and the absence in the early phase but delayed of p38 signaling pathway response to LPS in the elderly may play important roles in increased susceptibility of aged lungs to inflammatory injury. PMID- 24802990 TI - Cross-population validation of statistical distance as a measure of physiological dysregulation during aging. AB - Measuring physiological dysregulation during aging could be a key tool both to understand underlying aging mechanisms and to predict clinical outcomes in patients. However, most existing indices are either circular or hard to interpret biologically. Recently, we showed that statistical distance of 14 common blood biomarkers (a measure of how strange an individual's biomarker profile is) was associated with age and mortality in the WHAS II data set, validating its use as a measure of physiological dysregulation. Here, we extend the analyses to other data sets (WHAS I and InCHIANTI) to assess the stability of the measure across populations. We found that the statistical criteria used to determine the original 14 biomarkers produced diverging results across populations; in other words, had we started with a different data set, we would have chosen a different set of markers. Nonetheless, the same 14 markers (or the subset of 12 available for InCHIANTI) produced highly similar predictions of age and mortality. We include analyses of all combinatorial subsets of the markers and show that results do not depend much on biomarker choice or data set, but that more markers produce a stronger signal. We conclude that statistical distance as a measure of physiological dysregulation is stable across populations in Europe and North America. PMID- 24802991 TI - Self-regulatory fatigue, quality of life, health behaviors, and coping in patients with hematologic malignancies. AB - BACKGROUND: Self-regulatory fatigue may play an important role in a complex medical illness. PURPOSE: Examine associations between self-regulatory fatigue, quality of life, and health behaviors in patients pre- (N = 213) and 1-year post hematopoietic stem cell transplantation (HSCT; N = 140). Associations between self-regulatory fatigue and coping strategies pre-HSCT were also examined. METHOD: Pre- and 1-year post-HSCT data collection. Hierarchical linear regression modeling. RESULTS: Higher self-regulatory fatigue pre-HSCT associated with lower overall, physical, social, emotional, and functional quality of life pre- (p's < .001) and 1-year post-HSCT (p's < .01); lower physical activity pre-HSCT (p < .02) and post-HSCT (p < .03) and less healthy nutritional intake post-HSCT (p < .01); changes (i.e., decrease) in quality of life and healthy nutrition over the follow-up year; and use of avoidance coping strategies pre-HSCT (p's < .001). CONCLUSION: This is the first study to show self-regulatory fatigue pre-HSCT relating to decreased quality of life and health behaviors, and predicting changes in these variables 1-year post-HSCT. PMID- 24802992 TI - Inappropriate use of anticoagulant drugs in older adults. PMID- 24802993 TI - Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice. AB - Little is known regarding the role of NK cells during primary and secondary disseminated Candida albicans infection. We assessed the role of NK cells for host defense against candidiasis in immunocompetent, as well as immunodeficient, hosts. Surprisingly, depletion of NK cells in immunocompetent WT mice did not increase susceptibility to systemic candidiasis, suggesting that NK cells are redundant for antifungal defense in otherwise immunocompetent hosts. NK-cell depleted mice were found to be protected as a consequence of attenuation of systemic inflammation. In contrast, the absence of NK cells in T/B/NK-cell deficient NSG (NOD SCID gamma) mice led to an increased susceptibility to both primary and secondary systemic C. albicans infections compared with T/B-cell deficient SCID mice. In conclusion, this study demonstrates that NK cells are an essential and nonredundant component of anti-C. albicans host defense in immunosuppressed hosts with defective T/B-lymphocyte immunity, while contributing to hyperinflammation in immunocompetent hosts. The discovery of the importance of NK cells in hosts with severe defects of adaptive immunity might have important consequences for the design of adjunctive immunotherapeutic approaches in systemic C. albicans infections targeting NK-cell function. PMID- 24802994 TI - Psychosocial safety climate, emotional demands, burnout, and depression: a longitudinal multilevel study in the Malaysian private sector. AB - This multilevel longitudinal study investigates a newly identified climate construct, psychosocial safety climate (PSC), as a precursor to job characteristics (e.g., emotional demands), and psychological outcomes (i.e., emotional exhaustion and depression). We argued that PSC, as an organizational climate construct, has cross-level effects on individually perceived job design and psychological outcomes. We hypothesized a mediation process between PSC and emotional exhaustion particularly through emotional demands. In sequence, we predicted that emotional exhaustion would predict depression. At Time 1, data were collected from employees in 36 Malaysian private sector organizations (80% responses rate), n = 253 (56%), and at Time 2 from 27 organizations (60%) and n = 117 (46%). Using hierarchical linear modeling (HLM), we found that there were cross-level effects of PSC Time 1 on emotional demands Time 2 and emotional exhaustion Time 2, but not on depression Time 2, across a 3-month time lag. We found evidence for a lagged mediated effect; emotional demands mediated the relationship between PSC and emotional exhaustion. Emotional exhaustion did not predict depression. Finally, our results suggest that PSC is an important organizational climate construct, and acts to reduce employee psychological problems in the workplace, via working conditions. PMID- 24802995 TI - Lipidomics reveals mitochondrial membrane remodeling associated with acute thermoregulation in a rodent with a wide thermoneutral zone. AB - Mongolian gerbils (Meriones unguiculatus) have high physiological flexibility in response to acute temperature changes, and have the widest thermoneutral zone (TNZ, 26.5-38.9 degrees C) reported among small mammals. At the upper critical temperature (T(uc), 38.9 degrees C), body temperatures of gerbils were significantly increased (39-41 degrees C) while metabolic rates were maintained at the basal level. In contrast, below the lower critical temperature (T(lc), 26.5 degrees C), metabolism was elevated and body temperature stable. Rapid changes in mitochondrial membrane lipidome were hypothesized to play an important role during acute thermoregulation of gerbils. Taking advantage of a recent lipidomic technique, we examined changes in the membrane phospholipids environment and free fatty acids (FFA) production in mitochondria between 38 and 27 degrees C (in the TNZ), and between 27 and 16 degrees C (below the TNZ). At 38 degrees C, acute heat stress elicited distinct remodeling in mitochondrial membrane lipidome which related to a potential decrease in mitochondrial respiration and membrane fluidity compared to 27 degrees C. At 16 degrees C, a sharply decreased unsaturation index and increased chain lengths were detected in mitochondrial FFA production both in muscle and brown adipose tissue. Our results suggest that mitochondrial membrane lipid remodeling may stabilize membrane function and activity of respiration related membrane protein to maintain a stable metabolic rate at T(uc), and improve heat production by decomposing less fluid fatty acid conjugates of membrane lipids under acute cold exposure. These data therefore imply an important role of membrane remodeling during acute thermoregulation in a non-hibernating endotherm. PMID- 24802996 TI - Physiological, biochemical, and genome-wide transcriptional analysis reveals that elevated CO2 mitigates the impact of combined heat wave and drought stress in Arabidopsis thaliana at multiple organizational levels. AB - Climate changes increasingly threaten plant growth and productivity. Such changes are complex and involve multiple environmental factors, including rising CO2 levels and climate extreme events. As the molecular and physiological mechanisms underlying plant responses to realistic future climate extreme conditions are still poorly understood, a multiple organizational level analysis (i.e. eco physiological, biochemical, and transcriptional) was performed, using Arabidopsis exposed to incremental heat wave and water deficit under ambient and elevated CO2 . The climate extreme resulted in biomass reduction, photosynthesis inhibition, and considerable increases in stress parameters. Photosynthesis was a major target as demonstrated at the physiological and transcriptional levels. In contrast, the climate extreme treatment induced a protective effect on oxidative membrane damage, most likely as a result of strongly increased lipophilic antioxidants and membrane-protecting enzymes. Elevated CO2 significantly mitigated the negative impact of a combined heat and drought, as apparent in biomass reduction, photosynthesis inhibition, chlorophyll fluorescence decline, H2 O2 production, and protein oxidation. Analysis of enzymatic and molecular antioxidants revealed that the stress-mitigating CO2 effect operates through up regulation of antioxidant defense metabolism, as well as by reduced photorespiration resulting in lowered oxidative pressure. Therefore, exposure to future climate extreme episodes will negatively impact plant growth and production, but elevated CO2 is likely to mitigate this effect. PMID- 24802998 TI - Treatment failure in leishmaniasis: drug-resistance or another (epi-) phenotype? AB - Two major leishmaniasis treatments have shown a significant decrease in effectiveness in the last few decades, mostly in the Indian subcontinent but also in other endemic areas. Drug resistance of Leishmania correlated only partially to treatment failure (TF) of pentavalent antimonials, and has so far proved not to be important for the increased miltefosine relapse rates observed in the Indian subcontinent. While other patient- or drug-related factors could also have played a role, recent studies identified several parasite features such as infectivity and host manipulation skills that might contribute to TF. This perspective aims to discuss how different parasitic features other than drug resistance can contribute to TF of leishmaniasis and how this may vary between different epidemiological contexts. PMID- 24802997 TI - Tnfa signaling through tnfr2 protects skin against oxidative stress-induced inflammation. AB - TNFalpha overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new onset psoriasis and lichen planus following TNFalpha antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2 deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-kappaB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFalpha/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders. PMID- 24802999 TI - Flexible sensors for chronic wound management. AB - Chronic nonhealing wounds are a major source of morbidity and mortality in bed ridden and diabetic patients. Monitoring of physical and chemical parameters important in wound healing and remodeling process can be of immense benefit for optimum management of such lesions. Low-cost flexible polymeric and paper-based substrates are attractive platforms for fabrication of such sensors. In this review, we discuss recent advances in flexible physiochemical sensors for chronic wound monitoring. After a brief introduction to wound healing process and commercial wound dressings, we describe various flexible biocompatible substrates that can be used as the base platform for integration of wound monitoring sensors. We will then discuss several fabrication methods that can be utilized to integrate physical and chemical sensors onto such substrates. Finally, we will present physical and chemical sensors developed for monitoring wound microenvironment and outline future development venues. PMID- 24803001 TI - Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma. AB - Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma. It is not known if there are differences in outcome between early versus delayed BEV treatment of recurrent glioblastoma. We examined the relationship between the time of starting BEV treatment and outcomes in patients with recurrent glioblastoma. In this retrospective chart review, we identified patients with recurrent glioblastoma diagnosed between 2005 and 2011 who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of starting BEV. A total of 298 patients were identified, 112 patients received early BEV, 133 patients received delayed BEV, and 53 patients were excluded because they either progressed within 3 months of radiation or received BEV at the time of diagnosis. There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.2 vs. 4.3 months, p = 0.2). Patients treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 vs. 20.8 months, p = 0.005). In patients with recurrent glioblastoma, there was no significant difference in PFS from the time of starting BEV between early and delayed BEV. Although patients treated with delayed BEV seemed to have longer OS, a conclusion regarding OS outcome requires further prospective trials. These results may indicate that delaying treatment with BEV is not detrimental for survival of patients with recurrent glioblastoma. PMID- 24803002 TI - Clinical result of stereotactic radiosurgery for spinal metastasis from hepatocellular carcinoma: comparison with conventional radiation therapy. AB - We investigated the clinical outcome following stereotactic radiosurgery (SRS) for spinal metastasis from hepatocellular carcinoma (HCC) and compared it with that of conventional radiation therapy (cRT). Thirty-nine metastatic spine tumors from 27 HCC patients were treated with SRS from 2002 to 2011. Their medical records and radiological data were retrospectively analyzed. Median tumor volume was 49.7 cc, and a mean marginal dose of 28.7 Gy was delivered to the tumor mass. We analyzed overall survival (OS), local progression-free survival, and the rate of pain control following SRS. Factors relating to clinical outcomes were also investigated. Clinical results following cRT were obtained from 32 patients. The cRT protocol consisted of 30 Gy in 10 fractions or 39 Gy in 13 fractions. OS and local progression-free survival were compared between SRS and cRT. OS was a median of 7 months following SRS. Significant prognostic factors relating to OS included Child-Pugh class and Karnofsky performance scale. Tumor recurrence was noted in nine lesions during follow-up. The median local progression-free survival was 7 months. Previous irradiation was a significant prognostic factor for local recurrence (P = 0.043). The overall pain control rate was 85 % and no factors were found to be significantly correlated with the pain control rate. The median OS was 3 months in the cRT group and 7 months in the SRS group (P = 0.035). The median local progression-free survival was 2.0 months in the cRT group, and 7.0 months in the SRS group, which were significantly different (P = 0.033). SRS showed better local control than cRT in the treatment of HCC spinal metastasis. PMID- 24803000 TI - Vaccines for the 21st century. AB - In the last century, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases. It is believed that vaccines save at least 2-3 million lives per year worldwide. Smallpox has been eradicated and polio has almost disappeared worldwide through global vaccine campaigns. Most of the viral and bacterial infections that traditionally affected children have been drastically reduced thanks to national immunization programs in developed countries. However, many diseases are not yet preventable by vaccination, and vaccines have not been fully exploited for target populations such as elderly and pregnant women. This review focuses on the state of the art of recent clinical trials of vaccines for major unmet medical needs such as HIV, malaria, TB, and cancer. In addition, we describe the innovative technologies currently used in vaccine research and development including adjuvants, vectors, nucleic acid vaccines, and structure-based antigen design. The hope is that thanks to these technologies, more diseases will be addressed in the 21st century by novel preventative and therapeutic vaccines. PMID- 24803003 TI - Crop monoculture rather than agriculture reduces the spatial turnover of soil bacterial communities at a regional scale. AB - The goal of this study was to investigate the spatial turnover of soil bacterial communities in response to environmental changes introduced by the practices of soybean monoculture or crop rotations, relative to grassland soils. Amplicon sequencing of the 16S rRNA gene was used to analyse bacterial diversity in producer fields through three successive cropping cycles within one and a half years, across a regional scale of the Argentinean Pampas. Unlike local diversity, which was not significantly affected by land use type, agricultural management had a strong influence on beta-diversity patterns. Distributions of pairwise distances between all soils samples under soybean monoculture had significantly lower beta-diversity and narrower breadth compared with distributions of pairwise distances between soils managed with crop rotation. Interestingly, good agricultural practices had similar degree of beta-diversity as natural grasslands. The higher phylogenetic relatedness of bacterial communities in soils under monoculture across the region was likely determined by the observed loss of endemic species, and affected mostly to phyla with low regional diversity, such as Acidobacteria, Verrucomicrobia and the candidates phyla SPAM and WS3. These results suggest that the implementation of good agricultural practices, including crop rotation, may be critical for the long-term conservation of soil biodiversity. PMID- 24803004 TI - Co-crystal formation between poly(ethylene glycol) and a small molecular drug griseofulvin. AB - Most of the pharmaceutical co-crystals are formed between drug molecules and small molecular compounds. Here, we demonstrated that a small molecular drug griseofulvin and poly(ethylene glycol) can also form co-crystals. PMID- 24803006 TI - 4-Amino-1-(3-mercapto-propyl)-pyridine hexafluorophosphate ionic liquid functionalized gold nanoparticles for IgG immunosensing enhancement. AB - A novel ionic liquid, 4-amino-1-(3-mercapto-propyl)-pyridine hexafluorophosphate (AMPPH), was successfully synthesized and characterized. Subsequently, AMPPH was used as a functional monomer to fabricate AMPPH-modified gold nanoparticles (AMPPH-AuNPs) via a one-pot synthesis method. The as-prepared AMPPH-AuNPs were confirmed with transmission electron microscopy and X-ray photoelectron spectroscopy. AMPPH-AuNPs were used to construct a biocompatible interface to immobilize rabbit anti-human IgG (anti-HIgG) onto a glassy carbon electrode (GCE) surface, followed by a cross-linking step with glutaraldehyde to fabricate an anti-HIgG-AMPPH-AuNPs/GCE. The nonspecific binding sites were enclosed with bovine serum albumin (BSA) to develop an immunosensor for human IgG. Electrochemical impedance spectroscopy, cyclic voltammetry and differential pulse voltammetry were used to investigate the electrochemical properties of the developed immunosensor. The results indicate that AMPPH-AuNPs can improve the immunosensing performance. The current response of the immunosensor was found linearly related to human IgG concentration in the range of 0.1-5.0 ng mL(-1) and 5.0-100.0 ng mL(-1). The detection limit is estimated to be 0.08 ng mL(-1) (S/N = 3). The obtained immunosensor was successfully applied to the analysis human IgG immunoglobulin in human serum, and the results were well consistent with ELISA method. PMID- 24803007 TI - Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis. AB - OBJECTIVE: This retrospective cohort study evaluated the obstetric outcomes in women with polycystic ovary syndrome (PCOS) and isolated polycystic ovaries (PCO) undergoing in vitro fertilization (IVF) treatment. METHODS: We studied 104 women with PCOS, 184 with PCO and 576 age-matched controls undergoing the first IVF treatment cycle between 2002 and 2009. Obstetric outcomes and complications including gestational diabetes (GDM), gestational hypertension (GHT), gestational proteinuric hypertension (PET), intrauterine growth restriction (IUGR), gestation at delivery, baby's Apgar scores and admission to the neonatal intensive care unit (NICU) were reviewed. RESULTS: Among the 864 patients undergoing IVF treatment, there were 253 live births in total (25 live births in the PCOS group, 54 in the PCO group and 174 in the control group). The prevalence of obstetric complications (GDM, GHT, PET and IUGR) and the obstetric outcomes (gestation at delivery, birth weight, Apgar scores and NICU admissions) were comparable among the three groups. Adjustments for age and multiple pregnancies were made using multiple logistic regression and we found no statistically significant difference among the three groups. CONCLUSION: Patients with PCO +/- PCOS do not have more adverse obstetric outcomes when compared with non-PCO patients undergoing IVF treatment. PMID- 24803008 TI - Maternal anthropometric characteristics as determinants of birth weight in north west Nigeria: prospective study. AB - OBJECTIVE: This study was undertaken to determine the sensitivity and specificity of anthropometric measurements in predicting birth weight. METHODS: This was a prospective study. Interviewer-administered questionnaires were used. Two hundred were used. The weight, height and BMI of the women were measured. Unclothed newborns were weighed immediately after delivery. The data obtained were analyzed using SPSS version 16.0 statistical software. The accuracy of maternal weight, height and body mass index in predicting birth weight was compared using chi squared test and p < 0.05 was considered statistically significant. RESULT: The mean maternal age was 28.2 +/- 5.7 years. The mean parity was 3 +/- 2. The mean gestational age at delivery was 38.5 +/- 2 years. The mean actual birth weight was 3.27 +/- 0.53 kg. The mean maternal weight was 72.03 +/- 11 kg. Maternal weight showed a strong positive correlation with birth weight (r = 0.48) and this was statistically significant (p < 0.001). The mean maternal height was 1.64 +/- 0.55 m. The mean maternal BMI was 27.9 +/- 4.33. Maternal weight, height and BMI had sensitivities of 50%, 40% and 50% and specificities of 48%, 57.9% and 67.3%, respectively. CONCLUSION: Maternal weight, height and BMI are not good predictors of birth weight and cannot be recommended for use as screening test in poor resource setting where ultrasound available. PMID- 24803009 TI - Preeclampsia enhances neuroglial marker expression in umbilical cord Wharton's jelly-derived mesenchymal stem cells. AB - OBJECTIVE: The aim of the study was to compare the neuroglial phenotype of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) from pregnancies complicated with preeclampsia and gestational age (GA)-matched controls. METHODS: WJ-MSC were isolated from umbilical cords from both groups and analyzed for the cell surface expression of MSC markers and the gene and protein expression of neuroglial markers. RESULTS: All WJ cells were highly positive for the MSC markers CD105, CD90 and CD73, but negative for markers specific for hematopoietic (CD34) and immunological cells (CD45, CD14, CD19 and HLA-DR). WJ-MSC from both groups expressed neuroglial markers (MAP-2, GFAP, MBP, Musashi-1 and Nestin) at the mRNA and protein level. The protein expressions of neuronal (MAP-2) and oligodendrocytic (MBP) markers were significantly increased in WJ-MSC from preeclampsia versus GA-matched controls. CONCLUSIONS: WJ-MSC from preeclamptic patients are possibly more committed to neuroglial differentiation through the activation of pathways involved both in the pathophysiology of the disease and in neurogenesis. PMID- 24803005 TI - Transient dynamics of Abeta contribute to toxicity in Alzheimer's disease. AB - The aggregation and deposition of the amyloid-beta peptide (Abeta) in the brain has been linked with neuronal death, which progresses in the diagnostic and pathological signs of Alzheimer's disease (AD). The transition of an unstructured monomeric peptide into self-assembled and more structured aggregates is the crucial conversion from what appears to be a harmless polypeptide into a malignant form that causes synaptotoxicity and neuronal cell death. Despite efforts to identify the toxic form of Abeta, the development of effective treatments for AD is still limited by the highly transient and dynamic nature of interconverting forms of Abeta. The variability within the in vivo "pool" of different Abeta peptides is another complicating factor. Here we review the dynamical interplay between various components that influence the heterogeneous Abeta system, from intramolecular Abeta flexibility to intermolecular dynamics between various Abeta alloforms and external factors. The complex dynamics of Abeta contributes to the causative role of Abeta in the pathogenesis of AD. PMID- 24803010 TI - Hypoxia-inducible factor-1alpha (HIF-1alpha) expression in placentae of women with iron deficiency anemia and beta-thalassemia trait. AB - OBJECTIVE: To investigate hypoxia-inducible factor-1alpha (HIF-1alpha) expression in placentae of women with iron-deficiency anemia and beta-thalassemia trait and to correlate the results with hematological parameters as well as with parameters associated with the outcome of pregnancy. METHODS: About 126 women who delivered in the Larissa University Hospital were divided in three groups: iron-deficiency anemia (n = 39), beta-thalassemia trait carriers (n = 53) and control group (n = 34). HIF-1alpha expression was assessed with immunochemical assays and statistical analysis was performed with chi-squared test and ANOVA. RESULTS: HIF 1alpha immunostaining was intense in the two groups of anemia. A statistically significant association was found between HIF-1alpha immunoreactivity and hematocrit (p < 0.001), hemoglobin (p < 0.001), MCV (p < 0.001), transferrin (p < 0.001) and its receptors (p = 0.040), whereas no significant correlations were observed between HIF-1alpha, iron serum levels (p = 0.256) and ferritin (p = 0.232). We found no association between HIF-1alpha and birthweight (p = 0.256), placental weight (p = 0.870) and Apgar score at 1' (p = 0.210) and 5' (p = 0.400). CONCLUSIONS: HIF-1alpha expression is affected by anemia, although this factor has no important direct effect on the perinatal outcome. PMID- 24803012 TI - Letter to the editor on "Demoulin JB, Essaghir A. PDGF receptor signaling networks in normal and cancer cells. Cytokine Growth Factor Rev (2014)". PMID- 24803011 TI - The impact of intestinal inflammation on the nutritional environment of the gut microbiota. AB - The intestinal epithelium is a single cell barrier separating a sterile mucosal tissue from a large microbial community dominated by obligate anaerobic bacteria, which inhabit the gut lumen. To maintain mucosal integrity, any breach in the epithelial barrier needs to be met with an inflammatory host response designed to repel microbial intruders from the tissue, protect the mucosal surface and repair injuries to the epithelium. In addition, inflammation induces mechanisms of nutritional immunity, which limit the availability of metals in the intestinal lumen, thereby imposing new selective forces on microbial growth. However, the inflammatory host response also has important side effects. A by-product of producing reactive oxygen and nitrogen species aimed at eradicating microbial intruders is the luminal generation of exogenous electron acceptors. The presence of these electron acceptors creates a new metabolic niche that is filled by facultative anaerobic bacteria. Here we review the changes in microbial nutrient utilization that accompany intestinal inflammation and the consequent changes in the composition of gut-associated microbial communities. PMID- 24803013 TI - The complex role of inflammasomes in the pathogenesis of Inflammatory Bowel Diseases - lessons learned from experimental models. AB - Inflammasomes are a large family of multiprotein complexes recognizing pathogen associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs). This leads to caspase-1 activation, promoting the secretion of mature IL-1beta, IL-18 and under certain conditions even induce pyroptosis. Inflammatory Bowel Diseases (IBD) is associated with alterations in microbiota composition, inappropriate immune responses and genetic predisposition associated to bacterial sensing and autophagy. Besides their acknowledged role in mounting microbial induced host responses, a crucial role in maintenance of intestinal homeostasis was revealed in inflammasome deficient mice. Further, abnormal activation of these functions appears to contribute to the pathology of intestinal inflammation including IBD and colitis-associated cancer. Herein, the current literature implicating the inflammasomes, microbiota and IBD is comprehensively reviewed. PMID- 24803014 TI - Prediction of compounds in different local structure-activity relationship environments using emerging chemical patterns. AB - Active compounds can participate in different local structure-activity relationship (SAR) environments and introduce different degrees of local SAR discontinuity, depending on their structural and potency relationships in data sets. Such SAR features have thus far mostly been analyzed using descriptive approaches, in particular, on the basis of activity landscape modeling. However, compounds in different local SAR environments have not yet been predicted. Herein, we adapt the emerging chemical patterns (ECP) method, a machine learning approach for compound classification, to systematically predict compounds with different local SAR characteristics. ECP analysis is shown to accurately assign many compounds to different local SAR environments across a variety of activity classes covering the entire range of observed local SARs. Control calculations using random forests and multiclass support vector machines were carried out and a variety of statistical performance measures were applied. In all instances, ECP calculations yielded comparable or better performance than controls. The approach presented herein can be applied to predict compounds that complement local SARs or prioritize compounds with different SAR characteristics. PMID- 24803015 TI - Secondary synovial chondromatosis of the shoulder. AB - Synovial chondromatosis is classified as either primary or secondary. Primary synovial chondromatosis results from a proliferation of chondrocytes in the synovial membrane leading to the formation of cartilaginous loose bodies. Secondary synovial chondromatosis is a rare condition characterized by the growth of separated particles from the articular cartilage or osteophytes in joint diseases. The present article aims to report the secondary chondromatosis of the shoulder and to discuss the clinical manifestations, pathogenesis, diagnosis, histological findings and management of this condition. PMID- 24803016 TI - A simplified arthroscopic bone graft transfer technique in chronic glenoid bone deficiency. AB - In severe shoulder instability, chronic glenoid bone deficiency is a challenge for arthroscopic shoulder surgeons. This paper presents a new all-arthroscopic technique of iliac crest bone graft transfer for those patients. Transportation through the rotator interval and repositioning into the glenoid defect is achieved by use of a tracking suture, while fixation of the graft is performed by biodegradable or titanium double-helix screws. Overall, the feasibility and reproducibility of this new reconstruction technique in recreating the bony and soft tissue anatomy of the antero-inferior glenoid could be demonstrated. So far, preliminary outcomes of 24 patients operated on using this technique are promising. Level of evidence Case series with no comparison group, Level IV. PMID- 24803018 TI - Progress and challenges in women's health: an analysis of levels and patterns of mortality and morbidity. AB - OBJECTIVE: The objective was to provide a summary description of the current status of women's health globally and trends since the 1990s. STUDY DESIGN: A compilation and analytic review of available information was performed. RESULTS: Globally, a woman born in 2010 could expect to live some 31/2 years longer than her sister born just a decade earlier in 2000 and over 8 years longer than her mother or aunt born in 1980. These huge gains in health have, however, been unevenly spread, and in many parts of the world, women's lives continue to be diminished by preventable illness and premature death due to social and gender inequalities and health system inadequacies. These are most acute in poor countries and among the poorest women everywhere. Health problems that are not adequately addressed in childhood, adolescence and the reproductive years have serious adverse repercussions for the children women bear and cast a long shadow on their own health as they age. CONCLUSION: Improvements in health, demographic, economic, social and environmental conditions have brought significant benefits to women in terms of their health and development but are also associated with new challenges, especially for the poorest women. As the causes of death and disability change from those associated with acute conditions--infectious diseases and pregnancy-related complications--to chronic, long-term conditions- cancer, cardiovascular diseases, diabetes and mental ill-health--women will be faced with accessing and paying for medical care and medicines. Many of these chronic conditions can, however, be prevented by a combination of behavioral change and early detection. Paying due attention to the health of girls and women today is an investment not just for the present but also for the future and for coming generations. IMPLICATIONS: The findings of this review have important implications for health systems as well as for broader policy dialogue on the underlying determinants of women's health including gender-based inequalities and discrimination. Health systems need to be structured and managed in ways that are responsive to the needs of girls and women, both for information and for care. Impediments to access--including distance, costs, lack of acceptability and discrimination--must be removed. Women themselves should be involved in designing and delivering health services that meet their needs as patients. They need support also in carrying out their roles as carers, both in the formal health care sector and within families and communities. Strategies to improve women's health must take full account of the underlying determinants of health- particularly gender inequality--and address the specific socioeconomic and cultural barriers that hamper women in protecting and improving their health. PMID- 24803019 TI - Treatment of chronic obstructive pulmonary disease in hospitalized geriatric patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is frequent in older subjects due to deterioration of pulmonary function and lifelong exposure to risk factors. Furthermore, COPD is often underreported because of the gradual onset of symptoms and reduced perception of symptoms in the elderly. There is thus a risk of undertreatment of COPD in older subjects. METHODS: We retrospectively analyzed dossiers of 229 hospitalized geriatric patients with COPD, complete assessment datasets and successful lung function tests. RESULTS: The sample comprised 78 men (38 %; mean age 77 +/- 7 years) and 151 women (66 %; mean age 81 +/- 6 years). The number of untreated patients decreased from 68 (28 %) at admission to 35 (14 %) at discharge (p < 0.01). Absence of treatment was associated with severity of disease: mild COPD was less likely to be treated. During the hospital stay, the prescription of metered dose inhalers (MDIs) decreased and the prescription of nebulizers increased, most likely due to the coordination problems associated with using inhalers. CONCLUSION: Undertreatment of COPD is frequent among hospitalized geriatric patients. There is a need for adaption of current guidelines to the needs of older patients with frailty or cognitive impairment. PMID- 24803021 TI - Calibration of miniature medical ultrasonic hydrophones for frequencies in the range 100 to 500 kHz using an ultrasonically absorbing waveguide. AB - Enhancements to the existing primary standard optical interferometer and narrowband tone-burst comparison calibration methods for miniature medical ultrasonic hydrophones of the membrane type over the frequency range 100 to 500 kHz are described. Improvements were realized through application of an ultrasonically absorbing waveguide made of a low-frequency-absorbing tile used in sonar applications which narrows the spatial extent of the broad acoustic field. The waveguide was employed in conjunction with a sonar multilayered polyvinylidene difluoride (PVDF) hydrophone used as a transmitting transducer covering a frequency range of 100 kHz to 1 MHz. The acoustic field emanating from the ultrasonically absorbing waveguide reduced the significance of diffracted acoustic waves from the membrane hydrophone ring and the consequent interference of this wave with the direct acoustic wave received by the active element of the hydrophone during calibration. Four membrane hydrophone make/ models with ring sizes (defined as the inner diameter of the annular mounting ring of the hydrophone) in the range 50 to 100 mm were employed along with a needle hydrophone. A reference membrane hydrophone, calibrated using the NPL primary standard optical interferometer in combination with the ultrasonically absorbing waveguide, was subsequently used to calibrate the other four hydrophones by comparison, again using the ultrasonically absorbing waveguide. In comparison to existing methods, the use of the ultrasonically absorbing waveguide enabled the low-frequency calibration limit of a membrane hydrophone with a ring diameter of 50 mm to be reduced from 400 kHz to 200 kHz. PMID- 24803020 TI - Caregiver experience during advanced chronic illness and last year of life. AB - OBJECTIVES: To compare the prevalence and predictors of caregiver esteem and burden during two different stages of care recipients' illnesses-advanced chronic illness and the last year of life. DESIGN: Longitudinal, observational cohort study. SETTING: Community sample recruited from outpatient clinics at Duke University and Durham Veterans Affairs Medical Centers. PARTICIPANTS: Individuals with advanced cancer, congestive heart failure, or chronic obstructive pulmonary disease and their primary caregiver, retrospectively coded as chronic-illness (n = 62) or end-of-life (EOL; n = 62) care recipient-caregiver dyads. MEASUREMENTS: Caregiver experience was measured monthly using the Caregiver Reaction Assessment, which includes caregiver esteem and four domains of burden: schedule, health, family, and finances. RESULTS: During chronic illness and at the end of life, high caregiver esteem was almost universal (95%); more than 25% of the sample reported health, family, and financial burden. Schedule burden was the most prevalent form of burden; EOL caregivers (58%) experienced it more frequently than chronic-illness caregivers (32%). Caregiver esteem and all dimensions of burden were relatively stable over 1 year. Few factors were associated with burden. CONCLUSION: Caregiver experience is relatively stable over 1 year and similar in caregivers of individuals in the last year of life and those earlier in the course of chronic illness. Schedule burden stands out as most prevalent and variable among dimensions of experience. Because prevalence of burden is not specific to stage of illness and is relatively stable over time, multidisciplinary healthcare teams should assess caregiver burden and refer burdened caregivers to supportive resources early in the course of chronic illness. PMID- 24803022 TI - MiR-142-3p functions as a potential tumor suppressor in human osteosarcoma by targeting HMGA1. AB - BACKGROUND/AIMS: Mounting evidence has shown that aberrant expression of miRNAs correlates with human cancers, and that miRNAs can function as tumor suppressors or oncogenes. Here, we investigated the role and mechanism of miR-142-3p in human osteosarcoma. METHODS: We used quantitative real-time RT-PCR to measure the expression of miR-142-3p in human osteosarcoma cell lines and tissues. The roles of miR-142-3p in osteosarcoma development were studied using cultured HOS, MG63 and Saos-2 cells and tumor xenograft analyses in nude mice; their target genes were also investigated. RESULTS: We found that miR-142-3p was significantly downregulated in osteosarcoma cell lines and clinical specimens. Overexpression of miR-142-3p suppressed osteosarcoma cell proliferation, migration and invasion, whereas miR-142-3p knockdown increased these parameters. The xenograft mouse model also revealed the suppressive effect of miR-142-3p on tumor growth. High mobility group AT-hook 1 (HMGA1) was identified as a target of miR-142-3p. Downregulation of HMGA1 induced effects on osteosarcoma cell lines similar to those induced by miR-142-3p. In contrast, restoration of HMGA1 abrogated the effects induced by miR-142-3p up-regulation. CONCLUSION: These results indicated that miR-142-3p may function as a tumor suppressor by targeting HMGA1 in osteosarcoma. PMID- 24803023 TI - An edge-based protein complex identification algorithm with gene co-expression data (PCIA-GeCo). AB - Recent studies have shown that protein complex is composed of core proteins and attachment proteins, and proteins inside the core are highly co-expressed. Based on this new concept, we reconstruct weighted PPI network by using gene expression data, and develop a novel protein complex identification algorithm from the angle of edge (PCIA-GeCo). First, we select the edge with high co-expressed coefficient as seed to form the preliminary cores. Then, the preliminary cores are filtered according to the weighted density of complex core to obtain the unique core. Finally, the protein complexes are generated by identifying attachment proteins for each core. A comprehensive comparison in term of F-measure, Coverage rate, P value between our method and three other existing algorithms HUNTER, COACH and CORE has been made by comparing the predicted complexes against benchmark complexes. The evaluation results show our method PCIA-GeCo is effective; it can identify protein complexes more accurately. PMID- 24803024 TI - Enhanced anti-cancer efficacy to cancer cells by doxorubicin loaded water-soluble amino acid-modified beta-cyclodextrin platinum complexes. AB - The effective targeted delivery of insoluble anticancer drugs to increase the intracellular drug concentration has become a focus in cancer therapy. In this system, two water-soluble amino acid-modified beta-cyclodextrin (beta-CD) platinum complexes were reported. They showed preferable binding ability to DNA and effective inhibition to cancer cells, and they could bind and unwind pBR322 DNA in a manner which was similar to cisplatin. Besides, our platinum complexes could effectively deliver the anticancer drug doxorubicin (Dox) into cells and had higher cell inhibition ratio, but less toxicity on the normal cells, compared with cancer cells. In this combination system, Dox was encapsulated into the hydrophobic cavities of beta-CD at the optimum molar ratio of 1:1, which were validated by UV-visible (UV-vis) absorption spectroscopy, fluorescence spectroscopy and MTT experiments. Moreover, the combination system had higher cell inhibition ratio than free Dox and amino acid-modified beta-CD platinum complexes, and the results of high content screening (HCS) showed that Dox-loaded amino acid-modified beta-CD platinum complexes could permeate the cell membrane and enter cells, suggesting the efficient transport of Dox across the membranes with the aid of the beta-CD. We expect that the amino acid-modified beta-CD platinum complexes will deliver the antitumor drug Dox to enhance intracellular drug accumulation and such combination system showed great potential as an antitumor drug. PMID- 24803025 TI - Inductively coupled plasma mass spectrometry for metallodrug development: albumin binding and serum distribution of cytotoxic cis- and trans-isomeric platinum(II) complexes. AB - Binding to plasma proteins is one of the major metabolic pathways of metallodrugs. In the case of platinum-based anticancer drugs, it is the interaction with serum albumin that affects most strongly their in vivo behavior. Since both the configuration, i.e. cis-trans-isomerism, and the nature of leaving groups have an effect on the reactivity of Pt(II) coordination compounds toward biomolecules, a set of cis- and trans-configured complexes with halide leaving groups (Cl(-), Br(-), and I(-)) and 2-propanone oxime as carrier ligands was chosen for this study. Binding experiments were performed both with albumin and human serum and the Pt content in ultrafiltrates was quantified using inductively coupled plasma mass spectrometry. In order to shed light on the binding mechanism, the albumin binding constant (KHSA) and the octanol-water partition coefficient (P) were experimentally determined and relationships between log KHSA and log P were explored. The correlation was found significant only for cis configured platinum complexes (R(2)=0.997 and standard deviation=0.02), indicating a certain contribution of the nonspecific binding which is largely dominated by the lipophilicity of compounds. In contrast, for trans-complexes a specific molecular recognition element plays a significant role. The participation of albumin in drug distribution in blood serum was assessed using an equilibrium distribution model and by comparing the percentage binding in the albumin and serum-protein fractions. Irrespective of the compound polarity, albumin contributes from 85 to 100% to the overall binding in serum. PMID- 24803026 TI - Two water-soluble copper(II) complexes: synthesis, characterization, DNA cleavage, protein binding activities and in vitro anticancer activity studies. AB - Two water-soluble ternary copper(II) complexes of [Cu(L)Cl](ClO4) (1) and [Cu(L)Br2] (2) (L=(2-((quinolin-8-ylimino)methyl)pyridine)) were prepared and characterized by various physico-chemical techniques. Both 1 and 2 were structurally characterized by X-ray crystallography. The crystal structures show the presence of a distorted square-pyramidal CuN3Cl2 (1) or CuN3Br2 (2) geometry in which Schiff-base L acts as a neutral tridentate ligand. Both complexes present intermolecular pi-pi stacking interactions between quinoline and pyridine rings. The interaction of two complexes with CT-DNA (calf thymus-DNA) and BSA (bovine serum albumin) was studied by means of various spectroscopy methods, which revealed that 1 and 2 could interact with CT-DNA through intercalation mode, and could quench the intrinsic fluorescence of BSA in a static quenching process. Furthermore, the competition experiment using Hoechst 33258 indicated that two complexes may bind to CT-DNA by a minor groove. DNA cleavage experiments indicate that the complexes exhibit efficient DNA cleavage activities without any external agents, and hydroxyl radical (HO) and singlet oxygen ((1)O2) may serve as the major cleavage active species. Notably, the in vitro cytotoxicity of the complexes on three human tumor cells lines (HeLa, MCF-7, and A549) demonstrates that two compounds have broad-spectrum antitumor activity with quite low IC50 ranges of 0.43-1.85MUM. Based on the cell cycle experiments, 1 and 2 could delay or inhibit cell cycle progression through the S phase. PMID- 24803027 TI - Editing our way to regeneration. AB - Transcription is the primary regulatory step to gene expression. However, there are numerous post-transcriptional mechanisms that are also crucial for developing the transcritptome, and the subsequent proteome, signature of any physiological setting. Organ and tissue regeneration is one such physiological setting that requires the rapid development of an environment that can supply all of the necessary molecular and cellular signalling needs necessary to attenuate infection, remove dead or necrotic cells, provide structural stability and finally replenish the compromised area with functional cells. The post transcriptional regulatory mechanisms that have the ability to heavily influence the molecular and cellular pathways associated with regeneration are slowly being characterized. This mini-review will further clarify the possible regulation of regeneration through adenosine-to-inosine (A-I) RNA editing; a post transcriptional mechanism that can affect the molecular and cellular pathways associated with functional restoration of damaged tissues and organs through discrete nucleotide changes in RNA transcripts. It is hoped that the intriguing links made between A-I RNA editing and regeneration in this mini-review will encourage further comparative studies into this infant field of research. PMID- 24803028 TI - Large scale and orientation-controllable nanotip structures on CuInS2, Cu(In,Ga)S2, CuInSe2, and Cu(In,Ga)Se2 by low energy ion beam bombardment process: growth and characterization. AB - One-step facile methodology to create nanotip arrays on chalcopyrite materials (such as CuInS2, Cu(In,Ga)S2, CuInSe2, and Cu(In,Ga)Se2) via a low energy ion beam bombardment process has been demonstrated. The mechanism of formation for nanotip arrays has been proposed by sputtering yields of metals and reduction of metals induced by the ion beam bombardment process. The optical reflectance of these chalcopyrite nanotip arrays has been characterized by UV-vis spectrophotometer and the efficient light-trapping effect has been observed. Large scale (~4'') and high density (10(10) tips/cm(2)) of chalcopyrite nanotip arrays have been obtained by using low ion energy (< 1 kV), short processing duration (< 30 min), and template-free. Besides, orientation and length of these chalcopyrite nanotip arrays are controllable. Our results can be the guide for other nanostructured materials fabrication by ion sputtering and are available for industrial production as well. PMID- 24803029 TI - Fluoroalkylated alpha,beta-unsaturated imines as synthons for the preparation of fluorinated triazinane-2,4-diones and dihydropyrimidin-2(1H)-ones. AB - A regioselective addition of isocyanates to fluoroalkylated alpha,beta unsaturated imines 1 is described. Fluoroalkyl-substituted triazinane-2,4-diones 4 are obtained by the reaction of phenyl isocyanate with fluorinated imines 1, while fluorinated dihydropyridin-2(1H)-ones 7 are prepared when tosyl isocyanate is used. Tetrahydro-pyridin-2(1H)-one 10 is obtained by catalytic reduction of dihydropyridin-2(1H)-one 7. Computational studies are performed to explain the different behaviors of both isocyanates and the mechanisms of the processes. PMID- 24803030 TI - Development of a SPE-LC/MS/MS method for simultaneous quantification of baicalein, wogonin, oroxylin A and their glucuronides baicalin, wogonoside and oroxyloside in rats and its application to brain uptake and plasma pharmacokinetic studies. AB - This study aims to identify and quantify the six major bioactive flavones of the traditional Chinese medicine Scutellariae Radix (RS), including baicalein, baicalin, wogonin, wogonoside, oroxylin A and oroxyloside in rat after oral administration of a standardized RS extract. A novel, sensitive and selective method for simultaneous determination of these six analytes in rat brain and plasma using solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC/MS/MS) was developed and fully validated. The lower limits of quantification (LLOQs) for the six RS flavones in brain tissue were 0.02nmol/g. The LLOQs in plasma were 0.005nmol/ml for B, W and OA, 0.025nmol/ml for WG and OAG, and 0.1875nmol/ml for BG. The current study provides novel evidence of the presence of all the tested RS flavones and an isoform of BG (BG', probably baicalein-6-O-glucuronide) in the rat brain after oral administration of RS extract, suggesting their ability to permeate through the blood-brain barrier. The method was also successfully applied to the pharmacokinetic study of all these analytes in plasma after oral administration of RS extract (300mg/kg) to Sprague-Dawley rats. The developed assay method provides a useful tool for both preclinical and clinical investigations on the disposition of RS flavones in brain and plasma. PMID- 24803031 TI - Development and validation of UFLC-MS/MS method for determination of bosentan in rat plasma. AB - A rapid, simple and sensitive UFLC-MS/MS method was developed and validated for the determination of bosentan in rat plasma using etodolac as an internal standard (IS) after liquid-liquid extraction with diethyl ether-chloroform (4:1, v/v). Bosentan and IS were detected using electrospray ionization in positive ion multiple reaction monitoring mode by monitoring the transitions m/z 551.90 >201.90 and 288.20->172.00, respectively. Chromatographic separation was performed on the inertsil ODS-4 column with a gradient mobile phase, which consisted of 0.1% acetic acid with 5mM ammonium acetate in water for solvent A and 5mM ammonium acetate in acetonitrile-methanol (50:50, v/v) for solvent B at a flow rate of 0.3mL/min. The method was sensitive with 0.5ng/mL as the lower limit of quantitation (LLOQ) and the standard calibration curve for bosentan was linear (r>0.997) over the studied concentration range (0.5-2000ng/mL). The proposed method was fully validated by determining specificity, linearity, LLOQ, precision and accuracy, recovery, matrix effect and stability. The validated method was successfully applied to plasma samples obtained from rats. PMID- 24803032 TI - Relative in vitro growth rates of duckweeds (Lemnaceae) - the most rapidly growing higher plants. AB - Relative growth rates (RGR), doubling times (DT) and relative weekly yields (RY) of 39 clones (ecotypes) from 13 species representing all five genera of duckweeds were determined under standardised cultivation conditions. RGR ranged overall from 0.153 to 0.519 day(-1) , DT from 1.34 to 4.54 days and RY from 2.9 to 37.8 week(-1) . The RGR and RY data can be compared directly to other published findings to only a limited extent on account of missing clonal designations for and limited accessibility to previously investigated clones, as well as the use of different data denominators. However, they are consistent with the published results of other comparative duckweed studies of similar scope in showing that RGR does not vary primarily at the level of the genus or species, but rather reflects the adaptation of individual clones to specific local conditions. The RGR data support the widely held assumption that duckweeds can grow faster than other higher plants and that they can thus surpass land-based agricultural crops in productivity. Duckweeds are highly promising for the production of biomass for nutrition and energy, but extensive clonal comparison will be required to identify the most suitable isolates for this purpose. PMID- 24803033 TI - Daily sodium butyrate enema for the prevention of radiation proctitis in prostate cancer patients undergoing radical radiation therapy: results of a multicenter randomized placebo-controlled dose-finding phase 2 study. AB - PURPOSE: To evaluate the efficacy of sodium butyrate enemas (NABUREN) in prostate cancer radiation therapy (RT) in reducing the incidence, severity, and duration of acute RT-induced proctitis. METHODS AND MATERIALS: 166 patients, randomly allocated to 1 of 4 groups (rectal sodium butyrate 1 g, 2 g, or 4 g daily or placebo), were treated with NABUREN during and 2 weeks after RT. The grade of proctitis was registered in a daily diary. The correlation between NABUREN and proctitis was investigated through chi(2) statistics. The toxicity endpoints considered were as follows: total number of days with grade >=1 proctitis (>=G1); total number of days with grade >=2 proctitis (>=G2); >=G1 and >=G2 proctitis lasting at least 3 and 5 consecutive days starting from week 4 (>=G1+3d, >=G2+3d); damaging effects of RT on rectal mucosa as measured by endoscopy. The relationship between endpoints and pretreatment morbidities, hormonal therapy, presence of diabetes or hypertension, abdominal surgery, or hemorrhoids was investigated by univariate analysis. RESULTS: The patients were randomly allocated to the 4 arms. No difference in the distribution of comorbidities among the arms was observed (P>.09). The mean >=G1 and >=G2 proctitis were 7.8 and 4.9 for placebo and 8.9 and 4.7 for the NABUREN group, respectively. No favorable trend in reduction of incidence, severity, and duration of >=G1 and >=G2 proctitis was observed with NABUREN use. In univariate analysis, >=G1+3d toxicity was found to be related to hemorrhoids (P=.008), and a slight correlation was found between >=G2 proctitis and hormonal therapy (P=.06). The RT effects on rectal mucosa as based on endoscopic assessment were mainly related to diabetes (P<.01). Endoscopy data at 6 week showed no significant difference between the placebo and butyrate arms. The other investigated endpoints were not correlated with any of the clinical risk factors analyzed. CONCLUSION: There was no evidence of efficacy of NABUREN in reducing the incidence, severity, and duration of acute radiation proctitis. There was a correlation between some endpoints and clinical risk factors. PMID- 24803034 TI - Neurochemical evidence of potential neurotoxicity after prophylactic cranial irradiation. AB - PURPOSE: To examine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid beta-related processes could characterize the neurochemical response to cranial radiation. METHODS AND MATERIALS: Before prophylactic cranial irradiation (PCI) of patients with small cell lung cancer, each patient underwent magnetic resonance imaging of the brain, lumbar puncture, and Mini-Mental State Examination of cognitive function. These examinations were repeated at approximately 3 and 12 months after radiation. RESULTS: The major findings were as follows. (1) Cerebrospinal fluid markers for neuronal and neuroglial injury were elevated during the subacute phase after PCI. Neurofilament and T-tau increased 120% and 50%, respectively, after PCI (P<.05). The same was seen for the neuroglial markers YKL-40 and glial fibrillary acidic protein, which increased 144% and 106%, respectively, after PCI (P<.05). (2) The levels of secreted amyloid precursor protein-alpha and -beta were reduced 44% and 46%, respectively, 3 months after PCI, and the levels continued to decrease as long as 1 year after treatment (P<.05). (3) Mini-Mental State Examination did not reveal any cognitive decline, indicating that a more sensitive test should be used in future studies. CONCLUSION: In conclusion, we were able to detect radiation therapy-induced changes in several markers reflecting neuronal injury, inflammatory/astroglial activation, and altered amyloid precursor protein/amyloid beta metabolism, despite the low number of patients and quite moderate radiation doses (20-30 Gy). These changes are hypothesis generating and could potentially be used to assess the individual risk of developing long-term symptoms of chronic encephalopathy after PCI. This has to be evaluated in large studies with extended clinical follow-up and more detailed neurocognitive assessments. PMID- 24803035 TI - Dosimetric consequences of interobserver variability in delineating the organs at risk in gynecologic interstitial brachytherapy. AB - PURPOSE: To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy. METHODS AND MATERIALS: The rectum, bladder, and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using kappa statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SD(TOT)) was calculated. RESULTS: The population mean +/- 1 standard deviation of kappa, CIgen, and volume CV were, respectively: 0.77 +/- 0.06, 0.70 +/- 0.08, and 20% +/- 6% for bladder; 0.74 +/- 06, 0.67 +/- 0.08, and 20% +/- 5% for rectum; and 0.33 +/- 0.20, 0.26 +/- 0.17, and 82% +/- 42% for sigmoid. Dosimetric variability was as follows: for bladder, CV = 31% +/- 19% (SD(TOT) = 72 +/- 64 Gy) for D0.1cc and CV = 16% +/- 10% (SD(TOT) = 9 +/- 6 Gy) for D2cc; for rectum, CV = 11% +/- 5% (SD(TOT) = 16 +/- 17 Gy) for D0.1cc and CV = 7% +/- 2% (SD(TOT) = 4 +/- 3 Gy) for D2cc; for sigmoid, CV = 39% +/- 28% (SD(TOT) = 12 +/- 18 Gy) for D0.1cc and CV = 34% +/- 19% (SD(TOT) = 4 +/- 4 Gy) for D2cc. CONCLUSIONS: Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low dose regions in the cases analyzed in this study. PMID- 24803036 TI - Linear accelerator-based radiosurgery alone for arteriovenous malformation: more than 12 years of observation. AB - PURPOSE: Although radiosurgery is an accepted treatment method for intracranial arteriovenous malformations (AVMs), its long-term therapeutic effects have not been sufficiently evaluated, and many reports of long-term observations are from gamma-knife facilities. Furthermore, there are few reported results of treatment using only linear accelerator (LINAC)-based radiosurgery (LBRS). METHODS AND MATERIALS: Over a period of more than 12 years, we followed the long-term results of LBRS treatment performed in 51 AVM patients. RESULTS: The actuarial obliteration rates, after a single radiosurgery session, at 3, 5, 10, and 15 years were 46.9%, 54.0%, 64.4%, and 68.0%, respectively; when subsequent radiosurgeries were included, the rates were 46.9%, 61.3%, 74.2%, and 90.3%, respectively. Obliteration rates were significantly related to target volumes >=4 cm(3), marginal doses >=12 Gy, Spetzler-Martin grades (1 vs other), and AVM scores >=1.5; multivariate analyses revealed a significant difference for target volumes >=4 cm(3). The postprocedural actuarial symptomatic radiation injury rates, after a single radiation surgery session, at 5, 10, and 15 years were 12.3%, 16.8%, and 19.1%, respectively. Volumes >=4 cm(3), location (lobular or other), AVM scores >=1.5, and the number of radiosurgery were related to radiation injury incidence; multivariate analyses revealed significant differences associated with volumes >=4 cm(3) and location (lobular or other). CONCLUSIONS: Positive results can be obtained with LBRS when performed with a target volume <=4 cm(3), an AVM score <=1.5, and >=12 Gy radiation. Bleeding and radiation injuries may appear even 10 years after treatment, necessitating long term observation. PMID- 24803037 TI - Refusal of curative radiation therapy and surgery among patients with cancer. AB - PURPOSE: Surgery and radiation therapy represent the only curative options for many patients with solid malignancies. However, despite the recommendations of their physicians, some patients refuse these therapies. This study characterized factors associated with refusal of surgical or radiation therapy as well as the impact of refusal of recommended therapy on patients with localized malignancies. METHODS AND MATERIALS: We used the Surveillance, Epidemiology, and End Results program to identify a population-based sample of 925,127 patients who had diagnoses of 1 of 8 common malignancies for which surgery and/or radiation are believed to confer a survival benefit between 1995 and 2008. Refusal of oncologic therapy, as documented in the SEER database, was the primary outcome measure. Multivariable logistic regression was used to investigate factors associated with refusal. The impact of refusal of therapy on cancer-specific mortality was assessed with Fine and Gray's competing risks regression. RESULTS: In total, 2441 of 692,938 patients (0.4%) refused surgery, and 2113 of 232,189 patients (0.9%) refused radiation, despite the recommendations of their physicians. On multivariable analysis, advancing age, decreasing annual income, nonwhite race, and unmarried status were associated with refusal of surgery, whereas advancing age, decreasing annual income, Asian American race, and unmarried status were associated with refusal of radiation (P<.001 in all cases). Refusal of surgery and radiation were associated with increased estimates of cancer-specific mortality for all malignancies evaluated (hazard ratio [HR], 2.80, 95% confidence interval [CI], 2.59-3.03; P<.001 and HR 1.97 [95% CI, 1.78-2.18]; P<.001, respectively). CONCLUSIONS: Nonwhite, less affluent, and unmarried patients are more likely to refuse curative surgical and/or radiation-based oncologic therapy, raising concern that socioeconomic factors may drive some patients to forego potentially life-saving care. PMID- 24803038 TI - Risk of radiation-induced malignancy with heterotopic ossification prophylaxis: a case-control analysis. AB - PURPOSE: To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). METHODS AND MATERIALS: A matched case-control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. RESULTS: A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. CONCLUSION: We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not. PMID- 24803039 TI - Patient-reported voice and speech outcomes after whole-neck intensity modulated radiation therapy and chemotherapy for oropharyngeal cancer: prospective longitudinal study. AB - PURPOSE: To describe voice and speech quality changes and their predictors in patients with locally advanced oropharyngeal cancer treated on prospective clinical studies of organ-preserving chemotherapy-intensity modulated radiation therapy (chemo-IMRT). METHODS AND MATERIALS: Ninety-one patients with stage III/IV oropharyngeal cancer were treated on 2 consecutive prospective studies of definitive chemoradiation using whole-field IMRT from 2003 to 2011. Patient reported voice and speech quality were longitudinally assessed from before treatment through 24 months using the Communication Domain of the Head and Neck Quality of Life (HNQOL-C) instrument and the Speech question of the University of Washington Quality of Life (UWQOL-S) instrument, respectively. Factors associated with patient-reported voice quality worsening from baseline and speech impairment were assessed. RESULTS: Voice quality decreased maximally at 1 month, with 68% and 41% of patients reporting worse HNQOL-C and UWQOL-S scores compared with before treatment, and improved thereafter, recovering to baseline by 12-18 months on average. In contrast, observer-rated larynx toxicity was rare (7% at 3 months; 5% at 6 months). Among patients with mean glottic larynx (GL) dose <=20 Gy, >20 30 Gy, >30-40 Gy, >40-50 Gy, and >50 Gy, 10%, 32%, 25%, 30%, and 63%, respectively, reported worse voice quality at 12 months compared with before treatment (P=.011). Results for speech impairment were similar. Glottic larynx dose, N stage, neck dissection, oral cavity dose, and time since chemo-IMRT were univariately associated with either voice worsening or speech impairment. On multivariate analysis, mean GL dose remained independently predictive for both voice quality worsening (8.1%/Gy) and speech impairment (4.3%/Gy). CONCLUSIONS: Voice quality worsening and speech impairment after chemo-IMRT for locally advanced oropharyngeal cancer were frequently reported by patients, underrecognized by clinicians, and independently associated with GL dose. These findings support reducing mean GL dose to as low as reasonably achievable, aiming at <=20 Gy when the larynx is not a target. PMID- 24803040 TI - Toward magnetic resonance-only simulation: segmentation of bone in MR for radiation therapy verification of the head. AB - PURPOSE: To develop a practical method to localize bones in magnetic resonance (MR) images, to create "computed tomography-like" MR images (ctMRI) that could be used for radiation therapy verification, and to generate MR-based digitally reconstructed radiographs (DRR). METHODS AND MATERIALS: Using T1-weighted MR images, an air mask was derived from the manual contouring of all airways within the head and neck region using axial images at 6 anatomic levels. Compact bone, spongy bone, and soft tissue masks were then automatically generated using the statistical data derived from MR intensities and the air mask. ctMRI were then generated by mapping the MR intensities of the voxels within these masks into the CT number ranges of corresponding tissues. MR-based DRRs created from ctMRI were quantitatively evaluated using the co-registered MR and CT head images of 20 stereotactic radiosurgery patients. Ten anatomical points, positioned on the skull segmented using a threshold of 300 HU, in CT and ctMRI, were used to determine the differences in distance between MR-based DRRs and CT-based DRRs, and to evaluate the geometric accuracy of ctMRI and MR-based DRRs. RESULTS: The bony structures were identified on ctMRI and were visible in the MR-based DRRs. From the 20 patient cases, the mean geometric difference and standard deviation between the 10 anatomical points on MR-based and CT-based DRRs was -0.05 +/- 0.85 mm, respectively. This included uncertainty in image fusion. The maximum distance difference was 1.88 mm. CONCLUSIONS: A practical method was developed to segment bone from MR images. The ctMRI created can be used for radiation treatment verification when MR-only simulation is performed. MR-based DRRs can be used in place of CT-based DRRs. PMID- 24803041 TI - Limited role for biliary stent as surrogate fiducial marker in pancreatic cancer: stent and intratumoral fiducials compared. AB - PURPOSE: Because of low soft-tissue contrast of cone beam computed tomography (CBCT), fiducial markers are often used for radiation therapy patient setup verification. For pancreatic cancer patients, biliary stents have been suggested as surrogate fiducials. Using intratumoral fiducials as standard for tumor position, this study aims to quantify the suitability of biliary stents for measuring interfractional and respiratory-induced position variations of pancreatic tumors. METHODS AND MATERIALS: Eleven pancreatic cancer patients with intratumoral fiducials and a biliary stent were included in this study. Daily CBCT scans (243 in total) were registered with a reference CT scan, based on bony anatomy, on fiducial markers, and on the biliary stent, respectively. We analyzed the differences in tumor position (ie, markers center-of-mass position) among these 3 registrations. In addition, we measured for 9 patients the magnitude of respiratory-induced motion (MM) of the markers and of the stent on 4-dimensional CT (4DCT) and determined the difference between these 2 magnitudes (DeltaMM). RESULTS: The stent indicated tumor position better than bony anatomy in 67% of fractions; the absolute difference between the markers and stent registration was >5 mm in 46% of fractions and >10 mm in 20% of fractions. Large PTV margins (superior-inferior direction, >19 mm) would be needed to account for this interfractional position variability. On 4DCT, we found in superior-inferior direction a mean DeltaMM of 0.5 mm (range, -2.6 to 4.2 mm). CONCLUSIONS: For respiratory-induced motion, the mean DeltaMM is small, but for individual patients the absolute difference can be >4 mm. For interfractional position variations, a stent is, on average, a better surrogate fiducial than bony anatomy, but large PTV margins would still be required. Therefore, intratumoral fiducials are recommended for online setup verification for all pancreatic patients scheduled for radiation therapy, including patients with a biliary stent. PMID- 24803044 TI - Introduction. PMID- 24803042 TI - ASCO 2013: bevacizumab and glioblastoma--a marriage dissolution? AB - The prognosis of patients affected by glioblastoma (GBM) is grim albeit the integrated therapeutic approaches now available. Standard surgery followed by chemoradiation median overall survival (OS) reaches 15 months in clinical trials. Despite primary treatment, recurrence is the rule in patients with GBM and for them OS ranges from 6 to 9 months. In recent years, the therapeutic scenario has been profoundly changed in view of the promising results obtained by bevacizumab (Avastin * *Avastin is a registered trade name of Bevacizumab, F. Hoffmann-La Roche Ltd, Basel, Switzerland. ), the most promising anti-angiogenesis agent, in two clinical trials. The results of both trials were presented at the last ASCO meeting in Chicago. Progression free survival was significantly improved with an acceptable safety and tolerability profile but surprisingly quality of life was preserved only in the AVAGlio trial. However, both studies showed that overall survival was not improved adding bevacizumab to temozolomide and radiotherapy. PMID- 24803045 TI - "Having a girlfriend without knowing it". AB - Abstract This article provides a qualitative analysis of the intimate friendships of 80 adolescent and young adult sexual-minority women who were interviewed as part of an ongoing longitudinal study. Many reported having participated in a same-sex best friendship that they considered as committed, intimate, passionate, and intense as a romantic relationship. These "passionate friendships" typically combined components of the normative heterosexual friendship script with components of the normative romantic relationship script. For example, although passionate friendships rarely involved sexual contact, they frequently involved forms of physical intimacy (such as cuddling and hand-holding) that are usually considered exclusive to romantic relationships. Although such intense friendships are typically interpreted as unrequited love affairs, this misrepresents the unique nature of these bonds. Because such relationships challenge conventional notions about the distinctions between friendship and romance, as well as distinctions between heterosexual and sexual-minority women, they have important implications for understanding the interplay between emotional and sexual feelings in the close relationships of all women. PMID- 24803046 TI - Against all odds. AB - Abstract Research with gay, lesbian and bisexual adolescents has tended to focus on their psychosocial risk factors, with little attention paid to their dating experiences. Unique in its focus on younger, high school-age women, the present study examined dating relationships among 112 lesbian and bisexual women, ages 13 to 18. Characteristics of the young women's dating relationships were explored, as well as dating stress, the presence of verbal and physical abuse in their dating relationships, and psychosocial factors associated with dating. Findings indicate that, despite potential barriers, adolescent lesbian and bisexual women actively date. Relationship concerns requiring supportive interventions by youth serving professionals are identified and study limitations are discussed. PMID- 24803047 TI - The impact of group membership on lesbians' physical appearance. AB - Abstract The impact of lesbian group membership upon physical appearance was examined among 81 young lesbians (ages 18-30) who participated in a questionnaire study. Most participants indicated making distinct but modest changes in their physical appearance after coming out as lesbians. These changes were in the direction of their pre-coming out conceptions of lesbians as being butch or androgynous in appearance. A majority reported cutting their hair shorter, wearing more comfortable shoes, or adopting a less traditionally feminine appearance after coming out. Participants also said they significantly less often wore dresses, used makeup, and shaved their legs and underarms. A significant decrease in body weight concern also occurred after coming out. Other changes in physical appearance are discussed. Participants believed that the changes were influenced by the opinions of other lesbians, their desire to signal prospective partners, and by becoming more comfortable with themselves. Implications of these results are discussed in terms of peer group norms, group identity, and sexual signaling. PMID- 24803048 TI - Butch/Femme in the personal advertisements of lesbians. AB - Abstract Personal advertisements placed by lesbians were examined to determine how often butch/femme descriptors were used: (a) as a form of self-identification or (b) to indicate the type of partner being sought. The 388 personal advertisements were drawn from 16 alternative newspapers around the U.S., as well as from one Internet site (Qworld) that contained personal ads by lesbians. Each advertisement was coded for the presence or absence of butch/femme descriptors. The majority of advertisers did not mention butch or femme labels either in terms of self-identity or type of partner sought. Among the minority of advertisers who self-identified as butch or femme, more described themselves as femme than butch. Among advertisers seeking butch or femme partners, femme partners were sought most often. Explanations for the preference for femme lesbians were explored. PMID- 24803049 TI - Lesbians in love. AB - Abstract Lesbians often begin romantic relationships with high hopes that their relationships will be satisfying and long-lasting. Why do some women maintain committed and stable relationships while others do not? This article considers factors that affect commitment and stability among lesbian couples. We begin by reviewing previous empirical research on the topic. Next, we test a leading model of commitment using survey data from 301 lesbian couples who participated in the American Couples Study (Blumstein & Schwartz, 1983). According to Caryl Rusbult's model (1983), an individual's commitment to a relationship is affected by three general factors: satisfaction, the quality of alternatives to the current relationship, and investments made in the relationship. In turn, a woman's degree of commitment influences relationship stability. Path analysis provided strong support for Rusbult's model. Nonetheless, this model did not fully explain the sources of commitment and stability in lesbian relationships. Consequently, we consider unique aspects of the social environment that may affect commitment and stability in lesbian relationships. PMID- 24803050 TI - Not any one thing. AB - Abstract The complex legacy of social class on African American lesbians in relationships was examined using a case study approach. Six highly educated, middle class African American lesbians in their mid-thirties to mid-fifties were interviewed in this exploratory study. Differences in social class were perceived as the reason for the conflict in these relationships. Conversely, similarities in social class were described as making relationships operate more smoothly. Although similarities in race can generate shared cultural values, it is the meaning given to a couple's perceived similarities and differences that influences the quality of the communication between partners. These preliminary findings highlight a previously unexplored contribution to the dynamics in African American lesbian relationships. PMID- 24803051 TI - A butch among the belles. AB - Abstract This memoir of a 65-year-old "butch" lesbian describes her growing-up days in the South and her subsequent professional identity as a university professor and psychologist. The article includes feelings about being raised as a girl while feeling male. Personal reactions to family pressures to conform to a rigid sex role are noted and some attention is given to the effects of living an adult life in the closet. PMID- 24803052 TI - Lesbian dating and courtship from young adulthood to midlife. AB - Abstract Lesbian dating and courtship were explored based on interviews with 38 predominantly white lesbians (ages 22-63) representing young adult, adult, and midlife age groups. Friendship was found to be the most widely used courtship script across all age groups, followed by the sexually explicit and romance scripts, with friendship and romance scripts being preferred. Unique aspects of lesbian dating cited by participants included freedom from gender roles, heightened intimacy/friendship, the rapid pace of lesbian relationship development, and the effects of prejudice. Friendship was found to be differentiated from romance by two main criteria: emotional intensity and sexual energy or contact. Verbal declarations of interest and nonverbal behaviors were the primary means of communicating sexual attraction. Few lesbians adhered to traditional gender roles in dating, and those who reported assuming the feminine reactive role nevertheless rejected the traditional notion that women should limit sexual contact. Overall, midlife lesbians were more purposive in their dating and more free from gender roles. Specifically, they were more concerned about the "attachment-worthiness" of a prospective partner and were significantly more likely than young adults to view dating as having a serious goal, to proceed at a rapid pace, to ask for a date, and to initiate physical intimacy. PMID- 24803053 TI - Beyond "lesbian bed death". AB - Abstract Myths about lesbian sexuality continue to exist but none have received such widespread discussion as "lesbian bed death", a myth that has become a clinical entity even though it lacks definitional clarity and empirical validity. Its users, often relying on gender socialization theory, overgeneralize and essentialize lesbian women's sexual experiences, obscuring the diversity of lesbian sexual experience. This paper critiques the use of the term "lesbian bed death" and provides examples from sex research and lesbian literature of the panoply of lesbian passions and play. PMID- 24803054 TI - Lesbian intimate partner violence. AB - Abstract Researchers have been investigating partner violence for more than 20 years, yet there is a discernible absence of research on interpersonal violence among lesbian couples. Three aspects of lesbian battering are reviewed here. First, the incidence rates and distinct forms that lesbian battering might assume are discussed. Next, the dynamics and correlates of lesbian abuse are highlighted. The concluding section focuses on suggestions for intervention. PMID- 24803055 TI - Couples therapy for lesbians. AB - Abstract Lesbian couples are similar to their heterosexual counterparts in many ways, but there are some ways in which lesbian relationships are unique. The focus here is on how couples therapists can be well informed about some key aspects of lesbian couples and their experiences, most notably their experience of homophobia, and the phenomenon of merger in the lesbian relationship. Because of the pervasive nature of homophobia, it is essential that therapists recognize that homophobia impacts lesbians and their relationships in a myriad of ways. Merger has often been viewed as a problem in lesbian relationships, but the emotional intensity of such relationships should not be misunderstood or interpreted as problematic; to do so assumes that heterosexual relationships are the norm and that relationship styles which differ from this norm are somehow aberrant (Burch, 1986). Therapists who understand these aspects of the lesbian relationship are better prepared to provide an affirmative therapy experience to the lesbian couple. PMID- 24803056 TI - Young Sexual Minority Women's Perceptions of Cross-Generational Friendships with Older Lesbians. AB - Abstract Perspectives on cross-generational friendships with older lesbians were explored using informal group interviews with two groups of young sexual minority women (N = 16), ages 15 to 25. A majority of the participants were women of color; all were regular members of weekly discussion groups at two lesbian, gay, bisexual and transgendered centers on the East Coast. About half of the young women were interested in having friendships with older lesbians, citing the importance of such relationships for helping younger women cope with coming out, providing a sense of community, and serving as role models and mentors. Others were less interested in becoming friends with older lesbians, citing the generation gap as being an insurmountable obstacle. The participants also perceived that many older lesbians were not interested in cross-generational friendships. Ways to create opportunities for forming cross-generational friendships were identified. PMID- 24803057 TI - Building bridges. AB - Abstract Friendships between lesbians and heterosexual women were explored using a sample of 47 mostly White women (23 lesbians and 24 heterosexual women), ages 18 to 25, that reported at least one close lesbian-heterosexual woman friendship. A majority of participants indicated that friendships between lesbians and heterosexual women had both uniquely positive and negative aspects that could be attributed to the difference in sexual identity. Positive aspects included socio emo-tional benefits, opportunities for learning, and societal benefits. Negative aspects included anxiety about sexuality, doubts regarding mutual understanding, clashes of perspectives and experience, and societal stressors. Implications of the findings for challenging current social inequities associated with sexual identities were explored. PMID- 24803059 TI - Temporal changes in microbial ecology and geochemistry in produced water from hydraulically fractured Marcellus shale gas wells. AB - Microorganisms play several important roles in unconventional gas recovery, from biodegradation of hydrocarbons to souring of wells and corrosion of equipment. During and after the hydraulic fracturing process, microorganisms are subjected to harsh physicochemical conditions within the kilometer-deep hydrocarbon-bearing shale, including high pressures, elevated temperatures, exposure to chemical additives and biocides, and brine-level salinities. A portion of the injected fluid returns to the surface and may be reused in other fracturing operations, a process that can enrich for certain taxa. This study tracked microbial community dynamics using pyrotag sequencing of 16S rRNA genes in water samples from three hydraulically fractured Marcellus shale wells in Pennsylvania, USA over a 328-day period. There was a reduction in microbial richness and diversity after fracturing, with the lowest diversity at 49 days. Thirty-one taxa dominated injected, flowback, and produced water communities, which took on distinct signatures as injected carbon and electron acceptors were attenuated within the shale. The majority (>90%) of the community in flowback and produced fluids was related to halotolerant bacteria associated with fermentation, hydrocarbon oxidation, and sulfur-cycling metabolisms, including heterotrophic genera Halolactibacillus, Vibrio, Marinobacter, Halanaerobium, and Halomonas, and autotrophs belonging to Arcobacter. Sequences related to halotolerant methanogenic genera Methanohalophilus and Methanolobus were detected at low abundance (<2%) in produced waters several months after hydraulic fracturing. Five taxa were strong indicators of later produced fluids. These results provide insight into the temporal trajectory of subsurface microbial communities after "fracking" and have important implications for the enrichment of microbes potentially detrimental to well infrastructure and natural gas fouling during this process. PMID- 24803060 TI - Accuracy of polimerase chain reaction for the diagnosis of pleural tuberculosis. AB - INTRODUCTION: Polymerase chain reaction (PCR)-based techniques to detect Mycobacterium tuberculosis DNA in respiratory specimens have been increasingly used to diagnose pulmonary tuberculosis. Their use in non-respiratory specimens to diagnose extrapulmonary tuberculosis is, however, controversial. In this study, we estimated the accuracy of three in-country commercialized PCR-based diagnostic techniques in pleural fluid samples for the diagnosis of pleural tuberculosis. METHODS: Patients underwent thoracenthesis for diagnosis purposes; pleural fluid aliquots were frozen and subsequently submitted to two real time PCR tests (COBAS((r))TAQMAN((r))MTB and Xpert((r))MTB/Rif) and one conventional PCR test (Detect-TB((r))). Two different reference standards were considered: probable tuberculosis (based on clinical grounds) and confirmed tuberculosis (bacteriologically or histologically). RESULTS: Ninety-three patients were included, of whom 65 with pleural tuberculosis, 35 of them confirmed. Sensitivities were 29% for COBAS((r))TAQMAN((r))MTB, 3% for Xpert((r))MTB/Rif and 3% for Detect-TB((r)); specificities were 86%, 100% and 97% respectively, considering confirmed tuberculosis. Considering all cases, sensitivities were 16%, 3% and 2%, and specificities, 86%, 100%, and 97%. DISCUSSION: Compared to the 95% sensitivity of adenosine deaminase, the most sensitive test for pleural tuberculosis, the sensitivities of the three PCR-based tests were very low. We conclude that at present, there is no major place for such tests in routine clinical use. PMID- 24803061 TI - Cutaneous malignant melanoma: update on diagnostic and prognostic biomarkers. AB - The incidence of cutaneous malignant melanoma has rapidly increased in recent years in all parts of the world, and melanoma is a leading cause of cancer death. As even relatively small melanomas may have metastatic potential, accurate assessment of progression is critical. Although diagnosis of cutaneous malignant melanoma is usually based on histopathologic criteria, these criteria may at times be inadequate in differentiating melanoma from certain types of benign nevi. As for prognosis, tumor (Breslow) thickness, mitotic rate, and ulceration have been considered the most important prognostic indicators among histopathologic criteria. However, there are cases of thin primary melanomas that have ultimately developed metastases despite complete excision. Given this, an accurate assessment of melanoma progression is critical, and development of molecular biomarkers that identify high-risk melanoma in its early phase is urgently needed. Large-scale genomic profiling has identified considerable heterogeneity in melanoma and suggests subgrouping of tumors by patterns of gene expression and mutation will ultimately be essential to accurate staging. This subgrouping in turn may allow for more targeted therapy. In this review, we aim to provide an update on the most promising new biomarkers that may help in the identification and prognostication of melanoma. PMID- 24803062 TI - Cutaneous plaques and ulnar neuropathy: challenge. PMID- 24803063 TI - Eccrine poroma and eccrine porocarcinoma in linear epidermal nevus. PMID- 24803064 TI - Negative pigment network and shiny white streaks: a dermoscopic-pathological correlation study. AB - It has been suggested that both negative pigment network (NPN) and shiny white streaks (SWS) were related to an increase of dermal collagen. To study precisely the dermoscopic-histopathologic correlation of NPN and SWS, we have performed a dermoscopic-pathological correlation study. A total of 25 skin lesions dermoscopically characterized by the presence of NPN and/or SWS, including histopathologically confirmed dermatofibroma (2), Spitz nevus (3), compound nevus (6), dysplastic nevus (7), and melanoma (7), were evaluated for the presence of NPN, SWS, and blue-white veil. The histopathologic features such as orthokeratosis, orthokeratosis plus nests of pigmented melanocytes at the junction, hypergranulosis, hypergranulosis plus nests of pigmented melanocytes at the junction, epidermal invagination plus orthokeratosis, fibrosis, lamellar fibrosis, and elongation and bridging of rete ridges were evaluated. We found a disagreement in 80% of skin lesions between NPN and fibrosis (P = 0.02). For SWS, a significant agreement emerged with hypergranulosis (76%; P = 0.01), and the same occurred with fibrosis (80%; P = 0.01). Moreover, blue-white veil also displayed a significant agreement with hypergranulosis (68%; P = 0.04). Our findings confirm the correlation of SWS with fibrosis, whereas a clear-cut histopathologic substrate of NPN could not be established. PMID- 24803066 TI - Cavernous hemangioma-like Kaposi sarcoma: a unique histopathologic variant. AB - Kaposi sarcoma (KS) is an angiolymphatic neoplasm with multifactorial etiology. Clinically, KS has been divided into 4 distinct types and 3 well-defined histologic stages. Rare reports in the literature have characterized additional unique histopathologic variants. The authors report a case of KS, confirmed with human herpesvirus type 8 and D2-40 staining, which resembled a cavernous hemangioma on histopathology. PMID- 24803067 TI - The use of fluorescence microscopy to evaluate elastic fiber pattern in melanocytic neoplasms. PMID- 24803068 TI - Intravascular natural killer cell lymphoma mimicking mycosis fungoides: a case report and review of the literature. AB - Intravascular lymphoma is a rare entity. Most cases constitute a variant of extranodal diffuse large B-cell lymphoma, and only 10% of the published cases are of T-cell or histiocytic origin. Even fewer cases of intravascular natural killer (NK) cell lymphoma have been reported. To date, only the intravascular lymphoma of B-cell linage is recognized as a distinct entity by the WHO Classification. Here, we report the clinical, morphological, immunohistochemical, and molecular findings of a 72-year-old male patient with intravascular NK-cell lymphoma of the skin who initially presented with red skin efflorescences suspicious of mycosis fungoides. A skin biopsy revealed large cell infiltrates of NK/T-cell phenotype (CD3epsilon, CD4, CD8, CD56, and TIA-1), which were localized strictly intravascularly and which were positive for Epstein-Barr virus nucleic acid EBER (Epstein-Barr virus-encoded small RNA). Molecular studies revealed a germline configuration for the T-cell receptor consistent with the possibility of an NK cell origin. At the beginning, the disease appeared to be limited to the skin with no sign of bone marrow involvement or leukemic dissemination. Chemotherapy was initiated; however, the patient subsequently developed meningiosis lymphomatosa with recurrent epileptic episodes and bone marrow infiltration with pancytopenia 7 months after primary admission. Finally, the patient passed away in a septic shock. PMID- 24803069 TI - Supraorbital cutaneous fetal rhabdomyoma of intermediate type: a case report. AB - A 7-year-old boy was presented with a long-standing slowly growing mass of the left supraorbital area. A biopsy specimen revealed a bland spindle cell proliferation with scattered polygonal cells with acidophilic cytoplasm and cross striations. Our differential diagnosis included rhabdomyoma of fetal type, leiomyoma with trapping of regenerating skeletal muscle elements, and rhabdomyomatous mesenchymal hamartoma of the skin. Immunohistochemistry demonstrated strong positivity of myoglobin and desmin as well as negativity of caldesmon, suggesting skeletal muscle lineage. The excisional specimen confirmed our diagnosis of cutaneous fetal rhabdomyoma of intermediate type. Additional immunostaining performed on the excisional specimen showed strong Wilms Tumor 1 but only a very faint and focal p63 expression. PMID- 24803070 TI - Chinese puzzle molecule: a 15 hydride, 28 copper atom nanoball. AB - The syntheses of the first rhombicuboctahedral copper polyhydride complexes [Cu28 (H)15 (S2 CNR)12 ]PF6 (NR=N(n) Pr2 or aza-15-crown-5) are reported. These complexes were analyzed by single-crystal X-ray and one by neutron diffraction. The core of each copper hydride nanoparticle comprises one central interstitial hydride and eight outer-triangular-face-capping hydrides. A further six face truncating hydrides form an unprecedented bridge between the inner and outer copper atom arrays. The irregular inner Cu4 tetrahedron is encapsulated within the Cu24 rhombicuboctahedral cage, which is further enclosed by an array of twelve dithiocarbamate ligands that subtends the truncated octahedron of 24 sulfur atoms, which is concentric with the Cu24 rhombicuboctahedron and Cu4 tetrahedron about the innermost hydride. For these compounds, an intriguing, albeit limited, H2 evolution was observed at room temperature, which is accompanied by formation of the known ion [Cu8 (H)(S2 CNR)6 ](+) upon exposure of solutions to sunlight, under mild thermolytic conditions, and on reaction with weak (or strong) acids. PMID- 24803071 TI - PEGylation of lysine residues improves the proteolytic stability of fibronectin while retaining biological activity. AB - Excessive proteolysis of fibronectin (FN) impairs tissue repair in chronic wounds. Since FN is essential in wound healing, our goal is to improve its proteolytic stability and at the same time preserve its biological activity. We have previously shown that reduced FN conjugated with polyethylene glycol (PEG) at cysteine residues is more proteolytically stable than native FN. Cysteine PEGylated FN supported cell adhesion and migration to the same extent as native FN. However, unlike native FN, cysteine-PEGylated FN was not assembled into an extracellular matrix (ECM) when immobilized. Here, we present an alternative approach in which FN is preferentially PEGylated at lysine residues using different molecular weight PEGs. We show that lysine PEGylation does not perturb FN secondary structure. PEG molecular weight, from 2 to 10 kDa, positively correlates with FN-PEG proteolytic stability. Cell adhesion, cell spreading, and gelatin binding decrease with increasing molecular weight of PEG. The 2-kDa FN PEG conjugate shows comparable cell adhesion to native FN and binds gelatin. Moreover, immobilized FN-PEG is assembled into ECM fibrils. In summary, lysine PEGylation of FN can be used to stabilize FN against proteolytic degradation with minimal perturbation to FN structure and retained biological activity. PMID- 24803073 TI - Correlation between hyperglycemia and retinopathy of prematurity. AB - BACKGROUND: Several risk factors are attributed to retinopathy of prematurity (ROP). This study was done to determine any association between hyperglycemia and ROP in premature infants. METHODS: In a retrospective case-control analysis, all infants with a gestational age (GA) < 34 weeks and a birthweight (BW) < 2000 g admitted and treated in the Neonatal Intensive Care Unit at Amirkola Children's Hospital, Iran, during March 2007-September 2010 were included. Hyperglycemia was defined as a plasma glucose level of >150 mg/dL during the hospital stay. The duration of being hyperglycemic was also recorded. All of these neonates were examined for ROP by a retinologist unaware of group assignment. The difference in the ROP incidence and also the severity of ROP was compared between the hyperglycemic and non-hyperglycemic infants. Matching was done for GA, BW, and also Clinical Risk Index for Babies score. The data were analyzed by t-test, chi(2) -test and logistic regression test and a P < 0.05 was considered significant. RESULTS: In total, 155 neonates were examined. Seventy (45.2%) of them developed ROP but 85 (54.8%) did not show any evidence of ROP. The frequency of hyperglycemia in patients with ROP was 33 (47.2%), but in those without ROP, hyperglycemia occurred in five (5.9%) (P = 0.0001). The severity of ROP showed no significant differences between the two groups (P = 0.35). The logistic regression for GA and BW showed a significant correlation between hyperglycemia and ROP (P = 0.0001). CONCLUSIONS: Hyperglycemia is an important risk factor for ROP that can be prevented along with other risk factors by accurate supervision. PMID- 24803072 TI - Gastrointestinal microbes interact with canine adipose-derived mesenchymal stem cells in vitro and enhance immunomodulatory functions. AB - Mesenchymal stem cells (MSCs) are somatic, multipotent stromal cells with potent immunomodulatory and regenerative properties. Although MSCs have pattern recognition receptors and are modulated by Toll-like receptor ligands, MSC microbial interactions are poorly defined. The objectives of this study were to determine the effect of bacterial association on MSC function. We hypothesized that gastrointestinal bacteria associate with MSCs and alter their immunomodulatory properties. The effect of MSC-microbial interactions on MSC morphology, viability, proliferation, migration, and immunomodulatory functions was investigated. MSCs associated with a remarkable array of enteric pathogens and commensal bacteria. MSC interactions with two model organisms, the pathogen Salmonella typhimurium and the probiotic Lactobacillus acidophilus, were further investigated. While ST readily invaded MSCs, LB adhered to the MSC plasma membrane. Neither microbe induced MSC death, degeneration, or diminished proliferation. Microbial association did not upregulate MHC-II, CD80/86, or CD1 expression. MSC-microbial interaction significantly increased transcription of key immunomodulatory genes, including COX2, IL6, and IL8, coupled with significantly increased prostaglandin E2 (PGE2), interleukin (IL)6, and IL8 secretion. MSC-ST coincubation resulted in increased MSC expression of CD54, and significant augmentation of MSC inhibition of mitogen-induced T-cell proliferation. T-cell proliferation was partially restored when PGE2 secretion was blocked from ST-primed MSCs. MSC-microbe interactions have a profound effect on MSC function and may be pivotal in a variety of clinical settings where MSCs are being explored as potential therapeutics in the context of microbial communities, such as Crohn's disease, chronic nonhealing wounds, and sepsis. PMID- 24803075 TI - Influence of ABO genotype and phenotype on angiotensin-converting enzyme plasma activity. AB - INTRODUCTION: ABO rs495828 polymorphism has recently been associated with risk of hypertension and cough induced by angiotensin-converting enzyme (ACE) inhibitors, which could be due to low ACE plasma activity. To study whether ABO rs495828 is associated with ACE activity. The association between ABO genotype and phenotype, and differences in ACE activity between the ABO phenotype groups were also studied. SUBJECTS AND METHODS: We genotyped 168 subjects for rs495828. ACE plasma activity and ABO histo-blood group were measured in all minor allele homozygous subjects (TT) that agreed to participate in the study (n=8) and in age- and gender-matched heterozygous subjects (GT; n=8) and major allele homozygous subjects (GG; n=8). RESULTS: A non-significant trend was found in ACE activity among rs495828 genotype groups; however the polymorphism was significantly associated with ABO phenotype (p=0.007), which in turn was associated with ACE activity (p=0.029). CONCLUSION: These results provide new evidence for the ABO ACE relationship. Although the genetic marker studied here may be involved somehow, ABO phenotype is shown to be a better predictor of ACE plasma activity. PMID- 24803076 TI - A quality-by-design approach to risk reduction and optimization for human embryonic stem cell cryopreservation processes. AB - It is well documented that cryopreservation and resuscitation of human embryonic stem cells (hESCs) is complex and ill-defined, and often suffers poor cell recovery and increased levels of undesirable cell differentiation. In this study we have applied Quality-by-Design (QbD) concepts to the critical processes of slow-freeze cryopreservation and resuscitation of hESC colony cultures. Optimized subprocesses were linked together to deliver a controlled complete process. We have demonstrated a rapid, high-throughput, and stable system for measurement of cell adherence and viability as robust markers of in-process and postrecovery cell state. We observed that measurement of adherence and viability of adhered cells at 1 h postseeding was predictive of cell proliferative ability up to 96 h in this system. Application of factorial design defined the operating spaces for cryopreservation and resuscitation, critically linking the performance of these two processes. Optimization of both processes resulted in enhanced reattachment and post-thaw viability, resulting in substantially greater recovery of cryopreserved, pluripotent cell colonies. This study demonstrates the importance of QbD concepts and tools for rapid, robust, and low-risk process design that can inform manufacturing controls and logistics. PMID- 24803078 TI - Barriers to the uptake of biosimilars and possible solutions: a Belgian case study. AB - BACKGROUND: Biosimilars are medicinal products that are similar to a biopharmaceutical that has already been authorised. As biopharmaceuticals are expected to dominate the best-selling pharmaceuticals worldwide by 2016, the emergence of biosimilars imposes an important challenge for governments. At this moment, the uptake of biosimilars in Belgium is limited, with market shares close to 0%. OBJECTIVE: This study aimed to identify the barriers that impede the uptake of biosimilars in Belgium. METHODS: Semi-structured interviews were conducted to investigate in depth the barriers to the uptake of biosimilars in Belgium. Respondents were selected through selective sampling so that all different stakeholders were represented (authorities, physicians, pharmacists, patients, academics and industry). Respondents were contacted by e-mail and letter with a request for participation. A thematic framework was used to analyze the data. RESULTS: Three main barriers to the uptake of biosimilars in the Belgian market were identified: a lack of confidence towards biosimilars by some stakeholders; uncertainty about the interchangeability and substitution of biosimilars; and a hospital financing system that discourages the use of them. Providing all stakeholders with objective information on the concept of biosimilars, reforming the financing of hospitals, developing and implementing prescription quota in hospitals, setting up patient registries for biosimilars and speeding up the pricing and reimbursement process of biosimilars are suggested solutions to increase the uptake of biosimilars in Belgium. CONCLUSIONS: To fully capture the potential savings of biosimilars, governments should take measures to increase their uptake. The Belgian government, and also the manufacturers of biosimilars, should take measures to reduce the uncertainties related to biosimilars and raise confidence among prescribers. In addition, the financing of hospitals should be reformed and incentives should be developed to stimulate physicians to prescribe biosimilars. PMID- 24803077 TI - Mechanical and mineral properties of osteogenesis imperfecta human bones at the tissue level. AB - Osteogenesis imperfecta (OI) is a genetic disorder characterized by an increase in bone fragility on the macroscopic scale, but few data are available to describe the mechanisms involved on the tissue scale and the possible correlations between these scales. To better understand the effects of OI on the properties of human bone, we studied the mechanical and chemical properties of eight bone samples from children suffering from OI and compared them to the properties of three controls. High-resolution computed tomography, nanoindentation and Raman microspectroscopy were used to assess those properties. A higher tissue mineral density was found for OI bone (1.131 gHA/cm3 vs. 1.032 gHA/cm3, p=0.032), along with a lower Young's modulus (17.6 GPa vs. 20.5 GPa, p=0.024). Obviously, the mutation-induced collagen defects alter the collagen matrix, thereby affecting the mineralization. Raman spectroscopy showed that the mineral-to-matrix ratio was higher in the OI samples, while the crystallinity was lower, suggesting that the mineral crystals were smaller but more abundant in the case of OI. This change in crystal size, distribution and composition contributes to the observed decrease in mechanical strength. PMID- 24803079 TI - Perforated tricuspid valve leaflet resulting from defibrillator leads: a review of the literature. AB - Tricuspid valve (TV) perforation is a rare complication after implantable cardioverter defibrillator (ICD) and permanent pacemaker implantation. In reported cases of lead-related TV perforations, patients' present with symptoms months to years postimplantation. We describe a case where a patient presented with signs of severe TV regurgitation secondary to traumatic perforation of the septal leaflet two weeks after ICD implantation and review of the literature associated with this complication. PMID- 24803080 TI - Online stochastic optimization of radiotherapy patient scheduling. AB - The effective management of a cancer treatment facility for radiation therapy depends mainly on optimizing the use of the linear accelerators. In this project, we schedule patients on these machines taking into account their priority for treatment, the maximum waiting time before the first treatment, and the treatment duration. We collaborate with the Centre Integre de Cancerologie de Laval to determine the best scheduling policy. Furthermore, we integrate the uncertainty related to the arrival of patients at the center. We develop a hybrid method combining stochastic optimization and online optimization to better meet the needs of central planning. We use information on the future arrivals of patients to provide an accurate picture of the expected utilization of resources. Results based on real data show that our method outperforms the policies typically used in treatment centers. PMID- 24803081 TI - Evaluation of toxicities from combined metronomic and maximal-tolerated dose chemotherapy in dogs with osteosarcoma. AB - OBJECTIVE: To evaluate the tolerability of a piroxicam and cyclophosphamide metronomic treatment protocol combined with carboplatin alone or carboplatin and doxorubicin at maximal-tolerated doses. METHODS: Retrospective study of 30 dogs diagnosed with osteosarcoma. All dogs underwent amputation and chemotherapy treatment with one of the two maximal-tolerated dose protocols. Metronomic chemotherapy was administered in conjunction with these protocols, and continued subsequently. The protocols included 0 . 3 mg/kg piroxicam and 10 to 12 mg/M(2) cyclophosphamide with 300 mg/M(2) carboplatin alone, or 300 mg/M(2) carboplatin alternating with 30 mg/M(2) doxorubicin. RESULTS: Fourteen dogs were treated with the carboplatin and metronomic protocol and 16 were treated with the carboplatin alternating with doxorubicin and metronomic protocol. Grades 3 and 4 toxicities overall were significantly (P = 0 . 018) more common in the former group. The disease-free interval of the carboplatin and metronomic group was 192 days, which was not significantly different (P = 0 . 916) to the 182 days for the carboplatin alternating with doxorubicin and metronomic group. The median survival times of the two groups were 217 and 189 days, respectively. CLINICAL SIGNIFICANCE: Piroxicam and cyclophosphamide metronomic protocols can be safely administered in combination with maximal-tolerated dose chemotherapy protocols. A significantly higher frequency of toxicities was observed in dogs treated with the carboplatin and metronomic protocol. PMID- 24803082 TI - Acute heart failure patients should be seen by specialist teams, says NICE. PMID- 24803083 TI - Optical trapping and Raman spectroscopy of solid particles. AB - The heterogeneous interactions of gas molecules on solid particles are crucial in many areas of science, engineering and technology. Such interactions play a critical role in atmospheric chemistry and in heterogeneous catalysis, a key technology in the energy and chemical industries. Investigating heterogeneous interactions upon single levitated particles can provide significant insight into these important processes. Various methodologies exist for levitating micron sized particles including: optical, electrical and acoustic techniques. Prior to this study, the optical levitation of solid micron scale particles has proved difficult to achieve over timescales relevant to the above applications. In this work, a new vertically configured counter propagating dual beam optical trap was optimized to levitate a range of solid particles in air. Silica (SiO2), alpha alumina (Al2O3), titania (TiO2) and polystyrene were stably trapped with a high trapping efficiency (Q = 0.42). The longest stable trapping experiment was conducted continuously for 24 hours, and there are no obvious constraints on trapping time beyond this period. Therefore, the methodology described in this paper should be of major benefit to various research communities. The strength of the new technique is demonstrated by the simultaneous levitation and spectroscopic interrogation of silica particles by Raman spectroscopy. In particular, the adsorption of water upon silica was investigated under controlled relative humidity environments. Furthermore, the collision and coagulation behaviour of silica particles with microdroplets of sulphuric acid was followed using both optical imaging and Raman spectroscopy. PMID- 24803084 TI - New compounds hybrids 1h-1,2,3-triazole-quinoline against Plasmodium falciparum. AB - Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost-effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine-resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3-triazole derivatives against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum has been reported in the literature. To enhance the anti-P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline-1H-1,2,3 triazole hybrids with different substituents in the 4-positions of the 1H-1,2,3 triazole ring, which were assayed against the W2-chloroquine-resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine-resistant, with IC50 values ranging from 1.4 to 46 MUm. None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound (11). PMID- 24803085 TI - Using self-consistency for an iterative trajectory adjustment (SCITA). AB - PURPOSE: To iteratively correct for deviations in radial trajectories with no need of additionally performed calibration scans. THEORY AND METHODS: Radially acquired data sets-even when undersampled to a certain extend-inherently feature an oversampled area in the center of k-space. Thus, for a perfectly measured trajectory and neglecting noise, information is consistent between multiple measurements gridded to the same Cartesian position within this region. In the case of erroneous coordinates, this accordance-and therefore a correction of the trajectory-can be enforced by an algorithm iteratively shifting the projections with respect to each other by applying the GRAPPA operator. The method was validated in numerical simulations, as well as in radial acquisitions of a phantom and in vivo images at 3T. The results of the correction were compared to a previously proposed correction method. RESULTS: The newly introduced technique allowed for a reliable trajectory correction in each of the presented examples. The method was able to remove artifacts as effectively as methods that are based on data from additional calibration scans. CONCLUSION: The iterative technique introduced in this paper allows for a correction of trajectory errors in radial imaging with no need for additional calibration data. PMID- 24803086 TI - The effects of an urban renewal project on health and health inequalities: a quasi-experimental study in Barcelona. AB - BACKGROUND: In the last decade, the Neighbourhoods Law in Catalonia (Spain) funded municipalities that presented urban renewal projects within disadvantaged neighbourhoods focusing on physical, social and economic improvements. The objective of the study was to evaluate the effects of this law on the health and health inequalities of residents in the intervened neighbourhoods in the city of Barcelona. METHODS: A quasi-experimental predesign and postdesign was used to compare adult residents in five intervened neighbourhoods with eight non intervened comparison neighbourhoods with similar socioeconomic characteristics. The Barcelona Health Survey was used for studying self-rated and mental health in pre (2001, 2006) and post (2011) years. Poisson regression models stratified by sex were used to compute prevalence ratios comparing 2011 with 2006, and later stratified by social class, to study health inequalities. RESULTS: The intervened neighbourhoods had a significant decrease in poor self-rated health in both sexes while no significant changes occurred in the comparison group. When stratified by social class, a significant improvement was observed in poor self-rated health in the manual group of the intervened neighbourhoods in both sexes, resulting in a decrease in self-rated health inequalities. Similar results were observed in poor mental health of women, while in men, poor mental health worsens in both neighbourhood groups but mostly in the comparison group. CONCLUSIONS: The Neighbourhoods Law had a positive effect on self-rated health and seems to prevent poor mental health increases in both sexes and especially among manual social classes. PMID- 24803087 TI - Late toxicity and quality of life after definitive treatment of prostate cancer: redefining optimal rectal sparing constraints for intensity-modulated radiation therapy. AB - The objective of this study was to assess late toxicity and quality of life (QOL) for patients receiving definitive intensity-modulated radiotherapy (IMRT) and image-guided radiation therapy (IGRT) with regard to normal tissue sparing objectives. Three hundred and seventy-two consecutive men treated with definitive IMRT for prostate adenocarcinoma. Toxicity was graded by CTC v3.0 genitourinary (GU) and gastrointestinal (GI) toxicity at each follow-up visit. Patient-reported QOL (EPIC-26) was prospectively collected for a subset of men. Dosimetric data for bladder and rectum were compared to toxicity and QOL global domain scores, specifically analyzing outcomes for men who met ideal rectal constraints (V70 <10%, V65 <20%, V40 <40%). The median age and prescription dose was 69 years and 76 Gy, respectively. Median follow-up was 47 months. At 4 years, freedom from Grade 2 (FFG2) GI toxicity was 92% and FFG2 GU toxicity was 76%. On univariate analysis, current smoking, larger bladder volume, and higher RT dose were associated with decreased FFG2 GU toxicity, while use of anticoagulation, increasing age, and not meeting ideal rectal constraints were associated with decreased FFG2 GI toxicity (all P <= 0.05). Bowel QOL remained stable over the 2 year follow-up period and was higher for patients who met ideal rectal constraints (P = 0.05). IMRT with IGRT is associated with low rates of severe toxicity and a high GI and GU QOL. The use of strict rectal constraints can further improve GI QOL and reduce GI toxicity. PMID- 24803088 TI - Is the age-related loss in olfactory sensitivity similar for light and heavy molecules? AB - The process of aging affects olfaction quite early and can lead to a major handicap. One may ask whether olfactory loss is general or if it affects some odors more specifically? We investigated whether an age-related increase in olfactory threshold could be more or less specific to heavy or light molecules, based on the idea that these odors would bind differently to olfactory receptors. One group of 30 older subjects (50-70 years) and one group of 30 young adults (18 30 years) were tested for their threshold to 4 odors. Two odorants were light molecules (<150 g/mol) and the 2 others were heavy molecules (>150 g/mol). Both sets contained a single molecule and a binary mixture. Older subjects performed worse than young adults in an odor identification task, confirming a decline in the olfactory function. As a major result, young adults were as sensitive to light and heavy molecules; on the contrary, older subjects were less sensitive to heavy molecules (single molecule and binary mixture). The results suggest that older people present a heterogeneous olfactory loss more specific to heavier molecules. PMID- 24803089 TI - Registration-based autofocusing technique for automatic correction of motion artifacts in time-series studies of high-resolution bone MRI. AB - PURPOSE: To develop a registration-based autofocusing (RAF) motion correction technique for high-resolution trabecular bone (TB) imaging and to evaluate its performance on in vivo MR data. MATERIALS AND METHODS: The technique combines serial registration with a previously developed motion correction technique - autofocusing - for automatic correction of subject movement degradation of MR images acquired in longitudinal studies. The method was tested on in vivo images of the distal radius to measure improvements in serial reproducibility of parameters in 12 women (ages 50-75 years), and to compare with the navigator echo based correction and autofocusing. Furthermore, the technique's ability to optimize the sensitivity to detect simulated bone loss was ascertained. RESULTS: The new technique yielded superior reproducibility of image-derived structural and mechanical parameters. Average coefficient of variation across all parameters improved by 12.5%, 27.0%, 33.5%, and 37.0%, respectively, following correction by navigator echoes, autofocusing, and the RAF technique (without and with correction for rotational motion); average intra-class correlation coefficient increased by 1.2%, 2.2%, 2.8%, and 3.2%, respectively. Furthermore, simulated bone loss (5%) was well recovered independent of the choice of reference image (4.71% or 4.86% with respect to using either the original or the image subjected to bone loss) in the time series. CONCLUSION: The data suggest that our technique simultaneously corrects for intra-scan motion corruption while improving inter scan registration. Furthermore, the technique is not biased by small changes in bone architecture between time-points. PMID- 24803090 TI - Modulated expression of human peripheral blood microRNAs from infancy to adulthood and its role in aging. AB - Accumulating evidence suggests a role for microRNAs (miRNAs) in regulating various processes of mammalian postnatal development and aging. To investigate the changes in blood-based miRNA expression from preterm infants to adulthood, we compared 365 miRNA expression profiles in a screening set of preterm infants and adults. Approximately one-third of the miRNAs were constantly expressed from postnatal development to adulthood, another one-third were differentially expressed between preterm infants and adults, and the remaining one-third were not detectable in these two groups. Based on their expression in infants and adults, the miRNAs were categorized into five classes, and six of the seven miRNAs chosen from each class except one with age-constant expression were confirmed in a validation set containing infants, children, and adults. Comparing the chromosomal locations of the different miRNA classes revealed two hot spots: the miRNA cluster on 14q32.31 exhibited age-constant expression, and the one on 9q22.21 exhibited up-regulation in adults. Furthermore, six miRNAs detectable in adults were down-regulated in older adults, and four chosen for individual quantification were verified in the validation set. Analysis of the network functions revealed that differentially regulated miRNAs between infants and adults and miRNAs that decreased during aging shared two network functions: inflammatory disease and inflammatory response. Four expression patterns existed in the 11 miRNAs from infancy to adulthood, with a significant transition in ages 9-20 years. Our results provide an overview on the regulation pattern of blood miRNAs throughout life and the possible biological functions performed by different classes of miRNAs. PMID- 24803091 TI - Combined umbilical cord blood and bone marrow from HLA-identical sibling donors for hematopoietic stem cell transplantation in children with hemoglobinopathies. AB - BACKGROUND: It is well established that umbilical cord blood and bone marrow are biologically different stem cell sources. PATIENTS AND METHODS: We analyzed the feasibility and outcome of hematopoietic stem cell transplantation (HSCT) in 13 children (median age 5.9 years) with hemoglobinopathies after the co- infusion of cord blood (CB) and bone marrow (BM) from the same human leucocyte antigen (HLA) identical sibling donor. We also compared outcomes of children with co transplantation to outcomes in children with hemoglobinopathies who had received a BM (n = 21) or CB (n = 22) transplant alone. RESULTS: Compared to CB transplant (CBT) recipients, the co-transplant group had more rapid neutrophil (17 vs. 25 days, P = 0.013) and platelet (29 vs. 48 days, P = 0.009) recovery and less transplant related mortality. Patients who received a co-transplant had a lower incidence of >= grade II acute (0% vs. 26.3%) and chronic (0% vs. 21%) graft versus host disease (GVHD) compared to BM transplant (BMT) recipients (P = 0.055 and 0.045, respectively). With a median follow-up of >60 months in each treatment group, the 5-year probability of event free survival (EFS) was 100% in the co transplant group, 90% after BMT and 86% after CBT (P = 0.42). CONCLUSION: Co transplantation of CB and BM from HLA-identical sibling donors appears to be a feasible and effective strategy to further optimize outcomes of HSCT for hemoglobinopathies. PMID- 24803093 TI - Tuning nanoparticle structure and surface strain for catalysis optimization. AB - Controlling nanoparticle (NP) surface strain, i.e. compression (or stretch) of surface atoms, is an important approach to tune NP surface chemistry and to optimize NP catalysis for chemical reactions. Here we show that surface Pt strain in the core/shell FePt/Pt NPs with Pt in three atomic layers can be rationally tuned via core structural transition from cubic solid solution [denoted as face centered cubic (fcc)] structure to tetragonal intermetallic [denoted as face centered tetragonal (fct)] structure. The high activity observed from the fct FePt/Pt NPs for oxygen reduction reaction (ORR) is due to the release of the overcompressed Pt strain by the fct-FePt as suggested by quantum mechanics molecular mechanics (QM-MM) simulations. The Pt strain effect on ORR can be further optimized when Fe in FePt is partially replaced by Cu. As a result, the fct-FeCuPt/Pt NPs become the most efficient catalyst for ORR and are nearly 10 times more active in specific activity than the commercial Pt catalyst. This structure-induced surface strain control opens up a new path to tune and optimize NP catalysis for ORR and many other chemical reactions. PMID- 24803092 TI - Post-operative left atrioventricular valve function after the staged repair of complete atrioventricular septal defect with tetralogy of Fallot. AB - OBJECTIVE: This study reviewed surgical outcomes of staged repair for complete atrioventricular septal defect with tetralogy of Fallot, especially with focusing on the post-operative left-sided atrioventricular valve function. METHODS: Between 1992 and 2013, 10 patients with complete atrioventricular septal defect with tetralogy of Fallot underwent total correction by the following surgical strategy. Systemic-to-pulmonary shunt was placed at first at the mean age of 1.5 +/- 1.3 months. Then confirming sufficient development of the left heart structures, the total correction was performed at the mean age of 1.4 +/- 0.6 years. Second shunt was required in 4 (40 %) patients to develop the left heart structures. RESULTS: The left ventricular end-diastolic volume before total correction was 127 +/- 30 % of normal size. The two-patch repair was applied in 8 (80 %) patients. There was no mortality, and 1 reoperation case for left-sided atrioventricular valve regurgitation. The follow-up was completed on all patients and the mean follow-up period was 7.4 +/- 7.0 years. The post-operative left sided atrioventricular valve regurgitation kept less than moderate for 10-year follow-up in all patients except one patient who required the repair of left sided atrioventricular valve 1 year after the total correction. CONCLUSIONS: The post-operative left-sided atrioventricular valve function after the repair of complete atrioventricular septal defect with tetralogy of Fallot maintained with the application of the two-patch repair, early and repeated palliative systemic to-pulmonary shunt, and the early definitive surgery. PMID- 24803094 TI - From nonfinite to finite 1D arrays of origami tiles. AB - CONSPECTUS: DNA based nanotechnology provides a basis for high-resolution fabrication of objects almost without physical size limitations. However, the pathway to large-scale production of large objects is currently unclear. Operationally, one method forward is to use high information content, large building blocks, which can be generated with high yield and reproducibility. Although flat DNA origami naturally invites comparison to pixels in zero, one, and two dimensions and voxels in three dimensions and has provided an excellent mechanism for generating blocks of significant size and complexity and a multitude of shapes, the field is young enough that a single "brick" has not become the standard platform used by the majority of researchers in the field. In this Account, we highlight factors we considered that led to our adoption of a cross-shaped, non-space-filling origami species, designed by Dr. Liu of the Seeman laboratory, as the building block ideal for use in the fabrication of finite one-dimensional arrays. Three approaches that can be employed for uniquely coding origami-origami linkages are presented. Such coding not only provides the energetics for tethering the species but also uniquely designates the relative orientation of the origami building blocks. The strength of the coding approach implemented in our laboratory is demonstrated using examples of oligomers ranging from finite multimers composed of four, six, and eight origami structures to semi infinite polymers (100mers). Two approaches to finite array design and the series of assembly steps that each requires are discussed. The process of AFM observation for array characterization is presented as a critical case study. For these soft species, the array images do not simply present the solution phase geometry projected onto a two-dimensional surface. There are additional perturbations associated with fluidic forces associated with sample preparation. At this time, reconstruction of the "true" or average solution structures for blocks is more readily achieved using computer models than using direct imaging methods. The development of scalable 1D-origami arrays composed of uniquely addressable components is a logical, if not necessary, step in the evolution of higher order fully addressable structures. Our research into the fabrication of arrays has led us to generate a listing of several important areas of future endeavor. Of high importance is the re-enforcement of the mechanical properties of the building blocks and the organization of multiple arrays on a surface of technological importance. While addressing this short list of barriers to progress will prove challenging, coherent development along each of these lines of inquiry will accelerate the appearance of commercial scale molecular manufacturing. PMID- 24803095 TI - Real-time PCR PCA3 assay is a useful test measured in urine to improve prostate cancer detection. AB - BACKGROUND: The usefulness of PCA3 in the management of early prostate cancer (PCa) is on debate. The aim of this study was to evaluate PCA3 in the detection of PCa and its relationship with tumor aggressiveness. METHODS AND PATIENTS: PCA3 score was measured by real time PCR in urinary sediments of 122 patients who underwent prostate biopsy for PSA >4MUg/L. RESULTS: Analysis of ROC curves showed an area under the curve (AUC) of 0.804 for PCA3 score, while the AUCs were 0.587 and 0.697 for PSA and % free PSA, respectively. The probability of positive biopsy increased in relation to PCA3 score, with variations from 37% to 96% for patients with PCA3 score lower than 0.90 or higher than 1.04, respectively. We chose the cut-off value of 0.90, corresponding to a sensitivity of 92.5%, for which we obtained a specificity of 41.5%. No significant differences in PCA3 score were found in relation to Gleason score or clinical stage. CONCLUSIONS: The results show a high probability of PCa in patients with an elevated PCA3 score, although we did not find any relationship with aggressiveness of the tumor. PCA3 score can help to select more precisely which patients will need to perform a biopsy of the prostate. PMID- 24803096 TI - Relationship between erythrocyte omega-3 content and obesity is gender dependent. AB - Epidemiological evidence of an inverse association between consumption of long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) and obesity has been conflicting, even though studies in animal models of obesity and limited human trials suggest that LC n-3 PUFA consumption may contribute to weight loss. We used baseline data from a convenience sample of 476 adults (291 women, 185 men) participating in clinical trials at our Centre to explore relationships between erythrocyte levels of LC n-3 PUFA (a reliable indicator of habitual intake) and measures of adiposity, viz. body mass index (BMI), waist circumference (WC) and body fat (BF) assessed by dual-energy X-ray absorptiometry. Means +/- SD of assessments were BMI: 34 +/- 7 and 31 +/- 5 kg/m2; WC: 105 +/- 16 and 110 +/- 13 cm; BF: 48 +/- 5 and 35% +/- 6% in women and men respectively. Erythrocyte levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were similar in men and women while docosapentaenoic acid (DPA) was higher and EPA + DHA (Omega-3 Index) slightly lower in men than in women. Both DHA and EPA + DHA correlated inversely with BMI, WC and BF in women while DPA correlated inversely with BF in men. Quartile distributions and curvilinear regression of the Omega-3 Index versus BMI revealed a steep rise of BMI in the lower range of the Omega-3 Index in women, but no association in men. Thus the results highlight important gender differences in relationships of specific LC n-3 PUFA in erythrocytes to markers of adiposity. If these reflect causal relationships between LC n-3 PUFA consumption and risk of obesity, gender specific targeted interventions should be considered. PMID- 24803097 TI - Vitamin B12-containing plant food sources for vegetarians. AB - The usual dietary sources of Vitamin B12 are animal-derived foods, although a few plant-based foods contain substantial amounts of Vitamin B12. To prevent Vitamin B12 deficiency in high-risk populations such as vegetarians, it is necessary to identify plant-derived foods that contain high levels of Vitamin B12. A survey of naturally occurring plant-derived food sources with high Vitamin B12 contents suggested that dried purple laver (nori) is the most suitable Vitamin B12 source presently available for vegetarians. Furthermore, dried purple laver also contains high levels of other nutrients that are lacking in vegetarian diets, such as iron and n-3 polyunsaturated fatty acids. Dried purple laver is a natural plant product and it is suitable for most people in various vegetarian groups. PMID- 24803098 TI - Red ginseng treatment for two weeks promotes fat metabolism during exercise in mice. AB - PURPOSE: Red ginseng (RG) has been reported to improve the blood and organ lipid profile when combined with exercise. However, the effect of RG on energy metabolism during exercise is poorly understood. Therefore, this study was designed to investigate whether RG treatment alters fat utilization during exercise; METHODS: We used seven-week-old ICR mice (n = 42). RG (1 g/kg) was administered orally daily during two weeks of endurance training. All mice were randomized into two groups: training only group (CON group) and training with RG group (RG group). Endurance training consisted of 20~25 m/min on a slope of 8 degrees for one hour five times a week. After a two-week experimental period, we measured substrate utilization during exercise at the same intensity and duration of training using a respiratory calorimetry chamber. Mice were dissected for glycogen measurement of muscles and liver before, immediately after, and one hour after the exercise; RESULT: Fat oxidation during the initial 20 min of the one hour exercise significantly increased in the RG group compared to the CON group. In addition, the liver glycogen stores significantly decreased immediately after the one-hour exercise compared to at rest in the RG group, but did not differ between immediately after the one-hour exercise and at rest in the RG group. The glycogen concentration in white and red gastrocnemius muscle did not differ between the groups immediately after the one-hour exercise; CONCLUSIONS: These results suggest that RG treatment for two weeks promotes fat oxidation and a glycogen-sparing effect during exercise. This might lead to a delay in peripheral fatigue during endurance exercise performance. PMID- 24803099 TI - Influence of posture and frequency modes in total body water estimation using bioelectrical impedance spectroscopy in boys and adult males. AB - The aim of the study was to examine differences in total body water (TBW) measured using single-frequency (SF) and multi-frequency (MF) modes of bioelectrical impedance spectroscopy (BIS) in children and adults measured in different postures using the deuterium (2H) dilution technique as the reference. Twenty-three boys and 26 adult males underwent assessment of TBW using the dilution technique and BIS measured in supine and standing positions using two frequencies of the SF mode (50 kHz and 100 kHz) and the MF mode. While TBW estimated from the MF mode was comparable, extra-cellular fluid (ECF) and intra cellular fluid (ICF) values differed significantly (p < 0.01) between the different postures in both groups. In addition, while estimated TBW in adult males using the MF mode was significantly (p < 0.01) greater than the result from the dilution technique, TBW estimated using the SF mode and prediction equation was significantly (p < 0.01) lower in boys. Measurement posture may not affect estimation of TBW in boys and adult males, however, body fluid shifts may still occur. In addition, technical factors, including selection of prediction equation, may be important when TBW is estimated from measured impedance. PMID- 24803101 TI - Measuring mechanical properties in cells: three easy methods for biologists. AB - The mechanism by which cells sense stresses and transmit them throughout the cytoplasm and the cytoskeleton (CSK) and by which these mechanical signals are converted into biochemical signaling responses is not clear. Specifically, there is little direct experimental evidence on how intracellular CSK structural elements in living cells deform and transmit stresses in response to external mechanical forces. Existing theories have invoked various biophysical and biochemical mechanisms to explain how cells spread, deform, divide, move, and change shape in response to mechanical inputs, but rigorous tests in cells are lacking. The lack of data and understanding is preventing the identification of mechanisms and sites of mechano-regulation in cells. Here, we introduce and describe three unique and easy methods for biologists to determine mechanical properties and signaling events in cells. PMID- 24803100 TI - Interaction of clopidogrel and statins in secondary prevention after cerebral ischaemia - a randomized, double-blind, double-dummy crossover study. AB - AIMS: Variability in responsiveness to clopidogrel is a clinical problem in secondary prevention after cerebral ischaemia which has been suggested to be linked to competitive metabolization of clopidogrel and cytochrome P450 (CYP) 3A4 oxidated statins such as simvastatin. We assessed the hypothesis that simvastatin, in contrast to CYP 2C9-metabolized fluvastatin, reduces clopidogrel mediated platelet inhibition. METHODS: We performed a randomized, double-blind, double-dummy, two period crossover study in 13 patients with cerebral ischaemia (8F, 5 M), aged 64.1 +/- 8.0 years (mean +/- SD). After a 14 day period in which all patients received 75 mg clopidogrel day(-1) , patients additionally received either 20 mg simvastatin day(-1) or 80 mg fluvastatin day(-1) for 14 days. Regimens were crossed over after a 14 day wash-out period and switched regimens were continued for another 14 days. Platelet aggregation, clopidogrel active metabolite (CAM) plasma concentrations and routine laboratory parameters including prothrombin time (PT) Quick percent value were assessed at baseline and following each treatment phase. RESULTS: Clopidogrel reduced platelet aggregation in all patients as expected. Platelet aggregation and CAM plasma concentrations were unaltered when simvastatin or fluvastatin was added to clopidogrel. Simvastatin decreased PT Quick percent value (decrease from 109 +/- 10.5% to 103 +/- 11%, P < 0.05) when combined with clopidogrel but there was no such change following treatment with fluvastatin and clopidogrel. CONCLUSIONS: Our data indicate that treatment with CYP 3A4-metabolized simvastatin does not jeopardize clopidogrel-mediated inhibition of platelet aggregation. After co-administration of simvastatin and clopidogrel we observed a decrease in the PT Quick percent value which could be due to simvastatin-induced reduction of activity of prothrombin fragment 1 + 2. PMID- 24803102 TI - Prevalence of tardive dyskinesia in chronic male inpatients with schizophrenia on long-term clozapine versus typical antipsychotics. AB - This study aimed to examine the prevalence and clinical associated variables of tardive dyskinesia (TD) in a large sample of Chinese inpatients with schizophrenia on long-term treatment with clozapine versus typical antipsychotics. A total of 584 male inpatients with schizophrenia on long-term clozapine (n=341) or typical antipsychotic (n=243) treatment were evaluated using the Abnormal Involuntary Movement Scale (AIMS). The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale. The overall prevalence of TD was 44.5%, with rates of 48.7% in the clozapine group and 38.7% in the typical antipsychotic group (P=0.017). The AIMS score was significantly lower in typical than in clozapine groups (P<0.005). A multiple regression analysis showed that the following variables were significantly associated with the AIMS score: clozapine versus typical medication (P=0.008), Positive and Negative Syndrome Scale negative subscore (P=0.017), and age (P=0.04). There are significant differences in the prevalence and clinical correlates of TD in schizophrenia treated with clozapine versus typical antipsychotics. PMID- 24803103 TI - Histological changes in the retina provoked by lithium treatment in a nocturnal rodent (Lagostomus maximus maximus). AB - Daily morphological variations have been previously described in the viscacha (Lagostomus maximus maximus) retina. The aim of this work was to determine the effects of lithium administration on the histology of retinas from this nocturnal rodent since lithium is a drug that has been shown to affect different parameters of circadian rhythms. Adult male viscachas were divided into 2 groups, injected daily with lithium chloride or vehicle for 35 days, and sacrificed at 08:00, 16:00, and 24:00 h for light and electron microscopy studies. The following morphometric parameters were analyzed: the thickness of the photoreceptor layer, the rod outer and inner segments, and the outer nuclear layer. The control group displayed a true daily cycle of photoreceptor renewal similar to that previously reported by us for (untreated) viscachas in their normal habitat. In all lithium treated groups, we did not observe histological changes in the thickness measurement of the retinal layers. In these groups, the retinas presented ultrastructural characteristics similar to those observed in control animals sacrificed at 24:00 h. In conclusion, chronic lithium administration abolished the daily histological rhythm in the viscacha retina, probably via inhibition of the phagocytosis process in pigment epithelial cells. PMID- 24803105 TI - Update on antiretroviral treatment during primary HIV infection. AB - Primary HIV-1 infection covers a period of around 12 weeks in which the virus disseminates from the initial site of infection into different tissues and organs. In this phase, viremia is very high and transmission of HIV is an important issue. Most guidelines recommend antiretroviral treatment in patients who are symptomatic, although the indication for treatment remains inconclusive in asymptomatic patients. In this article the authors review the main virological and immunological events during this early phase of infection, and discuss the arguments for and against antiretroviral treatment. Recommendations of different guidelines, the issue of the HIV transmission and transmission of resistance to antiretroviral drugs, as well as recently available information opening perspectives for functional cure in patients treated in very early steps of HIV infection are also discussed. PMID- 24803106 TI - Heterodinuclear complexes of 4,5-diazafluorene derivatives displaying eta(5),kappa(2)-[N,N] and eta(5),kappa(1)-N coordination modes. AB - The syntheses and structures for a series of heterodinuclear complexes of 4,5 diazafluorenyl (L(-)) and 3,6-dimesityl-4,5-diazafluorenyl (LMes(-)) ligands are reported herein. In all these heterodinuclear complexes, the Ru(II) centre is sandwiched between a pentamethylcyclopentadienyl (Cp*) ligand and the C5 ring of L(-) or LMes(-) in a double eta(5) fashion, while the other metal (Fe(II), Co(II), Pt(II), or Cu(I)) is bound to the N-donors. PMID- 24803104 TI - Magnetic-resonance-based electrical properties tomography: a review. AB - Frequency-dependent electrical properties (EPs; conductivity and permittivity) of biological tissues provide important diagnostic information (e.g., tumor characterization), and also play an important role in quantifying radiofrequency (RF) coil induced specific absorption rate (SAR), which is a major safety concern in high- and ultrahigh-field magnetic resonance imaging (MRI) applications. Cross sectional imaging of EPs has been pursued for decades. Recently introduced electrical properties tomography (EPT) approaches utilize the measurable RF magnetic field induced by the RF coil in an MRI system to quantitatively reconstruct the EP distribution in vivo and noninvasively with a spatial resolution of a few millimeters or less. This paper reviews the EPT approach from its basic theory in electromagnetism to the state-of-the-art research outcomes. Emphasizing on the imaging reconstruction methods rather than experimentation techniques, we review the developed imaging algorithms, validation results in physical phantoms and biological tissues, as well as their applications in in vivo tumor detection and subject-specific SAR prediction. Challenges for future research are also discussed. PMID- 24803108 TI - 'Going rural': driving change through a rural medical education innovation. AB - INTRODUCTION: Medical education across the globe is in a state of flux influenced by a number of drivers for change. In response, institutions are seeking to re align their curricula to address the prevailing imperatives. Against this backdrop, the training of practitioners for practice in rural communities was identified as an educational priority, and led to the establishment of a rural clinical school (RCS) within a Faculty of Medicine and Health Sciences in South Africa in 2011. This article describes the students' experiences in the first year that this innovative educational model was implemented and explores the extent to which it influenced their thinking and practice. METHODS: A qualitative, formative evaluation study of the first year of implementation was undertaken. Data was generated from in-depth interviews. This article focuses on individual interviews conducted with the eight students at the RCS, which explored their experiences during a year-long clerkship. Transcripts of interviews were thematically analysed. RESULTS: Four themes emerged from the analysis: a learning experience that differed from what was experienced at the tertiary training hospital, an enabling clinical environment in the district and regional hospital, the positive role played by the specialists, and the influence of the community immersion. Underlying all of the responses was the building of relationships over time both with supervisors and with patients. Evident from the responses was that students' confidence in their clinical skills and decision making abilities was heightened while their approaches to their own learning were enhanced. CONCLUSIONS: To respond to the call for educational reform and a heightened awareness of social realities, innovative approaches to the training of medical students, such as those adopted at the RCS, are indicated. It is argued that the learning facilitated by these rural medical education models has the potential to offer learning experiences that can lead to transformation through a change in practice and attitude among the students, and ultimately also enable curricular renewal at the institutional core. PMID- 24803110 TI - Controlling leucine-zipper partner recognition in cells through modification of a g interactions. AB - By focusing on the a-g interactions, successful design and selection were accomplished to obtain a leucine-zipper segment that discriminates the appropriate partner over another that provides very similar patterns of electrostatic interactions. PMID- 24803111 TI - A standardised static in vitro digestion method suitable for food - an international consensus. AB - Simulated gastro-intestinal digestion is widely employed in many fields of food and nutritional sciences, as conducting human trials are often costly, resource intensive, and ethically disputable. As a consequence, in vitro alternatives that determine endpoints such as the bioaccessibility of nutrients and non-nutrients or the digestibility of macronutrients (e.g. lipids, proteins and carbohydrates) are used for screening and building new hypotheses. Various digestion models have been proposed, often impeding the possibility to compare results across research teams. For example, a large variety of enzymes from different sources such as of porcine, rabbit or human origin have been used, differing in their activity and characterization. Differences in pH, mineral type, ionic strength and digestion time, which alter enzyme activity and other phenomena, may also considerably alter results. Other parameters such as the presence of phospholipids, individual enzymes such as gastric lipase and digestive emulsifiers vs. their mixtures (e.g. pancreatin and bile salts), and the ratio of food bolus to digestive fluids, have also been discussed at length. In the present consensus paper, within the COST Infogest network, we propose a general standardised and practical static digestion method based on physiologically relevant conditions that can be applied for various endpoints, which may be amended to accommodate further specific requirements. A frameset of parameters including the oral, gastric and small intestinal digestion are outlined and their relevance discussed in relation to available in vivo data and enzymes. This consensus paper will give a detailed protocol and a line-by-line, guidance, recommendations and justifications but also limitation of the proposed model. This harmonised static, in vitro digestion method for food should aid the production of more comparable data in the future. PMID- 24803112 TI - Turn-on fluorescent dopamine sensing based on in situ formation of visible light emitting polydopamine nanoparticles. AB - Dopamine is the principle biomarker for diseases such as schizophrenia, Huntington's, and Parkinson's, and the need is urgent for rapid and sensitive detection methods for diagnosis and monitoring of such diseases. In this Article, we report a turn-on fluorescent method for rapid dopamine sensing which is based on monitoring the intrinsic fluorescence of in situ synthesized polydopamine nanoparticles. The assay uses only a common base and an acid, NaOH and HCl to initiate and stop the polymerization reaction, respectively, which makes the assay extremely simple and low cost. First, we studied the in situ optical properties of polydopamine nanoparticles, for the first time, which formed under different alkaline conditions in order to determine optimum experimental parameters. Then, under optimized conditions we demonstrated high sensitivity (40 nM) and excellent selectivity of the assay. With its good analytical figures of merit, the described method is very promising for detection of dopamine related diseases. PMID- 24803113 TI - Comparative genome analysis of Pseudomonas knackmussii B13, the first bacterium known to degrade chloroaromatic compounds. AB - Pseudomonas knackmussii B13 was the first strain to be isolated in 1974 that could degrade chlorinated aromatic hydrocarbons. This discovery was the prologue for subsequent characterization of numerous bacterial metabolic pathways, for genetic and biochemical studies, and which spurred ideas for pollutant bioremediation. In this study, we determined the complete genome sequence of B13 using next generation sequencing technologies and optical mapping. Genome annotation indicated that B13 has a variety of metabolic pathways for degrading monoaromatic hydrocarbons including chlorobenzoate, aminophenol, anthranilate and hydroxyquinol, but not polyaromatic compounds. Comparative genome analysis revealed that B13 is closest to Pseudomonas denitrificans and Pseudomonas aeruginosa. The B13 genome contains at least eight genomic islands [prophages and integrative conjugative elements (ICEs)], which were absent in closely related pseudomonads. We confirm that two ICEs are identical copies of the 103 kb self transmissible element ICEclc that carries the genes for chlorocatechol metabolism. Comparison of ICEclc showed that it is composed of a variable and a 'core' region, which is very conserved among proteobacterial genomes, suggesting a widely distributed family of so far uncharacterized ICE. Resequencing of two spontaneous B13 mutants revealed a number of single nucleotide substitutions, as well as excision of a large 220 kb region and a prophage that drastically change the host metabolic capacity and survivability. PMID- 24803114 TI - Development of a peptide ELISA for the diagnosis of Equine arteritis virus. AB - A peptide-based indirect ELISA was developed to detect antibodies against Equine arteritis virus (EAV). Two peptides for epitope C of protein GP5 and fragment E of protein M were designed, synthesized, purified and used as antigens either alone or combined. Ninety-two serum samples obtained from the 2010 Equine viral arteritis outbreak, analyzed previously by virus neutralization, were evaluated by the ELISA here developed. The best resolution was obtained using peptide GP5. The analysis of the inter- and intraplate variability showed that the assay was robust. The results allow concluding that this peptide-based ELISA is a good alternative to the OIE-prescribed virus neutralization test because it can be standardized between laboratories, can serve as rapid screening, can improve the speed of diagnosis of EAV-negative horses and can be particularly useful for routine surveillance in large populations. PMID- 24803125 TI - The levels of the neutrophil elastase in the amniotic fluid of pregnant women whose infants develop bronchopulmonary dysplasia. AB - OBJECTIVE: To clarify the association between amniotic neutrophil elastase levels and the development of bronchopulmonary dysplasia (BPD). METHODS: The database between July 2001 and December 2012 was reviewed for women with amniocentesis on admission for amniotic fluid neutrophil elastase levels and with singleton deliveries between 22 + 0 and 31 + 6 weeks of gestation. Following deliveries, placentas were examined for histologic chorioamnionitis. The peripheral blood of the neonates was analyzed for acute phase reactants. RESULTS: Among 294 infants, no, mild, moderate or severe BPD was observed in 126, 89, 40 and 39 infants, respectively. The medians of gestational age on admission, at premature rupture of membranes and at delivery were significantly smaller in BPD (+) when compared with BPD (-) (p < 0.001). The median level of amniotic neutrophil elastase on admission was significantly greater in BPD (+) than that in BPD (-). Histologic chorioamnionitis and funisitis were both detected more frequently in BPD (+) patients than in BPD (-) patients. In a logistic regression model, the only variable that affected an increased chance of BPD was the gestational age at delivery (odds ratio, 0.58; 95% confidence interval, 0.36-0.92; p = 0.021). CONCLUSIONS: The level of amniotic neutrophil elastase cannot be a definitive risk factor for BPD. PMID- 24803126 TI - Double versus single cervical cerclage for the prevention of preterm births. AB - OBJECTIVE: To evaluate the effectiveness double cervical cerclage in reducing antenatal complications and improve perinatal outcomes. METHODS: We searched Medline, Scopus, Clinicaltrials.org, The Cochrane Central Register of Controlled Trials and Google Scholar search engines. RESULTS: Six studies were included that involved 880 women. Double cerclage was significantly superior to single cerclage in reducing preterm births <34 weeks (734 cases, OR 0.59, 95% CI 0.40, 0.86) and preterm births <28 weeks (645 cases, OR 0.43, 95% CI 0.26-0.73). It also significantly increased the gestational age (380 cases, MD 2.63, 95% CI 0.87, 4.39). However, as a technique, it failed to improve the rates of preterm births <37 weeks (740 cases, OR 0.98, 95% CI 0.72, 1.34) the incidence of chorioamnionitis (740 cases, OR 0.83, 95% CI 0.51, 1.36) and the occurrence of preterm premature rupture of the membranes (796 cases, OR 1.32, 95% CI 0.95, 1.82). CONCLUSIONS: It seems that double cerclage effectively increases the gestational age at delivery and decreases the rates of extremely premature births. However, as a procedure, it does not reduce the incidence of antenatal morbidity or the neonatal death rates. Further research is needed in the field as our meta-analysis is limited by the small number of enrolled studies. PMID- 24803127 TI - Number and size of uterine fibroids and obstetric outcomes. AB - OBJECTIVE: Estimating the impact of sonographically identified multiple or large (>=5 cm in diameter) fibroids on obstetric outcomes. METHODS: Retrospective cohort study of 219 women with uterine fibroids (identified on a routine second trimester ultrasound survey over a 3-year period, 2010-2012) and their age matched controls. Inclusion criteria were singleton pregnancy, delivery at >24 weeks of gestation and no pathological conditions (chronic hypertension, gestational diabetes or pre-existing diabetes mellitus, uterine anomalies or fetal malformations). RESULTS: Compared to women with no fibroids, women with multiple fibroids (n = 34) had a significantly higher rate of preterm birth (29.4% versus 5%, p < 0.001), cesarean section (73.5% versus 37%, p < 0.001) and breech presentation (11.8% versus 2.7%, p = 0.04). Women with large fibroids (n = 48) had a higher rate of preterm birth (16.7% versus 5%, p = 0.01) and pPROM (10.4% versus 0.5%, p < 0.001). By multivariate analysis, only multiple fibroids and previous preterm birth showed an independent significant association with preterm birth (OR = 7.37, 95% CI 2.50-21.68 and OR = 13.01, 95% CI 3.56-47.52, respectively). CONCLUSIONS: Women with uterine fibroids are at an increased risk of obstetric complications. In particular, multiple rather than large fibroids are associated with a significantly increased risk of preterm birth and cesarean delivery while large fibroids are associated with a higher risk of pPROM. No correlation with IUGR, placenta previa or placental abruption was found. PMID- 24803129 TI - Quantitative cascade energy transfer in semiconductor thin films. AB - In this contribution we report the photophysical study of three organic blend systems comprising [60]PCBM along with different combinations of five extended semiconducting arylacetylenes, i.e. p-[(2-{[m,p-didodecyloxyphenyl]ethynyl}-7 fluorenyl)ethynyl]benzonitrile, 4,7-bis(5-{[m,p-bis(hexyloxy)phenyl]ethynyl}thien 2-yl)-2,1,3-benzothiadiazole, 9,10-bis-[(m,m-bis{[m,m-bis (hexyloxy)phenyl]ethynyl}phenyl)ethynyl]-anthracene, pseudo-p-[(10-{[m,p-bis (hexyloxy)phenyl]ethynyl}-9-anthryl[2.2]paracyclophane, and oligo{2,5 bis(hexyloxy)[1,4- phenylene ethynylene]-alt-[9,10-anthraceneethynylene]}, and one semiconducting arylvinylene, i.e. 9,10-bis-{(E)-[m,p bis(hexyloxy)phenyl]vinyl}-anthracene, that evidenced an efficient quantitative energy transfer from the hypsochromic to the bathochromic species (the potential efficient charge-donor components), useful to extend the collection of sunlight. An interesting emission enhancement in thin films has been observed only for the arylvinylene derivative. PMID- 24803130 TI - Prevalence and predictors of concurrent sexual partnerships in a predominantly African American population in Jackson, Mississippi. AB - Concurrent sexual partnerships, or sexual partnerships that overlap in time, have been associated with HIV and sexually transmitted infections (STI). How best to measure concurrency and the personal characteristics and predictors of concurrency are not yet well understood. We compared two frequently used concurrency definitions, including a self-reported measure based on participant response regarding overlapping sex with partners, and the UNAIDS measure based on overlapping dates of last sex and intention to have sex again. We performed multivariable logistic regression analyses to identify socio-demographic, behavioral, and structural predictors of concurrency among 1,542 patients at an urban STI clinic in Jackson, Mississippi. Nearly half (44 %) reported concurrency based on self-reported sex with other partners, and 26 % reported concurrency according to the UNAIDS concurrency measure. Using the self-reported concurrency measure, the strongest predictors of concurrency were perceived partner concurrency, drug use at last sex, having more than 10 lifetime partners, and being recently incarcerated. Strongest predictors of concurrency using the UNAIDS measure were lifetime number of partners and perceived partner concurrency. Concurrency is highly prevalent in this population in the Deep South and social, structural and behavioral factors were important predictors of concurrency for both measures. Future research should use time anchored data collection methods and biomarkers to assess whether both definitions of concurrency are associated with HIV outcomes. PMID- 24803131 TI - Impact of respiration gating on image integration guided atrial fibrillation ablation. AB - BACKGROUND: Radiofrequency (RF) catheter ablation guided by electroanatomic mapping systems is an effective therapy for atrial fibrillation. However, it may be affected by respiration movements. The aim of this study was to determine the impact of respiratory gating on procedural parameters in patients undergoing catheter ablation of atrial fibrillation (AF). METHODS AND RESULTS: One-hundred forty consecutive patients undergoing pulmonary vein isolation were admitted to study. Respiratory gating module (AccuResp algorithm, Carto3, Biosense Webster) was enabled in 70 patients and disabled in 70 patients during procedures. Successful pulmonary vein isolation and sinus rhythm were obtained in all patients. A significant reduction in total procedure times [median 77, interquartile range (IQR 66-95) min vs median 82 (IQR 72-104) min, p < 0.05] and fluoroscopy times [median 14 (IQR 9-17) min vs median 16 (IQR 12-22) min, p < 0.05] were observed in the respiratory gated group. Although ablation times (duration between the first and last ablation) were significantly shorter in respiratory gated group [median 37 (IQR 32-53) min vs median 48 (IQR 39-65) min, p < 0.05], total RF application durations were not different between two groups [median 1,554 (IQR 1,213-2,196) s vs median 1,802 (IQR 1,344-2,448) s, p = 0.11]. Difference in electroanatomical map reconstruction times was not significant [median 14 (IQR 12-16) min in gated group vs median 13 (IQR 10-18) min in nongated group, p = 0.19]. CONCLUSION: Respiratory gating significantly improves fluoroscopy and ablation times during electroanatomic mapping guided AF ablation. Respiratory gated maps may provide uninterrupted continuous ablation applications. Furthermore, using automatic respiratory gating module does not prolong mapping times. PMID- 24803133 TI - A prospective randomised controlled trial of the LMA Supreme vs cuffed tracheal tube as the airway device during percutaneous tracheostomy. AB - We studied the performance of the LMA Supreme against a cuffed tracheal tube, our standard method of airway control during percutaneous tracheostomy, in 50 consecutive patients from three general critical care units. The primary outcome measure was adequacy of ventilation calculated as the difference in arterial carbon dioxide tension before and after tracheostomy. On an intention-to-treat analysis, there was no difference in the increase in arterial carbon dioxide tension between groups, with a median (IQR [range]) for the LMA Supreme of 0.9 (0.3-1.6 [0-2.8]) kPa, and for the tracheal tube of 0.8 (0.4-1.2 [0-2.5]) kPa, p = 0.82. Eight patients out of 25 (32%) crossed over from the LMA Supreme group to the tracheal tube group before commencement of tracheostomy due to airway or ventilation problems, compared with none out of 25 in the tracheal tube group, p = 0.01, and tracheostomy was postponed in two patients in the LMA Supreme group due to poor oxygenation. There were more clinically important complications in the LMA Supreme group compared with the tracheal tube group. PMID- 24803135 TI - Molecular composition, grafting density and film area affect the swelling-induced Au-S bond breakage. AB - In previous studies, we reported the first observation of the Au-S bond breakage induced mechanically by the swelling of the surface-tethered weak polyelectrolyte brushes in phosphate buffered saline (PBS), a phenomenon with broad applications in the fields of biosensors and functional surfaces. In this study, three factors, namely the molecular composition, grafting density and film area of the weak polyelectrolyte, carboxylated poly(oligo(ethylene glycol) methacrylate random-2-hydroxyethyl methacrylate) (poly(OEGMA-r-HEMA)), were studied systematically on how they affected the swelling-induced Au-S bond breakage (ABB). The results showed that, first, the swelling-induced ABB is applicable to a range of molecular compositions and grafting densities; but the critical thickness (Tcritical,dry) varied with both of the two factors. An analysis on the swelling ratio further revealed that the difference in the Tcritical,dry arose from the difference in the swelling ability. A film needed to swell to ~250 nm to induce ABB regardless of its composition or structure, thus a higher swelling ratio would lead to a lower Tcritical,dry value. Then, the impact of the film area was studied in micrometer- and sub-micrometer-scale brush patterns, which showed that only partial, rather than complete ABB was induced in these microscopic films, resulting in buckling instead of film detaching. These results demonstrated that the ABB is suitable to be used in the design of biosensors, stimulus-responsive materials and mechanochemical devices. Although the >160 MUm(2) required area for uniform ABB hinders the application of ABB in nanolithography, the irreversible buckling provides a facile method of generating rough surfaces. PMID- 24803132 TI - Cardiovascular sequelae of radiation therapy. AB - Radiotherapy (RT) is one of the main therapeutic options for malignancy treatment; nevertheless, RT is not free from side effects, including an increased risk for secondary neoplasms and other organs injury. Cardiovascular complications are the second most frequent fatal post-RT sequelae, which physicians should be aware of and ready to diagnose early and cure. This review therefore aims to examine epidemiology, pathogenesis and clinical dose-correlated manifestations of RT-induced cardiovascular disease. Future perspectives on screening, prevention and treatment are also provided. PMID- 24803134 TI - Radial modulation contrast imaging using a 20-MHz single-element intravascular ultrasound catheter. AB - Contrast-enhanced intravascular ultrasound imaging is a promising tool for the characterization of coronary vasa vasorum proliferation, which has been identified as a marker of, and possible etiologic factor in, the development of high-risk atherosclerotic plaques. Resonance-based nonlinear detection methods have required the development of prototype catheters which are not commercially available, thus limiting clinical translation. In this study, we investigated the performances of a radial modulation imaging approach (25/3 MHz combination) using simulations, implemented it on a clinical 20-MHz rotating catheter, and tested it in a wall-less tissue-mimicking flow phantom perfused with lipid-encapsulated microbubbles (MBs). The effects of the phase lag, low-frequency pressure, and MB concentration on the envelope subtracted radial modulation signals were investigated as a function of depth. Our dual-pulse dual-frequency approach produced contrast- specific images with contrast-to-tissue improvements over B mode of 15.1 +/- 2.1 dB at 2 mm and 6.8 +/- 0.1 dB at 4 mm depths. Using this imaging strategy, 200-MUm-diameter cellulose tubing perfused with MBs could be resolved while surrounding tissue scattering was suppressed. These results raise promise for the detection of coronary vasa vasorum and may ultimately facilitate the detection of plaque at risk for rupture. PMID- 24803136 TI - The blue light receptor Phototropin 1 suppresses lateral root growth by controlling cell elongation. AB - We investigated the relationship between the blue light receptor phototropin 1 (phot1) and lateral root growth in Arabidopsis thaliana seedlings. Fluorescence and confocal microscopy images, as well as PHOT1 mRNA expression studies provide evidence that it is highly expressed in the elongation zone of lateral roots where auxin is accumulating. However, treatment with the auxin transport inhibitor N-1-naphthylphthalamic acid significantly reduced PHOT1 expression in this zone. In addition, PHOT1 expression was higher in darkness than in light. The total number of lateral roots was higher in the phot1 mutant than in wild type Arabidopsis. Cells in the elongation zone of lateral roots of the phot1 mutant were longer than those of wild-type lateral roots. These findings suggest that PHOT1 plays a role(s) in elongation of lateral roots through the control of an auxin-related signalling pathway. PMID- 24803137 TI - Risk and management of intra-abdominal abscess in Crohn's disease treated with infliximab. AB - BACKGROUND AND AIMS: Infliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX. METHODS: CD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses. RESULTS: Intra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors. CONCLUSIONS: Abscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors. PMID- 24803138 TI - Quantitative analyses of ROS and RNS production in breast cancer cell lines incubated with ferrocifens. AB - Ferrocifens are an original class of ferrocifen-type breast cancer drugs. They possess anti-proliferative effects due to the association of the ferrocene moiety and the tamoxifen skeleton. In this work, fluorescence measurements indicated the production of reactive oxygen species (ROS) if hormone-dependent or -independent breast cancer cells were incubated with three hit ferrocifen compounds. Additionally, amperometry at ultramicroelectrodes was carried out to identify and quantify ROS and reactive nitrogen species (RNS) under stress conditions. Videomicroscopy was used to optimize the conditions employed for electrochemical investigations. Amperometry was then performed on two cell lines pre-incubated with each of the three ferrocifens. Interestingly, these results demonstrate that the presence of an aminoalkyl chain in the ferrocifen structure may confer a unique behavior toward both cell lines, in comparison with the two other compounds that lack this feature. PMID- 24803139 TI - Possible reason for the unusual regioselectivity in nucleophilic ring opening of trisubstituted aziridines under mildly basic conditions. AB - 2,2,3-Trisubstituted aziridines are known to undergo ring opening at the more substituted carbon under mildly basic conditions. However, the reason for the formation of the more sterically encumbered product has never been examined. Several trisubstituted aziridines, with different substitution patterns at the C 2 and C-3 carbons, were synthesized to change the electronics of the aziridine ring system. These changes had no effect on the regioselectivity of the ring opening reaction. Using the B3LYP/6-31G* DFT basis set it was determined that the transition state for opening at the more substituted carbon proceeds at a lower energy than the transition state at the less substituted carbon. PMID- 24803140 TI - Mercury sensing and toxicity studies of novel latex fabricated silver nanoparticles. AB - Safe and eco-friendly alternatives to currently used hazardous chemico-physical methods of silver nanoparticles (AgNPs) synthesis are need of time. Rapid, low cost, selective detection of toxic metals in environmental sample is important to take safety action. Toxicity assessment of engineered AgNPs is essential to avoid its side effects on human and non-target organisms. In the present study, biologically active latex from Euphorbia heterophylla (Poinsettia) was utilized for synthesis of AgNPs. AgNPs was of spherical shape and narrow size range (20-50 nm). Occurrence of elemental silver and crystalline nature of AgNPs was analyzed. Role of latex metabolites in reduction and stabilization of AgNPs was analyzed by FT-IR, protein coagulation test and phytochemical analysis. Latex-synthesized AgNPs showed potential in selective and sensitive detection of toxic mercury ions (Hg(2+)) with limit of detection around 100 ppb. Addition of Hg(2+) showed marked deviation in color and surface plasmon resonance spectra of AgNPs. Toxicity studies on aquatic non-target species Daphnia magna showed that latex-synthesized AgNPs (20.66 +/- 1.52% immobilization) were comparatively very less toxic than chemically synthesized AgNPs (51.66 +/- 1.52% immobilization). Similarly, comparative toxicity study on human red blood cells showed lower hemolysis (4.46 +/- 0.01%) by latex-synthesized AgNPs as compared to chemically synthesized AgNPs causing 6.14 +/- 0.01% hemolysis. PMID- 24803141 TI - Enhanced production of triterpenoid in submerged cultures of Antrodia cinnamomea with the addition of citrus peel extract. AB - In recent years, Antrodia cinnamomea has become a well-known medicinal mushroom in Taiwan. Triterpenoids are considered one of the most biologically active components found in A. cinnamomea. The aim of this research is to investigate the feasibility of enhancing triterpenoid production in shake flask cultures of A. cinnamomea by adding citrus peel extract. As a result of its containing essential oils, citrus peel extract is inhibitory to mycelial growth. In the experiments, the appropriate adding time is determined to be on day 7. Of the various citrus peel extracts tested, tangerine proves to be the most effective in enhancing polyphenol and triterpenoid production. With an addition of 2% (v/v), the content and production of total polyphenols rises from 5.95 mg/g DW of the control and 56.73 mg/L to 23.52 mg/g DW and 224.39 mg/L, respectively, on day 28. The production of triterpenoids also increases from 99.93 to 1,028.02 mg/L, for more than a tenfold increase. An optimal level of tangerine peel additive is determined to be around 4%. Furthermore, when compared with the mycelia of the control culture, the profiles of the HPLC analysis show that the mycelia cultured with the tangerine-peel addition contain more kinds of triterpenoids. This study demonstrates that the addition of citrus peel extract effectively enhances the production of bioactive metabolites in the submerged cultures of A. cinnamomea. PMID- 24803142 TI - A novel protein complex identification algorithm based on Connected Affinity Clique Extension (CACE). AB - A novel algorithm based on Connected Affinity Clique Extension (CACE) for mining overlapping functional modules in protein interaction network is proposed in this paper. In this approach, the value of protein connected affinity which is inferred from protein complexes is interpreted as the reliability and possibility of interaction. The protein interaction network is constructed as a weighted graph, and the weight is dependent on the connected affinity coefficient. The experimental results of our CACE in two test data sets show that the CACE can detect the functional modules much more effectively and accurately when compared with other state-of-art algorithms CPM and IPC-MCE. PMID- 24803143 TI - The therapeutic effects of human adipose-derived stem cells in a rat cervical spinal cord injury model. AB - Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study, we investigated the effects of adult human adipose-derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory dorsal root ganglia neurons. After transplantation into the lateral funiculus 1 mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express brain-derived neurotrophic factor, vascular endothelial growth factor, and fibroblast growth factor-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborizations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting. PMID- 24803145 TI - Features of multiple pregnancies obtained by in vitro fertilization or spontaneously. AB - BACKGROUND: The aim of this study was to investigate the prognosis of infants born to multiple pregnancies obtained by in vitro fertilization (IVF) or spontaneously. METHODS: The records of multiple pregnancies in Bakirkoy Maternity and Children's Hospital between February 2008 and January 2009 were investigated. Maternal, perinatal and postnatal data of multiple pregnancies were evaluated. The congenital anomalies determined by physical examination and/or imaging studies in the prenatal, natal and postnatal period and the difference between groups in terms of morbidity and mortality were investigated as well. RESULTS: A total of 401 spontaneous multiple pregnancies and 128 IVF multiple pregnancies were included in the study. Rate of multiple pregnancies for live births and IVF rate were 3.8% and 0.79%, respectively. The mean maternal age was 30.1 years (21 43) in the IVF group and 27.9 years (13-43) in the spontaneous group (P < 0.05). The cesarean delivery rate was 100% in the IVF group and 78% in the spontaneous group (P = 0.002). Premature rupture of membranes rate was 9.8% in the IVF group and 3.6% in the spontaneous group (P < 0.05). CONCLUSIONS: Multiple pregnancies constitute an important health problem due to high perinatal risks and increased health costs. We found maternal age, premature rupture of membranes and cesarean delivery rate significantly high in the IVF group. No significant differences were found between spontaneous and IVF multiple pregnancies in terms of demographic features, hospitalization stay and rate, admission to neonatal intensive care unit, mortality and congenital malformation. PMID- 24803146 TI - Dissociation in the DSM-5: your view S'Il Vous Plait, Docteur Janet? PMID- 24803147 TI - Main and interactive effects of anxiety sensitivity and physical distress intolerance with regard to PTSD symptoms among trauma-exposed smokers. AB - The present study examined the roles of anxiety sensitivity (AS; the tendency to misinterpret physical internal sensations of harmful) and distress tolerance (the capacity to tolerate aversive stimuli) in terms of the expression of posttraumatic stress disorder (PTSD) symptoms among a sample of trauma-exposed, treatment-seeking tobacco smokers (n = 137; Mage = 37.7 years, 48.2% female). It was hypothesized that higher AS and lower physical distress tolerance would interact to predict greater PTSD avoidance and hyperarousal symptoms. Results were partially consistent with this prediction. Specifically, there was a significant interactive effect of AS by physical distress tolerance in terms of PTSD hyperarousal symptom cluster severity. The form of the interaction was in the expected direction, with the highest levels of PTSD hyperarousal symptoms reported among smokers with higher levels of AS and a lower capacity to tolerate physical distress. Findings underscore the importance of considering AS and physical distress tolerance in terms of better understanding mechanisms underlying the expression of PTSD symptoms among trauma-exposed smokers. PMID- 24803152 TI - Author reply to: Retreatment with Ozurdex for macular edema secondary to retinal vein occlusion. PMID- 24803151 TI - Lowered humidity produces human epidermal equivalents with enhanced barrier properties. AB - Multilayered human keratinocyte cultures increasingly are used to model human epidermis. Until now, studies utilizing human epidermal equivalents (HEEs) have been limited because previous preparations do not establish a normal epidermal permeability barrier. In this report, we show that reducing environmental humidity to 50% relative humidity yields HEEs that closely match human postnatal epidermis and have enhanced repair of the permeability barrier. These cultures display low transepidermal water loss and possess a calcium and pH gradient that resembles those seen in human epidermis. These cultures upregulate glucosylceramide synthase and make normal-appearing lipid lamellar bilayers. The epidermal permeability barrier of these cultures can be perturbed, using the identical tools previously described for human skin, and recover in the same time course seen during in vivo barrier recovery. These cultures will be useful for basic and applied studies on epidermal barrier function. PMID- 24803153 TI - Retinal and choroidal thickness changes after single anti-VEGF injection in neovascular age-related macular degeneration: ranibizumab vs bevacizumab. AB - PURPOSE: To evaluate and compare the effects of single intravitreal injection of ranibizumab and bevacizumab on central retinal and choroidal thickness in patients with neovascular age-related macular degeneration (AMD). METHODS: Forty eyes of 40 patients with neovascular AMD that underwent intravitreal injection of vascular endothelial growth factor inhibitors (anti-VEGFs) were included. Patients were randomized into 2 groups: 20 eyes received ranibizumab and 20 eyes received bevacizumab injection. Central retinal and choroidal thicknesses of all eyes at baseline and 1 month postinjection scans were measured with Fourier domain optical coherence tomography (OCT). Student t test and Mann-Whitney U test were used to compare the data. RESULTS: The mean central retinal thickness (CRT) showed significant decrease after single injection of ranibizumab (from 345.0 um to 253.5 um, p<0.01) and bevacizumab (from 329.5 um to 251.0 um, p<0.01) at the first month, respectively. There was no significant difference regarding the CRT change between groups (p = 0.39). The mean choroidal thickness decreased from 158.6 um (115-317) to 155.5 um (111-322) in the ranibizumab group and from 211.5 um (143-284) to 201.5 um (93-338) in bevacizumab group. The decrease was not significant between groups (p = 0.35). CONCLUSIONS: Intravitreal injection of both ranibizumab and bevacizumab provided a significant decrease in CRT; however, the agents caused no significant change in choroidal thickness. Additionally, no difference between ranibizumab versus bevacizumab was observed related to macular edema inhibition. PMID- 24803154 TI - Decreased retinal nerve fiber layer thickness in patients with congenital isolated growth hormone deficiency. AB - PURPOSE: To evaluate the optic disc topography parameters of children with congenital isolated growth hormone deficiency (GHD) using the Heidelberg retina tomograph (HRT) in a controlled study. METHODS: This prospective study included 32 eyes of 32 patients with congenital isolated GHD and 36 eyes of 36 healthy subjects. The topographic optic disc parameters (mean cup volume, rim volume, cup area, disc area, rim area, mean cup-to-disc ratio and cup depth, retinal nerve fiber layer thickness [RNFL]) were imaged in all subjects with HRT-III (software 3.01 a-M). Pearson correlation analysis was used to investigate the correlation between right and left eyes regarding the optic disc parameters. Differences between the 2 groups were evaluated by independent t test, Mann-Whitney U test, and chi-square test. RESULTS: The mean RNFL thickness in children with congenital isolated GHD was found to be statistically significantly thinner than in healthy subjects (p<0.05). However, no statistically significant differences were found between the mean cup volume, rim volume, cup area, disc area, rim area, mean cup to-disc ratio and cup depth, and mean sectorial RNFL thickness (p>0.05). CONCLUSIONS: The results suggest that congenital GHD may lead to thinner RNFL thickness when compared with healthy subjects. This indicates that GH has an important role in the development of the neural retina. PMID- 24803155 TI - Intravitreal dexamethasone implant for acute exudative polymorphous vitelliform maculopathy. AB - PURPOSE: Acute exudative polymorphous vitelliform maculopathy is a rare retinal disease characterized by bilateral serous macular detachment and subretinal accumulation of yellowish deposits resembling Best dystrophy lesions. Corticosteroid systemic therapy has been used empirically in the attempt to treat this retinal disorder with mixed results. Thus, the benefit of corticosteroid remains undetermined. To our knowledge, we report the first case of acute exudative polymorphous vitelliform maculopathy (AEPVM) treated in one eye with intravitreal dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, California, USA). METHODS: A 28-year-old man with AEPVM underwent intravitreal dexamethasone implantation in the left eye. RESULTS: Compared with the fellow eye, intravitreal dexamethasone implant did not significantly modify the clinical course of the disease. No implant-related complication was experienced during follow-up. CONCLUSIONS: The lack of response to intravitreal dexamethasone seems to suggest that corticosteroids may be ineffective for the treatment of AEPVM. PMID- 24803156 TI - Ocular surface alterations in blepharospasm patients treated with botulinum toxin A injection. AB - PURPOSE: To evaluate ocular surface changes secondary to periocular botulinum toxin A injection in patients with essential blepharospasm. METHODS: Thirteen eyes of 13 patients with essential blepharospasm who underwent periocular botulinum toxin A injection were included in this prospective study. Patients were evaluated prior to and at 2-week and 1-, 3-, and 6-month time points following injections. Ocular surface tests were carried out in the order of tear break-up time (TBUT), lissamine green (LG) staining, Schirmer I test with anesthesia, and ocular surface disease index (OSDI) questionnaire for all patients. The Friedman test with Conover post hoc method was used for statistical comparisons of values at different time points. RESULTS: The TBUT was found to be increased at 1 month after the injection (8.5 +/- 2.1; p = 0.018) and decreased below baseline levels (6.4 +/- 2.1) at the 6-month visit (5.7 +/- 2.0; p = 0.018). None of the Schirmer test values at follow-up visits were significantly different as compared to baseline levels (11.3 +/- 5.5), although the 2-week measurement (14.3 +/- 5.6) was significantly higher as compared to that at the 6 month follow-up visit (9.6 +/- 4.9; p = 0.034). There was also a significant decrease in LG staining scores at 2-week (0.6 +/- 0.4; p = 0.012) and 1-month (0.6 +/- 0.4; p = 0.012) time points compared to the baseline levels (1.1 +/- 0.6). The OSDI scores improved at 2-week (5.4 +/- 6.8; p<0.001), 1-month (3.2 +/- 5.1; p<0.001), 3-month (2.5 +/- 4.4; p<0.001), and 6-month (5.5 +/- 5.4; p<0.001) time points as compared to baseline levels (11.6 +/- 8.5). CONCLUSIONS: Botulinum toxin A injection appears to have a positive but temporary effect on ocular surface parameters in patients with blepharospasm. PMID- 24803157 TI - Changes in the etiology of endophthalmitis from 2003 to 2010 in a large tertiary medical center. AB - PURPOSE: To ascertain the leading causes of endophthalmitis at the Tel Aviv Medical Center between 2003 and 2010. METHODS: The design of the study is retrospective chart review. The medical records of all patients diagnosed with endophthalmitis in our center between 2003 and 2010 were reviewed for visual acuity and results of ophthalmologic examination at admission, treatment, complications, laboratory investigations, and final visual results. The etiologies of endophthalmitis after cataract surgery were compared for each year from 2003 to 2010, and after intravitreal (IVT) injection from 2006 to 2010. RESULTS: Eighty patients were diagnosed with endophthalmitis between 2003 and 2010: 46 male and 34 female, average age 70.7 years. A total of 27.5% were treated with IVT antibiotic injection only and 68.8% needed pars plana vitrectomy. Final visual acuity was better than counting fingers in 56.3% of cases. Surgery was almost the sole cause of endophthalmitis until 2005, when IVT injection became an important etiology. The incidence of postcataract endophthalmitis decreased significantly after 2007 and that following IVT injection decreased significantly after 2008. CONCLUSIONS: The leading etiology of endophthalmitis changed from postoperative endophthalmitis to endophthalmitis after IVT injection from 2003 to 2010, and the incidence of the infection as a complication of those procedures decreased. PMID- 24803158 TI - Drinking stories: the importance of gender, narrative and epistemology. PMID- 24803159 TI - Regulation of microcystin-LR-induced toxicity in mouse spermatogonia by miR-96. AB - Microcystin (MC)-LR is a cyclic heptapeptide that acts as a potent reproductive system toxin, especially by decreasing sperm quality through affecting spermatogonia. However, the molecular mechanisms of MC-induced spermatogonial cytotoxicity still remain unclear. The present study was designed to investigate changes in microRNA (miRNA) profiles and their potential functions in spermatogonia (GC-1 cell line) following treatment with MC-LR. With microarray analysis, 101 miRNAs were identified to be significantly altered in GC-1 cells treated with MC-LR. Among the 25 miRNAs associated with spermatogenesis, miR-96 was down-regulated most dramatically and thus selected for further functional analysis. Deleted-in azoospermia-associated protein 2 (DAZAP2) was predicted to have a binding sequence for miR-96 within its 3'-untranslated region. Fluorescent reporter assay confirmed that DAZAP2 was the target gene of miR-96. The expression of DAZAP2 decreased significantly when miR-96 was up-regulated. Consistently, down-regulation of miR-96 significantly increased the level of DAZAP2. Up-regulation of miR-96 promoted cell viability in GC-1 cells as a result of exposure to MC-LR. Our study suggested a crucial role for miR-96 in the regulation of cytotoxic effects of MC-LR in spermatogonia, which provides new perspectives in the diagnosis and treatment strategies for MC-induced male infertility. PMID- 24803160 TI - Influence of a genomic classifier on post-operative treatment decisions in high risk prostate cancer patients: results from the PRO-ACT study. AB - OBJECTIVE: To assess the effect of an individualized genomic classifier (GC) test, for predicting metastasis following radical prostatectomy (RP), on urologists' adjuvant treatment decisions when caring for high-risk patients. PATIENTS AND METHODS: Data were submitted by US board-certified urologists in community practices (n = 15), who ordered the GC test for 146 prostate cancer patients with adverse pathologic features following RP (i.e., pathologic stage pT3 or positive surgical margins). Treatment recommendations were reported using an electronic data collection instrument, before and after reviewing the GC test report. Physicians also completed a Decision Conflict Scale (DCS), a decisional conflict measure, to assess their confidence with their treatment recommendations. RESULTS: Over 60% of high-risk patients were re-classified as low risk after review of the GC test results. Overall, adjuvant treatment recommendations were modified for 30.8% (95% CI = 23-39%) of patients. With GC test results, 42.5% of patients who were initially recommended adjuvant therapy were subsequently recommended observation. Although the number of patients recommended adjuvant therapy remained the same before and after review of the GC test results, it did influence patient treatment strategies. Multivariable analysis confirmed GC risk was the only significant predictor of treatment recommendations (OR = 4.04; 95% CI = 2.36, 6.92; p < 0.0001). Decisional conflict with regard to adjuvant treatment decisions was significantly less with the use of the GC test (p < 0.0001). CONCLUSIONS: Information on individualized metastasis risk based on a patient's tumor biology, with use of the GC test, significantly changed urologists' adjuvant treatment recommendations for post operative patients with prostate cancer, who were at high risk of metastasis. Namely, the results of this study provide evidence for the utility of the GC test, and show it may guide use of adjuvant radiation. PMID- 24803161 TI - When and for whom are relative age effects important? Evidence from a simple test of cardiorespiratory fitness. AB - OBJECTIVES: When individuals of different ages are combined into a single group and an ability that varies with age is measured, younger individuals are disadvantaged. This phenomenon is known as a relative age effect (RAE) and has been shown to be widespread in sport and education. METHODS: In this article, we examine RAEs in a large group of children tested repeatedly on the 20-m shuttle run, a common test of cardiorespiratory fitness. Following up on an earlier study that measured change with age, we add a growth curve model for change in variance, which makes it possible to derive RAEs for individuals of different ages and ability levels. RESULTS: Results show that a 1-year difference in age is associated with a change in performance of about 0.2 standard deviations. For 1 year age groups, this gives rise to ranking errors of 4 percentile ranks or less. We also show, however, that these relatively small ranking errors are capable of producing large age differences within groups identified as exceptional. Depending on the level of ability required for selection, children born in the first quarter of the year can be expected to outnumber those born in the last by 1.5 times, 2 times, or more. This finding is consistent with previously reported variation in RAEs at different performance levels. CONCLUSIONS: Results imply that RAEs are likely to be of relatively minor concern when people are graded or ranked but can produce substantial inequities and misclassifications when people with extremely high or extremely low ability levels undergo selection. PMID- 24803163 TI - Lateral orbitotomy for treatment of an orbital abscess in a dog. AB - A two-year-old Jack Russell terrier was diagnosed with a retrobulbar abscess and orbital cellulitis. The diagnosis was confirmed by ultrasound, magnetic resonance imaging examination and ultrasound-guided fine-needle aspiration. Transoral ventral drainage was attempted but was unsuccessful. The abscess was successfully treated by open drainage through a lateral orbitotomy. Despite the exposure of the orbital structures, the orbital soft tissues healed by second intention without further complications. The open drainage was well tolerated and resulted in immediate reduction of inflammation and pain, allowing a quick recovery. This report describes the diagnosis and, surgical management and the long-term (3 years) follow-up of an unusual case of orbital abscess associated with diffuse periorbital cellulitis successfully treated by open drainage through a lateral orbitotomy. PMID- 24803162 TI - Applied physiology of female soccer: an update. AB - The popularity and professionalism of female soccer has increased markedly in recent years, with elite players now employed on either a professional or semi professional basis. The previous review of the physiological demands of female soccer was undertaken two decades ago when the sport was in its relative infancy. Increased research coupled with greater training and competition demands warrants an updated review to consider the effect on physical performance and injury patterns. The physical demands of match-play along with the influence of factors such as the standard of competition, playing position and fatigue have been explored. Total distance covered for elite female players is approximately 10 km, with 1.7 km completed at high speed (>15 kmh(-1)) [corrected].Elite players complete 28% more high-speed running and 24 % more sprinting than moderate-level players. Decrements in high-speed running distance have been reported between and within halves, which may indicate an inability to maintain high-intensity activity. Although the physical capacity of female players is the most thoroughly researched area, comparisons are difficult due to differing protocols. Elite players exhibit maximal oxygen uptake (VO2max) values of 49.4-57.6 mL.kg(-1).min( 1), Yo Yo Intermittent Endurance test level 2 (YYIE2) scores of 1,774 +/- 532 m [mean +/- standard deviation (SD)] and 20 m sprint times of 3.17 +/- 0.03 s (mean +/- SD). Reasons for the increased prevalence of anterior cruciate ligament injuries in females (2-6 times greater than males) are discussed, with anatomical, biomechanical loading and neuromuscular activation differences being cited in the literature. This review presents an in-depth contemporary examination of the applied physiology of the female soccer player. PMID- 24803164 TI - The oxysterol receptor LXRbeta protects against DSS- and TNBS-induced colitis in mice. AB - We examined the function of the oxysterol receptors (LXRs) in inflammatory bowel disease (IBD) through studying dextran sodium sulfate (DSS)- and 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and by elucidating molecular mechanisms underlying their anti-inflammatory action. We observed that Lxr-deficient mice are more susceptible to colitis. Clinical indicators of colitis including weight loss, diarrhea and blood in feces appeared earlier and were more severe in Lxr-deficient mice and particularly LXRbeta protected against symptoms of colitis. Addition of an LXR agonist led to faster recovery and increased survival. In contrast, Lxr-deficient mice showed slower recovery and decreased survival. In Lxr-deficient mice, inflammatory cytokines and chemokines were increased together with increased infiltration of immune cells in the colon epithelium. Activation of LXRs strongly suppressed expression of inflammatory mediators including TNFalpha. While LXRalpha had anti-inflammatory effects in CD11b(+) immune cell populations, LXRbeta in addition had anti-inflammatory effects in colon epithelial cells. Lack of LXRbeta also induced CD4(+)/CD3(+) immune cell recruitment to the inflamed colon. Expression of both LXRA and LXRB was significantly suppressed in inflamed colon from subjects with IBD compared with non-inflamed colon. Taken together, our observations suggest that the LXRs could provide interesting targets to reduce the inflammatory responses in IBD. PMID- 24803165 TI - The homotropenylium cation: a system with a pinched pi ring current. AB - The homotropenylium cation (1, C8H9(+)) is a key species in the discussion of homoaromaticity. Constrained optimisations around the minimum structure have been performed, varying the size of the gap spanned by the CH2-bridge and optimising all other geometrical parameters. At each bridging distance, ab initio current density maps have been calculated and plotted using the ipsocentric approach. Analysis of the maps, including decomposition into localised orbital contributions, gives a clear indication of a global diatropic ring current passing through the gap. The change in ppi-ppi interaction, from conventional pi overlap around the conjugated seven-carbon perimeter to sigma overlap (psigma psigma) in the gap, results in a distinctive pinched topology, with two streams of current pinched down into one for part of the circuit. This ring current is diatropic and therefore the species 1 is aromatic on the magnetic criterion. PMID- 24803166 TI - Spatiotemporal pattern of TRAF3 expression after rat spinal cord injury. AB - TNF receptor associated factor 3 (TRAF3), a member of the TRAF family of intracellular signaling proteins, can directly influence the phosphorylation status and activation of c-Jun N-terminal kinase, participating in CD40-induced apoptosis in carcinoma. However, its expression profile and function are still unclear in spinal cord injury (SCI). In this study, we performed an acute spinal cord contusion injury model in adult rats and detected the dynamic change patterns of TRAF3 expression in spinal cord. Western blot and immunohistochemistry revealed a striking upregulation of TRAF3 after SCI. Double immunofluorescence staining prompted that TRAF3 immunoreactivity was found in neurons rather than astrocytes. Moreover, co-localization of TRAF3/active caspase 3 was detected in neuronal nuclei. To further investigate the function of TRAF3, a neuronal cell line PC12 was employed to establish an apoptosis model in vitro. We analyzed the association of TRAF3 with active caspase-3 on PC12 cells by western blot and immunofluorescent labeling, which was parallel with the data in vivo. Additionally, knocking TRAF3 down with siRNA demonstrated the probable pro apoptotic role of TRAF3 in the process of neuronal apoptosis. To summarize, we firstly uncover the temporal and spatial expression changes of TRAF3 in SCI. Our data suggest that TRAF3 might be implicated in central nervous system pathophysiology after SCI. PMID- 24803168 TI - Aortic root replacement using a modified composite valve graft. AB - OBJECTIVES: We used a modified technique of a composite graft by moving the valve prosthesis away from the end into the inside of the tube and compared the effectiveness of this surgical method with the standard valved conduits. METHODS: Through a prospective nonrandomized clinical study between March 2011 and June 2012, we performed replacement of the aortic valve and ascending aorta in 30 consecutive patients using a valved composite graft with a mechanical valve prosthesis. A modified self-assembled valved composite graft was employed in 20 patients (Modified group), while the remaining 10 patients received the standard composite graft (Control group). RESULTS: There was significantly less bleeding in the patients with modified grafts (184 vs. 415 mL, p < 0.05). Moreover, the mean transvalvular gradient of the composite graft patients was lower in the modified group than in the control group (9 vs. 14 mmHg, respectively, p < 0.05). CONCLUSIONS: The modified valve composite graft technique results in good hemodynamics and appears to limit blood loss. PMID- 24803167 TI - Serological and virological surveillance of avian influenza A virus H9N2 subtype in humans and poultry in Shanghai, China, between 2008 and 2010. AB - We report the serological evidence of low-pathogenic avian influenza (LPAI) H9N2 infection in an occupational poultry-exposed population and a general population. A serological survey of an occupational poultry-exposed population and a general population was conducted using a haemagglutinin-inhibiting (HI) assay in Shanghai, China, from January 2008 to December 2010. Evidence of higher anti-H9 antibodies was found in serum samples collected from poultry workers. During this period, 239 H9N2 avian influenza viruses (AIVs) were isolated from 9297 tracheal and cloacal paired specimens collected from the poultry in live poultry markets. In addition, a total of 733 influenza viruses were isolated from 1569 nasal and throat swabs collected from patients with influenza-like symptoms in a sentinel hospital, which include H3N2, H1N1, pandemic H1N1 and B, but no H9N2 virus was detected. These findings highlight the need for long-term surveillance of avian influenza viruses in occupational poultry-exposed workers. PMID- 24803169 TI - Safety modeling of suburban arterials in Shanghai, China. AB - As urbanization accelerates in Shanghai, land continues to develop along suburban arterials which results in more access points along the roadways and more congested suburban arterials; all these changes have led to deterioration in traffic safety. In-depth safety analysis is needed to understand the relationship between roadway geometric design, access features, traffic characteristics, and safety. This study examined 161 road segments (each between two adjacent signalized intersections) of eight suburban arterials in Shanghai. Information on signal spacing, geometric design, access features, traffic characteristics, and surrounding area types were collected. The effect of these factors on total crash occurrence was investigated. To account for the hierarchical data structure, hierarchical Bayesian models were developed for total crashes. To identify diverse effects on different crash injury severity, the total crashes were separated into minor injury and severe injury crashes. Bivariate hierarchical Bayesian models were developed for minor injury and severe injury to account for the correlation among different severity levels. The modeling results show that the density of signal spacing along arterials has a significant influence on minor injury, severe injury, and total crash frequencies. The non-uniform signal spacing has a significant impact on the occurrence of minor injury crashes. At the segment-level, higher frequencies of minor injury, severe injury, and total crashes tend to occur for the segments with curves, those with a higher density of access points, those with a higher percentage of heavy vehicles, and those in inner suburban areas. This study is useful for applications such as related engineering safety improvements and making access management policy. PMID- 24803170 TI - Are drivers aware of sleepiness and increasing crash risk while driving? AB - Drivers are advised to take breaks when they feel too tired to drive, but there is question over whether they are able to detect increasing fatigue and sleepiness sufficiently to decide when to take a break. The aim of this study was to investigate the extent to which drivers have access to cognitive information about their current state of sleepiness, likelihood of falling asleep, and the implications for driving performance and the likelihood of crashing. Ninety drivers were recruited to do a 2h drive in a driving simulator. They were divided into three groups: one made ratings of their sleepiness, likelihood of falling asleep and likelihood of crashing over the next few minutes at prompts occurring at 200s intervals throughout the drive, the second rated sleepiness and likelihood of falling asleep at prompts but pressed a button on the steering wheel at any time if they felt they were near to crashing and the third made no ratings and only used a button-press if they felt a crash was likely. Fatigue and sleepiness was encouraged by monotonous driving conditions, an imposed shorter than usual sleep on the night before and by afternoon testing. Drivers who reported that they were possibly, likely or very likely to fall asleep in the next few minutes, were more than four times more likely to crash subsequently. Those who rated themselves as sleepy or likely to fall asleep had a more than 9 fold increase in the hazards of a centerline crossing compared to those who rated themselves as alert. The research shows clearly that drivers can detect changes in their levels of sleepiness sufficiently to make a safe decision to stop driving due to sleepiness. Therefore, road safety policy needs to move from reminding drivers of the signs of sleepiness and focus on encouraging drivers to respond to obvious indicators of fatigue and sleepiness and consequent increased crash risk. PMID- 24803171 TI - Hapten optimization for cocaine vaccine with improved cocaine recognition. AB - In the absence of any effective pharmacotherapy for cocaine addiction, immunotherapy is being actively pursued as a therapeutic intervention. While several different cocaine haptens have been explored to develop anticocaine antibodies, none of the hapten was successfully designed, which had a protonated tropane nitrogen as is found in native cocaine under physiological conditions, including the succinyl norcocaine (SNC) hapten that has been tested in phase II clinical trials. Herein, we discuss three different cocaine haptens: hexyl norcocaine (HNC), bromoacetamido butyl norcocaine (BNC), and succinyl butyl norcocaine (SBNC), each with a tertiary nitrogen structure mimicking that of native cocaine which could optimize the specificity of anticocaine antibodies for better cocaine recognition. Mice immunized with these haptens conjugated to immunogenic proteins produced high titre anticocaine antibodies. However, during chemical conjugation of HNC and BNC haptens to carrier proteins, the 2beta methyl ester group is hydrolyzed, and immunizing mice with these conjugate vaccines in mice produced antibodies that bound both cocaine and the inactive benzoylecgonine metabolite. While in the case of the SBNC conjugate, vaccine hydrolysis of the methyl ester did not appear to occur, leading to antibodies with high specificity to cocaine over BE. Although we observed similar specificity with a SNC hapten, the striking difference is that SBNC carries a positive charge on the tropane nitrogen atom, and therefore, it is expected to have better binding of cocaine. The 50% cocaine inhibitory concentration (IC50 ) value for SBNC antibodies (2.8 MUm) was significantly better than the SNC antibodies (9.4 MUm) when respective hapten-BSA was used as a substrate. In addition, antibodies from both sera had no inhibitory effect from BE. In contrast to BNC and HNC, the SBNC conjugate was also found to be highly stable without any noticeable hydrolysis for several months at 4 degrees C and 2-3 days in pH 10 buffer at 37 degrees C. PMID- 24803173 TI - All cardiovascular risk factors are not consistently associated with aortic stiffness other than hypertension. PMID- 24803172 TI - Observation of true and pseudo NOE signals using CEST-MRI and CEST-MRS sequences with and without lipid suppression. AB - PURPOSE: To investigate the characteristics of nuclear Overhauser enhancement (NOE) imaging signals in the brain at 7T. METHODS: Fresh hen eggs, as well as six healthy, and six C6 glioma-bearing Wistar rats were scanned using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) and chemical exchange saturation transfer-magnetic resonance spectroscopy (CEST-MRS) sequences (saturation duration 3 s, power 1.47 uT) with and without lipid suppression. CEST data were acquired over an offset range of -6 to +6 ppm relative to the water resonance in 0.5 ppm steps. RESULTS: The water signals were not disrupted by other protons during the CEST-MRS sequences, and true NOE signals could be observed. Using the CEST-MRI sequence without lipid suppression, pseudo NOE imaging signals were observed in the lipid-containing regions (egg yolk, scalp, and even white matter). These pseudo NOE signals were almost (but incompletely) removed with the lipid suppression. Egg yolk results indicated the presence of the NOE to olefinic protons overlapping with the water signal. In vivo experiments showed that the amide proton transfer signal was larger in the tumor, whereas the NOE signal was larger in the normal white matter. CONCLUSIONS: True NOE signals can be detected using MRS sequences, and considerable pseudo NOE imaging signals may be observed using MRI sequences. PMID- 24803174 TI - RAN as a predictor of reading skills, and vice versa: results from a randomised reading intervention. AB - Although phonemic awareness is a well-known factor predicting early reading development, there is also evidence that Rapid Automatized Naming (RAN) is an independent factor that contributes to early reading. The aim of this study is to examine phonemic awareness and RAN as predictors of reading speed, reading comprehension and spelling for children with reading difficulties. It also investigates a possible reciprocal relationship between RAN and reading skills, and the possibility of enhancing RAN by intervention. These issues are addressed by examining longitudinal data from a randomised reading intervention study carried out in Sweden for 9-year-old children with reading difficulties (N = 112). The intervention comprised three main elements: training of phonics, reading comprehension strategies and reading speed. The analysis of the data was carried out using structural equation modelling. The results demonstrated that after controlling for autoregressive effects and non-verbal IQ, RAN predicts reading speed whereas phonemic awareness predicts reading comprehension and spelling. RAN was significantly enhanced by training and a reciprocal relationship between reading speed and RAN was found. These findings contribute to support the view that both phonemic awareness and RAN independently influence early phases of reading, and that both are possible to enhance by training. PMID- 24803176 TI - Two thirds of deaths from asthma are preventable, confidential inquiry finds. PMID- 24803175 TI - Antimicrobial stewardship - can we afford to do without it? AB - Antimicrobial resistance (AMR) is a rapidly developing and alarming global threat which has been highlighted by national governments and public health bodies including the World Health Organization. The spectre of a 'post-antibiotic era' is a real possibility unless curtailing the development and spread of these organisms is given high priority. Numerous studies have shown that AMR is associated with worse outcomes for patients and higher healthcare costs. While clinical data from low and middle income countries is lacking, there is increasing evidence that the problem in these areas is as great, or even greater, than in high income nations. Of the many drivers behind the development of AMR, the most significant is selection pressure caused by antibiotic use. Antimicrobial stewardship programmes are a set of interventions that aim to ensure the judicious use of antimicrobials by preventing their unnecessary use, and by providing targeted and limited therapy in situations where they are warranted. The ultimate goal of these programmes is to provide effective antimicrobial therapy whilst safeguarding their effectiveness for future generations. Whilst they do require an initial investment, they have been shown to be an effective way of controlling antimicrobial use, and have been associated with improved patient outcomes and reduced healthcare costs. PMID- 24803177 TI - Exchange reactions between alkanethiolates and alkaneselenols on Au{111}. AB - When alkanethiolate self-assembled monolayers on Au{111} are exchanged with alkaneselenols from solution, replacement of thiolates by selenols is rapid and complete, and is well described by perimeter-dependent island growth kinetics. The monolayer structures change as selenolate coverage increases, from being epitaxial and consistent with the initial thiolate structure to being characteristic of selenolate monolayer structures. At room temperature and at positive sample bias in scanning tunneling microscopy, the selenolate-gold attachment is labile, and molecules exchange positions with neighboring thiolates. The scanning tunneling microscope probe can be used to induce these place-exchange reactions. PMID- 24803178 TI - Excimer laser correction of astigmatism: consistent terminology for better outcomes. PMID- 24803179 TI - Meeting report--3rd Neuroblastoma Research Symposium, Liverpool, 6-7th November, 2013. AB - Neuroblastoma is an embryonal malignancy of the developing neural crest. Despite improvements in treatment, prognoses remain dire for patients with high-risk disease. Interest in this enigmatic cancer has led to a rapidly changing research landscape and we report on the recent advances in four themes that were discussed at the 3rd Neuroblastoma Research Symposium: (1) The epigenetic signature of neuroblastoma and the epigenetic control of tumour development, (2) novel approaches to targeting MYCN, (3) valuable in vivo modelling and (4) improving differentiation therapies based on a knowledge of normal sympathetic neuron development. Through lively discussion, the development of combined therapies with synergistic effects for which we have a good mechanistic understanding emerged as offering greatest promise. Drug synergies enhance efficacy but also specificity, the latter crucial for reducing long-term side effects in young children. PMID- 24803180 TI - Altered gene expression signature of early stages of the germ line supports the pre-meiotic origin of human spermatogenic failure. AB - The molecular basis of spermatogenic failure (SpF) is still largely unknown. Accumulating evidence suggests that a series of specific events such as meiosis, are determined at the early stage of spermatogenesis. This study aims to assess the expression profile of pre-meiotic genes of infertile testicular biopsies that might help to define the molecular phenotype associated with human deficiency of sperm production. An accurate quantification of testicular mRNA levels of genes expressed in spermatogonia was carried out by RT-qPCR in individuals showing SpF owing to germ cell maturation defects, Sertoli cell-only syndrome or conserved spermatogenesis. In addition, the gene expression profile of SpF was compared with that of testicular tumour, which is considered to be a severe developmental disease of germ cell differentiation. Protein expression from selected genes was evaluated by immunohistochemistry. Our results indicate that SpF is accompanied by differences in expression of certain genes associated with spermatogonia in the absence of any apparent morphological and/or numerical change in this specific cell type. In SpF testicular samples, we observed down-regulation of genes involved in cell cycle (CCNE1 and POLD1), transcription and post transcription regulation (DAZL, RBM15 and DICER1), protein degradation (FBXO32 and TM9SF2) and homologous recombination in meiosis (MRE11A and RAD50) which suggests that the expression of these genes is critical for a proper germ cell development. Interestingly, a decrease in the CCNE1, DAZL, RBM15 and STRA8 cellular transcript levels was also observed, suggesting that the gene expression capacity of spermatogonia is altered in SpF contributing to an unsuccessful sperm production. Altogether, these data point to the spermatogenic derangement being already determined at, or arising in, the initial stages of the germ line. PMID- 24803182 TI - Cited2 is required in trophoblasts for correct placental capillary patterning. AB - CITED2 is a transcriptional co-factor with important roles in many organs of the developing mammalian embryo. Complete deletion of this gene causes severe malformation of the placenta, and results in significantly reduced embryonic growth and death from E14.5. The placenta is a complex organ originating from cells derived from three lineages: the maternal decidua, the trophectoderm, and the extra-embryonic mesoderm. Cited2 is expressed in many of these cell types, but its exact role in the formation of the placenta is unknown. Here we use a conditional deletion approach to remove Cited2 from overlapping subsets of trophectoderm and extra-embryonic mesoderm. We find that Cited2 in sinusoidal trophoblast giant cells and syncytiotrophoblasts is likely to have a non-cell autonomous role in patterning of the pericytes associated with the embryonic capillaries. This function is likely to be mediated by PDGF signaling. Furthermore, we also identify that loss of Cited2 in syncytiotrophoblasts results in the subcellular mislocalization of one of the major lactate transporters in the placenta, SLC16A3 (MCT4). We hypothesize that the embryonic growth retardation observed in Cited2 null embryos is due in part to a disorganized embryonic capillary network, and in part due to abnormalities of the nutrient transport functions of the feto-maternal interface. PMID- 24803183 TI - Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival. AB - CYP19 catalyzes the conversion of androgens to estrogens and is a critical enzyme affecting the sex hormone milieu. In this study, we investigated the functions of CYP19A1 polymorphisms and their associations with prostate cancer risk and clinical outcome. This case-control study evaluated the effects of three single nucleotide polymorphisms (SNPs) in CYP19A1 on the risk of prostate cancer in 330 prostate cancer patients and 354 normal controls. The associations between each SNP and sex hormone levels were evaluated in 164 healthy male patients. The functions of the SNPs were determined by reporter gene assays in PC3 and DU145 cell lines. Prostate-specific antigen nadir was evaluated in 142 patients with metastatic prostate cancer treated with androgen deprivation therapy. Cancer specific survival (CSS) was determined in 166 patients with metastatic prostate cancer, to evaluate the influence of the three SNPs. Each variant allele of the three SNPs significantly decreased the risk of prostate cancer. Haplotype analysis showed that the T-A-G haplotype (corresponding to rs2470152-rs10459592 rs4775936) increased the risk of prostate cancer, while the C-C-A haplotype decreased the risk. The estrone/androstenedione ratio was significantly higher in men with the C allele of rs2470152, the C allele of rs10459592, and the A allele of rs4775936 in a gene-dosage-dependent manner. Patients with the variant allele at rs4775936 had significantly shorter CSS. These results indicate that CYP19A1 polymorphisms may influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone milieu. PMID- 24803181 TI - Effects of lithium on inflammation. AB - Lithium is an effective medication for the treatment of bipolar affective disorder. Accumulating evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that lithium has anti-inflammatory effects that may contribute to its therapeutic efficacy. This article summarizes the studies which examined the effects of lithium on pro- and anti-inflammatory mediators. Some of the summarized data suggest that lithium exerts anti inflammatory effects (e.g., suppression of cyclooxygenase-2 expression, inhibition of interleukin (IL)-1beta and tumor necrosis factor-alpha production, and enhancement of IL-2 and IL-10 synthesis). Nevertheless, there is a large body of data which indicates that under certain experimental conditions lithium also exhibits pro-inflammatory properties (e.g., induction of IL-4, IL-6 and other pro inflammatory cytokines synthesis). The reviewed studies utilized various experimental model systems, and it is thus difficult to draw an unequivocal conclusion regarding the effect of lithium on specific inflammatory mediators. PMID- 24803184 TI - Reappraisal of mechanical exfoliating cytology for the detection of peritoneal dissemination during the surgical staging of epithelial ovarian carcinomas and borderline tumours. AB - OBJECTIVE: This study aimed to evaluate the usability of peritoneal swabbing cytology (PSC) with cotton swabs as an effective method for the detection of peritoneal metastasis during the staging laparotomy of epithelial ovarian carcinomas and borderline tumours (EOC/BT). STUDY DESIGN: One hundred and ninety two patients with EOC/BT who underwent laparotomy at the Yokohama City University Hospital from 2004 to 2010 were analysed retrospectively. The positive rates of the PSC and ascites/peritoneal-wash cytology (A/PWC) were compared. RESULTS AND CONCLUSION: Both A/PWC and PSC were performed during laparotomy (n = 140). The rate of metastasis detection with A/PWC was significantly higher than with PSC (50.0 vs. 20.7%, p < 0.001 by chi(2) test). The superior detection ability of A/PWC was observed regardless of the presence of macroscopic peritoneal metastasis in 56 cases with macroscopic peritoneal metastasis, with A/PWC detecting 80.3% of cases versus PSC detecting 37.5% (p = 0.013). In 84 cases without macroscopic peritoneal metastasis, A/PWC detected 29.8% of cases versus 9.5% with PSC (p = 0.003). Our results suggest that PSC is insufficient to evaluate the peritoneal metastasis for the surgical staging of EOC/BT. Other procedures such as subdiaphragmatic A/PWC should be included when possible to maximize the accuracy of diagnosis. PMID- 24803185 TI - Affective lability in patients with bipolar disorders is associated with high levels of childhood trauma. AB - This study aimed to investigate associations between a history of childhood trauma and levels of affective lability in bipolar patients compared to controls. Forty-two patients and 14 controls were assessed using the Affective Lability Scale (ALS) and the Childhood Trauma Questionnaire (CTQ). Affective Lability Score was significantly associated with scores on the Childhood Trauma Questionnaire. A multivariate regression model indicated a relationship between childhood trauma scores and differences in affective lability between patients and controls. PMID- 24803186 TI - Characteristics of stress-coping behaviors in patients with bipolar disorders. AB - Appropriate stress-coping strategies are needed to improve the outcome in the treatment of bipolar disorders, as stressful life events may aggravate the course of the illness. The aim of this study was to compare stress-coping behaviors between bipolar patients and healthy controls. A total of 206 participants comprising 103 bipolar patients fulfilling the Diagnostic and Statistical Manual for Axis I disorder fourth edition (DSM-IV) diagnostic criteria for bipolar I and II disorders and controls matched by age and sex were included in this study. Stress-coping behaviors were assessed using a 53-item survey on a newly-designed behavioral checklist. The characteristics of stress-coping behaviors between the two groups were compared by using t-test and factor analysis. Social stress coping behaviors such as 'journey', 'socializing with friends', and 'talking something over' were significantly less frequent in bipolar patients than controls. On the other hand, pleasurable-seeking behaviors such as 'smoking', 'masturbation', and 'stealing' were significantly more frequent in bipolar patients than controls. These results suggest that bipolar patients may have more maladaptive stress-coping strategies than normal controls. It is recommended to develop and apply psychosocial programs to reduce maladaptive stress-coping behaviors of bipolar patients. PMID- 24803187 TI - Plant-based biopharming of recombinant human lactoferrin. AB - Recombinant proteins are currently recognized as pharmaceuticals, enzymes, food constituents, nutritional additives, antibodies and other valuable products for industry, healthcare, research, and everyday life. Lactoferrin (Lf), one of the promising human milk proteins, occupies the expanding biotechnological food market niche due to its important versatile properties. Lf shows antiviral, antimicrobial, antiprotozoal and antioxidant activities, modulates cell growth rate, binds glycosaminoglycans and lipopolysaccharides, and also inputs into the innate/specific immune responses. Development of highly efficient human recombinant Lf expression systems employing yeasts, filamentous fungi and undoubtedly higher plants as bioreactors for the large-scale Lf production is a biotechnological challenge. This review highlights the advantages and disadvantages of the existing non-animal Lf expression systems from the standpoint of protein yield and its biological activity. Special emphasis is put on the benefits of monocot plant system for Lf expression and the biosafety aspects of the transgenic Lf-expressing plants. PMID- 24803188 TI - Simultaneous magnetic resonance imaging and consolidation measurement of articular cartilage. AB - Magnetic resonance imaging (MRI) offers the opportunity to study biological tissues and processes in a non-disruptive manner. The technique shows promise for the study of the load-bearing performance (consolidation) of articular cartilage and changes in articular cartilage accompanying osteoarthritis. Consolidation of articular cartilage involves the recording of two transient characteristics: the change over time of strain and the hydrostatic excess pore pressure (HEPP). MRI study of cartilage consolidation under mechanical load is limited by difficulties in measuring the HEPP in the presence of the strong magnetic fields associated with the MRI technique. Here we describe the use of MRI to image and characterize bovine articular cartilage deforming under load in an MRI compatible consolidometer while monitoring pressure with a Fabry-Perot interferometer-based fiber-optic pressure transducer. PMID- 24803190 TI - A space weather forecasting system with multiple satellites based on a self recognizing network. AB - This paper proposes a space weather forecasting system at geostationary orbit for high-energy electron flux (>2 MeV). The forecasting model involves multiple sensors on multiple satellites. The sensors interconnect and evaluate each other to predict future conditions at geostationary orbit. The proposed forecasting model is constructed using a dynamic relational network for sensor diagnosis and event monitoring. The sensors of the proposed model are located at different positions in space. The satellites for solar monitoring equip with monitoring devices for the interplanetary magnetic field and solar wind speed. The satellites orbit near the Earth monitoring high-energy electron flux. We investigate forecasting for typical two examples by comparing the performance of two models with different numbers of sensors. We demonstrate the prediction by the proposed model against coronal mass ejections and a coronal hole. This paper aims to investigate a possibility of space weather forecasting based on the satellite network with in-situ sensing. PMID- 24803189 TI - Recent advances in plasmonic sensors. AB - Plasmonic sensing has been an important multidisciplinary research field and has been extensively used in detection of trace molecules in chemistry and biology. The sensing techniques are typically based on surface-enhanced spectroscopies and surface plasmon resonances (SPRs). This review article deals with some recent advances in surface-enhanced Raman scattering (SERS) sensors and SPR sensors using either localized surface plasmon resonances (LSPRs) or propagating surface plasmon polaritons (SPPs). The advances discussed herein present some improvements in SERS and SPR sensing, as well as a new type of nanowire-based SPP sensor. PMID- 24803191 TI - Application of ultrasound phase-shift analysis to authenticate wooden panel paintings. AB - Artworks are a valuable part of the World's cultural and historical heritage. Conservation and authentication of authorship are important aspects to consider in the protection of cultural patrimony. In this paper we present a novel application of a well-known method based on the phase-shift analysis of an ultrasonic signal, providing an integrated encoding system that enables authentication of the authorship of wooden panel paintings. The method has been evaluated in comparison with optical analysis and shows promising results. The proposed method provides an integrated fingerprint of the artwork, and could be used to enrich the cataloging and protection of artworks. Other advantages that make particularly attractive the proposed technique are its robustness and the use of low-cost sensors. PMID- 24803192 TI - Ubiquitous connected train based on train-to-ground and intra-wagon communications capable of providing on trip customized digital services for passengers. AB - During the last years, the application of different wireless technologies has been explored in order to enable Internet connectivity from vehicles. In addition, the widespread adoption of smartphones by citizens represents a great opportunity to integrate such nomadic devices inside vehicles in order to provide new and personalized on trip services for passengers. In this paper, a proposal of communication architecture to provide the ubiquitous connectivity needed to enhance the smart train concept is presented and preliminarily tested. It combines an intra-wagon communication system based on nomadic devices connected through a Bluetooth Piconet Network with a highly innovative train-to-ground communication system. In order to validate this communication solution, several tests and simulations have been performed and their results are described in this paper. PMID- 24803193 TI - Development of a micro-step voltage-fed actuator with a novel stepper motor for automobile AGS systems. AB - This paper presents an improved micro-step voltage-fed actuator for an automobile active grill shutter (AGS) system. A novel structured stepper motor, which contains both the main and auxiliary teeth in the stator, is proposed for the actuator. In a normal permanent magnet (PM) motor coils are generally wound on all the stator teeth, however, in the proposed motor, the winding is only on the main teeth. Because of the absence of coils in the auxiliary teeth, the proposed stepper motor possesses the following advantages: simple structure, lighter weight, smaller volume, and less time consumption. The unique auxiliary poles in the stepper motor supply the flux path to increase the step resolution even without any coils. The characteristics of the proposed stepper motor were investigated using finite element analysis. In particular, the effect of the magnetization distribution of the PM on the motor performance was investigated during the analysis. Cogging torque, which causes noise and vibration issues, was minimized by the tooth-shape optimization. In addition, a micro-step voltage-fed algorithm was implemented for a high-resolution position control. By employing a current close to a sine wave using space vector pulse-width modulation, a high quality current waveform with a high resolution was obtained. Finally, the proposed prototype was fabricated, and the cogging torque, back-electromotive force, and current characteristics were measured by mounting the prototype on the AGS system. Both the analysis and experimental results validate the performance improvement from the proposed motor and its possible application for the flap control of the AGS system. PMID- 24803194 TI - Cooperative spectrum sensing schemes with the interference constraint in cognitive radio networks. AB - In this paper, we propose cooperative spectrum sensing schemes, called decode-and forward cooperative spectrum sensing (DF-CSS) scheme and amplify-and-forward cooperative spectrum sensing (AF-CSS) scheme, in cognitive radio networks. The main goals and features of the proposed cooperative spectrum sensing schemes are as follows: first, we solve the problem of high demand for bandwidth in a soft decision scheme using in our proposed schemes. Furthermore, the impact of transmission power of relaying users which is determined by the interference constraint on sensing performance of cooperative spectrum sensing schemes is also investigated. Second, we analyze the sensing performance of our proposed cooperative spectrum sensing schemes in terms of detection probability and interference probability, respectively. We take into account the interference caused by secondary user (SU) to primary user (PU) in the case that the transmission power of the relaying users exceeds a predefined interference constraint assigned by the primary user. The simulation results show that in cooperative spectrum sensing schemes the total sensing performance depends not only on the interference tolerance level, but also on the relay protocols used. We also prove that high transmission power of relaying users increases the interference between the secondary networks and the primary network. PMID- 24803195 TI - Human movement detection and identification using pyroelectric infrared sensors. AB - Pyroelectric infrared (PIR) sensors are widely used as a presence trigger, but the analog output of PIR sensors depends on several other aspects, including the distance of the body from the PIR sensor, the direction and speed of movement, the body shape and gait. In this paper, we present an empirical study of human movement detection and identification using a set of PIR sensors. We have developed a data collection module having two pairs of PIR sensors orthogonally aligned and modified Fresnel lenses. We have placed three PIR-based modules in a hallway for monitoring people; one module on the ceiling; two modules on opposite walls facing each other. We have collected a data set from eight subjects when walking in three different conditions: two directions (back and forth), three distance intervals (close to one wall sensor, in the middle, close to the other wall sensor) and three speed levels (slow, moderate, fast). We have used two types of feature sets: a raw data set and a reduced feature set composed of amplitude and time to peaks; and passage duration extracted from each PIR sensor. We have performed classification analysis with well-known machine learning algorithms, including instance-based learning and support vector machine. Our findings show that with the raw data set captured from a single PIR sensor of each of the three modules, we could achieve more than 92% accuracy in classifying the direction and speed of movement, the distance interval and identifying subjects. We could also achieve more than 94% accuracy in classifying the direction, speed and distance and identifying subjects using the reduced feature set extracted from two pairs of PIR sensors of each of the three modules. PMID- 24803196 TI - Thermoresistive strain sensor and positioning method for roll-to-roll processes. AB - This study uses the Joule heating effect-generated temperature difference to monitor in real-time and localize both compressive and tensile strains for the polymer substrates used in the roll-to-roll process. A serpentine gold (Au) line was patterned on a polyethylenenaphthalate (PEN) substrate to form the strain sensor based on thermoresistive behavior. This strain sensor was then subjected to either current or voltage to induce the Joule heating effect on the Au resistor. An infrared (IR) detector was used to monitor the strain-induced temperature difference on the Au and PEN surfaces and the minimal detectable bending radius was 0.9 mm with a gauge factor (GF) of 1.46. The proposed design eliminates the judgment ambiguity from conventional resistive strain sensors where resistance is the only physical quantity monitored. This study precisely and successfully indicated the local strain quantitatively and qualitatively with complete simulations and measurements. PMID- 24803197 TI - Wayside bearing fault diagnosis based on a data-driven Doppler effect eliminator and transient model analysis. AB - A fault diagnosis strategy based on the wayside acoustic monitoring technique is investigated for locomotive bearing fault diagnosis. Inspired by the transient modeling analysis method based on correlation filtering analysis, a so-called Parametric-Mother-Doppler-Wavelet (PMDW) is constructed with six parameters, including a center characteristic frequency and five kinematic model parameters. A Doppler effect eliminator containing a PMDW generator, a correlation filtering analysis module, and a signal resampler is invented to eliminate the Doppler effect embedded in the acoustic signal of the recorded bearing. Through the Doppler effect eliminator, the five kinematic model parameters can be identified based on the signal itself. Then, the signal resampler is applied to eliminate the Doppler effect using the identified parameters. With the ability to detect early bearing faults, the transient model analysis method is employed to detect localized bearing faults after the embedded Doppler effect is eliminated. The effectiveness of the proposed fault diagnosis strategy is verified via simulation studies and applications to diagnose locomotive roller bearing defects. PMID- 24803198 TI - Evaluation of candidate measures for home-based screening of sleep disordered breathing in Taiwanese bus drivers. AB - BACKGROUND: Sleepiness-at-the-wheel has been identified as a major cause of highway accidents. The aim of our study is identifying the candidate measures for home-based screening of sleep disordered breathing in Taiwanese bus drivers, instead of polysomnography. METHODS: Overnight polysomnography accompanied with simultaneous measurements of alternative screening devices (pulse oximetry, ApneaLink, and Actigraphy), heart rate variability, wake-up systolic blood pressure and questionnaires were completed by 151 eligible participants who were long-haul bus drivers with a duty period of more than 12 h a day and duty shifting. RESULTS: 63.6% of professional bus drivers were diagnosed as having sleep disordered breathing and had a higher body mass index, neck circumference, systolic blood pressure, arousal index and desaturation index than those professional bus drivers without evidence of sleep disordered breathing. Simple home-based candidate measures: (1) Pulse oximetry, oxygen-desaturation indices by >=3% and 4% (r = 0.87~0.92); (2) Pulse oximetry, pulse-rising indices by >=7% and 8% from a baseline (r = 0.61~0.89); and (3) ApneaLink airflow detection, apnea hypopnea indices (r = 0.70~0.70), based on recording-time or Actigraphy-corrected total sleep time were all significantly correlated with, and had high agreement with, corresponding polysomnographic apnea-hypopnea indices [(1) 94.5%~96.6%, (2) 93.8%~97.2%, (3) 91.1%~91.3%, respectively]. Conversely, no validities of SDB screening were found in the multi-variables apnea prediction questionnaire, Epworth Sleepiness Scale, night-sleep heart rate variability, wake-up systolic blood pressure and anthropometric variables. CONCLUSIONS: The indices of pulse oximetry and apnea flow detection are eligible criteria for home-based screening of sleep disordered breathing, specifically for professional drivers. PMID- 24803199 TI - Resistance to beta-lactam antibiotic may influence nanH gene expression in Trueperella pyogenes isolated from bovine endometritis. AB - Virulence could be modulated by many instinctive and environmental factors including oxygen, osmolarity and antimicrobial agents. This study aimed to investigate the correlation between drug resistance and the nanH expression in Trueperella pyogenes (T. pyogenes). Minimum inhibitory concentrations (MICs) of 6 beta-lactam antimicrobial agents (penicillin G, amoxicillin, oxacillin, cefazolin, ceftiofur, and ampicillin) against T. pyogenes were tested by standard broth dilution method according to the protocols of the Clinical and Laboratory Standards Institute (CLSI), and real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR) was selected to investigate the mRNA expression levels of the nanH in T. pyogenes. All the isolates were resistant to atleast 2 of antimicrobial agents, and multidrug resistance (resistance to atleast 3 antimicrobials) was observed in 84.38% (27/32) of isolates. The mRNA expression levels of the nanH were significantly higher in comparison with that in ATCC19411, as the resistance profile enlarged, the nanH mRNA expression levels decreased in T. pyogenes. These results indicated that beta-lactam antibiotic resistance in T. pyogenes may alter the expression of the nanH. PMID- 24803200 TI - In vitro studies of epithelium-associated crystallization caused by uropathogens during urinary calculi development. AB - Infectious urinary stones account for about 10% of all urinary stones. In 50% of cases urolithiasis is a recurrent illness, which can lead to the loss of a kidney if not properly treated. One of the reasons for recurrence of the disease may be the ability of bacteria to invade urothelial cells, persist in the host cells and serve as potential reservoirs for infection. Various uropathogens are associated with the formation of bacteria-induced urinary stones but Proteus mirabilis is the most commonly isolated (70%). An in vitro model was used in this study to analyze intracellular growth and crystallization in the presence of P. mirabilis, Klebsiella pneumoniae and Escherichia coli. Human ureter (Hu 609) and bladder (HCV 29) epithelial cell lines were infected with bacteria and incubated (3-72 h) in the presence of synthetic urine and amikacin to prevent extracellular bacterial growth. During the incubation the number of bacteria (CFU/ml) inside epithelial cells and the intensity of crystallization were established. Crystallization was determined as an amount of a calcium radioisotope. The chosen strains of uropathogens were able to invade both types of epithelial cells but the Hu 609 cells were invaded to a higher extent. However, crystallization occurred only in the presence of P. mirabilis strains which were invasive and urease-positive. The highest intensity of cell-associated crystallization was observed when the number of bacteria within the urothelium remained stable during the time of incubation. These results show that P. mirabilis has an ability to form crystals inside the host cells. Under these conditions bacteria are protected from antibiotic killing, which leads to persistent and recurrent infections. We also suspect that this phenomenon may be an important stage of kidney stones formation. PMID- 24803202 TI - Incorporating the new lipid guidelines into practice. PMID- 24803201 TI - Inferior outcomes of stage III T lymphoblastic lymphoma relative to stage IV lymphoma and T-acute lymphoblastic leukemia: long-term comparison of outcomes in the JACLS NHL T-98 and ALL T-97 protocols. AB - T cell lymphoblastic lymphoma (T-LBL) accounts for 30 % of all childhood non Hodgkin's lymphomas (NHL) in Japan. Twenty-nine patients with T-LBL in stages III and IV were eligible for and enrolled in the JACLS NHL-T98 trial (1998-2002), and 72 patients with T-ALL were enrolled in the JACLS ALL-T97 trial (1997-2001). The 10-year overall survival (OS) (61.1 +/- 11.5 %) and the 10-year event-free survival (EFS) (44.4 +/- 11.7 %) of stage III LBL were lower than those of other diseases, and the OS and EFS were nearly the same when comparing stage IV LBL and ALL (OS: stage IV LBL, 80.0 +/- 12.7 % vs. ALL, 80.2 +/- 4.9 %; EFS: stage IV, LBL 70.0 +/- 14.5 % vs. ALL, 70.7 +/- 5.5 %). Outcomes were worse for stage III LBL than for stage IV LBL or T-ALL. Given that the treatment results of T-ALL and LBL stage IV did not differ when compared with previous reports, LBL stage III in Japanese children may differ from LBL stage III in children in other countries. PMID- 24803203 TI - Physician assistants in South Africa. PMID- 24803204 TI - Pathogenicity mechanisms and host response during oral Candida albicans infections. AB - Oral candidiasis remains one of the most common forms of Candida infections and occurs if the balance between host, Candida and microbiota is disturbed, e.g., by broad spectrum antibiotics or immunosuppression. In recent years, identification of fungal factors contributing to host cell damage and new insights into host defense mechanisms have significantly extended our understanding of the pathogenesis of oral candidiasis. In this review, we will provide an overview of the pathogenicity mechanisms during oral Candida infections and discuss some approaches by which this knowledge could be transferred into therapeutic approaches. PMID- 24803205 TI - 'I felt colonised': emerging clinical teachers on a new rural teaching platform. AB - INTRODUCTION: Studies that investigate the impact of long-term rural exposure for undergraduate medical students often focus largely on students' experiences and perspectives. Research focusing on the physician experience in clinical exposures appears to be limited. When the Ukwanda Rural Clinical School (RCS) at the Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa was implemented in 2011, the clinical specialists working at the rural hospitals were expected to take on the additional task of teaching the students in the year long rotation. The specialists were prepared for the task through a series of workshops. The objective of this study was to explore what the implementation of the RCS meant for the practice of these physicians and to what extent the shift from full-time practising clinician to clinical teacher required them to adapt and change. METHODS: This was a qualitative study. Semi-structured interviews were conducted with lead clinical specialists who were responsible for teaching medical students in the year-long RCS rotation. Following an interpretive approach, thematic content analysis was performed to obtain a clearer understanding of how these clinicians had experienced their first year as clinical teachers in the RCS. RESULTS: Four overarching themes were identified from the interviews with the clinicians: attitudes towards the implementation of the new medical education model, uncertainty and insecurity as a teacher, emergence of the clinician teacher, and a sense of responsibility for training a future colleague. These depict in part, the journey from clinician to clinician teacher travelled during the first year of implementation. CONCLUSIONS: Embracing the role of clinical teacher enabled the development of constructive relationships between clinicians and their students with a mutual sense of responsibility for learning, patient care and improvement in clinical practice. Understanding this journey ought to influence the thinking of those considering faculty development initiatives for novice clinical teachers. PMID- 24803207 TI - Why effectiveness of robot-mediated neurorehabilitation does not necessarily influence its adoption. AB - This paper discusses the reasons why evidence of clinical effectiveness is not enough to facilitate adequate adoption of robotic technologies for upper-limb neurorehabilitation. The paper also provides a short review of the state of the art technologies. In particular, the paper highlights the barriers to the adoption of these technologies by the markets in which they are, or should be, deployed. On the other hand, the paper explores how low rates of adoption may depend on communication biases between the producers of the technologies and potential adopters. Finally, it is shown that, although technology-efficacy issues are usually well-documented, barriers to adoption also originate from the lack of solid evidence of the economic implications of the new technologies. PMID- 24803208 TI - Target-specific imaging of transmembrane receptors using quinonyl glycosides functionalized quantum dots. AB - Here, we describe a novel "switch-on" biosensor based on quinonyl glycosides functionalized quantum dots (QDs) for the specific targeting and imaging of transmembrane glycoprotein receptors on the surface of cancer cells. The design of the quinonyl glycosides lies in that the quinone moiety serves as a quencher of QDs and the glycoside moiety as a biospecific ligand for targeting a receptor. We observed that the quenched photoluminescence of the quinone glycosides functionalized QDs could be significantly recovered by a specific lectin that selectively binds to the glycosides clustering the QDs but was not affected by a panel of nonspecific lectins. Moreover, we determined that quinonyl galactoside functionalized QDs could optically image the asialoglycoprotein receptors of a hepatoma cell line in a target-specific manner. This system might provide new insights into the fabrication of photoluminogenic biosensors for the analysis of the universal ligand-receptor recognitions in nature. PMID- 24803209 TI - The origin of the selectivity and activity of ruthenium-cluster catalysts for fuel-cell feed-gas purification: a gas-phase approach. AB - Gas-phase ruthenium clusters Ru(n)(+) (n=2-6) are employed as model systems to discover the origin of the outstanding performance of supported sub-nanometer ruthenium particles in the catalytic CO methanation reaction with relevance to the hydrogen feed-gas purification for advanced fuel-cell applications. Using ion trap mass spectrometry in conjunction with first-principles density functional theory calculations three fundamental properties of these clusters are identified which determine the selectivity and catalytic activity: high reactivity toward CO in contrast to inertness in the reaction with CO2; promotion of cooperatively enhanced H2 coadsorption and dissociation on pre-formed ruthenium carbonyl clusters, that is, no CO poisoning occurs; and the presence of Ru-atom sites with a low number of metal-metal bonds, which are particularly active for H2 coadsorption and activation. Furthermore, comprehensive theoretical investigations provide mechanistic insight into the CO methanation reaction and discover a reaction route involving the formation of a formyl-type intermediate. PMID- 24803210 TI - The Crc and Hfq proteins of Pseudomonas putida cooperate in catabolite repression and formation of ribonucleic acid complexes with specific target motifs. AB - The Crc protein is a global regulator that has a key role in catabolite repression and optimization of metabolism in Pseudomonads. Crc inhibits gene expression post-transcriptionally, preventing translation of mRNAs bearing an AAnAAnAA motif [the catabolite activity (CA) motif] close to the translation start site. Although Crc was initially believed to bind RNA by itself, this idea was recently challenged by results suggesting that a protein co-purifying with Crc, presumably the Hfq protein, could account for the detected RNA-binding activity. Hfq is an abundant protein that has a central role in post transcriptional gene regulation. Herein, we show that the Pseudomonas putida Hfq protein can recognize the CA motifs of RNAs through its distal face and that Crc facilitates formation of a more stable complex at these targets. Crc was unable to bind RNA in the absence of Hfq. However, pull-down assays showed that Crc and Hfq can form a co-complex with RNA containing a CA motif in vitro. Inactivation of the hfq or the crc gene impaired catabolite repression to a similar extent. We propose that Crc and Hfq cooperate in catabolite repression, probably through forming a stable co-complex with RNAs containing CA motifs to result in inhibition of translation initiation. PMID- 24803211 TI - Ameliorating effect of piperine on behavioral abnormalities and oxidative markers in sodium valproate induced autism in BALB/C mice. AB - Post natal exposure to VPA (valproic acid) in mice induces behavioral deficits, abnormal sensitivity to sensory stimuli and self-injurious behavior, observed in autism. Piperine has been reported to have protective effect on brain. The present study aimed at evaluating effect of piperine on VPA induced neurobehavioral and biochemical alterations in BALB/c mice. Young BALB/c mice 13 days old were procured from five different litters and segregated into five groups (n=6; 3 male, 3 female) i.e., Group I served as control group, received physiological saline on PND (Post natal day) 14 & Tween 80 p.o. from PND13-40. Group II served as normal treated group and received piperine (20mg/kg p.o.) from PND 13-40 and saline s.c. on PND 14. Group III served as valproate treated group received VPA (400mg/kg s.c.) on PND 14 and Tween 80 p.o. from PND 13-40. Group IV & V served as disease treated group received VPA (400mg/kg s.c.) on PND 14 & piperine (5 & 20mg/kg p.o.) from PND 13-40 respectively. BALB/c mice pups were subjected to behavioral testing to assess motor skill development, nociceptive response, locomotion, anxiety, and cognition on various postnatal days up to PND 40. At the end of behavioral evaluation, mice were sacrificed; brain was isolated for biochemical estimations (serotonin, glutathione, MDA and nitric oxide) and histopathological examination. Our study revealed that treatment with piperine significantly improved behavioral alterations, lowered oxidative stress markers, and restored histoarchitecture of cerebellum. This ameliorating effect of piperine is attributed to its anti-oxidant activity, cognition enhancing and neuroprotective activity. PMID- 24803212 TI - Social crowding in the night-time reduces an anxiety-like behavior and increases social interaction in adolescent mice. AB - Rearing in crowded conditions is a psychosocial stressor that affects biological functions. The effects of continuous crowding for many days have been studied, but those of crowding over a limited time have not. In this study, we examined the effects of night-time or daytime crowding over 2 weeks on behavior in adolescent and adult mice. Crowding (20 mice/cage) in either the night-time or daytime did not affect locomotor activity in the open field test or cognitive function in the fear conditioning test. In contrast, night-time crowding, but not daytime crowding, had an anxiolytic effect in the elevated plus-maze test and increased social interaction in adolescent mice, but not in adult mice. The first night-time, but not daytime, crowding increased plasma corticosterone levels in adolescent mice, although night-time crowding over 2 weeks did not affect the corticosterone levels. Furthermore, no significant effects of the first crowding were observed in adult mice. In a second crowding condition (six mice/small cage), the anxiolytic-like effects of night-time crowding and the change in plasma corticosterone levels were not observed, suggesting that the density of mice is not important for the behavioral consequences of crowding. Night-time crowding did not affect neurotrophic/growth factor levels and hippocampal neurogenesis in adolescent mice. These findings suggest that night-time crowding leads to anxiolytic-like behaviors in adolescent mice, and imply that night-time crowding stress in adolescence may be beneficial to brain functions. PMID- 24803213 TI - Short-term memory in zebrafish (Danio rerio). AB - Learning and memory represent perhaps the most complex behavioral phenomena. Although their underlying mechanisms have been extensively analyzed, only a fraction of the potential molecular components have been identified. The zebrafish has been proposed as a screening tool with which mechanisms of complex brain functions may be systematically uncovered. However, as a relative newcomer in behavioral neuroscience, the zebrafish has not been well characterized for its cognitive and mnemonic features, thus learning and/or memory screens with adults have not been feasible. Here we study short-term memory of adult zebrafish. We show animated images of conspecifics (the stimulus) to the experimental subject during 1 min intervals on ten occasions separated by different (2, 4, 8 or 16 min long) inter-stimulus intervals (ISI), a between subject experimental design. We quantify the distance of the subject from the image presentation screen during each stimulus presentation interval, during each of the 1-min post-stimulus intervals immediately following the stimulus presentations and during each of the 1-min intervals furthest away from the last stimulus presentation interval and just before the next interval (pre-stimulus interval), respectively. Our results demonstrate significant retention of short-term memory even in the longest ISI group but suggest no acquisition of reference memory. Because in the employed paradigm both stimulus presentation and behavioral response quantification is computer automated, we argue that high-throughput screening for drugs or mutations that alter short-term memory performance of adult zebrafish is now becoming feasible. PMID- 24803214 TI - Vesico-ureteral reflux in women with idiopathic high-pressure detrusor overactivity: prevalence, bladder function, and effect on the upper urinary tract. AB - INTRODUCTION AND HYPOTHESIS: To assess the prevalence of vesico-ureteral reflux (VUR) and upper urinary tract damage in women with idiopathic high-pressure detrusor overactivity (IHPDO) and to characterize their bladder function. METHODS: A retrospective chart review of women diagnosed with IHPDO (detrusor pressures > 40 cm H2O during involuntary bladder contractions) from 2007 to 2010 was conducted. Women were assessed for VUR by X-ray voiding cysto-urethrogram. Renal ultrasound or CT urogram, serum BUN/creatinine, and urinalyses were performed if reflux reached the renal pelvices. Cystometric and voiding pressure study data were reviewed for detrusor overactivity pressure and volume, voiding dysfunction, urethral relaxation, compliance, and bladder outlet obstruction. RESULTS: Sixty-five women were diagnosed with IHPDO, and 50 completed an X-ray voiding cysto-urethrogram. The median (range) detrusor overactivity pressure was 65 (41-251) cm H2O. Four (8.0%) women had IHPDO; none had upper urinary tract deterioration. The majority of women exhibited urethral relaxation with voiding, impaired compliance, and bladder outlet obstruction. CONCLUSIONS: Women with IHPDO are at risk of low-grade vesico-ureteral reflux. However, most women with IHPDO are likely protected from reflux by intermittent exposure to high detrusor pressures and the ability to decompress the bladder by urethral relaxation. PMID- 24803215 TI - Faecal incontinence 20 years after one birth: a comparison between vaginal delivery and caesarean section. AB - INTRODUCTION AND HYPOTHESIS: The aetiology of bowel incontinence in middle-aged women is multifactorial and the contribution of birth-related factors later in life is still poorly defined. The aim was to assess prevalence, risk factors and severity of faecal (FI, defined as the involuntary loss of faeces-solid or liquid) and anal incontinence (AI, includes FI as well as the involuntary loss of flatus) 20 years after one vaginal (VD) or one caesarean section (CS). METHODS: This was a registry-based national cohort study of primiparae giving birth in 1985-1988 and having no further births (n = 5,236). Data from the Swedish Medical Birth Register were linked to information from a pelvic floor disorder questionnaire in 2008 (response rate 65.2%). Analysis of variance and multivariate analysis were used to obtain adjusted prevalence and odds ratios (adj-OR). RESULTS: Overall prevalences of FI and AI were 13.6 and 47.0%. FI prevalence was higher after VD compared with CS [14.5 versus 10.6%, adj-OR 1.43, 95% confidence interval (CI) 1.16-1.77] but was not increased after acute versus elective CS. Perineal tear (>=second degree) increased the prevalence and risk of FI compared with no tear (22.8 versus 13.9%, adj-OR 1.95, 95% CI 1.33-2.85). The prevalence of FI was lower after VD with an episiotomy (11.1%) and similar to that after CS (10.6%). With each unit increase of current body mass index the odds of FI increased by 6% (OR 1.06, 95% CI 1.04-1.08). CONCLUSIONS: Late FI and AI prevalences were higher after VD compared with CS. Perineal tear (>=second degree) versus no tear doubled the prevalence of FI. FI prevalence was similar after a CS and a VD combined with episiotomy. PMID- 24803216 TI - The effect of oral solifenacin succinate treatment on intraocular pressure: glaucoma paradox during overactive bladder treatment. AB - INTRODUCTION AND HYPOTHESIS: Anticholinergic medication is the mainstay of pharmacotherapy for overactive bladder (OAB). The aim of the study is to investigate the effect of oral solifenacin succinate on intraocular pressure (IOP) in female OAB patients and to discuss the ocular drawbacks during treatment. METHODS: The female patients with a clinical diagnosis of OAB in whom use of oral solifenacin succinate 5 mg/day (group I) and age-matched healthy female subjects (group II) underwent complete ophthalmological examination, including IOP measurement at the beginning of the oral treatment and after 4 weeks. The patients with a history of previous ocular surgery and those with ocular diseases besides refraction disorders and presbyopia were excluded. RESULTS: The data from the right eyes of 60 consecutive patients in group I and 30 consecutive patients in group II were used for analysis. No statistically significant change was detected in the IOP (from 16.05 +/- 2.30 mmHg to 16.30 +/- 2.25 mmHg at the 4th week in group I, p = 0.160; from 15.60 +/- 2.14 mmHg to 15.60 +/- 2.09 mmHg at the 4th week in group II, p = 0.864) of the eyes in both groups. CONCLUSIONS: Since the power of the study is not enough to draw a clear conclusion, a 4-week course of solifenacin succinate treatment in women with OAB seemed to have no clinically significant effect on IOP values. Further larger studies are needed to determine the effect of anticholinergics on anterior chamber parameters and to evaluate their safety in glaucoma patients. PMID- 24803218 TI - The importance of knowing how to get things: information literacy and the healthcare professional. PMID- 24803217 TI - A retrospective comparison of ring pessary and multicomponent behavioral therapy in managing overactive bladder. AB - INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) is a physically, psychologically, and socially disabling condition that affects millions of women worldwide and is especially prevalent postmenopause. The objective of our study was to compare the cure rates of ring pessary with those of multicomponent behavioral therapy in managing overactive bladder. METHODS: We performed a comparative retrospective parallel cohort study of all women whose overactive bladder was treated with multicomponent behavioral therapy or ring pessary over a 42-month period. At the end of the 6-month treatment period, cure was defined as the subjective (self-reported) absence of urinary urgency, frequency, nocturia, and urge incontinence in the preceding 30 days; the objective absence of these symptoms in a 7-day voiding diary; and a Patient Global Impression of Improvement response of "much better" or "very much better." RESULTS: Ring pessary and multicomponent behavioral therapy had similar cure rates (29 out of 150 [19 %] vs 46 out of 231 [20 %] respectively, P = 0.889; OR of 1.04, 95 % confidence interval 0.618-1.742, P = 0.887). They also produced comparable cure rates in premenopausal (4 out of 31 [13 %] vs 14 out of 68 [21 %], P = 0.358) and postmenopausal subjects (25/ out of 19 [21 %] vs 32 out of 163 [20 %], P = 0.776), and in women who had undergone previous treatment (21 out of 108 [19 %] vs 31 out of 176 [18 %], P = 0.699) and those who had not (8 out of 42 [19 %] vs 15 out of 55 [27 %], P = 0.345). Logistic regression showed that neither treatment outcome is significantly associated with demographic characteristics; Pelvic Organ Prolapse Quantification at the anterior and posterior vaginal walls and at the vaginal cuff; previous treatment; overactive bladder symptoms; pad usage; or any combination thereof. CONCLUSIONS: Ring pessary has a cure rate similar to that of multicomponent behavioral therapy in managing overactive bladder. PMID- 24803219 TI - Implementation of an employment intervention in mental health teams: a naturalistic 1-year employment outcome study in people with severe mental illness. AB - BACKGROUND: In the UK, the severely mentally ill have high rates of unemployment. AIMS: To (1) evaluate implementation of an employment intervention and (2) test the effectiveness of training an existing staff member in providing the employment intervention (Model A) against the provision of a dedicated employment specialist to a team (Model B). METHODS: An employment service was implemented in five mental health teams, with three teams having an existing team member trained and two teams receiving an additional member of staff to carry out the employment intervention. Work outcomes for the two groups were compared at 1 year. RESULTS: Competitive employment was obtained by 17.7% receiving an employment intervention (10.3%, Model A versus 22.8% Model B). Rates of employment or training obtained were 25.6% (10/39) in Model A versus 35.1% (20/57) in Model B, but the difference was not statistically different. Type of employment service model was not significantly associated with working. CONCLUSION: An employment service can be introduced effectively into mental health teams in the UK and positive employment outcomes achieved in a short space of time. Providing an additional resource is more effective compared to asking existing staff to deliver the intervention alongside other roles. PMID- 24803220 TI - The relationships among depression, physical health conditions and healthcare expenditures for younger and older Americans. AB - BACKGROUND AND AIMS: Little is known about the extent depression adds to the costs of treatment for physical health conditions. This study examined the paths and the extent to which depression in conjunction with a physical health problem is associated with an increase in healthcare expenditures and how that is different between younger and older adults. METHODS: Data from the 2007 Medical Expenditure Panel Survey (MEPS) were analyzed. Depression status and physical health conditions were identified through ICD-9 codes. The multiple group structural equation modeling (SEM) was employed to examine the moderated mediation effects. RESULTS: Approximately 11% of adults had clinical depression. The multiple group SEM for both younger and older adult groups supports not only a direct effect of depression on expenditures but also an indirect effect via comorbid health conditions. Furthermore, the indirect effect was significantly more prominent among older respondents than among younger ones, indicating significant moderated mediation by age. CONCLUSIONS: Depression has greater effects on comorbid health conditions and an increase in total healthcare expenditures through comorbid conditions among older adults. Findings of this study suggest that proper detection and treatment of depression is beneficial in reducing overall healthcare expenditures, especially among older adults. PMID- 24803221 TI - The effectiveness of personal budgets for people with mental health problems: a systematic review. AB - BACKGROUND: Personal budgets are a key policy priority in adult social care in England and are expected to become increasingly important in the care of adults with mental health problems. AIMS: This article systematically reviews evidence for the effectiveness of personal budgets for people with mental health problems across diverse outcomes. METHODS: The review, conducted in 2013, used the EPPI Centre methodology for conducting a systematic review informed by Social Care Institute for Excellence guidelines. Data were extracted from studies and combined using meta-synthesis. RESULTS: Fifteen studies were included in the review which found mostly positive outcomes in terms of choice and control, quality of life, service use and cost-effectiveness. However, methodological limitations make these findings rather unreliable and insufficient to inform personal budgets policy and practice for mental health service users. CONCLUSIONS: Further high quality studies are required to inform policy and practice for mental health service users, which lags behind other adult social care groups in the use of personal budgets. PMID- 24803223 TI - Evaporation-induced formation of self-organized gradient concentric rings on sub micron pre-cast PMMA films. AB - A "particle-on-film" template is developed to fabricate self-organized surface patterns through solvent evaporation on initially featureless, sub-micron PMMA films. The small particle placed on the pre-cast PMMA film is able to confine a toluene droplet and influence the evaporative process. Well-ordered gradient concentric rings are formed around the particle due to the unconventional "advancing-receding" motion of the contact line in the "stick" state on the surface of the PMMA films. Both the center-to-center distance between adjacent rings (wavelength) and the height of the rings (amplitude) are strongly dependent on the particle size and the film thickness, and decrease with the decrease of the distance to the center of the particle. A linear dependence of the amplitude of the rings on the wavelength is observed under experimental conditions. The results demonstrate that the "particle-on-film" template has the potential to fabricate highly-ordered surface patterns economically and efficiently. PMID- 24803224 TI - Interglacial microrefugia and diversification of a cactus species complex: phylogeography and palaeodistributional reconstructions for Pilosocereus aurisetus and allies. AB - The role of Pleistocene climate changes in promoting evolutionary diversification in global biota is well documented, but the great majority of data regarding this subject come from North America and Europe, which were greatly affected by glaciation. The effects of Pleistocene changes on cold- and/or dry-adapted species in tropical areas where glaciers were not present remain sparsely investigated. Many such species are restricted to small areas surrounded by unfavourable habitats, which may represent potential interglacial microrefugia. Here, we analysed the phylogeographic structure and diversification history of seven cactus species in the Pilosocereus aurisetus complex that are restricted to rocky areas with high diversity and endemism within the Neotropical savannas of eastern South America. We combined palaeodistributional estimates with standard phylogeographic approaches based on two chloroplast DNA regions (trnT-trnL and trnS-trnG), exon 1 of the nuclear gene PhyC and 10 nuclear microsatellite loci. Our analyses revealed a phylogeographic history marked by multiple levels of distributional fragmentation, isolation leading to allopatric differentiation and secondary contact among divergent lineages within the complex. Diversification and demographic events appear to have been affected by the Quaternary climatic cycles as a result of isolation in multiple patches of xerophytic vegetation. These small patches presently harbouring P. aurisetus populations seem to operate as microrefugia, both at present and during Pleistocene interglacial periods; the role of such microrefugia should be explored and analysed in greater detail. PMID- 24803225 TI - Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings. AB - Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control. PMID- 24803227 TI - Do current therapeutic anti-Abeta antibodies for Alzheimer's disease engage the target? AB - Reducing amyloid-beta peptide (Abeta) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Abeta is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Abeta in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Abeta with high affinity. All of the antibodies were able to bind Abeta in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Abeta species, the Abeta detected using solanezumab was barely above detection limits while crenezumab did not detect any Abeta. None of the antibodies were able to detect any Abeta species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non Abeta related proteins. Bapineuzumab demonstrated target engagement with brain Abeta, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD. PMID- 24803228 TI - The curious case of blending inheritance. AB - For more than a century, geneticists have consistently identified the origins of their science with Gregor Mendel's experiments on peas. Mendelism, they have said, demonstrated at long last that biological inheritance was not, as had so often been supposed, "blending," but particulate. Many historians of biology continue to interpret the conflict of biometricians and Mendelians at the start of the twentieth century in these terms, identifying biometry with the (incorrect) blending mechanism. But this view of blending is history as war by other means. While Francis Galton's contrast between blended and alternate inheritance had become familiar by 1905, he and his interpreters understood the two forms as differing outcomes of breeding, not as rival theories. Only a few biologists in this period went beyond blending as a description of results of breeding to a blending mechanism, and these were not biometricians. Recognizing this, we can see also that statistical methods and models were central to evolutionary genetics right from the start. The evolutionary synthesis, while reshaping their role, did not create it. PMID- 24803226 TI - Focusing the amyloid cascade hypothesis on N-truncated Abeta peptides as drug targets against Alzheimer's disease. AB - Although N-truncated Abeta variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer's disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Abeta peptides based on mounting evidence that they may represent better targets than full-length Abeta. In addition to Abeta peptides starting with an Asp at position 1, a variety of different N-truncated Abeta peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Abeta, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Abetas dominate full-length Abeta in the brains of Alzheimer's patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides. PMID- 24803229 TI - Takayasu's arteritis in Arabs. AB - The objective of this study was to describe epidemiological and clinical features of Takayasu's arteritis (TA) among Arab populations and to compare it to other populations. We conducted a systematic review of reports about TA from Arab countries published in English and French until 2013. All published papers were reviewed including original research and case reports. There were 197 patients (176 females) reported in 28 publications that comprised 8 original research publications (with a total of 163 patients) and 20 case reports (reporting 34 patients). These patients were from countries with a total population of approximately 80 million (Tunisia, Morocco, Jordan, Lebanon, Kuwait, Saudi Arabia, and Bahrain). The female to male ratio was 7:1. Mean age at disease onset was 28 years, and the mean delay in diagnosis was 3.5 years. Clinical manifestations are constitutional symptoms in 44 %, limb claudication in 64 %, Raynaud's in 6 %, erythema nodosum in 3.6 %, visual disturbances in 30 %, carotidynia in 7 %, neurologic manifestations in 56 %, and hypertension in 34.5 % of patients. Involvement of the aortic arch and its branches were observed in about 80 % of patients. The overall mortality was very low over a period of 5.4 years of follow-up, and the course of the disease was quite stable in about 50 % of patients. The demographical and clinical findings of TA in Arabs are similar to what has been reported from different parts of the world. A relatively long delay in diagnosis may be in part due to low awareness of a relatively rare disease. PMID- 24803230 TI - Lack of association of vitamin D receptor gene polymorphisms/haplotypes in Sjogren's syndrome. AB - The vitamin D is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Vitamin D has several immunomodulatory effects through vitamin D receptor (VDR). A series of common single-nucleotide polymorphisms (SNPs) in the vitamin D receptor gene have been linked to numerous of diseases, including osteoarthritis, diabetes, cancer, cardiovascular diseases, tuberculosis, virus infections, urinary stones, and periodontitis. Several studies have reported that genetic variations of VDR might be a risk factor for the development of autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), psoriasis, and autoimmune thyroid diseases (AITD). However, no data is available on the possible relationship between primary Sjogren's syndrome and VDR gene polymorphisms. Our aim was to determine VDR gene BsmI, ApaI, TaqI, and FokI polymorphism genotypes in pSS patients and healthy controls to analyze whether a relationship exists between polymorphisms in the VDR gene and susceptibility to Sjogren's syndrome. In the current study, 105 patients with pSS and 93 healthy controls were tested for VDR gene polymorphisms (BsmI, ApaI, TaqI, and FokI) genotypes. There were no statistical differences in the distribution of BsmI, TaqI, ApaI, and FokI genotypes and the common haplotypes between pSS patients and healthy controls. We hypothesized that the TaqI, BsmI, ApaI, and FokI polymorphisms of the VDR gene are not associated with the development of primary Sjogren's syndrome in the Hungarian population studied. PMID- 24803231 TI - Glucocorticoid-resistant polymyalgia rheumatica: pretreatment characteristics and tocilizumab therapy. AB - Treatment with glucocorticoid (GC) is the preferred therapy for polymyalgia rheumatica (PMR), but some patients show poor responses to the initial GC regimen or experience flares on GC tapering. Alternative therapies for patients with GC resistance have not yet been established. To evaluate pretreatment characteristics and therapeutic outcomes of GC-resistant PMR, we followed all patients who had been diagnosed with PMR between October 2007 and February 2013, according to our standardized protocol. GC-resistant patients were defined as those who had responded poorly to the initial GC regimen (15 mg/day of prednisolone) or those who had responded to the initial regimen but had experienced a flare upon GC tapering to 5 mg/day of the maintenance dose or within the first 6 months of maintenance therapy. Out of 23 patients, nine were found to be GC-resistant cases and the others were GC responders. Baseline values of PMR activity score and its components, especially the ability to elevate the upper limbs (EUL), were significantly higher in GC-resistant patients compared with GC responders. The additional use of methotrexate (MTX, five cases), salazosulfapyridine (one case), and tocilizumab (TCZ, three cases) was effective for GC-resistant patients, although 13 to 39 weeks were required for the achievement of remission. We report the three GC-resistant cases in which TCZ was added to GC therapy with or without MTX. We also review the medical literature on the use of TCZ as of January 31, 2014 and discuss the utility of TCZ in the treatment of GC-resistant PMR. PMID- 24803232 TI - Prevalence of psoriatic arthritis in psoriasis patients according to newer classification criteria. AB - The aim of this study is to determine the prevalence of psoriatic arthritis (PsA) according to Classification of Psoriatic Arthritis (CASPAR) criteria, Assessment of Spondyloarthritis International Society (ASAS) peripheral and axial SpA criteria, and New York criteria for AS. The first 100 patients consecutively attending a psoriasis dermatology clinic were assessed. Demographic and clinical data were collected; all patients were questioned and examined for joint manifestations. Rheumatoid factor and radiographies of hands, feet, cervical spine, and pelvis for sacroiliac joints were obtained. X-rays were read independently by two experienced observers in blind fashion. Patients with objective joint manifestations, both axial and peripheral, were evaluated for fulfillment of CASPAR, ASAS peripheral and axial, and New York criteria. Median age 48 years; 93 % of patients had psoriasis vulgaris and 56 % had nail involvement. Seventeen patients had peripheral arthritis as follows: nine mono/oligoarticular and eight polyarthritis. Median arthritis duration was of 8 years. Seventeen percent of patients fulfilled CASPAR and ASAS peripheral criteria, 6 % New York, and 5 % ASAS axial criteria. Patients who met CASPAR criteria showed a significantly higher psoriasis duration compared to those without arthritis (M 16 vs 10 years, p = 0.02), and a higher frequency of nail involvement (88.2 vs 49.4 %, p = 0.003). Five patients (29.4 %) fulfilled ASAS axial criteria; all of them had peripheral involvement as follows: mono/oligoarticular in three patients and polyarticular in two. Patients with peripheral and axial involvement presented a significantly higher frequency of erythrodermic psoriasis compared to the other patients (35.3 vs 1.2 %, p = 0.0006 and 80 vs 16.7 %, p = 0.02). Prevalence of PsA, for CASPAR and ASAS peripheral criteria, was of 17 %. Five percent of patients met ASAS axial criteria, while 6 % met New York criteria. Worth noting, few patients without signs or symptoms of arthritis had radiological changes, both axial and peripheral, precluding a proper classification. PMID- 24803234 TI - Motivations for recreating on farmlands, private forests, and state or national parks. AB - This study explores the importance of different motivations to visit three types of recreational settings--farms, private forests, and state or national parks. Data were collected via a mail-back questionnaire administered to a stratified random sample of households in Missouri (USA). Descriptive and inferential statistics reveal both similarities and discontinuities in motivations for visiting farms, private forests, and state or national parks for recreation. Being with family, viewing natural scenery, and enjoying the smells and sounds of nature were all highly important motivations for visiting the three types of settings. However, all 15 motivations examined were perceived to be significantly more important for visits to state or national parks than to farms or private forests. Findings suggest that individuals are more strongly motivated to recreate at state and national parks relative to farmlands or forests. Post hoc paired t tests comparing motivations between both agricultural settings (farms and private forests) revealed significant differences in eight different recreational motivations. Individuals tended to place more importance on the ability to use equipment and test their skills when considering recreating on private forests. Conversely, social motivations (e.g., doing something with the family) were more important when individuals were considering recreating on farmland. Collectively, the findings suggest individuals expect distinctly different outcomes from their visits to farmlands, private forests, or state or national parks. Consequently, all three types of recreational settings have competitive advantages that their managers could capitalize on when making decisions about how to attract new visitors or produce the most desirable experiences for current recreationists. PMID- 24803233 TI - Extra-articular manifestations in psoriatic arthritis patients. AB - Psoriatic arthritis (PsA) is an inflammatory rheumatic disorder, associated with skin and/or nail psoriasis. It has been included in the spondyloarthropathies (SpA) group, with which it shares clinical, radiologic, and serologic features and familial and genetic relationship. Inclusion of disease among SpA is also based on their striking points of similarity for extra-articular manifestations (EAMs). The aim of study was to describe the EAMs in patients with PsA, evaluating the prevalence and clinical features associated with established and early PsA. The study was a retrospective analysis of case records of 387 PsA patients. Data recorded were demographic data, disease properties, laboratory tests, drug use, and presence of EAMs. Of 387 PsA patients, 190 have shown EAMs: 33.16 % had bowel involvement, 32.63 % ocular, 28.42 % cardiovascular, 25.79 % urogenital, 8.42 % skin (excluding psoriasis), 1.05 % pulmonary, and 0.53 % renal. A higher prevalence of EAMs was found in axial subset (p < 0.0001) and in established PsA patients (p = 0.03). The disease activity in PsA patients with EAMs was significantly higher (p < 0.0005). Smoker PsA patients had a significantly higher prevalence of EAMs than nonsmoker PsA patients (p < 0.0005). EAMs in PsA patients are common than expected and frequently associated with established form and axial subset. EAMs were more frequent in male gender, and the contemporary presence of male gender and axial subset showed a higher risk to develop EAMs. EAMS were more frequent in patients with a long disease duration and active disease. Moreover, these results suggest that in PsA patients, an initial checkup and a regular screening for EAMs are requested to ensure an appropriate management. PMID- 24803235 TI - A volumetric CMUT-based ultrasound imaging system simulator with integrated reception and MU-beamforming electronics models. AB - In modern ultrasound imaging devices, two-dimensional probes and electronic scanning allow volumetric imaging of anatomical structures. When dealing with the design of such complex 3-D ultrasound (US) systems, as the number of transducers and channels dramatically increases, new challenges concerning the integration of electronics and the implementation of smart micro-beamforming strategies arise. Hence, the possibility to predict the behavior of the whole system is mandatory. In this paper, we propose and describe an advanced simulation tool for ultrasound system modeling and simulation, which conjugates the US propagation and scattering, signal transduction, electronic signal conditioning, and beamforming in a single environment. In particular, we present the architecture and model of an existing 16-channel integrated receiver, which includes an amplification and micro-beamforming stage, and validate it by comparison with circuit simulations. The developed model is then used in conjunction with the transducer and US field models to perform a system simulation, aimed at estimating the performance of an example 3-D US imaging system that uses a capacitive micromachined ultrasonic transducer (CMUT) 2-D phased-array coupled to the modeled reception front-end. Results of point spread function (PSF) calculations, as well as synthetic imaging of a virtual phantom, show that this tool is actually able to model the complete US image reconstruction process, and that it could be used to quickly provide valuable system-level feedback for an optimized tuning of electronic design parameters. PMID- 24803236 TI - Ammonia-sensitive photonic structures fabricated in Nafion membranes by laser ablation. AB - Here we report the fabrication and characterization of photonic structures in Nafion membranes sensitive to ammonia in the 0.19%-12.5% concentration range. The photonic structures were recorded by laser ablation of silver nanoparticles synthesized in situ by diffusion. The particles showed an average diameter of 17 nm with a narrow size distribution. After ablation, the nanoparticles generated a diffracting structure giving colorful reflections at defined peak wavelengths. The reflectivity at these wavelengths was directly proportional to concentration after ammonia exposure. The concentration range that can be measured with these membranes encompasses the fatal limit of exposure and the lower flammable limit of gaseous ammonia. Interrogation by reflection spectroscopy makes them suitable for remote sensing and real-time monitoring of gases. PMID- 24803237 TI - Streptomyces calidiresistens sp. nov., isolated from a hot spring sediment. AB - A Streptomyces-like actinomycete strain, designated as YIM 78087(T), was isolated from a sediment sample collected from Hehua hot spring in Tengchong, Yunnan province, south-west China. The taxonomic position of strain YIM 78087(T) was investigated by a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain YIM 78087(T) belongs to the genus Streptomyces and is closely related to Streptomyces fimbriatus DSM 40942(T), Streptomyces marinus DSM 41968(T) and Streptomyces qinglanensis DSM 42035(T) (97.18, 97.05 and 97.1 % similarity, respectively). Combined with the low values of DNA-DNA hybridization between strain YIM 78087(T) and its closest neighbours, these analyses indicated that this new isolate represents a different genomic species in the genus Streptomyces. The predominant menaquinones of strain YIM 78087(T) were identified as MK-9 (H4) and MK-9 (H6). The major fatty acids were identified as anteiso-C15:0 (28.4 %), anteiso-C17:0 (23.0 %) and iso-C16:0 (15.1 %). The whole-cell hydrolysates found to contain glucose, mannose and ribose. The DNA G+C content was determined to be 73.0 mol%. Based on the comparative analysis of phenotypic and genotypic characteristics, it is proposed that strain YIM 78087(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces calidiresistens sp. nov., is proposed. The type strain is YIM 78087(T) (=BCRC 16955(T)=DSM 42108(T)=JCM 19629(T)). PMID- 24803238 TI - Effect of low shear modeled microgravity on phenotypic and central chitin metabolism in the filamentous fungi Aspergillus niger and Penicillium chrysogenum. AB - Phenotypic and genotypic changes in Aspergillus niger and Penicillium chrysogenum, spore forming filamentous fungi, with respect to central chitin metabolism were studied under low shear modeled microgravity, normal gravity and static conditions. Low shear modeled microgravity (LSMMG) response showed a similar spore germination rate with normal gravity and static conditions. Interestingly, high ratio of multiple germ tube formation of A. niger in LSMMG condition was observed. Confocal laser scanning microscopy images of calcofluor flurophore stained A. niger and P. chrysogenum showed no significant variations between different conditions tested. Transmission electron microscopy images revealed number of mitochondria increased in P. chrysogenum in low shear modeled microgravity condition but no stress related-woronin bodies in fungal hyphae were observed. To gain additional insight into the cell wall integrity under different conditions, transcription level of a key gene involved in cell wall integrity gfaA, encoding the glutamine: fructose-6-phosphate amidotransferase enzyme, was evaluated using qRT-PCR. The transcription level showed no variation among different conditions. Overall, the results collectively indicate that the LSMMG has shown no significant stress on spore germination, mycelial growth, cell wall integrity of potentially pathogenic fungi, A. niger and P. chrysogenum. PMID- 24803239 TI - Micromonospora violae sp. nov., isolated from a root of Viola philippica Car. AB - A novel actinomycete, designated strain NEAU-zh8(T), was isolated from a root of Viola philippica Car collected in China and characterized using a polyphasic approach. 16S rRNA gene sequence similarity studies showed that strain NEAU zh8(T) belongs to the genus Micromonospora, being most closely related to Micromonospora chokoriensis 2-9(6)(T) (99.9 %), Micromonospora saelicesensis Lupac 09(T) (99.3 %) and Micromonospora lupini Lupac 14N(T) (99.0 %). gyrB gene analysis also indicated that strain NEAU-zh8(T) should be assigned to the genus Micromonospora. The cell-wall peptidoglycan consisted of meso-diaminopimelic acid and glycine. The major menaquinones were MK-10(H4), MK-10(H2) and MK-10(H6). The phospholipid profile contained diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. The major fatty acids were iso-C15:0, C16:0 and C17:0 10-methyl. A combination of DNA-DNA hybridization results and some physiological and biochemical properties indicated that strain NEAU-zh8(T) could be readily distinguished from the closest phylogenetic relatives. Therefore, it is proposed that strain NEAU-zh8(T) represents a novel Micromonospora species, for which the name Micromonospora violae sp. nov. is proposed. The type strain is NEAU-zh8(T) (=CGMCC 4.7102(T)=DSM 45888(T)). PMID- 24803243 TI - Direct label-free electrical immunodetection of transplant rejection protein biomarker in physiological buffer using floating gate AlGaN/GaN high electron mobility transistors. AB - Monokine induced by interferon gamma (MIG/CXCL9) is used as an immune biomarker for early monitoring of transplant or allograft rejection. This paper demonstrates a direct electrical, label-free detection method of recombinant human MIG with anti-MIG IgG molecules in physiologically relevant buffer environment. The sensor platform used is a biologically modified GaN-based high electron mobility transistor (HEMT) device. Biomolecular recognition capability was provided by using high affinity anti-MIG monoclonal antibody to form molecular affinity interface receptors on short N-hydroxysuccinimide-ester functionalized disulphide (DSP) self-assembled monolayers (SAMs) on the gold sensing gate of the HEMT device. A floating gate configuration has been adopted to eliminate the influences of external gate voltage. Preliminary test results with the proposed chemically treated GaN HEMT biosensor show that MIG can be detected for a wide range of concentration varying from 5 ng/mL to 500 ng/mL. PMID- 24803240 TI - Improved bioactivity of antimicrobial peptides by addition of amino-terminal copper and nickel (ATCUN) binding motifs. AB - Antimicrobial peptides (AMPs) are promising candidates to help circumvent antibiotic resistance, which is an increasing clinical problem. Amino-terminal copper and nickel (ATCUN) binding motifs are known to actively form reactive oxygen species (ROS) upon metal binding. The combination of these two peptidic constructs could lead to a novel class of dual-acting antimicrobial agents. To test this hypothesis, a set of ATCUN binding motifs were screened for their ability to induce ROS formation, and the most potent were then used to modify AMPs with different modes of action. ATCUN binding motif-containing derivatives of anoplin (GLLKRIKTLL-NH2), pro-apoptotic peptide (PAP; KLAKLAKKLAKLAK-NH2), and sh-buforin (RAGLQFPVGRVHRLLRK-NH2) were synthesized and found to be more active than the parent AMPs against a panel of clinically relevant bacteria. The lower minimum inhibitory concentration (MIC) values for the ATCUN-anoplin peptides are attributed to the higher pore-forming activity along with their ability to cause ROS-induced membrane damage. The addition of the ATCUN motifs to PAP also increases its ability to disrupt membranes. DNA damage is the major contributor to the activity of the ATCUN-sh-buforin peptides. Our findings indicate that the addition of ATCUN motifs to AMPs is a simple strategy that leads to AMPs with higher antibacterial activity and possibly to more potent, usable antibacterial agents. PMID- 24803244 TI - The F-act's of nuclear actin. AB - The presence and state of actin in the nucleus has long been controversial. This is poised to change. Over the past two years, the regulation of nuclear actin and its polymerization have begun to be characterized. The transport of actin into and out of the nucleus has been defined and the importance of nuclear actin polymerization in the retention of the serum response factor coactivator MRTF-A is now quite clear. Moreover, serum-starved fibroblasts that are stimulated with serum rapidly form long actin bundles that can be visualized using the F-actin binding drug phalloidin. This provides the first compelling direct evidence that actin polymerizes in the nucleus and provides the foundation for a serious investigation of the function(s) of nuclear polymeric actin. PMID- 24803245 TI - Commentary: The association between high dietary intake of docosahexaenoic acid and reduced risk of Crohn's disease. PMID- 24803246 TI - Commentary: The association between high dietary intake of docosahexaenoic acid and reduced risk of Crohn's disease--authors' reply. PMID- 24803247 TI - Commentary: Adjunct antibiotic combination therapy for ulcerative colitis--is it time to investigate Fusobacterium varium? PMID- 24803248 TI - Commentary: Adjunct antibiotic combination therapy for ulcerative colitis--is it time to investigate Fusobacterium varium? Authors' reply. PMID- 24803249 TI - Commentary: Probing probiotics in cirrhosis--a template for future studies? PMID- 24803250 TI - Commentary: Probing probiotics in cirrhosis--a template for future studies? Author's reply. PMID- 24803251 TI - Letter: Response-guided treatment of hepatitis C virus genotype 5 may be feasible. PMID- 24803252 TI - Letter: Response-guided treatment of hepatitis C virus genotype 5 may be feasible -authors' reply. PMID- 24803253 TI - Letter: Treatment of HBeAg+ chronic hepatitis B--is tenofovir truly superior to entecavir? PMID- 24803254 TI - Letter: Treatment of HBeAg+ chronic hepatitis B--is tenofovir truly superior to entecavir? Authors' reply. PMID- 24803255 TI - Letter: Prognostic scores in alcoholic hepatitis. PMID- 24803256 TI - Letter: Prognostic scores in alcoholic hepatitis--authors' reply. PMID- 24803257 TI - Letter: Target of TIPSS for Budd-Chiari syndrome should be avoiding liver transplant. PMID- 24803258 TI - Letter: Telaprevir triple therapy in chronic hepatitis C genotype 1 patients receiving haemodialysis. PMID- 24803260 TI - Malignant catarrhal fever in American bison (Bison bison) experimentally infected with alcelaphine herpesvirus 2. AB - Malignant catarrhal fever (MCF), due to ovine herpesvirus 2 (OvHV-2), causes appreciable death loss in ranched bison (Bison bison) throughout North America. No vaccine exists to protect animals from disease. Since OvHV-2 has not been propagated in vitro, one strategy to develop a modified live vaccine is to use a closely related, non-pathogenic member of the malignant catarrhal fever virus family as a vector expressing potentially protective OvHV-2 epitopes. To date, no controlled experimental challenge studies with alcelaphine herpesvirus 2 (AlHV-2) derived from topi (Damaliscus lunatus jimela) have been reported The unique or light DNA segment of the AlHV-2 genome was sequenced and annotated and the virus was tested for its ability to infect and induce disease in American bison. Yearling bison were inoculated intranasally (n=4) or intramuscularly (n=3) with 2 * 10(-4.7) TCID50 of AlHV-2, and monitored for infection and the development of disease. Six inoculated bison became infected with AlHV-2. Two of the six animals developed clinical signs and had gross and histological lesions consistent with terminal MCF, which differed in distribution from those in bison with MCF due to OvHV-2. One other animal developed minor clinical signs and had gross and histological pulmonary lesions consistent with early (pre-clinical) stages of MCF. Unmodified low cell culture passage AlHV-2 derived from topi is an unsuitable vaccine vector for the prevention of MCF. However, the annotated genome might be useful in identifying genes which could be deleted to potentially attenuate the virus for bison. PMID- 24803261 TI - Diverse roles for Wnt7a in ventral midbrain neurogenesis and dopaminergic axon morphogenesis. AB - During development of the central nervous system, trophic, together with genetic, cues dictate the balance between cellular proliferation and differentiation. Subsequent to the birth of new neurons, additional intrinsic and extrinsic signals regulate the connectivity of these cells. While a number of regulators of ventral midbrain (VM) neurogenesis and dopaminergic (DA) axon guidance are known, we identify a number of novel roles for the secreted glycoprotein, Wnt7a, in this context. We demonstrate a temporal and spatial expression of Wnt7a in the VM, indicative of roles in neurogenesis, differentiation, and axonal growth and guidance. In primary VM cultures, and validated in Wnt7a-deficient mice, we show that the early expression within the VM is important for regulating VM progenitor proliferation, cell cycle progression, and cell survival, thereby dictating the number of midbrain Nurr1 precursors and DA neurons. During early development of the midbrain DA pathways, Wnt7a promotes axonal elongation and repels DA neurites out of the midbrain. Later, Wnt7a expression in the VM midline suggests a role in preventing axonal crossing while expression in regions flanking the medial forebrain bundle (thalamus and hypothalamus) ensured appropriate trajectory of DA axons en route to their forebrain targets. We show that the effects of Wnt7a in VM development are mediated, at least in part, by the beta-catenin/canonical pathways. Together, these findings identify Wnt7a as a new regulator of VM neurogenesis and DA axon growth and guidance. PMID- 24803271 TI - Redox status and antioxidant response in professional cyclists during training. AB - The aim of this study was to investigate whether different phases of training affect oxidative stress and antioxidant defences in professional cyclists. Ten professional cyclists, aged 21.8 +/- 2.5 years, were enrolled in the study. They were classified into two groups of five athletes each one with similar nutritional intake excepting for the overload of vitamin C (1000 mg day(-1)) and E (400 mg day(-1)) supplementation in one of them. The cyclists of both groups performed the same exercise design, consisting of hard, tapering and recovery training periods. Total antioxidant capacity (TAC) of the diet, plasma oxygen radical absorption capacity (ORAC), lipid peroxidation (LPO), DNA damage (8-OHdG) and erythrocyte glutathione disulfide/glutathione ratio (GSSG:GSH(-1)) were measured. During the intense exercise trainings, the cyclists without vitamin supplements had the TAC of diet significantly lower than the supplemented group. Plasma ORAC, LPO and 8-OHdG were similar in both groups of athletes. Athletes with supplements had a basal LPO:ORAC(-1) ratio lower than that without supplements, but this ratio converged to the same level at the end of the training in both groups of cyclists. Both groups of cyclists showed similar changes in GSSG:GSH(-1) ratio and in GSSG and GSH levels along the study. The data suggest that well-trained athletes with suitable ultra-endurance training volume and intensity do not require antioxidant vitamin supplements to adapt their endogenous antioxidant defenses to exercise-induced ROS. PMID- 24803272 TI - Effect of polyvinyl alcohol hydrogel as a biocarrier on volatile fatty acids production of a two-stage thermophilic anaerobic membrane bioreactor. AB - This work studied the effect of polyvinyl alcohol hydrogel (PVA-gel) beads, as an effective biocarrier for volatile fatty acid (VFA) production in hydrolytic reactor of a two-stage thermophilic anaerobic membrane bioreactor (TAnMBR). The two-stage TAnMBR, treating synthetic high strength particulate wastewater with influent chemical oxygen demand (COD) [16.4+/-0.8 g/L], was operated at 55 degrees C. Under steady state conditions, the reactor was operated at an organic loading rate of 8.2+/-0.4 kg COD/m(3) d. Operational performance of the system was monitored by assessing VFA composition and quantity, methane production and COD removal efficiency. Increment of VFA production was observed with PVA-gel addition. Hydrolytic effluent contained large amount of acetic acid and n-butyric acid. However, increase in VFA production adversely affected the methanogenic reactor performance due to lack of methanogenic archaea. PMID- 24803273 TI - Policy expectations and reality of telemedicine - a critical analysis of health care outcomes, costs and acceptance for congestive heart failure. AB - A critical review of evidence was carried out to discover whether the actual performance of telemedicine fulfils the expectations of German policy-makers. The analysis was conducted using the example of telemedicine for congestive heart failure (CHF). It was based on both German and international evidence. The PubMed, MEDLINE, Google Scholar and Cochrane Library databases were searched, as well as public sources from the German Federal Ministry of Health. Forty-five studies reporting patient outcomes, costs or acceptance of telemedicine for CHF were included in the review, of which 28 were interventional. The policy expectations of telemedicine generally are: high technology acceptance and improved patient outcomes at lower costs. However, in the field of CHF, policy makers underestimate the complexity of telemedicine and the technology has not yet lived up to its expectations. Although some studies show improvements in all cause mortality and CHF-related hospitalisations, there is excessive study heterogeneity and vagueness in the areas of costs and acceptance. Methodological insufficiencies as well as the scarcity of evidence in the German context do not allow definite conclusions to be drawn. Policy-makers and other stakeholders should increase their efforts to consolidate isolated telemedicine projects, establish guidelines for clinical treatment procedures and economic evaluations, and define industry/technical device standards to enhance the comparability of interventions. Imposing the use of telemedicine on patients and physicians is not likely to be fruitful. A successful adaptation requires an analysis of needs and continuous education on both sides. PMID- 24803274 TI - Integration of e-consultations into the outpatient care process at a tertiary medical centre. AB - An e-consultation is an asynchronous consultation performed by a specialist without a face-to-face patient visit. E-consultations have been available to primary care providers at the Mayo Clinic for several years. We reviewed e consultations performed by specialists at the Mayo Clinic for the first six months of 2013. We included only "internal" e-consultations, originating from within the Rochester practice. During the study period a total of 3242 e consultations were completed at the Mayo Clinic. After excluding those relating to patients who did not give research consent, 3008 e-consultations remained. We categorized our internal e-consultations into eight types. The most frequently used types were the first e-consultation processes to be implemented: the primary care to specialist e-consultation and the specialist to specialist e consultation, accounting for 74% of the total. As these two types of e consultation became widely used, the staff discovered that the e-consultation process could be adapted to meet specific practice needs and six more e consultation types emerged. For example, intra-specialty e-consultations and surgical e-consultations accounted for 16% of the total. E-consultations appear to have improved access to specialists, and they are integrated into care processes when timely expert opinions are needed. As e-consultations evolve, it will be important to develop a standard, well-defined terminology to compare outcomes of these processes across practices. PMID- 24803275 TI - Use of a telehealth system by older adults with hypertension. AB - We conducted a feasibility study of a home telehealth system that monitored blood pressure and bodyweight. A total of 34 participants with hypertension (10 males and 24 females) had the telemedicine system installed in their homes. Their mean age was 72 years and 94% of them self-identified as Hispanic. The telehealth system transmitted blood pressure and bodyweight data to a server. There was also a messaging function that was used to send a daily reminder to the participants. Participants used the telehealth system for six months. Ten participants were lost to follow up and 24 participants completed the entire study. Participants had strong positive perceptions regarding the usability and usefulness of the telemedicine system. Most of them (92%) found the device easy to use and 96% felt that the training they received prepared them to use the device. The providers indicated that use of the system improved their ability to manage their patients. The results of the study suggest that use of the telehealth system for home monitoring in Hispanic patients with hypertension is feasible. PMID- 24803276 TI - The effect of SMS messaging on the compliance with iron supplementation among pregnant women in Iran: a randomized controlled trial. AB - We examined the effect of SMS text messages on compliance with iron supplementation among pregnant women. A randomized controlled trial was conducted on 116 pregnant women referred from public health centres in Ahvaz. Their gestational age was 14-16 weeks. The subjects were randomly assigned to a control group who received usual care, or to a 12-week intervention with SMS reminders in addition to usual care. Participants in both groups were provided with iron supplements and taught how to take iron tablets. Most women in the intervention group (94%) had high compliance with iron supplements compared to the control group (66%); this difference was significant (P = 0.003). Although haemoglobin, haematocrit and ferritin decreased significantly in each group, there was no significant difference between them. Using SMS reminders is an efficient way of improving compliance of women with iron supplementation during pregnancy. However, in the present study better compliance did not improve anaemia. PMID- 24803277 TI - A systematic review of the cost and cost-effectiveness of telehealth for patients suffering from chronic obstructive pulmonary disease. AB - We conducted a systematic review of the evidence on the costs and cost effectiveness of telehealth for patients with chronic obstructive pulmonary disease (COPD). A literature search identified six relevant economic evaluations that were assessed according to the Consensus Health Economic Criteria list (CHEC list). Three studies were from North America and three studies were from Europe. All studies reported the use of home monitoring devices that measured and transmitted different physical indicators to nurses who provided personalised feedback to patients during weekdays. The six studies involved a total of 559 COPD patients of whom 281 were randomised to telehealth. The review demonstrated a potential for cost savings. All six studies reported a lower average cost per patient with telehealth plus usual care compared with usual care alone. However, the quality of the economic evidence was poor. Five studies were evaluated as low quality and one study was evaluated as moderate quality, with CHEC list scores of 21-68%. Caution is advised for healthcare decision-makers seeking large-scale implementation of telehealth in routine clinical practice. The clinical effectiveness of such implementations with follow-up exceeding 12 months has not yet been demonstrated. PMID- 24803278 TI - Genetic instability in peripheral lymphocytes as biological marker for non-small cell lung cancer patients in the South Indian state of Andhra Pradesh. AB - OBJECTIVES: This study aims, first, at evaluating the DNA and chromosomal damage in non-small cell lung cancer (NSCLC) patients from the South Indian state of Andhra Pradesh, and then at correlating these results with possible confounding factors that might potentially play a role in causing genetic damage. METHODS: The study included 246 NSCLC patients (177 men and 69 women) and 250 healthy controls (180 men and 70 women) for the analysis of DNA and chromosomal damage using the comet assay and micronucleus test. RESULTS: Both DNA and chromosomal damage were found to be increased in NSCLC patients compared to healthy controls, and the extent of the damage was higher in males than female patients. The smoking status had a profound effect on the extent of DNA and chromosomal damage in NSCLC patients. The degree of genetic damage correlated with the stage of the disease. However, the histological status had no effect on the extent of DNA and chromosomal damage among NSCLC patients. CONCLUSIONS: We here report, for the first time, that the NSCLC patients selected form the Andhra Pradesh population had increased DNA damage and higher mean micronucleus frequencies in peripheral lymphocytes, indicating a strong background level of genetic instability. PMID- 24803279 TI - Prognostic value of microvessel density in hepatocellular carcinoma patients: a meta-analysis. AB - INTRODUCTION: The identification of microvessel density (MVD) in patients suffering from different types of cancer has become a hot point as an emerging and promising biomarker. The aim of the present study is to clarify the prognostic relevance of MVD in hepatocellular carcinoma (HCC). METHODS: Relevant articles were screened in PubMed and EMBASE databases. Patients' clinical characteristics, overall survival (OS), disease/recurrence-free survival (DFS/RFS), and MVD levels were extracted for further analysis. The statistical analysis derived from the Kaplan-Meier survival curves was calculated indirectly with the methods developed by Parmar, Williamson, and Tierney. Multivariate Cox hazard regression analysis was used directly in Stata 11.0. The pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to evaluate the prognostic role of MVD in HCC. RESULTS: Our online literature search identified 12 articles including a total of 1,138 HCC patients. Meta-analysis of all the included studies considering survival outcomes showed a positive correlation between poor prognosis and higher-MVD levels. The pooled HRs (and 95% CIs) for OS and DFS/RFS were respectively 2.08 [1.77-2.45] and 2.64 [2.12-3.29]. Subgroup analyses considering tumor stage (I-II/III-IV), tumor size (<5 cm/>= 5 cm), differentiation (well/poor), or cirrhosis status (>= 20%/<20%) were also conducted, and all the above analyses supported the prognostic role of MVD in HCC. CONCLUSION: Our meta-analysis showed that the available evidence supports the proposition that MVD has a good predictive role in HCC, especially when the patients have late stage, large size, or poorly differentiated tumors. PMID- 24803280 TI - The presence of anti-GRP78 antibodies in the serum of patients with colorectal carcinoma: a potential biomarker for early cancer detection. AB - BACKGROUND: The identification of new biomarkers is required for early diagnosis of colorectal carcinoma patients (CRC), since about 20% of these patients are initially diagnosed with a distant metastatic disease. GRP78, a heat shock protein, functions also as a cell surface signaling receptor of cells under physiological stress. GRP78 was found to be expressed on the cell surface of various tumor cells. The presence of autoantibodies to GRP78 in cancer patient's serum was found to be correlated with a poor prognosis. In this study we aimed to identify anti-GRP78 antibodies in the serum of 85 patients diagnosed by colonoscopy, as an early detection biomarker. METHODS: We developed an ELISA assay with recombinant GRP78 immobilized on 96-well culture plates and used an anti-IgG antibody to measure the sole anti-GRP78 IgGs. RESULTS: Testing for anti GRP78 showed a significant increase in antibody titer in patients with a polyp and in CRC patients (p<0.001) compared to healthy subjects. CONCLUSIONS: This is the first study showing the presence of anti-GRP78 at the very early stages of CRC. PMID- 24803281 TI - Correlation of tumor-infiltrative lymphocyte subtypes alteration with neoangiogenesis before and after neoadjuvant chemotherapy treatment in breast cancer patients. AB - The two most important factors in tumor-stromal interactions are tumor infiltrating lymphocytes (TIL) and neoangiogenesis (NAng). While changes of these parameters in responders of neoadjuvant chemotherapy (NCTx) have been reported, their correlation with pathological response in breast cancer (BC) patients treated with NCTx have not been described. We therefore evaluated alterations of the TIL subtypes ratio and alterations of NAng using the vasohibin-1-positive ratio (VPR) in BC patients during the course of NCTx. To this aim we used: (i) double immunohistochemistry of CD8 cytotoxic T cells and T regulatory cells (Treg) with Foxp3, determining the CD8+/Foxp3 ratio; (ii) immunostaining of CD31 and vasohibin-1, yielding the VPR, which reflects the NAng status. Changes between the CD8+/Foxp3 ratio and VPR before and after therapy were then correlated with the pathological response of the patients. A concomitant significant decrement of Foxp3 and NAng, represented by VPR, were detected only in NCTx pathological responders (p<0.001 and p=0.044, respectively). The CD8+/Foxp3 ratio increased in both responders and non-responders, but to greater extent in responders (p=0.02). The changes of VPR in the NCTx-treated group differed from those recorded for the patients treated with aromatase inhibitors and shown in our earlier study; this indicates that the reactions of the tumor stromal interaction to therapy were different among different treatments in BC patients. Changes in Foxp3 and VPR in responders may reflect the dynamic activity of tumor stroma and host immune response to tumor antigens in the tumor microenvironment in response to the NCTx. VPR can be a potential surrogate marker in BC specimens for predicting the response to NCTx, incorporating both features of carcinoma and stromal cells. PMID- 24803282 TI - Lithium cation conducting TDI anion-based ionic liquids. AB - In this paper we present the synthesis route and electrochemical properties of new class of ionic liquids (ILs) obtained from lithium derivate TDI (4,5-dicyano 2-(trifluoromethyl)imidazolium) anion. ILs synthesized by us were EMImTDI, PMImTDI and BMImTDI, i.e. TDI anion with 1-alkyl-3-methylimidazolium cations, where alkyl meant ethyl, propyl and butyl groups. TDI anion contains fewer fluorine atoms than LiPF6 and thanks to C-F instead of P-F bond, they are less prone to emit fluorine or hydrogen fluoride due to the rise in temperature. Use of IL results in non-flammability, which is making such electrolyte even safer for both application and environment. The thermal stability of synthesized compounds was tested by DSC and TGA and no signal of decomposition was observed up to 250 degrees C. The LiTDI salt was added to ILs to form complete electrolytes. The structures of tailored ILs with lithium salt were confirmed by X-ray diffraction patterns. The electrolytes showed excellent properties regarding their ionic conductivity (over 3 mS cm(-1) at room temperature after lithium salt addition), lithium cation transference number (over 0.1), low viscosity and broad electrochemical stability window. The ionic conductivity and viscosity measurements of pure ILs are reported for reference. PMID- 24803283 TI - Clinical relevance of immune parameters in the tumor microenvironment of head and neck cancers. AB - BACKGROUND: The tumour microenvironment is a highly complex region where multiple interactions occur between host and cancer cells. The host response is defined by the presence and function of different tumour infiltrating lymphocytes and cytokines. Head and neck squamous cell carcinomas comprise a subgroup of human cancers with significant morbidity and mortality. METHOD: A literature review was performed to identify studies, which have investigated the impact of immune factors within the tumour microenvironment of head and neck squamous cell carcinomas on clinical outcomes. RESULTS: Higher counts of intratumoral dendritic cells and CD8+ T-lymphocytes are associated with a favorable prognosis in head and neck cancers. However, contrasting results have been found with T-regulatory cells whereby higher intratumoral counts appear favorable particularly in tumours of oropharyngeal origin. A number of studies have found a link between various biomarkers, e.g. IL-10 in oral cancers, and clinical outcome. CONCLUSIONS: We have identified immune factors within the tumour microenvironment, which are critically related to prognosis and also those, which require further work to elucidate their full relevance. Furthermore it is clear that if immunotherapy is to be introduced as an adjunct in the treatment of head and neck cancers, different immunological parameters will need to be selected for each distinct subsite. PMID- 24803284 TI - Tele-ICU: the way forward in geriatric care? AB - Aging population is set to increase in the near future, and will need specialized care when admitted to ICUs. The elderly are beset with chronic conditions, such as cardiovascular, COPD, diabetes, renal complications and depression. Specialist opinions can now be made available through telemedicine facilities. Tele-ICU is a specialized hub consisting of highly skilled staff trained in critical care able to deliver timely, quality care service to patients admitted to ICUs in remote areas using highly advanced information technology services. These specialists in the tele-ICU hub are able to analyze and gather data arriving at timely interventional management decisions and provide this vital feedback to the nursing staff and doctors manning remote ICU locations where specialized intensivist may not be available. Known clinical benefits of such a system include better patient outcomes, reduced medical errors, mortality and reduced hospital length of stay. The main disadvantage in implementation could be the upfront high cost involved, for which low-cost models are being explored. In the face of delivering such remote care, it is up to the local health policy to make legislative changes to include associated legal and ethical issues. Considering the burgeoning aging population, tele-ICU could become the way forward in delivering geriatric critical care. PMID- 24803285 TI - The effects of cognitive training on gait speed and stride variability in old adults: findings from a pilot study. AB - BACKGROUND: The interrelationship between gait performance and higher-order cognitive functions has been established through a number of different investigations. In turn, enabling gait by improving cognition is a new and emerging field of research. AIMS: Investigating if and to what extent a structured cognitive training program influences gait-related parameters in a sample of old and frail nursing home residents. METHODS: Twenty-one nursing home residents were quasi-randomized to an intervention group following a 6-week structured cognitive training program or a control group. Gait was investigated during normal pace and under two dual-task conditions (simple and complex dual task walking conditions), using the GAITRite((r)) system at three predefined time points (pre-intervention, post-intervention, 3-month follow-up). Outcome measures were gait speed and stride variabilities. RESULTS: Confirmation of the interrelationship between gait and cognition evidenced by decreased gait parameters during complex dual-task walking. Observation of clinical meaningful improvements in gait stability and gait speed after the training program under the complex dual-task situations, with only speed remaining stable over a period of 3 months. DISCUSSION: This study on the effects of cognitive training on gait is promising, with several results going in the expected direction. Our data corroborate previous findings and extend them to the group of frail old nursing home residents. CONCLUSIONS: The present pilot study's approach of improving gait under challenging walking situations by interventions designed to improve cognitions adds encouraging results to this emerging field of research, although restrictions in sample size and in the control group prevent us from drawing firm conclusions. PMID- 24803286 TI - Mobility, walking and physical activity in persons with multiple sclerosis. AB - OBJECTIVE: The effect of differing levels of mobility and walking disability on level of physical activity (PA) performed in persons with multiple sclerosis (PwMS) is unknown. We aimed to quantify the association between mobility and walking impairment and PA levels in PwMS. METHODS: We assessed mobility and walking impairment in >3000 North American Research Committee on Multiple Sclerosis registrants using the Patient Determined Disease Steps scale (score of 0-2 = no, 3-6 = moderate, >=7 = severe impairment) and 12-Item Multiple Sclerosis Walking Scale (MSWS-12) score (divided into quartiles, score of 0-25 = least walking impairment, 76-100 = most). Level of PA performance (metabolic equivalent [MET] minutes/week) was estimated using the Godin Leisure-Time Exercise Questionnaire. Multivariable regression and general linear models were used to assess the impact of walking and mobility impairment on PA levels. RESULTS: Moderate and severe mobility impairment was associated with performance of 183 and 319 fewer MET minutes/week and a 65% and 90% reduced odds of performing >=500 MET minutes/week of PA compared to no impairment (mean +/- SD: 447 +/- 413 MET minutes/week) (p < 0.05 for all). Compared to the first quartile of MSWS-12 score (mean +/- SD: 475 +/- 401), the second, third and fourth quartiles were associated with performance of 127, 216 and 268 fewer MET minutes/week and 51%, 71% and 77% reduced odds of achieving >= 500 MET minutes/week of PA (p < 0.05 for each). Limitations of our study include possible recall bias, use of a patient reported rather than objective outcome and assumptions made when calculating MET minutes. CONCLUSION: Mobility and walking impairment are associated with less physical activity in PwMS. PMID- 24803287 TI - High sensitivity of diesel soot morphological and optical properties to combustion temperature in a shock tube. AB - Carbonaceous particles produced from combustion of fossil fuels have strong impacts on air quality and climate, yet quantitative relationships between particle characteristics and combustion conditions remain inadequately understood. We have used a shock tube to study the formation and properties of diesel combustion soot, including particle size distributions, effective density, elemental carbon (EC) mass fraction, mass-mobility scaling exponent, hygroscopicity, and light absorption and scattering. These properties are found to be strongly dependent on the combustion temperature and fuel equivalence ratio. Whereas combustion at higher temperatures (~2000 K) yields fractal particles of a larger size and high EC content (90 wt %), at lower temperatures (~1400 K) smaller particles of a higher organic content (up to 65 wt %) are produced. Single scattering albedo of soot particles depends largely on their organic content, increasing drastically from 0.3 to 0.8 when the particle EC mass fraction decreases from 0.9 to 0.3. The mass absorption cross-section of diesel soot increases with combustion temperature, being the highest for particles with a higher EC content. Our results reveal that combustion conditions, especially the temperature, may have significant impacts on the direct and indirect climate forcing of atmospheric soot aerosols. PMID- 24803288 TI - Tough stimuli-responsive supramolecular hydrogels with hydrogen-bonding network junctions. AB - Hydrogels were prepared with physical cross-links comprising 2-ureido-4[1H] pyrimidinone (UPy) hydrogen-bonding units within the backbone of segmented amphiphilic macromolecules having hydrophilic poly(ethylene glycol) (PEG). The bulk materials adopt nanoscopic physical cross-links composed of UPy-UPy dimers embedded in segregated hydrophobic domains dispersed within the PEG matrix as comfirmed by cryo-electron microscopy. The amphiphilic network was swollen with high weight fractions of water (w(H2O) ~ 0.8) owing to the high PEG weight fraction within the pristine polymers (w(PEG) ~ 0.9). Two different PEG chain lengths were investigated and illustrate the corresponding consequences of cross link density on mechanical properties. The resulting hydrogels exhibited high strength and resilience upon deformation, consistent with a microphase separated network, in which the UPy-UPy interactions were adequately shielded within hydrophobic nanoscale pockets that maintain the network despite extensive water content. The cumulative result is a series of tough hydrogels with tunable mechanical properties and tractable synthetic preparation and processing. Furthermore, the melting transition of PEG in the dry polymer was shown to be an effective stimulus for shape memory behavior. PMID- 24803289 TI - Mirror neurons. PMID- 24803291 TI - Pol III Promoters to Express Small RNAs: Delineation of Transcription Initiation. AB - Pol III promoters such as U6 are commonly used to express small RNAs, including small interfering RNA, short hairpin RNA, and guide RNA, for the clustered regularly interspaced short palindromic repeats genome-editing system. However, whether the small RNAs were precisely expressed as desired has not been studied. Here, using deep sequencing to analyze small RNAs, we show that, for mouse U6 promoter, sequences immediately upstream of the putative initiation site, which is often modified to accommodate the restriction enzyme sites that enable easy cloning of small RNAs, are critical for precise transcription initiation. When the promoter is kept unmodified, transcription starts precisely from the first available A or G within the range of positions -1 to +2. In addition, we show that transcription from another commonly used pol III promoter, H1, starts at multiple sites, which results in variability at the 5' end of the transcripts. Thus, inaccuracy of 5' end of small RNA transcripts might be a common problem when using these promoters to express small RNAs based on currently believed concepts. Our study provides general guidelines for minimizing the variability of initiation, thereby enabling more accurate expression of small RNAs. PMID- 24803292 TI - Electronic and optical properties of TiO2 nanotubes and arrays: a first principles study. AB - Recently, the synthesis, properties, modifications, and applications of TiO2 nanomaterials have attracted much research attention. Here, based on extensive density functional theory calculations, we explored the stability, electronic structures and optical absorption properties of single-walled TiO2 nanotubes (SWTONTs) and TiO2 nanotube arrays (TONTAs), which are constructed from anatase TiO2(101) monolayers and bilayers, respectively. We obtained the stable Dnd (n = 3-5) and S2n(-n, n) (n = 3-9) SWTONTs, and found that SWTONTs energetically prefer S2n symmetry. Compared with S2n(-n, n) SWTONTs, the calculated Young's moduli of Dnd(-n, n) SWTONTs are more stiff due to their relatively large strain energies. The band gaps of hexagonal TONTAs are not sensitive to their apertures, which are less than that of TiO2 bilayers. The narrow band gaps of TONTAs originate from the edge states mainly contributed by the Ti and O atoms at the core region. The calculated optical absorptions of both SWTONTs and TONTAs display anisotropic features. These results clearly reveal that the electronic and optical properties of TiO2 nanostructures are strongly associated with their symmetry, dimensions and morphology, which provide useful insights into the understanding of the related experimental observations. PMID- 24803293 TI - A role for LATERAL ORGAN BOUNDARIES-DOMAIN 16 during the interaction Arabidopsis Meloidogyne spp. provides a molecular link between lateral root and root-knot nematode feeding site development. AB - Plant endoparasitic nematodes induce the formation of their feeding cells by injecting effectors from the esophageal glands into root cells. Although vascular cylinder cells seem to be involved in the formation of root-knot nematode (RKN) feeding structures, molecular evidence is scarce. We address the role during gall development of LATERAL ORGAN BOUNDARIES-DOMAIN 16 (LBD16), a key component of the auxin pathway leading to the divisions in the xylem pole pericycle (XPP) for lateral root (LR) formation. Arabidopsis T-DNA tagged J0192 and J0121 XPP marker lines, LBD16 and DR5::GUS promoter lines, and isolated J0192 protoplasts were assayed for nematode-dependent gene expression. Infection tests in LBD16 knock out lines were used for functional analysis. J0192 and J0121 lines were activated in early developing galls and giant cells (GCs), resembling the pattern of the G2/M-transition specific ProC yc B 1;1 :CycB1;1(NT)-GUS line. LBD16 was regulated by auxins in galls as in LRs, and induced by RKN secretions. LBD16 loss of function mutants and a transgenic line with defective XPP cells showed a significantly reduced infection rate. The results show that genes expressed in the dividing XPP, particularly LBD16, are important for gall formation, as they are for LR development. PMID- 24803294 TI - Andrographolide suppresses IL-6/Stat3 signaling in peripheral blood mononuclear cells from patients with chronic rhinosinusitis with nasal polyps. AB - The mechanisms underlying the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remain largely unknown. CRSwNP has garnered considerable public health concern owing to its high incidence and unsatisfactory treatment outcomes. Herbal remedies are promising candidates for the treatment of CRSwNP. We examined the utility of andrographolide, a diterpenoid lactone extracted from the Chinese herb Andrographis paniculata, an anti-inflammatory agent for CRSwNP treatment by evaluating interleukin (IL)-6 and IL-17 production and monitoring T helper 17 (Th17) differentiation of peripheral blood mononuclear cells (PBMCs) isolated from 20 Chinese CRSwNP patients and 11 control subjects. All CRSwNP patients exhibited clinical features of CRSwNP. Andrographolide significantly inhibited IL 6 and IL-17 production, suppressed p-Stat3 expression, and inhibited Th17 differentiation of PBMCs in vitro. These findings suggested that andrographolide has useful anti-inflammatory properties and could be used for the treatment of CRSwNP. PMID- 24803295 TI - Dexmedetomidine controls systemic cytokine levels through the cholinergic anti inflammatory pathway. AB - Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation, but the mechanism is not clear. This study intends to elucidate the anti-inflammatory mechanism of dexmedetomidine through the cholinergic anti-inflammatory pathway. To investigate this therapeutic potential of dexmedetomidine, a murine model of endotoxemia was established induced by lipopolysaccharide (LPS). Animals were assigned to one of four protocols. Protocol one: animals were randomly assigned to control group, dexmedetomidine group, and sterile saline group (n=20 each), and these animals were used for survival analysis. The survival rate was assessed up to 120 h after endotoxin injection. Protocol two: animals were randomly assigned to one of four groups (n=16 each): group 1 (group Saline), treated with sterile saline 15 min prior to endotoxin treatment (10 mg kg(-1) over 2 min); group 2 (group Dex), treated with dexmedetomidine 15 min prior to endotoxin treatment; group 3 (group alphaBGT+Dex), treated with alpha-7 nicotinic acetylcholine receptors (alpha7nAChR) antagonist alpha-bungarotoxin (alphaBGT, 1 MUg/kg) 15 min prior to dexmedetomidine treatment; group 4 (group saline+Dex), treated with equivalent sterile saline 15 min prior to dexmedetomidine treatment. Protocol three: animals were randomly assigned to one of two groups (n=16 each): vagotomy group (group VNX+Dex), right cervical vagus nerve was exposed and transected; sham-operated group (group SHAM+Dex), the cervical vagus nerve was visualized, but was neither isolated from the surrounding tissues nor transected. Protocol four: animals were treated with dexmedetomidine (40 MUg/kg) and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system (n=16 each). In the survival analysis groups, the survival rate of dexmedetomidine group was significantly higher than that of the endotoxemia group (65 versus 25 %, P<0.01). Preemptive administration of dexmedetomidine significantly attenuated the cytokine response after lipopolysaccharide (LPS) induced endotoxemia (TNF-alpha, IL-1beta, IL-6, P<0.01, respectively). However, preemptive administration of dexmedetomidine failed to suppress cytokine response in alpha-bungarotoxin group and vagotomy group (TNF-alpha, IL-1beta, IL-6, P>0.05, respectively). Furthermore, preemptive administration of dexmedetomidine significantly increased the discharge frequency of cervical vagus nerves in comparison with sterile saline treatment (P<0.01).Our results demonstrate that the preemptive administration of dexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release. However, administration of dexmedetomidine to vagotomy or alpha7 nAChR antagonist pretreatment mice failed to suppress TNF levels, indicating that the vagus nerve and alpha7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of dexmedetomidine. These findings show that central alpha-2 agonist dexmedetomidine suppresses systemic inflammation through vagal- and alpha7nAChR-dependent mechanism. PMID- 24803296 TI - Berberine ameliorates collagen-induced arthritis in rats associated with anti inflammatory and anti-angiogenic effects. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. In this study, we explored the effect of berberine on rats with bovine type II collagen-induced arthritis (CIA), an animal model for RA. Following treatment, berberine attenuates arthritic scores and suppresses collagen-specific immune responses in CIA rats. Compared with the un treated CIA group, berberine reversed pathological changes, which showed a significant improvement in synovial hyperplasia and inflammatory infiltration. The expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-6, IL-17 and vascular endothelial growth factor (VEGF) were obviously reduced in the sera of berberine-treated rats (all P<0.05). Moreover, berberine showed marked inhibition of the expression of VEGF and CD34 (all P<0.05). Interestingly, berberine significantly suppresses p-ERK, p-p38 and p-JNK activation (all P<0.05), which may partially explain the anti-RA activity of berberine. These results suggest that berberine ameliorates CIA in rats associated with anti-inflammatory and anti-angiogenic effects, which might be of great therapeutic value for RA. PMID- 24803297 TI - Increased serum GP88 (Progranulin) concentrations in rheumatoid arthritis. AB - GP88 (Progranulin; PGRN) is a secreted glycosylated protein with important functions in several processes, including immune response and cancer growth. Recent reports have shown that PGRN is a therapeutic target for rheumatoid arthritis (RA) because of its capability to bind with tumor necrosis factor receptor (TNFR). However, the serum PGRN level in RA patients has not been investigated. We used enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of PGRN in 417 healthy subjects, 56 patients with RA and 31 patients with osteoarthritis (OA). In RA patients, we also measured the serum TNF-alpha and sTNFR concentration. Immunohistochemical staining of PGRN was performed using synovectomy tissue of RA patients. The serum PGRN normal range was established as 40.1 +/- 8.7 ng/ml. PGRN levels were not influenced by sex or age. A significant increase in serum PGRN levels was observed in RA (50.2 +/- 11.1 ng/ml) and OA (45.4 +/- 6.6 ng/ml) groups compared to those in age-matched healthy controls (40.4 +/- 9.9 ng/ml) (p<0.05, Tukey). Further, PGRN levels in the synovial fluid of RA patients (68.4 +/- 3.4 ng/ml) were found to be significantly higher than those in OA patients (35.9 +/- 16.8 ng/ml). Immunohistochemical staining of PGRN revealed that the highest positive signal was detected in macrophages. Circulating PGRN in RA patients was weakly associated with TNF-alpha and sTNFR 2 concentration. Furthermore, PGRN/TNF-alpha ratio was correlated the stage of the disease in RA patients. The concentrations of serum PGRN in RA were found to be significantly higher than those in age-matched healthy controls, although it remains to be clarified how blood PGRN is related to the pathogenesis of RA. Our results showed that the serum PGRN may be a useful approach to monitor the disease activity in RA patients. PMID- 24803298 TI - Gabapentin, a synthetic analogue of gamma aminobutyric acid, reverses systemic acute inflammation and oxidative stress in mice. AB - The aim of this study was to investigate the potential anti-inflammatory and anti oxidant effects of gabapentin (GBP) in mice. The anti-inflammatory and anti oxidant effects were evaluated using various mediators that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, proinflammatory cytokine levels, glutathione (GSH) consumption, and malondialdehyde (MDA) production in mice. Pretreatment of mice with GBP (1 mg/kg) significantly reduced carrageenan or dextran-induced paw edema (P<0.05) when compared to vehicle group. Adding to this, GBP (1 mg/kg) significantly inhibited paw edema induced by histamine, serotonin, bradikinin, 48/80 compound, and prostaglandin E2. In the carrageenan induced peritonitis model, GBP significantly decreased total and differential leukocyte counts and reduced the levels of MPO activity in the plantar tissue and IL-1beta and TNF-alpha concentrations in the peritoneal exudate. The same dose of GBP also decreased the MDA concentration and increased the levels of GSH into the peritoneal fluid. In summary, our results demonstrated that GBP exhibited anti inflammatory activity in mice by reducing the action of inflammatory mediators, neutrophil migration and proinflammatory cytokine levels, and anti-oxidant properties by decreasing the concentration of MDA and increasing the GSH content. These observations raise the possibility that GBP could be used to improve tissue resistance to damage during inflammatory conditions. PMID- 24803299 TI - Arylazopyrazole AAP1742 inhibits CDKs and induces apoptosis in multiple myeloma cells via Mcl-1 downregulation. AB - Inhibitors of cyclin-dependent kinases 9 have been developed as potential anticancer drugs for the treatment of multiple myeloma. We have previously prepared a library of arylazo-3,5-diaminopyrazole inhibitors of CDKs. Here, we describe a novel member, AAP1742 (CDK9 inhibition with IC(50) = 0.28 MUm), that reduces the viability of multiple myeloma cell lines in low micromolar concentrations. Consistent with inhibition of CDK9, AAP1742 decreases the phosphorylation of RNA polymerase II and inhibits mRNA synthesis of anti apoptotic proteins Mcl-1, Bcl-2, and XIAP, followed by apoptosis in the RPMI-8226 cell line in a dose- and a time-dependent manner. These results are consistent with the biochemical profile of AAP1742 and further suggest cellular inhibition of CDK9 as a possible target for anticancer drugs. PMID- 24803300 TI - A framework for optimization-based design of motion encoding in magnetic resonance elastography. AB - PURPOSE: In conventional three-dimensional magnetic resonance elastography, motion encoding gradients (MEGs) synchronized to a mechanical excitation are applied separately in each direction to encode tissue displacement generated by the corresponding waves. This requires long acquisition times that introduce errors due to patient motion and may hinder clinical deployment of magnetic resonance elastography. In this article, a framework for MEGs sequence design is proposed to reduce scanning time and increase signal-to-noise ratio. THEORY AND METHODS: The approach is based on applying MEGs in all three directions simultaneously with varying parameters, and formulation of the problem as a linear estimation of the wave properties. Multidirectional MEGs sequences are derived by setting the problem in an experimental design framework. Such designs are implemented and evaluated on simulation and phantom data. RESULTS: Estimation error of the displacement using the proposed MEGs designs is reduced up to a factor of two in comparison with a unidirectional design with a same number of acquisitions. Alternatively, for the same error, scanning time is reduced up to a factor of three using the multidirectional designs. CONCLUSION: The proposed framework generalizes acquisition of magnetic resonance elastography, and allows quantification of design performance, and optimization-based derivation of designs. PMID- 24803301 TI - Changing a dangerous rural cultural tradition: a randomized control study of youth as extra riders on tractors. AB - PURPOSE: This study used a randomized control design to evaluate the effectiveness of AgTeen, an in-home, family-based farm safety intervention, in decreasing extra riding on tractors by youth. Having children as extra riders on tractors has deep roots in farm culture, but it can result in serious injury or death. METHODS: The study randomized 151 families into 3 groups: parent-led intervention (fathers taught their families about farm safety), staff-led intervention (staff members who were peer farmers taught families), and a no treatment control. Mothers, fathers, and all children aged 10-19 participated in the lessons. FINDINGS: At study entry, 93% of youth reported that they had been an extra rider on a tractor in the past year. Although they were aware of the injury risk, fathers frequently gave tractor rides to their children. After the intervention, fathers in both AgTeen groups were less likely than control fathers to give youth tractor rides. Intervention youth were less likely than control youth to be extra riders. The intervention positively affected the extra-riding attitudes and injury risk perceptions of mothers and fathers. The parent-led and staff-led groups did not significantly differ across study outcomes. CONCLUSIONS: Findings confirm the effectiveness of a family-based intervention in decreasing extra riding on tractors by youth. PMID- 24803303 TI - Function of the audiovestibular system in children with systemic lupus erythematosus. AB - Systemic lupus erythematosus can affect inner ear by disrupting either the hearing or balance system. Affection of hearing can be anatomically categorized into conductive and sensorineural hearing loss, while affection of the equilibrium system manifests either as an isolated manifestation like vertigo or as a part of a spectrum like Meniere's disease. Most cases show asymptomatic affection requiring an objective audiovestibular assessment. More focus should be given to routine evaluation especially with disease flares and for proper treatment. In pediatric patients, more concern should be given owing to the added effect of ototoxicity with several drugs and the educational impact of such comorbidity. PMID- 24803304 TI - Two-dimensional DNA-programmable assembly of nanoparticles at liquid interfaces. AB - DNA-driven assembly of nanoscale objects has emerged as a powerful platform for the creation of materials by design via self-assembly. Recent years have seen much progress in the experimental realization of this approach for three dimensional systems. In contrast, two-dimensional (2D) programmable nanoparticle (NP) systems are not well explored, in part due to the difficulties in creating such systems. Here we demonstrate the use of charged liquid interfaces for the assembly and reorganization of 2D systems of DNA-coated NPs. The absorption of DNA-coated NPs to the surface is controlled by the interaction between a positively charged lipid layer and the negatively charged DNA shells of particles. At the same time, interparticle interactions are switchable, from electrostatic repulsion between DNA shells to attraction driven by DNA complementarity, by increasing ionic strength. Using in situ surface X-ray scattering methods and ex situ electron microscopy, we reveal the corresponding structural transformation of the NP monolayer, from a hexagonally ordered 2D lattice to string-like clusters and finally to a weakly ordered network of DNA cross-linked particles. Moreover, we demonstrate that the ability to regulate 2D morphology yields control of the interfacial rheological properties of the NP membrane: from viscous to elastic. Theoretical modeling suggests that the structural adaptivity of interparticle DNA linkages plays a crucial role in the observed 2D transformation of DNA-NP systems at liquid interfaces. PMID- 24803302 TI - Clinical pharmacology of AMG 181, a gut-specific human anti-alpha4beta7 monoclonal antibody, for treating inflammatory bowel diseases. AB - AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181 antibody (ADA), alpha4 beta7 receptor occupancy (RO), target cell counts, serum C reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear beta-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 MUg ml(-1) . The PD effect on alpha4 beta7 RO showed an EC50 of 0.01 MUg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases. PMID- 24803305 TI - Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men. AB - PURPOSE: To develop an automatic segmentation algorithm to classify abdominal adipose tissues into visceral fat (VAT), deep (DSAT), and superficial (SSAT) subcutaneous fat compartments and evaluate its performance against manual segmentation. MATERIALS AND METHODS: Data were acquired from 44 normal (BMI 18.0 22.9 kg/m(2) ) and 38 overweight (BMI 23.0-29.9 kg/m(2) ) subjects at 3T using a two-point Dixon sequence. A fully automatic segmentation algorithm was developed to segment the fat depots. The first part of the segmentation used graph cuts to separate the subcutaneous and visceral adipose tissues and the second step employed a modified level sets approach to classify deep and superficial subcutaneous tissues. The algorithmic results of segmentation were validated against the ground truth generated by manual segmentation. RESULTS: The proposed algorithm showed good performance with Dice similarity indices of VAT/DSAT/SSAT: 0.92/0.82/0.88 against the ground truth. The study of the fat distribution showed that there is a steady increase in the proportion of DSAT and a decrease in the proportion of SSAT with increasing obesity. CONCLUSION: The presented technique provides an accurate approach for the segmentation and quantification of abdominal fat depots. PMID- 24803306 TI - Acute and chronic effects of agomelatine on intravenous penthylenetetrazol induced seizure in mice and the probable role of nitric oxide. AB - Agomelatine is a potent MT1 and MT2 melatonin receptor agonist as well as a 5 HT2C serotonin receptor antagonist. It was approved by the European Medicines Agency as an antidepressant drug in year 2009. On the other hand, the involvement of melatonin and serotonin receptors in the modulation of seizure threshold has been demonstrated previously. The purpose of this study was to investigate the effect of agomelatine on penthylenetetrazol-induced seizure threshold in male mice. Therefore, we evaluated the effect of acute (12.5, 25, 50, 75 and 100 mg/kg, p.o. and chronic (25, 50 and 75 mg/kg, p.o., once a day, for 7 days) agomelatine administration on mouse model of intravenous penthylenetetrazol induced seizure. For evaluation of nitrergic system involvement in the anticonvulsant effect of agomelatine, co-administration of multiple nitric oxide synthase (NOS) inhibitors [L-NAME, a non-selective NOS inhibitor, (5 mg/kg, p.o.), aminoguanidine, a selective iNOS inhibitor, (100 mg/kg, p.o.) or 7 nitroindazol, a selective nNOS inhibitor, (60 mg/kg, p.o.)] and agomelatine (50 and 75 mg/kg) were examined. In acute study, agomelatine (50 and 75 mg/kg) increased clonic seizure threshold compared to control group (P<0.05 and 0.01, respectively). In chronic study, agomelatine had no effect on clonic seizure threshold compared with control mice. Co-administration of L-NAME, aminoguanidine or 7-nitroindazol with agomelatine (50 and 75 mg/kg) prevented a agomelatine induced anti-convulsant effect. Our results suggest that agomelatine has anticonvulsant activity in intravenous penthylenetetrazol-induced seizure in acute therapy and this effect can be at least in part due to iNOS or nNOS induction. PMID- 24803307 TI - Reply to Dr Myers' commentary on the use of automated blood pressure machines in office blood pressure measurements. PMID- 24803308 TI - Age-related differences in urinary 11-dehydroxythromboxane B2 between infants, children, and adolescents: another example of developmental hemostasis? AB - Our study was developed to ascertain reference ranges of 11-dehydrothromboxane B2 (11-dhTXB2) in the urine of healthy pediatric subjects. Urine samples were analyzed using the AspirinWorksTM assay that measures levels of 11 dehydrothromboxane B2. 128 individuals (2 months to 18 years) were identified as healthy and not receiving aspirin. When adjusted as picograms/milligrams urine creatinine, there was a negative correlation between age and level of 11 dehydrothromboxane B2 (P = 0.0001). This study confirms a negative correlation between age and level of urinary 11-dehydrothromboxane B2 and provides a set of age-specific reference ranges. PMID- 24803309 TI - Different patient-reported outcomes in immigrants and patients born in Sweden: 18,791 patients with 1 year follow-up in the Swedish Hip Arthroplasty Registry. AB - BACKGROUND AND PURPOSE: Some patients have persistent symptoms after total hip arthroplsty (THA). We investigated whether the proportions of inferior clinical results after total hip arthroplasty-according to the 5 dimensions in the EQ-5D form, and pain and satisfaction according to a visual analog scale (VAS)-are the same in immigrants to Sweden as observed in those born in Sweden. METHODS: Records of total hip arthroplasties performed between 1992 and 2007 were retrieved from the Swedish Hip Arthroplasty Register (SHAR) and cross-matched with data from the National Board of Health and Welfare and also Statistics, Sweden. 18,791 operations (1,451 in immigrants, 7.7%) were eligible for analysis. Logistic and linear regression models including age, sex, diagnosis, type of fixation, comorbidity, surgical approach, marital status, and education level were analyzed. Outcomes were the 5 dimensions in EQ-5D, EQ-VAS, VAS pain, and VAS satisfaction. Preoperative data and data from 1 year postoperatively were studied. RESULTS: Preoperatively (and after inclusion of covariates in the regression models), all immigrant groups had more negative interference concerning self-care. Immigrants from the Nordic countries outside Sweden and Europe tended to have more problems with their usual activities and patients from Europe and outside Europe more often reported problems with anxiety/depression. Patients born abroad showed an overall tendency to report more pain on the VAS than patients born in Sweden. After the operation, the immigrant groups reported more problems in all the EQ-5D dimensions. After adjustment for covariates including the preoperative baseline value, most of these differences remained except for pain/discomfort and-concerning immigrants from the Nordic countries also anxiety/depression. After the operation, pain according to VAS had decreased substantially in all groups. The immigrant groups indicated more pain than those born in Sweden, both before and after adjustment for covariates. CONCLUSION: The frequency of patients who reported moderate to severe problems, both before and 1 year after the operation, differed for most of the dimensions in EQ-5D between patients born in Sweden and those born outside Sweden. PMID- 24803310 TI - Ovocalyxin-36 is an effector protein modulating the production of proinflammatory mediators. AB - Sepsis is a systemic inflammatory response syndrome during infection. Therapeutic agents are essential to protect the host from sepsis. Ovocalyxin-36 (OCX-36) is a chicken eggshell membrane protein and shares protein sequence and gene organization homology with bactericidal permeability-increasing protein (BPI), lipopolysaccharide-binding protein (LBP) and palate, lung and nasal epithelium clone (PLUNC) proteins that play a major role in innate immune protection. We recently reported that OCX-36 binds to both lipopolysaccharide (LPS) and lipoteichoic acid (LTA) (Cordeiro et al., 2013, PLoS ONE 8, e84112), which is an important activity to neutralize endotoxins and non-endotoxin pyrogens during an inflammatory response. Here we investigated the immune modulating effects of OCX 36 and enzymatically digested OCX-36 (dOCX-36) in vitro and in a mouse model of endotoxemia. OCX-36 alone dose-dependently induced both TNF-alpha and nitric oxide (NO) production by RAW 264.7 macrophage cells, and this immunostimulatory effect was reduced by enzymatic digestion. In the presence of LPS, dOCX-36 was more effective than intact OCX-36 at reducing LPS-induced secretion of TNF-alpha from RAW 264.7 cells, but did not reduce NO production. In contrast, OCX-36 increased LPS-induced NO production, both in the presence and absence of FBS, PCR array analysis confirmed that OCX-36 and dOCX-36 differentially regulated genes involved in innate immunity, and dOCX-36 down-regulated the expression of genes involved in LPS signaling and inflammatory responses. In vivo, dOCX-36 was more effective at reducing LPS-induced inflammatory symptoms and inhibiting the local production of pro-inflammatory mediators in the small intestine. These results suggest that OCX-36 and OCX-36 derived peptides may differentially modulate innate immune responses, and support our hypothesis that OCX-36 derived peptides have potential therapeutic applications in sepsis. PMID- 24803311 TI - Painful diabetic neuropathy. AB - Diabetes is a worldwide epidemic, and associated neuropathy is its most costly and disabling complication. Given the rising prevalence of painful diabetic neuropathy, it is increasingly important that we understand the best ways to diagnose and treat this condition. Diagnostic tests in this field are evolving rapidly. These include the use of skin biopsies to measure small unmyelinated fibers, as well as even newer techniques that can measure both small unmyelinated fibers and large myelinated fibers in the same biopsy. The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 1 diabetes than in those with type 2 disease [corrected]. This dichotomy emphasizes the need to study the pathophysiologic differences between the two types of diabetes, because different treatments may be needed for each condition. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study. Finally, neuropathic pain is under-recognized and undertreated despite an ever evolving list of effective drugs. Evidence exists to support several drugs, but the optimal sequence and combination of these drugs are still to be determined. PMID- 24803313 TI - Induction of dedifferentiated male mouse adipose stromal vascular fraction cells to primordial germ cell-like cells. AB - The adipose stromal vascular fraction (SVF) contains abundant mesenchymal stem cell populations that have a limited ability to self-renew and differentiate. Male mouse adipose SVF cells were dedifferentiated by reprogramming factors (c Myc, Oct4, Sox2, and Klf4) to form embryonic stem cell-like cells (ESCLCs), which upgraded their limited differentiation potential. The ESCLCs were induced to differentiate toward epiblast-like cells (EpiLCs) and primordial germ cell-like cells (PGCLCs) by culturing in media supplied with activin A and BMP-4, respectively. The derived ESCLCs possess embryonic stem cell features and can automatically form embryonic bodies. After culture in EpiLC induction medium for 2-3 days, ESCLCs formed flattened epithelial structures that were different from their original water drop-like colonies, and the expression of pluripotency related genes decreased. When the cells that had been cultured in EpiLC induction medium for 2 days were isolated and cultured in PGCLC induction medium for 4-6 days, they formed typical water drop-like colonies again. Moreover, expression of the pluripotency-related genes and the primordial germ cell (PGC) specification related genes increased. During progression from ESCLCs toward EpiLCs and PGCLCs, the levels of histone methylases H3K9me2 and H3K27me3 kept changing, which resembled those seen in PGC specification. The derived PGCLCs expressed SSEA-1, Blimp-1, and Stella. Furthermore, methylation of Igf2r and Snrpn was retained, but H19 and Kcnq1ot1 methylation levels were slightly reduced compared to non PGCLCs, suggesting that the derived PGCLCs may have initiated the process of imprint erasure. PMID- 24803312 TI - Osteopontin and latent-TGF beta binding-protein 2 as potential diagnostic markers for HBV-related hepatocellular carcinoma. AB - Chronic Hepatitis B (HB) is the main risk factor for chronic liver disease (CLD) and hepatocellular carcinoma (HCC) in many low-resource countries, where diagnosis is constrained by lack of clinical, histopathological and biomarker resources. We have used proteomics to detect plasma biomarkers that outperform alpha-Fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in low resource contexts. Deep-plasma proteome analysis was performed in HCC patients, patients with CLD and in HB-carrier controls from Thailand (South-East Asia) and The Gambia (West-Africa). Mass spectrometry profiling identified latent transforming growth factor beta binding-protein 2 (LTBP2) and Osteopontin (OPN) as being significantly elevated in HCC versus CLD and controls. These two proteins were further analyzed by ELISA in a total of 684 plasma samples, including 183 HCC, 274 CLD and 227 asymptomatic controls. When combined, LTBP2 and OPN showed an area under the receiver operating curve of 0.85 in distinguishing HCC from CLD in subjects with AFP <20 ng/mL. In a prospective cohort of 115 CLD patients from Korea, increased plasma levels of LTBP2 and/or OPN were detected in plasma collected over 2 years prior to diagnosis in 21 subjects who developed HCC. Thus, the combination of LTBP2 and OPN outperformed AFP for diagnosis and prediction of HCC and may therefore improve biomarker-based detection of HBV-related HCC. PMID- 24803314 TI - Percutaneous absorption of herbicides derived from 2,4-dichlorophenoxyacid: structure-activity relationship. AB - Ethyl to octyl esters of 2,4-dichlorophenoxy-acetic acids (2,4DAA), 2,4 dichlorophenoxy-propionic acids (2,4DPA) or 2,4-dichlorophenoxy-butyric acids (2,4DBA) are present in the most commonly used herbicides. Their use involves a significant risk of skin exposure, but little is known about the percutaneous flux of these substances. Studies have shown that percutaneous transition of esters may be dependent on their hydrolysis by esterases present in the skin. In this study, we describe ex vivo percutaneous absorption of seven pure esters (methyl to decyl) with a 2,4DA structure for rats (n=6) and humans (n=7). Esters were applied at 50 MUL cm(-2) to dermatomed skin (approximately 0.5 mm thick) for 24 h. The enzymatic constants for hydrolysis of each ester by skin esterases were determined in vitro using skin homogenates from both species. Structure-activity relationships linking the evolution of the ex vivo percutaneous flux of esters and the 2,4D structure with enzymatic (Vmax; Km) and/or physical parameters (molecular weight, molecular volume, size of the ester, log(kow)) were examined to develop a good flux estimation model. Although the percutaneous penetration of all of the esters of the 2,4D family are "esterase-dependent", the decreasing linear relationship between percutaneous penetration and hyrophobicity defined by the logarithm for the octanol-water partition coefficient (log(kow)) is the most pertinent model for estimating the percutaneous absorption of esters for both species. The mean flux of the free acid production by the esterases of the skin is not the limiting factor for percutaneous penetration. The rate of hydrolysis of the esters in the skin decreases linearly with log(kow), which would suggest that either the solubility of the esters in the zones of the skin that are rich in esterases or the accessibility to the active sites of the enzyme is the key factor. The structure-activity relationship resulting from this study makes it possible, in humans and in rats, to make a good estimate of the ex vivo percutaneous fluxes for all pure esters of this family of herbicides. PMID- 24803316 TI - Competitive inhibition of the nondepolarizing muscle relaxant rocuronium on nicotinic acetylcholine receptor channels in the rat superior cervical ganglia. AB - A number of case reports now indicate that rocuronium can induce a number of serious side effects. We hypothesized that these side effects might be mediated by the inhibition of nicotinic acetylcholine receptors (nAChRs) at superior cervical ganglion (SCG) neurons. Conventional patch clamp recordings were used to study the effects of rocuronium on nAChR currents from enzymatically dissociated rat SCG neurons. We found that ACh induced a peak transient inward current in rat SCG neurons. Additionally, rocuronium suppressed the peak ACh-evoked currents in rat SCG neurons in a concentration-dependent and competitive manner, and it increased the extent of desensitization of nAChRs. The inhibitory rate of rocuronium on nAChR currents did not change significantly at membrane potentials between -70 and -20 mV, suggesting that this inhibition was voltage independent. Lastly, rocuronium preapplication enhanced its inhibitory effect, indicating that this drug might prefer to act on the closed state of nAChR channels. In conclusion, rocuronium, at clinically relevant concentrations, directly inhibits nAChRs at the SCG by interacting with both opened and closed states. This inhibition is competitive, dose dependent, and voltage independent. Blockade of synaptic transmission in the sympathetic ganglia by rocuronium might have potentially inhibitory effects on the cardiovascular system. PMID- 24803315 TI - The stress-related hormone norepinephrine induced upregulation of Nix, contributing to ECM protein expression. AB - Organ fibrosis has been viewed as a major medical problem that leads to progressive dysfunction of the organ and eventually the death of patients. Stress related hormone norepinephrine (NE) has been reported to exert fibrogenic actions in the injured organ. Nix plays a critical role in pressure overload-induced cardiac remodeling and heart failure through mediating cardiomyocyte apoptosis. However, cardiac remodeling also includes fibrosis. Whether Nix is involved in stress-induced fibrosis remains unclear. The present study was designed to determine the role of Nix in NE-induced NIH/3T3 fibroblasts. The results showed that Nix was upregulated and closely associated with cell proliferation, collagen and fibronectin expression in NIH/3T3 fibroblasts following NE treatment. Overexpression of Nix promoted collagen and fibronectin expression, whereas the suppression of Nix resulted in a strong reduction in collagen and fibronectin expression. Moreover, the increases in collagen and fibronectin expression induced by NE were successively increased when Nix was overexpressed and reduced when Nix was inhibited. Furthermore, we demonstrated that the PKC activation is responsible for the upregulation of Nix induced by NE. Inhibition of Nix expression with alpha-adrenoceptor antagonist, beta-adrenoceptor antagonist or PKC inhibitor attenuated NE-induced collagen and fibronectin expression. Our data revealed that Nix is a novel mediator of NE-induced fibrosis. Thus, it would provide a new insight into the development of effective preventative measures and therapies of tissue fibrosis. PMID- 24803317 TI - Danhong injection inhibits the development of atherosclerosis in both Apoe-/- and Ldlr-/- mice. AB - Danhong injection (DHI), a certificated Chinese medical product made from radix salviae miltiorrhizae and flos carthami, is prescribed to patients with coronary heart disease in China. To investigate if DHI can inhibit atherosclerosis, apolipoprotein E-deficient (Apoe-/-) or low-density lipoprotein receptor deficient (Ldlr-/-) mice on high-fat diet were divided into 2 groups and received daily intraperitoneal injection of saline and DHI, respectively, for 16 or 20 weeks. After the treatment, mouse aortas were collected to determine lesions, expression of adenosine triphosphate-binding cassette transporter A1 and tumor necrosis factor-alpha (TNF-alpha), and macrophage accumulation. Additionally, serum lipid profiles and expression of hepatic HMG-CoA reductase messenger RNA and low-density lipoprotein receptor protein were determined. We observed that DHI inhibited lesions in both Apoe-/- and Ldlr-/- mice. Associated with the decreased lesions, the aortic adenosine triphosphate-binding cassette transporter A1 expression was increased, whereas the macrophage accumulation was decreased in male Apoe-/- mice and both male and female Ldlr-/- mice. Although DHI reduced HMG CoA reductase messenger RNA expression in both female Apoe-/- and Ldlr-/- mice, it decreased low-density lipoprotein cholesterol levels only in female Apoe-/- mice. In addition to attenuation of lipopolysaccharide-induced expression of TNF alpha, IL-1beta, IL-6 in macrophages, and human C-reactive protein in hepatocytes, respectively, at the transcriptional level in vitro, DHI also reduced TNF-alpha protein expression in aortic root of both Apoe-/- and Ldlr-/- mice, suggesting the importance of the anti-inflammatory properties of DHI in the inhibition of lesion development. Taken together, our study demonstrates that DHI inhibits atherosclerosis in both Apoe-/- and Ldlr-/- mice with various mechanisms, including anti-inflammation. The inhibition of atherosclerosis can be attributed to the cardioprotective properties of DHI. PMID- 24803318 TI - Comprehensive comparative and semiquantitative proteome of a very low number of native and matched epstein-barr-virus-transformed B lymphocytes infiltrating human melanoma. AB - Melanoma, the deadliest form of skin cancer, is highly immunogenic and frequently infiltrated with immune cells including B cells. The role of tumor-infiltrating B cells (TIBCs) in melanoma is as yet unresolved, possibly due to technical challenges in obtaining TIBCs in sufficient quantity for extensive studies and due to the limited life span of B cells in vitro. A comprehensive workflow has thus been developed for successful isolation and proteomic analysis of a low number of TIBCs from fresh, human melanoma tissue. In addition, we generated in vitro-proliferating TIBC cultures using simultaneous stimulation with Epstein Barr virus (EBV) and the TLR9 ligand CpG-oligodesoxynucleotide (CpG ODN). The FASP method and iTRAQ labeling were utilized to obtain a comparative, semiquantitative proteome to assess EBV-induced changes in TIBCs. By using as few as 100 000 B cells (~5 MUg protein)/sample for our proteomic study, a total number of 6507 proteins were identified. EBV-induced changes in TIBCs are similar to those already reported for peripheral B cells and largely involve changes in cell cycle proliferation, apoptosis, and interferon response, while most of the proteins were not significantly altered. This study provides an essential, further step toward detailed characterization of TIBCs including functional in vitro analysis. PMID- 24803320 TI - Short communication: Lower baseline CD4 count is associated with a greater propensity toward virological failure in a cohort of South African HIV patients. AB - The antiretroviral (ARV) service at Edendale Hospital in Pietermaritzburg, KwaZulu-Natal, South Africa has initiated more than 9,000 adults on therapy since 2004; however, virological outcomes among this patient cohort have not been systematically assessed. We conducted a retrospective chart review of patients initiating ARVs in recent years of the antiretroviral roll-out to determine the efficacy of this program. Clinic records were randomly selected for patients who had initiated ARVs between January 2009 and December 2012. Demographic and virological data were collected. Virological failure was defined as failure to achieve a plasma viral load (VL) <25 copies/ml after 6-12 months of ARV initiation or >=2 consecutive HIV-RNA VLs >=400 copies/ml following suppression of <25 copies/ml. Records for 228 individuals were reviewed. Twenty-one (9%) individuals experienced virological failure necessitating a regimen change. The median (interquartile range, IQR) duration of antiretroviral exposure was 19 (11 31) months. Individuals experiencing virological failure did not differ from individuals experiencing success with regards to sex, age, baseline hemoglobin, creatinine, alanine aminotransferase level, or weight (p>0.05) except for having a lower baseline CD4 [median 74 (IQR 31-94) versus 142 (IQR 61-211) cells/MUl; p=0.0036 (Mann-Whitney U test)]. No differences were observed between groups in type of ARV regimen, WHO stage at time of ARV initiation, or tuberculosis status. Therefore, using a relatively strict definition of virological failure, we observed that virological success was achievable in over 90% of individuals at the Edendale Hospital ARV clinic. Lower baseline CD4 was associated with greater propensity toward virological failure. PMID- 24803319 TI - Identification of specific corrinoids reveals corrinoid modification in dechlorinating microbial communities. AB - Cobalamin and other corrinoids are essential cofactors for many organisms. The majority of microbes with corrinoid-dependent enzymes do not produce corrinoids de novo, and instead must acquire corrinoids produced by other organisms in their environment. However, the profile of corrinoids produced in corrinoid-dependent microbial communities, as well as the exchange and modification of corrinoids among community members have not been well studied. In this study, we applied a newly developed liquid chromatography tandem mass spectrometry-based corrinoid detection method to examine relationships among corrinoids, their lower ligand bases and specific microbial groups in microbial communities containing Dehalococcoides mccartyi that has an obligate requirement for benzimidazole containing corrinoids for trichloroethene respiration. We found that p cresolylcobamide ([p-Cre]Cba) and cobalamin were the most abundant corrinoids in the communities. It suggests that members of the family Veillonellaceae are associated with the production of [p-Cre]Cba. The decrease of supernatant associated [p-Cre]Cba and the increase of biomass-associated cobalamin were correlated with the growth of D. mccartyi by dechlorination. This supports the hypothesis that D. mccartyi is capable of fulfilling its corrinoid requirements in a community through corrinoid remodelling, in this case, by importing extracellular [p-Cre]Cba and 5,6-dimethylbenzimidazole (DMB) (the lower ligand of cobalamin), to produce cobalamin as a cofactor for dechlorination. This study also highlights the role of DMB, the lower ligand produced in all of the studied communities, in corrinoid remodelling. These findings provide novel insights on roles played by different phylogenetic groups in corrinoid production and corrinoid exchange within microbial communities. This study may also have implications for optimizing chlorinated solvent bioremediation. PMID- 24803322 TI - Automated Identification of Infarcted Myocardium Tissue Characterization Using Ultrasound Images: A Review. AB - Myocardial infarction (MI) or acute myocardial infarction commonly known as heart attack is one of the major causes of cardiac death worldwide. It occurs when the blood supply to the portion of the heart muscle is blocked or stopped causing death of heart muscle cells. Early detection of MI will help to prevent the infarct expansion leading to left ventricle (LV) remodeling and further damage to the cardiac muscles. Timely identification of MI and the extent of LV remodeling are crucial to reduce the time taken for further tests, and save the cost due to early treatment. Echocardiography images are widely used to assess the differential diagnosis of normal and infarcted myocardium. The reading of ultrasound images is subjective due to interobserver variability and may lead to inconclusive findings which may increase the anxiety for patients. Hence, a computer-aided diagnostic (CAD) technique which uses echocardiography images of the heart coupled with pattern recognition algorithms can accurately classify normal and infarcted myocardium images. In this review paper, we have discussed the various components that are used to develop a reliable CAD system. PMID- 24803323 TI - Pyrosequencing is an accurate and reliable method for the analysis of heteroplasmy of the A3243G mutation in patients with mitochondrial diabetes. AB - Human mitochondrial DNA is a circular DNA molecule that encodes some of the proteins required for oxidative phosphorylation. Different mitochondrial DNA genotypes may coexist within a single cell, a condition known as heteroplasmy. An A-to-G transition at position 3243 of mitochondrial DNA (A3243G) can result in maternally inherited diabetes and deafness (mitochondrial diabetes). However, the commonly used methods of PCR restriction fragment length polymorphism and Sanger sequencing are neither sensitive nor reliable enough to detect this low level of heteroplasmy. Here, we developed a quantitative method based on pyrosequencing to analyze the heteroplasmy of the A3243G mutation in leukocyte DNA obtained from 83 persons of 15 unrelated pedigrees with mitochondrial diabetes. The accuracy and reliability of this method were also measured by comparing the results with those from high-resolution melting analysis, Sanger sequencing, and PCR restriction fragment length polymorphism with artificial heteroplasmy standard samples. The results showed that the accuracy of pyrosequencing was much higher than that of the other methods, and the limitation of heteroplasmy detection with this method reached 2%, based on our artificial control studies. An inverse correlation was found between the level of heteroplasmy and the age of the onset in our patients. This result suggested that the heteroplasmy of the A3243G mutation could become a significant prediction index for the onset of mitochondrial diabetes. PMID- 24803324 TI - Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States. AB - PURPOSE: To estimate the incidence of Cushing's syndrome (CS) and Cushing's disease (CD) in the US. METHODS: MarketScan Commercial database 2007-2010 (age <65 years) was used. CS patients were defined with >=2 claims of CS diagnosis, while CD patients were defined with CS plus a benign pituitary adenoma diagnosis or hypophysectomy in the same calendar year. Annual incidence was calculated by dividing the number of CS or CD cases by the total number of members with the same enrollment requirement during the calendar years. RESULTS: CS incidence rates per million person-years were 48.6 in 2009 and 39.5 in 2010. The lowest rates of CS were in <=17-year-olds and highest rates were in 35 to 44-year-olds. CD incidence rates were 7.6 in 2009 and 6.2 in 2010. The lowest rates of CD were in <=17-year-olds and highest rates were in 18 to 24-year-olds. The rates varied by sex (2.3-2.7 in males, 9.8-12.1 in females). In females, lowest rates ranged 2.5-4.0 in <=17-year-olds and highest 16.7-27.2 in 18-24 year olds. In males, there were too few cases to report estimates by age. CONCLUSIONS: In the first large US-based study, the annual incidence of CS in individuals <65 years old was nearly 49 cases per million, substantially higher than previous estimates, which were based primarily on European data. Using similar methods, we estimated the incidence of CD at nearly 8 cases per million US population. These estimates, if confirmed in other epidemiologic databases, represent a new data reference in these rare conditions. PMID- 24803325 TI - Azobenzene-functionalized metal-organic polyhedra for the optically responsive capture and release of guest molecules. AB - Stimuli-responsive metal-organic polyhedra (srMOPs) functionalized with azobenzene showed UV-irradiation-induced isomerization from the insoluble trans srMOP to the soluble cis-srMOP, whereas irradiation with blue light reversed this process. Guest molecules were trapped and released upon cis-to-trans and trans-to cis isomerization of the srMOPs, respectively. This study provides a new direction in the ever-diversifying field of MOPs, while laying the groundwork for a new class of optically responsive materials. PMID- 24803326 TI - A prospective comparative study of pin site infection in pediatric supracondylar humeral fractures: daily pin care vs. no pin care. AB - INTRODUCTION: Pin site infection is a critical issue for patients' safety in skeletal fixation using percutaneous pins or wires. Closed reduction and percutaneous Kirschner wires fixation are the mainstay of treatment in pediatric supracondylar humeral fractures. Little information is available in the literature about the optimal regimen of pin site care in children. MATERIALS AND METHODS: We performed a prospective comparative study of 61 children with supracondylar humeral fractures between June 2011 and March 2013 after approval by the institutional review board. They were allocated into two groups of different postoperative pin site care methods by the emergency department arrival date and received fracture fixation within 24 h. Postoperatively, 30 children underwent pin site cleaning every day whereas the other 31 patients did not have the pin sites cleaned until the pins removal 4-6 weeks later. RESULTS: Demographic data were not significantly different between the two groups. The infection rate was significantly higher in patients who underwent daily pin site care (90.3 vs. 53.3 %, p = 0.001). Of the 144 pin sites, infection occurred at 42 (57.5 %) pin sites in the daily care group and at 19 (26.8 %) pin sites in the non-care group. The number of telephone consultations for postoperative care was significantly higher in the daily care group (1.0 vs. 0.27 call/case, p = 0.007). CONCLUSIONS: Daily pin site care was associated with a higher infection rate and greater stress in postoperative care that required more telephone consultations. The study results could not support daily pin site care. Careful observation of pin sites was recommended in the treatment of pediatric supracondylar humeral fractures. PMID- 24803327 TI - Vitamin D and bisphosphonate response. PMID- 24803328 TI - Vitamin D levels and response to biphosphonates in postmenopausal women receiving glucocorticoid therapy. PMID- 24803329 TI - Testosterone levels increase in association with recovery from acute fracture in men. AB - In this longitudinal case-control study, acute fracture was associated with low serum testosterone, which was transient in 43% of men. While assessment of gonadal status is part of the assessment of bone fragility, measurement of testosterone in the early period after fracture may overestimate the prevalence of androgen deficiency. INTRODUCTION: Measurement of circulating testosterone is recommended in the evaluation of bone fragility in men. Since acute illness can transiently decrease circulating testosterone, we quantified the association of acute fracture and serum testosterone levels. METHODS: A case-control study was conducted involving 240 men with a radiologically confirmed minimal trauma fracture presenting to a tertiary referral hospital and 89 age-matched men without a history of minimal trauma fracture serving as controls. Follow-up testosterone levels 6 months after baseline were available for 98 cases and 27 controls. Results were expressed as the median and interquartile (IQR) range. RESULTS: Compared to controls, cases had lower total testosterone [TT, 7.2 (3.5, 10.8) vs 13.6 (10.9, 17.1) nmol/L, p < 0.001]. The 143 cases treated as inpatients had lower testosterone levels than the 97 cases treated as outpatients [TT 4.7 (2.3, 8.1) vs 10.3 (7.5, 12.7) nmol/L, p < 0.001]. Group differences in calculated free testosterone (cFT) were comparable to the group differences in TT. At follow-up, in 98 cases, median TT increased from 6.5 nmol/L (3.2, 8.5) to 9.6 nmol/L (6.9, 12.0) p < 0.0001, and SHBG remained unchanged. Of cases with low testosterone, 43% with TT <10 nmol/L and/or cFT <230 pmol/L at presentation were reclassified as androgen sufficient at follow-up. TT was unchanged in the controls. CONCLUSIONS: Low testosterone levels in men presenting with an acute fracture may, at least in part, be due to an acute, fracture-associated, stress response. To avoid over diagnosis, evaluation for testosterone deficiency should be deferred until recovery from the acute event. PMID- 24803330 TI - Critical impact of patient knowledge and bone density testing on starting osteoporosis treatment after fragility fracture: secondary analyses from two controlled trials. AB - Most patients are not treated for osteoporosis after their fragility fracture "teachable moment." Among almost 400 consecutive wrist fracture patients, we determined that better-than-average osteoporosis knowledge (adjusted odds = 2.6) and BMD testing (adjusted odds = 6.5) were significant modifiable facilitators of bisphosphonate treatment while male sex, working outside the home, and depression were major barriers. INTRODUCTION: In the year following fragility fracture, fewer than one quarter of patients are treated for osteoporosis. Although much is known regarding health system and provider barriers and facilitators to osteoporosis treatment, much less is understood about modifiable patient-related factors. METHODS: Older patients with wrist fracture not treated for osteoporosis were enrolled in trials that compared a multifaceted intervention with usual care controls. Baseline data included a test of patient osteoporosis knowledge. We then determined baseline factors that independently predicted starting bisphosphonate treatment within 1 year. RESULTS: Three hundred seventy-four patients were enrolled; mean age 64 years, 78 % women, 90 % white, and 54 % with prior fracture. Within 1 year, 86 of 374 (23 %) patients were treated with bisphosphonates. Patients who were treated had better osteoporosis knowledge at baseline (70 % correct vs 57 % for untreated, p < 0.001) than patients who remained untreated; conversely, untreated patients were more likely to be male, still working, and report depression. In fully adjusted models, osteoporosis knowledge was independently associated with starting bisphosphonates (adjusted OR 2.6, 95 %CI 1.3-5.3). Obtaining a BMD test (aOR 6.5, 95 %CI 3.4-12.2) and abnormal BMD results (aOR 34.5, 95 %CI 16.8-70.9) were strongly associated with starting treatment. CONCLUSIONS: The most important modifiable facilitators of osteoporosis treatment in patients with fracture were knowledge and BMD testing. Specifically targeting these two patient-level factors should improve post fracture treatment rates. PMID- 24803331 TI - Calcium supplement intake and risk of cardiovascular disease in women. AB - Some recent reports suggest that calcium supplement use may increase risk of cardiovascular disease. In a prospective cohort study of 74,245 women in the Nurses' Health Study with 24 years of follow-up, we found no independent associations between supplemental calcium intake and risk of incident coronary heart disease (CHD) and stroke. INTRODUCTION: Some recent reports suggest that calcium supplements may increase cardiovascular disease (CVD) risk. The objective was to examine the independent associations between calcium supplement use and risk of CVD. METHODS: We conducted a prospective cohort study of supplemental calcium use and incident CVD in 74,245 women in the Nurses' Health Study (1984 2008) free of CVD and cancer at baseline. Calcium supplement intake was assessed every 4 years. Outcomes were incident CHD (nonfatal or fatal MI) and stroke (ischemic or hemorrhagic), confirmed by medical record review. RESULTS: During 24 years of follow-up, 4,565 cardiovascular events occurred (2,709 CHD and 1,856 strokes). At baseline, women who took calcium supplements had higher levels of physical activity, smoked less, and had lower trans fat intake compared with those who did not take calcium supplements. After multivariable adjustment for age, body mass index, dietary calcium, vitamin D intake, and other CVD risk factors, the relative risk of CVD for women taking >1,000 mg/day of calcium supplements compared with none was 0.82 (95% confidence interval [CI] 0.74 to 0.92; p for trend <0.001). For women taking >1,000 mg/day of calcium supplements compared with none, the multivariable-adjusted relative risk for CHD was 0.71 (0.61 to 0.83; p for trend < 0.001) and for stroke was 1.03 (0.87 to 1.21; p for trend = 0.61). The relative risks were similar in analyses limited to non smokers, women without hypertension, and women who had regular physical exams. CONCLUSIONS: Our findings do not support the hypothesis that calcium supplement intake increases CVD risk in women. PMID- 24803332 TI - The association between critical illness and changes in bone turnover in adults: a systematic review. AB - SUMMARY: Critical illness may lead to altered bone turnover and associated adverse health outcomes. This systematic review found moderate evidence for a positive association between critical illness and increased bone turnover. Prospective cohort studies that identify the extent and risk factors for critical illness related bone loss are required. INTRODUCTION: Intensive care patients face health issues that extend beyond their critical illness and result in significant morbidity and mortality. Critical illness may result in altered bone turnover due to associated immobilisation, inflammation, exposure to medications that effect bone and calcium metabolism, and endocrine dysfunction. The aim of this study was to synthesise the existing evidence for altered bone turnover in adults admitted to intensive care. METHODS: A literature search using MEDLINE and EMBASE was performed from 1965 to March 2013. Reviewed studies investigated the relationship between critical illness and evidence of altered bone turnover (bone turnover markers, bone mineral density, or fracture). Studies were rated upon their methodological quality, and a best-evidence synthesis was used to summarise the results. RESULTS: Four cohort and seven case-control studies were identified for inclusion, of which five studies were rated as being of higher methodological quality. Ten of the studies measured bone turnover markers, and one study fracture rate. Findings were consistent across studies, and best-evidence analysis resulted in a conclusion that moderate evidence exists for an association between critical illness requiring admission to intensive care and altered bone turnover. CONCLUSION: A positive association between critical illness requiring intensive care admission and bone turnover exists, although data are limited, and the risk factors and the nature of the relationship are not yet understood. Prospective cohort studies that identify risk factors and extent of critical illness related bone turnover changes are required. PMID- 24803334 TI - Smurf2 regulates the degradation of YY1. AB - Transcription factor YY1 plays important roles in cell proliferation and differentiation. For example, YY1 represses the expression of muscle-specific genes and the degradation of YY1 is required for myocyte differentiation. The activity of YY1 can be regulated by various post-translational modifications; however, little is known about the regulatory mechanisms for YY1 degradation. In this report, we attempted to identify potential E3 ubiquitin ligases for YY1, and found that Smurf2 E3 ubiquitin ligase can negatively regulate YY1 protein level, but not mRNA level. Smurf2 interacted with YY1, induced the poly-ubiquitination of YY1 and shortened the half-life of YY1 protein. Conversely, an E3 ubiquitin ligase-defective mutant form of Smurf2 or knockdown of Smurf2 increased YY1 protein level. PPxY motif is a typical target recognition site for Smurf2, and the PPxY motif in YY1 was important for Smurf2 interaction and Smurf2-induced degradation of YY1 protein. In addition, Smurf2 reduced the YY1-mediated activation of a YY1-responsive reporter whereas Smurf2 knockdown increased it. Finally, Smurf2 relieved the suppression of p53 activity by YY1. Taken together, our results suggest a novel regulatory mechanism for YY1 function by Smurf2 in which the protein stability and transcriptional activity of YY1 are regulated by Smurf2 through the ubiquitin-proteasome-mediated degradation of YY1. PMID- 24803333 TI - Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength. AB - Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI causing defect. INTRODUCTION: Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. METHODS: Six month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2*/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. RESULTS: Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. CONCLUSION: Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI. PMID- 24803335 TI - Carotenoid metabolic profiling and transcriptome-genome mining reveal functional equivalence among blue-pigmented copepods and appendicularia. AB - The tropical oligotrophic oceanic areas are characterized by high water transparency and annual solar radiation. Under these conditions, a large number of phylogenetically diverse mesozooplankton species living in the surface waters (neuston) are found to be blue pigmented. In the present study, we focused on understanding the metabolic and genetic basis of the observed blue phenotype functional equivalence between the blue-pigmented organisms from the phylum Arthropoda, subclass Copepoda (Acartia fossae) and the phylum Chordata, class Appendicularia (Oikopleura dioica) in the Red Sea. Previous studies have shown that carotenoid-protein complexes are responsible for blue coloration in crustaceans. Therefore, we performed carotenoid metabolic profiling using both targeted and nontargeted (high-resolution mass spectrometry) approaches in four different blue-pigmented genera of copepods and one blue-pigmented species of appendicularia. Astaxanthin was found to be the principal carotenoid in all the species. The pathway analysis showed that all the species can synthesize astaxanthin from beta-carotene, ingested from dietary sources, via 3 hydroxyechinenone, canthaxanthin, zeaxanthin, adonirubin or adonixanthin. Further, using de novo assembled transcriptome of blue A. fossae (subclass Copepoda), we identified highly expressed homologous beta-carotene hydroxylase enzymes and putative carotenoid-binding proteins responsible for astaxanthin formation and the blue phenotype. In blue O. dioica (class Appendicularia), corresponding putative genes were identified from the reference genome. Collectively, our data provide molecular evidences for the bioconversion and accumulation of blue astaxanthin-protein complexes underpinning the observed ecological functional equivalence and adaptive convergence among neustonic mesozooplankton. PMID- 24803336 TI - Identification of functional haplotypes in the promoter region of the LST1 gene. AB - Psoriasis, an inflammatory skin disease, was associated with a promoter variant (rs9267502; P = 3.786 * 10(-19)) of LST1 that may regulate immune response and cellular morphogenesis. Promoter activity was examined to identify functional variants in the proximity of the associated variant. Five natural haplotypes (H1 H5) of four variants (rs7758790, rs9267502, rs41268884, rs17200775) in strong linkage disequilibrium were investigated. The most common haplotype (H1) was TGAG (frequency 0.78), and the second most frequent haplotype (H2) was CGGG (0.09). Luciferase assay was conducted using reporter constructs including each haplotype and firefly luciferase gene. As a result, promoter activity of H1 was smaller than the construct without the promoter region (P < 0.05). The promoter activities of H3, H4, and H5 corresponded to that of H1 (P > 0.05), and H2 promoter activity was larger than that of H1, H3, H4, and H5 (P < 0.05). This might result from changes in binding affinity to transcription factors by nucleotide substitutions of the promoter variants of the LST1 gene. PMID- 24803338 TI - Retrieval-induced forgetting in rats. AB - "Retrieval-induced forgetting" in rats was evaluated using a modified spontaneous object recognition test. The test consisted of a sample phase, retrieval or interference phase, and a test phase with 60-min delay period inserted between the phases. Rats were randomly assigned to one of three groups (control, retrieval and interference) and allowed to explore the field in which two different objects (A, B) were placed in the sample phase. In the retrieval phase, two identical objects (B, B), which were the same as one of the objects presented in the sample phase, were placed again. In the interference phase, two identical objects (C, C), which were novel for animals, were placed. In the test phase, two different objects (A, D), one of which was identical to that presented in sample phase (familiar object) and the other was novel, were placed and the time spent exploring each object was analyzed. While the exploration of the novel object was significantly longer than that of the familiar object in rats subjected to the interference phase, rats subjected to the retrieval phase could not discriminate between the familiar and the novel objects at the test phase. These results demonstrate the "retrieval-induced forgetting" phenomenon in a spontaneous object recognition test in rats. PMID- 24803339 TI - Magnetically induced structural anisotropy in binary colloidal gels and its effect on diffusion and pressure driven permeability. AB - We report on the synthesis, microstructure and mass transport properties of a colloidal hydrogel self-assembled from a mixture of colloidal silica and nontronite clay plates at different particle concentrations. The gel-structure had uniaxial long-range anisotropy caused by alignment of the clay particles in a strong external magnetic field. After gelation the colloidal silica covered the clay particle network, fixing the orientation of the clay plates. Comparing gels with a clay concentration between 0 and 0.7 vol%, the magnetically oriented gels had a maximum water permeability and self-diffusion coefficient at 0.3 and 0.7 vol% clay, respectively. Hence the specific clay concentration resulting in the highest liquid flux was pressure dependent. This study gives new insight into the effect of anisotropy, particle concentration and bound water on mass transport properties in nano/microporous materials. Such findings merit consideration when designing porous composite materials for use in for example fuel cell, chromatography and membrane technology. PMID- 24803340 TI - Magnetically actuated micropatterns for switchable wettability. AB - Arrays of actuated magnetic micropillars that can be tilted, twisted, and rotated in the presence of a magnetic field gradient were obtained. The type and extent of the movements are dependent on the distribution (isotropic, anisotropic) of the magnetizable particles inside the pillars and the strength and the direction of the magnetic field gradient. Independent motion of groups of pillars in the same or opposite directions or homogeneous motion of the whole pattern has been realized. Changing the pattern geometry causes changes in the roll-off angle (ROA) of water droplets on the surface. We show magnetically induced changes in the ROA and direction-dependent ROAs as a consequence of the anisotropy of tilted patterns. We also demonstrate transfer of microparticles between magnetically actuated neighboring pillars. PMID- 24803341 TI - Eight- and six-coordinated Mn(II) complexes of heteroaromatic alcohol and aldehyde: crystal structure, spectral, magnetic, thermal and antibacterial activity studies. AB - Crystal, molecular and electronic structure of new manganese(II) compounds: [Mn(2 CH2OHpy)2(NO3)2] (1), [Mn(4-CHO-5-MeIm)2(NO3)2] (2) and [Mn(4-CHO-5-MeIm)2Cl2] (3), where 2-hydroxymethylpyridine (2-CH2OHpy) and 5(4)-carbaldehyde-4(5) methylimidazole (5(4)-CHO-4(5)-MeIm), have been characterised using X-ray, spectroscopic, magnetic and TG/DTG data. In compounds 1 and 2, the Mn(II) ion is eight-coordinated forming distorted pseudo-dodecahedron, that is rather unusual for the manganese(II) complexes, whereas in 3 the Mn(II) ion environment is a distorted octahedron. The high coordination number (CN=8) of 1 and 2 results from bidentate character of the nitrate ligands. The X-band EPR spectra of compounds 2 and 3 exhibit fine structure signals resulting from zero-field splitting (ZFS) of the spin states for high spin d(5) Mn(II), whereas for 1 the broad isotropic signals were observed. The estimation of ZFS for individual Mn(II) ions was carried out for all compounds using DFT calculations. The free ligands and their manganese(II) complexes have been tested in vitro against gram-positive and gram negative bacteria in order to assess their antimicrobial properties. PMID- 24803342 TI - Reticular macular lesions: a review of the phenotypic hallmarks and their clinical significance. AB - Reticular macular lesions, also known as 'reticular macular disease', 'reticular drusen', 'reticular pseudodrusen', or 'subretinal drusenoid deposits', are a pattern of lesions commonly found in age-related macular degeneration and best visualized using at least two imaging techniques in combination. Reticular lesions have four stages of progression observable on spectral domain optical coherence tomography, but they do not show the usual signs of regression of soft drusen (calcification and pigment changes). Furthermore, reticular lesions correlate histologically with subretinal drusenoid deposits localized between the retinal pigment epithelium and the inner segment ellipsoid band. Reticular lesions are most commonly seen in older age groups of female patients with age related macular degeneration and are usually bilateral. They are not clearly associated with known age-related macular degeneration genes and are highly associated with late-stage age-related macular degeneration and an increased mortality rate. They are also associated with alterations in the neural retina and choroid. PMID- 24803343 TI - Elements for adequate informed consent in the surgical context. AB - Given a history of atrocities and violations of ethical principles, several documents and regulations have been issued by a wide variety of organizations. They aim at ensuring that health care and clinical research adhere to defined ethical principles. A fundamental component was devised to ensure that the individual has been provided the necessary information to make an informed decision regarding health care or participation in clinical research. This article summarizes the history and regulations for informed consent and discusses suggested components for adequate consent forms for daily clinical practice in surgery as well as clinical research. PMID- 24803344 TI - Trends in demographics and management of obstructing colorectal cancer. AB - INTRODUCTION: Obstructing colorectal cancer (CRC) has an aggressive clinical course and poorer prognosis. With the increasing incidence and differing clinical and pathologic spectrum of CRC among Black patients, as well as a paucity of African studies, regional analysis is required. Our aim was to describe the demographics and management of obstructing CRC among the different racial groups in South Africa and to compare these parameters with international standards. PATIENTS AND METHODS: Patients referred to Inkosi Albert Luthuli Central Hospital, Durban, South Africa, with CRC between 2000 and 2012 were followed prospectively. Demographic information, site of obstruction, and management of patients who underwent emergency surgery for malignant large bowel obstruction were analyzed separately. RESULTS: CRC was diagnosed in 1,425 patients. A total of 203 three patients (14.3 %) required emergent treatment for acute large bowel obstruction. The mean age at presentation with obstructing CRC was 59 years. Black patients presented significantly younger (50 years) than White (64), Indian (60), or Colored (61) patients (p < 0.001). The most common sites of obstruction were the sigmoid colon and rectum. A total of 58 patients (29 %) had concomitant metastatic disease. No difference was found between race, sex, and sex per race in patients with concurrent metastatic disease (p = 0.227, p = 0.415, p = 0.798, respectively). Of the 203 patients, 128 (63 %) were managed by resection, 37 (18 %) by colonic stenting, 35 (17 %) by colostomy, and 3 (2 %) by colonic bypass. Stenting was unsuccessful in six patients. CONCLUSION: Tumor location of patients presenting with obstruction is comparable to that cited in international literature; however, the age of presentation among Black patients is more than a decade earlier than in other ethnic groups. Surgical management should be individualized. Stenting remains a reliable alternative in select cases. PMID- 24803345 TI - High survival in patients operated for small isolated liver metastases from gastric cancer: a multi-institutional study. AB - BACKGROUND: Although several studies have reported the outcomes of surgery for the treatment of liver metastases of gastric cancer (GLM), indications for liver resection for gastric metastases remain controversial. This study was designed to identify prognostic determinants that identify operable hepatic metastases from gastric cancer and to evaluate the actual targets of surgical therapy. METHODS: Retrospective analysis was performed on outcomes for 24 consecutive patients at five institutions who underwent gastrectomy for gastric cancer followed by curative hepatectomy for GLM between 2000 and June 2012. RESULTS: Overall 5-year survival and median survival were 40.1 % and 22.3 months, respectively. Uni- and multivariate analyses showed that liver metastatic tumour size less than 5 cm was the most important predictor of overall survival (OS, p = 0.03). Four patients survived >5 years. Repeat hepatectomy was performed in three patients. Two of these patients have remained disease-free since the repeat hepatectomy. CONCLUSIONS: GLM patients with metastatic tumour diameter less than 5 cm maximum are the best candidates for hepatectomy. Hepatic resection should be considered as an option for gastric cancer patients with liver metastases. PMID- 24803346 TI - Japanese D3 lymph node dissection in low rectal cancer with inferior mesenteric lymph node metastases. AB - BACKGROUND: There is currently no consensus on the significance of Japanese D3 lymph node dissection in low rectal cancer with inferior mesenteric lymph node (IMLN) metastasis. This is partly because, despite a number of studies on the subject, cases of IMLN metastasis are relatively rare, and there are few cases of curative resection because of metastasis to other organs. A retrospective study involving a large number of patients was conducted. METHODS: The subjects were 2,743 patients registered in the national registry of the Japanese Society for Cancer of the Colon and Rectum. The data were analyzed for (1) prognostic factors for IMLN metastasis, and (2) outcomes in R0 cases with IMLN metastasis. RESULTS: In the control group, 67 patients (2.7 %) were considered positive for IMLN metastasis. The outcomes in the 35 R0 cases with IMLN metastasis were 50.8 % for 5-year relapse-free survival (RFS) and 61.9 % for 5-year overall survival (OS), which were each better than for R1+R2 cases (5-year RFS 16.1 %, p = 0.0001; 5 year OS 26.7 %, p = 0.0002). The outcomes for R0 cases (total metastatic lymph nodes >=7) with IMLN metastasis (5-year RFS 53.9 %, 5-year OS 68.8 %) did not differ significantly from those for IMLN(-) cases (5-year RFS 54.6 %, 5-year OS 57.1 %) (RFS: p = 0.9515, OS: p = 0.4621). CONCLUSIONS: It was confirmed that cases of IMLN metastasis in low rectal cancer tend to have a large total number of metastatic lymph nodes, but if curative resection can be performed, a good prognosis can be expected. These results demonstrate the value of radical Japanese D3 lymph node dissection in low rectal cancer with IMLN metastasis. PMID- 24803347 TI - A review of the current management and treatment options for superficial venous insufficiency. AB - The recognition of lower extremity venous disease as a significant cause of morbidity and lower quality of life, afflicting up to 25 % of Western populations, has led to rapid and drastic improvements in treatment options as well as an increasing awareness of the disease. Superficial venous disease, a frequent medical problem encountered in clinical practices, is now a common reason for referral to providers offering a spectrum of interventions. Venous guidelines have been set forth by the American Venous Forum and Society for Vascular Surgery covering simple spider veins to chronic venous ulcerations. (Gloviczki et al. J Vas Surg 53:2S-48S, 2011) This review provides an overview of the modern management of varicose veins and venous insufficiency. PMID- 24803348 TI - Gold(I) N-heterocyclic carbene complexes with naphthalimide ligands as combined thioredoxin reductase inhibitors and DNA intercalators. AB - Organometallic conjugates consisting of a gold(I) N-heterocyclic carbene (NHC) moiety and a naphthalimide were prepared and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The complexes were potent DNA intercalators related to their naphthalimide partial structure, inhibited TrxR as a consequence of the incorporation of the gold(I) moiety, and triggered efficient cytotoxic effects in MCF-7 breast and HT-29 colon adenocarcinoma cells. Strong effects on tumor cell metabolism were noted for the most cytotoxic complex, chlorido[1-(3'-(4'' ethylthio-1'',8''-naphthalimid-N''-yl))-propyl-3-methyl-imidazol-2 ylidene]gold(I) (4 d). In conclusion, the conjugation of naphthalimides with gold(I) NHC moieties provided a useful strategy for the design of bioorganometallic anticancer agents with multiple modes of action. PMID- 24803349 TI - Stillbirth rates among Haitians in Canada. AB - BACKGROUND: Data on cultural groups at risk of stillbirth in high-income countries are scarce. We sought to determine disparities in stillbirth by gestational age for Haitian vs. non-Haitian Canadians. METHODS: We used data on 10,287 stillbirths and 2,482,364 livebirths from 1981-2010 in the province of Quebec, Canada. Stillbirth rates for Haitians were compared with non-Haitians using fetuses at risk denominators, and Cox proportional hazards regression models with gestational age as the time scale. RESULTS: Stillbirth rates were much higher for Haitians than non-Haitians during the study period (7.2 vs. 3.9 per 1000 total births). Disparities between Haitians and non-Haitians were largest at 32-36 weeks of gestation [hazard ratio 2.22, 95% confidence interval 1.61, 3.07]. CONCLUSIONS: Stillbirth rates in Haitian Canadians giving birth in Quebec are exceptionally high. Disparities were greatest during the late preterm period. PMID- 24803351 TI - Dynamic and thermodynamic characteristics associated with the glass transition of amorphous trehalose-water mixtures. AB - The glass transition temperature Tg of biopreservative formulations is important for predicting the long-term storage of biological specimens. As a complementary tool to thermal analysis techniques, which are the mainstay for determining Tg, molecular dynamics simulations have been successfully applied to predict the Tg of several protectants and their mixtures with water. These molecular analyses, however, rarely focused on the glass transition behavior of aqueous trehalose solutions, a subject that has attracted wide scientific attention via experimental approaches. Important behavior, such as hydrogen-bonding dynamics and self-aggregation has yet to be explored in detail, particularly below, or in the vicinity of, Tg. Using molecular dynamics simulations of several dynamic and thermodynamic properties, this study reproduced the supplemented phase diagram of trehalose-water mixtures (i.e., Tg as a function of the solution composition) based on experimental data. The structure and dynamics of the hydrogen-bonding network in the trehalose-water systems were also analyzed. The hydrogen-bonding lifetime was determined to be an order of magnitude higher in the glassy state than in the liquid state, while the constitution of the hydrogen-bonding network exhibited no noticeable change through the glass transition. It was also found that trehalose molecules preferred to form small, scattered clusters above Tg, but self-aggregation was substantially increased below Tg. The average cluster size in the glassy state was observed to be dependent on the trehalose concentration. Our findings provided insights into the glass transition characteristics of aqueous trehalose solutions as they relate to biopreservation. PMID- 24803352 TI - A case of sleep-related painful erections with chronic daytime genital discomfort. AB - Sleep-related painful erections (SRPE) are an uncommon condition characterized by recurrent nocturnal penile tumescence accompanied by penile pain without penile pathology, which occurs during the rapid eye movement (REM) sleep stage. A report of a 59-year-old patient with SRPE is described. Turgid painful erections (five to seven episodes of tumescence) during the sleep hours caused pain together with burning and tingling sensations in the penis and perineal zone during the daytime hours. Swelling of the pubic and perineal area was recurrent. Sleep loss, chronic fatigue, mild anxiety, lack of concentration and decreased work occurred along with this condition. Polysomnographic findings indicated REM sleep fragmentation. Attempts to treat this condition with muscle relaxants or anxiolytics did not prompt an improvement of this disorder, but a single daily dose of gabapentin 300 mg in combination with 1 mg clonazepam at bedtime improved total sleep time and reduced full sleep erections. PMID- 24803353 TI - The prevalence of overactive bladder syndrome and urinary incontinence in a Turkish women population; associated risk factors and effect on Quality of life. AB - AIMS: To investigate the prevalence and risk factors of overactive bladder syndrome and urinary incontinence in Turkish women; furthermore, to assess the impact on the quality of life. MATERIALS AND METHODS: A cross-sectional, epidemiological study was carried out in women of reproductive age to define overactive bladder syndrome, urinary incontinence, ICIQ-SF score and medical care seeking. RESULTS: The women's average age was 34.4 +/- 5.26 years. The prevalence of UI was 26.9%. Stress UI was the predominant form. The prevalence of UI increased with age, BMI, number of pregnancies and children delivered. The prevalence of OAB was 20.7%. Women with OAB were older and had greater number of pregnancies than women without OAB. History of nocturnal enuresis was a significant risk factor for OAB and UUI. Women with MUI had more frequent and more abundant leakage of urine. 10.7% of women sought medical care for their condition. CONCLUSIONS: Although prevalence estimates differ across studies, the available evidence indicates that UI and OAB are highly prevalent conditions among women. UI had negative effect on QoL, but only severely-affected women sought medical care. Public health and clinical management programs are needed to determine diagnosis and management of these social problems. PMID- 24803354 TI - Impact of NK cell count on bladder cancer recurrence. AB - PURPOSE: The aim of the present study was to evaluate the prognostic value of the local NK cell count in patients with recurrent non-muscle-invasive bladder cancer. METHODS: The archival paraffin-embedded primary tumor specimens were derived from retrospectively-selected patients, who were treated between 1996 and 2001 for bladder cancer. The study group consisted of 46 patients who developed recurrent disease during their first two post-operative years. The control group consisted of 27 patients who did not develop recurrent disease during their first two post-operative years. Specimens were assessed immunohistochemically with standard "ABC" technique. The frequency of NK cells was expressed as total number, estimated for each tumor by counting the positive NK cells in 10 high power representative fields. Statistical analysis was done using Kruskal-Wallis test. RESULTS: Patients with recurrent non-muscle invasive bladder cancer in general have significantly higher values of stromal NK cell count than the control group. Patients with single tumor and smaller tumors show a statistically significant difference in NK cell count between study and control group. There also exists a statistically significant difference in stromal NK cell count in patients with clinical stage Ta tumor. CONCLUSIONS: Our results confirm an association of the bladder wall NK cell count in bladder cancer patients with the natural history of disease. Further well-performed, reproducible, large, prospective investigation stratified by clinical parameters, such as tumor number and diameter, is needed to display the true value of this marker in the clinical work-up of bladder cancer patients. PMID- 24803355 TI - [Positive surgical margins after radical prostatectomy]. AB - Positive surgical margins (PSMs) in radical prostatectomy specimens are usually considered a negative prognostic parameter. However, their definition and the management of patients with PSMs remain unclear. The aim of the present review is to define pathological features of PSMs,to report their incidence and risk factors and to update PSMs prognostic meaning and possible treatment modalities.The average incidence of PSMs in contemporary series ranges from 6.5% to 32%. The likelihood of PSMs is influenced by pre-operative PSA (total-PSA and PSA-density), tumor features (volume,grade and stage), previous prostatic surgery (open or TURP), patients' characteristics (BMI andpelvis shape) and surgeons' skill. Although PSMs are a predictor of biochemical recurrence, their impact on cause specific survival is highly variable and largely influenced by the tumor Gleason Score. Adjuvant radiotherapy is an effective treatment in PSMs patients but early salvage radiotherapy may be an alternative option that guarantees equivalent survival benefits with less side effects. Further studies are required to define the best candidates to adjuvant or early salvage radiation therapy. PMID- 24803356 TI - [5ARI and PSA: evidences]. AB - OBJECTIVE: The 5alpha-reductase inhibitors (5ARIs) represent a valid therapeutic option in the long-term treatment of benign prostatic hyperplasia (BPH). One of the most debated topics is the interpretation of the variation of the serum PSA during treatment with 5ARIs. The objective of this review was to analyze the change in serum PSA levels over time and to evaluate its sensitivity and specificity in the screening for prostate cancer (CaP) during treatment. METHODS: An extensive search using PubMed and Scopus was performed including the following key words: "5ARI", "finasteride", "dutasteride", "prostate cancer", "benign prostatic hyperplasia", "PSA", "kinetics", "PSA derivatives". RESULTS: The reduction of serum PSA during treatment with 5ARIs can be observed up to 48 months after the beginning of the therapy. This category of drugs seems to improve the diagnostic performance of PSA in screening CaP. On the other hand, there is a reduction of the diagnosis of indolent cancers. Any increase in PSA from nadir should be considered suspicious for malignancy. However, if the choice of a biopsy depended only on an increase of the values of serum PSA, a variable percentage of potentially aggressive tumors could not be diagnosed. Therefore, it is important to consider in the clinical and diagnostic follow-up other factors such as digital rectal examination, age, family history of CaP and imaging techniques. CONCLUSIONS: 5-ARIs have a positive impact on the specificity of PSA but they must not be the only tool that can identify CaPs with poor prognosis. PMID- 24803357 TI - [Positive surgical margins in nephron sparing surgery for renal cell carcinoma]. AB - Nephron sparing surgery (NSS) with a minimal tumor-free margin is considered the cornerstone in the contemporary management of renal cell carcinoma (RCC) stage T1. The aim of this study is to review incidence, predictive risk factors, clinical significance and oncologic outcomes of positive surgical margins (PSM) in NSS. English articles published before March 2014 have been searched in Medline Databank.PSM are present in 0-7% of patients in all surgical approaches considered. Some predictive factors,such as tumor size, localization, and histology have been identified in the past. Other topics concerning surgical technique and approach are discussed.The majority of patients with PSM do not experience disease recurrence and PSM impact on overall survival and cancer specific survival seems to be irrelevant. These results lead to more conservative clinical strategies. However, an active surveillance is mandatory for all patients with PSM and especially for those with high risk disease. Generalization of these results is limited by the low level of evidence of available studies. Further efforts are necessary to avoid PSM intraoperatively and to provide prospective information in order to standardize the postoperative management. PMID- 24803358 TI - Description of heteroaromaticity on the basis of pi-electron density anisotropy. AB - It is demonstrated that there is a direct connection between aromaticity and the anisotropy of the pi-electron density on planes parallel to the molecular ring. The electron density anisotropy on the plane is measured through the ratio of the in-plane Hessian eigenvalues associated with the eigenvectors lying in the plane. Computations on a wide-ranging set of well-characterized monocyclic systems containing heteroatoms validate the correlation between this one-electron density based descriptor and aromaticity; in aromatic compounds, the in-plane Hessian eigenvalues are degenerate (or near degenerate) and the anisotropy of the pi electron density is undirected, whereas the results for antiaromatic rings are reversed and the degeneracy of the eigenvalues completely disappears. This finding is in line with our very recent study on [n]annulenes and provides further evidence that the anisotropy of the pi-electron density should be considered as a new manifestation of aromaticity. PMID- 24803359 TI - Risk factors for tracheal necrosis after total pharyngolaryngectomy. AB - BACKGROUND: Tracheal necrosis is a severe complication of total pharyngolaryngectomy (TPL). The purpose of this retrospective study was to identify risk factors for tracheal necrosis after TPL. METHODS: We performed a retrospective chart review of 177 patients who had undergone TPL. The preoperative, operative, and postoperative variables were examined, and possible risk factors for tracheal necrosis were subjected to univariate analysis and multivariate logistic regression. RESULTS: Tracheal necrosis occurred in 35 patients (19.8%), and tracheoesophageal fistula subsequently developed in 3 of these patients. Multivariate logistic regression analysis identified total esophagectomy and diabetes mellitus as significant risk factors for tracheal necrosis after TPL. CONCLUSION: The findings of this study will be useful for assessing the risk of tracheal necrosis after TPL. In patients at high risk for tracheal necrosis, efforts should be made to preserve the tracheal circulation and to prevent life-threatening sequelae if tracheal necrosis occurs. PMID- 24803360 TI - Sources and transport of nitrogen in arid urban watersheds. AB - Urban watersheds are often sources of nitrogen (N) to downstream systems, contributing to poor water quality. However, it is unknown which components (e.g., land cover and stormwater infrastructure type) of urban watersheds contribute to N export and which may be sites of retention. In this study we investigated which watershed characteristics control N sourcing, biogeochemical processing of nitrate (NO3-) during storms, and the amount of rainfall N that is retained within urban watersheds. We used triple isotopes of NO3- (delta15N, delta18O, and Delta17O) to identify sources and transformations of NO3- during storms from 10 nested arid urban watersheds that varied in stormwater infrastructure type and drainage area. Stormwater infrastructure and land cover- retention basins, pipes, and grass cover--dictated the sourcing of NO3- in runoff. Urban watersheds were strong sinks or sources of N to stormwater depending on runoff, which in turn was inversely related to retention basin density and positively related to imperviousness and precipitation. Our results suggest that watershed characteristics control the sources and transport of inorganic N in urban stormwater but that retention of inorganic N at the time scale of individual runoff events is controlled by hydrologic, rather than biogeochemical, mechanisms. PMID- 24803361 TI - Neoflavonoids as potential osteogenic agents from Dalbergia sissoo heartwood. AB - The present study was undertaken to investigate and rationalize the in vitro antiosteoporotic activity of neoflavonoids, isolated from Dalbergia sissoo heartwood. Neoflavonoids were isolated using extensive column chromatography and identified as dalsissooal (1) a new compound and cearoin (2), dalbergin (3), 4 methoxy dalbergion (4), dalbergiphenol (5), dalbergichromene (6), methyl dalbergin (7) and latinone (8) as known compounds by comparison their spectroscopic data with those reported in the literature. Among the screened compounds, compounds 1, 3, 5-8 significantly increased proliferation as assessed by alkaline phosphatase activity and mineralization in calvarial osteoblast cells. PMID- 24803362 TI - Concise synthesis of C-1-cyano-iminosugars via a new Staudinger/aza Wittig/Strecker multicomponent reaction strategy. AB - A new Staudinger/aza Wittig/Strecker multicomponent reaction sequence to C-1 cyano iminoalditols has been developed. When applied to 5-azidodeoxy-d-xylose and -d-glucose as substrates the method leads smoothly in good yield and with excellent stereoselectivity to respectively, 1,5-dideoxy-1,5-imino-d-idurono nitrile and 2,6-didesoxy-2,6-imino-d-glycero-d-ido-heptononitrile. PMID- 24803363 TI - Design, synthesis and biological evaluation of small molecular polyphenols as entry inhibitors against H(5)N(1). AB - To find novel compounds against H5N1, three series of known or novel small molecular polyphenols were synthesized and tested in vitro for anti-H5N1 activity. In addition, the preliminary structure-antiviral activity relationships were elaborated. The results showed that some small molecular polyphenols had better anti-H5N1 activity, and could serve as novel virus entry inhibitors against H5N1, likely targeting to HA2 protein. Noticeably, compound 4a showed the strongest activity against H5N1 among these compounds, and the molecular modeling analysis also suggested that this compound might target to HA2 protein. Therefore, compound 4a is well qualified to serve as a lead compound or scaffold for the further development of H5N1 entry inhibitor. PMID- 24803364 TI - Preparation of ferrocene-functionalized gold nanoparticles by primer extension reaction on the particle surface. AB - DNA molecules possessing multiple ferrocene (Fc) molecules as a redox active probe were prepared by the primer extension (PEX) reaction using a 2' deoxyuridine-5'-triphosphate derivative in which Fc was connected to the C5 position of the uridine by a diethylene glycol linker. Gold nanoparticles (AuNP) covered with DNA possessing the Fc molecules were prepared by the PEX reaction on the surface. The AuNP-FcDNA conjugates exhibit a detectable electrochemical signal due to the Fc molecules. Possible application of the PEX reaction on AuNP is demonstrated for the detection of a single nucleotide mutation in the target DNA. PMID- 24803365 TI - Synthesis and radical scavenging activity of phenol-imidazole conjugates. AB - Novel hydroxylated benzylideneamino imidazole derivatives were synthesized and their radical scavenging activity was assessed against DPPH and hydroxyl radicals. In the DPPH assay, most of the synthesized compounds showed an IC50 in the range 3.2MUM?IC50?8.4MUM, lower than the reference compound trolox (IC50=9.5MUM) or the parent aldehydes (5.4MUM?IC50?11.6MUM). The activity depends mainly on the phenolic subunit (number and position of the hydroxyl groups) and the extent of conjugation with the imidazole ring. In the deoxyribose assay, all the compounds, including parent imidazoles and aldehydes, showed high activity against the hydroxyl radical and the ability to chelate iron ions. At 5MUM concentration, the compounds protected the deoxyribose from degradation by hydroxyl radical between 62% and 38%. PMID- 24803366 TI - Virtual reality job interview training in adults with autism spectrum disorder. AB - The feasibility and efficacy of virtual reality job interview training (VR-JIT) was assessed in a single-blinded randomized controlled trial. Adults with autism spectrum disorder were randomized to VR-JIT (n = 16) or treatment-as-usual (TAU) (n = 10) groups. VR-JIT consisted of simulated job interviews with a virtual character and didactic training. Participants attended 90 % of laboratory-based training sessions, found VR-JIT easy to use and enjoyable, and they felt prepared for future interviews. VR-JIT participants had greater improvement during live standardized job interview role-play performances than TAU participants (p = 0.046). A similar pattern was observed for self-reported self-confidence at a trend level (p = 0.060). VR-JIT simulation performance scores increased over time (R(2) = 0.83). Results indicate preliminary support for the feasibility and efficacy of VR-JIT, which can be administered using computer software or via the internet. PMID- 24803367 TI - Epilepsy among children and adolescents with autism spectrum disorders: a population-based study. AB - The present population-based study examines associations between epilepsy and autism spectrum disorders (ASD). The cohort includes register data of 4,705 children born between 1987 and 2005 and diagnosed as cases of childhood autism, Asperger's syndrome or pervasive developmental disorders--not otherwise specified. Each case was matched to four controls by gender, date of birth, place of birth, and residence in Finland. Epilepsy was associated with ASD regardless of the subgroup after adjusting for covariates. The associations were stronger among cases with intellectual disability, especially among females. Epilepsy's age at onset was similar between the cases and controls regardless of the ASD subgroup. These findings emphasize the importance to examine the neurodevelopmental pathways in ASD, epilepsy and intellectual disability. PMID- 24803368 TI - In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. AB - We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status. There were 1.5 % of cases and 0.7 % of controls exposed to SSRIs during the pregnancy period, and higher effect estimates observed with longer use. We found evidence that in utero exposure to SSRIs increases a child's risk associated with ASD. These results, while adding to the limited knowledge on prenatal pharmacological exposures as potential ASD risk factors, need to be balanced against the benefits of indicated medication use by pregnant mothers. PMID- 24803369 TI - Youth with autism spectrum disorder comprehend lexicalized and novel primary conceptual metaphors. AB - Individuals with autism spectrum disorder (ASD) have difficulty comprehending metaphors. However, no study to date has examined whether or not they understand conceptual metaphors (i.e. mappings between conceptual structures), which could be the building blocks of metaphoric thinking and understanding. We investigated whether 13 participants with ASD (age 7;03-22;03) and 13 age-matched typically developing (TD) controls could comprehend lexicalized conceptual metaphors (e.g., Susan is a warm person) and novel ones (e.g., Susan is a toasty person). Individuals with ASD performed at greater than chance levels on both metaphor types, although their performance was lower than TD participants. We discuss the theoretical relevance of these findings and educational implications. PMID- 24803370 TI - How do typically developing deaf children and deaf children with autism spectrum disorder use the face when comprehending emotional facial expressions in British sign language? AB - Facial expressions in sign language carry a variety of communicative features. While emotion can modulate a spoken utterance through changes in intonation, duration and intensity, in sign language specific facial expressions presented concurrently with a manual sign perform this function. When deaf adult signers cannot see facial features, their ability to judge emotion in a signed utterance is impaired (Reilly et al. in Sign Lang Stud 75:113-118, 1992). We examined the role of the face in the comprehension of emotion in sign language in a group of typically developing (TD) deaf children and in a group of deaf children with autism spectrum disorder (ASD). We replicated Reilly et al.'s (Sign Lang Stud 75:113-118, 1992) adult results in the TD deaf signing children, confirming the importance of the face in understanding emotion in sign language. The ASD group performed more poorly on the emotion recognition task than the TD children. The deaf children with ASD showed a deficit in emotion recognition during sign language processing analogous to the deficit in vocal emotion recognition that has been observed in hearing children with ASD. PMID- 24803371 TI - Synthesis, in vitro protoporphyrinogen oxidase inhibition, and herbicidal activity of N-(benzothiazol-5-yl)hexahydro-1H-isoindole-1,3-diones and N (benzothiazol-5-yl)hexahydro-1H-isoindol-1-ones. AB - Protoporphyrinogen oxidase (EC 1.3.3.4) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase-inhibiting herbicides, N-(benzothiazol-5 yl)tetrahydroisoindole-1,3-dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N-(benzothiazol-5 yl)hexahydro-1H-isoindole-1,3-diones (1a-o) and N-(benzothiazol-5-yl)hexahydro-1H isoindol-1-ones (2a-i). These newly prepared compounds were characterized by elemental analyses, (1) H NMR, and ESI-MS, and the structures of 1h and 2h were further confirmed by X-ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a, ethyl 2-((6-fluoro-5-(4,5,6,7-tetrahydro-1-oxo-1H-isoindol-2(3H) yl)benzo[d]thiazol-2-yl)-sulfanyl)acetate, was recognized as the most potent candidate with K(i) value of 0.0091 MUm. Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha. PMID- 24803372 TI - Biogeochemical impacts of wildfires over four millennia in a Rocky Mountain subalpine watershed. AB - Wildfires can significantly alter forest carbon (C) storage and nitrogen (N) availability, but the long-term biogeochemical legacy of wildfires is poorly understood. We obtained a lake-sediment record of fire and biogeochemistry from a subalpine forest in Colorado, USA, to examine the nature, magnitude, and duration of decadal-scale, fire-induced ecosystem change over the past c. 4250 yr. The high-resolution record contained 34 fires, including 13 high-severity events within the watershed. High-severity fires were followed by increased sedimentary N stable isotope ratios (delta15N) and bulk density, and decreased C and N concentrations--reflecting forest floor destruction, terrestrial C and N losses, and erosion. Sustained low sediment C : N c. 20-50 yr post-fire indicates reduced terrestrial organic matter subsidies to the lake. Low sedimentary delta15N c. 50 70 yr post-fire, coincident with C and N recovery, suggests diminishing terrestrial N availability during stand development. The magnitude of post-fire changes generally scaled directly with inferred fire severity. Our results support modern studies of forest successional C and N accumulation and indicate pronounced, long-lasting biogeochemical impacts of wildfires in subalpine forests. However, even repeated high-severity fires over millennia probably did not deplete C or N stocks, because centuries between high-severity fires allowed for sufficient biomass recovery. PMID- 24803373 TI - BCG, Latitude, and Environmental Mycobacteria. PMID- 24803374 TI - Problems with ascribing between-trial differences in BCG effectiveness to sensitization with environmental mycobacteria. PMID- 24803375 TI - Pathogenesis from the reactivation of chromosomally integrated human herpesvirus type 6: facts rather than fiction. PMID- 24803376 TI - Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency. AB - It has been unclear whether chromosomally integrated human herpesvirus 6 (ciHHV 6) can be activated with pathogenic effects on the human body. We present molecular and virological evidence of ciHHV-6A activation in a patient with X linked severe combined immunodeficiency. These findings have significant implications for the management of patients with ciHHV-6. PMID- 24803377 TI - Incidence and risk factors for the prozone phenomenon in serologic testing for syphilis in a large cohort. AB - BACKGROUND: The prozone phenomenon is known to be associated with high antibody titers; other associations, such as host factors, have not been elucidated. METHODS: A retrospective analysis was conducted to evaluate the incidence of the prozone phenomenon of the syphilis rapid plasma reagin (RPR) test among 46 856 clinical samples, between June 2010 and June 2013. Logistic regression was used to analyze the risk factors of the prozone phenomenon. RESULTS: Our results showed that the incidence of the prozone phenomenon was low (0.83%) and could occur during any clinical phase, particularly during primary and secondary syphilis. Pregnancy and neurosyphilis were associated with the prozone phenomenon; sex, age, and whether the patient had been treated were not. The results also revealed that the prozone phenomenon not only occurred in patients with a high titer but also could occur in patients with a moderate/low titer. In fact, almost 31% of the patients with the prozone phenomenon had titers <=1:16. CONCLUSIONS: The prozone phenomenon in the RPR test was associated with the phase of syphilis, pregnancy, and neurosyphilis as well as a range of RPR titers between 1:8 and 1:512. This latter finding is in contrast to previous reports that the prozone phenomenon is associated with very high RPR titers. PMID- 24803378 TI - Reply to Kernodle and von Reyn. PMID- 24803379 TI - Modeling the effect of different vaccine effectiveness estimates on the number of vaccine-prevented influenza-associated hospitalizations in older adults. AB - We compared influenza vaccine-prevented hospitalizations in adults aged >=65 years for a range of hypothetical effectiveness estimates. During 2012-2013, a vaccine with 10% effectiveness (66% coverage) would have averted approximately 13 000 hospitalizations, and a vaccine with 40% effectiveness would have averted approximately 60 000 hospitalizations. Annual vaccination is merited in this vulnerable population. PMID- 24803380 TI - Immune correlates of protection in human invasive aspergillosis. AB - Protective immunity against Aspergillus depends on a highly coordinated interaction between the innate and adaptive arms of the immune system. Fungal recognition via pattern recognition receptors, such as pentraxin 3, dectin-1, and Toll-like receptors, leads to complement activation, phagocytosis, and killing of ingested fungi. Aspergillus-specific T-helper 1 and 17 cells produce cytokines such as interferon gamma and interleukin 17, which facilitate macrophage activation and neutrophil recruitment, respectively. Genetic (or drug-induced) defects in components of these networks of antifungal immunity result in increased risk of invasive aspergillosis after chemotherapy or transplantation. We review the most important genetic, immunological, and pharmacological factors that influence human susceptibility to Aspergillus and discuss the potential role of immune biomarkers in risk stratification strategies that facilitate individualized antifungal therapy/prophylaxis in immunocompromised hosts. PMID- 24803381 TI - Voucher incentives improve linkage to and retention in care among HIV-infected drug users in Chennai, India. AB - BACKGROUND: Drug users (DUs), a population that accounts for some of the fastest growing human immunodeficiency virus (HIV) epidemics globally, lag behind other populations with regard to HIV-related outcomes. We evaluated the role of voucher incentives on linkage and retention in care among DUs in India. METHODS: In this randomized clinical trial, 120 DUs who were aged >=18 years, HIV-infected, antiretroviral therapy (ART) naive, and ART eligible and who reported drug use in the prior month were randomized to incentive (INC) or control (CTL) conditions for 12 months. Participants randomized to the INC arm received incentives (redeemable for food/household goods) ranging in value from USD4 to USD8 for achieving prespecified targets (eg, ART initiation, visits to ART center). Subjects in the CTL group could win vouchers in prize-bowl drawings, but HIV care behaviors were not incentivized. The primary endpoint was time to ART initiation. RESULTS: Sixty participants each were randomized to the INC and CTL arms between December 2009 and September 2010. Participants in the INC arm were more likely to visit the government ART center (49 vs 33; P = .002); 27 participants in the INC and 16 participants in the CTL arm initiated ART (P = .04; hazard ratio for ART = 2.33 [95% confidence interval, 1.15-4.73]). Participants in the INC arm also had significantly more visits to the ART center (median number of visits, 8 vs 3.5; P = .005). However, no difference in viral suppression was observed. CONCLUSIONS: Modest voucher incentives improved linkage to and retention in HIV care, but did not significantly impact viral suppression among DUs in India, a disenfranchised and difficult-to-treat population. CLINICAL TRIALS REGISTRATION: NCT01031745. PMID- 24803382 TI - Accelerated 4D quantitative single point EPR imaging using model-based reconstruction. AB - PURPOSE: Electron paramagnetic resonance imaging has surfaced as a promising noninvasive imaging modality that is capable of imaging tissue oxygenation. Due to extremely short spin-spin relaxation times, electron paramagnetic resonance imaging benefits from single-point imaging and inherently suffers from limited spatial and temporal resolution, preventing localization of small hypoxic tissues and differentiation of hypoxia dynamics, making accelerated imaging a crucial issue. METHODS: In this study, methods for accelerated single-point imaging were developed by combining a bilateral k-space extrapolation technique with model based reconstruction that benefits from dense sampling in the parameter domain (measurement of the T2 (*) decay of a free induction delay). In bilateral kspace extrapolation, more k-space samples are obtained in a sparsely sampled region by bilaterally extrapolating data from temporally neighboring k-spaces. To improve the accuracy of T2 (*) estimation, a principal component analysis-based method was implemented. RESULTS: In a computer simulation and a phantom experiment, the proposed methods showed its capability for reliable T2 (*) estimation with high acceleration (8-fold, 15-fold, and 30-fold accelerations for 61*61*61, 95*95*95, and 127*127*127 matrix, respectively). CONCLUSION: By applying bilateral k-space extrapolation and model-based reconstruction, improved scan times with higher spatial resolution can be achieved in the current single-point electron paramagnetic resonance imaging modality. PMID- 24803383 TI - Antihypertensive agents acting on the renin-angiotensin system and the risk of sepsis. AB - AIMS: In response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin-converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis-associated mortality and renal failure in hypertensive patients. METHODS: We performed a nested case-control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow-up were matched for age, sex, practice and duration of follow-up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs. RESULTS: From the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow-up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of beta-blockers, calcium-channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83-1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42-1.93). Users of ARBs, beta blockers, calcium-channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis-related 30 day mortality and renal failure. CONCLUSIONS: Hypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis-related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk. PMID- 24803384 TI - Quality of end-of-life care among rural Medicare beneficiaries with colorectal cancer. AB - BACKGROUND: Although previous research has documented rural disparities in hospice use, limited data exist on the roles of geographic access in different types of end-of-life indicators among cancer survivors. METHODS: Medicare claims data were used to identify beneficiaries with colorectal cancer who died in 2008 (N = 34,975). We evaluated rural-urban differences in ER visits 90 days before death, inpatient hospital admissions <=90 days before death, intensive care unit (ICU) use <=90 days before death, hospice care use at any time, and hospice enrollment <3 days before death. RESULTS: About 60% of beneficiaries in rural areas lived in counties with the 2 lowest socioecomonic levels compared to only 5.3% of beneficiaries in metropolitan areas. After adjusting for demographic factors and comorbidities, beneficiaries in rural counties had a lower number of ICU days (RR = 0.65) and were less likely to ever use hospice (OR = 0.78) compared to those in metropolitan counties. Beneficiaries from racial/ethnic minority groups, those with lower socioeconomic status, and those with a higher comorbidity index were less likely to ever use hospice but they tended to use ER, inpatient care, and ICU. CONCLUSIONS: Evidence for disparities due to geographic access and socioeconomic factors warrant increased efforts to remove systemic and structural barriers. Future research should focus on exploring and evaluating potential policy and practice interventions to improve the quality of life among elderly cancer survivors living in rural communities and those from socioeconomically disadvantaged backgrounds. PMID- 24803386 TI - Atomic structure control of size-selected gold nanoclusters during formation. AB - We report the ability to control the atomic structure of nanoclusters by systematically varying the gas-phase formation parameters during the generation of size-selected Au923. From aberration-corrected, scanning transmission electron microscopy (HAADF-STEM) imaging, we are able to identify the proportions of icosahedral (Ih), decahedral (Dh), and face-centered cubic (fcc) isomers within a set of populations, with each population corresponding to a specific set of formation conditions. We demonstrate that, by tuning the formation conditions, we can eliminate completely all icosahedral nanoclusters, which are commonly found under other conditions. In future, this approach may lead to the preparation of arrays or ensembles of nanoclusters containing a dominant or single isomer, thus enabling the investigation of nanocluster (or nanoparticle) properties as a function of both size and atomic configuration. PMID- 24803385 TI - Universal MI definition update for cardiovascular disease. AB - The new third universal definition of myocardial infarction (MI) is based on troponin elevation together with ischemic symptoms, ischemic ECG changes, and imaging evidence. MIs are classified into five types as to whether they are spontaneous, secondary to imbalance between coronary artery blood supply and demand, related to sudden death, or related to revascularization procedures. The definition is based on a rise and/or fall in troponin levels occurring in a clinical setting. There have been modifications over previous definitions with adding intracoronary thrombus as a criterion, adding a new type of MI type 4c, and raising the cutpoint for the diagnosis of MI related to percutaneous coronary intervention to five times the 99(th) percentile upper reference limit and requiring evidence of ischemia or angiographic complications. In clinical practice, trials, and registries, different definitions are used. There is a need for consistency with regard to the definition of MI and the universal definition should be implemented. PMID- 24803387 TI - Measuring the hospital length of stay/readmission cost trade-off under a bundled payment mechanism. AB - If patients are discharged from the hospital prematurely, many may need to return within a short period of time. This paper investigates the relationship between length of stay and readmission within 30 days of discharge from an acute care hospitalization. It applies a two-part model to data on Medicare patients treated for heart attack in New York state hospitals during 2008 to obtain the expected cost of readmission associated with length of stay. The expected cost of a readmission is compared with the marginal cost of an additional day in the initial stay to examine the cost trade-off between an extra day of care and the expected cost of readmission. The cost of an additional day of stay was offset by expected cost savings from an avoided readmission in the range of 15% to 65%. Results have implications for payment reform based on bundled payment reimbursement mechanisms. PMID- 24803388 TI - Association of miR-146a polymorphisms with systemic lupus erythematosus: a meta analysis. AB - OBJECTIVE: miR-146a may play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Several studies have examined the association of miR 146a gene polymorphisms with SLE, but these studies have shown inconclusive results. To verify whether an association exists, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed and EMBASE before August 2013. METHODS: Meta-analyses were performed on three published studies of the association between the miR-146a rs57095329 SNP and SLE for 5934 patients with SLE and 5591 controls as well as on four published studies of the association between miR-146a rs2910164 SNP and SLE for 2505 patients with SLE and 3248 controls. In addition, two studies involving 1920 SLE patients and 2472 controls were included in a meta-analysis of the association between miR-146a rs2431697 SNP and SLE. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were pooled by the inverse of their variance. RESULTS: Of three SNPs analyzed, rs57095329 (OR 1.25, 95%CI 1.17-1.35) and rs2431697 (OR 1.24, 95% CI 1.13-1.37) were genetically associated with SLE. However, no significant association was found between rs2910164 and SLE susceptibility (OR 0.98, 95% CI 0.90-1.06). There was no significant heterogeneity across studies and no evidence of publication bias. CONCLUSIONS: The results of our meta-analysis suggest that miR-146a rs57095329 and rs2431697 SNPs are associated with SLE susceptibility. In addition, our results suggest that there is an ethnical difference between Asian and European populations in the association between miR-146a SNPs and SLE susceptibility. PMID- 24803389 TI - Systemic lupus erythematosus presenting as erythema annulare centrifugum. AB - A case of systemic lupus erythematosus presenting as erythema annulare centrifugum involving atypical sites (face, palm and sole) and raised serum angiotensin-converting enzyme levels has been illustrated. PMID- 24803390 TI - Foxa1 contributes to the repression of Nanog expression by recruiting Grg3 during the differentiation of pluripotent P19 embryonal carcinoma cells. AB - Transcription factor Foxa1 plays a critical role during neural differentiation and is induced immediately after retinoic acid (RA)-initiated differentiation of pluripotent P19 embryonal carcinoma cells, correlated with the downregulated expression of pluripotency-related genes such as Nanog. To study whether Foxa1 participates in the repression of pluripotency factors, we expressed Foxa1 ectopically in P19 cells and identified that Nanog was repressed directly by Foxa1. We confirmed that Foxa1 was able to interact with Grg3, which is a transcriptional corepressor that expresses in P19 cells as well as during RA induced P19 cell differentiation. Knockdown of Foxa1 or Grg3 delayed the downregulation of Nanog expression during RA-induced P19 cell differentiation. Furthermore, we found that Foxa1 recruited Grg3 to the Nanog promoter -2kb upstream region and switched the promoter to an inactive chromatin status represented by typical modifications in histone H3. Together, our results suggested a critical involvement of Foxa1 in the negative regulation of Nanog expression during the differentiation of pluripotent stem cells. PMID- 24803392 TI - Computed tomography guided percutaneous lung biopsies and suspected fungal infections in pediatric cancer patients. AB - BACKGROUND: The spectrum of potential fungal pathogens known to cause invasive pulmonary infections has grown as a result of intensified immunosuppressive therapy and the emergence of antifungal resistance. PROCEDURE: In a retrospective single center study, we investigated computed tomography guided percutaneous lung biopsies in 16 childhood patients with suspected fungal infections. Microbiological analysis consisted of microscopic examination, culture, and a broad-range fungal polymerase chain reaction for detection of either Aspergillus or Mucorales species. RESULTS: In 14 patients (88%), invasive fungal infection with Aspergillus species including A. terreus, Mucormycetes, and Saccharomyces cerevisiae being the main pathogens was confirmed, including patients with a double infection (19%). In two cases, the most likely diagnosis of primary bronchiolitis obliterans organizing pneumonia was established based on the results of typical histopathologic features, negative culture results, and symptoms resolved after treatment with high-dose cortisone. Diagnosis of invasive fungal pneumonia led to an immediate interruption of antineoplastic treatment in 100%, reduction of antibiotic drugs in 76%, and change of empirical to targeted antifungal therapy in 63%. The safety of lung biopsy was guaranteed by lack of any complications, such as bleeding or pneumothorax. CONCLUSIONS: The increased detection of rare fungal infections by computed tomography guided biopsy supports the need for a rapid and precise diagnosis, as most of the fungal pathogens are at least partially resistant to available antifungal therapy and proper treatment is essential for best practice in patient management. PMID- 24803393 TI - Microbial lipid production from pretreated and hydrolyzed corn fiber. AB - With its high content of carbohydrates and low percentage of lignin, corn fiber represents a renewable feedstock that can be processed to produce biofuels. Through a combination of pretreatment by lime and enzymatic hydrolysis, total reducing sugars of 700 mg/g corn fiber were released. This amount is equivalent to 92.7% of theoretically available sugars in corn fiber. The resulting hydrolysate itself did not support any growth of Cryptococcus curvatus. But with addition of minerals, C. curvatus grew to a cell density of 6.6 g/L in 6 days. Using the adapted cells, rapid sugar consumption and cell growth were observed. This study demonstrated that it is feasible to produce microbial lipids from corn fiber through pretreatment, enzymatic hydrolysis, and fermentation. In addition, C. curvatus is an excellent candidate for this application since it can utilize all major sugars, glucose, xylose, and arabinose with yield of cells and lipids as 0.55 and 0.27 g/g sugars, respectively. PMID- 24803394 TI - Monocyte-derived dendritic cells identified as booster of T follicular helper cell differentiation. AB - Adjuvants play an essential role in the induction of acquired immunity upon vaccination with protein antigen. In this issue of EMBO Molecular Medicine, a classical type of adjuvant made of DNA oligonucleotide containing CpG motifs, which has already been used in humans, is shown to boost humoral immunity primarily by acting on monocyte-derived dendritic cells. This study provides novel insight on the mode of action of adjuvant targeting Toll-like receptors. PMID- 24803395 TI - VEGF sticky-trap: the first report of a non-systemically acting angiogenesis inhibitor. AB - Current therapeutic anti-angiogenic biologics used for the treatment of pathological ocular angiogenesis such as in diabetic retinopathy and wet macular degeneration often lead to detrimental side effects due to their interference with normal blood vessel physiology. In this issue of EMBO Molecular Medicine, Michael et al report on a novel angiogenesis inhibitor with unique properties that allow for local inhibition of angiogenesis without detectable systemic side effects. PMID- 24803391 TI - Oral epithelial stem cells - implications in normal development and cancer metastasis. AB - Oral mucosa is continuously exposed to environmental forces and has to be constantly renewed. Accordingly, the oral mucosa epithelium contains a large reservoir of epithelial stem cells necessary for tissue homeostasis. Despite considerable scientific advances in stem cell behavior in a number of tissues, fewer studies have been devoted to the stem cells in the oral epithelium. Most of oral mucosa stem cells studies are focused on identifying cancer stem cells (CSC) in oral squamous cell carcinomas (OSCCs) among other head and neck cancers. OSCCs are the most prevalent epithelial tumors of the head and neck region, marked by their aggressiveness and invasiveness. Due to their highly tumorigenic properties, it has been suggested that CSC may be the critical population of cancer cells in the development of OSCC metastasis. This review presents a brief overview of epithelium stem cells with implications in oral health, and the clinical implications of the CSC concept in OSCC metastatic dissemination. PMID- 24803398 TI - EYA1-related disorders: two clinical cases and a literature review. AB - OBJECTIVES: To delineate the diagnostic and rehabilitative aspects of syndromes that have overlapping features, we present the cases of two unrelated Caucasian males affected by hearing impairment, preauricular pits and cervical fistulae. Specific findings that are helpful in the diagnosis and management of EYA1 related disorders are highlighted. METHODS: Genetic, otologic, imaging, eye and renal evaluations were conducted to achieve a detailed and comprehensive assessment, leading to the most accurate diagnosis and appropriate treatment. A literature review was also carried out. RESULTS: Diagnostic criteria indicated that the two patients were affected by BOS1 (Branchio-Otic Syndrome 1). We also identified a novel sporadic missense mutation in the EYA1 gene: p.G533R (c.1597G>A, NM_000503.4), a highly conserved, heterozygotic amino acid substitution. In the other case, we identified the p.X593QextX6 (c.1777T>A, NM_000503.4) substitution. Both variants lead to isoform 1 (EYA1B and EYA1C) which is composed of 592 amino acids. Clinical and in silico evidence suggests a pathogenic role for the new mutations. Imaging evaluation revealed a complex pathology, characterized by external, inner and middle ear malformations, without renal anomalies. CONCLUSIONS: Our results demonstrate the importance of considering the imaging evaluation and the complete DNA sequencing of the EYA1 gene for the differential diagnosis of deafness and related branchio-oto-renal disorders. PMID- 24803399 TI - The strengths and weaknesses in verbal short-term memory and visual working memory in children with hearing impairment and additional language learning difficulties. AB - OBJECTIVES: To compare verbal short-term memory and visual working memory abilities of six children with congenital hearing-impairment identified as having significant language learning difficulties with normative data from typically hearing children using standardized memory assessments. METHODS: Six children with hearing loss aged 8-15 years were assessed on measures of verbal short-term memory (Non-word and word recall) and visual working memory annually over a two year period. All children had cognitive abilities within normal limits and used spoken language as the primary mode of communication. The language assessment scores at the beginning of the study revealed that all six participants exhibited delays of two years or more on standardized assessments of receptive and expressive vocabulary and spoken language. RESULTS: The children with hearing impairment scores were significantly higher on the non-word recall task than the "real" word recall task. They also exhibited significantly higher scores on visual working memory than those of the age-matched sample from the standardized memory assessment. CONCLUSIONS: Each of the six participants in this study displayed the same pattern of strengths and weaknesses in verbal short-term memory and visual working memory despite their very different chronological ages. The children's poor ability to recall single syllable words in relation to non words is a clinical indicator of their difficulties in verbal short-term memory. However, the children with hearing-impairment do not display generalized processing difficulties and indeed demonstrate strengths in visual working memory. The poor ability to recall words, in combination with difficulties with early word learning may be indicators of children with hearing-impairment who will struggle to develop spoken language equal to that of their normally hearing peers. This early identification has the potential to allow for target specific intervention that may remediate their difficulties. PMID- 24803400 TI - Clinicopathological and prognostic significance of circulating tumor cells in patients with gastric cancer: a meta-analysis. AB - The prognostic significance of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in patients with gastric cancer (GC) is controversial. The aims of our meta-analysis are to assess its correlation with clinicopathological characteristics and prognostic significance in GC. PubMed, Embase, the Cochrane database, the Science citation index, the CNKI database and the references of relevant studies were systematically searched (up to November, 2013). Using the random-effect model, the meta-analysis was completed with odds ratio (OR), risk ratio, hazard ratio (HR) and 95% confidence intervals (CI) as effect values. Twenty-six studies containing 2,566 patients with GC were analyzed. The overall analysis showed that the incidence difference of tumor cells (CTCs/DTCs) was significant when comparing the stage I/II group to the stage III/IV group (OR = 0.36, CI [0.23, 0.56]), the Lauren diffuse group to the intestinal group (OR = 2.06, CI [1.06, 4.00]), the poorly differentiated group to the well/moderate group (OR = 1.65, CI [1.10, 2.50]), the lymphatic involvement positive group to the positive group (OR = 2.92, CI [1.00, 8.55]). The detection of CTCs/DTCs was significantly related with the disease-free survival of patients (HR = 3.42, CI [2.39, 4.91]) and the detection of CTCs in peripheral blood was significantly related with the overall survival of patients (HR = 2.13, CI [1.13, 4.03]). Our meta-analysis indicates that detection of CTCs/DTCs is associated with prognosis for patients with GC and thus could act as a basis for GC staging. PMID- 24803401 TI - The human cost of overuse. PMID- 24803402 TI - Global ubiquity and local endemism of free-living terrestrial protists: phylogeographic assessment of the streptophyte alga Klebsormidium. AB - Despite considerable research attention during the last 10 years, the distribution and biogeography of protists remain as highly controversial issues. The presumably huge population sizes and unlimited dispersal capabilities should result in protist ubiquity. However, recent molecular investigations suggest that protist communities exhibit strong biogeographic patterns. Here, we examined the biogeographic pattern of a very common green algal genus Klebsormidium. We evaluated the geographic distribution of rbcL genotypes for 190 isolates sampled in six sampling regions located in Europe, North America and Asia. Measures of correlation between genetic and geographic distance matrices revealed a differential distribution pattern on two geographic levels. Globally, the populations were genetically homogeneous; locally, the genotypes were patchily distributed. We hypothesized that a local fine-scale structuring of genotypes may be caused by various ecological factors, in particular, by the habitat differentiation of particular genotypes. Our investigations also identified a large number of new, previously unrecognized lineages. A total of 44 genotypes were identified and more than 66% of these were reported for the first time. PMID- 24803403 TI - Perfluorooctanoate exposure and major birth defects. AB - Perfluorooctanoate (PFOA) is detectable in umbilical cord blood and amniotic fluid. Some toxicological findings suggest that perfluoroalkyl substances may be teratogenic. Using data from the C8 Health Project, a 2005-2006 survey in a Mid Ohio Valley community exposed to PFOA through contaminated drinking water, we examined the association between estimated prenatal PFOA concentration and maternally reported birth defects (n=325) among 10,262 live singleton or multiple births from 1990 to 2006. Logistic regression models accounted for siblings using generalized estimating equations. There was generally no association between estimated PFOA concentration and birth defects, with the possible exception of brain defects, where the odds ratio adjusted for year of conception was 2.6 (95% confidence interval 1.3-5.1) for an increase in estimated PFOA exposure from the 25th to 75th percentile. This estimate, however, was based on 13 cases and may represent a chance finding. Further investigation of this potential association may be warranted. PMID- 24803404 TI - Developmental neurotoxicity and anticonvulsant drugs: a possible link. AB - In utero exposure to antiepileptic drugs (AEDs) may affect neurodevelopment causing postnatal cognitive and behavioral alterations. Phenytoin and phenobarbital may lead to motor and learning dysfunctions in the pre-exposed children. These disorders may reflect the interference of these AEDs with the development of hippocampal and cerebellar neurons, as suggested by animal studies. Exposure to valproic acid may result in inhibition of neural stem cell proliferation and/or immature neuron migration in the cerebral cortex with consequent increased risk of neurodevelopmental impairment, such as autistic spectrum disorders. A central issue in the prevention of AED-mediated developmental effects is the identification of drugs that should be avoided in women of child-bearing potential and during pregnancy. The aim of this review is to explore the possible link between AEDs and neurodevelopmental dysfunctions both in human and in animal studies. The possible mechanisms underlying this association are also discussed. PMID- 24803405 TI - Introduction to the HESI DART Drugs in Semen Consortium. PMID- 24803406 TI - Stimulatory effect of HGF-overexpressing adipose tissue-derived mesenchymal stem cells on thymus regeneration in a rat thymus involution model. AB - The thymus is the central lymphoid organ providing a unique and essential microenvironment for T-cell precursor development into mature functionally competent T-lymphocytes. Thus, it is important to develop the strategies for enhancing thymic regeneration from involution induced by a variety of clinical treatments and conditions. Hepatocyte growth factor (HGF) promotes proliferation in a variety of cell types. We have used stem cell-based HGF gene therapy to enhance regeneration from acute thymic involution. HGF-overexpressing human adipose tissue-derived mesenchymal stem cells (HGF-hATMSCs) were generated by liposomal transfection with the pMEX expression vector, constructed by inserting the HGF gene. Significantly increased HGF expression in these cells was confirmed by reverse transcription-polymerase chain reaction and an enzyme-linked immunosorbent assay. HGF produced by HGF-hATMSCs enhanced the proliferation of a mouse thymic epithelial cell line and the expression of interleukin-7 in vitro. We also examined the effect of HGF-hATMSCs on thymic regeneration in rats with acute thymic involution. Significant increases in thymus size and weight, as well as the number of thymocytes (especially, early thymocyte progenitors), were seen in the HGF-hATMSCs-treated rats compared to saline-treated control animals. A stimulatory effect of HGF-hATMSCs on thymic regeneration has therefore been shown, highlighting the clinical value of HGF-hATMSCs for treating thymic involution. PMID- 24803407 TI - Interfacial and phase transfer behaviors of polymer brush grafted amphiphilic nanoparticles: a computer simulation study. AB - Nanoparticles' phase transfer behaviors at the oil-water interface have many respects in common with lipid bilayer crossing behavior and the Pickering emulsion formation. Hence, the interfacial behavior and phase transfer behavior are intuitive indicators for the application potential of nanoparticle materials, e.g., on the emulsion formation and biomedical applications. Polymer brush modification enables nanoparticles to behave differently in hydrophilic solvent, hydrophobic solvent, and their interface region. In the present work, phase transfer behaviors of triblock polymer brush modified gold nanoparticles are explored by using coarse-grained simulations. The nanoparticles grafted with hydrophobic/weak hydrophilic/hydrophobic triblock brushes are found to have the best phase transfer performance, and the enhanced flexibility and mobility of head blocks are found to be the most vital factors. The inherent mechanism of interfacial behavior and phase transfer process are investigated and explained as perturbation effect and traction effect. According to our results, middle blocks dominate the brush morphology and decide whether NPs can be transferred into another phase. However, the inner blocks show higher dominance for the phase transfer behavior of nanoparticles restricted in the interface region, while the outer ones shows higher dominance for the nanoparticles departing from the interface region. Otherwise, interesting flat-Janus morphologies are found. Special applications in two-phase interface including emulsion stabilization could be expected. This work could provide some guidance for the molecular design and applications of polymer-nanoparticle composite materials. PMID- 24803408 TI - The genotype of the transporter associated with antigen processing gene affects susceptibility to colorectal cancer in Japanese. AB - OBJECTIVE: Although colorectal cancer (CRC) is one of the most frequent malignancies in Japan, the associated genetic factors remain to be elucidated. Functional loss of the transporter associated with antigen processing (TAP) 1 gene induces carcinogenesis. We investigated whether single nucleotide polymorphisms (SNPs) in the TAP1 gene (rs735883) are associated with susceptibility to CRC in a Japanese population. METHODS: The study participants were 143 cases and 243 clinical controls. After extracting DNA from their peripheral blood cells, genotyping was conducted by the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: Participants with a mutated allele had an increased risk for CRC. The adjusted odds ratios for the C/T, T/T, and the mutation type (C/T + T/T) compared to that of wild type (C/C) were 2.27 [95 % confidence interval (CI), 1.43-3.67], 1.95 (95 % CI, 0.88-4.30), and 2.22 (95 % CI, 1.42-3.55), respectively. Furthermore, a significant trend in the rate of cases was observed with an increasing number of mutated alleles (P for trend = 0.0068). CONCLUSIONS: The genotype of the TAP1 gene is associated with susceptibility to CRC. PMID- 24803409 TI - Expression and localization of p-glycoprotein, multidrug resistance protein 4, and breast cancer resistance protein in the female lower genital tract of human and pigtailed macaque. AB - Antiretroviral drug absorption and disposition in cervicovaginal tissue is important for the effectiveness of vaginally or orally administered drug products in preexposure prophylaxis (PrEP) of HIV-1 sexual transmission to women. Therefore, it is imperative to understand critical determinants of cervicovaginal tissue pharmacokinetics. This study aimed to examine the mRNA expression and protein localization of three efflux transporters, P-glycoprotein (P-gp), multidrug resistance-associated protein 4 (MRP4), and breast cancer resistance protein (BCRP), in the lower genital tract of premenopausal women and pigtailed macaques. Along the human lower genital tract, the three transporters were moderately to highly expressed compared to colorectal tissue and liver, as revealed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In a given genital tract segment, the transporter with the highest expression level was either BCRP or P-gp, while MRP4 was always expressed at the lowest level among the three transporters tested. The immunohistochemical staining showed that P-gp and MRP4 were localized in multiple cell types including epithelial cells and vascular endothelial cells. BCRP was predominantly localized in the vascular endothelial cells. Differences in transporter mRNA level and localization were observed among endocervix, ectocervix, and vagina. Compared to human tissues, the macaque cervicovaginal tissues displayed comparable expression and localization patterns of the three transporters, although subtle differences were observed between the two species. The role of these cervicovaginal transporters in drug absorption and disposition warrants further studies. The resemblance between human and pigtailed macaque in transporter expression and localization suggests the utility of the macaque model in the studies of human cervicovaginal transporters. PMID- 24803410 TI - Transgenic Arabidopsis expressing osmolyte glycine betaine synthesizing enzymes from halophilic methanogen promote tolerance to drought and salt stress. AB - Glycine betaine (betaine) has the highest cellular osmoprotective efficiency which does not accumulate in most glycophytes. The biosynthetic pathway for betaine in higher plants is derived from the oxidation of low-accumulating metabolite choline that limiting the ability of most plants to produce betaine. Halophilic methanoarchaeon Methanohalophilus portucalensis FDF1(T) is a model anaerobic methanogen to study the acclimation of water-deficit stresses which de novo synthesize betaine by the stepwise methylation of glycine, catalyzed by glycine sarcosine N-methyltransferase (GSMT) and sarcosine dimethylglycine N methyltransferase. In this report, genes encoding these betaine biosynthesizing enzymes, Mpgsmt and Mpsdmt, were introduced into Arabidopsis. The homozygous Mpgsmt (G), Mpsdmt (S), and their cross, Mpgsmt and Mpsdmt (G * S) plants showed increased accumulation of betaine. Water loss from detached leaves was slower in G, S, and G * S lines than wild-type (WT). Pot-grown transgenic plants showed better growth than WT after 9 days of withholding water or irrigating with 300 mM NaCl. G, S, G * S lines also maintained higher relative water content and photosystem II activity than WT under salt stress. This suggests heterologously expressed Mpgsmt and Mpsdmt could enhance tolerance to drought and salt stress in Arabidopsis. We also found a twofold increase in quaternary ammonium compounds in salt-stressed leaves of G lines, presumably due to the activation of GSMT activity by high salinity. This study demonstrates that introducing stress activated enzymes is a way of avoiding the divergence of primary metabolites under normal growing conditions, while also providing protection in stressful environments. PMID- 24803412 TI - Error correction algorithm for high accuracy bio-impedance measurement in wearable healthcare applications. AB - Implantable and ambulatory measurement of physiological signals such as Bio impedance using miniature biomedical devices needs careful tradeoff between limited power budget, measurement accuracy and complexity of implementation. This paper addresses this tradeoff through an extensive analysis of different stimulation and demodulation techniques for accurate Bio-impedance measurement. Three cases are considered for rigorous analysis of a generic impedance model, with multiple poles, which is stimulated using a square/sinusoidal current and demodulated using square/sinusoidal clock. For each case, the error in determining pole parameters (resistance and capacitance) is derived and compared. An error correction algorithm is proposed for square wave demodulation which reduces the peak estimation error from 9.3% to 1.3% for a simple tissue model. Simulation results in Matlab using ideal RC values show an average accuracy of for single pole and for two pole RC networks. Measurements using ideal components for a single pole model gives an overall and readings from saline phantom solution (primarily resistive) gives an . A Figure of Merit is derived based on ability to accurately resolve multiple poles in unknown impedance with minimal measurement points per decade, for given frequency range and supply current budget. This analysis is used to arrive at an optimal tradeoff between accuracy and power. Results indicate that the algorithm is generic and can be used for any application that involves resolving poles of an unknown impedance. It can be implemented as a post-processing technique for error correction or even incorporated into wearable signal monitoring ICs. PMID- 24803411 TI - Virus induced gene silencing of three putative prolyl 4-hydroxylases enhances plant growth in tomato (Solanum lycopersicum). AB - Proline hydroxylation is a major posttranslational modification of hydroxyproline rich glycoproteins (HRGPs) that is catalyzed by prolyl 4-hydroxylases (P4Hs). HRGPs such as arabinogalactan proteins (AGPs) and extensios play significant roles on cell wall structure and function and their implication in cell division and expansion has been reported. We used tobacco rattle virus (TRV)-based virus induced gene silencing to investigate the role of three tomato P4Hs, out of ten present in the tomato genome, in growth and development. Eight-days old tomato seedlings were infected with the appropriate TRV vectors and plants were allowed to grow under standard conditions for 6 weeks. Lower P4H mRNA levels were associated with lower hydroxyproline content in root and shoot tissues indicating successful gene silencing. P4H-silenced plants had longer roots and shoots and larger leaves. The increased leaf area can be attributed to increased cell division as indicated by the higher leaf epidermal cell number in SlP4H1- and SlP4H9-silenced plants. In contrast, SlP4H7-silenced plants had larger leaves due to enhanced cell expansion. Western blot analysis revealed that silencing of SlP4H7 and SlP4H9 was associated with reduced levels of JIM8-bound AGP and JIM11 bound extensin epitopes, while silencing of SlP4H1 reduced only the levels of AGP proteins. Collectively these results show that P4Hs have significant and distinct roles in cell division and expansion of tomato leaves. PMID- 24803414 TI - A rechargeable hydrogen battery based on Ru catalysis. AB - Apart from energy generation, the storage and liberation of energy are among the major problems in establishing a sustainable energy supply chain. Herein we report the development of a rechargeable H2 battery which is based on the principle of the Ru-catalyzed hydrogenation of CO2 to formic acid (charging process) and the Ru-catalyzed decomposition of formic acid to CO2 and H2 (discharging process). Both processes are driven by the same catalyst at elevated temperature either under pressure (charging process) or pressure-free conditions (discharging process). Up to five charging-discharging cycles were performed without decrease of storage capacity. The resulting CO2/H2 mixture is free of CO and can be employed directly in fuel-cell technology. PMID- 24803413 TI - Usefulness of novel laser speckle flowgraphy-derived variables of the large vessel area in the optic nerve head in normal tension glaucoma. PMID- 24803415 TI - DNA-scaffolded multivalent ligands to modulate cell function. AB - We report a simple, versatile, multivalent ligand system that is capable of specifically and efficiently modulating cell-surface receptor clustering and function. The multivalent ligand is made of a polymeric DNA scaffold decorated with biorecognition ligands (i.e., antibodies) to interrogate and modulate cell receptor signaling and function. Using CD20 clustering-mediated apoptosis in B cell cancer cells as a model system, we demonstrated that our multivalent ligand is significantly more effective at inducing apoptosis of target cancer cells than its monovalent counterpart. This multivalent DNA material approach represents a new chemical biology tool to interrogate cell receptor signaling and functions and to potentially manipulate such functions for the development of therapeutics. PMID- 24803416 TI - Hot flushes and the menopause: how long should they be expected to last? PMID- 24803417 TI - Number of specimens required to estimate average follicular fluid high-density lipoprotein particle components in women undergoing in vitro fertilization. PMID- 24803418 TI - Using Society for Assisted Reproductive Technology data to track pregnancy outcomes in older recipients: is it justifiable? PMID- 24803419 TI - Seascape continuity plays an important role in determining patterns of spatial genetic structure in a coral reef fish. AB - Detecting patterns of spatial genetic structure (SGS) can help identify intrinsic and extrinsic barriers to gene flow within metapopulations. For marine organisms such as coral reef fishes, identifying these barriers is critical to predicting evolutionary dynamics and demarcating evolutionarily significant units for conservation. In this study, we adopted an alternative hypothesis-testing framework to identify the patterns and predictors of SGS in the Caribbean reef fish Elacatinus lori. First, genetic structure was estimated using nuclear microsatellites and mitochondrial cytochrome b sequences. Next, clustering and network analyses were applied to visualize patterns of SGS. Finally, logistic regressions and linear mixed models were used to identify the predictors of SGS. Both sets of markers revealed low global structure: mitochondrial PhiST=0.12, microsatellite FST=0.0056. However, there was high variability among pairwise estimates, ranging from no differentiation between sites on contiguous reef (PhiST=0) to strong differentiation between sites separated by ocean expanses>=20 km (maximum PhiST=0.65). Genetic clustering and statistical analyses provided additional support for the hypothesis that seascape discontinuity, represented by oceanic breaks between patches of reef habitat, is a key predictor of SGS in E. lori. Notably, the estimated patterns and predictors of SGS were consistent between both sets of markers. Combined with previous studies of dispersal in E. lori, these results suggest that the interaction between seascape continuity and the dispersal kernel plays an important role in determining genetic connectivity within metapopulations. PMID- 24803420 TI - Comment on "Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion". PMID- 24803421 TI - Association of the IL4R single-nucleotide polymorphism I50V with recurrent spontaneous abortion (RSA). AB - BACKGROUND: Recurrent spontaneous abortion (RSA) is defined as three or more consecutive abortions before the 20th week of gestation. There is increasing evidence to support an immunological mechanism for the occurrence of RSA. The purpose of our study was to examine whether single-nucleotide polymorphisms (SNPs) of the interleukin-4 receptor gene IL4R influence susceptibility to, recurrent spontaneous abortion. MATERIALS AND METHODS: This is a case-control study. We recruited 200 patients with RSA (case group) using established diagnostic criteria and 200, normal individuals (control group) at the fertility and infertility center in Yazd city and Isfahan city during 2012 to 2013. We screened the I50V variant in IL-4R in patients and controls by PCR-RFLF method, and we performed an association analysis between I50V variant and RSA.the data was analyzed by spss 16 software using Chi-square test. RESULTS: No differences in the genotype and allele frequencies of the I50V SNPs were identified between patients with RSA and healthy controls. CONCLUSIONS: The frequency of SNP in IL-4 receptor (I50V) in patients with recurrent spontaneous abortion did not differ significantly compared with the control group. Analysis of IL4R SNP haplotypes or complex alleles suggested no dominant protection in patients with RSA. PMID- 24803422 TI - Genetic study of Hormad1 and Hormad2 with non-obstructive azoospermia patients in the male Chinese population. AB - PURPOSE: To evaluate the association of the Hormad1 and Hormad2 single nucleotide polymorphisms (SNPs) variants with non-obstructive azoospermia (NOA) in the Chinese population. METHODS: In the present study, we assessed 10 single nucleotide polymorphisms (SNPs) of Hormad1 and Hormad2 using Sequenom iplex technology in 361 NOA cases and 368 normal controls from Chinese population. RESULTS: We observed no statistical differences in the distribution of allele frequencies. Further genetic model analysis and haplotype analysis also showed no significant difference between the two groups. However, we found that genotype distribution of rs718772 of Hormad2 was significantly different between the larger testis group (average testis volume >=10 ml) and the small testis group (average testis volume <10 ml) in the NOA patients (P = 0.035). CONCLUSIONS: In conclusion, Hormad1 and Hormad2 might not be the susceptible genes for the non obstructive azoospermia in our study population. However, rs718772 of Hormad2 variant might be associated with testis development in NOA patients. PMID- 24803423 TI - On the parity of structural persistence in language production and comprehension. AB - Structural priming creates structural persistence. That is, differences in experience with syntax can change subsequent language performance, and the changes can be observed in both language production and comprehension. However, the effects in comprehension and production appear to differ. In comprehension, persistence is typically found when the verbs are the same in primes and targets; in production, persistence occurs without verb overlap. The contrast suggests a theoretically important hypothesis: parsing in comprehension is lexically driven while formulation in production is structurally driven. A major weakness in this hypothesis about comprehension-production differences is that its empirical motivation rests on the outcomes of experiments in which the priming manipulations differ, the primed sentence structures differ, and the measures of priming differ. To sharpen the comparison, we examined structural persistence with and without verb overlap in both reading comprehension and spoken production, using the same prime presentation procedure, the same syntactic structures, the same sentences, and the same participants. These methods yielded abstract structural persistence in comprehension as well as production. A measure of the strength of persistence revealed significant effects of priming and verb overlap without significant comprehension-production differences. This argues for uniformity in the structural mechanisms of language processing. PMID- 24803424 TI - The Dow is Killing Me: Risky Health Behaviors and the Stock Market. AB - We investigate how risky health behaviors and self-reported health vary with the Dow Jones Industrial Average (DJIA) and during stock market crashes. Because stock market indices are leading indicators of economic performance, this research contributes to our understanding of the macroeconomic determinants of health. Existing studies typically rely on the unemployment rate to proxy for economic performance, but this measure captures only one of many channels through which the economic environment may influence individual health decisions. We find that large, negative monthly DJIA returns, decreases in the level of the DJIA, and stock market crashes are widely associated with worsening self-reported mental health and more cigarette smoking, binge drinking, and fatal car accidents involving alcohol. These results are consistent with predictions from rational addiction models and have implications for research on the association between consumption and stock prices. PMID- 24803426 TI - Isolation of C. elegans and related nematodes. AB - Isolating Caenorhabditis and other nematodes from the wild first requires field sampling (reviewed in Section 1). The easiest and most efficient way to recover the animals from any substrate is to place the sample onto a standard C. elegans culture plate (Section 2.1). Alternative methods used by nematologists to recover soil nematodes (Sections 2.2, 2.3, and 2.4) are in our hands more difficult to implement and only yield a fraction of the individuals in the sample. A tricky step is to recognize your species of interest out of the zoo of nematode species that comes with a typical sample (Section 3). Culture (Section 4) and freezing (Section 5) conditions are then reviewed. Finally, we briefly summarize the organization and timing of an isolation experiment (Section 6), as well as the available collections (Section 7). Bear in mind that this chapter is strongly focused towards the isolation of Caenorhabditis elegans and close relatives. PMID- 24803425 TI - Prenatal cocaine exposure: the role of cumulative environmental risk and maternal harshness in the development of child internalizing behavior problems in kindergarten. AB - This study examined the associations between prenatal exposure to cocaine and other substances and child internalizing behavior problems at kindergarten. We investigated whether maternal harshness or cumulative environmental risk mediated or moderated this association. Participants consisted of 216 (116 cocaine exposed, 100 non-cocaine exposed) mother-infant dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that, as hypothesized, maternal harshness moderated the association between prenatal cocaine exposure to child internalizing in kindergarten such that prenatal cocaine exposure increased risk for internalizing problems at high levels of maternal harshness from 7 to 36months and decreased risk at low levels of harshness. Contrary to hypothesis, the association between prenatal cocaine exposure and child internalizing in kindergarten was not mediated by maternal harshness or cumulative environmental risk. However, cumulative environmental risk (from 1month of child age to kindergarten) was predictive of child internalizing behavior problems at kindergarten. Results have implications for parenting interventions that may be targeted toward reducing maternal harshness in high risk samples characterized by maternal substance use in pregnancy. PMID- 24803427 TI - Implementing the Affordable Care Act in Central Pennsylvania. PMID- 24803428 TI - WHO declares polio a public health emergency. PMID- 24803429 TI - Communicating Relative Risk Changes with Baseline Risk: Presentation Format and Numeracy Matter. AB - BACKGROUND: Treatment benefits and harms are often communicated as relative risk reductions and increases, which are frequently misunderstood by doctors and patients. One suggestion for improving understanding of such risk information is to also communicate the baseline risk. We investigated 1) whether the presentation format of the baseline risk influences understanding of relative risk changes and 2) the mediating role of people's numeracy skills. METHOD: We presented laypeople (N = 1234) with a hypothetical scenario about a treatment that decreased (Experiments 1a, 2a) or increased (Experiments 1b, 2b) the risk of heart disease. Baseline risk was provided as a percentage or a frequency. In a forced-choice paradigm, the participants' task was to judge the risk in the treatment group given the relative risk reduction (or increase) and the baseline risk. Numeracy was assessed using the Lipkus 11-item scale. RESULTS: Communicating baseline risk in a frequency format facilitated correct understanding of a treatment's benefits and harms, whereas a percentage format often impeded understanding. For example, many participants misinterpreted a relative risk reduction as referring to an absolute risk reduction. Participants with higher numeracy generally performed better than those with lower numeracy, but all participants benefitted from a frequency format. Limitations are that we used a hypothetical medical scenario and a nonrepresentative sample. CONCLUSIONS: Presenting baseline risk in a frequency format improves understanding of relative risk information, whereas a percentage format is likely to lead to misunderstandings. People's numeracy skills play an important role in correctly understanding medical information. Overall, communicating treatment benefits and harms in the form of relative risk changes remains problematic, even when the baseline risk is explicitly provided. PMID- 24803431 TI - Ultrabroadband infrared nanospectroscopic imaging. AB - Characterizing and ultimately controlling the heterogeneity underlying biomolecular functions, quantum behavior of complex matter, photonic materials, or catalysis requires large-scale spectroscopic imaging with simultaneous specificity to structure, phase, and chemical composition at nanometer spatial resolution. However, as with any ultrahigh spatial resolution microscopy technique, the associated demand for an increase in both spatial and spectral bandwidth often leads to a decrease in desired sensitivity. We overcome this limitation in infrared vibrational scattering-scanning probe near-field optical microscopy using synchrotron midinfrared radiation. Tip-enhanced localized light matter interaction is induced by low-noise, broadband, and spatially coherent synchrotron light of high spectral irradiance, and the near-field signal is sensitively detected using heterodyne interferometric amplification. We achieve sub-40-nm spatially resolved, molecular, and phonon vibrational spectroscopic imaging, with rapid spectral acquisition, spanning the full midinfrared (700 5,000 cm(-1)) with few cm(-1) spectral resolution. We demonstrate the performance of synchrotron infrared nanospectroscopy on semiconductor, biomineral, and protein nanostructures, providing vibrational chemical imaging with subzeptomole sensitivity. PMID- 24803430 TI - Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. AB - The Notch signaling pathway is essential for many aspects of development, cell fate determination, and tissue homeostasis. Notch signaling can be modulated by posttranslational modifications to the Notch receptor, which are known to alter both ligand binding and receptor activation. We have modified the ligand-binding region (EGF domains 11-13) of human Notch1 (hN1) with O-fucose and O-glucose glycans and shown by flow cytometry and surface plasmon resonance that the Fringe catalyzed addition of GlcNAc to the O-fucose at T466 in EGF12 substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We have subsequently determined the crystal structures of EGF domains 11-13 of hN1 modified with either the O-fucose monosaccharide or the GlcNAc-fucose disaccharide at T466 of EGF12 and observed no change in backbone structure for each variant. Collectively, these data demonstrate a role for GlcNAc in modulating the ligand-binding site in hN1 EGF12, resulting in an increased affinity of this region for ligands Jagged1 and DLL1. We propose that this finding explains the Fringe-catalyzed enhancement of Notch-Delta signaling observed in flies and humans, but suggest that the inhibitory effect of Fringe on Jagged/Serrate mediated signaling involves other regions of Notch. PMID- 24803432 TI - Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex. AB - Pathogen recognition by nucleotide-binding oligomerization domain-like receptor (NLR) results in the formation of a macromolecular protein complex (inflammasome) that drives protective inflammatory responses in the host. It is thought that the number of inflammasome complexes forming in a cell is determined by the number of NLRs being activated, with each NLR initiating its own inflammasome assembly independent of one another; however, we show here that the important foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) simultaneously activates at least two NLRs, whereas only a single inflammasome complex is formed in a macrophage. Both nucleotide-binding domain and leucine-rich repeat caspase recruitment domain 4 and nucleotide-binding domain and leucine-rich repeat pyrin domain 3 are simultaneously present in the same inflammasome, where both NLRs are required to drive IL-1beta processing within the Salmonella-infected cell and to regulate the bacterial burden in mice. Superresolution imaging of Salmonella infected macrophages revealed a macromolecular complex with an outer ring of apoptosis-associated speck-like protein containing a caspase activation and recruitment domain and an inner ring of NLRs, with active caspase effectors containing the pro-IL-1beta substrate localized internal to the ring structure. Our data reveal the spatial localization of different components of the inflammasome and how different members of the NLR family cooperate to drive robust IL-1beta processing during Salmonella infection. PMID- 24803434 TI - Leucophores are similar to xanthophores in their specification and differentiation processes in medaka. AB - Animal body color is generated primarily by neural crest-derived pigment cells in the skin. Mammals and birds have only melanocytes on the surface of their bodies; however, fish have a variety of pigment cell types or chromatophores, including melanophores, xanthophores, and iridophores. The medaka has a unique chromatophore type called the leucophore. The genetic basis of chromatophore diversity remains poorly understood. Here, we report that three loci in medaka, namely, leucophore free (lf), lf-2, and white leucophore (wl), which affect leucophore and xanthophore differentiation, encode solute carrier family 2, member 15b (slc2a15b), paired box gene 7a (pax7a), and solute carrier family 2 facilitated glucose transporter, member 11b (slc2a11b), respectively. Because lf 2, a loss-of-function mutant for pax7a, causes defects in the formation of xanthophore and leucophore precursor cells, pax7a is critical for the development of the chromatophores. This genetic evidence implies that leucophores are similar to xanthophores, although it was previously thought that leucophores were related to iridophores, as these chromatophores have purine-dependent light reflection. Our identification of slc2a15b and slc2a11b as genes critical for the differentiation of leucophores and xanthophores in medaka led to a further finding that the existence of these two genes in the genome coincides with the presence of xanthophores in nonmammalian vertebrates: birds have yellow-pigmented irises with xanthophore-like intracellular organelles. Our findings provide clues for revealing diverse evolutionary mechanisms of pigment cell formation in animals. PMID- 24803435 TI - Randomized comparison between polymer-free versus polymer-based paclitaxel eluting stent: two-year final clinical results. AB - BACKGROUND: Most drug-eluting stents currently in use are coated with a polymer carrying the drug that is released for several weeks. However, a durable polymer may provoke hypersensitive reaction, delayed artery healing, and eventually stent thrombosis. The aim of this study was to investigate the safety and efficacy of a polymer-free paclitaxel-eluting stent (PF-PES) versus a polymer-based PES (PB PES). METHODS AND RESULTS: Eligible patients undergoing percutaneous coronary intervention were randomized 1:1 to receive either PF-PES or PB-PES. The primary end point was late loss at 9 months. Intravascular ultrasound analysis at 9 months and final 2-year clinical follow-up were also performed. From October 2007 to April 2009, 164 patients were enrolled and randomized into 2 groups (PF-PES: n = 84; PB-PES: n = 80). Mean in-stent lumen loss was 0.90 +/- 0.59 mm for PF-PES and 0.49 +/- 0.52 mm for PB-PES (P < 0.001). Mean neointimal area by intravascular ultrasound was higher in PF-PES than in PB-PES (1.42 +/- 1.09 versus 0.51 +/- 0.61 mm(2); P < 0.001). At 2 years, a composite end point of all cause death, any myocardial infarction, and target vessel revascularization occurred in 36.9% for PF-PES and 16.3% for PB-PES (P = 0.004), mainly driven by a higher rate of target vessel revascularization (PF-PES: 35.7%; PB-PES: 13.8%; P = 0.001). One late stent thrombosis was observed in PF-PES. CONCLUSIONS: Compared with PB-PES, PF-PES was associated with increased neointimal proliferation and subsequent clinical restenosis. Polymer plays an essential role in the performance of drug-eluting stents. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01375855. PMID- 24803433 TI - Antibiotics induce redox-related physiological alterations as part of their lethality. AB - Deeper understanding of antibiotic-induced physiological responses is critical to identifying means for enhancing our current antibiotic arsenal. Bactericidal antibiotics with diverse targets have been hypothesized to kill bacteria, in part by inducing production of damaging reactive species. This notion has been supported by many groups but has been challenged recently. Here we robustly test the hypothesis using biochemical, enzymatic, and biophysical assays along with genetic and phenotypic experiments. We first used a novel intracellular H2O2 sensor, together with a chemically diverse panel of fluorescent dyes sensitive to an array of reactive species to demonstrate that antibiotics broadly induce redox stress. Subsequent gene-expression analyses reveal that complex antibiotic induced oxidative stress responses are distinct from canonical responses generated by supraphysiological levels of H2O2. We next developed a method to quantify cellular respiration dynamically and found that bactericidal antibiotics elevate oxygen consumption, indicating significant alterations to bacterial redox physiology. We further show that overexpression of catalase or DNA mismatch repair enzyme, MutS, and antioxidant pretreatment limit antibiotic lethality, indicating that reactive oxygen species causatively contribute to antibiotic killing. Critically, the killing efficacy of antibiotics was diminished under strict anaerobic conditions but could be enhanced by exposure to molecular oxygen or by the addition of alternative electron acceptors, indicating that environmental factors play a role in killing cells physiologically primed for death. This work provides direct evidence that, downstream of their target specific interactions, bactericidal antibiotics induce complex redox alterations that contribute to cellular damage and death, thus supporting an evolving, expanded model of antibiotic lethality. PMID- 24803437 TI - Social media and health promotion. PMID- 24803438 TI - Intersectoral collaboration: a novel path to promote community health promotion. PMID- 24803439 TI - Demographic and lifestyle characteristics associated with non-willingness to participate in health promotion programmes among adults of a lower socioeconomic status in Singapore. AB - INTRODUCTION/OBJECTIVE: Lower socioeconomic groups have been found to have poorer health outcomes and engage in fewer health promoting behaviours. Understanding the reasons behind adverse lifestyle habits and non-willingness to participate in health promotion programmes among lower socioeconomic groups will enable administrators to modify the programmes and increase participation in this population. This study aimed to determine reasons for non-exercise, smoking and non-willingness to participate, and characteristics associated with non willingness to participate in health promotion programmes among residents in Singapore. METHOD: A cross-sectional survey was conducted on a purposive sample of residents living in four housing developments of one- and two-room households in Singapore from June to October 2009. The patterns of exercise and smoking, receptiveness towards health promotion programmes and the reasons for non willingness to participate were elicited. Chi-square tests and logistic regression analysis were performed to identify differences between groups. RESULTS: Seven hundred and seventy-eight responses were analysed. Only 36.1% of respondents were willing to participate in at least one health promotion programme (health screening, talk or workshop). Older respondents aged 45-64 years and more than 65 years were less likely to participate than their younger counterparts (18-44 years). Malays were more likely than Chinese to participate, and respondents who do not exercise were less likely to participate than respondents who exercise (regularly/occasionally). Reasons for non-willingness to participate were 'not interested' and 'no time'. CONCLUSION: Health promotion messages should adapt to the needs and situation of the disadvantaged, to increase participation. PMID- 24803440 TI - Disconnect between discourse and behavior regarding concurrent sexual partnerships and condom use: findings from a qualitative study among youth in Malawi. AB - The practice of concurrent sexual partnerships (CP) is posited to be a contributor to the elevated risk of HIV transmission among youth in Malawi. The lens through which Malawian youth conceptualize the practices of CP and condom use has yet to be fully explored. The current study--a secondary data analysis of semi-structured in-depth interviews (n = 19) with Malawian youth aged 18 to 22 years--addresses this gap. Participants were interviewed about their sexual relationships and behavior, as well as their perceptions and knowledge regarding condom use and CP. In order to ensure that youth engaged in CP were oversampled, the recruitment process asked potential respondents to self-identify whether they currently participated in CP. Of the total sample (n = 19), 13 self-identified as currently engaging in CP. Data were analyzed using a grounded theory approach. This qualitative study highlights a disconnect between the high level of knowledge youth exhibit about HIV prevention methods and their actual reported condom use and CP behaviors. While some youth claimed to use condoms, their discourse demonstrated fluidity in that use changed over time, or interest in changing behavior was expressed, or was inconsistent between partnerships. The disconnect between knowledge of the consequences of risky sexual behavior and actual behavior was most evident among inconsistent condom users engaged in CP. This finding indicates knowledge alone has a limited role in the adoption of lower risk behaviors such as condom use and reduction of CP among youth. Moreover, findings from this study can inform HIV prevention programs operating in Malawi and the sub-Saharan Africa region by enabling them to provide tailored, more persuasive health promotion and prevention messaging. PMID- 24803441 TI - Promoting the health of Aboriginal Australians through empowerment: eliciting the components of the family well-being empowerment and leadership programme. AB - Most policies addressing Aboriginal health in Australia promote initiatives that are based on empowerment principles. Articulated programme components are necessary to support personal and group empowerment and to assist individuals in gaining the sense of control and purposefulness needed to exert their political and personal power in the face of the severe stress and powerlessness faced by the Australian Aboriginal people. This paper aims to provide a detailed description of the mechanisms underpinning a 'bottom-up' empowerment initiative, the Family well-being empowerment and leadership programme (FWB), and to analyze how the programme supports empowerment. The five stages of FWB were described and the validity of this model was assessed through the combination of participatory observation, documentation analysis, literature review, semi-structured interviews and iterative feedback with different analytical perspectives. Our study results articulated four distinct programme components: the setting plus inter-relational, educational and experiential actions. FWB is an example of the promotion of both outcome and process pathways towards empowerment. Potential applications of the programme are discussed. PMID- 24803442 TI - Should pain be on the health promotion agenda? AB - Opportunities and liberties available to individuals allow them to function as full human beings and this should include freedom from persistent pain. Pain seems to be a downstream phenomenon which tells us that something has gone wrong. Health promoters, with their upstream perspective, should be concerned with pain. In this commentary we discuss conceptual issues concerning 'health' as the absence of pain, issues of health justice and issues of health education to raise awareness of pain. We suggest that pain should appear on the health promotion agenda and conclude that more awareness is needed in the epistemic health promotion community of physical pain as a factor in the distribution of health and well-being. We argue the need for more research on the extent to which pain follows the social gradient in the same way that other health inequalities do. PMID- 24803443 TI - Dengue and health care access: the role of social determinants of health in dengue surveillance in Colombia. AB - Based on a first-hand experience from Colombia in the context of a local dengue research project, this paper illustrates how social determinants of health are associated with public health and how they can affect disease surveillance systems. The paper shows how various issues related to dengue case notification procedures and health insurance systems in Colombia are intertwined with more structural socio-economic factors. We argue that there is a need for public health interventions and health related research to acknowledge and consider the important role social determinants play in public health dynamics. PMID- 24803444 TI - Multilateral development banks and socially responsible investments--the case of tobacco. AB - Globally, tobacco kills more people than HIV-related conditions or AIDS, tuberculosis and malaria combined. In 1991, The World Bank, the world's largest lender, pledged that it would no longer support tobacco-related projects. It was expected that other financial investors would follow, but most did not respond to this call. As a result, several financial institutions continue to invest in tobacco and fuel an epidemic to an unprecedented scale. Using tobacco as a case in point, this review highlights the continuing investments among financial institutions which do not conform to 'socially responsible investments' and calls for monitoring and reporting such unethical practices. The paper also underscores the need to harmonise the numerous criteria, principles and voluntary codes that govern socially responsible investing and ensure that financial institutions comply with them. PMID- 24803448 TI - [Promoting the consumption of fruits and vegetables in high school students: implementation of the mapping intervention protocol]. PMID- 24803436 TI - Long-term clinical outcomes after everolimus- and sirolimus-eluting coronary stent implantation: final 3-year follow-up of the Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial. AB - BACKGROUND: Long-term clinical outcomes of everolimus-eluting stent (EES) compared with sirolimus-eluting stent (SES) have not been evaluated fully yet, especially whether EES implantation could positively affect late adverse events reported after SES implantation occurring >1 year. METHODS AND RESULTS: In this all-comer prospective multicenter randomized open-label trial, 3196 patients were assigned randomly to implant either EES (n=1596) or SES (n=1600). At 3 years, EES was noninferior to SES on the primary safety end point (all-cause death or myocardial infarction; 10.1% versus 11.5%; noninferiority P <0.001; and superiority P=0.19). Cumulative incidence of definite stent thrombosis was low and was not significantly different between the 2 groups (0.5% versus 0.6%; P=0.81). There was no significant difference in the efficacy end point of target lesion revascularization between the EES and SES groups (6.6% versus 7.9%; P=0.16). However, the cumulative incidence of target-lesion failure (cardiac death/target-vessel myocardial infarction/ischemia-driven target-lesion revascularization) was significantly lower in the EES group than in the SES group (8.8% versus 11.4%; P=0.01). By a landmark analysis at 1 year, the cumulative incidence of very late stent thrombosis and late target-lesion revascularization was not significantly different between the 2 groups (0.2% versus 0.2%; P=0.99 and 2.2% versus 2.9%; P=0.21, respectively). CONCLUSIONS: The efficacy and safety outcomes for this trial after EES implantation remained comparable with those after SES implantation through 3-year follow-up. However, improvement of clinical outcome after EES implantation compared with SES implantation was suggested by the significantly lower cumulative incidences of target-lesion failure, which has been the most widely used primary end point in the stent-versus-stent trials. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035450. PMID- 24803452 TI - [Professionalizing health promotion? Reflections from the European context]. PMID- 24803454 TI - Mental health should be given as much weight as physical health, BMA says. PMID- 24803455 TI - Gait-specific adaptation of locomotor activity in response to dietary restriction in Caenorhabditis elegans. AB - Locomotion is crucial for the survival of living organisms, as it allows foraging, flight and mating behaviour. In response to environmental cues, many organisms switch between alternative forms of locomotion, referred to as gaits. The nematode Caenorhabditis elegans exhibits two gaits: swimming in liquids and crawling on dense gels. The kinematics and patterns of muscle activity differ between the two gaits, with swimming being less efficient than crawling. We found that C. elegans when grown on dietary restriction (DR) plates and then tested immediately for swimming activity exhibit an accelerated frequency of body bending swimming compared with ad libitum-fed worms, resulting in an increased swimming speed. This response is independent of the presence or absence of food bacteria in the assay liquid. In contrast, the crawling speed of DR worms on assay agar plates is decreased and influenced by food availability. Because DR also attenuates the disturbed swimming activity of worms that are deficient in the presynaptic dopamine transporter DAT-1, our data link DR-induced alterations of the swimming gait to synaptic processes. This strongly suggests a biochemical rather than a biomechanical response to DR provoked by changes in the worm's body structure. We conclude that the increase in locomotor activity in response to DR is specific to the swimming gait and might represent a survival strategy, allowing food-deprived nematodes to exit unfavourable environments. PMID- 24803456 TI - Multitasking in an eye: the unusual organization of the Thermonectus marmoratus principal larval eyes allows for far and near vision and might aid in depth perception. AB - Very few visual systems diverge fundamentally from the basic plans of well studied animal eyes. However, investigating those that do can provide novel insights into visual system function. A particularly unusual system exists in the principal larval eyes of a visually guided aquatic predator, the sunburst diving beetle, Thermonectus marmoratus (Coleoptera: Dystiscidae). These eyes are characterized by complex layered distal and proximal retinas. We previously reported that their principal eye E2 has a bifocal lens, and previous behavioral experiments suggested that these larvae have a unilateral range-finding mechanism that may involve their bizarre eye organization. In the present study, we expanded our optical measurements and found that: (1) E1 also has a bifocal lens, (2) E1 is best suited for far vision while E2 is best suited for near vision and (3) throughout their typical hunting range, the positions of focused images shift across specific retinal layers. This anatomical and optical organization in principle could support unilateral range finding. Taken together, our findings outline an unusual visual mechanism that is likely to be essential for the extraordinary hunting ability of these larvae. PMID- 24803457 TI - Living in warmer, more acidic oceans retards physiological recovery from tidal emersion in the velvet swimming crab, Necora puber. AB - The distribution patterns of many species in the intertidal zone are partly determined by their ability to survive and recover from tidal emersion. During emersion, most crustaceans experience gill collapse, impairing gas exchange. Such collapse generates a state of hypoxemia and a hypercapnia-induced respiratory acidosis, leading to hyperlactaemia and metabolic acidosis. However, how such physiological responses to emersion are modified by prior exposure to elevated CO2 and temperature combinations, indicative of future climate change scenarios, is not known. We therefore investigated key physiological responses of velvet swimming crabs, Necora puber, kept for 14 days at one of four pCO2/temperature treatments (400 MUatm/10 degrees C, 1000 MUatm/10 degrees C, 400 MUatm/15 degrees C or 1000 MUatm/15 degrees C) to experimental emersion and recovery. Pre-exposure to elevated pCO2 and temperature increased pre-emersion bicarbonate ion concentrations [HCO3(-)], increasing resistance to short periods of emersion (90 min). However, there was still a significant acidosis following 180 min emersion in all treatments. The recovery of extracellular acid-base via the removal of extracellular pCO2 and lactate after emersion was significantly retarded by exposure to both elevated temperature and pCO2. If elevated environmental pCO2 and temperature lead to slower recovery after emersion, then some predominantly subtidal species that also inhabit the low to mid shore, such as N. puber, may have a reduced physiological capacity to retain their presence in the low intertidal zone, ultimately affecting their bathymetric range of distribution, as well as the structure and diversity of intertidal assemblages. PMID- 24803458 TI - Hearing capacities and otolith size in two ophidiiform species (Ophidion rochei and Carapus acus). AB - Numerous studies have highlighted the diversity of fish inner ear morphology. However, the function of the shape, size and orientation of the different structures remains poorly understood. The saccule (otolithic endorgan) is considered to be the principal hearing organ in fishes and it has been hypothesized that sagitta (saccular otolith) shape and size affect hearing capacities: large sagittae are thought to increase sensitivity. The sagittae of many ophidiids and carapids occupy a large volume inside the neurocranium. Hence they are a good structure with which to test the size hypothesis. The main aim of this study was to investigate hearing capacities and inner ear morphology in two ophidiiform species: Ophidion rochei and Carapus acus. We used a multidisciplinary approach that combines dissections, MUCT-scan examinations and auditory evoked potential techniques. Carapus acus and O. rochei sagittae have similar maximal diameters; both species have larger otoliths than many non ophidiiform species, especially compared with the intra-neurocranium volume. Both species are sensitive to sounds up to 2100 Hz. Relative to the skull, O. rochei has smaller sagittae than the carapid, but better hearing capacities from 300 to 900 Hz and similar sensitivities at 150 Hz and from 1200 to 2100 Hz. Results show that hearing capacities of a fish species cannot be predicted only based on sagitta size. Larger otoliths (in size relative to the skull) may have evolved mainly for performing vestibular functions in fishes, especially those species that need to execute precise and complex movements. PMID- 24803459 TI - Highly extensible skeletal muscle in snakes. AB - Many snakes swallow large prey whole, and this process requires large displacements of the unfused tips of the mandibles and passive stretching of the soft tissues connecting them. Under these conditions, the intermandibular muscles are highly stretched but subsequently recover normal function. In the highly stretched condition we observed in snakes, sarcomere length (SL) increased 210% its resting value (SL0), and actin and myosin filaments no longer overlapped. Myofibrils fell out of register and triad alignment was disrupted. Following passive recovery, SLs returned to 82% SL0, creating a region of double overlapping actin filaments. Recovery required recoil of intracellular titin filaments, elastic cytoskeletal components for realigning myofibrils, and muscle activation. Stretch of whole muscles exceeded that of sarcomeres as a result of extension of folded terminal tendon fibrils, stretching of extracellular elastin and independent slippage of muscle fibers. Snake intermandibular muscles thus provide a unique model of how basic components of vertebrate skeletal muscle can be modified to permit extreme extensibility. PMID- 24803460 TI - Manipulation of BK channel expression is sufficient to alter auditory hair cell thresholds in larval zebrafish. AB - Non-mammalian vertebrates rely on electrical resonance for frequency tuning in auditory hair cells. A key component of the resonance exhibited by these cells is an outward calcium-activated potassium current that flows through large conductance calcium-activated potassium (BK) channels. Previous work in midshipman fish (Porichthys notatus) has shown that BK expression correlates with seasonal changes in hearing sensitivity and that pharmacologically blocking these channels replicates the natural decreases in sensitivity during the winter non reproductive season. To test the hypothesis that reducing BK channel function is sufficient to change auditory thresholds in fish, morpholino oligonucleotides (MOs) were used in larval zebrafish (Danio rerio) to alter expression of slo1a and slo1b, duplicate genes coding for the pore-forming alpha-subunits of BK channels. Following MO injection, microphonic potentials were recorded from the inner ear of larvae. Quantitative real-time PCR was then used to determine the MO effect on slo1a and slo1b expression in these same fish. Knockdown of either slo1a or slo1b resulted in disrupted gene expression and increased auditory thresholds across the same range of frequencies of natural auditory plasticity observed in midshipman. We conclude that interference with the normal expression of individual slo1 genes is sufficient to increase auditory thresholds in zebrafish larvae and that changes in BK channel expression are a direct mechanism for regulation of peripheral hearing sensitivity among fishes. PMID- 24803461 TI - Following the sun: a mathematical analysis of the tracks of clock-shifted homing pigeons. AB - We analysed the tracks of clock-shifted pigeons from six releases to determine how they cope with the conflict between their sun compass and other navigational cues. Time-lag embedding was used to calculate the short-term correlation dimension, a parameter that reflects the complexity of the navigational system, and with it, the number of factors involved. Initially, while pigeons were still at the release site, the short-term correlation dimension was low; it increased as the birds left the site, indicating that the birds were now actively navigating. Clock-shifted pigeons showed more scatter than the control birds, and their short-term correlation dimension became significantly smaller than that of the controls, remaining lower until the experimental birds reached their loft. This difference was small, but consistent, and suggests a different rating and ranking of the navigational cues. Clock-shifted pigeons do not seem to simply ignore the information from their manipulated sun compass altogether, but appear to merely downgrade it in favour of other cues, like their magnetic compass. This is supported by the observation that the final part of the tracks still showed a small deviation in the expected direction, indicating an effect of clock-shifting until the end of the homing flight. PMID- 24803462 TI - Circadian rhythms are not involved in the regulation of circannual reproductive cycles in a sub-tropical bird, the spotted munia. AB - Circannual rhythms regulate seasonal reproduction in many vertebrates. The present study investigated whether circannual reproductive phenotypes (rhythms in growth of gonads and molt) were generated independently of the circadian clocks in the subtropical non-photoperiodic spotted munia (Lonchura punctulata). Birds were subjected to light:dark (LD) cycles with identical light but varying dark hours, such that the period of LD cycle (T) equaled 16 h (T16; 12 h L:4 h D), 21 h (T21; 12 h L:9 h D), 24 h (T24; 12 h L:12 h D) and 27 h (T27; 12 h L:15 h D), or to continuous light (LL, 24 h L:0 h D) at ~18 degrees C. During the ~21 month exposure, munia underwent at least two cycles of gonadal development and molt; changes in body mass were not rhythmic. This was similar to the occurrence of annual cycles in reproduction and molt observed in wild birds. A greater asynchrony between circannual cycles of gonad development and molt indicated their independent regulation. Females showed reproductive rhythms with similar circannual periods, whilst in males, circannual periods measured between peak gonadal size were longer in T21 and T24 than in T16 or T27. This suggested a sex dependent timing of annual reproduction in the spotted munia. Also, food availability periods may not influence the circannual timing of reproduction, as shown by the results on the rhythm in gonadal growth and regression in munia under T-photocycles and LL that provided differential light (feeding) hours. Further, a short-term experiment revealed that activity-rest patterns in munia were synchronized with T-photocycles, but were arrhythmic under LL. We conclude that circadian rhythms are not involved in the timing of the annual reproductive cycle in the spotted munia. PMID- 24803463 TI - Chronic stress alters concentrations of corticosterone receptors in a tissue specific manner in wild house sparrows (Passer domesticus). AB - The physiological stress response results in release of glucocorticoid hormones such as corticosterone (CORT). Whereas short-term activation of this response helps animals cope with environmental stressors, chronic activation can result in negative effects including metabolic dysregulation and reproductive failure. However, there is no consensus hormonal profile of a chronically stressed animal, suggesting that researchers may need to look beyond hormone titers to interpret the impacts of chronic stress. In this study, we brought wild house sparrows (Passer domesticus) into captivity. We then compared glucocorticoid and mineralocorticoid receptor concentrations in sparrows exposed either to a standardized chronic stress protocol (n=26) or to standard husbandry conditions (controls; n=20). We used radioligand binding assays to quantify receptors in whole brain, liver, kidneys, spleen, gonads, gastrocnemius and pectoralis muscle, omental and subcutaneous fat, and bib and back skin. In most tissues, CORT receptors did not differ between controls and stressed animals, although we found marginal increases in receptor density in kidney and testes in stressed birds at some time points. Only in pectoralis muscle was there a robust effect of chronic stress, with both receptor types higher in stressed animals. Increased pectoralis sensitivity to CORT with chronic stress may be part of the underlying mechanism for muscle wasting in animals administered exogenous CORT. Furthermore, the change in pectoralis was not paralleled by gastrocnemius receptors. This difference may help explain previous reports of a greater effect of CORT on pectoralis than on other muscle types, and indicate that birds use this muscle as a protein reserve. PMID- 24803464 TI - Jumping mechanisms in flatid planthoppers (Hemiptera, Flatidae). AB - The jumping performance of three species of hemipterans from Australia and Europe belonging to the family Flatidae was analysed from images captured at a rate of 5000 s(-1). The shape of a flatid was dominated by large triangular or wedge shaped front wings, which, when folded, covered and extended above and behind the body to give a laterally compressed and possibly streamlined appearance. The body lengths of the three species of adults ranged from 7 to 9 mm and their mass from 8 to 19 mg. The propulsive hind legs were 30% longer than the front legs but only 36-54% of the body length. Jumps with the fastest take-off velocities of 2.8-3.2 m s(-1) had acceleration times of 1.4-1.8 ms. During such jumps, adults experienced an acceleration of 174-200 G: . These jumps required an energy expenditure of 76-225 MUJ, a power output of 13-60 mW and exerted a force of 9-37 mN. The required power output per mass of jumping muscle in adults ranged from 24,000 to 27,000 W kg(-1) muscle, 100 times greater than the maximum active contractile limit of normal muscle. The free-living nymphs were also proficient jumpers, reaching take-off velocities of 2.2 m s(-1). To achieve such a jumping performance requires a power amplification mechanism. The energy store for such a mechanism was identified as the internal skeleton linking a hind coxa to the articulation of a hind wing. These pleural arches fluoresced bright blue when illuminated with UV light, indicating the presence of the elastic protein resilin. The energy generated by the prolonged contractions of the trochanteral depressor muscles was stored in distortions of these structures, and the rapid elastic recoil of these muscles powered the synchronous propulsive movements of the hind legs. PMID- 24803465 TI - Mitochondrial phenotypic flexibility enhances energy savings during winter fast in king penguin chicks. AB - Energy conservation is a key priority for organisms that live in environments with seasonal shortages in resource supplies or that spontaneously fast during their annual cycle. The aim of this study was to determine whether the high fasting endurance of winter-acclimatized king penguin chicks (Aptenodytes patagonicus) is associated with an adjustment of mitochondrial bioenergetics in pectoralis muscle, the largest skeletal muscle in penguins. The rates of mitochondrial oxygen consumption, and ATP synthesis and mitochondrial efficiency (ATP/O ratio) were measured in winter-acclimatized chicks. We used pyruvate/malate and palmitoyl-l-carnitine/malate as respiratory substrates and results from naturally fasted chicks were compared to experimentally re-fed chicks. Bioenergetics analysis of pectoralis muscle revealed that mitochondria are on average 15% more energy efficient in naturally fasted than in experimentally fed chicks, indicating that fasted birds consume less nutrients to sustain their energy-demanding processes. We also found that moderate reductions in temperature from 38 degrees C to 30 degrees C further increase by 23% the energy coupling efficiency at the level of mitochondria, suggesting that king penguin chicks realize additional energy savings while becoming hypothermic during winter. It has been calculated that this adjustment of mitochondrial efficiency in skeletal muscle may contribute to nearly 25% of fasting-induced reduction in mass-specific metabolic rate measured in vivo. The present study shows that the regulation of mitochondrial efficiency triggers the development of an economical management of resources, which would maximize the conservation of endogenous fuel stores by decreasing the cost of living in fasted winter acclimatized king penguin chicks. PMID- 24803466 TI - Effects of load magnitude, muscle length and velocity during eccentric chronic loading on the longitudinal growth of the vastus lateralis muscle. AB - The present study investigated the longitudinal growth of the vastus lateralis muscle using four eccentric exercise protocols with different mechanical stimuli by modifying the load magnitude, lengthening velocity and muscle length at which the load was applied. Thirty-one participants voluntarily participated in this study in two experimental and one control group. The first experimental group (N=10) exercised the knee extensors of one leg at 65% (low load magnitude) of the maximum isometric voluntary contraction (MVC) and the second leg at 100% MVC (high load magnitude) with 90 deg s(-1) angular velocity, from 25 to 100 deg knee angle. The second experimental group (N=10) exercised one leg at 100% MVC, 90 deg s(-1), from 25 to 65 deg knee angle (short muscle length). The other leg was exercised at 100% MVC, 240 deg s(-1) angular velocity (high muscle lengthening velocity) from 25 to 100 deg. In the pre- and post-intervention measurements, we examined the fascicle length of the vastus lateralis at rest and the moment-angle relationship of the knee extensors. After 10 weeks of intervention, we found a significant increase (~14%) of vastus lateralis fascicle length compared with the control group, yet only in the leg that was exercised with high lengthening velocity. The findings provide evidence that not every eccentric loading causes an increase in fascicle length and that the lengthening velocity of the fascicles during the eccentric loading, particularly in the phase where the knee joint moment decreases (i.e. deactivation of the muscle), seems to be an important factor for longitudinal muscle growth. PMID- 24803467 TI - The spectral transmission of non-salticid spider corneas. AB - Although many salticid spiders have been shown to have corneas that transmit ultraviolet (UV) light, whether the corneas of non-salticid spiders transmit UV has not been previously investigated. In this study, we determined the spectral corneal transmission properties of 38 species belonging to 13 non-salticid families. We used these data to estimate the T50 transmission cut-off value, the wavelength corresponding to 50% maximal transmission for each species. The corneas of almost all species from the families Deinopidae, Lycosidae, Oxyopidae, Pisauridae, Sparassidae and Thomisidae, all of which have been reported to rely to a substantial extent on vision, transmitted short wavelength light below 400 nm, ranging from 306 to 381 nm. However, species from the families Atypidae and Ctenizidae are not known to rely substantially on vision, and the corneas of these species tended to absorb light of wavelengths below 380 nm, which may not allow UV sensitivity in these spiders. Liphistiidae, the family widely regarded as most basal among spiders, is of particular interest. The species in this family are not known to make substantial use of vision, and yet we found that liphistiid corneas transmitted UV light with a low T50 value (359 nm). T50 values of non-salticid spider corneas also varied with light habitat. Species living in dim environments tended to have UV-opaque corneas, but species inhabiting open areas had UV-transmitting corneas. However, there was no evidence of corneal transmission properties being related to whether a species is diurnal or nocturnal. PMID- 24803468 TI - Using accelerometers to determine the calling behavior of tagged baleen whales. AB - Low-frequency acoustic signals generated by baleen whales can propagate over vast distances, making the assignment of calls to specific individuals problematic. Here, we report the novel use of acoustic recording tags equipped with high resolution accelerometers to detect vibrations from the surface of two tagged fin whales that directly match the timing of recorded acoustic signals. A tag deployed on a buoy in the vicinity of calling fin whales and a recording from a tag that had just fallen off a whale were able to detect calls acoustically but did not record corresponding accelerometer signals that were measured on calling individuals. Across the hundreds of calls measured on two tagged fin whales, the accelerometer response was generally anisotropic across all three axes, appeared to depend on tag placement and increased with the level of received sound. These data demonstrate that high-sample rate accelerometry can provide important insights into the acoustic behavior of baleen whales that communicate at low frequencies. This method helps identify vocalizing whales, which in turn enables the quantification of call rates, a fundamental component of models used to estimate baleen whale abundance and distribution from passive acoustic monitoring. PMID- 24803469 TI - Ant-fungus species combinations engineer physiological activity of fungus gardens. AB - Fungus-gardening insects are among the most complex organisms because of their extensive co-evolutionary histories with obligate fungal symbionts and other microbes. Some fungus-gardening insect lineages share fungal symbionts with other members of their lineage and thus exhibit diffuse co-evolutionary relationships, while others exhibit little or no symbiont sharing, resulting in host-fungus fidelity. The mechanisms that maintain this symbiont fidelity are currently unknown. Prior work suggested that derived leaf-cutting ants in the genus Atta interact synergistically with leaf-cutter fungi (Attamyces) by exhibiting higher fungal growth rates and enzymatic activities than when growing a fungus from the sister-clade to Attamyces (so-called 'Trachymyces'), grown primarily by the non leaf cutting Trachymyrmex ants that form, correspondingly, the sister-clade to leaf-cutting ants. To elucidate the enzymatic bases of host-fungus specialization in leaf-cutting ants, we conducted a reciprocal fungus-switch experiment between the ant Atta texana and the ant Trachymyrmex arizonensis and report measured enzymatic activities of switched and sham-switched fungus gardens to digest starch, pectin, xylan, cellulose and casein. Gardens exhibited higher amylase and pectinase activities when A. texana ants cultivated Attamyces compared with Trachymyces fungi, consistent with enzymatic specialization. In contrast, gardens showed comparable amylase and pectinase activities when T. arizonensis cultivated either fungal species. Although gardens of leaf-cutting ants are not known to be significant metabolizers of cellulose, T. arizonensis were able to maintain gardens with significant cellulase activity when growing either fungal species. In contrast to carbohydrate metabolism, protease activity was significantly higher in Attamyces than in Trachymyces, regardless of the ant host. Activity of some enzymes employed by this symbiosis therefore arises from complex interactions between the ant host and the fungal symbiont. PMID- 24803470 TI - Brightness discrimination in the day- and night-adapted wandering spider Cupiennius salei. AB - Cupiennius salei is a nocturnal spider with eight eyes, which undergo a remarkable circadian cycle: the rhabdomeric membrane of the photoreceptor cells is dismantled during the day and rebuilt at the beginning of the night. Such drastic changes might influence the brightness discrimination ability. We tested this hypothesis by presenting square-shaped flickering stimuli with certain luminances on stationary backgrounds with other luminances to spiders with day- or night-adapted eyes. When the spider, through its three pairs of so-called secondary eyes, perceives a visible contrast between the stimulus and the background, its principal eye muscle activity should increase. We therefore recorded this activity in vivo to assess the brightness discrimination ability of Cupiennius salei. Our results show that this spider has good brightness discrimination ability, which is significantly better with dark-adapted eyes. A Michelson contrast of 0.1 to 0.2 at night, and of 0.2 to 0.3 for day-adapted eyes, is sufficient to elicit a significant response, except below a critical value of luminance (~16 cd m(-2)), where the minimal perceivable contrast needs to be higher. In the Discussion we compare these performances with those of other animals, in particular with jumping spiders. PMID- 24803471 TI - Variation in body condition during the post-moult foraging trip of southern elephant seals and its consequences on diving behaviour. AB - Mature female southern elephant seals (Mirounga leonina) come ashore only in October to breed and in January to moult, spending the rest of the year foraging at sea. Mature females may lose as much as 50% of their body mass, mostly in lipid stores, during the breeding season due to fasting and lactation. When departing to sea, post-breeding females are negatively buoyant, and the relative change in body condition (i.e. density) during the foraging trip has previously been assessed by monitoring the descent rate during drift dives. However, relatively few drift dives are performed, resulting in low resolution of the temporal reconstruction of body condition change. In this study, six post breeding females were equipped with time-depth recorders and accelerometers to investigate whether changes in active swimming effort and speed could be used as an alternative method of monitoring density variations throughout the foraging trip. In addition, we assessed the consequences of density change on the swimming efforts of individuals while diving and investigated the effects on dive duration. Both descent swimming speed and ascent swimming effort were found to be strongly correlated to descent rate during drift dives, enabling the fine-scale monitoring of seal density change over the whole trip. Negatively buoyant seals minimized swimming effort during descents, gliding down at slower speeds, and reduced their ascent swimming effort to maintain a nearly constant swimming speed as their buoyancy increased. One per cent of seal density variation over time was found to induce a 20% variation in swimming effort during dives with direct consequences on dive duration. PMID- 24803473 TI - Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients. AB - BACKGROUND: We evaluated the effectiveness of a computer clinical decision support system (CDSS) for reducing the risk of QT interval prolongation in hospitalized patients. METHODS AND RESULTS: We evaluated 2400 patients admitted to cardiac care units at an urban academic medical center. A CDSS incorporating a validated risk score for QTc prolongation was developed and implemented using information extracted from patients' electronic medical records. When a drug associated with torsades de pointes was prescribed to a patient at moderate or high risk for QTc interval prolongation, a computer alert appeared on the screen to the pharmacist entering the order, who could then consult the prescriber on alternative therapies and implement more intensive monitoring. QTc interval prolongation was defined as QTc interval >500 ms or increase in QTc of >=60 ms from baseline; for patients who presented with QTc >500 ms, QTc prolongation was defined solely as increase in QTc >=60 ms from baseline. End points were assessed before (n=1200) and after (n=1200) implementation of the CDSS. CDSS implementation was independently associated with a reduced risk of QTc prolongation (adjusted odds ratio, 0.65; 95% confidence interval, 0.56-0.89; P<0.0001). Furthermore, CDSS implementation reduced the prescribing of noncardiac medications known to cause torsades de pointes, including fluoroquinolones and intravenous haloperidol (adjusted odds ratio, 0.79; 95% confidence interval, 0.63 0.91; P=0.03). CONCLUSIONS: A computer CDSS incorporating a validated risk score for QTc prolongation influences the prescribing of QT-prolonging drugs and reduces the risk of QTc interval prolongation in hospitalized patients with torsades de pointes risk factors. PMID- 24803472 TI - Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are at low to intermediate risk. METHODS AND RESULTS: To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis who were not on aspirin at baseline and were free of diabetes mellitus. Using data from median 7.6-year follow-up, 5-year number-needed-to-treat estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC>=100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated 5 year number needed to treat of 173 for individuals <10% FRS and 92 for individuals >=10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated 5-year number needed to treat of 2036 for individuals <10% FRS and 808 for individuals >=10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Sex-specific and age-stratified analyses showed similar results. CONCLUSIONS: For the primary prevention of CHD, Multi-Ethnic Study of Atherosclerosis participants with CAC>=100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin. PMID- 24803475 TI - Clinical Outcomes in Critically Ill Patients Associated With the Use of Complex vs Weight-Only Predictive Energy Equations. AB - BACKGROUND: The energy intake goal is important to achieving energy intake in critically ill patients, yet clinical outcomes associated with energy goals have not been reported. METHODS: This secondary analysis used the Improving Nutrition Practices in the Critically III International Nutrition Surveys database from 2007-2009 to evaluate whether mortality or time to discharge alive is related to use of complex energy prediction equations vs weight only. The sample size was 5672 patients in the intensive care unit (ICU) >= 4 days and a subset of 3356 in the ICU >= 12 days. Mortality and time to discharge alive were compared between groups by regression, controlling for age, sex, admission type, Acute Physiology and Chronic Health Evaluation II score, ICU geographic region, actual energy intake, and obesity. RESULTS: There was no difference in mortality between the use of complex and weight-only equations (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.86-1.15), but obesity (OR, 0.83; 95% CI, 0.71-0.96) and higher energy intake (OR, 0.65; 95% CI, 0.56-0.76) had lower odds of mortality. Time to discharge alive was shorter in patients fed using weight-only equations (hazard ratio [HR], 1.11; 95% CI, 1.01-1.23) in patients staying >= 4 days and with greater energy intake (HR, 1.19; 95% CI, 1.06-1.34) in patients in the ICU >= 12 days. CONCLUSION: These data suggest that higher energy intake is important to survival and time to discharge alive. However, the analysis was limited by actual energy intake <70% of goal. Delivery of full goal intake will be needed to determine the relationship between the method of determining energy goal and clinical outcomes. PMID- 24803476 TI - Clinical prediction rules in community-acquired pneumonia: lies, damn lies and statistics. AB - A variety of prediction scores have been developed to identify at the time of presentation patients with community-acquired pneumonia at risk for intensive care unit (ICU) admission or death within 30 days. The effectiveness of each scoring score is typically assessed by calculation of the area under the receiver operator characteristic curve (AUROC). Although this statistical parameter is helpful in determining the discriminatory value of a score, it assumes equal importance of false negatives and false positives in the tradeoff between sensitivity and specificity. Because patient safety takes precedence over cost, the balance between limiting false negatives (unnecessarily strict ICU admission policy) and false positives (unnecessarily liberal ICU admission policy) should favor the reduction of false negatives. Instead of using AUROC as the primary measure to evaluate prediction rules, we propose the use of sensitivity as a more appropriate alternative. PMID- 24803474 TI - Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial. AB - BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 * 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment. PMID- 24803477 TI - Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis. AB - BACKGROUND: Although autologous stem cell transplantation (ASCT) may achieve disease control in severe treatment-resistant Crohn's disease (CD), relapse is frequent, and there is little information regarding long-term outcomes in terms of response to subsequent treatments and complications of ASCT. DESIGN: Retrospective evaluation of UK patients treated on a compassionate basis from three UK tertiary centres. METHODS: We summarize long-term outcomes of six previously unreported patients with severe treatment-resistant CD treated with ASCT according to international guidelines between 2003 and 2009. Median duration of CD before ASCT was 14 (7-22) years. Following stem cell mobilization, patients were treated with high-dose cyclophosphamide (200 mg/kg) and rabbit anti thymocyte globulin (7.5 mg/kg) followed by ASCT. RESULTS: All patients tolerated ASCT with routine toxicities and no treatment-related mortality and are alive at 50-123 months post-ASCT. Clinical and endoscopic remissions of CD were confirmed at 3 months post-ASCT in five patients, although median time to next treatment for inflammatory disease was 10 months (range: 3-16 months). Subsequently, disease control was achieved with previously ineffective and newer treatments, with surgery performed predominantly for pre-existing fibrotic strictures. Two patients became independent of home total parenteral nutrition (TPN). Reported late complications of ASCT included hypothyroidism and ovarian failure. CONCLUSION: Long-term follow-up supports the safety and feasibility of ASCT as a means of achieving short-term control of severe CD whilst potentially re sensitizing the disease to medical therapy and reducing requirements for surgery and TPN. Given the inevitability of relapse, pre-emptive salvage and/or maintenance treatments post-ASCT should be the focus of future trials. PMID- 24803478 TI - Unusual presentation of a recurrent squamous cell lung cancer. PMID- 24803479 TI - Do women who intermittently attend breast screening differ from those who attend every invitation and those who never attend? AB - OBJECTIVES: Analysis of screening uptake usually dichotomizes women into attenders and non-attenders, though many women respond positively to some but not all invitations. This paper studies these intermittent attenders. METHODS: A cohort of 8,571 women invited for consecutive breast screens in the Northern Ireland Breast Screening Programme were followed in a study linking screening and census records. Multivariate logistic analysis was used to analyze the characteristics of those who attended both times (consistent), once (intermittent or 'one-time only'), or not at all (non-attenders). RESULTS: Overall, 15.5% of women attended once and 13.4% were non-attenders. Non-attenders were characteristically disadvantaged (as measured by social renting, car access, and employment status), less likely to be married, and more likely to be healthy. One time attenders were younger, and suffering poor health, though there was no association with either social renting or employment status. Privately rented accommodation and city living was associated with both one-time attendance and non-attendance. CONCLUSIONS: One-time attenders are an important and distinct subgroup of screening invitees in this analysis. Their distinct characteristics suggest that transitory factors, such as change in marital status, ill-health, or addressing difficulties through change of residence are important. These distinct characteristics suggest the need for different approaches to increase attendance, among both intermittent attenders and those not attending at all. PMID- 24803480 TI - Deprivation and faecal haemoglobin: implications for bowel cancer screening. AB - OBJECTIVE: To investigate the relationship between deprivation and faecal haemoglobin concentration (f-Hb). SETTING: Scottish Bowel Screening Programme. METHODS: A total of 66725 men and women, aged 50 to 74, were invited to provide a single sample for a faecal immunochemical test. Deprivation was estimated using the Scottish Index of Multiple Deprivation quintiles: f-Hb was measured (OC Sensor, Eiken, Japan) on 38439 participants. The relationship between deprivation quintiles and f-Hb was examined. RESULTS: Median age was 60 years, 53.6% women, with 14.1%, 19.7%, 17.7%, 25.9% and 22.6% in the lowest to the highest deprivation quintiles respectively. No detectable f-Hb was found in 51.9%, ranging from 45.5% in the most deprived up to 56.5% in the least deprived. As deprivation increased, f-Hb increased (p < 0.0001). This trend remained controlling for sex and age (p < 0.001). Participants in the most deprived quintile were more likely to have a f-Hb above a cut-off of 80 ug Hb/g faeces compared with the least deprived, independent of sex and age (adjusted odds ratio 1.70, 95% confidence interval: 1.37 to 2.11). CONCLUSIONS: Deprivation and f-Hb are related. This has important implications for selection of cut-off f-Hb for screening programmes, and supports the inclusion of deprivation in risk-scoring systems. PMID- 24803481 TI - Effect of a pre-screening survey on attendance in colorectal cancer screening: a double-randomized study in Finland. AB - OBJECTIVES: To explore effects of a pre-screening life style survey on the subsequent attendance proportion in colorectal cancer screening. SETTING: Finnish colorectal cancer screening programme in 2011. DESIGN: Double randomized and controlled follow-up design. METHODS: The study population comprised of 31,951 individuals born in 1951. In 2010 to a random sample of every sixth (n = 5,312) person we sent a 7-paged life style questionnaire, and to another random sample of every sixth person (n = 5,336) a 10-paged life style and quality of life questionnaire. One year later, in 2011, 31,484 individuals of the original cohort were independently randomized (1:1) for colorectal cancer screening (n = 15,748) or control group (n = 15,736). Of those who were invited for screening, 5185 had received a questionnaire during the previous year. RESULTS: 5870 individuals (55.1 %) responded to the questionnaire in 2010. The overall attendance at screening in 2011 was 59.0 % in those born in 1951 (i.e. the 60-year-olds). In those who had been sent the survey the attendance in screening was 56.6% (57.3% for the short and 56.0% for the long questionnaire) and in those who had not received the questionnaire it was 60.2% (P < 0.001). CONCLUSIONS: We believe that the observed reduction in attendance in those who had been sent a questionnaire earlier is generally true. Thus, if any survey is enclosed in the screening invitation, this finding should be taken into account when planning the programme. Any extra effort requested may reduce the attendance proportion for screening, reducing the population level impact of screening. PMID- 24803482 TI - Clinicopathological differences between interval and screen-detected breast cancers diagnosed within a screening programme in Northern Portugal. AB - OBJECTIVE: To evaluate clinicopathological differences between screen-detected (SD) and interval (IC) breast cancers diagnosed in women enrolled in an organized breast screening programme in 2000--2007. SETTING: Breast Cancer Screening Programme of the north region of Portugal. METHODS: Using data from the screening programme and from the population-based North Region Cancer Registry, SD and IC were identified. Information on screening history, age, date of diagnosis, tumour size, histological type and grade, lymph node status, tumour stage, biomarkers, and treatment was obtained from the cancer registry and from clinical and pathological reports. Association between mode of detection and these clinicopathological characteristics was estimated by unconditional logistic regression. RESULTS: A total of 442 SD and 112 IC were identified in women aged 50--69. Compared with SD, IC were diagnosed in younger women (60.0 +/- 5.8 years and 58.4 +/- 6.0 years, respectively), were larger (tumour size >20 mm: 60.2% versus 25.1%), lobular (6.3% versus 16.1%), with a higher differentiation grade (grade 3: 17.7% versus 38.9%), had more lymph node metastases, more advanced stage, and oestrogen receptor (ER) negative (12.9% versus 29.0%) and progesterone negative, and HER2 positive. After multivariable analysis, compared with SD, IC were more likely to be larger than 20 mm, lobular, of grade 3 and negative for ER. CONCLUSION: Our results are consistent with other studies. IC's have a more aggressive biology than SDs. Our findings did not show any unexpected pattern requiring changes to our screening procedures, but continuous identification and characterization of IC is advisable. PMID- 24803483 TI - Cost-benefit analysis of hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency: for consideration of expanded newborn screening in Hong Kong. AB - OBJECTIVES: To evaluate the cost-benefit of implementing an expanded newborn screening programme for hyperphenylalaninemias due to 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency in Hong Kong. SETTING: Regional public hospitals in Hong Kong providing care for cases of inborn errors of metabolism. METHODS: Implementational and operational costs of a new expanded mass spectrometry-based newborn screening programme were estimated. Data on various medical expenditures for the mild and severe phenotypic subtypes were gathered from a case cohort diagnosed with PTPS deficiency from 2001 to 2009. Local incidence from a previously published study was used. RESULTS: Implementation and operational costs of an expanded newborn screening programme in Hong Kong were estimated at HKD 10,473,848 (USD 1,342,801) annually. Assuming a birthrate of 50,000 per year and an incidence of 1 in 29,542 live births, the medical costs and adjusted loss of workforce per year would be HKD 20,773,207 (USD 2,663,232). Overall the annual savings from implementing the programme would be HKD 9,632,750 (USD 1,234,968). CONCLUSIONS: Our estimates show that implementation of an expanded newborn screening programme in Hong Kong is cost-effective, with a significant annual saving for public expenditure. PMID- 24803484 TI - Undocumented Immigrants and Access to Health Care: Making a Case for Policy Reform. AB - The growth in undocumented immigration in the United States has garnered increasing interest in the arenas of immigration and health care policy reform. Undocumented immigrants are restricted from accessing public health and social service as a result of their immigration status. The Patient Protection and Affordability Care Act restricts undocumented immigrants from participating in state exchange insurance market places, further limiting them from accessing equitable health care services. This commentary calls for comprehensive policy reform that expands access to health care for undocumented immigrants based on an analysis of immigrant health policies and their impact on health care expenditures, public health, and the role of health care providers. The intersectional nature of immigration and health care policy emphasizes the need for nurse policymakers to advocate for comprehensive policy reform aimed at improving the health and well-being of immigrants and the nation as a whole. PMID- 24803485 TI - Enforcement of Hospital Nurse Staffing Regulations Across the United States: Progress or Stalemate? AB - Enactment of hospital nurse staffing regulations was brought about by changes in the U.S. health care system that resulted in large-scale reductions in nurse staffing. These reductions came at a time when studies were highlighting inadequacies in care that caused negative patient outcomes and raised questions about the safety of hospitalized patients. Nurse staffing regulations were enacted to ensure that adequate numbers of nurses were available to provide high quality and safe care. Although these regulations represent progress toward addressing staffing inadequacies, enforcement language is absent or weak and compliance data are either not collected or difficult to access. Explicit and funded enforcement measures need to be included in staffing regulations. Additionally, compliance monitoring and reporting are necessary to evaluate these types of staffing regulations and to determine if they actually achieve the goal of appropriate nurse staffing. PMID- 24803486 TI - Translating Evidence-Based Practice Guidelines Into a Summary of Recommendations for the Nutrition Management of Upper Gastrointestinal Cancers. AB - Background: Upper gastrointestinal (UGI) cancer has a profound effect on the function of major digestive organs with resulting deterioration in nutrition status. There are currently no known evidence-based guidelines specific to the nutrition management of people with UGI cancer. This article aimed to review the current guidelines related to the nutrition management of surgical and nonsurgical cancer patients with the aim to collate similar findings to produce a summary of recommendations for clinicians. Gaps in current evidence were also identified. Methods: Guidelines with evidence grading systems were identified from CINAHL, Medline, Web of Science, and a manual search. The quality of guidelines was assessed using the Appraisal of Guidelines Research and Evaluation (AGREE) tool. Results: Twenty-six guidelines were retrieved. Most guidelines showed strong rigor, but only 23% were considered current, having been developed or reviewed in the past 3 years. A summary of recommendations was extrapolated from retrieved guidelines, based on a standardized evidence grading system and the quality score for each guideline. Conclusion: This review of current guidelines shows that many areas of nutrition management still require more evidence to support high-level recommendations. These include immunonutrition, pancreatic enzyme replacement therapy, and postdischarge complication management. More research is needed before evidence-based guidelines can be developed. PMID- 24803487 TI - Commonly found variations/mutations in the HBsAg of hepatitis B virus in the context of effective immunization programs: questionable clinical and public health significance. PMID- 24803489 TI - Nanoparticle oxygen delivery to the ischemic heart. AB - OBJECTIVE: Currently there are no medications that can be administered to help deliver more oxygen to the myocardial region experiencing abnormal perfusion. The purpose of this study was to look at the nanoparticle dodecafluoropentane in an emulsion as an oxygen carrier. Using nanoparticles as an oxygen carrier is advantageous because they are able to carry oxygen past blockages that are obstructing red blood cells (6-8 um) due to their smaller size (250 nm). With the reintroduction of oxygen to the ischemic muscle tissue, a reduced infarct size should be seen. METHODS: Male C57BL/6J mice underwent left anterior descending artery (LAD) ligation using 8-0 monofilament nylon suture. Immediately after ligation of the LAD, the control group received a 200-ul intravenous injection of phosphate buffered saline (PBS). The treated group received a dose of 0.6 ml/kg of dodecafluoropentane diluted to a total volume of 200 ul in PBS. The mice were then allowed to recover from anesthesia and were sacrificed 24 hours after the time of ligation. After the mice were sacrificed, the heart was excised and placed at -20 degrees C for 20 minutes. The heart was then sliced into 1-mm sections and stained with tetrazolium red to identify the infarcted area. The area of infarct and ventricle were then analyzed using ImageJ software. RESULTS: The average area of infarct in comparison to the ventricle for the control mice was 29.3+/-0.04% compared to 11.7+/-0.02% for the dodecafluoropentane-treated mice. CONCLUSION: The use of dodecafluoropentane in this murine model of myocardial infarction showed a 60% reduction in infarct size (p<0.01). The possibility of using nanoparticles to deliver oxygen to hypoxic tissues has interesting implications and justifies further study. PMID- 24803490 TI - Distinct roles of ROCK1 and ROCK2 during development of porcine preimplantation embryos. AB - Cell-to-cell contact mediated by cell adhesion is fundamental to the compaction process that ensures blastocyst quality during embryonic development. In this study, we first showed that Rho-associated coiled-coil protein kinases (ROCK1 and ROCK2) were expressed both in porcine oocytes and IVF preimplantation embryos, playing different roles in oocytes maturation and embryo development. The amount of mRNA encoding ROCK1 and the protein concentration clearly increased between the eight-cell and morula stages, but decreased significantly when blastocysts were formed. Conversely, ROCK2 was more abundant in the blastocyst compared with other embryonic stages. Moreover, immunostaining showed that ROCK1 protein distribution changed as the embryo progressed through cleavage and compaction to the morula stage. Initially, the protein was predominantly associated with the plasma membrane but later became cytoplasmic. By contrast, ROCK2 protein was localized in both the cytoplasm and the spindle rotation region during oocyte meiosis, but in the cytoplasm and nucleus as the embryo developed. In addition, ROCK2 was present in the trophectoderm cells of the blastocyst. Treatment with 15 MUM Y27632, a specific inhibitor of ROCKs, completely blocked further development of early four-cell stage embryos. Moreover, we did not detect the expression of ROCK1 but did detect ROCK2 expression in blastocysts. Moreover, lysophosphatidic acid an activator of ROCKs significantly improved the rates of blastocyst formation. These data demonstrate that ROCKs are required for embryo development to the blastocyst stage. Together, our results indicate that ROCK1 and ROCK2 may exert different biological functions during the regulation of compaction and in ensuring development of porcine preimplantation embryos to the blastocyst stage. PMID- 24803491 TI - De novo morphogenesis of testis tissue: an improved bioassay to investigate the role of VEGF165 during testis formation. AB - De novo formation of testis tissue from single-cell suspensions allows manipulation of different testicular compartments before grafting to study testicular development and the spermatogonial stem cell niche. However, the low percentages of newly formed seminiferous tubules supporting complete spermatogenesis and lack of a defined protocol have limited the use of this bioassay. Low spermatogenic efficiency in de novo formed tissue could result from the scarcity of germ cells in the donor cell suspension, cell damage caused by handling or from hypoxia during tissue formation in the host environment. In this study, we compared different proportions of spermatogonia in the donor cell suspension and the use of Matrigel as a scaffold to support de novo tissue formation and spermatogenesis. Then, we used the system to investigate the role of vascular endothelial growth factor 165 (VEGF165) during testicular morphogenesis on blood vessel and seminiferous tubule formation, and on presence of germ cells in the de novo developed tubules. Our results show that donor cell pellets with 10*10(6) porcine neonatal testicular cells in Matrigel efficiently formed testis tissue de novo. Contrary to what was expected, the enrichment of the cell suspension with germ cells did not result in higher numbers of tubules supporting spermatogenesis. The addition of VEGF165 did not improve blood vessel or tubule formation, but it enhanced the number of tubules containing spermatogonia. These results indicate that spermatogenic efficiency was improved by the addition of Matrigel, and that VEGF165 may have a protective role supporting germ cell establishment in their niche. PMID- 24803492 TI - Involvement of VCAM1 in the bovine conceptus adhesion to the uterine endometrium. AB - Following bidirectional communication, the conceptus and the uterine epithelium must establish a proper cell-cell interaction, resulting in the progression of implantation processes. To clarify the mechanism of conceptus attachment to the uterine endometrium, we studied whether vascular cell adhesion molecule (VCAM1) was expressed in bovine conceptuses or endometrium during the peri-attachment period. Uterine VCAM1 expression was minimal in day 17 (day 0=day of estrus) cyclic and pregnant animals, but increased between days 20 and 22 of pregnancy. In the intercaruncular regions, VCAM1 protein was localized to the luminal and glandular epithelia, whereas in the caruncular regions, VCAM1 protein was detected in the stroma and endothelia of the uterine endometrium. In cultured endometrial epithelial cells (EECs), VCAM1 expression was up-regulated when treated with uterine flushings or growth factor and further increased when EECs were cocultured with bovine trophoblast CT1 cells. VCAM1 expression in CT1 cells was also up-regulated with the use of uterine flushings, and further increased when these cells were cocultured with EECs. Expression of VCAM1 receptor, integrin alpha 4 (ITGA4) mRNA, increased significantly in day 22 conceptuses. In day 22 pregnant uteri, VCAM1 protein was found in both EECs and conceptuses, but ITGA4 was localized only to trophoblasts. These observations indicate that cell cell interactions between conceptuses and uterine epithelial cells are required for sufficient VCAM1 and ITGA4 expression in the bovine species and suggest that uterine VCAM1 and conceptus ITGA4 play a role in the establishment of conceptus adhesion to the uterine endometrium. PMID- 24803493 TI - Either brain-derived neurotrophic factor or neurotrophin-3 only neurotrophin producing grafts promote locomotor recovery in untrained spinalized cats. AB - Background. Transplants of cellular grafts expressing a combination of 2 neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote and enhance locomotor recovery in untrained spinalized cats. Based on the time course of recovery and the absence of axonal growth through the transplants, we hypothesized that recovery was due to neurotrophin-mediated plasticity within the existing locomotor circuitry of the lumbar cord. Since BDNF and NT-3 have different effects on axonal sprouting and synaptic connectivity/strengthening, it becomes important to ascertain the contribution of each individual neurotrophins to recovery. Objective. We studied whether BDNF or NT-3 only producing cellular grafts would be equally effective at restoring locomotion in untrained spinal cats. Methods. Rat fibroblasts secreting one of the 2 neurotrophins were grafted into the T12 spinal transection site of adult cats. Four cats in each group (BDNF alone or NT-3 alone) were evaluated. Locomotor recovery was tested on a treadmill at 3 and 5 weeks post transection/grafting. Results. Animals in both groups were capable of plantar weight-bearing stepping at speed up to 0.8 m/s as early as 3 weeks and locomotor capabilities were similar at 3 and 5 weeks for both types of graft. Conclusions. Even without locomotor training, either BDNF or NT-3 only producing grafts promote locomotor recovery in complete spinal animals. More clinically applicable delivery methods need to be developed. PMID- 24803494 TI - Effect of intrathecal baclofen bolus injection on ankle muscle activation during gait in patients with acquired brain injury. AB - BACKGROUND: Intrathecal baclofen (ITB) bolus injection effectively decreases spinal excitability but the impact on lower limb muscle activation during gait has not been thoroughly investigated. OBJECTIVE: Examine activation of medial gastrocnemius (MG) and tibialis anterior (TA) muscles during gait before and after ITB bolus injection in patients with resting hypertonia after acquired brain injury. METHODS: Lower extremity Ashworth score, temporospatial gait parameters, characteristics of the linear relationship between electromyogram (EMG) and lengthening velocity (LV) in MG during stance, and the duration and magnitude of TA-MG coactivation were assessed before and at 2, 4, and 6 hours after a 50-ug ITB injection via lumbar puncture in 8 hemorrhagic stroke and 11 traumatic brain injury subjects. RESULTS: Temporospatial gait parameters did not significantly differ across the evaluation points (P >= .170). However, Ashworth score (P < .001), frequency and gain of significant positive EMG-LV slope (P <= .020), and duration of TA-MG coactivation (P <= .013) significantly decreased in the more-affected leg after ITB bolus. EMG changes were not significantly different between patients who did (n = 10) and did not (n = 9) increase gait speed after the injection. The timing of the largest decrease in Ashworth score and the largest decrease in EMG parameters coincided in 36% of cases, on average. CONCLUSIONS: ITB bolus injection alters the activation of MG and TA during gait. However, the changes in muscle activation are not closely related to the changes in gait speed or resting muscle hypertonia. The analysis of ankle muscle activation during gait better characterizes the response to ITB bolus injection than gait kinematics. PMID- 24803495 TI - The effect of combined somatosensory stimulation and task-specific training on upper limb function in chronic stroke: a double-blind randomized controlled trial. AB - BACKGROUND: Somatosensory stimulation (SS) is a potential adjuvant to stroke rehabilitation, but the effect on function needs further investigation. OBJECTIVE: To explore the effect of combining SS with task-specific training (TST) on upper limb function and arm use in chronic stroke survivors and determine underlying mechanisms. METHODS: In this double-blinded randomized controlled trial (ISRCTN 05542931), 33 patients (mean 37.7 months poststroke) were block randomized to 2 groups: active or sham SS. They received 12 sessions of 2 hours of SS (active or sham) to all 3 upper limb nerves immediately before 30 minutes of TST. The primary outcome was the Action Research Arm Test (ARAT) score. Secondary outcomes were time to perform the ARAT, Fugl-Meyer Assessment score (FM), Motor Activity Log (MAL), and Goal Attainment Scale (GAS). Underlying mechanisms were explored using transcranial magnetic stimulation stimulus response curves and intracortical inhibition. Outcomes were assessed at baseline, immediately following the intervention (mean 2 days), and 3 and 6 months (mean 96 and 190 days) after the intervention. RESULTS: The active group (n = 16) demonstrated greater improvement in ARAT score and time immediately postintervention (between-group difference; P < .05), but not at 3- or 6-month follow-ups (P > .2). Within-group improvements were seen for both groups for ARAT and GAS, but for the active group only for FM and MAL (P < .05). Corticospinal excitability did not change. CONCLUSIONS: Long-lasting improvements in upper limb function were observed following TST. Additional benefit of SS was seen immediately post treatment, but did not persist and the underlying mechanisms remain unclear. PMID- 24803496 TI - Effect of the anatomic reservoir on low-flow oxygen delivery via nasal cannula: constant flow versus pulse flow with portable oxygen concentrator. AB - BACKGROUND: The F(IO(2)) for a nasal cannula with constant flow (CF) depends on the anatomic reservoir (AR), which is affected by changes in frequency and end expiratory flow. Conversely, pulse flow (PF) devices do not require the AR. The purpose of this study was to compare the F(IO(2)) delivered by a nasal cannula supplied by CF via oxygen tank with that delivered by PF delivered via portable oxygen concentrator. Hypotheses were (1) a lung model of COPD with non-zero end expiratory flow decreases F(IO(2)) for CF more than for PF, and (2) CF and PF perform differently in terms of F(IO(2)) delivery, despite having equivalent settings. METHODS: Normal and COPD lung models were simulated (IngMar Medical ASL 5000) using published human data: normal: breathing frequency = 15 breaths/min, R(in) = 4 cm H2O . s . L(-1), R(out) = 4 cm H2O . s . L(-1), C = 60 mL . cm H2O( 1), tidal volume (VT) = 685 mL, P(max) = 11.95 cm H2O, increase = 33%, and release = 28; COPD: breathing frequency = 20 breaths/min, R(in) = 12 cm H2O . s . L(-1), R(out) = 25 cm H2O . s . L(-1), C = 66 mL . cm H2O(-1), VT = 685 mL, Pmax = 24.52 cm H2O, increase = 35%, and release = 23%. CF was 1-5 L/min. Portable oxygen concentrators used were Solo2 (Invacare), XPO2 (Invacare), FreeStyle (AirSep), Focus (AirSep), One G3 (Inogen), and LifeChoice ActivOx (Inova Labs). RESULTS: CF produced significantly higher F(IO(2)) at all settings for normal lungs but lower for COPD lungs compared with Solo2. COPD reduced the F(IO(2)) for CF but had a smaller variable effect for PF. Data show there is no equivalency between PF setting and CF rates for the portable oxygen concentrators tested. CONCLUSIONS: CF oxygen delivery via a nasal cannula is significantly reduced by elimination of the AR in a model of COPD, yielding clinically important decreases in F(IO(2)). PF (delivered with a portable oxygen concentrator) is relatively unaffected. This study supports the recommendation that clinicians and caretakers should titrate the PF setting to each patient's unique oxygen requirements. PMID- 24803497 TI - Impact of pulmonary rehabilitation in subjects with mild COPD. AB - BACKGROUND: Pulmonary rehabilitation (PR) is a core component of the management of patients with moderate-to-very-severe COPD. However, as impairments in quadriceps muscle strength and health-related quality of life (HRQOL) are already present in patients with mild COPD, there is a need to investigate whether PR could also be beneficial to these patients. Thus, this study assessed the impact of PR on patients with mild COPD. METHODS: A quasi-experimental study was conducted. Twenty-six participants (67.8 +/- 10.3 years old; FEV1 83.8 +/- 6.4% of predicted) enrolled in a 12-week PR program with exercise training and psychoeducation. Lung function was assessed by spirometry, dyspnea with the Modified Medical Research Council questionnaire, functional balance with the Timed Up and Go test, muscle strength with 10-repetition maximum testing, exercise tolerance with the 6-min walk test, emotional state with the Depression Anxiety Stress Scales, and HRQOL with the St George Respiratory Questionnaire (SGRQ). RESULTS: Significant effects were observed on participants' dyspnea (P = .003, effect size [ES] = 0.7), functional balance (P < .001, ES = 0.8), shoulder flexor/knee extensor strength (P < .001, ES = 1.2-1.3), and exercise tolerance (P < .001, ES = 0.5). With the exception of the SGRQ impact score, the symptom (P < .001, ES = 0.6), activity (P = .02, ES = 0.4), and total (P = .005, ES = 0.3) scores improved significantly after PR. The PR program had no significant effect on participants' lung function and emotional state. CONCLUSIONS: Patients with mild COPD benefit from PR and could therefore be routinely included in these programs. Studies with more robust designs and with long-term follow-ups are needed to inform guidelines for PR in mild COPD. PMID- 24803498 TI - MYB82 functions in regulation of trichome development in Arabidopsis. AB - Trichome initiation and patterning are controlled by the TTG1-bHLH-MYB regulatory complex. Several MYB transcription factors have been determined to function in trichome development via incorporation into this complex. This study examined the role of MYB82, an R2R3-MYB transcription factor, in Arabidopsis trichome development. MYB82 was revealed to be a nuclear-localized transcription activator. Suppression of MYB82 function by fusion with a dominant repression domain (SRDX) resulted in glabrous leaves, as did overexpression of N-terminal truncated MYB82. Overexpression of MYB82 genomic sequence, but not its cDNA sequence, led to reduced trichome numbers. Further investigation indicated that at least one of the two introns in MYB82 is essential to the protein's trichome developmental function. An MYB-binding box was identified in the third exon of MYB82, which was inferred to be crucial for MYB82 function because the mutation of this box interfered with the ability of MYB82 to rescue the gl1 mutant. Protein interaction analysis revealed that MYB82 physically interacts with GLABRA3 (GL3). In addition, MYB82 and GL1 can form homodimers and heterodimers at R2R3-MYB domains, which may explain why their overexpression reduces trichome numbers. These results demonstrate the functional diversification of MYB82 and GL1 in trichome development. PMID- 24803499 TI - Fusion, rupture, and degeneration: the fate of in vivo-labelled PSVs in developing barley endosperm. AB - Cereal endosperm is a highly differentiated tissue containing specialized organelles for the accumulation of storage proteins. The endosperm of barley contains hordeins, which are ultimately deposited within protein storage vacuoles (PSVs). These organelles have been characterized predominantly by the histochemical analysis of fixed immature tissue samples. However, little is known about the fate of PSVs during barley endosperm development, and in vivo imaging has not been attempted in order to gain further insight. In this report, young seeds were followed through development to characterize the dynamic morphology of PSVs from aleurone, subaleurone, and central starchy endosperm cells. TIP3-GFP was used as a PSV membrane marker and several fluorescent tracers were used to identify membranes and monitor endomembrane organelles in real time. Whereas the spherical appearance of strongly labelled TIP3-GFP PSVs in the aleurone remained constant, those in the subaleurone and central starchy endosperm underwent substantial morphological changes. Fusion and rupture events were observed in the subaleurone, and internal membranes derived from both the tonoplast and endoplasmic reticulum were identified within these PSVs. TIP3-GFP-labelled PSVs in the starchy endosperm cells underwent a dramatic reduction in size, so that finally the protein bodies were tightly enclosed. Potential desiccation-related membrane-altering processes that may be causally linked to these dynamic endomembrane events in the barley endosperm are discussed. PMID- 24803500 TI - Light quality modulates metabolic synchronization over the diel phases of crassulacean acid metabolism. AB - Temporal compartmentation of carboxylation processes is a defining feature of crassulacean acid metabolism and involves circadian control of key metabolic and transport steps that regulate the supply and demand for carbon over a 24h cycle. Recent insights on the molecular workings of the circadian clock and its connection with environmental inputs raise new questions on the importance of light quality and, by analogy, certain photoreceptors for synchronizing the metabolic components of CAM. The present work tested the hypothesis that optimal coupling of stomatal conductance, net CO2 uptake, and the reciprocal turnover of carbohydrates and organic acids over the diel CAM cycle requires both blue and red light input signals. Contrasting monochromatic wavelengths of blue, green, and red light (i.e. 475, 530, 630nm) with low fluence rates (10 MUmol m(-2) s( 1)) were administered for 16 hours each diel cycle for a total treatment time of 48 hours to the obligate CAM bromeliad, Aechmea 'Maya'. Of the light treatments imposed, low-fluence blue light was a key determinant in regulating stomatal responses, organic acid mobilization from the vacuole, and daytime decarboxylation. However, the reciprocal relationship between starch and organic acid turnover that is typical for CAM was uncoupled under low-fluence blue light. Under low-fluence red or green light, the diel turnover of storage carbohydrates was orchestrated in line with the requirements of CAM, but a consistent delay in acid consumption at dawn compared with plants under white or low-fluence blue light was noted. Consistent with the acknowledged influences of both red and blue light as input signals for the circadian clock, the data stress the importance of both red and blue-light signalling pathways for synchronizing the metabolic and physiological components of CAM over the day/night cycle. PMID- 24803502 TI - From proto-Kranz to C4 Kranz: building the bridge to C4 photosynthesis. AB - In this review, we examine how the specialized "Kranz" anatomy of C4 photosynthesis evolved from C3 ancestors. Kranz anatomy refers to the wreath-like structural traits that compartmentalize the biochemistry of C4 photosynthesis and enables the concentration of CO2 around Rubisco. A simplified version of Kranz anatomy is also present in the species that utilize C2 photosynthesis, where a photorespiratory glycine shuttle concentrates CO2 into an inner bundle-sheath like compartment surrounding the vascular tissue. C2 Kranz is considered to be an intermediate stage in the evolutionary development of C4 Kranz, based on the intermediate branching position of C2 species in 14 evolutionary lineages of C4 photosynthesis. In the best-supported model of C4 evolution, Kranz anatomy in C2 species evolved from C3 ancestors with enlarged bundle sheath cells and high vein density. Four independent lineages have been identified where C3 sister species of C2 plants exhibit an increase in organelle numbers in the bundle sheath and enlarged bundle sheath cells. Notably, in all of these species, there is a pronounced shift of mitochondria to the inner bundle sheath wall, forming an incipient version of the C2 type of Kranz anatomy. This incipient version of C2 Kranz anatomy is termed proto-Kranz, and is proposed to scavenge photorespiratory CO2. By doing so, it may provide fitness benefits in hot environments, and thus represent a critical first stage of the evolution of both the C2 and C4 forms of Kranz anatomy. PMID- 24803501 TI - Stress-responsive hydroxycinnamate glycosyltransferase modulates phenylpropanoid metabolism in Populus. AB - The diversity of phenylpropanoids offers a rich inventory of bioactive chemicals that can be exploited for plant improvement and human health. Recent evidence suggests that glycosylation may play a role in the partitioning of phenylpropanoid precursors for a variety of downstream uses. This work reports the functional characterization of a stress-responsive glycosyltransferase, GT1 316 in Populus. GT1-316 belongs to the UGT84A subfamily of plant glycosyltransferase family 1 and is designated UGT84A17. Recombinant protein analysis showed that UGT84A17 is a hydroxycinnamate glycosyltransferase and able to accept a range of unsubstituted and substituted cinnamic and benzoic acids as substrates in vitro. Overexpression of GT1-316 in transgenic Populus led to plant wide increases of hydroxycinnamoyl-glucose esters, which were further elevated under N-limiting conditions. Levels of the two most abundant flavonoid glycosides, rutin and kaempferol-3-O-rutinoside, decreased, while levels of other less abundant flavonoid and phenylpropanoid conjugates increased in leaves of the GT1-316-overexpressing plants. Transcript levels of representative phenylpropanoid pathway genes were unchanged in transgenic plants, supporting a glycosylation-mediated redirection of phenylpropanoid carbon flow as opposed to enhanced phenylpropanoid pathway flux. The metabolic response of N-replete transgenic plants overlapped with that of N-stressed wild types, as the majority of phenylpropanoid derivatives significantly affected by GT1-316 overexpression were also significantly changed by N stress in the wild types. These results suggest that UGT84A17 plays an important role in phenylpropanoid metabolism by modulating biosynthesis of hydroxycinnamoyl-glucose esters and their derivatives in response to developmental and environmental cues. PMID- 24803503 TI - Nitrosative stress triggers microtubule reorganization in Arabidopsis thaliana. AB - Microtubules (MTs) are essential components of the cytoskeleton and fulfil multiple cellular functions in developmental processes, readily responding to intrinsic and external cues. Nitric oxide signalling is well established in plants, and the MT cytoskeleton is one of its potential targets. To mimic low level nitrosative stress, growth medium was supplemented with 3-nitro-L-tyrosine (NO2-Tyr), a nitrated form of the amino acid tyrosine, and concentration dependent changes in root growth rate and a reduction in cell division frequencies in Arabidopsis thaliana were observed. In addition, it is reported that exposure to low NO2-Tyr concentrations was not detrimental to plant health and caused subtle and reversible defects. In contrast, growth defects caused by high NO2-Tyr concentrations could not be reversed. Live cell imaging of an MT reporter line revealed that treatment with a low concentration of NO2-Tyr correlated with disorganized cortical MT arrays and associated non-polar cell expansion in the elongation zone. NO2-Tyr treatment antagonized the effects of taxol and oryzalin, further supporting the association of NO2-Tyr with MTs. Furthermore, oblique division plane orientations were observed which were probably induced prior to cytokinesis. PMID- 24803504 TI - Salt stress and senescence: identification of cross-talk regulatory components. AB - Leaf senescence is an active process with a pivotal impact on plant productivity. It results from extensive signalling cross-talk coordinating environmental factors with intrinsic age-related mechanisms. Although many studies have shown that leaf senescence is affected by a range of external parameters, knowledge about the regulatory systems that govern the interplay between developmental programmes and environmental stress is still vague. Salinity is one of the most important environmental stresses that promote leaf senescence and thus affect crop yield. Improving salt tolerance by avoiding or delaying senescence under stress will therefore play an important role in maintaining high agricultural productivity. Experimental evidence suggests that hydrogen peroxide (H2O2) functions as a common signalling molecule in both developmental and salt-induced leaf senescence. In this study, microarray-based gene expression profiling on Arabidopsis thaliana plants subjected to long-term salinity stress to induce leaf senescence was performed, together with co-expression network analysis for H2O2 responsive genes that are mutually up-regulated by salt induced- and developmental leaf senescence. Promoter analysis of tightly co-expressed genes led to the identification of seven cis-regulatory motifs, three of which were known previously, namely CACGTGT and AAGTCAA, which are associated with reactive oxygen species (ROS)-responsive genes, and CCGCGT, described as a stress responsive regulatory motif, while the others, namely ACGCGGT, AGCMGNC, GMCACGT, and TCSTYGACG were not characterized previously. These motifs are proposed to be novel elements involved in the H2O2-mediated control of gene expression during salinity stress-triggered and developmental senescence, acting through upstream transcription factors that bind to these sites. PMID- 24803505 TI - Plastid casein kinase 2 knockout reduces abscisic acid (ABA) sensitivity, thermotolerance, and expression of ABA- and heat-stress-responsive nuclear genes. AB - Plastid casein kinase 2 (CK2) is a major Ser/Thr-specific enzyme for protein phosphorylation in the chloroplast stroma and its kinase activity is regulated by redox signals. To understand the role of CK2 phosphorylation of chloroplast proteins in abiotic stress signalling, an Arabidopsis plastid CK2 (CKA4) knockout mutant was investigated in terms of the plant response to abscisic acid (ABA) and heat stress. CKA4 expression was upregulated by ABA and heat treatment. The cka4 mutant showed reduced sensitivity to ABA during seed germination and seedling growth, and increased stomatal aperture and leaf water loss with a slightly reduced leaf ABA level. The cka4 mutant was more sensitive to heat stress than the wild-type Columbia-0. The expression levels of a number of genes in the ABA regulatory network were reduced in the cka4 mutant. Many heat-upregulated genes (heat-shock factors and heat-shock proteins) were also reduced in the cka4 mutant. The cka4 mutant showed reduced expression levels of plastid-encoded RNA polymerase target genes (atpB and psbA). CKA4 knockout mutation also resulted in a reduction in expression of some critical genes (PTM, ABI4, and PRS1) involved in retrograde signalling from the chloroplast to the nucleus. Similar results were observed in mutant plants with the knockout mutation in both CKA4 and CKA3, which encodes a nuclear CK2 alpha3 subunit. CKA3 expression was not responsive to ABA and heat stress. These results suggest that CKA4 is an enhancing factor in abiotic stress signalling through modulating the expression of some molecular players in retrograde signalling. PMID- 24803506 TI - Modeling the effect of cigarette smoke on hexose utilization in spermatocytes. AB - We set out to determine whether the addition of an aryl hydrocarbon receptor (AHR) antagonist has an effect on glucose/fructose utilization in the spermatocyte when exposed to cigarette smoke condensate (CSC). We exposed male germ cells to 5 and 40 MUg/mL of CSC +/- 10 MUmol/L of AHR antagonist at various time points. Immunoblot expression of specific glucose/fructose transporters was compared to control. Radiolabeled uptake of 2-deoxyglucose (2-DG) and fructose was also performed. Spermatocytes utilized fructose nearly 50-fold more than 2 DG. Uptake of 2-DG decreased after CSC + AHR antagonist exposure. Glucose transporters (GLUTs) 9a and 12 declined after CSC + AHR antagonist exposure. Synergy between CSC and the AHR antagonist in spermatocytes may disrupt the metabolic profile in vitro. Toxic exposures alter energy homeostasis in early stages of male germ cell development, which could contribute to later effects explaining decreases in sperm motility in smokers. PMID- 24803507 TI - Early life triclocarban exposure during lactation affects neonate rat survival. AB - Triclocarban (3,4,4'-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure. PMID- 24803508 TI - Altered methylation and expression patterns of genes regulating placental angiogenesis in preterm pregnancy. AB - INTRODUCTION: Altered angiogenesis has been implicated in the pathogenesis of various pregnancy complications, particularly preeclampsia. At present, there is a lack of data on the possible role of angiogenesis and its molecular mechanism in preterm pregnancy. We have previously reported reduced placental global DNA methylation levels in preterm pregnancy. Now, we have extended the study to examine plasma levels of angiogenic factors from maternal and cord blood and correlate them with placental promoter CpG methylation and messenger RNA expression of these angiogenic genes in preterm pregnancies. METHODS: We recruited 99 women delivering at term and 90 women delivering preterm. Plasma levels of angiogenic factors, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), fms-related tyrosine kinase 1 (FLT-1), and kinase insert domain receptor (KDR) were analyzed by enzyme-linked immunosorbent assay. Expression levels and promoter CpG methylation of angiogenic genes in placentae were determined by quantitative real-time polymerase chain reaction and by the Sequenom EpiTYPER technology, respectively. RESULTS: Maternal VEGF and PlGF levels (P < .01 for both) were lower but soluble FLT-1 (sFLT-1) levels and sFLT-1 PlGF ratio (P < .05 for both) were higher in the preterm group. Placental VEGF expression (P < .05) was lower, and CpG site 14 in the VEGF promoter was hypermethylated (P < .05) in the preterm group. The KDR expression (P < .05) was higher in women delivering preterm. CONCLUSIONS: Our study provides first evidence of differential placental CpG methylation patterns and expression of VEGF, FLT-1, and KDR genes in women delivering preterm. This may explain the possible mechanism for angiogenic imbalance in the pathophysiology of preterm pregnancy. PMID- 24803510 TI - Receiver operating characteristic curve estimation for time to event with semicompeting risks and interval censoring. AB - Semicompeting risks and interval censoring are frequent in medical studies, for instance when a disease may be diagnosed only at times of visit and disease onset is in competition with death. To evaluate the ability of markers to predict disease onset in this context, estimators of discrimination measures must account for these two issues. In recent years, methods for estimating the time-dependent receiver operating characteristic curve and the associated area under the ROC curve have been extended to account for right censored data and competing risks. In this paper, we show how an approximation allows to use the inverse probability of censoring weighting estimator for semicompeting events with interval censored data. Then, using an illness-death model, we propose two model-based estimators allowing to rigorously handle these issues. The first estimator is fully model based whereas the second one only uses the model to impute missing observations due to censoring. A simulation study shows that the bias for inverse probability of censoring weighting remains modest and may be less than the one of the two parametric estimators when the model is misspecified. We finally recommend the nonparametric inverse probability of censoring weighting estimator as main analysis and the imputation estimator based on the illness-death model as sensitivity analysis. PMID- 24803509 TI - RAID: a comprehensive resource for human RNA-associated (RNA-RNA/RNA-protein) interaction. AB - Transcriptomic analyses have revealed an unexpected complexity in the eukaryote transcriptome, which includes not only protein-coding transcripts but also an expanding catalog of noncoding RNAs (ncRNAs). Diverse coding and noncoding RNAs (ncRNAs) perform functions through interaction with each other in various cellular processes. In this project, we have developed RAID (http://www.rna society.org/raid), an RNA-associated (RNA-RNA/RNA-protein) interaction database. RAID intends to provide the scientific community with all-in-one resources for efficient browsing and extraction of the RNA-associated interactions in human. This version of RAID contains more than 6100 RNA-associated interactions obtained by manually reviewing more than 2100 published papers, including 4493 RNA-RNA interactions and 1619 RNA-protein interactions. Each entry contains detailed information on an RNA-associated interaction, including RAID ID, RNA/protein symbol, RNA/protein categories, validated method, expressing tissue, literature references (Pubmed IDs), and detailed functional description. Users can query, browse, analyze, and manipulate RNA-associated (RNA-RNA/RNA-protein) interaction. RAID provides a comprehensive resource of human RNA-associated (RNA-RNA/RNA protein) interaction network. Furthermore, this resource will help in uncovering the generic organizing principles of cellular function network. PMID- 24803511 TI - Comparison of models for analyzing two-group, cross-sectional data with a Gaussian outcome subject to a detection limit. AB - A potential difficulty in the analysis of biomarker data occurs when data are subject to a detection limit. This detection limit is often defined as the point at which the true values cannot be measured reliably. Multiple, regression-type models designed to analyze such data exist. Studies have compared the bias among such models, but few have compared their statistical power. This simulation study provides a comparison of approaches for analyzing two-group, cross-sectional data with a Gaussian-distributed outcome by exploring statistical power and effect size confidence interval coverage of four models able to be implemented in standard software. We found using a Tobit model fit by maximum likelihood provides the best power and coverage. An example using human immunodeficiency virus type 1 ribonucleic acid data is used to illustrate the inferential differences in these models. PMID- 24803512 TI - Radon water to air transfer measured in a bathroom in an energy-efficient home with a private well. AB - Monthly measurements of radon in kitchen and bath tap water along with indoor air concentrations were made from 1994 to 1996 in an energy-efficient home with a private well. The well supplies all water to the home. The radon in cold and hot kitchen water averaged 69+/-2 and 52+/-2 Bq l(-1), respectively. Radon in cold and hot water from the bath/shower room shower head averaged 60+/-1 and 38+/-2 Bq l(-1), respectively, whereas hot water collected in the shower at the tub base averaged 5+/-1 Bq l(-1) or a 92% radon loss to air. While the calculated transfer factor of 1/10,000, i.e. radon concentration in air to radon in water, conventionally applies to the whole house, measurements for the specific water release during showering in a bathroom exhibit a larger transfer factor of 1/2300, due to smaller room volume. PMID- 24803513 TI - Development and validation of an ex vivo electron paramagnetic resonance fingernail biodosimetric method. AB - There is an imperative need to develop methods that can rapidly and accurately determine individual exposure to radiation for screening (triage) populations and guiding medical treatment in an emergency response to a large-scale radiological/nuclear event. To this end, a number of methods that rely on dose dependent chemical and/or physical alterations in biomaterials or biological responses are in various stages of development. One such method, ex vivo electron paramagnetic resonance (EPR) nail dosimetry using human nail clippings, is a physical biodosimetry technique that takes advantage of a stable radiation induced signal (RIS) in the keratin matrix of fingernails and toenails. This dosimetry method has the advantages of ubiquitous availability of the dosimetric material, easy and non-invasive sampling, and the potential for immediate and rapid dose assessment. The major challenge for ex vivo EPR nail dosimetry is the overlap of mechanically induced signals and the RIS. The difficulties of analysing the mixed EPR spectra of a clipped irradiated nail were addressed in the work described here. The following key factors lead to successful spectral analysis and dose assessment in ex vivo EPR nail dosimetry: (1) obtaining a thorough understanding of the chemical nature, the decay behaviour, and the microwave power dependence of the EPR signals, as well as the influence of variation in temperature, humidity, water content, and O2 level; (2) control of the variability among individual samples to achieve consistent shape and kinetics of the EPR spectra; (3) use of correlations between the multiple spectral components; and (4) use of optimised modelling and fitting of the EPR spectra to improve the accuracy and precision of the dose estimates derived from the nail spectra. In the work described here, two large clipped nail datasets were used to test the procedures and the spectral fitting model of the results obtained with it. A 15-donor nail set with 90 nail samples from 15 donors was used to validate the sample handling and spectral analysis methods that have been developed but without the interference of a native background signal. Good consistency has been obtained between the actual RIS and the estimated RIS computed from spectral analysis. In addition to the success in RIS estimation, a linear dose response has also been achieved for all individuals in this study, where the radiation dose ranges from 0 to 6 Gy. A second 16-donor nail set with 96 nail samples was used to test the spectral fitting model where the background signal was included during the fitting of the clipped nail spectra data. Although the dose response for the estimated and actual RIS calculated in both donor nail sets was similar, there was an increased variability in the RIS values that was likely due to the variability in the background signal between donors. Although the current methods of sample handling and spectral analysis show good potential for estimating the RIS in the EPR spectra of nail clippings, there is a remaining degree of variability in the RIS estimate that needs to be addressed; this should be achieved by identifying and accounting for demographic sources of variability in the background nail signal and the composition of the nail matrix. PMID- 24803514 TI - Measuring the activity of inhaled 222Rn using a lung counting system. AB - A new method of directly measuring (222)Rn progeny in a worker's lung using a lung counting system is introduced. To determine the efficiency of the lung counting system, a torso phantom manufactured by the China Institute for Radiation Protection was used, where activated carbon that had been loaded in a radon chamber with a defined quantity of radon represented the lungs, which were usually made of urethane foam. The minimum detectable activity (MDA) of (214)Bi, one of the (222)Rn progenies, was estimated to be 7.3 Bq for a measurement time of 4000 s. Based on the time (222)Rn progenies stay in the lung, it may be concluded that the lung counting system described can be well used for directly measuring the activity of (214)Bi in the lung short time after a worker inhaled (222)Rn at his/her workplace. PMID- 24803515 TI - Differences in lactococcal cell wall polysaccharide structure are major determining factors in bacteriophage sensitivity. AB - ABSTRACT Analysis of the genetic locus encompassing a cell wall polysaccharide (CWPS) biosynthesis operon of eight strains of Lactococcus lactis, identified as belonging to the same CWPS type C genotype, revealed the presence of a variable region among the strains examined. The results allowed the identification of five subgroups of the C type named subtypes C1 to C5. This variable region contains genes encoding glycosyltransferases that display low or no sequence homology between the subgroups. In this study, we purified an acidic polysaccharide from the cell wall of L. lactis 3107 (subtype C2) and confirmed that it is structurally different from the previously established CWPS of subtype C1 L. lactis MG1363. The CWPS of L. lactis 3107 is composed of pentasaccharide repeating units linked by phosphodiester bonds with the structure 6-alpha-Glc-3 beta-Galf-3-beta-GlcNAc-2-beta-Galf-6-alpha-GlcNAc-1-P. Combinations of genes from the variable region of subtype C2 were introduced into a mutant of subtype C1 L. lactis NZ9000 deficient in CWPS biosynthesis. The resulting recombinant mutant synthesized a polysaccharide with a composition characteristic of that of subtype C2 L. lactis 3107 and not wild-type C1 L. lactis NZ9000. By challenging the recombinant mutant with various lactococcal phages, we demonstrated that CWPS is the host cell surface receptor of tested bacteriophages of both the P335 and 936 groups and that differences between the CWPS structures play a crucial role in determining phage host range. IMPORTANCE Despite the efforts of nearly 80 years of lactococcal phage research, the precise nature of the cell surface receptors of the P335 and 936 phage group receptors has remained elusive. This work demonstrates the molecular nature of a P335 group receptor while bolstering the evidence of its role in host recognition by phages of the 936 group and at least partially explains why such phages have a very narrow host range. The information generated will be instrumental in understanding the molecular mechanisms of how phages recognize specific saccharidic receptors located on the surface of their bacterial host. PMID- 24803516 TI - Within-host evolution of Pseudomonas aeruginosa reveals adaptation toward iron acquisition from hemoglobin. AB - ABSTRACT Pseudomonas aeruginosa airway infections are a major cause of mortality and morbidity of cystic fibrosis (CF) patients. In order to persist, P. aeruginosa depends on acquiring iron from its host, and multiple different iron acquisition systems may be active during infection. This includes the pyoverdine siderophore and the Pseudomonas heme utilization (phu) system. While the regulation and mechanisms of several iron-scavenging systems are well described, it is not clear whether such systems are targets for selection during adaptation of P. aeruginosa to the host environment. Here we investigated the within-host evolution of the transmissible P. aeruginosa DK2 lineage. We found positive selection for promoter mutations leading to increased expression of the phu system. By mimicking conditions of the CF airways in vitro, we experimentally demonstrate that increased expression of phuR confers a growth advantage in the presence of hemoglobin, thus suggesting that P. aeruginosa evolves toward iron acquisition from hemoglobin. To rule out that this adaptive trait is specific to the DK2 lineage, we inspected the genomes of additional P. aeruginosa lineages isolated from CF airways and found similar adaptive evolution in two distinct lineages (DK1 and PA clone C). Furthermore, in all three lineages, phuR promoter mutations coincided with the loss of pyoverdine production, suggesting that within-host adaptation toward heme utilization is triggered by the loss of pyoverdine production. Targeting heme utilization might therefore be a promising strategy for the treatment of P. aeruginosa infections in CF patients. IMPORTANCE Most bacterial pathogens depend on scavenging iron within their hosts, which makes the battle for iron between pathogens and hosts a hallmark of infection. Accordingly, the ability of the opportunistic pathogen Pseudomonas aeruginosa to cause chronic infections in cystic fibrosis (CF) patients also depends on iron scavenging systems. While the regulation and mechanisms of several such iron scavenging systems have been well described, not much is known about how the within-host selection pressures act on the pathogens' ability to acquire iron. Here, we investigated the within-host evolution of P. aeruginosa, and we found evidence that P. aeruginosa during long-term infections evolves toward iron acquisition from hemoglobin. This adaptive strategy might be due to a selective loss of other iron-scavenging mechanisms and/or an increase in the availability of hemoglobin at the site of infection. This information is relevant to the design of novel CF therapeutics and the development of models of chronic CF infections. PMID- 24803517 TI - Microbiome data distinguish patients with Clostridium difficile infection and non C. difficile-associated diarrhea from healthy controls. AB - Antibiotic usage is the most commonly cited risk factor for hospital-acquired Clostridium difficile infections (CDI). The increased risk is due to disruption of the indigenous microbiome and a subsequent decrease in colonization resistance by the perturbed bacterial community; however, the specific changes in the microbiome that lead to increased risk are poorly understood. We developed statistical models that incorporated microbiome data with clinical and demographic data to better understand why individuals develop CDI. The 16S rRNA genes were sequenced from the feces of 338 individuals, including cases, diarrheal controls, and nondiarrheal controls. We modeled CDI and diarrheal status using multiple clinical variables, including age, antibiotic use, antacid use, and other known risk factors using logit regression. This base model was compared to models that incorporated microbiome data, using diversity metrics, community types, or specific bacterial populations, to identify characteristics of the microbiome associated with CDI susceptibility or resistance. The addition of microbiome data significantly improved our ability to distinguish CDI status when comparing cases or diarrheal controls to nondiarrheal controls. However, only when we assigned samples to community types was it possible to differentiate cases from diarrheal controls. Several bacterial species within the Ruminococcaceae, Lachnospiraceae, Bacteroides, and Porphyromonadaceae were largely absent in cases and highly associated with nondiarrheal controls. The improved discriminatory ability of our microbiome-based models confirms the theory that factors affecting the microbiome influence CDI. IMPORTANCE The gut microbiome, composed of the trillions of bacteria residing in the gastrointestinal tract, is responsible for a number of critical functions within the host. These include digestion, immune system stimulation, and colonization resistance. The microbiome's role in colonization resistance, which is the ability to prevent and limit pathogen colonization and growth, is key for protection against Clostridium difficile infections. However, the bacteria that are important for colonization resistance have not yet been elucidated. Using statistical modeling techniques and different representations of the microbiome, we demonstrated that several community types and the loss of several bacterial populations, including Bacteroides, Lachnospiraceae, and Ruminococcaceae, are associated with CDI. Our results emphasize the importance of considering the microbiome in mediating colonization resistance and may also direct the design of future multispecies probiotic therapies. PMID- 24803518 TI - Enzymatic synthesis of bioinformatically predicted microcin C-like compounds encoded by diverse bacteria. AB - ABSTRACT The Trojan horse Escherichia coli antibiotic microcin C (McC) consists of a heptapeptide attached to adenosine through a phosphoramidate linkage. McC is synthesized by the MccB enzyme, which terminally adenylates the ribosomally synthesized heptapeptide precursor MccA. The peptide part is responsible for McC uptake; it is degraded inside the cell to release a toxic nonhydrolyzable aspartyl-adenylate. Bionformatic analysis reveals that diverse bacterial genomes encoding mccB homologues also contain adjacent short open reading frames that may encode MccA-like adenylation substrates. Using chemically synthesized predicted peptide substrates and recombinant cognate MccB protein homologs, adenylated products were obtained in vitro for predicted MccA peptide-MccB enzyme pairs from Helicobacter pylori, Streptococcus thermophilus, Lactococcus johnsonii, Bartonella washoensis, Yersinia pseudotuberculosis, and Synechococcus sp. Some adenylated products were shown to inhibit the growth of E. coli by targeting aspartyl-tRNA synthetase, the target of McC. IMPORTANCE Our results prove that McC-like adenylated peptides are widespread and are encoded by both Gram-negative and Gram-positive bacteria and by cyanobacteria, opening ways for analyses of physiological functions of these compounds and for creation of microcin C-like antibiotics targeting various bacteria. PMID- 24803519 TI - Chromosome segregation proteins of Vibrio cholerae as transcription regulators. AB - ABSTRACT Bacterial ParA and ParB proteins are best known for their contribution to plasmid and chromosome segregation, but they may also contribute to other cell functions. In segregation, ParA interacts with ParB, which binds to parS centromere-analogous sites. In transcription, plasmid Par proteins can serve as repressors by specifically binding to their own promoters and, additionally, in the case of ParB, by spreading from a parS site to nearby promoters. Here, we have asked whether chromosomal Par proteins can likewise control transcription. Analysis of genome-wide ParB1 binding in Vibrio cholerae revealed preferential binding to the three known parS1 sites and limited spreading of ParB1 beyond the parS1 sites. Comparison of wild-type transcriptomes with those of DeltaparA1, DeltaparB1, and DeltaparAB1 mutants revealed that two out of 20 genes (VC0067 and VC0069) covered by ParB1 spreading are repressed by both ParB1 and ParA1. A third gene (VC0076) at the outskirts of the spreading area and a few genes further away were also repressed, particularly the gene for an outer membrane protein, ompU (VC0633). Since ParA1 or ParB1 binding was not evident near VC0076 and ompU genes, the repression may require participation of additional factors. Indeed, both ParA1 and ParB1 proteins were found to interact with several V. cholerae proteins in bacterial and yeast two-hybrid screens. These studies demonstrate that chromosomal Par proteins can repress genes unlinked to parS and can do so without direct binding to the cognate promoter DNA. IMPORTANCE Directed segregation of chromosomes is essential for their maintenance in dividing cells. Many bacteria have genes (par) that were thought to be dedicated to segregation based on analogy to their roles in plasmid maintenance. It is becoming clear that chromosomal par genes are pleiotropic and that they contribute to diverse processes such as DNA replication, cell division, cell growth, and motility. One way to explain the pleiotropy is to suggest that Par proteins serve as or control other transcription factors. We tested this model by determining how Par proteins affect genome-wide transcription activity. We found that genes implicated in drug resistance, stress response, and pathogenesis were repressed by Par. Unexpectedly, the repression did not involve direct Par binding to cognate promoter DNA, indicating that the repression may involve Par interactions with other regulators. This pleiotropy highlights the degree of integration of chromosomal Par proteins into cellular control circuitries. PMID- 24803520 TI - Mycobacterial Esx-3 requires multiple components for iron acquisition. AB - ABSTRACT The type VII secretion systems are conserved across mycobacterial species and in many Gram-positive bacteria. While the well-characterized Esx-1 pathway is required for the virulence of pathogenic mycobacteria and conjugation in the model organism Mycobacterium smegmatis, Esx-3 contributes to mycobactin mediated iron acquisition in these bacteria. Here we show that several Esx-3 components are individually required for function under low-iron conditions but that at least one, the membrane-bound protease MycP3 of M. smegmatis, is partially expendable. All of the esx-3 mutants tested, including the DeltamycP3ms mutant, failed to export the native Esx-3 substrates EsxHms and EsxGms to quantifiable levels, as determined by targeted mass spectrometry. Although we were able to restore low-iron growth to the esx-3 mutants by genetic complementation, we found a wide range of complementation levels for protein export. Indeed, minute quantities of extracellular EsxHms and EsxGms were sufficient for iron acquisition under our experimental conditions. The apparent separation of Esx-3 function in iron acquisition from robust EsxGms and EsxHms secretion in the DeltamycP3ms mutant and in some of the complemented esx-3 mutants compels reexamination of the structure-function relationships for type VII secretion systems. IMPORTANCE Mycobacteria have several paralogous type VII secretion systems, Esx-1 through Esx-5. Whereas Esx-1 is required for pathogenic mycobacteria to grow within an infected host, Esx-3 is essential for growth in vitro. We and others have shown that Esx-3 is required for siderophore-mediated iron acquisition. In this work, we identify individual Esx-3 components that contribute to this process. As in the Esx-1 system, most mutations that abolish Esx-3 protein export also disrupt its function. Unexpectedly, however, ultrasensitive quantitation of Esx-3 secretion by multiple-reaction-monitoring mass spectrometry (MRM-MS) revealed that very low levels of export were sufficient for iron acquisition under similar conditions. Although protein export clearly contributes to type VII function, the relationship is not absolute. PMID- 24803521 TI - Detection of evolutionarily distinct avian influenza a viruses in antarctica. AB - ABSTRACT Distinct lineages of avian influenza viruses (AIVs) are harbored by spatially segregated birds, yet significant surveillance gaps exist around the globe. Virtually nothing is known from the Antarctic. Using virus culture, molecular analysis, full genome sequencing, and serology of samples from Adelie penguins in Antarctica, we confirmed infection by H11N2 subtype AIVs. Their genetic segments were distinct from all known contemporary influenza viruses, including South American AIVs, suggesting spatial separation from other lineages. Only in the matrix and polymerase acidic gene phylogenies did the Antarctic sequences form a sister relationship to South American AIVs, whereas distant phylogenetic relationships were evident in all other gene segments. Interestingly, their neuraminidase genes formed a distant relationship to all avian and human influenza lineages, and the polymerase basic 1 and polymerase acidic formed a sister relationship to the equine H3N8 influenza virus lineage that emerged during 1963 and whose avian origins were previously unknown. We also estimated that each gene segment had diverged for 49 to 80 years from its most closely related sequences, highlighting a significant gap in our AIV knowledge in the region. We also show that the receptor binding properties of the H11N2 viruses are predominantly avian and that they were unable to replicate efficiently in experimentally inoculated ferrets, suggesting their continuous evolution in avian hosts. These findings add substantially to our understanding of both the ecology and the intra- and intercontinental movement of Antarctic AIVs and highlight the potential risk of an incursion of highly pathogenic AIVs into this fragile environment. IMPORTANCE Avian influenza viruses (AIVs) are typically maintained and spread by migratory birds, resulting in the existence of distinctly different viruses around the world. However, AIVs have not previously been detected in Antarctica. In this study, we characterized H11N2 viruses sampled from Adelie penguins from two geographically different sites in Antarctica and show that the segmented AIV genome diverged between 49 and 80 years ago from other AIVs, with several genes showing similarity and shared ancestry with H3N8 equine influenza viruses. This study provides the first insight into the ecology of AIVs in Antarctica and highlights the potential risk of an introduction of highly pathogenic AIVs into the continent. PMID- 24803522 TI - Improving production of malonyl coenzyme A-derived metabolites by abolishing Snf1 dependent regulation of Acc1. AB - ABSTRACT Acetyl coenzyme A (acetyl-CoA) carboxylase (ACCase) plays a central role in carbon metabolism and has been the site of action for the development of therapeutics or herbicides, as its product, malonyl-CoA, is a precursor for production of fatty acids and other compounds. Control of Acc1 activity in the yeast Saccharomyces cerevisiae occurs mainly at two levels, i.e., regulation of transcription and repression by Snf1 protein kinase at the protein level. Here, we demonstrate a strategy for improving the activity of ACCase in S. cerevisiae by abolishing posttranslational regulation of Acc1 via site-directed mutagenesis. It was found that introduction of two site mutations in Acc1, Ser659 and Ser1157, resulted in an enhanced activity of Acc1 and increased total fatty acid content. As Snf1 regulation of Acc1 is particularly active under glucose-limited conditions, we evaluated the effect of the two site mutations in chemostat cultures. Finally, we showed that our modifications of Acc1 could enhance the supply of malonyl-CoA and therefore successfully increase the production of two industrially important products derived from malonyl-CoA, fatty acid ethyl esters and 3-hydroxypropionic acid. IMPORTANCE ACCase is responsible for carboxylation of acetyl-CoA to produce malonyl-CoA, which is a crucial step in the control of fatty acid metabolism. ACCase opened the door for pharmaceutical treatments of obesity and diabetes as well as the development of new herbicides. ACCase is also recognized as a promising target for developing cell factories, as its malonyl CoA product serves as a universal precursor for a variety of high-value compounds in white biotechnology. Yeast ACCase is a good model in understanding the enzyme's catalysis, regulation, and inhibition. The present study describes the importance of protein phosphorylation in regulation of yeast ACCase and identifies potential regulation sites. This study led to the generation of a more efficient ACCase, which was applied in the production of two high-value compounds derived from malonyl-CoA, i.e., fatty acid ethyl esters that can be used as biodiesel and 3-hydroxypropionic acid that is considered an important platform chemical. PMID- 24803523 TI - The effects of intraoperative esmolol administration on perioperative inflammatory responses in patients undergoing laparoscopic gastrectomy: a dose response study. AB - BACKGROUND: Surgical trauma elicits inflammatory responses, including the secretion of cytokines. Recent studies demonstrated that beta-blockers could reduce the expression of cytokines after injury. We therefore tested the effects of different doses of intraoperative esmolol on the inflammatory response after surgery. METHODS: Patients undergoing laparoscopic gastrectomy were randomly separated into 1 of 3 groups: saline, clinical dose, and subclinical dose groups. The levels of interleukin (IL)-6, IL-4, and IL-10 were quantified by sandwich enzyme-linked immunoassay after the induction of anesthesia (T0), at the end of peritoneal closure (T1), and 60 minutes after surgery (T2). Levels of C-reactive protein (CRP) were measured on postoperative day 1. RESULTS: At T2, the levels of IL-6 and IL-10 in the saline group were elevated significantly compared with at T0 or T1 (IL-6: 119.62 and 15.97 pg/mL at T2 and T0, respectively [P = .042]; IL 10: 27.27 and 7.03 pg/mL at T2 and T1, respectively [P = .037]). However, no changes were observed over time in the clinical dose group. In contrast, postoperative levels of IL-4 were decreased significantly in the clinical dose group compared with the saline group (2.14 vs 21.91 pg/mL, P = .022). In addition, the CRP levels on postoperative day 1 were lower in the esmolol-treated groups, in a dose-dependent manner. CONCLUSIONS: Serum IL-6 and IL-10 levels were increased over time, suggesting that laparoscopic surgery is a stressor, even though it causes minimal tissue injury. Treatment with esmolol decreased the inflammatory response and CRP production in a dose-dependent manner. PMID- 24803524 TI - A smart trocar for automatic tool recognition in laparoscopic surgery. AB - BACKGROUND: Operating rooms have become increasingly complex environments and more prone to errors because of loss of situation awareness. Adding computer intelligence to the operating room may help overcome these limitations particularly if the system can automatically track which step of an operation a surgeon is performing. To develop such a platform, it is necessary to track which laparoscopic instruments are being used and in which port they are inserted. This article describes the development and validation of a "Smart Trocar" that can automatically perform this function. METHODS: A Smart Trocar system prototype was developed that uses a wireless camera attached to a standard laparoscopic port and custom software algorithms. The system recognizes color wheels attached to the handle of a laparoscopic instrument and compares the unique color pattern to an instrument library for proper tool identification. The system was tested for reliability in a box trainer environment using a variety of tool positions and levels of room light illumination. RESULTS: Correct color classification was achieved in 96.7% of trials. There were no errors in detection of the color wheel in space. In addition, the distance of the color wheel from the camera did not influence results and correct classifications were evenly distributed among the 12 laparoscopic tool positions tested. CONCLUSION: This work describes a Smart Trocar system that identifies which laparoscopic tool is being used and in which port and proves its reliability. The system is an important element of a more comprehensive program being developed to automatically understand what step of an operation a surgeon is performing and use these data to improve situation awareness in the operating room. PMID- 24803526 TI - Creativity and schizophrenia. PMID- 24803525 TI - The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors. AB - The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization. Recent studies have demonstrated a transcriptional activation role for the TERT promoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications. Although telomerase activation is known in adrenal tumors, the underlying mechanisms are not established. We assessed C228T and C250T TERT mutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation. A total of 199 tumors were evaluated, including 34 adrenocortical carcinomas (ACC), 47 adrenocortical adenomas (ACA), 105 pheochromocytomas (PCC; ten malignant and 95 benign), and 13 abdominal paragangliomas (PGL; nine malignant and four benign). TERT expression levels were determined by quantitative RT-PCR. The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028). C228T was also observed in one benign PCC and in one metastatic PGL. The C250T mutation was not observed in any case. In the ACC and PGL groups, TERT mutation-positive cases exhibited TERT expression, indicating telomerase activation; however, since expression was also revealed in TERT WT cases, this could denote additional mechanisms of TERT activation. To conclude, the TERT promoter mutation C228T is a recurrent event associated with TERT expression in ACCs, but rarely occurs in PGL and PCC. The involvement of the TERT gene in ACC represents a novel mutated gene in this entity. PMID- 24803527 TI - Aquaporin 3 knockdown suppresses tumour growth and angiogenesis in experimental non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is one of the most common diseases encountered in medical oncology practice. The aim of the present study was to test the antitumour effects of short-hairpin RNA targeting aquaporin 3 (AQP3) in experimental NSCLC. Expression of AQP3 was suppressed in human A549 and H1299 NSCLC cell lines by short-hairpin RNA-mediated silencing. Therapeutic effects were assessed by examining tumorigenicity using a subcutaneous xenograft mouse model of NSCLC. Aquaporin 3 knockdown inhibited tumour growth and prolonged survival of mice with tumours. Aquaporin 3 knockdown suppressed tumour proliferation, marked by enhanced expression of p53, an increased ratio of cleaved caspase 3 to pro-caspase 3 and reduced expression of proliferating cell nuclear antigen and B-cell lymphoma-2 (bcl-2). Aquaporin 3 knockdown inhibited tumour angiogenesis, marked by decreased CD31 immunostaining and reduced expression of hypoxia-inducible factor-2alpha and vascular endothelial growth factor. Aquaporin 3 knockdown reduced cellular glycerol content and suppressed mitochondrial ATP formation. Aquaporin 3 knockdown in vitro significantly suppressed activities of matrix metalloproteinases MMP2 and MMP9, reduced AKT phosphorylation and decreased cell invasiveness of A549 and H1299 cells. In conclusion, AQP3 knockdown suppressed tumour growth and reduced angiogenesis in human NSCLS xenografts. Aquaporin 3 could thus be envisaged as a novel therapeutic target for NSCLC. PMID- 24803528 TI - Ethnic differences in microvascular function in apparently healthy South African men and women. AB - Microvascular dysfunction precedes the clinical manifestations of cardiovascular disease. Given the ethnic disparities in cardiovascular disease, we aimed to investigate ethnic differences in microvascular endothelial function in a group of young (18-33 years old), apparently healthy individuals (n = 33, nine Black African, 12 mixed ancestry and 12 Caucasian). Microvascular endothelium-dependent and -independent function was assessed by laser Doppler imagery and iontophoresis of ACh and sodium nitroprusside (SNP), respectively, adjusting for skin resistance. Microvascular reactivity was expressed as maximum absolute perfusion, percentage change from baseline and area under the curve (AUC). Skin resistance was significantly lower in the Caucasian group in response to ACh (Caucasian, mean 0.16 +/- 0.03 Omega versus Black, 0.21 +/- 0.04 Omega and mixed ancestry, 0.20 +/- 0.02 Omega, P < 0.01) and SNP (Caucasian, 0.08 +/- 0.01 Omega versus Black, 0.11 +/- 0.02 Omega and mixed ancestry, 0.12 +/- 0.01 Omega, P < 0.01). Microvascular function in response to ACh was significantly higher in the Caucasian group compared with the other two groups; however, after adjusting for skin resistance these differences were no longer significant. Conversely, the microvascular SNP response remained significantly higher in the Caucasian group, even after adjusting for skin resistance (P < 0.01). Diastolic blood pressure was inversely associated with the AUC of ACh (r = -0.4) and all SNP responses (r = 0.3 to -0.6). Skin resistance was inversely associated with AUC and maximum absolute ACh response (r = -0.59 and -0.64, respectively) and all SNP responses (r = -0.37 to -0.79). Ethnic differences in endothelium-independent microvascular function may contribute to ethnic disparities in cardiovascular disease. Moreover, skin resistance plays a significant role in the interpretation of the microvascular response to outcomes of iontophoresis in a multiethnic group. PMID- 24803529 TI - Lifestyles of Jamaican men with hypertension. AB - PURPOSE: Determine the extent to which the lifestyles of Jamaican men with hypertension met the guidelines of the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). DESIGN AND METHODS: Following informed consent, a convenience sample of Jamaican men with hypertension (n = 48), of African ethnicity, attending a Type 5 Health Center was interviewed over a four week period, using a 31-item interview schedule. RESULTS: Mean age of respondents was 65.2 (+/- 12.1) years (range = 35-89 years) with 33% having blood pressure (BP) controlled to 130/80 mmHg. Those meeting the guidelines were normal weight 23 (47.9%), DASH (dietary approaches to stop hypertension) diet zero, medication 7 (14.6%), exercise 14 (29.2%), alcohol restriction 38 (79.2%), and smoking cessation 40 (83.3%). Medication adherence was associated with BP control (r = -0.30, p < .04). More than half of the respondents believed that hypertension could be cured and that they could stop all treatment if their BP was normal. DISCUSSION AND CONCLUSIONS: Only a third of the sample had BP controlled to <=130/80 mmHg. Adherence to the JNC 7 lifestyle guidelines was inadequate. IMPLICATIONS FOR PRACTICE: A nurse led intervention, focusing on perceptions and lifestyle practices, is indicated. PMID- 24803530 TI - Cultural Preparation for Womanhood in Urban African American Girls: Growing Strong Women. AB - PURPOSE: Poor sexual health is a significant contributor to morbidity in young African American women. Knowing how sexual knowledge is transmitted to Black girls is needed to develop effective preventive interventions. The purpose of this study was to explore the ways in which Black mothers transmit sexual values and knowledge to their daughters. DESIGN: Interviews were conducted with 14 mothers, aged 25 to 34 years, with daughters aged 8 to 16 years. Data were analyzed using constant comparative analysis. FINDINGS: The themes derived were (a) truth telling, (b) building strength through self-esteem, and (c) spirituality as helper. The overarching cultural theme was "Growing Strong Black Women." DISCUSSION/CONCLUSIONS: Mothers' discussions with their daughters were infused with cultural meaning derived from their experiences. Black girls' behavioral responses to their mothers' strategies need to be studied. IMPLICATIONS: The findings will help nurses develop effective interventions that take into account the cultural realities of Black mothers. PMID- 24803531 TI - A Mixed Methods Study of Health Care Experience Among Asian Indians in the Southeastern United States. AB - PURPOSE: The study explored health care experiences among Asian Indian immigrants living in the Southeastern United States. DESIGN AND METHOD: A concurrent triangulation mixed methods design was used with a purposive sample of 125 Asian Indian immigrants aged between 40 and 64 years in the survey and 10 participants in the focus group. RESULTS: The majority of the participants had health insurance and higher socioeconomic status. They had a moderate level of knowledge on the U.S. health care system and health insurance while presenting moderate satisfaction with the system. Barriers to health care services and needs in the health care system were identified from both quantitative and qualitative data. Some of the barriers were high costs, dissatisfaction with services, and inconvenience in accessing services. Participants called for self-management and community-based health programs as well as culturally tailored health care services. DISCUSSION AND CONCLUSION: Findings congruent with prior studies further support the importance of comprehending Asian Indians' unique cultural background and experiences in the health care system. This study can be the foundation for culturally competent care to advance the body of transcultural nursing knowledge. IMPLICATIONS FOR PRACTICE: Culturally congruent community based health care programs are needed to provide better care for the ethnic minority to maintain and promote their health status. PMID- 24803532 TI - Urban American Indian Adolescent Girls: Framing Sexual Risk Behavior. AB - PURPOSE: The purpose of this study was to explore factors that influence urban adolescent American Indian (AI) girls' sexual risk behavior. DESIGN: A qualitative study was conducted with grounded theory methodology to reveal factors and processes that influence sexual risk behavior. METHOD: Talking circles, individual interviews, and event history calendars were used with 20 urban AI 15- to 19-year-old girls to explore influences on sexual risk behavior. RESULTS: The generated theory-framing sexual risk behavior-describes social and structural factors and processes that influenced the girls' sexual risk behavior. The theory extends Bronfenbrenner's ecological model by identifying microsystem, mesosystem, and macrosystem influences on sexual risk behavior. DISCUSSION: Urban AI girls reported similar social and structural influences on sexual risk behavior as urban adolescents from other racial and ethnic groups. However, differences were noted in the family structure, cultural heritage, and unique history of AIs. IMPLICATIONS: This theory can be used in culturally responsive practice with urban AI girls. PMID- 24803533 TI - Humanized staphylococcal enterotoxin B (SEB)-specific monoclonal antibodies protect from SEB intoxication and Staphylococcus aureus infections alone or as adjunctive therapy with vancomycin. AB - BACKGROUND: Staphylococcal enterotoxin B (SEB), a potential biological warfare agent, is a potent superantigen that contributes to the virulence of methicillin resistant Staphylococcus aureus (MRSA), which is a major health threat in the United States. Efforts to develop toxin-neutralizing antibodies as adjunctive therapies are justified, given the high mortality and frequent failure of therapy despite available antibiotics. METHODS: Murine SEB-specific mAb 20B1 was humanized, and treatment benefits of Hu-1.6/1.1 and Hu-1.4/1.1 variants were investigated in mice in an SEB intoxication model, as well as in sepsis and deep tissue infection models. RESULTS: Hu-1.6/1.1 and Hu-1.4/1.1 protected mice against SEB-induced lethal shock. Hu-1.6/1.1 also enhanced survival of mice that developed fatal sepsis after challenge with a SEB-producing MRSA strain. Combined treatment of Hu-1.6/1.1 with vancomycin further increased survival and altered cytokine responses, compared with monotherapy with either monoclonal antibody or vancomycin alone. Efficacy was also demonstrated in the deep-tissue infection model, where Hu-1.4/1.1 bound to SEB in vivo and decreased abscess formation, as well as proinflammatory cytokine levels. CONCLUSIONS: SEB-neutralizing mAb 20B1 was successfully humanized. The mAb affects outcome by modulating the proinflammatory host response in both the sepsis and the intoxication models, which justifies further development. PMID- 24803535 TI - Dimerization opens new avenues into Ras signaling research. AB - Several reports using recently developed physicochemical and imaging techniques have provided experimental evidence for the existence of dimers of Ras proteins, which was first postulated more than 25 years ago. These data have sparked renewed interest in the potential physiological and pathological importance of homo- or heterodimerization of Ras proteins. Understanding the structural and functional properties of Ras dimers should provide mechanistic explanations for unanswered questions regarding the involvement of Ras proteins in signaling pathways that contribute to both normal physiology and oncogenic processes. Furthermore, this knowledge should enable the development of new drugs targeting Ras proteins. PMID- 24803534 TI - Protection versus pathology in aviremic and high viral load HIV-2 infection-the pivotal role of immune activation and T-cell kinetics. AB - BACKGROUND: Many human immunodeficiency virus (HIV)-2-infected individuals remain aviremic and behave as long-term non-progressors but some progress to AIDS. We hypothesized that immune activation and T-cell turnover would be critical determinants of non-progressor/progressor status. METHODS: We studied 37 subjects in The Gambia, West Africa: 10 HIV-negative controls, 10 HIV-2-infected subjects with low viral loads (HIV-2-LV), 7 HIV-2-infected subjects with high viral loads (HIV-2-HV), and 10 with HIV-1 infection. We measured in vivo T-cell turnover using deuterium-glucose labeling, and correlated results with T-cell phenotype (by flow cytometry) and T-cell receptor excision circle (TREC) abundance. RESULTS: Immune activation (HLA-DR/CD38 coexpression) differed between groups with a significant trend: controls =21. In contrast, none of the factors associated with stage migration caused interinstitutional differences in the recurrence status according to the tumor stage. CONCLUSIONS: Considerable variety in the processing of surgical specimens existed even within one country, which could be a cause of stage migration in colon cancer. Better awareness of the clinical impact of the lymph node retrieval process is needed; an international guideline to standardize the treatment of surgical specimens might increase the value of tumor staging. PMID- 24803548 TI - In vitro chemoresponse assay based on the intrinsic subtypes in breast cancer. AB - OBJECTIVE: In vitro chemotherapy response assays are not widely accepted in making decisions regarding cytotoxic drugs. To evaluate the usefulness of chemotherapy response assays in breast cancer, we compared the chemotherapy response assay results according to subtypes. Human epidermal growth factor receptor-2 and Ki67 associated with chemosensitivity were also analyzed. METHODS: Four hundred and ninety-six patients were enrolled, and chemotherapy response assays based on adenosine triphosphate were performed in 500 tumors. Patients were classified as five subtypes: luminal A, luminal B/human epidermal growth factor receptor-2 negative, luminal B/human epidermal growth factor receptor-2 positive, human epidermal growth factor receptor-2 and triple negative. The cell death rate for various drugs was calculated. RESULTS: The mean cell death rate of the luminal A subtype was the lowest, and the mean cell death rates of the human epidermal growth factor receptor-2 and triple-negative subtypes were the highest for all tested drugs, except 5-fluorouracil and methotrexate. The cell death rate differed significantly among the subtypes in the types of drugs (doxorubicin, epirubicin, paclitaxel, docetaxel, gemcitabine, vinorelbine and cisplatin). In triple-negative tumors, the mean cell death rate of cisplatin was the highest among the tested drugs, and which was not observed in the other subtypes. Human epidermal growth factor receptor-2 positive tumors are associated with higher cell death rates for anthracyclines. High Ki67 expression (a cutoff of 14%) was associated with a high response in several tested drugs including epirubicin, paclitaxel, docetaxel, gemcitabine, vinorelbine and cisplatin. CONCLUSIONS: Our findings suggest that in vitro chemoresponse assays for breast tumors could effectively reflect the tumor response to chemotherapies observed in neoadjuvant settings. PMID- 24803549 TI - HER2 mutation status in Japanese HER2-negative breast cancer patients. AB - OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) gene amplification is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti human epidermal growth factor receptor 2 agents. Human epidermal growth factor receptor 2 somatic mutations have been reported in patients without human epidermal growth factor receptor 2 gene amplification. Since these are activating mutations, these patients may also benefit from human epidermal growth factor receptor 2-targeted drugs. METHODS: In this study, we searched for human epidermal growth factor receptor 2 mutations in a group of 286 Japanese breast cancer patients with human epidermal growth factor receptor 2-negative tumors. The activating mutations of human epidermal growth factor receptor 2 identified were analyzed by direct Sanger sequencing of two major areas: the extracellular domain at 309-310 and the kinase domain between 755 and 781. RESULTS: Two tumors were found to have a human epidermal growth factor receptor 2 somatic mutation; one with I767M mutation and another with D769Y. No mutation was observed in the extracellular domain. One of these patients with human epidermal growth factor receptor 2 mutation recurred early with liver metastasis. CONCLUSIONS: Better knowledge of human epidermal growth factor receptor 2 mutation status will help us to choose personalized molecular targeted therapy for use in human epidermal growth factor receptor 2-negative Japanese breast cancer patients. PMID- 24803550 TI - L-plastin is involved in NKG2D recruitment into lipid rafts and NKG2D-mediated NK cell migration. AB - Membrane rafts are microdomains of the plasma membrane that have multiple biological functions. The involvement of these structures in the biology of T cells, namely in signal transduction by the TCR, has been widely studied. However, the role of membrane rafts in immunoreceptor signaling in NK cells is less well known. We studied the distribution of the activating NKG2D receptor in lipid rafts by isolating DRMs in a sucrose density gradient or by raft fractionation by beta-OG-selective solubility in the NKL cell line. We found that the NKG2D-DAP10 complex and pVav are recruited into rafts upon receptor stimulation. Qualitative proteomic analysis of these fractions showed that the actin cytoskeleton is involved in this process. In particular, we found that the actin-bundling protein L-plastin plays an important role in the clustering of NKG2D into lipid rafts. Moreover, coengagement of the inhibitory receptor NKG2A partially disrupted NKG2D recruitment into rafts. Furthermore, we demonstrated that L-plastin participates in NKG2D-mediated inhibition of NK cell chemotaxis. PMID- 24803552 TI - Customized CT angiogram planning for intraoperative transesophageal echography guided endovascular exclusion of thoracic aorta penetrating ulcer. AB - The technique is demonstrated in a 78-year-old man; the preoperative CT angiogram showed a descending thoracic aorta ulcer of 5.9 cm in maximum diameter and 3.8 cm longitudinal extension. A ZTEG-2P-36-127-PF (Cook Medical) single tubular endograft was planned to be deployed. From the preoperative CT angiogram we planned to land 4.7 cm above the midline of the descending thoracic aorta ulcer and 8.0 cm below. In the operating room, under radioscopic vision the centre of the transesophageal echography probe was used as marker to identify the correspondent midline of the descending thoracic aorta ulcer and a centimeter sized pigtail catheter in the aorta was used to calculate the desired length above and below the ulcer midline. The endograft was introduced and placed in the desired position compared to the transesophageal echography probe and the catheter; under transesophageal echography vision the graft was finally deployed. The CT angiogram at 1 month showed the correct endograft position, descending thoracic aorta ulcer exclusion with no signs of endoleak. In selected cases, this method allows planning in advance safe stent graft positioning and deployment totally assisted by transesophageal echography, with no risk of periprocedural contrast-related renal failure and reduced radiation exposure for the patient and operators. PMID- 24803551 TI - Inhibitory effect of adenosine on intimal hyperplasia and proliferation of smooth muscle cells in a carotid arterial anastomosis animal model. AB - PURPOSE: The effect of adenosine (9-beta-0-ribifuranosyladenine) on the endothelial cell proliferation and neointimal hyperplasia is investigated in the rabbit carotid artery anastomosis model. METHODS: Twenty-eight New Zealand white rabbits were arranged in four groups of seven animals each. The right carotid arteries of each animal were transsected and re-anastomosed. The left sides remained as control. In Group A, no medication was used. In Group B, subcutaneous Adenosine was applied for 3 days. In Group C, the same dose was applied for 7 days, and in Group D for 21 days. After 28 days, the luminal diameters, luminal areas, intima/media ratios were all measured by using histopathological evaluation. FINDINGS: The mean luminal diameters and areas of the four groups were smaller than the control ones. Massive thickening of smooth muscle cell proliferation and dense intensifying in the connecting tissues were observed most prominently in Group A, in decreasing degrees within other groups. Intima/media ratio was highest in Group A. Scoring the quantity of e-NOS positive staining also revealed a significant difference between the experimental groups and their control associates. CONCLUSION: The process of endothelial cell proliferation and neointimal hyperplasia can be significantly reduced by the use of adenosine. PMID- 24803553 TI - Health promotion, power and political science. PMID- 24803554 TI - Priority action areas for the IUHPE. PMID- 24803555 TI - Partnership tools for health promotion: are they worth the effort? AB - In health promotion and community sector programs, working through partnerships has become a key strategy for capacity building and infrastructure development that is intended to achieve better health outcomes. Government and funding agencies are providing significant support for partnership work in the apparent belief that partnerships are more likely to improve sustainability of programs and their outcomes than single agencies working alone. Online partnership analysis tools are designed for organisations to measure the effectiveness of their collaborative endeavours, and to demonstrate to funding bodies that the partnership was worthwhile. The tools are predominantly self-assessment evaluation tools but there is a lack of clarity about what these tools actually set out to measure. Self-assessment tools assist partners to recognise strengths and weaknesses in their practice, but analysis of their intentions indicates that there are significant problems with the 'snapshot' data that is generated in terms of analysing effectiveness. Partnership work is complex, dynamic and context specific with varying synergistic rewards which cannot always be represented in survey tools. This article reports analysis of online self assessment partnership tools which have data-generating capacity, to determine just what they measure and to understand how effective they can be in evaluating collaborative practice. Criteria for analysis were developed from a review of the existing literature. The review and analysis has highlighted that practitioners must consider what they are measuring and for what purpose they seek to evaluate before utilising and implementing a partnership analysis tool. PMID- 24803556 TI - Research on workplace health promotion in the Nordic countries: a literature review, 1986-2008. AB - Workplace health promotion may include approaches focusing on behavioral change among employees and approaches with a holistic system-oriented thinking aiming at changing the physical, social and organizational factors of a setting. This literature review aimed to identify studies on workplace health promotion in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), to describe when, where and how the studies were performed and to further analyze the use of settings approaches and empowerment processes. Using scientific literature databases, we found 1809 hits when searching for Nordic studies published from 1986 to 2008 with the search term health promotion. Of these, 116 studies were related to workplace health promotion and 33 included interventions. We used content analysis to analyze the abstracts of all articles and the full articles of the intervention studies. Most studies were performed in Sweden and Finland. The focus was mainly on behavioral change rather than on holistic health promotion as defined by the Ottawa Charter for Health Promotion. This was especially obvious for the intervention studies. In addition to the intervention studies using non-settings approaches with top-down driven behavioral change, we identified studies with participatory settings approaches aimed at changing the setting. We categorized relatively few studies as having a non-participatory settings approach. The studies aiming specifically at improving employees' empowerment were evenly distributed between the categories market-oriented persuasion of empowerment, therapeutic empowerment and empowerment as a liberal management strategy. More studies on workplace health promotion using empowering and participatory settings approaches are needed in the Nordic countries, and a more theory-based approach towards this research field is needed. PMID- 24803557 TI - Substance use prevention through school and community-based health promotion: a transdisciplinary approach from Iceland. AB - During the last decade, Iceland has made impressive progress in reducing adolescent substance use. By engaging schools, youth organizations, and other community stakeholders concerned with youth development, Iceland has developed local partnerships that have worked assiduously to reduce risk factors and strengthen school and community-level protective factors for adolescent substance use that peaked in 1998. The nationwide implementation of this transdisciplinary approach to health promotion has led to a 60% decline in both experimentation and use of alcohol, tobacco and cannabis. This article describes the key components of the Icelandic approach to school and community-based health promotion. The potential for adapting elements of this approach to advance school-based healthcare policy and practice to prevent substance use and other health compromising behaviors in other countries is discussed. PMID- 24803558 TI - Powerful partnering: engaging the best to do the most in courting new realms to boost physical activity. AB - The central thesis of the commentary is that expanding engagement between the public and private sector, especially in the area of physical activity, is needed and important. Powerful partnering offers the perspective that business is reframing its priorities, moving from short-term gain to long-term sustainability; and that business leaders are regarding the term 'survival of the fittest' not in terms of who is the most competitive and strongest, but who is the most collaborative and adaptable. The commentary stakes a position that global problems in the 21(st) century need both a left and right brain approach, where leadership and the worldview must be connected and collaborative rather than sharply delineated and disconnected. Through a series of examples, the commentary seeks to share how and why business is currently involved in physical activity partnering; and approaches and guidelines public health can consider to build the collaboration bridge. PMID- 24803562 TI - [Methods for establishing a cardiovascular health promotion program in the French section of Belgium]. PMID- 24803563 TI - [Perception of each mechanism favorable to the reduction of social and health inequalities in France]. PMID- 24803568 TI - Tube under-filling and artefactual hyperkalaemia. PMID- 24803569 TI - Are commonly used paediatric reference intervals for water and electrolyte balance appropriate for clinical use? AB - BACKGROUND: Paediatric reference intervals are less well characterized than in adults. An initiative for harmonization of pathology across the United Kingdom has recommended an interval for sodium of 133-146 mmol/L at all ages. METHODS: To assess the validity of this, the laboratory database was interrogated for all renal profiles (sodium, potassium, urea and creatinine) for children presenting to primary care over a 13-year period. While the primary interest was in sodium results, sufficient current data were also available for potassium and creatinine and so these were included for study. The electrolyte results were filtered to include only normal renal function and the remaining data were analysed for age related differences. RESULTS: Sodium concentrations were observed to be lower for infants (1-5 years of age) with a mean of 138 mmol/L, increasing towards adult concentrations (mean 140 mmol/L) by teenage years. A similar pattern was seen for potassium results, and creatinine was seen to increase with age. At all ages, the distributions of sodium concentrations measured in this population were observably tighter than the interval of 133-146 mmol/L recommended by Pathology Harmony. CONCLUSIONS: We suggest that this interval is too wide, and more work is needed to establish more appropriate paediatric ranges. PMID- 24803570 TI - Comparative genomic analysis of malaria mosquito vector-associated novel pathogen Elizabethkingia anophelis. AB - Acquisition of Elizabethkingia infections in intensive care units (ICUs) has risen in the past decade. Treatment of Elizabethkingia infections is challenging due to the lack of effective therapeutic regimens, leading to a high mortality rate. Elizabethkingia infections have long been attributed to Elizabethkingia meningoseptica. Recently, we used whole-genome sequencing to reveal that E. anophelis is the pathogenic agent for an Elizabethkingia outbreak at two ICUs. We performed comparative genomic analysis of seven hospital-isolated E. anophelis strains with five available Elizabethkingia spp. genomes deposited in the National Center for Biotechnology Information Database. A pan-genomic approach was applied to identify the core- and pan-genome for the Elizabethkingia genus. We showed that unlike the hospital-isolated pathogen E. meningoseptica ATCC 12535 strain, the hospital-isolated E. anophelis strains have genome content and organization similar to the E. anophelis Ag1 and R26 strains isolated from the midgut microbiota of the malaria mosquito vector Anopheles gambiae. Both the core and accessory genomes of Elizabethkingia spp. possess genes conferring antibiotic resistance and virulence. Our study highlights that E. anophelis is an emerging bacterial pathogen for hospital environments. PMID- 24803571 TI - Selection on horizontally transferred and duplicated genes in sinorhizobium (ensifer), the root-nodule symbionts of medicago. AB - Structural variation, including variation in gene copy number and presence or absence of genes, is a widespread and important source of genomic variation. We used whole-genome DNA sequences from 48 strains of Sinorhizobium (recently renamed Ensifer), including 20 strains of Sinorhizobium meliloti and 12 strains of S. medicae that were the focus of the analyses, to study the fitness effects of new structural variants created by duplication and horizontal gene transfer. We find that derived duplicated and horizontally transferred (HT) genes segregate at lower frequency than synonymous and nonsynonymous nucleotide variants in S. meliloti and S. medicae. Furthermore, the relative frequencies of different types of variants are more similar in S. medicae than in S. meliloti, the species with the larger effective population size. These results are consistent with the hypothesis that most duplications and HT genes have deleterious effects. Diversity of duplications, as measured by segregating duplicated genes per gene, is greater than nucleotide diversity, consistent with a high rate of duplication. Our results suggest that the vast majority of structural variants found among closely related bacterial strains are short-lived and unlikely to be involved in species-wide adaptation. PMID- 24803572 TI - Massive losses of taste receptor genes in toothed and baleen whales. AB - Taste receptor genes are functionally important in animals, with a surprising exception in the bottlenose dolphin, which shows extensive losses of sweet, umami, and bitter taste receptor genes. To examine the generality of taste gene loss, we examined seven toothed whales and five baleen whales and sequenced the complete repertoire of three sweet/umami (T1Rs) and ten bitter (T2Rs) taste receptor genes. We found all amplified T1Rs and T2Rs to be pseudogenes in all 12 whales, with a shared premature stop codon in 10 of the 13 genes, which demonstrated massive losses of taste receptor genes in the common ancestor of whales. Furthermore, we analyzed three genome sequences from two toothed whales and one baleen whale and found that the sour taste marker gene Pkd2l1 is a pseudogene, whereas the candidate salty taste receptor genes are intact and putatively functional. Additionally, we examined three genes that are responsible for taste signal transduction and found the relaxation of functional constraints on taste signaling pathways along the ancestral branch leading to whales. Together, our results strongly suggest extensive losses of sweet, umami, bitter, and sour tastes in whales, and the relaxation of taste function most likely arose in the common ancestor of whales between 36 and 53 Ma. Therefore, whales represent the first animal group to lack four of five primary tastes, probably driven by the marine environment with high concentration of sodium, the feeding behavior of swallowing prey whole, and the dietary switch from plants to meat in the whale ancestor. PMID- 24803573 TI - Multiple episodic evolution events in V1R receptor genes of East-African cichlids. AB - Fish use olfaction to detect a variety of nonvolatile chemical signals, and thus, this sense is key to survival and communication. However, the contribution of the olfactory sense to social-especially reproductive-interactions in cichlids is still controversial. To obtain insights into this issue, we investigated the genes encoding V1Rs-possible candidates for reproductive pheromone receptors among East-African cichlids. Interestingly, we found an excess of nonsynonymous over synonymous substitutions in four of six V1R genes in multiple cichlid lineages. First, we found that highly dimorphic V1R2 allele groups were shared among the cichlids inhabiting all East-African Great Lakes emerged through the episodic accumulation of the nonsynonymous substitutions prior to the radiation of the Lake Tanganyika species flock. We further detected such episodic events in V1R1 of the tribe Tropheini, and in V1R3 and V1R6 of the tribe Trematocarini. The excess of nonsynonymous substitutions in these examples were indicated as dN/dS > 1, which were all statistically significant by Fisher's exact test. Furthermore, we speculate that the amino acid changes in these episodic events are likely functional switch because they occurred in the putative ligand-binding pocket. Our finding of the occurrence of multiple episodic events and the unexpected gene diversity in one unique gene family is suggestive of the contribution of the V1R to the species diversification and the social interaction in cichlids. PMID- 24803574 TI - Chromosome number reduction in Eremothecium coryli by two telomere-to-telomere fusions. AB - The genus Eremothecium belongs to the Saccharomyces complex of pre-whole-genome duplication (WGD) yeasts and contains both dimorphic and filamentous species. We established the 9.1-Mb draft genome of Eremothecium coryli, which encodes 4,682 genes, 186 tRNA genes, and harbors several Ty3 transposons as well as more than 60 remnants of transposition events (LTRs). The initial de novo assembly resulted in 19 scaffolds, which were assembled based on synteny to other Eremothecium genomes into six chromosomes. Interestingly, we identified eight E. coryli loci that bear centromeres in the closely related species E. cymbalariae. Two of these E. coryli loci, CEN1 and CEN8, however, lack conserved DNA elements and did not convey centromere function in a plasmid stability assay. Correspondingly, using a comparative genomics approach we identified two telomere-to-telomere fusion events in E. coryli as the cause of chromosome number reduction from eight to six chromosomes. Finally, with the genome sequences of E. coryli, E. cymbalariae, and Ashbya gossypii a reconstruction of three complete chromosomes of an Eremothecium ancestor revealed that E. coryli is more syntenic to this ancestor than the other Eremothecium species. PMID- 24803575 TI - Periocular extracranial cutaneous meningiomas in two dogs. AB - Cutaneous meningiomas are rare tumors in human beings and animals. Two canine cases of cutaneous meningiomas affecting the eyelid are described in the current study: the first from a 5-week-old female Springer Spaniel dog with an 8 cm in diameter congenital mass expanding the left upper eyelid and medial canthus; the second from a 10-year-old female spayed Maltese-Poodle mix dog with 3 firm subcutaneous nodules affecting the right upper eyelid. All masses were removed surgically. Histologically, tumors were composed of spindle-to-epithelioid cells arranged in small lobules forming solid concentric whorls. Neoplastic cells were positive for vimentin and S100 and negative for pancytokeratin, glial fibrillar acid protein, and neurofilament. Transmission electron microscopy revealed meningothelial cells with convoluted interdigitating processes, desmosomes, and hemidesmosomes, and moderate numbers of cytoplasmic microfilaments. None of the cases presented a primary neuroaxial meningioma. The first case presents clinicopathological features consistent with human type I (congenital) cutaneous meningioma. The second case is consistent with a type II (acquired ectopic) tumor, and both are hypothesized to arise from ectopic arachnoid cells displaced during development. PMID- 24803576 TI - Brucella placentitis and seroprevalence in northern fur seals ( Callorhinus ursinus) of the Pribilof Islands, Alaska. AB - Brucella species infect a wide range of hosts with a broad spectrum of clinical manifestations. In mammals, one of the most significant consequences of Brucella infection is reproductive failure. There is evidence of Brucella exposure in many species of marine mammals, but the outcome of infection is often challenging to determine. The eastern Pacific stock of northern fur seals (NFSs, Callorhinus ursinus) has declined significantly, spawning research into potential causes for this trend, including investigation into reproductive health. The objective of the current study was to determine if NFSs on St. Paul Island, Alaska have evidence of Brucella exposure or infection. Archived DNA extracted from placentas ( n = 119) and serum ( n = 40) samples were available for testing by insertion sequence (IS) 711 polymerase chain reaction (PCR) and the Brucella microagglutination test (BMAT), respectively. As well, placental tissue was available for histologic examination. Six (5%) placentas were positive by PCR, and a single animal had severe placentitis. Multilocus variable number tandem repeat analysis profiles were highly clustered and closely related to other Brucella pinnipedialis isolates. A single animal was positive on BMAT, and 12 animals had titers within the borderline range; 1 borderline animal was positive by PCR on serum. The findings suggest that NFSs on the Pribilof Islands are exposed to Brucella and that the organism has the ability to cause severe placental disease. Given the population trend of the NFS, and the zoonotic nature of this pathogen, further investigation into the epidemiology of this disease is recommended. PMID- 24803577 TI - The microenvironment matters: estrogen deficiency fuels cancer bone metastases. AB - Factors released during osteoclastic bone resorption enhance disseminated breast cancer cell progression by stimulating invasiveness, growth, and a bone resorptive phenotype in cancer cells. Postmenopausal bone loss may accelerate progression of breast cancer growth in bone, explaining the anticancer benefit of the bone-specific antiresorptive agent zoledronic acid in the postmenopausal setting. Clin Cancer Res; 20(11); 2817-9. (c)2014 AACR. PMID- 24803578 TI - Prognostic and therapeutic implications of aromatase expression in lung adenocarcinomas with EGFR mutations. AB - PURPOSE: Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis. EXPERIMENTAL DESIGN: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib. RESULTS: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib. CONCLUSIONS: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients. PMID- 24803580 TI - SNPs in PI3K-PTEN-mTOR and brain metastases in NSCLC--letter. PMID- 24803579 TI - Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. AB - PURPOSE: An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ specific therapeutic approaches. EXPERIMENTAL DESIGN: Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. RESULTS: The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases. CONCLUSIONS: These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors. PMID- 24803581 TI - SNPs in PI3K-PTEN-mTOR and brain metastases in NSCLC--response. PMID- 24803582 TI - TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. AB - PURPOSE: In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC). EXPERIMENTAL DESIGN: TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method. RESULTS: TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival [HR = 2.03; 95% confidence interval (CI), 1.65-2.48, P < 0.001], and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39-2.49, P < 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in IC1, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive. CONCLUSION: This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development. PMID- 24803584 TI - Assessment of Intervention by a Palliative Care Team Working in a Japanese General Hospital: A Retrospective Study. AB - Our objective was to explore the effectiveness of a palliative care team (PCT) by investigating potential differences in opioid prescription between patients who had had PCT involvement before admission to an inpatient hospice and those who had not. A total of 221 patients met the criteria; they were divided into an intervention group (n = 140) and a control group (n = 81). The daily dose of opioid before admission to the hospice was significantly higher in the intervention group (P < .001). The difference between the maximum opioid dose and the initial dose, the rate of increase in opioids until death, and the length of stay in the hospice were not significantly different between the groups. A PCT contributes to more appropriate use of opioids before admission to a hospice. PMID- 24803583 TI - Toward a drug development path that targets metastatic progression in osteosarcoma. AB - Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting. PMID- 24803585 TI - Hospice referral after inpatient psychiatric treatment of individuals with advanced dementia from a nursing home. AB - This report addresses the discharge disposition following inpatient psychiatric treatment for advanced dementia. The total population included 685 305 Medicare fee-for-service decedents with advanced cognitive and functional impairment, with a mean age of 85.9 years who had resided in a nursing home. In the last 90 days of life, 1027 (0.15%) persons received inpatient psychiatry treatment just prior to the place of care where the individual died. Discharge dispositions included 132 (12.9%) persons to a medical hospital, 728 (70.9%) to nursing home without hospice services, 73 (7.1%) to hospice services in a nursing home, 32 (3.1%) to home without hospice services, and 16 (1.6%) to hospice services at home. Overall, the rate of referral to hospice services for advanced dementia was relatively low. PMID- 24803586 TI - Supporting Family Caregivers With Palliative Symptom Management: A Qualitative Analysis of the Provision of an Emergency Medication Kit in the Home Setting. AB - PURPOSE: The purpose of this qualitative analysis was to examine the experiences of family caregivers supporting a dying person in the home setting. In particular, it explores caregivers' perceptions of receiving palliative care at home when supplied with an emergency medication kit (EMK). RESULTS: Most family caregivers described preexisting medication management strategies that were unable to provide timely intervention in symptoms. The EMK was largely viewed as an effective strategy in providing timely symptom control and preventing readmission to inpatient care. Caregivers reported varying levels of confidence in the administration of medication. CONCLUSION: The provision of an EMK is an effective strategy for improving symptom control and preventing inpatient admissions of home-dwelling palliative care patients. PMID- 24803587 TI - Neuroprogression in schizophrenia: Pathways underpinning clinical staging and therapeutic corollaries. AB - OBJECTIVE: Whilst dopaminergic dysfunction remains a necessary component involved in the pathogenesis of schizophrenia, our current pharmacological armoury of dopamine antagonists does little to control the negative symptoms of schizophrenia. This suggests other pathological processes must be implicated. This paper aims to elaborate on such theories. METHODS: Data for this review were sourced from the electronic database PUBMED, and was not limited by language or date of publication. RESULTS: It has been suggested that multiple 'hits' may be required to unveil the clinical syndrome in susceptible individuals. Such hits potentially first occur in utero, leading to neuronal disruption, epigenetic changes and the establishment of an abnormal inflammatory response. The development of schizophrenia may therefore potentially be viewed as a neuroprogressive response to these early stressors, driven on by changes in tryptophan catabolite (TRYCAT) metabolism, reactive oxygen species handling and N methyl d-aspartate (NMDA) circuitry. Given the potential for such progression over time, it is prudent to explore the new treatment strategies which may be implemented before such changes become established. CONCLUSIONS: Outside of the dopaminergic model, the potential pathogenesis of schizophrenia has yet to be fully elucidated, but common themes include neuropil shrinkage, the development of abnormal neuronal circuitry, and a chronic inflammatory state which further disrupts neuronal function. Whilst some early non-dopaminergic treatments show promise, none have yet to be fully studied in appropriately structured randomized controlled trials and they remain little more than potential attractive targets. PMID- 24803589 TI - De novo formation of nucleoli in developing mouse embryos originating from enucleolated zygotes. AB - The large, compact oocyte nucleoli, sometimes referred to as nucleolus precursor bodies (NPBs), are essential for embryonic development in mammals; in their absence, the oocytes complete maturation and can be fertilized, but no nucleoli are formed in the zygote or embryo, leading to developmental failure. It has been convincingly documented that zygotes inherit the oocyte nucleolar material and form NPBs again in pronuclei. It is commonly accepted that during early embryonic development, the original compact zygote NPBs gradually transform into reticulated nucleoli of somatic cells. Here, we show that zygote NPBs are not required for embryonic and full-term development in the mouse. When NPBs were removed from late-stage zygotes by micromanipulation, the enucleolated zygotes developed to the blastocyst stage and, after transfer to recipients, live pups were obtained. We also describe de novo formation of nucleoli in developing embryos. After removal of NPBs from zygotes, they formed new nucleoli after several divisions. These results indicate that the zygote NPBs are not used in embryonic development and that the nucleoli in developing embryos originate from de novo synthesized materials. PMID- 24803590 TI - Non-invasive long-term fluorescence live imaging of Tribolium castaneum embryos. AB - Insect development has contributed significantly to our understanding of metazoan development. However, most information has been obtained by analyzing a single species, the fruit fly Drosophila melanogaster. Embryonic development of the red flour beetle Tribolium castaneum differs fundamentally from that of Drosophila in aspects such as short-germ development, embryonic leg development, extensive extra-embryonic membrane formation and non-involuted head development. Although Tribolium has become the second most important insect model organism, previous live imaging attempts have addressed only specific questions and no long-term live imaging data of Tribolium embryogenesis have been available. By combining light sheet-based fluorescence microscopy with a novel mounting method, we achieved complete, continuous and non-invasive fluorescence live imaging of Tribolium embryogenesis at high spatiotemporal resolution. The embryos survived the 2-day or longer imaging process, developed into adults and produced fertile progeny. Our data document all morphogenetic processes from the rearrangement of the uniform blastoderm to the onset of regular muscular movement in the same embryo and in four orientations, contributing significantly to the understanding of Tribolium development. Furthermore, we created a comprehensive chronological table of Tribolium embryogenesis, integrating most previous work and providing a reference for future studies. Based on our observations, we provide evidence that serosa window closure and serosa opening, although deferred by more than 1 day, are linked. All our long-term imaging datasets are available as a resource for the community. Tribolium is only the second insect species, after Drosophila, for which non-invasive long-term fluorescence live imaging has been achieved. PMID- 24803588 TI - WT1 regulates the development of the posterior taste field. AB - Despite the importance of taste in determining nutrient intake, our understanding of the processes that control the development of the peripheral taste system is lacking. Several early regulators of taste development have been identified, including sonic hedgehog, bone morphogenetic protein 4 and multiple members of the Wnt/beta-catenin signaling pathway. However, the regulation of these factors, including their induction, remains poorly understood. Here, we identify a crucial role for the Wilms' tumor 1 protein (WT1) in circumvallate (CV) papillae development. WT1 is a transcription factor that is important in the normal development of multiple tissues, including both the olfactory and visual systems. In mice, WT1 expression is detectable by E12.5, when the CV taste placode begins to form. In mice lacking WT1, the CV fails to develop normally and markers of early taste development are dysregulated compared with wild type. We demonstrate that expression of the WT1 target genes Lef1, Ptch1 and Bmp4 is significantly reduced in developing tongue tissue derived from Wt1 knockout mice and that, in normal tongue, WT1 is bound to the promoter regions of these genes. Moreover, siRNA knockdown of WT1 in cultured taste cells leads to a reduction in the expression of Lef1 and Ptch1. Our data identify WT1 as a crucial transcription factor in the development of the CV through the regulation of multiple signaling pathways that have established roles in the formation and patterning of taste placodes. PMID- 24803591 TI - The tissue-specific transcriptomic landscape of the mid-gestational mouse embryo. AB - Differential gene expression is a prerequisite for the formation of multiple cell types from the fertilized egg during embryogenesis. Understanding the gene regulatory networks controlling cellular differentiation requires the identification of crucial differentially expressed control genes and, ideally, the determination of the complete transcriptomes of each individual cell type. Here, we have analyzed the transcriptomes of six major tissues dissected from mid gestational (TS12) mouse embryos. Approximately one billion reads derived by RNA seq analysis provided extended transcript lengths, novel first exons and alternative transcripts of known genes. We have identified 1375 genes showing tissue-specific expression, providing gene signatures for each of the six tissues. In addition, we have identified 1403 novel putative long noncoding RNA gene loci, 439 of which show differential expression. Our analysis provides the first complete transcriptome data for the mouse embryo. It offers a rich data source for the analysis of individual genes and gene regulatory networks controlling mid-gestational development. PMID- 24803593 TI - Letter by Kasprowicz et al regarding article, "reducing sodium intake to prevent stroke: time for action, not hesitation". PMID- 24803592 TI - Epistasis analysis for quantitative traits by functional regression model. AB - The critical barrier in interaction analysis for rare variants is that most traditional statistical methods for testing interactions were originally designed for testing the interaction between common variants and are difficult to apply to rare variants because of their prohibitive computational time and poor ability. The great challenges for successful detection of interactions with next generation sequencing (NGS) data are (1) lack of methods for interaction analysis with rare variants, (2) severe multiple testing, and (3) time-consuming computations. To meet these challenges, we shift the paradigm of interaction analysis between two loci to interaction analysis between two sets of loci or genomic regions and collectively test interactions between all possible pairs of SNPs within two genomic regions. In other words, we take a genome region as a basic unit of interaction analysis and use high-dimensional data reduction and functional data analysis techniques to develop a novel functional regression model to collectively test interactions between all possible pairs of single nucleotide polymorphisms (SNPs) within two genome regions. By intensive simulations, we demonstrate that the functional regression models for interaction analysis of the quantitative trait have the correct type 1 error rates and a much better ability to detect interactions than the current pairwise interaction analysis. The proposed method was applied to exome sequence data from the NHLBI's Exome Sequencing Project (ESP) and CHARGE-S study. We discovered 27 pairs of genes showing significant interactions after applying the Bonferroni correction (P-values < 4.58 * 10(-10)) in the ESP, and 11 were replicated in the CHARGE-S study. PMID- 24803594 TI - Statins improve survival in patients with cardioembolic stroke. AB - BACKGROUND AND PURPOSE: The objective of this study was to investigate the potential benefits of statin therapy on mortality and stroke recurrence after cardioembolic stroke. METHODS: In this retrospective observational study, we analyzed data from 535 patients with first-ever cardioembolic stroke. Patients were classified into nonstatin, low-potency statin, and high-potency statin groups. The primary outcomes were time to mortality and time to recurrent stroke. RESULTS: The mean duration of follow-up was 22.2 months. The cumulative mortality rate was 7% at the end of the first year and 10% at the end of the third year. Statin therapy was independently associated with reduced mortality (hazard ratio, 0.237; 95% confidence interval, 0.080-0.703 for nonstatin versus low-potency statin; hazard ratio, 0.158; 95% confidence interval, 0.037-0.686 for nonstatin versus high-potency statin). Statin treatment did not affect the incidence of recurrent stroke in patients with cardioembolic stroke. CONCLUSIONS: Statin therapy could be associated with reduced mortality in patients with cardioembolic stroke. PMID- 24803595 TI - Functional status and patient-reported outcome 10 years after stroke: the Lund Stroke Register. AB - BACKGROUND AND PURPOSE: Long-term studies of outcome after stroke are scarce. Our aim was to study functional status and patient-reported outcome 10 years after a first-ever stroke. METHODS: Ten-year follow-up was conducted among the survivors from a population-based group of 416 patients included in the Lund Stroke Register, Sweden, between March 1, 2001, and February 28, 2002. The Barthel index was used to assess the functional status and the modified Rankin Scale to assess the degree of disability. The EQ-5D scale was used for survivors' self-reports about health outcome and the specific Short-Form 36 (SF-36) question for rating their overall health. The patients also reported their frequency of physical activity. RESULTS: Among 145 survivors 10 years after stroke (median age, 78 years), 59% were men, 90% lived in their ordinary housing, 73% were assessed as independent, and 71% had no or slight disability. The need of assistance with mobility and self-care was reported by 14% and with usual activities by 22%. Moderate pain was reported by 39%, and 4% had a high degree of pain. Moderate anxiety/depression was reported by 28% and high degree only by 1%. Overall health status was reported in positive terms by more than two thirds of the survivors. Almost half the cohort reported the same frequency of physical activity (>=4* weekly) as before stroke onset. CONCLUSIONS: This study indicates that 10-year stroke survivors in Sweden are mostly independent in daily activities and report good overall health and frequent physical activity, although half of them are >=78 years. PMID- 24803596 TI - Response to letter regarding article, "reducing sodium intake to prevent stroke: time for action, not hesitation". PMID- 24803597 TI - Letter by DiNicolantonio et al regarding article, "reducing sodium intake to prevent stroke: time for action, not hesitation". PMID- 24803598 TI - A call for rigorous study of statins in resolution of cerebral cavernous malformation pathology. PMID- 24803600 TI - Apo-RBP, holo-RBP, and insulin resistance. PMID- 24803601 TI - Reply to "Apo-RBP, Holo-RBP, and insulin resistance". PMID- 24803602 TI - How free retinol behaves differently from rbp-bound retinol in RBP receptor mediated vitamin A uptake. PMID- 24803603 TI - Reply to "How free retinol behaves differently from RBP-bound retinol in RBP receptor-mediated vitamin A uptake". PMID- 24803605 TI - Chondrogenic predifferentiation of human mesenchymal stem cells in collagen type I hydrogels. AB - Hyaline cartilage displays a limited regenerative potential. Consequently, therapeutic approaches have been developed to treat focal cartilage lesions. Larger-sized lesions are commonly treated by osteochondral grafting/mosaicplasty, autologous chondrocyte implantation (ACI) or matrix-induced chondrocyte implantation (MACI). As an alternative cell source to chondrocytes, multipotent mesenchymal stem cells (MSCs) are regarded a promising option. We therefore investigated the feasibility of pre-differentiating human MSCs incorporated in hydrogels clinically applied for MACI (CaReS(r)). MSC-laden hydrogels were cast and cultured over 10 days in a defined chondrogenic differentiation medium supplemented with TGF-beta1. This was followed by an 11-day culture in TGF-beta1 free media. After 21 days, considerable contraction of the hydrogels was observed. Histochemistry showed cells of a chondrocyte-like morphology embedded in a proteoglycan-rich extracellular matrix. Real-time polymerase chain reaction (RT-PCR) analysis showed the expression of chondrogenic marker genes, such as collagen type II and aggrecan. In summary, we demonstrate that chondrogenic differentiation of human mesenchymal stem cells embedded in collagen type I hydrogels can be induced under the influence of TGF-beta1 over a period of 10 days. PMID- 24803606 TI - Nutrition, lifestyle factors, and mental health in adolescents and young adults living in Austria. AB - BACKGROUND: Due to an alarming trend of overweight and obesity in children and adolescents, along with the sparse data on dietary habits and lifestyle factors, the present study aims to analyze the current nutritional behavior as well as the lifestyle and mental health of adolescents and young adults living in Austria. MATERIALS AND METHODS: In this cross-sectional study, a total of 500 respondents (aged between 14 and 24 years) completed an anonymous questionnaire on nutrition behavior, mental health, and lifestyle factors by Internet survey. RESULTS: Only 50% of the participants ate breakfast daily and 10% did not eat breakfast at all. About 47% of the respondents consumed milk and milk products daily. Furthermore, only 31% ate fruit and 21% ate vegetables at least once a day, and 46% ate fish seldom or never. Nearly 28% of young people liked to eat fast food twice or thrice a week and more, with males more often replacing a meal with a fast food product (36%) than females (21%). About 46% of the respondents engaged in physical activity only once a week (or more rarely). A fifth of our respondents (23%) spent more than 2 h a day using various social networks, with Facebook being the most popular social network among the respondents. Around 27% claimed to be smokers, with more female (33%) than male (20%) smoker. In terms of sleeping habits, 19% slept <6 h a day. Regarding well-being, 44% were more likely to feel stressed, 35% stated that they were tense, and 43% felt tired and listless. Eating together, physical activity, and sleep patterns showed positive effects on well-being, whereas higher consumption of fast food/snacks/soft drinks and alcoholic drinks/energy drinks was associated with relatively lower well being. CONCLUSIONS: Unhealthy eating habits, suboptimal physical activity, and smoking are still prominent in a sample of Austrian adolescents and young people. In addition, stress and tiredness are also relevant problems in this collective. PMID- 24803607 TI - Predictive factors and psychosocial effects of Internet addictive behaviors in Cypriot adolescents. AB - BACKGROUND: Internet addictive behaviors are associated with a plethora of psychosocial adversities. The study objectives were to assess the determinants and psychosocial correlates associated with Internet addictive behaviors among adolescents. MATERIALS AND METHODS: A cross-sectional study design was applied among a random sample (n=805) of Cypriot adolescents (mean age: 14.7 years). Self completed questionnaires, including Internet use characteristics, Young Internet Addiction Test, and Strengths and Difficulties Questionnaire, were utilized. RESULTS: Among the study population, the prevalence rates of borderline addictive Internet use (BIU) and addictive Internet use (AIU) were 18.4% and 2%, respectively. Adolescents with BIU had an increased likelihood of concomitantly presenting with abnormal peer relations (AOR: 5.28; 95% confidence interval, CI: 3.37-23.38), conduct problems (AOR: 4.77; 95% CI: 2.82-8.08), hyperactivity (AOR: 5.58; 95% CI: 2.58-12.10) and emotional symptoms (AOR: 2.85; 95% CI: 1.53-5.32). Adolescent AIU was significantly associated with abnormal conduct (AOR: 22.31; 95% CI: 6.90-72.19), peer problems (AOR: 7.14; 95% CI: 1.36-37.50), emotional symptoms (AOR: 19.06; 95% 6.06-60.61), and hyperactivity (AOR: 9.49, 95% CI: 1.87 48.19). The determinants of BIU and AIU included accessing the Internet for the purposes of retrieving sexual information (AOR: 1.17; 95% CI: 1.17-3.23) and participating in games with monetary awards (AOR: 1.90; 95% CI: 1.15-3.14). CONCLUSIONS: Both BIU and AIU were adversely associated with notable behavioral and social maladjustment among adolescents. PMID- 24803608 TI - Physical self-esteem--a ten-year follow-up study from early adolescence to early adulthood. AB - INTRODUCTION: One variable that has been consistently associated with adolescents' physical activity is perceived activity competence. Perceived physical (or sport) competence is considered a sub-domain to the physical self esteem or self-worth (i.e., a person's valuation of what is good and worthy in their self-description). OBJECTIVE: This study aimed to describe levels of and inter-correlations among physical self-esteem, physical activity, and body mass index in a longitudinal design spanning adolescence to early adulthood. MATERIALS AND METHODS: At mean ages of 12.7, 15.7, 17.7 and 22.7 years, we measured perceived physical self-esteem in 39 (22 boys) Swedish adolescents. Physical activity (steps/day) for four consecutive schooldays, height, and weight were also measured. RESULTS: No significant difference between the four time points for any variable of perceived physical self-esteem was seen, neither in boys nor girls. In general, all physical self-variables revealed non-linear trajectories across time, where the general trend was an increase during the younger ages followed by a decrease during older ages. At ages 12 and 15 years in boys and girls physical condition and physical strength as well as body attractiveness and physical strength, respectively, had the strongest correlations to physical self esteem. At age 17 and 22 years sports competence had the strongest correlation to self-esteem in girls, while body attractiveness and physical strength had the strongest correlation to self-esteem in boys. CONCLUSION: An overall stability in physical self-esteem was found. However the impact of a sub-domain upon physical self-esteem vary during adolescence and early adulthood. Such information may be useful when creating physical activity programs that support and develop physical self-esteem. PMID- 24803609 TI - Value of reelin for assessing hepatic fibrogenesis in a group of Egyptian HCV infected patients. AB - BACKGROUND: Development of non-invasive markers that can predict the stages of hepatic fibrosis without resorting to repeated liver biopsies is still an important goal to evaluate the effectiveness of antifibrotic treatment. The present work investigates the value of the assessment of peripheral circulating reelin, in which the liver represents its prime source, as a marker for monitoring hepatic fibrogenesis. METHODS: Seventy-four cases with chronic hepatitis positive for serum HCV RNA and 15 healthy volunteers were enrolled in this study. Assessment of reelin in the harvested serum and in 64 corresponding liver biopsies using immunofluorescence technique was done. The results were evaluated in relation to the stages and quantitative morphometric analysis of hepatic fibrosis as well as the serum levels of the validated biomarker hyaluronic acid. RESULTS: Significant correlation was detected between the levels of serum reelin and the semiquantitative assessment of reelin immunoreactivity in liver tissue, the stages of hepatic fibrosis, the morphometrically determined collagen and serum hyaluronic acid with a correlation coefficient of 0.675, 0.623, 0.479, 0.772, respectively with p<0.001. The sensitivity and the specificity of reelin for the determination of advanced (F2+F3) and significant fibrosis (F2-F4) were nearly comparable to the result of hyaluronic acid. In addition the area under curve (AUC) were 0.859, 0.871 for the reelin versus 0.878, and 0.891 for the hyaluronic acid. CONCLUSIONS: In conclusion serum reelin may be considered an additional useful parameter for monitoring the progression of hepatic fibrosis in HCV-infected patients specially in those with active rheumatological conditions which result in an increase in serum hyaluronic acid. PMID- 24803610 TI - Copeptin decrease from admission to discharge has favorable prognostic value for 90-day events in patients admitted with dyspnea. AB - BACKGROUND: With patients referred to emergency departments (EDs) for acute dyspnea, emergency physicians should consider all possible diagnoses and assess patients' risk stratification. Copeptin has been shown to have prognostic power for subsequent events, such as death and rehospitalization in patients admitted for dyspnea. The aim of this study was to investigate prognostic role of copeptin variations during hospitalization in patients admitted for dyspnea. METHODS: We conducted a prospective, multicentric, observational study in acute dyspneic patients in three ED centers in Italy. Clinical data and copeptin assessments were performed at admission, and at discharge. A 90-day follow-up was performed. RESULTS: A total of 336 patients were enrolled, and on the basis of final diagnosis distinguished into two groups: acute heart failure and no acute heart failure. Compared to a control group, in all studied population copeptin values at admission resulted in a significantly (p<0.001) higher median (maximum minimum): 31 (0-905) versus 8 (0-13) pmol/L. Median copeptin value at admission was 42 (0-905) pmol/L in acute heart failure patients and 20 (0-887) pmol/L in no acute heart failure, respectively (p<0.001). In all studied patients and in each group copeptin at admission and discharge showed significant predictive value for 90-day events (p<0.001). Furthermore, in all patients population and in both groups Delta copeptin values from admission to discharge also showed significant predictive value for 90-day events (p<0.001). CONCLUSIONS: In patients admitted for acute dyspnea, admission, discharge and Delta copeptin variations have significant prognostic value from subsequent 90-day death and rehospitalization. PMID- 24803611 TI - Comparison between white blood cell count, procalcitonin and C reactive protein as diagnostic and prognostic biomarkers of infection or sepsis in patients presenting to emergency department. AB - BACKGROUND: Procalcitonin (PCT) is currently the most studied infection biomarker and its blood levels seem to mirror the severity of illness and outcome. PCT is widely used together with other biomarkers, such as white blood cells (WBC) count and C reactive protein (CRP), in order to guide antibiotic therapy. This study aimed to verify the diagnostic and prognostic power of WBC, CRP and PCT in patients with suspected infection in emergency department (ED). METHODS: A total of 513 patients presenting to the ED with signs/symptoms of local infections or sepsis were enrolled. APACHEII score and in-hospital death were recorded. Patients were subdivided into quartiles by age, and the biomarkers were measured at baseline. Receiver operating characteristics (ROC) curves for evaluating diagnostic and prognostic role of PCT, CRP and WBC were calculated for each variable alone and combined. RESULTS: When compared each other for PCT, CRP, and WBC there was no significant difference between the four subgroups. A direct correlation between PCT and WBC was found in the II, III, and IV quartiles (the highest correlation, r=0.34, p<0.0003). PCT alone or when combined with WBC showed the best diagnostic and prognostic power at ROC analysis. CONCLUSIONS: Our data demonstrate that WBC, but more CRP and PCT are reliable diagnostic and prognostic biomarkers, when considered in combination and with severity clinical score. PCT confirms its stronger usefulness as a diagnostic marker of sepsis. A multi-diagnostic tools approach is fundamental to perform a correct and rapid diagnosis of infection and sepsis in ED. PMID- 24803612 TI - The impact of exercise on the variation of serum free light chains. PMID- 24803613 TI - Present and future of cancer biomarkers. AB - The cancer biomarker field appears to be stagnant. Very few, if any, new cancer biomarkers have been introduced into clinical practice the last 20 years. The reason is that most of the newly discovered cancer biomarkers are inferior in terms of sensitivity and specificity to the classical cancer biomarkers that we currently use. The revolutionary technologies of proteomics, genomics, and other omics did not deliver on the promise to discover new and improved cancer biomarkers. However, more recently, the explosive growth of whole genome and exome sequencing has provided for the first time nearly complete mutational landscapes of many cancer types, in thousands of samples. We now know that many of these mutations are only found in cancer. It is thus possible that the mutant proteins encoded by these genes may represent the long-sought, highly specific cancer molecules that we may envision to use as cancer biomarkers. I here speculate that modern mass spectrometry may have the necessary sensitivity and specificity to detect mutant proteins in various biological fluids for the purpose of diagnosis, prognosis, and disease monitoring. PMID- 24803615 TI - In search of a health education model: teachers' conceptions in four Mediterranean countries. AB - School programs are defined to promote the health of the pupils and to develop their competencies so that they can adopt behaviors favorable to their health. With the European project FP6 Biohead-Citizen (2004-2007), we analyzed the conceptions of teachers as regards health education, in France, Lebanon, Morocco and Tunisia, in reference to the biomedical model and the social health model. These four countries were selected because their school curricula represented different models of health education. Lebanon and Tunisia addressed health education with the biomedical model. In Morocco, the curriculum was also primarily based on the biomedical model and enclosed a few instructions issued from the social health model. In France, the health education curriculum declared an approach based on the health promotion model. Our study was based on multivariate statistical analyses of questionnaires filled out by 2537 in-service and pre-service teachers. Our analysis showed that the conceptions of the teachers concerning health education were not structured and related to a specific model. We also found that the dominating factors of influence on the choices expressed with regards to health education were, among different sociocultural variables, the religion, the home country, and, to a lesser extent, the level of training. Thus, the conceptions of the teachers were not integrated into comprehensive approaches but related to individual characteristics. Consequently health education implementation would require thorough training for pre-service and in-service teachers and should also explicitly take into account their conceptions and values. PMID- 24803618 TI - [Educational barriers for general practitioners regarding essential and emergency obstetrical surgical procedures]. PMID- 24803619 TI - [Matrones and the reduction of maternal morality, a contribution to the debate]. PMID- 24803620 TI - [The role of matrones in the reduction of maternal mortality]. PMID- 24803623 TI - [Self care: conceptual base elements]. PMID- 24803624 TI - [The meaning of knowledge: the case of social determinants of health]. PMID- 24803627 TI - Eosinophilic meningitis after bovine dural graft placement in a 5-year-old male. PMID- 24803628 TI - Using parental perceptions of childhood allergic rhinitis to inform primary care management. AB - OBJECTIVE: To describe parents' experience with their child's allergic rhinitis (AR) to inform management by the primary care provider (PCP). STUDY DESIGN: Two hundred parents with a child 7 to 15 years old with AR symptoms within the past 12 months completed a paper survey. RESULTS: The child's AR was identified as a significant problem in spring (89.3%), fall (63.4%), summer (50.3%), and winter (21.4%); 51.3% had persistent disease. AR symptoms most commonly interfered with the child's outdoor activities and sleeping, and frequently bothered the parent and other family members. Most parents (88.3%) wanted to know what their child was allergic to and had many concerns about treatment options. A total of 62.9% had sought AR care from the PCP in the past 12 months. CONCLUSIONS: Many families experience significant morbidity from their child's AR and turn to their PCP for help. We identified opportunities for the PCP to reduce AR morbidity. PMID- 24803629 TI - Longitudinal study of nutrient intakes in infants aged 12 to 18 months. AB - OBJECTIVE: To examine the nutrient intakes in young children and to compare their intakes with the dietary reference intakes (DRIs). DESIGN: Longitudinal study observing the child's food and beverage intakes as he or she grows from 12 to 18 months. METHODS: Three interviewer-administered 24-hour dietary recalls over 1 week were collected from the mother to assess the child's intakes at 12 and 18 months of age. Intakes were calculated at the 10th, 25th, 50th, 75th, and 90th percentiles and compared with the DRIs to determine the proportions below and above cutoff values. RESULTS: Nutrient intakes met or exceeded energy and nutrient requirements, with some exceptions. Diets were deficient in healthy fats, iron, fiber, and potassium and excessive in calories, synthetic folate, preformed vitamin A, zinc, and sodium. CONCLUSIONS: Health professionals should emphasize foods that are nutrient dense while decreasing highly processed foods for children. PMID- 24803630 TI - Tetanus After Vaccine Refusal and an Opportunity for the Pediatric Infectious Diseases Specialist. PMID- 24803631 TI - Banana fibers masquerading as worms in the stool of a 14-month-old girl. PMID- 24803632 TI - Residencies with dual internal medicine and pediatrics programs outperform others on the American Board of Pediatrics Certifying Examination. AB - OBJECTIVE: The purpose was to evaluate American Board of Pediatrics Certifying Examination performance based on if a residency offers a dual internal medicine pediatrics program, hypothesizing that having a dual-accreditation program is associated with higher exam performance. METHODS: Pediatric residency programs in the United States were retrospectively evaluated from 2010 to 2012. The accreditation status was determined. Mann-Whitney U tests were performed for continuous variables, and chi(2) tests were performed for categorical variables, using an alpha = .05. RESULTS: For 190 residencies, 75 (39%) had dual Med-Peds accreditation whereas 115 (61%) did not. The median overall residency pass rate for Med-Peds accredited programs (83%; interquartile range = 74% to 91%) was higher than other programs (78%; interquartile range = 65% to 89%; P = .02). The pass rate for examinees from Med-Peds accredited programs (n = 4,108; 84.2%) was higher than examinees from other programs (n = 4,310; 79.6%; P < .001). CONCLUSIONS: The presence of a dual-accreditation residency program should be a consideration of future applicants. PMID- 24803633 TI - Clinically relevant pharmacogenomic testing in pediatric practice. AB - Clinicians and patients continue to convey interest in personalized medicine. The objective of personalized medicine is to improve healthcare by tailoring disease prevention, diagnosis, and treatment strategies for individuals based on their unique clinical history and genetic composition. This article offers an overview of pharmacogenomics, discusses caveats specific to pharmacogenomics in pediatric populations, provides evidence-based recommendations for pediatric clinicians, and offers insight regarding the future role of pharmacogenomics testing in pediatric medicine. Reviews of the current literature and thoughtful discussions are presented regarding the pharmacogenomics of antidepressants, codeine and oncologic, asthma, and immunomodulatory pharmacotherapies. PMID- 24803634 TI - Clinical excellence in pediatrics. AB - The 7 core domains of clinical excellence in academic medicine, as defined by the Miller-Coulson Academy of Clinical Excellence at Johns Hopkins, are applicable to the field of pediatrics. The authors use published case reports and teaching models from the pediatric literature to illustrate how thoughtful clinicians have realized distinction in each of the 7 clinical excellence domains, recognizing excellent pediatric patient care serves to strengthen all 3 arms of the tripartite academic mission. Clinicians who feel valued by their institution may be more likely to remain in an academic clinical setting, where they promote the health and well-being of their patients, provide support to families and caregivers, serve as role models for pediatric trainees, and integrate research into their practice with the overall aim of improving patient outcomes. PMID- 24803635 TI - Cerebral venous sinus thrombosis with ophthalmic manifestations in 18-year-olds on oral contraceptives. AB - Cerebral venous sinus thrombosis (CVST) is a rare and potentially life threatening cause of stroke. In the past few decades, the incidence and patient demographics have changed because of many factors, including the widespread use of oral contraceptives, improved detection of prothrombotic conditions, and advancement of imaging technology. The presentation of CVST is varied and can include ocular signs and symptoms. We present 2 cases of oral contraceptive induced CVST in 18-year-old women, whose main presenting findings were ophthalmologic. PMID- 24803636 TI - Asymmetric elevation of the eyes. PMID- 24803637 TI - Autism spectrum disorder: genetic versus environmental. PMID- 24803638 TI - Pediatric obesity and safety in inpatient settings: a systematic literature review. AB - OBJECTIVE: Pediatric obesity affects more than 16% of American children and is associated with worse outcomes in hospitalized patients. A systematic literature review was performed to identify studies of adverse care events affecting obese pediatric patients in the emergency room, operating room, or inpatient wards. EVIDENCE REVIEW: We systematically searched Medline for articles published from 1970 to 2013 regarding obesity and patient safety events in pediatric acute care settings. We determined the study design, number of patients studied, definition and prevalence of obesity, the relevant acute care setting, the specific association with obesity addressed, and the results of each study. RESULTS AND CONCLUSION: Thirty-four studies documented both procedural complications and issues with general hospital care. Most were retrospective and focused on surgery or anesthesia. Obese patients may have increased risk for a variety of adverse events. Further study could improve institutional patient safety guidelines to enhance care for obese children. PMID- 24803639 TI - Bulk de novo mitogenome assembly from pooled total DNA elucidates the phylogeny of weevils (Coleoptera: Curculionoidea). AB - Complete mitochondrial genomes have been shown to be reliable markers for phylogeny reconstruction among diverse animal groups. However, the relative difficulty and high cost associated with obtaining de novo full mitogenomes have frequently led to conspicuously low taxon sampling in ensuing studies. Here, we report the successful use of an economical and accessible method for assembling complete or near-complete mitogenomes through shot-gun next-generation sequencing of a single library made from pooled total DNA extracts of numerous target species. To avoid the use of separate indexed libraries for each specimen, and an associated increase in cost, we incorporate standard polymerase chain reaction based "bait" sequences to identify the assembled mitogenomes. The method was applied to study the higher level phylogenetic relationships in the weevils (Coleoptera: Curculionoidea), producing 92 newly assembled mitogenomes obtained in a single Illumina MiSeq run. The analysis supported a separate origin of wood boring behavior by the subfamilies Scolytinae, Platypodinae, and Cossoninae. This finding contradicts morphological hypotheses proposing a close relationship between the first two of these but is congruent with previous molecular studies, reinforcing the utility of mitogenomes in phylogeny reconstruction. Our methodology provides a technically simple procedure for generating densely sampled trees from whole mitogenomes and is widely applicable to groups of animals for which bait sequences are the only required prior genome knowledge. PMID- 24803640 TI - Distinct roles for SOS1 in the convergent evolution of salt tolerance in Eutrema salsugineum and Schrenkiella parvula. AB - Eutrema salsugineum and Schrenkiella parvula are salt-tolerant relatives of the salt-sensitive species Arabidopsis thaliana. An important component of salt tolerance is the regulation of Na(+) ion homeostasis, which occurs in part through proteins encoded by the Cation/Proton Antiporter-1 (CPA1) gene family. We used a combination of evolutionary and functional analyses to examine the role of CPA1 genes in the salt tolerance of E. salsugineum and Sc. parvula, and found evidence that changes in CPA1-mediated Na(+) extrusion may contribute to the salt tolerance of both species. Specifically, we found that a member of the CPA1 family, the Na(+)/H(+) antiporter gene Salt Overly Sensitive 1 (SOS1), evolved under positive selection in E. salsugineum. In the absence of activation by the SOS2 kinase/SOS3 calcium-binding protein complex, SOS1 from E. salsugineum (EsSOS1) confers greater salt tolerance than SOS1 from Sc. parvula (SpSOS1) and Ar. thaliana (AtSOS1) when expressed in a salt-sensitive strain of Saccharomyces cerevisiae. A single amino acid change in the putative autoinhibitory domain is required but not sufficient for the enhanced salt tolerance conferred by EsSOS1. When activated by SOS2 and SOS3, both EsSOS1 and SpSOS1 confer greater salt tolerance than AtSOS1. Enhanced SOS1-mediated Na(+) extrusion therefore appears to contribute to the salt tolerance of both E. salsugineum and Sc. parvula, although through apparently different mechanisms. PMID- 24803641 TI - How the mountain pine beetle (Dendroctonus ponderosae) breached the Canadian Rocky Mountains. AB - The mountain pine beetle (MPB; Dendroctonus ponderosae Hopkins), a major pine forest pest native to western North America, has extended its range north and eastward during an ongoing outbreak. Determining how the MPB has expanded its range to breach putative barriers, whether physical (nonforested prairie and high elevation of the Rocky Mountains) or climatic (extreme continental climate where temperatures can be below -40 degrees C), may contribute to our general understanding of range changes as well as management of the current epidemic. Here, we use a panel of 1,536 single nucleotide polymorphisms (SNPs) to assess population genetic structure, connectivity, and signals of selection within this MPB range expansion. Biallelic SNPs in MPB from southwestern Canada revealed higher genetic differentiation and lower genetic connectivity than in the northern part of its range. A total of 208 unique SNPs were identified using different outlier detection tests, of which 32 returned annotations for products with putative functions in cholesterol synthesis, actin filament contraction, and membrane transport. We suggest that MPB has been able to spread beyond its previous range by adjusting its cellular and metabolic functions, with genome scale differentiation enabling populations to better withstand cooler climates and facilitate longer dispersal distances. Our study is the first to assess landscape-wide selective adaptation in an insect. We have shown that interrogation of genomic resources can identify shifts in genetic diversity and putative adaptive signals in this forest pest species. PMID- 24803642 TI - Food and drug administration regulation of drugs that raise blood pressure. AB - Although it is recognized that a systolic blood pressure (SBP) increase >= 2 mm Hg or a diastolic blood pressure (DBP) increase >= 1 mm Hg increases the risk of heart attacks and strokes in middle-aged adults, the Food and Drug Administration (FDA) lacks an adequate policy for regulating medications that increase blood pressure (BP). Some FDA reviewers consider a clinically significant increase in BP to occur only if a drug raises SBP >= 20 mm Hg or if a drug raises DBP >= 10 to 15 mm Hg. In recent years, numerous drugs have been regulated or taken off the market due to cardiovascular safety concerns. The list includes rofecoxib (Vioxx), valdecoxib (Bextra), nonselective nonsteroidal anti-inflammatory drugs, sibutramine (Meridia), and phenylpropanolamine. It is probable that the hypertensive effect of these drugs explains why they increase the risk of adverse cardiovascular events. Other drugs, notably serotonin-norepinephrine reuptake inhibitors and drugs used to treat attention deficit hyperactivity disorder, were approved without cardiovascular safety data despite the fact that they raise BP comparable to valdecoxib and sibutramine. It is the responsibility of the FDA to ensure that drugs are properly labeled regarding risk. Even if a drug raises BP only modestly, FDA guidelines for new drug approvals should include a requirement for cardiovascular safety data. However, such guidelines will not address the problem of how to obtain cardiovascular safety data for the many already approved drugs that increase BP. The FDA should play a role in obtaining cardiovascular safety data for such drugs. PMID- 24803643 TI - CAF-secreted IGFBPs regulate breast cancer cell anoikis. AB - Carcinoma-associated fibroblasts (CAFs) are now widely appreciated for their contributions to tumor progression. However, the ability of CAFs to regulate anoikis, detachment-induced cell death, has yet to be investigated. Here, a new role for CAFs in blocking anoikis in multiple cell lines, facilitating luminal filling in three-dimensional cell culture, and promoting anchorage-independent growth is defined. In addition, a novel mechanism underlying anoikis inhibition is discovered. Importantly, it was demonstrated that CAFs secrete elevated quantities of insulin-like growth factor-binding proteins (IGFBPs) that are both necessary for CAF-mediated anoikis inhibition and sufficient to block anoikis in the absence of CAFs. Furthermore, these data reveal a unique antiapoptotic mechanism for IGFBPs: the stabilization of the antiapoptotic protein Mcl-1. In aggregate, these data delineate a novel role for CAFs in promoting cell survival during detachment and unveil an additional mechanism by which the tumor microenvironment contributes to cancer progression. These results also identify IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells. IMPLICATIONS: The ability of CAF secreted IGFBPs to block anoikis in breast cancer represents a novel target for the development of therapeutics aimed at specifically eliminating extracellular matrix-detached breast cancer cells. PMID- 24803644 TI - Virtual reality for upper extremity rehabilitation in early stroke: a pilot randomized controlled trial. AB - OBJECTIVES: To investigate the effect of virtual reality (VR) rehabilitation on upper extremity motor performance of patients with early stroke. DESIGN: Pilot randomized controlled trial. SETTING: Rehabilitation wards. PARTICIPANTS: Twenty three adults with stroke (mean age (SD) = 58.35 (13.45) years and mean time since stroke (SD) = 16.30 (7.44) days). INTERVENTIONS: Participants were randomly assigned to VR group (n=11) or control group (n=12). VR group received nine 30 minutes upper extremity VR therapy in standing (five weekdays in two weeks) plus conventional therapy, which included physical and occupational therapy. Control group received only conventional therapy, which was comparable to total training time received by VR group (mean training hours (SD):VR = 17.07 (2.86); control = 15.50 (2.79)). MAIN OUTCOME MEASURES: The main outcome measure was the Fugl-Meyer Assessment (FMA). Secondary outcomes included Action Research Arm Test, Motor Activity Log and Functional Independence Measure. Results were taken at baseline, post intervention and 1-month post intervention. Participants' feedback and adverse effects were recorded. RESULTS: All participants improved in FMA scores (mean change (SD) = 11.65 (8.56), P<.001). These effects were sustained at one month after intervention (mean (SD) change from baseline = 18.67 (13.26), P<.001). All other outcome measures showed similar patterns. There were no significant differences in improvement between both groups. Majority of the participants found VR training useful and enjoyable, with no serious adverse effects reported. CONCLUSION: Although additional VR training was not superior to conventional therapy alone, this study demonstrates the feasibility of VR training in early stroke. PMID- 24803645 TI - The relationship between the quality of the built environment and the quality of life of people with dementia in residential care. AB - While there is considerable evidence on the impact of specific design features on problems associated with dementia, the link between the quality of the built environment and quality of life of people with dementia is largely unexplored. This study explored the environmental and personal characteristics that are associated with quality of life in people with dementia living in residential aged care. Data were obtained from 275 residents of 35 aged care homes and analysed using linear regression. The quality of the built environment was significantly associated with the quality of life of the resident measured by global self-report. Environmental ratings were not associated with proxy or detailed self-report ratings. Higher quality of life is associated with buildings that facilitate engagement with a variety of activities both inside and outside, are familiar, provide a variety of private and community spaces and the amenities and opportunities to take part in domestic activities. PMID- 24803646 TI - The provision of assistive technology products and services for people with dementia in the United Kingdom. AB - In this review we explore the provision of assistive technology products and services currently available for people with dementia within the United Kingdom. A scoping review of assistive technology products and services currently available highlighted 171 products or product types and 331 services. In addition, we assimilated data on the amount and quality of information provided by assistive technology services alongside assistive technology costs. We identify a range of products available across three areas: assistive technology used 'by', 'with' and 'on' people with dementia. Assistive technology provision is dominated by 'telecare' provided by local authorities, with services being subject to major variations in pricing and information provision; few currently used available resources for assistive technology in dementia. We argue that greater attention should be paid to information provision about assistive technology services across an increasingly mixed economy of dementia care providers, including primary care, local authorities, private companies and local/national assistive technology resources. PMID- 24803647 TI - Adult neurogenesis: mechanisms and functional significance. AB - New neurons are generated throughout life in distinct regions of the mammalian brain. This process, called adult neurogenesis, has been implicated in physiological brain function, and failing or altered neurogenesis has been associated with a number of neuropsychiatric diseases. Here, we provide an overview of the mechanisms governing the neurogenic process in the adult brain and describe how new neurons may contribute to brain function in health and disease. PMID- 24803649 TI - Cell migration: from tissue culture to embryos. AB - Cell migration is a fundamental process that occurs during embryo development. Classic studies using in vitro culture systems have been instrumental in dissecting the principles of cell motility and highlighting how cells make use of topographical features of the substrate, cell-cell contacts, and chemical and physical environmental signals to direct their locomotion. Here, we review the guidance principles of in vitro cell locomotion and examine how they control directed cell migration in vivo during development. We focus on developmental examples in which individual guidance mechanisms have been clearly dissected, and for which the interactions among guidance cues have been explored. We also discuss how the migratory behaviours elicited by guidance mechanisms generate the stereotypical patterns of migration that shape tissues in the developing embryo. PMID- 24803650 TI - Sara endosomes and the asymmetric division of intestinal stem cells. AB - Tissue homeostasis is maintained by adult stem cells, which self-renew and give rise to differentiating cells. The generation of daughter cells with different fates is mediated by signalling molecules coming from an external niche or being asymmetrically dispatched between the two daughters upon stem cell mitosis. In the adult Drosophila midgut, the intestinal stem cell (ISC) divides to generate a new ISC and an enteroblast (EB) differentiating daughter. Notch signalling activity restricted to the EB regulates intestinal cell fate decision. Here, we show that ISCs divide asymmetrically, and Sara endosomes in ISCs are specifically dispatched to the presumptive EB. During ISC mitosis, Notch and Delta traffic through Sara endosomes, thereby contributing to Notch signalling bias, as revealed in Sara mutants: Sara itself contributes to the control of the ISC asymmetric division. Our data uncover an intrinsic endosomal mechanism during ISC mitosis, which participates in the maintenance of the adult intestinal lineage. PMID- 24803648 TI - Apical constriction: themes and variations on a cellular mechanism driving morphogenesis. AB - Apical constriction is a cell shape change that promotes tissue remodeling in a variety of homeostatic and developmental contexts, including gastrulation in many organisms and neural tube formation in vertebrates. In recent years, progress has been made towards understanding how the distinct cell biological processes that together drive apical constriction are coordinated. These processes include the contraction of actin-myosin networks, which generates force, and the attachment of actin networks to cell-cell junctions, which allows forces to be transmitted between cells. Different cell types regulate contractility and adhesion in unique ways, resulting in apical constriction with varying dynamics and subcellular organizations, as well as a variety of resulting tissue shape changes. Understanding both the common themes and the variations in apical constriction mechanisms promises to provide insight into the mechanics that underlie tissue morphogenesis. PMID- 24803651 TI - Identification of Ssm1b, a novel modifier of DNA methylation, and its expression during mouse embryogenesis. AB - The strain-specific modifier Ssm1 is responsible for the strain-dependent methylation of particular E. coli gpt-containing transgenic sequences. Here, we identify Ssm1 as the KRAB-zinc finger (ZF) gene 2610305D13Rik located on distal chromosome 4. Ssm1b is a member of a gene family with an unusual array of three ZFs. Ssm1 family members in C57BL/6 (B6) and DBA/2 (D2) mice have various amino acid changes in their ZF domain and in the linker between the KRAB and ZF domains. Ssm1b is expressed up to E8.5; its target transgene gains partial methylation by this stage as well. At E9.5, Ssm1b mRNA is no longer expressed but by then its target has become completely methylated. By contrast, in D2 embryos the transgene is essentially unmethylated. Methylation during B6 embryonic development depends on Dnmt3b but not Mecp2. In differentiating B6 embryonic stem cells methylation spreads from gpt to a co-integrated neo gene that has a similarly high CpG content as gpt, but neo alone is not methylated. In adult B6 mice, Ssm1b is expressed in ovaries, but in other organs only other members of the Ssm1 family are expressed. Interestingly, the transgene becomes methylated when crossed into some, but not other, wild mice that were kept outbred in the laboratory. Thus, polymorphisms for the methylation patterns seen among laboratory inbred strains are also found in a free-living population. This may imply that mice that do not have the Ssm1b gene may use another member of the Ssm1 family to control the potentially harmful expression of certain endogenous or exogenous genes. PMID- 24803652 TI - The development of zebrafish tendon and ligament progenitors. AB - Despite the importance of tendons and ligaments for transmitting movement and providing stability to the musculoskeletal system, their development is considerably less well understood than that of the tissues they serve to connect. Zebrafish have been widely used to address questions in muscle and skeletal development, yet few studies describe their tendon and ligament tissues. We have analyzed in zebrafish the expression of several genes known to be enriched in mammalian tendons and ligaments, including scleraxis (scx), collagen 1a2 (col1a2) and tenomodulin (tnmd), or in the tendon-like myosepta of the zebrafish (xirp2a). Co-expression studies with muscle and cartilage markers demonstrate the presence of scxa, col1a2 and tnmd at sites between the developing muscle and cartilage, and xirp2a at the myotendinous junctions. We determined that the zebrafish craniofacial tendon and ligament progenitors are neural crest derived, as in mammals. Cranial and fin tendon progenitors can be induced in the absence of differentiated muscle or cartilage, although neighboring muscle and cartilage are required for tendon cell maintenance and organization, respectively. By contrast, myoseptal scxa expression requires muscle for its initiation. Together, these data suggest a conserved role for muscle in tendon development. Based on the similarities in gene expression, morphology, collagen ultrastructural arrangement and developmental regulation with that of mammalian tendons, we conclude that the zebrafish tendon populations are homologous to their force-transmitting counterparts in higher vertebrates. Within this context, the zebrafish model can be used to provide new avenues for studying tendon biology in a vertebrate genetic system. PMID- 24803654 TI - Migrating cells mediate long-range WNT signaling. AB - In amniotes, it is widely accepted that WNTs secreted by the dorsal neural tube form a concentration gradient that regulates early somite patterning and myotome organization. Here we demonstrate in the chicken embryo that WNT protein is not secreted to act at a distance, but rather loaded onto migrating neural crest cells that deliver it to somites. Inhibiting neural crest migration or ablating their population has a profound impact on the WNT response in somites. Furthermore, we show that a central player in the efficient delivery of WNT to somites is the heparan sulfate proteoglycan GPC4, expressed by neural crest. Together, our data describe a novel mode of signaling whereby WNT proteins hitch a ride on migratory neural crest cells to pattern the somites at a distance from its source. PMID- 24803653 TI - The RNA-binding protein ELAV regulates Hox RNA processing, expression and function within the Drosophila nervous system. AB - The regulated head-to-tail expression of Hox genes provides a coordinate system for the activation of specific programmes of cell differentiation according to axial level. Recent work indicates that Hox expression can be regulated via RNA processing but the underlying mechanisms and biological significance of this form of regulation remain poorly understood. Here we explore these issues within the developing Drosophila central nervous system (CNS). We show that the pan-neural RNA-binding protein (RBP) ELAV (Hu antigen) regulates the RNA processing patterns of the Hox gene Ultrabithorax (Ubx) within the embryonic CNS. Using a combination of biochemical, genetic and imaging approaches we demonstrate that ELAV binds to discrete elements within Ubx RNAs and that its genetic removal reduces Ubx protein expression in the CNS leading to the respecification of cellular subroutines under Ubx control, thus defining for the first time a specific cellular role of ELAV within the developing CNS. Artificial provision of ELAV in glial cells (a cell type that lacks ELAV) promotes Ubx expression, suggesting that ELAV-dependent regulation might contribute to cell type-specific Hox expression patterns within the CNS. Finally, we note that expression of abdominal A and Abdominal B is reduced in elav mutant embryos, whereas other Hox genes (Antennapedia) are not affected. Based on these results and the evolutionary conservation of ELAV and Hox genes we propose that the modulation of Hox RNA processing by ELAV serves to adapt the morphogenesis of the CNS to axial level by regulating Hox expression and consequently activating local programmes of neural differentiation. PMID- 24803655 TI - Development of the prethalamus is crucial for thalamocortical projection formation and is regulated by Olig2. AB - Thalamocortical axons (TCAs) pass through the prethalamus in the first step of their neural circuit formation. Although it has been supposed that the prethalamus is an intermediate target for thalamocortical projection formation, much less is known about the molecular mechanisms of this targeting. Here, we demonstrated the functional implications of the prethalamus in the formation of this neural circuit. We show that Olig2 transcription factor, which is expressed in the ventricular zone (VZ) of prosomere 3, regulates prethalamus formation, and loss of Olig2 results in reduced prethalamus size in early development, which is accompanied by expansion of the thalamic eminence (TE). Extension of TCAs is disorganized in the Olig2-KO dorsal thalamus, and initial elongation of TCAs is retarded in the Olig2-KO forebrain. Microarray analysis demonstrated upregulation of several axon guidance molecules, including Epha3 and Epha5, in the Olig2-KO basal forebrain. In situ hybridization showed that the prethalamus in the wild type excluded the expression of Epha3 and Epha5, whereas loss of Olig2 resulted in reduction of this Ephas-negative area and the corresponding expansion of the Ephas-positive TE. Dissociated cultures of thalamic progenitor cells demonstrated that substrate-bound EphA3 suppresses neurite extension from dorsal thalamic neurons. These results indicate that Olig2 is involved in correct formation of the prethalamus, which leads to exclusion of the EphA3-expressing region and is crucial for proper TCA formation. Our observation is the first report showing the molecular mechanisms underlying how the prethalamus acts on initial thalamocortical projection formation. PMID- 24803656 TI - The RNA-binding protein Mex3b regulates the spatial organization of the Rap1 pathway. AB - The four related mammalian MEX-3 RNA-binding proteins are evolutionarily conserved molecules for which the in vivo functions have not yet been fully characterized. Here, we report that male mice deficient for the gene encoding Mex3b are subfertile. Seminiferous tubules of Mex3b-deficient mice are obstructed as a consequence of the disrupted phagocytic capacity of somatic Sertoli cells. In addition, both the formation and the integrity of the blood-testis barrier are compromised owing to mislocalization of N-cadherin and connexin 43 at the surface of Sertoli cells. We further establish that Mex3b acts to regulate the cortical level of activated Rap1, a small G protein controlling phagocytosis and cell-cell interaction, through the activation and transport of Rap1GAP. The active form of Rap1 (Rap1-GTP) is abnormally increased at the membrane cortex and chemically restoring Rap1-GTP to physiological levels rescues the phagocytic and adhesion abilities of Sertoli cells. Overall, these findings implicate Mex3b in the spatial organization of the Rap1 pathway that orchestrates Sertoli cell functions. PMID- 24803657 TI - The Drosophila MAST kinase Drop out is required to initiate membrane compartmentalisation during cellularisation and regulates dynein-based transport. AB - Cellularisation of the Drosophila syncytial blastoderm embryo into the polarised blastoderm epithelium provides an excellent model with which to determine how cortical plasma membrane asymmetry is generated during development. Many components of the molecular machinery driving cellularisation have been identified, but cell signalling events acting at the onset of membrane asymmetry are poorly understood. Here we show that mutations in drop out (dop) disturb the segregation of membrane cortical compartments and the clustering of E-cadherin into basal adherens junctions in early cellularisation. dop is required for normal furrow formation and controls the tight localisation of furrow canal proteins and the formation of F-actin foci at the incipient furrows. We show that dop encodes the single Drosophila homologue of microtubule-associated Ser/Thr (MAST) kinases. dop interacts genetically with components of the dynein/dynactin complex and promotes dynein-dependent transport in the embryo. Loss of dop function reduces phosphorylation of Dynein intermediate chain, suggesting that dop is involved in regulating cytoplasmic dynein activity through direct or indirect mechanisms. These data suggest that Dop impinges upon the initiation of furrow formation through developmental regulation of cytoplasmic dynein. PMID- 24803658 TI - Role of En2 in the tectal laminar formation of chick embryos. AB - The chick optic tectum consists of 16 laminae. Here, we report contribution of En2 to laminar formation in chick optic tecta. En2 is specifically expressed in laminae g-j of stratum griseum et fibrosum superficiale (SGFS). Misexpression of En2 resulted in disappearance of En2-expressing cells from the superficial layers (laminae a-f of SGFS), where endogenous En2 is not expressed. Misexpression of En2 before postmitotic cells had left the ventricular layer indicated that En2 misexpressing cells stopped at the laminae of endogenous En2 expression and that they did not migrate into the superficial layers. Induction of En2 misexpression using a tetracycline-inducible system after the postmitotic cells had reached superficial layers also resulted in disappearance of En2-expressing cells from the superficial layers. Time-lapse analysis showed that En2-misexpressing cells migrated back from the superficial layers towards the middle layers, where En2 is strongly expressed endogenously. Our results suggest a potential role of En2 in regulating cell migration and positioning in the tectal laminar formation. PMID- 24803660 TI - Scaling morphogen gradients during tissue growth by a cell division rule. AB - Morphogen gradients guide the patterning of tissues and organs during the development of multicellular organisms. In many cases, morphogen signaling is also required for tissue growth. The consequences of this interplay between growth and patterning are not well understood. In the Drosophila wing imaginal disc, the morphogen Dpp guides patterning and is also required for tissue growth. In particular, it was recently reported that cell division in the disc correlates with the temporal increase in Dpp signaling. Here we mathematically model morphogen gradient formation in a growing tissue, accounting also for morphogen advection and dilution. Our analysis defines a new scaling mechanism, which we term the morphogen-dependent division rule (MDDR): when cell division depends on the temporal increase in morphogen signaling, the morphogen gradient scales with the growing tissue size, tissue growth becomes spatially uniform and the tissue naturally attains a finite size. This model is consistent with many properties of the wing disc. However, we find that the MDDR is not consistent with the phenotype of scaling-defective mutants, supporting the view that temporal increase in Dpp signaling is not the driver of cell division during late phases of disc development. More generally, our results show that local coupling of cell division with morphogen signaling can lead to gradient scaling and uniform growth even in the absence of global feedbacks. The MDDR scaling mechanism might be particularly beneficial during rapid proliferation, when global feedbacks are hard to implement. PMID- 24803659 TI - Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis. AB - Sertoli cells (SCs) regulate testicular fate in the differentiating gonad and are the main regulators of spermatogenesis in the adult testis; however, their role during the intervening period of testis development, in particular during adult Leydig cell (ALC) differentiation and function, remains largely unknown. To examine SC function during fetal and prepubertal development we generated two transgenic mouse models that permit controlled, cell-specific ablation of SCs in pre- and postnatal life. Results show that SCs are required: (1) to maintain the differentiated phenotype of peritubular myoid cells (PTMCs) in prepubertal life; (2) to maintain the ALC progenitor population in the postnatal testis; and (3) for development of normal ALC numbers. Furthermore, our data show that fetal LCs function independently from SC, germ cell or PTMC support in the prepubertal testis. Together, these findings reveal that SCs remain essential regulators of testis development long after the period of sex determination. These findings have significant implications for our understanding of male reproductive disorders and wider androgen-related conditions affecting male health. PMID- 24803661 TI - Lipocalin 2 binds to membrane phosphatidylethanolamine to induce lipid raft movement in a PKA-dependent manner and modulates sperm maturation. AB - Mammalian sperm undergo multiple maturation steps after leaving the testis in order to become competent for fertilization, but the molecular mechanisms underlying this process remain unclear. In terms of identifying factors crucial for these processes in vivo, we found that lipocalin 2 (Lcn2), which is known as an innate immune factor inhibiting bacterial and malarial growth, can modulate sperm maturation. Most sperm that migrated to the oviduct of wild-type females underwent lipid raft reorganization and glycosylphosphatidylinositol-anchored protein shedding, which are signatures of sperm maturation, but few did so in Lcn2 null mice. Furthermore, we found that LCN2 binds to membrane phosphatidylethanolamine to reinforce lipid raft reorganization via a PKA dependent mechanism and promotes sperm to acquire fertility by facilitating cholesterol efflux. These observations imply that mammals possess a mode for sperm maturation in addition to the albumin-mediated pathway. PMID- 24803662 TI - High cancer drug prices in the United States: reasons and proposed solutions. AB - The increase in cancer drug prices in the last 15 years has many contributing factors and is harming our patients and our health care system. It represents to many cancer experts a crossing of a moral line between reasonable profits and profiteering, in a situation involving a human catastrophe: patients who have developed cancer, and who may die because they cannot afford the treatment. With typical out-of-pocket expenses of 20% to 30%, the financial burden of cancer treatment would be $20,000 to 30,000 a year, nearly half of the average annual household income in the United States. Many patients (estimated 10% to 20%) may decide not to take the treatment or may compromise significantly on the treatment plan. This difficult situation poses three relevant questions: (1) Are cancer drug prices too high? (2) Are they hurting patients and our health care system? and (3) Can we do something about it? The answer to each is affirmative. It is also our obligation as cancer doctors to keep patients from "harm and injustice." If high prices make drugs unaffordable and inaccessible, thus causing harm, then we should voice our concerns and advocate for solutions. PMID- 24803663 TI - AMEN in challenging conversations: bridging the gaps between faith, hope, and medicine. AB - All health care practitioners face patients and families in desperate situations who say, "We are hoping for a miracle." Few providers have any formal training in responding to this common, difficult, and challenging situation. We want to do our best to preserve hope, dignity, and faith while presenting the medical issues in a nonconfrontational and helpful way. We present the acronym AMEN (affirm, meet, educate, no matter what) as one useful tool to negotiate these ongoing conversations. PMID- 24803666 TI - The low molecular weight DNA diffusion assay as an indicator of cytotoxicity for the in vitro comet assay. AB - The low molecular weight DNA diffusion assay (LMW assay) has been recommended as a measure for cytotoxicity for the in vivo comet assay. To better understand the relationship between effects in the LMW assay, DNA migration in the comet assay and effects in established cytotoxicity tests, we performed in vitro experiments with cultured human cell lines (TK6, A549) and comparatively investigated five test substances (methyl methanesulfonate, (+/-)-benzo[a]pyrene diol epoxide, sodium dodecyl sulphate, menthol and sodium arsenite). We measured DNA migration (tail intensity) in the comet assay and the frequency of 'hedgehogs' (cells with almost all DNA in the tail), DNA diffusion in the LMW assay, cell viability (trypan blue and fluorescein diacetate/ethidium bromide staining) and inhibition of proliferation (relative cell counts). Our in vitro experiments indicate that effects in the LMW assay occur independently from DNA effects in the comet assay and are not related to the occurrence of hedgehogs. Results from the LMW assay are in good agreement with results from viability assays and seem to allow discriminating genotoxic from non-genotoxic substances when appropriate preparation times are considered. Measurements of cytotoxicity by these methods only at an early preparation time after exposure to genotoxic substances may lead to erroneous results. PMID- 24803665 TI - Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. AB - The Ras/MAPK syndromes ('RASopathies') are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen activated protein kinase (MAPK) pathway frequently involved in cancer. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either cancer or RASopathies. Here, we shed light on 956 RASopathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures. Using the protein design algorithm FoldX, we predict that most of the missense mutations with destabilising energies are in structural regions that control the activation of proteins, and only a few are predicted to compromise protein folding. We find a trend that energy changes are higher for cancer compared to RASopathy mutations. Through network modelling, we show that partly compensatory mutations in RASopathies result in only minor downstream pathway deregulation. In summary, we suggest that quantitative rather than qualitative network differences determine the phenotypic outcome of RASopathy compared to cancer mutations. PMID- 24803667 TI - Realistic artificial DNA sequences as negative controls for computational genomics. AB - A common practice in computational genomic analysis is to use a set of 'background' sequences as negative controls for evaluating the false-positive rates of prediction tools, such as gene identification programs and algorithms for detection of cis-regulatory elements. Such 'background' sequences are generally taken from regions of the genome presumed to be intergenic, or generated synthetically by 'shuffling' real sequences. This last method can lead to underestimation of false-positive rates. We developed a new method for generating artificial sequences that are modeled after real intergenic sequences in terms of composition, complexity and interspersed repeat content. These artificial sequences can serve as an inexhaustible source of high-quality negative controls. We used artificial sequences to evaluate the false-positive rates of a set of programs for detecting interspersed repeats, ab initio prediction of coding genes, transcribed regions and non-coding genes. We found that RepeatMasker is more accurate than PClouds, Augustus has the lowest false positive rate of the coding gene prediction programs tested, and Infernal has a low false-positive rate for non-coding gene detection. A web service, source code and the models for human and many other species are freely available at http://repeatmasker.org/garlic/. PMID- 24803668 TI - A web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies. AB - Whole-exome sequencing has become a fundamental tool for the discovery of disease related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/ PMID- 24803669 TI - Wiring miRNAs to pathways: a topological approach to integrate miRNA and mRNA expression profiles. AB - The production rate of gene expression data is nothing less than astounding. However, with the benefit of hindsight we can assert that, since we completely ignored the non-coding part of the transcriptome, we spent the last decade to study cell mechanisms having few data in our hands. In this scenario, microRNAs, which are key post-trascriptional regulators, deserve special attention. Given the state of knowledge about their biogenesis, mechanisms of action and the numerous experimentally validated target genes, miRNAs are also gradually appearing in the formal pathway representations such as KEGG and Reactome maps. However, the number of miRNAs annotated in pathway maps are very few and pathway analyses exploiting this new regulatory layer are still lacking. To fill these gaps, we present 'micrographite' a new pipeline to perform topological pathway analysis integrating gene and miRNA expression profiles. Here, micrographite is used to study and dissect the epithelial ovarian cancer gene and miRNA transcriptome defining and validating a new regulatory circuit related to ovarian cancer histotype specificity. PMID- 24803670 TI - Binding of an RNA aptamer and a partial peptide of a prion protein: crucial importance of water entropy in molecular recognition. AB - It is a central issue to elucidate the new type of molecular recognition accompanied by a global structural change of a molecule upon binding to its targets. Here we investigate the driving force for the binding of R12 (a ribonucleic acid aptamer) and P16 (a partial peptide of a prion protein) during which P16 exhibits the global structural change. We calculate changes in thermodynamic quantities upon the R12-P16 binding using a statistical-mechanical approach combined with molecular models for water which is currently best suited to studies on hydration of biomolecules. The binding is driven by a water-entropy gain originating primarily from an increase in the total volume available to the translational displacement of water molecules in the system. The energy decrease due to the gain of R12-P16 attractive (van der Waals and electrostatic) interactions is almost canceled out by the energy increase related to the loss of R12-water and P16-water attractive interactions. We can explain the general experimental result that stacking of flat moieties, hydrogen bonding and molecular-shape and electrostatic complementarities are frequently observed in the complexes. It is argued that the water-entropy gain is largely influenced by the geometric characteristics (overall shapes, sizes and detailed polyatomic structures) of the biomolecules. PMID- 24803671 TI - PEP-SiteFinder: a tool for the blind identification of peptide binding sites on protein surfaces. AB - Peptide-protein interactions are important to many processes of life, particularly for signal transmission or regulatory mechanisms. When no information is known about the interaction between a protein and a peptide, it is of interest to propose candidate sites of interaction at the protein surface, to assist the design of biological experiments to probe the interaction, or to serve as a starting point for more focused in silico approaches. PEP-SiteFinder is a tool that will, given the structure of a protein and the sequence of a peptide, identify protein residues predicted to be at peptide-protein interface. PEP SiteFinder relies on the 3D de novo generation of peptide conformations given its sequence. These conformations then undergo a fast blind rigid docking on the complete protein surface, and we have found, as the result of a benchmark over 41 complexes, that the best poses overlap to some extent the experimental patch of interaction for close to 90% complexes. In addition, PEP-SiteFinder also returns a propensity index we have found informative about the confidence of the prediction. The PEP-SiteFinder web server is available at http://bioserv.rpbs.univ-paris-diderot.fr/PEP-SiteFinder. PMID- 24803672 TI - STarMir: a web server for prediction of microRNA binding sites. AB - STarMir web server predicts microRNA (miRNA) binding sites on a target ribonucleic acid (RNA). STarMir is an implementation of logistic prediction models developed with miRNA binding data from crosslinking immunoprecipitation (CLIP) studies (Liu,C., Mallick, B., Long, D., Rennie, W.A., Wolenc, A., Carmack, C.S. and Ding, Y. (2013). CLIP-based prediction of mammalian microRNA binding sites. Nucleic Acids Res., 41(14), e138). In both intra-dataset and inter-dataset validations, the models showed major improvements over established algorithms in predictions of both seed and seedless sites. General applicability of the models was indicated by good performance in cross-species validations. The input data for STarMir is processed by the web server to perform prediction of miRNA binding sites, compute comprehensive sequence, thermodynamic and target structure features and a logistic probability as a measure of confidence for each predicted site. For each of seed and seedless sites and for all three regions of a mRNA (3' UTR, CDS and 5' UTR), STarMir output includes the computed binding site features, the logistic probability and a publication-quality diagram of the predicted miRNA:target hybrid. The prediction results are available through both an interactive viewer and downloadable text files. As an application module of the Sfold RNA package (http://sfold.wadsworth.org), STarMir is freely available to all at http://sfold.wadsworth.org/starmir.html. PMID- 24803673 TI - Haloarcula hispanica CRISPR authenticates PAM of a target sequence to prime discriminative adaptation. AB - The prokaryotic immune system CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated genes) adapts to foreign invaders by acquiring their short deoxyribonucleic acid (DNA) fragments as spacers, which guide subsequent interference to foreign nucleic acids based on sequence matching. The adaptation mechanism avoiding acquiring 'self' DNA fragments is poorly understood. In Haloarcula hispanica, we previously showed that CRISPR adaptation requires being primed by a pre-existing spacer partially matching the invader DNA. Here, we further demonstrate that flanking a fully-matched target sequence, a functional PAM (protospacer adjacent motif) is still required to prime adaptation. Interestingly, interference utilizes only four PAM sequences, whereas adaptation-priming tolerates as many as 23 PAM sequences. This relaxed PAM selectivity explains how adaptation-priming maximizes its tolerance of PAM mutations (that escape interference) while avoiding mis-targeting the spacer DNA within CRISPR locus. We propose that the primed adaptation, which hitches and cooperates with the interference pathway, distinguishes target from non-target by CRISPR ribonucleic acid guidance and PAM recognition. PMID- 24803674 TI - Development of synthetic selfish elements based on modular nucleases in Drosophila melanogaster. AB - Selfish genes are DNA elements that increase their rate of genetic transmission at the expense of other genes in the genome and can therefore quickly spread within a population. It has been suggested that selfish elements could be exploited to modify the genome of entire populations for medical and ecological applications. Here we report that transcription activator-like effector nuclease (TALEN) and zinc finger nuclease (ZFN) can be engineered into site-specific synthetic selfish elements (SSEs) and demonstrate their transmission of up to 70% in the Drosophila germline. We show here that SSEs can spread via DNA break induced homologous recombination, a process known as 'homing' similar to that observed for homing endonuclease genes (HEGs), despite their fundamentally different modes of DNA binding and cleavage. We observed that TALEN and ZFN have a reduced capability of secondary homing compared to HEG as their repetitive structure had a negative effect on their genetic stability. The modular architecture of ZFNs and TALENs allows for the rapid design of novel SSEs against specific genomic sequences making them potentially suitable for the genetic engineering of wild-type populations of animals and plants, in applications such as gene replacement or population suppression of pest species. PMID- 24803675 TI - Increased negative supercoiling of mtDNA in TOP1mt knockout mice and presence of topoisomerases IIalpha and IIbeta in vertebrate mitochondria. AB - Topoisomerases are critical for replication, DNA packing and repair, as well as for transcription by allowing changes in DNA topology. Cellular DNA is present both in nuclei and mitochondria, and mitochondrial topoisomerase I (Top1mt) is the only DNA topoisomerase specific for mitochondria in vertebrates. Here, we report in detail the generation of TOP1mt knockout mice, and demonstrate that mitochondrial DNA (mtDNA) displays increased negative supercoiling in TOP1mt knockout cells and murine tissues. This finding suggested imbalanced topoisomerase activity in the absence of Top1mt and the activity of other topoisomerases in mitochondria. Accordingly, we found that both Top2alpha and Top2beta are present and active in mouse and human mitochondria. The presence of Top2alpha-DNA complexes in the mtDNA D-loop region, at the sites where both ends of 7S DNA are positioned, suggests a structural role for Top2 in addition to its classical topoisomerase activities. PMID- 24803677 TI - Voice disorders in Nigerian primary school teachers. AB - BACKGROUND: The prolonged use or abuse of voice may lead to vocal fatigue and vocal fold tissue damage. School teachers routinely use their voices intensively at work and are therefore at a higher risk of dysphonia. AIMS: To determine the prevalence of voice disorders among primary school teachers in Lagos, Nigeria, and to explore associated risk factors. METHODS: Teaching and non-teaching staff from 19 public and private primary schools completed a self-administered questionnaire to obtain information on personal lifestyles, work experience and environment, and voice disorder symptoms. Dysphonia was defined as the presence of at least one of the following: hoarseness, repetitive throat clearing, tired voice or straining to speak. RESULTS: A total of 341 teaching and 155 non teaching staff participated. The prevalence of dysphonia in teachers was 42% compared with 18% in non-teaching staff. A significantly higher proportion of the teachers reported that voice symptoms had affected their ability to communicate effectively. School type (public/private) did not predict the presence of dysphonia. Statistically significant associations were found for regular caffeinated drink intake (odds ratio [OR] = 3.07; 95% confidence interval [CI]: 1.51-6.62), frequent upper respiratory tract infection (OR = 3.60; 95% CI: 1.39 9.33) and raised voice while teaching (OR = 10.1; 95% CI: 5.07-20.2). CONCLUSIONS: Nigerian primary school teachers were at risk for dysphonia. Important environment and personal factors were upper respiratory infection, the need to frequently raise the voice when teaching and regular intake of caffeinated drinks. Dysphonia was not associated with age or years of teaching. PMID- 24803676 TI - Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. AB - BACKGROUND: Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA. METHODS: Key eligibility criteria included age >= 2 years, progressive PLGA evaluable on MRI, and at least one prior chemotherapy treatment. Sorafenib was administered twice daily at 200 mg/m(2)/dose (maximum of 400 mg/dose) in continuous 28-day cycles. MRI, including 3-dimensional volumetric tumor analysis, was performed every 12 weeks. BRAF molecular testing was performed on tumor tissue when available. RESULTS: Eleven patients, including 3 with neurofibromatosis type 1 (NF1), were evaluable for response; 5 tested positive for BRAF duplication. Nine patients (82%) came off trial due to radiological tumor progression after 2 or 3 cycles, including 3 patients with confirmed BRAF duplication. Median time to progression was 2.8 months (95% CI, 2.1-31.0 months). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. Tumor tissue obtained from 4 patients after termination of the study showed viable pilocytic or pilomyxoid astrocytoma. CONCLUSIONS: Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to paradoxical ERK activation. Close monitoring for early tumor progression should be included in trials of novel agents that modulate signal transduction. PMID- 24803678 TI - Advanced methods for the analysis of chromatin-associated proteins. AB - DNA-protein interactions are central to gene expression and chromatin regulation and have become one of the main focus areas of the ENCODE consortium. Advances in mass spectrometry and associated technologies have facilitated studies of these interactions, revealing many novel DNA-interacting proteins and histone posttranslational modifications. Proteins interacting at a single locus or at multiple loci have been targeted in these recent studies, each requiring a separate analytical strategy for isolation and analysis of DNA-protein interactions. The enrichment of target chromatin fractions occurs via a number of methods including immunoprecipitation, affinity purification, and hybridization, with the shared goal of using proteomics approaches as the final readout. The result of this is a number of exciting new tools, with distinct strengths and limitations that can enable highly robust and novel chromatin studies when applied appropriately. The present review compares and contrasts these methods to help the reader distinguish the advantages of each approach. PMID- 24803679 TI - Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics. AB - Cancer is a complex disease; glioblastoma (GBM) is no exception. Short survival, poor prognosis, and very limited treatment options make it imperative to unravel the disease pathophysiology. The critically important identification of proteins that mediate various cellular events during disease is made possible with advancements in mass spectrometry (MS)-based proteomics. The objective of our study is to identify and characterize proteins that are differentially expressed in GBM to better understand their interactions and functions that lead to the disease condition. Further identification of upstream regulators will provide new potential therapeutic targets. We analyzed GBM tumors by SDS-PAGE fractionation with internal DNA markers followed by liquid chromatography-tandem mass spectrometry (MS). Brain tissue specimens obtained for clinical purposes during epilepsy surgeries were used as controls, and the quantification of MS data was performed by label-free spectral counting. The differentially expressed proteins were further characterized by Ingenuity Pathway Analysis (IPA) to identify protein interactions, functions, and upstream regulators. Our study identified several important proteins that are involved in GBM progression. The IPA revealed glioma activation with z score 2.236 during unbiased core analysis. Upstream regulators STAT3 and SP1 were activated and CTNNalpha was inhibited. We verified overexpression of several proteins by immunoblot to complement the MS data. This work represents an important step towards the identification of GBM biomarkers, which could open avenues to identify therapeutic targets for better treatment of GBM patients. The workflow developed represents a powerful and efficient method to identify biomarkers in GBM. PMID- 24803681 TI - Mimicking the mechanical properties of the cell cortex by the self-assembly of an actin cortex in vesicles. AB - The composite of the actin cytoskeleton and plasma membrane plays important roles in many biological events. Here, we employed the emulsion method to synthesize artificial cells with biomimetic actin cortex in vesicles and characterized their mechanical properties. We demonstrated that the emulsion method provides the flexibility to adjust the lipid composition and protein concentrations in artificial cells to achieve the desired size distribution, internal microstructure, and mechanical properties. Moreover, comparison of the cortical elasticity measured for reconstituted artificial cells to that of real cells, including those manipulated using genetic depletion and pharmacological inhibition, strongly supports that actin cytoskeletal proteins are dominant over lipid molecules in cortical mechanics. Our study indicates that the assembly of biological systems in artificial cells with purified cellular components provides a powerful way to answer biological questions. PMID- 24803680 TI - Transcriptional atlas of cardiogenesis maps congenital heart disease interactome. AB - Mammalian heart development is built on highly conserved molecular mechanisms with polygenetic perturbations resulting in a spectrum of congenital heart diseases (CHD). However, knowledge of cardiogenic ontogeny that regulates proper cardiogenesis remains largely based on candidate-gene approaches. Mapping the dynamic transcriptional landscape of cardiogenesis from a genomic perspective is essential to integrate the knowledge of heart development into translational applications that accelerate disease discovery efforts toward mechanistic-based treatment strategies. Herein, we designed a time-course transcriptome analysis to investigate the genome-wide dynamic expression landscape of innate murine cardiogenesis ranging from embryonic stem cells to adult cardiac structures. This comprehensive analysis generated temporal and spatial expression profiles, revealed stage-specific gene functions, and mapped the dynamic transcriptome of cardiogenesis to curated pathways. Reconciling known genetic underpinnings of CHD, we deconstructed a disease-centric dynamic interactome encoded within this cardiogenic atlas to identify stage-specific developmental disturbances clustered on regulation of epithelial-to-mesenchymal transition (EMT), BMP signaling, NF-AT signaling, TGFb-dependent EMT, and Notch signaling. Collectively, this cardiogenic transcriptional landscape defines the time-dependent expression of cardiac ontogeny and prioritizes regulatory networks at the interface between health and disease. PMID- 24803682 TI - Label-free, real-time detection of the dynamic processes of protein degradation using oblique-incidence reflectivity difference method. AB - Based on the requirements for studying the dynamic process of proteinase action substrates in life science, we selected six random proteins including 1L-10, SCGB2A2, CENPQ, GST, HK1, KLHL7, as well as five different concentrations of 1L 10 proteins of 1 mg/ml, 0.5 mg/ml, 0.25 mg/ml, 0.125 mg/ml, and 0.0625 mg/ml, and fabricated two types of substrate protein microarrays, respectively. We detected the dynamic processes of proteins degraded by proteinase K using oblique incidence reflectivity difference (OIRD) method in a label-free and real-time manner. We obtained the relevant degradation velocities and the degradation time. The experimental results demonstrate that OIRD has the ability to study proteinase action substrates which is out of reach of label methods and is expected to offer opportunities to determine protease-substrate relationships on the systems biology level. PMID- 24803683 TI - Fully automated, quantitative, noninvasive assessment of collagen fiber content and organization in thick collagen gels. AB - Collagen is the most prominent protein of human tissues. Its content and organization define to a large extent the mechanical properties of tissue as well as its function. Methods that have been used traditionally to visualize and analyze collagen are invasive, provide only qualitative or indirect information, and have limited use in studies that aim to understand the dynamic nature of collagen remodeling and its interactions with the surrounding cells and other matrix components. Second harmonic generation (SHG) imaging emerged as a promising noninvasive modality for providing high-resolution images of collagen fibers within thick specimens, such as tissues. In this article, we present a fully automated procedure to acquire quantitative information on the content, orientation, and organization of collagen fibers. We use this procedure to monitor the dynamic remodeling of collagen gels in the absence or presence of fibroblasts over periods of 12 or 14 days. We find that an adaptive thresholding and stretching approach provides great insight to the content of collagen fibers within SHG images without the need for user input. An additional feature-erosion and feature-dilation step is useful for preserving structure and noise removal in images with low signal. To quantitatively assess the orientation of collagen fibers, we extract the orientation index (OI), a parameter based on the power distribution of the spatial-frequency-averaged, two-dimensional Fourier transform of the SHG images. To measure the local organization of the collagen fibers, we access the Hough transform of small tiles of the image and compute the entropy distribution, which represents the probability of finding the direction of fibers along a dominant direction. Using these methods we observed that the presence and number of fibroblasts within the collagen gel significantly affects the remodeling of the collagen matrix. In the absence of fibroblasts, gels contract, especially during the first few days, in a manner that allows the fibers to remain mostly disoriented, as indicated by small OI values. Subtle changes in the local organization of fibers may be taking place as the corresponding entropy values of these gels show a small decrease. The presence of fibroblasts affects the collagen matrix in a manner that is highly dependent on their number. A low density of fibroblasts enhances the rate of initial gel contraction, but ultimately leads to degradation of collagen fibers, which start to organize in localized clumps. This degradation and reorganization is seen within the first days of incubation with fibroblasts at a high density and is followed by de novo collagen fiber deposition by the fibroblasts. These collagen fibers are more highly oriented and organized than the fibers of the original collagen gel. These initial studies demonstrate that SHG imaging in combination with automated image analysis approaches offer a noninvasive and easily implementable method for characterizing important features of the content and organization of collagen in tissuelike specimens. Therefore, these studies could offer important insights for improving tissue engineering and disease diagnostic efforts. PMID- 24803684 TI - Magnetic approaches to study collective three-dimensional cell mechanics in long term cultures (invited). AB - Contractile forces generated by cells and the stiffness of the surrounding extracellular matrix are two central mechanical factors that regulate cell function. To characterize the dynamic evolution of these two mechanical parameters during tissue morphogenesis, we developed a magnetically actuated micro-mechanical testing system in which fibroblast-populated collagen microtissues formed spontaneously in arrays of microwells that each contains a pair of elastomeric microcantilevers. We characterized the magnetic actuation performance of this system and evaluated its capacity to support long-term cell culture. We showed that cells in the microtissues remained viable during prolonged culture periods of up to 15 days, and that the mechanical properties of the microtissues reached and maintained at a stable state after a fast initial increase stage. Together, these findings demonstrate the utility of this microfabricated bio-magneto-mechanical system in extended mechanobiological studies in a physiologically relevant 3D environment. PMID- 24803685 TI - Standard Thermodynamic Functions of Tripeptides N-Formyl-l-methionyl-l-leucyl-l phenylalaninol and N-Formyl-l-methionyl-l-leucyl-l-phenylalanine Methyl Ester. AB - The heat capacities of tripeptides N-formyl-l-methionyl-l-leucyl-l-phenylalaninol (N-f-MLF-OH) and N-formyl-l-methionyl-l-leucyl-l-phenylalanine methyl ester (N-f MLF-OMe) were measured by precision adiabatic vacuum calorimetry over the temperature range from T = (6 to 350) K. The tripeptides were stable over this temperature range, and no phase change, transformation, association, or thermal decomposition was observed. The standard thermodynamic functions: molar heat capacity Cp,m, enthalpy H(T) - H(0), entropy S(T), and Gibbs energy G(T) - H(0) of peptides were calculated over the range from T = (0 to 350) K. The low temperature (T <= 50 K) heat capacities dependencies were analyzed using the Debye's and the multifractal theories. The standard entropies of formation of peptides at T = 298.15 K were calculated. PMID- 24803686 TI - Alcohol Pharmacology Education Partnership: Using Chemistry and Biology Concepts To Educate High School Students about Alcohol. AB - We developed the Alcohol Pharmacology Education Partnership (APEP), a set of modules designed to integrate a topic of interest (alcohol) with concepts in chemistry and biology for high school students. Chemistry and biology teachers (n = 156) were recruited nationally to field-test APEP in a controlled study. Teachers obtained professional development either at a conference-based workshop (NSTA or NCSTA) or via distance learning to learn how to incorporate the APEP modules into their teaching. They field-tested the modules in their classes during the following year. Teacher knowledge of chemistry and biology concepts increased significantly following professional development, and was maintained for at least a year. Their students (n = 14 014) demonstrated significantly higher scores when assessed for knowledge of both basic and advanced chemistry and biology concepts compared to students not using APEP modules in their classes the previous year. Higher scores were achieved as the number of modules used increased. These findings are consistent with our previous studies, demonstrating higher scores in chemistry and biology after students use modules that integrate topics interesting to them, such as drugs (the Pharmacology Education Partnership). PMID- 24803687 TI - Lines in the sand: Social representations of substance use boundaries in life narratives. AB - This study identifies social representations in interviews about alcohol and substance use in the discourse of 129 young adults, who were interviewed for 2.5 to 3.5 hours each for their life histories and use or non-use of alcoholic beverages and drugs. Respondents spontaneously delineated their substance use boundaries, creating a continuum of behaviors with boundary points separating acceptable from unacceptable behaviors. They used signaling expressions to indicate go and stop signs and movement along the substance use continuum and reported negotiating substance use boundaries both internally and with peers. A ubiquitous narrative element was the cautionary tale, in which a negative exemplar goes too far with alcohol and/or drugs, providing an example of the possible negative outcomes of transgressing boundaries. In general, the narratives revealed complex relationships to alcohol and other drugs that may be useful in refining messages for more effective communication in prevention and intervention programs. PMID- 24803688 TI - Paneer-An Indian soft cheese variant: a review. AB - Paneer, a popular indigenous dairy product of India, is similar to an unripened variety of soft cheese which is used in the preparation of a variety of culinary dishes and snacks. It is obtained by heat and acid coagulation of milk, entrapping almost all the fat, casein complexed with denatured whey proteins and a portion of salts and lactose. Paneer is marble white in appearance, having firm, cohesive and spongy body with a close-knit texture and a sweetish-acidic nutty flavour. Preparation of paneer using different types of milk and varied techniques results in wide variation in physico-chemical, microbiological and sensory quality of the product. Paneer blocks of required size are packaged in laminated plastic pouches, preferably vacuum packaged, heat sealed and stored under refrigeration. Paneer keeps well for about a day at ambient temperature and for about a week under refrigeration (7 degrees C). The spoilage of paneer is mainly due to bacterial action. Successful attempts have been made to enhance the shelf life of paneer. This review deals with the history, method of manufacture, factors affecting the quality, physico-chemical changes during manufacture, chemical composition and nutritional profile, packaging and shelf life of paneer. PMID- 24803689 TI - Shelf life study of hurdle treated ready-to-eat spiced buffalo meat product stored at 30 +/- 3 degrees C for 7 weeks under vacuum and aerobic packaging. AB - Shelf stable ready to eat spiced pickle type buffalo meat product was prepared after desorbing in infusion solution (glycerol 3.5%, sodium chloride 5.0%, honey2.0%, mango powder 2.2%, spices 1.0%, sodium nitrite 0.015%, phosphate 0.2%, Sorbic acid 0.2%.and acetic acid 1%), pressure cooking of meat in infusion solution for 20 min followed by frying for 2 min in mustard oil and mixing with prefried condiments and spices. The physico-chemical properties i.e. pH, water activity, proximate composition, FFA, Soluble hydroxyproline, TBA values, nitrite content, protein solubility, shear force value, haempigments, microbiological and sensory quality of the product remained good and hygienically safe and almost comparable in aerobic PET jars and multilayered nylon barrier pouches stored at 30 +/- 3 degrees C for 7 weeks .It can be suggested that storage of such product may be conveniently done even in food grade PET jars without going for vacuum packaging which is a bit costly. PMID- 24803690 TI - Evaluation of nutritional composition and antioxidant activity of Borage (Echium amoenum) and Valerian (Valerian officinalis). AB - The nutritional composition and antioxidant activity (in aqueose and solvent extracts) of two medicinal plants of Iranian origin Borage (Echium amoenum) and Valerian (Valerian officinalis) used as tea were determined. Samples were analyzed for antioxidant components viz. polyphenols, vitamin C, beta carotene, flavonoids, anthocyanins and tannins. Antioxidant assays such as free radical scavenging activity, reducing power and total antioxidant activity were carried out for ethanol, methanol, acetone, 80% methanol and 80% ethanolic extracts. In borage highest and least activity was observed in water and acetone extract respectively in all assays. In Valerian, 80% methanolic extract showed highest activity in reducing power and free radical scavenging activity assay. Total polyphenols in borage and valerian were 1,220 and 500 mg in ethanolic extracts and 25 and 130 mg in acetonic extracts respectively. Total carotenoids and vitamin C contents were 31.6 and 133.69 mg and 51.2 and 44.87 mg for borage and valerian respectively. Highest amount of tannins were extracted in 80% methanolic extract. It can be concluded that borage and valerian exhibited antioxidant activity in all extracts. The antioxidant activity could be attributed to their polyphenol and tannin and flavonoids contents. In all assays borage showed higher activity than valerian. PMID- 24803691 TI - Effect of boiling time on chemical composition and physico-functional properties of flours from taro (Colocasia esculenta cv foue) corm grown in Cote d'Ivoire. AB - Taro (Colocasia esculenta cv foue) corm was subjected to different boiling times and the changes in chemical composition and physico-functional properties were investigated using standard method. The change in boiling time led to a significant (P < 0.05) reduction in the moisture, reducing sugars, total sugars, crude fat, crude fibre, total phenolic compound contents and iodine affinity of starch, whereas the total carbohydrate content, water absorption capacity, water solubility index, paste clarity and foam capacity increased significantly (p < 0.05). The crude protein and total ash contents of the flours from taro corm were not affected significantly (p < 0.05) by the change in boiling time. Taro corm flours exhibited highest total carbohydrate, crude fibre, total ash contents, water absorption capacity, iodine affinity of starch and lowest crude protein and fat contents, foaming capacity and water solubility index. Principal component analysis showed that flours from taro corm boiled during 20 min and 15 min were located at the left of the score plot, while flours from raw and boiled taro corm during 10 min had a large positive score in the first principal component. PMID- 24803692 TI - Jilebi 3: Effect of frying conditions on physical characteristics. AB - The process of jilebi making includes the frying of specially shaped batter strands to obtain a crisp texture followed by absorption of sugar syrup. The effects of frying temperature (150-180 degrees C) and time (15-300 s) on the physical characteristics have been investigated; these are moisture and fat contents, density, colour, textural attributes and microstructure. Among the textural parameters obtained by shearing the jilebi strands, shear failure force and the number of minor fractures increase markedly with an increase in time of frying. The brightness of the sample is lower when fried at higher temperatures like 180 degrees C compared to that of 150 degrees C; the hue or dominant wavelength of batter prior to frying is 578.0 nm, and after frying, it is between 564.8 and 591.3 nm indicating an overall shift towards yellow colouration during frying. The density of the jilebi strands decreases along with moisture content, while fat content increases gradually with an increase in frying time. The microstructure and image analysis of the fried products indicate the creation of porous structure consisting of several pores that are separated by thin cell walls of thickness between 10 and 15 MUm. The eccentricity of pores/vacuoles in jilebi is between 0 and 0.92 indicating a close resemblance to elliptical shapes. The samples fried at 160 degrees C for 180-240 s have been judged as the best sample both as fried and fried-sugar syrup soaked products. PMID- 24803693 TI - Optimization of ingredients for formulating a diabetic dietary supplement. AB - A diabetic dietary supplement comprising of multiple ingredients was designed based on recommendation of Indian Council of Medical Research for a diabetic adult. Central composite rotatable design using three variables (ingredient source) and five responses comprising of sensory and physico-chemical attributes were used for computation of an optimized solution. All the responses fitted well into quadratic equation with R (2) > 0.80. The optimum levels of ingredient combinations recommended with 93% desirability were obtained. A total of 27 combinations were prepared and evaluated. The dietary supplement comprising of milk fat and groundnut oil (90:10), whey protein concentrate and sodium caseinate (50:50) and resistant starch and maltodextrin (70:30) were selected on 100 point sensory scale. The prepared supplement using recommended levels of ingredients contained 4.37 moisture, 15.93 protein, 10.15 fat, 66.15 carbohydrate and 3.39% ash. PMID- 24803695 TI - Process optimization for the manufacture of angoori petha. AB - Angoori petha (AP) is delicacy which is relished by large section of Indian population. Fully ripened ash gourd fruits were osmotically dehydrated at different lime water concentration, lime water treatment time and sugar concentration for the manufacture of AP. The response variables consisted of sensory parameter for flavour, body and texture, colour and appearance and overall acceptability and physico-chemical properties. A central composite rotatable design (CCRD) was used as experimental design to predict the optimum conditions for manufacture of petha. The interaction of lime water concentration and lime water treatment time had significant (P < 0.05) effect for flavour, body and texture, colour and appearance and overall acceptability score (OAA) score in AP. The colour and appearance score had declining trend with increase the lime water treatment time and lime water concentration. Reducing sugar varied from 1.0% to 2.0%. The mean values for total invert sugar, sucrose and total sugar were in the range of 31.6-68.3%, 30.6-66.9% and 31.6-68.4%, respectively in different runs of AP samples. The optimum osmotic diffusion treatment consisted of lime water concentration of 12.6%, lime water treatment time of 54.1 min and sugar concentration of 87.9% for maximum acceptability in AP. PMID- 24803694 TI - Inhibitory effect of some tropical green leafy vegetables on key enzymes linked to Alzheimer's disease and some pro-oxidant induced lipid peroxidation in rats' brain. AB - This study sought to investigate the inhibitory effect of some commonly consumed Nigerian green leafy vegetables (raw and blanched) on acetylcholinesterase and butyrylcholinesterase (key enzyme linked to Alzheimer's disease) activities and some pro-oxidants (FeSO4, Sodium nitroprusside and Quinolinic acid) induced lipid peroxidation in rat brain in vitro. Three commonly consumed green leafy vegetables in Nigeria [Amarantus cruentus (Arowojeja), Struchium sparganophora (Ewuro-odo) and Telfairia occidentalis (Ugwu] were blanched in hot water for 10 min, and the extracts of the raw and blanched vegetables were prepared and used for subsequent analysis. The result revealed that all the vegetables inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity as well as the pro-oxidants induced lipid peroxidation in rat brain in a dose dependent manner; however, Amarantus cruentus extract (EC50 = 97.9 MUg/ml) had the highest inhibitory effect on acetylcholinesterase activity while Telfairia occidentalis extract (EC50 = 52.7 MUg/ml) had the highest inhibitory effect on butyrylcholinesterase activity. However, blanching of the vegetables caused a significant (P < 0.05) decrease in the inhibitory effect of the vegetables on AChE activities while it enhanced the inhibition of the pro-oxidants induced lipid peroxidation in rat brain in vitro. Therefore, some of the possible mechanism by which green leafy vegetables exert their neuroprotective activities could be through the inhibition of acetylcholinesterase and butyrylcholinesterase activities and prevention of lipid peroxidation in the brain. However, blanching of the vegetables could reduce their ability to inhibit acetylcholinesterase and butyrylcholinesterase activity. PMID- 24803696 TI - Compositional, spectroscopic and rheological analyses of mucilage isolated from taro (Colocasia esculenta L. Schott) corms. AB - Tropical roots and tubers generally contain mucilage. These mucilages exhibit unique rheological properties with considerable potential as a food thickener and stabilizer. A one-step extraction procedure was used to isolate starch free mucilage and associated proteins from a number of taro (Colocasia esculenta) varieties. The monosaccharide and amino acid composition, the structural and flow properties were investigated. The results showed that yield of mucilage fraction varied from 30 to 190 g.kg(-1). A negative correlation (r = -0.87; p < 0.05) was observed between the crude protein level and the yield. The monosaccharide profiles revealed that galactose, mannose and arabinose were the main monosaccharides in the hydrolysate of the mucilage. From the 17 amino acids analyzed, aspartic acid/asparagine (14.4-17.2%) and glutamic acid/glutamine (10.3 13.6%) were prominent in the mucilage as well as the flour. No significant differences were observed in the FT-IR spectra and in the viscosity behavior of the mucilage dispersions. The greatest difference in the mucilage is based on its monosaccharide profile while the protein composition, which reflects that of the flour, is relatively stable. PMID- 24803697 TI - Ameliorating activity of ginger (Zingiber officinale) extract against lead induced renal toxicity in male rats. AB - Lead poisoning has been known to be associated with structural and functional abnormalities of multiple organ systems of human body. The aim of this investigation was to study the renal protective effects of ginger (Zingiber officinale) extract in lead induced toxicity rats. In this study renal glutathione (GSH) level, glutathione peroxidase (GPX), glutathione-s-transferase (GST), and catalase enzymes were measured in lead nitrate (300 mg/kg BW), and lead nitrate plus ginger extract (150 mg/kg BW) treated rat groups for 1 week and 3 weeks respectively. The glutathione level and GSH dependent antioxidant enzymes such as glutathione peroxidase, glutathione-s-transferase, and catalase significantly (P < 0.05) increased in ginger extract treated rat groups. In addition, histological studies showed lesser renal changes in lead plus ginger extract treated rat groups than that of lead alone treated rat groups. These results indicate that ginger extract alleviated lead toxic effects by enhancing the levels of glutathione, glutathione peroxidase, glutathione-s-transferase and catalase. PMID- 24803698 TI - Effect of sprouting of soybean on the chemical composition and quality of soymilk and tofu. AB - The effect of sprouting of soybean and preparing soymilk and tofu on the yield, nutritional quality, anti-nutritional profile, colour attributes, organoleptic quality and texture profile (tofu) of four commonly used varieties of India were studied to assess the feasibility of using sprouting as a non-chemical, non thermal tool to improve quality of soy products. Soymilk was prepared from sprouted and unsprouted seeds with process parameters of 121 degrees C for 25 min. Coagulation of soymilk was done with 3% CaSO4 at 80 degrees C. Products from sprouted varieties showed an increase in protein (fb) of 7% in milk and 13% in tofu across varieties; a reduction in fat (fb) of 24% in milk and 12% in tofu; in trypsin inhibitor (db) of 73% in milk and 81% in tofu; in phytic acid (db) of 59% in milk and 56% in tofu across varieties. Tofu from sprouted seeds had higher protein and whiteness index but tofu strength was around 43% lesser than its unsprouted counterpart. Taste acceptability showed an increase of 10% and 6.3%; flavour of 23.2% and 11.6% and overall acceptability of 9.9% and 4.4% in milk and in tofu respectively from sprouted varieties. The improvements in composition and quality parameters was seen in all the varieties tested showing that sprouting could be beneficial for product development across varieties. The time and temperature used for production of soymilk was conventional (121 degrees C for 25 min). Evaluation of time and/temperature reductions could be tried out to reduce the heat requirement and intensity, which could result in better nutritional and functional quality products. PMID- 24803699 TI - Studies on dhal recovery from pre-treated pigeon pea ( Cajanus cajan L .) cultivars. AB - Dhal recovery from three popular varieties of North Karnataka was studied using CFTRI mini dhal mill with five different treatments at three different levels. It was observed that Gulyal variety treated with mustard oil recorded maximum hulling efficiency (79.4%) and finished product (68.8%) when compared to a Maruti and Asha variety. However, acetic acid treatment recorded higher hulling efficiency (76.5%) for Maruti followed by Asha (56.9%). The plant growth promoting rhizobacteria (PGPR) treatment yielded minimum hulling efficiency and finished product recovery for all the varieties. PMID- 24803700 TI - Effects of refrigerated storage on the microstructure and quality of Grouper (Epinephelus coioides) fillets. AB - Refrigerated storage is the simplest method of preserving for short time handling and storage of fish. The objective of this study was to investigate the effects of refrigerated storage on the microstructure, physicochemical (proximate composition, pH, TVB-N, LHC), microbial (total mesophilic count, TMC and total psychrotrophic count, TPC) and sensory changes of grouper (Epinephelus coioides) fillets during a 14-day period at +4 degrees C. The estimated TVB-N value was significantly different in all days of storage. TPC value reached to a limiting level for human consumption (10(7) micro-organism/g) after the 10th day of storage while TMC remained under the limited acceptability until 14 days. Cellular tissue damage was observed after 7 days of storage. The shelf life of grouper was approximately ~8-9 days according to the results of sensory, chemical and microbial analysis. PMID- 24803701 TI - Effects of xanthan, guar, carrageenan and locust bean gum addition on physical, chemical and sensory properties of meatballs. AB - This study evaluated the effects of xanthan gum, guar gum, carrageenan and locust bean gum on physical, chemical and sensory properties of meatballs. Meatball samples were produced with three different formulations including of 0.5, 1, and 1.5% each gum addition and gum added samples were compared with the control meatballs. Physical and chemical analyses were carried out on raw and cooked samples separately. Moisture contents of raw samples decreased by addition of gums. There were significant decreases (p < 0.05) in moisture and fat contents of raw and cooked meatball samples formulated with gum when compared with control. Ash contents and texture values increased with gum addition to meatballs. Meatball redness decreased with more gum addition in raw and cooked meatball samples, which means that addition of gums resulted in a lighter-coloured product. According to sensory analysis results, locust bean gum added (1%) samples were much preferred by the panelists. PMID- 24803702 TI - Retention of iceberg lettuce quality by low temperature storage and postharvest application of 1-methylcyclopropene or gibberellic acid. AB - This study was conducted to evaluate the changes in quality of iceberg lettuce during storage at different temperatures and the effects of postharvest treatments of 1-methylcyclopropene or gibberellic acid at high temperature. The results showed that quality of the lettuce was remarkably retained during storage at 0 degrees C, but significantly declined at 20 degrees C. However, quality of the vegetable at shelf-temperature (20 degrees C, 85 ~ 95% RH) was effectively delayed by the treatment with 1-methylcyclopropene (1-MCP) or gibberellic acid (GA). Browning of the lettuce leaves was significantly inhibited by the storage at low temperature and by treatment with1-MCP and GA. The biochemical analysis further indicated that the reduction of soluble protein and sugar, decrease in activity of polyphenol oxidase (PPO) and peroxidase (POD) and accumulation of free amino acids in the lettuce leaves during storage could be remarkably prevented by low temperature, treatment with1-MCP or GA. Our result suggested that 1-MCP or GA treatment would provide a potential way for controlling quality of the lettuce under suboptimal postharvest temperature conditions. PMID- 24803703 TI - Antioxidant activities and phenolic compounds of date plum persimmon ( Diospyros lotus L.) fruits. AB - In the present study, phenolic compounds are extracted from the date plum persimmon fruits using water, methanol and acetone as solvents. Antioxidant activities of the phenolic extracts are measured using four different tests, namely, DPPH, hydroxyl radical scavenging activities, chelating and reducing power assays. All the extracts show dose dependent DPPH radical scavenging activity, reducing and chelating powers and moreover, they are well correlated with the total phenolic and total flavonoid substances, suggesting direct contribution of phenolic compounds to these activities. In further, the extracts are identified and quantified by HPLC-ECD. Results show that gallic acid is the most abundant phenolic compound, with amounts ranging between 45.49and 287.47 MUg/g dry sample. Myricetin is the dominant flavonoid in all extracts. Its level varied from 2.75 MUg/g dry sample in acetone extract to 5.28 MUg/g dry sample in water extract. On the basis of the results obtained, the date plum persimmon fruits phenolic extract is a potential source of natural antioxidants owing to its significant antioxidant activities. PMID- 24803704 TI - Use of essential oils and extracts from spices in meat protection. AB - The hydro distillation method was used in this study to get essential oils (EOs) from cumin (Cuminum cyminum L.), clove (Eugenia caryohyllata) and Elecampane (Inula helenium L.) and the co-hydro distillation method (addition of fatty acid ethyl esters as extraction cosolvents) to get functional extracts (EFs). The MIC (Minimum Inhibitory Concentration) and the MBC (Minimum Bactericidal Concentration) were determined on five pathogenic strains (Escherichia coli O157:H7, Salmonella, Listeria monocytogenes, Yersinia enterocolitica, Campylobacter jejuni, Clostridium perfringens, Staphylococcus aureus and Toxoplasma Gondi). The results showed that essential oils of cumin and clove and their functional extracts are effective on concentrations from 500 mg/L to 750 mg/L. The essential oils with functional extracts were used on meat samples at three different concentrations: 750, 1,500 and 2,250 MUL. The cumin essential oil produced a reduction of 3.78 log UFC/g with the application of 750 MUL, the clove essential oil produced a reduction of 3.78 log UFC/g with the application of 2,250 MUL and the cumin and clove functional extracts got a reduction of 3.6 log UFC/g. By chromatography, eugenol was identified in the clove oil, cuminaldehyde in the cumin oil and the isoalactolactones and alactolactones in the elecampane oil as main compounds on the chemical composition of the essential oils and functional extracts obtained. PMID- 24803705 TI - Monoclonal antibody based immunodot for specific detection of proteins of the shrimp Penaeus species. AB - Frozen shrimp continued to be the single largest item of export from India in terms of value accounting for about 44% of the total marine export earnings. Headless, peeled frozen shrimp is a common and dominant item in the market and there is need for differentiating peeled Penaeus sp from Metapenaeus, Parapenopsis and Macrobrachium sp as consumer preference and price vary. Furthermore, there is need to find out original species used in value addition of shrimp products. Hence, it is essential for development of simple and consumer friendly technique for the identification of shrimp and their products in the market. Two monoclonal antibodies (MAbs) C-15 (IgG3) and C-52 (IgG2a) reacting with 65 and 47 kD proteins of Penaeus monodon respectively in the Western blot were selected. In epitope analysis by immunodot, the two MAbs reacted and recognized specific proteins of P. monodon, Fenneropenaeus indicus and Littopenaeus vannamei and not that of Metapenaeus, Parapenopsis, Macrobrachium rosenbergii, crabs and fishes. The immunodot required 120 min for completion. The sensitivity of the immunodot to detect proteins of P. monodon was 0.225 mg with MAb C-15 and 0.028 mg with MAb C-52. The MAb based immunodot developed, could be used for identifying and differentiating meat of P. monodon, F. indicus, and L. vannamei from that of Metapenaeus, Parapenopsis, M. rosenbergii, crabs and fishes. PMID- 24803706 TI - Colour, myoglobin denaturation and storage stability of raw and cooked mutton chops at different end point cooking temperature. AB - In our study effect of different end point temperature (51 degrees C, 65 degrees C, 71 degrees C and 79 degrees C) on physicochemical and storage stability of mutton chops were evaluated. The L* (lightness) value and b* (yellowness) increased (P < 0.05) in cooked mutton chops than the raw mutton. The a* value (redness) decreased (P < 0.05) as end point temperature increased. As internal cooking temperature increased soluble myoglobin content decreased with a corresponding increase in percent myoglobin denatured. Raw mutton chops (uncooked) had lower level of oxidation (less TBA values) than cooked mutton irrespective of storage length. Initial APC of raw and cooked mutton chops ranged from log 1.75 to log 3.73 and was lower in higher end point cooking temperature. It can be concluded that as end point temperature increased, mutton chops appear less red and raw mutton had lower level of oxidation than cooked mutton chops. PMID- 24803707 TI - Influence of germination on bioaccessible iron and calcium in pearl millet (Pennisetum typhoideum). AB - Pearl millet is the staple for economically poorer section of the world's population and improving its mineral bioaccessibility is one of the important approaches to promote its utilization. In the absence of any data on the bioaccessible mineral content from commercially available millet, two varieties namely Kalukombu (native) and Maharastra Rabi Bajra (hybrid) were germinated and its effect on the bioaccessible iron and calcium content was explored using an in vitro method which simulates gastrointestinal digestion. The millet was germinated for 72 h to facilitate maximum mineral extraction. The bioaccessibility of iron and calcium was considerably enhanced upon sprouting. This higher bioaccessibility could be attributed to decrease in antinutritional factors like phytate and oxalate as a result of germination. Changes in mineral and antinutrient content during sprouting led to significant variations in the antinutrient/mineral molar ratios which had a positive impact on the bioaccessible mineral content. Use of tap water for soaking prior to germination revealed contamination of the millet with iron. Contaminant iron in Kalukombu variety appeared to be less accessible; while the same was potentially bioaccessible in Maharashtra Rabi Bajra variety. Hence bioaccessibility of iron depends on the form in which it is present. The actual bioaccessibility of contaminated iron needs to be further investigated. PMID- 24803708 TI - Influence of cryoprotectant levels on storage stability of surimi from Nemipterus japonicus and quality of surimi-based products. AB - A study was undertaken with the aim of reducing the concentration of cryoprotectants in surimi without adversely affecting frozen storage stability. Minced meat from a tropical fish, Nemipterus japonicus, was strained, water leached and mixed with different levels of sucrose-sorbitol (1:1) mixture (henceforth called sugar mixture), quick frozen at -35 degrees C and frozen stored at -20 degrees C. The surimi samples were subjected to storage stability studies for a period of 5 months. Water leaching resulted in slight absorption of water by meat and reduction in protein, fat and mineral contents. Surimi was found to have moderately white colour. Sensory evaluation studies were conducted on three products, viz., sausage, patty and cake, prepared using surimi containing different concentrations of sugar mixture. Sugar mixture content varying from 0% (control) to 4% in surimi resulted in products that were more acceptable to the taste panelists compared those with 6% and 8% sugar mixture. During frozen storage of surimi pH and total plate count remained nearly steady for all sugar mixture concentrations and throughout the storage period. Moisture content appeared to remain constant during storage, but decreased with increase in sugar concentration. The salt soluble nitrogen content of surimi and gel strength of sausage prepared from it decreased with storage period in all surimi samples, and increased with sugar mixture concentration. Expressible water content of surimi sausage showed an increasing trend with storage period of surimi and a decreasing trend with sugar mixture concentration. Sensory evaluation parameters-elasticity, sweetness and preference-remained more or less steady during storage. However elasticity and sweetness increased and preference decreased with sugar mixture concentration beyond 4%. Elasticity and gel strength of surimi sausage seemed to be much lower for control compared to even the lowest concentration of sugar (2%) used. A concentration of 2 to 4% sucrose-sorbitol mixture is well-accepted by the consumers in products-surimi sausage, patty and cake and at this range of concentration surimi could be well-preserved at -20 degrees C for at least 5 months. PMID- 24803709 TI - Influence of drying treatments on antioxidant capacity of forage legume leaves. AB - This study was aimed to investigate the antioxidant capacities of four common forage legume leaves namely, Arachis pintoi (Pintoi), Calapogonium mucunoides (Calapo), Centrosema pubescens (Centro), and Stylosanthes guanensis (Stylo). Two different drying methods (oven-drying and freeze-drying) were employed and antioxidant activities were determined by DPPH, Ferric Reducing Antioxidant Power (FRAP) and beta-carotene bleaching assays. Total phenolic content (TPC) was determined using Folin-Ciocalteu assay. Freeze-dried extract showed the highest antioxidant activities by DPPH (EC50 values 1.17-2.13 mg/ml), FRAP (147.08-246.42 MUM of Fe(2+)/g), and beta-carotene bleaching (57.11-78.60%) compared to oven drying. Hence, freeze drying treatment could be considered useful in retention of antioxidant activity and phenolic content. PMID- 24803710 TI - Iron binding capacity of dephytinised soy protein isolate hydrolysate as influenced by the degree of hydrolysis and enzyme type. AB - Soy protein is increasingly used in extended meat products and dairy type products due to the presence of high quality proteins with excellent functional properties. However, it has been shown to inhibit iron bioavailability because of phytic acid present in the protein. This present study investigated the effects of dephytinise from soy protein isolate (SPI) on iron binding capacity and degree of hydrolysis. Also the effects of enzyme type and degree of hydrolysis on iron binding capacity were studied. It was demonstrated that phytase and anion exchange resin could remove effectively the phytate from SPI. The dephytinise would decrease the degree of hydrolysis of SPI. The enzyme type and degree of hydrolysis influenced significantly the iron binding capacity of the hydrolysate. Flavourzyme might be the best choice for producing peptides with iron binding capacity from SPI and middle degree of hydrolysis would be benefitable to this process. PMID- 24803711 TI - Study on the effect of packaging materials on the physico-chemical, microbiological and sensory quality of kunda. AB - Kunda, an indigenous heat desiccated sweet product prepared from milk and sugar, has a shelf-life of a few days under market conditions. In this study, shelf-life of kunda packed in select packaging materials viz. LDPE, metallised polyester and tin cans and stored at 30 degrees and 5 degrees C was investigated. During storage, several changes took place in physico-chemical and sensory characteristics, the changes being faster at 30 degrees C than at 5 degrees C. The storage study indicated that kunda was acceptable throughout the storage period of 42 days at 30 degrees C and 90 days at 5 degrees C, irrespective of packaging material. However, the rate of changes in characteristics of the product packaged in tin cans and metalized polyester was slower. Hence, it was recommended that kunda be packed in tin cans and metallised polyester pouches which possess high barrier properties for achieving long shelf-life. PMID- 24803712 TI - Cryoprotective effect of trehalose on washed chicken meat. AB - The cryoprotective effects of trehalose (w = 0-10%) on washed chicken meat (WCM) were investigated. WCM was produced from broiler, frozen and stored for 360 days on -30 degrees C. Myofibrillar protein functional stability was monitored by salt extractable protein (SEP) and differential scanning calorimetry (DSC). Salt extractable protein (SEP) showed that the addition of trehalose caused smaller decrease in protein solubility during frozen storage. Peak thermal transition (T p) and denaturation enthalpy (DeltaH) of myofibrillar proteins were evaluated. Differential scanning calorimetry (DSC) revealed a shift in peak thermal transition temperature (T p) of myosin and actin to higher temperature as the mass fraction of trehalose increases. The transitions enthalpies of myosin and actin of WCM samples showed higher increase with the increase of mass fraction of trehalose. Since the value of denaturation enthalpy is directly related to amount of native proteins, higher values of DeltaH indicates to the higher cryoprotective effects of trehalose. PMID- 24803713 TI - Effect of enzyme concentration, addition of water and incubation time on increase in yield of starch from potato. AB - Enzymatic treatment process for starch extraction from potato was investigated using cellulase enzyme and compared with conventional process. The effects of three parameters, cellulase enzyme concentration, incubation time and addition of water were evaluated for increase in starch yield as compared to the conventional process i.e., without using enzyme. A two-level full factorial design was used to study the process. The results indicated that all the main parameters and their interactions are statistically significant. Enzyme concentration and incubation time had a positive effect on the increase in starch yield while addition of water had a negative effect. The increase in starch yield ranged from 1.9% at low enzyme concentration and incubation time and high addition of water to a maximum of 70% increase from conventional process in starch yield was achieved when enzyme concentration and incubation time were high and addition of water was low suggesting water present in the ground potato meal is sufficient for access to the enzyme with in the slurry ensuring adequate contact with the substrate. PMID- 24803714 TI - Optimization of germination time and heat treatments for enhanced availability of minerals from leguminous sprouts. AB - Germinated legumes are highly nutritious food especially for their enhanced iron bioavailability primarily because of reduction of phytates and increase in ascorbic acid with an advancement of germination period. Length of germination time followed by different heat treatments affect the nutritive value of leguminous sprouts. To optimize germination time and heat treatments for enhanced availability of iron from leguminous sprouts, three legumes namely, mungbean, chickpea and cowpea were germinated for three time periods followed by cooking of sprouts by two cooking methods ie. pressure cooking and microwaving. Optimized germination time for mungbean was 12, 16 and 20 h; 36, 48 and 60 h for chickpea and 16, 20 and 24 h for cowpea. Germination process increased ascorbic acid significantly in all the three legumes, the values being 8.24 to 8.87 mg/100 g in mungbean, 9.34 to 9.85 mg/100 g in chickpea and 9.12 to 9.68 mg/100 g in cowpea. Soaking and germination significantly reduced the phytin phosphorus in all the three legumes, the percent reduction being 5.3 to 16.1% during soaking and 25.7 to 46.4% during germination. The reduction in phytin phosphorus after pressure cooking was 9.6% in mungbean, 18.4% in chickpea and 6.1% in cowpea. The corresponding values during microwaving were 8.4, 19.7 and 4.5%. Mineral bioavailability as predicted by phytate:iron enhanced significantly with an increase in germination time. Further reduction i.e. 0.9 to 16.3% was observed in three legumes after the two heat treatments. The study concluded that the longer germination periods ie. 20 h for mungbean, 60 h for chickpea and 24 h for cowpea followed by pressure cooking for optimized time were suitable in terms of better iron availability. PMID- 24803715 TI - Evaluation of the smoking ban in public places in France one year and five years after its implementation: Findings from the ITC France survey. AB - France implemented a comprehensive smoke-free policy in public places in February 2007 for workplaces, shopping centres, airports, train stations, hospitals and schools. On January 2008, it was extended to meeting places (bars, restaurants, hotels, casinos, nightclubs). This paper evaluates France's smoke-free law based on the International Tobacco Control Policy Evaluation Project in France (the ITC France Project), which conducted a cohort survey of approximately 1,500 smokers and 500 non-smokers before the implementation of the laws (Wave 1, conducted December 2006 to February 2007) and two waves after the implementation (Wave 2, conducted between September-November 2008; and Wave 3, conducted between September-December 2012). Results show that the smoke-free law led to a very significant and near total elimination of indoor smoking in key venues such as bars (from 95.9% to 3.7%) and restaurants (from 64.7% to 2.3%) at Wave 2, which was sustained four years later at Wave 3 (1.4% in restaurants; 6.6% in bars). Smoking in workplaces declined significantly after the law (from 42.6% to 19.3%), which continued to decline at Wave 3 (to 12.8%). Support for the smoke-free law increased significantly after their implementation and continued to increase at Wave 3 (among smokers for bars and restaurants; among smokers and non-smokers for workplaces). The findings demonstrate that smoke-free policies that are implemented in ways consistent with the Guidelines for Article 8 of the WHO Framework Convention on Tobacco Control (WHO FCTC) lead to substantial and sustained reductions in tobacco smoke in public places while also leading to high levels of support by the public. PMID- 24803716 TI - Ferrous Carbonyl Dithiolates as Precursors to FeFe, FeCo, and FeMn Carbonyl Dithiolates. AB - Reported are complexes of the formula Fe(dithiolate)(CO)2(diphos) and their use to prepare homo- and heterobimetallic dithiolato derivatives. The starting iron dithiolates were prepared by a one-pot reaction of FeCl2 and CO with chelating diphosphines and dithiolates, where dithiolate = S2(CH2)22- (edt2-), S2(CH2)32- (pdt2-), S2(CH2)2(C(CH3)2)2- (Me2pdt2-) and diphos = cis-C2H2(PPh2)2 (dppv), C2H4(PPh2)2 (dppe), C6H4(PPh2)2 (dppbz), C2H4[P(C6H11)2]2 (dcpe). The incorporation of 57Fe into such building block complexes commenced with the conversion of 57Fe into 57Fe2I4( i PrOH)4, which then was treated with K2pdt, CO, and dppe to give 57Fe(pdt)(CO)2(dppe). NMR and IR analyses show that these complexes exist as mixtures of all-cis and trans-CO isomers, edt2- favoring the former and pdt2- the latter. Treatment of Fe(dithiolate)(CO)2(diphos) with the Fe(0) reagent (benzylideneacetone)Fe(CO)3 gave Fe2(dithiolate)(CO)4(diphos), thereby defining a route from simple ferrous salts to models for hydrogenase active sites. Extending the building block route to heterobimetallic complexes, treatment of Fe(pdt)(CO)2(dppe) with [(acenaphthene)Mn(CO)3]+ gave [(CO)3Mn(pdt)Fe(CO)2(dppe)]+ ([3d(CO)]+). Reduction of [3d(CO)]+ with BH4- gave the Cs -symmetric MU-hydride (CO)3Mn(pdt)(H)Fe(CO)(dppe) (H3d). Complex H3d is reversibly protonated by strong acids, the proposed site of protonation being sulfur. Treatment of Fe(dithiolate)(CO)2(diphos) with CpCoI2(CO) followed by reduction by Cp2Co affords CpCo(dithiolate)Fe(CO)(diphos) (4), which can also be prepared from Fe(dithiolate)(CO)2(diphos) and CpCo(CO)2. Like the electronically related (CO)3Fe(pdt)Fe(CO)(diphos), these complexes undergo protonation to afford the MU-hydrido complexes [CpCo(dithiolate)HFe(CO)(diphos)]+. Low-temperature NMR studies indicate that Co is the kinetic site of protonation. PMID- 24803717 TI - A Broadly Applicable Strategy for Entry into Homogeneous Nickel(0) Catalysts from Air-Stable Nickel(II) Complexes. AB - A series of air-stable nickel complexes of the form L2Ni(aryl) X (L = monodentate phosphine, X = Cl, Br) and LNi(aryl)X (L = bis-phosphine) have been synthesized and are presented as a library of precatalysts suitable for a wide variety of nickel-catalyzed transformations. These complexes are easily synthesized from low cost NiCl2.6H2O or NiBr2.3H2O and the desired ligand followed by addition of 1 equiv of Grignard reagent. A selection of these complexes were characterized by single-crystal X-ray diffraction, and an analysis of their structural features is provided. A case study of their use as precatalysts for the nickel-catalyzed carbonyl-ene reaction is presented, showing superior reactivity in comparison to reactions using Ni(cod)2. Furthermore, as the precatalysts are all stable to air, no glovebox or inert-atmosphere techniques are required to make use of these complexes for nickel-catalyzed reactions. PMID- 24803718 TI - Aquaporin-1 protein levels elevated in fresh urine of renal cell carcinoma patients: potential use for screening and classification of incidental renal lesions. AB - INTRODUCTION AND OBJECTIVES: There are over 65,000 new cases of renal cell carcinoma (RCC) each year, yet there is no effective clinical screening test for RCC. A single report claimed no overlap between urine levels of aquaporin-1 (AQP1) in patients with and without RCC (Mayo Clin Proc. 85:413, 2010). Here, we used archived and fresh RCC patient urine to validate this report. METHODS: Archived RCC, fresh prenephrectomy RCC, and non-RCC negative control urines were processed for Western blot analysis. Urinary creatinine concentrations were quantified by the Jaffe reaction (Nephron 16:31, 1976). Precipitated protein was dissolved in 1x SDS for a final concentration of 2 MUg/uL creatinine. RESULTS: Negative control and archived RCC patient urine failed to show any AQP1 protein by Western blot analysis. Fresh RCC patient urine is robustly positive for AQP1. There was no signal overlap between fresh RCC and negative control, making differentiation straightforward. CONCLUSIONS: Our data confirms that fresh urine of patients with RCC contains easily detectable AQP1 protein. However, archival specimens showed an absence of detectable AQP1 indistinguishable from negative control. These findings suggest that a clinically applicable diagnostic test for AQP1 in fresh urine may be useful for detecting RCC. PMID- 24803719 TI - p16INK4A and p14ARF gene promoter hypermethylation as prognostic biomarker in oral and oropharyngeal squamous cell carcinoma: a review. AB - Head and neck squamous cell carcinoma is a heterogeneous group of tumors with each subtype having a distinct histopathological and molecular profile. Most tumors share, to some extent, the same multistep carcinogenic pathways, which include a wide variety of genetic and epigenetic changes. Epigenetic alterations represent all changes in gene expression patterns that do not alter the actual DNA sequence. Recently, it has become clear that silencing of cancer related genes is not exclusively a result of genetic changes such as mutations or deletions, but it can also be regulated on epigenetic level, mostly by means of gene promoter hypermethylation. Results from recent studies have demonstrated that DNA methylation patterns contain tumor-type-specific signatures, which could serve as biomarkers for clinical outcome in the near future. The topic of this review discusses gene promoter hypermethylation in oral and oropharyngeal squamous cell carcinoma (OSCC). The main objective is to analyse the available data on gene promoter hypermethylation of the cell cycle regulatory proteins p16(INK4A) and p14(ARF) and to investigate their clinical significance as novel biomarkers in OSCC. Hypermethylation of both genes seems to possess predictive properties for several clinicopathological outcomes. We conclude that the methylation status of p16(INK4A) is definitely a promising candidate biomarker for predicting clinical outcome of OSCC, especially for recurrence-free survival. PMID- 24803720 TI - Association of fibrinogen with severity of stable coronary artery disease in patients with type 2 diabetic mellitus. AB - BACKGROUND: Some studies have suggested a relation of plasma fibrinogen to the severity of coronary artery disease (CAD). However, whether plasma fibrinogen can predict the presence and severity of CAD in patients with diabetes mellitus has not been determined. METHODS: A total of consecutive 373 diabetic patients with typical angina pectoris who received coronary angiography were enrolled and classified into three groups by tertiles of Gensini score (GS, low group <8; intermediate group 8~28; high group >28). The relationship between fibrinogen and GS was evaluated. RESULTS: There were correlations of fibrinogen with hemoglobin A1c, C-reactive protein, and GS (r = 0.17, r = 0.52, and r = 0.21, resp.; all P < 0.001). Area under the receivers operating characteristic curve of fibrinogen was 0.62 (95% CI 0.56-0.68, P < 0.001) for predicting a high GS. Multivariate analysis suggested that plasma fibrinogen was an independent predictor of a high GS for diabetic patients (OR = 1.40, 95% CI 1.04-1.88, and P = 0.026) after adjusting for traditional risk factors of CAD. CONCLUSIONS: The present data indicated that plasma fibrinogen, a readily measurable systematic inflammatory marker, appeared to be an independent predictor for the severity of CAD in diabetic patients. PMID- 24803721 TI - Assessment of lipocalin 2, clusterin, soluble tumor necrosis factor receptor-1, interleukin-6, homocysteine, and uric acid levels in patients with psoriasis. AB - BACKGROUND: Chronic inflammation may play a role in psoriasis pathogenesis. Lipocalin 2, clusterin, soluble tumor necrosis factor receptor-1 (sTNFR-1), interleukin-6, homocysteine, and uric acid are inflammatory and/or biochemical markers. However, both the roles of these markers and the pathogenesis of psoriasis are unknown. OBJECTIVE: The aim of this study was to investigate serum levels of lipocalin 2, clusterin, sTNFR-1, interleukin-6, homocysteine, and uric acid in patients and controls groups. METHODS: Fifty-six patients with psoriasis and 33 healthy controls were included in the study. Serum concentrations of the markers were evaluated by ELISA. The Psoriasis Area and Severity Index (PASI) was evaluated in all psoriasis patients. Body mass index (BMI) was calculated by dividing weight (kg) by height (m) squared. RESULTS: The serum value of lipocalin and sTNFR-1 were significantly higher in psoriasis patients than in controls (resp., P < 0.001, P < 0.05). The others showed no significant differences between psoriasis and the control groups (all of them P > 0.05). The mean PASI score in the patient group was 8.3 +/- 6.5. CONCLUSIONS: These findings suggest that lipocalin 2 and sTNFR-1 might play a role in the pathogenesis of psoriasis and can be used as markers of the disease. PMID- 24803722 TI - Matrix metalloproteinase-9: its interplay with angiogenic factors in inflammatory bowel diseases. AB - Matrix metalloproteinase- (MMP-) 9 is one of the main metalloproteinases reported to be involved in extracellular matrix degradation and recently also in triggering of angiogenic switch in the course of inflammatory bowel diseases (IBD). The goal of our studies was to estimate in one experimental setting the levels of MMP-9 in sera of Crohn's Disease (CD) and ulcerative colitis (UC) patients and to evaluate its possible diagnostic potential in comparison with other biochemical markers and selected proinflammatory and angiogenic factors. The study group included 176 subjects (CD = 64, UC = 85, control = 27). Concentrations of serum MMP-9 were significantly higher in active than inactive forms of IBD, being higher in active UC than in active CD. Both in the case of CD and UC serum MMP-9 positively correlated with disease activity, IL-6 levels, platelet and leukocyte count, midkine, and PDGF-BB, as well as in UC with ESR and in CD with CRP, IL-1, and VEGF-A. Diagnostic accuracy of MMP-9 in distinguishing active UC from active CD was 66%, and displayed higher specificity than CRP (79.0% versus 61.6%, resp.). Evaluation of serum MMP-9 concentrations could aid in differentiation of active UC from active CD. MMP-9 correlated better with inflammatory and angiogenic parameters in CD than in UC. PMID- 24803723 TI - Progress Report on the Generation of Polyfunctional Microscale Particles for Programmed Self-Assembly. AB - A process for 3D programmed self-assembly of lithographically printable microscale polymer particles using ssDNA hybridization as the associative force is described. We report our progress in establishing the unit processes required for 3D programmed self-assembly and demonstrate the successful fabrication and sequence-specific self-assembly of covalent ssDNA-functionalized parallelepipeds with dimensions in the sub 10 MUm regime characterized by optical microscopy and imaging flow cytometry. This technology has the potential to produce parallelepiped particles with different ssDNA on each facet. PMID- 24803724 TI - NaGdF4:Eu3+ Nanoparticles for Enhanced X-ray Excited Optical Imaging. AB - X-ray luminescent nanoparticles (NPs), including lanthanide fluorides, have been evaluated for application to deep tissue in vivo molecular imaging using optical tomography. A combination of high material density, higher atomic number and efficient NIR luminescence from compatible lanthanide dopant ions indicates that particles that consist of ALnF4 (A = alkaline, Ln = lanthanide element) may offer a very attractive class of materials for high resolution, deep tissue imaging with X-ray excitation. NaGdF4:Eu3+ NPs produced an X-ray excited luminescence that was among the most efficient of nanomaterials that have been studied thus far. We have systematically studied factors such as (a) the crystal structure that changes the lattice environment of the doped Eu3+ ions within the unit cell; and extrinsic factors such as (b) a gold coating (with attendant biocompatibility) that couples to a plasmonic excitation, and (c) changes in the NPs surface properties via changes in the pH of the suspending medium-all with a significant impact on the X-ray excited luminescence of NaGdF4:Eu3+NPs. The luminescence from an optimally doped hexagonal phase NaGdF4:Eu3+ nanoparticle was 25% more intense compared to that of a cubic structure. We observed evidence of plasmonic reabsorption of midwavelength emission by a gold coating on hexagonal NaGdF4:Eu3+ NPs; fortunately, the NaGdF4:Eu3+ @Au core-shell NPs retained the efficient 5D0->7F4 NIR (692 nm) luminescence. The NaGdF4:Eu3+ NPs exhibited sensitivity to the ambient pH when excited by X-rays, an effect not seen with UV excitation. The sensitivity to the local environment can be understood in terms of the sensitivity of the excitons that are generated by the high energy X-rays (and not by UV photons) to crystal structure and to the surface state of the particles. PMID- 24803725 TI - Synthesis and Crystal Structure of Gold Nanobelts. AB - Gold nanobelts were synthesized by the reduction of tetrachloroauric acid with ascorbic acid in the presence of the surfactants cetyltrimethylammonium bromide and sodium dodecylsulfate. The resulting structures have rectangular cross sectional dimensions that are tens of nanometers and lengths that are tens to hundreds of micrometers. We find that the nanobelt yield and resulting structures are very sensitive to temperature which is likely due to the transition of the surfactant solution from wormlike micelles to spherical micelles. The nanobelt crystal structure contains a mixture of face centered cubic and hexagonally close packed lattice phases that can be isolated and examined individually due to the unique nanobelt size and shape. PMID- 24803726 TI - The Magic-Size Nanocluster (CdSe)34 as a Low-Temperature Nucleant for Cadmium Selenide Nanocrystals; Room-Temperature Growth of Crystalline Quantum Platelets. AB - Reaction of Cd(OAc)2.2H2O and selenourea in primary-amine/secondary-amine cosolvent mixtures affords crystalline CdSe quantum platelets at room temperature. Their crystallinity is established by X-ray diffraction analysis (XRD), high-resolution transmission electron microscopy (TEM), and their sharp extinction and photoluminescence spectra. Reaction monitoring establishes the magic-size nanocluster (CdSe)34 to be a key intermediate in the growth process, which converts to CdSe quantum platelets by first-order kinetics with no induction period. The results are interpreted to indicate that the critical crystal-nucleus size for CdSe under these conditions is in the range of (CdSe)34 to (CdSe)68. The nanocluster is obtained in isolated form as [(CdSe)34(n octylamine)16(di-n-pentylamine)2], which is proposed to function as crystal nuclei that may be stored in a bottle. PMID- 24803727 TI - Synthesis, X-ray Opacity, and Biological Compatibility of Ultra-High Payload Elemental Bismuth Nanoparticle X-ray Contrast Agents. AB - Inorganic nanoscale X-ray contrast agents (XCAs) offer many potential advantages over currently used intravascular molecular contrast agents, including longer circulation and retention times, lower administration volumes, and greater potential for site directed imaging. Elemental bismuth nanoparticles (BiNPs) are particularly attractive candidate XCAs due to the low cost, the high atomic number and high density of bismuth, and the likelihood that BiNPs will oxidatively decompose to biocompatible bismuth(III) ions at controlled rates for renal excretion. Herein we describe the synthesis of ultrahigh payload BiNPs in 1,2-propanediol using a borane reducing agent and glucose as a biocompatible surface stabilizer. Both synthetic solvent (1,2-propanediol) and surfactant (glucose) are evident on the BiNP surfaces when analyzed by 1H NMR and FT-IR spectroscopies. These particles contain ~6 million Bi atoms per NP and have large inorganic cores (74 nm by TEM) compared to their hydrodynamic size (86 nm by DLS). Thus, the dense BiNP core constitutes the majority (~60%) of each particle's volume, a necessary property to realize the full potential of nanoscale XCAs. Using quantitative computed tomography in phantom and in vitro imaging studies, we demonstrate that these BiNPs have greater X-ray opacity than clinical small molecule iodinated contrast agents at the same concentrations. We furthermore demonstrate a favorable biocompatibility profile for these BiNPs in vitro. Altogether, these studies indicate that these ultrahigh payload BiNPs, synthesized from known biocompatible components, have promising physical and cytotoxicological properties for use as XCAs. PMID- 24803728 TI - Why are the right and left hemisphere conceptual representations different? AB - The present survey develops a previous position paper, in which I suggested that the multimodal semantic impairment observed in advanced stages of semantic dementia is due to the joint disruption of pictorial and verbal representations, subtended by the right and left anterior temporal lobes, rather than to the loss of a unitary, amodal semantic system. The main goals of the present review are (a) to survey a larger set of data, in order to confirm the differences in conceptual representations at the level of the right and left hemispheres, (b) to examine if language-mediated information plays a greater role in left hemisphere semantic knowledge than sensory-motor information in right hemisphere conceptual knowledge, and (c) to discuss the models that could explain both the differences in conceptual representations at the hemispheric level and the prevalence of the left hemisphere language-mediated semantic knowledge over the right hemisphere perceptually based conceptual representations. PMID- 24803729 TI - Effect of aneurysmal subarachnoid hemorrhage on word generation. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) survivors commonly exhibit impairment on phonemic and semantic fluency tests; however, it is unclear which of the contributing cognitive processes are compromised in aSAH patients. One method of disentangling these processes is to compare initial word production, which is a rapid, semiautomatic, frontal-executive process, and late phase word production, which is dependent on more effortful retrieval and lexical size and requires a more distributed neural network. METHODS: Seventy-two individuals with aSAH and twenty-five control subjects were tested on a cognitive battery including the phonemic and semantic fluency task. Demographic and clinical information was also collected. RESULTS: Compared to control subjects, patients with aSAH were treated by clipping and those with multiple aneurysms were impaired across the duration of the phonemic test. Among patients treated by coiling, those with anterior communicating artery aneurysms or a neurological complication (intraventricular hemorrhage, vasospasm, and edema) showed worse output only in the last 45 seconds of the phonemic test. Patients performed comparably to control subjects on the semantic test. CONCLUSIONS: These results support a "diffuse damage" hypothesis of aSAH, indicated by late phase phonemic fluency impairment. Overall, the phonemic and semantic tests represent a viable, rapid clinical screening tool in the postoperative assessment of patients with aSAH. PMID- 24803730 TI - Deep brain stimulation in persistent vegetative States: ethical issues governing decision making. AB - The aim of the present paper was to investigate the fundamental ethical issues of Deep Brain Stimulation (DBS) on patients remaining in Persistent Vegetative State (PVS). First, the purpose of this analysis was to discuss the nature of this intervention in order to classify it such as an ordinary clinical practice, or otherwise as an extraordinary clinical practice or as experimental research. Second, ethical issues, criticisms, and methodological issues of this intervention, also in the future perspectives, are discussed, attempting to identify who could give informed consent for a patient in PVS. PMID- 24803731 TI - Fahr's disease presenting with dementia at onset: a case report and literature review. AB - Fahr's disease (FD) is characterized by sporadic or familiar idiopathic calcification of the basal ganglia, dentate nuclei of the cerebellum, and centrum semiovale, mainly presenting with movement disorder, dementia, and behavioral abnormalities. We described a rare case of Fahr's disease presenting at onset only with behavioral and neuropsychological alterations, whose diagnosis was supposed only after a brain CT, which showed extensive bilateral calcifications in the dentate nuclei of the cerebellum and basal ganglia. Since the onset of Fahr's disease may be a dysexecutive syndrome with behavioral abnormalities, the clinical and radiological features are really important to do the appropriate diagnosis. PMID- 24803732 TI - Late onset bipolar disorder due to a lacunar state. AB - OBJECTIVE: To describe a patient with a new onset bipolar disorder (BD) type II, secondary to a lacunar state. BACKGROUND: Poststroke BD is rare and mainly associated with lesion in the prefrontal-striatal-thalamic circuit. MATERIALS AND METHODS: A 51-year-old woman came to our attention for a mood disorder of recent onset. At 49, she had suffered acute left-sided limb weakness that improved spontaneously four days later. Arterial hypertension was subsequently diagnosed. After 6 months, she began to suffer from alternating brief periods of expansive and elevated mood with longer periods of depressed mood, with a suicide attempt. We performed extensive laboratory and instrumental investigations, as well as, psychiatric consultation, and a cognitive assessment, which was repeated 9 months later. RESULTS: Brain magnetic resonance disclosed leukoaraiosis and a lacunar state of the basal ganglia. Transcranial Doppler showed a patent foramen ovale. A psychiatric consultation led to the diagnosis of BP type II. Neuropsychological evaluation detected deficits in attention/executive functions, verbal fluency, and memory. Nine months later, after specific psychiatric therapy, the psychiatric symptoms were remarkably improved. CONCLUSION: Our case sheds light on the role of the basal ganglia in mood disorders and the importance of ruling out brain injury in late onset BP. PMID- 24803733 TI - rTMS in the treatment of drug addiction: an update about human studies. AB - Drug addiction can be a devastating and chronic relapsing disorder with social, psychological, and physical consequences, and more effective treatment options are needed. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that has been assessed in a growing number of studies for its therapeutic potential in treating addiction. This review paper offers an overview on the current state of clinical research in treating drug addiction with rTMS. Because of the limited research in this area, all studies (including case reports) that evaluated the therapeutic use of rTMS in nicotine, alcohol, or illicit drug addiction were included in this review. Papers published prior to December 2012 were found through an NCBI PubMed search. A total of eleven studies were identified that met review criteria. There is nascent evidence that rTMS could be effective in reducing cocaine craving and nicotine and alcohol craving and consumption and might represent a potential therapeutic tool for treating addiction. Further studies are needed to identify the optimal parameters of stimulation for the most effective treatment of drug addiction, to improve our comprehension of the treatment neurophysiological effects, and to conduct rigorous, controlled efficacy studies with adequate power. PMID- 24803734 TI - A case of Gorlin-Goltz syndrome presented with psychiatric features. AB - We report a case of a 34-year-old male who presented with an acute onset of pleomorphic psychiatric features. Upon examination we later diagnosed him with Gorlin-Goltz syndrome based on clinical and radiological findings that are characteristic for this rare autosomal dominant syndrome. His psychiatric manifestations included irritability, aggressive behavior, labile mood, hallucinations, paranoid delusions, and transient cognitive impairment. His past history indicated surgical excision of pigmented lesion in the left lower eyelid which turned out to be a basal cell carcinoma. His past visits to dermatology clinics indicated pitted keratosis involving hands, callosities, and seborrheic dermatitis. There were numerous palmar pits, and Brain CT Head scan revealed extensive calcification along falx cerebri and around the cerebellar vermis. He had low (20 ng/L) vitamin D level and high parathyroid hormone level. The patient improved using antipsychotic medications and vitamin D supplementations for symptomatic management and was discharged with a plan for multispecialty outpatient follow-up. This case highlights the importance of considering rare organic etiologies in the differential diagnosis of patients presenting with psychiatric symptoms. This is of vital importance for early intervention to prevent complications and for better outcomes of the coexistent diseases. PMID- 24803735 TI - Anxiety changes depersonalization and derealization symptoms in vestibular patients. AB - BACKGROUND: Depersonalization and derealization are common symptoms reported in the general population. Objective. The aim of the present study was to establish the relationship between anxiety and depersonalization and derealization symptoms in patients with peripheral vestibular disorders. METHODS: Twenty-four vestibular patients with anxiety and 18 vestibular patients without anxiety were examined for depersonalization and derealization symptoms. They were also compared to healthy controls. RESULTS: The results revealed that anxiety consistently changes depersonalization and derealization symptoms in vestibular patients. They are more frequent, more severe, and qualitatively different in vestibular patients with anxiety than in those without anxiety. CONCLUSION: Anxiety has an effect on depersonalization and derealization symptoms in vestibular patients. The various hypotheses about the underlying mechanism of this effect were discussed. PMID- 24803736 TI - Intermittent alien hand syndrome and callosal apraxia in multiple sclerosis: implications for interhemispheric communication. AB - We report a case of a 47-year-old woman with 35-year history of multiple sclerosis, who showed alien hand signs, a rare behavioural disorder that involves unilateral goal-directed movements that are contrary to the individual's intention. Alien hand syndrome has been described in multiple sclerosis (MS) only occasionally and is generally suggestive of callosal disconnection. The patient presented also with bilateral limb apraxia and left hand agraphia, raising the possibility of cortical dysfunction or disconnection, in addition to corpus callosum and white matter involvement. Her specific pattern of symptoms supports the role of the corpus callosum in interhemispheric communication for complex as well as fine motor activities and may indicate that it can serve as both an inhibitory and excitatory function depending on task demands. PMID- 24803737 TI - Vocabulary is an appropriate measure of premorbid intelligence in a sample with heterogeneous educational level in Brazil. AB - Crystallized intelligence refers to one's knowledge base and can be measured by vocabulary tests. Fluid intelligence is related to nonverbal aspects of intelligence, depends very little on previously acquired knowledge, and can be measured by tests such as Block Design (BD) and Raven Colored Matrices (RCM). Premorbid intelligence quotient (IQ) refers to one's intellectual ability level previous to the onset of disorders like mild cognitive impairment (MCI) and Alzheimer's disease (AD) and it is important to estimate disease severity. The objective was to compare performance in tests that measure crystallized and fluid intelligence in healthy subjects and patients with amnestic MCI (aMCI) and AD. One hundred forty-four participants (aMCI (n = 38), AD (n = 45), and healthy controls (n = 61)) were submitted to neuropsychological tests (WAIS-III vocabulary, BD, and RCM). There were significant among groups, except for vocabulary, indicating a relative stability of crystallized intelligence in the continuum from normal to pathological cognitive decline. Vocabulary seems to be stable during the progression of the disease and useful as a measure of premorbid intelligence, that is, to estimate previous function in relation to the level of education and, as a collateral measure of cognition in people with low education. PMID- 24803738 TI - Effects of direction and index of difficulty on aiming movements after stroke. AB - BACKGROUND: Brain hemispheres play different roles in the control of aiming movements that are impaired after unilateral stroke. It is not clear whether those roles are influenced by the direction and the difficulty of the task. OBJECTIVE: To evaluate the influence of direction and index of difficulty (ID) of the task on performance of ipsilesional aiming movements after unilateral stroke. METHODS: Ten individuals with right hemisphere stroke, ten with left hemisphere stroke, and ten age- and gender-matched controls performed the aiming movements on a digitizing tablet as fast as possible. Stroke individuals used their ipsilesional arm. The direction (ipsilateral or contralateral), size (0.8 or 1.6 cm), and distance (9 or 18 cm) of the targets, presented on a monitor, were manipulated and determined to be of different ID (3.5, 4.5, and 5.5). Results. Individuals with right hemisphere lesion were more sensitive to ID of the task, affecting planning and final position accuracy. Left hemisphere lesion generated slower and less smooth movements and was more influenced by target distance. Contralateral movements and higher ID increased planning demands and hindered movement execution. CONCLUSION: Right and left hemisphere damages are differentially influenced by task constraints which suggest their complementary roles in the control of aiming movements. PMID- 24803739 TI - Inhibiting C-reactive protein for the treatment of cardiovascular disease: promising evidence from rodent models. AB - Raised blood C-reactive protein (CRP) level is a predictor of cardiovascular events, but whether blood CRP is causal in the disease process is unknown. The latter would best be defined by pharmacological inhibition of the protein in the context of a randomized case-control study. However, no CRP specific drug is currently available so such a prospective study cannot be performed. Blood CRP is synthesized primarily in the liver and the liver is an organ where antisense oligonucleotide (ASO) drugs accumulate. Taking advantage of this we evaluated the efficacy of CRP specific ASOs in rodents with experimentally induced cardiovascular damage. Treating rats for 4 weeks with a rat CRP-specific ASO achieved >60% reduction of blood CRP. Notably, this effect was associated with improved heart function and pathology following myocardial infarction (induced by ligation of the left anterior descending artery). Likewise in human CRP transgenic mice treated for 2 weeks with a human CRP-specific ASO, blood human CRP was reduced by >70% and carotid artery patency was improved (2 weeks after surgical ligation). CRP specific ASOs might pave the way towards a placebo controlled trial that could clarify the role of CRP in cardiovascular disease. PMID- 24803740 TI - Increased peripheral proinflammatory T helper subsets contribute to cardiovascular complications in diabetic patients. AB - BACKGROUND: Coronary atherosclerotic heart disease (CHD) is one of the major concerns in type 2 diabetes (T2D). The systemic chronic inflammation has been postulated to bridge the increased risk of cardiovascular disease and T2D. We formulated that increased peripheral proinflammatory T helper subsets contributed to the development of cardiovascular complications in diabetic patients. METHODS: The frequencies of peripheral total CD4+ T helper cells, proinflammatory Th1, Th17, and Th22 subsets were determined by flow cytometry in diabetic patients with or without CHD (n = 42 and 67, resp.). RESULTS: Both peripheral frequencies and total numbers of Th1, Th17, and Th22 cells were further increased in diabetic patients with CHD. Logistic regression and categorical cross-table analysis further confirmed that increased proinflammatory Th subsets, especially Th22, were independent risk factors of cardiovascular complication in diabetes. Elevated Th subsets also correlated with increased CRP levels and the atherogenic index of plasma. Moreover, Th1 frequency and Th22 numbers demonstrated remarkable potential in predicting CHD in diabetes. CONCLUSIONS: Increased peripheral proinflammatory T helper subsets act in concert and contribute to the increased prevalence of diabetic cardiovasculopathy. The recently identified Th22 cells might play an independent role in CHD and represent a novel proxy for cardiovascular risks in diabetes. PMID- 24803741 TI - Targeting TNF and its family members in autoimmune/inflammatory disease. PMID- 24803743 TI - Neutrophil cathepsin G, but not elastase, induces aggregation of MCF-7 mammary carcinoma cells by a protease activity-dependent cell-oriented mechanism. AB - We previously found that a neutrophil serine protease, cathepsin G, weakens adherence to culture substrates and induces E-cadherin-dependent aggregation of MCF-7 human breast cancer cells through its protease activity. In this study, we examined whether aggregation is caused by degradation of adhesion molecules on the culture substrates or through an unidentified mechanism. We compared the effect of treatment with cathepsin G and other proteases, including neutrophil elastase against fibronectin- (FN-) coated substrates. Cathepsin G and elastase potently degraded FN on the substrates and induced aggregation of MCF-7 cells that had been subsequently seeded onto the substrate. However, substrate-bound cathepsin G and elastase may have caused cell aggregation. After inhibiting the proteases on the culture substrates using the irreversible inhibitor phenylmethylsulfonyl fluoride (PMSF), we examined whether aggregation of MCF-7 cells was suppressed. PMSF attenuated cell aggregation on cathepsin G-treated substrates, but the effect was weak in cells pretreated with high concentrations of cathepsin G. In contrast, PMSF did not suppress cell aggregation on elastase treated FN. Moreover, cathepsin G, but not elastase, induced aggregation on poly L-lysine substrates which are not decomposed by these enzymes, and the action of cathepsin G was nearly completely attenuated by PMSF. These results suggest that cathepsin G induces MCF-7 aggregation through a cell-oriented mechanism. PMID- 24803744 TI - Evidences of +896 A/G TLR4 polymorphism as an indicative of prevalence of complications in T2DM patients. AB - T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for the 55.6%. Patients with A/A and A/G TLR4 genotypes showed significant differences in complication's prevalence. In particular, AG carriers had higher risk prevalence for neuropathy (P = 0.026), lower limb arteriopathy (P = 0.013), and the major cardiovascular pathologies (P = 0.017). Their cumulative risk was significant (P = 0.01), with a threefold risk to develop neuropathy, lower limb arteriopathy, and major cardiovascular events in AG cases compared to AA cases. The adjusted OR for the confounding variables was 3.788 (95% CI: 1.642-8.741). Thus, the rs4986790 polymorphism may be an indicative of prevalence of complications in T2DM patients. PMID- 24803742 TI - Modulation of endothelial glycocalyx structure under inflammatory conditions. AB - The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed. PMID- 24803747 TI - Anesthesia and cancer recurrence: What is the evidence? PMID- 24803746 TI - BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibiting NF-kappaB activation. AB - beta-Hydroxybutyric acid (BHBA) has neuroprotective effects, but the underlying molecular mechanisms are unclear. Microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory enzymes and proinflammatory cytokines. The current study investigates the potential mechanisms whereby BHBA affects the expression of potentially proinflammatory proteins by cultured murine microglial BV-2 cells stimulated with lipopolysaccharide (LPS). The results showed that BHBA significantly reduced LPS induced protein and mRNA expression levels of iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6. Blocking of GPR109A by PTX resulted in a loss of this anti-inflammatory effect in BV-2 cells. Western blot analysis showed that BHBA reduced LPS-induced degradation of IkappaB-alpha and translocation of NF-kappaB, while no effect was observed on MAPKs phosphorylation. All results imply that BHBA significantly reduces levels of proinflammatory enzymes and proinflammatory cytokines by inhibition of the NF-kappaB signaling pathway but not MAPKs pathways, and GPR109A is essential to this function. Overall, these data suggest that BHBA has a potential as neuroprotective drug candidate in neurodegenerative diseases. PMID- 24803745 TI - Experimental cannabinoid 2 receptor-mediated immune modulation in sepsis. AB - Sepsis is a complex condition that results from a dysregulated immune system in response to a systemic infection. Current treatments lack effectiveness in reducing the incidence and mortality associated with this disease. The endocannabinoid system offers great promise in managing sepsis pathogenesis due to its unique characteristics. The present study explored the effect of modulating the CB2 receptor pathway in an acute sepsis mouse model. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS) in mice and intestinal microcirculation was assessed through intravital microscopy. We found that HU308 (CB2 receptor agonist) reduced the number of adherent leukocytes in submucosal venules but did not restore muscular and mucosal villi FCD in endotoxemic mice. AM630 (CB2 receptor antagonist) maintained the level of adherent leukocytes induced by LPS but further reduced muscular and mucosal villi FCD. URB597 (FAAH inhibitor) and JZL184 (MAGL inhibitor) both reduced the number of adherent leukocytes in submucosal venules but did not restore the mucosal villi FCD. Using various compounds we have shown different mechanisms of activating CB2 receptors to reduce leukocyte endothelial interactions in order to prevent further inflammatory damage during sepsis. PMID- 24803748 TI - Translational research and anesthesia. PMID- 24803749 TI - Are we causing the recurrence-impact of perioperative period on long-term cancer prognosis: Review of current evidence and practice. AB - Newer developments in the field of chemotherapeutic drug regimes, radiotherapy, and surgical techniques have improved the prognosis of cancer patients tremendously. Today increasing numbers of patients with aggressive disease are posted for surgical resection. The advances in reconstructive flap surgery offer the patient a near normal dignified postresection life. Hence, the expectations from the patients are also on the rise. Anesthetic challenges known in oncosurgery are that of difficult airway, maintenance of hemodynamics and temperature during long surgical hours, pain management, and postoperative intensive care management. But, recently acquired data raised the possibility of the anesthetic technique and conduct of perioperative period as a possible contributory factor in the growth and possible recurrence of the primary tumor. The foundation of the concept is somewhat fragile and not supported by conclusive evidence. In fact, like any other controversial topic in medicine, contradictory reports of the favorable effects of anesthetic technique and medications are plenty in the literature. This is the basis of our article where we have analyzed the current evidence available in the literature and how these and the forthcoming large scale studies may revolutionize the practice of oncoanesthesia. PMID- 24803751 TI - Best of both worlds-endotracheal intubation without paralysis. PMID- 24803752 TI - Anesthesiologists, Anesthetics, and Cancer metastasis. PMID- 24803750 TI - Antioxidants: The new frontier for translational research in cerebroprotection. AB - It is important for the anesthesiologist to understand the etiology of free radical damage and how free-radical scavengers attenuate this, so that this knowledge can be applied to diverse neuro-pathological conditions. This review will concentrate on the role of reactive species of oxygen in the pathophysiology of organ dysfunction, specifically sub arachnoid hemorrhage (SAH), traumatic brain injury (TBI) as well as global central nervous system (CNS) hypoxic, ischemic and reperfusion states. We enumerate potential therapeutic modalities that are been currently investigated and of interest for future trials. Antioxidants are perhaps the next frontier of translational research, especially in neuro-anesthesiology. PMID- 24803753 TI - ProSeal laryngeal mask airwayTM insertion in the prone position: Optimal utilization of operation theatre personnel and time? AB - BACKGROUND: Positioning an anesthetized patient prone is challenging with regard to manpower requirement, time to surgical readiness and airway management. The ProSeal laryngeal mask airwayTM (PLMA) is emerging as a suitable alternative, both as a primary and a rescue airway device to the tracheal tube (TT) for patients undergoing surgery in the prone position. MATERIALS AND METHODS: In this prospective randomized study, 70 patients scheduled to undergo pilonidal sinus excision in prone position were allocated to two groups of 35 patients each, depending on the position of the patient at induction and device placement: Group S (device placed while supine) and Group P (device placed while prone). We compared the manpower requirement, time to surgical readiness, efficacy and safety of the PLMA for airway management in the two groups. RESULTS: The number of personnel [5 (4-6) vs. 3 (3-3); P < 0.001] required for positioning the patient and surgical readiness time (22.1 +/- 3 vs. 5.9 +/- 0.9 min; P < 0.001) was higher in group S. There was no difference between the two groups with regard to efficacy and safety of the PLMA. Incidence of blood on the PLMA cuff and sore throat was comparable in the two groups (P = 1.000). CONCLUSION: We conclude that induction and placing the PLMA in the prone position by experienced users require fewer personnel and reduces surgical readiness time. PMID- 24803754 TI - Comparison of I-gel with proseal LMA in adult patients undergoing elective surgical procedures under general anesthesia without paralysis: A prospective randomized study. AB - BACKGROUND: We compared i-gel and ProSeal laryngeal mask airway (PLMA) regarding time taken for insertion, effective seal, fiberoptic view of larynx, ease of Ryle's tube insertion, and postoperative sore throat assessment. MATERIALS AND METHODS: In a prospective, randomized manner, 48 adult patients of American Society of Anesthesiologists I-II of either gender between 18 and 60 years presenting for a short surgical procedure were assigned to undergo surgery under general anesthesia on spontaneous ventilation using either the i-gel or PLMA. An experienced nonblinded anesthesiologist inserted appropriate sized i-gel or PLMA in patients using standard insertion technique and assessed the intraoperative findings of the study regarding regarding time taken for respective device insertion, effective seal, fiberoptic view of larynx, ease of Ryle's tube insertion, and postoperative sore throat assessment. Postoperative assessment of sore throat was done by blinded anesthesia resident. RESULTS: The time required for insertion of i-gel was lesser (21.98 +/- 5.42 and 30.60 +/- 8.51 s in Group I and Group P, respectively; P = 0.001). Numbers of attempts for successful insertions were comparable and in majority, device was inserted in first attempt. The mean airway leak pressures were comparable. However, there were more number of patients in Group P who had airway leak pressure >20 cm H2O. The fiberoptic view of glottis, ease of Ryle's tube insertion, and incidence of complications were comparable. CONCLUSION: Time required for successful insertion of i-gel was less in adult patients undergoing short surgical procedure under general anesthesia on spontaneous ventilation. Patients with airway leak pressure >20 cm H2O were more in PLMA group which indicates its better suitability for controlled ventilation. PMID- 24803755 TI - Bedside prediction of airway length by measuring upper incisor manubrio-sternal joint length. AB - BACKGROUND: Malpositioning of endotracheal tube may lead to serious complications like endobronchial intubation or accidental extubation. Using anatomical measurements for prediction of airway length would be more practical in resource constrained settings. MATERIALS AND METHODS: One hundred adult patients of American Society of Anesthesiologists (ASA) grade 1 or 2, without any evidence of difficult airway, were randomly allocated to two cohorts - a model cohort of 70 (50 males) and test cohort of 30 (20 males) subjects. Height, the straight length from the upper incisor to manubrio-sternal joint in fully extended head position (IncManustL), the length from upper incisor to the carina in neutral head position (IncCarinaL), and degree of neck extension were measured in all subjects. Relationship between the two lengths in the model cohort was explored by Pearson's coefficient (r). Predictions were made for subjects in the test cohort and actual and predicted values assessed for agreement using intra-class correlation coefficient (ICC). RESULTS: Good agreement was found between IncManustL and IncCarinaL for both male (r = 0.69) and female (r = 0.54) subjects. Multiple regression analysis suggested height to be another significant predictor, unlike age, weight, and neck extension. The gender-specific regression equations were used to predict IncCarinaL for the test cohort. ICC for absolute agreement between the actual and predicted values was 0.723 (95% CI 0.495-0.858). CONCLUSIONS: It is possible to predict airway length in adult Indian subjects by making two simple anatomical measurements, namely stature and incisor manubrio sternal joint length. PMID- 24803756 TI - Comparison of i-gel supraglottic airway and LMA-ProSealTM in pediatric patients under controlled ventilation. AB - BACKGROUND: i-gelTM and the ProSealTM laryngeal mask airway (PLMA) are two supraglottic airway devices with gastric channel used for airway maintenance in anesthesia. This study was designed to evaluate the efficacy of i-gel compared with PLMA for airway maintenance in pediatric patients under general anesthesia with controlled ventilation. MATERIALS AND METHODS: A total of 60 American Society of Anesthesiologists physical status 1 and 2 patients were included in the study and randomized to either i-gel or PLMA group. After induction of anesthesia using a standardized protocol for all the patients, one of supraglottic airway devices was inserted. Insertion parameters, ease of gastric tube insertion and fiber-optic scoring of the glottis were noted. Airway parameters such as end-tidal carbon dioxide (EtCO2), peak airway pressures and leak airway pressures were noted. Patients were observed for any complications in the first 12 h of the post-operative period. RESULTS: Both groups were comparable in terms of ease of insertion, number of attempts and other insertion parameters. Ease of gastric tube insertion, EtCO2, airway pressures (peak and leak airway pressure) and fiber-optic view of the glottis were comparable in both groups. There were no clinically significant complications in the first 12 h of the post operative period. CONCLUSION: i-gel is as effective as PLMA in pediatric patients under controlled ventilation. PMID- 24803757 TI - Transtracheal lidocaine: An alternative to intraoperative propofol infusion when muscle relaxants are not used. AB - BACKGROUND: Facial nerve monitoring, often required during total parotidectomy, precludes use of long acting muscle relaxants and propofol infusion is used solely to ensure patient immobility. We aimed to compare intraoperative patient immobility, hemodynamic stability and propofol consumption during total parotidectomy following a transtracheal block. MATERIAL AND METHODS: Forty patients were allocated to 2 equal groups. Preoperatively, group A patients received transtracheal block with 4 ml of 4% lidocaine, while no block was given to patients in group B. If there was patient movement, tachycardia or hypertension, group A patients received a bolus of propofol 30 mg and propofol infusion was started (100mg/hr). In group B, propofol infusion was started (100mg/hr) soon after intubation. RESULT: Both group A and B were comparable with respect to patient immobility and hemodynamic stability. There was no intraoperative propofol requirement in group A. CONCLUSION: Transtracheal block is a safe and successful alternative to propofol infusion during surgeries where muscle relaxants are to be avoided. PMID- 24803758 TI - The efficacy and hemodynamic response to Dexmedetomidine as a hypotensive agent in posterior fixation surgery following traumatic spine injury. AB - AIM: This study was designed to evaluate the efficacy of dexmedetomidine (DEX) as a hypotensive agent in comparison to nitroglycerin (NTG) in posterior fixation surgery for traumatic spine injury. MATERIALS AND METHODS: Forty patients ASA I or II aged 18-65 years scheduled for posterior fixation surgery were randomly assigned to receive either DEX 1 MUg/kg over 10 min before induction of anesthesia followed by 0.2-0.7 MUg/kg/h infusion during maintenance in DEX group or NTG 3-5 MUg/kg/min infusion after induction of anesthesia in NTG group to maintain mean arterial blood pressure (MAP) between 65 and 70 mmHg. The two groups were compared for achievement of target MAP, intraoperative blood loss, and reversibility of hypotensive state. Student's t-test was used for continuous variables and chi-square test for categorical variables. P-value < 0.05 was considered significant. RESULTS: Patients in DEX group achieved the target MAP with better heart rate (HR) control, as compared to NTG group during the period of observation. The blood loss was significantly lesser in the DEX group (422.11 +/- 149.34 ml) than the NTG group (564.51 +/- 160.88 ml), P = 0.01. The time to hypotension reversal in NTG group (5.63 +/- 1.93 min) was lesser compared to DEX group (9.15 +/- 2.16 min), P = 0.65. CONCLUSION: DEX is an effective and safe agent in achieving controlled hypotension in adults undergoing posterior fixation spine surgery. PMID- 24803759 TI - Dexmedetomidine decreases requirement of thiopentone sodium and pentazocine followed with improved recovery in patients undergoing laparoscopic cholecystectomy. AB - BACKGROUND: Pain relief remains the most fundamental and consequential aspect of surgery for patients throughout perioperative period. Dexmedetomidine has created an interest in alpha2-adrenoceptor agonists in the management of pain and hence the aim of this study was to evaluate the effectiveness of the drug in hilly population of North India. MATERIALS AND METHODS: Patients, irrespective of gender, were randomly allocated to two groups, control and test, each having 30 patients. Test group received an infusion of dexmedetomidine at a rate of 0.5 MUg/kg/h 30 min before induction and 0.6 MUg/kg/h after inducing anesthesia. Control patients received a volume-matched infusion of normal saline as placebo. Approximately 2 min before induction, analgesia was provided in the form of pentazocine, 0.5 mg/kg in control and 0.3 mg/kg in the test group. Induction was performed by 2 mg/kg thiopentone sodium supplemented with intravenous boluses of 25 mg thiopentone sodium every 15 s until loss of eyelid reflex (determined every 15 s). Induction dose of thiopentone sodium and total pentazocine dose were recorded. Recovery was assessed on the clinical recovery score (CRS) scale. RESULTS: Infusion of dexmedetomidine decreased the induction dose of thiopentone approximately by 33% and of pentazocine dose by approximately 39% in patients undergoing laparoscopic cholecystectomy. Moreover, incidence of pain was also decreased significantly. Improved CRS from 4.33 to 6.87 was noticed immediately post-operatively in dexmedetomidine group of patients. CONCLUSION: Infusion of dexmedetomidine during the laparoscopic cholecystectomy decreases the requirement of thiopentone sodium and pentazocine and leads to early recovery of patients. PMID- 24803760 TI - Prevention of propofol injection pain: Comparison between lidocaine and ramosetron. AB - BACKGROUND: Propofol causes a high incidence of pain during intravenous (IV) injection. The aim of this randomized, placebo-controlled, double-blinded study was to determine whether pre-treatment with IV ramosetron, used for prophylaxis of postoperative nausea and vomiting (PONV), would reduce propofol-induced pain as an equivalent to lidocaine. MATERIALS AND METHODS: Hundred and twenty American Society of Anesthesiologists grade (ASA) I and II patients were randomly assigned into three groups (40 in each). Group N received 2 ml of 0.9% saline, Group L received 2 ml of lidocaine, and Group R received 2 ml of ramosetron. Mid forearm was occluded manually before injection and released after 1 min and then propofol was injected over 5 s. Patients were observed and questioned 15 s later if they had pain in the arm and pain was scored on a four-point scale: 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain. Unpaired Student's t-test and chi-square test/Fisher' exact test were used to analyze results. RESULTS: The incidence of pain in groups N, L, and R were 65, 35, and 30%, respectively. Pain was reduced significantly in the groups L and R (P < 0.05). Two patients each in Groups L and R (5% each) had moderate and severe pain. This difference in pain was statistically insignificant, but when compared to Group N (25 and 30%, respectively) it was statistically significant. CONCLUSION: Pretreatment with ramosetron 0.3 mg and lidocaine 40 mg are equally effective in preventing pain from propofol injection. PMID- 24803761 TI - Prophylactic effect of ephedrine to reduce hemodynamic changes associated with anesthesia induction with propofol and remifentanil. AB - BACKGROUND: One of the complications of anesthesia induction with propofol is a substantial decrease in arterial blood pressure and heart rate (HR), which can be intensified by adding remifentanil. This study aimed to assess the prophylactic effects of two doses of ephedrine to control the hypotension and bradycardia caused by anesthesia induced with propofol and remifentanil. MATERIALS AND METHODS: A total of 150 patients candidate for short-term minor elective orthopedic and ophthalmic surgery under general anesthesia were randomized to three groups receiving normal saline, low dose ephedrine (0.07 mg/kg) or high dose ephedrine (0.15 mg/kg). Anesthesia was induced in all groups with propofol 2.5 mg/kg and remifentanil 3 MUg/kg. No neuromuscular blocking agent was used. Patients' hemodynamic status was assessed in the following four steps: Immediately before, 2 min after induction of anesthesia, as well as 1 and 5 min after intubation. RESULTS: A total of 143 patients consisting of 46 patients in the low dose ephedrine (0.07 mg/kg) group, 49 patients in the high dose ephedrine (0.15 mg/kg) group and 48 controls completed the trial. In all three groups, after induction of anesthesia, significant decreases occurred in the mean systolic, diastolic and mean arterial pressures, as well as in the mean HR. This decline was highest in the control group and lowest in the high dose ephedrine (0.15 mg/kg) group. CONCLUSION: Our findings suggest that the administration of high dose ephedrine (0.15 mg/kg) may have a significant effect in preventing hypotension and bradycardia after anesthesia induction with propofol and remifentanil. PMID- 24803762 TI - Cost efficiency of target-controlled inhalational anesthesia. AB - BACKGROUND: Cost and environmental pollution are two prime concerns with general anesthesia. We hypothesized that target-controlled (TC) anesthesia drug delivery system also called as end-tidal (ET) control is an effective and safe system that would reduce the cost and also environmental pollution. MATERIALS AND METHODS: We studied 200 patients undergoing laparoscopic abdominal and pelvic surgeries and randomly distributed those in 2 groups of 100 each, TC and manual-controlled (MC) group. We reviewed the two groups in term of consumption of gases, time required to achieve the ET concentration of sevoflurane of 1.5%, maximum inspired concentration of sevoflurane achieved, and number of adjustments required to maintain the depth of anesthesia. RESULTS: We found that the consumption of nitrous oxide and sevoflurane was significantly less in TC group than MC group (P < 0.05), oxygen consumption was also less in TC group but not statistically significant. The time required to achieve the desired levels, maximum inspired sevoflurane concentration achieved, and the number of drug delivery adjustments required were statistically significant in TC group (P < 0.05). As the consumption reduced in TC group, the cost of the inhalational anesthesia reduced by approximately Rs. 64/h ($1.12) and thus the environmental pollution. CONCLUSION: We concluded from our study that ET control is a good system for conserving the consumption of gases and thus is efficient as it reduces both the cost and the environmental pollution. PMID- 24803763 TI - Minimum effective volume of normal saline for epidural volume extension. AB - BACKGROUND: Rescue strategies like changes in tilt of table are used to raise the level of an inadequate sensory block following intrathecal injection. Epidural volume extension (EVE) refers to an injection of normal saline through epidural catheter following an intrathecal block. It results in a rapid increase in the sensory level of subarachnoid block. Thus, it has been postulated that EVE may be used as a rescue strategy for an inadequate post-spinal sensory block. However, the minimum effective volume (MEV) of normal saline for EVE induced increase in level of spinal block has not been researched till date. We proposed to determine the MEV of normal saline required for EVE induced increase in post-spinal block sensory level. MATERIALS AND METHODS: This prospective sequential allocation study was conducted in consenting adult males after institutional ethical committee approval scheduled for lower limb surgery under combined spinal epidural (CSE) anesthesia, who had an inadequate level of sensory block. Herein, an inadequate level was defined as lower than T10 at 10 min after the intrathecal injection, with no ascent for two consecutive readings taken 2 min apart. The EVE was performed with normal saline injected through epidural catheter, and was considered successful if the level of sensory block increased by two or more dermatomal segments within 5 min of the injection. The volume of normal saline for EVE was decided by using the up-and-down method, with the first patient receiving 10 mL and a dosing interval of 1 mL in subsequent patients. The analysis was done using the formula of Dixon and Massey, which enabled calculation of the MEV with 95% CI. Quantitative parametric data is represented as mean +/- SD and nonparametric data as median (range). RESULTS AND CONCLUSION: The MEV of normal saline to raise the level of sensory block by two or more dermatomal segments within 5 min of EVE is 7.4 mL (95% CI: 5.5-9.9 mL). PMID- 24803764 TI - Low dose intrathecal clonidine and fentanyl added to hyperbaric bupivacaine prolongs analgesia in gynecological surgery. AB - BACKGROUND: We undertook this study to ascertain if a small dose of clonidine (30 MUg) when added to a bupivacaine-fentanyl mixture improves spinal analgesia, without producing side effects, as compared to a bupivacaine-fentanyl or a bupivacaine-clonidine mixture. MATERIALS AND METHODS: In this prospective, randomized, double-blind study, 75 (American Society of Anesthesiologists) ASA grade I-II patients, aged between 45 and 65 years, who were scheduled for vaginal hysterectomy with pelvic floor repair or non-descent vaginal hysterectomy under spinal anesthesia were recruited. The patients received hyperbaric bupivacaine (2.3 ml) with fentanyl 15 MUg (Group BF) or clonidine 30 MUg (Group BC) or both fentanyl (15 MUg) and clonidine (30 MUg) (Group BCF). The total amount of intrathecal mixture was constant (2.8 ml) in all the groups. Duration of sensory, motor block and effective analgesia, hemodynamic profile, postoperative pain score and analgesic requirements were recorded. RESULTS: The duration of effective analgesia, mean time till two-segment regression, and duration of sensory and motor block were significantly longer in group BCF as compared to group BC (P ~ 0.002), and in group BC as compared to group BF (P ~ 0.01). The incidence of intraoperative pain and requirement of postoperative analgesics in the first 24 hours was significantly more in group BF as compared to the other groups (P ~ 0.01). There was no difference in the hemodynamic profile between the groups. CONCLUSION: Low-dose clonidine (30 MUg) when added to a bupivacaine fentanyl mixture increased the duration of effective analgesia and the duration of sensory and motor block in gynecological surgery. The incidence of intraoperative pain and requirement of postoperative analgesics was significantly less when clonidine was added to intrathecal bupivacaine with or without fentanyl. PMID- 24803765 TI - A comparative evaluation of hyperbaric ropivacaine versus hyperbaric bupivacaine for elective surgery under spinal anesthesia. AB - BACKGROUND: Recently introduced ropivacaine is 40% less potent than bupivacaine. Ropivacaine made hyperbaric by the addition of dextrose is known to provide reliable spinal anesthesia (SA). This study was designed to compare the clinical efficacy of equal doses of hyperbaric 0.5% ropivacaine with 0.5% bupivacaine for SA. MATERIALS AND METHODS: Eighty American Society of Anesthesiologists grade I II patients undergoing elective infraumbilical surgeries under SA were recruited and randomized to receive 3ml of hyperbaric ropivacaine 5mg/ml containing dextrose 83 mg/ml (by the addition of desired dose of 25% dextrose) in Group R or 3ml of hyperbaric bupivacaine 5mg/ml containing dextrose 80 mg/ml in Group B. Monitoring of vitals and observation for the block parameters were carried out. The data were presented as mean with a standard deviation and frequency with percentage. Statistical analysis was performed using InStat computer software with appropriate tests and P < 0.05 was considered to be significant. RESULTS: Ropivacaine produced a slower onset of sensory block (ropivacaine 4.5 min; bupivacaine 3.2 min; P < 0.05) and the mean total duration of sensory block was significantly lesser (ropivacaine155 min; bupivacaine 190.5 min; P < 0.05). Patients in the ropivacaine Group R had significantly more rapid recovery from the motor blockade (ropivacaine120 min; bupivacaine 190 min; P < 0.05) and passed urine sooner than the patients in bupivacaine Group B (ropivacaine 257 min; bupivacaine 358 min; P < 0.05). CONCLUSION: Ropivacaine 15 mg in dextrose 8.3% provides reliable SA of shorter duration than bupivacaine 15 mg in 8% dextrose. PMID- 24803766 TI - Early post-operative relief of pain and shivering using diclofenac suppository versus intravenous pethidine in spinal anesthesia. AB - BACKGROUND: Pain and shivering are two challenging components in the post operative period. Many drugs were used for prevention and treatment of them. The aim of this study was to compare the effects of prophylactic prescription of diclofenac suppository versus intravenous (IV) pethidine in spinal anesthesia. MATERIALS AND METHODS: We conducted a multi central, prospective, double-blind, randomized clinical trial on a total of 180 patients who were scheduled for surgery under spinal anesthesia including 60 patients in three groups. Patients were randomly allocated to receive 100 mg sodium diclofenac suppository or 30 mg IV pethidine or placebo. Categorical and continuous variables were analyzed by Chi-square test, t-test, Mann-Whitney and ANOVA or Kruskal-Wallis tests. RESULTS: There was no statistical difference with regard to patient characteristics and hemodynamic indices among the three groups. Nine (15%), 10 (16.65%) and 24 (40%) of patients in diclofenac, pethidine and control groups reported pain and 2, 2, 7 patients received treatment due to it, respectively (P = 0.01). Prevalence of shivering in pethidine group and diclofenac group was the same and both of them were different from the control group (P < 0.001). Pruritus was repetitive in the pethidine group and was statistically significant (P = 0.036) but, post-operative nausea and vomiting was not significantly different among groups. CONCLUSION: A single dose of sodium diclofenac suppository can provide satisfactory analgesia immediately after surgery and decrease shivering without remarkable complications. This investigation highlights the role of pre-operative administration of a single dose of rectal diclofenac as a sole analgesic for early post-operative period. PMID- 24803767 TI - The association of gender and body mass index with postoperative pain scores when undergoing ankle fracture surgery. AB - BACKGROUND: Intraoperative administration of opiates for postoperative analgesia requires a dosing strategy without clear indicators of pain in an anesthetized patient. Preoperative patient characteristics such as body mass index (BMI), gender, age, and other patient characteristics may provide important information regarding opiate requirements. This study intends to determine if there is an association between gender or BMI and the immediate postoperative pain scores after undergoing an open reduction and internal fixation (ORIF) of an ankle fracture with general anesthesia and morphine only analgesia. MATERIALS AND METHODS: Using a retrospective cohort design, the perioperative records were reviewed at a university healthcare hospital. One hundred and thirty-seven cases met all inclusion and no exclusion criteria. Postanesthesia care unit (PACU) records were reviewed for pain scores at first report and 30 min later as well as PACU opiate requirements. T-test, chi-square, and Mann-Whitney tests compared univariate data and multivariate analysis was performed by linear regression. RESULTS: There were no statistically significant PACU pain score group differences based on gender or BMI. Post hoc analysis revealed that in the setting of similar pain scores, obese patients received a similar weight based intraoperative morphine dose when using adjusted body weight (ABW) compared to nonobese subjects. A further finding revealed a negative correlation between age and pain score (P = 0.001). CONCLUSION: This study did not find an association between obesity or gender and postoperative pain when receiving morphine only preemptive analgesia. This study does support the use of ABW as a means to calculate morphine dosing for obese patients and that age is associated with lower immediate pain scores. PMID- 24803768 TI - Respiratory complications associated with ketamine anesthesia for ophthalmic procedures following intraocular pressure measurement in children. AB - BACKGROUND: We compared respiratory complications (RCs) in children who received intramuscular (IM) versus intravenous (IV) or no ketamine for intraocular pressure (IOP) measurement to test our observation that IM ketamine is associated with higher incidence of RCs. MATERIALS AND METHODS: We analyzed 149 eye examinations under anesthesia with ketamine in 27 patients and 263 non-ketamine examinations under anesthesia in 81 patients using a mixed effects logistic regression model. RESULTS: IM KETAMINE WAS STRONGLY ASSOCIATED WITH INCREASED ODDS OF RCS COMPARED TO NO KETAMINE (ODDS RATIO (OR): 20.23, P < 0.0001) and to IV ketamine (OR: 6.78, P = 0.02), as were higher American Society of Anesthesiologists (ASA) classification (OR: 2.60, P = 0.04), and the use of volatile agents (OR: 3.32, P = 0.02). CONCLUSION: Further studies should be conducted to confirm our observation of increased RCs with IM ketamine. PMID- 24803769 TI - Perioperative management and post-operative course in preterm infants undergoing vitreo-retinal surgery for retinopathy of prematurity: A retrospective study. AB - BACKGROUND: Premature infants scheduled for surgery under general anesthesia are more prone to cardio-respiratory complications. Risk factors include post conception age (PCA), cardiac and respiratory disease, anemia and opioid administration. This retrospective study evaluates the perioperative management and post-operative course (apnea and bradycardia) in premature infants undergoing surgery for retinopathy of prematurity (ROP). MATERIALS AND METHODS: We analyzed the pre-operative data, anesthesia chart and post-operative course of 52 former premature infants for 56 general anesthesia exposures for ROP surgery. RESULTS: At the time of procedure, median PCA was 51 (36-60) weeks. 71% of the infants were above 46 weeks of PCA. Five infants had cardiac disease and four had a history of convulsion. Four infants had a pre-operative history of apneic spells. The airway was secured with either endotracheal tube (46) or supraglottic device (10). Fentanyl (0.5-1 MUg/kg), paracetamol, topical anesthetic drops and/or peribulbar block were administered for analgesia. Extubation was performed in the operating room for 54 cases. Three infants had apnea post-operatively. Seven infants were shifted to neonatal intensive care unit either for observation or due to delayed recovery, persistent apneic spells and pre-existing cardio respiratory disease. CONCLUSION: In the present study, intravenous paracetamol and topical anesthetics reduced the total intra-operative opioid requirement, which resulted in low incidence of post-operative apnea. Regional anesthesia may be considered in infants with high risk of post-operative apnea. Infants with PCA > 42 weeks and without any co-morbidity can be managed in post-anesthesia care unit. PMID- 24803770 TI - VEINROM: A possible solution for erroneous intravenous drug administration. AB - Erroneous intravenous drug administration has a high probability of causing substantial financial consequences along with patient morbidity or mortality. Anesthesiologists and hospital administrators need to be cognizant of the problem. National and international anesthesiology bodies should be involved with the medical device manufacturing industry to alleviate this long standing enigma. We propose our concept Vassopressors, Emergency drugs, Induction agents, Reversal agents, Opioids and Miscellaneous (VEINROM) as a conceivable solution to this paradox. PMID- 24803771 TI - Percutaneous retrieval of malpositioned, kinked and unraveled guide wire under fluoroscopic guidance during central venous cannulation. AB - The placement of central venous catheter using Seldinger's technique, remains a commonly performed procedure with its own risks and benefits. Various complications have been reported with the use of guide wire as well as catheter. We report a unique problem during subclavian vein cannulation due to guidewire malposition which led to its kinking and difficult retrieval requiring removal in fluoroscopy suit. The probable mechanism of guide wire entrapment and possible bedside management of similar problems is described. PMID- 24803772 TI - A rare occurrence of pyloric stenosis in an infant with osteogenesis imperfecta: Anesthetic implications. AB - Congenital anomalies pose many challenges during anesthesia due to anatomic and physiological alterations. The inherent complications associated with the disorders necessitate vigilance for providing anesthesia to even seemingly simple surgical intervention. Here, we share our experience of anesthesia management of an infant of congenital osteogenesis imperfecta with pyloric stenosis for pyloromyotomy. PMID- 24803773 TI - Transient unilateral brachial plexopathy and partial Horner's syndrome following spinal anesthesia for cesarean section. AB - A healthy 21-year-old primigravida presented for elective cesarean section. At 45 min after intrathecal (IT) injection of bupivacaine, morphine and fentanyl she developed dysphagia, right sided facial droop, ptosis and ulnar nerve weakness. This constellation of signs and symptoms resolved 2 h later. Based on the time course and laterality of her symptoms, as well as the pharmacologic properties of spinal opioids, we believe her symptoms can be attributed to the IT administration of fentanyl. PMID- 24803774 TI - Sevoflurane and thoracic epidural anesthesia for trans-sternal thymectomy in a child with juvenile myasthenia gravis. AB - Literature on anesthetic management of juvenile myasthenia gravis (JMG) for thymectomy is limited. Recently, use of inhalational agents and total intravenous anesthesia with propofol and remifentanyl has been reported. All these techniques individually or in combination have been tried to avoid the use of muscle relaxant. We report successful use of sevoflurane as sole anesthetic agent for intubation and in combination with thoracic epidural anesthesia for intraoperative anesthetic management in a 5-year-old child with JMG. PMID- 24803775 TI - Airway management of a child with frontometaphyseal dysplasia (Gorlin Cohen syndrome). AB - Frontometaphyseal dysplasia (FMD), also called Gorlin-Cohen syndrome, is a rare hereditary X-linked dominant craniotubular bone disorder. The presentation describes the airway management of a 2-year-old child suffering from FMD with significant retrognathia, posted for major long bone corrective osteotomy. Induction with a combination of dexmedetomidine and ketamine preceded a successful endotracheal intubation under spontaneous ventilation. PMID- 24803776 TI - Incidental thrombocytosis: Should it concern the anesthesiologist? AB - Preoperative thrombocytosis, often detected incidentally in surgical patients and inadvertently overlooked, has important implications for the anesthesiologists. The primary form is a chronic clonal myeloproliferative disorder usually affecting adults while the secondary type is a benign reactive disease commonly found in children. Serious perioperative hemostatic complications are reported in primary thrombocytosis and hence, a detailed preoperative evaluation and initiation of therapy to lower the platelet count (PC) is required before undertaking surgery. Patients with reactive thrombocytosis however, usually have complication-free surgeries, and if there is no prior evidence of hemostatic complications and the reactive cause can be identified, no specific perioperative intervention may be required. A thorough preanesthetic checkup and implementation of basic thrombo-prophylaxis measures in all patients with a raised PC is advocated. We present here our experience with three infants diagnosed with high preoperative PC, presumably due to reactive causes, who underwent uneventful neurosurgeries at our institution. PMID- 24803777 TI - Postoperative monitoring in pregnant patients undergoing surgery for advanced malignancy in last trimester: How long is enough? AB - Surgery for advanced breast malignancy in the last trimester of pregnancy is uncommon. We present successful management of a 32-year-old woman, 30 weeks pregnant with stage 3 breast malignancy, for surgery followed by normal labor and chemotherapy. Surgery and intraoperative period were uneventful. Patient had uterine contractions 36 h postsurgery, which were managed timely with active interventions and tocolytics. Risk of premature labor following nonobstetric surgery in pregnant patients is estimated to be 8.3%, but majority of the studies have been carried out in second trimester following appendectomy. There is insufficient data in literature regarding the estimation and duration of persistence of risk of premature labor in these patients. No guidelines are available regarding how long they need to be monitored for premature labor. There is some evidence, although little that risk of premature labor persists for 7 days postsurgery. In the absence of convincing studies and guidelines, we recommend postoperative monitoring for at least 7 days in patients undergoing major surgeries for malignancies in last trimester. Multidisciplinary approach is required to manage these patients. PMID- 24803778 TI - Modification in Laryngeal mask airway CTrach tube design. PMID- 24803780 TI - A clinical evaluation of the pediatric i-gelTM for airway management during MRI examination. PMID- 24803779 TI - Position of bite block in size 1 laryngeal mask airway ProSealTM and stability during insertion. PMID- 24803781 TI - Platelet function assessment for epidural catheter removal in patient receiving Plavix. PMID- 24803782 TI - Fatal mediastinal hematoma following right internal jugular vein cannulation. PMID- 24803783 TI - Hypobaric spinal anesthesia in a paraplegic patient. PMID- 24803784 TI - Intraoperative pulseless ventricular tachycardia after Ondansetron. PMID- 24803785 TI - Post thoracotomy cardiorespiratory arrest: Perhaps avoidable? PMID- 24803786 TI - Anesthetic management during electroconvulsive therapy in a patient with burn injury. PMID- 24803787 TI - Erdheim - Chester disease: Clinical pearls for the anesthesiologist. PMID- 24803788 TI - Ascaris: An unusual cause of airway obstruction during general anesthesia with ProSeal laryngeal mask airway. PMID- 24803789 TI - Regurgitant food particle causing intractable laryngospasm during emergence from anesthesia. PMID- 24803790 TI - Incidental finding of organized thrombus in right inferior pulmonary vein extending in left atrium in the patient scheduled for esophagectomy: What should an anesthesiologist look for? PMID- 24803791 TI - The fatigued anesthesiologist: Improve operating room climate to minimize effect of residual anesthetics. PMID- 24803792 TI - Anesthetic management for patients with perforation peritonitis. PMID- 24803794 TI - Retraction notice. PMID- 24803793 TI - In Reply: Anesthetic management of patients with perforation peritonitis. PMID- 24803795 TI - Anti-TNF alpha in the treatment of ulcerative colitis: a valid approach for organ sparing or an expensive option to delay surgery? AB - Ulcerative colitis (UC) is an inflammatory bowel disease affecting large bowel with variable clinical course. The history of disease has been modified by the introduction of biologic therapy, in particular Infliximab (IFX), that has demonstrated efficacy in inducing fast symptoms remission, promoting mucosal healing and maintaining long-term remission. However, surgery is still needed for UC patients: in case of failure of medical therapy and if acute complications or a malignancy occurred. Surgical treatment is associated with a short-term post operative mortality and morbidity respectively of 0%-4% and 30%. In this study we systematically analyzed: the role of IFX in reducing the colectomy rate, the risk of post-operative morbidity in pre-operatively IFX-treated patients and the cost effectiveness of IFX therapy. Four of 5 analyzed randomized controlled trials demonstrated that therapy with IFX significantly reduces the colectomy rate. Moreover, pre-operative treatment with IFX doesn't seem to increase post operative infectious complications. By an economic point of view, the cost effectiveness of IFX-therapy was demonstrated for UC patients suffering from moderate to severe UC in a study based on a cost estimation of the National Health Service of England and Wales. However, the argument is debated. PMID- 24803796 TI - Inflammatory bowel disease and celiac disease: overlaps and differences. AB - Recent findings demonstrate the common genetic basis for many immune-mediated diseases, and consequently, the partially shared pathogenesis. We collected these findings and reviewed the extension of these overlaps to other disease characteristics. Two autoimmune diseases were selected that also share the specific target organ, the bowel. The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation, inflammatory bowel disease (IBD) and celiac disease (CeD), are not completely understood. Both are complex diseases with genetics and environment contributing to dysregulation of innate and adaptive immune responses, leading to chronic inflammation and disease. CeD constitutes a particular disease because the main environmental and genetic triggers are largely known. IBD comprises two main clinical forms, Crohn's disease and ulcerative colitis, which most likely involve a complex interplay between some components of the commensal microbiota and other environmental factors in their origin. These multifactorial diseases encompass a broad spectrum of clinical phenotypes and ages of onset, although the clinical presentation often differs depending on childhood or adult onset, with greater heterogeneity commonly observed in adults. PMID- 24803797 TI - Venous thrombosis and prothrombotic factors in inflammatory bowel disease. AB - Patients with inflammatory bowel disease (IBD) may have an increased risk of venous thrombosis (VTE). PubMed, ISI Web of Knowledge and Scopus were searched to identify studies investigating the risk of VTE and the prevalence of acquired and genetic VTE risk factors and prothrombotic abnormalities in IBD. Overall, IBD patients have a two- to fourfold increased risk of VTE compared with healthy controls, with an overall incidence rate of 1%-8%. The majority of studies did not show significant differences in the risk of VTE between Crohn's disease and ulcerative colitis. Several acquired factors are responsible for the increased risk of VTE in IBD: inflammatory activity, hospitalisation, surgery, pregnancy, disease phenotype (e.g., fistulising disease, colonic involvement and extensive involvement) and drug therapy (mainly steroids). There is also convincing evidence from basic science and from clinical and epidemiological studies that IBD is associated with several prothrombotic abnormalities, including initiation of the coagulation system, downregulation of natural anticoagulant mechanisms, impairment of fibrinolysis, increased platelet count and reactivity and dysfunction of the endothelium. Classical genetic alterations are not generally found more often in IBD patients than in non-IBD patients, suggesting that genetics does not explain the greater risk of VTE in these patients. IBD VTE may have clinical specificities, namely an earlier first episode of VTE in life, high recurrence rate, decreased efficacy of some drugs in preventing further episodes and poor prognosis. Clinicians should be aware of these risks, and adequate prophylactic actions should be taken in patients who have disease activity, are hospitalised, are submitted to surgery or are undergoing treatment. PMID- 24803798 TI - New serological markers in pediatric patients with inflammatory bowel disease. AB - The spectrum of serological markers associated with inflammatory bowel disease (IBD) is rapidly growing. Due to frequently delayed or missed diagnoses, the application of non-invasive diagnostic tests for IBD, as well as differentiation between ulcerative colitis (UC) and Crohn's disease (CD), would be useful in the pediatric population. In addition, the combination of pancreatic autoantibodies and antibodies against Saccharomyces cerevisiae antibodies/perinuclear cytoplasmic antibody (pANCA) improved the sensitivity of serological markers in pediatric patients with CD and UC. Some studies suggested that age-associated differences in the patterns of antibodies may be present, particularly in the youngest children. In CD, most patients develop stricturing or perforating complications, and a significant number of patients undergo surgery during the disease course. Based on recent knowledge, serum antibodies are qualitatively and quantitatively associated with complicated CD behavior and CD-related surgery. Pediatric UC is characterized by extensive colitis and a high rate of colectomy. In patients with UC, high levels of anti-CBir1 and pANCA are associated with the development of pouchitis after ileal pouch-anal anastomosis. Thus, serologic markers for IBD can be applied to stratify IBD patients into more homogeneous subgroups with respect to disease progression. In conclusion, identification of patients at an increased risk of rapid disease progression is of great interest, as the application of early and more aggressive pharmaceutical intervention could have the potential to alter the natural history of IBD, and reduce complications and hospitalizations. PMID- 24803800 TI - Laparoscopic liver resections for hepatocellular carcinoma: current role and limitations. AB - Liver resection for hepatocellular carcinoma (HCC) is currently known to be a safer procedure than it was before because of technical advances and improvement in postoperative patient management and remains the first-line treatment for HCC in compensated cirrhosis. The aim of this review is to assess current indications, advantages and limits of laparoscopic surgery for HCC resections. We also discussed the possible evolution of this surgical approach in parallel with new technologies. PMID- 24803799 TI - Laparoscopic surgery for benign and malign diseases of the digestive system: indications, limitations, and evidence. AB - The laparoscopic technique was introduced in gastrointestinal surgery in the mid 1980s. Since then, the development of this technique has been extraordinary. Triggered by technical innovations (stapling devices or coagulation/dissecting devices), nowadays any type of gastrointestinal resection has been successfully performed laparoscopically and can be performed laparoscopically dependent on the patient's condition. This summary gives an overview over 30 years of laparoscopic surgery with focus on today's indications and evidence. Main indications remain the more common procedures, e.g., appendectomy, cholecystectomy, bariatric procedures or colorectal resections. For all these indications, the laparoscopic approach has become the gold standard with less perioperative morbidity. Regarding oncological outcome there have been several high-quality randomized controlled trials which demonstrated equivalency between laparoscopic and open colorectal resections. Less common procedures like esophagectomy, oncological gastrectomy, liver and pancreatic resections can be performed successfully as well by an experienced surgeon. However, the evidence for these special indications is poor and a general recommendation cannot be given. In conclusion, laparoscopic surgery has revolutionized the field of gastrointestinal surgery by reducing perioperative morbidity without disregarding surgical principles especially in oncological surgery. PMID- 24803801 TI - Role of laparoscopy in rectal cancer: a review. AB - Despite established evidence on the advantages of laparoscopy in colon cancer resection, the use of laparoscopy for rectal cancer resection is still controversial. The initial concern was mainly regarding the feasibility of laparoscopy to achieve an adequate total mesorectal excision specimen. These concerns have been raised following early studies demonstrating higher rates of circumferential margins positivity following laparoscopic resection, as compared to open surgery. Similar to colon resection, patients undergoing laparoscopic rectal cancer resection are expected to benefit from a shorter length of hospital stay, less analgesic requirements, and a faster recovery of bowel function. In the past decade there have been an increasing number of large scale clinical trials investigating the oncological and perioperative outcomes of laparoscopic rectal cancer resection. In this review we summarize the current literature available on laparoscopic rectal cancer surgery. PMID- 24803802 TI - Laparoscopic resection of pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (PNETs) are a rare heterogeneous group of endocrine neoplasms. Surgery remains the best curative option for this type of tumor. Over the past two decades, with the development of laparoscopic pancreatic surgery, an increasingly larger number of PNET resections are being performed by these minimally-invasive techniques. In this review article, the various laparoscopic surgical options for the excision of PNETs are discussed. In addition, a summary of the literature describing the outcome of these treatment modalities is presented. PMID- 24803803 TI - Peritoneal adhesions after laparoscopic gastrointestinal surgery. AB - Although laparoscopy has the potential to reduce peritoneal trauma and post operative peritoneal adhesion formation, only one randomized controlled trial and a few comparative retrospective clinical studies have addressed this issue. Laparoscopy reduces de novo adhesion formation but has no efficacy in reducing adhesion reformation after adhesiolysis. Moreover, several studies have suggested that the reduction of de novo post-operative adhesions does not seem to have a significant clinical impact. Experimental data in animal models have suggested that CO2 pneumoperitoneum can cause acute peritoneal inflammation during laparoscopy depending on the insufflation pressure and the surgery duration. Broad peritoneal cavity protection by the insufflation of a low-temperature humidified gas mixture of CO2, N2O and O2 seems to represent the best approach for reducing peritoneal inflammation due to pneumoperitoneum. However, these experimental data have not had a significant impact on the modification of laparoscopic instrumentation. In contrast, surgeons should train themselves to perform laparoscopy quickly, and they should complete their learning curves before testing chemical anti-adhesive agents and anti-adhesion barriers. Chemical anti-adhesive agents have the potential to exert broad peritoneal cavity protection against adhesion formation, but when these agents are used alone, the concentrations needed to prevent adhesions are too high and could cause major post-operative side effects. Anti-adhesion barriers have been used mainly in open surgery, but some clinical data from laparoscopic surgeries are already available. Sprays, gels, and fluid barriers are easier to apply in laparoscopic surgery than solid barriers. Results have been encouraging with solid barriers, spray barriers, and gel barriers, but they have been ambiguous with fluid barriers. Moreover, when barriers have been used alone, the maximum protection against adhesion formation has been no greater than 60%. A recent small, randomized clinical trial suggested that the combination of broad peritoneal cavity protection with local application of a barrier could be almost 100% effective in preventing post-operative adhesion formation. Future studies should confirm the efficacy of this global strategy in preventing adhesion formation after laparoscopy by focusing on clinical end points, such as reduced incidences of bowel obstruction and abdominal pain and increased fertility. PMID- 24803804 TI - Evolution of laparoscopy in colorectal surgery: an evidence-based review. AB - Open surgery for colorectal disease has progressed significantly over the past century from humble beginnings to form the mainstay of treatment for colorectal cancer and a number of benign conditions. Following the introduction of laparoscopic abdominal surgery, the next stage in the evolution of the specialty began in the 1990s with the first laparoscopic colonic resection. Following some early concerns regarding its safety and oncological efficacy during the latter part of that decade, laparoscopic colorectal surgery rapidly came into mainstream use in the early part of the current century with evidence supporting its use being made available from large scale randomised controlled trials. This article provides an evidence-based summary of this evolutionary process as it relates to both benign and malignant colorectal disease, as well as discussion of the next phase of new technologies such as robotic surgery. PMID- 24803805 TI - Vitamin D improves inflammatory bowel disease outcomes: basic science and clinical review. AB - Vitamin D deficiency is commonly diagnosed among patients with inflammatory bowel disease (IBD). Patients with IBD are at risk of low bone density and increased fractures due to low vitamin D levels, long standing disease, and frequent steroid exposures; as a result, it is well established that vitamin D supplementation in this population is important. There is increasing support for the role of vitamin D in strengthening the innate immune system by acting as an immunomodulator and reducing inflammation in experimental and human IBD. The active form of vitamin D, 1,25(OH)D3, acts on T cells to promote T helper (Th)2/regulatory T responses over Th1/Th17 responses; suppresses dendritic cell inflammatory activity; induces antibacterial activity; and regulates cytokine production in favor of an anti-inflammatory response. Murine and human IBD studies support a therapeutic role of vitamin D in IBD. Risk factors for vitamin D deficiency in this population include decreased sunlight exposure, disease duration, smoking, and genetics. Vitamin D normalization is associated with reduced risk of relapse, reduced risk of IBD-related surgeries, and improvement in quality of life. Vitamin D is an inexpensive supplement which has been shown to improve IBD outcomes. However, further research is required to determine optimal serum vitamin D levels which will achieve beneficial immune effects, and stronger evidence is needed to support the role of vitamin D in inducing disease response and remission, as well as maintaining this improvement in patients' disease states. PMID- 24803806 TI - Participation of microbiota in the development of gastric cancer. AB - There are a large number of bacteria inhabiting the human body, which provide benefits for the health. Alterations of microbiota participate in the pathogenesis of diseases. The gastric microbiota consists of bacteria from seven to eleven phyla, predominantly Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria and Fusobacteria. Intrusion by Helicobacter pylori (H. pylori) does not remarkably interrupt the composition and structure of the gastric microbiota. Absence of bacterial commensal from the stomach delays the onset of H. pylori-induced gastric cancer, while presence of artificial microbiota accelerates the carcinogenesis. Altered gastric microbiota may increase the production of N-nitroso compounds, promoting the development of gastric cancer. Further investigation of the carcinogenic mechanisms of microbiota would benefit for the prevention and management of gastric cancer. PMID- 24803807 TI - Naofen promotes TNF-alpha-mediated apoptosis of hepatocytes by activating caspase 3 in lipopolysaccharide-treated rats. AB - AIM: To investigate whether naofen is involved in tumor necrosis factor (TNF) alpha-mediated apoptosis of hepatocytes induced by lipopolysaccharide (LPS). METHODS: In vivo, rats were treated with LPS or anti-TNF-alpha antibody, whereas in vitro, primary hepatocytes and Kupffer cells (KCs) were separately isolated from rat livers using collagenase perfusion, and primary hepatocytes were cultured in medium containing LPS or TNF-alpha, or in conditioned medium from LPS treated KCs (KC-CM)/KC-CM + anti-TNF-alpha antibody. Naofen and TNF-alpha mRNA expression was examined by real-time reverse transcription-polymerase chain reaction. Immunoblotting was used to measure protein expression. Hepatocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. RESULTS: LPS significantly induced both naofen expression and caspase-3 activity in the rat liver, which coincided with an increase in the number of TUNEL-positive hepatocytes. The increase of TNF-alpha expression induced by LPS was preceded by increases in naofen and caspase-3 activity. Elevation of naofen expression and caspase-3 activity was abrogated by pretreatment with anti-TNF-alpha antibody. In KCs, LPS caused an increase in TNF alpha that was almost consistent with that in the liver of LPS-treated rats. In hepatocytes, neither LPS nor TNF-alpha alone affected either naofen expression or caspase-3 activation. The incubation of hepatocytes with KC-CM significantly enhanced both naofen expression and caspase-3 activity. Moreover, the effects of the KC-CM-induced increase in naofen expression and caspase-3 activity were blocked by anti-TNF-alpha antibody. CONCLUSION: TNF-alpha released from KCs treated with LPS may induce hepatic naofen expression, which then stimulates hepatocellular apoptosis through activation of caspase-3. PMID- 24803808 TI - Patient perceptions of stool DNA testing for pan-digestive cancer screening: a survey questionnaire. AB - AIM: To explore patient interest in a potential multi-organ stool-DNA test (MUST) for pan-digestive cancer screening. METHODS: A questionnaire was designed and mailed to 1200 randomly-selected patients from the Mayo Clinic registry. The 29 item survey questionnaire included items related to demographics, knowledge of digestive cancers, personal and family history of cancer, personal concern of cancer, colorectal cancer (CRC) screening behavior, interest in MUST, importance of test features in a cancer screening tool, and comparison of MUST with available CRC screening tests. All responses were summarized descriptively. chi(2) and Rank Sum Test were used for categorical and continuous variables, respectively. RESULTS: Completed surveys were returned by 434 (29% aged 50-59, 37% 60-69, 34% 70-79, 52% women). Most participants (98%) responded they would use MUST. In order of importance, respondents rated multi-cancer detection, absence of bowel preparation, safety and noninvasiveness as most attractive characteristics. For CRC screening, MUST was preferred over colorectal-only stool DNA testing (53%), occult blood testing (75%), colonoscopy (84%), sigmoidoscopy (91%), and barium enema (95%), P < 0.0001 for each. Among those not previously screened, most (96%) indicated they would use MUST if available. Respondents were confident in their ability to follow instructions to perform MUST (98%). Only 9% of respondents indicated that fear of finding cancer was a concern with MUST, and only 3% indicated unpleasantness of stool sampling as a potential barrier. CONCLUSION: Patients are receptive to the concept of MUST, preferred MUST over conventional CRC screening modalities and valued its potential feature of multi cancer detection. PMID- 24803809 TI - Histological healing favors lower risk of colon carcinoma in extensive ulcerative colitis. AB - AIM: To search for the answer in extensive ulcerative colitis as to whether histological inflammation persisting despite endoscopic mucosal healing serves to increase the risk of colon cancer (CC) or high grade dysplasia (HGD). METHODS: This is a single center (Lenox Hill Hospital) retrospective cohort and descriptive study of extensive ulcerative colitis (UC) for 20 years or more with a minimum of 3 surveillance colonoscopies and biopsies performed after the first 10 years of UC diagnosis. Data analyzed included: duration of UC, date of diagnosis of (CC) or (HGD), number of surveillance colonoscopies, and biopsies showing histological inflammation and its severity in each of 6 segments when endoscopic appearance is normal. Two subgroups of patients were compared: group 1 patients who developed CC/HGD and group 2 patients who did not develop CC/HGD. RESULTS: Of 115 patients with longstanding UC reviewed, 68 patients met the inclusion criteria. Twenty patients were in group 1 and 48 in group 2. We identified the number of times for each patient when the endoscopic appearance was normal but biopsies nevertheless showed inflammation. Overall, histological disease activity in the absence of gross/endoscopic disease was found in 31.2% (95%CI: 28%-35%) of colonoscopies performed on the entire cohort of 68 patients. Histological disease activity when the colonoscopy showed an absence of gross disease activity was more common in group 1 than group 2 patients, 88% (95%CI: 72%-97%) vs 59% (95%CI: 53%-64%). Only 3/20 (15%) of patients in group 1 ever had a colonoscopy completely without demonstrated disease activity (i.e., no endoscopic or histological activity) as compared to 37/48 (77%) of patients in group 2, and only 3.3% (95%CI: 0.09%-8.3%) of colonoscopies in group 1 had no histological inflammation compared to 23% (95%CI: 20%-27%) in group 2. CONCLUSION: Progression to HGD or CC in extensive ulcerative colitis of long standing was more frequently encountered among those patients who demonstrate persistent histological inflammation in the absence of gross mucosal disease. Our findings support including the elimination of histological inflammation in the definition of mucosal healing, and support this endpoint as an appropriate goal of therapy because of its risk of increasing dysplasia and colon cancer. PMID- 24803810 TI - NAFLD prevalence differs among hispanic subgroups: the Multi-Ethnic Study of Atherosclerosis. AB - AIM: To compare prevalence rates of non-alcoholic fatty liver disease (NAFLD) between Hispanics of Mexican origin and Hispanics of Dominican and Puerto Rican origin. METHODS: We evaluated prevalence rates of NAFLD between the two largest sub-populations of Hispanics in the United States; Hispanics of Mexican origin and Hispanics of Caribbean origin (Dominican and Puerto Rican), in the multi ethnic study of atherosclerosis (MESA) cohort. MESA is a large, population based, multi-center cohort study comprised of 6814 healthy Caucasian, African-American, Hispanic, and Asian men and women aged 45-84. We utilized the baseline serum, anthropometric and radiographic measurements obtained between 2000 and 2002. NAFLD was measured via computed tomography scan and was defined as liver/spleen attenuation ratio < 1. RESULTS: There were 788 Hispanic participants included in the study after exclusions. The prevalence of NAFLD was 29% (n = 225). Hispanics of Mexican origin had a significantly higher prevalence of NAFLD (33%), compared to Hispanics of Dominican origin (16%), (P < 0.01) and Hispanics of Puerto Rican origin (18%), (P < 0.01). After controlling for age, sex, BMI, waist circumference, hypertension, serum HDL, triglyceride and CRP level and insulin resistance, Hispanics of Mexican origin remained significantly more likely to have NAFLD than those of Dominican and Puerto Rican origin. CONCLUSION: United States Hispanics of Mexican origin have a significantly higher prevalence of NAFLD when compared to United States Hispanics of Dominican or Puerto Rican origin after controlling for known risk factors. Care should be taken when performing risk assessment in Hispanic populations not to make assumptions of homogeneity. PMID- 24803811 TI - Clinical and histopathological correlations of fecal calprotectin release in colorectal carcinoma. AB - AIM: To determine calprotectin release before and after colorectal cancer operation and compare it to tumor and histopathological parameters. METHODS: The study was performed on patients with diagnosed colorectal cancer admitted for operation. Calprotectin was measured in a single stool sample before and three months after the operation using an enzyme-linked immunosorbent assay (ELISA). Calprotectin levels greater than or equal to 50 MUg/g were considered positive. The compliance for collecting stool samples was assessed and the value of calprotectin was correlated to tumor and histopathological parameters of intra- and peri-tumoral inflammation. Surgical specimens were fixed in neutral buffered formalin and stained with hematoxylin and eosin. Staging was performed according to the Dukes classification system and the 7(th) edition tumor node metastasis classification system. Intra- and peri-tumoral inflammation was graded according to the Klintrup criteria. Immunohistochemical quantification was performed for MPO, CD45R0, TIA-1, CD3, CD4, CD8, CD57, and granzyme B. Statistical significance was measured using Wilcoxon signed rank test, Kruskal Wallis test and Spearman's rank correlation coefficient as appropriate. RESULTS: Between March 2009 and May 2011, 80 patients with colorectal cancer (46 men and 34 women, with mean age of 71 +/- 11.7 years old) were enrolled in the study. Twenty-six patients had rectal carcinoma, 29 had left-side tumors, 23 had right-side tumors, and 2 had bilateral carcinoma. In total, 71.2% of the patients had increased levels of calprotectin before the operation (median 205 MUg/g, range 50-2405 MUg/g) and experienced a significant decrease three months after the operation (46 MUg/g, range 10-384 MUg/g, P < 0001). The compliance for collecting stool samples was 89.5%. Patients with T3 and T4 tumors had significantly higher values than those with T1 and T2 cancers (P = 0.022). For all other tumor parameters (N, M, G, L, V, Pn) and location, no significant difference in calprotectin concentration was found. Furthermore, the calprotectin levels and histological grading of both peri- and intra-tumoral inflammation was not correlated. Additional testing with specific markers for lymphocytes and neutrophils also revealed no statistically significant correlation. CONCLUSION: Fecal calprotectin decreases significantly after colorectal cancer operation. Its value depends exclusively on the individual T-stage, but not on other tumor or histopathological parameters. PMID- 24803812 TI - Caecal pH is a biomarker of excessive colonic fermentation. AB - AIM: To ascertain whether caecal pH is different in patients with irritable bowel syndrome (IBS), whose primary symptoms are bloating and distension, to healthy controls. METHODS: Motility and pH data were reviewed from 16 patients with Rome III defined IBS and 16 healthy controls, who had undergone a wireless motility capsule (WMC) study using a standardized protocol. Motility measures were anchored around known anatomical landmarks as identified by compartmental pH changes. Sixty-minute epochs were used to quantify antral, duodenal, ileal, caecal and distal colonic contractility. The maximum and minimum pH was measured either side of the ileo-caecal junction. RESULTS: No differences were seen in motility parameters, compartmental transit times or maximal ileal pH between the two groups. Caecal pH was significantly lower in patients compared to controls (5.12 +/- 0.05 vs 6.16 +/- 0.15, P < 0.0001). The ileal:caecal Deltachange was greater in patients than controls (-2.63 +/- 0.08 vs -1.42 +/- 0.11, P < 0.0001). There was a significant correlation between caecal pH and right colonic contractility (r = 0.54, P = 0.002). CONCLUSION: Patients with bloating and distension have a lower caecal pH compared to controls. The measurement of caecal pH using the WMC provides a quantifiable biomarker of fermentation potentially identifying those patients that may preferentially benefit from antibiotic or dietary interventions. PMID- 24803813 TI - Prediction of Crohn's disease aggression through NOD2/CARD15 gene sequencing in an Australian cohort. AB - AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn's disease (CD) to identify patients who would benefit from early aggressive medical intervention. METHODS: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene. RESULTS: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020insC of the NOD2/CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2/CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries. CONCLUSION: These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn's disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery. PMID- 24803814 TI - Routine diagnosis of intestinal tuberculosis and Crohn's disease in Southern India. AB - AIM: To investigate whether routinely measured clinical variables could aid in differentiating intestinal tuberculosis (ITB) from Crohn's disease (CD). METHODS: ITB and CD patients were prospectively included at four South Indian medical centres from October 2009 to July 2012. Routine investigations included case history, physical examination, blood biochemistry, ileocolonoscopy and histopathological examination of biopsies. Patients were followed-up after 2 and 6 mo of treatment. The diagnosis of ITB or CD was re-evaluated after 2 mo of antituberculous chemotherapy or immune suppressive therapy respectively, based on improvement in signs, symptoms and laboratory variables. This study was considered to be an exploratory analysis. Clinical, endoscopic and histopathological features recorded at the time of inclusion were subject to univariate analyses. Disease variables with sufficient number of recordings and P < 0.05 were entered into logistic regression models, adjusted for known confounders. Finally, we calculated the odds ratios with respective confidence intervals for variables associated with either ITB or CD. RESULTS: This study included 38 ITB and 37 CD patients. Overall, ITB patients had the lowest body mass index (19.6 vs 22.7, P = 0.01) and more commonly reported weight loss (73% vs 38%, P < 0.01), watery diarrhoea (64% vs 33%, P = 0.01) and rural domicile (58% vs 35%, P < 0.05). Endoscopy typically showed mucosal nodularity (17/31 vs 2/37, P < 0.01) and histopathology more frequently showed granulomas (10/30 vs 2/35, P < 0.01). The CD patients more frequently reported malaise (87% vs 64%, P = 0.03), nausea (84% vs 56%, P = 0.01), pain in the right lower abdominal quadrant on examination (90% vs 54%, P < 0.01) and urban domicile (65% vs 42%, P < 0.05). In CD, endoscopy typically showed involvement of multiple intestinal segments (27/37 vs 9/31, P < 0.01). Using logistic regression analysis we found weight loss and nodularity of the mucosa were independently associated with ITB, with adjusted odds ratios of 8.6 (95%CI: 2.1-35.6) and 18.9 (95%CI: 3.5-102.8) respectively. Right lower abdominal quadrant pain on examination and involvement of >= 3 intestinal segments were independently associated with CD with adjusted odds ratios of 10.1 (95%CI: 2.0-51.3) and 5.9 (95%CI: 1.7-20.6), respectively. CONCLUSION: Weight loss and mucosal nodularity were associated with ITB. Abdominal pain and excessive intestinal involvement were associated with CD. ITB and CD were equally common. PMID- 24803815 TI - Dietary habits of colorectal neoplasia patients in comparison to their first degree relatives. AB - AIM: To compare the dietary habits between colorectal neoplasia patients, their first-degree relatives, and unrelated controls. METHODS: From July 2008 to April 2011, we collected epidemiological data relevant to colorectal cancer from patients with colorectal neoplasias, their first-degree relatives, and also from a control group consisting of people referred for colonoscopy with a negative family history of colorectal cancer and without evidence of neoplasia after colonoscopic examination. The first-degree relatives were divided into two groups following the colonoscopic examination: (1) patients with neoplasia or (2) patients without neoplasia. Dietary habits of all groups were compared. A chi (2) test was used to assess the association between two dichotomous categorical variables. RESULTS: The study groups consisted of 242 patients with colorectal neoplasias (143 men, 99 women; mean age: 64 +/- 12 years) and 160 first-degree relatives (66 men, 94 women; mean age: 48 +/- 11 years). Fifty-five of the first degree relatives were found to have a neoplastic lesion upon colonoscopy, while the remaining 105 were without neoplasia. The control group contained 123 individuals with a negative family history for neoplastic lesions (66 men, 57 women; mean age: 54 +/- 12 years). Two hypotheses were tested. In the first, the dietary habits of first-degree relatives with neoplasia were more similar to those of patients with neoplasia, while the dietary habits of first-degree relatives without neoplasia were similar to those of the control group. In the second, no sex-related differences in dietary habits were expected between the particular groups. Indeed, no significant differences were observed in the dietary habits between the groups of patients, controls and first-degree relatives with/without neoplastic lesions. Nevertheless, statistically significant sex-related differences were observed in all groups, wherein women had healthier dietary habits than men. CONCLUSION: In all groups examined, women had healthier dietary habits than men. Modification of screening guidelines according to sex may improve the efficiency of screening programs. PMID- 24803816 TI - Ecological study of gastric cancer in Brazil: geographic and time trend analysis. AB - AIM: To investigate the geographic distributions and time trends of gastric cancer (GC) incidence and mortality in Brazil. METHODS: An ecological study of the DATASUS registry was conducted by identifying hospitalizations for GC between January 2005 and December 2010. The data included information on the gender, age, and town of residence at the time of hospital admission and death. RESULTS: The GC rates, adjusted according to available hospital beds, decreased from 13.8 per 100000 in 2005 to 12.7 per 100000 in 2010. The GC rates decreased more among the younger age groups, in which the male-to-female difference also decreased in comparison to the older age groups. Although the lethality rates tended to increase with age, young patients were proportionally more affected. The spatial GC distribution showed that the rates were higher in the south and southeast. However, while the rates decreased in the central-west and south, they increased in the northern regions. A geographic analysis showed higher rates of GC in more urbanized areas, with a coast-to-inland gradient. Geographically, GC lethality overlapped greatly with the hospital admission rates. CONCLUSION: The results of this study support the hypothesis of a critical role for environmental factors in GC pathogenesis. The declining rates in young patients, particularly males, suggest a relatively recent decrease in the exposure to risk factors associated with GC. The spatial distribution of GC indicates an ongoing dynamic change within the Brazilian environment. PMID- 24803817 TI - Evaluation of preferable insertion routes for esophagogastroduodenoscopy using ultrathin endoscopes. AB - AIM: To evaluate the discomfort associated with esophagogastroduodenoscopy (EGD) using an ultrathin endoscope through different insertion routes. METHODS: This study (January 2012-March 2013) included 1971 consecutive patients [male/female (M/F), 1158/813, 57.5 +/- 11.9 years] who visited a single institute for annual health checkups. Transnasal EGD was performed in 1394 patients and transoral EGD in 577. EGD-associated discomfort was assessed using a visual analog scale score (VAS score: 0-10). RESULTS: Multivariate analysis revealed gender (M vs F: 4.02 +/- 2.15 vs 5.06 +/- 2.43) as the only independent predictor of the VAS score in 180 patients who underwent EGD for the first time; whereas it revealed gender (M vs F 3.60 +/- 2.20 vs 4.84 +/- 2.37), operator, age group (A: < 39 years; B: 40 49 years; C: 50-59 years; D: 60-69 years; E: > 70 years; A/B/C/D/E: 4.99 +/- 2.32/4.34 +/- 2.49/4.19 +/- 2.31/3.99 +/- 2.27/3.63 +/- 2.31), and type of insertion as independent predictors in the remaining patients. Subanalysis for gender, age group, and insertion route revealed that the VAS score decreased with age regardless of gender and insertion route, was high in female patients regardless of age and insertion route, and was low in males aged over 60 years who underwent transoral insertion. CONCLUSION: Although comprehensive analysis revealed that the insertion route may not be an independent predictor of the VAS score, transoral insertion may reduce EGD-associated discomfort in elderly patients. PMID- 24803818 TI - Simplified fistula dilation technique and modified stent deployment maneuver for EUS-guided hepaticogastrostomy. AB - AIM: To evaluate the success rates, procedural time and adverse event rates of the modified methods in endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS). METHODS: Twenty-eight patients in a prospective case series who underwent EUS-HGS (phase I). Forty-six patients in a matched case-control study (phase II). The simplified technique for fistula dilation was the primary use of a 4 mm balloon catheter with a stainless steel stylet. The stent deployment was modified by deploying the metal stent inside a bile duct (half of the stent) under EUS and fluoroscopic guidance and gently pulling the echoendoscope after full deployment of the stent inside the echoendoscope channel (remaining portion of the stent) under fluoroscopic guidance. This cohort was compared with a matched historical cohort. RESULTS: In phase I, the technical and clinical success with the modified method was 96% (27/28) and 89% (24/27 as per-protocol analysis). The overall adverse event rate was 7%. In phase II, there was no difference in technical and clinical success, stent patency and overall adverse events in each group. However, the procedural time (15.3 +/- 5.2 min vs 22.3 +/- 6.0 min, P < 0.001) and early adverse events (0% vs 26%, P = 0.02) were statistically improved in case cohort compared with control cohort. CONCLUSION: Compared with the conventional EUS-HGS technique, the procedural time was shorter and early adverse events were less frequent with our simplified and modified technique. PMID- 24803819 TI - Hepatitis B and C viruses are not risks for pancreatic adenocarcinoma. AB - AIM: To investigate whether hepatitis B virus (HBV) and hepatitis C virus (HCV) increase risk of pancreatic ductal adenocarcinoma (PDAC). METHODS: We recruited 585 patients with cytological and/or pathologically confirmed PDAC in National Taiwan University Hospital from September 2000 to September 2013, and 1716 age-, sex-, and race-matched controls who received a screening program in a community located in Northern Taiwan. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBsAg (anti-HBs), and hepatitis B core antigen (anti-HBc) in all cases and controls. The odds ratio (OR) of PDAC was estimated by logistic regression analysis with adjustment diabetes mellitus (DM) and smoking. RESULTS: HBsAg was positive in 73 cases (12.5%) and 213 controls (12.4%). Anti-HCV was positive in 22 cases (3.8%) and 45 controls (2.6%). Anti-HBs was positive in 338 cases (57.8%) and 1047 controls (61.0%). The estimated ORs of PDAC in multivariate analysis were as follows: DM, 2.08 (95%CI: 1.56-2.76, P < 0.001), smoking, 1.36 (95%CI: 1.02-1.80, P = 0.035), HBsAg(+)/anti-HBc(+)/anti-HBs(-), 0.89 (95%CI: 0.89-1.68, P = 0.219), HBsAg(-)/anti-HBc(+)/anti-HBs(+), 1.03 (95%CI: 0.84-1.25, P = 0.802). CONCLUSION: HBV and HCV infection are not associated with risk of PDCA after adjustment for age, sex, DM and smoking, which were independent risk factors of PDAC. PMID- 24803820 TI - Solitary fibrous tumors in abdomen and pelvis: imaging characteristics and radiologic-pathologic correlation. AB - AIM: To describe the imaging features of solitary fibrous tumors (SFTs) in the abdomen and pelvis, and the clinical and pathologic correlations. METHODS: Fifteen patients with pathologically confirmed SFTs in the abdomen and pelvis were retrospectively studied with imaging techniques by two radiologists in consensus. Patients underwent unenhanced and contrast-enhanced imaging, as follows: 3 with computed tomography (CT) and magnetic resonance imaging (MRI) examination, 8 with CT examination only, and 4 with MRI examination only. Image characteristics such as size, shape, margin, attenuation or intensity, and pattern of enhancement were analyzed and correlated with the microscopic findings identified from surgical specimens. In addition, patient demographics, presentation, and outcomes were recorded. RESULTS: Of the 15 patients evaluated, local symptoms related to the mass were found in 11 cases at admission. The size of the mass ranged from 3.4 to 25.1 cm (mean, 11.5 cm). Nine cases were round or oval, 6 were lobulated, and 10 displaced adjacent organs. Unenhanced CT revealed a heterogeneous isodense mass in 7 cases, homogeneous isodense mass in 3 cases, and punctuated calcification in one case. On MRI, most of the lesions (6/7) were heterogeneous isointense and heterogeneous hyperintense on T1-weighted images and T2-weighted images, respectively. All tumors showed moderate to marked enhancement. Heterogeneous enhancement was revealed in 11 lesions, and 7 of these had cysts, necrosis, or hemorrhage. Early nonuniform enhancement with a radial area that proved to be a fibrous component was observed in 4 lesions, which showed progressive enhancement in the venous and delayed phase. No statistical difference in the imaging findings was observed between the histologically benign and malignant lesions. Three patients had local recurrence or metastasis at follow-up. CONCLUSION: Abdominal and pelvic SFTs commonly appeared as large, solid, well-defined, hypervascular masses with variable degrees of necrosis or cystic change that often displaced adjacent structures. PMID- 24803821 TI - Evaluation of routine biopsies in endoscopic screening for esophagogastric junction cancer. AB - AIM: To explore whether routine biopsies at the high incidence spot of esophagogastric junction (EGJ) cancer are justified in endoscopic screening. METHODS: This was a multicenter population-based study conducted in eight high risk areas in China. A total of 37396 participants underwent endoscopic examination. Biopsies were obtained from visible mucosal abnormalities or from normal-appearing mucosa at the high incidence spot of esophagogastric junction cancer when no abnormality was detected. Specimens showing high-grade intraepithelial neoplasia (HIN) or higher grade lesions were deemed as pathologically "positive". The ratios of positive pathologic diagnosis between participants with abnormal and normal-appearing mucosa were compared using the Pearson chi(2) test. Odds ratios and 95% confidence intervals, adjusted for potential confounders, were calculated using logistic regression. RESULTS: A total of 37520 individuals participated in this study and 37396 (99.7%) participants had full information and were suitable for analysis. During endoscopic examinations, 9.11% (3405/37396) participants were found to have visible mucosal lesions. Of the participants who had normal-appearing mucosa at the EGJ, only 0.28% (94/33991) were diagnosed with HIN or higher grade lesions, whereas 6.05% (206/3405) of participants with abnormalities at the EGJ had a positive pathologic result. After controlling for other variables, visible abnormal mucosa detected under endoscopy strongly predicted a positive pathologic result (OR = 32.51, 95%CI: 23.96-44.09). The proportion of participants with "positive" pathologic diagnoses increased as the total number of endoscopic examinations performed by the doctors increased (< 5000 cases vs 5000-10000 cases vs > 10000 cases, Z = -2.7207, P = 0.0065, Cochran Armiger trend test). The same trend was found between the proportion of participants with positive pathologic diagnoses and the total number of years the doctors performed endoscopy (< 5 years vs 5-10 years vs > 10 years, Z = -10.3222, P < 0.001, Cochran Armiger trend test). CONCLUSION: Additional routine biopsies from the high incidence spot of EGJ cancer are of limited value and are unjustified. PMID- 24803822 TI - Prognostic analysis and comparison of colon cancer in Han and Hui patients. AB - AIM: To investigate the relevant prognostic factors and their differences between colorectal cancer (CRC) patients of Chinese Han and Hui ethnicities in the Beijing region. METHODS: A retrospective analysis of 880 patients diagnosed with CRC at Xuanwu Hospital, Capital Medical University between September 2001 and September 2011 was performed. Among the 880 patients, 398 and 482 were Hui and Han, respectively. Characteristics including sex, age, diet, tumor size, primary tumor site, Dukes' stage and degree of differentiation were analyzed for their influence on prognosis. Data on dietary structures were recorded through a questionnaire survey conducted during the patient's first visit, return visit or follow-up checkups. RESULTS: Among patients with colon cancer, the 5-year survival rate for patients of Hui ethnicity was lower than that for Han patients (P = 0.025). Six risk factors (age of onset, dietary structure, tumor size, Dukes' stage, location of cancer and degree of differentiation) in both Han and Hui patients were identified as prognostic factors (P < 0.05). Multivariate analysis showed that age of onset (P = 0.002), diet (P = 0.000), Dukes' stage (P = 0.000) and degree of differentiation (P = 0.000) are prognostic factors affecting both ethnic groups. Comparison of prognostic factors between Han and Hui patients with CRC showed that dietary structure was a statistically significant factor, and diet varied significantly between the two ethnic groups. CONCLUSION: Dietary structure has a significant influence on colon cancer prognosis among Han and Hui patients with colon cancer in Beijing, which may cause a difference in their survival rates. PMID- 24803823 TI - Value of a new stick-type rapid urine test for the diagnosis of Helicobacter pylori infection in the Vietnamese population. AB - AIM: To assess the value of a new test for the diagnosis of Helicobacter pylori (H. pylori) infection, Rapirun H. pylori Antibody Stick (Rapirun Stick), in a Vietnamese population. METHODS: Eligible patients without previous history of H. pylori eradication were recruited. Rapid urease test (RUT) and histologic examination were used to diagnose the H. pylori infection. Patients were considered H. pylori positive when the RUT results were positive and/or the bacteria were detected histologically. Rapirun Stick tests were performed using urine samples, and the results were compared with the other 2 methods. RESULTS: We enrolled 200 patients with a mean age of 36 (range, 18-76) years. There were 116 females and 84 males. Of the 200 patients, 111 (55.5%) were diagnosed as being H. pylori positive. The sensitivity, specificity, and accuracy of the Stick test were 84.7%, 89.9%, and 87.0%, respectively. There were 17 (8.5%) false negative patients and 9 (4.5%) false-positive patients. CONCLUSION: The Rapirun Stick test has high sensitivity, specificity, and accuracy for the diagnosis of H. pylori infection in the Vietnamese population. The test can be clinically applied in Vietnamese populations. PMID- 24803824 TI - Chromoendoscopy of gastric adenoma using an acetic acid indigocarmine mixture. AB - AIM: To investigate the usefulness of chromoendoscopy, using an acetic acid indigocarmine mixture (AIM), for gastric adenoma diagnosed by forceps biopsy. METHODS: A total of 54 lesions in 45 patients diagnosed as gastric adenoma by forceps biopsy were prospectively enrolled in this study and treated by endoscopic submucosal dissection (ESD) between January 2011 and January 2012. AIM chromoendoscopy (AIM-CE) was performed followed by ESD. AIM solution was sprinkled and images were recorded every 30 s for 3 min. Clinical characteristics such as tumor size (< 2 cm, >= 2 cm), surface color in white light endoscopy (WLE) (whitish, normochromic or reddish), macroscopic appearance (flat or elevated, depressed), and reddish change in AIM-CE were selected as valuables. RESULTS: En bloc resection was achieved in all 54 cases, with curative resection of fifty two lesions (96.3%). Twenty three lesions (42.6%) were diagnosed as well differentiated adenocarcinoma and the remaining 31 lesions (57.4%) were gastric adenoma. All adenocarcinoma lesions were well-differentiated tubular adenocarcinomas and were restricted within the mucosal layer. The sensitivity of reddish color change in AIM-CE is significantly higher than that in WLE (vs tumor size >= 2 cm, P = 0.016, vs normochromic or reddish surface color, P = 0.046, vs depressed macroscopic type, P = 0.0030). On the other hand, no significant differences were found in the specificity and accuracy. In univariate analysis, normochromic or reddish surface color in WLE (OR = 3.7, 95%CI: 1.2-12, P = 0.022) and reddish change in AIM-CE (OR = 14, 95%CI: 3.8-70, P < 0.001) were significantly related to diagnosis of early gastric cancer (EGC). In multivariate analysis, only reddish change in AIM-CE (OR = 11, 95%CI: 2.3-66, P = 0.0022) was a significant factor associated with diagnosis of EGC. CONCLUSION: AIM-CE may have potential for screening EGC in patients initially diagnosed as gastric adenoma by forceps biopsy. PMID- 24803825 TI - Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer. AB - AIM: To investigate the short-term efficacy and tolerability of radiotherapy plus thalidomide in patients with esophageal cancer (EC). METHODS: Serum samples from 86 EC patients were collected before, during, and after radiotherapy, and the vascular endothelial growth factor (VEGF) level was examined by ELISA. According to the change in serum VEGF level during radiotherapy, the patients were divided into two groups: in the drug group, VEGF level was increased or remained unchanged, and thalidomide was administered up to the end of radiotherapy; in the non-drug group, VEGF level was decreased and radiotherapy was given alone. Thirty healthy volunteers served as controls. The efficacy and safety of radiotherapy plus thalidomide therapy were investigated. RESULTS: The 86 EC patients had a significantly higher level of VEGF compared with the 30 healthy controls before radiotherapy (P < 0.01), and the VEGF level was significantly correlated with primary tumor size, lymph node metastasis, histopathologic type, and clinical stage (P < 0.01). Of 83 evaluable cases, VEGF level was significantly decreased after radiotherapy in 32 patients in the drug group (P < 0.05), with an effective rate of 71.88%. The incidence of dizziness and/or burnout in the drug group and non-drug group was 62.50% and 15.69%, respectively (P = 0.000), and the incidence of somnolence was 12.50% and 0%, respectively (P = 0.019). No significant differences were observed. CONCLUSION: Thalidomide can down-regulate serum VEGF level in EC patients, and combined with radiotherapy may improve treatment outcome. Thalidomide was well tolerated by EC patients. PMID- 24803826 TI - TNM staging of colorectal cancer should be reconsidered by T stage weighting. AB - AIM: To verify that the T stage has greater weight than the N stage in the staging of colorectal cancer. METHODS: Open data from the Surveillance, Epidemiology, and End Results program were reviewed and analyzed according to the T stage, N stage, and patients' observed survival (OS). The relative weights of the T and N stages were calculated by multiple linear regressions based on their impact on survival. Risk scores for 25 TN categories were then calculated from the T and N stage relative weights, and a rearranged tumor node metastasis (TNM) staging system was proposed via a cluster analysis of the TN scores. RESULTS: Both T and N stages significantly affect the OS of patients with colorectal cancer. Moreover, the T stage has greater weight than the N stage in the TNM staging system of colorectal cancer. For colon cancer, the relative T and N stage weights were 0.58 and 0.42, respectively, and for rectal cancer, the relative T and N stage weights were 0.61 and 0.39, respectively. On the basis of cluster analysis of the TN scores, T1N1a was classified to stage I, and T2N1a-1b and T1N1b-2a were classified to stage II in our revised TNM staging system for both colon and rectal cancer. For colon cancer, T4bN0 was classified to stage IIIa, but for rectal cancer, it was classified to stage IIIb. CONCLUSION: As the T stage affects colorectal cancer survival more significantly than the N stage, the TNM staging should be revised by relative T stage weight. PMID- 24803827 TI - Sedated vs unsedated colonoscopy: a prospective study. AB - AIM: To compare sedated to unsedated colonoscopy in terms of duration, pain and the patient's willingness to repeat the procedure. METHODS: Consecutive patients who underwent colonoscopies over a 2-year period were invited to participate. All patients who were to undergo our endoscopy unit were offered sedation with standard intravenous sedatives and analgesics, or an unsedated colonoscopy was attempted. Demographic details were recorded. The patient anxiety level prior to the procedure, time to reach the cecum, total discharge time, patient and endoscopist pain assessments, satisfaction after the examination and the patient's willingness to return for the same procedure in the future were recorded. RESULTS: Among the 403 observed patients, more males were observed in the unsedated group (66.2% vs 55.2%, P = 0.04). Additionally, the unsedated group patients were less anxious prior to the procedure (5.1 vs 6.0, P < 0.01). The colonoscopy completion rates were comparable between the 2 groups (85.9% vs 84.2%, P = 0.66). The time to reach the cecum was also comparable (12.2 min vs 11.8 min); however, the total discharge times were shorter in the unsedated group (20.7 min vs 83.0 min, P < 0.01). Moreover, the average patient pain score (3.4 vs 5.7, P < 0.01) was lower in the sedated group, while the satisfaction score (8.8 vs 7.8, P < 0.01) was significantly higher. There was no significant difference, however, between the groups in terms of willingness to repeat the procedure if another was required in the future (83.3% vs 77.3%, P = 0.17). CONCLUSION: Unsedated colonoscopy is feasible in willing patients. The option saves the endoscopy units up to one hour per patient and does not affect the patient willingness to return to the same physician again for additional colonoscopies if a repeated procedure is needed. PMID- 24803828 TI - Efficacy of ilaprazole in the treatment of duodenal ulcers: a meta-analysis. AB - AIM: To compare the efficacy and tolerance of ilaprazole compared with other proton pump inhibitors (PPIs) in the treatment of duodenal ulcer. METHODS: An electronic database search of Medline, Embase, the Cochrane controlled trials register, Web of Science, PubMed, and the Chinese Biomedical Literature Database (updated to July 2013), and manual searches were conducted. A meta-analysis of randomized controlled trials comparing the efficacy and tolerance of ilaprazole and other PPIs in the treatment of duodenal ulcers was performed. RESULTS: Five articles involving 1481 patients were included. The meta-analysis showed no difference in the 4-wk healing rate between ilaprazole and other PPIs [89.7% vs 87.0%; relative risk (RR) = 1.02; 95%CI: 0.98-1.06; Z = 1.00; P = 0.32]. The results did not change in the sensitivity analyses. The meta-analysis indicated that the adverse effect rate in the ilaprazole group was lower than that in the control group, but the difference was not significant (9.7% vs 13.0%; RR = 0.81; 95%CI: 0.60-1.07; Z = 1.47; P = 0.14). CONCLUSION: Ilaprazole is a highly effective and safe PPI in the treatment of duodenal ulcers. Ilaprazole can be recommended as a therapy for acid-related disorders, especially in Asian populations. PMID- 24803829 TI - Association between esophageal cancer risk and EPHX1 polymorphisms: a meta analysis. AB - AIM: To summarize the relationship between p.Tyr113His and p.His139Arg polymorphisms in microsomal epoxide hydrolase (EPHX1) and risk for esophageal cancer (EC). METHODS: The MEDLINE/PubMed and EMBASE databases were searched for studies of the association between EPHX1 polymorphisms and EC risk that were published from the database inception date to April 2013. A total of seven case control studies, including seven on p.Tyr113His (cases, n = 1118; controls, n = 1823) and six on p.His139Arg (cases, n = 861; controls, n = 1571), were included in the meta-analysis. After data extraction by two investigators working independently, the meta-analyses were carried out with STATA 11.0 software. Pooled odds ratios and 95%CI were calculated using a fixed-effects model or a random-effects model, as appropriate. RESULTS: The pooled EPHX1 p.Tyr113His polymorphism data showed no significant association with EC in any of the genetic models (OR = 1.00, 95%CI: 0.70-1.48 for Tyr/His vs Tyr/Tyr; OR = 1.10, 95%CI: 0.77-1.57 for His/His vs Tyr/Tyr; OR = 1.06, 95%CI: 0.75-1.49 for a dominant model; OR = 1.09, 95%CI: 0.89-1.34 for a recessive model). Similar results were obtained from the p.His139Arg polymorphism analysis (Arg/His vs His/His: OR = 1.02, 95%CI: 0.84-1.23; Arg/Arg vs His/His: OR = 0.96, 95%CI: 0.60-1.54; OR = 1.03, 95%CI: 0.78-1.37 for the dominant model; OR = 0.97, 95%CI: 0.61-1.56 for the recessive model). Subgroup analyses for ethnicity, subtype of EC, and source of controls (population-based or hospital-based) showed trends that were consistent with the pooled analysis (reported above), with no significant associations found. CONCLUSION: This meta-analysis suggests that the p.Tyr113His and p.His139Arg polymorphisms in EPHX1 may not be associated with EC development. PMID- 24803830 TI - One case of intrahepatic cholangiocarcinoma amenable to resection after radioembolization. AB - We report the case of a 57-year-old man who was diagnosed with a large unresectable cholangiocarcinoma associated with 2 satellite nodules and without clear margins with the right hepatic vein. Despite 4 cycles of GEMOX (stopped due to a hypertransaminasemia believed to be due to gemcitabine) and 4 cycles of FOLFIRINOX, the tumor remained stable and continued to be considered unresectable. Radioembolization (resin microspheres, SIRS-spheres) targeting the left liver (474 MBq) and segment IV (440 MBq) was performed. This injection was very well tolerated, and 4 more cycles of FOLFIRINOX were given while waiting for radioembolization efficacy. On computed tomography scan, a partial response was observed; the tumor was far less hypervascularized, and a margin was observed between the tumor and the right hepatic vein. A left hepatectomy enlarged to segment VIII was performed. On pathological exam, most of the tumor was acellular, with dense fibrosis around visible microspheres. Viable cells were observed only at a distance from beads. Radioembolization can be useful in the treatment of cholangiocarcinoma, allowing in some cases a secondary resection. PMID- 24803831 TI - Ulcerative colitis worsened after Clostridium difficile infection: efficacy of infliximab. AB - The incidence of Clostridium difficile (C. difficile) infection (CDI) is 1.8% 5.7% in admitted patients with ulcerative colitis (UC). CDI can worsen UC and increase the risk for colectomy or even death, thus necessitating therapy escalation, such as increasing the corticoid therapy or starting a biologic treatment. Several reported cases with infliximab therapy have provided favorable outcomes in UC patients with CDI, suggesting that infliximab treatment may be protective; however, the optimal infliximab treatment regimen for UC patients with CDI remains to be established. Here, we report a case of worsening UC in the presence of recurrent CDI. The patient had received prior ciprofloxacin and immunosuppressive therapy during a prolonged hospital stay. The deterioration in the patient's condition likely resulted from the ability of C. difficile to promote relapsing of UC by activating the immune response. Ultimately, the patient was treated with a high dose of infliximab after a low trough level of infliximab at week 8 was identified, yielding better clinical results. Infliximab was found to be safe after repetitive episodes of CDI. The trough level of infliximab was therefore a useful indicator to guide therapy and correlated well with the patient's outcome. PMID- 24803832 TI - 18F-FDG PET/CT imaging for a gastrointestinal mantle cell lymphoma with multiple lymphomatous polyposis. AB - Multiple lymphomatous polyposis (MLP) is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract. Most of this entity is in fact considered the counterpart of gastrointestinal tract involvement for mantle cell lymphoma (MCL). To our knowledge, there have been no reports on [fluorine-18]-fluorodeoxy-glucose ((18)F FDG)-positron emission tomography (PET)/computed tomography (CT) imaging for gastrointestinal MCL with MLP. We present the results of (18)F-FDG PET/CT imaging in a patient with gastrointestinal tract involvement of MCL showing continuous MLP from the stomach to the rectum and intestinal intussusception. FDG-PET/CT findings were false negative in typical MLP spreading widely over the gastrointestinal tract, but uptake was noted in large lesions with deep infiltration considered atypical as MLP. On FDG-PET/CT imaging, the Ki-67 proliferative index, which is a cell proliferation marker, showed neither correlation with the presence of uptake nor the maximum standardized uptake value. PMID- 24803833 TI - Intrathoracic caudate lobe of the liver: a case report and literature review. AB - Heterotopic supradiaphragmatic livers are rare. A total of 23 cases of primary supradiaphragmatic livers have been reported in the literature. The clinical presentations of heterotopic supradiaphragmatic liver are variable. The simultaneous detection of intrathoracic accessory liver and pulmonary sequestration is extremely rare, and only one case has previously been reported. It is difficult to make a correct diagnosis preoperatively. We presented a 53 year-old woman with complaints of an intermittent, productive cough and dyspnea for two months that was refractory to medical treatment. She had no previous history of trauma or surgery. A chest radiograph only showed a widening of the mediastinum. Contrast-enhanced computed tomography of the chest revealed a well circumscribed homogenous soft-tissue mass, approximately 4.35 cm * 2.5 cm * 6.14 cm in size, protruding through the right diaphragmatic crura to the right pleural cavity, attached to the inferior vena cava, esophagus and liver. There was no conclusive diagnosis before surgery. After the operation, we discovered that this patient was the first case of a supradiaphragmatic heterotopic liver, which passed through the inferior vena cava foramen and was coincidentally combined with an intralobar pulmonary sequestration that was found intraoperatively. We discussed its successful management with surgical resection via a thoracic approach and reviewed the published literature. PMID- 24803834 TI - Solitary plexiform neurofibroma of the stomach: a case report. AB - Plexiform neurofibroma (PN) of the digestive tract is very rare and usually part of the generalized syndrome of neurofibromatosis type 1 (von Recklinghausen disease). Solitary PN of the stomach is extremely rare and has not been reported in the literatures. Here we present a case of solitary PN of the stomach, which was not associated with von Recklinghausen disease. A 38-year-old male presented abdominal pain and distention for 7 d. The patient underwent endoscopy of the upper gastrointestinal tract, which revealed a 3.5 cm protruding and cauliflower shaped mass with a shallow 1 cm central ulcer in the greater curvature of the stomach. The lesion was removed by laparoscopic surgery. Histological examination demonstrated characteristic histological findings of spindle-shaped cells. Immunohistochemical analysis showed that the tumor cells were positive for S-100 protein, but negative for CD34, KI-67, CD117, and actin. Based on histological findings, gastrointestinal stromal tumor could be excluded, and thus the case was confirmed as PN. We described the clinical features, physical examination, endoscopic findings, and histopathological examination of this case. PMID- 24803835 TI - Clinical and computed tomography features of adult abdominopelvic desmoplastic small round cell tumor. AB - To investigate the clinical and computed tomography (CT) features of desmoplastic small round cell tumor (DSRCT), we retrospectively analyzed the clinical presentations, treatment and outcome, as well as CT manifestations of four cases of DSRCT confirmed by surgery and pathology. The CT manifestations of DSRCT were as follows: (1) multiple soft-tissue masses or diffuse peritoneal thickening in the abdomen and pelvis, with the dominant mass usually located in the pelvic cavity; (2) masses without an apparent organ-based primary site; (3) mild to moderate homogeneous or heterogeneous enhancement in solid area on enhanced CT; and (4) secondary manifestations, such as ascites, hepatic metastases, lymphadenopathy, hydronephrosis and hydroureter. The prognosis and overall survival rates were generally poor. Commonly used treatment strategies including aggressive tumor resection, polychemotherapy, and radiotherapy, showed various therapeutic effects. CT of DSRCT shows characteristic features that are helpful in diagnosis. Early discovery and complete resection, coupled with postoperative adjuvant chemotherapy, are important for prognosis of DSRCT. Whole abdominopelvic rather than locoregional radiotherapy is more effective for unresectable DSRCT. PMID- 24803836 TI - Hepatitis B surface antigen seroconversion after HBV reactivation in non Hodgkin's lymphoma. AB - Reactivation of hepatitis B virus (HBV) can occur in lymphoma patients infected with HBV when they receive chemotherapy or immunotherapy. Prophylactic administration of lamivudine (LAM) reduces the morbidity and mortality associated with HBV reactivation. However, what defines HBV reactivation and the optimal duration of treatment with LAM have not yet been clearly established. HBV reactivation may occur due to the cessation of prophylactic LAM, although re treatment with nucleoside analogs may sometimes result in hepatitis B surface antigen (HBsAg) seroconversion, which is a satisfactory endpoint for the management of HBV infection. We report a case of HBV reactivation in a 68-year old HBsAg-positive patient who received rituximab-based immunochemotherapy for follicular lymphoma. HBV reactivation developed following cessation of prophylactic LAM therapy. The patient subsequently received treatment with entecavir (ETV), which led to a rapid and sustained suppression of HBV replication and HBsAg seroconversion. We also appraised the literature concerning HBV reactivation and the role of ETV in the management of HBV reactivation in lymphoma patients. A total of 28 cases of HBV reactivation have been reported as having been treated with ETV during or after immunosuppressive chemotherapy in lymphoma patients. We conclude that ETV is an efficacious and safe treatment for HBV reactivation following LAM cessation in lymphoma patients treated with rituximab-based immunochemotherapy. PMID- 24803837 TI - Influence of Morbid Obesity on Surgical Outcomes in Robotic-Assisted Gynecologic Surgery. AB - Objective: The aim of this research was to estimate the impact of body mass index (BMI) on surgical outcomes in patients undergoing robotic-assisted gynecologic surgery. Materials and Methods: This study was a retrospective review of prospectively collected cohort data for a consecutive series of patients undergoing gynecologic robotic surgery in a single institution. BMI, expressed as kg/m2, was abstracted from the medical charts of all patients undergoing robotic hysterectomy. Data on estimated blood loss (EBL), hemoglobin (Hb) drop, procedure time, length of hospital stay, uterine weight, pain-medication use, and complications were also extracted. Results: Two hundred and eighty-one patients underwent robotic operations. Types of procedures were total hysterectomy with or without adnexal excision, and total hysterectomies with lymphadenectomies. Eighty four patients who were classified as morbidly obese (BMI>35) were compared with 197 patients who had a BMI of<35 (nonmorbidly obese). For patients with BMI<35, and BMI>35, the mean BMI was 27.1 and 42.5 kg/m2 (p<0.05), mean age was 49 and 50 (p=0.45), mean total operative time was 222 and 266 minutes (p<0.05), console time 115 and 142 minutes (p<0.05), closing time (from undocking until port-site fascia closure) was 30 and 41 minutes (p<0.05), EBL was 67 and 79 mL (p=0.27), Hb drop was 1.6 and 1.4 (p=0.28), uterine weight was 196.2 and 227 g (p=0.52), pain medication use 93.7 and 111 mg of morphine (p=0.46), and mean length of stay was 1.42 and 1.43 days (0.9), all respectively. No statistically significant difference was noted between the 2 groups for EBL, Hb drop, LOS, uterine weight, pain-medication use, or complications. The only statistically significant difference was seen in operating times and included docking, console, closing, and procedure times. There were no perioperative mortalities. Morbidity occurred in 24 patients (8%). In the morbidly obese group, there were 6 complications (7%) and, in the nonmorbidly obese group, there were 18 complications (9%). Conclusions: Morbid obesity does not appear to be associated with an increased risk of morbidity in patients undergoing robotically assisted gynecologic surgery. Morbid obesity is associated with increased procedure time, but otherwise appears to have no difference in outcomes. Robotic surgery offered an ideal approach, allowing minimally invasive surgery in these technically challenging patients, with no significant increase in morbidity. J GYNECOL SURG 30:81). PMID- 24803839 TI - Commentary on the last 25 years of Myology. PMID- 24803838 TI - Bioavailability of (Geno)toxic Contaminants in Polycyclic Aromatic Hydrocarbon Contaminated Soil Before and After Biological Treatment. AB - Contaminated soil from a former manufactured-gas plant site was treated in a laboratory-scale bioreactor. Desorbability and biodegradability of 14 polycyclic aromatic hydrocarbons (PAHs) and 4 oxygenated PAHs (oxy-PAHs) were investigated throughout a treatment cycle. Desorbability was determined using a mixed-function sorbent (Oasis(r) HLB) or a hydrophobic sorbent (Tenax(r)) in dialysis tubing suspended in the soil slurry. Toxicity and genotoxicity of the whole soil and the desorbable fractions were determined by DNA damage response analysis with the chicken DT40 B-lymphocyte isogenic cell line and its DNA repair-deficient mutant Rad54-/-. Biological treatment significantly removed both PAHs and oxy-PAHs, and their desorbability decreased throughout the bioreactor treatment cycle. Collectively, oxy-PAHs were more desorbable and biodegradable than the corresponding PAHs; for example, the oxy-PAH present at the highest concentration, 9,10-anthraquinone, was more desorbable and biodegradable than anthracene. For both PAHs and oxy-PAHs, the percentage removed in the bioreactor significantly exceeded the percentage desorbed from untreated soil, indicating that desorption did not control the extent of biodegradation. Consistent with previous results on the same soil, genotoxicity of the whole soil slightly increased after biological treatment. However, both toxicity and genotoxicity of the desorbable constituents in the soil decreased after treatment, suggesting that any genotoxic constituents that may have formed during treatment were primarily associated with less accessible domains in the soil. PMID- 24803840 TI - Epidemiology of muscular dystrophies in the Mediterranean area. AB - The Mediterranean countries are distinguished with their peculiar genetic pool and diversities. Recessive diseases often present with their own founder mutations. In some instances this is shared with neighboring populations. Dominant disorders in the area are increasingly recognized as health care providing systems and technology improve. Among muscular dystrophies Duchenne and Becker types constitute the major fraction in almost all societies. This is followed by various forms of limb-girdle muscular dystrophy. Congenital dystrophies and other related rare types are a matter of recognition. The identification and registry of facio-scapulo-humeral and myotonic dystrophies vary in different states. PMID- 24803841 TI - Atrial fibrillation burden in Myotonic Dystrophy type 1 patients implanted with dual chamber pacemaker: the efficacy of the overdrive atrial algorithm at 2 year follow-up. AB - The role that atrial pacing therapy plays on the atrial fibrillation (AF) burden is still unclear. Aim of the study was to evaluate the effect of the atrial preference pacing algorithm on AF burden in patients affected by Myotonic Dystrophy type 1 (DM1) followed for a long follow up period. Sixty DM1 patients were -implanted with a dual chamber pacemaker (PM) for first degree or symptomatic type 1/type 2 second degree atrio-ventricular blocks- were followed for 2-years after implantation, by periodical examination. After 1 month of stabilization, they were randomized into two groups: 1) Patients implanted with conventional dual-chamber pacing mode (DDDR group) and 2) Patients implanted with DDDR plus Atrial Preference Pacing (APP) algorithm (APP ON group). The results showed that atrial tachycardia (AT)/AF burden was significantly reduced at 1 year follow up in the APP ON group (2122 +/- 428 minutes vs 4127 +/- 388 minutes, P = 0.03), with a further reduction at the end of the 2 year follow up period (4652 +/- 348 minutes vs 7564 +/- 638 minutes, P = 0.005). The data here reported show that the APP is an efficient algorithm to reduce AT/AF burden in DM1 patients implanted with dual chamber pacemaker. PMID- 24803842 TI - Eosinophils in hereditary and inflammatory myopathies. AB - It is not known whether eosinophilic myositis is a specific histopathological feature of limb girdle muscular dystrophy 2A (LGMD2A). Number and location of eosinophils in skeletal muscle biopsies (n=100) was analysed by Giemsa and modified hematoxylin/eosin staining in patients with genetically confirmed myopathies (LGMD2A, LGMD2B, LGMD2L, facioscapulohumeral muscular dystrophy, dystrophinopathy), histologically confirmed idiopathic inflammatory myopathies (sporadic inclusion body myositis (sIBM), dermatomyositis (DM), polymyositis), amyotrophic lateral sclerosis (neurogenic control), and normal controls. The number of eosinophils/mm2 was significantly higher in LGMD2A, PM, DM, and sIBM compared to controls but not significantly higher than other myopathies. A large overlap in the number of eosinophils/mm2 between all groups was seen. In all disease groups eosinophils were mainly found endomysially (46- 88%) and intra- and perivascularly (4-37%). There was no correlation between the numbers of eosinophils/mm2 and (i) age at biopsy and (ii) the duration of the disease. The extent of myopathic, fibrotic, and inflammatory changes did not differ in samples with high and low eosinophil count. Eosinophils seem to represent an unspecific histological finding in hereditary and inflammatory myopathies, but also amyotrophic lateral sclerosis. PMID- 24803843 TI - Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies. AB - Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment. PMID- 24803845 TI - Differential diagnosis and treatment of muscle hypertonia as practiced in Zagreb's Centre/Institute for Neuromuscular Diseases. AB - Because I am a neuromyologist that has dealt for many years with muscle hypertonia, I decided to write my memories in order to motivate younger researchers to try to duplicate the same observations and experiences. We defined a whole range of conditions and symptoms, partly or in full. That is the first crucial step on the way to suppressing or relieving suffering. In some cases there was nothing we could do. In the other cases, we managed to diminish the uncomfortable symptoms. In still other cases, we cured the diseases, at least for a while. My conclusion is that great and systematic effort is always worth the trial. Maybe someone will follow us?! Always again, i used to repeat to myself and to the others that, when approaching the patient, always the following rules should be respected: watch, listen and use your own common sense to evaluate what you observe; analyse why the symptoms occur in a concrete case; include the therapy in the logic of symptom development; continue to follow the patient and ask questions of yourself and of your colleagues; consult the literature; find the differences; ask again and again what else could be done ... and the solutions will appear unexpectedly. PMID- 24803844 TI - A late-onset and mild form of Charcot-Marie-Tooth disease type 2 caused by a novel splice-site mutation within the Mitofusin-2 gene. AB - Charcot-Marie-Tooth type 2A disease (CMT2A) caused by mutations in the Mitofusin 2 gene (Mfn2) has been shown to be an early-onset axonal neuropathy with severe clinical course in the majority of the patients. In this study we present a unique phenotype of CMT2A disease characterized by late-onset polyneuropathy with a very mild clinical course. This rare form of CMT2A disease is caused by a new splice-site (c.311+1G>T) mutation within the MFN2 gene. Due to disturbance of the MFN2 splicing process, this mutation generates a short transcript which encodes a very short fragment of MFN2 protein. The c.311+1G>T mutation within the MFN2 gene results in the late -onset CMT2 disease. PMID- 24803847 TI - Noncentrosymmetric Packings Influenced by Electronic Properties of Products of Click Reactions. AB - Though 1,4-disubstituted 1,2,3-triazole rings have been utilized as electronic bridges in the solution phase, the use of a triazole ring to serve as an electronic bridge of small molecules in the crystalline state has been underdeveloped. Here two compounds with a central 1,4-disubstituted 1,2,3 triazole ring are synthesized to investigate the electronic bridging between terminal stilbazole and pyridine groups in the crystalline phase. The electronic properties of the molecules are characterized through solution phase UV-vis spectroscopy, single crystal X-ray diffractions, and density-of-state and gas phase DFT calculations. We show that the electronic bridging behavior of a 1,4 disubstituted 1,2,3-triazole ring derived from a click reaction is maintained in the solid state by rare head-to-head (hh) packing in noncentrosymmetric crystal environments. PMID- 24803846 TI - An antimethanogenic nutritional intervention in early life of ruminants modifies ruminal colonization by Archaea. AB - The aim of this work was to study whether feeding a methanogen inhibitor from birth of goat kids and their does has an impact on the archaeal population colonizing the rumen and to what extent the impact persists later in life. Sixteen goats giving birth to two kids were used. Eight does were treated (D+) with bromochloromethane after giving birth and over 2 months. The other 8 goats were not treated (D-). One kid per doe in both groups was treated with bromochloromethane (k+) for 3 months while the other was untreated (k-), resulting in four experimental groups: D+/k+, D+/k-, D-/k+, and D-/k-. Rumen samples were collected from kids at weaning and 1 and 4 months after (3 and 6 months after birth) and from does at the end of the treating period (2 months). Pyrosequencing analyses showed a modified archaeal community composition colonizing the rumen of kids, although such effect did not persist entirely 4 months after; however, some less abundant groups remained different in treated and control animals. The different response on the archaeal community composition observed between offspring and adult goats suggests that the competition occurring in the developing rumen to occupy different niches offer potential for intervention. PMID- 24803848 TI - Tracking Amorphous Precursor Formation and Transformation during Induction Stages of Nucleation. AB - Hydroxyapatite (HAP) participates in vertebral bone and tooth formation by a nonclassical hitherto unknown nucleation mechanism, in which amorphous precursors form and transform during long induction periods. Elucidation of the mechanism by which amorphous precursors assemble and transform is essential to understanding how hard tissues form in vivo and will advance the design and fabrication of new biomaterials. The combination of conductance and potentiometric techniques to monitor Ca-P mineral formation has given new insight into the mechanism of nucleation. Differences detected in the dehydration rates of calcium and phosphate ions indicate the formation of nonequilibrium calcium-deficient clusters. The aggregation of these clusters forms a calcium-deficient amorphous phase I [Ca-(HPO4)1+x .nH2O]2x-) early in the induction period, which slowly transforms to amorphous phase II [Ca-(HPO4).mH2O] by dehydration. Precritical nuclei form within amorphous phase II later in the induction period, leading to mineral formation. PMID- 24803849 TI - Crystallizing Membrane Proteins in the Lipidic Mesophase. Experience with Human Prostaglandin E2 Synthase 1 and an Evolving Strategy. AB - The lipidic mesophase or in meso method for crystallizing membrane proteins has several high profile targets to its credit and is growing in popularity. Despite its success, the method is in its infancy as far as rational crystallogenesis is concerned. Consequently, significant time, effort, and resources are still required to generate structure-grade crystals, especially with a new target type. Therefore, a need exists for crystallogenesis protocols that are effective with a broad range of membrane protein types. Recently, a strategy for crystallizing a prokaryotic alpha-helical membrane protein, diacylglycerol kinase (DgkA), by the in meso method was reported (Cryst. Growth. Des.2013, 14, 2846-2857). Here, we describe its application to the human alpha-helical microsomal prostaglandin E2 synthase 1 (mPGES1). While the DgkA strategy proved useful, significant modifications were needed to generate structure-quality crystals of this important therapeutic target. These included protein engineering, using an additive phospholipid in the hosting mesophase, performing multiple rounds of salt screening, and carrying out trials at 4 degrees C in the presence of a tight binding ligand. The crystallization strategy detailed here should prove useful for generating structures of other integral membrane proteins by the in meso method. PMID- 24803850 TI - Childhood Cogan syndrome with aortitis and anti-neutrophil cytoplasmic antibody associated glomerulonephritis. AB - Cogan syndrome is a systemic disease manifesting interstitial keratitis, sensorineural hearing loss, tinnitus, and rotatory vertigo. Renal complications of this syndrome are very rare. We encountered an adolescent with Cogan syndrome complicated by aortitis and anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis. At the age of 14, the patient showed proteinuria in a screening urinalysis at school and was found to lack a right radial pulse. Magnetic resonance angiography disclosed right subclavian artery stenosis. Examination of a renal biopsy specimen showed ANCA-positive crescentic glomerulonephritis. Steroid and immunosuppressant treatment improved renal function and histopathology, but repeated recurrences followed. At 18, the patient developed rotatory vertigo, a sense of ear fullness, and sensorineural hearing loss. The patient was diagnosed with Cogan syndrome. We know of no previous description of ANCA-positive crescentic glomerulonephritis in children with Cogan syndrome. Accordingly, evaluation of aortitis in childhood should include not only otolaryngologic and ophthalmologic examinations, but also periodic urine examination and renal function tests. PMID- 24803851 TI - Weighted Implementation of Suboptimal Paths (WISP): An Optimized Algorithm and Tool for Dynamical Network Analysis. AB - Allostery can occur by way of subtle cooperation among protein residues (e.g., amino acids) even in the absence of large conformational shifts. Dynamical network analysis has been used to model this cooperation, helping to computationally explain how binding to an allosteric site can impact the behavior of a primary site many angstroms away. Traditionally, computational efforts have focused on the most optimal path of correlated motions leading from the allosteric to the primary active site. We present a program called Weighted Implementation of Suboptimal Paths (WISP) capable of rapidly identifying additional suboptimal pathways that may also play important roles in the transmission of allosteric signals. Aside from providing signal redundancy, suboptimal paths traverse residues that, if disrupted through pharmacological or mutational means, could modulate the allosteric regulation of important drug targets. To demonstrate the utility of our program, we present a case study describing the allostery of HisH-HisF, an amidotransferase from T. maritima thermotiga. WISP and its VMD-based graphical user interface (GUI) can be downloaded from http://nbcr.ucsd.edu/wisp. PMID- 24803852 TI - Multiscale Factorization Method for Simulating Mesoscopic Systems with Atomic Precision. AB - Mesoscopic N-atom systems derive their structural and dynamical properties from processes coupled across multiple scales in space and time. A multiscale method for simulating these systems in the friction dominated regime from the underlying N-atom formulation is presented. The method integrates notions of multiscale analysis, Trotter factorization, and a hypothesis that the momenta conjugate to coarse-grained variables constitute a stationary process on the time scale of coarse-grained dynamics. The method is demonstrated for lactoferrin, nudaurelia capensis omega virus, and human papillomavirus to assess its accuracy. PMID- 24803853 TI - Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering. AB - With a view to improving the consistency of free energy perturbation calculations in Monte Carlo simulations of protein-ligand complexes, we have implemented the replica exchange with solute tempering (REST) method in the MCPRO software. By augmenting the standard REST approach with regular attempted jumps in selected dihedral angles, our combined method facilitates sampling of ligand binding modes that are separated by high free energy barriers and ensures that computed free energy changes are considerably less dependent on the starting conditions and the chosen mutation pathway than those calculated with standard Monte Carlo sampling. We have applied the enhanced sampling method to the calculation of the activities of seven non-nucleoside inhibitors of HIV-1 reverse transcriptase, and its Tyr181Cys variant, and have shown that a range of binding orientations is possible depending on the nature of the ligand and the presence of mutations at the binding site. PMID- 24803854 TI - Identification and Characterization of Noncovalent Interactions That Drive Binding and Specificity in DD-Peptidases and beta-Lactamases. AB - Bacterial resistance to standard (i.e., beta-lactam-based) antibiotics has become a global pandemic. Simultaneously, research into the underlying causes of resistance has slowed substantially, although its importance is universally recognized. Key to unraveling critical details is characterization of the noncovalent interactions that govern binding and specificity (DD-peptidases, antibiotic targets, versus beta-lactamases, the evolutionarily derived enzymes that play a major role in resistance) and ultimately resistance as a whole. Herein, we describe a detailed investigation that elicits new chemical insights into these underlying intermolecular interactions. Benzylpenicillin and a novel beta-lactam peptidomimetic complexed to the Stremptomyces R61 peptidase are examined using an arsenal of computational techniques: MD simulations, QM/MM calculations, charge perturbation analysis, QM/MM orbital analysis, bioinformatics, flexible receptor/flexible ligand docking, and computational ADME predictions. Several key molecular level interactions are identified that not only shed light onto fundamental resistance mechanisms, but also offer explanations for observed specificity. Specifically, an extended pi-pi network is elucidated that suggests antibacterial resistance has evolved, in part, due to stabilizing aromatic interactions. Additionally, interactions between the protein and peptidomimetic substrate are identified and characterized. Of particular interest is a water-mediated salt bridge between Asp217 and the positively charged N-terminus of the peptidomimetic, revealing an interaction that may significantly contribute to beta-lactam specificity. Finally, interaction information is used to suggest modifications to current beta-lactam compounds that should both improve binding and specificity in DD-peptidases and their physiochemical properties. PMID- 24803855 TI - Lipid14: The Amber Lipid Force Field. AB - The AMBER lipid force field has been updated to create Lipid14, allowing tensionless simulation of a number of lipid types with the AMBER MD package. The modular nature of this force field allows numerous combinations of head and tail groups to create different lipid types, enabling the easy insertion of new lipid species. The Lennard-Jones and torsion parameters of both the head and tail groups have been revised and updated partial charges calculated. The force field has been validated by simulating bilayers of six different lipid types for a total of 0.5 MUs each without applying a surface tension; with favorable comparison to experiment for properties such as area per lipid, volume per lipid, bilayer thickness, NMR order parameters, scattering data, and lipid lateral diffusion. As the derivation of this force field is consistent with the AMBER development philosophy, Lipid14 is compatible with the AMBER protein, nucleic acid, carbohydrate, and small molecule force fields. PMID- 24803857 TI - Probing the Conical Intersection Dynamics of the RNA Base Uracil by UV-Pump Stimulated-Raman-Probe Signals; Ab Initio Simulations. AB - Nonadiabatic electron and nuclear dynamics of photoexcited molecules involving conical intersections is of fundamental importance in many reactions such as the self-protection mechanism of DNA and RNA bases against UV irradiation. Nonlinear vibrational spectroscopy can provide an ultrafast sensitive probe for these processes. We employ a simulation protocol that combines nonadiabatic on-the-fly molecular dynamics with a mode-tracking algorithm for the simulation of femtosecond stimulated Raman spectroscopy (SRS) signals of the high frequency C-H and N-H-stretch vibrations of the photoexcited RNA base uracil. The simulations rely on a microscopically derived expression that takes into account the path integral of the excited state evolution and the pulse shapes. Analysis of the joint time/frequency resolution of the technique reveals a matter chirp contribution that limits the inherent temporal resolution. Characteristic signatures of relaxation dynamics mediated in the vicinity of conical intersection are predicted. The C-H and N-H spectator modes provide high sensitivity to their local environment and act as local probes with submolecular and high temporal resolution. PMID- 24803858 TI - Assessment of Quantum Mechanical Methods for Copper and Iron Complexes by Photoelectron Spectroscopy. AB - Broken-symmetry density functional theory (BS-DFT) calculations are assessed for redox energetics [Cu(SCH3)2]1-/0, [Cu(NCS)2]1-/0, [FeCl4]1-/0, and [Fe(SCH3)4]1 /0 against vertical detachment energies (VDE) from valence photoelectron spectroscopy (PES), as a prelude to studies of metalloprotein analogs. The M06 and B3LYP hybrid functionals give VDE that agree with the PES VDE for the Fe complexes, but both underestimate it by ~400 meV for the Cu complexes; other hybrid functionals give VDEs that are an increasing function of the amount of Hartree-Fock (HF) exchange and so cannot show good agreement for both Cu and Fe complexes. Range-separated (RS) functionals appear to give a better distribution of HF exchange since the negative HOMO energy is approximately equal to the VDEs but also give VDEs dependent on the amount of HF exchange, sometimes leading to ground states with incorrect electron configurations; the LRC-omegaPBEh functional reduced to 10% HF exchange at short-range give somewhat better values for both, although still ~150 meV too low for the Cu complexes and ~50 meV too high for the Fe complexes. Overall, the results indicate that while HF exchange compensates for self-interaction error in DFT calculations of both Cu and Fe complexes, too much may lead to more sensitivity to nondynamical correlation in the spin-polarized Fe complexes. PMID- 24803856 TI - Parametrization of an Orbital-Based Linear-Scaling Quantum Force Field for Noncovalent Interactions. AB - We parametrize a linear-scaling quantum mechanical force field called mDC for the accurate reproduction of nonbonded interactions. We provide a new benchmark database of accurate ab initio interactions between sulfur-containing molecules. A variety of nonbond databases are used to compare the new mDC method with other semiempirical, molecular mechanical, ab initio, and combined semiempirical quantum mechanical/molecular mechanical methods. It is shown that the molecular mechanical force field significantly and consistently reproduces the benchmark results with greater accuracy than the semiempirical models and our mDC model produces errors twice as small as the molecular mechanical force field. The comparisons between the methods are extended to the docking of drug candidates to the Cyclin-Dependent Kinase 2 protein receptor. We correlate the protein-ligand binding energies to their experimental inhibition constants and find that the mDC produces the best correlation. Condensed phase simulation of mDC water is performed and shown to produce O-O radial distribution functions similar to TIP4P EW. PMID- 24803859 TI - Modified Amber Force Field Correctly Models the Conformational Preference for Tandem GA pairs in RNA. AB - Molecular mechanics with all-atom models was used to understand the conformational preference of tandem guanine-adenine (GA) noncanonical pairs in RNA. These tandem GA pairs play important roles in determining stability, flexibility, and structural dynamics of RNA tertiary structures. Previous solution structures showed that these tandem GA pairs adopt either imino (cis Watson-Crick/Watson-Crick A-G) or sheared (trans Hoogsteen/sugar edge A-G) conformations depending on the sequence and orientation of the adjacent closing base pairs. The solution structures (GCGGACGC)2 [Biochemistry, 1996, 35, 9677 9689] and (GCGGAUGC)2 [Biochemistry, 2007, 46, 1511-1522] demonstrate imino and sheared conformations for the two central GA pairs, respectively. These systems were studied using molecular dynamics and free energy change calculations for conformational changes, using umbrella sampling. For the structures to maintain their native conformations during molecular dynamics simulations, a modification to the standard Amber ff10 force field was required, which allowed the amino group of guanine to leave the plane of the base [J. Chem. Theory Comput., 2009, 5, 2088-2100] and form out-of-plane hydrogen bonds with a cross-strand cytosine or uracil. The requirement for this modification suggests the importance of out of-plane hydrogen bonds in stabilizing the native structures. Free energy change calculations for each sequence demonstrated the correct conformational preference when the force field modification was used, but the extent of the preference is underestimated. PMID- 24803860 TI - Heterogeneous Hydration of p53/MDM2 Complex. AB - Water-mediated interactions play critical roles in biomolecular recognition processes. Explicit solvent molecular dynamics (MD) simulations and the variational implicit-solvent model (VISM) are used to study those hydration properties during binding for the biologically important p53/MDM2 complex. Unlike simple model solutes, in such a realistic and heterogeneous solute-solvent system with both geometrical and chemical complexity, the local water distribution sensitively depends on nearby amino acid properties and the geometric shape of the protein. We show that the VISM can accurately describe the locations of high and low density solvation shells identified by the MD simulations and can explain them by a local coupling balance of solvent-solute interaction potentials and curvature. In particular, capillary transitions between local dry and wet hydration states in the binding pocket are captured for interdomain distance between 4 to 6 A, right at the onset of binding. The underlying physical connection between geometry and polarity is illustrated and quantified. Our study offers a microscopic and physical insight into the heterogeneous hydration behavior of the biologically highly relevant p53/MDM2 system and demonstrates the fundamental importance of hydrophobic effects for biological binding processes. We hope our study can help to establish new design rules for drugs and medical substances. PMID- 24803861 TI - Bringing Clarity to the Prediction of Protein-Ligand Binding Free Energies via "Blurring" AB - We present a method to evaluate the free energies of ligand binding utilizing a Monte Carlo estimation of the configuration integrals concomitant with uncertainty quantification. Ensembles for integration are built through systematically perturbing an initial ligand conformation in a rigid binding pocket, which is optimized separately prior to incorporation of the ligand. We call the procedure producing the ensembles "blurring", and it is carried out using an in-house developed code. The Boltzmann factor contribution of each pose to the configuration integral is computed and from there the free energy is obtained. Potential function uncertainties are estimated using a fragment-based error propagation method. This method has been applied to a set of small aromatic ligands complexed with T4 Lysozyme L99A mutant. Microstate energies have been determined with the force fields ff99SB and ff94, and the semiempirical method PM6DH2 in conjunction with continuum solvation models including Generalized Born (GB), the Conductor-like Screening Model (COSMO), and SMD. Of the methods studied, PM6DH2-based scoring gave binding free energy estimates, which yielded a good correlation to the experimental binding affinities (R2 = 0.7). All methods overestimated the calculated binding affinities. We trace this to insufficient sampling, the single static protein structure, and inaccuracies in the solvent models we have used in this study. PMID- 24803862 TI - Constant pH Replica Exchange Molecular Dynamics in Explicit Solvent Using Discrete Protonation States: Implementation, Testing, and Validation. AB - By utilizing Graphics Processing Units, we show that constant pH molecular dynamics simulations (CpHMD) run in Generalized Born (GB) implicit solvent for long time scales can yield poor pKa predictions as a result of sampling unrealistic conformations. To address this shortcoming, we present a method for performing constant pH molecular dynamics simulations (CpHMD) in explicit solvent using a discrete protonation state model. The method involves standard molecular dynamics (MD) being propagated in explicit solvent followed by protonation state changes being attempted in GB implicit solvent at fixed intervals. Replica exchange along the pH-dimension (pH-REMD) helps to obtain acceptable titration behavior with the proposed method. We analyzed the effects of various parameters and settings on the titration behavior of CpHMD and pH-REMD in explicit solvent, including the size of the simulation unit cell and the length of the relaxation dynamics following protonation state changes. We tested the method with the amino acid model compounds, a small pentapeptide with two titratable sites, and hen egg white lysozyme (HEWL). The proposed method yields superior predicted pKa values for HEWL over hundreds of nanoseconds of simulation relative to corresponding predicted values from simulations run in implicit solvent. PMID- 24803863 TI - Multiscale Free Energy Simulations: An Efficient Method for Connecting Classical MD Simulations to QM or QM/MM Free Energies Using Non-Boltzmann Bennett Reweighting Schemes. AB - THE RELIABILITY OF FREE ENERGY SIMULATIONS (FES) IS LIMITED BY TWO FACTORS: (a) the need for correct sampling and (b) the accuracy of the computational method employed. Classical methods (e.g., force fields) are typically used for FES and present a myriad of challenges, with parametrization being a principle one. On the other hand, parameter-free quantum mechanical (QM) methods tend to be too computationally expensive for adequate sampling. One widely used approach is a combination of methods, where the free energy difference between the two end states is computed by, e.g., molecular mechanics (MM), and the end states are corrected by more accurate methods, such as QM or hybrid QM/MM techniques. Here we report two new approaches that significantly improve the aforementioned scheme; with a focus on how to compute corrections between, e.g., the MM and the more accurate QM calculations. First, a molecular dynamics trajectory that properly samples relevant conformational degrees of freedom is generated. Next, potential energies of each trajectory frame are generated with a QM or QM/MM Hamiltonian. Free energy differences are then calculated based on the QM or QM/MM energies using either a non-Boltzmann Bennett approach (QM-NBB) or non-Boltzmann free energy perturbation (NB-FEP). Both approaches are applied to calculate relative and absolute solvation free energies in explicit and implicit solvent environments. Solvation free energy differences (relative and absolute) between ethane and methanol in explicit solvent are used as the initial test case for QM NBB. Next, implicit solvent methods are employed in conjunction with both QM-NBB and NB-FEP to compute absolute solvation free energies for 21 compounds. These compounds range from small molecules such as ethane and methanol to fairly large, flexible solutes, such as triacetyl glycerol. Several technical aspects were investigated. Ultimately some best practices are suggested for improving methods that seek to connect MM to QM (or QM/MM) levels of theory in FES. PMID- 24803864 TI - Variational Implicit Solvation with Poisson-Boltzmann Theory. AB - We incorporate the Poisson-Boltzmann (PB) theory of electrostatics into our variational implicit-solvent model (VISM) for the solvation of charged molecules in an aqueous solvent. In order to numerically relax the VISM free-energy functional by our level-set method, we develop highly accurate methods for solving the dielectric PB equation and for computing the dielectric boundary force. We also apply our VISM-PB theory to analyze the solvent potentials of mean force and the effect of charges on the hydrophobic hydration for some selected molecular systems. These include some single ions, two charged particles, two charged plates, and the host-guest system Cucurbit[7]uril and Bicyclo[2.2.2]octane. Our computational results show that VISM with PB theory can capture well the sensitive response of capillary evaporation to the charge in hydrophobic confinement and the polymodal hydration behavior and can provide accurate estimates of binding affinity of the host-guest system. We finally discuss several issues for further improvement of VISM. PMID- 24803865 TI - Parameterization of DFTB3/3OB for Sulfur and Phosphorus for Chemical and Biological Applications. AB - We report the parametrization of the approximate density functional tight binding method, DFTB3, for sulfur and phosphorus. The parametrization is done in a framework consistent with our previous 3OB set established for O, N, C, and H, thus the resulting parameters can be used to describe a broad set of organic and biologically relevant molecules. The 3d orbitals are included in the parametrization, and the electronic parameters are chosen to minimize errors in the atomization energies. The parameters are tested using a fairly diverse set of molecules of biological relevance, focusing on the geometries, reaction energies, proton affinities, and hydrogen bonding interactions of these molecules; vibrational frequencies are also examined, although less systematically. The results of DFTB3/3OB are compared to those from DFT (B3LYP and PBE), ab initio (MP2, G3B3), and several popular semiempirical methods (PM6 and PDDG), as well as predictions of DFTB3 with the older parametrization (the MIO set). In general, DFTB3/3OB is a major improvement over the previous parametrization (DFTB3/MIO), and for the majority cases tested here, it also outperforms PM6 and PDDG, especially for structural properties, vibrational frequencies, hydrogen bonding interactions, and proton affinities. For reaction energies, DFTB3/3OB exhibits major improvement over DFTB3/MIO, due mainly to significant reduction of errors in atomization energies; compared to PM6 and PDDG, DFTB3/3OB also generally performs better, although the magnitude of improvement is more modest. Compared to high-level calculations, DFTB3/3OB is most successful at predicting geometries; larger errors are found in the energies, although the results can be greatly improved by computing single point energies at a high level with DFTB3 geometries. There are several remaining issues with the DFTB3/3OB approach, most notably its difficulty in describing phosphate hydrolysis reactions involving a change in the coordination number of the phosphorus, for which a specific parametrization (3OB/OPhyd) is developed as a temporary solution; this suggests that the current DFTB3 methodology has limited transferability for complex phosphorus chemistry at the level of accuracy required for detailed mechanistic investigations. Therefore, fundamental improvements in the DFTB3 methodology are needed for a reliable method that describes phosphorus chemistry without ad hoc parameters. Nevertheless, DFTB3/3OB is expected to be a competitive QM method in QM/MM calculations for studying phosphorus/sulfur chemistry in condensed phase systems, especially as a low-level method that drives the sampling in a dual level QM/MM framework. PMID- 24803866 TI - Improvement of DNA and RNA Sugar Pucker Profiles from Semiempirical Quantum Methods. AB - Neglect of diatomic differential overlap (NDDO) and self-consistent density functional tight-binding (SCC-DFTB) semiempirical models commonly employed in combined quantum mechanical/molecular mechanical simulations fail to adequately describe the deoxyribose and ribose sugar ring puckers. This failure limits the application of these methods to RNA and DNA systems. In this work, we provide benchmark ab initio gas-phase two-dimensional potential energy scans of the RNA and DNA sugar puckering. The benchmark calculations are compared with semiempirical models. Pucker corrections are introduced into the semiempirical models via B-spline interpolation of the potential energy difference surface relative to the benchmark data. The corrected semiempirical models are shown to well reproduce the ab initio puckering profiles. Furthermore, we demonstrate that the uncorrected semiempirical models do not usually produce a transition state between the A-form and B-form sugar puckers, but the ab initio transition state is reproduced when the B-spline correction is used. PMID- 24803867 TI - Quantum Mechanical Calculation of Noncovalent Interactions: A Large-Scale Evaluation of PMx, DFT, and SAPT Approaches. AB - Quantum mechanical (QM) calculations of noncovalent interactions are uniquely useful as tools to test and improve molecular mechanics force fields and to model the forces involved in biomolecular binding and folding. Because the more computationally tractable QM methods necessarily include approximations, which risk degrading accuracy, it is essential to evaluate such methods by comparison with high-level reference calculations. Here, we use the extensive Benchmark Energy and Geometry Database (BEGDB) of CCSD(T)/CBS reference results to evaluate the accuracy and speed of widely used QM methods for over 1200 chemically varied gas-phase dimers. In particular, we study the semiempirical PM6 and PM7 methods; density functional theory (DFT) approaches B3LYP, B97-D, M062X, and omegaB97X-D; and symmetry-adapted perturbation theory (SAPT) approach. For the PM6 and DFT methods, we also examine the effects of post hoc corrections for hydrogen bonding (PM6-DH+, PM6-DH2), halogen atoms (PM6-DH2X), and dispersion (DFT-D3 with zero and Becke-Johnson damping). Several orders of the SAPT expansion are also compared, ranging from SAPT0 up to SAPT2+3, where computationally feasible. We find that all DFT methods with dispersion corrections, as well as SAPT at orders above SAPT2, consistently provide dimer interaction energies within 1.0 kcal/mol RMSE across all systems. We also show that a linear scaling of the perturbative energy terms provided by the fast SAPT0 method yields similar high accuracy, at particularly low computational cost. The energies of all the dimer systems from the various QM approaches are included in the Supporting Information, as are the full SAPT2+(3) energy decomposition for a subset of over 1000 systems. The latter can be used to guide the parametrization of molecular mechanics force fields on a term-by-term basis. PMID- 24803868 TI - Dipeptide Aggregation in Aqueous Solution from Fixed Point-Charge Force Fields. AB - The description of aggregation processes with molecular dynamics simulations is a playground for testing biomolecular force fields, including a new generation of force fields that explicitly describe electronic polarization. In this work, we study a system consisting of 50 glycyl-l-alanine (Gly-Ala) dipeptides in solution with 1001 water molecules. Neutron diffraction experiments have shown that at this concentration, Gly-Ala aggregates into large clusters. However, general purpose force fields in combination with established water models can fail to correctly describe this aggregation process, highlighting important deficiencies in how solute-solute and solute-solvent interactions are parametrized in these force fields. We found that even for the fully polarizable AMOEBA force field, the degree of association is considerably underestimated. Instead, a fixed point charge approach based on the newly developed IPolQ scheme [Cerutti et al. J. Phys. Chem.2013, 117, 2328] allows for the correct modeling of the dipeptide aggregation in aqueous solution. This result should stimulate interest in novel fitting schemes that aim to improve the description of the solvent polarization effect within both explicitly polarizable and fixed point-charge frameworks. PMID- 24803869 TI - A Comparative Study of Transferable Aspherical Pseudoatom Databank and Classical Force Fields for Predicting Electrostatic Interactions in Molecular Dimers. AB - Accurate and fast evaluation of electrostatic interactions in molecular systems is one of the most challenging tasks in the rapidly advancing field of macromolecular chemistry and drug design. Electrostatic interactions are of crucial importance in biological systems. They are well represented by quantum mechanical methods; however, such calculations are computationally expensive. In this study, we have evaluated the University of Buffalo Pseudoatom Databank (UBDB)1,2 approach for approximation of electrostatic properties of macromolecules and their complexes. We selected the S663 and JSCH-20054 data sets (208 molecular complexes in total) for this study. These complexes represent a wide range of chemical and biological systems for which hydrogen bonding, electrostatic, and van der Waals interactions play important roles. Reference electrostatic energies were obtained directly from wave functions at the B3LYP/aug-cc-pVTZ level of theory using the SAPT (Symmetry-Adapted Perturbation Theory) scheme for calculation of electrostatic contributions to total intermolecular interaction energies. Electrostatic energies calculated on the basis of the UBDB were compared with corresponding reference results. Results were also compared with energies computed using a point charge model from popular force fields (AM1-BCC and RESP used in AMBER and CGenFF from CHARMM family). The energy trends are quite consistent (R2 ~ 0.98) for the UBDB method as compared to the AMBER5 and CHARMM force field methods6(R2 ~ 0.93 on average). The RSMEs do not exceed 3.2 kcal mol-1 for the UBDB and are in the range of 3.7-7.6 kcal mol-1 for the point charge models. We also investigated the discrepancies in electrostatic potentials and magnitudes of dipole moments among the tested methods. This study shows that estimation of electrostatic interaction energies using the UBDB databank is accurate and reasonably fast when compared to other known methods, which opens potential new applications to macromolecules. PMID- 24803870 TI - Predicting the Impact of Missense Mutations on Protein-Protein Binding Affinity. AB - The crucial prerequisite for proper biological function is the protein's ability to establish highly selective interactions with macromolecular partners. A missense mutation that alters the protein binding affinity may cause significant perturbations or complete abolishment of the function, potentially leading to diseases. The availability of computational methods to evaluate the impact of mutations on protein-protein binding is critical for a wide range of biomedical applications. Here, we report an efficient computational approach for predicting the effect of single and multiple missense mutations on protein-protein binding affinity. It is based on a well-tested simulation protocol for structure minimization, modified MM-PBSA and statistical scoring energy functions with parameters optimized on experimental sets of several thousands of mutations. Our simulation protocol yields very good agreement between predicted and experimental values with Pearson correlation coefficients of 0.69 and 0.63 and root-mean square errors of 1.20 and 1.90 kcal mol-1 for single and multiple mutations, respectively. Compared with other available methods, our approach achieves high speed and prediction accuracy and can be applied to large datasets generated by modern genomics initiatives. In addition, we report a crucial role of water model and the polar solvation energy in estimating the changes in binding affinity. Our analysis also reveals that prediction accuracy and effect of mutations on binding strongly depends on the type of mutation and its location in a protein complex. PMID- 24803872 TI - Letter from the editor. PMID- 24803871 TI - Introducing Charge Hydration Asymmetry into the Generalized Born Model. AB - The effect of charge hydration asymmetry (CHA)-non-invariance of solvation free energy upon solute charge inversion-is missing from the standard linear response continuum electrostatics. The proposed charge hydration asymmetric-generalized Born (CHA-GB) approximation introduces this effect into the popular generalized Born (GB) model. The CHA is added to the GB equation via an analytical correction that quantifies the specific propensity of CHA of a given water model; the latter is determined by the charge distribution within the water model. Significant variations in CHA seen in explicit water (TIP3P, TIP4P-Ew, and TIP5P-E) free energy calculations on charge-inverted "molecular bracelets" are closely reproduced by CHA-GB, with the accuracy similar to models such as SEA and 3D-RISM that go beyond the linear response. Compared against reference explicit (TIP3P) electrostatic solvation free energies, CHA-GB shows about a 40% improvement in accuracy over the canonical GB, tested on a diverse set of 248 rigid small neutral molecules (root mean square error, rmse = 0.88 kcal/mol for CHA-GB vs 1.24 kcal/mol for GB) and 48 conformations of amino acid analogs (rmse = 0.81 kcal/mol vs 1.26 kcal/mol). CHA-GB employs a novel definition of the dielectric boundary that does not subsume the CHA effects into the intrinsic atomic radii. The strategy leads to finding a new set of intrinsic atomic radii optimized for CHA-GB; these radii show physically meaningful variation with the atom type, in contrast to the radii set optimized for GB. Compared to several popular radii sets used with the original GB model, the new radii set shows better transferability between different classes of molecules. PMID- 24803873 TI - Frontiers in the treatment of hepatitis C virus infection. AB - In the United States, chronic hepatitis C virus (HCV) infection is the leading cause of blood-borne, virus-associated death related to advanced liver disease and the leading indication for liver transplantation. Although the diagnostic test for HCV has been available for more than 20 years, the majority of persons with HCV infection still have not received a diagnosis. This has led to a recent change in screening recommendations by the Centers for Disease Control and Prevention. Moreover, new medications were approved in 2011 after nearly a decade of minimal progress in the development of treatments for HCV infection. This was followed by the highly anticipated approval of sofosbuvir and simeprevir in 201 3. In the past 3 years, there has been an explosion of reports on medications from different classes, promising a dramatic expansion to an all-oral regimen for the treatment of HCV genotype 1 infection within the next few years. This article reviews the current screening recommendations and standard of care for treatment of HCV infection and highlights specific agents in the pipeline that should change the landscape of how HCV infection is treated in the near future. PMID- 24803875 TI - Gastrointestinal endoscopy in patients taking novel oral anticoagulants. PMID- 24803874 TI - Emerging therapeutic options for eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus that often occurs in atopic persons. Management strategies include pharmacotherapy, dietary modification, and endoscopic therapy, although patients will often have a relapsing and remitting course. Currently, the primary pharmacotherapy for EoE consists of corticosteroids. Immuno-modulators, leukotriene antagonists, biologies, and monoclonal antibodies are currently under study for treatment of EoE. The role of immunoglobulin E-mediated allergic reactions has been well documented and may provide insight into the etiology and effective therapy of EoE. PMID- 24803876 TI - Early detection of hepatocellular carcinoma through surveillance using biomarkers. PMID- 24803877 TI - Vitamin D Deficiency and Supplementation in Patients with IBD. PMID- 24803878 TI - Diffuse esophageal spasm in the era of high-resolution manometry. PMID- 24803879 TI - Advances in combination regimens in the management of HCV infection. PMID- 24803880 TI - Cutting-edge therapy concepts - cure metastatic breast cancer? PMID- 24803881 TI - Oligometastatic breast cancer: a shift from palliative to potentially curative treatment? AB - A distinctive subset of metastatic breast cancer is represented by the so called 'oligometastatic' disease, characterized by single/few detectable metastatic lesions. A more aggressive multidisciplinary approach can be considered in this patient population: available data report favorable results of 'radical' local therapy for limited metastatic disease at least in a subset of selected patients. Selection bias and the retrospective nature of data do not allow for generalization of the results: the use of such approaches must be individualized and managed within a multidisciplinary team of dedicated specialists. Improvement in surgical and radiation techniques, development of new tools to deliver local chemotherapy, and new procedures (i.e. cryosurgery, laser and microwave ablation) mandate careful evaluation of such single and combined modalities in controlled clinical trials. A more accurate identification of patients with limited metastases and better definition of treatment endpoints will also allow correct patient selection for locally aggressive therapies. This paper focusses on local treatment of the primary tumor and of the most frequent distant disease sites in the presence of oligometastatic disease. PMID- 24803882 TI - Monitoring in metastatic breast cancer: is imaging outdated in the era of circulating tumor cells? AB - In clinical practice imaging technologies such as computed tomography (CT), positron emission tomography (PET)/CT and magnetic resonance imaging (MRI) are well-established methods for monitoring metastatic breast cancer (MBC) patients and for assessing therapeutic efficacy. However, several weeks of treatment are required before these technologies can offer any reliable information on effective disease regression, and, in the meanwhile, the patients are exposed to potentially unnecessary therapy. Circulating tumor cells (CTCs) have been shown to be powerful prognostic and predictive markers and provide clinicians with valuable information. However, in one clinical trial, an early change of chemotherapy based on CTC detection did not result in improved survival. Currently, CTC detection outside clinical trials should be limited to selected clinical situations, i.e. increased treatment toxicity or as risk estimation. PMID- 24803883 TI - Primary metastatic breast cancer: the impact of locoregional therapy. AB - The impact of treatment for the primary tumor on distant metastases and survival in primary metastatic breast cancer patients is controversial. Previous retrospective studies and meta-analyses suggested a survival benefit for the removal of the primary tumor. Early follow-up data from 2 prospectively randomized trials presented at San Antonio Breast Cancer Symposium 2013 could not confirm this. Only a very small subgroup of patients with solitary bone metastases seemed to profit from surgery, while patients with multiple visceral metastases showed a worse prognosis with initial surgery. There are no studies available with the primary aim to investigate the impact of axillary lymph node surgery or locoregional radiotherapy on the survival of stage IV breast cancer patients. Based on current data, locoregional treatment in primary metastatic breast cancer should not be recommended in patients with asymptomatic primary tumor as a matter of routine. More solid conclusion of the impact of primary tumor treatment in stage IV breast cancer patients on their prognosis will be reached with the completion of the ongoing prospectively randomized trials. Until these studies are completed, locoregional therapy, which can provoke additional morbidity in a metastatic setting with limited live expectancy, is exclusively indicated for palliative reasons. PMID- 24803884 TI - Psychological impact of male breast disorders: literature review and survey results. AB - BACKGROUND: Referrals of men to breast assessment clinics are increasing. While most of the men will have benign disease, some of them will have breast cancer. Whichever pathology they have, men should be offered a service tailored to their needs, rather than being 'shoehorned' into a service designed to care for women. This paper explores the psychological impact on men of their condition and of attending a breast assessment clinic. METHODS: The literature regarding male experience of breast problems is reviewed, and screening for psychological morbidity is discussed. Results of a survey regarding an all-male breast assessment clinic are reported, with a plan for future research. RESULTS: Many of the 78 men surveyed described negative feelings relating to their condition although they did not want to be seen in an all-male breast assessment clinic if that meant a longer wait. Men reported feelings of anxiety, embarrassment, emasculation and even depression regarding their condition. CONCLUSIONS: Men are distressed by gynaecomastia and need psychological support for any breast-related presentation. More formalised research into this area is needed, although the men's distress does not translate into the desire to attend an all-male assessment clinic if this means a longer wait before being seen. PMID- 24803885 TI - Adjuvant tamoxifen influences the lipid profile in breast cancer patients. AB - BACKGROUND: Currently there is a debate regarding whether tamoxifen used in breast cancer has an impact on lipid profiles. The aim of this study was to determine whether tamoxifen has an impact on the serum lipid profile in Taiwanese women. PATIENTS AND METHODS: Data of 109 patients were collected from the routine clinical follow-up for women with hormone receptor-positive breast cancer who were treated between July 2005 and March 2008. These patients were divided into 2 subgroups, based on their tumor grade and lymph node status. Subgroup 1 patients had tumor grade I/II and a negative lymph node status. Those patients with tumor grade III or a positive lymph node status were defined as subgroup 2. RESULTS: In the 109 patients, the mean serum total cholesterol (TC) levels after tamoxifen treatment, as well as the serum low-density lipoprotein cholesterol (LDL-C) levels, were lower than the baseline levels, with statistically significant differences. Treatment with tamoxifen lowered the serum TC and LDL-C levels in both subgroups. CONCLUSIONS: The results indicate that tamoxifen has an impact on the serum lipid profile of breast cancer patients in Taiwan. Physicians should follow up the lipid profile in these patients. PMID- 24803886 TI - Prediction of resection weight in reduction mammaplasty based on anthropometric measurements. AB - BACKGROUND: The aim of this study was to develop a simple, clinically useful method to accurately predict resection weight in women undergoing reduction mammaplasty. PATIENTS AND METHODS: 39 women undergoing breast reduction participated in the study. Sternal notch to nipple distance, nipple to inframammary fold distance (NIMF), medial end point to nipple distance (MN), lateral endpoint to nipple distance (LN), superior border of the breast to nipple distance (SN), breast circumference (BC), and chest circumference (CC) were measured. 5 other predicting variables were also derived; horizontal breast measurement (H) by adding MN to LN, vertical breast measurement (V) by adding NIMF to SN, the product of H and V (H*V), the product of H and NIMF (H*NIMF), and the difference between BC and CC (D). Regression analysis was used to compose a formula for predicting resection weight. RESULTS: Among the predicting variables, H*NIMF measurements had the highest correlation coefficient value (Pearson correlation = 0.809) with the resection weight. The following formula was obtained with regression analysis: Predicted resection weight = (1.45 * H*NIMF) + (31.5 * D) - 576. CONCLUSION: Breast resection weights can be accurately predicted by the presented method based on anthropomorphic measurements. PMID- 24803887 TI - Cardiac tolerability of concurrent administration of trastuzumab and anthracycline-based regimen as adjuvant chemotherapy for breast cancer. AB - BACKGROUND: Retrospective analysis suggests that anthracycline-containing regimens may be superior to non-anthracycline-containing regimens in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, both trastuzumab and anthracycline have cardiotoxicity, and it remains unclear how to use trastuzumab in combination with an anthracycline to curtail their cardiotoxicity. PATIENTS AND METHODS: From 2010 to 2013, we administered weekly (q1w) paclitaxel (wP) followed by 75 mg/m(2) epirubicin, fluorouracil, and cyclophosphamide (FEC) every third week (q3w) and concurrent q1w trastuzumab (H) to 41 patients with HER2-positive breast cancer (H+ group), and wP followed by FEC100 without trastuzumab to 57 patients who were HER2-negative (H- group). We routinely assessed the left ventricular ejection fraction (LVEF) by echocardiography, at the time of initiation, after wP, and after FEC, and compared them between these 2 groups. RESULTS: LVEF decreased from 63.2 to 60.9% (p = 0.030) in the H+ group and from 63.9 to 61.9% (p = 0.009) in the H- group. These 2 groups showed no significant difference in the reduction rate of LVEF over the period of chemotherapy (0.968 vs. 0.978: NS, p = 0.6457). There was no severe cardiotoxicity or congestive heart failure in either group. CONCLUSION: Concurrent administration of epirubicin (q3w, 75 mg/m(2)) and trastuzumab showed no less cardiac tolerability in an adjuvant setting. PMID- 24803888 TI - Second International Consensus Conference on Advanced Breast Cancer (ABC2), Lisbon, 11/09/2013: The German Perspective. AB - The Advanced Breast Cancer Second International Consensus Conference (ABC2) on diagnosis and treatment of advanced breast cancer took place in Lisbon, Portugal, on November 7-9, 2013. The focus of the conference was inoperable, locally advanced breast cancer. The diagnosis and treatment of metastatic breast cancer had already been discussed 2 years before at the ABC1 Consensus and were only updated regarding special issues as part of this year's ABC2 Consensus. Like 2 years ago, a working group of German breast cancer experts commented on the voting results of the ABC panelists, with special consideration of the German guidelines for the diagnosis and treatment of breast cancer (German Gynecological Oncology Working Group (AGO) recommendations, S3 Guideline) in order to adapt them for daily clinical practice in Germany. The goal of both the ABC Consensus and the German comments is to facilitate evidence-based therapy decisions. PMID- 24803889 TI - Online survey of patients with breast cancer on complementary and alternative medicine. AB - About 50% of cancer patients use complementary and alternative medicine (CAM). Women with breast cancer use CAM more frequently than others. We linked a questionnaire to the largest internet portal for cancer patients in Germany. The questionnaire addresses attitude towards CAM, disclosure to the oncologist, source of information, and objectives for use of CAM. 80 patients with breast cancer took part in our study, 61 currently using CAM. Most frequently used CAM methods were selenium, relaxation techniques, prayer, vitamin C, and meditation. Satisfaction was highest with relaxation techniques, vitamin C, homeopathy, yoga and Chinese herbs, lowest with mistletoe and acupuncture. 70% of participants did not think their oncologist took time to discuss CAM. Only 16% believed that their oncologist was well-informed about CAM. 46% relied on naturopaths and non-medical practitioners concerning CAM. Objectives for the use of CAM were to reduce side effects, boost the immune system, and become active. PMID- 24803890 TI - Inherent Bias? Patients Who Use the Internet to Find Information on CAM. PMID- 24803891 TI - Successful Colectomy for Hemorrhagic Colitis with Hemolytic Uremic Syndrome and Acute Encephalopathy due to Escherichia coli O157 Infection. AB - An 81-year-old man was admitted to a primary care hospital due to bloody diarrhea. The findings of abdominal computed tomography indicated ischemic colitis, so conservative therapy was started. On the 4th hospital day, the patient was transferred to our hospital because of renal dysfunction. Physical examination showed clouding of consciousness and abdominal distention. Abdominal computed tomography revealed massive ascites and thickening of the whole colonic wall. With a diagnosis of acute abdomen, an emergent laparotomy was performed. Extended right hemicolectomy was performed because of severe ischemic change and necrosis of the right side of the colon. In the stool culture before the operation, Escherichia coli O157 and verotoxin were found, so this case was diagnosed as hemorrhagic colitis with hemolytic uremic syndrome and acute encephalopathy due to Escherichia coli O157 infection. Postoperatively, the hemolytic uremic syndrome and acute encephalopathy were prolonged. However, with intensive care, the patient recovered and was discharged on the 33rd postoperative day. PMID- 24803892 TI - Gastroduodenal intussusception caused by a gastric collision tumor consisting of adenocarcinoma and neuroendocrine carcinoma. AB - Adenocarcinoma is the most common histological type of gastric tumor. Gastric tumor arising from collision of an adenocarcinoma with a neuroendocrine carcinoma is extremely rare. Moreover, this uncommon gastric collision tumor in our case had prolapsed into the duodenum. A 77-year-old woman was admitted to our hospital complaining of vomiting and severe weight loss. Abdominal X-ray showed gastric distension, and computed tomography revealed a duodenal giant mass spreading from the bulb to the horizontal part of the duodenum. Upper gastrointestinal endoscopy was not helpful in confirming the diagnosis of the tumor. We suspected duodenal malignant tumor and performed laparotomy. The operative findings indicated that the gastric antrum was deeply invaginated into the duodenum because of the gastric tumor. Partial resection of the stomach and duodenum was performed because the tumor was irreducible. Intraoperative diagnosis of the frozen section was well-differentiated adenocarcinoma and undifferentiated carcinoma. Additional distal gastrectomy with lymphadenectomy was performed. We herein report the first case of gastroduodenal intussusception caused by a gastric collision tumor consisting of well-differentiated adenocarcinoma and poorly differentiated neuroendocrine carcinoma. PMID- 24803893 TI - Mycophenolate mofetil-induced segmental colitis mimicking ischemic colitis. AB - Mycophenolate mofetil (MMF) is a commonly used drug in the prevention of allograft rejection in patients with solid organ transplants. Although diffuse colitis has been described in MMF-related colitis, segmental colitis has not been reported. We report the case of a 64-year-old male on MMF therapy who presented for evaluation of afebrile diarrhea and abdominal pain. Flexible sigmoidoscopy revealed a segmental erythematous mucosa with ulceration in the sigmoid colon, descending colon, splenic flexure and proximal transverse colon. Biopsies of these areas showed dilated damaged crypts, eosinophilic epithelial changes and crypt abscesses with apoptotic bodies consistent with MMF-induced injury. MMF was discontinued, leading to a significant improvement of his symptoms. PMID- 24803894 TI - Simultaneous occurrence of early gastric carcinoma and mucosa-associated lymphoid tissue lymphoma of the omentum. AB - The simultaneous association of gastric carcinoma with omental mucosa-associated lymphoid tissue (MALT) lymphoma is a rare event that has not been reported previously. We focused on the hypothetic pathogenetic mechanisms, diagnosis and treatment of this rare condition. A 55-year-old woman with Helicobacter pylori infection underwent distal gastrectomy in our hospital. Three independent early gastric cancers and a mass near the cecum were diagnosed preoperatively. Pathological review of the resected stomach showed three independent early signet ring cell gastric carcinomas, and the mass in the omentum near the cecum was shown to be omental MALT lymphoma. Due to the nature of the patient's disease, she was started on medical eradication of H. pylori. Synchronous gastric adenocarcinoma and omental MALT lymphoma is a rare event. Special attention given to H. pylori-associated gastric cancer patients can avoid misdiagnosis and lead to adequate treatment. PMID- 24803895 TI - Circulating tumor cell data: integration with imaging and serum tumor markers for metastatic breast cancer patient management. AB - Management of metastatic breast cancer is critical to maximizing survival with good quality of life. Circulating tumor cell (CTC) levels in the peripheral blood hold promise for enabling improved patient care. We describe a case of a 47-year old female with infiltrating ductal carcinoma who developed metastatic disease. Serum tumor markers were discordant with imaging studies at several time points. CTC levels were used to support decision making in light of the discordant data. The use of this tool enabled prompt changes in therapy with progressive disease and supported suspending therapy to enable recovery from treatment adverse effects when a significant response was detected by imaging and CTCs were absent from the peripheral circulation. The additional information provided by CTC enumeration helped clarify disease status and provided support for treatment decisions. PMID- 24803896 TI - Tumor calcification: a new response pattern of myxoid liposarcoma to trabectedin. AB - INTRODUCTION: Myxoid/round-cell liposarcoma (MRCL) is a specific histological subtype that accounts for 30-35% of liposarcomas and whose virulence depends on the quantity of round-cells within the tumor. MRCL is associated with specific chromosomal translocations resulting in the formation of CHOP/FUS and CHOP/EWS fusion proteins. A high sensitivity of MRCL to trabectedin was reported. CASE REPORT: We report the case of a 63-year-old woman with a bulky and metastatic MRCL, treated with trabectedin 1.5 mg/m(2) as a first-line treatment. She experienced a long-lasting clinical benefit. The patients received 14 cycles of trabectedin and achieved a durable partial response to the metastases and a stable disease of the primary tumor, which is a very favorable safety profile. Also noteworthy is that we have observed a calcification of the primary tumor and the metastasis. The response, which lasted 30 months, led to a symptomatic improvement, associated with an excellent general condition and an absence of pain. CONCLUSION: To the best of our knowledge, this is the first report of a MRCL treated with trabectedin that resulted in a calcification of the primary tumor and the metastases, associated with an outstandingly long response. This case suggests that trabectedin may represent a feasible first-line therapeutic option for patients with MRCL, with meaningful clinical benefits and an acceptable safety profile. PMID- 24803897 TI - Durable response of human epidermal growth factor receptor-2-positive gastric adenosquamous carcinoma to trastuzumab-based chemotherapy. AB - Here, we report a patient with gastric adenosquamous carcinoma (ASC) with human epidermal growth factor receptor-2 (HER2) overexpression who was successfully treated with trastuzumab-based chemotherapy. The patient was a 66-year-old man preoperatively diagnosed with gastric adenocarcinoma with no evidence of distant metastases. On histopathological examination, the curatively resected tumor was identified as ASC with mixed adenocarcinoma and squamous cell carcinoma components. Multiple liver metastases developed 2.5 months after surgery. Because immunohistochemical staining for HER2 was strong in both components, combination chemotherapy with capecitabine, cisplatin, and trastuzumab was initiated. A partial response was confirmed after 6 treatment cycles and PET and CT scans performed after 13 cycles revealed disease resolution with no uptake in the metastatic lesions. No evidence of disease progression has been observed 16 months after initial chemotherapy. This report suggests the potential utility of trastuzumab-based chemotherapy for HER2-positive gastric ASC. PMID- 24803898 TI - Integrating circulating tumor cell data with imaging and serum prostate-specific antigen measurement for metastatic prostate cancer therapy management. AB - Optimal management of therapy can improve quality of life, and potentially survival, of patients with metastatic prostate cancer. Circulating tumor cell (CTC) enumeration in the peripheral blood holds promise for facilitating optimal therapy management based on high cancer specificity and prompt response to changes in disease status. We present the case of a 54-year-old male diagnosed with metastatic prostate cancer. The patient's disease status was monitored radiographically and by serial determinations of serum prostate-specific antigen concentration, performance status, and CTC enumeration. At multiple visits, the disease status was not clear due to discordance between standard assessments. The additional information provided by CTC enumeration helped clarify disease status and provided support for treatment decisions. PMID- 24803899 TI - Adrenocortical Carcinoma in an Adult: Eight Months without Recurrence after Resection and Adjuvant Chemotherapy. AB - Adrenocortical carcinoma is a rare, aggressive malignancy that features a correspondingly poor prognosis. The disease accounts for 0.2% of all malignancies and despite multimodal therapies, its prognosis remains poor, with a mean survival of <30 months. This paper reports on a patient submitted to surgical resection and adjuvant chemotherapy for adrenocortical carcinoma with an ongoing follow-up of 8 months after surgery and no signs of recurrence. PMID- 24803900 TI - Pegylated liposomal Doxorubicin-induced acute transient encephalopathy in a patient with breast cancer: a case report. AB - BACKGROUND: Pegylated liposomal doxorubicin (PLD) has a unique pharmacokinetic profile and is widely used to treat a variety of malignancies, alone or in combination with other agents. CASE REPORT: A 57-year-old female patient with metastatic breast cancer developed dural metastases to the brain and underwent craniotomy and whole-brain radiation. She continued to receive chemotherapy with carboplatin without any serious complications. Four months later, there was evidence of progression leading to the institution of PLD. During the first course of PLD, there was evidence of acute encephalopathy which resolved after 18 h with discontinuation of this agent. Interestingly, she did well when she was rechallenged with conventional doxorubicin in the following cycles. CONCLUSION: We hereby report, to the best of our knowledge, the first case of acute transient encephalopathy induced by PLD. We postulate that partial disruption of the blood brain barrier may have been responsible for PLD-induced encephalopathy. PMID- 24803901 TI - Surgery without Blood Transfusion for Giant Paraganglioma in a Jehovah's Witness Patient. AB - A retroperitoneal tumor was identified in a 57-year-old female belonging to Jehovah's Witnesses during a health check. Subsequent examination led to the suspicion of a right pheochromocytoma. The patient wished to be treated by bloodless surgery and consulted our hospital after being refused surgery by several hospitals. She signed a liability waiver for blood transfusion refusal. After obtaining consent for diluted autotransfusion and preoperative administration of erythropoietin, the surgery was scheduled. The tumor was attached to the inferior vena cava and left renal vein and engulfed the right renal artery and vein. The tumor and right kidney were removed en bloc. Operative time was 8 h and 18 min, with 1,770 ml of blood loss. The histopathological diagnosis was paraganglioma with the normal adrenal gland within the border of the tumor. The patient was discharged from the hospital with no postoperative complications. PMID- 24803902 TI - Malignant Triton Tumor of the Sciatic Nerve as a Secondary Malignancy after Extended Field Radiotherapy and Chemotherapy of Hodgkin's Disease. AB - Late effects of therapy for Hodgkin's disease include secondary malignancies like leukemia, lymphoma or solid tumors developing after long periods of latency. Ionizing radiation often causes the last group. The highest risks have been described for induced breast and lung cancers. We are the first to report a malignant triton tumor (MTT) as a secondary malignancy after radiotherapy and chemotherapy for Hodgkin's lymphoma. MTT is a very rare subtype of malignant peripheral nerve sheath tumors with rhabdomyoblastic differentiation and an aggressive course of disease. PMID- 24803903 TI - A Case of Gingival Metastasis from Rectal Cancer in Which Immunohistochemistry and PET-CT Were Useful for the Diagnostic Procedure. AB - A 50-year-old man was referred to our hospital because of a 2-month history of painful gingival swelling. Histopathological examination of the biopsy specimen showed a metastatic adenocarcinoma, and a chest-abdominopelvic CT showed multiple metastases in the lung, liver, and spleen, but failed to demonstrate the primary tumor. He had never complained of abdominal symptoms, and physical examination did not show any abnormality in the abdomen. However, immunohistochemical staining including caudal-related homeobox transcription factor (CDX-2) of the gingival tumor and PET-CT findings strongly suggested colorectal cancer as the origin. Colonoscopy then revealed a tumor in the rectum, and systemic chemotherapy was started immediately. PMID- 24803904 TI - Bilateral repetitive transcranial magnetic stimulation combined with intensive swallowing rehabilitation for chronic stroke Dysphagia: a case series study. AB - The purpose of this study was to clarify the safety and feasibility of a 6-day protocol of bilateral repetitive transcranial magnetic stimulation (rTMS) combined with intensive swallowing rehabilitation for chronic poststroke dysphagia. In-hospital treatment was provided to 4 poststroke patients (age at treatment: 56-80 years; interval between onset of stroke and treatment: 24-37 months) with dysphagia. Over 6 consecutive days, each patient received 10 sessions of rTMS at 3 Hz applied to the pharyngeal motor cortex bilaterally, followed by 20 min of intensive swallowing rehabilitation exercise. The swallowing function was evaluated by the Penetration Aspiration Scale (PAS), Modified Mann Assessment of Swallowing Ability (MMASA), Functional Oral Intake Scale (FOIS), laryngeal elevation delay time (LEDT) and Repetitive Saliva Swallowing Test (RSST) on admission and at discharge. All patients completed the 6-day treatment protocol and none showed any adverse reactions throughout the treatment. The combination treatment improved laryngeal elevation delay time in all patients. Our proposed protocol of rTMS plus swallowing rehabilitation exercise seems to be safe and feasible for chronic stroke dysphagia, although its efficacy needs to be confirmed in a large number of patients. PMID- 24803905 TI - Hemorrhagic onset of hemangioblastoma located in the dorsal medulla oblongata presenting with tako-tsubo cardiomyopathy and neurogenic pulmonary edema: a case report. AB - Here, we present a case of dorsal medulla oblongata hemangioblastoma with fourth ventricular hemorrhage. A 23-year-old female developed sudden consciousness disturbance, and CT revealed hemorrhage in all cerebral ventricles and a hyperdense mass in the cisterna magna. Although the reddish tumor located in the dorsal medulla oblongata was successfully removed, she suffered from severe tako tsubo cardiomyopathy (TTC) and neurogenic pulmonary edema (NPE) because of baroreflex failure and damage to the solitary tract nuclei. After intensive care for 12 weeks following surgery, she was discharged without any neurological or radiological deficits. Pathogenesis of TTC/NPE is discussed in this paper. PMID- 24803906 TI - Acute isolated bilateral mydriasis: case reports and review of the literature. AB - Isolated bilateral internal ophthalmoplegia is a rare and problematic condition affecting activities of daily living. Herein, we describe the cases of 2 patients with postinfectious isolated bilateral internal ophthalmoplegia, i.e., mydriasis without external ophthalmoplegia. One patient demonstrated no other neurological symptom, while the other patient showed mild gait ataxia. Magnetic resonance imaging revealed no abnormal findings in the brain or brainstem. Light-near dissociation of the pupils was not recognized in either patient, and supersensitivity to dilute pilocarpine was observed in 1 of the 2 patients. An increased titer of the anti-GQ1b IgG antibody was noted in 1 patient. A review of the literature revealed five similar cases; the symptomatic characteristics, ratio of positive anti-GQ1b IgG antibody, and effective treatment are discussed. PMID- 24803907 TI - An Abnormal MRI Signal in Both Lateral Geniculate Bodies Is a Diagnostic Indicator for Patients with Behcet's Disease. AB - A few case reports involving Behcet's disease have described visual field defects ascribed to the lateral geniculate body; however, no cases of lesions in both lateral geniculate bodies have been reported. A 50-year-old male who had fever and genital ulceration 3 months earlier noticed visual field defects. A T2 weighted MRI and FLAIR image showed high-intensity lesions in both lateral geniculate bodies. The posterior end of the optic tracts and lateral geniculate bodies were bilaterally enhanced with gadolinium. Because of the presence of three (aphthous stomatitis, genital ulceration and uveal inflammation) of the four major symptoms, the patient was diagnosed with an abortive type of Behcet's disease and started predonisolone at a dose of 0.5 mg/kg, after which he showed a rapid improvement of all symptoms. The lesions in the lateral geniculate bodies had disappeared on the MRI images taken 2 weeks after treatment onset. In addition to Behcet's disease, several case reports have observed lesions in both lateral geniculate bodies. Their visual field defects disappeared within half a year, in parallel with the healing process of the primary diseases. The pathogenesis of the lesions in both lateral geniculate bodies in these cases is believed to be related to the underlying disorders, especially vascular involvement from inflammation. The appearance of lesions in both lateral geniculate bodies on MRI scans may indicate the presence of systemic inflammatory diseases such as Behcet's disease, but further examinations are required. PMID- 24803908 TI - Xeroderma pigmentosum/de sanctis-cacchione syndrome: unusual cause of ataxia. AB - INTRODUCTION: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of DNA repair, with a prevalence of 1 in 1 million. It may also be a cause of neurological symptoms including sensorineural hearing loss, peripheral neuropathy, ataxia, and chorea. Severe neurological symptoms including mental retardation, short stature, and hypogonadism invoke De Sanctis-Cacchione syndrome (DCS). CASE REPORT: The patient was a 55-year-old woman with a history of mental retardation who developed chorea at age 32 and ataxia at age 37. She had numerous facial scars from 10 prior basal cell carcinoma excisions as well as diminished deep tendon reflexes, bilateral hearing loss, dysphagia, and skin freckling. Brain MRI revealed severe cortical, cerebellar, and brainstem atrophy. Supportive treatment and prevention of further damage from UV light is the mainstay of treatment in XP and DCS. CONCLUSION: XP and related disorders should be considered in the setting of neurological disorder and multiple cutaneous cancers. PMID- 24803910 TI - Proficiency in positive vs. negative emotion identification and subjective well being among long-term married elderly couples. AB - Evidence is accruing that positive emotions play a crucial role in shaping a healthy interpersonal climate. Inspired by this research, the current investigation sought to shed light on the link between proficiency in identifying positive vs. negative emotions and a close partner's well-being. To this end, we conducted two studies with neurologically intact elderly married couples (Study 1) and an age-matched clinical sample, comprising married couples in which one spouse had been diagnosed with Parkinson's Disease (Study 2), which tends to hinder emotional expressivity. To assess proficiency in identifying emotions from whole body postures, we had participants in both studies complete a pointlight walker task, featuring four actors (two male, two female) expressing one positive (i.e., happiness) and three negative (i.e., sadness, anger, fear) basic emotions. Participants also filled out measures of subjective well-being. Among Study 1's neurologically intact spouses, greater expertise in identifying positive (but not negative) emotions was linked to greater partner life satisfaction (but not hedonic balance). Spouses of PD patients exhibited increased proficiency in identifying positive emotions relative to controls, possibly reflective of compensatory mechanisms. Complementarily, relative to controls, spouses of PD patients exhibited reduced proficiency in identifying negative emotions and a tendency to underestimate their intensity. Importantly, all of these effects attenuated with longer years from PD onset. Finally, there was evidence that it was increased partner expertise in identifying negative (rather than positive) emotional states that predicted greater life satisfaction levels among the PD patients and their spouses. Our results thus suggest that positive vs. negative emotions may play distinct roles in close relationship dynamics as a function of neurological status and disability trajectory. PMID- 24803912 TI - Lack of c9orf72 repeat expansion in taiwanese patients with mixed neurodegenerative disorders. AB - BACKGROUND: The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is recognized as the most common genetic cause of frontotemporal dementia (FTD). There are overlapping clinical and pathological characteristics between FTD and Parkinsonism syndrome, and some FTD patients may present with Parkinsonism. The aim of this study was to analyze the hexanucleotide repeat numbers of C9orf72 gene in a mixed Taiwanese cohort with FTD, Parkinsonism syndrome, Parkinson's disease (PD), and Alzheimer's dementia (AD). METHOD: The number of hexanucleotide repeats was estimated in a total of 482 patients with mixed neurodegenerative disorders and 485 control subjects, using a two-step repeat-primed polymerase chain reaction-based genotyping strategy. The individual groups of patients included patients with Parkinsonism syndrome (n = 95), familial PD (n = 109), young-onset PD (n = 201), FTD (n = 9), sporadic AD (n = 61), and early-onset AD (n = 7). RESULTS: We did not identify any pathogenic repeats (>30 repeats) of C9orf72 in either the patients or control subjects. However, we found one young onset PD patient and one control subject that each had an intermediate number of repeats (25 and 21 repeats, respectively). The clinical phenotype of the young onset PD in this patient was similar to typical idiopathic PD without additional features, and the patient responded well to levodopa treatment. CONCLUSION: The repeat expansion in C9orf72 is not a common cause of PD, Parkinsonism syndrome, or dementia in our population. Further studies are needed to investigate the clinical and biological significance of intermediate repeats in C9orf72. PMID- 24803909 TI - The role of domain-general cognitive control in language comprehension. AB - What role does domain-general cognitive control play in understanding linguistic input? Although much evidence has suggested that domain-general cognitive control and working memory resources are sometimes recruited during language comprehension, many aspects of this relationship remain elusive. For example, how frequently do cognitive control mechanisms get engaged when we understand language? And is this engagement necessary for successful comprehension? I here (a) review recent brain imaging evidence for the neural separability of the brain regions that support high-level linguistic processing vs. those that support domain-general cognitive control abilities; (b) define the space of possibilities for the relationship between these sets of brain regions; and (c) review the available evidence that constrains these possibilities to some extent. I argue that we should stop asking whether domain-general cognitive control mechanisms play a role in language comprehension, and instead focus on characterizing the division of labor between the cognitive control brain regions and the more functionally specialized language regions. PMID- 24803911 TI - Cervical dystonia: a disorder of the midbrain network for covert attentional orienting. AB - While the pathogenesis of cervical dystonia remains unknown, recent animal and clinical experimental studies have indicated its probable mechanisms. Abnormal temporal discrimination is a mediational endophenotype of cervical dystonia and informs new concepts of disease pathogenesis. Our hypothesis is that both abnormal temporal discrimination and cervical dystonia are due to a disorder of the midbrain network for covert attentional orienting caused by reduced gamma aminobutyric acid (GABA) inhibition, resulting, in turn, from as yet undetermined, genetic mutations. Such disinhibition is (a) subclinically manifested by abnormal temporal discrimination due to prolonged duration firing of the visual sensory neurons in the superficial laminae of the superior colliculus and (b) clinically manifested by cervical dystonia due to disinhibited burst activity of the cephalomotor neurons of the intermediate and deep laminae of the superior colliculus. Abnormal temporal discrimination in unaffected first degree relatives of patients with cervical dystonia represents a subclinical manifestation of defective GABA activity both within the superior colliculus and from the substantia nigra pars reticulata. A number of experiments are required to prove or disprove this hypothesis. PMID- 24803914 TI - Thyroid-stimulating hormone, white matter hyperintensities, and functional outcome in acute ischemic stroke patients. AB - BACKGROUND: Thyroid-stimulating hormone (TSH) concentrations are frequently altered in acute ischemic stroke patients. It is becoming increasingly apparent that various hormones in the hypothalamus-pituitary-thyroid axis may be associated with functional stroke outcome. We have previously shown that white matter hyperintensities (WMH) of presumed vascular origin are strong indicators of functional outcome. It is unclear whether an association exists between WMH and TSH. We therefore sought to determine whether TSH levels, measured in acute ischemic stroke patients, are associated with WMH and functional outcome. METHODS: We analyzed all first ischemic stroke patients who participated in the Berlin 'Cream & Sugar' Study (NCT 01378468) and completed a 1-year follow-up assessment from January 2009 to March 2013. Patients were stratified into 3 groups: (1) low TSH (0.1-0.44 MUU/ml); (2) normal TSH (0.44-2.5 MUU/ml), and (3) high TSH (2.5-20 MUU/ml). WMH were assessed using the Fazekas and Wahlund visual rating scales. Functional outcome was assessed using the modified Rankin Scale and was performed via telephone at 1 year by a certified rater. RESULTS: 183 patients were included [median age 66, interquartile range (IQR) 54-75; 33% females; median National Institute of Health Stroke Scale 3, IQR 1-4, range 0 24]. Venous samples were collected a median of 4 days (IQR 3-5) following initial symptom onset between 8 and 9 a.m. following a 10-hour fast. Patients with normal TSH levels (n = 132; 72%) had significantly higher rates of prestroke diabetes than patients with high TSH levels (normal TSH 17%; high TSH 1%; p = 0.03). Additionally, patients with normal TSH levels tended to have higher estimated glomerular filtration rates than patients with high and low TSH concentrations (normal TSH median estimated glomerular filtration rates: 83 ml/min/1.73 m(2); high TSH median estimated glomerular filtration rates: 76 ml/min/1.73 m(2); low TSH median: 78 ml/min/1.73 m(2); p = 0.068). Logistical regression analysis force adjusted for age (quartiles), NIHSS (quartiles), prestroke diabetes status, and stroke subtype revealed significant associations between WMH and TSH [Wahlund scores: odds ratio 2.547, 95% confidence interval (CI) 1.159-5.598, p = 0.020; Fazekas scores: odds ratio 2.530, 95% CI 1.115-5.741, p = 0.003]. Functional outcome was not significantly associated with TSH levels in univariate or multivariate models. CONCLUSION: TSH levels are independently associated with WMH in acute ischemic stroke patients. Based on our findings, we cannot recommend assessing TSH to estimate the 1-year functional outcome following ischemic stroke. PMID- 24803913 TI - Lingual muscle activity across sleep-wake States in rats with surgically altered upper airway. AB - Obstructive sleep apnea (OSA) patients have increased upper airway muscle activity, including such lingual muscles as the genioglossus (GG), geniohyoid (GH), and hyoglossus (HG). This adaptation partially protects their upper airway against obstructions. Rodents are used to study the central neural control of sleep and breathing but they do not naturally exhibit OSA. We investigated whether, in chronically instrumented, behaving rats, disconnecting the GH and HG muscles from the hyoid (H) apparatus would result in a compensatory increase of other upper airway muscle activity (electromyogram, EMG) and/or other signs of upper airway instability. We first determined that, in intact rats, lingual (GG and intrinsic) muscles maintained stable activity levels when quantified based on 2 h-long recordings conducted on days 6 through 22 after instrumentation. We then studied five rats in which the tendons connecting the GH and HG muscles to the H apparatus were experimentally severed. When quantified across all recording days, lingual EMG during slow-wave sleep (SWS) was modestly but significantly increased in rats with surgically altered upper airway [8.6 +/- 0.7% (SE) vs. 6.1 +/- 0.7% of the mean during wakefulness; p = 0.012]. Respiratory modulation of lingual EMG occurred mainly during SWS and was similarly infrequent in both groups, and the incidence of sighs and central apneas also was similar. Thus, a weakened action of selected lingual muscles did not produce sleep-disordered breathing but resulted in a relatively elevated activity in other lingual muscles during SWS. These results encourage more extensive surgical manipulations with the aim to obtain a rodent model with collapsible upper airway. PMID- 24803915 TI - Cost-Minimization Analysis of Computed Tomography versus Magnetic Resonance Imaging in the Evaluation of Patients with Transient Ischemic Attacks at a Large Academic Center. AB - BACKGROUND: The type of neuroimaging for the evaluation of transient ischemic attack (TIA) is debatable. Many patients undergo head computed tomography (CT) with or without CT angiogram (CTA) while being at the emergency department (ED) and later magnetic resonance imaging (MRI) with MR angiogram (MRA) during admission. We hypothesized that evaluation with only one imaging modality (CT/CTA or MRI/MRA) is sufficient to formulate a treatment plan. We looked for the most cost-effective way to evaluate TIA patients. METHODS: We performed a retrospective chart review of 82 patients with TIA. All patients had completely resolved neurological deficit at the time of their evaluation in the ED. We divided the patients into two groups. In group 1, the evaluation included CT with CTA of the head and neck. In group 2, the evaluation included brain MRI with MRA or CTA of the head and neck. We compared these two groups for clinical characteristics and etiological evaluations of stroke/TIA. The outcomes were measured by the number of therapeutic adjustments for the prevention of another ischemic stroke/TIA at the time of discharge from the hospital and revascularization procedures. We counted the following as therapeutic adjustment: (1) antiplatelet therapy was started de novo; (2) anticoagulation was started; (3) arterial revascularization procedure was performed, and (4) one antiplatelet agent was substituted for another. We performed a cost-effectiveness analysis if the outcomes of the two groups were different and a cost-minimization analysis if there was no difference in the outcomes. All cost calculations were made based on Medicare CPT codes. RESULTS: Group 1 included 23 patients and group 2 59 patients. The patients in both groups had similar demographic and clinical characteristics. There was no difference in other etiological evaluations in groups 1 and 2. All patients underwent head CT as the first tool of evaluation whether MRI was done later or not. Therapeutic adjustments and revascularization procedures did not differ between the two groups. All head CTs showed no acute changes. MRI showed small ischemic infarcts in 44% of the patients in group 2. The average per-patient cost of neuroimaging with CT/CTA was USD 1,460.00, with CT and MRI/MRA USD 1,569 and with CT/CTA and brain MRI USD 2,090.00 (p < 0.01). CONCLUSION: Either MRI/MRA or CT/CTA might be sufficient for the evaluation of patients with TIA or small asymptomatic strokes. If head CT at the ED is bypassed, a brain MRI with MRA of the head and neck would be the most informative tool at the lowest cost. Prospective studies with larger numbers of patients are needed for a better understanding of the safety and cost of imaging tools used for patients with TIA. PMID- 24803916 TI - Immunoadsorption: a new strategy to induce remission in membranous lupus nephritis. AB - We report the case of an 11-year-old previously healthy girl who presented for microscopic hematuria and nephrotic proteinuria with normal renal function, which persisted after 6 months of steroids, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers, hydroxychloroquine, mycophenolic acid and a low-salt diet. A serum investigation suggested lupus nephritis and a renal biopsy, performed 2 weeks after the first proteinuria detection, revealed membranous lupus nephritis. We decided to perform ten sessions of daily immunoadsorption. Proteinuria decreased significantly over these ten sessions from 8 to 0.12 g/l. After the tenth immunoadsorption session, the patient received the first rituximab (RTX) infusion leading to complete B-cell depletion. The patient was maintained on ACEi associated with mycophenolic acid and hydroxychloroquine. Three RTX reinjections were performed when CD19-positive cells reappeared in peripheral blood. Despite complete B-cell recovery and positive anti-dsDNA-Ab, the patient remained in complete remission 18 months after the initial diagnosis with negative proteinuria and a normal renal function. PMID- 24803917 TI - Carotid thromboembolism associated with nephrotic syndrome treated with dabigatran. AB - Nephrotic syndrome (NS) may be complicated by thromboembolism, which occasionally manifests as stroke. Although the optimal, standardized approach to the prophylaxis and management of thromboembolic complications associated with NS has not been established, anticoagulation with heparin and subsequent warfarin is the de facto standard of treatment. Dabigatran, a novel direct thrombin inhibitor, has become a substitute for warfarin and heparin for many indications, including the prophylaxis of stroke associated with nonvalvular atrial fibrillation and postoperative thromboprophylaxis in orthopedic patients. We report a 35-year-old male with NS due to membranous nephropathy (MN) that presented with carotid thromboembolism. Because the patient developed drug-induced hepatitis due to warfarin, we attempted treatment with dabigatran and were successful in continuing the medication without any complications. We also reviewed the literature on stroke associated with NS. Twenty-one prior cases have been reported, and the review of these cases revealed some interesting points. The age of onset ranged from 19 to 59 years. Most of the reported cases sustained a stroke at earlier ages than patients with atherosclerosis and atrial fibrillation, which suggests that NS may independently predispose individuals to arterial and venous thromboses. MN was the most common underlying pathology. Given that a standardized approach to the prophylaxis and management of thrombotic complications associated with NS has not been established, our experience suggests that dabigatran is a valid new treatment option for thrombotic complications of NS. PMID- 24803918 TI - A case of bladder cancer after radiation therapy for prostate cancer. AB - An 86-year-old male who presented with the chief complaint of clot retention and had a history of prostate cancer treated with external beam radiation therapy 11 years previously is described. Cystoscopy revealed radiation cystitis in coexistence with bladder cancer. Since bladder cancer may be present in patients with macroscopic hematuria who have a history of radiation therapy, referral to an urologist is recommended. PMID- 24803919 TI - The effects of oral L-carnitine supplementation on physical capacity and lipid metabolism in chronic hemodialysis patients. AB - BACKGROUND: It is well known that the physical activity in chronic hemodialysis patients decreases compared to that in normal subjects. In order to investigate the effects of L-carnitine on physical capacity and lipid metabolism, a cardiopulmonary exercise test using a bicycle ergometer was performed before and after 3 months of oral L-carnitine supplementation under double-blind conditions. METHODS AND RESULTS: A total of 20 stable outpatients undergoing hemodialysis treatment were randomly divided into 2 groups: controls receiving placebo and patients receiving 900 mg L-carnitine p.o. daily. The levels of free and acyl carnitine increased significantly from 22.9 +/- 7.3 to 149.9 +/- 51.8 MUmol/l and from 16.0 +/- 2.8 to 100.3 +/- 50.2 MUmol/l, respectively, in the L-carnitine group; however, there was no significant change in other plasma lipid profiles. The exercise time was decreased and the heart rate at the anaerobic threshold was increased in the control group 3 months after the study period, but there were no such changes observed in the L-carnitine group. The minute ventilation/CO2 output slope increased significantly from 38.9 +/- 7.8 to 43.8 +/- 11.8 in the L carnitine group. It has been speculated that a shift in the energy source occurs from carbohydrate to lipid, in terms of an increase of oxygen demand. CONCLUSION: L-Carnitine supplementation might have some beneficial effects on the physical capacity of chronic hemodialysis patients due to the improvement of the lipid metabolism in the muscle. PMID- 24803920 TI - Risk factors and timing of native kidney biopsy complications. AB - BACKGROUND: The appropriate observation period, rate and risk factors of complications after a percutaneous renal biopsy remain debated. METHODS: We retrospectively studied native kidney biopsies performed in our institution between January 2007 and July 2011. Outpatients had either an 8- (67%) or a 24 hour (33%) observation period. RESULTS: 312 biopsies were reviewed (287 patients), 51% of patients were female and the mean age was 54 +/- 15 years. Half of these biopsies were performed in outpatients. A total of 15% of patients developed a symptomatic hematoma, 9% received a red blood cell transfusion and 1% required an angio-intervention. Eighty-four percent of the complications manifested within the first 8 h, 86% at 12 h and 94% at 24 h. Outpatients experienced significantly less complications, all manifesting within the first 8 h, 14% required an observation period longer than planned. The risk of symptomatic hematoma increased to 11, 20, 35 and 40% in patients with >200, 140 200, 100-140 and <100 * 10(9)/l platelets, respectively (p = 0.002). It also increased in hemodialysis patients (29% compared to 14%, p = 0.02). We found no association of risk with the number of biopsy passes and only a trend with needle size. CONCLUSION: Symptomatic hematomas occurred in 15% of kidney biopsies and were strongly associated with platelet count and hemodialysis. Outpatients experienced fewer complications; therefore, we can conclude that same-day discharge in selected patients is safe. PMID- 24803921 TI - Symptomatic central venous stenosis in a hemodialysis patient leading to loss of arteriovenous access: a case report and literature review. AB - Central venous stenosis is a well-described sequel to the placement of hemodialysis catheters in the central venous system. The presence of an ipsilateral arteriovenous fistula or graft often leads to severe venous dilatation, arm edema and recurrent infections. Vascular access thrombosis, compromised blood flow and inadequate dialysis delivery are dreaded complications that eventually render the access unusable. We report the case of a 58-year-old male hemodialysis patient who developed symptomatic central venous stenosis to illustrate the problem and review the pertinent literature. This patient developed severe enlargement of upper extremity veins due to central venous stenosis. The symptoms were refractory to multiple endovascular interventions and eventually necessitated ligation of his arteriovenous fistula. Central venous stenosis remains a pervasive problem despite advances in our understanding of its etiology and recognition of the enormity of its consequences. Due to the lack of effective therapeutic options, prevention is better than cure. PMID- 24803922 TI - Gene polymorphism of interleukin 1 and 8 in chronic gastritis patients infected with Helicobacter pylori. AB - BACKGROUND: Epidemiological investigations have indicated that Helicobacter pylori induces inflammation in the gastric mucosa regulated by several interleukins. The genes IL1B and IL8 are suggested as key factors in determining the risk of gastritis. The aim of this paper was to evaluate the association of gene polymorphism of interleukin-1 and interleukin-8 with chronic gastrits in H. pylori infected patients. A total of 60 patients underwent endoscopic procedure. Biopsy samples were collected for urease test, histopathological and molecular exams. The DNA of theses samples was extracted for detection of H. pylori and analysis of the genes mentioned above. Patients with gastritis had a higher frequency of H. pylori-positive samples. RESULTS: H. pylori was detected in 30/60 patients (50%) by PCR. As for polymorphism of interleukin 8 (-251) gene we observed a statistical difference when analyzed TA (p = 0.039) and TT (p = 0.047) genotypes. In the IL1B31 there was a statistical difference in TT (p = 0.01) genotype and in the IL1B-511 there wasn't any statistical difference. CONCLUSION: Our results suggest a strong correlation between the presence of chronic gastritis and infection by H. pylori and that IL1B-31TT and IL8-251TT genotypes appear to act as protective factors against H. pylori infection while IL8-251TA genotype may comprise a risk factor for infection with this bacterium. PMID- 24803923 TI - Detection and identification of huwentoxin-IV interacting proteins by biotin avidin chemistry combined with mass spectrometry. AB - BACKGROUND: Numerous spider toxins are of interest as tools for neurophysiological research or as lead molecules for the development of pharmaceuticals and insecticides. Direct detection and identification of the interacting proteins of a spider toxin are helpful for its action-mechanism analysis and practical application. The present study employed a combinative strategy for the analysis of interacting proteins of huwentoxin-IV (HWTX-IV), a peptidic neurotoxin from the venom of the spider Selenocosmia huwena. RESULTS: HWTX-IV was first lightly labeled with biotin under the optimized mild experimental conditions and the toxin labeled with a single biotin group (monobiotinylated HWTX-IV) was demonstrated by electrophysiological experiments to retain its original bioactivity and was used in combination with far-western blotting to detect its interacting proteins. Comparative experiments indicated that some membrane proteins from rat neuromuscular junction preparations bind to monobiotinylated HWTX-IV after being transferred onto a PVDF membrane from the SDS-gel. With capillary high performance liquid chromatography-tandem mass spectrometry, several membrane proteins with which HWTX-IV potentially interacted were identified from the preparations and then bioinformatically analyzed. CONCLUSIONS: This work has provided not only a new insight into the action mechanism of HWTX-IV but also a reference technology for the relevant researches. PMID- 24803924 TI - Peroxisome Proliferator Activator Receptor (PPAR)- gamma Ligand, but Not PPAR- alpha , Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver. AB - Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)- alpha and - gamma agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)- alpha , evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR- gamma , but not PPAR- alpha , conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy. PMID- 24803925 TI - Beneficial Effect of Cissus quadrangularis Linn. on Osteopenia Associated with Streptozotocin-Induced Type 1 Diabetes Mellitus in Male Wistar Rats. AB - Petroleum ether fraction of Cissus quadrangularis (PECQ) impact on the development of osteopenia in type 1 diabetic rat model has been evaluated. Diabetic rats were treated orally with two doses of PECQ. Another group of diabetic rats were treated with subcutaneous injection of synthetic human insulin. The cortical and trabecular bone thickness and bone strength were significantly decreased in diabetic rats. Treatment with two doses of PECQ significantly prevented these changes in diabetic rats. However, PECQ treatment (two doses) did not alter the glycemic levels in these diabetic rats. Increased levels of serum alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), and hydroxyproline were noted in diabetic rats when compared to normal control rats. The two doses of PECQ treatment further improved the serum ALP levels and significantly decreased the serum levels of TRAP and hydroxyproline. The effects of PECQ treatment on histological, biomechanical, and biochemical parameters are comparable to those of insulin. Since PECQ improves the bone health in hyperglycemic conditions by enhancing the cortical and trabecular bone growth and altering the circulating bone markers, it could be used as an effective therapy against diabetes-associated bone disorders. PMID- 24803926 TI - Does an Association between the Idiopathic Left-Sided Varicocele and Eye Colour Exist? AB - The possible interrelation between male reproductive disorders and iris pigmentation is poorly understood. We have found a link between eye colour and the existence of adolescent varicocele. Therefore, we aimed to extend our investigation on the relationship between the eye colour and varicocele in adult men. 231 andrology outpatients from Caucasian origin were included in the study. The presence of varicocele, sperm disturbances, and the iris pigment of the patients were investigated. Left-sided varicocele was found in 93 adults. In the group of light-eyed men the prevalence of varicocele was significantly lower than among the dark-eyed men (15% versus 59.5%, P < 0.001). No associations were found between the eye colour and disturbances in semen parameters in males with varicocele (P = 0.419) and in those without varicocele (P = 0.586). The present results in adult men suggest that the prevalence of varicocele could be associated with the iris pigment. A possible genetic linkage between the eye colour and the susceptibility to some disorders like varicocele could not be excluded. However, the iris pigmentation seems not to have a direct relationship with the sperm disturbances. PMID- 24803927 TI - Structured Self-Rated Response to Iontophoresis with Verapamil and Dexamethasone in Peyronie's Disease. AB - Introduction. New therapies evolve for the treatment of Peyronie's disease (PD) including the application of dexamethasone and verapamil using Electro Motive Drug Administration (EMDA). Patients and Methods. Patients with PD were routinely offered Potaba, Vitamin E, tamoxifen or colchicine for 6 to 18 months and for those with no improvement, 18 applications of dexamethasone and verapamil using EMDA occurred over a 6 week period. All 30 patients receiving EMDA therapy completed a questionnaire before and after treatment. The data was collected from December 2004 to November 2009 and analysed to evaluate the effectiveness of the treatment. Results. Median age of patients was 59 (range 39-71). Curvature was the most common presenting complaint (73.3%) followed by pain (23.3%), erectile dysfunction (13.3%), and lump (13.3%). 24/30 (80%) reported an improvement in symptoms after EMDA. 16 of the responders (66.7%) had a stable plaque for at least 6 months. The patients who complained of shortening of the penis (P = 0.003) or lowered sexual desire (P = 0.024) expressed subsequently significant response to treatment. There was statistically significant (P = 0.019) improvement of penile deviation reported by responding men. Conclusion. A significant proportion of patients who received EMDA reported decreased curvature following iontophoresis. No serious adverse reactions developed. PMID- 24803928 TI - Safety Evaluation of Artocarpus altilis as Pharmaceutical Agent in Wistar Rats. AB - This study was designed to elucidate the acute toxicity of Artocarpus altilis leaf and bark extracts. In acute toxicity study, no mortality or any toxic reaction was recorded in any group after 14 days of administering the extracts (2000 mg Kg(-1) BW). The extracts (ALA, ABA, ALM, and ABM) did not cause any behavioural or physical changes in experimental rats. There was no significant (P <= 0.05) difference in the biochemical parameters analysed between the groups. Slight elevation in activities of AST and ALT in extract treated groups was observed, but this did not exert any deleterious effect on the normal metabolism which was supported by the histopathology of liver. Histopathological studies showed no remarkable changes after 14 days of oral administration of ALA, ABA, ALM, and ABM extracts. The study contributes to establishing the nontoxic quality parameters of Artocarpus altilis leaf and bark parts and the results suggest the safety of the extracts in therapeutic uses. PMID- 24803929 TI - Subacute thyroiditis: clinical presentation and long term outcome. AB - Few studies have been reported from the Kingdom of Saudi Arabia (SA) to describe the clinical presentation and long term outcomes of subacute thyroiditis (SAT). Our aim was to review the demographic, anthropometric, clinical presentation, laboratory results, treatment, and disease outcome in Riyadh region and to compare those with results from different regions of the Kingdom and different parts of the world. We reviewed the medical files of patients who underwent thyroid uptake scan during an 8-year period in King Khalid University Hospital. Only 25 patients had confirmed diagnosis of thyroiditis. Age and gender distribution were similar to other studies. Most patients presented with palpitation, goiter, and weight change. Elevated thyroid hormones, suppressed thyroid-stimulating hormone, and elevated ESR were reported. Among those, 7 cases of SAT were recorded. beta -Blockers were prescribed to 57% and nonsteroidal anti inflammatory drugs to 29% of SAT. Long follow-up demonstrated that 85.7% of SAT cases recovered, while 14.3% developed permanent hypothyroidism. In conclusion, SAT is uncommon in the central region of SA. Compared to the western region, corticosteroid is not commonly prescribed, and permanent hypothyroidism is not uncommon. A nation-wide epidemiological study to explain these interprovincial differences is warranted. PMID- 24803930 TI - Neuropeptides and control of food intake. PMID- 24803931 TI - Androgen deprivation therapy and cardiovascular risk in chinese patients with nonmetastatic carcinoma of prostate. AB - Background. Androgen deprivation therapy (ADT) in nonmetastatic prostate cancer is unclear. Recent data suggests possible increase in the cardiovascular risks receiving ADT. The aim of the study was to investigate the cardiovascular outcomes in a cohort of Chinese nonmetastatic prostate cancer patients with no previously documented cardiovascular disease. Methods and Results. 745 patients with no previously documented cardiovascular disease and/or diabetes mellitus diagnosed to have nonmetastatic prostate cancer were recruited. Of these, 517 patients received ADT and the remaining 228 did not. After a mean follow-up of 5.3 years, 60 patients developed primary composite endpoint including (1) coronary artery disease, (2) congestive heart failure, and (3) ischemic stroke. Higher proportion of patients on ADT (51 patients, 9.9%) developed composite endpoint compared with those not on ADT (9 patients, 3.9%) with hazard ratio (HR) of 2.06 (95% confidence interval (CI): 1.03-3.24, P = 0.04). Furthermore, Cox regression analysis revealed that only the use of ADT (HR: 2.1, 95% CI: 1.03 4.25, P = 0.04) and hypertension (HR: 2.0, 95% CI: 1.21-3.33, P < 0.01) were independent predictors for primary composite endpoint. Conclusion. ADT in Chinese patients with nonmetastatic prostate cancer with no previously documented cardiovascular disease was associated with subsequent development of cardiovascular events. PMID- 24803932 TI - Diagnostic Applications of Cone-Beam CT for Periodontal Diseases. AB - Objectives. This paper aims to review the diagnostic application of cone beam computed tomography (CBCT) in the field of periodontology. Data. Original articles that reported on the use of CBCT for periodontal disease diagnosis were included. Sources. MEDLINE (1990 to January 2014), PubMed (using medical subject headings), and Google Scholar were searched using the following terms in different combinations: "CBCT," "volumetric CT," "periodontal disease ," and "periodontitis." This was supplemented by hand-searching in peer-reviewed journals and cross-referenced with the articles accessed. Conclusions. Bony defects, caters, and furcation involvements seem to be better depicted on CBCT, whereas bone quality and periodontal ligament space scored better on conventional intraoral radiography. CBCT does not offer a significant advantage over conventional radiography for assessing the periodontal bone levels. PMID- 24803934 TI - Virulence Factors Contributing to Pathogenicity of Candida tropicalis and Its Antifungal Susceptibility Profile. AB - The incidence of invasive candidiasis has increased over the past few decades. Although Candida albicans remains by far the most common species encountered, in recent years shift towards non-albicans Candida species like Candida tropicalis is noted. Here in this study we determined the virulence factors and antifungal susceptibility profile of 125 C. tropicalis isolated from various clinical specimens. Biofilm formation was seen in 53 (42.4%) isolates. Coagulase production was noted in 18 (14.4%) isolates. Phospholipase enzyme was the major virulent factor produced by C. tropicalis isolates. A total of 39 biofilm forming isolates showed phospholipase activity. Proteinase activity was demonstrated by 65 (52%) isolates. A total of 38 (30.4%) isolates showed haemolytic activity. Maximum isolates demonstrated resistance to fluconazole. Fluconazole resistance was more common in C. tropicalis isolated from blood cultures. Antifungal resistance was more in isolates possessing the ability to produce phospholipase and biofilm. C. tropicalis exhibit a great degree of variation not only in their pathogenicity but also in their antifungal susceptibility profile. The identification of virulence attributes specific for each species and their correlation with each other will aid in the understanding of the pathogenesis of infection. PMID- 24803935 TI - Gastric Decompression Decreases Postoperative Nausea and Vomiting in ENT Surgery. AB - There is a passive blood flow to the stomach during oral and nasal surgery. It may cause postoperative nausea and vomiting (PONV). We researched the relationship between gastric decompression (GD) and severity of PONV in ear, nose, and throat (ENT) surgery. 137 patients who have been into ENT surgery were included in the study. In Group I (n = 70), patients received GD after surgery before extubation; patients in Group II (n = 67) did not receive GD. In postoperative 2nd, 4th, 8th, and 12th hours, the number and ratio of patients demonstrating PONV were detected to be significantly more in Group II as compared to Group I. PONV was also significantly more severe in Group II as compared to Group I. In Group I, the PONV ratio in the 2nd hour was significantly more for those whose amounts of stomach content aspired were more than 10 mL as compared to those whose stomach content aspired was less than 10 mL. In the 4th, 8th, and 24th hours, there is no statistically significant difference between the stomach content aspired and PONV ratio. GD reduces the incidence and severity of PONV in ENT surgery. PMID- 24803936 TI - Carotid intima media thickness as a marker of atherosclerosis in ankylosing spondylitis. AB - Aim. Increased cardiovascular morbidity and mortality have been observed in ankylosing spondylitis because of accelerated atherosclerosis. We measured carotid intima media thickness (CIMT) as a surrogate marker of atherosclerosis in this study. Methods. In this study 37 cases of AS and the same number of matched individuals were recruited. CIMT measurements were done using B-mode ultrasound. Disease activity was assessed using Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), and Bath ankylosing spondylitis metrological index (BASMI) scores and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels. Results. Mean age of the study groups was 29.43 +/- 9.00 years. Average disease duration was 65.62 +/- 54.92 months. Twenty-eight (75.68%) of cases were HLA B-27 positive. A significantly increased CIMT was observed in cases as compared to control group (0.62 +/- 0.12 versus 0.54 +/- 0.04; P < 0.001). CIMT in the cases group positively correlated with age (r = 0.357; P < 0.05), duration of disease (r = 0.549; P < 0.01), and BASMI (r = 0.337; P < 0.05) and negatively correlated with ESR (r = -0.295; P < 0.05). Conclusions. Patients of AS had a higher CIMT than those of the control group. CIMT correlated with disease chronicity. PMID- 24803933 TI - The genetic architecture of multiple myeloma. AB - Multiple myeloma is a malignant proliferation of monoclonal plasma cells leading to clinical features that include hypercalcaemia, renal dysfunction, anaemia, and bone disease (frequently referred to by the acronym CRAB) which represent evidence of end organ failure. Recent evidence has revealed myeloma to be a highly heterogeneous disease composed of multiple molecularly-defined subtypes each with varying clinicopathological features and disease outcomes. The major division within myeloma is between hyperdiploid and nonhyperdiploid subtypes. In this division, hyperdiploid myeloma is characterised by trisomies of certain odd numbered chromosomes, namely, 3, 5, 7, 9, 11, 15, 19, and 21 whereas nonhyperdiploid myeloma is characterised by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which being 4, 6, 11, 16, and 20. Hyperdiploid and nonhyperdiploid changes appear to represent early or even initiating mutagenic events that are subsequently followed by secondary aberrations including copy number abnormalities, additional translocations, mutations, and epigenetic modifications which lead to plasma cell immortalisation and disease progression. The following review provides a comprehensive coverage of the genetic and epigenetic events contributing to the initiation and progression of multiple myeloma and where possible these abnormalities have been linked to disease prognosis. PMID- 24803937 TI - Dorsalis Pedis Free Flap: The Salvage Option following Failure of the Radial Forearm Flap in Total Lower Lip Reconstruction. AB - Reconstruction after resection of large tumors of the lower lip requires the use of free flaps in order to restore the shape and the function of the lip, with the free radial forearm flap being the most popular. In this study we describe our experience in using the dorsalis pedis free flap as a salvage option in reconstruction of total lower lip defect in a patient with an extended lower lip carcinoma after failure of the radial forearm free flap, that was initially used. The flap was integrated excellently and on the followup the patient was free of disease and fully satisfied with the aesthetic and functional result. PMID- 24803938 TI - Hypothyroidism induced severe rhabdomyolysis in a hemodialysis patient. AB - Hypothyroidism occurs relatively common and is a significant cause of morbidity and mortality during the course of chronic kidney disease. Rhabdomyolysis is a potentially life-threatening condition characterised by necrosis of muscular tissue and rarely associates with hypothyroidism. Here we describe a case of rhabdomyolysis due to severe hypothyroidism in a 56-year-old female hemodialysis patient. PMID- 24803939 TI - Role of Clinical Presentations and Routine CSF Analysis in the Rapid Diagnosis of Acute Bacterial Meningitis in Cases of Negative Gram Stained Smears. AB - Background and Aim. Bacterial meningitis is a lethal, disabling endemic disease needing prompt antibiotic management. Gram stained smears is rapid accurate method for diagnosis of bacterial meningitis. In cases of negative gram stained smears diagnosis is delayed till culture results. We aim to assess the role of clinical presentations and routine CSF analysis in the cost-effective rapid diagnosis of negative gram stained smears bacterial meningitis. Methods. Cross sectional study including 623 acute meningitis patients divided into two groups: bacterial meningitis and nonbacterial meningitis groups. The clinical presentations, systemic inflammatory parameters, and CSF analysis were evaluated and compared in both groups. Results. Altered conscious level, localizing neurological signs, Kernig's and Brudzinski's signs together with peripheral leucocytosis (>10.000/mm(3)), high CRP (>6) together with high CSF protein (>50 gl/dL), CSF neutrophilic count (>=50% of total CSF leucocytic count), and low CSF glucose level (<45 gm/dL) and CSF/serum glucose <=0.6 were significantly diagnostic in bacterial meningitis patients. From the significant CSF analysis variables CSF protein carried the higher accuracy of diagnosis 78% with sensitivity 88% and specificity 72%. Conclusions. High CSF protein (>50 mg/dL) together with plasma inflammatory markers and CSF cytochemical parameters can diagnose bacterial meningitis in gram stain negative smear till culture results. PMID- 24803940 TI - Hypersensitivity and the working environment for allergy nurses in sweden. AB - Background. Allergy nurses are exposed to allergens and respiratory irritants, and there are no national guidelines addressing personnel safety when working with these agents. Objective. To investigate the prevalence of allergies, asthma, and hypersensitivity symptoms among allergy nurses and the use of protective equipment and measures when working with allergen concentrates and respiratory irritants. Methods. A questionnaire survey was performed among the members of the Swedish Association of Allergy Nurses. Results. Diagnosed asthma was reported by 17%, while 18% had allergy to pets, 28% had allergy to pollens, and 26% reported nasal symptoms. Fifty-one percent reported a history of asthma, allergic diseases, or hypersensitivity symptoms in their family. Exhaust ventilation was used by 24% during skin prick tests, 17% during allergen specific immunotherapy, and 33% when performing methacholine challenge tests. Tightly closed containers for disposable waste were used by 58% during skin prick tests, by 60% during immunotherapy, and by 40% during Pc provocation tests. Conclusion. Allergy nurses had a tendency to increased prevalence of lower respiratory symptoms, asthma, and allergic rhinitis and more than half of the nurses had a family history of asthma, allergic diseases, or hypersensitivity symptoms. Additional studies are needed to evaluate the validity of these results. PMID- 24803941 TI - Industrially contaminated sites and health. PMID- 24803943 TI - Efficacy of different protocols of radioiodine therapy for treatment of toxic nodular goiter: systematic review and meta-analysis of the literature. AB - CONTEXT: To evaluate treatment success and hypothyroidism following main methods of radioiodine therapy of toxic nodular goiter (TNG); calculated versus fixed dose and high versus low dose of radioiodine. EVIDENCE ACQUISITIONS: We searched MEDLINE and SCOPUS databases from inception till July 2013, for clinical trials that compared two different methods of radioiodine administration in TNG. The trials were classified into two groups, those that compared fixed versus calculated dosimetry method and those that assessed high fixed dose versus low fixed dose method. Treatment response was defined as euthyroidism or hypothyroidism, one year after radioiodine administration. We calculated the risk ratio and risk difference of treatment response as well as permanent hypothyroidism as outcome variables. Random effects model was used for data pooling. RESULTS: The literature search yielded 2538 articles. Two randomized and five non-randomized clinical trials with 669 patients met the eligibility criteria for the meta-analysis. Patients with TNG who were treated according to the calculated method had 9.6% higher cure rate (risk ratio=1.17) and only 0.3% more permanent hypothyroidism compared to patients treated with the fixed dose method. There was no significant difference in the amount of administered radio iodine in the two groups. Patients treated with fixed high dose had 18.1% more cure rate (risk ratio = 1.2) and 23.9% more permanent hypothyroidism (risk ratio = 2.40) compared to patients treated by fixed low dose protocols. CONCLUSIONS: Calculated radioiodine therapy may be preferred to fixed dose method in patients with TNG. High dose methods are associated with more response and more hypothyroidism. PMID- 24803942 TI - Hormones and hemodynamics in pregnancy. AB - CONTEXT: Normal pregnancy is associated with sodium and water retention, which results in plasma volume expansion prior to placental implantation. The explanation offered for these events is that pregnancy 'resets' both volume and osmoreceptors. EVIDENCE ACQUISITION: The mechanisms for such an enigmatic 'resetting' in pregnancy have not previously been explained. However, recent human pregnancy studies have demonstrated that the earliest hemodynamic change in pregnancy is primary systemic arterial vasodilation. This arterial underfilling is associated with a secondary increase in cardiac output and activation of the neurohumoral axis, including stimulation of the renin-angiotensin-aldosterone, sympathetic, and non-osmotic vasopressin systems. Resistance to the pressor effects of angiotensin and sympathetic stimulation in pregnancy is compatible with an increase in endothelial nitric oxide synthase activity. RESULTS: In contrast to the sodium and water retention which occur secondary to the primary arterial vasodilation in cirrhosis, glomerular filtration and renal blood flow are significantly increased in normal pregnancy. A possible explanation for this difference in arterial vasodilation states is that relaxin, an arterial vasodilator which increases during pregnancy, has a potent effect on both systemic and renal circulation. Endothelial damage in pregnancy is pivotal in the pathogenesis of preeclampsia in pregnancy. CONCLUSIONS: Against a background of the primary arterial vasodilation hypothesis, it is obvious that reversal of the systemic vasodilatation in pregnancy, without subsequent activation of the renin angiotensin-aldosterone system (78), will evoke a reversal of all the links in the chain of events in normal pregnancy adaptation, thus, it may cause preeclampsia. Namely, a decrease of renal vasodilation will decrease glomerular filtration rate. PMID- 24803944 TI - A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients. AB - Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an "adjuvant" outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12 month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11-65) and a median follow-up time of 38.5 months (3-73). The median PRDSF is currently 4 months (1-47) in the Etoposide and 39 months (2-73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients. PMID- 24803945 TI - Patterns of Complementary and Alternative Medicine Use, Perceived Benefits, and Adverse Effects among Adult Users in Enugu Urban, Southeast Nigeria. AB - The use of complementary and alternative medicine (CAM) is now on the increase. Evidence from studies carried out globally has established that CAM use is very common and varies among populations. This study investigated patterns of CAM use, perceived benefits, and associated harm with CAM use among adults. A cross sectional study was conducted in three local government areas of Enugu urban, Southeast Nigeria. An interviewer-administered questionnaire was used to collect data from all consenting adult participants aged between 18 and 65 years. Of the 732 participants interviewed, 62.8% were females while 37.2% were males. Majority (84.7%) of the participants had used CAM at one time or another. The most commonly used CAM product was the biological products, followed by spiritual therapy. The major route of administration for CAM products was oral and about 40% of the participants combined CAM with conventional medicine. Majority (78.6%) of CAM users benefited from CAM products after using them while a few complained of adverse reactions. As CAM is gaining widespread acceptance and use, there is need for clinical trial on the benefits and adverse effects associated with the use of CAM to facilitate proof of efficacy and safety of the products. PMID- 24803946 TI - Neuroprotective effects of different modalities of acupuncture on traumatic spinal cord injury in rats. AB - Spinal cord injury (SCI) can induce a series of histological, biochemical, and functional changes. Acupuncture is commonly used for SCI patients. Using male rats of spinal cord injury with the New York University (NYU) Impactor, we investigated the response of electroacupuncture (EA), manual acupuncture (MA), and transcutaneous acupoint electrical stimulation (TAES) at Shuigou (DU26) and Fengfu (DU16) acupoints to understand the effects and mechanisms of acupuncture in neuroprotection and neuronal function recovery after SCI. Histological study showed a restored neural morphology and an increase in the quantity of neurons after EA, MA, and TAES administrations. Acupuncture's antioxidation effects were demonstrated by alleviation of the post-SCI superoxide dismutase (SOD) activity increase and malondialdehyde (MDA) level decrease. The anti-inflammation effect of acupuncture was shown as the reduced expression of inflammatory cytokines including interleukin-1 beta (IL-1 beta ), interleukin-6 (IL-6), and tumor necrosis factor- alpha (TNF- alpha ) when SCI was treated. And the antiapoptosis role was approved by TUNEL staining. Our data confirmed that the role of acupuncture in neuroprotection and dorsal neuronal function recovery after rat SCI, especially, EA stimulating at Shuigou (DU26) and Fengfu (DU16) can greatly promote neuronal function recovery, which may result from antioxidation, anti inflammation, and antiapoptosis effects of acupuncture. PMID- 24803947 TI - Effectiveness study of moxibustion on pain relief in primary dysmenorrhea: study protocol of a randomized controlled trial. AB - Dysmenorrhea is a prevalent problem in menstruating women. As a nonpharmacologic and free of relevant side effects intervention, moxibustion is considered as a safe treatment and has long been recommended for dysmenorrhea in China. However, the exact effects of moxibustion in PD have not been fully understood. Therefore we designed this random clinical trial aiming to (1) investigate whether moxibustion is safe and effective for pain relief in primary dysmenorrhea when compared to conventional pain-killers and (2) assess the acceptability and side effects associated with moxibustion. The results of this trial will contribute to a better understanding of the different effects of moxibustion in pain relief in primary dysmenorrhea when compared to conventional pharmacologic pain treatment. PMID- 24803948 TI - Treatment of rheumatoid arthritis with marine and botanical oils: an 18-month, randomized, and double-blind trial. AB - Objective. To determine whether a combination of borage seed oil rich in gamma linolenic acid (GLA) and fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is superior to either oil alone for treatment of rheumatoid arthritis (RA). Methods. Patients were randomized into a double-blind, 18-month trial. Mixed effects models compared trends over time in disease activity measures. Results. No significant differences were observed in changes in disease activity among the three randomized groups. Each group exhibited significant reductions in disease activity (DAS28) at 9 months (fish: -1.56[ 2.16, -0.96], borage: -1.33[-1.83, -0.84], combined: -1.18[-1.83, -0.54]) and in CDAI (fish: -16.95[-19.91, -13.98], borage: -11.20[-14.21, -8.19], and combined: 10.31[-13.61, -7.01]). There were no significant differences in change of RA medications among the three groups. Reduced disease activity in study patients was similar to matched patients from an RA registry, and reduction in DMARD use was greater (P < 0.03) in study patients. Conclusion. All 3 treatment groups exhibited similar meaningful clinical responses after 9 months, improvements which persisted for 18 months, and a response similar to matched patients from an RA registry. Study patients were able to reduce DMARD therapy given in combination with TNF antagonists to a greater extent than registry patients. This paper is dedicated to the memory of Dr. John T. Sharp, M.D., a pioneer and innovator in the field of musculoskeletal radiology. PMID- 24803949 TI - Possible delayed effect of unemployment on suicidal rates: the case of Hungary. AB - BACKGROUND: During the last few years, many countries in Europe suffered from a severe economic crisis which resulted in high unemployment rates. In this frame, the possible relationship between unemployment rate and suicidal rates at the level of the general population has been debated recently. MATERIAL AND METHODS: The official data concerning completed suicides and unemployment rates from the Hungarian Central Statistical Office for the years 2000-2011 were used. The percentage of changes from the previous year in the unemployment rate and the suicidal rates concerning both the general and the unemployed populations was calculated. Pearson correlation coefficient between the change in suicidal rates and change in unemployment rates was calculated both for the same year as well as after 1-6 years. RESULTS: The correlations between the unemployment rate and suicide rates were strongly negative both for the general and for the unemployed populations (-0.65 and -0.55, respectively). The correlation of unemployment change with suicidality change after 1-6 years gave a peak strong positive correlation at 5 years for the general population (0.78). At 4 years after the index year, there is a peak correlation with a moderate value for the unemployed population (0.47) and a similar moderate value for the general population (0.46). DISCUSSION: The current findings from Hungary suggest that unemployment might be associated with suicidality in the general population only after 3-5 years. It is possible that the distressing environment of the economic crisis increases suicidality in the general population rather than specifically in unemployed people. PMID- 24803950 TI - A nonparametric shape prior constrained active contour model for segmentation of coronaries in CTA images. AB - We present a nonparametric shape constrained algorithm for segmentation of coronary arteries in computed tomography images within the framework of active contours. An adaptive scale selection scheme, based on the global histogram information of the image data, is employed to determine the appropriate window size for each point on the active contour, which improves the performance of the active contour model in the low contrast local image regions. The possible leakage, which cannot be identified by using intensity features alone, is reduced through the application of the proposed shape constraint, where the shape of circular sampled intensity profile is used to evaluate the likelihood of current segmentation being considered vascular structures. Experiments on both synthetic and clinical datasets have demonstrated the efficiency and robustness of the proposed method. The results on clinical datasets have shown that the proposed approach is capable of extracting more detailed coronary vessels with subvoxel accuracy. PMID- 24803951 TI - A time-domain hybrid analysis method for detecting and quantifying T-wave alternans. AB - T-wave alternans (TWA) in surface electrocardiograph (ECG) signals has been recognized as a marker of cardiac electrical instability and is hypothesized to be associated with increased risk for ventricular arrhythmias among patients. A novel time-domain TWA hybrid analysis method (HAM) utilizing the correlation method and least squares regression technique is described in this paper. Simulated ECGs containing artificial TWA (cases of absence of TWA and presence of stationary or time-varying or phase-reversal TWA) under different baseline wanderings are used to test the method, and the results show that HAM has a better ability of quantifying TWA amplitude compared with the correlation method (CM) and adapting match filter method (AMFM). The HAM is subsequently used to analyze the clinical ECGs, and results produced by the HAM have, in general, demonstrated consistency with those produced by the CM and the AMFM, while the quantifying TWA amplitudes by the HAM are universally higher than those by the other two methods. PMID- 24803952 TI - Dynamics of high-risk nonvaccine human papillomavirus types after actual vaccination scheme. AB - Human papillomavirus (HPV) has been identified as the main etiological factor in the developing of cervical cancer (CC). This finding has propitiated the development of vaccines that help to prevent the HPVs 16 and 18 infection. Both genotypes are associated with 70% of CC worldwide. In the present study, we aimed to determine the emergence of high-risk nonvaccine HPV after actual vaccination scheme to estimate the impact of the current HPV vaccines. A SIR-type model was used to study the HPV dynamics after vaccination. According to the results, our model indicates that the application of the vaccine reduces infection by target or vaccine genotypes as expected. However, numerical simulations of the model suggest the presence of the phenomenon called vaccine-induced pathogen strain replacement. Here, we report the following replacement mechanism: if the effectiveness of cross-protective immunity is not larger than the effectiveness of the vaccine, then the high-risk nonvaccine genotypes emerge. In this scenario, further studies of infection dispersion by HPV are necessary to ascertain the real impact of the current vaccines, primarily because of the different high-risk HPV types that are found in CC. PMID- 24803953 TI - Global hopf bifurcation on two-delays leslie-gower predator-prey system with a prey refuge. AB - A modified Leslie-Gower predator-prey system with two delays is investigated. By choosing tau 1 and tau 2 as bifurcation parameters, we show that the Hopf bifurcations occur when time delay crosses some critical values. Moreover, we derive the equation describing the flow on the center manifold; then we give the formula for determining the direction of the Hopf bifurcation and the stability of bifurcating periodic solutions. Numerical simulations are carried out to illustrate the theoretical results and chaotic behaviors are observed. Finally, using a global Hopf bifurcation theorem for functional differential equations, we show the global existence of the periodic solutions. PMID- 24803954 TI - Multimodal spatial calibration for accurately registering EEG sensor positions. AB - This paper proposes a fast and accurate calibration method to calibrate multiple multimodal sensors using a novel photogrammetry system for fast localization of EEG sensors. The EEG sensors are placed on human head and multimodal sensors are installed around the head to simultaneously obtain all EEG sensor positions. A multiple views' calibration process is implemented to obtain the transformations of multiple views. We first develop an efficient local repair algorithm to improve the depth map, and then a special calibration body is designed. Based on them, accurate and robust calibration results can be achieved. We evaluate the proposed method by corners of a chessboard calibration plate. Experimental results demonstrate that the proposed method can achieve good performance, which can be further applied to EEG source localization applications on human brain. PMID- 24803955 TI - Automatic detection and quantification of WBCs and RBCs using iterative structured circle detection algorithm. AB - Segmentation and counting of blood cells are considered as an important step that helps to extract features to diagnose some specific diseases like malaria or leukemia. The manual counting of white blood cells (WBCs) and red blood cells (RBCs) in microscopic images is an extremely tedious, time consuming, and inaccurate process. Automatic analysis will allow hematologist experts to perform faster and more accurately. The proposed method uses an iterative structured circle detection algorithm for the segmentation and counting of WBCs and RBCs. The separation of WBCs from RBCs was achieved by thresholding, and specific preprocessing steps were developed for each cell type. Counting was performed for each image using the proposed method based on modified circle detection, which automatically counted the cells. Several modifications were made to the basic (RCD) algorithm to solve the initialization problem, detecting irregular circles (cells), selecting the optimal circle from the candidate circles, determining the number of iterations in a fully dynamic way to enhance algorithm detection, and running time. The validation method used to determine segmentation accuracy was a quantitative analysis that included Precision, Recall, and F-measurement tests. The average accuracy of the proposed method was 95.3% for RBCs and 98.4% for WBCs. PMID- 24803956 TI - A mathematical method for extracting cell secretion rate from affinity biosensors continuously monitoring cell activity. AB - Our laboratory has previously developed miniature aptasensors that may be integrated at the site of a small group of cells for continuous detection of cell secreted molecules such as inflammatory cytokine interferon gamma (IFN-gamma). In a system such as this, the signal measured at the sensor surfaces is a complex function of transport, reaction, as well as of cellular activity. Herein, we report on the development of a mathematical framework for extracting cell production rates from binding curves generated with affinity biosensors. This framework consisted of a diffusion-reaction model coupled to a root finding algorithm for determining cell production rates values causing convergence of a predetermined criterion. To experimentally validate model predictions, we deployed a microfluidic device with an integrated biosensor for measuring the IFN gamma release from CD4 T cells. We found close agreement between secretion rate observed theoretically and those observed experimentally. After taking into account the differences in sensor geometry and reaction kinetics, the method for cell secretion rate determination described in this paper may be broadly applied to any biosensor continuously measuring cellular activity. PMID- 24803957 TI - An unexpected particle oscillation for electrophoresis in viscoelastic fluids through a microchannel constriction. AB - Electrophoresis plays an important role in many applications, which, however, has so far been extensively studied in Newtonian fluids only. This work presents the first experimental investigation of particle electrophoresis in viscoelastic polyethylene oxide (PEO) solutions through a microchannel constriction under pure DC electric fields. An oscillatory particle motion is observed in the constriction region, which is distinctly different from the particle behavior in a polymer-free Newtonian fluid. This stream-wise particle oscillation continues until a sufficient number of particles form a chain to pass through the constriction completely. It is speculated that such an unexpected particle oscillating phenomenon is a consequence of the competition between electrokinetic force and viscoelastic force induced in the constriction. The electric field magnitude, particle size, and PEO concentration are all found to positively affect this viscoelasticity-related particle oscillation due to their respective influences on the two forces. PMID- 24803958 TI - The construction of an interfacial valve-based microfluidic chip for thermotaxis evaluation of human sperm. AB - Thermotaxis has been demonstrated to be an important criterion for sperm evaluation, yet clinical assessment of thermotaxis capacity is currently lacking. In this article, the on-chip thermotaxis evaluation of human sperm is presented for the first time using an interfacial valve-facilitated microfluidic device. The temperature gradient was established and accurately controlled by an external temperature gradient control system. The temperature gradient responsive sperm population was enriched into one of the branch channels with higher temperature setting and the non-responsive ones were evenly distributed into the two branch channels. We employed air-liquid interfacial valves to ensure stable isolation of the two branches, facilitating convenient manipulation of the entrapped sperm. With this device, thermotactic responses were observed in 5.7%-10.6% of the motile sperm moving through four temperature ranges (34.0-35.3 degrees C, 35.0 36.3 degrees C, 36.0-37.3 degrees C, and 37.0-38.3 degrees C, respectively). In conclusion, we have developed a new method for high throughput clinical evaluation of sperm thermotaxis and this method may allow other researchers to derive better IVF procedure. PMID- 24803959 TI - A microfluidic model for organ-specific extravasation of circulating tumor cells. AB - Circulating tumor cells (CTCs) are the principal vehicle for the spread of non hematologic cancer disease from a primary tumor, involving extravasation of CTCs across blood vessel walls, to form secondary tumors in remote organs. Herein, a polydimethylsiloxane-based microfluidic system is developed and characterized for in vitro systematic studies of organ-specific extravasation of CTCs. The system recapitulates the two major aspects of the in vivo extravasation microenvironment: local signaling chemokine gradients in a vessel with an endothelial monolayer. The parameters controlling the locally stable chemokine gradients, flow rate, and initial chemokine concentration are investigated experimentally and numerically. The microchannel surface treatment effect on the confluency and adhesion of the endothelial monolayer under applied shear flow has also been characterized experimentally. Further, the conditions for driving a suspension of CTCs through the microfluidic system are discussed while simultaneously maintaining both the local chemokine gradients and the confluent endothelial monolayer. Finally, the microfluidic system is utilized to demonstrate extravasation of MDA-MB-231 cancer cells in the presence of CXCL12 chemokine gradients. Consistent with the hypothesis of organ-specific extravasation, control experiments are presented to substantiate the observation that the MDA-MB-231 cell migration is attributed to chemotaxis rather than a random process. PMID- 24803960 TI - Finite element analysis of helical flows in human aortic arch: a novel index. AB - This study investigates the helical secondary flows in the aortic arch using finite element analysis. The relationship between helical flow and the configuration of the aorta in patients of whose three-dimensional images constructed from computed tomography scans was examined. A finite element model of the pressurized root, arch, and supra-aortic vessels was developed to simulate the pattern of helical secondary flows. Calculations indicate that most of the helical secondary flow was formed in the ascending aorta. Angle alpha between the zero reference point and the aortic ostium (correlation coefficient (r) = -0.851, P = 0.001), the dispersion index of the cross section of the ascending (r = 0.683, P = 0.021) and descending aorta (r = 0.732, P = 0.010), all correlated closely with the presence of helical flow (P < 0.05). Stepwise multiple linear regression analysis confirmed angel alpha to be independently associated with the helical flow pattern in therein (standardized coefficients = -0.721, P = 0.023). The presence of helical fluid motion based on the atherosclerotic risks of patients, including those associated with diabetes, hypertension, hyperlipidemia, or renal insufficiency, was also evaluated. Numerical simulation of the flow patterns in aortas incorporating the atherosclerotic risks may better explain the mechanism of formation of helical flows and provide insight into causative factors that underlie them. PMID- 24803961 TI - Inverting microwell array chip for the cultivation of human induced pluripotent stem cells with controlled aggregate size and geometrical arrangement. AB - We present a novel cell culture chip, namely, "inverting microwell array chip," for cultivation of human induced pluripotent stem cells. The chip comprises a lower hydrogel microwell array and an upper polystyrene culture surface. We demonstrate the formation of uniform cellular aggregates in the microwell array, and after inversion, a culture with controlled aggregate size and geometrical arrangement on the polystyrene surface. Here, we report effects of cell concentrations on a cultivation sequence in the chip. PMID- 24803962 TI - A microfluidic perfusion platform for cultivation and screening study of motile microalgal cells. AB - Systematic screening of algal cells is getting huge interest due to their capability of producing lipid-based biodiesel. Here, we introduce a new microfluidic platform composed of an array of perfusion chambers designed for long-term cultivation and preliminary screening of motile microalgal cells through loading and releasing of cells to and from the chambers. The chemical environment in each perfusion chamber was independently controlled for 5 days. The effect of nitrogen-depletion on the lipid production, phototaxis behavior in the absence of Ca(2+), and cytotoxic effect of herbicide on microalgal cells was successfully monitored and compared with simultaneous control experiments on the platform. The present methodology could be extended to effective screening of algal cells and various cell lines for the production of biodiesel and other useful chemicals. PMID- 24803963 TI - DNA translocation through short nanofluidic channels under asymmetric pulsed electric field. AB - Investigation of single molecule DNA dynamics in confined environments has led to important applications in DNA analysis, separation, and sequencing. Here, we studied the electrophoretic transport of DNA molecules through nanochannels shorter than the DNA contour length and calculated the associated translocation time curves. We found that the longer T4 DNA molecules required a longer time to traverse a fixed length nanochannel than shorter lambda DNA molecules and that the translocation time decreased with increasing electric field which agreed with theoretical predictions. We applied this knowledge to design an asymmetric electric pulse and demonstrate the different responses of lambda and T4 DNA to the pulses. We used Brownian dynamics simulations to corroborate our experimental results on DNA translocation behaviour. This work contributes to the fundamental understanding of polymer transport through nanochannels and may help in designing better separation techniques in the future. PMID- 24803964 TI - Facile fabrication processes for hydrogel-based microfluidic devices made of natural biopolymers. AB - We present facile strategies for the fabrication of two types of microfluidic devices made of hydrogels using the natural biopolymers, alginate, and gelatin as substrates. The processes presented include the molding-based preparation of hydrogel plates and their chemical bonding. To prepare calcium-alginate hydrogel microdevices, we suppressed the volume shrinkage of the alginate solution during gelation using propylene glycol alginate in the precursor solution along with sodium alginate. In addition, a chemical bonding method was developed using a polyelectrolyte membrane of poly-L-lysine as the electrostatic glue. To prepare gelatin-based microdevices, we used microbial transglutaminase to bond hydrogel plates chemically and to cross-link and stabilize the hydrogel matrix. As an application, mammalian cells (fibroblasts and vascular endothelial cells) were cultivated on the microchannel surface to form three-dimensional capillary embedding tissue models for biological research and tissue engineering. PMID- 24803965 TI - Characterizations of kinetic power and propulsion of the nematode Caenorhabditis elegans based on a micro-particle image velocimetry system. AB - Quantifying the motility of micro-organisms is beneficial in understanding their biomechanical properties. This paper presents a simple image-based algorithm to derive the kinetic power and propulsive force of the nematode Caenorhabditis elegans. To avoid unnecessary disturbance, each worm was confined in an aqueous droplet of 0.5 MUl. The droplet was sandwiched between two glass slides and sealed with mineral oil to prevent evaporation. For motion visualization, 3-MUm fluorescent particles were dispersed in the droplet. Since the droplet formed an isolated environment, the fluid drag and energy loss due to wall frictions were associated with the worm's kinetic power and propulsion. A microparticle image velocimetry system was used to acquire consecutive particle images for fluid analysis. The short-time interval (Deltat < 20 ms) between images enabled quasi real-time measurements. A numerical simulation of the flow in a straight channel showed that the relative error of this algorithm was significantly mitigated as the image was divided into small interrogation windows. The time-averaged power and propulsive force of a N2 adult worm over three swimming cycles were estimated to be 5.2 +/- 3.1 pW and 1.0 +/- 0.8 nN, respectively. In addition, a mutant, KG532 [kin-2(ce179) X], and a wild-type (N2) worm in a viscous medium were investigated. Both cases showed an increase in the kinetic power as compared with the N2 worm in the nematode growth medium due to the hyperactive nature of the kin-2 mutant and the high viscosity medium used. Overall, the technique deals with less sophisticated calculations and is automation possible. PMID- 24803966 TI - Individually addressable multi-chamber electroporation platform with dielectrophoresis and alternating-current-electro-osmosis assisted cell positioning. AB - A multi-functional microfluidic platform was fabricated to demonstrate the feasibility of on-chip electroporation integrated with dielectrophoresis (DEP) and alternating-current-electro-osmosis (ACEO) assisted cell/particle manipulation. A spatial gradient of electroporation parameters was generated within a microchamber array and validated using normal human dermal fibroblast (NHDF) cells and red fluorescent protein-expressing human umbilical vein endothelial cells (RFP-HUVECs) with various fluorescent indicators. The edge of the bottom electrode, coinciding with the microchamber entrance, may act as an on demand gate, functioning under either positive or negative DEP. In addition, at sufficiently low activation frequencies, ACEO vortices can complement the DEP to contribute to a rapid trapping/alignment of particles. As such, results clearly indicate that the microfluidic platform has the potential to achieve high throughput screening for electroporation with spatial control and uniformity, assisted by DEP and ACEO manipulation/trapping of particles/cells into individual microchambers. PMID- 24803967 TI - Ion diffusion coefficient measurements in nanochannels at various concentrations. AB - Diffusion is one of the most fundamental properties of ionic transport in solutions. Here, we present experimental studies and theoretical analysis on the ion diffusion in nanochannels. Based on Fick's second law, we develop a current monitoring method to measure ion diffusion coefficient of high solution concentrations in nanochannels. This method is further extended to the cases at medium and low concentrations. Through monitoring ionic current during diffusion, we obtain diffusion coefficients of potassium chloride solution at different concentrations in nanochannels. These diffusion coefficients within the confined space are close to theirs bulk values. It is also found that the apparent ion diffusion equilibrium in the present experiments is very slow at low concentration, which we attribute to the slow equilibrium of the nanochannel surface charge. Finally, we get a primary acknowledge of the equilibrium rate between the nanochannel surface charge and electrolyte solution. The results in this work have improved the understanding of nanoscale diffusion and nanochannel surface charge and may be useful in nanofluidic applications such as ion selective transport, energy conversion, and nanopore biosensors. PMID- 24803968 TI - Isolation of viable cancer cells in antibody-functionalized microfluidic devices. AB - Microfluidic devices functionalized with EpCAM antibodies were utilized for the capture of target cancer cells representing circulating tumor cells (CTCs). The fraction of cancer cells captured from homogeneous suspensions is mainly a function of flow shear rate, and can be described by an exponential function. A characteristic shear rate emerges as the most dominant parameter affecting the cell attachment ratio. Utilizing this characteristic shear rate as a scaling factor, all attachment ratio results for various combinations of receptor and ligand densities collapsed onto a single curve described by the empirical formula. The characteristic shear rate increases with both cell-receptor and surface-ligand densities, and empirical formulae featuring a product of two independent cumulative distributions described well these relationships. The minimum detection limit in isolation of target cancer cells from binary mixtures was experimentally explored utilizing microchannel arrays that allow high throughput processing of suspensions about 0.5 ml in volume, which are clinically relevant, within a short time. Under a two-step attachment/detachment flow rate, both high sensitivity (almost 1.0) and high specificity (about 0.985) can be achieved in isolating target cancer cells from binary mixtures even for the lowest target/non-target cell concentration ratio of 1:100 000; this is a realistic ratio between CTCs and white blood cells in blood of cancer patients. Detection of CTCs from blood samples was also demonstrated using whole blood from healthy donors spiked with cancer cells. Finally, the viability of target cancer cells released after capture was confirmed by observing continuous cell growth in culture. PMID- 24803969 TI - An equipment-free polydimethylsiloxane microfluidic spotter for fabrication of microarrays. AB - This paper presents a low-cost, power-free, and easy-to-use spotter system for fabrication of microarrays. The spotter system uses embedded dispensing microchannels combined with a polydimethylsiloxane (PDMS) membrane containing regular arrays of well-defined thru-holes to produce precise, uniform DNA or protein microarrays for disease diagnosis or drug screening. Powered by pre evacuation of its PDMS substrate, the spotter system does not require any additional components or external equipment for its operation, which can potentially allow low-cost, high-quality microarray fabrication by minimally trained individuals. Polyvinylpyrrolidone was used to modify the PDMS surface to prevent protein adsorption by the microchannels. Experimental results indicate that the PDMS spotter shows excellent printing performance for immobilizing proteins. The measured coefficient of variation (CV) of the diameter of 48 spots was 2.63% and that of the intensity within one array was 2.87%. Concentration gradient experiments revealed the superiority of the immobilization density of the PDMS spotter over the conventional pin-printing method. Overall, this low cost, power-free, and easy-to-use spotting system provides an attractive new method to fabricate microarrays. PMID- 24803970 TI - Polydimethyl siloxane wet etching for three dimensional fabrication of microneedle array and high-aspect-ratio micropillars. AB - Among various transdermal drug delivery (TDD) approaches, utilizing the microneedles (MNs) not only can penetrate the skin but also deliver the drug with reduced tissue damage, reduced pain, and no bleeding. However, the MNs with larger height are required to overcome the skin barrier for effective TDD. Unlike 2D patterning, etching polydimethyl siloxane (PDMS) micropillars for fabrication of 3D microstructures is presented. The PDMS micropillars were first constructed by casting PDMS on the computer numerical control-machined cylindrical microwells, which then went through etching process to obtain the MNs for subsequent fabrication of polymer MNs or high aspect ratio micropillars. PMID- 24803972 TI - Vibrational Analysis of Brucite Surfaces and the Development of an Improved Force Field for Molecular Simulation of Interfaces. AB - We introduce a nonbonded three-body harmonic potential energy term for Mg-O-H interactions for improved edge surface stability in molecular simulations. The new potential term is compatible with the Clayff force field and is applied here to brucite, a layered magnesium hydroxide mineral. Comparisons of normal mode frequencies from classical and density functional theory calculations are used to verify a suitable spring constant (k parameter) for the Mg-O-H bending motion. Vibrational analysis of hydroxyl librations at two brucite surfaces indicates that surface Mg-O-H modes are shifted to frequencies lower than the corresponding bulk modes. A comparison of DFT and classical normal modes validates this new potential term. The methodology for parameter development can be applied to other clay mineral components (e.g., Al, Si) to improve the modeling of edge surface stability, resulting in expanded applicability to clay mineral applications. PMID- 24803973 TI - Spin-State Effects on the Thermal Dihydrogen Release from Solid-State [MH(eta2 H2)dppe2]+ (M = Fe, Ru, Os) Organometallic Complexes for Hydrogen Storage Applications. AB - Mossbauer spectroscopy, experimental thermodynamic measurements, and computational studies were performed to investigate the properties of molecular hydrogen binding to the organometallic fragments [MHdppe2]+ (M = Fe, Ru, Os; dppe =1,2-bis(diphenylphosphino)ethane) to form the dihydrogen complex fragments [MH(eta2-H2)dppe2]+. Mossbauer spectroscopy showed that the dehydrogenated complex [FeHdppe2]+ adopts a geometry consistent with the triplet spin state, transitioning to a singlet state complex upon addition of the dihydrogen molecule in a manner similar to the previously studied dinitrogen complexes. From simulations, this spin transition behavior was found to be responsible for the strong binding behavior experimentally observed in the iron complex. Spin-singlet to spin-singlet transitions were found to exhibit thermodynamics consistent with the 5d > 3d > 4d binding trend observed for other transition metal dihydrogen complexes. Finally, the method for distinguishing between dihydrogen and dihydride complexes based on partial quadrupole splittings observed in Mossbauer spectra was confirmed, providing a tool for further characterization of these unique species for Mossbauer active compounds. PMID- 24803974 TI - Development of Hybrid Silver-Coated Gold Nanostars for Nonaggregated Surface Enhanced Raman Scattering. AB - In the ongoing search for ever-brighter surface-enhanced Raman scattering (SERS) nanoprobes, gold nanostars (AuNSs) have emerged as one of the best geometries for producing SERS in a nonaggregated state. Despite their high enhancement factor, optical extinction from plasmon-matched nanoparticles can greatly attenuate the overall SERS intensity. Herein, we report the development of a new hybrid bimetallic NS-based platform that exhibits superior resonant SERS (SERRS) properties. In this new nanoplatform, coating AuNSs with a subtotal layer of silver (AuNS@Ag) can further increase their SERRS brightness by an order of magnitude when being interrogated by an off-resonant excitation source. Silica encapsulated AuNS@Ag nanoprobes were injected intradermally into a rat pelt, where SERRS was readily detected with higher signal-to-noise than nanoprobes prepared from AuNS. Moreover, these off-resonance AuNS@Ag nanoprobes did not cause any gross photothermal damage to tissue, which was observed with the plasmon-matched AuNSs. This novel SERRS-active hybrid nanoprobe exhibits high SERRS brightness and offers promising properties for future applications in sensing and molecular imaging. PMID- 24803975 TI - Thermo-Active Behavior of Ethylene-Vinyl Acetate | Multiwall Carbon Nanotube Composites Examined by in Situ near-Edge X-ray Absorption Fine-Structure Spectroscopy. AB - NEXAFS spectroscopy was used to investigate the temperature dependence of thermally active ethylene-vinyl acetate | multiwall carbon nanotube (EVA|MWCNT) films. The data shows systematic variations of intensities with increasing temperature. Molecular orbital assignment of interplaying intensities identified the 1s -> pi*C=C and 1s -> pi*C=O transitions as the main actors during temperature variation. Furthermore, enhanced near-edge interplay was observed in prestrained composites. Because macroscopic observations confirmed enhanced thermal-mechanical actuation in prestrained composites, our findings suggest that the interplay of C=C and C=O pi orbitals may be instrumental to actuation. PMID- 24803976 TI - Nonequilibrium Ionic Response of Biased Mechanically Controllable Break Junction (MCBJ) Electrodes. AB - Novel experimental techniques allow for the manipulation and interrogation of biomolecules between metallic probes immersed in micro/nanofluidic channels. The behavior of ions in response to applied fields is a major issue in the use of these techniques in sensing applications. Here, we experimentally and theoretically elucidate the behavior of background currents in these systems. These large currents have a slowly decaying transient response, as well as noise that increases with ionic concentration. Using mechanically controllable break junctions (MCBJ), we study the ionic response in nanogaps with widths ranging from a few nanometers to millimeters. Moreover, we obtain an expression for the ionic current by solving time-dependent Nernst-Planck and Poisson equations. This expression shows that after turning on an applied voltage, ions rapidly respond to the strong fields near the electrode surface, screening the field in the process. Ions subsequently translocate in the weak electric field and slowly relax within the diffusion layer. Our theoretical results help to explain the short- and long-time behavior of the ionic response found in experiments, as well as the various length scales involved. PMID- 24803977 TI - A case report of esophageal perforation: Complication of nasogastric tube placement. AB - PATIENT: Male, 70 FINAL DIAGNOSIS: Esophageal perforation Symptoms: Abdominal pain * nausea * vomiting MEDICATION: - Clinical Procedure: - Specialty: Surgery. OBJECTIVE: Unusual clinical course. BACKGROUND: Esophageal perforation is a well defined and severe clinical condition. There are several etiologies of esophagus perforation. CASE REPORT: We report the case of a 70-year-old Caucasian man who underwent an emergency cholecystectomy due to acute cholecystitis. Two days after surgery, his condition deteriorated. Thorax computerized tomography revealed an esophageal perforation. CONCLUSIONS: Esophageal perforation due to nasogastric application is relatively rare but the consequences are potentially serious. The anatomy of the upper gastrointestinal system should be understood by all healthcare professionals involved in the treatment. PMID- 24803978 TI - The role of computed tomography in detecting splenic arteriovenous fistula and concomitant atrial myxoma. AB - PATIENT: Female, 45 FINAL DIAGNOSIS: Arterio-venous fistula of the splean Symptoms: Lef-side abdominal pain Medication: - Clinical Procedure: - Specialty: Surgery. OBJECTIVE: Rare disease. BACKGROUND: Splenic arterial-venous fistula and atrial myxoma are not rare cases but the co-existence of both lesions in the same patient is unpublished so far. CASE REPORT: A 45- year-old woman presented with vague left flank pain. She was initially scanned by B-dimensional echography, which revealed multiple enlarged hypo-echoic lesions in the splenic hilum. To further characterize the lesion, we performed computed tomography angiography (CTA). CTA showed dilatation of the splenic artery, and aneurismal dilatation of the splenic vein, associated with early opacification of the portal system. CTA showed also an intrasplenic venous aneurism, which was presumed to be the site of fistulous communication. Celiac arteriography confirmed the CTA findings. A left atrial mass was detected by cardiac echography, which was evaluated better by CTA, and was consistent with atrial myxoma. The patient underwent open surgery in different stage with resection of the atrial mass and spleen. The postoperative period was uneventful. CONCLUSIONS: This is a unique case in the literature, showing the coexistence of a dual-pathology splenic arterial venous fistula and atrial myxoma. PMID- 24803979 TI - Gallbladder agenesis with a primary choledochal stone in a patient with situs inversus totalis. AB - PATIENT: Female, 68 FINAL DIAGNOSIS: Gallbladder agenesis with situs inversus totalis Symptoms: Epigastric pain * jaundice MEDICATION: - Clinical Procedure: - Specialty: Surgery. OBJECTIVE: Rare disease. BACKGROUND: Situs inversus totalis is an inherited condition characterized by the mirror-image transposition of thoracic and abdominal organs. Gallbladder agenesis, which has normal bile ducts, is a rare congenital condition that occurs in 13 to 65 people out of 100 000. A common bile duct (CBD) stone or choledocholithiasis in patients with gallbladder agenesis is even rarer. CASE REPORT: We report the case of a 68-year-old woman who presented with epigastric pain and jaundice. She was not known to have situs inversus totalis. Abdominal ultrasound showed a large stone in the CBD, which could not be extracted by endoscopic retrograde cholangiopancreatography (ERCP), necessitating exploration. The gall-bladder and cystic duct were found to be absent. Incisional exploration of the CBD was performed, and a large stone was removed. A choledochoscope was used to identify the remnants and exclude the presence of ectopic gallbladder, and a T-tube was placed into the CBD. CONCLUSIONS: Gallbladder agenesis in a patient with situs inversus totalis is extremely rare, with no single reported case identified in the literature. In addition, our case showed a rare complication of ERCP - a failure to extract the CBD stone - and illustrates a way to overcome this complication. PMID- 24803980 TI - Oxidative stress-mediated reperfusion injury: mechanism and therapies. PMID- 24803981 TI - Oxidative modification of proteins in pediatric cystic fibrosis with bacterial infections. AB - Pseudomonas aeruginosa and Staphylococcus aureus cause chronic lung infection in cystic fibrosis (CF) patients, inducing chronic oxidative stress. Several markers of plasma protein oxidative damage and glycoxidation and activities of erythrocyte antioxidant enzymes have been compared in stable CF patients chronically infected with Pseudomonas aeruginosa (n = 12) and Staphylococcus aureus (n = 10) in relation to healthy subjects (n = 11). Concentration of nitric oxide was also measured in the exhaled air from the lower respiratory tract of patients with CF. Elevated glycophore (4.22 +/- 0.91 and 4.19 +/- 1.04 versus control 3.18 +/- 0.53 fluorescence units (FU)/mg protein; P < 0.05) and carbonyl group levels (1.9 +/- 0.64, 1.87 +/- 0.45 versus control 0.94 +/- 0.19 nmol/mg protein; P < 0.05) as well as increased glutathione S-transferase activity (2.51 +/- 0.88 and 2.57 +/- 0.79 U/g Hb versus 0.77 +/- 0.16 U/g Hb; P < 0.05) were noted in Pseudomonas aeruginosa and Staphylococcus aureus infected CF. Kynurenine level (4.91 +/- 1.22 versus 3.89 +/- 0.54 FU/mg protein; P < 0.05) was elevated only in Staphylococcus aureus infected CF. These results confirm oxidative stress in CF and demonstrate the usefulness of the glycophore level and protein carbonyl groups as markers of oxidative modifications of plasma proteins in this disease. PMID- 24803982 TI - The production of nitric oxide, IL-6, and TNF-alpha in palmitate-stimulated PBMNCs is enhanced through hyperglycemia in diabetes. AB - We examined nitric oxide (NO), IL-6, and TNF-alpha secretion from cultured palmitate-stimulated PBMNCs or in the plasma from type 2 diabetes mellitus (T2MD) patients or nondiabetic (ND) controls. Free fatty acids (FFA) have been suggested to induce chronic low-grade inflammation, activate the innate immune system, and cause deleterious effects on vascular cells and other tissues through inflammatory processes. The levels of NO, IL-6, TNF-alpha, and MDA were higher in supernatant of palmitate stimulated blood cells (PBMNC) or from plasma from patients. The results obtained in the present study demonstrated that hyperglycemia in diabetes exacerbates in vitro inflammatory responses in PBMNCs stimulated with high levels of SFA (palmitate). These results suggest that hyperglycemia primes PBMNCs for NO, IL-6, and TNF-alpha secretion under in vitro FFA stimulation are associated with the secretion of inflammatory biomarkers in diabetes. A combined therapy targeting signaling pathways activated by hyperglycemia in conjunction with simultaneous control of hyperglycemia and hypertriglyceridemia would be suggested for controlling the progress of diabetic complications. PMID- 24803983 TI - BL153 partially prevents high-fat diet induced liver damage probably via inhibition of lipid accumulation, inflammation, and oxidative stress. AB - The present study was to investigate whether a magnolia extract, named BL153, can prevent obesity-induced liver damage and identify the possible protective mechanism. To this end, obese mice were induced by feeding with high fat diet (HFD, 60% kcal as fat) and the age-matched control mice were fed with control diet (10% kcal as fat) for 6 months. Simultaneously these mice were treated with or without BL153 daily at 3 dose levels (2.5, 5, and 10 mg/kg) by gavage. HFD feeding significantly increased the body weight and the liver weight. Administration of BL153 significantly reduced the liver weight but without effects on body weight. As a critical step of the development of NAFLD, hepatic fibrosis was induced in the mice fed with HFD, shown by upregulating the expression of connective tissue growth factor and transforming growth factor beta 1, which were significantly attenuated by BL153 in a dose-dependent manner. Mechanism study revealed that BL153 significantly suppressed HFD induced hepatic lipid accumulation and oxidative stress and slightly prevented liver inflammation. These results suggest that HFD induced fibrosis in the liver can be prevented partially by BL153, probably due to reduction of hepatic lipid accumulation, inflammation and oxidative stress. PMID- 24803984 TI - Antioxidant strategies and respiratory disease of the preterm newborn: an update. AB - Preterm newborns are challenged by an excessive oxidative burden, as a result of several perinatal stimuli, as intrauterine infections, resuscitation, mechanical ventilation, and postnatal complications, in the presence of immature antioxidant capacities. "Oxygen radical disease of neonatology" comprises a wide range of conditions sharing a common pathway of pathogenesis and includes bronchopulmonary dysplasia (BPD) and other main complications of prematurity. Antioxidant strategies may be beneficial in the prevention and treatment of oxidative stress- (OS-) related lung disease of the preterm newborn. Endotracheal supplementation or lung-targeted overexpression of superoxide dismutase was proved to reduce lung damage in several models; however, the supplementation in preterm newborn failed to reduce the risk of BPD, although long-term respiratory outcomes were improved. Also melatonin administration to small cohorts of preterm newborns suggested beneficial effects on lung OS. The possibility to identify single nucleotide polymorphism affecting the risk of BPD may help to identify specific populations with particularly high risk of OS-related diseases and may pose the basis for individually targeted treatments. Finally, surfactant replacement may lead to local anti-inflammatory and antioxidant effects, thanks to specific enzymatic and nonenzymatic antioxidants naturally present in animal surfactants. PMID- 24803986 TI - Oxidative stress in aging. PMID- 24803985 TI - Antioxidant bioactivity of Samsum ant (Pachycondyla sennaarensis) venom protects against CCL4-induced nephrotoxicity in mice. AB - To assess whether SAV could influence the effects of carbon tetrachloride (CCL4) exposure, mice were treated with SAV in doses of 100, 200, 300 and 400 MUg/kg body weight and the effects on oxidative status and kidney function were studied. Serum levels of creatinine, malondialdehyde (MDA), and blood urea, together with renal and hepatic levels of MDA, glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were quantified in order to evaluate antioxidant activity. Results showed that the group injected with CCL4 exhibited significantly higher levels of oxidative stress markers, MDA, and significantly lower concentrations of GSH, SOD and catalase. SAV was found to significantly improve these oxidative markers, occasionally, in a dose-dependent manner. Furthermore, treatment with SAV was associated with the same behaviour in respect to kidney functions which had previously been impaired by CCL4. Histopathological examination demonstrated that SAV, in different groups, improved the renal tissue damage induced by CCL4 and histological scores confirmed that significant improvements were obtained after treatment with SAV, particularly with the lowest dose (100 MUg/kg body weight). In conclusion, SAV has the potential capability to restore oxidative stability and to improve kidney functions after CCL4 acute injury. PMID- 24803987 TI - Psoralea corylifolia L. seed extract ameliorates streptozotocin-induced diabetes in mice by inhibition of oxidative stress. AB - Pancreatic beta-cell death is known to be the cause of deficient insulin production in diabetes mellitus. Oxidative stress is one of the major causes of beta-cell death. In this study, we investigated the effects of Psoralea corylifolia L. seed (PCS) extract on beta-cell death. Oral administration of PCS extract resulted in a significant improvement of hyperglycemia in streptozotocin induced diabetic mice. PCS extract treatment improved glucose tolerance and increased serum insulin levels. To study the mechanisms involved, we investigated the effects of PCS extract on H2O2-induced apoptosis in INS-1 cells. Treatment with PCS extract inhibited cell death. PCS extract treatment decreased reactive oxygen species level and activated antioxidative enzymes. Among the major components of PCS extract, psoralen and isopsoralen (coumarins), but not bakuchiol, showed preventive effects against H2O2-induced beta-cell death. These findings indicate that PCS extract may be a potential pharmacological agent to protect against pancreatic beta-cell damage caused by oxidative stress associated with diabetes. PMID- 24803989 TI - Disentangling Peptide Configurations via Two-Dimensional Electronic Spectroscopy: Ab Initio Simulations Beyond the Frenkel Exciton Hamiltonian. AB - Two-dimensional (2D) optical spectroscopy techniques based on ultrashort laser pulses have been recently extended to the optical domain in the ultraviolet (UV) spectral region. UV-active aromatic side chains can thus be used as local highly specific markers for tracking dynamics and structural rearrangements of proteins. Here we demonstrate that 2D electronic spectra of a model proteic system, a tetrapeptide with two aromatic side chains, contain enough structural information to distinguish between two different configurations with distant and vicinal side chains. For accurate simulations of the 2DUV spectra in solution, we combine a quantum mechanics/molecular mechanics approach based on wave function methods, accounting for interchromophores coupling and environmental effects, with nonlinear response theory. The proposed methodology reveals effects, such as charge transfer between vicinal aromatic residues that remain concealed in conventional exciton Hamiltonian approaches. Possible experimental setups are discussed, including multicolor experiments and signal manipulation techniques for limiting undesired background contributions and enhancing 2DUV signatures of specific electronic couplings. PMID- 24803988 TI - Olive (Olea europaea) leaf extract induces apoptosis and monocyte/macrophage differentiation in human chronic myelogenous leukemia K562 cells: insight into the underlying mechanism. AB - Differentiation therapy is an attractive approach aiming at reversing malignancy and reactivating endogenous differentiation programs in cancer cells. Olive leaf extract, known for its antioxidant activity, has been demonstrated to induce apoptosis in several cancer cells. However, its differentiation inducing properties and the mechanisms involved are still poorly understood. In this study, we investigated the effect of Chemlali Olive Leaf Extract (COLE) for its potential differentiation inducing effect on multipotent leukemia K562 cells. Results showed that COLE inhibits K562 cells proliferation and arrests the cell cycle at G0/G1, and then at G2/M phase over treatment time. Further analysis revealed that COLE induces apoptosis and differentiation of K562 cells toward the monocyte lineage. Microarray analysis was conducted to investigate the underlying mechanism of COLE differentiation inducing effect. The differentially expressed genes such as IFI16, EGR1, NFYA, FOXP1, CXCL2, CXCL3, and CXCL8 confirmed the commitment of K562 cells to the monocyte/macrophage lineage. Thus our results provide evidence that, in addition to apoptosis, induction of differentiation is one of the possible therapeutic effects of olive leaf in cancer cells. PMID- 24803990 TI - Single-Molecule Fluorescence Using Nucleotide Analogs: A Proof-of-Principle. AB - Fluorescent nucleotide analogues, such as 2-aminopurine (2AP) and pyrrolo-C (PyC), have been extensively used to study nucleic acid local conformational dynamics in bulk experiments. Here we present a proof-of-principle approach using 2AP and PyC fluorescence at the single-molecule level. Our data show that ssDNA, dsDNA, or RNA containing both 2AP and PyC can be monitored using single-molecule fluorescence and a click chemistry immobilization method. We demonstrate that this approach can be used to monitor DNA and RNA in real time. This is the first reported assay using fluorescent nucleotide analogs at the single-molecule level. We anticipate that single 2AP or PyC fluorescence will have numerous applications in studies of DNA and RNA, including protein-induced base-flipping dynamics in protein-nucleic acid complexes. PMID- 24803991 TI - Dynamic Determination of Active-Site Reactivity in Semiquinone Photolyase by the Cofactor Photoreduction. AB - Photolyase contains a flavin cofactor in a fully reduced form as its functional state to repair ultraviolet-damaged DNA upon blue light absorption. However, after purification, the cofactor exists in its oxidized or neutral semiquinone state. Such oxidization eliminates the repair function, but it can be reverted by photoreduction, a photoinduced process with a series of electron-transfer (ET) reactions. With femtosecond absorption spectroscopy and site-directed mutagenesis, we completely recharacterized such photoreduction dynamics in the semiquinone state. Comparing with all previous studies, we identified a new intramolecular ET pathway, determined stretched ET behaviors, refined all ET time scales, and finally evaluated the driving forces and reorganization energies for eight elementary ET reactions. Combined with the oxidized-state photoreduction dynamics, we elucidated the different active-site properties of the reduction ability and structural flexibility in the oxidized and semiquinone states, leading to the dramatically different ET dynamics and photoreduction efficiency in the two states. PMID- 24803992 TI - Probing the Microenvironment in the Confined Pores of Mesoporous Silica Nanoparticles. AB - The microenvironment inside of the pores of mesoporous silica nanoparticles is probed using spectroscopic techniques. The probe molecules are sealed inside of the pores by a nanovalve system that is capable of controlling the access to the pore and ensuring the exclusive probing of the pore environment without any interference from the probe molecules on the outer surface of the particles or from the surrounding solution. Rigidochromism studies are used to evaluate the rigidity of the solvent matrix inside of the pore, and dynamic fluorescence anisotropy experiments are employed to determine the rotational diffusion freedom of the probe molecule. The data show that those probe molecules are neither completely free to move nor tightly attached to the pore wall, and their mobility is changed by altering the charge of the pore wall. PMID- 24803993 TI - Contraction-Induced Changes in Hydrogen Bonding of Muscle Hydration Water. AB - Protein-water interaction plays a crucial role in protein dynamics and hence function. To study the chemical environment of water and proteins with high spatial resolution, synchrotron radiation-Fourier transform infrared (SR-FTIR) spectromicroscopy was used to probe skeletal muscle myofibrils. Observing the OH stretch band showed that water inside of relaxed myofibrils is extensively hydrogen-bonded with little or no free OH. In higher-resolution measurements obtained with single isolated myofibrils, the water absorption peaks were relatively higher within the center region of the sarcomere compared to those in the I-band region, implying higher hydration capacity of thick filaments compared to the thin filaments. When specimens were activated, changes in the OH stretch band showed significant dehydrogen bonding of muscle water; this was indicated by increased absorption at ~3480 cm-1 compared to relaxed myofibrils. These contraction-induced changes in water were accompanied by splitting of the amide I (C=O) peak, implying that muscle proteins transition from alpha-helix to beta sheet-rich structures. Hence, muscle contraction can be characterized by a loss of order in the muscle-protein complex, accompanied by a destructuring of hydration water. The findings shed fresh light on the molecular mechanism of muscle contraction and motor protein dynamics. PMID- 24803994 TI - Magic Numbers in DNA-Stabilized Fluorescent Silver Clusters Lead to Magic Colors. AB - DNA-stabilized silver clusters are remarkable for the selection of fluorescence color by the sequence of the stabilizing DNA oligomer. Yet despite a growing number of applications that exploit this property, no large-scale studies have probed origins of cluster color or whether certain colors occur more frequently than others. Here we employ a set of 684 randomly chosen 10-base oligomers to address these questions. Rather than a flat distribution, we find that specific color bands dominate. Cluster size data indicate that these "magic colors" originate from the existence of magic numbers for DNA-stabilized silver clusters, which differ from those of spheroidal gold clusters stabilized by small-molecule ligands. Elongated cluster structures, enforced by multiple base ligands along the DNA, can account for both magic number sizes and color variation around peak wavelength populations. PMID- 24803995 TI - HNO/NO Conversion Mechanisms of Cu-Based HNO Probes with Implications for Cu,Zn SOD. AB - HNO has broad biological effects and pharmacological activities. Direct HNO probes for in vivo applications were recently reported, which are CuII-based complexes having fluorescence reporters with reaction to HNO resulting in CuI systems and the release of NO. Their coordination environments are similar to that in Cu,Zn-superoxide dismutase (SOD), which plays a significant role in cellular HNO/NO conversion. However, none of these conversion mechanisms are known. A quantum chemical investigation was performed here to provide structural, energetic, and electronic profiles of HNO/NO conversion pathways via the first CuII-based direct HNO probe. Results not only are consistent with experimental observations but also provide numerous structural and mechanistic details unknown before. Results also suggest the first HNO/NO conversion mechanism for Cu,Zn-SOD, as well as useful guidelines for future design of metal-based HNO probes. These results shall facilitate development of direct HNO probes and studies of HNO/NO conversions via metal complexes and metalloproteins. PMID- 24803996 TI - Signatures of the Protein Folding Pathway in Two-Dimensional Ultraviolet Spectroscopy. AB - The function of protein relies on their folding to assume the proper structure. Probing the structural variations during the folding process is crucial for understanding the underlying mechanism. We present a combined quantum mechanics/molecular dynamics simulation study that demonstrates how coherent resonant nonlinear ultraviolet spectra can be used to follow the fast folding dynamics of a mini-protein, Trp-cage. Two dimensional ultraviolet signals of the backbone transitions carry rich information of both local (secondary) and global (tertiary) structures. The complexity of signals decreases as the conformational entropy decreases in the course of the folding process. We show that the approximate entropy of the signals provides a quantitative marker of protein folding status, accessible by both theoretical calculations and experiments. PMID- 24803997 TI - Membrane Remodeling by Surface-Bound Protein Aggregates: Insights from Coarse Grained Molecular Dynamics Simulation. AB - The mechanism of curvature generation in membranes has been studied for decades due to its important role in many cellular functions. However, it is not clear if, or how, aggregates of lipid-anchored proteins might affect the geometry and elastic property of membranes. As an initial step toward addressing this issue, we performed structural, geometrical, and stress field analyses of coarse-grained molecular dynamics trajectories of a domain-forming bilayer in which an aggregate of lipidated proteins was asymmetrically bound. The results suggest a general mechanism whereby asymmetric incorporation of lipid-modified protein aggregates curve multidomain membranes primarily by expanding the surface area of the monolayer in which the lipid anchor is inserted. PMID- 24803998 TI - Longitudinal Study on Liver Functions in Patients with Thalassemia Major before and after Deferasirox (DFX) Therapy. AB - By performing regular blood transfusion and iron chelation therapy, most patients with beta thalassemia major (BTM) now survive beyond the third decade of life. Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are both important causes of liver pathology. Iron chelation with desferrioxamine (DFO) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox ( DFX ), an oral single dose therapy, has improved the compliance to chelation. AIMS: To study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX treatment in relation to ferritin level. METHODS: Only BTM patients with hepatitis negative screening (checked every year) and on treatment with DFO for at least five years and with DFX for four years were enrolled. Liver function tests including serum bilirubin, alanine transferase (ALT), aspartate transferase (AST), albumin, insulin-like growth factor - I (IGF-I) and serum ferritin concentrations were followed every six months in 40 patients with BTM. RESULTS: DFX treatment (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM; this was associated with a significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively, p < 0.05). IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels. The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis. CONCLUSIONS: Some impairment of liver function can occur in hepatitis negative thalassemic patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients. PMID- 24804000 TI - Immunology of tuberculosis. AB - MTB ranks as the first worldwide pathogen latently infecting one third of the population and the second leading cause of death from a single infectious agent, after the human immunodeficiency virus (HIV). The development of vigorous and apparently appropriate immune response upon infection with M. tuberculosis in humans and experimental animals conflict with failure to eradicate the pathogen itself and with its ability to undergo clinical latency from which it may exit. From a clinical standpoint, our views on MTB infection may take advantage from updating the overall perspective, that has quite changed over the last decade, following remarkable advances in our understanding of the manipulation of the immune system by M. tuberculosis and of the role of innate components of the immune response, including macrophages, neutrophils, dendritic cells and NK cells in the initial spread of MTB and its exit from latency. Scope of this review is to highlight the major mechanisms of MTB escape from immune control and to provide a supplementary translational perspective for the interpretation of innate immune mechanisms with particular impact on clinical aspects. PMID- 24803999 TI - Tuberculosis in patients with haematological malignancies. AB - Tuberculosis (TB) is an infectious disease that causes more than 1 million deaths worldwide every year. In addition, it is estimated that one third of the world population is infected with M. tuberculosis in a latent state, which involves an eventual risk of progressing to active TB disease. Patients with immunodeficiencies, such as those suffering from haematological malignancies, have a greater risk of progressing to TB disease once infected. It is estimated that the Relative Risk of TB disease in patients with hematologic malignancies is 2-40 times that of the general population. The diagnosis of TB in these patients is often challenging as they often present clinical characteristics that are distinct to those of patients without any other underlying disease. Mortality due to TB is higher. Therefore, it is recommended to diagnose latent TB infection and consider preventive therapy that could avoid the progression from a latent state to active TB disease. There are currently two methods for diagnosing latent TB infection: the Tuberculin Skin Test (TST) and the Interferon-Gamma Release Assays (IGRA). Due to the lack of sensitivity in patients with immunodeficient conditions, a combined TST-IGRA testing is probably the best way for latent TB diagnosis in order to gain sensitivity. Treatment of latent TB infection and TB disease should follow the general principles to that in the general population. PMID- 24804002 TI - Prognostic value of protease activated receptor-1 in children with acute lymphoblastic leukemia. AB - BACKGROUND: Acute Lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that proliferate and replace the normal hematopoietic cells of the bone marrow. Protease-activated receptors (PARs) comprise a family of trans-membrane G-protein coupled receptors. Protease-activated receptor 1 (PAR 1) is a typical member of this family of receptors that mediate cellular responses to thrombin and related proteases. PAR1 is expressed by a wide range of tumor cells and can promote tumor growth, invasion and metastasis. The aim of this work was to study the role of PAR-1 expression in newly diagnosed ALL patients. PATIENTS AND METHODS: This study was conducted on 44 children with newly diagnosed ALL who were admitted to Hematology Unit, Pediatric department, Tanta University Hospital including 24 males and 20 females with their age ranged from 4-17 years and their mean age value of 9.06+/-3.26. All patients were subjected to complete history taking, thorough clinical examination, bone marrow aspiration and flow cytometric analysis for detection of PAR-1 expression by malignant cells. RESULTS: PAR-1 was positive in 18 cases (41%) and negative in 26 cases (59%) of studied patients. This study showed no significant relation between PAR-1 expression and age, sex and most of the clinical data including hepatomegaly, splenomegaly and purpura while generalized lymphadenopathy was significantly higher in PAR-1 positive group. PAR-1 positive expression was associated with some bad prognostic laboratory parameters including higher hemoglobin, higher white blood cells, higher peripheral blood and bone marrow blast cells, higher serum LDH and lower platelets count. No significant association was detected between PAR-1 expression and immunophenotyping. There were significantly higher remission rates in PAR-1 negative group and significantly higher relapse and death rates in PAR-1 positive group. CONCLUSION: From this study, it could be concluded that PAR-1 expression on ALL cells represents an important adverse prognostic factor. RECOMMENDATIONS: PAR-1 expression should be routinely investigated for better prognostic assessment of ALL patients at diagnosis and should be taken in consideration in designing future therapeutic strategies based on patients- specific risk factors. PMID- 24804001 TI - Tyrosine kinase inhibitors and pregnancy. AB - The management of patients with chronic myeloid leukemia (CML) during pregnancy has become recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients; in fact, patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy, including the necessity to address issues relating to fertility and pregnancy. Physicians are frequently being asked for advice regarding the need for, and/or the appropriateness of, stopping treatment in order to conceive. In this report, we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for TKI treated CML patients, as well as how to manage a planned and/or unplanned pregnancy. PMID- 24804003 TI - Antifungal susceptibility testing: current role from the clinical laboratory perspective. AB - Despite availability of many antifungal agents, antifungal clinical resistance occurs, perhaps as a consequence of an infecting organism found to be resistant in vitro to one or more antifungals tested. From what derives the important current role of the in vitro antifungal susceptibility testing (AFST), that is to determine which agents are like to be scarcely effective for a given infection. Thus, AFST results, if timely generated by the clinical microbiology laboratory and communicated to clinicians, can aid them in the therapeutic decision making, especially for difficult-to-treat invasive candidiasis and aspergillosis. Although recently refined AFST methods are commercially available for allowing a close antifungal resistance surveillance in many clinical setting, novel assays such as flow cytometry or MALDI-TOF mass spectrometry are upcoming tools for AFST. Based on short-time antifungal drug exposure of fungal isolates, these assays could provide a reliable means for quicker and sensitive assessment of AFST. PMID- 24804004 TI - Bordetella bronchiseptica in the immunosuppressed population - a case series and review. AB - Organisms that are not known to cause serious infection in the immunocompetent population can, in fact, cause devastating illness in immunosuppressed neutropenic populations especially those who are undergoing hematopoietic stem cell transplantation (HSCT), and solid organ transplantation or a history of malignancy. One organism of interest isolated from immunosuppressed patients at our institution was Bordetella bronchiseptica. It is known to cause respiratory tract disease in the animal population which includes dogs, cats, and rabbits. This organism rarely causes serious infection in the immunocompetent population. However; in immunosuppressed patients, it can cause serious pulmonary disease. We present three cases of B. bronchiseptica pneumonia in patients with a history of malignancy. PMID- 24804005 TI - Acute Promyelocytic Leukemia (APL): Comparison Between Children and Adults. AB - The outcome of adults and children with Acute Promyelocytic Leukemia (APL) has dramatically changed since the introduction of all trans retinoic acid (ATRA) therapy. Based on the results of several multicenter trials, the current recommendations for the treatment of patients with APL include ATRA and anthracycline-based chemotherapy for the remission induction and consolidation, and ATRA combined with low-dose chemotherapy for maintenance. This has improved the prognosis of APL by increasing the complete remission (CR) rate, actually > 90%, decreasing the induction deaths and by reducing the relapse rate, leading to cure rates nowadays exceeding 80% considering both adults and children.1-9 More recently the combination of ATRA and arsenic trioxide (ATO) as induction and consolidation therapy has been shown to be at least not inferior and possibly superior to ATRA plus chemotherapy in adult patients with APL conventionally defined as non-high risk (Sanz score).10 Childhood APL has customarily been treated on adult protocols. Data from several trials have shown that the overall outcome in pediatric APL appears similar to that reported for the adult population; however, some clinical and therapeutic aspects differ in the two cohorts which require some important considerations and treatment adjustments. PMID- 24804007 TI - Gateway to multifaceted food science and nutrition challenges. PMID- 24804006 TI - Tuberculosis: medico-legal aspects. AB - Tuberculosis is a diffusive infectious disease whose typical behaviour differentiates it from other infectious diseases spread by human-to-human transmission (flu, chicken pox, cholera, etc.) that follow a classic epidemic pattern. Indeed, in the presence of a known source of Koch bacilli that is capable of spreading the bacteria by air, not all exposed individuals inhale the bacteria, not all those who inhale them absorb them, not all those who absorb the bacteria are unable to eliminate them, not all who are able to eliminate them do so using delayed hypersensitivity, not all those who react with delayed hypersensitivity suffer lasting tissue damage (among other things, minor), not all who suffer tissue damage have anatomical sequelae, and not all those who have anatomical sequelae, however minimal, become carriers of bacilli in the latent period. The vast majority (90-95%) of the latter - which are in any case a portion, not the totality of those exposed - remain asymptomatic throughout their lives and never develop active tuberculosis. Based on these biological characteristics and the legal concepts of "epidemic" and "disease," it becomes highly problematic, if not impossible, to assert both that tuberculosis can cause events of sufficient magnitude to be associated with the crime of "epidemic," and that the mere diagnosis of a latent tuberculosis infection is sufficient to assume the presence of an illness legally prosecutable in criminal proceedings or a disability prosecutable in civil proceedings. Furthermore, clinically apparent tuberculosis is a temporarily-and in some cases permanently-disabling condition, and in certain work environments, even with the difficulties caused by the lack of available effective diagnostic tools and the insidious behaviour of the disease in the early stages, targeted monitoring to identify other persons who may become ill is appropriate. PMID- 24804008 TI - Effects of agriculture production systems on nitrate and nitrite accumulation on baby-leaf salads. AB - Nitrate and nitrite are widespread contaminants of vegetables, fruits, and waters. The levels of these compounds are increased as a result of using organic wastes from chemical industries, domestic wastes, effluents, nitrogenous fertilizers, and herbicides in agriculture. Therefore, determining the nitrate and nitrite levels in biological, food, and environmental samples is important to protect human health and the environment. In this context, we set this study, in which we report the effect of production system (conventional and organic) on the accumulation of nitrates and nitrites in fresh baby-leaf samples. The average levels of the nitrate ([Formula: see text]) and nitrite ([Formula: see text]) contents in six different baby-leaf salads of a single species (green lettuce, red lettuce, watercress, rucola, chard, and corn salad) produced in organic and conventional agriculture system were evaluated. Spectrophotometric analytical method recently published was validated and used. Nitrates and nitrites were detected in all samples. The nitrates levels from organic production varied between 1.45 and 6.40 mg/kg fresh weight (FW), whereas those from conventional production ranged from 10.5 to 45.19 mg/kg FW. The nitrites content was lower than nitrates and ranged from 0.32 to 1.89 mg/kg FW in organic production system and between 0.14 and 1.41 mg/kg FW in conventional production system. Our results showed that the nitrate content was dependent on the agricultural production system, while for nitrites, this dependency was less pronounced. PMID- 24804009 TI - Physico-chemical and sensory properties of cookies made from blends of germinated pigeon pea, fermented sorghum, and cocoyam flours. AB - Cookies were produced from germinated pigeon pea, fermented sorghum, and cocoyam flour (CF) blends to determine their potentials in cookie manufacture. Ten flour formulations were produced and they were evaluated for their proximate and functional properties. Protein content ranged from 4.85% to 19.89% with 100% CF (100CF) having the least value, while 100% germinated pigeon pea flour (100GPF) had the highest value. Increase in levels of GPF to the flour blends resulted in increase in protein content of the blends. Cookies made with 100% fermented sorghum flour (100FSF) had the highest ash content of 2.73%, while cookies made with 100GPF had the least ash content. Energy values of the cookies ranged between 369.37 and 376.56 kcal/100 g, with cookie formulation 50%CF:50%FSF having the least value and cookies made with 16.7%CF:16.7%FSF:66.6GPF having the highest value. The control (cookies made with wheat) had the highest spread ratio of 24.13, while cookies made with 100FSF had the least spread ratio of 14.97. Cookies made with 100CF were the least fragile. Sensory ratings revealed that cookies containing up to 50% CF and above, compared favorably with those made with wheat flour. PMID- 24804010 TI - Supplementing long-chain n-3 polyunsaturated fatty acids in canned wild Pacific pink salmon with Alaska salmon oil. AB - Establishing n-3 polyunsaturated fatty acid contents in canned wild Alaska pink salmon products is challenging due to ample natural variation found in lipid content of pink salmon muscle. This study investigated the effect of adding salmon oil (SO) to canned pink salmon produced from fish exhibiting two opposite degrees of skin watermarking, bright (B) and dark (D). Specific goals of the study were to evaluate the benefits of adding SO to canned pink salmon with regard to nutritional value of the product, sensory characteristics, and the oxidative and hydrolytic stability of the lipids over thermal processing. Six groups of canned pink salmon were produced with variable levels of SO, either using bright (with 0, 1, or 2% SO) or dark (with 0, 2, or 4% SO) pink salmon. Compositional analysis revealed highest (P < 0.05) lipid content in sample B2 (8.7%) and lowest (P < 0.05) lipid content in sample D0 (3.5%). Lipid content of samples B0, B1, D2, and D4 was not significantly different (P > 0.05) ranging from 5.7% to 6.8%. Consequently, addition of SO to canned pink salmon allowed for consistent lipid content between bright and dark fish. Addition of 1% or 2% SO to canned bright pink salmon was not detrimental to the sensory properties of the product. It is recommended that canned bright pink salmon be supplemented with at least 1% SO, while supplementation with 2% SO would guarantee a minimum quantity of 1.9 g of n-3 fatty acids per 100 g of product. Addition of 4% SO to canned dark pink salmon was detrimental to product texture and taste, while supplementation with 2% SO did not negatively affect sensorial properties of the product. Accordingly, canned dark pink salmon should be supplemented with 2% SO so that a minimum n-3 fatty acids content of 1.5 g per 100 g of product. PMID- 24804011 TI - Comparative lethality kinetic curves and predictive models of F-value for Listeria monocytogenes using different sanitizers. AB - The objective of this work was to evaluate the kinetic of inactivation of Listeria monocytogenes using peracetic acid, chlorhexidine, and organic acids as active agent, determining the respective D-, Z-, and F-values. From our knowledge, these important results from an industrial view point are not available in the current literature, mainly for organic acids, pointing out the main contribution of the present work. Lower D-values were obtained for peracetic acid and chlorhexidine, compared with the organic acids. For the reduction of 6 log10 of L. monocytogenes using peracetic acid, at 0.2, 0.1, and 0.05% are necessary 7.08, 31.08, and 130.44 min of contact, respectively. The mathematical models of F-values showed that at concentrations lower than 0.15% one can verify an exponential increase in F-values, for both de chlorhexidine and peracetic acid. The organic acids presented a linear behavior, showing slight variation in F-values, is even more effective in under dosage. The results obtained are of fundamental importance in terms of industrial strategy for sanitization procedure, permitting to choose the best relation product concentration/exposure time, aiming at reducing costs without compromising the disinfectant efficiency. PMID- 24804012 TI - Effect of fat volume fraction, sodium caseinate, and starch on the optimization of the sensory properties of frankfurter sausages. AB - The effect of two important nonmeat constituents (starch and sodium caseinate) and fat content on the sensory perception of frankfurter sausages has been assessed for two mixture amounts (17% and 27%). A strong correlation among objective fattiness, elasticity, and chewiness has been established; these correlate negatively to consistency and hardness. This has been attributed to the protein gel disruption arising from local phase separations. Hedonic consistency, elasticity, and chewiness showed a very strong positive correlation to one another. Contour plots, based on responses of principal component axes, show that lard is important in increasing the objective sensory intensities of fattiness, chewiness, and elasticity, and for decreasing hardness and consistency. In higher lard proportions, caseinate and starch decrease the red color intensity and the acceptability of chewiness, elasticity, and consistency. Optimization of the component amounts was performed using response trace plots. After redundancy analysis, sensory and instrumental variables were found in very good mutual agreement; hardness was assessed as the most important mechanical variable, followed by chewiness. PMID- 24804013 TI - Applicability of near-infrared reflectance spectroscopy (NIRS) for determination of crude protein content in cowpea (Vigna unguiculata) leaves. AB - There is uncertainty on how generally applicable near-infrared reflectance spectroscopy (NIRS) calibrations are across genotypes and environments, and this study tests how well a single calibration performs across a wide range of conditions. We also address the optimization of NIRS to perform the analysis of crude protein (CP) content in a variety of cowpea accessions (n = 561) representing genotypic variation as well as grown in a wide range of environmental conditions in Tanzania and Uganda. The samples were submitted to NIRS analysis and a predictive calibration model developed. A modified partial least-squares regression with cross-validation was used to evaluate the models and identify possible spectral outliers. Calibration statistics for CP suggests that NIRS can predict this parameter in a wide range of cowpea leaves from different agro-ecological zones of eastern Africa with high accuracy (R (2)cal = 0.93; standard error of cross-validation = 0.74). NIRS analysis improved when a calibration set was developed from samples selected to represent the range of spectral variability. We conclude from the present results that this technique is a good alternative to chemical analysis for the determination of CP contents in leaf samples from cowpea in the African context, as one of the main advantages of NIRS is the large number of compounds that can be measured at once in the same sample, thus substantially reducing the cost per analysis. The current model is applicable in predicting the CP content of young cowpea leaves for human nutrition from different agro-ecological zones and genetic materials, as cowpea leaves are one of the popular vegetables in the region. PMID- 24804014 TI - Genetic characterization of Italian tomato varieties and their traceability in tomato food products-Sardaro-2012-Food Science & Nutrition-Wiley Online Library. AB - Genetic diversity underlies the improvement of crops by plant breeding. Landraces of tomato (Solanum lycopersicum L.) can contain valuable alleles not common in modern germplasms. The aim was to measure genetic diversity present in 47 most common tomato varieties grown in Italy, 35 were varieties used for processing and 12 were landraces considered "salad varieties". Furthermore, we demonstrated the possibility that the variety traceability can be extended through the entire production chain. Diversity was measured using 11 microsatellite markers and 94 genotypes. Among the markers used, a total of 48 alleles were detected. A dendrogram based on total microsatellite polymorphism grouped 47 varieties into three major clusters at 0.75 similarity coefficient, differentiating the modern varieties from tomatoes landraces. The DNA markers developed confirmed the possibility to support the genotype identification all along the tomato production chain. The number of alleles and genotypes identified in the present work is the largest considering papers on food traceability. PMID- 24804015 TI - Chemical composition of the giant red sea cucumber, Parastichopus californicus, commercially harvested in Alaska. AB - Giant red sea cucumbers, Parastichopus californicus, are commercially harvested in the U.S. Pacific Northwest; however, the nutritional and chemical properties of its edible muscle bands and body wall have not been fully elucidated. In particular are the fatty acid profiles of P. californicus tissues, which have not been documented. Sea cucumbers were delivered live and muscle bands and body wall freeze dried, vacuum packed, and stored at -30 degrees C until analyzed. Proximate composition of freeze-dried tissues varied greatly with muscle bands being composed of 68% protein, 12% ash, 9% carbohydrate, and 5% lipids, while the body wall was composed of 47% protein, 26% ash, 15% carbohydrate, and 8% lipids. The hydroxyproline, proline, and glycine contents of the body wall were much higher than those in muscle bands, consistent with the larger amount of connective tissue. Calcium, magnesium, sodium, and iron contents were higher in the body wall than those in muscle bands, whereas the opposite was observed for zinc content. Total long-chain n-3 fatty acid contents were 19% and 32% of total fatty acids in body wall and muscle bands, respectively. Muscle bands had higher content of eicosapentaenoic acid (20:5n-3) than body wall at 22.6% and 12.3%, respectively. High content of arachidonic acid (20:4n-6) was recorded in both body wall (7.1%) and muscle bands (9.9%). Overall, the fatty acid profiles of body wall and muscle bands of P. californicus resemble those described for other species; however, the distribution and occurrence of certain fatty acids is unique to P. californicus, being representative of the fatty acid composition of temperate-polar marine organisms. The chemical characterization of freeze-dried edible tissues from P. californicus demonstrated that these products have valuable nutritional properties. The body wall, a food product of lower market value than muscle bands, could be better utilized for nutraceutical and pharmaceutical applications. PMID- 24804016 TI - Cinnamon extract inhibits angiogenesis in zebrafish and human endothelial cells by suppressing VEGFR1, VEGFR2, and PKC-mediated MAP kinase. AB - Angiogenesis is a process of new blood vessel generation and under pathological conditions, lead to tumor development, progression, and metastasis. Many bioactive components have been studied for its antiangiogenic properties as a preventive strategy against tumor development. This study is focused on the effects of cinnamon extract in modulating the pathway involved in angiogenesis. Human umbilical vein endothelial cells (HUVEC) were treated with cinnamon extract at a concentration of 25 MUg/mL for 1, 3, or 6 h followed by treatment with phorbol ester (TPA) at a concentration of 10 nmol/L to induce mitogen-activated protein kinase (MAPK) expression. Results show that cinnamon extract inhibited TPA-induced phosphorylation of MAPK and AKT in a dose-dependent manner. Gene expression results in HUVEC showed that cinnamon extract treatment inhibited TPA induction of protein kinase C, PKCalpha and PKCeta messenger RNA (mRNA) expression in a dose-dependent manner along with suppression of vascular endothelial growth factor receptor 1 (VEGFR1/Flt1) and vascular endothelial growth factor receptor 2 (VEGFR2/KDR/Flk1) mRNA expression. Cinnamon extract was administered to zebrafish embryos during gastrulation at 6-8 h post fertilization (hpf). The embryos were observed for changes in morphology, toxicity, and blood vessel development. The intersegmental vessels in the zebrafish embryos were attenuated and underdeveloped at an effective cinnamon extract dose of 250 MUg/mL compared with the DMSO-treated control. Exposure to cinnamon extract for 36 h resulted in gross morphological deformities. The results suggest the effect of cinnamon extract on angiogenesis is mediated by PKC-dependent phosphorylation of MAPK. PMID- 24804017 TI - Sulfated glycosaminoglycans from crown-of-thorns Acanthaster planci - extraction and quantification analysis. AB - In this article, the novel inventive steps for the extraction and quantification of sulfated glycosaminoglycan (GAG) from Acanthaster planci starfish, generally known as crown-of-thorns (COT), are reported. Starfish have been implicated with collagenous distributions within their body anatomy, thus making it a prima facie fact searching for the possibility that GAGs can be isolated from COT. In this study, total-, N-, and O-sulfated GAGs were extracted from three anatomical regions of the COT (integument, internal tissue, and coelomic fluid) and comparison was made. The result showed that body region of COT seemed to contain higher amount of sulfated GAGs as opposed to the arm region (55.79 +/- 0.65 MUg/mg was the highest amount in the body extracted from its coelomic fluid and 32.28 +/- 3.14 MUg/mg was the highest amount in the arm extracted from its internal tissue). COT's integument and coelomic fluid from its body region possessed the highest total of sulfated GAGs content with no significant difference (P < 0.05) between the two. All GAGs from COT comprised a higher percentage of N-sulfated GAGs than its counterpart, the O-sulfated GAGs. When compared with a similar previous study that used sea cucumbers as the sulfated GAGs source, COT possessed more total sulfated GAGs content per milligram as compared with the sea cucumber generally. This result seems to unveil this marine species' advantage per se pertaining to GAGs extraction biomass applicability. Thus, COT could now be the better alternative source for production technology of total-, N-, and O-sulfated GAGs. PMID- 24804019 TI - Chemical characterization of commercial liquid smoke products. AB - The objective of this study was to determine important chemical characteristics of a full-strength liquid smoke, Code 10-Poly, and three refined liquid smoke products (AM-3, AM-10 and 1291) commercially available (Kerry Ingredients and Flavors, Monterey, TN). The pH of the products were significantly different (P < 0.05) and ranged from 2.3 (Code 10-Poly) to 5.7 (1291). The pH was inversely correlated with titratable acidity (R (2) = 0.87), which was significantly different (P < 0.05) among products ranging from 10.3% acetic acid (Code 10-Poly) to 0.7% acetic acid (1291). Total phenol content was quantified using the Gibbs reaction; the only liquid smoke containing appreciable level of phenolic compounds was Code 10-Poly at 3.22 mg mL(-1). Gas chromatography-mass spectrometry (GC-MS) analysis of liquid smoke dichloromethane extracts revealed that carbonyl-containing compounds were major constituents of all products, in which 1-hydroxy-2-butanone, 2(5H)-furanone, propanal and cyclopentenone predominated. Organic acids were detected by GC-MS in all extracts and correlated positively (R (2) = 0.98) with titratable acidity. The GC-MS data showed that phenolic compounds constituted a major portion of Code 10-Poly, and were detected only in trace quantities in 1291. The refined liquid smokes had lighter color, lower acidity, and reduced level of carbonyl-containing compounds and organic acids. Our study revealed major differences in pH, titratable acidity, total phenol content, color and chemical make-up of the full-strength and refined liquid smokes. The three refined liquid smoke products studied have less flavor and color active compounds, when compared with the full-strength product. Furthermore, the three refined products studied have unique chemical characteristics and will impart specific sensorial properties to food systems. Understanding the chemical composition of liquid smokes, be these refined or full strength products, is an important step to establish their functions and appropriate use in food systems. PMID- 24804020 TI - Sensory characteristics of high-amylose maize-resistant starch in three food products. AB - Type 2 resistant starch from high-amylose maize (HAM-RS2) is considered a functional ingredient due to its positive organoleptic and physiochemical modifications associated with food and physiological benefits related to human health. The sensory characteristics of three types of food products (muffins, focaccia bread, and chicken curry) with and without HAM-RS2 were evaluated using a 9-point hedonic scale. The HAM-RS2-enriched muffins, focaccia bread, and chicken curry contained 5.50 g/100 g, 13.10 g/100 g, and 8.94 g/100 g RS, respectively, based on lyophilized dry weight. The HAM-RS2-enriched muffin had higher moisture content and was perceived as being significantly moister than the control according to the sensory evaluation. The addition of HAM-RS2 to muffins significantly enhanced all sensory characteristics and resulted in a higher mean overall likeability score. The HAM-RS2-enriched focaccia bread appeared significantly darker in color, was more dense, and had the perception of a well done crust versus the control. A grainer texture was observed with the chicken curry containing HAM-RS2 which did not significantly affect overall likeability. We concluded that the addition of HAM-RS2 may not significantly alter consumer's acceptability in most food products. PMID- 24804018 TI - beta-Glucan supplementation, allergy symptoms, and quality of life in self described ragweed allergy sufferers. AB - This randomized, placebo-controlled, double-blind study compared the effects of daily supplementation for 4 week with 250 mg Wellmune WGP(r) beta-1,3/1,6-Glucan (WGP) with placebo 250 mg/day (rice flour) on physical and psychological health attributes of self-described "moderate" ragweed allergy sufferers. Study participants (mean age = 36 +/- 9 year; range 18-53 year) were recruited before the beginning of ragweed season (September) in Northeastern Ohio. Serum IgE concentration, allergy symptoms [via self-report, Visual Analog Scale (VAS), and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)], psychological well being [Profile of Mood States (POMS)], and physical function (RAND SF-36 Medical Outcomes Study) were measured immediately prior to and after supplementation with WGP (n = 24) or placebo (n = 24) for 4 weeks. Data were analyzed using repeated measures analyses of variance (ANOVA). Compared with placebo, WGP reduced total allergy symptoms (28%), symptom severity (52%), and symptom rating on the VAS (37%) (P < 0.05), but had no effect on serum IgE levels. As measured by the POMS, WGP increased participants' rating of vigor (10%), but reduced tension (34%), depression (45%), anger (41%), fatigue (38%), and confusion (34%) (P < 0.05). Study participants given WGP reported increased physical health (11%), energy (19%), and emotional well-being (7%) compared with study participants given the placebo (RAND SF-36 Medical Outcomes Study). The WGP group also reported decreased sleep problems (53%), reduced nasal symptoms (59%), eye symptoms (57%), non-nasal symptoms (50%), activities (53%), emotions (57%), and improved quality of life (QOL) (56%), as well as improved global mood state (13%). Supplementation with WGP for 4 weeks improved allergy symptoms, overall physical health, and emotional well-being compared with placebo in self-described "moderate" ragweed allergy sufferers during ragweed allergy season. PMID- 24804021 TI - Mass modeling of fig (Ficus carica L.) fruit with some physical characteristics. AB - Horticultural crops with the similar weight and uniform shape are in high demand in terms of marketing value, which are used as food. For proper design of grading systems, important relationships among the mass and other properties of fruits such as length, width, thickness, volumes, and projected areas must be known. The aim of this research was to measure and present some physical properties of fig fruits. In addition, Linear, Quadratic, S-curve, and Power models are used for mass predication of fig fruits based on measured physical properties. The results showed that all measured physical properties were statistically significant at the 1% probability level. For mass predication of fig fruits, the best and the worst models were obtained based on criteria projected area and thickness of the fruits with determination coefficients (R (2)) of 0.984 and 0.664, respectively. At last, from economical standpoint, mass modeling of fig fruits based on first projected area is recommended. PMID- 24804022 TI - Shelf life of air and modified atmosphere-packaged fresh tilapia (Oreochromis niloticus) fillets stored under chilled and superchilled conditions. AB - Optimal packaging and storage conditions for fresh tilapia fillets were established by evaluating sensory and microbiological changes, as well as monitoring physicochemical properties. Nile tilapia (Oreochromis niloticus) farmed in recirculation aquaculture system was filleted, deskinned, and packaged in air and 50% CO2/50% N2 prior to chilling and superchilling storage at 1 degrees C and -1 degrees C. Sensory analysis of cooked samples revealed a shelf life of 13-15 days for air-packaged fillets during storage at 1 degrees C and 20 days at -1 degrees C. At the end of shelf life in air-packaged fillets, total viable counts (TVC) and pseudomonads counts reached log 8 colony-forming units (CFU) g(-1). In 50% CO2/50% N2-packaged fillets, the lag phase and generation time of bacteria were extended and recorded counts were below the limit for consumption ( 0.05) in the cultivars studied while heating resulted in a significantly high reduction in the TIA level than in unheated condition. Polygonal or round shaped starch granules were in the range of 16.8 23.5 MUm and low level of starch digestion was shown in cultivars containing larger granules. Total amylose content lies in the range 15.4-19.6% and cultivars having higher percentage of amylose showed higher level of in vitro pancreatic digestion (Pallepola [swp4] and swp7). The starch digestibility of sweet potato flour was in the range of 36-55% and the highest digestion was observed in swp7. Orange fleshed cultivars (swp4 and swp7) were comparatively rich in nutrients and digestibility than the other three studied cultivars. PMID- 24804031 TI - Structure and physicochemical properties of starches in lotus (Nelumbo nucifera Gaertn.) rhizome. AB - The type and content of starch are believed to be the most critical factors in determining the storage and processing quality of lotus rhizome species, and the intention of this study is to survey the structure and properties of starches isolated from rhizomes of two lotus cultivars using X-ray powder diffraction, solid-state nuclear magnetic resonance spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscope, differential scanning calorimetry, and rapid viscosity analyzer (RVA). Starch in rhizome of cultivar Meirenhong exhibited C-type X-ray diffraction pattern, while starch in rhizome of cultivar Wawalian showed A-type pattern. (13)C cross polarization magic-angle spinning nuclear magnetic resonance ((13)C CP-MAS NMR) also confirmed the polymorphs. The relative crystallinity of two starches was quantitatively estimated from two methods and compared. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) results indicated that the external regions of the starch granules had a great level of ordered structure. Starch granules in Meirenhong showed oval-shaped granules, while starch granules in Wawalian were elongated and oval in shape with relatively large size. Gelatinization temperatures of starch in Meirenhong and Wawalian were 330.5 and 342.4 K, respectively, and the gelatinization temperature range of Meirenhong was significantly wider than that of Wawalian. Starch in rhizome of cultivar Meirenhong showed lower pasting temperature, lower hot and cool viscosities, lower setback, and higher peak viscosity and breakdown than those of Wawalian in RVA pasting profiles at 6% starch concentration. PMID- 24804033 TI - Effect of frying in different culinary fats on the fatty acid composition of silver carp. AB - The influence of frying with four different oils (sunflower oil, soybean oil, olive oil, and corn oil) on the fatty acid composition of silver carp was evaluated. The fat content of the fillets increased after frying while the moisture content decreased in all evaluated samples. Mean saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA) fatty acids, ?omega3, and ?omega6 contents of raw fish were 26.1 +/- 0.5, 52.1 +/- 1.1, 15.1 +/- 0.6, 8.9 +/- 0.1, and 6.1 +/- 0.4%, respectively. Frying led to exchange of fatty acids between the silver carp lipid and frying fats. As a result of interactions, MUFA, PUFA, ?omega6, and PUFA/SFA ratio of samples fried in sunflower, soybean, and corn oil significantly increased while the amounts of SFA decreased. Frying had a negative effect on the ?omega3/omega6 ratio but reduction in olive oil-fried samples is the least among the other samples. Except in soybean oil, long-chain omega3-PUFA content of samples was not affected by frying. PMID- 24804034 TI - Influence of good manufacturing practices on the shelf life of refrigerated fillets of tilapia (Oreochromis niloticus) packed in modified atmosphere and gamma-irradiated. AB - This study evaluated the influence of good manufacturing practices (GMP) on the shelf life of refrigerated fillets of Nile tilapia (Oreochromis niloticus) packed in modified atmosphere packaging (MAP) and irradiated. In a first series of experiments, 120 tilapia fillets kept under controlled sanitary conditions were purchased from a fish market managed by a cooperative. A second lot totaling 200 tilapia fillets was obtained under controlled storage conditions from a pilot plant. The combined effects of MAP (40% CO2 and 60% N2) and irradiation (1.5 kGy) were investigated by monitoring physical and chemical (total volatile bases and pH), bacteriological (aerobic heterotrophic mesophilic and psychrophilic bacteria) and sensory (acceptance test) changes in the samples. The quality of samples decreased with storage time regardless of the treatment, remaining higher in fillets produced in the pilot plant in comparison with the commercially produced fillets. The observed shelf life of nonirradiated commercially produced fillets was only 3 days, compared to 8 days for those produced in the pilot plant, probably due to GMP in the latter. It was concluded that, even with a combination of proven conservation methods for meats, the adoption of good manufacturing practices still remains essential before, during, and after the filleting process in order to ensure the effectiveness of the entire treatment. PMID- 24804036 TI - Quality assessment of butter cookies applying multispectral imaging. AB - A method for characterization of butter cookie quality by assessing the surface browning and water content using multispectral images is presented. Based on evaluations of the browning of butter cookies, cookies were manually divided into groups. From this categorization, reference values were calculated for a statistical prediction model correlating multispectral images with a browning score. The browning score is calculated as a function of oven temperature and baking time. It is presented as a quadratic response surface. The investigated process window was the intervals 4-16 min and 160-200 degrees C in a forced convection electrically heated oven. In addition to the browning score, a model for predicting the average water content based on the same images is presented. This shows how multispectral images of butter cookies may be used for the assessment of different quality parameters. Statistical analysis showed that the most significant wavelengths for browning predictions were in the interval 400 700 nm and the wavelengths significant for water prediction were primarily located in the near-infrared spectrum. The water prediction model was found to correctly estimate the average water content with an absolute error of 0.22%. From the images it was also possible to follow the browning and drying propagation from the cookie edge toward the center. PMID- 24804035 TI - Research into the functional components and antioxidant activities of North China rice wine (Ji Mo Lao Jiu). AB - Over the last decade, considerable experimental evidence has supported the view that grape wine and South China rice wine are rich in diverse nutrients and have powerful antioxidant activity. However, little research has been carried out for North China rice wine, of which Ji Mo Lao Jiu (JMLJ) is the outstanding representative. In this study, the functional components and antioxidant activity of JMLJ were investigated. Twenty-eight free amino acids were found in JMLJ, much more than that previously reported in other Chinese rice wines (16-21). Functional oligosaccharides (5290.222 mg/L), total phenols (722.431 +/- 10.970 mg/L), and mineral elements (9) were rich in JMLJ. When compared with synthetic antioxidants, such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), JMLJ showed effective 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging and reducing capacity. The results of this study lay the foundation for promoting the utilization of JMLJ and the development of North China rice wine in the food industry. PMID- 24804037 TI - Designer laying hen diets to improve egg fatty acid profile and maintain sensory quality. AB - The fatty acid composition of eggs is highly reflective of the diet of the laying hen; therefore, nutritionally important fatty acids can be increased in eggs in order to benefit human health. To explore the factors affecting the hen's metabolism and deposition of fatty acids of interest, the current research was divided into two studies. In Study 1, the fatty acid profile of eggs from Bovan White hens fed either 8%, 14%, 20%, or 28% of the omega-6 fatty acid, linoleic acid (LA) (expressed as a percentage of total fatty acids), and an additional treatment of 14% LA containing double the amount of saturated fat (SFA) was determined. Omega-6 fatty acids and docosapentaenoic acid (DPA) in the yolk were significantly (P < 0.05) increased, and oleic acid (OA) and eicosapentaenoic acid (EPA) were significantly decreased with an increasing dietary LA content. In Study 2, the fatty acid and sensory profiles were determined in eggs from Shaver White hens fed either (1) 15% or 30% of the omega-3 fatty acid, alpha-linolenic acid (ALA) (of total fatty acids), and (2) low (0.5), medium (1), or high (2) ratios of SFA: LA+OA. Increasing this ratio resulted in marked increases in lauric acid, ALA, EPA, DPA, and docosahexaenoic acid (DHA), with decreases in LA and arachidonic acid. Increasing the dietary ALA content from 15% to 30% (of total fatty acids) did not overcome the DHA plateau observed in the yolk. No significant differences (P >= 0.05) in aroma or flavor between cooked eggs from the different dietary treatments were observed among trained panelists (n = 8). The results showed that increasing the ratio of SFA: LA+OA in layer diets has a more favorable effect on the yolk fatty acid profile compared to altering the LA content at the expense of OA, all while maintaining sensory quality. PMID- 24804038 TI - Comparative sensory and proximate evaluation of spontaneously fermenting kunu zaki made from germinated and ungerminated composite cereal grains. AB - This study evaluated the sensory properties, proximate composition, and overall consumer acceptability of kunu-zaki using germinated and ungerminated Sorghum bicolor (sorghum), Pennisetum americanum (millet), and Digitaria exilis (acha) cereal grains. The three cereal grains were used in nongerminated and germinated composite and noncomposite proportions coded A (Acha), S (Sorghum), M (Millet), AS (Acha-Sorghum), AM (Acha-Millet), SM (Sorghum-Millet), ASG (Acha-Sorghum Germinated), AMG (Acha-Millet Germinated), and SMG (Sorghum-Millet Germinated). Proximate analysis determined the moisture content, ash, crude fiber, fat, and crude protein content of the fermented grains. The 9-point hedonic scale was used to judge the sensory parameters of taste, color, and aroma. The paired comparison test was used to judge consumer preference between kunu-zaki made from germinated grains and the ungerminated counterpart. Scores were statistically analyzed using the Kruskal-Wallis test in the SPSS analytical software package. Panelists ranked the ASG-coded drink highest in terms of taste and aroma, the AMG-coded drink highest in terms of color. SM ranked least in terms of taste; SMG ranked least in terms of aroma; and AM ranked the least in terms of color. Preference for each parameter was significantly different (P < 0.001). Panelists ranked overall preference for the drinks from the most liked to the least liked in the order ASG>AMG>A>AS>S>M>SMG>AM>SM. The overall preference for the drinks was also significantly different (P < 0.001). Panelists pairing both ungerminated drinks with the germinated drinks ranked the ungerminated drink AS as most preferred in terms of taste, color, and aroma above its germinated counterpart ASG with preference not significantly dependent on the parameters (P = 0.065 > 0.05). Ungerminated AM was also preferred above the germinated counterpart AMG in terms of taste, color, and aroma with preference not significantly dependent on parameters (P = 0.055 > 0.05). However, panelists showed preference for the taste and aroma of the germinated drink SMG but more preference for the color of the ungerminated drink SM with preference significantly dependent on the parameters (P = 0.028 < 0.05). Crude fiber values were higher - 11.3%, 13.1%, and 17.37% for SMG, AMG and ASG, respectively. Germination increased %Fat values slightly but the %Ash was relatively stable in both germinated and ungerminated drinks. Addition of germinated acha cereal grains to either sorghum or millet prior to fermentation offers desirable sensory and nutritional quality attributes in kunu zaki. PMID- 24804039 TI - Improvement in the traditional processing method and nutritional quality of traditional extruded cassava-based snack (modified Ajogun). AB - This study was carried out to investigate and improve the traditional processing method and nutritional quality of the traditional cassava snack (Ajogun). Cassava root (Manihot esculenta Crantz L.) of TME 419 variety was processed into mash (40% moisture content). The cassava mash was mixed into different blends to produce fried traditional "Ajogun", fried and baked extrudates (modified Ajogun) as snacks. These products were analyzed to determine the proximate composition including carbohydrate, fat, protein, fiber, ash, and moisture contents and functional properties such as bulk density. The results obtained for the moisture, fat, protein, and ash contents showed significant difference (P < 0.05) between the control sample and the extrudates. However, there was no significant difference (P > 0.05) in the carbohydrate and fiber contents between the three samples. There was no significant difference (P > 0.05) in the bulk density of the snacks. Also, sensory evaluation was carried out on the cassava-based snacks using the 9-point hedonic scale to determine the degree of acceptability. Results obtained showed significant difference (P < 0.05) between the extrudates and control sample in terms of appearance, taste, flavor, color, aroma, texture, and overall acceptability. The highest acceptability level of the product was at 8.04 for the control sample (traditional Ajogun). This study has shown that "Ajogun", which is a lesser known cassava product, is rich in protein and fat. PMID- 24804041 TI - Sensorial evolution of cassava flour (Manihot esculenta crantz) added to protein concentrate cassava leaves. AB - Cassava is regarded as the nutritional base of populations in developing countries, and flour, product made of cassava, is the most consumed in the world. The cassava leaves are very rich in vegetable proteins, but a big amount is lost in processing the crop. The objective of this study was to do a sensory evaluation of cassava flour to which a protein concentrate obtained from cassava leaves (CPML) was added. The CPML was obtained from cassava leaves by isoelectric precipitation and added to cassava paste for preparation of flour in three parts 2.5, 5, and 10%. The acceptance test was done by 93 consumers of flour, using hedonic scale of 7 points to evaluate characteristics like color, scent, flavor, bitterness, texture, and overall score. By the method of quantitative descriptive analysis (QDA), eight trained tasters evaluated the following characteristics: whitish color, greenish color, cassava flavor, bitter flavor, characteristic flavor, lumpiness, raw texture, leaf scent, and cassava scent. The acceptability test indicated that flour cassava with 2.5 was preferred. Whitish color, greenish color, cassava flavor, bitter flavor, salty flavor, characteristic flavor, lumpiness texture, raw texture, and the smell of the leaves and cassava flour were the main descriptors defined for flour cassava with CPML has better characteristics. PMID- 24804042 TI - Flaking process increases the NF-kappaB inhibition activity and melanoidin extractability of coffee. AB - Research on the health impacts of coffee has escalated. However, few studies were devoted to understanding the potential impact of mechanical processing on coffee's chemistry and subsequent health implications. Coffee flaking is a commonly used process to improve extractability and aroma characteristics. In this study, we studied the biochemical activity, chemical composition, and microstructure of coffee before and after flaking. We found that flaked coffee extract had 3.3-fold higher activity in inhibiting nuclear factor-kappa B (NF kappaB) activation than regular coffee extract. Interestingly, flaking did not significantly alter the amount of coffee phenolics. It increased coffee melanoidin, by 2.1-fold, which likely contributed to the observed higher activity in inhibiting NF-kappaB activation. Flaking crushed cell walls revealed by microscopy might possibly result in disruption of polysaccharide entanglement and release of high-molecular-weight compounds, such as melanoidins. Consequently, the increased melanoidin content in the brew resulted in the increased inhibition of NF-kappaB activation. Small molecules, like coffee phenolics, are readily soluble in water during coffee brewing even without flaking, suggesting that flaking has no effect on its extractability. In summary, our investigation revealed that flaking enhanced NF-kappaB inhibition activity, possibly through the release of melanoidins from crushed cell microstructures. PMID- 24804043 TI - Analyzing comprehensive palatability of cheese products by multivariate regression to its subdomains. AB - The present study explored the possibility of generating a novel sensory evaluation instrument for describing comprehensive food palatability via its subdomains (rewarding, cultural, and informational) while keeping physiological factors constant. Seventy-five Japanese participants were asked to taste cheese samples and to respond to a questionnaire that was developed to dissect the distinct subdomains of palatability. The subsequent factor analyses revealed that three major factors may serve as distinct subdomains of palatability: rewarding, cultural, and informational, although the informational factor was not sufficiently robust. Multivariate regression analysis on cheese samples with exactly the same ingredients but sold in different packages led to different comprehensive palatability ratings due to the contribution of the cultural, but not the rewarding, factor. These results suggest that palatability is not merely determined by the physical and chemical properties that are intrinsic to a food product itself, but also depends on psychological properties that can arise through interaction between humans and the food product. The current study presents the first experimental demonstration that palatability could be dissociated to its subdomains. PMID- 24804044 TI - Effect of gamma irradiation on physicochemical properties of stored pigeon pea (Cajanus cajan) flour. AB - The effect of gamma irradiation at various doses (5, 10, 15, 20 kGy) was observed on pigeon pea flour stored for 3 months on proximate composition, functional properties, and peroxide value. Sensory evaluation was also carried out on bean cake (moinmoin) made from nonirradiated and irradiated pigeon pea flour. The results showed that stored gamma-irradiated samples had significantly lower (P < 0.05) value of protein and little or no effect on moisture content. There were slight decreases in crude fiber and ash content of the irradiated samples compared with the control sample. The result of functional properties of the irradiated flours showed slight increase in water absorption capacity, swelling capacity and bulk density. The peroxide value of crude oil increased significantly with dose increases for the period of storage. The sensory evaluation of moinmoin samples prepared from irradiated pigeon pea flour showed no significant difference from the moinmoin sample prepared from nonirradiated flour. It can be concluded that gamma irradiation can extend the shelf life of pigeon pea flour. PMID- 24804045 TI - Formulation and nutritional evaluation of weaning food processed from cooking banana, supplemented with cowpea and peanut. AB - The possibility of processing a ready-to-eat nutrient-rich weaning food (WF) for infants within the age group of 0.5-0.9 years from cooking banana fortified with popular and affordable legumes (cowpea and peanut) was investigated with the aid of computer software and available technology in Nigeria. A composite of 47% cowpea, 40% ripe banana, and 13% peanut was processed, analyzed to compare the actual nutrient composition to that predicted by the software and that of two popular commercial WFs produced by Gerber Products Company: rice with banana (RB) and oats with banana (OB). Proximate composition was determined by Association of Official Analytical Chemists (AOAC) methods, in vitro digestibility by the pH drop method, and amino acid was determined using high performance liquid chromatography. Essential amino acid values were comparable to the predicted values. Protein and oil contents had values of 16.89% and 8.38%, 6.9% and 1.10%, and 12.03% and 3.16% for WF, RB, and OB, respectively. Octadecenoic (oleic) acid had the highest value of 3.65% followed by octadecadienoic (linoleic) acid with a value of 2.64% amounting to 76.69% of the total fatty acid. Total sugar content of WF was recorded as 15.96 g/100 g, with fructose having the highest value of 8.07 g/100 g, followed by dextrose with a value of 7.66 g/100 g. In vitro digestibility was in the order OB>WF>RB. The results show that it is feasible to produce precooked WF which has the potential to meet the nutritional needs of an infant, from local staples using computer-assisted technique and inexpensive technology available in Nigeria. PMID- 24804046 TI - New composite nitrite-free and low-nitrite meat-curing systems using natural colorants. AB - Nitrite-free and low-nitrite meat-curing systems were developed to eliminate or reduce nitrite in frankfurter-type sausages. Different composite meat-curing mixtures were formulated using cochineal and paprika as natural colorants, sodium hypophosphite (SHP) as antimicrobial agent, butylated hydroxyanisole (BHA) as antioxidant and sodium nitrite. The treatment, which contained 0.015% cochineal, most closely resembled the 120 ppm NaNO2 in its ability to create cured-meat color. BHA was found to be a strong antioxidant at the 30 ppm level in cooked sausages during refrigerated storage for 5 weeks. All treatments containing 40 ppm sodium nitrite were successful in replicating sensory attributes of frankfurter samples. Our findings support the use of SHP as possible antibotulinal agent in nitrite-free meat-curing systems. PMID- 24804047 TI - In-house-validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for survey of acrylamide in various processed foods from Korean market. AB - Acrylamide (AA) is a chemical found in starchy foods that have been cooked at high temperatures. The objective of this study is to monitor the levels of AA in a total of 274 samples of potato chips, chips (except potato chips), biscuits, French fries, breakfast cereals, chocolate products, tea, seasoned laver, and nut products sampled in Korean market. These processed foods include (1) potato chips, (2) chips (except potato chips), (3) biscuits, (4) French fries, (5) breakfast cereals, (6) chocolate products, (7) tea, (8) seasoned laver, and (9) nut products. Samples used for this study were cleaned up using HLB Oasis polymeric and Accucat mixed-mode anion and cation exchange solid-phase extraction cartridge. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was validated in-house as an efficient analytical method for the routine analysis of AA in various food products. AA was detected with a Fortis dC18 (1.7 MUm, 100 mm * 2.1 mm) column using 0.5% methanol/0.1% acetic acid in water as the mobile phase. Good results were obtained with respect to repeatability (RSDs < 5%). The recoveries obtained for a variety of food matrices ranged between 94.5% and 107.6%. Quantification during routine monitoring was sensitive enough to detect AA at a concentration of 10 MUg/kg. A total of 274 food samples were analyzed for AA. The AA levels in the food groups were in the following order: potato chips > French fries > biscuits > tea > chips (except potato chips) > seasoned laver > breakfast cereals > chocolate products > nut products. AA was detected at levels ranging from not detectable to 1435 MUg/kg. PMID- 24804049 TI - The bioaccessibility of eicosapentaenoic acid was higher from phospholipid food products than from mono- and triacylglycerol food products in a dynamic gastrointestinal model. AB - The bioaccessibility of eicosapentaenoic acid (EPA) in the forms of monoacylglycerol (EPA-MAG), triacylglycerol (EPA-TAG), and phospholipid (EPA-PL) during gastrointestinal passage was compared in this study using a dynamic gastrointestinal model (TIM system). The TIM system simulated the average upper gastrointestinal tract conditions of healthy human adults after intake of a meal (fed state conditions). In this study, the three EPA-rich oils were separately homogenized with full fat milk to obtain oil-in-water emulsions. Plain yogurt was added into the mixture at an emulsion/yogurt ratio of 4:1 (w/w) as the food matrix of the test products. The results show that the test meals containing EPA PL left the stomach compartment most efficiently in comparison with the gastric emptying of EPA-MAG and EPA-TAG. The PLs also showed a significantly (P < 0.05) higher bioaccessibility of EPA (75-80%) in comparison with MAG (30%) and TAG (38%). The better gastric emptying of EPA-PL was likely related to the more stable emulsion of EPA-PL in the test meal. EPA-PL was delivered within the meal matrix into the duodenum instead of floating on the top of the test meal matrix. EPA-MAG had the highest amount of EPA that did not leave the stomach (68% of the test meal). The results from this work indicate that EPA-PL is a more effective form of EPA for a higher lipid bioaccessibility than MAG and TAG under the test conditions. PMID- 24804050 TI - The inhibitory effect of a fermented papaya preparation on growth, hydrophobicity, and acid production of Streptococcus mutans, Streptococcus mitis, and Lactobacillus acidophilus: its implications in oral health improvement of diabetics. AB - Fermented papaya preparation (FPP) is a "natural health product." The high incidence of dental caries, gingivitis, periodontitis, and oral microbial infection cases among patients with diabetes mellitus continues to prevail. The potential role of FPP against common oral microbiota (Streptococcus mutans, Streptococcus mitis, and Lactobacillus acidophilus) isolated from the human oral cavity was investigated using in vitro simulation models of dental plaque and caries. FPP showed an inhibitory effect against the growth (at 0.05 mg/mL: S. mutans: -6.9%; S. mitis: -4.47%, P < 0.05), acid production (at 0.05 mg/mL: S. mutans: +6.38%; L. acidophilus: +2.25%), and hydrophobicity (at 50 mg/mL: S. mutans: 1.01%, P < 0.01; S. mitis: 7.66%, P < 0.05) of tested microbiota. The results of this study suggest that low doses of FPP may be a suitable complement to good oral hygiene practice for the effective prevention of dental caries, plaque, and gingivitis. The functional application of FPP as a constituent of a balanced diet and active lifestyle can make a positive contribution to the oral health status and well-being of patients with diabetes. PMID- 24804051 TI - Searching the best equilibrium moisture equation for lettuce seeds using measures of curvature and bias. AB - In the present work, we performed a discrimination analysis of the nonlinear equations used to describe sorption isotherms of the lettuce seeds. The equilibrium data were obtained by the static method using saturated salt solutions. The best model to describe the equilibrium moisture of lettuce seeds was selected using measures of curvature and bias. The obtained results showed that the Copace equation was the best model in terms of nonsignificance for bias and nonlinearity measures. PMID- 24804052 TI - Application of Lactobacillus acidophilus (LA 5) strain in fruit-based ice cream. AB - A study was performed to apply a probiotic strain into fermented ice cream mix with suitable fruit bases to develop a value-added product with a substantial level of viable organisms for a sufficient shelf life. Pure direct vat strain culture of Lactobacillus acidophilus (LA 5) in freeze-dried form was inoculated into a mixture of ice cream, frozen, and the number of viable organisms during frozen storage for a period of time was enumerated, using turbidity measurements with a spectrophotometer. An ice cream sample prepared without the probiotic culture was compared with the test sample for quality, by testing the basic quality parameters for ice cream. Results show a reduction in the over run of the probiotic ice cream compared to the nonprobiotic ice cream. Significantly high level (P < 0.05) of total solids (42%), proteins (16.5%), and titratable acidity (2.2%) was observed in the test sample compared to the nonprobiotic ice cream. Significantly low pH level in the probiotic sample may be due to the lactic acid produced by the probiotic culture. No significant difference (P > 0.05) in the fat content in the two types of ice cream was observed. A significantly low level (P < 0.05) of melting in the probiotic one may have resulted from less over run, than the nonprobiotic sample. Rapid reduction in the viable cells during frozen storage occurred at -18 degrees C and gradual adaptation occurred over the first 4 weeks. At the 10th week, 1.0 * 10(7) numbers of viable organisms were present in 1 g of the probiotic ice cream. Results show the presence of a sufficient number of viable organisms in the product for the 10-week period, which would be beneficial to consumers. PMID- 24804053 TI - Loop-mediated isothermal amplification (LAMP) method for detection of genetically modified maize T25. AB - The loop-mediated isothermal amplification (LAMP) assay indicates a potential and valuable means for genetically modified organism (GMO) detection especially for its rapidity, simplicity, and low cost. We developed and evaluated the specificity and sensitivity of the LAMP method for rapid detection of the genetically modified (GM) maize T25. A set of six specific primers was successfully designed to recognize six distinct sequences on the target gene, including a pair of inner primers, a pair of outer primers, and a pair of loop primers. The optimum reaction temperature and time were verified to be 65 degrees C and 45 min, respectively. The detection limit of this LAMP assay was 5 g kg(-1) GMO component. Comparative experiments showed that the LAMP assay was a simple, rapid, accurate, and specific method for detecting the GM maize T25. PMID- 24804054 TI - Antioxidant assays - consistent findings from FRAP and ORAC reveal a negative impact of organic cultivation on antioxidant potential in spinach but not watercress or rocket leaves. AB - Watercress (Rorippa nasturtium-aquaticum), wild rocket (Diplotaxis tenuifolia), and spinach (Spinacia oleracea) are commercial crops reported to have high concentrations of antioxidants, possibly contributing to disease prevention following human consumption. Following analysis of supermarket-purchased salad leaves, we report the antioxidant content potential of these species using two comparable techniques assessing the consistency between the assays - by the ferric reducing antioxidant power (FRAP) assay and the oxygen radical absorbance capacity (ORAC) assay. The leaves were harvested from both conventionally and organically managed crops, to investigate whether organic agriculture results in improved crop quality. Watercress had the highest FRAP and ability to scavenge free radicals, followed by spinach and rocket. For watercress and rocket, there was no significant effect of organic agriculture on FRAP and ORAC, but for spinach, the antioxidant potential was reduced and this was significant at the 5% level of probability for FRAP but not ORAC, although the trend was clear in both tests. We conclude that there is variation in salad crop antioxidant potential and that FRAP and ORAC are useful techniques for measuring antioxidants in these salad crops with similar ranking for each salad crop studied. PMID- 24804055 TI - Low-fat frankfurters from protein concentrates of tilapia viscera and mechanically separated tilapia meat. AB - In order to develop a healthy low-fat frankfurter-type sausage, different formulations were developed with tilapia viscera surimi (T1) and two with mechanically separated tilapia meat (MSTM) surimi (T2 and T3), all without pig lard addition. Due to technological problems observed for T1 sausage during cooking, it was not further investigated. The functionality of the other two formulations was evaluated based on proximate composition, pH, water activity, and texture. Finally, microbiological and sensory analyses based on acceptance tests were performed. Listeria monocytogenes and Salmonella spp. were found to be absent. T2 showed higher frequencies for the attributes color (90.0%) and overall acceptability (86.7%), while T3 showed higher frequencies for taste (86.7%) and texture (96.7%). The surimi concentration was reflected in the physical properties of the sausages. It was found that the addition of MSTM surimi to sausage favored greater cutting strength (3.9 N for T2 and 4.9 N for T3). Beyond the surimi utilization, the total replacement of pig lard by cassava starch and soybean protein had also contributed with the texture properties. PMID- 24804056 TI - Comparative study on nutrient composition, phytochemical, and functional characteristics of raw, germinated, and fermented Moringa oleifera seed flour. AB - Moringa oleifera seeds were processed as raw M. oleifera (RMO), germinated M. oleifera (GMO), and fermented M. oleifera (FMO), and were evaluated for proximate, minerals, amino acids, fatty acids, phytochemicals/antinutrients, and functional properties. Protein content of GMO (23.69 +/- 0.11 g/100 g) was higher than FMO (21.15 +/- 0.08 g/100 g) and that of RMO (18.86 +/- 0.09 g/100 g) (P < 0.05), respectively. Energy value of FMO (465.32 +/- 0.48 kcal) was higher than GMO (438.62 +/- 0.12 kcal) and that of RMO (409.04 +/- 1.61 kcal), respectively. Mineral contents in GMO were significantly higher in iron, sodium, potassium, magnesium, and copper, while FMO were higher in calcium, phosphorus, and magnesium, and both were significantly lower than those in RMO (P < 0.05). Total essential amino acids (TEAAs) in FMO (31.07 mg/g crude protein) were higher than in GMO (26.52 mg/g crude protein), and were higher than that in RMO (23.56 mg/g crude protein). Linoleic acid (58.79 +/- 0.02-62.05 +/- 0.01 g/100 g) and behenic acid (0.13 +/- 0.00-0.20 +/- 0.06 g/100 g) were the predominant and least fatty acids, respectively. Phytochemical/antinutrient compositions in FMO samples were significantly lower than GMO, and both were significantly lower when compared with RMO samples (P < 0.05). The bulk density (pack and loose), foaming capacity, swelling capacity, and water absorption capacity (WAC) of FMO were significantly higher than those of GMO, and there was no significant difference between GMO and RMO samples. The study established that fermentation processing methods increased the protein content, essential amino acid, and polyunsaturated fatty acid profiles, and reduced antinutrient compositions of M. oleifera seed than germination processing techniques; hence, fermentation techniques should be encouraged in processing moringa seeds in food processing. PMID- 24804057 TI - Production and evaluation of Ighu from selected cassava varieties using a motorized shredder-a response surface analysis. AB - Cassava varieties, TME419, TMS30572, and TMS98/0505, were planted and harvested at 3-month intervals of 10, 13, and 16 months, respectively. A central composite response surface design was used to study the effects of the variables cassava variety, harvesting time, and shredding aperture on selected physicochemical properties of Ighu samples. Regression models showed that the experimental variables had significant (P <= 0.05) effects on the hydrogen cyanide, moisture content, thickness, and width of dry Ighu. Minimum values obtainable for the physicochemical properties were 8.1195 mg/kg (10-month, 3-mm shredding aperture from TMS98/0505), 7.58% (13-month, 3-mm shredding aperture from TME419), 0.19 mm (13-month, 3-mm shredding aperture and from TMS30572), and 0.99 mm (16-month, 3 mm shredding aperture from TME419) for hydrogen cyanide, moisture content, thickness, and width, respectively. In addition, Ighu produced from 3-mm shredding aperture (TMS30572) at 10-month harvest was the most preferred of all the samples. PMID- 24804059 TI - Establishing a case for improved food phenolic analysis. AB - Future phenolic research findings using a multidisciplinary approach will ensure profitability and sustainability of specialty crop industries, while also improving the nutritional and economic choices available to increasingly health- and environmentally conscious consumers. Recent examples of phenolics used in commercial and research scenarios, and new phenolic research discoveries are discussed. Despite being a heavily researched topic, there remains a need to identify, develop, and define analyses targeted for specific quality-related plant metabolites. PMID- 24804060 TI - Effect of heat processing on selected grain amaranth physicochemical properties. AB - Grain amaranth is a pseudocereal with unique agricultural, nutritional, and functional properties. This study was undertaken to determine the effect of different heat-processing methods on physicochemical and nutraceutical properties in two main grain amaranth species, of Amaranthus hypochondriacus L. and Amaranthus cruentus L. Grains were prepared by roasting and popping, milled and analyzed for changes in in vitro protein digestibility, gruel viscosity, pasting characteristics, antioxidant activity, flavonoids, and total phenolics. In vitro protein digestibility was determined using the pepsin-pancreatin enzyme system. Viscosity and pasting characteristics of samples were determined using a Brookfield Viscometer and a Rapid Visco Analyzer, respectively. The grain methanol extracts were analysed for phenolics using spectrophotometry while antioxidant activity was determined using the DPPH (2,2-diphenyl-1 picrylhydrazyl) method. Heat treatment led to a reduction in protein digestibility, the effect being higher in popped than in roasted samples. Viscosities for roasted grain amaranth gruels were significantly higher than those obtained from raw and popped grain amaranth gruels. The results for pasting properties were consistent with the results for viscosity. In both A. hypochondriacus L. and A. cruentus L., the order of the viscosity values was roasted>raw>popped. The viscosities were also generally lower for A. cruentus L. compared to A. hypochondriacus L. Raw samples for both A. hypochondriacus L. and A. cruentus L. did not significantly differ in total phenolic content (TPC), total flavonoid content (TFC), and total antioxidant activity values. Thermal processing led to an increase in TFC and antioxidant activity. However, TPC of heat-processed samples remained unchanged. From the results, it can be concluded that heat treatment enhances antioxidant activity of grain amaranth and causes rheological changes dependent on the nature of heat treatment. PMID- 24804061 TI - Effects of sodium benzoate on storage stability of previously improved beverage from tamarind (Tamarindus indica L.). AB - The effect of sodium benzoate on the quality attributes of improved tamarind beverage during storage was investigated. Tamarind beverages were produced according to a previously reported improved method, with or without chemical preservatives (100 mg/100 mL sodium benzoate). Tamarind beverage produced according to traditional processing method served as the control. The tamarind beverages were stored for 4 months at room (29 +/- 2 degrees C) and refrigerated (4-10 degrees C) temperatures. Samples were analyzed, at regular intervals, for chemical, sensory, and microbiological qualities. Appearance of coliforms or overall acceptability score of 5.9 was used as deterioration index. The control beverages deteriorated by 2nd and 10th days at room and refrigerated temperatures, respectively. Improved tamarind beverage produced without the inclusion of sodium benzoate was stable for 3 and 5 weeks at room and refrigerated temperatures, respectively. Sodium benzoate extended the shelf life of the improved tamarind beverage to 6 and 13 weeks, respectively, at room and refrigerated temperatures. PMID- 24804062 TI - Use of pilot plant scale continuous fryer to simulate industrial production of potato chips: thermal properties of palm olein blends under continuous frying conditions. AB - Binary blends of palm olein (PO) with sunflower oil (SFO), canola oil (CNO), and cottonseed oil (CSO) were formulated to assess their stability under continuous frying conditions. The results were then compared with those obtained in PO. The oil blends studied were: (1) 60:40 for PO + SFO; (2) 70:30 for PO + CNO; and (3) 50:50 for PO + CSO. The PO and its blends were used to fry potato chips at 180 degrees C for a total of 56 h of operation. The evolution of analytical parameters such as tocols, induction period, color, p-anisidine value, free fatty acid, smoke point, polar compounds, and polymer compounds were evaluated over the frying time. Blending PO with unsaturated oils was generally proved to keep most qualitative parameters comparable to those demonstrated in PO. Indeed, none of the oils surpassed the legislative limits for used frying. Overall, it was noted that oil containing PO and SFO showed higher resistance toward oxidative and hydrolytic behaviors as compared to the other oil blends. PMID- 24804063 TI - Hydration kinetics of direct expanded tef flour breakfast cereals in water and milk. AB - Hydration kinetics of tef flour breakfast cereals extruded at barrel temperatures of 110, 130, and 150 degrees C was investigated by hydrating them in water and whole milk at 25 degrees C (+/-1 degrees C). The normalized Weibull model described the rehydration characteristics of the extrudates in water and milk adequately (R (2) = 0.98-0.99). Water absorption rate was significantly (P < 0.05) influenced by barrel temperature where extrudates processed at 150 degrees C barrel temperature exhibited high water absorption rate followed by those extruded at 130 and 100 degrees C, respectively. Hydration rate and equilibrium moisture content were higher for samples hydrated in water than those in milk. In view of the values of the shape parameter beta, the hydration process is predominantly controlled by diffusion (beta = 0.40-0.51) for samples extruded at 110 degrees C whereas external resistance to mass transfer dominated (beta = 0.60 0.73) those extruded using 150 and 130 degrees C. Extrudates processed at 130 and 150 degrees C exhibited better hydration characteristics. Thus, these temperature ranges could be used to produce extruded products from tef. PMID- 24804064 TI - Relating genes in the biosynthesis of the polyphenol composition of Andean colored potato collection. AB - The objective of this study was to evaluate total antioxidant capacity (TAC), total phenolic content (TPH), and the identification of anthocyanidin and polyphenolic compounds in 13 colored potatoes collected from the Andean region of Bolivia, and understand how the chemical composition correlated with the botanical classification and molecular characterization of genes, ans (anthocyanidin synthase) and stan1 (Solanum tuberosum anthocyanidin synthase), associated with the synthesis of anthocyanidins. The results show the existence of a limited correlation between botanical classification, based on morphological identification and polyphenol composition. No association between genetic grouping of the ans and stan genes and botanical classification was found. However, it was possible to identify a correlation between the ans gene clades and the levels of anthocyanidins as well as of other polyphenols. Thus, this result confirms the concept that potato color can be used in the search for high polyphenol potato cultivars. PMID- 24804065 TI - Antioxidant activities of chick embryo egg hydrolysates. AB - Chick embryo egg hydrolysates (CEEH) were obtained by enzymatic hydrolysis of chick embryo egg in vitro-simulated gastrointestinal digestion. The antioxidant activities of CEEH were investigated by employing three in vitro assays, including the 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate)/1,1-diphenyl-2 picrylhydrazyl (ABTS/DPPH)/hydroxyl radical-scavenging assays. The radical scavenging effect of CEEH (1.0 mg/mL) was in a dose-dependent manner, with the highest trolox equivalent antioxidant capacity for ABTS, DPPH, and that of hydroxyl radicals found to be 569, 2097, and 259.6 MUmol/L, respectively; whereas the trolox equivalent antioxidant capacity of unhatched egg for ABTS, DPPH, and that of hydroxyl radicals were found to be 199, 993, and 226.5 MUmol/L, respectively. CEEH showed stronger scavenging activity than the hydrolysates of unhatched egg against free radicals such as ABTS, DPPH, and hydroxyl radicals. The antioxidant amino acid analysis indicated that the 14-day CEEH possess more antioxidant amino acids than that of the unhatched egg. In addition, essential amino acids analysis showed that the 14-day CEEH have the highest nutritional value. Combined with the results of the amino acid profiles, CEEH were believed to have higher nutritive value in addition to antioxidant activities than the unhatched egg. PMID- 24804066 TI - Investigation of gelatin/multi-walled carbon nanotube nanocomposite films as packaging materials. AB - Gelatin composite films were prepared from gelatin solutions (10% w/v) containing multi-walled carbon nanotubes (MWCNT, 0.5, 1, 1.5, and 2% w/w gelatin) as nanofiller. The water solubility, water swelling, water uptake, water vapor permeability (WVP), mechanical, and antibacterial properties of the films were examined. Water solubility, water swelling, water uptake, and WVP for gelatin films were 45 +/- 1%, 821 +/- 42%, 45 +/- 1.1%, and 0.4 +/- 0.022 g mm/m(2) kPa h, respectively. Incorporation of MWCNT caused a significant decrease in water solubility, water swelling, water uptake, and WVP. Gelatin/MWCNT films containing 1-1.5% MWCNT showed the lowest water vapor transmission. Tensile strength, elongation at break, and Young's modulus for gelatin films were 13.4 +/- 1.2 MPa, 95 +/- 5%, and 45.4 +/- 7 MPa, respectively. Incorporation of MWCNT caused a significant increase in tensile strength and decrease in the elongation at break. The largest mechanical strength was found at 1.5% MWCNT. All gelatin/MWCNT films showed significant antibacterial activities against both gram-positive and gram negative bacteria. Our results suggest that the gelatin/MWCNT composites films could be used as a very attractive alternative to traditional materials for different biomedical and food applications. PMID- 24804067 TI - Food science & nutrition. PMID- 24804068 TI - Rice antioxidants: phenolic acids, flavonoids, anthocyanins, proanthocyanidins, tocopherols, tocotrienols, gamma-oryzanol, and phytic acid. AB - Epidemiological studies suggested that the low incidence of certain chronic diseases in rice-consuming regions of the world might be associated with the antioxidant compound contents of rice. The molecules with antioxidant activity contained in rice include phenolic acids, flavonoids, anthocyanins, proanthocyanidins, tocopherols, tocotrienols, gamma-oryzanol, and phytic acid. This review provides information on the contents of these compounds in rice using a food composition database built from compiling data from 316 papers. The database provides access to information that would have otherwise remained hidden in the literature. For example, among the four types of rice ranked by color, black rice varieties emerged as those exhibiting the highest antioxidant activities, followed by purple, red, and brown rice varieties. Furthermore, insoluble compounds appear to constitute the major fraction of phenolic acids and proanthocyanidins in rice, but not of flavonoids and anthocyanins. It is clear that to maximize the intake of antioxidant compounds, rice should be preferentially consumed in the form of bran or as whole grain. With respect to breeding, japonica rice varieties were found to be richer in antioxidant compounds compared with indica rice varieties. Overall, rice grain fractions appear to be rich sources of antioxidant compounds. However, on a whole grain basis and with the exception of gamma-oryzanol and anthocyanins, the contents of antioxidants in other cereals appear to be higher than those in rice. PMID- 24804069 TI - Chemical characterization of Brickellia cavanillesii (Asteraceae) using gas chromatographic methods. AB - A methanol extract of lyophilized Brickellia cavanillesii was quantitatively analyzed using gas chromatographic (GC) techniques. The chromatographic methods employed were (i) GC-flame ionization detector (GC-FID), (ii) GC-mass spectrometry (GC-MS), and (iii) purge and trap GC-MS (P&T GC-MS). Thirteen compounds were identified with a quality match of 90% and above using GC-MS. The compounds were (1) Cyclohexene, 6-ethenyl-6-methyl-1-(1-methylethyl)-3-(1 methylethylidene)-, (S)-; (2) Bicylo (2.2.1) heptan-2-one, 1, 7, 7-trimethyl-(1S, 4S)-; (3) Phenol, 2-methoxy-4-(1-propenyl)-; (4) Benzene, 1-(1, 5-dimethyl-4 hexenyl)-4-methyl-; (5) Naphthalene, 1, 2, 3, 5, 6, 8a-hexahydro4, 7-dimethyl-1-1 (1-methylethyl)-, (1S-cis)-; (6) Phenol, 2-methoxy-; (7) Benzaldehyde, 3-hydroxy 4-methoxy-; (8) 11, 13-Eicosadienoic acid, methyl ester; (9) 2 Furancarboxaldehyde, 5-methyl-; (10) Maltol; (11) Phenol; (12) Hydroquinone; (13) 1H-Indene, 1-ethylideneoctahydro-7a-methyl-, (1E, 3a.alpha, 7a.beta.). Other compounds (14) 3-methyl butanal; (15) (D)-Limonene; (16) 1-methyl-4-(1-methyl ethyl) benzene; (17) Butanoic acid methyl ester; (18) 2-methyl propanal; (19) 2 butanone; (20) 2-pentanone; and (21) 2-methyl butane were also identified when P&T GC-MS was performed. Of the 21 compounds identified, 12 were validated using chemical standards. The identified compounds were found to be terpenes, derivatives of terpenes, esters, ketones, aldehydes, and phenol-derived aromatic compounds; these are the primary constituents of the essential oils of many plants and flowers. PMID- 24804070 TI - Sensory evaluation and consumer acceptance of naturally and lactic acid bacteria fermented pastes of soybeans and soybean-maize blends. AB - Fermented pastes of soybeans and soybean-maize blends were evaluated to determine sensory properties driving consumer liking. Pastes composed of 100% soybeans, 90% soybeans and 10% maize, and 75% soybeans and 25% maize were naturally fermented (NFP), and lactic acid bacteria fermented (LFP). Lactic acid bacteria fermentation was achieved through backslopping using a fermented cereal gruel, thobwa. Ten trained panelists evaluated intensities of 34 descriptors, of which 27 were significantly different (P < 0.05). The LFP were strong in brown color, sourness, umami, roasted soybean-and maize-associated aromas, and sogginess while NFP had high intensities of yellow color, pH, raw soybean, and rancid odors, fried egg, and fermented aromas and softness. Although there was consumer (n = 150) heterogeneity in preference, external preference mapping showed that most consumers preferred NFP. Drivers of liking of NFP samples were softness, pH, fermented aroma, sweetness, fried egg aroma, fried egg-like appearance, raw soybean, and rancid odors. Optimization of the desirable properties of the pastes would increase utilization and acceptance of fermented soybeans. PMID- 24804071 TI - Chemical and functional properties of cassava starch, durum wheat semolina flour, and their blends. AB - High-quality cassava starch (HQCS) produced from high-yielding low-cyanide improved cassava variety, TMS 30572, was mixed with durum wheat semolina (DWS) on a replacement basis to produce flour samples containing 0, 20, 30, 50, 70, and 100% cassava starch. They were analyzed for chemical composition (proximate, amylose, free sugars, starch, wet gluten, and cyanide) and functional properties (pasting, swelling power, solubility, water absorption, water binding, starch damage, diastatic and alpha-amylase activity, dough mixing, and stability). Protein, carbohydrate, fat, and ash of flour samples ranged from 0.75-12.31%, 70.87-87.80%, 0.95-4.41%, and 0.12-0.83%, respectively. Cyanide levels in all the flour samples were less than 0.1 ppm. Amylose content varied between 19.49% for cassava and 28.19% for wheat, correlating significantly with protein (r = 0.95, P = 0.004) and ash contents (r = 0.92, P = 0.01) at 5%. DWS and HQCS had similar pasting temperatures (50.2-53 degrees C), while other pasting properties increased with increasing levels of HQCS. Dough mixing stability of samples decreased with increasing levels of HQCS. All the flour samples had alpha-amylase activity greater than 200. Both HQCS and DWS compare favorably well in swelling power (7.80-9.01%); but the solubility of wheat starch doubled that of cassava. Starch damage varied between 3.3 and 7.2 AACC for semolina and starch, with the latter having higher absorption rate (97%), and the former, higher absorption speed (67 sec). Results obtained showed positive insight into cassava-wheat blend characteristics. Data thus generated provide additional opportunities of exploiting cassava utilization and hence boost its value-addition potentials for product development. PMID- 24804072 TI - Aroma enhancement and enzymolysis regulation of grape wine using beta glycosidase. AB - Adding beta-glycosidase into grape wine for enhancing aroma was investigated using gas chromatography-mass spectrometry (GC-MS) and Kramer sensory evaluation. Compared with the extract from control wines, the extract from enzyme-treated wines increased more aromatic compounds using steam distillation extraction (SDE) and GC-MS analyses. Theses aromatic compounds were as follows: 3-methyl-1-butanol formate, 3-pentanol, furfural, 3-methyl-butanoic acid, 2-methyl-butanoic acid, 3 hydroxy-butanoic acid ethyl ester, hexanoic acid, hexanoic acid ethyl ester, benzyl alcohol, octanoic acid, octanoic acid ethyl ester, dodecanoic acid, and ethyl ester. The enzymolysis regulation conditions, including enzymolysis temperature, enzymolysis time, and enzyme amount, were optimized through L9(3(4)) orthogonal test. Kramer sensory evaluation was performed by an 11-man panel of judges. The optimum enzymolysis regulation conditions were found to be temperature of 45 degrees C, enzymolysis time of 90 min, and enzyme amount of 58.32 U/mL grape wine, respectively. The Kramer sensory evaluation supported that the enzyme-treated wines produced a stronger fragrance. PMID- 24804073 TI - Chemical composition, antioxidant, antimicrobial and cytotoxic activities of Tagetes minuta and Ocimum basilicum essential oils. AB - Chemical composition, antioxidant, antimicrobial and cytotoxic activities of Tagetes minuta (TM) essential oil (TMO) and Ocimum basilicum (OB) essential oil (OBO) were examined. The main components for TMO were dihydrotagetone (33.9%), E ocimene (19.9%), tagetone (16.1%), cis-beta-ocimene (7.9%), Z-ocimene (5.3%), limonene (3.1%) and epoxyocimene (2.03%). The main components for OBO were methylchavicol (46.9%), geranial (19.1%), neral (15.15%), geraniol (3.0%), nerol (3.0%), caryophyllene (2.4%). Inhibitory concentrations (IC50) for reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavenging were 12-17 and 200-250 MUg/mL of TMO and OBO, respectively. Minimal inhibitory concentration (MIC) against Salmonella typhi,Escherichia coli,Staphylococcus aureus,Bacillus subtilis,Aspergillus niger, and Candida albicans were 150 +/- 8, 165 +/- 9, 67 +/ 8, 75 +/- 7, 135 +/- 15, and 115 +/- 8 MUg/mL of TMO, respectively. MIC for S. typhi,E. coli,S. aureus,B. subtilis,A. niger, and C. albicans were 145 +/- 8, 160 +/- 7, 45 +/- 4, 40 +/- 3, 80 +/- 9, and 95 +/- 7 MUg/mL of OBO, respectively. IC50 for nasopharyngeal cancer cell line (KB) and liver hepatocellular carcinoma cell line (HepG2) were 75 +/- 5 and 70 +/- 4 MUg/mL of TMO, respectively. IC50 for KB and HepG2 were 45 +/- 4 and 40 +/- 3 MUg/mL of OBO, respectively. Thus, they could be used as an effective source of natural antioxidant and antibacterial additive to protect foods from oxidative damages and foodborne pathogens. Furthermore, they could be promising candidate for antitumor drug design. PMID- 24804074 TI - Quantification of isocyanates and amines in polyurethane foams and coated products by liquid chromatography-tandem mass spectrometry. AB - An analytical method for the identification and quantification of 10 different isocyanates and 11 different amines in polyurethane (PUR) foam and PUR-coated products was developed and optimized. Isocyanates were extracted and derivatized with di-n-butylamine, while amines were extracted with methanol. Quantification was subsequently performed by liquid chromatography-tandem mass spectrometry. Using this methodology, residual levels of isocyanates and amines in commercial PUR products were quantified. Although the recoveries of certain isocyanates and amines were low, the main compounds used as monomers in the production of PUR products, and their decomposition species, were clearly identified at quantifiable levels. 2,4-and 2,6-toluenediisocyanate were detected in most PUR foam samples and a pastry bag in the range of 0.02-0.92 mg/kg, with their decomposition compounds, 2,4-and 2,6-toluenediamine, detected in all PUR foam samples in the range of 9.5-59 mg/kg. PUR-coated gloves are manufactured using 4,4'-methylenebisphenyl diisocyanate as the main raw material, and a large amount of this compound, in addition to 4,4'-methylenedianiline and dicyclohexylmethane 4,4'-diamine were found in these samples. PMID- 24804075 TI - The characterization of the physicochemical and sensory properties of full-fat, reduced-fat and low-fat bovine, caprine, and ovine Greek yogurt (Labneh). AB - Concentrated/Greek yogurt or Labneh is a semisolid food produced from yogurt by eliminating part of its water and water-soluble compounds. Today's world is geared toward the production of lower fat foods without compromising the texture and flavor of these products. The objective of this study was to characterize the physicochemical and sensory properties of bovine, caprine, and ovine Labneh with different fat levels. Bovine, caprine, and ovine milks were used to produce two batches of full-fat (~10%), reduced-fat (~5%), and low-fat (<1%) concentrated yogurt samples. Chemical analyses of fat, moisture, protein, ash, syneresis, acidity, pH, sodium, magnesium, and calcium contents were conducted. Instrumental texture analysis using the back extrusion method was applied. Quantitative descriptive sensory analysis was used to profile samples by 11 trained panelists and the acceptability of samples was assessed by 47 panelists. Type of milk significantly affected (P < 0.001) all chemical attributes except moisture and nitrogen-free extract, and fat level significantly impacted moisture, fat, protein, ash, acidity, and magnesium contents of Labneh. Type of milk significantly affected apparent modulus, hardness, hardness work done, and adhesive force, whereas fat level significantly affected hardness. Type of milk significantly affected the sensory attributes of syneresis, compactness, goaty odor and flavor, rate of flow, color, shininess, bitter flavor, denseness, melting rate, and spreadability, whereas fat level affected only color, denseness, and melting rate. Type of milk had a significant effect on overall acceptability and acceptability of flavor and texture. PMID- 24804076 TI - Study to find the best extraction solvent for use with guava leaves (Psidium guajava L.) for high antioxidant efficacy. AB - The effects of guava leaves extracted using solvents of water, ethanol, methanol, and different concentrations of hydroethanolic solvents on phenolic compounds and flavonoids, and antioxidant properties have been investigated. The antioxidant capability was assessed based on 2,2-diphenyl-1-picrylhydrazyl radical and 2,2' azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging abilities, reducing power, and nitric oxide-and nitrate-scavenging activities. The results demonstrated that the antioxidant ability of guava leaf extracts has a strong relationship with phenolic compound content rather than flavonoid content. Phenolic compound content of water extracted guava leaves was higher compared to pure ethanol and methanol extracts. However, phenolic compound content extracted using hydroethanolic solvent was higher than water, whereas 50% hydroethanolic was observed to be the most effective solvent showing high antioxidant ability. PMID- 24804077 TI - Influence of storage temperature and time on the physicochemical and bioactive properties of roselle-fruit juice blends in plastic bottle. AB - Roselle-fruit juice blends were made from roselle extract and mango, papaya, and guava juices at the ratio of 80:20, 60:40, 40:60, and 20:80, % roselle: fruit juice, respectively. The blends were pasteurized at 82.5 degrees C for 20 min and stored in 100 mL plastic bottles at 28 and 4 degrees C for 6 months. The effects of storage time and temperature on physicochemical and bioactive properties were evaluated. Total soluble solids, pH, and reducing sugars increased significantly (P < 0.05) in some blends while titratable acidity decrease with increasing storage time. Vitamin C, total monomeric anthocyanins (TMA), total phenols (TPC), and antioxidant activity (ferric reducing ability of plasma, FRAP) in all roselle fruit blends (40% roselle) decreased significantly (P < 0.05) at 28 and 4 degrees C as storage progressed. Vitamin C in all roselle-fruit blends (40% roselle) decreased from 58-55% to 43-42% when stored at 28 and 4 degrees C, respectively. TMA losses were 86-65% at 28 degrees C and 75-53% at 4 degrees C while TPC losses were 66-58% at 28 degrees C and 51-22% at 4 degrees C. Loss of antioxidant capacity (FRAP) was 18-46% at 28 degrees C and 17-35% at 4 degrees C. A principal component analysis (PCA) differentiated roselle-juice fruit blends into two clusters with two principle components PC1 and PC2, which explained 97 and 3% (blends stored at ambient temperature) and 96 and 4% (blends stored at refrigerated temperature) of the variation, respectively. PC1 differentiated roselle-guava juice blends which were characterized by vitamin C, TPC, FRAP, and pH, while PC2 from another cluster of roselle-mango and roselle-papaya juice blends and was characterized by TSS, RS, and color parameters (L* a* b*). However, TMA was the main variable with the highest effect on all roselle-fruit juice blends regardless of the storage time and temperature. PMID- 24804079 TI - Human gaze following response is affected by visual acuity. AB - The present study investigated how gaze following eye movements are affected by stimulus contrast and spatial frequency and by aberrations in central visual acuity due to refractive errors. We measured 30 healthy subjects with a range of visual acuities but without any refractive correction. Visual acuity was tested using a Landolt-C chart. Subjects were divided into three groups with low, intermediate, or good visual acuity. Gaze following responses (GFR) to moving Gabor patches were recorded by video-oculography. In each trial, the subjects were presented with a single Gabor patch with a specific spatial frequency and luminance contrast that moved sinusoidally in the horizontal plane. We observed that GFR gain decreased with increasing spatial frequency and decreasing contrast and was correlated with visual acuity. GFR gain was lower and decreased more for subjects with lower visual acuity; this was especially so for lower stimulus contrasts that are not tested in standard acuity tests. The largest differences between the groups were observed at spatial frequencies around 4 cpd and at contrasts up to 10%. Aberrations in central visual acuity due to refractive errors affect the GFR response depending on the contrast and spatial frequency of the moving stimulus. Measuring this effect may contribute to a better estimate of changes in visual function as a result of aging, disease, or treatments meant to improve vision. PMID- 24804080 TI - Central corneal thickness measurements in nonarteritic anterior ischemic optic neuropathy patients: a controlled study. AB - Purpose. To measure central corneal thickness (CCT) in patients with history of nonarteritic anterior ischemic optic neuropathy (NAION). Patients and Methods. Patients older than 40 years with a history of NAION (group 1) were prospectively evaluated including full eye examination and central corneal thickness (CCT) pachymetry. Patients with a history of intraocular surgery, corneal disease, glaucoma, and contact lens wear were excluded. Measurements were also performed in a gender and age matched control group (group 2). Results. Thirty-one eyes of 31 NAION patients in group 1 were included and 30 eyes of 30 participants in group 2. There were 15 men in group 1 and 9 in group 2 (P = 0.141), and mean age of the patients was 59 +/- 10 years in group 1 versus 61 +/- 11 years in group 2 (P = 0.708). Mean CCT was 539 +/- 30 microns in group 1 and 550 +/- 33 microns in group 2 (P = 0.155). Conclusion. Patients with NAION have no special characteristic of CCT in contrast to the crowded optic disc known to be a significant anatomic risk factor for NAION. More studies should be carried out to investigate CCT and other structure related elements in NAION patients. PMID- 24804081 TI - Correlation between Optic Nerve Parameters Obtained Using 3D Nonmydriatic Retinal Camera and Optical Coherence Tomography: Interobserver Agreement on the Disc Damage Likelihood Scale. AB - Purpose. To compare stereometric parameters obtained by three-dimensional (3D) optic disc photography and optical coherence tomography (OCT) and assess interobserver agreement on the disc damage likelihood scale (DDLS). Methods. This retrospective study included 190 eyes from 190 patients classified as normal, glaucoma suspect, or glaucomatous. Residents at different levels of training completed the DDLS for each patient before and after attending a training module. 3D optic disc photography and OCT were performed on each eye, and correlations between the DDLS and various parameters obtained by each device were calculated. Results. We found moderate agreement (weighted kappa value, 0.59 +/- 0.03) between DDLS scores obtained by 3D optic disc photography and the glaucoma specialist. The weighted kappa values for agreement and interobserver concordance increased among residents after the training module. Interobserver concordance was the poorest at DDLS stages 5 and 6. The DDLS scored by the glaucoma specialist had the highest predictability value (0.941). Conclusions. The DDLS obtained by 3D optic disc photography is a useful diagnostic tool for glaucoma. A supervised teaching program increased trainee interobserver agreement on the DDLS. DDLS stages 5 and 6 showed the poorest interobserver agreement, suggesting that caution is required when recording these stages. PMID- 24804082 TI - Anti-transglutaminase 6 antibodies in children and young adults with cerebral palsy. AB - Objectives. We have previously reported a high prevalence of gluten-related serological markers (GRSM) in children and young adults with cerebral palsy (CP). The majority had no enteropathy to suggest coeliac disease (CD). Antibodies against transglutaminase 6 (anti-TG6) represent a new marker associated with gluten-related neurological dysfunction. The aim of this study was to investigate the prevalence of anti-TG6 antibodies in this group of individuals with an early neurological injury resulting in CP. Materials and Methods. Sera from 96 patients with CP and 36 controls were analysed for IgA/IgG class anti-TG6 by ELISA. Results. Anti-TG6 antibodies were found in 12/96 (13%) of patients with CP compared to 2/36 (6%) in controls. The tetraplegic subgroup of CP had a significantly higher prevalence of anti-TG6 antibodies 6/17 (35%) compared to the other subgroups and controls. There was no correlation of anti-TG6 autoantibodies with seropositivity to food proteins including gliadin. Conclusions. An early brain insult and associated inflammation may predispose to future development of TG6 autoimmunity. PMID- 24804083 TI - Celiac disease in adult patients: specific autoantibodies in the diagnosis, monitoring, and screening. AB - The increasing prevalence of celiac disease (CD), especially in adults, its atypical clinical presentation, and the strict, lifelong adherence to gluten-free diet (GFD) as the only option for healthy state create an imperative need for noninvasive methods that can effectively diagnose CD and monitor GFD. Aim. Evaluation of anti-endomysium (EmA) and anti-tissue transglutaminase IgA (tTG-A) antibodies in CD diagnosis, GFD monitoring, and first degree relatives screening in CD adult patients. Methods. 70 newly diagnosed Greek adult patients, 70 controls, and 47 first degree relatives were tested for the presence of EmA and tTG-A. The CD patients were monitored during a 3-year period. Results. EmA predictive ability for CD diagnosis was slightly better compared to tTG-A (P = 0.043). EmA could assess compliance with GFD already from the beginning of the diet, while both EmA and tTG-A had an equal ability to discriminate between strictly and partially compliant patients after the first semester and so on. Screening of first degree relatives resulted in the identification of 2 undiagnosed CD cases. Conclusions. Both EmA and tTG-A are suitable markers in the CD diagnosis, in the screening of CD among first degree relatives, having also an equal performance in the long term monitoring. PMID- 24804084 TI - The Potential Roles of Bisphenol A (BPA) Pathogenesis in Autoimmunity. AB - Bisphenol A (BPA) is a monomer found in commonly used consumer plastic goods. Although much attention in recent years has been placed on BPA's impact as an endocrine disruptor, it also appears to activate many immune pathways involved in both autoimmune disease development and autoimmune reactivity provocation. The current scientific literature is void of research papers linking BPA directly to human or animal onset of autoimmunity. This paper explores the impact of BPA on immune reactivity and the potential roles these mechanisms may have on the development or provocation of autoimmune diseases. Potential mechanisms by which BPA may be a contributing risk factor to autoimmune disease development and progression include its impact on hyperprolactinemia, estrogenic immune signaling, cytochrome P450 enzyme disruption, immune signal transduction pathway alteration, cytokine polarization, aryl hydrocarbon activation of Th-17 receptors, molecular mimicry, macrophage activation, lipopolysaccharide activation, and immunoglobulin pathophysiology. In this paper a review of these known autoimmune triggering mechanisms will be correlated with BPA exposure, thereby suggesting that BPA has a role in the pathogenesis of autoimmunity. PMID- 24804085 TI - Periconception weight loss: common sense for mothers, but what about for babies? AB - Obesity in the childbearing population is increasingly common. Obesity is associated with increased risk for a number of maternal and neonatal pregnancy complications. Some of these complications, such as gestational diabetes, are risk factors for long-term disease in both mother and baby. While clinical practice guidelines advocate for healthy weight prior to pregnancy, there is not a clear directive for achieving healthy weight before conception. There are known benefits to even moderate weight loss prior to pregnancy, but there are potential adverse effects of restricted nutrition during the periconceptional period. Epidemiological and animal studies point to differences in offspring conceived during a time of maternal nutritional restriction. These include changes in hypothalamic-pituitary-adrenal axis function, body composition, glucose metabolism, and cardiovascular function. The periconceptional period is therefore believed to play an important role in programming offspring physiological function and is sensitive to nutritional insult. This review summarizes the evidence to date for offspring programming as a result of maternal periconception weight loss. Further research is needed in humans to clearly identify benefits and potential risks of losing weight in the months before conceiving. This may then inform us of clinical practice guidelines for optimal approaches to achieving a healthy weight before pregnancy. PMID- 24804086 TI - Achieving cultural congruency in weight loss interventions: can a spirituality based program attract and retain an inner-city community sample? AB - Ethnic minorities continue to be disproportionately affected by obesity and are less likely to access healthcare than Caucasians. It is therefore imperative that researchers develop novel methods that will attract these difficult-to-reach groups. The purpose of the present study is to describe characteristics of an urban community sample attracted to a spiritually based, weight loss intervention. METHODS. Thirteen participants enrolled in a pilot version of Spiritual Self-Schema Therapy (3S) applied to disordered eating behavior and obesity. Treatment consisted of 12 one-hour sessions in a group therapy format. At baseline, participants were measured for height and weight and completed a battery of self-report measures. RESULTS: The sample was predominantly African American and Hispanic and a large percentage of the sample was male. Mean baseline scores of the EDE-Q, YFAS, and the CES-D revealed clinically meaningful levels of eating disordered pathology and depression, respectively. The overall attrition rate was quite low for interventions targeting obesity. DISCUSSION: This application of a spiritually centered intervention seemed to attract and retain a predominantly African-American and Hispanic sample. By incorporating a culturally congruent focus, this approach may have been acceptable to individuals who are traditionally more difficult to reach. PMID- 24804087 TI - Intrauterine growth restriction increases TNF alpha and activates the unfolded protein response in male rat pups. AB - Intrauterine growth restriction (IUGR) programs adult disease, including obesity and insulin resistance. Our group previously demonstrated that IUGR dysregulates adipose deposition in male, but not female, weanling rats. Dysregulated adipose deposition is often accompanied by the release of proinflammatory signaling molecules, such as tumor necrosis factor alpha (TNF alpha ). TNF alpha contributes to adipocyte inflammation and impaired insulin signaling. TNF alpha has also been implicated in the activation of the unfolded protein response (UPR), which impairs insulin signaling. We hypothesized that, in male rat pups, IUGR would increase TNF alpha , TNFR1, and components of the UPR (Hspa5, ATF6, p eIF2 alpha , and Ddit3) prior to the onset of obesity. We further hypothesized that impaired glucose tolerance would occur after the onset of adipose dysfunction in male IUGR rats. To test this hypothesis, we used a well characterized rat model of uteroplacental insufficiency-induced IUGR. Our primary findings are that, in male rats, IUGR (1) increased circulating and adipose TNF alpha , (2) increased mRNA levels of UPR components as well as p-eIF2a, and (3) impaired glucose tolerance after observed TNF alpha increased and after UPR activation. We speculate that programmed dysregulation of TNF alpha and UPR contributed to the development of glucose intolerance in male IUGR rats. PMID- 24804088 TI - Potentially ineffective care: time for earnest reexamination. AB - The rising costs and suboptimal quality throughout the American health care system continue to invite critical inquiry, and practice in the intensive care unit setting is no exception. Due to their relatively large impact, outcomes and costs in critical care are of significant interest to policymakers and health care administrators. Measurement of potentially ineffective care has been proposed as an outcome measure to evaluate critical care delivery, and the Patient Protection and Affordable Care Act affords the opportunity to reshape the care of the critically ill. Given the impetus of the PPACA, systematic formal measurement of potentially ineffective care and its clinical, economic, and societal impact merits timely reconsideration. PMID- 24804089 TI - Participating in online mental health interventions: who is most likely to sign up and why? AB - Internet-based interventions are increasingly recognized as effective in the treatment and prevention of mental disorders. However, little research has investigated who is most likely to participate in intervention trials. This study examined the characteristics of individuals interested in participating in an online intervention to improve emotional well-being and prevent or reduce the symptoms of depression, factors reported to encourage or discourage participation, and preferences for different intervention types. The study comprised 4761 Australians participating in a survey on emotional health. Comparisons are made between those who expressed an interest in participating in the trial and those who were not. Compared to those who declined to participate, interested participants were more likely older, females, separated/divorced, and highly educated, have reported current or past history of depression, report higher depressive symptoms, and have low personal stigma. Despite the flexibility of online interventions, finding time to participate was the major barrier to engagement. Financial compensation was the most commonly suggested strategy for encouraging participation. An increased understanding of factors associated with nonparticipation may inform the design of future e-mental health intervention trials. Importantly, consideration needs to be given to the competing time pressures of potential participants, in balance with the desired study design. PMID- 24804090 TI - Health Professionals Facing Burnout: What Do We Know about Nursing Managers? AB - Objective. To address the degree of burnout in nursing managers in hospitals of Western Switzerland, including comparison with medical managers, and its relationship with personal, work-related, and organizational characteristics. Methods. Statistical analysis of the scores of the Maslach Burnout Inventory Human Services Survey from 257 nursing managers who answered a standardized electronic questionnaire. Results. Nursing managers showed a low degree of burnout, which was similar to that of medical managers. Most of them had a low level of emotional exhaustion and a low level of depersonalization, while personal accomplishment was contrasted. Only 2.3% had a high degree of burnout. These findings challenge the hypothesis of high stress being associated with high burnout, as nursing managers can be supposed to have a highly demanding job due to their intermediary position within the hospital hierarchy. Variations of burnout by personal, work-related, and organizational characteristics mainly concerned emotional exhaustion. Conclusion. Though nursing managers face a highly demanding job, they may benefit from resources (including coping strategies and empowerment) which help counterbalance job stress. Unequal distribution of resources may play a central role when facing burnout. PMID- 24804092 TI - Video-assisted thoracic surgery for tubercular spondylitis. AB - The present study evaluated the outcome of video-assisted thoracic surgery (VATS) in 9 patients (males = 6, females = 3) with clinico-radiological diagnosis of tubercular spondylitis of the dorsal spine. The mean duration of surgery was 140.88 +/- 20.09 minutes, mean blood was 417.77 +/- 190.90 mL, and mean duration of postoperative hospital stay was 5.77 +/- 0.97 days, Seven patients had a preoperative Grade A neurological involvement, while at the time of final followup the only deficit was Grade D power in 2 patients. In patients without bone graft placement (n = 6), average increase in Kyphosis angle was 16 degrees , while in patients with bone graft placement (n = 3) the deformity remained stationary. At the time of final follow up, fusion was achieved in all patients, the VAS score for back pain improved from a pretreatment score of 8.3 to 2, and the function assessment yielded excellent (n = 4) to good (n = 5) results. In two patients minithoracotomy had to be resorted due to extensive pleural adhesions (n = 1) or difficulty in placement of graft (n = 1). Videoassisted thoracoscopic surgery provides a safe and effective approach in the management of spinal tuberculosis. It has the advantages of decreased blood loss and post operative morbidity with minimal complications. PMID- 24804093 TI - Vascular waveform analysis of flap-feeding vessels using color Doppler ultrasonography. AB - We performed vascular waveform analysis of flap-feeding vessels using color Doppler ultrasonography and evaluated the blood flow in the flaps prior to surgery. Vascular waveform analysis was performed in 19 patients. The analyzed parameters included the vascular diameter, flow volume, flow velocity, resistance index, pulsatility index, and acceleration time. The arterial waveform was classified into 5 types based on the partially modified blood flow waveform classification reported by Hirai et al.; in particular, D-1a, D-1b, and D-2 were considered as normal waveforms. They were 4 patients which observed abnormal vascular waveform among 19 patients (D-4 : 1, D-3 : 1, and Poor detect : 2). The case which presented D-4 waveform changed the surgical procedure, and a favorable outcome was achieved. Muscle flap of the case which presented D-3 waveform was partially necrosed. The case which detected blood flow poorly was judged to be the vascular obstruction of the internal thoracic artery. In the evaluation of blood flow in flaps using color Doppler ultrasonography, determination of not only basic blood flow information, such as the vascular distribution and diameter and flow velocity, but also the flow volume, vascular resistance, and arterial waveform is essential to elucidate the hemodynamics of the flap. PMID- 24804094 TI - Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. AB - The present study evaluated the effectiveness of micronized palmitoylethanolamide (PEA-m) treatment in reducing the painful symptoms experienced by diabetic patients with peripheral neuropathy. PEA-m, a fatty acid amide of the N acylethanolamine family, was administered (300 mg twice daily) to 30 diabetic patients suffering from painful diabetic neuropathy. Before treatment start, after 30 and 60 days the following parameters were assessed: painful symptoms of diabetic peripheral neuropathy using the Michigan Neuropathy Screening instrument; intensity of symptoms characteristic of diabetic neuropathic pain by the Total Symptom Score; and intensity of different subcategories of neuropathic pain by the Neuropathic Pain Symptoms Inventory. Hematological and blood chemistry tests to evaluate metabolic control and safety were also performed. Statistical analysis (ANOVA) indicated a highly significant reduction in pain severity (P < 0.0001) and related symptoms (P < 0.0001) evaluated by Michigan Neuropathy Screening instrument, Total Symptom Score, and Neuropathic Pain Symptoms Inventory. Hematological and urine analyses did not reveal any alterations associated with PEA-m treatment, and no serious adverse events were reported. These results suggest that PEA-m could be considered as a promising and well-tolerated new treatment for symptomatology experienced by diabetic patients suffering from peripheral neuropathy. PMID- 24804095 TI - Oscillatory shear stress-induced arginase activity may explain reduced exhaled nitric oxide levels after vest chest physiotherapy in cystic fibrosis. PMID- 24804096 TI - Cross-cultural validity, reliability, and psychometric properties of the persian version of the scales for outcomes in Parkinson's disease-psychosocial questionnaire. AB - Objectives. Considering the influence of different motor and nonmotor features of Parkinson's disease (PD), it is important to evaluate the psychosocial functioning of the patients. For this purpose, the scales for outcomes in Parkinson's disease-psychosocial questionnaire (SCOPA-PS) has been previously designed. The aim of our study was to assess the cross-cultural validation and psychometric properties of the Persian version of the SCOPA-PS. Methods. One hundred and ten nondemented idiopathic Parkinson's disease (IPD) patients were consecutively recruited from an outpatient referral movement disorder clinic. Eligible patients filled up a number of questionnaires including the Persian version of SCOPA-PS during the face-to-face interview session and clinical examination to measure disease severity, nonmotor psychiatric symptoms, and health-related quality of life (HRQoL). Results. The highest and lowest correlation coefficients of internal consistency were reported for item 7 on "asking for help" (r = 0.765) and item 5 on "sexual problems" (r = 0.553). Cronbach's alpha reliability coefficient of the entire scale was 0.87 (95% CI: 0.83-0.90). The Hoehn and Yahr stage (r = 0.34, P < 0.001), Schwab and England ADL scale (r = -0.55, P < 0.001), anxiety (r = 0.64, P < 0.001), depression (r = 0.71, P < 0.001), and fatigue (r = 0.35, P < 0.001) were significantly correlated with the total score of the SCOPA-PS questionnaire. Conclusions. The Persian version of SCOPA-PS is a highly reliable and valid scale to measure psychosocial functioning in IPD patients with different sex, age-group, and educational level, which could be applied in future researches. Disease severity scales, depression, anxiety, fatigue, and different domains of HRQoL were all associated with psychosocial functioning in PD patients. PMID- 24804097 TI - Apathy in Parkinson's disease: an electrophysiological study. AB - In Parkinson's disease (PD), apathy (or loss of motivation) is frequent. Nevertheless, the contribution of attentional disorders to its genesis is still not clearly known. We want to determine the relation existing between apathy and attentional disorders by using P300a (or novelty P3) as a marker of the attentional process. The study included 25 patients (13 women and 12 men) with PD for whom we have determined the relationship between automatic attention (represented by P300a) and motor status, apathy, executive dysfunction, mental flexibility, inhibitory control, and depression/anxiety. We have found a correlation between the apathy score and amplitude of novelty P300 during the ON period and also a correlation of the apathy score with a decrease in amplitude of P300 during the OFF period. In a linear regression model, changes in the P300a predicted the severity of apathy independently of any other variable. We concluded firstly that the reduction in amplitude of the P300a wave was a neurophysiological marker of apathy in PD and secondly that apathy led to both dopaminergic denervation (mesolimbic) and nondopaminergic (dorsolateral prefrontal-subcortical) dysfunction. PMID- 24804098 TI - Recognition of emotion from facial expressions with direct or averted eye gaze and varying expression intensities in children with autism disorder and typically developing children. AB - Eye gaze direction and expression intensity effects on emotion recognition in children with autism disorder and typically developing children were investigated. Children with autism disorder and typically developing children identified happy and angry expressions equally well. Children with autism disorder, however, were less accurate in identifying fear expressions across intensities and eye gaze directions. Children with autism disorder rated expressions with direct eyes, and 50% expressions, as more intense than typically developing children. A trend was also found for sad expressions, as children with autism disorder were less accurate in recognizing sadness at 100% intensity with direct eyes than typically developing children. Although the present research showed that children with autism disorder are sensitive to eye gaze direction, impairments in the recognition of fear, and possibly sadness, exist. Furthermore, children with autism disorder and typically developing children perceive the intensity of emotional expressions differently. PMID- 24804099 TI - Early COPD Diagnosis in Family Medicine Practice: How to Implement Spirometry? AB - Introduction. COPD is often diagnosed at an advanced stage because symptoms go unrecognized. Furthermore, spirometry is often not done. Methods. Study was conducted in diverse family medicine practice settings. Patients were targeted if respiratory symptoms were present. Patients had a spirometry to confirm the presence of airflow obstruction and COPD diagnosis. An evaluation of the process was done to better understand facilitating/limiting factors to the implementation of a primary care based spirometry program. Results. 12 of 19 primary care offices participated. 196 of 246 (80%) patients targeted based on the presence of smoking and respiratory symptoms did not have COPD; 18 (7%) and 32 (13%) had COPD, respectively, GOLD I and >=II. There was no difference in the type and number of respiratory symptoms between non-COPD and COPD patients. Most of the clinics did not have access to a trained healthcare professional to accomplish spirometry. They agreed that giving access to a trained healthcare professional was the easiest and most reliable way of doing spirometry. Conclusion. Spirometry, a simple test, is recommended in guidelines to make the diagnosis of COPD. The lack of allocated time and training of healthcare professionals makes its implementation challenging in family medicine practices. PMID- 24804100 TI - Blood transfusion reactions in elderly patients hospitalized in a multilevel geriatric hospital. AB - Background/Objectives. Blood transfusion is a critical issue for patients with chronic diseases such as heart failure, chronic kidney disease, and malignancy. However, side effects are not rare. The purpose of the study is to evaluate the frequency of adverse blood transfusion reactions in hospitalized elderly patients during a one-year period. Design/Setting/Participants. Blood transfusion reactions such as fever, chills, dyspnea, and others following blood transfusions in hospitalized geriatric patients during one-year period were examined. Results. 382 blood units (242 patients) were administered during the study period. In 40 (11%) cases, blood transfusion reactions occurred. Fever was the most common reaction in 29 cases (72%), four (10%) had shortness of breath, and 3 (8%) had vomiting and chills each. There were no lethal cases in the 24-hour period following blood transfusions. Conclusion. A relatively low rate of adverse blood transfusion reactions occurred in our geriatric patients. We may speculate that this is related to underreporting of minor symptoms due to the high percentage of demented patients in this population. PMID- 24804101 TI - A comparative study of phase States of the peribacteroid membrane from yellow lupin and broad bean nodules. AB - A comparative study of the lipid bilayer phase status and structure of the outer membrane of free-living Bradyrhizobium strain 359a (Nod(+)Fix(+)) and 400 (Nod(+)FixL) or Rhizobium leguminosarum 97 (Nod(+)Fix(+), effective) and 87 (Nod(+)FixL, ineffective) has been carried out. Also, the effect of the symbiotic pair combination on the lipid bilayer structure of the bacteroid outer membrane and peribacteroid membrane, isolated from the nodules of Lupinus luteus L. or Vicia faba L., has been studied. As a result, it is shown that the lipid bilayer status of the bacteroid outer membrane is mainly determined by microsymbiont, but not the host plant. In the contrast, the lipid bilayer status of the peribacteroid membrane and, as a consequence, its properties depend on interaction of both symbiotic partners. PMID- 24804102 TI - Angiographic and Clinical Impact of Successful Manual Thrombus Aspiration in Diabetic Patients Undergoing Primary PCI. AB - Background. Diabetes mellitus is associated with worse angiographic and clinical outcomes after percutaneous coronary intervention (PCI). Aim. To investigate the impact of manual thrombus aspiration on in-stent restenosis (ISR) and clinical outcome in patients treated by bare-metal stent (BMS) implantation for ST-segment elevation myocardial infarction (STEMI). Methods. 100 diabetic patients were prospectively enrolled. They were randomly assigned to undergo either standard primary PCI (group A, 50 patients) or PCI with thrombus aspiration using Export catheter (group B, 50 patients). The primary endpoint was the rate of eight-month ISR. The secondary endpoint included follow-up for major adverse cardiac events (MACE). Results. Mean age of the study cohort was 59.86 +/- 8.3 years, with 64 (64%) being males. Baseline characteristics did not differ between both groups. Eight-month angiogram showed that group B patients had significantly less late lumen loss (0.17 +/- 0.35 versus 0.60 +/- 0.42 mm, P < 0.001), with lower incidence of ISR (4% versus 16.6%, P < 0.001). There was a trend towards lower rate of MACE in the same group of patients. Conclusion. In diabetic patients undergoing primary PCI, manual thrombus aspiration (compared with standard PCI) was associated with better ISR rate after BMS implantation. PMID- 24804103 TI - Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA Specific Small Molecule in Tumor-Bearing Mice. AB - Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections. PMID- 24804104 TI - Comparing the efficacy of excitatory transcranial stimulation methods measuring motor evoked potentials. AB - The common aim of transcranial stimulation methods is the induction or alterations of cortical excitability in a controlled way. Significant effects of each individual stimulation method have been published; however, conclusive direct comparisons of many of these methods are rare. The aim of the present study was to compare the efficacy of three widely applied stimulation methods inducing excitability enhancement in the motor cortex: 1 mA anodal transcranial direct current stimulation (atDCS), intermittent theta burst stimulation (iTBS), and 1 mA transcranial random noise stimulation (tRNS) within one subject group. The effect of each stimulation condition was quantified by evaluating motor evoked-potential amplitudes (MEPs) in a fixed time sequence after stimulation. The analyses confirmed a significant enhancement of the M1 excitability caused by all three types of active stimulations compared to sham stimulation. There was no significant difference between the types of active stimulations, although the time course of the excitatory effects slightly differed. Among the stimulation methods, tRNS resulted in the strongest and atDCS significantly longest MEP increase compared to sham. Different time courses of the applied stimulation methods suggest different underlying mechanisms of action. Better understanding may be useful for better targeting of different transcranial stimulation techniques. PMID- 24804105 TI - Successful treatment of genitofemoral neuralgia using ultrasound guided injection: a case report and short review of literature. AB - A young male patient developed chronic, severe, and disabling right sided groin pain following resection of his left testicular cancer. Since there is considerable overlap, ultrasound guided, selective diagnostic nerve blocks were done for ilioinguinal, iliohypogastric, and genitofemoral nerves, to determine the involved nerve territory. It was revealed that genitofemoral neuralgia was the likely cause. As a therapeutic procedure, it was injected with local anesthetic and steroid using ultrasound guidance. The initial injection led to pain relief of 3 months. Subsequent blocks reinforced the existing analgesia and were sufficient to allow for maintenance with the use of analgesic medications. This case report describes the successful use of diagnostic selective nerve blocks for the assessment of groin pain, subsequent to which an ultrasound guided therapeutic injection of genitofemoral nerve led to long term pain relief. As a therapeutic procedure, genitofemoral nerve block is done in patients with genitofemoral neuralgia. Ultrasound allows for controlled administration and greatly enhances the technical ability to perform precise localization and injection. There are very few case reports of such a treatment in the published literature. Apart from the case report, we also highlight the relevant anatomy and a brief review of genitofemoral neuralgia and its treatment. PMID- 24804106 TI - Platypnea-orthodeoxia: an unusual case of hypoxemia. AB - A 52 year old female presented for two weeks of acute onset dyspnea on exertion. She was found to be hypoxic with a room air saturation of 88%. Baseline echocardiogram was normal with the exception of aortic root dilation. Right and left heart catheterizations were performed. The coronary arteries were normal in original and without disease. The right heart catheterization demonstrated normal pulmonary pressures and "no evidence of intra-cardiac shunt". Repeat echocardiogram was performed with agitated saline contrast and revealed a small amount of right to left shunting across the intra-atrial septum with cough while supine and significant right to left shunting while upright; these findings were consistent with the presence of a patent foramen ovale (PFO) and platypnea orthodeoxia syndrome. The patient underwent percutaneous closure of her PFO with an Amplatzer device, and exhibited rapid resolution of her symptoms and hypoxia. She is off oxygen and has returned to work as a nurse practitioner. The case highlights the importance of clinical vigilance and consideration of this syndrome in the differential diagnosis of unexplained hypoxia. Our patient had a dramatic and positive outcome: complete alleviation of dyspnea and oxygen dependence after PFO closure. PMID- 24804107 TI - Takotsubo cardiomyopathy "variations on a theme". AB - Takotsubo Cardiomyopathy (TTC) is a fairly new diagnosis in the cardiologist's repertoire. It can present itself in multiple different forms. We describe three cases of TTC with different etiologies illustrating the broad spectrum of presentations. PMID- 24804108 TI - Bilateral subclavian steal syndrome. AB - Bilateral subclavian steal syndrome is a rare condition. It is usually due to reversal of vertebral blood flow in the setting of bilateral proximal subclavian or left subclavian plus innominate artery severe stenosis or occlusion. This finding may cause cerebral ischemia related to upper extremities exercise. We report a case of bilateral subclavian steal secondary to total occlusion of the innominate and left subclavian arteries in a patient who presented with cardiomyopathy and flow reversal in the right carotid and bilateral vertebral arteries. PMID- 24804109 TI - Massive congenital bidirectional coronary arteriovenous malformation presenting with signs and symptoms of congestive heart failure in an adult: a case report and review of the literature. AB - Congenital anomalies of the coronary arteries are relatively rare. Mostly asymptomatic, however, some can cause problems, as heart failure, myocardial ischemia, and ventricular arrhythmia, and are associated with risk of complications, such as endocarditis and coronary rupture or sudden death. A case of a 69-year-old man with complaints of tiredness, dyspnea, and palpitation due to coronary artery fistula is presented with a review of the literature. PMID- 24804110 TI - Acute Cardiac Failure in a Pregnant Woman due to Thyrotoxic Crisis. AB - Introduction. Cardiac failure during pregnancy is usually related to preeclampsia/eclampsia, rarely to hyperthyroidism. While hyperthyroidism can easily lead to hypertensive cardiac failure and may harm the fetus, it is sometimes difficult to distinguish hyperthyroidism from normal pregnancy. Case Presentation. We encountered a case of 41-year-old pregnant woman with hypertensive cardiac failure. Because we initially diagnosed as pre eclampsia/eclampsia, Caesarian section was performed. However, her symptoms still persisted after delivery. After thyroid function test results taken on the day of admission were obtained on the fourth day, we could diagnose that her cardiac failure was caused by thyrotoxic crisis. Conclusions. Hypertensive cardiac failure due to hyperthyroidism during pregnancy is rare and difficult to diagnose because of similar presentation of normal pregnancy. However, physicians should be aware of the risks posed by hyperthyroidism during pregnancy. PMID- 24804111 TI - Leiomyosarcoma of pulmonary vein presenting as left atrial mass: an outline of management principles. AB - Leiomyosarcoma of the pulmonary vein is rare and has poor prognosis. Its clinical features are nonspecific and mimic benign conditions. Early diagnosis is challenging. Most cases have been diagnosed only at autopsy or on postoperative histology specimens. Treatment is essentially palliative complete surgical excision. We outline the principles of management with the case of a 39-year-old man with leiomyosarcoma of the left pulmonary veins extending into the left atrium. Extensive investigation to achieve early diagnosis and determine extent of disease is essential. Frozen section guided adequate excision of all cardiac tumours and resection of involved lung tissue achieve local disease control. Adjuvant chemoradiotherapy has been shown to enhance survival. PMID- 24804112 TI - Multiparity and spontaneous coronary artery dissection in the postpartum period. AB - Spontaneous coronary artery dissection (SCAD) is a deadly cause of myocardial infarction (MI) that mainly affects otherwise healthy, young females. Forty percent of patients die suddenly or within a few hours of symptom onset. We examine the case of a young female who presented with chest pain. She developed ST elevations in anterolateral leads mimicking ST elevation MI. Cardiac catheterization was done and showed a middle left anterior descending (LAD) dissection. The patient underwent primary percutaneous transluminal coronary angioplasty with coronary stent placed in the LAD. PMID- 24804113 TI - Hypereosinophilic Syndrome Leading to Severe Right-Sided Heart Failure in a Patient with Ebstein's Anomaly. AB - A 36-year-old male with mild Ebstein's anomaly developed severe right-sided heart failure, following a 5-year-long course of hypereosinophilic syndrome. No regular followups had been done, during the years of antineoplastic therapy. A year after being cured from the hypereosinophilic syndrome, the patient developed right sided heart failure symptoms and was found to have excessive fibrosis of the right ventricular endocardium and free tricuspid regurgitation. The findings were compatible with substantial scarring of the endocardium caused by the hypereosinophilic syndrome. Over a few years, the patient deteriorated significantly and was finally offered a heart transplant. Examination of the explanted heart revealed severe fibrosis of the right ventricle and almost complete sparing of the left. PMID- 24804114 TI - Sinus of Valsalva Fistula to the Right Ventricle along with Coronary Artery Fistula to the Pulmonary Artery in a Young Native American Female. AB - Sinus of Valsalva aneurysm is a rare condition and associated with a high rate of mortality if rupture occurs. The aneurysms are rarely diagnosed until rupture occurs. This case describes a young Native American female whose only symptom was intermittent chest pain prior to the detection of the aneurysm along with a small ventricular septal defect. The patient was also found to have a coexisting coronary artery fistula, and it is rare phenomenon to have these coexisting anomalies. The anomalies were demonstrated on both cardiac computed tomography and coronary angiography. The patient underwent surgical closure of both anomalies, which is the recommended treatment to avoid future complications. PMID- 24804115 TI - Development of ARDS after Excessive Kath Consumption: A Case Report. AB - Khat is a drug widely used in the Horn of Africa and the Arabian Peninsula. Khat leaves contain, among other substances, the psychoactive alkaloid cathinone, which induce central nervous system stimulation leading to euphoria, hyperactivity, restlessness, and insomnia. However, it also could cause psychological adverse effects such as lethargy, sleepiness, psychoses, and depression necessitating pharmacologic treatment. Here we report the case of a 35 year-old man from Somalia who became unconscious and developed aspiration pneumonia and subsequent ARDS after excessive consumption of khat leaves. His unconsciousness was possibly caused by the sleepiness developed after khat consumption and a benzodiazepine intake by the patient himself. Thus, khat induced adverse effects should not primarily be treated pharmacologically, but patients should be urged to quit khat consumption in order to eliminate or, at least, reduce the severity of present psychological adverse effects. PMID- 24804116 TI - Treatment of severe hypertriglyceridemia with continuous insulin infusion. AB - Severe hypertriglyceridemia (SH) represents a therapeutic emergency because of the possibility of developing cardiovascular events and hyperlipemic acute pancreatitis (PA). Most patients with SH suffer primary or genetic abnormality in lipid metabolism in combination with a precipitating factor such as uncontrolled diabetes mellitus, alcoholism, and drug intake. The standard treatment of hypertriglyceridemia (HTG) with omega 3 fatty acids and fibrates, along with dietary changes, has no effect on an emergency situation. There are no clinical guidelines to SH, but therapy with insulin, heparin, a combination of both, plasmapheresis, or octreotide have been tested succesfully. We report the case of a 10-year-old girl with clinical acute pancreatitis and diabetic ketoacidosis debut, along with incidental finding of an SH, who had a good outcome after treatment with insulin intravenous infusion. PMID- 24804117 TI - Neurogenic stunned myocardium associated with acute spinal cord infarction: a case report. AB - Introduction. Neurogenic stunned myocardium (NSM) is a reversible cardiomyopathy resulting in transient left ventricular apical ballooning presumed to result from catecholamine surge occurring under physiologic stress. Acute spinal cord ischemia is a rare ischemic vascular lesion. We report a case of neurogenic stunned myocardium occurring in the setting of acute spinal cord infarction. Methods. Singe case report was used. Results. We present the case of a 63-year old female with a history of prior lacunar stroke, hypertension, chronic back pain, and hypothyroidism who presented with a brief episode of diffuse abdominal and bilateral lower extremity pain which progressed within minutes to bilateral lower extremity flaccid paralysis. MRI of the spinal cord revealed central signal hyperintensity of T2-weighted imaging from conus to T8 region, concerning for acute spinal cord ischemia. Transthoracic echocardiogram was performed to determine if a cardiac embolic phenomenon may have precipitated this ischemic event and showed left ventricular apical hypokinesis and ballooning concerning for NSM. Conclusion. Neurogenic stunned myocardium is a reversible cardiomyopathy which has been described in patients with physiologic stress resulting in ventricular apical ballooning. Our case suggests that it is possible for neurogenic stunned myocardium to occur in the setting of acute spinal cord ischemia. PMID- 24804118 TI - Novel combination of impella and extra corporeal membrane oxygenation as a bridge to full recovery in fulminant myocarditis. AB - A 31-year-old male was transferred to our hospital with severe heart failure due to viral myocarditis. He progressed to multiorgan failure requiring intubation and maximal doses of multiple vasopressors. Circulatory support was provided with an Impella device as a bridge to an extracorporeal membrane oxygenation (ECMO) system. On full mechanical cardiovascular support, the patient's hemodynamic status improved and ECMO and Impella were explanted after 48 hours. Three days later, he was extubated and continued on to a full recovery. There are no specific therapies for fulminant myocarditis but first-line treatment is supportive care. ECMO is commonly used in patients with severe heart failure. In severe systolic dysfunction, left ventricular decompression is required to reduce myocardial wall stress, decrease myocardial oxygen requirements, and enhance the chances of recovery. The Impella, an active support system, is less invasive than classical decompressive techniques and is associated with lower requirements for blood products with fewer thromboembolic complications. This is the only case reported of the contemporary use of Impella and ECMO as a bridge to full recovery in an adult with myocarditis. It also presents a novel use of the Impella device in decompressing the left ventricle of an adult patient on ECMO. PMID- 24804119 TI - Contained Left Ventricular Free Wall Rupture following Myocardial Infarction. AB - Rupture of the free wall of the left ventricle occurs in approximately 4% of patients with infarcts and accounts for approximately 20% of the total mortality of patients with myocardial infractions. Relatively few cases are diagnosed before death. Several distinct clinical forms of ventricular free wall rupture have been identified. Sudden rupture with massive hemorrhage into the pericardium is the most common form; in a third of the cases, the course is subacute with slow and sometimes repetitive hemorrhage into the pericardial cavity. Left ventricular pseudoaneurysms generally occur as a consequence of left ventricular free wall rupture covered by a portion of pericardium, in contrast to a true aneurysm, which is formed of myocardial tissue. Here, we report a case of contained left ventricular free wall rupture following myocardial infarction. PMID- 24804120 TI - Fluctuation of spuriously elevated troponin I: a case report. AB - Serum troponin is a useful laboratory study for the diagnosis of acute myocardial infarction. However, elevations can also be seen in a variety of other diseases processes. Falsely positive troponin values caused by interference with current troponin assays have been reported. We report a unique case that demonstrates the fluctuation of falsely elevated troponin correlating with hemoglobin, serving as a marker of heterophile antibody levels. A 74-year-old gentleman presented to our Emergency Department with a several-day history of increasing shortness of breath associated with a new-onset chest pain and a troponin I level of 77.28 ng/mL. Throughout his stay, fluctuations in measured troponin levels correlated strongly with fluctuations in hemoglobin levels. Several investigations confirmed false elevated troponin levels secondary to heterophile antibody interference. We conclude that hemoglobin trending in our patient represented a surrogate measure of his heterophile antibody titers with time and that fluctuations in these levels correlated with respective fluctuations in the falsely elevated troponin levels. PMID- 24804121 TI - Reversible right-sided heart failure secondary to carcinoid crisis. AB - Carcinoid crisis is an infrequent and little-described complication of neuroendocrine tumors that can be life threatening. It may develop during induction of anesthesia, intraoperatively, during tumor manipulation and arterial embolization, or even spontaneously. The massive release of neuroendocrine substances can lead to potentially fatal complications. Somatostatin analogs inhibit the release of these substances and are the mainstay of treatment. The following case report describes a patient with reversible acute right-sided heart failure posterior to hepatic artery embolization. PMID- 24804122 TI - Hyperammonemic Coma in an Adult due to Ornithine Transcarbamylase Deficiency. AB - Objective. To report an unusual cause of coma in an adult. Design. Case report. Setting. University teaching hospital. Patient. A previously healthy 53-year-old man initially presented with altered mental status and progressed to coma. He was found to be substantially hyperammonemic and did not improve with lactulose therapy and continuous venovenous hemodialysis. Results. Biochemical testing revealed previously undiagnosed ornithine transcarbamylase deficiency, and the patient responded to arginine, sodium phenylacetate, and sodium benzoate. Conclusion. Even in adult patients with no known history, inborn errors of metabolism must be considered in the differential diagnosis of unexplained coma. Defects of the urea cycle can present with an unprovoked hyperammonemic coma. PMID- 24804123 TI - An unusual cause of pediatric stroke secondary to congenital basilar artery fenestration. AB - Basilar artery fenestration is an uncommon congenital variant that has been associated with aneurysms and posterior circulation infarcts in the adult literature. Little is known about the functional consequences of basilar artery fenestration, if any, in childhood. We present a case of a previously healthy 12 year-old boy who presented with diplopia, tinnitus, and ataxia who had subtle findings on diffusion-weighted magnetic resonance imaging consistent with posterior circulation territory infarction. Computed tomography angiography and magnetic resonance angiography revealed an area of signal abnormality in the basilar artery, which was confirmed on conventional angiography to be a type 2 basilar artery fenestration, without thrombus or aneurysm. The patient recovered from his neurologic deficits over two days and was placed on prophylactic aspirin therapy without recurrence of symptoms. This rare anatomic variant of the posterior circulation is important for physicians to recognize and may have associated neurologic consequences during childhood worthy of further investigation. PMID- 24804124 TI - Treatment of an extensive maxillary cyst using nasal airway and balloon catheter devices. AB - Introduction. Large maxillary cysts occasionally expand into the maxilla and erode the maxillary sinus and nasal cavity. The Caldwell-Luc procedure is the recommended treatment for large maxillary sinus cysts. However, it is hard to preserve the nasal space in the case of large maxillary sinus cysts that penetrate into the nasal cavity. Methods. A 22-year-old man who had large maxillary sinus cysts was referred to our department for a surgical treatment. After removing the cyst from the maxillary sinus using the Caldwell-Luc procedure, we used nasal airway and balloon catheter devices to preserve the space of the inferior nasal meatus and maxillary sinus. These devices were removed 10 days postoperatively. Insertion and removal of both devices were simple and painless. Findings. The nasal airway and balloon catheter devices were useful for performing maxillary sinus surgery to remove large cysts. Our method was satisfactorily safe and was an effective minimally invasive treatment that preserved the space of the inferior nasal meatus and maxillary sinus. PMID- 24804125 TI - Bilateral TMJ Involvement in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a systemic inflammatory, slowly progressive disease that results in cartilage and bone destruction. Temporomandibular joint (TMJ) involvement is not uncommon in RA, and it is present in about more than 50% of patients; however, TMJ is usually among the last joints to be involved and is associated with many varied clinical signs and symptoms. Hence, RA of TMJ presents to the dentist with great diagnostic challenges. This report presents a case of RA with bilateral TMJ involvement with its classical radiographic findings and review literature. PMID- 24804126 TI - Malignant transformation of an odontogenic cyst in a period of 10 years. AB - Primary intraosseous carcinoma of the jaws (PIOSCC) might arise from odontogenic epithelium, more commonly from a previous odontogenic cyst. The aim of this case is to illustrate that the clinician should consider that an apparent benign dentigerous cyst can suffer malignant transformation and that all material removed from a patient must be evaluated histologically. A 44-year-old man presented in a routine periapical X-ray an impacted lower left third molar with radiolucency over its crown. Ten years later, the patient complained of pain in the same region and the tooth was extracted. After one month, the patient still complained of pain and suffered a fracture of the mandible. A biopsy was performed and carcinoma was diagnosed. The patient was treated surgically with adjuvant radio- and chemotherapy and after 8 years, he is well without signs of recurrences. This report describes a central mandibular carcinoma probably developed from a previous dentigerous cyst. PMID- 24804127 TI - Acute and chronic fetal anemia as a result of fetomaternal hemorrhage. AB - Introduction. Fetomaternal hemorrhage represents a transfer of fetal blood to the maternal circulation. Although many etiologies have been described, most causes of fetomaternal hemorrhage remain unidentified. The differentiation between acute and chronic fetomaternal hemorrhage may be accomplished antenatally and may influence perinatal management. Case. A 36-year-old gravida 6 para 3 presented at 37 and 5/7 completed gestational weeks with ultrasound findings suggestive of chronic fetal anemia such as right ventricular enlargement, diminished cerebral vascular resistance, and elevated middle cerebral artery end-diastolic velocity. On the other hand, signs of acute fetal decompensation such as deterioration of the fetal heart tracing, diminished biophysical score, decreased cord pH, and increased cord base deficit were noted. Following delivery, the neonate's initial hemoglobin was 4.0 g/dL and the maternal KB ratio was 0.015 indicative of a significant fetomaternal hemorrhage. Discussion. One should consider FMH as part of the differential diagnosis for fetal or immediate neonatal anemia. We describe a unique case of FMH that demonstrated both acute and chronic clinical features. It is our hope that this case will assist practitioners in differentiating acute FMH that may require emergent delivery from chronic FMH which may be able to be expectantly managed. PMID- 24804129 TI - HELLP Syndrome Complicated by Subcapsular Hematoma of Liver: A Case Report and Review of the Literature. AB - Subcapsular liver hematoma (SLH) is a rare complication of severe preeclampsia and HELLP syndrome. These patients must be followed up in intensive care unit for advanced medical support with infused fluid, replacement of blood products, and treatment of underlying disorders. There are a lot of therapeutic options varying from conservative management to surgical treatment including hepatic resection, hepatic artery ligation, and liver transplantation. In this report we aimed to present a 26-year-old woman with SLH secondary to HELLP syndrome. PMID- 24804128 TI - Large mucocele of the appendix at laparoscopy presenting as an adnexal mass in a postmenopausal woman: a case report. AB - A 79-year-old female was referred to our Gynecologic Department presenting with a pelvic magnetic resonance imaging (MRI), showing an adnexal mass, later confirmed at the pelvic examination. The patient's routine laboratory tests were normal. A sonographic examination was performed with inconclusive results. Although the ultrasonography excluded the presence of vascularization and malignant degeneration, the adnexal localization appeared to be dubious. The laparoscopy and the subsequent histologic examination revealed the presence of a mucocele of the appendix. The following case report focuses the attention on a misdiagnosis of appendiceal mucocele. The misdiagnosis caused no negative impact on the treatment that in this case was adequate and successful. PMID- 24804130 TI - Combination therapy of albumin-bound Paclitaxel and Carboplatin as first line therapy in a patient with ovarian cancer. AB - Background. Ovarian cancer is the ninth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Albumin-bound paclitaxel is known to increase intratumoral concentration of the paclitaxel by a receptor-mediated transport process across the endothelial cell wall, thereby breaching the blood/tumor interface. We present below three cases in which nab paclitaxel based chemotherapy has been used in different settings for patients with ovarian cancer. Case Presentation. In the first case nab-paclitaxel was used along with carboplatin in adjuvant setting, in the second case, nab-paclitaxel was used along with carboplatin and bevacizumab as second line chemotherapy in a relapsed ovarian cancer case, and the third case delineates the use of nab paclitaxel along with cisplatin as third line chemotherapy. Conclusion. In all the three scenarios, patients tolerated the chemotherapy well, as well as responding well to nab-paclitaxel based chemotherapy. The patients are currently on long-term follow-up and have been having an uneventful postchemotherapy. PMID- 24804131 TI - Skin necrosis associated with thromboprophylaxis after total knee replacement. AB - Thromboprophylaxis are routinely given to prevent venous thromboembolism (VTE) in patients after total hip and knee replacement surgeries. Low molecular weight heparin (LMWH) (fractioned heparin) is effective in the prevention and treatment of VTE. The predicable effect of LMWH has popularized it for routine clinical use. Although LMWH has lesser complication rate, compared to unfractioned heparin (UFH), sporadic clinical complication has been reported. We report a rare case of skin necrosis secondary to use of LMWH tinzaparin used for routine thromboprophylaxis after total knee replacement. PMID- 24804132 TI - Bilateral simultaneous heterotopic ossification of the reflected head of rectus femoris muscle: a case report and review of the literature. AB - Lamellar bone formation in an abnormal location is defined as heterotopic ossification. It commonly occurs around the hip joint and most often involves the abductor muscles. It is a benign condition; however, its etiology remains largely unknown. Most previously reported cases have been due to trauma or intramuscular hemorrhage. In this paper, we present a case of bilateral heterotopic ossification of the reflected head of rectus femoris muscle without antecedent trauma or any other known cause, as the first and unique case in the literature. She was treated by excision of the right symptomatic bony mass via a modified Smith-Petersen approach. Postoperatively, she received 75 mg indomethacin daily for six weeks. She was pain-free and obtained full range of motion 3 weeks after the first intervention. PMID- 24804133 TI - Mixed large cell neuroendocrine carcinoma and adenocarcinoma with spindle cell and clear cell features in the extrahepatic bile duct. AB - Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP) were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6 cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9 postive) surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC). Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patient's poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas. PMID- 24804134 TI - HPV11 Positive Endometrioid Carcinoma of the Endometrium with Signet-Ring Cells: Diagnostic Criteria and Review of the Literature. AB - The presence of signet-ring cells in an endometrial adenocarcinoma is extremely uncommon and it is always necessary to rule out a metastatic neoplasm. We report a FIGO grade 2 endometrial carcinoma with a signet-ring cell component found in the curettage performed to a 53-year-old woman. The neoplastic proliferation was also found in the endometrium of the radical hysterectomy with bilateral salpingo oophorectomy and pelvic and para-aortic lymphadenectomy. The uterine neoplasm invaded less than one-half of the myometrium (FIGO stage I B). Alcian blue showed the presence of mucin in the signet-ring cells. The patient was alive and without evidence of recurrence 14 months after surgery. Polymerase chain reaction method from paraffin-embedded tissue revealed the presence of human papilloma virus type 11. We have discussed the differential diagnosis of this kind of neoplasm and we have reviewed the literature on signet-ring cell carcinoma of the endometrium. PMID- 24804135 TI - A Triad of Congenital Diaphragmatic Hernia, Meckel's Diverticulum, and Heterotopic Pancreas. AB - Congenital diaphragmatic hernia is a common developmental anomaly encountered by paediatric surgeons. It is known to be associated with extradiaphragmatic malformations, which include cardiac, renal, genital, and chromosomal abnormalities. Herein, we report a newborn born with concurrent congenital diaphragmatic hernia, Meckel's diverticulum, and heterotopic pancreatic tissue. This is the first case report of such a triad with description of possible mechanisms of the development. PMID- 24804136 TI - The Relationship between Endorsing Gambling as an Escape and the Display of Gambling Problems. AB - Previous research has reported a strong relationship between endorsing gambling as an escape and problem/pathological gambling as measured by the South Oaks Gambling Screen (SOGS). The present study recruited 249 university students to complete the Gambling Functional Assessment-Revised (GFA-R), which measures the function of the respondent's gambling, as well as the SOGS and the Problem Gambling Severity Index (PGSI), which was designed to identify gambling problems in the general population. Endorsing gambling as an escape on the GFA-R was again predictive of SOGS scores. The function of one's gambling was also predictive of the respondents' PGSI scores, but whether gambling for positive reinforcement or as an escape was the significant predictor differed between male and female respondents. Scores on the GFA-R subscales also accounted for a significant amount of variance in PGSI scores above and beyond that accounted for by SOGS scores. The present results support the idea that both practitioners and researchers should be interested in the function of an individual's gambling as well as the presence or the absence of pathology. They also suggest that differences in the function of gambling might also exist between the sexes. PMID- 24804137 TI - Everyday prospective memory and executive function deficits associated with exposure to second-hand smoke. AB - This study explored whether exposure to second-hand smoke (SHS) has a detrimental impact upon everyday memory in two groups of non-smokers; one which reported regular exposure to SHS and one that reported never having been exposed to SHS. Thirty-four non-smokers who reported having been regularly exposed to SHS (SHS group) and 34 non-smokers who reported never having been exposed to SHS (non-SHS group) were compared on self-reports of prospective memory (PM: remembering future intentions and/or activities) and executive function (EF: those processes involved in attention, multitasking and decision-making). The Prospective and Retrospective Memory Questionnaire (PRMQ) assessed everyday PM lapses; the Executive Function Questionnaire (EFQ) assessed self-reported problems in EF; a drug-use questionnaire and a mood questionnaire were also administered. Two univariate ANCOVAs were applied to the PM and EF data, controlling for between group differences in age, weekly alcohol use, anxiety and depression scores, and self-reported retrospective memory scores. The SHS group reported significantly more lapses on the PRMQ and more deficits on the EFQ than the non-SHS group. These findings provide new insights into PM and EF deficits associated with prolonged exposure to SHS in a group of non-smokers. Possible explanations and suggestions for future research are also considered. PMID- 24804138 TI - Parental factors associated with mexican american adolescent alcohol use. AB - The purpose of this study is to further the understanding of how parenting and the relationship between the parent and the youth influence adolescent alcohol use in Mexican American families, with particular attention to acculturation. Results indicated that parental warmth is a strong factor in predicting adolescent alcohol use among Mexican adolescents. The parent-youth relationship played an important role in lowering alcohol use for Mexican American youth. Acculturation has an impact on the level of warmth, control, and the parent-youth relationship for Mexican American families. Findings indicate that there are unique family mechanisms for Mexican American families that should be considered when developing prevention and treatment options. PMID- 24804139 TI - Association between Acculturation and Binge Drinking among Asian-Americans: Results from the California Health Interview Survey. AB - Objective. Evaluate the association between acculturation and binge drinking among six Asian-American subgroups. Methods. A cross-sectional analysis of public access adult portion of 2007, 2009, and 2011/2012 California Health Interview Survey data was conducted. Univariate and multivariable logistic regression analyses were utilized with any binge drinking in the past year as the outcome variable and language spoken at home and time in USA as proxy measures of acculturation. Results. A total of 1,631 Asian-Americans (N = 665,195) were identified as binge drinkers. Binge drinking was positively associated with being first generation South Asian (OR = 3.05, 95% CI = 1.55, 5.98) and monolingual (English only) Vietnamese (OR = 3.00; 95% CI = 1.58, 5.70), especially among females. Other factors associated with increased binge drinking were being female (Chinese only), not being current married (South Asian only), and being an ever smoker (all subgroups except South Asians). Conclusion. First generation South Asians and linguistically acculturated Vietnamese, especially females, are at an increased risk of binge drinking. Future studies and preventive measures should address the cultural basis of such health risk behaviors among Asian-American adults. PMID- 24804140 TI - An Association between Emotional Responsiveness and Smoking Behavior. AB - Introduction. Emotional responsiveness (ER) has been theorized to play a protective role in pathways to tobacco initiation, regular use, and dependence, yet a possible association between ER and smoking behavior has not been studied. Our aim was to test whether measuring ER to a neutral stimulus was associated with decreased odds of current smoking. Methods. We measured ER and smoking status (current, former, and never) in two datasets: a cross-sectional dataset of persons with diabetes (n = 127) and a prospective dataset of depressed patients (n = 107) from an urban primary care system. Because there were few former smokers in the datasets, smoking status was dichotomized (current versus former/never) and measured at baseline (cross-sectional dataset) or at 36 weeks after-baseline (prospective dataset). ER was ascertained with response to a neutral facial expression (any ER versus none). Results. Compared to their nonresponsive counterparts, adjusted odds of current smoking were lower among participants endorsing emotional responsiveness in both the cross-sectional and prospective datasets (ORs = .29 and .32, P's <.02, resp.). Discussion. ER may be protective against current smoking behavior. Further research investigating the association between ER and decreased smoking may hold potential to inform treatment approaches to improve smoking prevalence. PMID- 24804141 TI - Pattern and trend of substance abuse in eastern rural iran: a household survey in a rural community. AB - Introduction and Aim. Substance abuse imposes hazards on human health in all biopsychosocial aspects. Limited studies exist on epidemiology of substance abuse and its trend in rural areas. The present study aimed to compare substance abuse in one of the rural areas of southeast Iran, in a 12-year period (2000 and 2012). Design and Methods. In a household survey conducted in 2012, in Dashtkhak/Kerman, 1200 individuals above 12 years of age completed a questionnaire to determine their frequency of substance abuse. The questionnaire included the following three areas: demographic characteristics, frequency of substance abuse and ease of access to various drugs. Results. Among 900 completed questionnaires, majority of the participants (61.8%) were below 30 years of age and among them 54.4% were male. Cigarette (17.0%), opium (15.7%) and opium residue (9.0%) were the most frequent substances abused on a daily basis. Based on the participant's opinion, we conclude that the ease of access to cigarette, waterpipe and opium contributed to their increase in consumption compared with earlier years. Discussion and Conclusion. The steady rise in substance abuse in rural communities demands immediate attention and emergency preventive measures from policy makers. PMID- 24804142 TI - Early adolescents and substance use. AB - 1300 students (54.3% girls) 13-16 years old were interviewed in the urban area of Bologna during 2010. Random effect multiple logistic regression models were used. Results show a reciprocal relationship between alcohol use, tobacco, and cannabis. Most users were offered cannabis, began using at 14 years of age, and do not believe using is very dangerous. They live with only one parent, have more than 50 euros of spending money per month, and abuse alcohol, abuse that increases relative to the intensity of cigarette smoking. Legal/illegal dichotomy seems to overturn, where alcohol becomes a "drug" and the use of tobacco, similar to other drugs, is motivated as a solution to reduce anxiety, combat boredom, relax, and to ease loneliness. PMID- 24804143 TI - Exploring Spatial Associations between On-Sale Alcohol Availability, Neighborhood Population Characteristics, and Violent Crime in a Geographically Isolated City. AB - Objectives. Despite the increasing evidence of the associations between alcohol availability and violence, there are still inconsistent findings on the effects of on- and off-sale alcohol outlets on violent crime. The aim of this study was to examine spatial associations between on-sale alcohol availability, neighborhood characteristics, and violent crime in a geographically isolated city in Texas. Methods. Geographically weighted regression (GWR) and global regression models were employed to analyze the nature of the spatial relationship between violent crime, neighborhood sociocultural characteristics, and on-sale alcohol environment. Results. We found strong effects of neighborhood characteristics combined with on-sale alcohol availability on violence outcomes. Several neighborhood variables combined with alcohol availability explained about 63% of the variability in violence. An additional 7% was explained by the GWR model, while spatially nonstationary associations between violence and some predictor variables were observed. Conclusions. This study provided more credible evidence of the influence of on-sale alcohol outlets on violence in a unique setting. These findings have important policy implications in addressing the question of public health consequences of alcohol-related violence in local contexts. PMID- 24804144 TI - Filters in 2D and 3D Cardiac SPECT Image Processing. AB - Nuclear cardiac imaging is a noninvasive, sensitive method providing information on cardiac structure and physiology. Single photon emission tomography (SPECT) evaluates myocardial perfusion, viability, and function and is widely used in clinical routine. The quality of the tomographic image is a key for accurate diagnosis. Image filtering, a mathematical processing, compensates for loss of detail in an image while reducing image noise, and it can improve the image resolution and limit the degradation of the image. SPECT images are then reconstructed, either by filter back projection (FBP) analytical technique or iteratively, by algebraic methods. The aim of this study is to review filters in cardiac 2D, 3D, and 4D SPECT applications and how these affect the image quality mirroring the diagnostic accuracy of SPECT images. Several filters, including the Hanning, Butterworth, and Parzen filters, were evaluated in combination with the two reconstruction methods as well as with a specified MatLab program. Results showed that for both 3D and 4D cardiac SPECT the Butterworth filter, for different critical frequencies and orders, produced the best results. Between the two reconstruction methods, the iterative one might be more appropriate for cardiac SPECT, since it improves lesion detectability due to the significant improvement of image contrast. PMID- 24804146 TI - Dopamine Cytotoxicity Involves Both Oxidative and Nonoxidative Pathways in SH SY5Y Cells: Potential Role of Alpha-Synuclein Overexpression and Proteasomal Inhibition in the Etiopathogenesis of Parkinson's Disease. AB - Background. The cytotoxic effects of dopamine (DA) on several catecholaminergic cell lines involve DA oxidation products like reactive oxygen species (ROS) and toxic quinones and have implications in the pathogenesis of sporadic Parkinson's disease (PD). However, many molecular details are yet to be elucidated, and the possible nonoxidative mechanism of dopamine cytotoxicity has not been studied in great detail. Results. Cultured SH-SY5Y cells treated with DA (up to 400 MUM) or lactacystin (5 MUM) or DA (400 MUM) plus N-acetylcysteine (NAC, 2.5 mM) for 24 h are processed accordingly to observe the cell viability, mitochondrial dysfunctions, oxidative stress parameters, proteasomal activity, expression of alpha-synuclein gene, and intracellular accumulation of the protein. DA causes mitochondrial dysfunction and extensive loss of cell viability partially inhibited by NAC, potent inhibition of proteasomal activity marginally prevented by NAC, and overexpression with accumulation of intracellular alpha-synuclein partially preventable by NAC. Under similar conditions of incubation, NAC completely prevents enhanced production of ROS and increased formation of quinoprotein adducts in DA-treated SH-SY5Y cells. Separately, proteasomal inhibitor lactacystin causes accumulation of alpha-synuclein as well as mitochondrial dysfunction and cell death. Conclusions. DA cytotoxicity includes both oxidative and nonoxidative modes and may involve overexpression and accumulation of alpha-synuclein as well as proteasomal inhibition. PMID- 24804145 TI - The Renin-Angiotensin-aldosterone system in vascular inflammation and remodeling. AB - The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFalpha, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS's role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors. PMID- 24804147 TI - Surface electrical stimulation for treating swallowing disorders after stroke: a review of the stimulation intensity levels and the electrode placements. AB - Neuromuscular electrical stimulation (NMES) for treating dysphagia is a relatively new therapeutic method. There is a paucity of evidence about the use of NMES in patients with dysphagia caused by stroke. The present review aimed to introduce and discuss studies that have evaluated the efficacy of this method amongst dysphagic patients following stroke with emphasis on the intensity of stimulation (sensory or motor level) and the method of electrode placement on the neck. The majority of the reviewed studies describe some positive effects of the NMES on the neck musculature in the swallowing performance of poststroke dysphagic patients, especially when the intensity of the stimulus is adjusted at the sensory level or when the motor electrical stimulation is applied on the infrahyoid muscles during swallowing. PMID- 24804148 TI - Assessing the Effectiveness of Tuberculosis Management in Brushtail Possums (Trichosurus vulpecula), through Indirect Surveillance of Mycobacterium bovis Infection Using Released Sentinel Pigs. AB - In New Zealand, wild pigs acquire Mycobacterium bovis infection by scavenging tuberculous carrion, primarily carcasses of the main disease maintenance host, the brushtail possum (Trichosurus vulpecula). We investigated the utility of captive-reared, purpose-released pigs as sentinels for tuberculosis (TB) following lethal possum control and subsequent population recovery. Within 2-3 years of possum control by intensive poisoning, TB prevalence and the incidence rate of M. bovis infection in released sentinel pigs were lower than in an adjacent area where possums had not been poisoned. Unexpectedly, TB did not decline to near zero levels among pigs in the poisoned area, a fact which reflected an unanticipated rapid increase in the apparent abundance of possums. Monitoring infection levels among resident wild pigs confirmed that TB prevalence, while reduced due to possum control, persisted in the poisoned area at >20% among pigs born 2-3 years after poisoning, while remaining >60% among resident wild pigs in the nonpoisoned area. When fitted with radio-tracking devices, purpose-released pigs provided precise spatial TB surveillance information and facilitated effective killing of wild pigs when employed as "Judas" animals to help locate residents. Sentinel pigs offer value for monitoring disease trends in New Zealand, as TB levels in possums decline nationally due to large-scale possum control. PMID- 24804149 TI - Clinico Hemato Biochemical Findings, Clinical Management, and Production Performance of Bovines with Late Pregnancy Indigestion (Type IV Vagal Indigestion). AB - This prospective study was conducted on 15 animals (eight buffaloes and seven cows), diagnosed with late pregnancy indigestion. Ten buffaloes and 10 cows served as the control group. The animals were in advanced pregnancy and had partial or complete anorexia, reduced water intake, loss of defecation or scanty faecal output, and mild to moderate dehydration. Heart and respiration rates were increased and rumen motility was reduced. Five animals had persistent tympany and moderate distension of left abdomen, and two animals each had bilateral abdominal distension and papple shaped abdomen. Neutrophil and lymphocyte counts were significantly higher and lower than the control values. Total bilirubin, AST, total protein, globulin, BUN, glucose, and lactate were significantly higher, and chloride and calcium were significantly lower than the control values. Levels of ALP, GGT, albumin, creatinine, cholesterol, triglyceride, fibrinogen, fibrinogen ratio, sodium, potassium, phosphorus, and magnesium did not differ significantly from the control values. Rumen chloride concentration was higher than the reference range. Majority of animals were managed symptomatically until parturition. There was no effect on fetal survival or milk yield in current and subsequent lactation. So, late pregnancy indigestion causes clinical and hemato biochemical alterations which require special consideration when treating diseased animals. PMID- 24804150 TI - Studies on Antimicrobial and Immunomodulatory Effects of Hot Aqueous Extract of Acacia nilotica L. Leaves against Common Veterinary Pathogens. AB - Acacia nilotica is a plant species that is almost ubiquitously found in different parts of the world. Various preparations of it have been advocated in folk medicine for the treatment of tuberculosis, leprosy, smallpox, dysentery, cough, ophthalmia, toothache, skin cancer as astringent, antispasmodic, and aphrodisiac since immemorial times. The present study investigates the antibacterial, antifungal, antiviral, and immunomodulatory potential of hot aqueous extract (HAE) of Acacia nilotica leaves. On dry matter basis, the filtered HAE had a good extraction ratio (33.46%) and was found to have carbohydrates, glycosides, phytosterols, phenolic compounds, saponins, and flavonoids as major constituents. HAE produced dose dependent zone of inhibition against Klebsiella pneumoniae, Pseudomonas aeruginosa, E. coli, Bacillus cereus, Staphylococcus aureus, and Streptococcus uberis and fungal pathogens Aspergillus niger and Aspergillus fumigates; however, no antiviral activity was recorded against IBR virus. HAE of A. nilotica revealed both proliferative and inhibitory effects on the rat splenocytes and IL-10 release depending on the dose. Detailed studies involving wide spectrum of bacterial, fungal, and viral species are required to prove or know the exact status of each constituents of the plant extract. PMID- 24804151 TI - Mechanistic Insights into Carbonyl-Directed Rhodium-Catalyzed Hydroboration: ab Initio Study of a Cyclic gamma,delta-Unsaturated Amide. AB - A two-point binding mechanism for the cationic rhodium(I)-catalyzed carbonyl directed catalytic asymmetric hydroboration of a cyclic gamma,delta-unsaturated amide is investigated using density functional theory. Geometry optimizations and harmonic frequency calculations for the model reaction are carried out using the basis set 6-31+G** for C, O, P, B, N, and H and LANL2DZ for Rh atoms. The Gibbs free energy of each species in THF solvent is obtained based on the single-point energy computed using the PCM model at the ECP28MWB/6-311+G(d,p) level plus the thermal correction to Gibbs free energy by deducting translational entropy contribution. The Rh-catalyzed reaction cycle involves the following sequence of events: (1) chelation of the cyclic gamma,delta-unsaturated amide via alkene and carbonyl complexation in a model active catalytic species, [Rh(L2)2S2]+, (2) oxidative addition of pinacol borane (pinBH), (3) migratory insertion of the alkene double bond into Rh-H (preferred pathway) or Rh-B bond, (4) isomerization of the resulting intermediate, and finally, (5) reductive elimination to form the B-C or H-C bond with regeneration of the catalyst. Free energy profiles for potential pathways leading to the major gamma-borylated product are computed and discussed in detail. The potential pathways considered include (1) pathways proceeding via migratory insertion into the Rh-H bond (pathways I, I-1, and I-2), (2) a potential pathway proceeding via migratory insertion into the Rh-B bond (pathway II), and two potential competing routes to a beta-borylated byproduct (pathway III). The results find that the Rh-H migratory insertion pathway I-2, followed in sequence by an unanticipated isomerization via amide rotation and reductive elimination, is the most favorable reaction pathway. A secondary consequence of amide rotation is access to a competing beta-hydride elimination pathway. The pathways computed in this study are supported by and help explain related experimental results. PMID- 24804152 TI - Characterization and Engineering of the Adenylation Domain of a NRPS-Like Protein: A Potential Biocatalyst for Aldehyde Generation. AB - The adenylation (A) domain acts as the first "gate-keeper" to ensure the activation and thioesterification of the correct monomer to nonribosomal peptide synthetases (NRPSs). Our understanding of the specificity-conferring code and our ability to engineer A domains are critical for increasing the chemical diversity of nonribosomal peptides (NRPs). We recently discovered a novel NRPS-like protein (ATEG_03630) that can activate 5-methyl orsellinic acid (5-MOA) and reduce it to 2,4-dihydroxy-5,6-dimethyl benzaldehyde. A NRPS-like protein is much smaller than multidomain NRPSs, but it still represents the thioesterification half-reaction, which is otherwise missed from a stand-alone A domain. Therefore, a NRPS-like protein may serve as a better model system for A domain engineering. Here, we characterize the substrate specificity of ATEG_03630 and conclude that the hydrogen-bond donor at the 4-position is crucial for substrate recognition. Next, we show that the substrate specificity of ATEG_03630 can be engineered toward our target substrate anthranilate via bioinformatics analysis and mutagenesis. The resultant mutant H358A increased its activity toward anthranilate by 10.9-fold, which led to a 26-fold improvement in specificity. Finally, we demonstrate one pot chemoenzymatic synthesis of 4-hydroxybenzaldoxime from 4-hydroxybenzoic acid with high yield. PMID- 24804153 TI - Aggregation-prone proteins modulate huntingtin inclusion body formation in yeast. AB - Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (HTT) protein. The expression of mutant HTT in the baker's yeast Saccharomyces cerevisiae recapitulates many of the cellular phenotypes observed in mammalian HD models. Mutant HTT aggregation and toxicity in yeast is influenced by the presence of the Rnq1p and Sup35p prions, as well as other glutamine/asparagine-rich aggregation-prone proteins. Here we investigated the ability of a subset of these proteins to modulate mutant HTT aggregation and to substitute for the prion form of Rnq1p. We find that overexpression of either the putative prion Ybr016wp or the Sup35p prion restores aggregation of mutant HTT in yeast cells lacking the Rnq1p prion. These results indicate that an interchangeable suite of aggregation-prone proteins regulates mutant HTT aggregation dynamics in yeast, which may have implications for mutant HTT aggregation in human cells. PMID- 24804154 TI - Synthesis of Hydrophobic Carbohydrate Polymers and Their Formation of Thermotropic Liquid Crystalline Phases. AB - The first synthesis of enantiopure glucose octyl ether polyamido-saccharides (GOE PAS) with a defined molecular weight and narrow dispersity is reported using a controlled anionic ring-opening polymerization of a glucose-derived beta-lactam sugar monomer possessing octyl ether chains. This new polymer structure is characterized by NMR, infrared (IR), optical rotation, gel permeation chromatography (GPC), and thermogravimetric analysis (TGA). At room temperature, the polymers form lamellar (Lam) phases. Upon heating to mild temperatures (ca. 60 degrees C), the shortest polymer shows a direct transition to the isotropic (Iso) liquid state, while the longer polymers give rise to a hexagonal columnar (Colh) phase before becoming isotropic at higher temperatures (ca. 120 degrees C). PMID- 24804155 TI - Usability and Effects of an Exergame-Based Balance Training Program. AB - Background: Post-stroke recovery benefits from structured, intense, challenging, and repetitive therapy. Exergames have emerged as promising to achieve sustained therapy practice and patient motivation. This study assessed the usability and effects of exergames on balance and gait. Subjects and Methods: Sixteen elderly participants were provided with the study intervention based on five newly developed exergames. The participants were required to attend 36 training sessions; lasting for 20 minutes each. Adherence, attrition and acceptance were assessed together with (1) Berg Balance Scale, (2) 7-m Timed Up and Go, (3) Short Physical Performance Battery, (4) force platform stance tests, and (5) gait analysis. Results: Thirteen participants completed the study (18.8 percent attrition), without missing a single training session (100 percent adherence). Participants showed high acceptance of the intervention. Only minor adaptations in the program were needed based on the users' feedback. No changes in center of pressure area during quiet stance on both stable and unstable surfaces and no changes of walking parameters were detected. Scores for the Berg Balance Scale (P=0.007; r=0.51), the 7-m Timed Up and Go (P=0.002; r=0.56), and the Short Physical Performance Battery (P=0.013; r=0.48) increased significantly with moderate to large effect sizes. Conclusion: Participants evaluated the usability of the virtual reality training intervention positively. Results indicate that the intervention improves gait- and balance-related physical performance measures in untrained elderly. The present results warrant a clinical explorative study investigating the usability and effectiveness of the exergame-based program in stroke patients. PMID- 24804156 TI - Electrospun Tropoelastin for Delivery of Therapeutic Adipose-Derived Stem Cells to Full-Thickness Dermal Wounds. AB - Objective: To evaluate the physiological effects of electrospun tropoelastin scaffolds as therapeutic adipose-derived stem cell (ADSC) delivery vehicles for the treatment of full-thickness dermal wounds. Approach: Using the process of electrospinning, several prototype microfiber scaffolds were created with tropoelastin. Initial testing of scaffold biocompatibility was performed in vitro through ADSC culture, followed by scanning electron microscopy (SEM) for assessment of ADSC attachment, morphology, and new extracellular matrix (ECM) deposition. The wound healing effects of ADSC-seeded scaffolds were then evaluated in a murine dermal excisional wound model. Results: For the in vitro study, SEM revealed exceptional biocompatibility of electrospun tropoelastin for ADSCs. In the wound-healing study, ADSC-treated groups demonstrated significantly enhanced wound closure and epithelial thickness compared to controls. Innovation: This is the first report on the use of tropoelastin-based biomaterials as delivery vehicles for therapeutic ADSCs. Conclusion: We have demonstrated that tropoelastin-based ADSC delivery vehicles significantly accelerate wound healing compared to controls that represent the current clinical standard of care. Furthermore, the unique mechanical and biochemical characteristics of tropoelastin may favor its use over other biological or synthetic scaffolds for the treatment of certain pathologies due to its unique intrinsic mechanical properties. PMID- 24804157 TI - Visual Feedback of Continuous Bedside Pressure Mapping to Optimize Effective Patient Repositioning. AB - Objective: To evaluate the effectiveness of a new bedside pressure mapping technology for patient repositioning in a long-term acute care hospital. Approach: Bedside caregivers repositioned patients to the best of their abilities, using pillows and positioning aids without the visual feedback from a continuous bedside pressure mapping (CBPM) system. Once positioned, caregivers were shown the image from the CBPM system and allowed to make further adjustments to the patient position. Data from the CBPM device, in the form of visual screenshots and peak pressure values, were obtained after each repositioning phase. Caregivers provided feedback on repositioning with and without the CBPM system. Results: Screenshots displayed lower pressures when the visual feedback from the CBPM systems was utilized by caregivers. Lower peak pressure measurements were also evident when caregivers utilized the image from the CBPM systems. Overall, caregivers felt the system enabled more effective patient positioning and increased the quality of care they provided their patients. Innovation: This is the first bedside pressure mapping device to be continuously used in a clinical setting to provide caregivers and patients visual, instant feedback of pressure, thereby enhancing repositioning and offloading practices. Conclusion: With the visual feedback from the pressure mapping systems, caregivers were able to more effectively reposition patients, decreasing exposure to damaging high pressures. PMID- 24804158 TI - The Effect of Vacuum-Assisted Closure on the Bacterial Load and Type of Bacteria: A Systematic Review. AB - Significance: A high bacterial load interferes with the healing process of a wound. Vacuum-assisted closure (VAC) is a wound healing therapy that utilizes a dressing system that continuously or intermittently applies a negative pressure to the wound surface. Recent Advances: VAC stimulates wound healing, but data on changes in the bacterial load and changes in the bacterial spectrum are scarce. Critical Issues: While VAC supposedly removes bacteria from the treated wounds and therefore reduces the risk of infection, this relationship has not yet been clinically proven. If VAC increases the bacterial load instead of decreasing it, then this may be a reason not to use VAC on certain types of wounds. Only seven small and heterogeneous studies reporting on the relationship between VAC usage and the bacterial load and type of bacteria in the treated wounds in clinical practice were found in the literature. Although there is some low quality evidence that VAC therapy does not change the bacterial load, no definite conclusions on changes in the bacterial load and type of bacteria during VAC can be drawn. Future Directions: Prospectively monitoring changes in the bacterial load and bacterial spectrum in patients that will receive VAC treatment on indication might be an effective way to find out whether it should indeed be used on specific wounds. PMID- 24804160 TI - Integrating Structured Learning and Scholarly Activities into Clerkship Rotations: A Win-Win for Students and Preceptors. AB - Objective: To merge scholarly activity into the curriculum developed for medical students electing a rotation in wound care and/or dermatology. Approach: The authors adapted the unique wound care curriculum developed for medical student rotators and residents to incorporate structured scholarly projects, opportunities for mentorship, and feedback for continued improvement. Results: Benefits have been observed to both students and to the clinic, as reflected by online survey results, increased productivity in the form of posters and manuscripts, and opportunities for professional networking. Discussion: Rotations and clerkships can be transformed from haphazard, bystander observational experiences to active participation that enhances comprehension and retention, while also providing benefits to preceptors. Innovation: Integration between research, education, and clinical activities in a structured way can provide opportunity for enhanced learning experiences and promote the concept of evidence based practice. Conclusion: With observed benefits to students, researchers, and staff in this clinical setting, other clerkship rotation settings should consider an integrated and structured approach to learning, which includes scholarly activities. Further rigorous program evaluation is necessary to further quantify preliminary positive feedback regarding this approach. PMID- 24804159 TI - The Role of Hypoxia-Inducible Factor in Wound Healing. AB - Significance: Poor wound healing remains a significant health issue for a large number of patients in the United States. The physiologic response to local wound hypoxia plays a critical role in determining the success of the normal healing process. Hypoxia-inducible factor-1 (HIF-1), as the master regulator of oxygen homeostasis, is an important determinant of healing outcomes. HIF-1 contributes to all stages of wound healing through its role in cell migration, cell survival under hypoxic conditions, cell division, growth factor release, and matrix synthesis throughout the healing process. Recent Advances: Positive regulators of HIF-1, such as prolyl-4-hydroxylase inhibitors, have been shown to be beneficial in enhancing diabetic ischemic wound closure and are currently undergoing clinical trials for treatment of several human-ischemia-based conditions. Critical Issues: HIF-1 deficiency and subsequent failure to respond to hypoxic stimuli leads to chronic hypoxia, which has been shown to contribute to the formation of nonhealing ulcers. In contrast, overexpression of HIF-1 has been implicated in fibrotic disease through its role in increasing myofibroblast differentiation leading to excessive matrix production and deposition. Both positive and negative regulators of HIF-1 therefore provide important therapeutic targets that can be used to manipulate HIF-1 expression where an excess or deficiency in HIF-1 is known to correlate with pathogenesis. Future Directions: Targeting HIF-1 during wound healing has many important clinical implications for tissue repair. Counteracting the detrimental effects of excessive or deficient HIF-1 signaling by modulating HIF-1 expression may improve future management of poorly healing wounds. PMID- 24804161 TI - Two is better than one: Complementing oncolytic virotherapy with gemcitabine to potentiate antitumor immune responses. AB - Oncolytic viruses (OVs) preferentially infect and kill cancer cells. Additionally, OV-induced immune responses subvert cancer-associated immunosuppression and promote antitumor immunity. We have recently demonstrated that the complementation of oncolytic virotherapy with gemcitabine accentuates its immunostimulatory effects, hence exerting superior antineoplastic activity. PMID- 24804163 TI - Extracellular o-linked N-acetylglucosamine is enriched in stem cells derived from human umbilical cord blood. AB - Stem cells have a unique ability to self-renew and differentiate into diverse cell types. Currently, stem cells from various sources are being explored as a promising new treatment for a variety of human diseases. A diverse set of functional and phenotypical markers are used in the characterization of specific therapeutic stem cell populations. The glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA 3, SSEA-4, Tra 1-60, and Tra 1-81. We have now discovered by mRNA analysis that a novel glycosyltranferase, epidermal growth factor (EGF) domain-specific O-linked GlcNAc transferase (EOGT), is highly expressed in stem cells. EOGT is responsible for adding O-linked N-acetylglucosamine (O-GlcNAc) to folded EGF domains on extracellular proteins, such as those on the Notch receptors. We were able to show by immunological assays that human umbilical cord blood-derived mesenchymal stromal cells display O-GlcNAc, the product of EOGT, and that O-GlcNAc is further elongated with galactose to form O-linked N-acetyllactosamine. We suggest that these novel glycans are involved in the fine tuning of Notch receptor signaling pathways in stem cells. PMID- 24804162 TI - Obesity and renal cancer: Role of adipokines in the tumor-immune system conflict. AB - Epidemiological studies link obesity, as measured by increased body mass index (BMI) to the incidence of renal cell carcinoma (RCC) as well as to the cancer related mortality of RCC patients. RCC is the third cancer most robustly associated with increased BMI. Understanding the role of the adipose tissue in renal carcinogenesis is therefore of major importance for the development of novel paradigms of RCC prevention and treatment. Here, we discuss the current knowledge on the impact of obesity on the development and progression of RCC as well as the role of adipose tissue-derived hormones (adipokines) in the conflict between growing tumors and the immune system. PMID- 24804164 TI - MUC1 Is Expressed by Human Skin Fibroblasts and Plays a Role in Cell Adhesion and Migration. AB - The mucin MUC1 is expressed by normal and cancerous epithelial cells and some nonepithelial cells in which it plays roles in regulating adhesion, migration, and cell signaling. In the present studies we found that MUC1 is expressed by normal human neonatal and adult skin fibroblasts. Fibroblasts are usually considered negative for MUC1 expression. Reverse-transcription polymerase chain reaction and Western blot analyses indicate the presence of full-length MUC1, and immunofluorescence and subcellular fractionation studies show that the protein is expressed on the plasma membrane. Immunohistochemical analyses confirmed the expression of MUC1 by fibroblasts in cryosections of normal human skin. Silencing MUC1 expression in fibroblasts using MUC1 shRNA increased the adhesion of cells to collagen and laminin. Transfection with MUC1 shRNA also increased fibroblast migration on collagen as measured in a wound-healing assay. The expression of alpha2-integrin was increased in MUC1 shRNA-transfected fibroblasts in which it was localized to membrane ruffles, providing a possible explanation for the increased cell migration on collagen. These results extend the range of expression of MUC1 to skin fibroblasts and suggest a functional role for MUC1 in fibroblast adhesion and motility. PMID- 24804165 TI - Sonic hedgehog pathway contributes to gastric cancer cell growth and proliferation. AB - The Sonic Hedgehog (Shh) signaling pathway is commonly activated in gastrointestinal cancer. However, our understanding of the Shh pathway in gastric cancer remains limited. Here we examined the effects of cyclopamine, a specific inhibitor of the Shh signaling pathway, on cell growth and proliferation in gastric primary cancer cells GAM-016 and the MKN-45 cell line. The results showed that the Shh signaling molecules SHH, PTCH, SMO, GLI1, and GLI2 were intact and activated in both types of cells. Furthermore, we observed that cyclopamine inhibited gastric cancer cell proliferation through cell cycle arrest and apoptosis. An in vivo study using NOD/SCID mouse xenografts demonstrated that cyclopamine significantly prevented tumor growth and development. Our study indicated that Shh signaling pathway could promote gastric cancer cell proliferation and tumor development, and blocking this pathway may be a potential strategy in gastric cancer treatment. PMID- 24804166 TI - Human respiratory syncytial virus memphis 37 causes acute respiratory disease in perinatal lamb lung. AB - Respiratory syncytial virus (RSV) is the leading cause of hospitalization due to respiratory illness among infants and young children of industrialized countries. There is a lack of understanding of the severe disease mechanisms as well as limited treatment options, none of which are fully satisfactory. This is partly due to lack of a relevant animal model of perinatal RSV infection that mimics moderate to severe disease in infants. We and others have shown mild disease in perinatal lambs with either a bovine or a human A2 strain of RSV. The Memphis 37 clinical strain of human RSV has been used to produce mild to moderate upper respiratory disease in healthy adult volunteers. We hypothesized that the Memphis 37 strain of RSV would infect perinatal lambs and produce clinical disease similar to that in human infants. Perinatal (3- to 5-day-old) lambs were inoculated intranasally with 2 mL/nostril of 1*10(5) focus-forming units (FFU)/mL (n=2) or 2.1*10(8) FFU/mL (n=3) of RSV Memphis 37. Clinical signs, gross and histological lesions, and immune and inflammatory responses were assessed. Memphis 37 caused moderate to severe gross and histologic lesions along with increased mRNA expression of macrophage inflammatory protein. Clinically, four of the five infected lambs had a mild to severe increase in expiratory effort. Intranasally administered RSV strain Memphis 37 infects neonatal lambs with gross, histologic, and immune responses similar to those observed in human infants. PMID- 24804167 TI - Development of an animal fracture model for evaluation of cement augmentation femoroplasty: an in vitro biomechanical study. AB - Osteoporotic hip fracture is the most severe kind of fracture with high morbidity and mortality. Patients' ambulation and quality of life are significantly affected by the fracture because only 50% regain their prefracture functional status, even if they undergo surgeries. There are many issues associated with the current preventive methods e.g., cost, side effects, patient compliance, and time for onset of action. Femoroplasty, the injection of bone cement into the proximal femur to augment femoral strength and to prevent fracture, has been an option with great potential. However, until now femoroplasty has remained at the stage of biomechanical testing. No in vivo study has evaluated its safety and effectiveness; there is not even an animal model for such investigations. The objective of this study was to develop a proximal femur fracture goat model that consistently fractures at the proximal femur when subject to vertical load, simulating osteoporotic hip fractures in human. Six pairs of fresh frozen mature Chinese goats' femora were obtained and randomly assigned into two groups. For the experimental group, a cylindrical bone defect was created at the proximal femur, while the control was left untreated. In addition, a configuration to mimic the mechanical axis of the goat femur was developed. When subjected to load along the mechanical axis, all the specimens from the bone defect group experienced femoral neck fractures, while fractures occurred at the femoral neck or other sites of the proximal femur in the control group. The biomechanical property (failure load) of the bone defect specimens was significantly lower than that of the control specimens (p<0.05). Osteoporotic hip fractures of humans were simulated by a goat fracture model, which may serve as a reference for future femoroplasty studies in vivo. The newly developed configuration simulating a femoral mechanical axis for biomechanical tests was practicable during the study. PMID- 24804168 TI - Follow-up of implant survival comparing ficoll and bone marrow aspirate concentrate methods for hard tissue regeneration with mesenchymal stem cells in humans. AB - OBJECTIVE: Clinical follow-up of implant survival in 11 patients comparing two different methods for mesenchymal stem cell (MSC) isolation (Ficoll and bone marrow aspirate concentrate [BMAC]) applied in maxillary sinus augmentation. METHODS: Mononuclear cells, including MSCs, were concentrated with either Ficoll (control group, n=6 sinus) or BMAC (test group, n=12 sinus) and transplanted in combination with bovine bone mineral. A total of 50 implants were placed in a second surgical intervention (17 Ficoll/33 BMAC) and loaded after 4 months. Overall implant survival was assessed with a Kaplan-Meier model using package survival under R. RESULTS: Implant survival of the Ficoll group was 100% compared with the BMAC group, which had 93.4% survival (95% confidence interval, 0.849-1). The difference between the groups was not significant (p=0.381). CONCLUSION: The BMAC system is an effective and suitable "chair-side" method for clinical application in hard tissue regeneration. PMID- 24804171 TI - Prediction of hepatocellular carcinoma incidence risk by ultrasound elastography. PMID- 24804170 TI - An omnibus permutation test on ensembles of two-locus analyses can detect pure epistasis and genetic heterogeneity in genome-wide association studies. AB - This article presents the ability of an omnibus permutation test on ensembles of two-locus analyses (2LOmb) to detect pure epistasis in the presence of genetic heterogeneity. The performance of 2LOmb is evaluated in various simulation scenarios covering two independent causes of complex disease where each cause is governed by a purely epistatic interaction. Different scenarios are set up by varying the number of available single nucleotide polymorphisms (SNPs) in data, number of causative SNPs and ratio of case samples from two affected groups. The simulation results indicate that 2LOmb outperforms multifactor dimensionality reduction (MDR) and random forest (RF) techniques in terms of a low number of output SNPs and a high number of correctly-identified causative SNPs. Moreover, 2LOmb is capable of identifying the number of independent interactions in tractable computational time and can be used in genome-wide association studies. 2LOmb is subsequently applied to a type 1 diabetes mellitus (T1D) data set, which is collected from a UK population by the Wellcome Trust Case Control Consortium (WTCCC). After screening for SNPs that locate within or near genes and exhibit no marginal single-locus effects, the T1D data set is reduced to 95,991 SNPs from 12,146 genes. The 2LOmb search in the reduced T1D data set reveals that 12 SNPs, which can be divided into two independent sets, are associated with the disease. The first SNP set consists of three SNPs from MUC21 (mucin 21, cell surface associated), three SNPs from MUC22 (mucin 22), two SNPs from PSORS1C1 (psoriasis susceptibility 1 candidate 1) and one SNP from TCF19 (transcription factor 19). A four-locus interaction between these four genes is also detected. The second SNP set consists of three SNPs from ATAD1 (ATPase family, AAA domain containing 1). Overall, the findings indicate the detection of pure epistasis in the presence of genetic heterogeneity and provide an alternative explanation for the aetiology of T1D in the UK population. PMID- 24804172 TI - The beginning of a new era of digestive surgery guided by fluorescence imaging. PMID- 24804173 TI - Clinical trials of combined molecular targeted therapy and locoregional therapy in hepatocellular carcinoma: past, present, and future. AB - BACKGROUND: Sorafenib, a multikinase inhibitor that targets angiogenesis in hepatocellular carcinoma (HCC), has become a standard treatment for advanced stage HCC and has shown survival benefits in recent clinical trials. Transarterial chemoembolization (TACE) and sorafenib are currently standard treatments for intermediate and advanced-stage HCC, respectively. Combined locoregional therapy, including TACE and molecular targeted therapies such as sorafenib, is an issue under active investigation in an attempt to improve the outcomes of patients with unresectable HCC. SUMMARY: Various clinical trials of these combined strategies have been conducted; however, the designs of these studies are diverse in terms of treatment modalities and schedules; comparisons with controls, baseline tumor stages, and hepatic functional reserves; and outcome measures. KEY MESSAGES: This article reviews heterogeneity in the design of recent clinical trials of combined locoregional and molecular targeted therapies and briefly addresses future study directions. PMID- 24804174 TI - Radiotherapeutic options for hepatocellular carcinoma with portal vein tumor thrombosis. AB - Portal vein tumor thrombosis (PVTT) is a common paraneoplastic condition in advanced primary hepatocellular carcinoma or hepatobiliary tract malignancies. Tumors with PVTT are frequently associated with adverse and aggressive features such as intrahepatic tumor dissemination, early treatment failure, or deterioration of hepatic function. Therefore, the treatment outcomes for PVTT in historical series are often dismal and discouraging. More recently, beneficial effects and excellent outcomes of external beam radiation therapy (EBRT) for treating this disease have been reported, and the use of EBRT is becoming more common because of the non-invasive nature of RT and rapid advances in RT technology. We hope to be able to cure this devastating condition in the near future with more advanced and efficacious disease management strategies. The current status and clinical trial results for EBRT as a promising treatment option for managing PVTT will be discussed here. PMID- 24804175 TI - Hepatic iron overload and hepatocellular carcinoma. AB - In recent years it has become increasingly evident that excess body iron may be complicated by the supervention of hepatocellular carcinoma (HCC). Hereditary hemochromatosis (HH) was the first condition in which hepatic iron overload was shown to predispose to the development of HCC. The inherited predisposition to excessive absorption of dietary iron in HH is almost always the result of homozygosity of the C282Y mutation of the HFE gene, which causes inappropriately low secretion of hepcidin. HCC develops in 8-10% of patients with HH and is responsible for approximately 45% of deaths in the HCC patients. Cirrhosis is almost always present when HCC is diagnosed. Dietary iron overload is a condition which occurs in rural-dwelling Black Africans in southern Africa as a result of the consumption, over time, of large volumes of alcohol home-brewed in iron containers and having, as a consequence, a high iron content. Iron loading of the liver results and may be complicated by malignant transformation of the liver (relative risk of approximately 10.0). Accompanying cirrhosis does occur but is less common than that in HH. The development of HCC as a consequence of increased dietary iron, and the fact that it may develop in the absence of cirrhosis, has been confirmed in an animal model. Drinking water with a high iron content might contribute to the high incidence of HCC in parts of Taiwan. The metabolic syndrome [obesity, insulin resistance type 2 (or diabetes mellitus type 2), non alcoholic fatty liver or non-alcoholic steatohepatitis] has in recent years become a major public health problem in some resource-rich countries. A link between excess body iron and insulin resistance or the metabolic syndrome has become apparent. The metabolic syndrome may be complicated by the supervention of HCC, and recent evidence suggests that increased body iron may contribute to this complication. PMID- 24804176 TI - Quantitative Levels of Hepatitis B Virus DNA and Surface Antigen and the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Receiving Long-Term Nucleos(t)ide Analogue Therapy. AB - BACKGROUND: Serum levels of hepatitis B virus (HBV) DNA are an important predictor of the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV infection. However, little is known about whether high levels of hepatitis B surface antigen (HBsAg) increase the risk for HCC. METHODS: We investigated 167 patients who were treated with nucleos(t)ide analogues (NA) for at least 2 years (median: 5.8 years, range: 2-13.1 years). Relationships between reduced levels of HBsAg and various factors were evaluated. In addition, we evaluated the usefulness of quantitative serum levels of HBV DNA and HBsAg as predictors of HCC development in patients receiving long-term NA therapy. RESULTS: HCC developed in 9 of the 167 NA-treated patients. In the 9 patients with HCC, HBV DNA was undetectable (<2.1 log copies/mL), but HBsAg levels were >=2000 C.O.I. in 7 patients. No maternal transmission, long NA treatment period, HBV DNA levels <3.0 log copies/mL, and reduced hepatitis B e antigen levels during the first 24 weeks of treatment were a significant factor of HBsAg levels <2000 C.O.I.. CONCLUSIONS: Hepatocarcinogenesis was observed in patients with high HBsAg levels, despite the negative conversion of HBV DNA as a result of long-term NA therapy. Therefore, to suppress hepatocarcinogenesis, it is important to control not only HBV DNA levels but also HBsAg levels. PMID- 24804177 TI - Tracking Navigation Imaging of Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma Using Three-Dimensional Cone-Beam CT Angiography. AB - PURPOSE: New tracking navigation imaging software was used to evaluate the usefulness of three dimensional (3D) CT angiography for transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Fifty-two patients with 73 HCCs were enrolled in this study retrospectively. Rotational angiography was performed from the hepatic artery for evaluation of the tumor feeding vessels. Arteries feeding the tumor were traced automatically by adjusting the region of interest around the targeted tumor on axial and coronal images using tracking navigation imaging with 3D cone beam CT angiography. RESULTS: Using final selective angiographic findings as the gold standard, the detection of feeding vessels was 90.4% (66/73) for tracking navigation imaging and 50.7% (37/73) for celiac trunk angiography. This difference was statistically significant (Wilcoxon rank sum test, p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of feeding arteries were 97.1% (66/68), 80.0% (4/5), 98.5% (66/67), and 66.7% (4/6), respectively. The kappa coefficient had a value of 0.638 (95% CI: 0.471-0.805), which is considered to indicate a good degree of agreement. With the assistance of tracking navigation imaging, the disease control rate of TACE for HCC was 67.3% (35/52) according to the modified Response Evaluation Criteria in Solid Tumors. During follow-up periods of 1-11 months, 10 patients (19.2%) remained cancer-free after TACE. CONCLUSION: Tracking navigation imaging with 3D cone-beam CT angiography should be useful for TACE in HCC patients with complicated feeding arteries. PMID- 24804178 TI - Efficacy of fixed daily 20 mg of isotretinoin in moderate to severe scar prone acne. AB - BACKGROUND: Despite advances in acne therapy in recent years, treatment failure is common. Isotretinoin is the only drug that affects almost all factors in acne pathogenesis, but side-effects are common at the doses reported in published studies in the literature. The aim of this study was to investigate the efficacy of low daily dose isotretinoin in moderate to severe acne patients. The secondary objective was to measure the rate of relapse 5 years after the completion of therapy. MATERIALS AND METHODS: In this retrospective, noncomparative study, 146 patients with moderate to severe scare prone acne. Treatment regimen consisted of isotretinoin, fixed 20 mg daily, and duration of treatment-based on the weight of patient, until total cumulative dose of 120 mg/kg of body weight is achieved. No topical or other systemic therapy was allowed during the trial. Liver function tests (serum glutamic-oxalocetic transaminase, serum glutamate pyruvate transaminase, direct and total bilirubin), and lipid profiles (total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride) were evaluated for all patients, before the initiation of treatment and again after the 2(nd) month of treatment. All data analyzed by Microsoft Office Excel 2007; in descriptive statics frequency and SPSS.18 software. RESULTS: At the end of treatment course, (96.4%) demonstrated complete clearing of their acne, defined as no acne or occasional isolated lesions. In 5-year follow-up, relapse accrued in 11 (7.9%) of patients. All adverse effects were mild, and discontinuation of treatment was not necessary. CONCLUSION: Low dose isotretinoin was found to be a safe and effective choice for patients with moderate to severe scar prone acne vulgaris. PMID- 24804179 TI - Nail bed expansion: A new technique for correction of multiple isolated congenital micronychia. AB - Congenital micronychia may involve big toes or may involve other nails. The etiology of micronychia is not clear but amniotic bands, teratogens (drugs, alcohol), Nail Patella Syndrome etc. A 44-year-old woman with multiple isolated congenital micronychia over her hands and feet was selected. The major affected nails were thumbs and Index fingers. Surgical method were done step by step: Anesthesia of the area, extraction of short nail, elevation of nail bed, longitudinal nail bed incisions, suturing the lateral nail bed to the nail wall, covering the nail bed by a splint of plastic suction tube, bandage with gauze Vaseline. Finally, we hypnotized that in congenital micronychia, the main pathology is in nail bed; through this theory by nail bed expansion better outcomes are coming. PMID- 24804180 TI - Macroscopic effect of blue light cure on wound healing in NMRI mice NMRI. AB - BACKGROUND: Wound healing is a complex process and has been an ongoing challenge all over the world. Some studies have suggested light cure as a modality to accelerate wound repair. It can induce fibroblast proliferation, increase collagen synthesis and activate cellular processes involved in expression of procollagen type I and III mRNA. This study was designed to assess the macroscopic effect of halogen dental curing blue light on full-thickness open wound healing in NMRI mice. MATERIALS AND METHODS: Forty male NMRI mice were divided into control and treatment groups. A full-thickness wound of 6 mm in diameter was induced on the lower back of all mice under general anesthesia and sterile conditions. The mice of the treatment group received a 5-min exposure of halogen light Coltolux II (QHL), 420-500 nm, daily for 7 days. The diameter of the wound was measured in both the treatment and the control groups every second day up to Day 14. Data were analyzed by SPSS version 12 software using Student's t-test. A significance level of P <= 0.05 was considered for each comparison. RESULTS: There was a significant difference in wound diameter between the control and the treatment groups at all measurements after Day 3 (P <= 0/05). CONCLUSION: The results of this study suggest improvement of full-thickness wound healing by daily irradiation of halogen dental curing blue light of 420-500 nm for 7 days. PMID- 24804181 TI - Efficacy of intralesional injection of mumps-measles-rubella vaccine in patients with wart. AB - BACKGROUND: In the previous studies, it has been shown that mumps-measles-rubella (MMR) vaccine resulted in regression of warts via immunomodulatory effect and induction of immune system. Due to the high prevalence of warts in various populations, we evaluated the efficacy of MMR vaccine injection in the treatment of cutaneous warts. MATERIALS AND METHODS: This double-blind randomized controlled clinical trial was conducted in Hazrat-e-Rasoul Hospital in Tehran in 2011-2012 on 24 patients with warts who were allocated to two groups including MMR group and normal saline group. MMR vaccine was injected intralesionally in the MMR group, whereas normal saline was injected into the lesions in the second group. These injections were repeated every 2 weeks intervals for maximum 3 injections. All patients were followed up every 15-day interval up to 45 days and then up to 6 months regarding relapses and finally, side effects, probable relapse, and therapeutic outcomes were evaluated and compared. RESULTS: At the end of follow-up period, therapeutic outcomes in the MMR group included no cure in 2 cases, relative cure in 4 cases, and complete cure in 18 cases. In normal saline group, these rates included no cure in seven cases, relative cure in nine cases, and complete cure in six cases (P < 0.001). No significant complication occurred in the two groups. CONCLUSION: MMR vaccine may result in desirable therapeutic response. The hypothesis that is considered here is that MMR vaccine, via induction of cellular and humoral immune system, accelerates the destruction of virus and infected host cells. PMID- 24804182 TI - Should variation of serum lipid levels be considered a risk factor for the development of basal cell carcinoma? AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common cutaneous neoplasm in human beings. Ultraviolet radiation is one of the most important predisposing factors for BCC. Although some recent investigations have shown a high serum level of phospholipids in actinic keratosis and BCC, this subject is still debated and needs approval. This study aimed to evaluate the association between serum lipid level and development of cutaneous BCC. MATERIALS AND METHODS: In this case-control study, lipid profile including triglyceride (TG), Cholesterol (CHOL), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were measured in 30 patients with BCC and 30 healthy controls. Data were analyzed by descriptive statistical tests including t tests and Chi square test. RESULTS: This study shows that the mean age of the case and control groups were 63.93 +/- 12.09 and 61.57 +/- 21.1 years (mean +/- SD), respectively. The average amount of triglyceride, cholesterol, HDL and LDL in the BCC patients were 139.73 +/- 69.11 mg/dl, 179.20 +/- 43.42 mg/dl, 39.40 +/- 9.30 mg/dl and 110.70 +/- 34.13 mg/dl, respectively, whereas these amounts in the control group were 141.83 +/- 80.41 mg/dl, 173.60 +/- 96.32 mg/dl, 36.97 +/- 6.35 mg/dl, 110.70 +/- 34.13 mg/dl and 104.87 +/- 30.85 mg/dl, respectively. No significant difference was found in the lipid profile of the case and control groups (P > 0.05%). CONCLUSION: This study shows that the serum lipid levels in patients with BCC has no significant difference in comparison with the control group and, therefore, relevance between BCC and serum lipid level is not proven. Further studies with a larger sample size are necessary for evaluating this subject. PMID- 24804183 TI - A comparison study of lipid profile levels between skin tags affected people and normal population in Tehran, Iran. AB - BACKGROUND: For many years the association of skin tags and endocrynopathies has been postulated, although many reports are available but it has never been evaluated to mean normal population. Dyslipidemia is a frequent disorder among people and seemed to be necessary for screening within skin tag condition. This study is designed to find any possible association between skin tags and dyslipidemia. MATERIALS AND METHODS: From April 2009 to June 2011, 168 patients enrolled the study. Among the remaining 152 patients, there were 89 females (58.5%) and 63 males (%41.5). Based on the TLGS study 136 men and 220 women enrolled the control group of study. The mean age was 28.4 years. Patients trained to have normal free diet for at least 1 month then referred to the laboratory. Blood samples were taken over 12 hours fasting with 2 hours intervals. Hypertriglyceridemia was defined as plasma level >=160 mg/dl for men and >=130 mg/dl for women. Hypercholesterolemia pointed at its value >200 mg/dl. Normal HDL levels was defined as >39 mg/dl for men and >35 mg/dl to women. RESULTS: Mean skin tag number was 12.6 per subject. The most frequent localizations of skin tags were neck and upper chest (mean number: 13.4, 48.9%) followed by axilla (mean number: 11.6, 33%) and breast (10.2, 10.1%) in the patient group. The mean cholesterol level of case group was 192.2 +/- 33.1 mg/dl, while it was 187.0 +/- 42 mg/dl in the control group). The mean +/- SD for triglyceride was 132.1 +/- 69 mg/dl in comparison to 129 +/- 74 in the control group. CONCLUSION: The study showed no significant differences between normal population and patients' lipid profile. PMID- 24804184 TI - The effects and side effects of lidocaine tetracaine peel off on laser-assisted hair removal. AB - BACKGROUND: Lidocaine 7%-tetracaine 7% is one of the combinations recently offered for performing laser-assisted hair removal. The aim of this study was to compare the effects of this combination with placebo on the side effects of laser assisted hair removal. MATERIALS AND METHODS: This clinical trial was carried out on 110 women who referred to Isfahan Spadana laser clinic for laser-assisted hair removal. Lidocaine 7%-tetracaine 7% was applied on one-half of the face, whereas placebo was applied on the other side to create local anesthesia, and after 30 min, the place was cleaned and investigated for complications (edema, erythema, and pallor); then laser therapy was begun. At the end of the therapy, the patients' pain was estimated using Visual Analog Scale (VAS). The data were analyzed using SPSS software by Chi-square and paired t-tests. RESULTS: The mean age of patients was 27.74 +/- 10.8 years. Average levels of anesthesia at 30 min after using lidocaine 7%-tetracaine 7% and placebo based on VAS were 3.6 +/- 1.4 and 8.4 +/- 1.5, respectively (P = 0.001). In other words, patients felt less pain by using lidocaine 7%-tetracaine 7%. The frequency of complications in patients was not significantly different between the two groups. CONCLUSION: Considering the better effect of lidocaine 7%-tetracaine 7% compared to placebo and its minimal side effects, we can use it before performing laser-assisted hair removal. PMID- 24804185 TI - The efficacy of Achilles millefolium topical gel along with intralesional injection of glucantime in the treatment of acute cutaneous leishmaniasis major. AB - BACKGROUND: Leishmaniasis is still one of the endemic parasitic infections in many countries comprising Iran. During the past decades, several medical and surgical approaches have been applied and studied to achieve the best option to treat the cutaneous leishmaniasis in Iran and the world. This study was carried out to evaluate the effect of topical Achilles millefolium in conjunction with intralesional glucantime on acute cutaneous leishmanial lesions. MATERIALS AND METHODS: sixty patients with confirmed acute cutaneous leishmaniasis were recruited in the study. Patients were randomly allocated into two groups to receive twice daily topical gel of Achilles millefolium 5% (containing 5% poly phenol) (group A) or placebo (group B) for four weeks along with weekly injection of intralesional Glucantime. RESULTS: There was no significant difference between the two groups according to age, gender, and duration of the disease. Also, there was no significant difference in complete and relative cure rates between the two groups (P = 0.35) using Visual Analog Scale (VAS). Application site reactions were occurred in 12 patients including redness in 8 cases in group-A and 2 cases in group-B, severe itching in one case in group-A and increasing wound secretion in another case in group-A (P = 0.014). CONCLUSIONS: Given the result of the present study, there is no significant difference in cure rates of lesions between yarrow and placebo topical gels as an adjuvant drugs with intralesional glucantime in treatment of acute cutaneous leishmanial lesions. PMID- 24804186 TI - Leech therapy for epidermoid cysts and review of the literature. AB - Hirudo medicinalis sucks blood directly through the external mammalian skin. We recently observed a healthy 64-year-old Iranian man, who presented with numerous asymptomatic multilobular oval-to-round well-defined 0.5 to 1.5 cm cystic lesions with central umbilication (central black eschar) over the upper portion of his chest. We made the diagnosis of epidermoid cyst, giant comedone and leech bite on the basis of the constellation of clinical features. The patient was treated with oral ciprofloxacin at a dose of 2 g daily, and 2% topical erythromycin solution. Despite improvement, the evidence of cystic lesions persisted. There was no history of similar lesions in any other family member. There was no history of trauma. The patient was not using any topical or systemic medication. Two weeks before his visit, he had a history of leech therapy under the supervision of a general practitioner. His medical history was significant for leech therapy of the lesions, five days previously. He was followed up for another two weeks and after disappearance of the inflammation, with the patient under local anesthesia, the well-circumscribed mass was completely evacuated with a sharp curette and comedone extractor. The patient was subsequently lost to follow-up. CONCLUSION: Considering the efficacy of leeches, it would be favorable to breed a germ-free leech. In Iran, the use of the leeches in surgery, in recent years, has been infrequent. It appears that the positive effects of this ancient remedy may now be explained through scientific methods, promising potentially even more uses of this admirable creature in medicine. PMID- 24804187 TI - Evaluation of repair in duodenal perforation with human amniotic membrane: An animal model (dog). AB - BACKGROUND: There is a growing tendency toward application of human amniotic membrane (HAM) as a biologic substitute in various tissue injuries where a significant tissue loss is a matter of concern. In gastrointestinal injuries especially duodenal ones, some potential limitations in current surgical techniques contribute to not fully acceptable healing outcomes. Thus, this study was carried out to assess repair with HAM patch for duodenal defect in comparison with simple duodenoraphy in an animal model (dog). MATERIALS AND METHODS: A total of 15 male German shepherd dogs weighing 23-27 kg were randomly divided into two groups. Group A with 10 dogs, which were a candidate for duodenal repair by amniotic membrane patch and Group B consisted of 5 dogs perform simple duodenorraphy. A precise control was made to match all conditions except surgical technique. Macroscopic and microscopic features of the healed duodenal lumen in both groups were recorded. RESULTS: Gross evaluation revealed no difference in luminal diameter in both groups. Statistical analysis of duodenal diameter between both groups after operation also showed no significant difference (P v = 0.789). Histological assessment indicated less inflammation with better wound healing in Group A. CONCLUSION: It seems that repairing duodenal wall defect with HAM would result in better histological outcomes compared with what is seen in simple duodenoraphy in animal models. However, there is no significant difference regarding surgical findings. PMID- 24804188 TI - A new method to repair recto-vaginal fistula: Use of human amniotic membrane in an animal model. AB - BACKGROUND: Recto-vaginal fistula is primarily one of the co-morbidities of vaginal delivery. These patients suffer from persistent malodor vaginal discharge. Various surgical techniques have been employed by surgeons in the course of time. This is the first trial of applying Human Amniotic Membrane (HAM) as a bio-prosthesis in repairing recto-vaginal fistula. MATERIALS AND METHODS: In a prospective animal study, 8 mixed-breed female dogs weighing 23-27 kg with the age of 12-18 months were selected. They were randomly divided into two groups for standard recto-vaginal fistula repair and fistula repair with human amniotic membrane. The Kruskal-Wallis and Mann Whitney tests were performed to indicate statistical differences. RESULTS: After 6 weeks, fistulas were evaluated both grossly and microscopically. In gross examination, there were no difference between the two groups and healing of fistula seemed to have been occurred in all dogs expect for one which had a persistent patent fistulous tract. Microscopic healing was scored according to epithelialization, collagenization inflammation, ulcer and necrosis of samples. Healing score was significantly higher in the HAM group than the standard group (P = 0.029). CONCLUSION: Our findings revealed that using HAM as a bio-prosthesis to repair recto-vaginal fistula would result in better surgical and histological outcomes comparing to simple repair. PMID- 24804189 TI - Mary Ellen Avery's Research Career - Remembrance of Things Past. AB - Mary Ellen Avery's research is recognized as a milestone in biomedical research. She had discovered the underlying cause of hyaline membrane disease, surfactant deficiency, fostering ever more vigorous efforts to reduce neonatal mortality in the burgeoning practice of Neonatology. Neonatology is the only clinical discipline that began as an experiment, making it a model for biomedical research. Avery knew that the concerted effort to treat preterm newborns could potentially do more harm than good, violating her oath to Hippocrates, if not held to the highest scientific standards. She remained true to that pledge throughout her career, as recounted in this Review. PMID- 24804190 TI - Suicide risk assessment in Australian emergency departments: assessing clinicians' disposition decisions. AB - Objective. To determine (1) the uniformity of disposition decisions made by clinicians working in Australian emergency departments (EDs) using vignettes describing patients presenting with deliberate self-harm or suicide risk; (2) factors associated with these decisions; (3) factors associated with confidence in these decisions. Methodology. We validated and distributed by email an online survey tool to Australian emergency clinicians via their colleges. Participants were presented with five vignettes and asked to rate the level of risk and protective factors for suicide, the patient's disposition (admit/discharge/review), factors influencing this decision, their confidence in the decision, and factors that would have improved their confidence. Results. Percentages of participants choosing the modal disposition decision for each scenario ranged from 58.6% (136/232) to 92.4% (220/238), demonstrating uniformity in clinicians' disposition decisions. Predictors of disposition were consistently level of risk factors perceived and, infrequently, clinician factors including age and years experience. Confidence in disposition decisions was high across scenarios. Clinicians reported patient, clinician, contextual and decision support factors relevant to an Australian emergency context affected their disposition decisions and confidence in decisions. Conclusion. Emergency clinicians are uniform and confident in their disposition decisions for patient vignettes where there is risk of suicide or self harm. PMID- 24804191 TI - A Promoter Region Polymorphism in PDCD-1 Gene Is Associated with Risk of Rheumatoid Arthritis in the Han Chinese Population of Southeastern China. AB - Objective. Programmed cell death 1 (PD-1) induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the association of PDCD-1 polymorphisms with the risk of RA among Chinese patients and healthy controls. Methods. Using the PCR-direct sequencing analysis, 4 PDCD-1 SNPs (rs36084323, rs11568821, rs2227982, and rs2227981) were genotyped in 320 RA patients and 309 matched healthy controls. Expression of PD-1 was determined in peripheral blood lymphocytes by flow cytometry and quantitative real-time reverse transcriptase polymerase chain reaction. Results. We observed that the GG genotype of rs36084323 was associated with a increased risk for developing RA (OR 1.70, 95% 1.11-2.61, P = 0.049). Patients carrying G/G genotype displayed an increased mRNA level of PD-1 (P = 0.04) compared with A/A genotype and healthy controls. Meanwhile, patients homozygous for rs36084323 had induced basal PD-1 expression on activated CD4+ T cells. Conclusion. The PDCD-1 polymorphism rs36084323 was significantly associated with RA risk in Han Chinese population. This SNP, which effectively influenced the expression of PD-1, may be a biomarker of early diagnosis of RA and a suitable indicator of utilizing PD-1 inhibitor for treatment of RA. PMID- 24804193 TI - Metallothionein induction in the coelomic fluid of the earthworm Lumbricus terrestris following heavy metal exposure: a short report. AB - Earthworms are useful bioindicator organisms for soil biomonitoring. Recently the use of pollution biomarkers in earthworms has been increasingly investigated for soil monitoring and assessment. Earthworm coelomic fluid is particularly interesting from a toxicological perspective, because it is responsible for pollutant disposition and tissue distribution to the whole organism. The aim of the present work was to study the effect of heavy metal exposure on metallothionein (Mt) induction in the coelomic fluid of Lumbricus terrestris in view of future use as sensitive biomarker suitable for application to metal polluted soil monitoring and assessment. L. terrestris coelomic fluid showed a detectable Mt concentration of about 4.0 +/- 0.6 MUg/mL (mean +/- SEM, n = 10) in basal physiological condition. When the animals were exposed to CuSO4 or CdCl2 or to a mixture of the two metals in OECD soils for 72 h, the Mt specific concentration significantly (P < 0.001) increased. The Mt response in the coelomic fluid perfectly reflected the commonly used Mt response in the whole organism when the two responses were compared on the same specimens. These findings indicate the suitability of Mt determination in L. terrestris coelomic fluid as a sensitive biomarker for application to metal polluted soil monitoring and assessment. PMID- 24804192 TI - Mechanism of salinity tolerance in plants: physiological, biochemical, and molecular characterization. AB - Salinity is a major abiotic stress limiting growth and productivity of plants in many areas of the world due to increasing use of poor quality of water for irrigation and soil salinization. Plant adaptation or tolerance to salinity stress involves complex physiological traits, metabolic pathways, and molecular or gene networks. A comprehensive understanding on how plants respond to salinity stress at different levels and an integrated approach of combining molecular tools with physiological and biochemical techniques are imperative for the development of salt-tolerant varieties of plants in salt-affected areas. Recent research has identified various adaptive responses to salinity stress at molecular, cellular, metabolic, and physiological levels, although mechanisms underlying salinity tolerance are far from being completely understood. This paper provides a comprehensive review of major research advances on biochemical, physiological, and molecular mechanisms regulating plant adaptation and tolerance to salinity stress. PMID- 24804194 TI - Resistance training and testosterone levels in male patients with chronic kidney disease undergoing dialysis. AB - BACKGROUND: We investigated serum testosterone and insulin-like growth factor 1 (IGF-1) levels' associations with muscle fibre size and resistance training in male dialysis patients. METHODS: Male patients were included in a 16-week control period followed by 16 weeks of resistance training thrice weekly. Blood samples were obtained to analyse testosterone, luteinizing hormone (LH), IGF-1, and IGF binding protein 3. Muscle fibres' size was analysed in biopsies from m. vastus lateralis. RESULTS: The patients' testosterone levels were within the normal range at baseline (n = 20) (19.5 (8.2-52.1) nmol/L versus 17.6 (16.1-18.0), resp.) whereas LH levels were higher (13.0 (5.5-82.8) U/L versus 4.3 (3.3-4.6), P < 0.001, resp.). IGF-1 and IGF-binding protein 3 levels were higher in the patients compared with reference values (203 (59-590) ng/mL versus 151 (128-276), P = 0.014, and 5045 (3370-9370) ng/mL versus 3244 (3020-3983), P < 0.001, resp.). All hormone levels and muscle fibre size (n = 12) remained stable throughout the study. Age-adjusted IGF-1 was associated with type 1 and 2 fibre sizes (P < 0.05). CONCLUSION: Patients' total testosterone values were normal due to markedly increased LH values, which suggest a compensated primary insufficiency of the testosterone producing Leydig cell. Even though testosterone values were normal, resistance training was not associated with muscle hypertrophy. This trial is registered with ISRCTN72099857. PMID- 24804195 TI - Expressions of ABCG2, CD133, and podoplanin in salivary adenoid cystic carcinoma. AB - Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignant tumors with a high risk of recurrence and metastasis. Current studies on cancer stem cells (CSCs) have verified that CSCs are the driving force behind tumor initiation and progression, suggesting that new cancer therapies may be established by effectively targeting and killing the CSCs. The primary goal of this study is to investigate the expression patterns of ABCG2, CD133, and podoplanin in ACC of minor salivary glands by immunohistochemistry analysis. We found that ABCG2 was weakly expressed in normal looking salivary gland tissues. A significant upregulation of ABCG2 expression in ACC was observed with a similar expression pattern of Ki-67. CD133 was detected in apical membrane of epithelial cells and podoplanin was expressed positively in myoepithelial cells of both normal looking tissue and ACC. However, no significant difference was found of the expression pattern of CD133 and podoplanin between normal looking tissues and ACC. Our observations suggest that CSCs may exist in quiescent cells with ABCG2 positive staining, which are surrounded by cells with positive expression of ABCG2 and Ki-67 in ACC, and costaining with ABCG2 and Ki-67 may help predict the location of CSCs. PMID- 24804196 TI - Experimental study of local inner ear gene therapy for controlling autoimmune sensorineural hearing loss. AB - This study aimed to investigate the efficacy of gene therapy for treating autoimmune sensorineural hearing loss (ASHL) via local administration of a recombinant adenovirus vector containing the Fas ligand or interleukin IL-10 gene. Guinea pigs were divided into four groups, with different microinjections in the scala tympani. Group A were injected with FasL-EGFP, B with IL-10-EGFP, C with EGFP, and D with artificial perilymph. Seven days later, auditory brain-stem response (ABR) was tested, and the temporal bone was stained and observed by light microscopy. The spiral ligament and basement membrane were observed using transmission electron microscopy. FasL and IL-10 expression were examined using immunofluorescence histochemistry. Immunohistochemical analysis showed that the recombinant adenovirus vector in Groups A, B, and C can transfect the stria vascularis, the spiral ligament, the organ of Corti, the spiral ganglion, the region surrounding the small blood vessel in the modiolus, and the cochlear bone wall. Compared with those in Groups C and D, the ABR wave III mean thresholds were significantly lower and the inner ear immunoinflammatory responses in Groups A and B were significantly alleviated. Inhibition of immunoinflammatory response alleviated immunoinflammatory injury and auditory dysfunction. This technique shows potential as a novel therapy for ASHL. PMID- 24804197 TI - Phylogenetic analysis of entomoparasitic nematodes, potential control agents of flea populations in natural foci of plague. AB - Entomoparasitic nematodes are natural control agents for many insect pests, including fleas that transmit Yersinia pestis, a causative agent of plague, in the natural foci of this extremely dangerous zoonosis. We examined the flea samples from the Volga-Ural natural focus of plague for their infestation with nematodes. Among the six flea species feeding on different rodent hosts (Citellus pygmaeus, Microtus socialis, and Allactaga major), the rate of infestation varied from 0 to 21%. The propagation rate of parasitic nematodes in the haemocoel of infected fleas was very high; in some cases, we observed up to 1,000 juveniles per flea specimen. Our study of morphology, life cycle, and rDNA sequences of these parasites revealed that they belong to three distinct species differing in the host specificity. On SSU and LSU rRNA phylogenies, these species representing three genera (Rubzovinema, Psyllotylenchus, and Spilotylenchus), constitute a monophyletic group close to Allantonema and Parasitylenchus, the type genera of the families Allantonematidae and Parasitylenchidae (Nematoda: Tylenchida). We discuss the SSU-ITS1-5.8S-LSU rDNA phylogeny of the Tylenchida with a special emphasis on the suborder Hexatylina. PMID- 24804198 TI - Clinical use of skull tap vestibular evoked myogenic potentials for the diagnoses of the cerebellopontine angle tumor patients. AB - OBJECTIVE: To document our experiences using a new skull tapping induced Vestibular Evoked Myogenic Potentials (tap VEMPs) technique combined with standard Auditory Vestibular Evoked Myogenic Potentials (AC VEMPs) for advanced clinical assessment of cerebellopontine angle tumor (CPAT) patients. DESIGN AND STUDY SAMPLE: Three patients were selected in order to highlight observations shown in a larger patient population and to show the variability of the findings. Both tap VEMPs and AC VEMPs were acquired from the sternocleidomastoid muscle (SCM) with EMG-based biofeedback and monitoring. RESULTS: The usefulness of VEMPs was demonstrated, indicating the presence of a tumor and contributing additional information as to the involved nerve bundles in two out of the three cases. CONCLUSION: Due to the sensory organ dependency and related innervations differences, acquiring both AC VEMPs and tap VEMPs is likely to increase the probability of diagnosing CPATs and provide more information on the involved vestibular nerve bundles. This study demonstrates the feasibility of the possible expansion and combination of tap VEMPs and AC VEMPs techniques into a clinical diagnostic battery for advanced assessment of CPAT patients and its contribution as a guideline for the use of tap VEMPs in general. PMID- 24804199 TI - Bacteriological profile and drug resistance patterns of blood culture isolates in a tertiary care nephrourology teaching institute. AB - Blood stream infections can lead to life threatening sepsis and require rapid antimicrobial treatment. The organisms implicated in these infections vary with the geographical alteration. Infections caused by MDR organisms are more likely to increase the risk of death in these patients. The present study was aimed to study the profile of organisms causing bacteremia and understand antibiotic resistance patterns in our hospital. 1440 blood samples collected over a year from clinically suspected cases of bacteremia were studied. The isolates were identified by standard biochemical tests and antimicrobial resistance patterns were determined by CLSI guidelines. Positive blood cultures were obtained in 9.2% of cases of which Gram-positive bacteria accounted for 58.3% of cases with staph aureus predominance; gram negative bacteria accounted for 40.2% with enterobactereciea predominence; and 1.5% were fungal isolates. The most sensitive drugs for Gram-positive isolates were vancomycin, teicoplanin, daptomycin, linezolid, and tigecycline and for Gram-negative were carbapenems, colistin, aminoglycosides, and tigecycline. The prevalence of MRSA and vancomycin resistance was 70.6% and 21.6%, respectively. ESBL prevalence was 39.6%. Overall low positive rates of blood culture were observed. PMID- 24804200 TI - Effect of cyclic mechanical stimulation on the expression of osteogenesis genes in human intraoral mesenchymal stromal and progenitor cells. AB - We evaluated the effects of mechanical stimulation on the osteogenic differentiation of human intraoral mesenchymal stem and progenitor cells (MSPCs) using the Flexcell FX5K Tension System that mediated cyclic tensile stretch on the cells. MSPCs were isolated from human mandibular retromolar bones and characterized using flow cytometry. The positive expression of CD73, CD90, and CD105 and negativity for CD14, CD19, CD34, CD45, and HLA-DR confirmed the MSPC phenotype. Mean MSPC doubling time was 30.4 +/- 2.1 hrs. The percentage of lactate dehydrogenase (LDH) release showed no significant difference between the mechanically stimulated groups and the unstimulated controls. Reverse transcription quantitative real-time PCR revealed that 10% continuous cyclic strain (0.5 Hz) for 7 and 14 days induced a significant increase in the mRNA expression of the osteogenesis-specific markers type-I collagen (Col1A1), osteonectin (SPARC), bone morphogenetic protein 2 (BMP2), osteopontin (SPP1), and osteocalcin (BGLAP) in osteogenic differentiated MSPCs. Furthermore, mechanically stimulated groups produced significantly higher amounts of calcium deposited into the cultures and alkaline phosphatase (ALP). These results will contribute to a better understanding of strain-induced bone remodelling and will form the basis for the correct choice of applied force in oral and maxillofacial surgery. PMID- 24804201 TI - Efficacy of continuous epidural analgesia versus total intravenous analgesia on postoperative pain control in endovascular abdominal aortic aneurysm repair: a retrospective case-control study. AB - We reviewed our experience to compare the effectiveness of epidural analgesia and total intravenous analgesia on postoperative pain control in patients undergoing endovascular abdominal aortic aneurysm repair. Records of 32 patients during a 2 year period were retrospectively investigated. TIVA group (n = 18) received total intravenous anesthesia, and EA group (n = 14) received epidural anesthesia and sedation. Pain assessment was performed on all patients on a daily basis during rest and activity on postoperative days until discharge from ward using the numeric rating scale. Data for demographic variables, required anesthetic level, perioperative hemodynamic variables, postoperative pain, and morbidities were recorded. There were no relevant differences concerning hospital stay (TIVA group: 14.1 +/- 7.0, EA group: 13.5 +/- 7.1), perioperative blood pressure variability (TIVA group: 15.6 +/- 18.1, EA group: 14.8 +/- 11.5), and perioperative hemodynamic complication rate (TIVA group: 17%, EA group: 14%). Postoperative pain scores differed significantly (TIVA group: 5.4 +/- 0.9, EA group: 1.8 +/- 0.8, P < 0.001). Epidural anesthesia and postoperative epidural analgesia better reduce postoperative pain better compared with general anesthesia and systemic analgesia, with similar effects on hemodynamic status. PMID- 24804202 TI - Bone formation in a rat tibial defect model using carboxymethyl cellulose/BioC/bone morphogenic protein-2 hybrid materials. AB - The objective of this study was to assess whether carboxymethyl cellulose- (CMC-) based hydrogel containing BioC (biphasic calcium phosphate (BCP); tricalcium phosphate (TCP) : hydroxyapatite (Hap) = 70 : 30) and bone morphogenic protein-2 (BMP-2) led to greater bone formation than CMC-based hydrogel containing BioC without BMP-2. In order to demonstrate bone formation at 4 and 8 weeks, plain radiographs, microcomputed tomography (micro-CT) evaluation, and histological studies were performed after implantation of all hybrid materials on an 8 mm defect of the right tibia in rats. The plain radiographs and micro-CT analyses revealed that CMC/BioC/BMP-2 (0.5 mg) led to much greater mineralization at 4 and 8 weeks than did CMC/BioC or CMC/Bio/BMP-2 (0.1 mg). Likewise, bone formation and bone remodeling studies revealed that CMC/BioC/BMP-2 (0.5 mg) led to a significantly greater amount of bone formation and bone remodeling at 4 and 8 weeks than did CMC/BioC or CMC/BioC/BMP-2 (0.1 mg). Histological studies revealed that mineralized bone tissue was present around the whole circumference of the defect site with CMC/BioC/BMP-2 (0.5 mg) but not with CMC/BioC or CMC/BioC/BMP-2 (0.1 mg) at 4 and 8 weeks. These results suggest that CMC/BioC/BMP-2 hybrid materials induced greater bone formation than CMC/BioC hybrid materials. Thus, CMC/BioC/BMP-2 hybrid materials may be used as an injectable substrate to regenerate bone defects. PMID- 24804203 TI - 5-Aminolevulinic acid fluorescence in high grade glioma surgery: surgical outcome, intraoperative findings, and fluorescence patterns. AB - BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence is a validated technique for resection of high grade gliomas (HGG); the aim of this study was to evaluate the surgical outcome and the intraoperative findings in a consecutive series of patients. METHODS: Clinical and surgical data from patients affected by HGG who underwent surgery guided by 5-ALA fluorescence at our Department between June 2011 and February 2014 were retrospectively evaluated. Surgical outcome was evaluated by assessing the resection rate as gross total resection (GTR) > 98% and GTR > 90%. We finally stratified data for recurrent surgery, tumor location, tumor size, and tumor grade (IV versus III grade sec. WHO). RESULTS: 94 patients were finally enrolled. Overall GTR > 98% and GTR > 90% was achieved in 93% and 100% of patients. Extent of resection (GTR > 98%) was dependent on tumor location, tumor grade (P < 0.05), and tumor size (P < 0.05). In 43% of patients the boundaries of fluorescent tissue exceeded those of tumoral tissue detected by neuronavigation, more frequently in larger (57%) (P < 0.01) and recurrent (60%) tumors. CONCLUSIONS: 5-ALA fluorescence in HGG surgery enables a GTR in 100% of cases even if selection of patients remains a main bias. Recurrent surgery, and location, size, and tumor grade can predict both the surgical outcome and the intraoperative findings. PMID- 24804204 TI - Looking for celiac disease in Italian women with endometriosis: a case control study. AB - In the last years, a potential link between endometriosis and celiac disease has been hypothesized since these disorders share some similarities, specifically concerning a potential role of oxidative stress, inflammation, and immunological dysfunctions. We investigated the prevalence of celiac disease among Italian women with endometriosis with respect to general population. Consecutive women with a laparoscopic and histological confirmed diagnosis of endometriosis were enrolled; female nurses of our institution, without a known history of endometriosis, were enrolled as controls. IgA endomysial and tissue transglutaminase antibodies measurement and serum total IgA dosage were performed in both groups. An upper digestive endoscopy with an intestinal biopsy was performed in case of antibodies positivity. Presence of infertility, miscarriage, coexistence of other autoimmune diseases, and family history of autoimmune diseases was also investigated in all subjects. Celiac disease was diagnosed in 5 of 223 women with endometriosis and in 2 of 246 controls (2.2% versus 0.8%; P = 0.265). Patients with endometriosis showed a largely higher rate of infertility compared to control group (27.4% versus 2.4%; P < 0.001). Our results confirm that also in Italian population an increased prevalence of celiac disease among patients with endometriosis is found, although this trend does not reach the statistical significance. PMID- 24804205 TI - Relationship between GH/IGF-1 axis, graft recovery, and early survival in patients undergoing liver transplantation. AB - BACKGROUND: High levels of IGF-1 have been reported in patients with initial poor function of the graft after liver transplantation (LT). Correlation with other clinical variables or early survival has not been extensively investigated. AIM: To evaluate the GH/IGF-1 profile as a function of liver recovery and patients' early survival after LT. METHODS: 30 transplanted patients (23 survivors and 7 nonsurvivors), were retrospectively enrolled in the study. GH and IGF-1 serum levels were assessed at baseline, graft reperfusion, and 1, 7, 15, 30 , 90, and 360 days after LT. Individual biochemical variables were also recorded. RESULTS: After grafting, IGF-1 in blood linearly correlated with cholesterol (r = 0.6, P = 0.001). IGF-1 levels from day 15 after surgery were statistically higher in survivors as compared to nonsurvivors. ROC curves analysis identified an IGF-1 cut-off >90 MUg/L, from day 15 after surgery, as a good predictor of survival (sensitivity 86%, specificity 95%, and P < 0.001). CONCLUSIONS: After LT, GH levels correlate with the extent of cytolysis, while IGF-1 is an indicator of liver synthetic function recovery. IGF-1 levels >90 MUg/L (day 15-30) seem to be an indicator of short-term survival. PMID- 24804206 TI - Pu-erh tea extract induces the degradation of FET family proteins involved in the pathogenesis of amyotrophic lateral sclerosis. AB - FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins. PMID- 24804207 TI - Optimization of extraction and enrichment of steroidal alkaloids from bulbs of cultivated Fritillaria cirrhosa. AB - The bulbs of cultivated Fritillaria cirrhosa (BCFC) are used in China both for food and folk medicine due to its powerful biological activities. The aim of this study is to optimize the extraction and enrichment conditions of alkaloids from BCFC. Firstly, the orthogonal experimental design was used to optimize and evaluate four variables (ethanol concentration, solid-liquid ratio, extraction time, and temperature). Thereafter, resin adsorption was as a means to enrich alkaloids. Among 16 tested resins, H-103 resin presented higher adsorption capacity and desorption ratio. The equilibrium experimental data of the adsorption of total alkaloids, imperialine, and peimisine were well-fitted to the pseudo-first-order kinetics model, Langmuir and Freundlich isotherms models. Finally, in order to optimize the parameters for purifying alkaloids, dynamic adsorption and desorption tests were carried out. After one run treatment with H 103 resin, the contents of total alkaloids, imperialine, and peimisine in the product were 21.40-, 18.31-, and 22.88-fold increased with recovery yields of 94.43%, 90.57%, and 96.16%, respectively. PMID- 24804209 TI - Incidence, national trend, and outcome of nontraumatic subarachnoid haemorrhage in Taiwan: initial lower mortality, poor long-term outcome. AB - To investigate the longitudinal trend of nontraumatic subarachnoid haemorrhage (SAH), we analyzed the annual population-based incidence and mortality rate of nontraumatic subarachnoid hemorrhage in Taiwan. Logistic regression was used to identify independent predictors of mortality. The average incidence rate (IR) of nontraumatic SAH was 6.25 +/- 0.88 per 100,000 per year. The prevalence of female patients was higher than in the male population (54.5% versus 45.5%). The average age of these patients was 55.78 +/- 17.09 and females were older than males (58.50 +/- 15.9 versus 52.45 +/- 18.50, P < 0.001). Of these patients, 97.6% (611/626) were treated with surgical intervention with clipping procedure and 2.9% (18/626) with coiling. Total mortality of these patients was 13.4% (84/626). In adjusted analysis, age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.98-0.98; P < 0.001) and Charlson comorbidity index (OR, 0.709; 95% CI, 0.57 0.88; P = 0.002) remained independent predictors of the mortality. Patients with nontraumatic SAH had a much higher prevalence in older age groups and in females than in the general population. Patients with old age and more comorbidity have higher mortality. Aggressive management of patients might reduce the initial mortality; however, patient outcome still remains poor. PMID- 24804208 TI - Magnesium lithospermate B, an active extract of Salvia miltiorrhiza, mediates sGC/cGMP/PKG translocation in experimental vasospasm. AB - BACKGROUND: Soluble guanylyl cyclases (sGCs) and Ras homolog gene family, member A (rhoA)/Ras homolog gene family kinase(rho-kinase) plays a role in vascular smooth muscle relaxation in subarachnoid hemorrhage (SAH). It is of interest to examine the effect of MLB on rhoA/ROCK and sGC/cGMP/PKG expression. METHODS: A rodent SAH model was employed. Tissue samples were for sGC alpha 1, sGC beta 1, PKG, rhoA, ROCK (Western blot), and cGMP (ELISA) measurement. RESULTS: MLB morphologically improved convolution of the internal elastic lamina, distortion of endothelial wall, and necrosis of the smooth muscle in the SAH rats. Expressed cGMP, sGC alpha 1, sGC beta 1, and PKG in the SAH groups were reduced (P < 0.01), and MLB precondition significantly induced cGMP, sGCalpha1, sGCbeta1, and PKG. L NAME reversed the vasodilation effect of MLB, reduced the bioexpression of PKG and cGMP (P < 0.01), and tends to reduce sGCalpha1 level and induce rhoA, ROCK level in MLB precondition + SAH groups. CONCLUSION: These results demonstrate that sGC/cGMP/PKG and NO/ET pathways play pivotal roles in SAH-induced vasospasm. Through activating sGC/cGMP/PKG pathway and partially by inactivating rho-kinase in a NO-dependent mechanism, MLB shows promise to be an effective strategy for the treatment of this disease entity. PMID- 24804210 TI - An ANOCEF genomic and transcriptomic microarray study of the response to irinotecan and bevacizumab in recurrent glioblastomas. AB - BACKGROUND: We performed a retrospective study to assess whether the initial molecular characteristics of glioblastomas (GBMs) were associated with the response to the bevacizumab/irinotecan chemotherapy regimen given at recurrence. RESULTS: Comparison of the genomic and gene expression profiles of the responders (n = 12) and nonresponders (n = 13) demonstrated only slight differences and could not identify any robust biomarkers associated with the response. In contrast, a significant association was observed between GBMs molecular subtypes and response rates. GBMs assigned to molecular subtype IGS-18 and to classical subtype had a lower response rate than those assigned to other subtypes. In an independent series of 33 patients, neither EGFR amplification nor CDKN2A deletion (which are frequent in IGS-18 and classical GBMs) was significantly associated with the response rate, suggesting that these two alterations are unlikely to explain the lower response rate of these GBMs molecular subtypes. CONCLUSION: Despite its limited sample size, the present study suggests that comparing the initial molecular profiles of responders and nonresponders might not be an effective strategy to identify biomarkers of the response to bevacizumab given at recurrence. Yet it suggests that the response rate might differ among GBMs molecular subtypes. PMID- 24804211 TI - CGP 35348, GABA B receptor antagonist, has a potential to improve neuromuscular coordination and spatial learning in albino mouse following neonatal brain damage. AB - To study the effect of CGP 35348 on learning and memory in albino mice following hypoxia ischemia insult, 10 days old albino mice were subjected to right common carotid artery ligation followed by 8% hypoxia for 25 minutes. Following brain damage, mice were fed on normal rodent diet till they were 13 week old. At this time point, mice were divided into two groups. Group 1 received saline and group 2 intrapertoneally CGP 35348 (1 mg/mL solvent/Kg body weight) for 12 days. A battery of tests used to assess long term neurofunction (Morris water maze, Rota rod and open field) along with brain infarct measurement. Overall CGP 35348 has improved the motor function in male and female albino mice but effects were more pronounced in female albino mice. In open field, CGP 35348 treated female albino mice had demonstrated poor exploratory behavior. During Morris water maze test, gender specific effects were observed as CGP 35348 had improved spatial learning and memory and swimming speed in male albino mice but had no effect in female albino mice following hypoxia ischemia encephalopathy (HIE). We concluded that GABAB receptor antagonists CGP 35348 can be used to improve gender based spatial memory. PMID- 24804212 TI - Knowledge about health effects of cigarette smoking and quitting among Italian university students: the importance of teaching nicotine dependence and treatment in the medical curriculum. AB - Aims of the study were to compare medical students (MS) to non-MS with respect to their knowledge of smoking and to investigate the effect of a short educational intervention on MS knowledge. MS (n = 962) and students of architecture and law (n = 229) were asked to complete a 60-item questionnaire addressing knowledge of smoking epidemiology and health effects ("Score 1"), and effectiveness of cessation treatments ("Score 2"). Upon completion of questionnaire, fourth year MS received a lecture on tobacco dependence. These students were asked to complete the same questionnaire one and two years later. Mean values for Score 1 were 48.9 +/- 11.5% in MS and 40.5 +/- 11.4% in non-MS (P < 0.001; d = 0.69). Respective values for Score 2 were 48.1 +/- 10.8% and 42.6 +/- 10.6% (P < 0.001; d = 0.50). Fifth year students who had attended the lecture in year 4 scored higher than students who had not attended the lecture. Significant differences were noted one but not two years after the educational intervention. In conclusion, MS know slightly more about smoking-related diseases and methods to achieve cessation than nonmedical students; a short educational intervention was associated with better knowledge one year later, but the effect was moderate and short-lived. PMID- 24804213 TI - Association between peripheral oxidative stress and white matter damage in acute traumatic brain injury. AB - The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI. PMID- 24804214 TI - Streptomyces flavogriseus HS1: isolation and characterization of extracellular proteases and their compatibility with laundry detergents. AB - The present study describes the isolation of a new protease producing Streptomyces strain HS1 and the biochemical characterization of the secreted proteases. By sequencing of its noted 16S rDNA, HS1 strain was found to have a 100% identity with Streptomyces flavogriseus. The highest protease production was found using FermII media. In these conditions maximum protease production (99 U/mL) was obtained after 96 h incubation at 30 degrees C and 150 rpm. HS1 strain produced at least five proteases as revealed by zymogram technique. The enzyme preparation exhibited activity over a broad range of pH (5-11) and temperature (25-70 degrees C). Optimum activity was observed at a pH of 7.0 and a temperature of 50 degrees C. Proteolytic activity was significantly unaffected by Ca(2+) and Mg(2+). EDTA and PMSF highly decreased the original activity. The crude extracellular proteases showed high stability when used as a detergent additive. These properties offer an interesting potential for enzymatic hydrolysis at the industrial level. PMID- 24804215 TI - Extracellular matrix proteins expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line. AB - Ovarian cancer is the leading cause of death among gynaecological malignancies. Extracellular matrix (ECM) can affect drug resistance by preventing the penetration of the drug into cancer cells and increased resistance to apoptosis. This study demonstrates alterations in the expression levels of ECM components and related genes in cisplatin-, doxorubicin-, topotecan-, and paclitaxel resistant variants of the A2780 ovarian cancer cell line. Affymetrix Gene Chip Human Genome Array Strips were used for hybridisations. The genes that had altered expression levels in drug-resistant sublines were selected and filtered by scatter plots. The genes that were up- or downregulated more than fivefold were selected and listed. Among the investigated genes, 28 genes were upregulated, 10 genes were downregulated, and two genes were down- or upregulated depending on the cell line. Between upregulated genes 12 were upregulated very significantly--over 20-fold. These genes included COL1A2, COL12A1, COL21A1, LOX, TGFBI, LAMB1, EFEMP1, GPC3, SDC2, MGP, MMP3, and TIMP3. Four genes were very significantly downregulated: COL11A1, LAMA2, GPC6, and LUM. The expression profiles of investigated genes provide a preliminary insight into the relationship between drug resistance and the expression of ECM components. Identifying correlations between investigated genes and drug resistance will require further analysis. PMID- 24804216 TI - Inhibitory effects of edaravone in beta-amyloid-induced neurotoxicity in rats. AB - Amyloid protein can damage nerve cells through a variety of biological mechanisms including oxidative stress, alterations in calcium homeostasis, and proapoptosis. Edaravone, a potent free radical scavenger possessing antioxidant effects, has been proved neuroprotective effect in stroke patients. The current study aimed to investigate the effects of EDA in an Abeta-induced rat model of AD, by studying Abeta 1-40-induced voltage-gated calcium channel currents in hippocampal CA1 pyramidal neurons, learning and memory behavioral tests, the number of surviving cholinergic neurons in the basal forebrain, and the acetylcholine level in the hippocampus in this rat model of AD. The results showed that the Abeta 1-40 induced increase of I Ca can be inhibited by EDA in a dose-dependent manner. Treatment with EDA significantly improved Abeta 1-40-induced learning and memory performance. Choline acetyltransferase positive cells in basal forebrain and acetylcholine content in the hippocampus were increased by the administration of EDA as compared with the non-EDA treated Abeta 1-40 group. These results demonstrate that EDA can inhibit the neurotoxic effect of Abeta toxicity. Collectively, these findings suggest that EDA may serve as a potential complemental treatment strategy for AD. PMID- 24804217 TI - In silico modeling of the immune system: cellular and molecular scale approaches. AB - The revolutions in biotechnology and information technology have produced clinical data, which complement biological data. These data enable detailed descriptions of various healthy and diseased states and responses to therapies. For the investigation of the physiology and pathology of the immune responses, computer and mathematical models have been used in the last decades, enabling the representation of biological processes. In this modeling effort, a major issue is represented by the communication between models that work at cellular and molecular level, that is, multiscale representation. Here we sketch some attempts to model immune system dynamics at both levels. PMID- 24804218 TI - Macrophage capping protein CapG is a putative oncogene involved in migration and invasiveness in ovarian carcinoma. AB - The actin binding protein CapG modulates cell motility by interacting with the cytoskeleton. CapG is associated with tumor progression in different nongynecologic tumor entities and overexpression in breast cancer cell lines correlates with a more invasive phenotype in vitro. Here, we report a significant CapG overexpression in 18/47 (38%) of ovarian carcinomas (OC) analyzed by qRealTime-PCR analyses. Functional analyses in OC cell lines through siRNA mediated CapG knockdown and CapG overexpression showed CapG-dependent cell migration and invasiveness. A single nucleotide polymorphism rs6886 inside the CapG gene was identified, affecting a CapG phosphorylation site and thus potentially modifying CapG function. The minor allele frequency (MAF) of SNP rs6886 (c.1004A/G) was higher and the homozygous (A/A, His335) genotype was significantly more prevalent in patients with fallopian tube carcinomas (50%) as in controls (10%). With OC being one of the most lethal cancer diseases, the detection of novel biomarkers such as CapG could reveal new diagnostic and therapeutic targets. Moreover, in-depth analyses of SNP rs6886 related to FTC and OC will contribute to a better understanding of carcinogenesis and progression of OC. PMID- 24804219 TI - Dissociable self effects for emotion regulation: a study of Chinese major depressive outpatients. AB - Reappraisal is an adaptive emotion regulation strategy while the role of self perspective in reappraisal process of depressed patients is largely unknown in terms of goals (valence/arousal) and tactics (detachment/immersion). In this study, 12 depressed individuals and 15 controls were scanned with MRI during which they either attend naturally to emotional stimuli, or adopt detachment/immersion strategy. Behaviorally, no group differences in self reported emotion regulation effectiveness were found. In addition, we observed that (1) patients were less able to downregulate amygdala activation with recruitment of more dorsal lateral prefrontal cortex (dlPFC) when adopting detachment strategy regardless of valence, and this preserved ability to regulate emotion was inversely associated with severity of symptoms; (2) patients had deficits in upregulating amygdala activation when adopting immersion strategy, with less inferior frontal gyrus (IFG) activation and strengthening coupling of dlPFC and ventral medial prefrontal cortex (vmPFC) with amygdala; (3) comparison between groups yielded that patients showed stronger vmPFC activation under either self-detached or self-immersed condition. In conclusion, impaired modulatory effects of amygdala in depressed patients are compensated with strengthening cognitive control resources, with dissociable effects for different self-perspectives in reappraisal. These results may help clarify the role of self perspective underlying reappraisal in major depression. PMID- 24804220 TI - Resistance exercise with older fallers: its impact on intermuscular adipose tissue. AB - OBJECTIVE: Greater skeletal muscle fat infiltration occurs with age and contributes to numerous negative health outcomes. The primary purpose was to determine whether intermuscular adipose tissue (IMAT) can be influenced by an exercise intervention and if a greater reduction in IMAT occurs with eccentric versus traditional resistance training. METHODS: Seventy-seven older adults (age 75.5 +/- 6.8) with multiple comorbidities and a history of falling completed a three-month exercise intervention paired with either eccentric or traditional resistance training. MRI of the mid-thigh was examined at three time points to determine changes in muscle composition after intervention. RESULTS: No differences in IMAT were observed over time, and there were no differences in IMAT response between intervention groups. Participants in the traditional group lost a significant amount of lean tissue (P = 0.007) in the nine months after intervention, while participants in the eccentric group did not (P = 0.32). When IMAT levels were partitioned into high and low IMAT groups, there were differential IMAT responses to intervention with the high group lowering thigh IMAT. CONCLUSIONS: There is no decrease in thigh IMAT after a three-month exercise intervention in older adults at risk for falling and no benefit to eccentric training over traditional resistance training for reducing IMAT in these individuals. PMID- 24804221 TI - Comorbidities in chronic obstructive pulmonary disease from assessment to treatment. PMID- 24804222 TI - Measurement of cephalic indices in older children and adolescents of a Nigerian population. AB - BACKGROUND: A study on the cephalic index was carried out on subjects from school students in Ogbia tribe of Bayelsa state in the Niger Delta region of Nigeria. This study determined the cephalic indices among the school students. In the present study, seven hundred subjects were randomly selected from secondary schools comprising 350 males and 350 females, respectively, with age range from 11-20 years, with both parents and grandparents of Ogbia tribe. The length and breadth of the head were measured using a spreading caliper from standard bony landmarks. The measurable point for head length was measured between the glabella and inions while the head breadth was the widest biparietal diameter. The cephalic index was head breadth divided by the head length and multiplied by 100. The result showed that the mean cephalic index was 76.56. Males had a cephalic index of 77.21, while females had a cephalic index of 76.50. Based on this study, 78.68% of individuals were mesocephalic, 11.4% dolichocephalic, 9.0% Brachycephalic, and 0.43% hyperbrachycephalic. This research showed that the school students have mesocephalic phenotype. The data from this research will be useful in anthropology, genetics, forensic medicine, and clinical practice. PMID- 24804223 TI - Aetiology of bacteraemia as a risk factor for septic shock at the onset of febrile neutropaenia in adult cancer patients. AB - Septic shock (SS) at the onset of febrile neutropaenia (FN) is an emergency situation that is associated with high morbidity and mortality. The impact of the specific aetiology of bloodstream infections (BSIs) in the development of SS at the time of FN is not well established. The aim of this study was to evaluate the association between the aetiology of BSIs and SS at the time of FN in hospitalised adult cancer patients. This prospective cohort study was performed at a single tertiary hospital from October 2009 to August 2011. All adult cancer patients admitted consecutively to the haematology ward with FN were evaluated. A stepwise logistic regression was conducted to verify the association between the microbiological characteristics of BSIs and SS at the onset of FN. In total, 307 cases of FN in adult cancer patients were evaluated. There were 115 cases with documented BSI. A multivariate analysis showed that polymicrobial bacteraemia (P = 0.01) was associated with SS. The specific blood isolates independently associated with SS were viridans streptococci (P = 0.02) and Escherichia coli (P = 0.01). Neutropaenic cancer patients with polymicrobial bacteraemia or BSI by viridans streptococci or Escherichia coli are at increased risk for SS at the time of FN. PMID- 24804224 TI - Morphological and radiological study of ossified superior transverse scapular ligament as potential risk factor of suprascapular nerve entrapment. AB - The suprascapular notch is covered superiorly by the superior transverse scapular ligament. This region is the most common place of suprascapular nerve entrapment formation. The study was performed on 812 specimens: 86 dry scapulae, 104 formalin-fixed cadaveric shoulders, and 622 computer topography scans of scapulae. In the cases with completely ossified superior transverse scapular ligament, the following measurements were performed: proximal and distal width of the bony bridge, middle transverse and vertical diameter of the suprascapular foramen, and area of the suprascapular foramen. An ossified superior transverse scapular ligament was observed more often in men and in the right scapula. The mean age of the subjects with a completely ossified superior transverse scapular ligament was found to be similar than in those without ossification. The ossified band-shaped type of superior transverse scapular ligament was more common than the fan-shaped type and reduced the space below the ligament to a significantly greater degree. The ossified band-shaped type should be taken into consideration as a potential risk factor in the formation of suprascapular nerve entrapment. It could explain the comparable frequency of neuropathy in various populations throughout the world despite the significant differences between them in occurrence of ossified superior transverse scapular ligament. PMID- 24804225 TI - Antioxidant activity of essential oil and extracts of Valeriana jatamansi roots. AB - Valeriana jatamansi is an indigenous medicinal plant used in the treatment of a number of diseases. In the present study, chemical composition of the essential oil was determined by GC-MS. Seven major components were identified in Valeriana jatamansi essential oil, namely, beta-vatirenene, beta-patchoulene, dehydroaromadendrene, beta-gurjunene, patchoulic alcohol, beta-guaiene, and alpha muurolene. Methanolic, aqueous, and chloroform extracts of Valeriana jatamansi roots were also prepared and analyzed for their polyphenols and flavonoid content. Antioxidant activity of essential oil and different extracts of Valeriana jatamansi roots was determined by DPPH radical scavenging and chelation power assay. A linear correlation has been obtained by comparing the antioxidant activity and polyphenols and flavonoid content of the extracts. Results indicated that antioxidant activity of methanolic extract could be attributed to the presence of rich amount of polyphenols and flavonoid. Essential oil of Valeriana jatamansi roots showed moderate antioxidant activity. PMID- 24804226 TI - Silencing miR-21 sensitizes non-small cell lung cancer A549 cells to ionizing radiation through inhibition of PI3K/Akt. AB - We investigated the role of microRNA-21 (miR-21) in radiotherapy resistance of non-small cell lung cancers (NSCLC) and the underlying molecular mechanism. A549 cells were transfected with anti-miR-21 or the negative control oligonucleotides and real-time PCR was applied to detect miR-21 expression level. After ionizing radiation (IR), the survival fractions, proliferation, apoptosis, and expression of phosphorylated-Akt of A549 cells were determined by clonogenic survival analysis, MTT assay, flow cytometry, and Western blotting. Downregulation of miR 21 in radioresistant NSCLC A549 cells inhibited the colony-forming ability and proliferation of A549 cells after IR. Moreover, silencing miR-21 enhanced apoptosis of A549 cells induced by IR accompanied by decreased phosphorylated-Akt protein level. However, PI3K activator IGF-1 reversed suppression of phosphorylated-Akt protein level and promotion of apoptosis of A549 cells after IR caused by miR-21 knockdown. Silencing miR-21 in radioresistant NSCLC A549 cells sensitized them to IR by inhibiting cell proliferation and enhancing cell apoptosis through inhibition of PI3K/Akt signaling pathway. This might help in sensitization of NSCLC to radiotherapy. PMID- 24804227 TI - Angular velocity affects trunk muscle strength and EMG activation during isokinetic axial rotation. AB - OBJECTIVE: To evaluate trunk muscle strength and EMG activation during isokinetic axial rotation at different angular velocities. METHOD: Twenty-four healthy young men performed isokinetic axial rotation in right and left directions at 30, 60, and 120 degrees per second angular velocity. Simultaneously, surface EMG was recorded on external oblique (EO), internal oblique (IO), and latissimus dorsi (LD) bilaterally. RESULTS: In each direction, with the increase of angular velocity, peak torque decreased, whereas peak power increased. During isokinetic axial rotation, contralateral EO as well as ipsilateral IO and LD acted as primary agonists, whereas, ipsilateral EO as well as contralateral IO and LD acted as primary antagonistic muscles. For each primary agonist, the root mean square values decreased with the increase of angular velocity. Antagonist coactiviation was observed at each velocity; however, it appears to be higher with the increase of angular velocity. CONCLUSION: Our results suggest that velocity of rotation has great impact on the axial rotation torque and EMG activity. An inverse relationship of angular velocity was suggested with the axial rotation torque as well as root mean square value of individual trunk muscle. In addition, higher velocity is associated with higher coactivation of antagonist, leading to a decrease in torque with the increase of velocity. PMID- 24804228 TI - The chromosome 9p21 variant not predicting long-term cardiovascular mortality in Chinese with established coronary artery disease: an eleven-year follow-up study. AB - INTRODUCTION: We examined whether the variant at chromosome 9p21, rs4977574, was associated with long-term cardiovascular mortality in Han Chinese patients with coronary artery disease (CAD). METHODOLOGY: Subjects who underwent coronary angiography for chest pain were consecutively enrolled. Fasting blood samples were collected for laboratory and genotype assessments. The information was correlated with data collected from the national death database. RESULTS: There were 925 cases with CAD and 634 without CAD enrolled in the present study. The G allele conferred a significant increase in risk of CAD (odds ratio = 1.47, P = 0.003 in the dominant model; odds ratio = 1.36, P = 0.018 in the recessive model). During a median of 11 years (inter-quartile range between 5.2 and 12.5 years) of follow-up, neither the total nor the cardiovascular mortality was different among CAD subjects with different genotypes. Using Cox regression analysis, genotypes of rs4977574 still failed to predict cardiovascular mortality (hazard ratio = 1.25, P = 0.138 in the dominant model; hazard ratio = 1.05, P = 0.729 in the recessive model). CONCLUSIONS: The rs4977574 at chromosome 9p21 is associated with presence of CAD in Han Chinese. However, rs4977574 could not predict cardiovascular mortality in these CAD subjects during the eleven-year period of the study. PMID- 24804230 TI - Good preservation of stromal cells and no apoptosis in human ovarian tissue after vitrification. AB - The aim of this study was to develop a vitrification procedure for human ovarian tissue cryopreservation in order to better preserve the ovarian tissue. Large size samples of ovarian tissue retrieved from 15 female-to-male transgender subjects (18-38 years) were vitrified using two solutions (containing propylene glycol, ethylene glycol, and sucrose at different concentrations) in an open system. Light microscopy, transmission electron microscopy, and TUNEL assay were applied to evaluate the efficiency of the vitrification protocol. After vitrification/warming, light microscopy showed oocyte nucleus with slightly thickened chromatin and irregular shape, while granulosa and stromal cells appeared well preserved. Transmission electron microscopy showed oocytes with slightly irregular nuclear shape and finely dispersed chromatin. Clear vacuoles and alterations in cellular organelles were seen in the oocyte cytoplasm. Stromal cells had a moderately dispersed chromatin and homogeneous cytoplasm with slight vacuolization. TUNEL assay revealed the lack of apoptosis induction by vitrification in all ovarian cell types. In conclusion after vitrification/warming the stromal compartment maintained morphological and ultrastructural features similar to fresh tissue, while the oocyte cytoplasm was slightly damaged. Although these data are encouraging, further studies are necessary and essential to optimize vitrification procedure. PMID- 24804229 TI - Early preinvasive lesions in ovarian cancer. AB - Faced with the catastrophic prognosis for ovarian cancer due to the fact that it is most often diagnosed late at the peritoneal carcinomatosis stage, screening and early detection could probably reduce the mortality rate. A better understanding of the molecular characteristics of the different ovarian cancer subtypes and their specific molecular signatures is indispensable prior to development of new screening strategies. We discuss here the early natural history of ovarian cancer and its origins. PMID- 24804231 TI - Umbilical cord blood-derived stem cells improve heat tolerance and hypothalamic damage in heat stressed mice. AB - Heatstroke is characterized by excessive hyperthermia associated with systemic inflammatory responses, which leads to multiple organ failure, in which brain disorders predominate. This definition can be almost fulfilled by a mouse model of heatstroke used in the present study. Unanesthetized mice were exposed to whole body heating (41.2 degrees C for 1 hour) and then returned to room temperature (26 degrees C) for recovery. Immediately after termination of whole body heating, heated mice displayed excessive hyperthermia (body core temperature ~42.5 degrees C). Four hours after termination of heat stress, heated mice displayed (i) systemic inflammation; (ii) ischemic, hypoxic, and oxidative damage to the hypothalamus; (iii) hypothalamo-pituitary-adrenocortical axis impairment (reflected by plasma levels of both adrenocorticotrophic-hormone and corticosterone); (iv) decreased fractional survival; and (v) thermoregulatory deficits (e.g., they became hypothermia when they were exposed to room temperature). These heatstroke reactions can be significantly attenuated by human umbilical cord blood-derived CD34(+) cells therapy. Our data suggest that human umbilical cord blood-derived stem cells therapy may improve outcomes of heatstroke in mice by reducing systemic inflammation as well as hypothalamo pituitary-adrenocortical axis impairment. PMID- 24804233 TI - Biological basis for increased sensitivity to radiation therapy in HPV-positive head and neck cancers. AB - Although development of head and neck squamous cell carcinomas (HNSCCs) is commonly linked to the consumption of tobacco and alcohol, a link between human papillomavirus (HPV) infection and a subgroup of head and neck cancers has been established. These HPV-positive tumors represent a distinct biological entity with overexpression of viral oncoproteins E6 and E7. It has been shown in several clinical studies that HPV-positive HNSCCs have a more favorable outcome and greater response to radiotherapy. The reason for improved prognosis of HPV related HNSCC remains speculative, but it could be owned to multiple factors. One hypothesis is that HPV-positive cells are intrinsically more sensitive to standard therapies and thus respond better to treatment. Another possibility is that HPV-positive tumors uniquely express viral proteins that induce an immune response during therapy that helps clear tumors and prevents recurrence. Here, we will review current evidence for the biological basis of increased radiosensitivity in HPV-positive HNSCC. PMID- 24804234 TI - Patterns in the parathyroid response to sodium bicarbonate infusion test in healthy volunteers. AB - BACKGROUND: The sodium bicarbonate infusion test evaluates the function of the parathyroid glands. The present study aims to evaluate the range of parathyroid response in healthy individuals and the potential influence of various factors. METHODS: Fifty healthy volunteers were subjected to the test. Levels of vitamin D, calcium, albumin, and PTH were measured before infusion. PTH was measured at 3, 5, 10, 30, and 60 minutes after infusion. RESULTS: A curve describing the response of parathyroids to the test was drawn. Twenty percent of the subjects had blunted PTH response. No significant difference was observed between normal and blunted responders concerning age, BMI, baseline PTH, or calcium levels. Nonetheless, there was a significant difference in vitamin D levels (P = 0.024). INTERPRETATION: The test is easy to perform and may be used for everyday screening. It has to be clarified whether our observations are, at least partly, produced due to the presence of individuals with a constitutively blunted response or if low levels of vitamin D decrease the ability of the parathyroids to respond. Whichever the case, PTH response of normal individuals to sodium bicarbonate infusion test is more varied than previously thought and vitamin D levels influence it. PMID- 24804235 TI - Abnormal cardiac autonomic regulation in mice lacking ASIC3. AB - Integration of sympathetic and parasympathetic outflow is essential in maintaining normal cardiac autonomic function. Recent studies demonstrate that acid-sensing ion channel 3 (ASIC3) is a sensitive acid sensor for cardiac ischemia and prolonged mild acidification can open ASIC3 and evoke a sustained inward current that fires action potentials in cardiac sensory neurons. However, the physiological role of ASIC3 in cardiac autonomic regulation is not known. In this study, we elucidate the role of ASIC3 in cardiac autonomic function using Asic3(-/-) mice. Asic3(-/-) mice showed normal baseline heart rate and lower blood pressure as compared with their wild-type littermates. Heart rate variability analyses revealed imbalanced autonomic regulation, with decreased sympathetic function. Furthermore, Asic3(-/-) mice demonstrated a blunted response to isoproterenol-induced cardiac tachycardia and prolonged duration to recover to baseline heart rate. Moreover, quantitative RT-PCR analysis of gene expression in sensory ganglia and heart revealed that no gene compensation for muscarinic acetylcholines receptors and beta-adrenalin receptors were found in Asic3(-/-) mice. In summary, we unraveled an important role of ASIC3 in regulating cardiac autonomic function, whereby loss of ASIC3 alters the normal physiological response to ischemic stimuli, which reveals new implications for therapy in autonomic nervous system-related cardiovascular diseases. PMID- 24804236 TI - Potential synergy activity of the novel ceragenin, CSA-13, against carbapenem resistant Acinetobacter baumannii strains isolated from bacteremia patients. AB - Carbapenem-resistant Acinetobacter baumannii is an important cause of nosocomial infections, particularly in patients in the intensive care units. As chronic infections are difficult to treat, attempts have been made to discover new antimicrobials. Ceragenins, designed to mimic the activities of antimicrobial peptides, are a new class of antimicrobial agents. In this study, the in vitro activities of CSA-13 either alone or in combination with colistin (sulphate), tobramycin, and ciprofloxacin were investigated using 60 carbapenem-resistant A. baumannii strains isolated from bacteremia patients blood specimens. MICs and MBCs were determined by microbroth dilution technique. Combinations were assessed by using checkerboard technique. The MIC50 values (mg/L) of CSA-13, colistin, tobramycin, and ciprofloxacin were 2, 1, 1.25, and 80, respectively. The MIC90 (mg/L) of CSA-13 and colistin were 8 and 4. The MBCs were equal to or twice greater than those of the MICs. Synergistic interactions were mostly seen with CSA-13-colistin (55%), whereas the least synergistic interactions were observed in the CSA-13-tobramycin (35%) combination. No antagonism was observed. CSA-13 appears to be a good candidate for further investigations in the treatment of A. baumannii infections. However, future studies should be performed to correlate the safety, efficacy, and pharmacokinetic parameters of this molecule. PMID- 24804237 TI - The morphology and functions of articular chondrocytes on a honeycomb-patterned surface. AB - The present study investigated the potential of a novel micropatterned substrate for neocartilage formation. Articular chondrocytes were cultured on poly( E caprolactone) materials whose surfaces were either flat or honeycomb-patterned. The latter was prepared using a novel self-organization technique, while the former, was prepared by spin-coating. The chondrocytes attached and proliferated on both surfaces. On the honeycomb films, chondrocytes were found at the top surface and encased within the 10 MUm pores. Meanwhile, chondrocytes on the spin coated surface flattened out. Accumulation of DNA and keratin sulphate was comparatively higher on the honeycomb films within the first 7 days. At their respective peaks, DNA concentration increased on the honeycomb and flat surfaces by approximately 210% and 400% of their day 1 values, respectively. However, cultures on the flat surface took longer to peak. Extracellular Matrix (ECM) concentrations peaked at 900% and 320% increases for the honeycomb and flat cultures. Type II collagen was upregulated on the honeycomb and flat surfaces by as much as 28% and 25% of their day 1 values, while aggrecan was downregulated with time, by 3.4% and 7.4%. These initial results demonstrate the potential usefulness of honeycomb-based scaffolds during early cultures neocartilage and soft tissue engineering. PMID- 24804238 TI - Involvement of endocytosis and alternative splicing in the formation of the pathological process in the early stages of Parkinson's disease. AB - Parkinson's disease (PD) is the one of most widespread neurodegenerative pathologies. Because of the impossibility of studying the endogenous processes that occur in the brain of patients with PD in the presymptomatic stage, the mechanisms that trigger the disease remain unknown. Thus, the identification of the processes that play an important role in the early stages of the disease in these patients is extremely difficult. In this context, we performed a whole transcriptome analysis of the peripheral blood of untreated patients with stage 1 PD (Hoehn-Yahr scale). We demonstrated a significant change in the levels of transcripts included in the large groups of processes associated with the functioning of the immune system and cellular transport. Moreover, a significant change in the splicing of genes involved in cellular-transport processes was shown in our study. PMID- 24804239 TI - Beyond obesity and lifestyle: a review of 21st century chronic disease determinants. AB - The obesity epidemic and associated chronic diseases are often attributed to modern lifestyles. The term "lifestyle" however, ignores broader social, economic, and environmental determinants while inadvertently "blaming the victim." Seen more eclectically, lifestyle encompasses distal, medial, and proximal determinants. Hence any analysis of causality should include all these levels. The term "anthropogens," or "...man-made environments, their by-products and/or lifestyles encouraged by these, some of which may be detrimental to human health" provides a monocausal focus for chronic diseases similar to that which the germ theory afforded infectious diseases. Anthropogens have in common an ability to induce a form of chronic, low-level systemic inflammation ("metaflammation"). A review of anthropogens, based on inducers with a metaflammatory association, is conducted here, together with the evidence for each in connection with a number of chronic diseases. This suggests a broader view of lifestyle and a focus on determinants, rather than obesity and lifestyle per se as the specific causes of modern chronic disease. Under such an analysis, obesity is seen more as "a canary in a mineshaft" signaling problems in the broader environment, suggesting that population obesity management should be focused more upstream if chronic diseases are to be better managed. PMID- 24804240 TI - mTOR in viral hepatitis and hepatocellular carcinoma: function and treatment. AB - As the fifth most common cancer in men and the eighth most common cancer in women, hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, with standard chemotherapy and radiation being minimally effective in prolonging survival. Virus hepatitis, particularly HBV and HCV infection is the most prominent risk factor for HCC development. Mammalian target of rapamycin (mTOR) pathway is activated in viral hepatitis and HCC. mTOR inhibitors have been tested successfully in clinical trials for their antineoplastic potency and well tolerability. Treatment with mTOR inhibitor alone or in combination with cytotoxic drugs or targeted therapy drug scan significantly reduces HCC growth and improves clinical outcome, indicating that mTOR inhibition is a promising strategy for the clinical management of HCC. PMID- 24804241 TI - Induction of reparative dentin formation on exposed dental pulp by dentin phosphophoryn/collagen composite. AB - The ultimate goal of vital pulp therapy is to regenerate rapidly dentin possessing an excellent quality using a biocompatible, bioactive agent. Dentin phosphophoryn (DPP), the most abundant noncollagenous polyanionic protein in dentin, cross-linked to atelocollagen fibrils was applied to direct pulp capping in rats. After 1, 2, and 3 weeks, the teeth applied were examined on the induction of reparative dentin formation and the response of pulp tissue, compared to calcium hydroxide-based agent conventionally used. The reparative dentin formation induced by DPP/collagen composite was more rapid than by calcium hydroxide. In the morphometrical analysis, the formation rate of reparative dentin by DPP/collagen composite was approximately the same as that by calcium hydroxide at 3 weeks. Nevertheless, the compactness of reparative dentin formed by DPP/collagen composite was much superior to what resulted from calcium hydroxide. Also, DPP/collagen composite showed high covering ability of exposed pulp. Moreover, DPP/collagen composite led only to slight pulp inflammation at the beginning whereas calcium hydroxide formed necrotic layer adjacent to the material and induced severe inflammation in pulp tissue at 1 week. The present study demonstrates a potential for DPP/collagen composite as a rapid biocompatible inducer for the formation of reparative dentin of excellent quality in rats. PMID- 24804242 TI - Associations between GJB2, mitochondrial 12S rRNA, SLC26A4 mutations, and hearing loss among three ethnicities. AB - The epidemiological researches show that the mutations of GJB2, mitochondrial 12S rRNA, and SLC26A4 genes have played an important role in the hearing loss. This study aims to investigate the mutation spectrum of GJB2, mitochondrial 12S rRNA, and SLC26A4 genes of Han Chinese, Hui people, and Uyghur ethnicities in sensorineural hearing loss (SNHL) patients in northwest of China. Mutational analyses in the three genes were brought by direct sequencing and each fragment was analyzed using an ABI 3730 DNA Sequencer. The mutation frequencies for the three HL causative genes were 34.05% in Han Chinese participants, 27.47% in Hui people, and 14.44% in Uyghur participants, respectively. The prevalence of GJB2 mutations was 13.7%, 11.4%, and 11.4% in Han Chinese, Hui people, and Uyghur participants (chi(2) = 10.2, P < 0.05), respectively. The prevalence of mtDNA 12S rRNA A1555G homozygous mutations was 6.05%, 3.27%, and 1.44% in Han Chinese, Hui people, and Uyghur participants (chi(2) = 13.9, P < 0.05), respectively. The prevalence of SLC26A4 mutations was 14.3%, 12.8%, and 1.6% in Han Chinese, Hui people, and Uyghur participants, respectively. In summary, we find that Uyghur and Hui SNHL individuals vary significantly from Han Chinese patients in three causative HL genes' mutational spectrum, especially for Uyghur. PMID- 24804243 TI - Liraglutide suppresses obesity and hyperglycemia associated with increases in hepatic fibroblast growth factor 21 production in KKAy mice. AB - Social isolation contributes to the development of obesity and insulin independent diabetes in KKA(y) mice. Here we show that systemic administration of liraglutide, a long-acting human glucagon-like peptide-1 (GLP-1) analog, significantly decreased food intake, body weight, and blood glucose levels at 24 h after its administration while having no significant effects on plasma insulin and glucagon levels in individually housed KKA(y) mice. In addition, the systemic administration of liraglutide significantly increased plasma fibroblast growth factor (Fgf) 21 levels (1.8-fold increase) associated with increases in the expression of hepatic Fgf21 (1.9-fold increase) and Ppargamma (1.8-fold increase), while having no effects on the expression of hepatic Pparalpha and Fgf21 in white adipose tissue. Moreover, systemic administration of liraglutide over 3 days significantly suppressed food intake, body weight gain, and hyperglycemia in KKA(y) mice. On the other hand, despite remarkably increased plasma active GLP-1 levels (4.2-fold increase), the ingestion of alogliptin, a selective dipeptidyl peptidase-4 inhibitor, over 3 days had no effects on food intake, body weight, blood glucose levels, and plasma Fgf21 levels in KKA(y) mice. These findings suggest that systemic administration of liraglutide induces hepatic Fgf21 production and suppresses the social isolation-induced obesity and diabetes independently of insulin, glucagon, and active GLP-1 in KKA(y) mice. PMID- 24804244 TI - A novel bioinformatics method for efficient knowledge discovery by BLSOM from big genomic sequence data. AB - With remarkable increase of genomic sequence data of a wide range of species, novel tools are needed for comprehensive analyses of the big sequence data. Self Organizing Map (SOM) is an effective tool for clustering and visualizing high dimensional data such as oligonucleotide composition on one map. By modifying the conventional SOM, we have previously developed Batch-Learning SOM (BLSOM), which allows classification of sequence fragments according to species, solely depending on the oligonucleotide composition. In the present study, we introduce the oligonucleotide BLSOM used for characterization of vertebrate genome sequences. We first analyzed pentanucleotide compositions in 100 kb sequences derived from a wide range of vertebrate genomes and then the compositions in the human and mouse genomes in order to investigate an efficient method for detecting differences between the closely related genomes. BLSOM can recognize the species specific key combination of oligonucleotide frequencies in each genome, which is called a "genome signature," and the specific regions specifically enriched in transcription-factor-binding sequences. Because the classification and visualization power is very high, BLSOM is an efficient powerful tool for extracting a wide range of information from massive amounts of genomic sequences (i.e., big sequence data). PMID- 24804245 TI - Impact of HbA1c measurement on hospital readmission rates: analysis of 70,000 clinical database patient records. AB - Management of hyperglycemia in hospitalized patients has a significant bearing on outcome, in terms of both morbidity and mortality. However, there are few national assessments of diabetes care during hospitalization which could serve as a baseline for change. This analysis of a large clinical database (74 million unique encounters corresponding to 17 million unique patients) was undertaken to provide such an assessment and to find future directions which might lead to improvements in patient safety. Almost 70,000 inpatient diabetes encounters were identified with sufficient detail for analysis. Multivariable logistic regression was used to fit the relationship between the measurement of HbA1c and early readmission while controlling for covariates such as demographics, severity and type of the disease, and type of admission. Results show that the measurement of HbA1c was performed infrequently (18.4%) in the inpatient setting. The statistical model suggests that the relationship between the probability of readmission and the HbA1c measurement depends on the primary diagnosis. The data suggest further that the greater attention to diabetes reflected in HbA1c determination may improve patient outcomes and lower cost of inpatient care. PMID- 24804246 TI - Fabrication and characteristics of chitosan sponge as a tissue engineering scaffold. AB - Cells, growth factors, and scaffolds are the three main factors required to create a tissue-engineered construct. After the appearance of bovine spongiform encephalopathy (BSE), considerable attention has therefore been focused on nonbovine materials. In this study, we examined the properties of a chitosan porous scaffold. A porous chitosan sponge was prepared by the controlled freezing and lyophilization of different concentrations of chitosan solutions. The materials were examined by scanning electron microscopy, and the porosity, tensile strength, and basic fibroblast growth factor (bFGF) release profiles from chitosan sponge were examined in vitro. The morphology of the chitosan scaffolds presented a typical microporous structure, with the pore size ranging from 50 to 200 MUm. The porosity of chitosan scaffolds with different concentrations was approximately 75-85%. A decreasing tendency for porosity was observed as the concentration of the chitosan increased. The relationship between the tensile properties and chitosan concentration indicated that the ultimate tensile strength for the sponge increased with a higher concentration. The in vitro bFGF release study showed that the higher the concentration of chitosan solution became, the longer the releasing time of the bFGF from the chitosan sponge was. PMID- 24804247 TI - Glycosaminoglycan monosaccharide blocks analysis by quantum mechanics, molecular dynamics, and nuclear magnetic resonance. AB - Glycosaminoglycans (GAGs) play an important role in many biological processes in the extracellular matrix. In a theoretical approach, structures of monosaccharide building blocks of natural GAGs and their sulfated derivatives were optimized by a B3LYP6311ppdd//B3LYP/6-31+G(d) method. The dependence of the observed conformational properties on the applied methodology is described. NMR chemical shifts and proton-proton spin-spin coupling constants were calculated using the GIAO approach and analyzed in terms of the method's accuracy and sensitivity towards the influence of sulfation, O1-methylation, conformations of sugar ring, and omega dihedral angle. The net sulfation of the monosaccharides was found to be correlated with the (1)H chemical shifts in the methyl group of the N acetylated saccharides both theoretically and experimentally. The omega dihedral angle conformation populations of free monosaccharides and monosaccharide blocks within polymeric GAG molecules were calculated by a molecular dynamics approach using the GLYCAM06 force field and compared with the available NMR and quantum mechanical data. Qualitative trends for the impact of sulfation and ring conformation on the chemical shifts and proton-proton spin-spin coupling constants were obtained and discussed in terms of the potential and limitations of the computational methodology used to be complementary to NMR experiments and to assist in experimental data assignment. PMID- 24804248 TI - Evaluation of drought tolerance of the Vietnamese soybean cultivars provides potential resources for soybean production and genetic engineering. AB - Drought is one of the greatest constraints to soybean production in many countries, including Vietnam. Although a wide variety of the newly produced cultivars have been produced recently in Vietnam through classical breeding to cope with water shortage, little knowledge of their molecular and physiological responses to drought has been discovered. This study was conducted to quickly evaluate drought tolerance of thirteen local soybean cultivars for selection of the best drought-tolerant cultivars for further field test. Differences in drought tolerance of cultivars were assessed by root and shoot lengths, relative water content, and drought-tolerant index under both normal and drought conditions. Our data demonstrated that DT51 is the strongest drought-tolerant genotype among all the tested cultivars, while the highest drought-sensitive phenotype was observed with MTD720. Thus, DT51 could be subjected to further yield tests in the field prior to suggesting it for use in production. Due to their contrasting drought-tolerant phenotypes, DT51 and MTD720 provide excellent genetic resources for further studies underlying mechanisms regulating drought responses and gene discovery. Our results provide vital information to support the effort of molecular breeding and genetic engineering to improve drought tolerance of soybean. PMID- 24804249 TI - Antibacterial potential of northeastern Portugal wild plant extracts and respective phenolic compounds. AB - The present work aims to assess the antibacterial potential of phenolic extracts, recovered from plants obtained on the North East of Portugal, and of their phenolic compounds (ellagic, caffeic, and gallic acids, quercetin, kaempferol, and rutin), against bacteria commonly found on skin infections. The disk diffusion and the susceptibility assays were used to identify the most active extracts and phenolic compounds. The effect of selected phenolic compounds on animal cells was assessed by determination of cellular metabolic activity. Gallic acid had a higher activity, against gram-positive (S. epidermidis and S. aureus) and gram-negative bacteria (K. pneumoniae) at lower concentrations, than the other compounds. The caffeic acid, also, showed good antibacterial activity against the 3 bacteria used. The gallic acid was effective against the 3 bacteria without causing harm to the animal cells. Gallic and caffeic acid showed a promising applicability as antibacterial agents for the treatment of infected wounds. PMID- 24804250 TI - Staphylococcus aureus and staphylococcal food-borne disease: an ongoing challenge in public health. AB - Staphylococcal food-borne disease (SFD) is one of the most common food-borne diseases worldwide resulting from the contamination of food by preformed S. aureus enterotoxins. It is one of the most common causes of reported food-borne diseases in the United States. Although several Staphylococcal enterotoxins (SEs) have been identified, SEA, a highly heat-stable SE, is the most common cause of SFD worldwide. Outbreak investigations have found that improper food handling practices in the retail industry account for the majority of SFD outbreaks. However, several studies have documented prevalence of S. aureus in many food products including raw retail meat indicating that consumers are at potential risk of S. aureus colonization and subsequent infection. Presence of pathogens in food products imposes potential hazard for consumers and causes grave economic loss and loss in human productivity via food-borne disease. Symptoms of SFD include nausea, vomiting, and abdominal cramps with or without diarrhea. Preventive measures include safe food handling and processing practice, maintaining cold chain, adequate cleaning and disinfection of equipment, prevention of cross-contamination in home and kitchen, and prevention of contamination from farm to fork. This paper provides a brief overview of SFD, contributing factors, risk that it imposes to the consumers, current research gaps, and preventive measures. PMID- 24804251 TI - Supervised clustering based on DPClusO: prediction of plant-disease relations using Jamu formulas of KNApSAcK database. AB - Indonesia has the largest medicinal plant species in the world and these plants are used as Jamu medicines. Jamu medicines are popular traditional medicines from Indonesia and we need to systemize the formulation of Jamu and develop basic scientific principles of Jamu to meet the requirement of Indonesian Healthcare System. We propose a new approach to predict the relation between plant and disease using network analysis and supervised clustering. At the preliminary step, we assigned 3138 Jamu formulas to 116 diseases of International Classification of Diseases (ver. 10) which belong to 18 classes of disease from National Center for Biotechnology Information. The correlation measures between Jamu pairs were determined based on their ingredient similarity. Networks are constructed and analyzed by selecting highly correlated Jamu pairs. Clusters were then generated by using the network clustering algorithm DPClusO. By using matching score of a cluster, the dominant disease and high frequency plant associated to the cluster are determined. The plant to disease relations predicted by our method were evaluated in the context of previously published results and were found to produce around 90% successful predictions. PMID- 24804252 TI - Biology of ageing and role of dietary antioxidants. AB - Interest in relationship between diet and ageing is growing. Research has shown that dietary calorie restriction and some antioxidants extend lifespan in various ageing models. On the one hand, oxygen is essential to aerobic organisms because it is a final electron acceptor in mitochondria. On the other hand, oxygen is harmful because it can continuously generate reactive oxygen species (ROS), which are believed to be the factors causing ageing of an organism. To remove these ROS in cells, aerobic organisms possess an antioxidant defense system which consists of a series of enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). In addition, dietary antioxidants including ascorbic acid, vitamin A, vitamin C, alpha tocopherol, and plant flavonoids are also able to scavenge ROS in cells and therefore theoretically can extend the lifespan of organisms. In this connection, various antioxidants including tea catechins, theaflavins, apple polyphenols, black rice anthocyanins, and blueberry polyphenols have been shown to be capable of extending the lifespan of fruit flies. The purpose of this review is to brief the literature on modern biological theories of ageing and role of dietary antioxidants in ageing as well as underlying mechanisms by which antioxidants can prolong the lifespan with focus on fruit flies as an model. PMID- 24804255 TI - PCR and microscopic identification of isolated Leishmania tropica from clinical samples of cutaneous leishmaniasis in human population of Kohat region in Khyber Pakhtunkhwa. AB - Leishmania tropica was isolated from the clinical patients of cutaneous leishmaniasis in rural community of Kohat district in Khyber Pakhtunkhwa province and was identified through PCR, microscopy, and culture techniques. A total of 113 samples from the clinical patients were examined through PCR, microscopy, and culture which showed 87.61% (99/113), 53.98% (61/113), and 46.90% (53/113) prevalence. During the study, 186 bp Leishmania tropica was identified through PCR. Thus the sensitivity of PCR is very high as compared to the conventional techniques. PMID- 24804254 TI - Proteomes of animal oocytes: what can we learn for human oocytes in the in vitro fertilization programme? AB - Oocytes are crucial cells for mammalian reproduction, yet the molecular principles underlying oocyte development are only partially understood. Therefore, contemporary proteomic approaches have been used increasingly to provide new insights into oocyte quality and maturation in various species such as mouse, pig, and cow. Especially, animal studies have helped in elucidating the molecular status of oocytes during in vitro maturation and other procedures of assisted reproduction. The aim of this review is to summarize the literature on mammalian oocyte proteome and secretome research in the light of natural and assisted reproduction and on lessons to be learned for human oocytes, which have so far remained inaccessible for proteome analysis. PMID- 24804253 TI - Potential biomarkers and their applications for rapid and reliable detection of malaria. AB - Malaria has been responsible for the highest mortality in most malaria endemic countries. Even after decades of malaria control campaigns, it still persists as a disease of high mortality due to improper diagnosis and rapidly evolving drug resistant malarial parasites. For efficient and economical malaria management, WHO recommends that all malaria suspected patients should receive proper diagnosis before administering drugs. It is thus imperative to develop fast, economical, and accurate techniques for diagnosis of malaria. In this regard an in-depth knowledge on malaria biomarkers is important to identify an appropriate biorecognition element and utilize it prudently to develop a reliable detection technique for diagnosis of the disease. Among the various biomarkers, plasmodial lactate dehydrogenase and histidine-rich protein II (HRP II) have received increasing attention for developing rapid and reliable detection techniques for malaria. The widely used rapid detection tests (RDTs) for malaria succumb to many drawbacks which promotes exploration of more efficient economical detection techniques. This paper provides an overview on the current status of malaria biomarkers, along with their potential utilization for developing different malaria diagnostic techniques and advanced biosensors. PMID- 24804256 TI - Current trends in bone tissue engineering. AB - The development of tissue engineering and regeneration constitutes a new platform for translational medical research. Effective therapies for bone engineering typically employ the coordinated manipulation of cells, biologically active signaling molecules, and biomimetic, biodegradable scaffolds. Bone tissue engineering has become increasingly dependent on the merging of innovations from each of these fields, as they continue to evolve independently. This foreword will highlight some of the most recent advances in bone tissue engineering and regeneration, emphasizing the interconnected fields of stem cell biology, cell signaling biology, and biomaterial research. These include, for example, novel methods for mesenchymal stem cell purification, new methods of Wnt signaling pathway manipulation, and cutting edge computer assisted nanoscale design of bone scaffold materials. In the following special issue, we sought to incorporate these diverse areas of emphasis in order to reflect current trends in the field. PMID- 24804257 TI - SPECT- and PET-based approaches for noninvasive diagnosis of acute renal allograft rejection. AB - Molecular imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography are promising tools for noninvasive diagnosis of acute allograft rejection (AR). Given the importance of renal transplantation and the limitation of available donors, detailed analysis of factors that affect transplant survival is important. Episodes of acute allograft rejection are a negative prognostic factor for long-term graft survival. Invasive core needle biopsies are still the "goldstandard" in rejection diagnostics. Nevertheless, they are cumbersome to the patient and carry the risk of significant graft injury. Notably, they cannot be performed on patients taking anticoagulant drugs. Therefore, a noninvasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review SPECT- and PET-based approaches for noninvasive molecular imaging-based diagnostics of acute transplant rejection. PMID- 24804258 TI - Epidemiology of hospitalized traumatic pelvic fractures and their combined injuries in Taiwan: 2000-2011 National Health Insurance data surveillance. AB - BACKGROUND: From the viewpoint of prehospital emergency medicine, a greater proportion of pelvic fractures not of a life-threatening status but combined with other injuries need more comprehensive recognition. METHODS: A 12-year nationwide health database of inpatients was reviewed. All cases diagnosed as pelvic fractures were enrolled. The associated injuries classified into 20 categories were further analyzed. RESULTS: During 2000-2011, the hospitalized incidence of pelvic fractures in Taiwan ranged from 17.17 to 19.42 per 100,000, and an increasing trend with age was observed. The mean case-fatality rate was 1.6% for females and 2.1% for males; male patients with pelvic fractures had a significantly higher risk of death than female patients after adjusting for other covariates. 74.2% of these cases were combined with other injuries. The most common associated injuries in an identified body region were other orthopedic fractures of the lower limbs (21.50%), spine/trunk (20.97%), or upper limbs (18.18%), followed by significant head injuries (17.59%), intra-abdominal injuries (11.00%), and thoracic injuries (7.20%). CONCLUSION: The incidence of hospitalized pelvic fractures in Taiwan was low and the case-fatality rate was lower than those of other countries. Concurrently, coexistence of major combined injuries with pelvic fractures was easily treated at medical centers. PMID- 24804259 TI - Putative bronchopulmonary flagellated protozoa in immunosuppressed patients. AB - Flagellated protozoa that cause bronchopulmonary symptoms in humans are commonly neglected. These protozoal forms which were presumed to be "flagellated protozoa" have been previously identified in immunosuppressed patients in a number of studies, but have not been certainly classified so far. Since no human cases of bronchopulmonary flagellated protozoa were reported from Turkey, we aimed to investigate these putative protozoa in immunosuppressed patients who are particularly at risk of infectious diseases. Bronchoalveolar lavage fluid samples of 110 immunosuppressed adult patients who were admitted to the Department of Chest Diseases, Hafsa Sultan Hospital of Celal Bayar University, Manisa, Turkey, were examined in terms of parasites by light microscopy. Flagellated protozoal forms were detected in nine (8.2%) of 110 cases. Metronidazole (500 mg b.i.d. for 30 days) was given to all positive cases and a second bronchoscopy was performed at the end of the treatment, which revealed no parasites. In conclusion, immunosuppressed patients with bronchopulmonary symptoms should attentively be examined with regard to flagellated protozoa which can easily be misidentified as epithelial cells. PMID- 24804260 TI - Predicting the types of J-proteins using clustered amino acids. AB - J-proteins are molecular chaperones and present in a wide variety of organisms from prokaryote to eukaryote. Based on their domain organizations, J-proteins can be classified into 4 types, that is, Type I, Type II, Type III, and Type IV. Different types of J-proteins play distinct roles in influencing cancer properties and cell death. Thus, reliably annotating the types of J-proteins is essential to better understand their molecular functions. In the present work, a support vector machine based method was developed to identify the types of J proteins using the tripeptide composition of reduced amino acid alphabet. In the jackknife cross-validation, the maximum overall accuracy of 94% was achieved on a stringent benchmark dataset. We also analyzed the amino acid compositions by using analysis of variance and found the distinct distributions of amino acids in each family of the J-proteins. To enhance the value of the practical applications of the proposed model, an online web server was developed and can be freely accessed. PMID- 24804261 TI - Prevalence of past and reactivated viral infections and efficacy of cyclosporine A as monotherapy or in combination in patients with psoriatic arthritis--synergy study: a longitudinal observational study. AB - We have prospectively evaluated psoriatic arthritis (PsA) patients for (1) seropositivity for former viral infections and seroconversion and (2) efficacy of cyclosporine A (CsA) alone or in combination with other immunosuppressants in a time period of 12 months. Screening included HBV antibodies and antigens, HCV antibodies and RNA, HSV 1-2, HZV, EBV, and CMV IgG, and IgM, HHV-6 DNA, and HIV 1 2 antibodies. PsA was evaluated by the Psoriasis Area Severity Index (PASI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Visual Analogue Scale (VAS). At baseline, 126 (56%) out of 225 evaluable patients had 2 or more seropositivities indicative of former infections, and 31 patients (13.8%) presented seropositivity for HCV, HBV, HSV-1 and -2, HHV-6, EBV, or parvovirus infection; one of them, positive for HBAg, was treated with lamivudine, while the remaining 30 received no specific treatment. None of the 31 patients developed virus reactivation. A reduction (P < 0.001) of PASI, BASDAI, and VAS scores was observed at 6 and 12 months. The treatment of PsA with CsA as monotherapy or in combination was safe and effective. In vitro experiments and clinical findings, including those from our study, suggest that CsA as monotherapy or in combination with biologics might be the treatment of choice in PsA HCV-positive patients. PMID- 24804262 TI - Analysis of pericardial effusion from idiopathic pericarditis patients by two dimensional gel electrophoresis. AB - Pericardial fluid (PF) is often considered to be reflection of the serum by which information regarding the physiological status of the heart can be obtained. Some local and systemic disorders may perturb the balance between synthesis and discharge of PF and may cause its aberrant accumulation in the pericardial cavity as pericardial effusion (PE). PE may then lead to an increased intrapericardial pressure from which the heart function is undesirably affected. For some cases, the causes for the perturbance of fluid balance are well understood, but in some other cases, they are not apparent. It may, thus, be helpful to understand the molecular mechanisms behind this troublesome condition to elucidate a clinical approach for therapeutic uses. In this study, protein profiles of PEs from idiopathic pericarditis patients were analyzed. Control samples from patients undergoing elective cardiac surgery (ECS) were included for comparison. In addition to high abundant serum-originated proteins that may not hold significance for understanding the molecular mechanisms behind this disease, omentin-1 was identified and its level was higher for more than two-fold in PE of IP patients. Increased levels of omentin-1 in PE may open a way for understanding the molecular mechanisms behind idiopathic pericarditis (IP). PMID- 24804263 TI - Dose distributions of an 192Ir brachytherapy source in different media. AB - This study used MCNPX code to investigate the brachytherapy (192)Ir dose distributions in water, bone, and lung tissue and performed radiophotoluminescent glass dosimeter measurements to verify the obtained MCNPX results. The results showed that the dose-rate constant, radial dose function, and anisotropy function in water were highly consistent with data in the literature. However, the lung dose near the source would be overestimated by up to 12%, if the lung tissue is assumed to be water, and, hence, if a tumor is located in the lung, the tumor dose will be overestimated, if the material density is not taken into consideration. In contrast, the lung dose far from the source would be underestimated by up to 30%. Radial dose functions were found to depend not only on the phantom size but also on the material density. The phantom size affects the radial dose function in bone more than those in the other tissues. On the other hand, the anisotropy function in lung tissue was not dependent on the radial distance. Our simulation results could represent valid clinical reference data and be used to improve the accuracy of the doses delivered during brachytherapy applied to patients with lung cancer. PMID- 24804265 TI - Cancer diagnostic and predictive biomarkers. PMID- 24804264 TI - A plant-produced antigen elicits potent immune responses against West Nile virus in mice. AB - We described the rapid production of the domain III (DIII) of the envelope (E) protein in plants as a vaccine candidate for West Nile Virus (WNV). Using various combinations of vector modules of a deconstructed viral vector expression system, DIII was produced in three subcellular compartments in leaves of Nicotiana benthamiana by transient expression. DIII expressed at much higher levels when targeted to the endoplasmic reticulum (ER) than that targeted to the chloroplast or the cytosol, with accumulation level up to 73 MU g DIII per gram of leaf fresh weight within 4 days after infiltration. Plant ER-derived DIII was soluble and readily purified to > 95% homogeneity without the time-consuming process of denaturing and refolding. Further analysis revealed that plant-produced DIII was processed properly and demonstrated specific binding to an anti-DIII monoclonal antibody that recognizes a conformational epitope. Furthermore, subcutaneous immunization of mice with 5 and 25 MU g of purified DIII elicited a potent systemic response. This study provided the proof of principle for rapidly producing immunogenic vaccine candidates against WNV in plants with low cost and scalability. PMID- 24804266 TI - Cancer monitoring methods. PMID- 24804267 TI - Relation of asymmetric dimethylarginine levels to macrovascular disease and inflammation markers in type 2 diabetic patients. AB - AIM. We aimed to determine the relation of asymmetric dimethyl arginine (ADMA) levels to atherosclerotic vascular disease and inflammation markers in type 2 diabetes. METHODS. We recruited 50 type 2 diabetic patients with atherosclerosis, 50 type 2 diabetic patients without atherosclerosis, and 31 healthy control patients into our study. We obtained fasting serum and plasma samples and measured HbA1c, fasting blood glucose, C-peptide, creatinine, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, hsCRP, fibrinogen, erythrocyte sedimentation rate, total homocysteine, and ADMA levels. In addition, all of the patients were evaluated for carotid artery intima media thickness by ultrasound. We evaluated ADMA levels in healthy controls, diabetic patients with macrovascular complications, and diabetic patients without macrovascular complications and evaluated the relationship between ADMA levels and total homocysteine, inflammation markers, and macrovascular disease. RESULTS. Mean ADMA values in non-MVD and control groups were significantly lower than in MVD group (0.39 +/- 0.16, 0.32 +/- 0.13, 0.52 +/- 0.23, P < 0.05, resp.). These three variables (carotid intima-media thickness, inflammatory markers, and ADMA levels) were significantly higher in diabetes group than control (P < 0.05). CONCLUSION. There is a relationship between ADMA and macrovascular disease in type 2 diabetes, but further studies are needed to understand whether increased ADMA levels are a cause of macrovascular disease or a result of macrovascular disease. PMID- 24804268 TI - Ang (1-7) protects islet endothelial cells from palmitate-induced apoptosis by AKT, eNOS, p38 MAPK, and JNK pathways. AB - This study aimed to explore the effect of angiotensin (1-7) (Ang (1-7)) on palmitate-induced apoptosis in islet endothelial cells and the mechanism of action. MS-1 cells were treated with palmitate in the presence or absence of Ang (1-7). The percentage of apoptotic cells was determined by DNA fragmentation and flow cytometry. Reactive oxygen species (ROS) production was measured using a Reactive Oxygen Species Assay Kit. Expression of AKT, eNOS, C-Jun N-terminal kinase (JNK), and p38 was detected by western blotting. Compared with palmitate treated group, palmitate-induced apoptosis was decreased in MS-1 cells which were preincubated with Ang (1-7) (P < 0.05). Palmitate decreased the phosphorylation of AKT and eNOS, and Ang (1-7) increased the phosphorylation of these kinases (P < 0.05), with a concomitant reduction in MS-1 cells apoptosis. Ang (1-7) also inhibited the palmitate-induced ROS production and attenuated the apoptosis related signaling molecule JNK and p38 activation (all P < 0.05). PI3K/AKT, eNOS, p38 MAPK, and JNK inhibitors blocked the antilipoapoptosis of Ang (1-7) (all P < 0.05). Our findings suggest that Ang (1-7) reduces palmitate-induced islet endothelial cells apoptosis. AKT/eNOS/NO signaling and JNK and p38 pathway are involved in the Ang (1-7)-mediated modulation of islet endothelial cells lipoapoptosis. PMID- 24804270 TI - Anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) relation with extra-articular manifestations in rheumatoid arthritis. AB - We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group (P = 0.40 and P = 0.91, resp.). Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF); (P = 0.01), anti-CCP (P = 0.048), and anti-MCV (P = 0.02). Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di) (r = 0.154, P = 0.03), erythrocyte sedimentation rate (ESR); (r = 0.155, P = 0.03), and RF (P = 0.254, P < 0.001), whereas anti-MCV titres only correlated with RF (r = 0.169, P = 0.02). On adjusted analysis, ExRA was associated with longer age (P = 0.015), longer disease duration (P = 0.007), higher DAS-28 score (P = 0.002), and higher HAQ-DI score (P = 0.007), but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation. PMID- 24804273 TI - Is Open-angle Glaucoma Caused by the NO/ONOO(-) Cycle Acting at Two Locations in the Eye? PMID- 24804271 TI - Current vaccine trials in glioblastoma: a review. AB - Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease. PMID- 24804269 TI - The spectrum of anti-chromatin/nucleosome autoantibodies: independent and interdependent biomarkers of disease. AB - Autoantibodies directed to chromatin components date back to the discovery of the LE cell and the LE cell phenomenon circa 1950, and subsequent evidence that major components of that reaction were chromatin components and histones in particular. Over time, immunoassays ranging from ELISA and line immunoassays to more modern bead-based assays incorporated histone and DNA mixtures, purified histones, and purified nucleosomes leading to a more thorough understanding of the genesis and pathogenetic relationships of antibodies to chromatin components in systemic lupus erythematosus and other autoimmune conditions. More recently, interest has focussed on other components of chromatin such as high mobility group (HMG) proteins both as targets of B cell responses and pro-inflammatory mediators. This review will focus on immunoassays that utilize chromatin components, their clinical relationships, and newer evidence implicating HMG proteins and DNA neutrophil extracellular traps (NETs) as important players in systemic autoimmune rheumatic diseases. PMID- 24804272 TI - The impact of two different transfusion strategies on patient immune response during major abdominal surgery: a preliminary report. AB - Blood transfusion is associated with well-known risks. We investigated the difference between a restrictive versus a liberal transfusion strategy on the immune response, as expressed by the production of inflammatory mediators, in patients subjected to major abdominal surgery procedures. Fifty-eight patients undergoing major abdominal surgery were randomized preoperatively to either a restrictive transfusion protocol or a liberal transfusion protocol (with transfusion if hemoglobin dropped below 7.7 g dL(-1) or 9.9 g dL(-1), respectively). In a subgroup of 20 patients randomly selected from the original allocation groups, blood was sampled for measurement of IL-6, IL-10, and TNFalpha. Postoperative levels of IL-10 were higher in the liberal transfusion group on the first postoperative day (49.82 +/- 29.07 vs. 15.83 +/- 13.22 pg mL( 1), P < 0.05). Peak postoperative IL-10 levels correlated with the units of blood transfused as well as the mean duration of storage and the storage time of the oldest unit transfused (r(2) = 0.38, P = 0.032, r(2) = 0.52, P = 0.007, and r(2) = 0.68, P<0.001, respectively). IL-10 levels were elevated in patients with a more liberal red blood cell transfusion strategy. The strength of the association between anti-inflammatory IL-10 and transfusion variables indicates that IL-10 may be an important factor in transfusion-associated immunomodulation. This trial is registered under ClinicalTrials.gov Identifier: NCT02020525. PMID- 24804274 TI - The PEG-PCL-PEG Hydrogel as an Implanted Ophthalmic Delivery System after Glaucoma Filtration Surgery; a Pilot Study. AB - Currently, filtration surgery has been considered as the most effective therapy for glaucoma; however, the scar formation in the surgical area may often lead to failure to the procedure. An implanted drug delivery system may provide localized and sustained release of a drug over an extended period. Poly (ethylene glycol) poly (epsilon-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) hydrogel has been successfully synthesized and determined as thermosensitive and biocompatible. In order to overcome the limitations of common local ophthalmic medications, we investigated the function of a self-assembled PECE hydrogel as an intracameral injection-implanted drug carrier to inhibit the formation of postoperative scarring. Following bevacizumal-loaded hydrogel intracameral injection into rabbit eyes, the status of the bleb and filtration fistula formed following the filtering surgery were examined through pathologic evaluation. Due to the sustained release of bevacizumab from the hydrogel, neovascularization and scar formation were inhibited; moreover, there were no corneal abnormalities and other ocular tissue damage found in the rabbits. This suggests that the PECE hydrogel may be considered as the novel biomaterial with potential as a sustained release system in glaucoma filtering surgery. Further studies require in shedding the light on the subject. PMID- 24804275 TI - Focal laser photocoagulation in non-center involved diabetic macular edema. AB - This study was performed to evaluate the functional and anatomic outcomes of focal macular laser photocoagulation in eyes with non-center involved macular edema (non-CI ME). Forty-nine eyes of 43 patients with non-CI ME were included. Focal macular laser photocoagulation was conducted on twenty-nine eyes of 25 patients, while 20 eyes of 18 patients with non-CI ME were followed without treatment and served as the control group. Data relating to best corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study) and central subfield thickness (CST), inner zone thickness (IZT), outer zone thickness (OZT), and total macular volume (TMV) as determined by optical coherence tomography (OCT) were collected and compared between the groups. At 12 months, VA decreased by a mean of 0.4 letters in the treatment group and 3.3 letters in the control group (p=0.03). Gain in VA >=5 letters was noted in 6 (21%) of the eyes in the treatment group versus 1 (5%) eye in the control group (p=0.12). At 12 months, average IZT decreased by 22.6 microns in the treatment group and increased by 10.9 microns in the control group (p<0.001). The treatment group revealed significant reduction in CST, average OZT, and TMV as compared to the control group at 12 months (all p<0.05).Generally, focal laser photocoagulation may have more favourable visual outcomes in this specific group of diabetic patients than does observation. In addition, focal laser treatment provided better outcomes with improvement in OCT parameters as compared to the control group. PMID- 24804276 TI - A modified Middle Eastern contrast sensitivity chart. AB - The contrast sensitivity test has been used to examine vision in different clinical circumstances. Moreover, as contrast sensitivity is affected by several ocular states, its measurement has been considered practically for monitoring and assessment of a wide range of visual functions, predicting vision related abilities, diagnosing several ophthalmic conditions, and evaluating many ocular disorders including glaucoma, cataracts, diabetic retinopathy, optic neuritis and age-related degeneration. The Pelli-Robson standard chart has been translated and modified using Persian-Arabic characters since illiterates and children in the Middle East, Central Asia, and Africa are more likely to distinguish Arabic characters instead of English ones. The translation of these characters is expected to have more precise results, thereby improving the test's validity and provide early diagnoses of ocular problems. This manuscript is focused on conceptions relating to the project. Further studies are required to evaluate the sensitivity, specificity, and reliability of the revised chart to best compare it to the standard Pelli-Robson one. PMID- 24804277 TI - The management of patients with cataracts and medically uncontrolled glaucoma. AB - Trabeculectomy surgery has been shown to lower intraocular pressure and is the most commonly performed glaucoma procedure worldwide. However, giving a patient a 'bleb for life' is not without consequences and the failure of trabeculectomy to control IOP in the long term is well documented. In some instances, such as in patients with exfoliative glaucoma or primary angle closure glaucoma, cataract surgery alone can often lower IOP to acceptable levels. Cataract surgery in these instances can sometimes be combined with procedures such as goniosynechialysis or endoscopic cyclophotocoagulation which may provide additional IOP lowering. Such surgery has the distinct advantage of avoiding conjunctival incisions, so that subsequent trabeculectomy, if required, is more likely to be successful. In any case, it is preferable to perform trabeculectomy in a pseudophakic eye for several reasons. If trabeculectomy is performed in a phakic eye, patients should be warned that subsequent cataract is likely and if cataract surgery is performed it is preferable to wait at least a year or more after the trabeculectomy to reduce the risk of bleb failure. Combined phacotrabeculectomy should be reserved for end-stage glaucoma in most cases, in order to reduce the risk of 'wipe-out'. PMID- 24804278 TI - Dynamic assessment of binocular eye movement coordination: norms and functional implications. AB - Alignment of the two eyes is controlled by a finely tuned, fast acting system with components within the brain. Assessment of binocular alignment has classically been done statically. Eye positions are assessed in primary position and at eccentric angles to interpret the functional status of the oculomotor nerves and muscles. However, assessment of dynamic eye alignment, the coordination of the eyes during eye movements, has been less commonly carried out and has not been formalized with population norms. Clinicians are aware of slow eye movement dynamic alignment changes, such as that clinically observed in Intranuclear Ophthalmoplegia. But assessment of eye alignment during rapid eye movements, such as saccade or pursuit has not been part of neuro-ophthalmologic assessment. With the advent of inexpensive, high resolution recording systems, both eyes can be simultaneously recorded and their coordination during movement compared. Thus, we now have an opportunity to provide a laboratory based objective measurement of a gamut of binocular coordination systems. Recent research in humans has demonstrated increased variability of binocular coordination during divided attention. Variability is an interesting statistic that can be sensitively assessed in the velocity domain without extensive gaze position recalibration procedures during recording over long intervals. Variability can thus be used as a robust, long-term eye movement parameter with minimal intrusiveness to the subject. It is proposed that population studies of binocular coordination during eye movements be carried out to determine neurologic norms so that conditions such as brain injury and others can be assessed with a functional tool with objective parameters. PMID- 24804279 TI - Flame Retardant Applications in Camping Tents and Potential Exposure. AB - Concern has mounted over health effects caused by exposure to flame retardant additives used in consumer products. Significant research efforts have focused particularly on exposure to polybrominated diphenyl ethers (PBDEs) used in furniture and electronic applications. However, little attention has focused on applications in textiles, particularly textiles meeting a flammability standard known as CPAI-84. In this study, we investigated flame retardant applications in camping tents that met CPAI-84 standards by analyzing 11 samples of tent fabrics for chemical flame retardant additives. Furthermore, we investigated potential exposure by collecting paired samples of tent wipes and hand wipes from 27 individuals after tent setup. Of the 11 fabric samples analyzed, 10 contained flame retardant additives, which included tris(1,3-dichloroisopropyl) phosphate (TDCPP), decabromodiphenyl ether (BDE-209), triphenyl phosphate, and tetrabromobisphenol-A. Flame retardant concentrations were discovered to be as high as 37.5 mg/g (3.8% by weight) in the tent fabric samples, and TDCPP and BDE 209 were the most frequently detected in these samples. We also observed a significant association between TDCPP levels in tent wipes and those in paired hand wipes, suggesting that human contact with the tent fabric material leads to the transfer of the flame retardant to the skin surface and human exposure. These results suggest that direct contact with flame retardant-treated textiles may be a source of exposure. Future studies will be needed to better characterize exposure, including via inhalation and dermal sorption from air. PMID- 24804280 TI - Editorial: timely publication. PMID- 24804281 TI - Extraction site management in the esthetic zone using autogenous hard and soft tissue grafts: a 5-year consecutive clinical study. AB - This study evaluates whether alveolar ridge preservation and new bone formation is possible through extraction site management using autogenous hard and soft tissue grafts, in cases of buccal alveolar bone defects. Fifty-eight extraction sockets were consecutively completely filled with autogenous bone chips after tooth extraction in 49 patients from 2004 to 2006. At least half of the buccal alveolar wall was absent after tooth extraction in all cases. A free gingival connective tissue graft from the palate sealed the grafted extraction site. Approximately 10 to 12 (mean, 10.9) weeks after socket augmentation, implants were inserted. A histomorphometric analysis was performed on trephine bone cores removed from the grafted sockets in seven consecutive cases. Standardized volumetric measurements of the buccal alveolar contour were evaluated before tooth extraction, 1 year, and 5 years after prosthetic incorporation. Implants could be inserted into 47 (81.0%) treated extraction sockets without additional grafting procedures. In 11 patients (19.0%), implant placement was combined with local grafting techniques. Bone grafts were mature and well revascularized 10 to 12 (mean, 10.9) weeks after socket augmentation. The mean amount of vital bone was 52.0% +/- 8.6%. Standardized volumetric measurements showed that 83.3% of the reference points representing the outer alveolar contour did not change significantly from baseline to 1 year after prosthetic incorporation and from baseline to 5 years after prosthetic incorporation. None of the reference points showed a statistically significant change in volume from 1 to 5 years after prosthetic incorporation. Extraction site management using autogenous hard and soft tissue grafts enables new bone formation in cases of buccal alveolar bone defects, offers a long-term alveolar ridge preserving technique, and reduces total implant treatment time. PMID- 24804282 TI - Subepithelial connective tissue graft with purified rhPDGF-BB for the treatment of mandibular recession defects: a consecutive case series. AB - Anatomical characteristics, such as shallow vestibular depth, high frenum attachments, and thin labial bone tend to make treatment of mandibular gingival recession defects particularly challenging. Even though a number of recent systematic reviews have identified the connective tissue graft (CTG) in combination with coronally advanced flaps (CAF) as the most consistently effective treatment procedure for Miller Class I and II defects, they did not separate maxillary vs mandibular outcomes, reporting instead aggregate results. In this prospective consecutive case series, recombinant human platelet-derived growth factor-BB (rhPDGF-BB) was combined with CTGs for the treatment of Miller Class I or II mandibular gingival recession defects in 11 healthy patients. Changes for both mean recession depth and width from baseline to week 24 were statistically significant, with mean recession depth decreasing from 3.4 +/- 0.5 mm to 0.8 +/- 0.8 mm and mean recession width decreasing from 3.1 +/- 0.7 mm to 1.7 +/- 1.3 mm. As a result of the improvement in recession depth, the mean percent root coverage seen in this mandibular prospective consecutive case series at 6 months was 79.6%. Despite treatment results that were comparable to historical norms, the outcomes, especially percent root coverage at 24 weeks, were somewhat less favorable, emphasizing the anatomical challenges of mandibular recession defects. PMID- 24804283 TI - Flapless postextraction socket implant placement in the esthetic zone: part 1. The effect of bone grafting and/or provisional restoration on facial-palatal ridge dimensional change-a retrospective cohort study. AB - The dental literature has reported vertical soft tissue changes that can occur with immediate implant placement, bone grafting, and provisional restoration ranging from a gain or loss of 1.0 mm. However, little is known of the effects of facial-palatal collapse of the ridge due to these clinical procedures. Based upon treatment modalities rendered, an ensuing contour change can occur with significant negative esthetic consequences. The results of a retrospective clinical cohort study evaluating the change in horizontal ridge dimension associated with implant placement in anterior postextraction sockets are presented for four treatment groups: (1) group no BGPR = no bone graft and no provisional restoration; (2) group PR = no bone graft, provisional restoration; (3) group BG = bone graft, no provisional restoration; and (4) group BGPR = bone graft, provisional restoration. Bone grafting at the time of implant placement into the gap in combination with a contoured healing abutment or a provisional restoration resulted in the smallest amount of ridge contour change. Therefore, it is recommended to place a bone graft and contoured healing abutment or provisional restoration at the time of flapless postextraction socket implant placement. PMID- 24804284 TI - Zirconia ceramic single-retainer resin-bonded fixed dental prostheses (RBFDPs) after 4 years of clinical service: a retrospective clinical and volumetric study. AB - The aim of this study was a retrospective assessment of the up to 8-year clinical outcomes of zirconia ceramic single-retainer resin-bonded fixed dental prostheses (RBFDPs). Fifteen subjects (9 women, 6 men) with 15 anterior zirconia ceramic RBFDPs were included. The RBFDPs replaced 5 maxillary central incisors, 7 maxillary lateral incisors, and 3 mandibular lateral incisors. The patients willing to participate were recalled and the survival of the RBFDPs was assessed. The technical outcome was evaluated with modified United States Public Health Service criteria. Fracture and/or chipping of the restoration, occlusal wear, marginal adaptation, marginal discoloration, shape, surface texture, and esthetic integration were recorded. Biologic parameters were assessed, including vitality, probing pocket depth, gingival recession, plaque control record, bleeding on probing, and periodontal mobility. Data were descriptively analyzed using a paired t test (P < .05). Fifteen subjects with 15 RBFDPs were examined after a mean follow-up period of 53.3 months (SD, 23 months). No catastrophic failures occurred. The 4-year survival rate was 100%. Two early debondings occurred with successful recementation. No chipping of the veneering ceramic occurred. No differences in biologic outcomes between test and control teeth were found. The zirconia ceramic RBFDPs exhibited excellent clinical results in anterior regions and had a positive effect on the esthetic outcomes of the pontic regions. PMID- 24804285 TI - A mucogingival technique for the treatment of multiple recession defects in the mandibular anterior region: a case series with a 2-year follow-up. AB - In the mandibular anterior area, gingival recession can be associated with a minimal amount or lack of attached gingiva, a shallow vestibule, and high frenum insertion. These anatomical features may preclude the use of traditional root coverage procedures. This case series describes a a bilaminar technique with flap incision in the fornix for the treatment of adjacent gingival recession defects in patients with a shallow vestibule. It achieved high predictability in complete root coverage without decreasing the vestibular depth. At 24 months, the treatment resulted in 90.6% +/-16.8% root coverage, and 11 of the 15 treated teeth (73.3%) were completely covered. PMID- 24804286 TI - Piezoelectric surgery in autogenous bone block grafts. AB - This article describes alveolar ridge reconstruction in the esthetic zone using autogenous bone blocks harvested from the chin, taking into account the way the bone block is harvested, stabilized, and contoured in the recipient site. The 38 procedures were divided into two groups: group 1, using piezoelectric surgery, and group 2, using rotary instruments. The piezoelectric surgery technique made it possible to introduce surgical modifications. An observation of bone regeneration and follow-up clinical observations 5 to 7 years after the procedure revealed that the piezoelectric surgery technique provides better and more predictable clinical results for bone regeneration. PMID- 24804287 TI - Crown lengthening in the maxillary anterior region: a 6-month prospective clinical study. AB - The purpose of this study was to assess osseous parameters and stability of maxillary anterior teeth following crown lengthening surgery. Thirty-six patients requiring facial crown lengthening of 277 maxillary anterior and first premolar teeth were included. Presurgical and intraoperative clinical measurements were recorded at baseline and 1, 3, and 6 months postsurgery at midfacial, mesiofacial, and distofacial line angles. The data presented here suggest that when crown lengthening anterior maxillary teeth, the distance between the desired gingival margin and alveolar crest is usually insufficient to allow for biologic width. In addition, there is significant tissue rebound that may stabilize by 6 months. Tissue rebound appears related to flap position relative to the alveolar crest at suturing. These findings suggest that clinicians should establish proper anterior crown length with osseous resection. PMID- 24804288 TI - The feasibility of using coronally advanced flap with an extracellular matrix membrane for treating gingival recession defects: a preclinical study. AB - The guided tissue regeneration (GTR) procedure has been demonstrated to successfully correct gingival recession (GR) defects. The aim of this study was to assess the feasibility of using the combination of a coronally advanced flap (CAF) with an extracellular membrane (ECM) to correct GR. GR defects were induced in the maxillary posterior region in five baboons. A 3-month healing period followed before the ECM was placed over the defect and covered with a CAF. Probing depth (PD), recession depth (RD), recession width (RW), and keratinized tissue width (KTW) were measured at baseline and 3 months postoperatively. Block biopsies of the treated areas were submitted for histologic review after a healing period of 3 months. There were no significant differences between the test (ECM + CAF) and control (CAF) groups in terms of changes in PD, RD, RW, and KTW after 3 months of treatment. However, significant differences have been noted for preoperation and postsurgery RD and RW values for both the control and test groups. Histomorphometric results showed minimal alveolar bone and connective tissue replacing the ECM membrane. CAF (either with or without the use of an ECM) is effective for the treatment of GR defects. PMID- 24804289 TI - Finite element analysis relative to the crestal position of a 3.0-mm-diameter implant. AB - It has been shown that implant designs and different vertical positions have an influence on crestal bone. The purpose of this study was to use finite element (FE) analysis to biomechanically investigate the influence of the stress/strain distribution in a maxillary anterior 3.0-mm-diameter implant in relation to its apicocoronal level after oblique loading. Two different FE models, depending on implant position relative to bone crest, were applied. It can be concluded that placing the implant-abutment interface supracrestally provides decreased levels of stress and strain in the surrounding bone. However, placing the implant 0.5 mm supracrestally is also acceptable according to this analysis. PMID- 24804290 TI - Factors affecting treatment planning decisions for compromised anterior teeth. AB - The purpose of this study was to identify the factors that create differences in opinion between dental professionals when treatment planning for a patient whose problem is limited to one or more maxillary incisors. A series of computer generated scenarios was created in which anterior teeth were compromised for various reasons. The cases were used to survey a diverse group of practitioners regarding whether to treat or extract a tooth under the given circumstances. The results indicated that numerous patient-associated factors had statistically significant effects on the decision-making process. These included the patient's age, root length, root morphology, periodontal status, history of prior endodontic treatment, presence of posts, and size of periapical radiolucencies. The data also showed that a clinician's educational background had a dramatic impact on his or her treatment recommendation. PMID- 24804291 TI - Analysis of buccolingual dimensional changes of the extraction socket using the "ice cream cone" flapless grafting technique. AB - The socket or ridge preservation approach known as the "ice cream cone" technique was used in type 2 sockets in this retrospective analysis of 11 extraction sites. A type 2 extraction socket is defined as having the presence of facial soft tissue with a partial or complete dehiscence of the buccal bone plate. All teeth were extracted atraumatically without flap elevation. A resorbable collagen membrane was contoured into an ice cream cone- shape, placed into the socket defect, and grafted with human freeze-dried bone allograft. Buccolingual dimensional changes were measured manually with a digital caliper sensitive to 0.01 mm on pre- and posttreatment casts using an acrylic template and a three dimensional (3D) digital scanner, as well as radiographically with pre- and post cone beam computed tomography (CBCT) scans. All implants were placed 6 months after socket preservation and achieved primary stability with a minimum torque value of 35 Ncm with a mean buccal-lingual dimensional loss of 1.32 mm. The dimensional change of the ridge from pre- to postextraction reflective of the healed grafted site ranged from a loss of 0.46 to 2.25 mm with a mean of 1.28 mm (CBCT), 0.31 to 2.71 mm with a mean of 1.36 mm (digital calipers), and 0.21 to 2.80 mm with a mean of 1.32 mm (3D digital scanner). All 11 implants were immobile and clinically osseointegrated. The so-called ice cream cone technique allows for the reconstruction of a buccal plate dehiscence to enable the placement of an implant; however, the ridge dimension was diminished by 1.32 mm compared with the width of the extraction socket prior to tooth removal. PMID- 24804292 TI - A comparison of fracture resistance of endodontically treated teeth restored with bonded partial restorations and full-coverage porcelain-fused-to-metal crowns. AB - The aim of this study was to evaluate the use of bonded partial restorations compared with full-coverage porcelain-fused-to-metal (PFM) crowns as a viable treatment option for endodontically treated posterior teeth. Forty-five recently extracted maxillary first premolars were collected, endodontically treated, and mounted in acrylic blocks. The specimens were randomly divided into three groups and prepared to receive their respective restorations. The teeth in group 1 received full-coverage porcelain-fused-to-metal crowns. The teeth in group 2 received bonded partial restorations made from pressed ceramics (lithium disilicate) involving a functional cusp (palatal). Finally, group 3 received bonded partial restorations made from pressed ceramics involving the buccal cusp and keeping a functional cusp (palatal) intact. All group 1 restorations were cemented using glass ionomer cement. Restorations in groups 2 and 3 were bonded using a dual-cured resin cement. All specimens were subjected to an aging process and tested for shear bond strength using a universal loading machine. The mean force applied in Newtons to cause failure for group I was 674.90 +/- 94.16 N, for group 2, 463.46 +/- 61.11 N, and for group 3, 849.33 +/- 68.92 N. P values obtained using one-way analysis of variance showed a highly significant difference between groups 2 and 3 (P = .001), groups 1 and 2 (P = .001), and groups 1 and 3 (P = .001). The fracture modes observed in all groups involved restorations and tooth fracture. This in vitro study suggests that endodontically treated posterior teeth with intact functional cusps can be restored with bonded partial porcelain restorations. However, if the loss of tooth structure involves the functional cusp, full-coverage PFM crowns are the treatment of choice. PMID- 24804293 TI - Histologic assessment of alveolar bone remodeling around immediate implants placed in single and multiple contiguous extraction sites. AB - The aim of this study was to histologically assess alveolar bone remodeling around immediate implants placed in single and multiple contiguous extraction sites. Ten dogs were divided into three groups (with six sites per group) on the basis of premolar teeth extraction: group 1 = one tooth extracted, group 2 = two contiguous teeth extracted, and group 3 = more than two contiguous teeth extracted. Immediate implants were placed in each group. Histologic assessment of arches showed no evidence of vertical bone loss (VBL) around implants in group 1 compared with groups 2 (P < .001) and 3 (P < .001). Buccal and lingual bone thicknesses and bone-to-implant contact (BIC) were higher around implants in group 1 compared with groups 2 (P < .001) and 3 (P < .05). Buccal and lingual bone thicknesses, BIC, and VBL are compromised around implants in multiple contiguous extraction sites compared with those in a single extraction site. PMID- 24804294 TI - Modified apically repositioned flap technique: a surgical approach to enhance donor sites prior to employing a laterally positioned flap. AB - The goal of this study was to evaluate the ability of the modified apically repositioned flap (MARF) technique to increase keratinized tissue at the donor site and to analyze if this procedure would enhance the indication for and predictability of the laterally positioned flap (LPF) without any consequences to the donor area. Thirty isolated defects with recession and/or lack of attached gingiva were treated in 30 healthy patients. All donor areas adjacent to these defects lacked ideal gingival conditions both in height and width. The MARF technique was used to increase these areas 8 weeks before the LPF was performed. Clinical evaluation was done at the donor and receptor areas after 18 months. The results showed that the donor area increased from 2.78 to 5.01 mm at 8 weeks and remained at 3.28 mm after the use of the LPF. The marginal tissue recession and probing depth remained clinically unchanged. In the receptor area, the recession decreased from 1.86 to 0.57 mm, and the keratinized and attached tissue increased from 0.71 to 3.57 mm and from 0.05 to 2.49 mm, respectively. The use of the MARF technique to enhance keratinized tissue at the donor area proved to be an efficient and predicable technique that also augmented LPF use without any consequences to the donor site. PMID- 24804296 TI - Evaluation of buccal plate after human bone allografting: clinical and CBCT outcomes of immediate anterior implants in eight consecutive cases. AB - The aim of this clinical case series was to evaluate buccal bone thickness using cone beam computed tomography and to demonstrate optimal clinical outcomes for implants placed into extraction sockets in the anterior maxilla with a thin biotype, by placing a graft of mineralized and demineralized human bone allograft into the buccal gap. The preliminary outcomes showed good preservation of soft and hard tissue architecture after 1 year in function. In particular, in eight patients, this allograft mixture appeared to minimize the amount of buccal contour change in the extraction site ridge with a thin buccal plate. PMID- 24804295 TI - Histologic and immunohistochemical description of early healing at marginal defects around implants. AB - This study reports on the histologic characteristics of the early phases of implant osseointegration, focusing on osteopontin concentrations in the coronal area of implants placed with marginal defects and in control sites without defect preparation. In the mandibular right area of 12 dogs, two recipient sites were prepared and the margins were widened to obtain a gap of 0.5 mm at one site (small defect) and 1.25 mm at another site (large defect). Implants were placed and allowed a fully submerged healing. The procedure was subsequently performed in the left side in such a way as to obtain healing times of 5, 10, 20, and 30 days. Paraffin sections were stained with osteopontin antibodies and analyzed. At control implants, scarcely organized collagen fibers were observed in the space between the pristine bone and implant and were quickly replaced by mineralized tissue. In the small and large defects, the collagen fibers were organized in a layer that ran parallel to the implant at day 10 and became denser and thicker with time. Osteopontin was evenly distributed in the peri-implant tissue at control implants, while it was mainly located in the collagen bundle section around the implants placed in the defects. PMID- 24804297 TI - Highly sensitive and specific detection of histamine via the formation of a self assembled magic number cluster with thymine by mass spectrometry. AB - A novel method for the detection of histamine (HIM) via the formation of a self assembled magic number cluster with thymine (T) by electrospray ionization tandem mass spectrometry (ESI-MS/MS) is described. The formation of the magic number cluster [T17 + HIM + 2H](2+) shifts the MS signal of histamine to the interference-free higher mass range and the signal intensity is increased by four orders of magnitude. In addition, the formation of [T17 + HIM + 2H](2+) is highly specific to histamine compared with its metabolite and other similar biogenic amines, which may be attributed to both of its amino and imidazole groups. The linear dynamic range of the method is in the range of 1 nM-20 MUM, and the limit of detection can be as low as 0.1 nM. The feasibility of this method is further demonstrated by the quantitative analysis of histamine in a red wine sample. Since little sample preparation or separation is required before the analysis, this method provides a rapid new way for the sensitive and specific detection of histamine by MS. PMID- 24804298 TI - Managing body image difficulties of adult cancer patients. AB - BACKGROUND: Body image is a critical psychosocial issue for patients with cancer because they often undergo significant changes to appearance and functioning. The primary purpose of this review article was to identify empirically-supported approaches to treat body image difficulties of adult cancer patients that can be incorporated into high-quality comprehensive cancer care. METHODS: An overview was provided of theoretical models of body image relevant to cancer patients, and findings were presented from published literature on body image and cancer from 2003 to 2013. These data were integrated with information from the patient-doctor communication literature to delineate a practical approach for assessing and treating body image concerns of adult cancer patients. RESULTS: Body image difficulties were found across patients with diverse cancer sites, and were most prevalent in the immediate postoperative and treatment period. Age, body mass index, and specific cancer treatments have been identified as potential risk factors for body image disturbance in cancer patients. Current evidence supports the use of time-limited cognitive behavioral therapy interventions for addressing these difficulties. Other intervention strategies also show promise but require further study. Potential indicators of body image difficulties were identified to alert health care professionals when to refer patients for psychosocial care, and a framework was proposed for approaching conversations about body image that can be used by the oncologic treatment team. CONCLUSIONS: Body image issues affect a wide array of cancer patients. Providers can use available evidence combined with information from the health care communication literature to develop practical strategies for treating body image concerns of patients with cancer. PMID- 24804299 TI - The overexpression of 14-3-3zeta and Hsp27 promotes non-small cell lung cancer progression. AB - BACKGROUND: The 14-3-3zeta protein has been identified as a putative oncoprotein in several cancers, including non-small cell lung cancer (NSCLC). However, the mechanisms underlying its functions have not been well defined. METHODS: Proteins that interact with 14-3-3zeta were identified through coimmunoprecipitation and mass spectrometry in NSCLC cells. The interaction of 14-3-3zeta with these molecular partners and their roles in the invasiveness and metastasis of NSCLC cells were assayed through specific disruptions in the 14-3-3zeta signaling network. In addition, the clinical implications of this 14-3-3zeta complex were examined in samples from patients with NSCLC. RESULTS: Among the identified proteins that interacted with 14-3-3zeta, there were 230 proteins in 95-D cells, 181 proteins in 95-C cells, and 203 proteins in A549 cells; and 16 interacting proteins were identified that overlapped between all cell lines. Further studies revealed 14-3-3zeta complexes within the heat shock protein 27 (Hsp27) protein and demonstrated that the interference of Hsp27 or 14-3-3zeta inhibited the invasion and metastasis of NSCLC cells. The invasive and metastatic capabilities of cells with both Hsp27 and 14-3-3zeta interference could be completely restored only by Hsp27 and 14-3-3zeta complementary DNA transfection and not by either agent alone. Clinically, the postoperative 5-year overall survival (OS) in patients who had high expression of both 14-3-3zeta and Hsp27 was significantly lower than the 5-year OS in patients who had low expression of both 14-3-3zeta and Hsp27 (26.5% vs 59.7%, respectively). Multivariate analysis revealed that the combined expression of 14-3-3zeta and Hsp27 was an independent prognostic indicator of OS(P = .036). CONCLUSIONS: The current data suggest that the combined expression of 14-3-3zeta and Hsp27 may be a biomarker for predicting survival in patients with NSCLC, and this combination may have potential as a therapeutic target for NSCLC. PMID- 24804300 TI - MET amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy. AB - BACKGROUND: Several large studies have reported an extremely low incidence of MET gene amplification (GA) in patients with radically resected gastric cancer. This study was conducted to evaluate the prevalence and prognostic role of MET in patients with recurrent=metastatic gastric cancer who received chemotherapy. METHODS: MET GA and protein expression of recurrent=metastatic gastric cancer samples were evaluated by fluorescence in situ hybridization and immunohistochemistry (IHC), respectively. RESULTS: This retrospective study included 232 patients with recurrent=metastatic gastric cancer. MET GA and strong protein expression(IHC31) were observed in 8.3% (19 of 230 samples) and 9.6% (22 of 229 samples) of samples, respectively. A significant correlation was observed between MET GA and protein expression (r = 0.378; P<.001). MET GA was correlated with poor performance status(P<.001) and poorly differentiated tumors (P=.0015). Both MET GA and IHC 31 expression were associated with a substantially shorter median overall survival (OS) and progression-free survival (PFS). The median OS and PFS for patients with MET GA versus those without MET GA were 5.7 months versus 15.5 months (P<.001) and 3.6 months versus 6.9 months (P<.001), respectively. The median OS and PFS for patients with MET IHC 31 expression versus IHC 0 to 21 expression were 6.3 months versus 15.1 months(P<.001) and 3.6 months versus 7.0 months (P<.001), respectively. CONCLUSIONS: In patients with recurrent=metastatic gastric cancer,MET amplification and strong protein expression are not rare and appear to be significantly associated with unfavorable clinical outcomes. PMID- 24804301 TI - Does self-esteem mediate the relationship between interpersonal problems and symptoms of disordered eating? AB - It has been proposed that interpersonal problems play a role in the maintenance of disordered eating because of an adverse effect on self-esteem, which in turn encourages the pursuit of achievement in the valued domain of weight and shape. This study aimed to identify the types of interpersonal problems that are associated with disordered eating and to determine whether self-esteem mediates the relationship between interpersonal problems and eating disorder symptoms. Female university students (n = 227) completed the Inventory of Interpersonal Problems-32, Eating Disorder Examination Questionnaire and Rosenberg Self-Esteem Scale. Regression analysis identified two forms of interpersonal problems that were associated with disordered eating: difficulties being sociable and being too dependent on the opinion of others. Self-esteem mediated the relationship between interpersonal problems and overevaluation of weight and shape but did not mediate the relationship between interpersonal problems and dietary restraint. PMID- 24804302 TI - Leaf metallome preserved over 50 million years. AB - Large-scale Synchrotron Rapid Scanning X-ray Fluorescence (SRS-XRF) elemental mapping and X-ray absorption spectroscopy are applied here to fossil leaf material from the 50 Mya Green River Formation (USA) in order to improve our understanding of the chemistry of fossilized plant remains. SRS-XRF of fossilized animals has previously shown that bioaccumulated trace metals and sulfur compounds may be preserved in their original distributions and these elements can also act as biomarkers for specific biosynthetic pathways. Similar spatially resolved chemical data for fossilized plants is sparsely represented in the literature despite the multitude of other chemical studies performed. Here, synchrotron data from multiple specimens consistently show that fossil leaves possess chemical inventories consisting of organometallic and organosulfur compounds that: (1) map discretely within the fossils, (2) resolve fine scale biological structures, and (3) are distinct from embedding sedimentary matrices. Additionally, the chemical distributions in fossil leaves are directly comparable to those of extant leaves. This evidence strongly suggests that a significant fraction of the chemical inventory of the examined fossil leaf material is derived from the living organisms and that original bioaccumulated elements have been preserved in situ for 50 million years. Chemical information of this kind has so far been unknown for fossilized plants and could for the first time allow the metallome of extinct flora to be studied. PMID- 24804303 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24804304 TI - Stereoscopic visual acuity in types of ametropic amblyopia in children. AB - PURPOSE: To evaluate the presence of stereopsis in children with ametropic amblyopia, including hyperopia, myopia, and astigmatism. METHODS: A total of 205 children with the average age of 5.2 years were selected, including 65 cases of astigmatic amblyopia, 30 of myopic amblyopia, and 110 of hyperopic amblyopia. The near stereoacuity test (zero disparity stereoacuity, crossed disparity, and uncrossed disparity) and distance stereoacuity test by synoptophore with Yan's random-dot test in The Examination Chart of Stereoscopic Acuity were performed. Visual acuity was examined with the standard Snellen chart. Distance fusion was determined with the synoptophore. Correlations between amblyopia and stereopsis were performed with logistic procedure. RESULTS: Differences between zero disparity stereoacuity of hyperopia, myopia, and astigmatism were statistically significant in children with mild and moderate amblyopia determined by the near stereoacuity test (P < .05). Individuals with hyperopia have better central stereopsis and macular stereopsis, whereas children with astigmatism have significantly decreased stereoacuity. No difference was identified between the three types in children with severe amblyopia (P > .05). Results of different degrees of amblyopia at distance and near were approximate. In amblyopic eyes, difference between hyperopia, myopia, and astigmatism, determined with synoptophore, was not significant (P > .05). The types and degrees of amblyopia were closely related with stereopsis (P < .001). CONCLUSIONS: In mild and moderate amblyopic eyes, children with astigmatism had the worst stereoacuity. This group should pay more attention to visual stimulation training and stereopsis training. PMID- 24804305 TI - The importance of oxygen control reaffirmed: experience of ROP reduction at a single tertiary care center. AB - PURPOSE: To report the impact of the adoption of a low oxygen saturation policy on retinopathy of prematurity (ROP) incidence at a single tertiary care center. METHODS: ROP incidence, procedures for ROP, and neonatal outcome among very low birth weight infants were compared before and after the adoption of a low saturation policy, which took place in 2004. The Mann- Whitney test was performed to look for differences. RESULTS: The incidence of severe ROP significantly decreased from 5.3% of live very low birth weight infants between 1999 and 2004 to 1% of live very low birth weight infants between 2005 and 2012 (P = .003). The use of laser therapy for severe ROP between the same periods significantly decreased from 6.4% of live very low birth weight infants between 1999 and 2004 to 0.6% of live very low birth weight infants between 2005 and 2012 (P = .002). There was also a significant reduction of death or bronchopulmonary dysplasia from 33.8% between 1999 and 2004 to 24.2% between 2005 and 2012 (P = .02). CONCLUSIONS: Trained personnel and low and tailored oxygen saturation intervals for very low birth weight infants could play a pivotal role in reducing the incidence of severe ROP without increasing mortality. PMID- 24804306 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24804307 TI - Deregulation of biometal homeostasis: the missing link for neuronal ceroid lipofuscinoses? AB - Neuronal ceroid lipofuscinoses (NCLs), a group of genetically distinct fatal neurodegenerative disorders with no treatment or cure, are clinically characterised by progressive motor and visual decline leading to premature death. While the underlying pathological mechanisms are yet to be precisely determined, the diseases share several common features including inflammation, lysosomal lipofuscin deposits and lipid abnormalities. An important hallmark of most common neurodegenerative disorders including Alzheimer's, Parkinson's and motor neuron diseases is deregulation of biologically active metal homeostasis. Metals such as zinc, copper and iron are critical enzyme cofactors and are important for synaptic transmission in the brain, but can mediate oxidative neurotoxicity when homeostatic regulatory mechanisms fail. We previously demonstrated biometal accumulation and altered biometal transporter expression in 3 animal models of CLN6 NCL disease. In this study we investigated the hypothesis that altered biometal homeostasis may be a feature of NCLs in general using 3 additional animal models of CLN1, CLN3 and CLN5 disease. We demonstrated significant accumulation of the biometals zinc, copper, manganese, iron and cobalt in these mice. Patterns of biometal accumulation in each model preceded significant neurodegeneration, and paralleled the relative severity of disease previously described for each model. Additionally, we observed deregulation of transcripts encoding the anti-oxidant protein, metallothionein (Mt), indicative of disruptions to biometal homeostasis. These results demonstrate that altered biometal homeostasis is a key feature of at least 4 genetically distinct forms of NCL disease. PMID- 24804308 TI - Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. PMID- 24804311 TI - [Acyclovir resistance of HSV in immunocompetent patients: is prophylaxis incriminated?]. PMID- 24804312 TI - [Goodbye ceftriaxone, hello cefotaxime?]. PMID- 24804313 TI - Wind pollination and propagule formation in Rhizophora mangle L. (Rhizophoraceae): resource or pollination limitation? AB - Rhizophora mangle is considered as a self-compatible mangrove, and is pollinated by wind and insects. However, there is no information about fruit production by autogamy and agamospermy and on the foraging behavior of its flower visitors. Hence, the present study analyzed the pollination and reproductive systems of R. mangle in a mangrove community in northern Pernambuco, Brazil. Floral morphology, sequence of anthesis, and behavior of flower visitors were described; the proportion of flowers that resulted in mature propagules was also recorded. Autogamy, agamospermy, and wind pollination tests were performed, and a new anemophily index is proposed. The flowers of R. mangle are hermaphrodite, protandric, and have high P/O rate. Flies were observed on flowers only during the male phase, probably feeding on mites that consume pollen. Rhizophora mangle is not agamospermic and its fruit production rate by spontaneous self-pollination is low (2.56%) compared to wind pollination (19.44%). The anemophily index was high 0.98, and thus it was considered as a good indicator. Only 13.79% of the flowers formed mature propagules. The early stages of fruit development are the most critical and susceptible to predation. Rhizophora mangle is, therefore, exclusively anemophilous in the study area and the propagule dispersal seems to be limited by herbivory. PMID- 24804314 TI - Surfactant: a clinical report. PMID- 24804315 TI - And what about those oxygen saturation targets? PMID- 24804316 TI - Clinical nurse leaders? I think so! PMID- 24804317 TI - The dangers of alarm fatigue. PMID- 24804318 TI - 360-degree team building. PMID- 24804319 TI - Condition H is A-OK. PMID- 24804327 TI - This issue introduces the 12th year of Current Vascular Pharmacology. Introduction. PMID- 24804320 TI - Which certification is right for you? PMID- 24804328 TI - Trap-limited exciton diffusion in organic semiconductors. PMID- 24804329 TI - An evidence-based approach to acute aortic syndromes. AB - Aortic dissection, intramural hematoma, and penetrating atherosclerotic ulcer are parts of a spectrum of acute aortic syndromes that represent uncommon--but potentially deadly--diagnoses seen in the emergency department. The differential for acute aortic syndromes is large, as many conditions (including the much more common conditions of acute coronary syndromes and pulmonary embolism) present with many of the same chief complaints. This review looks at the features and classifications of acute aortic syndromes and presents evidence regarding the risk factors and chief complaints that can assist emergency clinicians in identifying the patients who require further investigation. Although no set of clinical factors has been shown to rule out aortic dissection, elements of a complete history and physical examination are critical in identifying patients who may be at risk for these diseases. In addition, the advantages and disadvantages of the various available advanced imaging strategies, the evidence regarding efficacy of laboratory testing (including D-dimer), as well as surgical and nonsurgical treatment options are reviewed. PMID- 24804330 TI - Location, location, location. PMID- 24804331 TI - The stress factor. PMID- 24804332 TI - An evidence-based approach to emergency department management of acute urinary retention. AB - Approximately 10% of men in their 70s and 33% of men in their 80s report at least 1 episode of acute urinary retention, and this urological emergency presents unique assessment and treatment challenges in the emergency department setting. Patients presenting with acute urinary retention are often in severe pain and require urgent diagnosis and prompt treatment. The differential diagnosis of acute urinary retention is vast, with some causes leading to permanent impairment if not dealt with in a timely manner. Quick recognition of the cause and timely bladder decompression are of utmost importance in preventing morbidity and relieving pain. This review analyzes the etiology, key historical and physical findings, differential diagnosis, and diagnostic studies for acute urinary retention in both men and women. Treatment algorithms for men and women, current controversies regarding urinary catheter usage, and recommendations on criteria for disposition are also presented. PMID- 24804333 TI - Asbestos: a continuing failure of ethics by McGill University. PMID- 24804334 TI - Safe exposure level for diacetyl. PMID- 24804335 TI - Egilman and Schilling respond. PMID- 24804336 TI - Exposure to PM10 as a risk factor for the development of nasal obstruction and chronic obstructive pulmonary disease. AB - OBJECTIVES: To investigate whether air pollution is a potential risk factor for airways obstruction. METHODS: A prospective cohort study (11.3 +/- 2.9 years) that took place in two areas (Eordea where concentration of PM10 was high and Grevena, Greece). We used the MRC questionnaire, spirometry, and anterior rhinomanometry at both visits. RESULTS: Initially we examined 3046 subjects. After excluding chronic obstructive pulmonary disease (COPD) patients, we re examined 872 subjects and 168 of them had developed COPD (Grevena: 24.3%, Eordea: 18.5%). Multivariable logistic regression analysis showed that the area of residence and thus exposure to air pollution was not a risk factor for the development of COPD (OR: 0.51, 95% CI: 0.18-1.46, P = 0.21). On the other hand, residence in Eordea was strongly related to the development of severe nasal obstruction (OR: 11.47, 95% CI: 6.15-21.40, P < 0.001). Similar results were found after excluding patients with COPD stage I as well as in the subgroup of never smokers. CONCLUSION: Air pollution was associated with severe nasal obstruction but not with COPD development. PMID- 24804337 TI - Outbreak of silicosis in Spanish quartz conglomerate workers. AB - OBJECTIVES: To describe the epidemiological and clinical characteristics of an outbreak of occupational silicosis and the associated working conditions. METHODS: Cases were defined as men working in the stone cutting, shaping, and finishing industry in the province of Cadiz, diagnosed with silicosis between July 2009 and May 2012, and were identified and diagnosed by the department of pulmonology of the University Hospital of Puerto Real (Cadiz). A census of workplaces using quartz conglomerates was carried out to determine total numbers of potentially exposed workers. A patient telephone survey on occupational exposures and a review of medical records for all participants were conducted. RESULTS: Silicosis was diagnosed in 46 men with a median age of 33 years and a median of 11 years working in the manufacturing of countertops. Of these cases, 91.3% were diagnosed with simple chronic silicosis, with an abnormal high resolution computerized tomography (HRCT) scan. One patient died during the study period. Employer non-compliance in prevention and control measures was frequently reported, as were environmental and individual protection failures. CONCLUSIONS: The use of new construction materials such as quartz conglomerates has increased silicosis incidence due to intensive occupational exposures, in the context of high demand fuelled by the housing boom. This widespread exposure poses a risk if appropriate preventive measures are not undertaken. PMID- 24804338 TI - Gynecologic pain related to occupational stress among female factory workers in Tianjin, China. AB - BACKGROUND: Dysmenorrhea, dyspareunia, and non-cyclic pelvic pain are health concerns for factory workers in China and may be increased by occupational stress. OBJECTIVES: To estimate the prevalence and demographic and occupational factors associated with three types of gynecologic pain among female factory workers in Tianjin. METHODS: The study included 651 female workers from three factories in Tianjin, China. Logistic regression models were estimated to determine associations between occupational stress and gynecologic pain. RESULTS: Occupational stress including high job strain, exhaustion, and stress related to working conditions was a risk factor for gynecologic pain. High job strain and poor job security were associated with an increased risk for dysmenorrhea. Compulsory overtime and exhaustion were associated with increased non-cyclic pelvic pain. Working overtime and exhaustion were associated with increased dyspareunia. CONCLUSIONS: As China's population of female factory workers grows, research on the reproductive health of this population is essential. PMID- 24804341 TI - The new strategy for statins: should you be taking one? Guidelines for taking cholesterol-lowering drugs now target overall risk rather than cholesterol values. PMID- 24804340 TI - Would banning atrazine benefit farmers? AB - Atrazine, an herbicide used on most of the US corn (maize) crop, is the subject of ongoing controversy, with increasing documentation of its potentially harmful health and environmental impacts. Supporters of atrazine often claim that it is of great value to farmers; most recently, Syngenta, the producer of atrazine, sponsored an "Atrazine Benefits Team" (ABT) of researchers who released a set of five papers in 2011, reporting huge economic benefits from atrazine use in US agriculture. A critical review of the ABT papers shows that they have underestimated the growing problem of atrazine-resistant weeds, offered only a partial review of the effectiveness of alternative herbicides, and ignored the promising option of nonchemical weed management techniques. In addition, the most complete economic analysis in the ABT papers implies that withdrawal of atrazine would lead to a decrease in corn yields of 4.4% and an increase in corn prices of 8.0%. The result would be an increase in corn growers' revenues, equal to US$1.7 billion annually under ABT assumptions. Price impacts on consumers would be minimal: at current levels of ethanol production and use, gasoline prices would rise by no more than US$0.03 per gallon; beef prices would rise by an estimated US$0.01 for a 4-ounce hamburger and US$0.05 for an 8-ounce steak. Thus withdrawal of atrazine would boost farm revenues, while only changing consumer prices by pennies. PMID- 24804339 TI - Hazardous substances in frequently used professional cleaning products. AB - BACKGROUND: A growing number of studies have identified cleaners as a group at risk for adverse health effects of the skin and the respiratory tract. Chemical substances present in cleaning products could be responsible for these effects. Currently, only limited information is available about irritant and health hazardous chemical substances found in cleaning products. We hypothesized that chemical substances present in cleaning products are known health hazardous substances that might be involved in adverse health effects of the skin and the respiratory tract. METHODS: We performed a systematic review of cleaning products used in the Swiss cleaning sector. We surveyed Swiss professional cleaning companies (n = 1476) to identify the most used products (n = 105) for inclusion. Safety data sheets (SDSs) were reviewed and hazardous substances present in cleaning products were tabulated with current European and global harmonized system hazard labels. RESULTS: Professional cleaning products are mixtures of substances (arithmetic mean 3.5 +/- 2.8), and more than 132 different chemical substances were identified in 105 products. The main groups of chemicals were fragrances, glycol ethers, surfactants, solvents; and to a lesser extent, phosphates, salts, detergents, pH-stabilizers, acids, and bases. Up to 75% of products contained irritant (Xi), 64% harmful (Xn) and 28% corrosive (C) labeled substances. Hazards for eyes (59%) and skin (50%), and hazards by ingestion (60%) were the most reported. CONCLUSIONS: Cleaning products potentially give rise to simultaneous exposures to different chemical substances. As professional cleaners represent a large workforce, and cleaning products are widely used, it is a major public health issue to better understand these exposures. The list of substances provided in this study contains important information for future occupational exposure assessment studies. PMID- 24804342 TI - Ask the doctor. I've noticed my belly getting larger in the last five years or so. I walk about half a mile every day and lift weights twice a week. I've cut back on big meals, but nothing gets rid of the belly fat. PMID- 24804343 TI - Ask the doctor. Is CPR safe for a person who has had coronary bypass surgery or who has a stent in place? PMID- 24804344 TI - Double trouble: coping with arthritis and heart disease together. Key treatments for both diseases--exercise and medications--demand extra attention and planning. PMID- 24804345 TI - Obesity as a cardiovascular disease: time to take your BMI seriously. Obesity now has an official designation as a disease. Learn how the new obesity guidelines may affect your heart health. PMID- 24804346 TI - 5 things you need to do after a heart attack. Your recovery after a heart attack doesn't end when you leave the hospital. To protect your heart over the long term, follow these steps. PMID- 24804347 TI - New options to reboot the heart. Implantable cardioverter-defibrillators can prevent sudden cardiac arrest. Now more people can benefit. PMID- 24804348 TI - FDA deems trans fats unsafe. These artery-clogging fats may linger in the food supply for a while. Learn how to avoid them. PMID- 24804349 TI - Testosterone therapy linked to heart trouble. PMID- 24804350 TI - Weight loss eases atrial fibrillation. PMID- 24804351 TI - MitraClip provides valve repair without surgery. PMID- 24804352 TI - Overdose deaths trigger state action. PMID- 24804353 TI - [Pharmacological evidence for the clinical effectiveness of Kampo drugs]. PMID- 24804354 TI - Older adults challenged financially when adult children move home. AB - This policy brief looks at the financial burdens imposed on older Californians when adult children return home, often due to a crisis not of their own making, to live with their parents. The findings show that on average in California, the amount of money that older adults need in order to maintain a minimally decent standard of living while supporting one adult child in their home increases their expenses by a minimum of 50 percent. Low-income older adults are usually on fixed incomes, so helping an adult child can provide the child with a critical safety net but at the cost of the parents' own financial well-being. Policy approaches to assisting this vulnerable population of older adults include implementing reforms to increase Supplemental Security Income (SSI), improving the availability of affordable housing, assuring that all eligible nonelderly adults obtain health insurance through health care reform's expansion of Medi-Cal and subsidies, and increasing food assistance through SNAP and senior meal programs. PMID- 24804355 TI - Trends in the supply of dentists in California. AB - More than 35,000 dentists were licensed to practice in California in 2012, a number higher than in any other state and representing about 15.6 percent of the total number of dentists nationwide. Despite these numbers, concerns over a sufficient supply of dentists in the state have not diminished. These concerns are due in part to the uneven distribution of dentists in areas with the highest level of need, as well as to demographic and practice characteristics that may limit availability of the dental workforce. This policy brief provides an overview of changes in selected demographic and practice characteristics of California dentists from 2008 to 2012, as well as in the distribution of dentists in California regions. The findings indicate an outward migration of dentists from California, a slowly aging workforce, and low dentist-to-population ratios in some regions of California. These findings highlight the need for the continuation and fine-tuning of policies aimed at both attracting young dentists to areas with low supply and retaining existing dentists in the state. PMID- 24804356 TI - Telehealth: into the mainstream? AB - Teleheath, and its subset telemedicine, extend across a range of technologies allowing patients to seek diagnosis, treatment, and other services from clinicians by electronic means. Telephone, videoconferencing, iPads, and apps are all employed. In its most established form, hospitals and medical centers use telehealth to reach patients in underserved rural areas. Proponents of telehealth suggest it can relieve medical workforce shortages; save patients time, money, and travel; reduce unnecessary hospital visits; improve the management of chronic conditions; and improve continuing medical education. But telehealth also faces ongoing challenges. States require physicians to be licensed in each state where they treat patients, even if from a distance. Most clinicians have not been trained in telehealth. Security concerns linger. Who should have access to telehealth and how it should be reimbursed are questions without fixed answers. This issue brief looks at telehealth's promise and its challenges and considers opportunities for policymakers to help in charting its future course. PMID- 24804357 TI - Social determinants of cardiovascular health among black and white women residing in Stroke Belt and Buckle regions of the South. AB - OBJECTIVE: To assess the associations of social determinants on cardiovascular health among White and Black residing in Stroke Belt (urban) and Stroke Buckle (rural) regions of the South. DESIGN: A cross-sectional observational analysis based on a random digit-dial telephone survey of a representative sample of White and Black adults residing in urban and rural Georgia conducted from 2004-2005. Separate logistic regression analyses examined the effects of social determinants on cardiovascular health within and between White and Black women and within and between urban and rural residential location. The main outcome measure was poor cardiovascular health defined as > or = 2 self-reported clinical cardiovascular disease risk factors (hypertension, diabetes, elevated cholesterol, overweight or obese). Social determinants were defined as socioeconomic status (SES), general daily stress, racial discrimination, and stress due to exposure to racial discrimination. Significance was established as a two-tailed P < .05. RESULTS: A total of 674 White and Black women aged 18-90 years were included in the sample. Results showed Black women with lower SES had worse cardiovascular health than White women in both rural and urban areas (rural odds ratio [OR] 2.68; confidence interval [CI] 1.44, 4.90; P = .001; urban OR = 2.92; CI = 1.62, 5.23; P = .0003). White women reporting high or very high exposure to general daily stress where more likely to have worse cardiovascular health than White women reporting very little to no daily stress (OR = 2.85; CI = 1.49, 5.44; P = .001). CONCLUSION: Our findings demonstrate the importance of social determinants associated with cardiovascular health. Tailored cardiovascular risk reduction intervention is needed among lower SES Black women in Stroke Belt and Buckle regions of the South, as well as stress-reduction intervention among White women in the South. PMID- 24804358 TI - Racial disparities in hospitalizations, procedural treatments and mortality of patients hospitalized with atrial fibrillation. AB - OBJECTIVES: To explore racial differences in characteristics, procedural treatments, and mortality of hospitalized atrial fibrillation (AF) patients. BACKGROUND: Despite a higher burden of AF risk factors, Black individuals have a lower prevalence of AF than their White counterparts. There is suggestion that AF may go undetected in minority groups, and there may be disparities in both diagnosis and treatment of AF. METHODS: The study sample was drawn from the Healthcare Cost and Utilization Project database created by the Agency for Healthcare Research and Quality. Outcomes included AF hospitalization rate, in hospital procedures performed, and in-hospital mortality within 6 defined sex race subgroups: Black males, Black females, White males, White females, other males, and other females. RESULTS: 165,319 hospitalizations (41% White male, 41% White female, 4% Black male, 4% Black female, 5% other male, 5% other female) with a primary discharge diagnosis of AF were identified. Black males and females were significantly younger than White patients and had more traditional and non traditional risk factors. Black males and females were significantly less likely to have an ablation procedure or cardioversion than White males. Black race was an independent predictor of in-hospital mortality (Odds Ratio [95% CI] of 1.90 [1.5, 2.5] for Black males and 1.38 [1.1, 1.8] for Black females). CONCLUSION: Using a large, contemporary sample of inpatients, we found significant racial differences in baseline characteristics, treatments, and outcomes of patients hospitalized with AF. There appear to be important racial disparities in the care of minorities who are hospitalized with AF that require further investigation. PMID- 24804359 TI - Subjective socioeconomic status predicts Framingham cardiovascular disease risk for whites, not blacks. AB - BACKGROUND: Higher rates of cardiovascular disease (CVD) and its risk factors are well documented among those with objective indicators of lower socioeconomic status (SES), such as income, education, and occupation. However, relatively little is known about the relationship of subjective SES to CVD risk, particularly within different racial groups. METHODS: Subjective SES and Framingham 10-year CVD risk profile were examined in 1,722 socioeconomically diverse Black and White adults enrolled in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. The sample had a mean age of 47.7 years, was 57% female, 56% African American, and 39% living in poverty. RESULTS: Subjective SES was associated with greater CVD risk after adjustment for poverty status, substance use, BMI, depression, antihypertensives, and co-morbidities (B = -.059, t[1,1711] = -2.44, P = .015). However, when the analysis was race stratified, subjective SES was associated with CVD risk in Whites (B = -.074, F[1,787] = -2.01, P = .045), but not Blacks. CONCLUSIONS: These results suggest that subjective SES may aid in predicting CVD risk in Whites, but not Blacks. It is important to note that these analyses were adjusted for poverty status, a potent indicator of objective SES. Thus, these findings further suggest that for Whites, subjective SES may influence CVD risk beyond that associated with objective SES. These findings highlight the potential importance of patients' subjective SES in CVD risk detection. PMID- 24804360 TI - Assessment of cardiovascular disease risk factors in the coastal region of South Carolina. AB - OBJECTIVE: To assess risk factors for cardiovascular disease, barriers to health care, and desired health care education topics for Hispanics in the coastal region of South Carolina known as the Lowcountry. METHODS: 174 Hispanic adults were surveyed at visits at the Mexican consulate using a novel interview instrument. The prevalence of cardiovascular risk factors was compared to the Behavioral Risk Factor Surveillance System (BRFSS), an annual telephone survey, to evaluate the validity of the survey instrument. RESULTS: Results are comparable to the BRFSS telephone study of the Hispanics in the same area. However, participants in our study were older (Age > 35 = 41.4% vs. 34.9%) and reported fewer years of formal education (higher level education = 12.9% vs. 44.2%). Cost of care (72.8%) and language barriers (46.8%) were the main difficulties reported in obtaining health care access. The main educational topics of interest were diabetes (61.5%), hypertension (43.7%), stress (42.5%), and cardiac disease (40.2%). CONCLUSION: Our study supports the evidence that there is a demand and need for cardiovascular disease and diabetes education among Hispanics. Our study also shows that a large proportion of Hispanics experience barriers to health care. and that large telephone studies may underrepresent higher risk Hispanic populations. PMID- 24804361 TI - Weight-based discrimination and medication adherence among low-income African Americans with hypertension: how much of the association is mediated by self efficacy? AB - OBJECTIVES: Much of the excessive morbidity and mortality from cardiovascular disease among African Americans results from low adherence to anti-hypertensive medications. Therefore, we examined the association between weight-based discrimination and medication adherence. METHODS: We used cross-sectional data from low-income African Americans with hypertension. Ordinal logistic regression estimated the odds of medication non-adherence in relation to weight-based discrimination adjusted for age, sex, education, income, and weight. RESULTS: Of all participants (n = 780), the mean (SD) age was 53.7 (9.9) years and the mean (SD) weight was 210.1 (52.8) lbs. Reports of weight-based discrimination were frequent (28.2%). Weight-based discrimination (but not weight itself) was associated with medication non-adherence (OR: 1.94; 95% CI: 1.41-2.67). A substantial portion 38.9% (95% CI: 19.0%-79.0%) of the association between weight based discrimination and medication non-adherence was mediated by medication self efficacy. CONCLUSION: Self-efficacy is a potential explanatory factor for the association between reported weight-based discrimination and medication non adherence. Future research should develop and test interventions to prevent weight-based discrimination at the societal, provider, and institutional levels. PMID- 24804362 TI - High factor VIII, von Willebrand factor, and fibrinogen levels and risk of venous thromboembolism in blacks and whites. AB - Venous thromboembolism (VTE) affects more than 300,000 people in the United States each year. However, it has been estimated that current diagnostic testing fails to identify prothrombotic risk in 50% of VTE patients. This article examines the relationship between levels of the pro-coagulant proteins factor VIII (FVIII), von Willebrand factor (VWF), and fibrinogen and risk of VTE in order to assess the impact of these novel risk factors. Data were collected from patients enrolled in the matched case-control Genetic Attributes and Thrombosis Epidemiology study. Crude and adjusted conditional logistic regression models were used to assess the impact of FVIII, VWF, and fibrinogen on risk of VTE. Before adjustment for independent predictors of VTE risk, high levels of FVIII, VWF, and fibrinogen were significantly associated with increased risk of VTE in both Blacks and Whites. After adjustment for ABO type, factor VII levels, hypertension, renal disease, recent surgery, diabetes, annual household income, alcohol use, and the other proteins of interest (FVIII, VWF, and/or fibrinogen), high FVIII and VWF levels were associated with increased risk of VTE in Blacks (OR: 1.97 [1.01-3.84] and 3.39 [1.58-7.27], respectively). High FVIII only was significantly associated with risk of VTE in Whites (OR: 2.35 [1.16-4.75]). Future research into the inclusion of these protein levels in risk models for VTE could help identify persons at highest risk. PMID- 24804363 TI - Diet and blood pressure: differences among whites, blacks and Hispanics in New York City 2010. AB - OBJECTIVES: Our study examined: 1) racial/ethnic differences in sodium and potassium intake; and 2) racial/ethnic differences in the relationship between dietary intake and blood pressure. DESIGN & METHODS: Data were collected in New York City in 2010, and included a telephone health survey, a 24-hour urine collection and an in-home clinical exam. Linear regression was used to examine the association of sodium and potassium intakes with blood pressure separately by race/ethnicity, age and sex among 1568 participants. RESULTS: The results indicate large differences by population subgroup in: 1) nutrient intake, and 2) the relationship between sodium and potassium intake and blood pressure. Black and Hispanic males aged < or = 50 consume considerably more sodium and less potassium than their White counterparts. The regression results indicate a strong association between diet and blood pressure among Blacks and Hispanics only. CONCLUSIONS: Based on our assessment of the association of sodium and potassium intakes and blood pressure measurements, we find that young Black and Hispanic males aged < or = 50 years have the poorest diet quality and may be the most at risk for developing diet-related hypertension. PMID- 24804364 TI - Diabetes control through an educational intervention. AB - OBJECTIVE: We evaluated the effect of an educational intervention administered to patients or/and physicians on the reduction in HbA(1c) and achieving diabetic control in a high-risk primarily Black inner-city population. METHODS: The study was designed as a four-arm randomized clinical trial where an educational program on diabetes was offered to physicians only, patients only, and both physicians and their patients, while the fourth arm did not receive any instruction. We built regression models at 24 months of follow-up to assess the likelihood of reaching glycemic goal as well as to measure the absolute reduction in HbA(1c) controlling for arm assignment, insulin use, race, age, sex, smoking, insulin use, and having achieved blood pressure control. RESULTS: Between April 2005 and July 2007, there were 823 patients randomized into the study. In multivariate analyses, the intervention group in which only patients received education showed a trend toward achieving a significant mean reduction in HbA(1c) with 49% (P = .06) higher odds of reaching glycemic control and .12 (P = .06) greater absolute percentage point drop in HbA(1c) compared to the no education group. CONCLUSION: Although our study reports positive results, it warrants a special emphasis on the behavior of the patient. Study results bring attention to disease management programs such as peer support networks that empower the patients that shift some of the responsibility to them. PMID- 24804365 TI - Racial/ethnic differences in multiple diabetes outcomes in patients with type 2 diabetes in the southeastern United States. AB - OBJECTIVE: To determine racial/ethnic differences in control of multiple diabetes outcomes in a large, diverse primary care sample. METHODS: 661 adults with type 2 diabetes (T2DM) were recruited from three primary care settings. The primary outcomes were individual and composite control of multiple diabetes outcomes. Control of individual diabetes outcomes were defined as hemoglobin A1c (HbA1c) < 7%, blood pressure (BP) < 130/80 mmHg and low-density lipoprotein (LDL) cholesterol < 100 mg/dL. Composite control was defined as having all three outcomes under control. Linear and logistic regression models were used to assess differences in individual means and individual and composite outcomes control between non-Hispanic Blacks (NHB) and Whites (NHW) adjusting for relevant covariates. RESULTS: NHBs were 67% of the sample, -61% earned < $20,000, and 78% earned < $35,000. Unadjusted mean HbA1c (8.0 vs 7.6, P = .024), SBP (134 vs 126 P < .001), DBP (76 vs 69, P < .001) and LDL (96 vs 87, P = .003) levels were significantly higher in NHBs. Adjusted linear regression showed that SBP (beta = 9.4; 4.5-8.6) and DBP (beta = 5.7; 3.5-7.9) were significantly higher in NHBs. 12.6% had composite control and NHBs had lower composite control (10.0% vs 17.6%). Adjusted logistic models showed that BP control (OR .45; .30-.67) and composite control (OR .57; .33-.98) were significantly lower in NHBs. CONCLUSIONS: In this diverse sample of primary care patients with T2DM, NHBs had significantly lower BP control and composite outcome control compared to NHWs adjusting for relevant confounding factors. Strategies are needed to optimize control of multiple outcomes and reduce disparities in patients with T2DM. PMID- 24804367 TI - Nutrient intake and lifestyle factors by diabetes status of Circassians and Chechans in Jordan. AB - OBJECTIVES: Diabetes is one of the most prevalent diseases in Jordan. However, little is known about nutrient intakes of minority groups in Jordan with and without diabetes. Our study aimed to examine if the intake of energy, macronutrients and some micronutrients differed between normal and diabetic adults among Circassians and Chechans in Jordan. DESIGN, SETTING, PARTICIPANTS: This cross-sectional study was conducted among 437 Circassians (160 males and 277 females) and 355 Chechans (119 males and 236 females) aged > or = 18 years. They were recruited from the Chechan and Circassian communities living in Jordan. MAIN OUTCOME MEASURES: A participant was defined as affected by type 2 diabetes mellitus if diagnosis was known to patient or if his or her condition complied with the American Diabetes Association definition. One 24-hour dietary recall for each participant was collected by face-to-face interview. RESULTS: Most of the measured anthropometric and biochemical parameters showed a significant difference between normal individuals and those with impaired fasting glucose or diabetes. Intakes of nutrients involved in the pathogenesis of diabetes including protein, fat and fiber did not differ between stratified participants according to blood glucose status for both Circassians and Chechans. CONCLUSIONS: Intake of nutrients did not differ in participants with normal blood glucose from those who had impaired fasting glucose or diabetes in the two studied populations. These two populations may need genetic studies to identify the risk factors other than dietary and lifestyle factors for type 2 diabetes. PMID- 24804366 TI - Community screening for pre-diabetes and diabetes using HbA1c levels in high-risk African Americans and Latinos. AB - OBJECTIVE: To evaluate community screening using HbA1c levels in high risk African Americans and Latinos in those not known to have diabetes. DESIGN: HbA1c levels were measured in 1542 African Americans and Latinos aged > or = 40 years with one or more of the following risk factors: family history in first degree relatives, waist circumference > or = 40 inches in males or > or = 35 inches in females, and hypertension, either treatment for or a measured BP of > or = 140/ 90 mm Hg. Oral glucose tolerance tests (OGTT) were offered to those meeting the HbA1c criterion for pre-diabetes. SETTING: Churches, community health fares, senior citizen sites. PARTICIPANTS: People without known diabetes. MAIN OUTCOME MEASURES: Proportion of people meeting the HbA1c criteria for prediabetes (5.8 6.4%) and diabetes (> or = 6.5%). RESULTS: 32% had one, 50% had two and 18% had three risk factors. By HbA1c criteria, 40% had pre-diabetes and 25% had diabetes. Increased waist circumference was the most common risk factor followed by a positive family history, and lastly, hypertension. Each individual risk factor was significantly (P < .001) and progressively more common as glycemia increased. Each additional risk factor increased the odds of pre-diabetes or diabetes by 2- to 4-fold. In individuals with pre-diabetes who underwent an OGTT, 59% were normal, 35% had pre-diabetes and only 6% had diabetes. CONCLUSIONS: Community screening of high risk African Americans and Latinos with HbA1c levels identifies a large proportion of people with pre-diabetes and diabetes. Those identified with pre-diabetes are unlikely to meet the OGTT criteria for diabetes. PMID- 24804368 TI - Usefulness of lipid ratios and atherogenic index of plasma in obese Moroccan women with or without metabolic syndrome. AB - OBJECTIVES: Our study aimed to study the impact of obesity and metabolic syndrome (MetS) on lipoprotein profiles and cardiovascular risk through lipid ratios and atherogenic index of plasma (AIP) in Moroccan women. METHODS: Our study included 240 Moroccan women, aged 53.31 +/- 8.51 years, divided into three groups: controls (group 1, n = 80), obese without MetS (group 2, n = 80) and obese with MetS (group 3, n = 80). Anthropometric and lipid measurements were taken and specific lipid ratios assessed, as well as Non-HDL cholesterol (Non-HDL-C) and atherogenic index of plasma (ALP). RESULTS: Group 2 presented similar lipoprotein profiles compared with group 1. Group 3 had higher triglyceride (TG) levels than group 1, which, in turn, increased HDL and AIP values. Dyslipidemia in group 3 was demonstrated by higher TG levels, lipid ratios and AIP and lower HDL-C levels compared with group 2. All of these abnormalities are responsible for elevations of risks of cardiovascular diseases. Closer associations were found between cardiovascular risk and lipid ratios and AIP than lipids alone. CONCLUSION: Our study confirms that MetS affects the serum lipoprotein profile of obese women. Lipid ratios, non HDL-C and AIP remain useful tools for the diagnosis and prognosis of cardiovascular disease by their associations with lipid parameters and their high predictive values. PMID- 24804369 TI - Hypertension prevalence and knowledge assessment in rural Haiti. AB - OBJECTIVE: Hypertension is an important risk factor for cardiovascular disease throughout the world. Little is known about the prevalence of hypertension in rural Haiti. Our study aims to estimate prevalence and knowledge of hypertension in Northern Haiti. DESIGN: Cross-sectional. SETTING: Four rural communities surrounding Milot, Haiti. PARTICIPANTS: Participants (69 males, 106 females, 175 total) were eligible to take part if they were aged > 18 years and not pregnant. Enrollment was voluntary. METHODS: Two initial blood pressure measurements were taken for each participant. Participants who had an average systolic blood pressure > or = 140 mm Hg or diastolic blood pressure > or = 90 mm Hg were instructed to return in 1 week for two additional confirmatory measurements. Based on these measures, participants were classified as either hypertensive or not. All participants were surveyed to assess their knowledge of hypertension. RESULTS: The prevalence of hypertension among the study sample was 36.6%. Overall, 47% of women and 21% of men were hypertensive. Approximately 30% of women of reproductive age (18-39 years) were hypertensive. Participants showed little knowledge of the asymptomatic nature of hypertension and the need for lifelong treatment. CONCLUSIONS: Hypertension is prevalent in Haiti. The high prevalence of hypertension among women of reproductive age is a concern since it is a risk factor for cardiovascular disease. Lack of knowledge surrounding hypertension indicates low awareness of the condition and is a possible target for future educational interventions. PMID- 24804370 TI - eGFR and chronic kidney disease stages among newly diagnosed asymptomatic hypertensives and diabetics seen in a tertiary health center in Nigeria. AB - OBJECTIVES: Moderate to severe CKD, may be symptomless and therefore may be undetected if effort is not made to assess kidney function. The aim of this study was to determine the eGFR of asymptomatic newly diagnosed hypertensives and diabetics with a view to creating awareness for early screening, evaluation and intervention especially in resource-poor settings where kidney replacement therapy is prohibitive. DESIGN, SETTING, PARTICIPANTS: This is a retrospective study. Records of all hypertensive and diabetic patients referred to the medical clinic were included in the study for analysis. They were considered newly diagnosed if they were just being referred and were not on antihypertensive therapy or had been on therapy only in the last one month. The diagnosis of diabetes mellitus was made according to the guideline of the American Diabetes Association. We included in the analysis patients who had anthropometric measurements and serum creatinine from which we calculated the eGFR. MAIN OUTCOME MEASURES: Use of eGFR and CKD stage in asymptomatic newly diagnosed hypertensives and diabetics. RESULTS: Six hundred and twenty eight patients were included in the study. The mean age (SD) for men and women were 50.19 (12.41) and 48.63 (14.43) respectively. A total of 242 (38.5%) had stage CKD stages 3a, 3b and 4 with a predominance of females: 184 (29.6%) vs 58 (9.2%). There was an association between CKD stage, sex (chi2 = 135.56, P < .001) and age (chi2 = 30.83, P = .01). CONCLUSION: A substantial number of asymptomatic patients with hypertension and diabetes have CKD stages 3 and 4, associated with age and sex, but not with the BP stage. Without a proper evaluation, which includes determination of GFR, significant deterioration of kidney function may be missed and an appropriate intervention may not be instituted. PMID- 24804371 TI - Commentary: the practice of dialysis in the intensive care unit in a developing country. AB - INTRODUCTION AND AIMS: In developing countries, little is known about renal replacement therapy (RRT) for acute kidney injury (AKI) in critically ill patients. The aim of this study is to describe characteristics of patients, clinical practice of renal support and outcomes in intensive care units (ICU) in a developing country. METHODS: Patients who underwent RRT for AKI from May 2003 to July 2008, in four ICUs in our institution were included in this retrospective study. Patients with end stage renal disease or younger than aged 18 years were exclueded. We have considered: patient demographics, indications of RRT, number of dialysis session, comorbidities, APACH II score for illness severity, mechanical ventilation, use of vasoactive drugs, and mortality rate. RESULTS: 105 critically ill patients admitted during the study period were treated with RRT, with a mean age of 56.13 +/- 16.8 (19-85) years. Sixty five were male and 40 female; all received intermittent hemodialysis. The total number of dialysis sessions was 284, and the mean number was 3.7 +/- 2.9; mean length of session was 225.22 +/- 75.16 (60-290) min. The majority of the cases (67%) were from medical ICU, followed by 30.2% from surgical ICUs (including cardiothoracic surgery ICU) and 2.8% were from burn ICU. The most common comorbidities were type 2 diabetes mellitus in 46 (44%) and hypertension in 35 (33.4%). Sepsis was a contributing factor to AKI in 60 patients (57.14%), hypovolemia in 30 (28.5%), and cardiogenic shock in 9 (8.5%). The APACHE II score was 25.86 +/- 11.8; the majority of patients (66.7%) were ventilated; 63 (60%) were under vasoactive drugs and 88 (83.8%) were oliguric. The most common indication for initiation of dialysis was hyperkalemia in 51 (48.5%) of the cases, followed by severe acidosis in 35 (33.3%) and acute pulmonary edema for 20 (19%). ICU mortality was 68.5% and increased to 95.2% when more than two organs were involved. CONCLUSIONS: Our experience suggests that indications for initiation of RRT in ICU are not greatly different from that in industrialized countries; yet, the big difference is in a high mortality rate among our patients. PMID- 24804372 TI - Low-income urban Latino parents' perceptions of immunization text reminders. AB - OBJECTIVE: Identify perceptions regarding benefits of and barriers to receiving text messages for immunization reminders and preferred content for such text messages. DESIGN: Structured interviews. SETTING: Outpatient pediatric resident and faculty clinic. PARTICIPANTS: A convenience sample of 54 low-income urban Latino parents of children aged < or = 2 years. MAIN OUTCOME MEASURES: Parent perspectives on text message reminders. RESULTS: Most respondents were female (70%), married (63%), and fluent only in Spanish (89%). Most (83%) had a health literacy score in the adequate range. All (100%) reported being interested in receiving immunization reminders by text message, and 81% reported being willing to receive general appointment reminders by text message. Parents made 72 comments regarding benefits of text message immunization reminders. The most common sub-category was usefulness of the reminders (53%). These comments reflected participants' busy schedules and the beneficial nature of text messages in reminding parents of appointments. Fifty-six comments were provided regarding barriers to receiving text message reminders. Most comments (77%) indicated no identifiable barriers. Twenty percent described barriers related to technology, such as costs or lack of text messaging service. Parents generated 108 comments regarding preferred content of reminders. The topics most frequently identified were appointment date and time (32%), names of the vaccines (19%), and the child's name (11%). CONCLUSIONS: Low-income Latino parents perceive text message immunization reminders as a feasible alternative to more traditional forms of communication. PMID- 24804373 TI - Associations of race and other socioeconomic factors with post-hospitalization hospice care settings. AB - OBJECTIVE: To examine patient characteristics post hospitalization between hospice home care and hospice care delivered in a medical facility. DESIGN, SETTING, AND PARTICIPANTS: A total of 3,613 hospital discharges to either hospice delivered at home or in a medical facility. Data was from the 2010 Nevada Hospital Inpatient Data. MAIN OUTCOME MEASURES: Our dependent variable was home based hospice care and medical facility-based hospice care. Our independent variables included race which was categorized as White, African American, Hispanic/Latino, Asian/Pacific Islander, and other race/ethnicity. Socioeconomic factors were marital status and health insurance. RESULTS: Hispanic patients were more likely to be discharged to home rather than a facility-based hospice (OR 1.39). Single patients and divorced patients were less likely to be discharged to a home-based hospice setting (OR .79, .67). Older patients were more likely to be discharged to a facility-based hospice (OR .91). The presence of anemia, paralysis, neurological disorders and weight loss were negatively associated with home discharge (OR 1.51). Patients with higher charges were less likely to be discharged to home (OR .96). CONCLUSIONS: Race, age, diagnosis and marital status influenced whether patients were discharged to home-based hospice or hospice delivered in a medical facility. These findings will assist hospice in anticipating which setting would be most appropriate for patients. Further research to determine whether patient preferences or characteristics determine hospice setting will be beneficial. PMID- 24804374 TI - An ecological analysis of the incidence of invasive squamous cell carcinoma of the cervix in Hispanic women in the United States. AB - PURPOSE: To evaluate the relationship between county-level characteristics and the incidence of invasive squamous cell carcinoma of the cervix among Hispanic women. METHODS: The Surveillance, Epidemiology and End Results (SEER) Program's 18 registries from 2000-2009 were queried. Average annual age-adjusted incidence rates for invasive squamous cell carcinoma of the cervix among Hispanic women were calculated. Patients were then stratified by residence in a county with high vs low percent language isolation (LI), income, and education levels. RESULTS: Among Hispanic women living in high LI, the highest incidence of cervical cancer was found among women residing in counties with low incomes and low education levels (11.3; CI: 10.8-11.8). CONCLUSIONS: County-level characteristics are associated with cervical cancer incidence in Hispanic women. A more precise understanding of contributing socioeconomic factors such as language may facilitate the design of targeted research studies and interventions, and community-level public policy interventions might be effective in reducing the unequal burden of cervical cancer in Hispanic women in the United States. PMID- 24804375 TI - 3D finite element model of human knee injuries in the traffic accident. AB - OBJECTIVE: To explore the injury mechanism of the human knee in a traffic accident by establishing a 3D finite element (FE) model. METHODS: The FE model, composed of femur, tibia, fibula, patella, meniscus, knee ligaments and surrounding soft tissues, was reconstructed by CT scanning data from a male volunteer. Validation was performed by the lateral impact simulation, and the stress and strain results were obtained to be compared with those previously reported for injury prediction. RESULTS: The results derived from the FE model were found to be similar with those previously reported, most of the ligaments and meniscus wounded at 40 m/s collision, which was readily observed. CONCLUSION: The simulation results generated by FE model can be effectively used for the injury mechanism analysis of initial contact. PMID- 24804376 TI - [Relationship between PMI and relative expression of myocardial various RNAs in rats died of different causes]. AB - OBJECTIVE: To observe the changes of relative expression of myocardial various RNAs in rats died of different causes and their relationship with PMI. METHODS: The rat models were established in which the rats were sacrificed by broken neck, asphyxia, and hemorrhagic shock. Total RNAs were extracted from myocardium. The quantitative real time PCR was used to calculate threshold cycle values of RNAs including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin, inducible nitric oxide synthase (iNOS), hypoxia-inducible factor-1 (HIF-1), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and U6 small nuclear RNA (U6 snRNA) and to study the changes of the relative expressions of various indexes with PMI. RESULTS: U6 snRNA with stable expression level could be used as appropriate internal control. In the early PMI, the relative expression of GAPDH, HIF-1, iNOS, TNF-alpha, and IL-6 more characteristically increased in groups of asphyxia and hemorrhagic shock than in group of broken neck, but the quantity of beta-actin decreased in all groups. In the late PMI, all the relative expressions significantly declined in correlation with the degradation of RNA. CONCLUSION: The characteristic changes of each RNA expression can be used as references to estimate PMI in deaths by different causes. PMID- 24804377 TI - [Endoplasmic reticulum stress mediates lipopolysaccharide-induced apoptosis in rat hepatocyte]. AB - OBJECTIVE: To investigate the role of endoplasmic reticulum stress (ERS) in lipopolysaccharide (LPS)-induced hepatocyte apoptosis. METHODS: Cells of the rat hepatocyte line BRL were cultured. The hepatocytes were treated with LPS, ERS inducer thapsigargin (TG), and ERS inhibitor 4-phenylbutyric acid (4-PBA), respectively or in their different combination. The cell viability was measured by MTT assay. The cyto-nuclear morphological changes of apoptosis cells were detected by the fluorescent dye Hoechst 33258. The apoptosis rate was assessed by flow cytometry with Annexin V-FITC/PI double-staining. Expressions of GRP78 as ERS marker protein, CHOP, caspase-12 and cleaved-caspase-3 as ERS related protein were detected by Western blotting. RESULTS: LPS could cause a decrease in cell viability and an increase in apoptosis rate in a dose- and time-dependent manner. The expression of GRP78, CHOP, caspase-12 and cleaved-caspase-3 proteins were significantly increased with LPS treatment. TG led to a marked decrease in cell viability and an increase in apoptosis rate, which aggravated the hepatocyte injury induced by LPS; whereas 4-PBA alleviated LPS-induced apoptosis. CONCLUSION: ERS mediates LPS-induced hepatocyte injuries, indicating that ERS may play a vital role in the pathogenesis of LPS-induced hepatocyte injuries. PMID- 24804378 TI - [Changes of MDA, SOD, TNF-alpha, and IL-1beta in rat brain tissue after concussion]. AB - OBJECTIVE: To observe the changes of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) in rat brain tissue and to explore the mechanism of secondary cerebral injury after brain concussion. METHODS: The brain concussion model was established with the pathological changes of rat brain tissue by Weil stain. The expressions of MDA and SOD in brain tissue were examined by photochemical method. The expressions of TNF-alpha and IL-1beta in cerebral cortex and hippocampus were examined by immunochemistry. RESULTS: Nerve myelin sheath showed disorder, disruption, gryposis and swelling by Weil stain. Above changes were more severe at 12h. The quantity of MDA in rat brain tissue after concussion was significantly higher than that in the control group. The activity of SOD was significantly lower than that in the control group. The expressions of TNF-alpha and IL-1beta increased more significantly in cerebral cortex and hippocampus in rat brain tissue after concussion than that in the control group. CONCLUSION: Oxidative stress and inflammatory injury in the rat brain tissue, which may play an important role in secondary cerebral injury after concussion. PMID- 24804379 TI - [Function disorder assessment on patients with mild psychiatric impairment due to road traffic accidents]. AB - OBJECTIVE: To explore the methods to assess the function disorder of patients with mild psychiatric impairment due to road traffic accidents. METHODS: In contrast to that of the patient with physical impairment, the function disorder of the patient with mild psychiatric impairment was assessed by the standard assessment instruments, such as the Barthel index of ADL (BI), Functional Activities Questionnaire (FAQ), Social Disability Screening Schedule (SDSS), Activity of Daily Living Scale (ADL), Physical Self-maintenance Scale (PSMS), and Instrumental Activities of Daily Living Scale (IADL). RESULTS: Except BI, the each total score of FAQ, SDSS, ADL, PSMS, and IADL correlated well with the rank of psychiatric impairment. The difference of each total score of rating scales among different physical impairment rank was not statistically significant. At the impairment rank of level 10, the difference of each total score of FAQ and ADL was not significant between the two groups; each total score of BI, SDSS, and IADL in psychiatric impairment was higher than that of physical impairment, while the total score of PSMS in psychiatric impairment was lower than that of physical impairment. At the level 9, except PSMS, the each total score of BI, FAQ, SDSS, IADL and ADL in psychiatric impairment was higher than that of physical impairment. At the level 8, except BI and PSMS, the each total score of FAQ, SDSS, IADL and ADL in psychiatric impairment was higher than that of physical impairment. CONCLUSION: The different criteria for assessment of mild psychiatric and physical impairment may exist, and appropriate indexes for assessment between physical and psychiatric impairment need to be further elucidated. PMID- 24804380 TI - [Correlation of NOS1AP gene polymorphisms with sudden unexpected death in Chinese Han population]. AB - OBJECTIVE: To investigate the single nucleotide polymorphism of NOS1AP gene with sudden unexpected death (SUD) during daily activities. METHODS: The heart blood samples were collected from 60 SUD cases in normal daily activities as SUD group and the peripheral blood samples from 80 random unrelated cases as control group. The genome DNAs from all cases were isolated and the gene sequences were analyzed from specific primers of some SNP (rs10494366, rs10918859, rs12143842, rs12742393, rs3751284, and rs348624) of NOS1AP. The allele frequency and genotype frequency were calculated and the difference in these SNP between SUD group and control group were analyzed. RESULTS: The allele frequency and genotype frequency of rs3751284 which located at the sixth exon domain had significant statistical differences between the two groups (P<0.05). The minor allele frequency of rs3751284 was 0.325 in SUD group and was 0.475 in control group. CONCLUSION: rs3751284 might be a susceptibility locus for SUD. PMID- 24804381 TI - [Relationship among ALDH2 gene polymorphism, alcohol metabolism and acetaldehyde level in peripheral blood]. AB - OBJECTIVE: To explore alcohol pharmacokinetics as well as acetaldehyde level in peripheral blood in human subjects with different ALDH2 genotypes after drinking. METHODS: Venous blood samples of 14 unrelated volunteers were collected. Polymerase chain reaction-restriction fragment length polymorphism technology was adopted for DNA extraction and ALDH2 genotyping. The volunteers were asked to drink beer at certain doses. The concentration of alcohol and acetaldehyde were assayed by headspace gas chromatography method at different time. The pharmacokinetic parameters were calculated. RESULTS: According to the results of electrophoresis, 5 people carried ALDH2*1/*1 as wild group and 9 people carried ALDH2*1/*2 as mutation group. The good linear range of alcohol and acetaldehyde were 0-1 570.7 microg/mL and 0-5.1772 microg/mL, respectively. The AUC values of alcohol and acetaldehyde and the t1/2Z value of alcohol were higher in the mutation group than that in the wild group. But the CL/F value of alcohol was lower in the mutation group than that in the wild group (P<0.05). CONCLUSION: After the consumption of alcohol, alcohol and acetaldehyde metabolism in blood slow down in ALDH2*1/*2 mutation group influenced by the inhibition of enzyme activity, leading to the accumulation of acetaldehyde in peripheral blood, thus reinforcing their effects in the body. PMID- 24804382 TI - Correlative factors for organic psychotic symptoms in patients following traumatic brain injury. AB - OBJECTIVE: To investigate the correlative factors for organic psychotic symptoms following traumatic brain injury (TBI). METHODS: In the current study, 391 subjects who had undergone forensic identification of the organic mental disorders due to TBI were included, both the demographic and post-traumatic information collected. The relevant data were statistically analyzed in those confirmed as organic psychotic syndrome according to Chinese Classification of Mental Disorders 3rd version (CCMD-3). RESULTS: Fifty-two subjects (13.3%) were identified as organic psychotic symptoms. The chi-square test showed that the detectable organic psychotic symptoms were associated with the marriage status, damage nature, injury severity and treatment, and the multivariate logistic regression analysis revealed good fitness of treatment and injury severity with the regression model (OR = 0.044, 95% CI: 0.017-0.114; OR = 2.145, 95% CI: 1.201 3.832, respectively). CONCLUSION: The risks of organic psychotic symptoms following TBI can be involved in the alternative of craniotomy for the cases with trauma and moderate brain injury. PMID- 24804383 TI - [Forensic analysis of 7 infant homicide cases in Suzhou]. AB - OBJECTIVE: To discuss and summarize the major characteristics, autopsy examination, and scene investigation in infant homicide cases. METHODS: From 2008 to 2013 in Suzhou, the information of seven detected infant homicide cases were collected and analyzed. RESULTS: The criminal suspects were victims' mothers with young ages and pregnancies were premarital. Infant homicide cases occurred at the same location of the delivery. The infants died of mechanical asphyxia in the majority of the cases. Most bodies were naked and their umbilical cords were not cut by iatrogenic method and didn't connect with the bodies. CONCLUSION: The standardization of forensic investigation can improve the analysis and detection of infant homicide cases. PMID- 24804384 TI - [1483 cases of paternity test with STR loci mutation]. AB - OBJECTIVE: To observe and analyze the mutation phenomenon of 17 STR loci of PowerPlex 18D Kit in paternity test of Yunnan population. METHODS: The DNA was extracted by Chelex-100 method. The PowerPlex 18D Kit was used to test 1,483 cases and their conclusions of paternity tests were verified. RESULTS: In the 1,483 cases, 1,047 were parental triplet and 436 were uniparental diad. A total of 2,530 times of meiosis was observed. One STR locus mutation was observed in 24 cases. And 11 mutation loci were found in the 17 STR loci. CONCLUSION: STR loci mutation is a common phenomenon. We should collect the data of STR loci mutation, choose other good polymorphism, low mutation rate of genetic markers, to ensure that the results are accurate and reliable. PMID- 24804385 TI - [Establishment of the multiplex genotyping system for 16 SNP loci on mtDNA]. AB - OBJECTIVE: To establish a multiplex genotyping system of mtDNA SNP. METHODS: A multiplex analysis system of 16-plex mtDNA SNP loci was established with allele specific PCR and capillary electrophoresis genotyping technology. Fifty samples from unrelated Chinese Han individuals were typed with the multiplex system. The multiplex assay was validated by comparing with the direct sequencing method. RESULTS: The genotypes of all 50 samples were correctly determined by the multiplex system. The optimal genotypic graphs were obtained with an input DNA of 0.5-10 pg, and the typing results were completely consistent with those by direct sequencing method. CONCLUSION: The established multiplex system by allele specific PCR has high sensitivity, operational simplicity and high accuracy. It provides an effective and high output method for mtDNA SNP typing. PMID- 24804386 TI - [Extraction of sperm DNA from mixed stain by the modified differential lysis method combined with silicon bead method]. AB - OBJECTIVE: To extract sperm DNA from mixed stain by the modified differential lysis method combined with silicon bead method and to evaluate its application value. METHODS: Fifty-two mixed stains containing female STR genotypes detected by differential lysis method were collected. The sperm DNA was extracted by the modified method combined with silicon bead method, then genotyped with the Identifiler Kit, and compared with the results of genotyping by the conventional differential lysis method as control. RESULTS: Of the 52 samples, 38 samples with sole male STR genotypes in all loci were detected. The detection rate of male STR genotypes was 98.08% through the modified method combined with silicon bead method. CONCLUSION: The modified differential lysis method combined with silicon bead method can be used in extraction of sperm DNA from mixed stain. PMID- 24804387 TI - [ApoB gene genetic polymorphism of Han nationality and Mongolian nationality in midwest area of Inner Mongolia]. AB - OBJECTIVE: To study ApoB gene genetic polymorphism of Han nationality and Mongolian nationality in midwest area of Inner Mongolia. METHODS: Some unrelated individuals of Han nationality and Mongolian nationality in midwest area of Inner Mongolia were selected. Polymerase chain reaction-restriction fragment length polymorphism technology was used to check the presence of Xba I (X+) and EcoR I (E-) sites of rare alleles. The genotype frequency, allelic frequency and population genetics parameters were calculated. RESULTS: The frequencies of Xba I (X+) and EcoR I (E-) rare alleles were 2% and 4.6% in Han population. There was no Xba I (X+) or EcoR I (E-) rare alleles found in Mongolian nationality. CONCLUSION: The allelic frequencies of ApoB gene Xba I and EcoR I sites are very different in different races. These sites may be used in identification of ethnicity. PMID- 24804388 TI - [Detection technologies of microRNA and their prospects for forensic applications]. AB - MicroRNA (miRNA) belongs to a class of small, non-coding RNA molecules that contains 18-25 nucleotides and regulates gene expression at post-transcriptional level. Many miRNAs are highly conserved and display timing- and tissue-specific expression. With the advance of the miRNA detection technologies, miRNA has been introduced to forensic science as a potentially novel set of genetic markers of forensic body fluid identification, species identification and PMI estimation. In this article, the detection methodologies of miRNA are reviewed, and their potential applications in forensic practice and research future are also discussed. PMID- 24804389 TI - [Drug related problems in Belgian community pharmacies]. AB - INTRODUCTION: The identification, the management and if possible the prevention of drug related problems (DRP), are the main responsibilities of pharmacists. AIM: The aims of the study were 1/to investigate the frequency and nature of drug related problems detected by community pharmacists, 2/to inventories the frequency and nature of the interventions by community pharmacists on prescribed medicines, and 3/to evaluate whether there is a difference between DRP detection at the moment of dispensing versus in a quiet setting (a posteriori detection). METHOD: All trainees of the participating universities of Belgian were asked to contribute to a observational study. Participating pharmacists quantified DRP's and their interventions on prescribed medicines for 5 days. Registrations were made by using a web tool based on an adapted version of the classification list of PCNE. The registration took place in two phases, at the time of delivery as well as in an a posteriori verification of the prescriptions with the pharmaceutical record file of the patients. RESULTS: The study was conducted from November 2012 to April 2013 in 534 community-pharmacies with internship. During this period 9.869 prescriptions (15%) with at least one DRP were detected on a total of 64.962 prescriptions treated by tutor pharmacists. Since there could be more than one problem on a prescription, 15.952 DRP's were registered. 2.597 of the DRP's were detected by a posteriori verification. 75% of all problems had a technical cause and 37% were clinical in nature. Under the technical causes an incomplete prescription was the most common. The most frequently registered clinical causes were a drug interaction, an inopportune time of intake, a too high or too low dose and an unsuitable drug. Participating pharmacists solved almost 3 of the 4 detected DRP's. In more than half of the DRP's, the patient was verbally and/or written informed. In 44% of the a posteriori discovered problems, the pharmacist intervened. CONCLUSION: Pharmacist detected one or more DRP's with 15% of the prescriptions. Analysis of a prescription prior to dispensing the medicines therefore appears necessary. The active intervention of the pharmacist in 83% of the problems indicates that he contributes to the optimization of drug therapy with a potential increase in the quality of life of the patient and a reduction in the cost of healthcare. The a posteriori discovered DRP's demonstrate the need for pharmacist lead meditation reviews possibly together with the physician and/or patient. PMID- 24804390 TI - [Vitalink: a digital platform to share patient health records in primary care. Report of the pilot projects for sharing medication schemes]. AB - Vitalink is a digital platform to share health patient data among health care professionals in primary care. The Flemish community started the development of this platform in collaboration with representatives of professional associations primary care. Sharing medication charts online was the first Vitalink project. In December 2012 four pilot regions in Flanders (Turnhout, Limburg, Aalst and Halle) tested medication chart sharing through Vitalink. Due to difficulties with software development effective sharing started only in April 2013. The test phase was ended in October 2013. Each pilot region made an evaluation report. Conclusions were similar: the realization business cases were limited. Integration in end user software was insufficiently performant. Moreover, interpretation of downloaded medication charts was found out to differ among participating software applications. Because of these problems exchange of patient records among primary care actors was limited. Therefore research questions could not be conclusively answered. Nevertheless the Vitalink pilot project can be considered successful in some ways. Collaboration and communication among health care professionals and their associations was ameliorated. The awareness of digital data sharing in primary care is growing. Pilot projects created buy in among patients, physicians, pharmacists and nurses. Uniform lay-out guidelines were established in deliberation with all participating actors. Since November 2013 Vitalink is in production. Medication charts, summarized electronic health records and vaccination data can be uploaded to the platform and health care professionals that are registered can consult them. End user software must still be developed to make broad use of the platform feasible. Meanwhile further deliberation with software vendors and professional associations can be organized in order to achieve the implementation and integration of user friendly Vitalink modules. PMID- 24804391 TI - [(Added) Value of a clinical pharmacist in the oncology department and optimalisation of the applicability of geriatric tools assessing potential inappropriate medication use in geriatric patients (Drug Burden Index and de Beers criteria)]. AB - In a pilot project, the value of a clinical pharmacist in the oncology department is examined. There is special attention given to two clinical pharmaceutical criteria concerning use of potential inappropriate drugs in this population. First of all, the Drug Burden Index (DBI), a measurement of the individual exposure to anticholinergic and sedative drugs. Second of all, the Beers criteria, an explicit criterion of potential inappropriate use of drugs by the geriatric patient. Criteria are adapted for application in Belgian practice. It can be concluded that the clinical pharmacist can be used to support the multidisciplinary approach to cancer patients. The use of the two criteria mentioned above in the estimation of the clinical impact of drugs on functional outcome and cognition on the (oncolgeriatric patient and the correlation with hard endpoints, still need to be investigated. PMID- 24804392 TI - [The mirages of the new oral anticoagulants]. PMID- 24804393 TI - [Standard doses applied to preparations of injectable drugs and their reconstitution in the hospital: methodology and implementation]. AB - INTRODUCTION: Improvement of healthcare quality and safety are two main goals for hospitals. High risk preparations of injectable drugs is one of the possible areas for improvement. In this context the production of batches of standard doses is a practical solution in response to the increased demand. Some toolkits exists to facilitate the implementation of dose banding, but, to our knowledge, no complete strategy was available until today. AIM AND PURPOSE: To propose a rational approach to analyse the possibility of implementing standard doses and choose the most relevant drugs for dose standardization. METHOD: The method is based on the analysis of literature focusing on different themes: safety, international guidelines, batch production regulation and stability studies. RESULTS: An approach on the strategies to develop is detailed for pharmacists willing to implement standard doses. All key stages are discussed: the needs of care units, the analysis and risk assessment, the stability studies and the practical implementation of the standard doses preparation and quality control. CONCLUSION: The implementation of standard doses seems a rational and necessary evolution of hospital pharmacy in response to the increase of compounding activity and the requirements of quality preparation. A global and all-inclusive approach is needed for this purpose. All parameters have to be considered to avoid errors. A process and a decision aid are suggested to facilitate the development of standard doses. PMID- 24804394 TI - [Dapoxetin (Priligy), oral]. PMID- 24804395 TI - Bruised by ICD-10 delay, healthcare execs huddle over what to do next. PMID- 24804396 TI - Uninsured rate dips 2.7 points. PMID- 24804397 TI - Ryan budget would overhaul Medicare and Medicaid, repeal the ACA. PMID- 24804398 TI - Denying access to big cancer centers may undermine narrow networks. PMID- 24804400 TI - 10 years after the revolution. PMID- 24804399 TI - Despite cuts, Medicare Advantage enrollment, insurers' stocks, still surging. PMID- 24804401 TI - After health ITs March madness. PMID- 24804402 TI - Changing the conversation about palliative care. PMID- 24804403 TI - Going beyond medicine to improve U.S. health. PMID- 24804404 TI - Time for a new test on hospitals' tax exemptions. PMID- 24804405 TI - Non-physician providers will pick up the slack for less-productive employed doctors. PMID- 24804406 TI - Most prescribed pharmaceuticals. PMID- 24804407 TI - [The treatment of acute diarrhea]. AB - Racecadotril has sufficient proven efficacy in the treatment of acute diarrhea in children. Treatment outcomes in adults are less convincing. The place of gelatin tannate is unclear. Some sources point to potential hepatotoxicity and diminished iron absorption, with a concomitant risk of anemia, at least in case of excessive or prolonged use. Loperamide still has a prominent place in the treatment of acute and chronic diarrhea. Attention should be payed to correct dosing and some well-known contra-indications. Probiotics are indicated in children, as well as in the prevention of antibiotics-induced diarrhea. There is no evidence to support their use in the treatment of acute diarrhea in adults. Up till now publications disagree on the efficacy in the prevention of travelers' diarrhea. Astringents and absorbents are no longer supported in guidelines. Oral rehydration systems have a part to play in pediatric treatment. PMID- 24804408 TI - [Recommendations for vitamin D supplementation in infants and young children]. AB - Vitamin D deficiency occurs rather commonly among healthy pregnant women, newborns and young children, especially in certain risk groups. Since vitamin D plays a role in calcium and phosphor metabolism essential for bone health and in the physiopathology of some autoimmune diseases it seems important to provide recommendations for prevention of vitamin D deficiency. Risk factors include maternal vitamin D deficiency, low intake of fortified food, eg. breastfeeding, low compliance of supplementation, dark skin, inadequate sun exposure, premature birth, overweight, living at high latitude. The aim of this paper is to summarize available data of vitamin D sources, known situations in which deficiency is common and published guidelines on vitamin D supplementation, and translate this information in recommendations for prevention of vitamin D deficiency in healthy paediatric population in Flanders. Infants should receive an oral supplementation of 400 IU/day of vitamin D from birth and this should be continued till the age of 6 years. In cases of dark skin the dose should be 600 IU/day. An healthy life style with outdoor activities and associated sun exposure and intake of fortified nutrition should be advised. The implementation should be promoted by all healthcare professionals working with young children. PMID- 24804409 TI - [Scientific evidence for influenza vaccination during pregnancy]. PMID- 24804410 TI - [Seasonal influenza: vaccines available for the winter 2013-2014]. PMID- 24804411 TI - [Raman spectroscopy applied to analytical quality control of injectable drugs: analytical evaluation and comparative economic versus HPLC and UV / visible FTIR]. AB - In France, central IV admixture of chemotherapy (CT) treatments at the hospital is now required by law. We have previously shown that the shaping of Therapeutic Objects (TOs) could profit from an Analytical Quality Assurance (AQA), closely linked to the batch release, for the three key parameters: identity, purity, and initial concentration of the compound of interest. In the course of recent and diversified works, we showed the technical superiority of non-intrusive Raman Spectroscopy (RS) vs. any other analytical option and, especially for both HPLC and vibrational method using a UV/visible-FTIR coupling. An interconnected qualitative and economic assessment strongly helps to enrich these relevant works. The study compares in operational situation, the performance of three analytical methods used for the AQC of TOs. We used: a) a set of evaluation criteria, b) the depreciation tables of the machinery, c) the cost of disposables, d) the weight of equipment and technical installations, e) the basic accounting unit (unit of work) and its composite costs (Euros), which vary according to the technical options, the weight of both human resources and disposables; finally, different combinations are described. So, the unit of work can take 12 different values between 1 and 5.5 Euros, and we provide various recommendations. A qualitative evaluation grid constantly places the SR technology as superior or equal to the 2 other techniques currently available. Our results demonstrated: a) the major interest of the non-intrusive AQC performed by RS, especially when it is not possible to analyze a TO with existing methods e.g. elastomeric portable pumps, and b) the high potential for this technique to be a strong contributor to the security of the medication circuit, and to fight the iatrogenic effects of drugs especially in the hospital. It also contributes to the protection of all actors in healthcare and of their working environment. PMID- 24804412 TI - [Ciclopirox (Mycosten), topically]. PMID- 24804413 TI - Whatever would induce you...? PMID- 24804414 TI - Increasing evidence of negative impacts of caesareans say midwives. PMID- 24804415 TI - Independent midwife 'fills in the gaps' after hospital suspends its home birth service. PMID- 24804416 TI - My daughter's daughter: the tragedy of late stage miscarriage. AB - This article sets out my observations of my daughter's difficult pregnancy and late-stage miscarriage. I share this information to raise awareness that the specialist support for women going through this is not always in place and doesn't fully prepare women for this experience. Even though this can be uncomfortable for maternity professionals, the care that women receive, especially during labour and birth, has a massive impact on them and their families. There are many opportunities for midwives to make a positive difference at this difficult time. My granddaughter, Jess, died at five months gestation and was later confirmed to have Turner Syndrome. Turner Syndrome is a chromosomal abnormality that only affects girls and is related to the partial or complete deletion of the X chromosome. Not all affected girls are miscarried and an estimated one in 2000 girls born in the UK has Turner Syndrome. PMID- 24804417 TI - Improving the experience of pregnancy and childbirth for deaf people and their families. AB - Deafness is unique in that it crosses barriers of age, gender, economic status and ethnicity. It is particularly complex in the context of the 'disabled/abled binary'. Generalisation is unhelpful since impairment is individualised and manifests itself in emotional, psychological, social and physical dimensions of a person's life. The 'Deaf Nest' project aims to improve deaf users' personal experience, equality of access, choice and control over maternity care. The implementation of clear guidance, an early assessment form, effective referrals, deaf awareness study days and 'Deaf Nest' support packs will result in improved deaf access to information, the ongoing assessment of need, improved health and lifestyle choices and greater family involvement. PMID- 24804418 TI - Time's up! Women's experience of induction of labour. AB - Induction of labour is a common obstetric intervention in the UK, occurring in approximately 22 per cent of labours (Birthchoice UK 2014). Much evidence exists regarding methods, efficacy, safety and outcomes, but very little is known about women's experience of induction of labour (National Institute of Health and Care Excellence (NICE) 2008). Qualitative interviews were carried out with low risk primigravid women being induced post-maturity. Women expressed fear about the induction process, described their midwife as being their primary source of information and reported that they had sufficient information prior to admission. PMID- 24804419 TI - Fearful birth? So what's new? AB - Significant fear of birth (tocophobia) appears to be increasing, coinciding with an increase in requests for non-medical indication caesarean section. It can arise from previous birth trauma, or be present in late childhood or early adulthood prior to pregnancy. This article explores some of its origins, presentations, effects and the importance of using a midwifery model of care with referral to specialist services as appropriate, to facilitate a positive birth experience which will enhance the woman's wellbeing and family life. PMID- 24804420 TI - Mobility and upright positioning in labour. AB - SUMMARY: A study by the Royal College of Midwives (RCM) (2010) concluded that 49 per cent of women gave birth in the supine position. The RCM advocates getting women 'off the bed' in its campaign for normal birth (RCM 2005a). There has been much speculation as to why women labour on the bed, with some suggesting it is because women feel it is expected of them (RCM 2012). Mobility and upright positioning in labour have countless benefits, with or without epidural anaesthesia, for both woman and fetus. The National Institute of Health and Care Excellence (NICE) supports the adoption of positions that women find most comfortable (NICE 2007). Both midwives and students should fully explain the benefits of mobility and upright positioning in labour to women, preferably antenatally, to enable them to make informed decisions as to the positions they wish to adopt when in labour. PMID- 24804421 TI - Examination of the newborn: the key skills--Part 4 the testes. AB - Midwives are increasingly performing the examination of the newborn. In the final of this four-part series, we consider the importance of the examination of the testes in the screening process. The significance of history taking, knowledge of risk factors and the testes examination will be explored, along with referral pathways that the National Screening Committee requires, as will be highlighted. The impact of late detection and poor referral of undescended testes on the lives of children and adults will also be considered. PMID- 24804422 TI - Proactive use of supervision. AB - Midwifery supervision is the 13th series of 'Midwifery basics' targeted at practising midwives. The aim of these articles is to provide information to raise awareness of the impact of the work of midwives on women's experience, and encourage midwives to seek further information through a series of activities relating to the topic. In this seventh article of the series, RachelJokhi discusses how to use statutory supervision proactively in order to gain maximum benefit. PMID- 24804423 TI - 'Promoting positive postpartum mental health through exercise in ethnically diverse priority groups'. PMID- 24804424 TI - Clinical guidelines: help or hindrance? PMID- 24804425 TI - [The effect of attainability on envy]. AB - Envy is an unpleasant emotion caused by comparison with a person who possesses something we desire. We conducted two studies to test our prediction that less envy would be felt when the person could attain what others had. In Study 1, participants read scenarios in which their friend could achieve a goal which they could not, and rated their emotions toward the friend. We manipulated the attainability according to whether the goal could be achieved by effort. In Study 2, participants competed with a confederate, and were informed that their performance was worse than that of the confederate. Afterwards the attainability was manipulated by either informing the participants that the possibility of improving their ability was very low or high. Then participants rated their emotions toward the confederate, and we also checked whether the participants had helped the confederate. As predicted, our findings demonstrated that those in the high attainability condition felt envy less than those in the low attainability condition, but showed no significant differences in helping behavior. PMID- 24804426 TI - [Demonstrating that monitoring and punishing increase non-cooperative behavior in a social dilemma game]. AB - This research demonstrated the negative influence of monitoring and punishing during a social dilemma game, taking the illegal dumping of industrial waste as an example. The first study manipulated three conditions: a producing-industries monitoring condition (PIM), an administrative monitoring condition (ADM), and a control condition (no monitoring). The results showed that non-cooperative behavior was more frequent in the PIM condition than in the control condition. The second study had three conditions: a punishing condition (PC), a monitoring condition (MC), and a control condition (no monitoring, no punishing). The results indicated that non-cooperative behavior was observed the most in the PC, and the least in the control condition. Furthermore, information regarding other players' costs and benefits was shared the most in the control conditions in both studies. The results suggest that sanctions prevent people from sharing information, which decreases expectations of mutual cooperation. PMID- 24804427 TI - [The effect of participation of the victims in trials on their confidence in the criminal justice system: procedural justice]. AB - To evaluate the effectiveness of the new victim participation systems, we examined whether the use of these systems had an effect on the confidence of the families of victims about the criminal justice system. The results of a questionnaire survey revealed that victims who participated in their criminal court cases had more confidence in the criminal justice system and were more accepting of the court decisions. Moreover, the present study examined the process of victims' confidence in criminal justice based on the value-expressive theory of procedural justice. In particular, the assumption was confirmed that the victims' feelings of expressing opinions resulted in their increased confidence in criminal justice through their confidence in the judges and their acceptance of court decisions. PMID- 24804428 TI - [The specificity of cognitive reactivity in recurrent major depressive episodes]. AB - The present study examined cognitive vulnerability to relapses of depression by clarifying the characteristics of "cognitive reactivity" in people with recurrent major depressive episodes. Study 1-1 and 1-2 developed a Japanese version of the Leiden Index of Depression Sensitivity-Revised (LEIDS-R), which assessed cognitive reactivity, and evaluated the reliability and validity of the scale. Study 2 examined the characteristics of cognitive reactivity which differentiate people with recurrent major depressive episodes from people with a single episode or none. The Japanese version of the LEIDS-R was shown to have reasonable reliability and validity. Participants with recurrent major depressive episodes showed more repetitive thoughts about negative issues and avoidance from internal and external aversive events when depressive mood was induced, compared to participants with only a single episode of depression. These results suggest that the characteristics of cognitive reactivity are important considerations for preventing relapse of depression. PMID- 24804429 TI - [Effect of positive and negative instances on rule discovery: investigation using eye tracking]. AB - This study investigated how participants would reject an initial rule when they faced positive and negative instances of an initial rule. Using eye movement data, we analyzed a perspective that indicated the type of rules that participants consider. Our experiments yielded the following results. A tendency to consider rules from the perspective that participants used for finding and confirming the initial rule was retained in the phase in which both positive and negative instances of the initial rule were given. This tendency was observed only when participants faced negative instances. We concluded that, when participants faced negative instances, they tried to change the initial rule peripherally to explain them. PMID- 24804430 TI - [Development and validation of the Japanese version of the Self-Compassion Scale]. AB - A Japanese version of the Self-Compassion Scale (SCS-J) was developed. In Survey 1, confirmatory factor analysis of data from 366 participants indicated that the SCS-J had an acceptable fit to the model, as well as good internal consistency, similar to the original. In Survey 2, a test-retest correlation of the SCS-J for 101 participants indicated good reliability for the scale. In Survey 3, 148 participants completed the SCS-J and the Narcissistic Personality Inventory, the Subjective Happiness Scale, the State-Trait Anxiety Inventory-Trait form, and the Beck Depression Inventory. The partial correlations between the SCS-J and the other scales were analyzed, using self-esteem, or self-criticism as the control variables. The results demonstrated that self-compassion was associated with self esteem and the mental health of the Japanese participants. These results indicate that the SCS-J has good reliability and validity as a measure of self-compassion. PMID- 24804431 TI - [Assessment of working memory capacity with a Japanese version of the Operation Span Test]. AB - The Operation Span Test (OSPAN) is widely used to assess working memory capacity. However, this instrument has been rarely used to test Japanese participants because its task was not sufficiently difficult. The mean score for the original computerized OSPAN often reached a ceiling when Japanese participants were tested. In this study, we developed a computerized version of OSPAN for Japanese participants by increasing the task difficulty of the arithmetic procedures. The OSPAN scores were normally distributed and the mean score was approximately 50%. There were positive correlations between OSPAN scores and other scores of working memory measurements, such as a reading span test and a digit span test. These results suggest that the Japanese OSPAN is a reliable and valid measurement of working memory to test Japanese participants. PMID- 24804432 TI - [The Hedonic and Eudaimonic Motives for Activities (HEMA) in Japan: the pursuit of well-being]. AB - Hedonia (seeking pleasure and relaxation) and eudaimonia (seeking to improve oneself in congruence with one's values) uniquely contribute to well-being. The authors developed and tested the construct validity of a Japanese version of the Hedonic and Eudaimonic Motives for Activities (HEMA) scale that had been originally developed in North America. Drawing on the theoretical and empirical evidence from research on emotion, we proposed that people would pursue well being in three different directions: pleasure, relaxation, and eudaimonia. In Study 1, we used the original HEMA scale to examine the Japanese attainment of well-being. The results supported the hypothesized three-factor model. Study 2 revealed that the Japanese version of the HEMA scale measured pleasure, relaxation, and eudaimonia. Each of these subscales showed statistically sufficient internal consistency. There was no gender difference in any of these measures. Scores on the scale systematically corresponded with external criterion variables, such as life satisfaction, affect, Ryff's psychological well-being, social support, and lifestyle. Implications for psychological research and public policies that cover the topic of the pursuit of well-being are discussed. PMID- 24804433 TI - [The relationship between narcissistic personality traits and risk-taking behavior is mediated by self-monitoring]. AB - This study investigated the hypothesis that narcissistic personality traits would affect risk-taking behaviors through self-monitoring. The Narcissistic Personality Inventory Short Version (NPI-S), the Self-monitoring Scale (SM), and the Risk-taking Behavior Scale for Undergraduates (RIBS-U) were administered to 192 university and graduate students. There were three NPI-S factors ("sense of superiority and competence", "need for attention and praise", and "self assertion"), two SM factors ("extraversion" and "other-directedness"), and the single risk-taking factor of the RIBS-U. Covariance structure analysis was then conducted to test whether narcissistic personality traits would affect risk taking behaviors through self-monitoring. Analysis showed that the factors of "sense of superiority and competence" and "need for attention and praise" affected risk-taking behavior through the "other-directedness" factor. However, the "self-assertion" factor was found to have a direct effect on risk-taking behavior. PMID- 24804434 TI - [The effect of interpersonal dependency on judgment of gaze direction]. AB - This study investigated the effect of interpersonal dependency on judgments of gaze direction of individuals with different facial expressions. Based on interpersonal dependency scores, 46 participants were divided into two groups (high interpersonal dependency and low interpersonal dependency). Participants judged the gaze direction of photographs of faces with angry, neutral or happy expressions. Relative to the low interpersonal dependency group, the high interpersonal dependency group was more accurate in the judgments of gaze direction. This tendency was more salient for the happy and neutral expressions than for the angry expressions. Since people with high interpersonal dependency are highly motivated to seek support from others, this result suggests that they are sensitive to signals with pro-social information such as the gaze direction of others with positive attitudes. PMID- 24804435 TI - [Relationships between explicit/implicit self-esteem discrepancy and measures of depression, loneliness, and in-group favoritism]. AB - The present study focused on the discrepancy between explicit self-esteem and implicit self-esteem, using the Name Letter Task with 86 graduate students. In line with suggestions from previous research, participants high in explicit self esteem but low implicit self-esteem (called "defensive high self-esteem") showed higher in-group favoritism than participants who had high explicit and implicit self-esteem (called "secure high self-esteem"). Participants with defensive self esteem reported higher levels of depression than secure self-esteem participants. These results strengthen the generalizability for the conceptualizations of "defensive" and "secure" high self-esteem. However, participants with low self esteem did not show significant interactions with any variables. PMID- 24804436 TI - [A test of the strong reciprocity model: relationship between cooperation and punishment]. AB - The strong reciprocity model of human cooperation (SRM) argues that strong reciprocators, who cooperate with others and punish non-cooperators, sustain within-group cooperation. However, the assumption that altruism and punishment are products of the same psychological mechanism of strong reciprocity has not been fully verified. Second-party punishment, for example as measured through rejection of unfair offers in the ultimatum game, has been demonstrated to have no relationship with cooperation in the prisoner's dilemma and other games. In this study, we tested the assumption of the SRM by comparing the participants' levels of cooperation in the prisoner's dilemma game and their inclination for punishment in a third-party punishment game. Non-student recruited from the general population (N = 182) participated in the study. The results show a weak but positive correlation between cooperation and third-party punishment, which is consistent with the SRM model. PMID- 24804437 TI - Evidence of maternal provisioning of alkaloid-based chemical defenses in the strawberry poison frog Oophaga pumilio. AB - Many organisms use chemical defenses to reduce predation risk. Aposematic dendrobatid frogs sequester alkaloid-based chemical defenses from a diet of arthropods, but research on these defenses has been limited to adults. Herein, we investigate chemical defense across development in a dendrobatid frog, Oophaga pumilio. This species displays complex parental care: at hatching, mothers transport tadpoles to phytotelmata, and then return to supply them with an obligate diet of nutritive eggs for about six weeks. We collected eggs, tadpoles, juveniles, and adults of O. pumilio, and detected alkaloids in all life stages. The quantity and number of alkaloids increased with frog and tadpole size. We did not detect alkaloids in the earliest stage of tadpoles, but alkaloids were detected as trace quantities in nutritive eggs and as small quantities in ovarian eggs. Tadpoles hand-reared with eggs of an alkaloid-free heterospecific frog did not contain alkaloids. Alkaloids that are sequestered from terrestrial arthropods were detected in both adults and phytotelm-dwelling tadpoles that feed solely on nutritive eggs, suggesting that this frog may be the first animal known to actively provision post-hatch offspring with chemical defenses. Finally, we provide experimental evidence that maternally derived alkaloids deter predation of tadpoles by a predatory arthropod. PMID- 24804438 TI - Predicting how altering propagule pressure changes establishment rates of biological invaders across species pools. AB - Biological invasions resulting from international trade can cause major environmental and economic impacts. Propagule pressure is perhaps the most important factor influencing establishment, although actual arrival rates of species are rarely recorded. Furthermore, the pool of potential invaders includes many species that vary in their arrival rate and establishment potential. Therefore, we stress that it is essential to consider the size and composition of species pools arriving from source regions when estimating probabilities of establishment and effects of pathway infestation rates. To address this, we developed a novel framework and modeling approach to enable prediction of future establishments in relation to changes in arrival rate across entire species pools. We utilized 13 828 border interception records from the United States and New Zealand for 444 true bark beetle (Scolytinae) and longhorned beetle (Cerambycidae) species detected between 1949 and 2008 as proxies for arrival rates to model the relationship between arrival and establishment rates. Nonlinearity in this relationship implies that measures intended to reduce the unintended transport of potential invaders (such as phytosanitary treatments) must be highly effective in order to substantially reduce the rate of future invasions, particularly if trade volumes continue to increase. PMID- 24804439 TI - Permafrost degradation stimulates carbon loss from experimentally warmed tundra. AB - A large pool of organic carbon (C) has been accumulating in the Arctic for thousands of years because cold and waterlogged conditions have protected soil organic material from microbial decomposition. As the climate warms this vast and frozen C pool is at risk of being thawed, decomposed, and released to the atmosphere as greenhouse gasses. At the same time, some C losses may be offset by warming-mediated increases in plant productivity. Plant and microbial responses to warming ultimately determine net C exchange from ecosystems, but the timing and magnitude of these responses remain uncertain. Here we show that experimental warming and permafrost (ground that remains below 0 degrees C for two or more consecutive years) degradation led to a two-fold increase in net ecosystem C uptake during the growing season. However, warming also enhanced winter respiration, which entirely offset growing-season C gains. Winter C losses may be even higher in response to actual climate warming than to our experimental manipulations, and, in that scenario, could be expected to more than double overall net C losses from tundra to the atmosphere. Our results highlight the importance of winter processes in determining whether tundra acts as a C source or sink, and demonstrate the potential magnitude of C release from the permafrost zone that might be expected in a warmer climate. PMID- 24804440 TI - P values, hypothesis testing, and model selection: it's deja vu all over again. PMID- 24804442 TI - The common sense of P values. PMID- 24804441 TI - In defense of P values. AB - Statistical hypothesis testing has been widely criticized by ecologists in recent years. I review some of the more persistent criticisms of P values and argue that most stem from misunderstandings or incorrect interpretations, rather than from intrinsic shortcomings of the P value. I show that P values are intimately linked to confidence intervals and to differences in Akaike's information criterion (deltaAIC), two metrics that have been advocated as replacements for the P value. The choice of a threshold value of deltaAIC that breaks ties among competing models is as arbitrary as the choice of the probability of a Type I error in hypothesis testing, and several other criticisms of the P value apply equally to deltaAIC. Since P values, confidence intervals, and deltaAIC are based on the same statistical information, all have their places in modern statistical practice. The choice of which to use should be stylistic, dictated by details of the application rather than by dogmatic, a priori considerations. PMID- 24804443 TI - To P or not to P? PMID- 24804444 TI - P values are only an index to evidence: 20th- vs. 21st-century statistical science. AB - Early statistical methods focused on pre-data probability statements (i.e., data as random variables) such as P values; these are not really inferences nor are P values evidential. Statistical science clung to these principles throughout much of the 20th century as a wide variety of methods were developed for special cases. Looking back, it is clear that the underlying paradigm (i.e., testing and P values) was weak. As Kuhn (1970) suggests, new paradigms have taken the place of earlier ones: this is a goal of good science. New methods have been developed and older methods extended and these allow proper measures of strength of evidence and multimodel inference. It is time to move forward with sound theory and practice for the difficult practical problems that lie ahead. Given data the useful foundation shifts to post-data probability statements such as model probabilities (Akaike weights) or related quantities such as odds ratios and likelihood intervals. These new methods allow formal inference from multiple models in the a prior set. These quantities are properly evidential. The past century was aimed at finding the "best" model and making inferences from it. The goal in the 21st century is to base inference on all the models weighted by their model probabilities (model averaging). Estimates of precision can include model selection uncertainty leading to variances conditional on the model set. The 21st century will be about the quantification of information, proper measures of evidence, and multi-model inference. Nelder (1999:261) concludes, "The most important task before us in developing statistical science is to demolish the P value culture, which has taken root to a frightening extent in many areas of both pure and applied science and technology". PMID- 24804445 TI - Model selection for ecologists: the worldviews of AIC and BIC. PMID- 24804446 TI - In defense of P values: comment on the statistical methods actually used by ecologists. PMID- 24804447 TI - Comment on Murtaugh. AB - Murtaugh and I agree on an important point: abandon accept/reject declarations. That alone will go a long way to improving statistical practice. (2) Don't confuse P values or deltaAIC with binary declarations. An argument against one is not necessarily an argument against the other. (3) Be careful interpreting a P value or deltaAIC as strength of evidence. That interpretation cannot be made formal and the connection between P, deltaAIC, and evidence must be recalibrated for each new problem. (4) Plot. Check models. Plot. Check assumptions. Plot. PMID- 24804448 TI - Recurring controversies about P values and confidence intervals revisited. AB - The paper focused primarily on certain charges, claims, and interpretations of the P value as they relate to CIs and the AIC. It as argued that some of these comparisons and claims are misleading because they ignore key differences in the procedures being compared, such as (1) their primary aims and objectives, (2) the nature of the question posed to the data, as well as (3) the nature of their underlying reasoning and the ensuing inferences. In the case of the P value, the crucial issue is whether Fisher's evidential interpretation of the P value as "indicating the strength of evidence against H0" is appropriate. It is argued that, despite Fisher's maligning of the Type II error, a principled way to provide an adequate evidential account, in the form of post-data severity evaluation, calls for taking into account the power of the test. The error statistical perspective brings out a key weakness of the P value and addresses several foundational issues raised in frequentist testing, including the fallacies of acceptance and rejection as well as misinterpretations of observed CIs: see Mayo-Spanos (2011). The paper also uncovers the connection between model selection procedures and hypothesis testing, revealing the inherent unreliability of the former. Hence, the choice between different procedures should not be "stylistic" (Murtaugh 2013), but should depend on the questions of interest, the answers sought, and the reliability of the procedures. PMID- 24804449 TI - Rejoinder. PMID- 24804450 TI - Discontinuities, cross-scale patterns, and the organization of ecosystems. AB - Ecological structures and processes occur at specific spatiotemporal scales, and interactions that occur across multiple scales mediate scale-specific (e.g., individual, community, local, or regional) responses to disturbance. Despite the importance of scale, explicitly incorporating a multi-scale perspective into research and management actions remains a challenge. The discontinuity hypothesis provides a fertile avenue for addressing this problem by linking measureable proxies to inherent scales of structure within ecosystems. Here we outline the conceptual framework underlying discontinuities and review the evidence supporting the discontinuity hypothesis in ecological systems. Next we explore the utility of this approach for understanding cross-scale patterns and the organization of ecosystems by describing recent advances for examining nonlinear responses to disturbance and phenomena such as extinctions, invasions, and resilience. To stimulate new research, we present methods for performing discontinuity analysis, detail outstanding knowledge gaps, and discuss potential approaches for addressing these gaps. PMID- 24804451 TI - Assessing nutrient limitation in complex forested ecosystems: alternatives to large-scale fertilization experiments. AB - Quantifying nutrient limitation of primary productivity is a fundamental task of terrestrial ecosystem ecology, but in a high carbon dioxide environment it is even more critical that we understand potential nutrient constraints on plant growth. Ecologists often manipulate nutrients with fertilizer to assess nutrient limitation, yet for a variety of reasons, nutrient fertilization experiments are either impractical or incapable of resolving ecosystem responses to some global changes. The challenges of conducting large, in situ fertilization experiments are magnified in forests, especially the high-diversity forests common throughout the lowland tropics. A number of methods, including fertilization experiments, could be seen as tools in a toolbox that ecologists may use to attempt to assess nutrient limitation, but there has been no compilation or synthetic discussion of those methods in the literature. Here, we group these methods into one of three categories (indicators of soil nutrient supply, organismal indicators of nutrient limitation, and lab-based experiments and nutrient depletions), and discuss some of the strengths and limitations of each. Next, using a case study, we compare nutrient limitation assessed using these methods to results obtained using large scale fertilizations across the Hawaiian Archipelago. We then explore the application of these methods in high-diversity tropical forests. In the end, we suggest that, although no single method is likely to predict nutrient limitation in all ecosystems and at all scales, by simultaneously utilizing a number of the methods we describe, investigators may begin to understand nutrient limitation in complex and diverse ecosystems such as tropical forests. In combination, these methods represent our best hope for understanding nutrient constraints on the global carbon cycle, especially in tropical forest ecosystems. PMID- 24804452 TI - Exotic plant invasions under enhanced rainfall are constrained by soil nutrients and competition. AB - To predict the net impact of climate change on invasions, it is critical to understand how its effects interact with environmental and biotic context. In a factorial field experiment, we examined how increased late-season rainfall influences the growth and reproductive success of two widespread invasive species (Centaurea solstitialis and Aegilops triuncialis) in heterogeneous Californian grasslands, and, in particular, how its impact depends on habitat type, nutrient addition, and competition with resident species. Rainfall enhancement alone exhibited only weak effects, especially in naturally infertile and relatively uninvaded grasslands. In contrast, watering and fertilization together exhibited highly synergistic effects on both invasive species. However, the benefits of the combined treatment were greatly reduced or offset by the presence of surrounding competitors. Our results highlight the roles of nutrient limitation and biotic resistance by resident competitors in constraining the responses of invasive species to changes in rainfall. In systems with strong environmental control by precipitation, enhanced rainfall may promote invasions mainly under nutrient-rich and disturbed conditions, while having lesser effects on nutrient-poor, native "refuges". PMID- 24804453 TI - An ecological regime shift resulting from disrupted predator-prey interactions in Holocene Australia. AB - The mass extinction events during human prehistory are striking examples of ecological regime shifts, the causes of which are still hotly debated. In Australia, human arrival approximately 50 thousand years ago was associated with the continental-scale extinction of numerous marsupial megafauna species and a permanent change in vegetation structure. An alternative stable state persisted until a second regime shift occurred during the late Holocene, when the largest two remaining marsupial carnivores, the thylacine and devil, disappeared from mainland Australia. These extinctions have been widely attributed to the human assisted invasion of a competing predator, the dingo. In this unusual case, the simultaneous effects of human "intensification" (population growth and technological advances) and climate change (particularly increased ENSO variability) have been largely overlooked. We developed a dynamic model system capable of simulating the complex interactions between the main predators (humans, thylacines, devils, dingoes) and their marsupial prey (macropods), which we coupled with reconstructions of human population growth and climate change for late-Holocene Australia. Because the strength of important interspecific interactions cannot be estimated directly, we used detailed scenario testing and sensitivity analysis to identify robust model outcomes and investigate competing explanations for the Holocene regime shift. This approach identified human intensification as the most probable cause, while also demonstrating the potential importance of synergies with the effects of climate change. Our models indicate that the prehistoric impact of humans on Australian mammals was not limited to the late Pleistocene (i.e., the megafaunal extinctions) but extended into the late Holocene. PMID- 24804454 TI - Genotype and spatial structure shape pathogen dispersal and disease dynamics at small spatial scales. AB - Many devastating pathogens are passively dispersed, and their epidemics are characterized by variation that is typically attributed to environmental factors. Here, by combining laboratory inoculations with wind tunnel and field trials using the wind-dispersed pathogen Podosphaera plantaginis, we demonstrated striking genetic variation affecting the unexplored microscale (< 2 m) of epidemics. Recipient and source host genotypes, as well as pathogen strain, explained a large fraction of variation in the three key dispersal phases: departure, movement, and settlement. Moreover, we found genotypic variation affecting group size of the pathogen dispersal unit, ultimately resulting in increased disease development on hosts close to the infection source. Together, our results show that genotypic variation may generate considerable variation in the rate of disease spread through space and time with disease hotspots emerging around initial foci. Furthermore, the extent of genetic variation affecting the entire dispersal process confirms that these traits may be targeted by selection. PMID- 24804455 TI - Groundwater discharge creates hotspots of riparian plant species richness in a boreal forest stream network. AB - Riparian vegetation research has traditionally focused on channel-related processes because riparian areas are situated on the edge of aquatic ecosystems and are therefore greatly affected by the flow regime of streams and rivers. However, due to their low topographic position in the landscape, riparian areas receive significant inputs of water and nutrients from uplands. These inputs may be important for riparian vegetation, but their role for riparian plant diversity is poorly known. We studied the relationship between the influx of groundwater (GW) from upland areas and riparian plant diversity and composition along a stream size gradient, ranging from small basins lacking permanent streams to a seventh-order river in northern Sweden. We selected riparian sites with and without GW discharge using a hydrological model describing GW flow accumulation to test the hypothesis that riparian sites with GW discharge harbor plant communities with higher species richness. We further investigated several environmental factors to detect habitat differences between sites differing in GW discharge conditions. Vascular plant species richness was between 15% and 20% higher, depending on the spatial scale sampled, at riparian sites with GW discharge in comparison to non-discharge sites, a pattern that was consistent across all stream sizes. The elevated species richness was best explained by higher soil pH and higher nitrogen availability (manifested as lower soil C/N ratio), conditions which were positively correlated with GW discharge. Base cations and possibly nitrogen transported by groundwater may therefore act as a terrestrial subsidy of riparian vegetation. The stable isotopes 15N and 13C were depleted in soils from GW discharge compared to non-discharge sites, suggesting that GW inputs might also affect nitrogen and carbon dynamics in riparian soils. Despite the fact that many flows of water and nutrients reaching streams are filtered through riparian zones, the importance of these flows for riparian vegetation has not been appreciated. Our results demonstrated strong relationships between GW discharge, plant species richness and environmental conditions across the entire stream size gradient, suggesting that both river hydrology and upland inputs should be considered to fully understand riparian vegetation dynamics. PMID- 24804456 TI - Phenology effects on invasion success: insights from coupling field experiments to coexistence theory. AB - Ecologists have identified a growing number of functional traits that promote invasion. However, whether trait differences between exotic and native species promote invasion success by enhancing niche differences or giving invaders competitive advantages is poorly understood. We explored the mechanisms by which phenology determines invasion success in a California annual plant community by quantifying how the seasonal timing of growth relates to niche differences that stabilize coexistence, and the competitive ability differences that drive dominance and exclusion. We parameterized models of community dynamics from experimentally assembled annual communities in which exotic plants displayed earlier, coincident, or later phenology than native residents. Using recent theoretical advances from the coexistence literature, we found that differences in phenology promote stabilizing niche differences between exotic and native species. However, phenology was more strongly related to competitive ability differences, allowing later invaders to outcompete earlier native competitors and native residents to outcompete earlier invaders in field experiments. Few of these insights could be inferred by comparing the competitive outcomes across invaders, highlighting the need to quantify niche and competitive ability differences when disentangling how species differences drive invasion success. PMID- 24804457 TI - Combined effects of climate, resource availability, and plant traits on biomass produced in a Mediterranean rangeland. AB - Biomass production in grasslands, a key component of food provision for domestic herbivores, is known to depend on climate, resource availability, and on the functional characteristics of communities. However, the combined effects of these different factors remain largely unknown. The aim of the present study was to unravel the causes of variations in the standing biomass of plant communities using a long-term experiment conducted in a Mediterranean rangeland of Southern France. Two management regimes, sheep grazing and grazing associated with mineral fertilization, were applied to different areas of the study site over the past 25 years. Abiotic (temperature, available water, nutrients) and biotic (components of the functional structure communities) factors were considered to explain interannual and spatial variations in standing biomass in these rangelands. Standing biomass was highly predictable, with the best model explaining -80% of variations in the amount of biomass produced, but the variation explained by abiotic and biotic factors was dependent on the season and on the management regime. Abiotic factors were found to have comparable effects in both management regimes: The amount of biomass produced in the spring was limited by cold temperatures, while it was limited by water availability and high temperatures in the summer. In the fertilized community, the progressive change in the functional structure of the communities had significant effects on the amount of biomass produced: the dominance of few productive species which were functionally close led to higher peak standing biomass in spring. PMID- 24804458 TI - Priming in the microbial landscape: periphytic algal stimulation of litter associated microbial decomposers. AB - Microbial communities associated with submerged detritus in aquatic ecosystems often comprise a diverse mixture of autotrophic and heterotrophic microbes, including algae, bacteria, protozoa, and fungi. Recent studies have documented increased rates of plant litter mass loss when periphytic algae are present. We conducted laboratory and field experiments to assess potential metabolic interactions between natural autotrophic and heterotrophic microbial communities inhabiting submerged decaying plant litter of Typha angustifolia and Schoenoplectus acutus. In the field, submerged plant litter was either exposed to natural sunlight or placed under experimental canopies that manipulated light availability and growth of periphytic algae. Litter was collected and returned to the laboratory, where algal photosynthesis was manipulated (light/dark incubation), while rates of bacterial and fungal growth and productivity were simultaneously quantified. Bacteria and fungi were rapidly stimulated by exposure to light, thus establishing the potential for algal priming of microbial heterotrophic decay activities. Experimental incubations of decaying litter with 14C- and 13C-bicarbonate established that inorganic C fixed by algal photosynthesis was rapidly transferred to and assimilated by heterotrophic microbial decomposers. Periphytic algal stimulation of microbial heterotrophs, especially fungal decomposers, is an important and largely unrecognized interaction within the detrital microbial landscape, which may transform our current conceptual understanding of microbial secondary production and organic matter decomposition in aquatic ecosystems. PMID- 24804459 TI - Modeling effects of climate change and phase shifts on detrital production of a kelp bed. AB - The exchange of energy and nutrients between ecosystems (i.e., resource subsidies) plays a central role in ecological dynamics over a range of spatial and temporal scales. Little attention has been paid to the role of anthropogenic impacts on natural systems in altering the magnitude, timing, and quality of resource subsidies. Kelp ecosystems are highly productive on a local scale and export over 80% of kelp primary production as detritus, subsidizing consumers across broad spatial scales. Here, we generate a model of detrital production from a kelp bed in Nova Scotia to hindcast trends in detrital production based on temperature and wave height recorded in the study region from 1976 to 2009, and to project changes in detrital production that may result from future climate change. Historical and projected increases in temperature and wave height led to higher rates of detrital production through increased blade breakage and kelp dislodgment from the substratum, but this reduced kelp biomass and led to a decline in detrital production in the long-term. We also used the model to demonstrate that the phase shift from a highly productive kelp bed to a low productivity barrens, driven by the grazing activity of sea urchins, reduces kelp detrital production by several orders of magnitude, an effect that would be exacerbated by projected increases in temperature and wave action. These results indicate that climate-mediated changes in ecological dynamics operating on local scales may alter the magnitude of resource subsidies to adjacent ecosystems, affecting ecological dynamics on regional scales. PMID- 24804460 TI - Phenotypic and phylogenetic evidence for the role of food and habitat in the assembly of communities of marine amphipods. AB - The study of community assembly processes currently involves (a) longstanding questions about the relative importance of environmental filtering vs. niche partitioning in a wide range of ecosystems, and (b) more recent questions about methodology. The rapidly growing field of community phylogenetics has generated debate about the choice between functional traits and phylogenetic relationships for understanding species similarities, and has raised additional questions about the contribution of experimental vs. observational approaches to understanding evolutionary constraints on community assembly. In this study, we use traits, a phylogeny, and field surveys to identify the forces structuring communities of herbivorous marine amphipods and isopods living in adjacent seagrass and macroalgae. In addition, we compare our field results to a recently published mesocosm experiment that tested the effects of both trait and phylogenetic diversity on coexistence using the same species and system. With respect to community assembly processes, we found that environmental filtering was the dominant process in macroalgae habitats, that niche partitioning was the dominant process in seagrass habitats, and that the strength of these assembly mechanisms varied with seasonal fluctuations in environmental conditions and resource availability. These patterns are indicated by both phylogenetic relationships and trait distances, but the type of resources being partitioned in seagrass habitats can only be deciphered using trait data. Species coexisting in seagrass in the field differed not in their feeding niche but in traits related to microhabitat use, providing novel evidence of the relative importance of competition for food vs. habitat in structuring communities of phytophagous invertebrates. With respect to methodology, the results for seagrass habitats conflict with those obtained in mesocosms, where feeding trait diversity did promote coexistence and phylogenetic diversity had no effect. This contrast arises because a greater range of traits (some of which have much stronger phylogenetic signal than feeding traits) contribute to community assembly in the field. This highlights a mismatch between the processes that drive community assembly in the field and the processes we isolated in experimental tests, and illustrates that using phylogeny as a single proxy in both contexts may impede the synthesis of observational and experimental results. PMID- 24804461 TI - Neutron diffraction analysis of residual stresses near unannealed welds in anhydrous ammonia nurse tanks. AB - Neutron diffraction analysis was employed to measure residual stresses near welds in used anhydrous ammonia nurse tanks. Tensile residual stresses contribute to stress corrosion cracking of nurse tanks, which can cause tanks to release toxic ammonia vapor. The analysis showed that tensile residual stresses were present in the tanks measured, and the magnitudes of these stresses approached the yield strength of the steel. Implications for agricultural safety and health are discussed. PMID- 24804462 TI - Dine (Navajo) parents' and community leaders' perceptions of agriculture-related injury risk to youth: a social narrative. AB - The purpose of this study was to provide a formative needs assessment of Dine (Navajo) parents for the prevention of childhood injuries resulting from livestock and horses. The research objectives were to identify parents' perceived livestock and horse related injury risks to Dine children and describe Dine community stakeholder input on prevention interventions for reducing injury risks to children associated with livestock and horse related activities on farms or ranches. The assessment used a survey constructed of closed and open-response questions to gauge Dine farmers' and ranchers' perceptions of injury risks to children who live or work on agricultural operations. Additional questions were asked to gauge Dine acceptance of an online training program as a prevention intervention to reduce livestock and horse related injuries to children. A total of 96 individuals agreed to participate in the survey and provided usable responses. A total of 53.2% (f = 50) of participants were female. Sixty-three percent of participants (f = 58) perceived that youth who work with intact male livestock were at high risk for injury. A total of 25 individuals perceived that youth who ride horses without equestrian helmets were at high risk for injury. Approximately 96% (f = 89) of those surveyed agreed or strongly agreed that they would use an online training program to promote agricultural health and safety for Dine youth. When participants were asked if there were safety issues associated with having youth working on a farm or ranch, a very large portion felt that the biggest issue was a lack of education and instruction from elders. A recommendation for an injury prevention practice included developing a user friendly online network, giving parents and community leaders access to resources to assist in educating youth in local agricultural traditions integrated with safety training. PMID- 24804463 TI - Why quad bike safety is a wicked problem: an exploratory study of attitudes, perceptions, and occupational use of quad bikes in northern Queensland, Australia. AB - Quad bike safety represents the quintessential wicked problem. To address this wicked problem, this research explores the use of quad bikes in the northwestern region of outback Queensland, Australia, concentrating efforts on the pastoral industry. Focus groups and interviews were conducted with pastoralists, farmers, retailers, repairers, healthcare professionals, and regulators. The discussions revealed the diverse activities currently undertaken in the region's pastoral enterprises while riding a quad bike, and that attitudes toward the purchase and use of quad bikes vary and may be influenced by retailers. Perceptions of risk and safety in the use of quad bikes in occupational settings also varied. The findings from this study provide insight into the decisions of local pastoralists and agriculturalists to use quad bikes in their workplaces, and attitudes toward safety and injury prevention relating to quad bike use in these industries in northwestern outback Queensland. This study is the first step toward understanding quad bike use in this region, with the goal of reducing injury and death, and will be used in policy and legislation development regarding the use and safety of quad bikes in Australia. PMID- 24804464 TI - A qualitative analysis of power take-off driveline shields: barriers and motivators to shield use for New York State farmers. AB - Machinery entanglements are one of the top three causes of death in farming. Education on the risks of unshielded power take-off (PTO) equipment does not appear to significantly alter farmers' willingness to replace missing or broken shielding. Different assessments conducted in various regions of the U.S. indicate that as many as one-third to one-half of PTOs are inadequately shielded. Qualitative research was conducted with New York farmers to identify the factors that influence the decision to replace damaged or missing PTO driveline shields. Interview topics included: knowledge of entanglement risks, decisions regarding safety in general, decisions relating to PTO driveline shielding specifically, and the barriers and motivators to replacing missing or broken PTO driveline shields. Interviews with 38 farmers revealed the following themes: (1) farmers are fully aware of PTO entanglement risk, (2) insufficient time and money are primary barriers to purchasing or replacing damaged or missing PTO driveline shields, (3) PTO driveline shield designs are problematic and have led to negative experiences with shielding, and (4) risk acceptance and alternate work strategies are preferred alternatives to replacing shields. Our findings indicate that more innovative approaches will be required to make PTO driveline shield use a viable and attractive choice for farmers. New shield designs that address the practical barriers farmers face, as well as the provision of logistical and financial assistance for shield replacement, may alter the decision environment sufficiently to make replacing PTO driveline shielding a more attractive option for farmers. PMID- 24804465 TI - [Interethnic analyses of distributions in children and adolescents mental disorders in a health care utilization]. AB - The study examines ethnic differences in mental disorders in a child and adolescent psychiatry population in a major German city from 2007 to 2011 (N = 5,680). Risks of developing specific mental disorders were calculated. African migrant children and adolescents showed higher risk in traumatic stress and adjustment disorders (F 43 in ICD-10), the Asiatic group in dissociative disorders (F 44-45). Compared to other European migrants the German children and adolescents without migration background had a higher risk of affective disorders (F 3). Adolescents (N = 3,556) with Russian and Polish background had a higher risk of disorders induced by psychotropic substances (F 1). Turkish and Arabic adolescents had a 4- to 5-times increasing risk in schizophrenia as well as schizotypal or delusional disorders (F 2). In addition, mental disorders were influenced by gender and nationality. These study results suggest that a different vulnerability to specific mental disorders is associated to ethnicity. PMID- 24804466 TI - [Differential indication and interventions in early support systems for young families]. AB - Networks of support for young families are established nationwide in Germany in the last years. It is shown that a coordinated approach--in the cooperation between health system and youth welfare system--is very important. The different programs to promote parental educational competencies or to foster parent-child interaction should be integrated in these systems. This article presents the results of the evaluation of one specific regional network ("Netzwerk Fruhe Hilfen im Ortenaukreis", Baden-Wurttemberg); the differential interventions were focused. Three different types of families could be identified empirically and it was possible to describe specific professional intervention strategies for these family-types. PMID- 24804467 TI - [Psychoanalytic single case studies of children and adolescents: characterisation with the "Inventory of Basic Information in Single Cases"]. AB - Right from its beginning single case studies on children and adolescents have been an highly esteemed means of communication in psychoanalysis; from the view of treatment research time and again critical arguments are brought forward. As single case studies may provide relevant answers for detailed process aspects, in this study we present a methodology for systematizing the reporting culture. PMID- 24804468 TI - Oral and maxillofacial pathology case of the month. Stafne defect (lingual mandibular bone depression). PMID- 24804469 TI - The JFK assassination from a dental perspective: an interview with an oral and maxillofacial surgeon--Jack Bolton, DDS, MSD--by T. Campbell Bourland. PMID- 24804470 TI - Restorative material and other tooth-specific variables associated with the decision to repair or replace defective restorations: findings from the dental PBRN. AB - OBJECTIVES: Using data from dentists participating in The Dental Practice-Based Research Network (DPBRN), the study had 2 main objectives: (1) to identify and quantify the types of restorative materials in the existing failed restorations; and (2) to identify and quantify the materials used to repair or replace those failed restorations. METHODS: This cross-sectional study used a consecutive patient/restoration recruitment design. Practitioner-investigators recorded data on consecutive restorations in permanent teeth that needed repair or replacement. Data included the primary reason for repair or replacement, tooth surface(s) involved, restorative materials used, and patient demographics. RESULTS: Data for 9,875 restorations were collected from 7,502 patients in 197 practices for which 75% of restorations were replaced and 25% repaired. Most of the restorations that were either repaired or replaced were amalgam (56%) for which most (56%) of the material used was direct tooth-colored. The restorative material was 5 times more likely to be changed when the original restoration was amalgam (OR = 5.2, p < .001). The likelihood of changing an amalgam restoration differed as a function of the tooth type (OR = 3.0, p < .001), arch (OR = 6.6, p < .001); and number of surfaces in the original restoration (OR = 12.2, p < .001). CONCLUSION: The probability of changing from amalgam to another restorative material differed with several characteristics of the original restoration. The change was most likely to take place when (1) the treatment was a replacement; (2) the tooth was not a molar; (3) the tooth was in the maxillary arch; and (4) the original restoration involved a single surface. PMID- 24804472 TI - Social media: why your practice needs to pay attention to digital moms. PMID- 24804471 TI - Electrical pulp testing has not been shown to be superior to cold test in diagnosing pulp vitality (UT CAT #2533). PMID- 24804473 TI - The challenges of COMPLIANCE: dentists in the eye of the storm. PMID- 24804474 TI - [Application of semi-supervised sparse representation classifier based on help training in EEG classification]. AB - Electroencephalogram (EEG) classification for brain-computer interface (BCI) is a new way of realizing human-computer interreaction. In this paper the application of semi-supervised sparse representation classifier algorithms based on help training to EEG classification for BCI is reported. Firstly, the correlation information of the unlabeled data is obtained by sparse representation classifier and some data with high correlation selected. Secondly, the boundary information of the selected data is produced by discriminative classifier, which is the Fisher linear classifier. The final unlabeled data with high confidence are selected by a criterion containing the information of distance and direction. We applied this novel method to the three benchmark datasets, which were BCI I, BCI II_IV and USPS. The classification rate were 97%, 82% and 84.7%, respectively. Moreover the fastest arithmetic rate was just about 0. 2 s. The classification rate and efficiency results of the novel method are both better than those of S3VM and SVM, proving that the proposed method is effective. PMID- 24804475 TI - [DWI LMMSE denoising using multiple magnitude directions]. AB - Because of the long acquisition time and spin-echo planar imaging sequence, diffusion weight magnetic resonance image (DWI) should be denoised effectively to ensure the follow-up applications. The commonly used denoising methods which induced from gray level image lack the use of the specific information from multiple magnitude directions. This paper, therefore, proposes a modified linear minimum mean square error (LMMSE) denosing method used for DWI. The proposed method uses the local information to estimate the parameter of the Rician noise and modifies the LMMSE using the information of multiple magnitude directions synthetically. The simulation and experiment of the synthetic DWI and real human brain DWI dataset demonstrate that the proposed method can more effectively remove the Rician noise compared to the commonly used denoising method and improve the robustness and validity of the diffusion tensor magnetic resonance image (DTI). PMID- 24804476 TI - [Testing method of human body's current threshold for perception based on EEG analysis]. AB - Electric and electronic products are required to pass through the certification on electrical safety performance before entering into the market in order to reduce electrical shock and electrical fire so as to protect the safety of people and property. The leakage current is the most important factor in testing the electrical safety performance and the test theory is based on the perception current effect and threshold. The traditional method testing the current threshold for perception only depends on the sensing of the human body and is affected by psychological factors. Some authors filter the effect of subjective sensation by using physiological and psychological statistical algorithm in recent years and the reliability and consistency of the experiment data are improved. We established an experiment system of testing the human hody's current threshold for perception based on EEG feature analysis, and obtained 967 groups of data. We used wavelet packet analysis to detect a wave from EEG, and used FFT to do spectral analysis on alpha wave before and after the current flew through the human body. The study has shown that about 97.72% alpha wave energy changes significantly when electrical stimulation occurs. It is well proved that when the EEG feature identification is applied to test the human body current threshold for perception, and meanwhile alpha wave energy change and human body sensing are used together to confirm if the current flowing through the human body reaches the perception threshold, the measurement of the human body current threshold for perception could be carried out objectively and accurately. PMID- 24804477 TI - [Study on nonlinear dynamic characteristic indexes of epileptic electroencephalography and electroencephalography subbands]. AB - Electroencephalogram (EEG) is the primary tool in investigation of the brain science. It is necessary to carry out a deepgoing study into the characteristics and information hidden in EEGs to meet the needs of the clinical research. In this paper, we present a wavelet-nonlinear dynamic methodology for analysis of nonlinear characteristic of EEGs and delta, theta, alpha, and beta sub-bands. We therefore studied the effectiveness of correlation dimension (CD), largest Lyapunov exponen, and approximate entropy (ApEn) in differentiation between the interictal EEG and ictal EEG based on statistical significance of the differences. The results showed that the nonlinear dynamic char acteristic of EEG and EEG subbands could be used as effective identification statistics in detecting seizures. PMID- 24804478 TI - [Data collection of signals in the multi-channel sEMG system of masticatory muscles and development and preliminary clinical application of an analytic system]. AB - The aim of this study was to design a simple, economic, with high Common Mode Rejection Ratio (CMRR), preamplifier and multi-channel masticatory muscle surface electromyography (sEMG) signal acquisition system assisting to diagnose temporomandibular disorders (TMD). We used the USB interface technology in the EMG data with the aid of the windows to operate system and graphical interface. Eight patients with TMD and eight controls were analyzed separately using this system. In this system, we analyzed sEMG by an optional combination of time domain, frequency domain, time-frequency, several spectral analysis, wavelets and other special algorithms under multi-parameter. Multi-channel sEMG System of Masticatory Muscles is a simple, economic system. It has high sensitivity and specificity. The sEMG signals were changed in patients with TMD. The system would pave the way for diagnosis TMD and help us to assess the treatment effect. A novel and objective method is provided for diagnosis and treatment of oral maxillofacial disease and functional reconstruction. PMID- 24804479 TI - [A detection method of liver iron overload based on static field magnetization principle]. AB - Magnetic induction method aims at the noninvasive detection of liver iron overload by measuring the hepatic magnetic susceptibility. To solve the difficulty that eddy current effects interfere with the measurement of magnetic susceptibility, we proposed an improved coil system based on the static field magnetization principle in this study. We used a direct current excitation to eliminate the eddy current effect, and a rotary receiver coil to get the induced voltage. The magnetic field for a cylindrical object due to the magnetization effect was calculated and the relative change of maximum induced voltage was derived. The correlation between magnetic susceptibility of object and maximum magnetic flux, maximum induced voltage and relative change of maximum induced voltage of the receiver coil were obtained by simulation experiments, and the results were compared with those of the theory calculation. The contrast shows that the simulation results fit the theory results well, which proves our method can eliminate the eddy current effect effectively. PMID- 24804480 TI - [Contingent negative variation: a brainwave associated with expectation]. AB - The present study used the experimental patterns of Go/No Go and no motion contingent negative variation (CNV) task into the research in order to study whether the CNV can express the implication of expectation. Through comparing the CNV under different conditions, the data collected from experiment showed that the key to evoked CNV was close to the warning signal and command signal. Whether the command signal was related to the task would impact on the amplitude of the CNV. This characteristics responses to the subjects' expectation. On this basis, CNV can be used as the electrophysiological index for the reflection of expected value in the conditions of this experiment. PMID- 24804481 TI - [Development and animal tests of a miniaturized electrical chest compression device]. AB - This paper introduces the development and animal tests of a miniaturized electrical chest compression device. Based on pulse width modulation technology produced by micro control unit, the device can control the frequency and depth of the compression accurately, as well as perform real-time adjustment. Therefore, it can perform continuous and stable chest compression for long time, which may increase the successful rate of cardiopulmonary resuscitation (CPR). Besides, the device can also produce different types of compression waveforms, including trapezoidal and triangular waveforms. Then, the performance and efficacy of the device was assessed with a rat model of asphyxial cardiac arrest (CA). PMID- 24804482 TI - [Analysis of sleep electroencephalograph signal based on detrended cross correlation]. AB - The quality of sleep has a great relationship with health and working efficiency. The result of sleep stage classification is an important indicator to measure the quality of sleep, and it is also an important way to diagnose and treat sleep disorders. In this paper, the method of detrended cross-correlation analysis (DCCA) was used to analyze sleep stage classification, sleep electroencephalograph signals, which were extracted from the MIT-BIH Polysomno graphic Database randomly. The results showed that the average DCCA exponent of the awake period is smaller than that of the first stage of non-rapid eye movement (NREM) sleeps. It is well concluded that the method of studying the sleep electroencephalograph with this method is of great significance to improve the quality of sleep, to diagnose and to treat sleep disorders. PMID- 24804483 TI - [Curative effects of pulsed electromagnetic fields on postmenopausal osteoporosis]. AB - We investigated the effects and optimal treatment frequency of pulsed electromagnetic fields (PEMFs) on postmenopausal osteoporosis (PMO). A comparison was performed with the cyclical alendronate and a course of PEMFs in the treatment for postmenopausal osteoporosis on bone mineral density (BMD), pain intensity and balance function. There was no significant difference between the two groups on mean percentage changes from baseline of BMD within 24 weeks after random treatments (P > or = 0.05). However, at the ends of 48 weeks and 72 weeks, the BMD of the PEMFs group were significantly lower than that of the alendronate group (P < 0.05). No significant difference was detected between the two groups with regard to treatment effects on Visual Analogue Scale score, the Timed Up & Go Test and Berg Balance Scale score. Compared with cyclical alendronate, a course of PEMFs was as effective as alendronate in treating PMO for at least 24 weeks. So its optimal treatment frequency for PMO may be one course per six months. PMID- 24804484 TI - [The parameter estimation method of Gaussian point spread function in microscopic images]. AB - As the most popular simplified model of the optical imaging system, the acquisition of the Gaussian point spread function (PSF) parameter is one of the hotspots and key points on which people do research in the field of image restoration. Based on the idea by which there exists deterministic mathematical relationship between Gaussian OTF feature points as well as its parameter and the frequency representation of the image in an existed literature, we proposed an automatic, accurate, stable, and improved approach. This method is able to give prominence to the related calculation feature by a Gaussian convolution and degeneration operation and finally realize the automatic esti mation of PSF parameter of a microscopic image. Experiments have proved that a good restoration result can be achieved utilizing the estimated PSF by the present method, which is of considerable application and reference value in restoration of other sorts with Gaussian approximate PSF model or 3D microscopic image restoration. PMID- 24804485 TI - [Assessment of left ventricular global systolic function using real-time three dimensional speckle-tracking echocardiography in patients with hypothyroidism]. AB - The present study aimed to investigate the impact of hypothyroidism on left ventricular systolic function using real-time three-dimensional speckle tracking imaging (RT3D-STI). Thirty hypothyroidism patients and forty healthy volunteers were recruited and received RT3DSTI measurement of global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS). A comparison of differences between the hypothyroidism patients and those in the healthy group was carried out and we obtained the results as followings. The values of GLS were (-18.93 +/- 3.89) vs. (-21.44 +/- 1.99), with P < 0.01, GRS were (51.13 +/- 11.95) vs. (56.10 +/- 5.76), with P < 0.0; and GAS were (-31.63 +/- 5.38) vs. (-34.40 +/- 2.32), with P < 0.01, i.e. they were lower in hypothyroidism group than those in the health group. While GCS were (-17.75 +/- 1.92) vs. 17.03 +/- 3.45), with P > 0.05, which were not significantly different between the two groups. In linear regres sion, GLS showed significant correlation with both TSH (b = -0.69, P < 0.01) and FT3 (b = 0.71, P < 0.01). Meanwhile, the GRS (b = 2.98, P < 0.05) and GAS (b = 3.11, P < 0.05) linearly correlated with FT3 level. In conclusion, the present study shows that the global longitudinal and radial moves of left ventricular are weaker in patients with hypothyroidism than healthy controls. And the impairment of left ventricular function would aggravate as FSH rises or FT3 declines. PMID- 24804486 TI - [Numerical finite element modeling of custom car seat using computer aided design]. AB - A good cushion can not only provide the sitter with a high comfort, but also control the distribution of the hip pressure to reduce the incidence of diseases. The purpose of this study is to introduce a computer-aided design (CAD) modeling method of the buttocks-cushion using numerical finite element (FE) simulation to predict the pressure distribution on the buttocks-cushion interface. The buttock and the cushion model geometrics were acquired from a laser scanner, and the CAD software was used to create the solid model. The FE model of a true seated individual was developed using ANSYS software (ANSYS Inc, Canonsburg, PA). The model is divided into two parts, i.e. the cushion model made of foam and the buttock model represented by the pelvis covered with a soft tissue layer. Loading simulations consisted of imposing a vertical force of 520N on the pelvis, corresponding to the weight of the user upper extremity, and then solving iteratively the system. PMID- 24804487 TI - [Research on data acquisition of portable uroflowmeter and accuracy of measurement]. AB - This paper presents the preliminary design of data acquisition system of a portable uroflowmeter. The system uses double-hole cantilever pressure sensor. The signal is transferred to ATmega644PA microprogrammed control unit (MCU), converted by A/D (analog to digital) convertor. Then the further data are processed and get the corresponding relationship of weight-time and two curves of urine flow and urinary flow rate. In the measurement accuracy of the device about urine flow, two factors about the placement and height of the data acquisition are analyzed to show the accuracy of the equipment through the Origin 8.0 data analysis software. The design is characterized by low cost and high speed of data collection, real-time, high accuracy. PMID- 24804488 TI - [Development of a software for 3D virtual phantom design]. AB - In this paper, we present a 3D virtual phantom design software, which was developed based on object-oriented programming methodology and dedicated to medical physics research. This software was named Magical Phan tom (MPhantom), which is composed of 3D visual builder module and virtual CT scanner. The users can conveniently construct any complex 3D phantom, and then export the phantom as DICOM 3.0 CT images. MPhantom is a user-friendly and powerful software for 3D phantom configuration, and has passed the real scene's application test. MPhantom will accelerate the Monte Carlo simulation for dose calculation in radiation therapy and X ray imaging reconstruction algorithm research. PMID- 24804489 TI - [Sonography of male breast lesions and the pathological diagnosis: a retrospective study of 10 years and literature review]. AB - The sonographic features of male breast lesions, which underwent ultrasound examination in our hospital for the past 10 years, were retrospectively analyzed. Sonographic features of these lesions were standardized as BI RADS image lexicon. The differences in ultrasonic malignant signs were assessed between the benign and the malig nant diseases. Between the two groups, incomplete boundary was statistically different. The specificity was above 95% within the two groups in terms of speculated margin, echogenic halo, calcification, axillary lymphadenopathy, thickening of skin and eccentric of mass to the nipple. High frequency sonographic examination has a high level of differential diagnosis for male breast lesions. PMID- 24804490 TI - [Application of improved locally linear embedding algorithm in dimensionality reduction of cancer gene expression data]. AB - Cancer gene expression data have the characteristics of high dimensionalities and small samples so it is necessary to perform dimensionality reduction of the data. Traditional linear dimensionality reduction approaches can not find the nonlinear relationship between the data points. In addition, they have bad dimensionality reduction results. Therefore a multiple weights locally linear embedding (LLE) algorithm with improved distance is introduced to perform dimensionality reduction in this study. We adopted an improved distance to calculate the neighbor of each data point in this algorithm, and then we introduced multiple sets of linearly independent local weight vectors for each neighbor, and obtained the embedding results in the low-dimensional space of the high-dimensional data by minimizing the reconstruction error. Experimental result showed that the multiple weights LLE algorithm with improved distance had good dimensionality reduction functions of the cancer gene expression data. PMID- 24804491 TI - [Research on acoustic source generating mechanism of magnetoacoustic tomography based on acoustic dipole theory]. AB - Magnetoacoustic tomography (MAT) has some advantages such as high sensitivity and high spatial resolution. The generating mechanism of acoustic source is the research foundation of forward and inverse problems. A coustic signals were respectively simulated by using monopole and dipole radiation theory in the experimental conditions, then the differences between their acoustic pressures were discussed, and furthermore the contrast and validation were conducted by physical experiments in this study. The physical experimental results showed that acoustic waveform of MAT had a certain directivity and therefore they indicated that dipole model showed higher approximation to the real facts than monopole model. It can be well concluded that this research has cardinal significance for the accurate algorithm of MAT. PMID- 24804492 TI - [Research on amplitude of low-frequency fluctuation in patients with major depression based on resting-state functional magnetic resonance imaging]. AB - We investigated the baseline brain activity level in patients with major depressive disorder (MDD) by am plitude of low-frequency fluctuation (ALFF) based on resting-state functional MRI (fMRI). We examined 13 patients in the MDD group and 14 healthy volunteers in the control group by resting-state fMRI on GE Signa 3.0T. We calculated and compared the ALFF values of the two groups. In the MDD group, ALFF values in the right medial prefrontal were higher than those in control group, with statistically significant differences (P < 0.001). ALFF values in the left parietal in the MDD group were lower than those in control group with statistically significant differences (P < 0.001). This resting-state fMRI study suggested that the alteration brain activity in the right medial prefrontal and left parietal ALFF contributed to the understanding of the pathophysiological mechanism of MDD patients. PMID- 24804493 TI - [Application of elastic registration based on Demons algorithm in cone beam CT]. AB - We applied Demons and accelerated Demons elastic registration algorithm in radiotherapy cone beam CT (CBCT) images, We provided software support for real time understanding of organ changes during radiotherapy. We wrote a 3D CBCT image elastic registration program using Matlab software, and we tested and verified the images of two patients with cervical cancer 3D CBCT images for elastic registration, based on the classic Demons algorithm, minimum mean square error (MSE) decreased 59.7%, correlation coefficient (CC) increased 11.0%. While for the accelerated Demons algorithm, MSE decreased 40.1%, CC increased 7.2%. The experimental verification with two methods of Demons algorithm obtained the desired results, but the small difference appeared to be lack of precision, and the total registration time was a little long. All these problems need to be further improved for accuracy and reducing of time. PMID- 24804494 TI - [CT imaging features and their correlation with pathological findings of solid pseudopapillary tumor of pancreas]. AB - To analyze the CT features of solid pseudopapillary tumor of pancreas (SPTP), and correlation with the pathological findings of the disease so as to improve the diagnostic abilities, the CT images and the clinical manifestations, we retrospectively analyzed the pathological materials of 23 cases with surgery and pathology proved SPTP. In the 23 patients, 21 cases were female (91.3%) and 2 were male (8.7%). The most common symptom was abdominal discomfort with dull pain in 12 patients (52.2%). Others included the pancreatic mass that was detected incidentally during physical examination in 9 patients (39.1%), nausea/vomiting in 2 patients (8.7%). And 1 case of female patients had 2 lesions. In the 24 tumors, 6 cases were located at the head (25.0%), 3 were at neck (12.5%), 8 cases were at body (33.3%), and 7 cases were at tail of pancreas respectively (29.2%). The long-axis diameter ranged from 2.1 cm to 20.1 cm (mean 6.4 cm). 9 tumors were mostly solid component (37.5%), 10 tumors were contained similar proportion of solid and cystic part (41.7%), and mainly cystic components in 5 tumors (20.8%). In 9 of the 23 patients, calcification was found in the tumor (39.1%). In 2 of the 23 patients, bleeding was seen in the mass (8.7%). The dilation of intrahepatic bile duct was found in 1 patient (8.7%). Liver metastasis was showed in one patient (8.7%). On post-contrast CT scan, solid parts demonstrated mild enhancement at the arterial phase. At the portal phase, solid parts were enhanced continuously in all cases, and the enhancement degrees were lower than normal pancreatic tissue. The cystic parts of all lesions showed no enhancement. Pseudo papillary structure, hemorrhage, necrosis, or cystic degeneration were found in all patients by histological study. In a word, SPTP has comparatively characteristic CT imaging features consistent with histological features, when combined with clinical manifestations, could be correctly diagnosed and differentially diagnosed. PMID- 24804496 TI - [Contact analysis between artificial humeral head and glenoid fossa during humeral external rotation]. AB - We developed a three-dimensional finite element model of the shoulder glenohumeral joint after shoulder arthroplasty including humerus shaft, scapular, scapular cartilage and eight muscles, while each of the muscles was simulated with 50 spring elements. To reduce the element number and improve the analytical precision, we used mixed tetrahedral and hexahedral elements in the model. We then used the model to calculate the biomechanics of the shoulder glenohumeral joint after hemiarthroplasty during humeral external rotation. Results showed that the maximum joint reaction force was 374.72 N and the maximum contact stress was 6. 573 MPa together with the contact areas at 40 degrees external rotation. These might be one of the reasons for prosthetic disarticulation, and would provide theoretical bases to prosthetic design. PMID- 24804495 TI - [A bibliometrics study of literature on medical image processing for the past ten years]. AB - We searched and retrieved literature on the topic of medical image processing published on SCI journals in the past 10 years. We then imported the retrieved literature into TDA for data cleanup before data analysis and pro cessing by EXCLE and UCINET to generate tables and figures that could indicate disciplinary correlation and research hotspots from the perspective of bibliometrics. The results indicated that people in Europe and USA were leading researchers on medical image processing with close international cooperation. Many disciplines contributed to the fast development of medical image processing with intense interdisciplinary researches. The papers that we found show recent research hotspots of the algorithm, system, model, image and segmentation in the field of medical image processing. Cluster analysis on key words of high frequency demonstrated complicated clustering relationship. PMID- 24804497 TI - [Stress analysis of cervical spine C4-C6 under frontal impact load]. AB - In order to check the neck response and injury during motor vehicle accidents, we developed a detailed finite element model for human cervical spine C4-C6. This model consisted of cortical bone, cancellous bone, annulus, nucleus, ligaments and articular facet, and it also set up contact in the contacting parts for simulating the movement perfectly under frontal impact. This model could be used for stress and strain distribution after the frontal impact load was applied on this model. During the process of frontal impact, the most displacement simulated data were in the interval range of experimental data. The experimental results showed that this model for the human cervical spine C4-C6 simulated the movement under the frontal impact with fidelity, and reflected the impact dynamics response on the whole. PMID- 24804498 TI - [Stress analysis of artificial bionic knee joint based on UG6.0 NX NASTRAN]. AB - This article introduces the basic principles of finite element analysis in biomechanics, focusing on the basic principles of a variety of finite element analysis software, and their respective characteristics. In addition, it also de scribes the basic stress analysis of UGNX6.0 NASTRAN analysis for artificial knee process, i. e. the choice of the type, material definition, the set of constants, finite element mesh division and the finite element results of the analysis. Finite element analysis and evaluation of the design of personalized artificial knee were carried out, so that the rationality of the geometric design of the structure of the experimental design of artificial knee has been verified. PMID- 24804499 TI - [Study on in vitro biomineralization of enamel-binding peptide]. AB - We present the binding ability of a new peptide (CMPQVMPMC-) with dental enamel after being evaluated in the present study. Under a standard procedure, the recovery of M13 filamentous phage was greatly enhanced by displaying the peptide in phage coat protein p III. Then the cyclic peptide was synthesized using a solid method. The effect of the cyclic peptide in vitro biomineralization was tested in a single-diffusion microtiter plate gel system. Absorbance at 405 nm of each sample was recorded for 24 h at every 6 h intervals. The relatively increased values of each sample were expressed as percentages relative to the blank group (100%). The cyclic peptide resulted in a concentration-dependent delayed nucleation. In addition, the overall values of peptide groups at the end of 24 h were lower than those in the control group but much higher than those in the BSA control group. PMID- 24804500 TI - [Isolation and purification of alpha-glycerophosphate oxidase in a polyethylene glycol/(NH4 )2SO4 aqueous two-phase system]. AB - Alpha-glycerophosphate oxidase (alpha-GPO) from Enterococcus casseli flavus was successfully isolated and purified by using polyethylene glycol (PEG)/(NH4)2SO4 aqueous two-phase system (ATPS). The results showed that the chosen PEG/(NH4)2SO4 ATPS could be affected by PEG molecular weight, pH, concentration of PEG and (NH4)2SO4, and inorganic salt as well as additional amount of crude enzyme. After evaluating these influencing factors, the final optimum purification strategy was formed by 16.5% (m/m) PEG2000, 13.2% (m/m) (NH4)2SO4, pH 7.5 and 30% (m/m) additive crude enzyme, respectively. The NaCl was a negative influencing factor which would lead to lower purification fold and activity recovery. These conditions eventually resulted in the activity recovery of 89% (m/m), distribution coefficient of 1.2 and purification fold of 7.0. PMID- 24804501 TI - [Promotion of rat skin healing by using natural polymer chitosan derivatives]. AB - We in the present study observed the effect of N-fructose modified chitosan quaternary ammonium derivatives on on rat skin wound healing through animal experiments. Forty rats were randomly divided into eight groups (5 in each group). Four groups among the all 8 groups were the experimental groups, while the other 4 groups were the control groups. Next to the skin along the back of the spine, 1.50 cm x 2.00 cm x 0.16 cm full-thickness skin was cut to make an excision wound model for every rat. Those in the experimental groups were treated with the N-fructose-modified chitosan quaternary ammonium derivatives ointment dressing the wound, while those in the control groups with sterile medical vaseline processing. We dressed the wounds twice a day to observe the wound healing of all rats in different groups. We then observed the wound healing and wound pathology after 3, 7, 10, 15 days re spectively in different groups. Results showed significant differences of the time of wound healing, area of wound healing and volume of wound healing between the experimental groups and control groups (P < 0.05). It can be well concluded that N-fructose-modified chitosan quaternary ammonium derivatives does not harm the skin, but could promote skin healing, so that they could be suitable skin repair materials and ideal raw materials for medical dressing. PMID- 24804502 TI - [Construction of stable expression of human thyrotropin receptor alpha-subunits on HEK 293T cells]. AB - The aim of this study was to establish stable expression of human thyroid stimulating hormone receptor (TSHR) alpha-subunit (hTSHRA) on human embryonic kidney 293T (HEK 293T). HEK 293T cell lines with stable expression of hTSHRA could be used for detecting affinity between hTSHRA and potential TSHR blocking peptide. We firstly constructed hTSHRA gene into lentiviral vectors GV218. The sequence comparison indicated that we had constructed GV218-hTSHRAA. Western blot demonstrated the 52 kD aim band of hTHSRA on over-expressed HEK 293T cells. GV218 hTSHRA constructions and pHelper were then co-transfected into HEK 293T cells to form packaging plasmid. The HEK 293T cells that stably expressed hTSHRA could also express green fluorescent pro tein. The titer of lentiviral packaging vector is 2 x 10(8) TU/mL with qPCR. The lentiviral packaging vector thereafter was transfected into HEK 293T cells again. The hTSHRA expressed on the HEK 293T cells. Human TSHRA stab ly expressed on HEK 293T upon continuously passaging. Therefore, we established hTSHRA stable expression on HEK 293T cells by constructing GV218-hTHSR lentiviral packaging vector. It is a useful tool for studying TSHR affinity with anti-thyroid peptide. PMID- 24804503 TI - [Analysis between transforming growth factor beta3 gene sfaNI polymorphism variant and non-syndromic cleft lip with or without cleft palate in people of Uygur's nationality and Han's in Xinjiang]. AB - The present study was aimed to explore the relationship of transforming growth factor (TGF) beta3 gene SfaNI polymorphism (rs3917201 locus) and non-syndromic cleft lip with or without cleft palate (NSCL/P) in people of the Uygur's Nationality and Han's in Xinjiang, China. TGFbeta3 gene fragment including SfaNI was amplified and purified as the template of the primer extension reaction thenafter. The single base extension reaction was carried out u sing SNP specific extension primer. The products were purified and analyzed by MALDI-TOF. The test showed that there were not significantly different frequencies of AA, AG, GG genotypes and alleles between the whole NSCL/P group and the whole control group (P > 0.05). Within the Uygurs or Hans, the frequencies of genotypes between the whole NSCL/P group and the whole control group were not significantly different (P > 0.05). The distributions of the A, G alleles between the NSCL/P group and the control group were not significantly different within the Uygurs (P > 0.05), but significant different within the Hans (P < 0.05). In all the NSCL/P patients, frequencies of genotypes and alleles were not significantly different between Uygurs and Hans (P > 0.05), and not significantly different (P > 0.05) either between Uygurs and Hans in all the healthy persons. The results proved that TGFbeta3 gene SfaNI polymorphism may not be related to NSCL/P in Xinjiang Uygur people, while the occurrence of NSCL/P in Han population may be related to frequency of the A and G allele of SfaNI polymorphism. PMID- 24804504 TI - [Construction and identification of helper-dependent adenoviral vector encoding hemagglutinin protein of swin-origin influenza virus A H1N1]. AB - Abstract: In order to investigate immune protection against swine-origin influenza virus (S-OIV) A H1N1, the helper-dependent adenovirus vector (HDAd) system was exploited to construct recombinant HDAd encoding hemagglutinin (HA). The HA gene was synthesized and cloned to the HDAd backbone. Then, the HDAd/HA DNA molecules were transfected into 293Cre4 cells with calcium phosphate. The cells were infected by helper virus 16 hours after the transfection. The 293Cre4 cells were coinfected with HDAd/HA and the helper virus for large-scale preparation of HDAd/HA. The HDAd/HA was obtained and purified twice with CsCI density ultracentrifugation and observed morphologically under transmission electron microscope, and the expression of HA protein was analyzed with RTPCR. Recombinant HDAd/HA expressing HA protein was successfully constructed which could pave the way for in vivo investigation on immunogenicity and efficacy against S-OIV A H1N1 infection. PMID- 24804505 TI - [Research on non-rigid registration of multi-modal medical image based on Demons algorithm]. AB - Non-rigid medical image registration is a popular subject in the research areas of the medical image and has an important clinical value. In this paper we put forward an improved algorithm of Demons, together with the conservation of gray model and local structure tensor conservation model, to construct a new energy function processing multi-modal registration problem. We then applied the L-BFGS algorithm to optimize the energy function and solve complex three-dimensional data optimization problem. And finally we used the multi-scale hierarchical refinement ideas to solve large deformation registration. The experimental results showed that the proposed algorithm for large de formation and multi-modal three-dimensional medical image registration had good effects. PMID- 24804506 TI - [Application of pencil beam model based on point kernel in intensity modified radiation therapy]. AB - In this paper, a method for dose calculation with pencil beam kernels constructed by point kernel superposition was proposed to accelerate the dose calculation during intensity optimization iteration. With this method, the direct aperture optimization method can be integrated in the planning system based on point kernel convolution/superposition model. The dose calculation time was also reduced during the iteration. From the result of the phantom and clinical patient data test, it was concluded that this method could be used for the intensity optimization of iteration dose calculation as the satisfied precision due to the optimization result coherence obtained. By implementing the method in the planning system product based on point kernel convolution/superposition model, a lot of additional research and development works for the pencil beam dose calculation model as well as the product maintenance cost can be avoided. PMID- 24804507 TI - [A novel method for the quantitative analysis of phase-locking relationship between neuronal spikes and local field potentials]. PMID- 24804508 TI - [Development and design of a new sonography rigid bronchoscopy and corollary vacuum-assisted biopsy device system]. AB - The present study was to develop and design a new sonography rigid bronchoscopy and corollary vacuum-assisted biopsy device system with less injury and complication. The system combined ultrasonic-probe with ultrasound catheter, a new medical ultrasound technique, and rigid bronchoscopy (RB) which is improved with an auxiliary vacuum-assisted biopsy device. The principle of the device is vacuum suction and rotary knife. The reduced outer diameter of the RB led to less pain and lower complications for the patient. With the help of ultrasonic-probe (30 MHz), lesions and blood vessels can be identified clearly and unintentional puncture and damage to blood vessels can be avoided. Plenty of lesions can be obtained quickly through the vacuum-assisted biopsy device without getting puncture needle in and out repeatedly. The novel endobronchial sonography rigid bronchoscopy and matched vacuum-assisted biopsy device has many remarkable advantages. It can enlarge the applied range of the RB from endobronchial to mediastinal lesions, avoiding unintentional puncture of vessels. Obtaining multiple samples with a higher accuracy rate than that by other sampling techniques, minimizing operation time, alleviating pain and decreasing the complication rate, the system makes up the technical deficiency for the diagnosis and treatment of the mediastinal lesions, to a certain degree. PMID- 24804509 TI - [Research on integrated application of tumor magnetic induction hyperthermia treatment planning system and modern medical information systems]. AB - Magnetic induction hyperthermia becomes a very important tumor treatment method at present. In order to ensure a successful operation, doctors should make hyperthermia treatment planning before surgery. Based on Integration Healthcare Enterprise (IHE) framework and Digital Imaging and Communications in Medcine (DICOM) standard, we proposed and carried out a network workflow integrated with modern medical information systems for the dissemination of information in magnetic induction hyperthermia like accurate accessing patient information and radiology image data, storing processed images, sharing and verifying hyperthermia reports. The results proved that our system could not only improve the efficiency of magnetic induction hyperthermia treatment planning, but also save medical resources and reduce labor costs. PMID- 24804510 TI - [Design of a testing system for antithrombotic pressure circulatory equipment]. AB - A new type of testing system used for antithrombotic pressure circulatory equipment has been developed, which realized a new method for the calibration of pressure sensor. Multi-path control and acquisition functions are achieved by this method based on human-computer interaction testing system. The precision of pressure sensor is ob tained by polynomial fitting for each test point using linear interpolation method. The result showed that the precision test of pressure sensor could be realized easily and efficiently, using the developed testing system, and the parameters of pressure sensor could be calibrated effectively, so that it could be accurately used in the antithrombotic pressure circulatory equipment. The developed testing system has a prosperous future in the aspects of promotion and application. PMID- 24804511 TI - [Application of an R-group search strategy into three-dimensional quantitative structure-activity relationship of HEA beta-secretase inhibitors and molecular virtual screening]. AB - The beta-secretase is one of prospective targets against Alzheimer's disease (AD). A three-dimensional quan titative structure-activity relationship (3D-QSAR) model of Hydroethylamines (HEAs) as beta-secretase inhibitors was established using Topomer CoMFA. The multiple correlation coefficient of fitting, cross validation and external validation were r2 = 0.928, q(loo)2 = 0.605 and r(pred)2 = 0.626, respectively. The 3D-QSAR model was used to search R groups from ZINC database as the source of structural fragments. As a result, a series of R groups with relatively high activity contribution was obtained to design a total of 15 new compounds, with higher activity than that of the template molecule. The molecular docking was employed to study the interaction mode between the new compounds as ligands and beta-secretase as receptors, displaying that hydrogen bond and hydrophobicity played important roles in the binding affinity between the new compounds and beta-secretase. The results showed that Topomer CoMFA and To pomer Search could be effectively used to screen and design new molecules of HEAs as beta-secretase inhibitors, and the designed compounds could provide new candidates for drug design targeting AD. PMID- 24804512 TI - [The present situation and future development of research on new algorithms of gait recognition with multi-angles]. AB - Gait recognition is a new technology in biometric recognition and medical treatment which has advantages such as long-distance and non-invasiveness. Depending on the differences between different people's walking pos tures, we can recognize individuals by characteristics extracted from the images of walking movement. A complete gait recognition process usually includes gait sequence acquisition, gait detection, feature extracting and recognition. In this paper, the commonly used methods of these four processes are introduced, and feature extraction methods are classified from different multi-angle views. And then the new algorithm of multi-view emerged in recent years is highlighted. In addition, this paper summarizes the existing difficulties of gait recognition, and looks into the future development trends of it. PMID- 24804513 TI - [The role of actigraphy in monitoring sleep and sleep disorders]. AB - The use of actigraphy, which can be used to estimate sleep-wake patterns from activity levels, has become common in sleep research. Actigraphy is a simple, cost-effective and non-invasive method for healthcare providers and researchers to assess patients sleep quality and screen for potential sleep disorders in recent years. But, there is no wide recognition and application of actigraphy in China up till now. This review summarized the application of actigraphy in evaluation of sleep and diagnosis of sleep disorders. PMID- 24804514 TI - [Research progress of probe design software of oligonucleotide microarrays]. AB - DNA microarray has become an essential medical genetic diagnostic tool for its high-throughput, miniaturization and automation. The design and selection of oligonucleotide probes are critical for preparing gene chips with high quality. Several sets of probe design software have been developed and are available to perform this work now. Every set of the software aims to different target sequences and shows different advantages and limitations. In this article, the research and development of these sets of software are reviewed in line with three main criteria, including specificity, sensitivity and melting temperature (Tm). In addition, based on the experimental results from literatures, these sets of software are classified according to their applications. This review will be helpful for users to choose an appropriate probe-design software. It will also reduce the costs of microarrays, improve the application efficiency of microarrays, and promote both the research and development (R&D) and commercialization of high-performance probe design software. PMID- 24804515 TI - [Advances in the application of smart phones in modern medicine]. AB - Since smart phones have been developed, significant advances in the function of mobile phone due to the development of software, hardware and accessories have been reached. Till now, smart phones have been engaged in daily life with an increasing impact. As a new medical model, mobile phone medicine is emerging and has found wide spread applications in medicine, especially in diagnosing, monitoring and screening various diseases. In addition, mo bile phone medical application shows great potential trend to improve healthcare in resource-limited regions due to its advantageous features of portability and information communication capability. Nowadays, the scientific and technological issues related to mobile phone medicine have attracted worldwide attention. In this review, we summarize state-of-the-art advances of mobile phone medicine with focus on its diagnostics applications in order to expand the fields of their applications and promote healthcare informatization. PMID- 24804516 TI - [Application of silk fibroin in biomedical areas]. AB - For a long period of time, silk fibroin has been applied in biomedical areas. Along with the development of biotechnology, new functions of silk fibroin are being found and developed. From the suture of surgery to the therapeutic drug and the ordinary tissue engineering frame to high grade frame with drug buffer system, exploitation of silk fibroin is constantly introduced with something new from the old ones. In our review, we summarize the applications of silk fibroin in tissue engineering, drug buffer system and medical care. PMID- 24804517 TI - [MUC4 research progress in tumor molecular markers]. AB - Mucin antigen 4 (MUC4) is a molecular marker for some malignant tumors for early tumor diagnosis, prognosis and targeted therapy. It provides a new research direction in tumor diagnosis and treatment that will have a wide application prospect. In recent years, there has been a large number of research reports on the basic and clini-a wide application prospect. In recent years, there has been a large number of research reports on the basic and clinical studies about MUC4, but the molecular imaging study about MUC4 is seldom reported. In this paper the recentcal studies about MUC4, but the molecular imaging study about MUC4 is seldom reported. In this paper the recent research about MUC4 on basic and clinical studies is briefly reviewed, and it is expected to promote the development of tumor molecular imaging. PMID- 24804518 TI - Heal the mother, heal the baby: epigenetics, breastfeeding and the human microbiome. PMID- 24804520 TI - Assumptions and advice: mothers and Queensland well-baby clinics. A review. AB - In 20th century Australia, free well-baby clinics were run by maternal and child health nurses, although the funding and organisational structure varied from state to state. It was assumed that women who attended followed the advice assiduously; yet attendance did not necessarily equate to practice. In Queensland, the state government's free Maternal and Child Welfare Service (MCW) advised mothers on infant feeding and care through well-baby clinics throughout the state, a correspondence section for mothers in remote areas and a railcar clinic to some western towns, under the state government's policy of covering every mother and baby in Queensland. Women in Queensland, as in other states, were exposed to other influences on how to feed babies and often exercised agency in making their own decisions according to their circumstances and their own judgment. This review will place research from Queensland on women's reasons for attending the clinics and adherence to the advice provided, during the period 1920-1965, within a wider context. This includes research on barriers to following advice, counselling versus imparting information and the mother's self efficacy. The message for today is that adherence to advice still cannot be assumed and mothers' own circumstances need to be factored in. PMID- 24804519 TI - 'A better alternative': why women use peer-to-peer shared milk. AB - The process by which women came to use internet-facilitated peer-to-peer shared milk was explored via a written questionnaire administered to 41 peer milk recipients from five countries. Respondents were universally unable to provide some or all of the milk their infants required. Twenty-nine dyads had a medical condition that could have affected their ability to breastfeed. Many respondents had had great difficulty in finding health workers who could assist them with their breastfeeding challenges. Before obtaining peer-shared milk, respondents had tried to increase their own milk supply, used infant formula or sought donor milk from personal contacts. Health workers dealing with breastfeeding women require greater training in the recognition and treatment of conditions that adversely affect breastfeeding including a physiological incapacity to fully breastfeed. Peer-to-peer milk recipients appear to be very satisfied with the solution milk sharing provides to their problem of being unable to fully breastfeed their infants. PMID- 24804521 TI - Early weight loss and weight gain in healthy, full-term, exclusively-breastfed infants. AB - All infants lose weight after they are born, no matter what or how they are fed. However, there are conflicting opinions about what constitutes a normal newborn weight loss, especially in exclusively-breastfed infants, and about when interventions, such as supplemental feedings, should be considered. This review will: Present evidence for the amount and timing of initial weight loss and timing of birth weight recovery. Explain the normal physiology of the newborn infant in the early days of life. Determine whether intrapartum intravenous (IV) fluids cause excessive weight loss in some newborn infants. Present information which should allow health professionals to make an informed assessment of what is contributing to an individual newborn infant's weight loss. PMID- 24804522 TI - The ethics and regulation of overcharging: issues in the commerciality of the health practitioner-patient relationship. AB - Overcharging by health practitioners is a difficult issue with few guidelines available for practitioners or patients. For the most part it has not been the subject of disciplinary censure and has been dealt with by conciliation processes. However, during 2013 the Singapore High Court twice addressed the commerciality of the health-practitioner-patient relationship, acknowledging that this is a fundamental attribute of the contemporary dynamic between providers and recipients of health services. In Lim Mey Lee Susan v Singapore Medical Council [2013] SGHC 122, it concluded that the obligation to refrain from overcharging is an inherent ethical responsibility of practitioners and affirmed the suspension for three years of a surgeon with Australian training and tertiary connections for what it classified as grossly excessive charging. In Pang Ah San v Singapore Medical Council [2013] SGHC 266, it observed that medical practitioners have a legitimate right to appropriate levels of remuneration but that the right balance has to be struck between professional virtues and business considerations. The Singapore High Court's decisions raise the question of whether professional associations and practitioner regulators have a responsibility to provide guidelines and, potentially, processes by which practical assistance can be provided to medical and other health care practitioners so that they can avoid unacceptable charging practices. PMID- 24804523 TI - Changing disciplinary responses to sexual misconduct by health practitioners in New Zealand. AB - In response to societal changes, a more flexible disciplinary response to sexual relationships between health practitioners and patients has developed over the last 15 years in New Zealand. The new approach involves a close focus on the circumstances of the particular case, balancing relevant aggravating and mitigating factors, to determine whether a disciplinary finding is called for and the appropriate penalty. Relationships between parties in relatively equal power positions, without strong evidence of patient exploitation or vulnerability, where prompt steps are taken to disengage the professional relationship, or involVe minor health services only, may not result in a disciplinary finding at all. Even where patient vulnerability is present, there has been movement away from automatic de-registration to suspension for periods often less than the maximum, provided there are sufficient mitigating factors. There is early indication of a stricter approach in the relatively new category of case of downloading and accessing objectionable material than in cases of sexual relationships, although there are too few cases yet to enable an appropriate disciplinary benchmark to have emerged. The rhetoric of the need for severity and public protection in one such case was not, however, matched by the imposition of the most serious of penalties. PMID- 24804524 TI - The Australian National Disability Insurance Scheme for cerebral palsy: an end to the "forensic lottery"? AB - The new Australian National Disability Insurance Scheme is set to revolutionise disability support for an estimated 440,000 disabled persons and in particular for over 35,000 victims of cerebral palsy. The current support for sufferers of cerebral palsy is fragmented and their families and carers expend great time and effort accessing a range of different support agencies. The present "forensic lottery" means that only a small percentage of cerebral palsy victims whose injuries have been caused by medical negligence can secure large settlements under civil tort litigation. The NDIS promises a much more equitable scheme where severely disabled children can receive the necessary early intervention, which is so important to their long-term outcome. Such support will be provided irrespective of "fault", although recouping the costs of lifelong care through civil litigation in medical negligence remains an option. Debate continues about the affordability of such an ambitious Scheme. This is no doubt fuelled by the perceived New Zealand experience of its no-fault Accident Compensation Scheme. The NDIS advantage over almost all "no fault" schemes internationally is that it provides unified comprehensive care and support to cerebral palsy sufferers irrespective of a "treatment injury". Determinations for eligibility will no doubt involve extensive medical documentation. Uncertainty remains about the preparedness of the Chief Executive Officer of the NDIS to pursue health providers in civil negligence where treatment injuries may have been causative. PMID- 24804525 TI - Sexual violence in armed conflict: the least condemned of war crimes. AB - Sexual violence in armed conflict has traditionally received poor attention until recent years. It has been the "least condemned of war crimes" although, with the inception of the International Criminal Court and various other international courts and tribunals, convictions of high-profile aggressors are increasing. Only recently Charles Taylor, the President of Liberia, was convicted of war crimes and crimes against humanity which included rape and sexual slavery. He was sentenced to 50 years imprisonment. Is prosecution of these crimes sufficient to minimise sexual violence in war? That seems unlikely given the potential for such violence to be a cheap and effective strategy to terrorise a civilian population and "ethnically cleanse" the newly won territory. However, there is a remarkable variation in the levels of sexual violence in armed conflicts. Some, such as the Israeli-Palestinian conflict, have extremely low levels, whereas in Bosnia and many African states the prevalence of sexual violence is at epidemic levels. The reasons for such differences are many, however, some precipitating factors may be improved by strong military discipline, improved gender balance in armed forces, better political awareness by combatants of the aims of a campaign and pre deployment ethical training. PMID- 24804526 TI - "See you next week--unless I'm dead". AB - The common law, statutes and professional codes of medical and health care uphold the right of competent patients to refuse treatment that they have been advised is in their best medical interests, recognising that they have the right to decide whether such medical advice aligns with their self-determined, global interests. But sometimes, there can be ambivalence within the treating practitioner's mind as to what the patient's best medical interests consist of in the first place. The case presented here of chronic mental health problems illustrates this ambivalence or clinical equipoise, and raises clinical, conceptual, ethical, legal and conscience issues for individual practitioners and the wider community. The case evades clarity and consensus over the doctor's legal obligations, but the complex emotional, psychodynamic, attachment and existential issues that it raises also render any ethical analysis ultimately unsatisfactory, unless it be agreed that some people can only be helped by suspending judgment and treatment, and by just being there. PMID- 24804527 TI - Aboriginal and Torres Strait Islander health practitioner regulation. AB - An aspect of the much needed efforts to "close the gap" in Indigenous health disadvantage in Australia has been workforce reform. This has included targeted training for general practitioners and has also been characterised by sensitising of psychiatrists to the particular mental health needs of persons of Aboriginal and Torres Strait Islander background. It has also incorporated increasing involvement by Indigenous persons in providing health services. In 2012, each Australian State and Territory constituted the Aboriginal and Torres Strait Islander Health Practice Board to regulate and register Indigenous health practitioners. This marked an important recognition of the contribution able to be made by this complementary component of the Australian health workforce which is particularly enabled to understand and meet the needs of Indigenous persons. This column chronicles the first steps of the new regulatory board and identifies issues which face it. PMID- 24804528 TI - Commissions of audit in Australia: health system privatisation directives and civil conscription protections. AB - The use of commissions of audit as vehicles to drive privatisation policy agendas in areas such as health service delivery has become popular with conservative federal and State governments. Such commissions have characteristically been established early in the terms of such governments with carefully planned terms of reference and membership. The policy directions they advocate, unlike election policies, have not come under the intense scrutiny, wide public debate or the opportunities for (dis)endorsement afforded by the electoral process. Governments do, however, anticipate and often accept recommendations from these reviews, and use them as justification to implement policy based on their findings. This highlights the power entrusted to review bodies and the risks to the public interest arising from limited public consultation. An example can be seen in the proposed privatisation of important aspects of Australia's public sector, particularly including those related to health systems delivery, currently entering a new iteration through the work of the National Commission of Audit appointed in October 2013. The NCA follows on from various State audit commissions which in recent years have directed the divestment of government responsibilities to the private and not-for-profit sectors. Through a discussion on the formation of policy frameworks by the NCA and the Queensland Commission of Audit, this column examines the ideological thrust of the commissions and how they synergise to produce a national directive on the future of public sector health services. The practical impacts on health service procurement and delivery in critical areas are examined, using the case of the federally contracted out medical service for asylum seekers and two hospitals in Western Australia, a State which is well advanced in the privatisation of public hospitals. The column then examines the release to the media early in the NCA's process of the submission to introduce a $6 general practitioner co-payment as a means of testing the response of the medical profession and public. The column also examines how the civil conscription clause in s 51 (xxiiiA) of the Australian Constitution may serve to protect practitioner and patient rights should some of these privatisation changes to Australia's health system be challenged in the High Court of Australia. PMID- 24804529 TI - Intake rigour: ensuring only "reportable deaths" become coroners' cases. AB - The failure of medical practitioners to discharge their obligation consistently to report sudden or unnatural deaths to coroners has rightly prompted concern. Following recent public scandals, coroners and health authorities have increasingly developed procedures to ensure that concerning deaths are reported to coroners. However, the negative consequences of deaths being unnecessarily reported have received less attention: unnecessary intrusion into bereavement; a waste of public resources; and added delay and hindrance to the investigation of matters needing a coroner's attention. Traditionally, coroners have largely unquestioningly assumed jurisdiction over any deaths for which a medical practitioner has not issued a cause of death certificate. The Office of the State Coroner in Queensland has recently trialled a system to assess more rigorously whether deaths apparently resulting from natural causes, which have been reported to a coroner, should be investigated by the coroner, rather than being finalised by a doctor issuing a cause of death certificate. This article describes that trial and its results. PMID- 24804530 TI - Coronial law and practice: a human rights perspective. AB - Coronial law and practice inevitably impact upon the human rights of those affected by deaths. It is important that such rights be incorporated in how death investigations, up to and including coronial inquests, take place. This article explores the significant impact of the jurisprudence emanating from the European Court of Human Rights, as well as the application of such law by the courts of the United Kingdom and potentially in other countries. It argues that viewing the work of coroners through the lens of human rights is a constructive approach and that, although in the coronial legislation of Australia and New Zealand, many human rights, especially those of family members, and civil liberties are explicitly protected, there remain real advantages in reflecting upon compliance with human rights by death investigation procedures and decision-making. PMID- 24804531 TI - An empirical approach to the New Zealand government's review of the coronial jurisdiction. AB - Given the public profile of New Zealand coroners, it is surprising that there has been limited empirical research about coroners' decision-making. This article uses evidence from New Zealand's first empirical study of coroners' recommendations to discuss the New Zealand government's recent review of the coronial jurisdiction. In June and October 2013, New Zealand's Courts Minister announced proposed changes to the coronial system. Several of the Minister's proposals are consistent with the empirical evidence, but there are also significant gaps in the review. The Minister's review acknowledges the importance of coroners' preventive function, but will the proposals enable New Zealand's coronial law to achieve its full preventive potential? The empirical evidence suggests that the prophylactic potential of coroners' recommendations is not being maximised. PMID- 24804532 TI - An absurd inconsistency in law: Nicklinson's case and deciding to die. AB - R (Nicklinson) v Ministry of Justice [2012] EWHC 2381 was a tragic case that considered a perennial question: whether voluntary active euthanasia is murder. The traditional position was affirmed, that is, it is indeed murder. The law's treatment of decisions to refuse treatment resulting in death is a stark contrast to the position in respect of voluntary, active euthanasia. In cases of refusing treatment, principles of individual autonomy are paramount. This article presents an overview of the legal distinction between refusing medical treatment and voluntary, active euthanasia. It questions the purported differences between what are described as acts of "active" or "passive" euthanasia. It also highlights the inconsistency of the law's treatment of different ways that people decide to die. PMID- 24804533 TI - Consent versus scrutiny: restricting liberties in post-Bournewood Victoria. AB - The article considers the problem of people with impaired capacity who face restrictions on their liberty but who are compliant with such practices. The issue has bedevilled courts and law reform commissions throughout the common law world since HL v United Kingdom [2004] ECHR 471 exposed the legal "gap" in which such people were languishing. Proposals to address it have either been excessively complex, or largely concerned with the mechanism for lawful consent to restrictive practices rather than scrutinising the practices themselves. The article critically discusses these proposals and argues that a suitable, if not ideal, regime for regulating the problem already exists in the Victorian Disability Act 2006. PMID- 24804534 TI - Safety, risk and mental health: decision-making processes prescribed by Australian mental health legislation. AB - Adverse events in mental health care occur frequently and cause significant distress for those who experience them, derailing treatment and sometimes leading to death. These events are clustered around particular aspects of care and treatment and are therefore avoidable if practices in these areas are strengthened. The research reported in this article takes as its starting point coronial recommendations made in relation to mental health. We report on those points and processes in treatment and discharge where coronial recommendations are most frequently made. We then examine the legislative requirements around these points and processes in three Australian States. We find that the key areas that need to be strengthened to avoid adverse events are assessment processes, communication and information transfer, documentation, planning and training. We make recommendations for improvements in these key areas. PMID- 24804535 TI - Medical practitioner regulation: is it all about protecting the public? AB - This article explores the purpose of professional regulation as it applies to medical practitioners in Australia and New Zealand. Purpose is considered in terms of regulatory theory legislative statement, judicial commentary, and the realities of who and what is regulated and by whom. It is considered both in relation to the regulatory framework as a whole, and more specifically in relation to the disciplinary system that operates as a critical component of that framework. The author concludes that the dominant purpose of medical practitioner regulation should be the protection of the public, particularly when it comes to disciplinary decision-making. While it may be reasonable for broader public interest considerations, such as workforce supply, to be taken into account when it comes to making registration decisions, extreme caution should be exercised in allowing such considerations to influence disciplinary decisions. PMID- 24804536 TI - An analysis of Australia's legal regime for imposing liability on manufacturers of pharmaceutical drugs. AB - Following a trial in June 2009 where the Federal Court heard submissions regarding whether Merck Sharpe and Dohme Australia should be held liable for an increased risk of cardiovascular conditions noted in patients who had taken the anti-inflammatory drug Vioxx, a judgment was handed down against MSDA in March 2010. MSDA then appealed to the Full Federal Court, where it was successful. A subsequent special leave to appeal application to the High Court of Australia was rejected in May 2012. This article examines the themes raised in the trial judgment and the appropriateness of Australia's statutory consumer protection regime through the lens of pharmaceutical drug injuries and side effects. PMID- 24804537 TI - The art of apportionment: working out responsibility for health care misadventures. AB - When something goes wrong in the provision of health care, it is often unclear who might be at fault, and whether they actually are at fault. A necessity and strength of modern health care is the variety of professionals who participate in it, who differ in their respective roles and expertise. Trying to work out who did what can be difficult, and whether they did something wrong often more so. So when one arrives at the task of working out whether one party is more to blame than the other, it is rarely a straightforward exercise. Arriving at a percentage figure to identify a party's blameworthiness might seem superficially simple, but it often requires the balancing of a bewildering array of various factors, over which different minds are commonly at odds. PMID- 24804538 TI - Ethical, legal and social issues to consider when designing a surrogacy law. AB - The aim of this article is to address the ethical, legal and social issues that arise when a woman becomes pregnant and gives birth to a child with the intention of surrendering this child to another woman or couple. The secondary aim is to offer some recommendations that will be beneficial for the lawmakers, policymakers and regulators who design and enforce the rules and regulations that govern surrogacy arrangements. The article considers both commercial and altruistic surrogacy and highlights some of the similarities and differences between the two. Beginning with the initial question of whether surrogacy should be legal, the controversial questions raised relate to the time before conception, during the pregnancy and after the birth of the child. The article concludes that surrogacy arrangements are ethical and should be legal because they enable the medically and socially infertile, including singles and same-sex couples, the opportunity to become parents and to enjoy the lifelong pleasures of parenthood. For many, this will be the strongest argument for the legalisation of surrogacy and the greatest benefit to arise from surrogacy arrangements. PMID- 24804539 TI - Scale/topography of substrates surface resembling extracellular matrix for tissue engineering. AB - Biomaterial matrices are being developed that mimic the key characteristics of the extracellular matrix, including presenting adhesion sites and displaying growth factors in the context of a viscoelastic hydrogel. This review focuses on two classes of materials: those that are derived from naturally occurring molecules and those that recapitulate key motifs of biomolecules within biologically active synthetic materials. We also discussed some of the most significant biological features of the ECM, and several engineering methods currently being implemented to design and tune synthetic scaffolds to mimic these features. Understanding the cell-protein-material interaction is fundamental for developing more powerful tools in tissue engineering and regenerative medicine strategies. The design of model substrates including the presence of well-defined properties (chemistry, topography, stiffness) and even the gradient of these properties in three dimensional environments must lead in the near future to learn more about the specific roles of protein adsorption and the very dynamic process related to the cell fate of synthetic substrates: cell adhesion, matrix reorganisation, deposition and degradation at the cell-material interface. These materials will open new doors to biosurgical therapeutics in tissue engineering and regenerative medicine. PMID- 24804540 TI - Novel biodegradable drug-eluting stent composed of poly-L-lactic acid and amorphous calcium phosphate nanoparticles demonstrates improved structural and functional performance for coronary artery disease. AB - Bioabsorbable drug-eluting stents (BDES) offer multiple advantages over a permanent bare metal stent (BMS) for coronary artery disease (CAD). However, current BDES remains two major issues: inferior radial strength and biocompatibility. PowerStent Absorb BDES, fabricated by co-formulating amorphous calcium phosphate (ACP) nanoparticles with poly-L-lactic acid (PLLA/ACP, 98/2, w/w) and 2% Paclitaxel (PAX, w/w) was designed to address these issues. Two cohorts of 6 miniature pigs were each implanted with PLLA/PAX (control, 2% PAX, w/w) or PowerStent Absorb BDES. After 1 month in-vivo study, histological analyses showed significantly reduced restenosis in the PowerStent Absorb BDES cohort relative to the control cohort (44.49 +/- 410.49% vs. 64.47 +/- 16.2%, p < 0.05). Stent recoil (21.57 +/- 5.36% vs. 33.81 +/- 11.49, P < 0.05) and inflammation (3.01 +/- 0.62 vs. 4.07 +/- 0.86, P < 0.01) were also obviously decreased. From in-vitro studies, PLLA/ACP/PAX stent tube maintained significantly greater radial strength than control group during 6 months in-vitro degradation (PLLA/ACP/PAX vs. PLLA/PAX: before hydrolysis: 82.4 +/- 1.9 N vs.74.8 +/- 3.8 N; 6 weeks: 73.9 +/- 1.8 N vs. 68.0 +/- 5.3 N; 3 months: 73.5 +/- 3.4 N vs.67.2 +/- 3.8 N; 6 months: 56.3 +/- 8.1 N vs. 57.5 +/- 4.9 N). Moreover, ACP facilitated the hydrolytic degradation of PLLA compared with control one (62.6% vs. 49.8%), meanwhile, it also increased the crystallinity of PLLA (58.4% vs. 50.7%) at 6 months. From SEM observations, ACP created nanometer pores that enlarge gradually to a micrometer scale as degradation proceeds. The changes of the porosity may result in greatly promoting re-endothelialization. PMID- 24804541 TI - Pegylated glucose gold nanoparticles for improved in-vivo bio-distribution and enhanced radiotherapy on cervical cancer. AB - Pharmacokinetics and bio-distribution are crucial factors affecting the performance of an intravenous drug. In this study, we explore the combined use of glucose and polyethylene glycol (PEG) ligands to further improve gold nanoparticle (GNP) pharmacokinetics and bio-distribution, with the aim of using the drug for in-vivo radiotherapy. The inclusion of PEG was found to significantly prolong the half-life period, where PEG-Glu-GNPs achieved 6.17 +/- 3.71 h, compared to 1.23 +/- 0.14 h for Glu-GNPs and 1.07 +/- 0.22 h for uncoated GNPs. Our data indicates that nanoparticle size impacts cell uptake performance, with 20 nm being the optimal diameter for cancer treatment applications. Although PEG-Glu-GNPs mainly distributed in the spleen, liver, lung, and kidneys, the concentration of PEG-Glu-GNPs in tumour tissue was 20 times higher than healthy cells in the uterus and ovaries, reaching 9.22 +/- 2.41 microg/g cancer tissue at 48 h after injection. This difference in uptake holds promise for selective tumor targeting which can in turn lead to more effective radiotherapy through the interaction of X-rays and GNPs. Specifically tumor size after 47 days of treatment had reduced to (769 +/- 92) mm3 compared to (1432 +/- 269) mm3 using X rays alone and (3514 +/- 1818) mm3 without any treatment. Moreover, the mice remained healthy without statistically significant weight loss. Results of our pharmacokinetic and bio-distribution study as well as therapeutic data for PEG Glu-GNPs in our tumor bearing animal model demonstrate that PEG-Glu-GNPs provide excellent in-vivo stability, tumor targeting function, and radiotherapeutic enhancement effects, providing useful insights for further clinical studies. PMID- 24804542 TI - TET1 exerts its tumor suppressor function by interacting with p53-EZH2 pathway in gastric cancer. AB - TET1 protein is reported to suppress cancer invasion and metastasis in prostate and breast cancer while EZH2, a polycomb group protein, has been identified as an oncogene in many types of cancers including gastric cancer. Here we report that there is an inverse relation of the expression pattern of TET1 and EZH2 in both normal gastric mucosa and gastric cancer. In gastric mucosa, EZH2 is selectively expressed in the proliferating neck cells while TET1 and 5-hydroxymethyl-cytosine (5-hmc) exhibit very low expression in the neck cells. In contrast, TET1 and 5 hmc expression is high in gastric glandular epithelium while EZH2 expression is absent in this cell population. On the other hand, in proliferating Ki67-positive gastric cancer cells, EZH2 is highly expressed while TET1 and 5-hmc expression is significantly down-regulated. When the mouse homologue of human TET1 protein Tet1 is overexpressed in a gastric cancer cell line MGC-803, we observed the dramatically down-regulation of EZH2 in one-third of the Tet1 overexpressed cells. In addition, Tet1 overexpressing cells also lost the H3K27 trimethylation mark and the cell proliferation protein Ki67. Furthermore, Tet1 overexpression induced p53 tumor suppressor protein. The increase of p53 protein level is accompanied by the phosphorylation of p53 by activated DNA-PK. Together, these results suggested a mechanism by which TET1 suppresses cancer formation by coupling DNA demethylation with DNA-PK activation of p53 and suppression of oncogenic protein EZH2. Conversely, loss of TET1 and 5-hmc expression might contribute to EZH2 up-regulation during gastric cancer development. PMID- 24804543 TI - Cytotoxicity of ultrafine monodispersed nanoceria on human gastric cancer cells. AB - The safety and toxicity of CeO2 nanoparticles (nanoceria) are of growing concern due to their potential applications in biological and medical fields based on the radical scavenging and UV-filtering properties. In this paper, the ultrafine monodisperse (2-5 nm) water-insoluble (CeO2-P) and water-soluble nanoceria modified with various functional groups of dextran (CeO2-dextran), polyacrylic acid (CeO2-PAA) and ethylenediamine (CeO2-EDA) on surface were synthesized via alkaline-based precipitation and inverse microemulsion methods. The cell uptaking, oxidative stress and cytotoxicity of these nanoceria on human gastric cancer cell line (BGC-803) were systematically investigated. It is found that the cell uptaking of nanoceria is largely relied on the function groups on its surfaces and followed the order: CeO2-P > CeO2-EDA > CeO2-dextran > CeO2-PAA. Moreover, the oxidative stress of BGC-803 cells is obviously affected by the antioxidant capacity of nanoceria determined by Ce3+/Ce4+ ratio, which eventually causes the cell viability variable once the nanoceria entered into BGC-803 cells. In addition, the cell viability is also closely correlated with the concentration and surface characteristics of nanoceria. The cytotoxicity of nanoceria on BGC 803 cells is largely dependent on its surface functional groups. Our work may provide guidance on the cytotoxicity of ultrafine monodisperse nanoceria for their uses in biological and medical fields. PMID- 24804544 TI - Development of novel nanoparticle for bone cancer. AB - Bone metastasis is responsible for up to 99% of bone tumors. As no cure has yet to be discovered, available treatments simply strive to improve quality of life. One of such treatments is the use of EDTMP (ethylenediamine tetramethylenephosphonic acid) labeled with Samarium-153, which has been shown to improve survival in 70-80% of patients treated. A major disadvantage of this radiopharmaceutical is its superficial delivery, resulting in the need for multiple doses. The current work describes novel polymeric nanoparticles of EDTMP and evaluation of their biodistribution in vivo. Nanoparticles were prepared using a double emulsion-solvent evaporation method and characterized by AFM (atomic force microscopy). Nanoparticles (200-500 nm) were then labeled with Technetium-99m for biodistribution analysis in healthy Wistar rats. Polymeric nanoparticles of EDTMP were observed to accumulate at bone tissue for long periods of time (150 min), resulting in prolonged release of EDTMP at the target site. This finding suggests that this novel pharmaceutical formulation of EDTMP provides better targeted delivery than free EDTMP and may be a more optimal treatment for management of bone metastasis pain. PMID- 24804545 TI - PRIMA-1 selectively induces global DNA demethylation in p53 mutant-type thyroid cancer cells. AB - The p53 tumor suppressor pathway blocks carcinogenesis by triggering apoptosis and cellular senescence in response to oncogenic stress. Over 50% of human cancers including thyroid cancer carry loss-of-function mutations in the p53 gene. Recently, the identification of mutant p53-reactivating small molecules such as PRIMA-1 (p53 reactivation and induction of massive apoptosis) renders possibilities for the development of more efficient anticancer drugs. Although PRIMA-1 has been widely used for cancer therapy and exhibits a promising anticancer activity, its biological effect, particularly the epigenetic aspect, remains to be well elucidated. The present study attempts to explore the effect of PRIMA-1 on DNA methylation in a panel of thyroid cancer cell lines using luminometric methylation assay (LUMA). Our results showed that only p53 mutant type cells were inhibited upon PRIMA-1 treatment. Conversely, p53 wild-type cells were non-sensitive to PRIMA-1. Moreover, our data demonstrated that PRIMA-1 selectively induced significant global DNA demethylation in p53 mutant-type cells. Mechanically, PRIMA-1 induced global DNA demethylation in these cells mainly through inhibiting the expression of DNA methyltransferase (DNMT) 1, 3a and 3b, and upregulating the expression of GADD45a. Notably, PRIMA-1 dramatically increased the expression of the ten-eleven translocation (TET) family of 5mC hydroxylases, particularly TET1, in p53 mutant-type cells, further contributing to DNA demethylation. Thus, this study uncovered a previously unrecognized and prominent biological effect of PRIMA-1 through which it can cause global DNA demethylation in p53 mutant-type cancer cells mainly by rescuing the function of mutant p53 protein. PMID- 24804547 TI - Functionalized gold nanorods for thermal ablation treatment of bladder cancer. AB - Nanomaterial-directed, photothermal ablation is a practical future approach for the treatment of early-stage bladder cancer. Using a new PEGylation technique with bi-functional nitrophenyl carbonate PEG (bi-NPC-PEG) that promotes uniform suspension of the nanomaterial in solution, we have shown that gold nanorods conjugated to an anti-EGFR antibody (nano-alphaEGFR) bind effectively to EGFR expressing bladder cancer cells. The subsequent application of infrared light, specifically tuned to the plasmon resonance of the nanorods used in this work, allows for the specific heating of nano-alphaEGFR to the point of localized cellular death. Such an approach, administering nano-alphaEGFR intravesically via a urinary catheter and infrared light via a modified cystoscope, represents a novel, future clinical application of this technology, which avoids the problem of systemic exposure and clearance of nanoparticles from body. PMID- 24804546 TI - Highly specific targeting of human leukocytes using gold nanoparticle-based biologically active conjugates. AB - In this study we demonstrate for the first time a new approach for highly specific targeting of viable human leukocytes by functionalised gold nanoconjugates made on the basis of citrate-stabilised gold nanoparticles. This immobilisation involves highly specific recognition of the cells of interest by plasma membrane-associated receptor ligands or functional antibodies attached to gold nanoconjugates. Using this technology we managed to deliver pharmacological inhibitors into the target cells. Also we immobilized fully functional human leukocytes utilising both cell lines and rare primary human cells (basophils). This approach demonstrates possibilities of using nanoconjugates for diagnostics, drug delivery and immune therapy. PMID- 24804548 TI - Influence of silver nanoparticles on osteogenic differentiation of human mesenchymal stem cells. AB - Silver nanoparticles (Ag NPs) have been widely used in bone grafts due to their antimicrobial/antiviral properties. Despite extensive research focused on the cytotoxicity and genotoxicity of Ag NPs, little is known of their effect on cell differentiation. In this study, the uptake of Ag NPs and its effect on the osteogenic differentiation of human mensenchymal stem cells (hMSCs) were investigated in vitro. Ag NPs with a diameter of -30 nm were prepared. The hMSCs were exposed to different concentrations of Ag NPs, i.e., 0, 10, 50 and 100 microg/mL. The results show that Ag NPs cause cytotoxicity of hMSCs. It is also demonstrated that the uptake of Ag NPs does not affect the alkaline phosphatase activity, osteocalcin gene expression, osteopontin expression and mineralization level of hMSCs. The uptake of Ag NPs does not influence the osteogenic differentiation of hMSCs. This will give a positive reference for the application of Ag NPs in bone tissue engineering, especially their incorporation with stem cells in bone grafts. PMID- 24804549 TI - Biophysical interactions of polyamidoamine dendrimer coordinated Fe3O4 nanoparticles with insulin. AB - Advanced delivery systems, such as nano/micro carriers have not been studied significantly for their molecular interactions with serum proteins and other biologically relevant macromolecules. Here, we investigated the effect of surface chemistry of iron oxide (Fe3O4) nanoparticles on molecular interactions with human insulin by fluorescence, XRD and FTIR spectroscopy. Nanoparticles of Fe3O4 were chemically modified as Fe3O4-glutathione (GSH) and Fe3O4-GSH-polyamidoamine generation 4 (PAMAM G4) dendrimer. Our results demonstrate that, Fe3O4 and its conjugates such as Fe3O4-GSH, Fe3O4-GSH-G4 quenched insulin fluorescence, indicating strong interactions between insulin protein molecule and Fe3O4. The fluorescence quenching constants Ksv were obtained as 0.0367 x 10(3), 0.0303 x 10(3) and 0.0131 x 10(3) M and the binding constant K were found to be 27.095, 8.404 and 6.026 mM for Fe3O4, Fe3O4-GSH and Fe3O4-GSH-PAMAM G4, respectively. Both the Ksv and K (binding constant) values revealed that the interaction of Fe3O4 with insulin to be stronger over to dendrimer conjugates. In addition, the FTIR spectra suggested that the presence of nanoparticles results in secondary structure alteration in the insulin conformation. The study implies the critical evaluation of new delivery systems in establishing the biocompatibility, especially when delivered by systemic route. PMID- 24804550 TI - Development of artificial dermis using 3D electrospun silk fibroin nanofiber matrix. AB - Several auto- or alloplastic dermal substitutes have been used for full thickness skin defects. However, there is no ideal dermal substitute that is biocompatible and offers adequate mechanical properties and sufficient thickness and volume. Silk fibroin can be considered a possible alternative material for the construction of dermal substitutes. Nanofibers fabricated by electrospinning silk fibroin were considered an excellent candidate due to their desirable biocompatibility. However, it is generally difficult for cells to infiltrate the electrospun silk fibroin due to its small pore size. To overcome this challenge, a key parameter is the control of the pore size of silk fibroin electrospun such that cells can easily infiltrate into the nanofibers and proliferate internally. In this work, a novel approach is introduced by dropping two different size NaCl crystals above the rotating collector, which become incorporated into the nanofibers. The structures and properties of the, resulting electrospun silk fibroin were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and its wound healing effect for a full thickness skin defect was compared with Matriderm. Although the dermal regenerative effect of the 3D-SF (3D electrospun silk fibroin nanofiber matrix) was similar to that of Matriderm, the 3D-SF was almost completely degraded and did not induce wound contracture like Matriderm. We suggest that 3D-SF can be applied to the treatment of full thickness skin defects. PMID- 24804551 TI - Novel dual drug-loaded block ionomer complex micelles for enhancing the efficacy of chemotherapy treatments. AB - Combination of two or more drugs has emerged as a promising strategy to elicit synergistic therapeutic responses that can overcome multidrug resistance of cancer cells at various stages of the growth cycle. In the current study, we investigated the efficacy of two drugs, mitoxantrone (MTX) and doxorubicin (DOX), co-encapsulated in a polyethylene oxide-b-polyacrylic acid polymer. The resulting block ionomer complex (BIC)-based combination chemotherapy provides a novel method for enhancing the therapeutic efficacy of chemotherapies. The BIC micelles were very stable at physiological pH, and showed a temporally sequenced release profile for the co-encapsulated drugs at tumor pH. This suggests that the micelles can deliver chemotherapeutic agents at the appropriate cellular stage. At a predetermined and carefully controlled ratio (MTX:DOX = 2:1), the two drugs worked synergistically within A549 small lung cancer cells. Taken together, these findings suggest that the synergistic activity of ratiometrically controlled drug combinations can enhance their chemotherapeutic action and overall therapeutic index. PMID- 24804552 TI - Design and in vitro evaluation of simvastatin-hydroxyapatite coatings by an electrochemical process on titanium surfaces. AB - The aim of this study was to deposit simvastatin-hydroxyapatite (sim-HA) coatings on titanium surfaces by an electrochemical process and evaluate osteoprogenitor cell responses to sim-HA-coated surfaces. Simvastatin was prepared onto titanium surfaces with varying concentration (10(-7), 10(-6), 10(-5) and 10(-4) mol/L). Surface characteristics were performed by FSEM, XRD and FTIR. LC-MS/MS method was used for simvastatin quantification in Sim-HA-coated surfaces. Murine calvaria derived pre-osteoblastic cell (MC3T3-E1) proliferation, alkaline phosphatase activity (ALP) and osteocalcin release were used to measure osteoblastic activities. FSEM observation showed rod-like HA crystals covered on all surfaces. As drug concentration increased, the crystal diameter decreased. XRD and FTIR observations showed all coatings consisted of HA. LC-MS/MS test showed the simvastatin concentration in 10(-6) mol/L group was 2.77 x 10(-7) mol/L/cm2, while in 10(-7) mol/L group was 1.89 x 10(-7) mol/L/cm2. MC3T3-E1 cells grown on 10(-7) mol/L and 10(-6) mol/L Sim-HA surfaces showed increased ALP activity as compared to HA-coated surfaces on day 7 (P < 0.05) while at 10 day, all Sim-HA groups were significantly increased than HA group (P < 0.05). Two Sim-HA groups showed significant increases in osteocalcin production on 7 10 and 14 day (P < 0.05). It showed that incubation with 10(-7) mol/L simvastatin enhanced the cell proliferation to a statistically significant extent (P < 0.05) compared with the HA group at day 7. It was concluded that simvastatin was successfully deposited into HA coatings using the electrochemical process and the sim-HA coatings enhanced differentiation of osteoprogenitor cells. PMID- 24804553 TI - Pre-adsorption of protein on electrochemically grooved nanostructured stainless steel implant and relationship to cellular activity. AB - The successful integration of a biomedical device is governed by the surface properties of the material and also depends on the interaction with the physiological fluid involving adsorption of proteins on the surface. Pre-adsorbed proteins act as pilots for cell adhesion and subsequently govern cellular activity. In this regard, nanograined materials are excellent vehicles to obtain an unambiguous understanding of protein adsorption, which regulate cell adhesion and cellular activity. Toward this end, we have used the concept of phase reversion-induced nanograined structure to understand grain structure-induced self-assembly of a model protein, bovine serum albumin. Furthermore, in the context of bio-mechanical interlocking between implant and bone, and osseointegration of the implant, grain boundaries were electrochemically grooved and studied for osteoblast functions. Experiments indicated that the significant differences in cell attachment, proliferation, and expression level of prominent proteins (actin, vinculin, and fibronectin) is related to synergistic effects of grain structure, pre-adsorbed protein, and grooving of grain boundaries such that the osteoblasts functions and cellular activity is promoted on the nanostructured surface in relation to the coarse-grained counterpart. PMID- 24804554 TI - Intracellular pH-sensing using core/shell silica nanoparticles. AB - An in-depth understanding of biochemical processes occurring within biological systems is key for early diagnosis of disease and identification of appropriate treatments. Nanobiophotonics offers huge potential benefits for intracellular diagnostics and therapeutics. Intracellular sensing using fluorescent nanoparticles is a potentially useful tool for real-time, in vivo monitoring of important cellular analytes. This work is focused on synthesis of optical chemical nanosensors for the quantitative analysis of pH inside living cells. The structure of the nanosensor comprises a biofriendly silica matrix with co encapsulated Texas Red, acting as a reference dye, and pH-sensitive fluorescein isothiocyanate enabling ratiometric quantitative environmental detection. In order to obtain silica-based nanoparticles -70 nm in size, a modified sol-gel based Stober method was employed. The potential of these nanosensors for intracellular pH monitoring is demonstrated inside a live human embryonic kidney cell line whereby a significant change in fluorescence is observed when the cell pH is switched from acidic to basic. High loading efficiencies of nanoparticles into the cells is seen, with little effect on cell morphology even following extended nanoparticle exposure (up to 72 h). Nanoparticle incubation time and the fast response of the nanosensor (-2 s) make it a very powerful tool in monitoring the processes occurring within the cytosol. PMID- 24804555 TI - Layer-by-layer immobilized catalase on electrospun nanofibrous mats protects against oxidative stress induced by hydrogen peroxide. AB - Catalase, a kind of redox enzyme and generally recognized as an efficient agent for protecting cells against hydrogen peroxide (H2O2)-induced cytotoxicity. The immobilization of catalase was accomplished by depositing the positively charged chitosan and the negatively charged catalase on electrospun cellulose nanofibrous mats through electrospining and layer-by-layer (LBL) techniques. The morphology obtained from Field emission scanning electron microscopy (FE-SEM) indicated that more orderly arranged three-dimension (3D) structure and roughness formed with increasing the number of coating bilayers. Besides, the enzyme-immobilized nanofibrous mats were found with high enzyme loading and activity, moreover, X ray photoelectron spectroscopy (XPS) results further demonstrated the successful immobilization of chitosan and catalase on cellulose nanofibers support. Furthermore, we evaluated the cytotoxicity induced by hydrogen peroxide in the Human umbilical vascular endothelial cells with or without pretreatment of nanofibrous mats by MTT assay, LDH activity and Flow cytometric evaluation, and confirmed the pronounced hydrogen peroxide-induced toxicity, but pretreatment of immobilized catalase reduced the cytotoxicity and protected cells against hydrogen peroxide-induced cytotoxic effects which were further demonstrated by scanning electron microscopy (SEM) and Transmission Electron Microscopy (TEM) images. The data pointed toward a role of catalase-immobilized nanofibrous mats in protecting cells against hydrogen peroxide-induced cellular damage and their potential application in biomedical field. PMID- 24804556 TI - Aptamer-fluorescent silica nanoparticles bioconjugates based dual-color flow cytometry for specific detection of Staphylococcus aureus. AB - This paper describes a sensitive and specific determination strategy for Staphylococcus aureus (S. aureus) detection using aptamer recognition and fluorescent silica nanoparticles (FSiNPs) label based dual-color flow cytometry assay (Aptamer/FSiNPs-DCFCM). In the protocol, an aptamer, having high affinity to S. aureus, was first covalently immobilized onto chloropropyl functionalized FSiNPs through a click chemistry approach to generate aptamer-nanoparticles bioconjugates (Aptamer/FSiNPs). Next, S. aureus was incubated with Aptamer/FSiNPs, and then stained with SYBR Green I (a special staining material for the duplex DNA). Upon target binding and nucleic acid staining with SYBR Green I, the S. aureus was determined using two-color flow cytometry. The method took advantage of the specificity of aptamer, signal amplification of FSiNPs label and decreased false positives of two-color flow cytometry assay. It was demonstrated that these Aptamer/FSiNPs could efficiently recognize and fluorescently label target S. aureus. Through multiparameter determination with flow cytometry, this assay allowed for detection of as low as 1.5 x 10(2) and 7.6 x 10(2) cells mL(-1) S. aureus in buffer and spiked milk, respectively, with higher sensitivity than the Aptamer/FITC based flow cytometry. PMID- 24804557 TI - Enhanced anticancer activity and circumvention of resistance mechanisms by novel polymeric/ phospholipidic nanocarriers of doxorubicin. AB - Severe toxic side effects and drug resistance are the major limitations of doxorubicin (Dox), one of the most potent anticancer agents in clinical use. Nanocarrier preparations offer the opportunity to overcome these drawbacks, which is reflected in the clinical approval of two liposomal Dox preparations. Additionally, there are many attempts to enhance the activity of Dox against multi-drug resistant (MDR) cancer cells. However, most of these strategies resulted in the increased uptake of Dox in resistant cells, only, while it remained unchanged in chemo-sensitive cells. Here, we present a new polymeric phospholipidic hybrid delivery system which distinctly enhanced the accumulation and activity of Dox in all tested cancer cell lines including several MDR cell models. Notably, the resistance levels against Dox were reduced from about 6-fold to about 2-fold. Moreover, the new nanocarriers were shown to rapidly (within 10 min) and effectively transport Dox into resistant as well as sensitive cancer cells. Consequently, treatment with the new Dox-containing nanocarriers resulted in effective cell cycle arrest in G2/M phase and ROS-induced cell death induction. Finally, the new nanocarriers were tested against NK/Ly lymphoma and L1210 leukemia cells in vivo. In both cell models, the nanoformulation of Dox resulted in 100% cured animals already at low concentrations (0.1 mg/kg), while free Dox solely extended survival time. This indicates that the incorporation of phospholipids into PEGylated polymeric nanocarriers is a promising strategy to enhance efficacy and reduce toxicity of Dox treatment against both sensitive and resistant cancer models in vitro and in vivo. PMID- 24804558 TI - Effect of iontophoresis on topical delivery of doxorubicin-loaded solid lipid nanoparticles. AB - The combination of iontophoresis with solid lipid nanoparticles (SLNs) for targeting drug delivery to the epidermis has not been explored. The goal of this paper was to study the influence of iontophoresis on the penetration of doxorubicin (DOX) delivered in SLNs (DOX-SLNs). We measured the contribution of electroosmotic flow to the transport of DOX, and the accumulation of DOX in the stratum corneum (SC) and in the viable epidermis was determined. In addition, we evaluated the cytotoxicity of DOX-SLNs against skin cancer cells. Iontophoresis of unloaded SLNs decreased the electroosmotic flow by a factor of 5 and increased the skin resistance. Nevertheless, iontophoresis of DOX-SLNs increased DOX delivery to the viable epidermis, with 56% of all DOX penetrating this skin layer. Only 26% of the drug was retained in the SC. In contrast, passive delivery retained 43% of DOX in the SC and 26% in the viable epidermis. DOX-SLNs increased DOX cytotoxicity against melanoma cells by 50%. These results suggest the use of DOX-SLN iontophoresis in the topical treatment of skin cancer. PMID- 24804559 TI - Gene therapy with biosynthetic nanoscale peptide Cecropin A driven by the survivin promoter for hepatocarcinoma cells. AB - The biosynthetic nanoscale peptide Cecropin A is postulated to disrupt microbial phospholipid membranes by forming stable or transient pores. We demonstrated previously that green fluorescent protein (GFP), driven by the survivin promoter, was expressed highly in HepG2 but not in LO2 cells when they were transfected with the recombinant plasmid reporter vector (pSURV-GFP). To investigate the selective killing effect of this survivin promoter-driven peptide toxin gene system on hepatocellular carcinoma (HCC) cells in vitro, the recombinant plasmid pSURV-Cecropin A was constructed. HepG2 and LO2 cells were then transfected with the recombinant plasmid, which was driven by the survivin promoter, and the effects of Cecropin A were evaluated. Forty-eight hours after transfection with pSURV-Cecropin A, the growth of HepG2 cells was inhibited significantly. This finding was confirmed further by immunoblotting, which revealed consistently suppressed expression of proliferating cell nuclear antigen (PCNA) and cysteinyl aspartate specific proteinase-3 (caspase-3). Data demonstrated that the plasmid carrying the gene for the Cecropin A fusion protein was constructed successfully, and that its specific expression in HepG2 cells could provide the basis for targeted gene therapy in HCC. The identification of novel gene therapies for cancer is highly desirable to reduce drug toxicity and improve therapeutic outcomes.. PMID- 24804560 TI - Molecular epidemiology and virulence factors of pyogenic liver abscess causing Klebsiella pneumoniae in China. AB - The molecular epidemiology and prevalence of virulence factors of isolates from patients with Klebsiella pneumoniae liver abscess (KLA) in mainland China are unknown. Klebsiella pneumoniae isolates were obtained from drainage samples aseptically collected from patients with pyogenic liver abscess (PLA). The genetic similarity of KLA isolates was analyzed by pulsed-field gel electrophoresis. The hypermucoviscosity (HV) phenotype was identified by a positive string test. The K1 and K2 genotypes, the pLVPK-derived genetic loci, aerobactin gene, kfu and alls were detected by PCR amplification. The sequence types (STs) were identified by multilocus sequence typing. Among the 51 non repetitive KLA isolates, 49 PFGE types have been identified. In total, 19 (37.2%) and 14 (27.4%) of the 51 KLA isolates belonged to clonal complex (CC) 23 and CC65, respectively, while the other 18 isolates (35.3%) were defined as other STs. CC23 consisted of only K1 strains, while CC65 included only K2 strains. All non-K1/K2 strains were classified as STs other than CC23 and CC65. Approximately 70.6% (36/51) of KLA isolates exhibited an HV phenotype. Both K1 and K2 isolates presented significantly higher prevalence of the pLVPK-derived loci than non K1/K2 isolates. The K1 isolates had a significantly higher prevalence of the kfu and allS genes than K2 and non-K1/K2 isolates, while the K2 isolates exhibited higher repA prevalence than K1 and non-K1/K2 isolates. The majority of KLA isolates belonged to CC23K1 and CC65K2, while other STs with non-K1/K2 capsular types have also been identified. The virulent factors exhibited diverse distribution among the different clones of KLA isolates. PMID- 24804561 TI - Audit and feedback intervention: An examination of differences in chiropractic record-keeping compliance. AB - Objective : The objective of this study was to investigate the association of a clinical documentation quality improvement program using audit-feedback with clinical compliance to indicators of quality chart documentation. Methods : This was an analysis of differences between adherence to quality indicators of chiropractic record documentation and audit-feedback intervention (feedback report only vs. feedback report with one-on-one educational consultation) at different campuses. Comparisons among groups were analyzed using analysis of variance (ANOVA), Tukey or Dunnett post hoc tests, and Cohen's d effect size estimates. Results : There was a significant increase in the mean percentile compliance in 2 of 5 compliance areas and 1 of 11 compliance objectives. Campus B demonstrated significantly higher levels of compliance relative to campus A and/or campus C in 5 of 5 compliance areas and 7 of 11 compliance objectives. Across-campus comparisons indicated that the compliance area Review (Non Medicare) Treatment Plan [F(2,18) = 17.537, p < .001] and compliance objective Treatment Plan Goals [F(2,26) = 5.653, p < .001] exhibited the highest practical importance for clinical compliance practice. Conclusions : Feedback of performance improved compliance to indicators of quality health record documentation, especially when baseline adherence is relatively low. Required educational consultations with clinicians combined with audit-feedback were no more effective at increasing compliance to indicators of quality health record documentation than audit-feedback alone. PMID- 24804562 TI - Blood lead levels in children attending a tertiary teaching hospital in Enugu, south-eastern Nigeria. AB - BACKGROUND: Reports have demonstrated widespread lead contamination of the Enugu environment and the possibility of childhood lead poisoning. OBJECTIVE: To determine the blood lead levels of children attending University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu, Enugu State. METHOD: Blood samples from 100 children were analysed for blood lead concentration using an atomic absorption spectrometer. RESULTS: The mean (SD) age was 6.2 (2.13) years (range 1 15) and the mean (SD) blood lead level was 8.7 (5.4) MUg/dl (range 0.3-17.7). Thirty-three per cent of the children had blood lead levels >10 MUg/dl, which is the United States Center for Disease Prevention and Control action limit, and 36% of the children had blood lead levels of 5-10 MUg/dl. Mean (SD) blood lead level in the 6-10-years age group was 11.3 (5.7) MUg/dl and 9.4 (4.6) MUg/dl in the >10 years age group, which is significantly higher than in the 1-5-years age group [7.5 (5.1) MUg/dl, P = 0.03]. Males had significantly higher mean (SD) blood lead levels than females [9.6 (5.8) vs 6.8 (3.8), P = 0.03]. CONCLUSION: One-third of children had blood lead levels >10 MUg/dl, particularly older and male children. Blood lead screening should be considered for sick children, and further screening of blood lead levels in children should be undertaken in Enugu and other parts of Nigeria, and efforts made to identify the sources of exposure. PMID- 24804563 TI - TROSY NMR with a 52 kDa sugar transport protein and the binding of a small molecule inhibitor. AB - Using the sugar transport protein, GalP, from Escherichia coli, which is a homologue of human GLUT transporters, we have overcome the challenges for achieving high-resolution [(15)N-(1)H]- and [(13)C-(1)H]-methyl-TROSY NMR spectra with a 52 kDa membrane protein that putatively has 12 transmembrane-spanning alpha-helices and used the spectra to detect inhibitor binding. The protein reconstituted in DDM detergent micelles retained structural and functional integrity for at least 48 h at a temperature of 25 degrees C as demonstrated by circular dichroism spectroscopy and fluorescence measurements of ligand binding, respectively. Selective labelling of tryptophan residues reproducibly gave 12 resolved signals for tryptophan (15)N backbone positions and also resolved signals for (15)N side-chain positions. For improved sensitivity isoleucine, leucine and valine (ILV) methyl-labelled protein was prepared, which produced unexpectedly well resolved [(13)C-(1)H]-methyl-TROSY spectra showing clear signals for the majority of methyl groups. The GalP/GLUT inhibitor forskolin was added to the ILV-labelled sample inducing a pronounced chemical shift change in one Ile residue and more subtle changes in other methyl groups. This work demonstrates that high-resolution TROSY NMR spectra can be achieved with large complex alpha-helical membrane proteins without the use of elevated temperatures. This is a prerequisite to applying further labelling strategies and NMR experiments for measurement of dynamics, structure elucidation and use of the spectra to screen ligand binding. PMID- 24804565 TI - Palladium-catalyzed C(sp2)-H pyridocarbonylation of N-aryl-2-aminopyridines: dual function of the pyridyl moiety. AB - An efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-one through palladium catalyzed C(sp(2))-H pyridocarbonylation of N-aryl-2-aminopyridines has been developed. The pyridyl group acts as an intramolecular nucleophile for the first time in C-H carbonylation reactions. PMID- 24804564 TI - Understanding the utility of emotional approach coping: evidence from a laboratory stressor and daily life. AB - BACKGROUND: Dispositional emotional approach coping (EAC) marks an adaptive tendency to process and express emotions. EAC's association with cognitions, affect, and intra- and interindividual characteristics that may account for its utility was examined in response to an acute stressor and in daily life. DESIGN: This study included a laboratory stress task and ecological momentary assessment. METHODS: Healthy undergraduate students (n = 124; mean age: 20; women: 56%) completed a laboratory component (baseline survey, speech stress task, pre- and posttask measures) and five subsequent days of surveys via palm pilot (six surveys/day). RESULTS: Controlling for sex, neuroticism, and social support, greater EAC was associated with more positive cognitive appraisals, personal resources, and positive affect and less-negative affect during the lab stressor, and with more perceived control and positive affect in daily life. Significant EAC * sex interactions were found for poststressor affect: men with high EAC reported more positive affect and women with high EAC reported less negative affect. CONCLUSIONS: Findings provide support that EAC's utility may be independent of intra- and interindividual characteristics, and that men and women may benefit from EAC in different ways in regards to affect. The proclivity to use EAC may come with a resiliency that protects against stress and promotes general well-being. PMID- 24804567 TI - Synergistic adsorption of MIBC/CTAB mixture at the air/water interface and applicability of Gibbs adsorption equation. AB - The synergistic adsorption of a binary surfactant mixture was investigated by tensiometry and neutron reflectometry. The results directly contradicted the conventional Gibbs adsorption equation. The accompanied molecular simulation demonstrated a multilayer arrangement at the synergic conditions, with three distinctively oriented water layers. The positive synergism can be explained by considering the relationship between water orientation and surface tension, in a similar manner to Langmuir's proposal in 1920s. In spite of the supporting evidence, the relationship has not been quantified in literature. The molecular orientation and arrangement are not included in the current theoretical framework, which simplifies the adsorbed zone into a single monolayer. A new theoretical framework is needed to properly quantify the interfacial adsorption for the mixed surfactant systems. PMID- 24804566 TI - Models of chromosome structure. AB - Understanding the mechanisms that control chromosome folding in the nucleus of eukaryotes and their contribution to gene regulation is a key open issue in molecular biology. Microscopy and chromatin-capture techniques have shown that chromatin has a complex organization, which dynamically changes across organisms and cell types. The need to make sense of such a fascinating complexity has prompted the development of quantitative models from physics, to find the principles of chromosome folding, its origin and function. Here, we concisely review recent advances in chromosome modeling, focusing on a recently proposed framework, the Strings & Binders Switch (SBS) model, which recapitulates key features of chromosome organization in space and time. PMID- 24804568 TI - Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA C donor-specific antibodies. AB - Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti HLA-C DSAs are likely to develop acute AMR during the first year after transplantation. PMID- 24804569 TI - Immunohistochemistry in the diagnosis of papillary lesions of the breast. AB - AIMS: Many immunohistochemical markers have been studied for differentiating papillary lesions. However, their differentiating power has not been evaluated comprehensively. Additionally, assessment of some markers will require the difficult task of identifying different cell types. In the current study, we aimed to devise a simple papillary panel which can aid in diagnosis irrespective of architectural pattern and cell type differentiation. METHODS AND RESULTS: Immunohistochemical analysis of papillary lesions using myoepithelial markers [p63 and smooth muscle actin (SMA)], high molecular weight cytokeratins (HMWCKs: CK5, CK5/6, CK14 and 34betaE12), hormone receptors (ER and PR) and neuroendocrine markers (chromogranin and synaptophysin) was performed. Among them, neuroendocrine markers showed high specificity but low sensitivity. HMWCK specificity was better than that for myoepithelial markers. Homogeneous staining pattern for hormonal receptors rather than their percentage positivity was more effective in identifying malignant lesions. Negative staining for two or more of HMWCKs, namely CK5/6, CK14 and 34betaE12, achieved the best overall specificity and sensitivity of 87.8% and 94.1%, respectively, irrespective of the architecture. Their discriminatory power was validated with an independent cohort of core needle biopsies. CONCLUSIONS: A marker panel with HMWCKs could be used in differentiating papillary lesions irrespective of architectural pattern or cell type differentiation. PMID- 24804570 TI - Coupled effects of aging and weak magnetic fields on sequestration of selenite by zero-valent iron. AB - The sequestration of Se(IV) by zero-valent iron (ZVI) is strongly influenced by the coupled effects of aging ZVI and the presence of a weak magnetic field (WMF). ZVI aged at pH 6.0 with MES as buffer between 6 and 60 h gave nearly constant rates of Se(IV) removal with WMF but with rate constants that are 10- to 100-fold greater than without. XANES analysis showed that applying WMF changes the mechanism of Se(IV) removal by ZVI aged for 6-60 h from adsorption followed by reduction to direct reduction. The strong correlation between Se(IV) removal and Fe2+ release suggests direct reduction of Se(IV) to Se(0) by Fe0, in agreement with the XANES analysis. The numerical simulation of ZVI magnetization revealed that the WMF influence on Se(IV) sequestration is associated mainly with the ferromagnetism of ZVI and the paramagnetism of Fe2+. In the presence of the WMF, the Lorentz force gives rise to convection in the solution, which narrows the diffusion layer, and the field gradient force, which tends to move paramagnetic ions (esp. Fe2+) along the higher field gradient at the ZVI particle surface, thereby inducing nonuniform depassivation and eventually localized corrosion of the ZVI surface. PMID- 24804571 TI - Comment on: the effect of vitamin D on non-specific low back pain. PMID- 24804572 TI - Responding for conditioned reinforcement in C57BL/6 and CD-1 mice, and Sprague Dawley rats: Effects of methylphenidate and amphetamine. AB - RATIONALE: Characterization of responding for conditioned reinforcement in mice is important to implement genetic tools in examining the neurobiological mechanisms underlying reward-related learning and incentive motivation. METHODS: Inbred C57BL/6 mice, outbred CD-1 mice, and outbred Sprague-Dawley rats underwent Pavlovian conditioning in which a conditioned stimulus (CS) was paired with saccharin. Subsequently, subjects were allowed to respond for that CS in tests of responding for conditioned reinforcement. Experiments measured the effects of methylphenidate (MPH) and amphetamine (AMPH) on lever pressing for conditioned reinforcement in mice and rats. We further examined the stability of responding for conditioned reinforcement in mice after repeated testing and the extinction of this behaviour following omission of the reinforcer. We also determined whether the CS exhibited reinforcing properties if it was not paired with saccharin. RESULTS: C57BL/6 and CD-1 mice learned to respond for a conditioned reinforcer similarly to rats, and the behaviour was stable over time. MPH increased responding in CD-1 mice and rats, but not in C57BL/6 mice. AMPH only increased responding in rats. Responding was reduced following omission of the conditioned reinforcer, and responding was only established when the CS was paired with saccharin. CONCLUSIONS: These experiments characterize a conditioned reinforcement test which produces stable responding in two different mouse backgrounds. These findings also show that dopaminergic psychomotor stimulants can differently affect rats and mice in tests of responding for conditioned reinforcement. PMID- 24804573 TI - The gap between births intended and births achieved in 22 European countries, 2004-07. AB - Using data from the 2004 and 2007 waves of the European Social Survey (ESS), we find that for every 100 births intended, about 60 births occur, on average, across 22 countries. This shortfall in fertility masks substantial heterogeneity between subgroups within the populations surveyed. Motherhood status, age, partnership status, and the strength of fertility intentions moderate the relationship between women's childbearing plans and births measured at the country level. Individual-level analyses using data from three countries included in the 2005 and 2008 waves of the Generations and Gender Survey are consistent with our country-level analyses. We demonstrate that repeat cross-sectional data can be used to analyse the correspondence between childbearing plans and births when longitudinal data are lacking. PMID- 24804574 TI - Brief review: chemotherapy-induced painful peripheral neuropathy (CIPPN): current status and future directions. AB - PURPOSE: Chemotherapy-induced painful peripheral neuropathy (CIPPN) affects up to 90% of cancer patients treated with chemotherapy agents. Despite the fact that it is relatively common, the underlying pathophysiology is still unclear and its treatment remains generic. Mechanisms of CIPPN are multifactorial, dependent on the specific chemotherapeutic agent used, and include multiple patient-related factors, including genetic factors that may predispose patients to either develop or not develop CIPPN. The purpose of this article is to review mechanisms, clinical signs and symptoms, diagnosis, treatment options, and prognosis for patients who develop CIPPN. We also offer research considerations for this complex and unpredictable phenomenon. PRINCIPAL FINDINGS: Chemotherapeutic agents can damage the peripheral nervous system, including the nerve terminals, axons, cell body, and myelin sheath of sensory nerves. Herein, we describe some of the anatomical and functional changes that are thought to take place at various levels of the nervous system. On a clinical level, patients with CIPPN report multiple symptoms. It is essential to obtain an accurate history from the patient and to perform a thorough physical examination in order to obtain the patient's subjective perspective. Additionally, objective measurements may be needed in order to articulate clearly the effects of this complex syndrome and to ensure an accurate diagnosis, treatment, and prognosis. CONCLUSIONS: The management of CIPPN remains a clinical challenge for pain practitioners. As more research is being carried out to elucidate its pathophysiology and therapy, the innovative use of several non-traditional categories of drugs seems promising in the management of this complex phenomenon. Studies addressing predictability and possible genetic predisposition are necessary not only for preventive measures but also for targeted treatments. PMID- 24804575 TI - Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity. AB - We report the synthesis of a family of D- and L-furano-D-apionucleosides, their 3'-deoxy, as well as their 2',3'-dideoxy analogues with thymine and adenine nucleobases. Single carbon homologation of 1,2-O-isopropylidene-D-glycero tetrafuranos-3-ulose (15) and optimized glycosylation conditions involving microwave irradiation were key to the successful synthesis of the target compounds. While all target nucleosides failed to show significant antiviral activity, we demonstrated that the triphosphate of 2',3'-deoxy-D-apio-D furanoadenosine (1), in contrast to that of its D-apio-L-furanose epimer 2, was readily incorporated into a DNA template by HIV reverse transcriptase to act as a DNA chain terminator. This led us to convert adenine derivative 1 into two phosphoramidate prodrugs. ProTide 9b was found active against HIV-1 and HIV-2 (EC50 = 0.5-1.5 MUM), indicating that the lack of activity of the parent nucleoside, and possibly also other members of the D-apio-D-furanose nucleoside family must be sought in the inefficient cellular conversion to the monophosphate. PMID- 24804578 TI - Chromosome-centric human proteome project: deciphering proteins associated with glioma and neurodegenerative disorders on chromosome 12. AB - In line with the aims of the Chromosome-centric Human Proteome Project (C-HPP) to completely annotate proteins of each chromosome and biology/disease driven HPP (B/D-HPP) to decipher their relation to diseases, we have generated a nonredundant catalogue of protein-coding genes for Chromosome 12 (Chr. 12) and further annotated proteins associated with major neurological disorders. Integrating high level proteomic evidence from four major databases (neXtProt, Global Proteome Machine (GPMdb), PeptideAtlas, and Human Protein Atlas (HPA)) along with Ensembl data resource resulted in the identification of 1066 protein coding genes, of which 171 were defined as "missing proteins" based on the weak or complete absence of experimental evidence. With functional annotations using DAVID and GAD, about 40% of the proteins could be grouped as brain related with implications in cancer or neurological disorders. We used published and unpublished high confidence mass spectrometry data from our group and other literature consisting of more than 5000 proteins derived from clinical specimens from patients with human gliomas, Alzheimer's disease, and Parkinson's disease and mapped it onto Chr. 12. We observed a total of 202 proteins mapping to human Chr. 12, 136 of which were differentially expressed in these disease conditions as compared to the normal. Functional grouping indicated their association with cell cycle, cell-to-cell signaling, and other important processes and networks, whereas their disease association analysis confirmed neurological diseases and cancer as the major group along with psycological disorders, with several overexpressed genes/proteins mapping to 12q13-15 amplicon region. Using multiple strategies and bioinformatics tools, we identified 103 differentially expressed proteins to have secretory potential, 17 of which have already been reported in direct analysis of the plasma or cerebrospinal fluid (CSF) from the patients and 21 of them mapped to cancer associated protein (CAPs) database that are amenable to selective reaction monitoring (SRM) assays for targeted proteomic analysis. Our analysis also reveals, for the first time, mass spectrometric evidence for two "missing proteins" from Chr. 12, namely, synaptic vesicle 2-related protein (SVOP) and IQ motif containing D (IQCD). The analysis provides a snapshot of Chr. 12 encoded proteins associated with gliomas and major neurological conditions and their secretability which can be used to drive efforts for clinical applications. PMID- 24804579 TI - First cloned swamp buffalo produced from adult ear fibroblast cell. AB - The world's first cloned swamp buffalo (Bubalus bubalis) derived from adult ear skin fibroblast has been reported. Donor fibroblast cells were produced from biopsies taken from adult male ear skin and in vitro matured oocytes obtained from a slaughterhouse were used as cytoplasts. A total of 39 blastocysts and 19 morulae fresh embryos were transferred into 12 recipient buffaloes. Progesterone assays indicated establishment of pregnancy in 10 of the 12 buffaloes (83.3%) after 45 days, with six animals still pregnant at 3 months. One recipient maintained pregnancy to term and naturally delivered a 40 kg male calf after 326 days of gestation. DNA analysis showed that the cloned calf was genetically identical to the donor cells. Genotype analyses, using 12 buffalo microsatellite markers, confirmed that the cloned calf was derived from the donor cell lines. In conclusion, the present study reports, for the first time, the establishment of pregnancy and birth of the first cloned Thai swamp buffalo derived from adult ear skin fibroblast cells. PMID- 24804580 TI - Magnetic control of flexoelectric domains in a nematic fluid. AB - The formation of flexoelectric stripe patterns (flexodomains) was studied under the influence of external electric and magnetic fields in a nematic liquid crystal. The critical voltage and wavevector of flexodomains were investigated in different geometries by both experiments and simulations. It is demonstrated that upon altering the orientation of the magnetic field with respect to the director, the critical voltage and wavenumber behave substantially differently. In the geometry of the twist Freedericksz transition, a non-monotonic behavior as a function of the magnetic field was found. PMID- 24804583 TI - Introduction. PMID- 24804584 TI - Allies in the struggle. AB - SUMMARY Providing a community that is committed to standards, diversity, and enhancement of the academic environment is often difficult. Offering an Allies or Safe Zone program is among of the first steps an institution can take to achieve a community that embraces diversity and creates a learning environment that is accepting of lesbian, gay, bisexual and transgendered individuals. While there are many opportunities in institutional group settings to address these issues, they often go either unnoticed or untapped. How can being an ally impact the greater institutional environment? This paper will discuss the campus environment for LGBT students, examine existing Allies and Safe Zone programs, and offer a framework to assist program coordinators and participants in establishing comprehensive programs to change the campus climate and develop institutional environments that are gay affirmative. PMID- 24804581 TI - Evaluating the promiscuous nature of tyrosine kinase inhibitors assessed in A431 epidermoid carcinoma cells by both chemical- and phosphoproteomics. AB - Deregulation of protein tyrosine kinase signaling has been linked to many diseases, most notably cancer. As a consequence, small molecule inhibitors of protein tyrosine kinases may provide powerful strategies for treatment. Following the successful introduction of imatinib in the treatment of chronic myelogenous leukemia, such drugs are also now evaluated for other types of cancer. However, many developed kinase inhibitors are not very target-specific and therefore may induce side effects. The importance of such side effects is certainly cell proteome dependent. Understanding the all-inclusive action of a tyrosine kinase inhibitor on each individual cell-type entails the identification of potential targets, combined with monitoring the downstream effects revealing the signaling networks involved. Here, we explored a multilevel quantitative mass spectrometry based proteomic strategy to identify the direct targets and downstream signaling effect of four tyrosine kinase inhibitors (imatinib, dasatinib, bosutinib, and nilotinib) in epidermoid carcinoma cells, as a model system for skin-cancer. More than 25 tyrosine kinases showed affinity to the drugs, with imatinib and nilotinib displaying a high specificity, especially when compared to dasatinib and bosutinib. Consequently, the latter two drugs showed a larger effect on downstream phosphotyrosine signaling. Many of the proteins affected are key regulators in cell adhesion and invasion. Our data represents a multiplexed view on the promiscuous action of certain tyrosine kinase inhibitors that needs to be taking into consideration prior to the application of these drugs in the treatment of different forms of cancer. PMID- 24804585 TI - Weaving a wide net. AB - SUMMARY Any single approach tostudents' heterosexism and homophobia, however well conceived and executed, is most successful when supported by an integrated campus approach to the problem. Taking as a model the multifaceted efforts at California State University, Fresno-a large public institution located in what can be considered the state's Bible Belt-this essay discusses the strengths and logistics of a campus-wide program to address homophobia and alleviate LGBTQ students' feelings of alienation from the institution and their oppression in society. The efforts of CSUF take place at a number of different levels classroom, academic department, student services, faculty networking-and can be considered a successful work in progress. PMID- 24804586 TI - The experiences of lesbian and bisexual women in college residence halls. AB - SUMMARY In-depth interviews were conducted with ten lesbian and bisexual women university students to learn about their experiences living in college residence halls. Many of the women reported experiencing a hostile environment as a result of direct and indirect harassment and lack of support from roommates, resident assistants, and other residents. Participants also reported supportive factors that helped to make the environment more comfortable. In particular, these students appreciated residence life staff who actively confronted homophobic acts and showed their support by providing information on lesbian, gay, and bisexual topics. Interviewees provided suggestions for improving the climate in residence halls and for training residence hall staff to work more effectively with lesbian, gay, and bisexual students. Implications are offered for addressing homophobia and heterosexism in women's residence halls. PMID- 24804587 TI - Updating college and university campus policies. AB - SUMMARY This article gathers information not only from my own personal experiences, but also from the experiences of trans students, staff and faculty members with whom I have worked as a human sexuality educator and consultant, and from my current qualitative research on trans youth for my PhD dissertation. As the trans community becomes more visible, and people become more comfortable in asserting their gender non-conforming characteristics, a backlash of harassment and discrimination has been evident across our campuses. Colleges and universities are often ignorant or ill-equipped without accurate knowledge of trans people, and as a result isolate students and employees, or ignore them altogether. This article discusses the current challenges of trans students, staff and faculty members, as well as addresses specific ways in which schools can improve work conditions and provide access to a safe education for all students. PMID- 24804588 TI - The role of lay theories of the etiologies of homosexuality in attitudes towards lesbians and gay men. AB - SUMMARY Previous research has demonstrated that those who believe that homosexuality is genetically or biologically caused have less negative attitudes towards gays and lesbians than those who believe it is acquired, learned, or chosen. This study, utilizing an undergraduate and graduate Psychology student sample, found significant relationships between attitudes towards lesbians and gay men and beliefs about causes and "treatments" for homosexuality. Level of personal contact with lesbians and gay men and demographic factors also influenced attitudes toward and beliefs about homosexuality. These results suggest that educational attempts to change attitudes towards lesbians and gay men should consider the role played by beliefs about the etiologies of homosexuality. PMID- 24804589 TI - A study of attitudes toward sexuality issues among health care students in australia. AB - SUMMARY This study examined the attitudes of 1132 higher education students enrolled in health profession education degree programs. Students were asked to indicate their anticipated level of comfort in a variety of interactions including working with a lesbian client or a homosexual male, and asking a client about his or her sexual orientation. Students also indicated whether they perceived their degree program had dealt adequately with these issues. High levels of discomfort were identified in our large sample of students. Approximately 30% of the sample indicated they would be uncomfortable working with a lesbian client and 27% of the sample indicated that they would feel uncomfortable if working with a male homosexual client. There were significant differences for these two items depending on the student's gender. Female students indicated significantly higher levels of comfort in dealing with homosexual male clients than did their male counterparts. Male students indicated significantly greater comfort in dealing with lesbian clients. More than half of our sample indicated that they would not be comfortable asking about a client's sexual orientation. Over 75% of senior-year students believed that their degree program had not adequately dealt with these issues. The impact of homophobia and discomfort on the quality of care health professionals provide for lesbian and gay clients and the role of educational strategies to reduce this are discussed. PMID- 24804590 TI - Lesbians, gays and religion. AB - SUMMARY This study measured the effects of religious affiliation and gender on attitudes about lesbians and gay men among 2,846 college graduates who were beginning graduate study in social work or counseling. Males were more negative than females in their attitudes toward both lesbians and gay men. Conservative Protestants were the most negative in their attitudes toward lesbians and gay men, while those who were Atheist, Agnostic, Jewish or claimed no religion were most positive. Beliefs that the Bible forbids homosexuality are discussed and readings and arguments challenging this belief that can be used as class content are presented. PMID- 24804591 TI - A lesbian/straight team approach to changing attitudes toward lesbian, gay, bisexual, and transgendered people. AB - SUMMARY Advantages of a lesbian/heterosexual team approach to education on lesbian, gay, bisexual and transgender issues are examined and a case study is analyzed. A lesbian guest lecturer provided a contact experience, personal anecdotes, passion, and expertise. Facilitation of later class discussion by the heterosexual instructor allowed for frank discussion among students, processing of presentation content, and modeling of gay-affirmative attitudes by the instructor and other students. Summaries of the guest lecture (fantasy exercise and informational lecture) and later discussion are provided. Student comments during discussion demonstrated evidence of deep challenge, attitude change, and heightened understanding. PMID- 24804592 TI - Practitioner training for counseling lesbian, gay, and bisexual clients. AB - SUMMARY The combined effects of heterosexual bias and lack of formal training on lesbian, gay, and bisexual (LGB) issues are hypothesized to manifest inappropriate mental health practitioner behaviors. Research on graduate therapist training and student attitudes has found heterosexual bias and inadequacies in preparation to serve LGB clients. The need for graduate level training of mental health practitioners is apparent. This article reviews recommended training methods for providing training in LGB issues. A psychoeducational model developed to concurrently increase trainee awareness, knowledge, and skills in counseling LGB people is presented. Suggestions for implementation of curricula and strategies for use in addressing heterosexism in the training environment are also provided. PMID- 24804593 TI - Policy and practice. AB - SUMMARY This article outlines a variety of structural approaches that together work to interrupt heterosexism and homophobia in social work programs. The approaches offered include policy development, recruitment and hiring practices, and the development of innovative student support services. Program evaluation is suggested as a way to assess program performance and target areas for change. While these strategies are targeted at social work programs, the recommendations in this article are appropriate to most academic disciplines. PMID- 24804594 TI - Addressing homophobia and heterosexism in the mental health classroom. AB - SUMMARY Homophobia and heterosexism among mental health students is addressed through recognizing the intersubjective nature of the instructor-student relationships in the classroom. Theories about human behavior and clinical practice often present heterosexist views that go unchallenged. Unexamined views and prejudices can impact group dynamics and stir internalized homophobia within the sexual minority instructor or student. This article applies an intersubjective perspective to classroom vignettes, and it invites the educator to examine his or her theories and unconscious views as a precursor to providing an open learning environment for discussion and critique. PMID- 24804595 TI - Homophobia and academic freedom. AB - SUMMARY Addressing homophobia and heterosexism as a teacher raises issues of respect for the intellectual freedom of your students. The central thesis of this article is that these issues are best addressed on the basis of general principles of academic freedom-that is, intellectual freedom in educational and research contexts. Three cases are analyzed on the basis of principles developed by the Academic Freedom Coalition of Nebraska (AFCON). These principles permit advocacy, rather than requiring neutrality, but do not permit indoctrination. That is, instructors may express and justify their own ideas relevant to the curriculum and try to convince students to adopt those ideas and/or abandon alternatives, but must not coerce or require belief, censor or punish students who remain unconvinced, or restrict access to alternative views. PMID- 24804596 TI - From homophobia and heterosexism to heteronormativity. AB - SUMMARY By examining homophobia and heterosexism within the larger context of heteronormativity at the intersections of race, class, and gender, I propose, in this article, a model of queer interventions in the university classroom. The article is divided into three sections. First, I describe the conceptual terrain of homophobia, heterosexism, and heteronormativity, and their potential limitations. Second, I present an integrative model, using heteronormativity as the central site of violence, to examine homophobia at the intersections of race, class, and gender within the larger social and cultural domain (macroscopic level) and interpersonal context (microscopic level) and illustrate this model with specific classroom activities. Finally, I discuss the implications of the model for teaching and theorizing about homophobia, heterosexism, and heteronormativity. PMID- 24804597 TI - Transcending heteronormativity in the classroom. AB - SUMMARY Although a growing body of work addresses heterosexism and homophobia in the classroom context, the majority of this literature neglects trans identities and issues. For various reasons, trans existence currently poses particular challenges to many college students and professors. Foremost among these are traditional assumptions about sex, gender, and sexual identities as stable, essential, binary entities, notions that are often grounded in scientific, religious, and political ideologies. In this essay, we first review various conceptualizations of transgenderism and explore the advantages of applying queer theory and critical pedagogical strategies to this subject. Second, based on our work together and our individual experiences, we offer suggestions for facilitating constructive classroom dialogues around "trans-anxieties" and provide examples of student responses to these methods. PMID- 24804598 TI - Journeying together. AB - SUMMARY Three women faculty from different disciplines assert the necessity of initiating a process to confront silence and create voice in order to address heterosexism and homophobia in the classroom. One advocates for the feminist construct of a consciously positional and political voice to improve students' sensitivity to multiculturalism in regard to lesbian, gay, bisexual, and transgendered people (LGBT). Another proposes a process of locating sexual orientation in the wider issues of sexuality and gender constructions, in order to form different assumptions and starting points. A third one challenges faculty members and students to accept that recognizing their own heterosexism and homophobia is the first step in the process of confronting and transforming what they fear. PMID- 24804599 TI - Teaching about heterosexism and creating an empathic experience of homophobia. AB - SUMMARY The concept of the "chilly campus climate" for students has long been used to describe women's experiences. The climate for lesbians and gays has not been assessed in this way; however, the attitudes of students toward diverse groups suggest that generally a hostile environment exists for this population. This paper discusses assessing students' attitudes and how this is essential to the process of teaching about heterosexism. Other pedagogical issues and concerns regarding teaching about heterosexism and homophobia are examined. These include examples of teaching exercises intended to create an empathic response from students that reinforces their cognitive understanding of homophobia. PMID- 24804600 TI - Beyond empathy. AB - SUMMARY Anti-homophobia education is rarely included in the anti-bias curriculum of Education faculties, a grave omission since education graduates will teach in a homophobic school system that oppresses gay and lesbian students. This article draws on my experience in using a range of anti-homophobia strategies to confront homophobia among religious students in critical education courses where the principle of respecting each and every child is foundational. I argue that strategies designed to produce empathy sometimes fail because of the extreme importance attached to homophobia in the religious discourses that structure the identities of these students. At such times we should shift our pedagogical efforts to confront the ethical conflicts between homophobia and the principle of respect. I describe how I focus on the discursive production of both the forms and limits of personal identity, feelings, and beliefs to handle the confrontation productively. Although confronting homophobia sometimes involves hearing hurtful speech, it usefully problematizes the ethical status of homophobic students who are otherwise committed to classroom democracy, often provoking them to adopt less oppressive behaviors. It also usefully exposes the existence of homophobia for other students who might have underestimated it. Both groups end up better prepared to fight homophobia in their work as teachers. PMID- 24804601 TI - The family lecture. AB - SUMMARY This paper describes a lecture about my extended family, in which I discuss a variety of configurations consisting of lesbian, gay, and bisexual adults, and our children. It raises an array of issues, including alternative insemination, biological and nonbiological parentage, donors and birthmothers, adoption, co-parenting and blended families, significant others, and gay marriage and domestic partnership. It helps many students obtain both a more expansive sense of family and adeeper understanding of homophobia. PMID- 24804603 TI - Feature films and documentaries list. PMID- 24804602 TI - Teaching the teachers. AB - SUMMARY This paper presents a conceptual tool designed to help teacher education students think critically about the roots and consequences of personal, parental, community, and institutional resistance to diverse sexual identities and behaviours. To explore the roots of sexualized and gendered prejudice and ground the conceptual tool theoretically, it begins with a careful examination of Judith Butler's work on performativity. The paper then describes and illustrates the conceptual tool. The Continuum of (Subversive) Drag Performance helps stimulate critical thinking about the power implications of people's sexed and gendered performances through its six ranges: Radical, Stealth, Commercial, Passing, Mainstream, and Privileged. Because these ranges are independent of common considerations of "normalcy," they offer teacher education students a relatively unthreatening framework for analyzing conceptions of sexuality and gender that, left unexamined, can contribute to sexism, heterosexism, and homophobia. PMID- 24804604 TI - Risk factors, clinical course and long-term prognosis in hidradenitis suppurativa: a cross-sectional study. AB - BACKGROUND: Hidradenitis suppurativa (HS) causes considerable morbidity. The long term prognosis is of obvious interest to both patients and physicians. We conducted this study to determine the prognosis and risk factors in patients diagnosed with HS. OBJECTIVES: To describe the long-term prognosis and the clinical course of HS and its association to known risk factors. METHODS: A postal follow-up survey with uncomplicated factual questions was conducted. As all of the patients were well acquainted with their long-standing disease, this was thought to be sufficient for meaningful results. All cases were diagnosed by a dermatologist. Overall, 212 patients diagnosed with HS between 1981 and 2001 were studied after a median follow-up period of 22 years (range 12-32). RESULTS: The overall response rate was 71.2%, with 60.8% (129/212) valid (fully completed) questionnaires. Remission was reported by 39.4% (50/127) and improvement by 31.5% (40/127). Unchanged severity was reported by 20.5% (26/127), and 8.7% (11/127) experienced worsening disease. Tobacco smoking was reported by 92.2% (119/129). Among nonsmokers, 40% (35/88) reported remission vs. 29% (17/59) of active smokers. A higher proportion of nonobese patients (45%) reported remission than obese patients (23%). CONCLUSIONS: We found that 39.4% of the sample reported remission of HS. Suspected risk factors appeared to influence the prognosis. Smoking and obesity were significantly linked to a lower rate of self-reported remission. The notion that lifestyle factors play a role in HS appears to be supported by this survey. PMID- 24804605 TI - Left ventricular mechanics in adolescents and young adults with a history of kawasaki disease: analysis by three-dimensional speckle tracking echocardiography. AB - BACKGROUND: Myocardial fibrosis and perfusion abnormalities can occur in patients with Kawasaki disease (KD). We explored using the new three-dimensional speckle tracking echocardiography (3DSTE) the left ventricular (LV) mechanics in adolescents and young adults with a history of KD. METHODS: Twenty-five KD patients (18 males) aged 17.0 +/- 5.2 years, 14 with (group I) and 11 without (group II) coronary aneurysms, were studied. The 3D volume datasets were acquired for quantification of LV global 3D strain, global and regional area strain, systolic dyssynchrony index (SDI), twist, twist gradient (twist/LV length), and ejection fraction. RESULTS: The results were compared with those of 14 age matched controls. Of the 14 group I patients, 6 had left, 2 had right, and 6 had both left and right coronary aneurysms. Compared with controls, group I patients had significantly lower LV systolic global 3D strain (43.7 +/- 7.3% vs. 50.4 +/- 6.6%, P = 0.02), twist (8.7 +/- 1.3 degrees vs. 11.4 +/- 2.0 degrees , P < 0.001), and twist gradient (1.5 +/- 0.3 degrees /cm vs. 1.9 +/- 0.4 degrees /cm, P = 0.01), greater SDI (6.8 +/- 1.9% vs. 4.7 +/- 1.9%, P < 0.001), and similar ejection fractions. Six patients in group I had perfusion defects, who had global 3DSTE parameters similar to those of the 8 patients without perfusion abnormalities (all P > 0.05). For group II patients, only the global area strain was significantly lower than that of controls (37.6 +/- 3.5% vs. 40.7 +/- 3.6%, P = 0.038). CONCLUSION: In adolescents and young adults with a history of KD, impairment of LV mechanics occurs and is worse in patients with than those without coronary complications. PMID- 24804606 TI - Systolic anterior motion of the posterior leaflet in hypertrophic cardiomyopathy. PMID- 24804607 TI - Effect of weekend physiotherapy provision on physiotherapy and hospital length of stay after total knee and total hip replacement. AB - OBJECTIVE: The aim of the present study was to investigate a change in physiotherapy provision from a 5- to 7-days-a-week service on both physiotherapy and hospital length of stay (LOS) after total knee (TKR) and total hip (THR) replacement. METHODS: A retrospective analysis of a clinical database was conducted for patients who received either a TKR or THR between July 2010 and June 2012 in one regional hospital. RESULTS: There was a significant decrease in physiotherapy LOS from 5.0 days (interquartile range (IQR) 5.0-6.0 days) for a 5 day physiotherapy service, to 5.0 days (IQR 4.0-5.0 days) for 7-day physiotherapy service (U=1443.5, z=-4.62, P=0.001). However, hospital LOS was not reduced (P=0.110). For TKR, physiotherapy LOS decreased significantly by 1 day with a 7 day physiotherapy service (U=518.0, z=-4.20, P=0.001). However, hospital LOS was again no different (P=0.309). For THR there was no difference in physiotherapy LOS (P=0.060) or hospital LOS (P=0.303) between the 5- and 7-day physiotherapy services. Where physiotherapy LOS was less than hospital LOS, delayed discharge was due primarily to non-medical issues (72%) associated with hospital organisational aspects. CONCLUSIONS: Increasing the provision of physiotherapy service after TKR provides an increase in physiotherapy sessions and has the potential to reduce hospital LOS. To be effective this must align with other administrative aspects of hospital discharge. PMID- 24804608 TI - More powerful than the American Society of Anesthesiology score. PMID- 24804609 TI - High-sucrose diets in pregnancy alter angiotensin II-mediated pressor response and microvessel tone via the PKC/Cav1.2 pathway in rat offspring. AB - This study determines the influence of a prenatal high-sucrose (HS) diet on angiotensin II (Ang II)-mediated pressor response and determine the underlying mechanism. Pregnant rats were provided with a 20% sucrose solution diet throughout gestation. Blood pressure and vascular response to Ang II were measured in 5-month-old adult offspring. Currents of L-type Ca(2+) channels (Cav1.2) were measured in smooth muscle cells of small mesenteric arteries from the offspring. Ang II-mediated pressor response was higher in the offspring exposed to prenatal high sugar compared with the control. In mesenteric arteries from the HS offspring, AT1 receptors (AT1R), not AT2 receptors, mediated the increased vasoconstriction; protein kinase C (PKC) antagonist GF109203X suppressed the Ang II-increased vasoconstriction; PKC agonist phorbol 12,13 dibutyrate produced a greater contractile response that was reversed by the Cav1.2 antagonist nifedipine. The expression of PKCalpha was increased, whereas PKCdelta was unchanged; KCl-induced vasoconstriction was stronger and was suppressed by nifedipine; nifedipine also reduced the enhanced vasoconstriction by Ang II. In addition, the Cav1.2 of smooth muscle cells in mesenteric arteries from the HS offspring showed larger current density, although its expression was unchanged. The data suggest that a HS diet during pregnancy alters Ang II mediated pressor response and microvessel tone acting through the PKC/Cav1.2 pathway in the offspring that may in part be because of alterations in AT1Rs, PKCalpha and Cav1.2. PMID- 24804610 TI - Five-year change in systolic blood pressure is independently associated with carotid atherosclerosis progression: a population-based cohort study. AB - The aim of this study was to investigate whether long-term changes in traditional risk factors affect the progression of carotid atherosclerosis in a Chinese population. This study included 1590 individuals (aged 56.9+/-8.1 years) with no evidence of carotid plaque at baseline (2002). In 2007, these individuals completed the second risk factors survey and underwent carotid plaque measurement. The incidence of carotid plaque and the total plaque area of maximum plaques (TPA) were used to evaluate the progression of carotid atherosclerosis. In addition to baseline age, systolic blood pressure (SBP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), common carotid intima-media thickness (CIMT) and current smoking, a 5-year change in SBP was also associated with the incidence of carotid plaque (odds ratio=1.01, 95% confidence interval: 1.01-1.02, P=0.029). Furthermore, multiple linear regression analysis revealed that a 5-year change in SBP had a linear association with TPA after adjusting for baseline risk factors (standardized regression coefficient=0.071, P=0.014). TPA increased both by increasing baseline SBP and by a 5-year SBP change when adjusted for sex, baseline age, TC, HDL-C, CIMT and current smoking (P for trend <0.001 and 0.004). Our study demonstrates that a 5 year change in SBP is independently associated with the progression of carotid atherosclerosis in the Chinese population. These findings underline the importance of early detection and control of SBP for the prevention of atherosclerosis progression. The progression of atherosclerosis is not only associated with hypertension but can also progress silently with the development of SBP. PMID- 24804611 TI - Deactivation of carotid body chemoreceptors by hyperoxia decreases blood pressure in hypertensive patients. AB - Previous studies have shown that hyperoxia-induced deactivation of carotid body chemoreceptors reduces sympathetic activity in hypertensive patients but it does not affect blood pressure. The maintenance of blood pressure can be explained by the direct, vasoconstrictive effect of hyperoxia, which offsets diminished sympathetic activity. This study compares the effect of acute hyperoxia on hemodynamic parameters between hypertensive and normotensive subjects. Twelve males with hypertension (age 39.4+/-2.4 years; body mass index 27.4+/-1.1 kg m( 2)) and 11 normotensive males (age 39.9+/-2.7 years; body mass index 25.4+/-0.7 kg m(-2)) received, via non-rebreathing mask ventilation, ambient air, followed by 100% oxygen for 20 min. The stroke volume, heart rate, cardiac output, blood pressure, total peripheral resistance, respiratory rate, baroreceptor control of heart rate and oxygen saturation were recorded continuously. Several 30 s periods were analyzed before, during and after inducing hyperoxia. At baseline, the hypertensive subject's blood pressure was higher and their baroreflex control of heart rate was lower when compared with the normotensive control group. After the first 30 s of hyperoxia, systolic, diastolic and mean blood pressures, as well as the total peripheral resistance, decreased significantly in hypertensives but not in normotensives. After 20 min of 100% oxygen ventilation, systolic and mean blood pressures and total peripheral resistance was increased in hypertensive patients, and the cardiac output and stroke volume had decreased in both groups. The results of this study confirm that deactivation of carotid body chemoreceptors can acutely decrease blood pressure in humans. PMID- 24804612 TI - Metabolic syndrome is associated with visit-to-visit systolic blood pressure variability in the US adults. AB - Epidemiological studies have shown that blood pressure is not a constant variable. Evidence has accumulated showing that the blood pressure variability is associated with organ damage. A substantial increase in the prevalence of the metabolic syndrome has been documented globally. We examined the association of visit-to-visit blood pressure variability with the metabolic syndrome and its components, using data collected in the Third National Health and Nutrition Examination Survey. A multivariable generalized linear model was performed. The metabolic syndrome and its components, particularly hypertension, increased waist circumference and hyperglycemia, were significantly associated with systolic blood pressure variability across study visits (P<0.05). After adjusting for the effect of age, gender, race and antihypertensive medication, the multivariable analyses did not show significant relationships between the metabolic syndrome and diastolic blood pressure variability (P-values >0.05). Additional research is required to verify the observed results in prospective studies and evaluate approaches to reduce blood pressure variability observed in clinical settings among persons with the metabolic syndrome to reduce its subsequent complications. PMID- 24804613 TI - Obstructive sleep apnea syndrome as a cause of resistant hypertension. AB - Evidence has consistently supported the association of obstructive sleep apnea syndrome (OSAS) with an increased prevalence of hypertension. It has also been shown that the severity of OSAS is directly correlated with the degree of blood pressure (BP) elevation and that hypertension occurring in subjects with OSAS is more likely to be severe, resistant to antihypertensive treatment and associated with alterations in day-to-night BP changes. Proposed mechanisms for the pathogenesis of OSAS-related hypertension include the activation of the sympathetic nervous system, alterations in autonomic cardiovascular (CV) modulation, the activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, systemic and vascular inflammation, oxidative stress, metabolic abnormalities, arterial stiffness and alterations in cardiac function and structure. Given the adverse prognostic implications of OSAS-related hypertension for CV morbidity and mortality, the confirmation of resistant hypertension by using ambulatory BP monitoring (ABPM) and the identification of alterations in day-to-night BP changes is of the utmost importance to implement more aggressive strategies for achieving BP control. In turn, the proper identification and implementation of specific treatment strategies for OSAS (that is, continuous positive airway pressure) in subjects with resistant hypertension may promote BP control and optimize CV protection. The present paper will review the evidence supporting the association of OSAS with resistant hypertension and the proposed mechanisms for this association. It will also address the role of ABPM in the confirmation of resistant hypertension in subjects with OSAS and whether the proper identification and management of OSAS in subjects with resistant hypertension will improve BP control. PMID- 24804614 TI - Unstable expression of transgene is associated with the methylation of CAG promoter in the offspring from the same litter of homozygous transgenic mice. AB - Transgenic animals have been established for studying gene function, improving animals' production traits, and providing organ models for the exploration of human diseases. However, the stability of inheritance and transgene expression in transgenic animals has gained extensive attention. The unstable expression of transgene through DNA methyltransferase (DNMT) targeting to the methylation of transgenic DNA such as CAG promoter and Egfp coding region in homozygous transgenic animals is still unknown. In the present study, the offspring from the same litter of homozygous transgenic mice carrying ubiquitously expressed enhanced green fluorescence protein driven by CMV early enhancer/chicken beta actin (CAG) promoter was observed to have unstable expression of transgene Egfp, quantitative PCR, western blot and bisulfite sequencing were conducted to quantify the expressional characteristics and methylation levels in various tissues. The correlation between transgene expression and methylation was analyzed. We have found that transgene expression is dependent on the methylation of CAG promoter, but not Egfp coding region. We have also characterized the correlation between the methylation of CAG promoter and DNMT, and found that only Dnmt3b expression is correlated with the methylation of CAG promoter. In conclusion, Dnmt3b-related methylation of CAG promoter can inhibit the transgene expression and may result in the unstable expression of transgene in the offspring from the same litter of homozygous transgenic mice. PMID- 24804615 TI - Directed migration of embryonic stem cell-derived neural cells in an applied electric field. AB - Spinal cord injury or diseases, such as amyotrophic lateral sclerosis, can cause the loss of motor neurons and therefore results in the paralysis of muscles. Stem cells may improve functional recovery by promoting endogenous regeneration, or by directly replacing neurons. Effective directional migration of grafted neural cells to reconstruct functional connections is crucial in the process. Steady direct current electric fields (EFs) play an important role in the development of the central nervous system. A strong biological effect of EFs is the induction of directional cell migration. In this study, we investigated the guided migration of embryonic stem cell (ESC) derived presumptive motor neurons in an applied EF. The dissociated mouse ESC derived presumptive motor neurons or embryoid bodies were subjected to EFs stimulation and the cell migration was studied. We found that the migration of neural precursors from embryoid bodies was toward cathode pole of applied EFs. Single motor neurons migrated to the cathode of the EFs and reversal of EFs poles reversed their migration direction. The directedness and displacement of cathodal migration became more significant when the field strength was increased from 50 mV/mm to 100 mV/mm. EFs stimulation did not influence the cell migration velocity. Our work suggests that EFs may serve as a guidance cue to direct grafted cell migration in vivo. PMID- 24804616 TI - MicroRNA-21 regulation of the progression of viral myocarditis to dilated cardiomyopathy. AB - MicroRNAs (miRNAs) comprise a broad class of small non-coding RNAs that control the expression of complementary target messenger RNAs. The dysregulation of miRNAs by several mechanisms has been described in various disease states, including cardiac disease. Although an etiological link between viral myocarditis (VMC) and idiopathic dilated cardiomyopathy (DCM) has long been recognized, the true extent of this association is uncertain. Previous studies of the two diseases have focused on protein degradation systems. In the present study, miR 21 expression and its potential role in VMC and DCM was investigated. The expression levels of miR-21, its target gene sprouty homolog 1 (SPRY1) and mitogen-activated protein kinase (MAPK) were measured by quantitative polymerase chain reaction. The protein levels of SPRY1 and MAPK were also determined by western blotting. miR-21 levels were significantly increased in cardiac myocytes from VMC and DCM in comparison with control samples. The levels of SPRY1 were decreased and MAPK activity was increased. Using a bioinformatics-based approach, an identical potential binding site was identified in mouse miR-21 and the SPRY 3' untranslated region (3' UTR), suggesting a regulatory role for miR-21. In cultured, miRNA-transfected myocardial cells, the overexpression of miR-21 was associated with a decrease in SPRY1 protein expression and an increased expression of the MAPK protein. These findings revealed that changes in the expression of miRNAs may contribute to the pathogenesis of VMC to DCM and establish the therapeutic efficacy of miRNA targeted intervention in a cardiovascular disease setting. PMID- 24804617 TI - Contralateral breast volume measurement during chest CT for postmastectomy breast reconstruction. AB - OBJECTIVE: Successful breast reconstruction after mastectomy may be guided by knowledge of the contralateral breast volume. Three-dimensional (3D) reconstruction based on a CT examination was used to determine the volume of the contralateral normal breast before postmastectomy breast reconstruction. MATERIALS AND METHODS: Seventeen female patients scheduled for postmastectomy breast reconstruction using silicon implant prostheses were using noncontrast CT scans of the chest for metastatic work-up. The CT scans were used to measure the volume of contralateral normal breast. The volume estimates were used to specify the proper implant size for cosmesis. The estimated CT volume was correlated with volume estimates obtained using water displacement, as well as anthropometric measurements performed by a plastic surgeon. RESULTS: Breast volume estimates obtained from CT scans were highly correlated with volumes measured by the two nonradiological methods, yielding a positive linear correlation coefficient (r = 0.99). CONCLUSION: Volume measurement of the intact breast should be added to reports of routine chest CT studies in patients who undergo mastectomy. CT imaging is a feasible method for contralateral normal breast volume measurement in these patients. PMID- 24804619 TI - Yoga-enhanced cognitive behavioural therapy (Y-CBT) for anxiety management: a pilot study. AB - Cognitive behavioural therapy (CBT) is an effective treatment for generalized anxiety disorder, but there is still room for improvement. The aim of the present study was to examine the potential benefit of enriching CBT with kundalini yoga (Y-CBT). Participants consisted of treatment resistant clients at a community mental health clinic. A total of 32 participants enrolled in the study and 22 completed the programme. After the Y-CBT intervention, pre-post comparisons showed statistically significant improvements in state and trait anxiety, depression, panic, sleep and quality of life. Results from this preliminary study suggest that Y-CBT may have potential as a promising treatment for those suffering from generalized anxiety disorder. KEY PRACTITIONER MESSAGES: Yoga enhanced cognitive behavioural therapy (Y-CBT) may be a promising new treatment for those suffering from generalized anxiety disorder. Y-CBT may also reduce depression in those suffering from generalized anxiety. Y-CBT may reduce depression and anxiety in a clinic population where clients suffer from multiple diagnoses including generalized anxiety disorder. PMID- 24804620 TI - Compound K-induced apoptosis of human hepatocellular carcinoma MHCC97-H cells in vitro. AB - An intestinal bacterial metabolite of ginseng protopanaxadiol saponin, 20-O-(beta D-glucopyranosyl)-20(S)-protopanaxadiol (compound K), has been reported to induce apoptosis in a variety of cancer cells. However, the precise mechanisms induced by compound K in human hepatocellular carcinoma (HCC) cells remain unclear. In order to examine possible apoptotic mechanisms, we investigated the anticancer effect of compound K in MHCC97-H. MTT assay showed that compound K inhibited the proliferation of MHCC97-H cells with a relatively low toxicity in normal hepatoma cells. Cell cycle progression and cell staining showed an increase in apoptotic sub-G1 fraction. Treatment of MHCC97-H with compound K also induced a reduction in mitochondrial membrane potential (Deltapsim) and DNA damage. Further study showed that compound K upregulated Fas, FasL, Bax/Bcl-2 ratio and downregulated pro-caspase-9, pro-caspase-3 in a dose-dependent manner, and it also inhibited Akt phosphorylation. These results suggest that compound K significantly inhibits cell proliferation and induces apoptosis in MHCC97-H cells through Fas- and mitochondria-mediated caspase-dependent pathways in human HCC cells. PMID- 24804622 TI - Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). AB - BACKGROUND: Venous thromboembolic disease has been extensively studied in surgical patients. The benefit of thromboprophylaxis is now generally accepted, but it is medical patients who make up the greater proportion of the hospital population. Medical patients differ from surgical patients with regard to their health and the pathogenesis of thromboembolism and the impact that preventative measures can have. The extensive experience from thromboprophylaxis studies in surgical patients is therefore not necessarily applicable to non-surgical patients. This is an update of a review first published in 2009. OBJECTIVES: To determine the effectiveness and safety of heparin (unfractionated heparin or low molecular weight heparin) thromboprophylaxis in acutely ill medical patients admitted to hospital, excluding those admitted to hospital with an acute myocardial infarction or stroke (ischaemic or haemorrhagic) or those requiring admission to an intensive care unit. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2013) and CENTRAL (2013, Issue 10). SELECTION CRITERIA: Randomised controlled trials comparing unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with placebo or no treatment, or comparing UFH with LMWH. DATA COLLECTION AND ANALYSIS: One review author identified possible trials and a second review author confirmed their eligibility for inclusion in the review. Two review authors extracted the data. Disagreements were resolved by discussion. We performed the meta-analysis using a fixed-effect model with the results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS: Sixteen studies with a combined total of 34,369 participants with an acute medical illness were included in this review. We identified 10 studies comparing heparin with placebo or no treatment and six studies comparing LMWH to UFH. Just under half of the studies had an open-label design, putting them at a risk of performance bias. Descriptions of random sequence generation and allocation concealment were missing in most of the studies. Heparin reduced the odds of deep vein thrombosis (DVT) (OR 0.38; 95% CI 0.29 to 0.51; P < 0.00001). The estimated reductions in symptomatic non-fatal pulmonary embolism (PE) (OR 0.46; 95% CI 0.19 to 1.10; P = 0.08), fatal PE (OR 0.71; 95% CI 0.43 to 1.15; P = 0.16) and in combined non-fatal PE and fatal PE (OR 0.65; 95% CI 0.42 to 1.00; P = 0.05) associated with heparin were imprecise. Heparin resulted in an increase in major haemorrhage (OR 1.81; 95% CI 1.10 to 2.98; P = 0.02). There was no clear evidence that heparin had an effect on all cause mortality and thrombocytopaenia. Compared with UFH, LMWH reduced the risk of DVT (OR 0.77; 95% CI 0.62 to 0.96; P = 0.02) and major bleeding (OR 0.43; 95% CI 0.22 to 0.83; P = 0.01). There was no clear evidence that the effects of LMWH and UFH differed for the PE outcomes, all-cause mortality and thrombocytopaenia. AUTHORS' CONCLUSIONS: The data from this review describe a reduction in the risk of DVT in patients presenting with an acute medical illness who receive heparin thromboprophylaxis. This needs to be balanced against an increase in the risk of bleeding associated with thromboprophylaxis. The analysis favoured LMWH compared with UFH, with a reduced risk of both DVT and bleeding. PMID- 24804623 TI - Dioxins and PCBs in feed and food--review from European perspective. AB - During the 1990s, a number of adverse contamination incidents focussed the attention of the media and the general public on food safety. This led to the evaluation of safety measures with regard to dioxin intake from food. Important aspects regarding dioxins and PCBs in the food chain are reviewed here, allowing a contextual understanding of the present situation through its chronological developments. About 90-98% of the average exposure of humans to dioxins and PCBs results from dietary intake, with food of animal origin being the predominant source. Therefore, animal feed contributes considerably to the presence of these compounds in food. The detection of the "real" source of a contamination event in the food chain is a complex scientific problem and requires specific knowledge on production processes and changes of patterns during bioaccumulation. This is demonstrated by complex investigations performed in three studies on two continents to identify the source (e.g. from contamination of cow's milk in Germany, to citrus pulp pellets from Brazil as an ingredient in feed, then to contaminated lime for neutralization and finally to a landfill with residues of vinyl chloride monomer production). This example shows also the substantial economic losses resulting from incidents in the food chain and the consequences to global trade. In 2001, the EU Scientific Committee on Food established a group tolerable weekly intake (TWI) of 14 pg WHO-TEQ/kg body weight and concluded that a considerable proportion of the European population would exceed this TWI. On the global level, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) provides scientific advice to the Codex Alimentarius Commission and therefore contributes to harmonized international food standards. In its evaluation of 2001, JECFA derived a provisional tolerable monthly intake (PTMI) of 70 pg TEQ/kg body weight. The sum of the median intake of PCDD/F-TEQ and PCB-TEQ exceeded the PTMI in Western European countries, was in the PTMI range in North America, but lower in Japan and New Zealand. The 90th percentile of PCDD/F-TEQ exceeded the PTMI in Western European countries and North America, the 90th percentile of coplanar PCBs in Western European countries. Therefore, in 2001 the EU Commission developed a strategy to reduce the presence of dioxins and PCBs in the environment and in the food chain. The legislative measures comprised maximum levels and action levels for feed and food, and a Rapid Alert System for detected incidents was introduced. The network of the EU Reference Laboratory and National Reference Laboratories contributes to harmonization within the EU Member States and developed analytical criteria for screening and confirmatory methods for control of feed and food. After all these efforts it is of general interest to see whether these measures had an effect. The 2012 evaluation of the European Food Safety Authority (EFSA) based on comprehensive monitoring data of 26 European countries shows a general decrease in dietary exposure of dioxins and DL PCBs between 2002-2004 and 2008-2010, estimated to be between 16.6% and 79.3% for the different population groups. A smaller decrease was observed for NDL-PCBs. The percentage of individuals exposed above the TWI of 14 pg TEQ/kg b.w. was estimated to be between 1.0 and 52.9%. Toddlers and other children were the most exposed groups (being at the upper end of these ranges). Fish, meat and dairy products appeared to be the highest contributing food groups to dietary exposure. PMID- 24804624 TI - Classification of genetic variation for cadmium tolerance in Bermudagrass [Cynodon dactylon (L.) Pers.] using physiological traits and molecular markers. AB - Cadmium (Cd) is one of the most toxic pollutants that caused severe threats to animal and human health. Bermudagrass is a dominant species in Cd contaminated soils, which can prevent Cd flow and spread. The objectives of this study were to determine the genetic variations in major physiological traits related to Cd tolerance in six populations of Bermudagrass collected from China, and to examine the genetic diversity and relationships among these accessions that vary in Cd tolerance using molecular markers. Plants of 120 accessions (116 natural accessions and 4 commercial cultivars) were exposed to 0 (i.e. control) or 1.5 mM CdSO4.8/3H2O for 3 weeks in hydroponic culture. Turf quality, transpiration rate, chlorophyll content, leaf water content and growth rate showed wide phenotypic variation. The membership function method was used to comprehensively evaluate Cd tolerance. According to the average subordinate function value, four accessions were classified as the most tolerant genotypes and four accessions as Cd sensitive genotypes. The trend of Cd tolerance among the six studied populations was as follows: Hunan > South China > North China > Central China > West South China and Xinjiang population. Phylogenetic analysis revealed that the majority of accessions from the same or adjacent regions were clustered into the same groups or subgroups, and the accessions with similar cadmium tolerance displayed a close phylogenetic relationship. Screening genetically diverse germplasm by combining the physiological traits and molecular markers could prove useful in developing Cd-tolerant Bermudagrass for the remediation of mill tailings and heavy metal polluted soils. PMID- 24804625 TI - Application of isolated bacterial consortium in UMBR for detoxification of textile effluent: comparative analysis of resultant oxidative stress and genotoxicity in catfish (Heteropneustes fossilis) exposed to raw and treated effluents. AB - A bacterial consortium isolated from activated sludge was identified to be Bacillus sp., Pseudomonas sp., Shigella sp. and E. coli. and was found capable of 98.62 % decolourization of highly toxic textile effluent, when applied in an ultrafiltration (UF) membrane bioreactor (UMBR). Ceramic capillary UF membranes prepared over low cost support proved to be highly efficient in adverse experimental conditions. The UMBR permeate and untreated textile effluent (40 % (v/v)) was then used to treat Heteropneustes fossilis for a comparative assessment of their toxicity. Micronucleus count in peripheral blood erythrocytes and comet assay carried out in liver and gill cells showed significantly lower nuclear and tissue specific DNA damage respectively in organisms exposed to membrane permeate and was further supported by considerably lower oxidative stress response enzyme activities in comparison to raw effluent treated individuals. The results indicate efficient detoxification of textile effluent by the UMBR treatment using the isolated bacterial consortium. PMID- 24804626 TI - From silk to satellite: half a century of ocean colour anomalies in the Northeast Atlantic. AB - Changes in phytoplankton dynamics influence marine biogeochemical cycles, climate processes, and food webs, with substantial social and economic consequences. Large-scale estimation of phytoplankton biomass was possible via ocean colour measurements from two remote sensing satellites - the Coastal Zone Colour Scanner (CZCS, 1979-1986) and the Sea-viewing Wide Field-of-view Sensor (SeaWiFS, 1998 2010). Due to the large gap between the two satellite eras and differences in sensor characteristics, comparison of the absolute values retrieved from the two instruments remains challenging. Using a unique in situ ocean colour dataset that spans more than half a century, the two satellite-derived chlorophyll-a (Chl-a) eras are linked to assess concurrent changes in phytoplankton variability and bloom timing over the Northeast Atlantic Ocean and North Sea. Results from this unique re-analysis reflect a clear increasing pattern of Chl-a, a merging of the two seasonal phytoplankton blooms producing a longer growing season and higher seasonal biomass, since the mid-1980s. The broader climate plays a key role in Chl-a variability as the ocean colour anomalies parallel the oscillations of the Northern Hemisphere Temperature (NHT) since 1948. PMID- 24804629 TI - A SIM-MOF: three-dimensional organisation of single-ion magnets with anion exchange capabilities. AB - The formation of a metal-organic framework (MOF) with nodes that have single molecule magnet (SMM) behaviour has been achieved by using mononuclear lanthanoid analogues, also known as single-ion magnets (SIMs), which enormously simplifies the challenging issue of making SMM-MOFs. Here we present a rational design of a family of MOFs, [Ln(bipyNO)4](TfO)3?x solvent (Ln=Tb (1); Dy (2); Ho (3); Er (4); TfO=triflate), in which the lanthanoid centres have an square-antiprismatic coordination environment suitable for SIM behaviour. Magnetic measurements confirm the existence of slow magnetic relaxation typical of SMMs, which has been rationalised by means of a radial effective charge model. In addition, we have explored the incorporation of bulky polyoxometalates (POMs) into the cavities of the SIM-MOF by anion exchange, finding that they do not interfere with the slow magnetic relaxation. This demonstrates the robustness of the frameworks and opens the possibility of incorporating non-innocent anions. PMID- 24804628 TI - Combining information from two data sources with misreporting and incompleteness to assess hospice-use among cancer patients: a multiple imputation approach. AB - Combining information from multiple data sources can enhance estimates of health related measures by using one source to supply information that is lacking in another, assuming the former has accurate and complete data. However, there is little research conducted on combining methods when each source might be imperfect, for example, subject to measurement errors and/or missing data. In a multisite study of hospice-use by late-stage cancer patients, this variable was available from patients' abstracted medical records, which may be considerably underreported because of incomplete acquisition of these records. Therefore, data for Medicare-eligible patients were supplemented with their Medicare claims that contained information on hospice-use, which may also be subject to underreporting yet to a lesser degree. In addition, both sources suffered from missing data because of unit nonresponse from medical record abstraction and sample undercoverage for Medicare claims. We treat the true hospice-use status from these patients as a latent variable and propose to multiply impute it using information from both data sources, borrowing the strength from each. We characterize the complete-data model as a product of an 'outcome' model for the probability of hospice-use and a 'reporting' model for the probability of underreporting from both sources, adjusting for other covariates. Assuming the reports of hospice-use from both sources are missing at random and the underreporting are conditionally independent, we develop a Bayesian multiple imputation algorithm and conduct multiple imputation analyses of patient hospice use in demographic and clinical subgroups. The proposed approach yields more sensible results than alternative methods in our example. Our model is also related to dual system estimation in population censuses and dual exposure assessment in epidemiology. PMID- 24804630 TI - US Medical Licensing Exam scores and performance on the Psychiatry Resident In Training Examination. AB - OBJECTIVE: This study explores relationships between US Medical Licensing Examination (USMLE) and Psychiatry Resident In-Training Examination (PRITE) scores over a 10-year period at a university-affiliated program. METHODS: For all MD general psychiatry residents who matriculated from 2003 to 2012 (n = 51), we extracted three-digit first-attempt and passing USMLE Step 1 and Step 2 clinical knowledge (CK) scores and PRITE percentile scores, stratified by global psychiatry and neurology scores, for postgraduate year (PGY)-1, 2, 3, and 4. A mixed model repeated measures analysis was performed to assess the association between USMLE and PRITE scores, adjusting for age, sex, and US medical graduate versus IMG status. Multiple linear regression models of USMLE and PGY-1 PRITE scores were also constructed. RESULTS: USMLE Steps 1 and 2 CK scores were significant predictors of PRITE psychiatry and neurology scores, both in PGY-1 as well as across all years of training (p < 0.01 for each). CONCLUSION: Given that PRITE scores are a significant predictor of success on the ABPN written examination, USMLE scores may be an important quantitative predictor of performance during residency. PMID- 24804631 TI - Usefulness of the Patient Health Questionnaire-9 for Korean medical students. AB - OBJECTIVE: Depression may be highly prevalent among medical students, lowering their functioning and quality of life. Using appropriate extant depression scales to screen for depression and determining factors associated with depression can be helpful in managing it. This study examines the validity and reliability of the Patient Health Questionnaire-9 (PHQ-9) for medical students and the relationship between their scores and sociodemographic variables. METHODS: This study surveyed 174 medical students using demographic questionnaires, the PHQ-9, the Beck Depression Inventory (BDI), the Patient Heath Questionnaire-15 (PHQ-15), the Beck Anxiety Inventory (BAI), and the Perceived Stress Scale (PSS). It calculated the Cronbach's alpha for internal consistency and Pearson's correlation coefficients for test-retest reliability and convergent validity of the PHQ-9. In order to examine the relationship between depression and demographic variables, this study performed independent t tests, one-way analysis of variance, chi-square, and binary logistic regressions. RESULTS: The PHQ-9 was reliable (Cronbach's alpha = 0.837, test-retest reliability, r = 0.650) and valid (r = 0.509-0.807) when employed with medical students. Total scores on the PHQ-9 were significantly higher among low-perceived academic achievers than among high perceived academic achievers (p < 0.01). Depression was more prevalent in poor perceived academic achievers than in high-perceived academic achievers. Similarly, poor-perceived academic achievers were at greater risk of depression than were high-perceived academic achievers (odds ratio [95 % confidence interval] 3.686 [1.092-12.439], p < 0.05). CONCLUSIONS: The PHQ-9 has satisfactory reliability and validity in medical students in South Korea. Depression is related to poor-perceived academic achievement when measured with the PHQ-9. Early screening for depression with the PHQ-9 in medical students and providing prompt management to high scorers may not only be beneficial to students' mental health but also improve their academic performance. PMID- 24804632 TI - Computed tomography angiography of lower extremities in the emergency room for evaluation of patients with gunshot wounds. AB - OBJECTIVE: To assess the role of CT angiography in the evaluation of patients with lower extremity gunshot wounds in the emergency room. MATERIALS AND METHODS: Eighty patients (73 male, 7 female, mean age 26 years) underwent CT angiography for the evaluation of lower extremity gunshot injuries. Imaging was conducted on the basis of standardized protocols utilizing 16-slice and 64-slice multidetector systems and images were qualitatively graded and assessed for various forms of arterial injury. RESULTS: CT angiography findings indicative of arterial injury were observed in 24 patients (30%) and a total of 43 arterial injuries were noted; the most common form was focal narrowing/spasm (n = 16, 37.2%); the most common artery involved was the superficial femoral artery (n = 12, 50%). In qualitative assessment of images based on a 4-point grading system, both readers considered CT angiography diagnostically excellent (grade 4) in most cases. Surgical findings were consistent with CT angiography and follow-up of patients' medical records showed no arterial injuries in patients with normal findings on initial imaging. CONCLUSION: Our findings demonstrate that CT angiography is an effective imaging modality for evaluation of lower extremity gunshot wounds and could help limit more invasive procedures such as catheter angiography to a select group of patients. KEY POINTS: * CT angiography efficiently evaluates lower extremity gunshot wounds. * CT angiography provides image quality sufficiently reliable for assessment of gunshot injuries. * CT angiography could help limit invasive procedures to select patients. PMID- 24804633 TI - Can single-phase dual-energy CT reliably identify adrenal adenomas? AB - PURPOSE: To evaluate whether single-phase dual-energy-CT-based attenuation measurements can reliably differentiate lipid-rich adrenal adenomas from malignant adrenal lesions. MATERIALS AND METHODS: We retrospectively identified 51 patients with adrenal masses who had undergone contrast-enhanced dual-energy CT (140/100 or 140/80 kVp). Virtual non-contrast and colour-coded iodine images were generated, allowing for measurement of pre- and post-contrast density on a single-phase acquisition. Adrenal adenoma was diagnosed if density on virtual non contrast images was <=10 HU. Clinical follow-up, true non-contrast CT, PET/CT, in and opposed-phase MRI, and histopathology served as the standard of reference. RESULTS: Based on the standard of reference, 46/57 (80.7%) adrenal masses were characterised as adenomas or other benign lesions; 9 malignant lesions were detected. Based on a cutoff value of 10 HU, virtual non-contrast images allowed for correct identification of adrenal adenomas in 33 of 46 (71%), whereas 13/46 (28%) adrenal adenomas were lipid poor with a density >=10 HU. Based on the threshold of 10 HU on the virtual non-contrast images, the sensitivity, specificity, and accuracy for detection of benign adrenal lesions was 73%, 100%, and 81% respectively. CONCLUSION: Virtual non-contrast images derived from dual energy-CT allow for accurate characterisation of lipid-rich adrenal adenomas and can help to avoid additional follow-up imaging. KEY POINTS: * Adrenal adenomas are a common lesion of the adrenal glands. * Differentiation of benign adrenal adenomas from malignant adrenal lesions is important. * Dual-energy based virtual non-contrast images help to evaluate patients with adrenal adenomas. PMID- 24804634 TI - Risk of ocular exposure to biologically effective UV radiation in different geographical directions. AB - To quantify ocular exposure to solar ultraviolet radiation (UVR) and to assess the risk of eye damage in different geographical directions due to UVR exposure, we used a spectrometer and a manikin to measure horizontal ambient and ocular exposure UVR in different geographical directions at four different locations at the Northern Hemisphere. Describing the relationship of exposure to risk of eye damage requires the availability of UV hazard weighting function. So, we used the UV hazard weighting function (ICNIRP) proposed by International Commission on Non Ionizing Radiation Protection to determine the biologically effective UV irradiance (UVBEeye ) and then cumulative effective radiant exposure (Heye ) to shown the risk of eye. We found that in different geographical directions, distributions of ocular exposure to UVR were markedly different from those of horizontal ambient UVR. When the midday maximum SEA > 50 degrees , eye received more UVR from the east and west directions during the morning and evening hours, respectively. However, when the midday maximum SEA < 50 degrees , eye received more UVR from the south direction at noon. The results of this research indicate that the higher risk of eye caused by UVR varies according to the midday maximum SEA corresponding to different geographical direction. PMID- 24804636 TI - Structural basis of PcsB-mediated cell separation in Streptococcus pneumoniae. AB - Separation of daughter cells during bacterial cell division requires splitting of the septal cross wall by peptidoglycan hydrolases. In Streptococcus pneumoniae, PcsB is predicted to perform this operation. Recent evidence shows that PcsB is recruited to the septum by the transmembrane FtsEX complex, and that this complex is required for cell division. However, PcsB lacks detectable catalytic activity in vitro, and while it has been proposed that FtsEX activates PcsB, evidence for this is lacking. Here we demonstrate that PcsB has muralytic activity, and report the crystal structure of full-length PcsB. The protein adopts a dimeric structure in which the V-shaped coiled-coil (CC) domain of each monomer acts as a pair of molecular tweezers locking the catalytic domain of each dimeric partner in an inactive configuration. This suggests that the release of the catalytic domains likely requires an ATP-driven conformational change in the FtsEX complex, conveyed towards the catalytic domains through coordinated movements of the CC domain. PMID- 24804637 TI - Infant locomotive development and its association with adult blood pressure. AB - Evidence from animal models suggests that locomotion and blood pressure share common neurophysiological regulatory systems. As a result of this common regulation, we hypothesized that the development of locomotion in human infants would be associated with blood pressure levels in adulthood. The study sample comprised 4,347 individuals with measures of locomotive and non-locomotive neuromotor development in infancy and adult blood pressure levels within a longitudinal birth cohort study, the Northern Finland Birth Cohort 1966. Later development in all three stages of locomotive development during infancy was associated with higher systolic and diastolic blood pressure levels at age 31. For age of walking without support, 0.34 (95 % CI 0.07 to 0.60)-mm Hg higher SBP and 0.38 (95 % CI 0.15 to 0.62)-mm Hg higher DBP were estimated for each month of later achievement (P = 0.012 for SBP; P = 0.001 for DBP). No association was identified for non-locomotive neuromotor development. CONCLUSION: These results highlight the positive sequelae of advanced locomotive development during infancy, suggesting that the common regulatory systems between locomotion and blood pressure may influence the development of raised blood pressure over time. PMID- 24804638 TI - A randomized controlled trial of the embrace advanced scar therapy device to reduce incisional scar formation. AB - BACKGROUND: Scarring represents a significant biomedical burden in clinical medicine. Mechanomodulation has been linked to scarring through inflammation, but until now a systematic approach to attenuate mechanical force and reduce scarring has not been possible. METHODS: The authors conducted a 12-month, prospective, open-label, randomized, multicenter clinical trial to evaluate abdominoplasty scar appearance following postoperative treatment with the embrace Advanced Scar Therapy device to reduce mechanical forces on healing surgical incisions. Incisions from 65 healthy adult subjects were randomized to receive embrace treatment on one half of an abdominoplasty incision and control treatment (surgeon's optimal care methods) on the other half. The primary endpoint for this study was the difference between assessments of scar appearance for the treated and control sides using the visual analogue scale scar score. RESULTS: Final 12 month study photographs were obtained from 36 subjects who completed at least 5 weeks of dressing application. The mean visual analogue scale score for embrace treated scars (2.90) was significantly improved compared with control-treated scars (3.29) at 12 months (difference, 0.39; 95 percent confidence interval, 0.14 to 0.66; p = 0.027). Both subjects and investigators found that embrace-treated scars demonstrated significant improvements in overall appearance at 12 months using the Patient and Observer Scar Assessment Scale evaluation (p = 0.02 and p < 0.001, respectively). No serious adverse events were reported. CONCLUSIONS: These results demonstrate that the embrace device significantly reduces scarring following abdominoplasty surgery. To the authors' knowledge, this represents the first level I evidence for postoperative scar reduction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 24804639 TI - The effects of whole-vault cranioplasty versus strip craniectomy on long-term neuropsychological outcomes in sagittal craniosynostosis. AB - BACKGROUND: The optimal type of surgical management for isolated sagittal synostosis remains a source of significant debate. There is a paucity of data regarding possible differences in long-term neuropsychological outcomes following treatment with whole-vault cranioplasty or endoscopic strip craniectomy. This study provides the first comparative analysis examining the effects of the two techniques related to long-term intellectual functioning. METHODS: A total of 70 patients were enrolled in this multicenter study, 29 of whom had previously undergone endoscopic strip craniectomy and 41 of whom had previously undergone whole-vault cranioplasty. All patients completed a battery of neurodevelopmental tests (Beery-Buktenica Developmental Test of Visual-Motor Integration, Wechsler Abbreviated Scale of Intelligence, and Wechsler Fundamentals) to evaluate various domains of neuropsychological function. RESULTS: In a group comparison of those treated before 6 months of age, whole-vault patients obtained higher scores relative to endoscopic strip craniectomy patients on visuomotor integration, full scale intelligence quotient, verbal intelligence quotient, word reading, and reading comprehension (p < 0.05 for all). When compared against strip craniectomy performed before 3 months of age, the whole-vault group still showed significantly higher scores in verbal intelligence quotient, reading comprehension, and word reading (p < 0.05 for all). CONCLUSIONS: The type of surgical intervention for isolated sagittal synostosis impacts long-term neuropsychological outcomes. Patients undergoing early whole-vault cranioplasty attained higher intelligence quotient and achievement scores relative to those undergoing strip craniectomy. Surgical management with whole-vault cranioplasty performed before 6 months of age provides the most favorable long-term intellectual outcomes in patients with isolated sagittal synostosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 24804640 TI - Patterns of Dupuytren disease in fingers: studying correlations with a multivariate ordinal logit model. AB - BACKGROUND: Dupuytren disease affects fingers in a variable fashion. Knowledge about specific disease patterns (phenotype) based on location and severity of the disease is lacking. METHODS: In this cross-sectional study, 344 primary affected hands with Dupuytren disease were physically examined. The Pearson correlation coefficient between the coexistence of Dupuytren disease in pairs of fingers was calculated, and agglomerative hierarchical clustering was applied to identify possible clusters of affected fingers. With a multivariate ordinal logit model, the authors studied the correlation on severity, taking into account age and sex, and tested hypotheses on independence between groups of fingers. RESULTS: The ring finger was most frequently affected by Dupuytren disease, and contractures were seen in 15.1 percent of affected rays. The severity of thumb and index finger, middle and ring fingers, and middle and little fingers was significantly correlated. Occurrences in pairs of fingers were highest in the middle and ring fingers and lowest in the thumb and index finger. Correlation between the ring and little fingers and a correlation between fingers from the ulnar and radial sides could not be demonstrated. CONCLUSIONS: Rays on the ulnar side of the hand are predominantly affected. The middle finger is substantially correlated with other fingers on the ulnar side, and the thumb and index finger are correlated; however, there was no evidence that the ulnar side and the radial side were correlated in any way, which suggests that occurrence on one side of the hand does not predict Dupuytren disease on the other side of the hand. CLINCIAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 24804641 TI - Aesthetic refinements in the treatment of graves ophthalmopathy. AB - BACKGROUND: Graves ophthalmopathy is a chronic, multisystem, autoimmune disorder characterized by increased volume of intraorbital fat and hypertrophic extraocular muscles. Proptosis, impaired ocular motility, diplopia, lid retraction, and impaired visual acuity are treated with orbit decompression and fat reduction. The authors present the addition of skeletal augmentation to further improve periorbital aesthetics. METHODS: Through a transconjunctival with lateral canthotomy incision, a balanced orbital decompression was executed, removing medial and lateral walls and medial floor. Intraorbital fat was excised. All patients underwent placement of porous polyethylene infraorbital rim implants and midface soft-tissue elevation, increasing inferior orbital rim projection and improving the globe-cheek relationship. From 2009 to 2012, 13 patients (11 female and two male; 26 eyes) with Graves ophthalmopathy underwent surgery at two institutions. Outcomes were evaluated for improvements of proptosis, diplopia, dry eye symptoms, and cosmetic satisfaction. RESULTS: Postoperative follow-up ranged from 0.5 to 3 years (median, 1.5 years). The mean improvement on Hertel exophthalmometry was 5.4 mm. Diplopia resolved in three patients (23 percent). No patients had worsening diplopia, and 12 (92 percent) discontinued use of eye lubricants. All patients had cosmetic satisfaction. One patient suffered temporary inferior orbital nerve paresthesia. There were no infections, hematomas, or ocular complications. CONCLUSIONS: Skeletal augmentation is a useful adjunct to orbital decompression and fat excision for treating Graves ophthalmopathy. Balanced orbital decompression with infraorbital rim implants is reliable, effective, and safe, with good, lasting results. Resolution of ocular symptoms is improved, as are the patient's personal well-being and social life, with a high-benefit-to-low-risk. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24804642 TI - Glycinergic inhibition tunes coincidence detection in the auditory brainstem. AB - Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing. PMID- 24804643 TI - Allelic association, DNA resequencing and copy number variation at the metabotropic glutamate receptor GRM7 gene locus in bipolar disorder. AB - Genetic markers at the GRM7 gene have shown allelic association with bipolar disorder (BP) in several case-control samples including our own sample. In this report, we present results of resequencing the GRM7 gene in 32 bipolar samples and 32 random controls selected from 553 bipolar cases and 547 control samples (UCL1). Novel and potential etiological base pair changes discovered by resequencing were genotyped in the entire UCL case-control sample. We also report on the association between GRM7 and BP in a second sample of 593 patients and 642 controls (UCL2). The three most significantly associated SNPs in the original UCL1 BP GWAS sample were genotyped in the UCL2 sample, of which none were associated. After combining the genotype data for the two samples only two (rs1508724 and rs6769814) of the original three SNP markers remained significantly associated with BP. DNA sequencing revealed mutations in three cases which were absent in control subjects. A 3'-UTR SNP rs56173829 was found to be significantly associated with BP in the whole UCL sample (P = 0.035; OR = 0.482), the rare allele being less common in cases compared to controls. Bioinformatic analyses predicted a change in the centroid secondary structure of RNA and alterations in the miRNA binding sites for the mutated base of rs56173829. We also validated two deletions and a duplication within GRM7 using quantitative-PCR which provides further support for the pre-existing evidence that copy number variants at GRM7 may have a role in the etiology of BP. PMID- 24804644 TI - Co-delivery of plasmid DNA and doxorubicin by solid lipid nanoparticles for lung cancer therapy. AB - The co-delivery of DNA and antitumor drugs has the potential to treat cancer. In this study, we aimed to develop surface-modified, co-encapsulated solid lipid nanoparticles (SLN) containing enhanced green fluorescence protein plasmid (pEGFP) and doxorubicin (DOX) in order to create a multifunctional delivery system that targets lung cancer cells, in an effort to improve the efficacy of cancer therapy. DOX- and pEGFP-loaded SLN were prepared separately and then mixed to form co-encapsulated SLN (SLN/DE). Transferrin (Tf)-containing ligands were used for the surface coating of the vectors. The in vitro transfection efficiency of the modified vectors was evaluated using a human alveolar adenocarcinoma cell line (A549 cells) and the in vivo transfection efficiency of the modified vectors was evaluated using mice bearing A549 tumors. The Tf-modified DOX and pEGFP co encapsulated SLN (T-SLN/DE) had a particle size of 267 nm with a 42 mV surface charge. The in vitro cytotoxicity of T-SLN/DE was low (cell viability was between 80 and 100% compared with the controls). T-SLN/DE displayed a remarkable therapeutic effect both in drug delivery and gene therapy. In conclusion, our results demonstrate that the multifunctional delivery system can improve the efficacy of cancer therapy through the combination of gene therapy and chemotherapy. In addition, the coating of active targeting ligands can improve the efficacy of the carriers at targeting lung cancer cells. Thus, the novel gene and drug delivery system offers an effective strategy for lung cancer gene therapy. PMID- 24804645 TI - A combined dual-port endoscope-assisted pre- and retrosigmoid approach to the cerebellopontine angle: an extensive anatomo-surgical study. AB - The use of the endoscope in the cerebellopontine angle (CPA) has been suggested to minimize cerebellar retraction and reduce the size of the craniotomy. 3D endoscopy combines the benefits of conventional 2D endoscopy with the added benefit of stereoscopic perception, though improved visualization alone does not guarantee improved surgical maneuverability and a better surgical outcome. We propose a new combined dual-port endoscope-assisted pre- and retrosigmoid approach to improve visualization and accessibility of the CPA with shortened distances and increased surgical maneuverability of neurovascular structures. We analyze surgical exposure and maneuverability of this approach and compare it with the surgical microscopic and a conventional single-port endoscope-assisted retrosigmoid approach. This combined pre- and retrosigmoid approach was performed on eight cadaveric heads (16 sides). The endoscopic probe was inserted through the presigmoid surgical port while surgical manipulation was performed through the retrosigmoid corridor. The CPA was divided into three compartments, from medial to lateral, the anteromedial, and the middle and the posterolateral. The microscope provided good visualization of the posterolateral and middle compartments, whereas poor visualization was offered of the anteromedial compartment. The dual-port endoscopic approach dramatically improved visualization and surgical maneuverability of the anteromedial compartments, clivus, and related neurovascular structures. Additionally, the 3D endoscope allowed for a better understanding of the surgical anatomy of the CPA and improved visualization of structures located in the anteromedial compartments towards the midline. This approach allowed for full realization of the benefits of endoscopic-assisted technique by improving surgical access and maneuverability. PMID- 24804646 TI - Comparative studies on the interactions of dihydroartemisinin and artemisinin with bovine serum albumin using spectroscopic methods. AB - The interactions of dihydroartemisinin (DHA) and artemisinin (ART) with bovine serum albumin (BSA) have been investigated using fluorescence, UV/vis absorption and Fourier transform infrared (FTIR) spectra under simulated physiological conditions. The binding characteristics of DHA/ART and BSA were determined by fluorescence emission and resonance light scattering (RLS) spectra. The quenching mechanism between BSA and DHA/ART is static. The binding constants and binding sites of DHA/ART-BSA systems were calculated at different temperatures (293, 298, 304 and 310 K). According to Forster non-radiative energy transfer theory, the binding distance of BSA to DHA/ART was calculated to be 1.54/1.65 nm. The effect of DHA/ART on the secondary structure of BSA was analyzed using UV/vis absorption, FTIR, synchronous fluorescence and 3D fluorescence spectra. In addition, the effects of common ions on the binding constants of BSA-DHA and BSA ART systems were also discussed. PMID- 24804647 TI - Sub-nanometer conformal TiO2 blocking layer for high efficiency solid-state perovskite absorber solar cells. PMID- 24804648 TI - Managing constipation: implementing a protocol in a geriatric rehabilitation setting. AB - This study examined the effect of implementing a constipation management protocol (CMP) within a geriatric rehabilitation setting. A convergent mixed-methods research design was used. Quantitative data on bowel activity, laxative use, opiate drug use, and nursing documentation regarding bowel care were gathered through a review of health records for 305 patients admitted to three geriatric rehabilitation units before (n = 137) and after (n = 168) protocol implementation over two 3-month periods. Focus groups were conducted examining nursing staff's experiences with such a protocol. Findings revealed that although implementation of the CMP did not reduce constipation rates among older patients, the average number of incidences of constipation per patient was reduced after implementation of the protocol. More importantly, it resulted in more due diligence by staff regarding patients' bowel patterns as well as improved bowel care documentation. Findings and recommendations extend current literature and have practical implications for nurses interested in improving management of patients' bowel care. PMID- 24804650 TI - Mechanisms of heavy metal removal using microorganisms as biosorbent. AB - Release and distribution of heavy metals through industrial wastewaters has adverse affects on the environment via contamination of surface- and ground-water resources. Biosorption of heavy metals from aqueous solutions has been proved to be very promising, offering significant advantages such as low cost, availability, profitability, ease of operation, and high efficiency, especially when dealing with low concentrations. Residual biomasses of industrial microorganisms including bacteria, algae, fungi, and yeast have been found to be capable of efficiently accumulating heavy metals as biosorbent. This paper presents and investigates major mechanisms of biosorption and most of the functional groups involved. The biosorption process includes the following mechanisms: transport across cell membrane, complexation, ion exchange, precipitation, and physical adsorption. In order to understand how metals bind to the biomass, it is essential to identify the functional groups responsible for metal binding. Most of these groups have been characterized on the cell walls. The biosorbent contains a variety of functional sites including carboxyl, imidazole, sulfydryl, amino, phosphate, sulfate, thioether, phenol, carbonyl, amide, and hydroxyl moieties that are responsible for metal adsorption. These could be helpful to improve biosorbents through modification of surface reactive sites via surface grafting and/or exchange of functional groups. PMID- 24804649 TI - Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. AB - Signal Transducer and Activator of Transcription-3 (STAT3) is constitutively activated in many cancers where it promotes growth, inflammation, angiogenesis and inhibits apoptosis. We have shown that STAT3 is constitutively activated in human gastric cancer, and that chronic IL-11-driven STAT3 transcriptional activity induces gastric tumourigenesis in the gp130(757FF) mouse model of gastric cancer development. Here we show that treatment of human AGS gastric cancer cells with the Janus Kinase (JAK) inhibitor WP1066 dose-, and time dependently inhibits STAT3 phosphorylation, in conjunction with reduced JAK2 phosphorylation, reduced proliferation and increased apoptosis. In addition, application of intraperitoneal WP1066 for 2 weeks, reduced gastric tumour volume by 50% in the gp130(757FF) mouse coincident with reduced JAK2 and STAT3 activation compared with vehicle-treated, littermate controls. Gastric tumours from WP1066- treated mice had reduced polymorphonuclear inflammation, coincident with inhibition of numerous proinflammatory cytokines including IL-11, IL-6 and IL-1beta, as well as the growth factors Reg1 and amphiregulin. These results show that WP1066 can block proliferation, reduce inflammation and induce apoptosis in gastric tumour cells by inhibiting STAT3 phosphorylation, and that many cytokines and growth factors that promote gastric tumour growth are regulated by STAT3 dependent mechanisms. WP1066 may form the basis for future therapeutics against gastric cancer. PMID- 24804651 TI - Tracking composition of microbial communities for simultaneous nitrification and denitrification in polyurethane foam. AB - The process of simultaneous nitrification and denitrification (SND) of immobilized microorganisms in polyurethane form is discussed. The effect of different positions within the polyurethane carrier on microbial community response for the SND process is investigated by a combination of denaturing gradient gel electrophoresis profiles of the 16S rRNA gene V3 region and scanning electron microscopy. Results show that polyurethane, which consists of a unique porous structure, is an ideal platform for biofilm stratification of aerobe, anaerobe and facultative microorganisms in regard to the SND process. The community structure diversity response to different positions was distinct. The distributions of various functional microbes, detected from the surface aerobic stratification to the interior anaerobic stratification of polyurethane, were mainly nitrifying and denitrifying bacteria. Meanwhile aerobic denitrifying bacteria such as Paracoccus sp., Agrobacterium rubi and Ochrobactrum sp. were also adhered to the interior and surface of polyurethane. The SND process occurring on polyurethane foam was carried out by two independent processes: nitrogen removal and aerobic denitrification. PMID- 24804652 TI - Modification of a Na-montmorillonite with quaternary ammonium salts and its application for organics removal from TNT red water. AB - Na-montmorillonite (Na-Mont) and organic montmorillonite modified by cetyltrimethylammonium bromide (CTAB-Mont) and tetramethylammonium bromide (TMAB Mont) were prepared as adsorbents to remove organic contaminants from 2,4,6 trinitrotoluene (TNT) red water. The characterizations of the samples were performed with X-ray diffraction and Fourier transform infrared spectroscopy. The adsorption capacity of CTAB-Mont (15.9 mg/g) was much larger than Na-Mont (0.26 mg/g) and TMAB-Mont (1.7 mg/g). Langmuir isotherm and the pseudo-second-order kinetic models fitted the experimental results well. The main factor in the adsorption promotion was the distribution phase in the interlayer of CTAB-Mont. The arrangement of molecules analyzed by molecular simulation corresponded to the experimental data and supported the adsorption mechanism. PMID- 24804653 TI - Study on the mutual interactions between the parameters of a CANON system and its coping strategy when operating at room temperature (15 to 25 degrees C) using response surface methodology. AB - The coping strategy of a CANON (completely autotrophic nitrogen removal over nitrite) reactor working at room temperature was investigated using response surface methodology. The total nitrogen (TN) removal efficiency was taken as a dependent variable. The temperature (X), dissolved oxygen (DO) concentration (Y), and influent nitrogen loading rate (Z) were taken as independent variables. Results showed that the relation of these three independent variables can be described by the TN removal efficiency expressed as -5.03 + 1.51X + 45.16Y + 30.13Z + 0.26XY + 1.84XZ - 0.04X(2) - 9.06Y(2) - 99.00Z(2). The analysis of variance proved that the equation is applicable. The response surface demonstrated that the temperature significantly interacts with the DO concentration and influent N loading rate. A coping strategy for the CANON reactor working at room temperature is thus proposed: altering the DO concentration and the N loading rate to counterbalance the impact of low temperature. The verification test proved the strategy is viable. The TN removal efficiency was 91.3% when the reactor was operated under a temperature of 35.0 degrees C, a DO of 3.0 mg/L, and a N loading rate of 0.70 kgN/(m3 d). When the temperature dropped from 35.0 to 19.2 degrees C, the TN removal efficiency was kept at 88.7% by regulating the influent N loading rate from 0.7 kgN/(m3 d) to 0.35 kgN/(m3 d) and the DO concentration from 3.0 to 2.6 mg/L. PMID- 24804654 TI - Biodiesel production by microalgae cultivated using permeate from membrane bioreactors in continuous system. AB - Microalgae in three submerged ceramic membrane photobioreactors (SCMPBRs) with different hydraulic retention times (HRTs) were fed with permeate of a submerged ceramic membrane bioreactor for a period of 3 months to investigate the lipid content and also the biodiesel quality produced at different HRTs. The lipid content, lipid productivity and fatty acid compositions for all three SCMPBRs were not significantly different at the 95% confidence level. These results suggested that insignificant change in the amount of fatty acids was observed at different HRTs that supplied varying concentration of nitrate in the medium. Among the fatty acids, palmitic acid, palmitoleic acid, oleic acid and linoleic acid were the main components, whereas stearic acid was a minor fatty acid. Since there was insignificant effect of HRT on lipid content, lipid productivity and fatty acid compositions, the optimum HRT for SCMPBRs can then be designed based on optimum nutrient removal performance and low membrane fouling propensity. PMID- 24804655 TI - HybridICE(r) filter: ice separation in freeze desalination of mine waste waters. AB - Freeze desalination is an alternative method for the treatment of mine waste waters. HybridICE((r)) technology is a freeze desalination process which generates ice slurry in surface scraper heat exchangers that use R404a as the primary refrigerant. Ice separation from the slurry takes place in the HybridICE filter, a cylindrical unit with a centrally mounted filter element. Principally, the filter module achieves separation of the ice through buoyancy force in a continuous process. The HybridICE filter is a new and economical means of separating ice from the slurry and requires no washing of ice with water. The performance of the filter at a flow-rate of 25 L/min was evaluated over time and with varied evaporating temperature of the refrigerant. Behaviours of the ice fraction and residence time were also investigated. The objective was to find ways to improve the performance of the filter. Results showed that filter performance can be improved by controlling the refrigerant evaporating temperature and eliminating overflow. PMID- 24804656 TI - Fate of organic matter during moderate heat treatment of sludge: kinetics of biopolymer and hydrolytic activity release and impact on sludge reduction by anaerobic digestion. AB - Temperature-phased anaerobic digestion with a 50-70 degrees C pre-treatment is widely proposed for sludge. Here, such a sludge pre-treatment (65 degrees C) was studied against the physical, enzymatic and biodegradation processes. The soluble and particulate fractions were analysed in terms of biochemical composition and hydrolytic enzymatic activities. Two kinetics of organic matter solubilisation were observed: a rapid transfer of the weak-linked biopolymers to the water phase, including sugars, proteins or humic acid-like substances, to the water phase, followed by a slow and long-term solubilisation of proteins and humic acid like substances. In addition, during the heat treatment a significant pool of thermostable hydrolytic enzymes including proteases, lipases and glucosidases remains active. Consequently, a global impact on organic matter was the transfer of the biodegradable chemical oxygen demand (COD) from the particulate to the soluble fraction as evaluated by the biological methane potential test. However, the total biodegradable COD content of the treated sludge remained constant. The heat process improves the bio-accessibility of the biodegradable molecules but doesn't increase the inherent sludge biodegradability, suggesting that the chemistry of the refractory proteins and humic acids seems to be the real limit to sludge digestion. PMID- 24804657 TI - Spatial variability of nutrients (N, P) in a deep, temperate lake with a low trophic level supported by global navigation satellite systems, geographic information system and geostatistics. AB - We investigated changes in the spatial distribution of phosphorus (P) and nitrogen (N) in the deep, mesotrophic Lake Hancza. The raw data collection, supported by global navigation satellite system (GNSS) positioning, was conducted on 79 sampling points. A geostatistical method (kriging) was applied in spatial interpolation. Despite the relatively small area of the lake (3.04 km(2)), compact shape (shore development index of 2.04) and low horizontal exchange of water (retention time 11.4 years), chemical gradients in the surface waters were found. The largest variation concerns the main biogenic element - phosphorus. The average value was 0.032 at the extreme values of 0.019 to 0.265 mg L(-1) (coefficient of variation 87%). Smaller differences are related to nitrogen compounds (0.452-1.424 mg L(-1) with an average value of 0.583 mg L(-1), the coefficient of variation 20%). The parts of the lake which are fed with tributaries are the richest in phosphorus. The water quality of the oligo mesotrophic Lake Hancza has been deteriorating in recent years. Our results indicate that inferences about trends in the evolution of examined lake trophic status should be based on an analysis of the data, taking into account the local variation in water chemistry. PMID- 24804658 TI - Simulation and optimization of airlift external circulation membrane bioreactor using computational fluid dynamics. AB - The airlift external circulation membrane bioreactor (AEC-MBR) is a new MBR consisting of a separated aeration tank and membrane tank with circulating pipes fixed between the two tanks. The circulating pipe is called a H circulating pipe (HCP) because of its shape. With the complex configuration, it was difficult but necessary to master the AEC-MBR's hydraulic characteristics. In this paper, simulation and optimization of the AEC-MBR was performed using computational fluid dynamics. The distance from diffusers to membrane modules, i.e. the height of gas-liquid mixing zone (h(m)), and its effect on velocity distribution at membrane surfaces were studied. Additionally, the role of HCP and the effect of HCP's diameter on circulation were simulated and analyzed. The results showed that non-uniformity of cross-flow velocity existed in the flat-plate membrane modules, and the problem could be alleviated by increasing hm to an optimum range (h(m)/B >= 0.55; B is total static depth). Also, the low velocity in the boundary layer on the membrane surface was another reason for membrane fouling. The results also suggested that HCP was necessary and it had an optimum diameter to make circulation effective in the AEC-MBR. PMID- 24804659 TI - Use of external carbon sources derived from biowaste for short-cut nutrient removal from anaerobic effluents. AB - This work evaluated the use of different external carbon sources to promote the via-nitrite nutrient removal from anaerobic effluents. The carbon sources consisted of fermentation liquid produced from the organic fraction of municipal solid waste (OFMSW FL), drainage liquid produced from OFMSW, fermentation liquid produced from vegetable and fruit waste (VFW FL) and acetic acid. Denitritation and phosphorus uptake via nitrite were evaluated in two sequencing batch reactors, one treating the anaerobic supernatant produced from the co-digestion of OFMSW and activated sludge (highly nitrogenous anaerobic effluent - HNAE), and the other one treating the weakly nitrogenous anaerobic effluent (WNAE) from an upflow anaerobic sludge blanket reactor. The use of OFMSW FL to treat HNAE resulted in high nitrite (27 mgN/(gVSS.h) (VSS - volatile suspended solids) and phosphate uptake (15 mgP/gVSS.h). In the WNAE, nutrient kinetics were much slower. The use of acetic acid and VFW FL performed poorly, while the use of OFMSW FL, which was rich in butyric acid and propionic acid, resulted in significant nutrient removal (7 mgN/gVSS.h and 6 mgP/gVSS.h). The economic evaluation showed that the use of OFMSW FL is a less expensive option than the acetic acid use. PMID- 24804660 TI - The thin-layer drying characteristics of sewage sludge by the appropriate foaming pretreatment. AB - As dewatered sludge is highly viscous and sticky, the combination of foaming pretreatment and drying process seems to be an alternative method to improve the drying performance of dewatered sludge. In this study, CaO addition followed by mechanical whipping was employed for foaming the dewatered sludge. It was found that the foams were stable and the diameters of bubbles mainly ranged from 0.1 to 0.3 mm. The drying experiments were carried out in a drying oven in the convective mode. The results indicated that foamed sludge at 0.70 g/cm(3) had the best drying performance at each level of temperature, which could save 35-45% drying time to reach 20% moisture content compared with the non-foamed sludge. The drying rate of foamed sludge at 0.70 g/cm(3) was improved with the increasing of drying temperature. The impact of sample thickness on drying rate was not obvious when the sample thickness increased from 2 to 8 mm. Different mathematical models were used for the simulation of foamed sludge drying curves. The Wang and Singh model represented the drying characteristics better than other models with coefficient of determination values over 0.99. PMID- 24804661 TI - Light attenuation - a more effective basis for the management of fine suspended sediment than mass concentration? AB - Fine sediment continues to be a major diffuse pollution concern with its multiple effects on aquatic ecosystems. Mass concentrations (and loads) of fine sediment are usually measured and modelled, apparently with the assumption that environmental effects of sediment are predictable from mass concentrations. However, some severe impacts of fine sediment may not correlate well with mass concentration, notably those related to light attenuation by suspended particles. Light attenuation per unit mass concentration of suspended particulate matter in waters varies widely with particle size, shape and composition. Data for suspended sediment concentration, turbidity and visual clarity (which is inversely proportional to light beam attenuation) from 77 diverse New Zealand rivers provide valuable insights into the mutual relationships of these quantities. Our analysis of these relationships, both across multiple rivers and within individual rivers, supports the proposition that light attenuation by fine sediment is a more generally meaningful basis for environmental management than sediment mass. Furthermore, optical measurements are considerably more practical, being much cheaper (by about four-fold) to measure than mass concentrations, and amenable to continuous measurement. Mass concentration can be estimated with sufficient precision for many purposes from optical surrogates locally calibrated for particular rivers. PMID- 24804662 TI - Advanced oxidation processes with coke plant wastewater treatment. AB - The aim of this study was to determine the most efficient method of coke wastewater treatment. This research examined two processes - advanced oxidation with Fenton and photo-Fenton reaction. It was observed that the use of ultraviolet radiation with Fenton process had a better result in removal of impurities. PMID- 24804663 TI - Highly efficient co-removal of copper (II) and phthalic acid with self synthesized polyamine resin. AB - A novel method was proposed for efficient co-removal of Cu (II) and phthalic acid (PA) using self-synthesized polyamine resin (R-NH(2)). The adsorption properties of R-NH(2) were thoroughly investigated by equilibrium, kinetic and dynamic tests in sole and binary systems at pH 5.0. The Freundlich model was a good fit for all the isotherm data, showing higher Kf values in the binary system than the sole system. The pseudo-second-order kinetic equation showed a better correlation to the experimental data in all cases and PA uptake was much faster than that of Cu (II). R-NH(2) showed highest adsorption capacities to both Cu (II) and PA among the five tested resins. Moreover, the presence of PA markedly enhanced the adsorption of Cu (II), being around 3.5 times of that of the sole system. The adsorption of PA was also slightly increased when Cu (II) was coexistent. Furthermore, using Fourier transform infrared spectrometry (FTIR) and species calculations, possible mechanisms were proposed that Cu (II) coordinated with NH(2) and negative PA species interacted with -NH(3)(+) by electrostatic attraction. [Cu-PA] complex in the binary system possessed a much higher affinity than free Cu (II) to chelating with -NH(2), resulting in mutual enhancement. PMID- 24804664 TI - Effect of operational pH on biohydrogen production from food waste using anaerobic batch reactors. AB - This study was performed to investigate the influence of operational pH on dark H(2) fermentation of food waste by employing anaerobic batch reactors. The highest maximum H(2) yield was 1.63 mol H(2)/mol hexoseadded at operational pH 5.3, whereas the lowest maximum H(2) yield was 0.88 mol H(2)/mol hexoseadded at operational pH 7.0. With decreasing operational pH values, the n-butyrate concentration tended to increase and the acetate concentration tended to decrease. The highest hydrogen conversion efficiency of 11.3% was obtained at operational pH 5.3, which was higher than that (8.3%) reported by a previous study (Kim et al. (2011) 'Effect of initial pH independent of operational pH on hydrogen fermentation of food waste', Bioresource Technology 102 (18), 8646 8652). The new result indicates that the dark fermentation of food waste was stable and efficient in this study. Fluorescence in situ hybridization (FISH) analysis showed that Clostridium species Cluster I accounted for 84.7 and 13.3% of total bacteria at operational pH 5.3 and pH 7.0, respectively, after 48 h operation. PMID- 24804665 TI - Suitability of anaerobic digestion effluent as process water for corn fuel ethanol fermentation. AB - A corn fuel ethanol plant integrated with anaerobic digestion treatment of thin stillage increases the net energy balance. Furthermore, the anaerobic digestion effluent (ADE) can be reused as a potential substitute for process water in the ethanol fermentation. In this study, the suitability of ADE as process water for corn ethanol fermentation was investigated by analyzing the potential inhibitory components in the ADE. It was found that ammonium influenced the growth and metabolism of Saccharomyces cerevisiae. Maximum ethanol production was obtained when the concentration of ammonium nitrogen was 200 mg/L, and ammonium could replace urea as the nitrogen source for S. cerevisiae under this concentration. In the ethanol fermentation with a higher concentration of ammonium, more glycerol was produced, thereby resulting in the decrease of ethanol production. In addition, components except ammonium in the ADE caused no inhibition to ethanol production. These results suggest that ADE could be reused as process water for corn ethanol fermentation without negative effect when ammonium concentration is well controlled. PMID- 24804666 TI - Different types of carbon nanotube-based anodes to improve microbial fuel cell performance. AB - The microbial fuel cell (MFC) is an innovative technology for producing electricity directly from biodegradable organic matter using bacteria. Among all the influenceable factors, anode materials play a crucial role in electricity generation. Recently, carbon nanotubes (CNTs) have exhibited promising properties as electrode material due to their unique structural, and physical and chemical properties. In this study, the impacts of CNT types in CNT-based anodes were investigated to determine their effect on both efficiency of wastewater treatment and power generation. The CNTs, namely single-walled CNT with carboxyl group (SWCNT), multi-walled CNT with carboxyl group (MWCNT-COOH) and multi-walled CNT with hydroxyl group (MWCNT-OH) were used to fabricate CNT-based anodes by a filtration method. Overall, MWCNTs provided better results than SWCNTs, especially in the presence of the -OH groups. The highest power and treatment efficiencies in MFC were achieved with an anode made of MWCNT-OH filtered on Poreflon membrane; the open circuit voltage attained was 0.75 V and the maximum power density averaged 167 mW/m(2), which was 130% higher than that obtained with plain carbon cloth. In addition, MWCNT-OH is more cost-effective, further suggesting its potential to replace plain carbon cloth generally used for the MFC anode. PMID- 24804667 TI - Grease waste and sewage sludge co-digestion enhancement by thermal hydrolysis: batch and fed-batch assays. AB - Grease waste (GW) is an adequate substrate for sewage sludge co-digestion since, coming from a waste water treatment plant, it has a high methane potential (489 NmLCH(4)/gVSin); however, no synergistic effect takes place when co-digesting with 52%VS grease. Conversely, thermal hydrolysis (TH) improves the anaerobic digestion of GW (43% higher kinetics) and biological sludge (29% more methane potential). Therefore, the application of TH to a co-digestion process was further studied. First, biochemical methane potential tests showed that the best configuration to implement the TH to the co-digestion process is pretreating the biological sludge alone, providing a 7.5% higher methane production (398 NmLCH(4)/gVSin), 20% faster kinetics and no lag-phase. Its implementation in a fed-batch operation resulted in considerable methane production (363 NmLCH(4)/gVSin) and TH improved the rheology and dewaterability properties of the digestate. This leads to important economical savings when combined with co digestion, reducing final waste management costs and showing interesting potential for full-scale application. PMID- 24804668 TI - Influence of extracellular polysaccharides (EPS) produced by two different green unicellular algae on membrane filtration in an algae-based biofuel production process. AB - In the present study, two strains of green algae named S1 and S2, categorized as the same species of Pseudo-coccomyxa ellipsoidea but showing 99% homology, were cultivated under the same conditions and filtrated with a microfiltration membrane. On the basis of the results of the extracellular polysaccharides (EPS) characteristics of these two green algae and the degree of fouling, the influence of these characteristics on the performance of membrane filtration was investigated. There was no difference in the specific growth rate between the S1 and S2 strains; however, large differences were seen in the amount and quality of EPS between S1 and S2. When the S1 and S2 strains were filtered with a membrane, the trend in the increase in transmembrane pressure (TMP) was quite different. The filtration of the S1 strain showed a rapid increase in TMP, whereas the TMP of the filtration of the S2 strain did not increase at all during the operation. This clearly demonstrated that the characteristics of each strain affect the development of membrane fouling. On the basis of the detailed characterization of solved-EPS (s-EPS) and bound-EPS (b-EPS), it was clarified that s-EPS mainly contributed to irreversible fouling for both operations and the biopolymer-like organic matter contained in b-EPS mainly contributed to reversible fouling. PMID- 24804669 TI - Performance of permeable media rotating reactors used for pretreatment of wastewaters. AB - The impact of organic loading rate (OLR) on carbonaceous materials and ammonia removal was assessed in bench scale rotating media biofilm reactors treating real wastewater. Media composition influences biofilm structure and therefore performance. Here, plastic mesh, reticulated coarse foam and fine foam media were operated concurrently at OLRs of 15, 35 and 60 g sCOD m(-2)d(-1) in three bench scale shaft mounted advanced reactor technology (SMART) reactors. The sCOD removal rate increased with loading from 6 to 25 g sCOD m(-2)d(-1) (P < 0.001). At 35 g BOD5m(-2)d(-1), more than double the arbitrary OLR limit of normal nitrifying conditions (15 g BOD5m(-2)d(-1)); the removal efficiency of NH(4)-N was 82 +/- 5, 27 +/- 19 and 39 +/- 8% for the mesh, coarse foam and fine foam media, respectively. Increasing the OLR to 35 gm(-2)d(-1) decreased NH(4)-N removal efficiency to 38 +/- 6, 21 +/- 4 and 21 +/- 6%, respectively. The mesh media achieved the highest stable NH(4)(+)-N removal rate of 6.5 +/- 1.6 gm(-2)d( 1) at a sCOD loading of 35 g sCOD m(-2)d(-1). Viable bacterial numbers decreased with increasing OLR from 2 * 10(10)-4 * 10(9) cells per ml of biofilm from the low to high loading, suggesting an accumulation of inert non-viable biomass with higher OLR. Increasing the OLR in permeable media is of practical benefit for high rate carbonaceous materials and ammonia removal in the pretreatment of wastewater. PMID- 24804670 TI - A methodology to assess the effects of biofilm roughness on substrate fluxes using image analysis, substrate profiling, and mathematical modelling. AB - We present a novel approach, based on image analysis and modelling, to study the impact of morphological variability (roughness) and fluid dynamics on substrate mass fluxes in biofilms. Specifically, we used this method to assess substrate fluxes in counter-diffusional autotrophic biofilms in a hydrogen-based membrane biofilm reactor. The physical structure of the biofilm was determined in situ at the meso-scale using stereomicroscopy. Image analysis was used to characterize the biofilm structure, and substrate profiles were obtained using microsensors. A two-dimensional, continuum biofilm model including microbial reactions, mass transport, and fluid dynamics was developed to compute substrate conversion in irregularly shaped counter-diffusional biofilms. Experimental biofilm structures were reproduced in the model and simulated under the prevailing substrate and hydrodynamic conditions for flow velocities varied over three orders of magnitude. Model calculations were consistent with experimental results and showed enhanced conversion rates with increased roughness at higher flow velocities. Also, modelling showed that conversion rates in counter-diffusional biofilms were typically higher than in co-diffusional biofilms. This study highlights the potential to use a simple image acquisition approach coupled to a theoretical model, to evaluate biofilm overall substrate utilization related to biofilm morphological heterogeneity. PMID- 24804671 TI - Effect of selective organic fractions on denitrification rates using Salsnes Filter as primary treatment. AB - The purpose of this project was to investigate the effect of selective particle removal during primary treatment on downstream biological nutrient removal processes. Bench-scale Salsnes Filter fine mesh sieves were used as a primary treatment to obtain different organic fractions to test the effect on denitrification. Activated sludge and moving bed biofilm reactor anoxic tests were performed on municipal wastewater collected from two full-scale wastewater treatment plants located around the Oslo region (Norway). About 43% of the suspended solids in the wastewater was less than 18 MUm, and 14% was between 18 and 150 MUm. The effect of particulate chemical oxygen demand (COD) removal on denitrification rates was very minor. PMID- 24804672 TI - Thermophilic anaerobic digestion of sewage sludge with high solids content. AB - The treatment performance of thermophilic anaerobic digestion (AD) of sewage sludge with high solids content was investigated with two laboratory-scale thermophilic anaerobic reactors (R1 and R2) with a feeding of pre-centrifuged sewage sludge. Reactor R1 was fed with sludge of 3.7% total solids (TS). The volatile solids (VS) removal ratio and methane yield in the stable state were 54.9% and 0.29 NL CH(4)/g VS(added), respectively. For reactor R2, when the TS content of fed sludge was 7.4%, the VS removal ratio and methane yield in the stable state were 73.2% and 0.38 NL CH(4)/g VS(added), respectively. When the TS content was increased to 9.5%, the VS removal ratio and methane yield slightly decreased to 69.3% and 0.32 NL CH(4)/g VS(added), respectively, but the reactor was stably operated. An increase of ammonia concentration was observed, but it was in the safe range without severe inhibition on the methane production. The result indicated that thermophilic AD could support sewage sludge with high TS content (9.5%) without abrupt deterioration of the treatment performance. The high-solids AD process is an economical method for centralized sewage sludge treatment with lower transport cost. PMID- 24804673 TI - Combined bio-regeneration and ion-exchange system for perchlorate removal. AB - In order to prove that perchlorate-laden resins could be bio-regenerated through direct contact with perchlorate-reducing bacteria (PRB), a combined bio regeneration and ion-exchange (IX) system was operated. Two kinds of perchlorate laden resins, nitrate-selective A520E and perchlorate-selective A530E, were successfully regenerated by PRB cultivated under anaerobic conditions. The bio regeneration efficiency of perchlorate-laden resins increased with the amount of flow passed through the IX column. When the fully exhausted resin was bio regenerated for 10 days at the flow rate of 2 BV (bed volume)/min and mixed liquor suspended solids concentration of 80 mg/L, almost 100% of IX capacity was recovered. A520E resin had higher bio-regeneration efficiency than A530E under all conditions, probably due to the fact that the perchlorate ion is more strongly bonded to the functional group of perchlorate-selective A530E resin. Measurement of perchlorate concentrations in the column effluents also revealed that the amount of perchlorate eluted from A520E resin was higher than that from A530E resin. Since only 10-20% of perchlorate was eluted from the resin during 10 days of bio-regeneration, the main mechanism of bio-regeneration appears to be the direct reduction of perchlorate by PRB on the resin. PMID- 24804674 TI - Co-optimisation of phosphorus and nitrogen removal in stormwater biofilters: the role of filter media, vegetation and saturated zone. AB - Biofilters have been shown to effectively treat stormwater and achieve nutrient load reduction targets. However, effluent concentrations of nitrogen and phosphorus typically exceed environmental targets for receiving water protection. This study investigates the role of filter media, vegetation and a saturated zone (SZ) in achieving co-optimised nitrogen and phosphorus removal in biofilters. Twenty biofilter columns were monitored over a 12-month period of dosing with semi-synthetic stormwater. The frequency of dosing was altered seasonally to examine the impact of hydrologic variability. Very good nutrient removal (90% total phosphorus, 89% total nitrogen) could be achieved by incorporating vegetation, an SZ and Skye sand, a naturally occurring iron-rich filter medium. This design maintained nutrient removal at or below water quality guideline concentrations throughout the experiment, demonstrating resilience to wetting drying fluctuations. The results also highlighted the benefit of including an SZ to maintain treatment performance over extended dry periods. These findings represent progress towards designing biofilters which co-optimise nitrogen and phosphorus removal and comply with water quality guidelines. PMID- 24804675 TI - Serum amyloid P: a systemic regulator of the innate immune response. AB - The pentraxin SAP reduces neutrophil adhesion to ECM proteins, inhibits the differentiation of monocytes into fibrocytes, attenuates profibrotic macrophages, activates the complement pathway, and promotes phagocytosis of cell debris. Together, these effects of SAP regulate key aspects of inflammation and set a threshold for immune cell activation. Here, we present a review of SAP biology with an emphasis on SAP receptor interactions and how the effect of SAP on monocytes and macrophages has been explored to develop this protein as a therapeutic for renal and lung injuries. We also discuss how there remain many unanswered questions about the role of SAP in innate immunity. PMID- 24804676 TI - Correlation of standardized uptake value and apparent diffusion coefficient in integrated whole-body PET/MRI of primary and recurrent cervical cancer. AB - BACKGROUND: To evaluate a potential correlation of the maximum standard uptake value (SUVmax) and the minimum apparent diffusion coefficient (ADCmin) in primary and recurrent cervical cancer based on integrated PET/MRI examinations. METHODS: 19 consecutive patients (mean age 51.6 years; range 30-72 years) with histopathologically confirmed primary cervical cancer (n = 9) or suspected tumor recurrence (n = 10) were prospectively enrolled for an integrated PET/MRI examination. Two radiologists performed a consensus reading in random order, using a dedicated post-processing software. Polygonal regions of interest (ROI) covering the entire tumor lesions were drawn into PET/MR images to assess SUVmax and into ADC parameter maps to determine ADCmin values. Pearson's correlation coefficients were calculated to assess a potential correlation between the mean values of ADCmin and SUVmax. RESULTS: In 15 out of 19 patients cervical cancer lesions (n = 12) or lymph node metastases (n = 42) were detected. Mean SUVmax (12.5 +/- 6.5) and ADCmin (644.5 +/- 179.7 * 10(-5) mm2/s) values for all assessed tumor lesions showed a significant but weak inverse correlation (R = 0.342, p < 0.05). When subdivided in primary and recurrent tumors, primary tumors and associated primary lymph node metastases revealed a significant and strong inverse correlation between SUVmax and ADCmin (R = -0.692, p < 0.001), whereas recurrent cancer lesions did not show a significant correlation. CONCLUSIONS: These initial results of this emerging hybrid imaging technique demonstrate the high diagnostic potential of simultaneous PET/MR imaging for the assessment of functional biomarkers, revealing a significant and strong correlation of tumor metabolism and higher cellularity in cervical cancer lesions. PMID- 24804677 TI - Calorie restriction decreases murine and human pancreatic tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression in an insulin-like growth factor-1-dependent manner. AB - Calorie restriction (CR) prevents obesity and has potent anticancer effects that may be mediated through its ability to reduce serum growth and inflammatory factors, particularly insulin-like growth factor (IGF)-1 and protumorigenic cytokines. IGF-1 is a nutrient-responsive growth factor that activates the inflammatory regulator nuclear factor (NF)-kappaB, which is linked to many types of cancers, including pancreatic cancer. We hypothesized that CR would inhibit pancreatic tumor growth through modulation of IGF-1-stimulated NF-kappaB activation and protumorigenic gene expression. To test this, 30 male C57BL/6 mice were randomized to either a control diet consumed ad libitum or a 30% CR diet administered in daily aliquots for 21 weeks, then were subcutaneously injected with syngeneic mouse pancreatic cancer cells (Panc02) and tumor growth was monitored for 5 weeks. Relative to controls, CR mice weighed less and had decreased serum IGF-1 levels and smaller tumors. Also, CR tumors demonstrated a 70% decrease in the expression of genes encoding the pro-inflammatory factors S100a9 and F4/80, and a 56% decrease in the macrophage chemoattractant, Ccl2. Similar CR effects on tumor growth and NF-kappaB-related gene expression were observed in a separate study of transplanted MiaPaCa-2 human pancreatic tumor cell growth in nude mice. In vitro analyses in Panc02 cells showed that IGF-1 treatment promoted NF-kappaB nuclear localization, increased DNA-binding of p65 and transcriptional activation, and increased expression of NF-kappaB downstream genes. Finally, the IGF-1-induced increase in expression of genes downstream of NF-kappaB (Ccdn1, Vegf, Birc5, and Ptgs2) was decreased significantly in the context of silenced p65. These findings suggest that the inhibitory effects of CR on Panc02 pancreatic tumor growth are associated with reduced IGF-1-dependent NF kappaB activation. PMID- 24804678 TI - Oral vaccination of white-tailed deer (Odocoileus virginianus) with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). AB - Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis from livestock, particularly cattle. In Michigan, USA tuberculous white-tailed deer transmit M. bovis to other deer and cattle. One approach in dealing with this wildlife reservoir is to vaccinate deer, thus interfering with the intraspecies and interspecies transmission cycles. Thirty three white-tailed deer were assigned to one of two groups; oral vaccination with 1 * 10(8) colony-forming units of M. bovis BCG Danish (n = 17); and non vaccinated (n = 16). One hundred eleven days after vaccination deer were infected intratonsilarly with 300 colony-forming units of virulent M. bovis. At examination, 150 days after challenge, BCG vaccinated deer had fewer gross and microscopic lesions, fewer tissues from which M. bovis could be isolated, and fewer late stage granulomas with extensive liquefactive necrosis. Fewer lesions, especially those of a highly necrotic nature should decrease the potential for dissemination of M. bovis within the host and transmission to other susceptible hosts. PMID- 24804679 TI - The effects of birth weight and maternal care on survival of juvenile Steller sea lions (Eumetopias jubatus). AB - Steller sea lions were listed as endangered following a collapse of the western distinct population beginning in the late 1970s. Low juvenile survival has been implicated as a factor in the decline. I conducted a multistate mark-recapture analysis to estimate juvenile survival in an area of the western population where sea lions are showing signs of recovery. Survival for males and females was 80% between 3 weeks and 1 year of age. Approximately 20% of juveniles continued to be nursed by their mothers between ages 1 and 2 and 10% between ages 2 and 3. Survival for juveniles that suckled beyond 1 year was 88.2% and 89.9% to ages 2 and 3, respectively. In contrast, survival for individuals weaned by age 1 was 40.6% for males and 64.2% for females between ages 1 and 2. Birth mass positively influenced survival for juveniles weaned at age 1 but had little effect on individuals continuing to suckle. Cumulative survival to age 4 was double that estimated during the population decline in this region. Evidence suggests that western Steller sea lions utilize a somewhat different maternal strategy than those in the eastern distinct population. Western adult females generally invest more in their pups during the first year but wean offspring by age 1 more often. This results in better survival to age 1, but greater mortality between ages 1 and 3 compared to the eastern population. Different maternal strategies may reflect density dependent pressures of populations at opposite levels of abundance. PMID- 24804680 TI - Plicidentine in the Early Permian parareptile Colobomycter pholeter, and its phylogenetic and functional significance among coeval members of the clade. AB - Once thought to be an exclusively anamniote characteristic, plicidentine, a pattern of infolding of dentine, is now known to be found in various amniote clades, including Parareptilia. In the absence of detailed analyses of parareptilian dentition, most parareptiles were assumed to lack plicidentine due to the absence of external indicators, such as plications on the tooth base. The clear presence of this dentinal feature in the largest premaxillary and maxillary teeth of Colobomycter pholeter, led us to the present detailed study within the dentition of this unusual parareptile, and those of coeval members of this clade. Our study reveals that there is large variability in the degree of dentine infolding within C. pholeter dentition, as well as within those of closely related parareptiles. This variability ranges from a lack of plications, to very complex anamniote-like plicidentine. Utilizing computed tomography scans in conjunction with histological sections we also demonstrate the utility of computed tomography scans in conducting non-destructive sampling in the identification of plicidentine. Given the variability of plicidentine in this sample of parareptiles, we hypothesize that one function of parareptilian plicidentine is to increase the surface area for attachment tissues, and we suggest that the use of plicidentine as a character in phylogenetic analyses of parareptiles may be misleading. PMID- 24804681 TI - [Effects of the periodical spread of rinderpest on famine, epidemic, and tiger disasters in the late 17th Century]. AB - This study clarifies the causes of the repetitive occurrences of such phenomena as rinderpest, epidemic, famine, and tiger disasters recorded in the Joseon Dynasty Chronicle and the Seungjeongwon Journals in the period of great catastrophe, the late 17th century in which the great Gyeongsin famine (1670~1671) and the great Eulbyeong famine (1695~1696) occurred, from the perspective that they were biological exchanges caused by the new arrival of rinderpest in the early 17th century. It is an objection to the achievements by existing studies which suggest that the great catastrophes occurring in the late 17th century are evidence of phenomena in a little ice age. First of all, rinderpest has had influence on East Asia as it had been spread from certain areas in Machuria in May 1636 through Joseon, where it raged throughout the nation, and then to the west part of Japan. The new arrival of rinderpest was indigenized in Joseon, where it was localized and spread periodically while it was adjusted to changes in the population of cattle with immunity in accordance with their life spans and reproduction rates. As the new rinderpest, which showed high pathogenicity in the early 17th century, was indigenized with its high mortality and continued until the late 17th century, it broke out periodically in general. Contrastively, epidemics like smallpox and measles that were indigenized as routine ones had occurred constantly from far past times. As a result, the rinderpest, which tried a new indigenization, and the human epidemics, which had been already indigenized long ago, were unexpectedly overlapped in their breakout, and hence great changes were noticed in the aspects of the human casualty due to epidemics. The outbreak of rinderpest resulted in famine due to lack of farming cattle, and the famine caused epidemics among people. The casualty of the human population due to the epidemics in turn led to negligence of farming cattle, which constituted factors that triggered rage and epidemics of rinderpest. The more the number of sources of infection and hosts with low immunity increased, the more lost human resources and farming cattle were lost, which led to a great famine. The periodic outbreak of the rinderpester along with the routine prevalence of various epidemics in the 17thcentury also had influenced on domestic and wild animals. Due to these phenomenon, full-fledged famines occurred that were incomparable with earlier ones. The number of domestic animals that were neglected by people who, faced with famines, were not able to take care of them was increased, and this might have brought about the rage of epidemics like rinderpest in domestic animals like cattle. The great Gyeongsin and Eulbyeong famines due to reoccurrence of the rinderpest in the late 17th century linked rinderpester, epidemics and great famines so that they interacted with each other. Furthermore, the recurring cycle of epidemics-famines-rinderpest great famines constituted a great cycle with synergy, which resulted in eco economic-historical great catastrophes accompanied by large scale casualties. Therefore, the Gyeongsin and Eulbyeong famines occurring in the late 17th century can be treated as events caused by the repetition of various periodic disastrous factors generated in 1670~1671 and in 1695~1696 respectively, and particularly as phenomena caused by biological exchanges based on rinderpester., rather than as little ice age phenomena due to relatively long term temperature lowering. PMID- 24804682 TI - [Birth and succession of a current of learning in Korean medicine: the supporting yang current of learning]. AB - In this study, I aim to reveal how Lee Gyoojoons medicine has given birth to a current of learning, the supporting yang current of learning, and describe its historical significance. Before anything, I'd like to throw the question of whether if there were any currents within the traditional Korean medicine. There are no records of medical currents being widely discussed until now in medical history of Korea; however, the current of Lee Jema's sasang medicine is the most noticeable one. Among the contemporaries of Lee Jema, during the late Chosun, there was also another famed medical practitioner called Lee Gyoojoon. Lee Gyoojoon mainly practiced his medicine within Pohang, Gyeongsangbuk-do area, his apprentices have formed a group and have succeeded his medical practice. Based on the analyses of Lee Gyoojoon's apprentices and the Somun Oriental Medical Society, which is known as a successor group to Lee Gyoojoon's medicine today, they are fully satisfying the five requirements to establish a medical current: first, they held Lee Gyoojoon as the first and foremost, representative practitioner of their current; second, they advocate the supporting yang theory suggested by Lee Gyoojoon, which is originated from his theory of Mind; third, books such as the Major Essentials of Huangdi's Internal Classic Plain Questions, and the Double Grinded Medical Mirror, were being used as the main textbooks to educate their students or to practice medicine. Fourth, Lee Gyoojoon's medical ideas were being transcended quite clearly within his group of apprentices, including Seo Byungoh, Lee Wonse, and the Somun Oriental Medical Society. Fifth, Lee Gyoojoon's apprentices were first produced through the Sukgok School, however, nowadays they are being produced through medical groups formed by Lee Wonse, the Somun Oriental Medical Society, regarding the propagation of medical theories, compilation of textbooks, publication of academic journals, etc. Then, what do the existence of the supporting yang current have their significances in history? First of all, Heo Joon, the great medical practitioner in 16th century Chosun, have revealed through his book the Treasured Mirror of Eastern Medicine (TMEM), that the essence of Eastern medicine differentiated from South and North medicine of China is being transcended in Korean medicine. However, we have not got a clear conclusion on what his views of the essence of Eastern medicine is. The TMEM is the legacy of Neo-confucianism, dominant in the Chosun at the time, and is considered the reference which covers from Taoism to Korean Medicine, that is practical as well as systematical in categorizing illnesses, their respective prescriptions, and herbs. Maybe, it seems that such characteristics of the TMEM naturally led the medical practitioners and Confucian scholars, Lee Jema and Lee Gyoojoon to adopt its principles, and furthermore, possibly contributed in materializing the tradition of Eastern Medicine. Secondly, both currents appeared in the late period of Chosun dynasty. Then, weren't there any preceding medical currents before them? The bureaucratic and centralized government of the Chosun dynasty demanded and supplied talents through a nationwide examination system. However, since the late-16th century, a few family from the Chungin class have come to dominate the important medical positions as inheritance doctors , bringing about the expansion of the private medical sector, as well as growth in the number of medical practitioners. This naturally brought about fierce competition among the practitioners, and it is probable that the competition sparked the need for standardized groups and societies that follow a single medical doctrine or theory, to differentiate from the others. Probably, the birth of current of learning, which succeeded to Lee Jema and Lee Gyoojoon's medical theory, exists as an extension of this social background. The major changes in systems to build a new Chosun in 1894 brought about the abolitions of old and antique institutions. Inheritance doctors naturally collapsed, and every medical practitioners had to compete in an open market. However, Lee Jema and Lee Gyoojoon, as a medical practitioner and Confucian scholar, weren't from medical families; instead, they have successfully established and led their medical groups. The Sasang medicine current, which first began in the Hamhung area, had creative medical theories and excellent practices, naturally led the discourses traditional medicine in the center areas of the Korean peninsula. In contrast, the supporting yang current, more popular in the Youngnam area at one time, struggled to keep their current during the period of Korean War, National Industrialization and Modernization. And it was only Lee Wonse's personal dedication to the current that made it survive through the times. It was not until the late 1990s, when the apprentices have gathered Lee Gyoojoon's accomplishments, that formed the Somun Oriental Medical Society as well as the supporting yang current. In summary, the birth and the succession of the supporting yang current clearly depicts how the various traditional medical groups and societies on the periphery have survived and transcended through difficult times. And at the same time, they can provide chance to ruminate the historical flow of traditional medicine in Korea. PMID- 24804683 TI - [Joining WHO of Republic of Korea and the projects in the 1950s]. AB - The Republic of Korea(ROK) and the World Health Organization(WHO) have done many projects successfully from 1949, in which the government of First Republic joined the WHO. However the relation between the ROK and the WHO have not been studied very much so far. The main purpose of this research, which could be done by the support of WHO, is connected with three questions. First research point would be "how could the ROK joined WHO in 1949 and what's the meaning of it? And the what's the difference in the process for the WHO between the ROK of 1949 and the DPRK(Democratic People's Republic of Korea) of 1973?" The first president of the ROK, Rhee Syngman, who had received his Ph. D.(about international politics) from Princeton University in 1910, was strongly interested in joining international institutes like UN, WHO. The ROK that could join WHO on 17 August 1949, with the approval of Assembly on 25 May 1949, was one of the founder members of the Western Pacific Region. By joining WHO, the ROK could get chance to increase the level of public health and its administration in 1950's. But the DPRK manage to became a member of WHO on 19 May 1973 and joined the South-East Asia Region. The joining of DPRK was influenced by the easing of the cold war after the Nixon Doctrine and the joining of the China(People's Republic of China). Second research point would be "What kind of roll did the WHO take in the First Republic?" Yet the public health administration of the First Republic that had been made in the period of US army military government was been strongly influenced by USA, the roll of WHO was also important in the 1950's. Last research point would be "What kind of the projects did the ROK and the WHO take part in during the period of he First Republic? How could evaluate the results?" The ROK and the WHO handled the projects including health services, communicable disease prevention and control, control of noncommunicable diseases, and protection of health. Specially for the efforts to prevent communicable disease, the WHO focused on leprosy, malaria, measles, smallpox, tuberculosis in 1950's. The First Republic could overcome the bad health condition after the Korea War successfully, supported by WHO. PMID- 24804685 TI - Gut microbiota and brain function: a new target for brain diseases? PMID- 24804684 TI - Imbalanced protein expression patterns of anabolic, catabolic, anti-catabolic and inflammatory cytokines in degenerative cervical disc cells: new indications for gene therapeutic treatments of cervical disc diseases. AB - Degenerative disc disease (DDD) of the cervical spine is common after middle age and can cause loss of disc height with painful nerve impingement, bone and joint inflammation. Despite the clinical importance of these problems, in current publications the pathology of cervical disc degeneration has been studied merely from a morphologic view point using magnetic resonance imaging (MRI), without addressing the issue of biological treatment approaches. So far a wide range of endogenously expressed bioactive factors in degenerative cervical disc cells has not yet been investigated, despite its importance for gene therapeutic approaches. Although degenerative lumbar disc cells have been targeted by different biological treatment approaches, the quantities of disc cells and the concentrations of gene therapeutic factors used in animal models differ extremely. These indicate lack of experimentally acquired data regarding disc cell proliferation and levels of target proteins. Therefore, we analysed proliferation and endogenous expression levels of anabolic, catabolic, ant catabolic, inflammatory cytokines and matrix proteins of degenerative cervical disc cells in three-dimensional cultures. Preoperative MRI grading of cervical discs was used, then grade III and IV nucleus pulposus (NP) tissues were isolated from 15 patients, operated due to cervical disc herniation. NP cells were cultured for four weeks with low-glucose in collagen I scaffold. Their proliferation rates were analysed using 3-(4, 5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide. Their protein expression levels of 28 therapeutic targets were analysed using enzyme-linked immunosorbent assay. During progressive grades of degeneration NP cell proliferation rates were similar. Significantly decreased aggrecan and collagen II expressions (P<0.0001) were accompanied by accumulations of selective catabolic and inflammatory cytokines (disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, matrix metalloproteinase 3, interleukin-1beta, interleukin-1 receptor) combined with low expression of anti catabolic factor (metalloproteinase inhibitor 3) (P<0.0001). This study might contribute to inhibit inflammatory catabolism of cervical discs. PMID- 24804686 TI - Is the Relationship Between ADHD Symptoms and Binge Eating Mediated by Impulsivity? AB - OBJECTIVE: Individuals with ADHD may be at risk of developing binge eating disorder (BED). Impulsivity correlates with both BED and ADHD; however, more research is needed to explore whether impulsivity plays an underlying role in the observed relationship between ADHD and BED. METHOD: Questionnaires were used to assess ADHD and BED symptoms. Multiple questionnaires and a behavioral task were used to assess impulsivity in undiagnosed undergraduate participants (n = 50). RESULTS: Expected correlations were found among ADHD symptoms, BED tendencies, and measures of impulsivity with the exception of impulsivity on the behavioral task and BED symptoms; however, none of the measures of impulsivity were found to be significant mediators between ADHD and BED symptoms. CONCLUSION: Although impulsivity may play an important role in the interrelationship of ADHD and binge eating, other factors may also be critical in the development of this comorbidity. Investigation of this research question in clinical samples is needed. PMID- 24804687 TI - Vitamin-Mineral Treatment of ADHD in Adults. AB - OBJECTIVE: Despite widespread use, there is little data investigating the long term impact of micronutrients on psychiatric disorders. This study investigated the naturalistic outcome 1-year post-baseline of a randomized controlled trials (RCT) that compared micronutrients with placebo in 80 adults with ADHD. METHOD: All participants were contacted and clinician-rated questionnaires completed. RESULTS: A total of 72 (90%) of the sample participated; although there was significant regression in psychiatric functioning from the end-of-trial on all measures, outcomes remained significantly improved from baseline. Dominant treatment from the end-of-treatment to follow-up was investigated as a mediator of outcome; those staying on the micronutrients performed better than those who switched to medications or discontinued micronutrients. Cost was the most substantial reason why people stopped micronutrient treatment. CONCLUSION: For the small number of participants who stayed on micronutrients, the benefits conferred through the controlled trial were maintained. The results are limited by small sample, lack of blinding, expectation, and reliance on self-report of symptoms. PMID- 24804691 TI - Hypothalamic protein profiles associated with inhibited feed intake of ducks fed with insufficient dietary arginine. AB - An experiment was conducted to investigate the effect of arginine on feed intake regulation. One hundred and twenty six 1-day-old male White Pekin ducks (Anas platyrhynchos domestica) were randomly were allotted to one of two dietary treatments. The birds were fed diets containing 0.71% (deficient) or 1.27% (sufficient) arginine for 3 weeks. At 21 days of age, feed intake was determined and hypothalamic protein profiles were analyzed using isobaric tags for relative and absolute quantification technique. The birds fed with arginine-deficient diet had a lower final live BW and cumulative feed intake (P1.5-fold expressional changes between arginine-deficient and -sufficient dietary treatments. Nine of these proteins were upregulated and seven of them were downregulated. The identified proteins could be regrouped into six categories: protein processing, carbohydrate metabolism and energy production, transporter, cytoskeleton, immunity and neuronal development. Dietary arginine deficiency decreased expression of proteins involved in energy production (glycine amidinotransferase, aldolase B fructose-bisphosphate, aconitase, transaldolase, 6-phosphofructokinase type C-like) and oxygen transportation (haemoglobin subunit alpha expression). The proteomic alterations described here provides valuable insights into the interactions of arginine with appetite. PMID- 24804692 TI - The future of Medicare: what's in store? PMID- 24804694 TI - The tapetal AHL family protein TEK determines nexine formation in the pollen wall. AB - The pollen wall, an essential structure for pollen function, consists of two layers, an inner intine and an outer exine. The latter is further divided into sexine and nexine. Many genes involved in sexine development have been reported, in which the MYB transcription factor Male Sterile 188 (MS188) specifies sexine in Arabidopsis. However, nexine formation remains poorly understood. Here we report the knockout of TRANSPOSABLE ELEMENT SILENCING VIA AT-HOOK (TEK) leads to nexine absence in Arabidopsis. TEK encodes an AT-hook nuclear localized family protein highly expressed in tapetum during the tetrad stage. Absence of nexine in tek disrupts the deposition of intine without affecting sexine formation. We find that ABORTED MICROSPORES directly regulates the expression of TEK and MS188 in tapetum for the nexine and sexine formation, respectively. Our data show that a transcriptional cascade in the tapetum specifies the development of pollen wall. PMID- 24804695 TI - Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial. AB - OBJECTIVE: To determine whether testosterone therapy improves glucose metabolism in men with type 2 diabetes (T2D) and lowered testosterone. RESEARCH DESIGN AND METHODS: We conducted a randomized, double-blind, parallel, placebo-controlled trial in 88 men with T2D, aged 35-70 years with an HbA1c <=8.5% (69 mmol/mol), and a total testosterone level, measured by immunoassay, of <=12.0 nmol/L (346 ng/dL). Participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). All study subjects were included in the primary analysis. Seven men assigned to testosterone and six men receiving placebo did not complete the study. Main outcome measures were insulin resistance by homeostatic model assessment (HOMA IR, primary outcome) and glycemic control by HbA1c (secondary outcome). RESULTS: Testosterone therapy did not improve insulin resistance (mean adjusted difference [MAD] for HOMA-IR compared with placebo -0.08 [95% CI -0.31 to 0.47; P = 0.23]) or glycemic control (MAD HbA1c 0.36% [0.0-0.7]; P = 0.05), despite a decrease in fat mass (MAD -2.38 kg [-3.10 to -1.66]; P < 0.001) and an increase in lean mass (MAD 2.08 kg [1.52-2.64]; P < 0.001). Testosterone therapy reduced subcutaneous (MAD -320 cm(3) [-477 to -163]; P < 0.001) but not visceral abdominal adipose tissue (MAD 140 cm(3) [-89 to 369]; P = 0.90). CONCLUSIONS: Testosterone therapy does not improve glucose metabolism or visceral adiposity in obese men with moderately controlled T2D and modest reductions in circulating testosterone levels typical for men with T2D. PMID- 24804696 TI - Life's Simple 7 and incidence of diabetes among American Indians: the Strong Heart Family Study. AB - OBJECTIVE: The American Heart Association's recommendations for optimal health, summarized in Life's Simple 7, have been associated with reduced risk of cardiovascular disease (CVD)-related end points, but no studies have examined the association of these goals with incident type 2 diabetes, which is associated with high risk for CVD. The purpose of this analysis was to examine the associations of Life's Simple 7 goals with incident diabetes among American Indians, a population at high risk of cardiometabolic diseases. RESEARCH DESIGN AND METHODS: Strong Heart Family Study participants without diabetes (n = 1,639) at baseline and who participated in a follow-up examination were included in the analysis. Risk scores ranging from 0 to 7 were created using physical activity, diet, BMI, smoking, blood pressure, fasting glucose, and cholesterol metrics in accordance with Life's Simple 7 goals. Diabetes was defined using 2003 American Diabetes Association criteria, including use of insulin or oral antidiabetes medication or a follow-up fasting plasma glucose level >=126 mg/dL. Generalized estimating equations were used to examine the association of risk scores with incident diabetes. RESULTS: During a mean 5-year follow-up (range 4-8 years), we identified 210 cases of incident type 2 diabetes. Compared with participants who achieved 0-1 goals, those who achieved 2-3 or 4+ goals had lower odds of diabetes, with odds ratios = 0.40 (95% CI 0.29-0.56) and 0.11 (95% CI 0.05-0.21), respectively. CONCLUSIONS: The adoption of as few as two or three Life's Simple 7 goals is associated with a lower risk of diabetes. PMID- 24804698 TI - Increased risk of fracture and postfracture adverse events in patients with diabetes: two nationwide population-based retrospective cohort studies. AB - OBJECTIVE: The relationship between diabetes and fracture is not completely understood. This study evaluated fracture risk and postfracture mortality in patients with diabetes. RESEARCH DESIGN AND METHODS: We identified 32,471 adults newly diagnosed with diabetes in 2000-2003 using Taiwan's National Health Insurance Research Database. A comparison cohort of 64,942 adults without diabetes was randomly selected from the same dataset, with frequency matched by age and sex. Fracture events in 2000-2008 were ascertained from medical claims. Adjusted hazard ratios (HRs) and 95% CIs of fracture associated with diabetes were calculated. A nested cohort study of 17,002 patients with fracture receiving repair surgeries between 2004 and 2010 calculated adjusted odds ratios (ORs) and 95% CIs of adverse events after fracture in patients with and without diabetes. RESULTS: During 652,530 person-years of follow-up, there were 12,772 newly diagnosed fracture cases. The incidences of fracture for people with diabetes and without were 24.2 and 17.1 per 1,000 person-years, respectively (P < 0.0001). Compared with people without diabetes, the adjusted HR of fracture was 1.66 (95% CI 1.60-1.72) for people with diabetes. The ORs of postfracture deep wound infection, septicemia, and mortality associated with diabetes were 1.34 (95% CI 1.06-1.71), 1.42 (95% CI 1.23-1.64), and 1.27 (95% CI 1.02-1.60), respectively. CONCLUSIONS: Diabetes was associated with fracture. Patients with diabetes had more adverse events and subsequent mortality after fracture. Prevention of fracture and postfracture adverse events is needed in this susceptible population. PMID- 24804697 TI - A randomized trial of a home system to reduce nocturnal hypoglycemia in type 1 diabetes. AB - OBJECTIVE: Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels. RESEARCH DESIGN AND METHODS: Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15-45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which >=1 CGM glucose values <=60 mg/dL occurred. RESULTS: Overnight hypoglycemia with at least one CGM value <=60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43-0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm. CONCLUSIONS: Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis. PMID- 24804699 TI - HDL-C and HDL-C/ApoA-I predict long-term progression of glycemia in established type 2 diabetes. AB - OBJECTIVE: Low HDL cholesterol (HDL-C) and small HDL particle size may directly promote hyperglycemia. We evaluated associations of HDL-C, apolipoprotein A-I (apoA-I), and HDL-C/apoA-I with insulin secretion, insulin resistance, HbA1c, and long-term glycemic deterioration, reflected by initiation of pharmacologic glucose control. RESEARCH DESIGN AND METHODS: The 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study followed 9,795 type 2 diabetic subjects. We calculated baseline associations of fasting HDL-C, apoA-I, and HDL C/apoA-I with HbA1c and, in those not taking exogenous insulin (n = 8,271), with estimated beta-cell function (homeostasis model assessment of beta-cell function [HOMA-B]) and insulin resistance (HOMA-IR). Among the 2,608 subjects prescribed lifestyle only, Cox proportional hazards analysis evaluated associations of HDL C, apoA-I, and HDL-C/apoA-I with subsequent initiation of oral hypoglycemic agents (OHAs) or insulin. RESULTS: Adjusted for age and sex, baseline HDL-C, apoA I, and HDL-C/apoA-I were inversely associated with HOMA-IR (r = -0.233, -0.134, and -0.230; all P < 0.001; n = 8,271) but not related to HbA1c (all P > 0.05; n = 9,795). ApoA-I was also inversely associated with HOMA-B (r = -0.063; P = 0.002; n = 8,271) adjusted for age, sex, and HOMA-IR. Prospectively, lower baseline HDL C and HDL-C/apoA-I levels predicted greater uptake (per 1-SD lower: hazard ratio [HR] 1.13 [CI 1.07-1.19], P < 0.001; and HR 1.16 [CI 1.10-1.23], P < 0.001, respectively) and earlier uptake (median 12.9 and 24.0 months, respectively, for quartile 1 vs. quartile 4; both P < 0.01) of OHAs and insulin, with no difference in HbA1c thresholds for initiation (P = 0.87 and P = 0.81). Controlling for HOMA IR and triglycerides lessened both associations, but HDL-C/apoA-I remained significant. CONCLUSIONS: HDL-C, apoA-I, and HDL-C/apoA-I were associated with concurrent insulin resistance but not HbA1c. However, lower HDL-C and HDL-C/apoA I predicted greater and earlier need for pharmacologic glucose control. PMID- 24804700 TI - Inhibitor of DNA-binding protein 1 knockdown arrests the growth of colorectal cancer cells and suppresses hepatic metastasis in vivo. AB - Inhibitor of DNA-binding protein 1 (ID1) is commonly abnormally overexpressed in colorectal cancer (CRC); yet, the functional significance of ID1 in the growth and invasive properties of CRC cells remains largely unclear. The present study investigated the effects of ID1 downregulation on the cell growth and metastatic features of CRC. Using lentiviral shRNA infection, stable ID1-knockdown (KD) HCT116 and SW620 cells, human metastatic CRC cell lines, were created. In vitro, the migration/invasion capacity of the ID1-KD CRC cells was assessed by a wound healing assay. The activities of MMP2 and MMP-9 were measured by gelatin zymography. The expression of CXC chemokine receptor 4 (CXCR4), PCNA and survivin were determined by immunoblot analysis and qRT-PCR. The effects of ID1 knockdown on tumor growth and hepatic metastasis were demonstrated by a xenograft study in mice. The results showed evident decreases in proliferation, migration and invasion and an increased apoptosis rate in the ID1-KD CRC cells. Similarly, ID1 knockdown significantly decreased mRNA and protein levels of PCNA, survivin, CXCR4, MMP2 and MMP9. Overexpression of CXCR4 antagonized the negative effect on the migration and invasion abilities of the ID1-KD cells. As compared with the control, ID1 knockdown prevented tumor growth and profoundly suppressed hepatic metastasis in vivo. The present study demonstrated the significance of ID1 in colon cancer progression, and its effect on tumor invasiveness and metastatic properties may be partly dependent on CXCR4. PMID- 24804701 TI - Sanguinarine protects against pressure overload-induced cardiac remodeling via inhibition of nuclear factor-kappaB activation. AB - Cardiac remodeling is a major determinant of heart failure characterized by cardiac hypertrophy and fibrosis. Sanguinarine exerts widespread pharmacological effects, including antitumor and anti-inflammatory responses. In the present study, the effect of sanguinarine on cardiac hypertrophy, fibrosis and heart function was determined using the model induced by aortic banding (AB) in mice. AB surgery and sham surgery were performed on male wild-type C57 mice, aged 8-10 weeks, with or without administration of sanguinarine from one week after surgery for an additional seven weeks. Sanguinarine protected against the cardiac hypertrophy, fibrosis and dysfunction induced by AB, as assessed by the heart weight/body weight, lung weight/body weight and heart weight/tibia length ratios, echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The inhibitory effect of sanguinarine on cardiac remodeling was mediated by inhibiting nuclear factor (NF) kappaB signaling pathway activation. The findings indicated that sanguinarine protected against cardiac hypertrophy and fibrosis via inhibiting NF-kappaB activation. These findings may be used to develop a potential therapeutic drug for treating cardiac remodeling and heart failure. PMID- 24804702 TI - A population of glomerular glutamatergic neurons controls sensory information transfer in the mouse olfactory bulb. AB - In sensory systems, peripheral organs convey sensory inputs to relay networks where information is shaped by local microcircuits before being transmitted to cortical areas. In the olfactory system, odorants evoke specific patterns of sensory neuron activity that are transmitted to output neurons in olfactory bulb (OB) glomeruli. How sensory information is transferred and shaped at this level remains still unclear. Here we employ mouse genetics, 2-photon microscopy, electrophysiology and optogenetics, to identify a novel population of glutamatergic neurons (VGLUT3+) in the glomerular layer of the adult mouse OB as well as several of their synaptic targets. Both peripheral and serotoninergic inputs control VGLUT3+ neurons firing. Furthermore, we show that VGLUT3+ neuron photostimulation in vivo strongly suppresses both spontaneous and odour-evoked firing of bulbar output neurons. In conclusion, we identify and characterize here a microcircuit controlling the transfer of sensory information at an early stage of the olfactory pathway. PMID- 24804703 TI - Complete mitogenome analysis of indigenous populations in Mexico: its relevance for the origin of Mesoamericans. AB - Mesoamerica has an important role in the expansion of Paleoamericans as the route to South America. In this study, we determined complete mitogenome sequences of 113 unrelated individuals from two indigenous populations of Mesoamerica, Mazahua and Zapotec. All newly sequenced mitogenomes could be classified into haplogroups A2, B2, C1 and D1, but one sequence in Mazahua was D4h3a, a subclade of haplogroup D4. This haplogroup has been mostly found in South America along the Pacific coast. Haplogroup X2a was not found in either population. Genetic similarity obtained using phylogenetic tree construction and principal component analysis showed that these two populations are distantly related to each other. Actually, the Mazahua and the Zapotec shared no sequences (haplotypes) in common, while each also showed a number of unique subclades. Surprisingly, Zapotec formed a cluster with indigenous populations living in an area from central Mesoamerica to Central America. By contrast, the Mazahua formed a group with indigenous populations living in external areas, including southwestern North America and South America. This intriguing genetic relationship suggests the presence of two paleo-Mesoamerican groups, invoking a scenario in which one group had expanded into South America and the other resided in Mesoamerica. PMID- 24804704 TI - Mutation spectrum and phenotypic variation in nine patients with SOX2 abnormalities. AB - Multiple mutations in SOX2 have been identified in patients with ocular anomalies and/or pituitary dysfunction. Here, we identified SOX2 abnormalities in nine patients. The molecular defects included one missense, one nonsense and four frameshift mutations, and three submicroscopic deletions involving SOX2. Three of the six mutations and all deletions were hitherto unreported. The breakpoints determined in one deletion were located within Alu repeats and accompanied by an overlap of 11 bp. Three of the six mutations encoded SOX2 proteins that lacked in vitro transactivation activity for the HESX1 promoter, whereas the remaining three generated proteins with ~15-~20% of transactivation activity. All cases manifested ocular anomalies of various severities, together with several complications including arachnoid cyst and hamartoma. There was no apparent correlation between the residual activity and clinical severity. The results indicate that molecular defects in SOX2 are highly variable and include Alu repeat-mediated genomic rearrangements. Our data provide further evidence for wide phenotypic variation of SOX2 abnormalities and the lack of genotype phenotype correlation in patients carrying SOX2 lesions. PMID- 24804706 TI - In search of glacial refuges of the land snail Orcula dolium (Pulmonata, Orculidae)--an integrative approach using DNA sequence and fossil data. AB - Harboring a large number of endemic species, the Alps and the Western Carpathians are considered as major centers of biodiversity. Nonetheless, the general opinion until the turn of the millennium was that both Central European mountain regions did not provide suitable habitat during the Last Glacial Maximum, but were colonized later from southern refuges. However, recent molecular genetic studies provide new evidence for peripheral Alpine refuges. We studied the phylogeography of the calciphilous land snail O. dolium across its distribution in the Alps and the Western Carpathians to assess the amount of intraspecific differentiation and to detect potential glacial refuges. A partial sequence of the mitochondrial COI was analyzed in 373 specimens from 135 sampling sites, and for a subset of individuals, partial sequences of the mitochondrial 16S and the nuclear histone H3 and H4 were sequenced. A molecular clock analysis was combined with a reconstruction of the species' geographic range history to estimate how its lineages spread in the course of time. In order to obtain further information on the species' past distribution, we also screened its extensive Pleistocene fossil record. The reconstruction of geographic range history suggests that O. dolium is of Western Carpathian origin and diversified already around the Miocene-Pliocene boundary. The fossil record supports the species' presence at more than 40 sites during the last glacial and earlier cold periods, most of them in the Western Carpathians and the Pannonian Basin. The populations of O. dolium display a high genetic diversity with maximum intraspecific p-distances of 18.4% (COI) and 14.4% (16S). The existence of various diverged clades suggests the survival in several geographically separated refuges. Moreover, the sequence patterns provide evidence of multiple migrations between the Alps and the Western Carpathians. The results indicate that the Southern Calcareous Alps were probably colonized only during the Holocene. PMID- 24804707 TI - Shared air: a renewed focus on ventilation for the prevention of tuberculosis transmission. AB - BACKGROUND: Despite an improvement in the overall TB cure rate from 40-74% between 1995 and 2011, TB incidence in South Africa continues to increase. The epidemic is notably disquieting in schools because the vulnerable population is compelled to be present. Older learners (age 15-19) are at particular risk given a smear-positive rate of 427 per 100,000 per year and the significant amount of time they spend indoors. High schools are therefore important locations for potential TB infection and thus prevention efforts. METHODS AND FINDINGS: Using portable carbon dioxide monitors, we measured CO2 in classrooms under non-steady state conditions. The threshold for tuberculosis transmission was estimated using a carbon dioxide-based risk equation. We determined a critical rebreathed fraction of carbon dioxide (f(c)) of 1 . 6%, which correlates with an indoor CO2 concentration of 1000 ppm. These values correspond with a ventilation rate of 8 . 6 l/s per person or 12 air exchanges per hour (ACH) for standard classrooms of 180 m(3). CONCLUSIONS: Given the high smear positive rate of high-school adolescents in South Africa, the proposal to achieve CO2 levels of 1000 ppm through natural ventilation (in the amount 12 ACH) will not only help achieve WHO guidelines for providing children with healthy indoor environments, it will also provide a low-cost intervention for helping control the TB epidemic in areas of high prevalence. PMID- 24804709 TI - Relation of distortion product otoacoustic emission and tinnitus in normal hearing patients: a pilot study. AB - INTRODUCTION: Tinnitus, the perception of the sound in the absence of an external acoustic source, disrupts the daily life 1 out of every 200 adults, yet its physiological basis remains largely a mystery. The generation of tinnitus is commonly linked with the impaired functioning of the outer hair cells (OHC) inside the cochlea. Otoacoustic emissions are the objective test used to assess their activity. OBJECTIVE: The objective of the investigation was to study the features of Distortion product OtoAcoustic emissions (DPOAE) in a group of tinnitus patients with normal hearing and to find out whether there is any difference in DPOAE findings in the tinnitus patients with normal hearing and in persons with normal hearing with no complaint of tinnitus. MATERIALS AND METHODS: The participants consisted of two groups. The subject group consisted of 16 ears of patients, in which 6 subjects were having tinnitus in both ears while 4 subjects were having tinnitus only in one ear. All subjects were aged between 20 to 60 years with complaint of tinnitus with audiometrically normal hearing. Control group was comprised of 16 audiometrically normal hearing ears of persons who were age and gender matched with the subject groups and had no complaint of tinnitus. Both the subject group as well as control group was subjected for DPOAE test. Findings of both the groups were compared using the unpaired t test. RESULT AND CONCLUSION: It was observed that the amplitudes of DPOAE were significantly lower in tinnitus patients than that of persons without complaint of tinnitus, at a frequency of 1281-1560, 5120-6250, 7243-8837 Hz, which imply that decrease of DPOAEs amplitudes may be related to the presence of tinnitus. It can be concluded that there is association between tinnitus and reduced OHC activity which indicate the OHC of cochlea are involved in the generation of tinnitus. PMID- 24804708 TI - Functional characterization improves associations between rare non-synonymous variants in CHRNB4 and smoking behavior. AB - Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (<5%) non-synonymous variants in CHRNB4 and investigated functional effects by co-expression with normal alpha3 or alpha4 subunits in human embryonic kidney cells. Voltage-clamp was used to obtain acetylcholine and nicotine concentration-response curves and qRT-PCR, western blots and cell surface ELISAs were performed to assess expression levels. These results were used to functionally weight genetic variants in a gene-based association test. We find that there is a highly significant correlation between carrier status weighted by either acetylcholine EC50 (beta = -0.67, r2 = 0.017, P = 2 * 10(-4)) or by response to low nicotine (beta = -0.29, r2 = 0.02, P = 6 * 10(-5)) when variants are expressed with the alpha3 subunit. In contrast, there is no significant association when carrier status is unweighted (beta = -0.04, r2 = 0.0009, P = 0.54). These results highlight the value of functional analysis of variants and the advantages to integrating such data into genetic studies. They also suggest that an increased sensitivity to low concentrations of nicotine is protective from the risk of developing nicotine dependence. PMID- 24804710 TI - Tinnitus among Serbian secondary school students in relation to their behavior and habits. AB - Although tinnitus is a very common symptom, risk factors related to behavior and habits have not been sufficiently investigated. As no investigation on this problem has been performed in Serbia, the aim of our study was to establish the prevalence of tinnitus among Serbian adolescents and to investigate the relationship between their behavior and habits and tinnitus. This investigation was designed as a cross-sectional interview study among secondary school students in Belgrade, Serbia (277 boys and 494 girls). An anonymous questionnaire was self administered at classes. The investigated variables were: The presence of tinnitus, sources of noise, night outs at noisy places, use of personal music players, smoking, second hand smoke (SHS), substance abuse, coffee and alcohol consumption. Spearman's rank-order correlations and multiple logistic regressions were performed with variables related to behavior and habits as independent ones and tinnitus as a dichotomized dependent variable. Tinnitus was reported by 99 students (12.8%), more frequently among girls compared with boys (P = 0.009). Multivariate logistic regression analysis in boys revealed a significant independent effect of a regular drug abuse on the onset of tinnitus. The chances of tinnitus were 13 times higher among drug addicts compared with non-drug users (odds ratio [OR] and 95% confidence interval [CI] for tinnitus = 13.072; 1.335 127.946). In girls, the significant independent effect on tinnitus was found for daily duration of exposure to SHS (OR and 95% CI for tinnitus = 1.328; 1.073 1.644 /per 2 hours of exposure/). PMID- 24804711 TI - Cognitive skills and the effect of noise on perceived effort in employees with aided hearing impairment and normal hearing. AB - The aim of the following study was to examine the relationship between working memory capacity (WMC), executive functions (EFs) and perceived effort (PE) after completing a work-related task in quiet and in noise in employees with aided hearing impairment (HI) and normal hearing. The study sample consisted of 20 hearing-impaired and 20 normally hearing participants. Measures of hearing ability, WMC and EFs were tested prior to performing a work-related task in quiet and in simulated traffic noise. PE of the work-related task was also measured. Analysis of variance was used to analyze within- and between-group differences in cognitive skills, performance on the work-related task and PE. The presence of noise yielded a significantly higher PE for both groups. However, no significant group differences were observed in WMC, EFs, PE and performance in the work related task. Interestingly, significant negative correlations were only found between PE in the noise condition and the ability to update information for both groups. In summary, noise generates a significantly higher PE and brings explicit processing capacity into play, irrespective of hearing. This suggest that increased PE involves other factors such as type of task that is to be performed, performance in the cognitive skill required solving the task at hand and whether noise is present. We therefore suggest that special consideration in hearing care should be made to the individual's prerequisites on these factors in the labor market. PMID- 24804712 TI - Raynaud's phenomenon among men and women with noise-induced hearing loss in relation to vibration exposure. AB - Raynaud's phenomenon is characterized by constriction in blood supply to the fingers causing finger blanching, of white fingers (WF) and is triggered by cold. Earlier studies found that workers using vibrating hand-held tools and who had vibration-induced white fingers (VWF) had an increased risk for hearing loss compared with workers without VWF. This study examined the occurrence of Raynaud's phenomenon among men and women with noise-induced hearing loss in relation to vibration exposure. All 342 participants had a confirmed noise induced hearing loss medico legally accepted as work-related by AFA Insurance. Each subject answered a questionnaire concerning their health status and the kinds of exposures they had at the time when their hearing loss was first discovered. The questionnaire covered types of exposures, discomforts in the hands or fingers, diseases and medications affecting the blood circulation, the use of alcohol and tobacco and for women, the use of hormones and whether they had been pregnant. The participation rate was 41% (n = 133) with 38% (n = 94) for men and 50% (n = 39) for women. 84 men and 36 women specified if they had Raynaud's phenomenon and also if they had used hand-held vibrating machines. Nearly 41% of them had used hand-held vibrating machines and 18% had used vibrating machines at least 2 h each workday. There were 23 men/6 women with Raynaud's phenomenon. 37% reported WF among those participants who were exposed to hand-arm vibration (HAV) and 15% among those not exposed to HAV. Among the participants with hearing loss with daily use of vibrating hand-held tools more than twice as many reports WF compared with participants that did not use vibrating hand-held tools. This could be interpreted as Raynaud's phenomenon could be associated with an increased risk for noise-induced hearing loss. However, the low participation rate limits the generalization of the results from this study. PMID- 24804713 TI - Neighborhood noise pollution as a determinant of displaced aggression: a pilot study. AB - Noise pollution is still a growing public health problem with a significant impact on psychological health and well-being. The aim of this study was to investigate the impact of noise on displaced aggression (DA) in different subgroups of residents in one of the neighborhoods of Plovdiv city. A cross sectional semi-structured interview survey was conducted using specially designed data registration forms and 33 close-ended and open-ended questions, divided into two major panels - one original and a modified version of the Displaced Aggression Questionnaire (DAQ). The mean score for DA was 61.12 (+/-19.97). Hearing noises above the perceived normal threshold, higher noise sensitivity and continuous noises were associated with higher levels of DA. Low frequency and high intensity noises were also associated with higher DA scores. Multiple regression model supported these findings. Contradictory to previous research age was positively correlated with noise sensitivity and aggression. We speculated that this might be due to the relatively lower socio-economic standard and quality of life in Bulgaria. Therefore, social climate might be modifying the way people perceive and react to environmental noise. Finally, the DAQ proved to be a viable measurement tool of these associations and might be further implemented and modified to suit the purposes of psychoacoustic assessment. PMID- 24804714 TI - Asymmetry in noise-induced hearing loss: evaluation of two competing theories. AB - Competing theories exist about why asymmetry is observed in noise-induced hearing loss (NIHL). We evaluated these theories using a cohort of young workers studied over 16 years. The study aim was to describe and evaluate patterns of hearing loss and asymmetry by gender, agricultural exposure and gunfire exposure. This was a secondary analysis of data collected from young adults during follow-up of a randomized controlled trial. This follow-up study evaluated long-term effects of a hearing conservation intervention for rural students. The sample consisted of 392 of 690 participants from the original trial. In total, 355 young adults (aged 29-33 years) completed baseline and follow-up noise exposure surveys and clinical audiometric examinations. Data are displayed graphically as thresholds by frequency and ear and degree of asymmetry between ears (left minus right). In the primary group comparisons, low and high frequency averages and mean high frequency asymmetry were analyzed using mixed linear models. At frequencies >2000 Hz, men showed more hearing loss, with greater asymmetry and a different asymmetry pattern, than women. For men with documented hearing loss, there was a trend toward increasing asymmetry with increasing levels of hearing loss. Asymmetry at high frequencies varied substantially by level of shooting exposure. While "head shadowing" is accepted as the primary explanation for asymmetric hearing loss in the audiologic and related public health literature, our findings are more consistent with physiological differences as the primary cause of asymmetric hearing loss, with greater susceptibility to NIHL in the left ear of men. PMID- 24804715 TI - Evaluation of the olivocochlear efferent reflex strength in the susceptibility to temporary hearing deterioration after music exposure in young adults. AB - The objective of the current study was to evaluate the predictive role of the olivocochlear efferent reflex strength in temporary hearing deterioration in young adults exposed to music. This was based on the fact that a noise-protective role of the medial olivocochlear (MOC) system was observed in animals and that efferent suppression (ES) measured using contralateral acoustic stimulation (CAS) of otoacoustic emissions (OAEs) is capable of exploring the MOC system. Knowing an individual's susceptibility to cochlear damage after noise exposure would enhance preventive strategies for noise-induced hearing loss. The hearing status of 28 young adults was evaluated using pure-tone audiometry, transient evoked OAEs (TEOAEs) and distortion product OAEs (DPOAEs) before and after listening to music using an MP3 player during 1 h at an individually determined loud listening level. CAS of TEOAEs was measured before music exposure to determine the amount of ES. Regression analysis showed a distinctive positive correlation between temporary hearing deterioration and the preferred gain setting of the MP3 player. However, no clear relationship between temporary hearing deterioration and the amount of ES was found. In conclusion, clinical measurement of ES, using CAS of TEOAEs, is not correlated with the amount of temporary hearing deterioration after 1 h music exposure in young adults. However, it is possible that the temporary hearing deterioration in the current study was insufficient to activate the MOC system. More research regarding ES might provide more insight in the olivocochlear efferent pathways and their role in auditory functioning. PMID- 24804716 TI - Possible psychological mechanisms for "wind turbine syndrome". On the windmills of your mind. AB - Throughout history, people have suffered from physical symptoms that they have attributed to modern technologies. Often these attributions are strongly held, but not supported by scientific evidence. Symptoms attributed to the operation of wind turbines (called "wind turbine syndrome" by some) may fit into this category. Several psychological mechanisms might account for symptoms attributed to wind turbines. First, the "nocebo effect" is a well-recognized phenomenon in which the expectation of symptoms can become self-fulfilling. Second, misattribution of pre-existing or new symptoms to a novel technology can also occur. Third worry about a modern technology increases the chances of someone attributing symptoms to it. Fourth, social factors, including media reporting and interaction with lobby groups can increase symptom reporting. For wind turbines, there is already some evidence that a nocebo effect can explain the attributed symptoms while misattribution seems likely. Although worry has not been directly studied, research has shown that people who are annoyed by the sound that turbines produce are more likely to report symptoms and that annoyance is associated with attitudes toward the visual impact of wind farms and whether a person benefits economically from a wind farm. Given that these mechanisms may be sufficient to account for the experiences reported by sufferers, policy-makers, clinicians and patients should insist on good-quality evidence before accepting a more direct causal link. PMID- 24804717 TI - Insights from the First International Conference on Hyperacusis: causes, evaluation, diagnosis and treatment. AB - The First International Conference on Hyperacusis gathered over 100 scientists and health care professionals in London, UK. Key conclusions from the conference included: (1) Hyperacusis is characterized by reduced tolerance of sound that has perceptual, psychological and social dimensions; (2) there is a growing awareness that children as well as adults experience symptoms of hyperacusis or misophonia; (3) the exact mechanisms that give rise to hyperacusis are not clear, but the available evidence suggests that functional changes within the central nervous system are important and in particular, hyperacusis may be related to increased gain in the central auditory pathways and to increased anxiety or emotional response to sound; (4) various counseling and sound therapy approaches seem beneficial in the management of hyperacusis, but the evidence base for these remains poor. PMID- 24804718 TI - Fit for the frontline? A focus group exploration of auditory tasks carried out by infantry and combat support personnel. AB - In order to preserve their operational effectiveness and ultimately their survival, military personnel must be able to detect important acoustic signals and maintain situational awareness. The possession of sufficient hearing ability to perform job-specific auditory tasks is defined as auditory fitness for duty (AFFD). Pure tone audiometry (PTA) is used to assess AFFD in the UK military; however, it is unclear whether PTA is able to accurately predict performance on job-specific auditory tasks. The aim of the current study was to gather information about auditory tasks carried out by infantry personnel on the frontline and the environment these tasks are performed in. The study consisted of 16 focus group interviews with an average of five participants per group. Eighty British army personnel were recruited from five infantry regiments. The focus group guideline included seven open-ended questions designed to elicit information about the auditory tasks performed on operational duty. Content analysis of the data resulted in two main themes: (1) the auditory tasks personnel are expected to perform and (2) situations where personnel felt their hearing ability was reduced. Auditory tasks were divided into subthemes of sound detection, speech communication and sound localization. Reasons for reduced performance included background noise, hearing protection and attention difficulties. The current study provided an important and novel insight to the complex auditory environment experienced by British infantry personnel and identified 17 auditory tasks carried out by personnel on operational duties. These auditory tasks will be used to inform the development of a functional AFFD test for infantry personnel. PMID- 24804719 TI - Piperine causes G1 phase cell cycle arrest and apoptosis in melanoma cells through checkpoint kinase-1 activation. AB - In this study, we determined the cytotoxic effects of piperine, a major constituent of black and long pepper in melanoma cells. Piperine treatment inhibited the growth of SK MEL 28 and B16 F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest by piperine treatment was associated with DNA damage as indicated by phosphorylation of H2AX at Ser139, activation of ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (Chk1). Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Similarly, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine. Piperine treatment caused down-regulation of E2F1 and phosphorylation of retinoblastoma protein (Rb). Apoptosis induced by piperine was associated with down-regulation of XIAP, Bid (full length) and cleavage of Caspase-3 and PARP. Furthermore, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS by tiron protected the cells from piperine mediated cell cycle arrest and apoptosis. These results suggest that piperine mediated ROS played a critical role in inducing DNA damage and activation of Chk1 leading to G1 cell cycle arrest and apoptosis. PMID- 24804720 TI - Multi-modal glioblastoma segmentation: man versus machine. AB - BACKGROUND AND PURPOSE: Reproducible segmentation of brain tumors on magnetic resonance images is an important clinical need. This study was designed to evaluate the reliability of a novel fully automated segmentation tool for brain tumor image analysis in comparison to manually defined tumor segmentations. METHODS: We prospectively evaluated preoperative MR Images from 25 glioblastoma patients. Two independent expert raters performed manual segmentations. Automatic segmentations were performed using the Brain Tumor Image Analysis software (BraTumIA). In order to study the different tumor compartments, the complete tumor volume TV (enhancing part plus non-enhancing part plus necrotic core of the tumor), the TV+ (TV plus edema) and the contrast enhancing tumor volume CETV were identified. We quantified the overlap between manual and automated segmentation by calculation of diameter measurements as well as the Dice coefficients, the positive predictive values, sensitivity, relative volume error and absolute volume error. RESULTS: Comparison of automated versus manual extraction of 2 dimensional diameter measurements showed no significant difference (p = 0.29). Comparison of automated versus manual segmentation of volumetric segmentations showed significant differences for TV+ and TV (p<0.05) but no significant differences for CETV (p>0.05) with regard to the Dice overlap coefficients. Spearman's rank correlation coefficients (rho) of TV+, TV and CETV showed highly significant correlations between automatic and manual segmentations. Tumor localization did not influence the accuracy of segmentation. CONCLUSIONS: In summary, we demonstrated that BraTumIA supports radiologists and clinicians by providing accurate measures of cross-sectional diameter-based tumor extensions. The automated volume measurements were comparable to manual tumor delineation for CETV tumor volumes, and outperformed inter-rater variability for overlap and sensitivity. PMID- 24804721 TI - Energy density of the Scottish diet estimated from food purchase data: relationship with socio-economic position and dietary targets. AB - Frequent consumption of energy-dense foods has been strongly implicated in the global increase of obesity. The World Cancer Research Fund suggests a population level energy density (ED) goal for diets of 523 kJ/100 g (125 kcal/100 g) as desirable for reducing weight gain and related co-morbidities. However, there is limited information about the ED of diets of contemporary populations. The aims of the present study were to (1) estimate the mean ED of the Scottish diet, (2) assess differences in ED over time by socio-economic position, by household (HH) composition and for HH meeting dietary targets for fat and fruit and vegetables, and (3) assess the relationship between ED and the consumption of foods and nutrients, which are indicative of diet quality. ED of the diet was estimated from food (including milk) from UK food purchase survey data. The average ED of the Scottish diet was estimated as 718 kJ/100 g with no change between the survey periods 2001 and 2009. Individuals living in the most deprived areas had a higher mean ED than those living in the least deprived areas (737 v. 696 kJ/100 g). Single-parent HH had the highest mean ED (765 kJ/100 g) of all the HH surveyed. The mean ED of HH achieving dietary targets for fat and fruit and vegetables was 576 kJ/100 g compared with 731 kJ/100 g for non-achievers. HH within the lowest quintile of ED were, on average, closest to meeting most dietary guidelines. Food purchase data can be used to monitor the quality of the diet in terms of dietary ED of the population and subgroups defined by an area-based measure of socio economic status. PMID- 24804723 TI - Editorial: "amniotic fluid embolism: novel biomarkers for future diagnostic investigation and therapy". PMID- 24804724 TI - Amniotic fluid embolism: moving diagnosis through the time. From the mechanical pulmonary vascular occlusion until an immuno - inflammatory pathogenesis? AB - Amniotic fluid embolism (AFE) is a rare, catastrophic syndrome that presents during labor and delivery or immediately postpartum. Efforts to develop a clinical diagnostic test are ongoing; however the diagnosis still relies on rapid bedside evaluation and depends on the exclusion of other diseases. Classically, the diagnosis was made at autopsy, with the demonstration of squamous cells or debris in the maternal pulmonary vasculature. Clinico-pathological correlations have strengthened the evidence for a role of the immune system in the pathogenesis of AFE and have lead to the development of new laboratory tests, such as the serum tryptase and complement measurements, which should provide scientific support for the presumed immunological mechanism of AFE. Recently, studies on the effects of amniotic fluid (AF) on platelet - neutrophil aggregation and neutrophil/platelet activation have opened new insight in the comprehension of the mechanisms underlying AFE, suggesting that a severe inflammatory response might have a paramount causative role, so opening new diagnostic and therapeutic perspectives. Considering the complex interplay between the different mechanisms involved in the pathogenesis of AFE, the diagnosis still arises from a complex diagnostic puzzle in which clinical, macroscopic, laboratory, histological and immunohistochemical data converge toward AFE. PMID- 24804722 TI - Evolution of mitochondria reconstructed from the energy metabolism of living bacteria. AB - The ancestors of mitochondria, or proto-mitochondria, played a crucial role in the evolution of eukaryotic cells and derived from symbiotic alpha-proteobacteria which merged with other microorganisms - the basis of the widely accepted endosymbiotic theory. However, the identity and relatives of proto-mitochondria remain elusive. Here we show that methylotrophic alpha-proteobacteria could be the closest living models for mitochondrial ancestors. We reached this conclusion after reconstructing the possible evolutionary pathways of the bioenergy systems of proto-mitochondria with a genomic survey of extant alpha-proteobacteria. Results obtained with complementary molecular and genetic analyses of diverse bioenergetic proteins converge in indicating the pathway stemming from methylotrophic bacteria as the most probable route of mitochondrial evolution. Contrary to other alpha-proteobacteria, methylotrophs show transition forms for the bioenergetic systems analysed. Our approach of focusing on these bioenergetic systems overcomes the phylogenetic impasse that has previously complicated the search for mitochondrial ancestors. Moreover, our results provide a new perspective for experimentally re-evolving mitochondria from extant bacteria and in the future produce synthetic mitochondria. PMID- 24804725 TI - Challenges in managing amniotic fluid embolism: an up-to-date perspective on diagnostic testing with focus on novel biomarkers and avenues for future research. AB - Amniotic fluid embolism (AFE) continues to pose a formidable clinical challenge with its high rate of morbidity and mortality. A novel biomarker that acts as an early warning system for the clinician would be a welcomed addition to our medical armamentarium. Here we review the state of diagnosing AFE with our current methods of evaluation and testing along with recently discovered potential biomarkers that may be clinically efficacious. Additionally we explore the future of proteomics, lipidomics, and transcriptomics as tools to identify potential novel signaling pathways and biomarkers. PMID- 24804726 TI - Amniotic fluid embolism: review. AB - Amniotic fluid embolism is a rare but dreadful syndrome in Obstetrics, which happens, in most of the cases, in the peripartum period. The actual "embolisation" of the pulmonary vessels does not explain the whole picture of the syndrome. An immune mechanism, similar to an anaphylactic reaction, is more convincingly the background of the event, but the pathogenesis is still ill defined. Similarly the initial symptoms are difficult to interpret and distinguish from other acute and life-threatening emergencies (i.e. pulmonary embolism, placental abruption, septic shock, stroke, myocardial ischemia, etc.), therefore the diagnosis is one of exclusion, very often on postmortem report. Thus the prevalence of the disease is difficult to establish, most of the reports being postmortem cases or National Registries data. These data, based either on autopsy series or on registries, are non representative of the true prevalence of the event and obviously confusing for the correct understanding of the disease process. Risk factors are all those conditions or manouvres, which contemplate a breech in the maternal-fetal barrier. Again, given the rarity of the syndrome, no single event is clearly identifiable as a case-effect risk factor. Prognosis, which is obviously biased by the reporting system, is particularly grim both in terms of survival and morbidity. The symptoms being often elusive at the beginning, but rapidly and progressively catastrophic, a multidisciplinary team approach is warranted in order to provide the best chance of survival both for mother and baby. Immediate and aggressive resuscitation is, therefore, advised whenever a mother in labour or in the early postpartum period experiences a sudden collapse. PMID- 24804727 TI - Epidemiological and clinical data of amniotic fluid embolism in forensic settings. AB - Amniotic fluid embolism (AFE) is a serious obstetric emergency, burdened with a high rate of mortality and morbidity and possible permanent neurological sequelae for those women who survive. The clinical presentation commonly includes: acute hypotension or cardiac arrest, acute hypoxia (dyspnea, cyanosis or respiratory arrest) and coagulopathy (intravascular coagulation or severe haemorrhage), which usually occur during labour, caesarean section or within 30 minutes of delivery. Some cases for the rapidity of clinical presentation, which can result in fatal outcome, run the risk of not being recognized, therefore a proper post mortem examination and histological investigation is fundamental in case of maternal death in order to make the diagnosis and should not be underestimated the incidence of this serious pathological condition. In this paper, firstly the Authors investigated the fatality rates in AFE patients and its incidence in pregnancy related deaths, extrapolating epidemiological data regarding the role of this pathology among the leading causes of maternal mortality. Secondly the contribution of autopsy has been evaluated and further investigation performed on post mortem in order to confirm or make the diagnosis of AFE to better understand this clinical entity that still remains unclear under numerous aspects. PMID- 24804728 TI - Not only a clinical nightmare: amniotic fluid embolism in court. AB - Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving usually women in labour or in the early post-partum period. Clinical consequences of this unpredictable and unpreventable pathology may be extremely serious with high morbidity and mortality rates. Data obtained from the US Amniotic Fluid Embolism Registry show that the process is more similar to anaphylaxis than to embolism, and the term anaphylactoid syndrome of pregnancy has been suggested because foetal tissue or amniotic fluid components are not universally found in women who present signs and symptoms related to AFE. The first aim of this paper has been to focus on the medico-legal aspects concerning the misdiagnosis and the treatment of the AFE and the Authors, with this purpose in mind, reviewed the main national law cases on medical malpractice claims involving both physicians and hospitals. The second aim has been to highlight the need to introduce a National register as a useful tool to raise the awareness of this disease among physicians and to improve the quality of care, which can be achieved through a proper identification and reporting of AFE cases. The application of a national register may limit the number of medico-legal litigations, which according to the national and foreign Jurisprudence are not currently based in favour of the predictability of AFE, but they focus their discussion on the importance of a prompt medical assistance when the effects of this disorder occur. PMID- 24804729 TI - Amniotic fluid embolism: what level of scientific evidence can be drawn? A systematic review. AB - Amniotic fluid embolism (AFE) is a rare and severe obstetric emergency and a significant cause of maternal mortality in developed countries and its incidence varies according to different studies. Presently, advances in the understanding of this pathology continue to be slowed down for the absence of generally accepted diagnostic criteria, the clinical analogies of this entity to other types of acute dangerous maternal illnesses and the presence of a wide range of disease severity. The aim of this review has been to evaluate the incidence of AFE, the role of possible risk factors, the clinical presentation (signs and symptoms) and outcome. Secondly the authors reviewed the management of these very difficult patients, including treatments and interventions in order to extrapolate sharable recommendations for the management of these complicated patients. PMID- 24804730 TI - Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SNC, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD. PMID- 24804731 TI - Fish food in the deep sea: revisiting the role of large food-falls. AB - The carcasses of large pelagic vertebrates that sink to the seafloor represent a bounty of food to the deep-sea benthos, but natural food-falls have been rarely observed. Here were report on the first observations of three large 'fish-falls' on the deep-sea floor: a whale shark (Rhincodon typus) and three mobulid rays (genus Mobula). These observations come from industrial remotely operated vehicle video surveys of the seafloor on the Angola continental margin. The carcasses supported moderate communities of scavenging fish (up to 50 individuals per carcass), mostly from the family Zoarcidae, which appeared to be resident on or around the remains. Based on a global dataset of scavenging rates, we estimate that the elasmobranch carcasses provided food for mobile scavengers over extended time periods from weeks to months. No evidence of whale-fall type communities was observed on or around the carcasses, with the exception of putative sulphide oxidising bacterial mats that outlined one of the mobulid carcasses. Using best estimates of carcass mass, we calculate that the carcasses reported here represent an average supply of carbon to the local seafloor of 0.4 mg m(-2)d(-1), equivalent to ~ 4% of the normal particulate organic carbon flux. Rapid flux of high-quality labile organic carbon in fish carcasses increases the transfer efficiency of the biological pump of carbon from the surface oceans to the deep sea. We postulate that these food-falls are the result of a local concentration of large marine vertebrates, linked to the high surface primary productivity in the study area. PMID- 24804732 TI - Novel avian influenza A (H7N9) virus induces impaired interferon responses in human dendritic cells. AB - In March 2013 a new avian influenza A(H7N9) virus emerged in China and infected humans with a case fatality rate of over 30%. Like the highly pathogenic H5N1 virus, H7N9 virus is causing severe respiratory distress syndrome in most patients. Based on genetic analysis this avian influenza A virus shows to some extent adaptation to mammalian host. In the present study, we analyzed the activation of innate immune responses by this novel H7N9 influenza A virus and compared these responses to those induced by the avian H5N1 and seasonal H3N2 viruses in human monocyte-derived dendritic cells (moDCs). We observed that in H7N9 virus-infected cells, interferon (IFN) responses were weak although the virus replicated as well as the H5N1 and H3N2 viruses in moDCs. H7N9 virus induced expression of pro-inflammatory cytokines remained at a significantly lower level as compared to H5N1 virus-induced "cytokine storm" seen in human moDCs. However, the H7N9 virus was extremely sensitive to the antiviral effects of IFN-alpha and IFN-beta in pretreated cells. Our data indicates that different highly pathogenic avian viruses may show considerable differences in their ability to induce host antiviral responses in human primary cell models such as moDCs. The unexpected appearance of the novel H7N9 virus clearly emphasizes the importance of the global influenza surveillance system. It is, however, equally important to systematically characterize in normal human cells the replication capacity of the new viruses and their ability to induce and respond to natural antiviral substances such as IFNs. PMID- 24804733 TI - The anti-proliferative effect of L-carnosine correlates with a decreased expression of hypoxia inducible factor 1 alpha in human colon cancer cells. AB - In recent years considerable attention has been given to the use of natural substances as anticancer drugs. The natural antioxidant dipeptide L-carnosine belongs to this class of molecules because it has been proved to have a significant anticancer activity both in vitro and in vivo. Previous studies have shown that L-carnosine inhibits the proliferation of human colorectal carcinoma cells by affecting the ATP and Reactive Oxygen Species (ROS) production. In the present study we identified the Hypoxia-Inducible Factor 1alpha (HIF-1alpha) as a possible target of L-carnosine in HCT-116 cell line. HIF-1alpha protein is over expressed in multiple types of human cancer and is the major cause of resistance to drugs and radiation in solid tumours. Of particular interest are experimental data supporting the concept that generation of ROS provides a redox signal for HIF-1alpha induction, and it is known that some antioxidants are able to suppress tumorigenesis by inhibiting HIF-1alpha. In the current study we found that L carnosine reduces the HIF-1alpha protein level affecting its stability and decreases the HIF-1 transcriptional activity. In addition, we demonstrated that L carnosine is involved in ubiquitin-proteasome system promoting HIF-1alpha degradation. Finally, we compared the antioxidant activity of L-carnosine with that of two synthetic anti-oxidant bis-diaminotriazoles (namely 1 and 2, respectively). Despite these three compounds have the same ability in reducing intracellular ROS, 1 and 2 are more potent scavengers and have no effect on HIF 1alpha expression and cancer cell proliferation. These findings suggest that an analysis of L-carnosine antioxidant pathway will clarify the mechanism underlying the anti-proliferative effects of this dipeptide on colon cancer cells. However, although the molecular mechanism by which L-carnosine down regulates or inhibits the HIF-1alpha activity has not been yet elucidated, this ability may be promising in treating hypoxia-related diseases. PMID- 24804736 TI - Apyrase protects against allergic airway inflammation by decreasing the chemotactic migration of dendritic cells in mice. AB - Recent studies have demonstrated that extracellular adenosine 5'-triphosphate (eATP) is involved in allergic airway inflammation by activating purinergic receptors. eATP can be hydrolyzed by ectonucleotidases, such as CD39. In this study, we investigated the expression and distribution of CD39 in the lungs of mice, as well as the effects of apyrase on airway inflammation and the chemotactic migration of dendritic cells (DCs). A mouse model of asthma was developed with chicken ovalbumin (OVA)/aluminum hydroxide using female C57BL/6 mice. Apyrase was administered to OVA-sensitized mice prior to each challenge by intraperitoneal injection. The distribution of CD39 was detected by immunofluorescence. The mRNA and protein expression of CD39 was determined by quantitative PCR and western blot analysis, respectively. The levels of Th2 cytokines in the bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay (ELISA). The effect of apyrase on the chemotactic migration of DCs towards ATP was explored by migration assay in vitro. In the lungs, CD39 was primarily located in the cytoplasm and cytomembrane of bronchial epithelial cells and CD39 expression was reduced in mice with allergic asthma. Treatment with apyrase markedly attenuated OVA-induced airway inflammation, including peribronchial eosinophilic inflammation and reduced the number of inflammatory cells, as well as the levels of cytokines in BALF. Furthermore, apyrase also markedly reduced the expression of GATA binding protein 3 (GATA3) and decreased the chemotactic migration of DCs towards ATP.Our data demonstrate that a reduction in CD39 expression may be associated with the development of allergic airway inflammation and that apyrase alleviates airway inflammation by decreasing the chemotactic migration of DCs towards eATP. Therefore, targeting at eATP or ectonucleotidases may provide a novel therapeutic approach for allergic asthma. PMID- 24804734 TI - Shorter men live longer: association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. AB - OBJECTIVES: To determine the relation between height, FOXO3 genotype and age of death in humans. METHODS: Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation. RESULTS: A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003-1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002-1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10 0.42; P = 0.001). CONCLUSION: Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway. PMID- 24804737 TI - Is your system calibrated? MRI gradient system calibration for pre-clinical, high resolution imaging. AB - High-field, pre-clinical MRI systems are widely used to characterise tissue structure and volume in small animals, using high resolution imaging. Both applications rely heavily on the consistent, accurate calibration of imaging gradients, yet such calibrations are typically only performed during maintenance sessions by equipment manufacturers, and potentially with acceptance limits that are inadequate for phenotyping. To overcome this difficulty, we present a protocol for gradient calibration quality assurance testing, based on a 3D printed, open source, structural phantom that can be customised to the dimensions of individual scanners and RF coils. In trials on a 9.4 T system, the gradient scaling errors were reduced by an order of magnitude, and displacements of greater than 100 um, caused by gradient non-linearity, were corrected using a post-processing technique. The step-by-step protocol can be integrated into routine pre-clinical MRI quality assurance to measure and correct for these errors. We suggest that this type of quality assurance is essential for robust pre-clinical MRI experiments that rely on accurate imaging gradients, including small animal phenotyping and diffusion MR. PMID- 24804738 TI - Mitochondrial manipulations. PMID- 24804739 TI - State challenges to painkiller could threaten FDA authority. PMID- 24804740 TI - FDA clearance paves way for computerized ADHD monitoring. PMID- 24804741 TI - Mystery around drug adherence still plagues medical literature. PMID- 24804742 TI - HIV researchers on edge after antigay raids across Africa. PMID- 24804743 TI - Straight talk with...Jamie Heywood. AB - Last month, Genentech launched an unusual five-year research pact. The San Francisco subsidiary of the drug giant Roche partnered with Cambridge, Massachusetts-based PatientsLikeMe to mine the online patient network's database of real-world experiences. In exchange for an undisclosed fee, Genentech now has access to nearly all of the information collected by PatientsLikeMe, which currently includes more than 250,000 members with 2,000 different conditions. The hope is that studying the network will help Genentech learn how to stratify patient populations more precisely and measure drug effectiveness better, among other things.At the helm of PatientsLikeMe is Jamie Heywood, a mechanical engineer by training who devised the idea for the platform ten years ago when he noticed some striking similarities between the information asked of online dating websites and clinical trial portals. With his brother Benjamin and friend Jeff Cole, Heywood founded PatientsLikeMe later that same year. Nicholette Zeliadt spoke to Heywood about where the crowdsourcing site stands a decade on from its inception and what this new partnership with Genentech will mean for open participation research. PMID- 24804745 TI - The mathematician versus the malignancy. PMID- 24804747 TI - The importance and challenge of pediatric trials of hemophilia drugs. PMID- 24804748 TI - The importance and challenge of pediatric trials of hemophilia drugs. PMID- 24804749 TI - Reply to: The importance and challenge of pediatric trials of hemophilia drugs. PMID- 24804750 TI - Tying up PGE2 with albumin to relieve immunosuppression in cirrhosis. PMID- 24804751 TI - Neonates, antibiotics and the microbiome. PMID- 24804752 TI - A protean protease: MMP-12 fights viruses as a protease and a transcription factor. PMID- 24804753 TI - A new role for the brain in metabolic control. PMID- 24804754 TI - Detecting cancer by monitoring circulating tumor DNA. PMID- 24804755 TI - CRISPR technology for gene therapy. PMID- 24804756 TI - Opening Fronts in HIV Vaccine Development: Tracking the development of broadly neutralizing antibodies. PMID- 24804757 TI - Opening Fronts in HIV Vaccine Development: Targeting reservoirs to clear and cure. PMID- 24804765 TI - Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. AB - Tumor cell extravasation into the brain requires passage through the blood-brain barrier (BBB). There is evidence that exercise can alter the oxidation status of the brain microvasculature and protect against tumor cell invasion into the brain, although the mechanisms are not well understood. In the current study, we focused on the role of microenvironment generated by exercise and metastasizing tumor cells at the levels of brain microvessels, influencing oxidative stress mediated responses and activation of redox-sensitive small GTPases. Mature male mice were exercised for four weeks using a running wheel with the average voluntary running distance 9.0 +/- 0.3 km/day. Mice were then infused with 1.0 * 10(6) D122 (murine Lewis lung carcinoma) cells into the brain microvasculature, and euthanized either 48 hours (in short-term studies) or 2-3 weeks (in long-term studies) post tumor cell administration. A significant increase in the level of reactive oxygen species was observed following 48 hours or 3 weeks of tumor cells growth, which was accompanied by a reduction in MnSOD expression in the exercised mice. Activation of the small GTPase Rho was negatively correlated with running distance in the tumor cell infused mice. Together, these data suggest that exercise may play a significant role during aggressive metastatic invasion, especially at higher intensities in pre-trained individuals. PMID- 24804768 TI - Risk factors for necrotising enterocolitis in an HIV-endemic region. AB - BACKGROUND: Several risk factors have been implicated in the development of necrotising enterocolitis (NEC). However, little has been reported on the risk factors for NEC in infants born in a setting where exposure to maternal human immunodeficiency virus (HIV) is prevalent. OBJECTIVES: To determine maternal and infant characteristics associated with NEC in a setting with a high prevalence of HIV infection and to compare clinical presentation and mortality of NEC in HIV exposed and unexposed infants. METHODS: This was a retrospective, case-control study. Infants with a confirmed diagnosis of NEC, admitted between January 2005 and December 2008 were identified as cases. Two controls for each case were selected by matching them for birthweight, gestational age and date of birth. Hospital records were reviewed for maternal and infant characteristics. RESULTS: One hundred and ten infants with confirmed NEC were identified and 220 were selected as controls. Median birthweight and gestational age were similar between cases and controls, (1370 and 1380 g, P = 0.96, and 31 weeks each, P = 0.62, respectively). Lack of use of antenatal corticosteroids (ANS) (OR 2.77, 95% CI 1.42-5.38, P = 0.003), presence of chorio-amnionitis (OR 7.28, 95% CI 2.16-24.51, P = 0.001) and not mechanically ventilated at birth (OR 3.54, 95% CI 1.29-9.69, P = 0.01) were independently associated with NEC. Maternal HIV status was not associated with NEC. Clinical presentation and mortality from NEC were similar between HIV-exposed and unexposed infants. CONCLUSIONS: Infants who develop NEC were less likely to have received mechanical ventilation at birth, suggesting that they were less critically ill when born. Use of ANS should be encouraged as it is protective against NEC. Infants born to HIV-infected mothers were not at increased risk of NEC. PMID- 24804767 TI - Response of human thalamic neurons to high-frequency stimulation. AB - Thalamic deep brain stimulation (DBS) is an effective treatment for tremor, but the mechanisms of action remain unclear. Previous studies of human thalamic neurons to noted transient rebound bursting activity followed by prolonged inhibition after cessation of high frequency extracellular stimulation, and the present study sought to identify the mechanisms underlying this response. Recordings from 13 thalamic neurons exhibiting low threshold spike (LTS) bursting to brief periods of extracellular stimulation were made during surgeries to implant DBS leads in 6 subjects with Parkinson's disease. The response immediately after cessation of stimulation included a short epoch of burst activity, followed by a prolonged period of silence before a return to LTS bursting. A computational model of a population of thalamocortical relay neurons and presynaptic axons terminating on the neurons was used to identify cellular mechanisms of the observed responses. The model included the actions of neuromodulators through inhibition of a non-pertussis toxin sensitive K(+) current (I(KL)), activation of a pertussis toxin sensitive K(+) current (I(KG)), and a shift in the activation curve of the hyperpolarization-activated cation current (I(h)). The model replicated well the measured responses, and the prolonged inhibition was associated most strongly with changes in I(KG) while modulation of I(KL) or I(h) had minimal effects on post-stimulus inhibition suggesting that neuromodulators released in response to high frequency stimulation are responsible for mediating the post-stimulation bursting and subsequent long duration silence of thalamic neurons. The modeling also indicated that the axons of the model neurons responded robustly to suprathreshold stimulation despite the inhibitory effects on the soma. The findings suggest that during DBS the axons of thalamocortical neurons are activated while the cell bodies are inhibited thus blocking the transmission of pathological signals through the network and replacing them with high frequency regular firing. PMID- 24804769 TI - Identification of isoxsuprine hydrochloride as a neuroprotectant in ischemic stroke through cell-based high-throughput screening. AB - Stroke is a leading cause of death and disability and treatment options are limited. A promising approach to accelerate the development of new therapeutics is the use of high-throughput screening of chemical libraries. Using a cell-based high-throughput oxygen-glucose deprivation (OGD) model, we evaluated 1,200 small molecules for repurposed application in stroke therapy. Isoxsuprine hydrochloride was identified as a potent neuroprotective compound in primary neurons exposed to OGD. Isoxsuprine, a beta2-adrenergic agonist and NR2B subtype-selective N-methyl D-aspartate (NMDA) receptor antagonist, demonstrated no loss of efficacy when administered up to an hour after reoxygenation in an in vitro stroke model. In an animal model of transient focal ischemia, isoxsuprine significantly reduced infarct volume compared to vehicle (137 +/- 18 mm3 versus 279 +/- 25 mm3, p < 0.001). Isoxsuprine, a peripheral vasodilator, was FDA approved for the treatment of cerebrovascular insufficiency and peripheral vascular disease. Our demonstration of the significant and novel neuroprotective action of isoxsuprine hydrochloride in an in vivo stroke model and its history of human use suggest that isoxsuprine may be an ideal candidate for further investigation as a potential stroke therapeutic. PMID- 24804770 TI - Association of relatives of hemodialysis patients with metabolic syndrome, albuminuria and Framingham Risk Score. AB - BACKGROUND AND AIM: Metabolic syndrome (MetS), albuminuria, and the Framingham Risk Score (FRS) are significant predictors for cardiovascular disease (CVD). However, the relationship and clinical significance of these CVD predictors in individuals with a family history of end-stage renal disease (ESRD) are unclear. We investigated the association of relatives of hemodialysis (HD) patients with MetS, albuminuria, and the FRS. METHODS: One hundred and sixty-six relatives of HD patients and 374 age- and sex- matched community controls were enrolled. MetS was defined using the Adult Treatment Panel III for Asians. Albuminuria was defined as urine albumin-to-creatinine ratio >= 30 mg/g. CVD risk was evaluated by the FRS. RESULTS: A significantly higher prevalence of MetS (19.9% vs. 12.5%, P = 0.026), albuminuria (12.7% vs. 5.1%, P = 0.002) and high FRS risk >= 10% of 10-year risk (15.7% vs. 8.5%, P = 0.013) was found in relatives of HD patients compared to their counterpart controls. In multivariate analysis, being relatives of HD patients (vs. controls) was an independent determinant for MetS (odds ratio [OR], 1.785; 95% confidence interval [CI], 1.045 to 3.050), albuminuria (OR, 2.891; 95% CI, 1.431 to 5.841), and high FRS risk (OR, 1.863; 95% CI, 1.015 to 3.418). Higher low-density lipoprotein cholesterol (OR, 1.034; 95% CI, 1.017 to 1.052) and betel nut chewing (OR, 13.994; 95% CI, 3.384 to 57.871) were independent determinants for having a high FRS risk in relatives of HD patients. CONCLUSIONS: Being relatives of HD patients was independently associated with MetS, albuminuria and high FRS risk, suggesting family members of ESRD patients may have higher CVD risks through the interactions of renal risk factors. Proactive surveillance of these CVD predictors and preventive strategies should be targeted to this high-risk population. PMID- 24804771 TI - A lack of immune system genes causes loss in high frequency hearing but does not disrupt cochlear synapse maturation in mice. AB - Early cochlear development is marked by an exuberant outgrowth of neurites that innervate multiple targets. The establishment of mature cochlear neural circuits is, however, dependent on the pruning of inappropriate axons and synaptic connections. Such refinement also occurs in the central nervous system (CNS), and recently, genes ordinarily associated with immune and inflammatory processes have been shown to play roles in synaptic pruning in the brain. These molecules include the major histocompatibility complex class I (MHCI) genes, H2-K(b) and H2 D(b), and the complement cascade gene, C1qa. Since the mechanisms involved in synaptic refinement in the cochlea are not well understood, we investigated whether these immune system genes may be involved in this process and whether they are required for normal hearing function. Here we report that these genes are not necessary for normal synapse formation and refinement in the mouse cochlea. We further demonstrate that C1qa expression is not necessary for normal hearing in mice but the lack of expression of H2-K(b) and H2-D(b) causes hearing impairment. These data underscore the importance of the highly polymorphic family of MHCI genes in hearing in mice and also suggest that factors and mechanisms regulating synaptic refinement in the cochlea may be distinct from those in the CNS. PMID- 24804773 TI - Partial unfolding of a monoclonal antibody: role of a single domain in driving protein aggregation. AB - We have examined the effect of incubating a monoclonal antibody (mAb) in low (0 2.0 M) concentrations of guanidine hydrochloride (GdnHCl) on the protein's conformation and aggregation during isothermal incubation. In GdnHCl solutions at concentrations from 1.2 to 1.6 M, the mAb was partially unfolded. As demonstrated by fluorescence and circular dichroism spectroscopy, the partially unfolded state of the antibody had perturbed tertiary structure but retained native secondary structure. Furthermore, partial unfolding of the antibody was documented by analytical ultracentrifugation, dynamic light scattering, and limited proteolysis. Subsequent aggregation of the antibody was characterized using size exclusion chromatography, analytical ultracentrifugation, and dynamic light scattering. Over the entire concentration range (0-2.0 M) of GdnHCl, protein protein interactions were attractive, as quantified by negative osmotic second virial coefficients measured with static light scattering. However, during isothermal incubation at 37 degrees C, the aggregation of the antibody was detected only in solutions that induced partial unfolding. Differential scanning calorimetry studies showed that the antibody's CH2 domains were unfolded in antibody molecules that had been incubated in 1.2 M and higher concentrations of GdnHCl. These results suggest that unfolding of the CH2 domains leads to aggregation. PMID- 24804772 TI - Manipulation therapy prior to diagnosis induced primary osteosarcoma metastasis- from clinical to basic research. AB - Osteosarcoma (OS) patients who suffer manipulation therapy (MT) prior to diagnosis resulted in poor prognosis with increasing metastasis or recurrence rate. The aim of the study is to establish an in vivo model to identify the effects of MT on OS. The enrolled 235 OS patients were followed up in this study. In vivo nude mice model with tibia injection of GFP-labeled human OS cells were randomly allocated into MT(+) that with repeated massage on tumor site twice a week and no treatment as MT(-) group. The five-year survival, metastasis and recurrence rates were recorded in clinical subjects. X-ray plainfilm, micro PET/CT scan, histopathology, serum metalloproteinase 2 (MMP2), metalloproteinase 9 (MMP9) level and human kinase domain insert receptor (KDR) pattern were assayed in mice model. The results showed that patient with MT decreased 5-year survival and higher recurrence or metastasis rate. Compatible with clinical findings, the decreased body weight (30.5 +/- 0.65 g) and an increased tumor volume (8.3 +/- 1.18 mm3) in MT(+) mice were observed. The increasing signal intensity over lymph node region of hind limb by micro-PET/CT and the tumor cells were detected in lung and bilateral lymph nodes only in MT(+) group. MMP2 (214 +/- 9.8 ng/ml) and MMP9 (25.5 +/- 1.81 ng/ml) were higher in MT(+) group than in MT(-) group (165 +/ 7.8 ng/ml and 16.9 +/- 1.40 ng/ml, individually) as well as KDR expression. Taking clinical observations and in vivo evidence together, MT treatment leads to poor prognosis of primary osteosarcoma; physicians should pay more attention on patients who seek MT before diagnosis. PMID- 24804774 TI - A regulatory transcriptional loop controls proliferation and differentiation in Drosophila neural stem cells. AB - Neurogenesis is initiated by a set of basic Helix-Loop-Helix (bHLH) transcription factors that specify neural progenitors and allow them to generate neurons in multiple rounds of asymmetric cell division. The Drosophila Daughterless (Da) protein and its mammalian counterparts (E12/E47) act as heterodimerization factors for proneural genes and are therefore critically required for neurogenesis. Here, we demonstrate that Da can also be an inhibitor of the neural progenitor fate whose absence leads to stem cell overproliferation and tumor formation. We explain this paradox by demonstrating that Da induces the differentiation factor Prospero (Pros) whose asymmetric segregation is essential for differentiation in one of the two daughter cells. Da co-operates with the bHLH transcription factor Asense, whereas the other proneural genes are dispensible. After mitosis, Pros terminates Asense expression in one of the two daughter cells. In da mutants, pros is not expressed, leading to the formation of lethal transplantable brain tumors. Our results define a transcriptional feedback loop that regulates the balance between self-renewal and differentiation in Drosophila optic lobe neuroblasts. They indicate that initiation of a neural differentiation program in stem cells is essential to prevent tumorigenesis. PMID- 24804775 TI - Candidate gene association analysis for milk yield, composition, urea nitrogen and somatic cell scores in Brown Swiss cows. AB - The aim of this study was to investigate 96 single-nucleotide polymorphisms (SNPs) from 54 candidate genes, and test the associations of the polymorphic SNPs with milk yield, composition, milk urea nitrogen (MUN) content and somatic cell score (SCS) in individual milk samples from Italian Brown Swiss cows. Milk and blood samples were collected from 1271 cows sampled once from 85 herds. Milk production, quality traits (i.e. protein, casein, fat and lactose percentages), MUN and SCS were measured for each milk sample. Genotyping was performed using a custom Illumina VeraCode GoldenGate approach. A Bayesian linear animal model that considered the effects of herd, days in milk, parity, SNP genotype and additive polygenic effect was used for the association analysis. Our results showed that 14 of the 51 polymorphic SNPs had relevant additive effects on at least one of the aforementioned traits. Polymorphisms in the glucocorticoid receptor DNA binding factor 1 (GRLF1), prolactin receptor (PRLR) and chemokine ligand 2 (CCL2) were associated with milk yield; an SNP in the stearoyl-CoA desaturase (SCD-1) was related to fat content; SNPs in the caspase recruitment domain 15 protein (CARD15) and lipin 1 (LPIN1) affected the protein and casein contents; SNPs in growth hormone 1 (GH1), lactotransferrin (LTF) and SCD-1 were relevant for casein number; variants in beta casein (CSN2), GH1, GRLF1 and LTF affected lactose content; SNPs in beta-2 adrenergic receptor (ADRB2), serpin peptidase inhibitor (PI) and SCD-1 were associated with MUN; and SNPs in acetyl-CoA carboxylase alpha (ACACA) and signal transducer and activator of transcription 5A (STAT5A) were relevant in explaining the variation of SCS. Although further research is needed to validate these SNPs in other populations and breeds, the association between these markers and milk yield, composition, MUN and SCS could be exploited in gene assisted selection programs for genetic improvement purposes. PMID- 24804776 TI - Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease. AB - Alzheimer's disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-gamma, IL 1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-alpha, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid beta (Abeta) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-gamma levels after anti-CD3/CD28 and CMV pp65 but not after Abeta stimulation, compared to CMV seropositive ND controls. When analysing IFN-gamma response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology. PMID- 24804777 TI - Rock glacier outflows may adversely affect lakes: lessons from the past and present of two neighboring water bodies in a crystalline-rock watershed. AB - Despite the fact that rock glaciers are one of the most common geomorphological expressions of mountain permafrost, the impacts of their solute fluxes on lakes still remain largely obscure. We examined water and sediment chemistry, and biota of two neighboring water bodies with and without a rock glacier in their catchments in the European Alps. Paleolimnological techniques were applied to track long-term temporal trends in the ecotoxicological state of the water bodies and to establish their baseline conditions. We show that the active rock glacier in the mineralized catchment of Lake Rasass (RAS) represents a potent source of acid rock drainage that results in enormous concentrations of metals in water, sediment, and biota of RAS. The incidence of morphological abnormalities in the RAS population of Pseudodiamesa nivosa, a chironomid midge, is as high as that recorded in chironomid populations inhabiting sites heavily contaminated by trace metals of anthropogenic origin. The incidence of morphological deformities in P. nivosa of ~70% persisted in RAS during the last 2.5 millennia and was ~40% in the early Holocene. The formation of RAS at the toe of the rock glacier most probably began at the onset of acidic drainage in the freshly deglaciated area. The present adverse conditions are not unprecedented in the lake's history and cannot be associated exclusively with enhanced thawing of the rock glacier in recent years. PMID- 24804778 TI - The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2. AB - The Mdm2 proto-oncoprotein is the primary negative regulator for p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrates that Mdm2 E3 ligase function is dispensable for self-degradation in vivo. Here, we show that the anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APC/C, binds to Mdm2 and is required for Mdm2 polyubiquitination and proteasomal degradation. Downregulation of APC2 by RNAi results in transcription-independent accumulation of Mdm2 and attenuation of stress-induced p53 stabilization, leading to decreased senescence and increased cell survival. Furthermore, APC2 expression is frequently downregulated in human cancers; in tumor cell lines, APC2 downregulation correlates with Mdm2 overexpression. Our study shows the regulation of Mdm2 by the E3 ubiquitin ligase APC/C and has important therapeutic implications for tumors with Mdm2 overexpression. PMID- 24804779 TI - Development of rapidly evolving intron markers to estimate multilocus species trees of rodents. AB - One of the major challenges in the analysis of closely related species, speciation and phylogeography is the identification of variable sequence markers that allow the determination of genealogical relationships in multiple genomic regions using coalescent and species tree approaches. Rodent species represent nearly half of the mammalian diversity, but so far no systematic study has been carried out to detect suitable informative markers for this group. Here, we used a bioinformatic pipeline to extract intron sequences from rodent genomes available in databases and applied a series of filters that allowed the identification of 208 introns that adequately fulfilled several criteria for these studies. The main required characteristics of the introns were that they had the maximum possible mutation rates, that they were part of single-copy genes, that they had an appropriate sequence length for amplification, and that they were flanked by exons with suitable regions for primer design. In addition, in order to determine the validity of this approach, we chose ten of these introns for primer design and tested them in a panel of eleven rodent species belonging to different representative families. We show that all these introns can be amplified in the majority of species and that, overall, 79% of the amplifications worked with minimum optimization of the annealing temperature. In addition, we confirmed for a pair of sister species the relatively high level of sequence divergence of these introns. Therefore, we provide here a set of adequate intron markers that can be applied to different species of Rodentia for their use in studies that require significant sequence variability. PMID- 24804780 TI - Prefrontal response and frontostriatal functional connectivity to monetary reward in abstinent alcohol-dependent young adults. AB - Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence. PMID- 24804782 TI - Anticipating the effects of Medicaid expansion on surgical care. PMID- 24804781 TI - Striatal neurodevelopment is dysregulated in purine metabolism deficiency and impacts DARPP-32, BDNF/TrkB expression and signaling: new insights on the molecular and cellular basis of Lesch-Nyhan Syndrome. AB - Lesch-Nyhan Syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This syndrome is characterized by an array of severe neurological impairments that in part originate from striatal dysfunctions. However, the molecular and cellular mechanisms underlying these dysfunctions remain largely unidentified. In this report, we demonstrate that HPRT-deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B cell leukemia 11b (Bcl11b). The data also reveal that the down-regulated expression of Bcl11b in HPRT-deficient immortalized mouse striatal (STHdh) neural stem cells is accompanied by aberrant expression of some of its transcriptional partners and other striatally-enriched genes, including the gene encoding dopamine- and cAMP-regulated phosphoprotein 32, (DARPP-32). Furthermore, we demonstrate that components of the BDNF/TrkB signaling, a known activator of DARPP-32 striatal expression and effector of Bcl11b transcriptional activation are markedly increased in HPRT-deficient cells and in the striatum of HPRT knockout mouse. Consequently, the HPRT-deficient cells display superior protection against reactive oxygen species (ROS)-mediated cell death upon exposure to hydrogen peroxide. These findings suggest that the purine metabolic defect caused by HPRT-deficiency, while it may provide neuroprotection to striatal neurons, affects key genes and signaling pathways that may underlie the neuropathogenesis of LNS. PMID- 24804788 TI - Cue-recruitment for extrinsic signals after training with low information stimuli. AB - Cue-recruitment occurs when a previously ineffective signal comes to affect the perceptual appearance of a target object, in a manner similar to the trusted cues with which the signal was put into correlation during training. Jain, Fuller and Backus reported that extrinsic signals, those not carried by the target object itself, were not recruited even after extensive training. However, recent studies have shown that training using weakened trusted cues can facilitate recruitment of intrinsic signals. The current study was designed to examine whether extrinsic signals can be recruited by putting them in correlation with weakened trusted cues. Specifically, we tested whether an extrinsic visual signal, the rotary motion direction of an annulus of random dots, and an extrinsic auditory signal, direction of an auditory pitch glide, can be recruited as cues for the rotation direction of a Necker cube. We found learning, albeit weak, for visual but not for auditory signals. These results extend the generality of the cue-recruitment phenomenon to an extrinsic signal and provide further evidence that the visual system learns to use new signals most quickly when other, long-trusted cues are unavailable or unreliable. PMID- 24804791 TI - Myocardial remodeling in hypertension. AB - Left ventricular (LV) hypertrophy and remodeling are frequently seen in hypertensive subjects and result from a complex interaction of several hemodynamic and non-hemodynamic variables. Although increased blood pressure is considered the major determinant of LV structural alterations, ethnicity, gender, environmental factors, such as salt intake, obesity and diabetes mellitus, as well as neurohumoral and genetic factors might influence LV mass and geometry. The conventional concept of hypertensive LV remodeling has been that hypertension leads to concentric hypertrophy, as an adaptive response to normalize wall stress, which is then followed by chamber dilation and heart failure. However, several lines of evidence have challenged this dogma. Concentric hypertrophy is not the most frequent geometric pattern and is less usually seen than eccentric hypertrophy in hypertensive subjects. In addition, data from recent studies suggested that transition from LV concentric hypertrophy to dilation and systolic dysfunction is not a common finding, especially in the absence of coronary heart disease. LV hypertrophy is also consistently associated with increased cardiovascular morbidity and mortality, raising doubts whether this phenotype is an adaptive response. Experimental evidence exists that a blunting of load induced cardiomyocyte hypertrophy does not necessarily result in LV dysfunction or failure. Furthermore, the hypertrophic myocardium shows fibrosis, alterations in the coronary circulation and cardiomyocyte apoptosis, which may result in heart failure, myocardial ischemia and arrhythmias. Overall, this body of evidence suggests that LV hypertrophy is a complex phenotype that predicts adverse cardiovascular outcomes and may not be necessarily considered as an adaptive response to systemic hypertension. PMID- 24804790 TI - MiR-101 regulates apoptosis of trophoblast HTR-8/SVneo cells by targeting endoplasmic reticulum (ER) protein 44 during preeclampsia. AB - To investigate a possible association between miR-101 and apoptosis of human trophoblast cells mediated by endoplasmic reticulum protein 44 (ERp44) in preeclampsia (PE), we explored the expression of miR-101 in PE placentas (n=30) compared with normotensive pregnant placentas (n=30) and the correlation between miR-101 and ERp44 was also analyzed. Furthermore, both the apoptotic rate of trophoblast cells and the ER stress-induced apoptotic proteins were assayed when the HTR-8/SVneo cells were treated with miR-101 mimics or inhibitors in vitro. We found a lower expression of miR-101 and an inverse correlation between miR-101 and ERp44 protein in PE placentas. Upregulation of miR-101 expression could inhibit trophoblast HTR-8/SVneo cell apoptosis and repress ER stress-induced apoptotic proteins by targeting ERp44 in vitro, whereas inhibition of miR-101 could induce HTR-8/SVneo cell apoptosis. Our findings indicated that overexpression of miR-101 could downregulate ERp44 and suppress apoptosis in trophoblast cells during PE. Therefore, loss of miR-101 expression could contribute to ER stress-induced trophoblast cell apoptosis by targeting ERp44. PMID- 24804792 TI - Anti-fibrotic effects of specific-siRNA targeting of the receptor for advanced glycation end products in a rat model of experimental hepatic fibrosis. AB - Since the receptor for advanced glycation end products (RAGE)-ligand axis has been demonstrated to be important in fibrogenesis, rat models may be used to assess whether specific small interfering RNAs (siRNAs) that target RAGE are able to reduce the progression of hepatic fibrosis. However, the effect of RAGE targeted siRNA on established hepatic fibrosis remains to be elucidated. In the present study, RAGE-specific siRNA expression vectors were constructed prior to the animal experiment. Sprague-Dawley rats were treated initially with olive oil (2 ml/kg) or 50% CCl4 (2 ml/kg; CCl4/olive oil=1:1) twice per week for six weeks to generate the fibrosis model. The rats were then treated with phosphate buffered saline, a RAGE-specific siRNA expression vector, at different doses or a non-specific siRNA expression vector twice weekly via tail vein injection for up to six weeks, and were sacrificed at week two, four or six. Compared with the control groups, RAGE-specific siRNA therapy significantly decreased RAGE mRNA and protein expression in rat livers (P<0.01). Following six weeks of RAGE gene silencing treatment, the liver function, which was assessed by analyzing serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL), improved to varying degrees (P<0.01). The expression of nuclear factor-kappaB (NF-kappaB) significantly decreased following RAGE gene-silencing therapy (P<0.01). In addition, the serum levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and extracellular matrix (ECM) components, including hyaluronic acid (HA), laminin (LN) and procollagen type III (PCIII) also decreased (P<0.01). Furthermore, the expression of alpha-smooth muscle actin (alpha-SMA) and collagen I, which indicate the activation of hepatic stellate cells (HSCs), were downregulated following RAGE gene-silencing therapy (P<0.01). Furthermore, the inflammatory activity grade and fibrosis stage of rat livers also significantly improved compared with the control groups following RAGE gene-silencing therapy. Specific targeting of RAGE using siRNA may inhibit RAGE gene expression effectively in the rat hepatic fibrosis model and attenuate the progression of established hepatic fibrosis. This therapeutic effect may be mediated via inhibition of the expression of NF-kappaB. These findings suggest that RAGE may be a new target to prevent hepatic fibrosis. PMID- 24804793 TI - Sequence and ionomic analysis of divergent strains of maize inbred line B73 with an altered growth phenotype. AB - Maize (Zea mays) is the most widely grown crop species in the world and a classical model organism for plant research. The completion of a high-quality reference genome sequence and the advent of high-throughput sequencing have greatly empowered re-sequencing studies in maize. In this study, plants of maize inbred line B73 descended from two different sets of seed material grown for several generations either in the field or in the greenhouse were found to show a different growth phenotype and ionome under phosphate starvation conditions and moreover a different responsiveness towards mycorrhizal fungi of the species Glomus intraradices (syn: Rhizophagus irregularis). Whole genome re-sequencing of individuals from both sets and comparison to the B73 reference sequence revealed three cryptic introgressions on chromosomes 1, 5 and 10 in the line grown in the greenhouse summing up to a total of 5,257 single-nucleotide polymorphisms (SNPs). Transcriptome sequencing of three individuals from each set lent further support to the location of the introgression intervals and confirmed them to be fixed in all sequenced individuals. Moreover, we identified >120 genes differentially expressed between the two B73 lines. We thus have found a nearly-isogenic line (NIL) of maize inbred line B73 that is characterized by an altered growth phenotype under phosphate starvation conditions and an improved responsiveness towards symbiosis with mycorrhizal fungi. Through next-generation sequencing of the genomes and transcriptomes we were able to delineate exact introgression intervals. Putative de novo mutations appeared approximately uniformly distributed along the ten maize chromosomes mainly representing G:C -> A:T transitions. The plant material described in this study will be a valuable tool both for functional studies of genes differentially expressed in both B73 lines and for research on growth behavior especially in response to symbiosis between maize and mycorrhizal fungi. PMID- 24804795 TI - Topographic factor analysis: a Bayesian model for inferring brain networks from neural data. AB - The neural patterns recorded during a neuroscientific experiment reflect complex interactions between many brain regions, each comprising millions of neurons. However, the measurements themselves are typically abstracted from that underlying structure. For example, functional magnetic resonance imaging (fMRI) datasets comprise a time series of three-dimensional images, where each voxel in an image (roughly) reflects the activity of the brain structure(s)-located at the corresponding point in space-at the time the image was collected. FMRI data often exhibit strong spatial correlations, whereby nearby voxels behave similarly over time as the underlying brain structure modulates its activity. Here we develop topographic factor analysis (TFA), a technique that exploits spatial correlations in fMRI data to recover the underlying structure that the images reflect. Specifically, TFA casts each brain image as a weighted sum of spatial functions. The parameters of those spatial functions, which may be learned by applying TFA to an fMRI dataset, reveal the locations and sizes of the brain structures activated while the data were collected, as well as the interactions between those structures. PMID- 24804794 TI - Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition. AB - BACKGROUND: Severe osteoarthritis and thoracic aortic aneurysms have recently been associated with mutations in the SMAD3 gene, but the full clinical spectrum is incompletely defined. METHODS: All SMAD3 gene mutation carriers coming to our centre and their families were investigated prospectively with a structured panel including standardized clinical workup, blood tests, total body computed tomography, joint X-rays. Electroneuromyography was performed in selected cases. RESULTS: Thirty-four SMAD3 gene mutation carriers coming to our centre were identified and 16 relatives were considered affected because of aortic surgery or sudden death (total 50 subjects). Aortic disease was present in 72%, complicated with aortic dissection, surgery or sudden death in 56% at a mean age of 45 years. Aneurysm or tortuosity of the neck arteries was present in 78%, other arteries were affected in 44%, including dissection of coronary artery. Overall, 95% of mutation carriers displayed either aortic or extra-aortic arterial disease. Acrocyanosis was also present in the majority of patients. Osteoarticular manifestations were recorded in all patients. Joint involvement could be severe requiring surgery in young patients, of unusual localization such as tarsus or shoulder, or mimicking crystalline arthropathy with fibrocartilage calcifications. Sixty eight percent of patients displayed neurological symptoms, and 9 suffered peripheral neuropathy. Electroneuromyography revealed an axonal motor and sensory neuropathy in 3 different families, very evocative of type II Charcot-Marie-Tooth (CMT2) disease, although none had mutations in the known CMT2 genes. Autoimmune features including Sjogren's disease, rheumatoid arthritis, Hashimoto's disease, or isolated autoantibodies- were found in 36% of patients. INTERPRETATION: SMAD3 gene mutations are associated with aortic dilatation and osteoarthritis, but also autoimmunity and peripheral neuropathy which mimics type II Charcot-Marie-Tooth. PMID- 24804796 TI - Molecular remodeling of left and right ventricular myocardium in chronic anthracycline cardiotoxicity and post-treatment follow up. AB - Chronic anthracycline cardiotoxicity is a serious clinical issue with well characterized functional and histopathological hallmarks. However, molecular determinants of the toxic damage and associated myocardial remodeling remain to be established. Furthermore, details on the different propensity of the left and right ventricle (LV and RV, respectively) to the cardiotoxicity development are unknown. Hence, the aim of the investigation was to study molecular changes associated with remodeling of the LV and RV in chronic anthracycline cardiotoxicity and post-treatment follow up. The cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg/week for 10 weeks) and animals were sacrificed either at the end of the treatment or after an additional 10 weeks. Daunorubicin induced severe and irreversible cardiotoxicity associated with LV dysfunction and typical morphological alterations, whereas the myocardium of the RV showed only mild changes. Both ventricles also showed different expression of ANP after daunorubicin treatment. Daunorubicin impaired the expression of several sarcomeric proteins in the LV, which was not the case of the RV. In particular, a significant drop was found in titin and thick filament proteins at both mRNA and protein level and this might be connected with persistent LV down-regulation of GATA-4. In addition, the LV was more affected by treatment-induced perturbations in calcium handling proteins. LV cardiomyocytes showed marked up-regulation of desmin after the treatment and vimentin was mainly induced in LV fibroblasts, whereas only weaker changes were observed in the RV. Remodeling of extracellular matrix was almost exclusively found in the LV with particular induction of collagen I and IV. Hence, the present study describes profound molecular remodeling of myocytes, non-myocyte cells and extracellular matrix in response to chronic anthracycline treatment with marked asymmetry between LV and RV. PMID- 24804798 TI - An approach to a bislactone skeleton: a scalable total synthesis of (+/-) penifulvin A. AB - An efficient and scalable total synthesis of the architecturally challenging sesquiterpenoid (+/-)-penifulvin A has been accomplished via a 12-step sequence with an overall yield of 16%. For the construction of this structurally complex tetracyclic molecule, the key steps used included 1,4-conjugate addition, a Pd(0) catalyzed cross-coupling reaction between an enol phosphate and trimethyl aluminum, Claisen rearrangement using the Johnson orthoester protocol, Ti(III) mediated reductive epoxide opening-cyclization, Lewis acid catalyzed epoxy aldehyde rearrangement, and finally a substrate controlled oxidative cascade lactonization process. PMID- 24804797 TI - Vaccines against invasive Salmonella disease: current status and future directions. AB - Though primarily enteric pathogens, Salmonellae are responsible for a considerable yet under-appreciated global burden of invasive disease. In South and South-East Asia, this manifests as enteric fever caused by serovars Typhi and Paratyphi A. In sub-Saharan Africa, a similar disease burden results from invasive nontyphoidal Salmonellae, principally serovars Typhimurium and Enteritidis. The existing Ty21a live-attenuated and Vi capsular polysaccharide vaccines target S. Typhi and are not effective in young children where the burden of invasive Salmonella disease is highest. After years of lack of investment in new Salmonella vaccines, recent times have seen increased interest in the area led by emerging-market manufacturers, global health vaccine institutes and academic partners. New glycoconjugate vaccines against S. Typhi are becoming available with similar vaccines against other invasive serovars in development. With other new vaccines under investigation, including live-attenuated, protein based and GMMA vaccines, now is an exciting time for the Salmonella vaccine field. PMID- 24804799 TI - Effect of water content and temperature on seed longevity of seven Brassicaceae species after 5 years of storage. AB - Maximising seed longevity is crucial for genetic resource preservation and longevity of orthodox seeds is determined by environmental conditions (water content and temperature). The effect of water content (down to 0.01 g.H2O.g(-1) ) on seed viability was studied at different temperatures for a 5-year storage period in taxonomically related species. Seeds of seven Brassicaceae species (Brassica repanda, Eruca vesicaria, Malcolmia littorea, Moricandia arvensis, Rorippa nasturtium-aquaticum, Sinapis alba, Sisymbrium runcinatum) were stored at 48 environments comprising a combination of eight water contents, from 0.21 to 0.01 g.H2O.g(-1) DW and six temperatures (45, 35, 20, 5, -25, -170 degrees C). Survival curves were modelled and P50 calculated for those conditions where germination was reduced over the 5-year assay period. Critical water content for storage of seeds of six species at 45 degrees C ranged from 0.02 to 0.03 g.H2O.g(-1) . The effect of extreme desiccation at 45 degrees C showed variability among species: three species showed damaging effects of drying below the critical water content, while for three species it was neither detrimental nor beneficial to seed longevity. Lipid content could be related to longevity, depending on the storage conditions. A variable seed longevity response to water content among taxonomically related species was found. The relative position of some of the species as long- or short-lived at 45 degrees C varied depending on the humidity at which storage behaviour was evaluated. Therefore, predictions of survival under desiccated conditions based on results obtained at high humidity might be problematic for some species. PMID- 24804802 TI - Daughters and Mothers Against Breast Cancer (DAMES): main outcomes of a randomized controlled trial of weight loss in overweight mothers with breast cancer and their overweight daughters. AB - BACKGROUND: Few studies to date have used the cancer diagnosis as a teachable moment to promote healthy behavior changes in survivors of cancer and their family members. Given the role of obesity in the primary and tertiary prevention of breast cancer, the authors explored the feasibility of a mother-daughter weight loss intervention. METHODS: A randomized controlled trial of a mailed weight loss intervention was undertaken among 68 mother-daughter dyads (n = 136), each comprised of a survivor of breast cancer (AJCC stage 0-III) and her adult biological daughter. All women had body mass indices >= 25 kg/m(2) and underwent in-person assessments at baseline, 6 months, and 12 months, with accelerometry and exercise capacity performed on a subset of individuals. All women received a personalized workbook and 6 newsletters over a 1-year period that promoted weight loss; exercise; and a nutrient-rich, low-energy density diet. A total of 25 dyads received individually tailored instruction (individual), 25 dyads received team tailored instruction (TEAM), and 18 dyads received standardized brochures (control). RESULTS: The trial met its accrual target, experienced 90% retention, and caused no serious adverse events. Significant differences in baseline to 12 month changes were observed between individual versus control mothers for body mass index, weight, and waist circumference (WC); significant differences also were observed in the WC of corresponding daughters (P < .05). Significant differences were found between individual versus control and team versus control dyads for WC (P = .0002 and .018, respectively), minutes per week of physical activity (P = .031 and .036, respectively), and exercise capacity (P = .047 for both). CONCLUSIONS: Significant improvements in lifestyle behaviors and health outcomes are possible with tailored print interventions directed toward survivors of cancer and their family members. For greater impact, more research is needed to expand this work beyond the mother-daughter dyad. PMID- 24804803 TI - The epidermal cell structure of the secondary pollen presenter in Vangueria infausta (Rubiaceae: Vanguerieae) suggests a functional association with protruding onci in pollen grains. AB - Secondary pollen presentation is a well-known phenomenon in the Rubiaceae with particularly conspicuous pollen presenters occurring in the tribe Vanguerieae. These knob-like structures are formed by a modification of the upper portion of the style and stigma, together known as the stylar head complex. In the flower bud and shortly before anthesis, the anthers surrounding the stylar head complex dehisce and release pollen grains which adhere to the pollen presenter. The epidermal cells of the pollen presenter facing the anthers are radially elongated with a characteristic wall thickening encircling the anticlinal walls of each cell towards the distal end. These cells were studied in the pollen presenter of Vangueria infausta using electron and light microscopy in conjunction with histochemical tests and immunohistochemical methods. Other prominent thickenings of the cell wall were also observed on the distal and proximal walls. All these thickenings were found to be rich in pectin and possibly xyloglucan. The terms "thickenings of Igersheim" and "bands of Igersheim" are proposed to refer, respectively, to these wall structures in general and those encircling the anticlinal walls of each cell near the distal end. The epidermal cells have an intricate ultrastructure with an abundance of organelles, including smooth and rough endoplasmic reticulum, Golgi apparatus, mitochondria and secretory vesicles. This indicates that these cells are likely to have an active physiological role. The pollen grains possess prominent protruding onci and observations were made on their structure and development. Walls of the protruding onci are also rich in pectin. Pectins are hydrophilic and known to be involved in the dehydration and rehydration of pollen grains. We hypothesise that the thickenings of Igersheim, as well as the protruding onci of the pollen grains, are functionally associated and part of the adaptive syndrome of secondary pollen presentation, at least in the Vanguerieae. PMID- 24804804 TI - Crystal structures, CO2 adsorption, and dielectric properties of [Cu(II)2(R benzoate)4(pyrazine)]infinity polymers (R = m-F, 2,3-F2, m-Cl, and m-CH3). AB - m-Fluorobenzoate (m-FBA), 2,3-difluorobenzoate (2,3-F2BA), m-methylbenzoate (m MBA), and m-chlorobenzoate (m-ClBA) were introduced into the Cu(II) binuclear unit as bridging ligands between two Cu(II) sites, which were further connected by an axial pyrazine (pz) ligand to form one-dimensional coordination polymers of [Cu(II)2(m-FBA)4(pz)]infinity (1), [Cu(II)2(2,3-F2BA)4(pz)]infinity (2), [Cu(II)2(m-MBA)4(pz)]infinity (3), and [Cu(II)2(m-ClBA)4(pz)]infinity (4), respectively. The parallel arrangements of one-dimensional (1D) polymers result in 1D channels between the polymers that crystallization CH3CN molecules can occupy to form single crystals of 1.4CH3CN, 2.4CH3CN, 3.2CH3CN, and 4.2CH3CN. Both pi-dimer and dipole-dipole interactions were simultaneously observed in the interchain interactions of m-FBA and/or 2,3-F2BA ligands in crystals 1 and 2. The sizes of the one-dimensional channels between the polymers are thus modulated according to the interchain interactions between the polar BA ligands. CH3CN molecules within the channels were easily replaced by H2O under ambient conditions. CO2 adsorption-desorption isotherms of crystals 1, 2, and 3 at 195 K indicated gate-adsorption with a hysteresis, whereas two-step gate-adsorption behavior was observed for CO2 in crystal 4. Temperature- and frequency-dependent dielectric responses were not observed in crystals 1-4 under vacuum conditions, whereas dielectric anomalies were observed around 290 K for crystals 1 and 2 with adsorbed CO2. CO2 desorption from the channels in crystals 1 and 2 activated the molecular motions of polar BA ligands and dielectric responses around 290 K, which were confirmed from CO2 adsorption-desorption isotherms around 290 K and differential scanning calorimetries under CO2 conditions. PMID- 24804805 TI - Stimuli-responsive host-guest systems based on the recognition of cryptands by organic guests. AB - CONSPECTUS: As the star compounds in host-guest chemistry, the syntheses of crown ethers proclaimed the birth of supramolecular chemistry. Crown ether-based host guest systems have attracted great attention in self-assembly processes because of their good selectivity, high efficiency, and convenient responsiveness, enabling their facile application to the "bottom-up" approach for construction of functional molecular aggregates, such as artificial molecular machines, drug delivery materials, and supramolecular polymers. Cryptands, as preorganized derivatives of crown ethers, not only possess the above-mentioned properties but also have three-dimensional spatial structures and higher association constants compared with crown ethers. More importantly, the introduction of the additional arms makes cryptand-based host-guest systems responsive to more stimuli, which is crucial for the construction of adaptive or smart materials. In the past decade, we designed and synthesized crown ether-based cryptands as a new type of host for small organic guests with the purpose of greatly increasing the stabilities of the host-guest complexes and preparing mechanically interlocked structures and large supramolecular systems more efficiently while retaining or increasing their stimuli-responsiveness. Organic molecules such as paraquat derivatives and secondary ammonium salts have been widely used in the fabrication of functional supramolecular aggregates. Many host molecules including crown ethers, cyclodextrins, calixarenes, cucurbiturils, pillararenes, and cryptands have been used in the preparation of self-assembled structures with these guest molecules, but among them cryptands exhibit the best stabilities with paraquat derivatives in organic solvents due to their preorganization and additional and optimized binding sites. They enable the construction of sophisticated molecules or supramolecules in high yields, affording a very efficient way to fabricate stimuli-responsive functional supramolecular systems. This Account mainly focuses on the application of cryptands in the construction of mechanically interlocked molecules such as rotaxanes and catenanes, and stimuli-responsive host-guest systems such as molecular switches and supramolecular polymers due to their good host-guest properties. These cryptands are bicyclic derivatives of crown ethers, including dibenzo-24-crown-8, bis(m-phenylene)-26-crown-8, dibenzo-30-crown-10, and bis(m-phenylene)-32-crown-10. The length of the third arm has a very important influence on the binding strength of these cryptands with organic guests, because it affects not only the size fit between the host and the guest but also the distances and angles that govern the strengths of the noncovalent interactions between the host and the guest. For example, for bis(m-phenylene)-32 crown-10-based cryptands, a third arm of nine atoms is the best. The environmental responsiveness of these cryptand-based host-guest systems arises from either the crown ether units or the third arms. For example, a dibenzo-24 crown-8 unit introduces potassium cation responsiveness and an azobenzene group on the third arm imbues photoresponsiveness. We believe that studies on stimuli responsive host-guest systems based on cryptands and organic guests will contribute significantly to future research on molecular devices, supramolecular polymers, and other functional supramolecular materials. PMID- 24804806 TI - The association between Mediterranean Diet Score and glucokinase regulatory protein gene variation on the markers of cardiometabolic risk: an analysis in the European Prospective Investigation into Cancer (EPIC)-Norfolk study. AB - Consumption of a Mediterranean diet (MD) and genetic variation in the glucokinase regulatory protein (GCKR) gene have been reported to be associated with TAG and glucose metabolism. It is uncertain whether there is any interaction between these factors. Therefore, the aims of the present study were to test the association of adherence to a MD and rs780094 (G>A) SNP in the GCKR gene with the markers of cardiometabolic risk, and to investigate the interaction between genetic variation and MD adherence. We studied 20 986 individuals from the European Prospective Investigation into Cancer (EPIC)-Norfolk study. The relative Mediterranean Diet Score (rMED: range 0-18) was used to assess MD adherence. Linear regression was used to estimate the association between the rMED, genotype and cardiometabolic continuous traits, adjusting for potential confounders. In adjusted analyses, we observed independent associations of MD adherence and genotype with cardiometabolic risk, with the highest risk group (AA genotype; lowest rMED) having higher concentrations of TAG, total cholesterol and apoB (12.5, 2.3 and 3.1%, respectively) v. those at the lowest risk (GG genotype; highest rMED). However, the associations of MD adherence with metabolic markers did not differ by genotype, with no significant gene-diet interactions for lipids or for glycated Hb. In conclusion, we found independent associations of the rMED and of the GCKR genotype with cardiometabolic profile, but found no evidence of interaction between them. PMID- 24804807 TI - A model of alcohol drinking under an intermittent access schedule using group housed mice. AB - Here, we describe a new model of voluntary alcohol drinking by group-housed mice. The model employs sensor-equipped cages that track the behaviors of the individual animals via implanted radio chips. After the animals were allowed intermittent access to alcohol (three 24 h intervals every week) for 4 weeks, the proportions of licks directed toward bottles containing alcohol were 50.9% and 39.6% for the male and female mice, respectively. We used three approaches (i.e., quinine adulteration, a progressive ratio schedule and a schedule involving a risk of punishment) to test for symptoms of compulsive alcohol drinking. The addition of 0.01% quinine to the alcohol solution did not significantly affect intake, but 0.03% quinine induced a greater than 5-fold reduction in the number of licks on the alcohol bottles. When the animals were required to perform increasing numbers of instrumental responses to obtain access to the bottle with alcohol (i.e., a progressive ratio schedule), they frequently reached a maximum of 21 responses irrespective of the available reward. Although the mice rarely achieved higher response criteria, the number of attempts was ~ 10 times greater in case of alcohol than water. We have developed an approach for mapping social interactions among animals that is based on analysis of the sequences of entries into the cage corners. This approach allowed us to identify the mice that followed other animals in non-random fashions. Approximately half of the mice displayed at least one interaction of this type. We have not yet found a clear correlation between imitative behavior and relative alcohol preference. In conclusion, the model we describe avoids the limitations associated with testing isolated animals and reliably leads to stable alcohol drinking. Therefore, this model may be well suited to screening for the effects of genetic mutations or pharmacological treatments on alcohol-induced behaviors. PMID- 24804808 TI - Genetic analyses of the FRNK motif function of Turnip mosaic virus uncover multiple and potentially interactive pathways of cross-protection. AB - Cross-protection triggered by a mild strain of virus acts as a prophylaxis to prevent subsequent infections by related viruses in plants; however, the underling mechanisms are not fully understood. Through mutagenesis, we isolated a mutant strain of Turnip mosaic virus (TuMV), named Tu-GK, that contains an Arg182Lys substitution in helper component-proteinase (HC-Pro(K)) that confers complete cross-protection against infection by a severe strain of TuMV in Nicotiana benthamiana, Arabidopsis thaliana Col-0, and the Arabidopsis dcl2 4/dcl4-1 double mutant defective in DICER-like ribonuclease (DCL)2/DCL4-mediated silencing. Our analyses showed that HC-Pro(K) loses the ability to interfere with microRNA pathways, although it retains a partial capability for RNA silencing suppression triggered by DCL. We further showed that Tu-GK infection triggers strong salicylic acid (SA)-dependent and SA-independent innate immunity responses. Our data suggest that DCL2/4-dependent and -independent RNA silencing pathways are involved, and may crosstalk with basal innate immunity pathways, in host defense and in cross-protection. PMID- 24804809 TI - Tomato ringspot virus coat protein binds to ARGONAUTE 1 and suppresses the translation repression of a reporter gene. AB - RNA silencing regulates plant gene expression and antiviral defenses and functions by cleaving target RNAs or repressing translation. As a counter defense, many plant viruses encode suppressor proteins that sequester small RNAs or inactivate Argonaute (AGO) proteins. All known plant virus silencing suppressor activities eventually inhibit the degradation of target mRNAs. Using a transiently expressed green fluorescent protein (GFP) reporter gene, we show that Tomato ringspot virus (ToRSV) coat protein (CP) is a suppressor of RNA silencing that enhances GFP expression but does not prevent the degradation of the GFP mRNA or the accumulation of GFP small interfering RNAs (siRNAs). Coexpression of the CP with GFP resulted in increased association of residual GFP mRNAs with polysome fractions and reduced association of GFP siRNAs with monosome fractions. AGO1 was co-immunoprecipitated with the CP and CP expression destabilized AGO1. A WG motif within the CP was critical for the enhanced GFP expression, AGO1 interaction, and AGO1 destabilization, suggesting that the ToRSV CP acts as an AGO-hook protein and competes for AGO binding with a plant cellular GW/WG protein involved in translation repression. PMID- 24804810 TI - Role of platelet-derived growth factor-BB (PDGF-BB) in human pulmonary artery smooth muscle cell proliferation. AB - Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and suppressed apoptosis. Platelet-derived growth factor (PDGF) is a potent mitogen involved in cell proliferation and migration. PDGF-BB induces the proliferation and migration of PASMCs and has been proposed to be a key mediator in the progression of PAH. Previous studies have shown that PDGF and its receptor are substantially elevated in lung tissues and PASMCs isolated from patients and animals with PAH, but the underlying mechanisms are still poorly manifested. MAP kinases, including extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2 terminal kinase1/2 (JNK1/2), and p38 are the key intracellular signals for stimuli-induced cell proliferation, survival, and apoptosis. Therefore, the purpose of this study is to determine whether PDGF-BB on cell proliferation process is mediated through the MAP kinases pathway in human PASMCs (HPASMCs). Our results showed PDGF-BB-induced proliferating cell nuclear antigen (PCNA), Cyclin A and Cyclin E expression in a concentration-dependent manner. The expression levels of phosphorylated JNK (p-JNK) was upregulated with 20 ng/ml PDGF-BB treatment, while PDGF-BB could not increase phosphorylated ERK1/2 (p ERK1/2) and p-38 (p-p38) expression. The effects of PDGF-BB on cell proliferation and survival were weakened after the administration of antagonist of the JNK pathway or si-JNK. In addition, PDGF-BB protected against the loss of mitochondrial membrane potentials evoked by serum deprivation (SD) in a JNK dependent manner. These results suggest that PDGF-BB promotes HPASMCs proliferation and survival, which is likely to be mediated via the JNK pathway. PMID- 24804811 TI - Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor. AB - Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HDMX, is an attractive strategy for drug development in oncology. Developing blockers towards conserved hydrophobic pockets of both HDMs has mainly focused on small synthetic compounds; however, this approach has proved challenging. Here we describe an approach to generate a potent HDM dual inhibitor, p53LZ2, by rational protein grafting of the p53 transactivation domain onto a homodimeric leucine zipper. p53LZ2 shows tight binding affinity to both HDMs compared with wild-type p53 in vitro. X-ray crystallographic, comparative modelling and small-angle X-ray scattering studies of p53LZ2-HDM complexes show butterfly-shaped structures. A cell-permeable TAT-p53LZ2 effectively inhibits the cancer cell growth in wild-type but not mutant p53 by arresting cell cycle and inducing apoptosis in vitro. Thus, p53LZ2, designed by rational grafting, shows a potential therapeutic approach against cancer. PMID- 24804813 TI - Nurses' computer literacy and attitudes towards the use of computers in health care. AB - This descriptive and cross-sectional study was designed to address nurses' computer literacy and attitudes towards the use of computers in health care and to determine the correlation between these two variables. This study was conducted with the participation of 688 nurses who worked at two university affiliated hospitals. These nurses were chosen using a stratified random sampling method. The data were collected using the Multicomponent Assessment of Computer Literacy and the Pretest for Attitudes Towards Computers in Healthcare Assessment Scale v. 2. The nurses, in general, had positive attitudes towards computers, and their computer literacy was good. Computer literacy in general had significant positive correlations with individual elements of computer competency and with attitudes towards computers. If the computer is to be an effective and beneficial part of the health-care system, it is necessary to help nurses improve their computer competency. PMID- 24804812 TI - Label-free quantitative proteomics reveals the dynamics of proteasome complexes composition and stoichiometry in a wide range of human cell lines. AB - The proteasome is the main proteolytic system involved in intracellular proteins homeostasis in eukaryotes. Although the structure of proteasome complexes has been well characterized, the distribution of its activators and associated proteins are less studied. Here, we determine the composition and the stoichiometry of proteasome complexes and their associated proteins in a wide range of human cell lines using a one-step affinity purification method and a label-free quantitative proteomic approach. We show that proteasome complexes are highly dynamic protein assemblies, the activity of which being regulated at different levels by variations in the stoichiometry of bound regulators, in the composition of catalytic subunits and associated proteins, and in the rate of the 20S catalytic core complex assembly. PMID- 24804814 TI - Axitinib alone or in combination with chemotherapeutic drugs exerts potent antitumor activity against human gastric cancer cells in vitro and in vivo. AB - OBJECTIVE: As the new oral selective VEGFR tyrosine kinase inhibitor, axitinib (AG-013736) exerts powerful antitumor activity in multiple solid tumors, while its' effect was unclear in gastric cancer. We aimed to investigate the antitumor activity of axitinib alone or combined with chemotherapeutic drugs against human gastric cancer cells in vitro and in vivo. METHODS: The IC50 values of drugs were determined by MTS assay. The median effect of Chou-Talalay was used to assess the synergistic effect of two drugs. Flow cytometry was employed to analyze cell cycle and cell apoptosis. Cell senescence and microvessel density were evaluated by SA-beta-gal staining and CD34 staining, respectively. BGC-823-derived xenografts in nude mice were established to investigate the effects of drugs in vivo. RESULTS: Axitinib alone could inhibit cell proliferation and retard tumor growth through inducing cell cycle arrest at G2/M phase, cell senescence, cell apoptosis, and antiangiogenesis in vitro and in vivo. Axitinib combined with 5 fluorouracil (5-FU) had synergistic inhibitory effect compared to axitinib or 5 FU alone. However, the highest inhibitory effect was found between axitinib and cisplatin (inhibitory ratio >80 % compared to control), which was significantly higher than any single drug (inhibitory ratio for single 5-FU, cisplatin, and axitinib >10, >40, and >40 %, respectively, compared to control) or axitinib combined with 5-FU (inhibitory ratio >50 % compared to control). CONCLUSION: We highlighted for the first time that axitinib alone or in combination with 5 fluorouracil or cisplatin has potent antitumor activity against human gastric cancer in vitro and in vivo, which provided solid evidence for future clinical trial. PMID- 24804815 TI - The clinical relevance and prognostic significance of adenosine triphosphate ATP binding cassette (ABCB5) and multidrug resistance (MDR1) genes expression in acute leukemia: an Egyptian study. AB - AIM: Multidrug resistance (MDR1) represents a major obstacle in the chemotherapeutic treatment of acute leukemia (AL). Adenosine triphosphate ATP binding cassette (ABCB5) and MDR1 genes are integral membrane proteins belonging to ATP-binding cassette transporters superfamily. PURPOSE: The present work aimed to investigate the impact of ABCB5 and MDR1 genes expression on the response to chemotherapy in a cohort of Egyptian AL patients. The study included 90 patients: 53 AML cases and 37 ALL cases in addition to 20 healthy volunteers as controls. METHODS: Quantitative assessment of MDR1 and ABCB5 genes expression was performed by quantitative real-time polymerase chain reaction. Additional prognostic molecular markers were determined as internal tandem duplications of the FLT3 gene (FLT3-ITD) and nucleophosmin gene mutation (NPM1) for AML cases, and mbcr abl fusion transcript for B-ALL cases. RESULTS: In AML patients, ABCB5 and MDR1 expression levels did not differ significantly between de novo and relapsed cases and did not correlate with the overall survival or disease-free survival. AML patients were stratified according to the studied genetic markers, and complete remission rate was found to be more prominent in patients having low expression of MDR1 and ABCB5 genes together with mutated NPM1 gene. In ALL patients, ABCB5 gene expression level was significantly higher in relapsed cases and MDR1 gene expression was significantly higher in patients with resistant disease. CONCLUSION: In conclusion, the results obtained by the current study provide additional evidence of the role played by these genes as predictive factors for resistance of leukemic cells to chemotherapy and hence treatment outcome. PMID- 24804816 TI - Expression of matrix metalloproteinase-2 and 9 in cervical intraepithelial neoplasia and cervical carcinoma among different age groups of premenopausal and postmenopausal women. AB - PURPOSE: The objective was to study the gelatinolytic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in preinvasive and invasive carcinoma of the uterine cervix. The expressions were analysed against different age groups, as to demonstrate whether the expression of MMP-2 and MMP-9 is an early or a late event during the progression of cervical cancer. Additionally, the diagnostic accuracy of MMP-2 and MMP-9 was evaluated with ROC curve. METHODS: A total number of 180 samples of cervical tissue were studied for MMP-2 and MMP-9 gelatinolytic activity. The cases were selected as to include 63 normal cases, 94 CIN cases and 23 cervical carcinoma cases. Among 94 CIN cases, 40 were CIN1, 26 were CIN2 and 28 were CIN3, as reported by histopathology. The gelatinolytic activities of MMP-2 and MMP-9 were evaluated by gelatin zymography in premenopausal and postmenopausal groups. RESULTS: MMP-2 expressions (latent and active) were very low in control samples, followed by increase in CIN1, decrease in CIN2 and further increase in advance stages. MMP-9 had also shown the same expression pattern that of MMP-2. While comparing the expression of MMP-2 and MMP-9 in different age groups, we found initial CIN stages were prevalent in early age that expressed considerable amount of MMP-2 and MMP-9, and advance stages of carcinoma cervix were prevalent at an elderly age. CONCLUSION: Both MMP 2 and MMP-9 have role in cancer progression and remodelling of the ectocervix. Although expression level varies intricately, a distinctive ROC curve demonstrated MMP-2 active form and MMP-9 form could be used in diagnostic purpose in detection of cervical lesion and cancer. PMID- 24804817 TI - Heat shock protein 22 overexpression is associated with the progression and prognosis in gastric cancer. AB - PURPOSE: The heat shock protein 22 (HSP22) is associated with tumor proliferation and protects tumor cell from apoptosis in many malignancies. However, the role of HSP22 in gastric cancer has not been thoroughly elucidated. The aim was to determine the relationship of HSP22 expression with clinicopathological parameters and prognosis in gastric cancer and estimate the alteration of HSP22 expression after neoadjuvant chemotherapy. METHODS: HSP22 and matrix metallopeptidase 9 (MMP-9) antigen expressions were evaluated by immunohistochemistry in 129 gastric carcinoma samples. Univariate and multivariate analyses were performed to determine the association between HSP22 expression and prognosis. The response of HSP22 was assessed in 47 patients who received neoadjuvant chemotherapy. RESULTS: HSP22 protein expression was significantly associated with tumor size, depth invasion, lymph node metastasis and stage of disease (all P < 0.05). In univariate and multivariate analyses, HSP22 was an independent prognostic factor for both overall survival (OS) and recurrence-free survival (RFS) (P = 0.003 and P = 0.004, respectively). Furthermore, HSP22 overexpression was associated with a poor prognosis in all patients and in patients subgroups stratified by tumor size, depth invasion and lymph node metastasis. In addition, HSP22 was significantly correlated with MMP-9 among 129 gastric cancer tissues (P < 0.001). Patients who had MMP-9 overexpression had poor OS and shorter RFS. Moreover, the alteration of HSP22 was not comparable in 47 patients who underwent neoadjuvant chemotherapy. CONCLUSIONS: HSP22 plays an important role on tumor aggressiveness and prognosis and may act as a promising target for prognostic prediction. PMID- 24804819 TI - Origin and sources of dissolved organic matter in snow on the East Antarctic ice sheet. AB - Polar ice sheets hold a significant pool of the world's carbon reserve and are an integral component of the global carbon cycle. Yet, organic carbon composition and cycling in these systems is least understood. Here, we use ultrahigh resolution mass spectrometry to elucidate, at an unprecedented level, molecular details of dissolved organic matter (DOM) in Antarctic snow. Tens of thousands of distinct molecular species are identified, providing clues to the nature and sources of organic carbon in Antarctica. We show that many of the identified supraglacial organic matter formulas are consistent with material from microbial sources, and terrestrial inputs of vascular plant-derived materials are likely more important sources of organic carbon to Antarctica than previously thought. Black carbon-like material apparently originating from biomass burning in South America is also present, while a smaller fraction originated from soil humics and appears to be photochemically or microbially modified. In addition to remote continental sources, we document signals of oceanic emissions of primary aerosols and secondary organic aerosol precursors. The new insights on the diversity of organic species in Antarctic snowpack reinforce the importance of studying organic carbon associated with the Earth's polar regions in the face of changing climate. PMID- 24804818 TI - High IGF2 and FGFR3 are associated with tumour progression in undifferentiated pleomorphic sarcomas, but EGFR and FGFR3 mutations are a rare event. AB - AIM: Pleomorphic undifferentiated sarcomas (formerly known as malignant fibrous histiocytomas) are recognised by the actual WHO classification as an undifferentiated, unclassifiable category of pleomorphic sarcomas which show no definable line of differentiation and are still a diagnosis of exclusion. Therefore, diagnostic, prognostic and therapeutic options of these tumours are urgently needed. METHODS: Three hundred and twenty-seven spindle cell tumours of a German consultation and reference centre of soft tissue tumours consisting of 200 undifferentiated pleomorphic sarcomas (UPS), 45 low-grade sarcomas (10 low grade fibromyxoid sarcomas, 32 low-grade myofibroblastic sarcomas and three myxoinflammatory fibroblastic sarcomas) and 82 tumours of the fasciitis family were revisited. The specimens were analysed immunohistochemically with distinct markers including tyrosine kinases and expression correlated with clinicopathological parameters. Additionally, mutational analysis was performed on specimens with high expression of EGFR and FGFR3. RESULTS: At the protein level high IGF2 expression was observed in 86 %, FGFR3 (69 %), PDGFRA (62 %), PDGFRB (39 %), FGFR1 (8 %), EGFR (5 %), KDR/VEGFR2 (3 %), ALK (0 %) and high Ki67 (63 %) in UPS. High expressions of IGF2 and FGFR3 are significantly correlated with a higher grading (p = 0.023 and p = 0.016, respectively) and a high Ki67 index (p = 0.017 and p = 0.001, respectively). No mutations were found in the hot spots of tumour specimens with a high expression of EGFR gene (exons 18-21) and FGFR3 gene (exons 7, 10 and 15). CONCLUSIONS: High expressions of IGF2 and FGFR3 are significantly associated with tumour progression, grading and Ki67 and might classify a subgroup of undifferentiated pleomorphic sarcoma. These markers might guide targeted therapies in these neoplasms. PMID- 24804820 TI - The cytoprotective role of gemcitabine-induced autophagy associated with apoptosis inhibition in triple-negative MDA-MB-231 breast cancer cells. AB - Triple-negative breast cancer (TNBC), which is estrogen receptor (ER)-negative, progesterone receptor-negative and is also negative for HER2 expression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. Gemcitabine has been approved by the FDA/SFDA for use as a first-line therapeutic drug against advanced or metastatic breast cancer. Therefore, the clarification of the mechanisms underlying gemcitabine-acquired resistance is of particular importance for the optimal management of TNBC. A number of studies have revealed that autophagy, which has been found to protect cancer cells from anti-cancer drug induced death, may contribute to the development of drug resistance. However, the association between autophagy and gemcitabine treatment in TNBC cells has yet to be defined. Our study clearly demonstrates that gemcitabine is able to induce mTOR-independent autophagy in human triple-negative MDA-MB-231 breast cancer cells. In addition, we demonstrate that autophagy protects MDA-MB-231 cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB-231 cells. Furthermore, as shown by our results, the inhibition of gemcitabine-induced autophagy by chloroquine shifts the expression of the p53 protein, Bcl-2 family proteins and the relative Bax/Bcl-xL ratio in favor of promoting apoptosis. These results reveal that the inhibition of apoptosis may be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231 cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that are exposed to gemcitabine. Thus, our study suggests that the combination of an autophagic inhibitor and gemcitabine as a therapeutic strategy may represent a promising approach with greater clinical efficacy for patients with TNBC. However, extended preclinical trials are required to further determine the positive effects of the inhibition of autophagy on the efficacy of gemcitabine. PMID- 24804821 TI - Metabolism of JWH-015, JWH-098, JWH-251, and JWH-307 in silico and in vitro: a pilot study for the detection of unknown synthetic cannabinoids metabolites. AB - This pilot study was performed to study the main metabolic reactions of four synthetic cannabinoids: JWH-015, JWH-098, JWH-251, and JWH-307 in order to setup a screening method for the detection of main metabolites in biological fluids. In silico prediction of main metabolic reactions was performed using MetaSite(TM) software. To evaluate the agreement between software prediction and experimental reactions, we performed in vitro experiments on the same JWHs using rat liver slices. The obtained samples were analyzed by liquid chromatography-quadrupole time-of-flight and the identification of metabolites was executed using Mass MetaSite(TM) software that automatically assigned the metabolite structures to the peaks detected based on their accurate masses and fragmentation. A comparison between the experimental findings and the in silico metabolism prediction using MetaSite(TM) software showed a good accordance between experimental and in silico data. Thus, the use of in silico metabolism prediction might represent a useful tool for the forensic and clinical toxicologist to identify possible main biomarkers for synthetic cannabinoids in biological fluids, especially urine, following their administration. PMID- 24804822 TI - Superconducting properties and electronic structure of NaBi. AB - Resistivity, dc magnetization, and heat capacity measurements are reported for superconducting NaBi. T(c), the electronic contribution to the specific heat gamma, the DeltaC(p)/gammaT(c) ratio, and the Debye temperature are found to be 2.15 K, 3.4 mJ mol(-1) K(-2), 0.78, and 140 K respectively. The calculated electron-phonon coupling constant (lambda(ep) = 0.62) implies that NaBi is a moderately coupled superconductor. The upper critical field and coherence length are found to be 250 Oe and 115 nm, respectively. Electronic structure calculations show NaBi to be a good metal, in agreement with the experiments; the p(x) and p(y) orbitals of Bi dominate the electronic states at the Fermi Energy. PMID- 24804823 TI - Predominance of a single phylogenetic species in colonization events among a sextet of decollate land snail, Rumina decollata (Mollusca: Pulmonata: Subulinidae), species. AB - The hermaphroditic, facultatively selfing, land snail Rumina decollata is a common, widespread species that is indigenous to the Mediterranean region and that has been introduced to many other regions of the world. However, recent DNA sequence analyses have indicated that R. decollata is a complex of several phylogenetic species, two of which correspond to previously distinguished allozyme strains with different body colors (light vs. dark) and life history characteristics. Against this background, this paper attempts to identify which of these phylogenetic species have been introduced elsewhere in the world. Based on a comparative DNA sequence analysis of putatively introduced populations from South America, North America, Japan, and the North Atlantic Islands versus native Mediterranean populations, it is shown that all putatively introduced populations belong to a single phylogenetic species that was previously recognized as the dark morph. Hence, the colonizing and invasive character of R. decollata seems to be due to this phylogenetic species. Nevertheless, in its native area the dark morph is supposed to be outcompeted when sympatric with the light morph of R. decollata. This issue is briefly discussed and the Iberian Peninsula is tentatively proposed as an important source for introduced R. decollata populations outside Europe. PMID- 24804824 TI - Amino acids as novel nucleophiles for silver nanoparticle-luminol chemiluminescence. AB - The use of noble metal nanoparticles (NPs) as reductants in chemiluminescence (CL) has been reported only rarely owing to their high oxidation potentials. Interestingly, nucleophiles could dramatically lower the oxidation potential of Ag NPs, such that in the presence of nucleophiles Ag NPS could be used as reductants to induce the CL emission of luminol, an important CL reagent widely used in forensic analysis for the detection of trace amounts of blood. Although nucleophiles are indispensible in Ag NP-luminol CL, only inorganic nucleophiles such as Cl(-), Br(-), I(-) and S2O3 (2-) have been shown to be efficient. The effects of organic nucleophiles on CL remain unexplored. In this study, 20 standard amino acids were evaluated as novel organic nucleophiles in Ag NP luminol CL. Histidine, lysine and arginine could initiate CL emission; the others could not. It is proposed that the different behaviors of 20 standard amino acids in the CL reactions derive from the interface chemistry between Ag NPs and these amino acids. UV/vis absorption spectra were studied to validate the interface chemistry. In addition, imidazole and histidine were chosen as a model pair to compare the behavior of the monodentate nucleophile with that of the corresponding multidentate nucleophile in Ag NP-luminol CL. PMID- 24804825 TI - A universal protocol for the combined isolation of metabolites, DNA, long RNAs, small RNAs, and proteins from plants and microorganisms. AB - Here, we describe a method for the combined metabolomic, proteomic, transcriptomic and genomic analysis from one single sample as a major step for multilevel data integration strategies in systems biology. While extracting proteins and DNA, this protocol also allows the separation of metabolites into polar and lipid fractions, as well as RNA fractionation into long and small RNAs, thus allowing a broad range of transcriptional studies. The isolated biomolecules are suitable for analysis with different methods that range from electrophoresis and blotting to state-of-the-art procedures based on mass spectrometry (accurate metabolite profiling, shot-gun proteomics) or massive sequencing technologies (transcript analysis). The low amount of starting tissue, its cost-efficiency compared with the utilization of commercial kits, and its performance over a wide range of plant, microbial, and algal species such as Chlamydomonas, Arabidopsis, Populus, or Pinus, makes this method a universal alternative for multiple molecular isolation from plant tissues. PMID- 24804826 TI - Monocytopenia as a diagnostic clue to pediatric B-lymphoblastic leukemia with rare circulating blasts. AB - B-lymphoblastic leukemia/lymphoma (B-LL) is the most common childhood cancer. Circulating blasts in the peripheral blood may be rare (<=1%) and missed, even when flow cytometric immunophenotyping is performed, leading to a false-negative report. The records from all patients with a new diagnosis of B-LL between January 2009 and December 2011 at our institution were reviewed. Of 130 cases with peripheral blood flow cytometry, 15 had a blast count of <=1%, with 14 having electronic files for gating monocytes. The percentage of monocytes by flow cytometry and absolute monocyte counts (AMCs) were compared with peripheral blood samples that were negative by flow cytometry, sent due to cytopenia of at least 1 lineage (n = 39). The monocytes from the patients with leukemia averaged 0.8% and were statistically fewer than the negative controls, which averaged 7.1% (P < 0.001). Eleven of the 14 (79%) patients with leukemia had monocytes <1%, compared to only 3 (8%) of the negative controls. The AMCs were also significantly lower (P < 0.001), with 93% of the leukemia group having an AMC <100 cells/uL, compared to only 28% of the negative controls. In patients with cytopenias, percentage of monocytes may be an important diagnostic clue in determining the presence of occult leukemia. If flow cytometry is performed, acquisition of more than the standard 10,000 events is necessary to adequately assess for leukemia. If monocytes are <1% by flow cytometry in the setting of cytopenias, bone marrow examination is recommended, even with negative peripheral blood flow cytometry. PMID- 24804828 TI - Hepatoprotective triterpenoid saponins from Callicarpa nudiflora. AB - Four new triterpenoid saponins, 2alpha,3alpha,19alpha,24-tetrahydroxyolean-12-en 28-oic-acid 28-O-beta-D-glucopyranosyl ester (1), 2alpha,3alpha,19alpha,23 tetrahydroxyolean-12-en-28-oic-acid 28-O-beta-D-xylopyranosyl-(1->2)-beta-D-glu copyranosyl ester (2), 2alpha,3alpha,19alpha-trihydroxyolean-12-en-28-oic-acid 28 O-beta-D-xylopyranosyl-(1->2)-beta-D-glucopyranosyl ester (3), 2alpha,3alpha,23,29-tetrahydroxyurs-12,19-dien-28-oic-acid 28-O-beta-D glucopyranosyl ester (4), together with three known compounds (5-7), were isolated from the leaves of Callicarpa nudiflora HOOK. Their structures were established by means of spectroscopic methods and chemical evidence. Hepatoprotective activities of the isolated compounds against D-galactosamine induced toxicity have been tested. Among them, compounds 1-3 showed pronounced hepatoprotective activities against D-galactosamine-induced toxicity in WB-F344 rat hepatic epithelial stem-like cells. PMID- 24804827 TI - Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure. AB - Interleukin 18 (IL-18) is a proinflammatory cytokine in the IL-1 family that has been implicated in a number of disease states. In animal models of acute myocardial infarction (AMI), pressure overload, and LPS-induced dysfunction, IL 18 regulates cardiomyocyte hypertrophy and induces cardiac contractile dysfunction and extracellular matrix remodeling. In patients, high IL-18 levels correlate with increased risk of developing cardiovascular disease (CVD) and with a worse prognosis in patients with established CVD. Two strategies have been used to counter the effects of IL-18:IL-18 binding protein (IL-18BP), a naturally occurring protein, and a neutralizing IL-18 antibody. Recombinant human IL-18BP (r-hIL-18BP) has been investigated in animal studies and in phase I/II clinical trials for psoriasis and rheumatoid arthritis. A phase II clinical trial using a humanized monoclonal IL-18 antibody for type 2 diabetes is ongoing. Here we review the literature regarding the role of IL-18 in AMI and heart failure and the evidence and challenges of using IL-18BP and blocking IL-18 antibodies as a therapeutic strategy in patients with heart disease. PMID- 24804830 TI - Probabilistic framework for assessing the arsenic exposure risk from cooked fish consumption. AB - Geogenic arsenic (As) contamination of groundwater is a major ecological and human health problem in southwestern and northeastern coastal areas of Taiwan. Here, we present a probabilistic framework for assessing the human health risks from consuming raw and cooked fish that were cultured in groundwater As contaminated ponds in Taiwan by linking a physiologically based pharmacokinetics model and a Weibull dose-response model. Results indicate that As levels in baked, fried, and grilled fish were higher than those of raw fish. Frying resulted in the greatest increase in As concentration, followed by grilling, with baking affecting the As concentration the least. Simulation results show that, following consumption of baked As-contaminated fish, the health risk to humans is <10(-6) excess bladder cancer risk level for lifetime exposure; as the incidence ratios of liver and lung cancers are generally acceptable at risk ranging from 10(-6) to 10(-4), the consumption of baked As-contaminated fish is unlikely to pose a significant risk to human health. However, contaminated fish cooked by frying resulted in significant health risks, showing the highest cumulative incidence ratios of liver cancer. We also show that males have higher cumulative incidence ratio of liver cancer than females. We found that although cooking resulted in an increase for As levels in As-contaminated fish, the risk to human health of consuming baked fish is nevertheless acceptable. We suggest the adoption of baking as a cooking method and warn against frying As-contaminated fish. We conclude that the concentration of contaminants after cooking should be taken into consideration when assessing the risk to human health. PMID- 24804829 TI - Release, deposition and elimination of radiocesium ((137)Cs) in the terrestrial environment. AB - Radionuclide contamination in terrestrial ecosystems has reached a dangerous level. The major artificial radionuclide present in the environment is (137)Cs, which is released as a result of weapon production related to atomic projects, accidental explosions of nuclear power plants and other sources, such as reactors, evaporation ponds, liquid storage tanks, and burial grounds. The release of potentially hazardous radionuclides (radiocesium) in recent years has provided the opportunity to conduct multidisciplinary studies on their fate and transport. Radiocesium's high fission yield and ease of detection made it a prime candidate for early radio-ecological investigations. The facility setting provides a diverse background for the improved understanding of various factors that contribute toward the fate and transfer of radionuclides in the terrestrial ecosystem. In this review, we summarize the significant environmental radiocesium transfer factors to determine the damaging effects of radiocesium on terrestrial ecosystem. It has been found that (137)Cs can trace the transport of other radionuclides that have a high affinity for binding to soil particles (silts and clays). Possible remedial methods are also discussed for contaminated terrestrial systems. This review will serve as a guideline for future studies of the fate and transport of (137)Cs in terrestrial environments in the wake of the Fukushima Nuclear Power Plant disaster in 2011. PMID- 24804831 TI - Salivary duct carcinoma and the concept of early carcinoma ex pleomorphic adenoma. AB - AIMS: The data on the histological type of carcinomatous component and the extent of extracapsular invasion for salivary carcinomas ex pleomorphic adenoma (PA) are conflicting. We aimed to determine the prognostic value of extracapsular invasion in salivary duct carcinomas (SDC) ex PA. METHODS AND RESULTS: A total of 117 patients with SDC were identified retrospectively; 44 cases involving major salivary glands had pre-existing PA (44 of 117, 37%). The morphological spectrum of SDC ex PA was characterized. The primary endpoint was overall survival (OS). Most SDC ex PA were widely invasive at presentation (27 of 44; 61%). Five patients with intracapsular SDC ex PA experienced no disease progression. The assessment of extracapsular invasion was precluded in eight cases (e.g. positive margins of resection). The rate of lymph node involvement was similar in cases with extracapsular invasion of <=2 mm (two of three) and >7 mm (22 of 26). Only pT correlated with OS [116 months, 95% confidence interval (CI) 22-210 months for pT1 versus 20 months (95% CI 6-34) for pT4; P = 0.013]. CONCLUSIONS: Intracapsular SDC ex PA are potentially indolent. SDC ex PA with extracapsular invasion of <=2 mm are rare, and appear to be clinically aggressive. Several histological parameters preclude assessment of extracapsular invasion. PMID- 24804833 TI - Increased CCL22 expression in psoriatic skin predicts a good response to infliximab therapy. PMID- 24804832 TI - Synthesis, characterization, in vitro cytotoxicity, and apoptosis-inducing properties of ruthenium(II) complexes. AB - Two new Ru(II) complexes, [Ru(bpy)2(FAMP)](ClO4)2 1 and 2, are synthesized and characterized by elemental analysis, electrospray mass spectrometry, and 1H nuclear magnetic resonance. The in vitro cytotoxicities and apoptosis-inducing properties of these complexes are extensively studied. Complexes 1 and 2 exhibit potent antiproliferative activities against a panel of human cancer cell lines. The cell cycle analysis shows that complexes 1 and 2 exhibit effective cell growth inhibition by triggering G0/G1 phase arrest and inducing apoptosis by mitochondrial dysfunction. The in vitro DNA binding properties of the two complexes are investigated by different spectrophotometric methods and viscosity measurements. PMID- 24804835 TI - Mean-field games for marriage. AB - This article examines mean-field games for marriage. The results support the argument that optimizing the long-term well-being through effort and social feeling state distribution (mean-field) will help to stabilize marriage. However, if the cost of effort is very high, the couple fluctuates in a bad feeling state or the marriage breaks down. We then examine the influence of society on a couple using mean-field sentimental games. We show that, in mean-field equilibrium, the optimal effort is always higher than the one-shot optimal effort. We illustrate numerically the influence of the couple's network on their feeling states and their well-being. PMID- 24804834 TI - Neurodegenerative aspects in vulnerability to schizophrenia spectrum disorders. AB - The neurodegenerative and neurotoxic aspects of schizophrenia and/or psychosis involve genetic, epigenetic, and neurotoxic propensities that impinge upon both the symptom domains and the biomarkers of the disorder, involving cellular apoptosis/excitotoxicity, increased reactive oxygen species formation, viral and bacterial infections, anoxic birth injury, maternal starvation, drugs of abuse, particularly cannabis, metabolic accidents, and other chemical agents that disrupt normal brain development or the integrity of brain tissues. Evidence for premorbid and prodromal psychotic phases, aspects of neuroimaging, dopamine, and psychosis vulnerability, and perinatal aspects provide substance for neurodegenerative influences. Not least, the agencies of antipsychotic contribute to the destructive spiral that disrupts normal structure and function. The etiopathogenesis of psychosis is distinguished also by disruptions of the normal functioning of the neurotrophins, in particular brain-derived neurotrophic factor, dyskinesic aspects, immune system disturbances, and metabolic aspects. Whether detrimental to neurodevelopment or tissue-destructive, or an acceleration of neurotoxic pathways, the notion of neurodegeneration in the pathophysiology of schizophrenia spectrum and psychotic disorders continues to gather momentum. PMID- 24804837 TI - Regaining confidence in confidence intervals for the mean treatment effect. AB - In many experiments, it is necessary to evaluate the effectiveness of a treatment by comparing the responses of two groups of subjects. This evaluation is often performed by using a confidence interval for the difference between the population means. To compute the limits of this confidence interval, researchers usually use the pooled t formulas, which are derived by assuming normally distributed errors. When the normality assumption does not seem reasonable, the researcher may have little confidence in the confidence interval because the actual one-sided coverage probability may not be close to the nominal coverage probability. This problem can be avoided by using the Robbins-Monro iterative search method to calculate the limits. One problem with this iterative procedure is that it is not clear when the procedure produces a sufficiently accurate estimate of a limit. In this paper, we describe a multiple search method that allows the user to specify the accuracy of the limits. We also give guidance concerning the number of iterations that would typically be needed to achieve a specified accuracy. This multiple iterative search method will produce limits for one-sided and two-sided confidence intervals that maintain their coverage probabilities with non-normal distributions. PMID- 24804836 TI - Cyclooxygenases: mediators of UV-induced skin cancer and potential targets for prevention. AB - Non-melanoma skin cancers (NMSCs) are among the most common human malignancies. Current methods for their prevention include avoidance of natural and artificial sources of UV radiation and using photoprotective clothing and sunscreens. However, these methods have proven to be inadequate in stemming the rise in skin cancer incidence over the past several years. There is accumulating evidence that cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis, may be involved in the pathogenesis of NMSC. In preclinical studies, animals genetically deficient in the COX-2 enzyme or that have been treated with pharmacological inhibitors of COX-2 develop significantly fewer tumors when subjected to a UV induced skin carcinogenesis protocol compared with control mice. Several epidemiological studies in humans support the concept that this enzyme is intimately involved in UV-induced skin cancer development, and UV radiation is known to augment COX-2 expression in human skin. Recent studies suggest that drugs that block COX-2 expression may prevent the development of NMSCs. Thus, pharmacologic agents that inhibit the enzyme COX-2 may be effective chemopreventive agents for NMSCs. PMID- 24804839 TI - Virulence profile: Rami Kantor. PMID- 24804838 TI - Tissue culture-induced heritable genomic variation in rice, and their phenotypic implications. AB - BACKGROUND: Somaclonal variation generally occurs in plants regenerated from tissue culture. However, fundamental issues regarding molecular characteristics, mutation rates and mutation spectra of plant somatic variation as well as their phenotypic relevance have been addressed only recently. Moreover, these studies have reported highly discrepant results in different plant species and even in the same plant genotype. METHODOLOGY/PRINCIPAL FINDINGS: We investigated heritable genomic variation induced by tissue culture in rice by whole genome re sequencing of an extensively selfed somaclonal line (TC-reg-2008) and its wild type (WT) donor (cv. Hitomebore). We computed the overall mutation rate, single nucleotide polymorphisms (SNPs), small scale insertions/deletions (Indels) and mobilization of transposable elements (TEs). We assessed chromosomal distribution of the various types of genomic variations, tested correlations between SNPs and Indels, and examined concomitancy between TE activity and its cytosine methylation states. We also performed gene ontology (GO) analysis of genes containing nonsynonymous mutations and large-effect mutations, and assayed effects of the genomic variations on phenotypes under both normal growing condition and several abiotic stresses. We found that heritable somaclonal genomic variation occurred extensively in rice. The genomic variations distributed non-randomly across each of the 12 rice chromosomes, and affected a large number of functional genes. The phenotypic penetrance of the genomic variations was condition-dependent. CONCLUSIONS/SIGNIFICANCE: Tissue culture is a potent means to generate heritable genetic variations in rice, which bear distinct difference at least in space (chromosomal distribution) from those occurred under natural settings. Our findings have provided new information regarding the mutation rate and spectrum as well as chromosomal distribution pattern of somaclonal variation in rice. Our data also suggest that rice possesses a strong capacity to canalize genetic variations under normal growing conditions to maintain phenotypic robustness, which however can be released by certain abiotic stresses to generate variable phenotypes. PMID- 24804840 TI - Dynamics of ferroelectric bis(imidazolium) pentachloroantimonate(III) by means of nuclear magnetic resonance 1H relaxometry and dielectric spectroscopy. AB - Some of haloantimonates(III) and halobismuthates(III) are ferroelectric. Bis(imidazolium) pentachloroantimonate(III), (C3N2H5)2SbCl5 (abbreviation: ICA) is the first example of such compounds with a one-dimensional anionic chain which exhibits ferroelectric properties. The relation between the ionic dynamics and network structure and the ferroelectric features is not clear. Here Nuclear Magnetic Resonance (NMR) (1)H spin-lattice relaxation experiments at 25 MHz are reported for ICA in the temperature range of 80 K-360 K, covering ferroelectric paraelectric and structural phase transitions of the compound occurring at 180 and 342 K, respectively. The relaxation process is biexponential in the whole temperature range indicating two dynamically nonequivalent types of imidazolium cations. Temperature dependences of both relaxation contributions allow for identifying three motional processes. Two of them are cation-specific - i.e. they are attributed to the two types of imidazolium cations, respectively. The third process involves both types of cations, and it is characterized by much lower activation energy. Moreover, the relaxation data (combined with (1)H second moment measurements) show that the ferroelectric-paraelectric phase transition mechanism is governed, to a large extent, by the anionic network arrangement. The NMR studies are complemented by dielectric spectroscopy experiments performed in the vicinity of the Curie temperature, TC = 180 K, to get insight into the mechanism of the ferroelectric-paraelectric phase transition. The dielectric dispersion data show critical slowing down of the macroscopic relaxation time, tau, in ICA when approaching TC from the paraelectric side, indicating an order disorder type of ferroelectrics. PMID- 24804841 TI - Sets of covariant residues modulate the activity and thermal stability of GH1 beta-glucosidases. AB - The statistical coupling analysis of 768 beta-glucosidases from the GH1 family revealed 23 positions in which the amino acid frequencies are coupled. The roles of these covariant positions in terms of the properties of beta-glucosidases were investigated by alanine-screening mutagenesis using the fall armyworm Spodoptera frugiperda beta-glycosidase (Sfbetagly) as a model. The effects of the mutations on the Sfbetagly kinetic parameters (kcat/Km) for the hydrolysis of three different p-nitrophenyl beta-glycosides and structural comparisons of several beta-glucosidases showed that eleven covariant positions (54, 98, 143, 188, 195, 196, 203, 398, 451, 452 and 460 in Sfbetagly numbering) form a layer surrounding the active site of the beta-glucosidases, which modulates their catalytic activity and substrate specificity via direct contact with the active site residues. Moreover, the influence of the mutations on the transition temperature (Tm) of Sfbetagly indicated that nine of the coupled positions (49, 62, 143, 188, 223, 278, 309, 452 and 460 in Sfbetagly numbering) are related to thermal stability. In addition to being preferentially occupied by prolines, structural comparisons indicated that these positions are concentrated at loop segments of the beta-glucosidases. Therefore, due to these common biochemical and structural properties, these nine covariant positions, even without physical contacts among them, seem to jointly modulate the thermal stability of beta-glucosidases. PMID- 24804842 TI - Nocturia improvement in the combination of Avodart((r)) and tamsulosin (CombAT) study. AB - PURPOSE: The purpose of the study was to assess the impact of dutasteride plus tamsulosin combination therapy, compared with dutasteride or tamsulosin monotherapy, on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) using data from the 4-year CombAT study. METHODS: Nocturia was assessed using Question 7 of the International Prostate Symptom Score questionnaire. Efficacy measures included as follows: mean change in nocturia at 3-month intervals up to 48 months; proportion of patients with improvement/worsening in nocturia; nocturnal voiding frequency at baseline and study end, overall and by baseline subgroups; and nocturnal voiding frequency <2 at study end in patients with a baseline score >= 2. RESULTS: In total, 4,722 patients with a mean age of 66 years were included. Mean nocturia improvements were significantly superior (p <= 0.01) with combination therapy than with either monotherapy (adjusted mean change from baseline in IPSS Question 7 score at month 48: combination therapy -0.5, dutasteride -0.4, tamsulosin -0.3). Reduction in nocturia score with combination therapy was significantly (p <= 0.01) better than tamsulosin monotherapy across all baseline subgroups tested, except for men with previous 5ARI use. Among those with a baseline IPSS Q7 score >= 2, more patients with combination therapy had a score <2 at month 48 (34 %) compared with dutasteride (30 %, p = 0.018) or tamsulosin (26 %, p < 0.0001). CONCLUSIONS: Combination therapy provided greater improvements and less worsening of nocturia compared with both dutasteride and tamsulosin monotherapies. These analyses are the first to show greater improvement with a 5ARI/alpha-blocker combination versus either agent alone for the management of nocturia in patients with LUTS/BPH. PMID- 24804844 TI - Multiple ambient hydrolysis deposition of tin oxide into nanoporous carbon to give a stable anode for lithium-ion batteries. AB - A novel ambient hydrolysis deposition (AHD) methodology that employs sequential water adsorption followed by a hydrolysis reaction to infiltrate SnO2 nanoparticles into the nanopores of mesoporous carbon in a conformal and controllable manner is introduced. The empty space in the SnO2/C composites can be adjusted by varying the number of AHD cycles. An SnO2/C composite with an intermediate SnO2 loading exhibited an initial specific delithiation capacity of 1054 mAh g(-1) as an anode for Li-ion batteries. The capacity contribution from SnO2 in the composite electrode approaches the theoretical capacity of SnO2 (1494 mAh g(-1)) if both Sn alloying and SnO2 conversion reactions are considered to be reversible. The composite shows a specific capacity of 573 mAh g(-1) after 300 cycles, that is, one of the most stable cycling performances for SnO2/mesoporous carbon composites. The results demonstrated the importance of well-tuned empty space in nanostructured composites to accommodate expansion of the electrode active mass during alloying/dealloying and conversion reactions. PMID- 24804843 TI - Significance of prostate-specific antigen-related factors in incidental prostate cancer treated by holmium laser enucleation of the prostate. AB - PURPOSE: Recently, more vaporization techniques are available for the treatment of benign prostate hyperplasia (BPH). However, the detection of incidental prostate cancer (Pca) is impossible in vaporization techniques because of unavailability prostate tissue for histopathological analysis. To evaluate the clinical backgrounds and the usefulness of prostate-specific antigen (PSA) related factors in incidental Pca, we employed our BPH patients cohort treated by holmium laser enucleation of the prostate (HoLEP). METHODS: A total of 365 HoLEPs were performed by a single surgeon. The pathological results and pre- and post HoLEP PSA, PSA density and PSA velocity were analyzed retrospectively. RESULTS: Incidental Pca was identified in 25 (6.8 %) of the 365 patients treated with HoLEP. There were significant differences between BPH and Pca in terms of prostate volume (55.5 vs. 47 ml, p = 0.0365), preoperative PSA (4.50 vs. 7.14 ng/ml, p = 0.0107), PSA density (0.079 vs. 0.155 ng/ml/cm(3), p = 0.0005), and postoperative PSA velocity (0.04 vs. 0.22 ng/ml/year, p = 0.0033), respectively. Comparisons of Gleason score subgroups in the 25 patients with incidental Pca identified significant differences in preoperative PSA (6.06 vs. 21.6 ng/ml, p = 0.0191) and postoperative PSA velocity (0.185 vs. 1.32 ng/ml/year, p = 0.0382) between the Gleason score 3 + 3 and Gleason score >3 + 3 groups, respectively. CONCLUSIONS: Risk factors associated with incidental Pca were smaller prostate volume, higher preoperative PSA, and higher PSA density. Postoperative PSA velocity was also significantly increased in patients with incidental Pca, especially those with higher Gleason score. These finding may be useful in incident Pca patients treated by the vaporization technique. PMID- 24804845 TI - ADHD pharmacogenetics across the life cycle: New findings and perspectives. AB - Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder, affecting individuals across the life cycle. Although its etiology is not yet completely understood, genetics plays a substantial role. Pharmacological treatment is considered effective and safe for children and adults, but there is considerable inter-individual variability among patients regarding response to medication, required doses, and adverse events. We present here a systematic review of the literature on ADHD pharmacogenetics to provide a critical discussion of the existent findings, new approaches, limitations, and recommendations for future research. Our main findings are: first, the number of studies continues to grow, making ADHD one of the mental health areas with more pharmacogenetic studies. Second, there has been a focus shift on ADHD pharmacogenetic studies in the last years. There is an increasing number of studies assessing gene-gene and gene-environment interactions, using genome-wide association approaches, neuroimaging, and assessing pharmacokinetic properties. Third and most importantly, the heterogeneity in methodological strategies employed by different studies remains impressive. The question whether pharmacogenetics studies of ADHD will improve clinical management by shifting from trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains unanswered. (c) 2014 Wiley Periodicals, Inc. PMID- 24804847 TI - Both butyrate incubation and hypoxia upregulate genes involved in the ruminal transport of SCFA and their metabolites. AB - Butyrate modulates the differentiation, proliferation and gene expression profiles of various cell types. Ruminal epithelium is exposed to a high intraluminal concentration and inflow of n-butyrate. We aimed to investigate the influence of n-butyrate on the mRNA expression of proteins involved in the transmembranal transfer of n-butyrate metabolites and short-chain fatty acids in ruminal epithelium. N-butyrate-induced changes were compared with the effects of hypoxia because metabolite accumulation after O2 depletion is at least partly comparable to the accumulation of metabolites after n-butyrate exposure. Furthermore, in various tissues, O2 depletion modulates the expression of transport proteins that are also involved in the extrusion of metabolites derived from n-butyrate breakdown in ruminal epithelium. Sheep ruminal epithelia mounted in Ussing chambers were exposed to 50 mM n-butyrate or incubated under hypoxic conditions for 6 h. Electrophysiological measurements showed hypoxia-induced damage in the epithelia. The mRNA expression levels of monocarboxylate transporters (MCT) 1 and 4, anion exchanger (AE) 2, downregulated in adenoma (DRA), putative anion transporter (PAT) 1 and glucose transporter (GLUT) 1 were assessed by RT-qPCR. We also examined the mRNA expression of nuclear factor (NF) kappaB, cyclooxygenase (COX) 2, hypoxia-inducible factor (HIF) 1alpha and acyl CoA oxidase (ACO) to elucidate the possible signalling pathways involved in the modulation of gene expression. The mRNA expression levels of MCT 1, MCT 4, GLUT 1, HIF 1alpha and COX 2 were upregulated after both n-butyrate exposure and hypoxia. ACO and PAT 1 were upregulated only after n-butyrate incubation. Upregulation of both MCT isoforms and NFkappaB after n-butyrate incubation could be detected on protein level as well. Our study suggests key roles for MCT 1 and 4 in the adaptation to an increased intracellular load of metabolites, whereas an involvement of PAT 1 in the transport of n-butyrate also seems possible. PMID- 24804846 TI - Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure. AB - Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking. PMID- 24804849 TI - Preferred choice of work setting among nurses in Thailand: A discrete choice experiment. AB - The shortage of health personnel and nurses is an important issue in many developed and developing countries. Understanding preferred choice of work setting is an important strategy for retaining nurses in their work. The purpose of this study was to determine choices made by nurses in Thailand relative to their preferences for a work setting. A discrete choice experiment was conducted to elicit attributes and levels of job characteristics expected to contribute to work-place preferences. The sample included 921 nurses and was selected using stratified random sampling. A random effects probit model was used to identify factors contributing to work-setting preferences. The results showed that nurses' first work-place preference was a high level of work setting. The second preference was to work in a hospital in the same province as their families. The results provide information for hospital and nurse administrators and policymakers seeking to address the nursing shortage. PMID- 24804850 TI - Combined effect of elevated UVB, elevated temperature and fertilization on growth, needle structure and phytochemistry of young Norway spruce (Picea abies) seedlings. AB - Simultaneously with warming climate, other climatic and environmental factors are also changing. Here, we investigated for the first time the effects of elevated temperature, increased ultraviolet-B (UVB) radiation, fertilization and all combinations of these on the growth, secondary chemistry and needle structure of 1-year-old Norway spruce (Picea abies (L.) Karst.) seedlings in an outdoor experiment. After one growing season, elevated temperature increased root : shoot ratio and concentrations of needle piperidine alkaloids, while concentrations of needle catechins and acetophenones and bark flavonoids decreased compared with ambient temperature seedlings. UVB-radiation increased concentrations of bark condensed tannins, while fertilization increased total biomass and concentrations of needle catechins. In addition to the main effects, concentrations of some individual phenolic compounds showed UV * temperature or UV * temperature * fertilization interactions, and fertilization modified temperature response on root : shoot ratio. All the treatments described here affected the defence chemistry profiles of the seedlings, which may imply some changes in plant herbivore interactions in connection with changing climate. The interactions between treatments indicate a need for further experiments involving several simultaneously affecting environmental changes. PMID- 24804852 TI - Towards genomic selection for facial eczema disease tolerance in the New Zealand sheep industry. AB - Pithomycotoxicosis, more commonly known as facial eczema (FE), is a liver disease that occurs predominantly in New Zealand because of its toxigenic Pithomyces chartarum strains. The first reported case was in sheep in 1887. Since the 1930s, a number of studies have been conducted in an attempt to mitigate the problems FE has on the sheep and dairy industries. The research in these studies included work on fungicide and biological control of the saprophytic fungus, use of different pasture plants to inhibit fungal growth, stock management with respect to pasture fungal spore counts and the use of zinc prophylaxis on animals. The finding that there was a genetic basis in FE sensitivity in sheep prompted research for a genetic approach to mitigation in the form of a diagnostic DNA test for susceptibility to the disease. Recently, we have used the Illumina OvineSNP50 BeadChip to develop a genome-enabled prediction approach to screen for FE-tolerant sheep. Our current best genomic prediction for FE is for the Romney breed and has an accuracy of 0.38. This prediction accuracy is not as high as the individual accuracy gained by an artificial challenge test (0.64). However, it has the advantage of being a non-invasive test and can be provided as part of genomic testing for other traits at minimal cost. PMID- 24804855 TI - Effect and mode of action of the Texel muscling QTL (TM-QTL) on carcass traits in purebred Texel lambs. AB - TM-QTL is a quantitative trait locus (QTL) on ovine chromosome 18 (OAR18) known to affect loin muscling in Texel sheep. Previous work suggested that its mode of inheritance is consistent with paternal polar overdominance, but this has yet to be formally demonstrated. This study used purebred Texel sheep segregating for TM QTL to confirm its presence in the chromosomal region in which it was first reported and to determine its pattern of inheritance. To do so, this study used the first available data from a Texel flock, which included homozygote TM-QTL carriers (TM/TM; n=34) in addition to homozygote non-carriers (+/+; n=40 and, heterozygote TM-QTL-carriers inheriting TM-QTL from their sire (TM/+; n=53) or their dam (+/TM; n=17). Phenotypes included a wide range of loin muscling, carcass composition and tissue distribution traits. The presence of a QTL affecting ultrasound muscle depth on OAR18 was confirmed with a paternal QTL effect ranging from +0.54 to +2.82 mm UMD (s.e. 0.37 to 0.57 mm) across the sires segregating for TM-QTL. Loin muscle width, depth and area, loin muscle volume and dissected M. longissimus lumborum weight were significantly greater for TM/+ than +/+ lambs (+2.9% to +7.9%; P<0.05). There was significant evidence that the effect of TM-QTL on the various loin muscling traits measured was paternally polar overdominant (P<0.05). In contrast, there was an additive effect of TM-QTL on both live weight at 20 weeks and carcass weight; TM/TM animals were significantly (P<0.05) heavier than +/+ (+11.1% and +7.3%, respectively) and +/TM animals (+11.9% and +11.7%, respectively), with TM/+ intermediate. Weights of the leg, saddle and shoulder region (corrected for carcass weight) were similar in the genotypic groups. There was a tendency for lambs inheriting TM-QTL from their sire to be less fat with slightly more muscle than non-carriers. For example, carcass muscle weight measured by live animal CT-scanning was 2.8% higher in TM/TM than +/+ lambs (P<0.05), carcass muscle weight measured by carcass CT scanning was 1.36% higher in TM/+ than +/+ lambs (P<0.05), and weight of fat trimmed from the carcass cuts was significantly lower for TM/+ than +/+ lambs ( 11.2%; P<0.05). No negative effects of TM-QTL on carcass traits were found. Optimal commercial use of TM-QTL within the sheep industry would require some consideration, due to the apparently different mode of action of the two main effects of TM-QTL (on growth and muscling). PMID- 24804853 TI - Management of mineral metabolism in hemodialysis patients: discrepancy between interventions and perceived causes of failure. AB - BACKGROUND: Mineral and bone disorders (MBD) in patients undergoing hemodialysis (HD) are a major clinical complication. Current therapeutic strategies do not attain the expected results. The Italian audit on mineral metabolism was implemented to investigate MBD management through a "patient-oriented" approach. METHODS: Clinical and laboratory data pertinent to MBD from 509 prevalent adult patients on chronic HD were recorded and examined (audit), after which individual strategies were elaborated to improve MBD control. Their effectiveness was evaluated 6 months after the audit (Post-6). RESULTS: The audit disclosed poor MBD control in a high percentage of patients (56 %). Low compliance to treatment was the major determinant of failure (in 43.5 % of cases). Logistic regression showed a direct correlation between high degree of compliance and the achievement of therapeutic targets, e.g. parathyroid hormone: odds ratio (OR) 2.48, p = 0.015. In contrast, a minority of the proposed interventions (14.7 %) included strategies to improve patient compliance. At Post-6, despite a significant increase in drug prescription (p < 0.05 vs. audit), the rate of successful MBD control was unchanged. CONCLUSIONS: Low compliance with treatment is a major, but still neglected, cause of failure in the achievement of MBD control in HD patients. PMID- 24804856 TI - Number of excised lymph nodes as a quality assurance measure for lymphadenectomy in melanoma. AB - IMPORTANCE: Although the number of excised lymph nodes (LNs) represents a quality assurance measure in lymphadenectomy for many solid tumors, the minimum number of LNs to be dissected has not been established for melanoma. OBJECTIVE: To investigate the distribution of the number of excised LNs in a large patient series (N = 2526) to identify values that may serve as benchmarks for monitoring the quality of lymphadenectomy in patients with melanoma. DESIGN, SETTING, AND PARTICIPANTS: A retrospective multicenter study was conducted (1992-2010) in tertiary referral centers for treatment of cutaneous melanoma. Medical records on 2526 patients who underwent lymphadenectomy for regional LN metastasis associated with cutaneous melanoma were examined. EXPOSURE: Patients had undergone lymphadenectomy for regional LN metastasis. MAIN OUTCOMES AND MEASURES: The mean, median, and 10th percentile of the number of excised LNs were calculated for the axilla (3 levels), neck (<=3 or >=4 dissected levels), inguinal, and ilioinguinal LN fields. RESULTS: After 3-level axillary (n = 1150), 3-level or less neck (n = 77), 4-level or more neck (n = 135), inguinal (n = 209), and ilioinguinal (n = 955) dissections, the median (interquartile range [IQR]) and mean (SD) number of excised LNs were as follows: 3-level axillary dissection, 20 (15-27) and 22 (8); 3-level or less neck, 21 (14-33) and 24 (15); 4-level or more neck, 29 (21-41) and 31 (14); inguinal, 11 ( 9-14) and 12 (5); and ilioinguinal, 21 (16-26) and 22 (4). A total of 90% of the patients had 12, 7, 14, 6, and 13 excised LNs (10th percentile of the distribution) after 3-level axillary, 3-level or less neck, 4 level or more neck, inguinal, and ilioinguinal dissections, respectively. More excised LNs were detected in younger (21 for those <54 years of age and 19 for >=54 years, P < .001) and male (21 for male sex and 19 for female sex, P < .001) patients from high-volume institutions (21 for volume of >=300 vs 18 for volume <300, P < .001) with a more recent year of diagnosis (21 for years 2002-2010 vs 18 for years 1992-2001, P < .001), LN micrometastasis vs macrometastasis (20 vs 19, P = .005), and more positive LNs (R2 = 0.03, P < .001); however, the differences between median values were small. CONCLUSIONS AND RELEVANCE: These minimum numbers of excised LNs are reproducible across the institution, patient, and tumor factors evaluated. They can be taken into consideration when monitoring the quality of lymphadenectomy in melanoma and can represent entry criteria for randomized trials investigating adjuvant therapies. PMID- 24804854 TI - mTOR inhibitors and renal allograft: Yin and Yang. AB - Mammalian target of rapamycin inhibitors (mTOR-I), everolimus and sirolimus, are immunosuppressive drugs extensively used in renal transplantation. Their main mechanism of action is the inhibition of cell signaling through the PI3 K/Akt/mTOR pathway. This interesting mechanism of action confers to these medications both great immunosuppressive potential and important anti-neoplastic properties. Although the clinical utility of this drug category, as with other antineoplastic/immunosuppressants, is clear, the use of mTOR-I commonly results in the development of several complications. In particular, these agents may determine severe renal toxicity that, as recent studies report, seems clearly correlated to dose and duration of drug use. The mTOR-I-induced renal allograft spectrum of toxicity includes the enhanced incidence of delayed graft function, nephrotoxicity in particular when co-administered with calcineurin inhibitors (CNI) and onset of proteinuria. The latter effect appears highly frequent in patients undergoing mTOR-I treatment and significantly associated with a rapid graft lost. The damage leading to this complication interests both the glomerular and tubular area. mTOR-I cause an inhibition of proliferation in podocytes and the epithelial-to-mesenchymal transition in tubular cells. Interestingly, all these side effects are mostly reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to maximize their important and specific therapeutic effects while minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in a CNI-free immunosuppressive protocol. PMID- 24804857 TI - Therapeutic effect of Zeng Ye decoction on primary Sjogren's syndrome via upregulation of aquaporin-1 and aquaporin-5 expression levels. AB - The aim of this study was to investigate the curative effect of Zeng Ye decoction on primary Sjogren's syndrome (pSS) and further explore its underlying mechanism involving aquaporin (AQP)-1 and AQP-5. The pSS model was established based on the immune induction method, and the saliva flow, submandibular gland index, morphological structures of salivary glands, and AQP-1 and AQP-5 protein expression levels in the salivary glands were determined. The saliva flow and the submandibular gland index were significantly reduced in the model group (P<0.01, compared with those in the control group), and significantly increased following interferon (IFN), Zeng Ye decoction extraction (ZYE) and Zeng Ye decoction (ZY) treatment (P<0.01, compared with those of the model group). Submandibular gland atrophy, fibrous tissue hyperplasia and multiple focal lymphocytic infiltration were observed in the model group and were attenuated when subjected to IFN, ZYE and ZY treatment. The AQP-1 and AQP-5 expression levels increased following IFN, ZYE and ZY treatment (P<0.01, compared with those of the model group), particularly in the ZYE-35 group. This result indicated that ZYE had a significant protective effect on pSS via upregulation of the expression levels of AQP-1 and/or AQP-5. However, the AQP-1 expression levels increased and the AQP-5 expression levels decreased in the model groups compared with those in the control group, which indicated different regulatory pathways of the salivary gland damage on the basis of AQP-1 and AQP-5. This study provided a significant reference for the prevention and treatment of pSS. PMID- 24804858 TI - Association between age at antiretroviral therapy initiation and 24-month immune response in West-African HIV-infected children. AB - OBJECTIVE: We describe the association between age at antiretroviral therapy (ART) initiation and 24-month CD4 cell response in West African HIV-infected children. METHODS: All HIV-infected children from the IeDEA paediatric West African cohort, initiating ART, with at least two CD4 cell count measurements, including one at ART initiation (baseline) were included. CD4 cell gain on ART was estimated using a multivariable linear mixed model adjusted for baseline variables: age, CD4 cell count, sex, first-line ART regimen. Kaplan-Meier survival curves and a Cox proportional hazards regression model compared immune recovery for age within 24 months post-ART. RESULTS: Of the 4808 children initiated on ART, 3014 were enrolled at a median age of 5.6 years; 61.2% were immunodeficient. After 12 months, children at least 4 years at baseline had significantly lower CD4 cell gains compared with children less than 2 years, the reference group (P<0.001). However, by 24 months, we observed higher CD4 cell gain in children who initiated ART between 3 and 4 years compared with those less than 2 years (P<0.001). The 24-month CD4 cell gain was also strongest in immunodeficient children at baseline. Among these children, 75% reached immune recovery: 12-month rates were significantly highest in all those aged 2-5 years at ART initiation compared with those less than 2 years. Beyond 12 months on ART, immune recovery was significantly lower in children initiated more than 5 years (adjusted hazard ratio: 0.69, 95% confidence interval: 0.56-0.86). CONCLUSION: These results suggest that both the initiation of ART at the earliest age less than 5 years and before any severe immunodeficiency is needed for improving 24 month immune recovery on ART. PMID- 24804859 TI - HIV sexual transmission risk among serodiscordant couples: assessing the effects of combining prevention strategies. AB - BACKGROUND: The number of strategies to prevent HIV transmission has increased following trials evaluating antiretroviral therapy (ART), preexposure prophylaxis (PrEP) and male circumcision. Serodiscordant couples need guidance on the effects of these strategies alone, and in combination with each other, on HIV transmission. METHODS: We estimated the sexual risk of HIV transmission over 1 year and 10-year periods among male-male and male-female serodiscordant couples. We assumed the following reductions in transmission: 80% from consistent condom use; 54% from circumcision in the negative male partner of a heterosexual couple; 73% from circumcision in the negative partner of a male-male couple; 71% from PrEP in heterosexual couples; 44% from PrEP in male-male couples; and 96% from ART use by the HIV-infected partner. FINDINGS: For couples using any single prevention strategy, a substantial cumulative risk of HIV transmission remained. For a male-female couple using only condoms, estimated risk over 10 years was 11%; for a male-male couple using only condoms, estimated risk was 76%. ART use by the HIV-infected partner was the most effective single strategy in reducing risk; among male-male couples, adding consistent condom use was necessary to keep the 10-year risk below 10%. CONCLUSION: Focusing on 1-year and longer term transmission probabilities gives couples a better understanding of risk than those illustrated by data for a single sexual act. Long-term transmission probabilities to the negative partner in serodiscordant couples can be high, though these can be substantially reduced with the strategic use of preventive methods, especially those that include ART. PMID- 24804861 TI - Blimp-1 overexpression is associated with low HIV-1 reservoir and transcription levels in central memory CD4+ T cells from elite controllers. AB - OBJECTIVES: The aim of the study was to determine the molecular mechanisms underlying the quasi-equilibrium between HIV and its host in the model of functional cure represented by elite controllers who spontaneously maintain exceptionally low levels of HIV reservoirs. DESIGN: Whole-genome transcriptional study and quantification of the cell-associated HIV DNA and HIV RNA levels of the four major resting CD4 T-cell subsets in HIV-1-infected elite controllers, viremic long-term nonprogressors (vir-LTNPs), and uninfected individuals. METHODS: We compared the whole-genome transcriptional profiles (ArrayExpress accession number E-MTAB-1480) of the four major resting CD4 T-cell subsets [naive (TN), central-memory (TCM), transitional-memory (TTM), and effector-memory (TEM)] from 14 HIV-1-infected individuals including seven elite controllers (E-LTNPs) and seven vir-LTNPs, and from seven uninfected individuals. The HIV-1 cellular DNA and mRNA levels were quantified in parallel in each sorted subset. RESULTS: Host gene transcriptomes followed subset differentiation and viremia except in E LTNPs wherein TCM, the main CD4 cell compartment, showed the highest activity with three specific signatures involving overexpression of T-cell receptor and costimulation signaling pathways, overexpression of the PRDM-1/Blimp-1 transcriptional repressor, and downmodulation of type-I IFN-related genes. Among subsets, the PRDM1/Blimp-1 upregulation was associated with lower levels of both cellular HIV-DNA and HIV mRNA levels. CONCLUSION: This unique Blimp-1 transcriptional repressor signature and the contrast between host and virus transcriptional activities in TCM from elite controllers suggest Blimp-1 might be involved in controlling the HIV reservoirs in the key TCM subset. PMID- 24804862 TI - WHO guidelines for antiretroviral therapy in serodiscordant couples in sub Saharan Africa: how many fit? AB - To evaluate the implication of WHO guidelines for serodiscordant couples, we interviewed HIV-infected adults on their partner's serostatus. We found that 12% with more than 500 CD4+ cells/MUl should be recommended antiretroviral treatment (ART) because their partner was seronegative; 24% could be recommended not to start ART because their partner was seropositive; and 64% could not be given any recommendation regarding ART early initiation because they had either no stable partnership (30%) or were in a stable partnership with a partner whose status they were not aware of (34%). PMID- 24804860 TI - Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cdelta-NF-kappaB signaling. AB - OBJECTIVE: Although HAART effectively suppresses viral replication, it fails to eradicate latent viral reservoirs. The 'shock and kill' strategy involves the activation of HIV from latent reservoirs and targeting them for eradication. Our goal was to develop new approaches for activating HIV from latent reservoirs. DESIGN: We investigated capacity of Ingenol B (IngB), a newly modified derivative of Ingenol ester that was originally isolated from a Brazilian plant in Amazon, for its capacity and mechanisms of HIV reactivation. METHODS: Reactivation of HIV 1 by IngB was evaluated in J-Lat A1 cell culture model of HIV latency as well as in purified primary CD4 T cells from long-term HAART-treated virologically suppressed HIV-infected individuals. The underlining molecular mechanisms of viral reactivation were investigated using flow cytometry, RT-qPCR and chromatin immunoprecipitation. RESULTS: IngB is highly effective in reactivating HIV in J Lat A1 cells with relatively low cellular toxicity. It is also able to reactivate latent HIV in purified CD4 T cells from HAART-treated HIV-positive individuals ex vivo. Our data show that IngB may reactivate HIV expression by both activating protein kinase C (PKC)delta-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathway and directly inducing NF-kappaB protein expression. Importantly, IngB has a synergistic effect with JQ1, a BET bromodomain inhibitor, in latent HIV reactivation. CONCLUSIONS: IngB is a new promising compound to activate latent HIV reservoirs. Our data suggest that formulating novel derivatives from Ingenol esters may be an innovative approach to develop new lead compounds to reactivate latent HIV. PMID- 24804863 TI - Women and NCDs: overcoming the neglect. AB - Two in every three deaths among women are caused by non-communicable diseases (NCDs) - largely heart disease, stroke, cancer, diabetes and chronic respiratory diseases. The global discourse on health, however, largely views women in terms of their reproductive capacity, a persisting myth reflecting gender bias that shifts the focus away from NCDs, violence, and other injuries. Risk factors for NCDs are similar for men and women. Because fewer women actively smoke than men, and drink in less harmful ways, in most parts of the world, the impact of major NCD risk factors is far less in women than in men. In the area of diagnosis and treatment, gender bias can result in women being asked fewer questions, and receiving fewer examinations and fewer diagnostic tests for coronary heart disease and other NCDs compared with men with similar symptoms. In response to a UN meeting in September 2011, member states of WHO have agreed to a global goal to reduce avoidable NCD mortality by 25% by 2025 ('25 by 25'). A set of voluntary targets and indictors have been agreed upon, although none of them are gender specific. Most require changes at the policy level that will ensure that women - and children - will also benefit. As the 2015 deadline for the Millennium Development Goals approaches, women and NCDs should be central to the sustainable human development agenda. PMID- 24804864 TI - Variations in the quality and sustainability of long-term glycaemic control with continuous subcutaneous insulin infusion. AB - AIMS: To investigate the pattern of changes in HbA1c in people with Type 1 diabetes managed by long-term Continuous subcutaneous insulin infusion. METHODS: We studied HbA1c changes using computerized clinic records in 35 adult people with Type 1 diabetes and an elevated HbA1c (>= 64 mmol/mol, 8.0%) on multiple daily insulin injections, who were then switched to continuous subcutaneous insulin infusion for at least 5 years. RESULTS: We identified three subgroups with similar baseline HbA1c but different long-term responses to pump therapy: group A--those with improvement followed by deterioration (57%); group B--those with improvement that was sustained throughout the 5 years (31%); and group C those where HbA1c did not change significantly from baseline (12%). The patients in group C had a higher BMI: 31.0 +/- 5.2 vs. 25.9 +/- 3.3 vs. 25.2 +/- 3.1 kg/m2 (group C vs. group A and group B; P = 0.02). CONCLUSIONS: Improved glycaemic control with continuous subcutaneous insulin infusion was maintained over 5 years by 88% of people with Type 1 diabetes in this study, but there were variations in the long-term efficacy, with some people improving and worsening, others maintaining strict control and a few subcutaneous insulin infusion 'non responders'. PMID- 24804868 TI - Major change in regiospecificity for the exo-1,3-beta-glucanase from Candida albicans following its conversion to a glycosynthase. AB - The exo-1,3-beta-glucanase (Exg) from Candida albicans is involved in cell wall beta-d-glucan metabolism and morphogenesis through its hydrolase and transglycosidase activities. Previous work has shown that both these activities strongly favor beta-1,3-linkages. The E292S Exg variant displayed modest glycosynthase activity using alpha-d-glucopyranosyl fluoride (alpha-GlcF) as the donor and pNP-beta-d-glucopyranoside (pNPGlc) as the acceptor but surprisingly showed a marked preference for synthesizing beta-1,6-linked over beta-1,3- and beta-1,4-linked disaccharide products. With pNPXyl as the acceptor, the preference became beta-1,4 over beta-1,3. The crystal structure of the glycosynthase bound to both of its substrates, alpha-GlcF and pNPGlc, is the first such ternary complex structure to be determined. The results revealed that the donor bound in the -1 subsite, as expected, while the acceptor was oriented in the +1 subsite to facilitate beta-1,6-linkage, thereby supporting the results from solution studies. A second crystal structure containing the major product of glycosynthesis, pNP-gentiobiose, showed that the -1 subsite allows another docking position for the terminal sugar; i.e., one position is set up for catalysis, whereas the other is an intermediate stage prior to the displacement of water from the active site by the incoming sugar hydroxyls. The +1 subsite, an aromatic "clamp", permits several different sugar positions and orientations, including a 180 degrees flip that explains the observed variable regiospecificity. The p-nitrophenyl group on the acceptor most likely influences the unexpectedly observed beta-1,6-specificity through its interaction with F229. These results demonstrate that tailoring the specificity of a particular glycosynthase depends not only on the chemical structure of the acceptor but also on understanding the structural basis of the promiscuity of the native enzyme. PMID- 24804867 TI - Expression of costimulatory molecules B7-H1, B7-H4 and Foxp3+ Tregs in gastric cancer and its clinical significance. AB - OBJECTIVE: Immune escape plays an important role in tumor progression. In the present study, the expression of B7-H1, B7-H4 and Foxp3 involved in immune escape in gastric carcinoma was investigated and the corresponding clinical significance was evaluated. METHODS: Immunohistochemistry was used to detect the expression of B7-H1, B7-H4 and Foxp3 in 100 gastric cancer specimens, and 30 paracarcinoma tissues were used as the control. RESULTS: Both B7-H1 and B7-H4 showed high expression levels in gastric cancer tissues (65.0 and 71.0 %, respectively), and the expressions of B7-H1 and B7-H4 were positively correlated with the depth of tumor invasion, lymph node metastasis and American Joint Committee on Cancer (AJCC) stage (P < 0.05). The number of Foxp3(+) Tregs was much higher in gastric cancer tissues than control tissues, which was positively correlated with lymph node metastasis (P < 0.05). Similarly, a positive correlation between B7-H1 or B7 H4 expression and the number of Foxp3(+) Tregs was observed. The median overall survival rate of patients with high expression of B7-H1, B7-H4 and Foxp3 was significantly poorer than that of patients with low expression of these proteins (P < 0.05). Cox regression multivariate analysis confirmed that lymph node metastasis, AJCC stage, and B7-H1 and Foxp3 overexpression were independent prognostic factors. CONCLUSION: B7-H1, B7-H4 and Foxp3 were overexpressed in gastric cancer tissues. B7-H1 and Foxp3 are negative prognostic factors for patients with gastric cancer. PMID- 24804869 TI - Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1beta transcription factor: chemosensitivity is regulated by checkpoint kinase CHK1. AB - OBJECTIVE: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor 1beta (HNF-1beta) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1beta in regulation of the cell cycle in CCA. METHODS: To clarify the effects of HNF-1beta on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1beta had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1beta (+) cells were arrested in G2 phase because of DNA damage. RESULTS: HNF-1beta (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1beta (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1beta (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. CONCLUSIONS: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1beta. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA. PMID- 24804870 TI - Thermo-triggered drug release from actively targeting polymer micelles. AB - How to deliver the drug to the target area at the right time and at the right concentration is still a challenge in cancer therapy. In this study, we present a facile strategy to control drug release by precisely controlling the thermo sensitivity of the nanocarriers to the variation of environmental temperature. One type of thermoresponsive Pluronic F127-poly(d,l-lactic acid) (F127-PLA, abbreviated as FP) copolymer micelles was developed and decorated with folate (FA) for active targeting. FP100 micelles assembled from FP with PLA segment having polymerization degree of 100 had a low critical solution temperature of 39.2 degrees C close to body temperature. At 37 degrees C, little amount of encapsulated anticancer drug DOX is released from the FP100 micelles, while at a slightly elevated temperature (40 degrees C), the shrinkage of thermoresponsive segments causes a rapid release of DOX and instantly increases the drug concentration locally. The cytocompatibility analysis and cellular uptake efficiency were characterized with the fibroblast cell line NIH 3T3 and human cervix adenocarcinoma cell line HeLa. The results demonstrate that this copolymer has excellent cytocompatibility, and FA-decorated FP100 micelles present much better efficiency of cellular uptake and higher cytotoxicity to folate receptor (FR)-overexpressed HeLa cells. In particular, under hyperthermia (40 degrees C) the cytotoxicity of DOX-loaded FA-FP100 micelles against HeLa cells was significantly more obvious than that upon normothermia (37 degrees C). Therefore, these temperature-responsive micelles have great potential as a drug vehicle for cancer therapy. PMID- 24804871 TI - Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double blind, placebo-controlled, cross-over investigation. AB - Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability. PMID- 24804873 TI - Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: a survey of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - BACKGROUND: Total body irradiation (TBI) is widely used for conditioning before hematopoietic cell transplantation. Its efficacy and toxicity may depend on many methodological aspects. The goal of the current study was to explore current clinical practice in this field. METHODS: A questionnaire was sent to all centers collaborating in the European Group for Blood and Marrow Transplantation and included 19 questions regarding various aspects of TBI. A total of 56 centers from 23 countries responded. RESULTS: All centers differed with regard to at least 1 answer. The total maximum dose of TBI used for myeloablative transplantation ranged from 8 grays (Gy) to 14.4 Gy, whereas the dose per fraction was 1.65 Gy to 8 Gy. A total of 16 dose/fractionation modalities were identified. The dose rate ranged from 2.25 centigrays to 37.5 centigrays per minute. The treatment unit was linear accelerator (LINAC) (91%) or cobalt unit (9%). Beams (photons) used for LINAC were reported to range from 6 to 25 megavolts. The most frequent technique used for irradiation was "patient in 1 field," in which 2 fields and 2 patient positions per fraction are used (64%). In 41% of centers, patients were immobilized during TBI. Approximately 93% of centers used in vivo dosimetry with accepted discrepancies between the planned and measured doses of 1.5% to 10%. In 84% of centers, the lungs were shielded during irradiation. The maximum accepted dose for the lungs was 6 Gy to 14.4 Gy. CONCLUSIONS: TBI is an extremely heterogeneous treatment modality. The findings of the current study should warrant caution in the interpretation of clinical studies involving TBI. Further investigation is needed to evaluate how methodological differences influence outcome. Efforts to standardize the method should be considered. PMID- 24804874 TI - Pretreatment MicroRNA Level and Outcome in Sorafenib-treated Hepatocellular Carcinoma. AB - Sorafenib represents the first effective targeted therapy for advanced stage hepatocellular carcinoma (HCC); however, adequate patient stratification regarding sorafenib-responsiveness is still missing. Our aim was to analyse the association between the pretreatment microRNA profile of HCC and patient survival under sorafenib treatment. Total RNA was extracted from diagnostic fine-needle aspiration biopsy (FNAB) cytological smears of 20 advanced stage HCC patients collected between June 2008 and July 2012. All patients underwent sorafenib administration after FNA. Clinicopathological and survival data were recorded. Fourteen frequently deregulated miRNAs in HCC (miR-17-5p, miR-18a, miR-21, miR 34a, miR-122, miR-195, miR-210, miR-214, miR-221, miR-222, miR-223, miR-224, miR 140, miR-328) were tested by qRT-PCR. NormFinder software was used to select proper miR (mir-140) as a reference. Satisfactory amount of total RNA was obtained from all the considered samples (mean 10.8 +/- 9.3 ug, range 0.2-32.2 ug). Among the analysed miRNAs, high miR-214 expression was associated with smaller tumor size (p=0.019), whereas high miR-17-5p expression correlated with better Eastern Cooperative Oncology Group performance status (p=0.003). The survival analysis revealed that high miR-224 expression was associated with increased progression-free and overall survival (PFS p=0.029; OS p=0.012). Pretreatment microRNA profiling, especially miR-224 expression, might serve as an ancillary tool for the better assessment of expected survival rates for patients under sorafenib treatment. PMID- 24804875 TI - A spin-crossover complex based on a 2,6-bis(pyrazol-1-yl)pyridine (1-bpp) ligand functionalized with a carboxylate group. AB - Combining Fe(ii) with the carboxylate-functionalized 2,6-bis(pyrazol-1 yl)pyridine (bppCOOH) ligand results in the spin-crossover compound [Fe(bppCOOH)2](ClO4)2 which shows an abrupt spin transition with a T1/2 of ca. 380 K and a TLIESST of 60 K due to the presence of a hydrogen-bonded linear network of complexes. PMID- 24804872 TI - The CD133+CD44+ precancerous subpopulation of oval cells is a therapeutic target for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a malignant tumor associated with a generally poor prognosis and a high rate of recurrence. HCC usually develops in the context of chronic liver diseases, and long-lasting premalignant conditions precede cancer development. A promising therapeutic approach is to eliminate precancerous cells, which are considered as the precursors of cancer stem cells, to prevent further malignant transformation. In this study, we identified a subpopulation of precancerous cells in a rat liver carcinogenesis model, which were enriched in CD133(+)CD44(+)CD45(-)HIS49(-) cells that formed part of the hepatic oval cells fraction. Prospective isolation of the precancerous cells using flow cytometry identified stem cell properties such as the ability to expand clonally and differentiate into bi-lineage cell types. Furthermore, an acyclic retinoid, which was recently shown to improve overall survival after HCC resection, directly inhibited the extensive expansion of the isolated precancerous cells in vitro and decreased the emergence of the precancerous cells and their progeny in vivo. Long term follow-up after the acyclic retinoid treatment confirmed reduction in precancerous changes, ultimately resulting in suppression of HCC development. These findings, together with data from recent clinical trials showing marked reduction in intrahepatic recurrence, suggest that acyclic retinoid directly prevents de novo HCC by inhibiting the development of precancerous cells. Given recent advances in diagnostic techniques and the establishment of surveillance programs, the targeting of precancerous cells may have a huge impact on preventative cancer therapies. PMID- 24804878 TI - Depressive symptoms in patients with cancer: does cortisol keep cytokines from singing the blues? AB - Depressive symptoms are common among patients with cancer, and both psychological stress and physiological factors have been implicated in the etiology of depression. Scientific progress in this area is challenged by the changing nature of psychological and physiological processes over the course of cancer diagnosis and treatment. The article by Wu and colleagues in the current issue of Psychosomatic Medicine provides an example of thoughtful consideration of the complex longitudinal relationships between psychological stress, physiology, and depressive symptoms. These findings are put into context by discussing broader challenges in this area, with a focus on the contribution of inflammatory processes caused by cancer and/or its treatment to depressive and related sickness behavior symptoms. We outline several regulatory pathways by which cortisol, inflammatory processes, and depressive symptoms may interact in the context of cancer and highlight implications of these interactions for tumor progression. Additional research is needed to delineate these pathways and advance scientific understanding of the biobehavioral mechanisms underlying depressive symptoms in the context of cancer, with important implications for the development of effective interventions for patients undergoing initial cancer treatment, as well as for long-term survivors. PMID- 24804879 TI - Association of the physiological stress response with depressive symptoms in patients with breast cancer. AB - OBJECTIVE: The literature on the relationship of depressive symptoms and stress hormones after cancer diagnosis has been mixed, with some studies showing a relationship and other studies showing none. Time since diagnosis may explain these contradictory findings. This study examined the relationship of depressive symptoms to stress hormones in patients with breast cancer using 12-month longitudinal data. METHODS: Patients with Stage II or III breast cancer (n = 227) were assessed every 4 months from diagnosis/surgery to 12 months. They completed the Centers for Epidemiological Studies Depression Scale (CES-D) Iowa Short Form and the Perceived Stress Scale and blood samples were obtained to measure stress hormones (i.e., cortisol, adrenocorticotropin hormone, norepinephrine, and epinephrine). RESULTS: Depressive symptoms were negatively related to cortisol levels (beta= -0.023, p = .002) but were positively related to rate of change in cortisol (beta = 0.003, p = .003). Adrenocorticotropin hormone, epinephrine, and norepinephrine did not covary with depressive symptoms (all p values > .05). When the CES-D and Perceived Stress Scale were both used to predict cortisol, only the CES-D was significantly related (beta = -0.025, p = .017). CONCLUSIONS: Depressive symptoms were negatively related to cortisol, but this relationship changed from the time of diagnosis/surgery through 12 months. Cortisol may initially provide a buffering effect against depression during the stress of initial diagnosis and treatment, but this relationship seems to change over time. PMID- 24804880 TI - A comparison of cook-medley hostility subscales and mortality in patients with coronary heart disease: data from the heart and soul study. AB - OBJECTIVE: Hostility is associated with adverse outcomes in patients with coronary heart disease (CHD). However, assessment tools used to evaluate hostility in epidemiological studies vary widely. METHODS: We administered nine subscales of the Cook-Medley Hostility Scale (CMHS) to 656 outpatients with stable CHD between 2005 and 2007. We used Cox proportional hazards models to determine the association between each hostility subscales and all-cause mortality. We also performed an item analysis using logistic regression to determine the association between each CMHS item and all-cause mortality. RESULTS: There were 136 deaths during 1364 person-years of follow-up. Four of nine CMHS subscales were predictive of mortality in age-adjusted analyses, but only one subscale (the seven-item Williams subscale) was predictive of mortality in multivariable analyses. After adjustment for age, sex, education, smoking, history of heart failure, diabetes, and high-density lipoprotein, each standard deviation increase in the Williams subscale was associated with a 20% increased mortality rate (hazard ratio = 1.20, 95% confidence interval = 1.00-1.43, p = .046), and participants with hostility scores in the highest quartile were twice as likely to die as those in the lowest quartile (hazard ratio = 2.00, 95% confidence interval = 1.10-3.65, p = .023). CONCLUSIONS: Among nine variations of the CMHS that we evaluated, a seven-item version of the Williams subscale was the most strongly associated with mortality. Standardizing the assessment of hostility in future epidemiological studies may improve our understanding of the relationship between hostility and mortality in patients with CHD. PMID- 24804881 TI - Heart rate variability characteristics in a large group of active-duty marines and relationship to posttraumatic stress. AB - OBJECTIVE: Heart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression. METHODS: Four battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5 minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively. RESULTS: When adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (beta = 0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033). CONCLUSIONS: This cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure. PMID- 24804883 TI - Association between endothelial dysfunction and depression-like symptoms in chronic mild stress model of depression. AB - OBJECTIVE: Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including "anhedonia"), whereas others are stress resilient. METHODS: After 8 weeks of chronic mild stress, anhedonic rats reduced their sucrose intake by 55% (7%), whereas resilient rats did not. Acetylcholine-induced endothelium-dependent relaxation of norepinephrine preconstricted mesenteric arteries was analyzed in nonstressed, anhedonic, and resilient rat groups. RESULTS: Small resistance arteries from anhedonic rats were less sensitive to acetylcholine than those of the nonstressed and resilient groups (p = .029). Pathways of endothelium-dependent relaxation were altered in arteries from anhedonic rats. Nitric oxide (NO)-dependent relaxation and endothelial NO synthase expression were increased in arteries from anhedonic rats (0.235 [0.039] arbitrary units and 155.7% [8.15%]) compared with the nonstressed (0.135 [0.012] arbitrary units and 100.0% [8.08%]) and resilient (0.152 [0.018] arbitrary units and 108.1% [11.65%]) groups (p < .001 and p = .002, respectively). Inhibition of cyclooxygenase (COX) activity revealed increased COX 2-dependent relaxation in the anhedonic group. In contrast, endothelial NO synthase- and COX-independent relaxation to acetylcholine (endothelium-dependent hyperpolarization-like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca activated K channels. CONCLUSIONS: Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed endothelium-dependent hyperpolarization-like relaxation despite up regulation of the NO and COX-2-dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major depression. PMID- 24804882 TI - Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and older with knee osteoarthritis: ethnic differences. AB - OBJECTIVE: Enhanced pain facilitation is reportedly an important contributor to the clinical pain experiences of individuals with knee osteoarthritis (OA). Ethnic differences in the prevalence and severity of knee OA in addition to associated pain are also well documented. Temporal summation (TS) of pain is a widely applicable quantitative sensory testing method that invokes neural mechanisms related to pain facilitatory processes. This study tested whether TS of pain, an index of pain facilitation, differentially predicts the clinical pain experiences of African Americans and non-Hispanic whites with symptomatic knee OA. METHODS: A total of 225 study participants underwent assessment of TS of mechanical and heat pain stimuli applied to their most symptomatic knee and their ipsilateral hand (mechanical) or forearm (heat). Using telephone-based surveys, participants subsequently reported their average and worst clinical pain severity across four consecutive weeks after the assessment of TS. RESULTS: In predicting future clinical pain, ethnicity interacted with TS of mechanical pain (but not heat pain), such that TS of mechanical pain at the knee significantly predicted greater clinical ratings of average (b = 0.02, p = .016) and worst (b = 0.02, p = .044) clinical pain for non-Hispanic whites but not African Americans (p values > .30). CONCLUSIONS: These results reveal the importance of considering ethnicity when examining pain facilitation and the clinical pain of individuals with symptomatic knee OA. The results of this study are discussed in terms of ethnic differences in the predictors of clinical pain experiences among African Americans and non-Hispanic whites with knee OA. PMID- 24804884 TI - A randomized wait-list controlled trial of feasibility and efficacy of an online mindfulness-based cancer recovery program: the eTherapy for cancer applying mindfulness trial. AB - OBJECTIVE: A treatment-as-usual randomized wait-list controlled trial was conducted to investigate the feasibility and impact of an online synchronous Mindfulness-Based Cancer Recovery (MBCR) group program for underserved distressed cancer survivors. METHODS: Sixty-two men and women exhibiting moderate to high distress within 3 years of completing primary cancer treatment without access to in-person MBCR were randomized to either immediate online MBCR (n = 30) or to wait for the next available program (n = 32). Participants completed questionnaires preintervention and postintervention or wait period online. Program evaluations were completed after MBCR. Feasibility was tracked through monitoring eligibility and participation through the protocol. Intent-to-treat mixed-model analyses for repeated measures were conducted. RESULTS: Feasibility targets for recruitment and retention were achieved, and participants were satisfied and would recommend online MBCR. There were significant improvements and moderate Cohen d effect sizes in the online MBCR group relative to controls after MBCR for total scores of mood disturbance (d = 0.44, p = .049), stress symptoms (d = 0.49, p = .021), spirituality (d = 0.37, p = .040), and mindfully acting with awareness (d = 0.50, p = .026). Main effects of time were observed for posttraumatic growth and remaining mindfulness facets. CONCLUSIONS: Results provide evidence for the feasibility and efficacy of an online adaptation of MBCR for the reduction of mood disturbance and stress symptoms, as well as an increase in spirituality and mindfully acting with awareness compared with a treatment-as usual wait-list. Future study using larger active control RCT designs is warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01476891. PMID- 24804885 TI - Risk of depressive disorder among patients with herpes zoster: a nationwide population-based prospective study. AB - OBJECTIVE: Herpes zoster results from reactivation of the endogenous varicella zoster virus infection. Previous studies have shown that herpes zoster and postherpetic neuralgia were associated with anxiety, depression, and insomnia. However, no prospective study has investigated the association between herpes zoster and the development of depressive disorder. METHODS: Subjects were identified through the Taiwan National Health Insurance Research Database. Patients 18 years or older with a diagnosis of herpes zoster and without a psychiatric history were enrolled in 2000 and compared with age-/sex-matched controls (1:4). These participants were followed up to the end of 2010 for new onset depressive disorder. RESULTS: A total of 1888 patients with herpes zoster were identified and compared with 7552 age-/sex-matched controls in 2000. Those with herpes zoster had a higher incidence of developing major depression (2.2% versus 1.4%, p = .018) and any depressive disorder (4.3% versus 3.2%, p = .020) than did the control group. The follow-up showed that herpes zoster was an independent risk factor for major depression (hazard ratio = 1.49, 95% confidence interval = 1.04-2.13) and any depressive disorder (hazard ratio = 1.32, 95% confidence interval = 1.03-1.70), after adjusting demographic data and comorbid medical diseases. CONCLUSIONS: This is the first study to investigate the temporal association between herpes zoster and depressive disorder. Further studies would be required to clarify the underlying pathophysiology about this association and whether proper treatment of herpes zoster could decrease the long term risk of depressive disorder. PMID- 24804886 TI - The effects of environmental enrichment on depressive and anxiety-relevant behaviors in socially isolated prairie voles. AB - OBJECTIVES: Social isolation is associated with depression, anxiety, and negative health outcomes. Environmental enrichment, including environmental and cognitive stimulation with inanimate objects and opportunities for physical exercise, may be an effective strategy to include in treatment paradigms for affective disorders as a function of social isolation. In a rodent model-the socially monogamous prairie vole-we investigated the hypothesis that depression- and anxiety-related behaviors after social isolation would be prevented and remediated with environmental enrichment. METHODS: Experiment 1 investigated the preventive effects of environmental enrichment on negative affective behaviors when administered concurrently with social isolation. Experiment 2 investigated the remediating effects of enrichment on negative affective behaviors when administered after a period of isolation. Behaviors were measured in three operational tests: open field, forced swim test (FST), and elevated plus maze. RESULTS: In isolated prairie voles, enrichment prevented depression-relevant (immobility in FST, group * housing interaction, p = .049) and anxiety-relevant behaviors (exploration in open field, group * housing interaction, p = .036; exploration in elevated plus maze, group * housing interaction, p = .049). Delayed enrichment also remediated these behaviors in isolated animals (immobility in FST, main effect of housing, p = .001; exploration in open field, main effect of housing, p = .047; exploration in elevated plus maze, main effect of housing, p = .001) and was slightly more effective than physical exercise alone in remediating anxiety-relevant behaviors. CONCLUSIONS: These findings provide insight into the beneficial effects of an enriched environment on depression- and anxiety-relevant behaviors using a translational rodent model of social isolation. PMID- 24804887 TI - Tissue regeneration: from synthetic scaffolds to self-organizing morphogenesis. AB - Regenerative medicine offers therapeutic approaches to treating non-regenerative diseases such as spinal cord injury and heart disease. Owing to the limited donor tissue available, cell-based therapy using cultured cells with supporting scaffolds has been proposed to rebuild damaged tissue. Early attempts at repairing skin and cartilage achieved significant success thanks to the simplicity of the tissue architecture, which later fueled enthusiasm for applying the same strategy to other types of tissue. However, more complex tissue functions require a more extensive vasculature and heterogeneous cell arrangements, which together constitute a significant hurdle in practical applications. Accordingly, recent years an increased interest has been in the use of decellularized matrices that retain the natural microarchitecture as the scaffold. However, although a number of engineering approaches have been suggested, self-organizing behavior such as cell proliferation, migration, and differentiation may still disorganize and frustrate the artificial attempts. This mini-review first provides examples of the early history of tissue engineering using skin and cartilage as examples, and then elaborates on the key technologies used to fabricate synthetic acellular scaffolds and cell/scaffold constructs with more complicated architectures. It also summarizes the progress achieved in the use of decellularized matrices for cell seeding as well as the recent success seen in self-organizing two- and three-dimensional tissue formation with the aid of biomathematical modeling. The review concludes by proposing the future integration of biomathematics, developmental biology, and engineering in concert with the self-organization approach to tissue regeneration. PMID- 24804888 TI - The involvement of DNA methylation and histone modification on the epigenetic regulation of embryonic stem cells and induced pluripotent stem cells. AB - Stem cell research has been developing rapidly in diverse areas such as the fields of genetics and molecular biology over the past decades. Genomic studies on both embryonic stem cells (ESCs) and terminally-differentiated cells illustrated that factors apart from their hereditary information disparity are associated with gene expression patterns of ESCs. Therefore, current research is trying to explore the effects of epigenetic processes in stem cell physiology and phenotypic changes. In-depth analyses of the molecular mechanisms underpinning such epigenetic-mediated functions have also been conducted. These findings suggest the importance of understanding the epigenetic influences in stem cell activities. Accordingly this review will describe the regulatory machineries of stem cells development targeting the two epigenetic processes: (1) DNA methylation and (2) histones modification. In addition, up-to-date findings concerning the functional roles of these processes in stem cells homeostasis will be covered. PMID- 24804889 TI - Interaction of Wharton's jelly derived fetal mesenchymal cells with tumor cells. AB - Currently, pre-clinical and clinical studies have demonstrated the importance of stem cell based therapies for the treatment of human diseases. Fetal Mesenchymal Stem Cells (Fetal MSCs) are potential candidates that can be utilized for the treatment of different types of cancer. Recently, Wharton's jelly (umbilical cord matrix) was proved to be a rich source of MSCs and they can be isolated by non invasive methods such as Ficoll density gradient and antibodies coupled magnetic beads without any ethical issues. Documentation based on various literatures emphasized that fetal MSCs isolated from fetal umbilical cord possess beneficial activity in cancer therapy than adult MSCs. Specific markers of fetal MSCs such as tumor tropism (exhibit tumor microenvironments which act similar to anti inflammation immune cells) and low immunogenicity conferred them as a promising tool in gene therapy based oncology research. Based on these facts, this review summarizes the potential interaction of fetal mesenchymal stem cells with tumor cells and their use in clinical protocols. PMID- 24804890 TI - Significance of biotic factors in mesenchymal stem cell fate in regenerative medicine. AB - Stem and progenitor cell research is a complex and exciting field which promises curative discoveries in numerous areas including cancer, diabetes, and regenerative medicine. Use of biotic factors or growth factors has played an essential role in the development of stem cell research. These biologically active components have been administered into stem cells either to improve or maintain the stem cell proliferation, or to encourage controlled differentiation into more defined cell types. Small molecules such as 6-Bromoindirubin-3'-oxime (BIO), cardiogenol-C, etc can help stem cell research by controlling or influencing the regulatory changes in a controlled manner and to help understand the mechanisms during stem cell differentiation. Extra cellular matrix (ECM) is another significant biotic factor, which mediates cell and tissue behavior by influencing cell-matrix interactions. Thus, in this review we would like to emphasize significance of various growth factors in stem cell research. PMID- 24804896 TI - Loss-of-heterozygosity facilitates passage through Haldane's sieve for Saccharomyces cerevisiae undergoing adaptation. AB - Haldane's sieve posits that the majority of beneficial mutations that contribute to adaptation should be dominant, as these are the mutations most likely to establish and spread when rare. It has been argued, however, that if the dominance of mutations in their current and previous environments are correlated, Haldane's sieve could be eliminated. We constructed heterozygous lines of Saccharomyces cerevisiae containing single adaptive mutations obtained during exposure to the fungicide nystatin. Here we show that no clear dominance relationship exists across environments: mutations exhibited a range of dominance levels in a rich medium, yet were exclusively recessive under nystatin stress. Surprisingly, heterozygous replicates exhibited variable-onset rapid growth when exposed to nystatin. Targeted Sanger sequencing demonstrated that loss-of heterozygosity (LOH) accounted for these growth patterns. Our experiments demonstrate that recessive beneficial mutations can avoid Haldane's sieve in clonal organisms through rapid LOH and thus contribute to rapid evolutionary adaptation. PMID- 24804897 TI - Biomimetic synthesis of (+/-)-merochlorin B. AB - A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a selective demethylation, an ortho-allylation, and an oxidative [3 + 2] cycloaddition mediated by an iodine(III) reagent. PMID- 24804898 TI - Enkephalin knockout male mice are resistant to chronic mild stress. AB - Enhanced stress reactivity or sensitivity to chronic stress increases the susceptibility to mood pathologies such as major depression. The opioid peptide enkephalin is an important modulator of the stress response. Previous studies using preproenkephalin knockout (PENK KO) mice showed that these animals exhibit abnormal stress reactivity and show increased anxiety behavior in acute stress situations. However, the consequence of enkephalin deficiency in the reactivity to chronic stress conditions is not known. In this study, we therefore submitted wild-type (WT) and PENK KO male mice to chronic stress conditions, using the chronic mild stress (CMS) protocol. Subsequently, we studied the CMS effects on the behavioral and hormonal level and also performed gene expression analyses. In WT animals, CMS increased the expression of the enkephalin gene in the paraventricular nucleus (PVN) of the hypothalamus and elevated the corticosterone levels. In addition, WT mice exhibited enhanced anxiety in the zero-maze test and depression-related behaviors in the sucrose preference and forced swim tests. Surprisingly, in PENK KO mice, we did not detect anxiety and depression-related behavioral changes after the CMS procedure, and even measured a decreased hormonal stress response. These results indicate that PENK KO mice are resistant to the CMS effects, suggesting that enkephalin enhances the reactivity to chronic stress. PMID- 24804899 TI - Immune globulins and same-day thrombotic events as recorded in a large health care database during 2008 to 2012. AB - BACKGROUND: Thrombotic events (TEs) are rare and serious adverse events after administration of immune globulin (IG) products. Our study evaluated the occurrence of same-day TEs for different IG products and ascertained potential risk factors. STUDY DESIGN AND METHODS: This retrospective cohort study utilized HealthCore's Integrated Research Database (HIRD) to assess individuals exposed to IGs during 2008 to 2012. IG products were identified using recorded procedure codes and TEs were ascertained using ICD-9-CM diagnosis codes. The unadjusted same-day TE rates (per 1000 persons exposed) were estimated overall and by IG products, age, and sex. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for same-day TEs by IG products. RESULTS: Of 14,944 individuals exposed to IG products, 233 (15.6 per 1000 persons) had TE diagnosis code(s) recorded on the same-day as the IG exposure. Compared to Gammagard Liquid, Gammaplex (OR, 20.96; 95% CI, 2.45 179.33) and Vivaglobin (OR, 2.74; 95% CI, 1.19-6.32) users had a significantly increased same-day TE risk. Elevated, but nonsignificant TE risks were identified for Octagam, Gamunex, Privigen, and Lyophilized IG(s). An increased TE risk was also found with older age (>=45 years), prior TEs, and other health conditions. CONCLUSION: Our claims-based cohort study suggests a potentially elevated TE risk with different IG products and shows importance of recipient factors such as older age, previous TE, hypercoagulable state(s), and other health conditions. The results of this study suggest the need for continuous evaluation of procoagulant activity and manufacturing processes for IG products to further assure their safety. PMID- 24804900 TI - pH-sensitive C-ON bond homolysis of alkoxyamines of imidazoline series: a theoretical study. AB - The pH-dependent kinetics of C-ON bond homolysis reactions of the four alkoxyamines (viz., the derivatives of 2-(4-(dimethylamino)-2-ethyl-5,5-dimethyl 2-(pyridin-4-yl)-2,5-dihydro-1H-imidazol-1-oxyl and 2-(2-carboxyethyl)-5,5 diethyl-2,4-dimethyl-2,5-dihydro-1H-imidazol-1-oxyl) in water solution have been scrutinized using DFT calculations (M06-2X/6-311++G(2df,p) level of theory with the PCM model). On the basis of computations, the experimental results obtained before (J. Org. Chem. 2011, 76, 5558) have been rationalized. The concentration dependence of all possible protonated forms of the four alkoxyamines was obtained from pH measurements. The contributions of particular protonated forms into the overall rate constants of thermolysis were estimated using the DFT calculated Gibbs free energies Delta(r)0G of C-ON bond homolysis reactions. The computations revealed that the observed rate constants of thermolysis of the two species at several pH values are dominated by decomposition reactions of two or even three protonated forms. The observed trends in reactivity of the alkoxyamines were mainly attributed to destabilization of the radical products of C-ON bond scission reactions. A linear correlation between the sum of radical stabilization energies (RSEs) of products of thermolysis and the calculated Gibbs free energies of reactions was found for various protonated forms of the species studied. Apart from this, the linear correlation exists between the relative RSE and nitrogen hyperfine constants aN of various protonated forms of the nitroxide radical products. PMID- 24804901 TI - The early history of Stanford Immunology. AB - From its 1960 beginnings in a pair of windowless Genetics Department laboratories under the Stanford Medical School Dean's Office to its current broad-based program, which joins faculty members from departments across the Medical School, the Stanford Immunology Program has played a central role in shaping both basic and clinical immunology thinking. In this article, we tell the story of the beginnings of this odyssey in a reminiscence-based format that brings the flavor of the time in the words of people who lived and built the history. PMID- 24804902 TI - Exercise training for chronic heart failure (ExTraMATCH II): protocol for an individual participant data meta-analysis. AB - BACKGROUND: Patients with chronic heart failure (HF) experience a marked reduction in their exercise capacity, health-related quality of life, and life expectancy. Despite substantive evidence supporting exercise training in HF, uncertainties remain in the interpretation and understanding of this evidence base. Clinicians and healthcare providers seek definitive estimates of impact on mortality, hospitalisation and health-related quality of life, and which HF patient subgroups are likely to most benefit. The original Exercise Training Meta Analysis for Chronic Heart Failure (ExTraMATCH) individual participant data (IPD) meta-analysis conducted in 2004 will be updated by the current collaboration (ExTraMATCH II), to investigate the effects of exercise training in HF. METHODS: Randomised controlled trials have been identified from the updated 2014 Cochrane systematic review and the original ExTraMATCH IPD meta-analysis with exercise training of 3 weeks' duration or more compared with a non-exercise control and a minimum follow-up of 6 months. Particular outcomes of interest are mortality, hospitalisation and health-related quality of life plus key baseline patient demographic and clinical data. Original IPD will be requested from the authors of all eligible trials; we will check original data and compile a master dataset. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modelled simultaneously whilst accounting for the clustering of participants with studies. DISCUSSION: The information from ExTraMATCH II will help inform future national and international clinical and policy decision-making on the use of exercise-based interventions in HF and improve the quality, design and reporting of future trials in this field. PMID- 24804903 TI - Takotsubo syndrome and sudden death: beyond angiography. PMID- 24804904 TI - Electrocardiographic criteria and outcome in patients with arrhythmogenic right ventricular cardiomyopathy. Re: Electrocardiographic predictors of electroanatomic scar size in arrhythmogenic right ventricular cardiomyopathy: implications for arrhythmic risk stratification. PMID- 24804905 TI - Rheumatic heart disease in modern urban America: a cohort study of immigrant and indigenous patients in Chicago. PMID- 24804906 TI - Prediction of heart rate variability on cardiac sudden death in heart failure patients: a systematic review. PMID- 24804909 TI - Factors influencing decision-making role preferences: A qualitative study of Malaysian patients with type 2 diabetes during insulin initiation. AB - Patient decision-making role preference (DMRP) is a patient's preferred degree of control when making medical decisions. This descriptive qualitative study aimed to explore Malaysian patients' views on their DMRP. Between January 2011 and March 2012, 22 individual face-to-face in-depth interviews were conducted with patients with type 2 diabetes who were deciding about insulin initiation. The interviews were audio-recorded and analysed using a thematic approach. The age range of participants was 28-67 years old with 11 men. Ten patients preferred to make the decision themselves, six patients indicated that the clinician should make the decision and only one patient expressed a preference for a collaborative role. The following factors influenced DMRP: trust in clinicians, responsibility for diabetes care, level of knowledge and awareness, involvement of family and personal characteristics. In conclusion, the concept of shared decision-making is still alien, and a more participative communication style might help to facilitate patients' expression of DMRP. PMID- 24804907 TI - Cilium adhesin P216 (MHJ_0493) is a target of ectodomain shedding and aminopeptidase activity on the surface of Mycoplasma hyopneumoniae. AB - MHJ_0493 (P216) is a highly expressed cilium adhesin in Mycoplasma hyopneumoniae. P216 undergoes cleavage at position 1074 in the S/T-X-F?-X-D/E-like motif (1072)T N-F?Q-E(1076) generating N-terminal and C-terminal fragments of 120 kDa (P120) and 85 kDa (P85) on the surface of M. hyopneumoniae. Here we show that several S/T-X-F?X-D/E-like motifs exist in P216 but only (1072)T-N-F?Q-E(1076) and (1344)I-T-F?A-D-Y(1349) were determined to be bona fide processing sites by identifying semitryptic peptides consistent with cleavage at the phenylalanine residue. The location of S/T-X-F?-X-D/E-like motifs within or abutting regions of protein disorder greater than 40 consecutive amino acids is consistent with our hypothesis that site access influences the cleavage efficiency. Approximately 20 cleavage fragments of P216 were identified on the surface of M. hyopneumoniae by LC-MS/MS analysis of biotinylated proteins and 2D SDS-PAGE. LC-MS/MS analysis of semitryptic peptides within P216 identified novel cleavage sites. Moreover, detection of a series of overlapping semitryptic peptides that differed by the loss a single amino acid at their N-terminus is consistent with aminopeptidase activity on the surface of M. hyopneumoniae. P120 and P85 and their cleavage fragments bind heparin and cell-surface proteins derived from porcine epithelial like cells, indicating that P216 cleavage fragments retain the ability to bind glycosaminoglycans. PMID- 24804910 TI - An investigation into the use of multi-source feedback (MSF) as a work-based assessment tool. AB - INTRODUCTION: This study compared Specialist Trainees' (STs) hand-selected multi source feedback (MSF) scores with those made by their clinical supervisors and explored perceptions of both those being assessed and those assessing. METHODS: Participating STs were asked to hand a mini-PAT questionnaire to a clinical colleague of their choice and also to their Clinical Supervisor. Statistical analysis was carried out on submitted paired assessments to determine any differences in responses between clinical supervisors and hand-chosen assessors. Semi-structured interviews were held with seven nurses, seven Consultants and six postgraduate doctors. RESULTS: Forty pairs of mini-PAT questionnaires were analysed. Hand-chosen assessors' ratings were significantly higher than those for clinical supervisors with respect to: "good clinical care" (p < 0.01), "good medical practice" (p < 0.05), "teaching and training" (p < 0.01), "relationship with patients" (p < 0.05) as well as for overall impression of the trainee (p < 0.05). Five themes were identified from interviews: validity of selecting assessors; anonymity of assessors; usefulness of feedback; the value of multi professional assessors; and grading. DISCUSSIONS: There is a systematic difference in the assessment scores for trainees in MSF between clinical supervisors and hand-chosen assessors, the former scoring trainees more harshly. Grading was open to interpretation. This raised questions, especially from nurse interviewees regarding appropriate benchmarking. PMID- 24804911 TI - Experiences with EPAs, potential benefits and pitfalls. AB - Reforms in postgraduate medical education (PGME) exposed a gap between educational theory and clinical practice. Entrustable Professional Activities (EPAs) were introduced to assist clinicians in bridging this gap and to create better consonance between the intended and the enacted curriculum. In this viewpoint paper, we discuss the potential and the pitfalls of using EPAs in PGME. EPAs promise an effective way of teaching abstract competencies in a curriculum based on real-life professional activities that are suitable for clinical assessment. Summative judgement is used to entrust a resident step by step in a certain EPA, resulting in an increase of independent practice. However, we argue that the success of EPAs depends on (1) a balance: brief focussed descriptions against the requirements for detail and (2) a precondition: a mature and flexible workplace for learning. PMID- 24804912 TI - Tomorrow's Doctors and diversity issues in medical education. PMID- 24804913 TI - Improving ward round skills. AB - BACKGROUND: Ward rounds represent an important task in clinical settings. Despite their importance, students show substantial deficits in ward round competencies (e.g. physical examination, drug prescription, documentation). Previously reported teaching methods such as ward round training with standardized patients or educational wards, however, are time-consuming and expensive. AIMS: To assess the effects of a structured on-ward supervision program for final-year students with specially trained supervising doctors focusing on ward round competencies. METHOD: A total of 36 medical students were randomly assigned to an intervention group (IG) and a control group (CG). During an eight-week-long training course, the intervention group (IG; n = 18) received structured ward round training while the control group (CG; n = 18) received on-ward training regarding how to take patient histories and perform physical examinations. Ward round competencies were assessed using simulated ward round scenarios with objective checklist ratings and standardized patient ratings. RESULTS: The IG achieved significantly more predefined learning goals compared to the CG. Standardized patient ratings did not differ significantly between groups. CONCLUSIONS: RESULTS provide evidence that the presented program is a feasible and efficient tool for teaching ward round skills at the bedside. Further research should focus on cost effectiveness compared to alternative models. PMID- 24804914 TI - Medical educators working abroad: a pilot study of educators' experiences in the Middle East. AB - Medical education is now a global enterprise, with many medical educators working internationally, either for short or longer periods or even permanently. In parallel, many medical schools are now involved in collaborations and partnerships with schools in other countries. With this in mind, we set out to explore what motivates, supports and inhibits medical educators who wish to or might work outside their "home country". This article reports on the pilot stage (in specific organizational contexts in Middle East) of a longitudinal project aimed at canvassing medical educators on a broader global scale, using reflective accounts and a questionnaire survey. The findings from this pilot study raise interesting issues about the lived experience of medical educators who have chosen to work in a different culture from their own. Respondents identify many advantages around skills, personal and professional development. Three main issues emerged in terms of educators' experiences: the academic environment, medical practice in a different cultural context and personal matters. Adapting to the local culture, gender segregation and the impact on learning and teaching was an overarching factor. We introduce an explanatory framework to explain the development of international educator identity, a cyclical process in which, through experiences and reflection, individual world views and perspectives are continually modified and developed. This pilot study tested the methodologies and developed a new conceptual model that will be used in a wider study across different cultures. PMID- 24804915 TI - A new level of evidence: systematic literature reviews (SLRs) with meta-analyses of directly-accessed data ("MA of DAD"). PMID- 24804916 TI - The multiple mini-interview for selecting medical residents: first experience in the Middle East region. AB - INTRODUCTION: Numerous studies have shown that multiple mini-interviews (MMI) provides a standard, fair, and more reliable method for assessing applicants. This article presents the first MMI experience for selection of medical residents in the Middle East culture and an Arab country. METHODS: In 2012, we started using the MMI in interviewing applicants to the residency program of Dubai Health Authority. This interview process consisted of eight, eight-minute structured interview scenarios. Applicants rotated through the stations, each with its own interviewer and scenario. They read the scenario and were requested to discuss the issues with the interviewers. Sociodemographic and station assessment data provided for each applicant were analyzed to determine whether the MMI was a reliable assessment of the non-clinical attributes in the present setting of an Arab country. RESULTS: One hundred and eighty-seven candidates from 27 different countries were interviewed for Dubai Residency Training Program using MMI. They were graduates of 5 medical universities within United Arab Emirates (UAE) and 60 different universities outside UAE. With this applicant's pool, a MMI with eight stations, produced absolute and relative reliability of 0.8 and 0.81, respectively. The person * station interaction contributed 63% of the variance components, the person contributed 34% of the variance components, and the station contributed 2% of the variance components. DISCUSSION: The MMI has been used in numerous universities in English speaking countries. The MMI evaluates non-clinical attributes and this study provides further evidence for its reliability but in a different country and culture. The MMI offers a fair and more reliable assessment of applicants to medical residency programs. The present data show that this assessment technique applied in a non-western country and Arab culture still produced reliable results. PMID- 24804917 TI - Assessing levels of support for residents following adverse outcomes: a national survey of anesthesia residency programs in the United States. AB - AIM: The impact of physician burnout is becoming apparent in the medical community, especially among anesthesiologists and young physicians. Anesthesia residents will experience emotionally charged adverse events during their training. The objective was to determine the prevalence, efficacy and utilization of support structures in place for residents following adverse events in order to develop a best-practices model of resident support. METHODS: We sent an anonymous internet-based survey to program directors (PDs) at all American College of Graduate Medical Education (ACGME)-approved Anesthesia Residency programs, with an optional secondary survey of residents. RESULTS: There was a 53% response rate among PDs with most reporting resource availability. The strongest support programs were the anesthesia support programs, morbidity and mortality (M&M) conference, and "individual meetings with department leadership." These results were mirrored in the responses of residents at the 32 programs who opted to participate in the secondary survey. Both also cited M&M conference as being highly utilized, but not efficacious. The strongest support programs had a low prevalence. CONCLUSIONS: These data suggest that a best-practices model of resident support entails establishing a department-based support program, facilitating comfortable meetings with departmental leadership and optimizing M&M conference. PMID- 24804918 TI - Impact of a formal mentoring program on academic promotion of Department of Medicine faculty: a comparative study. AB - PURPOSE: To evaluate the impact of a formal mentoring program on time to academic promotion and differences in gender-based outcomes. METHODS: Comparisons of time to promotion (i) before and after implementation of a formal mentoring program and (ii) between mentored and non-mentored faculty matched for covariates. Using paired-samples t-testing and mixed repeated measures ANCOVA, we explored the effect of mentor assignment and influence of gender on time to promotion. RESULTS: Promotional data from 1988 to 2010 for 382 faculty members appointed before 2003 were compared with 229 faculty members appointed in 2003 or later. Faculty appointed in 2003 or later were promoted 1.2 years (mean) sooner versus those appointed before 2003 (3.7 [SD = 1.7] vs. 2.5 [SD = 2], p < 0.0001). Regardless of year of appointment, mentor assignment appears to be significantly associated with a reduction in time to promotion versus non-mentored (3.4 [SD = 2.4] vs. 4.4 [SD = 2.6], p = 0.011). Gender effects were statistically insignificant. Post hoc analyses of time to promotion suggested that observed differences are not attributable to temporal effects, but rather assignment to a mentor. CONCLUSIONS: Mentoring was a powerful predictor of promotion, regardless of the year of appointment and likely benefited both genders equally. University resource allocation in support of mentoring appears to accelerate faculty advancement. PMID- 24804919 TI - Bridging the continuum: Analysis of the alignment of undergraduate and postgraduate accreditation standards. AB - Several influential national/international bodies including The Bologna Accord, The Carnegie Foundation and The Future of Medical Education in Canada (FMEC) have called for increased coordination across the medical education continuum. FMEC recognizes accreditation as a "powerful lever" and encourages the alignment of undergraduate and postgraduate standards. The Carnegie Foundation includes a similar call for the creation of a more coherent accreditation system. As a first step, using the Canadian context, we present a methodological approach that assesses the example of how well LCME/CACMS undergraduate accreditation standards align with the Royal College of Physician and Surgeons of Canada (RCPSC) postgraduate training standards. We analyzed how closely the 132 LCME/CACMS Medical School accreditation standards aligned with the 155 post-graduate standards from the RCPSC accreditation General Standards (A and B). This comparative evaluation demonstrates that the standards do not align closely. Gaps, redundancies and key differences are highlighted. These results are the first step in understanding how accreditation needs to be adapted and re-aligned across the education continuum to provide consistent and coordinated training and these methods could easily be applied to other contexts and jurisdictions. PMID- 24804920 TI - Views of doctors of varying disciplines on HPAT-Ireland as a selection tool for medicine. AB - BACKGROUND: Selection tools for medicine must achieve political validity and enjoy stakeholder acceptability. This qualitative study aimed to establish the perspectives of doctors, from various clinical specialities, on HPAT-Ireland, a new selection tool for undergraduate medical students. METHODS: Fifteen doctors participated over three iterative cycles of recruitment, interviewing and analysis. Prior to interview, participants sat a practice HPAT-Ireland test. HPAT Ireland has three sections: (1) Logical reasoning/problem solving; (2) Interpersonal understanding and (3): Non-verbal reasoning. SUMMARY OF RESULTS: Three themes emerged: job relatedness; utility of HPAT-Ireland and diversity. Sections 1 and 2 were considered very job related however Section 3 was widely criticised for lacking clinical relevance. Doctors did not think that the test would reliably predict future performance. However, one-third felt it was acceptable as a selection tool in conjunction with academic record. Those who found it unacceptable were influenced by its perceived narrow focus, limited job relatedness, potential for socioeconomic bias, impact on gender and potential for negative influence on student diversity. CONCLUSIONS: A selection tool that does not enjoy the confidence of the medical profession is unlikely to achieve political validity and may ultimately fail, regardless of other objective measures of its effectiveness such as predictive validity. PMID- 24804921 TI - Personal librarian curriculum. PMID- 24804922 TI - Helminth parasites of the European starling (Sturnus vulgaris) (Aves, Sturnidae), an invasive bird in Argentina. AB - The aim of this work is to contribute to the knowledge of gastrointestinal parasites of the European starling Sturnus vulgaris, an invasive bird from Argentina. Seventy-six birds were collected during the spring of 2007 and were examined for helminths. Six parasite species were found: one trematoda of the Echinostoma revolutum "group," four nematodes (Synhimantus nasuta, Microtetrameres sp., Pterothominx exilis, and Ornithocapillaria ovopunctata), and one acanthocephalan (Plagiorhynchus cylindraceus). All species found have been recorded in Eurasia and/or North America previously, although present reports enlarge their geographical distribution. As expected in an invasive host, the parasite community shows much lower species richness (n = 6) than those observed in their native area (79 and 35 in the Eurasia and North America, respectively). PMID- 24804923 TI - Role of wildlife in the epidemiology of Leishmania infantum infection in Europe. AB - Although dogs are considered the main reservoir of Leishmania infantum infection in endemic areas in Europe, the existence of other wild vertebrate reservoirs has been proposed as a possible cause of the lack of success of control measures. Evidence of L. infantum infection in European wildlife has been reported in carnivores, lagomorphs, and rodents. The red fox (Vulpes vulpes) received most attention, probably due to its taxonomic relationship with the dog and because it is the most abundant wild carnivore in Europe. Foxes and other wild carnivores often displayed high prevalences of infection but their infectiveness to the sandfly vector has never been demonstrated. However, xenodiagnosis demonstrated that black rats (Rattus rattus), are infectious to sandflies. This, together with their relative abundance, high rates of infection, and the fact that infected rats have been found on a Mediterranean island where dogs are not present, makes rats good candidate to be reservoirs of L. infantum. Recently, the Iberian hare (Lepus granatensis) has been recognized as the origin of a leishmaniosis outbreak in humans in Spain and xenodiagnosis showed that this species is also able to infect sandflies. In contrast, a recent survey in cave bats failed to detect infected individuals. In the future, the comparison of parasite isolates from humans, dogs and wildlife, xenodiagnosis studies in wild carnivores, and the study of other vertebrate taxonomic groups will help determine the current role of European wildlife in the epidemiology of leishmaniosis. PMID- 24804926 TI - Monitoring arsenic contamination in agricultural soils with reflectance spectroscopy of rice plants. AB - The objective of this study was to explore the feasibility and to investigate the mechanism for rapidly monitoring arsenic (As) contamination in agricultural soils with the reflectance spectra of rice plants. Several data pretreatment methods were applied to improve the prediction accuracy. The prediction of soil As contents was achieved by partial least-squares regression (PLSR) using laboratory and field spectra of rice plants, as well as linear regression employing normalized difference spectral index (NDSI) calculated from fild spectra. For laboratory spectra, the optimal PLSR model for predicting soil As contents was achieved using Savitzky-Golay smoothing (SG), first derivative and mean center (MC) (root-mean-square error of prediction (RMSEP)=14.7 mg kg(-1); r=0.64; residual predictive deviation (RPD)=1.31). For field spectra, the optimal PLSR model was also achieved using SG, first derivative and MC (RMSEP=13.7 mg kg(-1); r=0.71; RPD=1.43). In addition, the NDSI with 812 and 782 nm obtained a prediction accuracy with r=0.68, RMSEP=13.7 mg kg(-1), and RPD=1.36. These results indicated that it was feasible to monitor the As contamination in agricultural soils using the reflectance spectra of rice plants. The prediction mechanism might be the relationship between the As contents in soils and the chlorophyll-a/-b contents and cell structure in leaves or canopies of rice plants. PMID- 24804927 TI - Cylinder stress in nanostructures: effect on domains in nanowires, nanotubes, and nano-disks. AB - Since the work of Landau-Lifshitz in 1935, Kittel in 1946 and by Roytburd and Arlt more recently, we have understood that the width w of magnetic or ferroelectric or elastic domains and twins is proportional to the square root of the characteristic length d, which is thickness in a thin film or diameter in a small grain. This square root relationship is derived by balancing stress: larger area domains have larger stress, which can be minimized by having adjacent domains of reversed orientation, but at the cost of wall energy. Three dimensional objects undergo three kinds of stress: axial, radial, and azimuthal ('hoop stress'), the last of which has previously been ignored. Unlike axial stress, it is proportional to d, not d(2), and we show that it leads to w linear in d. PMID- 24804925 TI - Meta-analysis reveals the association of common variants in the uncoupling protein (UCP) 1-3 genes with body mass index variability. AB - BACKGROUND: The relationship between uncoupling protein (UCP) 1-3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes. METHODS: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models. RESULTS: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD -0.18, 95% CI -0.35, -0.01). There was no significant association of the UCP1 3826A/G polymorphism with BMI mean differences. CONCLUSIONS: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences. PMID- 24804929 TI - Teriparatide therapy for denosumab-induced osteonecrosis of the jaw in a male osteoporotic patient. AB - We report the first case of teriparatide adjuvant role in the management of a denosumab-induced osteonecrosis of the jaw in a male subject with idiopathic osteoporosis. Clinical benefits and CT healing were obtained within 2 months of teriparatide initiation and denosumab withdrawal. Increase in bone turnover previously described, when denosumab treatment is removed, might have a synergistic effect to the stimulating effect of teriparatide on bone remodeling to promptly heal osteonecrosis of the jaw. PMID- 24804928 TI - SCF increases cardiac stem cell migration through PI3K/AKT and MMP-2/-9 signaling. AB - The transplantation of cardiac stem cells (CSCs) is thought to be responsible for improving the performance of injured heart induced by myocardial infarction (MI). However, the mechanisms involved in the migration of activated CSCs post-MI remain to be clarified. In this study, CSCs were isolated from rat hearts and a cellular migration assay was performed using a 24-well Transwell system. Stem cell factor (SCF) induced CSC migration in a concentration-dependent manner, which could be blocked with an SCF antibody as well as a PI3K/AKT inhibitor, LY294002. Moreover, SCF induced the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 in a concentration- and time-dependent manner, as measured by quantitative RT-PCR, western blot analysis and gelatin zymography. Results of western blot analysis revealed phosphorylated AKT was markedly increased in SCF-treated CSCs and that inhibition of SCF/c-Kit signaling or phospho-AKT activity significantly attenuated the SCF-induced expression of MMP-2 and MMP-9. Thus, our results showed that SCF partially mediated CSC migration via the activation of PI3K/AKT/MMP-2/-9 signaling. PMID- 24804930 TI - Turn-off-on chemiluminescence determination of cyanide. AB - A flow injection chemiluminescence (FI-CL) method was developed for the determination of cyanide (CN(-) ) based on the recovered CL signal by Cu(2+) inhibiting a glutathione (GSH)-capped CdTe quantum dot (QD) and hydrogen peroxide system. In an alkaline medium, strong CL signals were observed from the reaction of CdTe QDs and H2O2 , and addition of Cu(2+) could cause significant CL inhibition of the CdTe QDs-H2O2 system. In the presence of CN(-) , Cu(2+) can be removed from the surface of CdTe QDs via the formation of particularly stable [Cu(CN)n ]((n-1)-) species, and the CL signal of the CdTe QDs-H2O2 system was efficiently recovered. Thus, the CL signals of CdTe QDs-H2O2 system were turned off and turned on by the addition of Cu(2+) and CN(-) , respectively. Further, the results showed that among the tested ions, only CN(-) could recover the CL signal, which suggested that the CdTe QDs-H2O2 -Cu(2+) CL system had highly selectivity for CN(-) . Under optimum conditions, the CL intensity and the concentration of CN(-) show a good linear relationship in the range 0.0-650.0 ng/mL (R(2) = 0.9996). The limit of detection for CN(-) was 6.0 ng/mL (3sigma). This method has been applied to detect CN(-) in river water and industrial wastewater with satisfactory results. PMID- 24804931 TI - In vitro evaluation of antimicrobial activity of the freshwater sponge Ochridaspongia rotunda (Arndt, 1937). AB - The antimicrobial activity of five crude extracts (aqueous, methanol, ethyl acetate, acetone and methylene chloride) of the freshwater sponge Ochridaspongia rotunda (Arndt, 1937) was evaluated in vitro by using microdilution method against eight bacterial and eight fungal strains for the first time. The extracts were proven to be active in varying degrees against all the bacteria and fungi tested. O. rotunda methanol extract exhibited the highest antibacterial activity (minimum inhibitory concentration (MIC) 7.5-15.0 MUg/mL and minimum bactericidal concentration 15-30 MUg/mL), while its acetone extract exhibited the most promising antifungal activity (MIC 7.5-45.0 MUg/mL and minimum fungicidal concentration 15-60 MUg/mL). The extracts were more effective against the bacteria and fungi screened compared with the positive controls (streptomycin and ampicillin for bacteria and bifonazole and ketoconazole for fungi, respectively). According to the experimental data obtained, this deepwater sponge species may be considered as a gold mine of new antimicrobial substances with significant and broad-range activity. PMID- 24804932 TI - Glycosylinositol phosphorylceramides from Rosa cell cultures are boron-bridged in the plasma membrane and form complexes with rhamnogalacturonan II. AB - Boron (B) is essential for plant cell-wall structure and membrane functions. Compared with its role in cross-linking the pectic domain rhamnogalacturonan II (RG-II), little information is known about the biological role of B in membranes. Here, we investigated the involvement of glycosylinositol phosphorylceramides (GIPCs), major components of lipid rafts, in the membrane requirement for B. Using thin-layer chromatography and mass spectrometry, we first characterized GIPCs from Rosa cell culture. The major GIPC has one hexose residue, one hexuronic acid residue, inositol phosphate, and a ceramide moiety with a C18 trihydroxylated mono-unsaturated long-chain base and a C24 monohydroxylated saturated fatty acid. Disrupting B bridging (by B starvation in vivo or by treatment with cold dilute HCl or with excess borate in vitro) enhanced the GIPCs' extractability. As RG-II is the main B-binding site in plants, we investigated whether it could form a B-centred complex with GIPCs. Using high voltage paper electrophoresis, we showed that addition of GIPCs decreased the electrophoretic mobility of radiolabelled RG-II, suggesting formation of a GIPC-B RG-II complex. Last, using polyacrylamide gel electrophoresis, we showed that added GIPCs facilitate RG-II dimerization in vitro. We conclude that B plays a structural role in the plasma membrane. The disruption of membrane components by high borate may account for the phytotoxicity of excess B. Moreover, the in-vitro formation of a GIPC-B-RG-II complex gives the first molecular explanation of the wall-membrane attachment sites observed in vivo. Finally, our results suggest a role for GIPCs in the RG-II dimerization process. PMID- 24804934 TI - Criminal justice becomes front line for mental health care. PMID- 24804933 TI - Co-expression of foreign proteins tethered to HIV-1 envelope glycoprotein on the cell surface by introducing an intervening second membrane-spanning domain. AB - The envelope glycoprotein (Env) of human immunodeficiency virus type I (HIV-1) mediates membrane fusion. To analyze the mechanism of HIV-1 Env-mediated membrane fusion, it is desirable to determine the expression level of Env on the cell surface. However, the quantification of Env by immunological staining is often hampered by the diversity of HIV-1 Env and limited availability of universal antibodies that recognize different Envs with equal efficiency. To overcome this problem, here we linked a tag protein called HaloTag at the C-terminus of HIV-1 Env. To relocate HaloTag to the cell surface, we introduced a second membrane spanning domain (MSD) between Env and HaloTag. The MSD of transmembrane protease serine 11D, a type II transmembrane protein, successfully relocated HaloTag to the cell surface. The surface level of Env can be estimated indirectly by staining HaloTag with a specific membrane-impermeable fluorescent ligand. This tagging did not compromise the fusogenicity of Env drastically. Furthermore, fusogenicity of Env was preserved even after the labeling with the ligands. We have also found that an additional foreign peptide or protein such as C34 or neutralizing single-chain variable fragment (scFv) can be linked to the C terminus of the HaloTag protein. Using these constructs, we were able to determine the required length of C34 and critical residues of neutralizing scFv for blocking membrane fusion, respectively. PMID- 24804935 TI - Serum neutrophil gelatinase associated lipocalin (NGAL) and cystatin C as early predictors of contrast-induced acute kidney injury in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Contrast-induced acute kidney injury (AKI) is diagnosed by estimating serum creatinine at 48-72h after diagnostic or interventional coronary angiography. It is too late for an early intervention. Neutrophil gelatinase associated lipocalin (NGAL) and cystatin C are novel markers of AKI. We determined the optimum cut-off level of NGAL and cystatin C in early diagnosis and prediction of AKI in patients undergoing coronary angiography followed by angioplasty. METHODS: In a nested case control study, serum NGAL, cystatin C by ELISA and serum creatinine by Jaffe's kinetic method were estimated at 0, 4, 24 and 48h of coronary angiography followed by angioplasty in 30 cases who developed contrast-induced AKI and 30 subjects who did not develop AKI. eGFR was estimated for both cases and controls by the MDRD equation. ROC was used to determine the optimum cut-off. RESULTS: Serum NGAL increased sharply at 4h after the procedure and then gradually declined to near normal level at 48h in AKI cases. The rise in cystatin C peaked at 24h and then declined but remained high till 48h. In controls, they remained static. The optimum cut-off of serum NGAL and cystatin C was 155.2ng/ml and 0.517mg/l respectively at 4h and 89.5ng/ml and 0.99mg/l respectively at 24h of angiography. Odds ratio for hypertensives to develop AKI was 3.57 (CI: 1.2-11.1, p=0.03). CONCLUSION: Serum NGAL and cystatin C may act as early markers of contrast-induced AKI in patients undergoing percutaneous coronary intervention. Patients with hypertension are susceptible to develop contrast-induced AKI. PMID- 24804936 TI - Preanalytical factors of importance for measurement of Chromogranin A. AB - BACKGROUND: Studies indicate that fasting and diurnal variation can influence serum Chromogranin A (CgA) concentrations and furthermore, stability of the CgA molecule has been questioned. We investigated the impact of pre-analytical conditions on a CgA assay. METHODS: Serum CgA concentrations were measured in blood samples collected from ten healthy subjects at three time points during three days with and without fasting. Samples were kept at 4 degrees C and re measured after 24 and 48 h in order to test the stability of the measured epitopes. For establishment of a reference interval, serum samples were collected from 120 healthy individuals. RESULTS: Serum CgA concentrations did not vary between fasting and non-fasting individuals (p=0.74), nor between gender (p=0.66). The analytical imprecision was 4.3%, the within-subject variability was 11.9%, while the between-subject variability was as high as 50.2%. Serum CgA concentrations measured during the day did however not differ (p=0.30). Of importance, re-analysis at 4 degrees C showed significant decay in the CgA concentrations after 24 h (mean decrease 15.6%) and 48 h (mean decrease 44%). The median CgA concentration in 120 healthy subjects was 41.2 ng/mL with a reference interval of 30.3-94.4 ng/mL (2.5-97.5 percentile). CONCLUSIONS: Fasting does not influence CgA concentrations significantly, while sample stability is a major issue with the assay tested. The biological variation of CgA was defined and a reference interval was established. PMID- 24804937 TI - "Would you test your children without their consent?" and other sticky dilemmas in the field of cancer genetic testing. AB - Cancer genetic testing is surrounded by myriad ethical, legal, and psychosocial implications which are being revisited as testing expands into an everyday practice and into more complicated areas like whole exome and direct-to-consumer testing. We chose to survey cancer genetic counselors and physicians from a wide range of non-genetics specialties to determine what they would do if faced with the complex decisions associated with cancer genetic testing, how their views compare, and how they align with current guidelines and data. Genetic counselors were significantly more likely than non-genetics physicians to bill their insurance for testing (94.9 vs. 86.8 %; p = 0.001) and purchase life insurance before testing (86.6 vs. 68.6 %; p = 0.000) and were less likely to use an alias (3.2 vs. 13.2 %; p = 0.000) or order testing on their own DNA (15.3 vs. 24.2 %; p = 0.004). They were also less likely to test their minor children (0.9 vs. 33.1 %; p = 0.000) or test their children without their knowledge and consent/assent (1.4 vs.11.5 %; p = 0.000). The results of our study indicate that there is wide variation regarding what clinicians predict they would do in the areas of ethical, legal and psychosocial issues in cancer genetic testing. Cancer genetic counselors' choices are more aligned with professional guidelines, likely due to their experience in the field and awareness of current guidelines. These data are a starting point for a broader discussion of who should offer cancer genetic counseling and testing to patients, particularly as the complexity of the available testing options and associated issues increase with whole exome sequencing. PMID- 24804938 TI - Epstein-Barr virus-associated lymphoepithelioma-like cholangiocarcinoma: a rare variant of intrahepatic cholangiocarcinoma with favourable outcome. AB - AIMS: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma (IHCC). Only 16 cases have reported previously in the literature, and about 62.5% of these cases were associated with Epstein-Barr virus (EBV). METHODS AND RESULTS: We present the largest series (seven cases) of LELCC with descriptions of clinical and pathological characteristics, investigations of aberrant DNA methylation and mutation analyses of EGFR and KRAS. The evaluation also included 11 cases of stage-matched conventional IHCC for comparison. RESULTS: All seven patients of LELCC were female and had stage I disease. LELCC had significantly better 2- and 5-year overall survival than IHCC (100% versus 52.8%, and 100% versus 13.2%, respectively, P = 0.003). All seven LELCCs were EBV-associated and composed exclusively of adenocarcinoma with varied glandular differentiation, dense lymphoplasmacytic infiltrate, and variable expression of biliary-type cytokeratins (CK7 and CK19) and stemness markers (CD133 and EpCAM). Gene hypermethylation was more frequent in LELCC than IHCC. CRBPI (85.7% versus 9.1%, P < 0.003) and CRBPIV (85.7% versus 0%, P < 0.001) showed statistically higher methylation frequencies in LELCC than IHCC. No LELCC harboured any EGFR or KRAS mutation. CONCLUSION: Epstein-Barr virus-associated LELCC is a variant of IHCC, characterized by marked female predominance, favourable overall survival and distinctively frequent DNA hypermethylation. PMID- 24804939 TI - Lymphomatoid papulosis with 6p25.3 rearrangement: a further case of the newly described variant. PMID- 24804940 TI - Molecular cloning of rat and porcine retina-derived POU domain factor 1 (POU6F2) from a pituitary cDNA library. AB - Homeobox transcription factors are known to play crucial roles in the anterior lobe of the pituitary gland. During molecular cloning with the Yeast One-Hybrid System using a 5'-upstream region of the porcine Fshbeta as a bait sequence, we have cloned a cDNA encoding a partial sequence of the retina-derived POU domain factor 1 (RPF1) from the porcine pituitary cDNA library and confirmed its specific binding to the bait sequence. In situ hybridization was performed to examine localization of Rpf1 and showed that this gene is expressed in the stem/progenitor cells of the rat pituitary primordium as well as the diencephalon and retina. In addition, real-time PCR demonstrated that Rpf1 transcripts are abundant in early embryonic periods but that this is followed by a decrease during pituitary development, indicating that this factor plays a role in differentiating cells of the pituitary. The transcriptional activity of RPF1 for genes of Prop1, Prrx1 and Prrx2, which were characterized as genes participating in the pituitary stem/progenitor cells by our group, was then examined with full length cDNA obtained from the rat pituitary. RPF1 showed regulatory activity for Prop1 and Prrx2, but not for Prrx1. These results indicate the involvement of this retina-derived factor in pituitary development. PMID- 24804942 TI - In color perception, size matters. AB - In designing colors for digital visualization systems. one of the most critical factors is the interaction between size and color appearance. Whereas artists and visual designers understand this, recommendations for using color in visualization rarely address the issue, or even recognize it. The goal is to keep the user focused on the data, with color simply one of many tools used toward problem solving and discovery. PMID- 24804941 TI - AKT-related autophagy contributes to the neuroprotective efficacy of hydroxysafflor yellow A against ischemic stroke in rats. AB - Hydroxysafflor yellow A (HSYA) has been approved clinically for treating cardiac patients in China since 2005. Recent studies have indicated that HSYA may be neuroprotective at 24 h in experimental stroke models. Autophagy is a vital degradation pathway of damaged intracellular macromolecules or organelles to maintain homeostasis in physiological or pathological conditions. The purpose of this study is to investigate the neuroprotection of HSYA at 72 h and its mechanism via activating the autophagy pathway using an acute ischemic reperfusion stroke rat model. Rats were treated with HSYA (2 mg/kg) during 90 min middle cerebral artery occlusion/72 h reperfusion by intravenous administration at four different time points (15 min post-ischemia, 15 min, 24 h, and 48 h post reperfusion), mimicking the potential treatment for acute ischemic stroke. HSYA administration reduced infarction volume and improved various neurological functions at 72 h of reperfusion. The possible molecular mechanism was investigated. We found that HSYA activated the AKT-autophagy pathway in penumbra tissue, which occurred in neuronal-specific cells. Moreover, blocking the AKT autophagy pathway by an AKT inhibitor abolished HSYA-induced neuroprotection after cerebral ischemia. HSYA may be a promising drug for treating acute ischemic stroke and the AKT-dependent autophagy pathway contributes to the HSYA-afforded neuroprotection. PMID- 24804943 TI - Digital media and the beginning designer. AB - Use and creation of computer graphics can be effectively taught to beginning design students in the context of discipline-specific design projects. In particular, a case study of the pedagogy implemented by the New Jersey Institute of Technology's College of Architecture + Design provides examples of how teachers harness the students' desire to create and provide educational opportunities for undergraduates to learn about the use of digital media in the processes and products of design. Employing a carefully constructed sequence, students are exposed to (and use) computer applications for raster imaging, vector drawing, 3D modeling and rendering, and eventually building information modeling and time-based sequential representation all while producing original work through analysis and synthesis. PMID- 24804944 TI - Modeling and verifying the polarizing reflectance of real-world metallic surfaces. AB - Using measurements of real-world samples of metals, the proposed approach verifies predictions of bidirectional reflectance distribution function (BRDF) models. It employs ellipsometry to verify both the actual polarizing effect and the overall reflectance behavior of the metallic surfaces. PMID- 24804945 TI - A parallel architecture for interactively rendering scattering and refraction effects. AB - A new method for interactive rendering of complex lighting effects combines two algorithms. The first performs accurate ray tracing in heterogeneous refractive media to compute high-frequency phenomena. The second applies lattice-Boltzmann lighting to account for low-frequency multiple-scattering effects. The two algorithms execute in parallel on modern graphics hardware. This article includes a video animation of the authors' real-time algorithm rendering a variety of scenes. PMID- 24804946 TI - Simulating how salt decay ages buildings. AB - Salt-based aging plays an important part in the realism of scenes featuring stone structures and monuments. A proposed model, based on physical behaviors and principles, replaces the simulation of complex physical formulations with ad hoc algorithms. It leads to plausible results, ultimately helping designers create aging patterns on affected objects. PMID- 24804947 TI - Visualizing the surface of a living human brain. AB - A proposed method visualizes the surface appearance of living human brain tissue. The goal is to investigate whether realistic models of living anatomy are possible and, if so, whether they provide added value to anatomy education and training simulators. From calibrated photography of exposed brain tissue and suitable alternatives, experiments provided data for a bidirectional reflectance distribution function, which was then used for rendering. Employing a GPU, real time visualization of the brain's surface supported ambient occlusion, advanced texturing, subsurface scattering, and specularity. PMID- 24804948 TI - User-friendly graph editing for procedural modeling of buildings. AB - A proposed rule-based editing metaphor intuitively lets artists create buildings without changing their workflow. It's based on the realization that the rule base represents a directed acyclic graph and on a shift in the development paradigm from product-based to rule-based representations. Users can visually add or edit rules, connect them to control the workflow, and easily create commands that expand the artist's toolbox (for example, Boolean operations or local controlling operators). This approach opens new possibilities, from model verification to model editing through graph rewriting. PMID- 24804949 TI - Sparse coding for flexible, robust 3D facial-expression synthesis. AB - Computer animation researchers have been extensively investigating 3D facial expression synthesis for decades. However, flexible, robust production of realistic 3D facial expressions is still technically challenging. A proposed modeling framework applies sparse coding to synthesize 3D expressive faces, using specified coefficients or expression examples. It also robustly recovers facial expressions from noisy and incomplete data. This approach can synthesize higher quality expressions in less time than the state-of-the-art techniques. PMID- 24804950 TI - Epinome: a visual-analytics workbench for epidemiology data. AB - Early detection and rapid response to infectious-disease outbreaks rely on effective decision making based on information from disparate sources. To improve decision-making in outbreak detection and response, it's important to understand how public health practitioners seek relevant information. Epinome, a user centric visual-analytics system, supports research on decision-making in public health, particularly evaluation of information search strategies. Epinome facilitates investigation of scripted high-fidelity large-scale simulated disease outbreaks. Its dynamic environment seamlessly evolves and adapts as the user's tasks and focus change. This video shows how the Epinome system facilitates interactive simulations of disease outbreaks. PMID- 24804951 TI - Prenatal exposure to airborne polycyclic aromatic hydrocarbons and IQ: estimated benefit of pollution reduction. AB - Outdoor air pollution, largely from fossil fuel burning, is a major cause of morbidity and mortality in the United States, costing billions of dollars every year in health care and loss of productivity. The developing fetus and young child are especially vulnerable to neurotoxicants, such as polycyclic aromatic hydrocarbons (PAH) released to ambient air by combustion of fossil fuel and other organic material. Low-income populations are disproportionately exposed to air pollution. On the basis of the results of a prospective cohort study in a low income population in New York City (NYC) that found a significant inverse association between child IQ and prenatal exposure to airborne PAH, we estimated the increase in IQ and related lifetime earnings in a low-income urban population as a result of a hypothesized modest reduction of ambient PAH concentrations in NYC of 0.25 ng/m(3). For reference, the current estimated annual mean PAH concentration is ~1 ng/m(3). Restricting to NYC Medicaid births and using a 5 per cent discount rate, we estimated the gain in lifetime earnings due to IQ increase for a single year cohort to be US$215 million (best estimate). Using much more conservative assumptions, the estimate was $43 million. This analysis suggests that a modest reduction in ambient concentrations of PAH is associated with substantial economic benefits to children. PMID- 24804952 TI - Non-infectious events under the International Health Regulations (2005) in Europe -a case for syndromic surveillance. AB - The scope of the International Health Regulations of 2005 (IHR (2005)) has been expanded. The IHR (2005) are no longer limited to a specific set of infectious diseases, instead they prescribe detection and assessment of any event of potential public health concern regardless of its source or origin. We examine events of non-infectious origin that might fulfill the criteria of a potential public health emergency of international concern under the IHR (2005). These comprise predominately events related to food safety, but also events related to drug safety or of chemical or industrial origin. We argue that to identify these events and assess health effects related to them, existing disease surveillance systems should be augmented with less specific indicator-based syndromic surveillance strategies that use available routine health-related service data for monitoring purposes. PMID- 24804953 TI - Multiple testing in fMRI: an empirical case study on the balance between sensitivity, specificity, and stability. AB - Functional Magnetic Resonance Imaging is a widespread technique in cognitive psychology that allows visualizing brain activation. The data analysis encompasses an enormous number of simultaneous statistical tests. Procedures that either control the familywise error rate or the false discovery rate have been applied to these data. These methods are mostly validated in terms of average sensitivity and specificity. However, procedures are not comparable if requirements on their error rates differ. Moreover, less attention has been given to the instability or variability of results. In a simulation study in the context of imaging, we first compare the Bonferroni and Benjamini-Hochberg procedures. Considering Bonferroni as a way to control the expected number of type I errors enables more lenient thresholding compared to familywise error rate control and a direct comparison between both procedures. We point out that while the same balance is obtained between average sensitivity and specificity, the Benjamini-Hochberg procedure appears less stable. Secondly, we have implemented the procedure of Gordon et al. () (originally proposed for gene selection) that includes stability, measured through bootstrapping, in the decision criterion. Simulations indicate that the method attains the same balance between sensitivity and specificity. It improves the stability of Benjamini-Hochberg but does not outperform Bonferroni, making this computationally heavy bootstrap procedure less appealing. Third, we show how stability of thresholding procedures can be assessed using real data. In a dataset on face recognition, we again find that Bonferroni renders more stable results. PMID- 24804954 TI - Induction of apoptosis by Fe(salen)Cl through caspase-dependent pathway specifically in tumor cells. AB - Iron-based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salen)Cl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti-tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salen)Cl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T-cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salen)Cl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC) remain largely unaffected by Fe(salen)Cl. Fe(salen)Cl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salen)Cl treatment suggests that Fe(salen)Cl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salen)Cl-treated tumor cells is mediated through caspase-dependent pathway. This is the first report demonstrating that Fe(salen)Cl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next-generation anti-tumor drug. PMID- 24804955 TI - Erratum to: remodeling pattern is related to the degree of coronary plaque regression induced by pitavastatin: a sub-analysis of the TOGETHAR trial with intravascular ultrasound and coronary angioscopy. PMID- 24804956 TI - 3,3'-Bi(1,2,4-oxadiazoles) featuring the fluorodinitromethyl and trinitromethyl groups. AB - Here we report on the preparation of two hydrogen atom free 3,3'-bi(1,2,4 oxadiazole) derivatives. 5,5'-Bis(fluorodinitromethyl)-3,3'-bi(1,2,4-oxadiazole) was synthesised by fluorination of diammonium 5,5'-bis(dinitromethanide)-3,3' bi(1,2,4-oxadiazole). For our previously reported analogue 5,5' bis(trinitromethyl)-3,3'-bi(1,2,4-oxadiazole), a new synthetic route starting from new 3,3'-bi(1,2,4-oxadiazolyl)-5,5'-diacetic acid was developed. In this course also hitherto unknown 5,5'-dimethyl-3,3'-bi(1,2,4-oxadiazole) was isolated. The compounds were characterised by multinuclear NMR spectroscopy, IR and Raman spectroscopy, elemental analysis as well as mass spectrometry. X-ray diffraction studies were performed and the crystal structures for the 5,5' dimethyl and 5,5'-(fluorodinitromethyl) derivatives are reported. The energetic 5,5'-(fluorodinitromethyl) and 5,5'-(trinitromethyl) compounds do not contain any hydrogen atoms and show remarkable high densities. Furthermore, the thermal stabilities and sensitivities were determined by differential scanning calorimetry (DSC) and standardised impact and friction tests. The heats of formation were calculated by the atomisation method based on CBS-4M enthalpies. With these values and the room-temperature X-ray densities, several detonation and propulsion parameters, such as the detonation velocity and pressure as well as the specific impulse of mixtures with aluminium, were computed using the EXPLO5 code. PMID- 24804957 TI - Periodate-oxidized ATP modulates macrophage functions during infection with Leishmania amazonensis. AB - Previously, we showed that treating macrophages with ATP impairs the intracellular growth of Leishmania amazonensis, and that the P2X7 purinergic receptor is overexpressed during leishmaniasis. In the present study, we directly evaluated the effect of periodate-oxidized ATP (oATP) on parasite control in Leishmania-infected macrophages. We found that oATP impaired the attachment/entrance of L. amazonensis promastigotes to C57BL/6 mouse macrophages in a P2X7 receptor-independent manner, as macrophages from P2X7(-/-) mice were similarly affected. Although oATP directly inhibited the growth of axenic promastigotes in culture, promoted rapid ultrastructural alterations, and impaired Leishmania internalization by macrophages, it did not affect intracellular parasite multiplication. Upon infection, phagosomal acidification was diminished in oATP-treated macrophages, accompanied by reduced endosomal proteolysis. Likewise, MHC class II molecules expression and ectoATPase activity was decreased by oATP added to macrophages at the time of parasite infection. These inhibitory effects were not due to a cytotoxic effect, as no additional release of lactate dehydrogenase was detected in culture supernatants. Moreover, the capacity of macrophages to produce nitric oxide and reactive oxygen species was not affected by the presence of oATP during infection. We conclude that oATP directly affects extracellular parasite integrity and macrophage functioning. PMID- 24804958 TI - Genetics: exosomally derived miR-105 destroys tight junctions. PMID- 24804959 TI - The role of probiotics in treating Candida-associated diseases: more evidences still needed. PMID- 24804962 TI - Proximal hyperdense middle cerebral artery sign predicts poor response to thrombolysis. AB - The aim of our study was to compare the rapid neurological improvement after intravenous recombinant tissue-type plasminogen activator (rtPA) in patients with proximal hyperdense middle cerebral artery sign (p-HMCAS) to those without the sign and those with the distal hyperdense middle cerebral artery sign (d-HMCAS). Admission and 24 hour non-contrast CT scans of 120 patients with middle cerebral artery (MCA) territory stroke who were treated with intravenous rtPA were assessed for the presence of p-HMCAS and d-HMCAS. The sign was classified according to the site of occlusion. Rapid neurological improvement was defined as >= 50% improvement in the NIHSS score at 24 hours after thrombolysis. Rapid neurological recovery after thrombolysis was assessed and compared between the subgroups. Rapid neurological recovery was less common in the pooled group of patients with either p-HMCAS or d-HMCAS than those without the sign (p<0.01). Patients with p-HMCAS were less likely to have rapid neurological recovery than those with d-HMCAS (p<0.01). However, there was no difference in early neurological recovery between patients with d-HMCAS and those without any hyperdense sign. Our study showed that poor neurological recovery post rtPA was confined to p-HMCAS and not to d-HMCAS, indicating that these signs have quite different prognostic significance. PMID- 24804963 TI - Tomato genome-wide transcriptional responses to Fusarium wilt and Tomato Mosaic Virus. AB - Since gene expression approaches constitute a starting point for investigating plant-pathogen systems, we performed a transcriptional analysis to identify a set of genes of interest in tomato plants infected with F. oxysporum f. sp. lycopersici (Fol) and Tomato Mosaic Virus (ToMV). Differentially expressed tomato genes upon inoculation with Fol and ToMV were identified at two days post inoculation. A large overlap was found in differentially expressed genes throughout the two incompatible interactions. However, Gene Ontology enrichment analysis evidenced specific categories in both interactions. Response to ToMV seems more multifaceted, since more than 70 specific categories were enriched versus the 30 detected in Fol interaction. In particular, the virus stimulated the production of an invertase enzyme that is able to redirect the flux of carbohydrates, whereas Fol induced a homeostatic response to prevent the fungus from killing cells. Genomic mapping of transcripts suggested that specific genomic regions are involved in resistance response to pathogen. Coordinated machinery could play an important role in prompting the response, since 60% of pathogen receptor genes (NB-ARC-LRR, RLP, RLK) were differentially regulated during both interactions. Assessment of genomic gene expression patterns could help in building up models of mediated resistance responses. PMID- 24804964 TI - An updated felCat5 SNP manifest for the Illumina Feline 63k SNP genotyping array. PMID- 24804966 TI - Identification of the origin and localization of chorion (egg envelope) proteins in an ancient fish, the white sturgeon, Acipenser transmontanus. AB - In many modern teleost fish, chorion (egg envelope) glycoproteins are synthesized in the liver of females, and the expression of those genes is controlled by endogenous estrogen released from the ovary during maturation. However, among the classical teleosts, such as salmonid, carp, and zebrafish, the chorion glycoproteins are synthesized in the oocyte, as in higher vertebrates. Sturgeon, which are members of the subclass Chondrostei, represent an ancient lineage of ray-finned fishes that differ from other teleosts in that their sperm possess acrosomes, their eggs have numerous micropyles, and early embryo development is similar to that of amphibians. In order to understand the molecular mechanisms of chorion formation and the phylogenetic relationship between sturgeon and other teleosts, we used specific antibodies directed against the primary components of sturgeon chorion glycoproteins, using immunoblotting and immunocytochemistry approaches. The origin of each chorion glycoprotein was determined through analyses of both liver and ovary, and their localization during ovarian development was investigated. Our data indicate that the origin of the major chorion glycoproteins of sturgeon, ChG1, ChG2, and ChG4, derive not only from the oocyte itself but also from follicle cells in the ovary, as well as from hepatocytes. In the follicle cell layer, granulosa cells were found to be the primary source of ChGs during oogenesis in white sturgeon. The unique origins of chorion glycoproteins in sturgeon suggest that sturgeons are an intermediate form in the evolution of the teleost lineage. PMID- 24804965 TI - Edaravone mitigates hexavalent chromium-induced oxidative stress and depletion of antioxidant enzymes while estrogen restores antioxidant enzymes in the rat ovary in F1 offspring. AB - Environmental contamination of drinking water with chromium (Cr) has been increasing in more than 30 cities in the United States. Previous studies from our group have shown that Cr affects reproductive functions in female Sprague Dawley rats. Although it is impossible to completely remove Cr from the drinking water, it is imperative to develop effective intervention strategies to inhibit Cr induced deleterious health effects. Edaravone (EDA), a potential inhibitor of free radicals, has been clinically used to treat cancer and cardiac ischemia. This study evaluated the efficacy of EDA against Cr-induced ovarian toxicity. Results showed that maternal exposure to CrVI in rats increased follicular atresia, decreased steroidogenesis, and delayed puberty in F1 offspring. CrVI increased oxidative stress and decreased antioxidant (AOX) enzyme levels in the ovary. CrVI increased follicle atresia by increased expression of cleaved caspase 3, and decreased expression of Bcl2 and Bcl2l1 in the ovary. EDA mitigated or inhibited the effects of CrVI on follicle atresia, pubertal onset, steroid hormone levels, and AOX enzyme activity, as well as the expression of Bcl2 and Bcl2l1 in the ovary. In a second study, CrVI treatment was withdrawn, and F1 rats were injected with estradiol (E2) (10 MUg in PBS/ethanol per 100 g body weight) for a period of 2 wk to evaluate whether E2 treatment will restore Cr-induced depletion of AOX enzymes. E2 restored CrVI-induced depletion of glutathione peroxidase 1, catalase, thioredoxin 2, and peroxiredoxin 3 in the ovary. This is the first study to demonstrate the protective effects of EDA against any toxicant in the ovary. PMID- 24804968 TI - Prophase I arrest of mouse oocytes mediated by natriuretic peptide precursor C requires GJA1 (connexin-43) and GJA4 (connexin-37) gap junctions in the antral follicle and cumulus-oocyte complex. AB - Fully grown germinal vesicle stage mouse oocytes remain arrested in meiotic prophase I until ovulation. This arrest is maintained by cGMP produced in cumulus granulosa cells surrounding the oocyte. Recently, it was found that cGMP production in cumulus cells depends on NPR2 guanylate cyclase activated by its ligand natriuretic peptide precursor C (NPPC). It is assumed that cGMP reaches the oocyte through gap junctions that couple cumulus granulosa cells to each other and to the oocyte. Previous work identified two main types of gap junctions in the follicle, connexin-43 gap junctions (GJA1 protein) between granulosa cells and connexin-37 gap junctions (GJA4) between cumulus cells and the oocyte. However, it had not been established that both types are required for meiotic arrest mediated by NPPC/NPR2 signaling. To investigate this, we used connexin mimetic peptides (CMPs) that specifically disrupt gap junction isoforms within cumulus-oocyte complexes (COCs) and isolated antral follicles in culture. We furthermore developed a punctured antral follicle preparation to permit CMP access to the antral cavity in an otherwise intact follicle. CMP directed against connexin-43 (Cx43 CMP) overcame NPPC-mediated meiotic arrest in both isolated COCs and antral follicles. Cx37 CMP, in contrast, had no effect when present in the medium, but released oocyte arrest in the presence of NPPC when microinjected into the perivitelline space near the oocyte surface in COCs. This is consistent with both connexin isoforms being required for meiotic arrest and with the reported localization of connexin-43 throughout the cumulus cells and connexin-37 at the oocyte surface. PMID- 24804969 TI - Depth determination of artificial periodontal pockets using cone-beam tomography and radio-opaque material: an in vitro feasibility study. AB - In general, periodontal tissues are clinically assessed using calibrated periodontal probes and radiographs. Due to technical developments and the availability of cone-beam computed tomography (CBCT), 3-D imaging has become feasible and offers some advantages and potential for the evaluation of complex anatomical structures. The present pilot study illustrates and validates the possibility of radiographically visualizing and metrically assessing hard and soft tissue. Artificial periodontal pockets were created in porcine mandibles and measured by clinical (i.e. pocket probing) and radiographic means (CBCT). For the latter method, pockets were filled with a radiopaque material allowing visualization by CBCT. Clinically simulated pocket depth probing and CBCT measurements were compared. The results showed no statistically significant differences between the two methods. Thus, the CBCT visualization approach points towards the development of a new and promising radiographic all- in-one evaluation system of the periodontal status. However, more research and development is required. PMID- 24804967 TI - Daily exposure to Di(2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. AB - Humans are exposed daily to di(2-ethylhexyl) phthalate (DEHP), a plasticizer found in many consumer, medical, and building products containing polyvinyl chloride. Large doses of DEHP disrupt normal ovarian function; however, the effects of DEHP at environmentally relevant levels, the effects of DEHP on folliculogenesis, and the mechanisms by which DEHP disrupts ovarian function are unclear. The present study tested the hypothesis that relatively low levels of DEHP disrupt estrous cyclicity as well as accelerate primordial follicle recruitment by dysregulating phosphatidylinositol 3-kinase (PI3K) signaling. Adult CD-1 mice were orally dosed with DEHP (20 MUg/kg/day-750 mg/kg/day) daily for 10 and 30 days. Following dosing, the effects on estrous cyclicity were examined, and follicle numbers were histologically quantified. Further, the ovarian mRNA and protein levels of PI3K signaling factors that are associated with early folliculogenesis were quantified. The data indicate that 10- and 30 day exposure to DEHP prolonged the duration of estrus and accelerated primordial follicle recruitment. Specifically, DEHP exposure decreased the percentage of primordial follicles and increased the percentage of primary follicles counted following 10-day exposure and increased the percentage of primary follicles counted following 30-day exposure. DEHP exposure, at doses that accelerate folliculogenesis, increased the levels of 3-phosphoinositide-dependent protein kinase-1, mammalian target of rapamycin complex 1, and protein kinase B and decreased the levels of phosphatase and tensin homolog, potentially driving PI3K signaling. Collectively, relatively low levels of DEHP disrupt estrous cyclicity and accelerate primordial follicle recruitment potentially via a mechanism involving dysregulation of PI3K signaling. PMID- 24804970 TI - Risk communication and crisis communication in infectious disease outbreaks in Germany: what is being done, and what needs to be done. AB - OBJECTIVE: Risk communication plays a central role in the management of infectious disease. The World Health Organization's 2005 International Health Regulations have highlighted the need for countries to strengthen their capacities in this area to ensure effective responses to public health emergencies. We surveyed laboratories, hospitals, and public health institutions in Germany to detail the current situation regarding risk communication and crisis management and to identify which areas require further development. METHODS: A mixed methods approach was adopted. An initial questionnaire was distributed to relevant persons in laboratories and hospitals, and semistructured interviews were conducted with selected participants. Representatives from state public health authorities, federal agencies, and media also were interviewed to add additional contextual information to the questionnaire responses. RESULTS: Based on the responses received, the universal sense among key stakeholders was that risk communication and crisis communication measures must be improved. Collaborative working was a consistent theme, with participants suggesting that a partnering strategy could help to improve performance. This approach could be achieved through better coordination between groups, for example, through a knowledge-sharing policy. CONCLUSIONS: More research is needed on how such collaboration might be implemented, along with a general conceptual framework for risk communication to underpin the overall strategy. PMID- 24804971 TI - Multidimensional frailty score for the prediction of postoperative mortality risk. AB - IMPORTANCE: The number of geriatric patients who undergo surgery has been increasing, but there are insufficient tools to predict postoperative outcomes in the elderly. OBJECTIVE: To design a predictive model for adverse outcomes in older surgical patients. DESIGN, SETTING, AND PARTICIPANTS: From October 19, 2011, to July 31, 2012, a single tertiary care center enrolled 275 consecutive elderly patients (aged >=65 years) undergoing intermediate-risk or high-risk elective operations in the Department of Surgery. MAIN OUTCOMES AND MEASURES: The primary outcome was the 1-year all-cause mortality rate. The secondary outcomes were postoperative complications (eg, pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned intensive care unit admission), length of hospital stay, and discharge to nursing facility. RESULTS: Twenty-five patients (9.1%) died during the follow-up period (median [interquartile range], 13.3 [11.5-16.1] months), including 4 in-hospital deaths after surgery. Twenty-nine patients (10.5%) experienced at least 1 complication after surgery and 24 (8.7%) were discharged to nursing facilities. Malignant disease and low serum albumin levels were more common in the patients who died. Among the geriatric assessment domains, Charlson Comorbidity Index, dependence in activities of daily living, dependence in instrumental activities of daily living, dementia, risk of delirium, short midarm circumference, and malnutrition were associated with increased mortality rates. A multidimensional frailty score model composed of the above items predicted all-cause mortality rates more accurately than the American Society of Anesthesiologists classification (area under the receiver operating characteristic curve, 0.821 vs 0.647; P = .01). The sensitivity and specificity for predicting all-cause mortality rates were 84.0% and 69.2%, respectively, according to the model's cutoff point (>5 vs <=5). High risk patients (multidimensional frailty score >5) showed increased postoperative mortality risk (hazard ratio, 9.01; 95% CI, 2.15-37.78; P = .003) and longer hospital stays after surgery (median [interquartile range], 9 [5-15] vs 6 [3-9] days; P < .001). CONCLUSIONS AND RELEVANCE: The multidimensional frailty score based on comprehensive geriatric assessment is more useful than conventional methods for predicting outcomes in geriatric patients undergoing surgery. PMID- 24804972 TI - Objective definition of rosette shape variation using a combined computer vision and data mining approach. AB - Computer-vision based measurements of phenotypic variation have implications for crop improvement and food security because they are intrinsically objective. It should be possible therefore to use such approaches to select robust genotypes. However, plants are morphologically complex and identification of meaningful traits from automatically acquired image data is not straightforward. Bespoke algorithms can be designed to capture and/or quantitate specific features but this approach is inflexible and is not generally applicable to a wide range of traits. In this paper, we have used industry-standard computer vision techniques to extract a wide range of features from images of genetically diverse Arabidopsis rosettes growing under non-stimulated conditions, and then used statistical analysis to identify those features that provide good discrimination between ecotypes. This analysis indicates that almost all the observed shape variation can be described by 5 principal components. We describe an easily implemented pipeline including image segmentation, feature extraction and statistical analysis. This pipeline provides a cost-effective and inherently scalable method to parameterise and analyse variation in rosette shape. The acquisition of images does not require any specialised equipment and the computer routines for image processing and data analysis have been implemented using open source software. Source code for data analysis is written using the R package. The equations to calculate image descriptors have been also provided. PMID- 24804973 TI - AP-4 predicts poor prognosis in non-small cell lung cancer. AB - The basic helix-loop-helix transcription factor activating enhancer-binding protein (AP)-4 has been found to be involved in tumor biology. However, the role of AP-4 in non-small cell lung cancer (NSCLC) has yet to be elucidated. The present study aimed to investigate the role of AP-4 expression in NSCLC. AP-4 expression as analyzed using quantitative polymerase chain reaction and western blot analyses of 42 fresh NSCLC samples and matched adjacent noncancerous tissues. Immunohistochemistry was performed to assess the clinical significance of AP-4 expression in tumor tissues of NSCLC patients (n=240) and matched adjacent noncancerous tissues. The correlation between AP-4 expression, clinicopathological features and clinical outcome were investigated. AP-4 expression was found to be increased in the NSCLC samples at the gene and protein levels compared with the matched adjacent noncancerous tissues. Immunohistochemistry revealed that the positive expression rates of AP-4 in the 240 NSCLC samples and the matched adjacent noncancerous tissues were 48.3 and 5.8%, respectively. Positive AP-4 expression was found to be significantly associated with the tumor, nodes and metastasis stage and nodal status. Furthermore, patients with NSCLC tumors expressing AP-4 were observed to have a poorer prognosis than those without AP-4 expression. Multivariate analysis revealed that AP-4 expression was an independent prognostic marker (hazard ratio, 2.543; 95% confidence interval, 1.18-5.016; P=0.016) in NSCLC. Thus, positive AP 4 expression may be a potential prognostic marker for NSCLC. PMID- 24804974 TI - Headache and refractive errors in children. AB - PURPOSE: To investigate the association between uncorrected or miscorrected refractive errors in children and headache, and to determine whether correction of refractive errors contributes to headache resolution. METHODS: Results of ophthalmic examination, including refractive error, were recorded at initial visit for headache. If resolution of headache on subsequent visits was not documented, a telephone call was placed to their caregivers to inquire whether headache had resolved. RESULTS: Of the 158 patients, 75.3% had normal or unchanged eye examinations, including refractions.Follow-up data were available for 110 patients. Among those, 32 received new or changed spectacle correction and 78 did not require a change in refraction.Headaches improved in 76.4% of all patients, whether with (71.9%) or without (78.2%) a change in refractive correction. The difference between these two groups was not statistically significant (P = .38). CONCLUSIONS: Headaches in children usually do not appear to be caused by ophthalmic disease, including refractive error. The prognosis for improvement is favorable, regardless of whether refractive correction is required. PMID- 24804975 TI - A continuous-exchange cell-free protein synthesis system based on extracts from cultured insect cells. AB - In this study, we present a novel technique for the synthesis of complex prokaryotic and eukaryotic proteins by using a continuous-exchange cell-free (CECF) protein synthesis system based on extracts from cultured insect cells. Our approach consists of two basic elements: First, protein synthesis is performed in insect cell lysates which harbor endogenous microsomal vesicles, enabling a translocation of de novo synthesized target proteins into the lumen of the insect vesicles or, in the case of membrane proteins, their embedding into a natural membrane scaffold. Second, cell-free reactions are performed in a two chamber dialysis device for 48 h. The combination of the eukaryotic cell-free translation system based on insect cell extracts and the CECF translation system results in significantly prolonged reaction life times and increased protein yields compared to conventional batch reactions. In this context, we demonstrate the synthesis of various representative model proteins, among them cytosolic proteins, pharmacological relevant membrane proteins and glycosylated proteins in an endotoxin-free environment. Furthermore, the cell-free system used in this study is well-suited for the synthesis of biologically active tissue-type-plasminogen activator, a complex eukaryotic protein harboring multiple disulfide bonds. PMID- 24804976 TI - Differential diagnosis, comorbidity, and treatment of attention deficit/hyperactivity disorder in relation to bipolar disorder or borderline personality disorder in adults. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in adults can resemble, and often co-occurs with, bipolar disorder (BD) and borderline personality disorder (BPD). This can lead to mistaken diagnoses and ineffective treatment, resulting in potentially serious adverse consequences. All three conditions can substantially impair well-being and functioning, while BD and BPD are associated with suicidality. OBJECTIVES: To update clinicians on the overlap and differences in the symptomatology of ADHD versus BD and BPD in adults; differential diagnosis of ADHD from BD and BPD in adults; and diagnosis and treatment of adults with comorbid ADHD-BD or ADHD-BPD. METHODS: We searched four databases, referred to the new Diagnostic and Statistical Manual of Mental Disorders, 5th edition, used other relevant literature, and referred to our own clinical experience. RESULTS: ADHD coexists in ~20% of adults with BD or BPD. BD is episodic, with periods of normal mood although not necessarily function. In patients with comorbid ADHD-BD, ADHD symptoms are apparent between BD episodes. BPD and ADHD are associated with chronic trait-like symptoms and impairments. Overlapping symptoms of BPD and ADHD include impulsivity and emotional dysregulation. Symptoms of BPD but not ADHD include frantically avoiding real/imagined abandonment, suicidal behavior, self-harm, chronic feelings of emptiness, and stress-related paranoia/severe dissociation. Consensus expert opinion recommends that BD episodes should be treated first in patients with comorbid ADHD, and these patients may need treatment in stages (e.g. mood stabilizer[s], then a stimulant/atomoxetine). Data is scarce and mixed about whether stimulants or atomoxetine exacerbate mania in comorbid ADHD-BD. BPD is primarily treated with psychotherapy. Principles of dialectical behavioral treatment for BPD may successfully treat ADHD in adults, as an adjunct to medication. No fully evidence-based pharmacotherapy exists for core BPD symptoms, although some medications may be effective for individual symptom domains, e.g. impulsivity (shared by ADHD and BPD). In our experience, treatment of ADHD should be considered when treating comorbid personality disorders. CONCLUSIONS: It is important to accurately diagnose ADHD, BD, and BPD to ensure correct targeting of treatments and improvements in patient outcomes. However, there is a shortage of data about treatment of adults with ADHD and comorbid BD or BPD. PMID- 24804977 TI - Yeast oropharyngeal colonization in human immunodeficiency virus-infected patients in central taiwan. AB - A prospective, cross-sectional study was conducted at a medical center in central Taiwan to understand the prevalence, associated factors, and microbiologic features for oropharyngeal yeast colonization in human immunodeficiency virus infected outpatients. Oral yeast colonization was detected in 127 (45 %) patients, including 21 (16.5 %) colonized by more than one species. Of the 154 isolates, Candida albicans was the most common species (114, 74 %), followed by Candida dubliniensis (10, 6.5 %), Candida glabrata (10, 6.5 %), Candida tropicalis (7, 4.5 %), and 13 others. We found that receiving antituberculous drug (p = 0.046) or atazanavir (p = 0.045) was two predictors for patients colonized by non-C. albicans species (p = 0.005) and risking mixed yeast colonization (p = 0.009). Even though our data showed that clinical antifungal drugs remained effective in vitro against the colonizing yeasts, the increased mixed yeast colonization indicates a potential issue for controlling mixed infections in hospital settings. PMID- 24804978 TI - Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients. AB - AIMS: To investigate the molecular and clinical characteristics of the largest series of Japanese patients with glucokinase maturity-onset diabetes of the young (GCK-MODY), and to find any features specific to Asian people. METHODS: We enrolled 78 Japanese patients with GCK-MODY from 41 families (55 probands diagnosed at the age of 0-14 years and their 23 adult family members). Mutations were identified by direct sequencing or multiplex ligation-dependent probe amplification of all exons of the GCK gene. Detailed clinical and laboratory data were collected on the probands using questionnaires, which were sent to the treating physicians. Data on current clinical status and HbA1c levels were also collected from adult patients. RESULTS: A total of 35 different mutations were identified, of which seven were novel. Fasting blood glucose and HbA1c levels of the probands were <=9.3 mmol/l and <=56 mmol/mol (7.3%), respectively, and there was considerable variation in their BMI percentiles (0.4-96.2). In total, 25% of the probands had elevated homeostatic assessment of insulin resistance values, and 58.3% of these had evidence of concomitant Type 2 diabetes in their family. The HbA1c levels for adults were slightly higher, up to 61 mmol/mol (7.8%). The incidence of microvascular complications was low. Out of these 78 people with GCK MODY and 40 additional family members with hyperglycaemia whose genetic status was unknown, only one had diabetic nephropathy. CONCLUSIONS: The molecular and clinical features of GCK-MODY in Japanese people are similar to those of other ethnic populations; however, making a diagnosis of GCK-MODY was more challenging in patients with signs of insulin resistance. PMID- 24804979 TI - Hotspot-engineered 3D multipetal flower assemblies for surface-enhanced Raman spectroscopy. AB - Novel 3D metallic structures composed of multipetal flowers consisting of nanoparticles are presented. The control of surface plasmon hotspots is demonstrated in terms of location and intensity as a function of petal number for uniform and reproducible surfaceenhanced Raman spectroscopy (SERS) with high field enhancement. PMID- 24804980 TI - miR-1, miR-10b, miR-155, and miR-191 are novel regulators of BDNF. AB - Brain-derived neurotrophic factor (BDNF) is a secreted protein of the neurotrophin family that regulates brain development, synaptogenesis, memory and learning, as well as development of peripheral organs, such as angiogenesis in the heart and postnatal growth and repair of skeletal muscle. However, while precise regulation of BDNF levels is an important determinant in defining the biological outcome, the role of microRNAs (miRs) in modulating BDNF expression has not been extensively analyzed. Using in silico approaches, reporter systems, and analysis of endogenous BDNF, we show that miR-1, miR-10b, miR-155, and miR 191 directly repress BDNF through binding to their predicted sites in BDNF 3'UTR. We find that the overexpression of miR-1 and miR-10b suppresses endogenous BDNF protein levels and that silencing endogenous miR-10b increases BDNF mRNA and protein levels. Furthermore, we show that miR-1/206 binding sites within BDNF 3'UTR are used in differentiated myotubes but not in undifferentiated myoblasts. Finally, our data from two cell lines suggest that endogenous miR-1/206 and miR 10 family miRs act cooperatively in suppressing BDNF through their predicted sites in BDNF 3'UTR. In conclusion, our results highlight miR-1, miR-10b, miR 155, and miR-191 as novel regulators of BDNF long and short 3'UTR isoforms, supporting future research in different physiological and pathological contexts. PMID- 24804981 TI - Electroactive nanobiomolecular architectures of laccase and cytochrome c on electrodes: applying silica nanoparticles as artificial matrix. AB - Fully electroactive multilayer architectures combining the redox protein cytochrome c and the enzyme laccase by the use of silica nanoparticles as artificial matrix have been constructed on gold electrodes capable of direct dioxygen reduction. Laccase form Trametes versicolor and cytochrome c from horse heart were electrostatically coimmobilized by alternate deposition with interlayers of silica nanoparticles in a multilayer fashion. The layer formation has been monitored by quartz crystal microbalance. The electrochemical properties and performance of the nanobiomolecular entities were investigated by cyclic voltammetry, indicating, that a multistep electron transfer cascade, from the electrode via cytochrome c in the layered system toward the enzyme laccase, and here to molecular dioxygen was achieved. The response of the novel architecture is based on direct electron exchange between immobilized proteins and can be tuned by the assembly process. PMID- 24804983 TI - Cohorts and community: a case study of community engagement in the establishment of a health and demographic surveillance site in Malaysia. AB - BACKGROUND: Community engagement is an increasingly important requirement of public health research and plays an important role in the informed consent and recruitment process. However, there is very little guidance about how it should be done, the indicators for assessing effectiveness of the community engagement process and the impact it has on recruitment, retention, and ultimately on the quality of the data collected as part of longitudinal cohort studies. METHODS: An instrumental case study approach, with data from field notes, policy documents, unstructured interviews, and focus group discussions with key community stakeholders and informants, was used to explore systematically the implementation and outcomes of the community engagement strategy for recruitment of an entire community into a demographic and health surveillance site in Malaysia. RESULTS: For a dynamic cohort, community engagement needs to be an ongoing process. The community engagement process has likely helped to facilitate the current response rate of 85% in the research communities. The case study highlights the importance of systematic documentation of the community engagement process to ensure an understanding of the effects of the research on recruitment and the community. CONCLUSIONS: A critical lesson from the case study data is the importance of relationships in the recruitment process for large population-based studies, and the need for ongoing documentation and analysis of the impact of cumulative interactions between research and community engagement. PMID- 24804985 TI - The pubic midline exposure for symphyseal open reduction and plate fixation. AB - BACKGROUND: Open reduction and plate fixation of the disrupted symphysis pubis is commonly performed through a horizontal Pfannenstiel incision. Certain clinical situations that complicate the soft tissue conditions of the lower abdomen may make the Pfannenstiel incision a less appealing option. We report on the use of a vertical pubic area midline skin incision in a series of patients undergoing open reduction and plate fixation of their traumatically disrupted symphysis pubis. MATERIALS AND METHODS: Institutional Review Board approval was obtained for a retrospective chart review of the charts of 25 patients treated between September 2011 and October 2012. Their charts were reviewed for patient age, gender, body mass index (BMI), pelvic injury type (as classified by Young and Burgess), mechanism of injury and associated traumatic injuries. The depth of the approach was estimated using the pelvic computed tomography (CT) scan. Details from the operative procedure were recorded, as was the length of follow-up and any perioperative complications. RESULTS: Twenty-five patients were eligible for inclusion during the defined study time period between September 2011 and October 2012. The patients' average age was 55.8 years (range 25-91). All patients were males. The average BMI was 29.3 (range 18.8-43.8). The depth measured on the axial pelvic CT scan from skin to symphysis was 57.6 mm (range 35.2-90.2 mm). Five of 25 patients had an isolated pelvic ring injury without other associated injuries. The injury pattern was APC2 in 18, APC3 in 3, LC2 in 2, LC3 in 1 and VS in 1 patient(s) [anterior posterior compression (APC), lateral compression (LC), vertical shear (VS)]. Urologic procedures were performed in the same surgical setting in four patients. The average blood loss was 244 ml (range 150-400 ml). The average follow-up was 2.5 months (range 1-12 months). Perioperative issues were noted in two patients. One patient died within a month of surgery as a result of his associated traumatic injuries. One patient developed a deep infection. CONCLUSION: The pubic midline skin exposure is a feasible alternative to the Pfannenstiel incision for open reduction and plate fixation of the pubic symphysis. LEVEL OF EVIDENCE: IV, Retrospective case series. PMID- 24804986 TI - Amyloid triangles, squares, and loops of apolipoprotein C-III. AB - While a significant component of atherosclerotic plaques has been characterized as amyloid, the specific proteins remain to be fully identified. Probable amyloidogenic proteins are apolipoproteins (Apos), which are vital for the formation and function of lipoproteins. ApoCIII is an abundant protein implicated in atherosclerosis, and we show it forms a ribbonlike looped amyloid, strikingly similar to that previously reported for ApoAI and ApoCII. Triangles and squares with a width of ~50 nm were also observed, which may be a novel form of amyloid or related to previously reported amyloid rings. PMID- 24804987 TI - Hospital discharges for Crohn's disease in States with high smoking prevalence. PMID- 24804988 TI - Recurrent hepatocellular carcinoma and poorer overall survival in patients undergoing left-sided compared with right-sided partial hepatectomy. AB - GOALS: We aimed to determine the incidence and predictors of recurrent hepatocellular carcinoma (HCC) after partial hepatectomy. BACKGROUND: Liver transplantation is the preferred treatment for selected patients with HCC, but access to donor organs is limited. Partial hepatectomy is another accepted treatment option; however, postoperative recurrence is frequently observed. METHODS: This is a retrospective cohort study of 107 consecutive patients who underwent partial hepatectomy for HCC between January 1993 and February 2011 at a US University Medical Center. Study endpoints were recurrent HCC, death, loss to follow-up, or last visit without HCC. RESULTS: The study cohort was 78% male with a median age of 61 years and 59% Asians. A total of 50 patients developed recurrent HCC (46.7%) after a median follow-up of 12 (1 to 69) months postresection. Recurrent HCC was significantly higher in patients with left-sided resection (41% at year 1, 54% at year 2, 62% at year 3, 81% at year 4, and 90% at year 5) compared with right-sided resection (18% at year 1, 34% at year 2, 36% at year 3, 44% at year 4, and 72% at year 5). In multivariate Cox proportional hazards model also inclusive of anatomic resection and TNM stage 3/4, left-sided resection was significantly associated with increased HCC recurrence (hazard ratio, 2.13; P=0.02; 95% confidence interval, 1.08-4.2) compared with right-sided resection. CONCLUSIONS: HCC recurrence rate is higher among those undergoing left sided resection: 54% at year 2 and 81% at year 4. Liver transplantation should be considered in patients who are at high risk for recurrence. PMID- 24804989 TI - Magnification endoscopy with acetic acid enhancement and a narrow-band imaging system for pit pattern diagnosis of colorectal neoplasms. AB - BACKGROUND AND GOALS: Pit pattern (PP) analysis of colorectal neoplasms using magnification chromoendoscopy with crystal violet (CV-MCE) is useful for predicting histologic features, but it is time consuming. Capillary pattern analysis by magnification endoscopy with narrow-band imaging (NBIME) is a useful and simpler procedure, but its diagnostic accuracy may be inferior to CV-MCE. NBIME with acetic acid enhancement (A-NBIME) is effective for rapid visualization of gastric mucosal microstructures. We performed a prospective study to compare the diagnostic reliability and feasibility of A-NBIME and CV-MCE in PP diagnosis of colorectal neoplasms. STUDY: The present study consisted of 3 protocols: Study 1 assessed 56 colorectal lesions photographed with A-NBIME and CV-MCE, and the endoscopic images were reviewed by 3 experts to compare the diagnostic concordance; study-2 assessed 202 colorectal lesions photographed with A-NBIME in 116 consecutive patients and the correlation between PP and histologic findings; study-3 randomly allocated 100 patients with colorectal lesions equally to A NBIME and CV-MCE, and compared the procedure time and visible ratio of PP. RESULTS: The kappa value for interobserver agreement for A-NBIME and CV-MCE was 0.71 (0.66 to 0.75) and 0.80 (0.75 to 0.85), respectively. Intraobserver agreement between modalities for each reviewer was 0.79 (0.70 to 0.88), 0.80 (0.71 to 0.90), and 0.74 (0.67 to 0.82). Non-neoplastic polyps and massively invasive submucosal adenocarcinomas were statistically related to type II and type VI-H/VN. The procedure time was statistically shorter with A-NBIME than with CV-MCE (31 vs. 81 s), and the visible ratio of PP was equivalent (98.9% vs. 98.3%). CONCLUSIONS: A-NBIME is comparable with CV-MCE in PP diagnosis of colorectal neoplasms and is a simpler technique. PMID- 24804990 TI - Role of prucalopride in treatment of chronic constipation and recurrent functional obstruction in a patient with steinert myotonic dystrophy. PMID- 24804992 TI - When longevity meets vitality. AB - Alarmed by the sustainability of our health and social security systems, longevity has become a great societal challenge. In line with evolutionary logic we see a continuous increase of average life expectancy and maximal lifespan. Striving for a healthy old age, however, is an infelicitous expression as for human subjects the ageing process cannot be ultimately postponed. Not disregarding the huge variation in health trajectories, in old age we will all suffer from frailty and infirmity. As yet efforts of the biomedical arena are almost exclusively focused on stalling the ageing process and preventing dysfunction. Too little effort is spend on how to inspire and coach the great majority of people who still feel relatively well notwithstanding the presence of multiple age-related disorders. There is a strong rationale to separate the quest to live in good health for longer from actively and effectively negotiating the challenge of functional decline in old age. In particular, we emphasise a focus on adjusting the environment in order to correct the gene-environment mismatch that contributes to ill health. An additional strategy is to empower people to set ambitions and to realise appropriate goals, in spite of infirmity. Striving for vitality presents a striking opportunity to achieve subjective feelings of life satisfaction when ageing. PMID- 24804991 TI - Stabilization and augmentation of circulating AIM in mice by synthesized IgM-Fc. AB - Owing to rapid and drastic changes in lifestyle and eating habits in modern society, obesity and obesity-associated diseases are among the most important public health problems. Hence, the development of therapeutic approaches to regulate obesity is strongly desired. In view of previous work showing that apoptosis inhibitor of macrophage (AIM) blocks lipid storage in adipocytes, thereby preventing obesity caused by a high-fat diet, we here explored a strategy to augment circulating AIM levels. We synthesized the Fc portion of the soluble human immunoglobulin (Ig)M heavy chain and found that it formed a pentamer containing IgJ as natural IgM does, and effectively associated with AIM in vitro. When we injected the synthesized Fc intravenously into mice lacking circulating IgM, it associated with endogenous mouse AIM, protecting AIM from renal excretion and preserving the circulating AIM levels. As the synthesized Fc lacked the antigen-recognizing variable region, it provoked no undesired immune response. In addition, a challenge with the Fc-human AIM complex in wild-type mice, which exhibited normal levels of circulating IgM and AIM, successfully maintained the levels of the human AIM in mouse blood. We also observed that the human AIM was effectively incorporated into adipocytes in visceral fat tissue, suggesting its functionality against obesity. Thus, our findings reveal potent strategies to safely increase AIM levels, which could form the basis for developing novel therapies for obesity. PMID- 24804994 TI - Aluminum complexes with bidentate amido ligands: synthesis, structure and performance on ligand-initiated ring-opening polymerization of rac-lactide. AB - A series of mononuclear aluminum dimethyl complexes bearing bidentate N-[2-(1 piperidinyl)benzyl]anilino or N-(2-morpholinobenzyl)anilino ligands were synthesized via reactions of the corresponding proligands with trimethylaluminum upon heating, while at ambient temperature two trimethylaluminum adducts with neutral N-[2-(1-piperidinyl)benzyl]aniline proligands were obtained. These complexes were well characterized by NMR spectroscopy, elemental analysis and occasionally by EI-HRMS. The molecular structures of the typical trimethylaluminum adduct 2b and aluminum dimethyl complex 3b were further confirmed by X-ray diffraction studies. All the aluminum dimethyl complexes could effectively initiate the ring-opening polymerization (ROP) of rac-lactide in a well-controlled manner to afford PLAs with narrow molecular weight distributions (PDI = 1.06-1.18). The polymer samples obtained are systematically end-capped with the bidentate ancillary ligands as characterized by (1)H NMR and ESI-TOF mass spectroscopy. Moreover, the introduction of substituent(s) at the ortho position(s) of the anilino moiety in the ligand results in an obvious decrease in the catalytic activity of the corresponding aluminum complex, and complexes with meta-chloro substituted anilino units show higher activities likely due to the enhanced electrophilicity of the metal centers induced by the anilino groups. PMID- 24804993 TI - Induction of mixed chimerism using combinatory cell-based immune modulation with mesenchymal stem cells and regulatory T cells for solid-organ transplant tolerance. AB - Establishment of mixed chimerism is an ideal approach to induce donor-specific tolerance while expanding its potential in various clinical settings. Despite the developments in partial conditioning regimens, improvements are still needed in reducing toxicity and bone marrow transplantation-related complications. Recently, cell-based therapies, including mesenchymal stem cells (MSCs), have been incorporated in establishing noncytoreductive mixed chimerism protocols; however, its efficacy is only partial and shows reversed immunosuppressive properties. This study demonstrates a novel approach to induce mixed chimerism and tolerance through combinatory cell-based immune modulation (CCIM) of MSCs and regulatory T cells (Tregs). We hypothesize that the interaction between these cells may lead to greater inhibition of host immune responses. Compared with single cell therapy, CCIM induced a higher engraftment rate and robust donor specific tolerance to skin allografts across full major histocompatibility complex barriers. These regulatory effects were associated with inhibition of natural killer cell cytotoxic activity, CD4(+)IL-17(+) cells, memory B cells, plasma cells, and immunoglobulin production levels along with increased frequencies of CD4(+)Foxp3(+) cells, IL-10-producing mature B cells, and myeloid derived suppressor cells. Furthermore, CCIM was able to regulate mortality in a graft-versus-host disease model through reciprocal regulation of Treg/Th17. Taken together, we suggest CCIM as a clinically applicable strategy for facilitating the induction of mixed chimerism and permanent tolerance. PMID- 24804995 TI - Relationship between cytokine gene polymorphisms and risk of postoperative pneumonia with esophageal cancer. AB - BACKGROUND: We retrospectively evaluated the relationship between cytokine gene polymorphisms and development of postoperative pneumonia after esophagectomy. METHODS: In 120 patients who underwent esophagectomy, serum samples were obtained to measure levels of serum interleukin (IL)-6 and IL-10 at four time points (preoperatively, postoperative day (POD)0, POD1, and POD3). DNA extracted from peripheral blood in all patients was analyzed to determine polymorphisms of cytokines such as tumor necrosis factor-alpha -1031 T/C, IL-1beta -511C/T, IL-6 634C/G, and IL-10 -819 T/C. RESULTS: Postoperative pneumonia arose in 34 patients (28.3 %). Perioperative serum IL-10 levels were significantly higher for IL-10 819 C/T + C/C genotypes than for T/T genotypes (POD0 16.7 +/- 2.84 vs. 8.54 +/- 0.87 pg/ml, p = 0.0002; POD1 14.0 +/- 2.64 vs. 8.8 +/- 0.87 pg/ml, p = 0.0143; POD3 8.9 +/- 2.67 vs. 4.4 +/- 0.52 pg/ml, p = 0.0076). The frequency of the IL-10 -819 T/T genotype was significantly higher in patients with postoperative pneumonia than in patients without pneumonia (p = 0.0323). Multivariate analysis of factors such as sex, smoking, length of operation, field of lymph node dissection, and IL-10 polymorphism identified IL-10 polymorphism as independent predictor of postoperative pneumonia. CONCLUSIONS: Patients with IL-10 -819 T/T genotype may be at high risk for postoperative pneumonia after esophagectomy. PMID- 24804997 TI - Reverence for the organ donor. PMID- 24804996 TI - Tumor necrosis factor-related apoptosis-inducing ligand on NK cells protects from hepatic ischemia-reperfusion injury. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) significantly contributes to graft dysfunction after liver transplantation. Natural killer (NK) cells are crucial innate effector cells in the liver and express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of hepatocyte cell death. Here, we investigated if TRAIL expression on NK cells contributes to hepatic IRI. METHODS: The outcome after partial hepatic IRI was assessed in TRAIL-null mice and contrasted to C57BL/6J wild-type mice and after NK cell adoptive transfer in RAG2/common gamma-null mice that lack T, B, and NK cells. Liver IRI was assessed by histological analysis, alanine aminotransferase, hepatic neutrophil activation by myeloperoxidase activity, and cytokine secretion at specific time points. NK cell cytotoxicity and differentiation were assessed in vivo and in vitro. RESULTS: Twenty-four hours after reperfusion, TRAIL-null mice exhibited significantly higher serum transaminases, histological signs of necrosis, neutrophil infiltration, and serum levels of interleukin-6 compared to wild-type animals. Adoptive transfer of TRAIL-null NK cells into immunodeficient RAG2/common gamma-null mice was associated with significantly elevated liver damage compared to transfer of wild-type NK cells. In TRAIL-null mice, NK cells exhibit higher cytotoxicity and decreased differentiation compared to wild-type mice. In vitro, cytotoxicity against YAC-1 and secretion of interferon gamma by TRAIL-null NK cells were significantly increased compared to wild-type controls. CONCLUSIONS: These experiments reveal that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI through modulation of NK cell cytotoxicity and NK cell differentiation. PMID- 24804998 TI - Six-Step Recanalization Manual Therapy: A Novel Method for Treating Plugged Ducts in Lactating Women. AB - BACKGROUND: Plugged ducts are a common, painful condition in lactating women, but no standard treatment is currently available. OBJECTIVE: This study aimed to evaluate the clinical efficacy of a newly established 6-step recanalization manual therapy (SSRMT) for treating plugged ducts. METHODS: This observational study included 3497 lactating women with plugged ducts. The SSRMT comprised the following well-defined steps: (1) preparation, (2) clearing the plugged duct outlets, (3) nipple manipulation, (4) pushing and pressing the areola, (5) pushing and kneading the breast, and (6) checking for residual milk stasis. The response to the treatment was graded as I (complete resolution), II (marked improvement), III (improvement), or IV (no response). RESULTS: Of the 3497 patients, the mean age was 26.7 years and 3284 (93.9%) patients were primiparas. Fever was present in 1231 (35.2%) patients. After a single SSRMT treatment, 3189 (91.2%), 173 (4.9%), and 83 (2.4%) patients achieved grade I, II, and III responses, respectively, with only 52 (1.5%) showing unresponsiveness. For the 308 (8.8% of total) non-grade I patients, a second SSRMT given 3 days later resulted in grade I, II, and III responses in 267 (7.6% of total), 28 (0.8% of total), and 13 (0.4% of total) patients, respectively, and none were absolutely unresponsive. No complications with clinical significance were observed. CONCLUSION: Based on this large-scale clinical observation, SSRMT appears to be a useful, safe, low-cost treatment for postpartum plugged milk ducts. PMID- 24805004 TI - Kinetic diastereomer differentiation in Au(III)- and Bi(III)-catalyzed benzylic arylation: concise and stereocontrolled synthesis of 2-amino-1,1-diarylalkanes. AB - Benzylic alcohols carrying an adjacent alpha-nitro or alpha-azido group on the alkane chain are converted into syn-1,1-diaryl-2-nitro- and 2-azidoalkanes with electron-rich arenes in stereoselective reactions catalyzed by Bronsted and Lewis acids. Gold(III) chloride and bismuth(III) triflate were found to be especially efficient as catalysts, showing kinetically controlled differentiation in the reactivity of diastereomeric alpha-substituted benzyl alcohols. Applications to therapeutically relevant syn- and anti- 2-amino-1,1-diarylalkanes are projected. PMID- 24804999 TI - Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels. AB - Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain. Decreased GSH levels are associated with neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Here we show that a diurnal fluctuation of GSH levels is correlated with neuroprotective activity against oxidative stress in dopaminergic cells. In addition, we found that the cysteine transporter excitatory amino acid carrier 1 (EAAC1), which is involved in neuronal GSH synthesis, is negatively regulated by the microRNA miR-96-5p, which exhibits a diurnal rhythm. Blocking miR-96-5p by intracerebroventricular administration of an inhibitor increased the level of EAAC1 as well as that of GSH and had a neuroprotective effect against oxidative stress in the mouse substantia nigra. Our results suggest that the diurnal rhythm of miR-96-5p may play a role in neuroprotection by regulating neuronal GSH levels via EAAC1. PMID- 24805005 TI - The interactive effect of MAOA-LPR genotype and childhood physical neglect on aggressive behaviors in Italian male prisoners. AB - Aggressive disorders are moderately heritable; therefore, identification of genetic influences is important. The X-linked MAOA gene, encoding the MAOA enzyme, has a functional 30 bp repeat polymorphism in the promoter region (MAOA LPR) that has been shown to influence aggression. Childhood trauma is a known risk factor for numerous psychopathologies in adulthood including aggressive behaviors. We investigated the interactive effect of MAOA-LPR genotype and a history of childhood trauma in predicting aggressive behaviors in a prisoner population. A total of 692 male prisoners were genotyped for MAOA-LPR with genotypes grouped into high and low transcriptional activity. Participant evaluations included measures of aggression (Brown-Goodwin Lifetime History of Aggression, BGHA), hostility (Buss-Durkee Hostility Inventory), impulsivity (Barratt Impulsiveness Scale), violence directed toward self and others, and childhood trauma [Childhood Trauma Questionnaire (CTQ)]. MAOA-LPR interacted with CTQ physical neglect (PN), the most common (47%) form of childhood trauma in this sample, to predict BGHA aggression (P = 0.002). Within the group not exposed to PN, carriers of the MAOA-LPR high-activity variant were more aggressive: (tR = 2.47, P < 0.014). We observed a crossover effect in that the increase in aggression scores with PN was greater in low-activity individuals (tR = 5.55, P < 0.0001) than in high-activity individuals (tR = 4.18, P < 0.0001). These findings suggest that childhood trauma and the functional MAOA-LPR polymorphism may interact to specifically increase risk for over aggressive behavior but not impulsivity or hostility. The MAOA-LPR low-activity variant may be protective against the development of aggressive behavior under low stress conditions, at least in this prisoner population. PMID- 24805006 TI - Biochemical comparison of four commercially available C1 esterase inhibitor concentrates for treatment of hereditary angioedema. AB - BACKGROUND: For safe and efficacious treatment of hereditary angioedema, C1 esterase inhibitor (C1-INH) concentrates should have high purity and high amounts of functional protein. As no pharmacopoeia requirements exist for C1-INH concentrate lot release, biochemical characteristics as declared by the manufacturers may not be compared directly. This study compared the characteristics and purity profiles of four commercially available C1-INH concentrates. STUDY DESIGN AND METHODS: The analysis included one transgenic (Ruconest) and three plasma-derived (Berinert, Cetor, Cinryze) C1-INH concentrates. C1-INH antigen concentration was determined by nephelometry, total protein (specific activity) with a Bradford assay, purity by size-exclusion chromatography and gel electrophoresis, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was performed. RESULTS: Functionality (inversely proportional to antigen-to-activity ratio) was lowest for Ruconest (1.67), followed by Cetor (1.42), Berinert (1.24), and Cinryze (1.22). Specific activity (U/mg) and purity (%) were highest in Ruconest (12.13; 98.6) and Berinert (11.57; 97.0), followed by Cinryze (10.41; 89.5) and Cetor (9.01; 88.6). Main protein bands were found for all plasma-derived products at approximately 105 kDa, and for Ruconest, at approximately 98 kDa. Additional bands in the plasma-derived products were alpha1-antichymotrypsin, ceruloplasmin, Factor C3 (Cinryze/Cetor), and immunoglobulin heavy constant mu (Berinert). CONCLUSION: Ruconest has a very high purity profile but is not identical to the human C1-INH protein. Of the plasma-derived products, Berinert has the highest purity profile. The impact of the nontherapeutic proteins identified has not yet been evaluated. For harmonization of the analysis for drug release, we recommend the establishment of regulatory requirements for purity determination and the implementation of threshold levels in C1-INH concentrates. PMID- 24805008 TI - Minimally invasive endoscopic surgery for treatment of spontaneous intracerebral hematomas: a single-center analysis. AB - BACKGROUND: Endoscopic minimally invasive surgery to evacuate ICH has been reported to be more effective than conservative treatment or standard surgical craniotomy. However, most of these reports are based on Asian populations, while European reports do not exist. Here, we, therefore, report our experience from a European neurosurgical stroke center. METHODS: The variables assessed were patient characteristics, technical aspects of surgery, surgical complications, the outcomes grade of hematoma evacuation, 30-day mortality, and functional outcome (defined by modified Rankin Scale, mRS). The mRS was dichotomized into favorable (0-3) and unfavorable outcome (4-6). Mortality was compared to external evidence on conservatively and surgically treated patients by Poisson regression analysis with adjustment for ICH score. RESULTS: Thirty-four patients with ICH were analyzed. The mean age was 62 (standard deviation [SD] 12) years, mean hematoma volume (SD) was 84 (35) ml, and mean time from onset to surgery (SD) was 17 (10) h. Operative times did not exceed 1.5 h. A significant mean hematoma reduction (SD) from 84 (35) ml to 21 (30) ml (p < 0.0001) could be achieved, resulting in a median evacuation rate of 87 %. Early complications related to surgery did not occur. A favorable outcome was observed in 44 % of the patients. Overall, 30-day mortality was 18 %. The relative risk of mortality compared to conventional treatment from other studies was 32 % (95 % confidence interval 23 43 %, p = 0.02). CONCLUSIONS: This European surgical stroke center series of an endoscopic operative technique demonstrates safety and efficacy with regard to reduction of hematoma size in patients with large and space-occupying spontaneous ICH. The study suggests that low mortality and acceptable outcomes may be achievable by minimally invasive hematoma surgery. Whether this technique reduces long-term morbidity compared to standard treatment needs to be further investigated in larger prospective randomized controlled trials. PMID- 24805009 TI - Gait adaptation during walking on an inclined pathway following spinal cord injury. AB - BACKGROUND: Individuals with incomplete spinal cord injury need to be assessed in different environments. The objective of this study was to compare lower-limb power generation in subjects with spinal cord injury and healthy subjects while walking on an inclined pathway. METHODS: Eleven subjects with spinal cord injury and eleven healthy subjects walked on an inclined pathway at their natural gait speed and at slow gait speed (healthy subjects only). Ground reaction forces were recorded by force plates embedded in the inclined pathway and a 3-D motion analysis system recorded lower-limb motions. Data analysis included gait cycle parameters and joint peak powers. Differences were identified by student t-tests. FINDINGS: Gait cycle parameters were lower in spinal cord injury subjects compared to healthy subjects at natural speed but similar at slow gait speed. Subjects with spinal cord injury presented lower power at the ankle, knee and hip compared to healthy subjects at natural gait speed while only the power generation at push-off remained lower when the two groups performed at similar speed. INTERPRETATION: The most important differences are associated with the fact that individuals with spinal cord injury walk at a slower speed, except for the ankle power generation. This study demonstrated that, even with a good motor recovery, distal deficits remain and may limit the ability to adapt to uphill and downhill walking. Inclined pathways are indicated to train patients with spinal cord injury. Clinicians should focus on the speed of uphill and downhill walking and on the use of plantar flexors. PMID- 24805011 TI - A day to celebrate the profession. PMID- 24805007 TI - Potentially inappropriate medication use is associated with clinical outcomes in critically ill elderly patients with neurological injury. AB - BACKGROUND: Limited data suggest that potentially inappropriate medications (PIMs) impact outcomes in critically ill elderly patients. No data are available on the association between PIM use as well as drug burden index (DBI), which is a measure of PIM use, and clinical outcomes in neurocritical care elderly patients. This study evaluates whether PIM use and a higher DBI are associated with poor clinical outcomes in neurocritical care elderly patients. METHODS: PIMs were retrospectively identified in critically ill elderly patients admitted to the neuroscience intensive care unit (NSICU) from March to July 2011. DBI was calculated based on PIM doses. Relationships with clinical outcomes were evaluated. RESULTS: PIMs were prescribed to a majority (81.3 %) of the 112 patients. Opioids were most commonly associated with a decrease in Richmond Agitation Sedation Scale (RASS) scores (56 % of PIM doses). Time to recovery was significantly longer in patients with a higher PIM burden (<=2 PIMs: 8 h, >2 PIMs: 29 h; p = 0.02). There was a significantly longer NSICU and hospital length of stay (9 vs 2; 15 vs 5 days; p < 0.0001) as well as a lower Glasgow Coma Scale score upon discharge (14 vs 15, p = 0.02) in patients with a higher DBI after 72 h of hospitalization. There was no difference in mortality. CONCLUSIONS: PIM use and higher DBI scores were associated with poor clinical outcomes and longer lengths of stay. Further studies are needed to determine the impact of PIMs and DBI on mortality in neurocritical care elderly patients. PMID- 24805019 TI - Service reorganisation puts school nurses under pressure to close gaps in provision. PMID- 24805024 TI - Research essentials. PMID- 24805026 TI - Family-centred care conflicts with need for parents to be a 'safe haven'. PMID- 24805028 TI - Student voice -- on my own. PMID- 24805031 TI - A school for health. PMID- 24805032 TI - The case for a children's multidisciplinary food allergy clinic. AB - In the UK, up to 6% of children are affected by food allergy. Accurate diagnosis, appropriate dietary management, family education, support and continuing follow up are essential to prevent further reactions and optimise the child's nutritional intake and growth. Setting up an improved, one- stop service to achieve these goals, which includes the multidisciplinary team, is feasible and cost neutral. This audit and service evaluation involved questionnaires with parents and staff focus groups to examine provision in one area of England. The views of children were not included. Practitioners involved should consider further training if necessary. PMID- 24805033 TI - Support requirements of parents caring for a child with disability and complex health needs. AB - AIM: To investigate the experiences of parents of children with complex health needs in relation to the help and support they receive when caring for their child. METHOD: A series of in-depth semi-structured interviews undertaken with the parents of 34 children (33 families) with a disability or a complex health need. Families were categorised into one of three subgroups: children with a disability, children with a life-limiting or life-threatening illness, or children with technology dependence. FINDINGS: In relation to parental experience of the need for help and support, two major categories were identified, namely 'people', and 'processes and resources', as well as a series of subcategories. Respite care was identified as the greatest unmet need. CONCLUSION: Parents identified a range of helping behaviours among key professional staff involved in support provision. The greatest area of unmet needs is for respite care. PMID- 24805034 TI - Service user input in pre-registration children's nursing education. AB - The Nursing and Midwifery Council pre-registration standards include service user involvement in all aspects of the curricula, and the subject has been high on the healthcare agenda for more than a decade. In 2008, service user involvement in a pre-registration children's nursing programme at a UK university was planned, implemented and further developed. The strategy was effective in recruiting and selecting students, but caution is needed to ensure the process is safe for all participants. PMID- 24805035 TI - Health literacy and its importance for effective communication. Part 2. AB - This is the second of two articles exploring the concept of health literacy, an often hidden barrier to effective healthcare communication. Part 1 was published in April ( Lambert and Keogh 2014 ). This article explains how to detect low levels of health literacy among parents and children, and outlines the challenges to assessing health literacy levels, including the stigma and discrimination some people experience. Some basic healthcare communication strategies for supporting health literacy in practice are suggested. PMID- 24805036 TI - Differential distribution of V-type H(+)-ATPase and Na (+)/K (+)-ATPase in the branchial chamber of the palaemonid shrimp Macrobrachium amazonicum. AB - V-H(+)-ATPase and Na(+)/K(+)-ATPase were localized in the gills and branchiostegites of M. amazonicum and the effects of salinity on the branchial chamber ultrastructure and on the localization of transporters were investigated. Gills present septal and pillar cells. In freshwater (FW), the apical surface of pillar cells is amplified by extensive evaginations associated with mitochondria. V-H(+)-ATPase immunofluorescence was localized in the membranes of the apical evaginations and in clustered subapical areas of pillar cells, suggesting labeling of intracellular vesicle membranes. Na(+)/K(+)-ATPase labeling was restricted to the septal cells. No difference in immunostaining was recorded for both proteins according to salinity (FW vs. 25 PSU). In the branchiostegite, both V-H(+)-ATPase and Na(+)/K(+)-ATPase immunofluorescence were localized in the same cells of the internal epithelium. Immunogold revealed that V-H(+)-ATPase was localized in apical evaginations and in electron-dense areas throughout the inner epithelium, while Na(+)/K(+)-ATPase occurred densely along the basal infoldings of the cytoplasmic membrane. Our results suggest that morphologically different cell types within the gill lamellae may also be functionally specialized. We propose that, in FW, pillar cells expressing V-H(+)-ATPase absorb ions (Cl(-), Na(+)) that are transported either directly to the hemolymph space or through a junctional complex to the septal cells, which may be responsible for active Na(+) delivery to the hemolymph through Na(+)/K(+)-ATPase. This suggests a functional link between septal and pillar cells in osmoregulation. When shrimps are transferred to FW, gill and branchiostegite epithelia undergo ultrastructural changes, most probably resulting from their involvement in osmoregulatory processes. PMID- 24805037 TI - Novel arylsulfonamide derivatives with 5-HT6/5-HT7 receptor antagonism targeting behavioral and psychological symptoms of dementia. AB - In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3 (piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro 1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population. PMID- 24805038 TI - Generalization characteristics of complex-valued feedforward neural networks in relation to signal coherence. AB - Applications of complex-valued neural networks (CVNNs) have expanded widely in recent years-in particular in radar and coherent imaging systems. In general, the most important merit of neural networks lies in their generalization ability. This paper compares the generalization characteristics of complex-valued and real valued feedforward neural networks in terms of the coherence of the signals to be dealt with. We assume a task of function approximation such as interpolation of temporal signals. Simulation and real-world experiments demonstrate that CVNNs with amplitude-phase-type activation function show smaller generalization error than real-valued networks, such as bivariate and dual-univariate real-valued neural networks. Based on the results, we discuss how the generalization characteristics are influenced by the coherence of the signals depending on the degree of freedom in the learning and on the circularity in neural dynamics. PMID- 24805039 TI - Tackling learning intractability through topological organization and regulation of cortical networks. AB - A key challenge in evolving control systems for robots using neural networks is training tractability. Evolving monolithic fixed topology neural networks is shown to be intractable with limited supervision in high dimensional search spaces. Common strategies to overcome this limitation are to provide more supervision by encouraging particular solution strategies, manually decomposing the task and segmenting the search space and network. These strategies require a supervisor with domain knowledge and may not be feasible for difficult tasks where novel concepts are required. The alternate strategy is to use self organized task decomposition to solve difficult tasks with limited supervision. The artificial neural tissue (ANT) approach presented here uses self-organized task decomposition to solve tasks. ANT inspired by neurobiology combines standard neural networks with a novel wireless signaling scheme modeling chemical diffusion of neurotransmitters. These chemicals are used to dynamically activate and inhibit wired network of neurons using a coarse-coding framework. Using only a global fitness function that does not encourage a predefined solution, modular networks of neurons are shown to self-organize and perform task decomposition. This approach solves the sign-following task found to be intractable with conventional fixed and variable topology networks. In this paper, key attributes of the ANT architecture that perform self-organized task decomposition are shown. The architecture is robust and scalable to number of neurons, synaptic connections, and initialization parameters. PMID- 24805040 TI - Neural learning circuits utilizing nano-crystalline silicon transistors and memristors. AB - Properties of neural circuits are demonstrated via SPICE simulations and their applications are discussed. The neuron and synapse subcircuits include ambipolar nano-crystalline silicon transistor and memristor device models based on measured data. Neuron circuit characteristics and the Hebbian synaptic learning rule are shown to be similar to biology. Changes in the average firing rate learning rule depending on various circuit parameters are also presented. The subcircuits are then connected into larger neural networks that demonstrate fundamental properties including associative learning and pulse coincidence detection. Learned extraction of a fundamental frequency component from noisy inputs is demonstrated. It is then shown that if the fundamental sinusoid of one neuron input is out of phase with the rest, its synaptic connection changes differently than the others. Such behavior indicates that the system can learn to detect which signals are important in the general population, and that there is a spike timing-dependent component of the learning mechanism. Finally, future circuit design and considerations are discussed, including requirements for the memristive device. PMID- 24805041 TI - Spiking neural network model of sound localization using the interaural intensity difference. AB - In this paper, a spiking neural network (SNN) architecture to simulate the sound localization ability of the mammalian auditory pathways using the interaural intensity difference cue is presented. The lateral superior olive was the inspiration for the architecture, which required the integration of an auditory periphery (cochlea) model and a model of the medial nucleus of the trapezoid body. The SNN uses leaky integrate-and-fire excitatory and inhibitory spiking neurons, facilitating synapses and receptive fields. Experimentally derived head related transfer function (HRTF) acoustical data from adult domestic cats were employed to train and validate the localization ability of the architecture, training used the supervised learning algorithm called the remote supervision method to determine the azimuthal angles. The experimental results demonstrate that the architecture performs best when it is localizing high-frequency sound data in agreement with the biology, and also shows a high degree of robustness when the HRTF acoustical data is corrupted by noise. PMID- 24805042 TI - Minimum data requirement for neural networks based on power spectral density analysis. AB - One of the most critical challenges ahead for diesel engines is to identify new techniques for fuel economy improvement without compromising emissions regulations. One technique is the precise control of air/fuel ratio, which requires the measurement of instantaneous fuel consumption. Measurement accuracy and repeatability for fuel rate is the key to successfully controlling the air/fuel ratio and real-time measurement of fuel consumption. The volumetric and gravimetric measurement principles are well-known methods for measurement of fuel consumption in internal combustion engines. However, the fuel flow rate measured by these methods is not suitable for either real-time control or real-time measurement purposes because of the intermittent nature of the measurements. This paper describes a technique that can be used to find the minimum data [consisting of data from just 2.5% of the non-road transient cycle (NRTC)] to solve the problem concerning discontinuous data of fuel flow rate measured using an AVL 733S fuel meter for a medium or heavy-duty diesel engine using neural networks. Only torque and speed are used as the input parameters for the fuel flow rate prediction. Power density analysis is used to find the minimum amount of the data. The results show that the nonlinear autoregressive model with exogenous inputs could predict the particulate matter successfully with R(2) above 0.96 using 2.5% NRTC data with only torque and speed as inputs. PMID- 24805043 TI - Feature extraction with deep neural networks by a generalized discriminant analysis. AB - We present an approach to feature extraction that is a generalization of the classical linear discriminant analysis (LDA) on the basis of deep neural networks (DNNs). As for LDA, discriminative features generated from independent Gaussian class conditionals are assumed. This modeling has the advantages that the intrinsic dimensionality of the feature space is bounded by the number of classes and that the optimal discriminant function is linear. Unfortunately, linear transformations are insufficient to extract optimal discriminative features from arbitrarily distributed raw measurements. The generalized discriminant analysis (GerDA) proposed in this paper uses nonlinear transformations that are learnt by DNNs in a semisupervised fashion. We show that the feature extraction based on our approach displays excellent performance on real-world recognition and detection tasks, such as handwritten digit recognition and face detection. In a series of experiments, we evaluate GerDA features with respect to dimensionality reduction, visualization, classification, and detection. Moreover, we show that GerDA DNNs can preprocess truly high-dimensional input data to low-dimensional representations that facilitate accurate predictions even if simple linear predictors or measures of similarity are used. PMID- 24805044 TI - Fast and efficient second-order method for training radial basis function networks. AB - This paper proposes an improved second order (ISO) algorithm for training radial basis function (RBF) networks. Besides the traditional parameters, including centers, widths and output weights, the input weights on the connections between input layer and hidden layer are also adjusted during the training process. More accurate results can be obtained by increasing variable dimensions. Initial centers are chosen from training patterns and other parameters are generated randomly in limited range. Taking the advantages of fast convergence and powerful search ability of second order algorithms, the proposed ISO algorithm can normally reach smaller training/testing error with much less number of RBF units. During the computation process, quasi Hessian matrix and gradient vector are accumulated as the sum of related sub matrices and vectors, respectively. Only one Jacobian row is stored and used for multiplication, instead of the entire Jacobian matrix storage and multiplication. Memory reduction benefits the computation speed and allows the training of problems with basically unlimited number of patterns. Several practical discrete and continuous classification problems are applied to test the properties of the proposed ISO training algorithm. PMID- 24805045 TI - General robot kinematics decomposition without intermediate markers. AB - The calibration of serial manipulators with high numbers of degrees of freedom by means of machine learning is a complex and time-consuming task. With the help of a simple strategy, this complexity can be drastically reduced and the speed of the learning procedure can be increased. When the robot is virtually divided into shorter kinematic chains, these subchains can be learned separately and hence much more efficiently than the complete kinematics. Such decompositions, however, require either the possibility to capture the poses of all end effectors of all subchains at the same time, or they are limited to robots that fulfill special constraints. In this paper, an alternative decomposition is presented that does not suffer from these limitations. An offline training algorithm is provided in which the composite subchains are learned sequentially with dedicated movements. A second training scheme is provided to train composite chains simultaneously and online. Both schemes can be used together with many machine learning algorithms. In the simulations, an algorithm using parameterized self-organizing maps modified for online learning and Gaussian mixture models (GMMs) were chosen to show the correctness of the approach. The experimental results show that, using a twofold decomposition, the number of samples required to reach a given precision is reduced to twice the square root of the original number. PMID- 24805046 TI - Feature extraction for change-point detection using stationary subspace analysis. AB - Detecting changes in high-dimensional time series is difficult because it involves the comparison of probability densities that need to be estimated from finite samples. In this paper, we present the first feature extraction method tailored to change-point detection, which is based on an extended version of stationary subspace analysis. We reduce the dimensionality of the data to the most nonstationary directions, which are most informative for detecting state changes in the time series. In extensive simulations on synthetic data, we show that the accuracy of three change-point detection algorithms is significantly increased by a prior feature extraction step. These findings are confirmed in an application to industrial fault monitoring. PMID- 24805047 TI - Tangent hyperplane kernel principal component analysis for denoising. AB - Kernel principal component analysis (KPCA) is a method widely used for denoising multivariate data. Using geometric arguments, we investigate why a projection operation inherent to all existing KPCA denoising algorithms can sometimes cause very poor denoising. Based on this, we propose a modification to the projection operation that remedies this problem and can be incorporated into any of the existing KPCA algorithms. Using toy examples and real datasets, we show that the proposed algorithm can substantially improve denoising performance and is more robust to misspecification of an important tuning parameter. PMID- 24805048 TI - Modified Kolmogorov's neural network in the identification of Hammerstein and Wiener systems. AB - This brief deals with the possibilities of using the modified Kolmogorov's neural network for the identification of non-linear dynamic systems, among them the Wiener and Hammerstein systems. The algorithm of training the network is simple, well convergent and with a small error of approximation. The modified neural network is characterized by a simple computer algorithm; it also omits complicated techniques of back propagation. The simulation results are shown to illustrate the modified Kolmogorov theorem. PMID- 24805049 TI - Mode and delay-dependent adaptive exponential synchronization in pth moment for stochastic delayed neural networks with Markovian switching. AB - In this brief, the analysis problem of the mode and delay-dependent adaptive exponential synchronization in th moment is considered for stochastic delayed neural networks with Markovian switching. By utilizing a new nonnegative function and the -matrix approach, several sufficient conditions to ensure the mode and delay-dependent adaptive exponential synchronization in th moment for stochastic delayed neural networks are derived. Via the adaptive feedback control techniques, some suitable parameters update laws are found. To illustrate the effectiveness of the -matrix-based synchronization conditions derived in this brief, a numerical example is provided finally. PMID- 24805050 TI - A priori guaranteed evolution within the neural network approximation set and robustness expansion via prescribed performance control. AB - A neuroadaptive control scheme for strict feedback systems is designed, which is capable of achieving prescribed performance guarantees for the output error while keeping all closed-loop signals bounded, despite the presence of unknown system nonlinearities and external disturbances. The aforementioned properties are induced without resorting to a special initialization procedure or a tricky control gains selection, but addressing through a constructive methodology the longstanding problem in neural network control of a priori guaranteeing that the system states evolve strictly within the compact region in which the approximation capabilities of neural networks hold. Moreover, it is proven that robustness against external disturbances is significantly expanded, with the only practical constraint being the magnitude of the required control effort. A comparative simulation study clarifies and verifies the approach. PMID- 24805051 TI - Analysis on the convergence time of dual neural network-based kWTA. AB - A k-winner-take-all (kWTA) network is able to find out the k largest numbers from n inputs. Recently, a dual neural network (DNN) approach was proposed to implement the kWTA process. Compared to the conventional approach, the DNN approach has much less number of interconnections. A rough upper bound on the convergence time of the DNN-kWTA model, which is expressed in terms of input variables, was given. This brief derives the exact convergence time of the DNN kWTA model. With our result, we can study the convergence time without spending excessive time to simulate the network dynamics. We also theoretically study the statistical properties of the convergence time when the inputs are uniformly distributed. Since a nonuniform distribution can be converted into a uniform one and the conversion preserves the ordering of the inputs, our theoretical result is also valid for nonuniformly distributed inputs. PMID- 24805052 TI - Reducing the number of support vectors of SVM classifiers using the smoothed separable case approximation. AB - In this brief, we propose a new method to reduce the number of support vectors of support vector machine (SVM) classifiers. We formulate the approximation of an SVM solution as a classification problem that is separable in the feature space. Due to the separability, the hard-margin SVM can be used to solve it. This approach, which we call the separable case approximation (SCA), is very similar to the cross-training algorithm explained in , which is inspired by editing algorithms . The norm of the weight vector achieved by SCA can, however, become arbitrarily large. For that reason, we propose an algorithm, called the smoothed SCA (SSCA), that additionally upper-bounds the weight vector of the pruned solution and, for the commonly used kernels, reduces the number of support vectors even more. The lower the chosen upper bound, the larger this extra reduction becomes. Upper-bounding the weight vector is important because it ensures numerical stability, reduces the time to find the pruned solution, and avoids overfitting during the approximation phase. On the examined datasets, SSCA drastically reduces the number of support vectors. PMID- 24805054 TI - Transboundary secondary organic aerosol in western Japan indicated by the delta13C of water-soluble organic carbon and the m/z 44 signal in organic aerosol mass spectra. AB - The stable carbon isotope ratio (delta13C) of low-volatile water-soluble organic carbon (LV-WSOC) was measured in filter samples of total suspended particulate matter, collected every 24 h in the winter of 2010 at an urban site and two rural sites in western Japan. Concentrations of the major chemical species in fine aerosol (<1.0 MUm) were also measured in real time by aerosol mass spectrometers. The oxidation state of organic aerosol was evaluated using f44; i.e., the proportion of the signal at m/z 44 (CO2+ ions from the carboxyl group) to the sum of all m/z signals in the organic mass spectra. A strong correlation between LV WSOC and m/z 44 concentrations was observed, which suggested that LV-WSOC was likely to be associated with carboxylic acids in fine aerosol. Plots of delta13C of LV-WSOC versus f44 showed random variation at the urban site and systematic trends at the rural sites. The systematic trends qualitatively agreed with a simple binary mixture model of secondary organic aerosol with background LV-WSOC with an f44 of ~0.08 and delta13C of -170/00 or higher. Comparison with reference values suggested that the source of background LV-WSOC was likely to be primary emissions associated with C4 plants. PMID- 24805055 TI - Many-body van der Waals interactions in molecules and condensed matter. AB - This work reviews the increasing evidence that many-body van der Waals (vdW) or dispersion interactions play a crucial role in the structure, stability and function of a wide variety of systems in biology, chemistry and physics. Starting with the exact expression for the electron correlation energy provided by the adiabatic connection fluctuation-dissipation theorem, we derive both pairwise and many-body interatomic methods for computing the long-range dispersion energy by considering a model system of coupled quantum harmonic oscillators within the random-phase approximation. By coupling this approach to density functional theory, the resulting many-body dispersion (MBD) method provides an accurate and efficient scheme for computing the frequency-dependent polarizability and many body vdW energy in molecules and materials with a finite electronic gap. A select collection of applications are presented that ascertain the fundamental importance of these non-bonded interactions across the spectrum of intermolecular (the S22 and S66 benchmark databases), intramolecular (conformational energies of alanine tetrapeptide) and supramolecular (binding energy of the 'buckyball catcher') complexes, as well as molecular crystals (cohesive energies in oligoacenes). These applications demonstrate that electrodynamic response screening and beyond-pairwise many-body vdW interactions--both captured at the MBD level of theory--play a quantitative, and sometimes even qualitative, role in describing the properties considered herein. This work is then concluded with an in-depth discussion of the challenges that remain in the future development of reliable (accurate and efficient) methods for treating many-body vdW interactions in complex materials and provides a roadmap for navigating many of the research avenues that are yet to be explored. PMID- 24805057 TI - The antibacterial activity of phytochemically characterised fractions from Folium Syringae. AB - To identify the most active antimicrobial fraction of Folium Syringae, four common pathogens were used in an in vitro screening. The results indicated that the combination of the 30% and 60% ethanol fraction (FSC) obtained from the water extraction was the most active fraction with a minimal inhibitory concentration of 0.65 mg mL(-1). FSC was also found to be able to protect mice from a lethal infection of Staphylococcus aureus at clinical dosage (0.2 g kg(-1)) with a survival rate of 83.3%. The antibacterial activity of FSC was then tested using the serum pharmacology method which revealed that FSC exhibits a more long lasting activity than the positive control (levofloxacin hydrochloride). The main components were confirmed to be iridoid glycosides and flavones by HPLC-MS analysis. PMID- 24805056 TI - Cripto haploinsufficiency affects in vivo colon tumor development. AB - Colorectal cancer is one of the most common and aggressive cancers arising from alterations in various signaling pathways, such as the WNT, RAS-MAPK, PI3K and transforming growth factor-beta (TGF-beta) pathways. Cripto (also called Teratocarcinoma-derived growth factor), the original member of the vertebrate EGF CFC family, plays a key role in all of these pathways and is deeply involved in early embryo development and cancer progression. The role of Cripto in colon and breast cancer, in particular, has been investigated, as it is still not clearly understood. In this article, we provide the first in vivo functional evidence of a role of Cripto in colon cancer development. We analyzed the effect of Cripto haploinsufficiency on colon tumor formation by treating Cripto heterozygous mice with the colonotropic carcinogen azoxymethane (AOM). Of note, in our model system, Cripto haploinsufficiency increased tumorigenesis. Moreover, we revealed a correlation between the differential AOM response found in wt and Cripto+/- mice and the expression levels of glucose regulated protein-78 (Grp78), a heat shock protein required for Cripto signaling pathways. We hypothesize that the balance between Cripto and Grp78 expression levels might be crucial in cancer development and may account for the increased tumorigenesis in Cripto heterozygous mice. In summary, our results highlight the heterogeneous effect of Cripto on tumorigenesis and the consequent high level of complexity in the Cripto regulatory pathway, whose imbalance causes tumors. PMID- 24805058 TI - ABA signaling is necessary but not sufficient for RD29B transcriptional memory during successive dehydration stresses in Arabidopsis thaliana. AB - Plants subjected to a prior dehydration stress were seen to have altered transcriptional responses during a subsequent dehydration stress for up to 5 days after the initial stress. The abscisic acid (ABA) inducible RD29B gene of Arabidopsis thaliana was strongly induced after the first stress and displayed transcriptional memory with transcript levels nine-fold higher during the second dehydration stress. These increased transcript levels were due to an increased rate of transcription and are associated with an altered chromatin template during the recovery interval between the dehydration stresses. Here we use a combination of promoter deletion/substitutions, mutants in the trans-acting transcription factors and their upstream protein kinases, and treatments with exogenous ABA or dehydration stress to advance our understanding of the features required for transcriptional memory of RD29B. ABA Response Elements (ABREs) are sufficient to confer transcriptional memory on a minimal promoter, although there is a context effect from flanking sequences. Different mutations in Snf1 Related Protein Kinase 2 (SnRK2) genes positively and negatively affected the response, suggesting that this effect is important for transcriptional memory. Although exogenous ABA treatments could prime transcriptional memory, a second ABA treatment was not sufficient to activate transcriptional memory. Therefore, we concluded that transcriptional memory requires ABA and an ABA-independent factor that is induced or activated by a subsequent dehydration stress and directly or indirectly results in a more active RD29B chromatin template. These results advance our knowledge of the cis- and trans-acting factors that are required for transcriptional memory of RD29B. PMID- 24805059 TI - In vitro human hepatocyte-based experimental systems for the evaluation of human drug metabolism, drug-drug interactions, and drug toxicity in drug development. AB - Species difference in drug metabolism and drug toxicity is a well-established phenomenon. As a result, the classical paradigm of preclinical testing of drug candidates in animals may not be appropriate. One preclinical approach to evaluate human drug properties, especially ADMET (absorption, disposition, metabolism, elimination, and toxicity) properties, is to apply in vitro experimental systems with relevant human properties. The latest advances include the use of human hepatocytes to evaluate hepatic uptake, metabolism, efflux and toxicity. Successful cryopreservation of human hepatocytes to retain high viability, metabolic capacity, as well as the ability to be cultured allow routine application of this relevant experimental system. This review summarizes the latest findings on human hepatocytes isolation, cryopreservation, culturing, as well as application in the evaluation of metabolic stability, metabolite profiling, hepatic uptake and efflux, metabolic drug-drug interactions, and drug toxicity. The use of hepatocyte to evaluate the role of metabolism in drug toxicity represents a major advance in drug toxicity evaluation. The use of the novel integrated discrete multiple organ coculture (IdMOC) system allows the evaluation of the role of hepatic metabolism on nonhepatic toxicity. PMID- 24805060 TI - Tuning HERG out: antitarget QSAR models for drug development. AB - Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDArequired procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aimed to generate predictive and well-characterized quantitative structure-activity relationship (QSAR) models for hERG blockage using the largest publicly available dataset of 11,958 compounds from the ChEMBL database. The models have been developed and validated according to OECD guidelines using four types of descriptors and four different machine learning techniques. The classification accuracies discriminating blockers from non-blockers were as high as 0.83-0.93 on external set. Model interpretation revealed several SAR rules, which can guide structural optimization of some hERG blockers into non-blockers. We have also applied the generated models for screening the World Drug Index (WDI) database and identify putative hERG blockers and non-blockers among currently marketed drugs. The developed models can reliably identify blockers and non-blockers, which could be useful for the scientific community. A freely accessible web server has been developed allowing users to identify putative hERG blockers and non-blockers in chemical libraries of their interest (http://labmol.farmacia.ufg.br/predherg). PMID- 24805061 TI - In vitro microsomal hepatic metabolism of antiasthmatic prototype LASSBio-448. AB - In this paper, the in vitro microsomal hepatic metabolism of the antiasthmatic prototype LASSBio-448 and the structural identification of its major phase I metabolites were described. Incubation with pooled rat liver microsomes converted LASSBio-448 to the following major metabolites: O-demethyl-LASSBio-448 (M1) and 3,4-dihydroxyphenyl- LASSBio-448 (M2). These metabolites were formed by the dealkylation step of 3,4-dimethoxyphenyl and 1,3- benzodioxole subunits, respectively, in agreement with the in silico prediction using MetaSite Program. The development of a reproducible analytical methodology for the major metabolites by using HPLC-MS showed that both reactions require NADPH generating system and appeared to be catalyzed by cytochrome P450 (CYP). The identification of which isoenzyme was involved in the oxidative metabolism of LASSBio-448 was carried out by pre-incubations with the selective inhibitors sulfaphenazole (CYP2C9), quinidine (CYP2D6), furafylline (CYP1A2), p-nitrophenol (CYP2E1), ticlopidine (CYP2C19) and ketoconazole (CYP3A4). CYP1A2, CYP2C19 and CYP3A4 were demonstrated to be involved in the oxidative biotransformation of LASSBio-448. PMID- 24805062 TI - Mutagenicity of N-oxide containing heterocycles and related compounds: experimental and theoretical studies. AB - In the development of new drugs, it is very important to know the effects these may bring to those who consume them. Drugs which act upon certain diseases must not cause toxic side effects on healthy organs. These toxic side effects can be quite varied, i.e. mutagenicity, clastogenicity, teratogenicity, etc., but undoubtedly the mutagenicity officiate in the selection process, during preclinical testing, to advance in clinical trials. Mutagenic compounds are removed and cannot continue its development. There are preclinical studies of mutagenicity and genotoxicity, ranging from in vitro to in vivo studies. Particularly, Ames test is recommended by ICH as the first input in these studies. Herein, we investigated the mutagenicity of an in-house chemical library of eighty five N-oxide containing heterocycles using Ames test in Salmonella thyphimurium TA 98 with and without S9 activation and the use of neural networks in order to predict this nondesired activity. N-oxide containing heterocycles are especially relevant regarding its pharmacological activities as antitrypanosoma, anti-leishmania, anti-tuberculosis, anti-cancer, chemopreventive, anti inflammatory, anti-atherogenic, and analgesic agents. In some cases, a relationship was found between the presence of N-oxide and mutagenicity. Specifically, benzofuroxan system seems to be responsible for the mutagenicity of certain agents against Chagas disease and certain anti-inflammatory agents. However other N-oxides, such as furoxans with anti-inflammatory and anti atherosclerosis activities, seem to lack mutagenicity. In other cases, such as quinoxaline dioxides with anti-parasitic activity, mutagenicity shows to be substituent dependent. Applying CODES neural network two models were defined, one without metabolism and other with metabolism. These models predict the mutagenicity with and without metabolism in an excellent manner. PMID- 24805063 TI - Prediction of cytochrome p450 mediated metabolism of designer drugs. AB - The analysis of designer drugs in human plasma is highly complex, as most of these drugs are metabolized quickly, and often into multiple products. For novel designer drugs, it is common that reference compounds for these metabolites are unavailable at the time of analysis. Hence, the usage of in silico procedures to accurately predict the chemical structures of these metabolites would be very useful. In this study, the differences between several methods for prediction of site of metabolism for cytochrome P450 mediated drug metabolism are described, and their prediction accuracies are analyzed on a set of designer drugs. It is found that ligand-based methods, which are simpler and faster, are better than or at least as good as much more complex structure-based methods. PMID- 24805065 TI - Ritonavir analogues as a probe for deciphering the cytochrome P450 3A4 inhibitory mechanism. AB - Inactivation of human drug-metabolizing cytochrome P450 3A4 (CYP3A4) could lead to serious adverse events such as drug-drug interactions and toxicity. However, when properly controlled, CYP3A4 inhibition may be beneficial as it can improve clinical efficacy of co-administered therapeutics that otherwise are quickly metabolized by CYP3A4. Currently, the CYP3A4 inhibitor ritonavir and its derivative cobicistat are prescribed to HIV patients as pharmacoenhancers. Both drugs were designed based on the chemical structure/activity relationships rather than the CYP3A4 crystal structure. To unravel the structural basis of CYP3A4 inhibition, we compared the binding modes of ritonavir and ten analogues using biochemical, mutagenesis and x-ray crystallography techniques. This review summarizes our findings on the relative contribution of the heme-ligating moiety, side chains and the terminal group of ritonavir-like molecules to the ligand binding process, and highlights strategies for a structure-guided design of CYP3A4 inactivators. PMID- 24805066 TI - QM/MM modelling of drug-metabolizing enzymes. AB - Making reliable predictions of drug metabolites requires detailed knowledge of the chemical reactivity of drug metabolizing enzymes. Cytochrome P450 enzymes (P450s) play an important role in drug metabolism. Numerous adverse drug reactions have been identified that occur as a result of interactions with P450s. These enzymes display complex reactivity and the active oxidizing species is highly reactive and difficult to isolate, making P450s ideal candidates for computational study. Hybrid quantum mechanics/molecular mechanics calculations (QM/MM) have provided valuable insight into the reactivity of P450s, and will assist in the development of simpler predictive models. QM/MM methods have been used to model the metabolism of several drug molecules in human P450s, and have successfully rationalized experimentally observed selectivity. QM/MM calculations have been used to investigate the reactivity of other drug metabolizing enzymes, such as soluble epoxide hydrolase and glutathione transferases. Here, we review the application of QM/MM methods to modelling reactions catalyzed by drug metabolizing enzymes. PMID- 24805064 TI - Integrative approaches for predicting in vivo effects of chemicals from their structural descriptors and the results of short-term biological assays. AB - Cheminformatics approaches such as Quantitative Structure Activity Relationship (QSAR) modeling have been used traditionally for predicting chemical toxicity. In recent years, high throughput biological assays have been increasingly employed to elucidate mechanisms of chemical toxicity and predict toxic effects of chemicals in vivo. The data generated in such assays can be considered as biological descriptors of chemicals that can be combined with molecular descriptors and employed in QSAR modeling to improve the accuracy of toxicity prediction. In this review, we discuss several approaches for integrating chemical and biological data for predicting biological effects of chemicals in vivo and compare their performance across several data sets. We conclude that while no method consistently shows superior performance, the integrative approaches rank consistently among the best yet offer enriched interpretation of models over those built with either chemical or biological data alone. We discuss the outlook for such interdisciplinary methods and offer recommendations to further improve the accuracy and interpretability of computational models that predict chemical toxicity. PMID- 24805067 TI - Editorial: drug metabolism, toxicology experimental determination and theoretical prediction: challenges and perspectives from a medicinal chemistry point of view. PMID- 24805068 TI - Ultrasound assessment of ex vivo lung tissue properties using a fluid-filled negative pressure bath. AB - A relationship between tendon stress and strain and ultrasonic echo intensity has previously been defined in tendons, demonstrating a correlation between tissue stiffness and echo intensity. An analogous relationship between volume-dependent pressure changes and echo intensity changes in inflating lungs would indicate a correlation between lung compliance and echo intensity. Lung compliance is an important metric to diagnose pathologies which affect lung tissue mechanics, such as emphysema and cystic fibrosis. The goal of this study is to demonstrate a correlation between ultrasound echo intensity and lung tissue mechanics in an ex vivo model using a fluid-filled negative pressure bath design which provides a controlled environment for ultrasonic and mechanical measurements. Lungs from 4 male Sprague-Dawley rats were removed and mechanically tested via inflation and deflation in a negative pressure chamber filled with hetastarch. Specific volumes (1, 2, 3, and 4 mL) were removed from the chamber using a syringe to create negative pressure, which resulted in lung inflation. A pressure transducer recorded the pressure around the lungs. From these data, lung compliance was calculated. Ultrasound images were captured through the chamber wall to determine echo intensity (grayscale brightness in the ultrasound image), which was then related to mechanical parameters. Ultrasound images of the lung were successfully captured through the chamber wall with sufficient resolution to deduce echo intensity changes in the lung tissue. Echo intensity (0-255 scale) increased with volumetric changes (18.4 +/- 5.5, 22.6 +/- 5.1, 26.1 +/- 7.5, and 42.9 +/- 19.5 for volumetric changes of 1, 2, 3, and 4 mL) in a pattern similar to pressure ( 6.8 +/- 1.7, -6.8 +/- 1.4, -9.4 +/- 0.7, and -16.9 +/- 6.8 cm H2O for 1, 2, 3, and 4 mL), reflecting changes in lung compliance. Measured rat lung tissue compliance was comparable to reported values from ex vivo lungs (0.178 +/- 0.067, 0.378 +/- 0.051, 0.427 +/- 0.062, and 0.350 +/- 0.160 mL/cm H20 for 1, 2, 3, and 4 mL), supporting proof of concept for the experimental method. Changes in echo intensity reflected changes in lung compliance in this ex vivo model, thus, supporting our hypothesis that the stiffness-related changes in echo intensity originally seen in tendon can be similarly detected in lung tissue. The presented ultrasound-based methods allowed measurement of local lung tissue compliance in a controlled environment, however, the methods could be expanded to facilitate both ex vivo and in vivo studies. PMID- 24805069 TI - Intermittent fasting attenuates inflammasome activity in ischemic stroke. AB - Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-kappaB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1beta and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. PMID- 24805072 TI - Grapevine red blotch-associated virus Is Widespread in the United States. AB - Grapevine red blotch disease has been recognized since 2008 as affecting North American grape production. The presence of the newly described Grapevine red blotch-associated virus (GRBaV) is highly correlated with the disease. To more effectively detect and monitor the presence of the virus, a sample processing strategy and multiplex polymerase chain reaction assay were developed. A total of 42 of 113 vine samples collected in or received from seven of the United States were shown to harbor the virus, demonstrating the virus is widely distributed across North America. Phylogenetic analyses of a viral replication-associated protein (Rep) gene fragment from the 42 isolates of GRBaV demonstrated distinct clades of the virus (1 and 2), with clade 1 showing the greatest variability. The full-length genome of six virus isolates was sequenced, and phylogenetic analyses of 14 whole genomes recapitulated results seen for the Rep gene. A comparison of GRBaV genomes revealed evidence of recombination underlying some of the variation seen among GRBaV genomes within clade 1. Phylogenetic analyses of coat and replicase-associated protein sequences among single-stranded DNA viruses showed GRBaV to group within the family Geminiviridae. This grouping is distinct from members of the families Nanoviridae and Circoviridae, with limited significant affinities to both recognized genera and novel plant-infecting, gemini-like viruses. PMID- 24805073 TI - Soybean Resistance to Cercospora sojina Infection Is Reduced by Silicon. AB - Frogeye leaf spot, caused by Cercospora sojina, is one of the most important leaf diseases of soybean worldwide. Silicon (Si) is known to increase the resistance of several plant species to pathogens. The cultivars Bossier and Conquista, which are susceptible and resistant, respectively, to frogeye leaf spot, supplied and nonsupplied with Si were examined for the activities of defense enzymes and the concentrations of total soluble phenolics (TSP) and lignin-thioglycolic acid (LTGA) derivatives at 8, 14, and 16 days after inoculation (dai) with C. sojina. The importance of cell wall degrading enzymes (CWDE) to the infection process of C. sojina and the effect of Si on their activities were also determined. Soybean plants were grown in hydroponic culture containing either 0 or 2 mM Si (-Si and +Si, respectively) and noninoculated or C. sojina inoculated. Severity of frogeye leaf spot was higher in cultivar Bossier plants than cultivar Conquista and also in the +Si plants compared with their -Si counterparts. Except for the concentrations of TSP and LTGA derivatives, activities of defense enzymes and the CWDE did not change for +Si noninoculated plants regardless of the cultivar. The activities of lipoxygenases, phenylalanine ammonia-lyases, chitinases, and polyphenoloxidases as well as the activities of CWDE decreased for the +Si inoculated plants. The results from this study demonstrated that defense enzyme activities decreased in soybean plants supplied with Si, which compromised resistance to C. sojina infection. PMID- 24805071 TI - N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma. AB - Mitochondrial dysfunction is becoming a pivotal target for neuroprotective strategies following contusion spinal cord injury (SCI) and the pharmacological compounds that maintain mitochondrial function confer neuroprotection and improve long-term hindlimb function after injury. In the current study we evaluated the efficacy of cell-permeating thiol, N-acetylcysteine amide (NACA), a precursor of endogenous antioxidant glutathione (GSH), on mitochondrial function acutely, and long-term tissue sparing and hindlimb locomotor recovery following upper lumbar contusion SCI. Some designated injured adult female Sprague-Dawley rats (n=120) received either vehicle or NACA (75, 150, 300 or 600mg/kg) at 15min and 6h post injury. After 24h the total, synaptic, and non-synaptic mitochondrial populations were isolated from a single 1.5cm spinal cord segment (centered at injury site) and assessed for mitochondrial bioenergetics. Results showed compromised total mitochondrial bioenergetics following acute SCI that was significantly improved with NACA treatment in a dose-dependent manner, with maximum effects at 300mg/kg (n=4/group). For synaptic and non-synaptic mitochondria, only 300mg/kg NACA dosage showed efficacy. Similar dosage (300mg/kg) also maintained mitochondrial GSH near normal levels. Other designated injured rats (n=21) received continuous NACA (150 or 300mg/kg/day) treatment starting at 15min post-injury for one week to assess long-term functional recovery over 6weeks post-injury. Locomotor testing and novel gait analyses showed significantly improved hindlimb function with NACA that were associated with increased tissue sparing at the injury site. Overall, NACA treatment significantly maintained acute mitochondrial bioenergetics and normalized GSH levels following SCI, and prolonged delivery resulted in significant tissue sparing and improved recovery of hindlimb function. PMID- 24805074 TI - Development of a Quantitative Polymerase Chain Reaction Detection Protocol for Cercospora kikuchii in Soybean Leaves and Its Use for Documenting Latent Infection as Affected by Fungicide Applications. AB - Cercospora leaf blight (CLB) of soybean, caused by Cercospora kikuchii, is a serious disease in the southern United States. A sensitive TaqMan probe-based real-time quantitative polymerase chain reaction (qPCR) assay was developed to specifically detect and quantify C. kikuchii in naturally infected soybean plants. The sensitivity was 1 pg of genomic DNA, which was equivalent to about 34 copies of genome of C. kikuchii. Using this qPCR assay, we documented a very long latent infection period for C. kikuchii in soybean leaves beginning at the V3 growth stage (as early as 22 days after planting). The levels of biomass of C. kikuchii remained low until R1, and a rapid increase was detected from the R2/R3 to R4/R5 growth stages shortly before the appearance of symptoms at R6. The efficacy of various fungicide regimens under field conditions also was evaluated over a 3-year period using this qPCR method. Our results showed that multiple fungicide applications beginning at R1 until late reproductive stages suppressed the development of C. kikuchii in leaves and delayed symptom expression. Different fungicide chemistries also had differential effects on the amount of latent infection and symptom expression during late reproductive growth stages. PMID- 24805070 TI - Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function. AB - Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson's disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive-behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of alpha4beta2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional-motor integration by striatal circuitry. PMID- 24805075 TI - Characterization of motor units in behaving adult mice shows a wide primary range. AB - The mouse is essential for genetic studies of motor function in both normal and pathological states. Thus it is important to consider whether the structure of motor output from the mouse is in fact analogous to that recorded in other animals. There is a striking difference in the basic electrical properties of mouse motoneurons compared with those in rats, cats, and humans. The firing evoked by injected currents produces a unique frequency-current (F-I) function that emphasizes recruitment of motor units at their maximum force. These F-I functions, however, were measured in anesthetized preparations that lacked two key components of normal synaptic input: high levels of synaptic noise and neuromodulatory inputs. Recent studies suggest that the alterations in the F-I function due to these two components are essential for recreating firing behavior of motor units in human subjects. In this study we provide the first data on firing patterns of motor units in the awake mouse, focusing on steady output in quiet stance. The resulting firing patterns did not match the predictions from the mouse F-I behaviors but instead revealed rate modulation across a remarkably wide range (10-60 Hz). The low end of the firing range may be due to changes in the F-I relation induced by synaptic noise and neuromodulatory inputs. The high end of the range may indicate that, unlike other species, quiet standing in the mouse involves recruitment of relatively fast-twitch motor units. PMID- 24805076 TI - The response of the anterior striatum during adult human vocal learning. AB - Research on mammals predicts that the anterior striatum is a central component of human motor learning. However, because vocalizations in most mammals are innate, much of the neurobiology of human vocal learning has been inferred from studies on songbirds. Essential for song learning is a pathway, the homolog of mammalian cortical-basal ganglia "loops," which includes the avian striatum. The present functional magnetic resonance imaging (fMRI) study investigated adult human vocal learning, a skill that persists throughout life, albeit imperfectly given that late-acquired languages are spoken with an accent. Monolingual adult participants were scanned while repeating novel non-native words. After training on the pronunciation of half the words for 1 wk, participants underwent a second scan. During scanning there was no external feedback on performance. Activity declined sharply in left and right anterior striatum, both within and between scanning sessions, and this change was independent of training and performance. This indicates that adult speakers rapidly adapt to the novel articulatory movements, possibly by using motor sequences from their native speech to approximate those required for the novel speech sounds. Improved accuracy correlated only with activity in motor-sensory perisylvian cortex. We propose that future studies on vocal learning, using different behavioral and pharmacological manipulations, will provide insights into adult striatal plasticity and its potential for modification in both educational and clinical contexts. PMID- 24805078 TI - Plane-specific Purkinje cell responses to vertical head rotations in the cat cerebellar nodulus and uvula. AB - We recorded simple spike (SS) and complex spike (CS) firing of Purkinje cell in the cerebellar nodulus and uvula of awake, head-restrained cats during sinusoidal vertical rotation of the head in four stimulus planes (pitch, roll, and two vertical canal planes). Two SS response types (position- and velocity-types) with response phases close to those of head position and velocity, respectively, were recognized. Optimal response planes and directions for SS and CS of each cell were estimated from the response amplitudes in the four stimulus planes by fitting with a sinusoidal function. The principal findings are as follows: (1) two rostrocaudally oriented functional zones of Purkinje cells can be distinguished; (2) the medially located parasagittal band is active during rotation in the pitch plane; (3) the laterally located band is active during rotation in the roll plane. These two zones are the same as previously reported zones in the cerebellar flocculus active during head rotation in the canal planes in the point that both cerebellar sagittal zones are plane-specific functional zones, suggesting that the anatomical sagittal zones serve as functional plane specific zones at least in the vestibulocerebellum. PMID- 24805077 TI - Neural coding of passive lump detection in compliant artificial tissue. AB - Here, we investigate the neural mechanisms of detecting lumps embedded in artificial compliant tissues. We performed a combined psychophysical study of humans performing a passive lump detection task with a neurophysiological study in nonhuman primates (Macaca mulatta) where we recorded the responses of peripheral mechanoreceptive afferents to lumps embedded at various depths in intermediates (rubbers) of varying compliance. The psychophysical results reveal that human lump detection is greatly degraded by both lump depth and decreased compliance of the intermediate. The neurophysiology results reveal that only the slowly adapting type 1 (SA1) afferents provide a clear spatial representation of lumps at all depths and that the representation is affected by lump size, depth, and compliance of the intermediate. The rapidly adapting afferents are considerably less sensitive to the lump. We defined eight neural response measures that we hypothesized could explain the psychophysical behavior, including peak firing rate, spatial spread of neural activity, and additional parameters derived from these measures. We find that peak firing rate encodes the depth of the lump, and the neural spatial spread of the SA1 response encodes for lump size but not lump shape. We also find that the perception of lump size may be affected by the compliance of the intermediate. The results show that lump detection is based on a spatial population code of the SA1 afferents, which is distorted by the depth of the lump and compliance of the tissue. PMID- 24805079 TI - Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. AB - Recent genetic studies suggest that dysfunction of ion channels and transporters may contribute to migraine pathophysiology. A migraine-associated frameshift mutation in the TWIK-related spinal cord K+ (TRESK) channel results in nonfunctional channels. Moreover, mutant TRESK subunits exert a dominant-negative effect on whole cell TRESK currents and result in hyperexcitability of small diameter trigeminal ganglion (TG) neurons, suggesting that mutant TRESK may increase the gain of the neuronal circuit underlying migraine headache. However, the nonmigraine-associated TRESK C110R variant exhibits the same effect on TRESK currents as the mutant subunits in Xenopus oocytes, suggesting that dysfunction of TRESK is not sufficient to cause migraine. Here, we confirmed that the C110R variant formed nonfunctional channels and exerted a dominant-negative effect on TRESK currents in HEK293T cells, similar to the migraine-associated mutant TRESK. To compare the functional consequences of TRESK mutations/variants in a more physiological setting, we expressed the mutant TRESK and the C110R variant in cultured mouse TG neurons and investigated their effects on background K+ currents and neuronal excitability. Both mutant TRESK and the C110R variant reduced the endogenous TRESK currents in TG neurons, but the effect of the C110R variant was significantly smaller. Importantly, only TG neurons expressing mutant TRESK subunits, but not those expressing the C110R variant, exhibited a significant increase in excitability. Thus only the migraine-associated TRESK mutation, but not the C110R variant, reduces the endogenous TRESK currents to a degree that affects TG excitability. Our results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility. PMID- 24805080 TI - Adrenoreceptor modulation of oromotor pathways in the rat medulla. AB - Regulation of feeding behavior involves the integration of multiple physiological and neurological pathways that control both nutrient-seeking and consummatory behaviors. The consummatory phase of ingestion includes stereotyped oromotor movements of the tongue and jaw that are controlled through brain stem pathways. These pathways encompass not only cranial nerve sensory and motor nuclei for processing feeding-related afferent signals and supplying the oromotor musculature but also reticular neurons for orchestrating ingestion and coordinating it with other behaviors that utilize the same musculature. Based on decerebrate studies, this circuit should be sensitive to satiety mechanisms mediated centrally by A2 noradrenergic neurons in the caudal nucleus of the solitary tract (cNST) that are potently activated during satiety. Because the first observable phase of satiety is inhibition of oromotor movements, we hypothesized that norepinephrine (NE) would act to inhibit prehypoglossal neurons in the medullary reticular formation. Using patch-clamp electrophysiology of retrogradely labeled prehypoglossal neurons and calcium imaging to test this hypothesis, we demonstrate that norepinephrine can influence both pre- and postsynaptic properties of reticular neurons through both alpha1- and alpha2 adrenoreceptors. The alpha1-adrenoreceptor agonist phenylephrine (PE) activated an inward current in the presence of TTX and increased the frequency of both inhibitory and excitatory miniature postsynaptic currents. The alpha2 adrenoreceptor agonist dexmedetomidine (DMT) inhibited cNST-evoked excitatory currents as well as spontaneous and miniature excitatory currents through presynaptic mechanisms. The diversity of adrenoreceptor modulation of these prehypoglossal neurons may reflect their role in a multifunctional circuit coordinating both ingestive and respiratory lingual function. PMID- 24805081 TI - Differential activation of an identified motor neuron and neuromodulation provide Aplysia's retractor muscle an additional function. AB - To survive, animals must use the same peripheral structures to perform a variety of tasks. How does a nervous system employ one muscle to perform multiple functions? We addressed this question through work on the I3 jaw muscle of the marine mollusk Aplysia californica's feeding system. This muscle mediates retraction of Aplysia's food grasper in multiple feeding responses and is innervated by a pool of identified neurons that activate different muscle regions. One I3 motor neuron, B38, is active in the protraction phase, rather than the retraction phase, suggesting the muscle has an additional function. We used intracellular, extracellular, and muscle force recordings in several in vitro preparations as well as recordings of nerve and muscle activity from intact, behaving animals to characterize B38's activation of the muscle and its activity in different behavior types. We show that B38 specifically activates the anterior region of I3 and is specifically recruited during one behavior, swallowing. The function of this protraction-phase jaw muscle contraction is to hold food; thus the I3 muscle has an additional function beyond mediating retraction. We additionally show that B38's typical activity during in vivo swallowing is insufficient to generate force in an unmodulated muscle and that intrinsic and extrinsic modulation shift the force-frequency relationship to allow contraction. Using methods that traverse levels from individual neuron to muscle to intact animal, we show how regional muscle activation, differential motor neuron recruitment, and neuromodulation are key components in Aplysia's generation of multifunctionality. PMID- 24805082 TI - Interference from mere thinking: mental rehearsal temporarily disrupts recall of motor memory. AB - Interference between successively learned tasks is widely investigated to study motor memory. However, how simultaneously learned motor memories interact with each other has been rarely studied despite its prevalence in daily life. Assuming that motor memory shares common neural mechanisms with declarative memory system, we made unintuitive predictions that mental rehearsal, as opposed to further practice, of one motor memory will temporarily impair the recall of another simultaneously learned memory. Subjects simultaneously learned two sensorimotor tasks, i.e., visuomotor rotation and gain. They retrieved one memory by either practice or mental rehearsal and then had their memory evaluated. We found that mental rehearsal, instead of execution, impaired the recall of unretrieved memory. This impairment was content-independent, i.e., retrieving either gain or rotation impaired the other memory. Hence, conscious recollection of one motor memory interferes with the recall of another memory. This is analogous to retrieval-induced forgetting in declarative memory, suggesting a common neural process across memory systems. Our findings indicate that motor imagery is sufficient to induce interference between motor memories. Mental rehearsal, currently widely regarded as beneficial for motor performance, negatively affects memory recall when it is exercised for a subset of memorized items. PMID- 24805084 TI - Structural and functional effects of early exposure to 4-nonylphenol on gonadal development of Nile tilapia (Oreochromis niloticus): a-histological alterations in ovaries. AB - The present study investigated the gonads alterations of mature female Oreochromis niloticus caused by different concentrations (0, 40, 60, 100 MUg/L) of 4-nonylphenol (NP) and also its effect on steroidogenesis. A tendency for a dose-dependent reduction in the gonadosomatic index, fecundity and oocytes diameter in the NP-exposed groups was observed. Histological examination revealed that NP impairs gonadal growth clearly shown in the oocyte development and differentiation. Also, the estrogenic activity of such NP was identified through 11-ketotestosterone, 17b-estradiol and vitellogenin which were affected significantly by the applied concentrations. The study indicates that NP has estrogenic potency-induced marked alteration in the sexual development including gonadal maturation, spawning time and egg production. PMID- 24805083 TI - Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current. AB - Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene para results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS. PMID- 24805085 TI - Structural and functional effects of early exposure to 4-nonylphenol on gonadal development of Nile tilapia (Oreochromis niloticus): b-histological alterations in testes. AB - The present study investigates the effects of different doses (0, 40, 60, 100 MUg/L) of 4-nonylphenol (NP) on testis histology and sperms motility of mature Oreochromis niloticus. A tendency for a dose-dependent reduction in the gonado somatic index (GSI) in the NP-exposed groups was observed. Histological examination revealed that high doses of NP (60 and 100 MUg/L) cause hyperplasia of interlobular connective tissue components coincide with decrease in the size of seminiferous lobules and amount of lumen spermatozoa in comparison with the control and low-dose (40 MUg/L)-exposed groups. In addition, within the seminiferous lobules, rupture of spermatogenic cysts, vacuolation and necrosis of primary spermatocytes due to damage of sertoli cells were clearly observed and lead to decrease in advanced spermatogenic cells. The highest dose caused significant decrease in the GSI associated with appearance of testis-ova (intersex) state. The percentage of abnormal sperms increased with increasing the dose of NP reaching to 96 % for those subjected to 100 MUg NP/L, while it was only 11 % for the control group specimens. The study indicates that NP has estrogenic potency induced marked alteration in the sexual development including inhibition in testicular growth and deformation in the sperms. PMID- 24805087 TI - Overexpression of G9a and MCM7 in oesophageal squamous cell carcinoma is associated with poor prognosis. AB - AIMS: Histone methyltransferase G9a has been primarily understood as a co repressor of gene expression, but it has been shown that G9a also positively regulates nuclear receptor-mediated transcription. MCM7, a critical component of the DNA replication licensing complex, is amplified and overexpressed in a variety of human malignancies. The objectives of the present study were to study the relationship between the expression of G9a and MCM7 and the pathological grade, clinical stage and prognosis of oesophageal squamous cell carcinoma (OSCC). METHODS AND RESULTS: We collected 139 formalin-fixed and paraffin embedded tissues from patients with OSCC and surveyed them by tissue microarray based immunohistochemical staining. Associations between the expression of MCM7 and G9a and clinicopathological parameters and prognosis of OSCC were examined. From tissue microarray immunohistochemistry staining results, we found that nuclear staining intensity for MCM7 and G9a was associated with histological grade (both P < 0.001), tumour depth (P = 0.050, 0.034), lymph node metastasis (P = 0.001, 0.009) and tumour stage (P < 0.001, =0.003). G9a expression was correlated with that of MCM7. G9a overexpression independently predicted poor cancer-specific survival in OSCC (hazard ratio 0.05, 95% confidence interval 0.006-0.417, P = 0.006) and MCM7 (hazard ratio 0.05, 95% confidence interval 0.013-0.441, P = 0.004). OSCC patients whose tumours showed double-positive expression of G9a and MCM7 (G9a(+) MCM7(+) ) had much shorter survival than those from either the G9a or MCM7 low expression groups (G9a(-) MCM7(-) , G9a(+) MCM7( ) , G9a(-) MCM7(+) ). CONCLUSIONS: MCM7 and G9a may serve as effective prognostic factors and could also be used as biomarkers for predicting various clinical outcomes of OSCCs in the Chinese population. PMID- 24805086 TI - Exploration of the mechanisms of protein quality control and osmoregulation in gills of Chromis viridis in response to reduced salinity. AB - Fish gills are the vital multifunctional organ in direct contact with external environment. Therefore, activation of the cytoprotective mechanisms to maintain branchial cell viability is important for fish upon stresses. Salinity is one of the major factors strongly affecting cellular and organismal functions. Reduction of ambient salinity may occur in coral reef and leads to osmotic stress for reef associated stenohaline fish. However, the physiological responses to salinity stress in reef-associated fish were not examined substantially. With this regard, the physiological parameters and the responses of protein quality control (PQC) and osmoregulatory mechanisms in gills of seawater (SW; 33-35 0/00)- and brackish water (BW; 20 0/00)-acclimated blue-green damselfish (Chromis viridis) were explored. The results showed that the examined physiological parameters were maintained within certain physiological ranges in C. viridis acclimated to different salinities. In PQC mechanism, expression of heat-shock protein (HSP) 90, 70, and 60 elevated in response to BW acclimation while the levels of ubiquitin-conjugated proteins were similar between the two groups. Thus, it was presumed that upregulation of HSPs was sufficient to prevent the accumulation of aggregated proteins for maintaining the protein quality and viability of gill cells when C. viridis were acclimated to BW. Moreover, gill Na(+)/K(+)-ATPase expression and protein amounts of basolaterally located Na(+)/K(+)/2Cl(-) cotransporter were higher in SW fish than in BW fish. Taken together, this study showed that the cytoprotective and osmoregulatory mechanisms of blue-green damselfish were functionally activated and modulated to withstand the challenge of reduction in salinity for maintaining physiological homeostasis. PMID- 24805088 TI - Development of a new rhodamine-based FRET platform and its application as a Cu2+ probe. AB - We have constructed a new rhodamine-based FRET platform, which was then used to develop a ratiometric fluorescent Cu(2+) probe. The novel Cu(2+) probe exhibits several favorable features including a large variation in the emission ratio, well-resolved emission peaks, high sensitivity, and high selectivity. Importantly, it is suitable for fluorescence imaging in living cells. PMID- 24805089 TI - Measurement properties of the Vitiligo Impact Scale-22 (VIS-22), a vitiligo specific quality-of-life instrument. AB - BACKGROUND: Vitiligo has a significant psychological impact which needs to be evaluated separately from the extent of depigmentation. We have developed a vitiligo-specific quality-of-life (QoL) instrument, Vitiligo Impact Scale-22 (VIS 22) for this purpose. OBJECTIVES: To study the measurement properties of VIS-22 and compare it with the Dermatology Life Quality Index (DLQI) and Skindex-16. METHODS: Item-reduction analysis was used to reduce the number of items in the original VIS from 27 to 22. The 5-point Physician's Global Assessment (PGA) was used to evaluate the QoL followed by a Visual Analogue Scale (VAS) to assess patient-perceived severity. VIS-22, DLQI and Skindex-16 were self-administered. The validity of the VIS-22 was assessed in 161 patients, reliability in 69 patients and responsiveness in 72 patients and compared with DLQI and Skindex-16. RESULTS: Criterion validity was shown by strong correlation of VIS-22 with VAS (r = 0.7076). Convergent validity was evidenced by strong correlations with DLQI (r = 0.71) and Skindex-16 (r = 0.72). Known-groups validity was demonstrated by significantly higher scores in females, those with less education, patients with progressive disease and patients with vitiligo compared with controls (P < 0.001). Reliability was shown by excellent correlation of the scores between baseline and 2 weeks (r = 0.9053). VIS-22 was found to be responsive with scores at 12 weeks moving parallel to scores on VAS. Similar trends were noted with DLQI and Skindex-16. CONCLUSIONS: VIS-22 is a valid, reliable and responsive QoL instrument. It is comparable to DLQI and Skindex-16 in its measurement properties, while being specific to the needs of patients with vitiligo. PMID- 24805090 TI - Simultaneous detection of different RNAs using a novel branched DNA in situ hybridization method. PMID- 24805091 TI - An extended family with familial medullary thyroid carcinoma and Hirschsprung's disease. AB - Familial medullary thyroid carcinoma (FMTC) is an autosomal dominant inherited disease that has highly characteristic clinical features, including medullary thyroid carcinoma (MTC). Mutation of the RET proto-oncogene is known to be responsible for development of FMTC and for multiple endocrine neoplasia types 2A and 2B. Hirschsprung's disease is the most common form of structural intestinal obstructive disease in human newborns. Hirschsprung's disease is defined by the absence of neural crest-derived enteric ganglia along a variable length of the bowel that invariably involves the rectoanal junction. Co-segregation of FMTC and Hirschsprung's disease is uncommon; nevertheless, in 3 generations of 1 family, we observed 5 patients with FMTC, 2 patients with Hirschsprung's disease, and 1 patient with characteristics of both FMTC and Hirschsprung's disease. Moreover, a Cys620Ser mutation in RET was identified in 4 of the 8 patients. This mutation had both activating and inactivating effects on the RET (REarranged during Transfection) protein. There were individual differences in the penetrance of Hirschsprung's disease due to the RET mutation, but the penetrance of MTC was uniform and high. Genetic testing is important for making decisions about treatment and follow-up in families of this kind. PMID- 24805092 TI - A new method for differentiating benign and malignant pleomorphic clustered calcifications in mammography. AB - OBJECTIVE: Retrospective study to determine whether new mammography imaging characteristics can improve identification of an isolated cluster of coarse heterogeneous and fine pleomorphic calcifications as benign or malignant. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. The study included 123 women (mean age, 50 years: age range, 34-79 years), in whom mammograms had found pleomorphic clustered calcifications, but without abnormal ultrasound findings and who underwent stereotactically-guided vaccum-assisted breast biopsy. Pleomorphic clustered calcifications were classified on the basis of 5 characteristics density, heterogeneity of density, number, heterogeneity of size, and distribution area size (DAS) of calcifications in the mediolateral oblique view (multiplication of the greatest length by the width of the total zone of clustered calcifications in mm(2)), and correlated with pathological findings. RESULTS: The chi-square test showed significant differences in whether a calcification was malignant or benign only in terms of DAS of calcification (p 0.009). There were significant differences in the association with malignancy of a DAS of 32- to 55 mm(2) (p=0.023, odds ratio=4.22), and the association more likely with a DAS of 56 mm(2) or larger (p=0.01, odds ratio=5.55) than with a DAS smaller than 18 mm(2) as a reference. CONCLUSION: The DAS is a new and reliable variable for differentiating between benign and malignant pleomorphic clustered calcifications. The DAS improves diagnostic accuracy and is useful for determining whether to proceed with biopsies. PMID- 24805093 TI - Amoeboid neutrophils with few granules in childhood acute precursor B cell leukemia. AB - BACKGROUND: We sometimes treat children with acute lymphoblastic leukemia in whom neutrophil function is impaired at diagnosis. Transmission electron microscopy enables more accurate assessment by providing greater morphological detail. Using transmission electron microscopy, we have found 2 types of neutrophils in the peripheral blood of children: 1) amoeboid neutrophils, which are characterized as amoeboid cells with pseudopodia and few granules, and 2) round neutrophils with many granules at different stages and glycogen particles. AIM: To assess the pathological role of amoeboid neutrophils, we investigated amoeboid neutrophils in the peripheral blood of children with leukemia. METHODS: Amoeboid neutrophils were examined in peripheral blood from 12 children with acute B-cell precursor lymphoblastic leukemia (BCP-ALL). Eight children with short stature served as healthy control subjects. RESULTS: The percentage of amoeboid neutrophils (per total neutrophil count) at onset or relapse of BCP-ALL was significantly higher than at remission. Children with short stature showed a lower percentage of amoeboid neutrophils than did children with acute leukemia. CONCLUSION: The presence of fewer intracellular granules in amoeboid neutrophils suggests lower neutrophil activity. These results indicate that amoeboid neutrophils in patients with BCP-ALL have lower function at onset and relapse. PMID- 24805094 TI - Identification of pathological and normal parathyroid tissue by fluorescent labeling with 5-aminolevulinic acid during endocrine neck surgery. AB - BACKGROUND: When performing parathyroid or thyroid surgery, surgeons must distinguish parathyroid tissue from the surrounding thyroid tissue, to preserve healthy parathyroid tissue while excising diseased thyroid tissue or to completely remove pathological parathyroid lesions. Here, we explored the feasibility of labeling the parathyroid glands for easy identification by administering 5-aminolevulinic acid (5-ALA) orally to patients undergoing endocrine neck surgery, because 5-ALA accumulates in the parathyroid and has a fluorescent metabolite, protoporphyrin IX. METHODS: Twenty-nine patients about to undergo endocrine (parathyroid or thyroid gland) neck surgery were orally given 5 ALA, a nontoxic substance that occurs naturally in the human body and has no known major side effects. During surgery, we used blue light to excite protoporphyrin IX, the fluorescent metabolite of 5-ALA, and viewed the resulting bright red fluorescence through an optical filter. RESULTS: In the majority of the patients, the parathyroid glands were defined by a clear fluorescence. In 23 patients with pathological parathyroid tissue, the fluorescence enabled us to identify and completely remove diseased parathyroid tissue. In 3 patients with thyroid disease, we were able to easily remove diseased thyroid tissue, and an accidentally removed parathyroid gland was autotransplanted during surgery. CONCLUSIONS: In all but a few cases, 5-ALA clearly labeled parathyroid tissue, allowing for its clean removal or preservation according to the purpose of the surgery. This simple, benign technique is extremely useful for identifying parathyroid tissue, whether pathological or normal, during endocrine neck surgery. PMID- 24805095 TI - Association between fibrinogen levels and severity of postpartum hemorrhage in singleton vaginal deliveries at a Japanese perinatal center. AB - OBJECTIVE AND METHODS: We examined the relationship between low fibrinogen levels (<200 mg/dL) and the severity of postpartum hemorrhage in singleton vaginal deliveries after 22 weeks' gestation complicated by postpartum hemorrhage requiring transfusion at our hospital. RESULTS: During a 10-year period, 61 women (0.38%) received transfusions owing to postpartum hemorrhage within the first 24 hours after delivery. Of these women, 13 (21%) had low fibrinogen levels (mean, 123 +/- 68 mg/dL) when postpartum hemorrhage was diagnosed, and the other 48 (79%) had normal fibrinogen levels (mean, 305 +/- 50 mg/dL). Neither total blood loss nor the incidence of additional therapies, such as hysterectomy, differed between the 2 groups of women. Women with low fibrinogen levels started to receive transfusions significantly earlier (98 +/- 58 minutes after delivery) than did women with normal fibrinogen levels (142 +/- 75 minutes after delivery, p=0.03) and received more units of fresh-frozen plasma (p=0.03). CONCLUSION: The early transfusion of fresh-frozen plasma in women with postpartum hemorrhage and low fibrinogen levels might help prevent adverse outcomes. PMID- 24805096 TI - Small cell carcinoma of the esophagus: a case report. AB - A case of esophageal small cell carcinoma successfully treated with combination therapy consisting of preoperative chemotherapy, radiation therapy, and surgical resection. A 76-year-old man presented with a small cell carcinoma measuring 6 cm in diameter in the middle third of the thoracic esophagus. After preoperative therapy, the gross tumor was completely resected. The patient eventually died of metastatic disease 25 months after diagosis. We discuss the treatment of esophageal small cell carcinoma. PMID- 24805097 TI - Spontaneous rupture of aneurysms of the ovarian artery at times remote from pregnancy. AB - Spontaneous rupture of an aneurysm of the ovarian artery is usually considered a rare complication of pregnancy and the puerperium. However, we observed this emergent condition in a 51-year-old postmenopausal woman. We report here our experiences and consider lessons about diagnosis and management that can be drawn from this case and 5 other published cases in multiparous middle-aged women. These lessons include application of contrast-enhanced computed tomography to focus emergent care, surgical intervention, and association with systemic inflammatory response syndrome. We also consider how the cases might shed new light on the pathogenesis and evolution of this condition. PMID- 24805098 TI - Hashimoto's thyroiditis with clinical manifestations resembling dermatomyositis: a case report. AB - We report on a 59-year-old man with a 1-year history of forearm erythema, bilateral limb arthralgia, and muscle weakness. During the initial examination we observed infiltrative erythema of the forearm and muscle weakness and atrophy of the limbs. Blood tests revealed marked increases in myogenic enzymes. Because histopathological studies showed lymphocytic infiltration around the small blood vessels in the dermis and mucin deposition, we made a tentative diagnosis of dermatomyositis. However, the specific cutaneous manifestations of dermatomyositis, including heliotrope erythema and Gottron's sign, were absent, and the findings of electromyography were normal. A subsequent detailed examination revealed hypothyroidism and high titers of antithyroglobulin and antimicrosome antibodies, and we made a definitive diagnosis of Hashimoto's thyroiditis. The thyroid function and skin manifestations both improved after treatment with levothyroxine sodium. Dermatomyositis and Hashimoto's thyroiditis can exhibit similar characteristics, and caution is required because of the possibility of misdiagnosis. PMID- 24805099 TI - Giant appendiceal mucocele: report of a case. AB - Mucoceles of the appendix are a group of mucus-filled lesions causing obstructive dilation of the ileocecal appendix. We report a rare case of giant appendiceal mucocele. A 48-year-old woman, with no discomfort, was admitted to our hospital after a mass was detected in the right lower quadrant of the abdomen. The patient underwent right hemicolectomy on the basis of the clinical diagnosis of a possible appendiceal tumor. The final pathologic diagnosis was mucocele of the appendix. PMID- 24805100 TI - The diagnostic usefulness of video capsule endoscopy in adolescent immunoglobulin A vasculitis (Henoch-Schonlein purpura). AB - Immunoglobulin (Ig) A vasculitis (IgAV), previously known as Henoch-Schonlein purpura, is a systemic IgA-mediated leukocytoclastic vasculitis that usually affects children. We report the usefulness of video capsule endoscopy in 2 adolescent patients with IgAV having gastrointestinal involvement. Both patient 1, a 15-year-old girl, and patient 2, a 14-year-old boy, presented with purpuric rash and abdominal pain. Video capsule endoscopy showed multiple areas of purpuric erythema throughout the small bowel in both patients and showed multiple ulcers with bleeding in patient 2. Patient 1 responded well to oral prednisolone at a dose of 0.5 mg/kg/day. However, in patient 2, prednisolone at a dose of 0.5 mg/kg/day failed to control the symptoms; therefore, the dose was increased to 1 mg/kg/day to provide relief. Video capsule endoscopy was safe in both cases and produced no side effects. In conclusion, video capsule endoscopy is a useful tool for evaluating small bowel lesions in patients with IgAV and provides valuable information for the treatment of IgAV with gastrointestinal involvement. PMID- 24805102 TI - Massive lindane overdose with toxicokinetics analysis. AB - BACKGROUND: Lindane is a possible carcinogen with known teratogenicity and immunologic and neurotoxic properties. Despite reports of seizures, coma, and death associated with its use as well as banning of its environmental use by the Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) still allows treatment with lindane as a second-line scabicide and pediculicide. We present a case of a massive suicidal ingestion of lindane in which the patient survived the ingestion, though he did expire shortly thereafter from an unrelated cause pre-discharge. METHODS: Pharmacokinetic analysis of serum lindane concentrations was performed with Phoenix(r) WinNONLIN(r). The estimated distribution half-life for lindane was 10.3 h, and the terminal half-life was 162.9 h, much longer than the previously reported terminal half-life of 25-36 h. Because of this long half-life, repeated lindane exposures may lead to accumulation of lindane in the tissues. RESULT: After overdose, toxicity may be delayed and full recovery may be prolonged. PMID- 24805101 TI - Basal gene expression by lung CD4+ T cells in chronic obstructive pulmonary disease identifies independent molecular correlates of airflow obstruction and emphysema extent. AB - Lung CD4+ T cells accumulate as chronic obstructive pulmonary disease (COPD) progresses, but their role in pathogenesis remains controversial. To address this controversy, we studied lung tissue from 53 subjects undergoing clinically indicated resections, lung volume reduction, or transplant. Viable single-cell suspensions were analyzed by flow cytometry or underwent CD4+ T cell isolation, followed either by stimulation with anti-CD3 and cytokine/chemokine measurement, or by real-time PCR analysis. In lung CD4+ T cells of most COPD subjects, relative to lung CD4+ T cells in smokers with normal spirometry: (a) stimulation induced minimal IFN-gamma or other inflammatory mediators, but many subjects produced more CCL2; (b) the T effector memory subset was less uniformly predominant, without correlation with decreased IFN-gamma production. Analysis of unstimulated lung CD4+ T cells of all subjects identified a molecular phenotype, mainly in COPD, characterized by markedly reduced mRNA transcripts for the transcription factors controlling TH1, TH2, TH17 and FOXP3+ T regulatory subsets and their signature cytokines. This mRNA-defined CD4+ T cell phenotype did not result from global inability to elaborate mRNA; increased transcripts for inhibitory CD28 family members or markers of anergy; or reduced telomerase length. As a group, these subjects had significantly worse spirometry, but not DLCO, relative to subjects whose lung CD4+ T cells expressed a variety of transcripts. Analysis of mRNA transcripts of unstimulated lung CD4+ T cell among all subjects identified two distinct molecular correlates of classical COPD clinical phenotypes: basal IL-10 transcripts correlated independently and inversely with emphysema extent (but not spirometry); by contrast, unstimulated IFN-gamma transcripts correlated independently and inversely with reduced spirometry (but not reduced DLCO or emphysema extent). Aberrant lung CD4+ T cells polarization appears to be common in advanced COPD, but also exists in some smokers with normal spirometry, and may contribute to development and progression of specific COPD phenotypes. TRIAL REGISTRATION: ClinicalTrials.gov as NCT00281229. PMID- 24805103 TI - Serotonin syndrome associated with metaxalone overdose. AB - INTRODUCTION: Serotonin syndrome is a potentially life-threatening entity associated with pro-serotonergic medications in therapeutic use, in overdose, or when co-administered with other drugs. A broad range of drugs and drug combinations have been associated with serotonin syndrome. Metaxalone overdose associated with serotonin syndrome has not been previously reported. CASE REPORT: (Case 1) A 23-year-old female overdosed on tramadol and metaxalone. She developed dysautonomia, diaphoresis, lower extremity rigidity and spontaneous clonus, flaccid upper extremities, and hyperthermia 5 h after ingestion. Her course was complicated by status epilepticus. (Case 2) A 56-year-old female overdosed on metaxalone and was found unresponsive. She developed dysautonomia, lower extremity rigidity and spontaneous clonus, flaccid upper extremities, rhabdomyolysis, acute renal failure, and hyperthermia. Non-depolarizing neuromuscular blockade and cooling blankets were required to control hyperthermia in both cases. Serum metaxalone levels were markedly elevated in both cases. CONCLUSION: These are the first reported cases of metaxalone overdose associated with serotonin syndrome, which may be related to monoamine oxidase inhibition. PMID- 24805104 TI - A population-based approach indicates an overall higher patient mortality with peritoneal dialysis compared to hemodialysis in Korea. AB - To date, only a few large-scale studies have measured the effect of dialysis modality on mortality in Asian populations. Here, we sought to compare survival between incident hemodialysis (HD) and peritoneal dialysis (PD) patients using the Korean Health Insurance Review & Assessment Service database. This enabled us to perform a population-based complete survey that included 32,280 incident dialysis patients and followed them for a median of 26.5 months. To reduce biases due to nonrandomization, we first matched 7049 patient pairs with similar propensity scores. Using the log-rank test, we found the mortality rate in PD patients was significantly higher than that in HD patients. Subsequent subgroup analyses indicated that in older patients (55 years and older), with the exception of the subgroup of patients with no comorbidities and the subgroup of patients with malignancy, PD was consistently associated with a higher mortality rate. In younger patients (under 55 years), regardless of the covariates, the survival rate of PD patients was comparable to that of HD patients. Thus, while the overall mortality rate was higher in incident PD patients, mortality rates of some incident PD and HD patients were comparable in Korea. PMID- 24805105 TI - Mice with an absent stress response are protected against ischemic renal injury. AB - Inducible heat shock proteins (HSPs), regulated by heat shock factor-1 (HSF-1), protect against renal cell injury in vitro. To determine whether HSPs ameliorate ischemic renal injury in vivo, HSF-1 functional knockout mice (HSF-KO) were compared with wild-type mice following bilateral ischemic renal injury. Following injury, the kidneys of wild-type mice had the expected induction of HSP70 and HSP25; a response absent in the kidneys of HSF-KO mice. Baseline serum creatinine was equivalent between strains. Serum creatinine at 24 h reflow in HSF-KO mice was significantly lower than that in the wild type. Histology showed similar tubule injury in both strains after ischemic renal injury but increased medullary vascular congestion in wild-type compared with HSF-KO mice. Flow cytometry of mononuclear cells isolated from kidneys showed no difference between strains in the number of CD4(+) and CD8(+) T cells in sham-operated animals. At 1 h of reflow, CD4(+) and CD8(+) cells were doubled in the kidneys of wild-type but not HSF-KO mice. Foxp3(+) T-regulatory cells were significantly more abundant in the kidneys of sham-operated HSF-KO than wild-type mice. Suppression of CD25(+)Foxp3(+) cells in HSF-KO kidneys with the anti-CD25 antibody PC61 reversed the protection against ischemic renal injury. Thus, HSF-KO mice are protected from ischemic renal injury by a mechanism that depends on an increase in the T regulatory cells in the kidney associated with altered T-cell infiltration early in reflow. Hence, stress response activation may contribute to early injury by facilitating T-cell infiltration into ischemic kidney. PMID- 24805106 TI - The NLRP3/ASC inflammasome promotes T-cell-dependent immune complex glomerulonephritis by canonical and noncanonical mechanisms. AB - Interleukin (IL)-1beta contributes to renal injury in immune complex glomerulonephritis. However, production of mature IL-1beta depends on activation of the inflammasome that cleaves pro-IL-1beta into its secretable form. A functional role of the NLRP3-containing inflammasome, which responds to various endogenous danger signals, was found in tubulointerstitial nephropathies, but its function in glomerular disease has not been established. To determine whether NLRP3 and its adapter molecule ASC contribute to glomerulonephritis, we induced T cell-dependent autologous nephrotoxic serum nephritis in Nlrp3- and Asc-deficient mice. Renal expression of NLRP3/ASC inflammasome components and pro-IL-1beta increased during nephrotoxic serum nephritis and was abundant in renal dendritic cells. This was associated with renal production of mature IL-1beta, indicating inflammasome activation. Nlrp3 and Asc deficiency significantly attenuated glomerular injury, renal leukocyte infiltration, and T-cell activation. Production of mature IL-1beta was abrogated in Asc-deficient mice, consistent with a loss of inflammasome-dependent IL-1beta activation. Surprisingly, renal IL 1beta secretion remained intact in Nlrp3-deficient mice, indicating noncanonical pro-inflammatory effects of NLRP3 in autologous nephrotoxic serum nephritis. This may include NLRP3-mediated glomerular release of pro-inflammatory high-mobility group box 1 protein as a noncanonical function of NLRP3/ASC in glomerulonephritis. Thus, therapeutic blockade of the NLRP3/ASC/IL-1beta axis may be beneficial in glomerulonephritis. PMID- 24805108 TI - Endothelin and endothelin antagonists in chronic kidney disease. AB - The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach. PMID- 24805107 TI - Temporary hemodialysis catheters: recent advances. AB - The insertion of non-tunneled temporary hemodialysis catheters (NTHCs) is a core procedure of nephrology practice. While urgent dialysis may be life-saving, mechanical and infectious complications related to the insertion of NTHCs can be fatal. In recent years, various techniques that reduce mechanical and infectious complications related to NTHCs have been described. Evidence now suggests that ultrasound guidance should be used for internal jugular and femoral vein NTHC insertions. The implementation of evidence-based infection-control 'bundles' for central venous catheter insertions has significantly reduced the incidence of bloodstream infections in the intensive care unit setting with important implications for how nephrologists should insert NTHCs. In addition, the Cathedia Study has provided the first high-level evidence about the optimal site of NTHC insertion, as it relates to the risk of infection and catheter dysfunction. Incorporating these evidence-based techniques into a simulation-based program for training nephrologists in NTHC insertion has been shown to be an effective way to improve the procedural skills of nephrology trainees. Nonetheless, there are some data suggesting nephrologists have been slow to adopt evidence-based practices surrounding NTHC insertion. This mini review focuses on techniques that reduce the complications of NTHCs and are relevant to the practice and training of nephrologists. PMID- 24805112 TI - Male claspers in clam shrimps (Crustacea, Branchiopoda) in the light of evolution: a case study on homology versus analogy. AB - Male "clam shrimps" possess highly modified first (and second) trunk limbs for clasping the carapace of females during copulation. Claspers are present in all three clam shrimp taxa (Laevicaudata, Spinicaudata, and Cyclestherida) but despite striking similarities in their morphology and function, the matter of their homology is controversial. In this study, we address the question of the homology and evolution of these structures by comparing the developmental transformation of an unspecialized trunk limb into a clasper. In addition, we study the musculature and the nervous system in trunk limbs and claspers using confocal laser scanning microscopy. We establish that most (but not all) of the various parts of the claspers are homologous between clam shrimp taxa. We suggest that a single pair of claspers was already present in the ground pattern of Diplostraca, probably most comparable to those in Cyclestherida. The claspers, therefore, do not represent a case of analogy. PMID- 24805111 TI - p62/SQSTM1 is involved in caspase-8 associated cell death induced by proteasome inhibitor MG132 in U87MG cells. AB - Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. Proteasome inhibitors are emerging as a new class of anti-glioma agents; however, the mechanisms of their killing malignant cells are still unclear. We treated U87MG cells with the proteasome inhibitor MG132 and found that cell death correlated with caspase-8 activation and autophagy protein p62/SQSTM1.To explore the role of autophagy and p62/SQSTM1 in MG132-induced cancer cell death, we measured the alteration of MG132's cytotoxicity by autophagy inhibition, autophagy induction or variation of p62/SQSTM1 gene expression. Autophagy was activated upon MG132 treatment for short periods, while inhibition of autophagy aggravated MG132-induced cell death followed by high levels of p62/SQSTM1 and active caspase-8 (p18). Moreover, U87MG cell death was dependent on p62/SQSTM1, and its function required its C-terminus UBA domain to attenuate the MG132 induced cell death. The results suggest that p62/SQSTM1 is a potential contributor in determining the fate of U87MG cells deficient in proteolytic activity. PMID- 24805109 TI - Whole blood gene expression and atrial fibrillation: the Framingham Heart Study. AB - BACKGROUND: Atrial fibrillation (AF) involves substantial electrophysiological, structural and contractile remodeling. We hypothesize that characterizing gene expression might uncover important pathways related to AF. METHODS AND RESULTS: We performed genome-wide whole blood transcriptomic profiling (Affymetrix Human Exon 1.0 ST Array) of 2446 participants (mean age 66 +/- 9 years, 55% women) from the Offspring cohort of Framingham Heart Study. The study included 177 participants with prevalent AF, 143 with incident AF during up to 7 years follow up, and 2126 participants with no AF. We identified seven genes statistically significantly up-regulated with prevalent AF. The most significant gene, PBX1 (P = 2.8 * 10(-7)), plays an important role in cardiovascular development. We integrated differential gene expression with gene-gene interaction information to identify several signaling pathways possibly involved in AF-related transcriptional regulation. We did not detect any statistically significant transcriptomic associations with incident AF. CONCLUSION: We examined associations of gene expression with AF in a large community-based cohort. Our study revealed several genes and signaling pathways that are potentially involved in AF-related transcriptional regulation. PMID- 24805114 TI - Surgical site infections in neonates and infants: is antibiotic prophylaxis needed for longer than 24 h? AB - PURPOSE: The purpose is to determine whether use of perioperative antibiotics for more than 24 h decreases the incidence of SSI in neonates and infants. METHODS: We studied neonates and infants who had clean-contaminated or contaminated gastrointestinal operations from 1996 to 2006. Patient- and operation-related variables, duration of perioperative antibiotics, and SSI within 30 days were ascertained by retrospective chart review. In assessing the effects of antibiotic duration, we controlled for confounding by indication using standard covariate adjustment and propensity score matching. RESULTS: Among 732 operations, the incidence of SSI was 13%. Using propensity score matching, the odds of SSI were similar (OR 1.1, 95% CI 0.6-1.9) in patients who received <=24 h of postoperative antibiotics compared to >24 h. No difference was also found in standard covariate adjustment. This multivariate model identified three independent predictors of SSI: preoperative infection (OR 3.9, 95% CI 1.4-10.9) and re-operation through the same incision, both within 30 days (OR 3.5, 95% CI 1.7-7.4) and later (OR 2.3, 95% CI 1.4-3.8). CONCLUSION: In clean-contaminated and contaminated gastrointestinal operations, giving >24 h of postoperative antibiotics offered no protection against SSI. An adequately powered randomized clinical trial is needed to conclusively evaluate longer duration antibiotic prophylaxis. PMID- 24805115 TI - Incarcerated inguinal hernia management in children: 'a comparison of the open and laparoscopic approach'. AB - PURPOSE: To compare the outcomes of management of incarcerated inguinal hernia by open versus laparoscopic approach. METHODS: This is a retrospective analysis of incarcerated inguinal hernina in a paediatric surgery centre involving four consultants. Manual reduction was attempted in all and failure was managed by emergency surgery. RESULTS: The laparoscopy group had 27 patients. Four patients failed manual reduction and underwent emergency laparoscopic surgery. Three of them had small bowel strangulation which was reduced laparoscopically. The strangulated bowel was dusky in colour initially but changed to normal colour subsequently under vision. The fourth patient required appendectomy for strangulated appendix. One patient had concomitant repair of umbilical hernia and one patient had laparoscopic pyloromyotomy at the same time. One patient had testicular atrophy, one had hydrocoele and one had recurrence of hernia on the asymptomatic side. The open surgery group had 45 patients. Eleven patients had failed manual reduction requiring emergency surgery, of these two required resection and anastomosis of small intestine. One patient in this group had concomitant repair of undescended testis. There was no recurrence in this group, one had testicular atrophy and seven had metachronous hernia. CONCLUSIONS: Both open herniotomy and laparoscopic repair offer safe surgery with comparable outcomes for incarcerated inguinal hernia in children. Laparoscopic approach and hernioscopy at the time of open approach appear to show the advantage of repairing the contralateral patent processus vaginalis at the same time and avoiding metachronous inguinal hernia. PMID- 24805116 TI - A case of small intestinal cast causing SBO in complicated intestinal graft versus-host disease. AB - We report an unusual case of small bowel obstruction caused by an intestinal cast in an 8-year-old female who developed intestinal graft-versus-host disease (GVHD) following two unrelated bone marrow transplants for aplastic anemia, and highlight the pathophysiology, common presentations, and surgical complications of intestinal GVHD from the surgeons' perspective. PMID- 24805117 TI - Child pedestrian injury and fatality in a developing country. AB - PURPOSE: Child pedestrian injuries and fatalities in developing countries continue to increase. We examined child pedestrian injuries and fatalities in the most populated urban agglomeration in Africa in order to develop control measures. METHODS: Two-year prospective study of injured child pedestrians (<=15 years) at the Surgical Emergency Room (SER) to determine demography, vehicles involved, road location, injury mechanism, pre-hospital transport, injury-arrival time, regions injured, injury severity and fatalities was done. RESULTS: Some 226 pedestrians (114 boys and 112 girls) comprising 42 children aged <=4 years, 91 aged 5-9 years and 93 aged 10-15 years were seen with car collisions (83 pedestrians, 36.7%), motorcycles (76, 33.6%), buses (41, 18.1%), others (15, 6.6%) and 11 undetermined vehicles. Injuries on the highways were 147 (65%); inner-city roads 77 (34.1%) and two undetermined roads. Crossing the road was responsible for 168 (74.3%) pedestrian injuries; while three other mechanisms produced 58 (25.7%) patients. Regions injured were head (42.9%), lower limbs (35.4%) and others (21.7%). Relatives, bystanders and police/ambulance brought 186 (82.3%), 31 (13.7%) and eight (3.5%) children, respectively; and within 6 h (43.4, 11.5 and 2.2%) and after (38.9, 2.2 and 1.3%). Nineteen deaths (10 brought in-dead, nine SER deaths) occurred; 15 of them girls, 15 had severe head injury, 15 were brought by relatives. However, fatality risks were truck collisions (OR 5.97), female child (OR 4.25), head injury (OR 4.18) and age <=4 years (OR 3.7). CONCLUSION: The equal sex incidence, worse female fatality despite similar exposure and injury severity with male, deserve further research. Improved pre hospital and SER care is needed. PMID- 24805119 TI - Synthetic biology: Cut up to bring together. PMID- 24805121 TI - Disease genetics: tRNA splicing defect underlies brain disorder. PMID- 24805120 TI - RNA-directed DNA methylation: an epigenetic pathway of increasing complexity. AB - RNA-directed DNA methylation (RdDM) is the major small RNA-mediated epigenetic pathway in plants. RdDM requires a specialized transcriptional machinery that comprises two plant-specific RNA polymerases - Pol IV and Pol V - and a growing number of accessory proteins, the functions of which in the RdDM mechanism are only partially understood. Recent work has revealed variations in the canonical RdDM pathway and identified factors that recruit Pol IV and Pol V to specific target sequences. RdDM, which transcriptionally represses a subset of transposons and genes, is implicated in pathogen defence, stress responses and reproduction, as well as in interallelic and intercellular communication. PMID- 24805123 TI - RNA: All sorts of mitochondrial RNA. PMID- 24805122 TI - Routes for breaching and protecting genetic privacy. AB - We are entering an era of ubiquitous genetic information for research, clinical care and personal curiosity. Sharing these data sets is vital for progress in biomedical research. However, a growing concern is the ability to protect the genetic privacy of the data originators. Here, we present an overview of genetic privacy breaching strategies. We outline the principles of each technique, indicate the underlying assumptions, and assess their technological complexity and maturation. We then review potential mitigation methods for privacy preserving dissemination of sensitive data and highlight different cases that are relevant to genetic applications. PMID- 24805124 TI - Facile synthesis of dibenzopentalene dianions and their application as new pi extended ligands. AB - Reduction of phenyl(silyl)ethynes with potassium followed by quenching with iodine gave dibenzopentalenes in moderate yields. The intermediates of the reactions, dipotassium dibenzopentalenides, were isolated. The first dibenzopentalene-transition-metal complex was successfully synthesized. The ruthenium atoms are located above the six-membered rings. However, X-ray diffraction analysis and theoretical calculations revealed that the aromatic nature of the five-membered rings was retained. The cyclic voltammetry of the Ru complex revealed two oxidation waves with relatively large separation. PMID- 24805125 TI - Sugar sweetened beverages and weight gain over 4 years in a Thai national cohort- a prospective analysis. AB - INTRODUCTION: Sugar sweetened beverages (SSBs) are implicated in the rising prevalence of obesity and diet-related chronic diseases worldwide. However, little is known about their contribution to weight gain in Asian populations. This study aimed to investigate weight change associated with SSB consumption between 2005 and 2009 in a large national cohort of Thai university students. METHODS: Questionnaire data were collected from a large Thai cohort (the Thai Health-Risk Transition: a National Cohort Study). The analysis was based on responses from 59 283 of the 60 569 (98%) cohort members who had valid SSB consumption and weight variables in 2005 and 2009. The relationship between SSB consumption in 2005 and self-reported weight change was analysed using multiple linear regression models controlled for socio-demographic, activity and (non validated) dietary factors shown to influence weight. RESULTS: Higher frequency of SSB consumption in 2005 was significantly associated with greater weight gain between 2005 and 2009 in all age groups and in both sexes (p<0.0001); persons who consumed SSBs at least once a day in 2005 gained 0.5 kg more than those who consumed SSBs less than once a month. The estimated weight gain for the average person in the sample was 1.9 kg (95% C I 1.95-1.96). The difference in weight gain between those who increased their consumption frequency ( once per day) between 2005 and 2009 compared to those who maintained it was 0.3 kgs, while persons who reduced their consumption frequency (once a day to > once a month) gained 0.2 kgs less than those whose consumption remained unchanged. CONCLUSION: SSB consumption is independently associated with weight gain in the Thai population. Research and health promotion in Thailand and other economically transitioning countries should focus on reducing their contribution to population weight gain and to diet-related chronic diseases. PMID- 24805127 TI - Systematic review: Sprue-like enteropathy associated with olmesartan. AB - BACKGROUND: The onset of a sprue-like enteropathy in association with olmesartan therapy has been recently reported. AIMS: To perform a systematic review of the literature and describe three additional cases of olmesartan-associated enteropathy. METHODS: Electronic and manual bibliographic searches were performed to identify original reports in which subjects who were undertaking olmesartan developed a sprue-like enteropathy. Because of the scarcity of studies with adequate sample size, case series with less than 10 patients and case reports were also considered. Data extraction was performed independently by two reviewers. RESULTS: A total of 11 publications met our pre-defined inclusion criteria, for an overall number of 54 patients (including our series). Almost all patients presented with diarrhoea and weight loss. Normocytic normochromic anaemia and hypoalbuminaemia were the commonest laboratory defects at presentation. Antibody testing for coeliac disease was always negative. Variable degrees of duodenal villous atrophy were present in 98% of patients, while increased intra-epithelial lymphocytes were documented in only 65% of cases. After discontinuation of olmesartan, all reported patients achieved resolution of signs and symptoms. CONCLUSIONS: Although the available evidence is limited, the olmesartan-associated sprue-like enteropathy may be considered as a distinct clinical entity, and should be included in the differential diagnosis when serological testing for coeliac disease is negative. PMID- 24805126 TI - Structural elucidation and antioxidant activities of proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves. AB - Proanthocyanidins in Chinese bayberry leaves (PCBLs) were qualitatively analyzed. NMR data suggest that PCBLs are mostly composed of (epi)gallocatechin gallate units. Matrix-assisted laser desorption time-of-flight MS data indicate 95 possible prodelphinidin structures, ranging from dimers to tridecamers. Preparative normal-phase HPLC and further analysis by reverse-phase HPLC together with electrospray ionization MS enabled detection of 20 compounds, including seven newly identified compounds in Chinese bayberry leaves. The antioxidant capacity of PCBLs was evaluated by (1,1-diphenyl-2-picryl-hydrazyl), ferric reducing antioxidant power, and oxygen radical absorption capacity assays. The EC50 of DPPH radical scavenging activities (as 50% decrease in the initial DPPH concentration) were 7.60 ug. The FRAP and ORAC values were 8859.33 +/- 978.39 and 12991.61 +/- 1553.34 umol Trolox equivalents per gram, respectively. The results indicate the high antioxidant potency of PCBLs. PMID- 24805128 TI - Narratives reflecting the lived experiences of people with brain disorders: common psychosocial difficulties and determinants. AB - BACKGROUND: People with brain disorders - defined as both, mental disorders and neurological disorders experience a wide range of psychosocial difficulties (PSDs) (e.g., concentrating, maintaining energy levels, and maintaining relationships). Research evidence is required to show that these PSDs are common across brain disorders. OBJECTIVES: To explore and gain deeper understanding of the experiences of people with seven brain disorders (alcohol dependency, depression, epilepsy, multiple sclerosis, Parkinson's disease, schizophrenia, stroke). It examines the common PSDs and their influencing factors. METHODS: Seventy seven qualitative studies identified in a systematic literature review and qualitative data derived from six focus groups are used to generate first person narratives representing seven brain disorders. A theory-driven thematic analysis of these narratives identifies the PSDs and their influencing factors for comparison between the seven disorders. RESULTS: First-person narratives illustrate realities for people with brain disorders facilitating a deeper understanding of their every-day life experiences. Thematic analysis serves to highlight the commonalities, both of PSDs, such as loneliness, anger, uncertainty about the future and problems with work activities, and their determinants, such as work opportunities, trusting relationships and access to self-help groups. CONCLUSIONS: The strength of the methodology and the narratives is that they provide the opportunity for the reader to empathise with people with brain disorders and facilitate deeper levels of understanding of the complexity of the relationship of PSDs, determinants and facilitators. The latter reflect positive aspects of the lives of people with brain disorders. The result that many PSDs and their influencing factors are common to people with different brain disorders opens up the door to the possibility of using cross-cutting interventions involving different sectors. This strengthens the message that 'a great deal can be done' to improve the lived experience of persons with brain disorders when medical interventions are exhausted. PMID- 24805129 TI - Sexual experience enhances Drosophila melanogaster male mating behavior and success. AB - Competition for mates is a wide-spread phenomenon affecting individual reproductive success. The ability of animals to adjust their behaviors in response to changing social environment is important and well documented. Drosophila melanogaster males compete with one another for matings with females and modify their reproductive behaviors based on prior social interactions. However, it remains to be determined how male social experience that culminates in mating with a female impacts subsequent male reproductive behaviors and mating success. Here we show that sexual experience enhances future mating success. Previously mated D. melanogaster males adjust their courtship behaviors and out compete sexually inexperienced males for copulations. Interestingly, courtship experience alone is not sufficient in providing this competitive advantage, indicating that copulation plays a role in reinforcing this social learning. We also show that females use their sense of hearing to preferentially mate with experienced males when given a choice. Our results demonstrate the ability of previously mated males to learn from their positive sexual experiences and adjust their behaviors to gain a mating advantage. These experienced-based changes in behavior reveal strategies that animals likely use to increase their fecundity in natural competitive environments. PMID- 24805130 TI - Sociodemographic characteristics and chronic medical conditions as risk factors for herpes zoster: a population-based study from primary care in Madrid (Spain). AB - The objectives of this study were to estimate incidence density rates (IDR) of herpes zoster (HZ) and to analyze the association with sociodemographic characteristics and selected chronic medical conditions. The study cohort consisted of the adult population included in the Public Health System of the Autonomous Community of Madrid, Spain on 1/10/2009 (5 244 402 persons). Data source were electronic medical records from primary care between 1/10/2009 31/12/2012. Individual socioeconomic status (SES) was inferred by geocoding. Poisson regression analyses were stratified by sex, to identify factors associated with HZ. We identified 81 541 incident cases of HZ (61.7% in women and 46.5% in the group aged 60 and over). IDR was 4.11 per 1000 person-years in men and 5.95 in women. IDR were higher with age, in autochthonous population, those with lower SES and in patients with immunodeficiencies. After adjustment, higher incidence rate ratios were found with age, autochthonous origin, lower SES, and in patients with HIV-infection/AIDS (3.20, CI95% 2.90-3.53 in men and 2.98, CI95% 2.58-3.45 in women), and other immunodeficiencies (1.57, CI95% 1.41-1.75 and 1.65, CI95% 1.50-1.80). COPD, asthma, DM, ischemic heart disease, other cardiovascular diseases, and cancer were also associated with an increased incidence of HZ. We conclude that older, autochthonous patients with lower SES and with certain underlying medical conditions had a higher probability of suffering HZ. Electronic databases are useful for estimating the incidence of HZ, and for finding associations with sociodemographic and clinical characteristics. Identifying unrecognized risk factors for HZ, such as asthma or cardiovascular diseases, is crucial to interpret the epidemiology of HZ, to target vaccination programs and to monitor their effect. PMID- 24805131 TI - Impact of estrogen-related receptor alpha on the biological characteristics of rat mandibular condylar chondrocytes. AB - It is well-known that estrogen-related receptor alpha (ERRalpha) affects numerous metabolic pathways and biological functions in the body, although the function of ERRalpha in the mandibular condylar chondrocytes (MCCs) of the temporomandibular joint remains unclear. The aim of the present study was to investigate the effect of ERRalpha on the biological characteristics of MCCs in female rats. Immunofluorescent staining was used to observe the expression level and distribution of ERRalpha in MCCs and tissues. Quantitative polymerase chain reaction (qPCR) was performed to detect the impact of estrogen intervention on the biological characteristics of female rat MCCs and ERRalpha expression levels. Liposome transfection and XCT-790 were used to overexpress and inhibit ERRalpha expression, respectively, and then qPCR was performed to detect changes in the biological characteristics of MCCs. ERRalpha expression was detected in the nucleus and cytoplasm of rat MCCs. 17-beta estradiol (E2) (10-8 M) increased the mRNA and protein expression levels of ERRalpha, Sox9, GDF-5 and aromatase during in vitro MCC cultivation. In addition, E2 affected MCC proliferation through the regulation of ERRalpha expression levels. Overexpression of ERRalpha positively regulated the mRNA and protein expression levels of Sox9 and GDF-5, but did not exhibit a significant effect on the mRNA and protein expression levels of aromatase and Col2a1. In conclusion, ERRalpha exhibited an important regulatory role in the proliferation and differentiation of female Sprague-Dawley rat MCCs in vitro through regulating Sox9 and GDF-5. PMID- 24805132 TI - CD30 expression in malignant vascular tumors and its diagnostic and clinical implications: a study of 146 cases. AB - Angiosarcoma (AS) is a rare malignant vascular tumor, whereas epithelioid hemangioendothelioma (EHE) is a vascular tumor of low-grade malignancy. CD30 is a member of the tumor necrosis factor receptor superfamily, member 8 (TNFRSF8). Although the expression of CD30 is most commonly associated with lymphoid malignancies or germ cell tumors, occasional ASs have been reported as CD30 positive. However, there are limited data to evaluate its role definitively in malignant vascular tumors. In this study, we evaluated 91 ASs, 30 EHEs from various sites, and 25 Kaposi sarcomas. Overall, CD30 was expressed in 31/91 cases (34%) of AS, in 7/30 cases (30%) of EHE, but in none of the Kaposi sarcomas. CD30 was expressed in a membranous staining pattern and positivity in tumor cells varied from focal to diffuse. The positive ASs included vasoformative more differentiated tumors and also solid, undifferentiated, lymphoma-like examples, one of which was classified as lymphoma before the era of immunohistochemistry. The CD30 expression was seen in >50% of tumor cells in a majority of ASs but only in 7% of EHEs. None of the 55 ASs studied were immunohistochemically positive for TIA-1 or Granzyme B, antigens used as more specific markers for anaplastic large cell lymphoma. Compared with AS, normal vascular endothelia of capillaries and muscular vessels showed variable positivity. Among hemangiomas, cavernous and spindle cell hemangiomas showed most frequent endothelial CD30 positivity, whereas in most other hemangiomas, CD30 positivity was scant. In conclusion, CD30 expression occurs in a significant subset of ASs and EHEs and needs to be included in the differential diagnosis with other CD30-positive malignancies to avoid a diagnostic pitfall. It remains to be determined whether patients with strongly CD30-positive ASs could be candidates for targeted therapy using the recently introduced CD30 antibody drug conjugates. PMID- 24805133 TI - p40 is the best marker for diagnosing pulmonary squamous cell carcinoma: comparison with p63, cytokeratin 5/6, desmocollin-3, and sox2. AB - Histologic distinction among non-small cell lung carcinomas, particularly between squamous cell carcinoma (SQC) and adenocarcinoma (ADC), has become more important. Recently, a p40 antibody was suggested to be a highly specific marker for SQC. We evaluated p40 expression and compared it with the expression of other SQC markers in 580 primary lung carcinomas, including 158 SQCs, 156 ADCs, 50 carcinoid tomors, 107 large cell neuroendocrine carcinomas, 68 small cell lung carcinomas, and 41 malignant mesotheliomas. Detailed histologic distributions of p40-positive cases were as follows: 153 (96.8%) of 158 SQCs, 7 (4.6%) of 152 ADCs, 0 (0%) of 50 carcinoid tomors, 4 (3.6%) of 107 large cell neuroendocrine carcinomas, 1 (1.5%) of 68 small cell lung carcinomas, and 1 (2.4%) of 41 mesotheliomas. p40 staining yields high sensitivity as well as high specificity for distinguishing SQC from ADC, neuroendocrine carcinomas, and malignant mesothelioma. PMID- 24805134 TI - The utility of BRAFV600E mutation-specific antibody for colon cancers with microsatellite instability. AB - This study's objective was to assess the performance of immunohistochemical staining with the BRAF mutation-specific antibody (clone VE1) in tissue from colon cancers, including those with a high degree of microsatellite instability (MSI-H). VE1 was applied to tissue microarrays of 152 colon cancers with known MSI status. Results of immunohistochemical analyses were scored as negative, positive, or equivocal. The results of VE1 immunohistochemical analysis were compared with BRAF mutation analysis by PCR. Fifteen of the 152 cases (10%) were positive with VE1 immunohistochemical analysis, 8 were equivocal, and 129 were negative. There was a single false-negative case and no false positives were identified when 74 VE1-positive or VE1-negative cases were tested by the BRAF PCR testing. Of the 8 equivocal VE1 cases identified, 3 were BRAF-positive. In the 17 MSI-H colon cancers, VE1 immunohistochemical analysis resulted in 7 true positive, 9 true-negative, and 1 false-negative case when compared with PCR results. The sensitivity and specificity of VE1 in the MSI-H colon cancer group were determined to be 88% and 100%, respectively. The BRAF positivity rate by VE1 immunohistochemical analysis in MSI-H colon cancers is consistent with that of published cohorts, which use molecular assays, and the accuracy of positive or negative VE1 staining is high. A small subset of equivocal cases (5% in our cohort) with heterogenous staining requires confirmation by the BRAF mutation analysis. We propose a testing algorithm for Lynch syndrome screening in MSI-H colorectal cancers that incorporates VE1 immunohistochemical analysis with PCR testing for equivocal cases. PMID- 24805135 TI - Current choices in robotic surgery: whether to increase use. PMID- 24805137 TI - Impact of Entomophaga maimaiga (Entomophthorales: Entomophthoraceae) on outbreak gypsy moth populations (Lepidoptera: Erebidae): the role of weather. AB - The fungal pathogen Entomophaga maimaiga Humber, Shimazu, and Soper is prevalent in gypsy moth [Lymantria dispar (L.)] populations throughout North America. To understand how weather-related variables influence gypsy moth-E. maimaiga interactions in the field, we measured fungal infection rates at 12 sites in central Pennsylvania over 3 yr, concurrently measuring rainfall, soil moisture, humidity, and temperature. Fungal mortality was assessed using both field collected larvae and laboratory-reared larvae caged on the forest floor. We found significant positive effects of moisture-related variables (rainfall, soil moisture, and relative humidity) on mortality due to fungal infection in both data sets, and significant negative effects of temperature on the mortality of field-collected larvae. Lack of a clear temperature relationship with the mortality of caged larvae may be attributable to differential initiation of infection by resting spores and conidia or to microclimate effects. These relationships may be helpful in understanding how gypsy moth dynamics vary across space and time, and in forecasting how the gypsy moth and fungus will interact as they move into warmer or drier areas, or new weather conditions occur due to climate change. PMID- 24805136 TI - Two novel anoxia-induced ethylene response factors that interact with promoters of deastringency-related genes from persimmon. AB - A hypoxic environment is generally undesirable for most plants and stimulates anaerobic metabolism. It is a beneficial treatment, however, for the removal of astringency from persimmon to improve the fruit quality after harvest. High soluble tannins (SCTs) content is one of most important causes of astringency. High CO2 (95%) treatment effectively reduced SCTs in both "Mopan" and "Gongcheng shuishi" persimmon fruit by causing increases in acetaldehyde. Using RNA-seq and realtime PCR, twelve ethylene response factor genes (DkERF11-22) were isolated and characterized, to determine those responsive to high CO2 treatment. Only two genes, DkERF19 and DkERF22, showed trans-activation effects on the promoters of deastringency-related genes pyruvate decarboxylase genes (DkPDC2 and DkPDC3) and the transcript levels of these genes was enhanced by hypoxia. Moreover, DkERF19 and the previously isolated DkERF9 had additive effects on activating the DkPDC2 promoter. Taken together, these results provide further evidence that transcriptome changes in the level of DkERF mRNAs regulate deastringency-related genes and their role in the mechanism of persimmon fruit deastringency is discussed. PMID- 24805138 TI - [Denticles: dental pulp calculi]. PMID- 24805139 TI - Syntheses and properties of 2-D and 3-D Pb-Ag heterometallic iodides decorated with ethylene polyamines at the Pb(II) center. AB - Hybrid organic-inorganic Pb-Ag heterometallic iodides [(en)2(PbAgI3)]2n.nH2O (1), [(pda)2(PbAgI3)]n (2), [(tmeda)(PbAgI3)]n (3), [(trien)(PbAgI3)]n (4), [(tepa)(PbAg2I4)]n (5), and [{(dien)3(CO3)}2(Pb6Ag8I15)]nIn (6) were prepared by the reactions of PbI2, AgI (or Ag2CO3) and KI with different polyamines in N,N' dimethylformamide (DMF) solution. In 1-4, two AgI4 tetrahedra share a common edge to form the bimeric Ag2I6 unit. It coordinates to the Pb(II) ion of [PbL2](2+) or [PbL'](2+) (L = en, pda; L' = tmeda, trien) via iodine atoms to form hybrid organic-inorganic heterometallic iodides 1, 2, 3 and 4, respectively. Compounds 1, 3, 4 and contain 2-D layered backbones of [PbAgI3]n, whereas 2 contains a backbone of [PbAgI3]n with a 3-D structure. Steric hindrance and denticity of the ethylene polyamines influence the coordination modes and connection strength between the iodoargentate aggregates and Pb(II) ions. In 5 the AgI4 units are joined via sharing common edges to form a 1-D polymeric [Ag2I4]n(2n-) anion. It is connected with [Pb(tepa)](2+)via iodine atoms to form a 3-D network of [(tepa)(PbAg2I4)]n. In 6, the CO3(2-) ion binds three [Pb(dien)](2+) units to form the novel trinuclear [{Pb(dien)}3(MU3-CO3)](4+) complex ion. Eight AgI4 tetrahedra are connected via sharing common edges to give a novel Ag8I15 cluster with C3 symmetry. The Ag8I15 cluster and the [{Pb(dien)}3(CO3)](4+) unit are connected to form a novel layered heterometallic iodometallate cation [{(dien)3(CO3)}2(Pb6Ag8I15)]n(n+)via sharing iodine atoms. Compounds 1-6 represent a new type of hybrid organic-inorganic heterometallic iodide containing coordinative organic components. Optical absorption spectra show a blue shift of the absorption edges for 1-6 compared with those of the bulk PbI2 and AgI solids. PMID- 24805140 TI - The effect of a dual combination of noninsulin antidiabetic drugs on lipids: a systematic review and network meta-analysis. AB - OBJECTIVE: As an ever widening array of anti-hyperglycemic agents are now available, the effect of these drugs on lipids is increasingly complex and controversial. The present meta-analysis was designed to clarify the effect of a dual combination of noninsulin anti-hyperglycemic agents on lipids in type 2 diabetes. METHODS: Randomized controlled trials comparing different dual combinations of antidiabetic drugs were identified by searching PubMed, Cochrane Library, and Embase. Study selection, data abstraction and quality assessment were carried out by two reviewers independently. Change in low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride and total cholesterol were pooled by both traditional meta-analysis and network meta analysis. RESULTS: Eighteen studies with a total of 10,222 patients were included. Network meta-analysis suggested that metformin + dipeptidyl peptidase-4 inhibitors (DPP-4) (LDL cholesterol: -0.19 mmol/L; HDL cholesterol: 0.06 mmol/L; triglycerides: -0.73 mmol/L; total cholesterol: -0.4 mmol/L) and metformin + glucagon-like peptide-1 (GLP-1) agonist (LDL cholesterol: -0.3 mmol/L; HDL cholesterol: 0.06 mmol/L; triglycerides: -0.64 mmol/L; total cholesterol: -0.5 mmol/L) were associated with relatively larger beneficial effects on the lipid profile among all combinations. Compared with metformin + thiazolidinedione, metformin + GLP-1 agonist (mean difference: -0.38; 95% confidence interval [CI]: 0.66 to -0.10) significantly decreased LDL cholesterol. Metformin + thiazolidinedione showed a larger increase than metformin + sulfonylurea in HDL cholesterol (mean difference: 0.1; 95% CI: 0.01 to 0.21). CONCLUSIONS: The effect of a dual combination of noninsulin anti-hyperglycemic agents on lipids is moderate to small, with metformin + DPP-4 inhibitor and metformin + GLP-1 agonist showing consistent beneficial effects on LDL cholesterol, HDL cholesterol, triglycerides and total cholesterol. Future trials are needed to confirm these findings. PMID- 24805141 TI - Coeliac disease presenting as severe hypoglycaemia in youth with type 1 diabetes. AB - BACKGROUND: Coeliac disease is an autoimmune disorder classically characterized by gastrointestinal symptoms and poor growth. The disease can be difficult to recognize in patients with Type 1 diabetes mellitus. Some clinicians find treatment of the disease in asymptomatic individuals controversial. CASE REPORTS: Two adolescent female patients with Type 1 diabetes experienced recurrent hypoglycaemic seizures. Neither patient reported gastrointestinal symptoms or poor growth. After diagnosis and treatment of coeliac disease, hypoglycaemia resolved. CONCLUSION: These cases illustrate how frequent unexplained severe hypoglycaemia can be an atypical presentation of coeliac disease in youth with Type 1 diabetes. Furthermore, they emphasize the importance of screening and treatment of coeliac disease in asymptomatic patients with Type 1 diabetes. Although controversial, management of coeliac disease in these asymptomatic patients can prevent the vicious cycle of recurrent hypoglycaemia and decrease risk for morbidity and death. PMID- 24805143 TI - Arctic tree rings as recorders of variations in light availability. AB - Annual growth ring variations in Arctic trees are often used to reconstruct surface temperature. In general, however, the growth of Arctic vegetation is limited both by temperature and light availability, suggesting that variations in atmospheric transmissivity may also influence tree-ring characteristics. Here we show that Arctic tree-ring density is sensitive to changes in light availability across two distinct phenomena: explosive volcanic eruptions (P<0.01) and the recent epoch of global dimming (P<0.01). In each case, the greatest response is found in the most light-limited regions of the Arctic. Essentially no late 20th century decline in tree-ring density relative to temperature is seen in the least light-limited regions of the Arctic. Consistent results follow from analysis of tree-ring width and from individually analysing each of seven tree species. Light availability thus appears an important control, opening the possibility for using tree rings to reconstruct historical changes in surface light intensity. PMID- 24805144 TI - IL-15: a novel prosurvival signaling pathway in cardiomyocytes. AB - Cardiovascular disease is the leading cause of death in Western countries. A major limitation of current treatments is the inability to efficiently repair or replace dead myocardium. Recently, stem cell-based therapies have been explored as an avenue to circumvent current therapeutic limitations. Overall, these therapies seem to result in small improvements in the contractile function of the heart. The exact mechanism(s) of action that underlie these improvements remain unknown, and it is believed that paracrine effects play a significant role. Previously, we had reported that an extract derived from bone marrow cells, in the absence of any live cell, contained cardioprotective soluble factors. In this study, we identify IL-15 as a putative cardioprotectant within the bone marrow cells paracrine profile. Using an in vitro culture system, we assessed the ability of IL-15 to protect cardiomyocytes under hypoxic conditions. For the first time, we have identified IL-15 receptors on the surface of cardiomyocytes and delineated the signaling system by which hypoxic cardiomyocytes may be protected from cellular death and rescued from oxidative stress with IL-15 treatment. PMID- 24805145 TI - Pyridostigmine ameliorates cardiac remodeling induced by myocardial infarction via inhibition of the transforming growth factor-beta1/TGF-beta1-activated kinase pathway. AB - Autonomic imbalance characterized by sympathetic predominance coinciding with diminished vagal activity is an independent risk factor in cardiovascular diseases. Several studies show that vagus nerve stimulation exerted beneficial effects on cardiac function and survival. In this study, we investigated the vagomimetic effect of pyridostigmine on left ventricular (LV) remodeling in rats after myocardial infarction. After myocardial infarction, surviving rats were treated with or without pyridostigmine (31 mg.kg-1.d-1) for 2 weeks, and hemodynamic parameters were measured. LV tissue was used to assess infarct size and interstitial fibrosis by Masson's trichrome and 0.1% picrosirius red staining. Protein expression of heart tissues was used to assess the efficacy of the treatment. Pyridostigmine markedly reduced myocardial infarct size and improved cardiac diastolic function. These improvements were accompanied with a significant decrease in matrix metalloproteinase-2 expression and collagen deposition. Additionally, pyridostigmine inhibited both transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-activated kinase expression in hearts postmyocardial infarction. Thus, pyridostigmine reduces collagen deposition, attenuates cardiac fibrosis, and improves LV diastolic function after myocardial infarction via TGF-beta1/TGF-beta1-activated kinase pathway inhibition. PMID- 24805146 TI - Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: comparison with class Ic and III drugs. AB - The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3-3 ug.kg-1.min-1) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 ug.kg-1.min-1) and flecainide (0.13 mg.kg-1.min-1) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling. PMID- 24805148 TI - The sympathetic nervous system as a target for the treatment of hypertension and cardiometabolic diseases. AB - The regulation of blood pressure by the sympathetic nervous system is reviewed with an emphasis on the role of the sympathetic nervous system in the development and maintenance of hypertension. Evidence from patients and animal models is summarized. Because it is clear that there is a neural contribution to many types of human hypertension and other cardiometabolic diseases, the case is presented for a renewed emphasis on the development of sympatholytic approaches for the treatment of hypertension and other conditions associated with hyperactivity of the sympathetic nervous system. PMID- 24805147 TI - Testosterone and atrial natriuretic peptide share the same pathway to induce vasorelaxation of human umbilical artery. AB - We recently observed in human umbilical artery smooth muscle cells that testosterone activates protein kinase G and stimulates large-conductance Ca2+ activated (BKCa) and voltage sensitive (KV) potassium channels. In the same work, we also show that atrial natriuretic peptide (ANP), an activator of particulate guanylate cyclase (pGC), stimulates the activity of BKCa and KV channels because of protein kinase G activation. The aim of this work was to prove that the relaxant effects of testosterone are also because of the increase of cGMP because of activation of the pGC. Subsarcolemmal cGMP signals were monitored in single cells by recording the cGMP-gated current (ICNG) in human umbilical artery smooth muscle cells expressing the wild-type rat olfactory cyclic nucleotide-gated (CNG) channel. Sodium nitroprusside (10 and 100 MUM), ANP (0.1 and 1 MUM), or testosterone (0.1, 1, and 10 MUM) induced activation of ICNG. This activation induced by testosterone and ANP is bigger than that elicited by sodium nitroprusside. In summary, our study reveals that testosterone and ANP activate the pGC and induce vasorelaxation of human umbilical artery. PMID- 24805149 TI - Memristor-integrated voltage-stabilizing supercapacitor system. AB - Voltage-stabilized supercapacitors: A single supercapacitor formed with PCBM/Pt/IPS nanorod-array electrodes is designed and delivers enhanced areal capacitance, capacitance retention, and excellent electrical stability under bending, while a significant voltage-decrease is observed during the discharging process. Once integrated with the memristor, the memristor-integrated supercapacitor systems deliver an extremely low voltage-drop, indicating greatly enhanced voltage-stabilizing features. PMID- 24805150 TI - Emergence of complex behavior in chemical cells: the system AlCl3-NaOH. AB - Chemical cells that spontaneously form in simple inorganic systems are presented. The cells are surrounded by semipermeable membranes that allow water and some ions to diffuse through. These cells exhibit dynamical behaviors that are typically associated with biological entities. These behaviors may be used to perform tasks such as rotation or linear translation in the vertical and horizontal directions. Yet another system builds "curtains". Behaviors are controlled by a complex network of physical and chemical processes that are organized in space and time. The type of dynamical behavior is determined by the chemical composition of the cell and the environment. By studying these systems we may learn general rules for the growth of living entities, or at least about the spontaneous growth of complex chemical structures. Understanding and mastering the synthesis of these systems may lead to new technologies where complex structures are grown rather than assembled. PMID- 24805151 TI - Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab. AB - While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Baseline and 3-6 week post treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Baseline ADC(L)/ADC(M) within nonenhancing T2/FLAIR volume (> or <=0.64) can stratify OS (HR = 2.24, p = 0.002) and PFS (HR = 1.90, p = 0.005). %ADC(H) within enhancing T1+C volume (> or <=25 %) can also stratify OS (HR = 0.59, p = 0.034) and PFS (HR = 0.56, p = 0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR = 0.17, p < 0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADC(H) within T1+C volume alone (1.3) or ADC(L)/ADC(M) within T2/FLAIR alone (1.86). ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma. PMID- 24805158 TI - Nitrate induction triggers different transcriptional changes in a high and a low nitrogen use efficiency maize inbred line. AB - In higher plants, NO3(-) can induce its own uptake and the magnitude of this induction is positively related to the external anion concentration. This phenomenon has been characterized in both herbaceous and woody plants. Here, different adaptation strategies of roots from two maize (Zea mays L., ZmAGOs) inbred lines differing in nitrogen use efficiency (NUE) and exhibiting different timing of induction were discussed by investigating NO3(-) -induced changes in their transcriptome. Lo5 line (high NUE) showing the maximum rate of NO3(-) uptake 4 h after the provision of 200 MUmol/L NO3(-) treatment modulated a higher number of transcripts relative to T250 (low NUE) that peaked after 12 h. The two inbred lines share only 368 transcripts that are modulated by the treatment with NO3(-) and behaved differently when transcripts involved in anion uptake and assimilation were analyzed. T250 line responded to the NO3(-) induction modulating this group of genes as reported for several plant species. On the contrary, the Lo5 line did not exhibit during the induction changes in this set of genes. Obtained data suggest the importance of exploring the physiological and molecular variations among different maize genotypes in response to environmental clues like NO3(-) provision, in order to understand mechanisms underlying NUE. PMID- 24805159 TI - Veterinary vaccines against toxoplasmosis. AB - Toxoplasma gondii is a cosmopolitan protozoan parasite that infects a wide range of mammal and bird species. Common infection leads to high economic (e.g., abortions in sheep) and human (e.g., congenital toxoplasmosis or neurotoxoplasmosis in humans) losses. With one exception (Toxovax for sheep), there are no vaccines to prevent human or animal toxoplasmosis. The paper presents the current state and challenges in the development of a vaccine against toxoplasmosis, designed for farm animals either bred for consumption or commonly kept on farms and involved in parasite transmission. So far, the trials have mostly revolved around conventional vaccines and, compared with the research using laboratory animals (mainly mice), they have not been very numerous. However, the results obtained are promising and could be a good starting point for developing an effective vaccine to prevent toxoplasmosis. PMID- 24805160 TI - [Personnel requirements of medical radiation physics in radiotherapy in comparison to the current guidelines "radiation protection in medicine" : Special consideration of intensity-modulated radiation therapy]. AB - In 1994 and 1998 reports on staffing levels in medical radiation physics for radiation therapy were published by the "Deutsche Gesellschaft fur Medizinische Physik" (DGMP, German Society for Medical Physics). Because of the technical and methodological progress, changes in recommended qualifications of staff and new governmental regulations, it was necessary to establish new staffing levels. The data were derived from a new survey in clinics. Some of the previously established results from the old reports were adapted to the new conditions by conversion.The staffing requirements were normalized to main components as in the earlier reports resulting in a simple method for calculation of staffing levels. The results were compared with the requirements in the "Richtlinie Strahlenschutz in der Medizin" (guidelines on radiation protection in medicine) and showed satisfactory agreement. PMID- 24805161 TI - The first one-pot synthesis of L-7-iodotryptophan from 7-iodoindole and serine, and an improved synthesis of other L-7-halotryptophans. AB - A simple and scalable one-pot biotransformation enables direct access to L halotryptophans, including L-7-iodotryptophan, from the corresponding haloindoles. The biotransformation utilizes an easy to prepare bacterial cell lysate that may be stored as the lyophilizate for several months and utilized as a catalyst as and when required. PMID- 24805162 TI - Molecular etching: a novel methodology for the generation of complex micropatterned growth surfaces for human cellular assays. PMID- 24805163 TI - Click modification of multifunctional liposomes bearing hyperbranched polyether chains. AB - Aiming at controlled modification of liposomal surface structures, we describe a postpreparational approach for surface derivatization of a new type of multifunctional, sterically stabilized liposomes. Application of dual centrifugation (DC) resulted in high encapsulation efficiencies above 50% at very small batch sizes with a total volume of 150 MUL, which were conductive to fast and efficient optimization of variegated surface modification reactions. Cholesterol-polymer amphiphiles, including complex hyperbranched polyether structures bearing 1-4 terminal alkynes, were used in DC formulations to provide steric stabilization. The alkyne moieties were explored as anchors for the conjugation of small molecules to the liposomal surface via click chemistry, binding 350-450 fluorophores per liposome as examples for surface active molecules. Using Forster resonance energy transfer (FRET) spectroscopy, the conjugation reaction as well as the uptake of FRET-labeled liposomes by RBE4 cells was monitored, and the distribution of the fluorescent lipids among cellular structures and membranes could be studied. Thus, the combination of clickable hyperbranched amphiphiles and dual centrifugation provides access to well-defined liposomal formulations with a variety of surface moieties. PMID- 24805164 TI - Probing the free energy landscape of the fast-folding gpW protein by relaxation dispersion NMR. AB - The topographic features of the free energy landscapes that govern the thermodynamics and kinetics of conformational transitions in proteins, which in turn are integral for function, are not well understood. This reflects the experimental challenges associated with characterizing these multidimensional surfaces, even for small proteins. Here we focus on a 62-residue protein, gpW, that folds very rapidly into a native structure with an alpha/beta topology in which alpha-helices are at the N- and C-terminal ends of the molecule with a central beta-hairpin positioned orthogonally to the helices. Using relaxation dispersion NMR spectroscopy to probe the conformational fluctuations in gpW at 1 degrees C, we found that the native state interconverts with a transiently formed, sparsely populated second state with a lifetime of 250 MUs, consistent with the global folding-unfolding rate under these conditions. In this low populated state, the beta-hairpin is unfolded whereas the alpha-helices remain predominantly formed. Our results argue for a hierarchical stability of secondary structural elements and demonstrate the existence of a complex free energy landscape even in this small, fast-folding single-domain protein. PMID- 24805165 TI - Income-related inequity in the use of GP services by children: a comparison of Ireland and Scotland. AB - Equity of access to health care is a key component of national and international health policy, with most countries subscribing to the principle that health care should be allocated on the basis of need, rather than ability to pay or other criteria. The issue of health care entitlements for children is particularly pertinent given the strong causal links that have been demonstrated between eligibility for free care, utilisation and health outcomes. The Irish health care system is unusual in requiring the majority of the population to pay the full out of-pocket cost of GP care. In contrast, all Scottish residents are entitled to free GP care at the point of use. This difference in public health care entitlements between Ireland and Scotland allows us to examine the impact of differences in financing structures on equity in GP care. In this paper, we use data from two nationally representative surveys of children in Ireland and Scotland to examine the degree of income-related inequity in the utilisation of GP services in both countries. We find that while the distribution of GP care is significantly pro-poor in Ireland, even after adjustment for health need, there is little or no significant inequity in GP utilisation among Scottish children. However, focusing just on children who pay the full price of GP care in Ireland, we find some evidence for a significant pro-rich distribution of GP visits. These results reflect the particular structure of health care entitlements that exist in two systems. PMID- 24805169 TI - Preoperative ostomy education and stoma site marking. PMID- 24805170 TI - Should we eliminate the word "predictability" when discussing pressure ulcer risk assessment scales? PMID- 24805167 TI - Isolation of adipose-derived stromal cells without enzymatic treatment: expansion, phenotypical, and functional characterization. AB - Stem cell therapy is a potential method for the treatment of numerous diseases. The most frequent cellular source is bone-marrow-derived mesenchymal stromal cells (BM-MSCs). Human adipose-derived stromal cells (ADSCs) share similar properties with BM-MSCs as they support hematopoiesis, modulate ongoing immune responses, and differentiate into cells of mesodermal origin. On the other hand, ADSCs have higher frequency in situ, higher availability, and very few ethical issues compared with BM-MSCs, giving them an advantage over BM-MSCs for clinical use. Most of the methods used to isolate ADSCs contain a collagenase digestion step, but the type of collagenase and time of sample digestion vary among studies and these differences could have an impact on the cell properties and thus in result comparison. To overcome this obstacle, we propose a new method to isolate ADSCs from lipoaspirate without collagenase digestion step. We compared ADSCs obtained with our method versus classical protocol using collagenase digestion. Cells obtained with our method are equivalent but they have a better long-term hematopoietic support than those obtained with classical method. Moreover, our method has an advantage over the classical one as it is easier, safer, faster, less expensive, and more consistent with good manufacturing practices to obtain large number of ADSCs ex vivo. PMID- 24805171 TI - Neonatal case studies using active leptospermum honey. AB - PURPOSE: Treatment of the neonatal patient with clinically complex wounds creates a challenge due to the safety and efficacy issues associated with the use of many advanced wound care products. The purpose of this case series was to present outcomes of 3 neonates with wounds of differing etiologies managed by Active Leptospermum Honey (ALH). DESIGN: Clinical case series. SUBJECTS AND SETTINGS: Clinical experiences with 3 neonates, 1 male and 2 females, are described. These premature infants received care at Rush University Medical Center, Houston, Texas, or Driscoll Children's Hospital, Corpus Christi, Texas. RESULTS: Each neonate presented with dissimilar wounds and differing treatment goals. For a premature infant with left foot ischemia, ALH dressings allowed for removal of nonviable tissue and facilitated the granulation of the open wounds. This removal of nonviable tissue coupled with the facilitation of granulation tissue enabled the premature infant's toe tips to be salvaged without requiring aggressive surgical intervention. For the 2 preterm infants with extravasation of intravenous solutions, ALH dressings allowed healing and increased tissue granulation without any noted toxicity to the wound bed. Further, the method of action of ALH includes an osmotic pull effect that reduced periwound erythema and edema. CONCLUSION: Although the use of ALH has been well documented in adult care, these case studies demonstrate its potential use in different wound etiologies in 3 neonatal patients. PMID- 24805173 TI - Necrotizing enterocolitis in a neonate: a case study using negative pressure wound therapy. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a disease of the intestine detrimental that occurs in approximately 10% of neonates who weigh 1500 g or less; it is associated with a 25% mortality rate. Additional abdominal wall defects and disturbance of environmental surroundings further compromise the likelihood of mortality. Early intervention and aggressive surgical treatment have been shown to decrease the mortality rate of this disease process. CASE STUDY: This case study describes wound and ostomy management on a neonate with NEC who, after bowel perforation, required a distal and proximal jejunostomy and a colostomy. Frequent dressing changes were disrupting the neonates' environmental factors that affect growth. Management began with an alginate dressing, but it was unsuccessful in containing the drainage. Negative pressure wound therapy was then applied to eliminate exudate and infectious material, control odor, and decrease environmental factors affecting growth, as well as to assist in wound closure. CONCLUSION: Necrotizing enterocolitis and potential complications such as perforation and dehiscence can be devastating for hospitalized neonates. In this case, negative pressure wound therapy promoted tissue growth and managed exudate and odor, while decreasing intervals between dressing changes. The abdominal wound healed, allowing for a better plane for stoma pouching. The neonate's ostomies were successfully reversed and he continues to thrive to date. PMID- 24805172 TI - Application of a pectin barrier for medical adhesive skin injury (epidermal stripping) in a premature infant. AB - BACKGROUND: Premature infants require, as part of their care, devices such as monitors and temperature probes to be attached to their skin. However, because of immaturity of the skin, they are especially vulnerable to medical adhesive related skin injury. CASE: This case discusses the application of a hydrocolloid (pectin) barrier between the adhesive surface of a silver reflective patch covering thermistor probe and the neonate's skin resulting in medical adhesive skin injury (epidermal stripping). CONCLUSIONS: The use of this pectin barrier proved to be a suitable surface to secure the temperature probe and avoid further medical adhesive-related skin injury. PMID- 24805174 TI - Negative pressure wound therapy in the treatment of diabetic foot ulcers: a systematic review of the literature. AB - Negative pressure wound therapy (NPWT) is an option for management of complex wounds such as diabetic foot ulcers; therefore, the nursing literature from 2000 to 2010 was reviewed for studies comparing clinical outcomes for diabetic foot ulcers treated with NPWT and those treated with standard moist wound therapy (SMWT). PubMed and OVID databases were explored using the following search terms: vacuum-assisted closure, NPWT, diabetic wounds, and standard most wound therapy. Research studies to judge efficacy were limited to the results from studies of experimental studies with randomized clinical trials on patients with diabetic foot wounds as the inclusion criteria. Four studies were identified that met the established criteria. Despite variations in patient population, methodology, and additional outcome variables studied, NPWT systems were shown to be more effective than SMWT with regard to proportion of healed wounds and rate of wound closure. PMID- 24805175 TI - Development and psychometric testing of the Honaker suspected deep tissue injury severity scale. AB - PURPOSE: This article describes the development of the Honaker Suspected Deep Tissue Injury Severity Scale (HSDTISS). The aims of the instrument are to (a) accurately evaluate the severity of the suspected deep tissue injury (SDTI), (b) determine progression of SDTI, and (c) demonstrate utility of the instrument in the clinical setting. INSTRUMENT: The HSDTISS contains 3 items: total surface area size, skin integrity, and wound color/tissue assessment. The total surface area size item is scored on a scale of 1 to 8, the skin integrity item is scored on a scale from 1 to 3, and the wound color/tissue assessment item is scored on a scale of 1 to 7. A cumulative score is calculated for the HSDTISS; it ranges from 3 to 18. METHODS: Content validity and interrater reliability testing were calculated. Content validity was evaluated by reviewing the items and scorings of the HSDTISS. Validation was derived from 10 content experts who participated in 2 rounds of evaluation and feedback. Intraclass correlation was used to evaluate the interrater reliability of the HSDTISS in a group of 21 clinicians (6 physical therapists and 15 RNs) by using the HSDTISS to evaluate photographs of 3 patients with SDTIs upon initial assessment and at discharge. The clinical utility of the instrument was determined by evaluation and subsequent comments received from 10 staff nurses within the hospital. RESULTS: Feedback from content experts supported content validity of the instrument. Calculation of an intraclass correlation coefficient showed strong interrater reliability (r = 0.997, P < .001). The time involved to complete assessment of 6 photographs was 8.2 +/- 2.3 minutes, suggesting that the HSDTISS is straightforward and easy to use. CONCLUSION: Findings from this study suggest that the HSDTISS accurately diagnoses wound severity among patients with SDTI. Further testing is needed to confirm these results in a larger group of clinicians with variable expertise in wound care. Further testing is needed to confirm these results among a larger group of clinicians. PMID- 24805176 TI - Assessment of common interventions and perceived barriers to pressure ulcer prevention in southwest Nigeria. AB - PURPOSE: We examined the interventions used by nurses to prevent pressure ulcers in 3 hospitals in south west Nigeria and perceived barriers to effective nursing pressure ulcer prevention interventions. SUBJECTS AND SETTINGS: One hundred ninety-three nurses were purposively selected from neurological, orthopedic, intensive care, and accident and emergency units of participating hospitals. Study sites were 3 teaching hospitals in south west Nigeria (Lagos State University Teaching Hospital, Lagos; University College Hospital, Ibadan; and Obafemi Awolowo Teaching Hospital Ile-Ife). METHODS: Data were collected via a structured questionnaire designed for this study. It included 3 sections: demographic information, practices used for pressure ulcer prevention, and perceived barriers to prevention. Sections of the questionnaire that queried interventions and perceived barriers to pressure ulcer prevention were evaluated for face and content validity. Reliability was evaluated via internal consistency; the split half reliability was 0.82. RESULTS: Similar practices regarding pressure ulcer prevention were found across the 3 hospitals. The most commonly used intervention was patient repositioning every 2 hours; the least used intervention was completion of a validated pressure ulcer risk scale. Nurses described using interventions that have not proved effective for pressure ulcer prevention such as massaging bony prominences and application of talcum powder. Nurses identified 2 principal factors that act as barriers to successful prevention of pressure ulcers: inadequate manpower and inadequate supply of linens on the wards. CONCLUSION: Nurses use a combination of evidence-based interventions, along with interventions that have not proved effective for pressure ulcer prevention. We recommend development of national standards for pressure ulcer prevention in Nigeria that are based on current best evidence and consistent with current international guidelines. PMID- 24805177 TI - Health-related quality of life in patients with urostomies. AB - PURPOSE: To assess health-related quality of life in patients with urothelial (bladder) cancer 6 months following radical cystectomy with construction of a urostomy. SUBJECTS: The target sample was 54 patients with urothelial cancer who underwent radical cystectomy with Bricker-type incontinent urinary diversion between December 2008 and December 2009; 37 out of 54 (68%) of potential respondents agreed to participate. Seven potential subjects died within the 6 month period and we were unable to locate 10 potential respondents. INSTRUMENT: The Stoma-Quality of Life was developed to be valid for measurement of 20 items that query the impact of the ostomy on the health-related quality of life and its impact on daily life. Scores were categorized as 70% to 100% (indicating good quality of life), 30% to 69% (indicating moderate quality of life), and 0 to 29% (indicating poor quality of life). METHODS: Subjects responded to the Stoma Quality of Life questionnaire by telephone 6 months after urostomy surgery. RESULTS: Thirty-five were ranked as having a good quality of life. The remaining 2 subjects had scores indicating moderate quality of life; no respondent was ranked as having a poor quality of life. CONCLUSIONS: Health-related quality of life was ranked as good in 95% of a group of patients managed by radical cystectomy and Bricker ileal conduit construction and moderate in 5%. Based on these findings, we conclude that the Bricker-type incontinent urinary diversion remains a viable treatment option for bladder cancer that allows an acceptable health-related quality of life. PMID- 24805178 TI - Cues to urinary urgency and urge incontinence: how those diagnosed with overactive bladder syndrome differ from undiagnosed persons. AB - PURPOSE: To investigate the extent to which cues are reported to be associated with urinary urgency incontinence and urinary urgency. DESIGN: Descriptive and correlational study comparing 2 groups. METHODS: An online questionnaire assessing the extent to which 19 environmental, 3 mood, 3 cognitive, 3 stress incontinence, 1 bladder volume cue, and 3 unlikely cues were associated with episodes of urinary urgency incontinence and urgency was administered. PARTICIPANTS: Three hundred six participants were randomly drawn from a panel of respondents maintained by Zoomerang, Inc. Approximately half (n = 150) had self reported diagnoses of overactive bladder syndrome (OAB) and half did not. Cue ratings were compared between persons with and without OAB and between likely and unlikely cues. RESULTS: The most frequently reported environmental cues were "On the way to the bathroom" and "Arrival at home/opening front door"; these cues were reported by both groups. Respondents with and without OAB showed significant differences in the mean number of cues associated with urinary urgency incontinence and with urinary urgency; persons with OAB were always higher. Significant differences between persons with and without OAB were found for 28 of 32 cues associated with incontinence and 25 of 32 cues associated with urinary urgency. To investigate response bias, within-subjects analyses compared mean responses to the 3 unlikely cues to means of all other cues. Analyses revealed that scores for unlikely cues were significantly lower than scores for likely cues. CONCLUSION: Cues associated with urgency incontinence and urgency were frequently reported by both groups. However, responding to cues was significantly more frequent among those who had been diagnosed with OAB. These findings may have implications for the diagnosis and treatment of urinary urgency incontinence. PMID- 24805179 TI - Effect of electroacupuncture combined with tolterodine on treating female mixed urinary incontinence. AB - PURPOSE: To examine the effectiveness of combination therapy of electroacupuncture and tolterodine in treating female patients with mixed urinary incontinence. MATERIALS AND METHODS: Seventy-one women with mixed urinary incontinence were recruited to receive electroacupuncture therapy or combination therapy with electroacupuncture and tolterodine 2 mg orally twice a day for 8 weeks. In electroacupuncture therapy, the acupoints, including BL32 (Ci Liao), BL35 (Hui Yang), SP6 (San Yin Jiao), and ST36 (Zu San Li), were selected with the stimulation of a low-frequency (20 Hz) disperse-dense wave. The International Consultation on Incontinence Questionnaire score, the number of incontinence episodes, and urine leakage were measured before and after the treatment to evaluate the effect. RESULTS: Response rates were 73.5% and 78.4% in electroacupuncture therapy group and in the combination therapy group respectively. No significant differences were found when group outcomes were compared. The International Consultation on Incontinence Questionnaire score, the number of incontinence episodes, and urine leakage improved significantly (P < .001) after 8 weeks compared with baseline values in both groups. Significantly more patients in the combination therapy group experienced more than 50% reduction in the number of incontinent episodes than in the electroacupuncture group (75.7% vs 58.8%, P < .01). They also had significantly less urine leakage than those in electroacupuncture therapy group (11.2 +/- 7.6 g vs 15 +/- 9.1 g) (P < .05). CONCLUSIONS: The effect of electroacupuncture for female mixed urinary incontinence may be enhanced by tolterodine. PMID- 24805183 TI - Loss of miR-100 enhances migration, invasion, epithelial-mesenchymal transition and stemness properties in prostate cancer cells through targeting Argonaute 2. AB - Evidence in literature has demonstrated that some microRNAs (miRNAs) play a pivotal role in most solid tumor metastasis. Previous studies have showed that miR-100 is downregulated in human prostate cancer tissue compared to normal prostate and also significantly decreased in bone metastatic prostate cancer samples compared with primary prostate cancer. Argonaute 2 (AGO2) is the core effector protein of the miRNA-induced silencing complex and overexpression of AGO2 might enhance tumor metastasis. However, it is unknown whether and how miR 100 and AGO2 regulates metastasis of prostate cancer. Here, we report that miR 100 negatively regulated migration, invasion, epithelial-mesenchymal transition (EMT), colony formation, spheroid formation and expression of the stemness factors c-Myc, Oct4 and Klf4 in PC-3 and DU145 cells. Furthermore, miR-100 expression was negatively correlated with bone metastasis of prostate cancer patients. Notably, luciferase assay showed that AGO2 was a direct target of miR 100. Downregulation of AGO2 repressed migration, invasion, EMT and stemness of prostate cancer cells, and reversed the effects seen with miR-100 downregulation. Downregulation of AGO2 enhanced expression of miR-34a and miR-125b which can suppress migration, invasion, EMT and stemness of cancer cells. Taken together, our findings indicate that loss of miR-100 promotes the metastatic ability of prostate cancer cells at least partially by upregulating AGO2 expression through modulating migration, invasion, EMT and stemness of cancer cells, and suggest that miR-100/AGO2 may play an important role in regulating the metastasis of prostate cancer and is a potential target of prevention and therapy. PMID- 24805184 TI - Comparing the efficacy of efavirenz and boosted lopinavir using viremia copy years. AB - INTRODUCTION: HIV-1 plasma viral load during treatment can be highly variable. Thus, there is the need to find a measure of cumulative viremia that can be used to assess both the short- and long-term efficacy of highly active antiretroviral therapy (HAART). Here, we validate a measure of cumulative viremia to evaluate HAART efficacy. METHODS: We accessed HAART efficacy using data from a randomized clinical trial conducted in Mexico. We compared the proportion of individuals achieving a viral load <50 and <400 copies/mL at week 48, against the cumulative plasma viral load, estimated as the area under the plasma viral load curve (AUVLC). High AUVLC indicates high cumulative viremia. RESULTS AND DISCUSSION: There was a strong and significant association between the proportion of individuals achieving a viral load <50 and <400 copies/mL at week 48, with individuals suppressed having significant lower cumulative viremia. The median area was 7513 (25th-75th percentile [Q1-Q3] 6634-8180) if viral load <50 copies/mL and 7679 (Q1-Q3 6899-9373) if viral load >=50 copies/mL (p-value 0.0284). When the analysis was stratified by study arm, individuals on efavirenz had lower cumulative viremia than those on boosted lopinavir. CONCLUSIONS: Our findings suggest that cumulative viremia should be explored further as a tool to simultaneously evaluate the individual and public health efficacy of HAART. This is particularly relevant to the implementation and evaluation of the Treatment 2.0 strategy recently proposed by UNAIDS and the WHO, as a means to maximize the individual and public health benefit of HAART. PMID- 24805185 TI - Helicobacter pylori susceptibility to fosfomycin, rifampin, and 5 usual antibiotics for H. pylori eradication. AB - The aim of the study was to assess Helicobacter pylori resistance to fosfomycin, rifampin, and 5 other antibiotics. Susceptibility of 50 consecutive H. pylori strains was tested by E test and breakpoint susceptibility testing method. Overall and primary resistance rates were amoxicillin 2.0 and 0%, metronidazole 34.0 and 31.2%, tetracycline 2.0 and 2.1%, levofloxacin 18.0 and 16.7%, rifampin 12.0 and 10.4%, and fosfomycin 8.3 and 6.5%, respectively. Clarithromycin resistance was >20.0% in all patients (22.0%) and in untreated subjects (20.8%). Rifampin resistance was higher than those usually reported. Quinolone resistance rose from 2005-2007 (8.7%) to 2012-2013 (18.0%). High double/multidrug resistance rates (overall 22.0% and 20.0% in untreated adults), including a 5-fold resistance, were found. In conclusion, fosfomycin and rifampin resistance rates were much lower than that of metronidazole and slightly lower than those of clarithromycin and levofloxacin. MICs90 of both fosfomycin and rifampin were lower than those of clarithromycin and metronidazole. Thus, in countries of high/increasing H. pylori resistance and multidrug resistance, both rifamycins and fosfomycin could be helpful in rescue regimens. PMID- 24805186 TI - Emergence of plasmid-mediated quinolone resistance genes in clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa in Henan, China. AB - A total of 216 clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa were collected from a general hospital in Henan, China, and screened for the plasmid-mediated quinolone resistance (PMQR) determinants. The presence of beta-lactamase genes and mutations in quinolone resistance-determining regions were investigated among the PMQR-positive isolates. PMID- 24805187 TI - Endoscopic removal of a solitary metastatic renal cell carcinoma lesion to the stomach. PMID- 24805188 TI - Intravitreal Gentamicin-Induced Macular Infarction: SD-OCT Features. AB - A 75-year-old woman developed acute-onset endophthalmitis following phacoemulsification in the left eye. She was treated with intravitreal injections of vancomycin, ceftazidime, and gentamicin. The patient had persistent visual loss in the left eye after treatment. Her best-corrected visual acuity was 2/200 in the left eye and examination revealed a pale disc, retinal hemorrhages, and multiple nerve fiber layer infarcts. Fluorescein angiography showed retinal vascular non-perfusion in the macula. On spectral-domain optical coherence tomography (SD-OCT), there was diffuse retinal thinning, absence of the foveal depression, and increased reflectivity of the nerve fiber and ganglion cell layers, but with an intact inner segment/outer segment junction. This case demonstrates SD-OCT features in macular infarction following intravitreal gentamicin, specifically changes involving the inner retina with a relatively intact outer retina. PMID- 24805190 TI - Thermal formation of carbynes. AB - We simulate the formation of sp carbon chains (carbynes) by thermal decomposition of sp(2) carbon heated by a hot discharge plasma, by means of tight-binding molecular dynamics. We obtain and analyze the total quantity of carbynes and their length distribution as a function of temperature and density. PMID- 24805191 TI - Transcriptional and epigenetic basis for restoration of G6PD enzymatic activity in human G6PD-deficient cells. AB - HDAC inhibitors (HDACi) increase transcription of some genes through histone hyperacetylation. To test the hypothesis that HDACi-mediated enhanced transcription might be of therapeutic value for inherited enzyme deficiency disorders, we focused on the glycolytic and pentose phosphate pathways (GPPPs). We show that among the 16 genes of the GPPPs, HDACi selectively enhance transcription of glucose 6-phosphate dehydrogenase (G6PD). This requires enhanced recruitment of the generic transcription factor Sp1, with commensurate recruitment of histone acetyltransferases and deacetylases, increased histone acetylation, and polymerase II recruitment to G6PD. These G6PD-selective transcriptional and epigenetic events result in increased G6PD transcription and ultimately restored enzymatic activity in B cells and erythroid precursor cells from patients with G6PD deficiency, a disorder associated with acute or chronic hemolytic anemia. Therefore, restoration of enzymatic activity in G6PD-deficient nucleated cells is feasible through modulation of G6PD transcription. Our findings also suggest that clinical consequences of pathogenic missense mutations in proteins with enzymatic function can be overcome in some cases by enhancement of the transcriptional output of the affected gene. PMID- 24805193 TI - A quality monitoring program for red blood cell components: in vitro quality indicators before and after implementation of semiautomated processing. AB - BACKGROUND: Canadian Blood Services has been conducting quality monitoring of red blood cell (RBC) components since 2005, a period spanning the implementation of semiautomated component production. The aim was to compare the quality of RBC components produced before and after this production method change. STUDY DESIGN AND METHODS: Data from 572 RBC units were analyzed, categorized by production method: Method 1, RBC units produced by manual production methods; Method 2, RBC units produced by semiautomated production and the buffy coat method; and Method 3, RBC units produced by semiautomated production and the whole blood filtration method. RBC units were assessed using an extensive panel of in vitro tests, encompassing regulated quality control criteria such as hematocrit (Hct), hemolysis, and hemoglobin (Hb) levels, as well as adenosine triphosphate, 2,3 diphosphoglycerate, extracellular K(+) and Na(+) levels, methemoglobin, p50, RBC indices, and morphology. RESULTS: Throughout the study, all RBC units met mandated Canadian Standards Association guidelines for Hb and Hct, and most (>99%) met hemolysis requirements. However, there were significant differences among RBC units produced using different methods. Hb content was significantly lower in RBC units produced by Method 2 (51.5 +/- 5.6 g/unit; p < 0.001). At expiry, hemolysis was lowest in Method 2-produced RBC units (p < 0.05) and extracellular K(+) levels were lowest in units produced by Method 1 (p < 0.001). CONCLUSION: While overall quality was similar before and after the production method change, the observed differences, although small, indicate a lack of equivalency across RBC products manufactured by different methods. PMID- 24805194 TI - Fatty acids composition of Tunisian Ziziphus lotus L. (Desf.) fruits and variation in biological activities between leaf and fruit extracts. AB - This study was conceived to evaluate the essential fatty acids, secondary metabolites, antiradical and antimicrobial activities of unexploited Tunisian Ziziphus lotus L. The obtained results indicated that the major components of fatty acids were oleic acid (88.12%) and elaidic acid (7.88%). Leaves contained higher amount of total phenols, flavonoids and tannins than fruits, although both methanolic extracts had significant antioxidant activities. Significant correlations were observed between the total phenol or flavonoid contents in methanolic extracts and antioxidant activity estimated by using both 2,2' diphenyl-1-picrylhydrazyl and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic radical-scavenging methods. In addition, both methanolic extracts exhibited strong antibacterial and antifungal activities. The inhibition zone diameters and the minimal inhibition concentration values were in the range of 10-17 mm and 3.1 50 mg/mL, respectively. PMID- 24805195 TI - Ablation of Akt2 protects against lipopolysaccharide-induced cardiac dysfunction: role of Akt ubiquitination E3 ligase TRAF6. AB - Lipopolysaccharide (LPS), an essential component of the outer membrane of Gram negative bacteria, plays a pivotal role in myocardial anomalies in sepsis. Recent evidence has depicted a role of Akt in LPS-induced cardiac sequelae although little information is available with regard to the contribution of Akt isoforms in the endotoxin-induced cardiac dysfunction. This study examined the effect of Akt2 knockout on LPS-induced myocardial contractile dysfunction and the underlying mechanism(s) with a focus on TNF receptor-associated factor 6 (TRAF6). Echocardiographic properties and cardiomyocyte contractile function [peak shortening (PS), maximal velocity of shortening/relengthening, time-to-PS, time to-90% relengthening] were examined in wild-type and Akt2 knockout mice following LPS challenge (4mg/kg, 4h). LPS challenge enlarged LV end systolic diameter, reduced fractional shortening and cardiomyocyte contractile capacity, prolonged TR90, promoted apoptosis, upregulated caspase-3/-12, ubiquitin, and the ubiquitination E3 ligase TRAF6 as well as decreased mitochondrial membrane potential without affecting the levels of TNF-alpha, toll-like receptor 4 and the mitochondrial protein ALDH2. Although Akt2 knockout failed to affect myocardial function, apoptosis, and ubiquitination, it significantly attenuated or mitigated LPS-induced changes in cardiac contractile and mitochondrial function, apoptosis and ubiquitination but not TRAF6. LPS facilitated ubiquitination, phosphorylation of Akt, GSK3beta and p38, the effect of which with the exception of p38 was ablated by Akt2 knockout. TRAF6 inhibitory peptide or RNA silencing significantly attenuated LPS-induced Akt2 ubiquitination, cardiac contractile anomalies and apoptosis. These data collectively suggested that TRAF6 may play a pivotal role in mediating LPS-induced cardiac injury via Akt2 ubiquitination. PMID- 24805196 TI - Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKalpha1. AB - Cardiac fibroblasts (CF) are crucial in left ventricular (LV) healing and remodeling after myocardial infarction (MI). They are typically activated into myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) microfilaments and contribute to the formation of contractile and mature collagen scars that minimize the adverse dilatation of infarcted areas. CF predominantly express the alpha1 catalytic subunit of AMP-activated protein kinase (AMPKalpha1), while AMPKalpha2 is the major catalytic isoform in cardiomyocytes. AMPKalpha2 is known to protect the heart by preserving the energy charge of cardiac myocytes during injury, but whether AMPKalpha1 interferes with maladaptative heart responses remains unexplored. In this study, we investigated the role of AMPKalpha1 in modulating LV dilatation and CF fibrosis during post-MI remodeling. AMPKalpha1 knockout (KO) and wild type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery. The absence of AMPKalpha1 was associated with increased CF proliferation in infarcted areas, while expression of the myodifferentiation marker alpha-SMA was decreased. Faulty maturation of myofibroblasts might derive from severe down-regulation of the non-canonical transforming growth factor-beta1/p38 mitogen-activated protein kinase (TGF beta1/p38 MAPK) pathway in KO infarcts. In addition, lysyl oxidase (LOX) protein expression was dramatically reduced in the scar of KO hearts. Although infarct size was similar in AMPK-KO and WT hearts subjected to MI, these changes resulted in compromised scar contractility, defective scar collagen maturation, and exacerbated adverse remodeling, as indicated by increased LV diastolic dimension 30days after MI. Our data genetically demonstrate the centrality of AMPKalpha1 in post-MI scar formation and highlight the specificity of this catalytic isoform in cardiac fibroblast/myofibroblast biology. PMID- 24805197 TI - The arrhythmogenic human HRC point mutation S96A leads to spontaneous Ca(2+) release due to an impaired ability to buffer store Ca(2+). AB - The Ser96Ala (S96A) mutation within the histidine rich Ca(2+) binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca(2+) release events. However, the molecular mechanism connecting the S96A mutation of HRC to increased Ca(2+) release events remains unclear. Previous findings by our group indicate that these spontaneous Ca(2+) release events may be linked to store overload induced Ca(2+) release (SOICR) via the cardiac ryanodine receptor (RyR2). Therefore, in the present study we sought to determine whether HRC wild type (HRC WT) and S96A mutant (HRC S96A) expression has a direct effect on SOICR. Using both cytosolic and intra-Ca(2+) store measurements in human embryonic kidney cells expressing RyR2, we found that HRC WT significantly inhibited the propensity for SOICR by buffering store free Ca(2+) and inhibiting store Ca(2+) uptake. In contrast, HRC S96A exhibited a markedly suppressed inhibitory effect on SOICR, which was attributed to an impaired ability to buffer store Ca(2+) and reduce store Ca(2+) uptake. In addition to impairing the ability of HRC to regulate bulk store Ca(2+), a proximity ligation assay demonstrated that the S96A mutation also disrupts the Ca(2+) microdomain around the RyR2, as it alters the Ca(2+) dependent association of RyR2 and HRC. Importantly, in contrast to previous reports, the absence of triadin in our experimental model illustrates that the S96A mutation in HRC can alter the propensity for SOICR without any interaction with triadin. Collectively, our results demonstrate that the human HRC mutation S96A leads to an increase in spontaneous Ca(2+) release and ultimately arrhythmias by disrupting the regulation of intra-store free Ca(2+). This is primarily due to an impaired ability to act as an effective bulk and local microdomain store Ca(2+) buffer. PMID- 24805198 TI - Fostering supportive community connections through mothers' groups and playgroups. AB - AIM: The aim of this study was to explore the ways that mothers' groups and playgroups support families with children aged 0-5 years and foster community connectedness in newer residential communities in Perth, Western Australia. BACKGROUND: The transition to parenthood is a time of increased support need. Changing community demography has resulted in a loss of traditional support structures and an increased need for local community initiatives to support families with young children. DESIGN: A qualitative descriptive design was used for this initial phase of a mixed methods sequential exploratory study. METHOD: Data were collected between December 2011-August 2012. Interviews and focus groups conducted with 39 mothers provided insights from 16 mothers' groups and 13 playgroups. In addition, interviews were undertaken with three child health nurses and four local government early childhood staff. FINDINGS: For the participants in this study, mothers' groups and playgroups provided opportunities to learn about parenting, to build a supportive network, to forge friendships and a connectedness to the local community. The families who relocated often experienced isolation until new groups and social networks were found. In general, where participation in mothers' groups and playgroups facilitated relationships with others from the local community, connectedness to that community was reported by participants to be enhanced. CONCLUSION: Mothers' groups and playgroups provide important community development opportunities and appear to help reduce potential isolation for mothers with young children. The findings are of interest to nurses and other health professionals working with families with young children. PMID- 24805200 TI - A computational method for predicting inferior vena cava filter performance on a patient-specific basis. AB - A computational methodology for simulating virtual inferior vena cava (IVC) filter placement and IVC hemodynamics was developed and demonstrated in two patient-specific IVC geometries: a left-sided IVC and an IVC with a retroaortic left renal vein. An inverse analysis was performed to obtain the approximate in vivo stress state for each patient vein using nonlinear finite element analysis (FEA). Contact modeling was then used to simulate IVC filter placement. Contact area, contact normal force, and maximum vein displacements were higher in the retroaortic IVC than in the left-sided IVC (144 mm(2), 0.47 N, and 1.49 mm versus 68 mm(2), 0.22 N, and 1.01 mm, respectively). Hemodynamics were simulated using computational fluid dynamics (CFD), with four cases for each patient-specific vein: (1) IVC only, (2) IVC with a placed filter, (3) IVC with a placed filter and model embolus, all at resting flow conditions, and (4) IVC with a placed filter and model embolus at exercise flow conditions. Significant hemodynamic differences were observed between the two patient IVCs, with the development of a right-sided jet, larger flow recirculation regions, and lower maximum flow velocities in the left-sided IVC. These results support further investigation of IVC filter placement and hemodynamics on a patient-specific basis. PMID- 24805199 TI - Influence of the length and positioning of the antiestrogenic side chain of endoxifen and 4-hydroxytamoxifen on gene activation and growth of estrogen receptor positive cancer cells. AB - Tamoxifen has biologically active metabolites: 4-hydroxytamoxifen (4OHT) and endoxifen. The E-isomers are not stable in solution as Z-isomerization occurs. We have synthesized fixed ring (FR) analogues of 4OHT and endoxifen as well as FR E and Z isomers with methoxy and ethoxy side chains. Pharmacologic properties were documented in the MCF-7 cell line, and prolactin synthesis was assessed in GH3 rat pituitary tumor cells. The FR Z-isomers of 4OHT and endoxifen were equivalent to 4OHT and endoxifen. Other test compounds used possessed partial estrogenic activity. The E-isomers of FR 4OHT and endoxifen had no estrogenic activity at therapeutic serum concentrations. None of the newly synthesized compounds were able to down-regulate ER levels. Molecular modeling demonstrated that some compounds would each create a best fit with a novel agonist conformation of the ER. The results demonstrate modulation by the ER complex of cell replication or gene transcription in cancer. PMID- 24805201 TI - Elevation impacts the balance between growth and oxidative stress in coal tits. AB - The short favorable period of time available for the growth in seasonal environments could constrain the resources allocation between growth and other life-history traits, and the short-term fitness benefits of increased growth rate may prevail over other functions. Accelerated growth rates have been associated with long-term deleterious consequences (e.g., decreased lifespan), and recently oxidative stress (the imbalance between pro-oxidants generation and antioxidant defenses) has been suggested as a mediator of these effects. Here, we examined the impact of elevation on growth rate and self-maintenance parameters (resting metabolism, oxidative damage, and antioxidant defenses) of coal tit chicks (Periparus ater). We predicted that the shorter favorable season at the higher elevation site could lead to a reallocation of resources towards growth at the expense of self-maintenance processes. We found that chicks at high elevation grew significantly faster in terms of body mass and body size. Chicks from the high-elevation site presented higher resting metabolism, higher oxidative damage level, but similar antioxidant defenses, compared to low-elevation chicks. Interestingly, the chicks exhibiting the better antioxidant defenses at 7 days were also those with the highest resting metabolic rate, and the chicks that grew at the faster rate within the high-elevation site were those with the highest levels of oxidative damage on DNA. Our study supports the idea that increasing elevation leads to a higher growth rate in coal tit chicks, possibly in response to a shorter favorable season. In accordance with life-history theory, a bigger investment in growth was done at the expense of body maintenance, at least in terms of oxidative stress. PMID- 24805202 TI - Increasing temperatures can improve seedling establishment in arid-adapted savanna trees. AB - Plant species are shifting their ranges in response to global climate change, thus intensifying the need to predict such changes accurately. As the environmental requirements controlling plant distribution act differently at each developmental stage, there is a need to acquire a demographic-specific understanding of the factors which determine these distributions. Here we investigated the germination niche of two common savanna species Acacia nigrescens and Colophospermum mopane, with the aims to disentangle the direct and indirect effects of temperature on seed germination and establishment and to explore the impact of higher temperatures on the establishment success of savanna trees. Under laboratory conditions, we used thermal gradient plates to determine the thermal germination niche of both species, and a water stress experiment was conducted on C. mopane to account for water-temperature interactions. Using these data we parameterised a soil-moisture model to determine germination and establishment success under field conditions at current and future temperatures (+4 degrees C). Based on this model, higher future temperatures will not limit germination directly, but they will reduce the number of germination events by reducing the time window of suitable available soil water. Conversely, warmer conditions will accelerate the rate of radicle extension and increase the frequency of seedling establishment events. An additional advantage of higher temperatures is that fewer seeds will germinate, resulting in slower seed bank depletion when successful seedling establishment events do occur. PMID- 24805203 TI - Conversion coefficients for determining organ doses in paediatric pelvis and hip joint radiography. AB - BACKGROUND: Knowledge of organ and effective doses achieved during paediatric X ray examinations is an important prerequisite for assessment of radiation burden to the patient. OBJECTIVE: Conversion coefficients for reconstruction of organ and effective doses from entrance doses for pelvis and hip joint radiographs of 0 , 1-, 5-, 10-, 15- and 30-year-old patients are provided regarding the Guidelines of Good Radiographic Technique of the European Commission. MATERIALS AND METHODS: Using the personal computer program PCXMC developed by the Finnish Centre for Radiation and Nuclear Safety (Sateilyturvakeskus STUK), conversion coefficients for conventional pelvis and hip joint radiographs were calculated by performing Monte Carlo simulations in mathematical hermaphrodite phantom models representing patients of different ages. The clinical variation of radiation field settings was taken into consideration by defining optimal and suboptimal standard field settings. RESULTS: Conversion coefficients for the reconstruction of organ doses in about 40 organs and tissues from measured entrance doses during pelvis and hip joint radiographs of 0-, 1-, 5-, 10-, 15- and 30-year-old patients were calculated for the standard sagittal beam projection and the standard focus detector distance of 115 cm. CONCLUSION: The conversion coefficients presented can be used for organ dose assessments from entrance doses measured during pelvis and hip joint radiographs of children and young adults with all field settings within the optimal and suboptimal standard field settings. PMID- 24805205 TI - Fast imine equilibration and its consequences for the evaluation of dynamic combinatorial libraries. AB - An example of the subtle interplay between the intended templation and a very fast reequilibration of a dynamic combinatorial library of imines that occurs upon a solvent change is reported. Such seemingly "irrelevant" details of the procedure like imine dissolution time prior to reduction may dictate the outcome of the whole reaction. PMID- 24805204 TI - Bedside upper gastrointestinal series in critically ill low birth weight infants. AB - BACKGROUND: The upper gastrointestinal (UGI) series is the preferred method for the diagnosis of malrotation. A bedside UGI technique was developed at our institution for use in low birth weight, critically ill neonates to minimize the risks of transportation from the neonatal intensive care unit (NICU) such as hypothermia and dislodgement of support lines and tubes. OBJECTIVE: To determine the ability of a bedside UGI technique to identify the position of the duodenojejunal junction (DJJ) in low birth weight, critically ill infants in the NICU. MATERIALS AND METHODS: We retrospectively reviewed bedside UGI examinations performed in premature infants weighing less than 1,500 g from 2008 to 2013 and correlated the findings with clinical data, imaging studies and surgical findings. RESULTS: Of 27 patients identified (weight range: 633-1,495 g), 21 (78%) bedside UGI series were diagnostic. Twenty of 27 cases (74%) demonstrated normal intestinal rotation. One case demonstrated malrotation with midgut volvulus, which was confirmed at surgery. In six cases (22%), the position of the DJJ could not be accurately determined. No cases of malrotation with midgut volvulus were missed. None of the patients with normal bedside UGI studies was found to have malrotation based on clinical follow-up (mean: 20 months), surgical findings or further imaging. CONCLUSION: The bedside UGI is a useful technique to exclude malrotation in critically ill neonates and minimizes potential risks of transportation to the radiology suite. Pitfalls that may preclude a diagnostic examination include incorrect timing of radiographs, patient rotation, suboptimal enteric tube position and bowel distention. In cases of diagnostic uncertainty, a follow-up study should be performed. PMID- 24805206 TI - Terpene composited lipid nanoparticles for enhanced dermal delivery of all-trans retinoic acids. AB - In the present study, terpene composited lipid nanoparticles and lipid nanoparticles were developed and evaluated for dermal delivery of all-trans retinoic acids (ATRA). Terpene composited lipid nanoparticles and lipid nanoparticles were investigated for size, size distribution, zeta potential, entrapment efficiency, photostability, and cytotoxicity. In vitro skin permeation of ATRA lipid formulations were also evaluated. To explore the ability of lipid nanocarriers to target the skin, the distribution of rhodamine B base in the skin was investigated using confocal laser scanning microscopy (CLSM). The results indicated that the physicochemical characteristics of terpene composited lipid nanoparticles influenced skin permeability. All lipid nanocarriers significantly protected ATRA from photodegradation and were non-toxic to normal human foreskin fibroblast cells in vitro. Solid lipid nanoparticles containing 10% limonene (10% L-SLN) had the highest ATRA skin permeability. Terpene composited SLN and nanostructured lipid carriers (NLC) showed higher epidermal permeation of rhodamine B across the skin based on CLSM image analysis. Our study suggests that terpene composited SLN and NLC can be potentially used as dermal drug delivery carriers for ATRA. PMID- 24805207 TI - Antibacterial activities of persimmon extracts relate with their hydrogen peroxide concentration. AB - Persimmon, a deciduous tree of the family Ebenaceae, is found throughout East Asia and contains high levels of tannins. This class of natural compounds exhibit favorable toxicity profiles along with bactericidal activity without the emergence of resistant bacteria, suggesting potential medical applications. Consistent with these observations, persimmon leaves show antibacterial activity. However, the mechanism of persimmon antibacterial activity remains unknown. In the present work, we demonstrate that the antibacterial activity of persimmon reflects the generation of reactive oxygen from tannins. The identification and quantification of reactive oxygen generated from persimmon and the level of antibacterial activity were determined. PMID- 24805208 TI - Distribution patterns of the contents of five active components in taproot and stolon of Glycyrrhiza uralensis. AB - Wild or cultivated Glycyrrhiza uralensis FISCHER (G. uralensis) are the main source of licorice, and they contain the similar compounds, such as the triterpenoid saponins and flavonoids, but above two kinds of the components contents are low level in the cultivated licorice. To produce the high quality cultivated licorices, researchers studied the affecting factors about the compounds producing in the plant of licorice, and then found that the growth years, genetic differences and water deficit are all the important factors. In this paper, we found that there were different distribution patterns of the main five active components (FAC) including glycyrrhizin, liquiritin, isoliquiritin, liquiritigenin and isoliquiritigenin in the taproot and stolon of G. uralensis and maybe they are also important influence factors to the FAC contents of the licorices. In wild G. uralensis, the contents of FAC tended to be lower in the younger parts of the stolon, and in the cultivated G. uralensis taproot, the contents of glycyrrhizin, liquiritin and isoliquiritin tended to increase from top to end, contrary to the contents of liquiritigenin and isoliquiritigenin, which increased first and then decreased. Our results will contribute to the analyses of factors which influence the quality of licorice, and provide some reference for cultivating high quality licorices for herbal medicine. PMID- 24805209 TI - Infectious granuloma caused by Burkholderia fungorum confirmed by laser-capture microdissection and polymerase chain reaction. PMID- 24805210 TI - Tuning the chiroptical and morphological properties of steroidal-porphyrin aggregates: a mechanistic, structural, and MM investigation. AB - The aggregation of a steroid-functionalised porphyrin derivative occurs with the formation of J-type chiral species. Spectroscopic and SEM studies indicate that the initial concentration of the macrocycle strongly influences the morphology of the final mesoscopic structures, as a consequence of a change in the mechanistic course of the self-assembly process. Fibrillar structures are obtained at low porphyrin concentration, whereas aggregates of globular shapes are formed on increasing the substrate concentration. Molecular mechanics investigations gave insights into the intimate nature of the driving forces that govern the self assembly process, pointing out the importance of ring distortion, of intramolecular steroidal OH-pi hydrogen bonds, as well as dispersion forces among the tetrapyrrolic platforms. PMID- 24805211 TI - Canonical correlation analysis on data with censoring and error information. AB - We developed a probabilistic model for canonical correlation analysis in the case when the associated datasets are incomplete. This case can arise where data entries either contain measurement errors or are censored (i.e., nonignorable missing) due to uncertainties in instrument calibration and physical limitations of devices and experimental conditions. The aim of our model is to estimate the true correlation coefficients, through eliminating the effects of measurement errors and abstracting helpful information from censored data. As exact inference is not possible for the proposed model, a modified variational Expectation Maximization (EM) algorithm was developed. In the algorithm developed, we approximated the posteriors of the latent variables as normal distributions. In the experiment, the modified E-step approximation accuracy is first empirically demonstrated by being compared to hybrid Monte Carlo (HMC) sampling. The following experiments were carried out on synthetic datasets with different numbers of censored data and different correlation coefficient settings to compare the proposed algorithm with a maximum a posteriori (MAP) solution and a Markov Chain-EM solution. Experimental results showed that the variational EM solution compares favorably against the MAP solution, approaching the accuracy of the Markov Chain-EM, while maintaining computational simplicity. We finally applied the proposed algorithm to finding the mostly correlated properties of galaxy group with the X-ray luminosity. PMID- 24805212 TI - Highly accurate moving object detection in variable bit rate video-based traffic monitoring systems. AB - Automated motion detection, which segments moving objects from video streams, is the key technology of intelligent transportation systems for traffic management. Traffic surveillance systems use video communication over real-world networks with limited bandwidth, which frequently suffers because of either network congestion or unstable bandwidth. Evidence supporting these problems abounds in publications about wireless video communication. Thus, to effectively perform the arduous task of motion detection over a network with unstable bandwidth, a process by which bit-rate is allocated to match the available network bandwidth is necessitated. This process is accomplished by the rate control scheme. This paper presents a new motion detection approach that is based on the cerebellar model-articulation-controller (CMAC) through artificial neural networks to completely and accurately detect moving objects in both high and low bit-rate video streams. The proposed approach is consisted of a probabilistic background generation (PBG) module and a moving object detection (MOD) module. To ensure that the properties of variable bit-rate video streams are accommodated, the proposed PBG module effectively produces a probabilistic background model through an unsupervised learning process over variable bit-rate video streams. Next, the MOD module, which is based on the CMAC network, completely and accurately detects moving objects in both low and high bit-rate video streams by implementing two procedures: 1) a block selection procedure and 2) an object detection procedure. The detection results show that our proposed approach is capable of performing with higher efficacy when compared with the results produced by other state-of the-art approaches in variable bit-rate video streams over real-world limited bandwidth networks. Both qualitative and quantitative evaluations support this claim; for instance, the proposed approach achieves Similarity and F1 accuracy rates that are 76.40% and 84.37% higher than those of existing approaches, respectively. PMID- 24805213 TI - Recurrent neural collective classification. AB - With the recent surge in availability of data sets containing not only individual attributes but also relationships, classification techniques that take advantage of predictive relationship information have gained in popularity. The most popular existing collective classification techniques have a number of limitations-some of them generate arbitrary and potentially lossy summaries of the relationship data, whereas others ignore directionality and strength of relationships. Popular existing techniques make use of only direct neighbor relationships when classifying a given entity, ignoring potentially useful information contained in expanded neighborhoods of radius greater than one. We present a new technique that we call recurrent neural collective classification (RNCC), which avoids arbitrary summarization, uses information about relationship directionality and strength, and through recursive encoding, learns to leverage larger relational neighborhoods around each entity. Experiments with synthetic data sets show that RNCC can make effective use of relationship data for both direct and expanded neighborhoods. Further experiments demonstrate that our technique outperforms previously published results of several collective classification methods on a number of real-world data sets. PMID- 24805214 TI - Online selective kernel-based temporal difference learning. AB - In this paper, an online selective kernel-based temporal difference (OSKTD) learning algorithm is proposed to deal with large scale and/or continuous reinforcement learning problems. OSKTD includes two online procedures: online sparsification and parameter updating for the selective kernel-based value function. A new sparsification method (i.e., a kernel distance-based online sparsification method) is proposed based on selective ensemble learning, which is computationally less complex compared with other sparsification methods. With the proposed sparsification method, the sparsified dictionary of samples is constructed online by checking if a sample needs to be added to the sparsified dictionary. In addition, based on local validity, a selective kernel-based value function is proposed to select the best samples from the sample dictionary for the selective kernel-based value function approximator. The parameters of the selective kernel-based value function are iteratively updated by using the temporal difference (TD) learning algorithm combined with the gradient descent technique. The complexity of the online sparsification procedure in the OSKTD algorithm is O(n). In addition, two typical experiments (Maze and Mountain Car) are used to compare with both traditional and up-to-date O(n) algorithms (GTD, GTD2, and TDC using the kernel-based value function), and the results demonstrate the effectiveness of our proposed algorithm. In the Maze problem, OSKTD converges to an optimal policy and converges faster than both traditional and up-to-date algorithms. In the Mountain Car problem, OSKTD converges, requires less computation time compared with other sparsification methods, gets a better local optima than the traditional algorithms, and converges much faster than the up-to date algorithms. In addition, OSKTD can reach a competitive ultimate optima compared with the up-to-date algorithms. PMID- 24805215 TI - Stability and synchronization of discrete-time neural networks with switching parameters and time-varying delays. AB - This paper is concerned with the problems of exponential stability analysis and synchronization of discrete-time switched delayed neural networks. Using the average dwell time approach together with the piecewise Lyapunov function technique, sufficient conditions are proposed to guarantee the exponential stability for the switched neural networks with time-delays. Benefitting from the delay partitioning method and the free-weighting matrix technique, the conservatism of the obtained results is reduced. In addition, the decay estimates are explicitly given and the synchronization problem is solved. The results reported in this paper not only depend upon the delay, but also depend upon the partitioning, which aims at reducing the conservatism. Numerical examples are presented to demonstrate the usefulness of the derived theoretical results. PMID- 24805216 TI - Artificial endocrine controller for power management in robotic systems. AB - The robots that operate autonomously for extended periods in remote environments are often limited to gather only small amounts of power through photovoltaic solar panels. Such limited power budgets make power management critical to the success of the robot's mission. Artificial endocrine controllers, inspired by the mammalian endocrine system, have shown potential as a method for managing competing demands, gradually switching between behaviors, synchronizing behavior with external events, and maintaining a stable internal state of the robot. This paper reports the results obtained using these methods to manage power in an autonomous sailing robot. Artificial neural networks are used for sail and rudder control, while an artificial endocrine controller modulates the magnitude of actuator movements in response to battery or sunlight levels. Experiments are performed both in simulation and using a real robot. In simulation a 13-fold reduction in median power consumption is achieved; in the robot this is reduced to a twofold reduction because of the limitations of the simulation model. Additional simulations of a long term mission demonstrate the controller's ability to make gradual behavioral transitions and to synchronize behaviors with diurnal and seasonal changes in sunlight levels. PMID- 24805217 TI - Operator control of interneural computing machines. AB - A dynamic representation of neural population responses asserts that motor cortex is a flexible pattern generator sending rhythmic, oscillatory signals to generate multiphasic patterns of movement. This raises a question concerning the design and control of new computing machines that mimic the oscillatory patterns and multiphasic patterns seen in neural systems. To address this issue, we design an interneural computing machine (INCM) made of plastic random interneural connections. We develop a mechanical way to measure collective ensemble firing of neurons in INCM. Two sorts of plasticity operators are derived from the measure of synchronous neural activity and the measure of self-sustaining neural activity, respectively. Such plasticity operators conduct activity-dependent operation to modify the network structure of INCM. The activity-dependent operation meets the neurobiological perspective of Hebbian synaptic plasticity and displays the tendency toward circulation breaking aiming to control neural population dynamics. We call such operation operator control of INCM and develop a population analysis of operator control for measuring how well single neurons of INCM can produce rhythmic, oscillatory activity, but at the level of neural ensembles, generate multiphasic patterns of population responses. PMID- 24805218 TI - Multiple graph label propagation by sparse integration. AB - Graph-based approaches have been most successful in semisupervised learning. In this paper, we focus on label propagation in graph-based semisupervised learning. One essential point of label propagation is that the performance is heavily affected by incorporating underlying manifold of given data into the input graph. The other more important point is that in many recent real-world applications, the same instances are represented by multiple heterogeneous data sources. A key challenge under this setting is to integrate different data representations automatically to achieve better predictive performance. In this paper, we address the issue of obtaining the optimal linear combination of multiple different graphs under the label propagation setting. For this problem, we propose a new formulation with the sparsity (in coefficients of graph combination) property which cannot be rightly achieved by any other existing methods. This unique feature provides two important advantages: 1) the improvement of prediction performance by eliminating irrelevant or noisy graphs and 2) the interpretability of results, i.e., easily identifying informative graphs on classification. We propose efficient optimization algorithms for the proposed approach, by which clear interpretations of the mechanism for sparsity is provided. Through various synthetic and two real-world data sets, we empirically demonstrate the advantages of our proposed approach not only in prediction performance but also in graph selection ability. PMID- 24805220 TI - Hinfinity state estimation for complex networks with uncertain inner coupling and incomplete measurements. AB - In this paper, the Hinfinity state estimation problem is investigated for a class of complex networks with uncertain coupling strength and incomplete measurements. With the aid of the interval matrix approach, we make the first attempt to characterize the uncertainties entering into the inner coupling matrix. The incomplete measurements under consideration include sensor saturations, quantization, and missing measurements, all of which are assumed to occur randomly. By introducing a stochastic Kronecker delta function, these incomplete measurements are described in a unified way and a novel measurement model is proposed to account for these phenomena occurring with individual probability. With the measurement model, a set of Hinfinity state estimators is designed such that, for all admissible incomplete measurements as well as the uncertain coupling strength, the estimation error dynamics is exponentially mean-square stable and the Hinfinity performance requirement is satisfied. The characterization of the desired estimator gains is derived in terms of the solution to a convex optimization problem that can be easily solved using the semidefinite program method. Finally, a numerical simulation example is provided to demonstrate the effectiveness and applicability of the proposed design approach. PMID- 24805219 TI - Universal blind image quality assessment metrics via natural scene statistics and multiple kernel learning. AB - Universal blind image quality assessment (IQA) metrics that can work for various distortions are of great importance for image processing systems, because neither ground truths are available nor the distortion types are aware all the time in practice. Existing state-of-the-art universal blind IQA algorithms are developed based on natural scene statistics (NSS). Although NSS-based metrics obtained promising performance, they have some limitations: 1) they use either the Gaussian scale mixture model or generalized Gaussian density to predict the nonGaussian marginal distribution of wavelet, Gabor, or discrete cosine transform coefficients. The prediction error makes the extracted features unable to reflect the change in nonGaussianity (NG) accurately. The existing algorithms use the joint statistical model and structural similarity to model the local dependency (LD). Although this LD essentially encodes the information redundancy in natural images, these models do not use information divergence to measure the LD. Although the exponential decay characteristic (EDC) represents the property of natural images that large/small wavelet coefficient magnitudes tend to be persistent across scales, which is highly correlated with image degradations, it has not been applied to the universal blind IQA metrics; and 2) all the universal blind IQA metrics use the same similarity measure for different features for learning the universal blind IQA metrics, though these features have different properties. To address the aforementioned problems, we propose to construct new universal blind quality indicators using all the three types of NSS, i.e., the NG, LD, and EDC, and incorporating the heterogeneous property of multiple kernel learning (MKL). By analyzing how different distortions affect these statistical properties, we present two universal blind quality assessment models, NSS global scheme and NSS two-step scheme. In the proposed metrics: 1) we exploit the NG of natural images using the original marginal distribution of wavelet coefficients; 2) we measure correlations between wavelet coefficients using mutual information defined in information theory; 3) we use features of EDC in universal blind image quality prediction directly; and 4) we introduce MKL to measure the similarity of different features using different kernels. Thorough experimental results on the Laboratory for Image and Video Engineering database II and the Tampere Image Database2008 demonstrate that both metrics are in remarkably high consistency with the human perception, and overwhelm representative universal blind algorithms as well as some standard full reference quality indexes for various types of distortions. PMID- 24805221 TI - Goal representation heuristic dynamic programming on maze navigation. AB - Goal representation heuristic dynamic programming (GrHDP) is proposed in this paper to demonstrate online learning in the Markov decision process. In addition to the (external) reinforcement signal in literature, we develop an adaptively internal goal/reward representation for the agent with the proposed goal network. Specifically, we keep the actor-critic design in heuristic dynamic programming (HDP) and include a goal network to represent the internal goal signal, to further help the value function approximation. We evaluate our proposed GrHDP algorithm on two 2-D maze navigation problems, and later on one 3-D maze navigation problem. Compared to the traditional HDP approach, the learning performance of the agent is improved with our proposed GrHDP approach. In addition, we also include the learning performance with two other reinforcement learning algorithms, namely Sarsa(lambda) and Q-learning, on the same benchmarks for comparison. Furthermore, in order to demonstrate the theoretical guarantee of our proposed method, we provide the characteristics analysis toward the convergence of weights in neural networks in our GrHDP approach. PMID- 24805222 TI - Accelerated canonical polyadic decomposition using mode reduction. AB - CANonical polyadic DECOMPosition (CANDECOMP, CPD), also known as PARAllel FACtor analysis (PARAFAC) is widely applied to Nth-order (N >= 3) tensor analysis. Existing CPD methods mainly use alternating least squares iterations and hence need to unfold tensors to each of their N modes frequently, which is one major performance bottleneck for large-scale data, especially when the order N is large. To overcome this problem, in this paper, we propose a new CPD method in which the CPD of a high-order tensor (i.e., N > 3) is realized by applying CPD to a mode reduced one (typically, third-order tensor) followed by a Khatri-Rao product projection procedure. This way is not only quite efficient as frequently unfolding to N modes is avoided, but also promising to conquer the bottleneck problem caused by high collinearity of components. We show that, under mild conditions, any Nth-order CPD can be converted to an equivalent third-order one but without destroying essential uniqueness, and theoretically they simply give consistent results. Besides, once the CPD of any unfolded lower order tensor is essentially unique, it is also true for the CPD of the original higher order tensor. Error bounds of truncated CPD are also analyzed in the presence of noise. Simulations show that, compared with state-of-the-art CPD methods, the proposed method is more efficient and is able to escape from local solutions more easily. PMID- 24805223 TI - Hardware friendly probabilistic spiking neural network with long-term and short term plasticity. AB - This paper proposes a probabilistic spiking neural network (PSNN) with unimodal weight distribution, possessing long- and short-term plasticity. The proposed algorithm is derived by both the arithmetic gradient decent calculation and bioinspired algorithms. The algorithm is benchmarked by the Iris and Wisconsin breast cancer (WBC) data sets. The network features fast convergence speed and high accuracy. In the experiment, the PSNN took not more than 40 epochs for convergence. The average testing accuracy for Iris and WBC data is 96.7% and 97.2%, respectively. To test the usefulness of the PSNN to real world application, the PSNN was also tested with the odor data, which was collected by our self-developed electronic nose (e-nose). Compared with the algorithm (K nearest neighbor) that has the highest classification accuracy in the e-nose for the same odor data, the classification accuracy of the PSNN is only 1.3% less but the memory requirement can be reduced at least 40%. All the experiments suggest that the PSNN is hardware friendly. First, it requires only nine-bits weight resolution for training and testing. Second, the PSNN can learn complex data sets with a little number of neurons that in turn reduce the cost of VLSI implementation. In addition, the algorithm is insensitive to synaptic noise and the parameter variation induced by the VLSI fabrication. Therefore, the algorithm can be implemented by either software or hardware, making it suitable for wider application. PMID- 24805224 TI - Neural network architecture for cognitive navigation in dynamic environments. AB - Navigation in time-evolving environments with moving targets and obstacles requires cognitive abilities widely demonstrated by even simplest animals. However, it is a long-standing challenging problem for artificial agents. Cognitive autonomous robots coping with this problem must solve two essential tasks: 1) understand the environment in terms of what may happen and how I can deal with this and 2) learn successful experiences for their further use in an automatic subconscious way. The recently introduced concept of compact internal representation (CIR) provides the ground for both the tasks. CIR is a specific cognitive map that compacts time-evolving situations into static structures containing information necessary for navigation. It belongs to the class of global approaches, i.e., it finds trajectories to a target when they exist but also detects situations when no solution can be found. Here we extend the concept of situations with mobile targets. Then using CIR as a core, we propose a closed loop neural network architecture consisting of conscious and subconscious pathways for efficient decision-making. The conscious pathway provides solutions to novel situations if the default subconscious pathway fails to guide the agent to a target. Employing experiments with roving robots and numerical simulations, we show that the proposed architecture provides the robot with cognitive abilities and enables reliable and flexible navigation in realistic time-evolving environments. We prove that the subconscious pathway is robust against uncertainty in the sensory information. Thus if a novel situation is similar but not identical to the previous experience (because of, e.g., noisy perception) then the subconscious pathway is able to provide an effective solution. PMID- 24805225 TI - An equivalence between adaptive dynamic programming with a critic and backpropagation through time. AB - We consider the adaptive dynamic programming technique called Dual Heuristic Programming (DHP), which is designed to learn a critic function, when using learned model functions of the environment. DHP is designed for optimizing control problems in large and continuous state spaces. We extend DHP into a new algorithm that we call Value-Gradient Learning, VGL(lambda), and prove equivalence of an instance of the new algorithm to Backpropagation Through Time for Control with a greedy policy. Not only does this equivalence provide a link between these two different approaches, but it also enables our variant of DHP to have guaranteed convergence, under certain smoothness conditions and a greedy policy, when using a general smooth nonlinear function approximator for the critic. We consider several experimental scenarios including some that prove divergence of DHP under a greedy policy, which contrasts against our proven convergent algorithm. PMID- 24805226 TI - Semisupervised multitask learning with Gaussian processes. AB - We present a probabilistic framework for transferring learning across tasks and between labeled and unlabeled data. The approach is based on Gaussian process (GP) prediction and incorporates both the geometry of the data and the similarity between tasks within a GP covariance, allowing Bayesian prediction in a natural way. We discuss the transfer of learning in a multitask scenario in the two cases where the underlying geometry is assumed to be the same across tasks and where different tasks are assumed to have independent geometric structures. We demonstrate the method on a number of real datasets, indicating that the semisupervised multitask approach can result in very significant improvements in performance when very few labeled training examples are available. PMID- 24805227 TI - Nonlinear projection trick in kernel methods: an alternative to the kernel trick. AB - In kernel methods such as kernel principal component analysis (PCA) and support vector machines, the so called kernel trick is used to avoid direct calculations in a high (virtually infinite) dimensional kernel space. In this brief, based on the fact that the effective dimensionality of a kernel space is less than the number of training samples, we propose an alternative to the kernel trick that explicitly maps the input data into a reduced dimensional kernel space. This is easily obtained by the eigenvalue decomposition of the kernel matrix. The proposed method is named as the nonlinear projection trick in contrast to the kernel trick. With this technique, the applicability of the kernel methods is widened to arbitrary algorithms that do not use the dot product. The equivalence between the kernel trick and the nonlinear projection trick is shown for several conventional kernel methods. In addition, we extend PCA-L1, which uses L1-norm instead of L2-norm (or dot product), into a kernel version and show the effectiveness of the proposed approach. PMID- 24805228 TI - Ecological modeling for the extrapolation of ecotoxicological effects measured during in situ assays in Gammarus. AB - Evaluating the effects of chemical contamination on populations and ecological communities still constitutes a challenging necessity in environmental management. However, the toxic effects of contaminants are commonly measured by means of organism-level responses. Linking such effects measures with ecological models is a promising way to determine population-level impacts. In this way, population models are currently increasingly used in predictive risk assessment procedures, but their use in environmental diagnostic framework remains limited due to their lack of ecological realism. The present study with the crustacean Gammarus fossarum, a sentinel species in freshwater monitoring, combines a dual field and laboratory experimental approach with a population modeling framework. In this way, we developed an ecologically relevant periodic matrix population model for Gammarus. This model allowed us to capture the population dynamics in the field, and to understand the particular pattern of demographic sensitivities induced by Gammarus life-history phenology. The model we developed provided a robust population-level assessment of in situ-based effects measures recorded during a biomonitoring program on a French watershed impacted by past mining activities. Thus, our study illustrates the potential of population modeling when seeking to decipher the role of environmental toxic contamination in ecological perturbations. PMID- 24805229 TI - Impact of primary care provider knowledge, attitudes, and beliefs about cancer clinical trials: implications for referral, education and advocacy. AB - Primary Care Providers (PCPs) can be instrumental in helping to prepare patients for referral to cancer treatment. It has been suggested that PCPs can have an important impact on priming patients about the possibility of receiving care within a cancer treatment clinical trial (CCT). However, little is understood about how to effectively engage primary care providers in educating patients about trials. Data were collected as part of two qualitative research projects about primary care providers' role in referral to treatment and to CCTs. Participants were 27 PCPs who agreed to take part in qualitative face-to-face or telephone interviews and serve predominantly underserved, minority populations. Interviews identified a number of factors influencing referral to oncologists, including patients' insurance coverage, location and proximity to treatment facilities, and the strength of ongoing relationships with and/or previous experience with a specialist. PCPs overwhelmingly expressed disinterest in discussing any treatment options, including CCTs. Misconceptions about quality of care received through trials were also common, presenting a deterrent to discussion. PCPs need targeted, evidence-based educational interventions to appropriately address their concerns about cancer clinical trials, enhance provider communication skills, and alter patient referral behavior. Steps must also be taken to strengthen communication between oncologists and referring PCPs. PMID- 24805230 TI - Sensory biology: Radio waves zap the biomagnetic compass. PMID- 24805231 TI - Increasing CO2 threatens human nutrition. AB - Dietary deficiencies of zinc and iron are a substantial global public health problem. An estimated two billion people suffer these deficiencies, causing a loss of 63 million life-years annually. Most of these people depend on C3 grains and legumes as their primary dietary source of zinc and iron. Here we report that C3 grains and legumes have lower concentrations of zinc and iron when grown under field conditions at the elevated atmospheric CO2 concentration predicted for the middle of this century. C3 crops other than legumes also have lower concentrations of protein, whereas C4 crops seem to be less affected. Differences between cultivars of a single crop suggest that breeding for decreased sensitivity to atmospheric CO2 concentration could partly address these new challenges to global health. PMID- 24805232 TI - Clonal selection in the germinal centre by regulated proliferation and hypermutation. AB - During immune responses, B lymphocytes clonally expand and undergo secondary diversification of their immunoglobulin genes in germinal centres (GCs). High affinity B cells are expanded through iterative interzonal cycles of division and hypermutation in the GC dark zone followed by migration to the GC light zone, where they are selected on the basis of affinity to return to the dark zone. Here we combine a transgenic strategy to measure cell division and a photoactivatable fluorescent reporter to examine whether the extent of clonal expansion and hypermutation are regulated during interzonal GC cycles. We find that both cell division and hypermutation are directly proportional to the amount of antigen captured and presented by GC B cells to follicular helper T cells in the light zone. Our data explain how GC B cells with the highest affinity for antigen are selectively expanded and diversified. PMID- 24805233 TI - Anthropogenic electromagnetic noise disrupts magnetic compass orientation in a migratory bird. AB - Electromagnetic noise is emitted everywhere humans use electronic devices. For decades, it has been hotly debated whether man-made electric and magnetic fields affect biological processes, including human health. So far, no putative effect of anthropogenic electromagnetic noise at intensities below the guidelines adopted by the World Health Organization has withstood the test of independent replication under truly blinded experimental conditions. No effect has therefore been widely accepted as scientifically proven. Here we show that migratory birds are unable to use their magnetic compass in the presence of urban electromagnetic noise. When European robins, Erithacus rubecula, were exposed to the background electromagnetic noise present in unscreened wooden huts at the University of Oldenburg campus, they could not orient using their magnetic compass. Their magnetic orientation capabilities reappeared in electrically grounded, aluminium screened huts, which attenuated electromagnetic noise in the frequency range from 50 kHz to 5 MHz by approximately two orders of magnitude. When the grounding was removed or when broadband electromagnetic noise was deliberately generated inside the screened and grounded huts, the birds again lost their magnetic orientation capabilities. The disruptive effect of radiofrequency electromagnetic fields is not confined to a narrow frequency band and birds tested far from sources of electromagnetic noise required no screening to orient with their magnetic compass. These fully double-blinded tests document a reproducible effect of anthropogenic electromagnetic noise on the behaviour of an intact vertebrate. PMID- 24805234 TI - Tracking excited-state charge and spin dynamics in iron coordination complexes. AB - Crucial to many light-driven processes in transition metal complexes is the absorption and dissipation of energy by 3d electrons. But a detailed understanding of such non-equilibrium excited-state dynamics and their interplay with structural changes is challenging: a multitude of excited states and possible transitions result in phenomena too complex to unravel when faced with the indirect sensitivity of optical spectroscopy to spin dynamics and the flux limitations of ultrafast X-ray sources. Such a situation exists for archetypal polypyridyl iron complexes, such as [Fe(2,2'-bipyridine)3](2+), where the excited state charge and spin dynamics involved in the transition from a low- to a high spin state (spin crossover) have long been a source of interest and controversy. Here we demonstrate that femtosecond resolution X-ray fluorescence spectroscopy, with its sensitivity to spin state, can elucidate the spin crossover dynamics of [Fe(2,2'-bipyridine)3](2+) on photoinduced metal-to-ligand charge transfer excitation. We are able to track the charge and spin dynamics, and establish the critical role of intermediate spin states in the crossover mechanism. We anticipate that these capabilities will make our method a valuable tool for mapping in unprecedented detail the fundamental electronic excited-state dynamics that underpin many useful light-triggered molecular phenomena involving 3d transition metal complexes. PMID- 24805235 TI - Genome-defence small RNAs exapted for epigenetic mating-type inheritance. AB - In the ciliate Paramecium, transposable elements and their single-copy remnants are deleted during the development of somatic macronuclei from germline micronuclei, at each sexual generation. Deletions are targeted by scnRNAs, small RNAs produced from the germ line during meiosis that first scan the maternal macronuclear genome to identify missing sequences, and then allow the zygotic macronucleus to reproduce the same deletions. Here we show that this process accounts for the maternal inheritance of mating types in Paramecium tetraurelia, a long-standing problem in epigenetics. Mating type E depends on expression of the transmembrane protein mtA, and the default type O is determined during development by scnRNA-dependent excision of the mtA promoter. In the sibling species Paramecium septaurelia, mating type O is determined by coding-sequence deletions in a different gene, mtB, which is specifically required for mtA expression. These independently evolved mechanisms suggest frequent exaptation of the scnRNA pathway to regulate cellular genes and mediate transgenerational epigenetic inheritance of essential phenotypic polymorphisms. PMID- 24805236 TI - PTEN action in leukaemia dictated by the tissue microenvironment. AB - PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype. PMID- 24805237 TI - Emergence of reproducible spatiotemporal activity during motor learning. AB - The motor cortex is capable of reliably driving complex movements yet exhibits considerable plasticity during motor learning. These observations suggest that the fundamental relationship between motor cortex activity and movement may not be fixed but is instead shaped by learning; however, to what extent and how motor learning shapes this relationship are not fully understood. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the activity of the same population of hundreds of layer 2/3 neurons while mice learned a forelimb lever-press task over two weeks. Excitatory and inhibitory neurons were identified by transgenic labelling. Inhibitory neuron activity was relatively stable and balanced local excitatory neuron activity on a movement-by-movement basis, whereas excitatory neuron activity showed higher dynamism during the initial phase of learning. The dynamics of excitatory neurons during the initial phase involved the expansion of the movement-related population which explored various activity patterns even during similar movements. This was followed by a refinement into a smaller population exhibiting reproducible spatiotemporal sequences of activity. This pattern of activity associated with the learned movement was unique to expert animals and not observed during similar movements made during the naive phase, and the relationship between neuronal activity and individual movements became more consistent with learning. These changes in population activity coincided with a transient increase in dendritic spine turnover in these neurons. Our results indicate that a novel and reproducible activity-movement relationship develops as a result of motor learning, and we speculate that synaptic plasticity within the motor cortex underlies the emergence of reproducible spatiotemporal activity patterns for learned movements. These results underscore the profound influence of learning on the way that the cortex produces movements. PMID- 24805238 TI - A semi-synthetic organism with an expanded genetic alphabet. AB - Organisms are defined by the information encoded in their genomes, and since the origin of life this information has been encoded using a two-base-pair genetic alphabet (A-T and G-C). In vitro, the alphabet has been expanded to include several unnatural base pairs (UBPs). We have developed a class of UBPs formed between nucleotides bearing hydrophobic nucleobases, exemplified by the pair formed between d5SICS and dNaM (d5SICS-dNaM), which is efficiently PCR-amplified and transcribed in vitro, and whose unique mechanism of replication has been characterized. However, expansion of an organism's genetic alphabet presents new and unprecedented challenges: the unnatural nucleoside triphosphates must be available inside the cell; endogenous polymerases must be able to use the unnatural triphosphates to faithfully replicate DNA containing the UBP within the complex cellular milieu; and finally, the UBP must be stable in the presence of pathways that maintain the integrity of DNA. Here we show that an exogenously expressed algal nucleotide triphosphate transporter efficiently imports the triphosphates of both d5SICS and dNaM (d5SICSTP and dNaMTP) into Escherichia coli, and that the endogenous replication machinery uses them to accurately replicate a plasmid containing d5SICS-dNaM. Neither the presence of the unnatural triphosphates nor the replication of the UBP introduces a notable growth burden. Lastly, we find that the UBP is not efficiently excised by DNA repair pathways. Thus, the resulting bacterium is the first organism to propagate stably an expanded genetic alphabet. PMID- 24805239 TI - Future increases in Arctic precipitation linked to local evaporation and sea-ice retreat. AB - Precipitation changes projected for the end of the twenty-first century show an increase of more than 50 per cent in the Arctic regions. This marked increase, which is among the highest globally, has previously been attributed primarily to enhanced poleward moisture transport from lower latitudes. Here we use state-of the-art global climate models to show that the projected increases in Arctic precipitation over the twenty-first century, which peak in late autumn and winter, are instead due mainly to strongly intensified local surface evaporation (maximum in winter), and only to a lesser degree due to enhanced moisture inflow from lower latitudes (maximum in late summer and autumn). Moreover, we show that the enhanced surface evaporation results mainly from retreating winter sea ice, signalling an amplified Arctic hydrological cycle. This demonstrates that increases in Arctic precipitation are firmly linked to Arctic warming and sea-ice decline. As a result, the Arctic mean precipitation sensitivity (4.5 per cent increase per degree of temperature warming) is much larger than the global value (1.6 to 1.9 per cent per kelvin). The associated seasonally varying increase in Arctic precipitation is likely to increase river discharge and snowfall over ice sheets (thereby affecting global sea level), and could even affect global climate through freshening of the Arctic Ocean and subsequent modulations of the Atlantic meridional overturning circulation. PMID- 24805240 TI - Quantitative flux analysis reveals folate-dependent NADPH production. AB - ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10 formyl-tetrahydrofolate is coupled to reduction of NADP(+) to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10 formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP(+) and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power. PMID- 24805241 TI - Epigenetics: Keeping one's sex. PMID- 24805242 TI - c-kit+ cells minimally contribute cardiomyocytes to the heart. AB - If and how the heart regenerates after an injury event is highly debated. c-kit expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit(+) cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit(+) cells amply generated cardiac endothelial cells. Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level. PMID- 24805243 TI - Space-time wiring specificity supports direction selectivity in the retina. AB - How does the mammalian retina detect motion? This classic problem in visual neuroscience has remained unsolved for 50 years. In search of clues, here we reconstruct Off-type starburst amacrine cells (SACs) and bipolar cells (BCs) in serial electron microscopic images with help from EyeWire, an online community of 'citizen neuroscientists'. On the basis of quantitative analyses of contact area and branch depth in the retina, we find evidence that one BC type prefers to wire with a SAC dendrite near the SAC soma, whereas another BC type prefers to wire far from the soma. The near type is known to lag the far type in time of visual response. A mathematical model shows how such 'space-time wiring specificity' could endow SAC dendrites with receptive fields that are oriented in space-time and therefore respond selectively to stimuli that move in the outward direction from the soma. PMID- 24805244 TI - Synthetic biology: New letters for life's alphabet. PMID- 24805246 TI - Cardiovascular imaging. PMID- 24805245 TI - A Ctf4 trimer couples the CMG helicase to DNA polymerase alpha in the eukaryotic replisome. AB - Efficient duplication of the genome requires the concerted action of helicase and DNA polymerases at replication forks to avoid stalling of the replication machinery and consequent genomic instability. In eukaryotes, the physical coupling between helicase and DNA polymerases remains poorly understood. Here we define the molecular mechanism by which the yeast Ctf4 protein links the Cdc45 MCM-GINS (CMG) DNA helicase to DNA polymerase alpha (Pol alpha) within the replisome. We use X-ray crystallography and electron microscopy to show that Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends on a beta-propeller domain in the carboxy-terminal half of the protein, which is fused to a helical extension that protrudes from one face of the trimeric disk. Critically, Pol alpha and the CMG helicase share a common mechanism of interaction with Ctf4. We show that the amino-terminal tails of the catalytic subunit of Pol alpha and the Sld5 subunit of GINS contain a conserved Ctf4 binding motif that docks onto the exposed helical extension of a Ctf4 protomer within the trimer. Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to three partner proteins, including the simultaneous association with both Pol alpha and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol alpha to one CMG helicase within the replisome, providing a new model for lagging-strand synthesis in eukaryotes that resembles the emerging model for the simpler replisome of Escherichia coli. The ability of Ctf4 to act as a platform for multivalent interactions illustrates a mechanism for the concurrent recruitment of factors that act together at the fork. PMID- 24805248 TI - Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. AB - BACKGROUND: There is no widely accepted treatment for non-alcoholic fatty liver disease (NAFLD) or its advanced form, non-alcoholic steatohepatitis (NASH). METHODS: We administered rosuvastatin (10 mg/day) for 1 year in patients with metabolic syndrome (MetS), NASH on liver biopsy and dyslipidaemia (but without diabetes or arterial hypertension). Patients also received lifestyle advice. RESULTS: We report preliminary results for 6 patients. The second biopsy (at the end of the study) showed complete resolution of NASH in 5 patients, while the 6(th), which had no improvement, developed arterial hypertension and substantial rise in triglyceride levels during the study. We suspect alcohol abuse despite advice to abstain. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were reduced by 76 and 61%, respectively (p < 0.001 for both), during treatment, while gamma-glutamyl transpeptidase (gamma-GT), and alkaline phosphatase (AP) showed smaller non significant reductions. Fasting plasma glucose and glycated haemoglobin (HbA1c) were significantly reduced (p<0.05). Lipid values were totally normalised and liver ultrasonography showed a complete resolution of NASH in 5 patients. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed to treatment with rosuvastatin. A substantial limitation of the study is the small number of patients. CONCLUSIONS: These preliminary findings suggest that rosuvastatin could ameliorate NASH within a year of treatment in MetS patients with dyslipidaemia. PMID- 24805247 TI - Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? AB - We have recently reported that therapeutic mesenchymal stromal cells (MSCs) have low engraftment and trigger the instant blood mediated inflammatory reaction (IBMIR) after systemic delivery to patients, resulting in compromised cell function. In order to optimize the product, we compared the immunomodulatory, blood regulatory, and therapeutic properties of freeze-thawed and freshly harvested cells. We found that freeze-thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties. Freeze-thawed MSCs demonstrated reduced responsiveness to proinflammatory stimuli, an impaired production of anti-inflammatory mediators, increased triggering of the IBMIR, and a strong activation of the complement cascade compared to fresh cells. This resulted in twice the efficiency in lysis of thawed MSCs after 1 hour of serum exposure. We found a 50% and 80% reduction in viable cells with freshly detached as opposed to thawed in vitro cells, indicating a small benefit for fresh cells. In evaluation of clinical response, we report a trend that fresh cells, and cells of low passage, demonstrate improved clinical outcome. Patients treated with freshly harvested cells in low passage had a 100% response rate, twice the response rate of 50% observed in a comparable group of patients treated with freeze-thawed cells at higher passage. We conclude that cryobanked MSCs have reduced immunomodulatory and blood regulatory properties directly after thawing, resulting in faster complement mediated elimination after blood exposure. These changes seem to be paired by differences in therapeutic efficacy in treatment of immune ailments after hematopoietic stem cell transplantation. PMID- 24805249 TI - Clinical response and sustainability of treatment with temperature-controlled radiofrequency energy (Secca) in patients with faecal incontinence: 3 years follow-up. AB - BACKGROUND: Controlled delivery of radio frequent energy (Secca) has been suggested as treatment for faecal incontinence (FI). OBJECTIVE: The objective of the study is to evaluate clinical response and sustainability of Secca for FI. DESIGN: This is a prospective cohort study. PATIENTS: This study involved patients who had failed full conservative management for FI. INTERVENTIONS: This study was performed between 2005 and 2010. MAIN OUTCOME MEASURES: FI was scored using the Vaizey score (VS). A clinically significant response to Secca was defined as >=50 % reduction in incontinence score. Impact of FI on quality of life (QOL) was measured using the FIQL. Data was obtained at baseline, at 6 months and at 1 and 3 years. Anal endosonography and anal manometry were performed at 3 months and compared to baseline. RESULTS: Thirty-one patients received Secca. During follow-up, 5/31 (16 %), 3/31 (10 %) and 2/31 (6 %) of patients maintained a clinically significant response after the Secca procedure. Mean VS of all patients was 18 (SD 3), 14 (SD 4), 14 (SD 4) and 15 (SD 4), at baseline, 6 months and 1 and 3 years. No increases in anorectal pressures or improvements in rectal compliance were found. Coping improved between baseline and t = 6 months. No predictive factors for success were found. LIMITATIONS: This is a non-randomised study design. CONCLUSION: This prospective non-randomised trial showed disappointing outcomes of the Secca procedure for the treatment of FI. The far minority of patients reported a clinically significant response of seemingly temporary nature. Secca might be valuable in combination with other interventions for FI, but this should be tested in strictly controlled randomised trials. PMID- 24805251 TI - The ribosome can prevent aggregation of partially folded protein intermediates: studies using the Escherichia coli ribosome. AB - BACKGROUND: Molecular chaperones that support de novo folding of proteins under non stress condition are classified as chaperone 'foldases' that are distinct from chaperone' holdases' that provide high affinity binding platform for unfolded proteins and prevent their aggregation specifically under stress conditions. Ribosome, the cellular protein synthesis machine can act as a foldase chaperone that can bind unfolded proteins and release them in folding competent state. The peptidyl transferase center (PTC) located in the domain V of the 23S rRNA of Escherichia coli ribosome (bDV RNA) is the chaperoning center of the ribosome. It has been proposed that via specific interactions between the RNA and refolding proteins, the chaperone provides information for the correct folding of unfolded polypeptide chains. RESULTS: We demonstrate using Escherichia coli ribosome and variants of its domain V RNA that the ribosome can bind to partially folded intermediates of bovine carbonic anhydrase II (BCAII) and lysozyme and suppress aggregation during their refolding. Using mutants of domain V RNA we demonstrate that the time for which the chaperone retains the bound protein is an important factor in determining its ability to suppress aggregation and/or support reactivation of protein. CONCLUSION: The ribosome can behave like a 'holdase' chaperone and has the ability to bind and hold back partially folded intermediate states of proteins from participating in the aggregation process. Since the ribosome is an essential organelle that is present in large numbers in all living cells, this ability of the ribosome provides an energetically inexpensive way to suppress cellular aggregation. Further, this ability of the ribosome might also be crucial in the context that the ribosome is one of the first chaperones to be encountered by a large nascent polypeptide chains that have a tendency to form partially folded intermediates immediately following their synthesis. PMID- 24805252 TI - Reply: To PMID 24273204. PMID- 24805253 TI - Effects of Escherichia coli on mixotrophic growth of Chlorella minutissima and production of biofuel precursors. AB - Chlorella minutissima was co-cultured with Escherichia coli in airlift reactors under mixotrophic conditions (glucose, glycerol, and acetate substrates) to determine possible effects of bacterial contamination on algal biofuel production. It was hypothesized that E. coli would compete with C. minutissima for nutrients, displacing algal biomass. However, C. minutissima grew more rapidly and to higher densities in the presence of E. coli, suggesting a symbiotic relationship between the organisms. At an initial 1% substrate concentration, the co-culture produced 200-587% more algal biomass than the axenic C. minutissima cultures. Co-cultures grown on 1% substrate consumed 23 737% more of the available carbon substrate than the sum of substrate consumed by E. coli and C. minutissima alone. At 1% substrate, total lipid and starch productivity were elevated in co-cultures compared to axenic cultures indicating that bacterial contamination was not detrimental to the production of biofuel precursors in this specific case. Bio-fouling of the reactors observed in co cultures and acid formation in all mixotrophic cultures, however, could present challenges for scale-up. PMID- 24805254 TI - Modeling Hawaiian ecosystem degradation due to invasive plants under current and future climates. AB - Occupation of native ecosystems by invasive plant species alters their structure and/or function. In Hawaii, a subset of introduced plants is regarded as extremely harmful due to competitive ability, ecosystem modification, and biogeochemical habitat degradation. By controlling this subset of highly invasive ecosystem modifiers, conservation managers could significantly reduce native ecosystem degradation. To assess the invasibility of vulnerable native ecosystems, we selected a proxy subset of these invasive plants and developed robust ensemble species distribution models to define their respective potential distributions. The combinations of all species models using both binary and continuous habitat suitability projections resulted in estimates of species richness and diversity that were subsequently used to define an invasibility metric. The invasibility metric was defined from species distribution models with <0.7 niche overlap (Warrens I) and relatively discriminative distributions (Area Under the Curve >0.8; True Skill Statistic >0.75) as evaluated per species. Invasibility was further projected onto a 2100 Hawaii regional climate change scenario to assess the change in potential habitat degradation. The distribution defined by the invasibility metric delineates areas of known and potential invasibility under current climate conditions and, when projected into the future, estimates potential reductions in native ecosystem extent due to climate driven invasive incursion. We have provided the code used to develop these metrics to facilitate their wider use (Code S1). This work will help determine the vulnerability of native-dominated ecosystems to the combined threats of climate change and invasive species, and thus help prioritize ecosystem and species management actions. PMID- 24805257 TI - Synthesis of silver embedded poly(o-anisidine) molybdophosphate nano hybrid cation-exchanger applicable for membrane electrode. AB - Poly(o-anisidine) molybdophosphate was expediently obtained by sol-gel mixing of Poly(o-anisidine) into the inorganic matrices of molybdophosphate, which was allowed to react with silver nitrate to the formation of poly(o-anisidine) molybdophosphate embedded silver nano composite. The composite was characterized by Fourier Transform Infrared Spectroscopy, X-ray powder diffraction, UV-Vis Spectrophotometry, Fluorescence Spectroscopy, Scanning Electron Microscopy/Energy dispersive X-ray Spectroscopy and Thermogravimertic Analysis. Ion exchange capacity and distribution studies were carried out to understand the ion-exchange capabilities of the nano composite. On the basis of highest distribution studies, this nano composite cation exchanger was used as preparation of heavy metal ion selective membrane. Membrane was characterized for its performance as porosity and swelling later on was used for the preparation of membrane electrode for Hg(II), having better linear range, wide working pH range (2-4.5) with fast response in the real environment. PMID- 24805259 TI - Response to: Jan Lerut, Laudatio for Prof. Raimund Margreiter on the occasion of the honorary membership of ESOT. PMID- 24805255 TI - Novel PCR primers for the archaeal phylum Thaumarchaeota designed based on the comparative analysis of 16S rRNA gene sequences. AB - Based on comparative phylogenetic analysis of 16S rRNA gene sequences deposited in an RDP database, we constructed a local database of thaumarchaeotal 16S rRNA gene sequences and developed a novel PCR primer specific for the archaeal phylum Thaumarchaeota. Among 9,727 quality-filtered (chimeral-checked, size >1.2 kb) archaeal sequences downloaded from the RDP database, 1,549 thaumarchaeotal sequences were identified and included in our local database. In our study, Thaumarchaeota included archaeal groups MG-I, SAGMCG-I, SCG, FSCG, RC, and HWCG III, forming a monophyletic group in the phylogenetic tree. Cluster analysis revealed 114 phylotypes for Thaumarchaeota. The majority of the phylotypes (66.7%) belonged to the MG-I and SCG, which together contained most (93.9%) of the thaumarchaeotal sequences in our local database. A phylum-directed primer was designed from a consensus sequence of the phylotype sequences, and the primer's specificity was evaluated for coverage and tolerance both in silico and empirically. The phylum-directed primer, designated THAUM-494, showed >90% coverage for Thaumarchaeota and <1% tolerance to non-target taxa, indicating high specificity. To validate this result experimentally, PCRs were performed with THAUM-494 in combination with a universal archaeal primer (ARC917R or 1017FAR) and DNAs from five environmental samples to construct clone libraries. THAUM-494 showed a satisfactory specificity in empirical studies, as expected from the in silico results. Phylogenetic analysis of 859 cloned sequences obtained from 10 clone libraries revealed that >95% of the amplified sequences belonged to Thaumarchaeota. The most frequently sampled thaumarchaeotal subgroups in our samples were SCG, MG-I, and SAGMCG-I. To our knowledge, THAUM-494 is the first phylum-level primer for Thaumarchaeota. Furthermore, the high coverage and low tolerance of THAUM-494 will make it a potentially valuable tool in understanding the phylogenetic diversity and ecological niche of Thaumarchaeota. PMID- 24805256 TI - Transmural intestinal wall permeability in severe ischemia after enteral protease inhibition. AB - In intestinal ischemia, inflammatory mediators in the small intestine's lumen such as food byproducts, bacteria, and digestive enzymes leak into the peritoneal space, lymph, and circulation, but the mechanisms by which the intestinal wall permeability initially increases are not well defined. We hypothesize that wall protease activity (independent of luminal proteases) and apoptosis contribute to the increased transmural permeability of the intestine's wall in an acutely ischemic small intestine. To model intestinal ischemia, the proximal jejunum to the distal ileum in the rat was excised, the lumen was rapidly flushed with saline to remove luminal contents, sectioned into equal length segments, and filled with a tracer (fluorescein) in saline, glucose, or protease inhibitors. The transmural fluorescein transport was determined over 2 hours. Villi structure and epithelial junctional proteins were analyzed. After ischemia, there was increased transmural permeability, loss of villi structure, and destruction of epithelial proteins. Supplementation with luminal glucose preserved the epithelium and significantly attenuated permeability and villi damage. Matrix metalloproteinase (MMP) inhibitors (doxycycline, GM 6001), and serine protease inhibitor (tranexamic acid) in the lumen, significantly reduced the fluorescein transport compared to saline for 90 min of ischemia. Based on these results, we tested in an in-vivo model of hemorrhagic shock (90 min 30 mmHg, 3 hours observation) for intestinal lesion formation. Single enteral interventions (saline, glucose, tranexamic acid) did not prevent intestinal lesions, while the combination of enteral glucose and tranexamic acid prevented lesion formation after hemorrhagic shock. The results suggest that apoptotic and protease mediated breakdown cause increased permeability and damage to the intestinal wall. Metabolic support in the lumen of an ischemic intestine with glucose reduces the transport from the lumen across the wall and enteral proteolytic inhibition attenuates tissue breakdown. These combined interventions ameliorate lesion formation in the small intestine after hemorrhagic shock. PMID- 24805260 TI - Proliferating pagetoid dyskeratosis: a new variant of pagetoid dyskeratosis associated with Bowen disease. AB - Pagetoid dyskeratosis refers to a characteristic pathologic aspect of keratinocytes of the epidermis and other stratified epithelia, that have a size larger than normal, a pale cytoplasm and a pycnotic nucleus surrounded by a clear halo. This aspect has been reported, often as an incidental finding, in benign conditions. We observed a case of Bowen disease featuring pagetoid dyskeratosis remarkable because the cells concerned were in mitosis, a finding so far unreported. We call this aspect "proliferating pagetoid dyskeratosis" to differentiate it from the usual pagetoid dyskeratosis and to highlight its association with mitotic nuclei. The significance of this rare finding warrants further study. PMID- 24805261 TI - Cross-conjugated hexaphyrins and their bis-rhodium complexes. AB - A cross-conjugated hexaphyrin that carries two meso-oxacyclohexadienylidenyl (OCH) groups 9 was synthesized from the condensation of 5,10 bis(pentafluorophenyl)tripyrrane with 3,5-di-tert-butyl-4-hydroxybenzaldehyde. The reduction of 9 with NaBH4 afforded the Mobius aromatic [28]hexaphyrin 10. Bis rhodium complex 11, prepared from the reaction of 10 with [{RhCl(CO)2}2], displays strong Huckel antiaromatic character because of the 28 pi electrons that occupy the conjugated circuit on the enforced planar structure. The oxidation of 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) yielded complexes 12 and 13 depending upon the reaction conditions. Both 12 and 13 are planar owing to bis rhodium metalation. Although complex 12 bears two meso-OCH groups at the long sides and is quinonoidal and nonaromatic in nature, complex 13 bears 3,5-di-tert butyl-4-hydroxyphenyl and OCH groups and exhibits a moderate diatropic ring current despite its cross-conjugated electronic circuit. The diatropic ring current increases upon increasing the solvent polarity, most likely due to an increased contribution of an aromatic zwitterionic resonance hybrid. PMID- 24805263 TI - Molecular phylogenetic profiling of gut-associated bacteria in larvae and adults of flesh flies. AB - Flesh flies of the genus Sarcophaga (Diptera: Sarcophagidae) are carrion breeding, necrophagous insects important in medical and veterinary entomology as potential transmitters of pathogens to humans and animals. Our aim was to analyse the diversity of gut-associated bacteria in wild-caught larvae and adult flesh flies using culture-dependent and culture-independent methods. Analysis of 16S rRNA gene sequences from cultured isolates and clone libraries revealed bacteria affiliated to Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes in the guts of larval and adult flesh flies. Bacteria cultured from larval and adult flesh fly guts belonged to the genera Acinetobacter, Bacillus, Budvicia, Citrobacter, Dermacoccus, Enterococcus, Ignatzschineria, Lysinibacillus, Myroides, Pasteurella, Proteus, Providencia and Staphylococcus. Phylogenetic analysis showed clone sequences of the genera Aeromonas, Bacillus, Bradyrhizobium, Citrobacter, Clostridium, Corynebacterium, Ignatzschineria, Klebsiella, Pantoea, Propionibacterium, Proteus, Providencia, Serratia, Sporosarcina, Weissella and Wohlfahrtiimonas. Species of clinically significant genera such as Ignatzschineria and Wohlfahrtiimonas spp. were detected in both larvae and adult flesh flies. Sequence analysis of 16S rRNA gene libraries supported culture-based results and revealed the presence of additional bacterial taxa. This study determined the diversity of gut microbiota in flesh flies, which will bolster the ability to assess microbiological risk associated with the presence of these flies. The present data thereby establish a platform for a much larger study. PMID- 24805262 TI - Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical trial. AB - IMPORTANCE: X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100,000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. OBJECTIVE: To determine whether high-dose docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTS: A 4-year, single site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to treat cohort (DHA group, n = 33; placebo group, n = 27). INTERVENTIONS: All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. RESULTS: Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log uV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found. CONCLUSIONS AND RELEVANCE: Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00100230. PMID- 24805264 TI - Preparation and characterization of luteinising-hormone releasing hormone nanoliposomal microbubbles specifically targeting ovarian cancer cells in vitro. AB - The aim of the present study was to prepare luteinizing-hormone releasing hormone (LHRH) nanoliposomal microbubbles specifically targeting ovarian cancer cells. The lyophilization/sonication method was used to prepare non-targeting nanoliposomal microbubbles (N-N-Mbs). Using the biotin-avidin bridge method, conjugated LHRH antibodies to N-N-Mbs generated LHRH nanoliposomal microbubbles (LHRH-N-Mbs) specifically targeting ovarian cancer cells. The morphology and physicochemical properties of the microbubbles was detected using an optical microscope and zeta detector. The binding affinity between the secondary antibody and LHRH-N-Mbs or N-N-Mbs was determined by flow cytometry. The binding of LHRH-N Mb to human ovarian cancer cells (OVCAR-3) was detected by light microscopy. The rounded and uniformly distributed N-N-Mbs and LHRH-N-Mbs were successfully generated. The particle size ranged from 295-468 nm with a mean of 360 nm for N-N Mbs or 369-618 nm with a mean of 508 nm for LHRH-N-Mbs. There was a significant difference in size between the two groups (P<0.05), although the surface potential of the two microbubbles remained the same (-14.6 mV). Following being kept at room temperature for 14 days, no significant difference in the physicochemical properties of the LHRH-N-Mbs was detected compared with that of freshly prepared microbubbles. The secondary antibody binding rate of LHRH-N-Mbs and N-N-Mbs was 75.6 and 0.83%, respectively. Furthermore, the formation of a rosette-like structure surrounding OVCAR-3 cells was observed after the cells were incubated with LHRH-N-Mbs, whereas pre-incubation with LHRH antibody blocked this rosette formation. In conclusion, LHRH-N-Mbs specifically targeting ovarian cancer cells were successfully prepared through biotin-avidin mediation and the lyophilization/sonication method. The key feature of LHRH-N-Mbs is their small size, stability and high efficiency in targeting human OVCAR-3 cells in vitro. PMID- 24805265 TI - Diagnosis, comorbidities, and management of restless legs syndrome. AB - OBJECTIVE: This narrative review describes the differential diagnosis of restless legs syndrome, and provides an overview of the evidence for the associations between RLS and potential comorbidities. Secondary causes of RLS and the characteristics of pediatric RLS are also discussed. Finally, management strategies for RLS are summarized. METHODS: The review began with a comprehensive PubMed search for 'restless legs syndrome/Willis-Ekbom disease' in combination with the following: anxiety, arthritis, attention-deficit hyperactivity disorder, cardiac, cardiovascular disease, comorbidities, depression, end-stage renal disease, erectile dysfunction, fibromyalgia, insomnia, kidney disease, liver disease, migraine, mood disorder, multiple sclerosis, narcolepsy, neuropathy, obesity, pain, Parkinson's disease, polyneuropathy, pregnancy, psychiatric disorder, sleep disorder, somatoform pain disorder, and uremia. Additional papers were identified by reviewing the reference lists of retrieved publications. RESULTS AND CONCLUSIONS: Although clinical diagnosis of RLS can be straightforward, diagnostic challenges may arise when patients present with comorbid conditions. Comorbidities of RLS include insomnia, depressive and anxiety disorders, and pain disorders. Differential diagnosis is particularly important, as some of the medications used to treat insomnia and depression may exacerbate RLS symptoms. Appropriate diagnosis and management of RLS symptoms may benefit patient well-being and, in some cases, may lessen comorbid disease burden. Therefore, it is important that physicians are aware of the presence of RLS when treating patients with conditions that commonly co-occur with the disorder. PMID- 24805266 TI - [Cone beam computed tomography and radiation dosage: application frequency and knowledge of dentists in Switzerland]. AB - The use of cone beam computed tomography (CBCT) among Swiss dentists increases from year to year. The aim of this study was to investigate the application frequency and the knowledge about CBCT and radiation dosage in a representative Swiss dentist sample. A standardized questionnaire about knowledge on CBCT was personally handed out or sent by post to 1,000 dentists in Switzerland (return postage was free of charge). 278 dentists returned the questionnaire. Descriptive statistics, correlation analysis of general variables and written answers of the questionnaires were evaluated. Most dentists were aware of radiation dosage and potential use of the CBCT and are interested in continuing education on CBCT. PMID- 24805267 TI - Three H2O2 molecules are involved in the "Fenton-like" reaction between Co(H2O)62+ and H2O2. AB - Co(II) complexes and Co(H2O)6(2+) are used as catalysts in advanced oxidation processes. Therefore it was decided to study the kinetics of reaction of Co(H2O)6(2+) with H2O2. Surprisingly, the kinetic results point out that the process involves three consecutive reactions, each of them requiring an H2O2 molecule, i.e. three H2O2 molecules ligate to the central cobalt cation prior to the formation of radicals. DFT analysis suggests that the transient (H2O)3Co(II)(OOH)2(H2O2) decomposes via: (H2O)3Co(II)(OOH)2(H2O2) -> (H2O)3Co(II)(OOH)(OOH)(OH) + OH DeltaG(0) = -5.975 kcal mol(-1), with no evidence for the formation of a Co(III) transient. It is proposed that analogous mechanisms are involved whenever the redox potential of the central cation is too high to enable the reaction: M(H2O)6(n+) + H2O2 -> M((n+1)+)aq + OH + OH(-). PMID- 24805269 TI - Confinement enhances dispersion in nanoparticle-polymer blend films. AB - Polymer nanocomposites constitute an important class of materials whose properties depend on the state of dispersion of the nanoparticles in the polymer matrix. Here we report the first observations of confinement-induced enhancement of dispersion in nanoparticle-polymer blend films. Systematic variation in the dispersion of nanoparticles with confinement for various compositions and matrix polymer chain dimensions has been observed. For fixed composition, strong reduction in glass transition temperature, Tg, is observed with decreasing blend film thickness. The enhanced dispersion occurs without altering the polymer particle interactions and seems to be driven by enhanced matrix-chain orientation propensity and a tendency to minimize the density gradients within the matrix. This implies the existence of two different mechanisms in polymer nanocomposites, which determines their state of dispersion and glass transition. PMID- 24805271 TI - 18-crown-6-sodium cholate complex: thermochemistry, structure, and stability. AB - 18-Crown-6, one of the most relevant crown ethers, and sodium cholate, a steroidal surfactant classified as a natural bile salt, are components of a novel, synthesized coordination complex: 18-crown-6-sodium cholate (18C6.NaCh). Like crown ethers, bile salts act as building blocks in supramolecular chemistry to design new functionalized materials with a desired structure and properties. In order to obtain thermal behavior of this 1:1 coordination complex, thermogravimetry and differential thermal analysis were used, as well as microscopic observations and differential scanning calorimetry. Temperature dependent infrared (IR) spectroscopy gave a detailed view into phase transitions. The structures during thermal treatment were observed with powder X-ray diffraction, and molecular models of the phases were made. Hard, glassy, colorless compound 18C6.NaCh goes through crystalline-crystalline polymorphic phase transitions at higher temperatures. The room temperature phase is indexed to a triclinic lattice, while in the high temperature phases molecules take randomly one of the two different configurations in the unit cell, resulting in the 2-fold symmetry. The formation of cholesteric liquid crystalline phase occurs simultaneously with partial decomposition, followed by the isotropization with simultaneous and complete decomposition at much higher temperature, as obtained by IR. The results provide valuable information about the relationship between molecular structure, thermal properties, and stability of the complex, indicating the importance of an appropriate choice of cation, amphiphilic, and crown ether unit in order to synthesize compounds with desired behavior. PMID- 24805274 TI - Carborane dyads for photoinduced electron transfer: photophysical studies on carbazole and phenyl-o-carborane molecular assemblies. AB - o-Carborane-based donor-acceptor dyads comprising an o-carboranyl phenyl unit combined with N-carbazole (1) or 4-phenyl-N-carbazole (2) were prepared, and their dyad characters were confirmed by steady-state photochemistry and photodynamic experiments as well as electrochemical studies. The absorption and electrochemical properties of the dyads were essentially the sum of those of the carbazole and o-carboranyl phenyl units; this indicates negligible interaction between the carbazole and o-carborane units in the ground state. However, the emission spectra of 1 and 2 indicated that carbazole fluorescence was effectively quenched and a new charge-transfer (CT) emission was observed in solvents, varying from hexane to acetonitrile, which exhibited large Stoke shifts. The CT emission properties of o-carborane-based dyads were further analyzed by using Lippert-Mataga plots to show that unit charge separation occurred to form a charge-separated species in the excited state, namely, 1?2. This excited-state species was confirmed by nanosecond transient absorption spectra and spectroelectrochemical measurements; the photoexcitation of carbazole generated the CT state in which a radical cation and anion were formed at the carbazole and o-carborane units, respectively, within a few nanoseconds. DFT calculations corroborated the presence of this CT species and showed localized populations of the highest singly occupied molecular orbital on 2 in the reduced anionic state. As a result, molecular assemblies formed by linking the carbazole group with the o-carborane cage through a phenylene or multi-phenylene spacer revealed that the photoinduced electron-transfer process occurred intramolecularly. PMID- 24805275 TI - Hierarchically ordered self-assembly of amphiphilic bifullerenes. AB - A series of novel functionalised dumbbell-shaped bifullerenes in which two [5.0] pentakis-adducts of C60 are covalently connected by cyclic bismalonates were synthesised. These dimeric compounds, carrying various combinations of hydrophilic and hydrophobic addends, self-assemble in aqueous solution towards supramolecular architectures of different structural complexity as observed by cryogenic transmission electron microscopy (cryo-TEM). The detailed analysis of the image data revealed an unprecedented hierarchical aggregation behaviour. Whereas completely hydrophilic substituted bifullerenes formed profoundly monodisperse populations of small oligomeric elementary micelles consisting of only three or four bifullerene molecules in a supposedly bent conformation, their amphiphilic equivalents underwent a hierarchical two-step assembly process towards larger spherical and even rod-like structures. The data suggest that the hierarchical assembly process is driven by hydrophobic interactions of preformed tetrameric elementary micelles. PMID- 24805277 TI - Cerium oxide nanoparticles inhibit adipogenesis in rat mesenchymal stem cells: potential therapeutic implications. AB - PURPOSE: Cerium oxide nanoparticles (nanoceria, NC) have extraordinary antioxidant activity that made them suitable as a therapeutic agent for several diseases where reactive oxygen species (ROS) act by impairing the normal redox balance. Among different functions, it has been proven that ROS are cellular messengers involved in the adipogenesis: we thus investigated the implication of NC administration in the potential inhibition of adipogenic differentiation of mesenchymal stem cells (MSCs) used as a model of adipogenesis. METHODS: We evaluated cytotoxic effects and adipogenic maturation of mesenchymal stem cells following in vitro NC administration, both at gene and at phenotype level. RESULTS: Overall, our results demonstrated that NC efficiently inhibit the maturation of MSCs toward adipocytes owing to their ability to reduce the production of the ROS necessary during adipogenesis. CONCLUSIONS: These findings, even if preliminary, represent an important step toward the potential pharmaceutical application of NC in the treatment of obesity. PMID- 24805278 TI - New strategy to surface functionalization of polymeric nanoparticles: one-pot synthesis of scFv anti-LDL(-)-functionalized nanocapsules. AB - PURPOSE: In general, the surface functionalization of polymeric nanoparticles is carried out by covalently bounding ligands to the nanoparticle surface. This process can cause a lack or decrease of the ligand specificity to its target receptor, besides the need of purification steps. We proposed a ligand-metal chitosan-lecithin complex as a new strategy to functionalize the surface of biodegradable nanoparticles. METHODS: One pot synthesis of scFv anti-LDL(-) functionalized nanocapsules was carried out by self-assembly and interfacial reactions. Particle sizing techniques, lipid peroxidation and molecular recognition by enzyme linked immuno sorbent assays were carried out. RESULTS: The selected formulation had unimodal size distribution with mean diameter of about 130 nm. The metals in the complex did not enhance the oxidative stress, and the scFv anti-LDL(-)-functionalized nanocapsules recognized LDL(-) and did not react with native LDL indicating the maintenance of the active site of the fragment. CONCLUSIONS: The one pot synthesis, using the ligand-metal-chitosan-lecithin complex to functionalize the surface of the biodegradable nanocapsules, maintained the active site of the antibody fragment making the device interesting for applications in nanomedicine. PMID- 24805279 TI - The bifunctional liposomes constructed by poly(2-ethyl-oxazoline)-cholesteryl methyl carbonate: an effectual approach to enhance liposomal circulation time, pH sensitivity and endosomal escape. AB - PURPOSE: A novel bifunctional liposome with long-circulating and pH-sensitive properties was constructed using poly(2-ethyl-oxazoline)-cholesteryl methyl carbonate (PEtOz-CHMC) in this study. METHODS: PEtOz-CHMC was synthesized and characterized by TLC, IR and (1)H-NMR. The obtained PEtOz lipid was inserted into liposomes by the post-insertion method. Through a series of experiments, such as drug release, tumor cell uptake, cytotoxicity, calcium-induced aggregation, pharmacokinetic experiments, etc., the pH-sensitive and long-circulating properties of PEtOzylated liposomes was identified. RESULTS: PEtOz-CHMC modified liposomes (PEtOz-L) showed increased calcein release at low pH. Flow cytometric analysis results showed that the fusion and cellular uptake of PEtOz-L could be promoted significantly at pH 6.4 compared with those at pH 7.4. Confocal laser scanning microscope observations revealed that PEtOz-L could respond to low endosomal pH and directly released the fluorescent tracer into the cytoplasm. MTT assays in HeLa cells demonstrated that doxorubicin hydrochloride (DOX) loaded PEtOz-L exhibited stronger anti-tumor activity in a medium at pH 6.4 than in a medium pH 7.4. PEtOz-L remained stable when these liposomes were incubated in calcium chloride solution. The cumulative calcein release rate of PEtOz-L was significantly lower than that of CL when the liposomes were dialysed in PBS. The pharmacokinetic experiments of liposomes in rats showed that t 1/2 and AUC of PEtOz-L were 4.13 times and 4.71 times higher than those of CL. CONCLUSIONS: PEtOzylated liposomes exhibits excellent long-circulating and pH-sensitive properties. Our results suggest that PEtOz is a promising biomaterial for the modification of liposome in drug delivery. PMID- 24805281 TI - Auxin production by the plant trypanosomatid Phytomonas serpens and auxin homoeostasis in infected tomato fruits. AB - Previously we have characterized the complete gene encoding a pyruvate decarboxylase (PDC)/indolepyruvate decarboxylase (IPDC) of Phytomonas serpens, a trypanosomatid highly abundant in tomato fruits. Phylogenetic analyses indicated that the clade that contains the trypanosomatid protein behaves as a sister group of IPDCs of gamma-proteobacteria. Since IPDCs are key enzymes in the biosynthesis of the plant hormone indole-3-acetic acid (IAA), the ability for IAA production by P. serpens was investigated. Similar to many microorganisms, the production of IAA and related indolic compounds, quantified by high performance liquid chromatography, increased in P. serpens media in response to amounts of tryptophan. The auxin functionality was confirmed in the hypocotyl elongation assay. In tomato fruits inoculated with P. serpens the concentration of free IAA had no significant variation, whereas increased levels of IAA-amide and IAA-ester conjugates were observed. The data suggest that the auxin produced by the flagellate is converted to IAA conjugates, keeping unaltered the concentration of free IAA. Ethanol also accumulated in P. serpens-conditioned media, as the result of a PDC activity. In the article we discuss the hypothesis of the bifunctionality of P. serpens PDC/IPDC and provide a three-dimensional model of the enzyme. PMID- 24805280 TI - Acid-responsive polymeric nanocarriers for topical adapalene delivery. AB - PURPOSE: The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery. METHODS: The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit(r) EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation. RESULTS: Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5 +/- 0.6 MUg.cm(-2).h(-1)) in comparison to that (3.9 +/ 0.4 MUg.cm(-2).h(-1)) in the control vehicle (Transcutol(r)). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did. CONCLUSIONS: The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy. PMID- 24805282 TI - [Guidance of axillary multiple injection technique for plexus anesthesia. Ultrasound versus nerve stimulation]. AB - BACKGROUND: Ultrasound guidance is still a young method in regional anesthesia when compared to nerve stimulation and only a few studies exist comparing these two techniques in an axillary multiple injection approach. AIM: This prospective, randomized, observer-blinded study compared an ultrasound-guided (SONO) quadruple injection axillary block (out of plane, perineural) with a nerve stimulation guided (STIM) triple injection axillary block for upper limb surgery. MATERIAL AND METHODS: A total of 60 patients were randomized to either the SONO (n = 30) or STIM (n = 30) group. For the block 40-50 ml mepivacaine 1.5 % (plexus) and 5 10 ml mepivacaine 0.5 % (subcutaneous in the medial skin of the arm) was used. Anesthesia time was recorded as the primary end point. After evaluation of block related pain using a visual analog scale (VAS) a blinded observer tested sensory and motor function of the median nerve (MED), ulnar nerve (ULN), radial nerve (RAD), musculocutaneous nerve of the upper limb (MUC) and medial cutaneous nerve of the forearm (CAM) at defined times. The main outcome variable was onset time (defined loss of sensory/motor function). RESULTS: No differences were observed between the groups in terms of onset time (single nerves 10-20 min, plexus 20-25 min) and success rate (SONO 90 %, STIM 89 %). Patient satisfaction as measured by block-related pain score (VAS 2 cm), complications (vascular puncture SONO 7 %, STIM 11 %; paresthesia SONO 21 %, STIM 22 %) and patient acceptance (SONO 92 %, STIM 91 %) showed no differences. Performance time was shorter in the SONO group (6.68 +/- 1.72 min vs. 8.05 +/- 2.58, p = 0.02). CONCLUSION: Nerve stimulation guided axillary plexus blocks performed by trained anesthesiologists may result in similar onset times and success rates compared to ultrasound-guided blocks. PMID- 24805283 TI - [Update on intensive care medicine. Most important publications from 2012-2014]. PMID- 24805284 TI - [Primary treatment of penetrating injuries. Part 1: blast trauma]. AB - Blast injuries may result from a variety of causes but the biomechanical impact and pathophysiological consequences do not differ between domestic or industrial accidents or even terrorist attacks. However, this differentiation relevantly affects the tactical procedures of the rescue teams. Focusing on further detonations, top priority is given to the personal safety of all rescue workers. The rareness of blast injuries in a civilian setting results in a lack of experience on the one hand but on the other hand the complexity of blast injuries to the human body places high demands on the knowledge and skills of the entire rescue team for competent treatment. The purpose of this article is to explain the physicochemical principles of explosions and to convey tactical and medical knowledge to emergency medical services. PMID- 24805285 TI - Palladium-catalyzed C-H homocoupling of furans and thiophenes using oxygen as the oxidant. AB - A general and efficient palladium-catalyzed intermolecular direct C-H homocoupling of furans and thiophenes has been developed. The reaction is characterized by using molecular oxygen as the sole oxidant and complete C5 position regioselectivity. Both C2- and C3-substituted furans or thiophenes are appropriate substrates. The approach provides a straightforward, facile, and economical route to bifurans and bithiophenes under mild reaction conditions. PMID- 24805286 TI - Biarmed poly(ethylene glycol)-(pheophorbide a)2 conjugate as a bioactivatable delivery carrier for photodynamic therapy. AB - In the study presented here, we developed a bioreducible biarmed methoxy poly(ethylene glycol)-(pheophorbide a)2 (mPEG-(ss-PhA)2) conjugate for cancer cell-specific photodynamic therapy (PDT). PhA molecules were chemically conjugated with biarmed linkages at one end of the mPEG molecule via disulfide bonds. Under aqueous conditions, the amphiphilic mPEG-(ss-PhA)2 conjugate self assembled to form core-shell-structured nanoparticles (NPs) with good colloidal stability. The mPEG-(ss-PhA)2 NPs exhibited intramolecular and intermolecular self-quenching effects that enabled the NPs to remain photoinactive in a physiological buffer. However, the dissociation of the NP structure was effectively induced by the cleavage of the disulfide bonds in response to intracellular reductive conditions, triggering the rapid release of PhA molecules in a photoactive form. In cell-culture systems, in addition to significant phototoxicity and intracellular uptake, we observed that the dequenching processes of PhA in the mPEG-(ss-PhA)2 NPs highly depended on the expression of intracellular thiols and that supplementation with glutathione monoethylester facilitated more rapid PhA release and enhanced the PhA phototoxicity. These findings suggest that the bioreducible activation mechanism of mPEG-(ss-PhA)2 NPs in cancer cells can maximize the cytosolic dose of active photosensitizers to achieve high cytotoxicity, thereby enhancing the treatment efficacy of photodynamic cancer treatment. PMID- 24805287 TI - Suppression of VEGF by reversible-PEGylated histidylated polylysine in cancer therapy. AB - A reversible-PEGylated polylysine is designed and developed for efficient delivery of siRNA. In this unique structure, the epsilon-amino groups of disulfide linked poly(ethylene glycol) (PEG) and polylysine (mPEG-SS-PLL) are partially replaced by histidine groups, in order to develop the histidylated reversible-PEGylated polylysine (mPEG-SS-PLH), for enhanced endosome escape ability. The transfection efficacy of mPEG-SS-PLH is found to closely correlate with histidine substitution. Its maximum transfection efficiencies are determined, respectively, to be 75%, 42%, and 24%, against 293T, MCF-7, and PC-3 cells. These data indicate that the transfection efficiencies can equal or even outweigh PEI-25k in the corresponding cells (80%, 38.5%, and 20%). The in vivo circulation and biodistribution of the polyplexes are monitored by fluorescent imaging. The in vivo gene transfection is carried out by intravenous injection of pEGFP to BALB/c mice using the xenograft models. The in vivo experimental results show effective inhibition of tumor growth by mPEG-SS-PLH/siRNA-VEGF, indicating its high potential for clinical applications. PMID- 24805288 TI - Pharmacokinetic analysis of 14C-ursodiol in newborn infants using accelerator mass spectrometry. AB - Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of (14) C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of (14) C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of (14) C-ursodiol: 8 ng (1.0 nCi), 26 ng (3.3 nCi), and 80 ng (10 nCi) 48 hours apart. Three additional infants with cholestasis were administered a single 80 ng (10.0 nCi) oral dose of (14) C ursodiol together with a therapeutic dose of 40 mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research. PMID- 24805291 TI - The European Academy of Neurology is founded: a fundamental step linking the glorious past with our future challenges. PMID- 24805292 TI - Cranial, axial and proximal myopathy and hypertrophic cardiomyopathy caused by a mutation in the globular head region of the MYH7 gene. PMID- 24805293 TI - Carotid web and stroke. PMID- 24805295 TI - Xist deficiency and disorders of X-inactivation in rabbit embryonic stem cells can be rescued by transcription-factor-mediated conversion. AB - The deficiency of X-inactive specific transcript (XIST) on the inactive X chromosome affects the behavior of female human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), and further chromosomal erosion can occur with continued passaging of these cells. However, X chromosome instability has not been identified in other species. In the present study, we investigated three female rabbit ESC (rbESC) lines and found that two of them expressed Xist normally and obtained both Xist RNA coating and H3K27me3 foci, thus defined as Xi(Xist)Xa. Interestingly, the third female rbESC line lacked Xist expression during ESC maintenance and differentiation. This line showed H3K27me3 foci but no Xist RNA coating in the early passages and was thus defined as Xi(w/oXist)Xa. Similar to Xi(w/oXist)Xa hESCs or hiPSCs, Xi(w/oXist)Xa rbESCs lose H3K27me3 and undergo Xi erosion (Xe) with passaging. Moreover, Xist deficient rbESCs also exhibit impaired differentiation ability and upregulation of cancer-related genes. By overexpressing OCT4, SOX2, KLF4, and c-MYC in Xist deficient rbESCs under optimized culture conditions, we successfully obtained mouse ESC-like (mESC-like) cells. The mESC-like rbESCs displayed dome-shaped colony morphology, activation of the LIF/STAT3-dependent pathway, and conversion of disordered X chromosome. Importantly, the defective differentiation potential was also greatly improved. Our data demonstrate that variations in X chromosome inactivation occur in early passage of rbESCs; thus, Xi disorders are conserved across species and are reversible using the proper epigenetic reprogramming and culture conditions. These findings may be very useful for future efforts toward deriving fully pluripotent rbESCs or rabbit iPSCs (rbiPSCs). PMID- 24805296 TI - The effect of Cordyceps extract and a mixture of Ganoderma lucidum/Agaricus Blazi Murill extract on human endometrial cancer cell lines in vitro. AB - Endometrial carcinoma is the most common gynaecological malignancy. Nevertheless there is a lack of curative therapies, especially for patients diagnosed with late stage, recurrent or aggressive disease, who have a poor prognosis. Cordyceps Sinensis, Ganoderma lucidum and Agaricus Blazi Murill are three fungi widely used in traditional Chinese medicine, and effects as adjuvants in tumour therapy have been demonstrated. However, the function and effects of these fungi in regard to endometrial cancer are not known. Three endometrial cancer cell lines, Ishikawa, Hec-1A and AN3-CA (derived from endometrial cancers grade I, II and III, respectively), were used to determine the effect of the fungi extracts on endometrial cancer cell function and to analyze the molecular mechanism. All fungi extracts had an inhibitory effect on cell viability and proliferation most probably exerted through induction of autophagy. Our data suggest that these fungi extracts may be used as adjuvants in endometrial tumour therapy. PMID- 24805299 TI - Pressure induced second-order structural transition in Sr3Ir2O7. AB - We conducted in situ angle dispersive high pressure x-ray diffraction experiments on Sr3Ir2O7 up to 23.1 GPa at 25 K with neon as the pressure transmitting medium. Pressure induces a highly anisotropic compressional behavior seen where the tetragonal plane is compressed much faster than the perpendicular direction. By analyzing different aspects of the diffraction data, a second-order structural transition is observed at approximately 14 GPa, which is accompanied by the insulating state to nearly metallic state at 13.2 GPa observed previously (Li et al 2013 Phys. Rev. B 87 235127). Our results highlight the coupling between electronic state and lattice structure in Sr3Ir2O7 under pressure. PMID- 24805300 TI - Synthesis of alpha,beta-unsaturated amides and iminocoumarins from N,N-disulfonyl ynamides with aldehydes via the ketenimine intermediate. AB - A novel synthesis of alpha,beta-unsaturated amides from N,N-disulfonyl ynamides with aldehydes was developed. By utilization of salicylaldehydes, a variety of substituted iminocoumarins were prepared. PMID- 24805298 TI - Vasoactive intestinal peptide maintains the nonpathogenic profile of human th17 polarized cells. AB - The cytokine microenvironment modulates CD4 T cell differentiation causing the shift of naive CD4 T cells into different cell subsets. This process is also regulated by modulators such as vasoactive intestinal peptide (VIP), a neuropeptide with known immunomodulatory properties on CD4 T cells that exert this action through specific receptors, vasoactive intestinal peptide receptor (VPAC)1 and VPAC2. Our results show that the pattern of VIP receptors expression ratio is modified during Th17 differentiation. In this report, we evaluate the capacity of VIP to modulate naive human cells into Th17 cells in vitro by analyzing their functional phenotype. The presence of VIP maintains the nonpathogenic profile of Th17-polarized cells, increases the proliferation rate, and decreases their Th1 potential. VIP induces the upregulation of the STAT3 gene interaction with the VPAC1 receptor during the onset of Th17 differentiation. Moreover, RAR-related orphan receptor C (RORC), RAR-related orphan receptor A (RORA), and interleukin (IL)-17A genes are upregulated in the presence of VIP through interaction with VPAC1 and VPAC2 receptors. Interestingly, VIP induces the expression of the IL-23R gene through interaction with the VPAC2 receptor during the expansion phase. This is the first report that describes the differentiation of naive human T cells to Th17-polarized cells in the presence of VIP and demonstrates how this differentiation regulates the expression of the VIP receptors. PMID- 24805301 TI - Variance of pain prevalence and associated severity during the transfusion cycle of adult thalassaemia patients. PMID- 24805303 TI - Development and psychometric testing of the 'Motivation and Self-Efficacy in Early Detection of Skin Lesions' index. AB - AIM: To develop and psychometrically test the Motivation and Self-Efficacy in Early Detection of Skin Lesions Index. BACKGROUND: Skin cancer is the most frequently diagnosed cancer worldwide. The primary strategy used to prevent skin cancer is promotion of sun avoidance and the use of sun protection. However, despite costly and extensive campaigns, cases of skin cancer continue to increase. If found and treated early, skin cancer is curable. Early detection is, therefore, very important. The study was conducted in 2013. DESIGN: Instrument Development. METHODS: A literature review and a survey identified barriers (factors that hinder) and levers (factors that help) to skin self-examination. These were categorized according to a the Theoretical Domains Framework and this formed the basis of an instrument, which was tested for validity and reliability using confirmatory factor analysis and Cronbach's alpha respectively. RESULTS: A five-factor 20-item instrument was used that tested well for reliability and construct validity. Test-retest reliability was good for all items and domains. The five factors were: (i) Outcome expectancies; (ii) Intention; (iii) Self efficacy; (iv) Social influences; (v) Memory. CONCLUSIONS: The Motivation and Self-Efficacy in Early Detection of Skin Lesions Index provides a reliable and valid method of assessing barriers and levers to skin self-examination. The next step is to design a theory-based intervention that can be tailored according to individual determinants to behaviour change identified by this instrument. PMID- 24805305 TI - Within-session spacing improves delayed recall in children. AB - Multiple retrievals of a memory over a spaced manner improve long-term memory performance in infants, children, younger and older adults; however, few studies have examined spacing effects with young school-age children. To expand the understanding of the spacing benefit in children, the current study presented weakly associated English word-pairs to children aged 7-11 and cued their recall two times immediately (massed), after a delay of 5 or 10 items (spaced) or not at all (control). After this encoding session with or without two retrievals, participants were tested two times for memory of all word-pairs: immediately and 30 minutes after the encoding session. Multiple retrievals significantly improved memory on the tests. However, words repeated in a spaced design were remembered at higher rates than those that were massed, while gap size between repetitions (5 or 10) did not differentially impact performance. The data show that a within session spacing strategy can benefit children's ability to remember word-pairs after 30 minutes. Thus, asking students to recall what they have learned within a lesson is a technique that can be used in a classroom to improve long-term recall. PMID- 24805304 TI - Preventive and therapeutic effects of a beta adrenoreceptor agonist, dobutamine, in carrageenan-induced inflammatory nociception in rats. AB - We hypothesized that locally administrated beta-adrenoreceptor agonist can modulate the inflammatory nociceptive parameters in carrageenan (CG)-induced peripheral inflammatory pain. This study was therefore aimed to assess the preventive and therapeutic effects of a beta-agonist, dobutamine, by investigating its pretreatment and posttreatment actions on the inflammation induced hypersensitivities (thermal hyperalgesia, mechanical allodynia) to cutaneous stimulation, edema, and several biochemical oxidant and anti-oxidant parameters in a rat model of CG-induced hind paw inflammation. Effects of dobutamine were compared with those of esmolol, a beta-adrenoreceptor antagonist. CG injection to healthy rats lowered the thermal latencies (from 10.1 +/- 0.2 to 4.9 +/- 0.1 s) and mechanical thresholds (from 32.9 +/- 0.5 to 18.9 +/- 1.3 g) and caused the hyperalgesia and allodynia. In CG-induced inflamed paws, while intraplantar esmolol treatment (1 mg) produced significant decreases in latencies (4.1 +/- 0.1 s) and thresholds (15.2 +/- 2.4 g), dobutamine (1 mg) increased the latencies (11.3 +/- 0.5 s) and thresholds (26.3 +/- 2.8 g). In contrast to esmolol, dobutamine increased the superoxide dismutase level and decreased the myeloperoxidase, malondialdehyde, and nitric oxide levels in CG-induced inflamed paws. The present results can reveal that beta-adrenoreceptors may play a role in inflammatory nociceptive processes, and locally treated beta-adrenoreceptor agonists such as dobutamine can be a preferable, appropriate choice for the management of inflammatory nociception due to their preventive and therapeutic effects on CG-induced peripheral inflammatory nociception. PMID- 24805306 TI - Role of helicity of alpha-helical antimicrobial peptides to improve specificity. AB - A major barrier to the use of antimicrobial peptides as antibiotics is the toxicity or ability to lyse eukaryotic cells. In this study, a 26-residue amphipathic alpha-helical antimicrobial peptide A12L/A20L (Ac KWKSFLKTFKSLKKTVLHTLLKAISS-amide) was used as the framework to design a series of D- and L-diastereomeric peptides and study the relationships of helicity and biological activities of alpha-helical antimicrobial peptides. Peptide helicity was measured by circular dichroism spectroscopy and demonstrated to correlate with the hydrophobicity of peptides and the numbers of D-amino acid substitutions. Therapeutic index was used to evaluate the selectivity of peptides against prokaryotic cells. By introducing D-amino acids to replace the original L amino acids on the non-polar face or the polar face of the helix, the hemolytic activity of peptide analogs have been significantly reduced. Compared to the parent peptide, the therapeutic indices were improved of 44-fold and 22-fold against Gram-negative and Gram-positive bacteria, respectively. In addition, D- and L-diastereomeric peptides exhibited lower interaction with zwitterionic eukaryotic membrane and showed the significant membrane damaging effect to bacterial cells. Helicity was proved to play a crucial role on peptide specificity and biological activities. By simply replacing the hydrophobic or the hydrophilic amino acid residues on the non-polar or the polar face of these amphipathic derivatives of the parent peptide with D-amino acids, we demonstrated that this method could have excellent potential for the rational design of antimicrobial peptides with enhanced specificity. PMID- 24805307 TI - Why is dimerization essential for class-C GPCR function? New insights from mGluR1 crystal structure analysis. PMID- 24805309 TI - Abstracts of the 37th Postgraduate Course and 51st Annual Meeting of the European Society of Paediatric Radiology, June 2-6, 2014, Amsterdam, The Netherlands. PMID- 24805310 TI - Time to settle the synthetic controversy. PMID- 24805322 TI - Antibiotic resistance sweeping developing world. PMID- 24805308 TI - Transitions between epithelial and mesenchymal states during cell fate conversions. AB - Cell fate conversion is considered as the changing of one type of cells to another type including somatic cell reprogramming (de-differentiation), differentiation, and trans-differentiation. Epithelial and mesenchymal cells are two major types of cells and the transitions between these two cell states as epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) have been observed during multiple cell fate conversions including embryonic development, tumor progression and somatic cell reprogramming. In addition, MET and sequential EMT-MET during the generation of induced pluripotent stem cells (iPSC) from fibroblasts have been reported recently. Such observation is consistent with multiple rounds of sequential EMT-MET during embryonic development which could be considered as a reversed process of reprogramming at least partially. Therefore in current review, we briefly discussed the potential roles played by EMT, MET, or even sequential EMT-MET during different kinds of cell fate conversions. We also provided some preliminary hypotheses on the mechanisms that connect cell state transitions and cell fate conversions based on results collected from cell cycle, epigenetic regulation, and stemness acquisition. PMID- 24805323 TI - Avalanche hotspot revealed. PMID- 24805324 TI - Indian elections fall flat on science. PMID- 24805325 TI - Universities seek to boost industry partnerships. PMID- 24805326 TI - Imaging: Cancer caught in the act. PMID- 24805327 TI - Synthetic biology: Beyond divisions. PMID- 24805328 TI - Synthetic biology: Cultural divide. PMID- 24805330 TI - Q&A: Canopy composer. PMID- 24805332 TI - India: Shed the bad science image. PMID- 24805333 TI - Collaborations: Aim for balance in Ukraine reports. PMID- 24805334 TI - India: Research split harmed universities. PMID- 24805335 TI - Communication: Help poster sessions to grab attention. PMID- 24805336 TI - India: Overhaul university teaching. PMID- 24805338 TI - Synthetic biology: Engineering explored. PMID- 24805339 TI - Climate science: The origin of regional Arctic warming. PMID- 24805340 TI - Synthetic biology: Construction of a yeast chromosome. PMID- 24805341 TI - Cosmology: A virtual Universe. PMID- 24805342 TI - Ecology: Diversity in the afterlife. PMID- 24805343 TI - Properties of galaxies reproduced by a hydrodynamic simulation. AB - Previous simulations of the growth of cosmic structures have broadly reproduced the 'cosmic web' of galaxies that we see in the Universe, but failed to create a mixed population of elliptical and spiral galaxies, because of numerical inaccuracies and incomplete physical models. Moreover, they were unable to track the small-scale evolution of gas and stars to the present epoch within a representative portion of the Universe. Here we report a simulation that starts 12 million years after the Big Bang, and traces 13 billion years of cosmic evolution with 12 billion resolution elements in a cube of 106.5 megaparsecs a side. It yields a reasonable population of ellipticals and spirals, reproduces the observed distribution of galaxies in clusters and characteristics of hydrogen on large scales, and at the same time matches the 'metal' and hydrogen content of galaxies on small scales. PMID- 24805344 TI - Classical shear cracks drive the onset of dry frictional motion. AB - Frictional processes entail the rupture of the ensemble of discrete contacts defining a frictional interface. There are a variety of views on how best to describe the onset of dry frictional motion. These range from modelling friction with a single degree of freedom, a 'friction coefficient', to theoretical treatments using dynamic fracture to account for spatial and temporal dynamics along the interface. We investigated the onset of dry frictional motion by performing simultaneous high-speed measurements of the real contact area and the strain fields in the region surrounding propagating rupture tips within the dry (nominally flat) rough interfaces formed by brittle polymer blocks. Here we show that the transition from 'static' to 'dynamic' friction is quantitatively described by classical singular solutions for the motion of a rapid shear crack. We find that these singular solutions, originally derived to describe brittle fracture, are in excellent agreement with the experiments for slow propagation, whereas some significant discrepancies arise as the rupture velocity approaches the Rayleigh wave speed. In addition, the energy dissipated in the fracture of the contacts remains nearly constant throughout the entire range in which the rupture velocity is less than the Rayleigh wave speed, whereas the size of the dissipative zone undergoes a Lorentz-like contraction as the rupture velocity approaches the Rayleigh wave speed. This coupling between friction and fracture is critical to our fundamental understanding of frictional motion and related processes, such as earthquake dynamics. PMID- 24805345 TI - Tropical forcing of the recent rapid Arctic warming in northeastern Canada and Greenland. AB - Rapid Arctic warming and sea-ice reduction in the Arctic Ocean are widely attributed to anthropogenic climate change. The Arctic warming exceeds the global average warming because of feedbacks that include sea-ice reduction and other dynamical and radiative feedbacks. We find that the most prominent annual mean surface and tropospheric warming in the Arctic since 1979 has occurred in northeastern Canada and Greenland. In this region, much of the year-to-year temperature variability is associated with the leading mode of large-scale circulation variability in the North Atlantic, namely, the North Atlantic Oscillation. Here we show that the recent warming in this region is strongly associated with a negative trend in the North Atlantic Oscillation, which is a response to anomalous Rossby wave-train activity originating in the tropical Pacific. Atmospheric model experiments forced by prescribed tropical sea surface temperatures simulate the observed circulation changes and associated tropospheric and surface warming over northeastern Canada and Greenland. Experiments from the Coupled Model Intercomparison Project Phase 5 (ref. 16) models with prescribed anthropogenic forcing show no similar circulation changes related to the North Atlantic Oscillation or associated tropospheric warming. This suggests that a substantial portion of recent warming in the northeastern Canada and Greenland sector of the Arctic arises from unforced natural variability. PMID- 24805346 TI - Consequences of biodiversity loss for litter decomposition across biomes. AB - The decomposition of dead organic matter is a major determinant of carbon and nutrient cycling in ecosystems, and of carbon fluxes between the biosphere and the atmosphere. Decomposition is driven by a vast diversity of organisms that are structured in complex food webs. Identifying the mechanisms underlying the effects of biodiversity on decomposition is critical given the rapid loss of species worldwide and the effects of this loss on human well-being. Yet despite comprehensive syntheses of studies on how biodiversity affects litter decomposition, key questions remain, including when, where and how biodiversity has a role and whether general patterns and mechanisms occur across ecosystems and different functional types of organism. Here, in field experiments across five terrestrial and aquatic locations, ranging from the subarctic to the tropics, we show that reducing the functional diversity of decomposer organisms and plant litter types slowed the cycling of litter carbon and nitrogen. Moreover, we found evidence of nitrogen transfer from the litter of nitrogen fixing plants to that of rapidly decomposing plants, but not between other plant functional types, highlighting that specific interactions in litter mixtures control carbon and nitrogen cycling during decomposition. The emergence of this general mechanism and the coherence of patterns across contrasting terrestrial and aquatic ecosystems suggest that biodiversity loss has consistent consequences for litter decomposition and the cycling of major elements on broad spatial scales. PMID- 24805348 TI - Acute transfusion reactions at a national referral hospital in Uganda: a prospective study. AB - BACKGROUND: Very little has been published about acute transfusion reactions (ATRs) in developing countries. This study was undertaken to determine the incidence, type, imputability, severity, and possible associated factors of ATRs observed in a university-affiliated hospital in Uganda. STUDY DESIGN AND METHODS: We prospectively followed the transfusion of blood units issued over a 7-week period from the hospital blood bank during regular working hours to nonbleeding patients. For each transfusion, we recorded the patient's status before, during, at the end of, and 4 hours after transfusion. Three physicians independently reviewed all reports of suspected ATRs and related hospital charts. Using predefined criteria, the presence, type, imputability, and severity of ATRs were adjudicated by consensus of two of three physicians. Factors potentially associated with ATRs were analyzed for statistical significance. RESULTS: A total of 507 transfusions were analyzed. Fifty-three acute transfusion events were recorded and 49 of 53 or 9.6% of the 507 transfusions were confirmed to be ATRs by physician consensus: 24 febrile, seven allergic, five hypertensive, three hypotensive, three transfusion-associated circulatory overload, two acute hemolytic, and five others. Imputability of ATRs was definite, probable, or possible in 45 of 49 ATRs (92% of ATRs or 8.9% of transfusions) and judged to be severe in nine of 45. No significant associated factors were identified. CONCLUSIONS: Our findings suggest that ATRs may occur more commonly in resource limited settings than in high-income countries. Although some reactions are unavoidable, improved surveillance of transfusions and implementation of transfusion guidelines could improve the safety of transfusions in these settings. PMID- 24805351 TI - In vitro quantification of time dependent thrombus size using magnetic resonance imaging and computational simulations of thrombus surface shear stresses. AB - Thrombosis and thromboembolization remain large obstacles in the design of cardiovascular devices. In this study, the temporal behavior of thrombus size within a backward-facing step (BFS) model is investigated, as this geometry can mimic the flow separation which has been found to contribute to thrombosis in cardiac devices. Magnetic resonance imaging (MRI) is used to quantify thrombus size and collect topographic data of thrombi formed by circulating bovine blood through a BFS model for times ranging between 10 and 90 min at a constant upstream Reynolds number of 490. Thrombus height, length, exposed surface area, and volume are measured, and asymptotic behavior is observed for each as the blood circulation time is increased. Velocity patterns near, and wall shear stress (WSS) distributions on, the exposed thrombus surfaces are calculated using computational fluid dynamics (CFD). Both the mean and maximum WSS on the exposed thrombus surfaces are much more dependent on thrombus topography than thrombus size, and the best predictors for asymptotic thrombus length and volume are the reattachment length and volume of reversed flow, respectively, from the region of separated flow downstream of the BFS. PMID- 24805349 TI - Emerging technologies to map the protein methylome. AB - Protein methylation plays an integral role in cellular signaling, most notably by modulating proteins bound at chromatin and increasingly through regulation of non histone proteins. One central challenge in understanding how methylation acts in signaling is identifying and measuring protein methylation. This includes locus specific modification of histones, on individual non-histone proteins, and globally across the proteome. Protein methylation has been studied traditionally using candidate approaches such as methylation-specific antibodies, mapping of post-translational modifications by mass spectrometry, and radioactive labeling to characterize methylation on target proteins. Recent developments have provided new approaches to identify methylated proteins, measure methylation levels, identify substrates of methyltransferase enzymes, and match methylated proteins to methyl-specific reader domains. Methyl-binding protein domains and improved antibodies with broad specificity for methylated proteins are being used to characterize the "protein methylome". They also have the potential to be used in high-throughput assays for inhibitor screens and drug development. These tools are often coupled to improvements in mass spectrometry to quickly identify methylated residues, as well as to protein microarrays, where they can be used to screen for methylated proteins. Finally, new chemical biology strategies are being used to probe the function of methyltransferases, demethylases, and methyl binding "reader" domains. These tools create a "system-level" understanding of protein methylation and integrate protein methylation into broader signaling processes. PMID- 24805352 TI - Morphology and histochemistry of the aesthetasc-associated epidermal glands in terrestrial hermit crabs of the genus Coenobita (Decapoda: Paguroidea). AB - Crustaceans have successfully adapted to a variety of environments including fresh- and saltwater as well as land. Transition from an aquatic to a terrestrial lifestyle required adaptations of the sensory equipment of an animal, particularly in olfaction, where the stimulus itself changes from hydrophilic to mainly hydrophobic, air-borne molecules. Hermit crabs Coenobita spp. (Anomura, Coenobitidae) have adapted to a fully terrestrial lifestyle as adults and have been shown to rely on olfaction in order to detect distant food items. We observed that the specialized olfactory sensilla in Coenobita, named aesthetascs, are immersed in a layer of mucous-like substance. We hypothesized that the mucous is produced by antennal glands and affects functioning of the aesthetascs. Using various microscopic and histochemical techniques we proved that the mucous is produced by aesthetasc-associated epidermal glands, which we consider to be modified rosette-type aesthetasc tegumental glands known from aquatic decapods. These epidermal glands in Coenobita are multicellular exocrine organs of the recto-canal type with tubulo-acinar arrangement of the secretory cells. Two distinct populations of secretory cells were clearly distinguishable with light and electron microscopy. At least part of the secretory cells contains specific enzymes, CUB-serine proteases, which are likely to be secreted on the surface of the aesthetasc pad and take part in antimicrobial defense. Proteomic analysis of the glandular tissue corroborates the idea that the secretions of the aesthetasc associated epidermal glands are involved in immune responses. We propose that the mucous covering the aesthetascs in Coenobita takes part in antimicrobial defense and at the same time provides the moisture essential for odor perception in terrestrial hermit crabs. We conclude that the morphological modifications of the aesthetasc-associated epidermal glands as well as the functional characteristics of their secretions are important adaptations to a terrestrial lifestyle. PMID- 24805354 TI - A double-taper optical fiber-based radiation wave other than evanescent wave in all-fiber immunofluorescence biosensor for quantitative detection of Escherichia coli O157:H7. AB - Cylindrical or taper-and-cylinder combination optical fiber probe based on evanescent wave has been widely used for immunofluorescence biosensor to detect various analytes. In this study, in contrast to the contradiction between penetration depth and analyte diameter of optical fiber probe-based evanescent wave, we demonstrate that double-taper optical fiber used in a radiation wave based all-fiber immunofluorescence biosensor (RWAIB) can detect micron-scale analytes using Escherichia coli O157:H7 as representative target. Finite difference time-domain method was used to compare the properties of evanescent wave and radiation wave (RW). Ray-tracing model was formulated to optimize the taper geometry of the probe. Based on a commercial multi-mode fiber, a double taper probe was fabricated and connected with biosensor through a "ferrule connector" optical fiber connector. The RWAIB configuration was accomplished using commercial multi-mode fibers and fiber-based devices according to the "all fiber" method. The standard sample tests revealed that the sensitivity of the proposed technique for E. coli O157:H7 detection was 10(3) cfu . mL(-1). Quantitation could be achieved within the concentration range of 10(3) cfu . mL( 1) to 107 cfu . mL(-1). No non-specific recognition to ten kinds of food-borne pathogens was observed. The results demonstrated that based on the double-taper optical fiber RWAIB can be used for the quantitative detection of micron-scale targets, and RW sensing is an alternative for traditional evanescent wave sensing during the fabrication of fiber-optic biosensors. PMID- 24805353 TI - Calponin-like Chd64 is partly disordered. AB - 20-hydroxyecdysone (20E) and juvenile hormone (JH) signaling pathways interact to regulate insect development. Recently, two proteins, a calponin-like Chd64 and immunophilin FKBP39 have been found to play a pivotal role in the cross-talk between 20E and JH, although the molecular basis of interaction remains unknown. The aim of this work was to identify the structural features that would provide understanding of the role of Chd64 in multiple and dynamic complex that cross links the signaling pathways. Here, we demonstrate the results of in silico and in vitro analyses of the structural organization of Chd64 from Drosophila melanogaster and its homologue from Tribolium castaneum. Computational analysis predicted the existence of disordered regions on the termini of both proteins, while the central region appeared to be globular, probably corresponding to the calponin homology (CH) domain. In vitro analyses of the hydrodynamic properties of the proteins from analytical size-exclusion chromatography and analytical ultracentrifugation revealed that DmChd64 and TcChd64 had an asymmetrical, elongated shape, which was further confirmed by small angle X-ray scattering (SAXS). The Kratky plot indicated disorderness in both Chd64 proteins, which could possibly be on the protein termini and which would give rise to specific hydrodynamic properties. Disordered tails are often involved in diverse interactions. Therefore, it is highly possible that there are intrinsically disordered regions (IDRs) on both termini of the Chd64 proteins that serve as platforms for multiple interaction with various partners and constitute the foundation for their regulatory function. PMID- 24805355 TI - Which score should be used for risk stratification of ischemic stroke in patients with atrial fibrillation. PMID- 24805356 TI - Acute kidney injury and acute myocardial infarction. PMID- 24805357 TI - Utilization of oxidative stress biomarkers is important to assess treatment effects on exercise capacity in patients with intermittent claudication. PMID- 24805358 TI - New era of oral anticoagulation for Japanese non-valvular atrial fibrillation patients. PMID- 24805359 TI - Cytotoxicity studies of semi-synthetic derivatives of theveside derived from the aqueous extract of leaves of 'suicide tree' Cerbera odollam. AB - We report the isolation of two known iridoid glucosides theviridoside (1) and theveside (2) from the aqueous extract of leaves of Cerbera odollam and semi synthetic derivatisation of theveside prepared in a single step under protection group-free conditions. Derivatives 2a-j were evaluated for cytotoxicity towards five human cancer cell lines of different origins, namely SKBR3 (breast), HeLa (cervical), A375 (skin), HepG2 (liver) and HCT-116 (colon), and IC50 values were determined. Derivatives 2b and 2h exhibited moderate cytotoxicity against HCT-116 and A375 cell lines, respectively. PMID- 24805360 TI - A new microfluidics-based droplet dispenser for ICPMS. AB - In this work, a novel droplet microfluidic sample introduction system for inductively coupled plasma mass spectrometry (ICPMS) is proposed and characterized. The cheap and disposable microfluidic chip generates droplets of an aqueous sample in a stream of perfluorohexane (PFH), which is also used to eject them as a liquid jet. The aqueous droplets remain intact during the ejection and can be transported into the ICP with >50% efficiency. The transport is realized via a custom-built system, which includes a membrane desolvator necessary for the PFH vapor removal. The introduction system presented here can generate highly monodisperse droplets in the size range of 40-60 MUm at frequencies from 90 to 300 Hz. These droplets produced very stable signals with a relative standard deviation (RSD) comparable to the one achieved with a commercial droplet dispenser. Using the current system, samples with a total volume of <1 MUL can be analyzed. Moreover, the capabilities of the setup for introduction and quantitative elemental analysis of single cells were described using a test system of bovine red blood cells. In the future, other modules of the modern microfludics can be integrated in the chip, such as on-chip sample pretreatment or parallel introduction of different samples. PMID- 24805361 TI - Estrogenic regulation of histamine receptor subtype H1 expression in the ventromedial nucleus of the hypothalamus in female rats. AB - Female sexual behavior is controlled by central estrogenic action in the ventromedial nucleus of the hypothalamus (VMN). This region plays a pivotal role in facilitating sex-related behavior in response to estrogen stimulation via neural activation by several neurotransmitters, including histamine, which participates in this mechanism through its strong neural potentiating action. However, the mechanism through which estrogen signaling is linked to the histamine system in the VMN is unclear. This study was undertaken to investigate the relationship between estrogen and histamine receptor subtype H1 (H1R), which is a potent subtype among histamine receptors in the brain. We show localization of H1R exclusively in the ventrolateral subregion of the female VMN (vl VMN), and not in the dorsomedial subregion. In the vl VMN, abundantly expressed H1R were mostly colocalized with estrogen receptor alpha. Intriguingly, H1R mRNA levels in the vl VMN were significantly elevated in ovariectomized female rats treated with estrogen benzoate. These data suggest that estrogen can amplify histamine signaling by enhancing H1R expression in the vl VMN. This enhancement of histamine signaling might be functionally important for allowing neural excitation in response to estrogen stimulation of the neural circuit and may serve as an accelerator of female sexual arousal. PMID- 24805364 TI - Autonomy and why you can "Never Let Me Go". AB - Kazuo Ishiguro's book Never Let Me Go is a thoughtful and provocative exploration of what it means to be human. Drawing on insights from the hermeneutic phenomenology of Martin Heidegger, I argue that the movement of Ishiguro's story can be understood in terms of actualising the human potential for autonomous action. Liberal theories take autonomy to be concerned with analytically and ethically isolatable social units directing their lives in accordance with self interested preferences, arrived at by means of rational calculation. However, I argue that such theories are simplistic abstractions from our human-life world, distorting the fundamental embodied, embedded, and relational nature of autonomy. When we attend closely to our concrete, lived existence we see instead that autonomy is about responding appropriately to others with whom we share a world. As we follow the path of Ishiguro's central character Kathy H., we are shown how an awareness and acceptance of our existential finitude as precarious and fallible creatures is necessary for guiding such appropriate interactions. As Kathy grows and is affirmed into her life-world, which grounds and supports her Being, she moves from heteronomy to autonomy; from being moved by external laws to embodying those laws, thereby becoming autonomous. This is exemplified by her appropriation of the carer role, through which she responds in a fitting way to those with whom she shares her world, bearing the weight of and dwelling responsibly within our human condition. PMID- 24805362 TI - Lactobacillus crispatus dominant vaginal microbiome is associated with inhibitory activity of female genital tract secretions against Escherichia coli. AB - OBJECTIVE: Female genital tract secretions inhibit E. coli ex vivo and the activity may prevent colonization and provide a biomarker of a healthy microbiome. We hypothesized that high E. coli inhibitory activity would be associated with a Lactobacillus crispatus and/or jensenii dominant microbiome and differ from that of women with low inhibitory activity. STUDY DESIGN: Vaginal swab cell pellets from 20 samples previously obtained in a cross-sectional study of near-term pregnant and non-pregnant healthy women were selected based on having high (>90% inhibition) or low (<20% inhibition) anti-E. coli activity. The V6 region of the 16S ribosomal RNA gene was amplified and sequenced using the Illumina HiSeq 2000 platform. Filtered culture supernatants from Lactobacillus crispatus, Lactobacillus iners, and Gardnerella vaginalis were also assayed for E. coli inhibitory activity. RESULTS: Sixteen samples (10 with high and 6 with low activity) yielded evaluable microbiome data. There was no difference in the predominant microbiome species in pregnant compared to non-pregnant women (n = 8 each). However, there were significant differences between women with high compared to low E. coli inhibitory activity. High activity was associated with a predominance of L. crispatus (p<0.007) and culture supernatants from L. crispatus exhibited greater E. coli inhibitory activity compared to supernatants obtained from L. iners or G. vaginalis. Notably, the E. coli inhibitory activity varied among different strains of L. crispatus. CONCLUSION: Microbiome communities with abundant L. crispatus likely contribute to the E. coli inhibitory activity of vaginal secretions and efforts to promote this environment may prevent E. coli colonization and related sequelae including preterm birth. PMID- 24805367 TI - Combined source apportionment and degradation quantification of organic pollutants with CSIA: 2. Model validation and application. AB - Compound-specific stable isotope analysis (CSIA) has proven a useful tool for the quantification of the extent of degradation (QED), and for source identification and source apportionment (SA) in contaminated environmental systems. However, the simultaneous occurrence of degradation processes and mixing of emission sources complicates the use of CSIA in combined SA and QED. In a companion study, we developed a mathematical model that allows for combined SA and QED of organic pollutants (and inorganic compounds such as nitrate) in a scenario of two emission sources and degradation via one reaction pathway. This work presents a validation of the model against virtual data from a two-dimensional reactive transport model. The model calculations for SA and QED were in good agreement with the simulation results, which suggests the correctness of the model assumptions. However, the application of the model to field data of benzene contamination was challenged by large uncertainties in CSIA data and the unknown interplay between competing degradation pathways. Nonetheless, the use of the model allowed for the identification of a prevailing contribution of one emission source and revealed a low overall extent of degradation at the field site. This indicates that the model can, for example, facilitate the characterization of air pollution or aquifer contamination with organic pollutants. PMID- 24805368 TI - Development of an allele-specific PCR assay for simultaneous sero-typing of avian pathogenic Escherichia coli predominant O1, O2, O18 and O78 strains. AB - Systemic infections by avian pathogenic Escherichia coli (APEC) are economically devastating to poultry industries worldwide. E. coli strains belonging to serotypes O1, O2, O18 and O78 are preferentially associated with avian colibacillosis. The rfb gene cluster controlling O antigen synthesis is usually various among different E. coli serotypes. In present study, the rfb gene clusters of E. coli serotypes O1, O2, O18 and O78 were characterized and compared. Based on the serotype-specific genes in rfb gene cluster, an allele specific polymerase chain reaction (PCR) assay was developed. This PCR assay was highly specific and reliable for sero-typing of APEC O1, O2, O18 and O78 strains. The sensitivity of the assay was determined as 10 pg DNA or 10 colony forming units (CFUs) bacteria for serotypes O2 and O18 strains, and 500 pg DNA or 1,000 CFUs bacteria for serotypes O1 and O78 strains. Using this PCR system, APEC isolates and the infected tissue samples were categorized successfully. Furthermore, it was able to differentiate the serotypes for the samples with multi-agglutination in the traditional serum agglutination assay. Therefore, the allele-specific PCR is more simple, rapid and accurate assay for APEC diagnosis, epidemiologic study and vaccine development. PMID- 24805369 TI - Diploid hybrid origin of Ostryopsis intermedia (Betulaceae) in the Qinghai-Tibet Plateau triggered by Quaternary climate change. AB - Despite the well-known effects that Quaternary climate oscillations had on shaping intraspecific diversity, their role in driving homoploid hybrid speciation is less clear. Here, we examine their importance in the putative homoploid hybrid origin and evolution of Ostryopsis intermedia, a diploid species occurring in the Qinghai-Tibet Plateau (QTP), a biodiversity hotspot. We investigated interspecific relationships between this species and its only other congeners, O. davidiana and O. nobilis, based on four sets of nuclear and chloroplast population genetic data and tested alternative speciation hypotheses. All nuclear data distinguished the three species clearly and supported a close relationship between O. intermedia and the disjunctly distributed O. davidiana. Chloroplast DNA sequence variation identified two tentative lineages, which distinguished O. intermedia from O. davidiana; however, both were present in O. nobilis. Admixture analyses of genetic polymorphisms at 20 SSR loci and sequence variation at 11 nuclear loci and approximate Bayesian computation (ABC) tests supported the hypothesis that O. intermedia originated by homoploid hybrid speciation from O. davidiana and O. nobilis. We further estimated that O. davidiana and O. nobilis diverged 6-11 Ma, while O. intermedia originated 0.5-1.2 Ma when O. davidiana is believed to have migrated southward, contacted and hybridized with O. nobilis possibly during the largest Quaternary glaciation that occurred in this region. Our findings highlight the importance of Quaternary climate change in the QTP in causing hybrid speciation in this important biodiversity hotspot. PMID- 24805371 TI - [Reflections on the topic of good housing conditions and growing old: Not everybody has a choice]. AB - BACKGROUND: The variety of options with regard to housing for elderly people has increased. This study was carried out to understand how individuals reflect on their own options within this growing market. MATERIAL AND METHODS: In a qualitative study design 26 single person households (65+ years) were interviewed. The aim of the study was to understand what influences the individual ideas about moving residence or staying put. RESULTS: A great majority of the elderly seem to reflect on their own living situation. There are not just spatial and constructional reasons that make people consider moving residence but also the financial situation, the possibility to spend the day with meaningful activities and the existence of a social network. The individual need for security and autonomy for the present and the future influences the interpretation of a given situation. CONCLUSION: The reflection on ones own housing situation is interlinked with the person's ability and capacity. One can only find solutions if one can think of them and one can only act if one has the potential. PMID- 24805373 TI - Ag-decorated TiO2 photocatalytic membrane with hierarchical architecture: photocatalytic and anti-bacterial activities. AB - Ag-decorated TiO2 (Ag-TiO2) photocatalytic membranes have been fabricated by using Pluronic P-123 as a pore-forming and structure-directing agent. Six different hierarchical architectures were obtained by multilayer coating of different Ag-TiO2 sols. The porous structure of the resulting layers could be fine-tuned by altering the amounts of P-123 and AgNO3 added during the preparation of TiO2 sols. Physico-chemical and morphological properties of different Ag-TiO2 layers were thoroughly investigated. Ag nanoparticles were successfully incorporated into the TiO2 matrix. The Ag-TiO2 membranes possessed multi-functionality of membrane retention, Ag-enhanced TiO2 photocatalytic activity and anti-bacterial action. They were evaluated through experiments using a batch reactor and a photocatalytic membrane reactor (PMR). The best performing membrane was able to remove up to 1007 mg m(-2) h(-1) of Rhodamine B in the PMR. Two phenomena (photocatalytic degradation and adsorptive-membrane retention) that were responsible for the RhB removal were evaluated. In the batch reactor operated in dark, the membranes were able to remove greater than 5-logs of Escherichia coli. The membrane with the highest percentage of Ag incorporated was able to remove close to 7-logs of E. coli when operated in the PMR. PMID- 24805374 TI - Trihalomethanes in marine mammal aquaria: occurrences, sources, and health risks. AB - Disinfecting water containing the high levels of dissolved organic carbon (DOC) commonly generated during pinniped husbandry may cause the formation of carcinogenic disinfection byproducts (DBPs). Little information is available on DBP levels, sources, and health risks in marine mammal aquaria. Using the commonly observed trihalomethanes (THMs) as a DBP indicator, we monitored concentrations for seven months at The Marine Mammal Center in Sausalito, California, one of the largest pinniped rehabilitation facilities in the world. Concentrations of THMs ranged 1.1-144.2 MUg/L in pool waters and generally increased with number of animals housed (P < 0.05). To identify the sources of THM precursors in marine mammal aquaria, we intensively monitored the mass flows of potential THM precursors (i.e. food and wastes) in an isolated system with nine individual California sea lions to evaluate the sources and reactivity of dissolved organic carbon (DOC) for 2-5 weeks. The common frozen foods used in feeding pinnipeds, including herring, sardine, and squid, produced an average of 22-34 mg-DOC/g-food in water and 836-1066 MUg-THM/g-food after chlorination, whereas the fecal materials, including fresh scat, decomposed scat, and urine, produced 2-16 mg-DOC/g-waste and 116-768 MUg-THM/g-waste. Food not eaten by animals could cause a sharp increase of DOC and DBP production and therefore should be removed rapidly from pools. Marine mammal husbandry staff and trainers are at risk (5.16 * 10(-4) to 1.30 * 10(-3)) through exposure of THMs, exceeding the negligible risk level (10(-6)) defined by the US Environmental Protection Agency. PMID- 24805772 TI - What are the preferred horizontal displacements of aromatic-aromatic interactions in proteins? Comparison with the calculated benzene-benzene potential energy surface. AB - The data from protein structures from the Protein Data Bank and quantum chemical calculations indicate the importance of aromatic-aromatic interactions at large horizontal displacements (offsets). The protein stacking interactions of the phenylalanine residue show preference for large offsets (3.5-5.0 A), while the calculations show substantially strong interactions, of about -2.0 kcal mol(-1). PMID- 24805773 TI - Uremic toxin p-cresol induces Akt-pathway-selective insulin resistance in bone marrow-derived mesenchymal stem cells. AB - We reported a functional incompetence in mesenchymal stem cells (MSCs) under uremia, but the mechanisms have not been explored. To study the mechanisms of dysfunctional MSCs induced by uremia, we characterized insulin signaling in MSCs and investigated the effect of uremic toxin, p-cresol, on the proangiogenic actions of insulin. In MSCs, insulin induced hypoxia-inducible factor (HIF) 1alpha, vascular endothelial growth factor, and stromal cell-derived factor 1alpha expressions via PI3K/Akt-dependent pathway. MSCs treated with p-cresol exhibited altered insulin signaling in a selective manner for insulin receptor substrate-1/PI3K/Akt pathway, whereas ERK pathway remained active. The insulin induced increase of HIF-1alpha was blunted by p-cresol treatment. This Akt selective insulin resistance was also observed in MSCs isolated from chronic kidney disease (CKD) mice. In mice model of hindlimb ischemia, blood flow recovery, capillary density, and local production of angiogenic factors in the ischemic limb treated with CKD MSCs were significantly inferior to those promoted by control MSCs. However, modifying CKD MSCs by overexpression of HIF-1alpha restored all of these changes. Taken together, these data suggest that p-cresol contributes to insulin resistance in a selective manner for Akt pathway. This might be a biological explanation for the functional incompetence of MSCs under uremia through defects in the insulin-induced elevation of HIF-1alpha protein expression. PMID- 24805774 TI - The clinical significance of downregulation of mir-124-3p, mir-146a-5p, mir-155 5p and mir-335-5p in gastric cancer tumorigenesis. AB - Dysregulated miRNAs in gastric cancer are usually screened by miRNA microarray from clinical samples, however, reports have indicated that results of each miRNA microarray screening are considerably different, and dysregulated miRNAs, especially downregulated miRNAs were contradictory. In view of this, the Human Cancer Pathway Finder miRNA PCR array was applied to compare 7 gastric cancer cell lines AGS, SGC-7901, MKN-45, MKN-28, MGC-803, BCG-823, and HGC-27 with an immortalized normal gastric cell line, GES-1 in cancer pathway-related miRNA expression profile, followed by qPCR verification, the clinical significance of downregulated miRNAs and the Enriched KEGG pathways and GO terms of their target genes were analyzed. Thirty-eight miRNAs were upregulated, and four miRNAs were downregulated in gastric cancer cell lines. Clinical significance of 4 miRNAs including mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p in gastric cancer tissue compared with adjacent non-tumor tissues of 58 patients indicated that the low-expression group of mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p showed more extensive lymph node metastasis, lymphatic invasion, venous invasion, high stage Borrmann type, lymphatic invasion and poor differentiation than that of the high-expression groups, respectively (P<0.05; chi2 test). Enriched KEGG pathway analyses showed that most of the targeted genes of the 4 miRNAs concentrated on 37 signaling pathways, and were involved in the same pathways related to cancer. Enriched GO terms showed that targeted genes of the 4 miRNAs concentrated on 339 terms, 24 of 339 terms are associated with cancer tumorigenesis. The Human Cancer Pathway Finder miRNA PCR array could be used to screen dysregulated miRNAs effectively, and 4 screened miRNAs, mir-124-3p, mir-146a-5p, mir-155-5p and mir 335-5p were found to be downregulated in gastric cancer. Clinical significance and bioinformatic analysis on the target genes of these 4 miRNAs indicated that they were deeply involved in tumorigenesis, suggesting roles such as miRNA tumor suppressors in gastric cancer tumorigenesis which could be applied in gastric cancer diagnosis and prognosis. PMID- 24805775 TI - The differential influence of vowels and palatal covering on nasalance scores. AB - Objective : To investigate whether nasalance scores would differ when the hard palate and soft palate were covered during speech. Design : Nasalance scores were obtained during production of sentence stimuli loaded with differing vowel content across three conditions: (1) hard and soft palate uncovered (U); (2) hard palate covered by acrylic appliance (H); (3) both hard and soft palate covered by acrylic appliance (B). Sentences were loaded with high front, low front, high back, low back, or mixed vowels. Velopharyngeal closure was verified by nasoendoscopy. Participants : Six female adults with normal speech and resonance provided the speech samples. Main Outcome Measures : Nasalance scores for each of five sentences in each of three palatal conditions. Results : Mixed and high front sentences had significantly higher mean nasalance scores in the U (P < .01) and H (P < .05) conditions but not in the B condition. For all sentence stimuli combined across palatal conditions, there was a significant difference in mean nasalance scores between H and B conditions (P < .05) but not between the U condition and either the H or B conditions (P > .05). Conclusions : Data suggest that the primary place of transpalatal transfer of acoustic energy was the soft palate but only sentences with high-front vowels were affected by this phenomenon. PMID- 24805776 TI - Radioulnar Synostosis and Brain Abnormalities in a Patient With 17q21.31 Microdeletion Involving EFTUD2. AB - Mandibulofacial dysostosis with microcephaly is a rare syndromic craniofacial condition caused by heterozygous loss-of-function mutations of the EFTUD2 gene on 17q21.31. Thus far, the described musculoskeletal findings in patients with this condition include proximally placed or duplicated thumbs, overlapping toes, and toe syndactyly. We describe a severe case of a patient with a 17q21.31 microdeletion and many of the phenotypic features described in mandibulofacial dysostosis with microcephaly who had bilateral proximal radioulnar synostosis and brain abnormalities. This provides further evidence of the clinical overlap among mandibulofacial and acrofacial dysostoses syndromes and expands the phenotype of EFTUD2 haploinsufficiency due to larger deletions. PMID- 24805777 TI - Photocatalytic degradation of organic dyes by La3+/Ce3+-H3PW12O40 under different light irradiation. AB - New photocatalysts (La(3+)-H3PW12O40 and Ce(3+)-H3PW12O40) were prepared, and the degradation activity of these products was evaluated. These photocatalysts were synthesized by the hydrothermal method assisted by PEG-1000 from the reactions of LaCl3 or CeCl3 and phosphotungstic acid. The prepared catalysts were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), ultraviolet-visible diffuse reflection spectroscopy (UV-vis) and thermal gravimetric analysis (TGA). The catalytic activity of La(3+)-H3PW12O40 and Ce(3+)-H3PW12O40 was evaluated by adopting methyl orange (MO) and Rhodamine B (RhB) as model dyes, and the reaction was carried out under UV- and visible light irradiation. PMID- 24805778 TI - Label-free quantitative proteomics and N-terminal analysis of human metastatic lung cancer cells. AB - Proteomic analysis is helpful in identifying cancer-associated proteins that are differentially expressed and fragmented that can be annotated as dysregulated networks and pathways during metastasis. To examine meta-static process in lung cancer, we performed a proteomics study by label-free quantitative analysis and N terminal analysis in 2 human non-small-cell lung cancer cell lines with disparate metastatic potentials-NCI--H1703 (primary cell, stage I) and NCI-H1755 (metastatic cell, stage IV). We identified 2130 proteins, 1355 of which were common to both cell lines. In the label-free quantitative analysis, we used the NSAF normalization method, resulting in 242 differential expressed proteins. For the N-terminal proteome analysis, 325 N-terminal peptides, including 45 novel fragments, were identified in the 2 cell lines. Based on two proteomic analysis, 11 quantitatively expressed proteins and 8 N-terminal peptides were enriched for the focal adhesion pathway. Most proteins from the quantitative analysis were upregulated in metastatic cancer cells, whereas novel fragment of CRKL was detected only in primary cancer cells. This study increases our understanding of the NSCLC metastasis proteome. PMID- 24805779 TI - A revised assay for monitoring autophagic flux in Arabidopsis thaliana reveals involvement of AUTOPHAGY-RELATED9 in autophagy. AB - Autophagy targets cytoplasmic cargo to a lytic compartment for degradation. Autophagy-related (Atg) proteins, including the transmembrane protein Atg9, are involved in different steps of autophagy in yeast and mammalian cells. Functional classification of core Atg proteins in plants has not been clearly confirmed, partly because of the limited availability of reliable assays for monitoring autophagic flux. By using proUBQ10-GFP-ATG8a as an autophagic marker, we showed that autophagic flux is reduced but not completely compromised in Arabidopsis thaliana atg9 mutants. In contrast, we confirmed full inhibition of autophagic flux in atg7 and that the difference in autophagy was consistent with the differences in mutant phenotypes such as hypersensitivity to nutrient stress and selective autophagy. Autophagic flux is also reduced by an inhibitor of phosphatidylinositol kinase. Our data indicated that atg9 is phenotypically distinct from atg7 and atg2 in Arabidopsis, and we proposed that ATG9 and phosphatidylinositol kinase activity contribute to efficient autophagy in Arabidopsis. PMID- 24805780 TI - Synthesis of novel fluoro analogues of MKC442 as microbicides. AB - Novel analogues of MKC442 (6-benzyl-1-(ethoxymethyl)-5-isopropylpyrimidine 2,4(1H,3H)-dione) were synthesized by reaction of 6-[(3,5 dimethylphenyl)fluoromethyl]-5-ethyluracil (5) with ethoxymethyl chloride and formaldehyde acetals. The Sonogashira reaction was carried out on the N1-(p iodobenzyl)oxy]methyl derivative of compound 5 using propagyl alcohol to afford compound 12 (YML220). The latter compound was selected for further studies since it showed the most potent and selective activity in vitro against wild-type HIV-1 and non-nucleoside reverse transcriptase inhibitor-, nucleoside reverse transcriptase inhibitor-, and protease inhibitor-resistant mutants and a wide range of HIV-1 clinical isolates. 12 also showed microbicidal activity in long term assays with heavily infected MT-4 cells. PMID- 24805781 TI - Supramolecular tetrad featuring covalently linked bis(porphyrin)-phthalocyanine coordinated to fullerene: construction and photochemical studies. AB - A multimodular donor-acceptor tetrad featuring a bis(zinc porphyrin)-(zinc phthalocyanine) ((ZnP-ZnP)-ZnPc) triad and bis-pyridine-functionalized fullerene was assembled by a "two-point" binding strategy, and investigated as a charge separating photosynthetic antenna-reaction center mimic. The spectral and computational studies suggested that the mode of binding of the bis-pyridine functionalized fullerene involves either one of the zinc porphyrin and zinc phthalocyanine (Pc) entities of the triad or both zinc porphyrin entities leaving ZnPc unbound. The binding constant evaluated by constructing a Benesi-Hildebrand plot by using the optical data was found to be 1.17*10(5) M(-1), whereas a plot of "mole-ratio" method revealed a 1:1 stoichiometry for the supramolecular tetrad. The mode of binding was further supported by differential pulse voltammetry studies, in which redox modulation of both zinc porphyrin and zinc phthalocyanine entities was observed. The geometry of the tetrad was deduced by B3LYP/6-31G* optimization, whereas the energy levels for different photochemical events was established by using data from the optical absorption and emission, and electrochemical studies. Excitation of the zinc porphyrin entity of the triad and tetrad revealed ultrafast singlet-singlet energy transfer to the appended zinc phthalocyanine. The estimated rate of energy transfer (k(ENT)) in the case of the triad was found to be 7.5*10(11) s(-1) in toluene and 6.3*10(11) s(-1) in o-dichlorobenzene, respectively. As was predicted from the energy levels, photoinduced electron transfer from the energy-transfer product, that is, singlet excited zinc phthalocyanine to fullerene was verified from the femtosecond transient spectral studies, both in o-dichlorobenzene and toluene. Transient bands corresponding to ZnPc(?+) in the 850 nm range and C60(?-) in the 1020 nm range were clearly observed. The rate of charge separation, k(CS), and rate of charge recombination, k(CR), for the (ZnP-ZnP)-ZnPc(?+):Py2C60(?-) radical ion pair (from the time profile of 849 nm peak) were found to be 2.20*10(11) and 6.10*10(8) s(-1) in toluene, and 6.82*10(11) and 1.20*10(9) s(-1) in o dichlorobenzene, respectively. These results revealed efficient energy transfer followed by charge separation in the newly assembled supramolecular tetrad. PMID- 24805782 TI - To see or not to see: investigating detectability of Ganges River dolphins using a combined visual-acoustic survey. AB - Detection of animals during visual surveys is rarely perfect or constant, and failure to account for imperfect detectability affects the accuracy of abundance estimates. Freshwater cetaceans are among the most threatened group of mammals, and visual surveys are a commonly employed method for estimating population size despite concerns over imperfect and unquantified detectability. We used a combined visual-acoustic survey to estimate detectability of Ganges River dolphins (Platanista gangetica gangetica) in four waterways of southern Bangladesh. The combined visual-acoustic survey resulted in consistently higher detectability than a single observer-team visual survey, thereby improving power to detect trends. Visual detectability was particularly low for dolphins close to meanders where these habitat features temporarily block the view of the preceding river surface. This systematic bias in detectability during visual-only surveys may lead researchers to underestimate the importance of heavily meandering river reaches. Although the benefits of acoustic surveys are increasingly recognised for marine cetaceans, they have not been widely used for monitoring abundance of freshwater cetaceans due to perceived costs and technical skill requirements. We show that acoustic surveys are in fact a relatively cost-effective approach for surveying freshwater cetaceans, once it is acknowledged that methods that do not account for imperfect detectability are of limited value for monitoring. PMID- 24805783 TI - Did parents and teachers struggle with child survivors 20 months after the 2011 earthquake and tsunami in Japan? A retrospective observational study. AB - BACKGROUND: On March 11, 2011, Japan was struck by the earthquake and tsunami. Twenty months after the disaster, we collected information on the difficulties faced by parents and teachers in dealing with the post-traumatic symptoms of child survivors. The aim of this study was to evaluate the relationship between post-traumatic symptoms in children and parents' and teachers' difficulties in dealing with children who survived the huge disaster. METHODS: The subjects included 12,524 children from elementary, middle, and junior high schools in Ishinomaki City. The Post Traumatic Stress Symptoms for Children 15 items (PTSSC 15), a self-rating questionnaire on post-traumatic symptoms, was distributed among the children, and Strength and Difficulties Questionnaire (SDQ), a self rating questionnaire on difficulties in dealing with children, was given to their parents and teachers. With PTSSC-15, a valid response was obtained from 10,909 (89.5%) participants. With SDQ for teachers and parents, valid responses were obtained from 10,577 (86.7%) and 7052 (83.9%) participants, respectively. RESULTS: PTSSC-15 scores were significantly higher (P<0.001) in girls than in boys from the junior high school. These effect sizes were less than 0.30. Correlations of teachers' SDQ scores and PTSSC-15 scores were significantly low (r<0.21, P<0.001) for both genders and all children. Likewise, correlations between SDQ scores assigned by parents (excluding "prosocial behavior") and PTSSC 15 scores were significantly low (r<0.21, P<0.001) for both genders and at all school levels. CONCLUSION: This study elucidated that the difficulties faced by parents and teachers while dealing with child survivors significantly low correlate with the child's post-traumatic symptoms caused by the 2011 earthquake and tsunami. Thus, it is important that clinicians should not only evaluate post traumatic symptoms with a self-rating questionnaire but also try to objectively evaluate whether there were day-to-day difficulties caused by the post-traumatic symptoms. PMID- 24805784 TI - Age-specific cancer incidence rates increase through the oldest age groups. AB - BACKGROUND: In the United States, from 2005 to 2009, nearly 8% of all cancers diagnosed and 15% of cancer deaths occurred in individuals aged 85 years and older (85+ age group). With the aging of the U.S. population, an analysis of incidence of cancer in the elderly population may provide information for clinical care and resource allocation. MATERIALS AND METHODS: Previously reported data were retrieved from the Surveillance Epidemiology and End Results (SEER) 18 Registry for years 2000 to 2010 and Central Brain Tumor Registry of the United States (CBTRUS) for years 2004 to 2008. Cancers included invasive cases only, except for nonmalignant meningiomas, and rates were per 100,000. RESULTS: The age specific cancer incidence rate (IR) increases with age until a decrease in the 85+ age group. IR for all cancers combined for this age group was 2,317 per 100,000. Statistically, males had significantly higher IR compared with females (3,194 versus 1,911 [P<=0.0001]). Blacks had an IR similar to whites (2,255 versus 2,340 [P=0.12]). Despite a drop in the overall IR in this oldest age group, IR for certain cancers continued to increase. Among these cancers, gastrointestinal cancers like colorectal, pancreatic and stomach had the highest incidence and mortality rates. CONCLUSIONS: This study contributes to measuring cancer burden in the oldest old population. In certain cancers, including meningiomas, the IR continues to rise with advancing age. Management of cancer in elderly is challenging and screening persons in the 85+ age group for frailty very thoroughly may help guide decisions of palliative versus aggressive therapies. PMID- 24805785 TI - New insight into volume overload and hepatorenal syndrome in cirrhosis, "the hepatorenal reflex hypothesis". AB - Increased kidney absorption of salt and solute-free water resulting in volume overload is frequently observed in cirrhosis, especially with progression of the disease. Although diuretic therapy is able to control volume overload in the early stages of cirrhosis, it fails in a significant proportion of patients in late stages, giving rise to a situation termed "diuretic resistant ascites." This situation represents a state of functional renal failure called hepatorenal syndrome, which is further classified into 2 subgroups based on the severity of renal failure. Although many proposed stimuli have been suggested in the past to explain the pathophysiology behind this maladaptive renal response to advanced liver disease, the peripheral arterial vasodilation hypothesis has been the one that gained wide popularity. Nevertheless, many pieces of evidence, both old and new, are not completely compatible with this hypothesis, suggesting that vascular bed vasodilation in cirrhosis could be a consequence of blood shunting from the portal to the systemic circulations rather than an etiology for volume overload. At the same time, an accumulating body of evidence has been pointing toward a direct interaction between the liver and the kidneys that may have an etiologic role for volume overload. Therefore, looking for a new hypothesis for volume overload in cirrhotics is of paramount importance to explain the pathophysiology behind this neat observation and to understand the available options to deal with this morbid complication of cirrhosis. PMID- 24805786 TI - Statins and hepatitis C virus infection: an old therapy with new scope. AB - Although their safety and efficacy have been extensively demonstrated, significant underutilization of statins is frequently seen in clinical practice for fears of hepatotoxicity. Research has not only shown statins' safety in patients with various forms of liver disease but also revealed the great benefits conferred by such therapy among liver disease patients. Chronic hepatitis C virus (HCV) infection is not an exception. In fact, evidence has pointed to a dysmetabolic syndrome in HCV-infected patients, which places them at an increased risk for cardiovascular disease and makes statins a life-saving therapy with excellent efficacy. Furthermore, statins have shown anti-HCV proliferative effects and other beneficial roles in different aspects of liver health, making them excellent drugs with minimal risks. In this review, we have discussed the newly described dysmetabolic syndrome associated with HCV infection, statins safety and efficacy in patients with chronic liver disease with special emphasis on HCV patients, the anti-HCV-proliferative effects of statins and finally, the benefits of statin therapy in other aspects of chronic liver disease. PMID- 24805787 TI - Unusual PET Images: Metastatic Squamous Cell Carcinoma. PMID- 24805788 TI - Predictive factors of outcomes in personalized radioactive iodine ((131)I) treatment for Graves' disease. AB - BACKGROUND: Graves' disease (GD) is the most common cause of hyperthyroidism in iodine-sufficient areas. Radioactive iodine I treatment (RIT), as the 1st therapeutic option, is widely accepted by doctors and patients. The aim of this study was to investigate factors influencing the success rate of calculated RIT in GD. METHODS: Thyroid function outcome (hyperthyroidism or euthyroidism/hypothyroidism) was verified retrospectively at least 1 year after RIT and was compared with presenting clinical characteristics and pre-RIT parameters in 167 patients with GD treated with I-iodide in the authors' institute. RESULTS: After RIT, 83 patients (49.7%) became euthyroid, 64 patients (38.3%) became hypothyroid and 20 (12.0%) remained hyperthyroid. Multiple logistic regression analyses demonstrated that there was no statistically significant association between RIT outcomes and sex, age, history of GD, previous antithyroid drug treatment, thyroid hormone levels, thyroid gland mass or radioactive iodine I dosage. The only variables associated with the success rate were the course of disease over 6 months (odds ratio, 3.70; confidence interval, 1.75-7.17; P = 0.014) and 2-hour radioactive iodine uptake (RAIU) >58.5% (odds ratio, 4.08; confidence interval, 2.03-7.83; P = 0.005). CONCLUSIONS: Our study has shown that a calculated approach for the treatment of GD was effective, but high failure rates were observed in patients presenting higher 2-hour RAIU, particularly those with 2-hour RAIU of more than 58.5%. PMID- 24805789 TI - Presentation of the 2014 Founders' Medal Award. PMID- 24805790 TI - Association of serum androgen concentrations with cardiovascular risk factors in elderly male patients with chronic systolic heart failure in China. AB - OBJECTIVE: To survey the serum androgen concentrations and investigate the relationship between androgen levels and cardiovascular risk factors in elderly male patients with chronic systolic heart failure (HF) in China. METHODS: 106 consecutive male patients hospitalized for chronic systolic HF aged from 60 to 87 were enrolled. About 400 healthy age-matched men were compared as a control group. Total testosterone (TT), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. Differences of androgen levels between HF patients and healthy men were determined by t-test and associations of androgen with cardiovascular risk factors were evaluated by partial correlations analyses. RESULTS: Compared with healthy men, TT, FT and DHEAS levels in patients with HF decreased, whereas SHBG level increased significantly (both p < 0.01). TT was negatively correlated with TC, TG and DBP (p < 0.05), FT was negatively correlated with TC, LDL-C and DBP (p < 0.05). SHBG correlated with BMI and smoking history positively (p < 0.05). CONCLUSIONS: Level of bio-available testosterone decreased with advancing age, especially in men with HF. Men with low levels of bio-available testosterone had worse profiles of cardiovascular risk factors. Treatment of HF is still challenging and testosterone supplementation therapy may be an effective therapeutic option. PMID- 24805791 TI - A wide range of 3243A>G/tRNALeu(UUR) (MELAS) mutation loads may segregate in offspring through the female germline bottleneck. AB - Segregation of mutant mtDNA in human tissues and through the germline is debated, with no consensus about the nature and size of the bottleneck hypothesized to explain rapid generational shifts in mutant loads. We investigated two maternal lineages with an apparently different inheritance pattern of the same pathogenic mtDNA 3243A>G/tRNALeu(UUR) (MELAS) mutation. We collected blood cells, muscle biopsies, urinary epithelium and hair follicles from 20 individuals, as well as oocytes and an ovarian biopsy from one female mutation carrier, all belonging to the two maternal lineages to assess mutant mtDNA load, and calculated the theoretical germline bottleneck size (number of segregating units). We also evaluated "mother-to-offspring" segregations from the literature, for which heteroplasmy assessment was available in at least three siblings besides the proband. Our results showed that mutation load was prevalent in skeletal muscle and urinary epithelium, whereas in blood cells there was an inverse correlation with age, as previously reported. The histoenzymatic staining of the ovarian biopsy failed to show any cytochrome-c-oxidase defective oocyte. Analysis of four oocytes and one offspring from the same unaffected mother of the first family showed intermediate heteroplasmic mutant loads (10% to 75%), whereas very skewed loads of mutant mtDNA (0% or 81%) were detected in five offspring of another unaffected mother from the second family. Bottleneck size was 89 segregating units for the first mother and 84 for the second. This was remarkably close to 88, the number of "segregating units" in the "mother-to-offspring" segregations retrieved from literature. In conclusion, a wide range of mutant loads may be found in offspring tissues and oocytes, resulting from a similar theoretical bottleneck size. PMID- 24805793 TI - Field evaluation of the response of Aedes albopictus (Stegomyia albopicta) to three oviposition attractants and different ovitrap placements using black and clear autocidal ovitraps in a rural area of Same, Timor-Leste. AB - Known oviposition attractants or stimulants were compared, singly and in combination, using inexpensive autocidal ovitraps designed to trap emerging adults, in a rural area of Timor-Leste during the dry season. In this area, the dengue vector Aedes albopictus (Stegomyia albopicta) Skuse (Diptera: Culicidae) was abundant, but Aedes aegypti (Stegomyia aegypti) L. was not detected. The attractants were: (a) a compound found in Aedes eggs (dodecanoic acid); (b) components of nitrogen, phosphorous and potassium-based (NPK) fertilizer, and (c) infusions of discarded cigarette butts. A solution of ammonium phosphate and potassium nitrate was significantly more attractive to gravid Ae. albopictus than water only. Dodecanoic acid and cigarette butt infusions were not significantly more attractive than the control; however, they attracted various other Diptera and many non-culicid larvae developed in ovitraps in which these substances were used; thus, the presence of eggs or larvae of other species may have deterred Aedes oviposition. Significantly more Aedes eggs were found in ovitraps under vegetation than in ovitraps placed inside houses or against external walls. Clear sided ovitraps in which black mesh was placed over a black ring floating on the water surface collected significantly fewer eggs than black ovitraps with identically placed mesh and rings. PMID- 24805794 TI - Design of a multi-dopamine-modified polymer ligand optimally suited for interfacing magnetic nanoparticles with biological systems. AB - We have designed a set of multifunctional and multicoordinating polymer ligands that are optimally suited for surface functionalizing iron oxide and potentially other magnetic nanoparticles (NPs) and promoting their integration into biological systems. The amphiphilic polymers are prepared by coupling (via nucleophilic addition) several amine-terminated dopamine anchoring groups, poly(ethylene glycol) moieties, and reactive groups onto a poly(isobutylene-alt maleic anhydride) (PIMA) chain. This design greatly benefits from the highly efficient and reagent-free one-step reaction of maleic anhydride groups with amine-containing molecules. The availability of several dopamine groups in the same ligand greatly enhances the ligand affinity, via multiple coordination, to the magnetic NPs, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation with target biomolecules. Iron oxide nanoparticles ligand exchanged with these polymer ligands have a compact hydrodynamic size and exhibit enhanced long-term colloidal stability over the pH range of 4-12 and in the presence of excess electrolytes. Nanoparticles ligated with terminally reactive polymers have been easily coupled to target dyes and tested in live cell imaging with no measurable cytotoxicity. Finally, the resulting hydrophilic nanoparticles exhibit large and size-dependent r2 relaxivity values. PMID- 24805795 TI - Brief report: impact of child problem behaviors and parental broad autism phenotype traits on substance use among parents of children with ASD. AB - Using data from the Simons Simplex Collection, the present study examined the impact of child externalizing behavior and parental broad autism phenotype traits on substance use among parents of children with autism spectrum disorder (n = 2,388). For both fathers and mothers, child externalizing behaviors predicted tobacco use (OR = 1.01 and OR = 1.02, respectively), whereas rigidity increased risk of tobacco use for fathers (OR = 1.29) but not mothers. Additionally, among mothers, child externalizing behaviors increased risk of illegal substance use (OR = 1.04), whereas maternal rigidity decreased risk of alcohol use (OR = .83). Collectively, results suggest that child externalizing behaviors and parental rigidity may have differing impacts on the types of substances used by parents. PMID- 24805798 TI - [Molecular imaging in oncological surgery: technical principles and importance]. AB - BACKGROUND: Diagnostic imaging with positron emission tomography (PET) is becoming increasingly more involved in oncological therapy management. OBJECTIVES: How can PET be helpful in oncological surgery? METHODS: After a short introduction into the basic principles of PET the current state of imaging as well as indications and limitations of the method are described. RESULTS: The PET is a functional and quantitative imaging technique, enabling detection and characterization of tumors. It is applied in pretherapeutic staging as well as in follow-up and therapy assessment. The use of PET changes the therapy management in about one third of all oncology patients. New radiopharmaceuticals and novel technologies expand the diagnostic potential. DISCUSSION: Hybrid imaging with PET computed tomography (CT) and PET magnetic resonance imaging (MRI) further improves diagnostic imaging and increases the acceptance of PET further. PMID- 24805799 TI - Molecular epidemiology of noroviruses in Northern Greece, 2005-2006. AB - Noroviruses (NoVs) are important human pathogens associated with acute viral gastroenteritis worldwide, displaying significant genetic heterogeneity. Genotype GII.4 is responsible for the majority of outbreaks reported to date. A total of 460 faecal samples from sporadic gastroenteritis cases were screened for the presence of NoV RNA. Four additional human samples collected during a waterborne NoV gastroenteritis outbreak observed in 2005 in northern Greece, were also included in the study. All PCR-positive samples were tested further using a multiplex RT-PCR, which targets the viral capsid VP1 region D. PCR products from all outbreak samples and from 20 randomly selected samples were sequenced. Phylogenetic analysis revealed that GII.4 genotype predominated (70%), while genotypes GII.2 (10%), GII.7 (15%), and GI.1 (5%) were also detected. All the outbreak NoV strains belonged to the GI.1 genotype. The present study provides a first insight into the epidemiology and genetic diversity of NoVs in Greece and shows that various strains are circulating in the country and cause sporadic cases or outbreaks. PMID- 24805797 TI - Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. AB - BACKGROUND: Despite omega-3 polyunsaturated fatty acids (PUFA) supplementation in depressed patients have been suggested to improve depressive symptomatology, previous findings are not univocal. OBJECTIVES: To conduct an updated meta analysis of randomized controlled trials (RCTs) of omega-3 PUFA treatment of depressive disorders, taking into account the clinical differences among patients included in the studies. METHODS: A search on MEDLINE, EMBASE, PsycInfo, and the Cochrane Database of RCTs using omega-3 PUFA on patients with depressive symptoms published up to August 2013 was performed. Standardized mean difference in clinical measure of depression severity was primary outcome. Type of omega-3 used (particularly eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and omega-3 as mono- or adjuvant therapy was also examined. Meta-regression analyses assessed the effects of study size, baseline depression severity, trial duration, dose of omega-3, and age of patients. RESULTS: Meta-analysis of 11 and 8 trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo (standardized difference in random-effects model 0.56 SD [95% CI: 0.20, 0.92] and 0.22 SD [95% CI: 0.01, 0.43], respectively; pooled analysis was 0.38 SD [95% CI: 0.18, 0.59]). Use of mainly EPA within the preparation, rather than DHA, influenced final clinical efficacy. Significant clinical efficacy had the use of omega-3 PUFA as adjuvant rather than mono therapy. No relation between efficacy and study size, baseline depression severity, trial duration, age of patients, and study quality was found. Omega-3 PUFA resulted effective in RCTs on patients with bipolar disorder, whereas no evidence was found for those exploring their efficacy on depressive symptoms in young populations, perinatal depression, primary disease other than depression and healthy subjects. CONCLUSIONS: The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD. PMID- 24805800 TI - Predictors of non-adherence to pharmacotherapy in patients with type 2 diabetes. AB - BACKGROUND: The prevalence of diabetes in Jordan is among the highest in the world, making it a particularly alarming health problem there. It has been indicated that poor adherence to the prescribed therapy lead to poor glycemic control and enhance the development of diabetes complications and unnecessary hospitalization. OBJECTIVE: To explore factors associated with medication nonadherence in patients with type 2 diabetes in Jordan. Findings would help guide the development of future pharmaceutical care interventions for patients with type 2 diabetes. SETTING: This study was conducted in an outpatient diabetes clinic at the Royal Medical Services Hospital. METHOD: Variables including sociodemographics, disease and therapy factors, diabetes knowledge, health related quality of life in addition to adherence assessment were collected for 171 patients with type 2 diabetes using medical records, custom-designed and validated questionnaires. Logistic regression was performed to develop a model with variables that best predicted medication non-adherence in patients with type 2 diabetes in Jordan. MAIN OUTCOME MEASURE: Variables which significantly and independently associated with medication nonadherence in patients with type 2 diabetes in Jordan. RESULTS: Patients were found four times less likely to adhere to their medications with each unit increase in the number of prescribed medications (OR = 0.244, CI = 0.08-0.63) and nine times less likely to adhere to their medications if they received more than once daily dosing of diabetic medication (OR = 0.111, CI = 0.04-2.01). Patients in the present study were also approximately three times less likely (OR = 0.362, CI = 0.24-0.87) and twice less likely (OR = 0.537, CI = 0.07-1.31) to adhere to their medications if they reported having concerns about side effects and if they were taking metformin therapy respectively. Finally, participants were found twice more likely to adhere to medications if they had one or more Microvascular complication (OR = 0.493, CI = 0.08-1.16). CONCLUSION: Simplifying dosage regimen, selecting treatments with lower side effects along with an emphasis on diabetes complications should be taken into account in future interventions designed to improve health outcomes for patients with type 2 diabetes. PMID- 24805801 TI - Frequency of use of QT-interval prolonging drugs in psychiatry in Belgium. AB - INTRODUCTION: Drug-induced QT-prolongation is an established risk factor for Torsade de pointes and sudden cardiac death. The list of QT-prolonging drugs is extensive and includes many drugs commonly used in psychiatry. AIM: In this study we performed a cross-sectional analysis of medication profiles to assess the prevalence of drug interactions potentially leading to QT-prolongation. SETTING: 6 psychiatric hospitals in Flanders, Belgium. METHODS: For each patient, the full medication list was screened for the presence of interactions, with special attention to those with an increased risk for QT-prolongation. Current practice on QT monitoring and prevention of drug-induced arrhythmia was assessed. MAIN OUTCOME MEASURE: Number of drug interactions with risk of QT-prolongation. RESULTS: 592 patients (46 % female; mean age 55.7 +/- 17.1 years) were included in the analysis. 113 QT-prolonging interactions were identified in 43 patients (7.3 %). QT-prolonging interactions occurred most frequently with antidepressants (n = 102) and antipsychotics (n = 100). The precautions and follow-up provided by the different institutions when combining QT-prolonging drugs were very diverse. CONCLUSION: Drug combinations that are associated with QT-prolongation are frequently used in the chronic psychiatric setting. Persistent efforts should be undertaken to provide caregivers with clear guidelines on how to use these drugs in a responsible and safe way. PMID- 24805802 TI - Spray-dried polyelectrolyte microparticles in oral antigen delivery: stability, biocompatibility, and cellular uptake. AB - During the past decade, extensive research has undeniably improved the formulation and delivery of oral vaccines. Nevertheless, several factors, such as the harsh gastrointestinal environment together with tolerance induction to exogenous antigens, have thus far impeded the optimal effectiveness and clinical application of oral delivery systems. The current study encompasses an initial evaluation of the stability, biocompatibility, and cellular uptake of two promising candidate systems for oral antigen delivery, that is, calcium carbonate (CP) and mannitol-templated (MP) porous microspheres. Both spray-dried formulations were efficiently internalized by human intestinal epithelial cells (Caco-2 and HT-29) and degraded into phagolysosomal intracellular compartments. In addition, cellular particle uptake and processing significantly up-regulated the expression of (HLA) class-II and costimulatory molecules on intestinal epithelial cells. Even though the high surface-area-to-volume ratio of the microspheres was expected to favor protease access, antigen release was remarkably limited in simulated intestinal fluid and was even absent under gastric conditions. Finally, neither CP nor MP exerted cytotoxicity upon prolonged in vitro incubation with high antigen concentration. Altogether, these data support the potential of CP and MP for oral antigen delivery and motivate the further development of these promising carrier systems in in vivo studies. PMID- 24805803 TI - Commissioners in Bristol face legal challenge for failing to involve patients. PMID- 24805804 TI - Coupling strategies to enhance single-molecule magnet properties of erbium cyclooctatetraenyl complexes. AB - Two different coupling strategies were employed to create Er(III) single-molecule magnets (SMMs) using high blocking temperature mononuclear precursors. The magnetic properties of three lanthanide-COT complexes, [Er(III)2(COT'')3] (1) (COT'' = 1,4-bis(trimethylsilyl)cyclooctatetraenyl dianion) and K2(THF)4[Ln(III)2(COT)4] (Ln = Gd (2), Er (3); THF = tetrahydrofuran, COT = cyclooctatetraenyl dianion), are reported. Both Er(III) complexes behave as SMMs and exhibit magnetic hysteresis at 12 K in solid state. In solution compound 1 exhibits hysteresis up to 14 K. Ac susceptibility data indicates a 100 s blocking temperature of 12.5 and 12.9 K for [Er(III)2(COT'')3] and K2(THF)4[Er(III)2(COT)4], respectively. Both Er(III) dimers display enhanced SMM properties over their mononuclear analogues due to their linear structure and strictly axial anisotropy. A 4 K increase in the magnetic blocking temperature of [Er(III)2(COT'')3] over the double-decker analogue is attributed to an additional mechanism of magnetization blocking arising from exchange coupling between Er(III) ions. PMID- 24805805 TI - Stamping surface-enhanced Raman spectroscopy for label-free, multiplexed, molecular sensing and imaging. AB - We report stamping surface-enhanced Raman spectroscopy (S-SERS) for label-free, multiplexed, molecular sensing and large-area, high-resolution molecular imaging on a flexible, nonplasmonic surface without solution-phase molecule transfer. In this technique, a polydimethylsiloxane (PDMS) thin film and nanoporous gold disk SERS substrate play the roles as molecule carrier and Raman signal enhancer, respectively. After stamping the SERS substrate onto the PDMS film, SERS measurements can be directly taken from the "sandwiched" target molecules. The performance of S-SERS is evaluated by the detection of Rhodamine 6G, urea, and its mixture with acetaminophen, in a physiologically relevant concentration range, along with the corresponding SERS spectroscopic maps. S-SERS features simple sample preparation, low cost, and high reproducibility, which could lead to SERS-based sensing and imaging for point-of-care and forensics applications. PMID- 24805806 TI - Evaluation of the marginal fit at implant-abutment interface by optical coherence tomography. AB - Vertical misfit of implant-abutment interface can affect the success of implant treatment; however, currently available modalities have limitations to detect these gaps. This study aimed to evaluate implant-abutment gaps in vitro using optical coherence tomography (OCT). Vertical misfit gaps sized 50, 100, 150, or 200 MUm were created between external hexagonal implants and titanium abutments (Nobel Biocare, Goteborg, Sweden). A porcine gingival tissue slice, 0.5, 1.0, 1.5, or 2.0 mm in thickness, was placed on each implant-abutment interface. The gaps were evaluated by swept-source OCT at a center wavelength of 1330 nm (Panasonic Healthcare, Ehime, Japan) with beam angles of 90, 75 and 60 deg to the implant long-axis. The results suggested that while the measurements were precise, gap size and gingival thickness affected the sensitivity of detection. Gaps sized 100 MUm and above could be detected with good accuracy under 0.5- or 1.0-mm-thick gingiva (GN). Around 70% of gaps sized 150 MUm and above could be detected under 1.5-mm-thick GN. On the other hand, 80% of gaps under 2.0-mm-thick GN were not detected due to attenuation of near-infrared light through the soft tissue. OCT appeared as an effective tool for evaluating the misfit of implant abutment under thin layers of soft tissue. PMID- 24805807 TI - Extratympanic observation of middle ear structure using a refractive index matching material (glycerol) and an infrared camera. AB - High-resolution computed tomography has been used mainly in the diagnosis of middle ear disease, such as high-jugular bulb, congenital cholesteatoma, and ossicular disruption. However, certain diagnoses are confirmed through exploratory tympanotomy. There are few noninvasive methods available to observe the middle ear. The purpose of this study was to investigate the effect of glycerol as a refractive index matching material and an infrared (IR) camera system for extratympanic observation. 30% glycerol was used as a refractive index matching material in five fresh cadavers. Each material was divided into four subgroups; GN (glycerol no) group, GO (glycerol out) group, GI (glycerol in) group, and GB (glycerol both) group. A printed letter and middle ear structures on the inside tympanic membrane were observed using a visible and IR ray camera system. In the GB group, there were marked a transilluminated letter or an ossicle on the inside tympanic membrane. In particular, a footplate of stapes was even transilluminated using the IR camera system in the GB group. This method can be useful in the diagnosis of diseases of the middle ear if it is clinically applied through further studies. PMID- 24805808 TI - Deep optical imaging of tissue using the second and third near-infrared spectral windows. AB - Light at wavelengths in the near-infrared (NIR) region allows for deep penetration and minimal absorption through high scattering tissue media. NIR light has been conventionally used through the first NIR optical tissue window with wavelengths from 650 to 950 nm. Longer NIR wavelengths had been overlooked due to major water absorption peaks and a lack of NIR-CCD detectors. The second NIR spectral window from 1100 to 1350 nm and a new spectral window from 1600 to 1870 nm, known as the third NIR optical window, were investigated. Optical attenuation measurements from thin tissue slices of normal and malignant breast and prostate tissues, pig brain, and chicken tissue were obtained in the spectral range from 400 to 2500 nm. Optical images of chicken tissue overlying three black wires were also obtained using the second and third spectral windows. Due to a reduction in scattering and minimal absorption, longer attenuation lengths and clearer optical images could be seen in the second and third NIR optical windows compared to the conventional first NIR optical window. A possible fourth optical window centered at 2200 nm was noted. PMID- 24805809 TI - Second harmonic generation polarization properties of myofilaments. AB - Second harmonic generation (SHG) polarization microscopy was used to investigate the organization of myosin nanomotors in myofilaments of muscle cells. The distribution of the second-order nonlinear susceptibility component ratio chizzz(2)/chizxx(2) along anisotropic bands of sarcomeres revealed differences between the headless and head-containing regions of myofilaments. The polarization-in polarization-out SHG measurements of headless myosin mutants of indirect flight muscle in Drosophila melanogaster confirmed a lower susceptibility component ratio compared to the head-containing myocytes with wild type myosins. The increase in the ratio is assigned to the change in the deflection angle of the myosin S2 domain and possible contribution of myosin heads. The nonlinear susceptibility component ratio is a sensitive indicator of the myosin structure, and therefore, it can be used for conformational studies of myosin nanomotors. The measured ratio values can also be used as the reference for ab initio calculations of nonlinear optical properties of different parts of myosins. PMID- 24805810 TI - Robot-assisted three-dimensional registration for cochlear implant surgery using a common-path swept-source optical coherence tomography probe. AB - Cochlear implantation offers the potential to restore sensitive hearing in patients with severe to profound deafness. However, surgical placement of the electrode array within the cochlea can produce trauma to sensorineural components, particularly if the initial turn of the cochlea is not successfully navigated as the array is advanced. In this work, we present a robot-mounted common-path swept-source optical coherence tomography endoscopic platform for three-dimensional (3-D) optical coherence tomography (OCT) registration and preoperative surgical planning for cochlear implant surgery. The platform is composed of a common-path 600-MUm diameter fiber optic rotary probe attached to a five degrees of freedom robot capable of 1 MUm precision movement. The system is tested on a dry fixed ex vivo human temporal bone, and we demonstrate the feasibility of a 3-D OCT registration of the cochlea to accurately describe the spatial and angular profiles of the canal formed by the scala tympani into the first cochlear turn. PMID- 24805811 TI - Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X). AB - Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms. PMID- 24805813 TI - Assessment of the sensitizing potential of processed peanut proteins in Brown Norway rats: roasting does not enhance allergenicity. AB - BACKGROUND: IgE-binding of process-modified foods or proteins is the most common method for examination of how food processing affects allergenicity of food allergens. How processing affects sensitization capacity is generally studied by administration of purified food proteins or food extracts and not allergens present in their natural food matrix. OBJECTIVES: The aim was to investigate if thermal processing increases sensitization potential of whole peanuts via the oral route. In parallel, the effect of heating on sensitization potential of the major peanut allergen Ara h 1 was assessed via the intraperitoneal route. METHODS: Sensitization potential of processed peanut products and Ara h 1 was examined in Brown Norway (BN) rats by oral administration of blanched or oil roasted peanuts or peanut butter or by intraperitoneal immunization of purified native (N-), heated (H-) or heat glycated (G-)Ara h 1. Levels of specific IgG and IgE were determined by ELISA and IgE functionality was examined by rat basophilic leukemia (RBL) cell assay. RESULTS: In rats dosed orally, roasted peanuts induced significant higher levels of specific IgE to NAra h 1 and 2 than blanched peanuts or peanut butter but with the lowest level of RBL degranulation. However, extract from roasted peanuts was found to be a superior elicitor of RBL degranulation. Process-modified Ara h 1 had similar sensitizing capacity as NAra h 1 but specific IgE reacted more readily with process-modified Ara h 1 than with native. CONCLUSIONS: Peanut products induce functional specific IgE when dosed orally to BN rats. Roasted peanuts do not have a higher sensitizing capacity than blanched peanuts. In spite of this, extract from roasted peanuts is a superior elicitor of RBL cell degranulation irrespectively of the peanut product used for sensitization. The results also suggest that new epitopes are formed or disclosed by heating Ara h 1 without glucose. PMID- 24805814 TI - BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1/2 and PI3K/AKT pathways. AB - Bone morphogenetic protein 9 (BMP9), a member of TGF-beta superfamily, is reported to inhibit the growth and migration of prostate cancer, osteosarcoma and triple-negative MDA-MB-231 breast cancer cells. However, little is known about the effect of on the biological behaviors of HER2-positive SK-BR-3 breast cancer cells and the underlying mechanisms. This study aimed to investigate the effects of BMP9 on the proliferation and metastasis of SK-BR-3 cells with BMP9 over expression or BMP9 down-regulated expression. Results indicated that exogenously expressed BMP9 inhibited the proliferation and metastasis of SK-BR-3 cells while decreased endogenous BMP9 expression in SK-BR-3 cells promoted the proliferation and migration of breast cancer cells in vitro and in vivo. In SK-BR-3 cells with BMP9 over-expression, the phosphorylation of HER2, ERK1/2 and AKT was markedly suppressed and the HER2 expression decreased at both mRNA and protein levels, while opposite results were observed in SK-BR-3 cells with BMP9 knock down. When the phosphorylation of ERK1/2 and PI3K/AKT was inhibited by PD98059 and LY294002, respectively, the decreased proliferation and invasion induced by BMP9 knock down were eliminated. These findings suggest that BMP9 can inhibit the proliferation and metastasis of SK-BR-3 cells via inactivating ERK1/2 and PI3K/AKT signaling pathways. Thus, BMP9 may serve as a useful agent in the treatment of HER-2 positive breast cancer. PMID- 24805815 TI - Hyperuricemia and transesophageal echocardiographic thromboembolic risk in patients with atrial fibrillation at clinically low-intermediate risk. AB - BACKGROUND: There is no clear consensus on thromboprophylaxis in patients with nonvalvular atrial fibrillation (AF) at low-intermediate thromboembolic risk. Although hyperuricemia is a risk factor for cardiovascular diseases, the relationship between serum uric acid (UA) levels and thromboembolic risk has not been fully elucidated in patients with AF. METHODS AND RESULTS: Serum UA levels and the score for congestive heart failure, hypertension, age, diabetes mellitus, prior stroke/transient ischemic attack, vascular disease and sex (ie, CHA2DS2 VASc score) were determined in 470 patients with nonvalvular AF who underwent transesophageal echocardiography (TEE) to evaluate their risk of thromboembolism. Serum UA levels were similar between the low-intermediate risk (CHA2DS2-VASc score=0 or 1) and high-risk (>=2) groups, although serum D-dimer levels were lower in the low-intermediate risk than in the high-risk group. Among patients at low-intermediate risk, serum UA levels were higher in those with TEE thromboembolic risk (TEE risk: low left atrial appendage flow, spontaneous echo contrast, thrombi, or aortic atherosclerosis) than in those without TEE risk. On multivariate analysis, the serum UA level was an independent predictor of TEE risk in AF patients at low-intermediate risk (odds ratio, 1.45; 95% confidence interval 1.09-2.00; P=0.016). CONCLUSIONS: The serum UA level was associated with thromboembolic risk on TEE in patients with nonvalvular AF at low-intermediate risk stratified by clinical risk factors. PMID- 24805816 TI - Massive mobile thrombus in the left ventricle due to Loffler endocarditis complicated with dilated cardiomyopathy. PMID- 24805817 TI - Wound healing and wound location in critical limb ischemia following endovascular treatment. AB - BACKGROUND: The differences in wound healing according to wound location remain unclear. METHODS AND RESULTS: Between April 2007 and October 2011, 138 patients (166 limbs) with critical limb ischemia with tissue loss were treated with endovascular treatment. On these limbs, 177 individual wounds were identified on the foot and were evaluated for wound healing rates and time to healing according to their locations. Wound locations were divided into 3 groups: group T (Toe wounds, n=112), group H (Heel wounds, n=25), and group E (Extensive wounds extending onto the fore- or mid-foot along with dorsum or plantar surfaces, n=40). The mean follow-up period was 23+/-19 months. At 3, 6, 9, and 12 months, wound healing rates were 51%, 64%, 75%, and 75%, respectively, in group T; 12%, 36%, 36%, and 52%, respectively, in group H; and 0%, 5%, 8%, and 13%, respectively, in group E. The median time to healing was 64 days (interquartile range 25-156 days) in group T, 168 days (interquartile range 123-316 days) in group H, and 267 days (interquartile range 177-316 days) in group E (P=0.038). CONCLUSIONS: Extensive wounds extending onto the fore- or mid-foot along with dorsum or plantar surfaces were the most difficult type of wound to heal. PMID- 24805818 TI - Resistance to reinfection in mice as a vaccine model for giardiasis. AB - Infection with Giardia is the most commonly diagnosed parasitic cause of diarrhea in the developed world, yet no vaccine exists for human use and a commercially available veterinary vaccine is of limited utility. We have used the adult C57BL/6 mouse model of infection with Giardia duodenalis to better understand immunity to secondary infections with this parasite. Mice were primed by infection with either the GS or WB strains of Giardia and treated with metronidazole on day 7-12 to eliminate the primary infections. Challenge infections on day 21 or day 60 after the primary infections resulted in ~50-fold fewer parasites at day 5 than were found in unprimed mice that only received the challenge infection. Resistance to challenge infections was also observed in B cell deficient uMT mice and when primed mice were challenged with parasites of a different strain. While primed mice developed IgA, mast cell, and T cell responses against the parasite, no specific responses correlated with protection against challenge infections. Together these data suggest that development of an effective vaccine for giardiasis should be feasible since strong immunity can be developed against reinfection in the adult mouse model. Moreover we show that antibody responses are not essential for a protective vaccine and that protection is not parasite strain-specific. PMID- 24805819 TI - Effects of different modes of ventilation and head position on the size of the vena jugularis interna. AB - PURPOSE: Right internal jugular vein (RIJV) catheterisation is a common procedure in patients undergoing surgery. We aimed to compare diameters and the cross sectional area (CSA) of the RIJV when the head is in a neutral or 30-degree rotated position during mechanical ventilation in various modes and spontaneous ventilation. METHODS: Thirty patients undergoing surgery were included in the study. In each patient, still ultrasound images of the vena jugularis interna were taken with the head in a neutral position and with the neck rotated 30 degrees to the left, first under spontaneous ventilation (group S), then after the induction of anaesthesia under volume-controlled ventilation (group V) and under pressure-controlled ventilation (group P). The six still images were evaluated in terms of transverse and anteroposterior diameters and CSA. RESULTS: Diameters in the neutral and lateral positions in group S were significantly smaller than in group P and group V (neutral transverse p = 0.01, anteroposterior p = 0.041, rotated transverse p = 0.01, anteroposterior p = 0.03). The CSAs of the RIJV in the neutral and lateral positions were significantly larger in group P and group V than Group S (lateral CSA p = 0.001, neutral CSA p = 0.002). CSA increased significantly only in group P when the head was rotated 30 degrees laterally (p = 0.002). CONCLUSION: We conclude that both pressure-controlled and volume-controlled mechanical ventilation have similar effects on the CSA and diameters of the RIJV. Positioning of the head with a 30-degree rotation laterally has different effects on CSA depending on the ventilation mode used. A neutral position should be preferred with spontaneous ventilation whereas 30 degree rotation should be preferred in patients under pressure-controlled and volume-controlled ventilation. PMID- 24805822 TI - A Haut-Doubs FVII variant depending on species-derived-thromboplastin reagent (F7:p.Arg337His). PMID- 24805823 TI - This first 2014 issue of Recent Patents in CNS Drug Discovery covers a range of rather diverse, but not necessarily unrelated topics. Introduction. PMID- 24805821 TI - Novel anti-apoptotic microRNAs 582-5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim. AB - Glioblastoma is the most common and lethal primary brain tumor. Tumor initiation and recurrence are likely caused by a sub-population of glioblastoma stem cells, which may derive from mutated neural stem and precursor cells. Since CD133 is a stem cell marker for both normal brain and glioblastoma, and to better understand glioblastoma formation and recurrence, we looked for dys-regulated microRNAs in human CD133+ glioblastoma stem cells as opposed to CD133+ neural stem cells isolated from normal human brain. Using FACS sorting of low-passage cell samples followed by microRNA microarray analysis, we found 43 microRNAs that were dys regulated in common in three separate CD133+ human glioblastomas compared to CD133+ normal neural stem cells. Among these were several microRNAs not previously associated with cancer. We then verified the microRNAs dys-regulated in glioblastoma using quantitative real time PCR and Taqman analysis of the original samples, as well as human GBM stem cell and established cell lines and many human specimens. We show that two candidate oncogenic microRNAs, miR-363 and miR-582-5p, can positively influence glioblastoma survival, as shown by forced expression of the microRNAs and their inhibitors followed by cell number assay, Caspase 3/7 assay, Annexin V apoptosis/fluorescence activated cell sorting, siRNA rescue of microRNA inhibitor treatment, as well as 3'UTR mutagenesis to show luciferase reporter rescue of the most successful targets. miR-582-5p and miR-363 are shown to directly target Caspase 3, Caspase 9, and Bim. PMID- 24805824 TI - New insights into glycopeptide antibiotic binding to cell wall precursors using SPR and NMR spectroscopy. AB - Glycopeptide antibiotics, such as vancomycin and teicoplanin, are used to treat life-threatening infections caused by multidrug-resistant Gram-positive pathogens. They inhibit bacterial cell wall biosynthesis by binding to the D-Ala D-Ala C-terminus of peptidoglycan precursors. Vancomycin-resistant bacteria replace the dipeptide with the D-Ala-D-Lac depsipeptide, thus reducing the binding affinity of the antibiotics with their molecular targets. Herein, studies of the interaction of teicoplanin, teicoplanin-like A40926, and of their semisynthetic derivatives (mideplanin, MDL63,246, dalbavancin) with peptide analogues of cell-wall precursors by NMR spectroscopy and surface plasmon resonance (SPR) are reported. NMR spectroscopy revealed the existence of two different complexes in solution, when the different glycopeptides interact with Ac2KdAlaDAlaOH. Despite the NMR experimental conditions, which are different from those employed for the SPR measurements, the NMR spectroscopy results parallel those deduced in the chip with respect to the drastic binding difference existing between the D-Ala and the D-Lac terminating analogues, confirming that all these antibiotics share the same primary molecular mechanism of action and resistance. Kinetic analysis of the interaction between the glycopeptide antibiotics and immobilized AcKdAlaDAlaOH by SPR suggest a dimerization process that was not observed by NMR spectroscopy in DMSO solution. Moreover, in SPR, all glycopeptides with a hydrophobic acyl chain present stronger binding with a hydrophobic surface than vancomycin, indicating that additional interactions through the employed surface are involved. In conclusion, SPR provides a tool to differentiate between vancomycin and other glycopeptides, and the calculated binding affinities at the surface seem to be more relevant to in vitro antimicrobial activity than the estimations from NMR spectroscopy analysis. PMID- 24805826 TI - Poor WOMAC scores in contralateral knee negatively impact TKA outcomes: data from the osteoarthritis initiative. AB - While total knee arthroplasty (TKA) has been shown to have excellent outcomes, a significant proportion of patients experience relatively poor post-operative function. In this study, we test the hypothesis that the level of osteoarthritic symptoms in the contralateral knee at the time of TKA is associated with poorer post-operative outcomes in the operated knee. Using longitudinal cohort data from the Osteoarthritis Initiative (OAI), we included 171 patients who received a unilateral TKA. We compared pre-operative Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the contralateral knee to post-operative WOMAC scores in the index knee. Pre-operative contralateral knee WOMAC scores were associated with post-operative index knee WOMAC Total scores, indicating that the health of the pre-operative contralateral knee is a significant factor in TKA outcomes. PMID- 24805825 TI - A Kruppel-like factor downstream of the E3 ligase WWP-1 mediates dietary restriction-induced longevity in Caenorhabditis elegans. AB - The HECT ubiquitin E3 ligase WWP-1 is a positive regulator of lifespan in response to dietary restriction (DR) in Caenorhabditis elegans. However, substrates of WWP-1 for ubiquitylation in the DR pathway have not yet been identified. Here we identify the C. elegans Kruppel-like factor, KLF-1, as an essential and specific regulator of DR-induced longevity and a substrate for ubiquitylation by WWP-1. Knockdown of klf-1 suppresses the extended lifespan of both DR animals and wwp-1-overexpressing animals, indicating that KLF-1 functions within the same pathway as WWP-1. In addition, overexpression of klf-1 in the intestine is sufficient to extend the lifespan of WT animals on an ad libitum diet, and requires wwp-1 or pha-4/FoxA. We demonstrate that WWP-1 directly interacts with KLF-1 and mediates multiple monoubiquitylation of KLF-1 in vitro and in cellulo. Our data support a model in which modulation of KLF-1 by WWP-1 regulates diet-restriction-induced longevity. PMID- 24805827 TI - Oxford unicompartmental knee arthroplasty versus age and gender matched total knee arthroplasty - functional outcome and survivorship analysis. AB - We compared the medium-term outcomes of age and gender matched patients with unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). We retrospectively reviewed the pain, function and total knee society scores (KSS) for 602 UKAs and age and gender matched TKAs between 2001 and 2013. Function scores remained significantly better in UKAs from preoperative until 3years follow up. The change of function scores was not significantly different. TKAs performed better than UKAs for pain scores. Total KSS for both groups were not significantly different in the study. Fewer medical complications were reported in UKA group. 6.30% of UKAs and 2.99% of TKAs were revised. The theoretical advantages of UKA were not borne out, other than in immediate postoperative complications. PMID- 24805828 TI - Novel microRNAs expression of patients with chemotherapy drug-resistant and chemotherapy-sensitive epithelial ovarian cancer. AB - The aim of this study is to examine the microRNA (miRNA) expression of epithelial ovarian cancer (EOC) in both drug-resistant and drug-sensitive tissues and to explore the pathogenic characteristics of drug-resistant miRNAs in EOC. The samples with 10 cases of drug-resistant and drug-sensitive EOC tissue were obtained from undergoing surgical resection of ovarian cancer (OC). Total miRNAs were extracted and isolated, respectively. Hybridization was carried out on miRNA microarray chip. Real-time polymerase chain reaction (RT-PCR) was performed to confirm the difference of miRNA expression. Bioinformatic software was used to predict the possible target genes of each miRNA which expressed differently. The results indicated that four miRNAs related drug-resistance been identified, and the expression of hsa-miR-152 and hsa-miR-381 in drug-resistant OC tissue was significantly higher compared with those in drug-sensitive tissue (P < 0.01). However, expression of hsa-miR-200a-3p and hsa-miR-429 were downregulated in drug resistant tissues (P < 0.01). The results obtained by miRNA microarrays of differential expression with hsa-miR-106b-3p, hsa-miR-152, hsa-miR-200a-3p, hsa miR-381, and hsa-miR-429 were confirmed by real-time PCR. There were 62 significantly different miRNAs, including 42 significant upregulated miRNAs and 20 significant downregulated miRNAs in the drug-resistant tissue. Five databases, including Target Scan, miRanda, miRDB, PicTar5, and RNA22, were used for bioinformatics prediction. In conclusion, miRNA microarray analysis has become a fast and efficient molecular biological technology for the study of biological information. hsa-miR-152, hsa-miR-200a-3p, hsa-miR-381, and hsa-miR-429 may participate in the formation of drug resistance in EOC through the target genes predicted. PMID- 24805829 TI - The apoptotic effect of apigenin on human gastric carcinoma cells through mitochondrial signal pathway. AB - This study aims to explore the apoptotic function of apigenin on the gastric cancer cells and the related mechanism. The gastric cancer cell lines HGC-27 and SGC-7901, and normal gastric epithelial cell line GES1 were treated with different concentrations of apigenin. Cell proliferation was tested. Morphological changes of the apoptotic cells were observed after Hoechst33342 staining. The apoptosis rate of the gastric cancer cells were measured with flow cytometry. Changes of the cell cycle were explored. The mitochondrial membrane potential changes were analyzed after JC-1 staining. Bcl-2 family proteins and caspases-3 expression with apigenin treatment was analyzed by real-time PCR. Cell proliferation of HGC-27 and SGC-7901 was inhibited by apigenin, and the inhibition was dose-time-dependent. Gastric carcinoma cells treated by apigenin had no obvious cell cycle arrest, but were observed with the higher apoptosis rate and the typical apoptotic morphological changes of the cell nucleus. JC-1 staining showed that apigenin could reduce mitochondrial membrane potential of gastric carcinoma cells. Real-time PCR results showed that apigenin significantly increased caspase-3 and Bax expression level, and down-regulated Bcl-2 expression in a dose-dependent manner in gastric carcinoma cells. However, the GES1 was almost not affected by apigenin treatment. Apigenin can inhibit cell lines HGC-27 and SGC-7901 proliferation in a time and dose-dependent manner, reduce anti apoptotic protein Bcl-2 levels, enhance apoptosis-promoting protein Bax level, result in mitochondrial membrane potential decreasing and caspase-3 enzyme activating, then lead to cell apoptosis. PMID- 24805830 TI - Genome-wide pathway analysis of breast cancer. AB - The aim of this study was to identify candidate single-nucleotide polymorphisms (SNPs) that might affect susceptibility to breast cancer and then elucidate their potential mechanisms and generate SNP-to-gene-to-pathway hypotheses. A genome wide association study (GWAS) dataset of breast cancer that included 453,852 SNPs from 1,145 breast cancer patients and 1,142 control subjects of European descent was used in this study. The identify candidate causal SNPs and pathways (ICSNPathway) method was applied to the GWAS dataset. ICSNPathway analysis identified 16 candidate SNPs, 13 genes, and 7 pathways, which together revealed 7 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs3168891 and rs2899849 alter the role of MBIP in the inactivation of mitogen-activated protein kinase (MAPK) (p < 0.001; false discovery rate (FDR) = 0.038). The second strongest mechanism was that rs2229714 modulates RPS6KA1 to affect its role in growth hormone signaling (p = 0.001; FDR = 0.039). The third strongest mechanism was that rs2230394 modulates ITGB1 to regulate the PTEN pathway and hsa04360 (axon guidance pathway) (p < 0.001; FDR = 0.039, 0.041). Use of the ICSNPathway to analyze breast cancer GWAS data identified 16 candidate SNPs, 13 genes (including MBIP, RPS6KA1, and ITGB1), and 7 pathways that might contribute to the susceptibility of patients to breast cancer. PMID- 24805831 TI - Association between MTHFR C677T polymorphism and thyroid cancer risk: a meta analysis. AB - In the light of the relationship between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and thyroid cancer (TC) exist objection, a meta analysis of the MTHFR C677T polymorphism with thyroid cancer risk was performed. All the available studies were identified through a search of the PubMed, Embase, Web of Science, and Chinese Biomedical Literature Database (CBM) up to March 2014. The association between the MTHFR C677T polymorphism and thyroid cancer risk was conducted by odds ratios (ORs) and 95 % confidence intervals (95 % CIs). A total of five independent studies with 2,554 cases and 2,671 controls were included in our meta-analysis. Significant association was found between MTHFR C677T polymorphism and thyroid cancer risk in recessive model in overall populations (TT vs. TC/CC: OR = 1.88, 95 % CI = 1.59-2.21, P = 0.00), but there was no association between MTHFR C677T polymorphism and thyroid cancer risk found in other four models in overall populations (T vs. C: OR = 1.25, 95 % CI = 0.96 1.62, P = 0.10; TT vs. CC: OR = 1.11, 95 % CI = 0.93-1.33, P = 0.26; TC vs. CC: OR = 1.23, 95 % CI = 0.84-1.82, P = 0.29; TT/TC vs. CC: OR = 1.28, 95 % CI = 0.89 1.84, P = 0.19). In the subgroup analysis base on the ethnicity, the results suggested that MTHFR C677T polymorphism was significantly associated with thyroid cancer risk both in Caucasian and Asian populations in recessive model: (Caucasians: TT vs. TC/CC: OR = 2.28, 95 % CI = 1.11-4.67, P = 0.025; Asians: TT vs. TC/CC: OR = 1.86, 95 % CI = 1.57-2.20, P = 0.00). In conclusions, our meta analysis suggested that the MTHFR C677T polymorphism is associated with thyroid cancer both in Caucasians and Asians. PMID- 24805832 TI - Age-specific reference values for serum FSH and estradiol levels throughout the reproductive period. AB - High serum day 3 FSH levels are associated with poor ovarian reserve and reduced fertility, but the interpretation of FSH values according to age is still not univocal. The purpose of this study was to determine age-dependent reference values in women with regular menstrual cycles and FSH as a guide for specialists. The study was performed at the Department of Mother-Infant of a University-based tertiary care centre. One-hundred ninety-two healthy normal menstruating women were recruited for the study. All patients attended the department on menstrual cycle day 3 for a blood sample for FSH and estradiol determination. A linear relationship between FSH or estradiol serum levels and age was observed. The FSH level increased by 0.11 IU for every year of age (1 IU for every 9 years of age). The values of FSH and estradiol corresponding to the 5th, 25th, 50th, 75th, 95th centiles for any specific age have been calculated. Serum FSH levels need to be interpreted according to age-dependent reference values. Serum FSH levels on 95th centile for any age may represent a warning sign for reduced ovarian reserve. PMID- 24805833 TI - Are the new IADPSG criteria for gestational diabetes useful in a country with a very high prevalence? AB - The International Association of Diabetes and Pregnancy Study Groups released new recommendations on screening methods and diagnostic criteria for gestational diabetes. The main objectives of the present study were to analyze characteristics of mothers who underwent the new screening test, and to assess the prevalence of gestational diabetes and related pregnancy complications such as the 5-minute Apgar score <7, in a urban maternity clinic in Djibouti. The effect of treating gestational diabetes was also evaluated. Totally, 231 mothers underwent the new screening test, and 106 were diagnosed as having gestational diabetes (45.9%). Mothers with gestational diabetes had an excess risk of low Apgar scores, even after adjustment for socio-economic and medical covariates, with an odds ratio of 6.34 (1.77-22.66), p value <0.005. Only 46.2% of mothers with gestational diabetes followed the recommendations regarding treatment. Among these patients, 18.6% of infants from untreated mothers had a 5-minute Apgar score <7, compared to 3.9% infants from treated mothers (p value = 0.017). After adjustment, untreated mothers still had a high excess risk of low Apgar scores, although non-significant, with an odds ratio of 4.67 (0.78-27.87), p value = 0.09. In conclusion, gestational diabetes is highly prevalent in Djibouti and is related to low Apgar scores. PMID- 24805834 TI - Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis. AB - Dienogest is a novel progestin that is highly selective for progesterone receptors and inhibits endometriosis. However, it remains unknown how the administration of dienogest to patients with endometriosis impacts on their lesion tissues. The aim of this study was to evaluate the in vivo effect of dienogest on endometriosis tissue. We collected endometrioma tissues from patients treated with dienogest (N = 7) or not treated (N = 11, controls). Cell proliferation, aromatase expression and blood vessel density were evaluated by staining for Ki67, aromatase and the von Willebrand factor, respectively. Apoptosis was detected using the TUNEL assay. The proportion of Ki67 and aromatase positive epithelial cells was significantly lower in the dienogest group than in controls (p < 0.05, respectively). The number of TUNEL positive cells was significantly higher in the dienogest group (p < 0.05). The density of blood vessels in endometrioma was marginally lower in the dienogest group compared with controls (p = 0.20). Our study demonstrates that endometrioma taken from patients treated with dienogest show remarkable histological features such as reduction of proliferation, aromatase expression and angiogenesis, and increase of apoptosis. This study clarified the impact of dienogest on local histological events that explain its therapeutic effect on endometriosis. PMID- 24805836 TI - Medical devices early assessment methods: systematic literature review. AB - OBJECTIVES: The aim of this study was to get an overview of current theory and practice in early assessments of medical devices, and to identify aims and uses of early assessment methods used in practice. METHODS: A systematic literature review was conducted in September 2013, using computerized databases (PubMed, Science Direct, and Scopus), and references list search. Selected articles were categorized based on their type, objective, and main target audience. The methods used in the application studies were extracted and mapped throughout the early stages of development and for their particular aims. RESULTS: Of 1,961 articles identified, eighty-three studies passed the inclusion criteria, and thirty were included by searching reference lists. There were thirty-one theoretical papers, and eighty-two application papers included. Most studies investigated potential applications/possible improvement of medical devices, developed early assessment framework or included stakeholder perspective in early development stages. Among multiple qualitative and quantitative methods identified, only few were used more than once. The methods aim to inform strategic considerations (e.g., literature review), economic evaluation (e.g., cost-effectiveness analysis), and clinical effectiveness (e.g., clinical trials). Medical devices were often in the prototype product development stage, and the results were usually aimed at informing manufacturers. CONCLUSIONS: This study showed converging aims yet widely diverging methods for early assessment during medical device development. For early assessment to become an integral part of activities in the development of medical devices, methods need to be clarified and standardized, and the aims and value of assessment itself must be demonstrated to the main stakeholders for assuring effective and efficient medical device development. PMID- 24805837 TI - Superconductivity in a new layered bismuth oxyselenide: LaO(0.5)F(0.5)BiSe2. AB - We report superconductivity at T(c) ~ 2.6 K in a new layered bismuth oxyselenide LaO(0.5)F(0.5)BiSe2 with the ZrCuSiAs-type structure composed of alternating superconducting BiSe2 and blocking LaO layers. The superconducting properties of LaO(0.5)F(0.5)BiSe2 were investigated by means of dc magnetization, resistivity and muon-spin rotation experiments, revealing the appearance of bulk superconductivity with a rather large superconducting volume fraction of ~ 70% at 1.8 K. PMID- 24805838 TI - Restraining the motion of a ligand for modulating the structural phase transition in two isomorphic polar coordination polymers. AB - A structural phase transition induced by ligand motion was found in a new polar coordination polymer: [Cu(NCS)2(4-APy)2]n (4-APy = 4-aminopyridine). Restraining such motion in an isomorphic compound [Cu(NCS)2(4-MeAPy)2]n (4-MeAPy = 4 methylaminopyridine) results in distinct phase transition behaviour. These findings provide a new clue for modulating phase transition behaviour in known materials. PMID- 24805839 TI - Sexual health risks and health-seeking behaviours among substance-misusing women. AB - AIMS: To report on a survey of sexual health service needs among substance misusing women attending a substance misuse service. BACKGROUND: Substance misusing women carry a disproportionate burden of sexual ill health, yet the range and frequency of their sexual health risks, morbidities and service engagement are poorly understood. DESIGN: A cross-sectional survey of a convenience sample of substance-misusing women attending a substance misuse service. METHODS: From 4 April 2010-17 September 2010, substance-misusing women in Hastings & Ore, UK, were invited to complete a paper questionnaire addressing: drug use; cervical cytology, sexually transmitted infection and HIV screening history; pregnancy history, perceived pregnancy risk and contraceptive advice and supply; sexual activity and assault. Of 91 respondents, 77 attended local drug treatment services - results comprise analysis of this sub-sample. RESULTS: The study sample was characterized by long-term opioid and crack cocaine use. Of 53% sexually active in the previous 4 weeks, 66% perceived they had experienced sexual intercourse that could lead to pregnancy during that time. Fifty-five per cent had been forced to have sex against their will during their lifetime. High rates of sexually transmitted infections, pregnancy termination, miscarriage and abnormal cervical cytology were reported. CONCLUSIONS: Findings indicate the need to recognize the breadth of elevated sexual health risks and morbidities experienced by substance-misusing women with long-term opioid/crack use, including those not identifying as intravenous drug users. Poor recall of drop-in and appointment times, reluctance to disclose substance misuse and likelihood of previous sexual assault present significant challenges to nurses, who must take a sensitive, opportunistic approach to referral and provision of sexual health interventions to substance-misusing women. PMID- 24805840 TI - Self-assembly of protein fibrils into suprafibrillar aggregates: bridging the nano- and mesoscale. AB - We report on in vitro self-assembly of nanometer-sized alpha-synuclein amyloid fibrils into well-defined micrometer-sized suprafibrillar aggregates with sheet like or cylindrical morphology depending on the ionic strength of the solution. The cylindrical suprafibrillar structures are heavily hydrated, suggesting swollen gel-like particles. In contrast to higher order structures formed by other negatively charged biopolymers, multivalent ions are not required for the suprafibrillar aggregates to form. Their formation is induced by both mono- and divalent counterions. The self-assembly process is not mediated by protein specific interactions but rather by the cooperative action of long-range electrostatic repulsion and short-range attraction. Understanding the mechanism driving the self-assembly might give us valuable insight into the pathological formation of fibrillar superstructures such as Lewy bodies and neurites-distinct signatures of Parkinson's disease-and will open the possibility to utilize the self-assembly process for the design of novel fibril-based smart nanostructured materials. PMID- 24805842 TI - Solving conservation's money problems. PMID- 24805843 TI - The effect of static and dynamic loading on degradation of PLLA stent fibers. AB - Understanding how polymers such as PLLA degrade in vivo will enhance biodegradable stent design. This study examined the effect of static and dynamic loads on PLLA stent fibers in vitro. The stent fibers (generously provided by TissueGen, Inc.) were loaded axially with 0 N, 0.5 N, 1 N, or 0.125-0.25 N (dynamic group, 1 Hz) and degraded in PBS at 45 degrees C for an equivalent degradation time of 15 months. Degradation was quantified through changes in tensile mechanical properties. The mechanical behavior was characterized using the Knowles strain energy function and a degradation model. A nonsignificant increase in fiber stiffness was observed between 0 and 6 months followed by fiber softening thereafter. A marker of fiber softening, beta, increased between 9 and 15 months in all groups. At 15 months, the beta values in the dynamic group were significantly higher compared to the other groups. In addition, the model indicated that the degradation rate constant was smaller in the 1-N (0.257) and dynamic (0.283) groups compared to the 0.5-N (0.516) and 0-N (0.406) groups. While the shear modulus fluctuated throughout degradation, no significant differences were observed. Our results indicate that an increase in static load increased the degradation of mechanical properties and that the application of dynamic load further accelerated this degradation. PMID- 24805844 TI - An application of capsid-specific artificial ankyrin repeat protein produced in E. coli for immunochromatographic assay as a surrogate for antibody. AB - Immunochromatographic strip test is a unique type of rapid test that has been developed for use as part of a diagnostic kit for the rapid detection of antibodies and/or other proteins of interest. For the detection of target proteins, most of the commercial tests are assembled based on the conjugation of colloidal gold particles to monoclonal antibodies embedded within the conjugate pad of a strip test. In this study, we tested the novel concept of using an artificial non-antibody structure for generating a colloidal gold conjugate (CGC). We exploited the property of an ankyrin repeat protein that specifically binds to the HIV-1 capsid protein termed Ank(GAG)1D4. This construct was applied as a model structure to create Ank1D4-CGC and used as a new type of visible detector system and termed it ankyrin-based immunochromatographic strip (ABIS) test. The ABIS test was shown to be highly sensitive with a lower limit of detection of the target protein at 0.1 MUg/ml. Moreover, the ABIS test was not only highly sensitive but also shared a level of specificity within the same range of the commercial test kit. The results of the studies presented herein therefore demonstrate the novel application of an artificial non-immunoglobulin structure (ankyrin repeat protein) as the new line of a visible detector using a rapid diagnostic test with characteristics that have the potential to be superior to those that utilize antibody-based tests. PMID- 24805845 TI - Ecological dynamics and biotechnological implications of thraustochytrids from marine habitats. AB - Thraustochytrids, a group of osmoheterotrophic marine protists, have recently gained increased attention owing to their spectacular biotechnological potentials. They possess enormous capability of producing omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and several other bioactive metabolites, known to have nutritional implications in human health. They have emerged lately as an efficient economic alternative compared with other fish and algal oil sources by virtue of their simpler PUFA profiles and cost-effective culture conditions. This review is an attempt to summarize the ecological significance of thraustochytrids with an emphasis on their cultured and uncultured diversity from various marine habitats accounted during the last few decades. Moreover, improved technologies such as media optimization in conjugation with metabolic engineering, adopted for biotechnological advancement of omega-3 products of thraustochytrids are highlighted with particular concern on the respective fatty acid biosynthetic pathways. One of the future prospects focuses on utilization of thraustochytrids for biodiesel production owing to their tremendous potentiality of yielding low carbon monounsaturated fatty acids (LC-MUFAs). However, there is utmost need of in-depth diversity assessments from various oceanic ecosystems in order to gain insight on potential thraustochytrids for ameliorated employment toward biotechnological applications. PMID- 24805846 TI - The plant beneficial effects of Metarhizium species correlate with their association with roots. AB - Metarhizium species have recently been found to be plant rhizosphere associates as well as insect pathogens. Because of their abundance, rhizospheric Metarhizium could have enormous environmental impact, with co-evolutionary implications. Here, we tested the hypothesis that some Metarhizium spp. are multifactorial plant growth promoters. In two consecutive years, corn seeds were treated with entomopathogenic Metarhizium spp. and field tested at the Beltsville Facility in Maryland. Seed treatments included application of green fluorescent protein (GFP) tagged strains of Metarhizium brunneum, Metarhizium anisopliae, Metarhizium robertsii, and M. robertsii gene disruption mutants that were either avirulent (Deltamcl1), unable to adhere to plant roots (Deltamad2), or poorly utilized root exudates (Deltamrt). Relative to seeds treated with heat-killed conidia, M. brunneum, M. anisopliae, and M. robertsii significantly increased leaf collar formation (by 15, 14, and 13 %), stalk length (by 16, 10, and 10 %), average ear biomass (by 61, 56, and 36 %), and average stalk and foliage biomass (by 46, 36, and 33 %). Their major impact on corn yield was during early vegetative growth by allowing the plants to establish earlier and thereby potentially outpacing ambient biotic and abiotic stressors. Deltamcl1 colonized roots and promoted plant growth to a similar extent as the parent wild type, showing that Metarhizium populations are plant growth promoters irrespective of their role as insect pathogens. In contrast, rhizospheric populations and growth promotion by Deltamrt were significantly reduced, and Deltamad2 failed to colonize roots or impact plant growth, suggesting that colonization of the root is a prerequisite for most, if not all, of the beneficial effects of Metarhizium. PMID- 24805847 TI - Characterization of ubiquitin-activating enzyme Uba1 in the nucleus by its mammalian temperature-sensitive mutant. AB - Temperature-sensitive (ts) CHO-K1 mutant tsTM3 exhibits chromosomal instability and cell-cycle arrest in the S to G2 phases with decreased DNA synthesis at the nonpermissive temperature, 39 degrees C. Previously, complementation tests with other mutants showed that tsTM3 harbors a genetic defect in the ubiquitin activating enzyme Uba1. Sequence comparison of the Uba1 gene between wild-type and mutant cells in this study revealed that the mutant phenotype is caused by a G-to-A transition that yields a Met-to-Ile substitution at position 256 in hamster Uba1. The ts defects in tsTM3 were complemented by expression of the wild type Uba1 tagged with green fluorescent protein. Expression of the Uba1 primarily in the nucleus appeared to rescue tsTM3 cells. Incubation at 39 degrees C resulted in a decrease of nuclear Uba1 in tsTM3 cells, suggesting that loss of Uba1 in the nucleus may lead to the ts defects. Analyses with the fluorescent ubiquitination-based cell cycle indicator revealed that loss of function of Uba1 leads to failure of the ubiquitin system in the nucleus. Incubation at 39 degrees C caused an increase in endogenous geminin in tsTM3 cells. A ts mutation of Uba1 found in tsTM3 cells appears to be a novel mutation reflecting the important roles of Uba1 in nucleus. PMID- 24805848 TI - Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy. AB - Effective anticancer therapy can be achieved by designing a targeted drug delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug delivery system, formed by multivalent host-guest interactions between a polymer cyclodextrin conjugate and a polymer-paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery. PMID- 24805849 TI - Synchronising movements with the sounds of a virtual partner enhances partner likeability. AB - Previous studies have demonstrated that synchronising movements with other people can influence affiliative behaviour towards them. While research has focused on synchronisation with visually observed movement, synchronisation with a partner who is heard may have similar effects. We replicate findings showing that synchronisation can influence ratings of likeability of a partner, but demonstrate that this is possible with virtual interaction, involving a video of a partner. Participants performed instructed synchrony in time to sounds instead of the observable actions of another person. Results show significantly higher ratings of likeability of a partner after moving at the same time as sounds attributed to that partner, compared with moving in between sounds. Objectively quantified synchrony also correlated with ratings of likeability. Belief that sounds were made by another person was manipulated in Experiment 2, and results demonstrate that when sounds are attributed to a computer, ratings of likeability are not affected by moving in or out of time. These findings demonstrate that interaction with sound can be experienced as social interaction in the absence of genuine interpersonal contact, which may help explain why people enjoy engaging with recorded music. PMID- 24805850 TI - Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. AB - Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1 G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1 G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases. PMID- 24805851 TI - Transcriptome analysis reveals differential splicing events in IPF lung tissue. AB - Idiopathic pulmonary fibrosis (IPF) is a complex disease in which a multitude of proteins and networks are disrupted. Interrogation of the transcriptome through RNA sequencing (RNA-Seq) enables the determination of genes whose differential expression is most significant in IPF, as well as the detection of alternative splicing events which are not easily observed with traditional microarray experiments. We sequenced messenger RNA from 8 IPF lung samples and 7 healthy controls on an Illumina HiSeq 2000, and found evidence for substantial differential gene expression and differential splicing. 873 genes were differentially expressed in IPF (FDR<5%), and 440 unique genes had significant differential splicing events in at least one exonic region (FDR<5%). We used qPCR to validate the differential exon usage in the second and third most significant exonic regions, in the genes COL6A3 (RNA-Seq adjusted pval = 7.18e-10) and POSTN (RNA-Seq adjusted pval = 2.06e-09), which encode the extracellular matrix proteins collagen alpha-3(VI) and periostin. The increased gene-level expression of periostin has been associated with IPF and its clinical progression, but its differential splicing has not been studied in the context of this disease. Our results suggest that alternative splicing of these and other genes may be involved in the pathogenesis of IPF. We have developed an interactive web application which allows users to explore the results of our RNA-Seq experiment, as well as those of two previously published microarray experiments, and we hope that this will serve as a resource for future investigations of gene regulation in IPF. PMID- 24805853 TI - How justice can affect jury: training abstract words promotes generalisation to concrete words in patients with aphasia. AB - Developing language treatments that not only improve trained items but also promote generalisation to untrained items is a major focus in aphasia research. This study is a replication and extension of previous work which found that training abstract words in a particular context-category promotes generalisation to concrete words but not vice versa (Kiran, Sandberg, & Abbott, 2009 ). Twelve persons with aphasia (five female) with varying types and degrees of severity participated in a generative naming treatment based on the Complexity Account of Treatment Efficacy (CATE; Thompson, Shapiro, Kiran, & Sobecks, 2003 ). All participants were trained to generate abstract words in a particular context category by analysing the semantic features of the target words. Two other context-categories were used as controls. Ten of the twelve participants improved on the trained abstract words in the trained context-category. Eight of the ten participants who responded to treatment also generalised to concrete words in the same context-category. These results suggest that this treatment is both efficacious and efficient. We discuss possible mechanisms of training and generalisation effects. PMID- 24805852 TI - Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers. AB - The effects of normothermic machine perfusion (NMP) on the postreperfusion hemodynamics and extrahepatic biliary duct histology of donation after cardiac death (DCD) livers after transplantation have not been addressed thoroughly and represent the objective of this study. Ten livers (5 per group) with 60 minutes of warm ischemia were preserved via cold storage (CS) or sanguineous NMP for 10 hours, and then they were reperfused for 24 hours with whole blood in an isolated perfusion system to simulate transplantation. In our experiment, the arterial and portal vein flows were stable in the NMP group during the entire reperfusion simulation, whereas they decreased dramatically in the CS group after 16 hours of reperfusion (P < 0.05); these findings were consistent with severe parenchymal injury. Similarly, significant differences existed between the CS and NMP groups with respect to the release of hepatocellular enzymes, the volume of bile produced, and the levels of enzymes released into bile (P < 0.05). According to histology, CS livers presented with diffuse hepatocyte congestion, necrosis, intraparenchymal hemorrhaging, denudated biliary epithelium, and submucosal bile duct necrosis, whereas NMP livers showed very mild injury to the liver parenchyma and biliary architecture. Most importantly, Ki-67 staining in extrahepatic bile ducts showed biliary epithelial regeneration. In conclusion, our findings advance the knowledge of the postreperfusion events that characterize DCD livers and suggest NMP as a beneficial preservation modality that is able to improve biliary regeneration after a major ischemic event and may prevent the development of ischemic cholangiopathy in the setting of clinical transplantation. PMID- 24805855 TI - TNF-alpha receptor 1 expression predicts poor prognosis of diffuse large B-cell lymphoma, not otherwise specified. AB - We have previously shown that in tumor specimens from patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), the tumor necrosis factor alpha (TNF-alpha)-positive type correlates with a poorer prognosis compared with the TNF-alpha-negative type. In the present study, we further evaluated 60 lymphoma tissue specimens from patients with DLBCL, NOS by immunohistochemical staining with antibodies against TNF-alpha receptor 1 (TNFR1) and TNF-alpha receptor 2 (TNFR2). Our results demonstrated that 31 cases (52%) were positive and 29 (48%) were negative for TNFR1 and that the TNFR1-positive cases were significantly correlated with a poorer overall survival (OS; P=0.0006, log rank test) than the TNFR1-negative cases. The TNFR2-positive cases tended to have a poorer OS than the TNFR2-negative cases, although the difference was not significant. TNFR1 expression in tumor cells was a significant prognostic factor for OS and was independent of the International Prognostic Index (IPI). Among 31 TNF-alpha-positive DLBCL, NOS cases, 27 (87%) were positive and 4 (13%) were negative for TNFR1. Both TNF-alpha-positive and TNFR1-positive cases were significantly correlated with a poorer OS compared with the TNF-alpha-positive but TNFR1-negative cases. Twenty-seven cases (45%) with the TNF-alpha-positive and TNFR1-positive subtype of DLBCL, NOS had a poorer prognosis for OS and progression-free survival compared with the 33 cases (55%) with the remaining subtypes, and the TNF-alpha-positive and TNFR1-positive subtype of DLBCL, NOS was also shown to be independent of the IPI. In addition to the IPI, the prognosis of patients can be more accurately identified by evaluating both TNF-alpha and TNFR1 expression. PMID- 24805854 TI - Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders. AB - Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information. PMID- 24805856 TI - Clinicopathologic features of pediatric oligodendrogliomas: a series of 50 patients. AB - Oligodendrogliomas are an important adult form of diffuse gliomas with a distinctive clinical and genetic profile. Histologically similar tumors occurring rarely in children are incompletely characterized. We studied 50 patients with oligodendrogliomas (median age at diagnosis 8 y, range 7 mo to 20 y). Tumors resembling dysembryoplastic neuroepithelial tumors or pilocytic astrocytomas or those having a "mixed" histology were excluded. Tumors at first diagnosis were low grade (n=38) or anaplastic (n=12). Histologic features included uniform round cells with perinuclear halos (100%), secondary structures (predominantly perineuronal satellitosis) (90%), calcifications (46%), and microcysts (44%). Sequential surgical specimens were obtained in 8 low-grade oligodendroglioma patients, with only 1 progressing to anaplasia. Studies for 1p19q performed in 40 cases demonstrated intact 1p19q loci in 29 (73%), 1p19q codeletion in 10 (25%), and 1p deletion with intact 19q in 1 (2%). Except for 2 young patients (3 and 11 y of age), patients with 1p19q codeletion were older than 16 years at diagnosis. Mutant IDH1 (R132H) protein immunohistochemistry was positive in 4 (of 22) (18%) cases, 3 of which also had 1p19q codeletion, whereas 1p19q status was not available on the fourth case. There was a nonsignificant trend for worse overall survival in grade III tumors, but no significant association with age, extent of resection, or 1p19q status. In summary, oligodendrogliomas with classic histology occur in the pediatric population but lack 1p19q codeletion and IDH1 (R132H) mutations in most instances. They are predominantly low grade, recur/clinically progress in a subset, but demonstrate a relatively low frequency of histologic progression. PMID- 24805857 TI - SALL4 immunoreactivity predicts prognosis in Western hepatocellular carcinoma patients but is a rare event: a study of 236 cases. AB - Prognostic biomarkers that stratify patients with cancer are needed. Recent studies from Asia have implicated SALL4, a stem cell marker, as useful in identifying aggressive cases of hepatocellular carcinoma (HCC), and >50% of the cases tested had upregulation by microarray or dense immunoreactivity. Given the differences in predominant etiologic factors between the Asian and Western HCC, we sought to determine the prevalence of SALL4 immunoreactivity and its clinical relevance in Western HCC patients. We constructed tissue microarrays from 236 adult HCCs. Two cores each of tumor and nontumor tissue were included for each case. SALL4 immunohistochemistry was scored in a semiquantitative manner and the results correlated with recurrence-free and overall survival, in addition to standard demographics. Among the 236 cases, 165 (70.0%) were male. The median age was 59 years (range: 19 to 83 y). The majority (78.4%) of patients were white, followed by African American (15.7%), Asian (3.8%), Hispanic (1.7%), and Native American (0.4%). The majority of patients had hepatitis C (42.8%), followed by alcoholic liver disease and hepatitis B (both 8.9%), and nonalcoholic steatohepatitis (3.8%). SALL4 immunoreactivity was detected in a total of 3 cases (1.3%), and nonreactivity was validated on tissue sections from 73 cases. By univariate analysis, the SALL4-positive cases had significantly higher tumor grade (P=0.0251), more frequent lymphovascular invasion (P=0.0150), and shorter recurrence-free survival (7.90 vs. 57.54 mo; P=0.0115) and overall survival (7.90 vs. 64.87 mo; P=0.0018). Although SALL4 immunoreactivity in Western HCC is correlated with higher grade and poor prognosis, this is a rare event. Therefore, universal application of SALL4 as a biomarker for HCC should be performed with caution. PMID- 24805858 TI - Primary pigmented nodular adrenocortical disease: the original 4 cases revisited after 30 years for follow-up, new investigations, and molecular genetic findings. AB - The original 4 patients with Cushing syndrome who underwent bilateral adrenalectomy for primary pigmented nodular adrenocortical disease were followed up for an average of 31 years to determine whether they or any of their primary relatives had developed Carney complex or its components. None had. Three of the patients were alive and well; the fourth had died of an unrelated condition. All the adrenal glands contained multiple small, black or brown cortical nodules, up to 4 mm in diameter. The extracapsular extension of the micronodules was limited to the immediate pericapsular adipose tissue and was not considered evidence of low-grade malignancy. Immunocytochemically, the nodules were positive for synaptophysin, inhibin-A, and melan A and negative for vimentin and CD56. Ki-67 antibody stained the cytoplasm of cells in the micronodules but not that of the atrophic cortical cells. The 4 patients had the PRKAR1A deletion that has been associated with the isolated form of primary pigmented nodular adrenocortical disease. PMID- 24805859 TI - BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. AB - BCOR-CCNB3 fusion transcripts resulting from an X-chromosomal paracentric inversion were recently identified in a series of unclassifiable soft tissue and bone sarcomas with Ewing sarcoma-like morphology. The morphologic and clinical features of these sarcomas are, as yet, not well characterized. Here we describe the clinicopathologic features of 10 cases of BCOR-CCNB3 sarcoma and compare their clinical course with typical Ewing sarcoma. Nine of 10 patients were male, and all were 11 to 18 years of age. Seven tumors were located in the bone and 3 in the deep soft tissues. The histomorphologic spectrum was quite wide, with 7 tumors predominately showing small primitive cell morphology with angulated nuclei simulating so-called atypical Ewing sarcoma and 3 predominately showing spindle cell morphology. Recurrent and metastatic lesions showed increased cellularity and marked pleomorphism. Immunohistochemistry showed expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%). Reverse transcription polymerase chain reaction for BCOR-CCNB3 fusion transcripts was positive in all 9 cases, which yielded sufficient extracted RNA. Five- and 10-year survival rates were 75% and 56%, respectively. BCOR-CCNB3 sarcomas located in axial skeleton and soft tissues showed a significantly shorter survival. The Ewing sarcoma overall survival was not statistically different, although there was a trend for longer survival of patients with BCOR-CCNB3 sarcomas in the extremities. In conclusion, this study provides a detailed description of the histologic spectrum, immunohistochemical features, and clinical characteristic of BCOR-CCNB3 sarcoma justifying distinction from Ewing sarcoma with its typical EWS/FUS-ETS translocations. Ideally immunohistochemistry is used in combination with reverse transcription polymerase chain reaction for definitive diagnosis. PMID- 24805860 TI - Collecting duct carcinoma versus renal medullary carcinoma: an appeal for nosologic and biological clarity. PMID- 24805862 TI - Suprabasal spread of melanocytes in dysplastic nevi and melanoma in situ: Ki-67 labeling rate of junctional melanocytes and suprabasal cells may be a helpful clue to the diagnosis. AB - Multiple criteria on routinely stained sections allow one to make a diagnosis of a dysplastic or "Clark" nevus (CN) versus melanoma in situ (MIS), and one of these is suprabasal spread of melanocytes. The extent of suprabasal spread of melanocytes in otherwise conventional CN and the combination of a sensitive marker of melanocytes combined with Ki-67 to assess the differences between the proliferation of melanocytes at the junction and those above it have not yet been studied. Fifty classic examples of CN and 27 cases of MIS were culled from the files of a university-based dermatopathology practice. All cases were stained with a 2-color method (MART-1/tyrosinase red, Ki-67 brown) to evaluate morphologic and immunohistochemical differences in these lesions. Fifteen of 50 cases of benign CN demonstrated suprabasal spread compared with 27 of 27 cases of MIS. The majority of CNs with suprabasal spread (13 of 15) showed a 0% Ki-67 labeling rate among the suprabasal melanocytes, and the majority of MISs (23 of 27) showed a 20% or greater Ki-67-labeling rate in suprabasal cells. Suprabasal melanocytes can be seen by immunostaining in otherwise unremarkable CN, wherein they are not notable in routinely stained sections, but their proliferation rate is much less than in MIS. PMID- 24805861 TI - Methotrexate-associated B-cell lymphoproliferative disorders presenting in the skin: A clinicopathologic and immunophenotypical study of 10 cases. AB - Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin, but their clinicopathologic features are still ill defined. Differentiation from primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is important, as MTX-associated B-LPD may show spontaneous regression after withdrawal of MTX therapy. In the present study, the clinicopathologic and phenotypical features of 10 patients with MTX-associated B-LPD first presenting in the skin, including 5 EBV(+) and 5 EBV(-) cases, were investigated. Six patients had skin-limited disease. Clinically, abrogation of MTX therapy resulted in a complete response in 4 cases and a partial response in another 2. The 5-year disease-specific survival was 90%. MTX-associated B-LPD differed from primary cutaneous follicle center lymphoma by the presence of ulcerating and/or generalized skin lesions, an infiltrate composed of centroblasts/immunoblasts rather than large centrocytes, reduced staining for CD79a, and expression of BCL2, IRF4, and FOXP1 in most cases. EBV(+) MTX-associated B-LPD differed from PCLBCL-LT by the presence ulcerative skin lesions, marked tumor cell polymorphism, reduced staining for CD79a, and expression of CD30 and EBV. EBV(-) cases showed morphologic and immunophenotypical similarities to PCLBCL-LT but differed by presentation with generalized skin lesions in 4 of 5 cases. The results of this study, showing a relatively good clinical outcome and spontaneous disease regression after only withdrawal of MTX in a considerable proportion of patients, underscores the importance of a careful wait-and-see policy before considering more aggressive therapies in patients with MTX-associated B-LPD of the skin. PMID- 24805863 TI - Lung tumors masquerading as desquamative interstitial pneumonia (DIP): report of 7 cases and review of the literature. AB - Malignant tumors in the lung (both primary and metastatic) rarely may be associated with markedly discohesive tumor cells, resulting in airspace filling reminiscent of "desquamative interstitial pneumonia" (DIP) on histopathology evaluation. A peculiar aspect of this growth pattern is the relatively bland appearance of the tumor cells, in many cases simulating benign alveolar macrophages at scanning magnification. We searched the Charles Carrington Memorial consultation files in the Department of Laboratory Medicine and Pathology at Mayo Clinic Arizona for instances of malignant tumors in lung simulating DIP, from 1992 to 2011. We identified 7 cases involving transbronchial biopsies, needle core samples, or resected lung specimens. Clinical, histopathologic, and immunohistochemical analyses of these 7 patients were performed, including detailed morphometric analysis of the individual tumor cells using calibrated measurement tools on digital images. We compared the results with those of a control group of 4 patients with benign DIP-macrophage reactions in smoking-related lung disease. The study group comprised 5 male and 2 female patients, 48 to 86 years in age (median: 67 y). The radiologic findings included lobar consolidation, localized ground-glass opacities, and 1 or more nodules. None of the patients had typical bilateral infiltrates of DIP. Microscopically, the lung parenchyma was dominated by the presence of prominent tumor cells filling alveolar spaces. Four patients had primary lung carcinoma (adenocarcinoma), whereas 3 had metastases from other sites, including a melanoma. Immunohistochemical staining studies were performed on 6 of 7 cases to establish the diagnosis. Nuclear diameter, cytoplasmic diameter, and nuclear/cytoplasmic (N/C) ratios in patient and control groups were compared using the Wilcoxon rank sum test. No significant difference in the diameters of nucleus and cytoplasm between cases and control groups (P=0.3447 and 0.7055, respectively) was seen, and only a marginally significant difference in N/C ratios (P=0.0890) was seen. A more complex analysis, generalized estimating equation analysis, showed a significant difference in N/C ratio between the 2 groups (P=0.0278). A "DIP-growth pattern" of malignant tumors in the lung is presented. Although the N/C ratio differences approached statistical significance when compared with controls, the key to diagnosis is the recognition of the malignant cytology of the tumor nuclei. Immunohistochemical studies (keratin or other markers) are helpful in establishing an accurate diagnosis in this setting. PMID- 24805864 TI - Optical chemosensor for the detection of cyanide in water based on ethyl(hydroxyethyl)cellulose functionalized with Brooker's merocyanine. AB - Ethyl(hydroxyethyl)cellulose was functionalized with Brooker's merocyanine. The modified polymer was easily transformed in a film, which could be used as a highly selective chromogenic and fluorogenic chemosensor for the detection of cyanide in water, with detection limits of 1.9 * 10(-5) and 1.0 * 10(-7) mol L( 1). The film was successfully applied to the detection of cyanide in cassava (Manihot esculenta Crantz) roots, which are a well-known source of endogenous biological cyanide. PMID- 24805865 TI - The second Austrian benchmark study for blood use in elective surgery: results and practice change. AB - BACKGROUND: Five years after the first Austrian benchmark study demonstrated relatively high transfusion rate and an abundance of nonindicated transfusions in elective surgeries, this study was conducted to investigate the effects of the first benchmark study. STUDY DESIGN AND METHODS: Data from 3164 patients undergoing primary unilateral total hip replacement (THR), primary unilateral noncemented total knee replacement (TKR), or coronary artery bypass graft (CABG) surgery at 15 orthopedic and six cardiac centers were collected and compared with the first study. RESULTS: Transfusion rates decreased in THR (41% to 30%) and TKR (41% to 25%), but remained unchanged in CABG surgery (57% vs. 55%) compared with the first study. More than 80% of all transfusions involved at least 2 units of red blood cells (RBCs). Marked variations were observed in transfusion rates among the centers. The prevalence of anemia was three times higher in patients who received transfusions versus those who did not. However, preoperative anemia was left untreated in the majority of patients. A considerable intercenter variability of RBC loss ranging from 26% to 43% in THR, from 24% to 40% in TKR, and from 30% to 49% in CABG procedures was observed. CONCLUSION: The second benchmark study demonstrates substantial intercenter variability and small but significant reductions in RBC transfusions and RBC loss. Even though the main independent predictors of transfusion were the relative lost RBC volume followed by the relative preoperative and the lowest relative postoperative hemoglobin, preoperative anemia was not adequately treated in many patients, underscoring the importance of patient blood management in these patients. PMID- 24805866 TI - Role and mechanism of Twist1 in modulating the chemosensitivity of FaDu cells. AB - Multidrug resistance (MDR) is one of the most important obstacles affecting the efficacy of chemotherapy treatments for numerous types of cancer. In the present study, we have demonstrated the possible function of Twist1 in the chemosensitivity of head and neck squamous cell carcinoma (HNSCC) and have identified that its mechanism maybe associated with MDR1/P-gp regulation. To investigate this, the hypopharyngeal cancer cell line, FaDu, and its MDR cell line induced by taxol, FaDu/T, were employed. Stable transfectants targeted to Twist1 overexpression and Twist1 silencing based on FaDu were also conducted. Morphological observation, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), western blotting and laser scanning confocal microscope detection were utilized to detect the associations between Twist1 and the chemosensitivity of FaDu cells. Our results demonstrated that Twist1 and MDR1/P gp were upregulated in FaDu/T cells in a MDR dose-dependent manner. The anti apoptotic capabilities of FaDu/T cells were enhanced during MDR progression, with apoptosis-related proteins (Bcl-2, Bax, activated caspase-3 and caspase-9) changing to resist apoptosis. Twist1 overexpression decreased the sensitivity of cells to taxol as revealed by a significant increase in MDR1/P-gp and IC50 (P<0.05). This overexpression also enhanced the resistance to apoptosis, with apoptotic proteins changing to resist cell death, and inhibited Ca2+ release induced by taxol (P<0.05). Detections in Twist1 silencing cells also confirmed this result. This study provided evidence that alterations of Twist1 expression modulates the chemosensitivity of FaDu cells to taxol. Therefore, Twist1 knockdown may be a promising treatment regimen for advanced hypopharyngeal carcinoma patients with MDR. PMID- 24805868 TI - Combinational effects of farnesoid X receptor antagonist and statin on plasma lipid levels and low-density lipoprotein clearance in guinea pigs. AB - AIMS: We previously reported anti-dyslipidemic effects of a farnesoid X receptor antagonist in monkeys. In this study, we compared the cholesterol-lowering effects of single and combined administration of a farnesoid X receptor antagonist, compound-T8, and the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor atorvastatin in a guinea pig model. MAIN METHODS: Plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7alpha hydroxylase activity, were measured after a single administration of compound-T8. The effects of compound-T8 or atorvastatin on plasma cholesterol levels and low density lipoprotein (LDL) clearance were investigated after 14 or 16 days of repeated dosing, respectively. Fractional catabolic rate of plasma LDL was estimated by intravenous injection of DiI-labeled human LDL. The cholesterol lowering effects of combination therapy were investigated after 7 days of repeated treatment. KEY FINDINGS: Compound-T8 (10 and 30 mg/kg) increased plasma 7alpha-hydroxy-4-cholesten-3-one levels in a dose-dependent manner. Single administration of compound-T8 (30 mg/kg) and atorvastatin (30 mg/kg) reduced plasma non-high-density lipoprotein (non-HDL) cholesterol levels by 48% and 46%, respectively, and increased clearance of plasma DiI-labeled LDL by 29% and 35%, respectively. Compound-T8 (10mg/kg) or atorvastatin (10mg/kg) reduced non-HDL cholesterol levels by 19% and 25%, respectively, and combination therapy showed an additive effect and lowered cholesterol levels by 48%. SIGNIFICANCE: Similar to atorvastatin, compound-T8 reduced plasma non-HDL cholesterol levels accompanied with accelerated LDL clearance in guinea pigs. Combination therapy additively decreased plasma non-HDL cholesterol levels. Therefore, monotherapy with a farnesoid X receptor antagonist and combination therapy of a farnesoid X receptor antagonist with atorvastatin would be attractive dyslipidemia treatment options. PMID- 24805869 TI - Genetic effect of transforming growth factor alpha gene variants on the risk of nonsyndromic cleft lip with or without palate in korean populations. AB - OBJECTIVE: To identify the contribution of TGFA gene variants to the risk of nonsyndromic cleft lip with or without palate (NS-CL+/-P). DESIGN: The samples were from 142 Korean NS-CL+/-P families and 119 control parents having nonaffected children. Minor allele frequency, heterozygosity, and chi(2) test for Hardy-Weinberg equilibrium were calculated for each of 10 selected single nucleotide polymorphisms (SNPs). Ten SNPs were used to examine the association of case-parent trios with the transmission disequilibrium test (TDT) and conditional logistic regression models (CLRMs). Both allelic and genotypic TDTs for individual SNPs and sliding windows of haplotypes consisting of two to five SNPs were tested using family- and haplotype-based association test programs. Genotypic odd ratios (GORs) were obtained from CLRMs using STATA software. The parent-of-origin effect was evaluated for 10 SNPs, and a comparison between 218 case parents and 119 control parents was performed to investigate paternal and maternal ORs. RESULTS: Family-based TDT and haplotype analysis exhibited no statistical significance, but a relatively meaningful association was shown with rs3771497 (all P < .05; two SNPs, rs3771497 and rs3755377; five SNPs, rs3771497, rs3755377, rs3771485, rs11466212, and rs3771475). G/G homozygotes at rs3771497 have a significant decreased risk of NS-CL+/-P (GOR = 0.30, P < .01). No SNPs showed parent-of-origin effects. However, in the comparison between case parents and control parents, a single-marker analysis of maternal line showed a significant association with NS-CL+/-P in rs3771497 (P < .001, recessive model). CONCLUSION: The association of the TGFA gene with NS-CL+/-P in Korean populations was not clearly found. However, the etiologic effect of the TGFA gene on NS-CL+/ P patients should be investigated in terms of maternal genotype influence. PMID- 24805870 TI - Measurement of health-related and oral health-related quality of life among individuals with nonsyndromic orofacial clefts: a systematic review and meta analysis. AB - Objective : To compare health-related quality of life and oral health-related quality of life between nonsyndromic individuals with and without cleft lip and/or cleft palate and to identify the most affected quality of life dimensions in individuals with cleft lip and/or palate. Design : Systematic review and meta analysis were conducted. Of the 314 identified citations, 23 articles were submitted to quality assessment. Data from nine studies on health-related quality of life and six on oral health-related quality of life were extracted for meta analysis. Main Outcome Measures : Pooled mean differences of health-related quality of life between adults with and without cleft lip and/or palate, pooled means of health-related quality of life dimensions of children and adults with cleft lip and/or palate and oral health-related quality of life dimensions of children and adolescents with cleft lip and/or palate with a 95% confidence interval were calculated. Results : Quality assessment revealed methodological differences between studies. Lack of subgroup stratification and absence of control for confounders were the main limitations. Heterogeneity was detected on the comparison of oral health-related quality of life and health-related quality of life between children with and without cleft lip and/or palate, and oral health-related quality of life between adolescents with and without cleft lip and/or palate. A random-effect model showed a significant difference on health related quality of life between adults with and without cleft lip and/or palate (mean difference = 0.10; 95% confidence interval, 0.16 to 0.05). Psychological health (mean, 78.9; 95% confidence interval, 70.1 to 87.7) and vitality (mean, 68.1; 95% confidence interval, 48.0 to 88.1) were the most affected health related quality of life dimensions in children and adults with cleft lip and/or palate, respectively. Means of health-related quality of life dimensions in children and adults with cleft lip and/or palate and oral health-related quality of life in children and adolescents with cleft lip and/or palate varied yet did not differ in indirect comparisons. Conclusion : The presence of cleft lip and/or palate negatively affected the health-related quality of life of adults, mainly on psychosocial dimensions. PMID- 24805871 TI - Presurgical cleft lip anthropometrics and dental arch relationships in patients with complete unilateral cleft lip and palate. AB - OBJECTIVE: To investigate associations between anthropometric lip measurements and dental arch relationships in patients with complete unilateral cleft lip and palate (CUCLP). DESIGN: Retrospective cross-sectional study. PATIENTS: Children with CUCLP. METHODS: Anthropometric lip measurements, made immediately prior to lip repair, were available for each patient. The dental arch relationships were evaluated on dental study casts (8.6 +/- 0.9 years) taken prior to any orthodontic treatment and prior to alveolar bone graft, using the modified Huddart and Bodenham (MHB) scoring system. The presence of associations between anthropometric lip measurements and dental arch relationships was determined using linear regression analysis. RESULTS: In the 63 patients included in the study, the cleft lateral lip element was deficient in height in 87% and in transverse width in 86% of patients. Patients with more deficient cleft-side lateral lip height were more likely to present with more negative MHB scores (r = .443; P < .001). Conversely, patients with more deficient cleft-side lateral lip transverse width more often presented with more positive MHB scores (r = .281; P = .025). CONCLUSIONS: In patients with CUCLP, there is a wide variability in the degree of deficiency of the cleft-side lateral lip element, both in the vertical and in the transverse dimension. The extent of this deficiency may, in part, predict the resulting dental arch relationships. PMID- 24805867 TI - The double-edged sword: conserved functions of extracellular hsp90 in wound healing and cancer. AB - Heat shock proteins (Hsps) represent a diverse group of chaperones that play a vital role in the protection of cells against numerous environmental stresses. Although our understanding of chaperone biology has deepened over the last decade, the "atypical" extracellular functions of Hsps have remained somewhat enigmatic and comparatively understudied. The heat shock protein 90 (Hsp90) chaperone is a prototypic model for an Hsp family member exhibiting a duality of intracellular and extracellular functions. Intracellular Hsp90 is best known as a master regulator of protein folding. Cancers are particularly adept at exploiting this function of Hsp90, providing the impetus for the robust clinical development of small molecule Hsp90 inhibitors. However, in addition to its maintenance of protein homeostasis, Hsp90 has also been identified as an extracellular protein. Although early reports ascribed immunoregulatory functions to extracellular Hsp90 (eHsp90), recent studies have illuminated expanded functions for eHsp90 in wound healing and cancer. While the intended physiological role of eHsp90 remains enigmatic, its evolutionarily conserved functions in wound healing are easily co opted during malignancy, a pathology sharing many properties of wounded tissue. This review will highlight the emerging functions of eHsp90 and shed light on its seemingly dichotomous roles as a benevolent facilitator of wound healing and as a sinister effector of tumor progression. PMID- 24805873 TI - Application of Linear Discriminant Analysis to the Nasometric Assessment of Resonance Disorders: A Pilot Study. AB - Objective : Nasalance scores have traditionally been used to assess hypernasality. However, resonance disorders are often complex, and hypernasality and nasal obstruction may co-occur in patients with cleft palate. In this study, normal speakers simulated different resonance disorders, and linear discriminant analysis was used to create a tentative diagnostic formula based on nasalance scores for nonnasal and nasal speech stimuli. Materials and Methods : Eleven female participants were recorded with the Nasometer 6450 while reading nonnasal and nasal speech stimuli. Nasalance measurements were taken of their normal resonance and their simulations of hyponasal, hypernasal, and mixed resonance. Results : A repeated-measures analysis of variance revealed a resonance condition-stimuli interaction effect (P < .001). A linear discriminant analysis of the participants' nasalance scores led to formulas correctly classifying 64.4% of the resonance conditions. When the hyponasal and mixed resonance conditions with obstruction of the less patent nostril were removed from the analysis, the resultant formulas correctly classified 88.6% of the resonance conditions. Conclusion : The simulations produced distinctive nasalance scores, enabling the creation of formulas that predicted resonance condition above chance level. The preliminary results demonstrate the potential of this approach for the diagnosis of resonance disorders. PMID- 24805872 TI - Hearing outcomes in patients with cleft lip/palate. AB - Objective : Children with cleft lip and palate or cleft palate only have a high incidence of conductive hearing loss from otitis media with effusion. Studies demonstrating longitudinal results are lacking. This study was undertaken to investigate long-term longitudinal hearing outcomes of children with cleft lip and/or cleft palate and cleft palate only. Design : Retrospective chart review. Setting : Clinical charts of patients born with cleft lip and palate or cleft palate only in 1985 to 1994 who were referred to the cleft team in Bergen, Norway. Study findings include 15 years of follow-up. Participants : The study population consisted of 317 children of whom 159 had nonsyndromic cleft lip and palate and 158 had nonsyndromic cleft palate. Main Outcome Measures : Pure tone average calculated from pure tone audiometry at ages 4, 6, and 15 years. Results : The median pure tone average significantly improved with increasing age. For the cleft lip and palate group, the median pure tone average at ages 4, 6, and 15 years was 16 dB hearing level (HL), 13 dB HL, and 9 dB HL, respectively (P <= .001). In the cleft palate group the median pure tone average at ages 4, 6, and 15 years was 15 dB HL, 12 dB HL, and 9 dB HL, respectively (P <= .001). There was no significant difference in the hearing levels between the two groups. Patients who had surgical closure of the palate at age 18 months had a significantly better pure tone average outcome at age 15 compared with patients who had surgery at 12 months. Conclusions : Hearing improves significantly from childhood to adolescence in patients with cleft lip and palate and cleft palate only. PMID- 24805874 TI - Clinical Features in Patients With 22q11.2 Deletion Syndrome Ascertained by Palatal Abnormalities. AB - OBJECTIVES: The aim of this study was to describe clinical features in subjects with palatal abnormalities and to assess the distribution of these features among those with and without 22q11.2 deletion. DESIGN: Descriptive cohort. PATIENTS: One hundred patients with palatal abnormalities and suspicion of 22q11.2 DS were included. METHODS: All patients were evaluated by a clinical geneticist, who completed a standardized clinical protocol. The 22q11.2 deletion screening was performed with fluorescence in situ hybridization using the TUPLE1 probe and multiplex ligation-dependent probe amplification using the P250-A1 kit. RESULTS: The 22q11.2 deletion was detected in 35 patients, in whom the most frequent clinical features were congenital heart disease (15/30 - 50%), developmental delay (19/35 - 54%), speech delay (20/35 - 57%), learning disabilities (27/35 - 77%), immunologic alterations (18/29 - 62%). In addition, the most common facial dysmorphisms in this group were long face (27/35 - 77%), typical nose (24/35 - 69%), and hooded eyelids (19/35 - 54%). Comparing features in patients with or without the deletion revealed significant differences (positively correlated with the deletion) for speech delay, learning disabilities, conductive hearing loss, number of dysmorphisms, long face, and hooded eyelids. Cleft lip and palate was negatively correlated with the deletion. CONCLUSIONS: The presence of speech delay, learning disabilities, conductive hearing loss, long face, and hooded eyelids should reinforce the suspicion of 22q11.2 DS in patients with palatal abnormalities and would help professionals direct clinical follow-up of these patients. PMID- 24805875 TI - Perioperative risk factors in patients with 22q11.2 deletion syndrome requiring surgery for velopharyngeal dysfunction. AB - Objective : To determine the prevalence of cardiac, cervical spine, and carotid artery abnormalities in patients with 22q11.2 deletion syndrome (22q11.2DS) undergoing surgery for velopharyngeal dysfunction (VPD), associations between the presence of these abnormalities, and whether these abnormalities caused changes in surgical management or perioperative complications. Design : Retrospective review. Setting : Tertiary pediatric hospital. Patients : Seventy patients with 22q11.2DS with complete preoperative cervical vascular and spine imaging and cardiac evaluation between 1998 and 2011. Main Outcome Measures : Incidence of cardiac, cervical spine, and vascular abnormalities; related perioperative complications; and resulting changes in surgical, anesthetic, or perioperative management plan. Results : Cardiac abnormalities occurred in 45 patients (64.3%), and 8 patients required cardiac anesthesia. Thirty-eight patients (54.3%) had at least one vascular abnormality of the neck, and 14% had medial deviation of the internal carotid artery. Surgery was not performed in one patient, and the surgical plan was altered in three patients because of carotid anomalies. Cervical spine abnormalities were found in 24 patients (34.3%); 8 patients demonstrated radiographic evidence of cervical instability and were treated with spinal precautions during surgery. The presence of one anomaly was not predictive of any other finding, and there were no complications related to the heart, cervical spine, or carotid arteries. Conclusions : Anomalies of the heart, cervical spine, and cervical vasculature occur frequently in 22q11.2DS, vary drastically in severity, and are impossible to predict based on other features of the syndrome. Preoperative diagnosis of these comorbidities with routine imaging can minimize the risk of avoidable surgical complications. PMID- 24805876 TI - Prognostic value of matrix metalloprotease-1/protease-activated receptor-1 axis in patients with prostate cancer. AB - The aim of this study was to investigate the associations of matrix metalloprotease-1 (MMP-1) and its receptor protease-activated receptor-1 (PAR-1) coexpression with the clinicopathological characteristics and prognosis of patients with prostate cancer (PCa). Immunohistochemistry was performed to detect the expression changes of MMP-1 and PAR-1 proteins in 180 pairs of human PCa tissues and matched non-cancerous prostate tissues. Then, the associations of combined MMP-1 and PAR-1 expression with selected clinicopathological characteristics and patient prognosis were evaluated. Both MMP-1 and PAR-1 proteins were positively localized in cytoplasm of tumor cells in PCa tissues. Compared with non-cancerous prostate tissues, MMP-1 (PCa vs. Normal: 4.15 +/- 1.28 vs. 2.37 +/- 1.16, P < 0.001) and PAR-1 (PCa vs. Normal: 3.71 +/- 1.21 vs. 1.55 +/- 1.12, P < 0.001) protein expression were both significantly upregulated. More interestingly, the expression levels of MMP-1 in PCa tissues were positively correlated with those of PAR-1 significantly (Spearman correlation coefficient r = 0.88, P < 0.001). In addition, the coexpression of MMP-1 and PAR-1 (MMP-1 high/PAR-1-high) in PCa tissues was significantly associated with the higher Gleason score (P < 0.001), the presence of metastasis (P < 0.001) and the advanced pathological stage (P = 0.009). Furthermore, both univariate and multivariate analyses showed that MMP-1-high/PAR-1-high expression was an independent predictor for both unfavorable overall survival and biochemical recurrence-free survival. These findings confirmed for the first time that the upregulation of MMP-1 protein combined with the overexpression of PAR-1 protein may contribute to the malignant progression of PCa. More importantly, MMP-1/PAR-1 axis may be a negative prognostic factor for patients with PCa. PMID- 24805877 TI - MicroRNA-148b expression is decreased in hepatocellular carcinoma and associated with prognosis. AB - MicroRNAs are small non-coding RNA molecules that have been shown to regulate the expression of genes linked to cancer. MicroRNA-148a (miR-148a) has recently been found to be involved in many critical processes in human malignancies. The present study is to clarify the expression pattern and prognostic role of miR 148b in human hepatocellular carcinoma (HCC). The expression of miR-148b was detected in 156 cases of HCC and 36 cases of normal control specimens by real time PCR. Results showed that miR-148b expression was significantly decreased in HCC compared with that in normal control. It was also demonstrated that aberrant miR-148b expression was associated with vein invasion and TNM stage of HCC. Kaplan-Meier analysis showed that decreased miR-148b expression was associated with poor overall survival of patients. A multivariate survival analysis also indicated that miR-148b could be an independent prognostic marker. These results proved that miR-148b expression was decreased in HCC and associated with tumor invasion and progression. The present study also provides the first evidence that miR-148b could be an independent prognostic factor for patients with HCC, indicating the potential role of miR-148b as a prognostic marker in clinical practice, and the inhibition of miR-148b may even become a new therapeutic method for the treatment of HCC. PMID- 24805878 TI - Final results from the 16-year sumatriptan, naratriptan, and treximet pregnancy registry. AB - OBJECTIVES: To monitor for a signal of major teratogenicity by determining the risk of all birth major defects following in utero exposure to sumatriptan, naratriptan, and the sumatriptan/naproxen sodium combination product (tablets marketed in the United States as Treximet [GlaxoSmithKline, Research Triangle Park, NC, USA]), and to monitor for unusual patterns of defects that might suggest teratogenicity. BACKGROUND: The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to anti-migraine drugs in pregnancy is likely. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry captured data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity. METHODS: In this primarily prospective, observational study, health care professionals from anywhere in the world enrolled, on a voluntary basis, women exposed to sumatriptan, naratriptan, or the sumatriptan/naproxen sodium combination product during their pregnancies. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The proportion of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure. RESULTS: The registry enrolled 680 evaluable exposed pregnant women, which resulted in 689 infants and fetuses (outcomes). Of these outcomes, 626 were exposed to sumatriptan, 57 were exposed to naratriptan (seven were exposed to both sumatriptan and naratriptan), and six were exposed to the sumatriptan/naproxen sodium combination product. Twenty outcomes with major birth defects were reported among 528 outcomes exposed in the first trimester to sumatriptan. The estimated risk of major birth defects following first-trimester sumatriptan exposure is 4.2% (20/478 [95% confidence interval [CI] 2.6%-6.5%]). Among 52 first-trimester exposures to naratriptan, major birth defects were reported in one outcome, an infant with exposure to both sumatriptan and naratriptan [birth defect risk of 2.2% (1/46 [95% CI 0.1%-13.0%]). No major defects were reported among the five outcomes with first-trimester exposure to the sumatriptan/naproxen sodium combination products. CONCLUSIONS: The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry detected no signal of teratogenicity associated with major birth defects for sumatriptan. This finding is consistent with results from other observational studies using a variety of control groups. Enrollment in the registry was insufficient to permit definitive conclusions of the risks associated with naratriptan or sumatriptan/naproxen sodium tablets, or to assess the risk of individual birth defects in any of the products studied. Low enrollment and high rates of loss to follow up within the registry over an extended period of time led the registry's scientific advisory committee to conclude that continuation of the registry beyond its 16 years would offer little additional power to rule out more moderate increases in the risk of birth defects. Data from the other ongoing surveillance sources constitute an important element of post-marketing surveillance of these medications. The lack of a signal of major teratogenicity with sumatriptan across these several sources of data is encouraging. PMID- 24805879 TI - Epidemiology of acute pancreatitis in hospitalized children in the United States from 2000-2009. AB - BACKGROUND: Single-center studies suggest an increasing incidence of acute pancreatitis (AP) in children. Our specific aims were to (i) estimate the recent secular trends, (ii) assess the disease burden, and (iii) define the demographics and comorbid conditions of AP in hospitalized children within the United States. METHODS: We used the Healthcare Cost and Utilization Project Kids' Inpatient Database, Agency for Healthcare Research and Quality for the years 2000 to 2009. Extracted data were weighted to generate national-level estimates. We used the Cochrane-Armitage test to analyze trends; cohort-matching to evaluate the association of AP and in-hospital mortality, length of stay, and charges; and multivariable logistic regression to test the association of AP and demographics and comorbid conditions. RESULTS: We identified 55,012 cases of AP in hospitalized children (1-20 years of age). The incidence of AP increased from 23.1 to 34.9 (cases per 10,000 hospitalizations per year; P<0.001) and for all diagnoses 38.7 to 61.1 (P<0.001). There was an increasing trend in the incidence of both primary and all-diagnoses of AP (P<0.001). In-hospital mortality decreased (13.1 to 7.6 per 1,000 cases, P<0.001), median length of stay decreased (5 to 4 days, P<0.001), and median charges increased ($14,956 to $22,663, P<0.001). Children with AP compared to those without the disease had lower in hospital mortality (adjusted odds ratio, aOR 0.86, 95% CI, 0.78-0.95), longer lengths of stay (aOR 2.42, 95% CI, 2.40-2.46), and higher charges (aOR 1.62, 95% CI, 1.59-1.65). AP was more likely to occur in children older than 5 years of age (aORs 2.81 to 5.25 for each 5-year age interval). Hepatobiliary disease was the comorbid condition with the greatest association with AP. CONCLUSIONS: These results demonstrate a rising incidence of AP in hospitalized children. Despite improvements in mortality and length of stay, hospitalized children with AP have significant morbidity. PMID- 24805881 TI - Theoretical criteria for scattering dark states in nanostructured particles. AB - Nanostructures with multiple resonances can exhibit a suppressed or even completely eliminated scattering of light, called a scattering dark state. We describe this phenomenon with a general treatment of light scattering from a multiresonant nanostructure that is spherical or nonspherical but subwavelength in size. With multiple resonances in the same channel (i.e., same angular momentum and polarization), coherent interference always leads to scattering dark states in the low-absorption limit, regardless of the system details. The coupling between resonances is inevitable and can be interpreted as arising from far-field or near-field. This is a realization of coupled-resonator-induced transparency in the context of light scattering, which is related to but different from Fano resonances. Explicit examples are given to illustrate these concepts. PMID- 24805882 TI - Novel chitosan hydrogel formed by ethylene glycol chitosan, 1,6-diisocyanatohexan and polyethylene glycol-400 for tissue engineering scaffold: in vitro and in vivo evaluation. AB - Traditional chitosan hydrogels were prepared by chemical or physical crosslinker, and both of the two kinds of hydrogels have their merits and demerits. In this study, researchers attempted to prepare one kind of chitosan hydrogel by slightly crosslinker, which could combine the advantages of the two kinds of hydrogels. In this experiment, the crosslinker was formed by a reaction between the isocyanate group of 1,6-diisocyanatohexan and the hydroxyl group of polyethylene glycol-400 (PEG-400), then the crosslinker reacted with the amidine and the hydroxyl group of ethylene glycol chitosan to form the network structure. Physical properties of the hydrogel were tested by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and biodegradation. Biocompatibility was assessed by cell implantation in vitro and the scaffold was used as a cartilage tissue engineering scaffold to repair a defect in rabbit knee joints in vivo. FTIR results show the formation of a covalent bond during thickening of the ethylene glycol chitosan. SEM and degradation experiments showed that the ethylene glycol chitosan hydrogel is a 3-D, porous, and degradable scaffold. The hydrogel contained 2% ethylene glycol chitosan and 10 MUl crosslinker was selected for the biocompatibility experiment in vitro and in vivo. After chondrocytes were cultured in the ethylene glycol chitosan hydrogel scaffold for 1 week cells exhibited clustered growth and had generated extracellular matrix on the scaffold in vitro. The results in vivo showed that hydrogel-chondrocytes promoted the repair of defect in rabbits. Based on these results, it could be concluded that ethylene glycol chitosan hydrogel is a scaffold with excellent physicochemical properties and it is a promising tissue engineering scaffold. PMID- 24805883 TI - Divergence of the expression and subcellular localization of CCR4-associated factor 1 (CAF1) deadenylase proteins in Oryza sativa. AB - Deadenylation, also called poly(A) tail shortening, is the first, rate-limiting step in the general cytoplasmic mRNA degradation in eukaryotic cells. The CCR4 NOT complex, containing the two key components carbon catabolite repressor 4 (CCR4) and CCR4-associated factor 1 (CAF1), is a major player in deadenylation. CAF1 belongs to the RNase D group in the DEDD superfamily, and is a protein conserved through evolution from yeast to humans and plants. Every higher plant, including Arabidopsis and rice, contains a CAF1 multigene family. In this study, we identified and cloned four OsCAF1 genes (OsCAF1A, OsCAF1B, OsCAF1G, and OsCAF1H) from rice. Four recombinant OsCAF1 proteins, rOsCAF1A, rOsCAF1B, rOsCAF1G, and rOsCAF1H, all exhibited 3'-5' exonuclease activity in vitro. Point mutations in the catalytic residues of each analyzed recombinant OsCAF1 proteins were shown to disrupt deadenylase activity. OsCAF1A and OsCAF1G mRNA were found to be abundant in the leaves of mature plants. Two types of OsCAF1B mRNA transcript were detected in an inverse expression pattern in various tissues. OsCAF1B was transient, induced by drought, cold, abscisic acid, and wounding treatments. OsCAF1H mRNA was not detected either under normal conditions or during most stress treatments, but only accumulated during heat stress. Four OsCAF1-reporter fusion proteins were localized in both the cytoplasm and nucleus. In addition, when green fluorescent protein fused with OsCAF1B, OsCAF1G, and OsCAF1H, respectively, fluorescent spots were observed in the nucleolus. OsCAF1B fluorescent fusion proteins were located in discrete cytoplasmic foci and fibers. We present evidences that OsCAF1B colocalizes with AtXRN4, a processing body marker, and AtKSS12, a microtubules maker, indicating that OsCAF1B is a component of the plant P-body and associate with microtubules. Our findings provide biochemical evidence that OsCAF1 proteins may be involved in the deadenylation in rice. The unique expression patterns of each OsCAF1 were observed in various tissues when undergoing abiotic stress treatments, implying that each CAF1 gene in rice plays a specific role in the development and stress response of a plant. PMID- 24805884 TI - Transformation of a mononitrosyl iron complex to a [2Fe-2S] cluster by a cysteine analogue. AB - Reversible modification of iron-sulfur clusters by nitric oxide acts as a genetic switch in a group of regulatory proteins. While the conversion of [Fe-S] clusters to iron-nitrosyls has been widely studied in the past, little is known about the reverse process, the repair of [Fe-S] clusters. Reported here is a system in which a mononitrosyl iron complex (MNIC), (PPN)[Fe(S(t)Bu)3(NO)] (1), is converted to a [2Fe-2S] cluster, (PPN)2[Fe2S2(SCH2CH2C(O)OMe)4] (2). This conversion requires only the addition of a cysteine analogue, 3 mercaptomethylpropionate (MMP), at room temperature without the need for any other reagents. The identity of 2 was confirmed spectroscopically, chemically, crystallographically, and analytically. Mass spectrometry and (34)S labeling studies support that the bridging sulfides in 2 derive from the added MMP, the cysteine analogue. The NO lost during the conversion of 1 to 2 is trapped in a dinitrosyl iron side product, (PPN)[Fe(SCH2CH2C(O)OMe)2(NO)2] (4). The present system implies that MNICs are likely intermediates in the repair of NO-damaged [2Fe-2S] clusters and that cysteine is a viable molecule responsible for the destabilization of MINCs and the formation of [2Fe-2S] clusters. PMID- 24805885 TI - Food availability as a determinant of weight gain among renal transplant recipients. AB - Excessive weight gain is common after renal transplantation, but it is unknown whether environmental factors, such as food availability, contribute to this important clinical problem. We evaluated the effects of food availability (fast food restaurants, convenience stores, and grocery stores within 1, 2, and 3 mile buffers of transplant recipients' residences) on body mass index (BMI) change during the first year post-transplant. Participants (n = 299) resided in Memphis, Tennessee. BMI increased by 1.42 units (p < .001) corresponding to an average weight gain of 9.25 lbs (5.43%) during the first year post-transplant. The number of grocery stores within 1 mile of recipient's residence was associated with an increase in BMI (p < .05), but fast food restaurants and convenience stores were not significantly associated with BMI change. PMID- 24805886 TI - Interactions of cytochrome C with N-acylated phosphatidylethanolamine lipids. AB - N-acylphosphatidylethanolamines (NAPEs) are naturally occurring derivatives of phosphatidylethanolmine (PE) in which the PE amino group is attached to an acyl chain. Given their occurrence in natural systems, there is interest in knowing the effect of NAPEs on membrane dynamic structure and function. This study examines the ability of NAPEs to affect the association of the cytochrome c and Zn-heme cytochrome c with the surface of bilayer membranes. Fluorescence titration experiments show that cationic cytochrome c has the same high affinity for the surfaces of anionic vesicles that are rich in NAPEs or diplalmitoyphosphatidylglycerol (DPPG) but the protein/membrane interaction in each case is quite different. Cytochrome c adsorption to DPPG membranes is relatively irreversible due to the DPPG molecules adopting an extended conformation that promotes strong hydrophobic contact with the adsorbed protein. In contrast, cytochrome c association with N-acyl DPPE membranes is due primarily to reversible electrostatic interactions with the anionic headgroup, and not hydrophobic contact with the N-acyl chain. The presence of a small mole fraction of an N-propionyl derivative of DPPE (N-C3:0-DPPE) diminishes cytochrome c affinity for vesicles containing a large amount of DPPG apparently by relieving the membrane packing strain that drives the extended DPPG conformation. PMID- 24805887 TI - Reversible disassembly of the yeast V-ATPase revisited under in vivo conditions. AB - Primary active proton transport by eukaryotic V-ATPases (vacuolar ATPases) is regulated via the reversible disassembly of the V1Vo holoenzyme into its peripheral catalytic V1 complex and its membrane-bound proton-translocating Vo complex. This nutrient-dependent phenomenon had been first detected in the midgut epithelium of non-feeding moulting tobacco hornworms (Manduca sexta) and in glucose-deprived yeast cells (Saccharomyces cerevisiae). Since reversible disassembly to date had been investigated mostly in vitro, we wanted to test this phenomenon under in vivo conditions. We used living yeast cells with V-ATPase subunits fused to green, yellow or cyan fluorescent protein and found that only the V1 subunit C (Vma5) was released into the cytosol after substitution of extracellular glucose with galactose, whereas the other V1 subunits remained at or near the membrane. FRET analysis demonstrated close proximity between V1 and Vo even under glucose-starvation conditions. Disassembly, but not reassembly, depended on functional microtubules. Results from overlay blots, pull-down assays and bimolecular fluorescence complementation support the assumption that subunit C interacts directly with microtubules without involvement of linker proteins. PMID- 24805888 TI - Does the orphan medicinal product regulation assist or hinder access to innovative haemophilia treatment in Europe? PMID- 24805890 TI - User ratings of prosthetic usability and satisfaction in VA study to optimize DEKA arm. AB - The Department of Veterans Affairs study to optimize the DEKA Arm provided feedback to inform optimization of the gen 2 (second-generation) prototype and evaluate the gen 3 (third-generation) prototype. This article summarizes recommendations to improve gen 2 and reports satisfaction and usability ratings of gen 2 and gen 3. Data were collected from 39 subjects; 37 subjects were included in this analysis. Of the subjects, 24 were fit with gen 2 (8 radial configuration [RC], 6 humeral configuration [HC], and 10 shoulder configuration [SC]), 13 were fit with gen 3 (4 RC, 5 HC, and 4 SC), and 5 were fit with both. Usability and satisfaction were evaluated using the Trinity Amputation and Prosthesis Experience Scale (TAPES) and study-specific usability and satisfaction scales. Descriptive statistics were examined and prototypes compared using Wilcoxon rank-sum. Results were stratified by configuration level and outcomes compared by prototype. Satisfaction and usability were greater for gen 3 than gen 2. Overall TAPES scores were similar; however, scores of the TAPES aesthetic satisfaction subscale were higher for gen 3. Compared with gen 2 users, gen 3 users were more satisfied with appearance, grips, and doffing and rated overall usability higher. Features of gen 3, including weight, external cables and wires, hand covering, and fingernails, would benefit from further optimization. PMID- 24805889 TI - Considerations for development of sensing and monitoring tools to facilitate treatment and care of persons with lower-limb loss: a review. AB - Sensing and monitoring technologies offer enormous potential to enhance the quality of healthcare provided to persons with lower-limb loss. Incorporation of these technologies into the rehabilitation process creates opportunities for a multidimensional exchange of timely, relevant, and meaningful health information between patients, their prostheses, and healthcare providers. Here, the authors envision a conceptual model for enhancing prosthetic rehabilitation through use of integrated physical and/or biological sensors and remote monitoring methods. Several specific applications that target treatment, diagnosis, and prognosis of health issues faced by persons with limb loss are proposed in an effort to demonstrate how collecting and using objective data can facilitate clinical decision making. Contemporary integrated sensors that may be used in these applications are reviewed and their limitations discussed. It is hoped that the considerations proposed here may serve to stimulate development of clinically useful monitoring and sensing technologies and promote their integration into routine amputation rehabilitation. PMID- 24805891 TI - User and clinician perspectives on DEKA arm: results of VA study to optimize DEKA arm. AB - This article summarizes feedback from Department of Veterans Affairs (VA) subjects and clinicians gathered during the VA optimization study of the DEKA Arm. VA subjects and clinicians tested two DEKA Arm prototypes (second-generation [gen 2] and third-generation [gen 3]). Features of the prototypes in three configurations are described. DEKA used feedback from the VA optimization study and from their own subjects to refine the gen 2 prototype. Thirty-three unique subjects participated in the VA evaluation; 26 participated in the gen 2 evaluation (1 subject participated twice), 13 participated in the gen 3 evaluation, and 5 participated in both gen 2 and gen 3 evaluations. Subject data were gathered through structured and open-ended surveys, interviews, and audio- and videotaped sessions. Study prosthetists and therapists provided ongoing feedback and completed surveys at the end of each subject's protocol. Eleven categories of feedback were identified: weight, cosmesis, hand grips, wrist design, elbow design, end-point control, foot controls, batteries and chargers, visual notifications, tactor, and socket features. Final feedback on the gen 3 was generally positive, particularly regarding improvements in wrist design, visual notifications, foot controls, end-point control, and cosmesis. Additional refinements to make the device lighter in weight, eliminate external wires and cables, and eliminate the external battery may further enhance its perceived usability and acceptability. PMID- 24805892 TI - Prediction of responders for outcome measures of locomotor Experience Applied Post Stroke trial. AB - The Locomotor Experience Applied Post Stroke rehabilitation trial found equivalent walking outcomes for body weight-supported treadmill plus overground walking practice versus home-based exercise that did not emphasize walking. From this large database, we examined several clinically important questions that provide insights into recovery of walking that may affect future trial designs. Using logistic regression analyses, we examined predictors of response based on a variety of walking speed-related outcomes and measures that captured disability, physical impairment, and quality of life. The most robust predictor was being closer at baseline to the primary outcome measure, which was the functional walking speed thresholds of 0.4 m/s (household walking) and 0.8 m/s (community walking). Regardless of baseline walking speed, a younger age and higher Berg Balance Scale score were relative predictors of responding, whether operationally defined by transitioning beyond each speed boundary or by a continuous change or a greater than median increase in walking speed. Of note, the cutoff values of 0.4 and 0.8 m/s had no particular significance compared with other walking speed changes despite their general use as descriptors of functional levels of walking. No evidence was found for any difference in predictors based on treatment group. PMID- 24805893 TI - Muscle activation during body weight-supported locomotion while using the ZeroG. AB - The ZeroG provides dynamic body weight support (BWS) using a harness while individuals with mobility impairments (e.g., spinal cord injury) ambulate overground. Muscle activity during locomotion using this device was studied in 13 nondisabled adults (age 23.8 +/- 2.7 yr). Electromyography (EMG) recordings were collected from tibialis anterior (TA), medial gastrocnemius (MG), rectus femoris (RF), and biceps femoris muscles during randomized walking trials at preferred speeds under five levels of BWS (0%, 20%, 40%, 60%, 80%). Filtered EMG signals from each trial were normalized to 0% BWS and correlated with gait phases. Muscle activity, averaged across muscles, decreased significantly at heel strike by 33.4% with increasing BWS. Offloading significantly decreased heel strike activity of RF (62.8%), MG (35.5%), and TA (25.9%). Gait cycle completion time increased with BWS primarily because of increased swing phase time. These results summarizing the effect of BWS on muscle activation during ambulation can now be compared with clinical populations using the ZeroG. PMID- 24805894 TI - Cognitive Symptom Management and Rehabilitation Therapy (CogSMART) for veterans with traumatic brain injury: pilot randomized controlled trial. AB - Traumatic brain injury (TBI) can result in cognitive impairments and persistent postconcussive symptoms that limit functional recovery, including return to work. We evaluated a 12 wk compensatory cognitive training intervention (Cognitive Symptom Management and Rehabilitation Therapy [CogSMART]) in the context of supported employment for Veterans with mild to moderate TBI. Participants were randomly assigned to receive 12 wk of supported employment plus CogSMART or enhanced supported employment that controlled for therapist attention (control). CogSMART sessions were delivered by the employment specialist and included psychoeducation regarding TBI; strategies to improve sleep, fatigue, headaches, and tension; and compensatory cognitive strategies in the domains of prospective memory, attention, learning and memory, and executive functioning. Compared with controls, those assigned to supported employment plus CogSMART demonstrated significant reductions in postconcussive symptoms (Cohen d = 0.97) and improvements in prospective memory functioning (Cohen d = 0.72). Effect sizes favoring CogSMART for posttraumatic stress disorder symptom severity, depressive symptom severity, and attainment of competitive work within 14 wk were in the small to medium range (Cohen d = 0.35-0.49). Those who received CogSMART rated the intervention highly. Results suggest that adding CogSMART to supported employment may improve postconcussive symptoms and prospective memory. These effects, as well as smaller effects on psychiatric symptoms and ability to return to work, warrant replication in a larger trial. PMID- 24805895 TI - Chronic visual dysfunction after blast-induced mild traumatic brain injury. AB - The purpose of this study was to investigate the long-term visual dysfunction in patients after blast-induced mild traumatic brain injury (mbTBI) using a retrospective case series of 31 patients with mbTBI (>12 mo prior) without eye injuries. Time since mbTBI was 50.5 +/- 19.8 mo. Age at the time of injury was 30.0 +/- 8.3 yr. Mean corrected visual acuity was 20/20. Of the patients, 71% (n = 22) experienced loss of consciousness; 68% (n = 15) of patients in this subgroup were dismounted during the blast injury. Overall, 68% (n = 21) of patients had visual complaints. The most common complaints were photophobia (55%) and difficulty with reading (32%). Of all patients, 25% were diagnosed with convergence insufficiency and 23% had accommodative insufficiency. Patients with more than one mbTBI had a higher rate of visual complaints (87.5%). Asymptomatic patients had a significantly longer time (62.5 +/- 6.2 mo) since the mbTBI than symptomatic patients (42.0 +/- 16.4 mo, p < 0.004). Long-term visual dysfunction after mbTBI is common even years after injury despite excellent distance visual acuity and is more frequent if more than one incidence of mbTBI occurred. We recommend obtaining a careful medical history, evaluation of symptoms, and binocular vision assessment during routine eye examinations in this prepresbyopic patient population. PMID- 24805896 TI - Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP VA). AB - Prevention and rehabilitation of hearing loss and tinnitus, the two most commonly awarded service-connected disabilities, are high priority initiatives in the Department of Veterans Affairs (VA). At least 4,000 Veterans, most with significant hearing loss, will receive cisplatin this year, with more than half sustaining permanent hearing shift and nearly 40% developing new tinnitus. With improved survivability following cancer treatment, Veterans treated with cisplatin are approached with the dual goals of effective treatment and preserved quality of life. This article describes COMP-VA, a comprehensive ototoxicity monitoring program developed for VA patients receiving cisplatin. The program includes an individualized pretreatment prediction model that identifies the likelihood of hearing shift given cisplatin dose and patient factors. It supports both manual and automated hearing testing with a newly developed portable audiometer capable of performing the recommended procedures on the chemotherapy unit during treatment. It also includes objective methods for identifying outer hair cell changes and predicting audiogram changes using distortion-product otoacoustic emissions. We describe this program of evidence-based ototoxicity monitoring protocols using a case example to give the reader an understanding of how this program would be applied, along with a plan for future work to accomplish the final stages of program development. PMID- 24805897 TI - Pressure casting technique for transtibial prosthetic socket fit in developing countries. AB - This study investigated a low-cost and low-skill dependent pressure casting technique (PCAST) to fabricate and fit transtibial (TT) prosthetic sockets in a developing country. Thirteen adult volunteers (average age 47 yr) with unilateral TT amputation participated. After fitting, five participants were lost to follow up (four rejected the prosthesis and one died). The eight remaining participants used the prosthesis for an average of 167 +/- 1 d and indicated regular use throughout this period. Success was evaluated by measures of satisfaction (Satisfaction with Prosthesis Questionnaire [SATPRO]), physical function, and gait recorded after fitting and following the usage period. SATPRO results showed high levels of satisfaction on both occasions. After the usage period, the timed up-and-go and six-minute walk performances increased by 1.7 +/- 2.0 s and 60 +/- 29 m (p = 0.001), respectively, whereas gait speed, cadence, step and stride length, support base, and percent gait cycle times remained unchanged. The results show that a TT PCAST socket (with some minor modifications) was successfully fitted to eight of the participants (success rate of 62%). It is reasonable to conclude that this technique may assist people with TT amputation in a developing country where there is a lack of trained personnel. Importantly, this technique may reduce TT prosthetic costs and increase fitting opportunity in a developing country. PMID- 24805898 TI - Biomechanical study of upper-limb exoskeleton for resistance training with three dimensional motion analysis system. AB - The world's population is aging rapidly, particularly in developed countries. The trend toward prolonged life expectancy will increase the elderly population and thereby lead to an increase in occurrences of age-related health problems such as chronic disease. Healthcare services and home-based rehabilitation are in high demand, and the demand for professional physical therapy is imposing an increasing burden on the healthcare system. Rehabilitation training devices must keep pace with standards of care, be cost effective, and meet the home-based training requirements of today's rehabilitation trends. This article presents an experimental study of a novel spring-loaded upper-limb exoskeleton meant to enable a patient or nondisabled individual to move a limb at multiple joints in different planes for resistance training in a free and unconstrained environment. To assess the functionality of the design, we have measured its kinematic data while performing designated movements and adopted a motion-capture system to verify the function of our mechanism. The collected data and analysis of the kinematic and dynamic joint torques may not only verify our mechanism but also provide a profound understanding of the design requirements for an appropriate spring-loaded exoskeleton for upper-limb resistance training. PMID- 24805899 TI - Comparison of mental health between individuals with spinal cord injury and able bodied controls in Neiva, Colombia. AB - Although research has investigated the mental health of individuals with spinal cord injury (SCI), an overwhelming majority of this research has been conducted in the United States, Western Europe, and other developed countries. The purpose of this study was to compare the mental health of individuals with SCI with able bodied controls in Neiva, Colombia, South America. Subjects included 40 Colombians with SCI and 42 age- and sex-matched controls (N = 82). The groups did not differ based on age, sex, years of education, or socioeconomic status. However, controls were twice as likely to be married. Four measures assessed mental health, including satisfaction with life (Satisfaction with Life Scale), depressive symptoms (Patient Health Questionnaire-9), self-esteem (Rosenberg Self Esteem Scale), and anxiety (State-Trait Anxiety Inventory). In comparison with able-bodied controls, individuals with SCI reported significantly lower mental health on both depressive symptoms and satisfaction with life. These effect sizes were medium and large, respectively. The groups did not differ significantly on measures of self-esteem or anxiety. Mental health of individuals with SCI should be considered a central part of SCI rehabilitation interventions, particularly in Latin America. PMID- 24805900 TI - Effects of a flat prosthetic foot rocker section on balance and mobility. AB - Previous studies have shown that the effective rocker shape of the physiologic ankle-foot system during standing and fore-aft swaying is much flatter than that used during walking, which indicates a more stable base of support for the standing/swaying activity. Previous work suggests that flat regions within the effective rocker shapes of prosthetic ankle-foot systems could provide enhanced stability for standing balance tasks. An experimental prosthetic foot was altered to provide three different flat region lengths within its effective rocker shape. It was hypothesized that longer flat regions of the effective rocker shape would lead to improved standing balance outcomes and reduced walking performance for unilateral transtibial prosthesis users. However, no significant changes were seen in the balance and mobility outcomes of 12 unilateral transtibial prosthesis users when using the three prosthetic foot conditions. Subjects in the study significantly preferred prosthetic feet with relatively low to moderate flat regions over those with long flat regions. All the subjects without loss of light touch or vibratory sensation selected the prosthetic foot with the shortest flat region. More work is needed to investigate the effects of prosthetic foot properties on balance and mobility of prosthesis users. PMID- 24805901 TI - Comparison of Veteran experiences of low-cost, home-based diet and exercise interventions. AB - Obesity is a significant health problem among Veterans who receive care from the Department of Veterans Affairs, as it is for so many other Americans. Veterans from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) experience a myriad of chronic conditions, which can make it difficult to maintain a physically active lifestyle. This pilot study tested the feasibility and user satisfaction with three low-cost, home-based diet and exercise programs, as well as point-of-decision prompts among these Veterans. The three programs target mechanisms that have been shown to improve healthy behavior change, including (1) online mediated social support, (2) objective monitoring of physical activity, and (3) structured high-intensity workouts. This was a randomized crossover trial; each participant used two of the three programs, and all used the point-of-decision prompts. Our qualitative results identified five overall themes related to social support, objective monitoring, structured activity, awareness and understanding, and the point-of-decision prompts. In general, participants were satisfied with and lost weight with each of the interventions. This study demonstrated that these low-cost interventions could be successful with the OIF/OEF Veteran population. A larger and longer study is planned to further investigate the effectiveness of these interventions. PMID- 24805902 TI - Health and well-being of homeless veterans participating in transitional and supported employment: Six-month outcomes. AB - Supported employment, specifically individual placement and support (IPS), improves competitive employment (CE) rates for individuals with serious mental illness, but has not shown greater improvement in non-vocational outcomes than other rehabilitation approaches. The Department of Veterans Affairs offers two types of vocational services, IPS and transitional work experience (TWE), but no study has compared the effectiveness of these approaches. This secondary analysis of data from a study of homeless veterans compared 6 mo improvement in diverse outcomes for five employment patterns: never worked, worked only in TWE, worked in TWE followed by CE, worked in CE without IPS, and worked in CE with IPS referral. Veterans referred to IPS were more likely to be competitively employed. Those who worked in CE (whether following TWE or with or without IPS referral) showed the greatest increase in days worked, employment income, and total income and the greatest decrease in public support income when compared with those who worked only in TWE or not at all. Veterans in TWE showed the greatest increase in residential treatment days, but there were no other differences in non-vocational outcomes between groups. There are multiple paths to CE, but few differences in non-vocational outcomes across employment experiences. PMID- 24805903 TI - Differentiation of tonsil-tissue-derived mesenchymal stem cells controlled by surface-functionalized microspheres in PEG-polypeptide thermogels. AB - Poly(ethylene glycol)-poly(l-alanine) diblock copolymer (PEG-L-PA; molecular weight of each block of 1000-1080 Da) aqueous solutions undergo sol-to-gel transition in a 3.0-8.0 wt % concentration range as the temperature increases. By incorporating the polystyrene microspheres with different functional groups with a size of 100-800 MUm in in situ formed PEG-L-PA thermogels, the differentiation of tonsil-tissue-derived mesenchymal stem cells (TMSCs) was investigated. The mRNA expression and immunohistochemical assays suggested that the TMSCs preferentially undergo adipogenesis in the ammonium (-NH3(+))- or thiol (-SH) functionalized microsphere incorporated thermogels; chondrogenesis in the thiol-, phosphate (PO3(2-))-, or carboxylate (-COO(-))-functionalized microsphere incorporated thermogels; and osteogenesis in the phosphate-, carboxylate functionalized, or neat polystyrene microsphere incorporated thermogels. This paper provides a new TMSC 3D culture system of a sol-gel reversible matrix and suggests that the surface-functional groups of microspheres in the thermogel can control the preferential differentiation of stem cells into specific cell types during the 3D culture. PMID- 24805904 TI - A study on Borna disease virus infection in domestic cats in Japan. AB - Borna disease virus (BDV) infection causes neurological disease in cats. Here, we report BDV infection in 199 hospitalized domestic cats in the Tokyo area. BDV infection was evaluated by detection of plasma antibodies against BDV-p24 or p40. BDV-specific antibodies were detected in 54 cats (27.1%). Interestingly, the percentage of seropositive cats was not significantly different among the three clinical groups, i.e., healthy (29.8%), neurologically asymptomatic disease (22.2%) and neurological disease (33.3%). The specific antibodies were present even in cats aged below one year. The seropositive ratio was constant, irrespective of age and sampling season. The present study suggests that additional factors are required for onset of Borna disease in naturally infected cats and that BDV is transmitted through vertical routes in cats. PMID- 24805905 TI - Follicular thyroid carcinoma characterized by abundant stromal components with chondroid and osseous metaplasia in a dog. AB - A dog developed a cervical mass, and computed tomography verified a mass surrounding the trachea with some pulmonary masses. Histopathologically, the cervical mass was composed of malignant neoplastic cells showing follicular appearance which reacted positive for thyroglobulin on immunohistochemistry. A characteristic feature of the tumor was abundant and metaplastic stromal components. Anastomosed collagenous tissues connecting to capsule of the tumor were abundant in the stroma. In parts of the collagenous tissues, mature cartilages and bones were continuously formed. There was no cellular atypia or invasion in the components. We diagnosed this case as follicular thyroid carcinoma with metaplastic stroma. This is the first case report that characterizes stromal components with chondroid and osseous metaplasia in a canine thyroid carcinoma. PMID- 24805906 TI - Application of reverse genetics for producing attenuated vaccine strains against highly pathogenic avian influenza viruses. AB - In this study, reverse genetics was applied to produce vaccine candidate strains against highly pathogenic avian influenza viruses (HPAIVs) of the H5N1 subtype. The H5 subtype vaccine strains were generated by a reverse genetics method in a biosafety level 2 facility. The strain contained the HA gene from the H5N1 subtype HPAIV attenuated by genetic modification at the cleavage site, the NA gene derived from the H5N1 subtype HPAI or the H5N3 subtype of avian influenza virus and internal genes from A/Puerto Rico/8/34. Vaccination with an inactivated recombinant virus with oil-emulsion completely protected chickens from a homologous viral challenge with a 640 HAU or 3,200 HAU/vaccination dose. Vaccination with a higher dose of antigen, 3,200 HAU, was effective at increasing survival and efficiently reduced viral shedding even when challenged by a virus of a different HA clade. The feasibility of differentiation of infected from vaccinated animals (DIVA) was demonstrated against a challenge with H5N1 HPAIVs when the recombinant H5N3 subtype viruses were used as the antigens of the vaccine. Our study demonstrated that the use of reverse genetics would be an option to promptly produce an inactivated vaccine with better matching of antigenicity to a circulating strain. PMID- 24805907 TI - Paroxysmal dyskinesia suspected as canine epileptoid cramping syndrome in a young Yorkshire terrier dog. AB - A 9-month-old intact female Yorkshire terrier dog was presented with episodic partial seizure-like cramping of the limbs. The patient's episodes began six months previously; the interval between episodes became shorter, and the duration of the episodes increased. Various tests including neurologic examination, blood examination, abdominal radiography, ultrasonographic examination, angiographic computed tomography (CT) and brain magnetic resonance imaging (MRI) detected no remarkable changes. After these tests were conducted, the patient's condition was suspected to be canine epileptoid cramping syndrome (CECS), which could be a form of paroxysmal dyskinesia (PD), and as a trial therapy, Science Diet k/d (Hill's Pet Nutrition, Topeka, KS, U.S.A.) was prescribed. The clinical signs were dramatically reduced after diet therapy, and we diagnosed the patient with CECS. This is the first case report of CECS in a Yorkshire terrier dog. PMID- 24805908 TI - How have pharmacists in different practice settings integrated prescribing privileges into practice in Alberta? A qualitative exploration. AB - WHAT IS KNOWN AND OBJECTIVE: Since 2007, pharmacists in Alberta have had authority to adapt existing prescriptions and independently prescribe medications after a peer review process. This study aimed to explore and characterize how pharmacists incorporated prescribing into practice 3 years after this legislation was approved. METHODS: We invited pharmacists to participate in semi-structured telephone interviews to discuss their prescribing practices. Pharmacists working in community, primary care network, hospital or other settings were selected using a mix of purposive and random sampling. Two investigators independently analysed each transcript using an Interpretive Description approach and thematically categorized prescribing practices according to the level of adoption. RESULTS AND DISCUSSION: Thirty-eight pharmacists (n = 13 independent prescribers) participated. Eighteen (47%) had a primary practice site from community practice, eight (21%) primary care, five (13%) hospital practice and seven (18%) from other settings including specialty clinics and long-term care. Twenty-eight participants were categorized as adopters and ten as non-adopters in their primary practice setting. Prescribing practices adopted were characterized as product focused, disease focused or patient focused. Sixteen (42%) described product-focused prescribing where they continued an existing therapy or substituted medications based on formulary guidelines. Seven (18%) described disease-focused prescribing where current therapies were adapted or initiated based on a protocol in a specific therapeutic area. Five (13%) described patient focused prescribing where they initiated therapy based on patient needs and values, their assessment of the patient and best evidence. Non-adopters were not prescribing, but many described provision of disease or patient-focused care where they influenced prescribing by interacting with other members of the healthcare team. Most commonly, community pharmacists participated in product focused prescribing, whereas hospital and primary care pharmacists practised disease-focused prescribing. WHAT IS NEW AND CONCLUSION: Our data suggest that there have been context-related differences in uptake across practice settings. Despite this, pharmacists in all studied settings engaged in prescribing activities using three approaches and many pharmacists who were not directly prescribing medications reported having involvement in drug therapy decision making. PMID- 24805909 TI - Hierarchical silicon nanospikes membrane for rapid and high-throughput mechanical cell lysis. AB - This letter reports an efficient and compatible silicon membrane combining the physical properties of nanospikes and microchannel arrays for mechanical cell lysis. This hierarchical silicon nanospikes membrane was created to mechanically disrupt cells for a rapid process with high throughput, and it can be assembled with commercial syringe filter holders. The membrane was fabricated by photoelectrochemical overetching to form ultrasharp nanospikes in situ along the edges of the microchannel arrays. The intracellular protein and nucleic acid concentrations obtained using the proposed membrane within a short period of time were quantitatively higher than those obtained by routine, conventional acoustic and chemical lysis methods. PMID- 24805910 TI - Correlates of resistance training in post-treatment breast cancer survivors. AB - PURPOSE: To explore demographic, health, social-cognitive and behavioural correlates of resistance training among post-treatment breast cancer survivors. METHODS: A sample of 330 post-treatment breast cancer survivors recruited from across Australia completed a mailed questionnaire. A multivariate logistical regression model was used to test associations between independent variables and meeting the resistance training guidelines. RESULTS: Less than a quarter of the participants were meeting the resistance training guidelines of at least two sessions of resistance training per week. Higher task self-efficacy for resistance training (p < 0.01) and greater goal-setting behaviour (p < 0.05) were identified as significant predictors of meeting the resistance training guidelines, with a one unit increase in task self-efficacy and goal setting, increasing the odds of meeting the resistance training guidelines by a factor of approximately 1.2 (odds ratio (OR) task self-efficacy = 1.23, 95 % confidence interval (CI) = 1.05-1.43; goal-setting OR = 1.20, 95 % CI = 1.04-1.38). No other variables significantly predicted meeting the resistance training guidelines in the multivariate analysis. CONCLUSIONS: Strategies targeting task self-efficacy and goal-setting behaviours are likely to be important intervention components in resistance training interventions for breast cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: The findings of this study will be useful for informing the development of evidence-based interventions aiming to promote resistance training among this group. PMID- 24805911 TI - A qualitative study investigating chemotherapy-induced nausea as a symptom cluster. AB - PURPOSE: The prevention of chemotherapy-induced vomiting has been improved by antiemetics, but nausea remains problematic. This study explores the concept that this is partly because patients use the term nausea to describe a cluster of symptoms. METHODS: A total of 42 cancer patients currently being treated (n = 21) or at least 6 months of past treatment (median 3.5 years; n = 21) with experience of chemotherapy-induced nausea consented to semi-structured interviews about nausea, which were transcribed and analysed. There were 24 females and 18 males. RESULTS: The nature, number, location, duration and intensity of experiences described as nausea varied. Physical and psychological symptoms included dry retching, vomiting, anorexia, indigestion, change of taste, dizziness, bloating, reflux, inability to concentrate, fatigue and restlessness. Patients located nausea in sites ranging from the head/neck, sternum and mid and lower abdomen to the whole body. Some patients identified symptoms as part of the experience of nausea, and others described symptoms associated with nausea but separate from it. For most, distinguishing features of chemotherapy-induced (as opposed to other) nausea were its constant presence over time, fatigue and emotional associations with the cancer diagnosis. Triggers varied and included food (smells), negative emotions including anxiety, movement, smells (e.g., hand cream, cleaning products), treatment-related events, tooth brushing and mentioning nausea. Prescribed antiemetics were consistently noted as reducing the intensity of, but for many, not completely alleviating, nausea. Distraction and relaxation were preferred management techniques. CONCLUSION: Control of nausea will require treating the particular cluster of symptoms which a patient is experiencing as nausea. PMID- 24805912 TI - Analysis of the five-year outcomes of sleeve gastrectomy and mini gastric bypass: a report from the Indian sub-continent. AB - BACKGROUND: Few reports have compared laparoscopic sleeve gastrectomy (LSG) to laparoscopic Roux-en-Y procedure (LRNY). This study aims at comparing the 5-year follow-up results of mini gastric bypass (MGB or omega gastric bypass (OGB)) and LSG in terms of weight loss, weight regain, complications, and resolution of co morbidities. METHODS: A retrospective analysis of the prospectively collected database was done from the start of our bariatric practice from February 2007 to August 2008 (minimum 5-year follow-up). During this period, 118 patients underwent LSG. These patients were matched in age, gender, preoperative weight, and BMI to 104 patients who underwent MGB in the same time period. The results were compared. RESULTS: Follow-up was achieved in 72 MGB vs 76 LSG patients up to 5 years. The mean BMI for the MGB and LSG group was 44 +/- 3.1 and 42 +/- 5.2 kg/m(2), respectively (P < 0.001). The average percentage of excess weight loss (%EWL) for MGB vs LSG was 63 vs 69 % at 1 year and 68 vs 51.2 % at 5 years (P = 0.166), respectively. Post-op gastro-esophageal reflux disease (GERD) was seen in 2.8 % MGB patients and marginal ulcer was diagnosed in 1 MGB patient (1.4 %). GERD was seen in 21 % post-LSG patients. CONCLUSIONS: Both MGB and LSG are safe, short, and simple operations. Weight loss is similar in MGB and LSG in the first years, but lesser %EWL with LSG at 5 years (68 % in MGB vs 51 % in LSG). Post-op GERD is more common after LSG. PMID- 24805913 TI - Bariatric surgical practice revisited: unrecorded or overlooked problems in the severely obese. AB - Severe loss of activities of daily living, if noted, is a potent reason for weight-loss surgery. PMID- 24805916 TI - [Acute cervical pain syndrome]. PMID- 24805917 TI - Tight and selective caging of chloride ions by a pseudopeptidic host. AB - The selective molecular recognition of chloride versus similar anions is a continuous challenge in supramolecular chemistry. We have designed and prepared a simple pseudopeptidic cage (1 a) that defines a cavity suitable for the tight encapsulation of chloride. The interaction of the protonated form of 1 a with different inorganic anions was studied in solution by (1)H NMR spectroscopy and ESI-MS, and in the solid state by X-ray diffraction. The solution binding data showed that the association constants of 1 a to chloride are more than two orders of magnitude higher than to any other tested inorganic anion. Remarkably, 1 a displayed a high selectivity for chloride over other closely related halides such as bromide (selectivity=111), iodide (selectivity=719), and fluoride (selectivity >1000). Binding experiments ((1)H NMR spectroscopy and ESI-MS) suggested that 1 a has a high-affinity (inner) binding site and an additional low-affinity (external) binding site. The supramolecular complexes with F(-), Cl(-), and Br(-) have been also characterized by the X-ray diffraction of the corresponding [1 a?nHX] crystalline salts. The structural data show that the chloride anion is tightly encapsulated within the host, in a binding site defined by a very symmetric array of electrostatic H-bonds. For the fluoride salt, the size of the cage cavity is too large and is occupied by a water molecule, which fits inside the cage efficiently competing with F(-). In the case of the bigger bromide, the mismatch of the anion inside the cage caused a geometrical distortion of the host and thus a large energetic penalty for the interaction. This minimalistic pseudopeptidic host represents a unique example of the construction of a simple well-defined binding pocket that allows the highly selective molecular recognition of a challenging substrate. PMID- 24805920 TI - Applying a Comprehensive Contextual Climate Change Vulnerability Framework to New Zealand's Tourism Industry. AB - Conceptualisations of 'vulnerability' vary amongst scholarly communities, contributing to a wide variety of applications. Research investigating vulnerability to climate change has often excluded non-climatic changes which may contribute to degrees of vulnerability perceived or experienced. This paper introduces a comprehensive contextual vulnerability framework which incorporates physical, social, economic and political factors which could amplify or reduce vulnerability. The framework is applied to New Zealand's tourism industry to explore its value in interpreting a complex, human-natural environment system with multiple competing vulnerabilities. The comprehensive contextual framework can inform government policy and industry decision making, integrating understandings of climate change within the broader context of internal and external social, physical, economic, and institutional stressors. PMID- 24805918 TI - The imaging of insulinomas using a radionuclide-labelled molecule of the GLP-1 analogue liraglutide: a new application of liraglutide. AB - OBJECTIVE: This study explores a new, non-invasive imaging method for the specific diagnosis of insulinoma by providing an initial investigation of the use of 125I-labelled molecules of the glucagon-like peptide-1 (GLP-1) analogue liraglutide for in vivo and in vitro small-animal SPECT/CT (single-photon emission computed tomography/computed tomography) imaging of insulinomas. METHODS: Liraglutide was labelled with 125I by the Iodogen method. The labelled 125I-liraglutide compound and insulinoma cells from the INS-1 cell line were then used for in vitro saturation and competitive binding experiments. In addition, in a nude mouse model, the use of 125I-liraglutide for the in vivo small-animal SPECT/CT imaging of insulinomas and the resulting distribution of radioactivity across various organs were examined. RESULTS: The labelling of liraglutide with 125I was successful, yielding a labelling rate of approximately 95% and a radiochemical purity of greater than 95%. For the binding between 125I liraglutide and the GLP-1 receptor on the surface of INS-1 cells, the equilibrium dissociation constant (Kd) was 128.8 +/- 30.4 nmol/L(N = 3), and the half inhibition concentration (IC50) was 542.4 +/- 187.5 nmol/L(N = 3). Small-animal SPECT/CT imaging with 125I-liraglutide indicated that the tumour imaging was clearest at 90 min after the 125I-liraglutide treatment. An examination of the in vivo distribution of radioactivity revealed that at 90 min after the 125I liraglutide treatment, the target/non-target (T/NT) ratio for tumour and muscle tissue was 4.83 +/- 1.30(N = 3). Our study suggested that 125I-liraglutide was predominantly metabolised and cleared by the liver and kidneys. CONCLUSION: The radionuclide 125I-liraglutide can be utilised for the specific imaging of insulinomas, representing a new non-invasive approach for the in vivo diagnosis of insulinomas. PMID- 24805921 TI - Long-term indigenous soil conservation technology in the Chencha area, southern Ethiopia: origin, characteristics, and sustainability. AB - The purpose of this study is to examine the origin, development, and characteristics of terraces (kella), plus their potentials and determinants for sustainable use in the Chencha-Dorze Belle area of southern Ethiopia. Field surveys were conducted to determine the various parameters of the indigenous terraces and in order to collect samples for radiocarbon dating. To identify farmers' views of the terrace systems, semi-structured interviews and group discussions were also carried out. Terraces were built and used-as radiocarbon dating proves-at least over the last 800 years. The long-term continued usage of the indigenous terraces is the result of social commitments, the structural features of the terraces, and the farmers' responses to the dynamics of social and cultural circumstances. We dubbed that the terraces are a success story of fruitful environmental management over generations. Thus, a strong need is to preserve and develop this important cultural heritage and example of sustainable land use. PMID- 24805922 TI - Homologous HOmologous Black-Bright-blood and flexible Interleaved imaging sequence (HOBBI) for dynamic contrast-enhanced MRI of the vessel wall. AB - PURPOSE: To present a HOmologous Black-Bright-blood and flexible Interleaved imaging (HOBBI) sequence for dynamic contrast-enhanced magnetic resonance imaging (MRI) of the vessel wall. THEORY AND METHODS: A HOBBI sequence is proposed to acquire high-spatial-resolution black-blood and high-temporal-resolution bright blood dynamic contrast-enhanced images in an interleaved fashion. Black-blood imaging allows for thin vessel wall evaluation, whereas bright-blood imaging obtains the arterial input function accurately. A simulation was performed to assess the accuracy of the pharmacokinetic parameters [transfer constant (K(trans) ) and fractional plasma volume (vp )] generated from HOBBI. In vivo evaluation was also used to validate HOBBI in an animal model of aortic atherosclerosis. RESULTS: In the simulation test, the estimated K(trans) and vp measured by HOBBI were more accurate than those from black-blood dynamic contrast enhanced-MRI. In the animal model testing, K(trans) and vp also demonstrated good interscan reproducibility (K(trans) : ICC = 0.77, vp : ICC = 0.72, respectively). Additionally, K(trans) showed a significant increase from 1 month (0.026 +/- 0.013 min(-1) ) to 2 months (0.069 +/- 0.018 min(-1) ) in animal model plaque progression after balloon injury. CONCLUSION: The proposed HOBBI sequence was demonstrated to be feasible and accurate in estimating the pharmacokinetic parameters of the atherosclerotic vessel wall, and has potential to become an early screening tool for atherosclerosis disease. PMID- 24805923 TI - Bio-inspired detoxification using 3D-printed hydrogel nanocomposites. AB - Rationally designed nanoparticles that can bind toxins show great promise for detoxification. However, the conventional intravenous administration of nanoparticles for detoxification often leads to nanoparticle accumulation in the liver, posing a risk of secondary poisoning especially in liver-failure patients. Here we present a liver-inspired three-dimensional (3D) detoxification device. This device is created by 3D printing of designer hydrogels with functional polydiacetylene nanoparticles installed in the hydrogel matrix. The nanoparticles can attract, capture and sense toxins, while the 3D matrix with a modified liver lobule microstructure allows toxins to be trapped efficiently. Our results show that the toxin solution completely loses its virulence after treatment using this biomimetic detoxification device. This work provides a proof-of-concept of detoxification by a 3D-printed biomimetic nanocomposite construct in hydrogel, and could lead to the development of alternative detoxification platforms. PMID- 24805924 TI - Site-specific RNase A activity was dramatically reduced in serum from multiple types of cancer patients. AB - Potent RNase activities were found in the serum of mammals but the physiological function of the RNases was never well illustrated, largely due to the caveats in methods of RNase activity measurement. None of the existing methods can distinguish between RNases with different target specificities. A systematic study was recently carried out in our lab to investigate the site-specificity of serum RNases on double-stranded RNA substrates, and found that serum RNases cleave double-stranded RNAs predominantly at 5'-U/A-3' and 5'-C/A-3' dinucleotide sites, in a manner closely resembling RNase A. Based on this finding, a FRET assay was developed in the current study to measure this site-specific serum RNase activity in human samples using a double stranded RNA substrate. We demonstrated that the method has a dynamic range of 10(-5) mg/ml- 10(-1) mg/ml using serial dilution of RNase A. The sera of 303 cancer patients were subjected to comparison with 128 healthy controls, and it was found that serum RNase activities visualized with this site-specific double stranded probe were found to be significantly reduced in patients with gastric cancer, liver cancer, pancreatic cancer, esophageal cancer, ovary cancer, cervical cancer, bladder cancer, kidney cancer and lung cancer, while only minor changes were found in breast and colon cancer patients. This is the first report using double stranded RNA as probe to quantify site-specific activities of RNase A in a serum. The results illustrated that RNase A might be further evaluated to determine if it can serve as a new class of biomarkers for certain cancer types. PMID- 24805925 TI - Solvate-dependent spin crossover and exchange in cobalt(II) oxazolidine nitroxide chelates. AB - Two oxazolidine nitroxide complexes of cobalt(II), [Co(II)(L(*))2](B(C6F5)4)2.CH2Cl2 (1) and [Co(II)(L(*))2](B(C6F5)4)2.2Et2O (2), where, L(*) is the tridentate chelator 4,4-dimethyl-2,2-bis(2-pyridyl)oxazolidine N-oxide, have been investigated by crystallographic, magnetic, reflectivity, and theoretical (DFT) methods. This work follows on from a related study on [Co(II)(L(*))2](NO3)2 (3), a multifunctional complex that simultaneously displays magnetic exchange, spin crossover, and single molecule magnetic features. Changing the anion and the nature of solvation in the present crystalline species leads to significant differences, not only between 1 and 2 but also in comparison to 3. Structural data at 123 and 273 K, in combination with magnetic data, show that at lower temperatures 1 displays low-spin Co(II)-to-radical exchange with differences in fitted J values in comparison to DFT (broken symmetry) calculated J values ascribed to the sensitive influence of a tilt angle (theta) formed between the Co(dz(2)) and the trans-oriented O atoms of the NO radical moieties in L(*). Spin crossover in 1 is evident at higher temperatures, probably influenced by the solvate molecules and crystal packing arrangement. Complex 2 remains in the high-spin Co(II) state between 2 and 350 K and undergoes antiferromagnetic exchange between Co-radical and radical-radical centers, but it is difficult to quantify. Calculations of the magnetic orbitals, eigenvalue plots, and the spin densities at the Co and radical sites in 1 and 2 have yielded satisfying details on the mechanism of metal-radical and radical-radical exchange, the radical spins being in pi*NO orbitals. PMID- 24805926 TI - Pharmacologic strategy for one repeated stent thrombosis patient with hyporesponsiveness to standard dual antiplatelet therapy. PMID- 24805927 TI - Warm white light generation from a single phase Dy3+ doped Mg2Al4Si5O18 phosphor for white UV-LEDs. AB - A series of Mg2-xAl4Si5O18:xDy(3+) (0 <=x<= 0.18) samples were synthesized, for the first time, by a solid state method both in a reducing atmosphere and in air. XRD, diffuse reflectance spectra, excitation spectra, emission spectra, decay times and thermal quenching were used to investigate the structure, photoluminescence, energy transfer and thermal properties. The results show that Mg2Al4Si5O18:Dy(3+) can efficiently absorb UV light and emit violet-blue light in the range of 400 to 500 nm from oxygen vacancies in the host as well as blue light (~480 nm) and yellow light (~576 nm) from the f-f transitions of Dy(3+). The emission intensities of the samples obtained under a reducing atmosphere are far superior to those of the samples obtained in air due to an efficient energy transition from oxygen vacancies in the host to Dy(3+). An analysis of the thermal quenching shows that the phosphor Mg2Al4Si5O18:Dy(3+) has excellent thermal properties. The emission intensities of typical samples synthesized in a reducing atmosphere and in air at 250 degrees C are 70% and 81% of their initial intensities at 20 degrees C, respectively. In addition, the emission colors of all of the samples are located in the white light region and the optimal chromaticity coordinates and Correlated Color Temperature are (x = 0.34, y = 0.33) and 5129 K, respectively. Therefore, these white Mg2Al4Si5O18:Dy(3+) phosphors could serve as promising candidates for white-light UV-LEDs. PMID- 24805928 TI - Evidence for adaptation from standing genetic variation on an antimicrobial peptide gene in the mussel Mytilus edulis. AB - Genome scans of population differentiation identify candidate loci for adaptation but provide little information on how selection has influenced the genetic structure of these loci. Following a genome scan, we investigated the nature of the selection responsible for the outlying differentiation observed between populations of the marine mussel Mytilus edulis at a leucine/arginine polymorphism (L31R) in the antimicrobial peptide MGD2. We analysed DNA sequence polymorphisms, allele frequencies and population differentiation of polymorphisms closely linked to L31R, and pairwise and third-order linkage disequilibria. An outlying level of population differentiation was observed at L31R only, while no departure from panmixia was observed at linked loci surrounding L31R, as in most of the genome. Selection therefore seems to affect L31R directly. Three hypotheses can explain the lack of differentiation in the chromosomal region close to L31R: (i) hitchhiking has occurred but migration and recombination subsequently erased the signal, (ii) selection was weak enough and recombination strong enough to limit the hitchhiking effect to a very small chromosomal region or (iii) selection acted on a pre-existing polymorphism (i.e. standing variation) at linkage equilibrium with its background. Linkage equilibrium was observed between L31R and linked polymorphisms in every population analysed, as expected under the three hypotheses. However, linkage disequilibrium was observed in some populations between pairs of loci located upstream and downstream to L31R, generating a complex pattern of third-order linkage disequilibria which is best explained by the hypothesis of selection on a pre-existing polymorphism. We hypothesise that selection could be either balanced, maintaining alleles at different frequencies depending on the pathogen community encountered locally by mussels, or intermittent, resulting in sporadic fluctuations in allele frequency. PMID- 24805929 TI - Daily time management and influence of environmental factors on use of electronic planning devices in adults with mental disability. AB - PURPOSE: To describe daily time management in adults with and without mental disability and to examine differences in the level of their daily time management; to describe the possessions and use of electronic planning devices (EPDs) in activities and how environmental factors influence the use of EPDs in adults with mental disability. METHODS: In a descriptive and cross-sectional design, 32 participants using EPDs and a matched comparison group of 32 healthy adults was recruited. Time-Self rating scale measuring daily time management was adapted for adults. A study specific questionnaire was applied to collect data on five ICF environmental factors. Rasch modelling, descriptive and non-parametric statistics were applied. RESULTS: Time-S has acceptable psychometric properties for use on adults with mental disability. People with mental disability and low level of daily time management who use advanced EPDs are more influenced by environmental factors. The study group perceived that encouragement and support from professionals as well as services influence their use of EPDs. CONCLUSIONS: Time-S can safely be used for people with mental disability. EPDs do not fully compensate the needs of the target-group. Prescribers need to give considerations to this and therefore they should be provided with more knowledge about this matter. Implications for Rehabilitation The Time-S can be applied for measuring daily time management in adults. Adults with mental disability provided with EPDs are not fully compensated in daily time management. Professional support and encouragement as well as backing from the services are important factors for the use of EPDs. Because the smart phones are not prescribed as assistive technology, the need for help from professionals to facilitate daily life is stressed. Therefore, the professionals should be provided with more knowledge about the use of EPDs. PMID- 24805930 TI - Ivabradine: a preliminary observation for a new terapeutic role in patients with multiple organ dysfunction syndrome. PMID- 24805931 TI - The assessment of sensory detection thresholds on the perineum and breast compared with control body sites. AB - INTRODUCTION: Few studies explored multiple sensory detection thresholds on the perineum and breast, but these normative data may provide standards for clinical conditions such as aging, genital and breast surgeries, pathological conditions affecting the genitals, and sexual function. AIMS: The aim of this study was to provide normative data on sensory detection thresholds of three sensory modalities on the perineum and breast. METHODS: Thirty healthy women aged between 18 and 35 years were assessed on the perineum (clitoris, labia minora, vaginal, and anal margin), breast (lateral, areola, nipple), and control body locations (neck, forearm, abdomen) for three sensory modalities (light touch, pressure, vibration). MAIN OUTCOME MEASURES: Average detection thresholds for each body location and sensory modality and statistical comparisons between the primary genital, secondary sexual, and neutral zones were the main outcome measures. RESULTS: Average detection thresholds for light touch suggest that the neck, forearm, and vaginal margin are most sensitive, and areola least sensitive. No statistical difference is found between the primary and secondary sexual zones, but the secondary sexual zone is significantly more sensitive than the neutral zone. Average detection thresholds for pressure suggest that the clitoris and nipple are most sensitive, and the lateral breast and abdomen least sensitive. No statistical difference is found between the primary and secondary sexual zone, but they are both significantly more sensitive than the neutral zone. Average detection thresholds for vibration suggest that the clitoris and nipple are most sensitive. The secondary sexual zone is significantly more sensitive than the primary and neutral zone, but the latter two show no difference. CONCLUSION: The current normative data from sensory detection threshold are discussed in terms of providing standard values for research and clinical conditions. Additional analysis from breast volume, body mass index, hormonal contraception, menstrual cycle, and sexual orientation do not seem to influence the results. Sexual abstinence and body piercing may have some impact. PMID- 24805932 TI - Patient's perspective on hyperbaric oxygen treatment of osteoradionecrosis. AB - Osteoradionecrosis (ORN) is a known complication to radiation therapy for head and neck cancer with a prevalence of 5-7% among radiated patients. Treatment might include dental surgery and reconstruction of the jawbone as well as hyperbaric oxygen treatment (HBOT). HBOT takes place in a closed compartment where patients are breathing 100% oxygen under pressure for 90 minutes once a day every weekday for 6 weeks. In Denmark, HBOT is available at two facilities with very different organizational set-ups. PMID- 24805941 TI - Optimal polarization conversion in coupled dimer plasmonic nanoantennas for metasurfaces. AB - We demonstrate that polarization conversion in coupled dimer antennas, used in phase discontinuity metasurfaces, can be tuned by careful design. By controlling the gap width, a strong variation of the coupling strength and polarization conversion is found between capacitively and conductively coupled antennas. A theoretical two-oscillator model is proposed, which shows a universal scaling of the degree of polarization conversion with the energy splitting of the symmetric and antisymmetric modes supported by the antennas. Using single antenna spectroscopy, we find good agreement for the scaling of mode splitting and polarization conversion with gap width over the range from capacitive to conductive coupling. Next to linear polarization conversion, we demonstrate single-antenna linear to circular polarization conversion. Our results provide strategies for phase-discontinuity metasurfaces and ultracompact polarization optics. PMID- 24805933 TI - Epigenetic high regulation of ATAD2 regulates the Hh pathway in human hepatocellular carcinoma. AB - ATAD2 is associated with many cellular progresses such as cell growth, differentiation and apoptosis. Some studies suggest ATAD2 is highly expressed in cancer cells. In our previous studies, we found that ATAD2 is highly expressed in HCC tissues, compared with adjacent normal tissues, and patients with high expression of ATAD2 had a poorer prognosis. Moreover, we found mir-372 can regulate the expression of ATAD2 in HCC cell lines. We also detected a relationship between the mRNA expression of ATAD2 and Ptch1 by gene microarray. Here, we completed the function studies of ATAD2 in vivo and in vitro, and tested whether ATAD2 could regulate the Hh pathway. ATAD2 and Hh pathway protein expressions in 80 HCC specimens were examined by immunohistochemistry (IHC). The mRNA expression of ATAD2 and Hh pathway members in paired-HCC tissues and cell lines were, respectively, analyzed using quantitative PCR. ATAD2-RNAi was transduced into HCCLM3 and Huh7 cells, using a lentiviral vector. The effect of ATAD2 in HCC cell lines on cell cycle and apoptosis were evaluated by flow cytometry. Tumorigenicity experiments in nude mice were performed to test the function of ATAD2 in vivo. Pharmacological regulation of Hh signaling was performed to test the relation between the ATAD2 and Hh pathways and C-myc. We found that ATAD2 and Ptch1 were both highly expressed in HCC tissues, compared with paired normal hepatic tissues. In addition, we found that ATAD2 could affect the expression of the Hh pathway by PCR and western blot anaysis in HCC cell lines, by observing the outcome before and after transfection. We speculate that ATAD2 cooperates with the MYC gene to regulate the expression of SMO and Gli, activating the Hh pathway and inducing an active feedback of the Hh pathway. PMID- 24805942 TI - Studies of protein folding and dynamics using single molecule fluorescence spectroscopy. AB - Single molecule fluorescence spectroscopy is emerging as an extremely powerful and sensitive tool to study complex biological problems. Single molecule fluorescence measurements can extract useful information that is hidden in the ensemble averaged biophysical or biochemical studies by virtue of their wide range of spatial and temporal resolution capabilities. With these advantages, single molecule fluorescence spectroscopy enables us to monitor the conformational states and their dynamics in the form of statistical distribution or time trajectory of physical observables. This review illustrates how the single molecule fluorescence spectroscopy has been used to solve questions on the complexity and heterogeneity of protein folding and dynamics. PMID- 24805943 TI - Growth factor receptor bound protein 2-associated binder 2, a scaffolding adaptor protein, negatively regulates host immunity against tuberculosis. AB - Cell-mediated immunity is indispensable for host protection against tuberculosis (TB). Growth factor receptor bound protein 2-associated binder (Gab) 2, a scaffolding adaptor protein, negatively regulates signaling pathways critical for T cell-mediated immunity. We sought to investigate the clinical significance and immunological role of Gab2 in Mycobacterium tuberculosis infection. We evaluated Gab2 protein and messenger RNA (mRNA) expression in human patients with pulmonary TB and determined the correlation of the mRNA expression pattern with antigen specific IFN-gamma secretion. Subsequently, we carried out M. tuberculosis infection in Gab2-deficient and wild-type control mice to explore the immunological role of Gab2 by examining bacterial load, histological changes, cytokine secretion, and gene expression of immune-associated transcription factors. mRNA levels of Gab2 and its correlated family member, Gab1, were markedly decreased in untreated patients with pulmonary TB compared with healthy control subjects. Importantly, this decreased Gab2 expression to normal levels after bacterial load in the patient's sputum became undetectable under the standard anti-TB treatment, which negatively correlated with the level of M. tuberculosis antigen-specific IFN-gamma secretion. In the M. tuberculosis infection mouse model, infected Gab2-deficient mice exhibited decreased bacterial load and milder lung pathological damage compared with infected wild-type mice, accompanied by decreased production of IL-2, IL-6, and granulocyte/macrophage colony-stimulating factor proinflammatory cytokines, and an increased T-cell specific T-box transcription factor/GATA binding protein 3 expression ratio. Overall, our study indicates that down-regulation of Gab2 relates to a protective function during M. tuberculosis infection, revealing a potential negative regulatory role for Gab2 in immunity to TB. PMID- 24805944 TI - sRNA-seq analysis of human embryonic stem cells and definitive endoderm reveals differentially expressed microRNAs and novel IsomiRs with distinct targets. AB - MicroRNAs (miRNAs) are noncoding, regulatory RNAs expressed dynamically during differentiation of human embryonic stem cells (hESCs) into defined lineages. Mapping developmental expression of miRNAs during transition from pluripotency to definitive endoderm (DE) should help to elucidate the mechanisms underlying lineage specification and ultimately enhance differentiation protocols. In this report, next generation sequencing was used to build upon our previous analysis of miRNA expression in human hESCs and DE. From millions of sequencing reads, 747 and 734 annotated miRNAs were identified in pluripotent and DE cells, respectively, including 77 differentially expressed miRNAs. Among these, four of the top five upregulated miRNAs were previously undetected in DE. Furthermore, the stem-loop for miR-302a, an important miRNA for both hESCs self-renewal and endoderm specification, produced several highly expressed miRNA species (isomiRs). Overall, isomiRs represented >10% of sequencing reads in >40% of all detected stem-loop arms, suggesting that the impact of these abundant miRNA species may have been overlooked in previous studies. Because of their relative abundance, the role of differential isomiR targeting was studied using the miR 302 cluster as a model system. A miRNA mimetic for miR-302a-5p, but not miR-302a 5p(+3), decreased expression of orthodenticle homeobox 2 (OTX2). Conversely, isomiR 302a-5p(+3) selectively decreased expression of tuberous sclerosis protein 1, but not OTX2, indicating nonoverlapping specificity of miRNA processing variants. Taken together, our characterization of miRNA expression, which includes novel miRNAs and isomiRs, helps establish a foundation for understanding the role of miRNAs in DE formation and selective targeting by isomiRs. PMID- 24805945 TI - Public satisfaction with hospital emergency departments drops in Britain. PMID- 24805947 TI - Nostalgic constructions of nurse education in British national newspapers. AB - AIM: To explore nostalgic constructions of nurse education in British National newspapers. BACKGROUND: British newspaper discourse relating to the increased academic level of nurse education in the UK is negative, evoking comparisons between negative constructions of nurse education in the present and an idealized nostalgic view of the past. DESIGN: Discussion paper. DATA SOURCES: This study used a critical discourse analysis approach to analyse 11 British Newspaper articles, which exemplify nostalgic constructions of nurse education. This was a purposive sample from a database search (LexisNexis) of British national newspaper articles relating to the increasing academic level of nurse education in the period from 1999-2012. IMPLICATIONS FOR NURSING: A dominant nostalgic discourse constructs a 'golden era' of nurse education, which idealizes the past, making the present flawed in comparison. Nostalgic constructions create group identities creating contrasting 'caring' nurses educated in the idealized past with those educated now, who are perceived as too educated to care. An inherent characteristic of the nostalgic discourse is the notion that the solution to current problems with nurse education is a return to an idealized version of the past. Another less common newspaper discourse views nostalgia as a problematic construct. CONCLUSION: Nostalgic discourse with a focus on the past potentially acts as a barrier to creating an effective nurse education system for the 21(st) Century. This focus on an idealized past also has potential consequences in terms of public opinion and legitimization of government policy, which might otherwise be viewed as retrograde. PMID- 24805946 TI - Establishment of a structure-activity relationship of 1H-imidazo[4,5-c]quinoline based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness. AB - Compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against Trypanosoma brucei cultures. With an eye toward using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, to improve the physicochemical properties, and to improve the selectivity profile over human kinases. In this work, we have developed structure activity relationships for analogues of 1 and have prepared analogues of 1 with improved solubility properties and good predicted central nervous system exposure. In this way, we have identified 4e, 9, 16e, and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases. PMID- 24805948 TI - Outcome of organs procured from donors on extracorporeal membrane oxygenation support: an analysis of kidney and liver allograft data. AB - INTRODUCTION: Extracorporeal membrane oxygenation has become rescue therapy for adults with overwhelming cardiac and/or respiratory failure. Not all patients are saved, creating a new cohort of potential organ donors. This study examines the outcomes of liver and kidney allografts procured from donors on extracorporeal membrane oxygenation (ECMO). METHODS: A retrospective review was conducted through the local organ procurement organization. Donors on ECMO prior to notification were classified into donation after brain death (DBD) and donation after cardiac death (DCD). We compared short-term outcome data against published standards. RESULTS: Between 1995 and 2012, 97 organs were procured from 41 donors supported on ECMO. There were 68 kidneys donated, 51 were transplanted and 17 discarded. Excluding extended criteria donors, 29 DBD and 13 DCD kidneys were transplanted from donors supported on ECMO. Delayed graft function occurred in 34% of DBD kidneys and 38% of DCD kidneys. Kidney allograft survival at one yr was 93%. Twenty-four livers were procured, nine discarded, and 15 transplanted. Ninety-three percent of liver transplant recipients were alive with graft function at one yr. CONCLUSIONS: Donation after brain death kidneys procured from donors on ECMO perform similarly to non-ECMO organs with regard to delayed graft function (DGF), one-yr graft survival and function. Livers from ECMO donors have a higher discard rate than non-ECMO donors, but function similarly at six months and one yr. PMID- 24805949 TI - Molecular chalcoxides (chalcopolyoxometalates): a family of functional materials with emergent properties. AB - Molecular chalcoxides (chalcoPOMs; POMs=polyoxometalates), a recently discovered new family of compounds with well-defined building block attributes, are discussed in terms of developing new functional materials. This is because the combination of sulfur-containing metallo-dimers with highly condensed metallo-oxo units allows the assembly of new clusters with hybrid properties intermediate between those of polyoxometalates and chalcogenides. Moreover, the prospect that the molecular chalcoxides could be excellent new models for a better understanding of chalcogenide's functionality, as well as promising candidates for the development of new functional molecule-based or composite nanomaterials, is proposed. The concepts that support my aim for further development of the new family of molecular chalcoxides as functional materials and my vision for their potential implications in the materials chemistry are discussed. PMID- 24805951 TI - Impaired nitric oxide production and increased blood pressure in systemic heterozygous ATP2B1 null mice. AB - BACKGROUND: In the 'Millennium Genome Project', we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions. METHOD: Since ATP2B1 knockout mice are reported to be embryo lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1(+/-)) mice, and evaluated the implication of ATP2B1 in blood pressure. RESULTS: ATP2B1(+/-) mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1(+/-) mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1(+/-) mice. In addition, cultured endothelial cells of ATP2B1(+/-) mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1(+/-) mice and control mice were not significantly different. CONCLUSION: These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure. PMID- 24805952 TI - Pheochromocytoma associated with pregnancy: unexpected favourable outcome in patients diagnosed after delivery. AB - OBJECTIVE: The objective of this study is to present the clinical findings and outcome of a large cohort of pregnant women with pheochromocytoma (PHEO) with the aim to contribute to the better recognition, detection and management of pregnancy-related PHEO in the population of pregnant patients with hypertension. METHODS: This is a longitudinal follow-up of a single cohort of 15 patients aged 19-40 years with PHEO associated with pregnancy. Urinary catecholamines and vanillylmandelic acid (VMA) were analysed. Ret proto-oncogene, SDHB and VHL mutations were determined in germline DNA from seven women using PCR followed by direct sequencing. RESULTS: During pregnancy, all women presented typical features of catecholamines excess. Nevertheless, biochemical diagnosis was performed only in four out of 15 cases during pregnancy and postpartum in the remaining 11. Paroxysmal hypertension was the predominant pattern. Urinary catecholamines and/or VMA were increased in all patients. Tumours were adrenal in 13 patients and extraadrenal in two. Mutations in the Ret proto-oncogene were found in four patients, in the VHL gene in one and in the SDHB gene in one. Antihypertensive treatment resulted in effective control of blood pressure and all women survived. In the group of women diagnosed postpartum, one foetus demised. Newborns from mothers receiving adequate treatment survived. One woman left the hospital after caesarean section but before PHEO surgery became pregnant again and this gestation ended with maternal-foetal dead. CONCLUSION: A high index of suspicion in all pregnant women presenting hypertension mainly paroxystic during any gestational phase and/or a history of familial PHEO are the keys to disclose this important diagnosis. PMID- 24805953 TI - Reduced telomere length is not associated with early signs of vascular aging in young men born after intrauterine growth restriction: a paradox? AB - OBJECTIVE: The mechanisms that increase cardiovascular risk in individuals born small for gestational age (SGA) are not well understood. Telomere shortening has been suggested to be a predictor of disease onset. Our aim was to determine whether impaired intrauterine growth is associated with early signs of vascular aging and whether telomere length could be a biomarker of this pathway. METHODS: One hundred and fourteen healthy young men born SGA or after normal pregnancy [appropriate for gestational age (AGA)] were enrolled. Patient data were gathered from questionnaires and clinical exams, including blood pressure (BP) measurement routine laboratory analyses, and carotid intima-media thickness (cIMT). Leukocyte telomere length (LTL) was assessed by quantitative PCR. Birth data were obtained from medical records. RESULTS: The SGA group had significantly higher pulse pressure and cIMT, and a trend to increased SBP and heart rate in comparison to the AGA group. Interestingly, SGA men exhibited a 42% longer LTL than the AGA group. LTL was inversely associated with age, BMI, BP and birth parameters. In multiple regression analysis, BMI was the key determinant of SBP and cIMT. CONCLUSION: Young men born SGA show early signs of vascular aging. Unexpectedly, in our cohort, the SGA group had longer telomeres than the normal controls. Although longer telomeres are predictive of better health in the future, our findings could indicate a faster telomere attrition rate and probable early onset of cardiovascular risk in SGA participants. Follow-up of this cohort will clarify hypothesis and validate telomere dynamics as indicators of future health risks. PMID- 24805954 TI - Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation? AB - Percutaneous ablation of the renal nerves [renal denervation (RDN)] has recently become available for treatment of (therapy-resistant) hypertension. In this review, the potential importance of RDN for patients with chronic kidney disease (CKD) is discussed. An overview of the role of the renal nerves is given, and the role of the kidneys as both generators and recipients of sympathetic hyperactivity is described. The clinical relevance of increased sympathetic nervous system activity in CKD is reviewed, and the effects of conventional treatment on sympathetic hyperactivity are summarized. Next, we present the current knowledge on the effect of RDN in CKD from both experimental and clinical studies. Finally, we discuss how this knowledge may help us in predicting the effect of RDN in hypertensive patients and ways to monitor the effect of the procedure itself. PMID- 24805955 TI - A polymorphism in the major gene regulating serum uric acid associates with clinic SBP and the white-coat effect in a family-based study. AB - OBJECTIVES: Hyperuricemia associates with hypertension, but it is uncertain whether this relationship is causal in nature. Glucose transporter 9 (GLUT9) gene is a major genetic determinant of plasma uric acid levels in humans. Since polymorphisms are randomly distributed at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and hypertension. METHODS: We tested the association between uric acid, the rs734553 polymorphism of the GLUT9 gene and arterial pressure in a family-based study including 449 individuals in a genetically homogenous population in Southern Italy. RESULTS: Serum uric acid levels were strongly associated (P < 0.001) with all components of clinic and 24 h ambulatory blood pressures (BPs). However, only clinic SBP and the white-coat effect (the difference in clinic systolic and daytime systolic ambulatory blood pressure monitoring) associations remained significant after adjustment for classical risk factor and the estimated glomerular filtration rate. Serum uric acid was strongly associated with the risk allele (T) of the rs734553 polymorphism (P < 0.001). Furthermore, TT individuals showed higher clinic SBP (129 + SEM 1 mmHg) than GT (125 + 1 mmHg) and GG individuals (122 + 3 mmHg), as well as a higher white-coat effect (P = 0.02), confirming that the association between uric acid and these BP components is unconfounded by environmental risk factors. CONCLUSION: Results in this family-based study are compatible with the hypothesis that uric acid is a causal risk factor for hypertension. Trials testing uric acid-lowering interventions are needed to definitively establish the causal implication of hyperuricemia in human hypertension. [Corrected] PMID- 24805956 TI - Overweight, adipocytokines and hypertension: a prospective population-based study. AB - OBJECTIVE: The adipocytokines, leptin, adiponectin, and interleukin-6, which stimulate liver C-reactive protein (CRP) production, are regarded as potential candidate intermediates between adipose tissue and overweight-induced hypertension. METHODS: We examined the associations between leptin, adiponectin, and CRP levels with both prevalent and 5-year incident hypertension (IHT) in a general population of Danish adults (n = 5,868, 51.3% women, mean age 45.8 +/- 7.9 years). RESULTS: We recorded 2195 prevalent and 379 incident cases of hypertension. In models including leptin, CRP, adiponectin, sex, age, lifestyle risk factors, lipids, insulin, hemoglobin A1c, and in the incident model also baseline heart rate and blood pressure, only leptin of the three candidate intermediates was significantly associated with both prevalent and IHT [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.32, P = 0.002, and OR = 1.24, 95% CI 1.01-1.54, P = 0.044] for one standard deviation increase in log transformed leptin levels, respectively. Log-transformed CRP was associated with prevalent (OR = 1.16, 95% CI 1.07-1.26, P < 0.001) but not IHT (OR = 0.98, 95% CI 0.84-1.14, P = 0.76). Log-transformed adiponectin was neither associated with prevalent nor IHT (OR = 0.94, 95% CI 0.87-1.02, P = 0.11 and OR = 0.93, 95% CI 0.80-1.08, P = 0.33). Comparing the lowest with the highest quintile of sex specific BMI levels, there was an almost two-fold increase in IHT (OR = 1.89, 95% CI 1.10-3.25, P = 0.023) in the fully adjusted model. The population attributable risk estimate of IHT owing to overweight was 31%. CONCLUSION: Leptin, but not adiponectin or CRP, may play a mediating role in overweight-induced hypertension. However, as BMI was a strong independent predictor of hypertension, other factors than leptin must be involved in the pathogenesis of overweight-related hypertension. PMID- 24805957 TI - Asymmetry in prevalence of femoral but not carotid atherosclerosis. AB - OBJECTIVE(S): Atherosclerotic disease is caused by a combination of systemic and local factors (e.g. geometry) affecting local flow conditions. In contrast to the carotid artery, at the iliac-femoral artery region, a large degree of bilateral asymmetry exists. Therefore, we aimed to determine the influence of body side on the prevalence of atherosclerosis (i.e. plaque and intima-media thickness; IMT) at the carotid and femoral arteries. METHODS: Data were used from the ASKLEPIOS study, including 2524 apparently healthy individuals with a mean age of 46 years (range 35-55 years). Echographic images were obtained bilaterally of the carotid and femoral arteries. A single observer approach was used for the acquisition and quantification of plaques and IMT. RESULTS: The carotid artery displays no significant left-right difference in IMT values nor plaque prevalence (right: 12.0 vs. left 13.3%; P = 0.18). In contrast, for the femoral artery, the IMT distribution at the right common femoral artery is more skewed (P90 right: 1.11 mm, left 1.01 mm; P < 0.001), which is mirrored by a significantly higher plaque prevalence (right: 21.9 vs. left: 15.7%; P < 0.001). CONCLUSION: In the present study, atherosclerotic lesions are more prevalent at the right than at the left femoral artery. This finding highlights the possible role of local arterial geometry in the development of atherosclerosis and underscores the importance of the choice of body side when assessing vascular health. PMID- 24805958 TI - Oxidized low-density lipoprotein in postmenopausal women. AB - BACKGROUND: Oxidized low-density lipoprotein (oxLDL) leads to atherosclerosis and cardiovascular disease, the most frequent causes of death worldwide. After menopause, lipid and lipoprotein metabolism changes and women are at greater risk of cardiovascular disease compared to fertile women. The aim of this study was to determine the prevalence of serum oxLDL in postmenopausal women and to identify possible associations of clinical and laboratory features with oxLDL in these patients. METHOD: After clinical examination and completing a clinical questionnaire, an ultrasound examination of both carotid arteries was conducted and blood was drawn from 533 postmenopausal women. oxLDL concentration was determined using proton NMR spectroscopy. RESULTS: Oxidized LDL was detected in 12.4% (95% confidence interval 9.7-15.5) of postmenopausal women with a median of 0.18 mg/dl (interquartile range 0.10-0.43). Although intima-media thickness did not differ, postmenopausal women with serous oxLDL had more often atherosclerotic plaques compared to women without oxLDL (6/66 vs. 0/467; P < 0.01). Higher concentrations of high-density lipoprotein, impaired glucose intolerance, and DBP were independently associated with the occurrence of oxLDL. If oxLDL was present, higher high-density lipoprotein and glucose intolerance were associated with higher concentrations of oxLDL. In contrast, higher blood urea concentrations were associated with lower concentrations of oxLDL. CONCLUSION: This study presents the prevalence and concentration of oxLDL in postmenopausal women and demonstrates that oxLDL concentration can be quantified by proton NMR spectroscopy in large patient samples. The data suggest that oxLDL may be a biomarker for incipient atherosclerotic changes in postmenopausal women. In contrary to the association of dyslipoproteinemia and diabetes, higher blood urea concentrations were associated with lower concentrations of oxLDL. PMID- 24805959 TI - Plasmin in urine from patients with type 2 diabetes and treatment-resistant hypertension activates ENaC in vitro. AB - BACKGROUND: Aberrant filtration of plasminogen from plasma and subsequent activation to plasmin in the urinary space may activate proteolytically the epithelial sodium channel, ENaC. In conditions with chronic albuminuria, this may cause hypertension. It was hypothesized that patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension excrete plasmin(ogen) in urine in proportion to albumin and that plasmin confers to urine the ability to activate ENaC. METHOD: Patients (n = 113) with T2DM and resistant hypertension, defined as systolic blood pressure (SBP) more than 130 mmHg and/or diastolic blood pressure (DBP) more than 80 mmHg despite use of at least three drugs with one diuretic and one renin-angiotensin system inhibitor, were included. Urine was analyzed for albumin, creatinine, plasmin(ogen), protease activity, and ability to activate inward current in single collecting duct cells. RESULTS: Mean ambulatory SBP/DBP was 143 +/- 1/77 +/- 0.7 mmHg; HbA1c 7.35%; and eGFR 81.0 ml/min per 1.73 m (geometric means). Patients with microalbuminuria (39%) and macroalbuminuria (13%) displayed significantly elevated levels of urinary plasmin(ogen) normalized to urine creatinine compared with patients with normal excretion of albumin (48%). Urinary plasminogen correlated significantly to urine albumin. Western immunoblotting and gelatine zymography confirmed active plasmin in urine samples from patients with microalbuminuria and macroalbuminuria. Single collecting duct cells displayed significantly increased, amiloride-sensitive, inward current when superfused with urine from albuminuric patients compared with patients with normal albumin excretion. Urinary plasminogen/creatinine ratio correlated significantly with 24-h ambulatory blood pressure. CONCLUSION: Aberrant presence of plasmin in preurine may inappropriately activate ENaC in patients with type 2 diabetes and microalbuminuria. This may contribute to treatment-resistant hypertension. PMID- 24805960 TI - Oxygen vacancy clustering and pseudogap behaviour at the LaAlO3/SrTiO3 interface. AB - The two-dimensional electron gas at the LaAlO3/SrTiO3 interface promises to add a new dimension to emerging electronic devices due to its high degree of tunability. Defects in the form of oxygen vacancies in titanate surfaces and interfaces, on the other hand, play a key role in the emergence of the ordered states and their tunability at the interface. On the basis of an effective model, we study the influence of oxygen vacancies on the superconductivity and ferromagnetism at the LaAlO3/SrTiO3 interface. Using the Bogoliubov-de Gennes formulation in conjunction with Monte Carlo simulation, we find a clustering of the oxygen vacancies at the interface that favours the formation of coexisting ferromagnetic puddles spatially separated from the superconductivity. We also find a carrier freeze-out at low temperatures, observed experimentally in a wide variety of samples. A sufficiently large amount of oxygen vacancies leads to pseudogap-like behaviour in the superconducting state. PMID- 24805962 TI - Smart drug delivery systems: from fundamentals to the clinic. AB - Forty years after the first reports on stimuli-responsive phase transitions in synthetic hydrogels, the first medicines based on responsive components are approaching the market. Sensitiveness to internal or external signals of the body can be achieved by means of materials (mostly polymers, but also lipids and metals) that modify their properties as a function of the intensity of the signal and that enable the transduction into changes in the delivery system that affect its ability to host/release a therapeutic substance. Integration of responsive materials into implantable depots, targetable nanocarriers and even insertable medical devices can endow them with activation-modulated and feedback-regulated control of drug release. This review offers a critical overview of therapeutically-interesting stimuli to trigger drug release and the evolution of responsive materials suitable as functional excipients, illustrated with recent examples of formulations in clinical trials or already commercially available, which can provide a perspective on the current state of the art on smart drug delivery systems. PMID- 24805961 TI - Microbial communities in sunken wood are structured by wood-boring bivalves and location in a submarine canyon. AB - The cornerstones of sunken wood ecosystems are microorganisms involved in cellulose degradation. These can either be free-living microorganisms in the wood matrix or symbiotic bacteria associated with wood-boring bivalves such as emblematic species of Xylophaga, the most common deep-sea woodborer. Here we use experimentally submerged pine wood, placed in and outside the Mediterranean submarine Blanes Canyon, to compare the microbial communities on the wood, in fecal pellets of Xylophaga spp. and associated with the gills of these animals. Analyses based on tag pyrosequencing of the 16S rRNA bacterial gene showed that sunken wood contained three distinct microbial communities. Wood and pellet communities were different from each other suggesting that Xylophaga spp. create new microbial niches by excreting fecal pellets into their burrows. In turn, gills of Xylophaga spp. contain potential bacterial symbionts, as illustrated by the presence of sequences closely related to symbiotic bacteria found in other wood eating marine invertebrates. Finally, we found that sunken wood communities inside the canyon were different and more diverse than the ones outside the canyon. This finding extends to the microbial world the view that submarine canyons are sites of diverse marine life. PMID- 24805963 TI - Improved detection of coastal acid sulfate soil hotspots through biomonitoring of metal(loid) accumulation in water lilies (Nymphaea capensis). AB - Anthropogenically disturbed coastal acid sulfate soils along the east coast of Australia, and worldwide, periodically result in the discharge of acid waters containing high concentrations of metals. Identifying priority sites (hotspots) within a catchment for acid sulfate soil remediation activities typically involves long-term monitoring of drainwater chemistry, including the capture of data on unpredictable rain-induced groundwater discharge events. To improve upon this monitoring approach, this study investigated using the water lily (Nymphaea capensis) as a biomonitor of drainage waters to identify hotspots in three acid sulfate soil impacted catchments (83 km(2)) in north-eastern New South Wales, Australia. In one catchment where the location of hotspots was known, water lily lamina concentrations of a suite of metal(loid)s were significantly (p<0.05) higher than plants collected from an unpolluted 'reference' drainage channel, thus validating the concept of using this species as a biomonitor. A catchment scale water lily sampling program undertaken in catchments with unidentified hotspots revealed within catchment variation of plant metal concentrations up to 70-fold. High resolution maps produced from these results, therefore, provided strong evidence for the location of potential hotspots which were confirmed with measurements of drainwater chemistry during rain-induced groundwater discharge events. Median catchment lily accumulation was ca. 160 mg Al kg(-1) and 1,300 mg Fe kg(-1), with hotspots containing up to 6- and 10-fold higher Al and Fe concentrations. These findings suggest that biomonitoring with N. capensis can be an important tool to rapidly identify priority sites for remediation in acid sulfate soil impacted landscapes. PMID- 24805965 TI - Shear behavior of bovine scleral tissue. AB - Ocular tissue properties have been widely studied in tension and compression for humans and a variety of animals. However, direct shear testing of the tissues of the sclera appear to be absent from the literature even though modeling, analyses, and anatomical studies have indicated that shear may play a role in the etiology of primary open angle glaucoma (POAG). In this work, the mechanical behavior of bovine scleral tissue in shear has been studied in both out-of-plane and in-plane modes of deformation. Stress-strain and relaxation tests were conducted on tissue specimens at controlled temperature and hydration focusing on trends related to specimen location and orientation. There was generally found to be no significant effect of specimen orientation and angular location in the globe on shear stiffness in both modes. The in-plane response, which is the primary load carrying mode, was found to be substantially stiffer than the out-of plane mode. Also, within the in-plane studies, tissue further from the optic nerve was stiffer than the near tissue. The viscosity coefficient of the tissue varied insignificantly with distance from the optic nerve, but overall was much higher in-plane than out-of-plane. PMID- 24805966 TI - Recurrent anterior glenohumeral instability: the quantification of glenoid bone loss using magnetic resonance imaging. AB - OBJECTIVE: To investigate the accuracy of conventional magnetic resonance imaging (MRI) in determining the severity of glenoid bone loss in patients with anterior shoulder dislocation by comparing the results with arthroscopic measurements. SUBJECTS AND METHODS: Institutional review board approval and written consent from all patients were obtained. Thirty-six consecutive patients (29 men, seven women; mean age, 34.5 [range, 18-55] years) with recurrent anterior shoulder dislocation (>=3 dislocations; mean, 37.9; range, 3-200) and suspected glenoid bone loss underwent shoulder MRI before arthroscopy (mean interval, 28.5 [range, 9-73] days). Assessments of glenoid bone loss by MRI (using the best-fit circle area method) and arthroscopy were compared. Inter- and intrareader reproducibility of MRI-derived measurements was evaluated using arthroscopy as a comparative standard. RESULTS: Glenoid bone loss was evident on MRI and during arthroscopy in all patients. Inter- and intrareader correlations of MRI-derived measurements were excellent (intraclass correlation coefficient = 0.80-0.82; r = 0.81-0.86). The first and second observers' measurements showed strong (r = 0.76) and moderate (r = 0.69) interreader correlation, respectively, with arthroscopic measurements. CONCLUSIONS: Conventional MRI can be used to measure glenoid bone loss, particularly when employed by an experienced musculoskeletal radiologist. PMID- 24805968 TI - Frequency domain optical parametric amplification. AB - Today's ultrafast lasers operate at the physical limits of optical materials to reach extreme performances. Amplification of single-cycle laser pulses with their corresponding octave-spanning spectra still remains a formidable challenge since the universal dilemma of gain narrowing sets limits for both real level pumped amplifiers as well as parametric amplifiers. We demonstrate that employing parametric amplification in the frequency domain rather than in time domain opens up new design opportunities for ultrafast laser science, with the potential to generate single-cycle multi-terawatt pulses. Fundamental restrictions arising from phase mismatch and damage threshold of nonlinear laser crystals are not only circumvented but also exploited to produce a synergy between increased seed spectrum and increased pump energy. This concept was successfully demonstrated by generating carrier envelope phase stable, 1.43 mJ two-cycle pulses at 1.8 MUm wavelength. PMID- 24805969 TI - Impaired functional capacity in potential liver transplant candidates predicts short-term mortality before transplantation. AB - Liver transplantation (LT) is a lifesaving treatment. Because of the shortage of donor organs, some patients will not survive long enough to receive a transplant. The identification of LT candidates at increased risk of short-term mortality without transplantation may affect listing decisions. Functional capacity, determined with cardiopulmonary exercise testing (CPET), is a measure of cardiorespiratory reserve and predicts perioperative outcomes. This study examined the association between functional capacity and short-term survival before LT and the potential for CPET to predict 90-day mortality without transplantation. A total of 176 patients who were assessed for nonacute LT underwent CPET. Ninety days after the assessment, 10 of the 164 patients who had not undergone transplantation were deceased (mortality rate = 6.1%). According to a comparison of survivors and nonsurvivors, the Model for End-Stage Liver Disease score, UK Model for End-Stage Liver Disease (UKELD) score, age, anaerobic threshold, and peak oxygen uptake (VO(2)) were significant univariate predictors of 90-day mortality without transplantation, but only the UKELD score and peak VO(2) retained significance in a multivariate analysis. The mean peak VO(2) was significantly lower for nonsurvivors versus survivors (15.2 +/- 3.3 versus 21.2 +/- 5.3 mL/minute/kg, P < 0.001). According to a receiver operating characteristic (ROC) curve analysis, peak VO(2) performed well as a diagnostic test (area under the ROC curve = 0.84, 95% confidence interval = 0.76-0.92, sensitivity = 0.90, specificity = 0.74, P < 0.001). The optimal cutoff value for predicting mortality was <=17.6 mL/minute/kg. The positive predictive value of a peak VO(2) <= 17.6 mL/minute/kg for 90-day mortality was greatest for patients with high UKELD scores: 38% of the patients with a UKELD score >= 57 and a peak VO(2) <= 17.6 mL/minute/kg died, whereas only 6% of the patients with a UKELD score >= 57 and a peak VO(2) > 17.6 mL/minute/kg died (P = 0.03). In conclusion, patients assessed for LT with an impaired functional capacity have poorer short term survival; this is particularly true for individuals with worse liver disease severity. PMID- 24805970 TI - Genetics in degenerative dementia: current status and applicability. AB - An increasing number of hereditary neurodegenerative diseases, including autosomal-dominant Alzheimer disease (AD), familial autosomal-dominant frontotemporal dementia (FTD), and heritable Lewy body disease (LBD) have been defined at the molecular level in recent years, making it possible to determine the genotype before the onset of symptoms. The identification of deterministic genes for these common adult-onset genetic diseases is moving the field of genetic counseling toward a new and challenging direction. With the identification of genes associated with AD and FTD, there is considerable interest in the clinical application of genetic information in genetic counseling and testing. Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians therefore increases the need for a better understanding of the multifaceted issues associated with genetic testing. The aims of this systematic review are: (1) to underline the need to consider a genetic etiology of AD, FTD, and LBD; (2) to provide clinicians with information necessary to effectively translate genetic diagnosis into clinical practice; and (3) to highlight gaps and uncertainties in the field which will need to be addressed by future research. PMID- 24805971 TI - Why are spousal caregivers more prevalent than nonspousal caregivers as study partners in AD dementia clinical trials? AB - OBJECTIVES: Most Alzheimer disease (AD) caregivers are not spouses and yet most AD dementia trials enroll spousal study partners. This study examines the association between caregiver relationship to the patient and willingness to enroll in an AD clinical trial and how caregiver burden and research attitudes modify willingness. DESIGN: Interviews with 103 AD caregivers who met criteria for ability to serve as a study partner. RESULTS: A total of 54% of caregivers were spouses or domestic partners and the remaining were adult children. Willingness to enroll a patient in a clinical trial was associated with being a spouse [odds ratio (OR)=2.53, P=0.01], increasing age (OR=1.39, P=0.01), and increasing scores on the Research Attitudes Questionnaire (OR=1.39, P<0.001). No measures of caregiver burden or patient health were significant predictors of willingness. In multivariate models both research attitudes (OR=1.37, P<0.001) and being a spouse, as opposed to an adult child, (OR=2.06, P=0.048) were independently associated with willingness to participate. CONCLUSIONS: Spousal caregivers had both a higher willingness to participate and a more positive attitude toward research. Caregiver burden had no association with willingness to participate. The strongest predictor of willingness was research attitudes. PMID- 24805973 TI - Classification of spent reactor fuel for nuclear forensics. AB - In this paper we demonstrate the use of pattern recognition and machine learning techniques to determine the reactor type from which spent reactor fuel has originated. This has been done using the isotopic and elemental measurements of the sample and proves to be very useful in the field of nuclear forensics. Nuclear materials contain many variables (impurities and isotopes) that are very difficult to consider individually. A method that considers all material parameters simultaneously is advantageous. Currently the field of nuclear forensics focuses on the analysis of key material properties to determine details about the materials processing history, for example, utilizing known half-lives of isotopes can determine when the material was last processed (Stanley, F. E. J. Anal. At. Spectrom. 2012, 27, 1821; Varga, Z.; Wallenius, M.; Mayer, K.; Keegan, E.; Millet, S. Anal. Chem. 2009, 81, 8327-8334). However, it has been demonstrated that multivariate statistical analysis of isotopic concentrations can complement these method and are able to make use of a greater level of information through dimensionality reduction techniques (Robel, M.; Kristo, M. J. J. Environ. Radioact. 2008, 99, 1789-1797; Robel, M.; Kristo, M. J.; Heller, M. A. Nuclear Forensic Inferences Using Iterative Multidimensional Statistics. In Proceedings of the Institute of Nuclear Materials Management 50th Annual Meeting, Tucson, AZ, July 2009; 12 pages; Nicolaou, G. J. Environ. Radioact. 2006, 86, 313 318; Pajo, L.; Mayer, K.; Koch, L. Fresenius' J. Anal. Chem. 2001, 371, 348-352). There has been some success in using such multidimensional statistical methods to determine details about the history of spent reactor fuel (Robel, M.; Kristo, M. J. J. Environ. Radioact. 2008, 99, 1789-1797). Here, we aim to expand on these findings by pursuing more robust dimensionality reduction techniques based on manifold embedding which are able to better capture the intrinsic data set information. Furthermore, we demonstrate the use of a number of classification algorithms to reliably determine the reactor type in which a spent fuel material has been irradiated. A number of these classification techniques are novel applications in nuclear forensics and expand on the existing knowledge in this field by creating a reliable and robust classification model. The results from this analysis show that our techniques have been very successful and further ascertain the excellent potential of these techniques in the field of nuclear forensics at least with regard to spent reactor fuel. PMID- 24805972 TI - Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis. AB - Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with pi pi interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89 kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3 pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3 pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3 pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg Asn) potential anticholinesterase and reactivator for AChE under the physiological pH. PMID- 24805974 TI - Hepatitis B virus DNA viral load determination in hepatitis B surface antigen negative Swiss blood donors. AB - BACKGROUND: Nucleic acid test (NAT) hepatitis B virus (HBV) screening for all blood donations with a sensitivity limit of 25 IU/mL in the individual donation is mandatory in Switzerland since 2009. The aims of the two studies were to define the percentage of antibody to hepatitis B core antigen (anti-HBc) or anti HBc and antibody to hepatitis B surface antigen (anti-HBs)-positive donors bearing HBV DNA and to gather HBV viral load data on HBV NAT yields during the routine screening since the introduction of the HBV NAT. STUDY DESIGN AND METHODS: Archive samples from anti-HBc-positive donors (Group I) were analyzed with a quantitative HBV DNA test and further with anti-HBc and anti-HBs assays. In addition, all the HBV NAT-only-yield samples (Group II) from the routine donor screening performed between July 2007 and May 2013 were included in the study. RESULTS: From the 667 samples investigated (131 donors), three donors (2.3%) had donated eight samples (1.2%) with detectable HBV DNA; however, all had very low viral loads (<= 10 IU/mL). From the 1,160,426 donations screened with the routine HBV NAT assay, 16 HBV NAT yields were detected: two window period (WP) and 14 occult hepatitis B infection (OBI) cases. In eight of these positive donations (two WP and six OBI), the HBV viral loads were not more than 10 IU/mL, in three cases between 10 and 25 IU/mL, and in the remaining five donations between 37 and 166 IU/mL. CONCLUSION: The highly sensitive HBV NAT assay with a threshold significantly below 10 IU/mL is a valuable alternative to anti-HBc and a less sensitive HBV NAT screening in blood donor screening. PMID- 24805975 TI - Inhibition of the Jagged/Notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/beta-catenin signaling pathways. AB - The Notch signaling pathway is a highly conserved developmental pathway, which is important in the regulation of cellular proliferation, differentiation and apoptosis. The aberrant expression of the Notch pathway has been associated with carcinogenesis in various types of cancer. In order to investigate the expression profiles and biological functions of Notch receptors and ligands in retinoblastoma, the expression levels of their proteins in the human retinoblastoma cell line SO-Rb50 using western blot analysis was assessed. The present study revealed that Notch1 and Jagged2 were highly expressed compared with human retinal pigment epithelial cells. When treated with DAPT, a specific inhibitor of Notch receptor cleavage, expression of Notch1 and Jagged2 were downregulated in a dose-dependent manner, which was accompanied by substantial cell growth arrest, as indicated by the Cell Counting kit-8 assay. In addition, phosphorylation of Akt, p38 mitogen-activated protein kinase and Src, together with the expression of phosphoinositide 3-kinase and beta-catenin, was abated in a dose-dependent manner. However, expression of either total extracellular signal regulated kinase (Erk)1/2 or phospho-Erk1/2 was not changed in SO-Rb50 cells. These findings demonstrated that the Jagged2/Notch1 pathway can promote oncogenesis in retinoblastoma in co-operation with multiple signaling pathways. The inhibition of the Notch signaling pathway by DAPT represents a potentially attractive strategy for the therapy of retinoblastoma. PMID- 24805976 TI - Temporal variability of forest communities: empirical estimates of population change in 4000 tree species. AB - Long-term surveys of entire communities of species are needed to measure fluctuations in natural populations and elucidate the mechanisms driving population dynamics and community assembly. We analysed changes in abundance of over 4000 tree species in 12 forests across the world over periods of 6-28 years. Abundance fluctuations in all forests are large and consistent with population dynamics models in which temporal environmental variance plays a central role. At some sites we identify clear environmental drivers, such as fire and drought, that could underlie these patterns, but at other sites there is a need for further research to identify drivers. In addition, cross-site comparisons showed that abundance fluctuations were smaller at species-rich sites, consistent with the idea that stable environmental conditions promote higher diversity. Much community ecology theory emphasises demographic variance and niche stabilisation; we encourage the development of theory in which temporal environmental variance plays a central role. PMID- 24805977 TI - Neuroendocrine changes upon exposure to predator odors. AB - Predator odors are non-intrusive and naturalistic stressors of high ethological relevance in animals. Upon exposure to a predator or its associated cues, robust physiological and molecular anti-predator defensive strategies are elicited thereby allowing prey species to recognize, avoid and defend against a possible predation threat. In this review, we will discuss the nature of neuroendocrine stress responses upon exposure to predator odors. Predator odors can have a profound effect on the endocrine system, including activation of the hypothalamic pituitary-adrenal axis, and induction of stress hormones such as corticosterone and adrenocorticotropic hormone. On a neural level, short-term exposure to predator odors leads to induction of the c-fos gene, while induction of DeltaFosB in a different brain region is detected under chronic predation stress. Future research should aim to elucidate the relationships between neuroendocrine and behavioral outputs to gage the different levels of anti-predator responses in prey species. PMID- 24805981 TI - ACPA 2014 Oral Presentation Abstracts. AB - The abstracts below were presented as podium presentations at the 71(st) Annual Meeting of the American Cleft Palate-Craniofacial Association from March 24(th) to 29(th), 2014. They are printed directly as they appeared in the program book. PMID- 24805978 TI - Stimulation of dopamine D4 receptors in the paraventricular nucleus of the hypothalamus of male rats induces hyperphagia: involvement of glutamate. AB - Obesity is a serious worldwide health problem, affecting 20-40% of the population in several countries. According to animal models, obesity is related to changes in the expression of proteins that control energy homeostasis and in neurotransmission associated to regulation of food intake. For example, it has been reported that diet-induced obesity produces overexpression of dopamine D4 receptor (D4R) mRNA in the ventromedial hypothalamic nucleus (VMH) of mice. Neurons in the VMH send dense glutamatergic projections to other hypothalamic regions as the paraventricular nucleus (PVN), where multiple signals are integrated to finely regulate energy homeostasis and food intake. Although it is well established that dopaminergic transmission in the hypothalamus plays a key role in modulating feeding, the specific mechanisms involved in the activation of D4R in the PVN and its modulatory action on glutamate release and feeding behavior have remained unexplored. To fill this gap, we characterize the behavioral and neurochemical role of D4R in the PVN. In behavioral experiments, we examined the effects of activation of dopamine D4 receptors in the PVN on food intake and on the behavioral satiety sequence in rats exposed to a food restricted feeding program. In vitro experiments were conducted to study the effects of activation of dopamine D4 receptors on [(3)H]glutamate release and on plasma corticosterone in explants of the PVN. We found that activation of D4R in the PVN induced inhibition of glutamate release and stimulated food intake by inhibiting satiety. Furthermore, activation of D4R in the PVN decreased plasma levels of corticosterone, and this effect was reverted by NMDA. According to our findings, D4R in the PVN may be a target for the pharmacotherapy for obesity as well as eating disorder patients who show restrictive patterns and overweight. PMID- 24805983 TI - J.-B. Pontalis, a thinker of psychoanalysis. PMID- 24805982 TI - Up-regulation of microRNA-183-3p is a potent prognostic marker for lung adenocarcinoma of female non-smokers. AB - BACKGROUND: Lung cancer in never smokers presents predominately as adenocarcinoma and in females. MicroRNA-183 (miR-183) has various expression patterns in types of human cancers. In the present study, we evaluated the expression of miR-183-3p in female lung adenocarcinoma and adjacent noncancerous tissues and explored its relationship with clinicopathological characteristics and prognosis. METHODS: In the present study, a hundred female nonsmoking patients who were newly diagnosed and histologically confirmed as lung adenocarcinoma at Tianjin Medical University Cancer Hospital were included. miR-183-3p expression of surgically removed NSCLC tissues and their corresponding normal lung tissues was measured by qRT-PCR assay. Associations of miR-183-3p expression with clinicopathological features were determined using the Student's t test. Log-rank test, and Cox proportional hazards model were used for survival analysis. RESULTS: At first, miR-183-3p was up-regulated in lung cancer tissues when compared with the corresponding noncancerous lung tissues. Moreover, the expression of miR-183-3p in tumor tissue was found to be associated with lymph node metastasis (P = 0.043), clinical stage (P = 0.015), and EGFR mutation (P = 0.003). At last, high miR-183-3p expression was also associated with both poor overall survival and progression-free survival of women with lung adenocarcinoma (P = 0.005 and P = 0.010, respectively). CONCLUSION: This study suggested that miR-183-3p expression might be involved in lung cancer pathogenesis and progression, and could be used as a potential prognostic biomarker of female lung adenocarcinoma. PMID- 24805984 TI - Candy flavorings in tobacco. PMID- 24805985 TI - Nicotine poisoning in an infant. PMID- 24805986 TI - Health care reform after the ACA. PMID- 24805987 TI - Here to stay - beyond the rough launch of the ACA. PMID- 24805988 TI - Ebola--a growing threat? PMID- 24805989 TI - Non-invasive prenatal detection of trisomy 13 using a single nucleotide polymorphism- and informatics-based approach. AB - PURPOSE: To determine how a single nucleotide polymorphism (SNP)- and informatics based non-invasive prenatal aneuploidy test performs in detecting trisomy 13. METHODS: Seventeen trisomy 13 and 51 age-matched euploid samples, randomly selected from a larger cohort, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex polymerase chain reaction assay that interrogated 19,488 SNPs covering chromosomes 13, 18, 21, X, and Y, and sequenced. Analysis and copy number identification involved a Bayesian-based maximum likelihood statistical method that generated chromosome- and sample specific calculated accuracies. RESULTS: Of the samples that passed a stringent DNA quality threshold (94.1%), the algorithm correctly identified 15/15 trisomy 13 and 49/49 euploid samples, for 320/320 correct copy number calls. CONCLUSIONS: This informatics- and SNP-based method accurately detects trisomy 13-affected fetuses non-invasively and with high calculated accuracy. PMID- 24805991 TI - Development of a transgenic Plasmodium berghei line (Pb pfpkg) expressing the P. falciparum cGMP-dependent protein kinase, a novel antimalarial drug target. AB - With the inevitable selection of resistance to antimalarial drugs in treated populations, there is a need for new medicines to enter the clinic and new targets to progress through the drug discovery pipeline. In this study we set out to develop a transgenic rodent model for testing inhibitors of the Plasmodium falciparum cyclic GMP-dependent kinase in vivo. A model was needed that would allow us to investigate whether differences in amino acid sequence of this enzyme between species influences in vivo efficacy. Here we report the successful development of a transgenic P. berghei line in which the cyclic GMP-dependent protein kinase (PKG) was replaced by the P. falciparum orthologue. We demonstrate that the P. falciparum orthologue was able to functionally complement the endogenous P. berghei pkg gene throughout blood stage development and early sexual development. However, subsequent development in the mosquito was severely compromised. We show that this is due to a defect in the female lineage of the transgenic by using genetic crosses with both male and female deficient P. berghei lines. This defect could be due to expression of a female-specific target in the mosquito stages of P. berghei that cannot be phosphorylated by the P. falciparum kinase. Using a previously reported anti-coccidial inhibitor of the cyclic GMP-dependent protein kinase, we show no difference in in vivo efficacy between the transgenic and control P. berghei lines. This in vivo model will be useful for screening future generations of cyclic GMP-dependent protein kinase inhibitors and allowing us to overcome any species-specific differences in the enzyme primary sequence that would influence in vivo efficacy in the rodent model. The approach will also be applicable to in vivo testing of other antimalarial compounds where the target is known. PMID- 24805994 TI - Redox cycling on recessed ring-disk nanoelectrode arrays in the absence of supporting electrolyte. AB - In canonical electrochemical experiments, a high-concentration background electrolyte is used, carrying the vast majority of current between macroscopic electrodes, thus minimizing the contribution of electromigration transport of the redox-active species being studied. In contrast, here large current enhancements are achieved in the absence of supporting electrolyte during cyclic voltammetry at a recessed ring-disk nanoelectrode array (RRDE) by taking advantage of the redox cycling effect in combination with ion enrichment and an unshielded ion migration contribution to mass transport. Three distinct transport regimes are observed for the limiting current as a function of the concentration of redox species, Ru(NH3)6(2+/3+), revealed through the strong dependence of ion transport on ionic strength. Behavior at low analyte concentrations is especially interesting. In the absence of supporting electrolyte, ions accumulate in the nanopores, resulting in significantly increased current amplification compared to redox cycling in the presence of supporting electrolyte. Current enhancements as large as 100-fold arising from ion enrichment and ion migration effects add to the ~20-fold enhancement due to redox cycling, producing a total current amplification as large as 2000-fold compared to a single microelectrode of the same total area, making these RRDE arrays interesting for electrochemical processing and analysis. PMID- 24805993 TI - What keeps a body moving? The brain-derived neurotrophic factor val66met polymorphism and intrinsic motivation to exercise in humans. AB - Individuals who are intrinsically motivated to exercise are more likely to do so consistently. In previous research, those with at least one copy of the methionine (met) allele in the brain-derived neurotrophic factor gene (BDNF; rs6265) had greater increases in positive mood and lower perceived exertion during exercise. This study examined whether genotype for BDNF is also related to intrinsic motivation, measured by self-report during a treadmill exercise session and a free-choice behavioral measure (continuing to exercise given the option to stop) among 89 regular exercisers (age M = 23.58, SD = 3.95). Those with at least one copy of the met allele reported greater increases in intrinsic motivation during exercise and were more likely to continue exercising when given the option to stop (55 vs. 33%). Results suggest that underlying genetic factors may partially influence perceptions of inherent rewards associated with exercise and might inform the development of individually targeted interventions. PMID- 24805990 TI - The ubiquitin-conjugating system: multiple roles in viral replication and infection. AB - Through the combined action of ubiquitinating and deubiquitinating enzymes, conjugation of ubiquitin to a target protein acts as a reversible post translational modification functionally similar to phosphorylation. Indeed, ubiquitination is more and more recognized as a central process for the fine regulation of many cellular pathways. Due to their nature as obligate intracellular parasites, viruses rely on the most conserved host cell machineries for their own replication. Thus, it is not surprising that members from almost every viral family are challenged by ubiquitin mediated mechanisms in different steps of their life cycle and have evolved in order to by-pass or exploit the cellular ubiquitin conjugating system to maximize their chance to establish a successful infection. In this review we will present several examples of the complex interplay that links viruses and the ubiquitin conjugation machinery, with a special focus on the mechanisms evolved by the human immunodeficiency virus to escape from cellular restriction factors and to exit from infected cells. PMID- 24805996 TI - Watch out for superman: first visualize, then analyze. AB - A visit from Superman shows why data visualization should come before data analysis. The Web extra is a dataset that comprises 100 observations of the quantitative variables y and x plus the qualitative variable group. When analyzed correctly, this dataset exhibits an interesting pattern. PMID- 24805997 TI - Rapid dissemination of light transport models on the web. AB - Light transport models are employed in applications in such varied areas as realistic image synthesis, noninvasive treatment of diseases, and remote sensing of natural resources. Openly accessible research resources can lead to significant advances involving these applications by fostering the cross fertilization of different scientific disciplines. However, few light transport models have their source code openly available for download. Moreover, simply making the code available might not be enough; these models' complexity usually prevents their use beyond the research groups that developed them. The NPSGD (Natural Phenomena Simulation Group Distributed) framework makes light transport models easily accessible for online use. NPSGD acts a front end, connecting model implementations to the Web. It lets researchers perform predictive and time intensive light transport simulations in a user-friendly, fault-tolerant way. More important, as a proof of concept, NPSGD demonstrates that the reproducibility of research results through model transparency is feasible. Such reproducibility can result in fruitful collaborations between model developers and users, regardless of their field of expertise. PMID- 24805995 TI - Association between N-terminal pro-brain natriuretic peptide levels and contrast induced nephropathy in patients undergoing percutaneous coronary intervention for acute coronary syndrome. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is associated with significantly increased morbidity and mortality after percutaneous coronary intervention (PCI). Patients with acute coronary syndrome (ACS) are at higher risk for CIN. N terminal pro-brain natriuretic peptide (NT-proBNP) is closely linked to the prognosis as a strong predictor of both short- and long-term mortality in patients with ACS. HYPOTHESIS: We hypothesized that NT-proBNP levels on admission can predict the development of CIN after PCI for ACS. METHODS: A total of 436 patients (age 62.27 +/- 13.01 years; 64.2% male) with ACS undergoing PCI enrolled in this study. Admission NT-proBNP levels were measured before PCI. Serum creatinine values were measured before and within 72 hours after the administration of contrast agents. Patients were divided into 2 groups: CIN group and no-CIN group. CIN was defined as an increase in serum creatinine level of >=0.5 mg/dL or >=25% above baseline within 72 hours after contrast administration. RESULTS: CIN developed in 63 patients (14.4%). Baseline NT-proBNP levels were significantly higher in patients who developed CIN compared to those who did not develop CIN (median 774 pg/mL, interquartile range 177.4-2184 vs median 5159 pg/mL, interquartile range 2282-9677, respectively; P < 0.001). Multivariate analysis found that NT-proBNP (odds ratio [OR]: 3.448, 95% confidence interval [CI]: 1.394-8.474, P = 0.007) and baseline creatinine (OR: 6.052, 95% CI: 1.860-19.686, P = 0.003) were independent predictors of CIN. CONCLUSIONS: Admission NT-proBNP level is an independent predictor of the development of CIN after PCI in ACS. PMID- 24805998 TI - Motion transplantation techniques: a survey. AB - During the past decade, researchers have developed several techniques for transplanting motions. These techniques transplant a partial auxiliary motion, possibly defined for a small set of degrees of freedom, on a base motion. Motion transplantation improves motion databases' expressiveness and allows more control in interactive applications by letting users synthesize body parts separately. However, the auxiliary motion must be properly aligned with the base motion, both temporally and spatially. This article provides an overview of example-based motion transplantation techniques and explains how they determine spatial and temporal alignment between the auxiliary and base motions. It also describes hybrid techniques that can transplant the motions resulting from procedural or physics-based techniques. PMID- 24805999 TI - High-fidelity interactive rendering on desktop grids. AB - Desktop grids combine arbitrary computational resources connected to a network. However, the prevalent interactive rendering algorithms can't seamlessly handle the variable computational power offered by a desktop grid's nondedicated resources. In this article, a method for achieving interactive high-fidelity rendering on nondedicated machines such as desktop grids is developed, without the expensive requirements of a dedicated render farm. The proposed algorithm is also fault-tolerant. PMID- 24806000 TI - Nonrigid-deformation recovery for 3D face recognition using multiscale registration. AB - Nonrigid deformation is a fundamental feature in face recognition. The proposed method extracts nonrigid deformation by finding the mapping between two shapes. To improve registration accuracy, it integrates geometric shape decomposition and nonrigid point-set registration. On the basis of manifold harmonics, the method first decomposes shapes into low-frequency and high-frequency parts. Then, it applies the modified registration algorithm to obtain deformation parameters. An extensive set of experiments evaluated the method's performance on the FRGC (Face Recognition Grand Challenge) v2 database. The method achieved not only higher accuracy for fitting but also 98.2 percent identification and 97.4 percent verification at a 0.001 false-acceptance rate. PMID- 24806001 TI - OCME: Out-of-Core Mesh Editing made practical. AB - OCME (Out-of-Core Mesh Editing) comprises a novel data structure and related algorithms for out-of-core editing of large meshes. Triangles are inserted in a multigrid on the basis of their size in average constant time. OCME maintains no explicit hierarchy, so inserting, modifying, or deleting data doesn't require costly refitting. PMID- 24806002 TI - Sketch-n-Stretch: sketching animations using cutouts. AB - Sketch-n-Stretch lets novices quickly and easily create 2D animations. The system has a seamless two-layer drawing interface that supports cutouts using a whiteboard metaphor. Cutout animations serve as building blocks to help users construct sophisticated animations. While manipulating cutout animations, users can draw and write text to create effects-such as articulated figures, multiple motions, and image objects-that have been difficult with previous sketching approaches. An intuitive timeline interface employs visually integrated motion cues and supports several traditional animation effects. Novices positively evaluated Sketch-n-Stretch's effectiveness in creating object motions, compared to an existing sketching tool. They also used its advanced features to animate complete stories. This video demonstrates the Sketch-n-Stretch tool for making sketch-based animations. PMID- 24806003 TI - Iterative consolidation of unorganized point clouds. AB - Unorganized point clouds obtained from 3D shape acquisition devices usually present noise, outliers, and nonuniformities. The proposed framework consolidates unorganized points through an iterative procedure of interlaced downsampling and upsampling. Selection operations remove outliers while preserving geometric details. The framework improves the uniformity of points by moving the downsampled particles and refining point samples. Surface extrapolation fills missed regions. Moreover, an adaptive sampling strategy speeds up the iterations. Experimental results demonstrate the framework's effectiveness. PMID- 24806004 TI - Leveraging multidisciplinarity in a visual analytics graduate course. AB - Demand is growing in engineering, business, science, research, and industry for students with visual analytics expertise. However, teaching VA is challenging owing to the multidisciplinary nature of the topic, students' diverse backgrounds, and the corresponding requirements for instructors. This article reports best practices from a VA graduate course at Purdue University, where instructors leveraged these challenges to their advantage instead of trying to mitigate them. PMID- 24806005 TI - Changing variables. AB - In computer graphics and geometric modeling, changing the variables is a useful technique that appears in many guises. It lets us change how we traverse curves or surfaces, modify their derivatives or place, and interpret textures or other properties associated with them. It is shown that while changing variables of a parametric curve or surface leaves its geometric shape untouched, changing the way we associate parameters to curves or surfaces does have an impact: computer graphics deals with sampled geometry, and the sampled geometry changes. We can take advantage of the change of variables to improve how the surface is textured. Moreover, change of variables makes it possible to combine curve segments or curved surface patches into a smooth ensemble when the shape is more general than the graph of a function. PMID- 24806006 TI - Prevention and screening programs for anterior cruciate ligament injuries in young athletes: a cost-effectiveness analysis. AB - BACKGROUND: Anterior cruciate ligament (ACL) injuries are common among young athletes. Biomechanical studies have led to the development of training programs to improve neuromuscular control and reduce ACL injury rates as well as screening tools to identify athletes at higher risk for ACL injury. The purpose of this study was to evaluate the cost-effectiveness of these training methods and screening strategies for preventing ACL injuries. METHODS: A decision-analysis model was created to evaluate three strategies for a population of young athletes participating in organized sports: (1) no training or screening, (2) universal neuromuscular training, and (3) universal screening, with neuromuscular training for identified high-risk athletes only. Risk of injury, risk reduction from training, and sensitivity and specificity of screening were based on published data from clinical trials. Costs of training and screening programs were estimated on the basis of the literature. Sensitivity analyses were performed on key model parameters to evaluate their effect on base case conclusions. RESULTS: Universal neuromuscular training of all athletes was the dominant strategy, with better outcomes and lower costs compared with screening. On average, the implementation of a universal training program would save $100 per player per season, and would reduce the incidence of ACL injury from 3% to 1.1% per season. Screening was not cost-effective within the range of reported sensitivity and specificity values. CONCLUSIONS AND CLINICAL RELEVANCE: Given its low cost and ease of implementation, neuromuscular training of all young athletes represents a cost-effective strategy for reducing costs and morbidity from ACL injuries. While continued innovations on inexpensive and accurate screening methods to identify high-risk athletes remain of interest, improving existing training protocols and implementing neuromuscular training into routine training for all young athletes is warranted. PMID- 24806007 TI - Association between advanced degenerative changes of the atlanto-dens joint and presence of dens fracture. AB - BACKGROUND: Dens fractures in elderly patients are often related to issues associated with aging. We examined the association between degenerative changes of the atlanto-dens joint and the risk of dens fracture. METHODS: We conducted a retrospective study of trauma patients, fifty-five years of age or older, who had undergone a computed tomography scan of the cervical spine as part of their admission to a single level-I trauma center. There were 1794 patients who met the inclusion criteria; scans were evaluated for all fifty-six who presented with a dens fracture and for a random sample of 736 without a dens fracture. Intraosseous cyst formation, synovitis, and joint space narrowing were recorded from the scans. The prevalence of degenerative changes was compared between patients with and patients without a dens fracture. RESULTS: An intraosseous cyst in the dens was found in 16.4% of the patients without a dens fracture and in 64.3% of those with a fracture (p < 0.001). The dens fracture extended through the existing cyst in twenty-four (66.7%) of thirty-six patients with a cyst and a dens fracture. Retro-dens synovitis was present in 4.2% of the patients without a dens fracture and 25.0% of those with a fracture (p < 0.001). After adjustment for age and sex, both cysts (odds ratio [OR] = 7.7, 95% confidence interval [CI] = 4.2 to 14.1) and synovitis (OR = 4.6, 95% CI = 2.1 to 10.0) were significantly associated with dens fracture. CONCLUSIONS: Intraosseous dens cysts and retro dens synovitis were associated with dens fracture; those with a dens fracture were nearly eightfold more likely to have an intraosseous cyst and nearly fivefold more likely to have synovitis compared with those without a dens fracture. Because the atlanto-dens joint is a synovial joint, its degeneration can lead to subchondral cyst formation and synovitis and predispose affected individuals to fracture. PMID- 24806008 TI - The effect of obesity on direct medical costs in total knee arthroplasty. AB - BACKGROUND: Obesity prevalence continues to rise in the United States. We sought to examine the effect of obesity on length of hospital stay and direct medical costs in a large cohort of patients who underwent total knee arthroplasty. METHODS: The study included 8129 patients who had undergone 6475 primary total knee arthroplasties and 1654 revision total knee arthroplasties at a large U.S. medical center from January 1, 2000, to September 30, 2008. Patients with bilateral procedures within ninety days following the index admission were excluded. Data on clinical and surgical characteristics and complications were obtained from the original medical records and the institutional joint registry. Patients were classified into eight groups based on their body mass index at the time of surgery. Direct medical costs were calculated in 2010 U.S. dollars by using standardized, inflation-adjusted costs for services and procedures billed during hospitalization and the ninety-day window. Study end points were hospital length of stay and direct medical costs. End points were compared across the eight body mass index categories in both unadjusted and multivariable risk adjusted analyses. Linear regression models were used to determine the cost impact associated with increasing body mass index and obesity accounting for comorbidities and complications. RESULTS: Body mass index data were available for 99.5% of patients and ranged from 15 to 73 kg/m2. Length of stay and the direct medical costs were lowest for patients with body mass index values in the normal to overweight range. Increasing body mass index was associated with significantly longer hospital stays and costs. Every 5-unit increase in body mass index beyond 30 kg/m2 was associated with approximately $250 to $300 higher hospitalization costs in primary total knee arthroplasty and $600 to $650 higher hospitalization costs in revision total knee arthroplasty. These estimates persisted after adjusting for comorbidities or complications. CONCLUSIONS: Obesity is associated with longer hospital stays and higher costs in total knee arthroplasty. The effect of obesity on costs appears to be independent of obesity-related comorbid conditions and complications. PMID- 24806009 TI - Trapeziometacarpal arthrodesis or trapeziectomy with ligament reconstruction in primary trapeziometacarpal osteoarthritis: a randomized controlled trial. AB - BACKGROUND: Both trapeziectomy with ligament reconstruction and tendon interposition and trapeziometacarpal arthrodesis are commonly performed procedures for the treatment of trapeziometacarpal osteoarthritis. The purpose of this study was to compare the outcomes of both treatments for symptomatic osteoarthritis of the thumb trapeziometacarpal joint in a randomized trial. METHODS: Women who were forty years of age or older were randomized either to trapeziectomy with ligament reconstruction and tendon interposition or to arthrodesis with plate and screws. Patients were evaluated preoperatively and at three and twelve months postoperatively with respect to pain, function (Patient Rated Wrist/Hand Evaluation [PRWHE] and Disabilities of the Arm, Shoulder and Hand [DASH] questionnaires), joint motion, strength, complication rate, and patient satisfaction. RESULTS: Forty-three patients were enrolled. Since we found significantly more moderate and severe complications following arthrodesis compared with trapeziectomy with ligament reconstruction and tendon interposition (71% versus 29%; p = 0.016), the study was prematurely terminated before the sample size necessary to validly compare the two groups was reached. The higher complication rate for arthrodesis led to an increase in revision surgery (two of seventeen patients). Significantly more patients in the ligament reconstruction and tendon interposition group (86%) than in the arthrodesis group (53%) indicated they would consider the same surgery again under the same circumstances (p = 0.025). In both groups, PRWHE and DASH scores significantly improved over time; however, comparison of the groups showed that the results were similar. CONCLUSIONS: Women who are forty years or older with trapeziometacarpal osteoarthritis have fewer moderate and severe complications after trapeziectomy with ligament reconstruction and tendon interposition and are more likely to consider the surgery again under the same circumstances than are those who undergo arthrodesis. Twelve months after surgery, the PRWHE and DASH scores were similar in both groups. We do not recommend routine use of arthrodesis with plate and screws in the treatment of women who are forty years or older with stage-II or III trapeziometacarpal osteoarthritis. PMID- 24806010 TI - Radiation dosimetry of intraoperative cone-beam compared with conventional CT for radiofrequency ablation of osteoid osteoma. AB - BACKGROUND: Radiofrequency (RF) ablation is the standard of care for the surgical treatment of non-spinal osteoid osteoma and has greatly reduced morbidity associated with surgical excision. Precise placement of the RF ablation probe is necessary to avoid incomplete ablation. Limiting radiation exposure is especially advantageous in the pediatric population in whom osteoid osteoma frequently occurs. The aim of this study was to compare the radiation dosimetry and clinical outcomes among patients treated with RF ablation using three different localization techniques. METHODS: Case-control methods were used to analyze sixty six cases. Patients were categorized into three treatment groups: (1) intraoperative three-dimensional cone-beam CT (computed tomography) imaging (O Arm) with surgical navigation (StealthStation S7), (2) intraoperative three dimensional imaging (O-Arm) only, and (3) radiology suite-based diagnostic CT imaging. Radiation dosimetry and clinical outcome were analyzed with use of the dose-length product and local-relapse-free survival, respectively. RESULTS: Mean age was nineteen years for the twenty-three patients in group 1, twenty years for the seven patients in group 2, and nineteen years for the thirty-six patients in group 3. Mean follow-up was fifty-three months. The mean radiation dose for groups 1, 2, and 3 was 446.62, 379.78, and 1058.83 mGy-cm, respectively. Significant (p < 0.05) differences in the radiation dose existed between groups 1 and 3 and between groups 2 and 3, whereas no difference was found between groups 1 and 2. Local-remission-free survival at three years for groups 1, 2, and 3 was 84.7% (95% confidence interval [CI], 64.5% to 100%), 100% (95% CI, 100% to 100%), and 90.7% (95% CI, 80.7% to 100%), respectively. Fifty-eight (92%) of the sixty three followed patients were asymptomatic at the latest follow-up visit. CONCLUSIONS: RF ablation using intraoperative cone-beam CT imaging, with or without surgical navigation, was associated with a significantly lower radiation dose compared with ablation using a radiology suite-based CT technique. Ablation using each of the three imaging techniques was equally effective in treating osteoid osteomas with a similar risk of relapse. PMID- 24806011 TI - MR-guided focused ultrasound (MRgFUS) ablation for the treatment of nonspinal osteoid osteoma: a prospective multicenter evaluation. AB - BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel imaging-guided surgical technique that allows the performance of noninvasive and radiation-free ablation. Presently, computed tomography (CT)-guided radiofrequency ablation, a minimally invasive percutaneous technique, is the standard for treating symptomatic osteoid osteomas. The purpose of this study was to evaluate the use of MRgFUS ablation for the treatment of nonspinal osteoid osteomas in terms of technical success, complications, and clinical success through one year of follow-up. METHODS: In this prospective multicenter study, thirty consecutive patients with a nonspinal osteoid osteoma were enrolled between May 2010 and April 2012 at three different university centers; twenty nine of the patients were treated with use of MRgFUS. Lesions had been previously diagnosed on the basis of imaging, including dynamic contrast-enhanced MR. The mean number of sonications and energy deposition were determined. Technical success was evaluated through an assessment of complications immediately after treatment. Clinical success was determined on the basis of pain reduction as measured with a visual analog scale (VAS), recurrence, and long-term complications through twelve months. RESULTS: Technical success of MRgFUS was observed for all twenty-nine patients. The mean number of sonications (and standard deviation) was 7 +/- 3, and the mean delivered acoustic energy was 1180 +/- 736 J. At the twelve-month follow-up, complete clinical success was observed in twenty-six (90%) of the twenty-nine patients (95% confidence interval [CI] = 84 to 95; mean VAS, 0 +/- 0 points). Partial success was observed in three (10%) of the twenty-nine patients (95% CI = 5 to 16; mean VAS score, 5 +/- 0 points); two of these patients subsequently underwent CT-guided radiofrequency ablation, and one underwent open surgery. Pain score values showed a significant reduction (p < 0.001) between baseline (mean VAS score, 8 +/- 1 points) and post treatment (mean VAS score, 1 +/- 2 points). No complications were observed. CONCLUSIONS: MRgFUS may be an effective and safe alternative approach in the treatment of nonspinal osteoid osteoma. A complete clinical success rate of 90% was demonstrated without adverse events. MRgFUS is totally noninvasive and eliminates radiation exposure. PMID- 24806012 TI - Anatomical dissection and CT imaging of the posterior cruciate and lateral collateral ligaments in skeletally immature cadaver knees. AB - BACKGROUND: Understanding the relationship of the posterior cruciate ligament (PCL) and the lateral collateral ligament (LCL) to the femoral and tibial physes is important to reducing the risk of physeal injury during surgical reconstruction. The purpose of this study was to identify the location of the attachments of the PCL and LCL in skeletally immature cadaveric knee specimens and to determine their position relative to the physes. METHODS: Seven skeletally immature cadaveric knee specimens were examined through gross dissection. These specimens were divided into two groups: infants (an age at death of one month for one specimen and eleven months for two specimens) and children (an age at death of eight years for one specimen, ten years for one specimen, and eleven years for two specimens). Metallic markers were placed at the femoral origins of the PCL and LCL and at the tibial insertion of the PCL. Computed tomography (CT) scans were made for each specimen and analyzed with the use of OsiriX imaging software. The width of the PCL tibial insertion footprint and the height of the PCL femoral origin footprint, the distance from the midpoints of the PCL and LCL femoral origin to the distal femoral physis, and the distance from the PCL insertion footprint midpoint to the proximal tibial physis were measured. RESULTS: The mean distance from the midpoint of the femoral origin footprint of the PCL to the femoral physis was 11.1 mm (range, 10.6 to 11.7 mm) and 18.8 mm (range, 18.2 to 19.2 mm) distal to the physis for infants and children, respectively. The mean distance from the midpoint of the tibial insertion footprint of the PCL to the tibial physis was 3.1 mm (range, 0.0 to 5.7 mm) and 5.8 mm (range, 2.5 to 8.9 mm) proximal to the physis for infants and children, respectively. The mean width of the tibial insertion of the PCL was 5.5 mm (range, 1.1 to 8.3 mm) for infants and 10.2 mm (range, 8.4 to 11.9 mm) for children. The mean distance from the midpoint of the femoral origin of the LCL to the femoral physis was 6.3 mm (range, 3.9 to 7.7 mm) and 5.9 mm (range, 0.0 to 10.0 mm) distal to the physis for infants and children, respectively. CONCLUSIONS: The relationship of the PCL and LCL attachments to physeal structures has not been well described. We found the midpoints of the PCL and LCL femoral origins at or distal to, and the midpoint of the PCL tibial insertion at or proximal to, the respective physis in all specimens. This study with CT-scan correlation provides unique information on the location of ligament attachments in relation to the physes. CLINICAL RELEVANCE: A better understanding of the spatial relationship between the PCL and LCL attachments and their respective physes may help guide drill-hole placement during ligament reconstructions and reduce the risk for iatrogenic physeal injury in skeletally immature patients. PMID- 24806013 TI - Stem cells and basic fibroblast growth factor failed to improve tendon healing: an in vivo study using lentiviral gene transfer in a rat model. AB - BACKGROUND: The aim of this controlled study was to investigate the influence of mesenchymal stem cells (MSCs) and lentiviral (LV) expression of basic fibroblast growth factor (bFGF) on tendon remodeling in an in vivo rat model of an Achilles tendon defect. METHODS: In eighty-four male Lewis rats, complete 2.4-mm tendon defects were created and were either left untreated (the phosphate-buffered saline solution [PBS] group) or were treated with mesenchymal stem cells expressing enhanced green fluorescent protein (the MSC-LV-eGFP group) or with mesenchymal stem cells expressing basic fibroblast growth factor lentivirally (the MSC-LV-bFGF group). After fourteen and twenty-eight days, the tendons were harvested and analyzed biomechanically and immunohistologically. RESULTS: After fourteen days, both mesenchymal stem cell groups were slightly superior in biomechanical testing. However, only the PBS control group showed a significant increase in biomechanical results over time (fourteen versus twenty-eight days; p = 0.012). Biomechanical results were better after twenty-eight days for the control group than for both MSC groups. However, the difference was significant only with regard to the stiffness results in the comparison of the PBS control and the eGFP stem cell group (p = 0.024). Histologically, the MSC groups had no better results than the control group after fourteen and twenty-eight days. In immunohistology, only labeling for type-I procollagen was strongly increased in both MSC groups in comparison with the PBS control group (p = 0.0009 for the MSC LV-bFGF group and p = 0.0041 for the MSC-LV-eGFP group at fourteen days, and p = 0.004 and p = 0.132, respectively, at twenty-eight days). There were no significant differences in the immunohistological results between the stem cell groups. CONCLUSIONS: The biomechanical and immunohistological results showed that mesenchymal stem cells in both groups had only partially positive effects on tendon remodeling in the initial stages; however, in later stages, stem cells had potentially negative effects on biomechanical results. The additional expression of bFGF in stem cells had negligible effects on tendon remodeling. CLINICAL RELEVANCE: Preliminary studies using stem cells are partially promising; however, there are no relevant clinical data showing that stem cells are of significant benefit. The present study should lead to a more critical evaluation and thoughtful use of stem cells in humans until more clinical data are available. PMID- 24806014 TI - Effect of immediate and delayed high-strain loading on tendon-to-bone healing after anterior cruciate ligament reconstruction. AB - BACKGROUND: We previously demonstrated, in a rat anterior cruciate ligament (ACL) graft reconstruction model, that the delayed application of low-magnitude-strain loading resulted in improved tendon-to-bone healing compared with that observed after immediate loading and after prolonged immobilization. The purpose of this study was to determine the effect of higher levels of strain loading on tendon-to bone healing. METHODS: ACL reconstruction was carried out in a rat model in three randomly assigned groups: high-strain daily loading beginning on either (1) postoperative day one (immediate-loading group; n = 7) or (2) postoperative day four (delayed-loading group; n = 11) or (3) after prolonged immobilization (immobilized group; n = 8). Animals were killed two weeks after surgery and micro computed tomography (micro-CT) and biomechanical testing of the bone-tendon-bone complex were carried out. RESULTS: The delayed-loading group had greater tissue mineral density than either the immediate-loading or immobilized group (mean [and standard deviation], 813.0 +/- 24.9 mg/mL compared with 778.4 +/- 32.6 mg/mL and 784.9 +/- 26.4 mg/mL, respectively; p < 0.05). There was a trend toward greater bone volume per total volume fraction in both the immobilized and the delayed loading group compared with the immediate-loading group (0.24 +/- 0.03 and 0.23 +/- 0.06 compared with 0.20 +/- 0.05; p = 0.06). Trabecular thickness was greater in the immobilized group compared with the immediate-loading group (106.5 +/- 23.0 MUm compared with 72.6 +/- 10.6 MUm; p < 0.01). There were no significant differences in failure load or stiffness between the immobilized group and either high-strain cyclic-loading group. CONCLUSIONS: Immediate application of high strain loading appears to have a detrimental effect on healing in this rat model. Any beneficial effects of delayed loading on the healing tendon-bone interface (after a brief period of immobilization) may be offset by the detrimental effects of excessive strain levels or by the detrimental effects of stress deprivation on the graft. CLINICAL RELEVANCE: The timing and magnitude of mechanical load on a healing rat ACL reconstruction graft may have important implications for postoperative rehabilitation. Avoidance of exercises that cause high graft strain in the early postoperative period may lead to improved tendon-to-bone healing in humans. PMID- 24806015 TI - Factors affecting rotator cuff healing. AB - Several studies have noted that increasing age is a significant factor for diminished rotator cuff healing, while biomechanical studies have suggested the reason for this may be an inferior healing environment in older patients. Larger tears and fatty infiltration or atrophy negatively affect rotator cuff healing. Arthroscopic rotator cuff repair, double-row repairs, performing a concomitant acromioplasty, and the use of platelet-rich plasma (PRP) do not demonstrate an improvement in structural healing over mini-open rotator cuff repairs, single-row repairs, not performing an acromioplasty, or not using PRP. There is conflicting evidence to support postoperative rehabilitation protocols using early motion over immobilization following rotator cuff repair. PMID- 24806017 TI - Three-dimensional preoperative planning software and a novel information transfer technology improve glenoid component positioning. AB - BACKGROUND: We hypothesized that a novel surgical method, in which three dimensional (3-D) preoperative planning software is generated to create a patient specific surgical model that is used with a reusable and adjustable tool, could substantially improve the positioning accuracy of the glenoid guide pin used in total shoulder arthroplasty. We tested this method using bone models from patients with shoulder pathology and compared the results with those achieved using surgical methods representing the current standard of care. METHODS: Three surgeons with a variety of surgical experience placed a guide pin in nine bone models from patients with a variety of glenohumeral arthritis severity using (1) standard instrumentation alone, (2) standard instrumentation and 3-D preoperative surgical planning, and (3) the reusable transfer device and 3-D preoperative surgical planning. A postoperative 3-D computed tomography scan of the bone model was made and registered to the preoperative plan, and the differences between the actual and planned pin locations and trajectories were measured. RESULTS: Use of the standard instrumentation combined with 3-D preoperative planning software improved guide pin positioning compared with standard instrumentation and preoperative planning using 2-D imaging. The accuracy of pin positioning increased by 4.5 degrees +/- 1.0 degrees in version (p < 0.001), 3.3 degrees +/- 1.3 degrees in inclination (p = 0.013), and 0.4 +/- 0.2 mm in location (p = 0.042). Use of the adjustable and reusable device and the 3-D software improved pin positioning by a further 3.7 degrees +/- 0.9 degrees in version, 8.1 degrees +/- 1.2 degrees in inclination, and 1.2 +/- 0.2 mm in location (p < 0.001 for all) compared with standard instrumentation and the 3-D software; the improvement compared with use of standard instrumentation with 2-D imaging was 8.2 degrees +/- 0.9 degrees in version, 11.4 degrees +/- 1.2 degrees in inclination, and 1.7 +/- 0.2 mm in location (p < 0.001 for all). CONCLUSIONS: Use of 3-D preoperative planning and use of the patient-specific bone model and transfer device both improved the positioning accuracy of the pin used to guide placement of the glenoid component in total shoulder arthroplasty. CLINICAL RELEVANCE: Proper positioning of the glenoid component would be expected to improve the function and durability of the joint replacement. PMID- 24806016 TI - Total elbow arthroplasty in obese patients. AB - BACKGROUND: The prevalence of obesity in the United States has increased in recent decades. The aim of this study was to evaluate the influence of obesity in patients undergoing primary total elbow arthroplasty. METHODS: From 1987 to 2006, 723 primary semiconstrained, linked total elbow arthroplasties were performed in 654 patients. The average patient age (and standard deviation) at the time of surgery was 62.3 +/- 13.7 years, with 550 total elbow arthroplasties (76%) performed in women. Total elbow arthroplasties were used to treat inflammatory conditions in patients undergoing 378 total elbow arthroplasties (52%) and to treat acute traumatic or posttraumatic conditions in patients undergoing 310 total elbow arthroplasties (43%). Patients were classified as non-obese (having a body mass index of <30 kg/m2) in 564 total elbow arthroplasties (78%) and as obese (having a body mass index of >=30 kg/m2) in 159 total elbow arthroplasties (22%). The median duration of follow-up was 5.8 years (range, zero to twenty-five years). Survivorship of total elbow arthroplasty was estimated with use of the Kaplan-Meier method. The effect of obesity on risk of total elbow arthroplasty revision was estimated with use of Cox regression models, adjusting for age, sex, body mass index, and indication. RESULTS: A total of 118 revisions (16%) were performed. The ten-year survival rate for total elbow arthroplasty revision for any reason was 86% (95% confidence interval, 82% to 89%) in non-obese patients compared with 70% (95% confidence interval, 60% to 79%) in obese patients (p < 0.05). The ten-year survival rate for total elbow arthroplasty revision for mechanical failure was 88% (95% confidence interval, 84% to 91%) in non-obese patients compared with 72% (95% confidence interval, 61% to 81%) in obese patients (p < 0.05). Severely obese patients (those with a body mass index of 35 to <40 kg/m2) had a significantly higher risk of total elbow arthroplasty revision for any reason (hazard ratio, 3.08 [95% confidence interval, 1.61 to 5.45]; p < 0.05) and mechanical failure (hazard ratio, 3.10 [95% confidence interval, 1.47 to 5.89]; p < 0.05) compared with non-obese patients. CONCLUSIONS: Obesity adversely influences the performance of elbow replacement after primary total elbow arthroplasty. Obese patients being considered for elbow replacement surgery should be counseled accordingly. PMID- 24806018 TI - Intraoperative three-dimensional imaging in the treatment of calcaneal fractures. AB - BACKGROUND: Displaced intra-articular calcaneal fractures are frequently treated by open reduction and internal fixation. The usual intraoperative monitoring by means of fluoroscopy does not always provide complete intraoperative information for the surgeon. The aims of this study were to analyze the percentage of patients for whom intraoperative three-dimensional imaging leads to intraoperative revision and whether the avoidance of an intra-articular step or gap influences the clinical outcome. METHODS: From August 2001 to June 2009, 377 consecutive, operatively treated calcaneal fractures were identified in a retrospective chart review. The results of the intraoperative three-dimensional scans were analyzed for the rate of and the reason for intraoperative revision. For the clinical evaluation, all patients with Sanders type-II and III fractures who were seen from October 2002 to January 2006 were included. When the outer shape of the calcaneus was successfully restored, the fractures were divided into two groups according to the reduction outcome for all joint surfaces (a step-off or gap of <2 mm or >=2 mm). RESULTS: The intraoperative revision rate was 40.3%. An additional fracture reduction was performed in 19.6% of the patients. Seventy seven fractures were followed clinically. The American Orthopaedic Foot & Ankle Society (AOFAS) score indicated that postoperative joint surface congruence had a significant influence on clinical outcome, in both the bivariate and the multivariate analysis. The same relationship was shown between the joint surface congruence and the degree of osteoarthritis. CONCLUSIONS: In many cases, intraoperative three-dimensional imaging identifies intra-articular incongruence and implants that are not detected by fluoroscopy. Due to the resulting options for better joint surface reconstruction, clinical outcomes may be improved, at times requiring repeat reduction, and posttraumatic osteoarthritis may be reduced. PMID- 24806020 TI - Syria's humanitarian crisis. PMID- 24806019 TI - Clinical characteristics of early-stage osteonecrosis of the ankle and treatment outcomes. AB - BACKGROUND: The purposes of this study were to describe the clinical manifestations of osteonecrosis involving the distal tibia and talus, to identify risk factors associated with the disease, and to evaluate the efficacy of percutaneous drilling for the treatment of ankles with early-stage symptomatic osteonecrosis. METHODS: One hundred and one ankles in seventy-three patients with symptomatic osteonecrosis of the talus and/or distal tibia treated with percutaneous drilling were identified. There were eighty-one ankles in fifty-nine patients treated only at our institution and twenty ankles in fourteen patients with a failed prior core decompression at outside institutions. The parameters evaluated included demographics, disease characteristics, clinical outcomes including the American Orthopaedic Foot & Ankle Society score, Short-Form-36 scores, University of California Los Angeles activity scores, and visual analog scale pain scores, and radiographic outcomes at a mean follow-up duration of five years (range, two to nine years). RESULTS: Eighty-five ankles had isolated talus osteonecrosis, eleven ankles had involvement of the distal tibia and talus, and five ankles had isolated distal tibial disease. Twenty-nine patients (40%) had initially presented with symptomatic osteonecrosis of another joint, most commonly the knee (37%), the hip (29%), and the shoulder (25%). The most common identifiable risk factors included chronic corticosteroid use (49.3%), alcohol abuse (35.6%), tobacco use (29%), and hypertension (20.5%). Overall, 83% of ankles did not demonstrate further disease progression after the procedure. There were significant improvements (p < 0.05) in clinical and patient-reported outcomes after surgical treatment. The presence of human immunodeficiency virus and sickle cell disease was associated with a higher odds ratio of disease progression to joint collapse. CONCLUSIONS: Osteonecrosis of the distal tibia and talus was usually part of multifocal disease, and concurrent knee osteonecrosis was more common than hip osteonecrosis. The results of the present study suggest that early-stage ankle osteonecrosis can be treated successfully with percutaneous drilling. PMID- 24806021 TI - Challenges in resident education: is the Next Accreditation System (NAS) the answer?: AOA critical issues. PMID- 24806022 TI - Development of a cast application simulator and evaluation of objective measures of performance. AB - BACKGROUND: Surgical simulation offers a low-risk learning environment with repetitive practice opportunities for orthopaedic residents. It is increasingly prevalent in many training programs, as acquisition of technical skills in the face of educational demands and reduced work hours becomes more challenging. In addition to surgical skills, orthopaedic residents must also learn the technique of cast application. Deficiencies in casting skill are risk factors for re displacement of fractures and cast-specific complications. Formal educational models to instruct or to evaluate casting technique have not been well described or tested. The purposes of this study were to develop a cast application simulator and to validate a novel method of evaluating casting skill. METHODS: A module that simulates short arm cast application on a synthetic forearm model was developed. An Objective Structured Assessment of Technical Skill checklist was created with use of Delphi methodology involving nine content experts (five orthopaedic surgeons and four orthopaedic technologists). Nine participants (three medical students, three orthopaedic residents, two orthopaedic fellows, and one orthopaedic technologist) were used to evaluate the reliability and validity of the checklist. Nine de-identified videos of cast application were recorded and were utilized to test the newly developed Objective Structured Assessment of Technical Skill checklist and Modified Global Rating Scale for reliability and validity. Participants were grouped by training level (medical students, orthopaedic residents, and orthopaedic fellows or orthopaedic technologists) and were evaluated twice. RESULTS: Reliability was high as shown by intraclass correlation. The inter-rater reliability was 0.85 for the Objective Structured Assessment of Technical Skill, 0.81 for the Modified Global Rating Scale performance, and 0.78 for the Modified Global Rating Scale final product; the intra-rater reliability was 0.88 for the Objective Structured Assessment of Technical Skill, 0.85 for the Modified Global Rating Scale performance, and 0.81 for the Modified Global Rating Scale final product. The Objective Structured Assessment of Technical Skill checklist scores were 9.28 points for the medical students, 17.46 points for the orthopaedic residents, and 18.85 points for the orthopaedic fellows or orthopaedic technologists (p < 0.05, F = 6.32). The Modified Global Rating Scale performance and final product scores also reflected the level of training. Post hoc analysis showed a significant difference between the medical students and orthopaedic fellows or orthopaedic technologists for the Objective Structured Assessment of Technical Skill checklist and Modified Global Rating Scale. CONCLUSIONS: This casting simulation model and evaluation instrument is a reliable assessment of casting skill in applying a short arm cast. However, given the inability to stratify all three groups on the basis of the level of training, further work is needed to establish construct validity. PMID- 24806023 TI - Neuromuscular training for the prevention of ACL injuries: commentary on the article by Eric Swart, MD, et al.: "prevention and screening programs for anterior cruciate ligament injuries in young athletes: a cost-effectiveness analysis". PMID- 24806024 TI - Degenerative changes in the atlanto-dens joint and dens fractures in the elderly: close relatives or just neighbors?: a commentary on an article by Matthew S. Shinseki et al.: "association between advanced degenerative changes of the atlanto-dens joint and presence of dens fracture". PMID- 24806025 TI - The cost of obesity: commentary on an article by Hilal Maradit Kremers, MD, MSc, et al. "the effect of obesity on direct medical costs in total knee arthroplasty". PMID- 24806026 TI - Prey capture and phagocytosis in the choanoflagellate Salpingoeca rosetta. AB - Choanoflagellates are unicellular and colonial aquatic microeukaryotes that capture bacteria using an apical flagellum surrounded by a feeding collar composed of actin-filled microvilli. Flow produced by the apical flagellum drives prey bacteria to the feeding collar for phagocytosis. We report here on the cell biology of prey capture in rosette-shaped colonies and unicellular "thecate" or substrate attached cells from the choanoflagellate S. rosetta. In thecate cells and rosette colonies, phagocytosis initially involves fusion of multiple microvilli, followed by remodeling of the collar membrane to engulf the prey, and transport of engulfed bacteria into the cell. Although both thecate cells and rosette colony cells produce ~ 70 nm "collar links" that connect and potentially stabilize adjacent microvilli, only thecate cells were observed to produce a lamellipod-like "collar skirt" that encircles the base of the collar. This study offers insight into the process of prey ingestion by S. rosetta, and provides a context within which to consider potential ecological differences between solitary cells and colonies in choanoflagellates. PMID- 24806027 TI - Hypoxia-inducible regulation of placental BOK expression. AB - BOK (BCL-2-related ovarian killer) is a member of the pro-apoptotic BCL-2 family that is highly expressed in the human placenta. BOK excess causes increased trophoblast autophagy and apoptosis in pre-eclampsia, a pathological condition of hypoxia and oxidative stress. In the present study, we identified an HRE (hypoxia response element) at the junction of exon-1 and intron-1 (+229 to +279) in the human BOK gene, as well as an antisense transcript driven by a promoter located in intron-2. The isolated BOK-HRE bound hypoxia-inducible HIF (hypoxia-inducible factor) proteins in vitro as well as in trophoblastic JEG3 cells and was functional in its natural position as well as in front of a heterologous promoter. Being a reverted repeat, the BOK-HRE functioned in both orientations. This directionless feature of the BOK-HRE facilitates hypoxia regulation via HIF of both BOK and its antisense transcript as demonstrated by RNAi knockdown of the HIF system. Although the antisense transcript was expressed in several human carcinoma cell lines, including choriocarcinoma-derived JEG3 cells, no antisense regulated mechanism for BOK expression was noted. Taken together, these findings indicate that hypoxia-induced expression of BOK in placental cells is regulated via HIF and is not affected by its antisense transcript. PMID- 24806029 TI - Polymerizable peptide copolymer coatings for the control of biointerfacial interactions. AB - The effective control over biointerfacial interactions is essential for a broad range of biomedical applications in vitro and in vivo such as biosensors, cell culture tools and implantable devices. Here, our aim was to develop a coating strategy that is transferable between different substrate materials and can effectively suppress nonspecific protein adsorption and hence reduce cell attachment while also presenting bioactive signals to enable specific cell material interactions. In a first step an allylamine plasma polymer coating was applied, followed by the covalent immobilization of a macroinitiator carrying iniferter functionalities in the side chains. Subsequently, copolymers with different molar ratios of acrylamide and a polymerizable peptide containing the sequence Arg-Gly-Asp (RGD) were grafted via surface initiated free radical polymerization. X-ray photoelectron spectroscopy (XPS) was used to confirm the success of each coating step. The cellular response to these coatings was evaluated using L929 mouse fibroblast cell culture assays for up to 24 h. Cell attachment was significantly reduced on acrylamide homopolymer coatings and negative control surfaces representing a polymerizable peptide containing the nonbioactive Arg-Ala-Asp (RAD) sequence. In contrast, cell attachment was increased with increasing polymerizable RGD peptide ratios in the copolymer. The combination of acrylamide-terminated peptide sequences in combination with acrylamide provides a simple and versatile route to surfaces that combine low nonspecific protein adsorption and the display of controlled densities of bioactive signals and is expected to be translated into a number of biomedical applications in vitro and in vivo. PMID- 24806028 TI - [The body concept for prostate carcinoma patients. Development and testing of a questionnaire which ascertains uro-oncological patients' attitudes to their own bodies under the influence of surgery-conditioned consequences]. AB - BACKGROUND: The aim of this study is the construction of a questionnaire which determines uro-oncological patients' attitudes to their own bodies. The questionnaire will be tested by means of psychometric criteria for suitability. In this way, the emotional-affective and perceptual--cognitive characteristics of the body concept will be detected more effectively. PARTICIPANTS AND METHODS: For the construction, 12 interviews with patients were conducted and items from four body concept questionnaires were analysed. Subsequently, a draft version, containing 133 items, was written. A total of 305 participants (PCa n=205; healthy n=100) were questioned in 2 studies. Thereafter the suitability of the items could be checked by psychometric and factor analytical criteria. RESULTS: The psychometric testing of the statements led to a selection of the items. 40 items could be established as applicable and were therefore accepted for the final questionnaire. CONCLUSION: The indentified scales show good psychometric characteristics and also differentiate between the healthy and the clinical samples. Preliminary analyses prove the validity of the scales, although this should be subjected to further testing for assurance. PMID- 24806030 TI - Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects. AB - WHAT IS KNOWN AND OBJECTIVE: Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. METHODS: A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18 45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by >=7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h ) and the maximal serum concentration (Cmax ) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax , AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0.8-1.25). RESULTS AND DISCUSSION: Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0.8-1.25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20.0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. WHAT IS NEW AND CONCLUSION: These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs. PMID- 24806031 TI - Nanofibrous microposts and microwells of controlled shapes and their hybridization with hydrogels for cell encapsulation. AB - A simple, robust, and cost-effective method is developed to fabricate nanofibrous micropatterns particularly microposts and microwells of controlled shapes. The key to this method is the use of an easily micropatternable and intrinsically conductive metal alloy as a template to collect electrospun fibers. The micropatterned alloy allows conformal fiber deposition with high fidelity on its topographical features and in situ formation of diverse, free-standing micropatterned nanofibrous membranes. Interestingly, these membranes can serve as structural frames to form robust hydrogel micropatterns that may otherwise be fragile on their own. These hybrid micropatterns represent a new platform for cell encapsulation where the nanofiber frames enhance the mechanical integrity of hydrogel and the micropatterns provide additional surface area for mass transfer and cell loading. PMID- 24806032 TI - A review of mixed-effects models of tumor growth and effects of anticancer drug treatment used in population analysis. AB - Population modeling of tumor size dynamics has recently emerged as an important tool in pharmacometric research. A series of new mixed-effects models have been reported recently, and we present herein a synthetic view of models with published mathematical equations aimed at describing the dynamics of tumor size in cancer patients following anticancer drug treatment. This selection of models will constitute the basis for the Drug Disease Model Resources (DDMoRe) repository for models on oncology. PMID- 24806034 TI - A young man with cough, fever and epigastric pain. PMID- 24806033 TI - The prospective randomized study on telaprevir at 1500 or 2250 mg with pegylated interferon plus ribavirin in Japanese patients with HCV genotype 1. AB - BACKGROUND: Triple therapy with telaprevir (TVR), pegylated interferon and ribavirin has improved antiviral efficacy in patients with chronic hepatitis C (CH-C). However, the severe adverse effects caused by TVR are important to resolve. In this prospective, randomized, multicenter, open-label study, the antiviral efficacy and safety in the reduced administration of TVR were examined. METHODS: A total of 81 CH-C Japanese patients with HCV genotype 1 were randomized into two regimens of TVR 2250 mg (TVR-2250) or 1500 mg (TVR-1500) and treated with triple therapy for 24 weeks. RESULTS: The mean HCV RNA at start, 2 and 4 weeks of treatment were 6.69 +/- 0.70, 1.05 +/- 0.74, 0.22 +/- 0.48 log10 IU/ml in the TVR-2250 group and 6.70 +/- 0.62, 1.02 +/- 0.62, 0.13 +/- 0.41 log10 IU/ml in the TVR-1500 group. The SVR rates were 85% in both groups (35/41 and 34/40, respectively). There were no patients with viral breakthrough in either group. As for adverse effects, rash more than moderate and severe anemia with <8.5 g/dl of hemoglobin were higher in the TVR-2250 group than in the TVR-1500 group (p = 0.046, p < 0.001, respectively). The increase in serum creatinine levels and decrease in estimated glomerular filtration rates were higher in the TVR-2250 group than in the TVR-1500 group. CONCLUSIONS: The lower dose of TVR (1500 mg/day) can result in similar SVR rates and lower treatment-related adverse effects compared to the higher dose of TVR (2250 mg/day) in triple therapy (UMIN: 000007313, 000007330). PMID- 24806035 TI - Citrulline as marker of atrophy in celiac disease. PMID- 24806036 TI - Diabetic worker with history of falls: a case study. AB - A 58-year old male employee presented to the occupational health clinic for evaluation after experiencing several falls. He had been diagnosed as having type II diabetes 5 years earlier. The physical examination noted peripheral neuropathy. This article reviews the effects of diabetes on peripheral nerves and discusses interventions that the occupational health nurse may use to monitor workers with diabetes. PMID- 24806037 TI - Assessing Hmong farmers' safety and health. AB - This pilot project investigated agricultural-related safety and health issues among Hmong refugees working on family-operated farms. Novel approaches, namely participatory rural appraisal and photovoice, were used to conduct a qualitative occupational hazard assessment with a group of Hmong farmers in Washington State. These two methods were useful in gathering participants' own perspectives about priority concerns. Several identified problems were related to musculoskeletal disorders, handling and operating heavy machinery, heat and cold stress, respiratory exposures, pest management, and socioeconomic and language concerns. Findings from this study provide insight into the work-related challenges that Hmong refugee farmers encounter and can serve as a basis for occupational health professionals to develop interventions to assist this underserved group. PMID- 24806038 TI - Stochastic resonance whole-body vibration improves postural control in health care professionals: a worksite randomized controlled trial. AB - Slip, trip, and fall injuries are frequent among health care workers. Stochastic resonance whole-body vibration training was tested to improve postural control. Participants included 124 employees of a Swiss university hospital. The randomized controlled trial included an experimental group given 8 weeks of training and a control group with no intervention. In both groups, postural control was assessed as mediolateral sway on a force plate before and after the 8 week trial. Mediolateral sway was significantly decreased by stochastic resonance whole-body vibration training in the experimental group but not in the control group that received no training (p < .05). Stochastic resonance whole-body vibration training is an option in the primary prevention of balance-related injury at work. PMID- 24806039 TI - Barriers to continuing education and continuing professional development among occupational health nurses in Japan. AB - As Japan's industries pursue technical innovations, the responsibilities of occupational health nurses are becoming increasingly complex. With such change, continuing professional development (CPD) and continuing education (CE) are crucial to the provision of appropriate care for workers. This study examined current practices of occupational health nurses and identified barriers to conducting occupational CPD and CE activities. A survey questionnaire was sent to 2,077 occupational health nurses late in 2010, asking about factors affecting attendance at and participation in CPD and CE activities, including challenges for occupational health nurses in practice. Findings demonstrated that many occupational health nurses do not work for companies that support CPD and CE. A significant finding was that occupational health nurses in Japan desire CPD activities and recognize the importance of attending CE activities. Continuing education is viewed by occupational health nurses as essential for their professional development and advancement with broader practice responsibilities and authority. Findings from this study are useful in crafting recommendations to increase occupational health nurse participation in both CPD and CE, leading to improvement in overall workplace health and safety in Japan. PMID- 24806040 TI - Disaster readiness for nurses in the workplace: preparing for the Zombie Apocalypse. AB - The Centers for Disease Control and Prevention (CDC) urges citizens everywhere to prepare for any emergency that might occur in their areas. In conjunction with the U.S. Federal Emergency Management Agency and the U.S. Department of Homeland Security, the CDC has designed a four-step plan ("Ready America") to assist all Americans in taking action. As the largest body of health care providers, nurses across the nation have the potential to contribute substantially to disaster readiness in the workplace and the community. This article reviews lessons learned from previous disasters and also presents an overview of ethical-legal considerations related to disaster nursing care. In addition, a preparation guide for nurses in the workplace and on the home front is presented. Disaster preparation resources are also provided. PMID- 24806042 TI - Industrialized farm animal production: health concerns. AB - Modern livestock farming industry practice continues to cause concern about hazardous exposures among workers and nearby residents. Occupational and environmental health nurses can join other advocates and encourage policies that protect workers, communities, and the environment from confined animal feeding operations health hazards. PMID- 24806045 TI - [Anatomy of the upper esophageal sphincter]. AB - The upper esophageal sphincter (UES) forms a barrier between the pharynx and the esophagus. When closed, the barrier function serves to prevent reflux and aerophagia; when open, swallowing, belching and vomiting are possible. The closing muscles include caudal parts of the inferior pharyngeal sphincter and cranial parts of the upper esophagus musculature. Sphincter opening is achieved by muscles that insert from the outside to connect to the larynx and pharynx in the sphincter region. The closing muscles are innervated by branches of the glossopharyngeal and vagal nerves, and central control is probably mediated by several reflexes. This article presents an overview of the current understanding of the complex UES anatomy. PMID- 24806046 TI - Analysis of high and selective uptake of CO2 in an oxamide-containing {Cu2(OOCR)4}-based metal-organic framework. AB - The porous framework [Cu2(H2O)2L]?4 H2O?2 DMA (H4L = oxalylbis(azanediyl)diisophthalic acid; DMA = N,N-dimethylacetamide), denoted NOTT-125, is formed by connection of {Cu2(RCOO)4} paddlewheels with the isophthalate linkers in L(4-). A single crystal structure determination reveals that NOTT-125 crystallises in monoclinic unit cell with a = 27.9161(6), b = 18.6627(4) and c = 32.3643(8) A, beta = 112.655(3) degrees , space group P2(1)/c. The structure of this material shows fof topology, which can be viewed as the packing of two types of cages (cage A and cage B) in three-dimensional space. Cage A is constructed from twelve {Cu2(OOCR)4} paddlewheels and six linkers to form an ellipsoid-shaped cavity approximately 24.0 A along its long axis and 9.6 A across its central diameter. Cage B consists of six {Cu2(OOCR)4} units and twelve linkers and has a spherical diameter of 12.7 A taking into account the van der Waals radii of the atoms. NOTT-125 incorporates oxamide functionality within the pore walls, and this, combined with high porosity in desolvated NOTT-125a, is responsible for excellent CO2 uptake (40.1 wt % at 273 K and 1 bar) and selectivity for CO2 over CH4 or N2. Grand canonical Monte Carlo (GCMC) simulations show excellent agreement with the experimental gas isotherm data, and a computational study of the specific interactions and binding energies of both CO2 and CH4 with the linkers in NOTT-125 reveals a set of strong interactions between CO2 and the oxamide motif that are not possible with a single amide. PMID- 24806048 TI - Compressive mass analysis on quadrupole ion trap systems. AB - Conventionally, quadrupole ion trap mass spectrometers eject ions of different mass-to-charge ratio (m/z) in a sequential fashion by performing a scan of the rf trapping voltage amplitude. Due to the inherent sparsity of most mass spectra, the detector measures no signal for much of the scan time. By exploiting this sparsity property, we propose a new compressive and multiplexed mass analysis approach--multi Resonant Frequency Excitation (mRFE) ejection. This new approach divides the mass spectrum into several mass subranges and detects all the subrange spectra in parallel for increased mass analysis speed. Mathematical estimation of standard mass spectrum is demonstrated while statistical classification on the parallel measurements remains viable because of the sparse nature of the mass spectra. This method can reduce mass analysis time by a factor of 3-6 and increase system duty cycle by 2*. The combination of reduced analysis time and accurate compound classification is demonstrated in a commercial quadrupole ion trap (QIT) system. PMID- 24806050 TI - Effects of kilovoltage, milliampere seconds, and focal spot size on image quality. AB - PURPOSE: To determine how kilovoltage (kV), milliampere seconds (mAs), and focal spot size affect perceptual image quality using a hand phantom. METHODS: Using computed radiography, 70 images of a posteroanterior (PA) oblique hand phantom were acquired with different kilovoltage and milliampere second values using large and small focal spot sizes. Images were displayed on quality-controlled monitors with dimmed ambient lighting. The look-up table for hand radiography was used for image display. Five diagnostic radiographers scored each image for perceptual image quality against a reference image using a 5-point Likert scale. RESULTS: No significant difference in image quality was found between small and large focal spot sizes at different kilovoltage (P = .46) and milliampere second (P = .56) values. As milliampere seconds increase, perceptual image quality increases gradually from 0.4 mAs to 4 mAs, after which perceptual image quality begins to deteriorate. When kilovoltage increases to within the range of 40 kV to 55 kV, perceptual image quality increases; image quality remains stable after 55 kV. DISCUSSION: This study shows that both large and small focal spot sizes produce images of similar quality, and a wide range of kilovoltage and milliampere seconds can be used to produce images of acceptable quality. The implications of these findings include the potential for extending the life of radiography equipment and the potential for reducing the dose patients receive during appendicular examinations. CONCLUSION: Large focal spot size can be used for PA oblique hand imaging without affecting perceptual image quality. Perceptual image quality remains acceptable and stable for a wide range of kilovoltage and milliampere second values. Optimization of these technical factors to achieve image quality is critical to avoiding higher radiation doses than necessary. PMID- 24806049 TI - Self-gated fat-suppressed cardiac cine MRI. AB - PURPOSE: To develop a self-gated alternating repetition time balanced steady state free precession (ATR-SSFP) pulse sequence for fat-suppressed cardiac cine imaging. METHODS: Cardiac gating is computed retrospectively using acquired magnetic resonance self-gating data, enabling cine imaging without the need for electrocardiogram (ECG) gating. Modification of the slice-select rephasing gradients of an ATR-SSFP sequence enables the acquisition of a one-dimensional self-gating readout during the unused short repetition time (TR). Self-gating readouts are acquired during every TR of segmented, breath-held cardiac scans. A template-matching algorithm is designed to compute cardiac trigger points from the self-gating signals, and these trigger points are used for retrospective cine reconstruction. The proposed approach is compared with ECG-gated ATR-SSFP and balanced steady-state free precession in 10 volunteers and five patients. RESULTS: The difference of ECG and self-gating trigger times has a variability of 13 +/- 11 ms (mean +/- SD). Qualitative reviewer scoring and ranking indicate no statistically significant differences (P > 0.05) between self-gated and ECG-gated ATR-SSFP images. Quantitative blood-myocardial border sharpness is not significantly different among self-gated ATR-SSFP ( 0.61+/-0.15 mm -1), ECG-gated ATR-SSFP ( 0.61+/-0.15 mm -1), or conventional ECG-gated balanced steady-state free precession cine MRI ( 0.59+/-0.15 mm -1). CONCLUSION: The proposed self gated ATR-SSFP sequence enables fat-suppressed cardiac cine imaging at 1.5 T without the need for ECG gating and without decreasing the imaging efficiency of ATR-SSFP. PMID- 24806051 TI - Perceived barriers to online education by radiologic science educators. AB - BACKGROUND: Radiologic science programs continue to adopt the use of blended online education in their curricula, with an increase in the use of online courses since 2009. However, perceived barriers to the use of online education formats persist in the radiologic science education community. PURPOSE: An electronic survey was conducted to explore the current status of online education in the radiologic sciences and to identify barriers to providing online courses. A random sample of 373 educators from radiography, radiation therapy, and nuclear medicine technology educational programs accredited by the Joint Review Committee on Education in Radiologic Technology and Joint Review Committee on Educational Programs in Nuclear Medicine Technology was chosen to participate in this study. METHODS: A qualitative analysis of self-identified barriers to online teaching was conducted. RESULTS: Three common themes emerged: information technology (IT) training and support barriers, student-related barriers, and institutional barriers. DISCUSSION: Online education is not prevalent in the radiologic sciences, in part because of the need for the clinical application of radiologic science course content, but online course activity has increased substantially in radiologic science education, and blended or hybrid course designs can effectively provide opportunities for student-centered learning. CONCLUSION: Further development is needed to increase faculty IT self-efficacy and to educate faculty regarding pedagogical methods appropriate for online course delivery. To create an excellent online learning environment, educators must move beyond technology issues and focus on providing quality educational experiences for students. PMID- 24806052 TI - Comparing left ventricular ejection fraction measurement using cardiovascular magnetic resonance imaging. AB - PURPOSE: To compare the accuracy of cardiovascular magnetic resonance (CMR) imaging methods for measuring left ventricular ejection fraction with multiple gated acquisition (MUGA). CMR imaging methods included in-line tracking, in-line automated tracking with manual adjustment (a semiautomatic technique), and manual drawing techniques. METHODS: Thirty patients were recruited for left ventricular ejection fraction (LVEF) assessment. The LVEF was measured by CMR imaging using in-line automated tracking, the semiautomatic technique, and manual contouring and segmentation. These methods were then followed by a MUGA scan. Results of all 4 methods were compared for LVEF percentage and measuring time. Repeated analysis of variance testing was used to determine any significant difference between the means of measuring the LVEF. A P value of less than .05 was considered statistically significant. RESULTS: The mean LVEF measured by CMR imaging using in-line automated tracking, a semiautomatic technique, and manual drawing were 52.9% (standard deviation [SD] 8.5), 62.3% (SD 8.1), and 62.2% (SD 7.8), respectively. The mean LVEF with the MUGA scan was 64.4% (SD 8.4). The MUGA scan, semiautomatic technique, and manual measurement using CMR imaging were statistically significantly different from the CMR imaging using in-line automated tracking for LVEF calculation (all P values < .01). DISCUSSION: Using in-line automated tracking, the end systolic volume was overestimated, which resulted in the underestimation of the LVEF. A therapeutic plan based on an inaccurate and low LVEF measurement could be dangerous because it might suggest a drug-related cardiotoxicity, and medication might be discontinued. CONCLUSION: A semiautomated technique with manual adjustment of the cardiac contours and basal slice selection in CMR imaging is time saving and comparable with the MUGA scan for the accurate documentation of LVEF. PMID- 24806053 TI - Current issues in radiation dose monitoring and reporting. AB - Minimizing radiation exposure while optimizing image quality is critical in diagnostic medical imaging. Radiologic technologists face complex challenges when implementing dose monitoring and reporting systems to assist in radiation safety efforts. Challenges include communicating the risks of radiation exposure, handling variations in dose measurement techniques, and working with a lack of standardized nomenclature for examination types. With increasing attention on radiation safety, many solutions have been presented. A team approach to dose optimization with professionals nationwide can help establish a culture of radiation safety in medical imaging. PMID- 24806054 TI - Pediatric upper gastrointestinal studies. AB - Upper gastrointestinal examinations are common procedures in many radiology departments. Performing this examination on pediatric patients requires understanding the formation of the gastrointestinal tract and the various disease processes and anatomical variances that can occur. The examination also requires a thorough patient history. This article discusses embryologic development and anatomy of the small bowel and colon, disease processes and conditions of the upper gastrointestinal tract, and fluoroscopic upper gastrointestinal tract examinations performed on the pediatric and neonatal patient. PMID- 24806055 TI - Organizing and leading a journal club. PMID- 24806056 TI - Image quality assessment tools for radiation dose optimization in digital radiography: an overview. PMID- 24806057 TI - Shielding in computed tomography: an update. PMID- 24806060 TI - Exposure tracking with digital radiography: how dose conscientious are you? PMID- 24806061 TI - Endotracheal intubation. PMID- 24806062 TI - Communicating with elderly patients. PMID- 24806066 TI - Articles strike a chord: conflicting research. PMID- 24806067 TI - Articles strike a chord: a closer look. PMID- 24806068 TI - Articles strike a chord: heartfelt thanks. PMID- 24806069 TI - Straight talk. PMID- 24806070 TI - Computed tomography of facial fractures. AB - Facial skeletal fractures are common, potentially serious, and frequently associated with other life-threatening conditions, such as traumatic brain injuries. Facial fractures can be simple or complex and sometimes involve serious complications. Computed tomography has revolutionized the rapid and precise assessment of craniofacial and neck fractures in patients with severe facial trauma. This article introduces readers to the epidemiology, skeletal anatomy and biomechanics, complications, and diagnostic imaging of facial fractures. In addition, this article describes efforts to develop and validate a quantitative scoring system for facial fracture severity and reviews treatment strategies for facial skeletal fractures. PMID- 24806071 TI - Advancements in molecular breast imaging. AB - Breast cancer is the most common cancer in women, but with early detection, it is a treatable disease. Mammography has long been the medical imaging standard for breast cancer screening, with other breast imaging modalities used as adjunct procedures to support diagnostic interpretation. Molecular breast imaging (MBI) was introduced in the past decade as a promising adjunct to mammography. Using a radiopharmaceutical and a dedicated imaging device, MBI technology helps physicians examine metabolic activity within the breast. This article provides a review of breast anatomy and composition, explores genetic factors related to breast cancer, and examines practice guidelines related to MBI. PMID- 24806072 TI - Use of FDG PET-CT in prostate lesion diagnosis. PMID- 24806073 TI - Variation of the Eu(II) emission wavelength by substitution of fluoride by hydride in fluorite-type compounds EuH(x)F(2-x) (0.20 <= x <= 0.67). AB - Mixed-hydride fluorides EuHxF2-x were prepared by the solid-state reaction of EuF2 and EuH2 under hydrogen gas pressure in an autoclave. Eu(II) luminescence is observed for 0.20 <= x <= 0.67, while pure EuF2 does not show any emission. The energy of the emission depends strongly on the degree of substitution x. For low hydride contents, yellow emission is observed, whereas higher hydride contents lead to red emission. The red shift is attributed to the nephelauxetic effect of the hydride anion. Remarkably, limited concentration quenching is observed in EuHxF2-x (0.20 <= x <= 0.67). This observation is explained by suppression of long-range energy migration due to disorder in the local environment of Eu(2+) in the mixed H/F crystals. The strong x dependence of the luminescence maxima proves hydride-fluoride substitution to be a valuable tool to tune the emission wavelength of Eu(II)-containing phosphors. PMID- 24806075 TI - Anesthesia for MRI enterography in children. PMID- 24806074 TI - S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. AB - Cell migration and invasion require increased plasma membrane dynamics and ability to navigate through dense stroma, thereby exposing plasma membrane to tremendous physical stress. Yet, it is largely unknown how metastatic cancer cells acquire an ability to cope with such stress. Here we show that S100A11, a calcium-binding protein upregulated in a variety of metastatic cancers, is essential for efficient plasma membrane repair and survival of highly motile cancer cells. Plasma membrane injury-induced entry of calcium into the cell triggers recruitment of S100A11 and Annexin A2 to the site of injury. We show that S100A11 in a complex with Annexin A2 helps reseal the plasma membrane by facilitating polymerization of cortical F-actin and excision of the damaged part of the plasma membrane. These data reveal plasma membrane repair in general and S100A11 and Annexin A2 in particular as new targets for the therapy of metastatic cancers. PMID- 24806076 TI - Nationwide use and outcomes of ambulatory surgery in morbidly obese patients in the United States. AB - STUDY OBJECTIVE: To compare the overall characteristics and perioperative outcomes in morbidly obese and nonobese patients undergoing ambulatory surgery in the United States. DESIGN: Retrospective, propensity-matched cohort study. SETTING: Academic medical center. MEASUREMENTS: The association between duration of surgical procedures, postoperative complications, and unplanned hospital admission was assessed in a propensity-matched cohort of morbidly obese and nonobese patients derived from the 2006 National Survey of Ambulatory Surgery. MAIN RESULTS: Only 0.32% of the ambulatory procedures were performed on morbidly obese patients. The morbidly obese were significantly younger but had a higher burden of comorbidities, were more likely to undergo the procedure in hospital based outpatient departments (HOPD; 80.1% vs 56.5%; P = 0.004), and had significantly shorter procedures than the nonobese (median [interquartile range], 28 [21-38] vs 42 [22-65] min; P < 0.0001). The incidences of postoperative hypertension, hypotension, hypoxia, cancellation of surgery, and unplanned hospital admissions did not differ significantly between groups. Similarly, adjusted rates of delayed discharge were similar in morbidly obese and nonobese patients (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.18 - 1.15; P = 0.09). In contrast, morbid obesity was associated with decreased odds of postoperative nausea and vomiting (OR, 0.27; CI, 0.09 - 0.84; P = 0.01). CONCLUSIONS: In 2006 in the U.S., the prevalence of ambulatory surgery in the morbidly obese was low, with most of the procedures being performed in the HOPD facilities, suggesting a conservative patient selection. The incidence of adverse postoperative outcomes and delayed discharge, as well as unplanned hospital admission after ambulatory surgery in the morbidly obese, was similar to that reported in the nonobese. PMID- 24806077 TI - Graphene oxide as an anti-shrinkage additive for resorcinol-formaldehyde composite aerogels. AB - In order to strengthen the nanostructure and suppress the collapse of nanopores of resorcinol-formaldehyde (RF) aerogels during the drying process, graphene oxide (GO) was incorporated into the RF matrix to prepare GO-RF composite aerogels by sol-gel polymerization. The influences of GO content on the sol-gel process, structure, and physical properties of RF aerogels were investigated. The morphologies of composite aerogels were characterized by scanning electron microscopy and transmission electron microscopy, and it was found that GO was well dispersed in the RF matrix. In addition, GO can obviously accelerate the gelation of the RF solution and reduce both the drying shrinkage and aerogel density. As the content of GO increased from 0 to 2 wt%, both the linear shrinkage and density of composite aerogels decreased progressively from 28.3% to 2.0% and 506 to 195 kg m(-3), respectively, implying that GO is an effective additive for inhibiting the volume shrinkage of aerogels during the drying process. PMID- 24806078 TI - Characteristics and Properties of Mesenchymal Stem Cells Derived From Microfragmented Adipose Tissue. AB - The subcutaneous adipose tissue provides a clear advantage over other mesenchymal stem cell sources due to the ease with which it can be accessed, as well as the ease of isolating the residing stem cells. Human adipose-derived stem cells (hADSCs), localized in the stromal-vascular portion, can be isolated ex vivo using a combination of washing steps and enzymatic digestion. In this study, we report that microfragmented human lipoaspirated adipose tissue is a better stem cell source compared to normal lipoaspirated tissue. The structural composition of microfragments is comparable to the original tissue. Differently, however, this procedure activates the expression of antigens, such as beta-tubulin III. The hADSCs derived from microfragmented lipoaspirate tissue were systematically characterized for growth features, phenotype, and multipotent differentiation potential. They fulfill the definition of mesenchymal stem cells, although with a higher neural phenotype profile. These cells also express genes that constitute the core circuitry of self-renewal such as OCT4, SOX2, and NANOG, and neurogenic lineage genes such as NEUROD1, PAX6, and SOX3. Such findings suggest further studies by evaluating Microfrag-AT hADSC action in animal models of neurodegenerative conditions. PMID- 24806079 TI - An holistic ecological analysis of the diet of Cory's shearwaters using prey morphological characters and DNA barcoding. AB - Knowledge of the dietary choices and trophic niches of organisms is the key to understanding their roles in ecosystems. In seabird diet studies, prey identification is a difficult challenge, often yielding results with technique specific biases. Additionally, sampling efforts are often not extensive enough to reveal intrapopulational variation. Immature animals, which may constitute up to 50% of a population, may occupy a significantly different trophic niche to more experienced birds, but this remains largely unexplored. We investigated the diet of Cory's shearwater (Calonectris diomedea) from Selvagem Grande, an island located off the northwest African coast, collecting a total of 698 regurgitate samples over three consecutive breeding seasons. The diet was assessed using two complementary approaches for prey identification: conventional morphological analysis (using fish vertebrae, otoliths and cephalopod beaks) and DNA barcoding of the 16S rRNA mitochondrial gene, in cases where a positive identification could not be retrieved. Species assignments employed BLAST and distance-based methods, as well as direct optimization of the tree length based on unaligned sequences in POY. This method resulted in robust tree estimates and species assignments, showing its potential for DNA barcoding of stomach contents using hypervariable markers such as the 16S. The molecular approach increased taxonomic resolution and revealed an additional 17 taxa. Diet differed significantly according to breeding status, sex, breeding phase (prelaying and chick rearing) and year. Such direct evidence of trophic segregation within the same population has rarely been shown in seabirds and highlights the importance of including such variables in ecosystem-based management approaches. PMID- 24806080 TI - Assessing variability in audiovisual speech integration skills using capacity and accuracy measures. AB - OBJECTIVE: While most normal-hearing listeners rely on the auditory modality to obtain speech information, research has demonstrated the importance that non auditory modalities have on language recognition during face-to-face communication. The efficient utilization of the visual modality becomes increasingly important in difficult listening conditions, and especially for older and hearing-impaired listeners with sensory or cognitive decline. First, this report will quantify audiovisual integration skills using a recently developed capacity measure that incorporates speed and accuracy. Second, to investigate sensory factors contributing to integration ability, high and low frequency hearing thresholds will be correlated with capacity, as well as gain measures from sentence recognition. DESIGN: Integration scores were obtained from a within-subjects design using an open-set sentence speech recognition experiment and a closed set speeded-word classification experiment, designed to examine integration (i.e. capacity). STUDY SAMPLE: A sample of 44 adult listeners without a self-reported history of hearing-loss was recruited. RESULTS: RESULTS demonstrated a significant relationship between measures of audiovisual integration and hearing thresholds. CONCLUSIONS: Our data indicated that a listener's ability to integrate auditory and visual speech information in the domains of speed and accuracy is associated with auditory sensory capabilities and possibly other sensory and cognitive factors. PMID- 24806081 TI - Associations between a posteriori defined dietary patterns and bone mineral density in adolescents. AB - PURPOSE: Dietary pattern analysis may uncover the joint effects of multiple dietary components on bone health, but such research is scarce and targets mostly adults. METHODS: We quantified prospective associations between dietary patterns and bone mineral density (BMD) in 1,007 adolescents of a cohort born in 1990 and recruited at schools in Porto during the 2003/2004 school year. Forearm BMD was measured using dual-energy X-ray absorptiometry. Participants' dietary patterns were classified "Healthier", "Dairy products", "Fast food and sweets" and "Lower intake" according to previously identified patterns obtained in a larger sample of 1,489 participants using the K-means method. Using dietary patterns at 13 years old as the main exposure, associations were estimated cross-sectionally (with BMD at the age of 13) and prospectively (with annual BMD variation between 13 and 17 years), using linear regression coefficients adjusted for height, weight, energy intake and, in girls, for menarche age. RESULTS: No significant associations between the a posteriori dietary patterns identified and mean BMD at 13 were found. However, among girls, adherence to a pattern characterized by low intake of energy and all food groups was negatively associated with annual BMD variation between 13 and 17 years [adjusted coefficient (95 % CI) -0.451 (-0.827; -0.074) mg.cm-2.year-1]. CONCLUSIONS: Although results showed that, in girls, adherence to a "Lower intake" dietary pattern is associated with lower annual BMD variation throughout adolescence, overall, there were no consistent associations between dietary patterns and forearm BMD in adolescents. PMID- 24806082 TI - Serum ghrelin levels and gender-related indices of body composition in prepubertal children: a cross-sectional study. AB - BACKGROUND: A wide variety of functions has been attributed to ghrelin, a peptide hormone secreted in the stomach. The objective of the study was to assess the association of ghrelin concentrations with body composition among Iranian children. METHODS: In this study, blood samples of 57 boys and 54 girls aged 6-10 were collected to measure ghrelin levels. Fat mass (FM) and fat-free mass (FFM) were examined by body composition analyzer. Actigraph GT3X was administered to assess children's physical activity and sleep. Data were analyzed using linear regression models. RESULTS: All measured parameters did not differ between genders except for sleep time which was higher and sleep efficacy which was lower in boys compared with girls. None of the FM and FFM indices studied in boys was significantly associated with ghrelin levels. In girls, however, ghrelin concentrations were significantly associated with FM (beta = 0.04, P = 0.01), fat mass index (beta = 0.07, P = 0.008), and fat-free mass index (beta = 0.08, P = 0.04) and near-significantly associated with FFM (beta = 0.03, P = 0.09) after adjusting for age, physical activity, sleep, and dietary intake. CONCLUSION: Girls with higher ghrelin levels were more likely to have increased total FM and FFM. Conversely, body composition was not associated with ghrelin levels in boys. Consequently, ghrelin may influence the gender-related differences of body composition during childhood in girls. But, further study is needed to confirm our findings. PMID- 24806083 TI - The intra-operative incidence of Fallopian canal dehiscence during surgery for cholesteatoma: a prospective case-control study and review of the literature. AB - OBJECTIVE: To investigate Fallopian canal dehiscence (FCD) during cholesteatoma surgery. STUDY DESIGN: Prospective case-control study. PATIENTS: Four hundred and one patients with cholesteatoma and 172 with otosclerosis. INTERVENTIONS: Therapeutic. SETTING: District general hospital. MAIN OUTCOME MEASURES: (i) Intra operative incidence of FCD during (a) surgery for cholesteatoma versus a homogeneous control group (patients with otosclerosis); (b) revision surgery for cholesteatoma as compared to primary surgery. (ii) Intra-operative incidence of a fistula if FCD is present. RESULTS: Data were prospectively collected and analysed using chi-square tests. FCD was found in 19% of cases versus 5.2% of controls. Intra-operative incidence of (i) FCD during cholesteatoma surgery versus otosclerosis surgery was statistically very highly significant (P < 0.0001, OR = 5.43); (ii) FCD during revision versus primary cholesteatoma surgery was not statistically significant (P = 0.83); and (iii) encountering a fistula in the presence of FCD during cholesteatoma surgery was statistically very highly significant (P < 0.0001, OR = 6.71). CONCLUSIONS: A surgeon is more likely to encounter FCD during cholesteatoma surgery than in stapes surgery. If during cholesteatoma surgery FCD is found, then a fistula is also more likely to be present, mainly of the semicircular canal. The incidence of FCD is not increased in revision surgery. These findings are very relevant for any otologist undertaking cholesteatoma surgery. PMID- 24806084 TI - Post-implementation surveillance of a non-pharmacological health technology within a national health service. AB - OBJECTIVES: The aim of this study was to describe 8-year results from post implementation surveillance of neuroreflexotherapy (NRT), a health technology proven effective for treating neck and back pain. METHODS: Post-implementation surveillance included all patients undergoing NRT across five regions within the Spanish National Health Service (SNHS). Validated methods were used to assess pain, disability, adverse events, use of health resources, and patient satisfaction. Logistic regression models were developed to identify the variables associated with the risk of a pain episode requiring more than one NRT intervention. The number of relapses among discharged patients during the 8-year period was calculated. RESULTS: Between January 1, 2004, and June 30, 2012, 9,023 patients (median age: 53 years), presenting 11,384 subacute (25.2 percent) and chronic (74.8 percent), neck or back pain episodes, were discharged after receiving NRT. Spinal pain improved in 89 percent of cases, 83 percent abandoned drugs, and 0.02 percent required spine surgery. The only adverse event was skin discomfort (8.0 percent of patients). Number of patient complaints was 0, and answers to a standardized questionnaire reflected a high degree of satisfaction (response rate: 76.7 percent). Of the pain episodes, 18.9 percent required more than one NRT intervention; logistic regression models identified the variables associated with this. Over the 8-year period, the proportion of discharged patients referred for treatment due to relapse at the same level for neck, thoracic, and low back pain, was 16.4 percent, 6.5 percent, and 14.5 percent respectively. CONCLUSIONS: Post-marketing surveillance for a non-pharmacological technology is feasible within the SNHS. These results support generalizing NRT across the entire SNHS under the current validated application conditions. PMID- 24806090 TI - Identification of a nuclear protein, LRRC42, involved in lung carcinogenesis. AB - On the basis of the gene expression profiles of 120 lung cancer cases using a cDNA microarray containing 27,648 genes or expressed sequence tags (ESTs), we identified LRRC42 (Leucine-rich repeat containing 42) to be significantly upregulated in the majority of lung cancers. Northern blot analysis demonstrated that LRRC42 was expressed only in testis among normal tissues examined. Knockdown of LRRC42 expression by siRNA against LRRC42 significantly suppressed the growth of lung cancer cells. On the other hand, stable induction of LRRC42 expression significantly promoted cell growth. LRRC42, which was found to localize in the nucleus of mammalian cells, is likely to interact with and stabilize GATAD2B (GATA zinc finger domain-containing 2B) and MBD3 (Methyl-CpG-binding domain protein 3) proteins that could contribute to lung cancer cell proliferation partly through the regulation of p21Waf1/Cip1. Our findings suggest that LRRC42 overexpression as well as its interaction with LRRC42-GATAD2B might play essential roles in lung carcinogenesis, and be a promising molecular target for lung cancer therapy. PMID- 24806092 TI - Influence of hydroxyls on Pd atom mobility and clustering on rutile TiO(2)(011)-2 * 1. AB - Understanding agglomeration of late transition metal atoms, such as Pd, on metal oxide supports, such as TiO2, is critical for designing heterogeneous catalysts as well as for controlling metal/oxide interfaces in general. One approach for reducing particle sintering is to modify the metal oxide surface with hydroxyls that decrease adatom mobility. We study by scanning tunneling microscopy experiments, density functional theory (DFT) calculations, and Monte Carlo (MC) computer simulations the atomistic processes of Pd sintering on a hydroxyl modified TiO2(011)-2 * 1 surface. The formation of small 1-3 atom clusters that are stable at room temperature is achieved on the hydroxylated surface, while much larger clusters are formed under the same conditions on a hydroxyl-free surface. DFT shows that this is a consequence of stronger binding of Pd atoms adjacent to hydroxyls and increased surface diffusion barriers for Pd atoms on the hydroxylated surface. DFT, kinetic MC, and ReaxFF-based NVT-MC simulations show that Pd clusters larger than single Pd monomers can adsorb the hydrogen from the oxide surface and form Pd hydrides. This depletes the surface hydroxyl coverage, thus allowing Pd to more freely diffuse and agglomerate at room temperature. Experimentally, this causes a bimodal cluster size distribution with 1-3 atom clusters prevalent at low Pd coverage, while significantly larger clusters become dominant at higher Pd concentrations. This study demonstrates that hydroxylated oxide surfaces can significantly reduce Pd cluster sizes, thus enabling the preparation of surfaces populated with metal clusters composed of single to few atoms. PMID- 24806091 TI - Spatio-temporally restricted expression of cell adhesion molecules during chicken embryonic development. AB - Differential cell adhesive properties are known to regulate important developmental events like cell sorting and cell migration. Cadherins and protocadherins are known to mediate these cellular properties. Though a large number of such molecules have been predicted, their characterization in terms of interactive properties and cellular roles is far from being comprehensive. To narrow down the tissue context and collect correlative evidence for tissue specific roles of these molecules, we have carried out whole-mount in situ hybridization based RNA expression study for seven cadherins and four protocadherins. In developing chicken embryos (HH stages 18, 22, 26 and 28) cadherins and protocadherins are expressed in tissue restricted manner. This expression study elucidates precise expression domains of cell adhesion molecules in the context of developing embryos. These expression domains provide spatio temporal context in which the function of these genes can be further explored. PMID- 24806093 TI - Integrated lab-on-chip biosensing systems based on magnetic particle actuation--a comprehensive review. AB - The demand for easy to use and cost effective medical technologies inspires scientists to develop innovative lab-on-chip technologies for point-of-care in vitro diagnostic testing. To fulfill medical needs, the tests should be rapid, sensitive, quantitative, and miniaturizable, and need to integrate all steps from sample-in to result-out. Here, we review the use of magnetic particles actuated by magnetic fields to perform the different process steps that are required for integrated lab-on-chip diagnostic assays. We discuss the use of magnetic particles to mix fluids, to capture specific analytes, to concentrate analytes, to transfer analytes from one solution to another, to label analytes, to perform stringency and washing steps, and to probe biophysical properties of the analytes, distinguishing methodologies with fluid flow and without fluid flow (stationary microfluidics). Our review focuses on efforts to combine and integrate different magnetically actuated assay steps, with the vision that it will become possible in the future to realize integrated lab-on-chip biosensing assays in which all assay process steps are controlled and optimized by magnetic forces. PMID- 24806094 TI - Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development. AB - In the postnatal hippocampus, newly generated neurons contribute to learning and memory. Disruptions in neurogenesis and neuronal development have been linked to cognitive impairment and are implicated in a broad variety of neurological and psychiatric disorders. To identify putative factors involved in this process, we examined hippocampal gene expression alterations in mice possessing a heterozygous knockout of the calcium/calmodulin-dependent protein kinase II alpha heterozygous knockout gene (CaMK2alpha-hKO), an established model of cognitive impairment that also displays altered neurogenesis and neuronal development. Using this approach, we identified gastrin-releasing peptide (GRP) as the most dysregulated gene. In wild-type mice, GRP labels NeuN-positive neurons, the lone exception being GRP-positive, NeuN-negative cells in the subgranular zone, suggesting GRP expression may be relevant to neurogenesis and/or neuronal development. Using a model of in vitro hippocampal neurogenesis, we determined that GRP signaling is essential for the continued survival and development of newborn neurons, both of which are blocked by transient knockdown of GRP's cognate receptor (GRPR). Furthermore, GRP appears to negatively regulate neurogenesis-associated proliferation in neural stem cells both in vitro and in vivo. Intracerebroventricular infusion of GRP resulted in a decrease in immature neuronal markers, increased cAMP response element-binding protein (CREB) phosphorylation, and decreased neurogenesis. Despite increased levels of GRP mRNA, CaMK2alpha-hKO mutant mice expressed reduced levels of GRP peptide. This lack of GRP may contribute to the elevated neurogenesis and impaired neuronal development, which are reversed following exogenous GRP infusion. Based on these findings, we hypothesize that GRP modulates neurogenesis and neuronal development and may contribute to hippocampus-associated cognitive impairment. PMID- 24806095 TI - Peak oxygen uptake test in the assessment of growth hormone deficiency. AB - This study aimed at evaluating a peak oxygen uptake test as a simple diagnostic tool to assess growth-hormone deficiency (GHD) in adults. Based on the findings of multiple growth hormone (GH) samplings after the exercise, a single GH sample taken 15 min postexercise revealed high accuracy in the diagnosis of GHD in the present study. A standardized peak oxygen uptake test may, therefore, provide an accurate alternative to more invasive tests of GHD. PMID- 24806098 TI - Nurse religiosity and spiritual care. AB - AIMS: To describe how the religiosity of Christian nurses motivates their practice and manifests during patient care, especially spiritual care. BACKGROUND: Nurses around the world are often religious. This religiosity inherently affects nursing practice. Ethical codes, however, direct that nurses ought to never proselytize their religion while caring for patients. Little is known about how the religion of nurses affects their nursing practice. DESIGN: Cross-sectional phenomenological study. METHODS: Data were collected during semi structured interviews in 2009-2011 with 14 Christian nurses in the USA. Data were coded and thematically analysed after transcription. FINDINGS: Informants described how they approached patients with religious conversation or spiritual care interventions that were overtly Christian in nature. With some awareness of the potential for harm in presenting their Christian beliefs and practices, these nurses also observed for patient cues before raising religious discourse and maintained caution so as to respect patient autonomy. Religiosity also was a personal resource for these nurses as they cared for very ill patients. The following themes were described: religious determinants and influences, perceptions of divine promptings and protection, religious approaches to spiritual care, respecting patient spirituality/religiosity and religious preparation for daily work. CONCLUSION: Understanding these religious motivations and religious spiritual care practices of Christian nurses provides evidence that can stimulate debate for policy makers and scholars. It can also inform educators teaching spiritual care and administrators supervising religious nurses. PMID- 24806096 TI - Genetic risk score of NOS gene variants associated with myocardial infarction correlates with coronary incidence across Europe. AB - Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65-85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition. PMID- 24806099 TI - Graft and viral outcomes in retransplantation for hepatitis C virus recurrence and HCV primary liver transplantation: a case-control study. AB - INTRODUCTION: The use of liver retransplantation (ReLT) for hepatitis C virus (HCV) recurrence is controversial because of subsequent viral recurrence after ReLT. METHODS: Case-control analysis between patients undergoing ReLT for HCV reinfection between 1993 and 2012 (ReLT group: 26 patients) and patients undergoing liver transplantation (LT) for HCV infection immediately before and after each ReLT (LT group: 52 patients). RESULTS: ReLT group had worse hepatocellular function, higher preoperative viral load, higher transfusion requirements, and increased number of postoperative complications than LT group. ReLT patients showed a trend toward worse graft survival compared with LT (five yr graft survival: 42.3% vs. 64.3%, p = 0.145), but the rate of severe HCV recurrence and infection-free survival (IFS) was similar. The use of donors older than 60 yr led to a lower IFS and graft survival in both groups. Early severe HCV infection rate was similar in both groups, but it affected prognosis in ReLT more markedly than in LT (three-yr graft survival: 0% vs. 66.7%, p = 0.003). CONCLUSIONS: ReLT for HCV reinfection has acceptable results when strict selection policies of donor and recipient are applied. However, early severe recurrence more markedly impairs prognosis in ReLT patients than in LT. PMID- 24806100 TI - Counterions control whether self-assembly leads to formation of stable and well defined unilamellar nanotubes or nanoribbons and nanorods. AB - Self-assembly of the amphiphilic pi-conjugated carbenium ion ATOTA-1(+) in aqueous solution selectively leads to discrete and highly stable nanotubes or nanoribbons and nanorods, depending on the nature of the counterion (Cl(-) vs. PF6(-), respectively). The nanotubes formed by the Cl(-) salt illustrate an exceptional example of a structural well-defined (29+/-2 nm in outer diameter) unilamellar tubular morphology featuring pi-conjugated functionality and high stability and flexibility, in aqueous solution. PMID- 24806101 TI - Integrated fluorescence detection of labeled biomolecules using a prism-like PDMS microfluidic chip and lateral light excitation. AB - Microfabricated amorphous silicon photodiodes were integrated with prism-like PDMS microfluidics for the detection and quantification of fluorescence signals. The PDMS device was fabricated with optical quality surfaces and beveled sides. A 405 nm laser beam perpendicular to the lateral sides of the microfluidic device excites the fluorophores in the microchannel at an angle of 70 degrees to the normal to the microchannel/photodiode surface. This configuration, which makes use of the total internal reflection of the excitation beam and the isotropy of the fluorescence emission, minimizes the intensity of excitation light that reaches the integrated photodetector. A difference of two orders of magnitude was achieved in the reduction of the detection noise level as compared with a normally incident excitation configuration. A limit-of-detection of 5.6 * 10(10) antibodies per square centimeter was achieved using antibodies labeled with a model organic fluorophore. Furthermore, the results using the lateral excitation scheme are in good proportionality agreement with those by fluorescence quantification using wide-field fluorescence microscopy. PMID- 24806103 TI - Comparative study of trigeminocardiac reflex after trigeminal ganglion compression during total intravenous anesthesia. AB - BACKGROUND: Percutaneous compression of the trigeminal ganglion (PCTG) is an alternative surgical treatment for trigeminal neuralgia (TN). Manipulation of PCTG can lead to significant hemodynamic changes, which may increase the risk of cardiovascular complications. However, to our knowledge, few studies have focused on anesthesia experience during PCTG as treatment for TN so far. It was our primary focus on how to ensure the stability of hemodynamics during our clinical anesthesia experience. This study aimed to compare the study group (using sodium nitroprusside [SNP] as soon as the puncture began) with the control group (without using SNP as soon as the puncture began) to investigate cardiovascular parameters (systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate [HR]) at 5 periods during total intravenous anesthesia. METHODS: A total of 256 patients who underwent PTCG were enrolled and randomly assigned into the study group (n=137) (using SNP as soon as the puncture began) and the control group (n=119) (without using SNP as soon as puncture began); the relationship between the hemodynamic changes and using SNP or without using SNP was compared. Blood pressure and HR were measured at 5 periods: preoperative (T1), before puncture (T2), during compression (T3), 1 minute after compression ended (T4), and 1 minute after the procedure ended (T5). Multivariate analysis of variance and the Pearson chi test were used, and a value of P<0.05 was considered statistically significant. RESULTS: The mean values of SBP were higher in the control group at the evaluation during T3 (P<0.001 vs. control), T4 (P<0.05 and P=0.040 vs. control), and T5 (P<0.05 and P=0.037 vs. control) and DBP was the only observed significant difference during T3 (P<0.001 vs. control), when compared with the study group. Meanwhile, means of SBP, DBP, and HR comparison in the same group were observed between T2 and T3. In the control group, means of SBP (P<0.001 vs. T2), DBP (P<0.001 vs. T2), and HR (P<0.001 vs. T2) showed significant differences in comparison with control group; means of HR (P<0.001 vs. T2) was the only observed significant difference between T2 and T3 in the study group. However, PTCG elicited significant abrupt bradycardia during T3 in almost all patients. CONCLUSIONS: The control group and the study group were not able to prevent bradycardia elicited during PTCG. Compared with control group, dramatic elevations of the systemic blood pressure can be prevented using intravenous drip SNP as soon as the puncture began during total intravenous anesthesia in the study group. Our findings verify that intravenous drip SNP is an effective method to control abrupt rise of blood pressure. PMID- 24806105 TI - Airtraq and pediatric cervical spine surgery. PMID- 24806106 TI - Magnetic response of zigzag nanoribbons under electric fields. AB - Spin excitations in zigzag graphene nanoribbons are studied when the system is subjected to an electric field in the transversal direction. The magnetic properties and the lifetime of the spin excitations are systematically investigated and compared using a tight-binding electron-electron model treated by a mean-field Hubbard model. The effects of electron-hole asymmetry introduced by next-nearest neighbor hopping are also investigated. We show that by increasing the electric field, the antiferromagnetic correlations between the edges of the nanoribbons are decreased due to a reduction of the magnetic moments. The results show that the spin wave lifetime may be controlled by the intensity of the transversal electric field, indicating that zigzag nanoribbons may be considered great candidates for future spintronic applications. PMID- 24806107 TI - Alternating copolymerization of dihydrocoumarin and epoxides catalyzed by chromium salen complexes: a new route to functional polyesters. AB - We report the alternating ring-opening copolymerization of dihydrocoumarin with epoxides catalyzed by chromium(III) salen complexes. This process provides access to a range of perfectly alternating polyesters with high molecular weights and narrow molecular weight distributions. Atactic poly(cyclohexene dihydrocoumarate) and poly(cyclopentene dihydrocoumarate) were found to be semi-crystalline by differential scanning calorimetry. PMID- 24806108 TI - Clinical teaching can provide an alternative route to authenticity. PMID- 24806109 TI - Distress intolerance, kynurenic acid, and schizophrenia. PMID- 24806110 TI - 18F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma. AB - PURPOSE: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. METHODS: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. RESULTS: Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis. CONCLUSION: (18)F FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment. PMID- 24806111 TI - Whither peptide receptor radionuclide therapy for neuroendocrine tumors: an Einsteinian view of the facts and myths. PMID- 24806112 TI - Extrastriatal binding of [123I]FP-CIT in the thalamus and pons: gender and age dependencies assessed in a European multicentre database of healthy controls. AB - PURPOSE: Apart from binding to the dopamine transporter (DAT), [(123)I]FP-CIT shows moderate affinity for the serotonin transporter (SERT), allowing imaging of both monoamine transporters in a single imaging session in different brain areas. The aim of this study was to systematically evaluate extrastriatal binding (predominantly due to SERT) and its age and gender dependencies in a large cohort of healthy controls. METHODS: SPECT data from 103 healthy controls with well defined criteria of normality acquired at 13 different imaging centres were analysed for extrastriatal binding using volumes of interest analysis for the thalamus and the pons. Data were examined for gender and age effects as well as for potential influence of striatal DAT radiotracer binding. RESULTS: Thalamic binding was significantly higher than pons binding. Partial correlations showed an influence of putaminal DAT binding on measured binding in the thalamus but not on the pons. Data showed high interindividual variation in extrastriatal binding. Significant gender effects with 31 % higher binding in women than in men were observed in the thalamus, but not in the pons. An age dependency with a decline per decade (+/-standard error) of 8.2 +/- 1.3 % for the thalamus and 6.8 +/- 2.9 % for the pons was shown. CONCLUSION: The potential to evaluate extrastriatal predominant SERT binding in addition to the striatal DAT in a single imaging session was shown using a large database of [(123)I]FP-CIT scans in healthy controls. For both the thalamus and the pons, an age-related decline in radiotracer binding was observed. Gender effects were demonstrated for binding in the thalamus only. As a potential clinical application, the data could be used as a reference to estimate SERT occupancy in addition to nigrostriatal integrity when using [(123)I]FP-CIT for DAT imaging in patients treated with selective serotonin reuptake inhibitors. PMID- 24806113 TI - Impact of viral hepatitis on outcomes after liver resection for hepatocellular carcinoma: results from a north american center. AB - BACKGROUND: Hepatitis B (HBV) and hepatitis C (HCV) are well-recognized risk factors for hepatocellular carcinoma (HCC). The characteristics and clinical outcomes of HCC arising from these conditions may differ. This study was conducted to compare the outcomes of HCC associated with HBV and HCV after liver resection. METHODS: Of 386 liver resections for HCC performed between July 1992 and April 2011, 181 patients had HBV and 74 patients had HCV. Patients with HBV/HCV coinfections (n = 20), non-HBV/HCV etiology (n = 94), and postoperative death within 3 months (n = 17) were excluded. Patient, tumor characteristics, and perioperative and oncologic outcomes were compared between patients with HBV and HCV. RESULTS: The patients with HBV had better overall survival (OS) than patients with HCV (68 vs. 59 months, p = 0.03); however, there was no difference in recurrence-free survival (RFS) between the groups (44 vs. 45 months, p = 0.1). The factors predictive of OS based on multivariate analyses included: vascular invasion [p < 0.01, hazard ratio (HR) = 3.4], Child-Pugh Score (p < 0.01, HR = 4.8), and underlying liver disease (HCV vs HBV) (p = 0.01, HR = 1.9). Vascular invasion and tumor number (p < 0.01, HR = 2.3 and p < 0.01, HR = 2.1) were independent predictors of RFS. CONCLUSIONS: OS but not RFS after liver resection for HCC is better in patients with HBV than HCV. This survival advantage for HBV patients may be due to differences in tumor biology and outcomes after disease recurrence. PMID- 24806115 TI - Utilization of accelerated partial breast irradiation for ductal carcinoma in situ, 2003-2011: report from the national cancer database. AB - BACKGROUND: Data on recent trends and correlates of utilization for accelerated partial breast irradiation using brachytherapy (APBI-b) for ductal carcinoma in situ (DCIS) are lacking. METHODS: This study included 113,841 DCIS patients from the National Cancer Data Base, of whom 8,709 (6.5 %) underwent APBI-b and 105,132 (93.5 %) underwent external beam irradiation after lumpectomy between 2003 and 2011. Trends in APBI-b use, American Society for Radiation Oncology (ASTRO) guideline concordance, and independent factors related to APBI-b use were examined. RESULTS: APBI-b use increased from 1.6 % in 2003 to 11.9 % in 2008 and then decreased to 9.1 % in 2011 (p < 0.001). Before 2009, 24.6 % of patients undergoing APBI-b were in the ASTRO guideline 'unsuitable' category, but this proportion decreased to 14.6 % after 2009 (p < 0.001). When adjusting for year of diagnosis, patient, tumor, and facility factors, the four strongest independent factors for APBI-b use were year of diagnosis followed by facility location, facility volume, and facility type. APBI-b use was highest in the East South Central census region (13.1 %) and lowest in the New England region (2.0 %). A statistically significant interaction was identified between facility type and volume. Patients in community cancer programs of large volume were more likely to receive APBI-b, whereas patients in larger academic programs were less likely to receive APBI-b. CONCLUSION: APBI-b for DCIS decreased from 2008 to 2011. After year of diagnosis, facility factors were most strongly associated with APBI-b use as opposed to patient and tumor factors. Reasons for these trends are multifactorial and deserve further study. PMID- 24806114 TI - Diagnostic accuracy and utility of intraoperative microscopic margin analysis of gastric and esophageal adenocarcinoma. AB - BACKGROUND: Positive resection margins are amongst the strongest predictors of cancer-related mortality for adenocarcinoma of the stomach and esophagus. Although intraoperative pathology consultation with frozen section of margins can predict final permanent section pathology, the accuracy of this approach is not known. We sought to determine the diagnostic accuracy of frozen section margin analysis in esophagogastric adenocarcinoma and the impact that it had on surgical therapy. METHODS: Patients with resection of esophagogastric adenocarcinoma at a single centre from 1998 to 2008 were identified. Clinicopathologic data were collected. Frozen section results were compared to permanent section assessment, and sensitivity, specificity, positive, and negative predictive values were calculated. Patients with positive margins by frozen section were reviewed to assess the impact on surgical decision-making. RESULTS: Of 220 patients who underwent surgery for adenocarcinoma of the esophagus and stomach (esophagus: 34/220, EGJ: 106/220, stomach 80/220), 56 % had an intraoperative consultation. Of these 122 patients, 66 % underwent frozen section. All errors on frozen section occurred on the interpretation of the proximal margin. The diagnostic accuracy of frozen section at the proximal margin was 93 % with sensitivity = 67 %, specificity = 100 %, positive predictive value = 100 %, and negative predictive value = 91 %. Signet ring cells were present in 83 % of false-negative readings. Surgical management was altered in 10 of the 13 of patients who had a true positive frozen section and 9 of these patients were converted to R0 resections. CONCLUSIONS: Although very specific, negative results on frozen section require greater caution when signet ring cells are present. For esophagogastric adenocarcinoma, frozen section alters management and may increase the rate of complete resection. PMID- 24806117 TI - Bethesda III thyroid nodules: the role of ultrasound in clinical decision making. AB - BACKGROUND: Assessment for thyroid nodules includes ultrasound (US) and cytology according to the Bethesda classification. There is no firm consensus regarding clinical management for nodules classified as Bethesda III. Our aim was investigate the value of US to predict malignancy in these nodules. METHODS: Patients with Bethesda III nodules who underwent thyroid surgery from July 2011 to July 2013 were included. Inclusion criteria mandated that US were available for review by two observers blinded to each other's results and histological outcome. The nodules were scrutinized with six US criteria: hypoechoic attenuation (HA), irregular margins (IM), taller than wide, microcalcifications (MC), loss of halo, and increased central vascularity. Disagreements between observers were solved by consensus. RESULTS: There were 141 patients (121 women) with a mean age of 55 years. Mean nodule size was 25 mm. The malignancy rate was 13 %. Interobserver ratios were moderate to very strong for all six predictors (kappa = 0.60-0.94). However, only HA, IM, and MC were predictors of malignancy by univariate analysis (all p < 0.002). Logistic regression revealed an odds ratio of malignancy versus no malignancy for HA 4.8, IM 3.3, and MC 4.0 (all p < 0.05). The positive and negative predictive value for malignancy when having one or more of these three criteria was 22 % and 98 %, respectively. CONCLUSION: HA, IM, and MC were predictors of malignancy in Bethesda III nodules. In addition, the negative predictive value for any of these three criteria was high; a nodule that lacks all of these three criteria is thus unlikely to be malignant. PMID- 24806119 TI - New semi-supervised classification method based on modified cluster assumption. AB - The cluster assumption, which assumes that "similar instances should share the same label," is a basic assumption in semi-supervised classification learning, and has been found very useful in many successful semi-supervised classification methods. It is rarely noticed that when the cluster assumption is adopted, there is an implicit assumption that every instance should have a crisp class label assignment. In real applications, however, there are cases where it is difficult to tell that an instance definitely belongs to one class and does not belong to other neighboring classes. In such cases, it is more adequate to assume that "similar instances should share similar label memberships" rather than sharing a crisp label assignment. Here "label memberships" can be represented as a vector, where each element corresponds to a class, and the value at the element expresses the likelihood of the concerned instance belonging to the class. By adopting this modified cluster assumption, in this paper we propose a new semi-supervised classification method, that is, semi-supervised classification based on class membership (SSCCM). Specifically, we try to solve the decision function and adequate label memberships for instances simultaneously, and constrain that an instance and its "local weighted mean" (LWM) share the same label membership vector, where the LWM is a robust image of the instance, constructed by calculating the weighted mean of its neighboring instances. We formulate the problem in a unified objective function for the labeled, unlabeled data and their LWMs based on the square loss function, and take an alternating iterative strategy to solve it, in which each step generates a closed-form solution, and the convergence is guaranteed. The solution will provide both the decision function and the label membership function for classification, their classification results can verify each other, and the reliability of semi supervised classification learning might be enhanced by checking the consistency between those two predictions. Experiments show that SSCCM obtains encouraging results compared to state-of-the-art semi-supervised classification methods. PMID- 24806116 TI - Role of a multidisciplinary clinic in the management of patients with pancreatic cysts: a single-center cohort study. AB - BACKGROUND: Incidental pancreatic cysts are common, a small number of which are premalignant or malignant. Multidisciplinary care has been shown to alter management and improve outcomes in many types of cancers, but its role has not been examined in patients with pancreatic cysts. We assessed the effect of a multidisciplinary pancreatic cyst clinic (MPCC) on the diagnosis and management of patients with pancreatic cysts. METHODS: The referring institution and MPCC diagnosis and management plan were recorded. Patient were placed into one of five categories-no, low, intermediate, or high risk of malignancy within the cyst, and malignant cyst-on the basis of their diagnosis. Patients were assigned one of four management options: surveillance, surgical resection, further evaluation, or discharge with no further follow-up required. The MPCC was deemed to have altered patient care if the patient was assigned a different risk or management category after the MPCC review. RESULTS: Referring institution records were available for 262 patients (198 women; mean age 62.7 years), with data on risk category available in 138 patients and management category in 225. The most common diagnosis was branch duct intraductal papillary mucinous neoplasm. MPCC review altered the risk category in 11 (8.0%) of 138 patients. The management category was altered in 68 (30.2%) of 225 patients. Management was increased in 52 patients, including 22 patients who were recommended surgical resection. Management was decreased in 16 patients, including 10 who had their recommendation changed from surgery to surveillance. CONCLUSIONS: MPCC is helpful and alters the management over 30% of patients. PMID- 24806120 TI - Variational regularized 2-D nonnegative matrix factorization. AB - A novel approach for adaptive regularization of 2-D nonnegative matrix factorization is presented. The proposed matrix factorization is developed under the framework of maximum a posteriori probability and is adaptively fine-tuned using the variational approach. The method enables: (1) a generalized criterion for variable sparseness to be imposed onto the solution; and (2) prior information to be explicitly incorporated into the basis features. The method is computationally efficient and has been demonstrated on two applications, that is, extracting features from image and separating single channel source mixture. In addition, it is shown that the basis features of an information-bearing matrix can be extracted more efficiently using the proposed regularized priors. Experimental tests have been rigorously conducted to verify the efficacy of the proposed method. PMID- 24806118 TI - Pressure-induced semiconducting to metallic transition in multilayered molybdenum disulphide. AB - Molybdenum disulphide is a layered transition metal dichalcogenide that has recently raised considerable interest due to its unique semiconducting and opto electronic properties. Although several theoretical studies have suggested an electronic phase transition in molybdenum disulphide, there has been a lack of experimental evidence. Here we report comprehensive studies on the pressure dependent electronic, vibrational, optical and structural properties of multilayered molybdenum disulphide up to 35 GPa. Our experimental results reveal a structural lattice distortion followed by an electronic transition from a semiconducting to metallic state at ~19 GPa, which is confirmed by ab initio calculations. The metallization arises from the overlap of the valance and conduction bands owing to sulphur-sulphur interactions as the interlayer spacing reduces. The electronic transition affords modulation of the opto-electronic gain in molybdenum disulphide. This pressure-tuned behaviour can enable the development of novel devices with multiple phenomena involving the strong coupling of the mechanical, electrical and optical properties of layered nanomaterials. PMID- 24806121 TI - Neural CMOS-integrated circuit and its application to data classification. AB - Implementation and new applications of a tunable complementary metal-oxide semiconductor-integrated circuit (CMOS-IC) of a recently proposed classifier core cell (CC) are presented and tested with two different datasets. With two algorithms-one based on Fisher's linear discriminant analysis and the other based on perceptron learning, used to obtain CCs' tunable parameters-the Haberman and Iris datasets are classified. The parameters so obtained are used for hard classification of datasets with a neural network structured circuit. Classification performance and coefficient calculation times for both algorithms are given. The CC has 6-ns response time and 1.8-mW power consumption. The fabrication parameters used for the IC are taken from CMOS AMS 0.35-MUm technology. PMID- 24806122 TI - Hinfinity state estimation for discrete-time complex networks with randomly occurring sensor saturations and randomly varying sensor delays. AB - In this paper, the state estimation problem is investigated for a class of discrete time-delay nonlinear complex networks with randomly occurring phenomena from sensor measurements. The randomly occurring phenomena include randomly occurring sensor saturations (ROSSs) and randomly varying sensor delays (RVSDs) that result typically from networked environments. A novel sensor model is proposed to describe the ROSSs and the RVSDs within a unified framework via two sets of Bernoulli-distributed white sequences with known conditional probabilities. Rather than employing the commonly used Lipschitz-type function, a more general sector-like nonlinear function is used to describe the nonlinearities existing in the network. The purpose of the addressed problem is to design a state estimator to estimate the network states through available output measurements such that, for all probabilistic sensor saturations and sensor delays, the dynamics of the estimation error is guaranteed to be exponentially mean-square stable and the effect from the exogenous disturbances to the estimation accuracy is attenuated at a given level by means of an Hinfinity-norm. In terms of a novel Lyapunov-Krasovskii functional and the Kronecker product, sufficient conditions are established under which the addressed state estimation problem is recast as solving a convex optimization problem via the semidefinite programming method. A simulation example is provided to show the usefulness of the proposed state estimation conditions. PMID- 24806123 TI - Error analysis for matrix elastic-net regularization algorithms. AB - Elastic-net regularization is a successful approach in statistical modeling. It can avoid large variations which occur in estimating complex models. In this paper, elastic-net regularization is extended to a more general setting, the matrix recovery (matrix completion) setting. Based on a combination of the nuclear-norm minimization and the Frobenius-norm minimization, we consider the matrix elastic-net (MEN) regularization algorithm, which is an analog to the elastic-net regularization scheme from compressive sensing. Some properties of the estimator are characterized by the singular value shrinkage operator. We estimate the error bounds of the MEN regularization algorithm in the framework of statistical learning theory. We compute the learning rate by estimates of the Hilbert-Schmidt operators. In addition, an adaptive scheme for selecting the regularization parameter is presented. Numerical experiments demonstrate the superiority of the MEN regularization algorithm. PMID- 24806124 TI - Hybrid dimensionality reduction method based on support vector machine and independent component analysis. AB - This paper presents a new hybrid dimensionality reduction method to seek projection through optimization of both structural risk (supervised criterion) and data independence (unsupervised criterion). Classification accuracy is used as a metric to evaluate the performance of the method. By minimizing the structural risk, projection originated from the decision boundaries directly improves the classification performance from a supervised perspective. From an unsupervised perspective, projection can also be obtained based on maximum independence among features (or attributes) in data to indirectly achieve better classification accuracy over more intrinsic representation of the data. Orthogonality interrelates the two sets of projections such that minimum redundancy exists between the projections, leading to more effective dimensionality reduction. Experimental results show that the proposed hybrid dimensionality reduction method that satisfies both criteria simultaneously provides higher classification performance, especially for noisy data sets, in relatively lower dimensional space than various existing methods. PMID- 24806125 TI - Variational learning for finite Dirichlet mixture models and applications. AB - In this paper, we focus on the variational learning of finite Dirichlet mixture models. Compared to other algorithms that are commonly used for mixture models (such as expectation-maximization), our approach has several advantages: first, the problem of over-fitting is prevented; furthermore, the complexity of the mixture model (i.e., the number of components) can be determined automatically and simultaneously with the parameters estimation as part of the Bayesian inference procedure; finally, since the whole inference process is analytically tractable with closed-form solutions, it may scale well to large applications. Both synthetic and real data, generated from real-life challenging applications namely image databases categorization and anomaly intrusion detection, are experimented to verify the effectiveness of the proposed approach. PMID- 24806126 TI - Class of widely linear complex Kalman filters. AB - Recently, a class of widely linear (augmented) complex-valued Kalman filters (KFs), that make use of augmented complex statistics, have been proposed for sequential state space estimation of the generality of complex signals. This was achieved in the context of neural network training, and has allowed for a unified treatment of both second-order circular and noncircular signals, that is, both those with rotation invariant and rotation-dependent distributions. In this paper, we revisit the augmented complex KF, augmented complex extended KF, and augmented complex unscented KF in a more general context, and analyze their performances for different degrees of noncircularity of input and the state and measurement noises. For rigor, a theoretical bound for the performance advantage of widely linear KFs over their strictly linear counterparts is provided. The analysis also addresses the duality with bivariate real-valued KFs, together with several issues of implementation. Simulations using both synthetic and real world proper and improper signals support the analysis. PMID- 24806127 TI - Chaotic time series prediction based on a novel robust echo state network. AB - In this paper, a robust recurrent neural network is presented in a Bayesian framework based on echo state mechanisms. Since the new model is capable of handling outliers in the training data set, it is termed as a robust echo state network (RESN). The RESN inherits the basic idea of ESN learning in a Bayesian framework, but replaces the commonly used Gaussian distribution with a Laplace one, which is more robust to outliers, as the likelihood function of the model output. Moreover, the training of the RESN is facilitated by employing a bound optimization algorithm, based on which, a proper surrogate function is derived and the Laplace likelihood function is approximated by a Gaussian one, while remaining robust to outliers. It leads to an efficient method for estimating model parameters, which can be solved by using a Bayesian evidence procedure in a fully autonomous way. Experimental results show that the proposed method is robust in the presence of outliers and is superior to existing methods. PMID- 24806128 TI - Regularization path for nu-support vector classification. AB - The v-support vector classification (v-SVC) proposed by Scholkopf has the advantage of using a regularization parameter v for controlling the number of support vectors and margin errors. However, compared to C-SVC, its formulation is more complicated, and to date there are no effective methods for computing its regularization path. In this paper, we propose a new regularization path algorithm, which is designed on the basis of a modified formulation of v-SVC and traces the solution path with respect to the parameter v. Through theoretical analysis and confirmatory experiments, we show that our algorithm can avoid the infeasible updating path under several assumptions (i.e., Assumptions 1 and 2), and fit the entire solution path in a finite number of steps. When the regularization path of v-SVC is available, a novel approach proposed by Yang and Ong can be applied to obtain the global optimal solution of common validation functions for v-SVC, and the computation for the whole process is minimal. Numerical experiments show that it is more efficient than various kinds of grid search methods for selecting the optimal regularization parameter v. PMID- 24806129 TI - Discrete-time neural network for fast solving large linear L1 estimation problems and its application to image restoration. AB - There is growing interest in solving linear L1 estimation problems for sparsity of the solution and robustness against non-Gaussian noise. This paper proposes a discrete-time neural network which can calculate large linear L1 estimation problems fast. The proposed neural network has a fixed computational step length and is proved to be globally convergent to an optimal solution. Then, the proposed neural network is efficiently applied to image restoration. Numerical results show that the proposed neural network is not only efficient in solving degenerate problems resulting from the nonunique solutions of the linear L1 estimation problems but also needs much less computational time than the related algorithms in solving both linear L1 estimation and image restoration problems. PMID- 24806130 TI - Solving the assignment problem using continuous-time and discrete-time improved dual networks. AB - The assignment problem is an archetypal combinatorial optimization problem. In this brief, we present a continuous-time version and a discrete-time version of the improved dual neural network (IDNN) for solving the assignment problem. Compared with most assignment networks in the literature, the two versions of IDNNs are advantageous in circuit implementation due to their simple structures. Both of them are theoretically guaranteed to be globally convergent to a solution of the assignment problem if only the solution is unique. PMID- 24806131 TI - Estimator design for discrete-time switched neural networks with asynchronous switching and time-varying delay. AB - This brief deals with the estimator design problem for discrete-time switched neural networks with time-varying delay. One main problem is the asynchronous mode switching between the neuron state and the estimator. Our goal is to design a mode-dependent estimator for the switched neural networks under average dwell time switching such that the estimation error system is exponentially stable with a prescribed l2 gain (in the Hinfinity sense) from the noise signal to the estimation error. A new Lyapunov functional is constructed that may increase during the mismatched switchings. New results on the stability and l2 gain analysis are then obtained. The admissible estimator gains are computed by solving a set of linear matrix inequalities. The relations among the switching law, the maximal delay upper bound, and the optimal Hinfinity disturbance attenuation level are established. The effectiveness of the proposed design method is finally illustrated by a numerical example. PMID- 24806132 TI - Weighted least-squares approach for identification of a reduced-order adaptive neuronal model. AB - This brief is focused on the parameter estimation problem of a second-order adaptive quadratic neuronal model. First, it is shown that the model discontinuities at the spiking instants can be recast as an impulse train driving the system dynamics. Through manipulation of the system dynamics, the membrane voltage can be obtained as a realizable model that is linear in the unknown parameters. This linearly parameterized realizable model is then utilized inside a prediction error-based framework to design a dynamic estimator that allows for rapid estimation of model parameters under a persistently exciting input current injection. Simulation results show the feasibility of this approach to predict multiple neuronal firing patterns. Results using both synthetic data (obtained from a detailed ion-channel-based model) and experimental data (obtained from in vitro embryonic rat motoneurons) suggest directions for further work. PMID- 24806133 TI - Complete synchronization of Boolean networks. AB - We examine complete synchronization of two deterministic Boolean networks (BNs) coupled unidirectionally in the drive-response configuration. A necessary and sufficient criterion is presented in terms of algebraic representations of BNs. As a consequence, we show that complete synchronization can occur only between two conditionally identical BNs when the transition matrix of the drive network is nonsingular. Two examples are worked out to illustrate the obtained results. PMID- 24806134 TI - Data-driven cluster reinforcement and visualization in sparsely-matched self organizing maps. AB - A self-organizing map (SOM) is a self-organized projection of high-dimensional data onto a typically 2-dimensional (2-D) feature map, wherein vector similarity is implicitly translated into topological closeness in the 2-D projection. However, when there are more neurons than input patterns, it can be challenging to interpret the results, due to diffuse cluster boundaries and limitations of current methods for displaying interneuron distances. In this brief, we introduce a new cluster reinforcement (CR) phase for sparsely-matched SOMs. The CR phase amplifies within-cluster similarity in an unsupervised, data-driven manner. Discontinuities in the resulting map correspond to between-cluster distances and are stored in a boundary (B) matrix. We describe a new hierarchical visualization of cluster boundaries displayed directly on feature maps, which requires no further clustering beyond what was implicitly accomplished during self organization in SOM training. We use a synthetic benchmark problem and previously published microbial community profile data to demonstrate the benefits of the proposed methods. PMID- 24806135 TI - Decision aids for organ transplant candidates. PMID- 24806136 TI - Copper(II) directs formation of toxic amorphous aggregates resulting in inhibition of hen egg white lysozyme fibrillation under alkaline salt-mediated conditions. AB - Hen egg white lysozyme (HEWL) adopts a molten globule-like state at high pH (~12.75) and is found to form amyloid fibrils at alkaline pH. Here, we report that Cu(II) inhibits self-association of HEWL at pH 12.75 both at 37 and 65 degrees C. A significant reduction in Thioflavin T fluorescence intensity, attenuation in beta-sheet content and reduction in hydrophobic exposure were observed with increasing Cu(II) stoichiometry. Electron paramagnetic resonance spectroscopy suggests a 4N type of coordination pattern around Cu(II) during fibrillation. Cu(II) is also capable of altering the cytotoxicity of the proteinaceous aggregates. Fibrillar species of diverse morphology were found in the absence of Cu(II) with the generation of amorphous aggregates in the presence of Cu(II), which are more toxic compared to the fibrils alone. PMID- 24806137 TI - Nefopam and meperidine are infra-additive on the shivering threshold in humans. AB - BACKGROUND: Induction of therapeutic hypothermia is often complicated by shivering. Nefopam, a nonsedative benzoxazocine analgesic, reduces the shivering threshold (triggering core temperature) with minimal side effects. Consequently, nefopam is an attractive drug for inducing therapeutic hypothermia. However, nefopam alone is insufficient and thus needs to be combined with another drug. Meperidine also reduces the shivering threshold. We therefore determined whether the combination of nefopam and meperidine is additive, infra-additive, or synergistic on the shivering threshold. METHODS: Ten volunteers were each studied on 4 randomly assigned days. In random order, they were given the following treatments: (1) control, no drug; (2) nefopam to a target concentration of 0.1 MUg/mL; (3) meperidine to a target concentration of 0.1 MUg/mL; and (4) both nefopam and meperidine at target concentrations of 0.1 MUg/mL each. Lactated Ringer's solution at 4 degrees C was infused to decrease core temperature while mean skin temperature was kept near 30.5 degrees C. The core temperature that increased oxygen consumption >25% defined the shivering threshold. RESULTS: Nefopam reduced the shivering thresholds by 0.7 degrees C +/- 0.3 degrees C compared with no drug. Meperidine reduced the shivering thresholds by 0.4 degrees C +/- 0.3 degrees C compared with no drug. When combined, the shivering threshold decreased by only 0.6 degrees C +/- 0.4 degrees C, which was about half what would have been expected based on the individual effects of each drug (P < 0.001). The effect of combined nefopam and meperidine on the shivering threshold was thus infra-additive. CONCLUSIONS: The combination of nefopam and meperidine should be avoided for induction of therapeutic hypothermia. Better options would be combinations of drugs that are at least additive or even synergistic. PMID- 24806138 TI - In vitro evaluation of a novel system for monitoring surgical hemoglobin loss. AB - BACKGROUND: Accurate measurement of intraoperative blood loss is an important clinical variable in managing fluid resuscitation and avoiding unnecessary transfusion of blood products. In this study, we measured surgical blood loss using a tablet computer programmed with a unique algorithm modeled after facial recognition technology. The aim of the study was to assess the accuracy and performance of the system on surgical laparotomy sponges in vitro. METHODS: Whole blood samples of premeasured hemoglobin (Hb) and volume were reconstituted from units of human packed red blood cells and plasma and distributed across surgical laparotomy sponges. Normal saline was added to simulate the presence of varying levels of hemodilution and/or irrigation use. Soaked sponges from 4 different manufacturers were scanned using the Triton System with Feature Extraction Technology (Gauss Surgical, Inc., Palo Alto, CA) under 3 different ambient light conditions in an operating room. Accuracy of Hb loss measurement was evaluated relative to the premeasured values using linear regression and Bland-Altman analysis. Correlations between studied variables and measurement bias were analyzed using nonparametric tests. RESULTS: The overall mean percent error for measure of Hb loss for the Triton System was 12.3% (95% confidence interval [CI], 8.2%-16.4%). A strong positive linear correlation between the premeasured and actual Hb masses was noted across the full range of intraoperative lighting conditions, including (A) high (r = 0.95 [95% CI, 0.93-0.96]), (B) medium (r = 0.94 [95% CI, 0.93-0.96]), and (C) low (r = 0.90 [95% CI, 0.87-0.93]) mean ambient light intensity. Bland-Altman analysis revealed a bias of 0.01 g [95% CI, -0.03 to 0.06 g] of Hb per sponge between the 2 measures. The corresponding lower and upper limits of agreement were -1.16 g (95% CI, -1.21 to -1.12 g) per sponge and 1.19 g (95% CI, 1.15-1.24 g) per sponge, respectively. Measurement bias of estimated blood loss and Hb mass using the new system were not associated with the volume of saline used to reconstitute the samples (P = 0.506 and P = 0.469, respectively), suggesting that the system is robust under a wide range of sponge saturation conditions. CONCLUSIONS: Mobile blood loss monitoring using the Triton system is accurate in assessing Hb mass on surgical sponges across a range of ambient light conditions, sponge saturation, saline contamination, and initial blood Hb. Utilization of this tool could significantly improve the accuracy of blood loss estimates. PMID- 24806139 TI - Abdominal girth, vertebral column length, and spread of spinal anesthesia in 30 minutes after plain bupivacaine 5 mg/mL. AB - BACKGROUND: The spread of spinal anesthesia is highly unpredictable. In patients with increased abdominal girth and short stature, a greater cephalad spread after a fixed amount of subarachnoidally administered plain bupivacaine is often observed. We hypothesized that there is a strong correlation between abdominal girth/vertebral column length and cephalad spread. METHODS: Age, weight, height, body mass index, abdominal girth, and vertebral column length were recorded for 114 patients. The L3-L4 interspace was entered, and 3 mL of 0.5% plain bupivacaine was injected into the subarachnoid space. The cephalad spread (loss of temperature sensation and loss of pinprick discrimination) was assessed 30 minutes after intrathecal injection. Linear regression analysis was performed for age, weight, height, body mass index, abdominal girth, vertebral column length, and the spread of spinal anesthesia, and the combined linear contribution of age up to 55 years, weight, height, abdominal girth, and vertebral column length was tested by multiple regression analysis. RESULTS: Linear regression analysis showed that there was a significant univariate correlation among all 6 patient characteristics evaluated and the spread of spinal anesthesia (all P < 0.039) except for age and loss of temperature sensation (P > 0.068). Multiple regression analysis showed that abdominal girth and the vertebral column length were the key determinants for spinal anesthesia spread (both P < 0.0001), whereas age, weight, and height could be omitted without changing the results (all P > 0.059, all 95% confidence limits < 0.372). CONCLUSIONS: Multiple regression analysis revealed that the combination of a patient's 5 general characteristics, especially abdominal girth and vertebral column length, had a high predictive value for the spread of spinal anesthesia after a given dose of plain bupivacaine. PMID- 24806140 TI - The sevoflurane washout profile of seven recent anesthesia workstations for malignant hyperthermia-susceptible adults and infants: a bench test study. AB - BACKGROUND: Preoperative flushing of an anesthesia workstation is an alternative for preparation of the anesthesia workstation before use in malignant hyperthermia-susceptible patients (MHS). We studied in vitro, using a test lung, the washout profile of sevoflurane in 7 recent workstations during adult and, for the first time, pediatric ventilation patterns. METHODS: Anesthesia workstations were first primed with 3% sevoflurane for 2 hours and then prepared according to the recommendations of the Malignant Hyperthermia Association of the United States. The flush was done with maximal fresh gas flow (FGF) with a minute ventilation equal to 600 mL * 15, to reach a sevoflurane concentration of <5 parts per million. After flush, 2 clinical situations were simulated in vitro to test the efficiency of preparation: decrease of FGF from max to 10 L/min, or decrease of minute ventilation to 50 mL * 30, to simulate the ventilation of an MHS infant. RESULTS: We report washout delays for MHS patients for previously studied workstations (Primus(r), Avance(r), and Zeus(r)) and more interestingly, for machines not previously tested (Felix(r), Flow-I(r), Perseus(r), and Leon(r)). An increase of sevoflurane concentration was observed when decreasing FGF (except for flow-I(r) and Leon(r)) and during simulation of MHS infant ventilation (except for Felix(r)). CONCLUSIONS: This descriptive study strongly suggests that washout profiles may differ for each anesthesia workstation. We advise the use of maximal FGF during preparation and anesthesia. Required flushing times are longer when preparing an anesthesia workstation before providing anesthesia for MHS infants. PMID- 24806141 TI - Sequence-dependent anesthesia-controlled times: a retrospective study in an ophthalmology department of a single-site hospital. AB - BACKGROUND: Anesthesia-controlled time (ACT) generally refers to the time durations before and after the period of surgery. The ACT is typically dependent on the sequence of 2 consecutive surgeries and thus adds to the complexity of operating room scheduling. We report a study on sequence-dependent ACTs at the West China Hospital (WCH), focusing on elective surgeries (also referred to as "procedures" below) performed by the ophthalmology department of WCH over a 5 year period, 2007 to 2012. METHODS: ACTs associated with 4 high-volume procedures: phacoemulsification, vitrectomy, strabismus correction, and glaucoma filtration. A total of 29,452 cases were studied, classified into 4 groups according to the sequence of the procedures involved. Specifically, P-P plots were used to determine the distributions of the ACTs, Kruskal-Wallis H test, Nemenyi test, and Student t test were performed to examine the sequence-dependent nature of the ACTs, and the t test was also applied to examine the advantage of sequencing the same procedures consecutively. Permutations were enumerated to identify the best sequence when different procedures were involved. Monte Carlo simulation was used to compute the total completion time, ACTs plus surgical periods, of any given sequence of procedures. RESULTS: We confirm via statistical tests that the ACTs follow lognormal distributions, and identify their corresponding means and variances. Furthermore, we verify that the ACTs are statistically different in means: they are sequence dependent in general. Using statistical tests, we conclude that it is best to sequence identical procedures consecutively, and we also identify the best sequence involving different procedures. Using Monte Carlo simulation, we compared the daily completion times using the best sequences we have identified against actual data from WCH over a 2 year period; the average reduction is 4.7% (with a standard error (SE) of +/- +/- 0.5%). CONCLUSIONS: ACTs are usually sequence dependent and hence should be considered in operating room scheduling. Although identifying the best sequence in general is a difficult optimization problem, in certain departments (such as the ophthalmology department of WCH) where a set of high-volume small-variety procedures is present, the best sequences can be systematically identified using a combination of statistical tests and Monte Carlo simulation as illustrated in this study. PMID- 24806143 TI - Modified short-axis out-of-plane ultrasound versus conventional long-axis in plane ultrasound to guide radial artery cannulation: a randomized controlled trial. AB - BACKGROUND: Currently, short-axis out-of-plane (SA-OOP) and long-axis in-plane (LA-IP) ultrasound techniques are used to guide radial artery cannulation. In this study, we compared the success rate of a modified SA-OOP technique with that of traditional LA-IP. METHODS: One hundred sixty-four patients who were to undergo liver surgery or splenic resection under general anesthesia were included. Using a sealed envelope method, patients were randomly divided into 2 groups: the modified SA-OOP or the LA-IP ultrasound guidance approaches. The number of cannula insertion attempts until success was recorded in both groups. The primary end point to compare the groups was the rate of cannula insertion successes on the first attempt. The secondary end points were also recorded and compared: insertion failure rate, inner diameter of the radial artery, depth of artery from the skin, ultrasonic location time, cannulation time, and vascular complications including thrombosis, hematoma, edema, and vasospasm. RESULTS: The cannula insertion success rate on the first attempt was significantly higher in the modified SA-OOP group compared with the LA-IP group (proportion difference 15.7%, 95% confidence interval [CI], 0.6%-30.7%, P = 0.0158). However, the insertion failure rate was not different between groups (95% CI, -17.7% to 12.8%, P = 0.4969). The ultrasonic location time was significantly decreased in the modified SA-OOP group compared with the LA-IP group (mean difference -9.5 seconds, 95% CI, -10.6 to -8.5 seconds, P < 0.0001). However, there was no significant difference between groups for cannulation time (95% CI, -0.6 to 7.6 seconds, P = 0.1152), depth of artery (95% CI, -0.07 to 0.57 mm, P = 0.1050), and the diameter of the radial artery (95% CI, -0.30 to 0.03 mm, P = 0.1153). CONCLUSION: The modified SA-OOP technique may improve the success rate of cannula insertion into the radial artery on the first attempt. PMID- 24806142 TI - Impaired red blood cell deformability after transfusion of stored allogeneic blood but not autologous salvaged blood in cardiac surgery patients. AB - BACKGROUND: Both cardiopulmonary bypass (CPB) and red blood cell (RBC) storage are associated with detrimental changes in RBC structure and function that may adversely affect tissue oxygen delivery. We tested the hypothesis that in cardiac surgery patients, RBC deformability and aggregation are minimally affected by CPB with autologous salvaged blood alone but are negatively affected by the addition of stored allogeneic blood. METHODS: In this prospective cohort study, 32 patients undergoing cardiac surgery with CPB were divided into 3 groups by transfusion status: autologous salvaged RBCs alone (Auto; n = 12), autologous salvaged RBCs + minimal (<5 units) stored allogeneic RBCs (Auto+Allo min; n = 10), and autologous salvaged RBCs + moderate (>=5 units) stored allogeneic RBCs (Auto+Allo mod; n = 10). Ektacytometry was used to measure RBC elongation index (deformability) and critical shear stress (aggregation) before, during, and for 3 days after surgery. RESULTS: In the Auto group, RBC elongation index did not change significantly from the preoperative baseline. In the Auto+Allo min group, mean elongation index decreased from 32.31 +/- 0.02 (baseline) to 30.47 +/- 0.02 (nadir on postoperative day 1) (P = 0.003, representing a 6% change). In the Auto+Allo mod group, mean elongation index decreased from 32.7 +/- 0.02 (baseline) to 28.14 +/- 0.01 (nadir on postoperative day 1) (P = 0.0001, representing a 14% change). Deformability then dose-dependently recovered toward baseline over the first 3 postoperative days. Changes in aggregation were unrelated to transfusion (no difference among groups). For the 3 groups combined, mean critical shear stress decreased from 359 +/- 174 mPa to 170 +/- 141 mPa (P = 0.01, representing a 54% change), with the nadir at the end of surgery and returned to baseline by postoperative day 1. CONCLUSIONS: In cardiac surgery patients, transfusion with stored allogeneic RBCs, but not autologous salvaged RBCs, is associated with a decrease in RBC cell membrane deformability that is dose-dependent and may persist beyond 3 postoperative days. These findings suggest that autologous salvaged RBCs may be of higher quality than stored RBCs, since the latter are subject to the so-called storage lesions. PMID- 24806145 TI - Nanomolar detection of hypochlorite by a rhodamine-based chiral hydrazide in absolute aqueous media: application in tap water analysis with live-cell imaging. AB - By employing the oxidation property of hypochlorite (OCl(-)), a novel rhodamine based hydrazide of the chiral acid ((S)-(-)-2-pyrrolidone-5-carboxylic acid) (RHHP) was designed and synthesized for detection of OCl(-) absolutely in aqueous medium at nanomolar level. The structure of the chiral sensor was also proved by the X-ray crystallography. The bioactivity and the application of the probe for detection of OCl(-) in natural water system have been demonstrated. A plausible mechanism for oxidation of the sensor followed by hydrolysis is also proposed. The sensibility of the receptor toward OCl(-) was studied in absolute aqueous media, and the detection limit of hypochlorite-mediated oxidation to the receptor in nanomolar level makes this platform (RHHP) an ultrasensitive and unique system for OCl(-) oxidation. PMID- 24806144 TI - The urine protein NGAL predicts renal replacement therapy, but not acute kidney injury or 90-day mortality in critically ill adult patients. AB - BACKGROUND: Urine neutrophil gelatinase-associated lipocalin (uNGAL) is increasingly used as a biomarker for acute kidney injury (AKI). However, the clinical value of uNGAL with respect to AKI, renal replacement therapy (RRT), or 90-day mortality in critically ill patients is unclear. Accordingly, we tested the hypothesis that uNGAL is a clinically relevant biomarker for these end points in a large, nonselected cohort of critically ill adult patients. METHODS: We prospectively obtained urine samples from 1042 adult patients admitted to 15 Finnish intensive care units. We analyzed 3 samples (on admission, at 12 hours, and at 24 hours) with NGAL ELISA Rapid Kits (BioPorto(r) Diagnostics, Gentofte, Denmark). We chose the highest uNGAL (uNGAL24) for statistical analyses. We calculated the areas under receiver operating characteristics curves (AUC) with 95% confidence intervals (95% CIs), the best cutoff points with the Youden index, positive likelihood ratios (LR+), continuous net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). We performed sensitivity analyses excluding patients with AKI or RRT on day 1, sepsis, or with missing baseline serum creatinine concentration. RESULTS: In this study population, the AUC of uNGAL24 (95% CI) for development of AKI (defined by the Kidney Disease: Improving Global Outcomes [KDIGO] criteria) was 0.733 (0.701 0.765), and the continuous NRI for AKI was 56.9%. For RRT, the AUC of uNGAL24 (95% CI) was 0.839 (0.797-0.880), and NRI 56.3%. For 90-day mortality, the AUC of uNGAL24 (95% CI) was 0.634 (0.593 to 0.675), and NRI 15.3%. The LR+ (95% CI) for RRT was 3.81 (3.26-4.47). CONCLUSION: In this study, we found that uNGAL associated well with the initiation of RRT but did not provide additional predictive value regarding AKI or 90-day mortality in critically ill patients. PMID- 24806146 TI - Complement inhibition significantly decreases red blood cell lysis in a rat model of acute intravascular hemolysis. AB - BACKGROUND: Prevention of acute hemolytic transfusion reactions is a worldwide concern. The objective of this study was to develop a simple rat model of complement-mediated acute intravascular hemolysis. STUDY DESIGN AND METHODS: Human AB red blood cells (RBCs) were incubated with complement-sufficient or complement-deficient Wistar rat serum (WRS) in the presence and absence of human RBC antibody in vitro to elucidate the mechanism of hemolysis. To study the role of complement in acute intravascular hemolysis in vivo, Wistar rats were treated either with or without cobra venom factor (CVF) to deplete complement activity. Human AB RBCs were then injected into both groups of rats, followed by serial blood draws up to 2 hours. Venous blood clearance and lysis of transfused RBCs at each time point were measured by flow cytometry and spectrophotometry. RBC sequestration was determined in the liver, spleen, and kidney by immunohistochemistry. RESULTS: In vitro incubation of human RBCs with WRS demonstrated that RBC lysis was mediated via the classical complement pathway and that hemolysis was antibody dependent. Transfusion of human RBCs into rats showed significantly less hemolysis in the CVF group versus untreated group. RBC sequestration in the spleen and liver 2 hours posttransfusion were not quantitatively different between the two groups. CONCLUSIONS: Given the much higher degree of similarity for rat and human complement compared to mice, this simple rat model is ideal for testing novel inhibitors of classical pathway activation for the prevention and treatment of acute intravascular hemolysis. PMID- 24806148 TI - MicroRNA-155 inhibits migration of trophoblast cells and contributes to the pathogenesis of severe preeclampsia by regulating endothelial nitric oxide synthase. AB - The aim of the present study was to characterize the role of microRNA (miR)-155 in the pathogenesis of severe preeclampsia (PE). A total of 19 severe preeclampsic and 22 normal placentas were collected to measure miR-155 and endothelial nitric oxide synthase (eNOS) expression using quantitative (q)PCR and western blot analysis. The results demonstrated a significant increase in the levels of miR-155 and decreased eNOS expression in the severe preeclampsic placentas, as compared with the normal controls. In order to examine the function of miR-155 in the human placenta, the HTR8/Svneo cell line was transiently transfected with an miR-155 mimic or its inhibitor, anti-miR-155. It was confirmed that miR-155 may suppress the expression of eNOS in HTR-8/SVneo cells. Furthermore, a transwell insert invasion assay demonstrated that miR-155 inhibited cell invasion in trophoblast cells, and the effect was rescued by over expression of eNOS. The present study revealed that miR-155 has a negative regulatory role in the migratory behavior of HTR-8/SVneo cells via modulating eNOS. PMID- 24806147 TI - Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions. AB - Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-alpha and IFN-gamma, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type. PMID- 24806149 TI - Towards the safe introduction of transanal total mesorectal excision: the role of a clinical registry. PMID- 24806150 TI - A ten year experience of cecal neovagina procedures for the restoration of sexual function on a gynecology oncology service. AB - OBJECTIVE: We seek to describe the procedure, complications, and functional outcomes of utilizing the cecum and ascending colon for creation of a neovagina on a gynecologic oncology service. METHODS: A search of all the cases on the gynecologic oncology service over a ten year period yielded fourteen cases of cecal neovagina. A retrospective chart review was performed. Post-operatively, each patient was evaluated at regular intervals. At each visit, they were asked standardized questions, a physical exam was performed by the same provider, and they were advised to follow a uniform regimen of physical rehabilitation. RESULTS: Eight of the fourteen cases were performed for surgical stricture or vaginectomy, while the indication for the other six patients was radiation fibrosis. The patients were followed for a median length of 37 months. The percentage having intercourse was between 86% and 100% over the course of the first year. Thirteen of the fourteen patients reported intercourse as "comfortable", eleven of the fourteen stated that intercourse was "pleasurable", and seven patients reported having orgasms. The major reported complaint was mucusy discharge, which all patients reported as moderate to severe for the first six weeks. Over time, this improved, and only one patient required the use of pads at twelve months. There were no intestinal anastomotic leaks in the group. CONCLUSIONS: The functional outcomes in our case series show that the cecal neovagina is a safe, uncomplicated, and viable option for those patients who have lost sexual function due to stricture formation or surgical removal of the vagina. PMID- 24806151 TI - Meningitis related ventriculitis--experience from a tertiary care centre in northern India. AB - OBJECTIVE: To assess clinical profile and short term outcome of patients with meningitis related ventriculitis. METHODS: Case records of 47 patients admitted with a diagnosis of ventriculitis (complicating meningitis) over 3 y were analysed retrospectively. RESULTS: The mean age of patients was 4.96 mo (20 d - 42 mo). The common symptoms were fever (27/47), enlarging head (23/47) and seizures (12/47) with signs of raised intracranial pressure (29/47). Ventricular cerebro-spinal fluid (CSF) showed mean cells - 237 cells/MUL, sugar - 36 mg/dL and protein - 568 mg/dL. Gram stain and/or culture were positive in 5 patients. Ultrasonography of the head (done in 32 of 47 patients) showed hydrocephalus in 29 and internal echoes, debris or septations in ventricles in 5 patients. Computed tomography (CT) of brain (done in 42 of 47 patients) showed hydrocephalus in 36, abscesses in 7, ependymal enhancement in 4, infarcts in 4 and subdural empyema in 3 patients. MRI brain (done in 13 patients) showed hydrocephalus in all, 6 had cysts and 3 had ependymal enhancement. Thirty seven patients were started on ceftriaxone combined with vancomycin/cloxacillin with/without amikacin, and 10 patients received vancomycin and meropenem. Mean duration of antibiotics treatment was 4.17 wk (range; 0.8-12 wk). External ventricular drainage (EVD) was done in 22/47 patients. Cure rate (improvement in clinical and CSF parameters) in patients with external ventricular drainage was 59% as against 50% in patients who received antibiotics alone. At least 19 patients required ventriculoperitoneal (VP) shunt for unresolved significant hydrocephalus by discharge. There were 10 deaths, four of them occurred within first 2 wk of admission, one in 3rd wk and 5 within few months of discharge from hospital. CONCLUSIONS: Ventriculitis associated with meningitis is a difficult to treat infection with significant mortality and morbidity. It requires prolonged administration of antibiotics. External ventricular drainage may improve cure rate and hasten clearing of CSF infection. PMID- 24806152 TI - Profile of hemophagocytic lymphohistiocytosis; efficacy of intravenous immunoglobulin therapy. AB - OBJECTIVE: To study the profile of children with Hemophagocytic lymphohistiocytosis (HLH) and compare the outcome of treatment with intravenous immunoglobulin therapy and Dexamethasone vs. HLH-2004 protocol. METHODS: The present retrospective cohort study was conducted in a tertiary care pediatric hospital in Chennai. Children with a diagnosis of HLH admitted to the hospital from June 2008 through June 2011 were included. Medical records of the subjects were reviewed and their clinical and demographic profile studied. Difference in outcome between treatment modalities was analysed. RESULTS: Of the 40 children studied, all had fever of 38.5 degrees C for more than 7 d. Splenomegaly was noted in 25 children at admission, but eventually occurred in all the patients. All children had bicytopenia. Mean laboratory values were as follows- neutrophil count 3,400/cu.mm, hemoglobin 8.75 g/dl, platelet count 84,000/cu.mm, fasting triglycerides 358 mg/dl, ferritin 8,139 mg/dl and fibrinogen 137 mg/dl. All children had evidence of hemophagocytosis in bone marrow smear. Good outcome was seen in 19/22 children treated with IVIG therapy (Group 1) vs. 10/12 children treated with HLH-2004 protocol with etoposide, cyclosporine and Dexamethasone (Group 2), P = 1.00. Good outcome was seen in 4/6 children treated with IVIG therapy followed by HLH-2004 protocol (Group 3). Serum ferritin levels of more than 3,000 mg/dl were present in 13 children. In this group, good outcome was seen in 7/8 patients treated with IVIG vs. 4/5 treated with the HLH-2004 protocol (P = 1.00). CONCLUSIONS: IVIG and HLH-2004 protocol may be equally effective in the management of HLH. IVIG may be a preferable initial regimen, to avoid the risk of secondary malignancy associated with etoposide. PMID- 24806153 TI - Laryngoscope bulb - an unusual foreign body in nasopharynx. PMID- 24806155 TI - Growth trajectory influences temperature preference in fish through an effect on metabolic rate. AB - Most animals experience temperature variations as they move through the environment. For ectotherms, in particular, temperature has a strong influence on habitat choice. While well studied at the species level, less is known about factors affecting the preferred temperature of individuals; especially lacking is information on how physiological traits are linked to thermal preference and whether such relationships are affected by factors such feeding history and growth trajectory. This study examined these issues in the common minnow Phoxinus phoxinus, to determine the extent to which feeding history, standard metabolic rate (SMR) and aerobic scope (AS), interact to affect temperature preference. Individuals were either: 1) food deprived (FD) for 21 days, then fed ad libitum for the next 74 days; or 2) fed ad libitum throughout the entire period. All animals were then allowed to select preferred temperatures using a shuttle-box, and then measured for SMR and AS at 10 degrees C, estimated by rates of oxygen uptake. Activity within the shuttle-box under a constant temperature regime was also measured. In both FD and control fish, SMR was negatively correlated with preferred temperature. The SMR of the FD fish was increased compared with the controls, probably due to the effects of compensatory growth, and so these growth compensated fish preferred temperatures that were on average 2.85 degrees C cooler than controls fed a maintenance ration throughout the study. Fish experiencing compensatory growth also displayed a large reduction in activity. In growth-compensated fish and controls, activity measured at 10 degrees C was positively correlated with preferred temperature. Individual fish prefer temperatures that vary predictably with SMR and activity level, which are both plastic in response to feeding history and growth trajectories. Cooler temperatures probably allow individuals to reduce maintenance costs and divert more energy towards growth. A reduction in SMR at cooler temperatures, coupled with a decrease in spontaneous activity, could also allow individuals to increase surplus AS for coping with environmental stressors. In warming climates, however, aquatic ectotherms could experience frequent fluctuations in food supply with long-lasting effects on metabolic rate due to compensatory growth, while simultaneously having limited access to preferred cooler habitats. PMID- 24806156 TI - The trans-fat ban--food regulation and long-term health. PMID- 24806157 TI - Insourcing health care innovation. PMID- 24806158 TI - FDA approval of paroxetine for menopausal hot flushes. PMID- 24806159 TI - Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. METHODS: In this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection. RESULTS: The reduction in the incidence of all cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity. CONCLUSIONS: Letermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.). PMID- 24806161 TI - Obliterative bronchiolitis. PMID- 24806160 TI - Parasite burden and severity of malaria in Tanzanian children. AB - BACKGROUND: Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial. METHODS: We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years. RESULTS: Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman's second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections. CONCLUSIONS: Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.). PMID- 24806162 TI - Images in clinical medicine. Abdominal-wall varices in the Budd-Chiari syndrome. PMID- 24806163 TI - Case records of the Massachusetts General Hospital. Case 14-2014. An 11-month-old girl with developmental delay. PMID- 24806164 TI - Taming the transplantation troll by targeting terminase. PMID- 24806165 TI - The axes of access--improving care for patients with disabilities. PMID- 24806166 TI - Stenting for renal-artery stenosis. PMID- 24806167 TI - Stenting for renal-artery stenosis. PMID- 24806168 TI - Stenting for renal-artery stenosis. PMID- 24806169 TI - Stenting for renal-artery stenosis. PMID- 24806170 TI - Stenting for renal-artery stenosis. PMID- 24806171 TI - Stenting for renal-artery stenosis. PMID- 24806172 TI - Variant GADL1 and response to lithium in bipolar I disorder. PMID- 24806173 TI - Variant GADL1 and response to lithium in bipolar I disorder. PMID- 24806174 TI - Variant GADL1 and response to lithium in bipolar I disorder. PMID- 24806175 TI - Variant GADL1 and response to lithium in bipolar I disorder. PMID- 24806177 TI - Variant GADL1 and response to lithium in bipolar I disorder. PMID- 24806178 TI - Prevention of preterm parturition. PMID- 24806179 TI - Prevention of preterm parturition. PMID- 24806176 TI - Variant GADL1 and response to lithium in bipolar I disorder. PMID- 24806180 TI - Prevention of preterm parturition. PMID- 24806181 TI - Community-acquired pneumonia. PMID- 24806182 TI - Community-acquired pneumonia. PMID- 24806183 TI - Community-acquired pneumonia. PMID- 24806184 TI - Community-acquired pneumonia. PMID- 24806185 TI - Resistance to arsenic therapy in acute promyelocytic leukemia. PMID- 24806189 TI - Images in clinical medicine. Traumatic tension pneumothorax causing heart rotation. PMID- 24806190 TI - Facilitators and barriers to effective smoking cessation: counselling services for inpatients from nurse-counsellors' perspectives--a qualitative study. AB - Tobacco use has reached epidemic levels around the World, resulting in a world wide increase in tobacco-related deaths and disabilities. Hospitalization presents an opportunity for nurses to encourage inpatients to quit smoking. This qualitative descriptive study was aimed to explore nurse-counsellors' perspectives of facilitators and barriers in the implementation of effective smoking cessation counselling services for inpatients. In-depth interviews were conducted with 16 nurses who were qualified smoking cessation counsellors and who were recruited from eleven health promotion hospitals that were smoke-free and located in the Greater Taipei City Area. Data were collected from May 2012 to October 2012, and then analysed using content analysis based on the grounded theory approach. From nurse-counsellors' perspectives, an effective smoking cessation program should be patient-centred and provide a supportive environment. Another finding is that effective smoking cessation counselling involves encouraging patients to modify their lifestyles. Time constraints and inadequate resources are barriers that inhibit the effectiveness of smoking cessation counselling programs in acute-care hospitals. We suggest that hospitals should set up a smoking counselling follow-up program, including funds, facilities, and trained personnel to deliver counselling services by telephone, and build a network with community smoking cessation resources. PMID- 24806191 TI - Spatio-temporal variation and prediction of ischemic heart disease hospitalizations in Shenzhen, China. AB - Ischemic heart disease (IHD) is a leading cause of death worldwide. Urban public health and medical management in Shenzhen, an international city in the developing country of China, is challenged by an increasing burden of IHD. This study analyzed the spatio-temporal variation of IHD hospital admissions from 2003 to 2012 utilizing spatial statistics, spatial analysis, and space-time scan statistics. The spatial statistics and spatial analysis measured the incidence rate (hospital admissions per 1,000 residents) and the standardized rate (the observed cases standardized by the expected cases) of IHD at the district level to determine the spatio-temporal distribution and identify patterns of change. The space-time scan statistics was used to identify spatio-temporal clusters of IHD hospital admissions at the district level. The other objective of this study was to forecast the IHD hospital admissions over the next three years (2013-2015) to predict the IHD incidence rates and the varying burdens of IHD-related medical services among the districts in Shenzhen. The results show that the highest hospital admissions, incidence rates, and standardized rates of IHD are in Futian. From 2003 to 2012, the IHD hospital admissions exhibited similar mean centers and directional distributions, with a slight increase in admissions toward the north in accordance with the movement of the total population. The incidence rates of IHD exhibited a gradual increase from 2003 to 2012 for all districts in Shenzhen, which may be the result of the rapid development of the economy and the increasing traffic pollution. In addition, some neighboring areas exhibited similar temporal change patterns, which were also detected by the spatio-temporal cluster analysis. Futian and Dapeng would have the highest and the lowest hospital admissions, respectively, although these districts have the highest incidence rates among all of the districts from 2013 to 2015 based on the prediction using the GM (1,1). In addition, the combined analysis of the prediction of IHD hospital admissions and the general hospital distributions shows that Pingshan and Longgang might experience the most serious burden of IHD hospital services in the near future, although Futian would still have the greatest number and the highest incidence rate of hospital admissions for IHD. PMID- 24806192 TI - Surveillance of social and geographic inequalities in housing-related issues: the case of the Eastern Townships, Quebec (Canada). AB - Even though health inequalities are conditioned by many aspects of the environment, much of the existing research focuses on the social environment. This emphasis has the effect to neglect other environmental aspects such as its physical dimension. The physical environment, which is linked to housing conditions, may contribute to the uneven distribution of health. In this study, we examined 19 housing-related issues among a representative sample of 2,000 adults residing in a Quebec (Canada) health region characterized by a mix of rural, semi-rural, and urban areas. The distribution of these issues was examined according to socioeconomic and geographic indicators of social position. Summary measures of inequalities were assessed. Our results showed that the prevalence of nearly all housing-related issues was higher among low-income households compared to more affluent ones. Highly educated individuals showed better housing conditions, whereas different issues tended to cluster in deprived or densely populated areas. To conclude, we observed steep gradients between social class and poor housing conditions. This may explain a substantial part of health inequality on the regional scale. The surveillance of housing-related issues is therefore essential to properly inform and mobilize local stakeholders and to develop interventions that target vulnerable groups on this level. PMID- 24806193 TI - A GIS based approach for assessing the association between air pollution and asthma in New York State, USA. AB - Studies on asthma have shown that air pollution can lead to increased asthma prevalence. The aim of this study is to examine the association between air pollution (fine particulate matter (PM2.5), sulfur dioxide (SO2) and ozone (O3)) and human health (asthma emergency department visit rate (AEVR) and asthma discharge rate (ADR)) among residents of New York, USA during the period 2005 to 2007. Annual rates of asthma were calculated from population estimates for 2005, 2006, and 2007 and number of asthma hospital discharge and emergency department visits. Population data for New York were taken from US Bureau of Census, and asthma data were obtained from New York State Department of Health, National Asthma Survey surveillance report. Data on the concentrations of PM2.5, SO2 and ground level ozone were obtained from various air quality monitoring stations distributed in different counties. Annual means of these concentrations were compared to annual variations in asthma prevalence by using Pearson correlation coefficient. We found different associations between the annual mean concentration of PM2.5, SO2 and surface ozone and the annual rates of asthma discharge and asthma emergency visit from 2005 to 2007. A positive correlation coefficient was observed between the annual mean concentration of PM2.5, and SO2 and the annual rates of asthma discharge and asthma emergency department visit from 2005 to 2007. However, the correlation coefficient between annual mean concentrations of ground ozone and the annual rates of asthma discharge and asthma emergency visit was found to be negative from 2005 to 2007. Our study suggests that the association between elevated concentrations of PM2.5 and SO2 and asthma prevalence among residents of New York State in USA is consistent enough to assume concretely a plausible and significant association. PMID- 24806194 TI - Hematological and biochemical data obtained in rural northern Uganda. AB - Reference intervals for common hematological and clinical chemistry parameters constitute an important basis for health care. Moreover, with increasing priority in drug and vaccine development for infectious diseases in Africa, the first priority is the safety evaluation and tolerability of the candidate interventions in healthy populations. To accurately assess health status and address adverse events, clinical reference intervals in the target population are necessary. We report on hematological and biochemical indices from healthy volunteers who participated in a clinical trial in Lira, northern Uganda. Median and nonparametric 95% percentiles on five hematology and 15 biochemistry analytes are shown. Although most hematological analytes conformed to reported reference intervals and trends in Africa, literature review from different African countries highlight the need for a region-specific children reference interval that can be appropriate for the population. PMID- 24806196 TI - First total syntheses of chrestifoline-B and (+/-)-chrestifoline-C, and improved synthetic routes to bismurrayafoline-A, bismurrayafolinol and chrestifoline-D. AB - We describe an efficient synthesis of the methylene-bridged biscarbazole alkaloids bismurrayafoline-A, bismurrayafolinol and chrestifoline B-D using an Ullmann-type coupling at the benzylic position. PMID- 24806195 TI - Combination of a fast cleanup procedure and a DR-CALUX(r) bioassay for dioxin surveillance in Taiwanese soils. AB - Our goal was to determine dioxin levels in 800 soil samples collected from Taiwan. An in vitro DR-CALUX(r) assay was carried out with the help of an automated Soxhlet system and fast cleanup column. The mean dioxin level of 800 soil samples was 36.0 pg-bioanalytical equivalents (BEQs)/g dry weight (d.w.). Soil dioxin-BEQs were higher in northern Taiwan (61.8 pg-BEQ/g d.w.) than in central, southern, and eastern Taiwan (22.2, 24.9, and 7.80 pg-BEQ/g d.w., respectively). Analysis of multiple linear regression models identified four major predictors of dioxin-BEQs including soil sampling location (beta = 0.097, p < 0.001), land use (beta = 0.065, p < 0.001), soil brightness (beta = 0.170, p < 0.001), and soil moisture (beta = 0.051, p = 0.020), with adjusted R2 = 0.947 (p < 0.001) (n = 662). An univariate logistic regression analysis with the cut-off point of 33.4 pg-BEQ/g d.w. showed significant odds ratios (ORs) for soil sampling location (OR = 2.43, p < 0.001), land use (OR = 1.47, p < 0.001), and soil brightness (OR = 2.83, p = 0.009). In conclusion, four variables, including soil sampling location, land use, soil brightness, and soil moisture, may be related to soil-dioxin contamination. Soil samples collected in northern Taiwan, and especially in Bade City, soils near industrial areas, and soils with darker color may contain higher dioxin-BEQ levels. PMID- 24806198 TI - Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high-fat diet-fed mice. AB - The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high fat (HF) diet for 90 d. DRSP and spiro curbed HF diet-induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion. Notably, either MR antagonist induced up-regulation of brown adipocyte-specific transcripts and markedly increased protein levels of uncoupling protein 1 (UCP1) in visceral and inguinal fat depots when compared with the HF diet group. Positron emission tomography and magnetic resonance spectroscopy confirmed acquisition of brown fat features in WAT. Interestingly, MR antagonists markedly reduced the autophagic rate both in murine preadipocytes in vitro (10(-5) M) and in WAT depots in vivo, with a concomitant increase in UCP1 protein expression. Moreover, the autophagy repressor bafilomycin A1 (10(-8) M) mimicked the effect of MR antagonists, increasing UCP1 protein expression in primary preadipocytes. Hence, we showed that adipocyte MR regulates brown remodeling of WAT through a modulation of autophagy. These results provide a rationale for the use of MR antagonists to prevent the adverse metabolic consequences of adipocyte dysfunction. PMID- 24806199 TI - Accumulation of heptaprenyl diphosphate sensitizes Bacillus subtilis to bacitracin: implications for the mechanism of resistance mediated by the BceAB transporter. AB - Heptaprenyl diphosphate (C35 -PP) is an isoprenoid intermediate in the synthesis of both menaquinone and the sesquarterpenoids. We demonstrate that inactivation of ytpB, encoding a C35 -PP utilizing enzyme required for sesquarterpenoid synthesis, leads to an increased sensitivity to bacitracin, an antibiotic that binds undecaprenyl pyrophosphate (C55 -PP), a key intermediate in cell wall synthesis. Genetic studies indicate that bacitracin sensitivity is due to accumulation of C35 -PP, rather than the absence of sesquarterpenoids. Sensitivity is accentuated in a ytpB menA double mutant, lacking both known C35 PP consuming enzymes, and in a ytpB strain overexpressing the HepST enzyme that synthesizes C35 -PP. Conversely, sensitivity in the ytpB background is suppressed by mutation of hepT or by supplementation with 1,4-dihydroxy-2-naphthoate, a co substrate with C35 -PP for MenA. Bacitracin sensitivity results from impairment of the BceAB and BcrC resistance mechanisms by C35 -PP: in a bceAB bcrC double mutant disruption of ytpB no longer increases bacitracin sensitivity. These results suggest that C35 -PP inhibits both BcrC (a C55 -PP phosphatase) and BceAB (an ABC transporter that confers bacitracin resistance). These findings lead to a model in which BceAB protects against bacitracin by transfer of the target, C55 PP, rather than the antibiotic across the membrane. PMID- 24806200 TI - Chemical synthesis of the beta-subunit of human luteinizing (hLH) and chorionic gonadotropin (hCG) glycoprotein hormones. AB - Human luteinizing hormone (hLH) and human chorionic gonadotropin (hCG) are human glycoprotein hormones each consisting of two subunits, an identical alpha-subunit and a unique beta-subunit, that form noncovalent heterodimers. Structurally, beta hCG shares a high degree of sequence similarity with beta-hLH, including a common N-glycosylation site at the N-terminus but differs mainly in the presence of an extended C-terminal portion incorporating four closely spaced O-linked glycans. These glycoproteins play important roles in reproduction and are used clinically in the treatment of infertility. In addition, the role of hCG as a tumor marker in a variety of cancers has also attracted significant interest for the development of cancer vaccines. In clinical applications, these hormones are administered as mixtures of glycoforms due to limitations of biological methods in producing homogeneous samples of these glycoproteins. Using the powerful tools of chemical synthesis, the work presented herein focuses on the highly convergent syntheses of homogeneous beta-hLH and beta-hCG bearing model glycans at all native glycosylation sites. Key steps in these syntheses include a successful double Lansbury glycosylation en route to the N-terminal fragment of beta-hCG and the sequential installation of four O-linked glycosyl-amino acid cassettes into closely spaced O-glycosylation sites in a single, high-yielding solid-supported synthesis to access the C-terminal portion of the molecule. The final assembly of the individual glycopeptide fragments involved a stepwise native chemical ligation strategy to provide the longest and most complex human glycoprotein hormone (beta-hCG) as well as its closely related homologue (beta-hLH) as discrete glycoforms. PMID- 24806206 TI - C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction. AB - AIMS: Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C-reactive protein (CRP) in patients with HFpEF. METHODS AND RESULTS: Plasma levels of CRP were determined in 459 patients with HFpEF in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study using a high sensitivity assay. During a median follow-up of 9.7 years 40% of these patients died. CRP predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.20 [95% confidence interval (CI) 1.02-1.40, P = 0.018] and cardiovascular mortality with a HR of 1.32 (95% CI 1.08-1.62, P = 0.005) per increase of one standard deviation. CRP was a significantly stronger mortality predictor in HFpEF patients than in a control group of 522 HFrEF patients (for interaction, P = 0.015). Furthermore, CRP added prognostic value to N-terminal pro B-type natriuretic peptide (Nt-proBNP): the lowest 5-year mortality rate of 6.8% was observed for patients in the lowest tertile of Nt-proBNP as well as CRP. The mortality risk peaked in the group combining the highest values of Nt-proBNP and CRP with a 5-year rate of 36.5%. CONCLUSION: It was found that CRP was an independent and strong predictor of mortality in HFpEF. This observation may reflect immunological processes with an adverse impact on the course of HFpEF. PMID- 24806207 TI - The repressive effect of miR-148a on TGF beta-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of cancer stem cells (CSCs)-mediated post-surgical recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs like properties has become a new approach for the treatment of HCC. GLA exhibits anti-tumor effects in that it attenuates the proliferation, migration, invasion, and angiogenesis of human cancer cells. However, the functions of GLA in the regulation of CSCs-like properties in HCC cells, and the molecular mechanisms underlying in remain obscure. Here we found that GLA attenuated the CSCs-like properties by the microRNA-148a (miR-148a)-mediated inhibition of transforming growth factor beta (TGF-beta)/SMAD2 signal pathway in HCC cell lines (HepG2, Huh 7, and MHCC97H). Indeed, GLA inhibited the activations/expressions of both TGFbeta-induced and the endogenous SMAD2. Further, GLA improved the expression of miR-148a in a dose/time-dependent manner. MiR-148a, which targeted the SMAD2 3'UTR, decreased the expression and function of SMAD2. Knockdown of miR-148a abolished the GLA-induced inhibition of TGF-beta/SMAD2 signal pathway and the CSCs-like properties in HCC cells. Our study found a novel mechanism that GLA inhibits the CSCs-like properties of HCC cells by miR-148a-mediated inhibition of TGF-beta/SMAD2 signal pathway, which may help to identify potential targets for the therapies of HCC. PMID- 24806210 TI - Girl with cat and Young girl at the window: Balthus. PMID- 24806211 TI - A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. AB - IMPORTANCE: Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, informative and complementary estimates can be derived from population-based registers. OBJECTIVE: To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders. DESIGN, SETTING, AND PARTICIPANTS: We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320,543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489,006 persons were censored owing to death; and 69,987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders. EXPOSURES: Age and sex. MAIN OUTCOMES AND MEASURES: Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks. RESULTS: During the course of life, 37.66% of females (95% CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life. CONCLUSIONS AND RELEVANCE: This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research. PMID- 24806212 TI - Mortality risk of mirtazapine: guilt by association? PMID- 24806213 TI - Dose reduction/discontinuation for first-episode psychosis. PMID- 24806217 TI - The effect of five probiotic lactobacilli strains on the growth and biofilm formation of Streptococcus mutans. AB - OBJECTIVE: To compare the effects of five probiotic lactobacilli strains on the growth and biofilm formation of Streptococcus mutans (MS). MATERIALS AND METHODS: Five probiotic lactobacilli bacteria (LB), Lactobacillus casei Shirota, Lactobacillus casei LC01, Lactobacillus plantarum ST-III, Lactobacillus paracasei Lpc-37, and Lactobacillus rhamnosus HN001, were used as test strains effecting on the Streptococci strain S. mutans UA159 in this study. The effect of LB strains and their supernatants on the viability of the MS was evaluated. Then, the effect of LB strains on the growth of MS biofilm formation was observed by fluorescence microscope. RESULTS: All of the LB strains inhibited the growth of MS at concentrations of 1 * 10(8) and 3 * 10(8) CFU ml(-1) (P < 0.05). Untreated (without pH adjustment and ultrafiltration) LB supernatants from all of the LB strains inhibited the growth of MS (P < 0.05) as well. After pH adjustment and ultrafiltration (treated), only supernatants from L. casei Shirota and L. rhamnosus HN001 inhibited the growth of MS (P < 0.05). MS biofilm formation was also inhibited by all untreated supernatants and by the treated supernatants of L. casei Shirota and L. rhamnosus HN001 (P < 0.05). CONCLUSION: All five probiotic lactobacilli strains inhibited the growth and biofilm formation of MS, likely through the production of an acid environment, bacteriocin-like poly peptides, or both, and the effects on MS were dependent on the LB strains used. PMID- 24806216 TI - Use of wild bird surveillance, human case data and GIS spatial analysis for predicting spatial distributions of West Nile virus in Greece. AB - West Nile Virus (WNV) is the causative agent of a vector-borne, zoonotic disease with a worldwide distribution. Recent expansion and introduction of WNV into new areas, including southern Europe, has been associated with severe disease in humans and equids, and has increased concerns regarding the need to prevent and control future WNV outbreaks. Since 2010, 524 confirmed human cases of the disease have been reported in Greece with greater than 10% mortality. Infected mosquitoes, wild birds, equids, and chickens have been detected and associated with human disease. The aim of our study was to establish a monitoring system with wild birds and reported human cases data using Geographical Information System (GIS). Potential distribution of WNV was modelled by combining wild bird serological surveillance data with environmental factors (e.g. elevation, slope, land use, vegetation density, temperature, precipitation indices, and population density). Local factors including areas of low altitude and proximity to water were important predictors of appearance of both human and wild bird cases (Odds Ratio = 1,001 95%CI = 0,723-1,386). Using GIS analysis, the identified risk factors were applied across Greece identifying the northern part of Greece (Macedonia, Thrace) western Greece and a number of Greek islands as being at highest risk of future outbreaks. The results of the analysis were evaluated and confirmed using the 161 reported human cases of the 2012 outbreak predicting correctly (Odds = 130/31 = 4,194 95%CI = 2,841-6,189) and more areas were identified for potential dispersion in the following years. Our approach verified that WNV risk can be modelled in a fast cost-effective way indicating high risk areas where prevention measures should be implemented in order to reduce the disease incidence. PMID- 24806218 TI - Gelatin-based biomaterial engineering with anhydride-containing oligomeric cross linkers. AB - Chemically cross-linked gelatin hydrogels are versatile cell-adhesive hydrogel materials that have been established for a variety of biomedical applications. The most prominent cross-linker is glutaraldehyde, which, however, has been described to cause compatibility problems and loss of microscopic but relevant structural features. A recently developed oligomeric cross-linker that contains anhydride functionalities was evaluated as cross-linker for the fabrication of gelatin-based hydrogels and microparticles. In a fast curing reaction, hydrogels composed of gelatin and oligomeric cross-linker were fabricated with good conversion over a wide concentration range of constituents and with cross-linkers of different anhydride contents. Hydrogel properties, such as dry weight and mechanics, could be controlled by hydrogel composition and rheological properties correlated to elastic moduli from 1 to 10 kPa. The gels were shown to be cytocompatible and promoted cell adhesion. In soft formulations, cells migrated into the hydrogel bulk. Gelatin microparticles prepared by a standard water-in oil emulsion technique were also treated with the novel oligomers, and cross linking degrees matching those obtained with glutaraldehyde were obtained. At the same time, fewer interparticular cross-links were observed. Fluorescein derivatized cross-linkers yielded labeled microparticles in a concentration dependent manner. The oligomeric cross-linkers are presented as an efficient and possibly more functional and compatible alternative to glutaraldehyde. The engineered hydrogel materials hold potential for various biomedical applications. PMID- 24806221 TI - [Increased BMI: Which effect do additional risk factors have? - Obese patients: Additional risk factors are highly involved]. PMID- 24806220 TI - Efficacy and safety of gabapentin 1800 mg treatment for post-herpetic neuralgia: a meta-analysis of randomized controlled trials. AB - WHAT IS KNOWN AND OBJECTIVE: Gabapentin has been used for the management of post herpetic neuralgia (PHN). However, inconsistent results have been reported. This meta-analysis was performed to assess the efficacy and safety of gabapentin 1800 mg/day in PHN patients by conducting a meta-analysis. METHODS: Electronic databases were searched for relevant randomized controlled trials (RCTs) that compared gabapentin 1800 mg/day to placebo for PHN. The primary outcomes were reduction in 24-h average pain intensity scores, 50% and 30% pain intensity reduction and gabapentin-related side effects. The secondary outcomes were reduction in sleep rating scores and improvement in Patient Global Impression of Change (PGIC) or Clinician Global Impression of Change (CGIC). RESULTS AND DISCUSSION: Six RCTs were included. Gabapentin 1800 mg/day reduced the 24-h average pain intensity scores [standard mean differences (SMD) -0.50; 95% confidence interval (CI) -0.88, -0.13; I(2) = 86.3%] and average daily sleep rating scores [weighted mean differences (WMD) -0.71; 95% CI -1.11, -0.32; I(2) = 0%]. Gabapentin treatment yielded an improvement in pain intensity (risk ratio (RR) 1.88; 95% CI 1.35, 2.29; I(2) = 64.8%; for 50% reduction and RR 1.43; 95% CI 1.12, 1.83; I(2) = 0% for 30% reduction, respectively), PGIC (RR 1.49; 95% CI 1.28, 1.74; I(2) = 0%), and CGIC (RR 1.58; 95% CI 1.29, 1.92; I(2) = 30.9%). However, gabapentin increased the somnolence (RR 2.03; 95% CI 1.39, 2.98; I(2) = 2%), dizziness (RR 2.68; 95% CI 1.95, 3.69; I(2) = 15%), peripheral oedema (RR 9.10; 95% CI 3.23, 25.60; I(2) = 2%), total adverse effects (RR 1.28; 95% CI 1.16, 1.42; I(2) = 0%) and withdrawal due to adverse events (RR 1.51; 95% CI 1.06, 2.16; I(2) = 6%), but these adverse effects were often mild to moderate. WHAT IS NEW AND CONCLUSION: Treatment with gabapentin 1800 mg/day yielded a significant reduction in PHN up to 14 weeks. Gabapentin 1800 mg appeared safe in treating PHN for up to 24 weeks. PMID- 24806222 TI - Misfolded protein? We have a chemical for that. AB - Can small molecule studies decipher protein folding landscapes and perhaps identify the next wonder drug? Nathan Blow looks at how chemical biology is changing our view of protein folding. PMID- 24806223 TI - Simultaneous isolation of mRNA and native protein from minute samples of cells. AB - Precious biological samples often lack a sufficient number of cells for multiple procedures, such as extraction of mRNA while maintaining protein in a non denatured state suitable for subsequent characterization. Here we present a new method for the simultaneous purification of mRNA and native proteins from samples containing small numbers of cells. Our approach utilizes oligodeoxythymidylate [oligo(dT)25]-coated paramagnetic beads in an optimized reaction buffer to isolate mRNA comparable in quantity and quality to mRNA isolated with existing methods, while maintaining the proteins in their native state for traditional protein assays. We validated the procedure using neonatal rat ovaries and small numbers of human granulosa cells, demonstrating the extraction of mRNA suitable for gene expression analysis with simultaneous isolation of native proteins suitable for downstream characterization using different protein assays. PMID- 24806224 TI - Isolation and characterization of mammalian cells expressing the Arf promoter during eye development. AB - Although many researchers have successfully uncovered novel functions of the tumor suppressor p19(Arf) utilizing various types of cultured cancer cells and immortalized fibroblasts, these systems do not accurately reflect the endogenous environment in which Arf is developmentally expressed. We addressed this by isolating perivascular cells (PVCs) from the primary vitreous of the mouse eye. This rare cell type normally expresses the p19(Arf) tumor suppressor in a non pathological, developmental context. We utilized fluorescence activated cell sorting (FACS) to purify the cells by virtue of a GFP reporter driven by the native Arf promoter and then characterized their morphology and gene expression pattern. We further examined the effects of reintroduction of Arf expression in the Arf(GFP/GFP) PVCs to verify expected downstream effectors of p19(Arf) as well as uncover novel functions of Arf as a regulator of vasculogenesis. This methodology and cell culture model should serve as a useful tool to examine p19(Arf) biology. PMID- 24806226 TI - A simple filtration technique for obtaining purified human chromosomes in suspension. AB - Here we present a simple method for cleaning polyamine human mitotic chromosomes in solution. This was achieved by filtering intact (unburst) nuclei along with both large and small cytoplasmic debris through a series of different pore sized filters. Pure human chromosomes were recovered using a simple reverse filtration step. Fluorescence microscopy was used to validate the chromosome suspension after each filtration step. This reverse filtration technique is an improvement in both procedure time and chromosome recovery compared to currently used post purification methods. Chromosomes purified by our method could be used for many applications, such as structural studies using microfluidics and high resolution imaging or generation of chromosome paints and sequencing after flow cytometry. PMID- 24806225 TI - Lessons learned from vivo-morpholinos: How to avoid vivo-morpholino toxicity. AB - Vivo-morpholinos are a promising tool for gene silencing. These oligonucleotide analogs transiently silence genes by blocking either translation or pre-mRNA splicing. Little to no toxicity has been reported for vivo-morpholino treatment. However, in a recent study conducted in our lab, treatment of mice with vivo morpholinos resulted in high mortality rates. We hypothesized that the deaths were the result of oligonucleotide hybridization, causing an increased cationic charge associated with the dendrimer delivery moiety of the vivo-morpholino. The cationic charge increased blood clot formation in whole blood treated with vivo morpholinos, suggesting that clotting could have caused cardiac arrest in the deceased mice. Therefore, we investigate the mechanism by which some vivo morpholinos increase mortality rates and propose techniques to alleviate vivo morpholino toxicity. PMID- 24806227 TI - Efficient construction of rAAV-based gene targeting vectors by Golden Gate cloning. AB - The recombinant adeno-associated virus (rAAV) has proven to be an efficient and attractive tool for targeted genome engineering. Here we present a novel method employing the Golden Gate cloning strategy for fast and efficient construction of rAAV-based gene knockout or single-nucleotide knockin vectors. Two vectors, pGolden-Neo and pGolden-Hyg, were generated as common assembling modules to confer antibiotic resistance to the targeting vector. To validate the method, we then generated two rAAV-based targeting vectors: pAAV-pTP53-KO and pAAV hTau(P301L)-KI. Furthermore, we generated a pGolden-AAV plasmid that allows one step generation of an rAAV-based targeting vector. Our new methodology for rAAV targeting vector assembly is efficient, accurate, time-saving, and cost effective. PMID- 24806228 TI - Comparative next-generation sequencing of adeno-associated virus inverted terminal repeats. AB - The inverted terminal repeats (ITRs) of adeno-associated virus (AAV) are notoriously difficult to sequence owing to their high GC-content (70%) and palindromic sequences that result in the formation of a very stable, 125 bp long, T-shaped hairpin structure. Here we evaluate the performance of two widely used next-generation sequencing platforms, 454 GS FLX (Roche) and MiSeq Benchtop Sequencer (Illumina), in analyzing ITRs in comparatively sequencing linear amplification-meditated PCR (LAM-PCR) amplicons derived from AAV-concatemeric structures. While our data indicate that both platforms can sequence complete ITRs, efficiencies (MiSeq: 0.11% of sequence reads; 454: 0.02% of reads), frequencies (MiSeq: 171 full ITRs, 454: 3 full ITRs), and rates of deviation from the derived ITR consensus sequence (MiSeq: 0.8%-1.3%; 454: 0.5%) did differ. These results suggest that next-generation sequencing platforms can be used to specifically detect ITR mutations and sequence complete ITRs. PMID- 24806229 TI - [Best practices in liver transplantation for hepatocellular carcinoma]. PMID- 24806230 TI - [Outcome of downstaging therapy in liver transplantation]. PMID- 24806231 TI - [Liver transplantation in the patients with hepatocellular carcinoma beyond Milan criteria -with special reference to extended criteria]. PMID- 24806232 TI - [Impact of desensitization for ABO-blood barrier on living donor liver transplantation for hepatocellular carcinoma]. PMID- 24806233 TI - [Acute gastric mucosal lesions caused by acute Helicobacter pylori infection clinical outcomes of six cases and problems in the diagnosis of H. pylori infection]. AB - We analyzed the ratio of positive test results in various diagnostic methods for Helicobacter pylori infection and the clinical presentations in six cases of acute gastric mucosal lesions (AGML) caused by acute H. pylori. At onset, five cases tested negative for serum antibodies; one had a positive result, but the antibody titer increased with time. Some false negative results were obtained with the following tests: urea breath test, rapid urease test, microscopy, culture, and immunostaining; however, the feces antigen test gave positive results in all five cases. These data suggest that feces antigen test should be performed in all cases suspected of acute H. pylori infection. Where progress was monitored without eradication therapy, subjective symptoms were exacerbated in some patients, and one patient developed a persistent infection. Consequently, eradication therapy should be performed at an early stage of AGML. PMID- 24806234 TI - [Non-erosive gastroesophageal reflux disease in a teenager misdiagnosed as anorexia nervosa]. AB - A middle school girl started a diet; she developed an eating disorder, and was diagnosed with anorexia nervosa. Endoscopic examination revealed no esophagitis due to gastric reflux, but slackness was seen in the cardiac region. Multichannel intraluminal impedance pH monitoring revealed marked non-acidic reflux. On the basis of positive symptom index (SI) and symptom association probability (SAP) values, the patient was diagnosed with non-erosive gastroesophageal reflux. The patient was afraid to eat because of the reflux; therefore, laparoscopic reflux prevention surgery was performed. The symptoms completely disappeared after surgery, and normal oral ingestion was possible. PMID- 24806235 TI - [Two cases of colonic diverticular bleeding in which the combination of a planned marking clip and dynamic computed tomography was useful for identification of the bleeding site]. AB - We experienced two cases of shock secondary to colonic diverticular bleeding. Both patients showed signs of shock after each episode of melena; however, the bleeding site could not be initially identified because multiple diverticula were present and the bleeding spontaneously ceased during each examination. Therefore, we subsequently performed planned clipping and dynamic computed tomography scanning of the area surrounding the potential bleeding sites to look for signs of vascular leakage and to determine the clip location. The use of this method enabled us to successfully identify the bleeding site in both cases. Thus, this method can be useful in identifying the site of colonic diverticular bleeding that may cause shock. PMID- 24806236 TI - [An adult case of intussusception due to inverted Meckel's diverticulum observed by colonoscopy]. AB - A man in his twenties had intermittent abdominal pain in the right lower quadrant for more than 4 years. The abdominal pain persisted after a meal, and he visited our hospital emergency department. We performed an emergency colonoscopy and found a 3-cm mobile polypoid lesion located on the antimesenteric side of the ileum 40 cm from the ileocecal valve and was 85*26*23 mm in size. On the basis of characteristic ultrasound and contrast-enhanced CT findings, our preoperative diagnosis was intussusception due to Meckel's diverticulum translation and performed a laparoscopic ileocecal resection. The pathological diagnosis was Meckel's diverticulum translation with ectopic pancreatic and gastric tissue. Furthermore, we aggregated the cases of adult intussusception due to Meckel's diverticulum translation reported in Japan, and investigated preoperative diagnoses and treatment plans. PMID- 24806237 TI - [Hepatic artery pseudoaneurysm after endoscopic biliary stenting for pancreatic cancer]. AB - A man in his sixties presented to our hospital with obstructive jaundice and was diagnosed with inoperable pancreatic cancer. Chemoradiotherapy was initiated, and an expandable metallic stent was inserted endoscopically to drain the biliary system. Six months later, he was referred to our hospital with 1-week history of epigastric pain and obstructive jaundice. On admission for further evaluation, he experienced hematemesis and went into severe shock. Upper gastrointestinal endoscopy and endoscopic retrograde cholangiopancreatography showed active bleeding from the duodenal papilla. Therefore, we performed endoscopic nasobiliary drainage (ENBD). On day 4, blood was detected in the ENBD tube, and the patient again experienced hematemesis. Emergent enhanced computed tomography revealed a right hepatic arterial aneurysm that had likely ruptured and caused the hemobilia. The aneurysm was successfully embolized, and the patient was discharged on hospital day 21. PMID- 24806238 TI - [Three cases of hepatocellular carcinoma with nodules showing different signal intensities in the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI]. AB - We report three cases of resected hepatocellular carcinomas with nodules showing different signal intensities in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI (EOB-MRI). One case involved a nodule-in-nodule type hepatocellular carcinoma that showed high signal intensity for the outer tumor and low intensity for the inner tumor in the hepatobiliary phase of EOB-MRI. The inner tumor was more dedifferentiated than the outer. The other two cases involved similar nodules, which showed different signal intensities in the hepatobiliary phase of EOB-MRI. In all three cases, the expression of OATP8 showed good correlation with high signal intensity in the hepatobiliary phase of EOB-MRI, whereas MRP2, MRP3, or both were also highly expressed. However, in the two nodules showing low intensities, the expression of one excreting transporter was independently high even though that of OATP8 was not high. The expression of excreting transporters is usually characterized by passive correspondence to OATP8 expression levels; nevertheless, it sometimes shows expression independent of OATP8. PMID- 24806239 TI - [A case of previous infection with schistosomiasis japonica diagnosed holistically on the basis of various clinical examination findings]. AB - A 66-year-old male was referred to our hospital because of a high CRP level. CT and MRI revealed cord-like contrast effects along the periphery of the liver, and peripheral portal vein occlusion was suspected. Histopathological analysis revealed fibrotic occlusion and eosinophil and histiocytic infiltration of the portal vein. Taking into account various clinical imaging tests, blood tests, and histopathological tests and of his current clinical history, he was diagnosed with previous infection of schistosomiasis japonica. We believe that this case illustrates the importance of a comprehensive diagnosis; in addition, we implemented real-time virtual sonography and EOB-MRI that provided useful visual information. PMID- 24806240 TI - [A case of gallbladder carcinoma following cholecystogastric fistula]. AB - A 79-year-old woman with pneumobilia and liver dysfunction was admitted to our hospital. ERCP and gastrointestinal endoscopy revealed choledochal stones and a cholecystogastric fistula at the greater curvature of the gastric antrum. The risk of cholecystectomy and fistulectomy appeared to be extremely high for this patient because of her advanced age and low respiratory function due to interstitial pneumonia. Therefore, only an endoscopic lithotomy was performed, and the cholecystogastric fistula remained. However, after 2 years of follow-up, she developed an advanced gallbladder carcinoma. This finding suggests that cholecystogastric fistula is a risk factor for gallbladder carcinoma. Because of the difficulty of early detection of gallbladder carcinoma associated with cholecystogastric fistula, both fistulectomy and cholecystectomy are necessary when cholecystogastric fistula is diagnosed. PMID- 24806241 TI - Fully printed, rapid-response sensors based on chemically modified graphene for detecting NO2 at room temperature. AB - Reduced graphene oxide (RGO) has proven to be effective in trace gas detection at room temperature ambient conditions. However, the slow response-recovery characteristic is a major hurdle for the RGO-based gas sensors. Herein, we report a gravure-printed chemoresistor-type NO2 sensor based on sulfonated RGO (S-RGO) decorated with Ag nanoparticles (Ag-S-RGO). Large amounts of silver nanoparticles with an average particle size of 10-20 nm were uniformly assembled on flat S-RGO surfaces. The printed Ag-S-RGO sensor possesses a high sensitivity and fast response-recovery characteristic over NO2 concentrations ranging from 0.5 to 50 ppm. Upon exposure to 50 ppm NO2 at room temperature, the Ag-S-RGO sensor shows a sensitivity of 74.6%, a response time of 12 s and a recovery time of 20 s. In addition, the Ag-S-RGO sensors exhibit satisfactory flexibility with an almost constant resistance after 1000 bending cycles. The printed and high-performance Ag-S-RGO sensors described here will be a good prospect in environmental monitoring of NO2. PMID- 24806242 TI - The sugar debate and nutrition: obesity and 'empty calories'. PMID- 24806243 TI - Advice to reduce total and saturated fat, revisited. PMID- 24806244 TI - Weight and height measurement: potential impact in obstetric care. AB - AIM: To assess the accuracy of reported weight and height in a pregnant population. METHODS: Participants were recruited when attending their nuchal translucency scan if they attended with an 'antenatal screening for Down syndrome and other conditions' laboratory form (used for the maternal serum screening in the first trimester (MSS1) blood test) that had weight and/or height recorded. Participants' weight and height were measured by trained recruitment centre staff and body mass index (BMI) was calculated. Differences in reported (MSS1) and measured weight, height and BMI were analysed using Bland-Altman plots. RESULTS: 248 women participated. Only 23% (n=56) of participants had a weight recorded on the MSS1 laboratory form that was within plus or minus 0.5 kg of measured weight: 62% (n=155) had an under-reported weight, and 15% (n=37) an over-reported weight. 30% (n=74) of participants had a correctly reported height: 26% (n=63) an under reported height, and 44% (n=107) an over-reported height. 6% (n=14) of participants had a correctly reported BMI: 69% (n=166) had an under-reported BMI, and 25% (n=60) an over-reported BMI. 17% of participants (n=40) were incorrectly classified by BMI category based on MSS1 data. CONCLUSION: Our study suggests that there are considerable inaccuracies in the recording of weight and height during pregnancy in New Zealand. This results in a false reduction in BMI in many women which can affect clinical care. PMID- 24806245 TI - Management of excess weight in pregnancy in Otago, New Zealand: a qualitative study with lead maternity carers. AB - AIM: To investigate the knowledge and practice of midwives providing lead maternity care (LMC) in Otago, regarding gestational weight gain (GWG). METHODS: A qualitative study was conducted using three semi-structured focus groups and one in-depth interview. A total of 12 midwives, including one student midwife, were interviewed. Transcripts were analysed using generic coding and thematic analysis. At the conclusion of the focus groups no new themes were emerging. RESULTS: Themes discussed included midwives' knowledge of GWG, methods used to identify BMI and weight gain throughout pregnancy, current management, barriers to management and tools used to overcome these barriers. There was satisfactory knowledge of the risks associated with excess GWG, however, adherence to current New Zealand guidelines and awareness of international guidelines in this area was limited. Management of GWG was highly varied and the weighing of pregnant women was not common practice. Sensitivity around the topic of weight management was identified as a major barrier to care. CONCLUSIONS: The management inconsistencies highlighted in this study have identified a need for New Zealand guidelines for the management of GWG. Clear guidelines along with increased education and collaboration between health professionals would help alleviate the current uncertainty regarding weight management in pregnancy. PMID- 24806246 TI - Duodenal switch--the initial experience in New Zealand. AB - AIMS: The duodenal switch (DS) has now established itself as an effective, durable and safe bariatric procedure. We present our initial experience on 60 patients from May 2008 to November 2012. METHODS: Retrospective case series from a prospective database. 94.8% follow-up over 4 years. RESULTS: 45 patients have completed 1-year follow-up and 28 patients completed 2-year follow-up. The mean initial body mass index (BMI) was 52.8 kg/m(2) (range 40=66 kg/m(2)). The excess weight loss has been 69.5% at 1 year (n=45) and 73.1% at 2 years (n=28) respectively. The mean hospital stay is 5.08 days (range 3-18). The range of bowel motions at 1 year is one to two movements per day. Comorbidity resolution rates were 95% (n=18) for diabetes, 100% (n=9) for obstructive sleep apnoea, 72% (18/25) or hypertension, and 92% (33/36) or dyslipidaemia. One death from liver failure occurred 9 months following surgery resulting from poor compliance with follow-up and intake of multivitamins. CONCLUSION: In our short-term analysis DS appears to be very efficient in terms of cure rate for morbid obesity and its comorbidities. In terms of risk/benefit DS has appeared safe with adherence to the appropriate follow-up regimen. PMID- 24806247 TI - Timely cholecystectomy for acute gallstone disease: an ongoing challenge in a New Zealand provincial centre. AB - AIMS: To review the prior management of patients who underwent cholecystectomy for gallstone disease at a provincial centre over a 1-year period, with a particular focus on potentially preventable morbidity by performing index cholecystectomy (IC). METHODS: Retrospective case note review was performed for patients who underwent cholecystectomy at Hawke's Bay's hospitals between 1 March 2009 and 1 March 2010. RESULTS: 148 cholecystectomies were performed over the study period. Ninety-one patients (61%) were admitted acutely prior to receiving cholecystectomy. The IC rate was 15%. Seventy-seven patients who were admitted acutely could have been suitable for IC, but were discharged. These 77 patients subsequently had an additional 17 readmissions (72 bed-days), 26 ED presentations and 51 outpatient clinic (OPC) visits prior to receiving their eventual operation. Ten patients (13%) developed a complication or recurrence of their acute gallstone disease whilst awaiting surgery. CONCLUSION: Hawke's Bay has a low rate of IC and fails to meet current international standards for timely surgical management of acute gallstone disease. A large proportion of those not operated on during their index admission re-present with further morbidity. There are significant barriers to improving these standards in a provincial centre with limited acute surgical resources. PMID- 24806248 TI - When medical reports become expert medical evidence: judgments of the Court. AB - AIM: This paper analyses what happens when medical reports are reframed to become expert evidence in the New Zealand District Court. The aim is to understand what judges do with, and want from, medical reports. METHOD: Fifty medical reports were analysed for their properties as instances of a specialised genre. Twenty judgments of the District Court were then analysed to see how medical reports are edited and reframed in such judgments. The analytic techniques used were those of genre analysis. RESULTS: When they are edited and become expert evidence in a court, medical reports written for one purpose are used for a different purpose. In a court, medical reports are assessed for the way they bear on the matter at issue and for their quality as expert evidence. CONCLUSIONS: The judgments of the medical reports made by judges can provide guidelines which may assist medical professionals in writing medical reports. PMID- 24806249 TI - Measurement of kidney cadmium in embalmed New Zealand cadavers. AB - Cadmium (Cd) is a toxic (carcinogenic) metal found in food because of its presence in the environment. New Zealand has elevated levels of Cd in soil due to the long term use of Cd-containing phosphate fertilisers. It is therefore likely that New Zealanders have a high Cd body burden which might have health implications. The aims of this study were to determine whether Cd levels in kidney cortex samples are affected by the embalming process and whether kidney cortex samples from embalmed cadavers (e.g. those used for medical student teaching purposes) can be used as a reliable indicator of Cd body burden. Kidney cortex samples from cadavers preserved with different embalming fluids were analysed for Cd by inductively coupled plasma mass spectrometry (ICP-MS). A perfused pig kidney model was used to investigate the effects of embalming on kidney cortex Cd levels. We report considerable variability in Cd levels in kidney cortex samples according to the embalming fluid used; this suggests that the embalming fluid influences tissue Cd concentrations. All pig kidney model perfusions resulted in leaching of Cd from the kidney cortex. We conclude that analysis of Cd in embalmed tissues does not give a reliable indication of in-life Cd levels. PMID- 24806250 TI - Are the amounts of vitamins in commercially available dietary supplement formulations relevant for the management of psychiatric disorders in children? AB - AIM: To investigate whether micronutrient supplements shown through research to have perceived benefits in the treatment of psychological/psychiatric symptoms in children have similar vitamin ingredients and doses to over-the-counter dietary supplements. METHODS: We conducted a systematic review to identify studies that used micronutrients for the treatment of psychological/psychiatric symptoms in children with documented benefits; 13 different supplements were identified that included vitamin ingredients. They were compared with the vitamin composition of 22 over-the-counter child-targeted supplements available in New Zealand. RESULTS: The vitamin ingredients were comparable across the research and commercially available supplements. However, the median vitamin daily doses in research supplements were found to be greater than those of over-the-counter supplements, with most mean differences being significant, including vitamins B1, B3, B6, B7, B12, C and D (p<0.05), B5 and B9 (p<0.001), but not vitamins A or B2. CONCLUSIONS: Micronutrient supplements found to show potential benefit in research with a focus on improving psychological/psychiatric symptoms in children have a significantly greater vitamin dose than over-the-counter supplements. Therefore, the results found in micronutrient research studies cannot be extrapolated to over-the-counter supplements. Comparing the myriad ingredients and dosages in micronutrient supplements is, however, a complex process and further investigation is required to understand fully the importance of our findings. PMID- 24806251 TI - Medically facilitated discharge of adult diabetic ketoacidosis admissions: precipitants and average length of stay. AB - AIMS: To assess the impact of medically facilitated discharge by a specialist registrar on diabetic ketoacidosis (DKA) length of stay (LOS) and to collect data from these DKA admissions for a descriptive summary of their clinical and biochemical characteristics. METHOD: DKA admissions were identified through the electronic patient management system, Monday to Friday over a 9 month period. The admitting team was then offered assistance with discharge planning ('study intervention'). The registrar also collected clinical information for all identified DKA admissions. RESULTS: There were 71 DKA admissions; 92% had type 1 diabetes and 56% were overnight admissions. Following exclusion of four admissions with prolonged LOS secondary to major comorbidities, mean LOS fell from 3.7 (+/- 1.0) to 2.8 (+/- 0.3) days. Facilitated discharge had no major impact on LOS. The commonest precipitant for admission was insulin omission, accounting for 65% of admissions. Local practice was to discharge patients following resolution of acidosis, but prior to complete abolition of ketosis. CONCLUSIONS: The majority of DKA admissions were of short duration. Achieving further reduction in LOS is therefore difficult. Insulin omission was the commonest DKA precipitant. Diabetes clinical resources may be best allocated on preventing DKA admissions, rather than facilitating early discharge. PMID- 24806252 TI - Hepatic complications in poorly controlled type 1 diabetes mellitus: a case report. AB - We present the case of a 13-year-old male with poorly controlled type 1 diabetes mellitus who developed significantly deranged liver transaminases following an episode of diabetic ketoacidosis. A liver biopsy diagnosed glycogenic hepatopathy (GH). We believe the combination of GH and ischaemic hepatitis led to his presentation. PMID- 24806253 TI - FIZZ Sugary Drink Free Pacific by 2030--Symposium Declaration. PMID- 24806254 TI - Healthiness of popular fast food items in New Zealand: plenty of room for improvement. PMID- 24806255 TI - Employment, poverty and health: ideology or science? PMID- 24806256 TI - Diagnostic testing of blood donor specimens. PMID- 24806257 TI - Public attitudes to new smokefree outdoor places policies in New Zealand: an analysis of 217 online comments. PMID- 24806258 TI - Emergency and stroke physician combined consensus statement on thrombolysis for acute stroke. AB - The New Zealand Faculty of the Australasian College for Emergency Medicine (ACEM) is the professional body representing the specialist emergency medicine physicians who work in and lead emergency departments of New Zealand. The National Stroke Network Leadership Group represents New Zealand stroke clinicians including stroke physicians and neurologists who work within and lead district health board (DHB) stroke services. In an effort to promote their shared goal of ensuring patient safety while striving to achieve improved stroke outcomes, the two communities have set up a consensus group to develop this combined emergency physician and neurologist/stroke physician consensus statement on the use of intravenous alteplase in stroke ('stroke thrombolysis'). PMID- 24806260 TI - Tridimensional trunk surface acquisition for brace manufacturing in idiopathic scoliosis. AB - INTRODUCTION: Brace manufacturing for idiopathic scoliosis requires trunk surface acquisition. Two methods are currently available to design the trunk shape: craft made technique based on a plaster mold and computer-aided design with 3-D reconstruction of the trunk by optical scanning. The objective of the present review was to compare these two methods. METHODOLOGY: We describe the different steps to design and manufacture braces used for spinal deformities. RESULTS: Our prospective evaluation showed good results in terms of the correction achieved and regarding patients' in-brace comfort. DISCUSSION: Optical scanning for computer-aided design and manufacturing (CAD-CAM) of trunk orthoses have proven their effectiveness. These technologies may help in monitoring conservative treatment and may enhance the brace interaction with the spinal deformity when orthopedic treatment is indicated. PMID- 24806259 TI - The effects of osteoporosis and disc degeneration on vertebral cartilage endplate lesions in rats. AB - PURPOSE: Evidence has shown that osteoporosis or intervertebral disc degeneration (IDD) led to cartilage endplate lesions (CEL), but their combined effects on the lesion remain unknown. This study developed an innovative rat model combined ovariectomy (OVX) and cervical muscle section (CMS), and aimed to evaluate the combined effects of osteoporosis and IDD on cartilage endplate lesions of cervical spine. METHODS: Fifty-two Sprague-Dawley female rats were assigned randomly into four groups as follows: the sham group (n = 10) underwent sham surgery; the OVX group (n = 14) was subjected to bilateral ovariectomy; the CMS group (n = 14) had posterior paraspinal muscles cut from C2 to C7; the CMS-OVX group (n = 14) underwent the OVX and CMS surgeries consecutively. Samples of C6 C7 segments were harvested at 12, 18 and 24 weeks post-surgery. Micro-CT analysis was performed to evaluate the CEL, intervertebral disc height (IDH) and structural indices. Histological analysis with Safranine O/fast green stain and histological score were used to observe the characteristics of the degenerative discs. RESULTS: Ovariectomy surgery resulted in significant changes of most structural indices of the C6 body, such as decrease of percent bone volume and number of bone trabecula at 12 weeks, and greater changes at 18 and 24 weeks. The CEL following CMS surgery was seen on the ventral, while the CEL in the OVX and sham groups on the peripheral. The CEL was greatest in the CMS-OVX group and significantly greater than that in the CMS and OVX groups at 12 and 18 weeks (P < 0.05). The CMS surgery resulted in significant IDH decrease at 12, 18 and 24 weeks (P < 0.05), while the OVX surgery resulted in mild IDH decrease when compared with the sham group. The IDH in the CMS-OVX group was significantly lower than that in the CMS group at 24 weeks (P < 0.05). Histological evaluation suggested cartilage endplate abrasion at 12 weeks, and in situ calcification at 18 and 24 weeks in the CMS and CMS-OVX groups. Disc degenerative scores were higher following CMS or OVX surgery, and correlated with the CEL and IDH (P < 0.01), respectively. CONCLUSIONS: The present study suggested that a combination of OVX and CMS led to more lesion of cartilage endplate than any one thereof, as well as more decrease of IDH. The lesion and IDH decrease were associated with the disc degeneration levels. The cartilage endplate was worn out at the early stage and calcified in situ later. The results indicate that osteoporosis may deteriorate the disc degeneration at specific time. PMID- 24806261 TI - Pre- to post-diagnosis weight change and associations with physical functional limitations in breast cancer survivors. AB - PURPOSE: We investigated pre- to post-diagnosis weight change and functional limitations in a cohort of breast cancer survivors. METHODS: A cohort of 1,841 early-stage breast cancer survivors provided information on pre- and post diagnosis weight and physical function on average 2 years post-diagnosis. The mean number of limitations for each BMI category and each weight change category were compared using the Wilcoxon test. Cross-sectional associations between weight change, from 1 year prior to diagnosis to 2 years post-diagnosis, and functional limitations were determined using logistic regression. RESULTS: Women with BMI >= 30 kg/m(2) had significantly higher physical limitations compared to women with BMI < 25 kg/m(2) (2.06 vs 0.96 for moderate/severe limitations, 3.92 vs 3.27 for mild limitations, 1.31 vs 0.47 for lower body limitations, and 0.76 vs 0.49 for all other limitations; P < 0.0001). Women who reported a large weight gain (>=10% of pre-diagnosis weight) were more likely to report any limitation (OR = 1.79; 95% confidence interval (CI) = 1.23-2.61), a moderate/severe limitation (OR = 2.30; 95% CI = 1.75-3.02), and a lower body limitation (OR = 2.05; 95% CI = 1.53-2.76) compared to women who maintained weight within 5% of pre-diagnosis weight. However, associations between weight loss and functional limitations depended on pre-diagnosis BMI and comorbidity status. Among women without comorbidity, large weight loss (>=10% of pre-diagnosis weight) in normal weight women was associated with higher risk of functional limitations, whereas among overweight/obese women, large weight loss appeared to be associated with a lower risk of limitations. Among women with comorbidity, moderate weight loss in overweight/obese women was associated with a higher risk of a moderate/severe physical limitation. CONCLUSIONS: Large weight gain was associated with a higher risk of physical functional limitations, but associations between weight loss and functional limitations may depend on initial BMI and comorbidity status. IMPLICATIONS FOR CANCER SURVIVORS: In this study we found that both weight loss and weight gain among breast cancer survivors were associated with a higher risk of physical functional limitations. Weight maintenance, therefore, may be an important factor in preventing and/or reducing the risk of functional decline in breast cancer survivors. PMID- 24806262 TI - Seamless integration of clinical care and research in an innovative fertility preservation program: the Colorado Oncofertility Program model. AB - PURPOSE: The purpose of this study is to describe a model of care for fertility preservation (FP) that integrates clinical care and research through the establishment of the Colorado Oncofertility Program's (COP) patient registry. METHODS: To integrate research and clinical care, the COP developed a multidisciplinary organizational structure and established a prospective registry of demographic information and clinical data of patients who agree to participate in future studies. RESULTS: The patient registry allows for the integration of clinical care and research as well as streamlined data collection. Since the program launch in January 2012, over 285 patients have been evaluated and >95% of approached patients have agreed to participate in the registry. Data collected are used for research, systematic program evaluation, and utilization of services. IMPLICATIONS FOR CANCER SURVIVORS: As one of the fastest growing oncofertility programs in the country, there is great potential for the COP's registry to contribute to expanding the limited body of literature on the late effects of cancer treatment on fertility and reproductive health in the adolescent and young adult (AYA) oncology population. With the use of web-based bioinformatics, objective data are captured for clinical care, future studies, program evaluation, and quality assurance, without compromising patient autonomy, privacy, and confidentiality or the commitment to personalized care. PMID- 24806263 TI - A visual ERP study of impulse inhibition following a zaleplon-induced nap after sleep deprivation. AB - The side effects of a zaleplon-induced nap as a countermeasure in the reduction of impulse inhibition function decline following 30 h of sleep deprivation (SD) were examined by event-related brain potentials. Sixteen adult participants performed a Go/NoGo task at five time points: (1) baseline; (2) after 30 h of SD; (3) upon sudden awakening, also called 2 h post-drug; (4) 4 h post-drug; and (5) 6 h post-drug. Behavior results show an increase in both reaction time and false alarm rates after SD and sudden awakening, and a marked decrease at 4 h and 6 h post-drug in zaleplon and placebo conditions. However, no difference was observed between the zaleplon condition and the placebo condition. In event-related potential (ERP) reults compared with results obtained under control conditions, NoGo-P3 latencies significantly increased, whereas the Nogo-P3 amplitude decreased after 30 h of SD and sudden awakening in both the zaleplon condition and the placebo condition. These results indicate that SD attenuates resource allocation and error monitoring for NoGo stimuli. In addition, NoGo-P3 latencies were longer in the zaleplon condition compared with the placebo condition at sudden awakening. Additionally, the NoGo-P3 latencies were shorter in the zaleplon condition than in the placebo condition at 4 h and 6 h post-drug. These results indicate that zaleplon at a dose of 10 mg/day may help subjects achieve a better recovery or maintain better impulse inhibition function, although the side effects of zaleplon last at least 2 h post-drug. PMID- 24806265 TI - Perspectives on Federal Funding for State Health Care-Associated Infection Programs: Achievements, Barriers, and Implications for Sustainability. AB - In September 2009, federal funding for health care-associated infection (HAI) program development was dispersed through a cooperative agreement to 51 state and territorial health departments. From July to September 2011, 69 stakeholders from six states-including state health department employees, representatives from partner organizations, and health care facility employees-were interviewed to assess state HAI program achievements, implementation barriers, and strategies for sustainability. Respondents most frequently cited enhanced HAI surveillance as a program achievement and resource constraints as an implementation barrier. To sustain programs, respondents recommended ongoing support for HAI prevention activities, improved surveillance processes, and maintenance of partnerships. Findings suggest that state-level HAI program growth was achieved during the cooperative agreement but that maintenance of programs faces challenges. PMID- 24806267 TI - On ammonia binding to the oxygen-evolving complex of photosystem II: a quantum chemical study. AB - A recent EPR study (M. Perrez Navarro et al., Proc. Natl. Acad. Sci. 2013, 110, 15561) provided evidence that ammonia binding to the oxygen-evolving complex (OEC) of photosystem II in its S2 state takes place at a terminal-water binding position (W1) on the "dangler" manganese center MnA. This contradicted earlier interpretations of (14)N electron-spin-echo envelope modulation (ESEEM) and extended X-ray absorption fine-structure (EXAFS) data, which were taken to indicate replacement of a bridging oxo ligand by an NH2 unit. Here we have used systematic broken-symmetry density functional theory calculations on large (ca. 200 atom) model clusters of an extensive variety of substitution patterns and core geometries to examine these contradictory pieces of evidence. Computed relative energies clearly favor the terminal substitution pattern over bridging ligand arrangements (by about 20-30 kcal mol(-1)) and support W1 as the preferred binding site. Computed (14)N EPR nuclear-quadrupole coupling tensors confirm previous assumptions that the appreciable asymmetry may be accounted for by strong, asymmetric hydrogen bonding to the bound terminal NH3 ligand (mainly by Asp61). Indeed, bridging NH2 substitution would lead to exaggerated asymmetries. Although our computed structures confirm that the reported elongation of an Mn-Mn distance by about 0.15 A inferred from EXAFS experiments may only be reproduced by bridging NH2 substitution, it seems possible that the underlying EXAFS data were skewed by problems due to radiation damage. Overall, the present data clearly support the suggested terminal NH3 coordination at the W1 site. The finding is significant for the proposed mechanistic scenarios of OEC catalysis, as this is not a water substrate site, and effects of this ammonia binding on catalysis thus must be due to more indirect influences on the likely substrate binding site at the O5 bridging-oxygen position. PMID- 24806268 TI - The use of a 20-gauge valved cannula during pars plana phacofragmentation with a 23-gauge ultrasonic fragmatome. AB - BACKGROUND AND OBJECTIVE: To evaluate the usefulness of a 20-gauge cannula to maintain a self-sealing sclerotomy wound after 23-gauge phacofragmentation. PATIENTS AND METHODS: This retrospective study compared the suture rates after 23 gauge phacofragmentation when the 23-gauge cannula was temporarily replaced with a 20-gauge valved metal cannula versus when the 23-gauge fragmatome was inserted at the sclerotomy site without a cannula. RESULTS: Whereas a sclerotomy was sutured in all 31 eyes in the without-cannula group, only one eye of 14 in the cannula group required a sclerotomy suture (P < .0001). However, there was one case of fragmatome tip fracture during fragmentation in the cannula group. CONCLUSION: A self-sealing sclerotomy wound can be maintained without suturing by using a 20-gauge metal cannula, but fragmatome tip fracture can occur during fragmentation. PMID- 24806269 TI - [Holistic therapy of chronic heart failure]. AB - The rising prevalence and increasing disease-related costs render chronic heart failure a rapidly growing socioeconomic challenge. The concerted action of guideline-adjusted therapy and holistic patient care is essential to achieve improvements in mortality, morbidity, functional status and quality of life of patients with symptomatic heart failure. Holistic care strategies comprise consideration of comorbidities and individual needs, lifestyle recommendations and multidisciplinary management programs for high-risk symptomatic patients in addition to basic medication and surgical therapies. For optimal patient care and coaching, seamless interaction is required between in-hospital treatment and outpatient facilities. Moreover, the palliative needs of heart failure patients need to be considered, a topic that is currently not receiving enough attention. PMID- 24806270 TI - [Diastolic heart failure]. AB - BACKGROUND: Heart failure with preserved ejection fraction (i.e. diastolic heart failure) accounts for about half of heart failure cases. The aim of this review is to reflect current knowledge regarding the epidemiology, pathophysiology and treatment. RESULTS: Diastolic heart failure patients are principally elderly and predominantly female. Numerous pathophysiological alterations in this disease have been shown and recent therapeutic recommendations include control of cardiovascular risk factors and symptoms. New therapeutic options, such as inhibition of late sodium current, aldosterone receptor blockade, combined inhibition of AT1 receptor and the enzyme neprilysin, and phosphodiesterase 5 inhibition are discussed in this review and ongoing clinical trials are also briefly presented. CONCLUSION: Diastolic heart failure remains a cardiac disease which is difficult to treat; however, new study results allow a better definition of a population of patients who could benefit from specific therapies. PMID- 24806271 TI - [Medical treatment of Parkinson's disease in elderly and multimorbid patients]. AB - BACKGROUND: Parkinson's disease is a frequent neurodegenerative disease, which typically occurs in older age. With progression of the disease, therapeutic complications, such as dyskinesias and fluctuations in the response to medication are common. To embed the medication of Parkinson's disease into a complex treatment plan of a patient suffering from multimorbidity can be challenging. OBJECTIVES: Not only the cardinal motor symptoms have to be treated properly but also the non-motor symptoms e.g. depression, dementia, autonomic dysregulations and gastrointestinal disorders. Pharmacological treatment and their risks are presented. CONCLUSION: Especially in older patients the symptoms need to be treated with regard to multimorbidity and the risks of polypharmacotherapy. The therapeutic strategy needs to be carefully planned in order to achieve a high quality of life and social interaction. PMID- 24806272 TI - Hemorrhagic and ischemic stroke secondary to herpes simplex virus type 2 meningitis and vasculopathy. AB - Herpes simplex virus type 2 (HSV-2) meningitis dogmatically is benign and self limited in the immune competent patient. However, we describe how left untreated HSV-2 meningitis can be complicated by vasculitis and both ischemic and hemorrhagic stroke. We report a 57-year-old woman with lymphocytic meningitis complicated by ischemic stroke and intracerebral hemorrhage in the setting of vasculopathy and HSV-2 DNA detected in CSF successfully treated with acyclovir and corticosteroids. Subsequent angiographic magnetic resonance imaging revealed improvement in the vasculopathy after treatment. This case demonstrates that HSV 2 meningitis may take a less benign course and further provides the first evidence of angiographic improvement in addition to clinical improvement after definitive treatment. PMID- 24806275 TI - Oxidative induction of pro-inflammatory cytokine formation by human monocyte derived macrophages following exposure to manganese in vitro. AB - Manganese (as Mn(2+)), a superoxide dismutase mimetic, catalyzes the formation of the relatively stable membrane-permeable reactive oxygen species (ROS) hydrogen peroxide (H2O2), a mediator of intracellular redox signaling in immune and inflammatory cells. The goal of this study was to investigate the potential for Mn(2+), via its pro-oxidative properties, to activate production of pro inflammatory cytokines/chemokines IL-1beta, IL-6, IL-8, IFNgamma, TNFalpha, and G CSF by human monocyte-derived macrophages in vitro. For these studies, the cells were isolated from peripheral blood mononuclear leukocytes and matured to generate a population of large CD14/CD16 co-expressing cells. The monocyte derived macrophages were then exposed to bacterial lipopolysaccharide (LPS, 1 MUg/ml) or MnCl2 (25-100 MUM)-alone or in combination-for 24 h at 37 degrees C, after which cell-free supernatants were analyzed using a multiplex cytokine assay procedure. Exposure of the cells to LPS caused modest statistically insignificant increases in cytokine production; MnCl2 caused dose-related increases in production of all six cytokines (achieving statistical significance of p < 0.0171 < 0.0005 for IL-1beta, IL-6, IL-8, IFNgamma, and TNFalpha). In the case of LPS and MnCl2 combinations, the observed increases in production of IL-1beta, IL-6, IL-8, IFNgamma, and G-CSF were greater than those seen with cells exposed to the individual agents. The Mn(2+)-mediated induction of cytokine production was associated with increased production of H2O2 and completely attenuated by inclusion of the H2O2-scavenger dithiothreitol, and partially by inhibitors of NF kappaB and p38MAP kinase. The findings from the studies here help to further characterize the pro-inflammatory mechanisms that may underpin clinical disorders associated with excess exposure to Mn(2+), particularly those disorders seen in the central nervous and respiratory systems. PMID- 24806276 TI - Land use change alters functional gene diversity, composition and abundance in Amazon forest soil microbial communities. AB - Land use change in the Amazon rainforest alters the taxonomic structure of soil microbial communities, but whether it alters their functional gene composition is unknown. We used the highly parallel microarray technology GeoChip 4.0, which contains 83,992 probes specific for genes linked nutrient cycling and other processes, to evaluate how the diversity, abundance and similarity of the targeted genes responded to forest-to-pasture conversion. We also evaluated whether these parameters were reestablished with secondary forest growth. A spatially nested scheme was employed to sample a primary forest, two pastures (6 and 38 years old) and a secondary forest. Both pastures had significantly lower microbial functional genes richness and diversity when compared to the primary forest. Gene composition and turnover were also significantly modified with land use change. Edaphic traits associated with soil acidity, iron availability, soil texture and organic matter concentration were correlated with these gene changes. Although primary and secondary forests showed similar functional gene richness and diversity, there were differences in gene composition and turnover, suggesting that community recovery was not complete in the secondary forest. Gene association analysis revealed that response to ecosystem conversion varied significantly across functional gene groups, with genes linked to carbon and nitrogen cycling mostly altered. This study indicates that diversity and abundance of numerous environmentally important genes respond to forest-to pasture conversion and hence have the potential to affect the related processes at an ecosystem scale. PMID- 24806277 TI - The nuclear electric quadrupole moment of copper. AB - The nuclear electric quadrupole moment (NQM) of the (63)Cu nucleus was determined from an indirect approach by combining accurate experimental nuclear quadrupole coupling constants (NQCCs) with relativistic Dirac-Coulomb coupled cluster calculations of the electric field gradient (EFG). The data obtained at the highest level of calculation, DC-CCSD-T, from 14 linear molecules containing the copper atom give rise to an indicated NQM of -198(10) mbarn. Such result slightly deviates from the previously accepted standard value given by the muonic method, 220(15) mbarn, although the error bars are superimposed. PMID- 24806274 TI - Loss of Gsalpha early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors. AB - In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit Gs alpha activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of Gs alpha in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage. PMID- 24806278 TI - nab-Paclitaxel for the treatment of aggressive metastatic breast cancer. AB - Despite advances in early diagnosis, prevention, and treatment, breast cancer remains the second-leading cause of cancer-related deaths in women. The 5-year survival rate for patients with metastatic breast cancer (MBC) is just 24%. However, some forms of MBC appear to be more aggressive than others. Triple negative breast cancer (TNBC; lacking overexpression of human epidermal growth factor receptor 2 [HER2] and expression of estrogen and progesterone receptors) and breast cancers that overexpress HER2 are the 2 biologically defined subtypes with the worst prognoses. Although a number of effective options have been developed for the treatment of HER2-overexpressing disease, TNBC remains a difficult-to-treat subtype. In addition to hormone receptor and HER2 status, multiple other factors are predictive of relatively poorer clinical outcomes, including visceral metastasis, short disease-free interval between the end of treatment for early-stage disease and diagnosis of MBC, and higher number of metastatic sites. There is an urgent need to improve therapy for patients with aggressive forms of breast cancer. Taxanes are considered among the most active classes of compounds against breast cancer. This review specifically examines the clinical trials in which nab-paclitaxel was used to treat patients with MBC and factors associated with poor prognosis. PMID- 24806279 TI - Subfemtosecond steering of hydrocarbon deprotonation through superposition of vibrational modes. AB - Subfemtosecond control of the breaking and making of chemical bonds in polyatomic molecules is poised to open new pathways for the laser-driven synthesis of chemical products. The break-up of the C-H bond in hydrocarbons is an ubiquitous process during laser-induced dissociation. While the yield of the deprotonation of hydrocarbons has been successfully manipulated in recent studies, full control of the reaction would also require a directional control (that is, which C-H bond is broken). Here, we demonstrate steering of deprotonation from symmetric acetylene molecules on subfemtosecond timescales before the break-up of the molecular dication. On the basis of quantum mechanical calculations, the experimental results are interpreted in terms of a novel subfemtosecond control mechanism involving non-resonant excitation and superposition of vibrational degrees of freedom. This mechanism permits control over the directionality of chemical reactions via vibrational excitation on timescales defined by the subcycle evolution of the laser waveform. PMID- 24806285 TI - Strong second harmonic generation (SHG) originating from combined second-order Jahn-Teller (SOJT) distortive cations in a new noncentrosymmetric tellurite, InNb(TeO4)2. AB - Pure polycrystalline bulk samples and single crystals of a novel polar noncentrosymmetric (NCS) indium niobium tellurium oxide, InNb(TeO4)2, have been synthesized through solid-state reactions with In2O3, Nb2O5, and TeO2. InNb(TeO4)2 exhibits a three-dimensional structural backbone consisting of layers of corner-shared InO6 octahedra, layers of corner-shared NbO6 octahedra, and chains of corner-shared TeO4 polyhedra. The infrared spectrum shows In-O, Nb-O, and Te-O vibrations, and the UV-vis diffuse reflectance spectrum shows a band gap of 3.5 eV for the reported material. Thermal analysis indicates that InNb(TeO4)2 is thermally stable to 740 degrees C. Powder second-order nonlinear optical (NLO) measurements reveal that InNb(TeO4)2 has a strong second harmonic generation (SHG) efficiency, 100 times that of alpha-SiO2. A detailed structural examination indicates that the strong SHG is due to the combined net polarization originating from the distorted environment of second-order Jahn-Teller (SOJT) cations such as Nb(5+) and Te(4+). Elemental analysis, the magnitude of distortion, and calculations of dipole moments for InNb(TeO4)2 are also presented. PMID- 24806286 TI - Do immature platelet levels in chest pain patients presenting to the emergency department aid in the diagnosis of acute coronary syndrome? AB - INTRODUCTION: Early and accurate identification of acute coronary syndrome (ACS) vs. noncardiac chest pain in patients presenting to the emergency department (ED) is problematic and new diagnostic markers are needed. Previous studies reported that elevated mean platelet volume (MPV) is associated with ACS and predictive of cardiovascular risk. MPV is closely related to the immature platelet fraction (IPF), and recent studies have suggested that IPF may be a more sensitive marker of ACS than MPV. The objective of the present study was to determine whether the measurement of IPF assists in the diagnosis of ACS in patients presenting to the ED with chest pain. METHODS: In this single-center, prospective, cross-sectional study, adult patients presenting to the ED with chest pain and/or suspected ACS were considered for enrollment. Blood samples from 236 ACS-negative and 44 ACS positive patients were analyzed in a Sysmex XE-2100 for platelet count, MPV, IPF, and the absolute count of immature platelets (IPC). RESULTS: Total platelet counts, MPV, IPF, and IPC were not statistically different between ACS-negative and ACS-positive patients. The IPF was 4.6 +/- 2.7% and 5.0 +/- 2.8% (mean +/- SD, P = 0.24), and the IPC was 10.0 +/- 4.6 and 11.5 +/- 7.5 * 10(3) /MUL (P = 0.27) for ACS-negative and ACS-positive patients, respectively. CONCLUSION: In 280 patients presenting to the ED with chest pain and/or suspected ACS, no differences in IPF, IPC or MPV were observed in ACS-negative vs. ACS-positive patients, suggesting that these parameters do not assist in the diagnosis of ACS. PMID- 24806287 TI - Health technology assessment of medicines in Greece: pharmaceutical industry executives' views. AB - OBJECTIVES: The aim of this study was to investigate originator pharmaceutical companies' practices in relation to health technology assessment (HTA) and the views and perceptions of their executives on the importance of HTA in pricing and reimbursement of medicines in Greece. METHODS: A qualitative study was performed, using individual semi-structured interviews based on an interview schedule with open-ended questions. The target population was market access departments' executives of originator pharmaceutical companies. Our target sample consisted of sixteen executives, of whom ten agreed to participate. Saturation point was reached after eight interviews. Data were audio recorded, transcribed verbatim, and analyzed using content analysis. RESULTS: Participants considered HTA as a very important complementary tool for decision making in health policy, particularly in the field of pharmaceuticals and medical devices. They believed that, in Greece, HTA could be institutionalized for the reimbursement mechanism of medicines under certain conditions relating to current health policy-making attitudes and conditions pertaining in the country. They considered that there are many constraints which must be overcome as well as opportunities to be exploited. CONCLUSIONS: Decisions in pharmaceutical policy should be scientifically substantiated and HTA should be institutionalized primarily for reimbursement decisions. Development of guidelines for conducting pharmaco economic evaluation, change in health policy goals, recording of cost and epidemiological data, and broader participation of all stakeholders in HTA decision-making processes are suggested as prerequisites for a successful implementation of HTA in Greece. PMID- 24806288 TI - Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. AB - NRAS mutations occur in 3-5% of colorectal cancer. Differently from KRAS and BRAF mutations, the role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer (mCRC) has been investigated to a lesser extent. A retrospective series suggested the role of NRAS mutations as predictors of resistance to anti-EGFR monoclonal antibodies (MoAbs) in chemo-refractory patients with mCRC. In our study, KRAS codons 12, 13, 61 and BRAF codon 600 mutational status were evaluated in mCRCs referred to our Institution from 2009 to 2012. NRAS codons 12, 13 and 61 mutational status was analyzed in KRAS/BRAF wt patients. We collected pathological and clinical features in the overall population and outcome data in a subset of NRAS mutated chemo-refractory patients treated with anti-EGFR MoAbs in advanced lines. NRAS was mutated in 47/786 (6%) mCRCs. NRAS and KRAS mutated tumors did not show significant differences in terms of clinical and pathological characteristics, except for a lower prevalence of mucinous histology (p = 0.012) and lung metastases (p = 0.012) among NRAS mutated tumors. In the uni- and multivariate model, NRAS mutations were associated with shorter overall survival (OS) compared to all wt patients (median OS 25.6 vs 42.7 months; univ: HR = 1.91, 95% CI 1.39-3.86, p = 0.0013; multiv: HR = 1.75, 95% CI 1.1.3-2.72, p = 0.013). None of the chemo-refractory NRAS mutated patients evaluable for response to anti-EGFRs achieved response. In conclusion, NRAS mutations have a relevant incidence in patients with mCRC and showed an association with specific clinical and pathological features. NRAS mutations affect mCRC patients' prognosis and predict lack of response to anti-EGFRs. PMID- 24806289 TI - Erythropoietin responsive cardiomyogenic cells contribute to heart repair post myocardial infarction. AB - The role of erythropoietin (Epo) in myocardial repair after infarction remains inconclusive. We observed high Epo receptor (EPOR) expression in cardiac progenitor cells (CPCs). Therefore, we aimed to characterize these cells and elucidate their contribution to myocardial regeneration on Epo stimulation. High EPOR expression was detected during murine embryonic heart development followed by a marked decrease until adulthood. EPOR-positive cells in the adult heart were identified in a CPC-enriched cell population and showed coexpression of stem, mesenchymal, endothelial, and cardiomyogenic cell markers. We focused on the population coexpressing early (TBX5, NKX2.5) and definitive (myosin heavy chain [MHC], cardiac Troponin T [cTNT]) cardiomyocyte markers. Epo increased their proliferation and thus were designated as Epo-responsive MHC expressing cells (EMCs). In vitro, EMCs proliferated and partially differentiated toward cardiomyocyte-like cells. Repetitive Epo administration in mice with myocardial infarction (cumulative dose 4 IU/g) resulted in an increase in cardiac EMCs and cTNT-positive cells in the infarcted area. This was further accompanied by a significant preservation of cardiac function when compared with control mice. Our study characterized an EPO-responsive MHC-expressing cell population in the adult heart. Repetitive, moderate-dose Epo treatment enhanced the proliferation of EMCs resulting in preservation of post-ischemic cardiac function. PMID- 24806290 TI - Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo. AB - Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs. PMID- 24806291 TI - Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles. AB - Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine. PMID- 24806293 TI - Grief and attitudes toward suicide in peers affected by a cluster of suicides as adolescents. AB - Eighty-five young adults exposed to a cluster of peer suicides as adolescents completed measures of attitudes toward suicide, grief, and social support. Closeness to the peers lost to suicide was positively correlated with grief and the belief that suicide is not preventable, with grief further elevated in close individuals with high social support from friends. Overall, social support was related to healthy attitudes about suicide including preventability, yet it was also related to some stigmatizing beliefs. Compared with 67 young adults who had not been exposed to a suicide cluster, the exposed sample was more likely to think that suicide is normal but more likely to think of it as incomprehensible. PMID- 24806292 TI - Disentangling Peronospora on Papaver: phylogenetics, taxonomy, nomenclature and host range of downy mildew of opium poppy (Papaver somniferum) and related species. AB - Based on sequence data from ITS rDNA, cox1 and cox2, six Peronospora species are recognised as phylogenetically distinct on various Papaver species. The host ranges of the four already described species P. arborescens, P. argemones, P. cristata and P. meconopsidis are clarified. Based on sequence data and morphology, two new species, P. apula and P. somniferi, are described from Papaver apulum and P. somniferum, respectively. The second Peronospora species parasitizing Papaver somniferum, that was only recently recorded as Peronospora cristata from Tasmania, is shown to represent a distinct taxon, P. meconopsidis, originally described from Meconopsis cambrica. It is shown that P. meconopsidis on Papaver somniferum is also present and widespread in Europe and Asia, but has been overlooked due to confusion with P. somniferi and due to less prominent, localized disease symptoms. Oospores are reported for the first time for P. meconopsidis from Asian collections on Papaver somniferum. Morphological descriptions, illustrations and a key are provided for all described Peronospora species on Papaver. cox1 and cox2 sequence data are confirmed as equally good barcoding loci for reliable Peronospora species identification, whereas ITS rDNA does sometimes not resolve species boundaries. Molecular phylogenetic data reveal high host specificity of Peronospora on Papaver, which has the important phytopathological implication that wild Papaver spp. cannot play any role as primary inoculum source for downy mildew epidemics in cultivated opium poppy crops. PMID- 24806294 TI - Efficient Engraftment of Human Induced Pluripotent Stem Cell-Derived Hepatocyte Like Cells in uPA/SCID Mice by Overexpression of FNK, a Bcl-xL Mutant Gene. AB - Human liver chimeric mice are expected to be applied for drug toxicity tests and human hepatitis virus research. Human induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs) are a highly attractive donor source for the generation of human liver chimeric mice because they can be produced on a large scale and established from an individual. Although these cells have been successfully used to generate human liver chimeric mice, there is still room for improvement in the repopulation efficiency. To enhance the repopulation efficacy, the human iPSC-HLCs were transduced with an adenovirus vector (Ad-FNK) expressing FNK, a hyperactive mutant gene from Bcl-xL, which was expected to inhibit apoptosis in the process of integration into liver parenchyma. We then transplanted Ad-FNK-transduced human iPSC-HLCs into urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice (FNK mice) and evaluated the repopulation efficacy. The antiapoptotic effects of the human iPSC-HLCs were enhanced by FNK overexpression in vitro. Human albumin levels in the transplanted mice were significantly increased by transplantation of Ad-FNK transduced human iPSC-HLCs (about 24,000 ng/ml). Immunohistochemical analysis with an anti-human alphaAT antibody revealed greater repopulation efficacy in the livers of FNK mice than control mice. Interestingly, the expression levels of human hepatocyte-related genes in the human iPSC-HLCs of FNK mice were much higher than those in the human iPSC-HLCs before transplantation. We succeeded in improving the repopulation efficacy of human liver chimeric mice generated by transplanting the Ad-FNK-transduced human iPSC-HLCs into uPA/SCID mice. Our method using ectopic expression of FNK was useful for generating human chimeric mice with high chimerism. PMID- 24806296 TI - A centrifugal fluidic immunoassay for ocular diagnostics with an enzymatically hydrolyzed fluorogenic substrate. AB - We present a novel "Lab-on-a-Disk" platform and demonstrate its capability for rapid and sensitive measurement of vascular endothelial growth factor (VEGF) intended for patients suffering from diabetic retinopathy (DR) and age-related macular degeneration (AMD). This approach combines sedimentation principles applied to microspheres under centrifugal force with signal amplification using an enzyme and a fluorogenic substrate for readout. The simple single channel per assay platform separates, washes and concentrates antibody-coated microspheres from excess label to produce a sensitive fluorogenic response proportional to the amount of VEGF in the sample. This platform has comparable sensitivity to conventional ELISA and can generate a readout within 16-18 min with no sample preparation beyond mixing assay reagents and loading on the disk. In the context of ocular diagnostics, this device has the potential to facilitate accurate dosing of anti-VEGF medications utilized to treat DR and AMD, as well as identify patients whose ocular VEGF levels are not elevated and who would therefore not benefit from standard anti-VEGF medications. PMID- 24806295 TI - Disrupted functional brain connectivity and its association to structural connectivity in amnestic mild cognitive impairment and Alzheimer's disease. AB - Although anomalies in the topological architecture of whole-brain connectivity have been found to be associated with Alzheimer's disease (AD), our understanding about the progression of AD in a functional connectivity (FC) perspective is still rudimentary and few study has explored the function-structure relations in brain networks of AD patients. By using resting-state functional MRI (fMRI), this study firstly investigated organizational alternations in FC networks in 12 AD patients, 15 amnestic mild cognitive impairment (aMCI) patients, and 14 age matched healthy aging subjects and found that all three groups exhibit economical small-world network properties. Nonetheless, we found a decline of the optimal architecture in the progression of AD, represented by a more localized modular organization with less efficient local information transfer. Our results also show that aMCI forms a boundary between normal aging and AD and represents a functional continuum between healthy aging and the earliest signs of dementia. Moreover, we revealed a dissociated relationship between the overall FC and structural connectivity (SC) in AD patients. In this study, diffusion tensor imaging tractography was used to map the structural network of the same individuals. The decreased FC-SC coupling may be indicative of more stringent and less dynamic brain function in AD patients. Our findings provided insightful implications for understanding the pathophysiological mechanisms of brain dysfunctions in aMCI and AD patients and demonstrated that functional disorders can be characterized by multimodal neuroimaging-based metrics. PMID- 24806297 TI - Self-assembly of pyridinium-functionalized anthracenes: molecular-skeleton directed formation of microsheets and microtubes. AB - Two amphiphilic regioisomers, 9-AP (1-[11-(9-anthracenylmethoxy)-11 oxoundecyl]pyridinium bromide), and 2-AP (1-[11-(2-anthracenyl methoxy)-11 oxoundecyl]pyridinium bromide), were synthesized and their assembly behaviors were studied. Due to the anisotropic features of the anthracene structure, different substituted positions on the anthracene ring lead 9-AP and 2-AP to adapt "shaver" and "spatula"-like molecular shapes, respectively, which consequently dictate the structure of their final assemblies. While "shaver" shaped 9-AP assembled into microsheets, driven by pi-pi interactions, "spatula" shaped 2-AP assembled into microtubular structures, promoted primarily by charge transfer interactions. PMID- 24806299 TI - N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis. AB - Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination--when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis. PMID- 24806298 TI - Ischemia/Reperfusion-induced neovascularization in the cerebral cortex of the ovine fetus. AB - Information on the effects of injury on neovascularization in the immature brain is limited. We investigated the effects of ischemia on cerebral cortex neovascularization after the exposure of fetuses to 30 minutes of cerebral ischemia followed by 48 hours of reperfusion (I/R-48), 30 minutes of cerebral ischemia followed by 72 hours of reperfusion (I/R-72), or sham control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortex sections included immunostaining for glial fibrillary acidic protein and collagen type IV (a molecular component of the vascular basal lamina) to determine the glial vascular network in fetal brains and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non I/R fetuses. Cell bodies of reactive proliferating astrocytes, along with large end-feet, surrounded the walls of cerebral cortex microvessels in addition to the thick collagen type IV-enriched basal lamina. Morphometric analysis of the Non I/R group with the I/R-48 and I/R-72 groups revealed increased collagen type IV density in I/R-72 cerebral cortex microvessels (p < 0.01), which also frequently displayed a sprouting appearance characterized by growing tip cells and activated pericytes. Increases in cerebral cortex basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization in fetal cerebral cortices occurs within 72 hours of ischemia. PMID- 24806300 TI - Abnormalities in early markers of muscle involvement support a delay in myogenesis in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is characterized by loss of motor neurons in the spinal cord that results in muscle denervation and profound weakness in affected patients. We sought evidence for primary muscle involvement in the disease during human development by analyzing the expression of several muscle cytoskeletal components (i.e. slow, fast, and developmental myosin, desmin, and vimentin) in fetal or postnatal skeletal muscle samples from 5 SMA cases and 6 controls. At 14 weeks' gestation, SMA samples had higher percentages of myotubes expressing fast myosin and lower percentages of myotubes expressing slow myosin versus control samples. Desmin and vimentin were highly expressed at prenatal stages without notable differences between control and SMA samples, although both proteins showed persistent immunostaining in atrophic fibers in postnatal SMA samples. We also studied the expression of Pax7-positive nuclei as a marker of satellite cells and found no differences between control and SMA prenatal samples. There was, however, a significant increase in satellite cells in postnatal atrophic SMA fibers, suggesting an abnormal myogenic process. Together, these results support the hypothesis of a delay in muscle maturation as one of the primary pathologic components of SMA. Furthermore, myosins and Pax7 may be useful research markers of muscle involvement in this disease. PMID- 24806301 TI - CNS lymphoma: a practical diagnostic approach. AB - The concept and understanding of central nervous system (CNS) lymphoma have greatly evolved in the past few years. Better characterization of a number of lymphoproliferative neoplasms through clinical, immunophenotyping, and molecular studies is reflected in a much more complex WHO Classification of Tumours of Hematopoietic and Lymphoid Tissue. The term "primary CNS lymphoma" is now restricted to primary diffuse large B-cell lymphoma confined to the CNS (and/or to the eye) that occurs in immunocompetent patients. Many other lymphoma subtypes, some of which are primary or exclusive to the CNS, such as lymphomas of the dura and immunodeficiency-associated lymphomas, are excluded from this definition. We describe the clinical and morphologic features of a diverse group of lymphomas occurring in the CNS, including primary CNS lymphoma, primary vitreoretinal lymphoma, lymphomatosis cerebri, Epstein-Barr virus-associated lymphoproliferative disorders, low-grade B-cell lymphoma, T-cell lymphoma, anaplastic large cell lymphoma, intravascular large B-cell lymphoma, and Hodgkin lymphoma. The purpose of this review is to provide a practical approach to the diagnosis of an often-challenging entity, focusing on how to maximize the use of small tissue biopsies and prevent diagnostic traps, which we have encountered with similar cases. Clinical, radiologic, and histologic examples are presented. PMID- 24806302 TI - Mechanisms involved in spinal cord central synapse loss in a mouse model of spinal muscular atrophy. AB - Motoneuron (MN) cell death is the histopathologic hallmark of spinal muscular atrophy (SMA), although MN loss seems to be a late event. Conversely, disruption of afferent synapses on MNs has been shown to occur early in SMA. Using a mouse model of severe SMA (SMNDelta7), we examined the mechanisms involved in impairment of central synapses. We found that MNs underwent progressive degeneration in the course of SMA, with MN loss still occurring at late stages. Loss of afferent inputs to SMA MNs was detected at embryonic stages, long before MN death. Reactive microgliosis and astrogliosis were present in the spinal cord of diseased animals after the onset of MN loss. Ultrastructural observations indicate that dendrites and microglia phagocytose adjacent degenerating presynaptic terminals. Neuronal nitric oxide synthase was upregulated in SMNDelta7 MNs, and there was an increase in phosphorylated myosin light chain expression in synaptic afferents on MNs; these observations implicate nitric oxide in MN deafferentation and suggest that the RhoA/ROCK pathway is activated. Together, our observations suggest that the earliest change occurring in SMNDelta7 mice is the loss of excitatory glutamatergic synaptic inputs to MNs; reduced excitability may enhance their vulnerability to degeneration and death. PMID- 24806303 TI - FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle. AB - Rosette-forming glioneuronal tumors (RGNTs) are rare glioneuronal tumors of the fourth ventricle region that preferentially affect young adults. Despite their histologic similarity with pilocytic astrocytomas (PAs), RGNTs do not harbor KIAA1549-BRAF fusions or BRAF mutations, which represent the most common genetic alteration in PAs. Recently, mutations affecting the hotspot codons Asn546 and Lys656 of fibroblast growth factor receptor 1 (FGFR1) have been described in PAs. They are considered to be the most frequent mechanism of mitogen-activated protein kinase activation, alternative to KIAA1549-BRAF fusion and BRAF mutations. To uncover possible molecular similarities between RGNTs and PAs, we performed a mutational study of FGFR1 in 8 RGNTs. An FGFR1 N546K mutation and an FGFR1 K656E mutation were found in the tumors of 2 patients. Notably, the patient with an FGFR1 K656E mutated RGNT had undergone a resection of a diencephalic pilocytic astrocytoma with pilomyxoid features 5 years before the discovery of the fourth ventricle tumor; the mutational analysis uncovered the presence of the same FGFR1 K656E mutation in the diencephalic tumor. These results indicate that, in addition to histologic similarities, at least a subgroup of RGNTs may show close molecular relationships with PAs. Whether FGFR1 mutated RGNTs represent a specific subset of this rare tumor entity remains to be determined. PMID- 24806304 TI - Chronic proximal axonopathy in rats is associated with long-standing neurofilament depletion in neuromuscular junctions and behavioral deficits. AB - In rodents exposed to 3,3'-iminodipropionitrile (IDPN), neurofilaments (NFs) accumulate in swollen proximal axon segments; this also occurs in motor neurons of patients with amyotrophic lateral sclerosis. We hypothesized that early loss of NFs in neuromuscular junctions (NMJs) in IDPN proximal neuropathy would result in neuromuscular dysfunction and lead to neuromuscular detachment. Adult male rats were given 0 or 15 mmol/L IDPN in drinking water for up to 1 year. The IDPN exposed rats dragged their tails and had impaired endurance in a grip test. Neuromuscular junctions and distal axons were examined in the levator auris longus muscle after 3, 6, 9, and 12 months. Neuromuscular junctions showed a progressive reduction in NF immunolabeling, which became undetectable in up to 70% of the NMJs after 12 months. Neurofilament labeling was also reduced in preterminal axons and in a more proximal axon level within the muscle. Triple label analysis with antisyntaxin demonstrated that the terminals remained in place and usually contained a few minute NF bundles. Electron microscopy revealed the disappearance of terminal NFs, reduced content in synaptic vesicles, and accumulation of multilamellar bodies, but scant degeneration. Thus, IDPN proximal neurofilamentous axonopathy is associated with NF depletion in motor terminals; motor weakness and structural changes in the NMJs suggest impaired synaptic function despite long-term preservation of the NMJs. PMID- 24806305 TI - Reduced ischemic injury after stroke in mice by angiogenic gene delivery via ultrasound-targeted microbubble destruction. AB - Angiogenic gene therapy in patients with cerebral infarcts may have clinical benefit, but its potential is diminished by the difficulty of introducing genes into the brain. We evaluated the safety and efficacy of ultrasound-targeted microbubble destruction (UTMD) for delivery of genes to the brains of normal mice and after transient middle cerebral artery occlusion. In normal mice, disruption of the blood-brain barrier detected with trypan blue staining was reversible within 24 hours of a single UTMD administration. Expression of reporter genes in the brain after UTMD demonstrated successful targeted gene delivery and transfection. Decreased neurologic function after transient middle cerebral artery occlusion was attenuated versus controls at 7 days after UTMD delivery of vascular endothelial growth factor. Ultrasound-targeted microbubble destruction delivery of the VEGF gene resulted in decreased infarct areas, increased vessel density, and reduced apoptosis versus controls. There was no evidence of permanent brain injury throughout the study. Thus, UTMD was a safe, minimally invasive, effective technique for gene delivery to the brain. Vascular endothelial growth factor transfection of brain cells conferred beneficial effects on histopathologic parameters and neurologic function, and stimulated angiogenesis in a mouse stroke model. PMID- 24806307 TI - Exercise training starting at weaning age preserves cardiac pacemaker function in adulthood of diet-induced obese rats. AB - Peripheral sympathetic overdrive in young obese subjects contributes to further aggravation of insulin resistance, diabetes, and hypertension, thus inducing worsening clinical conditions in adulthood. Exercise training has been considered a strategy to repair obesity autonomic dysfunction, thereby reducing the cardiometabolic risk. Therefore, the aim of this study was to assess the effect of early exercise training, starting immediately after weaning, on cardiac autonomic control in diet-induced obese rats. Male Wistar rats (weaning) were divided into four groups: (i) a control group (n = 6); (ii) an exercise-trained control group (n = 6); (iii) a diet-induced obesity group (n = 6); and (iv) an exercise-trained diet-induced obesity group (n = 6). The development of obesity was induced by 9 weeks of palatable diet intake, and the training program was implemented in a motor-driven treadmill (5 times per week) during the same period. After this period, animals were submitted to vein and artery catheter implantation to assess cardiac autonomic balance by methylatropine (3 mg/kg) and propranolol (4 mg/kg) administration. Exercise training increased running performance in both groups (p < 0.05). Exercise training also prevented the increased resting heart rate in obese rats, which seemed to be related to cardiac pacemaker activity preservation (p < 0.05). Additionally, the training program preserved the pressure and bradycardia responses to autonomic blockade in obese rats (p < 0.05). An exercise program beginning at weaning age prevents cardiovascular dysfunction in obese rats, indicating that exercise training may be used as a nonpharmacological therapeutic strategy for the treatment of cardiometabolic diseases. PMID- 24806306 TI - Oligodendrocyte loss during the disease course in a canine model of the lysosomal storage disease fucosidosis. AB - Hypomyelination is a poorly understood feature of many neurodegenerative lysosomal storage diseases, including fucosidosis in children and animals. To gain insight into hypomyelination in fucosidosis, we investigated lysosomal storage, oligodendrocyte death, and axonal and neuron loss in CNS tissues of fucosidosis-affected dogs aged 3 weeks to 42 months using immunohistochemistry, electron microscopy, and gene expression assays. Vacuole accumulation in fucosidosis oligodendrocytes commenced by 5 weeks of age; all oligodendrocytes were affected by 16 weeks. Despite progressive vacuolation, mature oligodendrocyte loss by apoptosis (caspase-6 positive) in the corpus callosum and cerebellar white matter stabilized by 16 weeks, with no further subsequent loss. Axonal neurofilament loss progressed only in late disease, suggesting that disturbed axon-oligodendrocyte interactions are unlikely to be the primary cause of hypomyelination. A 67% decline in the number of Purkinje cell layer oligodendrocytes coincided with a 67% increase in the number of caspase-6 positive Purkinje cells at 16 weeks, suggesting that early oligodendrocyte loss contributes to Purkinje cell apoptosis. Fucosidosis hypomyelination appeared to follow normal spatiotemporal patterns of myelination, with greater loss of oligodendrocytes and larger downregulation of CNP, MAL, and PLP1 genes at 16 weeks in the cerebellum versus the frontal cortex. These studies suggest that survival of oligodendrocytes in fucosidosis is limited during active myelination, although the mechanisms remain unknown. PMID- 24806308 TI - Langevin spin dynamics based on ab initio calculations: numerical schemes and applications. AB - A method is proposed to study the finite-temperature behaviour of small magnetic clusters based on solving the stochastic Landau-Lifshitz-Gilbert equations, where the effective magnetic field is calculated directly during the solution of the dynamical equations from first principles instead of relying on an effective spin Hamiltonian. Different numerical solvers are discussed in the case of a one dimensional Heisenberg chain with nearest-neighbour interactions. We performed detailed investigations for a monatomic chain of ten Co atoms on top of a Au(0 0 1) surface. We found a spiral-like ground state of the spins due to Dzyaloshinsky Moriya interactions, while the finite-temperature magnetic behaviour of the system was well described by a nearest-neighbour Heisenberg model including easy axis anisotropy. PMID- 24806309 TI - Synaptic health. PMID- 24806310 TI - Dammarane-type triterpenoids from Gentianella azurea. AB - Thirteen new dammarane-type triterpenoids (1-13) and four known analogues, gentirigenic acid (14) and the gentirigeosides A, B, and E (15-17), were isolated from Gentianella azurea. Their structures were elucidated by detailed analysis of the NMR, MS, and X-ray crystallographic data. This is the first report of dammarane-type triterpenoids in the Gentianella genus. In addition, the known structures of gentirigenic acid (14) and the gentirigeosides A, B, and E (15-17) were revised based on the X-ray diffraction analysis. Gentirigeoside A (15) was found to inhibit nitric oxide production in RAW 264.7 macrophages with an IC50 value of 6.6 +/- 2.1 MUM. PMID- 24806311 TI - Incisional hernia after liver transplantation: risk factors and health-related quality of life. AB - The aim of this cross-sectional study was to analyze the incidence of incisional hernia after liver transplantation (LT), to determine potential risk factors for their development, and to assess their impact on health-related quality of life (HRQoL). Patients who underwent LT through a J-shaped incision with a minimum follow-up of three months were included. Follow-up was conducted at the outpatient clinic. Short Form 36 (SF-36) and body image questionnaire (BIQ) were used for the assessment of HRQoL. A total of 140 patients was evaluated. The mean follow-up period was 33 (SD 20) months. Sixty patients (43%) were diagnosed with an incisional hernia. Multivariate analysis revealed surgical site infection (OR 5.27, p = 0.001), advanced age (OR 1.05, p = 0.003), and prolonged ICU stay (OR 1.54, p = 0.022) to be independent risk factors for development of incisional hernia after LT. Patients with an incisional hernia experienced significantly diminished HRQoL with respect to physical, social, and mental aspects. In conclusion, patients who undergo LT exhibit a high incidence of incisional hernia, which has a considerable impact on HRQoL. Development of incisional hernia was shown to be related to surgical site infection, advanced age, and prolonged ICU stay. PMID- 24806312 TI - Hepatic cysticercosis: a rare entity. AB - Hepatic cysticercosis is a very rare entity; only four cases have been reported to date. High-resolution ultrasonography of the abdomen is the initial and most reliable modality for evaluation of hepatic cysticercosis. Medical therapy is the mainstay of treatment. We report a case of hepatic cysticercosis in a 28-year-old male who presented with right upper quadrant pain, fever, and jaundice. The article also describes the imaging patterns of hepatic cysticercosis based on different stages of evolution. PMID- 24806314 TI - Plasma irregularities in the D-region ionosphere in association with sprite streamer initiation. AB - Sprites are spectacular optical emissions in the mesosphere induced by transient lightning electric fields above thunderstorms. Although the streamer nature of sprites has been generally accepted, how these filamentary plasmas are initiated remains a subject of active research. Here we present observational and modelling results showing solid evidence of pre-existing plasma irregularities in association with streamer initiation in the D-region ionosphere. The video observations show that before streamer initiation, kilometre-scale spatial structures descend rapidly with the overall diffuse emissions of the sprite halo, but slow down and stop to form the stationary glow in the vicinity of the streamer onset, from where streamers suddenly emerge. The modelling results reproduce the sub-millisecond halo dynamics and demonstrate that the descending halo structures are optical manifestations of the pre-existing plasma irregularities, which might have been produced by thunderstorm or meteor effects on the D-region ionosphere. PMID- 24806315 TI - Hyperemia-free delineation of epicardial and microvascular impairments using a basal index. AB - The assessment of functional coronary lesion severity using intracoronary hemodynamic parameters like the pressure-derived fractional flow reserve and the flow-derived coronary flow reserve are known to rely critically on the establishment of maximal hyperemia. We evaluated a hyperemia-free index, basal pressure drop coefficient (bCDP), that combines pressure and velocity for simultaneous assessment of the status of both epicardial and microvascular circulations. In 23 pigs, simultaneous measurements of distal coronary arterial pressure and flow were performed using a dual-sensor tipped guidewire in the settings of both normal and abnormal microcirculation with the presence of epicardial lesions of area stenosis (AS) < 50% and AS > 50%. The bCDP, a parameter based on fundamental fluid dynamics principles, was calculated as the transtenotic pressure-drop divided by the dynamic pressure in the distal vessel, measured under baseline (without hyperemia) conditions. The group mean values of bCDP for normal (84 +/- 18) and abnormal (124.5 +/- 15.6) microcirculation were significantly different. Similarly, the mean values of bCDP from AS < 50% (72.5 +/- 16.1) and AS > 50% (136 +/- 17.2) were also significantly different (p < 0.05). The bCDP could significantly distinguish between lesions of AS < 50% to AS > 50% under normal microcirculation (52.1 vs. 85.8; p < 0.05) and abnormal microcirculation (84.9 vs. 172; p < 0.05). Further, the bCDP correlated linearly and significantly with the hyperemic parameters FFR (r = 0.42, p < 0.05) and CDP (r = 0.50, p < 0.05). The bCDP is a promising clinical diagnostic parameter that can independently assess the severity of epicardial stenosis and microvascular impairment. We believe that it has an immediate appeal for detection of coronary artery disease if validated clinically. PMID- 24806316 TI - Physicians should declare financial incentives for recruiting minority ethnic patients into clinical trials. PMID- 24806318 TI - Impact of withdrawing antithrombin III administration from management of septic patients with or without disseminated intravascular coagulation. AB - Antithrombin III (ATIII) of low doses (1500-3000 units per day for 3-5 days) has been used for treatment of disseminated intravascular coagulation (DIC) for decades in Japan. In this study, we have examined the impact of ATIII practice change on outcome in critically ill patients with sepsis and DIC. From April 2005 to September 2008, all septic patients admitted to our ICU were divided into two groups: before withdrawing ATIII (period 1) and after withdrawing ATIII (period 2). Patients treated with ATIII in the period 1 and those not treated with ATIII in the period 2 were then matched according to the similar Acute Physiology and Chronic Health Evaluation II scores (+/- 3) and the same diagnosis grouping. Sensitivity analysis was also conducted for patients with DIC. Forty-one out of 98 patients (41.8%) in the period 1 and only one out of 80 patients (1.3%) in the period 2 were treated with ATIII. Thirty pairs of the patients were matched. There was no difference between the two groups regarding the platelet counts and Sepsis-related Organ Failure Assessment scores at day 1 and day 4. A subgroup analysis was conducted with 12 patients diagnosed with DIC out of the 30 pairs. There was no difference between the two DIC groups for platelet counts, Sepsis related organ failure assessment scores and DIC score at day 1 and also day 4. Although not significant, hospital mortality tended lower in the period 2. This study found that withdrawing ATIII administration from management of septic patients with or without DIC did not influence outcome. PMID- 24806317 TI - Effects of CD14 macrophages and proinflammatory cytokines on chondrogenesis in osteoarthritic synovium-derived stem cells. AB - We investigated the effects of CD14 macrophages and proinflammatory cytokines on chondrogenic differentiation of osteoarthritic synovium-derived stem cells (SDSCs). Osteoarthritic synovial fluid was analyzed for interleukin-1beta (IL 1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6. Levels of stem cell surface markers in osteoarthritic SDSCs were evaluated using flow cytometry. CD14 negative cells were obtained using magnetically activated cell sorting. We compared chondrogenic potentials between whole cells and CD14-negative cells in CD14(low) cells and CD14(high) cells, respectively. To assess whether nuclear factor-kappaB (NF-kappaB) and CCAAT/enhancer-binding protein beta (C/EBPbeta) modulate IL-1beta-induced alterations in chondrogenic potential, we performed small interfering RNA transfection. We observed a significant correlation between the CD14 ratio in osteoarthritic SDSCs and IL-1beta and TNF-alpha in osteoarthritic synovial fluid. Phenotypic characterization of whole cells and CD14-negative cells showed no significant differences in levels of stem cell markers. mRNA expression of type II collagen was higher in CD14-negative cell pellets than in whole cell pellets. Immunohistochemical staining indicated higher levels of type II collagen in the CD14-negative cell pellets of CD14(high) cells than in whole cell pellets of CD14(high) cells. As expected, IL-1beta and TNF alpha significantly inhibited the expression of chondrogenic-related genes in SDSCs, an effect which was antagonized by knockdown of NF-kappaB and C/EBPbeta. Our results suggest that depletion of CD14(+) synovial macrophages leads to improved chondrogenic potential in CD14(high) cell populations in osteoarthritic SDSCs, and that NF-kappaB (RelA) and C/EBPbeta are critical factors mediating IL 1beta-induced suppression of the chondrogenic potential of human SDSCs. PMID- 24806319 TI - Microvascular anastomosis using Ankaferd blood stopper: demonstration of long term histopathologic effects on vascular tissue. AB - Ankaferd blood stopper (ABS) (Ankaferd Ilac Kozmetik A.S., Turkey) is a medicinal plant extract, which is used in Turkish traditional medicine as a haemostatic agent. The aim of this study was to investigate the haemostatic effect of ABS in preventing microvascular leakage on an anastomosis site and to look into its long term impact on vascular tissue. Twenty-one Wistar albino rats were randomly divided into three groups. The animals in the second and third groups were pretreated with acetylsalicylic acid. All of the right femoral arteries were divided and anastomosed in an end-to-end fashion. Following microvascular anastomosis, saline-soaked gauze tampons were applied in the first and second groups. In the third group, ABS-soaked tampons were applied to the anastomosis sites. The mean bleeding time of group 3 was significantly shorter than group 2 and group 1. Three weeks after the operation, there were aneurysms on all of the anastomosis sites in group 3 and none of the anastomoses were patent. Histologic examination demonstrated increased inflammatory cell infiltration, tunica media degeneration and contraction of tunica intima in group 3. This is the first study reporting the long-term effects of ABS on microvascular anastomosis. Contrary to previously reported studies, this agent is not appropriate for use on injured or anastomosed vessels. PMID- 24806320 TI - Evaluating and monitoring the efficacy of recombinant activated factor VIIa in patients with haemophilia and inhibitors. AB - Although the use of bypassing agents has dramatically improved the management of haemophilia in patients with inhibitors, questions remain regarding optimal dosing regimens and methodology for monitoring their clinical effectiveness. In this study, we evaluated the efficacy and safety of two different doses of recombinant activated factor VIIa (rFVIIa) in patients with haemophilia and inhibitors and assessed the feasibility of using thromboelastography (TEG) and thrombin generation assays (TGA) for monitoring the response to rFVIIa. Six patients aged 9-49 years with congenital or acquired haemophilia with inhibitors who experienced a total of nine bleeding episodes were included. Seven episodes were treated with conventional rFVIIa dosing (72.7-109.1 MUg/kg), and two episodes were treated with a single high-dose regimen (254.6-264.0 MUg/kg). Clinical and haemostatic responses were evaluated. Haemostasis was assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT), factor VII coagulant activity (FVII:C), TEG, and TGA. Six out of seven (85.7%) bleeding episodes responded to conventional rFVIIa dosing, and half (50%) responded to the high-dose regimen. No relationships between PT, aPTT, and FVII:C levels and clinical outcome were observed. However, changes in TEG and TGA parameters tended to correspond to clinical response, although large inter-individual variation in rFVIIa efficacy was noted. A good response was seen with rFVIIa in treating acute bleeding episodes in patients with haemophilia and inhibitors. Because changes in TEG and TGA may correlate with clinical outcomes of rFVIIa, TEG and TGA may be useful for monitoring rFVIIa activity in inhibitor-positive haemophilia. PMID- 24806321 TI - Tissue factor and tissue factor pathway inhibitor in women with a past history of preeclampsia: implication for a hypercoagulable state postpregnancy. AB - Preeclampsia (P-EC) is a multisystem disorder of pregnancy whose cause and pathogenesis remain poorly understood. However, abnormal haemostasis and endothelial dysfunction are thought to be implicated. Women with a past medical history of P-EC have a baseline hypercoagulable state postpregnancy. The aim of this study is to examine the relationship between tissue factor (TF) and TF pathway inhibitor (TFPI) in women who have had P-EC within the last 3 years (more than 6 months postpartum) and their normal counterparts. Blood specimens were collected from women known to have had P-EC within the last 3 years (n = 26) and aged-matched healthy women without past history of P-EC in previous pregnancy (n = 26). Plasma TF and TFPI levels were measured using ELISAs. Women who have had P EC showed increased TF levels compared with their normal counterparts, whereas TFPI levels were reduced. Neither parameter differed significantly when the groups were tested against each other. Interestingly, the TF/TFPI ratio was significantly increased (P = 0.024) when the two groups were compared. In summary, there was a trend towards increased TF and reduced TFPI levels in the P EC group. Such a tendency was not statistically significant. However, the TF/TFPI ratio was significantly increased when the groups were compared. Our findings suggest an imbalance between TF/TFPI levels in women with past history of P-EC postpregnancy. This may contribute to the development of maternal hypercoagulable states and may predispose women with a history of P-EC to cardiovascular risks later in life. PMID- 24806322 TI - Clinical experience with recombinant tissue plasminogen activator in the management of intracardiac and arterial thrombosis in children. AB - Thrombotic events may complicate the clinical course of many pediatric diseases. Drugs for therapeutic thrombolysis include streptokinase, urokinase and tissue plasminogen activator (t-PA). There is less experience with recombinant t-PA (rt PA) in children. We aimed to present our experiences with rt-PA in children with intracardiac or peripheral arterial thrombus. We retrospectively reviewed the children who received rt-PA for thrombus. Twenty-two children (13 boys, 9 girls; age range: 1 day-17 years) with intracardiac (n = 5), prosthetic heart valve (n = 2) and peripheral arterial (n = 15) thrombus were evaluated. Twelve (54%) had congenital heart disease, two (9%) had rheumatic heart disease, three (14%) had leukemia and five (23%) had documented sepsis, prematurity or meconium aspiration syndrome. Ten of the 15 peripheral arterial thromboses were observed following cardiac catheterization. Three of the five intracardiac thrombi were detected in children with leukemia. All children received low-molecular-weight heparin. rt-PA (alteplase) infusion (at a dose of 0.01-0.5 mg/kg per h) was administered for different time periods (3-66 h). Ten of 11 patients with peripheral arterial occlusion and three of five patients with intracardiac thrombus showed full recovery. However, there was no response in two patients with intracardiac thrombus and in two patients with heart valve thrombus. Nose bleeding, melena and decreased serum fibrinogen concentration were observed in seven patients during the rt-PA infusion. All bleedings stopped after cessation of rt-PA infusion, and no blood transfusion was required in any patient. We conclude that rt-PA infusion seems effective and well tolerated in children for the treatment of peripheral arterial and intracardiac thrombus. PMID- 24806323 TI - miR-96 and miR-330 overexpressed and targeted AQP5 in lipopolysaccharide-induced rat lung damage of disseminated intravascular coagulation. AB - Disseminated intravascular coagulation (DIC) is a severe clinical condition that can lead to or aggravate the development of multiple organ dysfunction syndrome. Of all types of organ damage, lung damage is the most frequent and most severe. In DIC patients, lung damage is primarily characterized by pulmonary edema. Aquaporin (AQP) 5 is the chief AQP in the lungs and it plays a key role in many processes, including water transport in normal and abnormal lungs. Here we demonstrate that expression of AQP5 and two microRNAs, miR-96 and miR-330, in rat lung of lipopolysaccharide (LPS)-induced DIC. We also show that both miR-96 and miR-330 can regulate the expression of AQP5 by binding with its 3'-untranslated region (UTR) by luciferase activity assay. These results suggest that microRNAs are involved in lung damage in LPS-induced rat DIC and can be a potential target for molecular therapy. PMID- 24806324 TI - Soluble adhesion molecules as markers of native arteriovenous fistula thrombosis in children on uremia. AB - Vascular access represents a lifeline for children undergoing hemodialysis. A failure of vascular access among patients receiving regular hemodialysis is associated with increased morbidity, mortality and costs. We assessed the possibility of using soluble adhesion molecules as reliable predictors of vascular access failure in children on hemodialysis. Moreover, we evaluated whether there is an association among the different studied adhesion molecules in hemodialysis patients with thrombosed and non-thrombosed arteriovenous fistula fistulas (AVFs). This study included 55 hemodialysis children, 36 with good access and 19 with access failure, and 20 healthy volunteers. Forty-four patients had native AVFs and 11 patients had tunneled permanent catheter (11with thrombosed and 33 with non-thrombosed AVFs). Serum-soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin) and soluble P-selectin (sP-selectin) were measured using ELISA technique. A significant increase was found in the levels of sVCAM-1, sICAM-1, sE-selectin and sP-selectin versus controls and all hemodialysis patients, hemodialysis patients with good access and hemodialysis patients with access failure (P=0.001 for sVCAM-1 and sICAM-1 and P=0.0001 for sE selectin and sP-selectin). A significant increase was found in the levels of sVCAM-1, sE-selectin and sP-selectin in both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs versus controls (P=0.0001 for all parameters). There was significant difference between both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs as regard to sVCAM-1 (54.64+/-30.82 versus 25.69+/-27.96ng/ml, P=0.04). Both sICAM-1 and sP-selectin were positively correlated with the erythropoietin (EPO) dose in hemodialysis children (r=0.31, P=0.04 and r=0.32, P=0.04, respectively). A significant positive association was found between E-selectin and sP-selectin in hemodialysis patients with thrombosed AVFs (r=0.83, P=0.04). There was a significant correlation between sVCAM-1 and EPO dose in thrombosed AVF group (r=0.84, P=0.01). The assessment of serum sVCAM-1 might be useful for the identification of the chronic hemodialysis patients at an increased risk for native AVFs thrombosis. The role of EPO in vascular access failure should be taken into consideration. The clinical relevance of these observations warrants further investigations. PMID- 24806325 TI - Endovascular treatment of chronic cerebro spinal venous insufficiency in patients with multiple sclerosis modifies circulating markers of endothelial dysfunction and coagulation activation: a prospective study. AB - We performed a monocentric observational prospective study to evaluate coagulation activation and endothelial dysfunction parameters in patients with multiple sclerosis undergoing endovascular treatment for cerebro-spinal-venous insufficiency. Between February 2011 and July 2012, 144 endovascular procedures in 110 patients with multiple sclerosis and chronical cerebro-spinal venous insufficiency were performed and they were prospectively analyzed. Each patient was included in the study according to previously published criteria, assessed by the investigators before enrollment. Endothelial dysfunction and coagulation activation parameters were determined before the procedure and during follow-up at 1, 3, 6, 9, 12, 15 and 18 months after treatment, respectively. After the endovascular procedure, patients were treated with standard therapies, with the addition of mesoglycan. Fifty-five percent of patients experienced a favorable outcome of multiple sclerosis within 1 month after treatment, 25% regressed in the following 3 months, 24.9% did not experience any benefit. In only 0.1% patients, acute recurrence was observed and it was treated with high-dose immunosuppressive therapy. No major complications were observed. Coagulation activation and endothelial dysfunction parameters were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. Endovascular procedures performed by a qualified staff are well tolerated; they can be associated with other currently adopted treatments. Correlations between inflammation, coagulation activation and neurodegenerative disorders are here supported by the observed variations in plasma levels of markers of coagulation activation and endothelial dysfunction. PMID- 24806326 TI - Predictors of thrombus burden and no-reflow of infarct-related artery in patients with ST-segment elevation myocardial infarction: importance of platelet indices. AB - Preprocedural high-thrombus burden (HTB) of infarct-related artery (IRA) is a harbinger of procedural complications following primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI). The HTB of IRA can lead to poor outcomes by various mechanisms, including no reflow phenomenon, increased myocardial necrosis and with subsequent reduced survival benefit at follow-up. In this study, we investigated the relationship between all platelet indices on admission and thrombus burden and the no-reflow phenomenon after primary PCI of IRA in patients with STEMI. We retrospectively enrolled 475 patients with STEMI undergoing primary PCI. Study population was divided into two groups according to the thrombolysis in myocardial infarction thrombus grade of IRA as low-thrombus burden or HTB. There were no statistically significant differences in platelet indices, including platelet count, platelet large cell ratio (P-LCR), mean platelet volume (MPV) and platelet distribution with (PDW) among the groups. However, in the subgroup analysis, P-LCR, MPV and PDW were significantly higher in the no-reflow patients than reflow patients despite similar platelet count (P for all < 0.001). The cutoff value of P-LCR for predicting no-reflow was 26.5% with a sensitivity of 67.0% and a specificity of 62% (area under the curve, 0.689; 95% confidence interval, 0.614-0.765; P < 0.001). Furthermore, P-LCR, MPV and PDW had similar AUC (0.689, P < 0.001; 0.688, P < 0.001; and 0.677, P < 0.001; respectively) for predicting no-reflow phenomenon after primary PCI. As a result, all of the platelet indices have no effect on thrombus load of IRA, however, these parameters seem to impair epicardial perfusion after primary PCI. PMID- 24806327 TI - Development of an engineered bioluminescent reporter phage for the sensitive detection of viable Salmonella typhimurium. AB - Because foodborne illnesses continuously threaten public health, rapid and sensitive detection of pathogens in food has become an important issue. As an alternative to time-consuming and laborious conventional detection methods, a technique using recombinant reporter phages has been developed. Here, we developed an advanced bioluminescent reporter phage SPC32H-CDABE by inserting a bacterial luxCDABE operon into the Salmonella temperate phage SPC32H genome. Whole SPC32H genome sequencing enabled the selection of nonessential genes, which can be replaced with approximately 6-kb luxCDABE operon, which provides both luciferase (LuxAB) and its substrate, fatty aldehyde, as generated by fatty acid reductase (LuxCDE). Thus, the SPC32H-CDABE detection assay is simpler and more efficient compared to the luxAB-based assay because the substrate addition step is excluded. At least 20 CFU/mL of pure S. Typhimurium culture was detectable using SPC32H-CDABE within 2 h, and the signals increased proportionally to the number of cells contaminated in lettuce, sliced pork, and milk. These results thereby demonstrate that this phage successfully detects live Salmonella without appreciable interference from food components. Furthermore, the presented data suggest that SPC32H-CDABE represents a promising easy-to-use diagnostic tool for the detection of Salmonella contamination in food. PMID- 24806328 TI - Pathogen inactivation efficacy of Mirasol PRT System and Intercept Blood System for non-leucoreduced platelet-rich plasma-derived platelets suspended in plasma. AB - BACKGROUND AND OBJECTIVES: This study was conducted to evaluate the efficacy of pathogen inactivation (PI) in non-leucoreduced platelet-rich plasma-derived platelets suspended in plasma using the Mirasol PRT System and the Intercept Blood System. METHODS: Platelets were pooled using the Acrodose PL system and separated into two aliquots for Mirasol and Intercept treatment. Four replicates of each viral strain were used for the evaluation. For bacteria, both low-titre (45-152 CFU/unit) inoculation and high-titre (7.34-10.18 log CFU/unit) inoculation with two replicates for each bacterial strain were used. Platelets with non-detectable bacterial growth and platelets inoculated with a low titre were stored for 5 days, and culture was performed with the BacT/ALERT system. RESULTS: The inactivation efficacy expressed as log reduction for Mirasol and Intercept systems for viruses was as follows: human immunodeficiency virus 1, >=4.19 vs. >=4.23; bovine viral diarrhoea virus, 1.83 vs. >=6.03; pseudorabies virus, 2.73 vs. >=5.20; hepatitis A virus, 0.62 vs. 0.76; and porcine parvovirus, 0.28 vs. 0.38. The inactivation efficacy for bacteria was as follows: Escherichia coli, 5.45 vs. >=9.22; Staphylococcus aureus, 4.26 vs. >=10.11; and Bacillus subtilis, 5.09 vs. >=7.74. Postinactivation bacterial growth in platelets inoculated with a low titre of S. aureus or B. subtilis was detected only with Mirasol. CONCLUSION: Pathogen inactivation efficacy of Intercept for enveloped viruses was found to be satisfactory. Mirasol showed satisfactory inactivation efficacy for HIV-1 only. The two selected non-enveloped viruses were not inactivated by both systems. Inactivation efficacy of Intercept was more robust for all bacteria tested at high or low titres. PMID- 24806329 TI - Droplet topology control of Janus emulsion prepared in one-step high energy mixing. AB - Droplet topology of a Janus emulsion in a vegetable oil (VO)/silicone oil (SO)/Tween 80 aqueous solution (Aq) system prepared in a one-step high energy mixing was investigated, mainly by image observation. Quantitative information of the topology was analyzed referring to the curvature of VO/SO interface, the location of contact plane, and the volume ratio of VO/SO within individual droplets. The results show that the "stable Janus emulsion" region in the phase map enlarges with surfactant concentration. The average volume ratio of two oil lobes within an individual Janus droplet agrees with the emulsion composition in the "stable Janus emulsion" region, which means that the droplet topology can be controlled by the emulsion preparation process within realistic limits. The volume ratio of VO/SO within individual droplet ranges from about 0.54 to 0.17 in the VO/SO/3 wt% Tween 80(Aq) system, beyond which separate VO and SO droplets are observed. The topology of a Janus droplet is found to be determined by both the contact angle of three liquids in the contact line and the location of the contact plane. The contact angle of the oil cap is determined by the interfacial tension referring to the local equilibrium. The location of the contact plane is the dominant factor determining the volume ratio of two oil lobes. Composition change in the emulsion results in the corresponding tune of the location of contact plane and subsequently, the volume ratio of two oils within Janus droplets. PMID- 24806331 TI - Explaining racial and ethnic disparities in cholesterol screening. AB - OBJECTIVE: To determine whether racial and ethnic disparities in cholesterol screening persist after controlling for socioeconomic status, access to care and language. METHODS: Data were obtained from the 2011 Behavioral Risk Factor Surveillance System for men aged 35 and older and women aged 45 and older in accordance with the United States Preventive Services Task Force guidelines. Self reported cholesterol screening data are presented for 389,039 respondents reflecting over 141million people. Sequential logistic regression models of the likelihood of never having been screened are presented adjusted for demographic characteristics, health status, behavioral risk factors, socioeconomic status, health care access, and questionnaire language. RESULTS: A total of 9.1% of respondents, reflecting almost 13million individuals, reported never having been screened. After adjustment for socioeconomic status, health care access and Spanish language, disparities between whites and Blacks and Hispanics, but not Asians and Pacific Islanders, were eliminated. CONCLUSIONS: Lower socioeconomic status, lack of healthcare access and language barriers explained most of the racial and ethnic disparities in cholesterol screening. Expanding insurance coverage, simplifying cardiac risk assessment and improving access to culturally and linguistically appropriate care hold the greatest promise for improving cardiovascular disease screening and treatment for vulnerable populations. PMID- 24806330 TI - Evaluation of urinary prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG score changes when starting androgen-deprivation therapy with triptorelin 6-month formulation in patients with locally advanced and metastatic prostate cancer. AB - OBJECTIVE: To assess prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG scores in patients with advanced and metastatic prostate cancer at baseline and after 6 months of treatment with triptorelin 22.5 mg, and analyse these scores in patient groups defined by different disease characteristics. PATIENTS AND METHODS: The Triptocare study was a prospective, open-label, multicentre, single-arm, Phase III study of triptorelin 22.5 mg in men with locally advanced or metastatic prostate cancer, who were naive to androgen-deprivation therapy (ADT). The primary objective was to model the urinary PCA3 change at 6 months, according to baseline variables. Other outcome measures included urinary PCA3 and TMPRSS2-ERG scores and statuses, and serum testosterone and prostate-specific antigen (PSA) levels at baseline and at 1, 3 and 6 months after initiation of ADT. Safety was assessed by recording adverse events and changes in laboratory parameters. RESULTS: The intent-to-treat population comprised 322 patients; 39 (12.1%) had non-assessable PCA3 scores at baseline, and 109/322 (33.9%), 215/313 (68.7%) and 232/298 (77.9%) had non-assessable PCA3 scores at 1, 3 and 6 months, respectively. Baseline Gleason score was the only variable associated with non assessability of PCA3 score at 6 months (P = 0.017) - the hazard of having a non assessable PCA3 score at 6 months was 1.824-fold higher (95% confidence interval 1.186-2.805) in patients with a Gleason score >=8 vs those with a Gleason score <=6. The median PCA3 scores at baseline were significantly higher in patients aged >=65 years vs those aged <65 years and in patients with a serum PSA level <100 ng/mL vs those with serum PSA level of >200 ng/mL. The median PCA3 score was significantly lower in patients with metastasis than in patients with no metastasis or unknown metastasis status. TMPRSS2-ERG scores >=35 were considered positive (n = 149 [51.6%]). Age, presence of metastasis, PSA level and Gleason score at baseline were not associated with a significant difference in the proportion of TMPRSS2-ERG-positive scores. The median serum PSA levels decreased from 45.5 ng/mL at baseline to 1.2 ng/mL after 6 months, and as expected, >90% of patients achieved castrate levels of testosterone (<50 ng/dL) at 1, 3, and 6 months during triptorelin treatment. The safety profile reported from this study is consistent with the known safety profile of triptorelin. CONCLUSION: These data from the Triptocare study suggest that urinary PCA3 or TMPRSS2-ERG score are not reliable markers of cancer stage in advanced prostate cancer. Urinary PCA3 and TMPRSS2-ERG scores do not appear to be useful in assessing response to ADT in advanced prostate cancer, with most patients having non-assessable scores after 6 months of treatment. PMID- 24806332 TI - Knockdown of IRX2 inhibits osteosarcoma cell proliferation and invasion by the AKT/MMP9 signaling pathway. AB - Osteosarcoma is the most common type of human primary malignant bone tumor with a potential propensity for local invasion and distant metastasis. Thus, this study focused on the expression and roles of IRX2 in the development of osteosarcoma. The mRNA expression levels of IRX2 in tissue samples of 69 cases of human osteosarcoma were detected by a quantitative polymerase chain reaction assay. The associations between the expression levels of IRX2 and the pathological features of the tumor tissues were analyzed. Functional studies were performed by MTT and Matrigel invasion assays following IRX2 knockdown with a lentivirus vector. Western blotting was used to assay the protein expression levels of IRX2, p-AKT and matrix metalloproteinases (MMP). The results revealed that the expression levels of IRX2 were significantly increased in the primary human osteosarcoma tissues compared with those in the normal tissues, and the increase was significantly correlated with the tumor progression and prognosis of the patients. Furthermore, the proliferation and invasion of the cells were suppressed following IRX2 knockdown. Additionally, the mechanism by which IRX2 promoted cell proliferation and invasion by activating AKT and MMP9 was detected. In conclusion, these results indicated that IRX2 promotes proliferation and invasion in osteosarcoma and implicated the potential of IRX2 in cancer therapy. PMID- 24806333 TI - Improvements in the application and reporting of advanced Bland-Altman methods of comparison. AB - Bland and Altman have developed a measure called "limits of agreement" to assess correspondence of two methods of clinical measurement. In many circumstances, comparisons are made using several paired measurements in each individual subject. If such measurements are considered as statistically independent pairs, rather than as sets of measurements from separate individuals, limits of agreement will be too narrow. In addition, the confidence intervals for these limits will also be too narrow. Suitable software to compute valid limits of agreement and their confidence intervals is not readily available. Therefore, we set out to provide a freely available implementation accompanied by a formal description of the more advanced Bland-Altman comparison methods. We validate the implementation using simulated data, and demonstrate the effects caused by failing to take the presence of multiple paired measurements per individual properly into account. We propose a standard format of reporting that would improve analysis and interpretation of comparison studies. PMID- 24806336 TI - Synergistic effect of dual-functionalized fibrous scaffold with BCP and RGD containing peptide for improved osteogenic differentiation. AB - Over the last decade, bone tissue engineering scaffolds have been advanced owing to the bioceramic incorporation and biomimetic modification. In this report, a dual-functional fibrous scaffold with a bioceramic and biomolecule is developed, and a combined effect of a dual-modification is investigated. Biphasic calcium phosphate (BCP) is incorporated in electrospun poly (L-lactide) scaffolds, and Arg-Gly-Asp (RGD) peptide is then conjugated through the graft polymerization of acrylic acid by gamma-ray irradiation. The scaffolds exhibit the intrinsic properties of BCP as well as RGD peptide, and only RGD peptide improves an adhesion and proliferation of the human mesenchymal stem cell. However, alkaline phosphatase activity and calcium formation are synergistically improved by the BCP and RGD peptide indicating that a favorable microenvironment is constructed for bone formation. Therefore, this combination strategy with bioceramic and biomolecule can be a useful tool for the bone tissue engineering. PMID- 24806334 TI - Prognostic utility of Hyams histological grading and Kadish-Morita staging systems for esthesioneuroblastoma outcomes. AB - Esthesioneuroblastoma (ENB) is derived from the specialized olfactory neuroepithelium. Hyams grading and Kadish staging have been used to prognosticate and to guide treatment decisions. In this study, we sought to validate the prognostic utility of these systems in a large ENB cohort. We retrospectively analyzed the records of patients with ENB who had been evaluated and treated at our institution. The association of grade and stage with prognostic outcome was assessed; the Kaplan-Meier estimator was used to generate 5-year OS and DFS curves. Out of 124 cases we identified, 121 were assessed for grading and 109 for staging. Review of the tissue samples revealed that 62 % of tumors were low grade (I/II) and 21 % were high grade (III/IV); 17 % of tumors were metastasis. The OS rate was 75 % at 5 years. The DFS was 60 % at 5 years. The OS was significantly worse for metastatic ENB (low-grade ENB vs metastatic ENB p = 0.01598); the DFS was significantly worse for high grade versus low grade ENB. Of the 109 cases that had been staged, 16 % were stage A, 33 % stage B, 43 % stage C, and 8 % stage D. In the A, B, and C groups, there were no significant differences between recurrence, distant metastasis, or 5-year survival rates. Statistical significance was not reached with the T, N, M and overall staging system. Age cutoff of 65 years reliably predicted OS. High grade of ENB was significantly associated with poor outcome, while advanced stage was not associated with poor outcome in this large cohort. Grading should certainly be considered in prognostication and treatment decisions for ENB. PMID- 24806337 TI - Measuring the speed of aging across population subgroups. AB - People in different subgroups age at different rates. Surveys containing biomarkers can be used to assess these subgroup differences. We illustrate this using hand-grip strength to produce an easily interpretable, physical-based measure that allows us to compare characteristic-based ages across educational subgroups in the United States. Hand-grip strength has been shown to be a good predictor of future mortality and morbidity, and therefore a useful indicator of population aging. Data from the Health and Retirement Survey (HRS) were used. Two education subgroups were distinguished, those with less than a high school diploma and those with more education. Regressions on hand-grip strength were run for each sex and race using age and education, their interactions and other covariates as independent variables. Ages of identical mean hand-grip strength across education groups were compared for people in the age range 60 to 80. The hand-grip strength of 65 year old white males with less education was the equivalent to that of 69.6 (68.2, 70.9) year old white men with more education, indicating that the more educated men had aged more slowly. This is a constant characteristic age, as defined in the Sanderson and Scherbov article "The characteristics approach to the measurement of population aging" published 2013 in Population and Development Review. Sixty-five year old white females with less education had the same average hand-grip strength as 69.4 (68.2, 70.7) year old white women with more education. African-American women at ages 60 and 65 with more education also aged more slowly than their less educated counterparts. African American men with more education aged at about the same rate as those with less education. This paper expands the toolkit of those interested in population aging by showing how survey data can be used to measure the differential extent of aging across subpopulations. PMID- 24806338 TI - Development of a traceable linker containing a thiol-responsive amino acid for the enrichment and selective labelling of target proteins. AB - A traceable linker that is potentially applicable to identification of a target protein of bioactive compounds was developed. It enabled not only thiol-induced cleavage of the linker for enrichment of the target protein but also selective labelling to pick out the target from contaminated non-target proteins for facile identification. PMID- 24806339 TI - Timing of stereotactic radiosurgery and surgery and wound healing in patients with spinal tumors: a systematic review and expert opinions. AB - BACKGROUND AND PURPOSE: Stereotactic radiosurgery (SRS) and surgery may be used in combination to manage cord compression due to spinal tumors. Procedure sequence and interval affect wound healing. We aimed to review the evidence on effects of timing and sequence of surgery and SRS on wound healing and bone fusion in patients with spine tumors. MATERIALS AND METHODS: We performed a comprehensive literature search (Medline, Embase, Google Scholar, Cochrane Database of Systematic Reviews) to identify relevant studies published in 2000 2011. Additional reports were identified in reference lists from relevant papers. Case reports and series discussing patients aged ?18 with primary or metastatic tumors to the spine who underwent surgical excision with/without instrumentation and SRS before or after surgery were included. The apparent relationship of procedure sequence and interval on wound healing and bone fusion was assessed. RESULTS: Evidence on outcomes following treatment with SRS and surgery was provided in 31 studies; neither wound healing nor bone fusion were endpoints in any study. Wound healing complications were discussed in six studies (20%) including 88 patients treated with both modalities. Animal studies and limited evidence in humans suggest that at least 1 week is indicated between SRS and surgery or surgery and SRS. CONCLUSIONS: Evidence to guide decisions regarding the sequence and timing of surgery and SRS with respect to wound healing is limited. Consistent reporting of wound healing complications will improve ability to develop guidelines for optimal treatment of spinal tumors. PMID- 24806340 TI - Effects of estradiol and methoxychlor on Leydig cell regeneration in the adult rat testis. AB - The objective of the present study is to determine whether methoxychlor (MXC) exposure in adulthood affects rat Leydig cell regeneration and to compare its effects with estradiol (E2). Adult 90-day-old male Sprague-Dawley rats received ethane dimethane sulfonate (EDS) to eliminate the adult Leydig cell population. Subsequently, rats were randomly assigned to four groups and gavaged with corn oil (control), 0.25 mg/kg E2 and 10 or 100 mg/kg MXC daily from days 5 to 30 post EDS treatment. The results showed that MXC and E2 reduced serum testosterone levels on day 58 post-EDS treatment. qPCR showed Hsd17b3 mRNA levels were downregulated 7-15 fold by E2 and MXC, indicating that development of the new population of Leydig cells was arrested at the earlier stage. This observation was supported by the results of histochemical staining, which demonstrated that Leydig cells in MXC-treated testis on day 58 post-EDS treatment were mostly progenitor Leydig cells. However, Pdgfb mRNA levels were downregulated, while Lif transcript levels were increased by MXC. In contrast, E2 did not affect gene expression for these growth factors. In conclusion, our findings indicated that both MXC and E2 delayed rat Leydig cell regeneration in the EDS-treated model, presumably acting by different mechanisms. PMID- 24806341 TI - Treatment with Panax ginseng antagonizes the estrogen decline in ovariectomized mice. AB - Ginseng is a popular herb for alleviating menopausal symptoms; however, no conclusive scientific data has shown ginseng as being efficient in such therapies. The present study was designed to evaluate the estrogenic efficacy of ginseng on reproductive target tissues of ovariectomized (OVX) mice. The OVX mice were treated with ginseng at doses of 12.0, 18.0 and 24.0 g/kg per day for four weeks. Ginseng treatments restored the estrus cycle and demonstrated significant estrogenic activity, as indicated by the reversal of the atrophy of the uterus and vagina, upregulation of estrogen receptor (ER) alpha and ER beta expression at the protein and mRNA level in the reproductive tissues, where ER alpha upregulation was stronger than that of ER beta. Meanwhile, treatment with ginseng significantly increased adrenal gland weight and serum estradiol and clearly decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in circulation. Notably, the largest changes in these parameters were found at the highest dose of 24.0 g/kg. Moreover, ginseng at 18.0 g/kg resulted in the greatest decrease in weight gain caused by ovariectomy. The data suggest that ginseng estrogenic responses show tissue variation that reflects different affinities of ERs for ginseng components. This study demonstrates that ginseng activity is mediated through estrogenic components and provides further evidence for ginseng treatment of postmenopausal symptoms. PMID- 24806342 TI - Alpha-bulges in G protein-coupled receptors. AB - Agonist binding is related to a series of motions in G protein-coupled receptors (GPCRs) that result in the separation of transmembrane helices III and VI at their cytosolic ends and subsequent G protein binding. A large number of smaller motions also seem to be associated with activation. Most helices in GPCRs are highly irregular and often contain kinks, with extensive literature already available about the role of prolines in kink formation and the precise function of these kinks. GPCR transmembrane helices also contain many alpha-bulges. In this article we aim to draw attention to the role of these alpha-bulges in ligand and G-protein binding, as well as their role in several aspects of the mobility associated with GPCR activation. This mobility includes regularization and translation of helix III in the extracellular direction, a rotation of the entire helix VI, an inward movement of the helices near the extracellular side, and a concerted motion of the cytosolic ends of the helices that makes their orientation appear more circular and that opens up space for the G protein to bind. In several cases, alpha-bulges either appear or disappear as part of the activation process. PMID- 24806344 TI - The canonical Notch signaling was involved in the regulation of intestinal epithelial cells apoptosis after intestinal ischemia/reperfusion injury. AB - Notch signaling plays a critical role in the maintenance of intestinal homeostasis. The aim of the present study was to investigate the role of Notch signaling in the apoptosis of intestinal epithelial cells after intestinal ischemia reperfusion (I/R) injury. Male C57BL/6 mice were subjected to sham operation or I/R injury. Intestinal tissue samples were collected at 12 h after reperfusion. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) staining showed that intestinal I/R injury induced significantly increased apoptosis of intestinal epithelial cells. Meanwhile, the mRNA expression of Jagged1, DLL1, Notch2, and Hes5, and protein expression of NICD2 and Hes5 were increased significantly after I/R injury in intestinal epithelial cells. In an in vitro IEC-6 culture model, flow cytometry analyses showed that inhibition of Notch signaling by gamma-secretase inhibitor DAPT and the suppression of Hes5 expression using siRNA both significantly increased the apoptosis of IEC-6 cells under the condition of hypoxia/ reoxygenation (H/R). In conclusion, the Notch2/Hes5 signaling pathway was activated and involved in the regulation of intestinal epithelial cells apoptosis in intestinal I/R injury. PMID- 24806343 TI - Biomarkers in Alzheimer's disease analysis by mass spectrometry-based proteomics. AB - Alzheimer's disease (AD) is a common chronic and destructive disease. The early diagnosis of AD is difficult, thus the need for clinically applicable biomarkers development is growing rapidly. There are many methods to biomarker discovery and identification. In this review, we aim to summarize Mass spectrometry (MS)-based proteomics studies on AD and discuss thoroughly the methods to identify candidate biomarkers in cerebrospinal fluid (CSF) and blood. This review will also discuss the potential research areas on biomarkers. PMID- 24806346 TI - Aryl hydrocarbon receptor repressor and TiPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. AB - The aryl hydrocarbon receptor (AHR) regulates the toxic effects of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). The AHR repressor (AHRR) is an AHR target gene and functions as a ligand-induced repressor of AHR; however, its mechanism of inhibition is controversial. Recently, we reported that TCDD-inducible poly (ADP-ribose) polymerase (TiPARP; ARTD14) also acts as a repressor of AHR, representing a new player in the mechanism of AHR action. Here we compared the ability of AHRR- and TiPARP-mediated inhibition of AHR activity. TCDD increased AHRR mRNA levels and recruitment of AHRR to cytochrome P450 1A1 (CYP1A1) in MCF7 cells. Knockdown of TiPARP, but not AHRR, increased TCDD-induced CYP1A1 mRNA and AHR protein levels. Similarly, immortalized TiPARP(-/-) mouse embryonic fibroblasts (MEFs) and AHRR(-/-) MEFs exhibited enhanced AHR transactivation. However, unlike TiPARP(-/-) MEFs, AHRR(-/-) MEFs did not exhibit increased AHR protein levels. Overexpression of TiPARP in AHRR(-/-) MEFs or AHRRDelta8, the active isoform of AHRR, in TiPARP(-/-) MEFs reduced TCDD-induced CYP1A1 mRNA levels, suggesting that they independently repress AHR. GFP-AHRRDelta8 and GFP TiPARP expressed as small diffuse nuclear foci in MCF7 and HuH7 cells. GFP AHRRDelta8_Delta1-49, which lacks its putative nuclear localization signal, localized to both the nucleus and the cytoplasm, while the GFP-AHRRDelta8_Delta1 100 mutant localized predominantly in large cytoplasmic foci. Neither GFP AHRRDelta8_Delta1-49 nor GFP-AHRRDelta8_Delta1-100 repressed AHR. Taken together, AHRR and TiPARP repress AHR transactivation by similar, but also different mechanisms. PMID- 24806345 TI - Homology modeling study of bovine MU-calpain inhibitor-binding domains. AB - The activated mammalian CAPN-structures, the CAPN/CAST complex in particular, have become an invaluable target model using the structure-based virtual screening of drug candidates from the discovery phase to development for over activated CAPN linked to several diseases, such as post-ischemic injury and cataract formation. The effect of Ca2+-binding to the enzyme is thought to include activation, as well as the dissociation, aggregation, and autolysis of small regular subunits. Unfortunately, the Ca2+-activated enzyme tends to aggregate when provided as a divalent ion at the high-concentration required for the protease crystallization. This is also makes it very difficult to crystallize the whole-length enzyme itself, as well as the enzyme-inhibitor complex. Several parameters that influence CAPN activity have been investigated to determine its roles in Ca2+-modulation, autoproteolysis, phosphorylation, and intracellular distribution and inhibition by its endogenous inhibitor CAST. CAST binds and inhibits CAPN via its CAPN-inhibitor domains (four repeating domains 1-4; CAST1 4) when CAPN is activated by Ca2+-binding. An important key to understanding CAPN1 inhibition by CAST is to determine how CAST interacts at the molecular level with CAPN1 to inhibit its protease activity. In this study, a 3D structure model of a CAPN1 bound bovine CAST4 complex was built by comparative modeling based on the only known template structure of a rat CAPN2/CAST4 complex. The complex model suggests certain residues of bovine CAST4, notably, the TIPPKYQ motif sequence, and the structural elements of these residues, which are important for CAPN1 inhibition. In particular, as CAST4 docks near the flexible active site of CAPN1, conformational changes at the interaction site after binding could be directly related to CAST4 inhibitory activity. These functional interfaces can serve as a guide to the site-mutagenesis in research on bovine CAPN1 structure-function relationships for the design of small molecules inhibitors to prevent uncontrolled and unspecific degradation in the proteolysis of key protease substrates. PMID- 24806347 TI - Attitudes of Saudi parents with a deaf child towards prenatal diagnosis and termination of pregnancy. AB - OBJECTIVE: The aim of this study was to assess the attitudes of Muslim parents from Saudi Arabia with a deaf child towards prenatal diagnosis (PND) and termination of pregnancy (TOP) for deafness and 29 other genetic and medical conditions. METHODS: A questionnaire mainly focused on parent's attitude toward PND and TOP for 30 different hypothetical scenarios for a series of genetic, non genetic and non-medical conditions was completed by 70 Saudi parents with a deaf child. The results were compared and scored, and parents' comments were noted. RESULTS: The attitude for PND was favorable (81.4%) and was influenced by the severity of the condition among men. Among women, it was influenced by cultural considerations. For TOP, average acceptance rate (25.2%) was lower than for PND. Attitudes toward TOP were fairly similar for men and women, as both groups would consider TOP for Alzheimer disease, cleft lip and palate, and cystic fibrosis. In addition, women also ranked high deafness and thalassemia for consideration of TOP. Acceptance for TOP was not influenced by gender, income, education level, number of children, or partner attending clinic. CONCLUSION: In the Saudi society, cultural consideration influences attitudes towards PND and TOP rather than the severity of the condition. PMID- 24806348 TI - Replication fork inhibition in seqA mutants of Escherichia coli triggers replication fork breakage. AB - SeqA protein negatively regulates replication initiation in Escherichia coli and is also proposed to organize maturation and segregation of the newly replicated DNA. The seqA mutants suffer from chromosomal fragmentation; since this fragmentation is attributed to defective segregation or nucleoid compaction, two ended breaks are expected. Instead, we show that, in SeqA's absence, chromosomes mostly suffer one-ended DNA breaks, indicating disintegration of replication forks. We further show that replication forks are unexpectedly slow in seqA mutants. Quantitative kinetics of origin and terminus replication from aligned chromosomes not only confirm origin overinitiation in seqA mutants, but also reveal terminus under-replication, indicating inhibition of replication forks. Pre-/post-labelling studies of the chromosomal fragmentation in seqA mutants suggest events involving single forks, rather than pairs of forks from consecutive rounds rear-ending into each other. We suggest that, in the absence of SeqA, the sister-chromatid cohesion 'safety spacer' is destabilized and completely disappears if the replication fork is inhibited, leading to the segregation fork running into the inhibited replication fork and snapping the latter at single-stranded DNA regions. PMID- 24806350 TI - Analysis of trace metals and perfluorinated compounds in 43 representative tea products from South China. AB - Six trace metals (Cd, Pb, Cr, Cu, Zn, and Mn) and 2 perfluorinated compounds (PFCs), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), were analyzed in 43 representative tea products (including 18 green, 12 Oolong, and 13 black teas) from 7 main tea production provinces in China, using the atomic absorption spectrophotometer for trace metals analysis and HPLC-MS/MS for PFOS and PFOA analysis. The average contents of the 3 essential metals Mn, Cu, and Zn ions in the tea samples were 629.74, 17.75, and 37.38 mg/kg, whereas 3 toxic metals Cd, Cr, and Pb were 0.65, 1.02, and 1.92 mg/kg, respectively. The contents of heavy metals in the 3 types of tea were in the order of black tea > Oolong tea > green tea. Both PFOS and PFOA contents were low and PFOA content was higher than PFOS in the tea samples. The highest concentration of PFOA was 0.25 ng/g dry weight found in a Hunan green tea. The Principal component analysis was performed with the trace metals and PFCs to analyze the relationships of these indices. The results showed that black teas had higher trace metals and PFCs than green and Oolong teas, and the teas from Hunan and Zhejiang provinces had higher Pb and Cr than others. PRACTICAL APPLICATION: This paper reports trace metals, and perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in wide range of tea products produced in the south China area. This paper also warns the low PFOS and PFOA pollution in tea. PMID- 24806349 TI - Characterization of a cross-linked protein-nucleic acid substrate radical in the reaction catalyzed by RlmN. AB - RlmN and Cfr are methyltransferases/methylsynthases that belong to the radical S adenosylmethionine superfamily of enzymes. RlmN catalyzes C2 methylation of adenosine 2503 (A2503) of 23S rRNA, while Cfr catalyzes C8 methylation of the exact same nucleotide, and will subsequently catalyze C2 methylation if the site is unmethylated. A key feature of the unusual mechanisms of catalysis proposed for these enzymes is the attack of a methylene radical, derived from a methylcysteine residue, onto the carbon center undergoing methylation to generate a paramagnetic protein-nucleic acid cross-linked species. This species has been thoroughly characterized during Cfr-dependent C8 methylation, but does not accumulate to detectible levels in RlmN-dependent C2 methylation. Herein, we show that inactive C118S/A variants of RlmN accumulate a substrate-derived paramagnetic species. Characterization of this species by electron paramagnetic resonance spectroscopy in concert with strategic isotopic labeling shows that the radical is delocalized throughout the adenine ring of A2503, although predominant spin density is on N1 and N3. Moreover, (13)C hyperfine interactions between the radical and the methylene carbon of the formerly [methyl-(13)C]Cys355 residue show that the radical species exists in a covalent cross-link between the protein and the nucleic acid substrate. X-ray structures of RlmN C118A show that, in the presence of SAM, the substitution does not alter the active site structure compared to that of the wild-type enzyme. Together, these findings have new mechanistic implications for the role(s) of C118 and its counterpart in Cfr (C105) in catalysis, and suggest involvement of the residue in resolution of the cross-linked species via a radical mediated process. PMID- 24806351 TI - Assessment of the drug loading, in vitro and in vivo release behavior of novel pH sensitive hydrogel. AB - CONTEXT: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure. OBJECTIVE: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel. MATERIALS AND METHODS: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)-poly(lactide acid)-acryloyl chloride macromonomer, itaconic acid (IA) and MPEG-methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels. In vitro drug release behavior and in vivo pharmacokinetic study were also investigated in detail. RESULTS: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5 mg/g). Both the in vitro release study and the in vivo pharmacokinetic study showed the good colon-targeting character of the pH sensitive P(LE-IA-MEG) hydrogel (T max = 1.0 h, C max = 2.16 ug/ml of dexamethasone; T max = 3.9 h, C max = 0.43 ug/ml of dexamethasone hydrogel). DISCUSSION: Dexamethasone could be targeted to the colon site by P(LE-IA-MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects. CONCLUSION: P(LE-IA-MEG) hydrogel might have great potential application in colon targeted drug delivery systems. PMID- 24806352 TI - Burden of new hospitalization for heart failure: a population-based investigation from Italy. AB - AIMS: Heart failure has been described as one of the emerging pandemics of the 21st century. This report aims to measure the burden of new hospitalization for heart failure in the population of an Italian region of nearly 10 million inhabitants. METHODS AND RESULTS: Data were retrieved from healthcare utilization databases covering the population of the Italian region of Lombardy. We identified patients who were hospitalized for the first time with a primary diagnosis of heart failure (hospitalized heart failure, HHF) during 2011. Incident HHF cases were used for measuring incidence rates and exploring mortality, re-hospitalizations, and healthcare costs on the 1-year time horizon after the index hospitalization. Out-of-hospital mortality, hospitalizations, and healthcare costs were also measured in a referent cohort free from heart failure hospitalization and matched 1:1 by gender and age with the HHF cohort. The overall HHF incidence rate was 32 and 20 events per 10,000 person-years in men and women, respectively. The incidence increased steeply with age in both genders. Among newly hospitalized patients, 7% died during hospitalization. Among survivors, cumulative out-of-hospital mortality and hospital readmission were 24% and 59%, respectively. The average per capita cost was ?11,000, the main cost being hospitalizations. Mortality, readmissions, and costs experienced by HHF patients of 88, 75, and 79%, respectively, exceeded those of the referent cohort. CONCLUSIONS: The main burden associated with HHF is related to hospitalizations. Effective treatment options that decrease hospitalization rates could reduce patients' suffering and offer considerable cost savings. PMID- 24806354 TI - The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS FOCUS) Questionnaire: item reduction and further validation. AB - PURPOSE: The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire is a patient and parent-completed disease-specific instrument used in Hunter syndrome (mucopolysaccharidosis II), a rare paediatric progressive multi-systemic lysosomal storage disease. The objective of this study was to shorten the number of items of the Questionnaire to reduce response burden while maintaining its content validity. METHODS: Data collected in a clinical trial were used. An iterative process helped identifying redundant or low performing items based on content validity and psychometric properties. Validation on the retained items was assessed using patients and parent's responses in terms of reliability, validity and responsiveness. RESULTS: The HS FOCUS was completed by 49 patients and 84 parents. Items were mainly removed owing to high floor effects, high inter-item correlations (>0.80) or inadequate content. The shortened patient and parent versions (18 and 21 items) each contained five function domains. Internal consistency and test-retest reliability were >0.70 for most domains, except Breathing and School/work. Concurrent validity was demonstrated by significant correlations (>0.30) with similar concepts of previously validated measures. Significant differences were found in all domain scores across levels of disability. CONCLUSIONS: The shortened HS FOCUS is a reliable, valid and responsive measure, where burden in answering the Questionnaire was reduced without compromising its validity. PMID- 24806353 TI - Predictors of perceived asthma control among patients managed in primary care clinics. AB - OBJECTIVE: To estimate the extent to which symptom status, physical activity, beliefs about medications, self-efficacy, emotional status, and healthcare utilization predict perceived asthma control over a period of 16 months among a primary care population. METHODS: The current study is a secondary analysis of data from a longitudinal study that examined health outcomes of asthma among participants recruited from primary care clinics. Path analysis, based on the Wilson and Cleary and International Classification of Functioning, Disability and Health frameworks, was used to estimate the predictors of perceived asthma control. RESULTS: The path analysis identified initial perceived asthma control asthma (beta = 0.43, p < 0.0001), symptoms (beta = 0.35, p < 0.0001), physical activity (beta = 0.27, p < 0.0001), and self-efficacy (beta = 0.29, p < 0.0001) as significant predictors of perceived asthma control (total effects, i.e., direct and indirect), while emotional status (beta = 0.08, p = 0.03) was a significant indirect predictor through physical activity. The model explained 24 % of the variance of perceived asthma control. Overall, the model fits the data well (chi (2) = 6.65, df = 6, p value = 0.35, root-mean-square error of approximation = 0.02, Comparative Fit Index = 0.999, and weighted root-mean square residual = 0.27). CONCLUSION: Initial perceived asthma control, current symptoms status, physical activity, and self-efficacy can be used to identify individuals likely to have good perceived asthma control in the future. Emotional status also has an impact on perceived asthma control mediated through physical activity and should be considered when planning patient management. Identifying these predictors is important to help the care team tailor interventions that will allow individuals to optimally manage their asthma, to prevent exacerbations, to prevent other respiratory-related chronic disease, and to maximize quality of life. PMID- 24806355 TI - Direct relation of acute effects of static stretching on isokinetic torque production with initial flexibility level. AB - PURPOSE: To examine the acute effect of a single static-stretching session of hamstring muscles on torque production in relation with individual flexibility. METHODS: Maximal voluntary concentric torque of hamstring muscles was measured before and after a static-stretching session (6 * 30 s). Torque changes were correlated with the flexibility level determined at the onset of the experimental procedure. RESULTS: The hamstring-stretching intervention significantly reduced maximal concentric torque in participants with low and high hamstring flexibility. Hamstring flexibility and torque decrease, determined immediately after the stretching procedure, were negatively correlated. CONCLUSIONS: Torque decrease measured after the static-stretching session is dependent on participant flexibility. Participants with low flexibility are much more likely to demonstrate large torque decreases poststretching. PMID- 24806356 TI - Lichen planopilaris is associated with HLA DRB1*11 and DQB1*03 alleles. AB - There are no studies of the possible association of the human leukocyte antigen (HLA) system with lichen planopilaris (LPP). To determine whether the HLA system is associated with LPP, 40 consecutive Jewish Israeli patients with LPP (study group) and 252 volunteers (controls) were typed for DRB1*and DQB1* loci by molecular methods. Compared with controls, the study group had a significantly higher frequency of the DRB1*11 allele (62% vs. 21%, corrected p-value (pc) = 0.001) owing to increased frequencies of DRB1*11: 01 and DRB1*11: 04. The DQB1*03 allele was also expressed at a significantly higher frequency in the study group (70% vs. 33%, pc = 0.0005); specifically, the frequency of DQB1*03: 01 was increased. The majority (82.5%) of the patients were of non-Ashkenazi origin. We conclude that LPP appears to be over-represented in non-Ashkenazi Jewish patients and is associated with an increased frequency of HLA DRB1*11 and DQB1*03 alleles. These findings suggest that immunogenetic factors play a role in LPP. PMID- 24806357 TI - Decorin mimic regulates platelet-derived growth factor and interferon-gamma stimulation of vascular smooth muscle cells. AB - Following balloon injury, smooth muscle cells (SMCs) serve as targets for many of the pro-inflammatory and pro-fibrotic factors, including platelet-derived growth factor (PDGF) and interferon-gamma (IFN-gamma) released from activated inflammatory cells and platelets. Previously, our lab designed a mimic of the proteoglycan decorin, termed DS-SILY20, that suppressed vascular SMC proliferation, migration, and protein synthesis in vitro, and injured vessels treated with DS-SILY20 demonstrated reduced hyperplasia in vivo. Here we characterize the effects of DS-SILY20 on modulating PDGF and IFN-gamma stimulation in both proliferative and quiescent human SMCs to further evaluate the potential impact of DS-SILY20-SMC interaction on restenosis. Nanomolar dissociation constants were observed between DS-SILY20 and both PDGF and IFN gamma. PDGF significantly increased migration, proliferation, and protein and cytokine expression, as well as increased ERK-1/2 and p38 MAPK phosphorylation in both quiescent and proliferative cultures. However, DS-SILY20 inhibited these increases, presumably through sequestration of the PDGF. Consistent with the complex responses seen with IFN-gamma in SMC physiology in the literature, the response of SMC cultures to IFN-gamma was variable and complex. However, where increased activity was seen with IFN-gamma, DS-SILY20 attenuated this activity. Overall, the results suggest that DS-SILY20 would be an ideal alternative to traditional therapeutics used and may be an effective therapy for the prevention of intimal hyperplasia after balloon angioplasty. PMID- 24806358 TI - Methods for inducing alcohol craving in individuals with co-morbid alcohol dependence and posttraumatic stress disorder: behavioral and physiological outcomes. AB - Alcohol addiction is a chronic relapsing disorder that presents a substantial public health problem, and is frequently co-morbid with posttraumatic stress disorder (PTSD). Craving for alcohol is a predictor of relapse to alcohol use, and is triggered by cues associated with alcohol and trauma. Identification of reliable and valid laboratory methods for craving induction is an important objective for alcoholism and PTSD research. The present study compares two methods for induction of craving via stress and alcohol cues in individuals with co-morbid alcohol dependence (AD) and PTSD: the combined Trier social stress test and cue reactivity paradigm (Trier/CR), and a guided imagery (Scripts) paradigm. Outcomes include self-reported measures of craving, stress and anxiety as well as endocrine measures. Subjects were 52 individuals diagnosed with co-morbid AD and PTSD seeking treatment at the National Institute on Alcohol Abuse and Alcoholism inpatient research facility. They participated in a 4-week inpatient study of the efficacy of a neurokinin 1 antagonist to treat co-morbid AD and PTSD, and which included the two challenge procedures. Both the Trier/CR and Scripts induced craving for alcohol, as well as elevated levels of subjective distress and anxiety. The Trier/CR yielded significant increases in adrenocorticotropic hormone and cortisol, while the Scripts did not. Both paradigms are effective laboratory means of inducing craving for alcohol. Further research is warranted to better understand the mechanisms behind craving induced by stress versus alcohol cues, as well as to understand the impact of co-morbid PTSD and AD on craving. PMID- 24806359 TI - Age-related decrease of meiotic cohesins in human oocytes. AB - Aneuploidy in fetal chromosomes is one of the causes of pregnancy loss and of congenital birth defects. It is known that the frequency of oocyte aneuploidy increases with the human maternal age. Recent data have highlighted the contribution of cohesin complexes in the correct segregation of meiotic chromosomes. In mammalian oocytes, cohesion is established during the fetal stages and meiosis-specific cohesin subunits are not replenished after birth, raising the possibility that the long meiotic arrest of oocytes facilitates a deterioration of cohesion that leads to age-related increases in aneuploidy. We here examined the cohesin levels in dictyate oocytes from different age groups of humans and mice by immunofluorescence analyses of ovarian sections. The meiosis specific cohesin subunits, REC8 and SMC1B, were found to be decreased in women aged 40 and over compared with those aged around 20 years (P<0.01). Age-related decreases in meiotic cohesins were also evident in mice. Interestingly, SMC1A, the mitotic counterpart of SMC1B, was substantially detectable in human oocytes, but little expressed in mice. Further, the amount of mitotic cohesins of mice slightly increased with age. These results suggest that, mitotic and meiotic cohesins may operate in a coordinated way to maintain cohesions over a sustained period in humans and that age-related decreases in meiotic cohesin subunits impair sister chromatid cohesion leading to increased segregation errors. PMID- 24806361 TI - Review of computerized clinical decision support in community pharmacy. AB - WHAT IS KNOWN AND OBJECTIVE: Clinical decision support software (CDSS) has been increasingly implemented to assist improved prescribing practice. Reviews and studies report generally positive results regarding prescribing changes and, to a lesser extent, patient outcomes. Little information is available, however, concerning the use of CDSS in community pharmacy practice. Given the apparent paucity of publications examining this topic, we conducted a review to determine whether CDSS in community pharmacy practice can improve medication use and patient outcomes. METHODS: A literature search of articles on CDSS relevant to community pharmacy and published between 1 January 2005 and 21 October 2013 was undertaken. Articles were included if the healthcare setting was community pharmacy and the article indicated that pharmacy use of CDSS was part of the study intervention. RESULTS AND DISCUSSION: Eight studies were found which assessed counselling, selected drug interactions, inappropriate prescribing and under-prescribing. One study was halted due to insufficient data collection. Six studies showed statistically significant improvements in the measured outcomes: increased patient counselling, 31% reduced frequency of drug-drug interactions (DDIs), reduced frequency of inappropriate medications in the elderly (2.2-1.8% patients) and in pregnant women (5.5-2.9% patients), and increased pharmacists' interventions for under-prescribed low-dose aspirin (1.74 vs. 0.91 per 100 patients with type 2 diabetes) and over-prescribed high-dose proton-pump inhibitors (PPIs) (1.67 vs. 0.17 interventions per 100 high-dose PPI prescriptions). WHAT IS NEW AND CONCLUSION: Most studies showed improved prescribing practice, via direct communication between pharmacists and doctors or indirectly via patient education. Factors limiting the impact of improved prescribing included alert fatigue and clinical inertia. No study investigated patient outcomes and little investigation had been undertaken on how CDSS could be best implemented. Few studies have been undertaken in community pharmacy practice, and based on the positive findings reported, further research should be directed in this area, including investigation of patient outcomes. PMID- 24806362 TI - Simultaneous detection of images and Raman spectra of colliding droplets: composition analysis of protrusions emerging during collisions of ethanol and water droplets. AB - Processes involved between colliding droplets were investigated using simultaneous analysis of spectra and images of Raman-scattered light emitted by irradiation with a pulsed laser. This enabled spatially and temporally resolved Raman spectra of the colliding droplets to be obtained. Colliding droplets of ethanol and water produce a characteristic protrusion from the contact point to the antipode of the water droplet in the course of interaction. From its Raman spectrum, the protrusion is seen to be composed of water. This result supports our surface-tension release model previously proposed to describe the mechanism of protrusion formation because the protrusion is the result of positive interference of a capillary wave propagating over the surface of the water droplet in this model. PMID- 24806360 TI - Protein kinase D1 (PKD1) phosphorylation promotes dopaminergic neuronal survival during 6-OHDA-induced oxidative stress. AB - Oxidative stress is a major pathophysiological mediator of degenerative processes in many neurodegenerative diseases including Parkinson's disease (PD). Aberrant cell signaling governed by protein phosphorylation has been linked to oxidative damage of dopaminergic neurons in PD. Although several studies have associated activation of certain protein kinases with apoptotic cell death in PD, very little is known about protein kinase regulation of cell survival and protection against oxidative damage and degeneration in dopaminergic neurons. Here, we characterized the PKD1-mediated protective pathway against oxidative damage in cell culture models of PD. Dopaminergic neurotoxicant 6-hydroxy dopamine (6-OHDA) was used to induce oxidative stress in the N27 dopaminergic cell model and in primary mesencephalic neurons. Our results indicated that 6-OHDA induced the PKD1 activation loop (PKD1S744/S748) phosphorylation during early stages of oxidative stress and that PKD1 activation preceded cell death. We also found that 6-OHDA rapidly increased phosphorylation of the C-terminal S916 in PKD1, which is required for PKD1 activation loop (PKD1S744/748) phosphorylation. Interestingly, negative modulation of PKD1 activation by RNAi knockdown or by the pharmacological inhibition of PKD1 by kbNB-14270 augmented 6-OHDA-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 (PKD1WT) or constitutively active PKD1 (PKD1S744E/S748E) attenuated 6-OHDA induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury. Collectively, our results demonstrate that PKD1 signaling plays a cell survival role during early stages of oxidative stress in dopaminergic neurons and therefore, positive modulation of the PKD1-mediated signal transduction pathway can provide a novel neuroprotective strategy against PD. PMID- 24806363 TI - Endoscopic ultrasound-guided fine-needle tissue acquisition from a subepithelial lesion in the distal ileum using the forward-viewing echoendoscope. PMID- 24806364 TI - A fish bone perforation of the esophagus. PMID- 24806365 TI - Endoscopic intracavitary pull-through vacuum treatment of an insufficient pancreaticogastrostomy. PMID- 24806366 TI - Signet-ring cell cancer of the colon presenting as facial and gastroduodenal metastasis 7 years after sigmoidectomy. PMID- 24806367 TI - Successful ERCP in a patient with situs inversus. PMID- 24806368 TI - Obscure gastrointestinal bleeding due to small-bowel phlebectasias. PMID- 24806369 TI - Use of the Ella Danis stent in severe esophageal bleeding caused by acute necrotizing esophagitis. PMID- 24806370 TI - Successful endoscopic treatment of a 12-cm small-bowel Crohn stricture with a custom-made biodegradable stent. PMID- 24806371 TI - Endoscopic treatment of Zenker's diverticulum by LigaSure scalpel. PMID- 24806372 TI - Optimizing resection of sessile serrated polyps. PMID- 24806373 TI - Endoscopic retrieval of a proximally migrated biliary plastic stent using a guidewire loop technique. PMID- 24806374 TI - Safe technique to treat occlusion of metallic endoscopic ultrasound-guided hepaticogastrostomy stent using a novel basket catheter (with video). PMID- 24806375 TI - Recanalization using diathermic dilator for stent obstruction due to tumor ingrowth. PMID- 24806376 TI - Scarce scientific evidence for the use of cardiotocography plus fetal ECG ST interval analysis (STAN). PMID- 24806377 TI - Effects of intravenous amiodarone and ibutilide on action potential duration and atrial conduction kinetics in patients with persistent atrial fibrillation. AB - Class III antiarrhythmic drugs have been shown to be effective for termination of atrial fibrillation (AF). The aim of this study was to determine the steady state and non-steady state effects of amiodarone and ibutilide on the atrial monophasic action potential (MAP) duration (MAPD), effective refractory period (ERP), and intra-atrial conduction time (IACT) in human persistent AF.Fourteen patients with persistent AF who underwent internal atrial defibrillation were included in the study. The atrial MAP was recorded at the high right atrium. IACT was measured from the pacing spike to the distal coronary sinus. MAPD and IACT were assessed during the steady state and at the shortest diastolic interval (DI) at a basic cycle length (CL) of 600 msec and after a premature stimulus. Amiodarone did not affect MAPD or the ERP at the basic CL, but it increased MAPD at the shortest DI. Amiodarone increased IACT at both the basic CL and the shortest DI. Ibutilide increased the MAPD and ERP at the basic CL and at the shortest DI. Ibutilide did not affect IACT at the basic CL or the shortest DI.Ibutilide increases atrial MAPD not only in the steady state but also at the shortest DI, but it does not affect IACT in patients with persistent AF. Amiodarone does not affect MAPD or ERP, but it increases IACT in the steady state, and it increases MAPD and IACT at the shortest DI. PMID- 24806379 TI - Role of stromal cell-derived factor-1 in patients with non-ST elevation acute coronary syndrome. AB - The predictive value of stromal cell-derived factor-1 (SDF-1) has not been established in patients with non-ST elevation acute coronary syndrome (non STEACS). A total of 678 consecutive patients with non-STEACS and moderate to high TIMI (Thrombolysis In Myocardial Infarction) risk scores were recruited. All patients underwent an early invasive strategy and then were followed-up for 18 months for clinical events. Left ventricular remodeling was assessed by echocardiography. Plasma concentrations of SDF-1 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were analyzed. SDF-1 level was an independent predictor of left ventricular remodeling (OR = 2.95, 95% CI = 2.02-4.30, P < 0.001). Cox regression analysis demonstrated that both SDF-1 and NT-proBNP levels were significant independent predictors of death, myocardial infarction, or heart failure (HR = 2.45, 95% CI = 1.71-3.50, P < 0.001; HR = 3.71, 95% CI = 2.41-5.70, P < 0.001, respectively). The area under the ROC curves for SDF-1 (0.776) and NT proBNP (0.817) were similar. The logistic model with both markers yielded a larger area under the ROC curve (0.862) than that of SDF-1 (P < 0.001) or NT proBNP (P = 0.0001) alone. In patients stratified by NT-proBNP (above 615.4 pmol/L), SDF-1 (above 2175.1 pg/mL) was associated with poorer outcome (P < 0.001). Findings were similar for death and heart failure as individual endpoints. In non-STEACS, higher SDF-1 levels were a significant predictor of death, myocardial infarction, or heart failure independently of baseline clinical characteristics and NT-proBNP, and the combination of SDF-1 and NTproBNP significantly improved risk stratification. These data highlight the prognostic value of multiple, complementary biomarkers in non-ST elevation acute coronary syndrome. PMID- 24806380 TI - The associations of epicardial adipose tissue with coronary artery disease and coronary atherosclerosis. AB - Epicardial adipose tissue (EAT) is presumed to play an important role in the development of coronary artery disease (CAD). The purpose of our study was to examine the influence of EAT volume measured by cardiac CT on the severity and presence of CAD. A total of 209 subjects (114 normal subjects and 95 patients with CAD) underwent cardiac and abdominal computed tomography (CT) scan before diagnostic coronary angiography. Pixels with a threshold range of -190 to -30 Hounsfield units were identified as EAT. CAGE >= 20, CAGE >= 50, and modified Gensini index were used to define the extent and severity of CAD. While there was no significant difference in BMI and WC between the two groups, the mean EAT volume was higher in the CAD group than in the normal subjects (102.4 +/- 41.87 cm(3) versus 125.36 +/- 47.64 cm(3), P < 0.001). EAT was significantly associated with CAGE >= 20, CAGE >= 50, and Gensini score by linear regression analyses after adjusting for age, gender, smoking, and alcohol use. The severity of CAD increased linearly with each tertile increase in EAT volume (P for trend < 0.05). Similarly, the coronary artery calcium (CAC) score was also increased with each increase in EAT tertile (P = 0.002). In multivariate logistic regression models, EAT and VAT were significantly associated with the presence of CAD and CAC in age, gender, smoking, alcohol use, and BMI adjusted models. In conclusion, EAT volume measured by CT is associated with the presence and severity of CAD. EAT may give important information for risk evaluation in CAD. PMID- 24806378 TI - Renin-angiotensin-aldosterone system polymorphisms and 5-year mortality in survivors of acute myocardial infarction: a report from the Osaka Acute Coronary Insufficiency Study. AB - This study sought to evaluate whether genetic variants in the renin-angiotensin aldosterone system (RAAS) have an impact on long-term mortality after acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era. We investigated the impacts of individual and combinations of 4 major RAAS genetic variants, angiotensinogen (AGT) T1311C, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensin 2 type 1 receptor A1166C, and aldosterone synthase T4660C on 5-year mortality in 3149 post-AMI patients using multivariate Cox regression analysis. The predictive accuracy of all possible RAAS genetic combinations was evaluated using Cox regression analysis, and the best combination that affected prognosis was determined based on the minimal Akaike Information Criterion. There were 220 deaths during a median follow-up of 4.9 years. Independent analyses of any single RAAS variant did not show significant impacts on 5-year mortality. However, analyses in combination revealed that absence of both AGT CC genotype and ACE D allele was associated with lower 5-year mortality (log-rank P = 0.005). Patients with at least either of the AGT CC or ACE D allele had increased mortality with adjusted hazard ratios of 2.07 (95% confidence interval 1.18-3.65, P = 0.012), compared with those with neither the AGT CC nor ACE D allele. Among the 4 RAAS genetic variants examined, a combination of AGT and ACE polymorphisms was associated with 5-year mortality after AMI. PMID- 24806381 TI - Predictors for cardiac resynchronization therapy response: the importance of QRS morphology and left ventricular lead position. AB - Although cardiac resynchronization therapy (CRT) is a well-established treatment for a subset of patients with chronic heart failure, a considerable proportion of eligible patients still fail to benefit from this treatment. The aim of this study was to identify potential independent predictors for being a responder to CRT. A single-center, retrospective analysis was conducted in 193 consecutive patients with heart failure and wide QRS complex who successfully underwent CRT device implantation from January 2006 to October 2012. Clinical characteristics, left ventricular lead position (LV-Ps), electrocardiography and echocardiography were evaluated before and 12 months after CRT. Response to CRT was defined as an absolute increase of >= 5% in left ventricular ejection fraction (LVEF) compared with baseline at 12 months after CRT implantation without heart failure rehospitalization or any cause of death. There were 132 responders (68%) and 61 nonresponders (32%). By univariate logistic analysis, the presence of non-left bundle branch block (non-LBBB) and QRS duration, chronic atrial fibrillation (AF), history of ventricular tachycardia (VT), degree of tricuspid regurgitation and left atrium dimension (LAD) at baseline, DeltaQRS duration, and LV-Ps were associated with predicting a response to CRT. However, on multivariate analysis, only optimal LV-Ps and presence of non-LBBB remained independently predictive for a CRT response, with an odds ratio of 2.53 (95% confidence interval [CI]: 1.13 5.66, P = 0.023), 0.15(95% CI: 0.05-0.45, P = 0.001), respectively. Kaplan-Meier analysis revealed that patients with nonoptimal LV-Ps or non-LBBB morphology had a significantly higher rate of mortality or heart failure rehospitalization as compared with those with optimal LV-Ps or LBBB morphology (P < 0.05). PMID- 24806382 TI - Stent thrombosis in patients with coronary artery disease treated with biodegradable polymer drug-eluting stents: an update meta-analysis. AB - Delayed re-endothelialization may be the pathophysiological cause of stent thrombosis (ST). Biodegradable polymer drug-eluting stents (BP-DES) may reduce the risk of ST. The aim of this study was to evaluate the risk of ST in patients treated with BP-DES. Studies were retrieved from the PubMed, Cochrane Library, and EMBASE online databases. Twelve studies (15,155 patients) with long-term follow-up (>= 12 months) were included. Compared with durable polymer drug eluting stents (DP-DES), BP-DES did not significantly decrease the risk of definite and probable ST (RR, 0.89; 95% CI, 0.68 to 1.18; P = 0.425) and definite ST (RR, 0.92; 95% CI, 0.66 to 1.30; P = 0.648). Furthermore, there was no difference in the risk of late ST (RR, 1.17; 95% CI, 0.39 to 3.53; P = 0.780). However, the rate of early ST was slightly higher in the BP-DES group (RR, 1.60; 95% CI, 0.94 to 2.73; P = 0.084) than in the DP-DES group. A significant reduction in very late ST (> 12 months) was evident with the BP-DES group (RR, 0.27; 95% CI, 0.10 to 0.68; P = 0.006). Subgroup analysis showed that there was no difference in the rate of definite and probable ST between the BP-DES and first- or second-generation DES groups.Biodegradable polymer stents were associated with a significantly lower risk of very late ST. However, there was no difference in the risk of definite and probable ST between the two groups. PMID- 24806383 TI - Assessment of quality of life during long-term treatment of tolvaptan in refractory heart failure: design and rationale of the AQUA-TLV study. AB - The vasopressin type 2 receptor antagonist tolvaptan (TLV) has recently become available to treat congestion in in-hospital patients with heart failure (HF). However, there is no evidence confirming the long-term efficacy of TLV. The Assessment of Quality of life during long-term treatment of TLV in refractory heart failure (AQUA-TLV) study is a multicenter, open-labeled, randomized, controlled clinical trial that will enroll 100 patients from 18 hospitals in Japan. Patients with HF assigned to New York Heart Association class III or IV, who had a previous history of hospitalization due to congestive HF during the past 1 year and ongoing symptomatic congestion with baseline urine osmolality > 350 mOsm/L regardless of being prescribed daily furosemide >= 60 mg are randomized to the conventional diuretics group (50 patients) and TLV add-on group (50 patients), and their quality of life will be assessed using the Minnesota Living with Heart Failure Questionnaire after 6 months of treatment. This study is the first multicenter prospective randomized study in Japan to evaluate the long-term clinical effectiveness of TLV compared with conventional treatment in patients with congestive HF (UMIN Clinical Trial Registry Number: UMIN 000009604). PMID- 24806384 TI - Etiology and clinical implications of microvascular dysfunction in patients with acute myocardial infarction. AB - In patients with acute myocardial infarction (MI), coronary microvasculatures are often damaged irreversibly due to myocardial ischemia and reperfusion, and flow to the previously ischemic myocardium is markedly reduced, a phenomenon known as the "no-reflow phenomenon". Percutaneous coronary intervention (PCI) may accelerate embolization of plaque gruels and microthrombi to the microvessels, which further reduces tissue perfusion. The extent of the no-reflow zone correlates with infarct size, and it has additional prognostic information. Recent advances in imaging modalities have enabled us to diagnose the no-reflow phenomenon and to assess the mechanisms of the no-reflow phenomenon. Pharmacological interventions and catheter-based devices to retrieve embolic materials have been proposed, and some of them are associated with improvement in clinical outcomes. Thus, we should keep in mind that only the achievement of complete microvascular perfusion is associated with better functional and clinical outcomes in patients with acute MI. PMID- 24806385 TI - Apelin: a potential marker of coronary artery stenosis and atherosclerotic plaque stability in ACS patients. AB - Apelin was shown to play an important role in atherosclerosis in mice. However, the involvement of apelin in atherosclerosis in humans has not been investigated. AIMS: To characterize plasma apelin levels following acute coronary syndrome (ACS) and to examine their relationship with coronary stenosis and atherosclerotic plaque stability.The study enrolled 196 patients admitted with ACS, and another 171 outpatients with no coronary heart disease as control. Plasma concentrations of apelin, N-terminal pro-brain natriuretic peptide (NT proBNP), and matrix metalloproteinase-9 (MMP-9) were measured 2 hours and 6 months after admission, respectively. The severity of coronary artery stenosis of ACS patients was evaluated using the Gensini score. The stability and components of atherosclerotic plaque was assessed by intravascular ultrasound (IVUS). All statistical analyses were performed using SPSS version 16.0.Apelin concentration was reduced compared with healthy controls following ACS (0.54 +/- 0.25 versus 3.22 +/- 1.08 ng/mL, P < 0.001) and remained low to 6 months. The plasma level of apelin in the ACS group was negatively correlated with the Gensini score (r = 0.382, P = 0.009). Moreover, in the ACS patients, apelin levels were significantly lower in the group with the ruptured plaque than in those with the nonruptured plaque (0.42 +/- 0.24 versus 0.68 +/- 0.30 ng/mL, P = 0.042). Apelin levels were negatively correlated with plaque cross-sectional area (CSA) (r = 0.425, P = 0.018) and positively correlated with external elastic membrane (EEM) CSA (r = 0.311, P = 0.037). CONCLUSIONS: Plasma apelin levels were inversely correlated with the severity of coronary artery stenosis and positively related with the stability of atherosclerotic plaque in humans with ACS. PMID- 24806386 TI - Association between adiponectin production in coronary circulation and future cardiovascular events in patients with coronary artery disease. AB - Adiponectin has antiatherosclerotic properties and is also produced in the local coronary circulation. We previously reported that significantly less adiponectin was produced in the coronary circulation of patients with than without coronary artery disease (CAD). The goal of this study was to determine whether adiponectin production in the coronary circulation could predict future cardiovascular events in patients with CAD.Forty-eight CAD patients whose left anterior descending coronary arteries required percutaneous coronary intervention (PCI) were enrolled. The amount of adiponectin production in the coronary circulation was defined as the plasma adiponectin level at the great cardiac vein minus that at the orifice of the left coronary artery. All patients were divided by adiponectin production level in the coronary circulation into the adiponectin-positive production group (> 0 ug/ mL) and adiponectin-negative production group (<= 0 ug/mL). Median follow-up period was 66 months (maximum, 108 months). The primary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization due to unstable angina, heart failure, nonfatal myocardial infarction, revascularization with PCI or coronary artery bypass grafting, ischemic stroke, and cardiovascular death.Sixteen MACE occurred. The incidence of MACE was significantly higher in the adiponectin-negative production group than in the adiponectin-positive production group (P = 0.02). In multivariate analysis, adiponectin-negative production was a predictor of MACE (P = 0.03). Kaplan-Meier analysis revealed that the MACE-free rate was significantly lower in the adiponectin-negative production group than in the adiponectin positive production group.Adiponectin production in the coronary circulation with CAD may be associated with MACE. PMID- 24806387 TI - Effects of eicosapentaenoic acid on platelet function in patients taking long term aspirin following coronary stent implantation. AB - Eicosapentaenoic acid (EPA) has been widely accepted to have antiatherosclerotic effects. The aim of this study was to investigate the antiplatelet effect of EPA combined with acetylsalicylic acid (ASA) following stent implantation. Eighteen patients who had undergone coronary stent implantation at least 8 months previously were included. All patients were given EPA ethyl ester (EPA-E) 1.8 g/day in addition to ASA 100 mg/day for 12 weeks. After the treatment, the plasma EPA/arachidonic acid (AA) ratio increased significantly from 0.40 +/- 0.2 to 1.08 +/- 0.39 (P < 0.001). There were no changes in the maximum platelet aggregation (MPA) induced by adenosine diphosphate (5 and 20 umol/L), AA (0.3 and 0.5 mg/mL), or collagen (2 and 4 ug/mL). Furthermore, no significant differences were observed in the expression of PAC-1 and CD62P on the platelet surface membranes or in the soluble P-selectin concentration. With further analysis, a significant negative correlation was found between collagen (2 ug/mL)-induced MPA and plasma EPA/AA ratio (r = -0.507, P = 0.032). The patients were then divided into 2 groups according to the median EPA/AA ratio value of 0.92. In the high EPA/AA ratio group (n = 10), collagen-induced MPA was significantly suppressed after EPA E administration (45.3 +/- 15.9 versus 39.0 +/- 16.3, P = 0.033). In contrast, there were no significant changes in platelet aggregation (56.0 +/- 9.8 versus 57.1 +/- 11.4, P = 0.745) in the low EPA/AA ratio group (n = 8). EPA treatment had a potential to suppress collagen-induced platelet aggregation in patients with a high plasma EPA/AA ratio. PMID- 24806388 TI - High incidence of periodontitis in Japanese patients with abdominal aortic aneurysm. AB - Periodontitis is known to be a risk factor for abdominal aortic aneurysm (AAA). However, the influence of periodontitis on AAA in Japanese patients has not yet been elucidated. The aim of this clinical investigation was to assess the relationship between periodontal bacterial burden in AAA patients.We studied 12 AAA patients and 24 age- and sex-matched non-AAA cardiovascular patients. We examined periodontitis and the presence of the periodontal pathogens Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia in oral samples using polymerase chain reaction assays.We found that the AAA patients had deeper pocket depth compared to the non-AAA patients (3.53 +/- 0.38 mm versus 2.67 +/- 0.17 mm, P < 0.05). However, the populations of periodontal bacteria were comparable between the two groups. Periodontitis may have a greater effect on aneurysm progression compared to other cardiovascular diseases. PMID- 24806389 TI - Nerve guidance conduits based on double-layered scaffolds of electrospun nanofibers for repairing the peripheral nervous system. AB - Compared to the nerve guidance conduits (NGCs) constructed from a single layer of aligned nanofibers, bilayer NGCs with random and aligned nanofibers in the outer and inner layers are more robust and tear-resistant during surgical procedures thanks to an isotropic mechanical property provided by the random nanofibers. However, it remains unclear whether the random nanofibers will interfere with the aligned nanofibers to alter the extension pattern of the neurites and impede regeneration. To answer this question, we seeded dorsal root ganglia (DRG) on a double-layered scaffold, with aligned and random nanofibers on the top and bottom layers, respectively, and evaluated the outgrowth of neurites. The random nanofibers in the bottom layer exerted a negative impact on the extension of neurites projecting from the DRG, giving neurites a less ordered structure compared to those cultured on a single layer of aligned nanofibers. The negative impact of the random nanofibers could be effectively mitigated by preseeding the double-layered scaffold with Schwann cells. DRG cultured on top of such a scaffold exhibited a neurite outgrowth pattern similar to that for DRG cultured on a single layer of aligned nanofibers. We further fabricated bilayer NGCs from the double-layered scaffolds and tested their ability to facilitate nerve regeneration in a rat sciatic nerve injury model. Both histomorphometric analysis and functional characterization demonstrated that bilayer NGCs with an inner surface that was preseeded with Schwann cells could reach 54%, 64.2%, and 74.9% of the performance of isografts in terms of nerve fiber number, maximum isometric tetanic force, and mass of the extensor digitorum longus muscle, respectively. It can be concluded that the bilayer NGCs hold great potential in facilitating motor axon regeneration and functional motor recovery. PMID- 24806390 TI - Diclofenac on boron-doped diamond electrode: from electroanalytical determination to prediction of the electrooxidation mechanism with HPLC-ESI/HRMS and computational simulations. AB - Using square-wave voltammetry coupled to the boron-doped diamond electrode (BDDE), it was possible to develop an analytical methodology for identification and quantification of diclofenac (DCL) in tablets and synthetic urine. The electroanalytical procedure was validated, with results being statistically equal to those obtained by chromatographic standard method, showing linear range of 4.94 * 10(-7) to 4.43 * 10(-6) mol L(-1), detection limit of 1.15 * 10(-7) mol L( 1), quantification limit of 3.85 * 10(-7) mol L(-1), repeatability of 3.05% (n = 10), and reproducibility of 1.27% (n = 5). The association of electrochemical techniques with UV-vis spectroscopy, computational simulations and HPLC-ESI/HRMS led us to conclude that the electrooxidation of DCL on the BDDE involved two electrons and two protons, where the products are colorful and easily hydrolyzable dimers. Density functional theory calculations allowed to evaluate the stability of dimers A, B, and C, suggesting dimer C was more stable than the other two proposed structures, ca. 4 kcal mol(-1). The comparison of the dimers stabilities with the stabilities of the molecular ions observed in the MS, the compounds that showed retention time (RT) of 15.53, 21.44, and 22.39 min were identified as the dimers B, C, and A, respectively. Corroborating the observed chromatographic profile, dimer B had a dipole moment almost twice higher than that of dimers A and C. As expected, dimer B has really shorter RT than dimers A and C. The majority dimer was the A (71%) and the C (19.8%) should be the minority dimer. However, the minority was the dimer B, which was formed in the proportion of 9.2%. This inversion between the formation proportion of dimer B and dimer C can be explained by preferential conformation of the intermediaries (cation-radicals) on the surface. PMID- 24806391 TI - Intercalation study of low-molecular-weight hyperbranched polyethyleneimine into graphite oxide. AB - We report for the first time the intercalation of low-molecular-weight hyperbranched polyethyleneimine (PEI) into graphite oxide (GO) for the facile, bulk synthesis of novel graphene-based hybrid (GO-PEI) materials exhibiting tailored interlayer galleries. The size of the intercalant as well as the loading in GO were systematically investigated to determine their contribution to the basal spacing of the resulting materials. Powder X-ray diffraction measurements demonstrated the generation of constrained hybrid systems along the c axis that exhibit considerably increased interlayer distances compared with the starting, pristine GO. The results of X-ray photoelectron and FTIR studies are consistent with a "grafting-to" process of the intercalated PEI with the oxygen functional groups present along the GO framework. Furthermore, it was found that a great number of the nitrogen-containing groups in PEI still remain available within the newly formed, confined micro-environment of intercalated GO galleries. The increased surface area of the GO-PEI hybrids in conjunction with the remaining available active groups of intercalated PEI render the synthesised hybrids very attractive candidates as nanostructured adsorbents. PMID- 24806394 TI - Management of metastatic spinal cord compression: awareness of NICE guidance. AB - OBJECTIVE: The spine is the most common site for bony metastases. It can lead to the development of significant complications and morbidity if appropriate treatment is not provided. National Institute for Health and Clinical Excellence (NICE) issued new guidance in 2008 with regard to the management of patient with metastatic spinal cord compression (MSCC) to assess the awareness of the NICE guidelines for MSCC. METHODS: We contacted doctors in oncology, trauma and orthopaedics, palliative care and general medicine and assessed their knowledge of MSCC using a questionnaire based on the salient points of the NICE guidance. This was a UK-wide questionnaire. RESULTS: We contacted 96 trainee doctors (oncology, palliative care, general medicine and orthopaedics) and found that 74 % felt adequately informed to diagnose metastatic cord compression although only 11 % considered a sensory level as a potential sign of cord compression. Neurological symptoms (91 %) were the main reason for referral to a tertiary spinal service. MRI was the investigation of choice. There was a poor knowledge of metastatic scoring systems and only 8 % would consider assessing the patient's fitness for surgery. Most of the respondents felt that they had been poorly taught at undergraduate and postgraduate level on MSSC. CONCLUSION: Our audit shows that MSCC is poorly understood in general and that greater understanding of the NICE guidance is required to allow for better management of these patients and more prompt referral for appropriate surgical assessment. PMID- 24806395 TI - Epidemiology and risk factors for surgical site infections in patients requiring orthopedic surgery. AB - INTRODUCTION: Surgical site infection (SSI) is the most common complication following surgical procedures. The aim of this study was to determine the incidence and associated risk factors of SSI in orthopedic patients admitted in a tertiary care center. MATERIALS AND METHODS: Data were collected which focused on demographic details, lifestyle factors, diagnosis, surgical procedure, duration of surgery, prophylactic antibiotics, postoperative antibiotics and comorbidity obtained from the patients hospital records. Univariate analysis and multinomial logistic regression tests were performed to identify independent risk factors for orthopedic incisional SSIs. RESULTS: The overall rate of SSI was 2.1%. Univariate analysis showed diabetes, smoking and duration of hospital stay to be significantly associated with patients in whom SSI developed than in uninfected control patients. Independent risk factors for SSI that were identified by multinomial logistic regression were diabetes (OR 3.953) and smoking (OR 38.319). CONCLUSION: Diabetes and smoking were independent risk factors for SSIs. Therefore, it is recommended to tightly regulate blood glucose levels and stop smoking to reduce the SSIs. PMID- 24806397 TI - Risk of Osteoporotic Fractures With Angiotensin II Receptor Blockers Versus Angiotensin-Converting Enzyme Inhibitors in Hypertensive Community-Dwelling Elderly. AB - Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used to treat hypertension; however, in vivo and clinical studies suggest that ARBs and ACE inhibitors may exert different effects on bone. The association between long-term use of ARBs and ACE inhibitors and fracture requiring medical attention is limited. We conducted a population-based, retrospective cohort study with propensity score matching using administrative databases in Ontario, Canada, to examine the risk of osteoporosis-related fractures in hypertensive elderly treated with ARBs versus ACE inhibitors. We identified a cohort of newly treated hypertensive patients aged 66 years and older who initiated an ACE inhibitor from May 1, 2004, to March 31, 2012, and matched them to ARB users on propensity score, sex, and age at drug initiation. The primary outcome was hip fracture, and secondary outcomes were non-hip major osteoporotic fractures (other femoral, clinical vertebral, forearm, wrist, humerus) and other osteoporotic fractures (pelvis, clavicle, patella, shoulder, upper arm, tibia, fibula, ankle, scapula, ribs, sternum, trunk). We calculated hazard ratios (HRs) using Cox proportional hazards model with robust standard errors. Of the 87,635 patients who initiated treatment, 28,819 (32.9%) started ARBs and 58,816 (67.1%) started ACE inhibitors. Among new ARB users, 27,815 (96.5%) were successfully matched to ACE inhibitor users. Without dose adjustment, no significant association was observed for ARBs relative to ACE inhibitor users for hip fractures (HR = 0.88; 95% confidence interval [CI] 0.70 1.11), with a decreased risk of other major osteoporotic fractures (HR = 0.81; CI 0.70-0.93) and no significant association for other osteoporotic fractures (HR = 0.88; CI 0.74-1.05). When adjusted for dosage, there was no significant difference between the effects of ARBs and ACE inhibitors on hip (HR = 0.99; CI 0.78-1.25), other major osteoporotic (HR = 0.87; CI 0.75-1.01), and other osteoporotic fractures (HR = 0.90; CI 0.74-1.08). PMID- 24806398 TI - Initiation of activities and alertness in individuals with profound intellectual and multiple disabilities. AB - BACKGROUND: When providing activities to individuals with profound intellectual and multiple disabilities (PIMD), direct support persons (DSPs) often face questions that are, among other things, related to the alertness of the person with PIMD. While previous studies have revealed that stimulation might have a greater impact on levels of alertness than the internal conditions of the individual, they have also emphasized the importance of interaction in order to influence the level of alertness. Because the initiation of this interaction has been described as one of its core components, the present study has focused on the relationship between the stimuli presented, the initiation of the activity (by the person with PIMD or the DSP), and the level of alertness of the person with PIMD. METHOD: Videotapes of the one-to-one interactions of 24 individuals with PIMD and their DSPs in multisensory environments have been scored using the Alertness Observation List. In a sequential analysis, the percentages of stimuli presented were related to the percentages of initiation. Furthermore, two other analyses focused on the relationship between the level of alertness and the preceding and subsequent percentages of initiation respectively. RESULTS: The results show that high percentages of the activities are initiated by the DSPs. In addition, activities that were initiated by the individual with PIMD were preceded and followed by higher percentages of alert behaviour than those initiated by the DSP. Outcomes differed for the different types of stimuli. CONCLUSIONS: These results have striking implications for the lives of individuals with PIMD. It is quite possible that DSPs often act too quickly, whereas they would be better off waiting for a reaction on the part of their client. In general, DSPs need to find a balance between being passive themselves and promoting in the individual with PIMD a state of being as active and alert as possible. PMID- 24806400 TI - Impact of enzalutamide administration on primary prostate cancer volume: a metabolic evaluation by choline positron emission tomography in castration resistant prostate cancer patients. AB - BACKGROUND: Enzalutamide is active in advanced castration-resistant prostate cancer (CRPC) patients, in whom it has shown to be able to increase survival. We report the enzalutamide effect on primary prostate tumors, assessed by changes of metabolic tumor activity detected by (18)F-fluorocholine-positron emission tomography/computerized tomography ((18)F-FCH PET/CT). PATIENTS AND METHODS: We treated 31 patients with pretreated metastatic CRPC in an enzalutamide named patient program. All patients were initially evaluated and then followed up by means of repeated (18)F-FCH PET/CT examinations. We identified most radiotracer avid lesions, which were defined as specific regions of interest (ROIs): for each ROI we defined the maximum radiotracer standardized uptake value (SUVmax) and the threshold-based volume of interest (VOI) with a cutoff SUV value >= 2.5. In the 12 patients who did not receive a radical treatment for localized disease, the prostate was also considered an ROI. RESULTS: The baseline prostate median SUVmax of 7.25 showed reductions of 25% (P = .012) and 43% (P = .009) after 3 and 7 months of enzalutamide treatment, respectively. The baseline median prostate VOI of 12.73 cm(3) showed a reduction of 73% (P = .002) at 3 months and a reduction of 90% (P = .005) at 7 months. CONCLUSION: In addition to the metabolic changes of metastatic lesions observed with enzalutamide in CRPC patients, our data have shown significant volume reductions of the primary tumors according to (18)F-FCH PET/CT evaluation. These results could suggest the potential of enzalutamide therapy for localized prostate cancer. PMID- 24806399 TI - Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer. AB - BACKGROUND: We retrospectively evaluated the prognostic impact of neutrophil lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. METHODS: The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. RESULTS: Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. CONCLUSION: High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation. PMID- 24806401 TI - Binaural loudness gain measured by simple reaction time. AB - In order to yield equal loudness, different studies using scaling or matching methods have found binaural level differences between monaural and diotic presentations ranging from less than 2 dB to as much as 10 dB. In the present study, a reaction time methodology was employed to measure the binaural level difference producing equal reaction time (BLDERT). Participants had to respond to the onset of 1-kHz pure tones with sound pressure levels ranging from 45 to 85 dB, and being presented to the right, the left, or both ears. Equal RTs for monaural and diotic presentation (BLDERTs) were obtained with a level difference of approximately 5 dB. A second experiment showed that different results obtained for the left and right ear are largely due to the responding hand, with ipsilateral responses being faster than contralateral ones. A third experiment investigated the BLDERT for dichotic stimuli, tracing the transition between binaural and monaural stimulation. The results of all three RT experiments are consistent with current models of binaural loudness and contradict earlier claims of perfect binaural summation. PMID- 24806402 TI - Knowing and avoiding: the influence of distractor awareness on oculomotor capture. AB - Kramer, Hahn, Irwin, and Theeuwes (2000) reported that the interfering effect of distractors is reduced when participants are aware of the to-be-ignored information. In contrast, recent evidence indicates that distractor interference increases when individuals are aware of the distractors. In the present investigation, we directly assessed the influence of distractor awareness on oculomotor capture, with the hope of resolving this contradiction in the literature and gaining further insight into the influence of awareness on attention. Participants completed a traditional oculomotor capture task. They were not informed of the presence of the distracting information (unaware condition), were informed of distractors (aware condition), or were informed of distractor information and told to avoid attending to it (avoid condition). Being aware of the distractors yielded a performance benefit, relative to the unaware condition; however, this benefit was eliminated when participants were told to actively avoid distraction. This pattern of results reconciles past contradictions in the literature and suggests an inverted-U function of awareness in distractor performance. Too little or too much emphasis yields a performance decrement, but an intermediate level of emphasis provides a performance benefit. PMID- 24806405 TI - Infants' discrimination of crossed and uncrossed horizontal disparity. AB - In a series of preferential-looking experiments, infants 5 to 6 months of age were tested for their responsiveness to crossed and uncrossed horizontal disparity. In Experiments 1 and 2, infants were presented with dynamic random dot stereograms displaying a square target defined by either a 0.5 degrees crossed or a 0.5 degrees uncrossed horizontal disparity and a square control target defined by a 0.5 degrees vertical disparity. In Experiment 3, infants were presented with the crossed and the uncrossed horizontal disparity targets used in Experiments 1 and 2. According to the results, the participants looked more often at the crossed (Experiment 1), as well as the uncrossed (Experiment 2), horizontal disparity targets than at the vertical disparity target. These results suggest that the infants were sensitive to both crossed and uncrossed horizontal disparity information. Moreover, the participants exhibited a natural visual preference for the crossed over the uncrossed horizontal disparity (Experiment 3). Since prior research established natural looking and reaching preferences for the (apparently) nearer of two objects, this finding is consistent with the hypothesis that the infants were able to extract the depth relations specified by crossed (near) and uncrossed (far) horizontal disparity. PMID- 24806404 TI - Body ownership affects visual perception of object size by rescaling the visual representation of external space. AB - Size perception is most often explained by a combination of cues derived from the visual system. However, this traditional cue approach neglects the role of the observer's body beyond mere visual comparison. In a previous study, we used a full-body illusion to show that objects appear larger and farther away when participants experience a small artificial body as their own and that objects appear smaller and closer when they assume ownership of a large artificial body ("Barbie-doll illusion"; van der Hoort, Guterstam, & Ehrsson, PLoS ONE, 6(5), e20195, 2011). The first aim of the present study was to test the hypothesis that this own-body-size effect is distinct from the role of the seen body as a direct familiar-size cue. To this end, we developed a novel setup that allowed for occlusion of the artificial body during the presentation of test objects. Our results demonstrate that the feeling of ownership of an artificial body can alter the perceived sizes of objects without the need for a visible body. Second, we demonstrate that fixation shifts do not contribute to the own-body-size effect. Third, we show that the effect exists in both peri-personal space and distant extra-personal space. Finally, through a meta-analysis, we demonstrate that the own-body-size effect is independent of and adds to the classical visual familiar size cue effect. Our results suggest that, by changing body size, the entire spatial layout rescales and new objects are now perceived according to this rescaling, without the need to see the body. PMID- 24806403 TI - Audition dominates vision in duration perception irrespective of salience, attention, and temporal discriminability. AB - Whereas the visual modality tends to dominate over the auditory modality in bimodal spatial perception, the auditory modality tends to dominate over the visual modality in bimodal temporal perception. Recent results suggest that the visual modality dominates bimodal spatial perception because spatial discriminability is typically greater for the visual than for the auditory modality; accordingly, visual dominance is eliminated or reversed when visual spatial discriminability is reduced by degrading visual stimuli to be equivalent or inferior to auditory spatial discriminability. Thus, for spatial perception, the modality that provides greater discriminability dominates. Here, we ask whether auditory dominance in duration perception is similarly explained by factors that influence the relative quality of auditory and visual signals. In contrast to the spatial results, the auditory modality dominated over the visual modality in bimodal duration perception even when the auditory signal was clearly weaker, when the auditory signal was ignored (i.e., the visual signal was selectively attended), and when the temporal discriminability was equivalent for the auditory and visual signals. Thus, unlike spatial perception, where the modality carrying more discriminable signals dominates, duration perception seems to be mandatorily linked to auditory processing under most circumstances. PMID- 24806406 TI - The attentional boost effect really is a boost: evidence from a new baseline. AB - In the attentional boost effect, participants encode images into memory as they perform an unrelated target-detection task. Later memory is better for images that coincided with a target rather than a distractor. This advantage could reflect a broad processing enhancement triggered by target detection, but it could also reflect inhibitory processes triggered by distractor rejection. To test these possibilities, in four experiments we acquired a baseline measure of image memory when neither a target nor a distractor was presented. Participants memorized faces presented in a continuous series (500- or 100-ms duration). At the same time, participants monitored a stream of squares. Some faces appeared on their own, and others coincided with squares in either a target or a nontarget color. Because the processes associated with both target detection and distractor rejection were minimized when faces appeared on their own, this condition served as a baseline measure of face encoding. The data showed that long-term memory for faces coinciding with a target square was enhanced relative to faces in both the baseline and distractor conditions. We concluded that detecting a behaviorally relevant event boosts memory for concurrently presented images in dual-task situations. PMID- 24806407 TI - How do people order stimuli? AB - People may find it easier to construct an order after first representing stimuli on a scale or categorizing them, particularly when the number of stimuli to be ordered is large or when some of them must be remembered. Five experiments tested this hypothesis. In two of these experiments (1 and 3), we asked participants to rank line lengths or to rank photographs by artistic value. The participants provided evidence of how they performed these tasks, and this evidence indicated that they often made use of some preliminary representation--either a metric or a categorization. Two further experiments (2 and 4) indicated that people rarely produced rankings when given a choice of assessment measures for either the length of lines or the artistic value of photographs. In Experiment 5, when the number of lines was larger or lines were only visible one at a time, participants were faster at estimating line lengths as a percentage of the card covered than at rank ordering the lengths. Overall, the results indicate that ordering stimuli is not an easy or natural process when the number of stimuli is large or when the stimuli are not all perceptible at once. An implication is that the psychological measures available to individuals are not likely to be purely ordinal when many of the elements being measured must be recalled. PMID- 24806410 TI - Translation-independent circadian control of the cell cycle in a unicellular photosynthetic eukaryote. AB - Circadian rhythms of cell division have been observed in several lineages of eukaryotes, especially photosynthetic unicellular eukaryotes. However, the mechanism underlying the circadian regulation of the cell cycle and the nature of the advantage conferred remain unknown. Here, using the unicellular red alga Cyanidioschyzon merolae, we show that the G1/S regulator RBR-E2F-DP complex links the G1/S transition to circadian rhythms. Time-dependent E2F phosphorylation promotes the G1/S transition during subjective night and this phosphorylation event occurs independently of cell cycle progression, even under continuous dark or when cytosolic translation is inhibited. Constitutive expression of a phospho mimic of E2F or depletion of RBR unlinks cell cycle progression from circadian rhythms. These transgenic lines are exposed to higher oxidative stress than the wild type. Circadian inhibition of cell cycle progression during the daytime by RBR-E2F-DP pathway likely protects cells from photosynthetic oxidative stress by temporally compartmentalizing photosynthesis and cell cycle progression. PMID- 24806411 TI - Thermoresponsive fluorescence of a graphene-polymer composite based on a local surface plasmon resonance effect. AB - A water-processable blue fluorescent silver nanoparticle@graphene-polymer composite (Ag@G-pNIPAM) consisting of graphene coated with a thermally responsive poly-(N-isopropylacrylamide) (pNIPAM) shell is prepared. The pNIPAM shell swells or collapses as a function of temperature, serving as a means to trap silver nanoparticles in solution and get them sufficiently close to the graphene core to provide fluorescence enhancement based on the local surface plasmon resonance (LSPR) effect. The unique thermoresponsive properties and high enhancement ratio of the material should find application in solution fluorescence enhancers and a variety of biomedical applications, such as cellular uptake, sensing and imaging. PMID- 24806409 TI - C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. AB - Hexanucleotide repeat expansions of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal degeneration. The mutation is associated with reduced C9orf72 expression and the accumulation of potentially toxic RNA and protein aggregates. CpG methylation is known to protect the genome against unstable DNA elements and to stably silence inappropriate gene expression. Using bisulfite cloning and restriction enzyme-based methylation assays on DNA from human brain and peripheral blood, we observed CpG hypermethylation involving the C9orf72 promoter in cis to the repeat expansion mutation in approximately one-third of C9orf72 repeat expansion mutation carriers. Promoter hypermethylation of mutant C9orf72 was associated with transcriptional silencing of C9orf72 in patient-derived lymphoblast cell lines, resulting in reduced accumulation of intronic C9orf72 RNA and reduced numbers of RNA foci. Furthermore, demethylation of mutant C9orf72 with 5-aza-deoxycytidine resulted in increased vulnerability of mutant cells to oxidative and autophagic stress. Promoter hypermethylation of repeat expansion carriers was also associated with reduced accumulation of RNA foci and dipeptide repeat protein aggregates in human brains. These results indicate that C9orf72 promoter hypermethylation prevents downstream molecular aberrations associated with the hexanucleotide repeat expansion, suggesting that epigenetic silencing of the mutant C9orf72 allele may represent a protective counter-regulatory response to hexanucleotide repeat expansion. PMID- 24806420 TI - Health technology assessment and personalized medicine: are economic evaluation guidelines sufficient to support decision making? AB - BACKGROUND: Many jurisdictions delivering health care, including Canada, have developed guidance for conducting economic evaluation, often in the service of larger health technology assessment (HTA) and reimbursement processes. Like any health intervention, personalized medical (PM) interventions have costs and consequences that must be considered by reimbursement authorities with limited resources. However, current approaches to economic evaluation to support decision making have been largely developed from population-based approaches to therapy that is, evaluating the costs and consequences of single interventions across single populations. This raises the issue as to whether these methods, as they are or more refined, are adequate to address more targeted approaches to therapy, or whether a new paradigm for assessing value in PM is required. OBJECTIVES: We describe specific issues relevant to the economic evaluation of diagnostics-based PM and assess whether current guidance for economic evaluation is sufficient to support decision making for PM interventions. METHODS: Issues were identified through literature review and informal interviews with national and international experts (n = 10) in these analyses. This article elaborates on findings and discussion at a workshop held in Ottawa, Canada, in January 2012. RESULTS: Specific issues related to better guiding economic evaluation of personalized medicine interventions include: how study questions are developed, populations are characterized, comparators are defined, effectiveness is evaluated, outcomes are valued and how resources are measured. Diagnostics-based PM also highlights the need for analyses outside of economic evaluation to support decision making. CONCLUSIONS: The consensus of this group of experts is that the economic evaluation of diagnostics-based PM may not require a new paradigm. However, greater complexity means that existing approaches and tools may require improvement to undertake these more analyses. PMID- 24806421 TI - Copper phenanthrene oxidative chemical nucleases. AB - Here we report the synthesis and isolation of a series of bis-chelate Cu(2+) phenanthroline-phenazine cationic complexes of [Cu(DPQ)(Phen)](2+), [Cu(DPPZ)(Phen)](2+), and [Cu(DPPN)(Phen)](2+) (where Phen = 1,10-phenanthroline, DPQ = dipyridoquinoxaline, DPPZ = dipyridophenazine, and DPPN = benzo[i]dipyridophenazine). These compounds have enhanced DNA recognition relative to the well-studied chemical nuclease, [Cu(Phen)2](2+) (bis-Phen), with calf thymus DNA binding constants of DPQ and DPPZ agents (~10(7) M(bp)(-1)) being the highest currently known for Cu(2+) phenanthrene compounds. Complex DNA binding follows DPQ ~ DPPZ > DPPN > bis-Phen, with fluorescence quenching and thermal melting experiments on poly[d(A-T)2] and poly[d(G-C)2] supporting intercalation at both the minor and major groove. Phenazine complexes, however, show enhanced targeting and oxidative cleavage on cytosine-phosphate-guanine-rich DNA and have comparable in vitro cytotoxicity toward the cisplatin-resistant ovarian cancer line, SKOV3, as the clinical oxidative DNA-damaging drug doxorubicin (Adriamycin). In this study we also describe how a novel "on-chip" method devised for the Bioanalyser 2100 was employed to quantify double-stranded DNA damage, with high precision, by the complex series on pUC19 DNA (49% A-T, 51% G-C). Both DPQ and bis-Phen complexes are highly efficient oxidizers of pUC19, with DPQ being the most active of the overall series. It is apparent, therefore, that oxidative chemical nuclease activity on homogeneous canonical DNA is not entirely dependent on dynamic nucleotide binding affinity or intercalation, and this observation is corroborated through catalytic interactions with the superoxide anion radical and Fenton breakdown of hydrogen peroxide. PMID- 24806422 TI - Females that experience threat are better teachers. AB - Superb fairy-wren (Malurus cyaneus) females use an incubation call to teach their embryos a vocal password to solicit parental feeding care after hatching. We previously showed that high call rate by the female was correlated with high call similarity in fairy-wren chicks, but not in cuckoo chicks, and that parent birds more often fed chicks with high call similarity. Hosts should be selected to increase their defence behaviour when the risk of brood parasitism is highest, such as when cuckoos are present in the area. Therefore, we experimentally test whether hosts increase call rate to embryos in the presence of a singing Horsfield's bronze-cuckoo (Chalcites basalis). Female fairy-wrens increased incubation call rate when we experimentally broadcast cuckoo song near the nest. Embryos had higher call similarity when females had higher incubation call rate. We interpret the findings of increased call rate as increased teaching effort in response to a signal of threat. PMID- 24806423 TI - Sex hormone influence on human infants' sound characteristics: melody in spontaneous crying. AB - The specific impact of sex hormones on brain development and acoustic communication is known from animal models. Sex steroid hormones secreted during early development play an essential role in hemispheric organization and the functional lateralization of the brain, e.g. language. In animals, these hormones are well-known regulators of vocal motor behaviour. Here, the association between melody properties of infants' sounds and serum concentrations of sex steroids was investigated. Spontaneous crying was sampled in 18 healthy infants, averaging two samples taken at four and eight weeks, respectively. Blood samples were taken within a day of the crying samples. The fundamental frequency contour (melody) was analysed quantitatively and the infants' frequency modulation skills expressed by a melody complexity index (MCI). These skills provide prosodic primitives for later language. A hierarchical, multiple regression approach revealed a significant, robust relationship between the individual MCIs and the unbound, bioactive fraction of oestradiol at four weeks as well as with the four to-eight-week difference in androstenedione. No robust relationship was found between the MCI and testosterone. Our findings suggest that oestradiol may have effects on the development and function of the auditory-vocal system in human infants that are as powerful as those in vocal-learning animals. PMID- 24806424 TI - Morphological disparity opposes latitudinal diversity gradient in lacertid lizards. AB - While global variation in taxonomic diversity is strongly linked to latitude, the extent to which morphological disparity follows geographical gradients is less well known. We estimated patterns of lineage diversification, morphological disparity and rates of phenotypic evolution in the Old World lizard family Lacertidae, which displays a nearly inverse latitudinal diversity gradient with decreasing species richness towards the tropics. We found that lacertids exhibit relatively constant rates of lineage accumulation over time, although the majority of morphological variation appears to have originated during recent divergence events, resulting in increased partitioning of disparity within subclades. Among subclades, tropical arboreal taxa exhibited the fastest rates of shape change while temperate European taxa were the slowest, resulting in an inverse relationship between latitudinal diversity and rates of phenotypic evolution. This pattern demonstrates a compelling counterexample to the ecological opportunity theory of diversification, suggesting an uncoupling of the processes generating species diversity and morphological differentiation across spatial scales. PMID- 24806425 TI - Male-female relatedness and patterns of male reproductive investment in guppies. AB - Inbreeding can cause reductions in fitness, driving the evolution of pre- and postcopulatory inbreeding avoidance mechanisms. There is now considerable evidence for such processes in females, but few studies have focused on males, particularly in the context of postcopulatory inbreeding avoidance. Here, we address this topic by exposing male guppies (Poecilia reticulata) to either full sibling or unrelated females and determining whether they adjust investment in courtship and ejaculates. Our results revealed that males reduce their courtship but concomitantly exhibit short-term increases in ejaculate quality when paired with siblings. In conjunction with prior work reporting cryptic female preferences for unrelated sperm, our present findings reveal possible sexually antagonistic counter-adaptations that may offset postcopulatory inbreeding avoidance by females. PMID- 24806426 TI - How interactions between animal movement and landscape processes modify local range dynamics and extinction risk. AB - Forecasts of range dynamics now incorporate many of the mechanisms and interactions that drive species distributions. However, connectivity continues to be simulated using overly simple distance-based dispersal models with little consideration of how the individual behaviour of dispersing organisms interacts with landscape structure (functional connectivity). Here, we link an individual based model to a niche-population model to test the implications of this omission. We apply this novel approach to a turtle species inhabiting wetlands which are patchily distributed across a tropical savannah, and whose persistence is threatened by two important synergistic drivers of global change: predation by invasive species and overexploitation. We show that projections of local range dynamics in this study system change substantially when functional connectivity is modelled explicitly. Accounting for functional connectivity in model simulations causes the estimate of extinction risk to increase, and predictions of range contraction to slow. We conclude that models of range dynamics that simulate functional connectivity can reduce an important source of bias in predictions of shifts in species distributions and abundances, especially for organisms whose dispersal behaviours are strongly affected by landscape structure. PMID- 24806428 TI - Melanoma incidence trends and survival in adolescents and young adults in Queensland, Australia. AB - Cutaneous melanoma is a relatively common cancer in adolescents and young adults in Australia, but detailed information about occurrence patterns and prognosis is limited. We evaluated incidence trends from 1982 to 2010 and recent survival rates in those aged 15-24 years in the state of Queensland. In situ and invasive melanoma cases were identified from the Queensland Cancer Registry. Incidence rates were age-standardised to the 2000 World population and trends calculated using joinpoint regression. Five-year relative survival was estimated by the period method and Poisson models were used to produce adjusted mortality hazard ratios. Average annual incidence rates for the 5-year period 2006-2010 were 6.3 per 100,000 [95% confidence interval (CI) 5.4, 7.2] for in situ and 10.1 per 100,000 (95% CI 9.0, 11.3) for invasive melanoma. Since the mid-1990s, incidence rates for in situ melanomas have been stabilizing while invasive melanoma has decreased in both sexes, mainly owing to declining rates of thin tumours (<=1 mm) (-5.4% per year, 95% CI -8.3%, -2.4%). Incidence rates of melanomas >1 mm in thickness have remained relatively unchanged since 1991 however. In the period 2006-2010, relative 5-year survival of 15-24 year olds with invasive melanoma was 95.7% (95% CI 92.9%, 97.5%). The subgroup with tumours >1 mm was nearly six times more likely to die within 5 years than those with thin tumours (adjusted hazard ratio = 5.53, 95% CI 1.72, 17.80). Incidence of thin melanoma in young people in Queensland is declining, suggesting benefits of primary prevention efforts are being realised. PMID- 24806427 TI - Complement component 3 is necessary to preserve myocardium and myocardial function in chronic myocardial infarction. AB - Activation of the complement cascade (CC) with myocardial infarction (MI) acutely initiates immune cell infiltration, membrane attack complex formation on injured myocytes, and exacerbates myocardial injury. Recent studies implicate the CC in mobilization of stem/progenitor cells and tissue regeneration. Its role in chronic MI is unknown. Here, we consider complement component C3, in the chronic response to MI. C3 knockout (KO) mice were studied after permanent coronary artery ligation. C3 deficiency exacerbated myocardial dysfunction 28 days after MI compared to WT with further impaired systolic function and LV dilation despite similar infarct size 24 hours post-MI. Morphometric analysis 28 days post-MI showed C3 KO mice had more scar tissue with less viable myocardium within the infarct zone which correlated with decreased c-kit(pos) cardiac stem/progenitor cells (CPSC), decreased proliferating Ki67(pos) CSPCs and decreased formation of new BrdU(pos) /alpha-sarcomeric actin(pos) myocytes, and increased apoptosis compared to WT. Decreased CSPCs and increased apoptosis were evident 7 days post MI in C3 KO hearts. The inflammatory response with MI was attenuated in the C3 KO and was accompanied by attenuated hematopoietic, pluripotent, and cardiac stem/progenitor cell mobilization into the peripheral blood 72 hours post-MI. These results are the first to demonstrate that CC, through C3, contributes to myocardial preservation and regeneration in response to chronic MI. Responses in the C3 KO infer that C3 activation in response to MI expands the resident CSPC population, increases new myocyte formation, increases and preserves myocardium, inflammatory response, and bone marrow stem/progenitor cell mobilization to preserve myocardial function. PMID- 24806429 TI - Injection force comparison of the old and new dexamethasone implant insertion needles in porcine eyes and synthetic sclera. AB - BACKGROUND AND OBJECTIVE: Determine whether the new dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA) injector needle design can reduce the force needed for insertion when compared to the original needle design. MATERIALS AND METHODS: In vitro testing assessed the force required for insertion from five new-design and five old-design Ozurdex needles on a synthetic test medium and explanted porcine eyes. Maximum penetration force was measured in grams-force, while the total work of the needle was measured in joules. RESULTS: The new design required 29% and 68% less overall work to perform an injection in the synthetic medium (P = .0002) and porcine eyes (P = .009), respectively. The maximum force required to insert the new needle was 25% and 61% that of the old needle in the synthetic medium (P = .001) and porcine eyes (P = .007), respectively. CONCLUSION: The new needle design significantly reduces the force and work needed for insertion, which should improve physician control as well as patient safety and comfort. PMID- 24806430 TI - Near-infrared light-triggered "on/off" motion of polymer multilayer rockets. AB - We describe an approach to modulating the on-demand motion of catalytic polymer based microengines via near-infrared (NIR) laser irradiation. The polymer multilayer motor was fabricated by the template-assisted layer-by-layer assembly and subsequently deposition of platinum nanoparticles inside and a thin gold shell outside. Then a mixed monolayer of a tumor-targeted peptide and an antifouling poly(ethylene glycol) was functionalized on the gold shell. The microengines remain motionless at the critical peroxide concentration (0.1%, v/v); however, NIR illumination on the engines leads to a photothermal effect and thus rapidly triggers the motion of the catalytic engines. Computational modeling explains the photothermal effect and gives the temperature profile accordingly. Also, the photothermal effect can alone activate the motion of the engines in the absence of the peroxide fuel, implying that it may eliminate the use of toxic fuel in the future. The targeted recognition ability and subsequently killing of cancer cells by the photothermal effect under the higher power of a NIR laser were illustrated. Our results pave the way to apply self-propelled synthetic engines in biomedical fields. PMID- 24806431 TI - Function of chemokine (CXC motif) ligand 12 in periodontal ligament fibroblasts. AB - The periodontal ligament (PDL) is one of the connective tissues located between the tooth and bone. It is characterized by rapid turnover. Periodontal ligament fibroblasts (PDLFs) play major roles in the rapid turnover of the PDL. Microarray analysis of human PDLFs (HPDLFs) and human dermal fibroblasts (HDFs) demonstrated markedly high expression of chemokine (CXC motif) ligand 12 (CXCL12) in the HPDLFs. CXCL12 plays an important role in the migration of mesenchymal stem cells (MSCs). The function of CXCL12 in the periodontal ligament was investigated in HPDLFs. Expression of CXCL12 in HPDLFs and HDFs was examined by RT-PCR, qRT-PCR and ELISA. Chemotactic ability of CXCL12 was evaluated in both PDLFs and HDFs by migration assay of MSCs. CXCL12 was also immunohistochemically examined in the PDL in vivo. Expression of CXCL12 in the HPDLFs was much higher than that in HDFs in vitro. Migration assay demonstrated that the number of migrated MSCs by HPDLFs was significantly higher than that by HDFs. In addition, the migrated MSCs also expressed CXCL12 and several genes that are familiar to fibroblasts. CXCL12 was immunohistochemically localized in the fibroblasts in the PDL of rat molars. The results suggest that PDLFs synthesize and secrete CXCL12 protein and that CXCL12 induces migration of MSCs in the PDL in order to maintain rapid turnover of the PDL. PMID- 24806433 TI - Quantitative proteomic analysis reveals mitochondrial protein changes in MPP(+) induced neuronal cells. AB - Parkinson's disease (PD) is a common neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. To further explore potential functional mechanisms of PD, we performed a comparative proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) combined with nano-LC tandem mass spectrometry (nano-LC MS). In total, 1740 proteins were identified in MPP(+)-treated SH-SY5Y cells. Our comparative proteomic analysis indicated that a total of 39 proteins were differentially expressed in SH-SY5Y cells responding to MPP(+) treatment. Of these, 14 altered proteins were clustered in the mitochondria, 5 proteins were already reported as related to PD, and the remaining proteins were newly identified in this study. Together, our data further define that the mitochondria play an important role in regulating PD through multiple and complex mechanisms and provide new insights into the functional contribution of mitochondrial proteins in PD. PMID- 24806432 TI - Extracellular signal-regulated kinase signaling-mediated induction and interaction of FOXO3a and p53 contribute to the inhibition of nasopharyngeal carcinoma cell growth by curcumin. AB - Curcumin, one of the main bioactive components extracted from a traditional Chinese medicinal herb, exhibits potent anticancer activity against many types of cancer cells including nasopharyngeal carcinoma (NPC). However, the detailed molecular mechanism underlying this is not clearly understood. In this study, we showed that curcumin significantly inhibited the growth of NPC cells in a dose- and time-dependent manner as determined by MTT assays, while increasing apoptosis was also observed as measured by flow cytometry for the FITC-Annexin V and propidium iodide (PI) label and Hoechst 33258 staining. To further explore the potential mechanism, we showed that curcumin increased the phosphorylation of ERK1/2 but not p38 MAPK in a time-dependent manner, and induced protein expression of the tumor suppressors FOXO3a and p53 in a dose-dependent manner, which were not observed in the presence of PD98059, an inhibitor of ERK1/2. Furthermore, silencing of FOXO3a and p53 genes by siRNAs overcame the inhibitory effect of curcumin on cell proliferation. Silencing or blockade of p53 using siRNA or chemical inhibitor abrogated the effect of curcumin on expression of FOXO3a protein; silencing or overexpression of FOXO3a had no further effect on curcumin-induced p53 protein expression. Furthermore, blockade of ERK1/2 and exogenous expression of FOXO3a restored the effect of curcumin on growth of cells. Together, our studies show that curcumin inhibits growth and induces apoptosis of NPC cells through ERK1/2-mediated increase in the protein expression and interaction of p53 and FOXO3a. p53 is upstream of FOXO3a, which form a regulatory loop that mediates the effect of curcumin. This study unveils a new mechanism by which curcumin inhibits the proliferation and induces apoptosis of human NPC cells. PMID- 24806434 TI - The standardized extract of Ziziphus jujuba fruit (jujube) regulates pro inflammatory cytokine expression in cultured murine macrophages: suppression of lipopolysaccharide-stimulated NF-kappaB activity. AB - The fruit of Ziziphus jujuba Mill., known as jujube or Chinese date, is commonly consumed as a health supplement or herbal medicine worldwide. To study the beneficial role of jujube in regulating immune response, we investigated its roles on the expressions of pro-inflammatory cytokines in cultured macrophages. Application of chemically standardized jujube water extract for 24 h stimulated the transcriptional expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in cultured RAW 264.7 macrophages. In contrast, the pretreatment with jujube water extract suppressed the expression of IL-1beta and IL-6, but not for TNF-alpha in lipopolysaccharide (LPS)-stimulated macrophages. The IL-1beta and IL-6 cytokines in LPS-induced macrophages were suppressed by jujube water extract in both mRNA and protein levels. In parallel, the inhibition of jujube water extract on the transcriptional activity of nuclear factor-kappa B was revealed in LPS-induced macrophages. These results verified the bidirectional immune-modulatory roles of jujube by regulating the expressions of pro inflammatory cytokines in macrophages. PMID- 24806435 TI - An Evidence-Based Systematic Review of Goji (Lycium spp.) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review of goji (Lycium spp.) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 24806436 TI - Application of Digital Image Analysis to Determine Pancreatic Islet Mass and Purity in Clinical Islet Isolation and Transplantation. AB - Pancreatic islet mass, represented by islet equivalent (IEQ), is the most important parameter in decision making for clinical islet transplantation. To obtain IEQ, the sample of islets is routinely counted under a microscope and discarded thereafter. Islet purity, another parameter in islet processing, is routinely assessed by estimation only. In this study, we validated our digital image analysis (DIA) system by using the software of Image Pro Plus and a custom designed Excel template to assess islet mass and purity to better comply with current good manufacturing practice (cGMP) standards. Human islet samples (60 collected from a single isolation and 24 collected from 12 isolations) were captured as calibrated digital images for the permanent record. Seven trained technicians participated in determination of IEQ and purity by the manual counting method (manual image counting, Manual I) and DIA. IEQ count showed statistically significant correlations between the Manual I and DIA in all sample comparisons (r > 0.819 and p < 0.0001). A statistically significant difference in IEQ between Manual I and DIA was not found in all sample groups (p > 0.05). In terms of purity determination, statistically significant differences between assessment and DIA measurement were found in high-purity 100-ul samples (p < 0.005) and low-purity 100-ul samples (p < 0.001) of the single isolation. In addition, islet particle number (IPN) and the IEQ/IPN ratio did not differ statistically between Manual I and DIA. In conclusion, the DIA used in this study is a reliable technique to determine IEQ and purity. Islet sample preserved as a digital image and results produced by DIA can be permanently stored for verification, technical training, and information exchange among islet centers. Therefore, DIA complies better with cGMP requirements than the manual counting method. We propose DIA as a quality control tool to supplement the established standard manual method for islet counting and purity estimation. PMID- 24806437 TI - From motor learning to physical therapy and back again: the state of the art and science of motor learning rehabilitation research. PMID- 24806438 TI - Sleep matters. PMID- 24806439 TI - Sign of canted ferromagnetism in the quasicrystal approximants Au-SM-R (SM = Si, Ge and Sn / R = Tb, Dy and Ho). AB - Magnetic susceptibility and magnetization of the quasicrystal approximants Au-SM R (SM = Si, Ge or Sn / R = Gd, Tb, Dy or Ho) are investigated. Ferromagnetic transitions are observed in all of these compounds, in contrast to the spin-glass behavior reported in similar compounds, Ag-In-R (R = Eu, Gd, Tb or Dy). Au-SM-Gd (SM = Si, Ge or Sn) exhibit a simple ferromagnetic transition at 22.5, 13 and 9 K, respectively, whereas Au-Si-(Tb, Dy or Ho) show indications of a canted ferromagnetic transition at 8.3, 5.9 and 3.8 K, respectively. The latter are attributed to a crystal electric field effect that is absent in the Gd-bearing compounds. The ferromagnetic behavior in Au-SM-R may be understood to be a consequence of the short R-R distances compared to those for Cd-R and Ag-In-R. PMID- 24806440 TI - Beyond muscle hypertrophy: why dietary protein is important for endurance athletes. AB - Recovery from the demands of daily training is an essential element of a scientifically based periodized program whose twin goals are to maximize training adaptation and enhance performance. Prolonged endurance training sessions induce substantial metabolic perturbations in skeletal muscle, including the depletion of endogenous fuels and damage/disruption to muscle and body proteins. Therefore, increasing nutrient availability (i.e., carbohydrate and protein) in the post training recovery period is important to replenish substrate stores and facilitate repair and remodelling of skeletal muscle. It is well accepted that protein ingestion following resistance-based exercise increases rates of skeletal muscle protein synthesis and potentiates gains in muscle mass and strength. To date, however, little attention has focused on the ability of dietary protein to enhance skeletal muscle remodelling and stimulate adaptations that promote an endurance phenotype. The purpose of this review is to critically discuss the results of recent studies that have examined the role of dietary protein for the endurance athlete. Our primary aim is to consider the results from contemporary investigations that have advanced our knowledge of how the manipulation of dietary protein (i.e., amount, type, and timing of ingestion) can facilitate muscle remodelling by promoting muscle protein synthesis. We focus on the role of protein in facilitating optimal recovery from, and promoting adaptations to strenuous endurance-based training. PMID- 24806442 TI - A broad spectrum high-SPF photostable sunscreen with a high UVA-PF can protect against cellular damage at high UV exposure doses. AB - BACKGROUND: Advances in sunscreen technologies have yielded broad spectrum sunscreens at high-sun protection factor (SPF) and ultraviolet A protection factor (UVA-PF) levels that are photostable and powerful in protecting skin from erythema. Questions arise whether these sunscreens protect proportionally against cellular skin damage caused by high ultraviolet exposures. OBJECTIVE: The objective of this study is to evaluate if high-SPF sunscreen can protect skin at a cellular level under UV exposure doses [>50 minimal erythema dose (MED)] similarly to the SPF value. METHODS: Sunburn cells, Langerhans cells, thymine dimers, protein 53 (p53), and matrix metalloproteinase (MMP)-1 and MMP-9 endpoints were evaluated in biopsies from 12 subjects following four treatments: unprotected exposed to 0, 1 and 3 MED and sunscreen (SPF 55) protected exposed to 55 MED of UV radiation. RESULTS: All the markers showed significantly more damage for the 3 MED-untreated sites when compared with non-irradiated control, and majority of the markers showed marked damage following unprotected 1 MED exposure. After 55 MEDs, sunscreen-protected sites showed significantly less p53 and MMP-9 (keratinocyte) staining than the 1 MED-exposed unprotected sites, while all the other biomarkers in sunscreen protected sites showed no statistical differences from 1 MED-exposed unprotected sites. CONCLUSIONS: A high-SPF photostable sunscreen with high UVA-PF can provide proportionately high protection against multiple cellular damage markers. PMID- 24806441 TI - Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. AB - IMPORTANCE: Several lines of evidence have linked the endogenous neuromodulator kynurenic acid (KYNA) to schizophrenia. The pathophysiology of schizophrenia is commonly associated with stress, and stress plays a key regulatory role in the first, rate-limiting step of the kynurenine pathway, which produces KYNA. OBJECTIVE: To determine whether the level of KYNA changes following psychological stress and whether this change is associated with stress-related behavior. DESIGN, SETTING, AND PARTICIPANTS: The KYNA level was measured in saliva samples taken at baseline and at 2 times following a laboratory-based psychological stress challenge in 128 participants (64 patients with schizophrenia from outpatient clinics and 64 healthy controls from the community). EXPOSURE: Laboratory-based psychological stress challenge. MAIN OUTCOMES AND MEASURES: Quitting the stressful task early was used as a behavioral marker of distress intolerance. RESULTS: Patients with schizophrenia showed a significantly higher rate of distress intolerance compared with healthy controls (P = .003). Salivary KYNA levels increased significantly between baseline and 20 minutes following the stress task in both patients and controls (mean [SEM], 6.72nM [0.65nM] vs 8.43nM [1.05nM], respectively; P = .007). Patients who were unable to tolerate the stressful tasks and quit early showed significantly higher levels of KYNA than patients who tolerated the psychological stressor (P = .02) or healthy controls (P = .02). In patients with distress intolerance, KYNA elevation significantly correlated with the severity of clinical symptoms (rho = 0.64; P = .008). CONCLUSIONS AND RELEVANCE: Distress intolerance is more common in patients with schizophrenia. Patients with this behavioral phenotype have elevated salivary KYNA levels. This stress response behavior-linked biomarker may aid heterogeneity reduction in schizophrenia and other stress-related psychiatric conditions. PMID- 24806443 TI - Specific epiblast loss and hypoblast impairment in cattle embryos sensitized to survival signalling by ubiquitous overexpression of the proapoptotic gene BAD. AB - Early embryonic lethality is common, particularly in dairy cattle. We made cattle embryos more sensitive to environmental stressors by raising the threshold of embryo survival signaling required to overcome the deleterious effects of overexpressing the proapoptotic protein BAD. Two primary fibroblast cell lines expressing BAD and exhibiting increased sensitivity to stress-induced apoptosis were used to generate transgenic Day 13/14 BAD embryos. Transgenic embryos were normal in terms of retrieval rates, average embryo length or expression levels of the trophectoderm marker ASCL2. However both lines of BAD-tg embryos lost the embryonic disc and thus the entire epiblast lineage at significantly greater frequencies than either co-transferrred IVP controls or LacZ-tg embryos. Embryos without epiblast still contained the second ICM-derived lineage, the hypopblast, albeit frequently in an impaired state, as shown by reduced expression of the hypoblast markers GATA4 and FIBRONECTIN. This indicates a gradient of sensitivity (epiblast > hypoblast > TE) to BAD overexpression. We postulate that the greater sensitivity of specifically the epiblast lineage that we have seen in our transgenic model, reflects an inherent greater susceptibility of this lineage to environmental stress and may underlie the epiblast-specific death seen in phantom pregnancies. PMID- 24806444 TI - AmotL2 links VE-cadherin to contractile actin fibres necessary for aortic lumen expansion. AB - The assembly of individual endothelial cells into multicellular tubes is a complex morphogenetic event in vascular development. Extracellular matrix cues and cell-cell junctional communication are fundamental to tube formation. Together they determine the shape of endothelial cells and the tubular structures that they ultimately form. Little is known regarding how mechanical signals are transmitted between cells to control cell shape changes during morphogenesis. Here we provide evidence that the scaffold protein amotL2 is needed for aortic vessel lumen expansion. Using gene inactivation strategies in zebrafish, mouse and endothelial cell culture systems, we show that amotL2 associates to the VE cadherin adhesion complex where it couples adherens junctions to contractile actin fibres. Inactivation of amotL2 dissociates VE-cadherin from cytoskeletal tensile forces that affect endothelial cell shape. We propose that the VE cadherin/amotL2 complex is responsible for transmitting mechanical force between endothelial cells for the coordination of cellular morphogenesis consistent with aortic lumen expansion and function. PMID- 24806446 TI - TIPE2 negatively regulates inflammation by switching arginine metabolism from nitric oxide synthase to arginase. AB - TIPE2, the tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2), plays an essential role in maintaining immune homeostasis. It is highly expressed in macrophages and negatively regulates inflammation through inhibiting Toll-like receptor signaling. In this paper, we utilized RAW264.7 cells stably transfected with a TIPE2 expression plasmid, as well as TIPE2 deficient macrophages to study the roles of TIPE2 in LPS-induced nitric oxide (NO) and urea production. The results showed that TIPE2-deficiency significantly upregulated the levels of iNOS expression and NO production in LPS-stimulated macrophages, but decreased mRNA levels of arginase I and urea production. However, TIPE2 overexpression in macrophages was capable of downregulating protein levels of LPS-induced iNOS and NO, but generated greater levels of arginase I and urea production. Furthermore, TIPE2-/- mice had higher iNOS protein levels in lung and liver and higher plasma NO concentrations, but lower levels of liver arginase I compared to LPS-treated WT controls. Interestingly, significant increases in IkappaB degradation and phosphorylation of JNK, p38, and IkappaB were observed in TIPE2-deficient macrophages following LPS challenge. These results strongly suggest that TIPE2 plays an important role in shifting L arginase metabolism from production of NO to urea, during host inflammatory response. PMID- 24806447 TI - Integrated testing strategy (ITS) for bioaccumulation assessment under REACH. AB - REACH (registration, evaluation, authorisation and restriction of chemicals) regulation requires that all the chemicals produced or imported in Europe above 1 tonne/year are registered. To register a chemical, physicochemical, toxicological and ecotoxicological information needs to be reported in a dossier. REACH promotes the use of alternative methods to replace, refine and reduce the use of animal (eco)toxicity testing. Within the EU OSIRIS project, integrated testing strategies (ITSs) have been developed for the rational use of non-animal testing approaches in chemical hazard assessment. Here we present an ITS for evaluating the bioaccumulation potential of organic chemicals. The scheme includes the use of all available data (also the non-optimal ones), waiving schemes, analysis of physicochemical properties related to the end point and alternative methods (both in silico and in vitro). In vivo methods are used only as last resort. Using the ITS, in vivo testing could be waived for about 67% of the examined compounds, but bioaccumulation potential could be estimated on the basis of non-animal methods. The presented ITS is freely available through a web tool. PMID- 24806448 TI - Interleukin-2-stimulated natural killer cells are less susceptible to mycophenolate mofetil than non-activated NK cells: possible consequences for immunotherapy. AB - In a clinical phase I/II trial, pediatric patients with high-risk malignancies were treated with ex vivo IL-2-stimulated donor natural killer (NK) cells after transplantation with haploidentical stem cells. To evaluate the potential negative effects of the immunosuppressive drug mycophenolate mofetil (MMF) used for immunotherapy, the functionality and signaling of ex vivo NK cells was investigated. Our results show that during NK cell expansion, long-term (9 days) incubation with mycophenolic acid (MPA), the active metabolite of MMF, in therapeutically relevant concentrations led to the severe inhibition of NK cell proliferation. This correlated with a significantly reduced cytokine/chemokine secretion and the inhibited acquisition of surface receptors regarding cytotoxicity (e.g., NKp30, NKp44, NKp46, NKG2D), adhesion/migration (e.g., ICAM 1/CD54, LFA-1/CD11a, CD62L, CXCR3) and activation (e.g., CD25). Moreover, MPA prevented phosphorylation of the central signaling molecules STAT-3/-4/-5, AKT and ERK1/2. In contrast, short-term (24 h) MPA incubation of IL-2-stimulated NK cells had no or only marginal effects on the activated NK cell phenotype, including receptor expression, cytokine/chemokine secretion and intracellular signaling. Further, short-term MPA incubation only moderately affected the highly cytotoxic activity of previously IL-2-stimulated NK cells. In conclusion, while long-term MPA incubation significantly compromised ex vivo NK cell functionality, previously IL-2-activated NK cells seemed to be rather resistant to short-term MPA treatment. This finding supports the use of IL-2-activated NK cells as immunotherapy, especially for patients treated with MMF after haploidentical stem cell transplantation. PMID- 24806450 TI - Role of glycolipids in the pathogenesis of Enterococcus faecalis urinary tract infection. AB - BACKGROUND: After uropathogenic Escherichia coli (UPEC), Enterococcus faecalis is the second most common pathogen causing urinary tract infections. Monoglucosyl diacylglycerol (MGlcDAG) and diglucosyl-diacylglycerol (DGlcDAG) are the main glycolipids of the E. faecalis cell membrane. Examination of two mutants in genes bgsB and bgsA (both glycosyltransferases) showed that these genes are involved in cell membrane glycolipid biosynthesis, and that their inactivation leads to loss of glycolipids DGlcDAG (bgsA) or both MGlcDAG and DGlcDAG (bgsB). Here we investigate the function of bgsB and bgsA regarding their role in the pathogenesis in a mouse model of urinary tract infection and in bacterial adhesion to T24 bladder epithelial cells. RESULTS: In a mouse model of urinary tract infection, we showed that E. faecalis 12030DeltabgsB and E. faecalis 12030DeltabgsA mutants, colonize uroepithelial surfaces more efficiently than wild-type bacteria. We also demonstrated that these mutants showed a more than three-fold increased binding to human bladder carcinoma cells line T24 compared to the wild-type strain. Bacterial binding could be specifically inhibited by purified glycolipids. Lipoteichoic acid (LTA), wall-teichoic acid (WTA), and glycosaminoglycans (GAGs) were not significantly involved in binding of E. faecalis to the bladder epithelial cell line. CONCLUSIONS: Our data show that the deletion of bgsB and bgsA and the absence of the major glycolipid diglucosyl diacylglycerol increases colonization and binding to uroepithelial cells. We hypothesize that secreted diglucosyl-diacylglycerol blocks host binding sites, thereby preventing bacterial adhesion. Further experiments will be needed to clarify the exact mechanism underlying the adhesion through glycolipids and their cognate receptors. PMID- 24806449 TI - The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation. AB - A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH SY5Y neuroblastoma cells within 24 h and arrested the cells in G1 phase. Sustained overexpression of DYRK1A induced G0 cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27(Kip1) on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27(Kip1) Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome. PMID- 24806452 TI - Common distribution patterns of marsupials related to physiographical diversity in Venezuela. AB - The aim of this study is to identify significant biotic regions (groups of areas with similar biotas) and biotic elements (groups of taxa with similar distributions) for the marsupial fauna in a part of northern South America using physiographical areas as Operational Geographical Units (OGUs). We considered Venezuela a good model to elucidate this issue because of its high diversity in landscapes and the relatively vast amount of information available on the geographical distribution of marsupial species. Based on the presence-absence of 33 species in 15 physiographical sub-regions (OGUs) we identified Operational Biogeographical Units (OBUs) and chorotypes using a quantitative analysis that tested statistical significance of the resulting groups. Altitudinal and/or climatic trends in the OBUs and chorotypes were studied using a redundancy analysis. The classification method revealed four OBUs. Strong biotic boundaries separated: i) the xerophytic zone of the Continental coast (OBU I); ii) the sub regions north of the Orinoco River (OBU III and IV); and those south to the river (OBU II). Eleven chorotypes were identified, four of which included a single species with a restricted geographic distribution. As for the other chorotypes, three main common distribution patterns have been inferred: i) species from the Llanos and/or distributed south of the Orinoco River; ii) species exclusively from the Andes; and iii) species that either occur exclusively north of the Orinoco River or that show a wide distribution throughout Venezuela. Mean altitude, evapotranspiration and precipitation of the driest month, and temperature range allowed us to characterize environmentally most of the OBUs and chorotypes obtained. PMID- 24806451 TI - FMRP S499 is phosphorylated independent of mTORC1-S6K1 activity. AB - Hyperactive mammalian target of rapamycin (mTOR) is associated with cognitive deficits in several neurological disorders including tuberous sclerosis complex (TSC). The phosphorylation of the mRNA-binding protein FMRP reportedly depends on mTOR complex 1 (mTORC1) activity via p70 S6 kinase 1 (S6K1). Because this phosphorylation is thought to regulate the translation of messages important for synaptic plasticity, we explored whether FMRP phosphorylation of the S6K1 dependent residue (S499) is altered in TSC and states of dysregulated TSC-mTORC1 signaling. Surprisingly, we found that FMRP S499 phosphorylation was unchanged in heterozygous and conditional Tsc1 knockout mice despite significantly elevated mTORC1-S6K1 activity. Neither up- nor down-regulation of the mTORC1-S6K1 axis in vivo or in vitro had any effect on phospho-FMRP S499 levels. In addition, FMRP S499 phosphorylation was unaltered in S6K1-knockout mice. Collectively, these data strongly suggest that FMRP S499 phosphorylation is independent of mTORC1 S6K1 activity and is not altered in TSC. PMID- 24806453 TI - Dietary exposure and risk assessment to lead of the population of Jiangsu province, China. AB - The paper's main purpose is to estimate the dietary exposure to lead for the inhabitants of Jiangsu province, China. Lead concentration data were obtained from the national food contamination monitoring programme during 2007-10. Food samples (n = 2077) were collected from 23 food categories in Jiangsu province. Consumption data were derived from Chinese national nutrition and health survey in 2002, which included 3938 inhabitants from 1451 households in Jiangsu province. Concentration data were combined with consumption data to estimate the dietary intake for the inhabitants of 2-6, 7-17 and 18-80 years, respectively. The beta-binomial-normal (BBN) model was used to estimate the long-term intake for the population in Jiangsu province. The distribution of individual margin of exposure (IMoE) was introduced to assess the health effect. Uncertainty of IMoE was quantified by Monte Carlo and bootstrap methods. The mean levels of dietary exposure to lead were estimated at 3.019 ug kg(-1) bw day(-1) for children aged 2 6 years, 2.104 ug kg(-1) bw day(-1) for teenagers aged 7-17 years, and 1.601 ug kg(-1) bw day(-1) for adults aged 18-80 years. The mean intakes for the urban and rural populations were 1.494 and 1.822 ug kg(-1) bw day(-1), respectively. From the 25th to 99.9th percentiles, IMoE was 0.125-2.057 for 2-6 years and 0.473 7.998 for 18-80 years, respectively. The distribution of IMoE could indicate a public health concern on lead for the Chinese population in Jiangsu. Control measures should be taken to reduce lead exposure in Jiangsu province. PMID- 24806454 TI - Men who have sex with mens' exposure to, use of, and subjective experiences with the 'NYC Condom'. AB - In 2007, the New York City (NYC) Department of Health introduced the 'NYC Condom' -a Lifestyles(r) condom with a 'NYC' logo. Few studies have evaluated attitudes toward or distribution of the 'NYC Condom' among men who have sex with men (MSM)- a population at increased risk for HIV/STIs. 148 MSM completed a survey about their exposure to, use of, and experiences using the 'NYC Condom.' The majority (93.2 %) had seen the 'NYC Condom;' 82.4 % of said men had used it. Among MSM who used it, 82.1 % rated it average or above. Exposure did not statistically differ by race/ethnicity, HIV status, gay or barebacker identification, or sex role. Use was neither significantly associated with demographic characteristics nor recruitment source, suggesting distributional success in reaching various sub populations of MSM. Among those who had not used the 'NYC Condom,' 22.2 % reported size or quality concerns, suggesting a demand for alternative prevention campaigns. PMID- 24806455 TI - A new representative of star-shaped fungi: Astraeus sirindhorniae sp. nov. from Thailand. AB - Phu Khieo Wildlife Sanctuary (PKWS) is a major hotspot of biological diversity in Thailand but its fungal diversity has not been thouroughly explored. A two-year macrofungal study of this remote locality has resulted in the recognition of a new species of a star-shaped gasteroid fungus in the genus Astraeus. This fungus has been identified based on a morphological approach and the molecular study of five loci (LSU nrDNA, 5.8S nrDNA, RPB1, RPB2 and EF1-a). Multigene phylogenetic analysis of this new species places it basal relative to other Astraeus, providing additional evidence for the SE Asian origin of the genus. The fungus is named in honour of Her Majesty Princess Sirindhorn on the occasion the 84th birthday of her father, who have both been supportive of natural heritage studies in Thailand. PMID- 24806456 TI - Comparative pharmacokinetic study of two boswellic acids in normal and arthritic rat plasma after oral administration of Boswellia serrata extract or Huo Luo Xiao Ling Dan by LC-MS. AB - Huo Luo Xiao Ling Dan (HLXLD), a Chinese herbal formula composed of 11 different herbs, has been used traditionally for the treatment of arthritis and other chronic inflammatory diseases. However, the pharmacokinetic profile of its anti inflammatory bioactive compounds has not been elucidated. Boswellic acids are the bioactive compounds with potent anti-inflammatory activity isolated from Boswellia serrate which is one of the 11 herbs of HLXLD. The objective of the study was to compare the pharmacokinetics of the two bioactive bowsellic acids: 11-keto-beta-boswellic acid and 3-O-acetyl-11-keto-beta-boswellic following oral administration of HLXLD or Boswellia serrata extract alone in normal and arthritic rats. An LC-MS method was developed and validated for the determination of 11-keto-beta-boswellic acid and 3-O-acetyl-11-keto-beta-boswellic in the comparative pharmacokinetic study. The results showed that there were significant differences in pharmacokinetic parameters between normal and arthritic groups. Interestingly, the absorptions of two boswellic acids were significantly higher in HLXLD than Boswellia serrata extract alone, indicating the synergistic effect of other herbal ingredients in HLXLD. This comparative pharmacokinetic study provided direct evidence supporting the notion that the efficacy of a complex mixture such as HLXLD is better than that of single components in treating human diseases. PMID- 24806457 TI - c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. AB - Although transplantation of c-kit+ cardiac stem cells (CSCs) has been shown to alleviate left ventricular (LV) dysfunction induced by myocardial infarction (MI), the number of exogenous CSCs remaining in the recipient heart following transplantation and their mechanism of action remain unclear. We have previously developed a highly sensitive and accurate method to quantify the absolute number of male murine CSCs in female recipient organs after transplantation. In the present study, we used this method to monitor the number of donor CSCs in the recipient heart after intracoronary infusion. Female mice underwent a 60-min coronary occlusion followed by reperfusion; 2 days later, 100,000 c-kit+/lin- syngeneic male mouse CSCs were infused intracoronarily. Only 12.7% of the male CSCs present in the heart immediately (5 min) after infusion were still present in the heart at 24 h, and their number declined rapidly thereafter. By 35 days after infusion, only ~ 1,000 male CSCs were found in the heart. Significant numbers of male CSCs were found in the lungs and kidneys, but only in the first 24 h. The number of CSCs in the lungs increased between 5 min and 24 h after infusion, indicating recirculation of CSCs initially retained in other organs. Despite the low retention and rapid disappearance of CSCs from the recipient heart, intracoronary delivery of CSCs significantly improved LV function at 35 days (Millar catheter). These results suggest that direct differentiation of CSCs alone cannot account for the beneficial effects of CSCs on LV function; therefore, paracrine effects must be the major mechanism. The demonstration that functional improvement is dissociated from survival of transplanted cells has major implications for our understanding of cell therapy. In addition, this new quantitative method of stem cell measurement will be useful in testing approaches of enhancing CSC engraftment and survival after transplantation. PMID- 24806459 TI - Mortality risk and survival in the aftermath of the medieval Black Death. AB - The medieval Black Death (c. 1347-1351) was one of the most devastating epidemics in human history. It killed tens of millions of Europeans, and recent analyses have shown that the disease targeted elderly adults and individuals who had been previously exposed to physiological stressors. Following the epidemic, there were improvements in standards of living, particularly in dietary quality for all socioeconomic strata. This study investigates whether the combination of the selective mortality of the Black Death and post-epidemic improvements in standards of living had detectable effects on survival and mortality in London. Samples are drawn from several pre- and post-Black Death London cemeteries. The pre-Black Death sample comes from the Guildhall Yard (n = 75) and St. Nicholas Shambles (n = 246) cemeteries, which date to the 11th-12th centuries, and from two phases within the St. Mary Spital cemetery, which date to between 1120-1300 (n = 143). The St. Mary Graces cemetery (n = 133) was in use from 1350-1538 and thus represents post-epidemic demographic conditions. By applying Kaplan-Meier analysis and the Gompertz hazard model to transition analysis age estimates, and controlling for changes in birth rates, this study examines differences in survivorship and mortality risk between the pre- and post-Black Death populations of London. The results indicate that there are significant differences in survival and mortality risk, but not birth rates, between the two time periods, which suggest improvements in health following the Black Death, despite repeated outbreaks of plague in the centuries after the Black Death. PMID- 24806458 TI - Survival on home dialysis in New Zealand. AB - BACKGROUND: New Zealand (NZ) has a high prevalence of both peritoneal dialysis (PD) and home haemodialysis (HD) relative to other countries, and probably less selection bias. We aimed to determine if home dialysis associates with better survival than facility HD by simultaneous comparisons of the three modalities. METHODS: We analysed survival by time-varying dialysis modality in New Zealanders over a 15-year period to 31-Dec-2011, adjusting for patient co-morbidity by Cox proportional hazards multivariate regression. RESULTS: We modelled 6,419 patients with 3,254 deaths over 20,042 patient-years of follow-up. Patients treated with PD and facility HD are similar; those on home HD are younger and healthier. Compared to facility HD, home dialysis (as a unified category) associates with an overall 13% lower mortality risk. Home HD associates with a 52% lower mortality risk. PD associates with a 20% lower mortality risk in the early period (<3 years) that is offset by a 33% greater mortality risk in the late period (>3 years), with no overall net effect. There was effect modification and less observable benefit associated with PD in those with diabetes mellitus, co morbidity, and in NZ Maori and Pacific People. There was no effect modification by age or by era. CONCLUSION: Our study supports the culture of home dialysis in NZ, and suggests that the extent and duration of survival benefit associated with early PD may be greater than appreciated. We are planning further analyses to exclude residual confounding from unmeasured co-morbidity and other sociodemographic factors using database linkage to NZ government datasets. Finally, our results suggest further research into the practice of PD in NZ Maori and Pacific People, as well as definitive study to determine the best timing for switching from PD in the late phase. PMID- 24806460 TI - Improving the secretion of a methyl parathion hydrolase in Pichia pastoris by modifying its N-terminal sequence. AB - Pichia pastoris is commonly used to express and secrete target proteins, although not all recombinant proteins can be successfully produced. In this study, we used methyl parathion hydrolase (MPH) from Ochrobactrum sp. M231 as a model to study the importance of the N-terminus of the protein for its secretion. While MPH can be efficiently expressed intracellularly in P. pastoris, it is not secreted into the extracellular environment. Three MPH mutants (N66-MPH, D10-MPH, and N9-MPH) were constructed through modification of its N-terminus, and the secretion of each by P. pastoris was improved when compared to wild-type MPH. The level of secreted D10-MPH was increased to 0.21 U/mL, while that of N9-MPH was enhanced to 0.16 U/mL. Although N66-MPH was not enzymatically active, it was secreted efficiently, and was identified by SDS-PAGE. These results demonstrate that the secretion of heterologous proteins in P. pastoris may be improved by modifying their N-terminal structures. PMID- 24806462 TI - A simple and versatile 2-dimensional platform to study plant germination and growth under controlled humidity. AB - We describe a simple, inexpensive, but remarkably versatile and controlled growth environment for the observation of plant germination and seedling root growth on a flat, horizontal surface over periods of weeks. The setup provides to each plant a controlled humidity (between 56% and 91% RH), and contact with both nutrients and atmosphere. The flat and horizontal geometry of the surface supporting the roots eliminates the gravitropic bias on their development and facilitates the imaging of the entire root system. Experiments can be setup under sterile conditions and then transferred to a non-sterile environment. The system can be assembled in 1-2 minutes, costs approximately 8.78$ per plant, is almost entirely reusable (0.43$ per experiment in disposables), and is easily scalable to a variety of plants. We demonstrate the performance of the system by germinating, growing, and imaging Wheat (Triticum aestivum), Corn (Zea mays), and Wisconsin Fast Plants (Brassica rapa). Germination rates were close to those expected for optimal conditions. PMID- 24806461 TI - Epithelial SCAP/INSIG/SREBP signaling regulates multiple biological processes during perinatal lung maturation. AB - Pulmonary surfactant is required for lung function at birth and throughout postnatal life. Defects in the surfactant system are associated with common pulmonary disorders including neonatal respiratory distress syndrome and acute respiratory distress syndrome in children and adults. Lipogenesis is essential for the synthesis of pulmonary surfactant by type II epithelial cells lining the alveoli. This study sought to identify the role of pulmonary epithelial SREBP, a transcriptional regulator of cellular lipid homeostasis, during a critical time period of perinatal lung maturation in the mouse. Genome wide mRNA expression profiling of lung tissue from transgenic mice with epithelial-specific deletions of Scap (Scap(Delta/Delta), resulting in inactivation of SREBP signaling) or Insig1 and Insig2 (Insig1/2(Delta/Delta), resulting in activation of SREBP signaling) was assessed. Differentially expressed genes responding to SREBP perturbations were identified and subjected to functional enrichment analysis, pathway mapping and literature mining to predict upstream regulators and transcriptional networks regulating surfactant lipid homeostasis. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified. SREBP signaling influences epithelial development, cell death and cell proliferation at E17.5, while primarily influencing surfactant physiology, lipid/sterol synthesis, and phospholipid transport after birth. SREBP signaling integrated with the Wnt/beta catenin and glucocorticoid receptor signaling pathways during perinatal lung maturation. SREBP regulates perinatal lung lipogenesis and maturation through multiple mechanisms by interactions with distinct sets of regulatory partners. PMID- 24806463 TI - Motor network plasticity and low-frequency oscillations abnormalities in patients with brain gliomas: a functional MRI study. AB - Brain plasticity is often associated with the process of slow-growing tumor formation, which remodels neural organization and optimizes brain network function. In this study, we aimed to investigate whether motor function plasticity would display deficits in patients with slow-growing brain tumors located in or near motor areas, but who were without motor neurological deficits. We used resting-state functional magnetic resonance imaging to probe motor networks in 15 patients with histopathologically confirmed brain gliomas and 15 age-matched healthy controls. All subjects performed a motor task to help identify individual motor activity in the bilateral primary motor cortex (PMC) and supplementary motor area (SMA). Frequency-based analysis at three different frequencies was then used to investigate possible alterations in the power spectral density (PSD) of low-frequency oscillations. For each group, the average PSD was determined for each brain region and a nonparametric test was performed to determine the difference in power between the two groups. Significantly reduced inter-hemispheric functional connectivity between the left and right PMC was observed in patients compared with controls (P<0.05). We also found significantly decreased PSD in patients compared to that in controls, in all three frequency bands (low: 0.01-0.02 Hz; middle: 0.02-0.06 Hz; and high: 0.06 0.1 Hz), at three key motor regions. These findings suggest that in asymptomatic patients with brain tumors located in eloquent regions, inter-hemispheric connection may be more vulnerable. A comparison of the two approaches indicated that power spectral analysis is more sensitive than functional connectivity analysis for identifying the neurological abnormalities underlying motor function plasticity induced by slow-growing tumors. PMID- 24806464 TI - Biological responses of human gingival fibroblasts (HGFs) in an innovative co culture model with Streptococcus mitis to thermosets coated with a silver polysaccharide antimicrobial system. AB - This study sought to evaluate the in vitro biological response of human gingival fibroblasts (HGFs) co-coltured with Streptococcus mitis to bisphenol A glycidylmethacrylate/triethylene glycol dimethacrylate (BisGMA/TEGDMA) thermosets coated with Chitlac-nAg, a nanocomposite system with antimicrobial properties. To avoid bacterial adhesion to dental devices and to reduce cytotoxicity against eukaryotic cells, we coated BisGMA/TEGDMA methacrylic thermosets with a new material, Chitlac-nAg, formed by stabilizing silver nanoparticles, which have well-known antimicrobial properties, with a polyelectrolyte solution containing Chitlac. Cytotoxicity, cell morphology, cell migration and inflammatory interleukine-6 (IL-6) and prostaglandin E2 (PGE2) secretion were evaluated. Our results showed that the cytotoxicity exerted on HGFs by our nanocomposite material was absent in our co-culture model, where fibroblasts are able to adhere and migrate. After 24 h thermosets coated with Chitlac as well as those coated with Chitlac-nAg exerted a minimal cytotoxic effect on HGFs, while after 48 h LDH release rises up 20%. Moreover the presence of S. mitis reduced this release in a greater amount with Chitlac-nAg coated thermosets. The secretion of IL-6 was significant in both Chitlac and Chitlac-nAg coated thermosets, but PGE2 production was minimal, suggesting that the IL-6 production was not related to an inflammatory response. Co-culture and the addiction of saliva did not influence IL-6 and PGE2 secretion. Data obtained in the present work suggest that Chitlac n Ag coated thermosets could significantly improve the success rates of restorative dentistry, since they limit bacterial adhesion and are not toxic to HGFs. PMID- 24806466 TI - Pain, mind, and movement in musculoskeletal pain: is physical activity always health-promoting or are there detrimental aspects? PMID- 24806465 TI - Real-world efficiency of pharmacogenetic screening for carbamazepine-induced severe cutaneous adverse reactions. AB - OBJECTIVES: We evaluated the cost and efficiency of routine HLA-B*15 ? 02 screening to prevent carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-SJS/TEN) in Hong Kong. METHODS: Data were extracted from patients who commenced CBZ as the first-ever AED treatment or tested for HLA B*15 ? 02 allele in three years before policy implementation (pre-policy: 16 September 2005 to 15 September 2008) and three years after (post-policy: 16 September 2008 to 15 September 2011). Using published unit costs, we estimated the cost of screening by comparing the costs to prevent and treat CBZ-SJS/TEN. We compared the number of person-tests needed and the cost to prevent resultant death with cancer screening programs. RESULTS: The number of screening tests needed to prevent one case of CBZ-SJS/TEN was 442, and to prevent one resultant death was 1,474 to 8,840. The screening cost was $332 per person, of which 42% was attributed to an additional consultation to review result and prescribe appropriate medication. HLA-B*15 ? 02 screening expended $146,749 to prevent a case of CBZ-SJS/TEN, and $489,386- $2,934,986 to prevent a resultant death. The corresponding numbers of tests and costs for mammography and Pap smear to prevent death due to breast and cervical cancers were 7,150 and 7,000, and $614,900 and $273,000, respectively. Comparing to the SJS/TEN treatment cost, HLA-B*15 ? 02 screening would become cost saving if a point-of-care test of less than $37 was available. CONCLUSIONS: HLA-B*15 ? 02 screening is as efficient as mammography and Pap smear in preventing death. Development of point-of-care testing will vastly improve efficiency. PMID- 24806467 TI - Ability of the central sensitization inventory to identify central sensitivity syndromes in an outpatient chronic pain sample. AB - OBJECTIVES: The aim of this study was to determine the ability of the central sensitization inventory (CSI), a new screening instrument, to assist clinicians in identifying patients with central sensitivity syndromes (CSSs). METHODS: Patients from a psychiatric medical practice (N=161), which specialized in the assessment and treatment of complex pain and psychophysiological disorders, were assessed for the presence of a CSS. CSI scores, using a previously determined cutoff of "40" of "100," were compared between the CSS patient group (n=99) and the non-CSS patient group (n=62). Information on false positives, false negatives, true positives, and true negatives were analyzed, and sensitivity and specificity analyses were conducted. In addition, CSS-relevant variables such as depression, abuse, and substance abuse were examined. RESULTS: A large percentage of CSS patients had comorbid major depressive disorder (80%) and abuse history (43%), which was higher than rates for the patients without a CSS (55% and 24%, respectively). The CSI correctly identified 82.8% (n=82) of CSS patients as having a CSS (ie, sensitivity) and 54.8% (n=28) of non-CSS patients as not having a CSS (ie, specificity). False-positive patients (not diagnosed with a CSS, but scoring >40 on the CSI) reported more severe pain, interference in daily functioning, and abuse history, compared with the non-CSS patients who scored below 40 (ie, true negatives). CONCLUSIONS: The CSI is a useful and valid instrument for screening patients for the possibility of a CSS, although the chances of false positives are relatively high when evaluating patients with complex pain and psychophysiological disorders. PMID- 24806468 TI - The shared neuroanatomy and neurobiology of comorbid chronic pain and PTSD: therapeutic implications. AB - Chronic pain and posttraumatic stress disorder (PTSD) are disabling conditions that affect biological, psychological, and social domains of functioning. Clinical research demonstrates that patients who are affected by chronic pain and PTSD in combination experience greater pain, affective distress, and disability than patients with either condition alone. Additional research is needed to delineate the interrelated pathophysiology of chronic pain and PTSD, with the goal of facilitating more effective therapies to treat both conditions more effectively; current treatment strategies for chronic pain associated with PTSD have limited efficacy and place a heavy burden on patients, who must visit various specialists to manage these conditions separately. This article focuses on neurobiological factors that may contribute to the coprevalence and synergistic interactions of chronic pain and PTSD. First, we outline how circuits that mediate emotional distress and physiological threat, including pain, converge. Secondly, we discuss specific neurobiological mediators and modulators of these circuits that may contribute to chronic pain and PTSD symptoms. For example, neuropeptide Y, and the neuroactive steroids allopregnanolone and pregnanolone (together termed ALLO) have antistress and antinociceptive properties. Reduced levels of neuropeptide Y and ALLO have been implicated in the pathophysiology of both chronic pain and PTSD. The potential contribution of opioid and cannabinoid system factors also will be discussed. Finally, we address potential novel methods to restore the normal function of these systems. Such novel perspectives regarding disease and disease management are vital to the pursuit of relief for the many individuals who struggle with these disabling conditions. PMID- 24806469 TI - Which behavior change techniques are associated with changes in physical activity, diet and body mass index in people with recently diagnosed diabetes? AB - BACKGROUND: Meta-analyses have identified promising behavior change techniques (BCTs) in changing obesity-related behaviors from intervention descriptions. However, it is unclear whether these BCTs are used by intervention participants and are related to outcomes. PURPOSE: The purpose of this study is to investigate BCT use by participants of an intervention targeting physical activity and diet and whether BCT use was related to behavior change and weight loss. METHODS: Intervention participants (N = 239; 40-69 years) with recently diagnosed type 2 diabetes in the ADDITION-Plus trial received a theory-based intervention which taught them a range of BCTs. BCT usage was reported at 1 year. RESULTS: Thirty six percent of the participants reported using all 16 intervention BCTs. Use of a higher number of BCTs and specific BCTs (e.g., goal setting) were associated with a reduction in body mass index (BMI). CONCLUSIONS: BCT use was associated with weight loss. Future research should identify strategies to promote BCT use in daily life. ( TRIAL REGISTRATION: ISRCTN99175498.). PMID- 24806470 TI - Associations between central nervous system serotonin, fasting glucose, and hostility in African American females. AB - BACKGROUND: Previous research has shown an association between hostility and fasting glucose in African American women. Central nervous system serotonin activity is implicated both in metabolic processes and in hostility related traits. PURPOSE: The purpose of this study is to determine whether central nervous system serotonin influences the association between hostility and fasting glucose in African American women. METHODS: The study consisted of 119 healthy volunteers (36 African American women, 27 White women, 21 White males, and 35 African American males, mean age 34 +/- 8.5 years). Serotonin related compounds were measured in cerebrospinal fluid. Hostility was measured by the Cook-Medley Hostility Scale. RESULTS: Hostility was associated with fasting glucose and central nervous system serotonin related compounds in African American women only. Controlling for the serotonin related compounds significantly reduced the association of hostility to glucose. CONCLUSIONS: The positive correlation between hostility and fasting glucose in African American women can partly be explained by central nervous system serotonin function. PMID- 24806471 TI - MIDER: network inference with mutual information distance and entropy reduction. AB - The prediction of links among variables from a given dataset is a task referred to as network inference or reverse engineering. It is an open problem in bioinformatics and systems biology, as well as in other areas of science. Information theory, which uses concepts such as mutual information, provides a rigorous framework for addressing it. While a number of information-theoretic methods are already available, most of them focus on a particular type of problem, introducing assumptions that limit their generality. Furthermore, many of these methods lack a publicly available implementation. Here we present MIDER, a method for inferring network structures with information theoretic concepts. It consists of two steps: first, it provides a representation of the network in which the distance among nodes indicates their statistical closeness. Second, it refines the prediction of the existing links to distinguish between direct and indirect interactions and to assign directionality. The method accepts as input time-series data related to some quantitative features of the network nodes (such as e.g. concentrations, if the nodes are chemical species). It takes into account time delays between variables, and allows choosing among several definitions and normalizations of mutual information. It is general purpose: it may be applied to any type of network, cellular or otherwise. A Matlab implementation including source code and data is freely available (http://www.iim.csic.es/~gingproc/mider.html). The performance of MIDER has been evaluated on seven different benchmark problems that cover the main types of cellular networks, including metabolic, gene regulatory, and signaling. Comparisons with state of the art information-theoretic methods have demonstrated the competitive performance of MIDER, as well as its versatility. Its use does not demand any a priori knowledge from the user; the default settings and the adaptive nature of the method provide good results for a wide range of problems without requiring tuning. PMID- 24806472 TI - The near-eastern roots of the Neolithic in South Asia. AB - The Fertile Crescent in the Near East is one of the independent origins of the Neolithic, the source from which farming and pottery-making spread across Europe from 9,000 to 6,000 years ago at an average rate of about 1 km/yr. There is also strong evidence for causal connections between the Near-Eastern Neolithic and that further east, up to the Indus Valley. The Neolithic in South Asia has been far less explored than its European counterpart, especially in terms of absolute (14)C) dating; hence, there were no previous attempts to assess quantitatively its spread in Asia. We combine the available (14)C data with the archaeological evidence for early Neolithic sites in South Asia to analyze the spatio-temporal continuity of the Neolithic dispersal from the Near East through the Middle East and to the Indian subcontinent. We reveal an approximately linear dependence between the age and the geodesic distance from the Near East, suggesting a systematic (but not necessarily uniform) spread at an average speed of about 0.65 km/yr. PMID- 24806473 TI - CX3CR1 is a modifying gene of survival and progression in amyotrophic lateral sclerosis. AB - The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27 +/- 4.90) than patients with 249V/V genotype (67.65 +/- 7.42; diff -25.49 months 95%CI [-42.79,-8.18]; p = 0.004; adj-p = 0.018). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff = 29.78 months; 95%CI [-49.42,-10.14]; p = 0.003). The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff = -27.02 months; 95%CI [-49.57, -4.48]; p = 0.019). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis. PMID- 24806474 TI - Missed opportunities for retention in pre-ART care in Cape Town, South Africa. AB - BACKGROUND: Few studies have evaluated access to and retention in pre-ART care. OBJECTIVES: To evaluate the proportion of People Living With HIV (PLWH) in pre ART and ART care and factors associated with retention in pre-ART and ART care from a community cohort. METHODS: A cross sectional survey was conducted from February - April 2011. Self reported HIV positive, negative or participants of unknown status completed a questionnaire on their HIV testing history, access to pre-ART and retention in pre-ART and ART care. RESULTS: 872 randomly selected adults who reported being HIV positive in the ZAMSTAR 2010 prevalence survey were included and revisited. 579 (66%) reconfirmed their positive status and were included in this analysis. 380 (66%) had initiated ART with 357 of these (94%) retained in ART care. 199 (34%) had never initiated ART of whom 186 (93%) accessed pre-ART care, and 86 (43%) were retained in pre-ART care. In a univariable analysis none of the factors analysed were significantly associated with retention in care in the pre-ART group. Due to the high retention in ART care, factors associated with retention in ART care, were not analysed further. CONCLUSION: Retention in ART care was high; however it was low in pre-ART care. The opportunity exists, if care is better integrated, to engage with clients in primary health care facilities to bring them back to, and retain them in, pre-ART care. PMID- 24806476 TI - Significance of ubiquitin carboxy-terminal hydrolase L1 elevations in athletes after sub-concussive head hits. AB - The impact of sub-concussive head hits (sub-CHIs) has been recently investigated in American football players, a population at risk for varying degrees of post traumatic sequelae. Results show how sub-CHIs in athletes translate in serum as the appearance of reporters of blood-brain barrier disruption (BBBD), how the number and severity of sub-CHIs correlate with elevations of putative markers of brain injury is unknown. Serum brain injury markers such as UCH-L1 depend on BBBD. We investigated the effects of sub-CHIs in collegiate football players on markers of BBBD, markers of cerebrospinal fluid leakage (serum beta 2 transferrin) and markers of brain damage. Emergency room patients admitted for a clinically-diagnosed mild traumatic brain injury (mTBI) were used as positive controls. Healthy volunteers were used as negative controls. Specifically this study was designed to determine the use of UCH-L1 as an aid in the diagnosis of sub-concussive head injury in athletes. The extent and intensity of head impacts and serum values of S100B, UCH-L1, and beta-2 transferrin were measured pre- and post-game from 15 college football players who did not experience a concussion after a game. S100B was elevated in players experiencing the most sub-CHIs; UCH L1 levels were also elevated but did not correlate with S100B or sub-CHIs. Beta-2 transferrin levels remained unchanged. No correlation between UCH-L1 levels and mTBI were measured in patients. Low levels of S100B were able to rule out mTBI and high S100B levels correlated with TBI severity. UCH-L1 did not display any interpretable change in football players or in individuals with mild TBI. The significance of UCH-L1 changes in sub-concussions or mTBI needs to be further elucidated. PMID- 24806477 TI - Hidden among sea anemones: the first comprehensive phylogenetic reconstruction of the order Actiniaria (Cnidaria, Anthozoa, Hexacorallia) reveals a novel group of hexacorals. AB - Sea anemones (order Actiniaria) are among the most diverse and successful members of the anthozoan subclass Hexacorallia, occupying benthic marine habitats across all depths and latitudes. Actiniaria comprises approximately 1,200 species of solitary and skeleton-less polyps and lacks any anatomical synapomorphy. Although monophyly is anticipated based on higher-level molecular phylogenies of Cnidaria, to date, monophyly has not been explicitly tested and at least some hypotheses on the diversification of Hexacorallia have suggested that actiniarians are para- or poly-phyletic. Published phylogenies have demonstrated the inadequacy of existing morphological-based classifications within Actiniaria. Superfamilial groups and most families and genera that have been rigorously studied are not monophyletic, indicating conflict with the current hierarchical classification. We test the monophyly of Actiniaria using two nuclear and three mitochondrial genes with multiple analytical methods. These analyses are the first to include representatives of all three currently-recognized suborders within Actiniaria. We do not recover Actiniaria as a monophyletic clade: the deep-sea anemone Boloceroides daphneae, previously included within the infraorder Boloceroidaria, is resolved outside of Actiniaria in several of the analyses. We erect a new genus and family for B. daphneae, and rank this taxon incerti ordinis. Based on our comprehensive phylogeny, we propose a new formal higher-level classification for Actiniaria composed of only two suborders, Anenthemonae and Enthemonae. Suborder Anenthemonae includes actiniarians with a unique arrangement of mesenteries (members of Edwardsiidae and former suborder Endocoelantheae). Suborder Enthemonae includes actiniarians with the typical arrangement of mesenteries for actiniarians (members of former suborders Protantheae, Ptychodacteae, and Nynantheae and subgroups therein). We also erect subgroups within these two newly-erected suborders. Although some relationships among these newly-defined groups are still ambiguous, morphological and molecular results are consistent enough to proceed with a new higher-level classification and to discuss the putative functional and evolutionary significance of several morphological attributes within Actiniaria. PMID- 24806478 TI - Confirming the cognition of rising scores: Fox and Mitchum (2013) predicts violations of measurement invariance in series completion between age-matched cohorts. AB - The trend of rising scores on intelligence tests raises important questions about the comparability of variation within and between time periods. Descriptions of the processes that mediate selection of item responses provide meaningful psychological criteria upon which to base such comparisons. In a recent paper, Fox and Mitchum presented and tested a cognitive theory of rising scores on analogical and inductive reasoning tests that is specific enough to make novel predictions about cohort differences in patterns of item responses for tests such as the Raven's Matrices. In this paper we extend the same proposal in two important ways by (1) testing it against a dataset that enables the effects of cohort to be isolated from those of age, and (2) applying it to two other inductive reasoning tests that exhibit large Flynn effects: Letter Series and Word Series. Following specification and testing of a confirmatory item response model, predicted violations of measurement invariance are observed between two age-matched cohorts that are separated by only 20 years, as members of the later cohort are found to map objects at higher levels of abstraction than members of the earlier cohort who possess the same overall level of ability. Results have implications for the Flynn effect and cognitive aging while underscoring the value of establishing psychological criteria for equating members of distinct groups who achieve the same scores. PMID- 24806479 TI - Hybrid modeling for quality by design and PAT-benefits and challenges of applications in biopharmaceutical industry. AB - This report highlights the drivers, challenges, and enablers of the hybrid modeling applications in biopharmaceutical industry. It is a summary of an expert panel discussion of European academics and industrialists with relevant scientific and engineering backgrounds. Hybrid modeling is viewed in its broader sense, namely as the integration of different knowledge sources in form of parametric and nonparametric models into a hybrid semi-parametric model, for instance the integration of fundamental and data-driven models. A brief description of the current state-of-the-art and industrial uptake of the methodology is provided. The report concludes with a number of recommendations to facilitate further developments and a wider industrial application of this modeling approach. These recommendations are limited to further exploiting the benefits of this methodology within process analytical technology (PAT) applications in biopharmaceutical industry. PMID- 24806480 TI - Transition from intravenous or subcutaneous prostacyclin therapy to inhaled treprostinil in patients with pulmonary arterial hypertension: a retrospective case series. AB - WHAT IS KNOWN AND OBJECTIVE: Inhaled treprostinil represents an attractive alternative to the other available prostacyclin formulations by obviating the use of continuous infusions and its associated risks. Published evidence describing the process of transition from infusion prostacyclin therapy to inhaled treprostinil is limited. The purpose of this report is to describe an inpatient protocol for transitioning patients with pulmonary arterial hypertension (PAH) from intravenous (IV) or subcutaneous (SQ) prostacyclin therapy to inhaled treprostinil. METHODS: A retrospective case cohort study was performed evaluating medical records of three patients undergoing transition from IV/SQ continuous infusion prostacyclin therapy to inhaled treprostinil. The transition protocol and clinical data were collected prospectively. RESULTS AND DISCUSSION: Haemodynamics, six-min walk distance (6MWD), World Health Organization (WHO) functional class, modified Borg Dyspnea Score and brain natriuretic peptide prior to and after transition remained similar. All patients were receiving concomitant oral PAH medications prior to and after conversion. Adverse effects during the change were mild. No patients discontinued inhaled treprostinil following transition. At long-term follow-up, functional class remained stable at WHO functional class II or better. Patient 1 and Patient 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. The transition to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients. WHAT IS NEW AND CONCLUSION: Our report describes a standard method used to transition patients from IV/SQ infusion prostacyclin to inhaled treprostinil. PMID- 24806481 TI - Effect of graphic cigarette warnings on smoking intentions in young adults. AB - INTRODUCTION: Graphic warnings (GWs) on cigarette packs are widely used internationally and perhaps will be in the US but their impact is not well understood. This study tested support for competing hypotheses in different subgroups of young adults defined by their history of cigarette smoking and individual difference variables (e.g., psychological reactance). One hypothesis predicted adaptive responding (GWs would lower smoking-related intentions) and another predicted defensive responding (GWs would raise smoking-related intentions). METHODS: Participants were an online sample of 1,169 Americans ages 18-24, who were randomly assigned either to view nine GWs designed by the FDA or to a no-label control. Both the intention to smoke in the future and the intention to quit smoking (among smokers) were assessed before and after message exposure. RESULTS: GWs lowered intention to smoke in the future among those with a moderate lifetime smoking history (between 1 and 100 cigarettes), and they increased intention to quit smoking among those with a heavy lifetime smoking history (more than 100 cigarettes). Both effects were limited to individuals who had smoked in some but not all of the prior 30 days (i.e., occasional smokers). No evidence of defensive "boomerang effects" on intention was observed in any subgroup. CONCLUSION: Graphic warnings can reduce interest in smoking among occasional smokers, a finding that supports the adaptive-change hypothesis. GWs that target occasional smokers might be more effective at reducing cigarette smoking in young adults. PMID- 24806482 TI - The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications. AB - Over the last decade carboxymethyl chitosan (CMCS) has emerged as a promising biopolymer for the development of new drug delivery systems and improved scaffolds along with other tissue engineering devices for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. CMCS is amphiprotic ether, derived from chitosan, exhibiting enhanced aqueous solubility, excellent biocompatibility, controllable biodegradability, osteogenesis ability and numerous other outstanding physicochemical and biological properties. More strikingly, it can load hydrophobic drugs and displays strong bioactivity which highlight its suitability and extensive usage for preparing different drug delivery and tissue engineering formulations respectively. This review provides a comprehensive introduction to various types of CMCS based formulations for delivery of therapeutic agents and tissue regeneration and further describes their preparation procedures and applications in different tissues/organs. Detailed information of CMCS based nano/micro systems for targeted delivery of drugs with emphasis on cancer specific and organ specific drug delivery have been described. Further, we have discussed various CMCS based tissue engineering biomaterials along with their preparation procedures and applications in different tissues/organs. The article then, gives a brief account of therapy combining drug delivery and tissue engineering. Finally, identification of major challenges and opportunities for current and ongoing application of CMCS based systems in the field are summarised. PMID- 24806483 TI - Current advances in the fabrication of microneedles for transdermal delivery. AB - The transdermal route is an excellent site for drug delivery due to the avoidance of gastric degradation and hepatic metabolism, in addition to easy accessibility. Although offering numerous attractive advantages, many available transdermal systems are not able to deliver drugs and other compounds as desired. The use of hypodermic needles, associated with phobia, pain and accidental needle-sticks has been used to overcome the delivery limitation of macromolecular compounds. The means to overcome the disadvantages of hypodermic needles has led to the development of microneedles for transdermal delivery. However, since the initial stages of microneedle fabrication, recent research has been conducted integrating various fabrication techniques for generating sophisticated microneedle devices for transdermal delivery including progress on their commercialization. A concerted effort has been made within this review to highlight the current advances of microneedles, and to provide an update of pharmaceutical research in the field of microneedle-assisted transdermal drug delivery systems. PMID- 24806484 TI - pH-dependent spectroscopy of tetracycline and its analogs. AB - Tetracyclines (TCs), broad spectrum antibiotics widely used in the prevention and treatment of infectious diseases, are amphoteric molecules containing several ionizable functional groups that exist predominantly as zwitterions at a given pH value. TCs are reported to undergo a wide variety of reactions at different pH values i.e. TCs form to anhydrotetracyclines at low pH, 4-epitetracyclines at pH 3-5 and isotetracyclines at high pH values. The pH-dependent absorbance and emission properties of tetracycline and its 10 analogs (4-epitetracycline, doxycyline, oxytetracycline, chlortetracycline, 4-epichlortetracycline, isochlortetracycline, methacycline, rolitetracycline, minocycline, and demeclocycline) were investigated and reported in this paper. The main focus of the study was on the pH dependent transformation of epichlortetracycline, chlortetracycline and isotetracycline at basic pH. Absorption, emission and time resolved spectroscopy were used to determine the behavior of the three TC derivatives at this condition. Increasing the buffer's ionic concentration leads to faster transformation to iCTC. A pH dependent transformation of CTC to iCTC was observed and the lifetimes of CTC and iCTC were determined to be 3.0 and 5.89 ns respectively. The distribution factor of CTC to iCTC at basic pH was also reported for the first time. PMID- 24806485 TI - Colorectal polyp model established by transplacental BMP4 RNAi. AB - Previous studies have shown that disruption of the bone morphogenetic protein (BMP) signaling pathway is an important cause of intestinal cancer in human and animal models. Thus, the purpose of this study was to construct a Balb/C model of colorectal polyps. Pregnant mice at 9.5 days gestation were injected via the tail vein with the pSES-Si BMP4 plasmid bearing a fluorochrome (DsRed) reporter, in order to silence the BMP4 gene in the first generation (F1); this group of mice was named the pSES-BMP4 group Intestinal fluorescence was detected at 1-, 4- and 8-week-old F1 mice, and reverse transcription-polymerase chain reaction (RT-PCR) and western-blotting assays were used to determine changes in the expression of BMP4. A dissecting microscope and hematoxylin and eosin (H&E) staining were used to observe the cell morphology and appearance of the polyps. DsRed fluorescence was observed in the intestines of 1-week-old F1 mice of the pSES-BMP4 group. BMP4 expression at the mRNA and protein level was reduced in 1-, 4- and 8-week-old F1 mice (P<0.05). However, the level of Smad4 mRNA was only reduced in 8-week-old F1 mice (P<0.05). Multiple hyperplasic polyps emerged in the colon and rectum of the intestines of 4-week-old F1 mice in the pSES-BMP4 group. The size of colorectal polyps increased at 8 weeks, when vessels and polyp pedicles became apparent. In conclusion, silencing of the BMP4 gene using transplacental RNAi injection can induce formation of colorectal polyps in mice. PMID- 24806486 TI - Species origin of genomic factors in Nicotiana nudicaulis Watson controlling hybrid lethality in interspecific hybrids between N. nudicaulis Watson and N. tabacum L. AB - Hybrid lethality is expressed at 28 degrees C in the cross Nicotiana nudicaulis * N. tabacum. The S subgenome of N. tabacum has been identified as controlling this hybrid lethality. To clarify the responsible genomic factor(s) of N. nudicaulis, we crossed N. trigonophylla (paternal progenitor of N. nudicaulis) with N. tabacum, because hybrids between N. sylvestris (maternal progenitor of N. nudicaulis) and N. tabacum are viable when grown in a greenhouse. In the cross N. trigonophylla*N. tabacum, approximately 50% of hybrids were vitrified, 20% were viable, and 20% were nonviable at 28 degrees C. To reveal which subgenome of N. tabacum was responsible for these phenotypes, we crossed N. trigonophylla with two progenitors of N. tabacum, N. sylvestris (SS) and N. tomentosiformis (TT). In the cross N. sylvestris * N. trigonophylla, we confirmed that over half of hybrids of N. sylvestris * N. trigonophylla were vitrified, and none of the hybrids of N. trigonophylla * N. tomentosiformis were. The results imply that the S subgenome, encoding a gene or genes inducing hybrid lethality in the cross between N. nudicaulis and N. tabacum, has one or more genomic factors that induce vitrification. Furthermore, in vitrified hybrids of N. trigonophylla * N. tabacum and N. sylvestris * N. trigonophylla, we found that nuclear fragmentation, which progresses during expression of hybrid lethality, was accompanied by vitrification. This observation suggests that vitrification has a relationship to hybrid lethality. Based on these results, we speculate that when N. nudicaulis was formed approximately 5 million years ago, several causative genomic factors determining phenotypes of hybrid seedlings were inherited from N. trigonophylla. Subsequently, genome downsizing and various recombination-based processes took place. Some of the causative genomic factors were lost and some became genomic factor(s) controlling hybrid lethality in extant N. nudicaulis. PMID- 24806488 TI - Disorder- and dynamics-based regulatory mechanisms in toxin-antitoxin modules. PMID- 24806487 TI - Identification of selective small molecule inhibitors of the nucleotide-binding oligomerization domain 1 (NOD1) signaling pathway. AB - NOD1 is an intracellular pattern recognition receptor that recognizes diaminopimelic acid (DAP), a peptidoglycan component in gram negative bacteria. Upon ligand binding, NOD1 assembles with receptor-interacting protein (RIP)-2 kinase and initiates a signaling cascade leading to the production of pro inflammatory cytokines. Increased NOD1 signaling has been associated with a variety of inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. We utilized a cell-based screening approach with extensive selectivity profiling to search for small molecule inhibitors of the NOD1 signaling pathway. Via this process we identified three distinct chemical series, xanthines (SB711), quinazolininones (GSK223) and aminobenzothiazoles (GSK966) that selectively inhibited iE-DAP-stimulated IL-8 release via the NOD1 signaling pathway. All three of the newly identified compound series failed to block IL-8 secretion in cells following stimulation with ligands for TNF receptor, TLR2 or NOD2 and, in addition, none of the compound series directly inhibited RIP2 kinase activity. Our initial exploration of the structure-activity relationship and physicochemical properties of the three series directed our focus to the quinazolininone biarylsulfonamides (GSK223). Further investigation allowed for the identification of significantly more potent analogs with the largest boost in activity achieved by fluoro to chloro replacement on the central aryl ring. These results indicate that the NOD1 signaling pathway, similarly to activation of NOD2, is amenable to modulation by small molecules that do not target RIP2 kinase. These compounds should prove useful tools to investigate the importance of NOD1 activation in various inflammatory processes and have potential clinical utility in diseases driven by hyperactive NOD1 signaling. PMID- 24806489 TI - A comparison of obesity prevalence: military health system and United States populations, 2009-2012. AB - Overweight and obesity prevalence has increased over the past 30 years. Few studies have looked at the enrolled Military Health System (MHS) population (2.2 million per year). This descriptive study examined trends in overweight and obesity in both children and adults from fiscal years 2009 to 2012 and compared them to the U.S. population. Prevalence in MHS children decreased over time for overweight (14.2-13.8%) and obesity (11.7-10.9%). Active duty adults showed an increase in overweight prevalence (52.7-53.4%) and a decrease in obesity prevalence (18.9-18.3%). For nonactive duty, both overweight and obesity prevalence remained relatively unchanged around 33%. For both children and adults, overweight and obesity prevalence increased with age, except for obesity in the nonactive duty >= 65 subgroup. When compared to the United States by gender and age, MHS children generally had a lower overweight and obesity prevalence, active duty adults had higher overweight and lower obesity prevalence, and nonactive duty adults had comparable overweight and obesity prevalence, except for obesity in both men in the 40 to 59 subgroup and women in >= 60 subgroup. More research on the MHS population is needed to identify risk factors and modifiable health behaviors that could defeat the disease of obesity. PMID- 24806490 TI - No wrong door to smoking cessation care: a Veterans Affairs Chaplain survey. AB - Cigarette smoking disproportionately affects veterans, particularly those with psychiatric diagnoses. Chaplains working within the Department of Veterans Affairs (VA) play key roles in emotional, physical, and spiritual health care of veterans, and veterans often turn to chaplains with mental health concerns. The VA/Department of Defense Integrated Mental Health Care Strategy is working to understand how collaboration between chaplains and mental health professionals may improve services to veterans, and one interest area is the role chaplains might play in facilitating the dissemination of smoking cessation programs. We report the survey results of 321 VA chaplains regarding their interest and willingness to be involved in smoking cessation efforts. Results indicated that over 80% of responding chaplains would feel "somewhat" or "very comfortable" providing information to veterans about VA smoking cessation programs, and that a smaller majority (between 55% and 85%) would feel this level of comfort engaging in smoking cessation-related activities. Findings suggest the potential for collaboration among chaplains and mental health providers in smoking cessation efforts, and also point to the need for further discussion and deeper mutual understanding between these professionals in how they view their roles in contributing to the overall health and well-being of veterans. PMID- 24806491 TI - Challenges to improving combat casualty survival on the battlefield. PMID- 24806492 TI - Transgender veterans are inadequately understood by health care providers. PMID- 24806493 TI - Amino acids as biomarker candidates for suicidality in male OEF/OIF Veterans: relevance to NMDA receptor modulation and nitric oxide signaling. AB - Veteran populations are exposed to multiple stressful events, and suicidality among veterans is a serious problem. Identifying biomarkers of suicidality may enhance detection, prevention, and treatment. Multiple neurotransmitter systems are implicated in the neurobiology of suicidality, including amino acid neurotransmitter systems. Amino acids as biomarker candidates for suicidality were quantified using mass spectrometry in serum samples from 90 male U.S. Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans. Amino acid levels in veterans reporting suicidal ideation (SI) on the Beck Scale for Suicidal Ideation (BSS) (BSS score > 0, n = 19) were compared with those reporting no SI (BSS score = 0, n = 71). Glycine, an excitatory amino acid and N methyl-d-aspartate receptor modulator, was significantly elevated in serum samples from veterans reporting SI (p = 0.043). Serine and aspartate/asparagine, also excitatory neurotransmitters, were nonsignificantly increased in veterans reporting SI (p = 0.082 and p = 0.097, respectively). In contrast, arginine (nitric oxide [NO] precursor) and citrulline (by-product of NO formation) were nonsignificantly decreased in veterans reporting SI (p = 0.097 and p = 0.093, respectively). Profiling amino acids as possible biomarker candidates for suicidality in OEF/OIF veterans may have clinical utility for identifying suicidal risk. Glutamatergic neurotransmission and NO signaling may be relevant to the neurobiology of suicidality in OEF/OIF veterans. PMID- 24806494 TI - Posttraumatic epilepsy in Operation Enduring Freedom/Operation Iraqi Freedom veterans. AB - Penetrating traumatic brain injury (TBI) is a well-established risk factor for post-traumatic epilepsy (PTE). However, many veterans in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) who suffer from TBI do so from blast injury, and its consequences are not fully known. Two neurologists performed a chart review to describe patterns of injury and health care among all 16 OEF/OIF veterans at the VA Greater Los Angeles Healthcare System who were assigned an outpatient diagnosis of both epilepsy and TBI in 2008-2009. All Veterans were male, and the mean age was 30 years. Blast exposure was the most common mechanism of TBI (81%). Although all Veterans were assigned a diagnosis code of seizures, the diagnosis of PTE was clinically confirmed in only 3 veterans. On the other hand, the diagnosis of post-traumatic stress disorder was confirmed in 81% of the sample and a diagnosis of nonepileptic seizures was suspected in 44% of the sample. Researchers who study PTE among the OEF/OIF population using administrative data also should perform chart reviews to account for the prevalence of psychogenic nonepileptic seizures. PMID- 24806495 TI - Review of new topical hemostatic dressings for combat casualty care. AB - This review analyzes the new (2008-2013) hemostatic agents and dressings for enhanced efficacy in preclinical studies, and investigates supportive findings among case reports of effectiveness and safety in hospital and prehospital literature. A literature search was conducted using PubMed, National Library of Medicine using key words and phrases. The search revealed a total of 16 articles that fit the criteria established for third-generation hemostatic dressings. There were a total of 9 preclinical, 5 clinical, and 2 prehospital studies evaluated. Evaluation of these third-generation studies reveals that mucoadhesive (chitosan) dressings, particularly Celox Gauze and ChitoGauze, clearly show equal efficacy to Combat Gauze across many dependent variables. Chitosan-based products are ideal prehospital dressings because they are shown to work independently from the physiological clotting mechanisms. Many first-, second-, and third-generation chitosan-based dressings have been in use for years by the United States and other NATO militaries at the point of injury, and during tactical evacuation, in Operation Enduring Freedom and Operation Iraqi Freedom without reported complications or side effects. Based on the reported efficacy and long-term safety of chitosan-based products, increased use of Celox Gauze and ChitoGauze within the Department of Defense and civilian venues merits further consideration and open debate. PMID- 24806496 TI - Utilization of VA mental health and primary care services among Iraq and Afghanistan veterans with depression: the influence of gender and ethnicity status. AB - The objective of this study is to examine gender and ethnic differences in Veterans Affairs (VA) health services utilization among Iraq and Afghanistan military Veterans diagnosed with depression. With VA administrative data, sociodemographics, utilization of outpatient primary care, specialty mental health and mental health treatment modalities (psychotherapy and antidepressant prescriptions) were collected from electronic medical records of 1,556 depressed Veterans treated in one VA regional network from January 2008 to March 2009. Health care utilization patterns were examined 90 days following being diagnosed with depression. chi(2) and t-tests were used to evaluate unadjusted differences in VA service use by gender and ethnicity. Logistic regression was used to fit study models predicting VA service utilization. Study results indicate no ethnic or gender differences in the use of specialty mental health services or in the use of mental health treatments. However, women Veterans, especially those from ethnic minority groups, were less likely to use primary care than white and nonwhite male Veterans. Collectively, these findings signal a decrease in historically documented disparities within VA health care, especially in the use of mental health services. PMID- 24806497 TI - Feasibility and preliminary real-world promise of a manualized group-based cognitive behavioral therapy for insomnia protocol for veterans. AB - Insomnia is increasingly common among the general population, even more so among veterans. Given the adverse impact of insomnia on both mental and physical health of veterans, it is important to provide effective treatments within the Veterans Health Administration (VHA) system. Group-based cognitive behavioral therapy for insomnia (CBT-I) provides a viable option for treatment. This study reports the feasibility, acceptability, initial effectiveness, and durability of group-based CBT-I in a clinical sample of veterans with comorbid medical and mental health diagnoses; the treatment was provided in a real-world VHA hospital setting using a manualized protocol that was explicitly adapted from the existing 1:1 CBT-I VHA protocol. Overall, we found the treatment to be feasible and acceptable to veterans, as well as effective. We found medium to large effect sizes for both questionnaire and sleep diary measures, including sleep onset latency, awakenings during the night, sleep efficiency, insomnia scores, and dysfunctional beliefs about sleep. Improvements in insomnia symptoms were maintained over 1 month. PMID- 24806498 TI - Evaluation of the Behavioral Risk Factor Surveillance System as a potential index model for Total Force Fitness. AB - This article reports the results of an evaluation of the Behavioral Risk Factor Surveillance System (BRFSS) as a potential "index model" for the assessment of Total Force Fitness (TFF) in military personnel. The evaluation was conducted using descriptive categories developed by Firth and Smith for appraisal of potential TFF index models, and documents and publications related to BRFSS survey measures and methodology. Secondary analysis of data from military personnel responding to the 2010 BRFSS was used as "sample" data to assess relationships between the domains of TFF. Findings from this evaluation support that the BRFSS is a potential index model for TFF. Additional research is needed to determine the usefulness of BRFSS survey measures and resulting data in assessing TFF in military personnel. PMID- 24806499 TI - A retrospective cohort study of military deployment and postdeployment medical encounters for respiratory conditions. AB - Deployed military personnel are exposed to inhalational hazards that may increase their risk of chronic lung conditions. This evaluation assessed associations between Operation Iraqi Freedom (OIF) deployment and postdeployment medical encounters for respiratory symptoms and medical conditions. This retrospective cohort study was conducted among military personnel who, between January 2005 and June 2007, were deployed to either of two locations with burn pits in Iraq, or to either of two locations without burn pits in Kuwait. Incidence rate ratios (IRRs) were estimated using two nondeployed reference groups. Rates among personnel deployed to burn pit locations were also compared directly to those among personnel deployed to locations without burn pits. Significantly elevated rates of encounters for respiratory symptoms (IRR = 1.25; 95% confidence interval [CI]: 1.20-1.30) and asthma (IRR = 1.54; 95% CI: 1.33-1.78) were observed among the formerly deployed personnel relative to U.S.-stationed personnel. Personnel deployed to burn pit locations did not have significantly elevated rates for any of the outcomes relative to personnel deployed to locations without burn pits. These results are consistent with the hypothesis that OIF deployment is associated with subsequent risk of respiratory conditions. Elevated medical encounter rates were not uniquely associated with burn pits. PMID- 24806500 TI - Incidence of admission to the Physical Training and Rehabilitation Programs in Initial Entry Training during fiscal year 2011. AB - The Physical Training and Rehabilitation Program (PTRP) is a recovery and reintegration program for recruits in Initial Entry Training (IET) who are unable to continue training because of serious injury. This investigation examined PTRP admission incidence among recruits in IET at Forts Jackson, Leonard Wood, Benning, and Sill during Fiscal Year 2011 (FY11). PTRP admission data were collected from a spreadsheet completed monthly by PTRP commanders. Total number of recruits was obtained from each post's Directorate of Programs, Training, and Management. In FY11, 368 men and 268 women were admitted into PTRPs at all installations. For Forts Jackson, Leonard Wood, Benning, and Sill, male admission incidences (cases/1,000 recruits) were 2.6, 3.0, 6.2, and 5.4, respectively; female admission incidences for Forts Jackson, Leonard Wood, and Sill, were 11.1, 10.1, and 22.6, respectively. Most injuries sent to PTRP were bone stress injuries (65%) or fractures (21%). 76% of recruits were returned to duty. Differences in admission incidence between posts appear primarily related to different local policies regarding convalescent leave and admission criteria. PTRP admission rates are lower than in the past, presumably related to policy changes and injury-reduction efforts. A cost-benefit analysis would assist in determining the value of the PTRP. PMID- 24806501 TI - Pain management and opioid risk mitigation in the military. AB - Opioid analgesics misuse is a significant military health concern recognized as a priority issue by military leadership. Opioids are among those most commonly prescribed medications in the military for pain management. The military has implemented opioid risk mitigation strategies, including the Sole Provider Program and the Controlled Drug Management Analysis and Reporting Tool, which are used to identify and monitor for risk and misuse. However, there are substantial opportunities to build on these existing systems to better ensure safer opioid prescribing and monitor for misuse. Opioid risk mitigation strategies implemented by the civilian sector include establishing clinical guidelines for opioid prescribing and prescription monitoring programs. These strategies may help to inform opioid risk mitigation in the military health system. Reducing the risk of opioid misuse and improving quality of care for our Warfighters is necessary. This must be done through evidence-based approaches with an investment in research to improve patient care and prevent opioid misuse as well as its sequelae. PMID- 24806502 TI - Syndrome of acute anxiety among marines after recent arrival at high altitude. AB - Management of mental health is critical for maintenance of readiness in austere military environments. Emerging evidence implicates hypoxia as an environmental trigger of anxiety spectrum symptomatology. One thousand thirty-six unacclimatized infantry Marines ascended from sea level to the Marine Corps Mountain Warfare Training Center (2,061-3,383 m) for a 30-day exercise. Within the first 6 days of training, 7 servicemen presented with severe, acute anxiety/panic with typical accompanying signs of sympathetic activation and no classic symptoms of acute mountain sickness (including headache). Four had a history of well-controlled psychiatric diagnoses. Invariably, cardiopulmonary and neurological evaluations were unrevealing, and acute cardiopulmonary events were excluded within limits of expeditionary diagnostic capabilities. All patients responded clinically to oxygen, rest, and benzodiazepines, returning to baseline function the same day. The unexpected onset of 7 cases of acute anxiety symptomatology coincident with recent arrival at moderate-to-high altitudes represents a highly unusual incidence and temporal distribution, suggestive of hypobaric hypoxemia as the proximal cause. We propose acute hypoxic physiological anxiety (AHPA) as a unique member of the spectrum of altitude-associated neurological disorders. Recognition of AHPA is particularly relevant in a military population; warfighters with anxiety spectrum diagnoses may have a recognizable and possibly preventable vulnerability. PMID- 24806503 TI - National surveys of military personnel, nursing students, and the public: drivers of military nursing careers. AB - OBJECTIVES: The U.S. health care system is facing a projected nursing shortage of unprecedented magnitude. Although military nursing services recently have been able to meet their nursing recruitment quotas, national studies have predicted a long-term nursing shortage that may affect future recruitment for the Nurse Corps of the three military services. Data are needed to plan for recruitment incentives and the impact of those incentives on targeted populations of likely future nurses. METHODS: Data are drawn from three online surveys conducted in 2011-2012, including surveys of 1,302 Army, Navy, and Air Force personnel serving on major military bases, 914 nursing students at colleges with entry Bachelor of Science in Nursing programs located nearby major military bases, and a qualitative survey of 1,200 young adults, age 18-39, in the general public. FINDINGS: The three populations are different in several demographic characteristics. We explored perceptions of military careers, nursing careers and barriers, and incentives to pursue military nursing careers in all populations. Perceptions differ among the groups. CONCLUSION: The results of this study may help to inform strategies for reaching out to specific populations with targeted messages that focus on barriers and facilitators relevant to each to successfully recruit a diverse Nurse Corps for the future. PMID- 24806504 TI - Attention deficit hyperactivity disorder and medication use by children during parental military deployments. AB - OBJECTIVE: Parental deployment is associated with children's increased mental health needs. Attention Deficit Hyperactivity Disorder (ADHD) is the most common pediatric mental health diagnosis. We hypothesize children with ADHD will have increased mental health and medication needs during parental deployment. METHODS: Retrospective cohort study of children with ADHD aged 4-8 years in the Military Health System. RESULTS: Of 413,665 children aged 4-8 years, 34,205 (8.3%) had ADHD and 19,123 (55.9%) of these were prescribed ADHD medications. During parental deployments, children with ADHD had a 13% increased rate of mental and behavioral health care visits (IRR 1.13 [95% CI 1.12-1.14; p < 0.00001]) and a decreased rate of medication changes (IRR 0.94 [95% CI 0.91-0.96; p < 0.00001]) compared to when parents were at home. Medication changes related to deployment varied by age; school-aged children had decreased medication events (IRR 0.88 [95% CI 0.86-0.91; p < 0.00001]) and preschool-aged children had increased medication events (IRR 1.05 [95% CI 1.02-1.10; p = .006]) during parental deployment. CONCLUSIONS: During parental deployment, children with ADHD aged 4-8 years have increased mental health visits and decreased ADHD medication changes. Younger children have increased medication changes, whereas older children have decreased changes during a parent's deployment. PMID- 24806505 TI - The association of neighborhood social capital and ethnic (minority) density with pregnancy outcomes in the Netherlands. AB - BACKGROUND: Perinatal morbidity rates are relatively high in the Netherlands, and significant inequalities in perinatal morbidity and mortality can be found across neighborhoods. In socioeconomically deprived areas, 'Western' women are particularly at risk for adverse birth outcomes. Almost all studies to date have explained the disparities in terms of individual determinants of birth outcomes. This study examines the influence of neighborhood contextual characteristics on birth weight (adjusted for gestational age) and preterm birth. We focused on the influence of neighborhood social capital--measured as informal socializing and social connections between neighbors--as well as ethnic (minority) density. METHODS: Data on birth weight and prematurity were obtained from the Perinatal Registration Netherlands 2000-2008 dataset, containing 97% of all pregnancies. Neighborhood-level measurements were obtained from three different sources, comprising both survey and registration data. We included 3.422 neighborhoods and 1.527.565 pregnancies for the birth weight analysis and 1.549.285 pregnancies for the premature birth analysis. Linear and logistic multilevel regression was performed to assess the associations of individual and neighborhood level variables with birth weight and preterm birth. RESULTS: We found modest but significant neighborhood effects on birth weight and preterm births. The effect of ethnic (minority) density was stronger than that of neighborhood social capital. Moreover, ethnic (minority) density was associated with higher birth weight for infants of non-Western ethnic minority women compared to Western women (15 grams; 95% CI: 12,4/17,5) as well as reduced risk for prematurity (OR 0.97; CI 0,95/0,99). CONCLUSIONS: Our results indicate that neighborhood contexts are associated with birth weight and preterm birth in the Netherlands. Moreover, ethnic (minority) density seems to be a protective factor for non-Western ethnic minority women, but not for Western women. This helps explain the increased risk of Western women in deprived neighborhoods for adverse birth outcomes found in previous studies. PMID- 24806506 TI - Graphene-based nanocomposite as an effective, multifunctional, and recyclable antibacterial agent. AB - The development of new antibacterial agents that are highly effective are of great interest. Herein, we present a recyclable and synergistic nanocomposite by growing both iron oxide nanoparticles (IONPs) and silver nanoparticles (AgNPs) on the surface of graphene oxide (GO), obtaining GO-IONP-Ag nanocomposite as a novel multifunctional antibacterial material. Compared with AgNPs, which have been widely used as antibacterial agents, our GO-IONP-Ag shows much higher antibacterial efficiency toward both Gram-negative bacteria Escherichia coli (E. coli) and Gram-positive bacteria Staphylococcus aureus (S. aureus). Taking the advantage of its strong near-infrared (NIR) absorbance, photothermal treatment is also conducted with GO-IONP-Ag, achieving a remarkable synergistic antibacterial effect to inhibit S. aureus at a rather low concentration of this agent. Moreover, with magnetic IONPs existing in the composite, we can easily recycle GO IONP-Ag by magnetic separation, allowing its repeated use. Given the above advantages as well as its easy preparation and cheap cost, GO-IONP-Ag developed in this work may find potential applications as a useful antibacterial agent in the areas of healthcare and environmental engineering. PMID- 24806507 TI - Realising our social and occupational value: could a graduate over-supply push occupational therapy in the right direction? PMID- 24806508 TI - Physiological, psychometric, and performance effects of the Christmas break in Australian football. AB - PURPOSE: The aim of the current study was to quantify the physiological, psychometric, and performance effects of a 2-wk Christmas break in a professional Australian Football League club. METHODS: A series of physiological (eg, heart rate [HR] response to a 5-min submaximal run and skinfold thicknesses), psychometric (rating-of-perceived-exertion [RPE] responses and wellness variables), and performance (running activity during standardized handball games, isometric midthigh pull [IMTP] peak force, and countermovement jump [CMJ]) measures were conducted in the weeks before and after the break. RESULTS: There was a possible and small increase in the sum of 7 skinfolds, while body mass and fat-free mass remained possible and likely unchanged, respectively. Sleep and stress scores remained likely to almost certainly unchanged, but there were some small, possible to likely decreases in fatigue and soreness scores. HR and RPE responses to the 5-min submaximal run were likely slightly lower (ie, improved) after the break. High-intensity running and acceleration distance during a standard handball game were very likely slightly greater, while HR and RPE responses to the game were possibly to very likely unchanged. HR responses to a high-intensity training session remained very likely unchanged. There was also a likely small increase in IMTP peak force but likely to very likely no change in CMJ variables. CONCLUSIONS: The results show that players returned from a 2-wk break during preseason well recovered, with preserved to improved levels of strength and cardiorespiratory fitness, despite small increases in skinfold thickness. PMID- 24806509 TI - Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in Klinefelter syndrome. AB - Although the expected skeletal manifestations of testosterone deficiency in Klinefelter's syndrome (KS) are osteopenia and osteoporosis, the structural basis for this is unclear. The aim of this study was to assess bone geometry, volumetric bone mineral density (vBMD), microarchitecture, and estimated bone strength using high-resolution peripheral quantitative computed tomography (HR pQCT) in patients with KS. Thirty-one patients with KS confirmed by lymphocyte chromosome karyotyping aged 35.8 +/- 8.2 years were recruited consecutively from a KS outpatient clinic and matched with respect to age and height with 31 healthy subjects aged 35.9 +/- 8.2 years. Dual-energy X-ray absorptiometry (DXA) and HR pQCT were performed in all participants, and blood samples were analyzed for hormonal status and bone biomarkers in KS patients. Twenty-one KS patients were on long-term testosterone-replacement therapy. In weight-adjusted models, HR-pQCT revealed a significantly lower cortical area (p < 0.01), total and trabecular vBMD (p = 0.02 and p = 0.04), trabecular bone volume fraction (p = 0.04), trabecular number (p = 0.05), and estimates of bone strength, whereas trabecular spacing was higher (p = 0.03) at the tibia in KS patients. In addition, cortical thickness was significantly reduced, both at the radius and tibia (both p < 0.01). There were no significant differences in indices of bone structure, estimated bone strength, or bone biomarkers in KS patients with and without testosterone therapy. This study showed that KS patients had lower total vBMD and a compromised trabecular compartment with a reduced trabecular density and bone volume fraction at the tibia. The compromised trabecular network integrity attributable to a lower trabecular number with relative preservation of trabecular thickness is similar to the picture found in women with aging. KS patients also displayed a reduced cortical area and thickness at the tibia, which in combination with the trabecular deficits, compromised estimated bone strength at this site. PMID- 24806510 TI - Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM. AB - Cellular microenvironments, particularly those found in tumors, elicit a tolerogenic DC phenotype which can attenuate immune responses. Central to this process is the STAT3-mediated signaling cascade. As a transcription factor and oncogene, STAT3 promotes the expression of genes which allow tumor cells to proliferate, migrate and evade apoptosis. More importantly, activation of STAT3 in tumor infiltrating immune cells has been shown to be responsible, in part, for their immune-suppressed phenotype. The ability of STAT3 to orchestrate a diverse set of immunosuppressive instructions has made it an attractive target for cancer vaccines. Using a conditional hematopoietic knockout mouse model of STAT3, we evaluated the impact of STAT3 gene ablation on the differentiation of dendritic cells from bone marrow precursors. We also assessed the impact of STAT3 deletion on phagocytosis, maturation, cytokine secretion and antigen presentation by GM CSF derived DCs in vitro. In addition to in vitro studies, we compared the therapeutic efficacy of DC vaccination using STAT3 deficient DCs to wild type counterparts in an intracranial mouse model of GBM. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells which lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation as both wild type and STAT3 null bone marrow cells gave rise to similar number of DCs. STAT3 also appeared to regulate the response of GM-CSF derived DCs to CpG. STAT3 null DCs expressed high levels of MHC-II, secreted more IL-12p70, IL-10, and TNFalpha were better antigen presenters in vitro. Although STAT3 deficient DCs displayed an enhanced activated phenotype in culture, they elicited comparable therapeutic efficacy in vivo compared to their wild type counterparts when utilized in vaccination paradigms in mice bearing intracranial glioma tumors. PMID- 24806513 TI - Improved multifrequency phase-modulation method that uses rectangular-wave signals to increase accuracy in luminescence spectroscopy. AB - We propose a novel multifrequency phase-modulation method for luminescence spectroscopy that uses a rectangular-wave modulated excitation source with a short duty cycle. It is used for obtaining more detailed information about the luminescence system: the information provided by different harmonics allows estimating a model for describing the global frequency response of the luminescent system for a wide range of analyte concentration and frequencies. Additionally, the proposed method improves the accuracy in determination of the analyte concentration. This improvement is based on a simple algorithm that combines multifrequency information provided by the different harmonics of the rectangular-wave signal, which can be easily implemented in existing photoluminescence instruments by replacing the excitation light source (short duty cycle rectangular signal instead of sinusoidal signal) and performing appropriate digital signal processing after the transducer (implemented in software). These claims have been demonstrated by using a well-known oxygen sensing film coated at the end of an optical fiber [a Pt(II) porphyrin immobilized in polystyrene]. These experimental results show that use of the proposed multifrequency phase-modulation method (1) provides adequate modeling of the global response of the luminescent system (R(2) > 0.9996) and (2) decreases the root-mean-square error in analytical determination (from 0.1627 to 0.0128 kPa at 0.5 kPa O2 and from 0.9393 to 0.1532 kPa at 20 kPa O2) in comparison with a conventional phase-modulation method based on a sinusoidally modulated excitation source (under equal luminous power conditions). PMID- 24806514 TI - Gas-Phase Synthesis of Boronylallene (H2CCCH(BO)) under Single Collision Conditions: A Crossed Molecular Beams and Computational Study. AB - The gas phase reaction between the boron monoxide radical (11BO; X2Sigma+) and allene (H2CCCH2; X1A1) was investigated experimentally under single collision conditions using the crossed molecular beam technique and theoretically exploiting ab initio electronic structure and statistical (RRKM) calculations. The reaction was found to follow indirect (complex forming) scattering dynamics and proceeded via the formation of a van der Waals complex (11BOC3H4). This complex isomerized via addition of the boron monoxide radical (11BO; X2Sigma+) with the radical center located at the boron atom to the terminal carbon atom of the allene molecule forming a H2CCCH211BO intermediate on the doublet surface. The chemically activated H2CCCH211BO intermediate underwent unimolecular decomposition via atomic hydrogen elimination from the terminal carbon atom holding the boronyl group through a tight exit transition state to synthesize the boronylallene product (H2CCCH11BO) in a slightly exoergic reaction (55 +/- 11 kJ mol-1). Statistical (RRKM) calculations suggest that minor reaction channels lead to the products 3-propynyloxoborane (CH2(11BO)CCH) and 1-propynyloxoborane (CH3CC11BO) with fractions of 1.5% and 0.2%, respectively. The title reaction was also compared with the cyano (CN; X2Sigma+)-allene and boronyl-methylacetylene reactions to probe similarities, but also differences of these isoelectronic systems. Our investigation presents a novel gas phase synthesis and characterization of a hitherto elusive organyloxoborane (RBO) monomer boronylallene-which is inherently tricky to isolate in the condensed phase except in matrix studies; our work further demonstrates that the crossed molecular beams approach presents a useful tool in investigating the chemistry and synthesis of highly reactive organyloxoboranes. PMID- 24806512 TI - Studying the nucleated mammalian cell membrane by single molecule approaches. AB - The cell membrane plays a key role in compartmentalization, nutrient transportation and signal transduction, while the pattern of protein distribution at both cytoplasmic and ectoplasmic sides of the cell membrane remains elusive. Using a combination of single-molecule techniques, including atomic force microscopy (AFM), single molecule force spectroscopy (SMFS) and stochastic optical reconstruction microscopy (STORM), to study the structure of nucleated cell membranes, we found that (1) proteins at the ectoplasmic side of the cell membrane form a dense protein layer (4 nm) on top of a lipid bilayer; (2) proteins aggregate to form islands evenly dispersed at the cytoplasmic side of the cell membrane with a height of about 10-12 nm; (3) cholesterol-enriched domains exist within the cell membrane; (4) carbohydrates stay in microdomains at the ectoplasmic side; and (5) exposed amino groups are asymmetrically distributed on both sides. Based on these observations, we proposed a Protein Layer-Lipid Protein Island (PLLPI) model, to provide a better understanding of cell membrane structure, membrane trafficking and viral fusion mechanisms. PMID- 24806515 TI - Comparative assessments of crucial factors for a functional ligand-targeted nanocarrier. AB - We previously developed a ligand-targeted liposome, referred to as a prohibitin targeted nanoparticle (PTNP), for specifically delivering encapsulated drugs into vascular endothelial cells in adipose tissue. In this study, we explored the critical factors for the successful development and application of ligand targeted nanocarriers through comparative assessments of PTNP prepared by the reverse-phase evaporation (REV) and lipid film hydration (HYD) methods with reference to physicochemical characteristics and in vivo and in vitro behavior. The in vivo delivery and therapeutic properties of HYD-PTNP were dramatically inferior to those of REV-PTNP, although the size, zeta-potential, fixed aqueous layer thickness and surface ligand density of the two preparations were similar. Circular dichroism spectral analyses revealed that the irreversible alteration in ligand conformation was caused by the organic solvent used to prepare the thin lipid film. In addition, perturbation of the ligand by the organic solvent resulted in a reduced internalization of PTNP into adipose endothelial cells. Alteration of the ligand conformation did not appear to affect the physicochemical characteristics of nanocarriers. Therefore, appropriate handling of ligands and appropriate evaluation of their conformations are critical for the successful development and application of such targeted nanocarriers. PMID- 24806516 TI - Glucose transporter and folic acid receptor-mediated Pluronic P105 polymeric micelles loaded with doxorubicin for brain tumor treating. AB - In this study, glucose transporter and folic acid (FA) receptor-mediated Pluronic P105 polymeric micelles loaded with DOX (GF-DOX) were prepared for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. The pH-triggered DOX release of GF-DOX indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The transport of GF-DOX across the in vitro BBB model showed that GF-DOX exhibited higher BBB transportation ability with the transporting ratio of 21.47% in 4 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model for the combined effect of the brain targeting by transportation of glucose transporter and active tumor cell targeting by FA receptor-mediated endocytosis. Moreover, minimized weight changes and high suppression ratio of tumor growth were observed after intravenous injection of GF DOX. In conclusion, the glucose transporter and FA dual-targeting micelles would provide a safe and effective strategy for new modalities to treat brain tumor. PMID- 24806518 TI - Is there an effect of glucose lowering treatment on incidence and prognosis of tuberculosis? A systematic review. AB - The association between diabetes and incidence of tuberculosis is well established, and observational studies have shown poor treatment outcome in tuberculosis related to hyperglycemia. The WHO recommends screening for diabetes among all patients with tuberculosis and optimized glycemic control aiming at improving tuberculosis outcome. However, no intervention studies support this notion. Patients with tuberculosis are often vulnerable with high degree of comorbidity, and, therefore, at high risk of adverse effects of intensive glucose control. Controlled intervention studies of the effect of glucose lowering treatment on tuberculosis outcomes are clearly warranted to justify screening for and tight control of diabetes. PMID- 24806519 TI - Improving positive blood culture removal time significantly decreases total processing time. AB - CONTEXT: Timely processing of blood cultures with positive results, including Gram staining and notification of clinicians, is a critical function of the clinical microbiology laboratory. Analysis of processing time in our laboratory revealed opportunities to enhance workflow efficiency. We found that the average time from positive blood culture result to removal of the bottle for processing (positive-to-removal [PR] time) was inadequate for our rapid pathogen identification program. OBJECTIVE: To determine whether increased vigilance about PR time and prioritization of laboratory resources would decrease PR time and total processing time. DESIGN: We performed a retrospective analysis of blood culture PR time 7 months before and 7 months after an in-service meeting during which the importance of PR time was emphasized, and corrective measures were implemented. RESULTS: Before the in-service meeting, the average PR time for 5057 samples was 38 minutes, with an aggregate time of 192,251 minutes. Unexpectedly, we discovered that only 51.8% (2617 of 5057) of the positive blood cultures were removed in less than 10 minutes. After the in-service meeting, for 5293 samples, the average PR time improved to 8 minutes, the aggregate time improved to 44,630 minutes, and 84.5% (4470 of 5293) of the positive blood cultures were removed in less than 10 minutes. These improvements reduced the time to telephone notification of the Gram stain results to a caregiver by 46.7% (from 105 minutes to 56 minutes). CONCLUSIONS: Increased awareness of barriers to rapid pathogen identification and interventions for improving performance time significantly enhanced care of patients with bloodstream infections. PMID- 24806520 TI - Atom-light interactions in photonic crystals. AB - The integration of nanophotonics and atomic physics has been a long-sought goal that would open new frontiers for optical physics, including novel quantum transport and many-body phenomena with photon-mediated atomic interactions. Reaching this goal requires surmounting diverse challenges in nanofabrication and atomic manipulation. Here we report the development of a novel integrated optical circuit with a photonic crystal capable of both localizing and interfacing atoms with guided photons. Optical bands of a photonic crystal waveguide are aligned with selected atomic transitions. From reflection spectra measured with average atom number N=1.1+/-0.4, we infer that atoms are localized within the waveguide by optical dipole forces. The fraction of single-atom radiative decay into the waveguide is Gamma1D/Gamma'?(0.32+/-0.08), where Gamma1D is the rate of emission into the guided mode and Gamma' is the decay rate into all other channels. Gamma1D/Gamma' is unprecedented in all current atom-photon interfaces. PMID- 24806521 TI - Cell invasion in the spheroid sprouting assay: a spatial organisation analysis adaptable to cell behaviour. AB - The endothelial cell spheroid assay provides a suitable in vitro model to study (lymph) angiogenesis and test pro- and anti-(lymph) angiogenic factors or drugs. Usually, the extent of cell invasion, observed through optical microscopy, is measured. The present study proposes the spatial distribution of migrated cells as a new descriptor of the (lymph) angiogenic response. The utility of this novel method rests with its capacity to locally characterise spheroid structure, allowing not only the investigation of single and collective cell invasion but also the evolution of the spheroid core itself. Moreover, the proposed method can be applied to 2D-projected spheroid images obtained by optical microscopy, as well as to 3D images acquired by confocal microscopy. To validate the proposed methodology, endothelial cell invasion was evaluated under different experimental conditions. The results were compared with widely used global parameters. The comparison shows that our method prevents local spheroid modifications from being overlooked and leading to the possible misinterpretation of results. PMID- 24806523 TI - Preparation using pectinase and characterization of nanofibers from orange peel waste in juice factories. AB - This study reports the preparation and characterization of nanofibers consisting mainly of cellulose microfibrils from orange peel (OP), which is a significant byproduct of orange juice production. Three treatments (boiling, alkaline, and pectinase) were investigated with and without subsequent grinding treatment. It was possible to prepare the cellulose nanofibers (CNFs) using these methods, except for the boiling treatment with grinding. Interestingly, only pectinase and a mild-physical blender treatment without grinding produced nanofibers. The width of the nanofibers from OP was approximately 10 to 50 nm. The microfibril bundles of OP were considered to be thinner than those of commercial CNFs. Our data indicated that the removal of pectic polysaccharides and hemicelluloses covering the cellulose microfibrils was important for the preparation of nanofibers from OP. These nanofibers from OP using pectinase are proposed to be applicable as food materials, pharmaceuticals, and filters for the tractive characteristics of the sheet. PRACTICAL APPLICATION: This study demonstrates: (1) it was possible to prepare the nanofibers from orange peel using pectinase and (2) the width of the nanofibers from orange peel was approximately 10 to 50 nm. (3) Removal of polysaccharides such as pectin and hemicelluloses covering cellulose microfibrils was very important for preparation of nanofibers from OP. Considering the tractive characteristics of the sheets from nanofibers and the origin of orange peel, they are suitable for application of food materials, pharmaceuticals, and filters. PMID- 24806525 TI - Lewis acid-promoted cyclization/halogenation of allenyl ethenetricarboxylates and the corresponding amides: stereoselective synthesis of haloalkenyl five-membered heterocycles. AB - Lewis acid-promoted intramolecular reactions of allenyl ethenetricarboxylates and the corresponding amides have been examined. Reactions of allenyl ethenetricarboxylates and the amides with Lewis acids such as AlCl3, AlBr3 and ZnX2 (X = Cl, Br, I) gave 3,4-trans haloalkenyl five-membered heterocycles stereoselectively. The stereochemistry was determined by NOE experiments and reduction of the cyclized products. Various transformations of the haloalkenyl functionalized cyclic compounds have also been performed. PMID- 24806524 TI - Adapting to new threats: the generation of memory by CRISPR-Cas immune systems. AB - Clustered, regularly interspaced, short palindromic repeats (CRISPR) loci and their associated genes (cas) confer bacteria and archaea with adaptive immunity against phages and other invading genetic elements. A fundamental requirement of any immune system is the ability to build a memory of past infections in order to deal more efficiently with recurrent infections. The adaptive feature of CRISPR Cas immune systems relies on their ability to memorize DNA sequences of invading molecules and integrate them in between the repetitive sequences of the CRISPR array in the form of 'spacers'. The transcription of a spacer generates a small antisense RNA that is used by RNA-guided Cas nucleases to cleave the invading nucleic acid in order to protect the cell from infection. The acquisition of new spacers allows the CRISPR-Cas immune system to rapidly adapt against new threats and is therefore termed 'adaptation'. Recent studies have begun to elucidate the genetic requirements for adaptation and have demonstrated that rather than being a stochastic process, the selection of new spacers is influenced by several factors. We review here our current knowledge of the CRISPR adaptation mechanism. PMID- 24806528 TI - Combined pharmacotherapy and psychotherapy in the treatment of mild to moderate major depression? PMID- 24806526 TI - Hyaluronan polymer length, grafting density, and surface poly(ethylene glycol) coating influence in vivo circulation and tumor targeting of hyaluronan-grafted liposomes. AB - Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44 overexpressing tumor cells in vitro via receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5-8, 50-60, and 175-350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA liposomes was HA polymer length-dependent; high MW (175-350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5 8, 50-60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability in vivo. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of ex vivo tumor cells showed that PEG-HA liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery. PMID- 24806527 TI - Natural hazards in a changing world: a case for ecosystem-based management. AB - Communities worldwide are increasingly affected by natural hazards such as floods, droughts, wildfires and storm-waves. However, the causes of these increases remain underexplored, often attributed to climate changes or changes in the patterns of human exposure. This paper aims to quantify the effect of climate change, as well as land cover change, on a suite of natural hazards. Changes to four natural hazards (floods, droughts, wildfires and storm-waves) were investigated through scenario-based models using land cover and climate change drivers as inputs. Findings showed that human-induced land cover changes are likely to increase natural hazards, in some cases quite substantially. Of the drivers explored, the uncontrolled spread of invasive alien trees was estimated to halve the monthly flows experienced during extremely dry periods, and also to double fire intensities. Changes to plantation forestry management shifted the 1:100 year flood event to a 1:80 year return period in the most extreme scenario. Severe 1:100 year storm-waves were estimated to occur on an annual basis with only modest human-induced coastal hardening, predominantly from removal of coastal foredunes and infrastructure development. This study suggests that through appropriate land use management (e.g. clearing invasive alien trees, re vegetating clear-felled forests, and restoring coastal foredunes), it would be possible to reduce the impacts of natural hazards to a large degree. It also highlights the value of intact and well-managed landscapes and their role in reducing the probabilities and impacts of extreme climate events. PMID- 24806529 TI - Distinctive patterns of dominant frequency trajectory behavior in drug-refractory persistent atrial fibrillation: preliminary characterization of spatiotemporal instability. AB - INTRODUCTION: The role of substrates in the maintenance of persistent atrial fibrillation (persAF) remains poorly understood. The use of dominant frequency (DF) mapping to guide catheter ablation has been proposed as a potential strategy, but the characteristics of high DF sites have not been extensively studied. This study aimed to assess the DF spatiotemporal stability using high density noncontact mapping (NCM) in persAF. METHODS AND RESULTS: Eight persAF patients were studied using NCM during AF. Ventricular far-field cancellation was performed followed by the calculation of DF using Fast Fourier Transform. Analysis of DF stability and spatiotemporal behavior were investigated including characteristics of the highest DF areas (HDFAs). A total of 16,384 virtual electrograms (VEGMs) and 232 sequential high density 3-dimensional DF maps were analyzed. The percentage of DF stable points decreased rapidly over time. Repetition or reappearance of DF values were noted in some instances, occurring within 10 seconds in most cases. Tracking the HDFAs' center of gravity revealed 3 types of propagation behavior, namely (i) local, (ii) cyclical, and (iii) chaotic activity, with the former 2 patterns accounting for most of the observed events. CONCLUSIONS: DF of individual VEGMs was temporally unstable, although reappearance of DF values occurred at times. Hence, targeting sites of 'peak DF' from a single time frame is unlikely to be a reliable ablation strategy. There appears to be a predominance of local and cyclical activity of HDFAs hinting a potentially nonrandom temporally periodic behavior that provides further mechanistic insights into the maintenance of persAF. PMID- 24806531 TI - Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN-beta. AB - The importance of neutrophils in tumor immune surveillance, invasive growth and angiogenesis becomes increasingly clear. Many of neutrophil activities are controlled by endogenous IFN-beta. Here, we provide evidence that endogenous IFN beta is regulating the apoptosis of pro-angiogenic tumor infiltrating neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Accordingly, the life span of tumor associated neutrophils (TANs) is remarkably prolonged in tumor bearing Ifnb1(-/-) mice compared to wild type controls. Lower expression of Fas, reactive oxygen species, active Caspase 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl 2 family and the major apoptosome constituent Apaf-1 is observed under such conditions. In line with inhibition of apoptosis and the prolonged neutrophil survival, in the absence of endogenous IFN-beta, a strong enhancement of G-CSF expression and PI3 Kinase phosphorylation is detected. These data explain the increased longevity of tumor infiltrating neutrophils and the accumulation of such cells in tumors. Taken together, our findings add to the important role of Type I IFN in immune surveillance against cancer. PMID- 24806530 TI - Distinguishing ventricular arrhythmia originating from the right coronary cusp, peripulmonic valve area, and the right ventricular outflow tract: utility of lead I. AB - INTRODUCTION: Outflow tract ventricular arrhythmia (OTVA) can be complicated to target for ablation when originating from either the periaortic or pulmonary valve (PV) region. Both sites may present with a small R wave in lead V1. However, the utility of lead I in distinguishing these arrhythmia locations is unknown. METHODS AND RESULTS: Thirty-six consecutive patients (mean age 41 +/- 14 years, 13 male) underwent catheter ablation for OTVA. OTVA origin was determined from intracardiac electrogram tracings and electroanatomic maps. Observers blinded to results measured QRS waveform amplitude and duration from standard 12 lead ECG tracings. Measurements with highest diagnostic performance were modeled into an algorithm. Sites of successful ablation were anterior right ventricular outflow tract (RVOT; n = 6), posterior RVOT (n = 4), PV (n = 18), and right coronary cusp (RCC; n = 8). Highest performing surface ECG discriminators were from lead I to V1 vectors: RCC, lead I R wave >= 1.5 mV, and V1 R wave >=2.0 mV (sensitivity 87%, specificity 93%); PV, V1 R wave > 0 mV, and lead I R/(R+S) <= 0.75 (sensitivity 78%, specificity 72%); anterior RVOT, V1 R wave = 0 mV, and lead I R/(R+S) <0.4 (sensitivity 67%, specificity 97%); posterior RVOT, V1 R wave > 0 mV, and lead I R/(R+S) > 0.75 (sensitivity 75%, specificity 84%). Sequential algorithmic application of these criteria resulted in an overall accuracy of 72% in predicting site of OTVA origin. CONCLUSIONS: A relatively large R wave in lead I is seen with RCC origin but not PV origin. A sequential algorithm has limited but potentially significant value beyond assessment of lead I in approaching OTVA. PMID- 24806532 TI - Effect of storage temperature and antibiotic impregnation on the quantity of bone morphogenetic protein seven in human bone grafts. AB - PURPOSE: The aim of this study was to quantify the amount of bone morphogenic protein 7 (BMP-7) in bone samples in different storage and treatment conditions used in bone banks and thereby evaluate the benefit of this test as a routine measure before bone grafting. METHODS: Fresh as well as frozen bone chips, each with and without antibiotic impregnation, were screened for their BMP-7 content. Human bone chips were produced from femoral heads of two female donors who had undergone total hip replacement surgery. The amount of BMP-7 was detected using a commercially available enzyme-linked immunosorbent assay (ELISA) test. RESULTS: There were no significant differences between groups in samples obtained from the first femoral head. Bone-chip samples derived from the second femoral head showed significant differences between groups. The actual amount of these differences was small and most likely biologically irrelevant. It is important to note that there was a significant difference between groups when comparing both femoral heads, reflecting donor-to-donor variability. CONCLUSION: ELISA testing for BMP-7 as a qualitative measurement of bone grafts should be considered a routine quality-control test for bone banks. PMID- 24806533 TI - Comparison of clinical and radiologic outcomes among stent-assisted, double catheter, and balloon-assisted coil embolization of wide neck aneurysms. AB - BACKGROUND: Endovascular treatment of intracranial aneurysms can be technically challenging in cases of wide necks or unfavorable dome-to-neck ratio. Coils deployed without supporting devices may herniate from the aneurysm sac into the parent artery, causing thromboembolic complications or vessel occlusion. Therefore, alternative strategies for managing wide-necked aneurysms have been introduced such as stent-assisted coil embolization (SAC), balloon-assisted coil embolization (BAC), and double-catheter coil embolization (DCC). METHODS: SAC, BAC, or DCC were used to treat 201 patients with 207 wide-neck aneurysms between 2008 and 2013. Initial occlusion rates, recanalization rates, and periprocedural complications were retrospectively evaluated. The mean follow-up periods for SAC, BAC, and DCC were 16.2 months, 11.6 months, and 14.3 months, respectively. RESULTS: Clinical and anatomical analyses were conducted in 201 patients with 207 anuerysms. Complete occlusion rates of SAC, DCC, and BAC were 63.8 %, 46.7 %, and 63.2 %, respectively, and incomplete occlusion rates were 13.4 %, 15.5 %, 10.5 %, respectively (p value = 0.798). No rebleeding or hemorrhage occurred after coil embolization. Recanalization rates did not differ among the SAC, DCC, and BAC groups (7.1 % vs. 11.1 % vs. 7.9 %, p value = 0.696). Statistically insignificant results were observed in the rate of periprocedural complications among SAC, DCC, and BAC (11.0 % vs. 13.3 % vs. 15.8 %, p value = 0.578). CONCLUSIONS: There were no significant differences in the recurrence rate and periprocedural complication rate, and no rebleeding or aneurysmal rupture after treatment. Sufficient occlusion rates were achieved with SAC, DCC, and BAC. Notably, DCC does not require the use of antiplatelet agents and achieves coil stability without compromising the parent artery or major branch. Thus, we believe that the double catheter technique was found to be a feasible and safe treatment modality for branching wide-neck aneurysms. PMID- 24806535 TI - Biofeedback for psychiatric disorders: a systematic review. AB - Biofeedback potentially provides non-invasive, effective psychophysiological interventions for psychiatric disorders. The encompassing purpose of this review was to establish how biofeedback interventions have been used to treat select psychiatric disorders [anxiety, autistic spectrum disorders, depression, dissociation, eating disorders, schizophrenia and psychoses] to date and provide a useful reference for consultation by clinicians and researchers planning to administer a biofeedback treatment. A systematic search of EMBASE, MEDLINE, PsycINFO, and WOK databases and hand searches in Applied Psychophysiology and Biofeedback, and Journal of Neurotherapy, identified 227 articles; 63 of which are included within this review. Electroencephalographic neurofeedback constituted the most investigated modality (31.7%). Anxiety disorders were the most commonly treated (68.3%). Multi-modal biofeedback appeared most effective in significantly ameliorating symptoms, suggesting that targeting more than one physiological modality for bio-regulation increases therapeutic efficacy. Overall, 80.9% of articles reported some level of clinical amelioration related to biofeedback exposure, 65.0% to a statistically significant (p < .05) level of symptom reduction based on reported standardized clinical parameters. Although the heterogeneity of the included studies warrants caution before explicit efficacy statements can be made. Further development of standardized controlled methodological protocols tailored for specific disorders and guidelines to generate comprehensive reports may contribute towards establishing the value of biofeedback interventions within mainstream psychiatry. PMID- 24806534 TI - Dorsal striatal dopamine, food preference and health perception in humans. AB - To date, few studies have explored the neurochemical mechanisms supporting individual differences in food preference in humans. Here we investigate how dorsal striatal dopamine, as measured by the positron emission tomography (PET) tracer [(18)F]fluorometatyrosine (FMT), correlates with food-related decision making, as well as body mass index (BMI) in 16 healthy-weight to moderately obese individuals. We find that lower PET FMT dopamine synthesis binding potential correlates with higher BMI, greater preference for perceived "healthy" foods, but also greater healthiness ratings for food items. These findings further substantiate the role of dorsal striatal dopamine in food-related behaviors and shed light on the complexity of individual differences in food preference. PMID- 24806536 TI - The clinical outcomes of early internal fixation for undisplaced femoral neck fractures and early full weight-bearing in elderly patients. AB - OBJECTIVE: The purpose of the present study was to evaluate the clinical outcomes of early internal fixation for undisplaced femoral neck fractures and early full weight-bearing in patients aged 65 years and older. PATIENTS AND METHODS: The records of consecutive patients who underwent surgery for undisplaced femoral neck fractures between 1999 and 2011 were retrospectively reviewed. The patients underwent the surgery as early as possible, and allowed early full weight bearing. The interval between initial injury and surgery, time to admission and operation, operation time, decrease in hemoglobin, the postoperative day starting to walk, postoperative walking status, and the incidence of any secondary procedures were evaluated. The average patient age was 77.5 years and the average duration of postoperative follow-up was 46.8 months. The patients were divided to two groups to determine the effect of early operation: the early operation group within 24 h on admission, and the late operation group done 24 h after admission. RESULTS: Eighty-six percent of surgeries were performed within 48 h of admission. The average operation time was 46 min (range 20-95 min). Transfusions were performed in 6.9 % (4/58) of patients. The mortality rate was 6.9 %, and the rate of complications was 9.3 % (5/54): four cases of avascular necrosis (AVN) and one case of fixation failure. The rate of secondary procedures was 7.4 % (4/54). Seventy-two percent (39/54) of patients recovered their postoperative walking ability to pre-injury levels. CONCLUSION: This study demonstrated that early internal fixation of undisplaced femoral neck fractures in elderly patients produced satisfactory clinical outcomes. PMID- 24806538 TI - Density of state determination of two types of intra-gap traps in dye-sensitized solar cells and its influence on device performance. AB - The density of state (DOS) of intra-gap traps and the dynamics of electron transport of a dye-sensitized TiO2 solar cell were investigated by means of time resolved charge extraction (TRCE). The intrinsic chemical capacitance of the TiO2 layer was separated from the parasitic capacitance of the FTO electrode, and was found to be dependent biexponentially on the photovoltage. It was shown that the shallow traps (>700 meV) differ from the deep ones (<350 meV) by the respective characteristic energy of 48 meV and 765 meV, and that the amount of shallow traps is more than an order of magnitude larger than that of the deep ones. Our results support the mechanism of shallow-trap dominant multiple-trap limited charge transport, and suggest a substantial margin for the short-circuit photocurrent density to reach its theoretical limit. PMID- 24806537 TI - Overexpression of sweetpotato expansin cDNA (IbEXP1) increases seed yield in Arabidopsis. AB - Results of transcriptome analyses suggest that expansin genes play an active role in seed development and yield, but gain- or loss-of-function studies have not yet elucidated the functional role(s) of the expansin gene(s) in these processes. We have overexpressed a sweetpotato expansin gene (IbEXP1) in Arabidopsis under the control of cauliflower mosaic 35S promoter in an attempt to determine the effect of the expansin gene in seed development and yield in heterologous plants. The growth rate was enhanced in IbEXP1-overexpressing (ox) plants relative to wild type Col-0 plants during early vegetative growth stage. At the reproductive stage, the number of rosette leaves was higher in IbEXP1-ox plants than that in Col-0 plants, and siliques were thicker. IbEXP1-ox plants produced larger seeds, accumulated more protein and starch in each seed, and produced more inflorescence stems and siliques than Col-0 plants, leading to a 2.1-2.5-fold increase in total seed yield per plant. The transcript level of IbEXP1 was up-regulated in response to brassinosteroid (BR) treatment in sweetpotato, and the transcript levels of three BR-responsive genes, fatty acid elongase 3-ketoacyl-CoA synthase 1, HAIKU1 and MINISEED3, were also increased in IbEXP1-ox Arabidopsis plants, suggesting a possible involvement of IbEXP1 in at least one of the BR signaling pathways. Based on these results, we suggest that overexpression of IbEXP1 gene in heterologous plants is effective in increasing seed size and number and, consequently, seed yield. PMID- 24806539 TI - Giant congenital juvenile xanthogranuloma presenting as a yellowish atrophic plaque. PMID- 24806540 TI - Development of a full-length human protein production pipeline. AB - There are many proteomic applications that require large collections of purified protein, but parallel production of large numbers of different proteins remains a very challenging task. To help meet the needs of the scientific community, we have developed a human protein production pipeline. Using high-throughput (HT) methods, we transferred the genes of 31 full-length proteins into three expression vectors, and expressed the collection as N-terminal HaloTag fusion proteins in Escherichia coli and two commercial cell-free (CF) systems, wheat germ extract (WGE) and HeLa cell extract (HCE). Expression was assessed by labeling the fusion proteins specifically and covalently with a fluorescent HaloTag ligand and detecting its fluorescence on a LabChip((r)) GX microfluidic capillary gel electrophoresis instrument. This automated, HT assay provided both qualitative and quantitative assessment of recombinant protein. E. coli was only capable of expressing 20% of the test collection in the supernatant fraction with >=20 MUg yields, whereas CF systems had >=83% success rates. We purified expressed proteins using an automated HaloTag purification method. We purified 20, 33, and 42% of the test collection from E. coli, WGE, and HCE, respectively, with yields >=1 MUg and >=90% purity. Based on these observations, we have developed a triage strategy for producing full-length human proteins in these three expression systems. PMID- 24806541 TI - Oral healthcare challenges for older Punjabi-speaking immigrants. AB - This study explored how older Punjabi-speaking South-Asian immigrants (four focus groups; 33 participants) in Surrey, British Columbia, perceive oral health and related problems. Content analysis revealed two umbrella themes: (a) interpretations of mouth conditions and (b) challenges to oral health. The umbrella themes had four sub-themes: damage caused by heat (wai), disturbances caused by caries, coping with dentures, and quality of life. Three challenges were considered: home remedies, Western dentistry, and difficulties accessing dentists. Participants explained oral diseases in terms of a systemic infection (resha), and preferred to decrease imbalances of wai in the mouth with home remedies from India. We conclude that older Punjabi-speaking immigrants interpret oral health and disease in the context of both Western and Ayurvedic traditions, and that they manage dental problems with a mix of traditional remedies supplemented, if possible, by elective oral health care in India, and by emergency dental care in Canada. PMID- 24806542 TI - Is eye gaze direction always determined without intent? AB - It is widely assumed that processing of gaze direction occurs "automatically," in the sense that it is reflexive (unfolds in the absence of intention). We assessed this view in a task in which participants saw a schematic face in which the eyes were gazing left or right, along with a second directional target (an arrow in Experiment 1; a directional word in Experiment 2). The eyes and other directional target were sometimes congruent and other times incongruent. On each trial, participants were cued with a tone to respond to either the direction the eyes were gazing, or the direction the noneye target indicated. The time between the onset of the task cue and the onset of the face was manipulated so that on half the trials the face and the cue were presented at the same time. Regardless of the type of target, the congruency effect was the same size at the zero SOA as it was at the 750 SOA, suggesting that eyes were not processed until participants knew what task to perform. These results are consistent with the claim that processing of gaze direction is, at least some of the time, secondary to an intent (i.e., it is not reflexive). PMID- 24806543 TI - Adverse family experiences among children in nonparental care, 2011-2012. AB - OBJECTIVE: This report presents estimates of the proportion of children who have experienced selected adverse family events by the number of biological parents in the household, with a focus on comparisons among subgroups of children in nonparental care defined by caregiver type. DATA SOURCES: Data were drawn from the 2011-2012 National Survey of Children's Health, a nationally representative telephone survey of households with children conducted by the National Center for Health Statistics. RESULTS: Children in nonparental care were 2.7 times as likely as children living with two biological parents to have had at least one adverse experience, and more than 2 times as likely as children living with one biological parent and about 30 times as likely as children living with two biological parents to have had four or more adverse experiences. More than one half of children in foster care had experienced caregiver violence or caregiver incarceration and almost two-thirds had lived with someone with an alcohol or drug problem. Estimates for children in other nonparental care subgroups were lower than for foster care, but still elevated above those of children living with biological parents. CONCLUSIONS: Children in nonparental care, especially those in foster care, are particularly likely to have experienced adverse family events. These events could have occurred at any time in the child's life and could have preceded or contributed to the child's current living situation. Nevertheless, children in nonparental care may be vulnerable to poorer health and well-being outcomes that are often associated with having had adverse experiences. PMID- 24806544 TI - Deviations from STAN guidelines are frequent but results cannot be excluded when the effectiveness of the method should be evaluated. PMID- 24806545 TI - Contamination of groundwater systems in the US and Canada by enteric pathogens, 1990-2013: a review and pooled-analysis. AB - BACKGROUND: Up to 150 million North Americans currently use a groundwater system as their principal drinking water source. These systems are a potential source of exposure to enteric pathogens, contributing to the burden of waterborne disease. Waterborne disease outbreaks have been associated with US and Canadian groundwater systems over the past two decades. However, to date, this literature has not been reviewed in a comprehensive manner. METHODS AND PRINCIPAL FINDINGS: A combined review and pooled-analysis approach was used to investigate groundwater contamination in Canada and the US from 1990 to 2013; fifty-five studies met eligibility criteria. Four study types were identified. It was found that study location affects study design, sample rate and studied pathogen category. Approximately 15% (316/2210) of samples from Canadian and US groundwater sources were positive for enteric pathogens, with no difference observed based on system type. Knowledge gaps exist, particularly in exposure assessment for attributing disease to groundwater supplies. Furthermore, there is a lack of consistency in risk factor reporting (local hydrogeology, well type, well use, etc). The widespread use of fecal indicator organisms in reported studies does not inform the assessment of human health risks associated with groundwater supplies. CONCLUSIONS: This review illustrates how groundwater study design and location are critical for subsequent data interpretation and use. Knowledge gaps exist related to data on bacterial, viral and protozoan pathogen prevalence in Canadian and US groundwater systems, as well as a need for standardized approaches for reporting study design and results. Fecal indicators are examined as a surrogate for health risk assessments; caution is advised in their widespread use. Study findings may be useful during suspected waterborne outbreaks linked with a groundwater supply to identify the likely etiological agent and potential transport pathway. PMID- 24806546 TI - In vivo and in vitro activity of an immunoglobulin Fc fragment (Fcab) with engineered Her-2/neu binding sites. AB - Antigen-binding Fc fragments (Fcabs) are a new unique class of immunotherapeutics. They are small (50 kD) fully functional antibody alternatives that bind antigen and elicit effector functions such as antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity. Since Fcabs carry the natural FcRn binding site of antibodies, they have very favorable pharmacokinetics. We showed recently that Fcab H10-03-6 is a high-affinity binder of Her-2/neu (ErbB2/neu) mediating killing of Her-2/neu-overexpressing tumor cells in the presence of immune effector cells, strongly suggesting that the mechanism of killing is due to ADCC. The present study further confirms ADCC as the mechanism by which H10-03-6 mediates tumor cell killing, since H10-03-6 was shown to interact simultaneously with Her-2/neu and the Fc receptor CD16a. The epitope recognized by H10-03-6 overlaps with that of the clinically used monoclonal antibody trastuzumab. However, unlike trastuzumab, Fcab H10-03-6 did not inhibit proliferation of human tumor cells in vitro even under conditions favoring Her-2/neu crosslinking. Treatment of mice harboring human BT-474 cell xenograft tumors with Fcab H10-03-6 led to statistically significant retardation of tumor growth. For the first time, in vivo properties of an Fcab are presented, supporting the view that Fcabs could become highly efficacious immunotherapeutics for human use. PMID- 24806547 TI - The comparative analyses of the auditory evoked potentials and color Doppler sonography findings in patients diagnosed with vertebrobasilar insufficiency. AB - Auditory evoked potentials (AEP) represent an electrophysiological method used in the diagnostics of pathological changes of the brainstem. Patients with vertebrobasilar insufficiency (VBI) show changes in the AEP-caused ischemia of the brain structures that generate their responses. The aim of the study was to determine the diagnostic significance and correlation among the findings of AEP in patients with VBI established by color Doppler sonography. The cross-sectional and prospective research included 48 inpatients and outpatients treated at the Clinic of Neurology, Clinical Center Nis. Ultrasound Doppler of blood vessels in the neck included an examination of the carotid blood vessels, the outcome and all sonographically available parts of the vertebral artery (VA) with particular emphasis on the intravertebral segment (V2). The morphological and hemodynamic characteristics of VA in this segment were monitored, and it was important to test the systolic velocity in two adjacent intervertebral spaces. Auditory evoked potentials were used to monitor the amplitudes, absolute latencies of waves I, II, III, IV, and V, as well as interwave latencies (IWLs) I-III, III-V, and I-V. There is statistically significant difference in the more frequent pathological finding of AEP in patients with higher degree of the reduced flow of VA established by color Doppler (P < 0.05) compared to patients with less reduction in the flow. Pathological findings of AEP are well correlated with pathological findings of VBI in color Doppler, and it may be applied as an additional and useful marker in diagnosis of VBI. PMID- 24806548 TI - Cadmium-zinc exchange and their binary relationship in the structure of Zn related proteins: a mini review. AB - Research on cadmium-zinc exchange in proteins is important for understanding one of the main sources of Cd's biological toxicity. Because of the similar properties of these two elements, most living organisms must prevent Cd from replacing Zn in Zn-requiring proteins in order for those proteins to function normally. Recent structural studies of a variety of proteins associated with the versatile physiological functions of Zn have revealed widespread instances of Cd Zn exchange in proteins of a large number of living organisms. Ongoing work is focused on discovering the structural mechanisms of Cd-Zn exchange and the potentially diverse roles of Cd at Zn functional sites in proteins. This research is a prerequisite to understanding the evolution of Cd-tolerant species (e.g., Cd hyperaccumulating plants) and to the engineering of optimal strategies for protecting the public heath against Cd pollution. PMID- 24806549 TI - Neutralization of nerve growth factor impairs proliferation and differentiation of adult neural progenitors in the subventricular zone. AB - Adult neurogenesis is a multistep process regulated by several extrinsic factors, including neurotrophins. Among them, little is known about the role of nerve growth factor (NGF) in the neurogenic niches of the mouse. Here we analyzed the biology of adult neural stem cells (NSCs) from the subventricular zone (SVZ) of AD11 anti-NGF transgenic mice, in which the expression of the recombinant antibody aD11 leads to a chronic postnatal neutralization of endogenous NGF. We showed that AD11-NSCs proliferate 10-fold less, with respect to their control counterparts, and display a significant impairment in their ability to differentiate into beta-tubulin positive neurons. We found a considerable reduction in the number of SVZ progenitors and neuroblasts also in vivo, which correlates with a lower number of newborn neurons in the olfactory bulbs of AD11 mice and a severe deficit in the ability of these mice to discriminate between different odors. We also demonstrated that, in AD11 mice, the morphology of both SVZ-resident and neurosphere-derived astrocytes is significantly altered. We were able to reproduce the AD11 phenotype in vitro, by acutely treating wild type NSCs with the anti-NGF antibody, further demonstrating that both the proliferation and the differentiation defects are due to the NGF deprivation. Consistently, the proliferative impairment of AD11 progenitors, as well as the atrophic morphology of AD11 astrocytes, can be partly rescued in vitro and in vivo by exogenous NGF addition. Altogether, our results demonstrate a causal link between NGF signaling and proper proliferation and differentiation of neural stem cells from the SVZ. PMID- 24806550 TI - Heart failure with preserved ejection fraction: the impact of stricter definitions. AB - AIMS: To determine the impact of internationally recognized criteria for the diagnosis of heart failure with preserved ejection fraction (HF-PEF) on the feasibility of recruitment into a HF-PEF trial. METHODS AND RESULTS: We reviewed the medical records of 5883 consecutive patients admitted with heart failure across eight hospitals in the U.K. From those who had an EF >=50% (filter 1), patients who had an alternative cardiac cause of symptoms or an over-riding co morbidity were excluded (filter 2). The remaining patients had to satisfy the following selection criteria (filter 3): the presence of a non-dilated left ventricle; structural remodelling (LV hypertrophy or dilated left atrium); and evidence of impaired diastolic function or raised BNP. Overall, 20.5% (n = 1203) of patients admitted with heart failure had an EF >=50%. There was significant heterogeneity between the hospitals as this proportion varied from 42.4% in the teaching hospitals to 13.8% in the district general hospitals (P < 0.0001). Applying filter 2, the cohort size was reduced from 1203 to 122 patients. Of the latter 122, only 45 people had evidence of structural cardiac remodelling and evidence of either raised cardiac filling pressures on echocardiography or raised BNP consistent with HF-PEF. CONCLUSION: Applying our filters, only 0.8% of all patients admitted with heart failure would be eligible for a HF-PEF trial. These data have important implications for the feasibility of clinical trials for HF PEF and for the generalizability of the results of such studies. PMID- 24806551 TI - Radical-cation dimerization overwhelms inclusion in [N]pseudorotaxanes. AB - Suppression of the dimerization of the viologen radical cation by cucurbit[7]uril (CB7) in water is a well-known phenomenon. Herein, two counter-examples are presented. Two viologen-containing thread molecules were designed, synthesized, and thoroughly characterized by (1)H DOSY NMR spectrometry, UV/Vis absorption spectrophotometry, square-wave voltammetry, and chronocoulometry: BV(4+), which contains two viologen subunits, and HV(12+), which contains six. In both threads, the viologen subunits are covalently bonded to a hexavalent phosphazene core. The corresponding [3]- and [7]pseudorotaxanes that form on complexation with CB7, that is, BV(4+)?(CB7)2 and HV(12+)?(CB7)6, were also analyzed. The properties of two monomeric control threads, namely, methyl viologen (MV(2+)) and benzyl methyl viologen (BMV(2+)), as well as their [2]pseudorotaxane complexes with CB7 (MV(2+)?CB7 and BMV(2+)?CB7) were also investigated. As expected, the control pseudorotaxanes remained intact after one-electron reduction of their viologen recognition stations. In contrast, analogous reduction of BV(4+)?(CB7)2 and HV(12+)?(CB7)6 led to host-guest decomplexation and release of the free threads BV(2(.+)) and HV(6(.+)), respectively. (1)H DOSY NMR spectrometric and chronocoulometric measurements showed that BV(2(.+)) and HV(6(.+)) have larger diffusion coefficients than the corresponding [3]- and [7]pseudorotaxanes, and UV/Vis absorption studies provided evidence for intramolecular radical-cation dimerization. These results demonstrate that radical-cation dimerization, a relatively weak interaction, can be used as a driving force in novel molecular switches. PMID- 24806552 TI - Mesenchymal stem cell therapies: the quest for fine-tuning. AB - Mesenchymal stem cells (MSCs) have a vastly unharnessed therapeutic potential with close to 400 studies currently registered on clinicaltrials.gov for evaluation of their clinical promises. While many of these investigations are for immune-mediated disorders, there is no established consensus on how to optimize the immunomodulatory properties of MSCs. Factors that could be used to predict efficacy of MSC therapies include donor heterogeneity, recipient environment and drug interactions. Incorporating pertinent quality control parameters to maximize the clinical potential of MSCs through good manufacturing practice (GMP) production of clinical grade cells could lead to the realization of greater therapeutic success. PMID- 24806554 TI - Bis(trifluoromethyl)methylene addition to vinyl-terminated SAMs: a gas-phase C-C bond-forming reaction on a surface. AB - Vinyl-terminated self-assembled monolayers (SAMs) on silicon oxide substrates were chemically modified by the addition of a bis(trifluoromethyl)methylene group in a rare gas-phase C-C bond-forming reaction to directly generate films carrying terminal CF3 groups. The vinyl-terminated films were treated with hexafluoroacetone azine (HFAA) for modification. The films were characterized with ellipsometry, contact angle measurements, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). In this study, we find that for optimized conditions clean reactions occur on a surface between SAMs with terminal olefins and HFAA, and the product is consistent with bis(trifluoromethyl)cyclopropanation formation after nitrogen extrusion. PMID- 24806555 TI - Photopolymerization of polydiacetylene in hybrid liposomes: effect of polymerization on stability and response to pathogenic bacterial toxins. AB - Liposomes containing lipids and polydiacetylene (PDA) are hybrid systems encompassing both a fluid phospholipid membrane and a polymer scaffold (PDA). However, the biophysical role of PDA in such liposomes is not well understood. In this report, we studied the effects of photopolymerization of PDA on the stability of lipid-PDA liposomes, and their sensitivity to selected purified toxins and bacterial supernatants, using a fluorescence assay. Of the three different types of liposomes with variable lipid chain lengths that were chosen, the degree of polymerization had a significant impact on the long-term stability, and response, to external microbial exotoxins secreted by pathogenic bacteria, namely, Staphylococcus aureus and Pseudomonas aeruginosa. The degree of polymerization of TCDA played an important role in lipid-chain-length-dependent stabilization of lipid-PDA liposomes, as well as in their response to bacterial toxins of S. aureus and P. aeruginosa. PMID- 24806556 TI - Effect of physician-dispensed medication on workers' compensation claim outcomes in the state of Illinois. AB - OBJECTIVE: To evaluate differences between physician-dispensed and non-physician dispensed medication with regard to lost time, prescription volume, and pharmaceutical, medical, indemnity costs in the Illinois workers' compensation system. METHODS: We studied a sample of 6824 workers' compensation indemnity claims that were opened and closed between January 1, 2007, and December 31, 2012, by Accident Fund Holdings in the State of Illinois. RESULTS: The number of prescriptions per claim and pharmaceutical, medical, and indemnity costs, as well as time out from work, were significantly higher in claims where a pharmaceutical was dispensed by the physician within 90 days of injury than in claims where physician dispensing did not occur. These differences persisted controlling for age, sex, attorney involvement, and injury complexity. CONCLUSION: Physician dispensing is associated with higher costs and more lost time than pharmacy dispensed medications in workers' compensation claims. PMID- 24806557 TI - Urinary polycyclic aromatic hydrocarbon (OH-PAH) metabolite concentrations and the effect of GST polymorphisms among US Air Force personnel exposed to jet fuel. AB - OBJECTIVE: To evaluate the association between inhalation exposure to jet propulsion fuel 8 (JP-8) and urinary metabolites among US Air Force (USAF) personnel, and investigate the role of glutathione S-transferase polymorphisms. METHODS: Personal air samples were collected from 37 full-time USAF personnel during 4 consecutive workdays and analyzed for JP-8 constituents and total hydrocarbons. Pre- and postshift urine samples were collected each day and analyzed for polycyclic aromatic hydrocarbon urinary metabolites. RESULTS: Work shift exposure to total hydrocarbons was significantly associated with postshift urinary 1-naphthol (beta = 0.17; P = <0.0001), 2-naphthol (beta = 0.09; P = 0.005), and 2-hydroxyfluorene concentrations (beta = 0.08; P = 0.006), and a significant gene-environment interaction was observed with glutathione S transferase mu-1. CONCLUSIONS: USAF personnel experience inhalation exposure to JP-8, which is associated with absorption of JP-8 constituents while performing typical job-related tasks, and in our data the glutathione S-transferase mu-1 polymorphism was associated with differential metabolism of naphthalene. PMID- 24806558 TI - Frequent headache and work ability: a population-based study in Sweden. AB - OBJECTIVE: The aim of this study was to analyze the association between frequent headache and self-reported mental and physical work ability in a general population sample in Sweden. METHODS: The study was conducted in western Sweden in 2008. Frequent headache was analyzed in relation to mental and physical work ability. Covariates included demographics and socioeconomic variables, work related variables, and a symptom index. Self-reported and register-based sickness absence data were also analyzed. RESULTS: Sixteen per cent of those who answered the question about headache (n = 2590) had frequent headache (at least once a week). Regression analyses showed that frequent headache sufferers were twice more likely to have poor mental and physical work ability than those having infrequent headache. CONCLUSIONS: Frequent headache was associated with poor mental and physical work ability but not with sickness absence. PMID- 24806559 TI - Relationship between carbon dioxide levels and reported headaches on the international space station. AB - OBJECTIVE: Because of anecdotal reports of CO(2)-related symptoms onboard the International Space Station (ISS), the relationship between CO(2) and in-flight headaches was analyzed. METHODS: Headache reports and CO(2) measurements were obtained, and arithmetic means and single-point maxima were determined for 24 hour and 7-day periods. Multiple imputation addressed missing data, and logistic regression modeled the relationship between CO(2), headache probability, and covariates. RESULTS: CO(2) level, age at launch, time in-flight, and data source were significantly associated with headache. For each 1-mm Hg increase in CO(2), the odds of a crew member reporting a headache doubled. To keep the risk of headache below 1%, average 7-day CO(2) would need to be maintained below 2.5 mm Hg (current ISS range: 1 to 9 mm Hg). CONCLUSIONS: Although headache incidence was not high, results suggest an increased susceptibility to physiological effects of CO(2) in-flight. PMID- 24806560 TI - Expression levels of surfactant-associated proteins and inflammation cytokines in serum and bronchoalveolar lavage fluid among coal miners: a case-control study. AB - OBJECTIVE: To investigate whether the Th1/Th2 balance and expressions of surfactant-associated proteins and cytokines in serum and bronchoalveolar lavage fluid (BALF) are associated with the development of coal workers' pneumoconiosis (CWP). METHODS: A case-control study was conducted among 72 CWP cases and 68 controls. Th1 and Th2 populations were measured by flow cytometry. Expressions of surfactant-associated proteins A and D (SPA and SPD) and cytokines in serum and BALF were detected by enzyme-linked-immunosorbent serologic assay. Data were analyzed by t test and logistic regression. RESULTS: Higher Th2 and lower Th1/Th2 were observed in CWP (P < 0.05). Increased CWP risk was associated with elevated BALF-interleukin-10 (odds ratio [OR]: 25.97; 95% confidence interval [CI]: 2.17 to 49.77), serum-SPA/BALF-SPA (OR: 12.87; 95% CI: 1.11 to 148.72), and serum SPD/BALF-SPD (OR: 77.91; 95% CI: 5.64 to 161.46), decreased BALF-SPA (OR: 0.06; 95% CI: 0.01 to 0.31) and BALF-SPD (OR: 0.07; 95% CI: 0.02 to 0.36). CONCLUSIONS: The development of CWP might be associated with Th1/Th2 imbalance and increased BALF-interleukin-10, serum-SPA/BALF-SPA, and serum-SPD/BALF-SPD. PMID- 24806561 TI - Relationship between urinary nickel and methylation of p15, p16 in workers exposed to nickel. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between urinary nickel and methylation of p15, p16 in workers exposed to nickel. METHODS: In this study, 165 nickel-exposed workers and 67 workers without exposure were recruited. The levels of urinary nickel were analyzed using dimethylglyoxime spectrophotometric method. Methylation-specific polymerase chain reaction was used to detect the methylation of p15 and p16. RESULTS: The median concentration of urinary nickel in the exposed group (4.58 MUg/L) was significantly higher than that in the control group (1.78 MUg/L; P < 0.01). The rate of methylation of p15 in the exposed group was significantly higher than that in the control group (P = 0.023). The multiple logistic analysis showed that workers having higher urinary nickel were at the higher risk of methylation of p15 (P = 0.024). CONCLUSIONS: The levels of urinary nickel were significantly associated with the methylation of p15. PMID- 24806562 TI - Association between inflammatory biomarkers in plasma, radiological severity, and duration of exposure in patients with silicosis. AB - OBJECTIVE: To evaluate the plasma levels of CCL2, CCL3, CCL11, CCL24, tumor necrosis factor alpha, sTNFR1, and sTNFR2 in subjects exposed to silica (SES) with and without silicosis compared with unexposed reference control group, and their associations with the radiological severity and duration of exposure to silica. METHODS: Fifty-seven SES; 36 with silicosis and 22 subjects in control group, were included in the study. RESULTS: CCL3, CCL24, sTNFR1, and sTNFR2 were increased in SES and in SES with silicosis than in controls. There were no differences in the levels of CCL2, CCL11, or tumor necrosis factor alpha. The sTNFR2 level was greater in SES with silicosis than in SES without silicosis. There was a positive correlation between sTNFR1 and sTNFR2 and the radiological severity and time of exposure to silica. sTNFR2 was associated with all categories of radiological severity. CONCLUSION: sTNFR2 is associated with silicosis severity and early exposure to silica. PMID- 24806563 TI - How healthy is the Singaporean worker? Results from the Singapore national health survey 2010. AB - OBJECTIVE: To compare the prevalence of common medical conditions (including mental health and self-rated health) and lifestyle risk factors for disease of the Singapore workforce with the nonworking population, and evaluate the association of these factors with occupation class. METHODS: Data were obtained from a population-representative cross-sectional survey in 2010. Adjusted prevalence ratios (PRs) were obtained by modified Breslow-Cox proportional hazards regression model. RESULTS: Within the workforce, after adjustment for age, sex, and ethnicity, daily smoking (PR = 1.87; 95% confidence interval [CI], 1.40 to 2.51; P < 0.001), no regular exercise (PR = 1.13; 95% CI, 1.07 to 1.20; P < 0.001), and poor self-rated health (PR = 1.46, 95% CI, 1.22 to 1.76; P < 0.001) were more prevalent in the lower-skilled occupation classes. CONCLUSIONS: Lower skilled occupation classes in Singapore are associated with lifestyle risk factors, and tailored workplace health promotion programs addressing their specific health needs are needed. PMID- 24806564 TI - Association of sleep habits with accidents and near misses in United States transportation operators. AB - OBJECTIVE: To explore sleep risk factors and their association with adverse events in transportation operators. METHODS: Self-reported sleep-related behaviors were analyzed in transportation operators (drivers, pilots, and rail operators) aged 26 to 78 years who completed the National Sleep Foundation's 2012 "Planes, Trains, Automobiles, and Sleep" survey. Regression analyses were used to assess the associations of various sleep-related variables with the combined outcome of self-reported accidents and near misses. RESULTS: Age- and body mass adjusted predictors of accidents/near misses included an accident while commuting (odds ratio [OR] = 4.6; confidence interval [CI], 2.1 to 9.8), driving drowsy (OR = 4.1; CI, 2.5 to 6.7), and Sheehan Disability Scale score greater than 15 (OR = 3.5; CI, 2.2 to 5.5). Sleeping more than 7 hours nightly was protective for accident/near misses (OR = 0.6; CI, 0.4 to 0.9). CONCLUSION: Recognized risk factors for poor sleep or excessive daytime sleepiness were significantly associated with self-reported near misses and/or accidents in transportation operators. PMID- 24806565 TI - Evaluation of booster breaks in the workplace. AB - OBJECTIVE: This study elicited information regarding benefits of and barriers to participation in health-promoting work breaks, known as Booster Breaks, from participants with extensive experience (6 months to 1 year) with these types of breaks. METHODS: On the basis of the story path method of inquiry, data were collected regarding past, present, and future time frames during extensive face to-face interviews. Group consensus processes identified themes. RESULTS: The top ranked benefit theme was experiencing positive feelings, followed by improved health and sense of team camaraderie. The three barrier themes were time constraints/interruption of work flow, lack of interest, and absence of organizational support. CONCLUSIONS: As decision makers plan and implement health promoting work breaks such as Booster Breaks, these findings indicate the benefits to emphasize and the barriers to counteract. Management support to sustain engagement is a priority. PMID- 24806566 TI - Prevalence of undiagnosed cardiovascular risk factors and 10-year CVD risk in male steel industry workers. AB - OBJECTIVE: To assess the prevalence of undiagnosed cardiovascular disease (CVD) in a cohort of male steelworkers in South Wales, UK. METHODS: Male steel industry workers (n = 221) with no prior diagnosis of CVD or diabetes accepted a CVD risk assessment within the work environment. Demographic, anthropometric, family, and medical histories were all recorded and capillary blood samples obtained. The 10 year CVD risk was predicted using the QRISK2-2012 algorithm. RESULTS: Up to 81.5% of workers were either overweight or obese. More than 20% of workers were found to have diastolic hypertension, high total cholesterol, and/or a total cholesterol/high-density lipoprotein ratio of six or more. Over one quarter of workers assessed had an increased 10-year CVD risk. CONCLUSIONS: Despite a physically demanding occupation, risk assessment in the workplace uncovered significant occult factors in CVD risk in a sample of male heavy industry workers. PMID- 24806567 TI - Motivations for health and their associations with lifestyle, work style, health, vitality, and employee productivity. AB - OBJECTIVE: Investigate employees' underlying motivational regulatory styles toward healthy living and their associations with lifestyle, work style, health, vitality, and productivity. METHODS: Regression analyses on cross-sectional data from Dutch employees (n = 629), obtained as baseline measurement before a workplace health promotion project. RESULTS: Controlled regulation was not associated with smoking and alcohol use, and negatively associated with physical activity, healthy dietary habits, relaxation, and a balanced work style. Autonomous regulation was positively associated with physical activity, healthy dietary habits, and relaxation, and negatively associated with smoking and alcohol use. Healthy lifestyle and work style were associated with perceived health and vitality, which in turn were associated with employees' productivity (absenteeism and presenteeism). CONCLUSIONS: Internalization of the value of health is important to promote a healthy lifestyle and work style among employees, and has meaningful business implications. PMID- 24806568 TI - Heart healthy online: an innovative approach to risk reduction in the workplace. AB - OBJECTIVES: To examine whether a Web-based cardiovascular health promotion program was associated with changes in self-reported behaviors, attitudes, and biometric indicators in a population of working adults. METHODS: Employees (n = 210) were recruited and randomized into either an Internet-based or control condition. Participants completed pre- and postintervention self-report assessments on diet, exercise, smoking, and mental health. Pre- and postintervention biometric screenings were also obtained on blood pressure, heart rate, weight, and hip/waist circumference. RESULTS: The intervention was associated with significant improvements in dietary attitudes (P = 0.003; F = 8.83), dietary intentions (P = 0.031; F = 4.72), dietary self-efficacy (P = 0.015; F = 5.97), exercise self-efficacy (P = 0.002; F = 9.51), exercise habits (P = 0.016; F = 5.94), and coping with stress (P = 0.003; F = 8.85) and depression (P = 0.036; F = 4.46). CONCLUSIONS: The program showed promise for promoting cardiovascular risk reduction behaviors. These results are consistent with similar Web-based interventions. PMID- 24806572 TI - American College of Occupational and Environmental Medicine's Occupational and Environmental Medicine Competencies-2014: ACOEM OEM Competencies Task Force*. PMID- 24806569 TI - Estimating the return on investment from a health risk management program offered to small Colorado-based employers. AB - OBJECTIVE: To determine whether changes in health risks for workers in small businesses can produce medical and productivity cost savings. METHODS: A 1-year pre- and posttest study tracked changes in 10 modifiable health risks for 2458 workers at 121 Colorado businesses that participated in a comprehensive worksite health promotion program. Risk reductions were entered into a return-on investment (ROI) simulation model. RESULTS: Reductions were recorded in 10 risk factors examined, including obesity (-2.0%), poor eating habits (-5.8%), poor physical activity (-6.5%), tobacco use (-1.3%), high alcohol consumption (-1.7%), high stress (-3.5%), depression (-2.3%), high blood pressure (-0.3%), high total cholesterol (-0.9%), and high blood glucose (-0.2%). The ROI model estimated medical and productivity savings of $2.03 for every $1.00 invested. CONCLUSIONS: Pooled data suggest that small businesses can realize a positive ROI from effective risk reduction programs. PMID- 24806574 TI - A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition. AB - An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. PMID- 24806575 TI - The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey. AB - INTRODUCTION: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements. AREAS COVERED: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment. EXPERT OPINION: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments. PMID- 24806576 TI - The compositional mosaic of Fusarium species and their mycotoxins in unprocessed cereals, food and feed products in Belgium. AB - Global food safety depends on continuous monitoring of food contaminants such as mycotoxins in cereals and cereal-derived products. Here, we combine this type of investigation with quantitative occurrence data on Fusarium infestation of these products in extensive correlation studies. Finally, this contributes to a thorough understanding of the presence, origin and physiology of Fusarium Head Blight (FHB) related mycotoxins and the correlations within their ranks. Two hundred and thirty-seven samples were analyzed from diverse cereal matrices, representing the most important stages of the cereal food and feed chain in Belgium. Food, feed and non-processed field samples were investigated, with a strong emphasis on whole-grain food products. Two approaches were pursued to estimate the full scope of FHB and its repercussions: UPLC-MS/MS was applied to detect twelve different mycotoxins, and Q-PCR was used to measure the presence of ten Fusarium species. We found that different matrices have different characteristic contamination profiles, and extensive correlation studies identified certain mycotoxins for future assessment (e.g. moniliformin produced by the Fusarium avenaceum/Fusarium tricinctum species group). The investigated harvest year of 2012 yielded many non-processed field materials containing elevated levels of deoxynivalenol (DON), while even in a so-called DON-year less prevalent toxins such as T-2 and HT-2 might be considered problematic due to their consistent co-occurrence with related mycotoxins. Our data illustrate complex interactions between the many Fusarium species that are responsible for FHB and their mycotoxins. Correlation studies demonstrate that consistent co occurrence of mycotoxins is not to be neglected, and pinpoint issues for future surveillance and legislation. PMID- 24806577 TI - Modeling the effect of a prosthetic limb on 4-km pursuit performance. AB - The individual pursuit is a 4-km cycling time trial performed on a velodrome. Parathletes with transtibial amputation (TTA) have lost physiological systems, but this may be offset by the reduced aerodynamic drag of the prosthesis. This research was performed to understand the effect of a unilateral TTA on Olympic 4 km pursuit performance. A forward-integration model of pursuit performance explored the interplay between power loss and aerodynamic gains in parathletes with TTA. The model is calibrated to a 4-km pursuit time of 4:10.5 (baseline), then adjusted to account for a TTA. Conditions simulated were based on typical pedal asymmetry in TTA (AMP), if foot stiffness were decreased (FLEX), if pedaling asymmetries were minimized (ASYM), if the prosthesis were aerodynamically optimized (AERO), if the prosthesis had a cosmetic cover (CC), and if all variables were optimized (OPT). A random Monte Carlo analysis was performed to understand model precision. Four-kilometer pursuit performances predicted by the model were 4:10.5, 4:20.4, 4:27.7, 4:09.2, 4:19.4, 4:27.9, and 4:08.2 for the baseline, AMP, FLEX, ASYM, AERO, CC, and OPT models, respectively. Model precision was +/-3.7 s. While the modeled time decreased for ASYM and OPT modeled conditions, the time reduction fell within model precision and therefore was not significant. Practical application of these results suggests that parathletes with a TTA could improve performance by minimizing pedaling asymmetry and/or optimizing aerodynamic design, but, at best, they will have performance similar to that of intact cyclists. In conclusion, parathletes with TTA do not have a net advantage in the individual pursuit. PMID- 24806578 TI - Postsurgical hypoparathyroidism--risk of fractures, psychiatric diseases, cancer, cataract, and infections. AB - Data on co-morbidity in patients with postsurgical hypoparathyroidism (HypoPT) are sparse. We aimed to assess risk of fractures, spinal stenosis, cataract, neuropsychiatric diseases, cancer, and infections within the historic cohort of patients with postsurgical HypoPT due to non-malignant causes that we previously have characterized. Patients were identified through the Danish National Patient Registry and regional prescription databases, with subsequent validation of their individual hospital records. Identified cases were matched with three age- (+/- 2 yr) and gender-matched controls from the general background population. Compared with controls, patients did not have an increased risk of cataract (p = 0.52), spinal stenosis (p = 0.59), or any fracture (p = 0.98). However, the risk of fractures at the upper extremities was significantly decreased in patients (HR 0.69, 95% CI 0.49-0.97). Compared with controls, patients had a significantly increased risk of hospitalization due to infections (HR 1.42, 95% CI 1.20-1.67) and depression/bipolar affective disorders (HR 1.99, 95% CI 1.14-3.46). The risk of malignant diseases did not differ between groups although the risk of gastrointestinal cancers was significantly lower in patients compared with controls (HR 0.63, 95% CI 0.44-0.93). In conclusion, HypoPT is associated with an increased risk of depression and other types of neuropsychiatric diseases as well as infections, whereas patients seem to be protected against fractures at the upper extremities and gastrointestinal malignancies. PMID- 24806579 TI - An isoflavone from Dipteryx alata Vogel is active against the in vitro neuromuscular paralysis of Bothrops jararacussu snake venom and bothropstoxin I, and prevents venom-induced myonecrosis. AB - Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of these venoms. In this work, we examined the ability of 7,8,3'-trihydroxy-4'-methoxyisoflavone (TM), an isoflavone from Dipteryx alata, to neutralize the neurotoxicity (in mouse phrenic nerve-diaphragm preparations) and myotoxicity (assessed by light microscopy) of Bothrops jararacussu snake venom in vitro. The toxicity of TM was assessed using the Salmonella microsome assay (Ames test). Incubation with TM alone (200 MUg/mL) did not alter the muscle twitch tension whereas incubation with venom (40 MUg/mL) caused irreversible paralysis. Preincubation of TM (200 MUg/mL) with venom attenuated the venom-induced neuromuscular blockade by 84% +/- 5% (mean +/- SEM; n = 4). The neuromuscular blockade caused by bothropstoxin-I (BthTX-I), the major myotoxic PLA2 of this venom, was also attenuated by TM. Histological analysis of diaphragm muscle incubated with TM showed that most fibers were preserved (only 9.2% +/- 1.7% were damaged; n = 4) compared to venom alone (50.3% +/- 5.4% of fibers damaged; n = 3), and preincubation of TM with venom significantly attenuated the venom-induced damage (only 17% +/- 3.4% of fibers damaged; n = 3; p < 0.05 compared to venom alone). TM showed no mutagenicity in the Ames test using Salmonella strains TA98 and TA97a with (+S9) and without (-S9) metabolic activation. These findings indicate that TM is a potentially useful compound for antagonizing the neuromuscular effects (neurotoxicity and myotoxicity) of B. jararacussu venom. PMID- 24806580 TI - Anti-Candida, anti-enzyme activity and cytotoxicity of 3,5-diaryl-4,5-dihydro-1H pyrazole-1-carboximidamides. AB - Because of the need for more effective and less harmful antifungal therapies, and interest in the synthesis of new carboximidamides, the goal of this study was to determine the antifungal and anti-enzyme activities of some new pyrazole carboximidamides and their cytotoxicity. For this purpose, tests were performed to evaluate: minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC); production of proteinases and phospholipase, and cytotoxicity of the extracts. Data were analyzed by ANOVA and Tukey Tests (alpha = 5%). The results were: MIC and MFC >= 62.5 MUg/mL (C. albicans, C. parapsilosis, C. famata, C. glabrata, and Rhodotorula mucillaginosa) and MIC and MFC >= 15.6 MUg/mL (C. lipolytica). The values of proteinase and phospholipase (Pz) of C. albicans before and after exposure to the compounds were: 0.6 (+/ 0.024) and 0.2 (+/-0.022) and 0.9 (+/-0.074) and 0.3 (+/-0.04), respectively. These proteinase results were not significant (p = 0.69), but those of phospholipase were (p = 0.01), and 15.6 MUg/mL was the most effective concentration. The cytotoxicity means were similar among the tests (p = 0.32). These compounds could be useful as templates for further development through modification or derivatization to design more potent antifungal agents. Data from this study provide evidence that these new pyrazole formulations could be an alternative source for the treatment of fungal infections caused by Candida. However, a specific study on the safety and efficacy of these in vivo and clinical trials is still needed, in order to evaluate the practical relevance of the in vitro results. PMID- 24806581 TI - Significance and therapeutic value of miRNAs in embryonal neural tumors. AB - Embryonal tumors of the nervous system are the leading cause of childhood cancer related morbidity and mortality. Medulloblastoma, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumor and neuroblastoma account for more than 20% of childhood malignancies and typify the current neural embryonal tumor model in pediatric oncology. Mechanisms driving the formation of these tumors point towards impaired differentiation of neuronal and neuron associated cells during the development of the nervous system as an important factor. The importance of microRNAs (miRNAs) for proper embryonic cell function has been confirmed and their aberrant expressions have been linked to tumor development. The role of miRNAs in controlling essential regulators of key pathways implicated in tumor development makes their use in diagnostics a powerful tool to be used for early detection of cancer, risk assessment and prognosis, as well as for the design of innovative therapeutic strategies. In this review we focus on the significance of miRNAs involved in the biology of embryonal neural tumors, delineate their clinical significance and discuss their potential as a novel therapeutic target. PMID- 24806582 TI - Norditerpenoids from Flickingeria fimbriata and their inhibitory activities on nitric oxide and tumor necrosis factor-alpha production in mouse macrophages. AB - Bioassay-guided fractionation of the ethanolic extract of the leaves of Flickingeria flimbriata led to the isolation of two new degraded diterpenoids 1 and 2, a new ent-pimarane type diterpenoid 3, and four known steroids 4-7. The structures of 1-3 were elucidated by spectroscopic analysis, and their absolute configurations were determined by chemical methods, TDDFT quantum chemical calculations of ECD spectra, and CD exiton chirality method. Compounds 1 and 2, named flickinflimilins A and B, possess a rare 15,16-dinor-ent-pimarane skeleton. Compounds 1-7 were screened for the inhibitory activity against lipopolysaccharide (LPS)-induced NO and TNF-alpha production in RAW264.7 cells. Compounds 1-3 exhibited potent inhibitory activities, with IC50 values of less than 10 uM. PMID- 24806583 TI - Cobalt-catalyzed methoxycarbonylation of substituted dichlorobenzenes as an example of a facile radical anion nucleophilic substitution in chloroarenes. AB - A thorough mechanistic study on cobalt-catalysed direct methoxycarbonylation reactions of chlorobenzenes in the presence of methyl oxirane on a wide range of substrates, including poly- and monochloro derivatives with multiple substituents, is reported. The results demonstrate that the reaction is potentially useful as it proceeds under very mild conditions (t = 62 degrees C, PCO = 1 bar) and converts aryl chlorides to far more valuable products (especially ortho-substituted benzoic acids and esters) in high yields. This transformation also offers another opportunity for the utilization of environmentally harmful polychlorinated benzenes and biphenyls (PCBs). This study is the first to discover an unexpected universal positive ortho-effect: the proximity of any substituent (including Me, Ph, and MeO groups and halogen atoms) to the reaction centre accelerates the methoxycarbonylation in chlorobenzenes. The effect of the ortho-substituents is discussed in detail and explained in terms of a radical anion reaction mechanism. The advantages of the methoxycarbonylation as a model for the mechanistic study of radical anion reactions are also illustrated. PMID- 24806590 TI - Topological field-effect quantum transistors in HgTe nanoribbons. AB - We propose practical designs to realize topological field-effect quantum transistors in an HgTe nanoribbon with an inverted band structure. Our theoretical calculations show that, as a strip-shape top gate is placed on the HgTe nanoribbon and with an increasing gate voltage, two new conductance channels develop in the HgTe nanoribbon and are localized to the lattice sites neighboring the boundaries of the gate, leading to an additional quantization of the conductance of 2e(2)/h. The quantum states in the new channels are not only robust against a short-range Anderson disorder, but can also couple with the intrinsic helical edge states in the boundaries of the HgTe nanoribbon to open a gap in the energy spectrum, indicating their topological characteristics. More importantly, the newly developed conductance channels can be turned on or off easily by adjusting the gate voltage. The proposal of controllable topological edge states produced by the gate voltage opens a new route for future topological field-effect quantum transistors in nanoelectronics and spintronics. PMID- 24806591 TI - Determination of chloramphenicol and zeranols in pig muscle by immunoaffinity column clean-up and LC-MS/MS analysis. AB - An immunoaffinity column clean-up and LC-MS/MS method was successfully developed for simultaneous determination of chloramphenicol, zearalanone, alpha-zearalanol, beta-zearalanol, zearalenone, alpha-zearalenol and beta-zearalenol in pig muscle. The sample was extracted with diethyl ether after enzymatic digestion by beta glucuronidase/sulfatase. The extracted solution was evaporated to dryness and the residue was then dissolved in 1 ml of 50% acetonitrile solution. After filtration and dilution with phosphate buffer solution (PBS), the reconstituted solution was cleaned-up with an IAC-CZ immunoaffinity column and then analysed by HPLC-MS/MS. The established method were validated by linearity (r >= 0.9990), precision (RSD >= 2.9%), average recovery (74.5-105.0%) and limit of detection (0.04-0.10 MUg kg(-1)). The developed method is rapid, reliable, sensitive, accurate and has good applicability for real samples. PMID- 24806592 TI - Genital psoriasis awareness program: physical and psychological care for patients with genital psoriasis. AB - Genital psoriasis is a neglected manifestation of psoriasis, although it affects numerous patients and has major effects on sexual quality of life (SQoL). We aimed to assess the value of specialised care for patients with genital psoriasis. Patients were treated for at least one year at a specialised research outpatient clinic with extensive attention for genital lesions and SQoL. The genital lesions were treated according to a stepwise algorithm. First follow-up was planned after 6 weeks; subsequent follow-up visits were scheduled every 3 months. At every visit, psoriasis severity and SQoL were measured with validated tools. Differences in scores between visits were analysed by a mixed model for repeated measures. Forty-two patients were included (M:F = 25:17). All objective and subjective genital psoriasis severity and QoL parameters improved significantly within the first follow-up period of approximately 6 weeks. In female patients, SQoL also significantly improved. In conclusion, genital psoriasis can relatively easy be treated within limited time exposure, resulting in significant improvement of QoL. Prompt and simple adjustments in the provided care are enough to accomplish this. PMID- 24806593 TI - Nanopore biosensor for label-free and real-time detection of anthrax lethal factor. AB - We report a label-free real-time nanopore sensing method for the detection of anthrax lethal factor, a component of the anthrax toxin, by using a complementary single-stranded DNA as a molecular probe. The method is rapid and sensitive: sub nanomolar concentrations of the target anthrax lethal factor DNA could be detected in ~1 min. Further, our method is selective, which can differentiate the target DNA from other single-stranded DNA molecules at the single-base resolution. This sequence-specific detection approach should find useful application in the development of nanopore sensors for the detection of other pathogens. PMID- 24806594 TI - [FIMA--questionnaire for health-related resource use in an elderly population: development and pilot study]. AB - AIM: Due to demographic trends towards an ageing population resource use of health care will increase. By collecting health-related costs via questionnaires, the impact of socio-economic variables and other medical factors can be examined. In addition, only patient reported resource use accounts for out-of-pocket payments. Thus, it is necessary to develop an appropriate tool to collect the health-related resource use in an elderly population. METHODS: The development of the FIMA (questionnaire for the use of medical and non-medical services in old age) was carried out in 6 steps. These included the determination of necessary questionnaire contents based on a literature review and the wording and layout were defined. Finally the questionnaire was tested in a pilot study and was modified. RESULTS: All direct medical and non-medical resource use excluding transportation and time costs were recorded. Productivity losses were not included. The recall time frames differed according to resource categories (7 days, 3 months, 12 months). For the pilot study, 63 questionnaires were analysed. The response rate was 69%. The questionnaire took an average of 21 min to complete. Three quarters of respondents completed the questionnaire without help and 90% rated the difficulty as easy or even very simple. There was good agreement between self-reported health-related quality of life and the resource use of nursing and domestic help (phi coefficient values between 0.52 and 0.58). CONCLUSION: The FIMA is a generic questionnaire which collects the health-related resource use within the older population groups. PMID- 24806596 TI - Rapid identification of glycerophospholipids from RAW264.7 cells by UPLC/ESI QTOF-MS. AB - The study aims to develop a rapid, sensitive ultra-performance liquid chromatography coupled with an electrospray ionization quadruple time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS) analytical method for identifying glycerophospholipids (GPLs) from RAW264.7 cells. A total of 78 GPLs including 22 phosphatidylethanolamines (PEs), 49 phosphatidylcholines (PCs), four phosphatidylglycerols, one phosphatidylinositol and two unknown GPLs were identified. PC (14:0/16:1), PC (14:0/16:0), PE (0:0/20:3), PE (22:5/0:0) and PE (22:3/0:0) were identified for the first time. The UPLC/Q-TOF-MS method is suitable for targeting analysis of GPLs from RAW264.7 cells, which allows us to find out new GPLs compositions related to inflammatory diseases and to explain their pharmacological roles in inflammatory process. PMID- 24806597 TI - Generation of liver-specific TGF-alpha and c-Myc-overexpressing fibroblasts for future creation of a liver cancer porcine model. AB - Liver cancer is one of the most serious life-threatening diseases in the world. Although the rodent model of hepatocellar carcinoma (HCC) is commonly used, it is limited when considering preclinical applications, including transarterial chemoembolization. The pig is a more appropriate model for applying preclinical procedures as it has similar anatomical and physiological characteristics to humans. In the current study, transgenic fibroblasts were generated that overexpressed two proto-oncogenes specifically in hepatocytes. Porcine TGF-alpha and c-myc genes were isolated and these were linked with the porcine albumin promoter, which has exhibited selective activity in liver cells. Targeting vectors were introduced into the porcine fibroblasts using a liposome-mediated delivery system and the transgenic cell line was screened with 3 weeks of G-418 treatment. Selected vector-positive colonies were further confirmed with polymerase chain reaction-based genotyping. Thus, the transgenic cell lines created in the current study should induce liver cancer in pig models following somatic cell nuclear transfer. PMID- 24806598 TI - Kinetic Studies on the Synthesis of Monoclinic Li3V2(PO4)3 via Solid-State Reaction. AB - The data obtained by thermogravimetry (TG), differential thermal analysis (DTA), and X-ray diffraction (XRD) measurements of the stoichiometric mixture of LiNO3, NH4VO3, and NH4H2PO4 were analyzed by both the Flynn-Wall-Ozawa (FWO) and Friedman-Reich-Levi (FRL) methods. The whole solid state reaction process could be divided into four stages corresponding to alpha values of 0.03-0.20, 0.30 0.60, 0.70-0.80, and 0.90-0.99. The nucleation of LiVP2O7 (alpha = 0.70-0.80) is a determining step of the four-reaction processes, for which the mechanism of random nucleation and subsequent growth, described by the Avrami-Erofeev equation (n = 4) G(alpha) = [-ln(1 - alpha)]4, was assumed. Moreover, the Gibbs free energy of activation DeltaG*, enthalpy of activation DeltaH*, and entropy of activation DeltaS* at maximum temperature of the peak for the determining step were 99.24 kJ.mol-1, 199.97 kJ.mol-1, and 136.30 J.mol-1.K-1, respectively. Finally, XRD analyses confirmed that the Li3V2(PO4)3 synthesized by the precursor route is a pure phase. PMID- 24806599 TI - An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. AB - A variety of reactive organic compounds, called haptens, can cause allergic contact dermatitis. However, the innate immune mechanisms by which haptens stimulate dendritic cells (DCs) to sensitize T cells remain unclear. Here we show that the coupling of ITAM-Syk-CARD9 signalling to interleukin-1 (IL-1) secretion in DCs is crucial for allergic sensitization to haptens. Both MyD88 and Caspase recruitment domain-containing protein 9 (CARD9) signalling are required for contact hypersensitivity (CHS). Naive T cells require signals received through IL 1R1-MyD88 for effector differentiation, whereas DCs require CARD9 and spleen tyrosine kinase (Syk) signalling for hapten-induced IL-1alpha/beta secretion and their ability to prime T cells. DC-specific deletion of CARD9, DAP12, Syk or NLRP3, but not MyD88, is sufficient to abolish CHS. All tested haptens, but not irritants, can induce Syk activation, leading to both the CARD9/BCL10-dependent pro-IL-1 synthesis (signal1) and reactive oxygen species-mediated NLRP3 inflammasome activation (signal2), required for IL-1 secretion. These data unveil an innate immune mechanism crucial for allergic contact sensitization to chemical compounds. PMID- 24806601 TI - Prevalence and profile of ophthalmic disorders in oculocutaneous albinism: a field report from South-Eastern Nigeria. AB - To assess the burden and spectrum of refractive and non-refractive ophthalmic disorders in south-eastern Nigerians with oculocutaneous albinism. In a population-based survey in Enugu state, between August, 2011 and January, 2012, albinos were identified using the database of the Enugu state's Albino Foundation, and mass media-based mobilisation. The participants were enrolled at the Eye Clinics of the University of Nigeria Teaching Hospital and Enugu State University of Science and Technology Teaching Hospital using a defined protocol. Relevant socio-demographic and clinical data were obtained from each participant. Descriptive and comparative statistics were performed. Statistical significance was indicated by p < 0.05. The participants (n = 153; males, 70) were aged 23.5 + 10.4 SD years (range 6-60 years). Both refractive and non-refractive disorders were present in all participants. Non-refractive disorders comprised nystagmus, foveal hypoplasia, hypopigmented fundi and prominent choroidal vessels in 100.0% participants; and strabismus in 16.3% participants. Refractive disorders comprised astigmatism -73.2% eyes, myopia -23.9% and hypermetropia 2.9%. Spherical refractive errors ranged from -14.00 DS to +8.00 DS while astigmatic errors ranged from -6.00 DC to +6 DC. Mixed refractive and non-refractive disorder i.e. presenting visual impairment was present in 100.0% participants. Overall, refractive error was associated with non-possession of tertiary education (OR 0.61; 95% CI 0.38-0.96; p = 0.0374). There is high prevalence of refractive, non-refractive and mixed ophthalmic disorders among albinos in south eastern Nigeria. This underscores the need for tailored provision of resources to address their eye care needs, and creation of needs awareness amongst them. PMID- 24806602 TI - Prediction of survival and cancer recurrence using metabolic volumetric parameters measured by 18F-FDG PET/CT in patients with surgically resected rectal cancer. AB - OBJECTIVE: The goal of the present study was to determine whether the volumetric parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured by F-FDG PET/CT could be used as prognostic factors for the recurrence free survival (RFS) and overall survival (OS) in patients with surgically resected rectal cancer. PATIENTS AND METHODS: A retrospective review identified 73 patients with surgically resected rectal cancer who received F-FDG PET/CT. Survival analysis was conducted using Kaplan-Meier analysis, and survival curves stratified by age, sex, lymph node status, surgical resection margin, American Joint Committee on Cancer (AJCC) stage, and volumetric parameters of F-FDG PET/CT were generated for the estimation of OS and RFS. Independent predictive factors for survival were determined using Cox proportional hazards model. RESULTS: High MTV, high TLG, advanced AJCC stage, lymph node (+), and surgical margin (+) group showed shorter OS in rectal cancer patients. Cox proportional hazards regression analysis showed that only surgical margin (+) was associated with poor OS. The early AJCC stage, lower MTV, and lower TLG were associated with better RFS in the current study. Cox proportional hazards regression analysis reveals that the surgical margin (+) was the potent predictor of OS. However, none of the factors was associated with RFS. CONCLUSIONS: In conclusion, the results of this study suggest that volumetric parameters of F-FDG PET/CT could be significant prognostic factors in surgically resected rectal cancer. PMID- 24806603 TI - State of the art epilepsy imaging: an update. AB - Drug-resistant epilepsy is a chronic debilitating disorder, but many cases are potentially curable by surgery. The key to the successful epilepsy surgery with complete postoperative seizure-free status is precise localization of the epileptic zone that must be resected and the adjacent eloquent areas of gray and white matter that must be preserved to avoid neurological defects. This article reviews the current state of the art epilepsy imaging techniques facilitating successful epilepsy surgery. The overview of the imaging appearances of the most common epileptogenic etiologies that are amenable to surgical resection is also included in this review. PMID- 24806605 TI - When and why to use FDG PET/CT in locally advanced rectal cancer: two scenarios. PMID- 24806606 TI - A case of immunogammaglobulin 4-related disease. AB - An 81-year-old woman with history of thyroiditis and a putative diagnosis of retroperitoneal fibrosis presented with abdominal pain, progressive shoulder pain, back pain, and lower extremity weakness. Abdominal and pelvic MRI revealed periaortic inflammation and a left renal mass, which were F-FDG avid on PET/CT. Renal biopsy was compatible with immunogammaglobulin 4 (IgG4)-related disease. Total spine MRI revealed postcontrast meningeal enhancement, correlating with FDG activity. Epidural biopsy showed chronic inflammation and scattered but not abnormal IgG4-positive cells, possibly related to posttreatment changes. This case exemplifies multiorgan involvement in IgG4-related disease. PMID- 24806607 TI - 18F-FDG PET imaging in a patient with late omental infarction after treatment of pancreatic adenocarcinoma. AB - We report a case of late omental infarction visualized by F-FDG PET/CT during follow-up for pancreatic adenocarcinoma. The 65-year-old patient was referred for imaging 8 months after pancreaticoduodenectomy and 2 months after completion of a course of chemotherapy. PET/CT showed an FDG-avid omental lesion that suggested peritoneal carcinomatosis. The appearance and evolution at follow-up studies confirmed the diagnosis of omental infarction, a rare complication of pancreatic surgery. This case revealed the possibility of late FDG uptake in omental infarction. PMID- 24806608 TI - Widespread gouty tophi on 18F-FDG PET/CT imaging. AB - A 72-year-old man was admitted to our hospital because of worsening polyarticular swelling pain. An F-FDG PET/CT was performed to evaluate the extent of a suspected gouty attack and to exclude any unexpected malignancy. The images showed multiple juxta-articular and subcutaneous foci of elevated F-FDG activity in both upper and lower extremities, including the hands, elbows, shoulders, hips, knees, ankles, and feet. Diagnosis of an acute, severe gouty attack was eventually made. The patient responded well to antigouty therapy. PMID- 24806609 TI - Heteroglucan-dendrimer glycoconjugate: a modulated construct with augmented immune responses and signaling phenomena. AB - BACKGROUND: Newer strategies for augmenting immune responses of pharmacologically active glucans may serve to improve the medicinal potential of these biomolecules. With this aim, the present work was focused on generating targeted high molecular size glucan particles with magnified immune response activity. METHODS: Heteroglucans were conjugated with PAMAM dendrimers using a Schiff base reductive amination reaction to generate a polytethered molecule with multiple glucan motifs. The modulated construct was characterized by FTIR, TEM, (1)H NMR and dynamic light scattering (DLS) methods. Effects of conjugated glucans were examined in RAW 264.7 macrophage cells as well as in S-180 murine tumor models. RESULTS: Dendrimer-conjugated glucans were found to exhibit a two-fold increase in immune stimulation in comparison to unconjugated glucans. This may be corroborated by the predominant enhancement in immunological functions such as nitric oxide production, ROS generation and immune directed tumor inhibition in murine models. Immune cell surface markers (CD4, CD8, CD19, MHC-II) and cytokine levels were also found to be highly up-regulated in the splenocytes of mice subjected to particulate glucan administration. Our study also demonstrated that conjugated glucan treatment to RAW 264.7 cells strongly enhanced the phosphorylation of two downstream signalling molecules of the mitogen activated protein kinase (MAPKs) family: p38 and MEK1/2 relative to single glucans thereby relating molecular mechanisms with enhanced immune stimulation. CONCLUSIONS AND GENERAL SIGNIFICANCE: The results obtained thus support that particulate format of soluble heteroglucan will thereby improve its functionality and identify leads in therapeutic competence. PMID- 24806610 TI - Lead-induced morphological changes and amyloid precursor protein accumulation in adult rat hippocampus. AB - Lead is an important environmental pollutant that exerts potent toxic effects on many organs. The toxic effects of lead are less well known for adult brain than for children. We investigated the morphological changes and amyloid precursor protein (APP) accumulation in the adult rat hippocampus following exposure to lead. Forty rats were divided into two groups of 20. One group was exposed to 580 parts per million (ppm) lead acetate and other group to an identical concentration of sodium acetate as a control group. After exposure to lead for 3 months, the hippocampus was examined by electron microscopy and APP levels in the hippocampus were detected using immunohistochemistry. Lead levels in the blood of rats exposed to lead were significantly higher than in the controls. The morphological changes in the hippocampus included mitochondrial degeneration, apoptosis and abnormal synapses in the rats exposed to lead. APP in hippocampus was increased significantly in the group exposed to lead compared to controls. We determined that lead exposure causes accumulation of APP and morphological changes in the adult rat hippocampus. PMID- 24806611 TI - Changing your mind before it is too late: the electrophysiological correlates of online error correction during response selection. AB - Inhibiting actions when they are no longer appropriate is essential for adaptive goal-directed behavior. In this study, we used high-density EEG and a standard flanker task to explore the spatiotemporal dynamics of cognitive control and inhibitory mechanisms aimed to prevent the commission of errors. By recording hand-related electromyographic activity, we could disentangle successful from unsuccessful inhibition attempts. Our results confirm that (a) the latency of the error-related negativity (ERN; or Ne) component is too late to be associated with these online inhibitory mechanisms, and (b) instead, a frontal slow negative component with an earlier time course was associated with the implementation of online inhibition. These findings are consistent with single-cell recordings in monkeys showing that the supplementary motor area provides cognitive control signals to the primary motor cortex to exert online inhibition and in turn rectify the course of erroneous actions. PMID- 24806612 TI - Correlated loss of ecosystem services in coupled mutualistic networks. AB - Networks of species interactions promote biodiversity and provide important ecosystem services. These networks have traditionally been studied in isolation, but species are commonly involved in multiple, diverse types of interaction. Therefore, whether different types of species interaction networks coupled through shared species show idiosyncratic or correlated responses to habitat degradation is unresolved. Here we study the collective response of coupled mutualistic networks of plants and their pollinators and seed dispersers to the degradation of Europe's last relict of old-growth lowland forest (Bialowieza, Poland). We show that logging of old-growth forests has correlated effects on the number of partners and interactions of plants in both mutualisms, and that these effects are mediated by shifts in plant densities on logged sites. These results suggest bottom-up-controlled effects of habitat degradation on plant-animal mutualistic networks, and predict that the conversion of primary old-growth forests to secondary habitats may cause a parallel loss of multiple animal mediated ecosystem services. PMID- 24806613 TI - National Institute of Mental Health clinical trials: new opportunities, new expectations. PMID- 24806616 TI - Regulation of peroxisome proliferator-activated receptor beta/delta expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes. AB - Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a potential regulator of neuroinflammation. Toll-like receptors (TLR) are innate immunity-related receptors of inflammatory stimuli. In the present report, we evaluate the molecular mechanisms of regulation of mRNA, protein, and transcriptional activity levels of PPARbeta/delta by agonists of TLR4, TLR1/2, and TLR5, using lipopolysaccharide (LPS), peptidoglycan, and flagellin, respectively. We found that these stimuli increase the PPARbeta/delta levels in astrocytes. Expression and activity of PPARbeta/delta are separately regulated by inhibitors of p38, MEK1/2, extracellular signal-regulated kinases 1/2, and c-Jun N-terminal Kinase mitogen-activated protein kinases. The LPS-induced kinetics of PPARbeta/delta expression is similar to that of the proinflammatory gene cyclooxygenase 2. Moreover, for both genes the expression depends on nuclear factor kappa-light-chain-enhancer of activated B cells and p38, and is induced after inhibition of protein synthesis. The up-regulation of the expression after inhibition of protein synthesis signifies the participation of a labile protein in regulation of PPARbeta/delta expression. In contrast to cyclooxygenase 2, the cycloheximide-sensitive PPARbeta/delta expression was not responsive to nuclear factor kappa-light-chain-enhancer of activated B cells inhibition. Measurements of PPARbeta/delta mRNA stability showed that the PPARbeta/delta mRNA levels are regulated post-transcriptionally. We found that in LPS-stimulated astrocytes, the half-life of PPARbeta/delta mRNA was 50 min. Thus, we demonstrate that PPARbeta/delta expression and activity are regulated in TLR agonist-stimulated astrocytes by mechanisms that are widely used for regulation of proinflammatory genes. Protein expression level of nuclear receptor PPARbeta/delta is important for functions of this transcription factor. We investigate the regulatory mechanisms of PPARbeta/delta in rat primary astrocytes stimulated by agonists of toll-like receptors (TLR): TLR4, TLR1/2, and TLR5. Expression, activity, mRNA stability, and superinduction of PPARbeta/delta were up-regulated after TLR stimulation. These processes are sensitive to MAPKs and NF-kB inhibitors. Superinduction is up-regulation of mRNA expression after inhibition of protein synthesis. PMID- 24806614 TI - DNA dendrimer: an efficient nanocarrier of functional nucleic acids for intracellular molecular sensing. AB - Functional nucleic acid (FNA)-based sensing systems have been developed for efficient detection of a wide range of biorelated analytes by employing DNAzymes or aptamers as recognition units. However, their intracellular delivery has always been a concern, mainly in delivery efficiency, kinetics, and the amount of delivered FNAs. Here we report a DNA dendrimer scaffold as an efficient nanocarrier to deliver FNAs and to conduct in situ monitoring of biological molecules in living cells. A histidine-dependent DNAzyme and an anti-ATP aptamer were chosen separately as the model FNAs to make the FNA dendrimer. The FNA embedded DNA dendrimers maintained the catalytic activity of the DNAzyme or the aptamer recognition function toward ATP in the cellular environment, with no change in sensitivity or specificity. Moreover, these DNA dendrimeric nanocarriers show excellent biocompatibility, high intracellular delivery efficiency, and sufficient stability in a cellular environment. This FNA dendrimeric nanocarrier may find a broad spectrum of applications in biomedical diagnosis and therapy. PMID- 24806617 TI - p38 MAPK inhibits breast cancer metastasis through regulation of stromal expansion. AB - p38 MAPK signaling controls cell growth, proliferation and the cell cycle under stress conditions. However, the function of p38 activation in tumor metastasis is still not well understood. We report that p38 activation in breast cancer cells inhibits tumor metastasis but does not substantially modulate primary tumor growth. Stable p38 knockdown in breast cancer cells suppressed NF-kappaB p65 activation, inhibiting miR-365 expression and resulting in increased IL-6 secretion. The inhibitory effect of p38 signaling on metastasis was mediated by suppression of mesenchymal stem cell (MSC) migration to the primary tumor and sites of metastasis, where MSCs can differentiate into cancer-associated fibroblasts to promote tumor metastasis. The migration of MSCs to these sites relies on CXCR4-SDF1 signaling in the tumor microenvironment. Analysis of human primary and metastatic breast cancer tumors showed that p38 activation was inversely associated with IL-6 and vimentin expression. This study suggests that combination analysis of p38 MAPK and IL-6 signaling in patients with breast cancer may improve prognosis and treatment of metastatic breast cancer. PMID- 24806618 TI - Deletion of the cyclic di-AMP phosphodiesterase gene (cnpB) in Mycobacterium tuberculosis leads to reduced virulence in a mouse model of infection. AB - Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. The pathogenesis by the causative agent, Mycobacterium tuberculosis, is still not fully understood. We have previously reported that M. tuberculosis Rv3586 (disA) encodes a diadenylate cyclase, which converts ATP to cyclic di-AMP (c-di-AMP). In this study, we demonstrated that a protein encoded by Rv2837c (cnpB) possesses c di-AMP phosphodiesterase activity and cleaves c-di-AMP exclusively to AMP. Our results showed that in M. tuberculosis, deletion of disA abolished bacterial c-di AMP production, whereas deletion of cnpB significantly enhanced the bacterial c di-AMP accumulation and secretion. The c-di-AMP levels in both mutants could be corrected by expressing the respective gene. We also found that macrophages infected with DeltacnpB secreted much higher levels of IFN-beta than those infected with the wild type (WT) or the complemented mutant. Interestingly, mice infected with M. tuberculosis DeltacnpB displayed significantly reduced inflammation, less bacterial burden in the lungs and spleens, and extended survival compared with those infected with the WT or the complemented mutant. These results indicate that deletion of cnpB results in attenuated virulence, which is correlated with elevated c-di-AMP levels. PMID- 24806619 TI - The endosymbionts Wolbachia and Cardinium and their effects in three populations of the predatory mite Neoseiulus paspalivorus. AB - Whereas endosymbiont-induced incompatibility is known to occur in various arthropod taxa, such as spider mites, insects and isopods, it has been rarely reported in plant-inhabiting predatory mites (Acari: Phytoseiidae). Recent cross breeding studies with the phytoseiid mite Neoseiulus paspalivorus De Leon revealed a complete post-mating reproductive isolation between specimens collected from three geographic origins-Northeast Brazil (South America), Benin and Ghana (West Africa)-even though they are morphologically similar. We carried out a study to assess to what extent these populations exhibit genetic differences and whether endosymbionts are involved in the incompatibility. First, we used the mitochondrial cytochrome oxidase I (COI) gene to assess genetic diversity among the three populations. Second, we used a PCR-based method to check for the presence of Wolbachia and/or Cardinium in these populations, and we determined their phylogenetic relationships using specific primers for Wolbachia and Cardinium 16S rDNA genes. Third, we also conducted a test using an antibiotic (tetracycline) in an attempt to eliminate the symbionts and evaluate their effects on the reproductive compatibility of their host. Based on the DNA sequences of their COI genes, specimens of the three populations appear to be genetically similar. However, the 16S rDNA gene sequences of their associated endosymbionts differed among the three populations: the Benin and Brazil populations harbour different strains of Wolbachia symbionts, whereas the Ghana population harbours Cardinium symbionts. In response to antibiotic treatment females of each of the three populations became incompatible with untreated males of their own population, similar to that observed in crossings between females from one geographic population and males from another. Compatibility was restored in crosses involving uninfected Brazil females and uninfected Benin males, whereas the reciprocal crosses remained incompatible. Cardinium symbionts seem to be essential for oviposition in the Ghana population. It is concluded that their associated bacterial symbionts are the cause of the post-mating reproductive isolation previously observed among the three geographic populations. This insight is relevant to biological control of coconut mites for which N. paspalivorus is an effective predator, because introducing one geographic strain into the population of another (e.g. in field releases or mass cultures) may cause population growth depression. PMID- 24806620 TI - Functional outcomes of posterior vaginal wall repair and prespinous colpopexy with biological small intestinal submucosal (SIS) graft. AB - PURPOSE: Surgical management of posterior vaginal wall prolapse has variable functional outcomes. Synthetic and biological grafts are used to improve outcomes and reduce failures. The objective of this study was to determine the functional outcomes and its implications on patient-reported quality of life of a technique of posterior vaginal wall repair and prespinous colpopexy with biological small intestinal submucosal (SIS) graft in the management of posterior vaginal wall prolapse. METHODS: This prospective cohort study was conducted in a urogynaecology subspecialty center in the UK. Women with moderate degree rectocele or more, with or without other compartmental prolapse underwent posterior vaginal wall repair and prespinous colpopexy with SIS graft over a 3 year period. ICIQ vaginal symptoms questionnaires were used pre-operatively and at 6 months post-operatively to assess functional outcomes. The Wilcoxon signed R test was used to analyze the results. RESULTS: 50 women underwent posterior repair with SIS graft (27 with concomitant procedures). There was a statistically significant improvement (p < 0.0001) in the vaginal symptoms and sexual matters scores at 6-month follow-up in all the women. The quality of life scores also improved significantly (p < 0.0001) in all the women. Concomitant pelvic surgery did not affect the outcomes (p < 0.0001). There were no significant intra- or post-operative complications. CONCLUSION: Posterior vaginal wall repair and prespinous colpopexy with biological SIS graft is an effective surgical option for managing women with posterior vaginal wall prolapse with or without other concomitant compartmental defects. PMID- 24806621 TI - MiR-1246 promotes SiHa cervical cancer cell proliferation, invasion, and migration through suppression of its target gene thrombospondin 2. AB - PURPOSE: To investigate the effects of miR-1246 on proliferation, invasion, and migration in the human (CSCC) cell line SiHa. METHODS: SiHa cells were assigned into three groups: miR-1246 analog; miR-1246 antagonist; and control. The MTT, transwell, and wound healing assays were performed to evaluate the proliferation, invasion, and migration abilities of SiHa cells, respectively. Western blot was carried out to detect protein expression of thrombospondin-2 (THBS2) before and after transfection with miR-1246 analog, antagonist, or control. In addition, a THBS2 3'-UTR-containing dual luciferase plasmid was generated and co-transfected with miR-1246, the inhibitor, or non-specific miRNA, into SiHa cells to observe its effects on THBS2-driven luciferase enzyme activity. RESULTS: MTT, transwell, and wound healing assays revealed that proliferation, migration, and invasion were all significantly enhanced (P < 0.01) in SiHa cells transfected with miR 1246 analog, but were suppressed in those transfected with the miR-1246 antagonist. Western blot data showed that miR-1246 analog-transfected SiHa cells had significantly decreased THBS2 expression when compared with control transfected cells (gray value = 6.28 +/- 10.22 vs. 9.58 +/- 17.58; P = 0.013) while those transfected with the miR-1246 antagonist had significantly increased THBS2 expression (gray value = 12.90 +/- 19.81; P = 0.037). Moreover, SiHa cells co-transfected with miR-1246 and the THBS2 3'-UTR-containing plasmid exhibited decreased luciferase enzyme activity compared with the control. CONCLUSION: MiR 1246 induced CSCC SiHa cell proliferation, invasion and migration. Preliminary evidence suggests that miR-1246 might promote CSCC tumorigenesis and progression by the suppression of its target gene THBS2. PMID- 24806622 TI - The effect of hesperetin on ischemia-reperfusion injury in rat ovary. AB - PURPOSE: Hesperidin (HES), a citrus fruit extract, has beneficial effects on various ischemia/reperfusion (I/R) models. We aimed to evaluate the possible positive effects of hesperetin (HPT), an active metabolite of HES, on a rat ovarian I/R model. METHODS: We divided 24 Wistar Albino rats into four groups. Group I (n = 6) was sham operated, Group II (n = 6) was the I/R group, Group III (n = 6) was the I/R + solvent group and Group IV (n = 6) was the I/R + HPT group. Three hours of ischemia and 3 h of reperfusion were performed on each rat in Groups II, III, and IV. Dimethyl sulfoxide (DMSO) was given intraperitoneally to the rats in the III. Group, and 50 mg/kg of HPT dissolved in DMSO was given intraperitoneally to the rats in the IV. Group 30 min before reperfusion. After 3 h of reperfusion, the ipsilateral ovaries of the rats were examined immunohistochemically to detect apoptosis. RESULTS: Hematoxylin and eosin (H and E) staining demonstrated less edema and hemorrhage in the group where HPT was applied. Caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining showed significantly lower apoptosis in the group where HPT was used when compared to either the I/R or solvent group. CONCLUSIONS: To the best of our knowledge, this is the first study that shows the beneficial effects of HPT in an ovarian I/R injury. HPT improved tissue damage and apoptosis caused by I/R injury. To identify the possible positive effects of HPT in ovarian torsion of humans and use in clinical practice, more studies must be performed. PMID- 24806623 TI - Randomized clinical trial: nasoenteric tube or jejunostomy as a route for nutrition after major upper gastrointestinal operations. AB - BACKGROUND: Curative treatment of upper gastrointestinal tract neoplasms is complex and associated with high morbidity and mortality. In general, the patients are already malnourished, and early postoperative enteral nutrition is recommended. However, there is no consensus concerning the best enteral access route in these cases. METHODS: A prospective randomized trial was performed from 2008 to 2012 with 59 patients who underwent esophagectomy, total gastrectomy, or pancreaticoduodenectomy. In all, 4 patients declined to participate, and 13 did not meet the inclusion criteria and were excluded. Of the 42 included patients, 21 had nasoenteric tubes, and 21 had a jejunostomy. RESULTS: The two groups were similar in demographic and clinical aspects. The nasoenteric (NE) and jejunostomy groups underwent early enteral therapy in 71 and 62 % of cases (p > 0.05), respectively. The median length of enteral therapy use was less in the NE group (5.0 vs. 8.5 days), but the difference was not statistically significant. The NE group required introduction of parenteral therapy more frequently than the jejunostomy group (p < 0.05). Complications related to the enteral route occurred in 38.0 and 28.5 % of patients (p > 0.05) in the NE and jejunostomy groups, respectively. In the NE group, there were four losses and four tube obstructions. In the jejunostomy group, there were two losses, four obstructions, and two cases of leakage around the tube. In the latter group, patients who underwent therapy for a longer time had tubal complications (p < 0.05) and longer intensive care unit and hospital stays (p < 0.05). CONCLUSION: The two enteral routes were associated with the same number of complications. However, the presence of a jejunostomy allowed enteral therapy for longer periods, especially in patients with complications, thus avoiding the need for parenteral nutrition. PMID- 24806624 TI - Management of the pulmonary artery during video-assisted thoracoscopic left upper lobectomy. AB - BACKGROUND: Complete video-assisted thoracoscopic surgery (c-VATS) for left upper lobectomy is difficult due to the branching pattern of the left pulmonary artery. OBJECTIVE: Our purpose was to report outcomes of a modified technique of c-VATS left upper lobectomy. METHODS: We retrospectively compared the outcomes of 83 patients with stage I/II non-small-cell lung cancer (NSCLC) who received left upper lobectomy between 2008 and 2011; 32 underwent conventional c-VATS and 50 received modified c-VATS. In the modified procedure, the order in which hilum of lung was treated was from the lingular segmental artery to the superior pulmonary vein to the bronchus, and then finally the pulmonary artery. RESULTS: The mean patient age was 63.6 +/- 8.4 years, and no differences were observed in age, gender, and largest tumor diameter between the two groups. No conversion occurred in either group. The surgical time for modified c-VATS was significantly shorter than that for conventional c-VATS (210 vs. 270 min, p < 0.001). Drainage time after surgery and length of hospitalization for the modified c-VATS group were significantly less than those for the conventional group (drainage 3 vs. 4 days, respectively, p = 0.041; length of hospitalization 7 versus 12 days, respectively; p < 0.001). Surgical margins were clear in all cases. Four (8.0 %) complications occurred in the modified procedure group compared with ten (31.3 %) in the conventional group (p = 0.015). CONCLUSION: This new technique offers shorter surgical and postoperative drainage time, shorter hospital stays, and fewer complications than conventional c-VATS upper left lobectomy. PMID- 24806625 TI - Unmet burden of cleft lip and palate in rural Gujarat, India: a population-based study. AB - BACKGROUND: The burden of cleft lip and palate (CLP) in the developing world is being tackled by local hospitals and international surgical missions. However, the unmet surgical burden of these conditions is not known, because there are few population-based studies. We conducted this study to find the incidence and prevalence of cleft lip (CL), cleft palate (CP), and CLP and also estimate the unmet burden of these conditions. METHODS: Four blocks comprising of half a million people in the Patan district of Gujarat were chosen as the study areas. This study was conducted over a period of 3 months in 2009. Patients with CL, CP, and CLP were identified by community health workers using snowball sampling method. Data collected included demographics, type of cleft, operated or not, and place of operation. Disability adjusted life years (DALY) was calculated to measure the unmet burden of this disease. RESULTS: The most common among the three conditions was CL (69.4 %). Overall, cleft abnormalities were more common in males (61 %). The overall incidence and prevalence of cleft deformity was 0.73 per 1,000 live births and 0.1 per 1,000 people respectively. The unmet burden of surgical disease of these four blocks was 230 to 494 DALYs. CONCLUSIONS: The incidence of CL with or without palate was found to be 0.7 per 1,000 live births. The large number of unoperated cases (backlog) of cleft deformities suggests a big burden of unmet need in rural India. PMID- 24806627 TI - Astragalus membranaceus as a cause of increased CA19-9 and liver and kidney cysts: a case report. AB - WHAT IS KNOWN AND OBJECTIVE: Astragalus membranaceus, one of the most common Chinese herbs, is widely used to prevent and treat a variety of diseases. Very few adverse reactions, caused by A. membranaceus, have been reported in the literature. The purpose of this article was to report a case of marked increase in carbohydrate antigen 19-9 (CA19-9) and the formation of liver and kidney cysts following oral administration of A. membranaceus. CASE SUMMARY: A 38-year-old woman was found to have a high serum CA19-9 level (156 U/mL) at her routine annual examination. On follow-up, several small cysts were found in her left kidney and liver by CT scan. Her medical history showed that she had taken Astragalus tea every day for 1 month. One month after she stopped taking it, the CA19-9 level decreased to 40.19 U/mL. Ten months later, PET-CT showed that there were no liver and kidney cysts. However, she took Astragalus powder again in the second year and 1 month later her CA19-9 level increased again to more than 1000 U/mL. Several small cysts were again seen in her left kidney and liver by enhanced CT. Her CA19-9 level gradually became normal after she stopped taking the Astragalus powder. WHAT IS NEW AND CONCLUSION: This case strongly suggests that oral administration of A. membranaceus may lead to increase in CA19-9 and the formation of liver and kidney cysts. PMID- 24806628 TI - Real-time visualization of domain coverage by dynamically moving sensors. AB - A collection of algorithms, visualizations, and interactive operations allow operators controlling the movement of a collection of sensors through an environment to monitor in real time the portion of the environment that can or can't be seen by some subset of the sensors. The visualization allows preattentive detection of the number of sensors that can see a given location, and the coloring lets users identify the sensors' exact identities. This method employs two ray-tracing-based algorithms. A GPU implementation using CUDA (Compute-Unified Device Architecture) allows real-time processing and display of all scene updates and sensor movements. PMID- 24806626 TI - Antireflux surgery for dysplastic Barrett. AB - INTRODUCTION: Barrett's esophagus (BE) is the result of continuous injury of the esophageal mucosa by gastric refluxate. This condition can progress to low-grade (LGD) and high-grade dysplasia (HGD) and eventually to adenocarcinoma. While excellent results are reported in terms of reflux and symptom control in patients with BE undergoing antireflux surgery (ARS), the impact of a fundoplication on progression and regression of dysplasia is debated. The aim of this article is to review the effects of ARS on regression and progression of LGD to HGD or cancer in patients with dysplastic BE. MATERIALS AND METHODS: A review of the literature in PubMed/Medline electronic databases has been performed. RESULTS: ARS might decrease but not eliminate the risk of progression to dysplasia or cancer in BE patients. ARS may promote regression of dysplastic BE only in short-segment BE, but not in long-segment BE. Modulation of gene expression is involved in the genesis and reversion of short-segment intestinal metaplasia after ARS. CONCLUSIONS: Close and long-term surveillance by 24-hour pH monitoring and upper endoscopy is recommended in BE patients who undergo ARS to identify postoperative pathological reflux, and to early detect dysplasia or even adenocarcinoma. Further studies are requested to assess the molecular effects of ARS in dysplastic BE. PMID- 24806629 TI - Large-scale visualization projects for teaching software engineering. AB - The University of Stuttgart's software engineering major complements the traditional computer science major with more practice-oriented education. Two semester software projects in various application areas offered by the university's different computer science institutes are a successful building block in the curriculum. With this realistic, complex project setting, students experience the practice of software engineering, including software development processes, technologies, and soft skills. In particular, visualization-based projects are popular with students. Such projects offer them the opportunity to gain profound knowledge that would hardly be possible with only regular lectures and homework assignments. PMID- 24806630 TI - A graph algebra for scalable visual analytics. AB - Visual analytics (VA), which combines analytical techniques with advanced visualization features, is fast becoming a standard tool for extracting information from graph data. Researchers have developed many tools for this purpose, suggesting a need for formal methods to guide these tools' creation. Increased data demands on computing requires redesigning VA tools to consider performance and reliability in the context of analysis of exascale datasets. Furthermore, visual analysts need a way to document their analyses for reuse and results justification. A VA graph framework encapsulated in a graph algebra helps address these needs. Its atomic operators include selection and aggregation. The framework employs a visual operator and supports dynamic attributes of data to enable scalable visual exploration of data. PMID- 24806631 TI - Visual analytics for finding critical structures in massive time-varying turbulent-flow simulations. AB - Visualization and data analysis are crucial in analyzing and understanding a turbulent-flow simulation of size 4,096(3) cells per time slice (68 billion cells) and 17 time slices (one trillion total cells). The visualization techniques used help scientists investigate the dynamics of intense events individually and as these events form clusters. PMID- 24806632 TI - Geometric quantification of features in large flow fields. AB - Interactive exploration of flow features in large-scale 3D unsteady-flow data is one of the most challenging visualization problems today. To comprehensively explore the complex feature spaces in these datasets, a proposed system employs a scalable framework for investigating a multitude of characteristics from traced field lines. This capability supports the examination of various neighborhood based geometric attributes in concert with other scalar quantities. Such an analysis wasn't previously possible because of the large computational overhead and I/O requirements. The system integrates visual analytics methods by letting users procedurally and interactively describe and extract high-level flow features. An exploration of various phenomena in a large global ocean-modeling simulation demonstrates the approach's generality and expressiveness as well as its efficacy. PMID- 24806633 TI - Exploratory visualization involving incremental, approximate database queries and uncertainty. AB - Large datasets can mean slow queries, for which users must wait. Incremental visualization systems can give faster results at a cost of accuracy. This article asked analysts to use one and report on their results. Their feedback provides suggestions for alternative visualizations to represent a query still in progress. PMID- 24806634 TI - Fast rendering of diffusion curves with triangles. AB - Diffusion curves are a new kind of primitive in vector graphics, capable of representing smooth color transitions among boundaries. Their rendering requires solving Poisson's equation; much previous research relied on traditional solvers, which commonly require GPU acceleration to achieve real-time rasterization. This obviously restricts deployment on the Internet—for example, as rich Internet applications, in which various computing environments are involved. Diffusion effects are similar to locally defined interpolation with a particular orientation and magnitude. Inspired by that observation, a mesh-based framework combined with mean value coordinates (MVC) interpolants efficiently renders diffusion curve images on a CPU. This method employs a visibility algorithm to efficiently find and sort neighboring curve nodes for each vertex. It then assigns the vertex colors according to MVC interpolation with the neighboring curve nodes. Experiments produced rendering results comparable to traditional solvers, but this method is computationally more efficient and runs much faster on a CPU. PMID- 24806635 TI - Forensic-case analysis: from 3D imaging to interactive visualization. AB - An interactive framework prepares raw computed-tomography and magnetic-resonance imaging scans for courtroom presentations. The framework makes use of combined computer graphics and computer vision techniques to enable a forensic case analysis workflow. PMID- 24806636 TI - Introduction to geometric processing through optimization. AB - As an introduction to the field, this article shows how to formulate several geometry-processing operations to solve systems of equations in the "least squares" sense. The equations are derived from local geometric relations using elementary concepts from analytic geometry, such as points, lines, planes, vectors, and polygons. Simple and useful tools for interactive polygon mesh editing result from the most basic descent strategies to solve these optimization problems. Throughout the article, the author develops the mathematical formulations incrementally, keeping in mind that the objective is to implement simple software for interactive editing applications that works well in practice. Readers can implement higher-performance versions of these algorithms by replacing the simple solvers proposed here with more advanced ones. PMID- 24806637 TI - Novel insights into the ontogeny of nestmate recognition in Polistes social wasps. AB - The importance of early experience in animals' life is unquestionable, and imprinting-like phenomena may shape important aspects of behaviour. Early learning typically occurs during a sensitive period, which restricts crucial processes of information storage to a specific developmental phase. The characteristics of the sensitive period have been largely investigated in vertebrates, because of their complexity and plasticity, both in behaviour and neurophysiology, but early learning occurs also in invertebrates. In social insects, early learning appears to influence important social behaviours such as nestmate recognition. Yet, the mechanisms underlying recognition systems are not fully understood. It is currently believed that Polistes social wasps are able to discriminate nestmates from non-nestmates following the perception of olfactory cues present on the paper of their nest, which are learned during a strict sensitive period, immediately after emergence. Here, through differential odour experience experiments, we show that workers of Polistes dominula develop correct nestmate recognition abilities soon after emergence even in absence of what have been so far considered the necessary cues (the chemicals spread on nest paper). P. dominula workers were exposed for the first four days of adult life to paper fragments from their nest, or from a foreign conspecific nest or to a neutral condition. Wasps were then transferred to their original nests where recognition abilities were tested. Our results show that wasps do not alter their recognition ability if exposed only to nest material, or in absence of nest material, during the early phase of adult life. It thus appears that the nest paper is not used as a source of recognition cues to be learned in a specific time window, although we discuss possible alternative explanations. Our study provides a novel perspective for the study of the ontogeny of nestmate recognition in Polistes wasps and in other social insects. PMID- 24806640 TI - Guest editorial. Learning in nonstationary and evolving environments. PMID- 24806638 TI - Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: involving mTORC1 and mTORC2. AB - Leucine, a branched-chain amino acid, has been shown to promote glucose uptake and increase insulin sensitivity in skeletal muscle, but the exact mechanism remains unestablished. We addressed this issue in cultured skeletal muscle cells in this study. Our results showed that leucine alone did not have an effect on glucose uptake or phosphorylation of protein kinase B (AKT), but facilitated the insulin-induced glucose uptake and AKT phosphorylation. The insulin-stimulated glucose uptake and AKT phosphorylation were inhibited by the phosphatidylinositol 3-kinase inhibitor, wortmannin, but the inhibition was partially reversed by leucine. The inhibitor of mammalian target of rapamycin complex 1 (mTORC1), rapamycin, had no effect on the insulin-stimulated glucose uptake, but eliminated the facilitating effect of leucine in the insulin-stimulated glucose uptake and AKT phosphorylation. In addition, leucine facilitation of the insulin-induced AKT phosphorylation was neutralized by knocking down the core component of the mammalian target of rapamycin complex 2 (mTORC2) with specific siRNA. Together, these findings show that leucine can facilitate the insulin-induced insulin signaling and glucose uptake in skeletal muscle cells through both mTORC1 and mTORC2, implicating the potential importance of this amino acid in glucose homeostasis and providing new mechanistic insights. PMID- 24806641 TI - COMPOSE: A semisupervised learning framework for initially labeled nonstationary streaming data. AB - An increasing number of real-world applications are associated with streaming data drawn from drifting and nonstationary distributions that change over time. These applications demand new algorithms that can learn and adapt to such changes, also known as concept drift. Proper characterization of such data with existing approaches typically requires substantial amount of labeled instances, which may be difficult, expensive, or even impractical to obtain. In this paper, we introduce compacted object sample extraction (COMPOSE), a computational geometry-based framework to learn from nonstationary streaming data, where labels are unavailable (or presented very sporadically) after initialization. We introduce the algorithm in detail, and discuss its results and performances on several synthetic and real-world data sets, which demonstrate the ability of the algorithm to learn under several different scenarios of initially labeled streaming environments. On carefully designed synthetic data sets, we compare the performance of COMPOSE against the optimal Bayes classifier, as well as the arbitrary subpopulation tracker algorithm, which addresses a similar environment referred to as extreme verification latency. Furthermore, using the real-world National Oceanic and Atmospheric Administration weather data set, we demonstrate that COMPOSE is competitive even with a well-established and fully supervised nonstationary learning algorithm that receives labeled data in every batch. PMID- 24806642 TI - Active learning with drifting streaming data. AB - In learning to classify streaming data, obtaining true labels may require major effort and may incur excessive cost. Active learning focuses on carefully selecting as few labeled instances as possible for learning an accurate predictive model. Streaming data poses additional challenges for active learning, since the data distribution may change over time (concept drift) and models need to adapt. Conventional active learning strategies concentrate on querying the most uncertain instances, which are typically concentrated around the decision boundary. Changes occurring further from the boundary may be missed, and models may fail to adapt. This paper presents a theoretically supported framework for active learning from drifting data streams and develops three active learning strategies for streaming data that explicitly handle concept drift. They are based on uncertainty, dynamic allocation of labeling efforts over time, and randomization of the search space. We empirically demonstrate that these strategies react well to changes that can occur anywhere in the instance space and unexpectedly. PMID- 24806643 TI - Online Bayesian learning with natural sequential prior distribution. AB - Online Bayesian learning has been successfully applied to online learning for multilayer perceptrons and radial basis functions. In online Bayesian learning, typically, the conventional transition model has been used. Although the conventional transition model is based on the squared norm of the difference between the current parameter vector and the previous parameter vector, the transition model does not adequately consider the difference between the current observation model and the previous observation model. To adequately consider this difference between the observation models, we propose a natural sequential prior. The proposed transition model uses a Fisher information matrix to consider the difference between the observation models more naturally. For validation, the proposed transition model is applied to an online learning problem for a three layer perceptron. PMID- 24806644 TI - PANFIS: a novel incremental learning machine. AB - Most of the dynamics in real-world systems are compiled by shifts and drifts, which are uneasy to be overcome by omnipresent neuro-fuzzy systems. Nonetheless, learning in nonstationary environment entails a system owning high degree of flexibility capable of assembling its rule base autonomously according to the degree of nonlinearity contained in the system. In practice, the rule growing and pruning are carried out merely benefiting from a small snapshot of the complete training data to truncate the computational load and memory demand to the low level. An exposure of a novel algorithm, namely parsimonious network based on fuzzy inference system (PANFIS), is to this end presented herein. PANFIS can commence its learning process from scratch with an empty rule base. The fuzzy rules can be stitched up and expelled by virtue of statistical contributions of the fuzzy rules and injected datum afterward. Identical fuzzy sets may be alluded and blended to be one fuzzy set as a pursuit of a transparent rule base escalating human's interpretability. The learning and modeling performances of the proposed PANFIS are numerically validated using several benchmark problems from real-world or synthetic datasets. The validation includes comparisons with state-of-the-art evolving neuro-fuzzy methods and showcases that our new method can compete and in some cases even outperform these approaches in terms of predictive fidelity and model complexity. PMID- 24806645 TI - PCA feature extraction for change detection in multidimensional unlabeled data. AB - When classifiers are deployed in real-world applications, it is assumed that the distribution of the incoming data matches the distribution of the data used to train the classifier. This assumption is often incorrect, which necessitates some form of change detection or adaptive classification. While there has been a lot of work on change detection based on the classification error monitored over the course of the operation of the classifier, finding changes in multidimensional unlabeled data is still a challenge. Here, we propose to apply principal component analysis (PCA) for feature extraction prior to the change detection. Supported by a theoretical example, we argue that the components with the lowest variance should be retained as the extracted features because they are more likely to be affected by a change. We chose a recently proposed semiparametric log-likelihood change detection criterion that is sensitive to changes in both mean and variance of the multidimensional distribution. An experiment with 35 datasets and an illustration with a simple video segmentation demonstrate the advantage of using extracted features compared to raw data. Further analysis shows that feature extraction through PCA is beneficial, specifically for data with multiple balanced classes. PMID- 24806646 TI - Reacting to different types of concept drift: the Accuracy Updated Ensemble algorithm. AB - Data stream mining has been receiving increased attention due to its presence in a wide range of applications, such as sensor networks, banking, and telecommunication. One of the most important challenges in learning from data streams is reacting to concept drift, i.e., unforeseen changes of the stream's underlying data distribution. Several classification algorithms that cope with concept drift have been put forward, however, most of them specialize in one type of change. In this paper, we propose a new data stream classifier, called the Accuracy Updated Ensemble (AUE2), which aims at reacting equally well to different types of drift. AUE2 combines accuracy-based weighting mechanisms known from block-based ensembles with the incremental nature of Hoeffding Trees. The proposed algorithm is experimentally compared with 11 state-of-the-art stream methods, including single classifiers, block-based and online ensembles, and hybrid approaches in different drift scenarios. Out of all the compared algorithms, AUE2 provided best average classification accuracy while proving to be less memory consuming than other ensemble approaches. Experimental results show that AUE2 can be considered suitable for scenarios, involving many types of drift as well as static environments. PMID- 24806647 TI - Mining recurring concepts in a dynamic feature space. AB - Most data stream classification techniques assume that the underlying feature space is static. However, in real-world applications the set of features and their relevance to the target concept may change over time. In addition, when the underlying concepts reappear, reusing previously learnt models can enhance the learning process in terms of accuracy and processing time at the expense of manageable memory consumption. In this paper, we propose mining recurring concepts in a dynamic feature space (MReC-DFS), a data stream classification system to address the challenges of learning recurring concepts in a dynamic feature space while simultaneously reducing the memory cost associated with storing past models. MReC-DFS is able to detect and adapt to concept changes using the performance of the learning process and contextual information. To handle recurring concepts, stored models are combined in a dynamically weighted ensemble. Incremental feature selection is performed to reduce the combined feature space. This contribution allows MReC-DFS to store only the features most relevant to the learnt concepts, which in turn increases the memory efficiency of the technique. In addition, an incremental feature selection method is proposed that dynamically determines the threshold between relevant and irrelevant features. Experimental results demonstrating the high accuracy of MReC-DFS compared with state-of-the-art techniques on a variety of real datasets are presented. The results also show the superior memory efficiency of MReC-DFS. PMID- 24806648 TI - Dynamic learning from adaptive neural network control of a class of nonaffine nonlinear systems. AB - This paper studies the problem of learning from adaptive neural network (NN) control of a class of nonaffine nonlinear systems in uncertain dynamic environments. In the control design process, a stable adaptive NN tracking control design technique is proposed for the nonaffine nonlinear systems with a mild assumption by combining a filtered tracking error with the implicit function theorem, input-to-state stability, and the small-gain theorem. The proposed stable control design technique not only overcomes the difficulty in controlling nonaffine nonlinear systems but also relaxes constraint conditions of the considered systems. In the learning process, the partial persistent excitation (PE) condition of radial basis function NNs is satisfied during tracking control to a recurrent reference trajectory. Under the PE condition and an appropriate state transformation, the proposed adaptive NN control is shown to be capable of acquiring knowledge on the implicit desired control input dynamics in the stable control process and of storing the learned knowledge in memory. Subsequently, an NN learning control design technique that effectively exploits the learned knowledge without re-adapting to the controller parameters is proposed to achieve closed-loop stability and improved control performance. Simulation studies are performed to demonstrate the effectiveness of the proposed design techniques. PMID- 24806649 TI - Learning in the model space for cognitive fault diagnosis. AB - The emergence of large sensor networks has facilitated the collection of large amounts of real-time data to monitor and control complex engineering systems. However, in many cases the collected data may be incomplete or inconsistent, while the underlying environment may be time-varying or unformulated. In this paper, we develop an innovative cognitive fault diagnosis framework that tackles the above challenges. This framework investigates fault diagnosis in the model space instead of the signal space. Learning in the model space is implemented by fitting a series of models using a series of signal segments selected with a sliding window. By investigating the learning techniques in the fitted model space, faulty models can be discriminated from healthy models using a one-class learning algorithm. The framework enables us to construct a fault library when unknown faults occur, which can be regarded as cognitive fault isolation. This paper also theoretically investigates how to measure the pairwise distance between two models in the model space and incorporates the model distance into the learning algorithm in the model space. The results on three benchmark applications and one simulated model for the Barcelona water distribution network confirm the effectiveness of the proposed framework. PMID- 24806650 TI - Adaptive approximation for multiple sensor fault detection and isolation of nonlinear uncertain systems. AB - This paper presents an adaptive approximation-based design methodology and analytical results for distributed detection and isolation of multiple sensor faults in a class of nonlinear uncertain systems. During the initial stage of the nonlinear system operation, adaptive approximation is used for online learning of the modeling uncertainty. Then, local sensor fault detection and isolation (SFDI) modules are designed using a dedicated nonlinear observer scheme. The multiple sensor fault isolation process is enhanced by deriving a combinatorial decision logic that integrates information from local SFDI modules. The performance of the proposed diagnostic scheme is analyzed in terms of conditions for ensuring fault detectability and isolability. A simulation example of a single-link robotic arm is used to illustrate the application of the adaptive approximation-based SFDI methodology and its effectiveness in detecting and isolating multiple sensor faults. PMID- 24806651 TI - Dealing with concept drifts in process mining. AB - Although most business processes change over time, contemporary process mining techniques tend to analyze these processes as if they are in a steady state. Processes may change suddenly or gradually. The drift may be periodic (e.g., because of seasonal influences) or one-of-a-kind (e.g., the effects of new legislation). For the process management, it is crucial to discover and understand such concept drifts in processes. This paper presents a generic framework and specific techniques to detect when a process changes and to localize the parts of the process that have changed. Different features are proposed to characterize relationships among activities. These features are used to discover differences between successive populations. The approach has been implemented as a plug-in of the ProM process mining framework and has been evaluated using both simulated event data exhibiting controlled concept drifts and real-life event data from a Dutch municipality. PMID- 24806652 TI - Adaptive convex combination approach for the identification of improper quaternion processes. AB - Data-adaptive optimal modeling and identification of real-world vector sensor data is provided by combining the fractional tap-length (FT) approach with model order selection in the quaternion domain. To account rigorously for the generality of such processes, both second-order circular (proper) and noncircular (improper), the proposed approach in this paper combines the FT length optimization with both the strictly linear quaternion least mean square (QLMS) and widely linear QLMS (WL-QLMS). A collaborative approach based on QLMS and WL QLMS is shown to both identify the type of processes (proper or improper) and to track their optimal parameters in real time. Analysis shows that monitoring the evolution of the convex mixing parameter within the collaborative approach allows us to track the improperness in real time. Further insight into the properties of those algorithms is provided by establishing a relationship between the steady state error and optimal model order. The approach is supported by simulations on model order selection and identification of both strictly linear and widely linear quaternion-valued systems, such as those routinely used in renewable energy (wind) and human-centered computing (biomechanics). PMID- 24806653 TI - Developmental perception of the self and action. AB - This paper describes a developmental framework for action-driven perception in anthropomorphic robots. The key idea of the framework is that action generation develops the agent's perception of its own body and actions. Action-driven development is critical for identifying changing body parts and understanding the effects of actions in unknown or nonstationary environments. We embedded minimal knowledge into the robot's cognitive system in the form of motor synergies and actions to allow motor exploration. The robot voluntarily generates actions and develops the ability to perceive its own body and the effect that it generates on the environment. The robot, in addition, can compose this kind of learned primitives to perform complex actions and characterize them in terms of their sensory effects. After learning, the robot can recognize manipulative human behaviors with cross-modal anticipation for recovery of unavailable sensory modality, and reproduce the recognized actions afterward. We evaluated the proposed framework in the experiments with a real robot. In the experiments, we achieved autonomous body identification, learning of fixation, reaching and grasping actions, and developmental recognition of human actions as well as their reproduction. PMID- 24806654 TI - Linguistic decision making for robot route learning. AB - Machine learning enables the creation of a nonlinear mapping that describes robot environment interaction, whereas computing linguistics make the interaction transparent. In this paper, we develop a novel application of a linguistic decision tree for a robot route learning problem by dynamically deciding the robot's behavior, which is decomposed into atomic actions in the context of a specified task. We examine the real-time performance of training and control of a linguistic decision tree, and explore the possibility of training a machine learning model in an adaptive system without dual CPUs for parallelization of training and control. A quantified evaluation approach is proposed, and a score is defined for the evaluation of a model's robustness regarding the quality of training data. Compared with the nonlinear system identification nonlinear auto regressive moving average with eXogeneous inputs model structure with offline parameter estimation, the linguistic decision tree model with online linguistic ID3 learning achieves much better performance, robustness, and reliability. PMID- 24806655 TI - An interval type-2 neural fuzzy chip with on-chip incremental learning ability for time-varying data sequence prediction and system control. AB - This paper proposes a new circuit to implement a Mamdani-type interval type-2 neural fuzzy chip with on-chip incremental learning ability (IT2NFC-OL) for applications in changing environments. Traditional interval type-2 fuzzy systems use an iterative procedure to find the system outputs, which is computationally expensive, especially for hardware implementation. To address this problem, the IT2NFC-OL uses a simplified type reduction operation to reduce the hardware implementation cost without degrading the learning performance. The software implemented IT2NFC-OL is characterized by online structure learning and parameter learning using a gradient descent algorithm. The learned fuzzy model is then implemented in a field-programmable gate array (FPGA) chip. The FPGA-implemented IT2NFC-OL performs not only fuzzy inference but also online consequent parameter learning for applications in changing environments. Novel circuits for the computation of system outputs and the update of interval consequent values are proposed. The learning performance of the software-implemented IT2NFC-OL and the on-chip learning ability are verified with applications to time-varying data sequence prediction and system control problems and by comparisons with different software-implemented type-1 and type-2 neural fuzzy systems and interval type-2 fuzzy chips. PMID- 24806656 TI - Learning geotemporal nonstationary failure and recovery of power distribution. AB - Smart energy grid is an emerging area for new applications of machine learning in a nonstationary environment. Such a nonstationary environment emerges when large scale failures occur at power networks because of external disruptions such as hurricanes and severe storms. Power distribution networks lie at the edge of the grid, and are especially vulnerable to external disruptions. Quantifiable approaches are lacking and needed to learn nonstationary behaviors of large-scale failure and recovery of power distribution. This paper studies such nonstationary behaviors in three aspects. First, a novel formulation is derived for an entire life cycle of large-scale failure and recovery of power distribution. Second, spatial-temporal models of failure and recovery of power distribution are developed as geolocation-based multivariate nonstationary GI(t)/G(t)/infinity queues. Third, the nonstationary spatial-temporal models identify a small number of parameters to be learned. Learning is applied to two real-life examples of large-scale disruptions. One is from Hurricane Ike, where data from an operational network is exact on failures and recoveries. The other is from Hurricane Sandy, where aggregated data is used for inferring failure and recovery processes at one of the impacted areas. Model parameters are learned using real data. Two findings emerge as results of learning: 1) failure rates behave similarly at the two different provider networks for two different hurricanes but differently at the geographical regions and 2) both the rapid and slow-recovery are present for Hurricane Ike but only slow recovery is shown for a regional distribution network from Hurricane Sandy. PMID- 24806657 TI - Continuous dynamical combination of short and long-term forecasts for nonstationary time series. AB - This brief generalizes the forecasting method that has been awarded first-place winner in the International Competition of Time Series Forecasting (ICTSF 2012). It is based on a short-term forecasting approach of multilayer perceptrons (MLP) ensembles, combined dynamically with a long-term forecasting. The main feature of this general approach is the original concept of continuous dynamical combination of forecasts, in which the weights of the forecasting combination are a function of forecast horizon. Experiments in ICTSFs and NN5s nonstationary time series show that this new combination method improves the performance in multistep forecasting of MLP ensembles when compared to the MLP ensembles alone. PMID- 24806658 TI - Serum copper and ferroportin in monocytes of hemodialysis patients are both decreased but unassociated. AB - PURPOSE: Disturbed iron homeostasis contributes to resistance to recombinant human erythropoietin (rHuEpo) in hemodialysis (HD) patients. Although increased hepcidin, which downregulates the iron exporter ferroportin, had been incriminated, such an association has not been confirmed. Albeit not universally accepted, it has been supported that in case of copper deficiency, decreased activity of multicopper oxidases induces endocytosis and degradation of ferroportin. Ferroportin in monocytes, serum copper, ceruloplasmin and markers of iron status were measured, and associations with rHuEpo resistance index (ERI) were evaluated. METHODS: After a 4-week washout period from iron treatment, 34 HD patients and 20 healthy volunteers enrolled in the study. Ferroportin was assessed by means of Western blotting, copper colorimetrically, whereas ceruloplasmin with enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin and transferrin saturation (TSAT) were also measured. RESULTS: Ferroportin in monocytes of HD patients was decreased. Serum copper, ceruloplasmin, iron and TSAT were decreased. No correlation between copper or ceruloplasmin and ferroportin was detected. ERI was negatively correlated with ferroportin and all the markers of iron adequacy, but not with copper or ceruloplasmin. CONCLUSION: Although copper deficiency and decreased ferroportin are common in HD patients, copper might not play role in ferroportin level in monocytes and in iron metabolism in this population. PMID- 24806660 TI - Pathways of energy transfer in LHCII revealed by room-temperature 2D electronic spectroscopy. AB - We present here the first room-temperature 2D electronic spectroscopy study of energy transfer in the plant light-harvesting complex II, LHCII. Two-dimensional electronic spectroscopy has been used to study energy transfer dynamics in LHCII trimers from the chlorophyll b Qy band to the chlorophyll a Qy band. Observing cross-peak regions corresponding to couplings between different excitonic states reveals partially resolved fine structure at the exciton level that cannot be isolated by pump-probe or linear spectroscopy measurements alone. Global analysis of the data has been performed to identify the pathways and time constants of energy transfer. The measured waiting time (Tw) dependent 2D spectra are found to be composed of 2D decay-associated spectra with three timescales (0.3 ps, 2.3 ps and >20 ps). Direct and multistep cascading pathways from the high-energy chlorophyll b states to the lowest-energy chlorophyll a states have been resolved occurring on time scales of hundreds of femtoseconds to picoseconds. PMID- 24806659 TI - Behavioral and neural correlates of acute and scheduled hunger in C57BL/6 mice. AB - In rodents, daily feeding schedules induce food anticipatory activity (FAA) rhythms with formal properties suggesting mediation by food-entrained circadian oscillators (FEOs). The search for the neuronal substrate of FEOs responsible for FAA is an active area of research, but studies spanning several decades have yet to identify unequivocally a brain region required for FAA. Variability of results across studies leads to questions about underlying biology versus methodology. Here we describe in C57BL/6 male mice the effects of varying the 'dose' of caloric restriction (0%, 60%, 80%, 110%) on the expression of FAA as measured by a video-based analysis system, and on the induction of c-Fos in brain regions that have been implicated in FAA. We determined that more severe caloric restriction (60%) leads to a faster onset of FAA with increased magnitude. Using the 60% caloric restriction, we found little evidence for unique signatures of neuronal activation in the brains of mice anticipating a daily mealtime compared to mice that were fasted acutely or fed ad-libitum-even in regions such as the dorsomedial and ventrolateral hypothalamus, nucleus accumbens, and cerebellum that have previously been implicated in FAA. These results underscore the importance of feeding schedule parameters in determining quantitative features of FAA in mice, and demonstrate dissociations between behavioral FAA and neural activity in brain areas thought to harbor FEOs or participate in their entrainment or output. PMID- 24806661 TI - Hypopigmented interface T-cell dyscrasia: a form of cutaneous T-cell dyscrasia distinct from hypopigmented mycosis fungoides. AB - Hypopigmentation in cutaneous T-cell lymphoproliferative disease should not always be equated with hypopigmented mycosis fungoides (MF). A form of hypopigmented pre-lymphomatous T-cell dyscrasia falling under the designation of the so-called hypopigmented interface variant of T-cell dyscrasia has recently been proposed. The aim of the present study was to establish hypopigmented interface T-cell dyscrasia as its own entity apart from other T-cell dyscrasias and MF using a patient case series. Twenty four cases of hypopigmented interface T-cell dyscrasia were identified in the dermatopathology database of Weill Medical College of Cornell University. There were 17 females and seven males (mean age, 36 years). In children and adolescents, the patients were most commonly of African American extraction. Truncal photo-protected areas manifesting as large solitary patches or multiple smaller macules were characteristic; disease progression to MF occurred in only one patient. The lesions responded to topical steroids and light therapy. The pathology was defined by a cell poor interface associated with degeneration of keratinocytes and melanocytes, and by lymphocytes whose nuclei showed low-grade cerebriform atypia, and which expressed a significant reduction in CD7 and CD62L expression. In 50% of the cases, the implicated cell type was of the CD8 subset. Clonality was not identified. Hypopigmented interface T-cell dyscrasia is a distinct entity separate from and rarely progressive to MF. PMID- 24806662 TI - Factors associated with metabolic syndrome in a mediterranean population: role of caffeinated beverages. AB - BACKGROUND: Intake of caffeinated beverages, such as coffee and tea, has been related to improvements in components of metabolic syndrome (MetS), but studies conducted in the Mediterranean region are scarce. The aim of this study was to evaluate whether or not consumption of a variety of beverages containing caffeine was associated with components of MetS in an Italian population. METHODS: From May 2009 to December 2010, a cross-sectional survey was conducted on 1889 inhabitants living in Sicily, southern Italy. Data regarding demographic characteristics, habitual beverage intake, and adherence to the Mediterranean diet were collected, and clinical information was retrieved from the general practitioners' computer records. RESULTS: After adjusting for all covariates, coffee (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.27-0.70) and tea (OR 0.51, 95% CI 0.34-0.78) were associated with MetS, whereas no association was observed between caffeine intake and MetS. Among other factors, age, body mass index, physical activity, current smoking, and adherence to Mediterranean diet were associated with having MetS. Triglycerides were inversely associated with consumption of both espresso coffee and tea. The healthy effects of such beverages were more evident in individuals with unhealthy dietary habits. CONCLUSIONS: Although no direct association between caffeine intake and MetS or its components was observed, coffee and tea consumption was significantly related to reduced odds of MetS. PMID- 24806663 TI - The acetylenic tricyclic bis(cyano enone), TBE-31 inhibits non-small cell lung cancer cell migration through direct binding with actin. AB - The migratory and invasive potential of the epithelial-derived tumor cells depends on epithelial-to-mesenchymal transition (EMT) as well as the reorganization of the cell cytoskeleton. Here, we show that the tricyclic compound acetylenic tricyclic bis(cyano enone), TBE-31, directly binds to actin and inhibits linear and branched actin polymerization in vitro. Furthermore, we observed that TBE-31 inhibits stress fiber formation in fibroblasts as well as in non-small cell lung cancer cells during TGFbeta-dependent EMT. Interestingly, TBE 31 does not interfere with TGFbeta-dependent signaling or changes in E-cadherin and N-cadherin protein levels during EMT. Finally, we observed that TBE-31 inhibits fibroblast and non-small cell lung tumor cell migration with an IC50 of 1.0 and 2.5 MUmol/L, respectively. Taken together, our results suggest that TBE 31 targets linear actin polymerization to alter cell morphology and inhibit cell migration. PMID- 24806664 TI - It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco. AB - The Family Smoking Prevention and Tobacco Control Act gives the U.S. Food and Drug Administration power to regulate tobacco products. This commentary calls for immediate regulation of the carcinogenic tobacco-specific nitrosamines 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) in cigarette tobacco as a logical path to cancer prevention. NNK and NNN, powerful carcinogens in laboratory animals, have been evaluated as "carcinogenic to humans" by the International Agency for Research on Cancer. NNK and NNN are present in the tobacco of virtually all marketed cigarettes; levels in cigarette smoke are directly proportional to the amounts in tobacco. The NNK metabolite NNAL, itself a strong carcinogen, is present in the urine of smokers and nonsmokers exposed to secondhand smoke. Some of the highest levels of NNK and NNN are found in U.S. products. It is well established that factors such as choice of tobacco blend, agricultural conditions, and processing methods influence levels of NNK and NNN in cigarette tobacco and cigarette smoke. Therefore, it is time to control these factors and produce cigarettes with 100 ppb or less each of NNK and NNN in tobacco, which would result in an approximate 15- to 20-fold reduction of these carcinogens in the mainstream smoke of popular cigarettes sold in the United States. PMID- 24806666 TI - Contributions of the Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment (CANS-MCI) for the diagnosis of MCI in Brazil. AB - ABSTRACT Background: The Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment (CANS-MCI) is a computer-based cognitive screening instrument that involves automated administration and scoring and immediate analyses of test sessions. The objective of this study was to translate and culturally adapt the Brazilian Portuguese version of the CANS-MCI (CANS-MCI-BR) and to evaluate its reliability and validity for the diagnostic screening of MCI and dementia due to Alzheimer's disease. Methods: The test was administered to 97 older adults (mean age 73.41 +/- 5.27 years) with at least four years of formal education (mean education 12.23 +/- 4.48 years). Participants were classified into three diagnostic groups according to global cognitive status (normal controls, n = 41; MCI, n = 35; AD, n = 21) based on clinical data and formal neuropsychological assessments. Results: The results indicated high internal consistency (Cronbach's alpha = 0.77) in the total sample. Three-month test retest reliability correlations were significant and robust (0.875; p < 0.001). A moderate level of concurrent validity was attained relative to the screening test for MCI (MoCA test, r = 0.76, p < 0.001). Confirmatory factor analysis supported the three-factor model of the original test, i.e., memory, language/spatial fluency, and executive function/mental control. Goodness of fit indicators were strong (Bentler Comparative Fit Index = 0.96, Root Mean Square Error of Approximation = 0.09). Receiver operating characteristic curve analyses suggested high sensitivity and specificity (81% and 73% respectively) to screen for possible MCI cases. Conclusions: The CANS-MCI-BR maintains adequate psychometric characteristics that render it suitable to identify elderly adults with probable cognitive impairment to whom a more extensive evaluation by formal neuropsychological tests may be required. PMID- 24806665 TI - Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer. AB - We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of patients with colon cancer and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 patients with cancer and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of ten of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r = 0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy. PMID- 24806667 TI - Choroidal thickness changes in patients with migraine. AB - This observational study evaluated choroidal thickness using spectral domain optical coherence tomography (SD-OCT) in patients with migraine and compared the results with healthy controls. The study population consisted of 42 migraine patients (36 females and 6 males) who were referred from neurology clinics and 42 controls (36 female and 6 male) with no systemic or ocular disease and no headache of any type. All 84 patients underwent complete ophthalmic examination as well as determination of choroidal thickness using a high-speed, high resolution SD-OCT device (lambda = 840 nm, 27.000 A-scans/s, 5-um axial resolution). The migraine patients were classified into the migraine with aura group or the migraine without aura group, and a pain score from 1 to 10 was determined for each patient based on the Visual Analogue Scale (VAS). The mean choroidal thicknesses were 276.81 +/- 37.76 um in the migraine group and 300.44 +/- 24.93 um in controls. The difference in choroidal thickness between the migraine patients and the controls was significant (P = 0.001). Choroidal thickness measurements of five patients during an attack showed an acute decrease (mean 45.50 um) in choroidal thickness from the values in the same patients during the attack-free period. There was no correlation between VAS score and the type of migraine with choroidal thickness (P > 0.05). The decrease in mean choroidal thickness in patients with migraine compared to controls may be related to the vascular pathology of the migraine. The acute decrease in choroidal thickness during an attack also lends support to this hypothesis of reduced ocular blood flow in these patients. PMID- 24806668 TI - Predictive coding explains auditory and tactile influences on vision during binocular rivalry. PMID- 24806669 TI - A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer's disease-related pathophysiology in murine models. AB - Recent studies implicate death receptor 6 (DR6) in an amyloid precursor protein (APP)-dependent pathway regulating developmental axon pruning, and in a pruning pathway operating during plastic rearrangements in adult brain. DR6 has also been suggested to mediate toxicity in vitro of Abeta peptides derived from APP. Given the link between APP, Abeta, and Alzheimer's disease (AD), these findings have raised the possibility that DR6 contributes to aspects of neurodegeneration in AD. To test this possibility, we have used mouse models to characterize potential function(s) of DR6 in the adult CNS and in AD-related pathophysiology. We show that DR6 is broadly expressed within the adult CNS and regulates the density of excitatory synaptic connections onto pyramidal neurons in a genetic pathway with APP. DR6 knock-out also gives rise to behavioral abnormalities, some of which are similar to those previously documented in APP knock-out animals. However, in two distinct APP transgenic models of AD, we did not observe any alteration in the formation of amyloid plaques, gliosis, synaptic loss, or cognitive behavioral deficits with genetic deletion of DR6, though we did observe a transient reduction in the degree of microglial activation in one model. Our results support the view that DR6 functions with APP to modulate synaptic density in the adult CNS, but do not provide evidence for a role of DR6 in the pathophysiology of AD. PMID- 24806670 TI - Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of beta secretase. AB - In the developing brain, initial neuronal projections are formed through extensive growth and branching of developing axons, but many branches are later pruned to sculpt the mature pattern of connections. Despite its widespread occurrence, the mechanisms controlling pruning remain incompletely characterized. Based on pharmacological and biochemical analysis in vitro and initial genetic analysis in vivo, prior studies implicated a pathway involving binding of the Amyloid Precursor Protein (APP) to Death Receptor 6 (DR6) and activation of a downstream caspase cascade in axonal pruning. Here, we further test their involvement in pruning in vivo and their mechanism of action through extensive genetic and biochemical analysis. Genetic deletion of DR6 was previously shown to impair pruning of retinal axons in vivo. We show that genetic deletion of APP similarly impairs pruning of retinal axons in vivo and provide evidence that APP and DR6 act cell autonomously and in the same pathway to control pruning. Prior analysis had suggested that beta-secretase cleavage of APP and binding of an N terminal fragment of APP to DR6 is required for their actions, but further genetic and biochemical analysis reveals that beta-secretase activity is not required and that high-affinity binding to DR6 requires a more C-terminal portion of the APP ectodomain. These results provide direct support for the model that APP and DR6 function cell autonomously and in the same pathway to control pruning in vivo and raise the possibility of alternate mechanisms for how APP and DR6 control pruning. PMID- 24806671 TI - Astrocytic TDP-43 pathology in Alexander disease. AB - Alexander disease (AxD) is a rare neurodegenerative disorder characterized pathologically by the presence of eosinophilic inclusions known as Rosenthal fibers (RFs) within astrocytes, and is caused by dominant mutations in the coding region of the gene encoding glial fibrillary acidic protein (GFAP). GFAP is the major astrocytic intermediate filament, and in AxD patient brain tissue GFAP is a major component of RFs. TAR DNA binding protein of 43 kDa (TDP-43) is the major pathological protein in almost all cases of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and ~50% of frontotemporal lobar degeneration (FTLD), designated as FTLD-TDP. In ALS and FTLD-TDP, TDP-43 becomes insoluble, ubiquitinated, and pathologically phosphorylated and accumulates in cytoplasmic inclusions in both neurons and glia of affected brain and spinal cord regions. Previously, TDP-43 was detected in RFs of human pilocytic astrocytomas; however, involvement of TDP-43 in AxD has not been determined. Here we show that TDP-43 is present in RFs in AxD patient brains, and that insoluble phosphorylated full length and high molecular weight TDP-43 accumulates in white matter of such brains. Phosphorylated TDP-43 also accumulates in the detergent-insoluble fraction from affected brain regions of Gfap(R236H/+) knock-in mice, which harbor a GFAP mutation homologous to one that causes AxD in humans, and TDP-43 colocalizes with astrocytic RF pathology in Gfap(R236H/+) mice and transgenic mice overexpressing human wild-type GFAP. These findings suggest common pathogenic mechanisms in ALS, FTLD, and AxD, and this is the first report of TDP 43 involvement in a neurological disorder primarily affecting astrocytes. PMID- 24806672 TI - Hippocampal replay captures the unique topological structure of a novel environment. AB - Hippocampal place-cell replay has been proposed as a fundamental mechanism of learning and memory, which might support navigational learning and planning. An important hypothesis of relevance to these proposed functions is that the information encoded in replay should reflect the topological structure of experienced environments; that is, which places in the environment are connected with which others. Here we report several attributes of replay observed in rats exploring a novel forked environment that support the hypothesis. First, we observed that overlapping replays depicting divergent trajectories through the fork recruited the same population of cells with the same firing rates to represent the common portion of the trajectories. Second, replay tended to be directional and to flip the represented direction at the fork. Third, replay associated sharp-wave-ripple events in the local field potential exhibited substructure that mapped onto the maze topology. Thus, the spatial complexity of our recording environment was accurately captured by replay: the underlying neuronal activities reflected the bifurcating shape, and both directionality and associated ripple structure reflected the segmentation of the maze. Finally, we observed that replays occurred rapidly after small numbers of experiences. Our results suggest that hippocampal replay captures learned information about environmental topology to support a role in navigation. PMID- 24806673 TI - beta-Catenin is required for hair-cell differentiation in the cochlea. AB - The development of hair cells in the auditory system can be separated into steps; first, the establishment of progenitors for the sensory epithelium, and second, the differentiation of hair cells. Although the differentiation of hair cells is known to require the expression of basic helix-loop-helix transcription factor, Atoh1, the control of cell proliferation in the region of the developing cochlea that will ultimately become the sensory epithelium and the cues that initiate Atoh1 expression remain obscure. We assessed the role of Wnt/beta-catenin in both steps in gain- and loss-of-function models in mice. The canonical Wnt pathway mediator, beta-catenin, controls the expression of Atoh1. Knock-out of beta catenin inhibited hair-cell, as well as pillar-cell, differentiation from sensory progenitors but was not required to maintain a hair-cell fate once specified. Constitutive activation of beta-catenin expanded sensory progenitors by inducing additional cell division and resulted in the differentiation of extra hair cells. Our data demonstrate that beta-catenin plays a role in cell division and differentiation in the cochlear sensory epithelium. PMID- 24806674 TI - Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Delta9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys. AB - Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8 [(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil) 1H-purine-2,6-dione] were found previously to either decrease or increase self administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4 methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC. PMID- 24806675 TI - GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy. AB - gamma-Hydroxybutyrate (GHB) is an approved therapeutic for the excessive sleepiness and sudden loss of muscle tone (cataplexy) characteristic of narcolepsy. The mechanism of action for these therapeutic effects is hypothesized to be GABAB receptor dependent. We evaluated the effects of chronic administration of GHB and the GABAB agonist R-baclofen (R-BAC) on arousal state and cataplexy in two models of narcolepsy: orexin/ataxin-3 (Atax) and orexin/tTA; TetO diphtheria toxin mice (DTA). Mice were implanted for EEG/EMG monitoring and dosed with GHB (150 mg/kg), R-BAC (2.8 mg/kg), or vehicle (VEH) bid for 15 d-a treatment paradigm designed to model the twice nightly GHB dosing regimen used by human narcoleptics. In both models, R-BAC increased NREM sleep time, intensity, and consolidation during the light period; wake bout duration increased and cataplexy decreased during the subsequent dark period. GHB did not increase NREM sleep consolidation or duration, although NREM delta power increased in the first hour after dosing. Cataplexy decreased from baseline in 57 and 86% of mice after GHB and R-BAC, respectively, whereas cataplexy increased in 79% of the mice after VEH. At the doses tested, R-BAC suppressed cataplexy to a greater extent than GHB. These results suggest utility of R-BAC-based therapeutics for narcolepsy. PMID- 24806676 TI - Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. AB - The sleep disorder narcolepsy results from loss of hypothalamic orexin/hypocretin neurons. Although narcolepsy onset is usually postpubertal, current mouse models involve loss of either orexin peptides or orexin neurons from birth. To create a model of orexin/hypocretin deficiency with closer fidelity to human narcolepsy, diphtheria toxin A (DTA) was expressed in orexin neurons under control of the Tet off system. Upon doxycycline removal from the diet of postpubertal orexin tTA;TetO DTA mice, orexin neurodegeneration was rapid, with 80% cell loss within 7 d, and resulted in disrupted sleep architecture. Cataplexy, the pathognomic symptom of narcolepsy, occurred by 14 d when ~5% of the orexin neurons remained. Cataplexy frequency increased for at least 11 weeks after doxycycline. Temporary doxycycline removal followed by reintroduction after several days enabled partial lesion of orexin neurons. DTA-induced orexin neurodegeneration caused a body weight increase without a change in food consumption, mimicking metabolic aspects of human narcolepsy. Because the orexin/hypocretin system has been implicated in the control of metabolism and addiction as well as sleep/wake regulation, orexin tTA; TetO DTA mice are a novel model in which to study these functions, for pharmacological studies of cataplexy, and to study network reorganization as orexin input is lost. PMID- 24806677 TI - Complementary interactions between command-like interneurons that function to activate and specify motor programs. AB - Motor activity is often initiated by a population of command-like interneurons. Command-like interneurons that reliably drive programs have received the most attention, so little is known about how less reliable command-like interneurons may contribute to program generation. We study two electrically coupled interneurons, cerebral-buccal interneuron-2 (CBI-2) and CBI-11, which activate feeding motor programs in the mollusk Aplysia californica. Earlier work indicated that, in rested preparations, CBI-2, a powerful activator of programs, can trigger ingestive and egestive programs. CBI-2 reliably generated ingestive patterns only when it was repeatedly stimulated. The ability of CBI-2 to trigger motor activity has been attributed to the two program-promoting peptides it contains, FCAP and CP2. Here, we show that CBI-11 differs from CBI-2 in that it contains FCAP but not CP2. Furthermore, it is weak in its ability to drive programs. On its own, CBI-11 is therefore less effective as a program activator. When it is successful, however, CBI-11 is an effective specifier of motor activity; that is, it drives mostly ingestive programs. Importantly, we found that CBI-2 and CBI-11 complement each other's actions. First, prestimulation of CBI-2 enhanced the ability of CBI-11 to drive programs. This effect appears to be partly mediated by CP2. Second, coactivation of CBI-11 with CBI-2 makes CBI-2 programs immediately ingestive. This effect may be mediated by specific actions that CBI-11 exerts on pattern-generating interneurons. Therefore, different classes of command-like neurons in a motor network may make distinct, but potentially complementary, contributions as either activators or specifiers of motor activity. PMID- 24806678 TI - Modulation of C. elegans touch sensitivity is integrated at multiple levels. AB - Sensory systems can adapt to different environmental signals. Here we identify four conditions that modulate anterior touch sensitivity in Caenorhabditis elegans after several hours and demonstrate that such sensory modulation is integrated at multiple levels to produce a single output. Prolonged vibration involving integrin signaling directly sensitizes the touch receptor neurons (TRNs). In contrast, hypoxia, the dauer state, and high salt reduce touch sensitivity by preventing the release of long-range neuroregulators, including two insulin-like proteins. Integration of these latter inputs occurs at upstream neurohormonal cells and at the insulin signaling cascade within the TRNs. These signals and those from integrin signaling converge to modulate touch sensitivity by regulating AKT kinases and DAF-16/FOXO. Thus, activation of either the integrin or insulin pathways can compensate for defects in the other pathway. This modulatory system integrates conflicting signals from different modalities, and adapts touch sensitivity to both mechanical and non-mechanical conditions. PMID- 24806679 TI - Combined effects of Alzheimer risk variants in the CLU and ApoE genes on ventricular expansion patterns in the elderly. AB - The C allele at the rs11136000 locus in the clusterin (CLU) gene is the third strongest known genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent genome-wide association study of LOAD found the strongest evidence of association with CLU at rs1532278, in high linkage disequilibrium with rs11136000. Brain structure and function are related to the CLU risk alleles, not just in LOAD patients but also in healthy young adults. We tracked the volume of the lateral ventricles across baseline, 1-year, and 2-year follow-up scans in a large sample of elderly human participants (N = 736 at baseline), from the Alzheimer's Disease Neuroimaging Initiative, to determine whether these CLU risk variants predicted longitudinal ventricular expansion. The rs11136000 major C allele-previously linked with reduced CLU expression and with increased risk for dementia-predicted faster expansion, independently of dementia status or ApoE genotype. Further analyses revealed that the CLU and ApoE risk variants had combined effects on both volumetric expansion and lateral ventricle surface morphology. The rs1532278 locus strongly resembles a regulatory element. Its association with ventricular expansion was slightly stronger than that of rs11136000 in our analyses, suggesting that it may be closer to a functional variant. Clusterin affects inflammation, immune responses, and amyloid clearance, which in turn may result in neurodegeneration. Pharmaceutical agents such as valproate, which counteract the effects of genetically determined reduced clusterin expression, may help to achieve neuroprotection and contribute to the prevention of dementia, especially in carriers of these CLU risk variants. PMID- 24806680 TI - DAPK1-p53 interaction converges necrotic and apoptotic pathways of ischemic neuronal death. AB - Necrosis and apoptosis are two distinct types of mechanisms that mediate ischemic injury. But a signaling point of convergence between them has yet to be identified. Here, we show that activated death-associated protein kinase 1 (DAPK1), phosphorylates p53 at serine-23 (pS(23)) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that the pS(23) acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus, pS(23) induces the expression of proapoptotic genes, such as Bax, whereas in the mitochondrial matrix, pS(23) triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1(DDDelta)) or application of Tat p53DM that interrupts DAPK1-p53 interaction blocks these dual pathways of pS(23) actions in mouse cortical neurons. Thus, the DAPK1-p53 interaction is a signaling point of convergence of necrotic and apoptotic pathways and is a desirable target for the treatment of ischemic insults. PMID- 24806681 TI - Scale-free bursting in human cortex following hypoxia at birth. AB - The human brain is fragile in the face of oxygen deprivation. Even a brief interruption of metabolic supply at birth challenges an otherwise healthy neonatal cortex, leading to a cascade of homeostatic responses. During recovery from hypoxia, cortical activity exhibits a period of highly irregular electrical fluctuations known as burst suppression. Here we show that these bursts have fractal properties, with power-law scaling of burst sizes across a remarkable 5 orders of magnitude and a scale-free relationship between burst sizes and durations. Although burst waveforms vary greatly, their average shape converges to a simple form that is asymmetric at long time scales. Using a simple computational model, we argue that this asymmetry reflects activity-dependent changes in the excitatory-inhibitory balance of cortical neurons. Bursts become more symmetric following the resumption of normal activity, with a corresponding reorganization of burst scaling relationships. These findings place burst suppression in the broad class of scale-free physical processes termed crackling noise and suggest that the resumption of healthy activity reflects a fundamental reorganization in the relationship between neuronal activity and its underlying metabolic constraints. PMID- 24806682 TI - Fear from the heart: sensitivity to fear stimuli depends on individual heartbeats. AB - Cognitions and emotions can be influenced by bodily physiology. Here, we investigated whether the processing of brief fear stimuli is selectively gated by their timing in relation to individual heartbeats. Emotional and neutral faces were presented to human volunteers at cardiac systole, when ejection of blood from the heart causes arterial baroreceptors to signal centrally the strength and timing of each heartbeat, and at diastole, the period between heartbeats when baroreceptors are quiescent. Participants performed behavioral and neuroimaging tasks to determine whether these interoceptive signals influence the detection of emotional stimuli at the threshold of conscious awareness and alter judgments of emotionality of fearful and neutral faces. Our results show that fearful faces were detected more easily and were rated as more intense at systole than at diastole. Correspondingly, amygdala responses were greater to fearful faces presented at systole relative to diastole. These novel findings highlight a major channel by which short-term interoceptive fluctuations enhance perceptual and evaluative processes specifically related to the processing of fear and threat and counter the view that baroreceptor afferent signaling is always inhibitory to sensory perception. PMID- 24806683 TI - Arc regulates experience-dependent persistent firing patterns in frontal cortex. AB - The brain encodes information about past experience in specific populations of neurons that communicate with one another by firing action potentials. Studies of experience-dependent neural plasticity have largely focused on individual synaptic changes in response to neuronal input. Indicative of the neuronal output transmitted to downstream neurons, persistent firing patterns are affected by prior experience in selective neuronal populations. However, little is known about the molecular and cellular mechanisms by which experience-related persistent firing patterns are regulated in specific neuronal populations. Using frontal cortical slices prepared from transgenic mice carrying a fluorescent reporter of Arc gene expression, this study investigates how behavioral experience and the activity-regulated Arc gene affect patterns of neuronal firing. We found that motor training increases Arc expression in subsets of excitatory neurons. Those neurons exhibit persistent firing in contrast to Arc negative neurons from the same mice or neurons from the untrained mice. Furthermore, in mice carrying genetic deletion of Arc, the frontal cortical circuitry is still in place to initiate experience-dependent gene expression, but the level of persistent firing thereafter is diminished. Finally, our results showed that the emergence of persistent activity is associated with Arc-dependent changes in the function of NMDA-type glutamate receptors, rather than changes in AMPA-type receptors or membrane excitability. Our findings therefore reveal an Arc-dependent molecular pathway by which gene-experience interaction regulates the emergence of persistent firing patterns in specific neuronal populations. PMID- 24806684 TI - Imaging light responses of foveal ganglion cells in the living macaque eye. AB - The fovea dominates primate vision, and its anatomy and perceptual abilities are well studied, but its physiology has been little explored because of limitations of current physiological methods. In this study, we adapted a novel in vivo imaging method, originally developed in mouse retina, to explore foveal physiology in the macaque, which permits the repeated imaging of the functional response of many retinal ganglion cells (RGCs) simultaneously. A genetically encoded calcium indicator, G-CaMP5, was inserted into foveal RGCs, followed by calcium imaging of the displacement of foveal RGCs from their receptive fields, and their intensity-response functions. The spatial offset of foveal RGCs from their cone inputs makes this method especially appropriate for fovea by permitting imaging of RGC responses without excessive light adaptation of cones. This new method will permit the tracking of visual development, progression of retinal disease, or therapeutic interventions, such as insertion of visual prostheses. PMID- 24806685 TI - Human memory retrieval and inhibitory control in the brain: beyond correlational evidence. AB - Retrieving information from long-term memory can result in the episodic forgetting of related material. One influential account states that this retrieval-induced forgetting (RIF) phenomenon reflects inhibitory mechanisms called into play to decrease retrieval competition. Recent neuroimaging studies suggested that the prefrontal cortex, which is critically engaged in inhibitory processing, is also involved in retrieval competition situations. Here, we used transcranial direct current stimulation (tDCS) to address whether inhibitory processes could be causally linked to RIF. tDCS was administered over the right dorsolateral prefrontal cortex during the retrieval-practice phase in a standard retrieval-practice paradigm. Sixty human participants were randomly assigned to anodal, cathodal, or sham-control groups. The groups showed comparable benefits for practiced items. In contrast, unlike both the sham and anodal groups, the cathodal group exhibited no RIF. This pattern is interpreted as evidence for a causal role of inhibitory mechanisms in episodic retrieval and forgetting. PMID- 24806686 TI - Distinct Kv channel subtypes contribute to differences in spike signaling properties in the axon initial segment and presynaptic boutons of cerebellar interneurons. AB - The discrete arrangement of voltage-gated K(+) (Kv) channels in axons may impart functional advantages in action potential (AP) signaling yet, in compact cell types, the organization of Kv channels is poorly understood. We find that in cerebellar stellate cell interneurons of mice, the composition and influence of Kv channels populating the axon is diverse and depends on location allowing axonal compartments to differentially control APs in a local manner. Kv1 channels determine AP repolarization at the spike initiation site but not at more distal sites, limiting the expression of use-dependent spike broadening to the most proximal axon region, likely a key attribute informing spiking phenotype. Local control of AP repolarization at presynaptic boutons depends on Kv3 channels keeping APs brief, thus limiting Ca(2+) influx and synaptic strength. These observations suggest that AP repolarization is tuned by the local influence of distinct Kv channel types, and this organization enhances the functional segregation of axonal compartments. PMID- 24806687 TI - Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain. AB - Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity. PMID- 24806688 TI - Selective modulation of auditory cortical alpha activity in an audiovisual spatial attention task. AB - Despite substantial research on attentional modulations of visual alpha activity, doubts remain as to the existence and functional relevance of auditory cortical alpha-band oscillations. It has been argued that auditory cortical alpha does not exist, cannot be measured noninvasively, or that it is dependent on visual alpha generators. This study aimed to address these remaining doubts concerning auditory cortical alpha. A magnetoencephalography study was conducted using a combined audiovisual spatial cueing paradigm. In each trial, a cue indicated the side (left or right) and the modality (auditory or visual) to attend, followed by a short lateralized auditory or visual stimulus. Participants were instructed to respond to the stimuli by a button press. Results show that auditory cortical alpha power is selectively modulated by the audiospatial, but not the visuospatial, attention task. These findings provide further evidence for a distinct auditory cortical alpha generator, which can be measured noninvasively. PMID- 24806689 TI - Repetition probability effects depend on prior experiences. AB - The magnitude of repetition suppression (RS) in the Fusiform Face Area is influenced by the probability of repetitions of faces (Summerfield et al., 2008), implying that perceptual expectations affect repetition-related processes. Surprisingly, however, macaque single-cell (Kaliukhovich and Vogels, 2011) and human fMRI (Kovacs et al., 2013) studies have failed to find repetition probability [P(rep)] modulations of RS with nonface stimuli in the occipitotemporal cortex, suggesting that the effect is face specific. One possible explanation of this category selectivity is that the extensive experience humans have with faces affects the neural mechanisms of RS specifically, creating P(rep) modulatory effects. To address this question, we used fMRI to test the P(rep) effects for another well trained stimulus category, upright letters of the roman alphabet as well as for unfamiliar false fonts. We observed significant RS for both stimulus sets in the Letter Form Area as well as in the caudodorsal part of the lateral occipital complex. Interestingly, the influence of P(rep) on RS was dependent on the stimulus: while we observed P(rep) modulations for the roman letters, no such effects were found for the unfamiliar false fonts in either area. Our findings suggest that P(rep) effects on RS are manifest for nonface stimuli as well, but that they depend on the experience of the subjects with the stimulus category. This shows, for the first time, that prior experience affects the influence of contextual predictive information on RS in the human occipitotemporal cortex. PMID- 24806690 TI - Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories. AB - Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse. PMID- 24806691 TI - Social stress and CRF-dopamine interactions in the VTA: role in long-term escalation of cocaine self-administration. AB - The nature of neuroadaptations in the genesis of escalated cocaine taking remains a topic of considerable interest. Intermittent social defeat stress induces both locomotor and dopaminergic cross-sensitization to cocaine, as well as escalated cocaine self-administration. The current study examines the role of corticotropin releasing factor receptor subtypes 1 and 2 (CRFR1, CRFR2) within the ventral tegmental area (VTA) during social defeat stress. This study investigated whether injecting either a CRFR1 or CRFR2 antagonist directly into the VTA before each social defeat would prevent the development of later (1) locomotor sensitization, (2) dopaminergic sensitization, and (3) escalated cocaine self-administration in rats. CRFR1 antagonist CP376395 (50 or 500 ng/side), CRFR2 antagonist Astressin2 B (100 or 1000 ng/side), or vehicle (aCSF) was microinjected into the VTA 20 min before social defeat stress (or handling) on days 1, 4, 7, and 10. Ten days later, rats were injected with cocaine (10 mg/kg, i.p.) and assessed for either locomotor sensitization, measured by walking activity, or dopaminergic sensitization, measured by extracellular dopamine (DA) in the nucleus accumbens shell (NAcSh) through in vivo microdialysis. Locomotor sensitization testing was followed by intravenous cocaine self-administration. Intra-VTA antagonism of CRFR1, but not CRFR2, inhibited the induction of locomotor cross-sensitization to cocaine, whereas both prevented dopaminergic cross-sensitization and escalated cocaine self-administration during a 24 h "binge." This may suggest dissociation between locomotor sensitization and cocaine taking. These data also suggest that interactions between CRF and VTA DA neurons projecting to the NAcSh are essential for the development of dopaminergic cross-sensitization to cocaine. PMID- 24806692 TI - Ionic mechanisms of microsecond-scale spike timing in single cells. AB - Electric fish image their environments and communicate by generating electric organ discharges through the simultaneous action potentials (APs) of electric organ cells (electrocytes) in the periphery. Steatogenys elegans generates a biphasic electrocyte discharge by the precisely regulated timing and waveform of APs generated from two excitable membranes present in each electrocyte. Current clamp recordings of electrocyte APs reveal that the posterior membrane fires first, followed ~30 MUs later by an AP on the anterior membrane. This delay was maintained even as the onset of the first AP was advanced >5 ms by increasing stimulus intensity and across multiple spikes during bursts of APs elicited by prolonged stimulation. Simultaneous cell-attached loose-patch recordings of Na(+) currents on each membrane revealed that activation voltage for Na(+) channels on the posterior membrane was 10 mV hyperpolarized compared with Na(+) channels on the anterior membrane, with no differences in activation or inactivation kinetics. Computational simulations of electrocyte APs demonstrated that this difference in Na(+) current activation voltage was sufficient to maintain the proper firing order and the interspike delay. A similar difference in activation threshold has been reported for the Na(+) currents of the axon initial segment compared with somatic Na(+) channels of pyramidal neurons, suggesting convergent evolution of spike initiation and timing mechanisms across different systems of excitable cells. PMID- 24806693 TI - Diacylglycerol activates the light-dependent channel TRP in the photosensitive microvilli of Drosophila melanogaster photoreceptors. AB - Drosophila light-dependent channels, TRP and TRPL, reside in the light-sensitive microvilli of the photoreceptor's rhabdomere. Phospholipase C mediates TRP/TRPL opening, but the gating process remains unknown. Controversial evidence has suggested diacylglycerol (DAG), polyunsaturated fatty acids (PUFAs, a DAG metabolite), phosphatidylinositol bisphosphate (PIP2), and H(+) as possible channel activators. We tested each of them directly in inside-out TRP-expressing patches excised from the rhabdomere, making use of mutants and pharmacology. When patches were excised in darkness TRP remained closed, while when excised under illumination it stayed constitutively active. TRP was opened by DAG and silenced by ATP, suggesting DAG-kinase (DGK) involvement. The ATP effect was abolished by inhibiting DGK and in the rdgA mutant, lacking functional DGK, implicating DGK. DAG activated TRP even in the presence of a DAG-lipase inhibitor, inconsistent with a requirement of PUFAs in opening TRP. PIP2 had no effect and acidification, pH 6.4, activated TRP irreversibly, unlike the endogenous activator. Complementary liquid-chromatography/mass-spectrometry determinations of DAG and PUFAs in membranes enriched in rhabdomere obtained from light- and dark-adapted eyes showed light-dependent increment in six DAG species and no changes in PUFAs. The results strongly support DAG as the endogenous TRP agonist, as some of its vertebrate TRPC homologs of the same channel family. PMID- 24806694 TI - Target-distractor competition in the oculomotor system is spatiotopic. AB - In natural scenes, multiple visual stimuli compete for selection; however, each saccade displaces the stimulus representations in retinotopicaly organized visual and oculomotor maps. In the present study, we used saccade curvature to investigate whether oculomotor competition across eye movements is represented in retinotopic or spatiotopic coordinates. Participants performed a sequence of saccades and we induced oculomotor competition by briefly presenting a task irrelevant distractor at different times during the saccade sequence. Despite the intervening saccade, the second saccade curved away from a spatial representation of the distractor that was presented before the first saccade. Furthermore, the degree of saccade curvature increased with the salience of the distractor presented before the first saccade. The results suggest that spatiotopic representations of target-distractor competition are crucial for successful interaction with objects of interest despite the intervening eye movements. PMID- 24806695 TI - Cyclic AMP and afferent activity govern bidirectional synaptic plasticity in striatopallidal neurons. AB - Recent experimental evidence suggests that the low dopamine conditions in Parkinson's disease (PD) cause motor impairment through aberrant motor learning. Those data, along with computational models, suggest that this aberrant learning results from maladaptive corticostriatal plasticity and learned motor inhibition. Dopaminergic modulation of both corticostriatal long-term depression (LTD) and long-term potentiation (LTP) is proposed to be critical for these processes; however, the regulatory mechanisms underlying bidirectional corticostriatal plasticity are not fully understood. Previously, we demonstrated a key role for cAMP signaling in corticostriatal LTD. In this study, mouse brain slices were used to perform a parametric experiment that tested the impact of varying both intracellular cAMP levels and the strength of excitatory inputs on corticostriatal plasticity. Using slice electrophysiology in the dorsolateral striatum, we demonstrate that both LTP and LTD can be sequentially induced in the same D2-expressing neuron and that LTP was strongest with high intracellular cAMP and LFS, whereas LTD required low intracellular cAMP and high-frequency stimulation. Our results provide a molecular and cellular basis for regulating bidirectional corticostriatal synaptic plasticity and may help to identify novel therapeutic targets for blocking or reversing the aberrant synaptic plasticity that likely contributes to motor deficits in PD. PMID- 24806696 TI - Global selection of saccadic target features by neurons in area v4. AB - Psychophysical and neurophysiological studies indicate that during the preparation of saccades, visual processing at the target location is facilitated automatically by the deployment of attention. It has been assumed that the neural mechanisms involved in presaccadic shifts of attention are purely spatial in nature. Saccade preparation modulates the visual responses of neurons within extrastriate area V4, where the responses to targets are enhanced and responses to nontargets are suppressed. We tested whether this effect also engages a nonspatial form of modulation. We measured the responses of area V4 neurons to oriented gratings in two monkeys (Macaca mulatta) making delayed saccades to targets distant from the neuronal receptive field (RF). We varied the orientation of both the RF stimulus and the saccadic target. We found that, in addition to the spatial modulation, saccade preparation involves a feature-dependent modulation of V4 neuronal responses. Specifically, we found that the suppression of area V4 responses to nontarget stimuli during the preparation of saccades depends on the features of the saccadic target. Presaccadic suppression was absent when the features of the saccadic target matched the features preferred by individual V4 neurons. This feature-dependent modulation occurred in the absence of any feature-attention task. We show that our observations are consistent with a computational framework in which feature-based effects automatically emerge from saccade-related feedback signals that are spatial in nature. PMID- 24806697 TI - An intact action-perception coupling depends on the integrity of the cerebellum. AB - It is widely accepted that action and perception in humans functionally interact on multiple levels. Moreover, areas originally suggested to be predominantly motor-related, as the cerebellum, are also involved in action observation. However, as yet, few studies provided unequivocal evidence that the cerebellum is involved in the action perception coupling (APC), specifically in the integration of motor and multisensory information for perception. We addressed this question studying patients with focal cerebellar lesions in a virtual-reality paradigm measuring the effect of action execution on action perception presenting self generated movements as point lights. We measured the visual sensitivity to the point light stimuli based on signal detection theory. Compared with healthy controls cerebellar patients showed no beneficial influence of action execution on perception indicating deficits in APC. Applying lesion symptom mapping, we identified distinct areas in the dentate nucleus and the lateral cerebellum of both hemispheres that are causally involved in APC. Lesions of the right ventral dentate, the ipsilateral motor representations (lobules V/VI), and most interestingly the contralateral posterior cerebellum (lobule VII) impede the benefits of motor execution on perception. We conclude that the cerebellum establishes time-dependent multisensory representations on different levels, relevant for motor control as well as supporting action perception. Ipsilateral cerebellar motor representations are thought to support the somatosensory state estimate of ongoing movements, whereas the ventral dentate and the contralateral posterior cerebellum likely support sensorimotor integration in the cerebellar parietal loops. Both the correct somatosensory as well as the multisensory state representations are vital for an intact APC. PMID- 24806698 TI - SCF/C-KIT signaling modulates tryptase expression in acute myeloid leukemia cells. AB - Tryptase is a serine protease with a variety of biological functions. Recently, elevated serum tryptase has been detected in certain patients with acute myeloid leukemia (AML). However, the underlying mechanism for the regulation of tryptase expression remains elusive. In this study, we aimed to investigate the role of stem cell factor (SCF)/C-KIT signaling in regulating the expression of tryptase in AML cells. We found a significant positive correlation between tryptase and C KIT expression levels in AML patients. Furthermore, real-time PCR, Western blot and ELISA analysis showed that SCF upregulated tryptase mRNA and protein expression in U937 cells, and that this effect was abolished by pretreatment with PD98059 and SB230580. In addition, levels of phosphorylated ERK1/2 and p38MAPK correlated with tryptase levels. Taken together, these data suggest that the expression of tryptase is regulated by SCF/C-KIT signaling via the ERK1/2 and p38MAPK pathways. PMID- 24806699 TI - Blurry vision after orbital decompression surgery. AB - Pathologic myopia may be associated with abnormal vitreomacular adhesions that can portend a higher risk of retinal detachment. The authors report a case of rhegmatogenous retinal detachment with a complex macular tear after orbital decompression surgery in a patient with pathologic myopia. This case highlights the importance of retinal detachment in the setting of orbital decompression. PMID- 24806700 TI - Fibrotic encapsulation of a dexamethasone intravitreal implant following vitrectomy and silicone oil for rhegmatogenous retinal detachment. AB - Steroids are commonly used as adjunct therapy in the management of proliferative vitreoretinopathy. The authors report a case of proliferative vitreoretinopathy treated with an intravitreal dexamethasone implant following vitrectomy in a silicone oil-filled eye. Epiretinal fibrosis developed around the implant at 6 weeks postoperatively, resulting in a recurrent retinal detachment. This was repaired by vitrectomy, removal of the implant, and peeling of epiretinal proliferation. PMID- 24806701 TI - Serous retinal detachment accompanied by MEWDS in a myopic patient with dome shaped macula. AB - Macular serous retinal detachment (MSRD) is a rare complication in highly myopic patients with an inferior staphyloma, tilted disc, or dome-shaped macula. Multiple evanescent white dot syndrome (MEWDS) presents with sudden visual loss and multiple yellowish dots that resolve spontaneously within several weeks. The authors report the development and spontaneous resolution of subretinal fluid accompanied by MEWDS in a myopic patient with a dome-shaped macula. Dysfunction of the retinal pigment epithelium due to MEWDS likely induced temporary MSRD in this patient. PMID- 24806702 TI - Fetal scalp blood sampling during labor: an appraisal of the physiological basis and scientific evidence. AB - Fetal cardiotocography is characterized by low specificity; therefore, in an attempt to ensure fetal well-being, fetal scalp blood sampling has been recommended by most obstetric societies in the case of a non-reassuring cardiotocography. The scientific agreement on the evidence for using fetal scalp blood sampling to decrease the rate of operative delivery for fetal distress is ambiguous. Based on the same studies, a Cochrane review states that fetal scalp blood sampling increases the rate of instrumental delivery while decreasing neonatal acidosis, whereas the National Institute of Health and Clinical Excellence guideline considers that fetal scalp blood sampling decreases instrumental delivery without differences in other outcome variables. The fetal scalp is supplied by vessels outside the skull below the level of the cranial vault, which is likely to be compressed during contractions. The self-regulated redistribution of oxygenated blood from peripheral to central organs causes peripheral ischemia, thus theoretically bringing into question the scalp capillary bed as representative of the central circulation. PMID- 24806703 TI - Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review. AB - BACKGROUND: The randomised controlled trial (RCT) is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to the design and validity of a RCT is a calculation of the number of participants needed (the sample size). The value used to determine the sample size can be considered the 'target difference'. From both a scientific and an ethical standpoint, selecting an appropriate target difference is of crucial importance. Determination of the target difference, as opposed to statistical approaches to calculating the sample size, has been greatly neglected though a variety of approaches have been proposed the current state of the evidence is unclear. OBJECTIVES: The aim was to provide an overview of the current evidence regarding specifying the target difference in a RCT sample size calculation. The specific objectives were to conduct a systematic review of methods for specifying a target difference; to evaluate current practice by surveying triallists; to develop guidance on specifying the target difference in a RCT; and to identify future research needs. DESIGN: The biomedical and social science databases searched were MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, Education Resources Information Center (ERIC) and Scopus for in-press publications. All were searched from 1966 or the earliest date of the database coverage and searches were undertaken between November 2010 and January 2011. There were three interlinked components: (1) systematic review of methods for specifying a target difference for RCTs - a comprehensive search strategy involving an electronic literature search of biomedical and some non-biomedical databases and clinical trials textbooks was carried out; (2) identification of current trial practice using two surveys of triallists - members of the Society for Clinical Trials (SCT) were invited to complete an online survey and respondents were asked about their awareness and use of, and willingness to recommend, methods; one individual per triallist group [UK Clinical Research Collaboration (UKCRC)-registered Clinical Trials Units (CTUs), Medical Research Council (MRC) UK Hubs for Trials Methodology Research and National Institute for Health Research (NIHR) UK Research Design Services (RDS)] was invited to complete a survey; (3) production of a structured guidance document to aid the design of future trials - the draft guidance was developed utilising the results of the systematic review and surveys by the project steering and advisory groups. SETTING: Methodological review incorporating electronic searches, review of books and guidelines, two surveys of experts (membership of an international society and UK- and Ireland-based triallists) and development of guidance. PARTICIPANTS: The two surveys were sent out to membership of the SCT and UK- and Ireland-based triallists. INTERVENTIONS: The review focused on methods for specifying the target difference in a RCT. It was not restricted to any type of intervention or condition. MAIN OUTCOME MEASURES: Methods for specifying the target difference for a RCT were considered. RESULTS: The search identified 11,485 potentially relevant studies. In total, 1434 were selected for full-text assessment and 777 were included in the review. Seven methods to specify the target difference for a RCT were identified - anchor, distribution, health economic, opinion-seeking, pilot study, review of evidence base (RoEB) and standardised effect size (SES) - each having important variations in implementation. A total of 216 of the included studies used more than one method. A total of 180 (15%) responses to the SCT survey were received, representing 13 countries. Awareness of methods ranged from 38% (n =69) for the health economic method to 90% (n =162) for the pilot study. Of the 61 surveys sent out to UK triallist groups, 34 (56%) responses were received. Awareness ranged from 97% (n =33) for the RoEB and pilot study methods to only 41% (n =14) for the distribution method. Based on the most recent trial, all bar three groups (91%, n =30) used a formal method. Guidance was developed on the use of each method and the reporting of the sample size calculation in a trial protocol and results paper. CONCLUSIONS: There is a clear need for greater use of formal methods to determine the target difference and better reporting of its specification. Raising the standard of RCT sample size calculations and the corresponding reporting of them would aid health professionals, patients, researchers and funders in judging the strength of the evidence and ensuring better use of scarce resources. FUNDING: The Medical Research Council UK and the National Institute for Health Research Joint Methodology Research programme. PMID- 24806704 TI - A novel strategy to fabricate multifunctional Fe3O4@C@TiO2 yolk-shell structures as magnetically recyclable photocatalysts. AB - Using poly(acrylic acid) (PAA) as a template, a novel Fe3O4@C@TiO2 yolk-shell structure derived from heat treatment on Fe2O3@PAA@TiO2 core-shell structures is constructed, where the interior void volume and shell thickness are readily tuned. In this method, the PAA shell between the original spherical alpha-Fe2O3 nanoparticle (NP) core and the outer TiO2 shell replaces the common SiO2 template leaving out the tedious treatment procedure of the template. After calcination, the alpha-Fe2O3 core was reduced to the Fe3O4 core providing the NPs with magnetic properties and the middle carbon coating around the magnetic core could avoid the occurrence of photodissolution. Moreover, the obtained Fe3O4@C@TiO2 yolk-shell nanocomposites (NCs) exhibit fine photocatalytic activity for the photodegradation of organic contaminants in waste water. PMID- 24806705 TI - Dopamine mobilizes mesenchymal progenitor cells through D2-class receptors and their PI3K/AKT pathway. AB - As the nervous system exerts direct and indirect effects on stem cells mobilization and catecholamines mobilize hematopoietic stem cells, we hypothesized that dopamine might induce mesenchymal progenitor cells (MPCs) mobilization. We show that dopamine induced in vitro MPCs migration through D2 class receptors, and their alternative phosphoinositide 3-kinase/Akt pathways. Also, administration of catecholamines induced in vivo mobilization of colony forming unit-fibroblast in mice. In contrast, in vitro and in vivo MPCs migration was suppressed by D2-class receptors antagonists and blocking antibodies, consistent with dopamine signaling pathway implication. In humans, patients treated with L-dopa or catecholaminergic agonists showed a significant increase of a MPC-like population (CD45-CD31-CD34-CD105+) in their peripheral blood. These findings reveal a new link between catecholamines and MPCs mobilization and suggest the potential use of D2-class receptors agonists for mobilization of MPCs in clinical settings. PMID- 24806706 TI - Chemical warfare and survival strategies in bacterial range expansions. AB - Dispersal of species is a fundamental ecological process in the evolution and maintenance of biodiversity. Limited control over ecological parameters has hindered progress in understanding of what enables species to colonize new areas, as well as the importance of interspecies interactions. Such control is necessary to construct reliable mathematical models of ecosystems. In our work, we studied dispersal in the context of bacterial range expansions and identified the major determinants of species coexistence for a bacterial model system of three Escherichia coli strains (toxin-producing, sensitive and resistant). Genetic engineering allowed us to tune strain growth rates and to design different ecological scenarios (cyclic and hierarchical). We found that coexistence of all strains depended on three strongly interdependent factors: composition of inoculum, relative strain growth rates and effective toxin range. Robust agreement between our experiments and a thoroughly calibrated computational model enabled us to extrapolate these intricate interdependencies in terms of phenomenological biodiversity laws. Our mathematical analysis also suggested that cyclic dominance between strains is not a prerequisite for coexistence in competitive range expansions. Instead, robust three-strain coexistence required a balance between growth rates and either a reduced initial ratio of the toxin producing strain, or a sufficiently short toxin range. PMID- 24806708 TI - Reconciling the concurrent fast and slow cycling of proteins on gene promoters. AB - During gene transcription, proteins appear to cycle on and off some gene promoters with both long (tens of minutes) and short periods (no more than several minutes). The essence of these phenomena still remains unclear. Here, we propose a stochastic model for the state evolution of promoters in terms of DNA protein interactions. The model associates the characteristics of microscopic molecular interactions with macroscopic measurable quantities. Through theoretical derivation, we reconcile the contradictory viewpoints on the concurrent fast and slow cycling; both the cycling phenomena are further reproduced by fitting simulation results to the experimental data on the pS2 gene. Our results suggest that the fast cycling dictates how the proteins behave on the promoter and that stable binding hardly occurs. Different kinds of proteins rapidly bind/unbind the promoter at distinct transcriptional stages fulfilling specific functions; this feature is essentially manifested as the slow cycling of proteins when detected by chromatin immunoprecipitation assays. Thus, the slow cycling represents neither stable binding of proteins nor external modulation of the fast cycling. This work also reveals the relationship between the essence and measurement of transcriptional dynamics. PMID- 24806707 TI - Mathematical models of the transitions between endocrine therapy responsive and resistant states in breast cancer. AB - Endocrine therapy, targeting the oestrogen receptor pathway, is the most common treatment for oestrogen receptor-positive breast cancers. Unfortunately, these tumours frequently develop resistance to endocrine therapies. Among the strategies to treat resistant tumours are sequential treatment (in which second line drugs are used to gain additional responses) and intermittent treatment (in which a 'drug holiday' is imposed between treatments). To gain a more rigorous understanding of the mechanisms underlying these strategies, we present a mathematical model that captures the transitions among three different, experimentally observed, oestrogen-sensitivity phenotypes in breast cancer (sensitive, hypersensitive and independent). To provide a global view of the transitions between these phenotypes, we compute the potential landscape associated with the model. We show how this oestrogen response landscape can be reshaped by population selection, which is a crucial force in promoting acquired resistance. Techniques from statistical physics are used to create a population level state-transition model from the cellular-level model. We then illustrate how this population-level model can be used to analyse and optimize sequential and intermittent oestrogen-deprivation protocols for breast cancer. The approach used in this study is general and can also be applied to investigate treatment strategies for other types of cancer. PMID- 24806709 TI - Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates. AB - Current understanding of bone healing and remodelling strategies in vertebrates has traditionally relied on morphological observations through the histological analysis of thin sections. However, chemical analysis may also be used in such interpretations, as different elements are known to be absorbed and used by bone for different physiological purposes such as growth and healing. These chemical signatures are beyond the detection limit of most laboratory-based analytical techniques (e.g. scanning electron microscopy). However, synchrotron rapid scanning-X-ray fluorescence (SRS-XRF) is an elemental mapping technique that uniquely combines high sensitivity (ppm), excellent sample resolution (20-100 um) and the ability to scan large specimens (decimetre scale) approximately 3000 times faster than other mapping techniques. Here, we use SRS-XRF combined with microfocus elemental mapping (2-20 um) to determine the distribution and concentration of trace elements within pathological and normal bone of both extant and extinct archosaurs (Cathartes aura and Allosaurus fragilis). Results reveal discrete chemical inventories within different bone tissue types and preservation modes. Chemical inventories also revealed detail of histological features not observable in thin section, including fine structures within the interface between pathological and normal bone as well as woven texture within pathological tissue. PMID- 24806710 TI - Aromatic nitrogen mustard-based prodrugs: activity, selectivity, and the mechanism of DNA cross-linking. AB - Three novel H2O2-activated aromatic nitrogen mustard prodrugs (6-8) are reported. These compounds contain a DNA alkylating agent connected to a H2O2-responsive trigger by different electron-withdrawing linkers so that they are inactive towards DNA but can be triggered by H2O2 to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross-link (ICL) formation in the presence or absence of H2O2. An electron-withdrawing linker unit, such as a quaternary ammonia salt (6), a carboxyamide (7), and a carbonate group (8), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5 % cross-linking formation. However, H2O2 can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross-linking efficiency (>20 %). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard (15) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI50 of less than 1 MUM, whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications. PMID- 24806714 TI - Vitiligo treatment demystified: a flowchart for stratified treatment approaches. AB - The recent publication by Anbar et al. in the April issue of this journal, delineating and prioritizing treatment options for vitiligo, is both timely and significant. First and foremost, this work brings to the forefront the important message that vitiligo truly is a treatable disease. All too often, patients refrain from seeking treatment as public opinion dictates that vitiligo is not an important disease, there are no effective treatments available, and insurance will not cover attempts to treat. By providing clear guidelines of treatments to be considered, practicing physicians seeing an occasional vitiligo patient will be more readily inclined to explore the possibilities currently available for enhancing the quality of life of this patient group. PMID- 24806716 TI - Ion solvation in polymer blends and block copolymer melts: effects of chain length and connectivity on the reorganization of dipoles. AB - We studied the thermodynamic properties of ion solvation in polymer blends and block copolymer melts and developed a dipolar self-consistent field theory for polymer mixtures. Our theory accounts for the chain connectivity of polymerized monomers, the compressibility of the liquid mixtures under electrostriction, the permanent and induced dipole moments of monomers, and the resultant dielectric contrast among species. In our coarse-grained model, dipoles are attached to the monomers and allowed to rotate freely in response to electrostatic fields. We demonstrate that a strong electrostatic field near an ion reorganizes dipolar monomers, resulting in nonmonotonic changes in the volume fraction profile and the dielectric function of the polymers with respect to those of simple liquid mixtures. For the parameter sets used, the spatial variations near an ion can be in the range of 1 nm or larger, producing significant differences in the solvation energy among simple liquid mixtures, polymer blends, and block copolymers. The solvation energy of an ion depends substantially on the chain length in block copolymers; thus, our theory predicts the preferential solvation of ions arising from differences in chain length. PMID- 24806717 TI - Inversion of supramolecular chirality in bichromophoric perylene bisimides: influence of temperature and ultrasound. AB - The supramolecular helicity in the self-assembled nanostructures of two perylene bisimide bichromophoric systems could be controlled by varying the preparatory methods. The self-assembly of the compounds under different conditions was investigated in detail by using absorption, fluorescence, CD, FTIR, XRD, TEM, and SEM techniques. These studies reveal that the heating-cooling method results in aggregates with ordered molecular packing and enhanced optical chirality. Ultrasonication leads to molecular aggregates with less ordered packing wherein the supramolecular chirality was reversed relative to the sample prepared via a heating-cooling method. This heating-cooling method proved to be superior in terms of nanofiber synthesis, yielding fibers with extended length and a prominent helical twist. At higher concentration, both compounds exhibited a gelation property in benzonitrile. The tunable chiroptical properties in these supramolecular systems make them potential candidates for applications in the field of optical and electronic device fabrication based on organic nanostructures. PMID- 24806718 TI - Hierarchical molecular self-assemblies: construction and advantages. AB - Hierarchical molecular self-assembly offers many exotic and complicated nanostructures which are of interest in nanotechnology and material science. In the past decade, various strategies leading to hierarchical molecular self assemblies have been developed. In this review we summarize the recent advances in the creation and application of solution-based self-assembled nanostructures that involve more than one level of arrangement of building blocks. The strategies for construction hierarchical self-assembled structures and the advantages brought up by these assemblies are focused on. The following contents are included: (1) general approaches to fabricate hierarchical self-assembly, including self-assemblies based on supramolecules and specially designed block copolymers; (2) the advantages brought about by the hierarchical self-assembly, including the fabrication of special self-assembled structures, rich responsiveness to external stimuli, and the materials' performance. PMID- 24806719 TI - Journal of Occupational & Environmental Medicine. Foreword. PMID- 24806720 TI - Bauxite mining and alumina refining: process description and occupational health risks. AB - OBJECTIVE: To describe bauxite mining and alumina refining processes and to outline the relevant physical, chemical, biological, ergonomic, and psychosocial health risks. METHODS: Review article. RESULTS: The most important risks relate to noise, ergonomics, trauma, and caustic soda splashes of the skin/eyes. Other risks of note relate to fatigue, heat, and solar ultraviolet and for some operations tropical diseases, venomous/dangerous animals, and remote locations. Exposures to bauxite dust, alumina dust, and caustic mist in contemporary best practice bauxite mining and alumina refining operations have not been demonstrated to be associated with clinically significant decrements in lung function. Exposures to bauxite dust and alumina dust at such operations are also not associated with the incidence of cancer. CONCLUSIONS: A range of occupational health risks in bauxite mining and alumina refining require the maintenance of effective control measures. PMID- 24806721 TI - Health risk assessments for alumina refineries. AB - OBJECTIVE: To describe contemporary air dispersion modeling and health risk assessment methodologies applied to alumina refineries and to summarize recent results. METHODS: Air dispersion models using emission source and meteorological data have been used to assess ground-level concentrations (GLCs) of refinery emissions. Short-term (1-hour and 24-hour average) GLCs and annual average GLCs have been used to assess acute health, chronic health, and incremental carcinogenic risks. RESULTS: The acute hazard index can exceed 1 close to refineries, but it is typically less than 1 at neighboring residential locations. The chronic hazard index is typically substantially less than 1. The incremental carcinogenic risk is typically less than 10(-6). CONCLUSIONS: The risks of acute health effects are adequately controlled, and the risks of chronic health effects and incremental carcinogenic risks are negligible around referenced alumina refineries. PMID- 24806722 TI - The aluminum smelting process. AB - This introduction to the industrial primary aluminum production process presents a short description of the electrolytic reduction technology, the history of aluminum, and the importance of this metal and its production process to modern society. Aluminum's special qualities have enabled advances in technologies coupled with energy and cost savings. Aircraft capabilities have been greatly enhanced, and increases in size and capacity are made possible by advances in aluminum technology. The metal's flexibility for shaping and extruding has led to architectural advances in energy-saving building construction. The high strength to-weight ratio has meant a substantial reduction in energy consumption for trucks and other vehicles. The aluminum industry is therefore a pivotal one for ecological sustainability and strategic for technological development. PMID- 24806723 TI - The aluminum smelting process and innovative alternative technologies. AB - OBJECTIVE: The industrial aluminum production process is addressed. The purpose is to give a short but comprehensive description of the electrolysis cell technology, the raw materials used, and the health and safety relevance of the process. METHODS: This article is based on a study of the extensive chemical and medical literature on primary aluminum production. RESULTS: At present, there are two main technological challenges for the process--to reduce energy consumption and to mitigate greenhouse gas emissions. A future step may be carbon dioxide gas capture and sequestration related to the electric power generation from fossil sources. CONCLUSIONS: Workers' health and safety have now become an integrated part of the aluminum business. Work-related injuries and illnesses are preventable, and the ultimate goal to eliminate accidents with lost-time injuries may hopefully be approached in the future. PMID- 24806724 TI - Community health risk assessment of primary aluminum smelter emissions. AB - OBJECTIVE: Primary aluminum production is an industrial process with high potential health risk for workers. We consider in this article how to assess community health risks associated with primary aluminum smelter emissions. METHODS: We reviewed the literature on health effects, community exposure data, and dose-response relationships of the principal hazardous agents emitted. RESULTS: On the basis of representative measured community exposure levels, we were able to make rough estimates on health risks associated with specific agents and categorize these as none, low, medium, or high. CONCLUSIONS: It is possible to undertake a rough-estimate community Health Risk Assessment for individual smelters on the basis of information available in the epidemiological literature and local community exposure data. PMID- 24806726 TI - Occupational and environmental health in the aluminum industry: key points for health practitioners. PMID- 24806725 TI - Cancer risks in aluminum reduction plant workers: a review. AB - OBJECTIVE AND METHODS: This review examines epidemiological evidence relating to cancers in the primary aluminum industry where most of what is known relates to Soderberg operations or to mixed Soderberg/prebake operations. RESULTS AND CONCLUSIONS: Increased lung and bladder cancer risks have been reported in Soderberg workers from several countries, but not in all. After adjustment for smoking, these cancer risks still increase with cumulative exposure to benzo(a)pyrene, used as an index of coal tar pitch volatiles exposure. Limited evidence has been gathered in several cohorts for an increased risk of tumors at other sites, including stomach, pancreas, rectum/rectosigmoid junction, larynx, buccal cavity/pharynx, kidney, brain/nervous system, prostate, and lymphatic/hematopoietic tissues (in particular non-Hodgkin lymphoma, Hodgkin disease, and leukemia). Nevertheless, for most of these tumor sites, the relationship with specific exposures has not been demonstrated clearly and further follow-up of workers is warranted. PMID- 24806727 TI - Respiratory disorders in aluminum smelter workers. AB - OBJECTIVES: Summarizing the knowledge status, including the morphology, possible etiological factors, and clinical expression of aluminum potroom asthma and chronic obstructive pulmonary disease related to aluminum potroom exposure. METHODS: A review of the literature from the last two decades as it appears in PubMed. RESULTS: There is substantial evidence for the existence of potroom asthma, although the incidence seems to decline over the last 10 years. Increased mortality from chronic obstructive pulmonary disease and longitudinal decline in forced expiratory volume in the first second of expiration has been shown in aluminum potroom workers. Morphological manifestations in bronchial biopsies and the inflammatory markers NO and eosinophils in airway tissue and blood are consistent with asthma in general. The causative agent(s) is (are) not known. CONCLUSIONS: Reduction of exposure and cessation of smoking seem to be the major preventive measures to avoid respiratory disorders in the aluminum industry. PMID- 24806728 TI - Diffuse parenchymal diseases associated with aluminum use and primary aluminum production. AB - Aluminum use and primary aluminum production results in the generation of various particles, fumes, gases, and airborne materials with the potential for inducing a wide range of lung pathology. Nevertheless, the presence of diffuse parenchymal or interstitial lung disease related to these processes remains controversial. The relatively uncommon occurrence of interstitial lung diseases in aluminum exposed workers--despite the extensive industrial use of aluminum--the potential for concurrent exposure to other fibrogenic fibers, and the previous use of inhaled aluminum powder for the prevention of silicosis without apparent adverse respiratory effects are some of the reasons for this continuing controversy. Specific aluminum-induced parenchymal diseases described in the literature, including existing evidence of interstitial lung diseases, associated with primary aluminum production are reviewed. PMID- 24806731 TI - 1,2-Addition of dihydrogen across rhodium(III)-OMe bonds. AB - The Rh(III) complexes [((t)bpy)2Rh(OMe)(L)][X]n ((t)bpy = 4,4'-di-tert-butyl-2,2' bipyridyl; L = MeOH, n = 2, X = OTf (OTf = trifluoromethanesulfonate), TFA (TFA = trifluoroacetate); L = TFA, n = 1, X = OTf) have been shown to activate dihydrogen via net 1,2-addition of the H-H bond across the Rh(III)-OMe bond. The bis(methoxide) complex [((t)bpy)2Rh(OMe)2][OTf] was synthesized by addition of CsOH.H2O in methanol to [((t)bpy)2Rh(OTf)2][OTf] in CH3CN. The addition of HTFA to [((t)bpy)2Rh(OMe)2][OTf] leads to the formation of [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA], which exists in equilibrium with [((t)bpy)2Rh(OMe)(TFA)][OTf]. The mixture of [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA] and [((t)bpy)2Rh(OMe)(TFA)][OTf] activates dihydrogen at 68 degrees C to give methanol and [((t)bpy)2Rh(H)(TFA)][OTf]. Studies indicate that the activation of dihydrogen has a first-order dependence on the Rh(III) methoxide complex and a dependence on hydrogen that is between zero and first order. Combined experimental and computational studies have led to a proposed mechanism for hydrogen activation by [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA] that involves dissociation of MeOH, coordination of hydrogen, and 1,2-addition of hydrogen across the Rh-OMe bond. DFT calculations indicate that there is a substantial energy penalty for MeOH dissociation and a relatively flat energy surface for subsequent hydrogen coordination and activation. PMID- 24806733 TI - CCL5 secreted from bone marrow stromal cells stimulates the migration and invasion of Huh7 hepatocellular carcinoma cells via the PI3K-Akt pathway. AB - Bone metastases from hepatocellular carcinoma (HCC) seem to be increasing. Previous studies showed that soluble factors secreted by host cells and direct cell-to-cell interactions contributed to the preferential metastasis and growth of cancer cells in bone, while the underlying mechanism(s) of the metastasis of HCC in the bone are poorly understood. Here, we determined the effect of HS-5 cells on Huh7 cell proliferation, and investigated the role of CCL5 from HS-5 cells on the development of Huh7 cells. In addition, the underlying mechanisms on the influence in Huh7 cells were investigated. Our results showed that HS-5 cells could promote the proliferation, migration and invasion of Huh7 cells, and inhibited apoptosis. CCL5 downregulation was able to inhibit the effects of HS-5 cells on Huh7 cell migration and invasion via the PI3K-Akt signaling pathway and reduce MMP-2 expression. Therefore, these findings suggest that CCL5 secreted from MSCs can promote the migration and invasion of Huh7 cells and could be an important factor in HCC related to occurrence of bone metastases. PMID- 24806729 TI - Is the Aluminum Hypothesis dead? AB - The Aluminum Hypothesis, the idea that aluminum exposure is involved in the etiology of Alzheimer disease, dates back to a 1965 demonstration that aluminum causes neurofibrillary tangles in the brains of rabbits. Initially the focus of intensive research, the Aluminum Hypothesis has gradually been abandoned by most researchers. Yet, despite this current indifference, the Aluminum Hypothesis continues to attract the attention of a small group of scientists and aluminum continues to be viewed with concern by some of the public. This review article discusses reasons that mainstream science has largely abandoned the Aluminum Hypothesis and explores a possible reason for some in the general public continuing to view aluminum with mistrust. PMID- 24806734 TI - Wnt/beta-catenin pathway regulates cementogenic differentiation of adipose tissue deprived stem cells in dental follicle cell-conditioned medium. AB - The formation and attachment of new cementum is crucial for periodontium regeneration. Tissue engineering is currently explored to achieve complete, reliable and reproducible regeneration of the periodontium. The capacity of multipotency and self-renewal makes adipose tissue-deprived stem cells (ADSCs) an excellent cell source for tissue regeneration and repair. After rat ADSCs were cultured in dental follicle cell-conditioned medium (DFC-CM) supplemented with DKK-1, an inhibitor of the Wnt pathway, followed by 7 days of induction, they exhibited several phenotypic characteristics of cementoblast lineages, as indicated by upregulated expression levels of CAP, ALP, BSP and OPN mRNA, and accelerated expression of BSP and CAP proteins. The Wnt/beta-catenin signaling pathway controls differentiation of stem cells by regulating the expression of target genes. Cementoblasts share phenotypical features with osteoblasts. In this study, we demonstrated that culturing ADSCs in DFC-CM supplemented with DKK-1 results in inhibition of beta-catenin nuclear translocation and down-regulates TCF-4 and LEF-1 mRNA expression levels. We also found that DKK-1 could promote cementogenic differentiation of ADSCs, which was evident by the up-regulation of CAP, ALP, BSP and OPN gene expressions. On the other hand, culturing ADSCs in DFC CM supplemented with 100 ng/mL Wnt3a, which activates the Wnt/beta-catenin pathway, abrogated this effect. Taken together, our study indicates that the Wnt/beta-catenin signaling pathway plays an important role in regulating cementogenic differentiation of ADSCs cultured in DFC-CM. These results raise the possibility of using ADSCs for periodontal regeneration by modifying the Wnt/beta catenin pathway. PMID- 24806735 TI - Individualizing antihypertensive combination therapies: clinical and hemodynamic considerations. AB - While there are strong trial data to guide the selection of initial hypertension treatment choice and limited data to support second agent choice, beyond the first two agents, subsequent steps are empiric. As medications are added, the resulting polypharmacy may be complex, inefficient and poorly tolerated, resulting in low treatment adherence rates. The selection of antihypertensive drug therapy based on hemodynamic mechanisms is not new but became practical with the availability of noninvasive hemodynamic parameters using impedance cardiography. Individualized therapy based on hormonal or hemodynamic measurements can effectively control hypertension as shown in several small clinical trials. Hemodynamic measurements are obtained quickly, painlessly and can be used in a serial fashion to guide treatment adjustments. Current limitations relate to availability of the measurement device and personnel trained in its use, reimbursement for the measurements, expertise in interpretation of the measurements and systems to adjust medication and repeat measurements in a serial fashion until targets are attained. The potential utility of this approach increases with greater complexity of the medication regimen. Further studies are indicated and may advance options for individualized treatment of hypertensive patients. PMID- 24806736 TI - Current status of drugs in development for celiac disease. AB - INTRODUCTION: Gluten is the main trigger for celiac disease, and the current treatment is based on its elimination from the diet. Although the symptoms usually disappear during the diet, it is restrictive and difficult to maintain. Further, despite a strict treatment the small-bowel mucosal damage does now always heal. Consequently, adherence is often poor and new treatment approaches are needed. With an increased understanding of the disease pathogenesis, several novel treatments have been suggested, and some of them have already entered Phase II clinical trials. AREAS COVERED: This article reviews the latest status of the drugs in development for celiac disease. The article focuses mainly on synthetic drugs currently entering in clinical trials. EXPERT OPINION: It is anticipated that some of the treatments under investigation will soon enter Phase III clinical trials, although challenges remain. For instance, histological studies are problematic in wide-scale clinical studies. On the other hand, the existing non-invasive serological methods and clinical outcome measures might be too insensitive for monitoring responses to the possible drug candidates. There is also no animal model which would accurately reflect celiac disease. Well conducted basic and clinical research is required to develop better non-invasive surrogate markers and patient-related outcomes for future pharmacological studies. PMID- 24806737 TI - Cross-country skiing and postexercise heart-rate recovery. AB - Postexercise heart-rate (HR) recovery (HRR) indices have been associated with running and cycling endurance-exercise performance. The current study was designed (1) to test whether such a relationship also exists in the case of cross country skiing (XCS) and (2) to determine whether the magnitude of any such relationship is related to the intensity of exercise before obtaining HRR indices. Ten elite male cross-country skiers (mean +/- SD; 28.2 +/- 5.4 y, 181 +/ 8 cm, 77.9 +/- 9.4 kg, 69.5 +/- 4.3 mL . min-1 . kg-1 maximal oxygen uptake [VO2max]) performed 2 sessions of roller-skiing on a treadmill: a 2 * 3-km time trial and the same 6-km at an imposed submaximal speed followed by a final 800-m time trial. VO2 and HR were monitored continuously, while HRR and blood lactate (BLa) were assessed during 2 min immediately after each 6-km and the 800-m time trial. The 6-km time-trial time was largely negatively correlated with VO2max and BLa. On the contrary, there was no clear correlation between the 800-m time-trial time and VO2, HR, or BLa. In addition, in no case was any clear correlation between any of the HRR indices and performance time or VO2max observed. These findings confirm that XCS performance is largely correlated with VO2max and the ability to tolerate high levels of BLa; however, postexercise HRR showed no clear association with performance. The homogeneity of the group of athletes involved and the contribution of the arms and upper body to the exercise preceding determination of HRR may explain this absence of a relationship. PMID- 24806738 TI - Botulinum toxin induces muscle paralysis and inhibits bone regeneration in zebrafish. AB - Intramuscular administration of Botulinum toxin (BTx) has been associated with impaired osteogenesis in diverse conditions of bone formation (eg, development, growth, and healing), yet the mechanisms of neuromuscular-bone crosstalk underlying these deficits have yet to be identified. Motivated by the emerging utility of zebrafish (Danio rerio) as a rapid, genetically tractable, and optically transparent model for human pathologies (as well as the potential to interrogate neuromuscular-mediated bone disorders in a simple model that bridges in vitro and more complex in vivo model systems), in this study, we developed a model of BTx-induced muscle paralysis in adult zebrafish, and we examined its effects on intramembranous ossification during tail fin regeneration. BTx administration induced rapid muscle paralysis in adult zebrafish in a manner that was dose-dependent, transient, and focal, mirroring the paralytic phenotype observed in animal and human studies. During fin regeneration, BTx impaired continued bone ray outgrowth, morphology, and patterning, indicating defects in early osteogenesis. Further, BTx significantly decreased mineralizing activity and crystalline mineral accumulation, suggesting delayed late-stage osteoblast differentiation and/or altered secondary bone apposition. Bone ray transection proximal to the amputation site focally inhibited bone outgrowth in the affected ray, implicating intra- and/or inter-ray nerves in this process. Taken together, these studies demonstrate the potential to interrogate pathological features of BTx-induced osteoanabolic dysfunction in the regenerating zebrafish fin, define the technological toolbox for detecting bone growth and mineralization deficits in this process, and suggest that pathways mediating neuromuscular regulation of osteogenesis may be conserved beyond established mammalian models of bone anabolic disorders. PMID- 24806740 TI - Sensor saturation compensated smoothing algorithm for inertial sensor based motion tracking. AB - In this paper, a smoothing algorithm for compensating inertial sensor saturation is proposed. The sensor saturation happens when a sensor measures a value that is larger than its dynamic range. This can lead to a considerable accumulated error. To compensate the lost information in saturated sensor data, we propose a smoothing algorithm in which the saturation compensation is formulated as an optimization problem. Based on a standard smoothing algorithm with zero velocity intervals, two saturation estimation methods were proposed. Simulation and experiments prove that the proposed methods are effective in compensating the sensor saturation. PMID- 24806739 TI - Membrane thickness dependence of nanopore formation with a focused helium ion beam. AB - Solid-state nanopores are emerging as a valuable tool for the detection and characterization of individual biomolecules. Central to their success is the realization of fabrication strategies that are both rapid and flexible in their ability to achieve diverse device dimensions. In this paper, we demonstrate the membrane thickness dependence of solid-state nanopore formation with a focused helium ion beam. We vary membrane thickness in situ and show that the rate of pore expansion follows a reproducible trend under all investigated membrane conditions. We show that this trend shifts to lower ion dose for thin membranes in a manner that can be described quantitatively, allowing devices of arbitrary dimension to be realized. Finally, we demonstrate that thin, small-diameter nanopores formed with our approach can be utilized for high signal-to-noise ratio resistive pulse sensing of DNA. PMID- 24806741 TI - Quinap and congeners: atropos PN ligands for asymmetric catalysis. AB - Among the range of P,N-chelating ligands that have been employed in asymmetric catalysis, those relying on atropisomerism for the stability of individual enantiomers form a definable class. These APN (atropos P,N) ligands require a specific type of biaryl, with one component carrying a pendant phosphine unit, most commonly diaryl substituted, and the other bearing an sp(2)-nitrogen adjacent to the biaryl link. When substituents in the biaryl inhibit rotation about the linking bond, stable nonracemizing six-membered ring chelates can be formed. This Perspective relates the background to the initial synthesis in 1993 of Quinap, the original member of the series, and initial observations on its effectiveness in asymmetric catalysis. The current state of play in development of syntheses of this and other members of the APN ligand family is assessed, and their applications in asymmetric catalysis are presented. These include hydroboration and diboration of alkenes, 1,3-dipolar cycloadditions, alkynylation of iminium salts in a three-component (A(3)) condensation, and conjugate additions of Cu acetylides. PMID- 24806742 TI - Europium doping induced symmetry deviation and its impact on the second harmonic generation of doped ZnO nanowires. AB - In this work, we investigated the effects of europium doping on the second harmonic generation (SHG) of ZnO nanowires (NWs). A non-monotonic enhancement in the SHG is observed with the increase of the europium concentration. Maximum SHG is observed from the 1 at.% europium doped ZnO NWs with an enhancement factor of 4.5. To understand the underlying mechanism, the effective second order non linear coefficient (deff) is calculated from the theoretical fitting with consideration of the absorption effect. Microstructural characterization reveals the structural deformation of the ZnO NWs caused by europium doping. We estimated the deviation in the crystal site symmetry around the Eu(3+) ions (defined as the asymmetric factor) from photoluminescence measurement and it is found to be strongly correlated with the calculated deff value. A strong linear dependence between the magnitudes of deff and the asymmetric factor suggests that deviation in the local site symmetry of the ZnO crystal by europium doping could be the most probable origin of the observed large second order non-linearity. PMID- 24806743 TI - Persistence of alpha-cypermethrin residues in milk of lactating donkeys (Equus asinus) using UHPLC-MS/MS. AB - The aim of this study was to measure the persistence of residues of the pyrethroid insecticide alpha-cypermethrin (ACYP) in the milk of lactating donkeys following pour-on treatment. Milk was collected from animals (n = 7) before the treatment and at 12, 24, 36, 48, 60, 72 and 84 h post-treatment. The last sampling was taken 7 days post-treatment (168 h). Milk samples were analysed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The analytical method was validated following requirements of Commission Decision 2002/657/EC. All samples showed levels of ACYP below the maximum residue limit (MRL) of 20 MUg kg(-1) established for bovine milk (Commission Regulation (EU) No. 37/2010). The results demonstrate that there is minimal partitioning of ACYP into milk in lactating donkeys from pour-on treatment. PMID- 24806744 TI - Vorinostat for refractory or relapsing epidermotropic T-cell lymphoma: a retrospective cohort study of 15 patients. AB - Since the approval of vorinostat for the treatment of refractory cutaneous epidermotropic T-cell lymphoma (CTCL) in 2006, very little data about this treatment have been published. The aim of this retrospective study was to assess the efficacy and safety of vorinostat in patients with CTCL treated between 2007 and 2013 in our department. Fifteen patients (median age 64 years) were included: 9 with Sezary syndrome and 6 with mycosis fungoides. They were all in progression and the median number of systemic treatments previously administered was 3 (range 1-7). With vorinostat treatment, the best response was partial remission in 5 patients (33%) and stabilization in 4 patients (27%). Six patients experienced disease progression. The mean time to response and response duration were 70 (range 31-140) and 300 days (range 157-663), respectively. The most frequent adverse events were asthenia, weight loss, nausea and anaemia. Vorinostat could be a therapeutic alternative for CTCL after treatment failure. PMID- 24806745 TI - Boron nanoparticles with high hydrogen loading: mechanism for B-H binding and potential for improved combustibility and specific impulse. AB - Ball milling of boron in an H2 atmosphere was found to result in hydrogen uptake of up to 5% by weight (36 mol %). The nature of the hydrogen binding to boron was probed by a combination of ab initio theory, IR spectroscopy, thermogravimetric analysis, and mass spectral measurements of gases evolved during sample heating. The dominant binding mode is found to be H atoms bound to B atoms in the surface layer of the particles, and the high hydrogen loading results from production of very high surface area, indicating that gaseous H2 is an effective agent promoting size reduction in milling. Hydrogen incorporated in the samples was found to be stable for at least a month under ambient conditions. Desorption is observed beginning at ~60 degrees C and continuing as the temperature is increased, with broad desorption features peaking at ~250 and ~450 degrees C, and ending at ~800 degrees C. Unprotected hydrogenated boron nanoparticles were found to be reactive with O2 producing a hydrated boron oxide surface layer that decomposed readily at 100 degrees C leading to desorption of H2O. Hydrogenated boron nanoparticles were found to promote a higher flame height in the hypergolic ignition of ionic liquids upon contact with nitric acid. PMID- 24806746 TI - Circulating gonadal and adrenal steroids in amyotrophic lateral sclerosis: possible markers of susceptibility and outcome. AB - Although changes of circulating steroids have been reported in patients with sporadic amyotrophic lateral sclerosis (ALS), a full comparison of the adrenal and gonadal steroid profile between control subjects and ALS patients is lacking. Considering that respiratory failure is the most frequent cause of death in ALS, we looked into whether a relationship emerged between circulating steroids and respiratory parameters. Serum levels of adrenal and gonadal steroids were measured in 52 age- and gender-matched subjects (28 ALS and 24 controls) using radioimmunoassay techniques. We also evaluated respiratory parameters in ALS patients, including forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). We found increased levels of testosterone in female ALS patients compared to healthy female subjects. Furthermore, control subjects showed a significant decline of testosterone, dehydroepiandrosterone and its sulfate, and a borderline decline of progesterone with increasing age. Instead, testosterone did not decline with increasing age in ALS patients. We also found that the dehydroepiandrosterone sulfate/cortisol ratio was positively associated with FVC, MIP, and MEP. Moreover, ALS patients showing higher testosterone levels and lower progesterone/free testosterone ratio presented a more rapid worsening of the monthly FVC. In conclusion, first our study revealed a differential steroid profile with age and gender in ALS patients relative to controls. Second, we demonstrated an association between some steroids and their ratios with respiratory function and disease progression. Thus, we hypothesize that the endogenous steroid profile could be a marker of susceptibility and prognosis in ALS patients. PMID- 24806748 TI - CTCF-regulating endocrine function of pancreatic islet cells in transgenic mice. AB - Pancreatic islet endocrine cells play crucial roles in regulation of glucose homeostasis. The differentiation and function of islet cells are regulated by various transcription factors, including Pax6, a member of the homeobox gene family. Pax6 plays a key role in the control of gene expression and islet cell development in the pancreas. Recent studies from our lab demonstrate for the first time that Pax6 transcription is regulated by CCCTC binding factor (CTCF), a nuclear protein and transcription regulator. CTCF downregulates Pax6 transcription through interaction with a repressor element located in Pax6 gene P0 promoter region. To further investigate the effect of CTCF on regulating Pax6 function in pancreatic islet cells, we measured blood glucose, insulin, and glucagons levels in newly established transgenic mice overexpressing CTCF. When compared to wild type mice, CTCF transgenic mice demonstrate an increase in insulin level and decrease in glucagon level resulting in lower blood glucose levels (hypoglycemia). In insulin tolerance test, hypoglycemia occurs quickly in CTCF transgenic mice and takes a recovery time. In the mean time, glucagon levels in CTCF mutant mice were significantly lower compared to its wild type counterpart. Our results indicate that CTCF transgenic mice are disordered in glucose homeostasis and suggest that CTCF is involved in regulating endocrine function of pancreatic islet cells by suppression of Pax6 expression. PMID- 24806747 TI - Nicotinic acid effects on insulin sensitivity and hepatic lipid metabolism: an in vivo to in vitro study. AB - Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan((r)) on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan((r)) (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan((r)) treatment with a significant-28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri glyceride production rate was markedly reduced after Niaspan((r)) (-68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7+/-0.4 vs. 1.0+/-0.5 mg/kg . min, p<0.05) and decrease in fasting hepatic insulin sensitivity index (4.8+/-1.8 vs. 3.2+/-1.6, p<0.05) in the Niaspan((r)) condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCepsilon. This effect was associated with an increase in diacylglycerol and a decrease in tri-glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan((r)) treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes. PMID- 24806749 TI - Extracellular redox state regulates catecholamine biosynthesis in PC12 cells with insulin resistance. AB - Extracellular cysteine (Cys)/cystine (CySS) redox potential (Eh) plays a crucial role in maintaining redox homeostasis and an alteration of redox state occurs in various physiological conditions, including diabetes, cancer, and aging. This study was designed to determine whether a variation in extracellular redox state would alter the function of insulin-resistant PC12 cells. Various redox states were established by providing different extracellular Cys/CySS Eh to insulin resistant PC12 cells. We intensively investigated the relationship between redox state and catecholamine biosynthesis in PC12 cells, and evaluated the changes in cellular reactive oxygen species (ROS), catecholamine (CA) synthesis, tyrosine hydroxylase (TH) expressions, and the activity of rate-limiting enzyme in CA synthesis by using DCF-fluorescence, HPLC, and the real-time PCR, respectively. We also determined the protein levels of NF-E2-related factor 2 (Nrf2), a redox sensitive transcription factor, using an ELISA assay. We found that the oxidized Cys/CySS Eh (0 mV) pretreatment decreased CA, TH, and Nrf2 levels, but induced ROS overproduction. Insulin induced a significant increase in CA synthesis and ROS production, blocked by more reducing redox conditions. The paradox of CA and TH alterations between insulin and 0 mV groups may be attributed to degree of redox imbalance as evidenced by different ROS levels in 2 groups, which is further confirmed by CA alterations in different concentrations of hydrogen peroxide. Additionally, dithiole-3-thione (D3T, an inducer of Nrf2) corrected 0 mV-induced TH inhibition. In conclusion, CA biosynthesis in insulin-resistant PC12 cells could be influenced by extracellular Cys/CySS redox effects on cellular redox sensitive transcription factors. PMID- 24806751 TI - Spousal overprotection is indirectly associated with poorer dietary adherence for patients with type 2 diabetes via diabetes distress when active engagement is low. AB - OBJECTIVES: The current study sought to explore the indirect association of spousal overprotection on patient dietary adherence through the mechanism of diabetes distress and whether the link between overprotection and diabetes distress was moderated by spouse active engagement. METHOD: Participants were 117 married couples in which one member had been diagnosed with type 2 diabetes and were recruited from a patient registry at a Midwestern (USA) medical centre. Data were gathered from spouses and patients through a self-report survey instrument. The research questions were answered with structural equation modelling using the latent moderated structural equations (LMS) approach and dyadic data analytic procedures. RESULTS: Overprotection was associated with reduced dietary adherence indirectly via increased diabetes distress only at low levels of active engagement. The proposed model also proved superior when compared to two plausible alternatives. CONCLUSIONS: These findings highlight the importance of understanding the nuanced associations among the different ways spouses cope with illness to achieve better diabetes outcomes and the mechanisms responsible for linking coping and dietary adherence. Statement of contribution What is already known on this subject? Spousal coping behaviour can influence dietary adherence among patients diagnosed with type 2 diabetes, positively and negatively. Spouses simultaneously engage in different ways of coping with partner illness, but little is known about the interactive nature of coping styles or possible mechanisms that might link coping with illness outcomes. What does this study add? Spousal overprotection is only associated with reduced patient dietary adherence when spouses are also engaging in low levels of active engagement. Diabetes distress is an important mechanism linking spousal coping with patient dietary adherence. PMID- 24806752 TI - Preparing for the uncertain yet inevitable: off-label combinations of antiviral agents in hepatitis C virus. PMID- 24806753 TI - FAM3A activates PI3K p110alpha/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis. AB - FAM3A belongs to a novel cytokine-like gene family, and its physiological role remains largely unknown. In our study, we found a marked reduction of FAM3A expression in the livers of db/db and high-fat diet (HFD)-induced diabetic mice. Hepatic overexpression of FAM3A markedly attenuated hyperglycemia, insulin resistance, and fatty liver with increased Akt (pAkt) signaling and repressed gluconeogenesis and lipogenesis in the livers of those mice. In contrast, small interfering RNA (siRNA)-mediated knockdown of hepatic FAM3A resulted in hyperglycemia with reduced pAkt levels and increased gluconeogenesis and lipogenesis in the livers of C57BL/6 mice. In vitro study revealed that FAM3A was mainly localized in the mitochondria, where it increases adenosine triphosphate (ATP) production and secretion in cultured hepatocytes. FAM3A activated Akt through the p110alpha catalytic subunit of PI3K in an insulin-independent manner. Blockade of P2 ATP receptors or downstream phospholipase C (PLC) and IP3R and removal of medium calcium all significantly reduced FAM3A-induced increase in cytosolic free Ca(2+) levels and attenuated FAM3A-mediated PI3K/Akt activation. Moreover, FAM3A-induced Akt activation was completely abolished by the inhibition of calmodulin (CaM). CONCLUSION: FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PI3K-Akt signaling pathway by way of a Ca(2+) /CaM-dependent mechanism. Up-regulating hepatic FAM3A expression may represent an attractive means for the treatment of insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). PMID- 24806754 TI - Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. AB - ABCB4 flops phosphatidylcholine into the bile canaliculus to protect the biliary tree from the detergent activity of bile salts. Homozygous-null ABCB4 mutations cause the childhood liver disease, progressive familial intrahepatic cholestasis, but cause and effect is less clear, with many missense mutations linked to less severe cholestatic diseases. ABCB4(S320F), in particular, is described in 13 patients, including in heterozygosity with ABCB4(A286V), ABCB4(A953D), and null mutants, whose symptoms cover the spectrum of cholestatic disease. We sought to define the impact of these mutations on the floppase, explain the link with multiple conditions at the molecular level, and investigate the potential for reversal. ABCB4(S320F), ABCB4(A286V), and ABCB4(A953D) expression was engineered in naive cultured cells. Floppase expression, localization, and activity were measured by western blot, confocal microscopy, and lipid transport assays, respectively. ABCB4(S320F) was fully active for floppase activity but expression at the plasma membrane was reduced to 50%. ABCB4(A286V) expressed and trafficked efficiently but could not flop lipid, and ABCB4(A953D) expressed poorly and was impaired in floppase activity. Proteasome inhibition stabilized nascent ABCB4(S320F) and ABCB4(A953D) but did not improve plasma membrane localization. Cyclosporin-A improved plasma membrane localization of both ABCB4(S320F) and ABCB4(A953D), but inhibited floppase activity. CONCLUSION: The level of ABCB4 functionality correlates with, and is the primary determinant of, cholestatic disease severity in these patients. ABCB4(S320F) homozygosity, with half the normal level of ABCB4, is the tipping point between more benign and potentially fatal cholestasis and makes these patients more acutely sensitive to environmental effects. Cyclosporin-A increased expression of ABCB4(S320F) and ABCB4(A953D), suggesting that chemical chaperones could be exploited for therapeutic benefit to usher in a new era of personalized medicine for patients with ABCB4-dependent cholestatic disease. PMID- 24806755 TI - Localization and expression patterns of prolactin-like protein J in mouse testis. AB - Prolactin (PRL)-like protein J (PLP-J) is a member of the prolactin family, mainly expressed in the placental decidua tissues of females, and is involved in gestation. To the best of our knowledge, it has not previously been shown to be expressed in males. Preliminary experiments of the present study indicated that PLP-J is expressed in the testis of male mice and is implicated in the regulation of testicular function. To definitively address whether PLP-J is expressed in the mouse testis, the expression pattern and cellular localization of PLP-J in mouse testes during postnatal development were characterized in the current study using molecular and immunological methods. Reverse transcription (RT)-polymerase chain reaction (PCR) was performed to amplify gene fragments from mouse testis specimens, which yielded sequences matching those of the PLP-J gene in Genbank. Subsequently, in situ hybridization showed that PLP-J was localized in interstitial tissue of the mouse testis. Immunofluorescence results indicated that PLP-J and 3beta-hydroxysteroid dehydrogenase 1 were colocalized in testis Leydig cells, confirming PLP-J expression in Leydig cells. In addition, PLP-J gene expression levels were examined at different stages of postnatal mouse development in male testis tissues using quantitative RT-PCR and western blotting. The results revealed that PLP-J expression levels were lowest in 18-day old mice and highest in adults aged 4 months. Levels observed in 16-month-old individuals were lower than those observed in the 4-month-old mice, but remained significantly higher than the levels observed in 18-day-old mice. Furthermore, the roles of PLP-J in the murine testis TM3 Leydig cell line were studied. The results demonstrated that the upregulation of PLP-J expression in TM3 Leydig cells did not affect testosterone production or the cell cycle. In conclusion, this study demonstrated that PLP-J, a known member of the PRL family that was previously considered to be expressed solely in females, is also expressed in the testis of males with an age-dependent expression profile. Nevertheless, the physiological role of PLP-J in males remains unclear. PMID- 24806756 TI - Theoretical investigation of the competitive mechanism between dissociation and ionization of H2+ in intense field. AB - The competitive mechanism between dissociation and ionization of hydrogen molecular ion in intense field has been theoretically investigated by using an accurate non-Born-Oppenheimer method. The relative yield of fragments indicates that the dissociation and ionization channels are competitive with the increasing laser intensity from 5.0 * 10(13) to 2.0 * 10(14) W/cm(2). In the case of intensity lower than 1.0 * 10(14) W/cm(2), the dissociation channel is dominant, with a minor contribution from ionization. The mechanism of dissociation includes the contributions from the bond softening, bond hardening, below-threshold dissociation, and above-threshold dissociation, which are strongly dependent on the laser intensity and initial vibrational state. Furthermore, the ionization dominates over the dissociation channel at the highest intensity of 2.0 * 10(14) W/cm(2). The reasonable origin of ionization is ascribed as the above-threshold Coulomb explosion, which has been demonstrated by the space-time dependent ionization rate. Moreover, the competition mechanism between dissociation and ionization channels are displayed on the total kinetic energy resolved (KER) spectra, which could be tested at current experimental conditions. PMID- 24806757 TI - Bacterial twitching motility is coordinated by a two-dimensional tug-of-war with directional memory. AB - Type IV pili are ubiquitous bacterial motors that power surface motility. In peritrichously piliated species, it is unclear how multiple pili are coordinated to generate movement with directional persistence. Here we use a combined theoretical and experimental approach to test the hypothesis that multiple pili of Neisseria gonorrhoeae are coordinated through a tug-of-war. Based on force dependent unbinding rates and pilus retraction speeds measured at the level of single pili, we build a tug-of-war model. Whereas the one-dimensional model robustly predicts persistent movement, the two-dimensional model requires a mechanism of directional memory provided by re-elongation of fully retracted pili and pilus bundling. Experimentally, we confirm memory in the form of bursts of pilus retractions. Bursts are seen even with bundling suppressed, indicating re elongation from stable core complexes as the key mechanism of directional memory. Directional memory increases the surface range explored by motile bacteria and likely facilitates surface colonization. PMID- 24806758 TI - Global stability of complex-valued recurrent neural networks with time-delays. AB - Since the last decade, several complex-valued neural networks have been developed and applied in various research areas. As an extension of real-valued recurrent neural networks, complex-valued recurrent neural networks use complex-valued states, connection weights, or activation functions with much more complicated properties than real-valued ones. This paper presents several sufficient conditions derived to ascertain the existence of unique equilibrium, global asymptotic stability, and global exponential stability of delayed complex-valued recurrent neural networks with two classes of complex-valued activation functions. Simulation results of three numerical examples are also delineated to substantiate the effectiveness of the theoretical results. PMID- 24806759 TI - Robust exponential stability of uncertain delayed neural networks with stochastic perturbation and impulse effects. AB - This paper focuses on the hybrid effects of parameter uncertainty, stochastic perturbation, and impulses on global stability of delayed neural networks. By using the Ito formula, Lyapunov function, and Halanay inequality, we established several mean-square stability criteria from which we can estimate the feasible bounds of impulses, provided that parameter uncertainty and stochastic perturbations are well-constrained. Moreover, the present method can also be applied to general differential systems with stochastic perturbation and impulses. PMID- 24806760 TI - Sparse tensor discriminant color space for face verification. AB - As one of the fundamental features, color provides useful information and plays an important role for face recognition. Generally, the choice of a color space is different for different visual tasks. How can a color space be sought for the specific face recognition problem? To address this problem, we propose a sparse tensor discriminant color space (STDCS) model that represents a color image as a third-order tensor in this paper. The model cannot only keep the underlying spatial structure of color images but also enhance robustness and give intuitionistic or semantic interpretation. STDCS transforms the eigenvalue problem to a series of regression problems. Then one spare color space transformation matrix and two sparse discriminant projection matrices are obtained by applying lasso or elastic net on the regression problems. The experiments on three color face databases, AR, Georgia Tech, and Labeled Faces in the Wild face databases, show that both the performance and the robustness of the proposed method outperform those of the state-of-the-art TDCS model. PMID- 24806761 TI - Programming time-multiplexed reconfigurable hardware using a scalable neuromorphic compiler. AB - Scalability and connectivity are two key challenges in designing neuromorphic hardware that can match biological levels. In this paper, we describe a neuromorphic system architecture design that addresses an approach to meet these challenges using traditional complementary metal-oxide-semiconductor (CMOS) hardware. A key requirement in realizing such neural architectures in hardware is the ability to automatically configure the hardware to emulate any neural architecture or model. The focus for this paper is to describe the details of such a programmable front-end. This programmable front-end is composed of a neuromorphic compiler and a digital memory, and is designed based on the concept of synaptic time-multiplexing (STM). The neuromorphic compiler automatically translates any given neural architecture to hardware switch states and these states are stored in digital memory to enable desired neural architectures. STM enables our proposed architecture to address scalability and connectivity using traditional CMOS hardware. We describe the details of the proposed design and the programmable front-end, and provide examples to illustrate its capabilities. We also provide perspectives for future extensions and potential applications. PMID- 24806762 TI - Laplacian embedded regression for scalable manifold regularization. AB - Semi-supervised learning (SSL), as a powerful tool to learn from a limited number of labeled data and a large number of unlabeled data, has been attracting increasing attention in the machine learning community. In particular, the manifold regularization framework has laid solid theoretical foundations for a large family of SSL algorithms, such as Laplacian support vector machine (LapSVM) and Laplacian regularized least squares (LapRLS). However, most of these algorithms are limited to small scale problems due to the high computational cost of the matrix inversion operation involved in the optimization problem. In this paper, we propose a novel framework called Laplacian embedded regression by introducing an intermediate decision variable into the manifold regularization framework. By using ?-insensitive loss, we obtain the Laplacian embedded support vector regression (LapESVR) algorithm, which inherits the sparse solution from SVR. Also, we derive Laplacian embedded RLS (LapERLS) corresponding to RLS under the proposed framework. Both LapESVR and LapERLS possess a simpler form of a transformed kernel, which is the summation of the original kernel and a graph kernel that captures the manifold structure. The benefits of the transformed kernel are two-fold: (1) we can deal with the original kernel matrix and the graph Laplacian matrix in the graph kernel separately and (2) if the graph Laplacian matrix is sparse, we only need to perform the inverse operation for a sparse matrix, which is much more efficient when compared with that for a dense one. Inspired by kernel principal component analysis, we further propose to project the introduced decision variable into a subspace spanned by a few eigenvectors of the graph Laplacian matrix in order to better reflect the data manifold, as well as accelerate the calculation of the graph kernel, allowing our methods to efficiently and effectively cope with large scale SSL problems. Extensive experiments on both toy and real world data sets show the effectiveness and scalability of the proposed framework. PMID- 24806763 TI - Neural assembly computing. AB - Spiking neurons can realize several computational operations when firing cooperatively. This is a prevalent notion, although the mechanisms are not yet understood. A way by which neural assemblies compute is proposed in this paper. It is shown how neural coalitions represent things (and world states), memorize them, and control their hierarchical relations in order to perform algorithms. It is described how neural groups perform statistic logic functions as they form assemblies. Neural coalitions can reverberate, becoming bistable loops. Such bistable neural assemblies become short- or long-term memories that represent the event that triggers them. In addition, assemblies can branch and dismantle other neural groups generating new events that trigger other coalitions. Hence, such capabilities and the interaction among assemblies allow neural networks to create and control hierarchical cascades of causal activities, giving rise to parallel algorithms. Computing and algorithms are used here as in a nonstandard computation approach. In this sense, neural assembly computing (NAC) can be seen as a new class of spiking neural network machines. NAC can explain the following points: 1) how neuron groups represent things and states; 2) how they retain binary states in memories that do not require any plasticity mechanism; and 3) how branching, disbanding, and interaction among assemblies may result in algorithms and behavioral responses. Simulations were carried out and the results are in agreement with the hypothesis presented. A MATLAB code is available as a supplementary material. PMID- 24806764 TI - Extracting representative information to enhance flexible data queries. AB - Extracting representative information is of great interest in data queries and web applications nowadays, where approximate match between attribute values/records is an important issue in the extraction process. This paper proposes an approach to extracting representative tuples from data classes under an extended possibility-based data model, and to introducing a measure (namely, relation compactness) based upon information entropy to reflect the degree that a relation is compact in light of information redundancy. Theoretical analysis and data experiments show that the approach has desirable properties that: 1) the set of representative tuples has high degrees of compactness (less redundancy) and coverage (rich content); 2) it provides a way to obtain data query outcomes of different sizes in a flexible manner according to user preference; and 3) the approach is also meaningful and applicable to web search applications. PMID- 24806765 TI - Robust synchronization for 2-D discrete-time coupled dynamical networks. AB - In this paper, a new synchronization problem is addressed for an array of 2-D coupled dynamical networks. The class of systems under investigation is described by the 2-D nonlinear state space model which is oriented from the well-known Fornasini-Marchesini second model. For such a new 2-D complex network model, both the network dynamics and the couplings evolve in two independent directions. A new synchronization concept is put forward to account for the phenomenon that the propagations of all 2-D dynamical networks are synchronized in two directions with influence from the coupling strength. The purpose of the problem addressed is to first derive sufficient conditions ensuring the global synchronization and then extend the obtained results to more general cases where the system matrices contain either the norm-bounded or the polytopic parameter uncertainties. An energy-like quadratic function is developed, together with the intensive use of the Kronecker product, to establish the easy-to-verify conditions under which the addressed 2-D complex network model achieves global synchronization. Finally, a numerical example is given to illustrate the theoretical results and the effectiveness of the proposed synchronization scheme. PMID- 24806766 TI - Network-based high level data classification. AB - Traditional supervised data classification considers only physical features (e.g., distance or similarity) of the input data. Here, this type of learning is called low level classification. On the other hand, the human (animal) brain performs both low and high orders of learning and it has facility in identifying patterns according to the semantic meaning of the input data. Data classification that considers not only physical attributes but also the pattern formation is, here, referred to as high level classification. In this paper, we propose a hybrid classification technique that combines both types of learning. The low level term can be implemented by any classification technique, while the high level term is realized by the extraction of features of the underlying network constructed from the input data. Thus, the former classifies the test instances by their physical features or class topologies, while the latter measures the compliance of the test instances to the pattern formation of the data. Our study shows that the proposed technique not only can realize classification according to the pattern formation, but also is able to improve the performance of traditional classification techniques. Furthermore, as the class configuration's complexity increases, such as the mixture among different classes, a larger portion of the high level term is required to get correct classification. This feature confirms that the high level classification has a special importance in complex situations of classification. Finally, we show how the proposed technique can be employed in a real-world application, where it is capable of identifying variations and distortions of handwritten digit images. As a result, it supplies an improvement in the overall pattern recognition rate. PMID- 24806767 TI - Neural network structure for spatio-temporal long-term memory. AB - This paper proposes a neural network structure for spatio-temporal learning and recognition inspired by the long-term memory (LTM) model of the human cortex. Our structure is able to process real-valued and multidimensional sequences. This capability is attained by addressing three critical problems in sequential learning, namely the error tolerance, the significance of sequence elements and memory forgetting. We demonstrate the potential of the framework with a series of synthetic simulations and the Australian sign language (ASL) dataset. Results show that our LTM model is robust to different types of distortions. Second, our LTM model outperforms other sequential processing models in a classification task for the ASL dataset. PMID- 24806768 TI - Feedback optimal control of distributed parameter systems by using finite dimensional approximation schemes. AB - Optimal control for systems described by partial differential equations is investigated by proposing a methodology to design feedback controllers in approximate form. The approximation stems from constraining the control law to take on a fixed structure, where a finite number of free parameters can be suitably chosen. The original infinite-dimensional optimization problem is then reduced to a mathematical programming one of finite dimension that consists in optimizing the parameters. The solution of such a problem is performed by using sequential quadratic programming. Linear combinations of fixed and parameterized basis functions are used as the structure for the control law, thus giving rise to two different finite-dimensional approximation schemes. The proposed paradigm is general since it allows one to treat problems with distributed and boundary controls within the same approximation framework. It can be applied to systems described by either linear or nonlinear elliptic, parabolic, and hyperbolic equations in arbitrary multidimensional domains. Simulation results obtained in two case studies show the potentials of the proposed approach as compared with dynamic programming. PMID- 24806769 TI - Generalized SMO algorithm for SVM-based multitask learning. AB - Exploiting additional information to improve traditional inductive learning is an active research area in machine learning. In many supervised-learning applications, training data can be naturally separated into several groups, and incorporating this group information into learning may improve generalization. Recently, Vapnik proposed a general approach to formalizing such problems, known as "learning with structured data" and its support vector machine (SVM) based optimization formulation called SVM+. Liang and Cherkassky showed the connection between SVM+ and multitask learning (MTL) approaches in machine learning, and proposed an SVM-based formulation for MTL called SVM+MTL for classification. Training the SVM+MTL classifier requires the solution of a large quadratic programming optimization problem which scales as O(n(3)) with sample size n. So there is a need to develop computationally efficient algorithms for implementing SVM+MTL. This brief generalizes Platt's sequential minimal optimization (SMO) algorithm to the SVM+MTL setting. Empirical results show that, for typical SVM+MTL problems, the proposed generalized SMO achieves over 100 times speed-up, in comparison with general-purpose optimization routines. PMID- 24806770 TI - Complexity-reduced scheme for feature extraction with linear discriminant analysis. AB - Owing to the singularity of the within-class scatter, linear discriminant analysis (LDA) becomes ill-posed for small sample size (SSS) problems. Null-space based LDA (NLDA), which is an extension of LDA, provides good discriminant performances for SSS problems. Yet, as the original scheme for the feature extractor (FE) of NLDA suffers from a complexity burden, a few modified schemes have since been proposed for complexity reduction. In this brief, by transforming the problem of finding the FE of NLDA into a linear equation problem, a novel scheme is derived, offering a further reduction of the complexity. PMID- 24806772 TI - Employment-related concerns of HIV-positive people in the Netherlands: input for a multidisciplinary guideline. AB - PURPOSE: Finding and keeping employment is difficult for people with HIV. To improve supportive care for people with HIV and employment-related problems, a multidisciplinary guideline was developed in the Netherlands in 2010/2011. To identify the employment-related concerns of people with HIV and to formulate the key questions for the guideline, we conducted a qualitative study. The results of this study are described in this article. METHODS: This study was performed in three HIV-treatment centers in the Netherlands. In total 18 participants participated in three focus-group interviews and nine participants were interviewed individually. The data were transcribed ad verbatim and were analyzed according to the principle of constant comparison. RESULTS: Our findings indicate that people with HIV in the Netherlands face many work-related concerns. The themes which emerged from this study were disclosure, stigma and discrimination, knowledge about HIV, physical and psychological factors, working conditions, absenteeism, reintegration, and dismissal and counselling. CONCLUSIONS: This study provides insight into employment-related concerns for people with HIV living in a Western country. It formed the basis for the key questions which were addressed in a multidisciplinary, evidence-based guideline "HIV and work". Finally, it gives leads for further scientific research and opportunities for improving the vocational guidance of people with HIV. PMID- 24806773 TI - Soft as a whisper. PMID- 24806774 TI - Voreen: a rapid-prototyping environment for ray-casting-based volume visualizations. PMID- 24806775 TI - In situ visualization at extreme scale: challenges and opportunities. PMID- 24806776 TI - Building on realism and magic for designing 3D interaction techniques. AB - Imagination-based interaction can complement reality-based interaction in the design of 3D user interfaces. This hybrid approach could lead to interface design guidelines that promote higher-level consistency, and thus usability, for a large range of diverse interfaces. PMID- 24806777 TI - Efficient 3D pointing selection in cluttered virtual environments. PMID- 24806778 TI - Insights from dividing 3D goal-directed movements into meaningful phases. AB - A new method for analyzing 3D goal-directed movements provides more insights than existing approaches by dividing them into meaningful phases. An experiment applying a simple 3D task, resembling a standardized 2D multidirectional pointing task, yielded insights that can help researchers better identify input devices' and interaction techniques' strengths and weaknesses. PMID- 24806779 TI - Spatial input for temporal navigation in scientific visualizations. AB - Scientific-visualization tools can make time-varying simulations easier to understand. The growing efficiency of today's high-performance computers enables simulation of physical phenomena with a high temporal resolution. Consequently, visualization systems require efficient navigation in the temporal dimension. This 3D user interface employs direct-manipulation metaphors for temporal navigation in scientific visualizations. By interacting with objects using their 3D trajectory, users can navigate in time by specifying spatial inputs. PMID- 24806780 TI - Navigation tools for viewing augmented CAD models. PMID- 24806781 TI - Texture synthesis for mobile data communications. AB - This paper presents an approach to image coding that first paints a regularly arranged dotted pattern, using colors picked from a texture sample with features corresponding to the embedded data. It then camouflages the dotted pattern using the same texture sample while preserving quality comparable to that of existing synthesis techniques. PMID- 24806782 TI - Unique character instances for crowds. AB - Real-time crowd simulations are realistic only if each human instance looks unique. A proposed solution varies the shape of human instances by attaching accessories. It also modifies the instances' appearance with a generic technique based on segmentation maps that can generate detailed color variety and patterns. PMID- 24806783 TI - Environ: integrating VR and CAD in engineering projects. PMID- 24806784 TI - Emerging biomarkers for acute heart conditions. AB - PURPOSE OF REVIEW: Acute cardiac conditions such as acute myocardial infarction and heart failure are associated with significant morbidity and mortality. Rapid diagnosis allows risk stratification and initiation of treatment in a timely manner. Numerous novel biomarkers have been identified to predict outcomes. These may assist in tailoring of appropriate therapy to high-risk patients. RECENT FINDINGS: This study reviews several novel biomarkers - galectin-3, ST2 and copeptin. The scope of this review is to identify and underline the clinical aspects of these emerging biomarkers. SUMMARY: Galectin-3 is an active biomarker found in inflammatory and fibrotic processes, and is a marker of mortality. ST2 is released by stressed cardiac myocytes and also predicts mortality in heart failure and myocardial infarction. Copeptin is a stable arginine vasopressin precursor associated with increased risk of heart failure. It may also be useful to exclude acute myocardial infarction. PMID- 24806785 TI - Altitude and cold weather: are they vascular risks? AB - PURPOSE OF REVIEW: The relationship of altitude and cold to cardiovascular risk is complex. Cold is hard to separate from altitude. This review highlights the latest information on cardiovascular disease associated with high altitude and cold; both represent unique clinical situations. RECENT FINDINGS: Evolution and genetics are relevant to high altitude, with much new information available. Specific physiology explains some congenital heart disease at altitude. New reports of hematological changes associated with altitude and cold help clarify thrombosis, which is relevant to reports of very late in-stent thrombosis at altitude. Multiple cardiovascular risk factors are affected by altitude and cold, and an increased incidence of myocardial infarction occurs. There is new research on acute mountain sickness associated with inflammation with relevance for clinical study of pulmonary edema. Socioeconomics plays a part in altitude and cold effects on cardiovascular disease. In addition to acute disease, high altitude involves chronic mountain sickness with new knowledge of associated cardiovascular endothelial abnormalities. SUMMARY: High altitude and cold involve acute disease, chronic disease, and public health issues. Continued research is essential to enable the best clinical management in this era of rapid worldwide travel. PMID- 24806786 TI - Age-related differences in rates of torque development and rise in EMG are eliminated by normalization. AB - The purpose of this study was to compare the voluntary and evoked, absolute and normalized leg extension rates of torque development (RTD) and rates of rise in electromyography (RER) during commonly reported time intervals in young and old men. Fourteen young men (21.9+/-3.2years) and 16 older men (72.3+/-7.3years) completed three evoked and three voluntary isometric leg extension muscle actions to quantify absolute voluntary (peak, 30, 50, 100, and 200ms) and evoked (peak, 30, 50, and 100ms) RTD and RER. All RTD values were normalized (nRTD) to peak torque, while RER values were normalized (nRER) to peak-to-peak M-wave amplitude (MPP). Absolute voluntary RTDs and RERs were 58-122% and 70-76% greater (p<=0.05) for the young men, respectively. However, there were no age-related differences (p>0.05) for voluntary nRTDs, absolute and normalized evoked RTDs, or voluntary nRER. MPP and evoked RER and nRER were greater (p<=0.05) for the young men. In addition, voluntary RTD was more reliable in the young than the older men. Normalizing RTD to peak torque and RER to M-wave amplitude eliminated the age related differences and suggested that the age-related declines in RTD and RER were a result of reduced muscle strength and M-wave amplitude, respectively. Therefore, our findings questioned the value of RTD and RER measurements in the various time intervals for explaining sarcopenia and suggested that maximal strength and M-wave amplitude may be sufficient. PMID- 24806787 TI - Interference in immunoassays to support therapeutic antibody development in preclinical and clinical studies. AB - During preclinical and clinical studies, immunoassays are used to measure the concentration of the therapeutic antibody, anti-drug antibodies and soluble protein biomarkers. The reliability of these assays is crucial since the results are routinely used for safety assessment and dose selection. Furthermore, soluble protein biomarkers can provide information about target engagement, proof of mechanism, proof of principle and prediction of response. Study samples mostly consist of complex matrices that can exhibit considerable interference, resulting in inaccurate measurements. This perspective discusses the source of interference and strategies to mitigate or eliminate interference in immunoassays used during preclinical and clinical drug development of drugs with a focus on the development of therapeutic antibodies. PMID- 24806788 TI - The curved shape of Caulobacter crescentus enhances surface colonization in flow. AB - Each bacterial species has a characteristic shape, but the benefits of specific morphologies remain largely unknown. To understand potential functions for cell shape, we focused on the curved bacterium Caulobacter crescentus. Paradoxically, C. crescentus curvature is robustly maintained in the wild but straight mutants have no known disadvantage in standard laboratory conditions. Here we demonstrate that cell curvature enhances C. crescentus surface colonization in flow. Imaging the formation of microcolonies at high spatial and temporal resolution indicates that flow causes curved cells to orient such that they arc over the surface, thereby decreasing the distance between the surface and polar adhesive pili, and orienting pili to face the surface. C. crescentus thus repurposes pilus retraction, typically used for surface motility, for surface attachment. The benefit provided by curvature is eliminated at high flow intensity, raising the possibility that diversity in curvature adapts related species for life in different flow environments. PMID- 24806789 TI - A miss is as good as a mile? Processing of near and full outcomes in a gambling paradigm. AB - Studies investigating the feedback-related negativity (FRN) and the P300 following near misses, full misses, and wins have yielded inconsistent results. Furthermore, the P300 results were likely confounded by an oddball effect due to the probabilities of the different outcomes. We introduced a fourth outcome (narrow win), which allows for balanced outcome probabilities and thus rules out potential oddball effects. We measured the FRN and P300 as well as subjective ratings while participants were gambling on a wheel of fortune. The FRN was larger following misses compared to wins and larger following near compared to full outcomes. For the P300, we observed a larger positivity following wins compared to misses and full compared to near outcomes. These findings further corroborate that near and full outcomes are processed as distinct events even though they result in the same monetary outcomes. PMID- 24806790 TI - Editorial: treatment of cancer in the elderly. PMID- 24806791 TI - Acquired bilateral telangiectatic macules: a distinct clinical entity. AB - IMPORTANCE: We evaluated 13 distinct patients with multiple telangiectatic pigmented macules confined mostly to the upper arms to determine if the clinical and histopathological features of these cases might represent a specific clinical entity. OBSERVATIONS: We retrospectively investigated the clinical, histopathologic, and immunohistochemical features of 13 patients with multiple telangiectatic pigmented macules on the upper arms who presented between January 2003 and December 2012. Epidermal pigmentation, melanogenic activity, melanocyte number, vascularity, epidermal thickness, and perivascular mast cell number of the specimens were evaluated. Clinically, the condition favored middle-aged men. On histopathologic examination, the lesional skin showed capillary proliferation and telangiectasia in the upper dermis. Histochemical and immunohistochemical analysis revealed basal hyperpigmentation and increased melanogenic activity in the lesional skin (P < .05). No significant difference in epidermal thickness or mast cell number was observed between the normal perilesional skin and the lesional skin. CONCLUSIONS AND RELEVANCE: The clinical and histopathologic features of these lesions were relatively consistent in all patients. In addition, the features are quite distinct from other diseases. Based on clinical and histologic features, we suggest the name acquired bilateral telangiectatic macules for this new entity. PMID- 24806792 TI - Diffusion-assisted photoexcitation transfer in coupled semiconducting carbon nanotube thin films. AB - We utilize femtosecond transient absorption spectroscopy to study dynamics of photoexcitation migration in films of semiconducting single-wall carbon nanotubes. Films of nanotubes in close contact enable energy migration such as needed in photovoltaic and electroluminescent devices. Two types of films composed of nanotube fibers are utilized in this study: densely packed and very porous. By comparing exciton kinetics in these films, we characterize excitation transfer between carbon nanotubes inside fibers versus between fibers. We find that intrafiber transfer takes place in both types of films, whereas interfiber transfer is greatly suppressed in the porous one. Using films with different nanotube composition, we are able to test several models of exciton transfer. The data are inconsistent with models that rely on through-space interfiber energy transfer. A model that fits the experimental results postulates that interfiber transfer occurs only at intersections between fibers, and the excitons reach the intersections by diffusing along the long-axis of the tubes. We find that time constants for the inter- and intrafiber transfers are 0.2-0.4 and 7 ps, respectively. In total, hopping between fibers accounts for about 60% of all exciton downhill transfer prior to 4 ps in the dense film. The results are discussed with regards to transmission electron micrographs of the films. This study provides a rigorous analysis of the photophysics in this new class of promising materials for photovoltaics and other technologies. PMID- 24806793 TI - Protein kinase CK2 contributes to diminished small conductance Ca2+-activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension. AB - Small conductance calcium-activated K(+) (SK) channels regulate neuronal excitability. However, little is known about changes in SK channel activity of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) in essential hypertension. SK channels, calmodulin, and casein kinase II (CK2) form a molecular complex. Because CK2 is up-regulated in the PVN in spontaneously hypertensive rats (SHRs), we hypothesized that CK2 increases calmodulin phosphorylation and contributes to diminished SK channel activity in PVN pre sympathetic neurons in SHRs. Perforated whole-cell recordings were performed on retrogradely labeled spinally projecting PVN neurons in Wistar-Kyoto (WKY) rats and SHRs. Blocking SK channels with apamin significantly increased the firing rate of PVN neurons in WKY rats but not in SHRs. CK2 inhibition restored the stimulatory effect of apamin on the firing activity of PVN neurons in SHRs. Furthermore, apamin-sensitive SK currents and depolarization-induced medium after hyperpolarization potentials of PVN neurons were significantly larger in WKY rats than in SHRs. CK2 inhibition significantly increased the SK channel current and medium after-depolarization potential of PVN neurons in SHRs. In addition, CK2 mediated calmodulin phosphorylation level in the PVN was significantly higher in SHRs than in WKY rats. Although SK3 was detected in the PVN, its expression level did not differ significantly between SHRs and WKY rats. Our findings suggest that CK2-mediated calmodulin phosphorylation is increased and contributes to diminished SK channel function of PVN pre-sympathetic neurons in SHRs. This information advances our understanding of the mechanisms underlying hyperactivity of PVN pre-sympathetic neurons and increased sympathetic vasomotor tone in hypertension. Small conductance calcium-activated K(+) (SK) channels, calmodulin, and protein kinase CK2 form a molecular complex and regulate neuronal excitability. Our study suggests that augmented CK2 activity in hypertension can increase calmodulin (CaM) phosphorylation, which leads to diminished SK channel function in pre-sympathetic neurons. Diminished SK channel activity plays a role in hyperactivity of pre-sympathetic neurons in the hypothalamus in hypertension. PMID- 24806794 TI - The role of tissue factor isoforms in cancer biology. AB - Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally occurring protein isoforms, membrane-bound "full-length" (fl)TF and soluble alternatively spliced (as)TF. The TF isoform expression is differentially modulated on post-transcriptional level via regulatory factors, such as serine/arginine-rich (SR) proteins, SR protein kinases and micro (mi)RNAs. Both isoforms mediate a variety of physiologic- and pathophysiologic-relevant functions, such as thrombogenicity, angiogenesis, cell signaling, tumor cell proliferation and metastasis. In this review, we will depict the main mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic relevant conditions. Moreover, we will summarize and discuss the latest findings regarding the role of TF and its isoforms in cancer biology. PMID- 24806797 TI - [Need for revision: Structured crisis management as a contribution to physician and patient safety]. PMID- 24806798 TI - [New patients' rights act--what do we have to consider?]. AB - The controversially discussed act of improving the rights of patients entered into force in Germany on 26 February 2013 without any transitional period. The current law of patients "rights brings together patients" rights at one uniform place in the civil code (BGB, "Burgerlichen Gesetzbuch") and should, therefore, attract the medical stakeholders' interest. The new patients "rights law improves the patients" position concerning both treatment and doctor's liability law and is supposed to strengthen a new "error culture" in health care. Similarly, clinical and daily practice becomes more complex with high levels of bureaucracy and the patient-physician relation shifts in favour of meticulous documentation. PMID- 24806796 TI - The bacterial septal ring protein RlpA is a lytic transglycosylase that contributes to rod shape and daughter cell separation in Pseudomonas aeruginosa. AB - Rare lipoprotein A (RlpA) is a widely conserved outer membrane protein of unknown function that has previously only been studied in Escherichia coli, where it localizes to the septal ring and scattered foci along the lateral wall, but mutants have no phenotypic change. Here we show rlpA mutants of Pseudomonas aeruginosa form chains of short, fat cells when grown in low osmotic strength media. These morphological defects indicate RlpA is needed for efficient separation of daughter cells and maintenance of rod shape. Analysis of peptidoglycan sacculi from an rlpA deletion mutant revealed increased tetra and hexasaccharides that lack stem peptides (hereafter called 'naked glycans'). Incubation of these sacculi with purified RlpA resulted in release of naked glycans containing 1,6-anhydro N-acetylmuramic acid ends. RlpA did not degrade sacculi from wild-type cells unless the sacculi were subjected to a limited digestion with an amidase to remove some of the stem peptides. Thus, RlpA is a lytic transglycosylase with a strong preference for naked glycan strands. We propose that RlpA activity is regulated in vivo by substrate availability, and that amidases and RlpA work in tandem to degrade peptidoglycan in the division septum and lateral wall. PMID- 24806799 TI - [Employees in high-reliability organizations: systematic selection of personnel as a final criterion]. AB - Employees represent an important safety factor in high-reliability organizations. The combination of clear organizational structures, a nonpunitive safety culture, and psychological personnel selection guarantee a high level of safety. The cockpit personnel selection process of a major German airline is presented in order to demonstrate a possible transferability into medicine and urology. PMID- 24806800 TI - [Hydrocele, spermatocele, and vasectomy: management of complications]. AB - Indications for hydrocele and spermatocele treatment are based on diagnosis with high-resolution ultrasonography. It must be clear whether hydrocele or spermatocele lead to impairment of the patient - asymptomatic findings do not need correction. In case of younger men, the wish for children must be taken into account as both surgical procedures may lead to infertility, especially spermatocele resection may lead to epididymal obstruction. Advantages and disadvantages of the intervention must be discussed with the patient in detail. In men with a planned vasectomy, the physician must be certain that the patient understands the definitive character of this form of contraception. Men who are not aware of this condition or have conflicts with their partners may not be the best candidates for surgical vasectomy. All three treatment options (hydrocelectomy, spermatocele resection, and vasectomy) may be accompanied by fertility preservation procedures (e.g., cryopreservation of semen prior to surgery). Alternatively, the surgery should not be performed if any doubts exist. Postoperative management includes follow-up examinations and in case of vasectomy after 6-12 weeks and several ejaculations at least two semen analysis with proven azoospermia after centrifugation (or <100,000 immotile spermatozoa) should be documented. Compliance of men is best when this follow-up appointment is already scheduled at the time of surgery. PMID- 24806801 TI - [Transurethral resection of bladder tumors: management of complications]. AB - As a frequent endourological procedure, transurethral resection of bladder tumors (TURB) represents a major field of activity for urological surgeons. Although TURB represents an endoscopic training procedure for urology residents, there are clear requirements for the quality of the surgical procedure as such. The knowledge of possible complications and their management are essential for urologists active in the clinical field. Bleeding complications, bladder perforation, infections and injuries to the ureteral orifice are the most frequently observed complications. This article summarizes the essential risks and complications as well as the corresponding preventive and therapeutic measures. PMID- 24806802 TI - [Transurethral prostatectomy: management of complications]. AB - BACKGROUND: Transurethral resection of the prostate (TURP) is still the most common surgical method for the treatment of benign prostatic syndrome. Despite a significant reduction of mortality rate, the morbidity of TURP is still about 15%. OBJECTIVES: Based on current data, the goal of this article is to analyze which complications are expected today from the standpoint of improved high frequency surgery and loop technology and what preventive or therapeutic measures should be undertaken. RESULTS: The use of the bipolar resection technique reduces the risk of TUR syndrome. However, cardiac risk due to possible irrigation fluid uptake remains unchanged. The blood transfusion rate has been reduced to 1% by a decreased risk of bleeding due to ongoing technical development in high-frequency surgery and a stricter indication for transfusion. Postoperative urethral strictures, which are generally caused by mechanical and electrical mucosal lesions, should be avoided by using an atraumatic surgical technique. To prevent bladder neck sclerosis, the additional routine incision of the internal sphincter is recommended for all smaller prostates. CONCLUSIONS: Due to a modern high frequency technology, subsequently avoiding TUR syndrome and enabling a blood sparing cut, a further reduction of complication rates can be expected. PMID- 24806803 TI - [Nephrectomy: complication management]. AB - BACKGROUND: Nephrectomy is a standard procedure that is associated with a low complication rate. OBJECTIVES: Based on an analysis of the literature, expert recommendations, and our own experience, the management of complications during and after nephrectomy is described. RESULTS: Complications during and after nephrectomy can be avoided by careful surgical planning, optimal approach and exposure, and precise knowledge of the principles of anatomy. The treatment of bleeding complications and injuries to neighboring structures are essential elements in the management of complications. Hernia and relaxation of the lumbar muscles should be avoided. CONCLUSION: Morbidity associated with nephrectomy can be reduced by careful surgical planning and paying attention to the basic anatomical and surgical principles. PMID- 24806804 TI - [Metastatic castration-resistant prostate cancer: position paper for structured therapy monitoring]. AB - This position paper is intended to help to structure and to standardize therapy monitoring in patients with metastatic castration-resistant prostate cancer (mCRPC). With the treatment options available today, patients with metastatic disease can often maintain good quality of life and stable disease for several years. It is crucial that once a therapy becomes insufficiently effective that it be replaced in a timely manner by a new treatment option. From a prognostic point of view, it is important that patients receive as many as possible and in the ideal case all currently available treatment options. PMID- 24806806 TI - Loading of the centromeric histone H3 variant during meiosis-how does it differ from mitosis? AB - In eukaryotic phyla studied so far, the essential centromeric histone H3 variant (CENH3) is loaded to centromeric nucleosomes after S-phase (except for yeast) but before mitotic segregation (except for metazoan). While the C-terminal part of CENH3 seems to be sufficient for mitotic centromere function in plants, meiotic centromeres neither load nor tolerate impaired CENH3 molecules. However, details about CENH3 deposition in meiocytes are unknown (except for Drosophila). Therefore, we quantified fluorescence signals after the immunostaining of CENH3 along meiotic and mitotic nuclear division cycles of rye, a monocotyledonous plant. One peak of fluorescence intensity appeared in the early meiotic prophase of pollen mother cells and a second one during interkinesis, both followed by a decrease of CENH3. Then, the next loading occurred in the male gametophyte before its first mitotic division. These data indicate that CENH3 loading differs between mitotic and meiotic nuclei. Contrary to the situation in mitotic cycles, CENH3 deposition is biphasic during meiosis and apparently linked with a quality check, a removal of impaired CENH3 molecules, and a general loss of CENH3 after each loading phase. These steps ensure an endowment of centromeres with a sufficient amount of correct CENH3 molecules as a prerequisite for centromere maintenance during mitotic cycles of the microgametophyte and the progeny. From a comparison with data available for Drosophila, we hypothesise that the post divisional mitotic CENH3 loading in metazoans is evolutionarily derived from the post-divisional meiotic loading phase, while the pre-divisional first meiotic loading has been conserved among eukaryotes. PMID- 24806808 TI - Production of lycopene by metabolically-engineered Escherichia coli. AB - Escherichia coli strain CAR001 that produces beta-carotene was genetically engineered to produce lycopene by deleting genes encoding zeaxanthin glucosyltransferase (crtX) and lycopene beta-cyclase (crtY) from the crtEXYIB operon. The resulting strain, LYC001, produced 10.5 mg lycopene/l (6.5 mg/g dry cell weight, DCW). Modulating expression of genes encoding alpha-ketoglutarate dehydrogenase, succinate dehydrogenase and transaldolase B within central metabolic modules increased NADPH and ATP supplies, leading to a 76 % increase of lycopene yield. Ribosome binding site libraries were further used to modulate expression of genes encoding 1-deoxy-D-xylulose-5-phosphate synthase (dxs) and isopentenyl diphosphate isomerase (idi) and the crt gene operon, which improved the lycopene yield by 32 %. The optimal strain LYC010 produced 3.52 g lycopene/l (50.6 mg/g DCW) in fed-batch fermentation. PMID- 24806807 TI - The contribution of maternal birth cohort to term small for gestational age in the United States 1989-2010: an age, period, and cohort analysis. AB - BACKGROUND: After decades of steady increase, mean birthweight in the US declined throughout the 1990s and early 2000s, a trend not fully explained by changes in length of gestation, medical practice, demographics, or maternal behaviours. We hypothesised that secular changes in health or social factors across women's life courses may have contributed to this unexplained trend and examined maternal birth cohort as a proxy measure of life-course determinants of fetal growth in the US. METHODS: We used the age, period, and cohort (APC) intrinsic estimator (IE) approach to estimate the contribution of maternal birth cohort (independent of maternal age and period of birth) to small for gestational age (SGA), overall and among term births, in the US from 1989 to 2010. We conducted analyses separately among foreign- and US-born Hispanic, non-Hispanic black (NHB), and non Hispanic white mothers. RESULTS: We found evidence of a U-shaped relationship between maternal birth cohort and SGA among NHB women only. After accounting for maternal age and period of birth, risk of SGA among NHB women born in 1950 was 21.1% and decreased to 15.9% in 1970. However, NHB women born after 1970 experienced increasing risk (19.6% by the 1986 birth cohort). CONCLUSIONS: Our findings suggest that NHB women born after 1970 have experienced increasing risk of SGA. Declining risk of SGA across NHB maternal birth cohorts from 1950 to 1970, however, suggests the potential to reverse this trend. Results illustrate the need for research on health and social risk factors for SGA across the pre pregnancy life course. PMID- 24806809 TI - Effects of antioxidants of bamboo leaves and flavonoids on 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP) formation in chemical model systems. AB - The inhibitory effects of antioxidants of bamboo leaves (AOB) and flavonoids against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation were investigated in creatinine and phenylalanine model systems. AOB and the tested flavonoids (orientin, homoorientin, vitexin, isovitex, apigenin, luteolin, isorhamnetin, fisetin, and hesperetin) had significant dose-dependent inhibition effects on PhIP formation with different IC50 values. The superoxide anion (O2(* )) scavenging activities of these nine flavonoids were evaluated using the pyrogallol autoxidation system. The EC50 values of compounds that showed antioxidant activity were found to correlate well (R(2) = 0.8003) with the corresponding IC50 values representing their inhibition of PhIP formation. It was assumed that the inhibitory effects of flavonoids on PhIP formation were probably achieved by scavenging free radicals generated in the reaction system. These findings provide valuable information for the development of effective strategies to minimize heterocyclic amine content in thermally processed food. PMID- 24806810 TI - Azithromycin suppresses P. gingivalis LPS-induced pro-inflammatory cytokine and chemokine production by human gingival fibroblasts in vitro. AB - OBJECTIVE: Azithromycin is a macrolide antibiotic that appears to have both antibacterial and anti-inflammatory properties. This study aimed to investigate the effect of azithromycin on the production of pro-inflammatory cytokines and chemokines by human gingival fibroblasts (HGF) in vitro. MATERIALS AND METHODS: The effects of azithromycin (0.1 to 10 MUg/mL) on the production of interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), and growth-regulated oncogene (GRO) by human gingival fibroblasts cultured in the presence or absence of Porphyromonas gingivalis lipopolysaccharide (LPS) was studied. Cytokine and chemokine protein levels in the culture supernatant were assessed using a Luminex(r) multiplex immunoassay. RESULTS: P. gingivalis LPS induced cytokine/chemokine (IL-6, IL-8, MCP-1, and GRO) protein production in HGFs, and this effect was suppressed by azithromycin at all concentrations tested. CONCLUSIONS: This study demonstrates that azithromycin suppresses P. gingivalis LPS-induced cytokine/chemokine protein production in HGF, which may explain some of the clinical benefits observed with the adjunctive use of azithromycin in the treatment of periodontitis. CLINICAL RELEVANCE: The current study examines the anti-inflammatory properties of azithromycin which may make it useful as an adjunct treatment to periodontitis. Specifically, we used azithromycin to modulate the production of pro-inflammatory cytokines by gingival fibroblasts known to be important in periodontal inflammation. PMID- 24806812 TI - Microencapsulation by spray drying of nitrogen-fixing bacteria associated with lupin nodules. AB - Plant growth promoting bacteria and nitrogen-fixing bacteria (NFB) used for crop inoculation have important biotechnological potential as a sustainable fertilization tool. However, the main limitation of this technology is the low inoculum survival rate under field conditions. Microencapsulation of bacterial cells in polymer matrices provides a controlled release and greater protection against environmental conditions. In this context, the aim of this study was to isolate and characterize putative NFB associated with lupin nodules and to evaluate their microencapsulation by spray drying. For this purpose, 21 putative NFB were isolated from lupin nodules and characterized (16S rRNA genes). Microencapsulation of bacterial cells by spray drying was studied using a mixture of sodium alginate:maltodextrin at different ratios (0:15, 1:14, 2:13) and concentrations (15 and 30% solids) as the wall material. The microcapsules were observed under scanning electron microscopy to verify their suitable morphology. Results showed the association between lupin nodules of diverse known NFB and nodule-forming bacteria belonging to Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria and Bacteroidetes. In microencapsulation assays, the 1:14 ratio of sodium alginate:maltodextrin (15% solids) showed the highest cell survival rate (79%), with a microcapsule yield of 27% and spherical microcapsules of 5-50 um in diameter. In conclusion, diverse putative NFB genera and nodule forming bacteria are associated with the nodules of lupine plants grown in soils in southern Chile, and their microencapsulation by spray drying using sodium alginate:maltodextrin represents a scalable process to generate a biofertilizer as an alternative to traditional nitrogen fertilization. PMID- 24806813 TI - Autoimmunity in atopic dermatitis: biomarker or simply epiphenomenon? AB - The idea that a mechanism of autoimmunity could play a role in the pathogenesis of atopic dermatitis gained support from the observation that patients with atopic dermatitis display IgE reactivity to a variety of human protein antigens, several of which have been characterized at molecular level. A broad spectrum of at least 140 IgE-binding self-antigens associated with atopic dermatitis has been demonstrated; they might promote, perpetuate, or both, skin inflammation by binding IgE antibodies or activating specific T cells. Even if the presence of autoreactivity seems to be associated with the severity of the disease and may be used as a parameter reflecting chronic tissue damage, at the state of art the role of autoimmunity in atopic dermatitis is far from clear. Data from the literature show that the use of autoantibodies as biomarkers of atopic dermatitis are still limited by the evidence that the epiphenomenon of autoreactivity is detectable only in a percentage of patients and that the involved self-allergens often are not the same; further longitudinal case-control studies are needed to investigate and to clarify the pathogenethic role of autoimmunity in the course of atopic dermatitis. PMID- 24806814 TI - Nanoporous dual-electrodes with millimetre extensions: parallelized fabrication and area effects on redox cycling. AB - We present a nanoporous dual-electrode device for highly sensitive electrochemical detection via redox cycling. The individual sensors comprise one billion nanopores in an area of 9 mm(2). Pores feature an approximate lateral distance of 100 nm and pore radii down below 20 nm. The sensor's fabrication process is based on porous alumina membranes, which are formed via anodization of aluminum films. Novel processing steps are combined enabling high-throughput fabrication of the nanoporous sensors on the wafer scale. In this context, we present an electrochemical approach for the selective passivation of nanostructured electrode areas and introduce an etching process with tuneable selectivity for the removal of titania versus alumina. The devices exhibit sensitivities of up to 330 MUA mM(-1) for the redox-active probe Fe(CN)6(3-/4-) making use of highly efficient redox cycling amplification inside the nanopores. Furthermore, the large-scale interplay of the sensor's nanopores in millimetre dimensions facilitates analyte enrichment and depletion at the sensor surface. The large-area sensor therefore provides an interesting opportunity for determining the oxidation-state-dependent diffusion coefficients of redox-active molecules. PMID- 24806816 TI - Neurologic disease in HIV-infected children and the impact of combination antiretroviral therapy. AB - The prevalence of HIV-associated neurocognitive impairment in perinatally HIV infected children has declined since the introduction of combination antiretroviral therapy (cART). Early initiation of cART in infancy has been shown to positively impact neurodevelopment; however, children continue to be diagnosed with HIV outside of the early infancy period and can experience subtle to severe neurocognitive deficits despite cART. The causes of these neurocognitive deficits despite effective cART are multifactorial and likely include continued viral replication in the CNS, ongoing neuroinflammation, irreversible CNS injury prior to cART initiation, neurotoxic effects of cART, and socioeconomic and psychosocial effects. Many aspects of our understanding of HIV-associated neurocognitive disorders have emerged from research in adult patients, but perinatally HIV-infected children represent a very different population. These children were exposed to HIV during a period of rapid brain development and have lifelong infection and potential lifelong cART exposure. HIV is no longer a rapidly fatal disease, and most HIV-infected children in resource-rich countries are living into adulthood. It is therefore critical to optimize neurocognitive outcomes of these youth. This review summarizes current understanding of the pathogenesis of HIV-associated CNS infection and the impact of cART on neurocognitive function in children and adolescents and discusses important areas for future research. PMID- 24806815 TI - Mdb1, a fission yeast homolog of human MDC1, modulates DNA damage response and mitotic spindle function. AB - During eukaryotic DNA damage response (DDR), one of the earliest events is the phosphorylation of the C-terminal SQ motif of histone H2AX (H2A in yeasts). In human cells, phosphorylated H2AX (gammaH2AX) is recognized by MDC1, which serves as a binding platform for the accumulation of a myriad of DDR factors on chromatin regions surrounding DNA lesions. Despite its important role in DDR, no homolog of MDC1 outside of metazoans has been described. Here, we report the characterization of Mdb1, a protein from the fission yeast Schizosaccharomyces pombe, which shares significant sequence homology with human MDC1 in their C terminal tandem BRCT (tBRCT) domains. We show that in vitro, recombinant Mdb1 protein binds a phosphorylated H2A (gammaH2A) peptide, and the phospho-specific binding requires two conserved phospho-binding residues in the tBRCT domain of Mdb1. In vivo, Mdb1 forms nuclear foci at DNA double strand breaks (DSBs) induced by the HO endonuclease and ionizing radiation (IR). IR-induced Mdb1 focus formation depends on gammaH2A and the phospho-binding residues of Mdb1. Deleting the mdb1 gene does not overtly affect DNA damage sensitivity in a wild type background, but alters the DNA damage sensitivity of cells lacking another gammaH2A binder Crb2. Overexpression of Mdb1 causes severe DNA damage sensitivity in a manner that requires the interaction between Mdb1 and gammaH2A. During mitosis, Mdb1 localizes to spindles and concentrates at spindle midzones at late mitosis. The spindle midzone localization of Mdb1 requires its phospho-binding residues, but is independent of gammaH2A. Loss of Mdb1 or mutating its phospho binding residues makes cells more resistant to the microtubule depolymerizing drug thiabendazole. We propose that Mdb1 performs dual roles in DDR and mitotic spindle regulation. PMID- 24806817 TI - Fatal case of necrotizing fasciitis due to Myroides odoratus. AB - Myroides sp., previously known as Flavobacterium odoratum, is a relatively unknown organism with unclear human pathogenicity. While Myroides sp. has been implicated in human infections, many reports have described the organism as a relatively avirulent opportunistic pathogen. We present an unusual case of rapidly fatal necrotizing fasciitis and septic shock due to Myroides odoratus. Our case demonstrates the pathogenicity of Myroides, and highlights potential risk factors for infection including underlying liver disease and open wounds. The recognition of Myroides is of particular importance given its resistance to multiple antibiotics. We review the literature on Myroides sp. skin and soft tissue infections, including necrotizing forms, and discuss the clinical presentation and management of this potentially emerging pathogen. PMID- 24806818 TI - Food insecurity among veterans of the US wars in Iraq and Afghanistan. AB - OBJECTIVE: Food insecurity, or lack of access to sufficient food for a healthful lifestyle, has been associated with many aspects of poor health. While the economic struggles among veterans of the wars in Iraq and Afghanistan have been documented, it is unknown how commonly this population struggles to afford food. Our purpose was to document the prevalence and correlates of food insecurity among US veterans of the wars in Iraq and Afghanistan. DESIGN: A cross-sectional survey. SUBJECTS: US military veterans who had served in the wars in Iraq and Afghanistan since October 2001. SETTING: Subjects responded to a survey mailed to them in summer 2012. Food security was measured by the US Household Food Security Module: Six Item Short Form. Demographic and behavioural health items were also included. Survey data were matched to medical record data from the Department of Veterans Affairs. RESULTS: Over one in four veterans reported past-year food insecurity with 12 % reporting very low food security. Food-insecure veterans tended to be younger, not married/partnered, living in households with more children, earning lower incomes, had a lower final military pay grade, were more likely to use tobacco, reported more frequent binge drinking and slept less, compared with those who were food secure (P<0.05 for all associations listed). CONCLUSIONS: Previously undocumented, the problem of hunger among our newest veterans deserves attention. PMID- 24806819 TI - Polymorphisms of neonatal Fc receptor in cynomolgus and rhesus macaques. AB - Neonatal Fc receptor (FcRn), a heterodimer of MHC class I-like protein and beta2 microglobulin, encoded by FCGRT and B2M, respectively, is important for recycling immunoglobulin G (IgG) antibodies by binding with the Fc region of IgG. Cynomolgus macaques are important animal species used in the evaluation of therapeutic antibodies, largely due to sequence similarities of target proteins to those of humans. Because the function of FcRn could be modified by mutations in FCGRT or B2M, 71 cynomolgus and 24 rhesus macaques were analyzed in the present study. A total of 21 variants were identified, of which 4 were non synonymous in FCGRT. Fifteen variants were unique to cynomolgus macaques, of which 3, 2, and 5 were unique to cynomolgus macaques bred in China (MacfaCHN), Cambodia (MacfaCAM), and Indonesia (MacfaIDN), respectively. Five variants were shared by MacfaCHN and MacfaCAM, but not by MacfaIDN. In B2M, only 5 variants were found, including 2 non-synonymous variants. Tissue expression analysis showed that cynomolgus FCGRT and B2M were widely expressed in the 10 tissue types analyzed. None of the non-synonymous variants of FCGRT or B2M found changes in the amino acid residues known to be important for FcRn function, suggesting that substantial inter-animal variability of FcRn is not expected for the cynomolgus macaques analyzed. PMID- 24806820 TI - Decrease in ciprofloxacin absorption by polyvalent metal cations is not fully attributable to chelation or adsorption. AB - The drug interaction between new quinolone antibiotics (NQs) and polyvalent metal cation products, leading to a significant decrease in the absorption of NQ, is considered to be attributable to the formation of poorly absorbable chelate and physicochemical adsorption of NQs to cation products. To clarify the mechanisms of this drug interaction in detail, we investigated the effects of Al(3+) or Mg(2+) on the membrane permeation profile of ciprofloxacin (CPFX) across human colon carcinoma cell lines (Caco-2) in monolayer culture, and characterized the adsorption nature of CPFX to polyvalent metal cation products under physiological conditions. As a result, Al(3+) or Mg(2+) partially but not fully impaired the permeation of CPFX across Caco-2 monolayer up to 30% or 60% of control, respectively. Physicochemical adsorption of CPFX to cation products was not observed under physiological pH. In conclusion, two possible mechanisms investigated, the decrease in the permeability of CPFX by chelate formation and adsorption of CPFX to polyvalent metal cation products, may partially but not fully explain the extent of the drug interaction clinically observed. PMID- 24806821 TI - Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates. AB - In central nervous system drug discovery, cerebrospinal fluid (CSF) drug concentration (C(CSF)) has been widely used as a surrogate for unbound brain concentrations (C(u,brain)). However, previous rodent studies demonstrated that when drugs undergo active efflux by transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier, the C(CSF) overestimates the corresponding C(u,brain). To investigate the utility of C(CSF) as a surrogate for interstitial fluid (ISF) concentration (C(ISF)) in nonhuman primates, this study simultaneously determined the C(CSF) and C(ISF) of 12 compounds, including P-gp substrates, under steady-state conditions in cynomolgus monkeys using intracerebral microdialysis coupled with cisternal CSF sampling. Unbound plasma concentrations of non- or weak P-gp substrates were within 2.2-fold of the C(ISF) or C(CSF), whereas typical P-gp substrates (risperidone, verapamil, desloratadine, and quinidine) showed ISF-to-plasma unbound (K(p,uu,ISF)) and CSF to-plasma unbound concentration ratios (K(p,uu,CSF)) that were appreciably lower than unity. Although the K(p,uu,CSF) of quinidine, verapamil, and desloratadine showed a trend of overestimating the K(p,uu,ISF), K(p,uu,CSF) showed a good agreement with K(p,uu,ISF) within 3-fold variations for all compounds examined. C(u,brain) of some basic compounds, as determined using brain homogenates, overestimated the C(ISF) and C(CSF). Therefore, C(CSF) could be used as a surrogate for C(ISF) in nonhuman primates. PMID- 24806822 TI - Novel simvastatin inhalation formulation and characterisation. AB - Simvastatin (SV), a drug of the statin class currently used orally as an anti cholesterolemic via the inhibition of the 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase, has been found not only to reduce cholesterol but also to have several other pharmacological actions that might be beneficial in airway inflammatory diseases. Currently, there is no inhalable formulation that could deliver SV to the lungs. In this study, a pressurised metered-dose inhaler (pMDI) solution formulation of SV was manufactured, with ethanol as a co-solvent, and its aerosol performance and physico-chemical properties investigated. A pMDI solution formulation containing SV and 6% w/w ethanol was prepared. This formulation was assessed visually and quantitatively for SV solubility. Furthermore, the aerosol performance (using Andersen Cascade impactor at 28.3 L/min) and active ingredient chemical stability up to 6 months at different storage temperatures, 4 and 25 degrees C, were also evaluated. The physico chemical properties of the SV solution pMDI were also characterised by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and laser diffraction. The aerosol particles, determined using scanning electron microscopy (SEM), presented a smooth surface morphology and were spherical in shape. The aerosol produced had a fine particle fraction of 30.77 +/- 2.44% and a particle size distribution suitable for inhalation drug delivery. Furthermore, the short-term chemical stability showed the formulation to be stable at 4 degrees C for up to 6 months, whilst at 25 degrees C, the formulation was stable up to 3 months. In this study, a respirable and stable SV solution pMDI formulation for inhalation has been presented that could potentially be used clinically as an anti-inflammatory therapy for the treatment of several lung diseases. PMID- 24806823 TI - Human fetoplacental and fetal liver blood flow after maternal glucose loading: a cross-sectional observational study. AB - OBJECTIVE: To study umbilical vein and fetal liver blood flow related to fetal anthropometric measures following maternal oral glucose loading. DESIGN: Experimental design in a cross-sectional observational study. SETTING: University hospital. POPULATION: A total of 113 low-risk pregnancies (30-32 weeks of gestation). METHODS: Ultrasound Doppler measurements of umbilical vein and ductus venosus blood flow (ml/min) before and 2 h after completed 75-g oral glucose tolerance test (OGTT). Liver blood flow was defined as the umbilical vein blood flow minus ductus venosus blood flow. MAIN OUTCOME MEASURES: Changes in umbilical vein and fetal liver blood flow following OGTT related to fetal biometric measurements. RESULTS: In the fasting state, fetal abdominal circumference z scores did not correlate with any of the flow parameters; 120 min after glucose loading, the z-scores correlated positively with the changes in umbilical vein (r = 0.25, p = 0.010) and fetal liver blood flow (r = 0.25, p = 0.009), but not with those in ductus venosus (p = 0.84). In simultaneous multiple linear regression analyses, the effects of the changes in umbilical vein or fetal liver blood flow after OGTT on the fetal abdominal circumference z-scores were almost equal to or greater than other parameters related to fetal size (body mass index, fasting plasma glucose, parity, and sex). Fetal heart rate increased after OGTT, but did not influence the association between the blood flow parameters and fetal abdominal circumference z-scores. CONCLUSIONS: Changes in umbilical vein and fetal liver blood flow after glucose loading were positively related to fetal abdominal size. PMID- 24806824 TI - Highly graphitized nitrogen-doped porous carbon nanopolyhedra derived from ZIF-8 nanocrystals as efficient electrocatalysts for oxygen reduction reactions. AB - Nitrogen-doped graphitic porous carbons (NGPCs) have been synthesized by using a zeolite-type nanoscale metal-organic framework (NMOF) as a self-sacrificing template, which simultaneously acts as both the carbon and nitrogen sources in a facile carbonization process. The NGPCs not only retain the nanopolyhedral morphology of the parent NMOF, but also possess rich nitrogen, high surface area and hierarchical porosity with well-conducting networks. The promising potential of NGPCs as metal-free electrocatalysts for oxygen reduction reactions (ORR) in fuel cells is demonstrated. Compared with commercial Pt/C, the optimized NGPC 1000-10 (carbonized at 1000 degrees C for 10 h) catalyst exhibits comparable electrocatalytic activity via an efficient four-electron-dominant ORR process coupled with superior methanol tolerance as well as cycling stability in alkaline media. Furthermore, the controlled experiments reveal that the optimum activity of NGPC-1000-10 can be attributed to the synergetic contributions of the abundant active sites with high graphitic-N portion, high surface area and porosity, and the high degree of graphitization. Our findings suggest that solely MOF-derived heteroatom-doped carbon materials can be a promising alternative for Pt-based catalysts in fuel cells. PMID- 24806825 TI - Rehabilitation aimed at improving outdoor mobility for people after stroke: a multicentre randomised controlled study (the Getting out of the House Study). AB - BACKGROUND: One-third of stroke patients are dependent on others to get outside their homes. This can cause people to become housebound, leading to increased immobility, poor health, isolation and misery. There is some evidence that outdoor mobility rehabilitation can reduce these limitations. OBJECTIVE: To test the clinical effectiveness and cost-effectiveness of an outdoor mobility rehabilitation intervention for stroke patients. DESIGN: Multicentre, parallel group randomised controlled trial, with two groups allocated at a 1 : 1 ratio plus qualitative participant interviews. SETTING: Fifteen UK NHS stroke services throughout England, Scotland and Wales. PARTICIPANTS: A total of 568 stroke patients who wished to get out of the house more often, mean age of 71 years: 508 reached the 6-month follow-up and 10 were interviewed. INTERVENTION: Control was delivered prior to randomisation to all participants, and consisted of verbal advice and transport and outdoor mobility leaflets. Intervention was a targeted outdoor mobility rehabilitation programme delivered by 29 NHS therapists to 287 randomly chosen participants for up to 12 sessions over 4 months. MAIN OUTCOME MEASURES: Primary outcome was participant health-related quality of life, measured by the Short Form questionnaire-36 items, version 2 (Social Function domain), 6 months after baseline. Secondary outcomes were functional ability, mobility, number of journeys (from monthly travel diaries), satisfaction with outdoor mobility (SWOM), psychological well-being and resource use [health care and Personal Social Services (PSS)] 6 months after baseline. Carer well-being was recorded. All outcome measures were collected by post and repeated 12 months after baseline. Outcomes for the groups were compared using statistical significance testing and adjusted for multiple membership to account for the effect of multiple therapists at different sites. Interviews were analysed using interpretive phenomenology to explore confidence. RESULTS: A median of seven intervention sessions [interquartile range (IQR) 3-7 sessions], median duration of 369 minutes (IQR 170-691.5 minutes) per participant was delivered. There was no significant difference between the groups on health-related quality of life (social function). There were no significant differences between groups in functional ability, psychological well-being or SWOM at 6- or 12-month follow ups. There was a significant difference observed for travel journeys with the intervention group being 42% more likely to make a journey compared with the control group [rate ratio 1.42, 95% confidence interval (95% CI) 1.14 to 1.67] at 6 months and 76% more likely (rate ratio 1.76, 95% CI 1.36 to 1.95) at 12 months. The number of journeys was affected by the therapist effect. The mean incremental cost (total NHS and PSS cost) of the intervention was L3413.75 (95% CI -L448.43 to L7121.00), with an incremental quality-adjusted life-year gain of -0.027 (95% CI -0.060 to 0.007) according to the European Quality of Life-5 Dimensions and 0.003 (95% CI -0.016 to 0.006) according to the Short Form questionnaire-6 Dimensions. At baseline, 259 out of 281 (92.2%) participants in the control group were dissatisfied with outdoor mobility but at the 6-month assessment this had reduced to 77.7% (181/233), a 15% reduction. The corresponding reduction in the intervention group was slightly greater (21%) than 268 out of 287 (93.4%) participants dissatisfied with outdoor mobility at baseline to 189 out of 261 (72.4%) at 6 months. Participants described losing confidence after stroke as being detrimental to outdoor mobility. Recruitment and retention rates were high. The intervention was deliverable by the NHS but had a neutral effect in all areas apart from potentially increasing the number of journeys. This was dependent on the therapist effect, meaning that some therapists were more successful than others. The control appeared to affect change. CONCLUSIONS: The outdoor mobility intervention provided in this study to these stroke patients was not clinically effective or cost-effective. However, the provision of personalised information and monthly diaries should be considered for all people who wish to get out more. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58683841. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 29. See the NIHR Journals Library website for further project information. PMID- 24806826 TI - One plus one makes three: adding value by co-transfection of anti-apoptotic genes during transient gene expression. PMID- 24806828 TI - New polydentate trimethylsilyl chalcogenide reagents for the assembly of polyferrocenyl architectures. AB - A series of polychalcogenotrimethylsilane complexes Ar(CH2ESiMe3)n, (Ar = aryl; E = S, Se; n = 2, 3, and 4) can be prepared from the corresponding polyorganobromide and M[ESiMe3] (M = Na, Li). These represent the first examples of the incorporation of such a large number of reactive -ESiMe3 moieties onto an organic molecular framework. They are shown to be convenient reagents for the preparation of the polyferrocenylseleno- and thioesters from ferrocenoyl chloride. The synthesis, structures, and spectroscopic properties of the new silyl chalcogen complexes 1,4-(Me3SiECH2)2(C6Me4) (E = S, 1; E = Se, 2), 1,3,5 (Me3SiECH2)3(C6Me3) (E = S, 3; E = Se, 4) and 1,2,4,5-(Me3SiECH2)4(C6H2) (E = S, 5; E = Se, 6) and the polyferrocenyl chalcogenoesters [1,4-{FcC(O)ECH2}2(C6Me4)] (E = S, 7; E = Se, 8), [1,3,5-{FcC(O)ECH2}3(C6Me3)] (E = S, 9; E = Se, 10) and [1,2,4,5-{FcC(O)ECH2}4(C6H2)] (E = S, 11 illustrated; E = Se, 12) are reported. The new polysilylated reagents and polyferrocenyl chalcogenoesters have been characterized by multinuclear NMR spectroscopy ((1)H, (13)C, (77)Se), electrospray ionization mass spectrometry and, for complexes 1, 2, 3, 4, 7, 8, and 11, single-crystal X-ray diffraction. The cyclic voltammograms of complexes 7 11 are presented. PMID- 24806827 TI - Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis. AB - The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In this study, we used bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Reconstitution of lethally irradiated apoE(-/-) mice with NOR1 deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C(+) monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C(+) monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local proatherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation. PMID- 24806829 TI - Photoswitching CO2 capture and release in a photochromic diarylethene metal organic framework. AB - We demonstrate herein a promising pathway towards low-energy CO2 capture and release triggered by UV and visible light. A photosensitive diarylethene ligand was used to construct a photochromic diarylethene metal-organic framework (DMOF). A local photochromic reaction originating from the framework movement induced by the photoswitchable diarylethene unit resulted in record CO2-desorption capacity of 75% under static irradiation and 76% under dynamic irradiation. PMID- 24806832 TI - Extension of Fresnel's formulas for turbid colloidal suspensions: a rigorous treatment. AB - We provide new expressions for the reflection amplitudes of a half space of randomly located identical spherical particles that can be regarded as an extension of Fresnel's formulas when scattering is prominent. We derive them rigorously from Maxwell's equations by solving an integral equation for the electric field within the effective-field approximation. The integral equation is given in terms of the nonlocal conductivity tensor of an isolated sphere. Approximate expressions for the reflection amplitudes are also proposed and their accuracy is analyzed, first for the case of a self-sustained suspension of silver particles, and then for the more realistic situation of silver particles in water. In this latter case the integral equation is modified by introducing the half-space Green's function dyadic instead of the one in free-space, but the method of solution is analogous in both. This extension of Fresnel's formulas, together with the numerical comparison of the different approximations proposed here, is necessary for an accurate interpretation of reflection-spectroscopy measurements in dilute colloidal suspensions of practical interest. The connection between the nonlocal conductivity tensor and the T-matrix operator of scattering theory is also made manifest. PMID- 24806830 TI - Islet cell xenotransplantation: a serious look toward the clinic. AB - Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and year-long survival in clinically relevant pig-to-primate model systems. These proof-of concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation. PMID- 24806833 TI - Specific adhesion of carbohydrate hydrogel particles in competition with multivalent inhibitors evaluated by AFM. AB - Synthetic glycooligomers have emerged as valuable analogues for multivalent glycan structures in nature. These multivalent carbohydrates bind to specific receptors and play a key role in biological processes. In this work, we investigate the specific interaction between mannose ligand presenting soft colloidal probes (SCPs) attached to an atomic force microscope (AFM) cantilever and a Concanavalin A (ConA) receptor surface in the presence of competing glycooligomer ligands. We studied the SCP-ConA adhesion energy via the JKR approach and AFM pull-off experiments in combination with optical microscopy allowing for simultaneous determination of the contact area between SCP and ConA surface. We varied the contact time, loading rate and loading force and measured the resulting mannose/ConA interaction. The average adhesion energy per mannose ligand on the probe was 5 kJ/mol, suggesting that a fraction of mannose ligands presented on the SCP bound to the receptor surface. Adhesion measurements via competitive binding of the SCP in the presence of multivalent glycooligomer ligands did not indicate an influence of their multivalency on the glycooligomer displacement from the ConA surface. The absence of this "multivalency effect" indicates that glycooligomers and ConA do not associate via chelate complexes and shows that steric shielding by the glycooligomers does not slow their displacement upon competitive binding of a ligand presenting surface. These results highlight the high reversibility of carbohydrate-surface interactions, which could be an essential feature of recognition processes on the cell surface. PMID- 24806834 TI - Aptamer-based exonuclease protection and enzymatic recycling cleavage amplification homogeneous assay for the highly sensitive detection of thrombin. AB - Critical challenges in homogeneous solution-based biomolecular detection are the separation and sensitivity compared to biomolecular detection in heterogeneous solutions. In this work, a novel, separation-free and sensitive homogeneous protein detection assay based on combining aptameric exonuclease protection with nicking enzyme assisted fluorescence signal amplification (NEFSA) is developed for highly sensitive protein detection. We applied a special oligonucleotide probe containing a protein aptamer sequence at the 3'-terminus, which has the capacity to recognize the protein target with high affinity and specificity. Specifically, the aptamer probe is protected from exonuclease-catalyzed digestion upon binding to the protein target. The protected aptamer probe hybridizes with the molecular beacon (MB) probe, a reporter signal oligo-DNA. Consequently, the NEFSA process is triggered in the presence of a nicking enzyme, resulting in the continuous enzyme cleavage of many MBs, providing a fluorescent cascadic amplification detection signal for the target. Thrombin was used as the model analyte in the current proof-of-concept experiments. This method permits the detection of human thrombin specifically with a detection limit as low as 1.0 pM without using washes or separations. Our method exhibits excellent sensitivity. In addition, this new method is simple and avoids the specific conformational design of an aptasensor probe for the elimination of washing and separation steps. The mechanism, moreover, may be generalized and used for other forms of protein analysis by changing the corresponding aptamer without changing the other conditions. So our new strategy may provide a homogeneous fluorescence detection platform for many proteins. PMID- 24806836 TI - Effect of fat- and carbohydrate-rich diets on metabolism and running performance in trained adolescent boys. AB - OBJECTIVES: A randomized crossover trial was designed to analyze the impact of a short-term, isoenergetic fat-rich or carbohydrate (CHO)-rich diet on substrate oxidation rates during submaximal exercise and on performance in a 10,000-m running time trial in trained, mid- to late-pubertal boys. METHODS: An incremental test was performed to determine the peak oxygen uptake (VO2peak). After 2 days on a fat-rich (24.2% +/- 0.8% CHO, 60.4% +/- 0.3% fat, and 15.5% +/- 1.0% protein), CHO-rich (69.3% +/- 1.2% CHO, 15.9% +/- 2.1% fat, and 15.1% +/- 1.1% protein), or habitual (56.1% +/- 7.0% CHO, 27.5% +/- 4.9% fat, and 16.5% +/- 4.0% protein) diet, 19 trained adolescent boys (15.2 +/- 1.5 years) performed a 10-minute constant run at 65% VO2peak to determine the respiratory exchange ratio (RER) during exercise and 10,000-m running on an outdoor track. RESULTS: During the constant run, the RER and CHO contribution to energy expenditure were lower, and fat contribution higher, in the fat-rich diet than in the CHO-rich diet (P < 0.05), but the results were not different from those of the habitual diet. Performance in the 10,000-m run after consuming CHO- and fat-rich diets was similar to performance after a habitual diet (50.0 +/- 7.0, 51.9 +/- 8.3, and 50.9 +/- 7.4 minutes, respectively), but consuming a CHO-rich diet enhanced performance compared with that after a fat-rich diet (P = 0.03). CONCLUSIONS: These findings indicate that a CHO-rich diet provides additional benefits to 10,000-m running performance in trained adolescent boys compared with a fat-rich diet. PMID- 24806835 TI - Liver disease in autosomal recessive polycystic kidney disease: clinical characteristics and management in relation to renal failure. AB - OBJECTIVES: We correlated liver and kidney manifestations in a national cohort of patients with autosomal recessive polycystic kidney disease (ARPKD). METHODS: A total of 27 consecutive patients with ARPKD were included. Hepatobiliary disorders were comparatively evaluated in 2 groups: children in group 1 (n = 10) displayed renal failure as infants and those in group 2 (n = 17) had normal kidney function through the first year of life. RESULTS: Median follow-up time was 10.6 (range, 0.4-40) years. Portal hypertension was diagnosed in 13 patients (48%) at the median age 5.0 (1.5-27.9) years. Esophageal varices developed in 8 patients (30%) at age 8.0 (2.1-11.9) years; 4 patients (15%) had variceal bleeding, and hypersplenism/splenomegaly occurred in 52%, similarly in both groups. Biliary tract dilatation was detected at 2.8 years in group 1 and at 7.9 years in group 2, significantly more frequently in group 1 (60% vs 18%, P = 0.039), causing cholangitis in 2 (20%) versus none in group 2 (P = 0.055). A total of 10 patients (37%) underwent cadaveric liver transplantation (LT) at a median age of 6.6 (1.0-20.0) years. In 1 patient LT was performed because of hepatoblastoma. Nine of these were combined liver-kidney transplantations (CLKT). Patients in group 1 required LT earlier (4.1 years vs 18.2 years, P = 0.017) and more frequently (70% vs 18%, P = 0.01). Overall survival beyond neonatal period was 85%. Two patients died because of infectious complications after CLKT, and 1 patient because of recurrent hepatoblastoma. CONCLUSIONS: Although correlation of renal and liver manifestations was variable, biliary dilatation was associated with early renal failure. CLKT may be a treatment for patients with ARPKD with marked hepatobiliary complications. PMID- 24806837 TI - PedsQL gastrointestinal symptoms module: feasibility, reliability, and validity. AB - OBJECTIVE: The objective of this study was to report on the measurement properties of the Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module for patients with functional gastrointestinal (GI) disorders (FGIDs) and organic GI diseases, hereafter referred to as "GI disorders," for patient self-report ages between 5 and 18 and parent proxy-report for ages between 2 and 18 years. METHODS: The 74-item PedsQL GI Module and 23-item PedsQL Generic Core Scales were completed in a 9-site study by 584 patients and 682 parents. Patients had physician-diagnosed GI disorders (such as chronic constipation, functional abdominal pain, irritable bowel syndrome, functional dyspepsia, Crohn disease, ulcerative colitis, gastroesophageal reflux disease). RESULTS: Fourteen unidimensional scales were derived measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood, diarrhea, worry, medicines, and communication. The PedsQL GI Module Scales evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report alpha = 0.97, parent proxy-report alpha = 0.97), and good-to excellent reliability for the 14 individual scales (patient self-report alpha = 0.67-0.94, parent proxy-report alpha = 0.77-0.95). Intercorrelations with the Generic Core Scales supported construct validity. Individual Symptoms Scales known-groups validity across 7 GI disorders was generally supported. Factor analysis supported the unidimensionality of the individual scales. CONCLUSIONS: The PedsQL GI Module Scales demonstrated acceptable-to-excellent measurement properties and may be used as common metrics to compare GI-specific symptoms in clinical research and practice both within and across patient groups for FGIDs and organic GI diseases. PMID- 24806841 TI - Mild solvothermal syntheses and characterization of layered copper thioantimonates(III) and thioarsenate(III). AB - The new copper thioantimonates(III) and thioarsenate(III) Rb2Cu2Sb2S5 (1), Cs2Cu2Sb2S5 (2), and Rb8Cu6As8S19 (3) have been synthesized solvothermally. Compound 1 contains a [Cu2SbS3] net to which [Sb2S4] chains adhere through Cu-S bonds and Sb-Cu interactions to give a layered structure. In compound 2, the layer is formed by edge-sharing tetrahedral CuS4 chains linked by dimeric [Sb2S5] units. The layered structure in compound 3 is constructed by helical chains built from [Cu3S7] moieties and dimeric [As2S5] units which are further connected by tetrameric [As4S9] groups. Their optical and thermal properties have been investigated. PMID- 24806839 TI - Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers. AB - The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred. Those genes and proteins that have survived from the 2R-WGD-termed 2R-ohnologues-belong to families of two to four members, and are enriched in signalling components relevant to cancer. Here, we find that while only approximately 30% of human transcript-coding genes are 2R-ohnologues, they carry 42-60% of the gene mutations in 30 different cancer types. Across a subset of cancer datasets, including melanoma, breast, lung adenocarcinoma, liver and medulloblastoma, we identified 673 2R-ohnologue families in which one gene carries mutations at multiple positions, while sister genes in the same family are relatively mutation free. Strikingly, in 315 of the 322 2R-ohnologue families displaying such a skew in multiple cancers, the same gene carries the heaviest mutation load in each cancer, and usually the second-ranked gene is also the same in each cancer. Our findings inspire the hypothesis that in certain cancers, heterogeneous combinations of genetic changes impair parts of the 2R-WGD signalling networks and force information flow through a limited set of oncogenic pathways in which specific non-mutated 2R-ohnologues serve as effectors. The non-mutated 2R ohnologues are therefore potential therapeutic targets. These include proteins linked to growth factor signalling, neurotransmission and ion channels. PMID- 24806840 TI - PINK1 deficiency in beta-cells increases basal insulin secretion and improves glucose tolerance in mice. AB - The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in beta-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1 deficient beta-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic beta-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in beta-cell function. PMID- 24806843 TI - Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma. AB - Epithelial-mesenchymal transition (EMT) is an important process in the invasion and metastasis of human cervical carcinoma. The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown as an EMT inducer in multiple carcinomas. However, whether the EMT program can be induced by IL-6 and the mechanisms underlying the IL-6-induced EMT in human cervical carcinoma remain to be determined. In this study, we show that IL-6 receptor (IL-6R) and signal transducer and activator of transcription 3 (Stat3) were highly expressed in human cervical squamous cell carcinoma (CSCC) tissues, and the expression of EMT markers was reversed in well-differentiated and poorly-differentiated human CSCC. Additional experiments showed that IL-6 exposure in cervical carcinoma cell lines induced IL-6R and Stat3 expression, markedly promoted cell growth, and altered cell morphology. The treatment of cervical carcinoma cell lines with IL-6 resulted in downregulation of E-Cadherin and upregulation of Vimentin. Importantly, knockdown of Stat3 significantly reversed the IL-6-induced EMT program, suggesting that Stat3 is necessary for IL-6-induced EMT in the progression of human cervical carcinoma. Moreover, Slug, a member of the Snail family of EMT regulators, was observed to be associated with the expression of Stat3. We concluded that IL-6 plays an important role through Stat3 in the EMT induction and can be a potential therapeutic target and biomarker for human cervical carcinoma. PMID- 24806844 TI - SimRAD: an R package for simulation-based prediction of the number of loci expected in RADseq and similar genotyping by sequencing approaches. AB - Application of high-throughput sequencing platforms in the field of ecology and evolutionary biology is developing quickly with the introduction of efficient methods to reduce genome complexity. Numerous approaches for genome complexity reduction have been developed using different combinations of restriction enzymes, library construction strategies and fragment size selection. As a result, the choice of which techniques to use may become cumbersome, because it is difficult to anticipate the number of loci resulting from each method. We developed SimRAD, an R package that performs in silico restriction enzyme digests and fragment size selection as implemented in most restriction site associated DNA polymorphism and genotyping by sequencing methods. In silico digestion is performed on a reference genome or on a randomly generated DNA sequence when no reference genome sequence is available. SimRAD accurately predicts the number of loci under alternative protocols when a reference genome sequence is available for the targeted species (or a close relative) but may be unreliable when no reference genome is available. SimRAD is also useful for fine-tuning a given protocol to adjust the number of targeted loci. Here, we outline the functionality of SimRAD and provide an illustrative example of the use of the package (available on the CRAN at http://cran.r-project.org/web/packages/SimRAD). PMID- 24806846 TI - Regulatory authority reports on breakdown of care at Belfast hospital. PMID- 24806845 TI - How much advice should we give? PMID- 24806847 TI - Call for more nurses to bolster number of military reservists. PMID- 24806849 TI - Warning for people with asthma when air pollution levels are high. PMID- 24806851 TI - Hand in glove with Jedward. PMID- 24806852 TI - Government asks whistleblowers to follow guidance. PMID- 24806853 TI - Major trauma network could save up to 40 lives a year. PMID- 24806854 TI - Should more people who need psychiatric help be brought to emergency departments? PMID- 24806855 TI - Extra funds have failed to cut level of demand, warns RCN. PMID- 24806856 TI - Success of services will depend on outcomes, not times to treatment. PMID- 24806857 TI - Making services fit for purpose. PMID- 24806860 TI - Top of the agenda - updating care of older people. PMID- 24806863 TI - Journal scan. PMID- 24806864 TI - Managing patients with cervical spine injury. AB - Common measures to establish spinal immobilisation at the scene of an accident include keeping the patient's head still, applying a rigid cervical collar and transporting the patient on a rigid spinal board to an emergency department. This article reviews the literature about spinal immobilisation practices in emergency settings, including best-practice guidance and papers on immobilisation, imaging, rapport with patients and complications. PMID- 24806865 TI - Treatment for burn blisters: debride or leave intact? AB - This article presents findings from a systematic literature review of whether blisters arising from minor burns should be de-roofed or left intact. It discusses the risks of infection, healing outcomes, discomfort, choice of dressings and costs associated with each method, and reveals that debriding blisters larger than the patient's little fingernail while leaving smaller ones intact is generally agreed to be the best option. The article also explains external factors that influence the choice of whether to debride or leave blisters intact, reviews policy at the trust where one of the authors works in the context of the research and makes recommendations for practice. PMID- 24806866 TI - Improving communication between emergency department staff. AB - During redevelopment of the emergency department at the Royal Sussex County Hospital, Brighton, it was deemed vital that its internal communication system should be as effective as possible. An audit of staff perceptions of the existing communication system and a relevant literature review were undertaken, therefore, to inform a proposal for the development of a new online system. This article describes the development and implementation of the system. PMID- 24806867 TI - Back on dry land. PMID- 24806868 TI - Time-motion analysis of a 2-hour surfing training session. AB - PURPOSE: To provide a descriptive and quantitative time-motion analysis of surfing training with the use of global positioning system (GPS) and heart-rate (HR) technology. METHODS: Fifteen male surfing athletes (22.1 +/- 3.9 y, 175.4 +/ 6.4 cm, 72.5 +/- 7.7 kg) performed a 2-h surfing training session, wearing both a GPS unit and an HR monitor. An individual digital video recording was taken of the entire surfing duration. Repeated-measures ANOVAs were used to determine any effects of time on the physical and physiological measures. RESULTS: Participants covered 6293.2 +/- 1826.1 m during the 2-h surfing training session and recorded measures of average speed, HRaverage, and HRpeak as 52.4 +/- 15.2 m/min, 128 +/- 13 beats/min, and 171 +/- 12 beats/ min, respectively. Furthermore, the relative mean times spent performing paddling, sprint paddling to catch waves, stationary, wave riding, and recovery of the surfboard were 42.6% +/- 9.9%, 4.1% +/- 1.2%, 52.8% +/- 12.4%, 2.5% +/- 1.9%, and 2.1% +/- 1.7%, respectively. CONCLUSION: The results demonstrate that a 2-h surfing training session is performed at a lower intensity than competitive heats. This is likely due to the onset of fatigue and a pacing strategy used by participants. Furthermore, surfing training sessions do not appear to appropriately condition surfers for competitive events. As a result, coaches working with surfing athletes should consider altering training sessions to incorporate repeated-effort sprint paddling to more effectively physically prepare surfers for competitive events. PMID- 24806869 TI - Carboxylated multi-walled carbon nanotubes aggravated biochemical and subcellular damages in leaves of broad bean (Vicia faba L.) seedlings under combined stress of lead and cadmium. AB - Increasing industrialization of multi-walled carbon nanotubes (MWCNTs) would inevitably lead to their release into the environment and combination with heavy metals. However, studies concerning the combined effects of MWCNTs and heavy metals on agricultural crops are limited. Herein, effects and mechanisms of carboxylated MWCNTs (MWCNTs-COOH) (2.5, 5 and 10mg/L) and their combination with 20 MUM Pb and 5 MUM Cd (shortened as Pb+Cd) on Vicia faba L. seedlings were investigated. The results showed that the MWCNTs-COOH disturbed the imbalance of nutrient elements, and caused oxidative stress and damages in the leaves. Additionally, the combination of MWCNTs-COOH with Pb+Cd resulted in enrichment of Pb and Cd, and deterioration of oxidative damages compared with the treatments of MWCNTs-COOH or Pb+Cd alone in the leaves. As the results, the concentrations of MWCNTs-COOH not only caused oxidative stress, but also exacerbated the biochemical and subcellular damages due to the treatment of Pb+Cd in the leaves. It also suggests that persistent release of MWCNTs-COOH into the environment may cause phytotoxicity and aggravate ecological risks due to combination of heavy metals. PMID- 24806870 TI - Modeling precipitate-dominant clogging for landfill leachate with NICA-Donnan theory. AB - Bioclogging of leachate drains is ubiquitous in landfills for municipal solid wastes. Formation of calcium precipitates and biofilms in pore space is the principal reason for clogging. But the calcium speciation in leachte rich in dissolved organic matters (DOM) remains to be uncovered. In spite of its complexity, NICA-Donnan model has been used to compute the speciation of metals and the binding capacities of humic substances. This study applies NICA-Donnan theory into the simulation of calcium speciation during the formation of precipitate-dominant clogging in leachate drainage aggregates for the first time. The consideration of DOC-Ca complexation gives reasonable explanation to the speciation of calcium, which is viewed as oversaturated, in leachate with concentrated DOM. The modeling results for calcium speciation are in good agreement with a large collection of experimental observations, suggesting that NICA-Donnan theory could be used in the modelings of reactive transport and clogging of landfill leachate collection systems. PMID- 24806871 TI - Chromate enhanced visible light driven TiO2 photocatalytic mechanism on Acid Orange 7 photodegradation. AB - When hexavalent chromium (Cr(VI)) is added to a TiO2 photocatalytic reaction, the decolorization and mineralization efficiencies of azo dyes Acid Orange 7 (AO7) are enhanced even though the mechanism is unclear. This study used 5,5-dimethyl-l pyrroline-N-oxide (DMPO) as the scavenger and the analysis of Electron Spin Resonance (ESR) to investigate this enhancement effect by observing the hydroxyl radical (OH) generation of the Cr(VI)/TiO2 system under UV and visible light (Vis) irradiation. With Cr(VI), the decolorization efficiencies were approximately 95% and 62% under UV and Vis, and those efficiencies were 25% less in the absence of Cr(VI). The phenomena of the DMPO-OH signals during the ESR analysis under Vis 405 and 550 nm irradiation were obviously the enhancement effects of Cr(VI) in aerobic conditions. In anoxic conditions, the catalytic effects of Cr(VI) could not be achieved due to the lack of a redox reaction between Cr(VI) and the adsorbed oxygen at the oxygen vacancy sites on the TiO2 surfaces. The results suggest that by introducing the agents of redox reactions such as chromate ions, we could lower the photoenergy of TiO2 needed and allow Vis irradiation to activate photocatalysis. PMID- 24806872 TI - Clonal spread of Klebsiella pneumoniae producing KPC-2 beta-lactamase in Croatian University Hospital. PMID- 24806873 TI - Efficacy of pain treatment on mood syndrome in patients with dementia: a randomized clinical trial. AB - BACKGROUND: Depression is common in nursing home (NH) patients with dementia, and often clustered with anxiety and other mood symptoms. An association between pain and depressive symptoms has been reported, but the impact of pain management on depression and other mood symptoms has not been investigated. OBJECTIVE: Secondary analyses of a cluster randomized clinical trial examine the response of dementia-related mood symptoms to a Stepwise Protocol of Treating Pain. METHOD: Three-hundred fifty-two patients with moderate and severe dementia and significant behavioural disturbances, related to 60 clusters (i.e. clusters defined as single independent NH units) in 18 NHs of Western Norway, were included. All patients in the intervention group received individual daily pain treatment with paracetamol, extended release morphine, buprenorphine transdermal patch or pregabaline for 8 weeks, with additional follow-up assessment 4 weeks after completion of the intervention. Clusters randomized to control received usual treatment. A mood cluster consisting of depression, anxiety, sleep disorders, apathy and appetite items from the Neuropsychiatric Inventory-Nursing Home (NPI-NH) was the primary outcome. RESULTS: Analysed by Mann-Whitney U-tests, Stepwise Protocol of Treating Pain conferred significant benefit in treatment of the NPI-NH mood cluster (F = 13.4, df = 1;299, p < 0.001) and depression (F = 2.0, df = 1;301, p = 0.025). Further analyses highlighted improvements in apathy (F = 5.3, df = 1;300, p = 0.017), night-time behaviours (F = 3.1, df = 1;301, p = 0.050), and appetite items (F = 11.6, df = 1;301, p = 0.005), but not irritability (p = 0.092) and anxiety (p = 0.125). CONCLUSION: Mood symptoms including depression significantly improved with pain treatment, emphasizing the importance of more rigorous treatment of pain in agitated people with dementia. Findings have potentially immediate clinical relevance. PMID- 24806875 TI - A facile approach for screening isolated nanomagnetic behavior for bit-patterned media. AB - Bit-patterned media (BPM) fabricated by the direct deposition of magnetic material onto prepatterned arrays of nanopillars is a promising approach for increasing magnetic recording of areal density. One of the key challenges of this approach is to identify and control the magnetic interaction between the bits (on top of the nanopillars) and the trench material between the pillars. Using independent techniques, including magnetic force microscopy, the variable-angle magneto-optic Kerr effect, and remanence curves, we were able to determine the presence and relative intensities of exchange and dipolar interactions in Co-Pd multilayer-based BPM fabricated by direct deposition. We found that for pitches of 30 nm or less, there were negligible exchange interactions, and the bits were found to be magnetically isolated. As we move to higher densities, the absence of exchange interactions indicates that direct deposition is a promising approach to BPM fabrication. PMID- 24806874 TI - Rapid enzyme-linked immunosorbent assay for the detection of hantavirus-specific antibodies in divergent small mammals. AB - We assessed the utility of an enzyme-linked immunosorbent assay (ELISA) for the detection of hantavirus-specific antibodies from sera of Oligoryzomys longicaudatus, the principal reservoir of Andes virus (ANDV), using an antigen previously developed for detection of antibodies to Sin Nombre virus (SNV) in sera from Peromyscus maniculatus. The assay uses a protein A/G horseradish peroxidase conjugate and can be performed in as little as 1.5 hours. Serum samples from Oligoryzomys longicaudatus collected in central-south Chile were used and the assay identified several that were antibody positive. This assay can be used for the rapid detection of antibodies to divergent hantaviruses from geographically and phylogenetically distant rodent species. PMID- 24806877 TI - Multifunctional and recollectable carbon nanotube ponytails for water purification. AB - Carbon nanotubes (CNTs) are promising nanomaterials that have the potential to revolutionize water treatment practices in the future. The direct use of unbounded CNTs, however, poses health risks to humans and ecosystems because they are difficult to separate from treated water. Here, we report the design and synthesis of carbon nanotube ponytails (CNPs) by integrating CNTs into micrometer sized colloidal particles, which greatly improves the effectiveness of post treatment separation using gravitational sedimentation, magnetic attraction, and membrane filtration. We further demonstrate that CNPs can effectively perform major treatment tasks including adsorption, disinfection, and catalysis. Using model pollutants such as methylene blue, Escherichia coli, and p-nitrophenol, we show that all the surfaces of individual CNTs in CNPs are accessible during water treatment. Our results suggest that the rational design of hierarchical structures represents a feasible approach to develop nanomaterials for engineering applications such as water and wastewater treatment. PMID- 24806876 TI - A review and critique of U.S. EPA's risk assessments for asbestos. AB - U.S. Environmental Protection Agency (EPA) recently conducted a risk assessment for exposure to Libby amphibole asbestos that is precedent-setting for two reasons. First, the Agency has not previously conducted a risk assessment for a specific type of asbestos fiber. Second, the risk assessment includes not only an inhalation unit risk (IUR) for the cancer endpoints, but also a reference concentration (RfC) for nonmalignant disease. In this paper, we review the procedures used by the Agency for both cancer and nonmalignant disease and discuss the strengths and limitations of these procedures. The estimate of the RfC uses the benchmark dose method applied to pleural plaques in a small subcohort of vermiculite workers in Marysville, Ohio. We show that these data are too sparse to inform the exposure-response relationship in the low-exposure region critical for estimation of an RfC, and that different models with very different exposure-response shapes fit the data equally well. Furthermore, pleural plaques do not represent a disease condition and do not appear to meet the EPA's definition of an adverse condition. The estimation of the IUR for cancer is based on a subcohort of Libby miners, discarding the vast majority of lung cancers and mesotheliomas in the entire cohort and ignoring important time related factors in exposure and risk, including effect modification by age. We propose that an IUR based on an endpoint that combines lung cancer, mesothelioma, and nonmalignant respiratory disease (NMRD) in this cohort would protect against both malignant and nonmalignant disease. However, the IUR should be based on the entire cohort of Libby miners, and the analysis should properly account for temporal factors. We illustrate our discussion with our own independent analyses of the data used by the Agency. PMID- 24806878 TI - A case of tinea imbricata in an Italian woman. PMID- 24806879 TI - [Test your knowledge]. PMID- 24806881 TI - Can't stop believing: inhibitory control and resistance to misleading testimony. AB - Why are some young children consistently willing to believe what they are told even when it conflicts with first-hand experience? In this study, we investigated the possibility that this deference reflects an inability to inhibit a prepotent response. Over the course of several trials, 2.5- to 3.5-year-olds (N = 58) heard an adult contradict their report of a simple event they had both witnessed, and children were asked to resolve this discrepancy. Those who repeatedly deferred to the adult's misleading testimony had more difficulty on an inhibitory control task involving spatial conflict than those who responded more skeptically. These results suggest that responding skeptically to testimony that conflicts with first-hand experience may be challenging for some young children because it requires inhibiting a normally appropriate bias to believe testimony. PMID- 24806882 TI - The dimerization domain in DapE enzymes is required for catalysis. AB - The emergence of antibiotic-resistant bacterial strains underscores the importance of identifying new drug targets and developing new antimicrobial compounds. Lysine and meso-diaminopimelic acid are essential for protein production and bacterial peptidoglycan cell wall remodeling and are synthesized in bacteria by enzymes encoded within dap operon. Therefore dap enzymes may serve as excellent targets for developing a new class of antimicrobial agents. The dapE encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) converts N succinyl-L,L-diaminopimelic acid to L,L-diaminopimelic acid and succinate. The enzyme is composed of catalytic and dimerization domains, and belongs to the M20 peptidase family. To understand the specific role of each domain of the enzyme we engineered dimerization domain deletion mutants of DapEs from Haemophilus influenzae and Vibrio cholerae, and characterized these proteins structurally and biochemically. No activity was observed for all deletion mutants. Structural comparisons of wild-type, inactive monomeric DapE enzymes with other M20 peptidases suggest that the dimerization domain is essential for DapE enzymatic activity. Structural analysis and molecular dynamics simulations indicate that removal of the dimerization domain increased the flexibility of a conserved active site loop that may provide critical interactions with the substrate. PMID- 24806883 TI - Clinicopathological characteristics and prognostic impact of colorectal cancers with NRAS mutations. AB - At present, molecular markers of colorectal cancer (CRC), including KRAS, NRAS and BRAF mutations, and the microsatellite status are evaluated for the development of personalized treatments. However, clinicopathological and molecular characteristics and the prognostic role of NRAS mutations remain unclear. In the present study, a total of 1,304 consecutive stage 0-IV CRC tumor samples were analyzed for KRAS (exon 2, 3 and 4), NRAS (exon 2 and 3) and BRAF (exon 15) mutations. Multivariate analysis was performed to assess the prognostic impact of NRAS mutations. KRAS, NRAS and BRAF mutations were identified in 553 (42.4%), 35 (2.7%), and 59 (4.5%) of 1,304 CRC cases, respectively. Tumors with NRAS mutations were more frequently located in the distal colorectum compared with those with KRAS or BRAF mutations. Multivariate analysis indicated that KRAS and BRAF mutations were found to be associated with poor prognosis [hazard ratio (HR)=1.44, 95% confidence interval (CI), 1.18-1.76 and HR=2.09; 95% CI, 1.33 3.28, respectively], whereas NRAS mutations were associated with a trend toward favorable prognosis (HR=0.53; 95% CI, 0.27-1.03). Characteristics and prognosis of CRC with NRAS mutations are different from those with KRAS or BRAF mutations. PMID- 24806885 TI - Accurate ab initio structural parameters of the diatomic and triatomic van der Waals molecules (11)BNg (X(2)Pi, A(2)Sigma(+)) and (11)BNg2 (X(2)B1), Ng = (4)He, (20)Ne, (40)Ar, (84)Kr, and (132)Xe. AB - The weakly interacting BNg and BNg2 molecular systems, Ng = He, Ne, Ar, Kr, and Xe, have been thoroughly studied through coupled-cluster RCCSD(T) calculations and large correlation consistent basis sets. For the BNg diatomics, the states examined are the X(2)Pi and A(2)Sigma(+), and the X(2)B1 state for the C2v BNg2 triatomics. A series of corrections render our final results reliable, judging as well from the (limited) experimental numbers available. Both BHe and BHe2 are marginally unbound, whereas the attractive interactions of the BNg X(2)Pi states, where Ng = Ne, Ar, Kr, and Xe, are D0 = 19.8, 98.2, 141.9, and 209.1 cm(-1), respectively. For the BRn (Rn = radon) species, an estimated value of interaction energy D0 ~ 280 cm(-1) is obtained by a D0 versus static polarizability (alpha) extrapolation. Corresponding atomization energies of the BNg2 (X(2)B1) molecules are AE0 = 52.0 (BNe2), 263.4 (BAr2), 384.6 (BKr2), and 576.9 (BXe2) cm(-1). PMID- 24806884 TI - Transcriptional control of ROS homeostasis by KUODA1 regulates cell expansion during leaf development. AB - The final size of an organism, or of single organs within an organism, depends on an intricate coordination of cell proliferation and cell expansion. Although organism size is of fundamental importance, the molecular and genetic mechanisms that control it remain far from understood. Here we identify a transcription factor, KUODA1 (KUA1), which specifically controls cell expansion during leaf development in Arabidopsis thaliana. We show that KUA1 expression is circadian regulated and depends on an intact clock. Furthermore, KUA1 directly represses the expression of a set of genes encoding for peroxidases that control reactive oxygen species (ROS) homeostasis in the apoplast. Disruption of KUA1 results in increased peroxidase activity and smaller leaf cells. Chemical or genetic interference with the ROS balance or peroxidase activity affects cell size in a manner consistent with the identified KUA1 function. Thus, KUA1 modulates leaf cell expansion and final organ size by controlling ROS homeostasis. PMID- 24806886 TI - In vivo imaging of multidrug resistance using a third generation MDR1 inhibitor. AB - Cellular up-regulation of multidrug resistance protein 1 (MDR1) is a common cause for resistance to chemotherapy; development of third generation MDR1 inhibitors several of which contain a common 6,7-dimethoxy-2-phenethyl-1,2,3,4 tetrahydroisoquinoline substructure-is underway. Efficacy of these agents has been difficult to ascertain, partly due to a lack of pharmacokinetic reporters for quantifying inhibitor localization and transport dynamics. Some of the recent third generation inhibitors have a pendant heterocycle, for example, a chromone moiety, which we hypothesized could be converted to a fluorophore. Following synthesis and teasing of a small set of analogues, we identified one lead compound that can be used as a cellular imaging agent that exhibits structural similarity and behavior akin to the latest generation of MDR1 inhibitors. PMID- 24806889 TI - Exploring the relationships among food insecurity, alcohol use, and sexual risk taking among men and women living in South African townships. AB - South African townships have among the highest rates of HIV infection in the world. Considerable research on understanding the high rates of HIV transmission in this country has identified alcohol use as a critical factor in driving the HIV epidemic. Although the relationship between alcohol use and sexual risk taking is well documented, less is known about how other factors, such as food insecurity, might be important in understanding alcohol's role in sexual risk taking. Furthermore, prior research has highlighted how patterns of alcohol use and sexual risk-taking tend to vary by gender. We examined how food insecurity is related to both alcohol use and sexual risk-taking. We administered anonymous community surveys to men (n = 1,137) and women (n = 458) residing within four contiguous Black African townships outside of Cape Town, South Africa. In multivariate linear regression, we found that food insecurity was related to having higher numbers of male sex partners and condom-protected sex acts among women only. These relationships, however, were fully mediated by women's alcohol use. Among men, we found that food insecurity was negatively related to unprotected sex; that is, men with greater food security reported more unprotected sex acts. Unlike the results found among women, this relationship was not mediated by alcohol use. Food insecurity appears to be an important factor in understanding patterns of sexual risk-taking in regards to gender and alcohol use, and may serve as an important point of intervention for reducing HIV transmission rates. PMID- 24806890 TI - 3,6-Substituted-1,2,4,5-tetrazines: tuning reaction rates for staged labeling applications. AB - Cycloaddition reactions involving tetrazines have proven to be powerful bioorthogonal tools for various applications. Conceivably, sequential and selective labeling using tetrazine-based reactions can be achieved by tuning the reaction rate. By varying the substituents on tetrazines, cycloaddition rate variations of over 200 fold have been achieved with the same dienophile. Upon coupling with different dienophiles, such as norbornene, the reaction rate difference can be over 14,000 fold. These substituted tetrazines can be very useful for selective labeling under different conditions. PMID- 24806891 TI - Walking through trabecular meshwork biology: Toward engineering design of outflow physiology. AB - According to the World Health Organization, glaucoma remains the second leading cause of blindness in the world. Glaucoma belongs to a group of optic neuropathies that is characterized by chronic degeneration of the optic nerve along with its supporting glia and vasculature. Despite significant advances in the field, there is no available cure for glaucoma. The trabecular meshwork has been implicated as the primary site for regulation of intraocular pressure, the only known modifiable factor in glaucoma development. In this review, we describe the current models for glaucoma studies, primary culture, anterior eye segments, and animal studies and their limitations. These models, especially anterior eye segments and animal tissues, often require careful interpretation given the inter species variation and are cumbersome and expensive. The lack of an available in vitro 3D model to study trabecular meshwork cells and detailed mechanisms of their regulation of intraocular pressure has limited progress in the field of glaucoma research. In this paper, we review the current status of knowledge of the trabecular meshwork and how the current advances in tissue engineering techniques might be applied in an effort to engineer a synthetic trabecular meshwork as a 3D in vitro model to further advance glaucoma research. In addition, we describe strategies for selection and design of biomaterials for scaffold fabrication as well as extracellular matrix components to mimic and support the trabecular architecture. We also discuss possible uses for a bioengineered trabecular meshwork for both developing a fundamental understanding of trabecular meshwork biology as well as high-throughput screening of glaucoma drugs. PMID- 24806892 TI - Dietary fish intake and the risk for type 2 diabetes and cardiovascular disease: new insights. PMID- 24806893 TI - Bariatric surgery and cardiovascular risk reduction. PMID- 24806894 TI - Atherosclerosis: cell biology and lipoproteins - epigenetics and oxidation in atherosclerosis. PMID- 24806895 TI - Management of homozygous familial hypercholesterolaemia. PMID- 24806897 TI - Circular strand displacement polymerization reaction: a promising technique? PMID- 24806898 TI - Platinum porous nanoparticles for the detection of cancer biomarkers: what are the advantages over existing techniques? PMID- 24806899 TI - Using bioanalysis for cancer diagnosis and prognosis. PMID- 24806901 TI - Conference Report: 4th Japan Bioanalysis Forum Symposium: Japanese guidelines on bioanalytical method validation and latest discussion within the Japanese bioanalyst community. AB - The Japan Bioanalysis Forum (JBF) was established in 2011 as a group for the purpose of discussion on regulated bioanalysis in Japan. The forum has played a prominent role in the development of Japanese bioanalytical method validation guidelines and has supported Japanese Harmonization Team members of the Global Bioanalysis Consortium. At the 4th JBF Symposium, the outline of the bioanalytical method validation guideline for small molecules in Japan, which was just published in July 2013, and that of the JBF draft guideline for ligand binding assay, were presented. In addition, the outcomes of discussion groups, in which regulated bioanalysis issues were scientifically discussed, were also presented to about 250 attendees from industry, government and academia. PMID- 24806902 TI - Quantification of urinary mevalonic acid as a biomarker of HMG-CoA reductase activity by a novel translational LC-MS/MS method. AB - BACKGROUND: Mevalonic acid (MVA), as a product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, represents a potential multipurpose biomarker in health and disease. A translational urinary MVA quantification method was developed, validated and used to demonstrate the diurnal variation of urinary MVA excretion in rats and healthy children. METHODS: Urinary MVA was converted to mevalonolactone at pH 2, extracted with ethyl acetate and quantified by reversed phase liquid chromatography-tandem mass spectrometry. RESULTS: The assay had a dynamic range of 0.0156-10 ug/ml with precision <15% CV, accuracy 85-115% and was transferred between laboratories. Urinary MVA excretion in rats and healthy children displayed a diurnal variation consistent with the known diurnal variation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. CONCLUSION: Urinary MVA can be quantified accurately over a wide dynamic range by a validated translational and transferable method with biomarker capability. PMID- 24806903 TI - Development of methods for the bioanalysis of RRx-001 and metabolites. AB - BACKGROUND: Bioanalytical methods were required to study the novel anticancer drug, RRx-001 preclinically and for clinical pharmacokinetic analysis; however, RRx-001 quickly and completely disappeared on intravenous administration in preclinical species. RESULTS: Quantification of RRx-001 directly or by derivatization was unsuccessful. On exposure to whole blood, RRx-001 formed the glutathione (GSH) adduct very rapidly, suggesting this metabolite as the bioanalyte. However, rapid enzymatic degradation in the blood matrix of RRx-001 GSH posed significant technical problems. Herein, we describe a novel and broadly applicable solution to stabilize GSH conjugates in blood samples by inhibiting the degrading enzyme. Liquid chromatography-tandem mass spectrometry methods for analysis of RRx-001-GSH in rat, dog and human plasma were developed and successfully validated to good laboratory practice standards. CONCLUSION: Extensive breakdown of RRx-001-GSH was effectively stopped by addition of the enzyme inhibitor, acivicin. The developed liquid chromatography-tandem mass spectrometry assay for RRx-001-GSH was validated for use in preclinical toxicology studies and the Phase I first-in-human clinical trial. PMID- 24806904 TI - Fluoroplast-polyaniline-coated adsorbent for one-step isolation of DNA for PCR detection of viral hepatitides (HBV and TTV). AB - AIMS: To demonstrate the effectiveness of application of the adsorbent successively modified with nano-layers of fluoroplast and polyaniline for one step isolation of DNA of hepatitis B virus and transfusion-transmitted virus from human serum. MATERIALS & METHODS: The technique is based on the application of the spin-cartridges containing porous adsorbent for one-step viral DNA isolation from serum followed by polymerase chain reaction. RESULTS: The developed adsorbent was shown to be effective for one-step isolation of viral DNA from serum samples for polymerase chain reaction diagnostics. CONCLUSION: The effectiveness of the developed adsorbent application for isolation of viral DNA from serum for polymerase chain reaction diagnostics was confirmed in comparison with standard methods. Thus, the facile sample preparation method of viral DNA isolation was elaborated. PMID- 24806905 TI - Advances in tissue section preparation for MALDI imaging MS. AB - Enriched by a decade of remarkable developments, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) has witnessed a phenomenal expansion. Initially introduced for the mapping of peptides and intact proteins from mammalian tissue sections, MALDI IMS applications now extend to a wide range of molecules including peptides, lipids, metabolites and xenobiotics. Technology and methodology are quickly evolving to push the limits of the technique forward. Within a short period of time, numerous protocols and concepts have been developed and introduced in tissue section preparation, nonexhaustively including in situ tissue chemistries and solvent-free matrix depositions. Considering the past progress and current capabilities, this Review aims to cover the different aspects and challenges of tissue section preparation for MALDI IMS. PMID- 24806906 TI - Conjugated critical reagent characterization for ligand-binding assays: using MALDI-TOF-MS as an orthogonal tool to assess assay performance. AB - Large-molecule biotherapeutics are forming an increasingly large percentage of emerging pharmaceutical pipelines. These molecules present specific challenges to the bioanalysts charged with measuring in vivo concentrations of the biotherapeutic. The challenges are typically met using ligand-binding assays in support of pharmacokinetic, pharmacodynamic and immunogenicity assays. Ligand binding assays employ complex biological molecules that specifically recognize the biotherapeutic for quantitation. Generally, a minimum of one of these critical reagents must be chemically modified to generate a signal that is measured in the assay. Once chemically modified it is necessary to characterize the reagent prior to use in an assay. The concentration, purity and molar incorporation ratio of chemical modification are key characteristics. This article presents mass spectral techniques for determining the molar incorporation ratio. Case studies are provided to demonstrate the time and cost savings that can be realized with timely and detailed characterization of critical reagents for ligand-binding assays. PMID- 24806907 TI - Quantification of taxanes in biological matrices: a review of bioanalytical assays and recommendations for development of new assays. AB - Since the isolation of paclitaxel and its approval for the treatment of breast cancer, various taxanes and taxane formulations have been developed. To date, almost 100 bioanalytical assays have been published with the method development and optimization often extensively discussed by the authors. This Review presents an overview of assays published between January 1970 and September 2013 that described method development and validation of assays used to quantify taxanes in biological matrices such as plasma, urine, feces and tissue samples. For liquid chromatography assays, sample pretreatment, chromatographic separation and assay performance are compared. Since this Review discusses the limitations of previously developed liquid chromatography assays and gives recommendations for future assay development, it can be used as a reference for future development of liquid chromatography assays for the quantification of taxanes in various biological matrices to support preclinical and clinical studies. PMID- 24806908 TI - Recent developments in liquid-phase separation techniques for metabolomics. AB - Metabolomics is the comprehensive analysis of low molecular weight compounds in biological samples such as cells, body fluids and tissues. Comprehensive profiling of metabolites in complex sample matrices with the current analytical toolbox remains a huge challenge. Over the past few years, liquid chromatography mass spectrometry (LC-MS) and capillary electrophoresis-mass spectrometry (CE-MS) have emerged as powerful complementary analytical techniques in the field of metabolomics. This Review provides an update of the most recent developments in LC-MS and CE-MS for metabolomics. Concerning LC-MS, attention is paid to developments in column technology and miniaturized systems, while strategies are discussed to improve the reproducibility and the concentration sensitivity of CE MS for metabolomics studies. Novel interfacing techniques for coupling CE to MS are also considered. Representative examples illustrate the potential of the recent developments in LC-MS and CE-MS for metabolomics. Finally, some conclusions and perspectives are provided. PMID- 24806909 TI - Quantum state majorization at the output of bosonic Gaussian channels. AB - Quantum communication theory explores the implications of quantum mechanics to the tasks of information transmission. Many physical channels can be formally described as quantum Gaussian operations acting on bosonic quantum states. Depending on the input state and on the quality of the channel, the output suffers certain amount of noise. For a long time it has been conjectured, but never proved, that output states of Gaussian channels corresponding to coherent input signals are the less noisy ones (in the sense of a majorization criterion). Here we prove this conjecture. Specifically we show that every output state of a phase-insensitive Gaussian channel is majorized by the output state corresponding to a coherent input. The proof is based on the optimality of coherent states for the minimization of strictly concave output functionals. Moreover we show that coherent states are the unique optimizers. PMID- 24806910 TI - Pharmacokinetics of tramadol and its major metabolite after intramuscular administration in piglets. AB - Tramadol (T) is a centrally acting atypical opioid used for treatment of dogs. Piglets might experience pain following castration, tooth clipping and tail docking and experimental procedures. The aim of this study was to assess the pharmacokinetics of T and its active metabolite M1 in male piglets after a single intramuscular injection. Six healthy male piglets were administered T (5 mg/kg) intramuscularly. Blood was sampled at scheduled time intervals and drug plasma concentrations evaluated by a validated HPLC method. T plasma concentration was quantitatively detectable from 0.083 to 8 h. M1 was quantified over a shorter time period (0.083-6 h) with a Tmax at 0.821 h. The study demonstrated that piglets produce a larger amount of M1 compared with dogs, horses and goats. The human minimum effective concentration of M1 (40 ng/mL) was exceeded for over 3 h in piglets. If it is assumed to also apply to piglets, it could be speculated that the drug efficacy might exert its action over 3 h or longer. This assumption has to be confirmed by further specific pharmacokinetic/pharmacodynamic studies. PMID- 24806911 TI - Cryoinsufflation for Hurley stage II hidradenitis suppurativa: a useful treatment option when systemic therapies should be avoided. PMID- 24806912 TI - Bioactive silica nanoparticles promote osteoblast differentiation through stimulation of autophagy and direct association with LC3 and p62. AB - We recently identified an engineered bioactive silica-based nanoparticle formulation (designated herein as NP1) that stimulates in vitro differentiation and mineralization of osteoblasts, the cells responsible for bone formation, and increases bone mineral density in young mice in vivo. The results demonstrate that these nanoparticles have intrinsic biological activity; however, the intracellular fate and a complete understanding of the mechanism(s) involved remains to be elucidated. Here we investigated the cellular mechanism(s) by which NP1 stimulates differentiation and mineralization of osteoblasts. We show that NP1 enters the cells through a caveolae-mediated endocytosis followed by stimulation of the mitogen activated protein kinase ERK1/2 (p44/p42). Our findings further revealed that NP1 stimulates autophagy including the processing of LC3beta-I to LC3beta-II, a key protein involved in autophagosome formation, which is dependent on ERK1/2 signaling. Using a variant of NP1 with cobalt ferrite magnetic metal core (NP1-MNP) to pull down associated proteins, we found direct binding of LC3beta and p62, two key proteins involved in autophagosome formation, with silica nanoparticles. Interestingly, NP1 specifically interacts with the active and autophagosome associated form of LC3beta (LC3beta-II). Taken together, the stimulation of autophagy and associated signaling suggests a cellular mechanism for the stimulatory effects of silica nanoparticles on osteoblast differentiation and mineralization. PMID- 24806913 TI - Biophysical studies reveal new evidence for one-way revolution mechanism of bacteriophage phi29 DNA packaging motor. PMID- 24806914 TI - How to get oscillators in a multicellular clock to agree on the right period. PMID- 24806915 TI - The many faces of lipid rafts. PMID- 24806917 TI - Permeation redux: thermodynamics and kinetics of ion movement through potassium channels. AB - The fundamental biophysics underlying the selective movement of ions through ion channels was launched by George Eisenman in the 1960s, using glass electrodes. This minireview examines the insights from these early studies and the explosive progress made since then. PMID- 24806916 TI - Mechanical operation and intersubunit coordination of ring-shaped molecular motors: insights from single-molecule studies. AB - Ring NTPases represent a large and diverse group of proteins that couple their nucleotide hydrolysis activity to a mechanical task involving force generation and some type of transport process in the cell. Because of their shape, these enzymes often operate as gates that separate distinct cellular compartments to control and regulate the passage of chemical species across them. In this manner, ions and small molecules are moved across membranes, biopolymer substrates are segregated between cells or moved into confined spaces, double-stranded nucleic acids are separated into single strands to provide access to the genetic information, and polypeptides are unfolded and processed for recycling. Here we review the recent advances in the characterization of these motors using single molecule manipulation and detection approaches. We describe the various mechanisms by which ring motors convert chemical energy to mechanical force or torque and coordinate the activities of individual subunits that constitute the ring. We also examine how single-molecule studies have contributed to a better understanding of the structural elements involved in motor-substrate interaction, mechanochemical coupling, and intersubunit coordination. Finally, we discuss how these molecular motors tailor their operation-often through regulation by other cofactors-to suit their unique biological functions. PMID- 24806918 TI - Dynamic mechanical responses of Arabidopsis thylakoid membranes during PSII specific illumination. AB - Remodeling of thylakoid membranes in response to illumination is an important process for the regulation of photosynthesis. We investigated the thylakoid network from Arabidopsis thaliana using atomic force microscopy to capture dynamic changes in height, elasticity, and viscosity of isolated thylakoid membranes caused by changes in illumination. We also correlated the mechanical response of the thylakoid network with membrane ultrastructure using electron microscopy. We find that the elasticity of the thylakoid membranes increases immediately upon PSII-specific illumination, followed by a delayed height change. Direct visualization by electron microscopy confirms that there is a significant change in the packing repeat distance of the membrane stacks in response to illumination. Although experiments with Gramicidin show that the change in elasticity depends primarily on the transmembrane pH gradient, the height change requires both the pH gradient and STN7-kinase-dependent phosphorylation of LHCII. Our studies indicate that lumen expansion in response to illumination is not simply a result of the influx of water, and we propose a dynamic model in which protein interactions within the lumen drive these changes. PMID- 24806919 TI - Chromatin hydrodynamics. AB - Following recent observations of large scale correlated motion of chromatin inside the nuclei of live differentiated cells, we present a hydrodynamic theory the two-fluid model-in which the content of a nucleus is described as a chromatin solution with the nucleoplasm playing the role of the solvent and the chromatin fiber that of a solute. This system is subject to both passive thermal fluctuations and active scalar and vector events that are associated with free energy consumption, such as ATP hydrolysis. Scalar events drive the longitudinal viscoelastic modes (where the chromatin fiber moves relative to the solvent) while vector events generate the transverse modes (where the chromatin fiber moves together with the solvent). Using linear response methods, we derive explicit expressions for the response functions that connect the chromatin density and velocity correlation functions to the corresponding correlation functions of the active sources and the complex viscoelastic moduli of the chromatin solution. We then derive general expressions for the flow spectral density of the chromatin velocity field. We use the theory to analyze experimental results recently obtained by one of the present authors and her co workers. We find that the time dependence of the experimental data for both native and ATP-depleted chromatin can be well-fitted using a simple model-the Maxwell fluid-for the complex modulus, although there is some discrepancy in terms of the wavevector dependence. Thermal fluctuations of ATP-depleted cells are predominantly longitudinal. ATP-active cells exhibit intense transverse long wavelength velocity fluctuations driven by force dipoles. Fluctuations with wavenumbers larger than a few inverse microns are dominated by concentration fluctuations with the same spectrum as thermal fluctuations but with increased intensity. PMID- 24806920 TI - Oxygen concentration inside a functioning photosynthetic cell. AB - The excess oxygen concentration in the photosynthetic membranes of functioning oxygenic photosynthetic cells was estimated using classical diffusion theory combined with experimental data on oxygen production rates of cyanobacterial cells. The excess oxygen concentration within the plesiomorphic cyanobacterium Gloeobactor violaceus is only 0.025 MUM, or four orders of magnitude lower than the oxygen concentration in air-saturated water. Such a low concentration suggests that the first oxygenic photosynthetic bacteria in solitary form could have evolved ~2.8 billion years ago without special mechanisms to protect them against reactive oxygen species. These mechanisms instead could have been developed during the following ~500 million years while the oxygen level in the Earth's atmosphere was slowly rising. Excess oxygen concentrations within individual cells of the apomorphic cyanobacteria Synechocystis and Synechococcus are 0.064 and 0.25 MUM, respectively. These numbers suggest that intramembrane and intracellular proteins in isolated oxygenic photosynthetic cells are not subjected to excessively high oxygen levels. The situation is different for closely packed colonies of photosynthetic cells. Calculations show that the excess concentration within colonies that are ~40 MUm or larger in diameter can be comparable to the oxygen concentration in air-saturated water, suggesting that species forming colonies require protection against reactive oxygen species even in the absence of oxygen in the surrounding atmosphere. PMID- 24806921 TI - A computational study of stress fiber-focal adhesion dynamics governing cell contractility. AB - We apply a recently developed model of cytoskeletal force generation to study a cell's intrinsic contractility, as well as its response to external loading. The model is based on a nonequilibrium thermodynamic treatment of the mechanochemistry governing force in the stress fiber-focal adhesion system. Our computational study suggests that the mechanical coupling between the stress fibers and focal adhesions leads to a complex, dynamic, mechanochemical response. We collect the results in response maps whose regimes are distinguished by the initial geometry of the stress fiber-focal adhesion system, and by the external load on the cell. The results from our model connect qualitatively with recent studies on the force response of smooth muscle cells on arrays of polymeric microposts. PMID- 24806922 TI - The role of dyadic organization in regulation of sarcoplasmic reticulum Ca(2+) handling during rest in rabbit ventricular myocytes. AB - The dyadic organization of ventricular myocytes ensures synchronized activation of sarcoplasmic reticulum (SR) Ca(2+) release during systole. However, it remains obscure how the dyadic organization affects SR Ca(2+) handling during diastole. By measuring intraluminal SR Ca(2+) ([Ca(2+)]SR) decline during rest in rabbit ventricular myocytes, we found that ~76% of leaked SR Ca(2+) is extruded from the cytosol and only ~24% is pumped back into the SR. Thus, the majority of Ca(2+) that leaks from the SR is removed from the cytosol before it can be sequestered back into the SR by the SR Ca(2+)-ATPase (SERCA). Detubulation decreased [Ca(2+)]SR decline during rest, thus making the leaked SR Ca(2+) more accessible for SERCA. These results suggest that Ca(2+) extrusion systems are localized in T tubules. Inhibition of Na(+)-Ca(2+) exchanger (NCX) slowed [Ca(2+)]SR decline during rest by threefold, however did not prevent it. Depolarization of mitochondrial membrane potential during NCX inhibition completely prevented the rest-dependent [Ca(2+)]SR decline. Despite a significant SR Ca(2+) leak, Ca(2+) sparks were very rare events in control conditions. NCX inhibition or detubulation increased Ca(2+) spark activity independent of SR Ca(2+) load. Overall, these results indicate that during rest NCX effectively competes with SERCA for cytosolic Ca(2+) that leaks from the SR. This can be explained if the majority of SR Ca(2+) leak occurs through ryanodine receptors in the junctional SR that are located closely to NCX in the dyadic cleft. Such control of the dyadic [Ca(2+)] by NCX play a critical role in suppressing Ca(2+) sparks during rest. PMID- 24806923 TI - Automated identification of subcellular organelles by coherent anti-stokes Raman scattering. AB - Coherent anti-Stokes Raman scattering (CARS) is an emerging tool for label-free characterization of living cells. Here, unsupervised multivariate analysis of CARS datasets was used to visualize the subcellular compartments. In addition, a supervised learning algorithm based on the "random forest" ensemble learning method as a classifier, was trained with CARS spectra using immunofluorescence images as a reference. The supervised classifier was then used, to our knowledge for the first time, to automatically identify lipid droplets, nucleus, nucleoli, and endoplasmic reticulum in datasets that are not used for training. These four subcellular components were simultaneously and label-free monitored instead of using several fluorescent labels. These results open new avenues for label-free time-resolved investigation of subcellular components in different cells, especially cancer cells. PMID- 24806924 TI - Insights into the excitonic states of individual chlorosomes from Chlorobaculum tepidum. AB - Green-sulfur bacteria have evolved a unique light-harvesting apparatus, the chlorosome, by which it is perfectly adapted to thrive photosynthetically under extremely low light conditions. We have used single-particle, optical spectroscopy to study the structure-function relationship of chlorosomes each of which incorporates hundreds of thousands of self-assembled bacteriochlorophyll (BChl) molecules. The electronically excited states of these molecular assemblies are described as Frenkel excitons whose photophysical properties depend crucially on the mutual arrangement of the pigments. The signature of these Frenkel excitons and its relation to the supramolecular organization of the chlorosome becomes accessible by optical spectroscopy. Because subtle spectral features get obscured by ensemble averaging, we have studied individual chlorosomes from wild type Chlorobaculum tepidum by polarization-resolved fluorescence-excitation spectroscopy. This approach minimizes the inherent sample heterogeneity and allows us to reveal properties of the exciton states without ensemble averaging. The results are compared with predictions from computer simulations of various models of the supramolecular organization of the BChl monomers. We find that the photophysical properties of individual chlorosomes from wild-type Chlorobaculum tepidum are consistent with a (multiwall) helical arrangement of syn-anti stacked BChl molecules in cylinders and/or spirals of different size. PMID- 24806925 TI - In vivo kinetics of segregation and polar retention of MS2-GFP-RNA complexes in Escherichia coli. AB - The cytoplasm of Escherichia coli is a crowded, heterogeneous environment. From single cell live imaging, we investigated the spatial kinetics and heterogeneities of synthetic RNA-protein complexes. First, although their known tendency to accumulate at the cell poles does not appear to introduce asymmetries between older and newer cell poles within a cell lifetime, these emerge with cell divisions. This suggests strong polar retention of the complexes, which we verified in their history of positions and mean escape time from the poles. Next, we show that the polar retention relies on anisotropies in the displacement distribution in the region between midcell and poles, whereas the speed is homogeneous along the major cell axis. Afterward, we establish that these regions are at the border of the nucleoid and shift outward with cell growth, due to the nucleoid's replication. Overall, the spatiotemporal kinetics of the complexes, which is robust to suboptimal temperatures, suggests that nucleoid occlusion is a source of dynamic heterogeneities of macromolecules in E. coli that ultimately generate phenotypic differences between sister cells. PMID- 24806926 TI - A predicted binding site for cholesterol on the GABAA receptor. AB - Modulation of the GABA type A receptor (GABAAR) function by cholesterol and other steroids is documented at the functional level, yet its structural basis is largely unknown. Current data on structurally related modulators suggest that cholesterol binds to subunit interfaces between transmembrane domains of the GABAAR. We construct homology models of a human GABAAR based on the structure of the glutamate-gated chloride channel GluCl of Caenorhabditis elegans. The models show the possibility of previously unreported disulfide bridges linking the M1 and M3 transmembrane helices in the alpha and gamma subunits. We discuss the biological relevance of such disulfide bridges. Using our models, we investigate cholesterol binding to intersubunit cavities of the GABAAR transmembrane domain. We find that very similar binding modes are predicted independently by three approaches: analogy with ivermectin in the GluCl crystal structure, automated docking by AutoDock, and spontaneous rebinding events in unbiased molecular dynamics simulations. Taken together, the models and atomistic simulations suggest a somewhat flexible binding mode, with several possible orientations. Finally, we explore the possibility that cholesterol promotes pore opening through a wedge mechanism. PMID- 24806927 TI - Differential effects of RGK proteins on L-type channel function in adult mouse skeletal muscle. AB - Work in heterologous systems has revealed that members of the Rad, Rem, Rem2, Gem/Kir (RGK) family of small GTP-binding proteins profoundly inhibit L-type Ca(2+) channels via three mechanisms: 1), reduction of membrane expression; 2), immobilization of the voltage-sensors; and 3), reduction of Po without impaired voltage-sensor movement. However, the question of which mode is the critical one for inhibition of L-type channels in their native environments persists. To address this conundrum in skeletal muscle, we overexpressed Rad and Rem in flexor digitorum brevis (FDB) fibers via in vivo electroporation and examined the abilities of these two RGK isoforms to modulate the L-type Ca(2+) channel (CaV1.1). We found that Rad and Rem both potently inhibit L-type current in FDB fibers. However, intramembrane charge movement was only reduced in fibers transfected with Rad; charge movement for Rem-expressing fibers was virtually identical to charge movement observed in naive fibers. This result indicated that Rem supports inhibition solely through a mechanism that allows for translocation of CaV1.1's voltage-sensors, whereas Rad utilizes at least one mode that limits voltage-sensor movement. Because Rad and Rem differ significantly only in their amino-termini, we constructed Rad-Rem chimeras to probe the structural basis for the distinct specificities of Rad- and Rem-mediated inhibition. Using this approach, a chimera composed of the amino-terminus of Rem and the core/carboxyl terminus of Rad inhibited L-type current without reducing charge movement. Conversely, a chimera having the amino-terminus of Rad fused to the core/carboxyl terminus of Rem inhibited L-type current with a concurrent reduction in charge movement. Thus, we have identified the amino-termini of Rad and Rem as the structural elements dictating the specific modes of inhibition of CaV1.1. PMID- 24806928 TI - Molecular modeling of lipid membrane curvature induction by a peptide: more than simply shape. AB - Molecular dynamics simulations of an amphipathic helix embedded in a lipid bilayer indicate that it will induce substantial positive curvature (e.g., a tube of diameter 20 nm at 16% surface coverage). The induction is twice that of a continuum model prediction that only considers the shape of the inclusion. The discrepancy is explained in terms of the additional presence of specific interactions described only by the molecular model. The conclusion that molecular shape alone is insufficient to quantitatively model curvature is supported by contrasting molecular and continuum models of lipids with large and small headgroups (choline and ethanolamine, respectively), and of the removal of a lipid tail (modeling a lyso-lipid). For the molecular model, curvature propensity is analyzed by computing the derivative of the free energy with respect to bending. The continuum model predicts that the inclusion will soften the bilayer near the headgroup region, an effect that may weaken curvature induction. The all atom predictions are consistent with experimental observations of the degree of tubulation by amphipathic helices and variation of the free energy of binding to liposomes. PMID- 24806929 TI - Critical behaviour in DOPC/DPPC/cholesterol mixtures: static (2)H NMR line shapes near the critical point. AB - Static (2)H NMR spectroscopy is used to study the critical behavior of mixtures of 1,2-dioleoyl-phosphatidylcholine/1,2-dipalmitoyl-phosphatidylcholine (DPPC)/cholesterol in molar proportion 37.5:37.5:25 using either chain perdeuterated DPPC-d62 or chain methyl deuterated DPPC-d6. The temperature dependence of the first moment of the (2)H spectrum of the sample made with DPPC d62 and of the quadrupolar splittings of the chain-methyl-labeled DPPC-d6 sample are directly related to the temperature dependence of the critical order parameter eta, which scales as [Formula: see text] near the critical temperature. Analysis of the data reveals that for the chain perdeuterated sample, the value of Tc is 301.51 +/- 0.1 K, and that of the critical exponent, betac = 0.391 +/- 0.02. The line shape analysis of the methyl labeled (d6) sample gives Tc = 303.74 +/- 0.07 K and betac = 0.338 +/- 0.009. These values obtained for betac are in good agreement with the predictions of a three-dimensional Ising model. The difference in critical temperature between the two samples having nominally the same molar composition arises because of the lowering of the phase transition temperature that occurs due to the perdeuteration of the DPPC. PMID- 24806930 TI - Macroscopic phase separation, modulated phases, and microemulsions: a unified picture of rafts. AB - We simulate a simple phenomenological model describing phase behavior in a multicomponent membrane, a model capable of producing macroscopic phase separation, modulated phases, and microemulsions, all of which have been discussed in terms of raft phenomena. We show that one effect of thermal fluctuations on the mean-field phase diagram is that it permits a direct transition between either one of the coexisting liquid phases to a microemulsion. This implies that one system exhibiting phase separation can be related to a similar system exhibiting the heterogeneities characteristic of a microemulsion. The two systems could differ in their average membrane composition or in the relative compositions of their exoplasmic and cytoplasmic leaves. The model provides a unified description of these raft-associated phenomena. PMID- 24806931 TI - Organelle size scaling of the budding yeast vacuole is tuned by membrane trafficking rates. AB - Organelles serve as biochemical reactors in the cell, and often display characteristic scaling trends with cell size, suggesting mechanisms that coordinate their sizes. In this study, we measure the vacuole-cell size scaling trends in budding yeast using optical microscopy and a novel, to our knowledge, image analysis algorithm. Vacuole volume and surface area both show characteristic scaling trends with respect to cell size that are consistent among different strains. Rapamycin treatment was found to increase vacuole-cell size scaling trends for both volume and surface area. Unexpectedly, these increases did not depend on macroautophagy, as similar increases in vacuole size were observed in the autophagy deficient mutants atg1Delta and atg5Delta. Rather, rapamycin appears to act on vacuole size by inhibiting retrograde membrane trafficking, as the atg18Delta mutant, which is defective in retrograde trafficking, shows similar vacuole size scaling to rapamycin-treated cells and is itself insensitive to rapamycin treatment. Disruption of anterograde membrane trafficking in the apl5Delta mutant leads to complementary changes in vacuole size scaling. These quantitative results lead to a simple model for vacuole size scaling based on proportionality between cell growth rates and vacuole growth rates. PMID- 24806932 TI - Nuclear pore complex protein sequences determine overall copolymer brush structure and function. AB - The transport of cargo across the nuclear membrane is highly selective and accomplished by a poorly understood mechanism involving hundreds of nucleoporins lining the inside of the nuclear pore complex (NPC). Currently, there is no clear picture of the overall structure formed by this collection of proteins within the pore, primarily due to their disordered nature. We perform coarse-grained simulations of both individual nucleoporins and grafted rings of nups mimicking the in vivo geometry of the NPC and supplement this with polymer brush modeling. Our results indicate that different regions or blocks of an individual NPC protein can have distinctly different forms of disorder and that this property appears to be a conserved functional feature. Furthermore, this block structure at the individual protein level is critical to the formation of a unique higher order polymer brush architecture that can exist in distinct morphologies depending on the effective interaction energy between the phenylalanine glycine (FG) domains of different nups. Because the interactions between FG domains may be modulated by certain forms of transport factors, our results indicate that transitions between brush morphologies could play an important role in regulating transport across the NPC, suggesting novel forms of gated transport across membrane pores with wide biomimetic applicability. PMID- 24806933 TI - Single-molecule spectroscopy unmasks the lowest exciton state of the B850 assembly in LH2 from Rps. acidophila. AB - We have recorded fluorescence-excitation and emission spectra from single LH2 complexes from Rhodopseudomonas (Rps.) acidophila. Both types of spectra show strong temporal spectral fluctuations that can be visualized as spectral diffusion plots. Comparison of the excitation and emission spectra reveals that for most of the complexes the lowest exciton transition is not observable in the excitation spectra due to the cutoff of the detection filter characteristics. However, from the spectral diffusion plots we have the full spectral and temporal information at hand and can select those complexes for which the excitation spectra are complete. Correlating the red most spectral feature of the excitation spectrum with the blue most spectral feature of the emission spectrum allows an unambiguous assignment of the lowest exciton state. Hence, application of fluorescence-excitation and emission spectroscopy on the same individual LH2 complex allows us to decipher spectral subtleties that are usually hidden in traditional ensemble spectroscopy. PMID- 24806934 TI - Crowding activates ClpB and enhances its association with DnaK for efficient protein aggregate reactivation. AB - Reactivation of intracellular protein aggregates after a severe stress is mandatory for cell survival. In bacteria, this activity depends on the collaboration between the DnaK system and ClpB, which in vivo occurs in a highly crowded environment. The reactivation reaction includes two steps: extraction of unfolded monomers from the aggregate and their subsequent refolding into the native conformation. Both steps might be compromised by excluded volume conditions that would favor aggregation of unstable protein folding intermediates. Here, we have investigated whether ClpB and the DnaK system are able to compensate this unproductive effect and efficiently reactivate aggregates of three different substrate proteins under crowding conditions. To this aim, we have compared the association equilibrium, biochemical properties, stability, and chaperone activity of the disaggregase ClpB in the absence and presence of an inert macromolecular crowding agent. Our data show that crowding i), increases three to four orders of magnitude the association constant of the functional hexamer; ii), shifts the conformational equilibrium of the protein monomer toward a compact state; iii), stimulates its ATPase activity; and iv), favors association of the chaperone with substrate proteins and with aggregate-bound DnaK. These effects strongly enhance protein aggregate reactivation by the DnaK ClpB network, highlighting the importance of volume exclusion in complex processes in which several proteins have to work in a sequential manner. PMID- 24806935 TI - Transient antibody-mucin interactions produce a dynamic molecular shield against viral invasion. AB - Given the difficulty in finding a cure for HIV/AIDS, a promising prevention strategy to reduce HIV transmission is to directly block infection at the portal of entry. The recent Thai RV144 trial offered the first evidence that an antibody based vaccine may block heterosexual HIV transmission. Unfortunately, the underlying mechanism(s) for protection remain unclear. Here we theoretically examine a hypothesis that builds on our recent laboratory observation: virus specific antibodies (Ab) can trap individual virions in cervicovaginal mucus (CVM), thereby reducing infection in vivo. Ab are known to have a weak-previously considered inconsequential-binding affinity with the mucin fibers that constitute CVM. However, multiple Ab can bind to the same virion at the same time, which markedly increases the overall Ab-mucin binding avidity, and creates an inheritable virion-mucin affinity. Our model takes into account biologically relevant length and timescales, while incorporating known HIV-Ab affinity and the respective diffusivities of viruses and Ab in semen and CVM. The model predicts that HIV-specific Ab in CVM leads to rapid formation and persistence of an HIV concentration front near the semen/CVM interface, far from the vaginal epithelium. Such an HIV concentration front minimizes the flux of HIV virions reaching target cells, and maximizes their elimination upon drainage of genital secretions. The robustness of the result implies that even exceedingly weak Ab mucin affinity can markedly reduce the flux of virions reaching target cells. Beyond this specific application, the model developed here is adaptable to other pathogens, mucosal barriers, and geometries, as well as kinetic and diffusional effects, providing a tool for hypothesis testing and producing quantitative insights into the dynamics of immune-mediated protection. PMID- 24806936 TI - Variable cell morphology approach for individual-based modeling of microbial communities. AB - An individual-based, mass-spring modeling framework has been developed to investigate the effect of cell properties on the structure of biofilms and microbial aggregates through Lagrangian modeling. Key features that distinguish this model are variable cell morphology described by a collection of particles connected by springs and a mechanical representation of deformable intracellular, intercellular, and cell-substratum links. A first case study describes the colony formation of a rod-shaped species on a planar substratum. This case shows the importance of mechanical interactions in a community of growing and dividing rod shaped cells (i.e., bacilli). Cell-substratum links promote formation of mounds as opposed to single-layer biofilms, whereas filial links affect the roundness of the biofilm. A second case study describes the formation of flocs and development of external filaments in a mixed-culture activated sludge community. It is shown by modeling that distinct cell-cell links, microbial morphology, and growth kinetics can lead to excessive filamentous proliferation and interfloc bridging, possible causes for detrimental sludge bulking. This methodology has been extended to more advanced microbial morphologies such as filament branching and proves to be a very powerful tool in determining how fundamental controlling mechanisms determine diverse microbial colony architectures. PMID- 24806937 TI - Systems modeling of Ca(2+) homeostasis and mobilization in platelets mediated by IP3 and store-operated Ca(2+) entry. AB - Resting platelets maintain a stable level of low cytoplasmic calcium ([Ca(2+)]cyt) and high dense tubular system calcium ([Ca(2+)]dts). During thrombosis, activators cause a transient rise in inositol trisphosphate (IP3) to trigger calcium mobilization from stores and elevation of [Ca(2+)]cyt. Another major source of [Ca(2+)]cyt elevation is store-operated calcium entry (SOCE) through plasmalemmal calcium channels that open in response to store depletion as [Ca(2+)]dts drops. A 34-species systems model employed kinetics describing IP3 receptor, DTS-plasmalemma puncta formation, SOCE via assembly of STIM1 and Orai1, and the plasmalemma and sarco/endoplasmic reticulum Ca(2+)-ATPases. Four constraints were imposed: calcium homeostasis before activation; stable in zero extracellular calcium; IP3-activatable; and functional SOCE. Using a Monte Carlo method to sample three unknown parameters and nine initial concentrations in a 12 dimensional space near measured or expected values, we found that model configurations that were responsive to stimuli and demonstrated significant SOCE required high inner membrane electric potential (>-70 mV) and low resting IP3 concentrations. The absence of puncta in resting cells was required to prevent spontaneous store depletion in calcium-free media. Ten-fold increases in IP3 caused saturated calcium mobilization. This systems model represents a critical step in being able to predict platelets' phenotypes during hemostasis or thrombosis. PMID- 24806938 TI - High-resolution two-dimensional J-resolved NMR spectroscopy for biological systems. AB - NMR spectroscopy is a principal tool in metabolomic studies and can, in theory, yield atom-level information critical for understanding biological systems. Nevertheless, NMR investigations on biological tissues generally have to contend with field inhomogeneities originating from variations in macroscopic magnetic susceptibility; these field inhomogeneities broaden spectral lines and thereby obscure metabolite signals. The congestion in one-dimensional NMR spectra of biological tissues often leads to ambiguities in metabolite identification and quantification. We propose an NMR approach based on intermolecular double-quantum coherences to recover high-resolution two-dimensional (2D) J-resolved spectra from inhomogeneous magnetic fields, such as those created by susceptibility variations in intact biological tissues. The proposed method makes it possible to acquire high-resolution 2D J-resolved spectra on intact biological samples without recourse to time-consuming shimming procedures or the use of specialized hardware, such as magic-angle-spinning probes. Separation of chemical shifts and J couplings along two distinct dimensions is achieved, which reduces spectral crowding and increases metabolite specificity. Moreover, the apparent J coupling constants observed are magnified by a factor of 3, facilitating the accurate measurement of small J couplings, which is useful in metabolic analyses. Dramatically improved spectral resolution is demonstrated in our applications of the technique on pig brain tissues. The resulting spectra contain a wealth of chemical shift and J-coupling information that is invaluable for metabolite analyses. A spatially localized experiment applied on an intact fish (Crossocheilus siamensis) reveals the promise of the proposed method in in vivo metabolite studies. Moreover, the proposed method makes few demands on spectrometer hardware and therefore constitutes a convenient and effective manner for metabonomics study of biological systems. PMID- 24806940 TI - Biophysical journal and the biophysics community. PMID- 24806939 TI - Molecular mechanisms that regulate the coupled period of the mammalian circadian clock. AB - In mammals, most cells in the brain and peripheral tissues generate circadian (~24 h) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the population mean of cells' intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important because the SCN must entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression in the intracellular feedback loop plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g., oligomer- or phosphorylation-based repression), as widely assumed in previous mathematical models. Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals, and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms and syncytia. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (~24 h). PMID- 24806941 TI - Tracking single serotonin transporter molecules at the endoplasmic reticulum and plasma membrane. AB - Transmembrane proteins are synthesized and folded in the endoplasmic reticulum (ER), an interconnected network of flattened sacs or tubes. Up to now, this organelle has eluded a detailed analysis of the dynamics of its constituents, mainly due to the complex three-dimensional morphology within the cellular cytosol, which precluded high-resolution, single-molecule microscopy approaches. Recent evidences, however, pointed out that there are multiple interaction sites between ER and the plasma membrane, rendering total internal reflection microscopy of plasma membrane proximal ER regions feasible. Here we used single molecule fluorescence microscopy to study the diffusion of the human serotonin transporter at the ER and the plasma membrane. We exploited the single-molecule trajectories to map out the structure of the ER close to the plasma membrane at subdiffractive resolution. Furthermore, our study provides a comparative picture of the diffusional behavior in both environments. Under unperturbed conditions, the majority of proteins showed similar mobility in the two compartments; at the ER, however, we found an additional 15% fraction of molecules moving with 25-fold faster mobility. Upon degradation of the actin skeleton, the diffusional behavior in the plasma membrane was strongly influenced, whereas it remained unchanged in the ER. PMID- 24806943 TI - Method or madness: does OTU delineation bias our perceptions of fungal ecology? PMID- 24806942 TI - Breast carcinoma cells modulate the chemoattractive activity of human bone marrow derived mesenchymal stromal cells by interfering with CXCL12. AB - We investigated whether breast tumor cells can modulate the function of mesenchymal stromal cells (MSCs) with a special emphasis on their chemoattractive activity towards hematopoietic stem and progenitor cells (HSPCs). Primary MSCs as well as a MSC line (SCP-1) were cocultured with primary breast cancer cells, MCF 7, MDA-MB231 breast carcinoma or MCF-10A non-malignant breast epithelial cells or their conditioned medium. In addition, the frequency of circulating clonogenic hematopoietic progenitors was determined in 78 patients with breast cancer and compared with healthy controls. Gene expression analysis of SCP-1 cells cultured with MCF-7 medium revealed CXCL12 (SDF-1) as one of the most significantly downregulated genes. Supernatant from both MCF-7 and MDA-MB231 reduced the CXCL12 promoter activity in SCP-1 cells to 77% and 47%, respectively. Moreover, the CXCL12 mRNA and protein levels were significantly reduced. As functional consequence of lower CXCL12 levels, we detected a decreased trans-well migration of HSPCs towards MSC/tumor cell cocultures or conditioned medium. The specificity of this effect was confirmed by blocking studies with the CXCR4 antagonist AMD3100. Downregulation of SP1 and increased miR-23a levels in MSCs after contact with tumor cell medium as well as enhanced TGFbeta1 expression were identified as potential molecular regulators of CXCL12 activity in MSCs. Moreover, we observed a significantly higher frequency of circulating colony-forming hematopoietic progenitors in patients with breast cancer compared with healthy controls. Our in vitro results propose a potential new mechanism by which disseminated tumor cells in the bone marrow may interfere with hematopoiesis by modulating CXCL12 in protected niches. PMID- 24806944 TI - Recognition at the leaf surface. PMID- 24806945 TI - Changing ecology. PMID- 24806946 TI - Frontiers in chemical ecology and coevolution. PMID- 24806948 TI - Performance of an anthropometric assessment method as a predictor of low birthweight and being small for gestational age. AB - BACKGROUND: The present study aimed to evaluate the performance of the method proposed in 2009 by the Institute of Medicine for the anthropometric assessment of pregnant women, predicting perinatal outcomes: adequacy of birthweight, adequacy of birthweight according to gestational age [small for gestational age (SGA), large for gestational age (LGA)] and gestational and neonatal complications. METHODS: The study comprised a cross-sectional study involving 827 post-partum women (>20 years) who were treated in a public maternity hospital in the city of Rio de Janeiro. Data collection occurred by interviews and record consultation. Adequacy of weight gain during pregnancy was determined as being insufficient and excessive for the recommended range according to nutritional status category. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for logistic regression. RESULTS: Some 36.2% of women initiated gestation with some weight deviation. The prevalence of the outcomes studied was 4.6% (n = 35) for low birthweight, 3.7% (n = 31) for SGA, 5.7% (n = 47) for LGA, 45.2% (n = 374) for pregnancy complications and 15.2% (n = 85) for neonatal complications. For women with insufficient weight gain, the new recommendation indicated a correlation in the prediction of low birthweight (OR = 3.76, 95% CI = 1.53-9.21), SGA newborns (OR = 5.77, 95% CI = 2.10-15.8) and gestational complications (OR = 1.72, 95% CI = 1.20-2.48). CONCLUSIONS: The method evaluated demonstrated a better sensitivity and specificity for the main outcomes related to insufficient weight gain (low birthweight and SGA). Regarding excessive foetal growth (LGA), gestational and neonatal complications demonstrated sensitivity for an intermediate value. PMID- 24806949 TI - Patterns of victimization, suicide attempt, and posttraumatic stress disorder in Greenlandic adolescents: a latent class analysis. AB - AIM: The current study had two main aims. The first was to identify groups of adolescents based on their similarity of responding across a number of victimizing and potentially traumatic events (PTEs). In doing so, we employed the statistical technique of Latent Class Analysis (LCA). The second aim was to assess the relationship between our resultant classes and the covariates of gender, suicide attempt, and PTSD. METHODS: Two hundred and sixty-nine Greenlandic school students, aged 12-18 (M = 15.4, SD = 1.84) were assessed for their level of exposure to PTEs. In addition, adolescents were assessed for the psychological impact of these events. A LCA was performed on seven binary indicators representing PTEs. Logistic regression was subsequently implemented to ascertain the relationships between latent classes and covariates. RESULTS: Three distinct classes were uncovered: a violence, neglect, and bullying class (class 1), a wide-ranging multiple PTE class (class 2), and a normative/baseline class (class 3). Notably, classes 1 and 2 were largely separated by the presence or absence of sexual PTEs. Individuals who reported having previously attempted suicide were almost six times more likely to be members of class 1 (OR = 5.97) and almost four times more likely to be members of class 2 (OR = 3.87) compared to the baseline class (class 3). Individuals who met the diagnostic criteria for PTSD were five times as likely to be members of class 1 and class 2 (OR = 5.09) compared to the baseline class. No significant associations were found between classes and gender. CONCLUSION: The results underline the complexity of the interplay between multiple victimization experiences, traumatization, and suicide attempts. PMID- 24806950 TI - Rehospitalization risk of former voluntary and involuntary patients with schizophrenia. AB - BACKGROUND: The aim of the study was to examine the differences between former involuntary and voluntary patients with a schizophrenic disorder with regard to time to and frequency of rehospitalization. METHODS: In this prospective observational study, 374 patients with a diagnosis of schizophrenia or schizoaffective disorder were included. At the time of inclusion, 290 (77.5 %) were hospitalized voluntarily and 84 (22.5 %) involuntarily. Follow-up assessments were conducted half-yearly over a 2-year period with measures of PANSS, GAF, sociodemographic data and cognitive functioning. These data served as covariates for adjustment in statistical models that included a Cox regression model, a random-effect logit model and a random-effect tobit model. RESULTS: After adjustment for other relevant covariates, the Cox regression showed that involuntary treatment is a significant risk factor of subsequent rehospitalization (HR = 1.53; CI = 1.06, 2.19; p = 0.02). The involuntary group had higher half-year incidence rates of rehospitalization, and in case of rehospitalization the duration of hospital stay was longer. CONCLUSIONS: Involuntary hospitalization seems to be associated with a higher risk of rehospitalization and longer subsequent hospital stays in patients with schizophrenia and schizoaffective disorders. Further studies are needed to examine in detail the processes and interventions that are suitable for interrupting circles of repeated hospitalizations, especially in former involuntary patients. PMID- 24806951 TI - Terrestrial laser scanning to model sunlight irradiance on cadavers under conditions of natural decomposition. AB - Human decomposition is a dynamic process that is influenced by both abiotic and biotic factors. Measuring these influences, in particular abiotic factors, on the decomposition process is often a challenge for scientists. Recently, researchers have turned to the use of advanced remote sensing technologies in forensic investigations. In this study, a new methodology is described that utilizes precise 3D images captured using terrestrial laser scanning (TLS) to calculate total solar irradiance on a cadaver in a partially forested environment. To test this new measurement approach under actual field conditions, three cadavers were placed in an outdoor environment to decompose. Laser scans were taken the day of placement and used to calculate the total solar irradiance at time points of 24 h, 1 week, and 1 month from placement. The results show that as time progresses, different cadavers at the field site and different areas of the same cadaver receive varying amounts of solar irradiance. The modeling based on these laser scans can be used to create predictive images of solar irradiance that may provide researchers with a new tool to help quantitatively assess the effect of solar irradiance on a cadaver ecosystem. PMID- 24806952 TI - District nurses' views on quality of primary healthcare encounters. AB - Good encounters are fundamental for good and professional nursing care, and can be described as treating patients with respect and protecting their integrity and autonomy. This study describes district nurses' views on quality of healthcare encounters in primary healthcare. A purposive sample of 27 district nurses participated in five focus group interviews. The focus groups interviews were digitally recorded and transcribed verbatim. The interview texts were analysed using a thematic content analysis. The analysis resulted in four themes, including being aware of the importance and difficulties during encounters, being the patient's advocate, being attentive to the unique person and being informed when a meeting turned out poorly. The results show that district nurses believed that encounters formed the basis of their work and it was vital for them to be aware of any difficulties. District nurses found that acting in a professional manner during encounters is the most significant factor, but this type of interaction was sometimes difficult because of stress and lack of time. The district nurses considered themselves to be the patients' advocate in the healthcare system; in addition, the acts of seeing, listening, believing and treating the patient seriously were important for providing good quality care. If a poor encounter occurred between the district nurse and the patient, the district nurses found that it was necessary to arrange a meeting to properly communicate what problems arose during the interaction. The district nurses highlighted that providing an apology and explanation could improve future encounters and establish a better nurse-patient relationship. In conclusion, this study shows the importance of confirming and respecting patients' dignity as the fundamental basis for a good quality encounter in primary healthcare. PMID- 24806953 TI - Real-time US-CT/MRI image fusion for guidance of thermal ablation of liver tumors undetectable with US: results in 295 cases. AB - PURPOSE: This study was designed to assess feasibility of US-CT/MRI fusion-guided ablation in liver tumors undetectable with US. METHODS: From 2002 to 2012, 295 tumors (162 HCCs and 133 metastases; mean diameter 1.3 +/- 0.6 cm, range 0.5-2.5 cm) detectable on contrast-enhanced CT/MRI, but completely undetectable with unenhanced US and either totally undetectable or incompletely conspicuous with contrast-enhanced US (CEUS), were treated in 215 sessions using either internally cooled radiofrequency or microwave with standard ablation protocols, guided by an image fusion system (Virtual Navigation System, Esaote S.p.A., Genova, Italy) that combines US with CT/ MRI images. Correct targeting and successful ablation of tumor were verified after 24 hours with CT or MRI. RESULTS: A total of 282 of 295 (95.6 %) tumors were correctly targeted with successful ablation achieved in 266 of 295 (90.2 %). Sixteen of 295 (5.4 %) tumors were correctly targeted, but unsuccessfully ablated, and 13 of 295 (4.4 %) tumors were unsuccessfully ablated due to inaccurate targeting. There were no perioperative deaths. Major complications were observed in 2 of the 215 treatments sessions (0.9 %). CONCLUSIONS: Real-time virtual navigation system with US-CT/MRI fusion imaging is precise for targeting and achieving successful ablation of target tumors undetectable with US alone. Therefore, a larger population could benefit from ultrasound guided ablation procedures. PMID- 24806954 TI - Anticoagulation is not mandatory after stenting for malignant superior vena cava syndrome. PMID- 24806955 TI - Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. AB - PURPOSE: This study was designed to assess the effect of calcium on the efficacy of DEB during revascularization of steno-obstructive SFA lesions. METHODS: Sixty patients with de novo lesions of the superficial femoral artery underwent endovascular treatment with drug eluting balloons (DEB). DEB was selected according to vessel reference diameter (1:1). In case of residual stenosis > 50 % or flow-limiting dissection, postdilatation with conventional balloon or provisional stenting was done. Patients were classified into eight groups according to circumferential distribution of calcium on CT-angiography axial images (from 0 degrees to 360 degrees ) and to its length (length < or > 3 cm) evaluated with digital-subtraction-angiography. Ankle-brachial index (ABI), late lumen loss (LLL), target lesion revascularization (TLR), primary (PP) and secondary (SP) patency, major adverse events (MAE), and Rutherford shift were evaluated at 1-year follow-up and correlated with the amount of calcium. RESULTS: Revascularization was successful in all cases. Flow-limiting dissection occurred in five cases (8.3 %) with a higher circumferential degree of calcium and solved in three cases with postdilatation and in the other two with provisional stenting. DEB effect was lower in patients with higher degree of calcium (>270 degrees vs. <90 degrees ): ABI 0.71 +/- 0.07 versus 0.92 +/- 0.07; LLL 0.75 +/- 0.21 versus 0.45 +/- 0.1; PP 50 versus 100 %; SP 50 versus 100 %; TLR 25 versus 0 %; MAE 25 versus 0 %. CONCLUSIONS: Calcium represents a barrier to optimal drug absorption. Circumferential distribution seems to be the most influencing factor with the worst effect noticed in 360 degrees calcium presence. PMID- 24806956 TI - [Not Available]. PMID- 24806958 TI - [Not Available]. PMID- 24806957 TI - [Not Available]. PMID- 24806959 TI - Effects of nitrogen on the distribution and chemical speciation of iron and zinc in pearling fractions of wheat grain. AB - Increasing nitrogen supply can increase Fe and Zn concentrations in wheat grain, but the underlying mechanisms remain unclear. Size-exclusion chromatography coupled with inductively coupled plasma mass spectrometry was used to determine Fe and Zn speciation in the soluble extracts of grain pearling fractions of two wheat cultivars grown at two N rates (100 and 350 kg of N ha(-1)). Increasing N supply increased the concentrations of total Fe and Zn and the portions of Fe and Zn unextractable with a Tris-HCl buffer and decreased the concentrations of Tris HCl-extractable (soluble) Fe and Zn. Within the soluble fraction, Fe and Zn bound to low molecular weight compounds, likely to be Fe-nicotianamine and Fe deoxymugineic acid or Zn-nicotianamine, were decreased by 5-12% and 4-37%, respectively, by the high N treatment, whereas Fe and Zn bound to soluble high molecular weight or soluble phytate fractions were less affected. The positive effect of N on grain Fe and Zn concentrations was attributed to an increased sink in the grain, probably in the form of water-insoluble proteins. PMID- 24806960 TI - BAG6 regulates the quality control of a polytopic ERAD substrate. AB - BAG6 participates in protein quality control and, here, we address its role in endoplasmic-reticulum-associated degradation (ERAD) by using the polytopic membrane protein OpD, an opsin degron mutant. Both BAG6 knockdown and BAG6 overexpression delay OpD degradation; however, our data suggest that these two perturbations are mechanistically distinct. Hence, BAG6 knockdown correlates with reduced OpD polyubiquitylation, whereas BAG6 overexpression increases the level of polyubiquitylated OpD. The UBL- and BAG-domains of exogenous BAG6 are dispensable for OpD stabilisation and enhanced levels of polyubiquitylated OpD. Thus, although endogenous BAG6 normally promotes OpD degradation, exogenous BAG6 expression delays this process. We speculate that overexpressed BAG6 subunits might associate with the endogenous BAG6 complex, resulting in a dominant negative effect that inhibits its function. Interestingly, cellular levels of BAG6 also correlate with total steady-state polyubiquitylation, with Rpn10 (officially known as PSMD4) overexpression showing a similar effect. These findings suggest that perturbations of the levels of ubiquitin-binding proteins can impact upon cellular ubiquitin homeostasis. We propose that exogenous BAG6 perturbs the function of the BAG6 complex at a stage subsequent to substrate recognition and polyubiquitylation, most likely the BAG6-dependent delivery of OpD to the proteasome. PMID- 24806961 TI - DNA polymerase alpha interacts with PrSet7 and mediates H4K20 monomethylation in Drosophila. AB - In human cells, appropriate monomethylation of histone H4 lysine 20 by PrSet7 (also known as SET8 and SETD7) is important for the correct transcription of specific genes and timely progression through the cell cycle. Over-methylation appears to be prevented through the interaction of PrSet7 with proliferating cell nuclear antigen (PCNA), which targets PrSet7 for destruction through the pathway mediated by CRL4(C) (dt2) (the cullin ring finger ligase-4 complex containing Cdt2). However, the factors involved in positive regulation of PrSet7 histone methylation remain undefined. Here, we present biochemical and genetic evidence for a previously undocumented interaction between Drosophila PrSet7 (dPrSet7) and DNA polymerase alpha in Drosophila. Depletion of the polymerase reduces H4K20 monomethylation suggesting that it is required for dPrSet7 histone methylation activity. We also show that the interaction between PCNA and PrSet7 is conserved in Drosophila, but is only detectable in chromatin fractions. Consistent with this, S2 cells show a significant loss of chromatin-bound dPrSet7 protein as S phase progresses. Based on these data we suggest that interaction with the DNA polymerase represents an important route for stimulation of PrSet7 histone methylase activity that is mediated by allowing loading of dPrSet7 onto chromatin or its subsequent activation. PMID- 24806962 TI - Cellular microenvironments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors. AB - The mechanisms underlying the cell response to mechanical forces are crucial for muscle development and functionality. We aim to determine whether mutations of the LMNA gene (which encodes lamin A/C) causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts embedded in soft matrix did not align along the gel axis, whereas control myoblasts did. LMNA mutated myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft two-dimensional (2D) and/or static three dimensional (3D) conditions, LMNA-mutated myoblasts showed enhanced activation of the yes-associated protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. siRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in LMNA-mutated myoblasts. PMID- 24806963 TI - Peptide-independent stabilization of MHC class I molecules breaches cellular quality control. AB - The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, K(b)-Y84C, in which two alpha-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound high-affinity peptide. K(b)-Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (beta2m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and beta2m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by beta2m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that beta2m association is also tested by the cell surface quality control that leads to MHC-I endocytosis. PMID- 24806964 TI - IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. AB - Mitochondria contribute to cell signaling by controlling store-operated Ca(2+) entry (SOCE). SOCE is activated by Ca(2+) release from the endoplasmic reticulum (ER), whereupon stromal interacting molecule 1 (STIM1) forms oligomers, redistributes to ER-plasma-membrane junctions and opens plasma membrane Ca(2+) channels. The mechanisms by which mitochondria interfere with the complex process of SOCE are insufficiently clarified. In this study, we used an shRNA approach to investigate the direct involvement of mitochondrial Ca(2+) buffering in SOCE. We demonstrate that knockdown of either of two proteins that are essential for mitochondrial Ca(2+) uptake, the mitochondrial calcium uniporter (MCU) or uncoupling protein 2 (UCP2), results in decelerated STIM1 oligomerization and impaired SOCE following cell stimulation with an inositol-1,4,5-trisphosphate (IP3)-generating agonist. Upon artificially augmented cytosolic Ca(2+) buffering or ER Ca(2+) depletion by sarcoplasmic or endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitors, STIM1 oligomerization did not rely on intact mitochondrial Ca(2+) uptake. However, MCU-dependent mitochondrial sequestration of Ca(2+) entering through the SOCE pathway was essential to prevent slow deactivation of SOCE. Our findings show a stimulus-specific contribution of mitochondrial Ca(2+) uptake to the SOCE machinery, likely through a role in shaping cytosolic Ca(2+) micro-domains. PMID- 24806965 TI - TMEM115 is an integral membrane protein of the Golgi complex involved in retrograde transport. AB - Searching and evaluating the Human Protein Atlas for transmembrane proteins enabled us to identify an integral membrane protein, TMEM115, that is enriched in the Golgi complex. Biochemical and cell biological analysis suggested that TMEM115 has four candidate transmembrane domains located in the N-terminal region. Both the N- and C-terminal domains are oriented towards the cytoplasm. Immunofluorescence analysis supports that TMEM115 is enriched in the Golgi cisternae. Functionally, TMEM115 knockdown or overexpression delays Brefeldin-A induced Golgi-to-ER retrograde transport, phenocopying cells with mutations or silencing of the conserved oligomeric Golgi (COG) complex. Co-immunoprecipitation and in vitro binding experiments reveals that TMEM115 interacts with the COG complex, and might self-interact to form dimers or oligomers. A short region (residues 206-229) immediately to the C-terminal side of the fourth transmembrane domain is both necessary and sufficient for Golgi targeting. Knockdown of TMEM115 also reduces the binding of the lectins peanut agglutinin (PNA) and Helix pomatia agglutinin (HPA), suggesting an altered O-linked glycosylation profile. These results establish that TMEM115 is an integral membrane protein of the Golgi stack regulating Golgi-to-ER retrograde transport and is likely to be part of the machinery of the COG complex. PMID- 24806969 TI - Cisplatin Properties in a Nanobiotechnological Approach to Cancer: A Mini-Review. AB - For many years, cisplatin has been used to treat many types of cancer, including urogenital, skin and lung cancers. Unfortunately, treatment with this drug causes serious side effects, such as severe toxicity; including nephrotoxicity, neurotoxicity, gastrointestinal toxicity, peripheral neuropathy, ototoxicity, asthenia and hematological toxicity.Therefore, the clinical use of cisplatin has been hampered.The incidence of nephrotoxicity frequently prevents the use of high enough doses to maximize the antineoplastic effects, and strict attention must be given to the hydration of cisplatin-treated patients to minimize kidney damage.Nanobiotechnology, or nanomedicine, was developed to mitigate, or even eliminate,the toxic effects of pharmaceutical compounds; for example, drug targeting systems were developed to enable site specificity and to control the delivery drug. Therefore, biomedical nanotechnology researchers attempted to develop nanostructures not only to deliver chemotherapeutics to the desired treatment site but also to control when and how quickly the compounds are released. To achieve these ends, a drug can either be encapsulated in a matrix or attached to a particle surface. Studies concerning the encapsulation of cisplatin in liposomes, polymeric nanoparticles, solid lipid nanoparticles and carbon nanotubes, as well as the immobilization of cisplatin on metallic nanoparticles, have already been published. The association of cancer treatment, particularly chemotherapeutics, with nanotechnology is currently one of the most exciting areas of research. In this mini-review, cisplatin will be discussed in terms of its efficacy against many cancers, including bladder cancer. Additionally, established nanostructure-based drug delivery systems for cisplatin and their efficacy against different types of cancer will be reviewed. Because cisplatin is a standard treatment with good performance statistics and with an effective renal function-glomerular filtration rate, we expect that this review will be helpful for future research. PMID- 24806966 TI - The extent of error-prone replication restart by homologous recombination is controlled by Exo1 and checkpoint proteins. AB - Genetic instability, a hallmark of cancer, can occur when the replication machinery encounters a barrier. The intra-S-phase checkpoint maintains stalled replication forks in a replication-competent configuration by phosphorylating replisome components and DNA repair proteins to prevent forks from catastrophically collapsing. Here, we report a novel function of the core Schizosaccharomyces pombe checkpoint sensor kinase, Rad3 (an ATR orthologue), that is independent of Chk1 and Cds1 (a CHK2 orthologue); Rad3(ATR) regulates the association of recombination factors with collapsed forks, thus limiting their genetic instability. We further reveal antagonistic roles for Rad3(ATR) and the 9 1-1 clamp - Rad3(ATR) restrains MRN- and Exo1-dependent resection, whereas the 9 1-1 complex promotes Exo1 activity. Interestingly, the MRN complex, but not its nuclease activity, promotes resection and the subsequent association of recombination factors at collapsed forks. The biological significance of this regulation is revealed by the observation that Rad3(ATR) prevents Exo1-dependent genome instability upstream of a collapsed fork without affecting the efficiency of recombination-mediated replication restart. We propose that the interplay between Rad3(ATR) and the 9-1-1 clamp functions to fine-tune the balance between the need for the recovery of replication through recombination and the risk of increased genome instability. PMID- 24806970 TI - Novel mutation in the STAT3 gene in a Chinese boy with hyper-immunoglobulin E syndrome. PMID- 24806967 TI - Innate immunity in the vagina (Part II): Anti-HIV activity and antiviral content of human vaginal secretions. AB - PROBLEM: Whether the concentrations of antiviral proteins, and anti-HIV activity, within human vaginal secretions change across the menstrual cycle is unknown. METHOD OF STUDY: Using a menstrual cup, vaginal secretions from pre-menopausal women were recovered at the proliferative (d6-8), mid-cycle (d13-15), and secretory (d21-23) stages of the menstrual cycle. Antiviral protein concentration was determined by ELISA, and anti-HIV activity assessed using the TZM-bl reporter cell line. RESULTS: CCL20, RANTES, elafin, HBD2, SDF-1alpha, and IL-8 levels were detectable in the secretions. Vaginal secretions had anti-HIV activity against specific clade B strains of HIV, with significant inhibition of IIIB and increased infectivity of transmitted/founder CH077.t. No significant differences in either antiviral protein concentration or anti-HIV activity with respect to menstrual cycle stage were measured, but marked differences were observed in both parameters over the course of the cycle between different women and in consecutive cycles from the same woman. CONCLUSION: The vagina contains a complement of antiviral proteins. The variation in anti-HIV activity demonstrates that immune protection in the vagina is not constant. Intra- and interindividual variations suggest that factors in addition to sex hormones influence antiviral protection. Lastly, the menstrual cup is a new model for recovering undiluted vaginal secretions from women throughout their reproductive life. PMID- 24806971 TI - CO2 activation and carbonate intermediates: an operando AP-XPS study of CO2 electrolysis reactions on solid oxide electrochemical cells. AB - Through the use of ambient pressure X-ray photoelectron spectroscopy and specially designed ceria-based solid oxide electrochemical cells, carbon dioxide (CO2) electrolysis reactions (CO2 + 2e(-)-> CO + O(2-)) and carbon monoxide (CO) electro-oxidation reactions (CO + O(2-)-> CO2 + 2e(-)) over cerium oxide electrodes have been investigated in the presence of 0.5 Torr CO-CO2 gas mixtures at ~600 degrees C. Carbonate species (CO3(2-)) are identified on the ceria surface as reaction intermediates. When CO2 electrolysis is promoted on ceria electrodes at +2.0 V applied bias, we observe a higher concentration of CO3(2-) over a 400 MUm-wide active region on the ceria surface, accompanied by Ce(3+)/Ce(4+) redox changes. This increase in the CO3(2-) steady-state concentration suggests that the process of pre-coordination of CO2 to the ceria surface to form a CO3(2-) intermediate (CO2(g) + O(2-)(surface)-> CO3(2 )(surface)) precedes a rate-limiting electron transfer process involving CO3(2-) reduction to give CO and oxide ions (CO3(2-)(surface) + 2Ce(3+)-> CO(g) + 2O(2 )(surface) + 2Ce(4+)). When the applied bias is switched to -1.5 V to promote CO electro-oxidation on ceria, the surface CO3(2-) concentration slightly decreases from the equilibrium value, suggesting that the electron transfer process is also a rate-limiting process in the reverse direction. PMID- 24806972 TI - Activation of endogenous type I IFN signaling contributes to persistent HCV infection. AB - HCV infection is a major world health problem, leading to both end-stage liver disease and primary liver cancer. Great efforts have been made in developing new therapies for HCV infection; however, combination therapy with pegylated IFN alpha and ribavirin (pegIFN-RBV) remains the first choice of treatment for chronic HCV infection in most countries. The treatment response to pegIFN-RBV remains relatively low. Understanding the molecular mechanisms of persistent HCV infection and pegIFN-RBV resistance will suggest ways of improving the current standard of care and offers new antiviral therapies for both HCV and other viral infections. Recent data suggest that increased expression of hepatic IFN stimulated genes (ISGs) before treatment is associated with treatment nonresponse in patients chronically infected with HCV. Although ISGs are generally antiviral in nature, in the case of HCV, the virus may exploit some of them to its benefit. This is not unique to HCV: Blockade of type I IFN signaling has been shown to control persistent LCMV infection. Thus, in certain viral infections, preactivation or overactivation of type I IFN signaling may contribute to viral persistence. In this review, we briefly summarize the findings from high throughput gene expression profiling from patients chronically infected with HCV, then focus on a novel ubiquitin-like signaling pathway (ISG15/USP18) and its potential role in HCV persistence. Finally, the role of activation of endogenous type I IFN signaling in persistent HCV infection will be discussed in the context of recent studies indicating that blocking IFN signaling controls persistent LCMV infection. PMID- 24806974 TI - Changes in gait variability with anti-dementia drugs: a systematic review and meta-analysis. AB - BACKGROUND: Studies have examined the effects of anti-dementia drugs on gait performance. No structured critical evaluation of these studies has been done so far. The objectives of this study were (1) to perform a qualitative analysis of all published studies on changes in stride time variability (STV) with anti dementia drugs among patients with Alzheimer disease through a systematic review, and (2) to quantitatively synthesize anti-dementia drug-related changes in STV. METHODS: An English and French MEDLINE search was conducted on November 2013, with no limit of date, using the Medical Subject Headings term "pharmaceutical preparations" combined with "delirium", "dementia", "amnestic", "cognitive disorders" AND "gait" OR "gait disorders, neurologic" OR "gait apraxia". Fixed effects meta-analyses were performed to compare STV before and after the use of anti-dementia drugs, and to compare the final STV among participants in intervention and control groups. RESULTS: Of the 110 originally identified abstracts, four studies (i.e., one assessing galantamine, one donepezil, one memantine, and one memantine and acetylcholinesterase inhibitors) were included in the qualitative review, and three studies in the quantitative synthesis. Results were mixed, as two studies showed significant between-visit improvements (i.e., decrease in mean value) in STV, while one study did not, and the last one reported mixed results. In the meta-analysis, there was no difference between intervention and control groups (summary mean difference of final STV = -0.38 % [95 % confidence interval -1.14 to 0.37]) and no before-after difference in the intervention group (summary mean difference of STV = 0.66 [95 % confidence interval -0.17 to 1.49]). CONCLUSIONS: Our findings showed inconclusive effects of anti-dementia drugs on STV. PMID- 24806975 TI - Toward single mode, atomic size electron vortex beams. AB - We propose a practical method of producing a single mode electron vortex beam suitable for use in a scanning transmission electron microscope (STEM). The method involves using a holographic "fork" aperture to produce a row of beams of different orbital angular momenta, as is now well established, magnifying the row so that neighboring beams are separated by about 1 um, selecting the desired beam with a narrow slit, and demagnifying the selected beam down to 1-2 A in size. We show that the method can be implemented by adding two condenser lenses plus a selection slit to a straight-column cold-field emission STEM. It can also be carried out in an existing instrument, the monochromated Nion high-energy resolution monochromated electron energy-loss spectroscopy-STEM, by using its monochromator in a novel way. We estimate that atom-sized vortex beams with >= 20 pA of current should be attainable at 100-200 keV in either instrument. PMID- 24806973 TI - Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. AB - INTRODUCTION: The effectiveness of valproate (VPA) in the treatment of focal and generalized epilepsies is well established. The drug has a wide spectrum of action, good tolerability, and has been available as an injectable formulation since 1993. Despite the lack of class A evidence, it has been used extensively in various forms of status epilepticus (SE). AIM: Our aim was to present a systematic review of data from randomized and non-randomized controlled trials to evaluate the efficacy and safety of intravenous VPA for the treatment of SE. METHODS: Data sources included MEDLINE, back tracing of references in pertinent studies, and contact with the manufacturer of VPA (Sanofi-Aventis). RESULTS: Overall, the search strategy yielded 433 results (425 MEDLINE, seven congress abstracts, one unpublished study); after excluding duplicate publications and case reports, 30 studies were identified (the earliest was published in 1993, the most recent in 2012); ten were controlled (six randomized controlled trials, four non-randomized controlled studies), and 20 uncontrolled trials (eight prospective observational studies, 12 retrospective case series). The cumulative literature describes the experiences of 860 patients with various forms of SE treated with intravenous VPA. The overall response rate to abrogate SE was 70.9% (601/848; 95% confidence interval [CI] 67.8-73.9). Response rates to intravenous VPA were better in children than in adults and did not differ between the SE types. The most commonly reported effective doses were between 15 and 45 mg/kg in bolus (6 mg/kg/min) followed by 1-3 mg/kg/h infusion. Safety studies of intravenous VPA administration in patients with SE showed a low incidence of adverse events overall (<10%), mainly dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Of note, good cardiovascular and respiratory tolerability was observed in these studies, even at high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg/min), despite multiple morbidities or other antiepileptic drugs. The most serious concern relates to the possibility of acute encephalopathy, sometimes related to hepatic abnormalities or hyperammonemia. CONCLUSIONS: The published experience is consistent with VPA being a safe and effective therapeutic option for patients with established SE who have previously failed conventional first-line treatment with benzodiazepines, but high-quality randomized controlled trials are needed to inform clinicians on its comparative effectiveness in SE. PMID- 24806976 TI - Investigating the relationship between mortality from respiratory diseases and childhood acute lymphoblastic leukaemia in Hungary. AB - Our aim was to investigate the ecological association between death from infectious disease of the respiratory system and the risk of acute lymphoid leukaemia (ALL) in children aged less than 7 years. Poisson regression analyses were carried out using overall data and gender-specific models. The study included 176 cases (92(52.3 %) boys and 84 (47.7 %) girls) of ALL in those aged 0 6 years in South Hungary. Eight cases were diagnosed before the age of 1 year. A significant risk of ALL disease was observed with higher levels of mortality from the chronic respiratory diseases (p = 0.035) and pneumonia (p = 0.010) among children aged 2-5 years (Odds Ratio for trend was 1.001 and 95%CI [1.000-1.002] and Odds ratio for trend was 1.013 and 95%CI [1.003-1.023], respectively). Significantly increased risk of childhood ALL was detected among children under 1 year of age residing in areas around birth with higher levels of mortality from influenza (Odds Ratio (OR) for trend was 1.05; 95%CI [1.01-1.09]; p = 0.012). This risk was also detected in girls (p < 0.001), but not in boys (p = 0.43). Our findings provide new evidence that will help to understand the different pattern of female and male childhood ALL occurrence , but further studies are needed using detailed individual medical history to clarify the role of influenza and other infectious diseases in the etiology of childhood ALL and to explain gender specific effects. PMID- 24806977 TI - [Happy workplace program: workplace health promotion program driven by Thai Health Promotion Foundation]. PMID- 24806979 TI - gamma-Fe2O3-MWNT/poly(p-phenylenebenzobisoxazole) composites with excellent microwave absorption performance and thermal stability. AB - Ferromagnetic gamma-Fe2O3 nanoparticles were successfully loaded into multi walled carbon nanotubes (MWNTs) as probed by transmission electron microscopy. Upon incorporation of the gamma-Fe2O3-MWNTs into poly(p-phenylenebenzobisoxazole) (PBO), a conjugated polymer with high mechanical strength and outstanding thermal and oxidative stability, microwave absorbing materials were obtained. Attributed to the special structure of the gamma-Fe2O3-MWNTs, synergistic effects on dielectric loss and magnetic loss, and a better matched characteristic impedance of the composites were achieved. The optimal minimum reflection loss reached 32.7 dB at 12.09 GHz on a composite containing 12 wt% gamma-Fe2O3-MWNTs with a thickness of 2.7 mm, and the corresponding bandwidth below -5 dB was 6.2 GHz. This demonstrated its potential applications as a low-density microwave absorbing material operating under extreme environments. PMID- 24806978 TI - Fetal scalp blood sampling in labor--a review. AB - During the 1970s and 1980s, electronic fetal monitoring and fetal scalp blood sampling were introduced without robust evidence. With a methodical review of the published literature, and using one randomized controlled trial, seven controlled studies, nine randomized studies of various surveillance methods and data from the Danish National Birth Registry, we have assessed the usefulness of fetal scalp blood sampling as a complementary tool to improve the specificity and sensitivity of electronic cardiotocography. Based on heterogeneous studies of modest quality with somewhat inconsistent results, we conclude that fetal scalp blood sampling in conjunction with cardiotocography can reduce the risk of operative delivery. Fetal scalp blood sampling can provide additional information on fetal wellbeing and fetal reserves at a time before decisions are made concerning the need for and timing of operative delivery and the choice of anesthesia, and be an adjunct in the interpretation of cardiotocography patterns. PMID- 24806980 TI - Tracking the patient journey by combining multiple hospital database systems. AB - With new national targets for patient flow in public hospitals designed to increase efficiencies in patient care and resource use, better knowledge of events affecting length of stay will support improved bed management and scheduling of procedures. This paper presents a case study involving the integration of material from each of three databases in operation at one tertiary hospital and demonstrates it is possible to follow patient journeys from admission to discharge. PMID- 24806981 TI - Partitioning of polychlorinated biphenyls into human cells and adipose tissues: evaluation of octanol, triolein, and liposomes as surrogates. AB - Whereas octanol, triacylglycerides, and liposomes have all been proposed as surrogates for measuring the affinity of hydrophobic organic contaminants to human lipids, no comparative evaluation of their suitability exists. Here we conducted batch sorption experiments with polyoxymethylene passive samplers to determine the partition coefficients at 37 degrees C of 18 polychlorinated biphenyls (PCBs) from water into (i) triolein (Ktriolein/water), (ii) eight types of liposomes (Kliposome/water), (iii) human abdominal fat tissues (KAFT/water) from seven individuals, and (iv) human MCF-7 cells cultured in vitro (Kcell/water). Differences between KAFT/water among individuals and between Kliposome/water among liposome types were very small and not correlated to structural attributes of the PCBs. Similarly, the length and degree of saturation of the phospholipid carbon chains, the headgroup, and the composition of the liposome did not affect the partitioning of PCBs into the studied liposomes. Whereas Kliposome/water values were similar to literature values of Koctanol/water adjusted to 37 degrees C, they both were lower than KAFT/water and Kcell/water by a factor of 3 on average. Partitioning of PCBs into triolein on the other hand closely mimicked that into human lipids, for which triolein is thus a better surrogate than either octanol or liposomes. Previously published polyparameter linear free energy relationships for partitioning from water into storage lipids and liposomes predicted the measured partition coefficients with a root-mean-square error of less than 0.15 log units, if the chosen equations and solute descriptors do not allow chlorine substitution in the ortho-position to influence the prediction. By guiding the selection of (i) a surrogate for the experimental determination and (ii) a method for the prediction of partitioning into human lipids, this study contributes to a better assessment of hydrophobic organic contaminant bioaccumulation in humans. PMID- 24806982 TI - Compressive light field displays. AB - Light fields are the multiview extension of stereo image pairs: a collection of images showing a 3D scene from slightly different perspectives. Depicting high resolution light fields usually requires an excessively large display bandwidth; compressive light field displays are enabled by the codesign of optical elements and computational-processing algorithms. Rather than pursuing a direct "optical" solution (for example, adding one more pixel to support the emission of one additional light ray), compressive displays aim to create flexible optical systems that can synthesize a compressed target light field. In effect, each pixel emits a superposition of light rays. Through compression and tailored optical designs, fewer display pixels are necessary to emit a given light field than a direct optical solution would require. PMID- 24806983 TI - 2011 IEEE Visualization Contest winner: Visualizing unsteady vortical behavior of a centrifugal pump. AB - In the 2011 IEEE Visualization Contest, the dataset represented a high-resolution simulation of a centrifugal pump operating below optimal speed. The goal was to find suitable visualization techniques to identify regions of rotating stall that impede the pump's effectiveness. The winning entry split analysis of the pump into three parts based on the pump's functional behavior. It then applied local and integration-based methods to communicate the unsteady flow behavior in different regions of the dataset. This research formed the basis for a comparison of common vortex extractors and more recent methods. In particular, integration based methods (separation measures, accumulated scalar fields, particle path lines, and advection textures) are well suited to capture the complex time dependent flow behavior. This video (http://youtu.be/oD7QuabY0oU) shows simulations of unsteady flow in a centrifugal pump. PMID- 24806984 TI - Mesh processing in medical-image analysis--a tutorial. AB - Medical-image analysis requires an understanding of sophisticated scanning modalities, constructing geometric models, building meshes to represent domains, and downstream biological applications. These four steps form an image-to-mesh pipeline. For research in this field to progress, the imaging, modeling, and simulation communities will need to work together more closely. PMID- 24806985 TI - Simulating liver deformation during respiration using sparse local features. AB - A new method deforms a 3D liver mesh in an arbitrary phase of respiration. During preprocessing, the method step defines a patient-specific deformation space using two polar shapes of the liver during respiration. 3D magnetic resonance imaging captures patient livers during exhaling and inhaling. Next, using a fully automated nonrigid mesh registration, this method creates the two phases' corresponding surface meshes. Then, it defines the respiration's deformation space by extracting deformation gradients between the exhalation and inhalation meshes. At runtime, the method uses sparse local features suitably obtained from 2D ultrasound imaging to solve the constraint optimization problem that minimizes dissimilarity of deformation gradients between the target deformation and the patient-specific deformation space. Researchers used real patient data to evaluate this method, which could be applicable to image-guided tumor ablations. PMID- 24806986 TI - Visualizing cells and humans in 3D: biomedical image analysis at nanometer and meter scales. AB - Researchers analyzed and presented volume data from the Visible Human Project (VHP) and data from high-resolution 3D ion-abrasion scanning electron microscopy (IA-SEM). They acquired the VHP data using cryosectioning, a destructive approach to 3D human anatomical imaging resulting in whole-body images with a field of view approaching 2 meters and a minimum resolvable feature size of 300 microns. IA-SEM is a type of block-face imaging microscopy, a destructive approach to microscopic 3D imaging of cells. The field of view of IA-SEM data is on the order of 10 microns (whole cell) with a minimum resolvable feature size of 15 nanometers (single-slice thickness). Despite the difference in subject and scale, the analysis and modeling methods were remarkably similar. They are derived from image processing, computer vision, and computer graphics techniques. Moreover, together we are employing medical illustration, visualization, and rapid prototyping to inform and inspire biomedical science. By combining graphics and biology, we are imaging across nine orders of magnitude of space to better promote public health through research. PMID- 24806987 TI - uPy: a ubiquitous CG Python API with biological-modeling applications. AB - The uPy Python extension module provides a uniform abstraction of the APIs of several 3D computer graphics programs (called hosts), including Blender, Maya, Cinema 4D, and DejaVu. A plug-in written with uPy can run in all uPy-supported hosts. Using uPy, researchers have created complex plug-ins for molecular and cellular modeling and visualization. uPy can simplify programming for many types of projects (not solely science applications) intended for multihost distribution. It's available at http://upy.scripps.edu. The first featured Web extra is a video that shows interactive analysis of a calcium dynamics simulation. YouTube URL: http://youtu.be/wvs-nWE6ypo. The second featured Web extra is a video that shows rotation of the HIV virus. YouTube URL: http://youtu.be/vEOybMaRoKc. PMID- 24806988 TI - Molli: interactive visualization for exploratory protein analysis. AB - Many programs have been designed to view the 3D structures of protein molecules in 2D. However, three types of linked information haven't been previously defined in a systematic way that highlights the interface design challenge. Specifically, a scientist must have sequence, structure, and homology information in working memory to manipulate and understand a protein structure or related protein structures. Categorizing information types enables the application of classical interaction principles to the design of an intuitive interface for both expert and novice users. In a comparative user evaluation, their Molli system enhances the exploratory process of manipulating proteins of varying complexity by preserving the underlying data's linkages and relations. PMID- 24806989 TI - Teaching 3D computer animation to illustrators: the instructor as translator and technical director. AB - An art instructor discusses the difficulties he's encountered teaching computer graphics skills to undergraduate art students. To help the students, he introduced an automated-rigging script for character animation. PMID- 24806990 TI - Toward visualization in policy modeling. AB - This article looks at the current and future roles of information visualization, semantics visualization, and visual analytics in policy modeling. Many experts believe that you can't overestimate visualization's role in this respect. PMID- 24806991 TI - Domain coloring of complex functions: an implementation-oriented introduction. AB - This article gives a short overview of domain coloring for complex functions that have four-dimensional function graphs and therefore can't be visualized traditionally. The authors discuss several color schemes, focus on various aspects of complex functions, and provide Java-like pseudocode examples explaining the crucial ideas of the coloring algorithms to allow for easy reproduction. PMID- 24806992 TI - Graphics performance in rich Internet applications. AB - Rendering performance for rich Internet applications (RIAs) has recently focused on the debate between using Flash and HTML5 for streaming video and gaming on mobile devices. A key area not widely explored, however, is the scalability of raw bitmap graphics performance for RIAs. Does Flash render animated sprites faster than HTML5? How much faster is WebGL than Flash? Answers to these questions are essential for developing large-scale data visualizations, online games, and truly dynamic websites. A new test methodology analyzes graphics performance across RIA frameworks and browsers, revealing specific performance outliers in existing frameworks. The results point toward a future in which all online experiences might be GPU accelerated. PMID- 24806993 TI - Antibacterial, antifungal, phytotoxic, and genotoxic properties of two complexes of Ag(I) with sulfachloropyridazine (SCP): X-ray diffraction of [Ag(SCP)]n. AB - We report the synthesis, characterization, antibacterial and antifungal activities, phytotoxicity, and genotoxicity of two new complexes of silver(I) with sulfachloropyridazine (SCP), one of which is heteroleptic with SCP and SCN( ) ligands (Ag-SCP-SCN), the other of which is homoleptic (Ag-SCP); furthermore, the crystal structure of the homoleptic complex is disclosed. The heterocyclic N atom nearest to the Cl atom and the N(sulfonamide) atom could be coordination sites for the silver ion in the Ag-SCP-SCN complex. The Ag-SCP complex is a polymeric compound with metal-metal bonds, and the heterocyclic and sulfonamide N atoms are points of coordination for Ag(I) . Both complexes showed activity against all the tested bacteria, and in the cases of Escherichia coli and Pseudomonas aeruginosa, the action was better than that of SCP. In all cases, both silver-SCP complexes showed better antifungal activity than SCP, which was inactive against the tested fungi. Notably, the activity against P. aeruginosa, a nosocomial multidrug-resistant pathogen, was better than that of the reference antibiotic cefotaxim. Both silver-sulfa complexes displayed moderate activity against the tested yeast, especially for C. neoformans, which is an important fact considering the incidence of cryptococcosis, mainly in immune-deficient patients. No chromosomal aberrations were observed with the Allium cepa test, which is auspicious for further study of these complexes as potential drugs. PMID- 24806996 TI - A rare example of the formation of polystyrene-grafted aliphatic polyester in one pot by radical polymerization. AB - The radical copolymerization of cyclic ester beta-propiolactone (beta-PL) with styrene (St) at 120 degrees C, with a complete range of monomer ratios, is a rare example of a system providing graft copolymers (PSt-g-beta-PL) in one pot. The structure of the resulting beta-PL-St copolymers was proven by using a combination of different characterization techniques, such as 1D and 2D NMR spectroscopy and gel permeation chromatography (GPC), before and after alkaline hydrolysis of the polymers. The number of grafting points increased with an increasing amount of beta-PL in the feed. A significant difference in the reactivity of St and beta-PL and radical chain-transfer reactions at the polystyrene (PSt) backbone, followed by combination with the active growing poly(beta-PL) chains, led to the formation of graft copolymers by a grafting-onto mechanism. PMID- 24806994 TI - CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury. AB - Traumatic brain injury (TBI) provokes inflammatory responses, including a dramatic rise in brain macrophages in the area of injury. The pathway(s) responsible for macrophage infiltration of the traumatically injured brain and the effects of macrophages on functional outcomes are not well understood. C-C chemokine receptor 2 (CCR2) is known for directing monocytes to inflamed tissues. To assess the role of macrophages and CCR2 in TBI, we determined outcomes in CCR2 deficient (Ccr2(-/-)) mice in a controlled cortical impact model. We quantified brain myeloid cell numbers post-TBI by flow cytometry and found that Ccr2(-/-) mice had greatly reduced macrophage numbers (~80-90% reduction) early post-TBI, compared with wild-type mice. Motor, locomotor, and cognitive outcomes were assessed. Lack of Ccr2 improved locomotor activity with less hyperactivity in open field testing, but did not affect anxiety levels or motor coordination on the rotarod three weeks after TBI. Importantly, Ccr2(-/-) mice demonstrated greater spatial learning and memory, compared with wild-type mice eight weeks after TBI. Although there was no difference in the volume of tissue loss, Ccr2(-/ ) mice had significantly increased neuronal density in the CA1-CA3 regions of the hippocampus after TBI, compared with wild-type mice. These data demonstrate that Ccr2 directs the majority of macrophage homing to the brain early after TBI and indicates that Ccr2 may facilitate harmful responses. Lack of Ccr2 improves functional recovery and neuronal survival. These results suggest that therapeutic blockade of CCR2-dependent responses may improve outcomes following TBI. PMID- 24806995 TI - The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors. AB - Chronic myeloid leukemia (CML) is initiated and maintained by the tyrosine kinase BCR-ABL which activates a number of signal transduction pathways, including PI3K/AKT signaling and consequently inactivates FOXO transcription factors. ABL specific tyrosine kinase inhibitors (TKIs) induce minimal apoptosis in CML progenitor cells, yet exert potent antiproliferative effects, through as yet poorly understood mechanisms. Here, we demonstrate that in CD34+ CML cells, FOXO1 and 3a are inactivated and relocalized to the cytoplasm by BCR-ABL activity. TKIs caused a decrease in phosphorylation of FOXOs, leading to their relocalization from cytoplasm (inactive) to nucleus (active), where they modulated the expression of key FOXO target genes, such as Cyclin D1, ATM, CDKN1C, and BCL6 and induced G1 arrest. Activation of FOXO1 and 3a and a decreased expression of their target gene Cyclin D1 were also observed after 6 days of in vivo treatment with dasatinib in a CML transgenic mouse model. The over-expression of FOXO3a in CML cells combined with TKIs to reduce proliferation, with similar results seen for inhibitors of PI3K/AKT/mTOR signaling. While stable expression of an active FOXO3a mutant induced a similar level of quiescence to TKIs alone, shRNA-mediated knockdown of FOXO3a drove CML cells into cell cycle and potentiated TKI-induced apoptosis. These data demonstrate that TKI-induced G1 arrest in CML cells is mediated through inhibition of the PI3K/AKT pathway and reactivation of FOXOs. This enhanced understanding of TKI activity and induced progenitor cell quiescence suggests that new therapeutic strategies for CML should focus on manipulation of this signaling network. PMID- 24806997 TI - Structural isomerization of the gas-phase 2-norbornyl cation revealed with infrared spectroscopy and computational chemistry. AB - In an attempt to produce the 2-norbornyl cation (2NB(+)) in the gas phase, protonation of norbornene was accomplished in a pulsed discharge ion source coupled with a supersonic molecular beam. The C7H11(+) cation was size-selected in a time-of-flight mass spectrometer and investigated with infrared laser photodissociation spectroscopy using the method of "tagging" with argon. The resulting vibrational spectrum, containing sharp bands in the C-H stretching and fingerprint regions, was compared to that predicted by computational chemistry. However, the measured spectrum did not match that of 2NB(+), prompting a detailed computational study of other possible isomers of C7H11(+). This study finds five isomers more stable than 2NB(+). The spectrum obtained corresponds to the 1,3 dimethylcyclopentenyl cation, the global minimum-energy structure for C7H11(+), which is produced through an unanticipated ring-opening rearrangement path. PMID- 24807000 TI - A comparative ultrasonic relaxation study of lower vicinal and terminal alkanediols at 298.15 K in relation to their molecular structure and hydrogen bonding. AB - Ultrasonic relaxation spectra were determined for lower vicinal and terminal alkanediols at ambient pressure and a temperature of 298.15 K. The ultrasound absorption measurements were made by means of the standard pulse technique for 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 2,3-butanediol, and 1,5-pentanediol within the frequency range of 5-300 or 10-300 MHz. Relaxation processes were observed for all compounds except 1,2-ethanediol. The relaxation regions were dependent on both the carbon chain length and the position of hydroxyl groups. In addition, the terminal diols showed lower absorption than the adequate vicinal diols did. The results are discussed in terms of molecular structure and molecular interactions, as well as compared with the behavior of adequate lower 1-alkanols. A comparison with classical absorption is also made. The results are discussed in term of shear viscosity relaxation. PMID- 24807001 TI - High-performance Hg(2+) FET-type sensors based on reduced graphene oxide polyfuran nanohybrids. AB - A new type of field-effect transistor (FET) sensor, based on reduced graphene oxide (rGO)-polyfuran (PF) nanohybrids, was strategically developed. The sensing transducer exhibited a rapid response (<1 s) and high sensitivity (10 pM) in a liquid-ion-gated FET-type Hg(2+) sensor. Excellent Hg(2+) discrimination in heavy metal mixtures was also monitored in real time. PMID- 24806998 TI - Rhesus monkeys and baboons develop clotting factor VIII inhibitors in response to porcine endothelial cells or islets. AB - BACKGROUND: Xenotransplantation of porcine organs holds promise of solving the human organ donor shortage. The use of alpha-1,3-galactosyltransferase knockout (GTKO) pig donors mitigates hyperacute rejection, while delayed rejection is currently precipitated by potent immune and hemostatic complications. Previous analysis by our laboratory suggests that clotting factor VIII (FVIII) inhibitors might be elicited by the structurally restricted xenoantibody response which occurs after transplantation of either pig GTKO/hCD55/hCD59/hHT transgenic neonatal islet cell clusters or GTKO endothelial cells. METHODS: A recombinant xenoantibody was generated using sequences from baboons demonstrating an active xenoantibody response at day 28 after GTKO/hCD55/hCD59/hHT transgenic pig neonatal islet cell cluster transplantation. Rhesus monkeys were immunized with GTKO pig endothelial cells to stimulate an anti-non-Gal xenoantibody response. Serum was collected at days 0 and 7 after immunization. A two-stage chromogenic assay was used to measure FVIII cofactor activity and identify antibodies which inhibit FVIII function. Molecular modeling and molecular dynamics simulations were used to predict antibody structure and the residues which contribute to antibody-FVIII interactions. Competition ELISA was used to verify predictions at the domain structural level. RESULTS: Antibodies that inhibit recombinant human FVIII function are elicited after non-human primates are transplanted with either GTKO pig neonatal islet cell clusters or endothelial cells. There is an apparent increase in inhibitor titer by 15 Bethesda units (Bu) after transplant, where an increase greater than 5 Bu can indicate pathology in humans. Furthermore, competition ELISA verifies the computer modeled prediction that the recombinant xenoantibody, H66K12, binds the C1 domain of FVIII. CONCLUSIONS: The development of FVIII inhibitors is a novel illustration of the potential impact the humoral immune response can have on coagulative dysfunction in xenotransplantation. However, the contribution of these antibodies to rejection pathology requires further evaluation because "normal" coagulation parameters after successful xenotransplantation are not fully understood. PMID- 24807002 TI - Editor's Note: enteral feeding tubes and parenteral nutrition (PN). PMID- 24807005 TI - ATG-Fresenius S combined with cyclosporine a: an effective immunosuppressive therapy for children with aplastic anemia. AB - For the first time, we conducted a 2-center retrospective study to show the efficacy of antithymocyte globulin (ATG)-Fresenius S plus cyclosporine treatment of children with severe aplastic anemia. From March 1997 to May 2011, a total of 124 patients (median age, 7.5 y; range, 1.5 to 16 y) from 2 centers with acquired AA treated with an immunosuppressive therapy (IST) regimen, consisting of ATG Fresenius S (5 mg/kg per day for 5 d) and cyclosporine, were enrolled. The response rate was 55.6%. The median time between IST and response was 6 (0.5 to 18) months. After a median follow-up time of 29 (6 to 153) months, the rates of relapse and clonal evolution were 3.2% and 0.8%, respectively. Overall, 17 patients (13.7%) died in this study: 14 resulted from sepsis, 1 resulted from intracranial hemorrhage, 1 occurred after hematopoietic stem cell transplantation, and 1 resulted from clonal disease progression. The 5-year overall survival rate for the entire cohort was 74.7%. IST responders had a better survival rate (100%) than nonresponders (70.7%). The use of ATG-Fresenius S plus cyclosporine as a first-line immunosuppressive treatment appeared to be effective for children with severe aplastic anemia in our study. ATG-Fresenius S could be another option in the treatment arsenal, especially in countries where the other ATG products are harder to acquire. PMID- 24807006 TI - Two pairs of monozygotic twins with concordant acute lymphoblastic leukemia (ALL): case report. AB - The occurrence of leukemia in twins is rare but has a crucial implication in the genetic research of leukemia. This report presents 2 pairs of monozygotic twins with precursor B-cell acute lymphoblastic leukemia. Mixed lineage leukemia (MLL) AF4 fusion genes were found in the twin sisters. This study is the first to report on infant ALL harboring the 46,XY, -4, +10, -13, del(14)(q24), -15, +2mar[4 cells] complex chromosome abnormality. Our report showed that the unified cytogenetic features in monozygotic twins and MLL-AF4 fusion gene may be necessary but insufficient for the clinical development and prognosis of identical twins with leukemia. PMID- 24807004 TI - Peripheral and integral membrane binding of peptides characterized by time dependent fluorescence shifts: focus on antimicrobial peptide LAH4. AB - Positioning of peptides with respect to membranes is an important parameter for biological and biophysical studies using model systems. Our experiments using five different membrane peptides suggest that the time-dependent fluorescence shift (TDFS) of Laurdan can help when distinguishing between peripheral and integral membrane binding and can be a useful, novel tool for studying the impact of transmembrane peptides (TMP) on membrane organization under near-physiological conditions. This article focuses on LAH4, a model alpha-helical peptide with high antimicrobial and nucleic acid transfection efficiencies. The predominantly helical peptide has been shown to orient in supported model membranes parallel to the membrane surface at acidic and, in a transmembrane manner, at basic pH. Here we investigate its interaction with fully hydrated large unilamellar vesicles (LUVs) by TDFS and fluorescence correlation spectroscopy (FCS). TDFS shows that at acidic pH LAH4 does not influence the glycerol region while at basic pH it makes acyl groups at the glycerol level of the membrane less mobile. TDFS experiments with antimicrobial peptides alamethicin and magainin 2, which are known to assume transmembrane and peripheral orientations, respectively, prove that changes in acyl group mobility at the glycerol level correlate with the orientation of membrane-associated peptide molecules. Analogous experiments with the TMPs LW21 and LAT show similar effects on the mobility of those acyl groups as alamethicin and LAH4 at basic pH. FCS, on the same neutral lipid bilayer vesicles, shows that the peripheral binding mode of LAH4 is more efficient in bilayer permeation than the transmembrane mode. In both cases, the addition of LAH4 does not lead to vesicle disintegration. The influence of negatively charged lipids on the bilayer permeation is also addressed. PMID- 24807007 TI - Patient-centered approach to designing sickle cell transition education. AB - INTRODUCTION: It is vital to engage patients with sickle cell disease (SCD) in the transition process from pediatric to adult care. To better understand the patient perspective during the time of transition, we conducted this research with the goal of incorporating patient comprehension and desires for transition education. MATERIALS AND METHODS: We surveyed 37 adolescent patients with SCD about their understanding of SCD and transition education preferences. In addition, patient responses were analyzed to understand differences among urban and rural patients. RESULTS: The mean age of surveyed participants was 14.9 years (SD=2.1). Forty-three percent of participants responded that the topic of transition had been introduced to them, and only 21% responded that they received education about transition. Despite the poor awareness about transition, almost all participants were interested in learning more about the transition process through a technology-based transition education platform where individual health topics could be explored. DISCUSSION: Despite a didactic teaching approach to transition education, we identified that sickle cell participants had poor recognition of receiving transition education and poor understanding of their basic medical history. However, patients can identify specific health topics that should be addressed during an individualized transition education program. PMID- 24807008 TI - On pathologic diagnoses by image-guided core needle biopsies. PMID- 24807009 TI - In reply: the role of whole-body MRI in pediatric oncology. PMID- 24807011 TI - Are ligand-stabilized carboxylic acid derivatives with Ge?Te bonds isolable? AB - The stability of ligand-stabilized carboxylic acid derivatives (such as esters, amides, anhydrides, and acid halides) with terminal Ge?Te bonds is highly questionable as there is no report on such compounds. Nevertheless, we are able to isolate germatelluroester [LGe(Te)Ot-Bu] (4), germatelluroamide [LGe(Te)N(SiMe3)2] (5), and germatelluroacid anhydride [LGe(Te)OGe(Te)L] (6) complexes (L = aminotroponiminate (ATI)) as stable species. Consequently, the synthetic details, structural characterization, and UV-vis spectroscopic and theoretical studies on them are reported for the first time. PMID- 24807012 TI - Sorafenib increases efficacy of vorinostat against human hepatocellular carcinoma through transduction inhibition of vorinostat-induced ERK/NF-kappaB signaling. AB - Sorafenib is effective for patients with advanced hepatocellular carcinoma (HCC) and particularly for those who are unsuitable to receive life-prolonging transarterial chemo-embolization. The survival benefit of sorafenib, however, is unsatisfactory. Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anti-HCC efficacy in preclinical studies. SAHA induces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity in vitro, which may lead to cancer cell progression and jeopardize cytotoxic effect of SAHA in HCC. The goal of this study was to investigate whether sorafenib enhances SAHA cytotoxicity against HCC through inhibition of SAHA-induced NF-kappaB activity. The human HCC cell line Huh7 transfected with dual reporter genes, luciferase (luc) and thymidine kinase (tk) with NF-kappaB response elements, was co-transfected with red fluorescent protein (rfp) gene for non-invasive molecular imaging to assess NF-kappaB activity and living cells simultaneously. Cell viability assay, DNA fragmentation, western blotting, electrophoretic mobility shift assay (EMSA) and multiple modalities of molecular imaging were used to assess the combination efficacy and mechanism of sorafenib and SAHA. The administration of high-dose SAHA (10 uM) with long treatment time (48 h) in vitro, and 25 mg/kg/day by gavage in HCC-bearing nude mice to induce NF-kappaB activity were performed. Sorafenib inhibited SAHA induced NF-kappaB activity and the expression of NF-kappaB-regulated effector proteins while it increased the efficacy of SAHA against HCC both in vitro and in vivo. The mechanism of sorafenib to enhance SAHA efficacy on HCC is through the suppression of ERK/NF-kappaB pathway, which induces extrinsic and intrinsic apoptosis. Combination of sorafenib and SAHA may have the potential as new strategy against HCC. PMID- 24807014 TI - Effect of pH on elementary steps of dopachrome conversion from first-principles calculation. AB - Dopachrome conversion, in which dopachrome is converted into 5,6-dihydroxyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA) upstream of eumelanogenesis, is a key step in determining the DHI/DHICA monomer ratio in eumelanin, which affects the antioxidant activity. Although the ratio of DHI/DHICA formed and the conversion rate can be regulated depending on pH, the mechanism is still unclear. To clarify the mechanism, we carried out first principles calculations. The results showed the kinetic preference of proton rearrangement to form quinone methide intermediate via beta-deprotonation. We also identified possible pathways to DHI/DHICA from the quinone methide. The DHI formation can be achieved by spontaneous decarboxylation after proton rearrangement from carboxyl group to 6-oxygen. alpha-Deprotonation, which leads to DHICA formation, can also proceed with a significantly reduced activation barrier compared with that of the initial dopachrome. Considering the rate of the proton rearrangements in a given pH, we conclude that the conversion is suppressed at acidic pH. PMID- 24807016 TI - Is the current prevention strategy based on vaccination coverage and epidemiological surveillance sufficient to achieve measles and rubella elimination in Europe? AB - Elimination of measles and rubella in Europe is a feasible objective, but it requires achieving a maintaining a high prevalence of protected individuals in order to prevent cases and outbreaks from imported cases. The epidemiology of measles and rubella in Europe in the period 2003-2013 suggests that we are far away from the elimination target for measles, while the situation is better for rubella. In this situation, a new preventive strategy based on serological surveillance systems should be developed in Europe in order to identify and immunise individuals in population groups without sufficient herd immunity against measles and rubella. PMID- 24807017 TI - The O in our name. PMID- 24807015 TI - The efficacy and safety of EGFR inhibitor monotherapy in non-small cell lung cancer: a systematic review. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but what it is still unclear is the efficacy of (EFGR-TKIs: gefitinib or erlotinib) monotherapy in previously treated non-small-cell lung cancer (NSCLC). In December 2013, we performed a search in the PubMed, EMBASE, Cochrane library databases and Web of Science for randomized trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through strict inclusion and exclusion criteria, fourteen trials (three front-line, two second-line, nine maintenance, n = 8970 patients) were eligible. EGFR-TKIs significantly increased overall survival (OS) [hazard ratio (HR) 0.88, 95%confidence interval (CI) 0.82-0.96, I (2) = 50.5%] and progression-free survival (PFS) (HR 0.71, 95% CI 0.63-0.81, I (2) = 81.2%] compared with placebo or best support care (BSC). Patients with clinical features such as never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced OS and PFS benefit. The main adverse reactions were diarrhea, rashes, anorexia and anemia, [odds ratio (OR) = 3.635, 95% confidence interval (CI) = (2.377 to 5.557)], [OR = 15.664, 95%CI = (8.869 to 27.665)], [OR = 1.555, 95%CI = (1.060 to 2.283)], [OR = 1.481, 95%CI = (1.114 to 1.969)], respectively. The results show that monotherapy therapy with EFGR-TKIs produce a significant OS and PFS benefit for patients with NSCLC compared with placebo or BSC, especially for the patients who had adenocarcinomas, non-smokers and patients with EGFR gene mutations. PMID- 24807018 TI - Differentiating ultrasound technologies. PMID- 24807019 TI - A multicenter, retrospective study to evaluate the effect of preoperative stoma site marking on stomal and peristomal complications. AB - Even though preoperative marking of the stoma area is considered important for the prevention of postoperative complications, not all healthcare institutions have universally adopted this practice. A multicenter, retrospective, descriptive study was conducted to determine the effect of stoma site marking on stomal and peristomal complications. The 1-year study included 748 patients (408 [54.5%] male, mean age 56.60 +/- 16.73 years) from eight stomatherapy units in Turkey. Patient data, including age, gender, diagnosis, type of surgery, history of preoperative stoma site marking, person performing the marking, and postoperative complications, were obtained from patient records, abstracted, and analyzed. Cancer was the reason for the operation in 545 (72.9%) of the cases. In 287 patients (38.4%), the stoma and wound care nurse and/or surgeon marked the stoma area; this occurred 1 day before or on the day of surgery according to Wound Ostomy Continence Nurses Society and American Society of Colon and Rectal Surgeons recommendations. Stomal/ peristomal complications developed in 248 (33.2%) persons; the most frequently observed complications in patients were parastomal skin problems (136, 48.7%), mucocutaneous separation (52, 18.6%), and retraction (31, 11.1%). The rate of complications was higher among patients whose stoma site was not marked than among those whose stoma site was marked (22.9% and 46%, respectively; P <0.001). The results of this study confirm the stoma area should be marked preoperatively in all planned surgical interventions in order to reduce the risk of postoperative complications. Additional prospective and experimental studies on effectiveness of preoperative stoma site marking should be conducted with larger sample groups. PMID- 24807020 TI - A survey to assess knowledge among international colorectal clinicians and enterostomal therapy nurses about stoma-related faith needs of Muslim patients. AB - Quality of life after the creation of a stoma can be influenced by religious factors. Enterostomal specialist nurses often offer holistic preoperative counseling to discuss religious concerns with Muslim patients, which requires a sound working knowledge of relevant Islamic practices. To assess colorectal surgeon and enterostomal specialist nurse awareness of Islamic practices that influence quality of life in Muslim patients with stomas, a questionnaire comprised of 16 multiplechoice questions was developed and face and content validity established. In addition to the knowledge questionnaire, participant demographic data, including practice setting and geographical location, years in practice, and personal religious affiliation, were included in the data collection instrument. The questionnaires were sent to all members of the World Council of Enterostomal Therapists (WCET) and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) via association-directed emails. Data were collected over a 5-month period; 132 responses (90 enterostomal nurses and 42 surgeons) were received. Among the 90 WCET respondents, 29 (32%) were from the United Kingdom and Europe, 24 (27%) from the United States, and 10 (11%) from Australasia, and 10 (11%) from South East Asia. All 42 ACPGBI respondents were consultant colorectal surgeons from the UK and Ireland. Eight (8) out of 42 surgeons (20%) and 11 out of 85 nurses (11%) did not feel confident to discuss religious practices before surgery. Of the 127 respondents who answered the question, only four (<5%) correctly identified all Islamic prayer positions. Thirty-two (32, 52%) of the 62 enterostomal therapists and 27 (73%) of the 37 surgeons responding did not discuss fasting with Muslim stoma patients. More than one third of all respondents (48 out of 126) did not feel it was necessary to include religious leaders in the counseling process. Awareness of Islamic practices relevant to Muslim persons with ostomies may be suboptimal among colorectal specialists, which may negatively affect patient experiences after stoma surgery. Further research is required to assess the impact of faith-based counseling on postoperative quality of life in Muslim patients. PMID- 24807022 TI - Eyes on new product development. PMID- 24807023 TI - The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. AB - It is a widespread notion that the proportion of glial to neuronal cells in the brain increases with brain size, to the point that glial cells represent "about 90% of all cells in the human brain." This notion, however, is wrong on both counts: neither does the glia/neuron ratio increase uniformly with brain size, nor do glial cells represent the majority of cells in the human brain. This review examines the origin of interest in the glia/neuron ratio; the original evidence that led to the notion that it increases with brain size; the extent to which this concept can be applied to white matter and whole brains and the recent supporting evidence that the glia/neuron ratio does not increase with brain size, but rather, and in surprisingly uniform fashion, with decreasing neuronal density due to increasing average neuronal cell size, across brain structures and species. Variations in the glia/neuron ratio are proposed to be related not to the supposed larger metabolic cost of larger neurons (given that this cost is not found to vary with neuronal density), but simply to the large variation in neuronal sizes across brain structures and species in the face of less overall variation in glial cell sizes, with interesting implications for brain physiology. The emerging evidence that the glia/neuron ratio varies uniformly across the different brain structures of mammalian species that diverged as early as 90 million years ago in evolution highlights how fundamental for brain function must be the interaction between glial cells and neurons. PMID- 24807024 TI - Pressing the nerve alters muscle fiber types of the peroneus longus in rats: preliminary evidence for external anal sphincteroplasty. AB - BACKGROUND: Studies have demonstrated that anal reconstruction with a gracilis graft pressing the dominant nerve could be used to treat fecal incontinence. However, the detailed mechanism by this remains unknown. Herein, we evaluated the alteration in muscle fiber types and contractility of the peroneus longus muscle in rats after pressing its dominant nerves. MATERIAL AND METHODS: The rat soleus and peroneus longus were exposed during surgery. The superficial peroneal nerve was pressed so that the peroneus longus temporarily lost its innervation. The epimysium between the soleus and the peroneus longus was removed. The end point of the soleus was cut off and the epimysium of the contact surfaces of the soleus and the peroneus longus were sutured. Five months later, peroneus longus contractility was recorded by the myograph system, and types of muscle fibers were observed using the myosin ATPase staining method. RESULTS: The skeletal muscle fiber type underwent adaptive changes due to double innervations with both fast and slow muscle nerves. Compared with other groups, the percentage of type I fibers in the peroneus longus increased significantly in the group of rats with the pressure on the nerve and removal of the sarcolemma. The maximal contraction and relaxation time at the single twitch and complete tetanus of the peroneus longus were also increased. CONCLUSIONS: Our results show that pressing dominant nerves alter the skeletal muscle fiber types of the peroneus longus, which lead to increased maximal contraction and relaxation time, and significantly improve the ability in resistance to fatigue in rats. This study provides a basis for future clinical studies for external anal sphincter reconstruction using gracilis grafts that are doubly innervated by pressing on its dominant nerve. PMID- 24807025 TI - Self-assembly of nano/micro-structured Fe3O4 microspheres among 3D rGO/CNTs hierarchical networks with superior lithium storage performances. AB - Nano/micro-structured Fe3O4 microspheres among three-dimensional (3D) reduced graphene oxide (rGO)/carbon nanotubes (CNTs) hierarchical networks (the ternary composite is denoted as rGCFs) have been synthesized using a facile, self assembled and one-pot hydrothermal approach. The rGCFs composite exhibits superior lithium storage performances: initial discharge and charge capacities of 1452 and 1036 mAh g(-1), respectively, remarkable rate capability at current densities from 100 mA g(-1) to 10 A g(-1) and outstanding cycling performance up to 200 cycles. The highly enhanced electrochemical performances of rGCFs depend heavily on the robust 3D rGO/CNTs hierarchical networks, the stable nano/microstructures of active Fe3O4 microspheres and the positive synergistic effects of building components. The systematic structure characterizations and electrochemical investigations provide insightful understanding towards the relationship between structure/morphology and lithium storage performances, which may pave the way for the rational design of composite materials with desirable goals. PMID- 24807026 TI - What are the differences between Bayesian classifiers and mutual-information classifiers? AB - In this paper, both Bayesian and mutual-information classifiers are examined for binary classifications with or without a reject option. The general decision rules are derived for Bayesian classifiers with distinctions on error types and reject types. A formal analysis is conducted to reveal the parameter redundancy of cost terms when abstaining classifications are enforced. The redundancy implies an intrinsic problem of nonconsistency for interpreting cost terms. If no data are given to the cost terms, we demonstrate the weakness of Bayesian classifiers in class-imbalanced classifications. On the contrary, mutual information classifiers are able to provide an objective solution from the given data, which shows a reasonable balance among error types and reject types. Numerical examples of using two types of classifiers are given for confirming the differences, including the extremely class-imbalanced cases. Finally, we briefly summarize the Bayesian and mutual-information classifiers in terms of their application advantages and disadvantages, respectively. PMID- 24807027 TI - Multikernel least mean square algorithm. AB - The multikernel least-mean-square algorithm is introduced for adaptive estimation of vector-valued nonlinear and nonstationary signals. This is achieved by mapping the multivariate input data to a Hilbert space of time-varying vector-valued functions, whose inner products (kernels) are combined in an online fashion. The proposed algorithm is equipped with novel adaptive sparsification criteria ensuring a finite dictionary, and is computationally efficient and suitable for nonstationary environments. We also show the ability of the proposed vector valued reproducing kernel Hilbert space to serve as a feature space for the class of multikernel least-squares algorithms. The benefits of adaptive multikernel (MK) estimation algorithms are illuminated in the nonlinear multivariate adaptive prediction setting. Simulations on nonlinear inertial body sensor signals and nonstationary real-world wind signals of low, medium, and high dynamic regimes support the approach. PMID- 24807028 TI - Quantum neural network-based EEG filtering for a brain-computer interface. AB - A novel neural information processing architecture inspired by quantum mechanics and incorporating the well-known Schrodinger wave equation is proposed in this paper. The proposed architecture referred to as recurrent quantum neural network (RQNN) can characterize a nonstationary stochastic signal as time-varying wave packets. A robust unsupervised learning algorithm enables the RQNN to effectively capture the statistical behavior of the input signal and facilitates the estimation of signal embedded in noise with unknown characteristics. The results from a number of benchmark tests show that simple signals such as dc, staircase dc, and sinusoidal signals embedded within high noise can be accurately filtered and particle swarm optimization can be employed to select model parameters. The RQNN filtering procedure is applied in a two-class motor imagery-based brain computer interface where the objective was to filter electroencephalogram (EEG) signals before feature extraction and classification to increase signal separability. A two-step inner-outer fivefold cross-validation approach is utilized to select the algorithm parameters subject-specifically for nine subjects. It is shown that the subject-specific RQNN EEG filtering significantly improves brain-computer interface performance compared to using only the raw EEG or Savitzky-Golay filtered EEG across multiple sessions. PMID- 24807029 TI - Multiclass from binary: expanding one-versus-all, one-versus-one and ECOC-based approaches. AB - Recently, there has been a lot of success in the development of effective binary classifiers. Although many statistical classification techniques have natural multiclass extensions, some, such as the support vector machines, do not. The existing techniques for mapping multiclass problems onto a set of simpler binary classification problems run into serious efficiency problems when there are hundreds or even thousands of classes, and these are the scenarios where this paper's contributions shine. We introduce the concept of correlation and joint probability of base binary learners. We learn these properties during the training stage, group the binary leaner's based on their independence and, with a Bayesian approach, combine the results to predict the class of a new instance. Finally, we also discuss two additional strategies: one to reduce the number of required base learners in the multiclass classification, and another to find new base learners that might best complement the existing set. We use these two new procedures iteratively to complement the initial solution and improve the overall performance. This paper has two goals: finding the most discriminative binary classifiers to solve a multiclass problem and keeping up the efficiency, i.e., small number of base learners. We validate and compare the method with a diverse set of methods of the literature in several public available datasets that range from small (10 to 26 classes) to large multiclass problems (1000 classes) always using simple reproducible scenarios. PMID- 24807030 TI - Short-term load and wind power forecasting using neural network-based prediction intervals. AB - Electrical power systems are evolving from today's centralized bulk systems to more decentralized systems. Penetrations of renewable energies, such as wind and solar power, significantly increase the level of uncertainty in power systems. Accurate load forecasting becomes more complex, yet more important for management of power systems. Traditional methods for generating point forecasts of load demands cannot properly handle uncertainties in system operations. To quantify potential uncertainties associated with forecasts, this paper implements a neural network (NN)-based method for the construction of prediction intervals (PIs). A newly introduced method, called lower upper bound estimation (LUBE), is applied and extended to develop PIs using NN models. A new problem formulation is proposed, which translates the primary multiobjective problem into a constrained single-objective problem. Compared with the cost function, this new formulation is closer to the primary problem and has fewer parameters. Particle swarm optimization (PSO) integrated with the mutation operator is used to solve the problem. Electrical demands from Singapore and New South Wales (Australia), as well as wind power generation from Capital Wind Farm, are used to validate the PSO-based LUBE method. Comparative results show that the proposed method can construct higher quality PIs for load and wind power generation forecasts in a short time. PMID- 24807031 TI - HRLSim: a high performance spiking neural network simulator for GPGPU clusters. AB - Modeling of large-scale spiking neural models is an important tool in the quest to understand brain function and subsequently create real-world applications. This paper describes a spiking neural network simulator environment called HRL Spiking Simulator (HRLSim). This simulator is suitable for implementation on a cluster of general purpose graphical processing units (GPGPUs). Novel aspects of HRLSim are described and an analysis of its performance is provided for various configurations of the cluster. With the advent of inexpensive GPGPU cards and compute power, HRLSim offers an affordable and scalable tool for design, real time simulation, and analysis of large-scale spiking neural networks. PMID- 24807032 TI - Sliding-mode control design for nonlinear systems using probability density function shaping. AB - In this paper, we propose a sliding-mode-based stochastic distribution control algorithm for nonlinear systems, where the sliding-mode controller is designed to stabilize the stochastic system and stochastic distribution control tries to shape the sliding surface as close as possible to the desired probability density function. Kullback-Leibler divergence is introduced to the stochastic distribution control, and the parameter of the stochastic distribution controller is updated at each sample interval rather than using a batch mode. It is shown that the estimated weight vector will converge to its ideal value and the system will be asymptotically stable under the rank-condition, which is much weaker than the persistent excitation condition. The effectiveness of the proposed algorithm is illustrated by simulation. PMID- 24807033 TI - Nanophotonic reservoir computing with photonic crystal cavities to generate periodic patterns. AB - Reservoir computing (RC) is a technique in machine learning inspired by neural systems. RC has been used successfully to solve complex problems such as signal classification and signal generation. These systems are mainly implemented in software, and thereby they are limited in speed and power efficiency. Several optical and optoelectronic implementations have been demonstrated, in which the system has signals with an amplitude and phase. It is proven that these enrich the dynamics of the system, which is beneficial for the performance. In this paper, we introduce a novel optical architecture based on nanophotonic crystal cavities. This allows us to integrate many neurons on one chip, which, compared with other photonic solutions, closest resembles a classical neural network. Furthermore, the components are passive, which simplifies the design and reduces the power consumption. To assess the performance of this network, we train a photonic network to generate periodic patterns, using an alternative online learning rule called first-order reduced and corrected error. For this, we first train a classical hyperbolic tangent reservoir, but then we vary some of the properties to incorporate typical aspects of a photonics reservoir, such as the use of continuous-time versus discrete-time signals and the use of complex-valued versus real-valued signals. Then, the nanophotonic reservoir is simulated and we explore the role of relevant parameters such as the topology, the phases between the resonators, the number of nodes that are biased and the delay between the resonators. It is important that these parameters are chosen such that no strong self-oscillations occur. Finally, our results show that for a signal generation task a complex-valued, continuous-time nanophotonic reservoir outperforms a classical (i.e., discrete-time, real-valued) leaky hyperbolic tangent reservoir (normalized root-mean-square errors=0.030 versus NRMSE=0.127). PMID- 24807034 TI - Efficient probabilistic classification vector machine with incremental basis function selection. AB - Probabilistic classification vector machine (PCVM) is a sparse learning approach aiming to address the stability problems of relevance vector machine for classification problems. Because PCVM is based on the expectation maximization algorithm, it suffers from sensitivity to initialization, convergence to local minima, and the limitation of Bayesian estimation making only point estimates. Another disadvantage is that PCVM was not efficient for large data sets. To address these problems, this paper proposes an efficient PCVM (EPCVM) by sequentially adding or deleting basis functions according to the marginal likelihood maximization for efficient training. Because of the truncated prior used in EPCVM, two approximation techniques, i.e., Laplace approximation and expectation propagation (EP), have been used to implement EPCVM to obtain full Bayesian solutions. We have verified Laplace approximation and EP with a hybrid Monte Carlo approach. The generalization performance and computational effectiveness of EPCVM are extensively evaluated. Theoretical discussions using Rademacher complexity reveal the relationship between the sparsity and the generalization bound of EPCVM. PMID- 24807035 TI - Zhang neural network for online solution of time-varying linear matrix inequality aided with an equality conversion. AB - In this paper, for online solution of time-varying linear matrix inequality (LMI), such an LMI is first converted to a time-varying matrix equation by introducing a time-varying matrix, of which each element is greater than or equal to zero. Then, by employing Zhang et al.'s neural dynamic method, a special recurrent neural network termed Zhang neural network (ZNN) is proposed and investigated for solving online the converted time-varying matrix equation as well as the time-varying LMI. Such a ZNN model showed in an explicit dynamics exploits the time-derivative information of time-varying coefficients. In addition, theoretical analysis and results of the proposed ZNN model are discussed and presented to show its excellent performance on solving the time varying LMI. Computer simulation results further demonstrate the efficacy of the proposed ZNN model for online solution of the time-varying LMI and the converted time-varying matrix equation. PMID- 24807036 TI - Robust pole assignment for synthesizing feedback control systems using recurrent neural networks. AB - This paper presents a neurodynamic optimization approach to robust pole assignment for synthesizing linear control systems via state and output feedback. The problem is formulated as a pseudoconvex optimization problem with robustness measure: i.e., the spectral condition number as the objective function and linear matrix equality constraints for exact pole assignment. Two coupled recurrent neural networks are applied for solving the formulated problem in real time. In contrast to existing approaches, the exponential convergence of the proposed neurodynamics to global optimal solutions can be guaranteed even with lower model complexity in terms of the number of variables. Simulation results of the proposed neurodynamic approach for 11 benchmark problems are reported to demonstrate its superiority. PMID- 24807037 TI - Efficient dual approach to distance metric learning. AB - Distance metric learning is of fundamental interest in machine learning because the employed distance metric can significantly affect the performance of many learning methods. Quadratic Mahalanobis metric learning is a popular approach to the problem, but typically requires solving a semidefinite programming (SDP) problem, which is computationally expensive. The worst case complexity of solving an SDP problem involving a matrix variable of size D*D with O(D) linear constraints is about O(D(6.5)) using interior-point methods, where D is the dimension of the input data. Thus, the interior-point methods only practically solve problems exhibiting less than a few thousand variables. Because the number of variables is D(D+1)/2, this implies a limit upon the size of problem that can practically be solved around a few hundred dimensions. The complexity of the popular quadratic Mahalanobis metric learning approach thus limits the size of problem to which metric learning can be applied. Here, we propose a significantly more efficient and scalable approach to the metric learning problem based on the Lagrange dual formulation of the problem. The proposed formulation is much simpler to implement, and therefore allows much larger Mahalanobis metric learning problems to be solved. The time complexity of the proposed method is roughly O(D(3)), which is significantly lower than that of the SDP approach. Experiments on a variety of data sets demonstrate that the proposed method achieves an accuracy comparable with the state of the art, but is applicable to significantly larger problems. We also show that the proposed method can be applied to solve more general Frobenius norm regularized SDP problems approximately. PMID- 24807038 TI - Event-based visual flow. AB - This paper introduces a new methodology to compute dense visual flow using the precise timings of spikes from an asynchronous event-based retina. Biological retinas, and their artificial counterparts, are totally asynchronous and data driven and rely on a paradigm of light acquisition radically different from most of the currently used frame-grabber technologies. This paper introduces a framework to estimate visual flow from the local properties of events' spatiotemporal space. We will show that precise visual flow orientation and amplitude can be estimated using a local differential approach on the surface defined by coactive events. Experimental results are presented; they show the method adequacy with high data sparseness and temporal resolution of event-based acquisition that allows the computation of motion flow with microsecond accuracy and at very low computational cost. PMID- 24807039 TI - Decentralized stabilization for a class of continuous-time nonlinear interconnected systems using online learning optimal control approach. AB - In this paper, using a neural-network-based online learning optimal control approach, a novel decentralized control strategy is developed to stabilize a class of continuous-time nonlinear interconnected large-scale systems. First, optimal controllers of the isolated subsystems are designed with cost functions reflecting the bounds of interconnections. Then, it is proven that the decentralized control strategy of the overall system can be established by adding appropriate feedback gains to the optimal control policies of the isolated subsystems. Next, an online policy iteration algorithm is presented to solve the Hamilton-Jacobi-Bellman equations related to the optimal control problem. Through constructing a set of critic neural networks, the cost functions can be obtained approximately, followed by the control policies. Furthermore, the dynamics of the estimation errors of the critic networks are verified to be uniformly and ultimately bounded. Finally, a simulation example is provided to illustrate the effectiveness of the present decentralized control scheme. PMID- 24807040 TI - Novel adaptive strategies for synchronization of linearly coupled neural networks with reaction-diffusion terms. AB - In this paper, two types of linearly coupled neural networks with reaction diffusion terms are proposed. We respectively investigate the adaptive synchronization of these two types of complex network models. With local information of node dynamics, some novel adaptive strategies to tune the coupling strengths among network nodes are designed. By constructing appropriate Lyapunov functionals and using inequality techniques, several sufficient conditions are given for reaching synchronization by using the designed adaptive laws. Finally, two examples with numerical simulations are provided to demonstrate the effectiveness of the theoretical results. PMID- 24807041 TI - Highlighting the C in ICT: key communication and culture questions in ICT for health. PMID- 24807042 TI - ITGB4-associated junctional epidermolysis bullosa without pylori atresia but profound genito-urinary involvement. PMID- 24807043 TI - Understanding the electrochemical mechanism of K-alphaMnO2 for magnesium battery cathodes. AB - Batteries based on magnesium are an interesting alternative to current state-of the-art lithium-ion systems; however, high-energy-density cathodes are needed for further development. Here we utilize TEM, EDS, and EELS in addition to soft-XAS to determine electrochemical magnesiation mechanism of a high-energy density cathode, K-alphaMnO2. Rather than following the typical insertion mechanism similar to Li(+), we propose the gradual reduction of K-alphaMnO2 to form Mn2O3 then MnO at the interface of the cathode and electrolyte, finally resulting in the formation of K-alphaMnO2@(Mg,Mn)O core-shell product after discharge of the battery. Understanding the mechanism is a vital guide for future magnesium battery cathodes. PMID- 24807045 TI - In vitro evaluation of the mucin-adhesion ability and probiotic potential of Lactobacillus mucosae LM1. AB - AIMS: In this report, we characterized the probiotic potential of Lactobacillus mucosae LM1, focusing on its in vitro mucin-adhesion abilities. METHODS AND RESULTS: Screening assays were used to evaluate LM1. Previous studies on Lact. mucosae species have been performed, but few have examined the ability of this species to adhere to and colonize the intestinal mucosa. Thus, adhesion, aggregation and pathogen inhibition assays of LM1 along with microbial adhesion to solvents (MATS) assay were carried out in comparison with another putative probiotic, Lactobacillus johnsonii PF01, and the commercial strain, Lactobacillus rhamnosus GG. Based on MATS assay, the cell surfaces of the lactobacilli strains were found to be hydrophobic and highly electron-donating, but the average hydropathy (GRAVY) index of predicted surface-exposed proteins in the LM1 genome indicated that most were hydrophilic. LM1 showed the highest adhesion, aggregation and hydrophobicity among the strains tested and significantly inhibited the adhesion of Escherichia coli K88 and Salmonella enterica serovar Typhimurium KCCM 40253. Correlations among adhesion, aggregation and hydrophobicity, as well as between coaggregation and displacement of E. coli, were observed. CONCLUSIONS: Increased adhesion may not always correlate with increased pathogen inhibition due to various strain-specific mechanisms. Nevertheless, LM1 has promising probiotic properties that can be explored further using a genomics approach. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data on adhesion of LM1 strain showed a significant correlation between adhesion, hydrophobicity of cell surface and autoaggregation. This study gives basic knowledge for the elucidation of the adhesion mechanism of Lactobacillus sp. and prediction of its adherence in specific host models. PMID- 24807046 TI - Pruritus in cholestasis: facts and fiction. AB - Pruritus is a common symptom in patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, or hereditary pediatric cholestatic disorders and may accompany, although less frequently, many other liver diseases. Recent findings indicate that lysophosphatidic acid (LPA), a potent neuronal activator, and autotaxin (ATX; ectonucleotide pyrophosphatase/phosphodiesterase 2), the enzyme which forms LPA, may form a key element of the long-sought pruritogenic signaling cascade in cholestatic patients suffering from itch. Serum ATX, but no other pruritogen candidate studied so far, correlates with pruritus intensity and responds to therapeutic interventions. In this comprehensive review, we provide a short update on actual insights in signal transmission related to pruritus and discuss pruritogen candidates in cholestasis. We also summarize evidence-based and guideline-approved as well as experimental therapeutic approaches for patients suffering from pruritus in cholestasis. PMID- 24807047 TI - Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer. AB - Scirrhous type gastric cancer is highly aggressive and has a poorer prognosis than many other types of gastric carcinoma, due to its characteristic rapid cancer cell infiltration and proliferation, extensive stromal fibrosis, and frequent peritoneal dissemination. The aim of the present study was to identify novel prognostic markers or therapeutic targets for scirrhous type gastric cancer. We reviewed a list of genes with upregulated expression in scirrhous type gastric cancer and compared their expression with that in normal stomach from our previous Escherichia coli (E. coli) ampicillin secretion-trap (CAST) analysis. We focused on the ZDHHC14 gene, which encodes zinc finger, DHHC-type containing 14 protein. qRT-PCR analysis of ZDHHC14 in 41 gastric cancer cases revealed that compared to mRNA levels in normal non-neoplastic gastric mucosa, ZDHHC14 mRNA was overexpressed in 27% of gastric cancer tissue samples. The overexpression of ZDHHC14 was significantly associated with depth of tumor invasion, undifferentiated histology and scirrhous pattern. The invasiveness of ZDHHC14 knockdown HSC-44PE and 44As3 gastric cancer cells was decreased in comparison with that of the negative control siRNA-transfected cells, together with downregulation of MMP-17 mRNA. Integrins alpha5 and beta1 were also downregulated in ZDHHC14-knockdown 44As3 cells. Forced expression of ZDHHC14 activated gastric cancer cell migration and invasion in vitro. These results indicate that ZDHHC14 is involved in tumor progression in patients with scirrhous type gastric cancer. PMID- 24807048 TI - Gas Phase Structure of Metal Mediated (Cytosine)2Ag+ Mimics the Hemiprotonated (Cytosine)2H+ Dimer in i-Motif Folding. AB - The study of metal ion-DNA interaction aiming to understand the stabilization of artificial base pairing and a number of noncanonical motifs is of current interest, due to their potential exploitation in developing new technological devices and expanding the genetic code. A successful strategy has been the synthesis of metal-mediated base pairs, in which a coordinative bond to a central metal cation replaces a H-bond in a natural pair. In this work, we characterized, for the first time, the gas phase structure of the cytosine...Ag+...cytosine (C Ag+-C) complex by means of InfraRed-MultiPhoton-Dissociation (IR-MPD) spectroscopy and theoretical calculation. The IR-spectrum was confidently assigned to one structure with the Ag+ acting as a bridge between the heteronitrogen atoms in each cytosine (both in the keto-amino form). This structure is biologically relevant since it mimics the structure of the hemiprotonated C-H+-C dimer responsible for the stabilization of the i-motif structure in DNA, with the replacement of the NH...N bond by a stronger N...Ag+...N bond. Moreover, since the structure of the C-Ag+-C complex is planar, it allows an optimum intercalation between pairs of the two antiparallel strand duplex in the DNA i-motif structure. PMID- 24807049 TI - claMP Tag: a versatile inline metal-binding platform based on the metal abstraction peptide. AB - Molecularly targeted research and diagnostic tools are essential to advancing understanding and detection of many diseases. Metals often impart the desired functionality to these tools, and conjugation of high-affinity chelators to proteins is carried out to enable targeted delivery of the metal. This approach has been much more effective with large lanthanide series metals than smaller transition metals. Because chemical conjugation requires additional processing and purification steps and yields a heterogeneous mixture of products, inline incorporation of a peptide tag capable of metal binding is a highly preferable alternative. Development of a transition metal binding tag would provide opportunity to greatly expand metal-based analyses. The metal abstraction peptide (MAP) sequence was genetically engineered into recombinant protein to generate the claMP Tag. The effects of this tag on recombinant epidermal growth factor (EGF) protein expression, disulfide bond formation, tertiary structural integrity, and transition metal incorporation using nickel were examined to confirm the viability of utilizing the MAP sequence to generate linker-less metal conjugates. PMID- 24807050 TI - Single-vesicle architecture of synaptobrevin2 in astrocytes. AB - Exocytic transmitter release is regulated by the SNARE complex, which contains a vesicular protein, synaptobrevin2 (Sb2). However, Sb2 vesicular arrangement is unclear. Here we use super-resolution fluorescence microscopy to study the prevalence and distribution of endogenous and exogenous Sb2 in single vesicles of astrocytes, the most abundant glial cells in the brain. We tag Sb2 protein at C- and N termini with a pair of fluorophores, which allows us to determine the Sb2 length and geometry. To estimate total number of Sb2 proteins per vesicle and the quantity necessary for the formation of fusion pores, we treat cells with ATP to stimulate Ca2+-dependent exocytosis, increase intracellular alkalinity to enhance the fluorescence presentation of yellow-shifted pHluorin (YpH), appended to the vesicle lumen domain of Sb2, and perform photobleaching of YpH fluorophores. Fluorescence intensity analysis reveals that the total number of endogenous Sb2 units or molecules per vesicle is <=25. PMID- 24807051 TI - Multilaboratory assessment of threshold versus fold-change algorithms for minimizing analytical variability in multiplexed pneumococcal IgG measurements. AB - Pneumococcal vaccination is frequently used to assess a patient's humoral immune function. The comparison of pre- and postvaccination levels of antipneumococcal antibodies is widely held to be the gold standard for documenting a response. However, many of the published criteria for defining an adequate response are based on assays that are no longer widely available. We compared the clinical classification of patient response by multiplex pneumococcal assays currently performed at three large reference laboratories using a variety of published criteria for defining responses in adults. The classification of responders agreed for 79% of the patients when using a threshold-based algorithm compared to 57 to 96% of the patients when using various fold-change-based algorithms. The highest rate of discordance was seen when the most stringent criteria for response were used (4-fold increase postvaccination in 70% of serotypes). The discordant samples tended to show similar patterns of response across all three assays, with small variations in the final number of serotypes converting postvaccination. We conclude that the use of published cut points for documenting response to pneumococcal vaccination can be affected by interlaboratory differences in pneumococcal assays, particularly for algorithms that require large fold changes for a response to be documented. However, the overall patterns of response were similar in virtually all samples, regardless of the assay used. PMID- 24807052 TI - Mapping of epitopes recognized by antibodies induced by immunization of mice with PspA and PspC. AB - Pneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC) are important candidates for an alternative vaccine against pneumococcal infections. Since these antigens show variability, the use of variants that do not afford broad protection may lead to the selection of vaccine escape bacteria. Epitopes capable of inducing antibodies with broad cross-reactivities should thus be the preferred antigens. In this work, experiments using peptide arrays show that most linear epitopes recognized by antibodies induced in mice against different PspAs were located at the initial 44 amino acids of the mature protein and that antibodies against these linear epitopes did not confer protection against a lethal challenge. Conversely, linear epitopes recognized by antibodies to PspC included the consensus sequences involved in the interaction with human factor H and secretory immunoglobulin A (sIgA). Since linear epitopes of PspA were not protective, larger overlapping fragments containing 100 amino acids of PspA of strain Rx1 were constructed (fragments 1 to 7, numbered from the N terminus) to permit the mapping of antibodies with conformational epitopes not represented in the peptide arrays. Antibodies from mice immunized with fragments 1, 2, 4, and 5 were capable of binding onto the surface of pneumococci and mediating protection against a lethal challenge. The fact that immunization of mice with 100-amino-acid fragments located at the more conserved N-terminal region of PspA (fragments 1 and 2) induced protection against a pneumococcal challenge indicates that the induction of antibodies against conformational epitopes present at this region may be important in strategies for inducing broad protection against pneumococci. PMID- 24807053 TI - Epitope mapping of the HSP83.1 protein of Leishmania braziliensis discloses novel targets for immunodiagnosis of tegumentary and visceral clinical forms of leishmaniasis. AB - Gold standard serological diagnostic methods focus on antigens that elicit a strong humoral immune response that is specific to a certain pathogen. In this study, we used bioinformatics approaches to identify linear B-cell epitopes that are conserved among Leishmania species but are divergent from the host species Homo sapiens and Canis familiaris and from Trypanosoma cruzi, the parasite that causes Chagas disease, to select potential targets for the immunodiagnosis of leishmaniasis. Using these criteria, we selected heat shock protein 83.1 of Leishmania braziliensis for this study. We predicted three linear B-cell epitopes in its sequence. These peptides and the recombinant heat shock protein 83.1 (rHSP83.1) were tested in enzyme-linked immunosorbent assays (ELISAs) against serum samples from patients with tegumentary leishmaniasis (TL) and visceral leishmaniasis (VL) and from dogs infected with Leishmania infantum (canine VL [CVL]). Our data show that rHSP83.1 is a promising target in the diagnosis of TL. We also identified specific epitopes derived from HSP83.1 that can be used in the diagnosis of human TL (peptide 3), both human and canine VL (peptides 1 and 3), and all TL, VL, and CVL clinical manifestations (peptide 3). Receiver operating characteristic (ROC) curves confirmed the superior performance of rHSP83.1 and peptides 1 and 3 compared to that of the soluble L. braziliensis antigen and the reference test kit for the diagnosis of CVL in Brazil (EIE-LVC kit; Bio Manguinhos, Fiocruz). Our study thus provides proof-of-principle evidence of the feasibility of using bioinformatics to identify novel targets for the immunodiagnosis of parasitic diseases using proteins that are highly conserved throughout evolution. PMID- 24807054 TI - Interleukin 1 (IL-1)- and IL-23-mediated expansion of filarial antigen-specific Th17 and Th22 cells in filarial lymphedema. AB - Lymphatic filarial disease is known to be associated with elevated Th1 responses and normal or diminished Th2 responses to parasite-specific antigens. The roles of Th17 cells and the recently described Th22 cells have not been examined in detail in either filarial infection itself or in filarial disease (e.g., lymphedema and elephantiasis). To explore the roles of Th17 and Th22 cells and their subsets, we examined the frequencies of these cells in individuals with filarial lymphedema (chronic pathology [CP]), in clinically asymptomatic infected (INF) individuals, and in uninfected (UN) individuals ex vivo and in response to parasite and nonparasite antigens. Those with disease (CP) had significantly expanded frequencies of Th17 and Th22 cells, compared with either INF or UN individuals, at baseline (ex vivo) and in response to parasite antigens. This antigen-driven expansion of Th17 and Th22 cells was dependent on interleukin 1 (IL-1), IL-23, and, to lesser extent, transforming growth factor beta (TGF-beta), as blockade of any of these cytokines resulted in significantly diminished frequencies of Th17 and Th22 cells. Our findings, therefore, suggest that filarial parasite-driven expansion of Th17 and Th22 cells is associated with the pathogenesis of filarial infections and disease. PMID- 24807055 TI - Pertussis toxin improves immune responses to a combined pneumococcal antigen and leads to enhanced protection against Streptococcus pneumoniae. AB - Pneumococcal surface protein A (PspA) is a candidate antigen for the composition of protein-based vaccines against Streptococcus pneumoniae. While searching for efficient adjuvants for PspA-based vaccines, our group has described the potential of combining PspA with the whole-cell pertussis vaccine (wP). When given to mice through the nasal route, a formulation composed of PspA from clade 5 (PspA5) and wP (PspA5-wP) induced high levels of antibodies and protection against challenges with different pneumococcal strains. PspA5-wP also induced the secretion of interleukin 17 (IL-17) by splenocytes and the infiltration of leukocytes in the lungs after challenge. Here, we show that protection against a pneumococcal invasive challenge was completely abrogated in MUMT(-/-) mice, which are deficient in the maturation of B cells, illustrating the importance of antibodies in the survival elicited by the PspA5-wP vaccine. Moreover, passive immunization showed that IgG purified from the sera of mice immunized with PspA5 wP conferred significant protection to naive mice, whereas the respective F(ab')2 did not. Additionally, in vivo depletion of complement abolished protection against the pneumococcal challenge. The combination of PspA5 with wild-type or mutant Bordetella pertussis strains or with purified components showed that the pertussis toxin (PT)-containing formulations induced the highest levels of antibodies and protection. This suggests that the adjuvant activity of wP in the PspA5 model is mediated at least in part by PT. The sera from mice immunized with such formulations displayed high IgG binding and induction of complement deposition on the pneumococcal surface in vitro, which is consistent with the in vivo results. PMID- 24807056 TI - Neisseria adhesin A variation and revised nomenclature scheme. AB - Neisseria adhesin A (NadA), involved in the adhesion and invasion of Neisseria meningitidis into host tissues, is one of the major components of Bexsero, a novel multicomponent vaccine licensed for protection against meningococcal serogroup B in Europe, Australia, and Canada. NadA has been identified in approximately 30% of clinical isolates and in a much lower proportion of carrier isolates. Three protein variants were originally identified in invasive meningococci and named NadA-1, NadA-2, and NadA-3, whereas most carrier isolates either lacked the gene or harbored a different variant, NadA-4. Further analysis of isolates belonging to the sequence type 213 (ST-213) clonal complex identified NadA-5, which was structurally similar to NadA-4, but more distantly related to NadA-1, -2, and -3. At the time of this writing, more than 89 distinct nadA allele sequences and 43 distinct peptides have been described. Here, we present a revised nomenclature system, taking into account the complete data set, which is compatible with previous classification schemes and is expandable. The main features of this new scheme include (i) the grouping of the previously named NadA 2 and NadA-3 variants into a single NadA-2/3 variant, (ii) the grouping of the previously assigned NadA-4 and NadA-5 variants into a single NadA-4/5 variant, (iii) the introduction of an additional variant (NadA-6), and (iv) the classification of the variants into two main groups, named groups I and II. To facilitate querying of the sequences and submission of new allele sequences, the nucleotide and amino acid sequences are available at http://pubmlst.org/neisseria/NadA/. PMID- 24807058 TI - Nano-optical conveyor belt, part II: Demonstration of handoff between near-field optical traps. AB - Optical tweezers have been widely used to manipulate biological and colloidal material, but the diffraction limit of far-field optics makes focused beams unsuitable for manipulating nanoscale objects with dimensions much smaller than the wavelength of light. While plasmonic structures have recently been successful in trapping nanoscale objects with high positioning accuracy, using such structures for manipulation over longer range has remained a significant challenge. In this work, we introduce a conveyor belt design based on a novel plasmonic structure, the resonant C-shaped engraving (CSE). We show how long range manipulation is made possible by means of handoff between neighboring CSEs, and we present a simple technique for controlling handoff by rotating the polarization of laser illumination. We experimentally demonstrate handoff between a pair of CSEs for polystyrene spheres 200, 390, and 500 nm in diameter. We then extend this technique and demonstrate controlled particle transport down a 4.5 MUm long "nano-optical conveyor belt." PMID- 24807060 TI - Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. AB - The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. PMID- 24807059 TI - Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. AB - Intra-arterial (IA) delivery of mesenchymal stem cells (MSCs) for acute ischemic stroke is attractive for clinical translation. However, studies using rat model of stroke have demonstrated that IA MSCs delivery can decrease middle cerebral artery (MCA) flow, which may limit its clinical translation. The goal of this study is to identify a dose of IA MSCs (maximum tolerated dose; MTD) that does not compromise MCA flow and evaluate its efficacy and optimal timing in a rat model of reversible middle cerebral artery occlusion (rMCAo). We sought to determine if there is a difference in efficacy of acute (1 h) versus sub-acute (24 h) IA MSCs treatment after rMCAo. Adult female Sprague-Dawley rats underwent rMCAo (90 min) and an hour later a single dose of MSCs (at de-escalating doses 1 * 10(6), 5 * 10(5), 2 * 10(5), 1 * 10(5) and 5 * 10(4)) was given using IA route. MSCs were suspended in phosphate buffered saline (PBS) and PBS alone was used for control experiments. We measured the percent change in mean laser Doppler flow signal over the ipsilateral MCA in de-escalating doses groups to determine MTD. The results demonstrated that the lowering of IA MSC dose to 1 * 10(5) and below did not compromise MCA flow and hence an IA MSC dose of 1 * 10(5) considered as MTD. Subsequently, 1 h and 24 h after rMCAo, rats were treated with IA MSCs or PBS. The 24 h delivery of IA MSCs significantly improved neurodeficit score and reduced the mean infarct volume at one month as compared to control, but not the 1 h delivery. Overall, this study suggests that the IA delivery of MSCs can be performed safely and efficaciously at the MTD of 1 * 10(5) delivered at 24 hours in rodent model of stroke. PMID- 24807061 TI - Using Implicit Instructional Cues to Influence False Memory Induction. AB - Previous research has shown that explicit cues specific to the encoding process (endogenous) or characteristic of the stimuli themselves (exogenous) can be used to direct a reader's attentional resources towards either relational or item specific information. By directing attention to relational information (and therefore away from item-specific information) the rate of false memory induction can be increased. The purpose of the current study was to investigate if a similar effect would be found by manipulating implicitly endogenous cues. An instructional manipulation was used to influence the perceptual action participants performed on word stimuli during the encoding of DRM list words. Results demonstrated that the instructional conditions that encouraged faster processing also led to an increased rate of false memory induction for semantically related words, supporting the hypothesis that attention was directed towards relational information. This finding supports the impoverished relational processing account of false memory induction. This supports the idea that implicitly endogenous cues, exogenous cues (like font) or explicitly endogenous cues (like training) can direct attentional resources during encoding. PMID- 24807062 TI - An update on postrefractive surgery intraocular pressure determination. AB - PURPOSE OF REVIEW: Due to alterations in corneal structure and biomechanics, intraocular pressure (IOP) measurement after refractive surgery has questionable accuracy. Numerous devices and techniques have been evaluated in the past decade. Whereas some methods clearly underestimate postoperative IOPs, other promising leads have emerged that are less affected by laser ablative procedures. RECENT FINDINGS: It is well established that Goldmann applanation tonometry (GAT) underestimates IOP after refractive surgery. The discussion on the accuracy of different techniques of IOP measurement after refractive surgery remains ongoing. Evidence suggests that techniques that are less reliant on corneal structure and biomechanics may provide less altered IOPs postoperatively. Therefore, devices such as Dynamic Contour Tonometry and tonopen may have great utility after laser ablative surgery. SUMMARY: GAT may not be the best method of measuring IOP after refractive surgery. Other devices may be superior to the GAT in providing more accurate IOP postoperatively. It is imperative that clinicians are aware of the possible inaccuracy of IOP acquisition after refractive surgery, in order to provide optimal monitoring for the development and progression of glaucoma. PMID- 24807063 TI - Descemet membrane endothelial transfer. AB - PURPOSE OF REVIEW: To elaborate on the recent concept of Descemet membrane endothelial transfer (DMET) and to explore the concepts that underpin its success through reviewing the key articles that have challenged our current understanding of corneal endothelial cell behavior. RECENT FINDINGS: DMET challenges the paradigm that complete graft-host apposition is required for successful corneal clearance in endothelial keratoplasty. It offers the promise of a simpler procedure to restore corneal clarity. Its success may lie in the ability of endothelial cells to migrate and proliferate. Endothelial host cells have been found in isolation and at disparate locations among donor cells within the corneal buttons of patients who have had a penetrating keratoplasty. New evidence for the continued slow proliferation of endothelial cells from the corneal periphery throughout life comes from the microanatomy of the peripheral cornea, and the demonstration of stem cell markers and markers of DNA synthesis in this area. SUMMARY: DMET offers us a tantalizing taste of a simpler way of treating corneal endothelial disease by harnessing the ability of corneal endothelial cells to migrate and proliferate. An understanding of these processes will be the key stepping stone to developing future treatments for corneal endothelial disease. PMID- 24807064 TI - Alternatives to corneal transplantation for the management of bullous keratopathy. AB - PURPOSE OF REVIEW: Corneal transplantation remains the gold-standard treatment for bullous keratopathy patients as it provides symptomatic relief and visual rehabilitation. As corneas are not always available for transplant, alternative treatments have to be considered for alleviation of discomfort and pain. RECENT FINDINGS: Various treatment options available in such cases include conjunctival flaps, anterior stromal puncture, amniotic membrane transplantation, phototherapeutic keratectomy, bandage contact lenses, and hypertonic saline eye drops. A combination of the above treatments can be employed depending upon the severity of bullous keratopathy and co-existing corneal edema. New potential treatments include collagen cross-linking (CXL), cultured endothelial cell injection, and topical treatment with Rho-associated kinase (ROCK) inhibitor. SUMMARY: There is a lack of clinical trials comparing the safety and efficacy of the currently available treatment options for the management of bullous keratopathy. The effect of these treatments on subsequent corneal transplant has not been observed. CXL seems to offer short-term benefit for relief of pain. Newer potential treatment modalities such as ROCK inhibitors are claimed to be useful for the reversal of early edema associated with corneal endothelial dysfunction; however, long-term clinical trials are awaited. PMID- 24807065 TI - Endothelial keratoplasty in children. AB - PURPOSE OF REVIEW: Descemet stripping endothelial keratoplasty has superseded penetrating keratoplasty (PKP) in adults as the procedure of choice for treating endothelial dysfunction, but endothelial keratoplasty despite the multitude of advantages has undergone a much slower adoption in pediatric patients. This review focuses on the recent advances made in the field of pediatric endothelial keratoplasty and the associated surgical challenges. RECENT FINDINGS: Pediatric endothelial keratoplasty does not require as many sutures as PKP, and the wound size is smaller and more stable. Endothelial keratoplasty grafts clear faster, possibly allowing for a more effective management of amblyopia. Visual outcomes appear to be comparable with PKP but with a lower complication rate. SUMMARY: As corneal surgeons grow more and more familiar with the nuances of pediatric endothelial keratoplasty, our understanding of this procedure will become more complete. The limited data available suggest that endothelial keratoplasty is a suitable surgical alternative to PKP in children. PMID- 24807066 TI - Accuracy and stability of hyperopic treatments. AB - PURPOSE OF REVIEW: Treatment of hyperopia presents greater challenges than treatment of myopia for multiple reasons, including the fact that hyperopia tends to progress with age and becomes more symptomatic with the loss of accommodation. RECENT FINDINGS: Despite these issues, surgeons have multiple options to treat hyperopia successfully. Modern laser vision correction has high success rates for most patients and performs acceptably in the presence of high hyperopia or high cylinder. Early studies combining excimer laser treatment with collagen cross linking (CXL) suggest that this may improve refractive stability. Recent studies have also described femtosecond lenticule extraction and use of a solid-state laser in place of the excimer. In addition to cornea-based treatment, long-term studies of a hyperopic phakic intraocular lens have shown excellent visual outcomes and good safety. Cross-linking is increasingly being applied to the hyperopia that follows radial keratotomy. SUMMARY: The established treatments for hyperopia continue to accumulate evidence supporting their safety and efficacy. The next step forward in treatment may arise from combining these treatments with CXL to stabilize the cornea long-term. PMID- 24807067 TI - Image-guided high-dose-rate brachytherapy in inoperable endometrial cancer. AB - Inoperable endometrial cancer may be treated with curative aim using radical radiotherapy alone. The radiation techniques are external beam radiotherapy (EBRT) alone, EBRT plus brachytherapy and brachytherapy alone. Recently, high dose-rate brachytherapy has been used instead of low-dose-rate brachytherapy. Image-guided brachytherapy enables sufficient coverage of tumour and reduction of dose to the organs at risk, thus increasing the therapeutic ratio of treatment. Local control rates with three-dimensional brachytherapy appear better than with conventional techniques (about 90-100% and 70-90%, respectively). PMID- 24807068 TI - Dosimetric audit in brachytherapy. AB - Dosimetric audit is required for the improvement of patient safety in radiotherapy and to aid optimization of treatment. The reassurance that treatment is being delivered in line with accepted standards, that delivered doses are as prescribed and that quality improvement is enabled is as essential for brachytherapy as it is for the more commonly audited external beam radiotherapy. Dose measurement in brachytherapy is challenging owing to steep dose gradients and small scales, especially in the context of an audit. Several different approaches have been taken for audit measurement to date: thimble and well-type ionization chambers, thermoluminescent detectors, optically stimulated luminescence detectors, radiochromic film and alanine. In this work, we review all of the dosimetric brachytherapy audits that have been conducted in recent years, look at current audits in progress and propose required directions for brachytherapy dosimetric audit in the future. The concern over accurate source strength measurement may be essentially resolved with modern equipment and calibration methods, but brachytherapy is a rapidly developing field and dosimetric audit must keep pace. PMID- 24807069 TI - Structural signatures of dynamic heterogeneities in monolayers of colloidal ellipsoids. AB - When a liquid is supercooled towards the glass transition, its dynamics drastically slows down, whereas its static structure remains relatively unchanged. Finding a structural signature of the dynamic slowing down is a major challenge, yet it is often too subtle to be uncovered. Here we discover the structural signatures for both translational and rotational dynamics in monolayers of colloidal ellipsoids by video microscopy experiments and computer simulations. The correlation lengths of the dynamic slowest-moving clusters, the static glassy clusters, the static local structural entropy and the dynamic heterogeneity follow the same power-law divergence, suggesting that the kinetic slowing down is caused by a decrease in the structural entropy and an increase in the size of the glassy cluster. Ellipsoids with different aspect ratios exhibit single- or double-step glass transitions with distinct dynamic heterogeneities. These findings demonstrate that the particle shape anisotropy has important effects on the structure and dynamics of the glass. PMID- 24807070 TI - Dermatitis and dangerous diets: a case of kwashiorkor. PMID- 24807071 TI - Hydrogen-catalyzed, pilot-scale production of small-diameter boron nitride nanotubes and their macroscopic assemblies. AB - Boron nitride nanotubes (BNNTs) exhibit a range of properties that are as compelling as those of carbon nanotubes (CNTs); however, very low production volumes have prevented the science and technology of BNNTs from evolving at even a fraction of the pace of CNTs. Here we report the high-yield production of small diameter BNNTs from pure hexagonal boron nitride powder in an induction thermal plasma process. Few-walled, highly crystalline small-diameter BNNTs (~5 nm) are produced exclusively and at an unprecedentedly high rate approaching 20 g/h, without the need for metal catalysts. An exceptionally high cooling rate (~10(5) K/s) in the induction plasma provides a strong driving force for the abundant nucleation of small-sized B droplets, which are known as effective precursors for small-diameter BNNTs. It is also found that the addition of hydrogen to the reactant gases is crucial for achieving such high-quality, high-yield growth of BNNTs. In the plasma process, hydrogen inhibits the formation of N2 from N radicals and promotes the creation of B-N-H intermediate species, which provide faster chemical pathways to the re-formation of a h-BN-like phase in comparison to nitridation from N2. We also demonstrate the fabrication of macroscopic BNNT assemblies such as yarns, sheets, buckypapers, and transparent thin films at large scales. These findings represent a seminal milestone toward the exploitation of BNNTs in real-world applications. PMID- 24807072 TI - Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frameshift mutations. AB - The CC-chemokine receptor CCR5 has been associated with cancer progression and metastasis. CCR5 blockers such as Maraviroc are tested in metastatic cancer patients. A mutant allele of CCR5, CCR5-delta32 (CCR5del32), which encodes for a protein with a trans-dominant negative effect on the wildtype protein, is frequently found in populations of northern European origin. We set out to determine if the CCR5del32 genotype is associated with progression of breast cancer. Here, we genotyped 414 breast cancer patients and investigated whether the CCR5 genotype had an association with the likelihood to metastasize within specific subgroups of this cohort. The findings were subsequently confirmed in an independent cohort of 1,017 breast cancer patients. Specifically within the postmenopausal subgroup of the initial cohort (n = 325) individuals carrying the CCR5del32 genotype exhibited a significantly longer metastasis-free survival (MFS, p = 0.038). In an independent cohort, CCR5del32 genotype was confirmed to be associated with prolonged MFS only in postmenopausal patients (n = 579, hazard ratio [HR] = 0.61, 95% confidence interval [95% CI] = 0.38-0.99, p = 0.044), and not in premenopausal patients (n = 438, HR = 1.01, 95% CI = 0.70-1.48, p = 0.94). Our results indicate that CCR5del32 genotype is associated with good prognosis in postmenopausal breast cancer patients. Considering this result, postmenopausal breast cancer patients who are wildtype for CCR5 genotype might benefit from CCR5 blockers, such as Maraviroc. PMID- 24807073 TI - A new twist in the assembly of type IV pilus-like fibers. AB - The type II secretion system (T2SS) and the type IV pilus system (T4PS) are structurally related molecular machines that reversibly assemble helical fibers in an ATP-dependent manner. In this issue of Structure, Nivaskumar and colleagues provide support for a "spooling" model of T2SS pseudopilus assembly and suggest that the T2S-and by extension, T4P-system motors may operate in a rotary manner to assemble filaments. PMID- 24807074 TI - Bacterial warfare again targets the ribosome. AB - In this issue of Structure, Beck and colleagues describe the structure of the Enterobacter cloacae contact-dependent growth inhibition (CDI) toxin in complex with its immunity protein. Further functional studies reveal that CDI targets translation by cleaving 16S ribosomal RNA. PMID- 24807075 TI - RNase AS versus RNase T: similar yet different. AB - In this issue of Structure, Romano and colleagues show that RNase AS specifically hydrolyses adenylate-containing RNA and affects mycobacterial virulence. This study reveals the structural basis underlying the substrate specificity of this enzyme. PMID- 24807076 TI - Membrane interaction and functional plasticity of inositol polyphosphate 5 phosphatases. AB - In this issue of Structure, Tresaugues and colleagues determined the interaction of membrane-bound phosphoinositides with three clinically significant human inositol polyphosphate 5-phosphatases (I5Ps). A comparison to the structures determined with soluble substrates revealed differences in the binding mode and suggested how the I5Ps and apurinic endonuclease (APE1) activities evolved from the same metal-binding active center. PMID- 24807077 TI - Gas-phase structure of the E. coli OmpA dimer. AB - In this issue of Structure, Marcoux and colleagues use gas-phase collisional cross section (CCS) measured by ion-mobility mass spectrometry to analyze the CCS of oligomeric states of E. coli outer membrane OmpA. CCS of the dimer supports a model of paired periplasmic C-terminal domains projecting away from the transmembrane porins. PMID- 24807078 TI - Characterization of FAB1 phosphatidylinositol kinases in Arabidopsis pollen tube growth and fertilization. AB - In yeast and animal cells, phosphatidylinositol-3-monophosphate 5-kinases produce phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P2) and have been implicated in endomembrane trafficking and pH control in the vacuole. In plants, PtdIns(3,5)P2 is synthesized by the Fab1 family, four orthologs of which exist in Arabidopsis: FAB1A and FAB1B, both from the PIKfyve/Fab1 family; FAB1C and FAB1D, both without a PIKfyve domain and of unclear role. Using a reverse genetics and cell biology approach, we investigated the function of the Arabidopsis genes encoding FAB1B and FAB1D, both highly expressed in pollen. Pollen viability, germination and tube morphology were not significantly affected in homozygous mutant plants. In vivo, mutant pollen fertilized ovules leading to normal seeds and siliques. The same result was obtained when mutant ovules were fertilized with wild-type pollen. Double mutant pollen for the two genes was able to fertilize and develop plants no different from the wild-type. At the cellular level, fab1b and fab1d pollen tubes were found to exhibit perturbations in membrane recycling, vacuolar acidification and decreased production of reactive oxygen species (ROS). Subcellular imaging of FAB1B-GFP revealed that the protein localized to the endomembrane compartment, whereas FAB1D-GFP localized mostly to the cytosol and sperm cells. These results were discussed considering possible complementary roles of FAB1B and FAB1D. PMID- 24807081 TI - Defining death: the importance of scientific candor and transparency. PMID- 24807079 TI - Impact of supplementation with amino acids or their metabolites on muscle wasting in patients with critical illness or other muscle wasting illness: a systematic review. AB - Muscle wasting during critical illness impairs recovery. Dietary strategies to minimise wasting include nutritional supplements, particularly essential amino acids. We reviewed the evidence on enteral supplementation with amino acids or their metabolites in the critically ill and in muscle wasting illness with similarities to critical illness, aiming to assess whether this intervention could limit muscle wasting in vulnerable patient groups. Citation databases, including MEDLINE, Web of Knowledge, EMBASE, the meta-register of controlled trials and the Cochrane Collaboration library, were searched for articles from 1950 to 2013. Search terms included 'critical illness', 'muscle wasting', 'amino acid supplementation', 'chronic obstructive pulmonary disease', 'chronic heart failure', 'sarcopenia' and 'disuse atrophy'. Reviews, observational studies, sport nutrition, intravenous supplementation and studies in children were excluded. One hundred and eighty studies were assessed for eligibility and 158 were excluded. Twenty-two studies were graded according to standardised criteria using the GRADE methodology: four in critical care populations, and 18 from other clinically relevant areas. Methodologies, interventions and outcome measures used were highly heterogeneous and meta-analysis was not appropriate. Methodology and quality of studies were too varied to draw any firm conclusion. Dietary manipulation with leucine enriched essential amino acids (EAA), beta-hydroxy-beta methylbutyrate and creatine warrant further investigation in critical care; EAA has demonstrated improvements in body composition and nutritional status in other groups with muscle wasting illness. High-quality research is required in critical care before treatment recommendations can be made. PMID- 24807082 TI - Posttraumatic stress disorder among survivors of critical illness: creation of a conceptual model addressing identification, prevention, and management. AB - Quality of life is frequently impaired among survivors of critical illness, and psychiatric morbidity is an important element contributing to poor quality of life in these patients. Among potential manifestations of psychiatric morbidity following critical illness, symptoms of posttraumatic stress are prevalent and intricately linked to the significant stressors present in the intensive care unit (ICU). As our understanding of the epidemiology of post-ICU posttraumatic stress disorder improves, so must our ability to identify those at highest risk for symptoms in the period of time following critical illness and our ability to implement strategies to prevent symptom development. In addition, a focus on strategies to address clinically apparent psychiatric morbidity will be essential. Much remains to be understood about the identification, prevention, and management of this significant public health problem. This article addresses the importance of uniformity in future epidemiologic studies, proposes framing of risk factors into those likely to be modifiable versus non-modifiable, and provides an assessment of modifiable risk factors in the context of a novel conceptual model that offers insight into potential strategies to attenuate symptoms of posttraumatic stress among survivors of critical illness. PMID- 24807083 TI - A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. AB - PURPOSE: Candida is the most common cause of severe yeast infections worldwide, especially in critically ill patients. In this setting, septic shock attributable to Candida is characterized by high mortality rates. The aim of this multicenter study was to investigate the determinants of outcome in critically ill patients with septic shock due to candidemia. METHODS: This was a retrospective study in which patients with septic shock attributable to Candida who were treated during the 3-year study period at one or more of the five participating teaching hospitals in Italy and Spain were eligible for enrolment. Patient characteristics, infection-related variables, and therapy-related features were reviewed. Multiple logistic regression analysis was performed to identify the risk factors significantly associated with 30-day mortality. RESULTS: A total of 216 patients (mean age 63.4 +/- 18.5 years; 58.3 % males) were included in the study. Of these, 163 (75 %) were admitted to the intensive care unit. Overall 30 day mortality was 54 %. Significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores, dysfunctional organs, and inadequate antifungal therapy were compared in nonsurvivors and survivors. No differences in survivors versus nonsurvivors were found in terms of the time from positive blood culture to initiation of adequate antifungal therapy. Multivariate logistic regression identified inadequate source control, inadequate antifungal therapy, and 1-point increments in the APACHE II score as independent variables associated with a higher 30-day mortality rate. PMID- 24807084 TI - Long-term outcomes in patients with severe sepsis randomised to resuscitation with hydroxyethyl starch 130/0.42 or Ringer's acetate. AB - PURPOSE: We assessed long-term mortality and hospitalisation in patients with severe sepsis resuscitated with hydroxyethyl starch (HES) or Ringer's acetate. METHODS: This was an investigator-initiated, parallel-grouped, blinded randomised trial using computer-generated allocation sequence and centralised allocation data that included 804 patients with severe sepsis needing fluid resuscitation in 26 general intensive care units (ICUs) in Scandinavia. Patients were allocated to fluid resuscitation using either 6% HES 130/0.42 or Ringer's acetate during ICU admission. We assessed mortality rates at 6 months, 1 year and at the time of longest follow-up and days alive and out of hospital at 1 year. RESULTS: The vital status of all patients was obtained at a median of 22 (range 13-36) months after randomisation. Mortality rates in the HES versus Ringer's groups at 6 months were 53.3 (212/398 patients) versus 47.5% (190/400) [relative risk 1.12; 95% confidence interval (CI) 0.98-1.29; P = 0.10], respectively; at 1 year, 56.0 (223/398) versus 51.5% (206/400) (1.09; 95% CI 0.96-1.24; P = 0.20), respectively; at the time of longest follow-up, 59.8 (238/398) versus 56.3% (225/400) (1.06; 95% CI 0.94-1.20; P = 0.31), respectively. Percentage of days alive and out of hospital at 1 year in the HES versus Ringer's groups was 24 (0 87 days) versus 63% (0-90) (P = 0.07). CONCLUSIONS: The long-term mortality rates did not differ in patients with severe sepsis assigned to HES 130/0.42 versus Ringer's acetate, but we could not reject a 24% relative increased or a 4% relative decreased mortality at 1 year with HES at the 95% confidence level. PMID- 24807085 TI - How precise is "precision" of hemodynamic measurements in clinical validation studies? PMID- 24807086 TI - Time intervals from subarachnoid hemorrhage to rebleed. AB - The most threatening early complication and predictor of poor outcome after an aneurysmal subarachnoid hemorrhage (aSAH) is a rebleed. To evaluate what proportion of rebleeds might be prevented by early treatment, we assessed the time interval from the initial hemorrhage to rebleed, and the location of the patient at the time of rebleed. Patient characteristics, World Federation of Neurological Surgeons grade on admission and modified Rankin Scale outcome scores, referring hospitals and time intervals from initial hemorrhage to treatment of 293 patients treated between 2008 and 2011 were evaluated. Time intervals to rebleeds and location of the patients at the time of rebleed were retrieved. Rebleeds were confirmed by CT in 12% of patients, and an additional 4% of patients was diagnosed as having a possible rebleed. Sixty percent of rebleeds occurred after admission to the treatment center. Almost all rebleeds occurred within 24 h, with a median time interval between initial hemorrhage and rebleed of 180 min. A significantly shorter time to treatment and a higher mortality were seen in the group of patients with a rebleed. Approximately, one in six patients with an aSAH had a rebleed, of which a majority might have been preventable because they occurred after admission to the treatment center. A reduction in the rebleed rate seems feasible by securing the aneurysm as soon as possible by improving in-hospital logistics for early aneurysm treatment. Alternative options, such as immediate administration of antifibrinolytics, are being explored in a multicenter trial. PMID- 24807088 TI - Visual classification: expert knowledge guides machine learning. AB - Humans use intuition and experience to classify everything they perceive, but only if the distinguishing patterns are visible. Machine-learning algorithms can learn class information from data sets, but the created classes' meaning isn't always clear. A proposed mixed-initiative approach combines intuitive visualizations with machine learning to tap into the strengths of human and machine classification. The use of visualizations in an expert-guided clustering technique allows the display of complex data sets in a way that allows human input into machine clustering. Test participants successfully employed this technique to classify analytic activities using behavioral observations of a creative-analysis task. The results demonstrate how visualization of the machine learned classification can help users create more robust and intuitive categories. PMID- 24807089 TI - Guest editors' introduction: knowledge-assisted visualization. PMID- 24807087 TI - Cerebrospinal fluid analysis in Alzheimer's disease: technical issues and future developments. AB - Alzheimer's disease (AD) is a leading cause of morbidity, mortality, and a major epidemic worldwide. Although clinical assessment continues to remain the keystone for patient management and clinical trials, such evaluation has important limitations. In this context, cerebrospinal fluid (CSF) biomarkers are important tools to better identify high-risk individuals, to diagnose AD promptly and accurately, especially at the prodromal mild cognitive impairment stage of the disease, and to effectively prognosticate and treat AD patients. Recent advances in functional genomics, proteomics, metabolomics, and bioinformatics will hopefully revolutionize unbiased inquiries into several putative CSF markers of cerebral pathology that may be concisely informative with regard to the various stages of AD progression through years and decades. Moreover, the identification of efficient drug targets and development of optimal therapeutic strategies for AD will increasingly rely on a better understanding and integration of the systems biology paradigm, which will allow predicting the series of events and resulting responses of the biological network triggered by the introduction of new therapeutic compounds. In this scenario, unbiased systems biology-based diagnostic and prognostic models in AD will consist of relevant comprehensive panels of molecules and key branches of the disease-affected cellular neuronal network. Such characteristic and unbiased biomarkers will more accurately and comprehensively reflect pathophysiology from the early asymptomatic and presymptomatic to the final prodromal and symptomatic clinical stages in individual patients (and their individual genetic disease predisposition), ultimately increasing the chances of success of future disease modifying and preventive treatments. PMID- 24807090 TI - Knowledge-assisted reconstruction of the human rib cage and lungs. PMID- 24807091 TI - Knowledge-assisted visualization and segmentation of geologic features. AB - A 3D visualization environment contains domain information about geologic features in seismic data and lets users interactively steer segmentations on the basis of visual sources of information and knowledge. A user study demonstrates this approach's ability to transfer domain knowledge to non experts. PMID- 24807092 TI - Visual analysis of flow features using information theory. PMID- 24807093 TI - Prajna: adding automated reasoning to the visual- analysis process. AB - Developers who create applications for knowledge representation must contend with challenges in both the abundance of data and the variety of toolkits, architectures, and standards for representing it. Prajna is a flexible Java toolkit designed to overcome these challenges with an extensible architecture that supports both visualization and automated reasoning. PMID- 24807094 TI - Application-driven compression for visualizing large-scale time-varying data. PMID- 24807095 TI - Volumetric ambient occlusion for real-time rendering and games. AB - This new algorithm, based on GPUs, can compute ambient occlusion to inexpensively approximate global-illumination effects in real-time systems and games. The first step in deriving this algorithm is to examine how ambient occlusion relates to the physically founded rendering equation. The correspondence stems from a fuzzy membership function that defines what constitutes nearby occlusions. The next step is to develop a method to calculate ambient occlusion in real time without precomputation. The algorithm is based on a novel interpretation of ambient occlusion that measures the relative volume of the visible part of the surface's tangent sphere. The new formula's integrand has low variation and thus can be estimated accurately with a few samples. PMID- 24807096 TI - Dynamic terrain for multiuser real-time environments. PMID- 24807097 TI - We all live in a virtual submarine. PMID- 24807098 TI - CancerSpace: a simulation-based game for improving cancer-screening rates. PMID- 24807099 TI - Advanced graphics technology. PMID- 24807100 TI - Effect of rhBMP-2 dose on bone formation/maturation in a rat critical-size calvarial defect model. AB - BACKGROUND: Application of recombinant human bone morphogenetic protein-2 (rhBMP 2) has been associated with significant adverse events in craniofacial settings, including swelling and seroma formation. Recent work has demonstrated an inverse relationship between bone formation/maturation and rhBMP-2 dose, frequency/severity of adverse events increasing with rising dose. OBJECTIVE: The objective of this study was to determine the most effective dose for rhBMP-2 soak loaded onto an absorbable collagen sponge (ACS) carrier for bone formation/maturation using an established defect model. METHODS: One hundred sixty-eight outbred male Sprague-Dawley rats, age 11-13 weeks, weight 325-375 g randomized into seven groups of 24 subdivided into groups of eight, were used to provide radiographic and light microscopy observations of bone formation/maturation and aberrant healing events at 2, 4 and 8 weeks following application of rhBMP-2/ACS into critical-size, o8-mm, through-through, calvarial osteotomy defects for a dose of 1.25, 2.5, 5.0, 10.0 and 20.0 MUg rhBMP-2/defect, or serve as ACS or sham-surgery controls. RESULTS: rhBMP-2 dosages >= 2.5 MUg/defect showed histological defect closure >90% within 2 weeks, and complete resolution within 4 weeks. Adverse healing events including swelling, excessive bone formation or seroma formation could not be determined with certainty in this defect model. Notably ACS control sites showed complete defect closure at the 8 week healing interval. CONCLUSIONS: rhBMP-2/ACS accelerates local bone formation in the rat critical-size through-through calvarial defect model once reaching an osteoinductive dose threshold. This threshold may already be reached at a 1.25 /2.5-MUg dose in this model. No further enhancement to bone formation/maturation may be observed adding rhBMP-2 above the 2.5-MUg dose. The 1.25-20.0 MUg dose range did not invoke appreciable aberrant healing events. PMID- 24807102 TI - Effect of boron neutron capture therapy for recurrent anaplastic meningioma: an autopsy case report. AB - A 70-year-old woman died of systemic metastasis from anaplastic meningioma and underwent autopsy. The patient underwent twice total removal of the right sphenoid ridge meningioma 2 years ago. The tumor recurred 3 times, and then stereotactic radiotherapy was employed. Boron neutron capture therapy (BNCT) was performed for the fourth local recurrence and an additional new lesion. Proliferative activity of the newly developed meningioma, which had been treated with BNCT only, was significantly lower than that of untreated metastatic liver tumor, as well as that of the meningioma specimen obtained at the second surgery. Our pathological findings demonstrated, for the first time, the therapeutic effect of BNCT on anaplastic meningioma at an early stage (2.5 months). PMID- 24807101 TI - Rapid immunohistochemistry based on alternating current electric field for intraoperative diagnosis of brain tumors. AB - Rapid immunohistochemistry (R-IHC) can contribute to the intraoperative diagnosis of central nervous system (CNS) tumors. We have recently developed a new IHC method based on an alternating current electric field to facilitate the antigen antibody reaction. To ensure the requirement of R-IHC for intraoperative diagnosis, 183 cases of CNS tumors were reviewed regarding the accuracy rate of diagnosis without R-IHC. The diagnostic accuracy was 90.7 % (166/183 cases) [corrected] in which definitive diagnoses were not provided in 17 cases because of the failure of glioma grading and differential diagnosis of lymphoma and glioma. To establish the clinicopathological application, R-IHC for frozen specimens was compared with standard IHC for permanent specimens. 33 gliomas were analyzed, and the Ki-67/MIB-1 indices of frozen specimens by R-IHC were consistent with the grade and statistically correlated with those of permanent specimens. Thus, R-IHC provided supportive information to determine the grade of glioma. For discrimination between glioma and lymphoma, R-IHC was able to provide clear results of CD20 and Ki-67/MIB-1 in four frozen specimens of CNS lymphoma as well as standard IHC. We conclude that the R-IHC for frozen specimens can provide important information for intraoperative diagnosis of CNS tumors. PMID- 24807103 TI - Anaplastic meningioma with rapid growth after omental flap transposition: a case report and experimental study. AB - Meningiomas occasionally display aggressive behavior, but the mechanisms of malignant transformation remain unclear. We encountered the case of a 65-year-old man with a 10-year history of recurrent meningioma. The patient had undergone multiple tumor resections, radiotherapy treatments, and reconstructive surgeries due to wound infection. After the third resection of the tumor and reconstruction with an omental flap, the tumor demonstrated rapid growth and lung metastasis. The final pathological diagnosis was anaplastic meningioma. Because the drastic change of the tumor was observed after omental flap transposition, we investigated the effect of the omentum on tumor cells and performed histopathological analyses of meningiomas using a mouse model. We found that meningioma cells have a high affinity to the omentum and show a growth advantage when co-cultured with adipocytes. Immunohistochemical staining revealed that meningioma cells adjacent to the omentum strongly expressed fatty acid-binding protein 4, a lipid transfer protein, in both mouse and human. Our results suggest that tumor cells can receive lipid supply from omental adipocytes, and the surrounding tissues may induce tumor progression. We conclude that although omental tissue is an ideal material for reconstruction surgery, close follow-up is recommended in meningioma patients when used for cranioplasty. PMID- 24807104 TI - Histiocytic sarcoma of the cavernous sinus: case report and literature review. AB - Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. We describe the 2nd case of primary histiocytic sarcoma of the cavernous sinus/Meckel's cave, and the 8th case involving the CNS. A 61-year-old Caucasian man presented with numbness on the entire left side of his face, shooting pain in the left frontal region, and headaches. Imaging revealed an enhancing extra axial soft tissue mass located in the left cavernous sinus and left Meckel's cave. Diagnosis was established through open biopsy, after failed attempts via CT-guided trans-foramen ovale fine-needle aspiration biopsy and keyhole biopsy. The tumor was composed of large non-cohesive epithelioid cells invading nerves and ganglion cells. Tumor cells were immunopositive for CD68, CD163, and immunonegative for the anaplastic large cell lymphoma marker ALK-1 as well as other lymphoid, myeloid, and dendritic cell markers. Histiocytic sarcoma has strong potential for systemic spread; early diagnosis and treatment are important. Our patient was initially treated with radiation therapy but subsequently developed metastases. PMID- 24807105 TI - Health-related quality of life and persistent symptoms in relation to (R-)CHOP14, (R-)CHOP21, and other therapies among patients with diffuse large B-cell lymphoma: results of the population-based PHAROS-registry. AB - The increasing number of longer-living patients with diffuse large B-cell lymphoma (DLBCL) and serious side effects of treatment urged us to study the health-related quality of life (HRQoL) and persistent (treatment-related) symptoms in unselected patients after different treatment modalities and compare HRQoL of patients with a normative population. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with DLBCL from 2004 to 2010. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was completed twice, with a 1-year interval. Detailed data on treatment were extracted from the Population-based HAematological Registry for Observational Studies. Two hundred fifty-six patients responded (84 %, T1). Compared to patients treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days ((R )CHOP21), those who underwent (R-)CHOP14 more often reported tingling in the hands and feet (27 vs 42 %, p = 0.02) and fatigue (35 vs 46 %, p = 0.03) and reported a lower global health status/HRQoL. Mean HRQoL was statistically and clinically relevantly lower among DLBCL patients compared to a normative population (p < 0.01). Persistent tingling in hands/feet was reported more often by older patients and patients treated with (R-)CHOP14 independently of the other characteristics. Furthermore, patients who reported symptoms exhibited significantly lower HRQoL compared to patients without symptoms/worries. Patients treated with (R-)CHOP14 reported more neuropathic symptoms, more fatigue, and a lower HRQoL than patients treated with (R-)CHOP21. Alertness for persistent symptoms that occur during and after treatment of DLBCL patients is needed and may help to avoid lasting negative influence on their HRQoL. PMID- 24807106 TI - The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines. AB - Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5 aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability. PMID- 24807107 TI - Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. AB - NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged <=60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I-IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age <=50 or >=1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African-American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (<=50 years), 11.4 % (51-60 years), and 4.9 % (>=61 years). Using SFH or age <=50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC. PMID- 24807108 TI - Hydrolysis reaction mechanism in atrazine metabolism and prediction of its metabolites' toxicities. AB - Atrazine (ATR) is a widely used herbicide. There are several types of reactions in its metabolism. Herein, the mechanism of three paths of hydrolysis reactions in its metabolism and predictions of toxicities of its metabolites in the three paths will be presented. The calculation results by B3LYP (Becke, 3-parameter, Lee-Yang-Parr), one of the approaches in density functional theory, indicated that (1) there were three models in the three hydrolysis paths of ATR. The dissociation mechanisms of C(9/11)-N(8/10), C(4/6)-N(8/10), and C-Cl were dealkylation, deamination, and Cl substitution, respectively. (2) The energy barrier of C-Cl dissociation was lower. The dissociation was advantageous in dynamics and the primary reaction in the three hydrolysis paths. In these hydrolysis reactions, the different intermediates had different concentrations because of the impact of the reaction rate. (3) In addition, it was necessary to consider the solvent effect to investigate hydrolysis reaction. The conductor like polarizable continuum model (CPCM) was used to simulate the hydrolysis reaction in bond length and energy barrier because of the solvent effect. Experimental or predictive results showed that atrazine and its metabolites in the three hydrolysis paths were carcinogenic. PMID- 24807109 TI - Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis. AB - PROBLEM: Uterine natural killer cells (uNK) have been thought to play a key role in endometriosis and infertility. We investigated the expression of CD56, CD16, and NKp46 in endometrial tissues from 61 women with unexplained recurrent pregnancy loss (uRPL) or infertility (UI) and correlated this with the presence or absence of endometriosis. The results from the patients with subfertility were compared with those from 10 fertile patients. METHOD OF STUDY: Mid-secretory phase endometrial biopsies were obtained, and the endometrial expression of CD56, CD16, or NKp46 was identified by immunohistochemistry and quantified (ImageJ Software). RESULTS: The percentage of CD16(+) cells was higher in women with uRPL (7.9 +/- 3.2) and UI (9.0 +/- 5.5), even when these conditions were associated with endometriosis (8.9 +/- 5.3), compared with fertile patients (5.6 +/- 2.4, P < 0.05). Likewise, the ratio of NKp46(+) :CD56(+) cells was higher in women with uRPL (0.28 +/- 0.25) and UI (0.21 +/- 0.2), even when these conditions were associated with endometriosis (0.19 +/- 0.14), compared with fertile patients (0.1 +/- 0.1, P < 0.05). No differences were observed when comparing CD56. CONCLUSIONS: Women, with or without endometriosis, who have larger populations of cytotoxic CD16(+) uNK cells and/or higher populations of NKp46(+) CD56(+) cells may be at greater risk of infertility disorders resulting from an inflammatory environment occurring during implantation or later during decidualization. PMID- 24807110 TI - Genetic and genomic tools for the marine annelid Platynereis dumerilii. AB - The bristle worm Platynereis dumerilii displays many interesting biological characteristics. These include its reproductive timing, which is synchronized to the moon phase, its regenerative capacity that is hormonally controlled, and a slow rate of evolution, which permits analyses of ancestral genes and cell types. As a marine annelid, Platynereis is also representative of the marine ecosystem, as well as one of the three large animal subphyla, the Lophotrochozoa. Here, we provide an overview of the molecular resources, functional techniques, and behavioral assays that have recently been established for the bristle worm. This combination of tools now places Platynereis in an excellent position to advance research at the frontiers of neurobiology, chronobiology, evo-devo, and marine biology. PMID- 24807115 TI - A new spin on vection in depth. AB - Previous research has shown that adding lateral viewpoint changes to visual displays simulating self-motion in depth can increase the strength of linear vection. We performed experiments to determine whether these vection increases are caused by reduced adaptation to retinal motion, rather than increased motion parallax in the visual display. In Experiment 1, we added increasing amplitudes of sinusoidal angular viewpoint oscillation around the viewing axis (up to 94.2 degrees /s) to radial flow simulating self-motion in depth. We found that angular viewpoint oscillation systematically reduced the onset latencies and increased the overall strength of vection in depth, compared with pure radial flow. In Experiment 2, we compared vection strength between radial flow displays with either added angular oscillation or continuous spiral rotation of equivalent peak velocity around the viewing axis (62.8 degrees /s), and found that angular viewpoint oscillation generated the strongest vection. In Experiment 3, we found that pure radial flow with or without continuous spiral rotation produced radial motion aftereffects that lasted longer than that produced by radial flow with angular viewpoint oscillation. These findings support the view that the way viewpoint oscillation increases vection does not critically depend on motion parallax, but rather, on a changing pattern of retinal motion that serves to reduce visual adaptation and sustain sensitivity to optic flow. PMID- 24807111 TI - Budding yeast for budding geneticists: a primer on the Saccharomyces cerevisiae model system. AB - The budding yeast Saccharomyces cerevisiae is a powerful model organism for studying fundamental aspects of eukaryotic cell biology. This Primer article presents a brief historical perspective on the emergence of this organism as a premier experimental system over the course of the past century. An overview of the central features of the S. cerevisiae genome, including the nature of its genetic elements and general organization, is also provided. Some of the most common experimental tools and resources available to yeast geneticists are presented in a way designed to engage and challenge undergraduate and graduate students eager to learn more about the experimental amenability of budding yeast. Finally, a discussion of several major discoveries derived from yeast studies highlights the far-reaching impact that the yeast system has had and will continue to have on our understanding of a variety of cellular processes relevant to all eukaryotes, including humans. PMID- 24807116 TI - Hypoxia: a consequence of obesity and also a tool to treat excessive weight loss. PMID- 24807117 TI - Changes of visual field and optic nerve fiber layer in patients with OSAS. AB - BACKGROUND: The prevalence of primary open-angle glaucoma (POAG) increases in obstructive sleep apnea syndrome (OSAS). OSAS could increase cerebrospinal fluid pressure (CSFP) and binocular papilledema. METHODS: In this cross-sectional study, intraocular pressure (IOP), CSFP, mean deviation (MD), pattern standard deviation (PSD), optic disc indices, and retinal nerve fiber layer (RNFL) were compared among four groups with different extents of OSAS. Regression analysis was performed to correlate MD, PSD, and RNFL to polysomnography (PSG) index. For subgroups with severe OSAS, IOP and CSFP were compared. The prevalence of POAG was calculated. RESULTS: The severe OSAS had a significantly higher CSFP than the other three groups (p = 0.002, 0.036, and 0.017). Both moderate and severe groups showed significantly higher IOP than control group (p = 0.022 and 0.001). MD was correlated with average oxygen saturation (MSaO2) (p = 0.001). PSD was correlated with oxygen desaturation index (ODI) (p = 0.004). Significant differences were found in nasal RNFL and inferior RNFL among the four groups (p = 0.013, p = 0.004). Nasal RNFL correlated with the ODI (p = 0.048). For severe group, compared to normal RNFL group, CSFP was significantly lower in the thinned RNFL group (p = 0.039) and higher in the thickened RNFL group (p = 0.034). Totally, the prevalence of POAG was 5.49 %. CONCLUSIONS: OSAS had a high prevalence of POAG. Visual field was damaged and the RNFL was thinned. Due to diverse CSFP, RNFL changed differently in the patients with severe OSAS. PMID- 24807118 TI - Factors affecting blood pressure profile in pre and postmenopausal women with obstructive sleep apnea hypopnea syndrome. AB - PURPOSE: Obstructive sleep apnea hypopnea syndrome (OSAHS) is an independent risk factor for development of hypertension. Epidemiological surveys have found that risk of cardiovascular diseases increased in postmenopausal women. However, it is not well known about the profiles of hypertension of women with OSAHS in their different reproductive stages. This study aimed to investigate the difference of blood pressure profile between pre and postmenopausal women with OSAHS. METHODS: Women who were tested by polysomnography (PSG) (n = 207) in Ruijin Hospital were recruited in the study. The subjects were divided into two groups of premenopausal women (24 with and 30 without OSAHS), and two groups of postmenopausal women (116 with and 37 without OSAHS). Among the groups, the differences of demographic and PSG variables were compared. The factors influencing blood pressure were further studied. RESULTS: The prevalence of hypertension (56.9 %) in postmenopausal OSAHS patients was higher than the other three groups. Among OSAHS patients, both average systolic blood pressure (SBP) and diastolic blood pressure (DBP) of postmenopausal women were higher than those of premenopausal ones [(129.9 +/- 16.16 mmHg vs. 123.7 +/- 18.89), (84.96 +/- 9.88 mmHg vs. 78.81 +/- 10.34), P = 0.05, P < 0.01, respectively], with the elevation of DBP being more pronounced. For premenopausal women, body mass index (BMI) was the only factor affecting blood pressure (p < 0.05); in postmenopausal women, BMI was a factor affecting SBP, while BMI and apnea hypopnea index (AHI) affecting DBP (P < 0.05). CONCLUSION: Blood pressure profile of postmenopausal women with OSAHS was affected by both BMI and AHI. But those of premenopausal ones were predominantly related to BMI. PMID- 24807119 TI - Real-time prediction of disordered breathing events in people with obstructive sleep apnea. AB - PURPOSE: Conventional therapies for obstructive sleep apnea (OSA) are effective but suffer from poor patient adherence and may not fully alleviate major OSA associated cardiovascular risk factors or improve certain aspects of quality of life. Predicting the onset of disordered breathing events in OSA patients may lead to improved strategies for treating OSA and inform our understanding of underlying disease mechanisms. In this work, we describe a deployable system capable of performing real-time predictions of sleep disordered breathing events in patients diagnosed with OSA, providing a novel approach for gaining insight into OSA pathophysiology, discovering population subgroups, and improving therapies. METHODS: LArge Memory STorage and Retrieval artificial neural networks with 864 different configurations were applied to polysomnogram records from 64 patients. Wavelet transforms, measures of entropy, and other statistics were applied to six physiological signals to provide network inputs. Approximate statistical tests were used to determine the best performing network for each patient. The most important predictors of disordered breathing events in OSA patients were determined by analyzing internal network parameters. RESULTS: The average optimized individual prediction sensitivity and specificity were 0.81 and 0.77, respectively. Predictions were better than random guessing for all OSA patients. Analysis of internal network parameters revealed a high degree of heterogeneity among disordered breathing event predictors and may reveal patient subgroups. CONCLUSIONS: We report the first practical system to predict individual disordered breathing events in a heterogeneous group of patients diagnosed with OSA. The pattern of disordered breathing predictors suggests variable underlying pathophysiological mechanisms and highlights the need for an individualized approach to OSA diagnosis, therapy, and management. PMID- 24807120 TI - Favre-Racouchot syndrome concurrent with chronic granulomatous reaction. AB - Favre-Racouchot syndrome (FRS) is a disorder consisting of solar elastosis with the presence of multiple cysts and open comedones. Although the exact mechanism of the condition is not known, FRS has been specifically connected to sun exposure, smoking and radiation exposure. The histological changes present in FRS reveal an atrophic epidermis and large masses of keratinous material, causing follicular plugging, as well as solar elastotic changes and possible basophilic degeneration of connective tissue. Herein, we report an unusual case of FRS concurrent with chronic granulomatous reaction and review relevant published works. PMID- 24807121 TI - Direct measurements of the total rate constant of the reaction NCN + H and implications for the product branching ratio and the enthalpy of formation of NCN. AB - The overall rate constant of the reaction (2), NCN + H, which plays a key role in prompt-NO formation in flames, has been directly measured at temperatures 962 K < T < 2425 K behind shock waves. NCN radicals and H atoms were generated by the thermal decomposition of NCN3 and C2H5I, respectively. NCN concentration-time profiles were measured by sensitive narrow-line-width laser absorption at a wavelength of lambda = 329.1302 nm. The obtained rate constants are best represented by the combination of two Arrhenius expressions, k2/(cm(3) mol(-1) s( 1)) = 3.49 * 10(14) exp(-33.3 kJ mol(-1)/RT) + 1.07 * 10(13) exp(+10.0 kJ mol( 1)/RT), with a small uncertainty of +/-20% at T = 1600 K and +/-30% at the upper and lower experimental temperature limits.The two Arrhenius terms basically can be attributed to the contributions of reaction channel (2a) yielding CH + N2 and channel (2b) yielding HCN + N as the products. A more refined analysis taking into account experimental and theoretical literature data provided a consistent rate constant set for k2a, its reverse reaction k1a (CH + N2 -> NCN + H), k2b as well as a value for the controversial enthalpy of formation of NCN, DeltafH = 450 kJ mol(-1). The analysis verifies the expected strong temperature dependence of the branching fraction phi = k2b/k2 with reaction channel (2b) dominating at the experimental high-temperature limit. In contrast, reaction (2a) dominates at the low-temperature limit with a possible minor contribution of the HNCN forming recombination channel (2d) at T < 1150 K. PMID- 24807123 TI - Oxytocin and vasopressin modulate the social response to threat: a preclinical study. AB - Individuals in many species increase their proximity to others in threatening situations (defensive aggregation), increasing their chance of survival and reducing the adverse psychological impact of stressors. However, the basic neurobiology of defensive aggregation is not well understood. Here we examined the role of the social neuropeptides oxytocin (OT) and vasopressin (AVP) in this response. Groups of rats were exposed to a ball of cat fur (an innate threat stimulus) in a large arena, causing prolonged periods of tight social grouping (huddling). The modulatory effects of OT and AVP on huddling were examined both alone and in conjunction with relevant antagonists. To determine specificity of treatment effects to social grouping, the effects of the same treatments were also assessed in individual rats exposed to cat fur and given the opportunity to hide. OT (0.5 mg/kg, i.p.) and AVP (0.01 mg/kg, i.p.) increased huddling in rats socially exposed to cat fur, whereas the selective V1A AVP receptor antagonist SR49059 (3 mg/kg, i.p.) decreased huddling. The effects of OT were prevented by pre-treatment with SR49059 (3 mg/kg), while those of AVP were prevented by the V1B receptor antagonist SSR149415 (30 mg/kg, i.p.). OT had no effect on huddling when groups of four rats were tested with no cat fur present whereas AVP increased huddling under these conditions. Neither OT, nor SR49059, affected hiding in individual rats exposed to cat fur. However, AVP increased hiding, an effect prevented by SSR149415 (30 mg/kg, i.p.). These results suggest that OT acts on V1A receptors to promote a social response to threat without altering the more general defensive response. Conversely, AVP appears to increase generalised anxiety via V1B receptors, which subsequently results in huddling. A hitherto unrecognised function of oxytocin is therefore to promote social affiliation during threatening situations. PMID- 24807122 TI - The myelin membrane-associated enzyme 2',3'-cyclic nucleotide 3' phosphodiesterase: on a highway to structure and function. AB - The membrane-anchored myelin enzyme 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) was discovered in the early 1960s and has since then troubled scientists with its peculiar catalytic activity and high expression levels in the central nervous system. Despite decades of research, the actual physiological relevance of CNPase has only recently begun to unravel. In addition to a role in myelination, CNPase is also involved in local adenosine production in traumatic brain injury and possibly has a regulatory function in mitochondrial membrane permeabilization. Although research focusing on the CNPase phosphodiesterase activity has been helpful, several open questions concerning the protein function in vivo remain unanswered. This review is focused on past research on CNPase, especially in the fields of structural biology and enzymology, and outlines the current understanding regarding the biochemical and physiological significance of CNPase, providing ideas and directions for future research. PMID- 24807125 TI - The Predictors of the Job Stress among Female Married Hospital Nurses. AB - The purposes of this study were to explore the relationships among family stress, social support and job stress in female married hospital nurses. Married female nurses had to face both paid hospital work and unpaid domestic work, and double workloads might lead to more stress of female married nurses. Most studies were limited to explore the correlations of job stresses caused from jobs only, and ignored the affecting factors from family stresses. 233 hospital nurses were recruited in this study. The results showed that the family stresses (p<0.01) and working units (p=0.01) were important predictors of the Effort-Reward imbalance (high job stress). Nurses' ladder levels (p=0.004) and family stress (p=0.002) were the main factors related to married female nurses' presence of high overcommitment. Family stress, working units and nurse's ladder levels have a significant difference on job stresses among hospital married female nurses. Nurse managers may provide educational programs related to family stress reliefs to married female nurses and their husbands to alleviate their family stresses. Future studies might incorporate personalities and coping strategies to further investigate the relationships between social supports and job stresses. PMID- 24807124 TI - Occupational risk factors for upper-limb and neck musculoskeletal disorder among health-care staff in nursing homes for the elderly in France. AB - This study investigated the relation between working conditions, in terms of physical and psychological demand, and upper-limb and neck musculoskeletal disorders (ULNMD) in female staff working in direct contact with the elderly in nursing homes. A cross-sectional survey was conducted in 105 nursing homes in France. Data on nursing-home working conditions were collected by questionnaire from occupational physicians and by self-administered questionnaire from staff. Psychosocial demand at work was assessed on Siegrist's questionnaire and ULNMD on the Nordic questionnaire. 2,328 employees were included: 628 housekeepers, 1,372 nursing assistants and 328 nurses. During the previous 12 months, 50% of the subjects (1,160) had presented with a musculoskeletal complaint concerning the neck, 38% (881) the shoulders, 10% (246) the elbows and 22% (520) the wrists. 9% (219) reported effort/reward imbalance on the 2004 Siegrist questionnaire and 42% were in a situation of over-commitment. ULNMD complaints were associated not only with physical occupational factors but also with psychosocial factors (effort/reward imbalance and over-commitment), both before and after adjustment on individual and occupational factors. Prospective studies are needed to clarify the causal role of occupational, including, organizational, psychosocial factors in ULNMD outcomes. Preventive approaches should take account of both physical and psychosocial occupational factors. PMID- 24807127 TI - The structural transitions of C60 nanowhiskers under an electric field characterized by in situ transmission electron microscopy and electron energy loss spectroscopy. AB - In situ electrical transport measurements for individual C60 nanowhiskers are performed using a transmission electron microscope which monitors the crystal and electronic structural changes of the C60 nanowhiskers simultaneously. Electron diffraction combined with electron energy-loss spectroscopy shows that under the external electric current, the C60 nanowhiskers first transform from a face centered-cubic structure to a disordered arrangement of C60 molecules. The cage structure of the C60 molecules then collapses to an amorphous carbon and finally, the amorphous carbon turns into graphene stacks. This process indicates the hybridization transformation from sp(2.278) to sp(2), which is different from the transition process of C60 materials under high pressure. The obtained results also suggest that the stability of the C60 nanowhiskers should be of crucial concern when they work as electrical devices. PMID- 24807126 TI - Discrepancy in term calculation from second trimester ultrasound scan versus last menstrual period in women with type 1 diabetes. AB - OBJECTIVE: To study differences in ultrasound-based compared to menstrual-based term estimation in women with type 1 diabetes. DESIGN: Nationwide register study. SETTING: Norway. POPULATION: Deliveries in Norway 1999-2004 by women registered in the Norwegian Childhood Diabetes Registry (n = 342) and the background population (n = 307 248), with data on both ultrasound-based and menstrual-based gestational age notified in the Birth Registry of Norway. Births with major malformations were excluded. METHODS: Linkage of two nationwide registries, the Medical Birth Registry of Norway and the Norwegian Childhood Diabetes Registry. MAIN OUTCOME MEASURES: Estimated gestational age at delivery based on routine second trimester ultrasound measurements and last menstrual period. RESULTS: In women with type 1 diabetes, the distribution of gestational age at delivery was shifted considerably towards a lower gestational age when using second trimester ultrasound data for estimation, compared with last menstrual period data. The difference between the two estimation methods was larger among women with type 1 diabetes, although also evident in the general population. One in four women with diabetes and a certain last menstrual period date had their ultrasound-calculated term postponed 1 week or more, while one in 10 had it postponed 2 weeks or more. Corresponding numbers in the background population were one in five and one in 20. CONCLUSIONS: We found a systematic postponement of ultrasound-based compared with menstrual-based term estimation in women with type 1 diabetes. Relying solely on routine ultrasound-based term calculation for delivery decision may imply a risk of going beyond an optimal pregnancy length. PMID- 24807128 TI - Governance, transparency and alignment in the Council of Australian Governments (COAG) 2011 National Health Reform Agreement. AB - OBJECTIVE This article provides a policy analysis of the Australian government's National Health Reform Agreement (NHRA) by bringing to the foreground the governance arrangements underpinning the two arms of the national reforms, to primary health care and hospital services. METHODS The article analyses the NHRA document and mandate, and contextualises the changes introduced vis-a-vis the complex characteristics of the Australian health care system. Specifically, it discusses the coherence of the agreement and its underlying objectives, and the consistency and logic of the governance arrangements introduced. RESULTS The policy analysis highlights the rationalisation of the responsibilities between the Commonwealth and states and territories, the commitment towards a funding arrangement based on uniform measures of performance and the troubled emergence of a more decentralised nation-wide homogenisation of governance arrangements, plus efforts to improve transparency, accountability and statutory support to increase the standards of quality of care and safety. CONCLUSIONS It is suggested that the NHRA falls short of adequately supporting integration between primary, secondary and tertiary health care provision and facilitating greater integration in chronic disease management in primary care. Successfully addressing this will unlock further value from the reforms. PMID- 24807129 TI - L1/2 regularization: a thresholding representation theory and a fast solver. AB - The special importance of L1/2 regularization has been recognized in recent studies on sparse modeling (particularly on compressed sensing). The L1/2 regularization, however, leads to a nonconvex, nonsmooth, and non-Lipschitz optimization problem that is difficult to solve fast and efficiently. In this paper, through developing a threshoding representation theory for L1/2 regularization, we propose an iterative half thresholding algorithm for fast solution of L1/2 regularization, corresponding to the well-known iterative soft thresholding algorithm for L1 regularization, and the iterative hard thresholding algorithm for L0 regularization. We prove the existence of the resolvent of gradient of ||x||1/2(1/2), calculate its analytic expression, and establish an alternative feature theorem on solutions of L1/2 regularization, based on which a thresholding representation of solutions of L1/2 regularization is derived and an optimal regularization parameter setting rule is formulated. The developed theory provides a successful practice of extension of the well- known Moreau's proximity forward-backward splitting theory to the L1/2 regularization case. We verify the convergence of the iterative half thresholding algorithm and provide a series of experiments to assess performance of the algorithm. The experiments show that the half algorithm is effective, efficient, and can be accepted as a fast solver for L1/2 regularization. With the new algorithm, we conduct a phase diagram study to further demonstrate the superiority of L1/2 regularization over L1 regularization. PMID- 24807130 TI - Toward automatic time-series forecasting using neural networks. AB - Over the past few decades, application of artificial neural networks (ANN) to time-series forecasting (TSF) has been growing rapidly due to several unique features of ANN models. However, to date, a consistent ANN performance over different studies has not been achieved. Many factors contribute to the inconsistency in the performance of neural network models. One such factor is that ANN modeling involves determining a large number of design parameters, and the current design practice is essentially heuristic and ad hoc, this does not exploit the full potential of neural networks. Systematic ANN modeling processes and strategies for TSF are, therefore, greatly needed. Motivated by this need, this paper attempts to develop an automatic ANN modeling scheme. It is based on the generalized regression neural network (GRNN), a special type of neural network. By taking advantage of several GRNN properties (i.e., a single design parameter and fast learning) and by incorporating several design strategies (e.g., fusing multiple GRNNs), we have been able to make the proposed modeling scheme to be effective for modeling large-scale business time series. The initial model was entered into the NN3 time-series competition. It was awarded the best prediction on the reduced dataset among approximately 60 different models submitted by scholars worldwide. PMID- 24807131 TI - Novel cascade FPGA accelerator for support vector machines classification. AB - Support vector machines (SVMs) are a powerful machine learning tool, providing state-of-the-art accuracy to many classification problems. However, SVM classification is a computationally complex task, suffering from linear dependencies on the number of the support vectors and the problem's dimensionality. This paper presents a fully scalable field programmable gate array (FPGA) architecture for the acceleration of SVM classification, which exploits the device heterogeneity and the dynamic range diversities among the dataset attributes. An adaptive and fully-customized processing unit is proposed, which utilizes the available heterogeneous resources of a modern FPGA device in efficient way with respect to the problem's characteristics. The implementation results demonstrate the efficiency of the heterogeneous architecture, presenting a speed-up factor of 2-3 orders of magnitude, compared to the CPU implementation. The proposed architecture outperforms other proposed FPGA and graphic processor unit approaches by more than seven times. Furthermore, based on the special properties of the heterogeneous architecture, this paper introduces the first FPGA-oriented cascade SVM classifier scheme, which exploits the FPGA reconfigurability and intensifies the custom-arithmetic properties of the heterogeneous architecture. The results show that the proposed cascade scheme is able to increase the heterogeneous classifier throughput even further, without introducing any penalty on the resource utilization. PMID- 24807132 TI - Robust GRBF static neurocontroller with switch logic for control of robot manipulators. AB - A new Gaussian radial basis function static neurocontroller is presented for stable adaptive tracking control. This is a two-stage controller acting in a supervisory fashion by means of a switch logic and allowing arbitration between a neural network (NN) and a robust proportional-derivative controller. The structure is intended to reduce the effects of the curse of dimensionality in multidimensional systems by fully exploiting the mechanical properties of the robot manipulator. A new factorization of the Coriolis/centripetal matrix is used, leading to an NN model that is much smaller than the dynamic ones. By resorting to the extended multivariate Shannon theorem and the computation of the effective bandwidth of the revolute robot manipulators, the network parameters are tuned. Stability and convergence properties are analyzed. This provides the assurance of reliability and effectiveness to make such controller viable. A robot manipulator with two degrees of freedom is employed to study the adaptive features of the neural control algorithm. Finally, the effectiveness of the proposed method is compared to the nonadaptive case. PMID- 24807133 TI - VLSI implementation of a bio-inspired olfactory spiking neural network. AB - This paper presents a low-power, neuromorphic spiking neural network (SNN) chip that can be integrated in an electronic nose system to classify odor. The proposed SNN takes advantage of sub-threshold oscillation and onset-latency representation to reduce power consumption and chip area, providing a more distinct output for each odor input. The synaptic weights between the mitral and cortical cells are modified according to an spike-timing-dependent plasticity learning rule. During the experiment, the odor data are sampled by a commercial electronic nose (Cyranose 320) and are normalized before training and testing to ensure that the classification result is only caused by learning. Measurement results show that the circuit only consumed an average power of approximately 3.6 MUW with a 1-V power supply to discriminate odor data. The SNN has either a high or low output response for a given input odor, making it easy to determine whether the circuit has made the correct decision. The measurement result of the SNN chip and some well-known algorithms (support vector machine and the K-nearest neighbor program) is compared to demonstrate the classification performance of the proposed SNN chip.The mean testing accuracy is 87.59% for the data used in this paper. PMID- 24807134 TI - Transductive ordinal regression. AB - Ordinal regression is commonly formulated as a multiclass problem with ordinal constraints. The challenge of designing accurate classifiers for ordinal regression generally increases with the number of classes involved, due to the large number of labeled patterns that are needed. The availability of ordinal class labels, however, is often costly to calibrate or difficult to obtain. Unlabeled patterns, on the other hand, often exist in much greater abundance and are freely available. To take benefits from the abundance of unlabeled patterns, we present a novel transductive learning paradigm for ordinal regression in this paper, namely transductive ordinal regression (TOR). The key challenge of this paper lies in the precise estimation of both the ordinal class label of the unlabeled data and the decision functions of the ordinal classes, simultaneously. The core elements of the proposed TOR include an objective function that caters to several commonly used loss functions casted in transductive settings, for general ordinal regression. A label swapping scheme that facilitates a strictly monotonic decrease in the objective function value is also introduced. Extensive numerical studies on commonly used benchmark datasets including the real-world sentiment prediction problem are then presented to showcase the characteristics and efficacies of the proposed TOR. Further, comparisons to recent state-of-the art ordinal regression methods demonstrate the introduced transductive learning paradigm for ordinal regression led to the robust and improved performance. PMID- 24807135 TI - Online nonnegative matrix factorization with robust stochastic approximation. AB - Nonnegative matrix factorization (NMF) has become a popular dimension-reduction method and has been widely applied to image processing and pattern recognition problems. However, conventional NMF learning methods require the entire dataset to reside in the memory and thus cannot be applied to large-scale or streaming datasets. In this paper, we propose an efficient online RSA-NMF algorithm (OR NMF) that learns NMF in an incremental fashion and thus solves this problem. In particular, OR-NMF receives one sample or a chunk of samples per step and updates the bases via robust stochastic approximation. Benefitting from the smartly chosen learning rate and averaging technique, OR-NMF converges at the rate of in each update of the bases. Furthermore, we prove that OR-NMF almost surely converges to a local optimal solution by using the quasi-martingale. By using a buffering strategy, we keep both the time and space complexities of one step of the OR-NMF constant and make OR-NMF suitable for large-scale or streaming datasets. Preliminary experimental results on real-world datasets show that OR NMF outperforms the existing online NMF (ONMF) algorithms in terms of efficiency. Experimental results of face recognition and image annotation on public datasets confirm the effectiveness of OR-NMF compared with the existing ONMF algorithms. PMID- 24807136 TI - SSC: a classifier combination method based on signal strength. AB - We propose a new classifier combination method, the signal strength-based combining (SSC) approach, to combine the outputs of multiple classifiers to support the decision-making process in classification tasks. As ensemble learning methods have attracted growing attention from both academia and industry recently, it is critical to understand the fundamental issues of the combining rule. Motivated by the signal strength concept, our proposed SSC algorithm can effectively integrate the individual vote from different classifiers in an ensemble learning system. Comparative studies of our method with nine major existing combining rules, namely, geometric average rule, arithmetic average rule, median value rule, majority voting rule, Borda count, max and min rule, weighted average, and weighted majority voting rules, is presented. Furthermore, we also discuss the relationship of the proposed method with respect to margin based classifiers, including the boosting method (AdaBoost.M1 and AdaBoost.M2) and support vector machines by margin analysis. Detailed analyses of margin distribution graphs are presented to discuss the characteristics of the proposed method. Simulation results for various real-world datasets illustrate the effectiveness of the proposed method. PMID- 24807137 TI - Online optimal control of affine nonlinear discrete-time systems with unknown internal dynamics by using time-based policy update. AB - In this paper, the Hamilton-Jacobi-Bellman equation is solved forward-in-time for the optimal control of a class of general affine nonlinear discrete-time systems without using value and policy iterations. The proposed approach, referred to as adaptive dynamic programming, uses two neural networks (NNs), to solve the infinite horizon optimal regulation control of affine nonlinear discrete-time systems in the presence of unknown internal dynamics and a known control coefficient matrix. One NN approximates the cost function and is referred to as the critic NN, while the second NN generates the control input and is referred to as the action NN. The cost function and policy are updated once at the sampling instant and thus the proposed approach can be referred to as time-based ADP. Novel update laws for tuning the unknown weights of the NNs online are derived. Lyapunov techniques are used to show that all signals are uniformly ultimately bounded and that the approximated control signal approaches the optimal control input with small bounded error over time. In the absence of disturbances, an optimal control is demonstrated. Simulation results are included to show the effectiveness of the approach. The end result is the systematic design of an optimal controller with guaranteed convergence that is suitable for hardware implementation. PMID- 24807138 TI - Reproducing kernel hilbert space approach for the online update of radial bases in neuro-adaptive control. AB - Classical work in model reference adaptive control for uncertain nonlinear dynamical systems with a radial basis function (RBF) neural network adaptive element does not guarantee that the network weights stay bounded in a compact neighborhood of the ideal weights when the system signals are not persistently exciting (PE). Recent work has shown, however, that an adaptive controller using specifically recorded data concurrently with instantaneous data guarantees boundedness without PE signals. However, the work assumes fixed RBF network centers, which requires domain knowledge of the uncertainty. Motivated by reproducing kernel Hilbert space theory, we propose an online algorithm for updating the RBF centers to remove the assumption. In addition to proving boundedness of the resulting neuro-adaptive controller, a connection is made between PE signals and kernel methods. Simulation results show improved performance. PMID- 24807139 TI - Simple proof of convergence of the SMO algorithm for different SVM variants. AB - In this brief, we give a new proof of the asymptotic convergence of the sequential minimum optimization (SMO) algorithm for both the most violating pair and second order rules to select the pair of coefficients to be updated. The proof is more self-contained, shorter, and simpler than previous ones and has a different flavor, partially building upon Gilbert's original convergence proof of its algorithm to solve the minimum norm problem for convex hulls. It is valid for both support vector classification (SVC) and support vector regression, which are formulated under a general problem that encompasses them. Moreover, this general problem can be further extended to also cover other support vector machines (SVM) related problems such as -SVC or one-class SVMs, while the convergence proof of the slight variant of SMO needed for them remains basically unchanged. PMID- 24807140 TI - RBF networks under the concurrent fault situation. AB - Fault tolerance is an interesting topic in neural networks. However, many existing results on this topic focus only on the situation of a single fault source. In fact, a trained network may be affected by multiple fault sources. This brief studies the performance of faulty radial basis function (RBF) networks that suffer from multiplicative weight noise and open weight fault concurrently. We derive a mean prediction error (MPE) formula to estimate the generalization ability of faulty networks. The MPE formula provides us a way to understand the generalization ability of faulty networks without using a test set or generating a number of potential faulty networks. Based on the MPE result, we propose methods to optimize the regularization parameter, as well as the RBF width. PMID- 24807141 TI - Neural network-based distributed attitude coordination control for spacecraft formation flying with input saturation. AB - This brief considers the attitude coordination control problem for spacecraft formation flying when only a subset of the group members has access to the common reference attitude. A quaternion-based distributed attitude coordination control scheme is proposed with consideration of the input saturation and with the aid of the sliding-mode observer, separation principle theorem, Chebyshev neural networks, smooth projection algorithm, and robust control technique. Using graph theory and a Lyapunov-based approach, it is shown that the distributed controller can guarantee the attitude of all spacecraft to converge to a common time-varying reference attitude when the reference attitude is available only to a portion of the group of spacecraft. Numerical simulations are presented to demonstrate the performance of the proposed distributed controller. PMID- 24807142 TI - Universal neural network control of MIMO uncertain nonlinear systems. AB - In this brief, a continuous tracking control law is proposed for a class of high order multi-input-multi-output uncertain nonlinear dynamic systems with external disturbance and unknown varying control direction matrix. The proposed controller consists of high-gain feedback, Nussbaum gain matrix selector, online approximator (OLA) model and a robust term. The OLA model is represented by a two layer neural network. The continuousness of the control signal is guaranteed to relax the requirement for the actuator bandwidth and avoid the incurred chattering effect. Asymptotic tracking performance is achieved theoretically by standard Lyapunov analysis. The control feasibility is also verified in simulation environment. PMID- 24807143 TI - Spectral graph optimization for instance reduction. AB - The operation of instance-based learning algorithms is based on storing a large set of prototypes in the system's database. However, such systems often experience issues with storage requirements, sensitivity to noise, and computational complexity, which result in high search and response times. In this brief, we introduce a novel framework that employs spectral graph theory to efficiently partition the dataset to border and internal instances. This is achieved by using a diverse set of border-discriminating features that capture the local friend and enemy profiles of the samples. The fused information from these features is then used via graph-cut modeling approach to generate the final dataset partitions of border and nonborder samples. The proposed method is referred to as the spectral instance reduction (SIR) algorithm. Experiments with a large number of datasets show that SIR performs competitively compared to many other reduction algorithms, in terms of both objectives of classification accuracy and data condensation. PMID- 24807144 TI - Prognostic and Predictive Biomarkers in Cancer. AB - With the recent emergence of novel technologies, the field of biomarker discovery has been the subject of intense research and activity. Major advances in cancer control will be greatly aided by early detection for the diagnosis and treatment of cancer in its pre-invasive state. Cancer being a diverse disease involves alterations in three classes of genes viz. (proto) oncogenes, tumour suppressor genes and DNA repair genes offering a wide variety of opportunities for the development of biomarkers. The emergence of innovative technologies in genomics, proteomics, metabolomics and imaging allows researchers to facilitate inclusive analysis of cancer cells. These approaches have already demonstrated its power to discriminate cancer cells from normal cells and to identify specific genetic elements involved in cancer progression. Cancer evolves via manifold pathways and is a culmination of a variety of genetic, molecular and clinical events. In the past few years, several reports have led to identification of novel cancer signatures via high throughput biology. Current review gives an overview of the bioinformatics tools, cancer database and available software package tools and further summarizes about different strategies involved in Omics research (genomics, proteomics, metabolomics) for the development of cancer biomarkers. We also discuss about the current and emerging biomarkers in breast cancer with fundamental insight into different markers used in breast cancer detection. In addition, we focus upon the systematic integration of various omic data for accelerating cancer biomarker discovery with evidence based cancer management. The above strategies may lead to significant improvement in cancer screening, prognosis and management of therapeutic response in cancer patients. PMID- 24807145 TI - Trinuclear [CoIII 2 -LnIII] (Ln=Tb, Dy) single-ion magnets with mixed 6-chloro-2 hydroxypyridine and Schiff base ligands. AB - The Schiff base ligand N1,N3-bis(3-methoxysalicylidene)diethylenetriamine (H(2)valdien) and the co-ligand 6-chloro-2-hydroxypyridine (Hchp) were used to construct two 3d-4f heterometallic single-ion magnets [Co(2) Dy(valdien)2 (OCH(3))(2) (chp)(2)]?ClO(4)?5 H(2)O 1 and [Co(2) Tb(valdien)(2) (OCH(3))(2)(chp)(2)]?ClO(4)?(2) H(2)O?CH(3)OH(2). The two trinuclear [Co(III) 2 Ln(III)] complexes behave as a mononuclear Ln(III) magnetic system because of the presence of two diamagnetic cobalt(III) ions. Complex 1 has a molecular symmetry center, and it crystallizes in the C2/c space group, whereas complex 2 shows a lower molecular symmetry and crystallizes in the P(2)1/c space group. Magnetic investigations indicated that both complexes are field-induced single-ion magnets, and the Co(III)(2)-Dy(III) complex possesses a larger energy barrier [74.1(4.2) K] than the Co(III)(2) -Tb(III) complex [32.3(2.6) K]. PMID- 24807146 TI - An investigation of photo- and pressure-induced effects in a pair of isostructural two-dimensional spin-crossover framework materials. AB - Two new isostructural iron(II) spin-crossover (SCO) framework (SCOF) materials of the type [Fe(dpms)2(NCX)2] (dpms = 4,4'-dipyridylmethyl sulfide; X = S (SCOF 6(S)), X = Se (SCOF-6(Se))) have been synthesized. The 2D framework materials consist of undulating and interpenetrated rhomboid (4,4) nets. SCOF-6(S) displays an incomplete SCO transition with only approximately 30 % conversion of high-spin (HS) to low-spin iron(II) sites over the temperature range 300-4 K (T1/2 = 75 K). In contrast, the NCSe(-) analogue, SCOF-6(Se), displays a complete SCO transition (T1/2 = 135 K). Photomagnetic characterizations reveal quantitative light- induced excited spin-state trapping (LIESST) of metastable HS iron(II) sites at 10 K. The temperature at which the photoinduced stored information is erased is 58 and 50 K for SCOF-6(S) and SCOF-6(Se), respectively. Variable-pressure magnetic measurements were performed on SCOF-6(S), revealing that with increasing pressure both the T1/2 value and the extent of spin conversion are increased; with pressures exceeding 5.2 kbar a complete thermal transition is achieved. This study confirms that kinetic trapping effects are responsible for hindering a complete thermally induced spin transition in SCOF-6(S) at ambient pressure due to an interplay between close T1/2 and T(LIESST) values. PMID- 24807147 TI - Nitric oxide-induced neuronal to glial lineage fate-change depends on NRSF/REST function in neural progenitor cells. AB - Degeneration of central nervous system tissue commonly occurs during neuroinflammatory conditions, such as multiple sclerosis and neurotrauma. During such conditions, neural stem/progenitor cell (NPC) populations have been suggested to provide new cells to degenerated areas. In the normal brain, NPCs from the subventricular zone generate neurons that settle in the olfactory bulb or striatum. However, during neuroinflammatory conditions NPCs migrate toward the site of injury to form oligodendrocytes and astrocytes, whereas newly formed neurons are less abundant. Thus, the specific NPC lineage fate decisions appear to respond to signals from the local environment. The instructive signals from inflammation have been suggested to rely on excessive levels of the free radical nitric oxide (NO), which is an essential component of the innate immune response, as NO promotes neuronal to glial cell fate conversion of differentiating rat NPCs in vitro. Here, we demonstrate that the NO-induced neuronal to glial fate conversion is dependent on the transcription factor neuron-restrictive silencing factor-1 (NRSF)/repressor element-1 silencing transcription (REST). Chromatin modification status of a number of neuronal and glial lineage restricted genes was altered upon NO-exposure. These changes coincided with gene expression alterations, demonstrating a global shift toward glial potential. Interestingly, by blocking the function of NRSF/REST, alterations in chromatin modifications were lost and the NO-induced neuronal to glial switch was suppressed. This implicates NRSF/REST as a key factor in the NPC-specific response to innate immunity and suggests a novel mechanism by which signaling from inflamed tissue promotes the formation of glial cells. PMID- 24807148 TI - Synthesis, structure, and applications of pyridiniophosphines. AB - A new family of cationic ligands, N-alkyl/aryl pyridiniophosphines, has been synthesized through a short, scalable, and highly modular route. Evaluation of their electronic properties evidenced weak sigma-donor and quite strong pi acceptor character when used as ancillary ligands. These attributes confer a substantially enhanced pi-acidity to the Pt(II) and Au(I) complexes thereof derived and, as result, they depict an improved ability to activate alkynes towards nucleophilic attack. This superior performance has been demonstrated along several mechanistically diverse Pt(II)- and Au(I)-catalyzed transformations. PMID- 24807149 TI - Rat islets are not rejected by anti-islet antibodies in mice treated with costimulation blockade. AB - BACKGROUND: Costimulation blockade can prevent rejection of islet xenografts in naive but not sensitized recipients. Donor-specific antibodies (DSA) may partly explain this observation. The effect of DSA on rat islet xenograft survival in mice receiving costimulation blockade was investigated. METHODS: Naive C57BL/6 mice with alloxan-induced diabetes were transplanted under the left kidney capsule with 100 Lewis rat islets. Recipients were divided into three groups receiving: (i) isotype control antibodies (Abs); (ii) anti-CD154 and CTLA4Ig; or (iii) anti-CD154, CTLA4Ig, and anti-LFA-1 every second day, day 0-8. At the time of transplantation (Tx), half of the animals in each group received naive mouse serum and half xenoimmune serum derived from mice previously transplanted with rat islets. Non-fasting blood glucose levels and body weight were followed daily. Cured mice were examined by intraperitoneal glucose tolerance (IPGT) tests at 1 and 4 months after transplantation. RESULTS: Donor-specific antibodies were detected in immune serum-injected recipients up to at least 96 h post-Tx. Short term (<=96 h), there was no significant difference with regard to graft mass, infiltrating and apoptotic cells between groups of mice receiving naive and immune sera. A moderate infiltration of polymorphonuclear and mononuclear cells was seen 96 h post-Tx in mice given control Abs, whether or not they received immune or naive mouse serum. Mice given costimulation blockade had well maintained endocrine tissue and very little cell infiltration. There was no significant difference in islet xenograft function and survival long term between groups receiving naive and immune sera in combination with costimulation blockade. About half of the mice receiving costimulation blockade lost graft function within 110 days. CONCLUSION: The presence at Tx of DSA does not appear to negatively influence early and late islet xenograft survival in mice receiving costimulation blockade. PMID- 24807151 TI - Split aptazyme-based catalytic molecular beacons for amplified detection of adenosine. AB - Combining the elements of split aptazyme and molecular beacons (MBs contain an adenine ribonucleotide (rA) as the cleavage site), we developed a versatile sensing strategy for amplified detection of the biotarget adenosine. PMID- 24807152 TI - Comparative study of protein unfolding in aqueous urea and dimethyl sulfoxide solutions: surface polarity, solvent specificity, and sequence of secondary structure melting. AB - Elucidation of possible pathways between folded (native) and unfolded states of a protein is a challenging task, as the intermediates are often hard to detect. Here, we alter the solvent environment in a controlled manner by choosing two different cosolvents of water, urea, and dimethyl sulfoxide (DMSO) and study unfolding of four different proteins to understand the respective sequence of melting by computer simulation methods. We indeed find interesting differences in the sequence of melting of alpha helices and beta sheets in these two solvents. For example, in 8 M urea solution, beta-sheet parts of a protein are found to unfold preferentially, followed by the unfolding of alpha helices. In contrast, 8 M DMSO solution unfolds alpha helices first, followed by the separation of beta sheets for the majority of proteins. Sequence of unfolding events in four different alpha/beta proteins and also in chicken villin head piece (HP-36) both in urea and DMSO solutions demonstrate that the unfolding pathways are determined jointly by relative exposure of polar and nonpolar residues of a protein and the mode of molecular action of a solvent on that protein. PMID- 24807153 TI - Electronic control over detachment of a self-doped water-soluble conjugated polyelectrolyte. AB - Water-soluble conducting polymers are of interest to enable more versatile processing in aqueous media as well as to facilitate interactions with biomolecules. Here, we report a substituted poly(3,4-ethylenedioxythiophene) derivative (PEDOT-S:H) that is fully water-soluble and self-doped. When electrochemically oxidizing a PEDOT-S:H thin film, the film detaches from the underlying electrode. The oxidation of PEDOT-S:H starts with an initial phase of swelling followed by cracking before it finally disrupts into small flakes and detaches from the electrode. We investigated the detachment mechanism and found that parameters such as the size, charge, and concentration of ions in the electrolyte, the temperature, and also the pH influence the characteristics of detachment. When oxidizing PEDOT-S:H, the positively charged polymer backbone is balanced by anions from the electrolyte solution and also by the sulfonate groups on the side chains (more self-doping). From our experiments, we conclude that detachment of the PEDOT-S:H film upon oxidation occurs in part due to swelling caused by an inflow of solvated anions and associated water and in part due to chain rearrangements within the film, caused by more self-doping. We believe that PEDOT-S:H detachment can be of interest in a number of different applications, including addressed and active control of the release of materials such as biomolecules and cell cultures. PMID- 24807154 TI - Impact of chronic obstructive pulmonary disease on the mortality of patients with non-small-cell lung cancer. AB - INTRODUCTION: The impact of chronic obstructive pulmonary disease (COPD) on the mortality of patients with lung cancer has not been studied extensively. The objective of this study is to compare the mortality and clinical characteristics of patients with non-small-cell lung cancer (NSCLC) according to the presence of COPD. METHODS: The medical records of 221 smokers diagnosed with NSCLC were reviewed. Eligible patients were dichotomized into the COPD group (n = 111) and the non-COPD group (n = 110). The overall survival and clinical characteristics were compared, and predictors of worse survival were analyzed using Cox proportional hazards regression. RESULTS: COPD was present in 50.2% of all patients with NSCLC, and most of the patients (92.8%) with COPD were unaware of the disease before the diagnosis of lung cancer. Patients in the COPD group were older and had a lower body mass index, higher pack-years smoking history, higher frequency of dyspnea, and higher incidence of previous malignancy. The overall survival of enrolled patients and propensity score-matched subjects was comparable between the two groups (log-rank test, p = 0.2 and 0.396, respectively). Old age, low body mass index, advanced disease stage (stages III and IV), non-squamous histology, Eastern Cooperative Oncology Group performance status of greater than or equal to 2, weight loss, and coexistence of interstitial lung disease were independent risk factors for shorter survival. CONCLUSION: COPD frequently and subliminally coexists with NSCLC. Although differences in clinical characteristic did exist, there was no impact of COPD on the mortality of patients with NSCLC with a positive smoking history in this study. PMID- 24807155 TI - GATA2 is epigenetically repressed in human and mouse lung tumors and is not requisite for survival of KRAS mutant lung cancer. AB - INTRODUCTION: GATA2 was recently described as a critical survival factor and therapeutic target for KRAS mutant non-small-cell lung cancer (NSCLC). However, whether this role is affected by epigenetic repression of GATA2 in lung cancer is unclear. METHODS: GATA2 expression and promoter CpG island methylation were evaluated using human and mouse NSCLC cell lines and tumor-normal pairs. In vitro assays were used to study GATA2 repression on cell survival and during tobacco carcinogen-induced transformation. RESULTS: GATA2 expression in KRAS wild-type (n = 15) and mutant (n = 10) NSCLC cell lines and primary lung tumors (n = 24) was significantly lower, 1.3- to 33.6-fold (p = 2.2 * 10(9)), compared with corresponding normal lung. GATA2 promoter was unmethylated in normal lung (0 of 10) but frequently methylated in lung tumors (96%, 159 of 165) and NSCLC cell lines (97%, 30 of 31). This highly prevalent aberrant methylation was independently validated using The Cancer Genome Atlas data for 369 NSCLC tumor normal pairs. In vitro studies using an established carcinogen-induced premalignancy model revealed that GATA2 expression was initially repressed by chromatin remodeling followed by cytosine methylation during transformation. Similarly, expression of GATA2 in NNK-induced mouse lung tumors (n = 6) and cell lines (n = 5) was fivefold and 100-fold lower, respectively, than normal mouse lung. Finally, siRNA-mediated knockdown of GATA2 in KRAS mutant (human [n = 4] and murine [n = 5]) and wild-type (human [n = 4]) NSCLC cell lines showed that further reduction of expression (up to 95%) does not induce cell death. CONCLUSION: GATA2 is epigenetically repressed in human and mouse lung tumors and its further inhibition is not a valid therapeutic strategy for KRAS mutant lung cancer. PMID- 24807156 TI - A correlative biomarker analysis of the combination of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small-cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). AB - INTRODUCTION: Avastin Biomarkers In lunG And 3D Innovative anaLysis (ABIGAIL), which is a phase II, open-label, randomized study, investigated correlations between biomarkers and best overall response to bevacizumab plus platinum-doublet chemotherapy for patients with advanced/recurrent non-small-cell lung cancer. METHODS: Patients received bevacizumab (7.5 or 15 mg/kg, 3-weekly until disease progression/unacceptable toxicity) plus carboplatin/gemcitabine or carboplatin/paclitaxel (maximum six cycles). Plasma samples (baseline/throughout treatment) were analyzed for vascular endothelial growth factor (VEGF)-A (baseline only), VEGF receptors (VEGFR-1/VEGFR-2), basic fibroblast growth factor, E-selectin, intercellular adhesion molecule-1, and placental growth factor (baseline only). Tumor samples (primary specimen) were analyzed for VEGF A, VEGFR-1/VEGFR-2, neuropilin (NRP), and CD31. Response was evaluated at baseline and every 6 weeks (Response Evaluation Criteria in Solid Tumors). RESULTS: Patients were randomized to receive chemotherapy plus 7.5 mg/kg (n =154) or 15 mg/kg (n =149) bevacizumab. For the primary analysis, none of the baseline plasma biomarkers correlated with best overall response. Exploratory analyses showed that low VEGF-A levels were associated with longer progression-free survival (7.4 versus 6.1 months; hazard ratio, 1.57; 95% confidence intervals, 1.17 to 2.09; p = 0.002) and overall survival (19.8 versus 11.1 months; hazard ratio, 1.57; 95% confidence interval, 1.15-2.13; p = 0.004) compared with these in high baseline plasma VEGF-A levels. No plasma biomarkers changed significantly over time. No significant correlations were observed between tumor biomarkers and clinical outcomes. No new safety signals were observed. CONCLUSION: Baseline and/or dynamic changes in plasma basic fibroblast growth factor, E-selectin, intercellular adhesion molecule-1, placental growth factor, VEGFR-1 and VEGFR-2, and tumor biomarkers did not correlate statistically with treatment outcomes for bevacizumab plus chemotherapy. Only baseline plasma VEGF-A was significantly correlated with progression-free survival/overall survival. PMID- 24807157 TI - Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. AB - INTRODUCTION: The staging system for malignant pleural mesothelioma is controversial. To revise this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. This report analyzes prognostic variables in a surgical population, which are supplementary to previously published CORE variables (stage, histology, sex, age, and type of procedure). METHODS: Supplementary prognostic variables were studied in three scenarios: (1) all data available, that is, patient pathologically staged and other CORE variables available (2) only clinical staging available along with CORE variables, and (3) only age, sex, histology, and laboratory parameters are known. Survival was analyzed by Kaplan-Meier, prognostic factors by log rank and stepwise Cox regression modeling after elimination of nonsignificant variables. p value less than 0.05 was significant. RESULTS: A total of 2141 patients with best tumor, node, metastasis (TNM) stages (pathologic with/without clinical staging) had nonmissing age, sex, histology, and type of surgical procedure. Three prognostic models were defined. Scenario A (all parameters): best pathologic stage, histology, sex, age, type of surgery, adjuvant treatment, white blood cell count (WBC) (>=15.5 or not), and platelets (>=400 k or not) (n = 550). Scenario B (no surgical staging): clinical stage, histology, sex, age, type of surgery, adjuvant treatment, WBC, hemoglobin (<14.6 or not), and platelets (n = 627). Scenario C (limited data): histology, sex, age, WBC, hemoglobin, and platelets (n = 906). CONCLUSION: Refinement of these models could define not only the appropriate patient preoperatively for best outcomes after cytoreductive surgery but also stratify surgically treated patients after clinical and pathologic staging who do or do not receive adjuvant therapy. PMID- 24807159 TI - Tridentate benzimidazole-pyridine-tetrazolates as sensitizers of europium luminescence. AB - We report on new anionic tridentate benzimidazole-pyridine-tetrazolate ligands that form neutral 3:1 complexes with trivalent lanthanides. The ligands are UV absorbing chromophores that sensitize the red luminescence of europium with energy-transfer efficiency of 74-100%. The lifetime and quantum yield of the sensitized europium luminescence increase from 0.5 ms and 12-13% for the as prepared solids to 2.8 ms and 41% for dichloromethane solution. From analysis of the data, the as-prepared solids can be described as aqua-complexes [Ln(kappa(3) ligand)2(kappa(1)-ligand)(H2O)x] where the coordinated water molecules are responsible for the strong quenching of the europium luminescence. In solution, the coordinated water molecules are replaced by the nitrogen atoms of the kappa(1)-ligand to give anhydrous complexes [Ln(kappa(3)-ligand)3] that exhibit efficient europium luminescence. X-ray structures of the anhydrous complexes confirm that the lanthanide ion (La(III), Eu(III)) is nine-coordinate in a distorted tricapped trigonal prismatic environment and that coordination of the lanthanide ion by tetrazolate is weaker than by carboxylate. PMID- 24807158 TI - Poor prognosis patients with inoperable locally advanced NSCLC and large tumors benefit from palliative chemoradiotherapy: a subset analysis from a randomized clinical phase III trial. AB - INTRODUCTION: Poor prognosis patients with bulky stage III locally advanced non small-cell lung cancer may not be offered concurrent chemoradiotherapy (CRT). Following a phase III trial concerning the effect of palliative CRT in inoperable poor prognosis patients, this analysis was performed to explore how tumor size influenced survival and health-related quality of life (HRQOL). METHODS: A total of 188 poor prognosis patients recruited in a randomized clinical trial received four courses intravenous carboplatin day 1 and oral vinorelbine day 1 and 8, at 3 week intervals. The experimental arm (N = 94) received radiotherapy with fractionation 42 Gy/15, starting at the second chemotherapy course. This subset study compares outcomes in patients with tumors larger than 7 cm (N = 108) versus tumors 7 cm or smaller (N = 76). RESULTS: Among those with tumors larger than 7 cm, the median overall survival in the chemotherapy versus CRT arm was 9.7 and 13.4 months, respectively (p = 0.001). The 1-year survival was 33% and 56%, respectively (p = 0.01). Except for a temporary decline during treatment, HRQOL was maintained in the CRT arm, regardless of tumor size. Among those who did not receive CRT, patients with tumors larger than 7 cm experienced a gradual decline in the HRQOL. The CRT group had significantly more esophagitis and hospitalizations because of side effects regardless of tumor size. CONCLUSION: In patients with poor prognosis and inoperable locally advanced non-small-cell lung cancer, large tumor size should not be considered a negative predictive factor. Except for performance status 2, patients with tumors larger than 7 cm apparently benefit from CRT. PMID- 24807161 TI - Loss of E-cadherin expression is not a prerequisite for c-erbB2-induced epithelial-mesenchymal transition. AB - Recent research into the mechanisms of tumour cell invasiveness has highlighted the parallels between carcinogenesis and epithelial-mesenchymal transition (EMT), originally described as a developmental transdifferentiation program but also implicated in fibrosis and cancer. In a model system for mammary carcinogenesis, we previously observed that induced signalling from a homodimer of the c-erbB2 (HER2) receptor tyrosine kinase in an initially non-malignant mammary cell line caused EMT where i) cell scattering occurred before downregulation of the cell cell adhesion molecule E-cadherin and ii) the progress of EMT was dramatically delayed when cells were grown at high density. Here, we have further analysed these phenomena. Ectopic expression of E-cadherin concomitant with c-erbB2 signalling was unable to impede the progression of EMT, suggesting that E cadherin downregulation is not required for EMT. Furthermore, fibroblast-like cells isolated after EMT induced in the presence or absence of ectopic E-cadherin expression showed highly similar morphology and vimentin expression. E-cadherin expressed in these fibroblastic cells had a subcellular localisation similar to that found in epithelial cells, but it exhibited a much weaker attachment to the cytoskeleton, suggesting cytoskeletal rearrangements as an important mechanism in EMT-associated cell scattering. We also investigated whether density-dependent inhibition of EMT is mediated by E-cadherin as a sensor for cell-cell contact, by expressing dominant-negative E-cadherin. While expression of this mutant weakened cell-cell adhesion, it failed to facilitate EMT at high cell densities. These results indicate that loss of E-cadherin expression is a consequence rather than a cause of c-erbB2-induced EMT and that density-dependent inhibition of EMT is not mediated by E-cadherin signalling. PMID- 24807165 TI - Intra-operative tumour localisation in robot-assisted minimally invasive surgery: A review. AB - Robot-assisted minimally invasive surgery has many advantages compared to conventional open surgery and also certain drawbacks: it causes less operative trauma and faster recovery times but does not allow for direct tumour palpation as is the case in open surgery. This article reviews state-of-the-art intra operative tumour localisation methods used in robot-assisted minimally invasive surgery and in particular methods that employ force-based sensing, tactile-based sensing, and medical imaging techniques. The limitations and challenges of these methods are discussed and future research directions are proposed. PMID- 24807164 TI - Management of hepatic encephalopathy. AB - OPINION STATEMENT: Hepatic encephalopathy management varies depending on the acuity of liver failure. However, in patients with either acute or chronic liver failure five basic steps in management are critical: stabilization, addressing modifiable precipitating factors, lowering blood ammonia, managing elevated intracranial pressure (ICP) (if present), and managing complications of liver failure that can contribute to encephalopathy, particularly hyponatremia. Because liver failure patients are prone to a variety of other medical problems that can lead to encephalopathy (such as coagulopathy associated intracranial hemorrhage, electrolyte disarray, renal failure, hypotension, hypoglycemia, and infection), a thorough history, physical and neurologic examination is mandated in all encephalopathic liver failure patients. There should be a low threshold for brain imaging in patients with focal neurological deficits given the propensity for spontaneous intracranial hemorrhage. In patients with acute liver failure and high grade encephalopathy, identification of the etiology of acute liver failure is essential to guide treatment and antidote administration, particularly in the case of acetaminophen poisoning. Equally critical is management of elevated ICP in acute liver failure. Intracranial hypertension can be treated with hypertonic saline and/or adjustment of the dialysis bath. Placement of an intracranial monitor to guide ICP therapy is risky because of concomitant coagulopathy and remains controversial. Continuous renal replacement therapy may help lower serum ammonia, treat coexisting uremia, and improve symptoms. Liver transplantation is the definitive treatment for patients with acute liver failure and hepatic encephalopathy. In patients with chronic hepatic encephalopathy, lactulose and rifaxamin remain a mainstay of therapy. In these patients, it is essential to identify reversible causes of hepatic encephalopathy such as increased ammonia production and/or decreased clearance (eg, infection, GI bleed, constipation, hypokalemia, dehydration). Chronic hyponatremia should be managed by gradual sodium correction of no more than 8-12 meq/L per day to avoid central myelinolysis syndrome. Free water restriction and increased dietary sodium are reasonable, cost effective treatment options. Many emerging therapies, both pharmacologic and interventional, are currently being studied to improve management of hepatic encephalopathy. PMID- 24807166 TI - The role of Toll-like receptors (TLRs) in stroke. AB - Toll-like receptors (TLRs) recognizing the exogenous pathogen-associated molecular patterns (PAMPs) are part of the innate immune system that plays a role in various challenging interactions between the neurons and the immune system. Stroke as a major injury to the central nervous system (CNS) is one of the hot points of such cross-talk. The various roles of the different types of TLRs in stroke can be classified into three major categories: (1) the hazardous effect of TLRs with a focus on the part in poststroke neurodegeneration, (2) the beneficial effect of those types of TLRs that exert a neuroprotective effect following an ischemic insult, and (3) the role of TLRs in immunomodulation on one hand and the possible autoimmunity as a consequence of neuronal injury due to an ischemic attack on the other hand. However, the mentioned functions of TLRs, similar to many other parts of the immune system, might overlap in many aspects. The current review article, including both experimental and clinical studies, is an attempt to bring together the studies that have investigated the roles of TLRs in stroke while referring to the apparent controversies in this field, with pointing out the new ideas for further considerations. PMID- 24807167 TI - Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors. AB - BACKGROUND: The potential of tyrosine kinase inhibitors (TKIs) interacting with other therapeutics through hepatic uptake transporter inhibition has not been fully delineated in drug-drug interactions (DDIs). This study was designed to estimate the half-maximal inhibitory concentration (IC50) values of five small molecule TKIs (pazopanib, nilotinib, vandetanib, canertinib and erlotinib) interacting with organic anion-transporting polypeptides (OATPs): OATP-1B1 and 1B3. METHODS: The IC50 values of TKIs and rifampicin (positive control) were determined by concentration-dependent inhibition of TKIs on cellular accumulation of radiolabeled probe substrates [3H]estrone sulfate and [3H]cholecystokinin octapeptide. Chinese hamster ovary cells transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins, respectively, were utilized to carry out these studies. RESULTS: Pazopanib and nilotinib show inhibitory activity on OATP-1B1 transporter protein. IC50 values for rifampicin, pazopanib and nilotinib were 10.46+/-1.15, 3.89+/-1.21 and 2.78+/-1.13 MUM, respectively, for OATP-1B1 transporter. Vandetanib, canertinib and erlotinib did not exhibit any inhibitory potency toward OATP-1B1 transporter protein. Only vandetanib expressed inhibitory potential toward OATP-1B3 transporter protein out of the five selected TKIs. IC50 values for rifampicin and vandetanib for OATP-1B3 transporter inhibition were 3.67+/-1.20 and 18.13+/-1.21 MUM, respectively. No significant inhibition in the presence of increasing concentrations of pazopanib, nilotinib, canertinib and erlotinib were observed for OATP-1B3 transporter. CONCLUSIONS: Because selected TKIs are inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated DDIs. These findings provide the basis for further preclinical and clinical studies investigating the transporter-based DDI potential of TKIs. PMID- 24807163 TI - MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation. AB - The melanocortin 1 receptor (MC1R) is a G protein-coupled receptor crucial for the regulation of melanocyte proliferation and function. Upon binding melanocortins, MC1R activates several signaling cascades, notably the cAMP pathway leading to synthesis of photoprotective eumelanin. Polymorphisms in the MC1R gene are a major source of normal variation of human hair color and skin pigmentation, response to ultraviolet radiation (UVR), and skin cancer susceptibility. The identification of a surprisingly high number of MC1R natural variants strongly associated with pigmentary phenotypes and increased skin cancer risk has prompted research on the functional properties of the wild-type receptor and frequent mutant alleles. We summarize current knowledge on MC1R structural and functional properties, as well as on its intracellular trafficking and signaling. We also review the current knowledge about the function of MC1R as a skin cancer, particularly melanoma, susceptibility gene and how it modulates the response of melanocytes to UVR. PMID- 24807168 TI - D-Dimer in normal pregnancy: determination of reference values for three commercially available assays. PMID- 24807169 TI - Reticulated platelets: analytical aspects and clinical utility. AB - Reticulated platelets are immature platelets circulating in blood; they reflect the activity of megakaryopoiesis in the bone marrow. Therefore, they can be used as a non-invasive test in patients with thrombocytopenia in various clinical conditions. The preferred method of analysis is by flow cytometry. However, there is an evident lack of analytical standardization, making it difficult to compare results obtained in different laboratories. Currently, two types of hematology analyzers are on the market offering fully automated measurement of reticulated or immature platelets: the high end analyzers manufactured by Sysmex (XE- and XN series) and Abbott (CELL-DYN Sapphire). Although the methods are essentially different and cannot be used interchangeably, both have been proven to have clinical utility. Reticulated or immature platelet assays are useful for the differential diagnosis of thrombocytopenia and for monitoring bone marrow recovery after chemotherapy or stem cell transplantation. These assays may aid clinicians in platelet transfusion decisions when recovery from thrombocytopenia is imminent. In addition, preliminary findings indicate that there is a rationale for reticulated or immature platelets for risk stratification in acute coronary syndromes and for monitoring the effect of treatment with antiplatelet drugs in patients with coronary artery diseases. The aim of this paper is to present the present technology available for measuring reticulated platelets as well as an overview of the current status of clinical application. This overview also indicates that more research is needed before reticulated or immature platelet assays can be applied in other clinical conditions than thrombocytopenia and after transplantation. PMID- 24807170 TI - The 3rd International Standard for serum IgE: international collaborative study to evaluate a candidate preparation. AB - BACKGROUND: The measurement of serum IgE aids in the diagnosis and management of atopic allergic disease and hyper-IgE immunodeficiency syndromes. The 2nd World Health Organization (WHO) International Reference Reagent (IRR) for serum IgE (75/502; 5000 IU/ampoule), is widely used to calibrate assays for serum IgE. Exhaustion of stocks of the 2nd IRR necessitated the production of a replacement preparation and its evaluation in an international collaborative study to determine its suitability to serve as the 3rd International Standard (IS) for serum IgE. METHODS: Sera and defibrinated plasma with elevated IgE levels were pooled and lyophilised in ampoules. This preparation, coded 11/234, was assayed by 18 laboratories in 11 countries using commercial assay methodology for IgE, along with the 2nd IRR, 75/502, and two lyophilised serum samples. RESULTS: Overall, there were no consistent differences in the way that the candidate IS (11/234), the IRR (75/502), and the two serum samples behaved in the assays with respect to linearity and parallelism. The mean IgE value of the candidate IS, 11/234, relative to the IRR, 75/502, was 13,411 IU/mL based on parallel line analysis of raw assay data at NIBSC, and 13,551 IU/mL based on the laboratories' own estimates after correcting for the values obtained for 75/502. CONCLUSIONS: The use of 11/234 will ensure that assays for serum IgE continue to be well standardised. The preparation was established by the WHO Expert Committee on Biological Standardization as the 3rd IS for serum IgE with an assigned value of 13,500 IU/mL, corresponding to 6750 IU/ampoule. PMID- 24807171 TI - Paraoxonase 2 sequence variation (c.311 C>G) is associated with a modest decrease in circulating LDL size in children and adolescents. PMID- 24807172 TI - Health assessment of the Christmas Island flying fox (Pteropus melanotus natalis). AB - During July-August 2010, 28 Christmas Island flying foxes (Pteropus melanotus natalis) were captured and anesthetized for examination, sample collection, and release to determine the potential role of disease in recent population declines. Measurements and samples were taken for morphologic, hematologic, biochemical, and parasitologic analysis. These are the first blood reference ranges reported for this species. These data are being used to inform investigations into conservation status and population management strategies for the Christmas Island flying fox. PMID- 24807173 TI - Central nervous system mucormycosis caused by Cunninghamella bertholletiae in a bottlenose dolphin (Tursiops truncatus). AB - In May 2012, an adult, male bottlenose dolphin (Tursiops truncatus) was found stranded and dead on the Spanish Mediterranean coast. At necropsy, several areas of malacia were macroscopically observed in the periventricular parenchyma of the cerebrum. Microscopically a severe, diffuse, pyogranulomatous, and necrotizing meningoencephalomyelitis was associated with numerous intralesional highly pleomorphic fungal structures. After culture, the fungus, Cunninghamella bertholletiae, was identified by culture and PCR. To our knowledge, this is the first reported case of central nervous system mucormycosis due to Cunninghamella bertholletiae in a cetacean. PMID- 24807174 TI - Capillaria hepatica in wild Norway rats (Rattus norvegicus) from Vancouver, Canada. AB - Capillaria hepatica is a parasitic nematode that infects the liver of rats (Rattus spp.), and occasionally other mammalian species, including humans. Despite its broad geographic distribution and host range, the ecology of this parasite remains poorly understood. We characterized the ecology of C. hepatica in urban Norway rats (Rattus norvegicus) in Vancouver, Canada. The overall prevalence of C. hepatica among Norway rats was 36% (241/671); however, there was significant variation in prevalence among city blocks. Using a generalized linear mixed model to control for clustering by block (where OR is odds ratio and CI is confidence interval), we found C. hepatica infection was negatively associated with season (spring [OR=0.14, 95% CI=0.05-0.39]; summer [OR=0.14, 95% CI=0.03 0.61]; winter [OR=0.34, 95% CI=0.13-0.84], compared to fall) and positively associated with sexual maturity (OR: 7.29, 95% CI=3.98-13.36) and presence of cutaneous bite wounds (OR=1.87, 95% CI=1.11-3.16). Our understanding of the ecology of C. hepatica in rats is hindered by a paucity of data regarding the main mechanisms of transmission (e.g., environmental exposure vs. active cannibalism). However, associations among infection, season, maturity, and bite wounds could suggest that social interactions, possibly including cannibalism, may be important in transmission. PMID- 24807175 TI - Molecular typing of epizootic hemorrhagic disease virus serotypes by one-step multiplex RT-PCR. AB - Epizootic hemorrhagic disease virus (EHDV) causes a highly infectious noncontagious hemorrhagic disease in wild and captive deer (Cervidae) populations in the US. Although rapid and accurate identification of the disease is important, identification of the serotype is equally important for understanding the epidemiology of the disease in white-tailed deer (Odocoileus virginianus) populations. We developed a one-step multiplex reverse transcriptase PCR assay for rapid differentiation and identification of EHDV serotypes 1, 2, and 6 in cell culture and clinical samples by targeting the viral gene segment 2 (L2) that encodes for the structural protein VP2. From 2009 to 2012, 427 clinical samples including tissue and blood (in ethylenediaminetetraacetic acid) from white-tailed deer, found EHDV positive by real-time PCR, were used to evaluate this subtyping assay. Eighteen percent of the positive samples tested were EHDV-1, 59% were EHDV 2, and 21% were EHDV-6; 2% of the samples were positive for more than one subtype, indicating mixed infection. This assay provides a rapid, sensitive, specific diagnostic tool for differentiation and identification of EHDV serotypes in field samples and virus isolates. PMID- 24807176 TI - Isolation of Leptospira from a phocid: acute renal failure and mortality from Leptospirosis in rehabilitated northern elephant seals (Mirounga angustirostris), California, USA. AB - During rehabilitation, acute renal failure due to leptospirosis occurred in eight male northern elephant seals (Mirounga angustirostris) that stranded along the central California coast in 2011. Characteristic histologic lesions including renal tubular degeneration, necrosis, and mineralization, and mild lymphoplasmacytic interstitial nephritis were noted in the six animals examined. Immunohistochemistry, bacterial culture, and PCR were positive in 2/3, 2/3, and 3/4 seals, respectively, and 6/8 had high serum antibody titers to Leptospira interrogans serovar pomona. Pulsed-field gel electrophoresis confirmed one isolate as serovar pomona. Variable number tandem repeat (VNTR) analysis showed both elephant seal isolates were identical to each other but distinct from those isolated from California sea lions (Zalophus californianus). The time from stranding to onset of azotemia was 1 to 38 (median=24) days, suggesting some seals were infected at the rehabilitation facility. Based on temporal and spatial incidence of infection, transmission among elephant seals likely occurred during rehabilitation. Molecular (VNTR) analysis of the two isolates indicates there is a unique L. interrogans serovar pomona genotype in elephant seals, and sea lions were not the source of infection prior to or during rehabilitation. This study confirms the susceptibility of northern elephant seals to leptospirosis, indicates intraspecies transmission during rehabilitation, and reports the first isolation and preliminary characterization of leptospires from elephant seals. PMID- 24807177 TI - Undomesticated animals as a reservoir of multidrug-resistant Enterococcus in eastern Poland. AB - To assess implications for public health we compared the resistance of Enterococcus spp. strains to antibacterial drugs in wild and exotic animals with strains originating in domesticated animals and characterized correlations between Enterococcus species, the source of the isolate, and the degree of resistance to selected antibiotics. All strains, regardless of source, were susceptible to beta-lactams, gentamicin, linezolid, and teicoplanin; the highest resistance was to kanamycin, quinupristin, and rifampicin. Thirteen strains from undomesticated animals were resistant to vancomycin, and one strain, from a fox, was resistant to streptomycin (high-dose). Multidrug-resistant strains accounted for 46% of the strains from wild animals and 59% of the strains from an exotic animal (the Russian tortoise; Testudo horsfieldii). Despite the relatively low level of resistance in the strains isolated from wild and exotic animals, the large number of intermediately susceptible strains in these groups is an indication of the evolutionary character of the development of resistance, suggesting that these animals may be potential reservoirs of Enterococcus strains resistant to a wide panel of currently used antibiotics. PMID- 24807178 TI - Safety and immunogenicity of Ontario Rabies Vaccine Bait (ONRAB) in the first us field trial in raccoons (Procyon lotor). AB - In 2011, we conducted a field trial in rural West Virginia, USA to evaluate the safety and immunogenicity of a live, recombinant human adenovirus (AdRG1.3) rabies virus glycoprotein vaccine (Ontario Rabies Vaccine Bait; ONRAB) in wild raccoons (Procyon lotor) and striped skunks (Mephitis mephitis). We selected ONRAB for evaluation because of its effectiveness in raccoon rabies management in Ontario and Quebec, Canada, and significantly higher antibody prevalence rates in raccoons compared with a recombinant vaccinia-rabies glycoprotein (V-RG) vaccine, Raboral V-RG(r), in US-Canada border studies. Raccoon rabies was enzootic and oral rabies vaccination (ORV) had never been used in the study area. We distributed 79,027 ONRAB baits at 75 baits/km(2) mostly by fixed-wing aircraft along parallel flight lines at 750-m intervals. Antibody prevalence was significantly higher at 49.2% (n=262) in raccoons after ONRAB was distributed than the 9.6% (n=395) before ORV. This was the highest antibody prevalence observed in raccoons by US Department of Agriculture Wildlife Services for areas with similar management histories evaluated before and after an initial ORV campaign at 75 baits/km(2) with Raboral V-RG. Tetracycline biomarker (TTCC) was significantly higher among antibody-positive raccoons after ONRAB baiting and was similar among raccoons before ORV had been conducted, an indication of vaccine induced rabies virus-neutralizing antibody production following consumption of bait containing TTCC. Skunk sample size was inadequate to assess ONRAB effects. Safety and immunogenicity results supported replication of this field trial and led to a recommendation for expanded field trials in 2012 to evaluate safety and immunogenicity of ground-distributed ONRAB at 150 baits/km(2) in residential and commercial habitats in Ohio, USA and aerially distributed ONRAB at 75 baits/km(2) in rural habitats along US-Quebec border. PMID- 24807179 TI - Toward a modernized definition of wildlife health. AB - There has been, to date, little discussion about the defining features and measures of wildlife health in the literature or legislation. Much wildlife health work focuses on the detection and response to infectious or parasitic diseases; this perspective has been reinforced by the focus of the One Health initiative on wildlife as sources of emerging infections. The definition of health as "the absence of disease" lags 70 yr behind modern concepts of human health and emerging concepts of wildlife health in terms of vulnerability, resilience, and sustainability. Policies, programs, and research that focus on the integration of wildlife health with natural resource conservation, ecosystem restoration, and public health need a working definition of health that recognizes the major threats to fish and wildlife are the result of many other drivers besides pathogens and parasites, including habitat loss, globalization of trade, land-use pressure, and climate change. A modern definition of wildlife health should emphasize that 1) health is the result of interacting biologic, social, and environmental determinants that interact to affect capacity to cope with change; 2) health cannot be measured solely by what is absent but rather by characteristics of the animals and their ecosystem that affect their vulnerability and resilience; and 3) wildlife health is not a biologic state but rather a dynamic social construct based on human expectations and knowledge. PMID- 24807180 TI - Novel poxvirus infection in northern and southern sea otters (Enhydra lutris kenyoni and Enhydra lutris neiris), Alaska and California, USA. AB - Small superficially ulcerated skin lesions were observed between October 2009 and September 2011 during captive care of two orphaned sea otter pups: one northern (Enhydra lutris kenyoni) in Alaska and one southern (Enhydra lutris nereis) in California. Inclusions consistent with poxviral infection were diagnosed by histopathology in both cases. Virions consistent with poxvirus virions were seen on electron microscopy in the northern sea otter, and the virus was successfully propagated in cell culture. DNA extraction, pan-chordopoxviral PCR amplification, and sequencing of the DNA-dependent DNA polymerase gene revealed that both cases were caused by a novel AT-rich poxvirus. Bayesian and maximum likelihood phylogenetic analyses found that the virus is divergent from other known poxviruses at a level consistent with a novel genus. These cases were self limiting and did not appear to be associated with systemic illness. To our knowledge, this is the first report of a poxvirus in a mustelid species. The source of this virus, mode of transmission, zoonotic potential, and biological significance are undetermined. PMID- 24807181 TI - Helicobacter cetorum infection in striped dolphin (Stenella coeruleoalba), Atlantic white-sided dolphin (Lagenorhynchus acutus), and short-beaked common dolphin (Delphinus delphus) from the southwest coast of England. AB - Helicobacter infection in cetaceans was first reported from the US in 2000 when the isolation of a novel Helicobacter species was described from two Atlantic white-sided dolphins (Lagenorhynchus acutus). Since then, Helicobacter species have been demonstrated in cetaceans and pinnipeds from around the world. Since 1990, the Animal Health and Veterinary Laboratories Agency Polwhele, Truro, has been involved in the UK Cetacean Strandings Investigation Programme to establish the cause of death of cetacean species stranded along the coast of Cornwall, England. We describe the isolation of Helicobacter cetorum in a striped dolphin (Stenella coeruleoalba) and evidence of H. cetorum infection in cetaceans from European waters. PMID- 24807182 TI - Use of PCR to identify Leptospira in kidneys of big brown bats (Eptesicus fuscus) in Kansas and Nebraska, USA. AB - Bats have been implicated as potential carriers of Leptospira as a result of surveys, mostly in Australia and South America. We measured the prevalence of pathogenic leptospires in kidneys of bats from Kansas and Nebraska. From 7 August 2012 to 21 August 2012, we extracted DNA from kidneys of 98 big brown bats (Eptesicus fuscus) submitted and found negative for rabies. The DNA was processed in a two-step, seminested PCR assay with a dual-labeled Taqman probe specific for pathogenic leptospires. As a negative control, we used a saprophytic leptospire (Leptospira biflexa Patoc) and, as a pathogenic control, Leptospira interrogans Canicola. All bat kidneys were negative for pathogenic leptospires, suggesting that it is unlikely that the big brown bat, one of the most prevalent bat species in North America, is a reservoir for transmission of leptospires to dogs or humans. PMID- 24807183 TI - Acute die-off of chamois (Rupicapra rupicapra) in the Eastern Austrian Alps due to bacterial bronchopneumonia with Pasteurellaceae. AB - Monitoring circulating pathogens in wildlife populations is important in evaluating causes and sources of disease as well as understanding transmission between wild and domestic animals. In spring 2010, a sudden die-off in a chamois (Rupicapra rupicapra) population sharing habitat with livestock occurred in northeastern Austria. Nineteen animals were submitted for examination. Necropsy and pathohistologic and bacteriologic results yielded lesions associated with Pasteurellaceae species. Additional testing included enterobacterial repetitive intergenic consensus and random amplification of polymorphic DNA PCR analysis to evaluate the circulating strains. The isolated strains were most closely related to Mannheimia glucosida and Bibersteinia trehalosi. Reports of mass mortalities in chamois due to pneumonia have been reported previously in the northern Alpine area of Italy. To the authors' knowledge, this is the first report of acute mortality due to strains of Mannheimia and Bibersteinia in Austrian chamois. PMID- 24807184 TI - Recent host range expansion of canine distemper virus and variation in its receptor, the signaling lymphocyte activation molecule, in carnivores. AB - The signaling lymphocyte activation molecule (SLAM) is a receptor for morbilliviruses. To understand the recent host range expansion of canine distemper virus (CDV) in carnivores, we determined the nucleotide sequences of SLAMs of various carnivores and generated three-dimensional homology SLAM models. Thirty-four amino acid residues were found for the candidates binding to CDV on the interface of the carnivore SLAMs. SLAM of the domestic dog (Canis lupus familiaris) were similar to those of other members of the suborder Caniformia, indicating that the animals in this group have similar sensitivity to dog CDV. However, they were different at nine positions from those of felids. Among the nine residues, four of domestic cat (Felis catus) SLAM (72, 76, 82, and 129) and three of lion (Panthera leo persica) SLAM (72, 82, and 129) were associated with charge alterations, suggesting that the felid interfaces have lower affinities to dog CDV. Only the residue at 76 was different between domestic cat and lion SLAM interfaces. The domestic cat SLAM had threonine at 76, whereas the lion SLAM had arginine, a positively charged residue like that of the dog SLAM. The cat SLAM with threonine is likely to have lower affinity to CDV-H and to confer higher resistance against dog CDV. Thus, the four residues (72, 76, 82, and 129) on carnivore SLAMs are important for the determination of affinity and sensitivity with CDV. Additionally, the CDV-H protein of felid strains had a substitution of histidine for tyrosine at 549 of dog CDV-H and may have higher affinity to lion SLAM. Three-dimensional model construction is a new risk assessment method of morbillivirus infectivity. Because the method is applicable to animals that have no information about virus infection, it is especially useful for morbillivirus risk assessment and wildlife conservation. PMID- 24807185 TI - Reptile reservoirs and seasonal variation in the environmental presence of Salmonella in an island ecosystem, Stephens Island, New Zealand. AB - A wide variety of Salmonella serotypes occurs within reptilian hosts, but their ecology is poorly understood. We collected cloacal swabs from tuatara (Sphenodon punctatus), fairy prions (Pachyptila turtur), and skinks (Oligosoma spp.) on Stephens Island, New Zealand, to screen for Salmonella. Soil samples were also collected from inside burrows of tuatara and fairy prions and tested for Salmonella. We sampled repeatedly from October 2009 to October 2011. Cloacal swabs were collected from 620 tuatara, and no intestinal shedding of Salmonella was detected. Similarly, no Salmonella was detected in fairy prions. In contrast, we isolated Salmonella from 6.5% of skinks and 8.4% of soil samples. We identified two serovars of Salmonella from 52 isolates, Salmonella Saintpaul and Salmonella Mississippi. Salmonella Mississippi was isolated from skinks only and S. Saintpaul was found in skinks and soil samples. Salmonella persists in this ecosystem with skinks as the main wildlife reservoir, and an environmental reservoir exists in the soil from burrows used by skinks, tuatara, and fairy prions. Salmonella was absent from skinks and the soil in winter, raising the question of bacteria persisting through winter. PMID- 24807186 TI - Susceptibility to the amphibian chytrid fungus varies with ontogeny in the direct developing frog, Eleutherodactylus coqui. AB - Age-related differences in susceptibility to infectious disease are known from a wide variety of plant and animal taxonomic groups. For example, the immature immune systems of young vertebrates, along with limited prior exposure to pathogens and behavioral factors, can place juveniles at greater risk of acquiring and succumbing to a pathogen. We studied the ontogenetic susceptibility of terrestrial direct-developing frogs (Eleutherodactylus coqui) to the fungal pathogen, Batrachochytrium dendrobatidis (Bd), which is responsible for the decline of amphibian species worldwide. By exposing juvenile and adult frogs to the same dose and strain of Bd, we uncovered ontogenetic differences in susceptibility. Froglets exposed to the pathogen had significantly lower survival rates compared with control froglets, while adult frogs largely cleared infection and had survival rates indistinguishable from control frogs, even when exposed to a much higher dose of Bd. The high disease-induced mortality rate of juveniles may explain ongoing population declines in eastern Puerto Rico, where Bd is endemic and juveniles experience higher prevalence and infection intensity compared to adults. Our results have important implications for understanding and modeling the decline, possibly to extinction, of amphibian populations and species. PMID- 24807187 TI - Oxygen supplementation in anesthetized brown bears (Ursus arctos)-how low can you go? AB - Hypoxemia is anticipated during wildlife anesthesia and thus should be prevented. We evaluated the efficacy of low flow rates of supplemental oxygen for improvement of arterial oxygenation in anesthetized brown bears (Ursus arctos). The study included 32 free-ranging brown bears (yearlings, subadults, and adults; body mass 12-250 kg) that were darted with medetomidine-zolazepam-tiletamine (MZT) from a helicopter in Sweden. During anesthesia, oxygen was administered intranasally from portable oxygen cylinders at different flow rates (0.5-3 L/min). Arterial blood samples were collected before (pre-O2), during, and after oxygen therapy and immediately processed with a portable analyzer. Rectal temperature, respiratory rate, heart rate, and pulse oximetry-derived hemoglobin oxygen saturation were recorded. Intranasal oxygen supplementation at the evaluated flow rates significantly increased the partial pressure of arterial oxygen (PaO2) from pre-O2 values of 9.1 +/- 1.3 (6.3-10.9) kPa to 20.4 +/- 6.8 (11.1-38.7) kPa during oxygen therapy. When oxygen therapy was discontinued, the PaO2 decreased to values not significantly different from the pre-O2 values. In relation to the body mass of the bears, the following oxygen flow rates are recommended: 0.5 L/min to bears <51 kg, 1 L/min to bears 51-100 kg, 2 L/min to bears 101-200 kg, and 3 L/min to bears 201-250 kg. In conclusion, low flow rates of intranasal oxygen were sufficient to improve arterial oxygenation in brown bears anesthetized with MZT. Because hypoxemia quickly recurred when oxygen was discontinued, oxygen supplementation should be provided continuously throughout anesthesia. PMID- 24807188 TI - Consumer assessment of beef palatability from four beef muscles from USDA Choice and Select graded carcasses. AB - Consumer sensory analysis was conducted to determine differences in beef palatability between two quality grade categories [Upper 2/3 (Top) Choice and Select] and four muscles [longissimus lumborum (LL), gluteus medius (GM), serratus ventralis (SV), and semimembranosus (SM)]. Generally, tenderness, flavor, and overall liking scores were more desirable for Top Choice compared to Select, regardless of muscle. Consumers rated LL as more tender (P<0.05) than SV and SM, but similar to GM (P=0.52). Overall and flavor acceptability were similar (P>0.05) between LL, GM, and SV, regardless of quality grade. Consumer overall liking was most highly correlated with flavor liking (r=0.85). When tenderness was acceptable, flavor and juiciness played a major role in determining overall acceptability. Overall liking of GM and SV from Top Choice carcasses was superior to LL from Select carcasses and comparable to LL from Top Choice carcasses. PMID- 24807190 TI - Synthesis and oxygen reduction properties of three-dimensional sulfur-doped graphene networks. AB - Novel three-dimensional sulfur-doped graphene networks were synthesized using an ion-exchange/activation combination method using a 732-type sulfonic acid ion exchange resin as the carbon precursor, which showed high electrocatalytic activity, good stability and excellent methanol tolerance for four-electron oxygen reduction in alkaline solution. PMID- 24807189 TI - Systemic inflammation regulates microglial responses to tissue damage in vivo. AB - Microglia, the resident immune cells of the central nervous system, exist in either a "resting" state associated with physiological tissue surveillance or an "activated" state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under proinflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A , but not A1 or A3 receptors, mediate process retraction in LPS activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders. PMID- 24807191 TI - Effect of non-specific species competition from total RNA on the static mode hybridization response of nanomechanical assays of oligonucleotides. AB - We investigate here the nanomechanical response of microcantilever sensors in real-time for detecting a range of ultra-low concentrations of oligonucleotides in a complex background of total cellular RNA extracts from cell lines without labeling or amplification. Cantilever sensor arrays were functionalized with probe single stranded DNA (ssDNA) and reference ssDNA to obtain a differential signal. They were then exposed to complementary target ssDNA strands that were spiked in a fragmented total cellular RNA background in biologically relevant concentrations so as to provide clinically significant analysis. We present a model for prediction of the sensor behavior in competitive backgrounds with parameters that are indicators of the change in nanomechanical response with variation in the target and background concentration. For nanomechanical assays to compete with current technologies it is essential to comprehend such responses with eventual impact on areas like understanding non-coding RNA pharmacokinetics, nucleic acid biomarker assays and miRNA quantification for disease monitoring and diagnosis to mention a few. Additionally, we also achieved a femtomolar sensitivity limit for online oligonucleotide detection in a non-competitive environment with these sensors. PMID- 24807192 TI - Sirolimus-induced inflammatory lymphoedema of the breast resolved after switching to cyclosporine. PMID- 24807193 TI - Characterization of knee meniscal pathology: correlation of gross, histologic, biochemical, molecular, and radiographic measures of disease. AB - Meniscal pathology is an extremely prevalent problem, which inevitably leads to osteoarthritis and associated pain, swelling, and disability. Relatively little data are available regarding the molecular, biochemical, and histologic aspects of meniscal disease. This study characterizes meniscal pathology in the presence of symptomatic osteoarthritis and correlates clinical and basic science data in an attempt to delineate clinically relevant mechanisms of disease. Twenty-seven knees from 23 patients who underwent total knee arthroplasty comprised the affected group and 6 aged nonsymptomatic knees were used as controls. All meniscal tissues were harvested and subjectively scored for gross and histologic pathology. Biochemical analyses were performed to determine glycosaminoglycan (GAG) content, collagen (hydroxyproline) content, and water content. Real-time polymerase chain reaction analysis was conducted for genes involved in synthesis (collagens [col] 1, 2, 3, and 6), degradation (matrix metalloproteinases [MMP-1, 2, -3, -13]), and angiogenesis (vascular endothelial growth factor). Weight bearing, anterior-posterior radiographic views were used to determine joint space measurements for lateral and medial compartments, and were subjectively scored for osteoarthritic changes. Data were compared for statistically significant differences and to determine the presence and strength of correlations among variables assessed. Affected menisci had significantly higher gross and histologic pathology scores compared with control menisci. Affected menisci had significantly higher water, proteoglycan, and collagen content compared with control menisci. Col 1, 3, and 6 gene expression levels for the affected group were significantly increased compared with controls. MMP-13 expression was significantly increased for the affected group. MMP-2 and -3 expression levels were significantly lower in the affected group compared with controls. The affected group had significantly more joint space narrowing and higher radiographic scores for medial compared with lateral compartments. Several strong and moderately strong correlations were present between variables. These data suggest that in vitro measures of meniscal pathology have potential value for understanding disease mechanisms and predicting clinical disease. PMID- 24807194 TI - Comparison of Efficacy and Tolerability of Hylan G-F 20 in Patients with and without Effusions at the Time of Initial Injection. AB - An effusion at the onset of viscosupplementation has been thought to diminish the efficacy and increase adverse event rates. This study compares efficacy of hylan G-F 20 in patients with and without an effusion. Patients with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. A total of 50 patients with an effusion requiring aspiration were compared with 50 matched patients without an effusion. Outcome measurements included Western Ontario and McMaster's Universities Osteoarthritis index (WOMAC) and visual analog scale (VAS). Patients were followed for 26 weeks. Both effusion and control group VAS was significantly lowered at all time points. WOMAC scores improved (p < 0.025) at all visits in the effusion group except for WOMAC A-1 week 14. Control WOMAC scores also significantly improved at all visits (p < 0.027), except for full WOMAC and WOMAC A-1 at week 1. Neither group experienced an adverse event. Presence of an effusion at onset of viscosupplementation requiring aspiration does not negatively impact efficacy of hylan G-F 20 or increase adverse event rates. PMID- 24807195 TI - Facile spray-coating process for the fabrication of tunable adhesive superhydrophobic surfaces with heterogeneous chemical compositions used for selective transportation of microdroplets with different volumes. AB - In this paper, tunable adhesive superhydrophobic ZnO surfaces have been fabricated successfully by spraying ZnO nanoparticle (NP) suspensions onto desired substrates. We regulate the spray-coating process by changing the mass percentage of hydrophobic ZnO NPs (which were achieved by modifying hydrophilic ZnO NPs with stearic acid) in the hydrophobic/hydrophilic ZnO NP mixtures to control heterogeneous chemical composition of the ZnO surfaces. Thus, the water adhesion on the same superhydrophobic ZnO surface could be effectively tuned by controlling the surface chemical composition without altering the surface morphology. Compared with the conventional tunable adhesive superhydrophobic surfaces, on which there were only three different water sliding angle values: lower than 10 degrees , 90 degrees (the water droplet is firmly pinned on the surface at any tilted angles), and the value between the two ones, the water adhesion on the superhydrophobic ZnO surfaces has been tuned effectively, on which the sliding angle is controlled from 2 +/- 1 degrees to 9 +/- 1 degrees , 21 +/- 2 degrees , 39 +/- 3 degrees , and 90 degrees . Accordingly, the adhesive force can be adjusted from extremely low (~2.5 MUN) to very high (~111.6 MUN). On the basis of the different adhesive forces of the tunable adhesive superhydrophobic surfaces, the selective transportation of microdroplets with different volumes was achieved, which has never been reported before. In addition, we demonstrated a proof of selective transportation of microdroplets with different volumes for application in the droplet-based microreactors via our tunable adhesive superhydrophobic surfaces for the quantitative detection of AgNO3 and NaOH. The results reported herein realize the selective transportation of microdroplets with different volumes and we believe that this method would potentially be used in many important applications, such as selective water droplet transportation, biomolecular quantitative detection and droplet-based biodetection. PMID- 24807197 TI - High incidence of discontinuations due to adverse events in patients treated with ceftaroline. AB - STUDY OBJECTIVE: To determine clinical outcomes in patients who received ceftaroline (Teflaro) 600 mg intravenously every 8 or 12 hours after failing or developing intolerance to first-line agents including vancomycin, daptomycin, or linezolid. DESIGN: Retrospective chart review and review of the literature. SETTING: Large academic medical center and regional Level 1 trauma and burn center. PATIENTS: Twelve patients who received ceftaroline for the treatment of refractory methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus infections between March 2011 and October 2012. MEASUREMENTS AND MAIN RESULTS: Ceftaroline was discontinued in 9 (75%) of 12 patients secondary to adverse effects. The average age of patients who discontinued ceftaroline was 53 years, with a mean body mass index of 29 kg/m(2) and an average of four comorbidities (range one to eight). The median time to discontinuation due to perceived adverse effect was 22 days (range 5-62 days). The reasons for discontinuation of therapy were hematologic toxicities in seven patients and severe rash in two patients. Two patients completed therapy without documented adverse events, and one patient died on day 9 of ceftaroline therapy. CONCLUSION: When given for off-label indications to 12 patients at our institutions, ceftaroline was associated with an unexpectedly high rate (75%) of discontinuation due to perceived adverse events, including hematologic toxicities and rash. PMID- 24807198 TI - MiR-101, downregulated in retinoblastoma, functions as a tumor suppressor in human retinoblastoma cells by targeting EZH2. AB - Accumulating evidence indicates that microRNAs are involved in multiple processes in cancer development and progression, and several miRNAs have emerged as candidate components of oncogene or tumor-suppressor networks in retinoblastoma. miR-101 has been identified as a tumor suppressor in several types of human cancer. However, the specific function of miR-101 in retinoblastoma remains unclear. In the present study, we found that the expression of miR-101 in retinoblastoma tissues was much lower than that in the normal controls. In addition, downregulation of miR-101 more frequently occurred in retinoblastoma specimens with adverse clinicopathological and histopathological features. In addition, miR-101 inhibited cell viability and progression in retinoblastoma cells by promoting cell apoptosis and arresting the cell cycle. Finally, we found that miR-101 directly inhibited EZH2 expression by targeting its 3'-UTR, and EZH2 was upregulated and inversely correlated with miR-101 expression in the retinoblastoma tissues. Thus, for the first time, we provide convincing evidence that downregulation of miR-101 is associated with tumor aggressiveness in retinoblastoma and inhibits cell growth and proliferation of retinoblastoma cells by targeting EZH2. In conclusion, all the evidence supports the tumor-suppressor role of miR-101 in human retinoblastoma. PMID- 24807199 TI - Study of the Ne((3)P2) + CH3F electron-transfer reaction below 1 K. AB - Relatively little is known about the dynamics of electron-transfer reactions at low collision energy. We present a study of Penning ionization of ground-state methyl fluoride molecules by electronically excited neon atoms in the 13 MUeV-4.8 meV (150 mK-56 K) collision energy range, using a neutral-neutral merged beam setup. Relative cross sections have been measured for three Ne((3)P2) + CH3F reaction channels by counting the number of CH3F(+), CH2F(+), and CH3(+) product ions as a function of relative velocity between the neon and methyl fluoride molecular beams. Experimental cross sections markedly deviate from the Langevin capture model at collision energies above 20 K. The branching ratios are constant. In other words, the chemical shape of the CH3F molecule, as seen by the Ne((3)P2) atom, appears not to change as the collision energy is varied, in contrast to related Ne((3)PJ) + CH3X (X = Cl and Br) reactions at higher collision energies. PMID- 24807200 TI - Rapid (18)F-labeling and loading of PEGylated gold nanoparticles for in vivo applications. AB - Water-soluble 3 nm maleimide-terminated PEGylated gold nanoparticles (maleimide AuNP) were synthesized in both partially hydrolyzed and nonhydrolyzed forms. Both of these maleimide-AuNPs, when reacted with the silicon-fluorine prosthetic group [(18)F]SiFA-SH, resulted in radiolabeled AuNPs. These NPs were readily purified with high radiochemical yields (RCY) of 60-80% via size exclusion chromatography. Preliminary small animal positron emission tomography (PET) measurements in healthy rats gives information about the pathway of excretion and the stability of the radioactive label in vivo. The partially hydrolyzed [(18)F]SiFA-maleimide AuNPs shows uptake in the brain region of interest (ROI) (> 0.13%ID/g) which was confirmed by ex vivo examination of the thoroughly perfused rat brain. The multiple maleimide end groups on the AuNP surface also allows for the simultaneous incorporation of [(18)F]SiFA-SH and a bioactive peptide (cysteine modified octreotate, cys-TATE, which can bind to somatostatin receptor subtypes 2 and 5) in a proof-of-concept study. The well-defined Michael addition reaction between various thiol containing molecules and the multifunctionalized maleimide AuNPs thus offers an opportunity to develop a new bioconjugation platform for new diagnostics as well as therapeutics. PMID- 24807201 TI - An order parameter for impurity systems at quantum criticality. AB - A quantum phase transition may occur in the ground state of a system at zero temperature when a controlling field or interaction is varied. The resulting quantum fluctuations which trigger the transition produce scaling behaviour of various observables, governed by universal critical exponents. A particularly interesting class of such transitions appear in systems with quantum impurities where a non-extensive term in the free energy becomes singular at the critical point. Curiously, the notion of a conventional order parameter that exhibits scaling at the critical point is generically missing in these systems. Here we explore the possibility to use the Schmidt gap, which is an observable obtained from the entanglement spectrum, as an order parameter. A case study of the two impurity Kondo model confirms that the Schmidt gap faithfully captures the scaling behaviour by correctly predicting the critical exponent of the dynamically generated length scale at the critical point. PMID- 24807202 TI - Anti-ribosomal P protein antibody: an autoreactivity devoid of prognostic value in patients with autoimmune hepatitis. PMID- 24807203 TI - Nano-optical conveyor belt, part I: Theory. AB - We propose a method for peristaltic transport of nanoparticles using the optical force field over a nanostructured surface. Nanostructures may be designed to produce strong near-field hot spots when illuminated. The hot spots function as optical traps, separately addressable by their resonant wavelengths and polarizations. By activating closely packed traps sequentially, nanoparticles may be handed off between adjacent traps in a peristaltic fashion. A linear repeating structure of three separately addressable traps forms a "nano-optical conveyor belt"; a unit cell with four separately addressable traps permits controlled peristaltic transport in the plane. Using specifically designed activation sequences allows particle sorting. PMID- 24807204 TI - Imaging features of HER2 overexpression in breast cancer: a systematic review and meta-analysis. AB - Breast cancer imaging phenotype is diverse and may relate to molecular alterations driving cancer behavior. We systematically reviewed and meta-analyzed relations between breast cancer imaging features and human epidermal growth factor receptor type 2 (HER2) overexpression as a marker of breast cancer aggressiveness. MEDLINE and EMBASE were searched for mammography, breast ultrasound, magnetic resonance imaging (MRI), and/or [(18)F]fluorodeoxyglucose positron emission tomography studies through February 2013. Of 68 imaging features that could be pooled (85 articles, 23,255 cancers; random-effects meta analysis), 11 significantly related to HER2 overexpression. Results based on five or more studies and robustness in subgroup analyses were as follows: the presence of microcalcifications on mammography [pooled odds ratio (pOR), 3.14; 95% confidence interval (CI), 2.46-4.00] or ultrasound (mass-associated pOR, 2.95; 95% CI, 2.34-3.71), branching or fine linear microcalcifications (pOR, 2.11; 95% CI, 1.07-4.14) or extremely dense breasts on mammography (pOR, 1.37; 95% CI, 1.07 1.76), and washout (pOR, 1.57; 95% CI, 1.11-2.21) or fast initial kinetics (pOR, 2.60; 95% CI, 1.43-4.73) on MRI all increased the chance of HER2 overexpression. Maximum [(18)F]fluorodeoxyglucose standardized uptake value (SUVmax) was higher upon HER2 overexpression (pooled mean difference, +0.76; 95% CI, 0.10-1.42). These results show that several imaging features relate to HER2 overexpression, lending credibility to the hypothesis that imaging phenotype reflects cancer behavior. This implies prognostic relevance, which is especially relevant as imaging is readily available during diagnostic work-up. PMID- 24807205 TI - A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering. AB - A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI. PMID- 24807206 TI - Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model. AB - Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-beta (Abeta) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Abeta pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Abeta species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1 initiated oxidative stress and normalizing memory-related AT4 receptors. PMID- 24807207 TI - Small mitochondrial-targeted RNAs modulate endogenous mitochondrial protein expression in vivo. AB - Endogenous mitochondrial genes encode critical oxidative phosphorylation components and their mutation results in a set of disorders known collectively as mitochondrial encephalomyopathies. There is intensive interest in modulating mitochondrial function as organelle dysfunction has been associated with numerous disease states. Proteins encoded by the mitochondrial genome cannot be genetically manipulated by current techniques. Here we report the development of a mitochondrial-targeted RNA expression system (mtTRES) utilizing distinct non coding leader sequences (NCLs) and enabling in vivo expression of small mitochondrial-targeted RNAs. mtTRES expressing small chimeric antisense RNAs was used as translational inhibitors (TLIs) to target endogenous mitochondrial protein expression in vivo. By utilizing chimeric antisense RNA we successfully modulate expression of two mitochondrially-encoded proteins, ATP6 and COXII, and demonstrate the utility of this system in vivo and in human cells. This technique has important and obvious research and clinical implications. PMID- 24807209 TI - Stress Symptoms Among Adolescent: A Study from Islamic Perspective. AB - Rapid social changes in current times which can be quite abrupt present a challenge to adolescent life. Adolescents who are unable to adapt themselves experience stress which may affect their health. Psychological issues of adolescents require attention because the long-term consequence is worse than the short-term effects, namely, there will be a group of people within society who live under stress. Stressed people show symptoms such as being aggressive, prone to rebel, uncontrollable anger, depression, mental disorders and health problems. Early recognition of adolescent stress symptoms is vital. Pursuant to this, a study is conducted among adolescents in Kajang, Selangor, Malaysia for the purpose of determining whether they experience stress or otherwise, based on stress symptoms in terms of psychology, physiology and social behaviour. An analysis is conducted on 403 respondents who comprise of male and female adolescents aged 16-17 years. The required data are gathered through questionnaire and structured interview. Analysis is based on descriptive statistical method and is explained in a table in terms of frequency, percentage and mode. Research results show that adolescents do experience stress and that the majority of them exhibit psychological stress symptoms. PMID- 24807208 TI - CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila. AB - Aminoacyl-tRNA synthetases are ubiquitously expressed proteins that charge tRNAs with their cognate amino acids. By ensuring the fidelity of protein synthesis, these enzymes are essential for the viability of every cell. Yet, mutations in six tRNA synthetases specifically affect the peripheral nerves and cause Charcot Marie-Tooth (CMT) disease. The CMT-causing mutations in tyrosyl- and glycyl-tRNA synthetases (YARS and GARS, respectively) alter the activity of the proteins in a range of ways (some mutations do not impact charging function, while others abrogate it), making a loss of function in tRNA charging unlikely to be the cause of disease pathology. It is currently unknown which cellular mechanisms are triggered by the mutant enzymes and how this leads to neurodegeneration. Here, by expressing two pathogenic mutations (G240R, P234KY) in Drosophila, we generated a model for GARS-associated neuropathy. We observed compromised viability, and behavioral, electrophysiological and morphological impairment in flies expressing the cytoplasmic isoform of mutant GARS. Their features recapitulated several hallmarks of CMT pathophysiology and were similar to the phenotypes identified in our previously described Drosophila model of YARS-associated neuropathy. Furthermore, CG8316 and CG15599 - genes identified in a retinal degeneration screen to modify mutant YARS, also modified the mutant GARS phenotypes. Our study presents genetic evidence for common mutant-specific interactions between two CMT associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies. PMID- 24807210 TI - Remaining connected despite separation - former family caregivers' experiences of aspects that facilitate and hinder the process of relinquishing the care of a person with dementia to a nursing home. AB - OBJECTIVES: This qualitative study aimed to illuminate former family caregivers' experiences of aspects that facilitate and hinder the process of relinquishing the care of a person with dementia to a nursing home. METHOD: Ten narrative interviews with former family caregivers were performed and subjected to qualitative content analysis. RESULTS: An overall theme showed that family caregivers were remaining connected to the person with dementia despite separation. They experienced being 'caught by surprise' when the placement occurred. Negative expectations of dementia care made the separation more difficult. Lacking adequate information increased feelings of insecurity. Despite these hurdles, family caregivers found meaning in the new situation as they felt that they could remain connected to their loved one. Being recognized as partners in care of the person with dementia after placement was a facilitating aspect. Family caregivers regarded a well-functioning interaction with staff and a supportive social network as reassuring since they facilitated staying in touch. CONCLUSION: Knowledge of the relinquishing process and adequate information about dementia and its progression may help family caregivers better prepare for and adapt to the situation. Family caregivers need to be recognized as partners in care and a welcoming nursing home environment is of utmost importance. PMID- 24807211 TI - Living donor liver transplantation. AB - PURPOSE OF REVIEW: Living donor liver transplantation (LDLT) continues to evolve, generating interesting issues on the applicability and safety of new techniques. RECENT FINDINGS: Specific selection criteria and standardized surgical techniques with high ethical and medical standards are needed to minimize donor risk. In this aspect, minimally invasive donor hepatectomy has caused controversies. The reproducibility and safety of pure laparoscopic major hepatectomy in LDLT remains uncertain. Therefore, a stepwise approach is needed to avoid unnecessary donor risk. To expand the living donor pool, dual graft and ABO-incompatible LDLT have emerged as well tolerated and effective methods. The extended selection criteria for hepatocellular carcinoma in LDLT appear acceptable to balance donor risk and recipient outcome. However, these criteria should be validated based on the risk benefit ratio. Despite technical advances, technical challenges persist such as Budd-Chiari syndrome and portal vein thrombosis. To address these issues, several innovative surgical techniques have been proposed and have shown promising results. SUMMARY: LDLT is associated with donor safety concerns, technical complexity, and small-for-size issues. Nonetheless, accumulated experience and technical know-how from large-volume Asian LDLT centers have led to progress in LDLT. Further technical refinement and investigation to overcome the disadvantages of partial grafts will broaden the applicability of LDLT. PMID- 24807212 TI - Liver transplantation for metastatic liver malignancies. AB - PURPOSE OF REVIEW: Liver transplantation is a validated treatment of primary hepatobiliary tumours. Over the last decade, a renewed interest for liver transplantation as a curative treatment of colorectal liver metastasis (CR-LM) and neuro-endocrine metastasis (NET-LM) has developed. RECENT FINDINGS: The ELTR and UNOS analyses showed that liver transplantation may offer excellent disease free survival (ranging from 30 to 77%) in case of NET-LM, on the condition that stringent selection criteria are implemented. The interest for liver transplantation in the treatment of CR-LM has been fostered by the Norwegian SECA study. Five-year A 5-year survival rate of 60% could be reached. Despite the high recurrence rate (90%), one-third of patients were disease free following pulmonary surgery for metastases. SUMMARY: Liver transplantation will take a more prominent place in the therapeutic algorithm of CR-LM and NET-LM. Larger experiences are necessary to improve knowledge about tumour biology and to refine selection criteria. A multimodal approach adding neo and adjuvant medical treatment to the transplant procedure will be key to bring this oncologic transplant project into the clinical arena. The preserved liver function in these patients will allow a more deliberate access to split liver and living donation for these indications. PMID- 24807213 TI - Updates on acute and chronic rejection in small bowel and multivisceral allografts. AB - PURPOSE OF REVIEW: The surgical management of short bowel syndrome now includes intestinal (ITx) and multivisceral transplantation (MVTx), which has advanced and is now a sustainable option for the treatment of intestinal failure. Improvements in immunosuppressive therapies, excellence in surgical and medical management and enhanced post-transplant monitoring have all contributed to optimizing this solid organ transplant as a means of supplanting the diseased native bowel and alimentary tract with a functional alternative. RECENT FINDINGS: Post-transplant management is a critical and challenging phase of gastrointestinal transplantation, and the transplant pathologist is an essential member of the transplant team who identifies many of the early and late complications after ITx and MVTx. Among the most injurious and common complications of ITx and MVTx is acute rejection and, to a lesser degree, chronic rejection. Both of these broad categories of rejection are principally identified by histopathological changes in the allograft; however, biomarkers and other laboratory analytes are rapidly evolving into critical ancillary tools in identifying and further characterizing the rejection process. Thus, the transplant pathologist must also be able to utilize numerous other laboratory tests and panels of molecular biomarkers that provide supplementary information to accompany the biopsy interpretation and clinical suspicion of rejection. SUMMARY: Using biopsies and an assortment of additional approaches, the transplant pathologist is now able to provide swift and detailed information regarding the rejection process in the gastrointestinal transplant. This enables the clinical team to properly and successfully intercede, contributing to enhanced patient and graft survival. PMID- 24807216 TI - New blue-black nodule in a patient with a history of melanoma. PMID- 24807215 TI - Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer. AB - Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we perform exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumours and 32 cell lines. Meta-analysis of exome data and previously published data sets reveals 24 significantly mutated genes in microsatellite stable (MSS) tumours and 16 in microsatellite instable (MSI) tumours. Over half the patients in our collection could potentially benefit from targeted therapies. We identify 55 splice site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumours. ZAK kinase isoform TV1 is preferentially upregulated in gastric tumours and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder and breast cancers. Overexpression of this particular isoform activates multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibits proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform specific oncogenic properties of ZAK. PMID- 24807217 TI - Factor structure and psychometric properties of english and spanish versions of the edinburgh postnatal depression scale among Hispanic women in a primary care setting. AB - BACKGROUND: Although a number of studies have examined the factor structure of the Edinburgh Postnatal Depression Scale (EPDS) in predominately White or African American samples, no published research has reported on the factor structure among Hispanic women who reside in the United States. OBJECTIVE: The current study examined the factor structure of the EPDS among Hispanic mothers in the United States. METHOD: Among 220 Hispanic women, drawn from a pediatric primary care setting, with an infant aged 0 to 10 months, 6 structural models guided by the empirical literature were evaluated using confirmatory factor analysis. RESULTS: Results supported a 2-factor model of depression and anxiety as the best fitting model. Multigroup models supported the factorial invariance across women who completed the EDPS in English and Spanish. CONCLUSION: These findings provide initial support for the 2-factor structure of the EPDS among Hispanic women in the United States. PMID- 24807218 TI - Obesity corrupts myelopoiesis. AB - Ongoing monocyte infiltration and subsequent macrophage seeding of adipose tissue is thought to be a key feature of obesity pathophysiology. Nagareddy et al. (2014) show that adipose cells locally activate IL-1beta in macrophages in part through the alarmin S100A8/A9, which stimulates bone marrow myelopoiesis to perpetuate nonresolving inflammation. PMID- 24807219 TI - Translating glycolytic metabolism to innate immunity in dendritic cells. AB - Growing evidence supports a role for glycolysis in immune activation. Everts et al. (2014) now show that TLR-mediated stimulation of dendritic cells rapidly induces glycolysis, which regenerates NADPH and TCA intermediates to support fatty acid production. This enhances ER and Golgi membrane synthesis and innate activation of dendritic cells. PMID- 24807220 TI - Knock, knock to reset the clock: mechanosensation and circadian rhythms. AB - Circadian clocks, which underlie the daily rhythms in virtually all organisms, are entrained by diurnal changes in light, temperature, nutrients, and even sound. Simoni et al. (2014) demonstrate that diurnal variation in mechanical vibrations can reset circadian clock phase, providing a potential mechanism for integrating diverse clock-entraining stimuli. PMID- 24807223 TI - Seipin promotes adipose tissue fat storage through the ER Ca2+-ATPase SERCA. AB - Adipose tissue is central to the regulation of lipid metabolism. Berardinelli Seip congenital lipodystrophy type 2 (BSCL2), one of the most severe lipodystrophy diseases, is caused by mutation of the Seipin gene. Seipin plays an important role in adipocyte differentiation and lipid homeostasis, but its exact molecular functions are still unknown. Here, we show that Seipin physically interacts with the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in both Drosophila and man. SERCA, an endoplasmic reticulum (ER) calcium pump, is solely responsible for transporting cytosolic calcium into the ER lumen. Like dSeipin, dSERCA cell-autonomously promotes lipid storage in Drosophila fat cells. dSeipin affects dSERCA activity and modulates intracellular calcium homeostasis. Adipose tissue-specific knockdown of the ER-to-cytosol calcium release channel ryanodine receptor (RyR) partially restores fat storage in dSeipin mutants. Our results reveal that Seipin promotes adipose tissue fat storage by regulating intracellular calcium homeostasis. PMID- 24807224 TI - From systematic to ecological wood anatomy and finally plant hydraulics: are we making progress in understanding xylem evolution? PMID- 24807221 TI - Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice. AB - Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l+/- mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l+/- mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus. PMID- 24807222 TI - Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. AB - Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known regarding the origin of AT macrophages (ATMs). We discovered that murine models of obesity have prominent monocytosis and neutrophilia, associated with proliferation and expansion of bone marrow (BM) myeloid progenitors. AT transplantation conferred myeloid progenitor proliferation in lean recipients, while weight loss in both mice and humans (via gastric bypass) was associated with a reversal of monocytosis and neutrophilia. Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1beta production. IL-1beta interacted with the IL-1 receptor on BM myeloid progenitors to stimulate the production of monocytes and neutrophils. These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1beta signaling axis could reduce AT inflammation and insulin resistance in obesity. PMID- 24807225 TI - What have studies of non-industrialized countries told us about the cause of allergic disease? AB - The increase in allergic diseases that was observed in countries that had experienced rapid economic growth since the mid-20th century initiated a search for environmental exposures that may explain these phenomena that continues to the present day. Societies that are in the earlier stages of the process of industrialization provide an opportunity to compare the initial stages of economic development and the lifestyle changes that may accompany this, with other communities whose way of life may not have changed appreciably for centuries. These studies have consistently demonstrated higher levels of allergic disease in the relatively affluent populations compared with those who maintain a more traditional lifestyle. Environmental changes that have emerged from these studies that may modify the risk of allergic disease include microbial exposures including parasite infection, pollution, diet and obesity. In addition, food and drug allergies represent a neglected area of research in these countries that may be causing a relatively high burden of disease. PMID- 24807226 TI - Metabolic syndrome and chronic kidney disease in an adult Korean population: results from the Korean National Health Screening. AB - BACKGROUND: This study was aimed to examine the prevalence of metabolic syndrome (MS) and chronic kidney disease (CKD), and the association between MS and its components with CKD in Korea. METHODS: We excluded diabetes to appreciate the real impact of MS and performed a cross-sectional study using the general health screening data of 10,253,085 (48.86 +/- 13.83 years, men 56.18%) participants (age, >= 20 years) from the Korean National Health Screening 2011. CKD was defined as dipstick proteinuria >= 1 or an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). RESULTS: The prevalence of CKD was 6.15% (men, 5.37%; women, 7.15%). Further, 22.25% study population had MS (abdominal obesity, 27.98%; hypertriglyceridemia, 30.09%; low high-density cholesterol levels, 19.74%; high blood pressure, 43.45%; and high fasting glucose levels, 30.44%). Multivariate-adjusted analysis indicated that proteinuria risk increased in participants with MS (odds ratio [OR] 1.884, 95% confidence interval [CI] 1.867 1.902, P<0.001). The presence of MS was associated with eGFR<60 mL/min/1.73 m(2) (OR 1.364, 95% CI 1.355-1.373, P<0.001). MS individual components were also associated with an increased CKD risk. The strength of association between MS and the development of CKD increase as the number of components increased from 1 to 5. In sub-analysis by men and women, MS and its each components were a significant determinant for CKD. CONCLUSIONS: MS and its individual components can predict the risk of prevalent CKD for men and women. PMID- 24807228 TI - Assessment of neuromuscular risk factors for anterior cruciate ligament injury through tensiomyography in male soccer players. AB - PURPOSE: To investigate the role of mechanical and contractile properties of skeletal muscles of the thigh, assessed through tensiomyography (TMG), as risk factors for anterior cruciate ligament (ACL) injury in male soccer players. METHODS: Male soccer players with confirmed ACL tear included in this study underwent resting TMG assessment of thigh muscles of the uninjured side. The same values were obtained from a sex-, sports level-matched control group in both sides. The maximal displacement (Dm), delay time (Td), contraction time (Tc), sustained time (Ts), and half-relaxation time (Tr) were obtained for the following muscles in all subjects: vastus medialis (VM), vastus laterals (VL), rectus femoris (RF), semitendinosus (ST), and biceps femoris (BF). TMG values of the uninjured side in ACL-injured group were compared to mean values between both sides in the control subjects. RESULTS: There were 40 ACL-injured and 38 control individuals. The vast majority of TMG parameters were higher in the uninjured side of ACL-injured individuals compared to the control group. The VL-Tr, RF-Tc, RF-Ts, RF-Tr, and BF-Dm values were significantly higher in the uninjured side compared to the control group. Quadriceps muscles demonstrated more significant between-group differences than hamstring muscles. Specifically, RF was the muscle where most significant between-group differences were found. CONCLUSIONS: Resistance to fatigue and muscle stiffness in the hamstring muscles may be risk factors for ACL injury in male soccer players. In addition, a predominant impairment in TMG characteristics of the quadriceps over hamstrings may indicate an altered muscular co-contraction (imbalance) between both muscle groups, which might be another risk factor for ACL injury in this population. These findings should be taken into account when screening athletes at high risk of ACL injury and also to design adequate prevention programs for ACL injury in male soccer players. PMID- 24807229 TI - A validated cadaveric model of trochlear dysplasia. AB - PURPOSE: Despite the high prevalence of trochlear dysplasia among patients with patellar instability, it is not well studied and is infrequently addressed surgically. The lack of a validated cadaveric model of trochlear dysplasia may be a contributing factor. The goal of this study was to develop a simple, reproducible, and realistic cadaveric model of trochlear dysplasia by surgically modifying cadaveric femora with normal anatomy and then to validate this model through the use of mechanical and fluoroscopic measurements. METHODS: The floor of the trochlear groove was surgically elevated using an inflatable bone tamp in eight cadaveric femora. The trochlear depth (TD) was measured with a custom designed measuring device, and radiographic markers of dysplasia (sulcus angle, crossing sign, and prominence) were assessed before and after surgical modification. RESULTS: The average TD was 3.6+/-1.4, 4.6+/-1.1, and 5.1+/-1.0 mm prior to reverse trochleoplasty (RT) and 1.0+/-1.8, 2.3+/-1.3, and 3.3+/-2.5 mm following RT at 0 degrees , 20 degrees , and 40 degrees of flexion, respectively. These direct measurements of TD were confirmed with fluoroscopy. The sulcus angle averaged 141 degrees prior to RT and 157 degrees after RT. The average prominence across all specimens was 3.3+/-0.7 mm before RT, and 5.5+/-1.5 mm after RT. Finally, the crossing sign was found to be absent in all knees prior to RT and present in 7 of the 8 after RT. CONCLUSIONS: The results of this study show that elevation of the trochlear floor with an inflatable bone tamp can reproducibly create a simulated dysplastic trochlea. This model may be useful in biomechanical studies of treatments for patellofemoral instability. PMID- 24807230 TI - Cartilage status in knees with recurrent patellar instability using magnetic resonance imaging T2 relaxation time value. AB - PURPOSE: The purpose of the study was to analyse the patellar status in patients with recurrent patellar instability and in healthy controls using magnetic resonance imaging (MRI). METHODS: One hundred and thirteen patients with patellar instability (patellar instability group) and 50 healthy controls (control group) were studied. All patients underwent computed tomography (CT) to measure the patellofemoral joint anatomy. Meanwhile, MRI was used to investigate cartilage status and to determine the T2 relaxation time value of the patellar cartilage plate. The mean values of these parameters for the patellar instability group and the control group were compared. RESULTS: The CT images of the patellar instability group revealed greatly abnormal anatomy of the patellofemoral joint compared with the control group. By MRI assessment, 32 patients were determined to have a cartilage defect, which was confirmed under arthroscopy. Among the other 81 patients, the T2 relaxation time value of the patellar instability group was significantly higher than that of the control group on the middle (p = 0.032) or medial sites (p = 0.041) of the patellar cartilage. CONCLUSIONS: The patellar instability group exhibits a higher risk of cartilage lesions with abnormal patellofemoral joint anatomy. MRI may enable early detection of these cartilage defects within the patellofemoral joint, enabling clinicians to adopt strategies to delay or prevent cartilage degeneration. LEVEL OF EVIDENCE: III. PMID- 24807231 TI - Safety and efficiency of posterior arthroscopic ankle arthrodesis. AB - PURPOSE: To study the safety and efficiency of posterior arthroscopic ankle arthrodesis. METHODS: Ten fresh-frozen human lower leg specimens without evidence of previous surgery to the foot and ankle were selected. Arthroscopic debridement of the tibiotalar joint was performed in all specimens using a standardized protocol. Anatomical dissections were regarded the gold standard for safety analysis. To evaluate the efficacy of the posterior ankle arthroscopic arthrodesis, the debrided articular tibiotalar parts were resected and subsequently analysed using Image-analysis software, Image J (Wayne Rasband, National Institutes of Health, Bethesda, MD). RESULTS: In none of the specimens, iatrogenic damage was detected during the anatomical dissection following the posterior ankle arthroscopic procedure. A total talar joint surface area of 95 % and total tibial joint surface area of 96 % was addressed during the arthroscopic debridement. CONCLUSIONS: The posterior ankle arthroscopic arthrodesis can be regarded safe and is also highly effective in the debridement of cartilage, resulting in optimal biology for fusion to occur. Therefore, this new arthroscopic technique potentially will diminish existing non-union rates for the fusion of the ankle joint. PMID- 24807232 TI - Prevention and treatment of injection-related endophthalmitis. AB - BACKGROUND: Intravitreal injections are the fastest growing cause of endophthalmitis and can result in severe vision loss. The prevention, diagnosis and management of such infections remain unclear and at times controversial. METHODS: We searched Pubmed for keywords "prophylaxis," "endophthalmitis," "intravitreal injection." We focused on studies published in the last 2 years as well as other recent studies with particular attention to data on the incidence, microbiology, prevention, and treatment of injection-related endophthalmitis. RESULTS: Over 20 relevant studies were found. With povidone-iodine preparation, the per-injection endophthalmitis rate is low at about 0.03%. Antibiotics do not appear to be beneficial for prevention of post-injection endophthalmitis. The best timing of vitrectomy is unclear. CONCLUSIONS: Antibiotic prophylaxis is probably not needed when giving intravitreal injections. More data is needed to help determine the proper treatment for post-injection endophthalmitis. PMID- 24807233 TI - Unusual large uniocular elastoid and collagenous pinguecula. PMID- 24807234 TI - The association between stunting and psychosocial development among preschool children: a study using the South African Birth to Twenty cohort data. AB - BACKGROUND: A large literature in developing countries finds a strong association between stunting in early childhood and educational attainment and/or cognitive performance among children of school-going age. We contribute to the literature on the effects of stunting in childhood by exploring the links between linear growth retardation and measures of development among preschool-aged children. METHODS: We analyse the association between stunting (height-for-age z-score <-2) at age 2 years and children's scores on the Vineland Social Maturity Scale (VSMS) at age 4 years, a measure of social competence or 'daily living skills', and the Revised-Denver Prescreening Developmental Questionnaire (R-DPDQ) at age 5 years, a test which places greater emphasis on cognitive functioning. The sample is drawn from the Birth to Twenty cohort study, a prospective dataset of children born in 1990 in urban South Africa. We conduct multivariate regression analysis controlling for socio-economic status, various child-specific characteristics, home environment and caregiver inputs. RESULTS: No significant association between stunting and children's performance on the VSMS, but a large and significant association with the R-DPDQ scores, was found. A disaggregated analysis of the various components of the scores suggests that children with low height-for-age at 2 years do not fall behind in terms of daily living skills or social maturity, but do substantially worse on measures capturing higher order fine motor skills and cognitive functioning. CONCLUSIONS: Stunting in early childhood is strongly related to impaired cognitive functioning in children of preschool age, but does not seem to affect social maturity, at least as measured by the VSMS. These relationships between stunting at 2 years and psychosocial development at 4 and 5 years hold with extensive controls for socio-economic status, home environment, caregiver inputs and child characteristics included in the multivariate analysis. PMID- 24807235 TI - Postural orthostatic tachycardia syndrome: additional phenotypic feature of neuromyelitis optica spectrum disorder. PMID- 24807236 TI - US diagnosis of sciatic nerve tumor proximal to gluteal fold. PMID- 24807237 TI - Expanding primary care capacity to treat hepatitis C virus infection through an evidence-based care model--Arizona and Utah, 2012-2014. AB - Hepatitis C virus (HCV) infection is the leading reason for liver transplantation and a common cause of hepatocellular carcinoma, the most rapidly increasing cause of cancer-related deaths in the United States. Of the approximately 3 million persons living with HCV infection in the United States, an estimated 38% are linked to care, 11% are treated, and 6% achieve cure. Recent development of highly effective and well-tolerated medications, such as sofosbuvir and simeprevir, to treat chronic HCV infection shows promise in curbing rising HCV related morbidity and mortality, with the potential to cure >90% of patients. To fully benefit from these new treatments, improvement in linkage to care and treatment is urgently needed.* Lack of provider expertise in HCV treatment and limited access to specialists are well-documented barriers to HCV treatment. In September 2012, CDC funded programs in Utah and Arizona to improve access to primary care providers with the capacity to manage and treat HCV infection. Both programs were modeled on the Extension for Community Healthcare Outcomes (Project ECHO), developed by the University of New Mexico's Health Sciences Center in 2003 to build primary care capacity to treat diseases among rural, underserved populations through videoconferencing and case-based learning in "teleECHO" clinics. To assess the effectiveness of these programs in improving primary care provider capacity and increasing the number of patients initiating treatment, process and patient outcome data for each state program were analyzed. In both states, Project ECHO was successfully implemented, training 66 primary care clinicians, predominantly from rural settings. Nearly all (93%) of the clinicians had no prior experience in care and treatment of HCV infection. In both states combined, 129 (46%) of HCV-infected patients seen in teleECHO clinics received antiviral treatment, more than doubling the proportion of patients expected to receive treatment. These findings demonstrate Project ECHO's ability to expand primary care capacity to treat HCV infection, notably among underserved populations. PMID- 24807238 TI - Early identification and linkage to care of persons with chronic hepatitis B virus infection--three U.S. sites, 2012-2014. AB - In the United States, an estimated 0.8-1.4 million persons are living with chronic hepatitis B virus (HBV) infection. Among these persons, as many as 70% were born in countries of Asia, Africa, or other regions where HBV is moderately or highly endemic (hepatitis B surface antigen [HBsAg] prevalence >=2%). HBV associated cirrhosis and liver cancer are major health problems for these populations. Most persons with HBV were infected at birth or during early childhood and are asymptomatic until advanced liver disease develops. To address these concerns, CDC recommends HBsAg testing for all persons born in these areas and linkage to medical care and preventive services for those who are infected. In 2012, CDC awarded funds to nine sites to implement this recommendation. This report describes programs at three sites (New York, New York; Minneapolis-St. Paul, Minnesota; and San Diego, California) that conducted HBV testing, in clinical or community settings, and referred for medical evaluation and care those persons whose HBsAg test results were positive. During October 2012-March 2014, the three sites tested 4,727 persons for HBV infection; 310 (6.6%) were HBsAg-positive. Among the HBsAg-positive persons, 94% were informed of their results, 90% were counseled, 86% were referred for care, and 66% attended their scheduled first medical visit. These projects demonstrate that community-based programs can identify infected persons among populations with a high prevalence of HBV infection and refer HBsAg-positive persons for care. Individualized efforts to assist patients with accessing and receiving health-care services ("patient navigation services") can increase the number of persons who follow up on referrals and receive recommended care. PMID- 24807239 TI - Primary and secondary syphilis--United States, 2005-2013. AB - In 2013, based on data reported as of April 28, 2014, the rate of reported primary and secondary syphilis in the United States was 5.3 cases per 100,000 population, more than double the lowest-ever rate of 2.1 in 2000. To characterize the recent epidemiology of syphilis in the United States, CDC analyzed data from the National Notifiable Diseases Surveillance System (NNDSS) for cases of primary and secondary syphilis diagnosed during 2005-2013 with a focus on states that reported the sex of sex partners during 2009-2012 to describe reported syphilis among gay, bisexual, and other men who have sex with men (collectively referred to as MSM). During 2005-2013, primary and secondary syphilis rates increased among men of all ages and races/ethnicities across all regions of the United States. Recent years have shown an accelerated increase in the number of cases, with the largest increases occurring among MSM. Among women, rates increased during 2005-2008 and decreased during 2009-2013, with different trends among different racial/ethnic groups. Racial/ethnic disparities in reported syphilis persisted during 2005-2013, likely reflecting social determinants of health, such as socioeconomic status, that might contribute to the burden of syphilis in a community. These findings underscore the need for continued syphilis prevention measures among MSM. PMID- 24807240 TI - Vital signs: disability and physical activity--United States, 2009-2012. AB - BACKGROUND: Adults with disabilities are less active and have higher rates of chronic disease than the general population. Given the health benefits of physical activity, understanding physical activity, its relationship with chronic disease, and health professional recommendations for physical activity among young to middle-age adults with disabilities could help increase the effectiveness of health promotion efforts. METHODS: Data from the 2009-2012 National Health Interview Survey (NHIS) were used to estimate the prevalence of, and association between, aerobic physical activity (inactive, insufficiently active, or active) and chronic diseases (heart disease, stroke, diabetes, and cancer) among adults aged 18-64 years by disability status and type (hearing, vision, cognitive, and mobility). The prevalence of, and association between, receiving a health professional recommendation for physical activity and level of aerobic physical activity was assessed using 2010 data. RESULTS: Overall, 11.6% of U.S. adults aged 18-64 years reported a disability, with estimates for disability type ranging from 1.7% (vision) to 5.8% (mobility). Compared with adults without disabilities, inactivity was more prevalent among adults with any disability (47.1% versus 26.1%) and for adults with each type of disability. Inactive adults with disabilities were 50% more likely to report one or more chronic diseases than those who were physically active. Approximately 44% of adults with disabilities received a recommendation from a health professional for physical activity in the past 12 months. CONCLUSIONS: Almost half of adults with disabilities are physically inactive and are more likely to have a chronic disease. Among adults with disabilities who visited a health professional in the past 12 months, the majority (56%) did not receive a recommendation for physical activity. IMPLICATIONS FOR PUBLIC HEALTH: These data highlight the need for increased physical activity among persons with disabilities, which might require support across societal sectors, including government and health care. PMID- 24807241 TI - Therapy of HIV-associated lymphoma-recommendations of the oncology working group of the German Study Group of Physicians in Private Practice Treating HIV-Infected Patients (DAGNA), in cooperation with the German AIDS Society (DAIG). AB - AIDS-related aggressive B cell lymphoma (HIV-NHL) is the second most common HIV associated malignancy. In contrast, Hodgkin-lymphoma (HL) is one of the most common non-AIDS-defining malignancies. Current evidence-based recommendations for the treatment of HIV-associated lymphoma (HIV-lymphoma) are not available. A panel of experts in the field of HIV-related lymphoma performed literature searches of the PubMed, Medline, and Cochrane databases. The consensus process was carried out as an e-mail and meeting-based discussion group. Six cycles of R CHOP or R-EPOCH are standard of care for patients (pts) with diffuse large B cell lymphoma (DLBCL). Pts with Burkitt lymphoma and good performance status should receive dose-intensive regimens such as the GMALL B-ALL/NHL protocol. Standard therapy has not been defined for pts with plasmablastic and primary effusion lymphoma. Pts with lymphoma in sensitive relapse should receive high-dose chemotherapy followed by autologous stem cell transplantation. Stage- and risk adapted treatment yields high remission and survival rates in pts with HIV-HL similar to those achieved in HIV-negative HL pts. Combination antiretroviral therapy (cART) should be applied concurrently to chemotherapy provided that pharmacokinetic interactions are being considered. Pts with HIV-lymphoma should usually be treated in an identical manner to HIV-negative patients. PMID- 24807242 TI - Decontamination of materials contaminated with Francisella philomiragia or MS2 bacteriophage using PES-Solid, a solid source of peracetic acid. AB - AIM: The aim of the study was to develop test methods and evaluate survival of Francisella philomiragia cells and MS2 bacteriophage after exposure to PES-Solid (a solid source of peracetic acid) formulations with or without surfactants. METHODS AND RESULTS: Francisella philomiragia cells (>=7.6 log10 CFU) or MS2 bacteriophage (>=6.8 log10 PFU) were deposited on seven different test materials and treated with three different PES-Solid formulations, three different preneutralized samples and filter controls at room temperature for 15 min. There were 0-1.3 log10 CFU (<20 cells) of cell survival, or 0-1.7 log10 (<51 PFU) of bacteriophage survival in all 21 test combinations (organism, formulation and substrate) containing reactive PES-Solid. In addition, the microemulsion (Dahlgren Surfactant System) showed <=2 log10 (100 cells) of viable F. philomiragia cells, indicating the microemulsion achieved <2 log10 CFU on its own. CONCLUSIONS: Three PES-Solid formulations and one microemulsion system (DSS) inactivated F. philomiragia cells and/or MS2 bacteriophage that were deposited on seven different materials. SIGNIFICANCE AND IMPACT OF THE STUDY: A test method was developed to show that reactive PES-Solid formulations and a microemulsion system (DSS) inactivated >6 log10 CFU/PFU F. philomiragia cells and/or MS2 bacteriophage on different materials. PMID- 24807243 TI - Temporal course of neointimal hyperplasia following drug-eluting stent implantation: a serial follow-up optical coherence tomography analysis. AB - We sought to evaluate the temporal course of neointimal hyperplasia (NIH) after drug-eluting stent (DES) implantation, using serial optical coherence tomography (OCT). We identified 89 DES (82 patients) that had at least three consecutive cross-sections with a mean NIH thickness >100 um on first follow-up OCT. Qualitative and quantitative changes in NIH were then assessed at a second follow up OCT. NIH regression and progression were defined as a decrease or increase in mean NIH cross-sectional area >0.2 mm2, respectively, between the two studies. Between the first and second OCT there was a decrease in NIH in 29 lesions (32.6%), and an increase in NIH in 37 lesions (41.6%). Compared to patients with neointimal progression, those with regression showed lower levels of high sensitivity C-reactive protein (hsCRP) (p = 0.036) and higher levels of high density lipoprotein (p = 0.012). Between the first and the second OCT, there were no significant changes in NIH morphologic patterns in 67 (75.3%) of 89 DES. In lesions with NIH regression, the evolution of heterogeneous to homogeneous neointima was observed, while the evolution of heterogeneous or homogeneous to layered neointima or the evolution of heterogeneous, homogeneous, or layered neointima to neoatherosclerosis was detected in lesions with NIH progression (p < 0.001). The hsCRP level at index procedure was significantly associated with neointimal regression in multivariate model (odds ratio 0.891, 95% confidence interval 0.796-0.999, p = 0.048). During late follow-up, OCT shows both NIH progression and regression that are paralleled by qualitative changes indicating increasing stability (in regression) and increasing instability (in progression). PMID- 24807246 TI - The use of heterogeneous chemistry for the characterization of functional groups at the gas/particle interface of soot from a diesel engine at a particular running condition. AB - Two gases, O3 and NO2, were selected to probe the surface of a diesel fuel combustion aerosol sample, diesel soot, and amorphous carbon nanoparticles (PRINTEX XE2-B) using heterogeneous (i.e., gas-surface reactions). The gas uptake to saturation of the probes was measured under molecular flow conditions using a Knudsen flow reactor in order to quantify and characterize surface functional groups. Specifically, O3 and NO2 are used for the titration of oxidizable groups. Diesel soot samples interacted with the probe gases to various extents which points to the coexistence of different functional groups on the same aerosol surface such as reduced groups. The carbonaceous particles displayed significant differences: PRINTEX XE2-B amorphous carbon had a significantly lower surface functional group density of both total and strongly reducing groups despite its significantly larger internal surface area, compared to diesel soot. The uptake kinetics of the gas-phase probe molecules (uptake probabilities) were also measured in order to obtain further information on the reactivity of emitted soot aerosols in order to enable the potential prediction of health effects. PMID- 24807244 TI - Estradiol regulation of constitutive and keratinocyte growth factor-induced CCL20 and CXCL1 secretion by mouse uterine epithelial cells. AB - PROBLEM: Estradiol can directly affect epithelial cells or indirectly affect epithelial cells via stromal fibroblast secretion of growth factors, such as keratinocyte growth factor (KGF). The purpose of the present study was to determine whether estradiol regulates constitutive as well as KGF-induced uterine epithelial cell secretion of CCL20 and CXCL1. METHOD OF STUDY: Freshly isolated and polarized uterine epithelial cells from Balb/c mice were cultured with estradiol in the presence or absence of KGF. CCL20 and CXCL1 were measured by ELISA. RESULTS: Estradiol inhibited CCL20 secretion by freshly isolated and polarized uterine epithelial cells in the presence or absence of KGF. Unexpectedly, it enhanced KGF-induced CXCL1 secretion beyond that seen with KGF alone. Estradiol increased CXCL1 secretion at 24 hr and inhibited CCL20 at 48 hr. The effects of estradiol are specific in that progesterone, cortisol, dihydrotestosterone, and aldosterone had no effect on either CCL20 or CXCL1 secretion. The inhibitory effect of estradiol on CCL20 secretion was reversed with ICI 182,780, an estrogen receptor antagonist, indicating that this effect is estrogen receptor mediated. CONCLUSIONS: Our data indicate that estradiol is important in regulating the effects of KGF on mouse uterine epithelial cell secretion of CCL20 and CXCL1. PMID- 24807247 TI - Assessing host extinction risk following exposure to Batrachochytrium dendrobatidis. AB - Wildlife diseases are increasingly recognized as a major threat to biodiversity. Chytridiomycosis is an emerging infectious disease of amphibians caused by the fungus Batrachochytrium dendrobatidis (Bd). Using a mathematical model and simulations, we study its effects on a generic riparian host population with a tadpole and adult life stage. An analytical expression for the basic reproduction quotient, Qo, of the pathogen is derived. By sampling the entire relevant parameter space, we perform a statistical assessment of the importance of all considered parameters in determining the risk of host extinction, upon exposure to Bd. We find that Qo not only gives a condition for the initial invasion of the fungus, but is in fact the best predictor for host extinction. We also show that the role of tadpoles, which in some species tolerate infections, is ambivalent. While tolerant tadpoles may provide a reservoir for the fungus, thus facilitating its persistence or even amplifying its outbreaks, they can also act as a rescue buffer for a stressed host population. Our results have important implications for amphibian conservation efforts. PMID- 24807249 TI - Domestic dogs and puppies can use human voice direction referentially. AB - Domestic dogs are particularly skilled at using human visual signals to locate hidden food. This is, to our knowledge, the first series of studies that investigates the ability of dogs to use only auditory communicative acts to locate hidden food. In a first study, from behind a barrier, a human expressed excitement towards a baited box on either the right or left side, while sitting closer to the unbaited box. Dogs were successful in following the human's voice direction and locating the food. In the two following control studies, we excluded the possibility that dogs could locate the box containing food just by relying on smell, and we showed that they would interpret a human's voice direction in a referential manner only when they could locate a possible referent (i.e. one of the boxes) in the environment. Finally, in a fourth study, we tested 8-14-week-old puppies in the main experimental test and found that those with a reasonable amount of human experience performed overall even better than the adult dogs. These results suggest that domestic dogs' skills in comprehending human communication are not based on visual cues alone, but are instead multi modal and highly flexible. Moreover, the similarity between young and adult dogs' performances has important implications for the domestication hypothesis. PMID- 24807248 TI - The oxidative environment: a mediator of interspecies communication that drives symbiosis evolution. AB - Symbiotic interactions are ubiquitous in nature and play a major role in driving the evolution of life. Interactions between partners are often mediated by shared signalling pathways, which strongly influence both partners' biology and the evolution of the association in various environments. As an example of 'common language', the regulation of the oxidative environment plays an important role in driving the evolution of symbiotic associations. Such processes have been occurring for billions of years, including the increase in Earth's atmospheric oxygen and the subsequent evolution of mitochondria. The effect of reactive oxygen species and reactive nitrogen species (RONS) has been characterized functionally, but the molecular dialogue between partners has not been integrated within a broader evolutionary context yet. Given the pleiotropic role of RONS in cell-cell communication, development and immunity, but also their associated physiological costs, we discuss here how their regulation can influence the establishment, the maintenance and the breakdown of various symbiotic associations. By synthesizing recent developments in redox biology, we aim to provide an interdisciplinary understanding of the influence of such mediators of interspecies communication on the evolution and stability of symbioses, which in turn can shape ecosystems and play a role in health and disease. PMID- 24807250 TI - Parallel responses of bees to Pleistocene climate change in three isolated archipelagos of the southwestern Pacific. AB - The impacts of glacial cycles on the geographical distribution and size of populations have been explored for numerous terrestrial and marine taxa. However, most studies have focused on high latitudes, with only a few focused on the response of biota to the last glacial maximum (LGM) in equatorial regions. Here, we examine how population sizes of key bee fauna in the southwest Pacific archipelagos of Fiji, Vanuatu and Samoa have fluctuated over the Quaternary. We show that all three island faunas suffered massive population declines, roughly corresponding in time to the LGM, followed by rapid expansion post-LGM. Our data therefore suggest that Pleistocene climate change has had major impacts across a very broad tropical region. While other studies indicate widespread Holarctic effects of the LGM, our data suggest a much wider range of latitudes, extending to the tropics, where these climate change repercussions were important. As key pollinators, the inferred changes in these bee faunas may have been critical in the development of the diverse Pacific island flora. The magnitude of these responses indicates future climate change scenarios may have alarming consequences for Pacific island systems involving pollinator-dependent plant communities and agricultural crops. PMID- 24807251 TI - Testing synaptic plasticity in dynamic mate choice decisions: N-methyl D aspartate receptor blockade disrupts female preference. AB - Social behaviours such as mate choice require context-specific responses, often with evolutionary consequences. Increasing evidence indicates that the behavioural plasticity associated with mate choice involves learning. For example, poeciliids show age-dependent changes in female preference functions and express synaptic-plasticity-associated molecular markers during mate choice. Here, we test whether social cognition is necessary for female preference behaviour by blocking the central player in synaptic plasticity, NMDAR (N-methyl d-aspartate receptor), in a poeciliid fish, Xiphophorus nigrensis. After subchronic exposure to NMDAR antagonist MK-801, female preference behaviours towards males were dramatically reduced. Overall activity levels were unaffected, but there was a directional shift from 'social' behaviours towards neutral activity. Multivariate gene expression patterns significantly discriminated between females with normal versus disrupted plasticity processes and correlated with preference behaviours-not general activity. Furthermore, molecular patterns support a distinction between 'preference' (e.g. neuroserpin, neuroligin-3, NMDAR) and 'sociality' (isotocin and vasotocin) gene clusters, highlighting a possible conservation between NMDAR disruption and nonapeptides in modulating behaviour. Our results suggest that mate preference may involve greater social memory processing than overall sociality, and that poeciliid preference functions integrate synaptic-plasticity-oriented 'preference' pathways with overall sociality to invoke dynamic, context-specific responses towards favoured males and away from unfavoured males. PMID- 24807252 TI - Typical versions of learned swamp sparrow song types are more effective signals than are less typical versions. AB - The learned songs of songbirds often cluster into population-wide types. Here, we test the hypothesis that male and female receivers respond differently to songs depending on how typical of those types they are. We used computational methods to cluster a large sample of swamp sparrow (Melospiza georgiana) songs into types and to estimate the degree to which individual song exemplars are typical of these types. We then played exemplars to male and female receivers. Territorial males responded more aggressively and captive females performed more sexual displays in response to songs that are highly typical than to songs that are less typical. Previous studies have demonstrated that songbirds distinguish song types that are typical for their species, or for their population, from those that are not. Our results show that swamp sparrows also discriminate typical from less typical exemplars within learned song-type categories. In addition, our results suggest that more typical versions of song types function better, at least in male-female communication. This finding is consistent with the hypothesis that syllable type typicality serves as a proxy for the assessment of song learning accuracy. PMID- 24807253 TI - Sexual conflict over mating in Gnatocerus cornutus? Females prefer lovers not fighters. AB - Female mate choice and male-male competition are the typical mechanisms of sexual selection. However, these two mechanisms do not always favour the same males. Furthermore, it has recently become clear that female choice can sometimes benefit males that reduce female fitness. So whether male-male competition and female choice favour the same or different males, and whether or not females benefit from mate choice, remain open questions. In the horned beetle, Gnatocerus cornutus, males have enlarged mandibles used to fight rivals, and larger mandibles provide a mating advantage when there is direct male-male competition for mates. However, it is not clear whether females prefer these highly competitive males. Here, we show that female choice targets male courtship rather than mandible size, and these two characters are not phenotypically or genetically correlated. Mating with attractive, highly courting males provided indirect benefits to females but only via the heritability of male attractiveness. However, mating with attractive males avoids the indirect costs to daughters that are generated by mating with competitive males. Our results suggest that male-male competition may constrain female mate choice, possibly reducing female fitness and generating sexual conflict over mating. PMID- 24807254 TI - Can environmental conditions experienced in early life influence future generations? AB - The consequences of early developmental conditions for performance in later life are now subjected to convergent interest from many different biological sub disciplines. However, striking data, largely from the biomedical literature, show that environmental effects experienced even before conception can be transmissible to subsequent generations. Here, we review the growing evidence from natural systems for these cross-generational effects of early life conditions, showing that they can be generated by diverse environmental stressors, affect offspring in many ways and can be transmitted directly or indirectly by both parental lines for several generations. In doing so, we emphasize why early life might be so sensitive to the transmission of environmentally induced effects across generations. We also summarize recent theoretical advancements within the field of developmental plasticity, and discuss how parents might assemble different 'internal' and 'external' cues, even from the earliest stages of life, to instruct their investment decisions in offspring. In doing so, we provide a preliminary framework within the context of adaptive plasticity for understanding inter-generational phenomena that arise from early life conditions. PMID- 24807255 TI - Is discrimination enhanced at the boundaries of perceptual categories? A negative case. AB - The human visual system imposes discrete perceptual categories on the continuous input space that is represented by the ratios of excitations of the cones in the retina. Is discrimination enhanced at the boundaries between perceptual hues, in the way that discrimination may be enhanced at the boundaries between speech sounds in hearing? In the chromaticity diagram, the locus of unique green separates colours that appear yellowish from those that appear bluish. Using a two-alternative spatial forced choice and an adapting field equivalent to the Daylight Illuminant D65, we measured chromatic discrimination along lines orthogonal to the locus of unique green. In experimental runs interleaved with these performance measurements, we obtained estimates of the phenomenological boundary from the same observers. No enhancement of objectively measured discrimination was observed at the category boundary between yellowish and bluish hues. Instead, thresholds were minimal at chromaticities where the ratio of long wave to middle-wave cone excitation was the same as that for the background adapting field. PMID- 24807256 TI - A cross-culture, cross-gender comparison of perspective taking mechanisms. AB - Being able to judge another person's visuo-spatial perspective is an essential social skill, hence we investigated the generalizability of the involved mechanisms across cultures and genders. Developmental, cross-species, and our own previous research suggest that two different forms of perspective taking can be distinguished, which are subserved by two distinct mechanisms. The simpler form relies on inferring another's line-of-sight, whereas the more complex form depends on embodied transformation into the other's orientation in form of a simulated body rotation. Our current results suggest that, in principle, the same basic mechanisms are employed by males and females in both, East-Asian (EA; Chinese) and Western culture. However, we also confirmed the hypothesis that Westerners show an egocentric bias, whereas EAs reveal an other-oriented bias. Furthermore, Westerners were slower overall than EAs and showed stronger gender differences in speed and depth of embodied processing. Our findings substantiate differences and communalities in social cognition mechanisms across genders and two cultures and suggest that cultural evolution or transmission should take gender as a modulating variable into account. PMID- 24807258 TI - The use of network analysis to study complex animal communication systems: a study on nightingale song. AB - The singing of song birds can form complex signal systems comprised of numerous subunits sung with distinct combinatorial properties that have been described as syntax-like. This complexity has inspired inquiries into similarities of bird song to human language; but the quantitative analysis and description of song sequences is a challenging task. In this study, we analysed song sequences of common nightingales (Luscinia megarhynchos) by means of a network analysis. We translated long nocturnal song sequences into networks of song types with song transitions as connectors. As network measures, we calculated shortest path length and transitivity and identified the 'small-world' character of nightingale song networks. Besides comparing network measures with conventional measures of song complexity, we also found a correlation between network measures and age of birds. Furthermore, we determined the numbers of in-coming and out-going edges of each song type, characterizing transition patterns. These transition patterns were shared across males for certain song types. Playbacks with different transition patterns provided first evidence that these patterns are responded to differently and thus play a role in singing interactions. We discuss potential functions of the network properties of song sequences in the framework of vocal leadership. Network approaches provide biologically meaningful parameters to describe the song structure of species with extremely large repertoires and complex rules of song retrieval. PMID- 24807257 TI - Density of mushroom body synaptic complexes limits intraspecies brain miniaturization in highly polymorphic leaf-cutting ant workers. AB - Hymenoptera possess voluminous mushroom bodies (MBs), brain centres associated with sensory integration, learning and memory. The mushroom body input region (calyx) is organized in distinct synaptic complexes (microglomeruli, MG) that can be quantified to analyse body size-related phenotypic plasticity of synaptic microcircuits in these small brains. Leaf-cutting ant workers (Atta vollenweideri) exhibit an enormous size polymorphism, which makes them outstanding to investigate neuronal adaptations underlying division of labour and brain miniaturization. We particularly asked how size-related division of labour in polymorphic workers is reflected in volume and total numbers of MG in olfactory calyx subregions. Whole brains of mini, media and large workers were immunolabelled with anti-synapsin antibodies, and mushroom body volumes as well as densities and absolute numbers of MG were determined by confocal imaging and three-dimensional analyses. The total brain volume and absolute volumes of olfactory mushroom body subdivisions were positively correlated with head widths, but mini workers had significantly larger MB to total brain ratios. Interestingly, the density of olfactory MG was remarkably independent from worker size. Consequently, absolute numbers of olfactory MG still were approximately three times higher in large compared with mini workers. The results show that the maximum packing density of synaptic microcircuits may represent a species specific limit to brain miniaturization. PMID- 24807259 TI - Harnessing ant defence at fruits reduces bruchid seed predation in a symbiotic ant-plant mutualism. AB - In horizontally transmitted mutualisms, mutualists disperse separately and reassemble in each generation with partners genetically unrelated to those in the previous generation. Because of this, there should be no selection on either partner to enhance the other's reproductive output directly. In symbiotic ant plant mutualisms, myrmecophytic plants host defensive ant colonies, and ants defend the plants from herbivores. Plants and ants disperse separately, and, although ant defence can indirectly increase plant reproduction by reducing folivory, it is unclear whether ants can also directly increase plant reproduction by defending seeds. The neotropical tree Cordia alliodora hosts colonies of Azteca pittieri ants. The trees produce domatia where ants nest at stem nodes and also at the node between the peduncle and the rachides of the infloresence. Unlike the stem domatia, these reproductive domatia senesce after the tree fruits each year. In this study, I show that the tree's resident ant colony moves into these ephemeral reproductive domatia, where they tend honeydew producing scale insects and patrol the nearby developing fruits. The presence of ants significantly reduced pre-dispersal seed predation by Amblycerus bruchid beetles, thereby directly increasing plant reproductive output. PMID- 24807260 TI - Morphological and functional diversity in therizinosaur claws and the implications for theropod claw evolution. AB - Therizinosaurs are a group of herbivorous theropod dinosaurs from the Cretaceous of North America and Asia, best known for their iconically large and elongate manual claws. However, among Therizinosauria, ungual morphology is highly variable, reflecting a general trend found in derived theropod dinosaurs (Maniraptoriformes). A combined approach of shape analysis to characterize changes in manual ungual morphology across theropods and finite-element analysis to assess the biomechanical properties of different ungual shapes in therizinosaurs reveals a functional diversity related to ungual morphology. While some therizinosaur taxa used their claws in a generalist fashion, other taxa were functionally adapted to use the claws as grasping hooks during foraging. Results further indicate that maniraptoriform dinosaurs deviated from the plesiomorphic theropod ungual morphology resulting in increased functional diversity. This trend parallels modifications of the cranial skeleton in derived theropods in response to dietary adaptation, suggesting that dietary diversification was a major driver for morphological and functional disparity in theropod evolution. PMID- 24807263 TI - Treatment of acne vulgaris with fractional radiofrequency microneedling. AB - Fractional radiofrequency microneedling is a novel radiofrequency technique that uses insulated microneedles to deliver energy to the deep dermis at the point of penetration without destruction of the epidermis. It has been used for the treatment of various dermatological conditions including wrinkles, atrophic scars and hypertrophic scars. There have been few studies evaluating the efficacy of fractional radiofrequency microneedling in the treatment of acne, and none measuring objective parameters like the number of inflammatory and non inflammatory acne lesions or sebum excretion levels. The safety and efficacy of fractional radiofrequency microneedling in the treatment of acne vulgaris was investigated. In a prospective clinical trial, 25 patients with moderate to severe acne were treated with fractional radiofrequency microneedling. The procedure was carried out three times at 1-month intervals. Acne lesion count, subjective satisfaction score, sebum excretion level and adverse effects were assessed at baseline and at 4, 8 and 12 weeks after the first treatment as well as 4, 8 and 12 weeks after the last treatment. Number of acne lesions (inflammatory and non-inflammatory) decreased. Sebum excretion and subjective satisfaction were more favorable at every time point compared with the baseline values (P < 0.05). Inflammatory lesions responded better than non-inflammatory lesions (P < 0.05). Adverse effects such as pinpoint bleeding, pain and erythema were noted, but were transient and not severe enough to stop treatment. Fractional radiofrequency microneedling is a safe and effective treatment for acne vulgaris. PMID- 24807261 TI - The dual nature of haemocyanin in the establishment and persistence of the squid vibrio symbiosis. AB - We identified and sequenced from the squid Euprymna scolopes two isoforms of haemocyanin that share the common structural/physiological characteristics of haemocyanin from a closely related cephalopod, Sepia officinalis, including a pronounced Bohr effect. We examined the potential roles for haemocyanin in the animal's symbiosis with the luminous bacterium Vibrio fischeri. Our data demonstrate that, as in other cephalopods, the haemocyanin is primarily synthesized in the gills. It transits through the general circulation into other tissues and is exported into crypt spaces that support the bacterial partner, which requires oxygen for its bioluminescence. We showed that the gradient of pH between the circulating haemolymph and the matrix of the crypt spaces in adult squid favours offloading of oxygen from the haemocyanin to the symbionts. Haemocyanin is also localized to the apical surfaces and associated mucus of a juvenile-specific epithelium on which the symbionts gather, and where their specificity is determined during the recruitment into the association. The haemocyanin has an antimicrobial activity, which may be involved in this enrichment of V. fischeri during symbiont initiation. Taken together, these data provide evidence that the haemocyanin plays a role in shaping two stages of the squid-vibrio partnership. PMID- 24807264 TI - A sigma-hole interaction with radical species as electron donors: does single electron tetrel bonding exist? AB - A single-electron tetrel bond was predicted and characterized in FXH3...CH3 (X = C, Si, Ge, and Sn) complexes by performing quantum chemical calculations, where the methyl radical acts as the Lewis base and the sigma-hole on the X atom in FXH3 as the Lewis acid. The interaction between the methyl radical and FXH3 is characterized by a red shift of F-X stretching frequency. The strength of the tetrel bond becomes stronger by not only increasing the atomic number of the central atom X (X = C, Si, Ge, and Sn) but also by enhancing the electron withdrawing ability of substituents in the Lewis acid. The energy decomposition analysis highlights the importance of the electrostatic interaction in the formation of the tetrel bond, although the dispersion part is also non-negligible for the weak tetrel bond. There is a competition between the formation of single electron tetrel bonds and hydrogen bonds for the complexes composed of the methyl radical and CNCH3 or NCCH3. Furthermore, the single-electron tetrel bond exhibits the cooperative effect not only with the hydrogen bond in the complex of NCH...NCCH3...CH3, but also with the conventional tetrel bond in NCCH3...NCCH3...CH3. PMID- 24807266 TI - Ponatinib: a review of its use in adults with chronic myeloid leukaemia or Philadelphia chromosome-positive acute lymphoblastic leukaemia. AB - Oral ponatinib (Iclusig((r))) is a novel kinase inhibitor structurally designed with a carbon-carbon triple bond to accommodate the T315I mutation in the ABL kinase domain. It has demonstrated inhibitory activity against native BCR-ABL tyrosine kinase and a variety of BCR-ABL mutants, including T315I. Ponatinib is approved for the treatment of adults with T315I-positive chronic-, accelerated- or blast-phase chronic myeloid leukaemia (CML), or Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) [in the EU and the USA], as well as those with chronic-, accelerated- or blast-phase CML, or Ph+ ALL who are resistant or intolerant to prior tyrosine kinase inhibitor therapy (EU) or for whom no other tyrosine kinase inhibitor therapy is indicated (USA). In a noncomparative, multinational, phase II study, therapy with ponatinib was associated with a major cytogenetic response within the first 12 months in over half of adults with chronic-phase CML and major haematological responses within the first 6 months in at least 50% of adults with accelerated-phase CML and approximately 34% of adults with blast-phase CML or Ph+ ALL after a median follow up duration of 15, 16 and 6 months, respectively. Such benefits were observed regardless of whether the patients were resistant to dasatinib or nilotinib, or had the T315I mutation. Serious adverse reactions have been reported with ponatinib, with vascular occlusion, heart failure and hepatotoxicity prompting the US FDA to issue boxed warnings. Ponatinib is a valuable treatment option for adults with T315I-positive chronic-, accelerated- or blast-phase CML, or Ph+ ALL, as well as those with chronic-, accelerated- or blast-phase CML, or Ph+ ALL who are resistant or intolerant to prior tyrosine kinase inhibitor therapy, but before starting treatment, clinicians need to consider whether the potential benefits of therapy will outweigh the risks. PMID- 24807265 TI - Activation of the pleiotropic drug resistance pathway can promote mitochondrial DNA retention by fusion-defective mitochondria in Saccharomyces cerevisiae. AB - Genetic and microscopic approaches using Saccharomyces cerevisiae have identified many proteins that play a role in mitochondrial dynamics, but it is possible that other proteins and pathways that play a role in mitochondrial division and fusion remain to be discovered. Mutants lacking mitochondrial fusion are characterized by rapid loss of mitochondrial DNA. We took advantage of a petite-negative mutant that is unable to survive mitochondrial DNA loss to select for mutations that allow cells with fusion-deficient mitochondria to maintain the mitochondrial genome on fermentable medium. Next-generation sequencing revealed that all identified suppressor mutations not associated with known mitochondrial division components were localized to PDR1 or PDR3, which encode transcription factors promoting drug resistance. Further studies revealed that at least one, if not all, of these suppressor mutations dominantly increases resistance to known substrates of the pleiotropic drug resistance pathway. Interestingly, hyperactivation of this pathway did not significantly affect mitochondrial shape, suggesting that mitochondrial division was not greatly affected. Our results reveal an intriguing genetic connection between pleiotropic drug resistance and mitochondrial dynamics. PMID- 24807268 TI - Amphetamine induced endogenous opioid release in the human brain detected with [11C]carfentanil PET: replication in an independent cohort. AB - This study aimed to replicate a previous study which showed that endogenous opioid release, following an oral dose of amphetamine, can be detected in the living human brain using [11C]carfentanil positron emission tomography (PET) imaging. Nine healthy volunteers underwent two [11C]carfentanil PET scans, one before and one 3 h following oral amphetamine administration (0.5 mg/kg). Regional changes in [11C]carfentanil BPND from pre- to post-amphetamine were assessed. The amphetamine challenge led to significant reductions in [11C]carfentanil BPND in the putamen, thalamus, frontal lobe, nucleus accumbens, anterior cingulate, cerebellum and insula cortices, replicating our earlier findings. None of the participants experienced significant euphoria/'high', supporting the use of oral amphetamine to characterize in vivo endogenous opioid release following a pharmacological challenge. [11C]carfentanil PET is able to detect changes in binding following an oral amphetamine challenge that reflects endogenous opioid release and is suitable to characterize the opioid system in neuropsychiatric disorders. PMID- 24807269 TI - Pharmacokinetics of gadobenate dimeglumine in children 2 to 5 years of age undergoing MRI of the central nervous system. AB - PURPOSE: To determine the pharmacokinetic profile of gadobenate dimeglumine in children aged between 2 and 5 years. MATERIALS AND METHODS: Fifteen children scheduled to undergo contrast-enhanced MRI for suspected disease of the central nervous system received a single intravenous injection of 0.1 mmol/kg gadobenate dimeglumine. Children were stratified into three age groups: 2 to <3 years, 3 to <4 years, and 4 to 5 (i.e., <6 years). Serial blood and urine samples collected at prespecified time-points before and after contrast administration were analyzed for gadolinium concentrations. Pharmacokinetic parameters were calculated using noncompartmental and compartmental techniques. RESULTS: Mean values of 65.7 MUg/mL for highest blood gadolinium concentration, 0.2 L/h/kg for blood clearance, 0.32 L/kg for steady-state volume of distribution, and 1.2 h for terminal elimination half-life were determined across all age groups combined. On average, more than 80% of the dose was eliminated in the urine during the first 24 h after administration. All pharmacokinetic parameters were similar between age groups and no effects of gender were noted. No adverse events considered related to gadobenate dimeglumine administration were reported. CONCLUSION: In terms of pharmacokinetic profile no dosage adjustment from the approved adult gadobenate dimeglumine dose of 0.1 mmol/kg bodyweight is necessary in children aged between 2 and 5 years. PMID- 24807270 TI - [Concept, pathophysiology and treatment for branch atheromatous disease]. AB - Small deep brain infarcts are often caused by two different vascular pathologies: 1. atheromatous occlusion at the orifice of large caliber penetrating arteries termed branch atheromatous disease (BAD) and 2. lipohyallinotic degenerative changes within the course of penetrating arteries termed lipohyalinitic degeneration. Representative vascular territories of BAD type infarcts are lenticulostriate artery (LSA), pontine paremedian artery (PPA) and less frequently anterior choroidal artery. BAD type infarcts are strongly associated with progressive motor deficits (PMD) leading to a worse functional outcome, because they affect pyramidal tract at corona radiata, pontine base or internal capsule. In our study, female sex and initial severity of motor deficits were common predictors for PMD in both groups with LSA and PPA. Single infarcts without concomitant silent lacunar infarcts and preceding lacunar transient ischemic attack (TIA) in the LSA group, and diabetes mellitus in the PPA group were independent predictors for PMD in penetrating artery infarctions. There were different characteristics between the groups of LSA and PPA. Prevalence of male gender, diabetes mellitus and intracranial atherosclerosis were significantly higher in the PPA group than in the LSA group. The combined treatment of cilostazol and edarabone significantly improved functional outcome especially in the PPA infarct group. Adjoining clopidgrel on aforementioned combined treatment further improved functional outcome in the LSA group. The actions of vasodilatation and endothelial protection in cilostazol and inhibition of shear induced platelet activation in clopidogrel, as well as scavenging free radicals in edaravone might work effectively. PMID- 24807271 TI - [Disease notification and self-determination in treatment decisions for patients with Creutzfeldt-Jakob disease]. AB - We investigated disease notification and self-determination in treatment decisions of Creutzfeldt-Jakob disease (CJD). For this purpose, we retrospectively analyzed 18 patients with CJD (sporadic:familial = 14:4) who were admitted to our hospital. The durations from symptom onset to the time of diagnosis ranged from 0.3 to 48 months (median, 2 months). The Hasegawa Dementia Scale-revised (HDS-R) range was 0 to 29 (median, 5.0); however, 4 patients (22%), including 2 with familial CJD and 2 with sporadic CJD, maintained cognitive function (HDS-R score >= 21). Two patients (11%), who satisfied Lo's criteria for self-determination, were given a disease notification, and both of them archived self-determination in treatment decisions. In conclusion, we demonstrated that patients with CJD could be given a disease notification and archive self determination in treatment decisions upon early diagnosis using DWI. PMID- 24807272 TI - [Central respiratory failure occurred in the subacute phase of unilateral Wallenberg's syndrome: a case report]. AB - A 46-year-old man developed central respiratory failure in the subacute phase of unilateral lateral medullary infarction. He complained of sudden headache and nausea at first. Neurological examination revealed Wallenberg's syndrome. Acute right lateral medullary infarction caused by the dissecting right vertebral artery was identified by magnetic resonance images. He was transferred to our hospital on the 3rd day after the onset. He was alert and conscious on admission, and became restless gradually later. He was intubated for sudden respiratory failure on the 9th day. Blood gas analysis showed hypercapnia and hypoxia. Central respiratory failure was indicated by the fact that various examinations showed no change of his infarction, no subarachnoid hemorrhage, or no worsening of pneumonia. Ventilatory support was required for a month because of repetitive CO2 narcosis. He was weaned from the ventilator on the 39th day. Only a few reports are available on central respiratory failure associated with the subacute phase of unilateral medullary infarction. Delayed central respiratory failure may be lethal. Careful observation is required on the subacute phase of Wallenberg's syndrome. PMID- 24807273 TI - [Leptomeningeal gliomatosis with high levels of adenosine deaminase in the cerebrospinal fluid]. AB - A 61-year-old man developed disturbance of consciousness for 2 weeks. He showed neck stiffness and hyporeflexia. Analysis of his cerebrospinal fluid (CSF) revealed pleocytosis and markedly reduced glucose contents. Adenosine deaminase (ADA) levels in the CSF were elevated (28.8 IU/l). Brain magnetic resonance imagings showed enhancement of the leptomeninges. Tuberculous meningitis was considered, but antituberculous drug was not effective. Repeated cytological analysis of the CSF demonstrated atypical cells with enlarged unevenly distributed nuclei and immunoreactive with glial fibrillary acidic protein. We diagnosed him as leptomeningeal gliomatosis. CSF ADA may be elevated in this rare disorder, and here we emphasize that repeated cytological analysis with immunohistochemical staining was useful for diagnosis. PMID- 24807274 TI - [Patient with chronic sarcoid myopathy without other organ involvement]. AB - We herein report the patient of a 69-year-old woman who presented with the chronic myopathic form of sarcoid myopathy. She had experienced slowly progressive limb muscle weakness for three years. She was found to be thin, but otherwise normal, on a physical examination. Neurologically, proximal muscles are predominantly involved without any sensory or other focal deficits. Electromyography revealed myopathic motor unit potentials exhibiting spontaneous discharge. Muscle biopsy demonstrated extensive connective tissue and few residual muscle fibers with a hint of granuloma formation. Repeated sectioning of the muscle biopsy revealed noncaseatious granuloma with a multinucleated giant cell, confirming the diagnosis. The findings of all imaging studies, including a systemic PET (positron emission tomography) scan, were unremarkable. Without careful pathological observation with repeated sectioning, this patient would have been misdiagnosed with limb-girdle muscular dystrophy PMID- 24807275 TI - [Case of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome with cerebellar ataxia and facial dysesthesia]. AB - We report an 85-year-old man presenting with wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome with cerebellar ataxia and facial dysesthesia. He experienced an abrupt onset of double vision and exotropia of the right eye with unsteady gait and dysesthesia around upper lip. He was admitted to our hospital ten days after the onset of the double vision. On admission, he presented with WEBINO, left limb ataxia, and dysesthesia around upper lip on the right side. His exotropia was prominent on the right side. Diffusion weighted images of MRI revealed a high intensity lesion in the paramedian pontine tegmentum involving bilateral medial longitudinal fasciculus (MLF), consistent with acute ischemic lesion. Four months after the onset, the WEBINO persisted, without cerebellar ataxia and facial dysesthesia. Putative lesions of the WEBINO, cerebellar ataxia and facial dysesthesia were bilateral MLF, left superior cerebellar peduncle and trigeminothalamic tract, respectively, which were broader than the MRI lesion. Neurological examination is critical for evaluation of accurate ischemic area. PMID- 24807276 TI - [Case of an elderly woman with dementia showing episodic involuntary movement of the tongue]. AB - We report a 93-year-old woman with dementia who developed generalized convulsion and involuntary movement of her tongue. She could independently walk and eat meals until 8 months ago, however she turned into bedridden. When she was admitted to our emergency room due to status epilepticus, her tongue intermittently moved from the midline to the left. She could not eat or speak during this episodic tongue movement. MR imaging study revealed brain atrophy in the bilateral mesial temporal lobe, consistent with senile dementia of Alzheimer type. Despite her tongue movements seemingly developing to the generalized convulsion, EEG study did not indicate epileptiform discharges corresponding to this movement. Although antiepileptic drug therapy was effective, we needed polytherapy to control this movement. Paroxysmal tongue movements were previously reported in cases of epilepsy, brain tumor, and stroke, observed bilaterally in most cases. This episodic tongue movement would be rare in terms of the clear laterality. The etiology of this movement was presumed as focal seizure, palatal tremor, dyskinesia or others, but was undetermined. Episodic movements involving tongue decrease the quality of daily life especially in the elderly. Therefore, we should pay more attention to it and try to treat it earlier. PMID- 24807277 TI - [Autopsy case of frontotemporal lobar degeneration with motor neuron disease associated with numerous diffuse plaques, pretangles and neuropil threads]. AB - We report an autopsy case of dementia associated with amyotrophic lateral sclerosis (ALS) in a 73-year-old female. She developed memory impairment at the age of 68 years. Atrophy of her hand muscles was noted at the age of 71 years. She was not aware of her memory impairment or muscle weakness, and was loquacious and euphoric. She was clinically diagnosed as having Alzheimer disease (AD) complicated by ALS with dementia/frontotemporal lobar degeneration with motor neuron disease (ALS-D/FTLD-MND). A neuropathological study confirmed the presence of features of sporadic ALS. Furthermore, severe neuronal loss involving the subiculum and the rostral portion of the medial side of the temporal pole cortex was detected, and TAR DNA-binding protein-43-positive-neuronal cytoplasmic inclusions were identified in the granule cells of the dentate gyrus. These findings were compatible with the pathological features of ALS-D/FTLD-MND. Although many pretangles, neuropil threads and senile plaques were revealed in the degenerated areas, there were few neurofibrillary tangles and typical plaques (Braak stage III, C). Further discussion is required to determine whether AD with ALS-D/FTLD-MND is different from typical AD. This case might be helpful for diagnosing similar cases in the future. PMID- 24807278 TI - [Brain abscess mediated through a pulmonary arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia]. AB - The patient is a 66-year-old man with hereditary telangiectasia. He was diagnosed with pulmonary arteriovenous malformation (PAVM), which was revealed by contrast enhanced chest computed tomography at the age of 65. He developed headache, right homonymous hemianopsia, and right hemiparesis and was admitted to our hospital. Contrast-enhanced magnetic resonance imaging revealed multiple lesions in the left hemisphere, which indicates brain abscesses. Thus, the diagnosis of brain abscess mediated through PAVM was established. Following management with drainage and coil embolization, all neurological symptoms resolved. Therefore, coil embolization should be considered for PAVM at an early stage to prevent brain abscess, even if it is asymptomatic. PMID- 24807279 TI - [Relation of transcatheter atrial septal defect closure and migraine]. PMID- 24807280 TI - [Actual state and problems in neurology training in medical schools]. AB - To investigate the need for pre- and post-graduate education for neurologists, the subcommittee of the Japanese Society of Neurology for education performed a questionnaire-based survey in 80 medical universities throughout Japan. The response rate to the questionnaire was 82.5%. Textbooks for lectures for medical students were used in only 22.7% of those universities. If the Japanese Society of Neurology (JSN) made a standard text, 77.8% of universities would like to use it. Most of the training programs for residents were compatible with the minimum requirements of the JSN. Just 66.7% of those training programs were completed in their own institute, and 77.3% of universities required help from the JSN. PMID- 24807281 TI - [Actual state and problems in neurology training at hospital]. AB - To evaluate postgraduate neurological education, a questionnaire-based survey regarding junior and senior doctor-in-training and the Board Certification Examination in Neurology was carried out on the training supervisors of 690 insitutes, excluding 80 university hospitals. The institutes included 243 teaching hospitals, 326 semi-teaching hospitals and 121 education-associated institutes authorized by the Japanese Society of Neurology (JSN). The results were obtained from 388 institutes, and the response rate was 56.2%. The percentage of junior doctors-in-training that received training in neurology was 68.6% (the average of 2.1 months during 2 years). More than half of the institutes did not have any teaching programs for junior doctors-in-training who did not train in neurology. In senior doctors-in-training, the number of senior doctors-in-trainings per year per institute was 0.44 and was only able to experience limited types of disorders. Also, many institutes could not achieve training goals by the institutes themselves (56%). The problems were due to lack of teaching staffs and manpower, and there were many requests to the Society regarding training methods. As for the Board Certification Examination in Neurology by the Society, it was revealed that there were small number of candidates per year per institute, and over half of institutes could not sufficiently teach and support them. Most requests to the Society were regarding teaching seminars and hands-on courses, and some institutes asked small group meetings for arts and techniques of neurology to be held the Regional Society. In conclusion, there are problems that cannot be solved by individual institutes alone, and we need procedures for postgraduate training in neurology that is organized by the Regional and JSN working as the central organization. PMID- 24807282 TI - [Actual state and problems in neurology training at graduate school]. AB - To understand the status of postgraduate education in neurology in Japan, the Committee for the Education of Undergraduate Students and Junior Residents within the Japanese Society of Neurology investigated the four-year trend at 80 medical schools from 2009 to 2012. The mean number of new students to each postgraduate school increased from 1.24 to 1.67 during these four years. After training clinical neurology, more than half of the neurological residents entered the postgraduate schools. Students in the postgraduate schools seemed to be researching major neurological diseases using various methods at each neurology laboratory. However, some problems were suggested. First, the mean number of newcomers to the neurology departments of the universities decreased gradually from 2.29/year to 1.96/year. Second, many of the postgraduate students were working in patient services at university hospitals or as part-time workers at other hospitals, and may not have sufficient time for their research projects. Third, many of the postgraduate students were carrying out research at each affiliated department of neurology, and may not have the opportunity to work in laboratories specializing in basic science. Finally, there may not be sufficient opportunities for further research at other laboratories in Japan or overseas after they finished their work at postgraduate school. PMID- 24807288 TI - Evaluation of changes in tidal volume during mask ventilation following administration of neuromuscular blocking drugs. AB - The practice of checking the ability to mask ventilate before administering neuromuscular blocking drugs remains controversial. We prospectively evaluated the changes in the expired tidal volume during pressure-controlled ventilation (two-handed mask ventilation technique) as a surrogate marker to assess the ease of mask ventilation following administration of rocuronium. After informed consent, 125 patients were anaesthetised using a standard induction technique consisting of fentanyl, propofol and rocuronium, with anaesthesia then maintained with isoflurane in oxygen. The mean (SD) expired tidal volume before administration of rocuronium increased by 61 (13) ml at 2 min following onset of neuromuscular block (p < 0.001). This supports the concept that neuromuscular blockade induced by rocuronium facilitates mask ventilation. PMID- 24807289 TI - Examination of the perception of communication and collaboration in a neonatal intensive care unit: a decade on, has it changed? AB - OBJECTIVE: The aim of this study was to ascertain the perception of communication and collaboration within and between the groups of medicine and nursing in a neonatal unit. METHODS The study used an analytical cross-sectional design involving both doctors and nursing staff in the neonatal clinical care unit (NCCU). A quantitative questionnaire using a Likert scale format, accompanied by an open-ended question, provided a snapshot of the perception of communication and collaboration within the NCCU. RESULTS Significant differences were noted between the two disciplines. Medical staff were satisfied overall with the communication. They perceived communication was more open, timely and that a mutual understanding existed. They thought teamwork was good. As time of employment in NCCU lengthened, the understanding between the groups lessened. Problems with the handover information emerged for both medical and nursing staff. Both groups felt problems were due to the hierarchical system. CONCLUSION Within the NCCU the perception of communication and collaboration is rated more highly by doctors. This has implications for the overall care of babies and for safety issues. Education is needed in the neonatal unit to identify and bridge gaps in communication and enhance teamwork. PMID- 24807290 TI - Covalently functionalized carbon nanotube supported Pd nanoparticles for catalytic reduction of 4-nitrophenol. AB - Carbon nanotubes (CNTs) were covalently functionalized via 1,3-dipolar cycloaddition reaction under microwave conditions. The functionalized CNTs were characterized by thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), N2 adsorption isotherms and Raman spectroscopy. The surface concentration of phenolic hydroxyl groups on the surface of CNTs was adjusted by varying the reaction temperature. In addition, we prepared Pd nanoparticle/CNT (Pd NP/CNT) nanocomposites through strong electrostatic adsorption and hydrogen reduction. The results indicated that the functional groups could not only improve the dispersion of CNTs in water, but also enhance the interaction between Pd precursors and CNTs, thus preventing small Pd NPs (average diameter of 1.5 nm) from agglomerating. Furthermore, the Pd NP/CNT-220 nanocomposites showed high catalytic activity for the reduction of 4-nitrophenol. The turnover frequency (TOF) of this catalyst was up to 18 min(-1), which was attributed to the small size and uniform distribution of Pd NPs on the surface of CNTs. PMID- 24807291 TI - Target-triggered NIR emission with a large stokes shift for the detection and imaging of cysteine in living cells. AB - Background autofluorescence from biological systems generally reduces the sensitivity of a fluorescent probe for imaging biological targets. Addressing this challenge requires the development of fluorescent probes that produce emission in the near-infrared region. Herein, we report the design and synthesis of a fluorescent probe that generates an NIR emission with a large Stokes shift upon the selective response to Cys over Hcy and GSH. The probe is designed to consist of two Cys-sensing sites, an acrylate ester and an aldehyde installed ortho to each other. The reaction of the probe with Cys triggers an excited state intramolecular proton transfer process upon photo-excitation, thereby producing an NIR emission with a large Stokes shift. Accordingly, this probe hold great promise for the selective detection of Cys in biological systems. We further demonstrate the capacity of this probe for Cys imaging in living cells. PMID- 24807292 TI - Facile preparation of core-shell magnetic metal-organic framework nanospheres for the selective enrichment of endogenous peptides. AB - Facile preparation of core-shell magnetic metal-organic framework nanospheres by a layer-by-layer approach is presented. The nanospheres have high surface area (285.89 cm(2) g(-1)), large pore volume (0.18 cm(3) g(-1)), two kinds of mesopores (2.50 and 4.72 nm), excellent magnetic responsivity (55.65 emu g(-1)), structural stability, and good dispersibility. The combination of porosity, hydrophobicity, and uniform magnetism was exploited for effective enrichment of peptides with simultaneous exclusion of high molecular weight proteins. The nanospheres were successfully applied in the selective enrichment of endogenous peptides in human serum. PMID- 24807294 TI - Treating chronic pain: what is left out of the patient encounter. PMID- 24807293 TI - Acute functional reactivation of the language network during awake intraoperative brain mapping. AB - Acute brain plasticity during resection of central lesions has been recently described. In the cases reported, perilesional latent networks, useful to preserve the neurological functions, were detected in asymptomatic patients. In this paper, we presented a case of acute functional reactivation (AFR) of the language network in a symptomatic patient. Tumor resection allowed to acutely restore the neurological deficit. Intraoperative direct cortical stimulation (DCS) and functional neuroimaging showed new epicentres of activation of the language network after tumor excision. DCS in awake surgery is mandatory to reveal AFR needful to improve the extent of resection preserving the quality of life. PMID- 24807295 TI - More than just being nice: the importance of rapport to understanding. PMID- 24807296 TI - Comment on Ryan et al., an investigation of association between chronic musculoskeletal pain and cardiovascular disease in the Health Survey for England (2008). PMID- 24807297 TI - Authors' reply to comment by Grant et al. PMID- 24807298 TI - The multivalent effect in glycosidase inhibition: a new, rapidly emerging topic in glycoscience. AB - A bunch of keys, one lock: The multivalent effect in glycosidase inhibition is a new, rapidly emerging area with exciting potential and scope. This review presents a description of the different types of neoglycoclusters and their evaluation as glycosidase inhibitors. The first promising therapeutic applications are discussed, as well as the mechanisms underlying the observed inhibitory multivalent effect. PMID- 24807301 TI - Solvent-induced red-shifts for the proton stretch vibrational frequency in a hydrogen-bonded complex. 1. A valence bond-based theoretical approach. AB - A theory is presented for the proton stretch vibrational frequency nuAH for hydrogen (H-) bonded complexes of the acid dissociation type, that is, AH...B <=> A(-)...HB(+)(but without complete proton transfer), in both polar and nonpolar solvents, with special attention given to the variation of nuAH with the solvent's dielectric constant epsilon. The theory involves a valence bond (VB) model for the complex's electronic structure, quantization of the complex's proton and H-bond motions, and a solvent coordinate accounting for nonequilibrium solvation. A general prediction is that nuAH decreases with increasing epsilon largely due to increased solvent stabilization of the ionic VB structure A( )...HB(+) relative to the neutral VB structure AH...B. Theoretical nuAH versus 1/epsilon slope expressions are derived; these differ for polar and nonpolar solvents and allow analysis of the solvent dependence of nuAH. The theory predicts that both polar and nonpolar slopes are determined by (i) a structure factor reflecting the complex's size/geometry, (ii) the complex's dipole moment in the ground vibrational state, and (iii) the dipole moment change in the transition, which especially reflects charge transfer and the solution phase proton potential shapes. The experimental proton frequency solvent dependence for several OH...O H-bonded complexes is successfully accounted for and analyzed with the theory. PMID- 24807299 TI - Recombinant human antithrombin prevents xenogenic activation of hemostasis in a model of pig-to-human kidney transplantation. AB - BACKGROUND: Xenogenic activation of hemostasis (XAH) represents a major hurdle for the transplantation of discordant animal organs into humans as it results in thrombotic microangiopathy (TMA). We have previously shown that recombinant human activated protein C (rhAPC) mitigates XAH and TMA in an ex vivo model of pig-to human kidney transplantation. However, the use of rhAPC may not be feasible in a perioperative setting due to possible bleeding complications. METHODS: Here, we explored the effects of another natural inhibitor of coagulation, human recombinant antithrombin (rhAT), in comparison with rhAPC. Unmodified porcine kidneys (n = 25) were perfused ex vivo with porcine blood, human blood, or human blood supplemented with rhAPC or rhAT. Surrogate parameters of organ survival, markers of XAH (D- Dimer, thrombin-antithrombin complex [TAT], fibrinogen, antithrombin activity, plasminogen), endothelial cell and platelet activation (E selectin, P-selectin), platelet function tests and histological signs of TMA were evaluated. RESULTS: Perfusion was feasible for > 240 min in all experiments with autologous porcine blood, but limited to 126 +/- 78 min with human blood due to increased vascular resistance. Addition of rhAT protected from TMA and allowed for perfusion times > 240 min. In addition, there were less signs of XAH with reduced release of P-selectin and overexpression of E-selectin, whereas the progressive loss of platelet function, observed during discordant perfusion, was prevented. The effect of rhAT was dose-dependent with maximum protection obtained at 3 IU/ml. CONCLUSION: In conclusion, in this ex vivo model of discordant xenotransplantation, rhAT reduced XAH and prevented TMA in doses that appear feasible for use in clinical or preclinical transplantation settings. PMID- 24807303 TI - Amphiprotic properties of a bis(MU-hydroxo)divanadium(IV)-substituted gamma Keggin-type silicodecatungstate containing two different kinds of hydroxyl moieties. AB - A bis(MU-hydroxo)divanadium(IV)-substituted gamma-Keggin-type silicodecatungstate, (TBA)4[gamma-SiV(IV)2W10O36(MU-OH)4] (1), possesses two different kinds of hydroxyl groups and can work as an amphiprotic species to accept and donate proton(s). Dehydrative condensation reactions of 1 with methanol and formic acid proceed on more basic hydroxyl groups between two vanadium atoms without the deprotonation of more acidic hydroxides between two tungsten atoms to form (TBA)4[gamma-SiV(IV)2W10O36(MU-OH)3(MU-OR)] (2.R, R = Me, Et, Pr; 3, R = C(O)H), showing Bronsted base properties of the hydroxyl groups between two vanadium atoms. On the other hand, the hydroxyl groups between tungsten atoms exhibit Bronsted acid properties and react with pyridine (Py) and TBAOH to form (TBA)4X[gamma-SiV(IV)2W10O37(MU-OH)3] (PyH.4, X = PyH; TBA.4, X = TBA). DFT calculations for [gamma-SiV(IV)2W10O36(MU-OH)4](4-) in water also support both the acidic and basic nature of hydroxyl groups in 1. PMID- 24807302 TI - Binding interaction of a prospective chemotherapeutic antibacterial drug with beta-lactoglobulin: results and challenges. AB - This Article reports a detailed characterization of the binding interaction of a potential chemotherapeutic antibacterial drug, norfloxacin (NOF), with the mammalian milk protein beta-lactoglobulin (betaLG). The thermodynamic parameters, DeltaH, DeltaS, and DeltaG, for the binding phenomenon as-evaluated on the basis of van't Hoff relationship reveal the predominance of electrostatic/ionic interactions underlying the binding process. However, the drug-induced quenching of the intrinsic tryptophanyl fluorescence of the protein exhibits intriguing characteristics on Stern-Volmer analysis (displays an upward curvature instead of conforming to a linear regression). Thus, an extensive time-resolved fluorescence spectroscopic characterization of the quenching process has been undertaken in conjugation with temperature-dependent fluorescence quenching studies to unveil the actual quenching mechanism. The invariance of the fluorescence decay behavior of betaLG as a function of the quencher (here NOF) concentration coupled with the commensurate dependence of the drug-protein binding constant (K) on temperature, the drug-induced fluorescence quenching of betaLG is argued to proceed through static mechanism. This postulate is aided further support from absorption, fluorescence, and circular dichroism (CD) spectral studies. The present study also throws light on the important issue of drug-induced modification in the native protein conformation on the lexicon of CD, excitation-emission matrix spectroscopic techniques. Concurrently, the drug-protein interaction kinetics and the energy of activation of the process are also explored from stopped-flow fluorescence technique. The probable binding locus of NOF in betaLG is investigated from AutoDock-based blind docking simulation. PMID- 24807304 TI - Introducing Google Chart Tools and Google Maps API in data visualization courses. AB - This article reports the experience of using Google Chart Tools and Google Maps in a data visualization course at Georgia State University. These visualization toolkits have many benefits but haven't been widely used in such courses. Students found them easy to use for creating a variety of interactive data visualizations. PMID- 24807305 TI - Beaming: an asymmetric telepresence system. AB - The Beaming project recreates, virtually, a real environment; using immersive VR, remote participants can visit the virtual model and interact with the people in the real environment. The real environment doesn't need extensive equipment and can be a space such as an office or meeting room, domestic environment, or social space. PMID- 24807306 TI - Efficiently modeling 3D scenes from a single image. AB - A proposed system lets users create a 3D scene easily and quickly from a single image. The scene model consists of background and foreground objects whose coordinates the system calculates on the basis of a boundary between the ground plane and a wall plane. The system quickly extracts foreground objects by combining image segmentation and graph-cut-based optimization. It enables efficient modeling of foreground objects, easy creation of their textures, and rapid construction of scene models that are simple but produce sufficient 3D effects. PMID- 24807307 TI - Mathematical marbling. AB - In this paper, the proposed method takes a mathematical approach with closed-form expressions to simulate marbling. This method improves control, ease of implementation, parallelism, and speed, enabling real-time visual feedback and creation of vivid flowing animations. Users can start designs from a blank sheet, raster images, or videos. PMID- 24807308 TI - Visual realism enhances realistic response in an immersive virtual environment- part 2. AB - Does realistic lighting in an immersive VR application enhance presence--that is, the participants' feeling that they're actually in the scene and behaving accordingly? Part 1 of this study indicated that presence is more likely with real-time ray tracing than with ray casting. However, that research couldn't separate the effects of overall illumination quality from the dynamic effects of real-time shadows and reflections. In a new experiment, 20 people experienced a scene rendered with either global or local illumination. Both conditions included dynamically changing shadows and reflections. Illumination quality didn't affect presence, so the earlier result must have been caused by dynamic shadows and reflections. Nevertheless, global illumination did result in greater plausibility -that is, participants were more likely to respond as if the virtual events were real. These results indicate that global illumination does affect participant responses and is worth the effort. PMID- 24807309 TI - Practical noise reduction for progressive stochastic ray tracing with perceptual control. AB - A proposed method reduces noise in stochastic ray tracing for interactive progressive rendering. The method accumulates high-variance light paths in a separate buffer, which is filtered by a high-quality edge-preserving filter. Then, this method adds a combination of the noisy unfiltered samples and the less noisy (but biased) filtered samples to the low-variance samples to form the final image. A novel per-pixel blending operator combines both contributions in a way that respects a user-defined threshold on perceived noise. This method can provide fast, reliable previews, even in the presence of complex features such as specular surfaces and high-frequency textures. At the same time, it's consistent in that the bias due to filtering vanishes in the limit. PMID- 24807310 TI - A catheterization-training simulator based on a fast multigrid solver. AB - A VR-based simulator helps trainees develop skills for catheterization, a fundamental but difficult procedure in vascular interventional radiology. A deformable model simulates the complicated behavior of guide wires and catheters, using the principle of minimum total potential energy. A fast, stable multigrid solver ensures realistic simulation and real-time interaction. In addition, the system employs geometrically and topologically accurate vascular models based on improved parallel-transport frames, and it implements efficient collision detection. Experiments evaluated the method's stability, the solver's execution time, how well the simulation preserved the catheter's curved tip, and the catheter deformation's realism. An empirical study based on a typical selective catheterization procedure assessed the system's feasibility and effectiveness. PMID- 24807311 TI - Exploratory visualization of surgical training databases for improving skill acquisition. AB - A new visualization system analyzes multidimensional surgical performance databases of information collected via emerging surgical robot and simulator technologies. In particular, it has visualized force, position, rotation, and synchronized video data from 300 bimanual laparoscopic surgery tasks performed by more than 50 surgeons. To explore data, the system uses a multiple-coordinated views framework. It provides techniques to select and filter multivariate time series data, visualize animated force plots in conjunction with contextual videos, encode multivariate bimanual tool trace data in 3D visualizations, and link visualizations to a database management system via a new generalizable data model. Insights and feedback from an interdisciplinary iterative design process and use case studies support the utility of visualization in this emerging area of data-driven surgical training. PMID- 24807312 TI - Visualizing marine environmental changes to the Saemangeum Coast. AB - The Saemangeum Coast, located on the west side of the Korean peninsula, is undergoing a 30-year land reclamation project involving approximately 40 kilohectares. Because this project will drastically change the marine environment, monitoring and analyzing the water quality and marine life forms are necessary. However, the observation data are accumulating past the terabyte level, and the simulation data based on that data are also growing. Moreover, the gathered data are heterogeneous, and combining the datasets is often critical for gaining a better understanding of the environmental situation and for making predictions and decisions. A new visual-analytics tool for analyzing this situation fuses geographic-information-system data with ocean environmental data. It has three main components: data collection, geoprocessing, and data visualization. Researchers have used it to monitor and analyze changes in water quality, zooplankton distribution, and seabed topography. PMID- 24807313 TI - Understanding visualization by understanding individual users. AB - Visualization is often seen as a tool to support complex thinking. Although different people can have very different ways of approaching the kind of complex task that visualizations support, as researchers and designers we still rarely consider individual differences in creating and evaluating visualizations. This article reviews recent research on individual differences in visualization and human-computer interaction, showing that both cognitive abilities and personality profiles might significantly affect performance with these tools. The study of individual differences has led to the conclusion that advances in this important area in visualization will require more focused research. Specifically, we must isolate the cognitive factors that are relevant to visualization and the design factors that make one visualization more suited to a user than another. In doing so, we could increase our understanding of the visualization user and reshape how we approach design and evaluation. PMID- 24807315 TI - Adherens junctional associated protein-1: a novel 1p36 tumor suppressor candidate in gliomas (Review). AB - In a broad range of human cancers 1p36 has been a mutational hotspot which strongly suggests that the loss of tumor suppressor activity maps to this genomic region during tumorigenesis. Adherens junctional associated protein-1 (AJAP1; also known as Shrew1) was initially discovered as a novel transmembrane protein of adherent junctions in epithelial cells. Gene profiling showed AJAP1 on 1p36 is frequently lost or epigenetically silenced. AJAP1 may affect cell motility, migration, invasion and proliferation by unclear mechanisms. AJAP1 may be translocated to the nucleus, via its interaction with beta-catenin complexes, where it can regulate gene transcription, then possibly have a potent impact on cell cycling and apoptosis. Significantly, loss of AJAP1 expression predicts poor clinical outcome of patients with malignant gliomas such as GBM and it may serve as a promising tumor suppressor-related target. In this review, we summarize and discuss current knowledge that may identify AJAP1 as a tumor suppressor in gliomas. PMID- 24807316 TI - Stabilization of carbenes via alpha-ylide substitutions: a computational quest for new divalents at DFT. AB - In our continued quest for novel stable carbenes, silylenes, and germylenes, here we compare and contrast multiplicities and relative stabilities of carbenes affected with four different alpha-ylides. The latter include carbon, immonium, phosphorus, and sulfur ylides substituted at the alpha positions of carbenes with acyclic, cyclic and cyclicunsaturated structural frameworks. Related thermodynamic data are calculated at B3LYP/6-311++G**//B3LYP/6-31+G* and B3LYP/AUG-cc-pVTZ//B3LYP/6-31+G* levels. Investigations reveal the enlargement of the singlet-triplet energy gaps (DeltaEpsilons-t) in the order of immonium > phosphorus > sulfur > carbon. The observed trend, which is taken as an indication of stability, is thoroughly analyzed by applying appropriate isodesmic reactions which differentiate the substituent effects on each of our singlet or triplet carbene. The effect of unsaturation is also probed in each series of the ylide carbenes. The reactivity of the species is discussed in terms of nucleophilicity and electrophilicity. PMID- 24807317 TI - Identification of candidates for progesterone: why, who, how, and when? AB - Recognition of preterm birth as the major underlying cause of infant mortality in the United States has placed responsibility for prevention in the hands of obstetrician-gynecologists. The advent of effective methods to identify and treat women with increased risk is a major advance that will alter the focus of prenatal care. Adoption of research findings into clinical practice, never an easy task, will be particularly challenging for efforts to reduce the risk of preterm birth. Historical risk factors for preterm birth are numerous and variably defined. Measurement of the length of the cervix with ultrasonography requires unique personnel and facilities. Care algorithms exist but lack the detailed information that comes with experience. This review offers perspective and detail to aid health care practitioners in developing a prematurity prevention strategy appropriate to their practice population. PMID- 24807318 TI - Incidence and prognosis of neonatal brachial plexus palsy with and without clavicle fractures. AB - OBJECTIVE: To report the incidence of neonatal brachial plexus palsy with and without ipsilateral clavicle fracture in a population of newborns and to compare the prognosis between these subgroups. METHODS: This was a retrospective review of 3,739 clavicle fractures and 1,291 brachial plexus palsies in neonates over a 24-year period from a geographically defined health care system with reference to county-wide population data. RESULTS: A referral clinic for children with brachial plexus palsies evaluated 1,383 neonates, of whom 320 also had ipsilateral clavicular fracture. As a result of referral patterns within the region, it is likely that this represents nearly all infants from the area with persistent brachial plexus injury after 2 months of age. Among the children evaluated without concomitant clavicular fracture, 72% resolved spontaneously (154/214); among those with concomitant clavicular fracture, 74% healed spontaneously (55/74). Limiting the analysis to neonates delivered at Parkland Memorial Hospital and assuming that those neonates with a discharge diagnosis of brachial plexus injury with or without clavicular fracture who did not present to the referral brachial plexus injury clinic had complete resolution, 94.4% without clavicular fracture resolved and 98.1% with clavicular fracture resolved (P=.005). CONCLUSIONS: The risk of persistent neurologic deficit from a birth related brachial plexus palsy is lower than what has been reported, and the presence of a clavicle fracture may improve the likelihood of recovery. LEVEL OF EVIDENCE: III. PMID- 24807319 TI - Validity and reliability of the robotic Objective Structured Assessment of Technical Skills. AB - OBJECTIVE: Objective Structured Assessments of Technical Skills have been developed to measure the skill of surgical trainees. Our aim was to develop an Objective Structured Assessments of Technical Skills specifically for trainees learning robotic surgery. METHODS: This is a multiinstitutional study conducted in eight academic training programs. We created an assessment form to evaluate robotic surgical skill through five inanimate exercises. Gynecology, general surgery, and urology residents, Fellows, and faculty completed five robotic exercises on a standard training model. Study sessions were recorded and randomly assigned to three blinded judges who scored performance using the assessment form. Construct validity was evaluated by comparing scores between participants with different levels of surgical experience; interrater and intrarater reliability were also assessed. RESULTS: We evaluated 83 residents, nine Fellows, and 13 faculty totaling 105 participants; 88 (84%) were from gynecology. Our assessment form demonstrated construct validity with faculty and Fellows performing significantly better than residents (mean scores 89+/-8 faculty, 74+/ 17 Fellows, 59+/-22 residents; P<.01). In addition, participants with more robotic console experience scored significantly higher than those with fewer prior console surgeries (P<.01). Robotic Objective Structured Assessments of Technical Skills demonstrated good interrater reliability across all five drills (mean Cronbach's alpha 0.79+/-0.02). Intrarater reliability was also high (mean Spearman's correlation 0.91+/-0.11). CONCLUSION: We developed a valid and reliable assessment form for robotic surgical skill. When paired with standardized robotic skill drills, this form may be useful to distinguish between levels of trainee performance. LEVEL OF EVIDENCE: II. PMID- 24807320 TI - Improving care for depression in obstetrics and gynecology: a randomized controlled trial. AB - OBJECTIVE: To evaluate an evidence-based collaborative depression care intervention adapted to obstetrics and gynecology clinics compared with usual care. METHODS: A two-site, randomized controlled trial included screen-positive women (Patient Health Questionnaire-9 score of at least 10) who met criteria for major depression, dysthymia, or both (Mini-International Neuropsychiatric Interview). Women were randomized to 12 months of collaborative depression management or usual care; 6-month, 12-month, and 18-month outcomes were compared. The primary outcomes were change from baseline to 12 months in depression symptoms and functional status. Secondary outcomes included at least 50% decrease and remission in depressive symptoms, global improvement, treatment satisfaction, and quality of care. RESULTS: Participants were, on average, 39 years old, 44% were nonwhite, and 56% had posttraumatic stress disorder. Intervention (n=102) compared with usual care (n=103) patients had greater improvement in depressive symptoms at 12 months (P<.001) and 18 months (P=.004). The intervention group compared with usual care group had improved functioning over the course of 18 months (P<.05), were more likely to have at least 50% decrease in depressive symptoms at 12 months (relative risk [RR] 1.74, 95% confidence interval [CI] 1.11 2.73), greater likelihood of at least four specialty mental health visits (6 month RR 2.70, 95% CI 1.73-4.20; 12-month RR 2.53, 95% CI 1.63-3.94), adequate dose of antidepressant (6-month RR 1.64, 95% CI 1.03-2.60; 12-month RR 1.71, 95% CI 1.08-2.73), and greater satisfaction with care (6-month RR 1.70, 95% CI 1.19 2.44; 12-month RR 2.26, 95% CI 1.52-3.36). CONCLUSION: Collaborative depression care adapted to women's health settings improved depressive and functional outcomes and quality of depression care. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01096316. LEVEL OF EVIDENCE: I. PMID- 24807321 TI - The case for universal prenatal genetic counseling. AB - Recent scientific advances in human genetics and prenatal diagnostic technologies challenge the counseling infrastructure of most obstetric services. In just the past several years, the American College of Obstetricians and Gynecologists has published guidelines on fragile X, spinal muscular atrophy, and cystic fibrosis screening, and new technologies including microarray analysis, cell-free fetal DNA, and carrier gene panels have become available. Obstetrics is at a crossroads, which requires consideration of new ways of providing genetic counseling. Currently a two-tiered process is used. Specific tests such as first- or second-trimester screening for aneuploidy are offered to virtually all women by a clinician who provides counseling and who may offer additional tests to patients in particular ethnic groups and those with unique obstetric or family histories. Frequently only this latter group and those who "screen positive" on the universally offered tests are sent to a genetic counselor. This approach worked well when screening focused on a relatively small number of diagnoses, but that is no longer the case. We argue that obstetricians, who were able to maintain mastery over the content of counseling when aneuploidies and karyotype analysis were the essential diagnoses and diagnostic tools available, are rarely able to offer the same level of expertise regarding the chromosomal, genomic, and genetic diseases now diagnosable and the newest available diagnostic methodologies. Therefore, all women, not just those surpassing some poorly defined level of risk, deserve genetic counseling. Approaches for achieving this goal are discussed. PMID- 24807322 TI - Bioinformatic approach to the genetics of preeclampsia. AB - OBJECTIVE: To identify candidate genes and genetic variants for preeclampsia using a bioinformatic approach to extract and organize genes and variants from the published literature. METHODS: Semantic data-mining and natural language processing were used to identify articles from the published literature meeting criteria for potential association with preeclampsia. Articles were manually reviewed by trained curators. Cluster analysis was used to aggregate the extracted genes into gene sets associated with preeclampsia or severe preeclampsia, early or late preeclampsia, maternal or fetal tissue sources, and concurrent conditions (ie, fetal growth restriction, gestational hypertension, or hemolysis, elevated liver enzymes, and low platelet count [HELLP]). Gene ontology was used to organize this large group of genes into ontology groups. RESULTS: From more than 22 million records in PubMed, with 28,000 articles on preeclampsia, our data-mining tool identified 2,300 articles with potential genetic associations with preeclampsia-related phenotypes. After curation, 729 articles were "accepted" that contained "statistically significant" associations with 535 genes. We saw distinct segregation of these genes by severity and timing of preeclampsia, by maternal or fetal source, and with associated conditions (eg, gestational hypertension, fetal growth restriction, or HELLP syndrome). CONCLUSION: The gene sets and ontology groups identified through our systematic literature curation indicate that preeclampsia represents several distinct phenotypes with distinct and overlapping maternal and fetal genetic contributions. LEVEL OF EVIDENCE: III. PMID- 24807323 TI - Treatment of cervical precancers: back to basics. AB - Both ablative (cervical cryotherapy, laser ablation) and excisional methods (loop electrosurgical excision procedure, cold knife conization) can be effective at treating cervical precancer. Excisional procedures are associated with adverse obstetric outcomes including preterm delivery and perinatal mortality with the depth of excision potentially contributing to the adverse outcomes. Ablative therapies are now used much less commonly than loop electrosurgical excision procedure but have less of an effect on adverse obstetric outcomes and hence are effective alternatives for treating cervical precancer in reproductive-aged women. Morphometric data indicate that the vast majority of precancerous lesions are less than 5 mm deep, suggesting that treatments that reach 6-7 mm below the epithelium are adequate in women with satisfactory colposcopy. Cone biopsies, "top-hat" loop electrosurgical excision procedures, or the use of loop electrodes greater than 10 mm are therefore unnecessary for the majority of reproductive aged women and increase risk of adverse obstetric outcomes. New consensus guidelines allow observation instead of treatment in appropriately selected young women. Until the association of excisional methods with adverse obstetric outcomes is clarified with more data, ablative methods should be revitalized and used by health care providers in appropriately selected patients. Treatment should be individualized based on patient's age, fertility desires, and colpopathologic findings. PMID- 24807324 TI - Oophorectomy and hysterectomy and cancer incidence in the Cancer Prevention Study II Nutrition Cohort. AB - OBJECTIVE: To examine associations of simple hysterectomy and hysterectomy with bilateral salpingo-oophorectomy (BSO), relative to no surgery, with total and site-specific cancer risk in the Cancer Prevention Study-II Nutrition Cohort. METHODS: We examined associations of hysterectomy with BSO and simple hysterectomy with total and site-specific cancer risk in 66,802 postmenopausal women from the Cancer Prevention Study-II Nutrition Cohort. RESULTS: During a median follow-up of 13.9 years, 8,621 cancers were diagnosed. Hysterectomy with BSO performed at any age (1,892 cases), compared with no hysterectomy (n=5,586 cases), is associated with a 10% reduction in all cancers (relative risk [RR] 0.90, 95% confidence interval [CI] 0.85-0.96). This inverse association does not hold if the surgery occurred at ages 55 years or older (583 cases; RR 1.02, 95% CI 0.94-1.12). Hysterectomy with BSO (715 cases) was associated with a 20% reduction in breast cancer performed at any age (RR 0.80, 95% CI 0.73-0.88). Hysterectomy without BSO was associated with a deceased cancer risk only if performed at age 45 years or younger (541 cases; RR 0.88, 95% CI 0.80-0.97) and overall was associated with a decreased risk of breast cancer (419 cases; RR 0.86, 95% CI 0.76-0.96). CONCLUSION: In a large prospective study, hysterectomy with BSO before age 55 years, relative to no surgery, is associated with a lower risk of total cancer. This information, particularly the lower risk in women younger than 45 years, should be considered in counseling women about ovarian management at the time of surgery. LEVEL OF EVIDENCE: II. PMID- 24807325 TI - Suture compared with staple skin closure after cesarean delivery: a randomized controlled trial. AB - OBJECTIVE: To compare the incidence of wound complications between suture and staple skin closure after cesarean delivery. METHODS: This prospective, randomized clinical trial conducted at three hospitals in the United States between 2010 and 2012 included women undergoing cesarean delivery at 23 weeks of gestation or greater through a low-transverse skin incision. Women were randomized to closure of the skin incision with suture or staples after stratifying by body mass index and primary compared with repeat cesarean delivery. The primary outcome was incidence of wound complications, predefined as a composite of infection, hematoma, seroma, separation of 1 cm or longer, or readmission for wound complications. Analysis was according to the intention-to treat principle; results were stratified by randomization group and adjusted for hospital by including it as a covariate. RESULTS: A total of 746 women were randomized, 370 to suture and 376 to staple closure. The median gestational age was 39 weeks. Fifty-eight women (7.8%) had wound complications-4.9% in the suture group and 10.6% in the staple group (adjusted odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.78); this was largely the result of the decreased incidence of wound separation in the respective groups (1.6% compared with 7.4%; adjusted OR 0.20, 95% CI 0.07-0.51). CONCLUSIONS: Suture closure of the skin incision at cesarean delivery is associated with a 57% decrease in wound complications compared with staple closure. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT01211600. LEVEL OF EVIDENCE: I. PMID- 24807326 TI - Prediction of fetal compromise in labor. AB - OBJECTIVE: The majority of intrapartum fetal hypoxia occurs in uncomplicated pregnancies. Current intrapartum monitoring techniques have not resulted in a reduction in the incidence of cerebral palsy in term neonates. We report the development of a composite risk score to allow risk stratification of normal pregnancies before labor. METHODS: Six hundred one women were recruited to this prospective observational study. All women underwent an ultrasound examination before active labor, during which fetal biometry and fetal Doppler flow resistance indices were measured. A composite risk score, amalgamating data from the umbilical artery, middle cerebral artery, and umbilical vein, was then developed and correlated with intrapartum outcomes. RESULTS: In cases with the highest composite risk scores, the incidence of fetal compromise (the primary outcome) was 80.0% compared with just 15.3% in cases with the lowest risk scores (relative risk 5.2, 95% confidence interval 2.7-10.1). These cases were also at increased risk of cesarean delivery (53.3% compared with 3.4%, P<.001) and of developing a fetal heart rate pattern considered pathologic by National Institute for Health and Clinical Excellence criteria (P=.003). No significant variation in Apgar scores or umbilical artery pH was observed. CONCLUSION: Intrapartum fetal compromise remains a significant global health issue. The composite risk score reported here can identify fetuses at both high risk and low risk of a subsequent diagnosis of intrapartum fetal compromise. This may enable more judicious use of current intrapartum fetal monitoring techniques, which are hampered by low specificity. LEVEL OF EVIDENCE: II. PMID- 24807327 TI - Foley catheter compared with the controlled-release dinoprostone insert: a randomized controlled trial. AB - OBJECTIVE: To assess efficacy of the Foley catheter compared with the dinoprostone vaginal insert for beginning labor inductions at or near term. METHODS: We performed a multicenter randomized controlled trial. We enrolled women at 36 weeks of gestation or greater with a singleton live fetus in cephalic presentation, intact membranes, an unfavorable cervix (dilation less than 3 cm; if 2 cm, less than 80% effaced), and no contraindication to labor or either study agent. Women were allocated to either a cervical Foley catheter inflated to 30 mL or dinoprostone for up to 12 hours. Oxytocin was allowed only after study agent removal. The primary outcome was time from agent placement to delivery. Secondary outcomes included delivery by 24 hours, vaginal delivery by 24 hours, time to vaginal delivery, cesarean delivery rate, and rate of tachysystole. Analysis was by intent-to-treat. RESULTS: We enrolled 376 patients, 185 allocated to Foley catheter and 191 to dinoprostone. In the Foley catheter group, time to delivery was shorter (median 21.6 compared with 26.6 hours; P=.003), more patients delivered within 24 hours (56% compared with 40%; P=.003), more delivered vaginally within 24 hours (44% compared with 30%; P=.004), and time to vaginal delivery was shorter (median 20.1 compared with 24.3 hours; P=.005). The cesarean delivery rates were 29% compared with 39% (P=.07). Uterine tachysystole occurred in 0% compared with 3% (P=.06). CONCLUSION: Starting labor inductions with a Foley catheter, compared with the dinoprostone vaginal insert, results in a shorter time to delivery and a higher proportion of women delivered and delivered vaginally within 24 hours. Cesarean delivery rates were not statistically significantly different. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01402050. LEVEL OF EVIEDENCE: I. PMID- 24807328 TI - Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor. AB - OBJECTIVE: To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor. METHODS: We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. RESULTS: Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk. CONCLUSION: Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days. LEVEL OF EVIDENCE: II. PMID- 24807329 TI - Locating pain in breast cancer survivors experiencing dyspareunia: a randomized controlled trial. AB - OBJECTIVE: To locate sites of genital tenderness in breast cancer survivors not using estrogen who experience dyspareunia and to test the hypothesis that tenderness is limited to the vulvar vestibule rather than the vagina and is reversed by topical anesthetic. METHODS: Postmenopausal survivors of breast cancer with moderate and severe dyspareunia were recruited for an examination including randomization to a double-blind intervention using topical aqueous 4% lidocaine or normal saline for 3 minutes to the areas found to be tender. Comparisons of changes in patients' reported numerical rating scale values were made with the Wilcoxon rank-sum test with significance set at P<.05. RESULTS: Forty-nine patients aged 37-69 years (mean 55.6+/-8.6 years) had a median coital pain score of 8 (interquartile range 7-9, scale 0-10). On examination, all women had tenderness in the vulvar vestibule (worst site 4 o'clock median 6, 4-7). In addition, one had significant vaginal mucosal tenderness and two had pelvic floor myalgia. All had vulvovaginal atrophy with 86% having no intravaginal discharge. Aqueous lidocaine 4% reduced the vestibular tenderness of all painful sites. For example, pain at the worst site changed from a median of 5 (4-7) to 0 (0-1) as compared with saline placebo, which changed the worst site score from 6 (4-7) to 4 (3-6) (P<.001). After lidocaine application, speculum placement was nontender in the 47 without either myalgia or vaginal mucosal tenderness. CONCLUSION: In breast cancer survivors with dyspareunia, exquisite sensitivity was vestibular and reversible with aqueous lidocaine. Vaginal tenderness was rare despite severe atrophy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01539317. LEVEL OF EVIDENCE: I. PMID- 24807330 TI - Indomethacin and antibiotics in examination-indicated cerclage: a randomized controlled trial. AB - OBJECTIVE: To evaluate whether perioperative indomethacin and antibiotic administration at the time of examination-indicated cerclage placement prolongs gestation. METHODS: This is a randomized controlled trial performed at a single tertiary care hospital between March 2010 and November 2012. Women older than 18 years of age with a singleton pregnancy between 16 0/7 and 23 6/7 weeks of gestation undergoing an examination-indicated cerclage were eligible. Women were randomly assigned to receive either perioperative indomethacin and antibiotics or no perioperative prophylactic medications. The primary outcome was gestational latency after cerclage placement. Fifty women were required to be randomized to show, with 80% power, a 28-day improvement in latency assuming a latency without intervention of 50+/-35 days. RESULTS: Fifty-three patients were enrolled with three lost to follow-up. A greater proportion of pregnancies were prolonged by at least 28 days among women who received indomethacin and perioperative antibiotics (24 [92.3%] compared with 15 [62.5%], P=.01). However, gestational age at delivery and neonatal outcomes were statistically similar between groups. CONCLUSIONS: Among women receiving an examination-indicated cerclage in the second trimester, gestation was significantly more likely to be prolonged by 28 days among women who received perioperative indomethacin and antibiotics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01114516. LEVEL OF EVIDENCE: I. PMID- 24807331 TI - Effect of excess gestational weight gain on pregnancy outcomes in women with type 1 diabetes. AB - OBJECTIVE: To evaluate the prevalence and clinical effects of excess gestational weight gain on birth weight and other pregnancy outcomes in women with type 1 diabetes. METHODS: We performed a retrospective cohort study of women with type 1 diabetes delivered between 2009 and 2012. Patients with excess weight gain were identified using the 2009 Institute of Medicine weight gain recommendations adjusted for gestational age at delivery and prepregnancy body mass index (BMI) category. Demographic and outcome data were abstracted from the medical record, and pregnancy outcomes were compared between women with and without excess gestational weight gain. RESULTS: Excess gestational weight gain occurred in 114 of 175 women (65.1%). Large-for-gestational-age (LGA) birth weight occurred in 48 of 114 (42.1%) of women with excess gestational weight gain and 5 of 61 (8.2%) of women with recommended weight gain (P<.001). The association between excess maternal weight gain and LGA birth weight remained significant after adjustment for prepregnancy BMI, gestational age at delivery, nulliparity, vascular complications, and hemoglobin A1c measurements (adjusted odds ratio 8.9, 95% confidence interval 3.1-26.2, P<.001). Stratified analyses demonstrated that excess maternal weight gain is associated with LGA neonates in both normal-weight and overweight or obese women. CONCLUSIONS: Excess maternal weight gain is common and leads to higher rates of LGA neonates in both normal-weight and overweight or obese women with type 1 diabetes. Interventions designed to limit excess gestational weight gain may reduce the risk for fetal overgrowth in women with type 1 diabetes. LEVEL OF EVIDENCE: II. PMID- 24807332 TI - Mode of delivery after successful external cephalic version: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the mode of delivery in women after a successful external cephalic version by performing a systematic review and meta-analysis. DATA SOURCES: We searched MEDLINE, Embase, ClinicalTrials.gov, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library for studies reporting on the mode of delivery in women after successful external cephalic version at term and women with a spontaneous cephalic-presenting fetus. METHODS OF STUDY SELECTION: Two reviewers independently selected studies, extracted data, and assessed study quality. The association between mode of delivery and successful external cephalic version was expressed as a common odds ratio with a 95% confidence interval (CI). TABULATION, INTEGRATION, AND RESULTS: We identified three cohort studies and eight case-control studies, reporting on 46,641 women. The average cesarean delivery rate for women with a successful external cephalic version was 21%. Women after successful external cephalic version were at increased risk for cesarean delivery for dystocia (odds ratio [OR] 2.2, 95% CI 1.6-3.0), cesarean delivery for fetal distress (OR 2.2, 95% CI 1.6-2.9), and instrumental vaginal delivery (OR 1.4, 95% CI 1.1-1.7). LEVEL OF EVIDENCE: Women who have had a successful external cephalic version for breech presentation are at increased risk for cesarean delivery and instrumental vaginal delivery as compared with women with a spontaneous cephalic presentation. Nevertheless, with a number needed to treat of three, external cephalic version still remains a very efficient procedure to prevent a cesarean delivery. PMID- 24807333 TI - Association of combined first-trimester screen and noninvasive prenatal testing on diagnostic procedures. AB - OBJECTIVE: To describe the changes over a 9-year period in the number and rate of diagnostic testing after the introduction of the combined first-trimester screen and subsequent noninvasive prenatal testing. METHODS: The number of prenatal screening and diagnostic tests was recorded over a 9-year period from billing records. Three time intervals were considered: 1) 20 months before a combined first-trimester screen was offered; 2) 72 months after a combined first-trimester screen was offered; and 3) 16 months after noninvasive prenatal testing introduction. Prenatal testing was compared per year, per time interval, and per 100 morphologic ultrasonograms to account for fluctuations in patient number. RESULTS: A total of 15,418 prenatal tests was recorded during the study period, consisting of 9,780 combined first-trimester screen, 1,265 noninvasive prenatal testing, 608 chorionic villus sampling (CVS), and 3,765 amniocenteses. Combined first-trimester screen peaked at 1,836 in 2009-2010 but declined by 48.1% after noninvasive prenatal testing was introduced. Combined first-trimester screen per 100 morphologic ultrasonograms also significantly decreased (P<.05) after noninvasive prenatal testing introduction. Chorionic villus sampling peaked after combined first-trimester screen introduction in 2007-2008 with 100 procedures, representing an 81.8% increase from prefirst-trimester screen. After the introduction of noninvasive prenatal testing, CVS declined by 68.6% during 2012 2013. Chorionic villus sampling per 100 morphologic ultrasonograms followed the same trend. Amniocentesis declined every year of the study period (78.8% overall), including 60.3% after combined first-trimester screen and a further 46.7% after noninvasive prenatal testing. Monthly amniocentesis procedures per 100 morphologic ultrasonograms significantly decreased (P<.05) after introduction of a combined first-trimester screen and noninvasive prenatal testing. CONCLUSION: The introduction of combined first-trimester screen was associated with an increase in CVS and a decrease in amniocentesis testing. Noninvasive prenatal testing was associated with a subsequent decrease in CVS and further decrease in amniocentesis. LEVEL OF EVIEDENCE: III. PMID- 24807334 TI - Responding to prenatal disclosure of past sexual abuse. AB - The American College of Obstetricians and Gynecologists recommends that physicians elicit a sexual abuse and rape trauma history for every patient, yet, in practice, physicians still may struggle to understand how best to obtain this history and what clinical obligations arise when a physician inquires and a woman discloses a remote history of childhood or adult sexual trauma during the course of her prenatal care. This commentary offers a practical strategy for responding to sexual trauma disclosure by developing a tailored obstetric care plan for avoiding retraumatization in labor. In this way, obstetricians may avoid causing harm and begin to meet the unique obstetric and psychological needs of sexual trauma survivors during pregnancy and delivery. PMID- 24807335 TI - Repeat midurethral sling compared with urethral bulking for recurrent stress urinary incontinence. AB - OBJECTIVE: To compare the effectiveness and safety of repeat midurethral sling with urethral bulking after failed midurethral sling. METHODS: This is a retrospective cohort study of patients within Kaiser Permanente Southern California Medical Group who underwent a midurethral sling for stress urinary incontinence (SUI) from 2008 to 2011 and subsequently had either a midurethral sling or urethral bulking for recurrent SUI. Current Procedural Terminology codes were used to identify patients and electronic medical records were queried for individual patient information. Our primary outcome was either subjective failure defined by SUI or objective failure defined as a positive cough stress test, urodynamic stress incontinence, or retreatment for SUI. Secondary outcomes included perioperative complications and adverse events. RESULTS: Of 6,914 midurethral slings performed, 165 patients underwent a repeat procedure for recurrent SUI, including 98 midurethral slings and 67 urethral bulking. Of the 165 patients who underwent repeat procedures, there were 11 failures (11.2%) in the midurethral sling group and 26 failures (38.8%) in the urethral bulking group (P=.004). There were no differences in perioperative complications or adverse events between the groups. In multivariable logistic regression, risk of failure was significantly higher in those undergoing urethral bulking compared with those undergoing midurethral sling (odds ratio 3.49, 95% confidence interval 1.34-9.09, P=.01). CONCLUSIONS: In a managed care population, urethral bulking was associated with higher risk of failure than repeat midurethral sling after primary midurethral sling failure with no differences in perioperative complications or adverse events. LEVEL OF EVIDENCE: II. PMID- 24807336 TI - Trends in glyburide compared with insulin use for gestational diabetes treatment in the United States, 2000-2011. AB - OBJECTIVE: To describe trends and identify factors associated with choice of pharmacotherapy for gestational diabetes (GDM) from 2000-2011 using a healthcare claims database. METHODS: This was a retrospective cohort study of a large nationwide population of commercially insured women with GDM and pharmacy claims for glyburide or insulin before delivery, 2000-2011. We excluded women younger than 15 years or older than 50 years, those with prior noninsulin-dependent diabetes mellitus, or those who had multiple gestations. We estimated trends over time in the use of glyburide compared with insulin and prevalence ratios and 95% confidence intervals (CIs) for the association between covariates of interest and treatment with glyburide compared with insulin. RESULTS: We identified 10,778 women with GDM treated with glyburide (n=5,873) or insulin (n=4,905). From 2000 to 2011, glyburide use increased from 7.4% to 64.5%, becoming the more common treatment in 2007. Women less likely to be treated with glyburide were those with metabolic syndrome (prevalence ratio 0.71, 95% CI 0.50-0.99), hyperandrogenism (prevalence ratio 0.77, 95% CI 0.62-0.97), polycystic ovarian syndrome (prevalence ratio 0.88, 95% CI 0.78-0.99), hypothyroidism (prevalence ratio 0.89, 95% CI 0.83-0.96), or undergoing infertility treatment (prevalence ratio 0.93, 95% CI 0.86-1.02). The probability of receiving glyburide decreased by 5% for every 10-year increase in maternal age (prevalence ratio 0.95, 95% CI 0.91-0.99). Among women prescribed with glyburide, 7.8% switched or augmented to a different drug class compared with 1.1% of insulin initiators. CONCLUSION: Glyburide has replaced insulin as the more common pharmacotherapy for GDM over the past decade among those privately insured. Given its rapid uptake and the potential implications of suboptimal glucose control on maternal and neonatal health, robust evaluation of glyburide's relative effectiveness is warranted to inform treatment decisions for women with gestational diabetes. LEVEL OF EVIDENCE: II. PMID- 24807337 TI - Preemptive use of gabapentin in abdominal hysterectomy: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the evidence of preemptive use of gabapentin in abdominal hysterectomy. DATA SOURCES: We conducted an electronic based search using the following databases: PubMed, EMBASE, Ovid MEDLINE, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials. The following medical subject heading terms, keywords, and their combinations were used: "postoperative pain, hysterectomy, gynecologic surgical procedures, gabapentin, preemptive analgesia, and preemptive anesthesia." We manually searched the reference lists of identified studies. METHODS OF STUDY SELECTION: Randomized controlled trials of women who underwent a total abdominal hysterectomy, with or without bilateral salpingo-oophorectomy, under general anesthesia were examined. Only trials with preoperative dose of gabapentin were included. TABULATION, INTEGRATION, AND RESULTS: The meta-analysis and systematic review were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Fourteen trials met the inclusion criteria. The pooled data consisted of 448 cases in the gabapentin group and 443 others in the control group. The 24 hour cumulative narcotic consumption and the visual analog scale scores at 24 hours postoperatively were used for postoperative pain assessment. There was a significant decrease in morphine consumption at 24 hours when gabapentin was administered before surgery (from 24.3-55.9 mg to 13.2-42.7 mg, standardized mean difference -0.69) as well before and after surgery (from 25.7-80 mg to 20.3-55 mg, standardized mean difference -1.45), respectively. Metaregression analysis showed that the effect of gabapentin in reducing morphine consumption (compared with placebo) at 24 hours was stronger in the preoperative only group than in the preoperative and postoperative groups. Preemptive gabapentin decreased visual analog scale from 9-42.7 to 2-25.3 (standardized mean difference -1.03, 95% confidence interval [CI] -1.36 to -0.71). Compared with the control group (16.1 96.7%), the rate of nausea was less in the gabapentin group (11.6-70%, relative risk 0.76, 95% CI 0.66-0.88). CONCLUSION: Preemptive administration of gabapentin is effective in decreasing postoperative pain scores, narcotic consumption, and nausea, and vomiting. LEVEL OF EVIDENCE: I. PMID- 24807338 TI - Adding injury to injury: ethical implications of the Medicaid sterilization consent regulations. AB - The need for contraceptive and family planning services is often unmet, especially among lower-income women. However, the history of the provision of these services is fraught with coercion and mistrust: in 1979, in response to forced sterilization practices among doctors working with poor and minority populations, the U.S. Department of Health, Education, and Welfare imposed regulations on the informed consent process for Medicaid recipients requesting sterilization. The government mandated, among other requirements, a 30-day waiting period between consent and surgery and proscribed laboring women from providing consent. Initially intended to prevent the exploitation of poor women, these rules have instead become a barrier to many women receiving strongly desired, effective, permanent contraception. More critically, the regulations are ethically flawed: by preventing women from accessing needed family planning services, the Medicaid consent rules violate the standards of beneficence and nonmaleficence; by treating publically insured women differently from privately insured women, they fail the justice standard; and by placing constraints on women's free choice of contraceptive methods, they run afoul of the autonomy standard. The current federal sterilization consent regulations warrant revising. The new rules must simultaneously reduce barriers to tubal ligation while safeguarding the rights of women who have historically suffered mistreatment at the hands of the medical profession. These goals could best be obtained through a combined approach of improved clinician ethics education and a new standardized sterilization consent policy, which applies to all women and which abolishes the 30-day waiting period and the prohibition on obtaining consent in labor. PMID- 24807339 TI - Mifepristone and oral, vaginal, or sublingual misoprostol for second-trimester abortion: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of the vaginal and sublingual administration of the synthetic prostaglandin misoprostol with the currently used oral administration route in second-trimester medical abortion. METHODS: This was a prospective randomized trial of medical abortion with misoprostol after mifepristone priming at 14-24 weeks of gestation. From 2009 to 2013, recruited women received 200 mg mifepristone orally followed 24-48 hours later by an 800 microgram vaginal loading dose of misoprostol. Women were then randomized to receive additional 400-microgram misoprostol doses orally every 3 hours, vaginally every 4 hours, or sublingually every 3 hours. The main outcome was the duration of abortion with emphasis on the proportion of women undelivered 12 hours after the misoprostol loading dose in the three groups. RESULTS: A total of 302 women were randomized: 100 to oral, 100 to vaginal, and 102 to sublingual misoprostol. The median gestation at recruitment was oral 19.1 weeks (interquartile range 17.2-20.8), vaginal 19.4 weeks (interquartile range 17.3 20.4), and sublingual 19.7 weeks (interquartile range 17.6-21.0). The overall abortion duration was longer in women receiving oral misoprostol: oral 9.5 hours (95% confidence interval [CI] 8.5-11.4), vaginal 7.4 hours (95% CI 6.5-8.2), and sublingual 7.8 hours (95% CI 7.0-9.2). Overall, 84 of 302 (27.8%) women were undelivered at 12 hours, comprising 37.0% (95% CI 28.7-47.8) oral, 20.5% (95% CI 14.0-30.1) vaginal, and 21.0% (95% CI 14.3-30.7) sublingual groups. CONCLUSION: Vaginal or sublingual misoprostol administered after a vaginal loading dose in second-trimester medical abortion with mifepristone priming is associated with a shorter time to pregnancy termination compared with an oral regimen. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00864799. LEVEL OF EVIDENCE: I. PMID- 24807340 TI - Ondansetron compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. AB - OBJECTIVE: To compare ondansetron with metoclopramide in the treatment of hyperemesis gravidarum. METHODS: We enrolled 160 women with hyperemesis gravidarum in a double-blind randomized trial. Participants were randomized to intravenous 4 mg ondansetron or 10 mg metoclopramide every 8 hours for 24 hours. Participants kept an emesis diary for 24 hours; at 24 hours, they expressed their well-being using a 10-point visual numeric rating scale and answered an adverse effects questionnaire. Nausea intensity was evaluated using a 10-point visual numeric rating scale at enrollment and at 8, 16, and 24 hours. Primary analysis was on an intention-to-treat basis. RESULTS: Eighty women each were randomized to ondansetron or metoclopramide. Median well-being visual numeric rating scale scores were 9 (range, 5-10) compared with 9 (range, 4-10) (P=.33) and vomiting episodes in the first 24 hours were 1 (range, 0-9) compared with 2 (range, 0-23) (P=.38) for ondansetron compared with metoclopramide, respectively. Repeat measures analysis of variance of nausea visual numeric rating scale showed no difference between study drugs (P=.22). Reported rates of drowsiness (12.5% compared with 30%; P=.01; number needed to treat to benefit, 6), xerostomia (10.0% compared with 23.8%; P<.01; number needed to treat to benefit, 8), and persistent ketonuria at 24 hours (12.5% compared with 30%; P=.01; number needed to treat to benefit, 6) were less frequent with ondansetron. Length of hospital stay was similar. CONCLUSION: Ondansetron and metoclopramide demonstrated similar antiemetic and antinauseant effects in hyperemesis gravidarum. However, the overall profile, particularly regarding adverse effects, was better with ondansetron. In our setting, metoclopramide was significantly less expensive than ondansetron and remained a reasonable antiemetic choice. CLINICAL TRIAL REGISTRATION: ISRCN Register, www.isrctn.org, ISRCTN00592566. LEVEL OF EVIDENCE: I. PMID- 24807341 TI - Lifetime risk of stress urinary incontinence or pelvic organ prolapse surgery. AB - OBJECTIVE: To estimate the lifetime risk of stress urinary incontinence (SUI) surgery, pelvic organ prolapse (POP) surgery, or both using current, population based surgical rates from 2007 to 2011. METHODS: We used a 2007-2011 U.S. claims and encounters database. We included women aged 18-89 years and estimated age specific incidence rates and cumulative incidence (lifetime risk) of SUI surgery, POP surgery, and either incontinence or prolapse surgery with 95% confidence intervals (CIs). We estimated lifetime risk until the age of 80 years to be consistent with prior studies. RESULTS: From 2007 to 2011, we evaluated 10,177,480 adult women who were followed for 24,979,447 person-years. Among these women, we identified 65,397 incident, or first, SUI and 57,755 incident prolapse surgeries. Overall, we found that the lifetime risk of any primary surgery for SUI or POP was 20.0% (95% CI 19.9-20.2) by the age of 80 years. Separately, the cumulative risk for SUI surgery was 13.6% (95% CI 13.5-13.7) and that for POP surgery was 12.6% (95% CI 12.4-2.7). For age-specific annual risk, SUI demonstrated a bimodal peak at age 46 years and then again at age 70-71 years with annual risks of 3.8 and 3.9 per 1,000 women, respectively. For POP, the risk increased progressively until ages 71 and 73 years when the annual risk was 4.3 per 1,000 women. CONCLUSION: Based on a U.S. claims and encounters database, the estimated lifetime risk of surgery for either SUI or POP in women is 20.0% by the age of 80 years. LEVEL OF EVIDENCE: III. PMID- 24807342 TI - What is new in patient safety?: best articles from the past year. AB - This month, we focus on current research in patient safety. Dr. Pridjian discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 24807343 TI - Whither bioinformatics?: the promise and peril of an informatics-driven inquiry. PMID- 24807344 TI - When pregnancy must end in the second trimester. PMID- 24807345 TI - Receipt of prescription contraception by commercially insured women with chronic medical conditions. AB - OBJECTIVE: To assess differences in receipt of prescription contraception among women with and without chronic medical conditions. METHODS: This observational study used 3 years of administrative claims records for insured women aged 21-45 years who were enrolled in a commercial insurance company in Michigan between 2004 and 2009. Women were considered to have a chronic medical condition if they had at least two claims for one of the following conditions, in order of prevalence in our study population: hypertension, asthma, hypothyroidism, diabetes, obesity, rheumatoid arthritis, inflammatory bowel disease, or systemic lupus erythematosus. Our primary outcome was receipt of prescription contraception, defined by a pharmacy claim or diagnostic or procedural code. We used multivariable logistic regression to estimate the association of chronic condition status with the odds of receiving prescription contraception within 3 years adjusting for age, community-level socioeconomic status, total outpatient visits, and cervical cancer screening. RESULTS: Of 11,649 women studied, 16.0% (n=1,862) had at least one of the chronic conditions we considered. Of those with a chronic condition, 33.5% (n=623) received prescription contraception during the 3-year study period compared with 41.1% (n=4,018) of those without a chronic condition (P<.001). After adjusting for covariates, women with a chronic condition remained less likely than women without a chronic condition to have received prescription contraception (adjusted odds ratio 0.85, 95% confidence interval 0.76-0.96, P=.010). CONCLUSION: Despite a greater risk for adverse outcomes with an unplanned pregnancy, women with these chronic conditions were less likely to receive prescription contraception. LEVEL OF EVIDENCE: III. PMID- 24807346 TI - Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. AB - OBJECTIVE: To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure. METHODS: Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography-tandem mass spectrometry. RESULTS: There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to maternal concentration ratio was 0.33 (interquartile range 0.29-0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15-0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges. CONCLUSION: This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation. PMID- 24807347 TI - Cochrane in CORR(r): Surgical versus conservative interventions for treating fractures of the middle third of the clavicle. PMID- 24807348 TI - Medicolegal sidebar: Physician competence and skill part II: Hospital corporate responsibility and new technologies. PMID- 24807350 TI - Testing for Aleutian mink disease virus in the river otter (Lontra canadensis) in sympatry with infected American mink (Neovison vison). AB - Aleutian mink disease virus (AMDV) occurs in the American mink (Neovison vison) in wild populations and on mink farms and can cause illness and death. The North American river otter (Lontra canadensis) may be exposed to AMDV because of shared space and habitat with mink. Using serology and real-time PCR, we tested river otters across Ontario for AMDV infection. We found no evidence of infection in otters, a surprising finding given the sympatric distribution, niche overlap, and close phylogenetic relationship of the river otter and the American mink. Our results are consistent with the hypothesis that the major point of spillover of AMDV between mink farms and wildlife is manure and composting carcasses on mink farms. Mink farms in Ontario are generally in agricultural landscapes; it is unlikely that river otter use these habitats and thus are likely not exposed to AMDV. We found no evidence that AMD is an important disease for the river otters in Ontario. PMID- 24807349 TI - Chromatin barcodes as biomarkers for melanoma. AB - The major barrier to effective cancer therapy is the presence of genetic and phenotypic heterogeneity within cancer cell populations that provides a reservoir of therapeutically resistant cells. As the degree of heterogeneity present within tumours will be proportional to tumour burden, the development of rapid, robust, accurate and sensitive biomarkers for cancer progression that could detect clinically occult disease before substantial heterogeneity develops would provide a major therapeutic benefit. Here, we explore the application of chromatin conformation capture technology to generate a diagnostic epigenetic barcode for melanoma. The results indicate that binary states from chromatin conformations at 15 loci within five genes can be used to provide rapid, non-invasive multivariate test for the presence of melanoma using as little as 200 MUl of patient blood. PMID- 24807351 TI - Orthopoxvirus antibodies in grey squirrels (Sciurus aureogaster) in Mexico City, Mexico. AB - Serum from Mexican grey squirrels (Sciurus aureogaster) from Mexico City reacted to Orthopoxvirus by enzyme-linked immunosorbent assay. Real-time PCR based on oral swabs and scabs did not detect viral DNA. Antibody prevalence was 30% (n=366), providing the first evidence of Orthopoxvirus antibodies in Mexican wild rodents. PMID- 24807352 TI - "Atypical" chronic wasting disease in PRNP genotype 225FF mule deer. AB - We compared mule deer (Odocoileus hemionus) of two different PRNP genotypes (225SS, 225FF) for susceptibility to chronic wasting disease (CWD) in the face of environmental exposure to infectivity. All three 225SS deer had immunohistochemistry (IHC)-positive tonsil biopsies by 710 days postexposure (dpe), developed classic clinical signs by 723-1,200 dpe, and showed gross and microscopic pathology, enzyme-linked immunosorbent assay (ELISA) results, and IHC staining typical of prion disease in mule deer. In contrast, although all three 225FF deer also became infected, the two individuals surviving >720 dpe had consistently negative biopsies, developed more-subtle clinical signs of CWD, and died 924 or 1,783 dpe. The 225FF deer were "suspect" by ELISA postmortem but showed negative or equivocal IHC staining of lymphoid tissues; both clinically affected 225FF deer had spongiform encephalopathy in the absence of IHC staining in the brain tissue. The experimental cases resembled three cases encountered among five additional captive 225FF deer that were not part of our experiment but also died from CWD. Aside from differences in clinical disease presentation and detection, 225FF mule deer also showed other, more-subtle, atypical traits that may help to explain the rarity of this genotype in natural populations, even in the presence of enzootic CWD. PMID- 24807353 TI - Aujeszky's disease in red fox (Vulpes vulpes): phylogenetic analysis unravels an unexpected epidemiologic link. AB - We describe Aujeszky's disease in a female of red fox (Vulpes vulpes). Although wild boar (Sus scrofa) would be the expected source of infection, phylogenetic analysis suggested a domestic rather than a wild source of virus, underscoring the importance of biosecurity measures in pig farms to prevent contact with wild animals. PMID- 24807354 TI - Prevalence of antibody to Toxoplasma gondii in black-headed gulls (Chroicocephalus ridibundus), Dianchi Lake, China. AB - Sera from 659 Black-headed Gulls (Chroicocephalus ridibundus) in Dianchi Lake, China were assayed for Toxoplasma gondii antibodies using the modified agglutination test (MAT). Specific T. gondii antibodies were detected in 131 (19.9%) Black-headed Gulls (MAT titer >= 1 ? 5). These results indicate that T. gondii infection is common in Black-headed Gulls. PMID- 24807355 TI - Evidence of Oxyspirura petrowi in migratory songbirds found in the rolling plains of West Texas, USA. AB - Three Northern Mockingbirds (Mimus polyglottos) and one Curve-billed Thrasher (Toxostoma curvirostre) from the Rolling Plains of Texas, USA were sampled for eyeworms in September 2013. All four birds were infected with the eyeworm Oxyspirura petrowi. PMID- 24807356 TI - Prevalence of antibodies to Leptospira in wild mammals trapped on livestock farms in Ontario, Canada. AB - To determine the prevalence and diversity of Leptospira serogroups circulating in wildlife on farms in Ontario, we tested samples from 51 raccoons (Procyon lotor), seven skunks (Mephitis mephitis), four rats (Rattus norvegicus), and three opossums (Didelphis virginiana) that were trapped on 27 livestock (swine [Sus scrofa], cattle [Bos taurus]) farms in 2010. Seventeen of 51 raccoons (33%; 95% confidence interval [CI], 21-48%) sampled were positive for at least one Leptospira serogroup using the microscopic agglutination test. None of the other 14 animals had detectable Leptospira antibodies. On swine farms, 13 of 30 raccoons (43%; 95% CI, 27-61%) were antibody positive, and on cattle farms, four of 21 raccoons (19%; 95% CI, 8-40%) were positive. Leptospira antibody prevalence in raccoons did not differ between swine and cattle farms. Raccoons were positive to serovars representative of serogroups Grippotyphosa, Australis, Icterohaemorrhagiae, and Pomona and were negative to serovars of serogroups Autumnalis, Canicola, and Sejroe. The prevalence of Leptospira antibodies in raccoons in this study is similar to what has been reported previously; however, the diversity of serogroups was higher in this study than what has been reported in raccoons from an urban area of Ontario, Canada. Understanding the prevalence and distribution of Leptospira serogroups in wildlife in Ontario, Canada, is important for the development and maintenance of appropriate disease management strategies in humans, livestock, and companion animals. PMID- 24807357 TI - Mycobacteriosis associated with Mycobacterium peregrinum infection in Red-crowned Cranes (Grus japonensis) in China. AB - We describe mycobacteriosis caused by Mycobacterium peregrinum in Red-crowned Cranes (Grus japonensis) in China. Isolates were identified by bacteriology, molecular identification methods, and phylogenetic analysis. This study shows that M. peregrinum is an important pathogen for mycobacteriosis and could represent a threat to conservation efforts of endangered species. PMID- 24807358 TI - Efficacy of a low-dosage combination of butorphanol, azaperone, and medetomidine (BAM) to immobilize Rocky Mountain elk. AB - We compared dosages of a combination of sedatives, which included butorphanol tartrate, azaperone tartrate, and medetomidine HCl (BAM) in captive adult Rocky Mountain elk (Cervus elaphus nelsoni). All three BAM dosages (low, medium, and high) effectively immobilized elk and produced an adequate level of sedation in all subjects. Induction times were similar among the three groups (mean +/- SD: low=6.9 +/- 1.1 min; medium=6.3 +/- 0.9 min; high=4.7 +/- 1.3 min). Most elk became hypoxemic regardless of BAM dosage, but hypoxemia tended to be most severe in the high-BAM group; regardless of BAM dosage, oxygen supplementation improved the percentage of oxygen saturation and stabilized the vital rates. Recovery after administration of antagonists (3 mg atipamezole/mg medetomidine and 2 mg/kg tolazoline) was comparable among groups (range of means=9 +/- 1.5-11.7 +/- 1 min). Based on the findings from clinical trials and field data from free-ranging elk immobilizations, we recommend low-dose BAM (2 mL dose; equivalent to 46 mg butorphanol, 30 mg azaperone, and 18 mg medetomidine) and supplemental oxygen for adult elk; immobilization should be antagonized using 3-5 mg atipamezole/mg medetomidine and 2 mg/kg tolazoline, with tolazoline injected about 5-10 min before atipamezole to smooth out recovery. PMID- 24807359 TI - Sylvatic plague in a Canadian black-tailed prairie dog (Cynomys ludovicianus). AB - In 2010, a black-tailed prairie dog (Cynomys ludovicianus) was found dead in Grasslands National Park, Saskatchewan, Canada. Postmortem gross and histologic findings indicated bacterial septicemia, likely due to Yersinia pestis, which was confirmed by molecular analysis. This is the first report of Y. pestis in the prairie dog population within Canada. PMID- 24807360 TI - Reemergence of rabies in the southern Han river region, Korea. AB - Recently, 11 cases of animal rabies were reported in the southern region (Suwon and Hwaseong cities) of Gyeonggi Province, South Korea. The cases were temporally separated into two cases in dogs (Canis lupus familiaris) in spring 2012 and nine cases in domestic animals and wildlife in winter 2012-13. All carcasses were submitted for histopathologic examination and viral antigen identification. Sequences of the glycoprotein, nucleoprotein, and glycoprotein-large polymerase protein intergenic noncoding loci of the 11 strains were determined and compared with published reference sequences. All rabies strains were closely related to the Gangwon strains isolated in 2008-09, suggesting that the rabies virus strains isolated in Gyeonggi were introduced from Gangwon Province. PMID- 24807361 TI - Interspecific aggression by a rabid eastern red bat (Lasiurus borealis). AB - On 16 March 2012 a rabid eastern red bat (Lasiurus borealis) was found attached to an evening bat (Nycticeius humeralis) in Randolph County, Arkansas, USA. This appears to be the first confirmed case of a rabid bat attacking a bat of another species. PMID- 24807362 TI - Avian influenza virus antibodies in Pacific Coast Red Knots (Calidris canutus roselaari). AB - Prevalence of avian influenza virus (AIV) antibodies in the western Atlantic subspecies of Red Knot (Calidris canutus rufa) is among the highest for any shorebird. To assess whether the frequency of detection of AIV antibodies is high for the species in general or restricted only to C. c. rufa, we sampled the northeastern Pacific Coast subspecies of Red Knot (Calidris canutus roselaari) breeding in northwestern Alaska. Antibodies were detected in 90% of adults and none of the chicks sampled. Viral shedding was not detected in adults or chicks. These results suggest a predisposition of Red Knots to AIV infection. High antibody titers to subtypes H3 and H4 were detected, whereas low to intermediate antibody levels were found for subtypes H10 and H11. These four subtypes have previously been detected in shorebirds at Delaware Bay (at the border of New Jersey and Delaware) and in waterfowl along the Pacific Coast of North America. PMID- 24807363 TI - Epizootic hemorrhagic disease in Alberta, Canada. AB - Epizootic hemorrhagic disease (EHD) virus serotype 2 was identified by reverse transcription (RT)-PCR in a white-tailed deer (Odocoileus virginianus) found dead in southern Alberta in September 2013. Field observations indicate at least 50 deer, primarily white-tailed deer, and three pronghorn antelope (Antilocapra americana) died during a suspected localized EHD outbreak. PMID- 24807364 TI - Red foxes (Vulpes vulpes) in Romania are carriers of Toxoplasma gondii but not Neospora caninum. AB - Brain samples from 182 red foxes (Vulpes vulpes) from Romania were examined using a standard PCR technique. Results provide evidence of Toxoplasma gondii (11 foxes=6.0%) and Neospora caninum (1 fox=0.5%) DNA in red foxes from Romania. No coinfections were found. PMID- 24807366 TI - [A perspective on acetylcholine]. AB - This special issue is focused on acetylcholine to mark the hundredth year since its discovery by Dr. Henry Hallett Dale. Some readers may be of the opinion that the available literature on acetylcholine is quite vast and, therefore, there is no scope for more interesting findings. However, when we consider the significance of its physiological roles and discuss its involvement in many severe diseases, acetylcholine remains an intriguing molecule worth to be kept in mind. PMID- 24807367 TI - [Acetylcholinesterase inhibitors for treatment of Alzheimer's disease]. AB - Alzheimer's disease (AD) is a neurodegenerative disorder, and is the commonest cause of dementia. Acetylcholinesterase inhibitors (AChEIs) were developed under the cholinergic hypothesis of AD. Therapeutic strategies with these drugs aimed to enhance cholinergic neurotransmission in specific parts of the brain, and to improve the clinical symptoms of AD. Donepezil, galantamine and rivastigmine are commonly used AChEIs in pharmacotherapy for AD, slowing the progression and controlling the symptoms of AD. Although these drugs have different pharmacological properties, there is no clear evidence of differences between them with respect to efficacy. It is possible to adapt AChEIs for the pharmacotherapy of other conditions, such as vascular dementia, dementia with Lewy bodies, and Down syndrome. PMID- 24807365 TI - Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. AB - Herpes virus type 1 (HSV-1) is one of the most widespread human pathogens and accounts for more than 90% of cases of herpes simplex encephalitis (HSE) causing severe and permanent neurologic sequelae among surviving patients. We hypothesize such CNS deficits are due to HSV-1 infection of neural progenitor cells (NPCs). In vivo, HSV-1 infection was found to diminish NPC numbers in the subventricular zone. Upon culture of NPCs in conditions that stimulate their differentiation, we found HSV-1 infection of NPCs resulted in the loss of neuronal precursors with no significant change in the percentage of astrocytes or oligodendrocytes. We propose this is due a direct effect of HSV-1 on neuronal survival without alteration of the differentiation process. The neuronal loss was prevented by the addition of microglia or conditioned media from NPC/microglia co-cultures. Using neutralizing antibodies and recombinant cytokines, we identified interleukin-6 (IL-6) as responsible for the protective effect by microglia, likely through its downstream Signal Transducer and Activator of Transcription 3 (STAT3) cascade. PMID- 24807368 TI - [Myasthenia gravis and acetylcholine]. AB - A century has passed since the discovery of the first neurotransmitter, acetylcholine, in 1914. Extensive research on acetylcholine and its function has provided us with important options to treat the formerly intractable neuromuscular disease myasthenia gravis (MG). In the first days of treatment for MG, acetylcholine esterase inhibitors are administered, which is only a symptomatic therapy. After overwhelming developments in immunology, the immunological mechanisms of MG at the molecular or genetic level were recognized. Destruction of the acetylcholine receptors through autoimmune attacks plays a pivotal role in the evolution of MG. Thus, a mainstay of the newly developing treatments for MG are effective immunosuppression or immunomodulation. However, these therapeutic approaches are still "symptomatic", and target immunological rather than specific myasthenic symptoms. Immunomodulation may result in fatal immunodeficiency. From this point of view, although they are somewhat removed from first-line MG treatment (cholinesterase inhibitors), future drug development should focus on the cancellation of autoimmunity in MG patients. PMID- 24807369 TI - [Neurology and the bladder: how to assess and manage neurogenic bladder dysfunction, with particular references to the neural control of micturition]. AB - Bladder dysfunctions are one of the most common autonomic dysfunctions. Among these, overactive bladder (OAB) (urinary urgency and frequency) significantly worsens the quality of life in patients, and large post-void residual/urinary retention causes urinary tract infections, kidney dysfunction, and may affect morbidity. In the present paper, we discuss the neural control of micturition, with particular reference to acetylcholine. Further, we discuss appropriate management of bladder dysfunction in diabetic neuropathy (a common cause of urinary retention), Alzheimer's disease, and white matter lesions (common causes of OAB in the elderly). For OAB, anti-cholinergics are the mainstay, whereas for large post-void residual/retention, alpha-blockers, cholinergic agents and clean, intermittent self-catheterization are the treatments of choice. Treatment of bladder dysfunctions is an important target for maximizing patients' quality of life. PMID- 24807370 TI - [Pure autonomic failure and acetylcholine: historical and current aspects]. AB - The discovery of acetylcholine was closely related to research on the autonomic nervous system. At the onset of the twentieth century, John Newport Langley (1852 1925), a patriarch of modern autonomic research, classified the autonomic nervous system into the sympathetic, parasympathetic, and enteral systems, proposed the concept of preganglionic and postganglionic autonomic nerves, and suggested the presence of a "receptive substance" allowing the interaction of postganglionic nerve terminals and effector visceral organs. Around the same time, Henry Hallett Dale (1875-1968) revealed the pharmacological properties of acetylcholine, and he and his colleague, Wilhelm Feldberg (1900-1993), demonstrated that acetylcholine acts as a mediator of nerve impulses across nerve junctions (synapses) between nerves (sympathetic ganglia), and between the vagus nerve and heart (parasympathetic nerve terminals). On the other hand, Bradbury and Eggleston first described 3 patients with orthostatic hypotension in 1925, introducing the term "idiopathic orthostatic hypotension". However, this term was used loosely. Therefore, Roger Bannister proposed "pure autonomic failure" as the term for idiopathic orthostatic hypotension without other neurological symptoms. Recently, autoimmune autonomic ganglionopathy associated with anti-ganglionic acetylcholine receptor antibodies has attracted attention as a differential diagnosis of pure autonomic failure, which is characterized by Lewy body pathology. PMID- 24807371 TI - [The adverse effects of anticholinergic drugs]. AB - Acetylcholine is one of the main neurotransmitters. It is involved in autonomic activities of the peripheral organs and forms a part of complicated neural networks in the central nervous system. Anticholinergic drugs are used in the treatment of various diseases, and many drugs have anticholinergic side effects. Thus, estimating the total burden of anticholinergic activity of drugs is important to assess the related adverse effects for patients taking such drugs. Serum anticholinergic activity (SAA) is measured using a competitive radioreceptor binding assay of muscarinic receptors. In addition to this direct measurement, several drug scales like the Anticholinergic Drug Scale (ADS), Anticholinergic Cognitive Burden Scale (ACB), and Anticholinergic Risk Scale (ARS) have been developed to estimate the total anticholinergic burden of drugs. These measurements have been used to demonstrate that certain drugs may be responsible for the cognitive impairment in the elderly or certain groups of patients with neurologic disorders. Clinicians should be aware of the impact of such drugs because central adverse effects are often obscure in these patient groups and are easily overlooked. PMID- 24807372 TI - [The nerve agent sarin: history, clinical manifestations, and treatment]. AB - Organic phosphate pesticides were used worldwide after World War II and experiences on poisoning and treatment have been accumulated. An organic phosphate "nerve agent" Sarin was used in two terrorist attacks in Japan in the 1990s. Sarin effects on humans were well documented in these two incidents. Sarin gas inhalation caused instantaneous death by respiratory arrest in several victims in Matsumoto. Severely injured victims presenting with coma and generalized convulsion were resuscitated and recovered rapidly without sequelae. Miosis and blurred-dark vision, ocular pain, copious secretions from respiratory and gastrointestinal tract (muscarinic effects), and headache were common in severely to slightly affected victims. Plasma cholinesterase (ChE) activity decreased in parallel with the severity of signs and symptoms in victims. Oximes, atropine sulphate, diazepam, and ample intravenous infusion were effective treatments. Follow-up examinations on victims were conducted up to 10 years in Matsumoto, and 5 years in Tokyo. No neurological sequelae or abnormalities were observed after 1 year, except for a few EEG abnormalities or delay in sensory nerve conduction velocity. Posttraumatic stress disorder (PTSD) was observed in several of the victims in the 5-year follow up, irrespective of the severity of poisoning at Matsumoto. Psychological symptoms continue in victims of both incidents. PMID- 24807373 TI - [Hereditary diffuse leukoencephalopathy with spheroids (HDLS): a review of the literature on its clinical characteristics and mutations in the colony stimulating factor-1 receptor gene]. AB - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an early-onset dementia that predominantly affects the cerebral white matter. After the discovery of a gene encoding the colony stimulating factor 1 receptor (CSF-1R) as a causative gene in patients with HDLS, gene analysis of CSF-1R enabled the diagnosis of HDLS without histopathological evidence. To clarify the genetic and clinical characteristics of HDLS, here, we reviewed the characteristics of patients with HDLS with CSF-1R mutations in the literature. Seventy-three patients from 54 pedigrees with HDLS from various ethnic backgrounds have been reported. Among them, Japanese patients account for 22% (16 patients from 15 pedigrees). Mean age at onset was 45 years (18 to 78 years). A wide range of clinical features including cognitive decline, behavioral changes, seizures, pyramidal signs, and parkinsonism have been described in these patients. Various kinds of mutations were found in the tyrosine kinase domain of CSF-1R. A frameshift mutation causing nonsense-mediated mRNA decay was also described. This suggests that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Neuropathological analysis revealed that microglia in the brains of patients demonstrated distinct morphology and distribution. These results suggest that primary microglial dysfunction due to CSF-1R signaling perturbation may underlie the pathogenesis of HDLS. PMID- 24807374 TI - [The epigenome in neurological disorders: a new marker for understanding neuronal dysfunction]. AB - An epigenome is a chemical modification pattern of genomic DNA that determines the on/off status of genes, and its abnormalities are known to cause congenital diseases. Recent studies have shown that epigenomic patterns are altered by various environmental factors, indicating that epigenomic abnormalities also cause acquired mental and neurological diseases. An epigenomic pattern that reflects past environmental insults is an epigenomic signature. Therefore, it will be used as a marker for preemptive medicine in that it is not based on the population but is instead based on individuals. PMID- 24807375 TI - [Successful treatment with anti-epileptic-drug of an 83-year-old man with musical hallucinosis]. AB - An 83-year-old man with 3 years symptomatic hearing loss suddenly experienced musical hallucinosis. He heard children's songs, folk songs, military songs, and the Japanese national anthem for seven months every day. He sometime had paroxysmal nausea, dull headaches and depressive mood. On examination he had no psychosis or neurological symptoms except sensorineural hearing loss in both ears. MRI brain imaging and electroencephalography showed no significant abnormalities, however 123I-IMP brain SPECT showed decreased activity in the right temporal lobe and increased activity in the left temporal and parietal lobes. Late phase 123I-iomazenil brain SPECT showed decreased accumulation in the right temporal lobe compared to the early phase. This indicates right temporal lobe epilepsy. He was diagnosed with epilepsy because of paroxysmal nausea and headache and the laterality of 123I-IMP brain SPECT and 123I-iomazenil brain SPECT. The musical hallucinosis was much reduced by carbamazepine 200mg per day. Nine months after beginning carbamazepine we detected decreased activity in the right temporal lobe and increased activity in left temporal and parietal lobes was improved. We do not believe he had epileptogenic musical hallucinosis because his musical hallusinosis was neither paroxysmal nor lateral. We diagnosed auditory Charles Bonnet syndrome with onset 3 years after sensorineural hearing loss due to reversible epileptic like discharge in temporal and parietal lobes. There is no established treatment for musical hallucinosis, but anti-epileptic drugs may be of some help. PMID- 24807376 TI - White lighting device from composite films embedded with hydrophilic Cu(In, Ga)S2/ZnS and hydrophobic InP/ZnS quantum dots. AB - Two types of non-Cd quantum dots (QDs)-In/Ga ratio-varied, green-to-greenish yellow fluorescence-tuned Cu-In-Ga-S (CIGS) alloy ones, and red-emitting InP ones are synthesized for use as down-converters in conjunction with a blue light emitting diode (LED). Among a series of Ga-rich CI1-xGxS/ZnS core/shell QDs (x = 0.7, 0.8, and 0.9), CI0.2G0.8S/ZnS QD is chosen for the hydrophobic-to hydrophilic surface modification via an in-situ ligand exchange and then embedded in a water-soluble polyvinyl alcohol (PVA). This free-standing composite film is utilized as a down-converter for the fabrication of a remote-type white QD-LED, but the resulting bi-colored device exhibits a cool white light with a limited color rendering index property. To improve white light qualities, another QD polymer film of hydrophobic red InP/ZnS QD-embedding polyvinylpyrrolidone is sequentially stacked onto the CI0.2G0.8S/ZnS QD-PVA film, producing a unique dual color-emitting, flexible and transparent bilayered composite film. Tri-colored white QD-LED integrated with the bilayered QD film possesses an exceptional color rendering property through reinforcing a red spectral component and balancing a white spectral distribution. PMID- 24807377 TI - Panchromatic donor-acceptor-donor conjugated oligomers for dye-sensitized solar cell applications. AB - We report on a sexithienyl and two donor-acceptor-donor oligothiophenes, employing benzothiadiazole and isoindigo as electron-acceptors, each functionalized with a phosphonic acid group for anchoring onto TiO2 substrates as light-harvesting molecules for dye sensitized solar cells (DSSCs). These dyes absorb light to wavelengths as long as 700 nm, as their optical HOMO/LUMO energy gaps are reduced from 2.40 to 1.77 eV with increasing acceptor strength. The oligomers were adsorbed onto mesoporous TiO2 films on fluorine doped tin oxide (FTO)/glass substrates and incorporated into DSSCs, which show AM1.5 power conversion efficiencies (PCEs) ranging between 2.6% and 6.4%. This work demonstrates that the donor-acceptor-donor (D-A-D) molecular structures coupled to phosphonic acid anchoring groups, which have not been used in DSSCs, can lead to high PCEs. PMID- 24807378 TI - The potential role of endometrial nerve fibers in the pathogenesis of pain during endometrial biopsy at office hysteroscopy. AB - We aimed to evaluate whether nerve fibers are present in the endometrial layer of patients submitted to office hysteroscopy and their potential contribution to the pathogenesis of pain during that procedure. Through a prospective case-control study performed in tertiary centers for women's health, endometrium samples were collected during operative office hysteroscopy from 198 cycling women who previously underwent laparoscopy and/or magnetic resonance imaging investigation for infertility assessment. Samples were classified according to the degree of the pain patients experienced and scored from values ranging from 0 (absence of discomfort/pain) to 10 (intolerable pain) on a 10-cm visual analog scale (VAS). The presence of nerve fiber markers (S100, NSE, SP, VIP, NPY, NKA, NKB, NKR1, NKR2, and NKR3) in the endometrium was also evaluated by morphologic and immunohistochemical analyses. We found that S-100, NSE, NKR1, NK-A, NK-B, VIP, and NPY, were immunolocalized in samples of endometrium, in significantly (P < .01, for all) higher levels in samples collected from patients with VAS score > 5 (group A) than <= 5 (group B) and significantly (P < .0001 for all) positively correlated with VAS levels. A statistically significant (P = .018) higher prevalence of endometriosis and/or adenomyosis was depicted in patients of group A than group B. Data from the present study led us to conclude that nerve fibers are expressed at the level of the functional layer of the endometrium and may contribute to pain generation during office hysteroscopy, mainly in women affected by endometriosis and adenomyosis. PMID- 24807379 TI - Follicle-stimulating hormone/luteinizing hormone ratio as an independent predictor of response to controlled ovarian stimulation. AB - AIM: To determine whether a follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratio over 3 in the setting of a normal FSH (<12 IU/l) is associated with a higher rate of failed controlled ovarian stimulation cycles. DESIGN: Retrospective cohort. MATERIALS & METHODS: A total of 676 patients were identified; 198 patients had a FSH/LH ratio >3 and 477 patients had a FSH/LH ratio <3. Exclusion criteria included: age >40 years; estradiol (E2) prime protocols; E2 at start >70 pg/ml; and FSH at start >12 IU/l. The main outcome measure was cycle cancellation. RESULTS: An elevated FSH/LH ratio >3 was more likely to result in the individual's cycle cancelled (15 vs 5.24%; p = 0.0001). The total gonadotropin dosage was greater in the higher ratio versus lower ratio group (2636 vs 2242 IU; significant). Peak E2 was significantly lower in the FSH/LH >3 group (peak E2: 1635 vs 1942 pg/ml). CONCLUSION: The value of the FSH/LH ratio in patients with normal FSH levels, may have a role in determining the appropriate stimulation protocol and predict cycle cancellations. PMID- 24807381 TI - [Emancipation or integration of geriatric psychiatry?]. PMID- 24807382 TI - [Treatment evaluation and clinical decision making using HKT-30-ROM]. AB - BACKGROUND: By means of repeated, well-supported measurements of clinical dynamic indicators from the Historical, Clinical and Future - 30 (HKT-30) it is possible to monitor behavioural changes on the basis of risks and needs. The addition of extra score parameters allows us to distinguish client-specific risks and needs. In treatment evaluation it is important to visualise changes in these indicators of treatment evaluation because they are the key to the clinical decision-making process that determines further treatment and rehabilitation. AIM: To investigate whether HKT-30 indicators can be used to measure and visualise behavioral changes for the purpose of treatment evaluation. METHOD: A case study is used to illustrate how clinicians at the Forensic Psychiatric Clinic (FPK), De Woenselse Poort, ascertain risks, needs and changes and clarify these factors for the purpose of treatment evaluation and clinical decision-making. RESULTS: Routine treatment evaluation aided by visualised clinical HKT-30 indicators give the treatment team and the client a clearer picture of the behavioral changes for which the forensic treatment was prescribed. This evaluation provides significant starting-points for clinical decision making. CONCLUSION: Routine treatment evaluation along with a suitably adjusted HKT-30 make behavioural changes visible, render clinical decisions more transparent and provide valuable starting points for a dialogue with the client about his treatment. PMID- 24807380 TI - Beneficial effects of muscone on cardiac remodeling in a mouse model of myocardial infarction. AB - Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice. Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta and nuclear factor (NF)-kappaB. Treatment with muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS). Our results demonstrate that muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti inflammatory and anti-apoptotic effects in the ischemic myocardium. PMID- 24807383 TI - ['I'll serve my time...' II. A replication study of recidivism in patients with a one-year hospital order]. AB - BACKGROUND: In the Netherlands a one-year hospital order is often imposed on forensic patients with a psychotic disorder. The purpose of the order is to reduce the patient's violence behaviour by forcing him/her to receive medical treatment for a year. A pilot study showed that the recidivism rate for this group, following discharge, was relatively high. Patients who re-offended had relatively high HCR-20 scores and were more often involved in incidents during treatment than patients who had not re-offended. AIM: To replicate the findings of the pilot study and to compare the recidivism rate of this group to the recidivism rate of patients who had been given a detention order for a longer time with possibilties for prolongation ('tbs'). METHOD: The study involved 95 patients with a psychotic disorder who had been treated in an FPA (Forensic Psychiatric Clinic) by reason of a one-year hospital order or a detention order for an unspecified time. Hospital records were consulted in order to complete the HKT-30 and the PCL-R and to check how many incidents had occurred during each patient's treatment. The HKT-30 is a dutch version of the HCR-20. The results were counted at a later date by persons not informed about the outcome. After the hospital records had been checked, the recidivism figures were obtained from the Information Service of the Ministry of Justice. RESULTS: Of the patients subject to the one-year hospital order 43.5% reoffended following discharge. Recidivism by patients who had been given the longer-term detention order was significantly lower, namely 23.1%. The seriousness of the offences committed following discharge differed significantly from the offence for which they were originally charged/convicted. The HKT-30 and factor 2 of the PCL-R predicted the possibility of recidivism, but the number of violent incidents that occurred on the ward did not. CONCLUSION: Our findings indicate that the recidivism among patients subject to a one-year hospital order is relatively high compared to the rate among patients who had received a longer-term detention order. The most likely explanation for this difference is that the hospital order was imposed for a shorter period. PMID- 24807384 TI - [Treatment strategies for auditory verbal hallucinations]. AB - BACKGROUND: Auditory verbal hallucinations (AVH) are experienced not only by patients diagnosed with schizophrenia, but also by patients with other disorders (some of which may be psychiatric) and in the general population. The ensuing affliction may be severe and can sometimes result in dangerous behaviour. Although various treatment options are available for AVH, only a few have been investigated in randomised placebo-controlled trials. AIM: To provide an overview of the literature relating to the effectiveness of antipsychotics, cognitive behavioural therapy (CBT), electroconvulsive therapy (ect), and transcranial magnetic stimulation (TMS) in the treatment of avh. METHOD: This review paper is based on the Ph.D. study of the first author; in addition, a literature search was carried out using PubMed. RESULTS: Antipsychotics have never been studied specifically with regard to their effect on AVH, but they are known to lead to a significant decrease in the severity and frequency of hallucinations in general. cbt can reduce the torment caused by AVH, but not the severity or frequency. ect can be helpful in the treatment of drug-resistant psychosis, but it has never been studied specifically with regard to its effect on avh or on other types of hallucinations. tms is effective for the treatment of drug-resistant AVH, but in the cases where it has been used so far, the beneficial effects seem to have been of limited duration. CONCLUSION: Very few of the available treatment strategies have been used specifically to relieve the distress caused by avh. tms and cbt have proved reasonably effective, but there is a need for further research into additional treatment strategies, particularly into those involving TMS. PMID- 24807385 TI - [The detection of people with an ultra-high risk of developing psychosis: detection methods and baseline characteristics of the population]. AB - BACKGROUND: It has proved possible to detect persons who are in an at risk mental state (arms) and who run the risk of developing a psychosis. We need to find out whether the detection can be successfully carried out when these patients are being cared for by the secondary mental health care services. AIM: To summarise three studies forming part of a Ph.D. thesis about persons with a high risk of developing psychosis and to explore whether a two-stage screening programme can detect arms-patients among a general help-seeking population. METHOD: The case register of Parnassia (in The Hague) was used to pick out all persons who had developed a first-episode psychosis between 2005 and 2009 and who had sought help for non-psychotic psychological problems during this phase preceding a first episode psychosis. Data from the Dutch edie-nl study were used to find out whether a two-stage screening method was able to detect arms-patients (aged 18 30) more accurately than the traditional screening method. The two-stage screening consisted of a Prodromal Questionnaire relating to all help-seeking subjects in the general population, followed by a gold-standard interview with patients who achieved a score higher than the cut-off level. RESULTS: 56.2% of the first-episode psychotic patients received help for non-psychotic psychiatric problems in the secondary mental health care services. Screening detected more arms-patients than did the referral method and the 'referred' patients developed three times as many psychotic symptoms over a period of 18 months. CONCLUSION: The secondary mental health care services care for 4% of the arms-patients and are in a position to detect arms-patients provided they use two-stage screening. Screening leads to fewer false-negative results than does the 'referral' method. PMID- 24807386 TI - [Screening requires more scientific evidence than diagnosis and treatment]. PMID- 24807387 TI - [Sexuality in eating-disorder patients]. AB - BACKGROUND: A link is suspected between eating disorders and dysfunctional sexuality. The grounds for this link are thought to be clinical, biological and psychological. AIM: To find out from the literature what is known about sexuality in patients with eating disorders, to identify differences related to subtypes of the disorders and to ascertain whether sexuality can play a role in the diagnosis and treatment of various types of eating disorders. METHOD: We studied the research literature with the help of PubMed. RESULTS: Patients with eating disorders are more likely to have sexual problems; these include reduced libido, reduced sexual activity and sexual dissatisfaction. The distorted body image leads to the avoidance of sexual activity. Anorexia patients are more negative about sexuality and have a greater loss of libido than do bulimia patients, who experiment more with sex. CONCLUSION: Patients with eating disorders experience sexual dysfunction, but there are clear differences between the various eating disorder subtypes. It is advisable that, in the future, sexuality should be included in the outcome of research in eating disorders. This step will help researchers to evaluate the effect that treatment can have on the outcome of the eating disorder. PMID- 24807388 TI - [Post-injection delirium/sedation syndrome following injection of olanzapine pamoate: a new syndrome in emergency psychiatry]. AB - The PDSS is a potential side-effect of the intramuscular injection of olanzapine pamoate. We saw the typical symptoms develop in a 46-year-old man 4 hours after the injection. The syndrome is caused by a toxic concentration of olanzapine, and is possibly the result of the direct injection of the substance in the bloodstream. The most important measures that can be taken to prevent such an emergency are: a careful injection procedure, a 3-hour observation period following the injection and good counselling of the patient and his family. The treatment is conservative. PMID- 24807389 TI - Bias-polarity dependent ultraviolet/visible switchable light-emitting devices. AB - By taking semiconductors with different band-gap energies as the active layers and controlling the electron-hole recombination region through the electric field, bias-polarity dependent ultraviolet/visible switchable light-emitting devices have been realized in Au/MgO/Mg0.49Zn0.51O/MgxZn1-xO/n-ZnO structures, of which the emission bands can be switched from the ultraviolet region to the orange region by changing the polarity of the applied bias. The results reported here may provide a feasible idea to multicolor-switchable light-emitting devices. PMID- 24807391 TI - Preadmission statin use does not improve functional outcomes or prevent delayed ischemic events in patients with spontaneous subarachnoid hemorrhage. AB - STUDY OBJECTIVE: To determine whether preadmission statin use in patients with spontaneous subarachnoid hemorrhage (SAH) is associated with improved functional outcomes and a lower incidence of delayed cerebral ischemic events compared with statin-naive patients with SAH. DESIGN: Prospective cohort study. SETTING: Neurosciences intensive care unit of a tertiary care hospital. PATIENTS: A total of 295 consecutive patients with SAH admitted between March 2006 and May 2013 who had complete medication histories; of these patients, 41 reported taking a statin prior to admission, and 254 were statin naive. INTERVENTION: All patients received clinical management for SAH according to hospital protocol for standard care that included acute statin therapy with enteral pravastatin 40 mg/day on hospital day 1 for up to 21 days. MEASUREMENTS AND MAIN RESULTS: Functional outcomes were assessed by using the modified Rankin Scale (mRS) at 14 days, 28 days, and 3 months. Delayed cerebral ischemia was assessed by using clinical evaluation and computed tomography. Patients taking statins prior to admission were more likely to have a history of diabetes mellitus, hypertension, coronary artery disease, and stroke. No significant difference in favorable neurologic outcome (mRS score 0-3) at 3 months was observed between the preadmission statin group compared with the statin-naive group (56.3% vs 72.4%, p=0.095). In multivariate logistic regression analysis, only age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome. No significant difference in the development of delayed cerebral ischemic events was observed between groups (p=0.48). CONCLUSION: Statin use prior to admission did not improve functional outcomes or prevent delayed cerebral ischemic events in patients with SAH. Age, severity of rupture, and coronary artery disease were less likely to predict a favorable neurologic outcome at 3 months after discharge. PMID- 24807392 TI - beta1 integrin modulates tumor growth and apoptosis of human colorectal cancer. AB - We aimed to ascertain whether beta1 integrin (ITGB1) induces apoptosis of colorectal cancer (CRC) through regulation of the mitochondrial pathway in vitro and in vivo. We generated lentiviral vectors expressing ITGB1 or ITGB1-specific RNAi and an unrelated control vector. After infection of the HT29 cells, we used western blot analysis and flow cytometric analysis to validate the patterns of ITGB1 expression. Proliferation and apoptosis were evaluated by colony formation assay, flow cytometry and western blot analysis. Upregulation of ITGB1 significantly increased the proliferation of HT29 cells; however, the levels of Bcl-2 and cyclin D1 proteins were upregulated while Bax, caspase-3, caspase-9 and p21 were downregulated in the HT29-ITGB1 cells compared to these levels in the controls. Hoechst 33258 staining and flow cytometric analysis showed that ITGB1 may play a significant role in the apoptosis of CRC cells. Moreover, ITGB1 promoted the proliferation of cells in a xenograft tumor mouse model. TUNEL staining revealed a marked increase in the percentage of positive cells in the HT29-RNAi group (84.3 +/- 4.0%), which were more significant than in the HT29 ITGB1 group (48.3 +/- 2.9%) and the other two control groups, HT29 (52.0 +/- 3.6%) and HT29-NC (49.7 +/- 4.5%). These results suggest that ITGB1 regulates the growth and apoptosis of human colorectal cancer cells. PMID- 24807393 TI - Gene silencing in fragile X syndrome explained: researchers pinpoint how excessive nucleotide repeats shut down protein production. PMID- 24807394 TI - Cell-free fetal DNA tests for trisomy show promise in women at lower risk of affected pregnancies: lower rates of false-positive returns, higher positive predictive value are associated with cfDNA tests versus standard screening panels, say experts. PMID- 24807396 TI - A Comparison of Fentanyl and Flurbiprofen Axetil on Serum VEGF-C, TNF-alpha, and IL-1beta Concentrations in Women Undergoing Surgery for Breast Cancer. AB - BACKGROUND: Vascular endothelial growth factor-C (VEGF-C), tumor necrosis factor alpha (TNF-alpha), and interleukin-1beta(IL-1beta) have been shown to be associated with the recurrence and metastasis of breast cancer after surgery. This study tested the hypothesis that patients undergoing surgery for breast cancer, who received postoperative analgesia with flurbiprofen axetil combined with small doses of fentanyl (FA), exhibited reduced levels of VEGF-C, TNF-alpha, and IL-1beta compared with those patients receiving fentanyl alone (F). METHOD: Forty-women with primary breast cancer undergoing a modified radical mastectomy were randomized to receive postoperative analgesia with flurbiprofen axetil combined with fentanyl or fentanyl alone. Venous blood was sampled before anesthesia, at the end of surgery, and at 48 hours after surgery, and the serum was analyzed. The primary endpoint was changes in the VEGF-C concentrations in serum. RESULTS: Group FA patients reported similar analgesic effects as group F patients at 2, 24, and 48 hours. At 48 hours, mean postoperative concentrations of VEGF-C in group F patients were higher than in group FA patients, 730.9 versus. 354.1 pg/mL (P = 0.003), respectively. The mean postoperative concentrations of TNF-alpha in group F patients were also higher compared with group FA patients 27.1 vs. 15.8 pg/mL (P = 0.005). Finally, the mean postoperative concentrations of IL-1beta in group F were also significantly higher than in group FA 497.5 vs. 197.7 pg/mL (P = 0.001). CONCLUSION: In patients undergoing a mastectomy, postoperative analgesia with flurbiprofen axetil, combined with fentanyl, were associated with decreases in serum concentrations of VEGF-C, TNF-alpha, and IL-1beta compared with patients receiving doses of only fentanyl. PMID- 24807397 TI - A thermal plasmonic sensor platform: resistive heating of nanohole arrays. AB - We have created a simple and efficient thermal plasmonic sensor platform by letting a DC current heat plasmonic nanohole arrays. The sensor can be used to determine thermodynamic parameters in addition to monitoring molecular reactions in real-time. As an application example, we use the thermal sensor to determine the kinetics and activation energy for desorption of thiol monolayers on gold. Further, the temperature of the metal can be measured optically by the spectral shift of the bonding surface plasmon mode (0.015 nm/K). We show that this resonance shift is caused by thermal lattice expansion, which reduces the plasma frequency of the metal. The sensor is also used to determine the thin film thermal expansion coefficient through a theoretical model for the expected resonance shift. PMID- 24807399 TI - Observation of a three-dimensional topological Dirac semimetal phase in high mobility Cd3As2. AB - Symmetry-broken three-dimensional (3D) topological Dirac semimetal systems with strong spin-orbit coupling can host many exotic Hall-like phenomena and Weyl fermion quantum transport. Here, using high-resolution angle-resolved photoemission spectroscopy, we performed systematic electronic structure studies on Cd3As2, which has been predicted to be the parent material, from which many unusual topological phases can be derived. We observe a highly linear bulk band crossing to form a 3D dispersive Dirac cone projected at the Brillouin zone centre by studying the (001)-cleaved surface. Remarkably, an unusually high in plane Fermi velocity up to 1.5*10(6) ms(-1) is observed in our samples, where the mobility is known up to 40,000 cm2 V(-1) s(-1), suggesting that Cd3As2 can be a promising candidate as an anisotropic-hypercone (three-dimensional) high spin orbit analogue of 3D graphene. Our discovery of the Dirac-like bulk topological semimetal phase in Cd3As2 opens the door for exploring higher dimensional spin orbit Dirac physics in a real material. PMID- 24807400 TI - Transcranial direct current stimulation over right posterior parietal cortex changes prestimulus alpha oscillation in visual short-term memory task. AB - Alpha band activity changes accompanied with the level attentional state, and recent studies suggest that such oscillation is associated with activities in the posterior parietal cortex. Here we show that artificially elevating parietal activity via positively-charged electric current through the skull can rapidly and effortlessly change people's prestimulus alpha power and improve subsequent performance on a visual short-term memory (VSTM) task. This modulation of alpha power and behavioral performance, however, is dependent on people's natural VSTM capability such that only the low performers benefitted from the stimulation, whereas high performers did not. This behavioral dichotomy is accounted by prestimulus alpha powers around the parieto-occipital regions: low performers showed decreased prestimulus alpha power, suggesting improvement in attention deployment in the current paradigm, whereas the high performers did not benefit from tDCS as they showed equally-low prestimulus alpha power before and after the stimulation. Together, these results suggest that prestimulus alpha power, especially in low performers, can be modulated by anodal stimulation and alter subsequent VSTM performance/capacity. Thus, measuring alpha before stimulus onset may be as important as measuring other VSTM-related electrophysiological components such as attentional allocation and memory capacity related components (i.e. N2 posterior-contralateral, N2pc, or contralateral delay activity, CDA). In addition, low VSTM performers perhaps do not suffer not only from poor VSTM capacity, but also from broad attentional mechanisms, and prestimulus alpha may be an useful tool in understanding the nature of individual differences in VSTM. PMID- 24807401 TI - Time to flourish: the relationship of temporal perspective to well-being and wisdom across adulthood. AB - OBJECTIVES: Despite the centrality of time to the aging process, the well-being consequences of different temporal orientations for optimal aging are poorly understood. We investigate one underexamined area of temporal orientation, namely a balanced time perspective, in a large, lifespan sample from the Netherlands. METHOD: Participants consisted of 512 Dutch adults ranging in age from 17 to 92 years (Mage = 46.46, SD = 21.37), including 186 male and 326 females. Participants completed a measure of balanced time perspective, mental health, and wisdom. RESULTS: RESULTS indicated that a balanced time perspective uniquely predicted both mental health and wisdom even after controlling for demographic, physical health, and personality variables. Younger adults tended to be more future-oriented relative to older adults while older adults tended to be more past-oriented relative to younger adults. Further, both midlife and younger adults were more likely to have a balanced time perspective relative to older adults. CONCLUSION: A balanced time perspective is associated with higher well being and wisdom across the adult age span. PMID- 24807402 TI - Osteoporosis epidemiology 2013: implications for diagnosis, risk assessment, and treatment. AB - PURPOSE OF REVIEW: To summarize the recently published studies that provide insights into the changing epidemiology of osteoporosis and fractures. RECENT FINDINGS: The main themes reviewed are fracture outcomes; trends in fractures rates; fracture risk assessment and monitoring; atypical femoral fractures; male osteoporosis; falls and physical activity; and sarcopenia, obesity, and metabolic syndrome. SUMMARY: Osteoporotic fractures were found to have long-term consequences on excess mortality (10 years) and economic costs (5 years). The large burden of nonhip nonvertebral fractures has been underestimated. Divergent (but mostly declining) trends in fracture rates were confirmed in several cohorts from around the world. This has significant implications for healthcare planners and clinicians responsible for the care of individuals with osteoporosis, and also impacts on the calibration of fracture prediction tools. Although fracture prediction tools differ in their complexity, performance characteristics are similar when applied to the general population. Large, high-quality comparative studies with different case mixes are needed. Fracture probability does not appear to be responsive enough to support goal-directed treatment at this time. A consensus on the diagnosis of osteoporosis in men has emerged, based upon the same absolute bone density cutoff for both men and women. Finally, a plethora of new data highlight the importance of falls, physical activity, and body composition as contributors to skeletal health. PMID- 24807403 TI - Inhibitors of sclerostin: emerging concepts. AB - PURPOSE OF REVIEW: Recent data suggest that inhibitors of sclerostin, an osteocyte-produced Wnt signaling pathway antagonist, can stimulate bone formation. This review provides rationale and summarizes recent evidence supporting this novel approach to skeletal anabolism. RECENT FINDINGS: Data from numerous preclinical models in rodents and monkeys consistently demonstrate that antisclerostin monoclonal antibody (Scl-Ab) treatment leads to improvements in bone mass and strength, as well as enhanced fracture repair. Delivery of Scl-Ab therapy either subcutaneously or intravenously in phase 1 and 2 human clinical trials demonstrates short-term anabolic responses in excess of those seen with teriparatide, the only currently available anabolic skeletal agent. Gains have been primarily at central (spine and hips) versus peripheral (wrist) sites. Strikingly, Scl-Ab treatment appears to both stimulate bone formation and inhibit bone resorption in humans. If proven, Scl-Ab would be the first pharmacologic agent with such dual properties. Data on fractures are not yet available. SUMMARY: Scl-Ab therapy represents a novel pharmacologic approach to skeletal anabolism. Although many questions remain before Scl-Ab treatment can be introduced into clinical practice, phase 3 human clinical trials are currently underway and could provide the necessary data to bring this exciting class of skeletal anabolic agents to patient care. PMID- 24807404 TI - Similarities and differences between nonradiographic and radiographic axial spondyloarthritis: a clinical, epidemiological and therapeutic assessment. AB - PURPOSE OF REVIEW: The concept of axial spondyloarthritis with two forms or subtypes (nonradiographic and radiographic) has been established over the last few years. However, debates concerning especially the nonradiographic form of the disease are still ongoing. Here we summarise recent data on similarities and differences (and their possible explanations) between nonradiographic axial spondyloarthritis and radiographic axial spondyloarthritis (ankylosing spondylitis). RECENT FINDINGS: Nonradiographic and radiographic forms are about equally frequent among patients first diagnosed with axial spondyloarthritis and have in general similar clinical characteristics, especially related to clinical signs of disease activity and similar rates of treatment response. Nonradiographic axial spondyloarthritis is characterised by a higher prevalence of females and lower percentage of patients with elevated C-reactive protein that might reflect the presence of a certain proportion of patients who develop structural damage in the axial skeleton very slowly or do not develop it at all. Elevated C-reactive protein and active sacroiliitis on magnetic resonance imaging are strongest predictors of structural damage development in the sacroiliac joints and, therefore, of progression from nonradiographic to radiographic stage. The same parameters predict a good clinical response to therapy with tumour necrosis factor alpha blocking agent in axial spondyloarthritis, but especially if used in nonradiographic disease. SUMMARY: Currently available data support the concept of axial spondyloarthritis as one entity. Nonradiographic axial spondyloarthritis seems to be, however, more heterogeneous than ankylosing spondylitis because of the presence of patients with a self-limiting disease or a slow disease course. PMID- 24807405 TI - Periodontal disease and subgingival microbiota as contributors for rheumatoid arthritis pathogenesis: modifiable risk factors? AB - PURPOSE OF REVIEW: Since the early 1900s, the role of periodontal disease in the pathogenesis of rheumatoid arthritis has been a matter of intense research. The last decade has witnessed many advances supporting a link between periodontitis, the presence of specific bacterial species (i.e. Porphyromonas gingivalis) and their effects in immune response. This review will examine available evidence on the individuals. RECENT FINDINGS: Epidemiological studies have stressed the commonalities shared by periodontal disease and rheumatoid arthritis. Many groups have focused their attention toward understanding the periodontal microbiota and its alterations in states of health and disease. The presence of circulating antibodies against periodontopathic bacteria and associated inflammatory response has been found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. Most recently, the periodontal microbiota of smokers and patients with RA has been elucidated, revealing profound changes in the bacterial communities compared with those of healthy controls. This has led to several small clinical trials of progressive disease treatment as adjuvant for disease modifying therapy in RA. SUMMARY: Smoking and periodontal disease are emerging risk factors for the development of RA. Epidemiological, clinical, and basic research has further strengthened this association, pointing toward changes in the oral microbiota as possible contributors to systemic inflammation and arthritis. PMID- 24807406 TI - Fish consumption and hair mercury levels in women of childbearing age, Martin County, Florida. AB - The health effects of mercury in humans are mostly on the developing nervous system. Pregnant women and women who are breastfeeding must be targeted in order to decrease mercury exposure to the populations at highest risk-infants, unborn fetuses, and young children. This purpose of this study is to understand the demographics of fish-consumption patterns among women of childbearing age (including pregnant women) in Martin County, Florida, and to analyze the associations of mercury levels in participants' hair with socio-demographic variables in order to better design prevention messages and campaigns. Mercury concentrations in hair samples of 408 women ages 18-49 were assessed. Data on demographic factors, pregnancy status, fish consumption, and awareness of fish advisories were collected during personal interviews. Data were analyzed using descriptive statistics and multivariate logistic regression. The geometric and arithmetic means of hair mercury concentration were 0.371 and 0.676 ug/g of hair. One-fourth of the respondents had a concentration >=1 ug/g of hair. Consuming a higher number of fish meals per month, consumption of commercially purchased or locally caught fish higher in mercury, White race and income >=$75,000 were positively associated with the likelihood of having higher hair mercury levels. This study confirms the existence of a higher overall mean hair mercury level and a higher percentage of women with >=1 ug/g hair mercury level than those reported at the national level and in other regional studies. This suggests the need for region-specific fish consumption advisories to minimize mercury exposure in humans. PMID- 24807407 TI - The total right/left-volume index: a new and simplified cardiac magnetic resonance measure to evaluate the severity of Ebstein anomaly of the tricuspid valve: a comparison with heart failure markers from various modalities. AB - BACKGROUND: The classification of clinical severity of Ebstein anomaly still remains a challenge. The aim of this study was to focus on the interaction of the pathologically altered right heart with the anatomically-supposedly-normal left heart and to derive from cardiac magnetic resonance (CMR) a simple imaging measure for the clinical severity of Ebstein anomaly. METHODS AND RESULTS: Twenty five patients at a mean age of 26+/-14 years with unrepaired Ebstein anomaly were examined in a prospective study. Disease severity was classified using CMR volumes and functional measurements in comparison with heart failure markers from clinical data, ECG, laboratory and cardiopulmonary exercise testing, and echocardiography. All examinations were completed within 24 hours. A total right/left-volume index was defined from end-diastolic volume measurements in CMR: total right/left-volume index=(RA+aRV+fRV)/(LA+LV). Mean total right/left volume index was 2.6+/-1.7 (normal values: 1.1+/-0.1). This new total right/left volume index correlated with almost all clinically used biomarkers of heart failure: brain natriuretic peptide (r=0.691; P=0.0003), QRS (r=0.432; P=0.039), peak oxygen consumption/kg (r=-0.479; P=0.024), ventilatory response to carbon dioxide production at anaerobic threshold (r=0.426; P=0.048), the severity of tricuspid regurgitation (r=0.692; P=0.009), tricuspid valve offset (r=0.583; P=0.004), and tricuspid annular plane systolic excursion (r=0.554; P=0.006). Previously described severity indices ([RA+aRV]/[fRV+LA+LV]) and fRV/LV end diastolic volume corresponded only to some parameters. CONCLUSIONS: In patients with Ebstein anomaly, the easily acquired index of right-sided to left-sided heart volumes from CMR correlated well with established heart failure markers. Our data suggest that the total right/left-volume index should be used as a new and simplified CMR measure, allowing more accurate assessment of disease severity than previously described scoring systems. PMID- 24807408 TI - Emergency department diagnosis and management of skin diseases with real-time teledermatologic expertise. AB - IMPORTANCE: Skin conditions are a common reason for patients to consult emergency department (ED) physicians. OBJECTIVE: To evaluate real-time teledermatologic expertise with the use of mobile telephones for the diagnosis and management of skin conditions in patients seen in the ED. DESIGN, SETTING, AND PARTICIPANTS: This observational study of adults who consecutively consulted in the ED for a dermatologic condition was conducted under routine conditions in the ED from May 1, 2008, through June 30, 2010. MAIN OUTCOMES AND MEASURES: Diagnosis agreement and management concordance. RESULTS: One hundred eleven patients were enrolled in the study. Eighty-three patients (74.8%) were evaluated using videoconferencing. Dermatologic remote expertise invalidated, enlarged, or clarified ED physicians' diagnosis and management in 75 of 110 cases (68.2%). Videoconferencing improved the diagnostic performance in 57 of 83 cases (68.7%) (P < 10(-4)). Management concordance was moderate between ED physicians and dermatologists for specialist consultation within 24 hours (kappa, 0.49; 95% CI, 0.14-0.84) and immediate hospitalization (kappa, 0.49; 95% CI, 0.41-0.57). Patients were significantly more often discharged by dermatologists (46.8% vs 39.1%) (P < 10(-4)). CONCLUSIONS AND RELEVANCE: Compared with standard hardware, new-generation mobile devices reduce the cost of videoconferencing, increase the versatility of teledermatology, and decrease general practitioner investment time. PMID- 24807409 TI - Beyond Bertin: seeing the forest despite the trees. PMID- 24807410 TI - Understanding and interpreting multivalued astronomical data. PMID- 24807411 TI - Spatial navigation for context-aware video surveillance. AB - Interactive spatial navigation for video surveillance networks can be difficult. This is especially true for live tracking of complex events along many cameras, in which operators must make quick, accurate navigation decisions on the basis of the actual situation. The proposed spatial navigation interface facilitates such video surveillance tasks. PMID- 24807412 TI - Newdle: interactive visual exploration of large online news collections. PMID- 24807413 TI - MediaTable: interactive categorization of multimedia collections. PMID- 24807414 TI - Multimedia analysis + visual analytics = multimedia analytics. AB - To deal with the extent and variety of digital media, researchers are combining multimedia analysis and visual analytics to form the new field of multimedia analytics. This article gives some historical background, discusses surveys of related research, describes initial multimedia analytics research, and reports on benchmark datasets. PMID- 24807415 TI - AniViz: a template-based animation tool for volume visualization. PMID- 24807416 TI - iFeel_IM!: augmenting emotions during online communication. PMID- 24807417 TI - Experimental platforms for computational photography. PMID- 24807419 TI - Brassinosteroid nuclear signaling recruits HSP90 activity. AB - Heat shock protein 90 (HSP90) controls a number of developmental circuits, and serves a sophisticated and highly regulatory function in signaling pathways. Brassinosteroids (BRs) control many aspects of plant development. Genetic, physiological, cytological, gene expression, live cell imaging, and pharmacological approaches provide conclusive evidence for HSP90 involvement in Arabidopsis thalianaBR signaling. Nuclear-localized HSP90s translocate to cytoplasm when their activity is blocked by the HSP90 inhibitor geldanamycin (GDA). GDA treatment promoted the export of BIN2, a regulator of BR signaling, from the nucleus into the cytoplasm, indicating that active HSP90 is required to sustain BIN2 in the nucleus. HSP90 nuclear localization was inhibited by brassinolide (BL). HSP90s interact with BIN2 in the nucleus of untreated cells and in the cytoplasm of BL-treated cells, showing that the site-specific action of HSP90 on BIN2 is controlled by BRs. GDA and BL treatments change the expression of a common set of previously identified BR-responsive genes. This highlights the effect of active HSP90s on the regulation of BR-responsive genes. Our observations reveal that HSP90s have a central role in sustaining BIN2 nuclear function. We propose that BR signaling is mediated by HSP90 activity and via trafficking of BIN2-HSP90 complexes into the cytoplasm. PMID- 24807418 TI - A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER associated protein degradation. AB - Misfolded ER proteins are retrotranslocated into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 exploits this ER-associated protein degradation (ERAD) pathway to downregulate HLA class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T lymphocytes. US11-mediated degradation of HLA class I has been instrumental in the identification of key components of mammalian ERAD, including Derlin-1, p97, VIMP and SEL1L. Despite this, the process governing retrotranslocation of the substrate is still poorly understood. Here using a high-coverage genome-wide shRNA library, we identify the uncharacterized protein TMEM129 and the ubiquitin conjugating E2 enzyme UBE2J2 to be essential for US11-mediated HLA class I downregulation. TMEM129 is an unconventional C4C4-type RING finger E3 ubiquitin ligase that resides within a complex containing various other ERAD components, including Derlin-1, Derlin-2, VIMP and p97, indicating that TMEM129 is an integral part of the ER-resident dislocation complex mediating US11-induced HLA class I degradation. PMID- 24807420 TI - Maternal body mass index in early pregnancy and offspring asthma, rhinitis and eczema up to 16 years of age. AB - BACKGROUND: Maternal obesity has been linked to offspring asthma; however, other allergy-related diseases, as well as the association beyond early school age, are largely unstudied. OBJECTIVE: To examine the associations between maternal body mass index (BMI) in pregnancy and offspring asthma, rhinitis, eczema and sensitization up to 16 years of age. METHODS: A total of 3294 children from the Swedish birth cohort BAMSE were included in the analyses. Maternal BMI was assessed around week 10 in pregnancy. Information on asthma, rhinitis, eczema, lifestyle factors and environmental exposures was obtained by parental questionnaires at 1, 2, 4, 8, 12 and 16 years. Sensitization was defined from IgE levels of inhalant allergens at 4, 8 and 16 years in a subsample of 2850 children. Generalized estimated equation models were used to analyse the associations between maternal BMI and the outcomes at 1-16 years. RESULTS: Maternal BMI was positively associated with overall risk of asthma up to age of 16 years (adj OR per 5 kg/m(2) increase: 1.23; 95% CI 1.07-1.40 for prevalent asthma) excluding underweight mothers. In contrast, no significant associations were found for rhinitis, eczema or sensitization. The association with asthma was restricted to obese, rather than overweight mothers, but was attenuated when adjusting for overweight in the offspring. A causal inference test at 16 years further indicated that the child's own overweight is a mediator in the suggested association between maternal BMI and offspring asthma at 16 years. CONCLUSIONS AND CLINICAL RELEVANCE: Maternal BMI is associated with an increased risk of asthma, but not rhinitis, eczema or sensitization; however, overweight in the offspring seems to have a mediating role. Prevention strategies of maternal pre pregnancy and childhood obesity might be important to reduce the prevalence of childhood asthma. PMID- 24807421 TI - Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion. AB - A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (~five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals. PMID- 24807423 TI - Vitamin D deficiency is associated with increased fecal incontinence symptoms. AB - INTRODUCTION AND HYPOTHESIS: Vitamin D is an important micronutrient in muscle function. We hypothesize that vitamin D deficiency may contribute to fecal incontinence (FI) symptoms by affecting the anal continence mechanism. Our goal was to characterize the association of vitamin D deficiency as a variable affecting FI symptoms and its impact on health-related quality of life (HR-QoL). METHODS: This case-control study assessed women seen at a tertiary-care referral center. Participants were identified as having had a serum vitamin D level obtained within a year of their visit: cases were women presenting for care for FI symptoms; controls were women without any pelvic floor symptoms presenting to the same clinical site for general gynecologic care. Cases completed the Modified Manchester Health Questionnaire (MMHQ) and the Fecal Incontinence Severity Index to measure symptom severity and burden on QoL. RESULTS: Among the 31 cases and 81 controls, no demographic or medical differences existed. Women with FI had lower vitamin D levels (mean 29.2 +/- 12.3 cases vs. 35 +/- 14.1 ng/ml controls p = 0.04). The odds of vitamin D deficiency were higher in women with FI compared with controls [odds ratio (OR) 2.77, 95 % confidence interval (CI) 1.08-7.09]. Among cases, women with vitamin D deficiency (35 %) had higher MMHQ scores, indicating greater FI symptom burden [51.3 +/- 29.3 (vitamin D deficient) vs. 30 +/- 19.5 (vitamin D sufficiency), p = 0.02]. No differences were noted for FI severity, p = 0.07. CONCLUSIONS: Vitamin D deficiency is prevalent in women with fecal incontinence and may contribute to patient symptom burden. PMID- 24807424 TI - Written versus oral disclosure of fecal and urinary incontinence in women with dual incontinence. AB - INTRODUCTION AND HYPOTHESIS: To compare fecal incontinence (FI) and urinary incontinence (UI) disclosure in women with dual incontinence (DI), and to assess UI disclosure in DI subjects compared with women with UI alone. We hypothesized that women with DI would be less likely to disclose FI in comparison to UI and as likely to disclose UI as women with UI alone. METHODS: We performed a retrospective chart review of new patient visits to an academic urogynecology clinic from 2007 to 2011. Clinical records were reviewed; demographic data and responses to the Incontinence Severity Index (ISI) and Wexner scales were recorded. Patients' written responses to the ISI and Wexner were compared with the diagnoses obtained from the oral history by the physician. RESULTS: Of 1,899 women in the database, 557 women were diagnosed with DI and 447 women were diagnosed with UI alone. Women with DI were less likely to orally disclose FI than UI (135 out of 557 [23 %], vs 485 out of 557 [87 %], p < 0.001), but were as likely as women with UI alone to disclose UI (385 out of 447 [86 %] vs 485 out of 557 [87 %], p = 0.66). In the multivariate analysis, DI subjects had greater odds of disclosing FI to their physicians if they had private insurance (OR 1.9, 95 %CI 1.2, 3.0) or Wexner score >7 (OR 9.0, 95 % CI 5.4,14.8) and lower ISI score (OR 1.5, CI 1.4, 1.6). CONCLUSIONS: Women with DI were less likely to report FI in comparison to UI. Patients were more likely to orally report FI when the symptoms were severe. PMID- 24807425 TI - Does urinary incontinence have fetal origins? Results from a nationwide twin study. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study is to evaluate the effect of birth weight and being born small for gestational age (SGA) on urinary incontinence (UI) among premenopausal women. METHODS: In 2005, a total of 14,094 female twins born 1959-1985 who had been included in the Swedish Twin Registry participated in a survey on common exposures and complex diseases, including urinary incontinence. Information regarding birth weight and gestational age was obtained from the Medical Birth Register (for twins born 1973-1985) and from the medical archives (for twins born 1959-1972). A logistic regression model based on generalized estimating equations was used to estimate odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: In both crude and adjusted analysis, birth weight and SGA had no effect on UI. An interaction between low birth weight (<2,500 g) and body mass index (BMI) later in life was found for overall and stress UI. Compared with women who were not overweight and had a birth weight above 2,500 g, overweight women (BMI >= 25) who had a normal birth weight had a 35 % higher odds of incontinence , while overweight women who had a low birth weight had an approximately 85 % higher odds of UI (OR = 1.84, 95 % CI 1.39-2.45 for overall UI; OR = 1.83, 95 % CI 1.35-2.48 for stress UI). CONCLUSIONS: Birth weight and SGA had no direct effect on urinary incontinence; however, low birth weight in combination with an elevated adult BMI may contribute to the risk of urinary incontinence later in life. PMID- 24807426 TI - Effect of different episiotomy techniques on perineal pain and sexual activity 3 months after delivery. AB - INTRODUCTION AND HYPOTHESIS: The effect of different episiotomy techniques on pain perception 3 months after delivery is unknown. Study aims were to explore the association between different episiotomy techniques and perineal pain 3 months after delivery and to assess female sexual activity in relation to episiotomy technique. METHODS: This is a prospective observational study, designed to investigate short- and long-term complications of different episiotomy techniques. All 300 participants were recruited and clinically examined during their postpartum hospital stay in order to evaluate episiotomy performance. A 3-month follow-up questionnaire addressing pain, sexual activity, and puerperal wound infection was distributed to 208 women who had scored perineal pain in a personal interview the first day after delivery. RESULTS: A response rate of 87.7 % was obtained. We found no difference in pain score distribution by Visual Analogue Scale (VAS) when comparing midline, mediolateral, and lateral episiotomy techniques (p = 0.32) or between midline and lateral incision points (p = 0.58). Dyspareunia was reported by 33 out of 179 women, but no difference between episiotomy techniques (p = 0.90), or between episiotomy incision points (p = 0.14), was found. Perineal wound infection was reported by 9.5 %, but there was no significant difference between episiotomy techniques (p = 0.73). CONCLUSIONS: No difference was found in perineal pain perception 3 months postpartum between different episiotomy techniques or when comparing midline and lateral incision points. Dyspareunia was not associated with any particular episiotomy technique or incision point. PMID- 24807428 TI - Michel Foucault: discourse in the modern medical consultation. PMID- 24807429 TI - Resistance is not futile: Foucault and a brave new world of medical education research. PMID- 24807430 TI - Interprofessional teamwork: still haven't decided what we are educating for? PMID- 24807431 TI - Attitude erosion in medical students: dwarf or devil, fact or fable? PMID- 24807432 TI - When I say ... metacognition. PMID- 24807433 TI - Medical education... meet Michel Foucault. AB - CONTEXT: There have been repeated calls for the greater use of conceptual frameworks and of theory in medical education. Although it is familiar to few medical educators, Michel Foucault's work is a helpful theoretical and methodological source. METHODS: This article explores what it means to use a 'Foucauldian approach', presents a sample of Foucault's historical-genealogical studies that are relevant to medical education, and introduces the work of four researchers currently undertaking Foucauldian-inspired medical education research. RESULTS: Although they are not without controversy, Foucauldian approaches are employed by an increasing number of scholars and are helpful in shedding light on what it is possible to think, say and be in medical education. CONCLUSIONS: Our hope in sharing this Foucauldian work and perspective is that we might stimulate a dialogue that is forward-looking and optimistic about the possibilities for change in medical education. PMID- 24807434 TI - Perceptions of interprofessional teamwork in low-acuity settings: a qualitative analysis. AB - CONTEXT: Working effectively in interprofessional teams is a core competency for all health care professionals, yet there is a paucity of instruments with which to assess the associated skills. Published medical teamwork skills assessment tools focus primarily on high-acuity situations, such as cardiopulmonary arrests and crisis events in operating rooms, and may not generalise to non-high-acuity environments, such as in-patient wards and out-patient clinics. OBJECTIVE: We undertook the current study to explore the constructs underlying interprofessional teamwork in non-high-acuity settings and team members' perspectives of essential teamwork attributes. METHODS: We used an ethnographic approach to study four interprofessional teams in two different low-acuity settings: women's HIV (human immunodeficiency virus) clinics and in-patient paediatric wards. Over a period of 17 months, we collected qualitative data through direct observations, focus groups and individual interviews. We analysed the data using qualitative thematic analysis, following an iterative process: data from our observations (20 hours in total) informed the focus group guide and focus group data informed the interview guide. To enhance the integrity of our analysis, we triangulated data sources and verified themes through member checking. RESULTS: We conducted seven focus groups and 27 individual interviews with a total of 39 study participants representing eight professions. Participants emphasised shared leadership and collaborative decision making, mutual respect, recognition of one's own and others' limitations and strengths, and the need to nurture relationships. Team members also discussed tensions around hierarchy and questioned whether doctor leadership is appropriate for interprofessional teams. Our findings indicate that there are differences in teamwork between low-acuity and high-acuity settings, and also provide insights into potential barriers to effective interprofessional teamwork. CONCLUSIONS: Our study delineates essential elements of teamwork in low-acuity settings, including desirable attributes of team members, thus laying the foundation for the development of an individual teamwork skills assessment tool. PMID- 24807435 TI - Western medical students' experiences on clinical electives in sub-Saharan Africa. AB - CONTEXT: Electives commonly represent a valued, enjoyed and formative part of medical training. However, there is little empirical evidence about students' preparedness, practices and perceptions of medical electives in resource-poor settings. Exploring what students do, why and under what circumstances is therefore worthwhile. OBJECTIVES: This study aimed to evaluate students' views on the processes, outcomes and impacts of medical electives in three low-income countries. METHODS: A qualitative study using purposeful sampling and semi structured interviews was conducted. Participants were 29 Western students on medical electives at seven host sites in sub-Saharan Africa. A framework approach was used to analyse 872 minutes of audio-recorded data. RESULTS: Students were highly positive about their experiences and seemed aware of their clinical limitations. Pre-departure training offered by some institutions was beneficial, but the content was perceived to be of little clinical relevance. Language barriers were the main challenges faced by students, even in places where English was the second language. Students who stayed longer, were nearer qualification or were based in rural units (rather than teaching centres) contributed more to patient care. Supervision was considered adequate but this appeared to be judged in a local context. Deliberate inappropriate practice was not encountered, but on occasion misunderstanding arose over the student's status. CONCLUSIONS: Students who undertake electives in resource-poor countries appear to have clearly thought out and positive intentions, but current systems cause concern with reference to student activities and staff time, and require improvement. Instead of focusing on education benefits alone, students (and their sending institutions) need to consider other approaches through which host communities can more clearly benefit. Effective pre-departure preparation should become a requirement. PMID- 24807436 TI - Multiple mini-interview test characteristics: 'tis better to ask candidates to recall than to imagine. AB - CONTEXT: The multiple mini-interview (MMI), used to facilitate the selection of applicants in health professional programmes, has been shown to be capable of generating reliable data predictive of success. It is a process rather than a single instrument and therefore its psychometric properties can be expected to vary according to the stations generated, the alignment between the stations and the qualities an institution prioritises, and the outcomes used. The purpose of this study was to explore the MMI's test characteristics when station type is manipulated. METHODS: A 12-station MMI was established in which four stations were presented in three different ways. These included: situational judgement (SJ) stations, in which applicants were asked to imagine what they would do in specific situations; behavioural interview (BI) stations, in which applicants were asked to recall what they did in experienced situations, and free form (FF) stations, which were unstructured in that the examiner was simply given a brief explanation of the intent of the station without further guidance on how to conduct the discussion. Four circuits of the 12 stations were run with one examiner within each station. Candidates and examiners were surveyed regarding their experience. The reliability of the scores derived from the assessment was analysed separately for each station type. RESULTS: A total of 41 medical school candidates participated after completing the regular admission process. Although the score assigned did not differ across station type, BI stations more reliably differentiated between candidates (g = 0.77) than did the other station types (SJ, g = 0.69; FF, g = 0.66). The correlation between actual MMI scores and BI stations was also greatest (BI, r = 0.57; SJ, r = 0.45; FF, r = 0.42). Candidates' opinions indicated that FF stations were more anxiety-provoking, less clear, and more difficult than structured stations (SJ and BI stations). Examiner opinions indicated equivalence on these measures. CONCLUSIONS: The results suggest that structuring stations has value, although that value was gained only through the use of BI stations, in which candidates were asked to recall and discuss a specific experience of relevance to the purpose of the interview station. PMID- 24807437 TI - Validity evidence of resident competency ratings and the identification of problem residents. AB - OBJECTIVES: This study examined validity evidence of end-of-rotation evaluations used to measure progress toward mastery of core competencies in residents. In addition, this study investigated whether end-of-rotation evaluations can be used to detect problem residents during their training. METHODS: Historical data for a 4-year period (2009-2012), containing 4986 observations of 291 internal medicine residents, were examined. Residents were observed and assessed by fellows, faculty members and programme directors on nine domains, including the six Accreditation Council for Graduate Medical Education core competencies, as part of their end-of-rotation evaluations. Descriptive statistics were used to collect evidence of the response process. Correlations between competencies and a generalisability study were used to examine the internal structure of the end-of rotation evaluations. Hierarchical regression was used to estimate the increase in scores across years of training. Scores on end-of-rotation evaluations were compared with trainees identified as problem residents by programme directors. RESULTS: Compared with fellows, faculty and programme directors had significantly greater variability in assigning scores across different competencies. Correlations between competencies ranged from 0.69 to 0.92. The reliability of end-of-rotation evaluations was adequate (fellows, phi coefficient [phi] = 0.68; faculty [including programme directors], phi = 0.71). Mean scores increased by 0.21 points (95% confidence interval 0.18-0.24) per postgraduate year. Mean scores were significantly correlated with classification as a problem resident (r = 0.33, p < 0.001); problem residents also had significantly lower ratings across all competencies during PGY-1 compared with all other residents. CONCLUSIONS: End of-rotation evaluations are a useful method of measuring the growth in resident performance associated with core competencies when sufficient numbers of end-of rotation evaluation scores are used. Furthermore, end-of-rotation evaluation scores provide preliminary evidence with which to detect and predict problem residents in subsequent postgraduate training years. PMID- 24807438 TI - Progress testing: is there a role for the OSCE? AB - CONTEXT: The shift from a time-based to a competency-based framework in medical education has created a need for frequent formative assessments. Many educational programmes use some form of written progress test to identify areas of strength and weakness and to promote continuous improvement in their learners. However, the role of performance-based assessments, such as objective structured clinical examinations (OSCEs), in progress testing remains unclear. OBJECTIVE: The aims of this paper are to describe the use of an OSCE to assess learners at different stages of training, describe a structure for reporting scores, and provide evidence for the psychometric properties of different rating tools. METHODS: A 10 station OSCE was administered to internal medicine residents in postgraduate years (PGYs) 1-4. Candidates were assessed using a checklist (CL), a global rating scale (GRS) and a training level rating scale (TLRS). Reliability was calculated for each measure using Cronbach's alpha. Differences in performance by year of training were explored using analysis of variance (anova). Correlations between scores obtained using the different rating instruments were calculated. RESULTS: Sixty-nine residents participated in the OSCE. Inter-station reliability was greater (0.88) using the TLRS compared with the CL (0.84) and GRS (0.79). Using all three rating instruments, scores varied significantly by year of training (p < 0.001). Scores from the different rating instruments were highly correlated: CL and GRS, r = 0.93; CL and TLRS, r = 0.90, and GRS and TLRS, r = 0.94 (p < 0.001). Candidates received feedback on their performance relative to examiner expectations for their PGY level. CONCLUSIONS: Scores were found to have high reliability and demonstrated significant differences in performance by year of training. This provides evidence for the validity of using scores achieved on an OSCE as markers of progress in learners at different levels of training. Future studies will focus on assessing individual progress on the OSCE over time. PMID- 24807439 TI - Compassionate care? A critical discourse analysis of accreditation standards. AB - CONTEXT: We rely upon formal accreditation and curricular standards to articulate the priorities of professional training. The language used in standards affords value to certain constructs and makes others less apparent. Leveraging standards can be a useful way for educators to incorporate certain elements into training. This research was designed to look for ways to embed the teaching and practice of compassionate care into Canadian family medicine residency training. METHODS: We conducted a Foucauldian critical discourse analysis of compassionate care in recent formal family medicine residency training documents. Critical discourse analysis is premised on the notion that language is connected to practices and to what is accorded value and power. We assembled an archive of texts and examined them to analyse how compassionate care is constructed, how notions of compassionate care relate to other key ideas in the texts, and the implications of these framings. RESULTS: There were very few words, metaphors or statements that related to concepts of compassionate care in our archive. Even potential proxies, notably the doctor-patient relationship and patient-centred care, were not primarily depicted in ways that linked them to ideas of compassion or caring. There was a reduction in language related to compassionate care in the 2013 standards compared with the standards published in 2006. CONCLUSIONS: Our research revealed negative findings and a relative absence of the construct of compassionate care in our archival documents. This work demonstrates how a shift in curricular focus can have the unintended consequence of making values that are taken for granted less visible. Given that standards shape training, we must pay attention not only to what we include, but also to what we leave out of formal documents. We risk losing important professional values from training programmes if they are not explicitly highlighted in our standards. PMID- 24807440 TI - Missed opportunities in health care education evidence synthesis. PMID- 24807441 TI - Faecal carriage of extended-spectrum beta-lactamase-producing enterobacteria among soldiers at admission in a French military hospital after aeromedical evacuation from overseas. AB - The aim of this study was to assess the faecal carriage of carbapenemase producing enterobacteria (CPE) and extended-spectrum beta-lactamase (ESBL) producing enterobacteria among soldiers at admission in a French military hospital after aeromedical evacuation from overseas. During a period of 1 year, 83 rectal swabs collected in French soldiers at admission were screened for multidrug-resistant enterobacteria with a chromogenic medium. ESBL detection was performed with the double-disc synergy test in the absence or presence of cloxacillin. The genotypic characterisation of resistance mechanisms, sequence typing and phylotyping was performed by polymerase chain reaction (PCR) and sequencing with bacterial DNA extracted from isolates. No CPE was detected. Eleven ESBL Escherichia coli isolates belonging to four phylogenetic groups were detected, including ten CTX-M-15 and one CTX-M-14. The overall gut colonisation with ESBL-producing bacteria (13.25 %) was 6-fold higher than that reported in soldiers in the suburbs of Paris in 2009. ESBL faecal carriage was particularly high (34.48 %) in soldiers repatriated from Afghanistan (risk ratio = 18.62; p = 0.0001). This study highlights the importance of systematic additional contact precautions and CPE/ESBL screening in soldiers repatriated from overseas in French hospitals. PMID- 24807442 TI - A survey on CPG-inspired control models and system implementation. AB - This paper surveys the developments of the last 20 years in the field of central pattern generator (CPG) inspired locomotion control, with particular emphasis on the fast emerging robotics-related applications. Functioning as a biological neural network, CPGs can be considered as a group of coupled neurons that generate rhythmic signals without sensory feedback; however, sensory feedback is needed to shape the CPG signals. The basic idea in engineering endeavors is to replicate this intrinsic, computationally efficient, distributed control mechanism for multiple articulated joints, or multi-DOF control cases. In terms of various abstraction levels, existing CPG control models and their extensions are reviewed with a focus on the relative advantages and disadvantages of the models, including ease of design and implementation. The main issues arising from design, optimization, and implementation of the CPG-based control as well as possible alternatives are further discussed, with an attempt to shed more light on locomotion control-oriented theories and applications. The design challenges and trends associated with the further advancement of this area are also summarized. PMID- 24807443 TI - Robust model predictive control of nonlinear systems with unmodeled dynamics and bounded uncertainties based on neural networks. AB - This paper presents a neural network approach to robust model predictive control (MPC) for constrained discrete-time nonlinear systems with unmodeled dynamics affected by bounded uncertainties. The exact nonlinear model of underlying process is not precisely known, but a partially known nominal model is available. This partially known nonlinear model is first decomposed to an affine term plus an unknown high-order term via Jacobian linearization. The linearization residue combined with unmodeled dynamics is then modeled using an extreme learning machine via supervised learning. The minimax methodology is exploited to deal with bounded uncertainties. The minimax optimization problem is reformulated as a convex minimization problem and is iteratively solved by a two-layer recurrent neural network. The proposed neurodynamic approach to nonlinear MPC improves the computational efficiency and sheds a light for real-time implementability of MPC technology. Simulation results are provided to substantiate the effectiveness and characteristics of the proposed approach. PMID- 24807444 TI - Multi-level fuzzy min-max neural network classifier. AB - In this paper a multi-level fuzzy min-max neural network classifier (MLF), which is a supervised learning method, is described. MLF uses basic concepts of the fuzzy min-max (FMM) method in a multi-level structure to classify patterns. This method uses separate classifiers with smaller hyperboxes in different levels to classify the samples that are located in overlapping regions. The final output of the network is formed by combining the outputs of these classifiers. MLF is capable of learning nonlinear boundaries with a single pass through the data. According to the obtained results, the MLF method, compared to the other FMM networks, has the highest performance and the lowest sensitivity to maximum size of the hyperbox parameter (theta), with a training accuracy of 100% in most cases. PMID- 24807445 TI - Adaptive identifier for uncertain complex nonlinear systems based on continuous neural networks. AB - This paper presents the design of a complex-valued differential neural network identifier for uncertain nonlinear systems defined in the complex domain. This design includes the construction of an adaptive algorithm to adjust the parameters included in the identifier. The algorithm is obtained based on a special class of controlled Lyapunov functions. The quality of the identification process is characterized using the practical stability framework. Indeed, the region where the identification error converges is derived by the same Lyapunov method. This zone is defined by the power of uncertainties and perturbations affecting the complex-valued uncertain dynamics. Moreover, this convergence zone is reduced to its lowest possible value using ideas related to the so-called ellipsoid methodology. Two simple but informative numerical examples are developed to show how the identifier proposed in this paper can be used to approximate uncertain nonlinear systems valued in the complex domain. PMID- 24807446 TI - Function approximation using combined unsupervised and supervised learning. AB - Function approximation is one of the core tasks that are solved using neural networks in the context of many engineering problems. However, good approximation results need good sampling of the data space, which usually requires exponentially increasing volume of data as the dimensionality of the data increases. At the same time, often the high-dimensional data is arranged around a much lower dimensional manifold. Here we propose the breaking of the function approximation task for high-dimensional data into two steps: (1) the mapping of the high-dimensional data onto a lower dimensional space corresponding to the manifold on which the data resides and (2) the approximation of the function using the mapped lower dimensional data. We use over-complete self-organizing maps (SOMs) for the mapping through unsupervised learning, and single hidden layer neural networks for the function approximation through supervised learning. We also extend the two-step procedure by considering support vector machines and Bayesian SOMs for the determination of the best parameters for the nonlinear neurons in the hidden layer of the neural networks used for the function approximation. We compare the approximation performance of the proposed neural networks using a set of functions and show that indeed the neural networks using combined unsupervised and supervised learning outperform in most cases the neural networks that learn the function approximation using the original high dimensional data. PMID- 24807447 TI - Active learning of Pareto fronts. AB - This paper introduces the active learning of Pareto fronts (ALP) algorithm, a novel approach to recover the Pareto front of a multiobjective optimization problem. ALP casts the identification of the Pareto front into a supervised machine learning task. This approach enables an analytical model of the Pareto front to be built. The computational effort in generating the supervised information is reduced by an active learning strategy. In particular, the model is learned from a set of informative training objective vectors. The training objective vectors are approximated Pareto-optimal vectors obtained by solving different scalarized problem instances. The experimental results show that ALP achieves an accurate Pareto front approximation with a lower computational effort than state-of-the-art estimation of distribution algorithms and widely known genetic techniques. PMID- 24807448 TI - Learning Harmonium models with infinite latent features. AB - Undirected latent variable models represent an important class of graphical models that have been successfully developed to deal with various tasks. One common challenge in learning such models is to determine the number of hidden units that are unknown a priori. Although Bayesian nonparametrics have provided promising results in bypassing the model selection problem in learning directed Bayesian Networks, very little effort has been made toward applying Bayesian nonparametrics to learn undirected latent variable models. In this paper, we present the infinite exponential family Harmonium (iEFH), a bipartite undirected latent variable model that automatically determines the number of latent units from an unbounded pool. We also present two important extensions of iEFH to 1) multiview iEFH for dealing with heterogeneous data, and 2) infinite maximum margin Harmonium (iMMH) for incorporating supervising side information to learn predictive latent features. We develop variational inference algorithms to learn model parameters. Our methods are computationally competitive because of the avoidance of selecting the number of latent units. Our extensive experiments on real image datasets and text datasets appear to demonstrate the benefits of iEFH and iMMH inherited from Bayesian nonparametrics and max-margin learning. Such results were not available until now and contribute to expanding the scope of Bayesian nonparametrics to learn the structures of undirected latent variable models. PMID- 24807449 TI - A class of quaternion Kalman filters. AB - The existing Kalman filters for quaternion-valued signals do not operate fully in the quaternion domain, and are combined with the real Kalman filter to enable the tracking in 3-D spaces. Using the recently introduced HR-calculus, we develop the fully quaternion-valued Kalman filter (QKF) and quaternion-extended Kalman filter (QEKF), allowing for the tracking of 3-D and 4-D signals directly in the quaternion domain. To consider the second-order noncircularity of signals, we employ the recently developed augmented quaternion statistics to derive the widely linear QKF (WL-QKF) and widely linear QEKF (WL-QEKF). To reduce computational requirements of the widely linear algorithms, their efficient implementation are proposed and it is shown that the quaternion widely linear model can be simplified when processing 3-D data, further reducing the computational requirements. Simulations using both synthetic and real-world circular and noncircular signals illustrate the advantages offered by widely linear over strictly linear quaternion Kalman filters. PMID- 24807450 TI - Neural network for nonsmooth, nonconvex constrained minimization via smooth approximation. AB - A neural network based on smoothing approximation is presented for a class of nonsmooth, nonconvex constrained optimization problems, where the objective function is nonsmooth and nonconvex, the equality constraint functions are linear and the inequality constraint functions are nonsmooth, convex. This approach can find a Clarke stationary point of the optimization problem by following a continuous path defined by a solution of an ordinary differential equation. The global convergence is guaranteed if either the feasible set is bounded or the objective function is level bounded. Specially, the proposed network does not require: 1) the initial point to be feasible; 2) a prior penalty parameter to be chosen exactly; 3) a differential inclusion to be solved. Numerical experiments and comparisons with some existing algorithms are presented to illustrate the theoretical results and show the efficiency of the proposed network. PMID- 24807451 TI - Nonbinary associative memory with exponential pattern retrieval capacity and iterative learning. AB - We consider the problem of neural association for a network of nonbinary neurons. Here, the task is to first memorize a set of patterns using a network of neurons whose states assume values from a finite number of integer levels. Later, the same network should be able to recall the previously memorized patterns from their noisy versions. Prior work in this area consider storing a finite number of purely random patterns, and have shown that the pattern retrieval capacities (maximum number of patterns that can be memorized) scale only linearly with the number of neurons in the network. In our formulation of the problem, we concentrate on exploiting redundancy and internal structure of the patterns to improve the pattern retrieval capacity. Our first result shows that if the given patterns have a suitable linear-algebraic structure, i.e., comprise a subspace of the set of all possible patterns, then the pattern retrieval capacity is exponential in terms of the number of neurons. The second result extends the previous finding to cases where the patterns have weak minor components, i.e., the smallest eigenvalues of the correlation matrix tend toward zero. We will use these minor components (or the basis vectors of the pattern null space) to increase both the pattern retrieval capacity and error correction capabilities. An iterative algorithm is proposed for the learning phase, and two simple algorithms are presented for the recall phase. Using analytical methods and simulations, we show that the proposed methods can tolerate a fair amount of errors in the input while being able to memorize an exponentially large number of patterns. PMID- 24807452 TI - A constrained backpropagation approach for the adaptive solution of partial differential equations. AB - This paper presents a constrained backpropagation (CPROP) methodology for solving nonlinear elliptic and parabolic partial differential equations (PDEs) adaptively, subject to changes in the PDE parameters or external forcing. Unlike existing methods based on penalty functions or Lagrange multipliers, CPROP solves the constrained optimization problem associated with training a neural network to approximate the PDE solution by means of direct elimination. As a result, CPROP reduces the dimensionality of the optimization problem, while satisfying the equality constraints associated with the boundary and initial conditions exactly, at every iteration of the algorithm. The effectiveness of this method is demonstrated through several examples, including nonlinear elliptic and parabolic PDEs with changing parameters and nonhomogeneous terms. PMID- 24807453 TI - A robust and scalable neuromorphic communication system by combining synaptic time multiplexing and MIMO-OFDM. AB - This paper describes a novel architecture for enabling robust and efficient neuromorphic communication. The architecture combines two concepts: 1) synaptic time multiplexing (STM) that trades space for speed of processing to create an intragroup communication approach that is firing rate independent and offers more flexibility in connectivity than cross-bar architectures and 2) a wired multiple input multiple output (MIMO) communication with orthogonal frequency division multiplexing (OFDM) techniques to enable a robust and efficient intergroup communication for neuromorphic systems. The MIMO-OFDM concept for the proposed architecture was analyzed by simulating large-scale spiking neural network architecture. Analysis shows that the neuromorphic system with MIMO-OFDM exhibits robust and efficient communication while operating in real time with a high bit rate. Through combining STM with MIMO-OFDM techniques, the resulting system offers a flexible and scalable connectivity as well as a power and area efficient solution for the implementation of very large-scale spiking neural architectures in hardware. PMID- 24807454 TI - ERNN: a biologically inspired feedforward neural network to discriminate emotion from EEG signal. AB - Emotions play an important role in human cognition, perception, decision making, and interaction. This paper presents a six-layer biologically inspired feedforward neural network to discriminate human emotions from EEG. The neural network comprises a shift register memory after spectral filtering for the input layer, and the estimation of coherence between each pair of input signals for the hidden layer. EEG data are collected from 57 healthy participants from eight locations while subjected to audio-visual stimuli. Discrimination of emotions from EEG is investigated based on valence and arousal levels. The accuracy of the proposed neural network is compared with various feature extraction methods and feedforward learning algorithms. The results showed that the highest accuracy is achieved when using the proposed neural network with a type of radial basis function. PMID- 24807455 TI - Policy iteration adaptive dynamic programming algorithm for discrete-time nonlinear systems. AB - This paper is concerned with a new discrete-time policy iteration adaptive dynamic programming (ADP) method for solving the infinite horizon optimal control problem of nonlinear systems. The idea is to use an iterative ADP technique to obtain the iterative control law, which optimizes the iterative performance index function. The main contribution of this paper is to analyze the convergence and stability properties of policy iteration method for discrete-time nonlinear systems for the first time. It shows that the iterative performance index function is nonincreasingly convergent to the optimal solution of the Hamilton Jacobi-Bellman equation. It is also proven that any of the iterative control laws can stabilize the nonlinear systems. Neural networks are used to approximate the performance index function and compute the optimal control law, respectively, for facilitating the implementation of the iterative ADP algorithm, where the convergence of the weight matrices is analyzed. Finally, the numerical results and analysis are presented to illustrate the performance of the developed method. PMID- 24807456 TI - Reinforcement learning output feedback NN control using deterministic learning technique. AB - In this brief, a novel adaptive-critic-based neural network (NN) controller is investigated for nonlinear pure-feedback systems. The controller design is based on the transformed predictor form, and the actor-critic NN control architecture includes two NNs, whereas the critic NN is used to approximate the strategic utility function, and the action NN is employed to minimize both the strategic utility function and the tracking error. A deterministic learning technique has been employed to guarantee that the partial persistent excitation condition of internal states is satisfied during tracking control to a periodic reference orbit. The uniformly ultimate boundedness of closed-loop signals is shown via Lyapunov stability analysis. Simulation results are presented to demonstrate the effectiveness of the proposed control. PMID- 24807457 TI - Prerequisites to implementing a pharmacogenomics program in a large health-care system. AB - Pharmacogenomics (PGx) technology is advancing rapidly; however, clinical adoption is lagging. The Indiana Institute of Personalized Medicine (IIPM) places a strong focus on translating PGx research into clinical practice. We describe what have been found to be the key requirements that must be delivered in order to ensure a successful and enduring PGx implementation within a large health-care system. PMID- 24807458 TI - Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans. AB - PURPOSE: Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR 67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment. METHODS: After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), gammaH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days. RESULTS: Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and gammaH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial. CONCLUSIONS: We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation. PMID- 24807459 TI - A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC). AB - INTRODUCTION: Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC. METHODS: Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m2) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients. RESULTS: Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 MUg/mL and AUC24 was 4.29 MUg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients. CONCLUSIONS: Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients. PMID- 24807460 TI - Beneficial effect of astragalosides on stroke condition using PC12 cells under oxygen glucose deprivation and reperfusion. AB - Astragalosides (AST) are reported to be neuroprotective in focal cerebral ischemic models in vivo. In this study, the direct effect of AST against oxygen and glucose deprivation (OGD) including neuronal injury and the underlying mechanisms in vitro were investigated. 5 h OGD followed by 24 h of reperfusion [adding back oxygen and glucose (OGD-R)] was used to induce in vitro ischemia reperfusion injury in differentiated rat pheochromocytoma PC12 cells. AST (1, 100, and 200 ug/mL) were added to the culture after 5 h of the OGD ischemic insult and was present during the reoxygenation phases. A key finding was that OGD-R decreased cell viability, increased lactate dehydrogenase, increased reactive oxygen species, apoptosis, autophagy, functional impairment of mitochondria, and endoplasmic reticulum stress in PC12 cells, all of which AST treatment significantly reduced. In addition, AST attenuated OGD-R-induced cell loss through P38 MAPK activation a neuroprotective effect blunted by SB203580, a specific inhibitor of P38 MAPK. Our data suggest that both apoptosis and autophagy are important characteristics of OGD-R-induced PC12 death and that treating PC12 cells with AST blocked OGD-R-induced apoptosis and autophagy by suppressing intracellular oxidative stress, functional impairment of mitochondria, and endoplasmic reticulum stress. Our data provide identification of AST that can concomitantly inhibit multiple cells death pathways following OGD injuries in neural cells. PMID- 24807461 TI - Neuroprotective effect of oxaloacetate in a focal brain ischemic model in the rat. AB - During an ischemic event, the well-regulated glutamate (Glu) homeostasis is disturbed, which gives rise to extremely high levels of this excitatory neurotransmitter in the brain tissues. It was earlier reported that the administration of oxaloacetate (OxAc) as a Glu scavenger reduces the Glu level in the brain by enhancing the brain-to-blood Glu efflux. Here, we studied the neuroprotective effect of OxAc administration in a new focal ischemic model in rats. Occlusion of the middle cerebral artery resulted in immediate reduction of the somatosensory-evoked responses (SERs), and the amplitudes remained at the reduced level throughout the whole ischemic period. On reperfusion, the SERs started to increase, but never reached the control level. OxAc proved to be protective, since the amplitudes started to recover even during the ischemia, and finally fully regained the control level. The findings of the histological measurements were in accordance with the electrophysiological data. After Fluoro Jade C staining, significantly fewer labeled cells were detected in the OxAc treated group relative to the control. These results provide new evidence of the neuroprotective effect of OxAc against ischemic injury, which strengthens the likelihood of its future applicability as a novel neuroprotective agent for the treatment of ischemic stroke patients. PMID- 24807462 TI - Longitudinal profiling of inflammatory cytokines and C-reactive protein during uncomplicated and preterm pregnancy. AB - PROBLEM: Previous studies have investigated the utility of inflammation markers as predictors of preterm birth, but none have compared trends in levels between uncomplicated and preterm pregnancy. METHOD OF STUDY: We explored longitudinal changes in plasma cytokines, including IL-1beta, IL-6, IL-10, and TNF-alpha, as well as C-reactive protein in pregnant women from a nested case-control study. RESULTS: IL-6 was associated with increased odds of spontaneous preterm birth, defined by presentation of spontaneous preterm labor and/or preterm premature rupture of the membranes. Associations were strongest later in pregnancy. IL-10 was associated with increased odds of placentally mediated preterm birth, defined by presentation with preeclampsia or intrauterine growth restriction, and odds ratios were also highest near the end of pregnancy. CONCLUSION: Maternal inflammation markers were associated with increased risk of preterm birth, and relationships differed by etiology of preterm delivery and gestational age at sample collection. PMID- 24807465 TI - Two and three dimensional network polymers for electrocatalysis. AB - Recently, two and three dimensional network polymers have started to gain traction in the research sphere as scientists look for ways to create materials with more tailored properties. These network polymers show high surface area and specific, sometimes periodic, functionality, providing perfect templates both to host electrocatalytic materials as well as function as electrocatalysts themselves. While doped carbon based materials such as graphene and carbon nanotubes, as well as diamond, have demonstrated their electrocatalytic potential, other network polymers have yet to be synthesized in a manner to optimize their potential. As these polymers are built of a periodic arrangement of appropriately functionalized monomers, an exact arrangement of functional sites should be possible, which combined with potentially high surface areas should lead to very high catalytic activity. This perspective will cover the synthesis and achievements of the mentioned doped carbon materials before taking a look at the strengths, shortcomings, and future goals in electrocatalysis as related to more novel network polymers. PMID- 24807464 TI - Plasma NT-proBNP as predictor of change in functional status, cardiovascular morbidity and mortality in the oldest old: the Leiden 85-plus study. AB - In the aging society, it is important to identify very old persons at high risk of functional decline, cardiovascular disease and mortality. However, traditional risk markers lose their predictive value with age. We investigated whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels predict change in functional status, cardiovascular morbidity and mortality in very old age. Here we present an observational prospective cohort study (Leiden 85-plus Study, 1997 2004) in a population-based sample of 560 individuals aged 85 years with a 5-year complete follow-up for functional status, cardiovascular morbidity and cause specific mortality. Median NT-proBNP for men was 351 pg/ml (cutoff values for low medium tertiles 201 pg/ml and medium-high tertiles 649 pg/ml) and, for women, 297 pg/ml (cutoffs 204 and 519 pg/ml, respectively). During the 5-year follow-up, participants with high NT-proBNP had an accelerated cognitive decline and increase of activities of daily living (ADL) disability over time (all at p < 0.01) and an increased risk of incident heart failure [hazard ratio (HR) 3.3 (95 % confidence interval (CI) 1.8-6.1)], atrial fibrillation [HR 4.1 (2.0-8.7)], myocardial infarction [HR 2.1 (1.2-3.7)], stroke [HR 3.4 (1.9-6.3)], cardiovascular mortality [HR 5.5 (3.1-10)], non-cardiovascular mortality [HR 2.0 (1.4-3.0)] and all-cause mortality [HR 2.9 (2.1-4.0)], independent of other known risk markers. All results remained similar after exclusion of participants with heart failure at baseline. In very old age, high-NT-proBNP levels predict accelerated cognitive and functional decline, as well as cardiovascular morbidity and mortality. Results suggest that NT-proBNP can help clinicians to identify very old people at high risk of functional impairment and incident cardiovascular morbidity. PMID- 24807466 TI - Trigeminal trophic syndrome: report of a case and review of the published work. AB - Trigeminal trophic syndrome is a rare complication of trigeminal nerve injury that causes facial ulceration, anesthesia and paresthesia in the same trigeminal dermatomes. We present a case of a 65-year-old woman with a history of meningioma resection 18 years prior who presented 16 years later with an intractable ulceration around her left nasolabial sulcus. Pain and light-touch sensations around the ulcer were decreased. She admitted to frequent manipulation due to a crawling sensation. A skin biopsy showed acanthotic changes and a decreased number of peripheral nerve fibers. Trigeminal trophic syndrome was diagnosed. Carbamazepine was not effective, and the ulcer persisted at 7 months after the initial presentation. We reviewed 36 English-language publications from 2003 to 2012, and analyzed 61 cases of trigeminal trophic syndrome, including this patient. The mean age was 53.3 +/- 19.7 years (range, 6-91). The right side of the face was more commonly affected (57%) than the left side. The ala nasi were involved in 48 cases (79%), followed by the cheek in 17 cases (28%). A corneal lesion was observed in 11 cases (18%), suggesting the importance of ophthalmologic consultations. The two major etiologies were trigeminal nerve ablation (18 cases; 30%) and cerebrovascular accidents (18 cases; 30%). The latent period ranged from days to 30 years. Gabapentin and carbamazepine were frequently administrated with variable efficacy. Application of thermoplastic dressings or negative pressure wound therapy demonstrated favorable outcomes. Surgery was an option with a high recurrence rate. Trigeminal trophic syndrome remains a clinical challenge. PMID- 24807467 TI - The current landscape of adipose-derived stem cells in clinical applications. AB - Adipose-derived stem cells (ASCs) are considered a great alternative source of mesenchymal stem cells (MSCs). Unlike bone marrow stem cells (BMSCs), ASCs can be retrieved in high numbers from lipoaspirate, a by-product of liposuction procedures. Given that ASCs represent an easily accessible and abundant source of multipotent cells, ASCs have garnered attention and curiosity from both scientific and clinical communities for their potential in clinical applications. Furthermore, their unique immunobiology and secretome are attractive therapeutic properties. A decade since the discovery of a stem cell reservoir residing within adipose tissue, ASC-based clinical trials have grown over the years around the world along with assessments made on their safety and efficacy. With the progress of ASCs into clinical applications, the aim towards producing clinical-grade ASCs becomes increasingly important. Several countries have recognised the growing industry of cell therapies and have developed regulatory frameworks to assure their safety. With more research efforts made to understand their effects in both scientific and clinical settings, ASCs hold great promise as a future therapeutic strategy in treating a wide variety of diseases. Therefore, this review seeks to highlight the clinical applicability of ASCs as well as their progress in clinical trials across various medical disciplines. PMID- 24807468 TI - A review of the economics of treating Clostridium difficile infection. AB - Clostridium difficile infection (CDI) is a costly result of antibiotic use, responsible for an estimated 14,000 deaths annually in the USA according to the Centers for Disease Control and Prevention. Annual costs attributable to CDI are in excess of $US 1 billion. This review summarizes appropriate utilization of prevention and treatment methods for CDI that have the potential to reduce the economic and humanistic costs of the disease. Some cost-effective strategies to prevent CDI include screening and isolation of hospital admissions based on C. difficile carriage to reduce transmission in the inpatient setting, and probiotics, which are potentially efficacious in preventing CDI in the appropriate patient population. The most extensively studied agents for treatment of CDI are metronidazole, vancomycin, and fidaxomicin. Most economic comparisons between metronidazole and vancomycin favor vancomycin, especially with the emergence of metronidazole-resistant C. difficile strains. Metronidazole can only be recommended for mild disease. Moderate to severe CDI should be treated with vancomycin, preferably the compounded oral solution, which provides the most cost effective therapeutic option. Fidaxomicin offers a clinically effective and potentially cost-effective alternative for treating moderate CDI in patients who do not have the NAP1/BI/027 strain of C. difficile. Probiotics and fecal microbiota transplant have variable efficacy and the US FDA does not currently regulate the content; the potential economic advantages of these treatment modalities are currently unknown. PMID- 24807469 TI - Economic evaluations of gastroesophageal reflux disease medical management. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) contributes to substantial medication use and costs worldwide. Economic evaluations provide insight into the value of healthcare, taking into account cost, quality, and benefits of particular treatments. OBJECTIVES: Our objectives were to systematically review the existing literature to identify economic evaluations of GERD management strategies, to assess the scientific quality of these reports, and to summarize the economic outcomes of these evaluations. METHODS: We identified economic evaluations and cost studies of GERD management strategies by searching PubMed and the UK NHS Economic Evaluation Database via the Cochrane Library. Searching was restricted to articles in English-language journals from July 2003 to July 2013. Cost-identification articles were excluded from the final analysis. RESULTS: Eighteen articles were included in the final analysis; 61 % of these met all criteria for quality reporting. Overall, proton pump inhibitor (PPI) therapy was preferred (most effective and least costly) as empiric therapy for patients with reflux symptoms, except in patient populations with high Helicobacter pylori prevalence (>40 %). Initial empiric PPI therapy (vs. initial endoscopy stratification or H. pylori testing) is likely the most cost-effective initial strategy for patients with typical GERD symptoms. Surgery may be cost effective in patients with chronic GERD symptoms at time horizons of 3-10 years. Endoscopic anti-reflux procedures were not cost effective based on available data. CONCLUSIONS: Further economic evaluations should adhere to standard reporting measures of cost estimates and outcomes, and should attempt to account for and compare the large heterogeneity of patient phenotypes and treatment effects seen with anti-reflux therapies. PMID- 24807470 TI - Spinal cord response to stepwise and block presentation of thermal stimuli: a functional MRI study. AB - PURPOSE: To examine the characteristics of the spinal cord and brainstem blood oxygenation level-dependent (BOLD) responses to peripheral stimulation in which the temperature is raised in a stepwise fashion, in order to enhance receptor responses, compared to a block design. MATERIALS AND METHODS: Functional magnetic resonance imaging (fMRI) studies of the spinal cord and brainstem were carried out in 14 healthy volunteers at 3T. Thermal sensory stimuli were applied to the right hand in a block-design paradigm, and in a stepwise paradigm to the same peak temperature. Data were analyzed by means of a general linear model, region of interest analyses, and by structural equation modeling. RESULTS: Results demonstrated BOLD responses in a number of consistent regions between the two paradigms as well as significant differences (P < .001) in the locations and magnitudes of some responses. Specifically, the BOLD response in the dorsal horn was significantly higher in the stepwise compared to the block condition (P < .001). However, more significant connections (T >2) between regions were observed in the block condition. CONCLUSION: Results from this study demonstrate the means to design thermal sensory paradigms to probe components of sensory processing in the brainstem and spinal cord. PMID- 24807471 TI - 'Happy' drug survival of adalimumab, etanercept and ustekinumab in psoriasis in daily practice care: results from the BioCAPTURE network. AB - BACKGROUND: Drug survival is a marker for treatment success. To date, no analyses relating dermatological quality-of-life measures to drug survival have been published. OBJECTIVES: (i) To describe 1-year drug survival for adalimumab, etanercept and ustekinumab in a daily practice psoriasis cohort, and (ii) to introduce the concept of 'happy' drug survival, defined as Dermatology Life Quality Index (DLQI) <= 5 combined with being 'on drug' at a specific time point. METHODS: Data were extracted from a prospective registry. Drug survival was analysed using Kaplan-Meier estimates. 'Happy' drug survival was calculated, with data split into 'happy' (DLQI <= 5) vs. 'unhappy' (DLQI > 5) at baseline and months 3, 6, 9 and 12. RESULTS: 249 treatment episodes were included (101 adalimumab, 82 etanercept, 66 ustekinumab). The 1-year drug survival rates for ustekinumab, adalimumab and etanercept were 85%, 74% and 68%, respectively. Ustekinumab showed a better confounder-corrected drug survival vs. etanercept [hazard ratio (HR) 3.8, P = 0.02] and a trend towards better survival vs. adalimumab (HR 2.3, P = 0.1). At baseline, the majority (n = 115, 73%) was considered 'unhappy' and a minority 'happy' (n = 42, 27%) (ratio 'happy':'unhappy' was 1 : 2.7). The percentage of treatment episodes with 'happy' on-drug patients increased to 79% after 1 year. CONCLUSIONS: Ustekinumab showed a better overall drug survival than etanercept, and a trend towards a better overall drug survival than adalimumab. After 1 year, patients reported to be 'happy' in 79% of episodes and 'unhappy' in 21%. We introduced the new concept of 'happy' drug survival because the proportion of on-drug patients with good quality of life is an important indicator for treatment success. PMID- 24807472 TI - Transbronchial needle aspiration through a guide sheath with endobronchial ultrasonography (GS-TBNA) for peripheral pulmonary lesions. AB - PURPOSE: Although, endobronchial ultrasonography with a guide sheath is becoming a common procedure for the diagnosis of peripheral pulmonary lesions, there remain to be some inaccuracies in cases wherein the probe is located outside the lesion. We tested whether adding transbronchial needle aspiration through a guide sheath to the conventional technique increases efficacy for diagnosing peripheral pulmonary lesions. METHODS: We performed transbronchial needle aspiration through a guide sheath for 37 subjects with peripheral pulmonary lesions between September 2012 and April 2013. The devices used were as follows (all Olympus Ltd., Tokyo, Japan): 1T-260 or LF-TP bronchoscope, K203 guide sheath kit and NA 1C-1 needle apparatus, customized by cutting the guide sheath 30 mm from the proximal end to fit well with the needle. RESULTS: The endobronchial ultrasound probe was located within the lesion in 21 cases (56.8%) and outside in 16 cases (43.2%). Overall accuracy was 86.5 percent; 90.5% in "within" cases compared to 81.3% in "outside" cases with no significant difference (P = 0.42). Pneumothorax occurred in 2 cases and pneumonia in 1 case. CONCLUSION: Transbronchial needle aspiration through a guide sheath is an effective and safe diagnostic procedure for peripheral pulmonary lesions, especially when the guide sheath is outside the lesion. PMID- 24807473 TI - The feasibility of extracorporeal membrane oxygenation support for inter-hospital transport and as a bridge to lung transplantation. AB - BACKGROUND: Regional lung transplantation centers should be equipped with an inter-hospital transport program that can provide life-support for lung transplant candidates who develop acute respiratory failure outside the hospital. The purpose of this study was to assess the value of extracorporeal membrane oxygenation (ECMO) as a means of support during transport and as a bridge to lung transplantation for transplant candidates who develop respiratory failure outside the transplantation center. METHODS: We retrospectively analyzed data from 7 patients who developed acute lung failure during treatment of end-stage lung diseases at other hospitals and for whom inter-hospital transport to the lung transplantation center at our hospital was requested between December 2011 and June 2013. RESULTS: All 7 patients were treated with ECMO via a Terumo Emergency Bypass System((r)) (EBS((r))) during transport, and all were transported without incident. There were no adverse events related to ECMO. All patients maintained stable vital signs during transport. Four patients received lung transplant within 10.5 +/- 2.3 days (range: 7 to 12 days) after transport, 1 patient was weaned from ECMO without transplant, and 2 patients died with multi-organ failure while awaiting donor lungs. CONCLUSION: ECMO was useful for transfer of lung transplant candidates who developed acute respiratory failure at other institutions and as a bridge to lung transplantation. An inter-hospital transport program involving ECMO may increase the likelihood of successful transport to regional transplantation centers for lung transplantation candidates who show respiratory failure. PMID- 24807474 TI - Endovenous laser ablation under general anesthesia for day surgery: feasibility and outcomes of the 300 patients. AB - PURPOSE: Endovenous laser ablation (EVLA) for superficial venous insufficiency is traditionally performed under tumescent local anesthesia as day case surgery. The aim of this study is to evaluate the feasibility of general anesthesia in addition to tumescent anesthesia in patients undergoing EVLA. METHODS: The anesthesia and clinical registration records of 341 extremities of 300 adult patients were reviewed and analyzed retrospectively. Demographic and clinical data, preoperative anesthetic evaluation data (ASA physical status, preoperative airway assessment, Mallampati score), type of supraglottic device, duration of anesthesia and surgery, any surgical and/or anesthetic complication, timing of mobilization and discharge, and postoperative course were evaluated. RESULTS: Mean duration of operation and anesthesia was 28 (12-55) and 40 (20-65) minutes, respectively. Mobilization and discharge timing was 25 (11-45) and 139 (110-200) minutes, respectively. All patients were discharged the same day of surgery. CONCLUSION: The combination technique of administering general anesthesia with supraglottic device and tumescent anesthesia is a safe and effective method to reduce the patients' pain and discomfort during the EVLT procedure within the scope of day case surgery. PMID- 24807475 TI - Interaction of nanoparticles with lipid membranes: a multiscale perspective. AB - Freestanding lipid bilayers were challenged with 15 nm Au nanospheres either coated by a citrate layer or passivated by a protein corona. The effect of Au nanospheres on the bilayer morphology, permeability and fluidity presents strong differences or similarities, depending on the observation length scale, from the colloidal to the molecular domains. These findings suggest that the interaction between nanoparticles and lipid membranes should be conveniently treated as a multiscale phenomenon. PMID- 24807476 TI - Effect of a maternity consumer representative training program on participants' confidence and engagement. AB - OBJECTIVE: This paper describes the effects of a maternity consumer representative training program on participants' confidence to fulfil this role and engagement in representative activities. METHODS: The present study was a descriptive, pre-post evaluation design with a 3-month follow-up. Fifty-eight people completed the program and 55 agreed to participate in the evaluation. Participants completed questionnaires to assess confidence to undertake consumer representative roles and reported on their engagement with consumer activities. RESULTS: Participants' perceived confidence to function in the role of consumer representative differed significantly before and after the workshop (F(2,18)=7.057, P<0.001), as did confidence in decision making (F(2,16)=7.615, P=0.005), confidence in negotiating outcomes and liaising with key people (F(2,18)=7.154, P=0.005), and confidence in making use of relevant networks (F(2,18)=4.319, P=0.029). There was a decline in confidence at 3 months, with confidence at this time no longer significantly different from that at the time of recruitment. Engagement with consumer organisations increased by 45% compared with rates at commencement of the project. CONCLUSIONS: The program enhanced participants' confidence to fulfil a maternity consumer representative role but was not sustained. Further research is needed as to how to best support maternity consumer representatives and assess their contribution to promoting woman-centred care. PMID- 24807477 TI - Cooperative catalysis: electron-rich Fe-H complexes and DMAP, a successful "joint venture" for ultrafast hydrogen production. AB - A series of defined iron-hydrogen complexes was prepared in a straightforward one pot approach. The structure and electronic properties of such complexes were investigated by means of quantum-chemical analysis. These new complexes were then applied in the dehydrogenative silylation of methanol. The complex (dppp)(CO)(NO)FeH showed a remarkable activity with a TOF of more than 600 000 h( 1) of pure hydrogen gas within seconds. PMID- 24807478 TI - When the well runs dry. PMID- 24807480 TI - Characteristic spectral patterns in the carbon-13 nuclear magnetic resonance spectra of hexagonal and crenellated graphene fragments. AB - Nuclear magnetic resonance (NMR) spectroscopy is an important molecular characterisation method that may aid the synthesis and production of graphenes, especially the molecular-scale graphene nanoislands that have gathered significant attention due to their potential electronic and optical applications. Herein, carbon-13 NMR chemical shifts were calculated using density functional theory methods for finite, increasing-size fragments of graphene, hydrogenated graphene (graphane) and fluorinated graphene (fluorographene). Both concentric hexagon-shaped (zigzag boundary) and crenellated (armchair) fragments were investigated to gain information on the effect of different types of flake boundaries. Convergence trends of the (13)C chemical shift with respect to increasing fragment size and the boundary effects were found and rationalised in terms of low-lying electronically excited states. The results predict characteristic behaviour in the (13)C NMR spectra. Particular attention was paid to the features of the signals arising from the central carbon atoms of the fragments, for graphene and crenellated graphene on the one hand and graphane and fluorographene on the other hand, to aid the interpretation of the overall spectral characteristics. In graphene, the central nuclei become more shielded as the system size increases whereas the opposite behaviour is observed for graphane and fluorographene. The (13)C signals from some of the perimeter nuclei of the crenellated fragments obtain smaller and larger chemical shift values than central nuclei for graphene and graphane/fluorographene, respectively. The diameter of the graphenic quantum dots with zigzag boundary correlates well with the predicted carbon-13 chemical shift range, thus enabling estimation of the size of the system by NMR spectroscopy. The results provide data of predictive quality for future NMR analysis of the graphene nanoflake materials. PMID- 24807482 TI - Development and pilot test of a new set of good practice indicators for chronic cancer pain management. AB - BACKGROUND: Pain is among the most important symptoms in terms of prevalence and cause of distress for cancer patients and their families. However, there is a lack of clearly defined measures of quality pain management to identify problems and monitor changes in improvement initiatives. METHODS: We built a comprehensive set of evidence-based indicators following a four-step model: (1) review and systematization of existing guidelines to list evidence-based recommendations; (2) review and systematization of existing indicators matching the recommendations; (3) development of new indicators to complete a set of measures for the identified recommendations; and (4) pilot test (in hospital and primary care settings) for feasibility, reliability (kappa), and usefulness for the identification of quality problems using the lot quality acceptance sampling (LQAS) method and estimates of compliance. RESULTS: Twenty-two indicators were eventually pilot tested. Seventeen were feasible in hospitals and 12 in all settings. Feasibility barriers included difficulties in identifying target patients, deficient clinical records and low prevalence of cases for some indicators. Reliability was mostly very good or excellent (k > 0.8). Four indicators, all of them related to medication and prevention of side effects, had acceptable compliance at 75%/40% LQAS level. Other important medication-related indicators (i.e., adjustment to pain intensity, prescription for breakthrough pain) and indicators concerning patient-centred care (i.e., attention to psychological distress and educational needs) had very low compliance, highlighting specific quality gaps. CONCLUSIONS: A set of good practice indicators has been built and pilot tested as a feasible, reliable and useful quality monitoring tool, and underscoring particular and important areas for improvement. PMID- 24807485 TI - Interstitial cystitis and the painful bladder: a brief history of nomenclature, definitions and criteria. AB - "Practically every author writing on this subject has suggested a new name which only adds to the confusion and multiplication" (Kretschmer H, 1922). Despite multiple names and many definitions and classifications over the past two centuries, the medical world is no closer to discovering the cause or causes of this enigmatic bladder disorder, currently known as interstitial cystitis, bladder pain syndrome or painful bladder syndrome and hypersensitive bladder. International consensus on nomenclature, definitions and diagnosis is now essential to ensure that studies are carried out on the same basis, thereby generating meaningful data that can be relied on for further use. In our electronic age, multiple names and definitions cause confusion for researchers, clinicians and patients, even leading to the patient's diagnosis being unrecognized by authorities, resulting in refusal to reimburse treatment or provide social benefits. As the key to the puzzle lies in the patients, with all their symptoms and comorbidities, and as patients are directly affected by changes in nomenclature and definitions, patient organization representatives should be given every opportunity to participate in discussions on guidelines, taxonomy, definitions and terminology. PMID- 24807486 TI - Urethral sensation: basic mechanisms and clinical expressions. AB - A prerequisite for conscious bladder control is adequate sensory input to the central nervous system, and it is well established that changes in sensory mechanisms can give rise to disturbances in bladder function. Impulses related to the desire to void are believed to course through the pelvic nerves, and those for sensation of a full bladder course through the pudendal nerves. The sense of imminent micturition most probably resides in the urethra, and the desire to void comes from stretching the bladder wall. In addition, a variety of structures play an important role in terms of urethral closure (such as the urethral epithelium, vasculature and smooth muscle) that are necessary to maintain continence. This overview will discuss mechanisms related in part to the urethra involved in activation of bladder reflexes and sensation with a discussion on the mucosa (urothelium and underlying lamina propria) and underlying cellular structures. PMID- 24807487 TI - Editorial comment to Urethral sensation: basic mechanisms and clinical expressions. PMID- 24807490 TI - Editorial comment to Mechanism of pain from urinary tract infection. PMID- 24807488 TI - Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis. AB - Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis. PMID- 24807489 TI - Mechanisms of pain from urinary tract infection. AB - The pain response to urinary tract infection is largely uncharacterized, but the symptomatic response to urinary tract infection contrasts with the lack of pain response among individuals with asymptomatic bacteriuria. Quantifying pelvic pain in a murine urinary tract infection model, uropathogenic Escerichia coli induces transient pelvic pain, whereas an asymptomatic bacteriuria E. coli isolate causes no pain, thus recapitulating the spectrum of clinical responses to intravesical E. coli. These differential pain responses are not correlated with bladder colonization or inflammation, but instead are intrinsic to E. coli lipopolysaccharide and dependent on the lipopolysaccharide receptor, TLR4. Epidemiological data suggest a link between interstitial cystitis and a history of urinary tract infection, so it was evaluated whether repetitive uropathogenic E. coli instillation would result in chronic pain through central sensitization. Although repeated infection with wild type uropathogenic E. coli results in only transient episodes of acute pain, a uropathogenic E. coli mutant lacking O antigen causes chronic, post-urinary tract infection pelvic pain. Similarly, a K 12 E. coli strain lacking O-antigen induces chronic pain that persisted long after bacterial clearance, and expressing O-antigen nullified the pain phenotype. Spinal cords isolated from mice with post-urinary tract infection chronic pain showed deficits in short-term depression consistent with central sensitization. Deleting O-antigen gene complex from a uropathogenic E. coli strain and subsequent heterologous expression of O-antigen gene clusters shows that a single bacterial isolate can exhibit pain phenotypes ranging from a null phenotype, an acute pain phenotype, to a chronic pain phenotype. Post-urinary tract infection chronic pain is also associated with voiding dysfunction and anxious/depressive behavior. These effects are also mediated by TRPV1 at the level of pain establishment and CCR2 at the level of pain maintenance. Together, these findings show that transient infection with E. coli might result in chronic visceral pain with the hallmarks of neuropathic pain. This pattern of behaviors mimics the spectrum of interstitial cystitis symptoms, thus supporting the possibility of an infectious etiology of interstitial cystitis. PMID- 24807491 TI - Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis. AB - There is a lack of consensus on the pathophysiology of bladder pain syndrome/interstitial cystitis. The chronic pain symptoms of bladder pain syndrome/interstitial cystitis refractory to local treatment could be a result of central nervous system sensitization and persisting abnormalities in the bladder wall, which activate the afferent sensory system. Evidence also shows that bladder pain syndrome/interstitial cystitis is a heterogeneous syndrome and that the two subtypes, the ulcerative (classic) and non-ulcerative types, represent different disease entities. There is a need for non-invasive markers for the differential diagnoses of the subtypes of bladder pain syndrome/interstitial cystitis, and between bladder pain syndrome/interstitial cystitis and bladder sensory disorders, such as hypersensitive bladder syndrome or overactive bladder. Bladder pain syndrome/interstitial cystitis, but not overactive bladder, involves an aberrant differentiation program in the bladder urothelium that leads to altered synthesis of several proteoglycans, cell adhesion and tight junction proteins, and bacterial defense molecules. These findings have led to the rationale for identifying urinary biomarkers to detect bladder pain syndrome/interstitial cystitis in patients with frequency urgency syndrome. Recently, the markers that have been the focus of the most research are antiproliferative factor, epidermal growth factor, heparin-binding epidermal growth factor, glycosaminoglycans and bladder nitric oxide. In addition, inflammatory proteins in the urine and serum play important roles in the pathogenesis of bladder pain syndrome/interstitial cystitis. The urinary proteome is an easily accessible source of biomarkers for differentiation between inflammatory bladder disorders. Analysis of multiple urinary proteins and serum cytokines could provide a diagnostic basis for bladder pain syndrome/interstitial cystitis, and could be a tool for the differential diagnosis of bladder pain syndrome/interstitial cystitis and other sensory bladder disorders. PMID- 24807492 TI - Editorial comment from Dr. Hanno to Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis. PMID- 24807493 TI - Editorial comment from Dr. Yoshimura to Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis. PMID- 24807494 TI - Hypersensitive bladder: a solution to confused terminology and ignorance concerning interstitial cystitis. AB - Taxonomy or nomenclature concerning interstitial cystitis and its related symptom syndromes is in a state of confusion. After analyzing the reasons for confusion in regard to three components (disease name, symptoms, Hunner's lesion), I would like to propose a new term, "hypersensitive bladder", taking after overactive bladder, as a solution. Hypersensitive bladder symptoms are defined as "increased bladder sensation, usually associated with urinary frequency and nocturia, with or without bladder pain." The proposal of hypersensitive bladder is based on: (i) it does not appear a symptom syndrome, but a disease by ending with an organ name, "bladder"; (ii) it does not contain confusable symptom terms (pain and urgency), but indicates irritative symptoms including pain and urgency; and (iii) it suggests pathophysiological hyperactivity of sensory nerves. Interstitial cystitis is defined by three requirements: (i) hypersensitive bladder symptoms; (ii) bladder pathology; and (iii) no other diseases, where bladder pathology should be clearly stated either as Hunner's lesion or glomerulations after hydrodistention. Hypersensitive bladder can be used for the condition with hypersensitive bladder symptoms, but no obvious disease explaining hypersensitive bladder symptoms identified. Interstitial cystitis is a representative disease causing hypersensitive bladder symptoms, most typically with pain, but might be painless and indistinguishable from overactive bladder. Introducing hypersensitive bladder as a counter concept of overactive bladder into bladder dysfunction taxonomy will facilitate clinical practice and research progress, and attract considerable attention from the medical world. PMID- 24807495 TI - Editorial comment from Dr. Nordling to hypersensitive bladder: a solution to confused terminology and ignorance concerning interstitial cystitis. PMID- 24807496 TI - Editorial comment from Dr. Hanno to hypersensitive bladder: a solution to confused terminology and ignorance concerning interstitial cystitis. PMID- 24807497 TI - Potential therapeutic effect of intravesical botulinum toxin type A on bladder pain syndrome/interstitial cystitis. AB - Bladder pain syndrome/interstitial cystitis is characterized by bladder pain associated with urgency, frequency, nocturia, dysuria and sterile urine. Recent studies have shown that these bladder dysfunctions could originate from chronic inflammation or urothelial insult and proceed to a cascade of tissue reactions, which finally ascends to the central nervous system. Pilot studies of intravesical injection of botulinum toxin type A for bladder pain syndrome/interstitial cystitis had been introduced since 2005 with a promising result. Recent evidence suggests that botulinum toxin type A could significantly improve symptoms such as daytime frequency, nocturia, pain, quality of life and bladder capacity in bladder pain syndrome/interstitial cystitis patients. Single injection of botulinum toxin could not achieve long-term successful therapeutic result, and repeat injections could provide a better long-term success rate. However, patients with ulcer type bladder pain syndrome/interstitial cystitis might not gain a benefit from botulinum toxin type A injection. Laboratory evidence showed that botulinum toxin type A for bladder pain syndrome/interstitial cystitis injection could induce peripheral desensitization, reduces bladder chronic inflammation and decreases apoptotic signal molecules in the urothelium. The present article reviewed the recent advances of botulinum toxin type A on bladder pain syndrome/interstitial cystitis. PMID- 24807498 TI - Editorial comment from professor Dinis to Potential therapeutic effect of intravesical botulinum toxin type A on bladder pain syndrome/interstitial cystitis. PMID- 24807499 TI - Editorial comment from Dr. Yoshimura to potential therapeutic effect of intravesical botulinum toxin type A on bladder pain syndrome/interstitial cystitis. PMID- 24807500 TI - Therapeutic efficacy of narrow band imaging-assisted transurethral electrocoagulation for ulcer-type interstitial cystitis/painful bladder syndrome. AB - OBJECTIVES: Narrow band imaging cystoscopy can increase the visualization and detection of Hunner's lesions. A single-center, prospective clinical trial was carried out aiming to show the effectiveness of narrow band imaging-assisted transurethral electrocoagulation for ulcer-type interstitial cystitis/painful bladder syndrome. METHODS: A total of 23 patients (19 women and 4 men) diagnosed as having ulcer-type interstitial cystitis/painful bladder syndrome were included. All typical Hunner's lesions and suspected areas identified by narrow band imaging were electrocoagulated endoscopically after the biopsy of those lesions. Therapeutic efficacy was assessed prospectively by using visual analog scale score of pain, O'Leary-Sant's symptom index, O'Leary-Sant's problem index and overactive bladder symptom score. RESULTS: The mean follow-up period was 22 months. All patients (100%) experienced a substantial improvement in pain. The average visual analog scale pain scores significantly decreased from 7.3 preoperatively to 1.2 1 month postoperatively. A total of 21 patients (91.3%) who reported improvement had at least a 50% reduction in bladder pain, and five reported complete resolution. Daytime frequency was significantly decreased postoperatively. O'Leary-Sant's symptom index, O'Leary-Sant's problem index and overactive bladder symptom score were significantly decreased postoperatively. However, during the follow-up period, a total of six patients had recurrence, and repeat narrow band imaging-assisted transurethral electrocoagulation of the recurrent lesions was carried out for five of the six patients, with good response in relieving bladder pain. CONCLUSIONS: Our results showed that narrow band imaging-assisted transurethral electrocoagulation could be a valuable therapeutic alternative in patients with ulcer-type interstitial cystitis/painful bladder syndrome, with good efficacy and reduction of recurrence rate. PMID- 24807501 TI - Editorial comment to Therapeutic efficacy of narrow band imaging-assisted transurethral electrocoagulation for ulcer-type painful bladder syndrome/interstitial cystitis. PMID- 24807502 TI - Development and evaluation of an E-health system to care for patients with bladder pain syndrome/interstitial cystitis. AB - OBJECTIVES: Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease that highly degrades the quality of life for patients. In the present study, Internet intervention was used to care for bladder pain syndrome/interstitial cystitis patients to alleviate their pain and bothering symptoms. METHODS: Healthcare education was carried out through the Internet by asking the patients, who were randomly divided into study (40 patients) and control (40 patients) groups, to check possible sensitive foods, habits, and behaviors weekly to remind and consolidate important rules for promoting quality of life. The symptom flares consultation through short message service with the Internet used to elevate healthcare efficiency was undertaken. Questionnaires, including Short Form 36 health survey, O'Leary-Sant symptom and problem indices, as well as visual analog scales pain and urgency scales, were used to evaluate quality of life and disease severity improvements before and after information and communication technology intervention. The outcome was evaluated at week 8. RESULTS: The quality of life of both the control and study groups was significantly improved. The quality of life and visual analog scales for the patients in the study group with information and communication technology intervention showed a much greater improvement compared with the patients in the control group (P < 0.05). CONCLUSIONS: The E-health system was shown to be effective in improving quality of life of bladder pain syndrome/interstitial cystitis patients through intervention of Internet healthcare education and short message service for the consolidation of healthy behavior and lifestyle in the 8 week follow up. PMID- 24807504 TI - Editorial comment to Efficacy and safety of augmentation ileocystoplasty combined with supratrigonal cystectomy for the treatment of refractory bladder pain syndrome/interstitial cystitis with Hunner's lesion. PMID- 24807503 TI - Efficacy and safety of augmentation ileocystoplasty combined with supratrigonal cystectomy for the treatment of refractory bladder pain syndrome/interstitial cystitis with Hunner's lesion. AB - OBJECTIVE: To evaluate the efficacy and safety of augmentation ileocystoplasty with supratrigonal cystectomy for the treatment of refractory bladder pain syndrome/interstitial cystitis patients with Hunner's lesion. METHODS: Of 45 patients who underwent augmentation ileocystoplasty with supratrigonal cystectomy between July 2006 and June 2012, 40 patients (33 women, 7 men) were included in the analysis. Primary outcome was the change in the O'Leary-Sant interstitial cystitis symptoms/problem index from baseline to 1, 3 and 6 months. Changes in pain, urgency, frequency, functional bladder capacity and maximal cystometric capacity were also assessed. Intraoperative and postoperative complications were evaluated. RESULTS: Median preoperative symptom duration was 5.0 years (range 3.0 6.0 years). Pain decreased significantly after surgery (8.3 vs. 1.3, P < 0.001). Functional bladder capacity and maximal cystometric capacity increased, whereas frequency, urgency and nocturia decreased significantly after surgery (all P < 0.001). At 6 months, significant improvements in the interstitial cystitis symptom index (17.8 vs. 9.9, P < 0.001) and interstitial cystitis problem index (14.6 vs. 6.5, P < 0.001) compared with baseline were noted. Seven patients developed vesicoureteral reflux and seven patients had acute pyelonephritis that resolved with antibiotic treatment. Five patients required clean intermittent self-catheterization. None of the preoperative factors were significant predictors of treatment failure. CONCLUSIONS: Augmentation ileocystoplasty with supratrigonal cystecomy decreased pain and frequency, and increased bladder capacity significantly. There were no severe complications related to surgery during follow up. Augmentation ileocystoplasty with supratrigonal cystectomy is therefore an appropriate final treatment strategy for refractory bladder pain syndrome/interstitial cystitis patients with Hunner's lesion. PMID- 24807505 TI - Inflammation characteristics in bladder pain syndrome ESSIC type 3C/classic interstitial cystitis. AB - OBJECTIVES: Interstitial cystitis is regarded as a heterogenous syndrome with two distinguishable forms: the non-ulcer and the classic form of interstitial cystitis, the latter with Hunner's lesions; or bladder pain syndrome type 3C and non-Hunner bladder pain syndrome, respectively. METHODS: A cohort of 379 patients diagnosed with interstitial cystitis was studied. Nitric oxide release from the bladder was measured using a chemiluminescence nitric oxide analyzer. Bladder biopsies from the patients and healthy controls were analyzed by routine histopathological examination. Biopsies from a subset of patients and controls were also analyzed by immunohistochemistry and cytokine gene expression by real time polymerase chain reaction. RESULTS: Patients with bladder pain syndrome type 3C/classic interstitial cystitis had considerably higher levels of nitric oxide as compared with non-Hunner bladder pain syndrome/non-ulcer interstitial cystitis patients and healthy individuals, and showed histologically a chronic inflammation in the bladder mucosa, with abundant mast cell infiltration in all layers of the bladder wall. No inflammation was noted in non-Hunner bladder pain syndrome/non-ulcer interstitial cystitis patients. The isoenzymes inducible nitric oxide synthase, the catalyst in the nitric oxide production, was strongly expressed in the inflammatory cells in the bladder mucosa of bladder pain syndrome type 3C/classic interstitial cystitis patients. In addition, the expression of the pro-inflammatory cytokines interleukin-6 and interleukin-17A messenger ribonucleic acid, and of anti-inflammatory interleukin-10 messenger ribonucleic acid showed significantly increased levels in bladder pain syndrome type 3C/classic interstitial cystitis compared with healthy controls. CONCLUSION: Bladder pain syndrome type 3C/classic interstitial cystitis is a distinct inflammatory disease and in many aspects shares features of inflammatory autoimmune diseases. These findings could open up novel research avenues with expectations for new targets for pharmacological treatment. PMID- 24807506 TI - Editorial comment to Inflammation characteristics in bladder pain syndrome European Society for the Study of Interstitial Cystitis type 3C/classic interstitial cystitis. PMID- 24807507 TI - Interstitial cystitis is bladder pain syndrome with Hunner's lesion. AB - The contents and understanding of the term, interstitial cystitis, have undergone major changes during the past 100 years, moving from a chronic, true inflammatory bladder disorder to an extensive syndrome with lower urinary tract pain. Comments on this development are presented. From examples in the literature, some important features of classic interstitial cystitis are outlined. The more inclusive attitude of later decades has drawn desirable attention to the entire spectrum of disorders resulting in bladder pain. The wish to include all of them into one handy entity has unfortunately resulted in much scientific and clinical confusion, though. It is noted that originally interstitial cystitis represented the Hunner type of disease. Today, there is agreement that the classic type of interstitial cystitis with Hunner's lesions, bladder pain syndrome type 3C according to current terminology, stands out as a well-defined phenotype; it has to evaluated separately in clinical studies and practice, as treatment requirements differ importantly between this and other phenotypes. PMID- 24807508 TI - Editorial comment from Dr. Hanno to Interstitial cystitis is bladder pain syndrome with Hunner's lesion. PMID- 24807509 TI - Editorial comment from Dr. Yoshimura to Interstitial cystitis is bladder pain syndrome with Hunner's lesion. PMID- 24807510 TI - Editorial comment from Dr. Ueda to Assessments of bladder pain syndrome/interstitial cystitis treatment in future trials. PMID- 24807511 TI - Gynecological disorders in bladder pain syndrome/interstitial cystitis patients. AB - OBJECTIVES: Bladder pain syndrome/interstitial cystitis, a chronic inflammatory condition of the bladder, is the source of pain in over 30% of female patients with chronic pelvic pain. The aim of the present study was to evaluate the most frequent associations between bladder pain syndrome/interstitial cystitis and gynecological disorders. METHODS: A literature review of the previous 10 years was carried out to evaluate the incidence of gynecological diseases in patients with bladder pain syndrome/interstitial cystitis. RESULTS: Hypertonic pelvic floor dysfunction with associated voiding dysfunction can be present in bladder pain syndrome/interstitial cystitis patients. It has been estimated that the prevalence ranges from 50% to 87%. Endometriosis affects 1-7% of the general population and up to 70% of women with endometriosis have some type of pain symptoms, a recent systematic review estimated the prevalence of bladder pain syndrome to be 61%, of endometriosis to be 70%, and coexisting bladder pain syndrome and endometriosis to be 48%. Vulvodynia is represented by pain, or an unpleasant altered sensation, in the vulva. Women with vestibulodynia are likely to have other additional pain conditions, such as fibromyalgia, irritable bowel syndrome or chronic fatigue syndrome. Recent data reported that vestibulodynia affects 25% of women with bladder pain syndrome/interstitial cystitis. CONCLUSIONS: Bladder pain syndrome/interstitial cystitis is a complex pathology often associated with vulvodynia, endometriosis and pelvic floor dysfunctions. Therefore, it is of utmost importance to obtain an accurate evaluation ruling out confusable disease, such as pudendal neuropathy. The optimal approach is a combined treatment oriented not only to treat the bladder, but also the other components responsible for the pain disorder. PMID- 24807515 TI - Dark states in ionic oligothiophene bioprobes--evidence from fluorescence correlation spectroscopy and dynamic light scattering. AB - Luminescent conjugated polyelectrolytes (LCPs) can upon interaction with biological macromolecules change their luminescent properties, and thereby serve as conformation- and interaction-sensitive biomolecular probes. However, to exploit this in a more quantitative manner, there is a need to better understand the photophysical processes involved. We report studies of the conjugated pentameric oligothiophene derivative p-FTAA, which changes optical properties with different p-FTAA concentrations in aqueous buffers, and in a pH and oxygen saturation dependent manner. Using dynamic light scattering, luminescence spectroscopy and fluorescence correlation spectroscopy, we find evidence for a monomer-dimer equilibrium, for the formation of large clusters of p-FTAA in aqueous environment, and can couple aggregation to changed emission properties of oligothiophenes. In addition, we observe the presence of at least two dark transient states, one presumably being a triplet state. Oxygen was found to statically quench the p-FTAA fluorescence but also to promote molecular fluorescence by quenching dark transient states of the p-FTAA molecules. Taken together, this study provides knowledge of fluorescence and photophysical features essential for applying p-FTAA and other oligothiophene derivatives for diagnostic purposes, including detection and staining of amyloid aggregates. PMID- 24807516 TI - Twenty years of mixture of experts. AB - In this paper, we provide a comprehensive survey of the mixture of experts (ME). We discuss the fundamental models for regression and classification and also their training with the expectation-maximization algorithm. We follow the discussion with improvements to the ME model and focus particularly on the mixtures of Gaussian process experts. We provide a review of the literature for other training methods, such as the alternative localized ME training, and cover the variational learning of ME in detail. In addition, we describe the model selection literature which encompasses finding the optimum number of experts, as well as the depth of the tree. We present the advances in ME in the classification area and present some issues concerning the classification model. We list the statistical properties of ME, discuss how the model has been modified over the years, compare ME to some popular algorithms, and list several applications. We conclude our survey with future directions and provide a list of publicly available datasets and a list of publicly available software that implement ME. Finally, we provide examples for regression and classification. We believe that the study described in this paper will provide quick access to the relevant literature for researchers and practitioners who would like to improve or use ME, and that it will stimulate further studies in ME. PMID- 24807517 TI - Constrained empirical risk minimization framework for distance metric learning. AB - Distance metric learning (DML) has received increasing attention in recent years. In this paper, we propose a constrained empirical risk minimization framework for DML. This framework enriches the state-of-the-art studies on both theoretic and algorithmic aspects. Theoretically, we comprehensively analyze the generalization by bounding the sample and the approximation errors with respect to the best model. Algorithmically, we carefully derive an optimal gradient descent by using Nesterov's method, and provide two example algorithms that utilize the logarithmic loss and the smoothed hinge loss, respectively. We evaluate the new framework on data classification and image retrieval experiments. Results show that the new framework has competitive performance compared with the representative DML algorithms, including Xing's method, large margin nearest neighbor classifier, neighborhood component analysis, and regularized metric learning. PMID- 24807518 TI - Scale-invariant amplitude spectrum modulation for visual saliency detection. AB - Saliency detection is one of the key issues in simulating visual attention selection. Most attention models adopt the competitive structure to simulate the human visual system. Although these models provide remarkable results and convincing biological plausibility, they are still confronted with many difficulties in practical applications because of their extreme time cost and parameter sensitivity. Recently, a new saliency detection approach based on Fourier transform, as represented by spectral residual (SR) and phase Fourier transform (PFT), has been attracting much attention for its excellent accuracy and computational speed. All these models can be unified into one framework called amplitude spectrum modulation (ASM). The aim of this paper is to explore the intrinsic mechanism of ASM and develop an advanced ASM model. After analyzing SR and PFT, we give a mathematical description for the fundamental idea and the inherent limitations of the existing ASM models. A new saliency detective model, based on the scale-invariant ASM, scene and context-based modulation, and competitive structure, is also proposed breaking through the limitations of the traditional ASM models. Simulation results suggest that the proposed model is more accurate in predicting human eye fixation and is more robust against different types of stimulus when compared with competing models. PMID- 24807519 TI - Relaxed fault-tolerant hardware implementation of neural networks in the presence of multiple transient errors. AB - Reliability should be identified as the most important challenge in future nano scale very large scale integration (VLSI) implementation technologies for the development of complex integrated systems. Normally, fault tolerance (FT) in a conventional system is achieved by increasing its redundancy, which also implies higher implementation costs and lower performance that sometimes makes it even infeasible. In contrast to custom approaches, a new class of applications is categorized in this paper, which is inherently capable of absorbing some degrees of vulnerability and providing FT based on their natural properties. Neural networks are good indicators of imprecision-tolerant applications. We have also proposed a new class of FT techniques called relaxed fault-tolerant (RFT) techniques which are developed for VLSI implementation of imprecision-tolerant applications. The main advantage of RFT techniques with respect to traditional FT solutions is that they exploit inherent FT of different applications to reduce their implementation costs while improving their performance. To show the applicability as well as the efficiency of the RFT method, the experimental results for implementation of a face-recognition computationally intensive neural network and its corresponding RFT realization are presented in this paper. The results demonstrate promising higher performance of artificial neural network VLSI solutions for complex applications in faulty nano-scale implementation environments. PMID- 24807520 TI - Mapping dynamic Bayesian networks to alpha-shapes: application to human faces identification across ages. AB - We propose to map a dynamic Bayesian network (DBN) to an ordered family of alpha shapes to improve DBNs classification power. This mission is achieved by: 1) embedding a DBN into a topological manifold and 2) applying the alpha-shape geometric constructor to build hierarchical structures assigned to the DBN. This continuous representation of traditional DBNs as alpha-shapes allows more information to be obtained about the objects to be classified. These latter are viewed as hierarchies of geometrical objects with different levels of detail. Topological signatures are therefore unraveled and classification accuracy is enhanced. We have applied the proposed formalism to the task of facial identification across ages. Preliminary results demonstrate that the proposed formalism is a powerful tool since it has outperformed some DBN models, the k-NN classifier, and some recent approaches. PMID- 24807521 TI - Predictive approach for user long-term needs in content-based image suggestion. AB - In this paper, we formalize content-based image suggestion (CBIS) as a Bayesian prediction problem. In CBIS, users provide the rating of images according to both their long-term needs and the contextual situation, such as time and place, to which they belong. Therefore, a CBIS model is defined to fit the distribution of the data in order to predict relevant images for a given user. Generally, CBIS becomes challenging when only a small amount of data is available such as in the case of "new users" and "new images." The Bayesian predictive approach is an effective solution to such a problem. In addition, this approach offers efficient means to select highly rated and diversified suggestions in conformance with theories in consumer psychology. Experiments on a real data set show the merits of our approach in terms of image suggestion accuracy and efficiency. PMID- 24807522 TI - SOMKE: kernel density estimation over data streams by sequences of self organizing maps. AB - In this paper, we propose a novel method SOMKE, for kernel density estimation (KDE) over data streams based on sequences of self-organizing map (SOM). In many stream data mining applications, the traditional KDE methods are infeasible because of the high computational cost, processing time, and memory requirement. To reduce the time and space complexity, we propose a SOM structure in this paper to obtain well-defined data clusters to estimate the underlying probability distributions of incoming data streams. The main idea of this paper is to build a series of SOMs over the data streams via two operations, that is, creating and merging the SOM sequences. The creation phase produces the SOM sequence entries for windows of the data, which obtains clustering information of the incoming data streams. The size of the SOM sequences can be further reduced by combining the consecutive entries in the sequence based on the measure of Kullback-Leibler divergence. Finally, the probability density functions over arbitrary time periods along the data streams can be estimated using such SOM sequences. We compare SOMKE with two other KDE methods for data streams, the M-kernel approach and the cluster kernel approach, in terms of accuracy and processing time for various stationary data streams. Furthermore, we also investigate the use of SOMKE over nonstationary (evolving) data streams, including a synthetic nonstationary data stream, a real-world financial data stream and a group of network traffic data streams. The simulation results illustrate the effectiveness and efficiency of the proposed approach. PMID- 24807523 TI - Reinforced two-step-ahead weight adjustment technique for online training of recurrent neural networks. AB - A reliable forecast of future events possesses great value. The main purpose of this paper is to propose an innovative learning technique for reinforcing the accuracy of two-step-ahead (2SA) forecasts. The real-time recurrent learning (RTRL) algorithm for recurrent neural networks (RNNs) can effectively model the dynamics of complex processes and has been used successfully in one-step-ahead forecasts for various time series. A reinforced RTRL algorithm for 2SA forecasts using RNNs is proposed in this paper, and its performance is investigated by two famous benchmark time series and a streamflow during flood events in Taiwan. Results demonstrate that the proposed reinforced 2SA RTRL algorithm for RNNs can adequately forecast the benchmark (theoretical) time series, significantly improve the accuracy of flood forecasts, and effectively reduce time-lag effects. PMID- 24807524 TI - Spatial Gaussian process regression with mobile sensor networks. AB - This paper presents a method of using Gaussian process regression to model spatial functions for mobile wireless sensor networks. A distributed Gaussian process regression (DGPR) approach is developed by using a sparse Gaussian process regression method and a compactly supported covariance function. The resultant formulation of the DGPR approach only requires neighbor-to-neighbor communication, which enables each sensor node within a network to produce the regression result independently. The collective motion control is implemented by using a locational optimization algorithm, which utilizes the information entropy from the DGPR result. The collective mobility of sensor networks plus the online learning capability of the DGPR approach also enables the mobile sensor network to adapt to spatiotemporal functions. Simulation results are provided to show the performance of the proposed approach in modeling stationary spatial functions and spatiotemporal functions. PMID- 24807525 TI - Adaptive data embedding framework for multiclass classification. AB - The objective of this paper is the design of an engine for the automatic generation of supervised manifold embedding models. It proposes a modular and adaptive data embedding framework for classification, referred to as DEFC, which realizes in different stages including initial data preprocessing, relation feature generation and embedding computation. For the computation of embeddings, the concepts of friend closeness and enemy dispersion are introduced, to better control at local level the relative positions of the intraclass and interclass data samples. These are shown to be general cases of the global information setup utilized in the Fisher criterion, and are employed for the construction of different optimization templates to drive the DEFC model generation. For model identification, we use a simple but effective bilevel evolutionary optimization, which searches for the optimal model and its best model parameters. The effectiveness of DEFC is demonstrated with experiments using noisy synthetic datasets possessing nonlinear distributions and real-world datasets from different application fields. PMID- 24807526 TI - Study on the impact of partition-induced dataset shift on k-fold cross validation. AB - Cross-validation is a very commonly employed technique used to evaluate classifier performance. However, it can potentially introduce dataset shift, a harmful factor that is often not taken into account and can result in inaccurate performance estimation. This paper analyzes the prevalence and impact of partition-induced covariate shift on different k-fold cross-validation schemes. From the experimental results obtained, we conclude that the degree of partition induced covariate shift depends on the cross-validation scheme considered. In this way, worse schemes may harm the correctness of a single-classifier performance estimation and also increase the needed number of repetitions of cross-validation to reach a stable performance estimation. PMID- 24807527 TI - Kernel recursive least-squares tracker for time-varying regression. AB - In this paper, we introduce a kernel recursive least-squares (KRLS) algorithm that is able to track nonlinear, time-varying relationships in data. To this purpose, we first derive the standard KRLS equations from a Bayesian perspective (including a sensible approach to pruning) and then take advantage of this framework to incorporate forgetting in a consistent way, thus enabling the algorithm to perform tracking in nonstationary scenarios. The resulting method is the first kernel adaptive filtering algorithm that includes a forgetting factor in a principled and numerically stable manner. In addition to its tracking ability, it has a number of appealing properties. It is online, requires a fixed amount of memory and computation per time step, incorporates regularization in a natural manner and provides confidence intervals along with each prediction. We include experimental results that support the theory as well as illustrate the efficiency of the proposed algorithm. PMID- 24807528 TI - Discrete-time neural inverse optimal control for nonlinear systems via passivation. AB - This paper presents a discrete-time inverse optimal neural controller, which is constituted by combination of two techniques: 1) inverse optimal control to avoid solving the Hamilton-Jacobi-Bellman equation associated with nonlinear system optimal control and 2) on-line neural identification, using a recurrent neural network trained with an extended Kalman filter, in order to build a model of the assumed unknown nonlinear system. The inverse optimal controller is based on passivity theory. The applicability of the proposed approach is illustrated via simulations for an unstable nonlinear system and a planar robot. PMID- 24807529 TI - Equilibria of perceptrons for simple contingency problems. AB - The contingency between cues and outcomes is fundamentally important to theories of causal reasoning and to theories of associative learning. Researchers have computed the equilibria of Rescorla-Wagner models for a variety of contingency problems, and have used these equilibria to identify situations in which the Rescorla-Wagner model is consistent, or inconsistent, with normative models of contingency. Mathematical analyses that directly compare artificial neural networks to contingency theory have not been performed, because of the assumed equivalence between the Rescorla-Wagner learning rule and the delta rule training of artificial neural networks. However, recent results indicate that this equivalence is not as straightforward as typically assumed, suggesting a strong need for mathematical accounts of how networks deal with contingency problems. One such analysis is presented here, where it is proven that the structure of the equilibrium for a simple network trained on a basic contingency problem is quite different from the structure of the equilibrium for a Rescorla-Wagner model faced with the same problem. However, these structural differences lead to functionally equivalent behavior. The implications of this result for the relationships between associative learning, contingency theory, and connectionism are discussed. PMID- 24807530 TI - Graphene from fingerprints: exhausting the performance of liquid precursor deposition. AB - Epitaxial graphene is expected to be the only way to obtain large-area sheets of this two-dimensional material for applications on an industrial scale. So far, there are different recipes for epitaxial growth of graphene, using either intrinsic carbon, such as the selective desorption of silicon from a SiC surface, or extrinsic carbon, as via the chemical vapor deposition (CVD) of simple hydrocarbons on transition metal surfaces. In addition, even liquid precursor deposition (LPD) provides well-ordered graphene monolayers. It will be shown that graphene formation on transition metal surfaces by LPD synthesis is a very robust mechanism that even works if carbon is provided in a quite undefined way, namely by using a human fingerprint as a liquid precursor. Graphene growth from fingerprints provides well-ordered monolayers with the same quality as LPD grown graphene using ultrapure synthetic single precursors. The reliability of the self assembly process of graphene growth on transition metals by LPD therefore offers a simple and extremely robust synthesis route for epitaxial graphene and may give access to production pathways for substrates for which the CVD method fails. PMID- 24807532 TI - The effects of fucodian on senescence are controlled by the p16INK4a-pRb and p14Arf-p53 pathways in hepatocellular carcinoma and hepatic cell lines. AB - Fucoidan is known to have various pharmacological effects, including antitumor activity. Although it has potential as a therapeutic agent for cancer cells, the anti-senescence effects and detailed mechanism of action remain poorly understood in normal hepatic cells. We investigated the anticancer functions of fucoidan using HepG2 cells as well as the mechanisms mediating the anti-senescent actions in Chang liver cells. Fucoidan effectively inhibited HepG2 cell viability and induced apoptosis. Also, fucoidan-induced G1 phase arrest was caused by the activity of the p16(INK4a)-Rb and p14(Arf)-p53 pathways. Furthermore, upregulation of p16(INK4a) was critical to the antitumor activity of HepG2 cells treated with fucoidan and was correlated with inhibition of Cdk4 and pRb and upregulation of p21 expression. Our results suggest that fucoidan upregulates INK4a locus genes to induce apoptosis through p38 MAPK in HepG2 cells. Moreover, it prevents cellular senescence of Chang-L cells, by decreasing p14(Arf) expression as cells enter quiescence, with the reduction of p16(INK4a). Fucoidan treatment also downregulated the expression of alpha2M. In conclusion, fucoidan can be considered a potential therapeutic agent against liver cancer that does not cause senescence in normal hepatic cells. Thus, it may be possible to use fucoidan therapeutically in both tumor suppression and aging. PMID- 24807533 TI - Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and beta-cell survival in gerbils. AB - Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic beta-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic beta-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and beta-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1beta and TNF-alpha levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased beta-cell mass due to increased beta-cell apoptosis. Ebselen prevented the increased beta-cell apoptosis, possibly by decreasing IL 1beta and TNF-alpha in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic beta-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease. PMID- 24807534 TI - Gene cloning, expression, and characterization of an exo-inulinase from Paenibacillus polymyxa ZJ-9. AB - An inulinase-producing strain, Paenibacillus polymyxa ZJ-9, was isolated from natural sources to produce R,R-2,3-butanediol via one-step fermentation of raw inulin extracted from Jerusalem artichoke tubers. The inulinase gene from P. polymyxa ZJ-9 was cloned and overexpressed in Escherichia coli BL21 (DE3), and the purified recombinant inulinase was estimated to be approximately 56 kDa by both sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and gel filtration chromatography. This result suggests that the active form of the inulinase is probably a monomer. Terminal hydrolysis fructose units from the inulin indicate that enzymes are exo-inulinase. The purified recombinant enzyme showed maximum activity at 25 degrees C and pH 6.0, which indicate its extreme suitability for industrial applications. Zn(2+), Fe(2+), and Mg(2+) stimulated the activity of the purified enzyme, whereas Co(2+), Cu(2+), and Ni(2+) inhibited enzyme activity. The K m and V max values for inulin hydrolysis were 1.72 mM and 21.69 MUmol min(-1) mg(-1) protein, respectively. The same parameters toward sucrose were 41.09 mM and 78.7 MUmol min(-1) mg(-1) protein, respectively. Considering its substrate specificity and other enzymatic characteristics, we believe that this inulinase gene from P. polymyxa ZJ-9 could be transformed into other special bacterial strains to allow inulin conversion to other biochemicals and bioenergy through one-step fermentation. PMID- 24807535 TI - Radiation-induced dedifferentiated chondrosarcoma with orbital invasion. AB - PURPOSE: To report 2 interventional cases of dedifferentiated chondrosarcoma with orbital involvement after radiotherapy performed in childhood and to review the literature on chondrosarcoma in the orbit following radiation treatment. METHODS: Retrospective analysis of medical records of 2 patients with chondrosarcoma of the orbits with review of the literature. RESULTS: The first patient developed chondrosarcoma of the orbital and maxillary sinus 36 years after external beam radiation therapy to the OS to treat retinoblastoma. The second patient developed a large orbital chondrosarcoma 35 years after external beam radiation therapy in the treatment of craniofacial fibrous dysplasia. CONCLUSIONS: These cases highlight the risk of secondary chondrosarcoma in patients following radiotherapy and the importance of lifetime monitoring. PMID- 24807536 TI - Long-term cicatrization analysis in periocular incisions for oculoplastic surgery performed with cold blade and Colorado needle. AB - PURPOSE: To compare the degree of satisfaction of patients and observers about scars secondary to skin incisions in oculoplastic surgery performed with cold blade versus Colorado microcautery needle. METHODS: A cross-sectional noninferiority comparative study was performed. Eighty patients undergoing surgery for blepharoptosis repair, lateral tarsal strip, or dacryocystorhinostomy with cold blade or Colorado needle between January 2011 and July 2011 were included. Groups were paired by sex and surgery type. Scars were assessed between January 2012 and July 2012 using 2 validated scales (Patient and Observer Scar Assessment Scale [POSAS] and Vancouver Scar Scale [VSS]) by the patient and 2 trained observers. Sample size was predetermined, and 38 patients were needed in each group to detect differences of at least 8 points in the POSAS with 90% power. RESULTS: Patients operated with Colorado needle were 7.3 years older than those operated with cold blade (p = 0.007). No statistically significant differences between both techniques were observed either in the individual items or in the composite scores, correcting for age (POSAS, p = 0.518; VSS, p = 0.367). Multiple linear regression analysis showed that patients undergoing dacryocystorhinostomy had significantly lower scores in OSAS (p= 0.034) and VSS (p = 0.034), independent of the other variables in the model. No association between the surgical instrument and the final score was observed for any of the analyzed scales. CONCLUSIONS: Esthetic results of periocular scars secondary to skin incisions performed with cold blade or Colorado needle are clinically similar in Spanish patients. Esthetic result of dacryocystorhinostomy scars showed lower scores in OSAS and VSS. PMID- 24807537 TI - Use of crawford tube for chronic suppurative lacrimal canaliculitis. AB - PURPOSE: To assess the effectiveness of the Crawford tube for the treatment of chronic suppurative lacrimal canaliculitis. METHODS: A prospective study was performed on 8 consecutive patients who accepted the Crawford tube to treat chronic suppurative lacrimal canaliculitis. Postoperatively, the patients were treated with 0.5% levofloxacin eyedrops 4 times per day and oral levofloxacin tablets 0.5 g once per day for 4 days. Follow-up times were >3 months after removing the Crawford tube. The condition of the lacrimal punctum and patient's symptoms were carefully evaluated. RESULTS: All patients had unilateral single canaliculus involvement and had excellent resolution of canaliculitis without the need for surgical treatment. Complications included lacrimal punctum granulation and lacrimal punctum dehiscence. CONCLUSIONS: The insertion of the Crawford tube may offer an alternative to surgery in the management of suppurative lacrimal canaliculitis. PMID- 24807538 TI - Conjunctivodacryocystorhinostomy and lacrimal sinus diversion via sinopsys surgical lacrimal stent: cadaveric proof of concept. AB - PURPOSE: To determine the viability of lacrimal sinus diversion by using a novel Sinopsys Surgical Lacrimal Stent. METHODS: Two disarticulated cadaveric heads were used in the laboratory. First, bilateral conjunctivodacryocystorhinostomies (CDCR) were performed by using a traditional Pyrex Jones tube and the Sinopsys Surgical Lacrimal Stent. The fluiditics were then evaluated by using contrast agent and fluroscopy. Subsequently, conjunctivoethmoidectomies (CE) and conjunctivomaxillectomies (CM) were performed by using the Sinopsys Surgical Lacrimal Stent, of which the fluiditics were also studied. RESULTS: The conjunctivodacryocystorhinostomy (CDCR) placement experience of the Jones tube and the Sinopsys Surgical Lacrimal Stent were similar. The CDCR fluiditics as measured by using contrast agent and fluoroscopy were identical with each draining 0.5 mL over 5 to 10 seconds. Placement of the Sinopsys Surgical Lacrimal Stent in the 4 ethmoid (CE) and 4 maxillary (CM) sinuses was similar to the CDCR experience. Fluiditics of lacrimal sinus diversion were similar to CDCR with drainage of 0.5 mL over 5 seconds. CONCLUSIONS: The Sinopsys Surgical Lacrimal Stent has flow characteristics that are similar to a Pyrex Jones tube. Drainage in the nose via a CDCR procedure is similar to drainage in the ethmoid and maxillary sinuses via a CE and CM, respectively. PMID- 24807539 TI - Subjective and objective outcome measures in the treatment of facial nerve synkinesis with onabotulinumtoxinA (Botox). AB - PURPOSE: To evaluate the Sunnybrook Facial Grading System (SFGS) and Facial Clinimetric Evaluation Scale (FaCE Scale) instrument outcome measures pre- and 30 day posttreatment of facial nerve synkinesis with botulinum toxin with attempts to correlate the 2 scales. METHODS: An IRB approved retrospective review of 22 patients with facial nerve synkinesis where the surgeon completed the SFGS and the patient completed the FaCE prior to receiving onabotulinumtoxinA therapy, the SFGS, and FaCE scales were completed again 1 month later. RESULTS: Of the 22 patients, 9 complete datasets were analyzed. Mean patient age was 59.8; 8 (89%) women and 1 (11%) men. Overall SFGS composite score decreased from 57.6 +/- 20.9 to 45.2 +/- 13.5, (p = 0.001). SFGS subdomain synkinesis significantly improved (p < 0.001), while voluntary movement significantly decreased (p = 0.002). A difference in the resting symmetry was not statistically significant (p = 0.08). The FaCE scale composite score significantly improved from 40.9 +/- 9.5 to 47.6 +/- 11.9, (p = 0.03). FaCE subdomains facial comfort (p = 0.005) and social function (p = 0.009) significantly improved, while oral function, eye comfort, facial movement, and lacrimal control did not. The Delta pre/post-SFGS composite score did not correlate with the Delta pre/post-FaCE composite score (rs= 0.318). Subdomain analysis demonstrated significant negative correlation between Delta pre/post-SFGS synkinesis score and Delta pre/post-FaCE eye comfort score (rs = -0.826, p < 0.01). CONCLUSIONS: Significant improvement was seen in objectively reported synkinesis following botulinum toxin therapy. An improvement was noted in the overall subjective facial nerve functioning following therapy along with improvement in social functioning and facial comfort. A meaningful negative correlation was noted when comparing the SFGS "synkinesis" subdomain with the FaCE scale subdomain "eye comfort", implying improvement in eye comfort with control of synkinesis. PMID- 24807541 TI - Globe retropulsion and eyelid depression (GRED)-a surgeon-controlled, unimanual maneuver to access postseptal fat in transconjunctival lower blepharoplasty. PMID- 24807540 TI - Clinicopathological features of inflammatory lesions of the lateral canthal subconjunctival area. AB - PURPOSE: To investigate the clinical and histopathological features of inflammatory lesions of the lateral canthal subconjunctival area. METHODS: This is a retrospective case series of 12 patients with inflammatory subconjunctival masses in the lateral canthal area. All patients included in this study were treated at Seoul National University Hospital or Seoul National University Bundang Hospital between 2006 and 2012. Clinical data were obtained from the medical records. Histopathologic findings were thoroughly reviewed. RESULTS: There was a woman predominance in the study group (10:2), and the median age at presentation was 39 years (range 33-70). Common symptoms included conjunctival injection, sticky discharge, and pain or discomfort. Histopathologically, all lesions originated from ductules of the lacrimal gland. Two cases showed cysts containing clear fluid with mild inflammation. One case showed lacrimal ductulitis without cyst formation. Nine cases showed lacrimal ductal cysts with varying periductal inflammation, and the contents were pinkish, amorphous materials in 7 cases. Embedded cilia were found in 8 cases. CONCLUSIONS: Inflammatory lesions of the lateral canthal subconjunctival area all originated from lacrimal gland ductules, showing a variable histopathologic spectrum of inflammation and cyst formation. Cilia impaction was a very frequently observed finding. PMID- 24807542 TI - Papillary cystadenocarcinoma of the lacrimal gland after radiation for bilateral retinoblastoma. AB - The authors report a case of papillary cystadenocarcinoma of the lacrimal gland after irradiation for bilateral retinoblastoma. A 32-year-old man with a history of bilateral retinoblastoma, diagnosed shortly after birth, was treated with enucleation of the OS and a single session of radiation to the OD. Over 30 years later, he presented with an orbital mass of the right lacrimal gland that on biopsy demonstrated papillary cystadenocarcinoma. PMID- 24807544 TI - Traumatic white matter injury and glial activation: from basic science to clinics. AB - An improved understanding and characterization of glial activation and its relationship with white matter injury will likely serve as a novel treatment target to curb post injury inflammation and promote axonal remyelination after brain trauma. Traumatic brain injury (TBI) is a significant public healthcare burden and a leading cause of death and disability in the United States. Particularly, traumatic white matter (WM) injury or traumatic axonal injury has been reported as being associated with patients' poor outcomes. However, there is very limited data reporting the importance of glial activation after TBI and its interaction with WM injury. This article presents a systematic review of traumatic WM injury and the associated glial activation, from basic science to clinical diagnosis and prognosis, from advanced neuroimaging perspective. It concludes that there is a disconnection between WM injury research and the essential role of glia which serve to restore a healthy environment for axonal regeneration following WM injury. Particularly, there is a significant lack of non-invasive means to characterize the complex pathophysiology of WM injury and glial activation in both animal models and in humans. An improved understanding and characterization of the relationship between glia and WM injury will likely serve as a novel treatment target to curb post injury inflammation and promote axonal remyelination. PMID- 24807545 TI - [Significance and management of concussion in sports-related head injuries]. PMID- 24807543 TI - Growth inhibitory effects of large subunit ribosomal proteins in melanoma. AB - Ribosome biogenesis can modulate protein synthesis, a process heavily relied upon for cancer cell proliferation. In this study, involvement of large subunit ribosomal proteins (RPLs) in melanoma has been dissected and RPLs categorized based on modulation of cell proliferation and therapeutic targeting potential. Based on these results, two categories of RPLs were identified: the first causing negligible effects on cell viability, p53 expression, and protein translation, while the second category decreased cell viability and inhibited protein synthesis mediated with or without p53 protein stabilization. RPL13 represents the second category, where siRNA-mediated targeting inhibited tumor development through decreased cellular proliferation. Mechanistically, decreased RPL13 levels increased p53 stability mediated by RPL5 and RPL11 binding to and preventing MDM2 from targeting p53 for degradation. The consequence was p53-dependent cell cycle arrest and decreased protein translation. Thus, targeting certain category 2 RPL proteins can inhibit melanoma tumor development mediated through the MDM2-p53 pathway. PMID- 24807546 TI - [Surgical complications of vagal nerve stimulation for intractable epilepsy: findings from 26 cases]. AB - INTRODUCTION: Vagal nerve stimulation (VNS) is a less invasive palliative treatment for intractable epilepsy and was approved for use in Japan in July 2010. Surgical complications of VNS such as vagal nerve dysfunction, cardiac arrhythmia with asystole, and vocal cord palsy as well as complications arising from fracture of the leads or generator and infections are well known in the West. The aim of the present report is to describe the surgical complications encountered in our hospital and discuss their countermeasures. MATERIAL AND METHODS: We reviewed the clinical records of 26 patients who underwent VNS therapy between March 2011 and June 2013. The cases involved 17 male and 9 female patients, including 8 children(<15 years of age). RESULTS: Three patients(11.5%)experienced severe bradycardia and cardiac asystole following test stimulations of the vagal nerve with a stainless-steel surgical hook left in place, to extend the operative field. It was believed that the current spread through the hook and stimulated the cardiac branch of the vagal nerve. In an adult patient with severe intellectual disability, inappropriate dermatological therapy for a superficial purulent wound on the neck caused lead infection 10 months postoperatively. In a child with moderate intellectual disability, lead fracture was noted in association with rotation of the pulse generator at one month postoperatively. In the former case, the lead was cut off whilst the electrode and anchoring coil on the vagal nerve remained;the whole VNS system was removed in the latter case. Subfascial implantation of the generator was recommended. In an adult patient, disconnection between the leads and generator head was noted at 10 months postoperatively. CONCLUSIONS: During intraoperative test stimulations of the vagal nerve, stainless-steel surgical hooks should be removed to avoid the spread of current. In intellectually disabled patients, the pulse generator should be placed in the subfascial area instead of the subcutaneous area, especially children. The connection between the leads and the generator should be performed with the aid of a microscope, after removal of the fluid and tissue. PMID- 24807547 TI - [A case of glioblastoma multiforme in the pineal region with intraventricular hemorrhage]. AB - INTRODUCTION: Glioblastoma multiforme (GBM) is a very rare type of tumor involving the pineal region. No case of pineal region GBM with tumoral hemorrhage has ever been reported. Here, we present the first such case report. CASE REPORT: A 65-year-old man presented with sudden-onset disturbance of consciousness. CT revealed intraventricular hemorrhage and acute hydrocephalus. The patient was treated by an emergent operation for ventricular drainage. MRI with contrast media showed a heterogeneous enhanced area in the pineal region. The patient underwent endoscopic biopsy surgery and a third ventriculostomy for non communicating hydrocephalus. The pathological diagnosis was high-grade glioma, indicating the need for tumor removal via the occipital transtentorial approach. The tumor was removed subtotally and radiation and chemotherapy courses were then started. CONCLUSION: Pineal GBM with tumoral hemorrhage has never been reported before. Endoscopic operations are useful for rapid decision making prior to radical surgery. PMID- 24807548 TI - [Selective coil embolization of a distal anterior choroidal artery aneurysm associated with moyamoya disease: a case report]. AB - Intracranial hemorrhage in patients with moyamoya disease is often caused by rupture of the associated aneurysms. Of these aneurysms, distal anterior choroidal artery (AChoA) aneurysms are rare. In patients with moyamoya disease, the AChoA constitutes collateral vessels and the aneurysm requires careful treatment strategy. However, reported cases of distal AChoA aneurysms include various procedures including conservative therapy, direct surgery, and endovascular therapy. Herein, we report a case of coil embolization of a distal AChoA aneurysm associated with moyamoya disease and discuss the treatment strategy. A 39-year-old female presented with severe headache and subsequent deep coma. Computed tomography (CT) revealed thick intraventricular hemorrhage, and three-dimensional CT angiography revealed a right distal AChoA aneurysm. Bilateral ventricular drainage was performed and subsequent ventriculoperitoneal (VP)shunt was performed. The persisting distal AChoA aneurysm was coil embolized without any complication. Rebleeding did not occur during the 1-year follow-up period. Endovascular treatment is effective for distal AChoA aneurysms associated with moyamoya disease to preserve collateral circulation. PMID- 24807549 TI - [Transient charles bonnet syndrome after excision of a right occipital meningioma: a case report]. AB - Charles Bonnet syndrome is a condition characterized by visual hallucinations. These simple or complex visual hallucinations are more common in elderly individuals with impaired peripheral vision. The current report describes a case of transient Charles Bonnet syndrome appearing after the removal of a meningioma. The patient was a 61-year-old man who already had impaired visual acuity due to diabetic retinopathy. Brain MRI revealed a cystic tumor severely compressing the right occipital lobe. Starting on day 2 postoperatively, the patient was troubled by recurring visual hallucinations involving people, flowers, pictures, and familiar settings(the train and a coffee shop). These continued for 3.5 months. This period roughly coincided with the time for the occipital lobe to recover from the compression caused by the tumor, a fact that was confirmed by several MRI scans. 123I-IMP SPECT performed 1 month after the surgical operation showed an area of hypoperfusion in the right parieto-occipital lobe. Based on the patient's clinical course and MRI findings, the mechanism of onset of visual hallucinations in this patient was put forward. The release of pressure in the brain by tumor removal and subsequent recovery changed the blood flow to the brain. This triggered visual hallucinations in the patient, who was already predisposed to developing Charles Bonnet syndrome because of diabetic retinopathy. This case is interesting since it indicates that central neurological factors, as well as visual deficits, may induce the appearance of visual hallucinations in Charles Bonnet syndrome. PMID- 24807550 TI - [A case of intracranial invasion from sinonasal small cell neuroendocrine carcinoma]. AB - Sinonasal neuroendocrine carcinomas (NECs) are rare tumors. We present a rare case of intracranial invasion of sinonasal small-cell NEC. A 61-year-old woman with nasal obstruction and bleeding was referred to our hospital. Computed tomography showed a polyp-like tumor occupying her left nasal cavity and extending to the paranasal sinuses and anterior cranial fossa. The tumor was removed using a transfacial approach by otolaryngologists and a bifrontal cranial approach by neurosurgeons. In histopathological analyses, we found that the tumor presented with both an epithelial and neuroendocrine nature, and was diagnosed as a small-cell NEC. Post-surgery, she received localized radiation therapy and chemotherapy, and is alive, 18 months after diagnosis. In cases where it is difficult to perform a differential diagnosis of tumors arising from the frontal cranial base and extending to the nasal and cranial sides, NEC should be considered as a possibility. PMID- 24807551 TI - [Two cases of anterior cerebral artery aneurysm associated with accessory anterior cerebral artery: review of the literature and points of diagnosis]. AB - The accessory anterior cerebral artery (AccACA) is an anomalous vessel arising from the anterior communicating artery. Although AccACA is not particularly rare, aneurysms arising from the AccACA is extremely rare. Here, we report two cases of unruptured AccACA aneurysms. Patient 1 was a 58-year-old woman with an unruptured distal AccACA aneurysm. Magnetic resonance imaging and three-dimensional computed tomography angiography(3D-CTA)demonstrated a left middle cerebral artery aneurysm that was subsequently clipped successfully by direct surgery. No aneurysm was detected in the distal anterior cerebral artery(ACA)due to the narrow imaging range at that time. Postoperatively, an aneurysm of the distal ACA was incidentally identified on 3D-CTA. This AccACA aneurysm was also clipped by direct surgery about 5 months later, and the patient was discharged without any neurological deficits. Patient 2 was a 46-year-old woman with an aneurysm at the proximal portion of the AccACA. Since the aneurysm was small and patient was asymptomatic, the observation-approach was selected. In introducing these cases, we discuss AccACA aneurysms and the process of diagnosis. Aneurysm can arise over the entire length of the ACA, from the anterior communicating artery to the peripheral portion, particularly the supracallosal portion, so observation and imaging of the peripheral region is important in cases where an AccACA is present. PMID- 24807552 TI - [Intradural arachnoid cyst associated with syringomyelia: a case report]. AB - An intradural arachnoid cyst is a relatively rare condition, occurring within the spinal subarachnoid space. We present the even-more rare case of an intradural arachnoid cyst associated with syringomyelia at the same spinal level. The patient was a 66-year-old man who presented with bilateral leg numbness and gait disturbance. Magnetic resonance imaging (MRI) revealed an intradural arachnoid cyst located dorsal to, and compressing, the thoracic spinal cord at the level of the 7th thoracic vertebra (Th 7). In addition, syringomyelia existed at the level of Th 8, slightly caudal to the intradural arachnoid cyst. We dissected the cyst but did not perform any surgical procedures for the syringomyelia. Post-operative MRI showed that the cyst had disappeared and the syringomyelia had spontaneously shrunk. The patient was discharged with improvement in his numbness and gait disturbance. There are a few case reports of intradural arachnoid cysts associated with syringomyelia, but recent evidence suggests that its occurrence is more common than previously thought. A combination of these two diseases is thought to be caused by blockage of cerebrospinal fluid (CSF) flow, which is also thought to cause adhesive arachnoiditis. For this reason, resection of the arachnoid cyst could improve the CSF flow and contribute to the shrinkage of syringomyelia. Furthermore, early treatment may correlate with improvement in radiological findings and neurological symptoms. PMID- 24807553 TI - [A case of pituitary adenoma in which epistaxis caused by the postoperative ruptured pseudoaneurysm of the sphenopalatine artery was treated by the endovascular embolization]. PMID- 24807554 TI - [Required knowledge for spinal surgeon (9) pediatric spinal surgery]. PMID- 24807555 TI - A long academic journey. AB - In this case study, an early-career electrical engineer interviews an established translational biomedical engineer. The discussion covered topics such as challenges associated with the merging of fundamental engineering science with the pursuit of clinically informed research, how best to train engineering students for future innovation, and how to establish international partnerships. PMID- 24807556 TI - Neutralizing the MERS coronavirus threat. AB - Human neutralizing monoclonal antibodies are candidates for prophylactic and therapeutic interventions against Middle East respiratory syndrome coronavirus (MERS-CoV) infection. PMID- 24807557 TI - T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. AB - Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans. PMID- 24807558 TI - CpG ODN nanorings induce IFNalpha from plasmacytoid dendritic cells and demonstrate potent vaccine adjuvant activity. AB - CpG oligodeoxynucleotides (ODN) are short single-stranded synthetic DNA molecules that activate the immune system and have been found to be effective for preventing and treating infectious diseases, allergies, and cancers. Structurally distinct classes of synthetic ODN expressing CpG motifs differentially activate human immune cells. K-type ODN (K-ODN), which have progressed into human clinical trials as vaccine adjuvants and immunotherapeutic agents, are strong activators of B cells and trigger plasmacytoid dendritic cells (pDCs) to differentiate and produce tumor necrosis factor-alpha (TNFalpha). In contrast, D-type ODN (D-ODN) stimulate large amounts of interferon-alpha (IFNalpha) secretion from pDCs. This activity depends on the ability of D-ODN to adopt nanometer-sized G quadruplex based structures, complicating their manufacturing and hampering their progress into the clinic. In search of a D-ODN substitute, we attempted to multimerize K ODN into stable nanostructures using cationic peptides. We show that short ODN with a rigid secondary structure form nuclease-resistant nanorings after condensation with the HIV-derived peptide Tat(47-57). The nanorings enhanced cellular internalization, targeted the ODN to early endosomes, and induced a robust IFNalpha response from human pDCs. Compared to the conventional K-ODN, nanorings boosted T helper 1-mediated immune responses in mice immunized with the inactivated foot and mouth disease virus vaccine and generated superior antitumor immunity when used as a therapeutic tumor vaccine adjuvant in C57BL/6 mice bearing ovalbumin-expressing EG.7 thymoma tumors. These results suggest that the nanorings can act as D-ODN surrogates and may find a niche for further clinical applications. PMID- 24807559 TI - Expression of the iron hormone hepcidin distinguishes different types of anemia in African children. AB - Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non-iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit. PMID- 24807560 TI - Rhodium(III)-catalyzed intermolecular amidation with azides via C(sp3)-H functionalization. AB - The amidation reactions of 8-methylquinolines with azides catalyzed by a cationic rhodium(III) complex proceed efficiently to give quinolin-8-ylmethanamine derivatives in good yields via C(sp(3))-H bond activation under external oxidant free conditions. A catalytically competent five-membered rhodacycle has been isolated and characterized, revealing a key intermediate in the catalytic cycle. PMID- 24807561 TI - Growth, structural and optical properties of ternary InGaN nanorods prepared by selective-area metalorganic chemical vapor deposition. AB - Ternary InGaN nanorods were prepared on dielectric-masked nano-holes with selective area metalorganic chemical vapor deposition. To overcome the tendency for random nucleation of GaN at low temperatures, a pulsed growth procedure was introduced to enhance the diffusion length of Ga adatoms on SiO2, resulting in good selectivity at typical temperature ranges for InGaN. Photoluminescence from the InGaN nanorods can be tuned from near ultraviolet (400 nm) to blue-green (~500 nm). Microstructural properties were characterized by transmission electron microscopy; threading dislocations from the underlying GaN template were terminated at the nanorod/template interface, resulting in dislocation-free nanorods. The height of dislocation-free InGaN nanorods is about 150 nm, which is much larger than the critical thickness for the onset of misfit dislocations in planar InGaN growth with typical thickness of less than 10 nm for an indium composition between 10 and 20%. The composition profile of In along the growth direction was examined by energy dispersive x-ray spectroscopic mapping and line scan. Oscillations of In composition along the growth direction were observed and are likely due to the kinetic competition between In and Ga adatoms. These InGaN nanorods are expected to be useful as templates for growing higher In composition nano-light-emitting diodes. PMID- 24807562 TI - Academic screening operations: RNAi screening. PMID- 24807563 TI - Hinemoa. AB - SUMMARY This is a retelling of the famous Maori legend, the romance of Hinemoa and Tutanekai. In this version, with an introductory text, the writer challenges the Victorian record, and subverts the contemporary story. She presents an alternate narrative. PMID- 24807564 TI - Unsettled women. AB - SUMMARY Amy Bock (alias Percy Redwood) created a media sensation when "The Case of the Woman Bridegroom" hit the newspapers throughout New Zealand in 1909. She was hailed as the "queerest and most interesting character that has ever been before the New Zealand public" and "pitiable in her freakish exploits." Debates ensued as to whether her crimes were evidence of a mania, a disease, or simply due to a flawed, criminal character. This article focuses on media portrayals of women who did not conform to normative constructions of acceptable womanhood within the latter decades of the nineteenth century and the early twentieth century in New Zealand, as a means of tracing the mutable boundaries of intelligible genders. Newspaper debates and emergent discourses around the medicalisation of social de-viancy are drawn upon to demonstrate how normative constructions of gender were premised upon a defining matrix of mad/bad/woman. PMID- 24807565 TI - Frances Mary hodgkins. AB - SUMMARY Frances Hodgkins was one of a number of expatriate New Zealanders during the early twentieth century who lived in Britain or Europe, where it was easier to find supportive friendship circles for their lives as artists or as people attracted to their own sex. In this article, I explore the primacy of women in Hodgkins' life and read this as lesbian and argue that many of these relationships were sexual, from the evidence of her letters, which suggest that she moved in lesbian worlds of work and friendship. I also discuss the financial and emotional support given by her male homosexual as well as her lesbian friends who made her life as an artist possible. PMID- 24807566 TI - New Zealand's Lost Lesbian Writers and Artists. AB - SUMMARY The paper discusses three New Zealand novelists, a poet, and a painter, whose identities as lesbians have been obliterated in the biographies and critical commentaries written on them. It considers whether the small and largely monocultural New Zealand literary and artistic scene made both coming out and being identified as a lesbian more difficult than in Europe or the United States. It concludes that even in the 1990s, "ghosting" the lesbians of the past is still prevalent. PMID- 24807567 TI - An astounding masquerade. AB - SUMMARY This paper considers the contribution of historical accounts and case studies to the development of lesbian historical knowledge and the amplification of lesbian experience. The author suggests that historical endeavours need to position such accounts and assert lesbian experience so that,Increasingly, public space is occupied by lesbian knowledge and lesbian concerns. The paper discusses a 1945 case of a New Zealand woman, known only as Mr. X, who dressed and acted as a man for over ten years, even having her breasts removed. She was criminally charged when legal authorities discovered she had fraudulently married another woman. The pattern of regulatory responses by the dominant hetero-culture is discussed in relation to this case and other similar cases and categorised into three strategies-einforcement, containment, and leverage. PMID- 24807568 TI - Lesbian plays and their players. AB - SUMMARY This discussion focuses on various texts for the theatre by women dramatists in Aotearoa/New Zealand. It raises a number of questions initially about lesbian plays and playwrights, and then about the per-formability of gender. Finally, I consider briefly some theoretical issues to do with textual reading,Including post-structural readings of "the lesbian." Much usage of the term "lesbian identity" presupposes that there is such a thing, and that it is fixed, univocal and stable. As my readings of these texts show, however, "the lesbian" constitutes a set of fluid identifications, expressed in heterogeneity and change. In these critical readings I examine dramatic texts generating lesbian identities, in the specific social context of Aotearoa/New Zealand. PMID- 24807569 TI - Introducing annamarie jagose. AB - SUMMARY Annamarie Jagose's fiction can be loosely divided into the early short stories and the later novels. The stories are generally feminist and lesbian in content and characters, and contain many traditional story elements. The novels, In Translation and Lulu,are more complex works. In these texts, Jagose is interested in "queering" identity, both heterosexual and homosexual, and in questioning the effectiveness of these traditional taxonomies. Both the stories and novels feature an exquisite control of language, a wry humour, and a deft understanding of human relationships. PMID- 24807570 TI - Lesbians and economic/social change. AB - SUMMARY This article discusses the globalisation juggernaut and its impacts on women in general and lesbians in particular. It outlines the inadequacies of the pink dollar g/luppie image of lesbians, and considers what lesbian economics involve. This leads to outlining some political implications for our own communities of globalisation and its individualistic world, internally, in coalitions, and in our dealings with governments. It concludes that economics is an important influence on our communities, for good and ill, and that values and politics should be critical to how we handle economic issues. Continuing the creation of lesbian economy and value systems and influencing those of the straight world are ongoing, difficult tasks. PMID- 24807571 TI - The Great, Late Lesbian and Bisexual Women's Discrimination Survey. AB - SUMMARY This 1992 New Zealand survey of discrimination against 261 lesbian and bisexual women found comparable rates of public abuse and workplace discrimination to those reported by surveys in other developed countries. The women reported higher rates of assault in public places than a random sample of New Zealand women. Indigenous Maori women reported higher rates of assault, threats, verbal abuse, and workplace discrimination than the non-Maori women surveyed. Aggression against the women was often in response to public expression of affection for another woman or to rejection of men's public sexual advances. The respondents reported hostile educational environments that coincided with peer harassment of students attracted to their own gender. Around two-thirds of the women had hidden their sexuality on some occasions at work to avoid discrimination. No significant differences between the discrimination experiences of lesbian and bisexual women emerged, although the bisexual sample was too small for statistical analysis. PMID- 24807572 TI - Lesbian access to justice. AB - SUMMARY Although some aspects of New Zealand family law have been criticised as discriminatory, the New Zealand legal system has yet to be critically examined from a lesbian perspective. This article begins a development of lesbian legal theory for Aotearoa/New Zealand by analysing the contribution that the 1999 Law Commission study, Women's Access to Legal Services,has made to our knowledge about the impact of the law on lesbian relationships and communities. PMID- 24807573 TI - Dangerous territories. AB - SUMMARY This paper considers both social work and the workplace as dangerous territory for lesbians. It is claimed that social work as a professional and occupational role is territorially claimed by heterodominant relations and discourses. Because of this, lesbian social workers are endangered within this environment and context. It draws on the experiences of lesbian social workers and examines the trends and themes of discrimination within a theoretical and analytical context that addresses the hetero-dominance of a professional and occupational role. The analysis shows the systematic patterning of discrimination and the psychological impact of social forms of oppression. PMID- 24807574 TI - The effects of coming out on relationships and health. AB - SUMMARY This study set out to ascertain how open lesbians were about their sexual orientation, using a snowball sample of lesbians in New Zealand. The research looked at how disclosure impacted on lesbian sexual behaviour, self assessed health status, relationships and use of health services. The questions were part of a large survey modelled on a North Health Study (Parr, Whittaker, and Jackson, 1998) which included the SF-36 survey instrument. A standardized set of questions and calculated scoring were used to measure the self-assessed health of respondents (Ware et al., 1993). The 795 return results were compared with a sample of women from Northern New Zealand and a sample of lesbians from the New Zealand Census. The respondents were coded into three groups according to their degree of openness: those who were out to everybody, those who were out to all but one person of significance, and those who were out to a few. Lesbians who were not open to their doctors were more likely to have reported being closeted to employers and parents, to smoke more, to drink more alcohol, to have less sex, and to earn less money. Respondents who labeled themselves gay reported that they were not so open. of the 77% that were out to their health professional, 5% had received a negative response. PMID- 24807575 TI - That four letter word-sons. AB - SUMMARY This title for this article has been inspired by pioneer feminist and lesbian mother of a son, Robin Morgan, who wrote, "[f]ew subjects so provoke anxiety among feminists as the four-letter word sons. Yet that subject goes to the crux of power and of patriarchy, even though it grazes the living nerves of love" (Morgan, 1997, p. 38). The article is based on the material gathered from interviews with lesbian mothers who participated in a doctoral research project investigating the mother/adolescent-son relationship. PMID- 24807576 TI - Ties that bind. AB - SUMMARY This paper explores how a group of Pakeha women who self-identify as lesbian, gay, or homosexual set about constructing new ways of being Christian, influenced by feminist world-views and an ethos of self-awareness. This construction meshes with new ways of being religious in modern societies, but it also demonstrates how lesbian women have much in common with other women within Christian churches. This paper, therefore, signals the continuing importance of gender as an intervening structure when exploring the relationship between sexuality and religion, specifically, the relationship between being lesbian and being Christian. PMID- 24807577 TI - A "labor from the heart". AB - SUMMARY While it is true that publications targeted to gay males historically were glossier, had more consistent advertising income, and claimed higher circulations than lesbian periodicals, the number of lesbian newsletters, newspapers, and magazines grew significantly during the nearly 50 years covered in this study. This study chronicles that origin, growth and disappearance of four significant lesbian publications-Vice Versa, The Ladder, Focus: A Journal for Lesbians, and Sinister Wisdom-from 1947 to 1994. These magazines illustrate varied genre in lesbian publishing history and represent three distinctly different geographical areas. They also span almost five decades during the inauspicious beginning and rapid growth of the lesbian press. This study argues that lesbian publications, although often tied to politically active organizations, existed primarily to help individual lesbians come to terms with a homophobic world and to provide social connections and essential support systems. Less financially secure than their counterparts in the gay male magazine industry, lesbian publications were labors of love and rarely survived. PMID- 24807580 TI - Sonic hedgehog secreted by neurons regulates angiopoietin expression in neighboring fibroblasts. AB - Lately, the importance of the communication between different cell types and the understanding of the cell communication pathway has been emphasized, as it may provide a novel therapeutic strategy for the regeneration of damaged tissue. In the present study, we suggest that sonic hedgehog (Shh) is a mediator of cell communication between neurons and fibroblasts. Recombinant Shh (rShh) affected the expression of the angiogenic factors, angiopoietin (Ang)-1 and Ang-2, in fibroblasts, but not in neurons or neural progenitor cells (NPCs). The expression of the Shh downstream transcription factor, Gli1, was markedly increased in neurons and NPCs, indicating that neurons and NPCs responded to rShh. However, rShh did not affect Ang-1 and Ang-2 expression in neurons and NPCs. It should be noted that Shh was strongly expressed in neurons, but that Shh expression was undetectable in fibroblasts. We performed a co-culture assay using neurons and fibroblasts to investigate whether the expression of Ang-1 and Ang-2 is regulated by cell communication, without rShh treatment. Ang-1 expression in fibroblasts was markedly upregulated by co-culture with neurons, whereas Ang-2 expression was decreased by co-culture with neurons. Moreover, when an Shh-neutralizing antibody was added, this effect was diminished. Collectively, our data suggest that Shh expressing neurons regulate angiopoietin expression in neighboring fibroblasts in a paracrine manner. PMID- 24807582 TI - Discovery of multifold modified sialosides as human CD22/Siglec-2 ligands with nanomolar activity on B-cells. AB - Sialic acids are abundant in higher domains of life and lectins recognizing sialosaccharides are heavily involved in the regulation of the human immune system. Modified sialosides are useful tools to explore the functions of those lectins, especially members of the Siglec (sialic acid binding immunoglobulin like lectin) family. Here we report design, synthesis, and affinity evaluation of novel sialoside classes with combined modification at positions 2, 4, and 9 or 2, 3, 4, and 9 of the sialic acid scaffold as human CD22 (human Siglec-2) ligands. They display up to 7.5 * 10(5)-fold increased affinity over alphaMe Neu5Ac (the minimal Siglec ligand). CD22 is a negative regulating coreceptor of the B-cell receptor (BCR). In vitro experiments with a human B-lymphocyte cell line showed functional blocking of CD22 upon B-cell receptor (BCR) stimulation in the presence of nanomolar concentrations of the novel ligands. The observed increased Ca(2+) response corresponds to enhanced cell activation, providing an opportunity to therapeutically modulate B-lymphocyte responses, e.g., in immune deficiencies and infections. PMID- 24807583 TI - Antimicrobial treatment of asymptomatic bacteriuria in noncatheterized adults: a systematic review. AB - Asymptomatic bacteriuria (ASB) is a common clinical finding characterized by the presence of bacteria in the urine of an individual without signs or symptoms suggestive of urinary tract infection. Despite available guidelines on the diagnosis and management of ASB, it is often managed inappropriately. We performed a systematic review of clinical trials evaluating antimicrobial therapy for ASB, identified translational barriers to evidence-based practice, and we offer strategies to optimize antimicrobial use for ASB. We conducted a systematic search of the PubMed, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health databases, and the Cochrane Library. Randomized controlled trials, cohort trials, case-control studies, and meta-analyses published in the English language were included in this review if they addressed treatment of ASB with at least one antimicrobial agent in nonpregnant adults. Articles were excluded if they evaluated patients with indwelling urinary catheters or were not clinical trials. Of the 304 articles identified from the search, 287 were excluded; thus 17 articles met the inclusion criteria. Although treatment of ASB with antimicrobial therapy may improve short-term microbiologic outcomes, the clinical significance is diminished because the effect is not sustained, there is no measurable improvement in morbidity or mortality, and some data indicate that therapy is deleterious. Several translational barriers that preclude adoption of evidence-based practice are identified. Treatment guidelines may not achieve their desired effect and underscore the need for additional methods to translate clinical trial data into practice. Clinical pharmacists are a core member of the antimicrobial stewardship team and in an important position to participate in initiatives that promote appropriate antimicrobial use. We suggest a multifaceted approach consisting of education and frequent routine prospective audits with feedback coupled with appropriate process and outcome measures. PMID- 24807584 TI - MMP-2/9-oriented combinations enhance antitumor efficacy of EGFR/HER2-targeting fusion proteins and gemcitabine. AB - To increase the antitumor efficacy, in the present study, we proposed several settings of matrix metalloproteinase (MMP)-2/9-oriented combinations that comprise the MMP-2/9-targeting fusion protein dFv-LDP and the MMP inhibitor doxycycline (DOX) in association with EGFR/HER2-bispecific fusion protein Ec-LDP Hr, its enediyne-energized analogue Ec-LDP-Hr-AE, and gemcitabine (GEM). The expressions of various fusion proteins were detected by western blot analysis. Proliferation and migration inhibition of cells were determined by MTT and Transwell assay, respectively. The binding capability of dFv-LDP and Ec-LDP-Hr to cancer cells was examined by ELISA, cell immunofluorescence coimmunoprecipitation and confocal assays. Animal experiments were set to investigate the antitumor efficacy of various combinations against colorectal carcinoma HCT-15 xenograft in athymic mice. These two targeting proteins dFv-LDP and Ec-LDP-Hr had strong binding capabilities and antiproliferation effects on various cancer cell lines. Enhanced therapeutic efficacy in vivo was observed in the MMP-2/9-targeting fusion protein dFv-LDP integrated combinations including: i) dFv-LDP and Ec-LDP Hr, ii) dFv-LDP and enediyne-energized fusion protein Ec-LDP-Hr-AE, iii) dFv-LDP and Ec-LDP-Hr-AE plus DOX, and iv) dFv-LDP and GEM plus DOX against colorectal cancer HCT-15 xenograft in athymic mice. In setting iii, DOX (20 mg/kg), dFv-LDP (20 mg/kg) and Ec-LDP-Hr-AE (0.3 mg/kg) alone suppressed tumor growth by 35, 49.7 and 67.5%, respectively. The combination of dFv-LDP and Ec-LDP-Hr-AE was 75.1%. Furthermore, this combination plus DOX showed stronger efficacy with an inhibitory rate of 82.7%. In setting iv, the combination of dFv-LDP and GEM suppressed tumor growth by 66.3%. Notably, the tumor inhibitory rate of the dFv LDP/GEM/DOX combination reached 85.5%, producing initial shrinkage after the first administration. The MMP-2/9-oriented combination strategy that employs the MMP-2/9-targeting antibody-based fusion protein and the small molecular inhibitor DOX as the basic composed agents may enhance antitumor efficacy in association with the EGFR/HER2-targeting fusion protein and GEM. This multiple targeting approach may be useful for enhancing antitumor efficacy against colorectal cancer. PMID- 24807585 TI - Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. AB - A 2 1/2-year-old girl with multiple congenital anomalies and a de novo 5.6-Mb deletion on chromosome 13q12.11-13q12.13 is reported. She showed choanal atresia, scalp aplasia cutis, mild dysmorphic features, severe malformation of the hands and feet, Sylvian aqueductal stenosis, hydrocephalus, small cerebellum with pointed cerebellar tonsils, cervical, lumbar and sacral clefting, single central incisor and mild developmental delay. The girl's anomalies were compared with: (A) one boy reported by each of Der Kaloustian et al. [2011] and Tanteles et al. [2011] with similar, albeit smaller, 2.1 to 2.9 Mb deletions in which the abnormalities consisted of mild facial dysmorphism, mild malformations of the fingers and/or toes, and developmental delay; (B) one girl reported by Friedman et al. [2006] with similar, albeit larger, 5.7 Mb deletion with mild developmental delay and haematological abnormalities; (C) one girl reported by Slee et al. [1991] with a deletion of band q12.2 in chromosome 13, who had Moebius syndrome with facial dysmorphism, high arched palate, micrognathia, and small tongue with no abnormalities of the extremities; and (D) seven additional individuals recorded in the DECIPHER 6.0 database who all had dysmorphic features and developmental delay plus a spectrum of clinical manifestations including deafness, ataxia/oculomotor apraxia, spasticity, small testes, and mild fingers' anomalies. The deleted region hereby reported encompassed 34 known genes, including GJA3, GJB2, and GJB6, which are responsible for autosomal recessive deafness, FGF9, which plays crucial roles in embryonic neurological development, and ATP8A2, which causes a cerebellar ataxia and disequilibrium syndrome. PMID- 24807586 TI - Subdiffusive exciton transport in quantum dot solids. AB - Colloidal quantum dots (QDs) are promising materials for use in solar cells, light-emitting diodes, lasers, and photodetectors, but the mechanism and length of exciton transport in QD materials is not well understood. We use time-resolved optical microscopy to spatially visualize exciton transport in CdSe/ZnCdS core/shell QD assemblies. We find that the exciton diffusion length, which exceeds 30 nm in some cases, can be tuned by adjusting the inorganic shell thickness and organic ligand length, offering a powerful strategy for controlling exciton movement. Moreover, we show experimentally and through kinetic Monte Carlo simulations that exciton diffusion in QD solids does not occur by a random walk process; instead, energetic disorder within the inhomogeneously broadened ensemble causes the exciton diffusivity to decrease over time. These findings reveal new insights into exciton dynamics in disordered systems and demonstrate the flexibility of QD materials for photonic and optoelectronic applications. PMID- 24807588 TI - A new clade of Asian late Cretaceous long-snouted tyrannosaurids. AB - The iconic tyrannosaurids were top predators in Asia and North America during the latest Cretaceous, and most species had deep skulls that allowed them to generate extreme bite forces. Two unusual specimens of Alioramus from Mongolia seem to indicate a divergent long-snouted body plan among some derived tyrannosaurids, but the rarity and juvenile nature of these fossils leaves many questions unanswered. Here, we describe a remarkable new species of long-snouted tyrannosaurid from the Maastrichtian of southeastern China, Qianzhousaurus sinensis. Phylogenetic analysis places Qianzhousaurus with both species of Alioramus in a novel longirostrine clade, which was geographically widespread across latest Cretaceous Asia and formed an important component of terrestrial ecosystems during this time. The new specimen is approximately twice the size as both Alioramus individuals, showing that the long-snouted morphology was not a transient juvenile condition of deep-snouted species, but a characteristic of a major tyrannosaurid subgroup. PMID- 24807589 TI - The effect of curcumin on the brain-gut axis in rat model of irritable bowel syndrome: involvement of 5-HT-dependent signaling. AB - Irritable bowel syndrome (IBS) is induced by dysfunction of central nervous and peripheral intestinal systems, which affects an estimated 10-15% population worldwide annually. Stress-related psychiatric disorders including depression and anxiety are often comorbid with gastrointestinal function disorder, such as IBS. However, the mechanism of IBS still remains unknown. Curcumin is a biologically active phytochemical presents in turmeric and has pharmacological actions that benefit patients with depression and anxiety. Our study found that IBS rats showed depression- and anxiety-like behaviors associated with decreased 5-HT (serotonin), BDNF (Brain-derived neurotrophic factor) and pCREB (phosphorylation of cAMP response element-binding protein) expression in the hippocampus after chronic acute combining stress (CAS). However, these decreased parameters were obviously increased in the colonic after CAS. Curcumin (40 mg/kg) reduced the immobility time of forced swimming and the number of buried marbles in behavioral tests of CAS rats. Curcumin also decreased the number of fecal output and abdominal withdrawal reflex (AWR) scores in response to graded distention. Moreover, curcumin increased serotonin, BDNF and pCREB levels in the hippocampus, but they were decreased in the colonic of CAS rats. 5-HT(1A) receptor antagonist NAN-190 reversed the effects of curcumin on behaviors and the changes of intestine, pCREB and BDNF expression, which are related to IBS. These results suggested that curcumin exerts the effects on IBS through regulating neurotransmitters, BDNF and CREB signaling both in the brain and peripheral intestinal system. PMID- 24807591 TI - Overcoming the challenges of primary tumor management in patients with metastatic colorectal cancer unresectable for cure and an asymptomatic primary tumor. AB - BACKGROUND: The management of asymptomatic primary tumor in patients with unresectable metastatic colorectal cancer remains inconsistent. OBJECTIVE: This study aimed to determine the rate of symptom-directed surgery after systemic chemotherapy and to estimate the impact of initial primary tumor resection on survival in patients with unresectable metastatic colorectal cancer and an asymptomatic primary tumor. DESIGN: This was a single-institution, retrospective observational study. SETTINGS: The study was conducted in a tertiary referral hospital. PATIENTS: Between 2005 and 2011, 191 consecutive patients with newly diagnosed stage IV colorectal cancer were identified. Of the 191, we analyzed 94 patients with unresectable, asymptomatic colorectal cancer. MAIN OUTCOME MEASURES: We measured symptom-directed surgery and overall survival. RESULTS: Forty-seven patients with an intact primary tumor received systemic chemotherapy (upfront chemotherapy group), 41 underwent primary tumor resection (upfront primary tumor resection group), and 6 underwent diversion enterostomy as first line therapy. After excluding the 6 patients undergoing diversion enterostomy before systemic chemotherapy, this left 88 patients for final analysis. Twelve upfront chemotherapy patients required symptom-directed late surgery. Overall, 1 year and 2-year rates of symptom-directed surgery were 19.1% and 26.1%. In patients with nontraversable lesions by colonoscope at diagnosis, 64.3% required late intervention within 1 year. Competing risk regression analysis revealed that only colonoscopic traversability at diagnosis was significantly associated with symptom-directed late surgery (subhazard ratio, 7.9; p = 0.004). Median overall survival time was comparable between the 2 groups at 23.9 months for the upfront primary tumor resection group and 22.6 months for the upfront chemotherapy group (HR, 0.84; 95% CI: 0.51-1.39). LIMITATIONS: This study was limited by its retrospective nature and small sample size. CONCLUSIONS: Approximately 75% of upfront chemotherapy patients with unresectable, asymptomatic stage IV colorectal cancer can be spared initial resection of the primary tumor. Colonoscopic findings of nontraversable lesions at diagnosis may predict the need for late surgical intervention. PMID- 24807590 TI - Pannexin1 as a novel cerebral target in pathogenesis of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) represents a nervous system disorder caused due to liver dysfunction. HE is broadly classified as acute/overt and moderate-minimal HE. Since HE syndrome severely affects quality of life of the patients and it may be life threatening, it is important to develop effective therapeutic strategy against HE. Mainly ammonia neurotoxicity is considered accountable for HE. Increased level of ammonia in the brain activates glutamate-NMDA (N-methyl-D aspartate) receptor (NMDAR) pathway leading to Ca(2+) influx, energy deficit and oxidative stress in the post synaptic neurons. Moreover, NMDAR blockage has been found to be a poor therapeutic option, as this neurotransmitter receptor plays important role in maintaining normal neurophysiology of the brain. Thus, searching new molecular players in HE pathogenesis is of current concern. There is an evolving concept about roles of the trans-membrane channels in the pathogenesis of a number of neurological complications. Pannexin1 (Panx1) is one of them and has been described to be implicated in stroke, epilepsy and ischemia. Importantly, the pathogenesis of these complications relates to some extent with NMDAR over activation. Thus, it is speculated that HE pathogenesis might also involve Panx1. Indeed, some recent observations in the animal models of HE provide support to this argument. Since opening of Panx1 channel is mostly associated with the neuronal dysfunctions, down regulation of this channel could serve as a relevant therapeutic strategy without producing any serious side effects. In the review article an attempt has been made to summarize the current information on implication of Panx1 in the brain disorders and its prospects for being examined as pharmacological target in HE pathogenesis. PMID- 24807592 TI - Impact of BMI on postoperative outcomes in patients undergoing proctectomy for rectal cancer: a national surgical quality improvement program analysis. AB - BACKGROUND: There is a mounting body of evidence that suggests worsened postoperative outcomes at the extremes of BMI, yet few studies investigate this relationship in patients undergoing proctectomy for rectal cancer. OBJECTIVE: We aimed to examine the relationship between BMI and short-term outcomes after proctectomy for cancer. DESIGN: This was a retrospective study comparing the outcomes of patients undergoing proctectomy for rectal cancer as they relate to BMI. SETTINGS: The American College of Surgeons-National Surgical Quality Improvement Program database was queried for this study. PATIENTS: Patients included were those who underwent proctectomy for rectal neoplasm between 2005 and 2011. MAIN OUTCOME MEASURES: Study end points included 30-day mortality and overall morbidity, including the receipt of blood transfusion, venous thromboembolic disease, wound dehiscence, renal failure, reintubation, cardiac complications, readmission, reoperation, and infectious complications (surgical site infection, intra-abdominal abscess, pneumonia, and urinary tract infection). Univariate logistic regression was used to analyze differences among patients of varying BMI ranges (kg/m; <=20, 20-24, 25-29, 30-34, and >=35). When significant differences were found, multivariable logistic regression, adjusting for preoperative demographic and clinical variables, was performed. RESULTS: A total of 11,995 patients were analyzed in this study. The incidences of overall morbidity, wound infection, urinary tract infection, venous thromboembolic event, and sepsis were highest in those patients with a BMI of >=35 kg/m (OR, 1.63, 3.42, 1.47, 1.64, and 1.50). Wound dehiscence was also significantly more common in heavier patients. Patients with a BMI <20 kg/m had significantly increased rates of mortality (OR, 1.72) and sepsis (OR, 1.30). LIMITATIONS: This study was limited by its retrospective design. Furthermore, it only includes patients from the American College of Surgeons-National Surgical Quality Improvement Program database, limiting its generalizability to nonparticipating hospitals. CONCLUSIONS: Obese and underweight patients undergoing proctectomy for neoplasm are at a higher risk for postoperative complications and death. PMID- 24807593 TI - The role of primary colectomy after successful endoscopic stenting in patients with obstructive metastatic colorectal cancer. AB - BACKGROUND: Although the initial clinical efficacy of self-expandable metal stents is acceptable, doubt still remains about long-term clinical outcomes and complications. OBJECTIVE: The aim of this study was to evaluate the stoma formation rate and risk factors for complications after successful stenting in patients with obstructive metastatic colorectal cancer. DESIGN: This was a tertiary-care center retrospective study. PATIENTS: From January 2000 to December 2010, 130 patients with unresectable obstructive colorectal cancer received successful self-expandable metal stent placement. Among them, 14 patients received primary colectomy after successful stenting. INTERVENTIONS: Self expandable metal stent placement and primary colectomy were performed. MAIN OUTCOME MEASURES: The stoma formation rate and complications were measured. RESULTS: In patients with successful stenting, stoma formation rates at 1 and 2 years were 15.6% (95% CI, 8.74-22.4) and 24.4% (95% CI, 13.8-35.0), and the median patency duration was 157 days (range, 2-1590 days). However, long-term complications occurred in 58 patients (44.6%), including reobstruction (32.6%), stent migration (10.3%), and perforation (7.8%), and a large number of reinterventions (45.7%) and hospitalizations (37/9%) were needed to manage complications. In multivariate analysis, primary colectomy after successful endoscopic stenting was a negative predictive factor for reobstruction (OR, 0.12; 95% CI, 0.02-0.99; p = 0.04). LIMITATIONS: This was a retrospective, single center study. CONCLUSIONS: To reduce stent-related late complications, primary colectomy after successful endoscopic stenting could be a therapeutic option in patients who have unresectable colorectal cancer with obstruction, especially in those who expect long-term survival. PMID- 24807594 TI - Development and implementation of a synoptic MRI report for preoperative staging of rectal cancer on a population-based level. AB - BACKGROUND: Colorectal cancer physician champions across the province of Ontario, Canada, reported significant concern about appropriate selection of patients for preoperative chemoradiotherapy because of perceived variation in the completeness and consistency of MRI reports. OBJECTIVE: The purpose of this work was to develop, pilot test, and implement a synoptic MRI report for preoperative staging of rectal cancer. DESIGN: This was an integrated knowledge translation project. SETTINGS: This study was conducted in Ontario, Canada. PATIENTS: Surgeons, radiologists, radiation oncologists, medical oncologists, and pathologists treating patients with rectal cancer were included in this study. INTERVENTIONS: A multifaceted knowledge translation strategy was used to develop, pilot test, and implement a synoptic MRI report. This strategy included physician champions, audit and feedback, assessment of barriers, and tailoring to the local context. A radiology webinar was conducted to pilot test the synoptic MRI report. MAIN OUTCOME MEASURES: Seventy-three (66%) of 111 Ontario radiologists participated in the radiology webinar and evaluated the synoptic MRI report. RESULTS: A total of 78% and 90% radiologists expressed that the synoptic MRI report was easy to use and included all of the appropriate items; 82% noted that the synoptic MRI report improved the overall quality of their information, and 83% indicated they would consider using this report in their clinical practice. An MRI report audit after implementation of the synoptic MRI report showed a 39% improvement in the completeness of MRI reports and a 37% uptake of the synoptic MRI report format across the province. LIMITATIONS: Radiologists evaluating the synoptic MRI report and participating in the radiology webinar may not be representative of gastroenterologic radiologists in other geographic jurisdictions. The evaluation of completeness and uptake of the synoptic MRI reports is limited because of unmeasured differences that may occur before and after the MRI. CONCLUSIONS: A synoptic MRI report for preoperative staging of rectal cancer was successfully developed and pilot tested in the province of Ontario, Canada. PMID- 24807595 TI - Evaluation of mesorectal fascia in mid and low anterior rectal cancer using endorectal ultrasound is feasible and reliable: a comparison with MRI findings. AB - BACKGROUND: Accuracy of MRI in assessing mesorectal fascia and predicting circumferential resection margin decreases in low anterior rectal tumors. OBJECTIVE: The purpose of this work was to evaluate the accuracy of endorectal ultrasound in predicting the pathologic circumferential resection margin in low rectal anterior tumors and to compare it with MRI findings. DESIGN: This was a prospective series comparing the preoperative circumferential resection margin assessed by endorectal ultrasound and MRI with pathologic examination. SETTINGS: The study was conducted by a specialized colorectal multidisciplinary team at a tertiary teaching hospital. PATIENTS: Between 2002 and 2008, 76 patients with mid to low rectal cancer were preoperatively evaluated by endorectal ultrasound and MRI and underwent total mesorectal excision without neoadjuvant radiochemotherapy. Twenty-seven patients with posterior or postero-lateral tumors were excluded, leaving 49 patients with anterior or antero-lateral tumors for the present subanalysis. We compared preoperative circumferential resection margin status using endorectal ultrasound and MRI with pathologic examination. INTERVENTIONS: We conducted a comparison between preoperative circumferential resection margin status and pathologic examination after total mesorectal excision surgery. MAIN OUTCOME MEASURES: Accuracy in predicting pathologic circumferential resection margin status was measured. RESULTS: Overall accuracy of endorectal ultrasound and MRI in assessing circumferential resection margin status was 83.7% and 91.8%, with negative predictive values of 97.2% and 97.5%. When focusing on low rectal tumors, the overall accuracy of endorectal ultrasound increased to 87.5%, whereas the accuracy of MRI decreased to 87.5%, with a negative predictive value of 95.6% for both diagnostic tests. LIMITATIONS: The sample size is small, and interobserver variability in radiologic assessment was not evaluated. CONCLUSIONS: Endorectal ultrasound can help MRI in predicting circumferential resection margin involvement in mid to low anterior rectal cancer, especially at the low third of the rectum, with a high negative predictive value. PMID- 24807596 TI - Barium enema and CT volumetry for predicting pathologic response to preoperative chemoradiotherapy in rectal cancer patients. AB - BACKGROUND: Preoperative chemoradiotherapy has been widely used for the prevention of local recurrence of locally advanced rectal cancer, and the effect of chemoradiotherapy is known to be associated with overall survival. OBJECTIVE: We aimed to evaluate the association of the pathologic response grade with tumor recurrence rate after chemoradiotherapy, using radiographic analysis and the Response Evaluation Criteria in Solid Tumors as the parameters. DESIGN: This study was conducted at a single tertiary care institution in Japan. SETTING: This was a retrospective cohort study of patients undergoing preoperative chemoradiotherapy. PATIENTS: A total of 101 low rectal cancer patients receiving preoperative chemoradiotherapy from July 2004 to August 2012 were enrolled. MAIN OUTCOME MEASURES: The tumor reduction rate was measured with the use of traditional Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry, and the correlation between the reduction rate and the pathologic response grade was examined. RESULTS: The tumor reduction rate assessed according to Response Evaluation Criteria in Solid Tumors showed no association with the pathologic response grade (p =0.61). In contrast, the radiographic response rate by both barium enema and CT volumetry strongly correlated with the pathologic response grade (p < 0.0001 and p = 0.001).In terms of local tumor recurrence, those diagnosed as high responders by the pathologic response grade, Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry had a lower recurrence rate (p =0.03, p =0.03, p =0.0002, and p =0.001). The difference between high responders and low responders was especially prominent by barium enema and CT volumetry. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: Double-contrast barium enema and CT volumetry were superior to Response Evaluation Criteria in Solid Tumors in evaluating the effect of chemoradiotherapy and predicting the likelihood of tumor recurrence. PMID- 24807597 TI - Abdominal- versus thigh-based reconstruction of perineal defects in patients with cancer. AB - BACKGROUND: An abdominoperineal resection is an invasive procedure that leaves the patient with vast pelvic dead space. Traditionally, the vertical rectus abdominus myocutaneous flap is used to reconstruct these defects. Oftentimes, this flap cannot be used because of multiple ostomy placements or previous abdominal surgery. The anterolateral thigh flap can be used; however, the efficacy of this flap has been questioned. OBJECTIVE: We report a single surgeon's experience with perineal reconstruction in patients with cancer with the use of either the vertical rectus abdominus myocutaneous flap or the anterolateral thigh flap to demonstrate acceptable outcomes with either repair modality. DESIGN: From 2010 to 2012, 19 consecutive patients with perineal defects secondary to cancer underwent flap reconstruction. A retrospective chart review of prospectively entered data was conducted to determine the frequency of short-term and long-term complications. SETTINGS: This study was conducted at an academic, tertiary-care cancer center. PATIENTS: Patients in the study were patients with cancer who were receiving perineal reconstruction. INTERVENTIONS: Interventions were surgical and included either abdomen- or thigh-based reconstruction. MAIN OUTCOME MEASURES: The main outcome measures included infection, flap failure, length of stay, and time to radiotherapy. RESULTS: Of the 19 patients included in our study, 10 underwent anterolateral thigh flaps and 9 underwent vertical rectus abdominus myocutaneous flaps for reconstruction. There were no significant differences in demographics between groups (p > 0.05). Surgical outcomes and complications demonstrated no significant differences in the rate of infection, hematoma, bleeding, or necrosis. The mean length of stay after reconstruction was 9.7 +/- 3.4 days (+/- SD) in the anterolateral thigh flap group and 13.4 +/- 7.7 days in the vertical rectus abdominus myocutaneous flap group (p > 0.05). LIMITATIONS: The limitations of this study include a relatively small sample size and retrospective evaluation. CONCLUSION: This study suggests that the anterolateral thigh flap is an acceptable alternative to the vertical rectus abdominus myocutaneous flap for perineal reconstruction (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A134). PMID- 24807598 TI - Is patient diagnosis a risk factor for organ space infection after colorectal resections? AB - BACKGROUND: Validated risk adjustment programs do not use patient diagnosis as a potential covariate in the evaluation of organ space infections. OBJECTIVE: We hypothesized that patient diagnosis is an important risk factor for organ space infection after colorectal resections. DESIGN: We conducted a retrospective cohort study abstracting data from the American College of Surgeons National Surgical Quality Improvement Program from January 2005 through December 2009. PATIENTS: Patients who underwent 1 of 3 types of colorectal resections (ileocolostomy, partial colectomy, and coloproctostomy) were identified by the use of Current Procedural Terminology codes. We excluded patients with concomitant formation of diverting or end stoma. OUTCOME MEASURES: The primary outcome measured was organ space infection. ANALYSIS: Validated risk adjustment models were used with the addition of diagnostic codes. RESULTS: We identified 52,056 patients who underwent a colorectal resection of whom 1774 patients developed an organ space infection (3.4%) and 894 (50.2%) returned to the operating room for further surgery. For ileocolostomy, operations for endometriosis (OR, 7.8; 95% CI, 1.7-36.6) and intra-abdominal fistula surgery (OR, 3.0; 95% CI, 1.5-6.0) were associated with increased risk of organ space infection. For partial colectomy, operations for intra-abdominal fistula surgery (OR, 2.3; 95% CI, 1.2-4.3), IBD (OR, 2.5; 95% CI, 1.6-3.8), and bowel obstruction (OR, 1.8; 95% CI, 1.2-2.6) were associated with an increased risk of organ space infection. For coloproctostomy, operations for malignant neoplasm (OR, 2.2; 95% CI, 1.1-4.3) and diverticular bleeding (OR, 3.1; 95% CI, 1.1-9.0) were associated with an increased risk of organ space infection. LIMITATIONS: This study was limited by the retrospective study design. CONCLUSIONS: After adjustment for National Surgical Quality Improvement Program covariates, intra-abdominal fistula, endometriosis, and diverticular bleeding were the diagnoses associated with the highest risk of organ space infection following colorectal resections. PMID- 24807599 TI - Minimally invasive colorectal resection for benign pathology is associated with persistent proangiogenic plasma compositional changes. AB - BACKGROUND: Minimally invasive colorectal resection for cancer is associated with increased plasma levels of numerous proangiogenic proteins for 3 to 4 weeks postoperatively, and plasma from postoperative weeks 2 and 3 stimulates proangiogenic endothelial cell behavior in vitro. It is unknown if similar plasma changes occur after minimally invasive colorectal resection for benign pathology. OBJECTIVE: The aim of this study is to assess 1) plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 after minimally invasive colorectal resection for benign pathology and 2) postoperative plasma's effects on in vitro endothelial cell proliferation (branch point formation), migration, and invasion. DESIGN: Prospectively gathered plasma samples taken from patients undergoing colorectal resection who consented to participate in an institutional review board-approved plasma and data bank were used for ELISAs and in vitro endothelial cell studies. SETTINGS: The plasma and clinical data used were collected at 3 hospitals. PATIENTS: Patients undergoing minimally invasive colorectal resection for benign indications who were enrolled in a plasma/data bank and for whom adequate samples and volumes of plasma were available were included in the study. MAIN OUTCOME MEASURES: Perioperative plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 were the primary outcomes measured. In vitro rates of endothelial cell branch point formation, migration, and invasion were determined after the addition of preoperative and postoperative plasma samples to endothelial cell cultures. RESULTS: Plasma from 86 patients undergoing minimally invasive colorectal resection for benign indications was assessed (diverticulitis, 30; benign polyps, 56). Plasma levels of angiopoetin-2, placental growth factor, and soluble vascular cell adhesion molecule-1 were significantly increased for 3 to 4 weeks postoperatively compared with preoperative levels. In regard to the endothelial cell culture assays, significantly increased endothelial cell branch point formation, invasion, and migration results were noted with plasma from the second and third weeks postoperatively in comparison with preoperative culture results. LIMITATIONS: The weaknesses of this study are the limited numbers of late postoperative plasma samples and the need to bundle late samples into 7- to 12-day time blocks. CONCLUSIONS: Minimally invasive colorectal resection for benign pathology is associated with persistent proangiogenic plasma alterations similar to those found in patients who have cancer. Surgical trauma and not the indication is the likely cause. PMID- 24807601 TI - Anal condyloma treatment and recurrence in HIV-negative men who have sex with men. AB - BACKGROUND: Men who have sex with men have increased prevalence of both human papillomavirus and anogenital condyloma. OBJECTIVE: Risk factors for multiple treatment and recurrence of anal condyloma were examined. DESIGN: This is a retrospective study of HIV-negative men who have sex with men who were treated for anal condyloma. SETTINGS: This study was conducted in a private surgical practice. PATIENTS: The patients were HIV-negative men who have sex with men, aged 18 years or older. INTERVENTION(S): Ablation with electrocautery or CO2 laser was performed, as well as excision and topical imiquimod condyloma treatment adjuvant. MAIN OUTCOME MEASURES: Primary clearance, defined as 4 months of condyloma-free survival posttreatment, and recurrence, defined as any anal condyloma diagnosis after primary clearance. RESULTS: Of 231 participants, 207 achieved primary clearance (median age, 32.0 years) and were followed (median, 18.2 months) after primary treatment. Most had intra-anal and perianal condyloma (56%), were treated with electrocautery ablation (79.2%), and required 1 treatment (range, 1-6) for clearance. There were 57 recurrences (median, 12 months). One-third each had minimal, moderate, or extensive disease. Forty-six percent of patients received imiquimod posttreatment adjuvant. High-grade dysplasia was found in 31% at presentation and 43% during follow-up. Factors associated with requiring multiple treatments for clearance were participants having moderate disease (adjusted odds ratio, 6.0 (1.7-21.4)) and receiving imiquimod adjuvant (adjusted odds ratio, 4.7 (2.0-10.6)). No single factor predicted recurrence, but those with moderate disease experienced recurrences significantly sooner (median, 25 months of follow-up). LIMITATIONS: This was a retrospective chart review, it was limited to a single practice, and it excluded those who did not achieve primary clearance. CONCLUSIONS: Most men who have sex with men have intra-anal and perianal condyloma and concomitant high-grade dysplasia is common. Most achieved clearance with 1 treatment. Having both intra anal and perianal condyloma, increased severity of disease, and imiquimod adjuvant were significant predictors of requiring multiple treatments for clearance. No identified risk factors proved a significant predictor of recurrence. PMID- 24807600 TI - Management and outcome of perianal Paget's disease: a 6-decade institutional experience. AB - BACKGROUND: Perianal Paget's disease (intraepithelial adenocarcinoma) is rare and sometimes difficult to diagnose because symptoms are nonspecific. It is often noninvasive but frequently recurs locally. Invasive disease can metastasize to distant sites. OBJECTIVE: The purpose of this work was to review the diagnosis, management, and outcomes of patients with perianal Paget's disease. DESIGN: Institutional databases were queried for all of the cases of perianal Paget's disease at Memorial Sloan-Kettering Cancer Center between 1950 and 2011. Clinicopathologic factors were investigated for association with recurrence and survival. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sixty-five patients with perianal Paget's disease were included in the study (35 women [54%]; median age at diagnosis, 66 years [range, 60-72 years]; and 41 with invasive disease/24 with noninvasive disease). A total of 56% with invasive disease were men. MAIN OUTCOME MEASURES: Measures included median follow-up, disease status, local and distant recurrence, sites of recurrence, disease specific survival, overall survival, and treatment modality. RESULTS: A total of 95% with invasive disease and 87% with noninvasive disease were symptomatic at presentation. The most common symptoms were pruritus and perianal bleeding. The duration of symptoms was longer in patients with invasive (12.0 months; range, 4.0-18.0 months) versus noninvasive (3.5 months; range, 1.0-10.0 months) disease. Synchronous malignancies unrelated to the primary disease were noted in 5 patients with invasive disease and 3 with noninvasive disease. Noninvasive disease was treated with a wide local excision and invasive disease with a wide local excision (n = 32, 78%) or abdominoperineal resection (n = 9, 22%). Forty one patients (27 invasive and 14 noninvasive) required multiple operations for tumor clearance. In those with invasive disease, the median time to recurrence was 5 years, and the median tumor-specific survival rate was 10 years. LIMITATIONS: This was a retrospective study, limited by selection bias. CONCLUSIONS: Perianal Paget's disease is associated with nonspecific symptoms, frequently delaying diagnosis. Wide local excision is the treatment of choice if negative margins can be obtained. Abdominoperineal resection should be considered for invasive disease. Local recurrence is common; follow-up includes periodic proctoscopy and digital examination. Invasive disease can metastasize to distant sites; follow-up should include the examination of inguinal lymph nodes and the imaging of liver and lungs. PMID- 24807602 TI - Hidradenitis suppurativa: MRI features in anogenital disease. AB - BACKGROUND: Hidradenitis suppurativa is a rare chronic inflammatory disorder of apocrine gland-bearing skin, which commonly affects the anogenital region. There has been very little literature to date on the MRI appearances of anogenital hidradenitis suppurativa. OBJECTIVE: The aim of this study was to assess the MRI features of anogenital hidradenitis suppurativa in the largest cohort of patients to be published to date. DESIGN: After an institutional review board waiver, patients with hidradenitis suppurativa who were undergoing MRI for anogenital disease between 2005 and 2012 were identified from our institutional database. The MRI appearances were recorded by 2 radiologists in consensus, blinded to clinical details. Location of disease, number of tracts, presence of anal fistula, and supralevator involvement were recorded. Patient demographics were also noted. SETTINGS: This study was conducted at the Department of Radiology, Guy's and St Thomas' National Health Service Foundation Trust. PATIENTS: Patients included were those undergoing MRI for anogenital disease in hidradenitis suppurativa between 2005 and 2012. MAIN OUTCOME MEASURES: The distribution of sinus tracts in anogenital hidradenitis suppurativa on MRI was measured. RESULTS: Thirty-one MRIs were performed in 18 patients (15 men; mean age, 46 years). On the baseline MRI, multiple tracts were seen in the natal cleft (16/18; 83%), the perianal (12/18; 61%), the perineal (13/18; 56%), and the gluteal (8/18; 44%) regions. A communication with the anal canal was present in only 4 patients. Three patients had supralevator extension. Seven patients had follow-up MRIs with variable response to interval treatment: 3 of 7 showed responding disease, 3 of 7 showed stable disease, and 1 of 7 showed progressive disease. LIMITATIONS: This study was limited by its relatively small cohort of patients. CONCLUSIONS: In hidradenitis suppurativa, anogenital disease is usually subcutaneous but extensive, with only a minority of patients demonstrating deeper involvement. MRI may help define the extent of anogenital disease and assess response to treatment. PMID- 24807603 TI - Predictive factors for successful sacral nerve stimulation in the treatment of fecal incontinence: lessons from a comprehensive treatment assessment. AB - BACKGROUND: Sacral nerve stimulation has a place in the treatment algorithm for fecal incontinence, but the predictive factors of its midterm and long-term success are unknown. OBJECTIVE: The purpose of this study was to investigate the effect of a 3-year sacral nerve stimulation treatment of fecal continence and to identify specific predictive factors from the pretreatment and per-treatment assessments for the midterm success of sacral nerve stimulation. DESIGN: A cohort analysis of consecutive patients treated with sacral nerve stimulation for fecal incontinence over a period of 3 years was performed. SETTINGS: This study was conducted at an academic colorectal unit in a tertiary care center. PATIENTS: Sixty patients were available for the assessment of 3-year outcomes. MAIN OUTCOME MEASURES: Clinical outcome (including Cleveland Clinic score) and anorectal physiological data were collected prospectively before and after treatment. RESULTS: At the 3-year follow-up, 33 of the 60 implanted patients had an improved outcome as defined by a >=30% improvement in the Cleveland Clinic score from baseline (37.1% on intention to treat and 55.0% per protocol), whereas 22 had an unsuccessful outcome as defined by a <30% improvement in the Cleveland Clinic score from baseline (24.7% on intention to treat and 36.7% per protocol), of whom 7 had their device explanted or switched off permanently before the 3-year assessment, and 3 were lost at follow-up. At 3 years, we failed to identify any factors that could predict the 3-year clinical outcome of sacral nerve stimulation based on preimplantation and postimplantation assessments. LIMITATIONS: This study involved a relatively small number of patients. There was a lack of consistency in the tool used to evaluate the efficacy of the test and permanent stimulations. CONCLUSIONS: Based on per-protocol assessments, 55% of the patients had improved outcomes at the 3-year follow-up. No predictor was identified by the pretreatment and posttreatment assessments (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A133). PMID- 24807604 TI - A concomitant treatment by CO2-releasing suppositories improves the results of anorectal biofeedback training in patients with dyschezia: results of a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Dyschezia is a defecatory disorder that places a heavy burden on a patient's quality of life. Biofeedback is the recommended treatment in most cases. OBJECTIVE: The objective of our study was to test whether a CO2-releasing suppository for patients with dyschezia could be effective in improving biofeedback training results. DESIGN: A randomized, double-blind, multicenter, placebo-controlled study was conducted in patients (18-75 years of age) with dyschezia defined according to the modified Rome III criteria. Patients were randomly assigned to either a CO2-releasing suppository or placebo suppository once per day for 21 days. SETTINGS: This was a multicenter trial. PATIENTS: A total of 122 patients were randomly assigned (62 intervention group and 60 placebo group). MAIN OUTCOME MEASURES: The primary end point was the change from day 0 to day 21 in intensity of symptoms on the basis of a self-assessed dyschezia using a visual analog scale (range, 0-100). Analyses were performed using intention-to-treat principles. RESULTS: A greater reduction from baseline to day 21 in symptom visual analog scale score was observed in the intervention group (-41.3 mm) than in the control group (-22.3 mm). Some secondary efficacy parameters improved more in the intervention group, including the percentage of patients who improved >=50%, symptom intensity over 21 days, stool stains on underwear or pads, and need to practice manual maneuvers to facilitate defecation at day 21. At day 21, rectal sensitivity in the intervention group (31.4 mL) was lower than in the control group (39.1 mL). LIMITATIONS: There was a lower number of patients recruited than planned by the protocol. The sponsor stopped the trial before the inclusion of 306 participants, with no intermediate analysis. In addition, the main analysis conducted on the full analysis set population could have led to a statistical bias. CONCLUSIONS: The results of this multicenter trial demonstrate the added benefits of a CO2-releasing suppository in patients with dyschezia who were treated by anorectal biofeedback training. PMID- 24807605 TI - Multiparametric MRI of rectal cancer in the assessment of response to therapy: a systematic review. AB - BACKGROUND: Conventional MRI is limited in the assessment of nodal status and T status after neoadjuvant chemoradiotherapy. Multiparametric MRI strives to overcome these issues by directly measuring the local microcirculation and cellular environment, thus possibly allowing for a more reliable evaluation of response to therapy. OBJECTIVE: We assessed the available literature for the value of multiparametric MRI sequences (diffusion-weighted and dynamic contrast enhanced imaging) in determining the response to neoadjuvant chemoradiotherapy in patients with rectal cancer. DATA SOURCES: We conducted a systematic literature research in the PubMed database. STUDY SELECTION: English-language publications of the years 2000-2013 that applied multiparametric MRI in the neoadjuvant setting were included in this study. INTERVENTION: Patients received neoadjuvant chemoradiotherapy and MRI examinations for staging and assessment of response. MAIN OUTCOME MEASURES: Accuracy, specificity, and sensitivity of MRI in prediction/assessment of response to therapy were the included measures. RESULTS: Forty-three studies were included in this review; 30 of them included diffusion weighted imaging sequences, and 13 included dynamic contrast-enhanced MRI. Conventional MRI is limited in the accuracy of both T and N stages and response assessment. Diffusion-weighted imaging and dynamic contrast-enhanced MRIs showed additional value in both the prediction and detection of (complete) response to therapy compared with conventional sequences alone, as well as in correct N staging along with new experimental contrast agents. LIMITATIONS: The lack of standardization represents an important technical limitation. Most studies are conducted in an experimental setting; therefore, larger multicenter prospective studies are needed to verify the present findings. CONCLUSIONS: Advanced, functional MRI techniques allow for the quantification of tumor biological processes, such as microcirculation, vascular permeability, and tissue cellularity. This new technology has begun to show potential advantages over standard morphologic imaging in the restaging of rectal cancer, allowing for more accurate prognostication of response and potentially introducing an era allowing earlier treatment alteration and more accurate noninvasive surveillance, which could improve patient outcomes. PMID- 24807606 TI - Laparoscopic total colectomy with brooke ileostomy for chronic ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis. PMID- 24807607 TI - Indication for the surgical management of parastomal hernias. PMID- 24807608 TI - Indication for the surgical management of parastomal hernias. PMID- 24807610 TI - Local excision of rectal cancer after chemoradiation. PMID- 24807611 TI - The authors reply. PMID- 24807612 TI - Should gum chewing be included in enhanced recovery after surgery programs for colorectal surgery? PMID- 24807613 TI - The author replies. PMID- 24807616 TI - Influence of dietary docosahexaenoic acid in combination with other long-chain polyunsaturated fatty acids on expression of biosynthesis genes and phospholipid fatty acid compositions in tissues of post-smolt Atlantic salmon (Salmo salar). AB - To investigate interactions of dietary LC-PUFA, a dose-response study with a range of docosahexaenoic acid (DHA; 22:6n-3) levels (1 g kg(-1), 5 g kg(-1), 10 g kg(-1), 15 g kg(-1) and 20 g kg(-1)) was performed with post-smolts (111 +/- 2.6g; mean +/- S.D.) over a nine-week feeding period. Additional diets included 10 g kg(-1) DHA in combination with 10 g kg(-1) of either eicosapentaenoic acid (EPA; 20:5n-3) or arachidonic acid (ARA; 20:4n-6), and a diet containing 5 g kg( 1) each of DHA and EPA. The liver, brain, head kidney and gill were collected at the conclusion of the trial, and lipid and fatty acid compositions were determined as well as expression of genes of LC-PUFA biosynthesis. Total lipid content and class composition were largely unaffected by changes in dietary LC PUFA. However, phospholipid (PL) fatty acid compositions generally reflected that of the diet, although the response varied between tissues. The liver most strongly reflected diet, followed by the head kidney. In both tissues increasing dietary DHA led to significantly increased DHA in PL and inclusion of EPA or ARA led to higher levels of these fatty acids. The brain showed the most conserved composition and gene expression profile, with increased dietary LC-PUFA resulting in only minor changes in PL fatty acids. Dietary LC-PUFA significantly affected the expression of Delta6 and Delta5 desaturases, Elovl 2, 4 and 5, and SREBPs although this varied between tissues with greatest effects observed in the liver followed by the head kidney, similar to PL fatty acid compositions. PMID- 24807617 TI - Fatty acids as tracers of trophic interactions between seston, mussels and biodeposits in a coastal embayment of mussel rafts in the proximity of fish cages. AB - We traced the food sources of mussel Mytilus galloprovincialis cultured in suspension in Ria Ares-Betanzos (N.W. Spain) by means of fatty acid (FA) biomarkers. The FA profile of seston, mussels' mantle, digestive gland and feces was analyzed during five seasons. Due to the proximity of a fish farm to the bivalve aquaculture site, we also tested if mussels and seston situated 170 m distant from the fish cages incorporated fish feed FA markers compared with samples obtained 550 m away. The principal FA in the mussels' organs were 16:0, 16:1omega7, EPA (20:5omega3) and DHA (22:6omega3), while 16:0 predominated in the feces. Seasonal fluctuations in the seston composition were mirrored in the FA signature of mussels' organs and feces, although the digestive gland had the closest resemblance to the seston FA profile. In general, diatom and bacteria derived-biomarkers predominated in mussels' organs and feces during the upwelling period (spring-summer), while dinoflagellates were the dominant dietary source during downwelling (autumn-winter). The higher concentration of EPA and DHA in both organs and the feces compared with the seston suggested a preferential accumulation of these omega3 FA in the mussels' tissues. The results showed a lack of assimilation of fish feed FA biomarkers in the seston and mussel samples. This might be due to the dispersion of uneaten feed particles by high current velocity, substantial distance between the fish and mussel culture, the limited amount of nutrient waste released by the fish farm and dilution of feed particles in the large mussel standing stock. PMID- 24807619 TI - Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma. AB - IMPORTANCE: Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine derived skin cancer with high rates of recurrence and associated mortality. Few published studies have used comprehensive patient data and long-term follow-up to examine factors that predict MCC outcomes. OBJECTIVE: To characterize MCC in a large defined-population cohort and analyze predictors of disease recurrence and survival. SETTING, DESIGN, AND PARTICIPANTS: Retrospective cohort study of 218 patients with MCC from the cancer registry of Kaiser Permanente Northern California, a large integrated health care delivery system. Patients were diagnosed as having MCC and followed up from January 1, 1995, through December 31, 2009. We examined host (age, sex, race, and immunosuppression), tumor (anatomic site, size, and extent), diagnostic (results of imaging and pathologic nodal evaluation), and treatment (surgery, radiation therapy, and chemotherapy) variables for their association with MCC outcomes. EXPOSURE: Host, tumor, diagnostic, and treatment factors. MAIN OUTCOMES AND MEASURES: Recurrence (locoregional and distant) of MCC and patient survival (overall and MCC specific). RESULTS: We estimated adjusted hazard ratios (AHRs) and 95% CIs for outcomes using Cox proportional hazards regression models. After adjustment for host, tumor, diagnostic, and treatment variables, tumor extent (categorized as local, regional, and distant) remained significantly associated with all outcomes. Immunosuppression was associated with higher MCC-specific mortality (AHR, 4.9 [95% CI, 1.7-14.4]), and an unknown primary site was associated with a lower risk for distant metastasis (0.1 [0.0-0.7]) and improved survival (0.4 [0.2 0.9]). Pathological nodal evaluation was associated with a lower risk for metastasis (AHR, 0.2 [95% CI, 0.0-1.0]) and improved survival. Radiation treatment was associated with a decreased risk for locoregional recurrence (AHR, 0.3 [95% CI, 0.1-0.6]), whereas chemotherapy was not associated with any alteration in outcomes. CONCLUSIONS AND RELEVANCE: Tumor site and extent, results of pathologic nodal evaluation, and the presence of radiation treatment were associated with MCC recurrence. Immunosuppression, tumor extent, and results of pathologic nodal evaluation were associated with MCC-specific survival, whereas chemotherapy was not associated with any outcomes. Our findings may help to inform diagnostic and therapeutic management of MCCs. PMID- 24807620 TI - The tobacco genome sequence and its comparison with those of tomato and potato. AB - The allotetraploid plant Nicotiana tabacum (common tobacco) is a major crop species and a model organism, for which only very fragmented genomic sequences are currently available. Here we report high-quality draft genomes for three main tobacco varieties. These genomes show both the low divergence of tobacco from its ancestors and microsynteny with other Solanaceae species. We identify over 90,000 gene models and determine the ancestral origin of tobacco mosaic virus and potyvirus disease resistance in tobacco. We anticipate that the draft genomes will strengthen the use of N. tabacum as a versatile model organism for functional genomics and biotechnology applications. PMID- 24807621 TI - Applying label-free quantitation to top down proteomics. AB - With the prospect of resolving whole protein molecules into their myriad proteoforms on a proteomic scale, the question of their quantitative analysis in discovery mode comes to the fore. Here, we demonstrate a robust pipeline for the identification and stringent scoring of abundance changes of whole protein forms <30 kDa in a complex system. The input is ~100-400 MUg of total protein for each biological replicate, and the outputs are graphical displays depicting statistical confidence metrics for each proteoform (i.e., a volcano plot and representations of the technical and biological variation). A key part of the pipeline is the hierarchical linear model that is tailored to the original design of the study. Here, we apply this new pipeline to measure the proteoform-level effects of deleting a histone deacetylase (rpd3) in S. cerevisiae. Over 100 proteoform changes were detected above a 5% false positive threshold in WT vs the Deltarpd3 mutant, including the validating observation of hyperacetylation of histone H4 and both H2B isoforms. Ultimately, this approach to label-free top down proteomics in discovery mode is a critical technical advance for testing the hypothesis that whole proteoforms can link more tightly to complex phenotypes in cell and disease biology than do peptides created in shotgun proteomics. PMID- 24807622 TI - Two-position supine/prone myocardial perfusion SPECT (MPS) imaging improves visual inter-observer correlation and agreement. AB - OBJECTIVES: We aimed to compare the inter-observer agreement between two experienced readers using supine vs combined supine/prone myocardial perfusion SPECT (MPS) in a large population. METHODS: 1,181 consecutive patients without known coronary artery disease (CAD) undergoing rest (201)Tl/stress (99m)Tc sestamibi MPS studies were evaluated. Visual reads were performed in two consecutive steps, with readers scoring the stress supine perfusion images during step 1 and rescoring the images using both supine/prone data during step 2. Visual summed stress scores (SSS) of two readers including regional scores in different vascular territories were compared. RESULTS: The specificity for both readers improved using combined supine/prone imaging (reader 1: 92% vs 86% [P = .0002], reader 2: 88% vs 72% [P < .0001]). The inter-observer correlation for SSS (0.90 vs 0.84, P < .0001) and inter-observer agreement for combined supine/prone reading (bias = 1.0, 95% confidence interval (CI) 0.9-1.2 vs bias = 3.1, 95% CI 2.8-3.4, P < .0001) were significantly better as compared to supine-only reading. The overall correlation between SSS scores for two readers improved with supine/prone imaging for both genders, as well as in the left anterior descending and right coronary territories. CONCLUSION: The inter-observer correlation and agreement significantly improve using two-position supine/prone vs supine-only imaging. PMID- 24807623 TI - Importance of correct patient positioning in myocardial perfusion SPECT when using a CZT camera. AB - INTRODUCTION: Myocardial perfusion single photon emission computed tomography (MPS) is one of the most widely used diagnostic methods in patients with suspected ischemic heart disease (IHD). Recently, a novel technique based on cadmium-zinc-telluride (CZT) detectors, pinhole collimators, and a stationary gantry was introduced for MPS. The aim of this work was to investigate how patient positioning affects the reconstructed MPS images using this novel technique. MATERIALS AND METHODS: Eighteen patients referred for a clinical MPS due to suspected IHD were included in the study. All patients underwent MPS imaging on a GE Discovery NM 530c CZT camera. After image acquisition with the heart positioned in the center of the quality field of view (QFOV), the patients were re-imaged in different positions 5-20 mm off-center. The heart was still positioned within the limits of the QFOV during the off-center scans. The summed stress score and/or the summed rest score (SSS and/or SRS) for the acquisition performed in the center was compared to the same parameter for the acquisitions performed off-center. RESULTS: There was a statistically significant increase in SSS and/or SRS when imaging was performed with the heart 5-20 mm outside the center of the QFOV compared to optimal positioning (7.7 +/- 1.3 vs 6.6 +/- 1.3, P = .006). The SSS and/or SRS increased with >=2 U in 35% (14/40) of the off-center examinations. CONCLUSION: It is important to carefully position the patient's heart within the center of the QFOV when performing MPS with the Discovery NM 530c CZT camera to avoid positioning-related image artifacts that could affect the diagnostic accuracy. PMID- 24807624 TI - Exploring N-acylhydrazone derivatives against clinical resistant bacterial strains. AB - Bacterial multiresistance is a health problem worldwide that demands new antimicrobials for treating bacterial-related infections. In this study, we evaluated the antimicrobial activity and the theoretical toxicology profile of N substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazide derivatives against gram-positive and gram-negative bacteria clinical strains. On that purpose we determined the minimum inhibitory (MIC) and bactericidal (MBC) concentrations, the in vitro cytotoxicity, and in silico risk profiles, also comparing with antimicrobial agents of clinical use. Among the 16 derivatives analyzed, four nitrofurans (N-H-FUR-NO(2), N-Br-FUR-NO(2), N-F-FUR-NO(2), N-Cl FUR-NO(2)) showed promising MIC and MBC values (MIC = MBC = 1-16 MUg/mL). The experimental data revealed the potential of these derivatives, which were comparable to the current antimicrobials with similar bactericidal and bacteriostatic profiles. Therefore, these molecules may be feasible options to be explored for treating infections caused by multiresistant strains. Our in vitro and in silico toxicity reinforced these results as these derivatives presented low cytotoxicity against human macrophages and low theoretical risk profile for irritant and reproductive effects compared to the current antimicrobials (e.g., vancomycin and ciprofloxacin). The molecular modeling analysis also revealed positive values for their theoretical druglikeness and drugscore. The presence of a 5-nitro-2-furfur-2-yl group seems to be essential for the antimicrobial activity, which pointed these acylhydrazone derivatives as promising for designing more potent and safer compounds. PMID- 24807625 TI - Comparative diversity analysis of gut microbiota in two different human flora associated mouse strains. AB - The Kunming (KM) mouse is a closed colony mouse strain widely used in Chinese pharmacology, toxicology, and microbiology research laboratories. However, few studies have examined human flora-associated (HFA) microbial communities in KM mice. In this study, HFA models were built from germ-free KM and C57BL/6J mouse strains, and gut microbial diversity was analyzed by denaturing gradient gel electrophoresis (DGGE) and DNA sequencing. We found that the two strains of HFA mice were significantly different based on the UPGMA dendrogram and the Richness index, but dice similarity coefficients of mouse replicates were not significantly different between HFA-KM and HFA-C57BL/6J. Most of the dominant phyla of human gut microflora could be transferred into the guts of the two mouse strains. However, the predominant genus that formed in HFA-KM was Clostridium sp. and that in HFA-C57BL/6J was Blautia sp. These results imply that genotypes difference between the two mice strains is a critical factor in shaping the intestinal microflora. However, genetic differences of individuals within KM mouse populations failed to lead to individual difference in microflora. Successful generation of HFA-KM mice will facilitate studies examining how diet affects gut microbial structure, and will enable comparative studies for uncovering genetic factors that shape gut microbial communities. PMID- 24807626 TI - Potential application in mercury bioremediation of a marine sponge-isolated Bacillus cereus strain Pj1. AB - Sponges are sessile marine invertebrates that can live for many years in the same location, and therefore, they have the capability to accumulate anthropogenic pollutants such as metals over a long period. Almost all marine sponges harbor a large number of microorganisms within their tissues. The Bacillus cereus strain Pj1 was isolated from a marine sponge, Polymastia janeirensis, and was found to be resistant to 100 MUM HgCl(2) and to 10 MUM methylmercury (MeHg). Pj1 was also highly resistant to other metals, including CdCl(2) and Pb(NO(3))(2), alone or in combination. The mer operon was located on the bacterial chromosome, and the volatilization test indicated that the B. cereus Pj1 was able to reduce Hg(2+) Hg(0). Cold vapor atomic absorption spectrometry demonstrated that Pj1 volatilized 80 % of the total MeHg that it was exposed to and produced elemental Hg when incubated with 1.5 MUM MeHg. Pj1 also demonstrated sensitivity to all antibiotics tested. In addition, Pj1 demonstrated a potential for biosurfactant production, presenting an emulsification activity better than synthetic surfactants. The results of this study indicate that B. cereus Pj1 is a strain that can potentially be applied in the bioremediation of HgCl(2) and MeHg contamination in aquatic environments. PMID- 24807627 TI - Once-weekly teriparatide administration for 24 weeks in postmenopausal women with osteoporosis: reply to T. Kawada. PMID- 24807628 TI - The effect of exercise and education on fear of falling in elderly women with osteoporosis and a history of vertebral fracture: results of a randomized controlled trial. AB - This article explores the effect of a group-based exercise program and an educational session on the fear of falling among 89 women with osteoporosis and a history of vertebral fracture. This randomized clinical trial showed that the intervention had a positive and durable effect on the fear of falling. INTRODUCTION: The aim of this study was to evaluate the effect of an intervention on fear of falling in women with osteoporosis and a history of vertebral fracture. METHODS: The study was a parallel-group randomized clinical trial with a blinded assessor. The participants were 89 community-dwelling elderly women with osteoporosis and a history of vertebral fracture. The intervention group (IT, n = 47) received a 3-month group-based circuit exercise program combined with a 3-h educational session focusing on the reduction of the risk of falls and challenges specific to osteoporosis and vertebral fractures. The control group (CT, n = 42) continued with their usual activities. Clinical outcomes were assessed at baseline, postintervention and 12 months after randomization. This article reports on the secondary outcome Falls Efficacy Scale-International (FES I) from a previously reported trial. RESULTS: We found a significantly better result for the IT group compared with the CT group, both at 3 months (p = 0.004) and 12 months (p < 0.001) follow-up. The effect size at 3 months was small (0.4) and at 12 months moderate (0.7). Multiple regression analysis confirmed the effect of the intervention. CONCLUSION: The intervention had a positive and durable effect on fear of falling as measured with the FES-I. PMID- 24807629 TI - A comparative study of Sr-incorporated mesoporous bioactive glass scaffolds for regeneration of osteopenic bone defects. AB - Recently, the use of the pharmacological agent strontium ranelate has come to prominence for the treatment of osteoporosis. While much investigation is focused on preventing disease progression, here we fabricate strontium-containing scaffolds and show that they enhance bone defect healing in the femurs of rats induced by ovariectomy. INTRODUCTION: Recently, the use of the pharmacological agent strontium ranelate has come to prominence for the treatment of osteoporosis due to its ability to prevent bone loss in osteoporotic patients. Although much emphasis has been placed on using pharmacological agents for the prevention of disease, much less attention has been placed on the construction of biomaterials following osteoporotic-related fracture. The aim of the present study was to incorporate bioactive strontium (Sr) trace element into mesoporous bioactive glass (MBG) scaffolds and to investigate their in vivo efficacy for bone defect healing in the femurs of rats induced by ovariectomy. METHODS: In total, 30 animals were divided into five groups as follows: (1) empty defect (control), (2) empty defects with estrogen replacement therapy, (3) defects filled with MBG scaffolds alone, (4) defects filled with MBG + estrogen replacement therapy, and (5) defects filled with strontium-incorporated mesopore-bioglass (Sr-MBG) scaffolds. RESULTS: The two groups demonstrating the highest levels of new bone formation were the defects treated with MBG + estrogen replacement therapy and the defects receiving Sr-MBG scaffolds as assessed by MU-CT and histological analysis. Furthermore, Sr scaffolds had a reduced number of tartrate-resistant acid phosphatase-positive cells when compared to other modalities. CONCLUSION: The results from the present study demonstrate that the local release of Sr from bone scaffolds may improve fracture repair. Future large animal models are necessary to investigate the future relationship of Sr incorporation into biomaterials. PMID- 24807630 TI - Rice fortification with zinc during parboiling may improve the adequacy of zinc intakes in Bangladesh. AB - BACKGROUND: Zinc deficiency is prevalent among children and women in Bangladesh and parboiled rice is the major staple food consumed. Parboiling offers an opportunity to increase the zinc and iron content of rice by adding fortificants to the soaking water. RESULTS: Rice zinc content increased with increasing amounts of zinc sulfate added to the parboil soaking water. Addition of 1300 mg zinc L(-1) increased raw polished rice zinc content from 16.6 to 44.9 mg kg(-1) and from 12.6 to 32.9 mg kg(-1) in the open and closed parboiling systems, equivalent to 170% and 161% increases, respectively. Retention of zinc after washing and cooking was 70-81% across all concentrations tested. Addition of iron ethylenediaminetetraacetic acid and zinc sulfate together increased zinc, but not iron, content of polished rice. The simulated prevalence of inadequate zinc intake was reduced by more than half among children and nearly two-thirds among women if 50% of the population were to consume the 1300 mg zinc L(-1) parboiled fortified rice. CONCLUSION: Addition of zinc sulfate to soaking water during parboiling increases the zinc content of rice and, if found to be bioavailable, could substantially reduce the prevalence of inadequate zinc intake by children and women in Bangladesh. PMID- 24807631 TI - Clusterin expression in gastrointestinal neuroendocrine tumours is highly correlated with location and is helpful in determining the origin of liver metastases. AB - AIMS: Clusterin (CLU) is a sulphated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. We have previously demonstrated that CLU is highly expressed in pancreatic neuroendocrine tumours (NETs). The aims of this study were: to investigate CLU expression in gastrointestinal NETs; the potential correlation between this expression and different clinicopathological parameters; and its usefulness in the differential diagnosis of liver metastases. METHODS AND RESULTS: Immunohistochemistry using an anti-CLU antibody was performed on paraffin sections from 108 primary NETs [G3 (13 cases), G2 (18 cases), and G1 (77 cases), according to the 2010 WHO classification] and 60 metastases. Cytoplasmic positivity was scored qualitatively and quantitatively. The pattern of staining was also assessed. Two step statistical analyses (univariate and multivariate logistic regression) were performed. More than 90% of small-intestine NETs were completely negative. The probability of obtaining a positive CLU score was higher for the appendix, the stomach, the duodenum and the rectum than for the small intestine and colon. All G3 NETs and most G2 NETs were negative as compared with G1. CLU expression in the metastatic foci was identical to that of the primary tumour. CONCLUSIONS: Clusterin expression in gastrointestinal NETs is highly correlated with location and probably also with grading, in both the primary tumour and metastases. Underexpression of CLU in small-intestine NETs is helpful for identifying the origin of liver metastases: a strong CLU score in a liver biopsy makes the small intestine highly unlikely as a primary site. PMID- 24807632 TI - Ocular surface squamous neoplasia: terminology that is conceptually friendly but clinically perilous. PMID- 24807633 TI - Exclusion of impurity particles in charged colloidal crystals. AB - Uniformly shaped, charged colloidal particles dispersed in water form ordered "crystal" structures when the interaction between the particles is sufficiently strong. Herein, we report the behavior of "impurity" particles, whose sizes and/or charge numbers are different from those of the bulk, on addition to the charged colloidal crystals. These impurities were excluded from the crystals during the homogeneous crystallization, crystal grain growth, and unidirectional crystallization processes. Such systems will be useful as models for studying the refinement of materials and crystal defects. PMID- 24807634 TI - Modeling the impedance response of mixed-conducting thin film electrodes. AB - In this paper a novel numerical impedance model is developed for mixed-conducting thin films working as electrodes for solid oxide fuel cells. The relative importance of interfaces is considered by incorporating double layer contributions at the film/gas boundary. Simulations are performed on a model system, namely doped ceria, in a symmetric cell configuration using geometrically well-defined patterned metal current collectors. Results reveal that experimentally consistent bulk impedances and surface capacitances can be extracted using the model. The impedance response depends strongly on the pattern spacing of the current collector, and is attributed to the electronic in-plane drift-diffusion as well as to the interplay between the surface reaction resistance and the electronic/ionic bulk drift-diffusion resistance. PMID- 24807635 TI - Comparison of dermatoscopic diagnostic algorithms based on calculation: The ABCD rule of dermatoscopy, the seven-point checklist, the three-point checklist and the CASH algorithm in dermatoscopic evaluation of melanocytic lesions. AB - Dermatoscopic analysis of melanocytic lesions using the CASH algorithm has rarely been described in the literature. The purpose of this study was to compare the sensitivity, specificity, and diagnostic accuracy rates of the ABCD rule of dermatoscopy, the seven-point checklist, the three-point checklist, and the CASH algorithm in the diagnosis and dermatoscopic evaluation of melanocytic lesions on the hairy skin. One hundred and fifteen melanocytic lesions of 115 patients were examined retrospectively using dermatoscopic images and compared with the histopathologic diagnosis. Four dermatoscopic algorithms were carried out for all lesions. The ABCD rule of dermatoscopy showed sensitivity of 91.6%, specificity of 60.4%, and diagnostic accuracy of 66.9%. The seven-point checklist showed sensitivity, specificity, and diagnostic accuracy of 87.5, 65.9, and 70.4%, respectively; the three-point checklist 79.1, 62.6, 66%; and the CASH algorithm 91.6, 64.8, and 70.4%, respectively. To our knowledge, this is the first study that compares the sensitivity, specificity and diagnostic accuracy of the ABCD rule of dermatoscopy, the three-point checklist, the seven-point checklist, and the CASH algorithm for the diagnosis of melanocytic lesions on the hairy skin. In our study, the ABCD rule of dermatoscopy and the CASH algorithm showed the highest sensitivity for the diagnosis of melanoma. PMID- 24807638 TI - The expression of succinate dehydrogenase in breast phyllodes tumor. AB - The purpose of this study is to investigate the expression of succinate dehydrogenase (SDH)A, SDHB, and HIF-1alpha in phyllodes tumors and the association with clinic-pathologic factors. Using tissue microarray (TMA) for 206 phyllodes tumor cases, we performed immunohistochemical stains for SDHA, SDHB, and HIF-1alpha and analyzed their expression in regard to clinicopathologic parameters of each case. The cases were comprised of 156 benign, 34 borderline, and 16 malignant phyllodes tumors. The expression of stromal SDHA and epithelial- and stromal- SDHB increased as the tumor progressed from benign to malignant (P?0.001). There were five stromal SDHA-negative cases and 31 stromal SDHB negative cases. SDHB negativity was associated with a lower histologic grade (P=0.054) and lower stromal atypia (P=0.048). Univariate analysis revealed that a shorter disease free survival (DFS) was associated with stromal SDHB high positivity (P=0.013) and a shorter overall survival (OS) was associated with high positivity of stromal SDHA and SDHB (P?0.001 and P?0.001, respectively). The multivariate Cox analysis with the variables stromal cellularity, stromal atypia, stromal mitosis, stromal overgrowth, tumor margin, stromal SDHA expression, and stromal SDHB expression revealed that stromal overgrowth was associated with a shorter DFS (hazard ratio: 24.78, 95% CI: 3.126-196.5, P=0.002) and a shorter OS (hazard ratio: 176.7, 95% CI: 8.466-3691, P=0.001). In conclusion, Tumor grade is positively correlated with SDHA and SDHB expression in the tumor stroma in phyllodes tumors of the breast. This result may be attributed to the increased metabolic demand in high grade tumors. PMID- 24807637 TI - IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses. AB - BACKGROUND: Interleukin-21 (IL-21) has been implicated in the development of Th2 mediated immune responses; however, the exact role it plays in allergic diseases is not well understood. OBJECTIVE: To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung. METHODS: We compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM). RESULTS: We demonstrate that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics. CONCLUSION: These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production. PMID- 24807640 TI - Prevention strategies for cytomegalovirus disease and long-term outcomes in the high-risk transplant patient (D+/R-): experience from the RESITRA-REIPI cohort. AB - BACKGROUND: Cytomegalovirus (CMV)-negative recipients of a graft from a CMV positive donor (D+/R-) are at high risk of CMV disease. Current preventive strategies include universal prophylaxis (UP) and preemptive therapy (PT). However, the best strategy to prevent CMV disease and achieve better long-term outcomes remains a matter of debate. METHODS: We analyzed the incidence of CMV disease and long-term outcomes including graft dysfunction and patient mortality at 5 years after transplantation with both preventive strategies. High-risk (D+/R ) kidney and liver transplant recipients from the RESITRA cohort were included. RESULTS: Of 2410 kidney or liver transplant patients, 195 (8.3%) were D+/R-. The final cohort included 58 liver and 102 kidney recipients. UP was given in 92 patients and 68 received PT; 10.9% and 36.8% developed CMV disease, respectively (P < 0.01). The independent risk factors for CMV disease were PT strategy (hazard ratio [HR], 3.30; 95% confidence interval [CI], 1.6-6.9), kidney transplantation (HR, 3.8; 95% CI, 1.4-9.9), and cyclosporine immunosuppression (HR, 2.4; 95% CI, 1.2-4.7). PT strategy was also a risk factor for CMV disease in both liver transplantation (HR, 11.0; 95% CI, 1.2-98.7) and kidney transplantation (HR, 2.7; 95% CI, 1.3-6.0), independently. The development of CMV replication during the first 2 years after transplantation was a risk factor for graft dysfunction at 5 years after transplantation (odds ratio, 3.4; 95% CI, 1.3-9.0). Nevertheless, no significant differences were seen in either graft dysfunction or mortality between the 2 strategies. CONCLUSIONS: The study supports the benefit of the UP strategy to prevent CMV disease in D+/R- liver or kidney transplant patients. The development of CMV replication during the first 2 years after transplantation was associated with graft dysfunction at 5 years after transplantation. PMID- 24807641 TI - Eggs: the uncracked potential for improving maternal and young child nutrition among the world's poor. AB - Eggs have been consumed throughout human history, though the full potential of this nutritionally complete food has yet to be realized in many resource-poor settings around the world. Eggs provide essential fatty acids, proteins, choline, vitamins A and B12 , selenium, and other critical nutrients at levels above or comparable to those found in other animal-source foods, but they are relatively more affordable. Cultural beliefs about the digestibility and cleanliness of eggs, as well as environmental concerns arising from hygiene practices and toxin exposures, remain as barriers to widespread egg consumption. There is also regional variability in egg intake levels. In Latin American countries, on average, greater proportions of young children consume eggs than in Asian or African countries. In China and Indonesia, nutrition education and social marketing have been associated with greater amounts of eggs in the diets of young children, though generally, evidence from interventions is minimal. Homestead chicken-and-egg production with appropriate vaccination, extension service, and other supports can simultaneously address poverty and nutrition in very poor rural households. With undernutrition remaining a significant problem in many parts of the world, eggs may be an uncracked part of the solution. PMID- 24807636 TI - Diabetic foot and exercise therapy: step by step the role of rigid posture and biomechanics treatment. AB - Lower extremity ulcers represent a serious and costly complication of diabetes mellitus. Many factors contribute to the development of diabetic foot. Peripheral neuropathy and peripheral vascular disease are the main causes of foot ulceration and contribute in turn to the growth of additional risk factors such as limited joint mobility, muscular alterations and foot deformities. Moreover, a deficit of balance, posture and biomechanics can be present, in particular in patients at high risk for ulceration. The result of this process may be the development of a vicious cycle which leads to abnormal distribution of the foot's plantar pressures in static and dynamic postural conditions. This review shows that some of these risk factors significantly improve after a few weeks of exercise therapy (ET) intervention. Accordingly it has been suggested that ET can be an important weapon in the prevention of foot ulcer. The aim of ET can relate to one or more alterations typically found in diabetic patients, although greater attention should be paid to the evaluation and possible correction of body balance, rigid posture and biomechanics. Some of the most important limitations of ET are difficult access to therapy, patient compliance and the transitoriness of the results if the training stops. Many proposals have been made to overcome such limitations. In particular, it is important that specialized centers offer the opportunity to participate in ET and during the treatment the team should work to change the patient's lifestyle by improving the execution of appropriate daily physical activity. PMID- 24807642 TI - The ability of video image analysis to predict lean meat yield and EUROP score of lamb carcasses. AB - A total of 862 lamb carcasses that were evaluated by both the VIAscan(r) and the current EUROP classification system were deboned and the actual yield was measured. Models were derived for predicting lean meat yield of the legs (Leg%), loin (Loin%) and shoulder (Shldr%) using the best VIAscan(r) variables selected by stepwise regression analysis of a calibration data set (n=603). The equations were tested on validation data set (n=259). The results showed that the VIAscan(r) predicted lean meat yield in the leg, loin and shoulder with an R 2 of 0.60, 0.31 and 0.47, respectively, whereas the current EUROP system predicted lean yield with an R 2 of 0.57, 0.32 and 0.37, respectively, for the three carcass parts. The VIAscan(r) also predicted the EUROP score of the trial carcasses, using a model derived from an earlier trial. The EUROP classification from VIAscan(r) and the current system were compared for their ability to explain the variation in lean yield of the whole carcass (LMY%) and trimmed fat (FAT%). The predicted EUROP scores from the VIAscan(r) explained 36% of the variation in LMY% and 60% of the variation in FAT%, compared with the current EUROP system that explained 49% and 72%, respectively. The EUROP classification obtained by the VIAscan(r) was tested against a panel of three expert classifiers (n=696). The VIAscan(r) classification agreed with 82% of conformation and 73% of the fat classes assigned by a panel of expert classifiers. It was concluded that VIAscan(r) provides a technology that can directly predict LMY% of lamb carcasses with more accuracy than the current EUROP classification system. The VIAscan(r) is also capable of classifying lamb carcasses into EUROP classes with an accuracy that fulfils minimum demands for the Icelandic sheep industry. Although the VIAscan(r) prediction of the Loin% is low, it is comparable to the current EUROP system, and should not hinder the adoption of the technology to estimate the yield of Icelandic lambs as it delivered a more accurate prediction for the Leg%, Shldr% and overall LMY% with negligible prediction bias. PMID- 24807644 TI - Do not turn out the lights on the public mental health system when the ACA is fully implemented. AB - When all of the insurance and health care reforms of the ACA are fully implemented, some public financing needs for behavioral health services will remain. This commentary outlines a number of the residual functions of the public mental health system in an ACA world, and it identifies opportunities for expansions of service areas not covered by traditional insurance or the health delivery reforms for behavioral health services within the scope of the ACA. PMID- 24807643 TI - Mental health problems and social resource factors among bullied children in the Nordic countries: a population based cross-sectional study. AB - This study estimated internalising and externalising mental health problems among bullied-, unclear if bullied- and not bullied children aged 4-16 in the Nordic countries, and identified resource factors to bullied children's mental health. Data comes from the cross-sectional NordChild survey 2011 and the Strength and Difficulties Questionnaire, including 6,214 children in the analyses. Mental health problems were most prevalent among children parent-reported as bullied (29.2-44.3 %), followed by children with unclear status if bullied (13.0-25.6 %) and not bullied children (5.3-7.9 %). Externalising problems were more prevalent in all groups except among bullied girls aged 7-16, where internalising problems were more prevalent. Ten potential resource factors to bullied children's mental health were analyzed, finding that (1) children with at least three close friends had higher odds to be mentally healthy than children with fewer close friends and (2) bullied boys had higher odds to be mentally healthy if they regularly practiced sport. PMID- 24807645 TI - Health care reform, behavioral health, and the criminal justice population. AB - The 2010 Patient Protection and Affordable Care Act (ACA) has a number of important features for individuals who are involved with the criminal justice system. Among the most important changes is the expansion of Medicaid to more adults. The current study estimates that 10% of the total Medicaid expansion could include individuals who have experienced recent incarceration. The ACA also emphasizes the importance of mental health and substance abuse benefits, potentially changing the landscape of behavioral health treatment providers willing to serve criminal justice populations. Finally, it seeks to promote coordinated care delivery. New care delivery and appropriate funding models are needed to address the behavioral health and other chronic conditions experienced by those in criminal justice and to coordinate care within the complex structure of the justice system itself. PMID- 24807646 TI - The Effects of Organizational Culture on Mental Health Service Engagement of Transition Age Youth. AB - Nationwide, there is a growing concern in understanding mental health service engagement among transition age youth. The ecological perspective suggests that there are multiple barriers to service engagement which exist on varying levels of the ecosystem. Based on the socio-technical theory and organizational culture theory, this study examined the impact of organization-level characteristics on perceived service engagement and the moderating role of organizational culture on practitioner-level characteristics affecting youth service engagement. A cross sectional survey research design was used to address the research questions. The data were collected from 279 practitioners from 27 mental health service organizations representing three major metropolitan areas in Ohio. Hierarchical linear modeling was used to address a nested structure. Findings revealed that location of organization, service setting, and organizational culture had significant effects on the continuation of services. In addition, the relationship between service coordination and resource knowledge and service engagement was moderated by organizational culture. PMID- 24807647 TI - Effect of the Exclusion of Behavioral Health from Health Information Technology (HIT) Legislation on the Future of Integrated Health Care. AB - Past research has shown abundant comorbidity between physical chronic health conditions and mental illness. The focal point of the conversation to reduce cost is better care coordination through the implementation of health information technology (HIT). At the policy level, the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH Act) was implemented as a way to increase the implementation of HIT. However, behavioral health providers have been largely excluded from obtaining access to the funds provided by the HITECH Act. Without further intervention, disjointed care coordination between physical and behavioral health providers will continue. PMID- 24807648 TI - Understanding Housing Delays and Relocations Within the Housing First Model. AB - This study explores factors contributing to delays and relocations during the implementation of the Housing First model in Toronto, Ontario. While interruptions in housing tenure are expected en route to recovery and housing stability, consumer and service provider views on finding and keeping housing remain largely unknown. In-person interviews and focus groups were conducted with 48 study participants, including 23 case managers or housing workers and 25 consumers. The following three factors contributed to housing delays and transfers: (1) the effectiveness of communication and collaboration among consumers and service providers, (2) consumer-driven preferences and ambivalence, and (3) provider prioritization of consumer choice over immediate housing access. Two strategies--targeted communications and consumer engagement in housing searches--supported the housing process. Several factors affect the timing and stability of housing. Communication between and among providers and consumers, and a shared understanding of consumer choice, can further support choice and recovery. PMID- 24807649 TI - Extracellular adenosine triphosphate affects systemic and kidney immune cell populations in pregnant rats. AB - PROBLEM: Changes in the systemic immune response are found in preeclampsia. This may be related to high extracellular adenosine triphosphate (ATP) levels. The question arose whether ATP could affect immune responses in pregnancy. Previously, we investigated whether ATP affected monocyte activation and subpopulations. Here, we investigated ATP-induced changes in other immune cell populations in pregnant rats, systemically and in the kidney, an affected organ in preeclampsia. METHOD OF STUDY: Using flow cytometry or immunohistochemistry, blood and kidney leukocytes were studied in pregnant and non-pregnant rats at different intervals after ATP or saline infusion. RESULTS: Adenosine triphosphate (ATP) infusion induced increased peripheral blood non-classical monocytes and decreased T lymphocyte subsets in pregnant rats only, higher glomerular macrophage and T lymphocyte numbers in non-pregnant animals 1 day after infusion, and higher glomerular macrophage numbers in pregnant rats 6 days after infusion. CONCLUSION: Adenosine triphosphate (ATP) infusion in pregnant rats induced a pregnancy-specific inflammatory response. Increased ATP levels could potentially contribute to development of the inflammatory response of preeclampsia. PMID- 24807650 TI - Realigning demand and supply side incentives to improve primary health care seeking in rural China. AB - China's recent and ambitious health care reform involves a shift from the reliance on markets to the reaffirmation of the central role of the state in the financing and provision of services. In collaboration with the Government of the Ningxia province, we examined the impact of two key features of the reform on health care utilisation using panel household data. The first policy change was a redesign of the rural insurance benefit package, with an emphasis on reorientating incentives away from inpatient towards outpatient care. The second policy change involved a shift from a fee-for-service payment method to a capitation budget with pay-for-performance amongst primary care providers. We find that the insurance intervention, in isolation, led to a 47% increase in the use of outpatient care at village clinics and greater intensity of treatment (e.g. injections). By contrast, the two interventions in combination showed no effect on health care use over and above that generated by the redesign of the insurance benefit package. PMID- 24807652 TI - Femme/Butch. PMID- 24807653 TI - Introduction. PMID- 24807654 TI - Dark chocolate. PMID- 24807655 TI - Prioritizing audiences. AB - SUMMARY In Leslie Feinberg's novel, Stone Butch Blues, the main character, Jess, can be read as either stone butch or transgendered, suggesting that stone butch and (female-born) transgender presentations are similar. Yet, with similar behaviors and expectations, it seems unclear what makes these two identifications distinct. In this paper, I suggest that one significant difference between these categories is the audience that is foregrounded in developing presentations of self. I suggest that stone butch identification prioritizes a lesbian, specifically butch and fem, audience in developing self, whereas transgender identification prioritizes a heterosexual audience, specifically people invested in the dominant paradigm of a rigid gender system (as a critique to that paradigm). Using Feinberg's character Jess as a prototype of both stone butch and transgender selves, I discuss the theoretical and political implications of foregrounding audiences. PMID- 24807656 TI - Explorations of lesbian-queer genders. AB - SUMMARY The purpose of this study was to explore the influence of gender expression on queer women's experiences of identity, social interaction and discrimination. This article presents the results of a questionnaire, completed by 149 queer women involved in a southeastern U.S. women's community in which interactions and norms are strongly influenced by butch-femme gendering. Questionnaires ascertained participants' age of first awareness of their queer orientation and their gender expression. In relation to their gender expressions, their experience of discrimination, from both the general population and the lesbian community, was assessed. Participants were asked to specify the degree to which their gender expression was important in their social interactions and to assess the impact of butch and femme identities upon the identifying women and the lesbian community. Results indicated that gender expression may relate to butch and femme women's age of first awareness of sexual orientation and gender expression; experience of discrimination and social interaction; and valuing of butch-femme identification within the queer community. PMID- 24807657 TI - Butches with babies. AB - SUMMARY This article is about butches who get pregnant and become mothers. It suggests that butch motherhood might widen the range of both maternal and butch subjectivities by linking a queer masculinity and sexuality to the attachments of the female body. A butch confrontation with the stigma that comes with the territory of femininity may also draw her in new ways to feminist struggles to provide social supports to those who mother. PMID- 24807658 TI - The butch/femme tango. PMID- 24807659 TI - Genesis of a femme and her desire. AB - SUMMARY This essay explores the erotically resignified roles of Mommy, Daddy, girl and boy in butch and femme. Using Freud's "Case of Homosexuality in a Woman" and personal narrative, the author focuses on the primal need for family and questions how, rather than why, butches and femmes inhabit these powerful, consensual roles in butch/femme relationships. PMID- 24807660 TI - Femme/Butch family romances. AB - SUMMARY My essay theorizes femme/butch family romances against the grain of dominant feminist and lesbian thought that desexualizes the space of mother/daughter desire. I do so through a reading/recoding of the infringing incestuous mommie-boy desires that surface in an archetypal lesbian novel, Jane Rule's Desert of the Heart. PMID- 24807661 TI - There once was a butch. PMID- 24807662 TI - Illustration. PMID- 24807663 TI - Female Fem(me)ininities. AB - SUMMARY This article critiques the historical authentication and political legitimization of exclusively masculinized dyke identities within lesbian subcultures. Seeking to create a new analysis of performative femininity, it explores the specificity of historical and contemporary femme gender transgression and offers positionalities from which to perceive femme practices and identities as politically subversive. PMID- 24807664 TI - Emotional butch. PMID- 24807665 TI - Listening to the "wives" of the "female husbands". AB - SUMMARY This article treats two of the central queer texts of eighteenth-century Britain, the autobiographical narrative of Charlotte Charke, a well-known cross dressing actress who spent a portion of her life as a husband to another woman, and Henry Fielding's pamphlet, The Female Husband. Focusing on these texts, this study moves away from the traditional subject of such work-the female husbands themselves- and instead centers on the wives and lovers of these figures. In this way, the author offers a model of what she calls a project of imaginary coalition building across time between contemporary femmes and the differ-ently-but still queerly-desiring feminine women in Charke's and Fielding's texts. Tracing two models of queer but gender-normative feminine subjectivity in these texts, the "wife" in a same-sex companionate marriage, and the "duped woman," this article challenges assumptions by mainstream as well as queer scholars about just who should be our subjects of study and why, ultimately calling into question definitions of both "heterosexuality" and "queer." PMID- 24807666 TI - I'll Set You Straight! PMID- 24807667 TI - Thoughts on lesbian genders in contemporary chinese cultures. AB - SUMMARY This article introduces readers to the debates on lesbian genders in Chinese cultures. Through an analysis of the dynamics of the tongzhimovement, as well as ethnographic and literary works not currently available in English translation, the article hopes to instigate dialogues between lesbian studies in diverse cultural contexts. PMID- 24807668 TI - Reflections on butch-femme and the emerging lesbian community in bulgaria. AB - SUMMARY This article features several women who are part of the present-day Bulgarian lesbian scene and discusses the significance of butch/femme identities in the absence of a tradition of lesbian community life. PMID- 24807669 TI - Ruth the butch. PMID- 24807670 TI - Clothes Make the (Wo)man. AB - SUMMARY Dietrich, like Madonna, has been called gender-bendingand androgynous, but Dietrich's on- and offscreen fluidity of gender identity, as reflected in her adoption of the "double drag," upsets the traditional dichotomy encoded more generally as that of male or female and more particularly as that of the butch or femme. PMID- 24807671 TI - The suit suits whom? AB - SUMMARY This paper is an excerpt from a larger cultural study that reads the figure of a woman wearing a suit with pants as a "text" that functions discursively to reveal the production of our sex/gender/desire system. There I argue that the woman-in-a-suit isolates the power of the heterosystem and offers a subject position for making visible, contesting, and producing new meanings and relations of power. Here, I use the contemporary cultural figure of a woman-in-a suit as a testing ground for asking questions about how current conceptualizations of lesbian gender and female masculinity affect and prescribe our reading of women ranging in genders and sexualities. PMID- 24807672 TI - The perfect child. PMID- 24807674 TI - Downregulation of galectin-3 causes a decrease in uPAR levels and inhibits the proliferation, migration and invasion of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. Galectin-3 (Gal-3), a multifunctional beta-galactoside binding protein, is highly expressed and associated with the prognosis of HCC. However, the functions of Gal-3 in HCC cells are not fully understood. To address the function of Gal-3 in HCC cells, we used small interfering RNA (siRNA) to knock down Gal-3 expression in HepG2, an HCC cell line. We found that in vitro the silencing of Gal-3 decreased the proliferative activity, colony formation ability, migratory and invasive potential of HepG2 cells. The silencing of Gal-3 significantly decreased the mRNA and protein levels of urokinase-type plasminogen activator receptor (uPAR) as well as uPAR's downstream signaling transduction pathway, including phosphorylation of AKT. Furthermore, the downregulation of Gal 3 by siRNA resulted in significantly decreased activity of the MEK/ERK signaling pathway, and the treatment of HepG2 cells with MEK/ERK inhibitor U0126 significantly reduced the mRNA and protein levels of uPAR. Taken together, our results suggest that Gal-3 modulates uPAR expression via the MEK/ERK pathway, and that Gal-3 may be a potential therapeutic target for the treatment of HCC. PMID- 24807675 TI - Robotic transanal total mesorectal excision for rectal cancer: experience with a first case. AB - BACKGROUND: A transanal approach for total mesorectal excision (TME) using a single incision port is feasible. The disadvantages are technical difficulties associated with limited manoeuvrability. METHODS: We present our first experience with robotic-assisted transanal total mesorectal excision. A 48 year-old woman with a tumour 8 cm from the anal verge was successfully operated using a transanal approach. A complete mesorectal excision was performed through a single incision port, using two robot arms. RESULTS: TME was performed successfully and the patient recovered quickly without any complications. The histological report showed a complete mesorectal excision with free distal and circumferential margins. A sigmoidoscopy showed an intact anastomosis and the patient was planned for reversal of her ileostomy. CONCLUSIONS: Transanal total mesorectal excision using the robot is feasible. Robotics may help to overcome technical difficulties associated with the single incision port. PMID- 24807676 TI - Surface orientation control of site-specifically immobilized nitro-reductase (NfsB). AB - We demonstrate the control of enzyme orientation for enzymes chemically immobilized on surfaces. Nitro-reductase (NfsB) has the ability to reduce a broad range of nitro-containing compounds and has potential applications in a broad range of areas including the detection and decomposition of explosives. The enzyme was tethered through unique surface cysteine residues to a self-assembled monolayer (SAM) terminated with maleimide groups. One cysteine was introduced close to the active site (V424C), and the other, at a remote site (H360C). The surface-tethered NfsB variants were interrogated by a combination of surface sensitive sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) to determine how the mode of attachment altered the enzyme's orientation. The activities of the two immobilized NfsB variants were measured and can be well correlated to the deduced orientations. The relationships among enzyme engineering, surface immobilization, enzyme orientation, and enzyme activity were revealed. PMID- 24807677 TI - Combination of oral vitamin D3 with photodynamic therapy enhances tumor cell death in a murine model of cutaneous squamous cell carcinoma. AB - Photodynamic therapy (PDT), in which 5-ALA (a precursor for protoporphyrin IX, PpIX) is administered prior to exposure to light, is a nonscarring treatment for skin cancers. However, for deep tumors, ALA-PDT is not always effective due to inadequate production of PpIX. We previously developed and reported a combination approach in which the active form of vitamin D3 (calcitriol) is given systemically prior to PDT to improve PpIX accumulation and to enhance PDT-induced tumor cell death; calcitriol, however, poses a risk of hypercalcemia. Here, we tested a possible strategy to circumvent the problem of hypercalcemia by substituting natural dietary vitamin D3 (cholecalciferol; D3 ) for calcitriol. Oral D3 supplementation (10 days of a 10-fold elevated D3 diet) enhanced PpIX levels 3- to 4-fold, and PDT-mediated cell death 20-fold, in subcutaneous A431 tumors. PpIX levels and cell viability in normal tissues were not affected. Hydroxylated metabolic forms of D3 were only modestly elevated in serum, indicating minimal hypercalcemic risk. These results show that brief oral administration of cholecalciferol can serve as a safe neoadjuvant to ALA-PDT. We suggest a clinical study, using oral vitamin D3 prior to PDT, should be considered to evaluate this promising new approach to treating human skin cancer. PMID- 24807679 TI - All-in-one graphene fiber supercapacitor. AB - A flexible all-in-one single fiber supercapacitor has been fabricated through region-specific reduction of graphene oxide (GO) fiber by laser irradiation, and thus reduced GO layers as electrodes and GO as the separator are integrated into one single fiber. This in-fiber supercapacitor with high mechanical flexibility and high performance could be woven into the textile for wearable electronics and beyond. PMID- 24807678 TI - Differentially-expressed genes identified by suppression subtractive hybridization in the bone marrow hematopoietic stem cells of patients with psoriasis. AB - Psoriasis is a T cell-mediated, chronic, relapsing and inflammatory cutaneous disorder. The dysfunctional activity of T cells in patients with psoriasis is attributed to bone marrow hematopoietic stem cells (BMHSCs). To understand the pathogenic roles of BMHSCs in psoriasis, a differential gene expression analysis was performed using suppression subtractive hybridization of the BMHSCs from a patient with psoriasis and a healthy control. Using a cDNA array dot blot screening to screen 600 genes from forward- and reverse-subtracted cDNA libraries, 17 differentially-expressed sequence tags (ESTs) were identified. The genes within the ESTs were observed to be the homologs of genes that are involved in various cellular processes, including hormone signaling, RNA catabolism, protein ADP DNA base melting, transcriptional regulation, cell cycle regulation and metabolism. CD45, which was overexpressed in the psoriatic BMHSCs, was further analyzed using relative quantitative polymerase chain reaction. In addition, the levels of CD45 in the peripheral blood cells (PBCs) of the patients with psoriasis were markedly increased and closely associated with disease severity. An abnormality of hematopoietic progenitor cells, e.g., CD45 overexpression, may be transferred to PBCs via hematopoiesis, and may account for the psoriasis-inducing properties of activated T cells. PMID- 24807681 TI - Public sector residential aged care: identifying novel associations between quality indicators and other demographic and health-related factors. AB - OBJECTIVE: To explore associations among quality indicators (QI; e.g. pressure ulcers, falls and/or fractures, physical restraint, use of multiple medications, unplanned weight loss) of the Victorian Public Sector Residential Aged Care Services (VPSRACS) with other demographic and health-related factors. METHODS: Data for 380 residents over a 3-month period were extracted retrospectively from client databases at four VPSRAC facilities. RESULTS: Four significant logistic regression models were developed. The strongest models related to falls and polypharmacy. Significant associations for these models included the following: (1) residents with a higher body mass index were 6% less likely (95% confidence interval (CI) 1%-11%) to fall, whereas high levels of cognitive impairment increased the risk of falling by 8% (95% CI 2%-14%); (2) being ambulant with a gait aid more than doubled the risk of falling compared with non-ambulant residents (95% CI 19%-546%); and (3) higher cognitive impairment was associated with a 6% (95% CI 1%-11%) reduction in the likelihood of polypharmacy. CONCLUSIONS: Identification of significant relationships between the VPSRACS QI and other demographic and health-related factors is a preliminary step towards a more in-depth understanding of the factors that influence the QI and predict adverse events. PMID- 24807680 TI - Preattentive dysfunction in patients with bipolar disorder as revealed by the pitch-mismatch negativity: a magnetoencephalography (MEG) study. AB - OBJECTIVES: Mismatch negativity (MMN) and its magnetic counterpart (MMNm) are thought to reflect an automatic process that detects a difference between an incoming stimulus and the sensory memory trace of preceding stimuli. In patients with schizophrenia, an attenuation of the MMN/MMNm amplitude has been repeatedly reported. Heschl's gyrus (HG) is one of the major generators of MMN and the functional alteration of HG has been reported in patients with bipolar disorder. The present study investigated the pitch-MMNm in patients with bipolar disorder using whole-head 306-ch magnetoencephalography (MEG). METHODS: Twenty-two patients and 22 healthy controls participated in this study. Subjects were presented with two types of auditory stimulus sequences. One consisted of 1,000 Hz standards (probability = 90%) and 1,200 Hz deviants (probability = 10%), and the other consisted of 1,000 Hz standards (90%) and 1,200 Hz deviants (10%). These two tasks were each performed twice. Event-related brain responses to standard tones were subtracted from responses to deviant tones. RESULTS: Patients with bipolar disorder showed a significant bilateral reduction in magnetic global field power (mGFP) amplitudes (p = 0.02) and dipole moments of the MMNm (p = 0.04) compared with healthy controls. Patients with admission experience showed significantly reduced mGFP amplitudes of MMNm compared with patients without admission experience (p = 0.004). Additionally, patients with more severe manic symptoms had smaller mGFP amplitudes of MMNm (rho = -0.50, p = 0.05). CONCLUSIONS: The results of this study suggest that patients with bipolar disorder may exhibit preattentive auditory dysfunction indexed by reduced pitch MMNm responses. Pitch-MMNm could be a potential trait marker reflecting the global severity of bipolar disorder. PMID- 24807682 TI - A case of pemphigus herpetiformis-like atypical pemphigus with IgG anti desmocollin 3 antibodies. PMID- 24807683 TI - Increased levetiracetam clearance associated with a breakthrough seizure in a pregnant patient receiving once/day extended-release levetiracetam. AB - The use of levetiracetam for the treatment of epilepsy in women of childbearing age has increased as more evidence of teratogenicity of other broad-spectrum antiepileptic medications becomes available. Levetiracetam appears to be associated with a low incidence of major congenital malformations based on data from pregnancy registries. Major pregnancy-related changes in the pharmacokinetics of levetiracetam have been described in several case series, demonstrating a role for careful therapeutic drug monitoring of levetiracetam in pregnant patients. Extended-release levetiracetam provides a way to improve medication adherence in adults with epilepsy by allowing once/day dosing and may be considered for use in pregnancy to minimize the fluctuation of levetiracetam levels throughout the day, thus potentially minimizing dose-related adverse effects. In this case report, we describe a 16-year-old, compliant, pregnant patient who experienced subtherapeutic levetiracetam blood concentrations that occurred with use of extended-release levetiracetam. She experienced a breakthrough seizure with once/day dosing during her third trimester with low subsequent trough levels despite multiple dose increases. After changing to twice/day dosing of extended-release levetiracetam at delivery, the patient experienced no seizures and delivered a healthy infant without complications. This is the first case report, to our knowledge, to describe seizure breakthrough during pregnancy with an extended-release formulation of an antiepileptic medication. Pharmacokinetic changes associated with pregnancy may increase apparent clearance of extended-release formulations of levetiracetam, leading to periods of subtherapeutic blood or central nervous system concentrations. These changes support the important role of therapeutic monitoring of levetiracetam plasma concentrations to help maintain seizure control in women with epilepsy during pregnancy. PMID- 24807684 TI - Does buccal cancer have worse prognosis than other oral cavity cancers? AB - OBJECTIVES/HYPOTHESIS: To determine whether buccal squamous cell carcinoma has worse overall survival (OS) and disease-specific survival (DSS) than cancers in the rest of the oral cavity. STUDY DESIGN: Retrospective analysis of a large population database. METHODS: We began with a Kaplan-Meier analysis of OS and DSS for buccal versus nonbuccal tumors with unmatched data, followed by an analysis of cases matched for race, age at diagnosis, stage at diagnosis, and treatment modality. This was supported by a univariate Cox regression comparing buccal cancer to nonbuccal cancer, followed by a multivariate Cox regression that included all significant variables studied. RESULTS: With unmatched data, buccal cancer had significantly lesser OS and DSS values than cancers in the rest of the oral cavity (P < .001). After case matching, the differences between OS and DSS for buccal cancer versus nonbuccal oral cancer were no longer significant. Univariate Cox regression models with respect to OS and DSS showed a significant difference between buccal cancer and nonbuccal cancer. However, with multivariate analysis, buccal hazard ratios for OS and DSS were not significant. CONCLUSIONS: With the largest series of buccal carcinoma to date, our study concludes that the OS and DSS of buccal cancer are similar to those of cancers in other oral cavity sites once age at diagnosis, tumor stage, treatment, and race are taken into consideration. The previously perceived poor prognosis of buccal carcinoma may be due to variations in tumor presentation, such as later stage and older patient age. LEVEL OF EVIDENCE: 2b. PMID- 24807685 TI - Effect of dietary nickel chloride on splenic immune function in broilers. AB - This study was designed to evaluate the effects of dietary nickel chloride (NiCl2) on the splenic immunity in broilers by observing changes of cytokine mRNA expression and protein levels, immunoglobulin (IgA, IgG, and IgM) contents, and IgA+ B cell and T-cell numbers using the methods of qRT-PCR, flow cytometry (FCM), and ELISA. A total of 240 1-day-old avian broilers were equally allocated into four groups and fed on a corn-soybean basal diet as the control diet or the same diet supplemented with 300, 600, and 900 mg/kg NiCl2 for 42 days. The mRNA expression and protein levels of IL-2, IL-6, IL-10, IL-12, TNF-alpha/LITAF, IFN gamma, and IgA, IgG, and IgM contents were significantly decreased (p<0.05 or p<0.01) in the 300-, 600-, and 900-mg/kg NiCl2 groups when compared with those of the control group, which was consistent with the reduction of T-cell subset percentages and IgA+ B cell numbers in the 300-, 600-, and 900-mg/kg NiCl2 groups. The abovementioned results showed that dietary NiCl2 in excess of 300 mg/kg caused damage on splenocytes and splenic immune function. The results of the present study provided new experimental evidences for further study on the effect mechanism of NiCl2 on splenic immunity. PMID- 24807686 TI - Effects of sodium selenite on aflatoxin B1-induced decrease of ileac T cell and the mRNA contents of IL-2, IL-6, and TNF-alpha in broilers. AB - The aim of this work was to assess the protective effect of sodium selenite on the ileum mucosal immunologic toxicity induced by aflatoxin B1 (AFB1). One hundred and eighty one-day-old healthy male avian broilers were divided into four groups of three replicates and 15 birds per replicate and fed with basal diet (control group), 0.3 mg/kg AFB1 (AFB1 group), 0.4 mg/kg Se (+Se group), and 0.3 mg/kg AFB1+0.4 mg/kg Se (AFB1+Se group), respectively. The ileac T-cell subsets were determined by the methods of flow cytometry (FCM), and the mRNA contents of interleukin-2 (IL-2), interleukin-6(IL-6), and tumor necrosis factor-alpha (TNF alpha) by quantitative real-time PCR. Compared with those in control group, the percentages of CD3+, CD3+CD4+, CD3+CD8+ intraepithelial lymphocytes (IELs) and LPLs, the CD4+/CD8+ ratio of IELs, and the mRNA contents of IL-2, IL-6, and TNF alpha were decreased in AFB1 group. However, compared with those in AFB1 group, these parameters of AFB1+Se group were increased to be close to those in control group. It was concluded that 0.3 mg/kg AFB1 could reduce the cellular immune function of the ileum mucosa, but 0.4 mg/kg supplemented dietary selenium showed protective effects on AFB1-induced immunologic injury. PMID- 24807687 TI - Global burden of skin disease as reflected in Cochrane Database of Systematic Reviews. AB - IMPORTANCE: Research prioritization should be guided by impact of disease. OBJECTIVE: To determine whether systematic reviews and protocol topics in Cochrane Database of Systematic Reviews (CDSR) reflect disease burden, measured by disability-adjusted life years (DALYs) from the Global Burden of Disease (GBD) 2010 project. DESIGN, SETTING, AND PARTICIPANTS: Two investigators independently assessed 15 skin conditions in the CDSR for systematic review and protocol representation from November 1, 2013, to December 6, 2013. The 15 skin diseases were matched to their respective DALYs from GBD 2010. An official publication report of all reviews and protocols published by the Cochrane Skin Group (CSG) was also obtained to ensure that no titles were missed. There were no study participants other than the researchers, who worked with databases evaluating CDSR and GBD 2010 skin condition disability data. MAIN OUTCOMES AND MEASURES: Relationship of CDSR topic coverage (systematic reviews and protocols) with percentage of total 2010 DALYs, 2010 DALY rank, and DALY percentage change from 1990 to 2010 for 15 skin conditions. RESULTS: All 15 skin conditions were represented by at least 1 systematic review in CDSR; 69% of systematic reviews and 67% of protocols by the CSG covered the 15 skin conditions. Comparing the number of reviews/protocols and disability, dermatitis, melanoma, nonmelanoma skin cancer, viral skin diseases, and fungal skin diseases were well matched. Decubitus ulcer, psoriasis, and leprosy demonstrated review/protocol overrepresentation when matched with corresponding DALYs. In comparison, acne vulgaris, bacterial skin diseases, urticaria, pruritus, scabies, cellulitis, and alopecia areata were underrepresented in CDSR when matched with corresponding DALYs. CONCLUSIONS AND RELEVANCE: Degree of representation in CDSR is partly correlated with DALY metrics. The number of published reviews/protocols was well matched with disability metrics for 5 of the 15 studied skin diseases, while 3 skin diseases were overrepresented, and 7 were underrepresented. Our results provide high-quality and transparent data to inform future prioritization decisions. PMID- 24807691 TI - Small molecule host materials for solution processed phosphorescent organic light emitting diodes. AB - Solution processed phosphorescent organic light-emitting diodes (OLEDs) have been actively developed due to merits of high quantum efficiency of phosphorescent materials and simple fabrication processes of solution processed OLEDs. The device performances of the solution processed phosphorescent OLEDs have been greatly improved in the last 10 years and the progress of the device performances was made by the development of small molecule host materials for solution processes. A hybrid host of polymer and small molecules, a single small molecule host and a mixed host of small molecule hosts have effectively enhanced the quantum efficiency of the solution processed phosphorescent OLEDs. Therefore, this paper reviews recent developments in small molecule host materials for solution processed phosphorescent OLEDs and provides future directions for the development of the small molecule host materials. PMID- 24807690 TI - Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections. AB - Host genetics has a key role in susceptibility to Salmonella Typhimurium infection. We previously used N-ethyl-N-nitrosourea (ENU) mutagenesis to identify a loss-of-function mutation within the gene ubiquitin-specific peptidase 18 (Usp18(Ity9)), which confers increased susceptibility to Salmonella Typhimurium. USP18 functions to regulate type I interferon (IFN) signaling and as a protease to remove ISG15 from substrate proteins. Usp18(Ity9) mice are susceptible to infection with Salmonella Typhimurium and have increased expression and function of ISG15, but Usp18(Ity9) mice lacking Isg15 do not show improved survival with Salmonella challenge. Type I IFN signaling is increased in Usp18(Ity9) mice and inhibition of type I IFN signaling is associated with improved survival in mutant mice. Hyperactivation of type I IFN signaling leads to increased IL-10, deregulated expression of autophagy markers and elevated interleukin (IL)-1beta and IL-17. Furthermore, Usp18(Ity9) mice are more susceptible to infection with Mycobacterium tuberculosis, have increased bacterial load in the lung and spleen, elevated inflammatory cytokines and more severe lung pathology. These findings demonstrate that regulation of type I IFN signaling is the predominant mechanism affecting the susceptibility of Usp18(Ity9) mice to Salmonella infection and that hyperactivation of signaling leads to increased IL-10, deregulation of autophagic markers and increased proinflammatory cytokine production. PMID- 24807692 TI - Primordial odontogenic tumour: clinicopathological analysis of six cases of a previously undescribed entity. AB - AIM: To describe the clinicopathological and immuno-histochemical features of six tumours that do not fulfil the criteria of any of the currently classified odontogenic tumours. METHODS AND RESULTS: The patients were three males and three females, whose ages ranged from 3 years to 18 years (mean, 11.05 years). In all cases there were well-defined radiolucencies associated with unerupted teeth apparently showing a pericoronal relationship. Microscopically, all tumours were composed of variably cellular loose fibrous tissue with areas similar to dental papilla, entirely surrounded by cuboidal to columnar epithelium resembling the internal epithelium of the enamel organ. Mesenchymal tissue was positive only for vimentin, and Ki67 expression was very low (<2%). The epithelium was positive for CK AE1/AE3, CK5, CK14, and CK19, but negative for CK18 and CK20. All cases showed clear demarcation from the surrounding bone, and were surgically removed, with no recurrences after follow-up ranging from 6 months to 20 years. CONCLUSIONS: These findings differ from those observed in other odontogenic lesions, such as ameloblastic fibroma, odontogenic myxoma, odontogenic fibroma, and hyperplastic dental follicles. The term primordial odontogenic tumour is proposed to describe this novel lesion. PMID- 24807693 TI - The molecular structure of a phosphatidylserine bilayer determined by scattering and molecular dynamics simulations. AB - Phosphatidylserine (PS) lipids play essential roles in biological processes, including enzyme activation and apoptosis. We report on the molecular structure and atomic scale interactions of a fluid bilayer composed of 1-palmitoyl-2-oleoyl sn-glycero-3-phosphatidylserine (POPS). A scattering density profile model, aided by molecular dynamics (MD) simulations, was developed to jointly refine different contrast small-angle neutron and X-ray scattering data, which yielded a lipid area of 62.7 A(2) at 25 degrees C. MD simulations with POPS lipid area constrained at different values were also performed using all-atom and aliphatic united-atom models. The optimal simulated bilayer was obtained using a model-free comparison approach. Examination of the simulated bilayer, which agrees best with the experimental scattering data, reveals a preferential interaction between Na(+) ions and the terminal serine and phosphate moieties. Long-range inter-lipid interactions were identified, primarily between the positively charged ammonium, and the negatively charged carboxylic and phosphate oxygens. The area compressibility modulus KA of the POPS bilayer was derived by quantifying lipid area as a function of surface tension from area-constrained MD simulations. It was found that POPS bilayers possess a much larger KA than that of neutral phosphatidylcholine lipid bilayers. We propose that the unique molecular features of POPS bilayers may play an important role in certain physiological functions. PMID- 24807694 TI - Prevalence of morphometric vertebral fractures in old men and the agreement between different methods in the city of Recife, Brazil. AB - Osteoporosis is relatively common in men and has a great impact on quality of life. Despite the importance of the subject, there are few studies regarding the prevalence of morphometric vertebral fractures in men and the associated risk factors. To determine the prevalence of morphometric vertebral fractures in elderly men by three different methods and the agreement between them, 234 asymptomatic men aged >60 years (mean age 69.4 +/- 6.5 years) were evaluated using lateral thoracolumbar radiograph that were analyzed by two experienced radiologists according to semiquantitative (SQ) Genant and algorithm-based qualitative (ABQ) Jiang methods. A third senior radiologist adjudicated Genant's method. The highest prevalence of fractures in ABQ Jiang and SQ Genant methods were 37.6 and 36.8 %, respectively (both examiner 2). The lowest prevalence rates were 26.5 % in ABQ Jiang method and 5.6 % in SQ Genant (both examiner 1). The prevalence found by the Genant adjudicated was 31.6 %. The agreement between the examiners were 69.2 % in ABQ Jiang method (kappa 0.30; 95 % CI 0.17-0.43) and 65.5 % in SQ Genant (kappa 0.09; 95 % CI 0.01-0.17). We evaluated skin phototype, waist circumference, hypertension, body mass index (BMI), history of fracture, calcium intake, serum 25 OHD and sun index. After multivariate regression analysis, we found that lower BMI (prevalence ratio = 1.41; p = 0.024; 95 % CI 1.05-2.03) and sun index (prevalence ratio = 1.45; p = 0.049; 95 % CI 1.01-1.95) were independently associated with morphometric vertebral fractures. PMID- 24807695 TI - Association of osteopontin with osteoarthritis. AB - The joint disease osteoarthritis (OA) is the most common form of arthritis, which mainly affects the older people. OA is becoming one of the major non-fatal health burdens of the world. The etiology of OA is mostly unclear, and it cannot be cured totally. Osteopontin (OPN) is a multifunctional phosphoprotein, of which overexpression and high level of presence in synovial fluid and articular cartilage were found to be associated with OA progression. Usually, in OA progression, OPN plays important role as an intrinsic regulator. Recent studies have taken attempt to use this protein as a diagnostic marker of OA and use OPN as a target for the drug development against OA. This review summarizes the role of OPN in OA, with focusing on the mechanism of action, and also discussing the diagnostic and therapeutic aspects of OA related to OPN. PMID- 24807696 TI - Novel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2. AB - ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRalpha/RXRalpha. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene. PMID- 24807697 TI - Sex bias in ultrasound measures of gestational age: assessment by sex ratio in post-term births. AB - BACKGROUND: Estimation of fetal age by ultrasound assumes identical biometries for both sexes at identical gestational ages. However, late in the first trimester male fetuses become larger overall than female fetuses, which may introduce a sex bias with clinical consequences. A recent study showed that using due-date estimates based on biparietal diameter from the second trimester increased the post-term male-to-female ratio and the risk of stillbirth among female fetuses born at 43 gestational weeks. We aimed to evaluate whether this increased male-to-female ratio was also present when the due date was based on crown-rump length from the first trimester. METHODS: The study population included 3987 women with a certain last menstrual period (LMP), as well as a crown-rump length measured in the first trimester and a biparietal diameter measured in the second trimester. We defined birth after 42 completed weeks estimated by LMP as post-term. Labor was not routinely induced until after 42 weeks. Male-to-female ratios were estimated using logistic regression. RESULTS: When gestational age was estimated by biparietal diameter, the sex ratio steadily increased from 0.98 (95% confidence interval = 0.87-1.11) in week 40 to 1.54 (1.09-2.17) in week 42. A similar increase did not occur when using certain LMP or crown-rump length. CONCLUSIONS: The use of crown-rump length for the estimation of gestational age is not associated with an increased post-term male to-female ratio. It can therefore be used for the estimation of due date without risk of the sex bias that occurs when using biparietal diameter in second trimester of pregnancy. PMID- 24807698 TI - PFOA and PFOS serum levels and miscarriage risk. AB - BACKGROUND: Serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were assessed in relation to miscarriage in a population of mid-Ohio River Valley residents highly exposed to PFOA through contaminated drinking water. METHODS: Serum PFOA and PFOS concentrations were measured in 1129 women in 2005-2006 who reported pregnancy outcomes in follow-up interviews between 2008 and 2011. In the analysis, we included 1438 reported live births, stillbirths, and miscarriages with estimated conception dates after the serum measurements. Preconception serum levels of PFOA and PFOS were analyzed in relation to miscarriage using logistic regression and generalized estimating equations. RESULTS: There was little evidence of association between PFOA and miscarriage. For PFOS, when including all reported prospective pregnancies, the odds ratio of miscarriage per log ng/ml increase was 1.21 (95% confidence interval = 0.94-1.55); in subanalyses restricted to each woman's first pregnancy conceived after the serum measurement, the odds ratio was 1.34 (1.02-1.76). Categorical analyses showed elevated odds ratios for the top 4 quintiles relative to the first quintile, without a monotonic trend. Positive associations between PFOS and miscarriage were strongest among nulligravid pregnancies. CONCLUSIONS: In this prospective study of miscarriage in a population exposed to high levels of PFOA and background levels of PFOS, we found little evidence of association with serum levels of PFOA and limited evidence of association with serum levels of PFOS. PMID- 24807699 TI - Adjusting the surface areal density of click-reactive azide groups by kinetic control of the azide substitution reaction on bromine-functional SAMs. AB - Azide-alkyne click chemistry has emerged as an important and versatile means for tethering a wide variety of guest molecules to virtually any substrate. In many of these applications, it is important to exercise control over the areal density of surface functional groups to achieve a desired areal density of the tethered guest molecule of interest. We demonstrate herein that the areal density of surface azide groups on flat germanium surfaces and nanoparticle substrates (silica and iron oxide) can be controlled kinetically by appropriately timed quenching of the S(N)2 substitution reaction of bromo-alkane-silane monolayers induced by the addition of sodium azide. The kinetics of the azide substitution reaction on monolayers formed on flat Ge substrates, determined by attenuated total reflection infrared spectroscopy (ATR-IR), are found to be identical to those for monolayers formed on both silica and iron oxide nanoparticles, the latter determined by transmission infrared spectroscopy. To validate the method, the percentages of surface bromine groups converted to azide groups after various reaction times were measured by quenching the S(N)2 reaction followed by analysis with ATR-IR (for Ge) and thermogravimetric analysis (after a subsequent click reaction with an alkyne-terminal polymer) for the nanoparticle substrates. The conversions found after quenching agree well with those expected from the standard kinetic curves. The latter result suggests that the kinetic method for the control of azide group areal density is a versatile means for functionalizing substrates with a prescribed areal density of azide groups for subsequent click reactions, and that the method is universal for any substrate, flat or nanoparticle, that can be modified with bromo-alkane-silane monolayers. Regardless of the surface geometry, we find that the azide substitution reaction is complete within 2-3 h, in sharp contrast to previous reports that indicate times of 48-60 h required for completion of the reaction. PMID- 24807701 TI - Species differentiation within the Staphylococcus intermedius group using a refined MALDI-TOF MS database. AB - Among coagulase-positive staphylococci of animal origin, the members of the Staphylococcus intermedius-group (SIG: S. intermedius, Staphylococcus pseudintermedius and Staphylococcus delphini) are important opportunistic pathogens in different animal hosts and occasionally in humans. However, the unambiguous species diagnosis of SIG is often challenging. Therefore, matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) -based SIG-identification with Bruker Microflex LT in combination with Biotyper 3.0 software (Bruker Daltonics, Bremen, Germany) was evaluated using (i) the original database content and (ii) the database after extension with distinct hierarchical clustered reference spectra for 60 SIG. A convenience sample comprising 200 isolates was used to compare both database performances. As a result, 17 isolates initially diagnosed as S. intermedius with the current content of the Bruker database were identified as S. pseudintermedius by applying the in-house reference spectra extended version. Furthermore, a significant improvement (average rise of log score value: 0.24) of the SIG identification score values was achieved, emphasizing that further sequence-based refinement of the Bruker database content allows improvement of MALDI-TOF MS-based identification. PMID- 24807702 TI - Modeling minority stress effects on homelessness and health disparities among young men who have sex with men. AB - Sexual minority youth are more likely to experience homelessness, and homeless sexual minority youth report greater risk for mental health and substance abuse symptoms than homeless heterosexual youth, yet few studies have assessed determinants that help explain the disparities. Minority stress theory proposes that physical and mental health disparities among sexual minority populations may be explained by the stress produced by living in heterosexist social environments characterized by stigma and discrimination directed toward sexual minority persons. We used data from a sample of 200 young men who have sex with men (YMSM) (38 % African American, 26.5 % Latino/Hispanic, 23.5 % White, 12 % multiracial/other) to develop an exploratory path model measuring the effects of experience and internalization of sexual orientation stigma on depression and substance use via being kicked out of home due to sexual orientation and current homelessness. Direct significant paths were found from experience of sexual orientation-related stigma to internalization of sexual orientation-related stigma, having been kicked out of one's home, experiencing homelessness during the past year, and major depressive symptoms during the past week. Having been kicked out of one's home had a direct significant effect on experiencing homelessness during the past 12 months and on daily marijuana use. Internalization of sexual orientation-related stigma and experiencing homelessness during the past 12 months partially mediated the direct effect of experience of sexual orientation-related stigma on major depressive symptoms. Our empirical testing of the effects of minority stress on health of YMSM advances minority stress theory as a framework for investigating health disparities among this population. PMID- 24807705 TI - Optimization and validation of immunocytochemical detection of oestrogen receptors on cytospins prepared from fine needle aspiration (FNA) samples of breast cancer. AB - OBJECTIVE: To optimize and validate immunocytochemical (ICC) assessment of oestrogen receptors (ERs) on cytospins prepared from fine needle aspiration (FNA) samples. METHODS: Optimal conditions and variability in ICC detection of ERs were established on cytospins prepared from the human breast cancer cell line MCF-7. Protocols that yielded adequate results were further validated on 52 FNA samples of resected breast cancer tumours using analysis of concordance with the ER status, determined by standard immunohistochemistry on corresponding formalin fixed, paraffin-embedded tissue (FFPET). On 37 diagnostic FNA samples, manual immunostaining with antibody 1D5 was compared with automated immunostaining with antibody 6F11. RESULTS: The highest percentage of ER-positive MCF-7 cells with lowest variability was obtained on methanol-fixed cytospins with or without microwave pre-treatment: 72 +/- 5% and 75 +/- 7%, respectively. Microwave pre treatment was mandatory for Papanicolaou-stained cytospins in order to achieve between 63 +/- 14% and 67 +/- 9% of ER-positive MCF-7 cells. The concordance between ICC assessment of ERs on FNA samples and corresponding FFPET sections was complete for methanol-fixed cytospins (100%, kappa = 1) and adequate for Papanicolaou-stained cytospins (94%, kappa = 0.84) and Papanicolaou-stained smears (92%, kappa = 0.75). Complete agreement in ICC detection of ERs was obtained for manual immunostaining with antibody 1D5 and automated immunostaining with antibody 6F11. CONCLUSIONS: Methanol-fixed cytospins prepared from FNA samples ensure highly reliable ICC assessment of ERs, whereas Papanicolaou stained cytospins or smears are conditionally suitable because of the small risk of false negative results. PMID- 24807704 TI - Increasing chemical space coverage by combining empirical and computational fragment screens. AB - Most libraries for fragment-based drug discovery are restricted to 1,000-10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC beta-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC beta-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources. PMID- 24807706 TI - Calibration of the torsional and lateral spring constants of cantilever sensors. AB - A method suitable for the calibration of the spring constants of all torsional and lateral eigenmodes of micro- and nanocantilever sensors is described. Such sensors enable nanomechanical measurements and the characterization of nanomaterials, for example with atomic force microscopy. The method presented involves the interaction of a flow of fluid from a microchannel with the cantilever beam. Forces imparted by the flow cause the cantilever to bend and induce a measurable change of the torsional and lateral resonance frequencies. From the frequency shifts the cantilever spring constants can be determined. The method does not involve physical contact between the cantilever or its tip and a hard surface. As such it is non-invasive and does not risk damage to the cantilever. Experimental data is presented for two rectangular microcantilevers with fundamental flexural spring constants of 0.046 and 0.154 N m(-1). The experimentally determined torsional stiffness values are compared with those obtained by the Sader method. We demonstrate that the torsional spring constants can be readily calibrated using the method with an accuracy of around 15%. PMID- 24807707 TI - The environmental biological signature: NGS profiling for forensic comparison of soils. AB - The identification of the source of a specific soil sample is a crucial step in forensic investigations. Rapid advances in next generation sequencing (NGS) technology and the strong reduction of the cost of sequencing have recently opened new perspectives. In the present work a metabarcoding approach has been successfully applied to forensic and environmental soil samples, allowing the accurate and sensitive analysis of microflora (mfDNA), plants, metazoa, and protozoa DNA. The identification of the biological component by DNA metabarcoding is a strong element for the discrimination of samples geologically very similar but coming for distinct environments. PMID- 24807708 TI - RIOK3 is an adaptor protein required for IRF3-mediated antiviral type I interferon production. AB - Detection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-beta production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-beta. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3. Importance: The innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection. PMID- 24807709 TI - Maintenance of dimer conformation by the dengue virus core protein alpha4-alpha4' helix pair is critical for nucleocapsid formation and virus production. AB - The virion of dengue virus (DENV) is composed of a viral envelope covering a nucleocapsid formed by a complex of viral genomic RNA and core protein (CP). DENV CP forms a dimer via the internal alpha2 and alpha4 helices of each monomer. Pairing of alpha2-alpha2' creates a continuous hydrophobic surface, while the alpha4-alpha4' helix pair joins the homodimer via side-chain interactions of the inner-edge residues. However, the importance of dimer conformation and the alpha4 helix of DENV CP in relation to its function are poorly understood. Loss of association between CP and lipid droplets (LDs) due to mutation suggests that the CP hydrophobic surface was not exposed, offering a possible explanation for the absence of dimers. Further assays suggest the connection between CP folding and protein stability. Attenuation of full-length RNA-derived virus production is associated with CP mutation, since no significant defects were detected in virus translation and replication. The in vitro characterization assays further highlighted that the alpha4-alpha4' helix pair conformation is critical in preserving the overall alpha-helical content, thermostability, and dimer formation ability of CP, features correlated with the efficiency of nucleocapsid formation. Addition of Tween 20 improves in vitro nucleocapsid-like particle formation, suggesting the role of the LD in nucleocapsid formation in vivo. This study provides the first direct link between the alpha4-alpha4' helix pair interaction and the CP dimer conformation that is the basis of CP function, particularly in nucleocapsid formation during virion production. Importance: Structure-based mutagenesis study of the dengue virus core protein (CP) reveals that the alpha4-alpha4' helix pair is the key to maintaining its dimer conformation, which is the basis of CP function in nucleocapsid formation and virus production. Attenuation of full-length RNA-derived virus production is associated with CP mutation, since no significant defects in virus translation and replication were detected. In vitro inefficiency and size of nucleocapsid like particle (NLP) formation offer a possible explanation for in vivo virus production inefficiency upon CP mutation. Further, the transition of NLP morphology from an incomplete state to an intact particle shown by alpha4-alpha4' helix pair mutants in the presence of a nonionic detergent suggests the regulatory role of the intracellular lipid droplet (LD) in CP-LD interaction and in promoting nucleocapsid formation. This study provides the first direct link between the alpha4-alpha4' helix pair interaction and CP dimer conformation that is the fundamental requirement of CP function, particularly in nucleocapsid formation during virion production. PMID- 24807710 TI - Role of CD8+ T cells and lymphoid dendritic cells in protection from ocular herpes simplex virus 1 challenge in immunized mice. AB - The development of immunization strategies to protect against ocular infection with herpes simplex virus 1 (HSV-1) must address the issue of the effects of the strategy on the establishment of latency in the trigeminal ganglia (TG). It is the reactivation of this latent virus that can cause recurrent disease and corneal scarring. CD8(+) T cells and dendritic cells (DCs) have been implicated in the establishment and maintenance of latency through several lines of inquiry. The objective of the current study was to use CD8alpha(-/-) and CD8beta(-/-) mice to further evaluate the contributions of CD8(+) T cells and the CD8alpha(+) and CD8alpha(-) subpopulations of DCs to the protection afforded against ocular infection by immunization against HSV-1 and their potential to increase latency. Neutralizing antibody titers were similar in immunized CD8alpha(-/-), CD8beta(-/ ), and wild-type (WT) mice, as was virus replication in the eye. However, on day 3 postinfection (p.i.), the copy number of HSV-1 glycoprotein B (gB) was higher in the corneas and TG of CD8alpha(-/-) mice than those of WT mice, whereas on day 5 p.i. it was lower. As would be anticipated, the lack of CD8alpha(+) or CD8beta(+) cells affected the levels of type I and type II interferon transcripts, but the effects were markedly time dependent and tissue specific. The levels of latent virus in the TG, as estimated by measurement of LAT transcripts and in vitro explant reactivation assays, were lower in the immunized, ocularly challenged CD8alpha(-/-) and WT mice than in their CD8beta(-/ ) counterparts. Immunization reduced the expression of PD-1, a marker of T-cell exhaustion, in the TG of ocularly challenged mice, and mock-immunized CD8alpha(-/ ) mice had lower levels of PD-1 expression and latency than mock-immunized WT or CD8beta(-/-) mice. The expansion of the CD8alpha(-) subpopulation of DCs through injection of WT mice with granulocyte-macrophage colony-stimulating factor (GM CSF) DNA reduced the amount of latency and PD-1 expression in the TG of infected mice. In contrast, injection of FMS-like tyrosine kinase 3 ligand (Flt3L) DNA, which expanded both subpopulations, was less effective. Our results suggest that the absence of both CD8alpha(+) T cells and CD8alpha(+) DCs does not reduce vaccine efficacy, either directly or indirectly, in challenged mice and that administration of GM-CSF appears to play a beneficial role in reducing latency and T-cell exhaustion. Importance: In the past 2 decades, two large clinical HSV vaccine trials were performed, but both vaccine studies failed to reach their goals. Thus, as an alternative to conventional vaccine studies, we have used a different strategy to manipulate the host immune responses in an effort to induce greater protection against HSV infection. In lieu of the pleiotropic effect of CD8alpha(+) DCs in HSV-1 latency, in this report, we show that the absence of CD8alpha(+) T cells and CD8alpha(+) DCs has no adverse effect on vaccine efficacy. In line with our hypothesis, we found that pushing DC subpopulations from CD8alpha(+) DCs toward CD8alpha(-) DCs by injection of GM-CSF reduced the amount of latent virus and T-cell exhaustion in TG. While these studies point to the lack of a role for CD8alpha(+) T cells in vaccine efficacy, they in turn point to a role for GM-CSF in reducing HSV-1 latency. PMID- 24807711 TI - Activation and repression of Epstein-Barr Virus and Kaposi's sarcoma-associated herpesvirus lytic cycles by short- and medium-chain fatty acids. AB - The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short- and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways. Importance: Lytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota. Small-molecule inducers of the lytic cycle are desired for oncolytic therapy. Inhibition of viral reactivation, alternatively, may prove useful in cancer treatment. Overall, our findings contribute to the understanding of pathways that control the latent-to-lytic switch and identify naturally occurring molecules that may regulate this process. PMID- 24807712 TI - Rules and exceptions: sialic acid variants and their role in determining viral tropism. AB - Sialic acids decorate the surfaces of most mammalian cells and are used by many viruses as attachment receptors. In contrast to other mammals, humans cannot synthesize a version of sialic acid known as N-glycolyl neuraminic acid. This difference is exploited by some viruses to establish tropism. Here we compare recently determined structures of closely related animal and human polyomaviruses and examine their strategies for engaging specific sialic acid variants. PMID- 24807713 TI - Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation. AB - Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4(+) T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation. Importance: The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection. PMID- 24807714 TI - Molecularly tagged simian immunodeficiency virus SIVmac239 synthetic swarm for tracking independent infection events. AB - Following mucosal human immunodeficiency virus type 1 transmission, systemic infection is established by one or only a few viral variants. Modeling single variant, mucosal transmission in nonhuman primates using limiting-dose inoculations with a diverse simian immunodeficiency virus isolate stock may increase variability between animals since individual variants within the stock may have substantial functional differences. To decrease variability between animals while retaining the ability to enumerate transmitted/founder variants by sequence analysis, we modified the SIVmac239 clone to generate 10 unique clones that differ by two or three synonymous mutations (molecular tags). Transfection- and infection-derived virus stocks containing all 10 variants showed limited phenotypic differences in 9 of the 10 clones. Twenty-nine rhesus macaques were challenged intrarectally or intravenously with either a single dose or repeated, limiting doses of either stock. The proportion of each variant within each inoculum and in plasma from infected animals was determined by using a novel real time single-genome amplification assay. Each animal was infected with one to five variants, the number correlating with the dose. Longitudinal sequence analysis revealed that the molecular tags are highly stable with no reversion to the parental sequence detected in >2 years of follow-up. Overall, the viral stocks are functional and mucosally transmissible and the number of variants is conveniently discernible by sequence analysis of a small amplicon. This approach should be useful for tracking individual infection events in preclinical vaccine evaluations, long-term viral reservoir establishment/clearance research, and transmission/early-event studies. Importance: Human immunodeficiency virus type 1 transmission is established by one or only a few viral variants. Modeling of limited variant transmission in nonhuman primates with a diverse simian immunodeficiency virus isolate stock may increase the variability between animals because of functional differences in the individual variants within the stock. To decrease such variability while retaining the ability to distinguish and enumerate transmitted/founder variants by sequence analysis, we generated a viral stock with 10 sequence-identifiable but otherwise genetically identical variants. This virus was characterized in vitro and in vivo and shown to allow discrimination of distinct transmission events. This approach provides a novel nonhuman primate challenge system for the study of viral transmission, evaluation of vaccines and other prevention approaches, and characterization of viral reservoirs and strategies to target them. PMID- 24807716 TI - Herpes simplex virus 1 protein kinase US3 hyperphosphorylates p65/RelA and dampens NF-kappaB activation. AB - Nuclear factor kappaB (NF-kappaB) plays important roles in innate immune responses by regulating the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation, and survival. To survive in the host cells, viruses have evolved multiple strategies to evade and subvert the host immune response. Herpes simplex virus 1 (HSV-1) bears a large DNA genome, with the capacity to encode many different viral proteins to counteract the host immune responses. In the present study, we demonstrated that HSV-1 protein kinase US3 significantly inhibited NF kappaB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 was also shown to hyperphosphorylate p65 at serine 75 and block its nuclear translocation. Two US3 mutants, K220M and D305A, still interacted with p65; however, they could not hyperphosphorylate p65, indicating that the kinase activity of US3 was indispensable for the function. The attenuation of NF-kappaB activation by HSV-1 US3 protein kinase may represent a critical adaptation to enable virus persistence within the host. Importance: This study demonstrated that HSV-1 protein kinase US3 significantly inhibited NF kappaB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 hyperphosphorylated p65 at serine 75 to inhibit NF kappaB activation. The kinase activity of US3 was indispensable for its hyperphosphorylation of p65 and abrogation of the nuclear translocation of p65. The present study elaborated a novel mechanism of HSV-1 US3 to evade the host innate immunity. PMID- 24807715 TI - Replication of many human viruses is refractory to inhibition by endogenous cellular microRNAs. AB - The issue of whether viruses are subject to restriction by endogenous microRNAs (miRNAs) and/or by virus-induced small interfering RNAs (siRNAs) in infected human somatic cells has been controversial. Here, we address this question in two ways. First, using deep sequencing, we demonstrate that infection of human cells by the RNA virus dengue virus (DENV) or West Nile virus (WNV) does not result in the production of any virus-derived siRNAs or viral miRNAs. Second, to more globally assess the potential of small regulatory RNAs to inhibit virus replication, we used gene editing to derive human cell lines that lack a functional Dicer enzyme and that therefore are unable to produce miRNAs or siRNAs. Infection of these cells with a wide range of viruses, including DENV, WNV, yellow fever virus, Sindbis virus, Venezuelan equine encephalitis virus, measles virus, influenza A virus, reovirus, vesicular stomatitis virus, human immunodeficiency virus type 1, or herpes simplex virus 1 (HSV-1), failed to reveal any enhancement in the replication of any of these viruses, although HSV 1, which encodes at least eight Dicer-dependent viral miRNAs, did replicate somewhat more slowly in the absence of Dicer. We conclude that most, and perhaps all, human viruses have evolved to be resistant to inhibition by endogenous human miRNAs during productive replication and that dependence on a cellular miRNA, as seen with hepatitis C virus, is rare. How viruses have evolved to avoid inhibition by endogenous cellular miRNAs, which are generally highly conserved during metazoan evolution, remains to be determined. Importance: Eukaryotic cells express a wide range of small regulatory RNAs, including miRNAs, that have the potential to inhibit the expression of mRNAs that show sequence complementarity. Indeed, previous work has suggested that endogenous miRNAs have the potential to inhibit viral gene expression and replication. Here, we demonstrate that the replication of a wide range of pathogenic viruses is not enhanced in human cells engineered to be unable to produce miRNAs, indicating that viruses have evolved to be resistant to inhibition by miRNAs. This result is important, as it implies that manipulation of miRNA levels is not likely to prove useful in inhibiting virus replication. It also focuses attention on the question of how viruses have evolved to resist inhibition by miRNAs and whether virus mutants that have lost this resistance might prove useful, for example, in the development of attenuated virus vaccines. PMID- 24807717 TI - Novel roles of cytoplasmic ICP0: proteasome-independent functions of the RING finger are required to block interferon-stimulated gene production but not to promote viral replication. AB - The immediate-early protein ICP0 from herpes simplex virus 1 (HSV-1) plays pleiotropic roles in promoting viral lytic replication and reactivation from latency. Most of the known actions of ICP0 occur in the nucleus and are thought to involve the E3 ubiquitin ligase activity of its RING finger domain, which targets proteins for degradation via the proteasome. Although ICP0 translocates to the cytoplasm as the infection progresses, little is known about its activities in this location. Here, we show that cytoplasmic ICP0 has two distinct functions. In primary cell cultures and in an intravaginal mouse model, cytoplasmic ICP0 promotes viral replication in the absence of an intact RING finger domain. Additionally, ICP0 blocks the activation of interferon regulatory factor 3 (IRF3), a key transcription factor of the innate antiviral response, in a mechanism that requires the RING finger domain but not the proteasome. To our knowledge, this is the first observation of a proteasome-independent function of the RING finger domain of ICP0. Collectively, these results underscore the importance of cytoplasm-localized ICP0 and the diverse nature of its activities. Importance: Despite ICP0 being a well-studied viral protein, the significance of its cytoplasmic localization has been largely overlooked. This is, in part, because common experimental manipulations result in the restriction of ICP0 to the nucleus. By overcoming this constraint, we both further characterize the ability of cytoplasmic ICP0 to inhibit antiviral signaling and show that ICP0 at this site has unexpected activities in promoting viral replication. This demonstrates the importance of considering location when analyzing protein function and adds a new perspective to our understanding of this multifaceted protein. PMID- 24807718 TI - Recombinant covalently closed circular hepatitis B virus DNA induces prolonged viral persistence in immunocompetent mice. AB - It remains crucial to develop a laboratory model for studying hepatitis B virus (HBV) chronic infection. We hereby produced a recombinant covalently closed circular DNA (rcccDNA) in view of the key role of cccDNA in HBV persistence. A loxP-chimeric intron was engineered into a monomeric HBV genome in a precursor plasmid (prcccDNA), which was excised using Cre/loxP-mediated DNA recombination into a 3.3-kb rcccDNA in the nuclei of hepatocytes. The chimeric intron was spliced from RNA transcripts without interrupting the HBV life cycle. In cultured hepatoma cells, cotransfection of prcccDNA and pCMV-Cre (encoding Cre recombinase) resulted in accumulation of nuclear rcccDNA that was heat stable and epigenetically organized as a minichromosome. A mouse model of HBV infection was developed by hydrodynamic injection of prcccDNA. In the presence of Cre recombinase, rcccDNA was induced in the mouse liver with effective viral replication and expression, triggering a compromised T-cell response against HBV. Significant T-cell hyporesponsiveness occurred in mice receiving 4 MUg prcccDNA, resulting in prolonged HBV antigenemia for up to 9 weeks. Persistent liver injury was observed as elevated alanine transaminase activity in serum and sustained inflammatory infiltration in the liver. Although a T-cell dysfunction was induced similarly, mice injected with a plasmid containing a linear HBV replicon showed rapid viral clearance within 2 weeks. Collectively, our study provides an innovative approach for producing a cccDNA surrogate that established HBV persistence in immunocompetent mice. It also represents a useful model system in vitro and in vivo for evaluating antiviral treatments against HBV cccDNA. Importance: (i) Unlike plasmids that contain a linear HBV replicon, rcccDNA established HBV persistence with sustained liver injury in immunocompetent mice. This method could be a prototype for developing a mouse model of chronic HBV infection. (ii) An exogenous intron was engineered into the HBV genome for functionally seamless DNA recombination. This original approach could be also extended to other viral studies. (iii) rcccDNA was substantially induced in the nuclei of hepatocytes and could be easily distinguished by its exogenous intron using PCR. This convenient model system affords the opportunity to test antivirals directly targeting HBV cccDNA. PMID- 24807719 TI - Antibody-mediated enhancement of parvovirus B19 uptake into endothelial cells mediated by a receptor for complement factor C1q. AB - Despite its strong host tropism for erythroid progenitor cells, human parvovirus B19 (B19V) can also infect a variety of additional cell types. Acute and chronic inflammatory cardiomyopathies have been associated with a high prevalence of B19V DNA in endothelial cells of the myocardium. To elucidate the mechanisms of B19V uptake into endothelium, we first analyzed the surface expression of the well characterized primary B19V receptor P antigen and the putative coreceptors alpha5beta1 integrins and Ku80 antigen on primary and permanent endothelial cells. The receptor expression pattern and also the primary attachment levels were similar to those in the UT7/Epo-S1 cell line regarded as functional for B19V entry, but internalization of the virus was strongly reduced. As an alternative B19V uptake mechanism in endothelial cells, we demonstrated antibody-dependent enhancement (ADE), with up to a 4,000-fold increase in B19V uptake in the presence of B19V-specific human antibodies. ADE was mediated almost exclusively at the level of virus internalization, with efficient B19V translocation to the nucleus. In contrast to monocytes, where ADE of B19V has been described previously, enhancement does not rely on interaction of the virus-antibody complexes with Fc receptors (FcRs), but rather, involves an alternative mechanism mediated by the heat-sensitive complement factor C1q and its receptor, CD93. Our results suggest that ADE represents the predominant mechanism of endothelial B19V infection, and it is tempting to speculate that it may play a role in the pathogenicity of cardiac B19V infection. Importance: Both efficient entry and productive infection of human parvovirus B19 (B19V) seem to be limited to erythroid progenitor cells. However, in vivo, the viral DNA can also be detected in additional cell types, such as endothelial cells of the myocardium, where its presence has been associated with acute and chronic inflammatory cardiomyopathies. In this study, we demonstrated that uptake of B19V into endothelial cells most probably does not rely on the classical receptor-mediated route via the primary B19V receptor P antigen and coreceptors, such as alpha5beta1 integrins, but rather on antibody-dependent mechanisms. Since the strong antibody-dependent enhancement (ADE) of B19V entry requires the CD93 surface protein, it very likely involves bridging of the B19V-antibody complexes to this receptor by the complement factor C1q, leading to enhanced endocytosis of the virus. PMID- 24807720 TI - The varicella-zoster virus portal protein is essential for cleavage and packaging of viral DNA. AB - The varicella-zoster virus (VZV) open reading frame 54 (ORF54) gene encodes an 87 kDa monomer that oligomerizes to form the VZV portal protein, pORF54. pORF54 was hypothesized to perform a function similar to that of a previously described herpes simplex virus 1 (HSV-1) homolog, pUL6. pUL6 and the associated viral terminase are required for processing of concatemeric viral DNA and packaging of individual viral genomes into preformed capsids. In this report, we describe two VZV bacterial artificial chromosome (BAC) constructs with ORF54 gene deletions, Delta54L (full ORF deletion) and Delta54S (partial internal deletion). The full deletion of ORF54 likely disrupted essential adjacent genes (ORF53 and ORF55) and therefore could not be complemented on an ORF54-expressing cell line (ARPE54). In contrast, Delta54S was successfully propagated in ARPE54 cells but failed to replicate in parental, noncomplementing ARPE19 cells. Transmission electron microscopy confirmed the presence of only empty VZV capsids in Delta54S-infected ARPE19 cell nuclei. Similar to the HSV-1 genome, the VZV genome is composed of a unique long region (UL) and a unique short region (US) flanked by inverted repeats. DNA from cells infected with parental VZV (VZVLUC strain) contained the predicted UL and US termini, whereas cells infected with Delta54S contained neither. This result demonstrates that Delta54S is not able to process and package viral DNA, thus making pORF54 an excellent chemotherapeutic target. In addition, the utility of BAC constructs Delta54L and Delta54S as tools for the isolation of site-directed ORF54 mutants was demonstrated by recombineering single-nucleotide changes within ORF54 that conferred resistance to VZV-specific portal protein inhibitors. Importance: Antivirals with novel mechanisms of action would provide additional therapeutic options to treat human herpesvirus infections. Proteins involved in the herpesviral DNA encapsidation process have become promising antiviral targets. Previously, we described a series of N-alpha methylbenzyl-N'-aryl thiourea analogs that target the VZV portal protein (pORF54) and prevent viral replication in vitro. To better understand the mechanism of action of these compounds, it is important to define the structural and functional characteristics of the VZV portal protein. In contrast to HSV, no VZV mutants have been described for any of the seven essential DNA encapsidation genes. The VZV ORF54 deletion mutant described in this study represents the first VZV encapsidation mutant reported to date. We demonstrate that the deletion mutant can serve as a platform for the isolation of portal mutants via recombineering and provide a strategy for more in-depth studies of VZV portal structure and function. PMID- 24807721 TI - HIV-1 vaccine-induced C1 and V2 Env-specific antibodies synergize for increased antiviral activities. AB - The RV144 ALVAC/AIDSVax HIV-1 vaccine clinical trial showed an estimated vaccine efficacy of 31.2%. Viral genetic analysis identified a vaccine-induced site of immune pressure in the HIV-1 envelope (Env) variable region 2 (V2) focused on residue 169, which is included in the epitope recognized by vaccinee-derived V2 monoclonal antibodies. The ALVAC/AIDSVax vaccine induced antibody-dependent cellular cytotoxicity (ADCC) against the Env V2 and constant 1 (C1) regions. In the presence of low IgA Env antibody levels, plasma levels of ADCC activity correlated with lower risk of infection. In this study, we demonstrate that C1 and V2 monoclonal antibodies isolated from RV144 vaccinees synergized for neutralization, infectious virus capture, and ADCC. Importantly, synergy increased the HIV-1 ADCC activity of V2 monoclonal antibody CH58 at concentrations similar to that observed in plasma of RV144 vaccinees. These findings raise the hypothesis that synergy among vaccine-induced antibodies with different epitope specificities contributes to HIV-1 antiviral antibody responses and is important to induce for reduction in the risk of HIV-1 transmission. Importance: The Thai RV144 ALVAC/AIDSVax prime-boost vaccine efficacy trial represents the only example of HIV-1 vaccine efficacy in humans to date. Studies aimed at identifying immune correlates involved in the modest vaccine-mediated protection identified HIV-1 envelope (Env) variable region 2-binding antibodies as inversely correlated with infection risk, and genetic analysis identified a site of immune pressure within the region recognized by these antibodies. Despite this evidence, the antiviral mechanisms by which variable region 2-specific antibodies may have contributed to lower rates of infection remain unclear. In this study, we demonstrate that vaccine-induced HIV-1 envelope variable region 2 and constant region 1 antibodies synergize for recognition of virus-infected cells, infectious virion capture, virus neutralization, and antibody-dependent cellular cytotoxicity. This is a major step in understanding how these types of antibodies may have cooperatively contributed to reducing infection risk and should be considered in the context of prospective vaccine design. PMID- 24807722 TI - Analysis of recombinant H7N9 wild-type and mutant viruses in pigs shows that the Q226L mutation in HA is important for transmission. AB - The fact that there have been more than 300 human infections with a novel avian H7N9 virus in China indicates that this emerging strain has pandemic potential. Furthermore, many of the H7N9 viruses circulating in animal reservoirs contain putative mammalian signatures in the HA and PB2 genes that are believed to be important in the adaptation of other avian strains to humans. To date, the definitive roles of these mammalian-signature substitutions in transmission and pathogenesis of H7N9 viruses remain unclear. To address this we analyzed the biological characteristics, pathogenicity, and transmissibility of A/Anhui/1/2013 (H7N9) virus and variants in vitro and in vivo using a synthetically created wild type virus (rAnhui-WT) and two mutants (rAnhui-HA-226Q and rAnhui-PB2-627E). All three viruses replicated in lungs of intratracheally inoculated pigs, yet nasal shedding was limited. The rAnhui-WT and rAnhui-PB2-627E viruses were transmitted to contact animals. In contrast, the rAnhui-HA-226Q virus was not transmitted to sentinel pigs. Deep sequencing of viruses from the lungs of infected pigs identified substitutions arising in the viral population (e.g., PB2-T271A, PB2 D701N, HA-V195I, and PB2-E627K reversion) that may enhance viral replication in pigs. Collectively, the results demonstrate that critical mutations (i.e., HA Q226L) enable the H7N9 viruses to be transmitted in a mammalian host and suggest that the myriad H7N9 genotypes circulating in avian species in China and closely related strains (e.g., H7N7) have the potential for further adaptation to human or other mammalian hosts (e.g., pigs), leading to strains capable of sustained human-to-human transmission. Importance: The genomes of the zoonotic avian H7N9 viruses emerging in China have mutations in critical genes (PB2-E627K and HA Q226L) that may be important in their pandemic potential. This study shows that (i) HA-226L of zoonotic H7N9 strains is critical for binding the alpha-2,6-linked receptor and enables transmission in pigs; (ii) wild-type A/Anhui/1/2013 (H7N9) shows modest replication, virulence, and transmissibility in pigs, suggesting that it is not well adapted to the mammalian host; and (iii) both wild-type and variant H7N9 viruses rapidly develop additional mammalian-signature mutations in pigs, indicating that they represent an important potential intermediate host. This is the first study analyzing the phenotypic effects of specific mutations within the HA and PB2 genes of the novel H7N9 viruses created by reverse genetics in an important mammalian host model. Finally, this study illustrates that loss of-function mutations can be used to effectively identify residues critical to zoonosis/transmission. PMID- 24807723 TI - Proteolytic activation of the porcine epidemic diarrhea coronavirus spike fusion protein by trypsin in cell culture. AB - Isolation of porcine epidemic diarrhea coronavirus (PEDV) from clinical material in cell culture requires supplementation of trypsin. This may relate to the confinement of PEDV natural infection to the protease-rich small intestine of pigs. Our study focused on the role of protease activity on infection by investigating the spike protein of a PEDV isolate (wtPEDV) using a reverse genetics system based on the trypsin-independent cell culture-adapted strain DR13 (caPEDV). We demonstrate that trypsin acts on the wtPEDV spike protein after receptor binding. We mapped the genetic determinant for trypsin-dependent cell entry to the N-terminal region of the fusion subunit of this class I fusion protein, revealing a conserved arginine just upstream of the putative fusion peptide as the potential cleavage site. Whereas coronaviruses are typically processed by endogenous proteases of the producer or target cell, PEDV S protein activation strictly required supplementation of a protease, enabling us to study mechanistic details of proteolytic processing. Importance: Recurring PEDV epidemics constitute a serious animal health threat and an economic burden, particularly in Asia but, as of recently, also on the North-American subcontinent. Understanding the biology of PEDV is critical for combatting the infection. Here, we provide new insight into the protease-dependent cell entry of PEDV. PMID- 24807724 TI - Hijacking of host calreticulin is required for the white spot syndrome virus replication cycle. AB - We have previously shown that multifunctional calreticulin (CRT), which resides in the endoplasmic reticulum (ER) and is involved in ER-associated protein processing, responds to infection with white spot syndrome virus (WSSV) by increasing mRNA and protein expression and by forming a complex with gC1qR and thereby delaying apoptosis. Here, we show that CRT can directly interact with WSSV structural proteins, including VP15 and VP28, during an early stage of virus infection. The binding of VP28 with CRT does not promote WSSV entry, and CRT-VP15 interaction was detected in the viral genome in virally infected host cells and thus may have an effect on WSSV replication. Moreover, CRT was detected in the viral envelope of purified WSSV virions. CRT was also found to be of high importance for proper oligomerization of the viral structural proteins VP26 and VP28, and when CRT glycosylation was blocked with tunicamycin, a significant decrease in both viral replication and assembly was detected. Together, these findings suggest that CRT confers several advantages to WSSV, from the initial steps of WSSV infection to the assembly of virions. Therefore, CRT is required as a "vital factor" and is hijacked by WSSV for its replication cycle. Importance: White spot syndrome virus (WSSV) is a double-stranded DNA virus and the cause of a serious disease in a wide range of crustaceans that often leads to high mortality rates. We have previously shown that the protein calreticulin (CRT), which resides in the endoplasmic reticulum (ER) of the cell, is important in the host response to the virus. In this report, we show that the virus uses this host protein to enter the cell and to make the host produce new viral structural proteins. Through its interaction with two viral proteins, the virus "hijacks" host calreticulin and uses it for its own needs. These findings provide new insight into the interaction between a large DNA virus and the host protein CRT and may help in understanding the viral infection process in general. PMID- 24807725 TI - Identification of amino acid substitutions with compensational effects in the attachment protein of canine distemper virus. AB - The hemagglutinin (H) gene of canine distemper virus (CDV) encodes the receptor binding protein. This protein, together with the fusion (F) protein, is pivotal for infectivity since it contributes to the fusion of the viral envelope with the host cell membrane. Of the two receptors currently known for CDV (nectin-4 and the signaling lymphocyte activation molecule [SLAM]), SLAM is considered the most relevant for host susceptibility. To investigate how evolution might have impacted the host-CDV interaction, we examined the functional properties of a series of missense single nucleotide polymorphisms (SNPs) naturally accumulating within the H-gene sequences during the transition between two distinct but related strains. The two strains, a wild-type strain and a consensus strain, were part of a single continental outbreak in European wildlife and occurred in distinct geographical areas 2 years apart. The deduced amino acid sequence of the two H genes differed at 5 residues. A panel of mutants carrying all the combinations of the SNPs was obtained by site-directed mutagenesis. The selected mutant, wild type, and consensus H proteins were functionally evaluated according to their surface expression, SLAM binding, fusion protein interaction, and cell fusion efficiencies. The results highlight that the most detrimental functional effects are associated with specific sets of SNPs. Strikingly, an efficient compensational system driven by additional SNPs appears to come into play, virtually neutralizing the negative functional effects. This system seems to contribute to the maintenance of the tightly regulated function of the H-gene encoded attachment protein. Importance: To investigate how evolution might have impacted the host-canine distemper virus (CDV) interaction, we examined the functional properties of naturally occurring single nucleotide polymorphisms (SNPs) in the hemagglutinin gene of two related but distinct strains of CDV. The hemagglutinin gene encodes the attachment protein, which is pivotal for infection. Our results show that few SNPs have a relevant detrimental impact and they generally appear in specific combinations (molecular signatures). These drastic negative changes are neutralized by compensatory mutations, which contribute to maintenance of an overall constant bioactivity of the attachment protein. This compensational mechanism might reflect the reaction of the CDV machinery to the changes occurring in the virus following antigenic variations critical for virulence. PMID- 24807726 TI - African green monkeys recapitulate the clinical experience with replication of live attenuated pandemic influenza virus vaccine candidates. AB - Live attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently, while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of ca vaccine candidates. Importance: Ferrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV. PMID- 24807728 TI - Sex, butterflies and molecular biology: when pigmentation met mimicry. PMID- 24807727 TI - Cytosolic PrP can participate in prion-mediated toxicity. AB - Prion diseases are characterized by a conformational change in the normal host protein PrPC. While the majority of mature PrPC is tethered to the plasma membrane by a glycosylphosphatidylinositol anchor, topological variants of this protein can arise during its biosynthesis. Here we have generated Drosophila transgenic for cytosolic ovine PrP in order to investigate its toxic potential in flies in the absence or presence of exogenous ovine prions. While cytosolic ovine PrP expressed in Drosophila was predominantly detergent insoluble and showed resistance to low concentrations of proteinase K, it was not overtly detrimental to the flies. However, Drosophila transgenic for cytosolic PrP expression exposed to classical or atypical scrapie prion inocula showed a faster decrease in locomotor activity than similar flies exposed to scrapie-free material. The susceptibility to classical scrapie inocula could be assessed in Drosophila transgenic for panneuronal expression of cytosolic PrP, whereas susceptibility to atypical scrapie required ubiquitous PrP expression. Significantly, the toxic phenotype induced by ovine scrapie in cytosolic PrP transgenic Drosophila was transmissible to recipient PrP transgenic flies. These data show that while cytosolic PrP expression does not adversely affect Drosophila, this topological PrP variant can participate in the generation of transmissible scrapie-induced toxicity. These observations also show that PrP transgenic Drosophila are susceptible to classical and atypical scrapie prion strains and highlight the utility of this invertebrate host as a model of mammalian prion disease. Importance: During prion diseases, the host protein PrPC converts into an abnormal conformer, PrPSc, a process coupled to the generation of transmissible prions and neurotoxicity. While PrPC is principally a glycosylphosphatidylinositol-anchored membrane protein, the role of topological variants, such as cytosolic PrP, in prion-mediated toxicity and prion formation is undefined. Here we generated Drosophila transgenic for cytosolic PrP expression in order to investigate its toxic potential in the absence or presence of exogenous prions. Cytosolic ovine PrP expressed in Drosophila was not overtly detrimental to the flies. However, cytosolic PrP transgenic Drosophila exposed to ovine scrapie showed a toxic phenotype absent from similar flies exposed to scrapie-free material. Significantly, the scrapie-induced toxic phenotype in cytosolic transgenic Drosophila was transmissible to recipient PrP transgenic flies. These data show that cytosolic PrP can participate in the generation of transmissible prion-induced toxicity and highlight the utility of Drosophila as a model of mammalian prion disease. PMID- 24807729 TI - Bacillus mesophilum sp. nov., strain IITR-54T, a novel 4-chlorobiphenyl dechlorinating bacterium. AB - The taxonomic position of a Gram-positive, endospore-forming bacterium isolated from soil sample collected from an industrial site was analyzed by a polyphasic approach. The strain designated as IITR-54T matched most of the phenotypic and chemical characteristics of the genus Bacillus and represents a novel species. It was found to biodegrade 4-chlorobiphenyl through dechlorination and was isolated through enrichment procedure from an aged polychlorinated biphenyl-contaminated soil. Both resting cell assay and growth under aerobic liquid conditions using 4 chlorobiphenyl as sole source of carbon along with 0.01% yeast extract, formation of chloride ions was measured. 16S rRNA (1,489 bases) nucleotide sequence of isolated strain was compared with those of closely related Bacillus type strains and confirmed that the strain belongs to the genus Bacillus. Strain IITR-54T differs from all other species of Bacillus by at least 2.1% at the 16S rRNA level, and the moderately related species are Bacillus oceanisediminis (97.9%) followed by Bacillus infantis (97.7%), Bacillus firmus (97.4%), Bacillus drentensis (97.3%), Bacillus circulans (97.2%), Bacillus soli (97.1%), Bacillus horneckiae (97.1%), Bacillus pocheonensis (97.1%) and Bacillus bataviensis (97.1%), respectively. The cell wall peptidoglycan contained meso-diaminopimelic acid and the major isoprenoid quinone was MK-7. Major fatty acids are iso-C15:0 (32.4%) and anteiso-C15:0 (27.4%). Predominant polar lipids are diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The results of physiological and biochemical tests allowed the genotypic and phenotypic distinctiveness of strain IITR-54T with its phylogenetic relatives and suggest that the strain IITR-54T should be recognized as a novel species, for which the name Bacillus mesophilum sp. nov. is proposed. The type strain is IITR 54T (=MTCC 11060T=JCM 19208T). PMID- 24807730 TI - Evaluation of staining susceptibility of resin artificial teeth and stain removal efficacy of denture cleansers. AB - OBJECTIVE: To assess the staining susceptibility of four acrylic resin (Ivostar, SR Vivodent PE, Major Dent, Integral) and a nanocomposite resin (Veracia) artificial teeth and to evaluate the stain removal efficacy of denture cleansers. MATERIALS AND METHODS: Sixty maxillary incisors of each brand (total = 300) were divided into three groups according to staining solution as coffee, red wine and tea. Baseline color measurements were performed with a spectrophotometer. Specimens were immersed in staining solutions for 14 h (2 h * 7 days) and then second color measurements were performed. Each group was further divided into four sub-groups according to denture cleanser as Corega tabs, Fittydent, NaOCl (0.5%) and distilled water (control) (n = 5). Specimens were immersed in denture cleansers for 8 h and third color measurements were made. Thus, the weekly simulation period was completed. This cycle was repeated 12 times to simulate a 3 month time period and measurements were performed at the end of the 4th, 8th and 12th cycles. DeltaE values were calculated and data were analyzed with 3-way repeated measures ANOVA and Bonferroni tests. RESULTS: Significant color differences were found among the teeth and staining solutions, but all of the color differences were in the clinically acceptable range (DeltaE < 5.5). Integral showed the highest DeltaE values for all solutions, while Ivostar and Vivodent demonstrated the lowest DeltaE values for red wine and tea solutions. There was no significant difference among the denture cleansers in terms of stain removal efficacy. CONCLUSIONS: Cross-linked acrylic (Integral) and nanocomposite (Veracia) resin teeth were more susceptible to staining. Denture cleansers were efficient on stain removal from artificial teeth. PMID- 24807732 TI - Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases. AB - The Ki-67 labeling index has been found to bear prognostic significance in gastrointestinal neuroendocrine tumors (NETs), and it was recently incorporated in NET histological grading. Nevertheless, a reliable preoperative determination of NET grading could be useful in clinical practice. The aim of this study is to compare the results of Ki-67 labeling index, as measured on cytological samples and on surgical specimens of patients with pancreatic NETs (P-NETs). We also investigated whether concordance might be improved, using a 5 % (instead of 2 %) cutoff value for defining G2 tumors. We retrospectively identified 48 consecutive patients with 53 P-NETs, from our five institutions, and we measured Ki-67 labeling index on their cytological samples and surgical specimens. The traditional 2 % and the alternative 5 % cutoff values were used to classify G2 tumors. The concordance rate between cytological and histological grading was 46/53 (86.8 %; weighted kappa statistic 0.77; 95 % confidence interval (95 % CI) 0.60-0.94). No cases of cytological G1-G2 NETs were upgraded to G3 neuroendocrine carcinoma (NEC) at histological grading. Cytology was found to be highly specific in the diagnosis of both G2 (94.1 %; 95 % CI 80.3-99.3) and G3 tumors (100.0 %; 95 % CI 92.8-100), but the sensitivity was poor for G2 NETs (66.7 %; 95 % CI 38.4 88.2) and high for the prediction of G3 NECs (100 %; 95 % CI 39.8-100.0). When the 5 % cutoff value was adopted, concordance rate was 49/53 (92.4 %; weighted kappa 0.82; 95 % CI 0.64-1.00). In conclusion, Ki-67 cytological expression can distinguish well-differentiated (both G1 and G2) from poorly differentiated P NETs, and it may be useful for their preoperative classification. PMID- 24807733 TI - Coronary cardiac allograft vasculopathy versus native atherosclerosis: difficulties in classification. AB - Cardiac allograft vasculopathy is regarded as a progressive and diffuse intimal hyperplastic lesion of arteries and veins that leads to insidious vessel narrowing and to allograft ischemic disease, such as acute myocardial infarction or sudden cardiac death. The coronary lesions in transplanted hearts are considered as a particular type of arteriosclerosis with many similarities but also significant differences compared to native coronary atherosclerosis. It is particularly difficult for pathologists to systematically classify the lesions and to elucidate their origins, since over time, the allograft immune responses cause vascular pathology characterized by not only the onset of de novo fibrocellular lesions but also remodeling of already-existing native atherosclerotic lesions in the donor heart. Intraplaque hemorrhages, which result from newly formed leaky microvessels, may cause rapid increase of stenosis and generate a substrate for plaque destabilization. Comparing cardiac allograft vasculopathy from explanted hearts at autopsy with native coronary atherosclerosis from hearts removed at transplantation has revealed that ongoing intraplaque hemorrhages are also an important feature of cardiac allograft vasculopathy and may be important factors in the rapid progression of cardiac allograft vasculopathy. PMID- 24807735 TI - A multifunctional magnetic material under pressure. AB - Fe(II)(Metz)6](Fe(III)Br4)2 (Metz = 1-methyltetrazole) is one of the rare systems combining spin-crossover and long-range magnetic ordering. A joint neutron and X ray diffraction and magnetometry study allows determining its collinear antiferromagnetic structure, and shows an increase of the Neel temperature from 2.4 K at ambient pressure, to 3.9 K at 0.95 GPa. Applied pressure also enables a full high-spin to low-spin switch at ambient temperature. PMID- 24807734 TI - Augmented expression of urokinase plasminogen activator and extracellular matrix proteins associates with multiple myeloma progression. AB - Multiple myeloma (MM) represents a B cell malignancy, characterized by a monoclonal proliferation of malignant plasma cells. Interactions between tumor cells and extracellular matrix (ECM) are of importance for tumor invasion and metastasis. Protein levels of urokinase plasminogen activator (uPA) and fibulin 1, nidogen and laminin in plasma and serum respectively and mRNA levels of these molecules in peripheral blood mononuclear cells were determined in 80 subjects by using ELISA and quantitative PCR and data was analyzed with severity of disease. Pearson correlation was determined to observe interrelationship between different molecules. A statistical significant increase for ECM proteins (laminin, nidogen and fibulin 1) and uPA at circulatory level as well as at mRNA level was observed compared to healthy controls. The levels of these molecules in serum might be utilized as a marker of active disease. Significant positive correlation of all ECM proteins with uPA was found and data also correlates with severity of disease. Strong association found between ECM proteins and uPA in this study supports that there might be interplay between these molecules which can be targeted. This study on these molecules may help to gain insight into processes of growth, spread, and clinical behavior of MM. PMID- 24807736 TI - Predictors of positive surgical margins and their location in Korean men undergoing radical prostatectomy. AB - OBJECTIVE: To evaluate preoperative predictors of positive surgical margins and their location in Korean men undergoing radical prostatectomy. METHODS: A total of 3227 patients who had undergone radical prostatectomy (open, robotic or laparoscopic) for clinically localized prostate cancer at three centers between 2000 and 2010 were analyzed. Patients were stratified by using the D'Amico risk criteria. Positive surgical margins were categorized according to their location. Patients were divided depending on their prostate volume: <29, 29-36, 36-46 and >=46 mL. All of the patients had a minimum of six. A total of 2041 patients (84.9%) underwent 12-14 core biopsies. In each patient, the number and location of positive cores with cancer were assessed. In the analysis of predictive factors for positive surgical margin locations, regression analysis was carried out using only open and robotic prostatectomy. RESULTS: The preoperative prostate specific antigen, prostate volume, biopsy Gleason scores and clinical stage were significantly associated with an increased risk of positive surgical margins. The predictive variables for positive apical margin were small prostate volume (less than 29 mL) and positive apical biopsy. There were no statistically significant predictors for positive posterolateral or basal margin. Positive apical biopsy was the predictor of positive apical margin in open (odds ratio 1.7, P = 0.009) and robotic prostatectomy (odds ratio 2.2, P = 0.041). Small prostate volume was the predictor of positive apical margin in open prostatectomy (odds ratio 1.6, P = 0.012), but for positive basal margin in robotic radical prostatectomy (odds ratio 4.5, P < 0.001). In survival analysis, positive basal margin showed worse prognoses on biochemical recurrence than positive apical margin. CONCLUSIONS: High prostate-specific antigen and small prostate volume are predictive factors of positive surgical margin in Korean patients undergoing radical prostatectomy. Apical positivity on extended transrectal biopsy represents a predictive factor of positive surgical margin. Small prostate volume is associated with higher risk of positive surgical margins at the apex in open radical prostatectomy and at the base in robotic-assisted laparoscopic radical prostatectomy. PMID- 24807738 TI - Variability in the effects of nicotine on different regions of the brain: changes in the concentration of superoxide dismutase isoforms. AB - Previous studies have shown that rats subjected to subchronic treatment with nicotine experience changes in COX-2 (a marker of pro-inflammatory systems) and accumulate lipid hydroperoxides (a marker of oxidative stress) in the CNS (CNSMC, 2010; 10:180-206) (hippocampus, frontoparietal cortex and cerebellar cortex). Such changes are specific to each region since each contains different types of neuronal and glial cells with different nicotine receptors. They also differ in animals exposed to a source of oxidative stress, such as D-amphetamine. This paper discusses the changes in other markers of oxidative stress - the isozymes of superoxide dismutase Mn-SOD and Cu/Zn-SOD - in nicotine- and nicotine + D amphetamine-treated rats. The biochemical and histochemical changes observed were specific to each region (in general very marked in the frontoparietal cortex and the hippocampus but less so in the cerebellar cortex) and each type of neuronal and glial cell. The SODs induced by nicotine may exert a neuroprotective effect via the reduction of oxidative stress. This might be beneficial in the treatment of neurodegenerative diseases. The fact that nicotine did not greatly increase the SODs in the rats treated with D-amphetamine may indicate that the effect of nicotine is partially or totally abolished in situations of oxidative stress. However, since ROS and lipid hydroperoxide levels are also reduced when nicotine is administered to such animals, it could be argued that nicotine is beneficial. PMID- 24807739 TI - Can monitoring consumer requests for opioid-replacement therapy improve access to treatment? AB - OBJECTIVE: This study examined data recorded by one urban publicly funded opioid replacement therapy clinic (from 2009 to 2011) to identify whether these data could be used to inform the rostering of clinicians more effectively to improve access to treatment. METHODS: Data analysis incorporated descriptive and inferential methods. RESULTS: There were trends in the times of the year consumers seek opioid-replacement therapy, similarity and differences between gender requests for treatment and variation in consumer wait time on triage. CONCLUSIONS: National reporting of opioid-replacement therapy triages would help gain a better understanding of the number of people in need of treatment. If opioid-replacement therapy providers monitored consumer triages, they could roster more effectively, have gender-specific clinicians available, acknowledge and inform consumers of wait time on triage and allow re-orientation of services to lower wait time. PMID- 24807740 TI - Chemically-bound xenon in fibrous silica. AB - High-level quantum chemical calculations reported here predict the existence and remarkable stability, of chemically-bound xenon atoms in fibrous silica. The results may support the suggestion of Sanloup and coworkers that chemically-bound xenon and silica account for the problem of "missing xenon" (by a factor of 20!) from the atmospheres of Earth and Mars. So far, the host silica was assumed to be quartz, which is in contradiction with theory. The xenon-fibrous silica molecule is computed to be stable well beyond room temperature. The calculated Raman spectra of the species agree well with the main features of the experiments by Sanloup et al. The results predict computationally the existence of a new family of noble-gas containing materials. The fibrous silica species are finite molecules, their laboratory preparation should be feasible, and potential applications are possible. PMID- 24807741 TI - Efficient solid acid catalyst containing Lewis and Bronsted Acid sites for the production of furfurals. AB - Self-assembled nanoparticulates of porous sulfonated carbonaceous TiO2 material that contain Bronsted and Lewis acidic sites were prepared by a one-pot synthesis method. The material was characterized by XRD, FTIR spectroscopy, NH3 temperature programmed desorption, pyridine FTIR spectroscopy, field-emission scanning electron microscopy, high-resolution transmission electron microscopy, N2 sorption, atomic absorbance spectroscopy, and inductively coupled plasma optical emission spectroscopy. The carbonaceous heterogeneous catalyst (Glu-TsOH-Ti) with a Bronsted-to-Lewis acid density ratio of 1.2 and more accessible acid sites was effective to produce 5-hydroxymethylfurfural and furfural from biomass-derived mono- and disaccharides and xylose in a biphasic solvent that comprised water and biorenewable methyltetrahydrofuran. The catalyst was recycled in four consecutive cycles with a total loss of only 3 % activity. Thus, Glu-TsOH-Ti, which contains isomerization and dehydration catalytic sites and is based on a cheap and biorenewable carbon support, is a sustainable catalyst for the production of furfurals, platform chemicals for biofuels and chemicals. PMID- 24807742 TI - The mycosphere constitutes an arena for horizontal gene transfer with strong evolutionary implications for bacterial-fungal interactions. AB - In the microhabitat that surrounds fungal hyphae in soil, coined the mycosphere, carbonaceous compounds that are released from the hyphae stimulate the growth of heterotrophic bacteria, and thus activate organism-to-organism contacts through genetic interactions. Therefore, the mycosphere is postulated to constitute a gene transfer arena, in which a plethora of genes, including locally adaptive ones, are swapped across the resident microbial communities. Such genetic transfers may have plasmids, in particular ones with broad host ranges, as the basis. Indeed, evidence is increasing for the contention that plasmids play crucial roles as accelerators of evolution in the mycosphere, serving as a horizontal gene pool and, therefore, providing competence factors to local bacteria as well as fungi. The evidence so far points at mycosphere roles for two major plasmid classes, the IncP-1 and PromA groups. Moreover, recent data indicate that bacterium-to-fungus gene transfers are detectable and have been evolutionarily important. The large gene pool present in the mycosphere, coupled with the chances for cell-to-cell contact between mycosphere dwellers allows enhanced recombination frequencies, and as such, organisms are selected locally for enhanced fitness. PMID- 24807743 TI - Using non-human primates to benefit humans: research and organ transplantation. AB - Emerging biotechnology may soon allow the creation of genetically human organs inside animals, with non-human primates (henceforth simply "primates") and pigs being the best candidate species. This prospect raises the question of whether creating organs in primates in order to then transplant them into humans would be more (or less) acceptable than using them for research. In this paper, we examine the validity of the purported moral distinction between primates and other animals, and analyze the ethical acceptability of using primates to create organs for human use. PMID- 24807745 TI - Health-care needs and shared decision-making in priority-setting. AB - In this paper we explore the relation between health-care needs and patients' desires within shared decision-making (SDM) in a context of priority setting in health care. We begin by outlining some general characteristics of the concept of health-care need as well as the notions of SDM and desire. Secondly we will discuss how to distinguish between needs and desires for health care. Thirdly we present three cases which all aim to bring out and discuss a number of queries which seem to arise due to the double focus on a patient's need and what that patient desires. These queries regard the following themes: the objectivity and moral force of needs, the prediction about what kind of patients which will appear on a micro level, implications for ranking in priority setting, difficulties regarding assessing and comparing benefits, and implications for evidence-based medicine. PMID- 24807744 TI - Scientific second-order 'nudging' or lobbying by interest groups: the battle over abdominal aortic aneurysm screening programmes. AB - The idea that it is acceptable to 'nudge' people to opt for the 'healthy choice' is gaining currency in health care policy circles. This article investigates whether researchers evaluating Abdominal Aortic Aneurysm Screening Programmes (AAASP) attempt to influence decision makers in ways that are similar to popular 'nudging' techniques. Comparing two papers on the health economics of AAASP both published in the BMJ within the last 3 years, it is shown that the values chosen for the health economics modelling are not representative of the literature and consistently favour the conclusions of the articles. It is argued (1) that this and other features of these articles may be justified within a Libertarian Paternalist framework as 'nudging' like ways of influencing decision makers, but also (2) that these ways of influencing decision makers raise significant ethical issues in the context of democratic decision making. PMID- 24807746 TI - Desmodesmus sp. 3Dp86E-1-a novel symbiotic chlorophyte capable of growth on pure CO2. AB - A novel chlorophyte Desmodesmus sp. 3Dp86E-1 isolated from a White Sea hydroid Dynamena pumila was cultivated at CO2 levels from atmospheric (the 'low-CO2' conditions) to pure carbon dioxide (the 5, 20, and 100 % CO2 conditions) under high (480 MUE/(m(2) s) PAR) light. After 7 days of cultivation, the '100 % CO2' (but not 5 or 20 % CO2) cells possessed ca. four times higher chlorophyll content per dry weight (DW) unit than the low-CO2 culture. The rate of CO2 fixation under 100 % CO2 comprised ca. 1.5 L/day per L culture volume. After a lag period which depended on the CO2 level, biomass accumulation and volumetric fatty acid (FA) content of the Desmodesmus sp. 3Dp86E-1 bubbled with CO2-enriched gas mixtures increased and was comparable to that of the culture continuously bubbled with air. Under the low-to-moderate CO2 conditions, the FA percentage of the algal cells increased (to 40 % DW) whereas under high-CO2 conditions, FA percentage did not exceed 15 % DW. A strong increase in oleate (18:1) proportion of total FA at the expense of linolenate (18:3) was recorded in the '100 % CO2' cells. Electron microscopy and pulse-amplitude-modulated chlorophyll fluorescence investigation revealed no damage to or significant downregulation of the photosynthetic apparatus in '100 % CO2' cells grown at the high-PAR irradiance. Possible mechanisms of high-CO2 tolerance of Desmodesmus sp. 3Dp86E-1 are discussed in view of its symbiotic origin and possible application for CO2 biomitigation. PMID- 24807747 TI - Antibiotics are not beneficial in the management of category III prostatitis: a meta analysis. AB - PURPOSE: To determine whether antibiotics are beneficial in the management of category III prostatitis. MATERIALS AND METHODS: The PubMed, Medline and Embase databases were searched for all published documents from January 1, 1965 to September 1, 2012 without language restriction. The randomized controlled trials that mentioned comparable groups of antibiotics treatment versus placebo or other control group for patients with category III prostatitis were included based on specific criteria. The quality of studies was assessed by the modified Jadad scale, and Revman 5.0 software was used for data syntheses and analysis. RESULTS: Seven studies which met the selection criteria were included in this review. All of them were high quality according to the modified Jadad scale. A random effect model was applied because of the high heterogeneity. The meta-analysis showed that summary association between category III prostatitis and antibiotics were not statistically significant. CONCLUSION: Our meta-analysis reveals that antibiotics are not beneficial in the management of category III prostatitis. Therefore, we may reduce the usage of antibiotics in such a population. PMID- 24807748 TI - Blind versus fluoroscopy-guided percutaneous nephrolithotomy: a randomized clinical trial. AB - PURPOSE: Due to the negative impact of radiation on the patient and the surgical team during percutaneous nephrolithotomy (PCNL), we aimed to evaluate success rate and complications of blind access for PCNL using lumbar notch landmark and compare with conventional fluoroscopy-guided access. MATERIALS AND METHODS: In a clinical trial, 100 patients who were candidate for PCNL, were randomly assigned into blind group (1) and fluoroscopy-guided group (2). In group 1 the lumbar notch was used to guide percutaneous access and in group 2 fluoroscopy performed after needle insertion, Amplatz placement and at the end of surgery. If the access failed, we would repeat puncturing up to 5 times. In group 2, access was achieved using full fluoroscopy guidance. All patients underwent postoperative assessment including kidney-ureter-bladder X-ray and ultrasonography. RESULTS: Both mean access time and mean operation time were statically similar in group 1 and group 2 (3.3 +/- 0.5 vs. 3.6 +/- 0.7 min and 35.2 +/- 4.6 vs. 38.9 +/- 4.1 min, respectively). A successful puncture was achieved in 86% and 94% of the patients in groups 1 and 2, respectively (P = .18). Total success rate of procedure was 80% and 88% of the patients in groups 1 and 2, respectively (P = .27). CONCLUSION: According to this study, it seems that blind access is a safe and effective PCNL method, and we recommend employment of this technique by skilled endourologist in urology centers especially for patient with large hydronephrotic kidney. PMID- 24807749 TI - Management of calculus anuria using ureteroscopic lithotripsy as a first line treatment: its efficacy and safety. AB - PURPOSE: To present our experience with emergency ureteroscopic lithotripsy (URSL) for ureteral calculi associated with acute kidney injury (AKI). MATERIALS AND METHODS: We retrospectively evaluated the 61 patients consisted of 90 ureteral units (UU), who underwent URSL. The cause of anuria was bilateral calculus obstructions in 29 cases, and unilateral calculus obstruction with, absent, nephrectomized contralateral kidney in 32 cases. In the case of bilateral synchronous ureteric calculi same-session bilateral ureteroscopy (SBBU) was done. The duration of anuria varied between 12 to 72 hours. At the end of the procedure, ureteral stent was systematically left in place in all patients. Surgery was performed 6-12 hours after admission to hospital. Patients were followed at least 1 month postoperatively. RESULTS: The stone free rates (SFR) were determined as baseline, on the first post-operative day, and as overall on the 30 days after procedure. The greatest success was achieved in the distal localization of stones up to 10 mm (93%). Renal function returned in 51 (83.6%) patients within 7 days. In 18 (29.5%) patients [18 (20%) UU] we performed second procedure as extracorporeal shockwave lithotripsy in 16.7% and open surgery in 2.2%. In 43 (70.5%) patients URSL was a successful therapeutic approach in dealing with pain, obstruction and calculus. CONCLUSION: Calculus anuria is a medical emergency that requires rapid diagnosis and prompt treatment for the purpose of decompression. URSL is the proper method of choice for selected patients and can be performed safely and has high success rates with minimal morbidity. PMID- 24807750 TI - The assessment of thiol status in children with neurogenic bladder caused by meningomyelocele. AB - PURPOSE: Oxidative stress can cause tissue damage in many diseases. Oxidative status depends on the balance between total oxygen radical absorbance capacity and antioxidants. Neurogenic bladder (NB) is a special state where oxidative status can influence urinary tract function. We decided to measure antioxidant (thiol) status in patients with NB and assess the effect of NB on the urinary antioxidant status and to correlate it with urodynamic findings. MATERIALS AND METHODS: The investigation was conducted on two groups. The first group, constituted of 41 children with NB. The second group, consisted of 20 healthy children with no abnormality in urinary and nervous systems. The antioxidant status was assessed based on the enzyme-linked immunosorbent assay of thiols. RESULTS: The median value of urinary protein thiol level was significantly lower in NB patients than in reference group [median 48 (0.0-633.33) and 221.55 (0.17 1293] MUmoL/g protein, respectively (P < .01). We found out the statistically significant differences in urinary thiol level between patients with and without overactivity (P = .017) and between catheterized and noncatheterized patients (P = .048). CONCLUSION: This study demonstrates that antioxidant status in patients with NB decreased and the level of thiol status depends on the grade of bladder overactivity. Oxidative stress may be involved in the pathophysiology of bladder dysfunction related to neurogenic damage. PMID- 24807751 TI - Circumcision in bleeding disorders: improvement of our cost effective method with diathermic knife. AB - PURPOSE: Circumcision is a very common surgical procedure that has been performed for thousands of years. In this paper, we report the long-term results of circumcision performed by using diathermic knife on patients with bleeding diathesis and the amount of blood factors used. MATERIALS AND METHODS: A total of 147 patients with bleeding diathesis circumcised under local anesthesia by using diathermic knife between 1996 and 2010 were recruited into this study. Age of the patients, type of the bleeding diathesis and the treatment protocols were recorded. Postsurgical infection and bleeding rates of 2 different factor replacement protocols were recorded. RESULTS: Mean age of the patients was 11.5 years (range, 1.5-37 years). In the group of protocol 1 applied patients, 3 patients (4%) had bleeding and one patient had infection whereas in group of protocol 2, 4 patients (5.4%) had bleeding. The bleeding cases were taken under control after the factor replacement and elastic bandage. CONCLUSION: Whenever it is necessary for an individual to be circumcised for any reason whatsoever, we think that circumcision can be performed in the patients with bleeding diathesis with lower costs and complication rates by using diathermic knife and the protocol that we used. PMID- 24807752 TI - Determining external genital abnormalities with a pre-circumcision examination in previously undiagnosed male school children. AB - PURPOSE: We investigated whether children getting ready for circumcision under local anesthesia had any additional genital region abnormalities not detected before the circumcision. MATERIALS AND METHODS: We performed circumcision under local anesthesia for children with normal physical examination findings, and together with corrective surgery for those with other genital anomalies among the children aged 6 years old and over presenting at the pediatric surgery department of our hospital during the school break. RESULTS: Circumcision was planned under local anesthesia in a total of 1,695 cases aged between 6 and 17 years during the June to September 2010 and 2011 periods. We found an external genital anomaly in the pre-circumcision physical examination in 58 patients (3.4%), with a mean age of 7.87 +/- 1.49 years. These patients were operated on with corrective surgery while 1,637 children underwent circumcision under local anesthesia. The most common anomaly was inguinal hernia seen in 14 (24.1%), followed by hypospadias in 11 (18.9%), hydrocele in 9 (15.9%) and undescended testis in 8 (13.8%). CONCLUSION: In countries where circumcision is traditional, an intervention room within the hospital to perform circumcision under local anesthesia can enable many children to be circumcised under hospital conditions and previously undetected genital abnormalities to be found with a pre-circumcision genital region examination. PMID- 24807753 TI - The effect of selective renal parenchymal clamping during laparoscopic partial nephrectomy on early postoperative renal function: a preliminary report. AB - PURPOSE: A major concern when performing laparoscopic partial nephrectomy (LPN) is potential postoperative renal dysfunction. The objective of this study was to compare the effects of LPN with selective renal parenchymal clamping (SRPC) (LPNSRPC) and LPN using microwave tissue coagulation (MTC) (LPNMTC) on postoperative renal function. MATERIALS AND METHODS: This study included 12 patients (5 men and 7 women) who underwent LPNSRPC (n = 6) or LPNMTC (n = 6) for exophytic tumors. Renal scanning with technetium-99m diethylenetriaminepentaacetic acid (Tc-99m DTPA) was performed preoperatively and postoperatively at 1 month in all patients. RESULTS: The mean tumor size, surgical duration, and intraoperative blood loss were similar in both groups. In the LPNMTC group, although not significant, the mean postoperative glomerular filtration rate (GFR) values in the affected kidneys were decreased compared to the preoperative values. When evaluating the affected renal function by split function (SF), the mean postoperative SF in the affected kidneys was significantly decreased compared to the preoperative value. In the LPNSRPC group, the mean postoperative GFR and SF in the affected kidneys were not significantly changed compared with the preoperative values. CONCLUSION: Our preliminary experience demonstrates that LPNSRPC facilitates maximal nephron-sparing surgery without collateral thermal damage causing renal impairment. PMID- 24807754 TI - Comparison of laparoscopic and open ureterolithotomy in impacted and very large ureteral stones. AB - PURPOSE: To compare the efficacy of laparoscopic and open ureterolithotomy in patients with ureteral stones. MATERIALS AND METHODS: Patients who had undergone open or laparoscopic ureterolithotomy between 2001 and 2013 in our clinic were enrolled in the study.Ureterolithotomy was performed due to the following reasons: failure to position the patient for ureteroscopy, unreachable stone with ureteroscopy also use of balloon dilatation, high stone volume, and the need for removal of kidney stones at the same session.. The patients' demographic data, the volume of the stones, the duration of the operation and the hospital stay, the amount of analgesics administered after the operation, and the need for another procedure were compared. RESULTS: Of study subjects 32 patients had undergone open and 20 patients had undergone laparoscopic ureterolithotomy. When the two groups were compared, there was no statistically significant difference with regard to the mean age (44.5-44 years), the body mass index (26-24.7 kg/m2), the stone volume (420-580 mm3), the duration of operation (122-123 min), the need for another procedure and complications. The mean amount of analgesics administered after the operation (3.6 and 1.81 doses, P = .02) and the mean hospital stay (6.1 and 2.9 days, P = .01) were significantly lower in the laparoscopic ureterolithotomy group. CONCLUSION: Laparoscopic ureterolithotomy is a good alternative with less need for analgesia and a shorter hospital stay when compared with open ureterolithotomy. PMID- 24807755 TI - Can non-urological doctors play a role in early prostate cancer detection? AB - PURPOSE: To evaluate the awareness of non-urological doctors for their role in evaluating prostate cancer (Pca) in scientific manner which may be a possible probability for late diagnosis of Pca. MATERIALS AND METHODS: A total of 936 non urological specialists working in 1 university and 4 education and research hospital who were able to evaluate male patients over 50 years of age were included to the survey. A face to face questionnaire had been administered to all participants. RESULTS: A total of 92 (9.8%) participants were evaluating prostate specific antigen (PSA) level to all their elderly male patients while 404 (43.2%) participants had never made this evaluation. Among the participants who were evaluating PSA, none was performing an informed decision making consult and even they did not have any idea about the meaning of this strategy. About the criteria for urological consultation, 56 (6%) reported that they consult all their elderly male patients, whereas 880 (94%) answered that they perform consultation if their patients has sought help for any urological symptom. CONCLUSION: Urologists must remind the non-urological specialists that their approaches to Pca evaluation may change mortality rates of this disease and give them proper information about the scientific evaluation of Pca. This may help us to decrease the mortality rates of Pca. PMID- 24807756 TI - Postoperative nomogram for disease recurrence and cancer-specific death for upper tract urothelial carcinoma: comparison to American Joint Committee on Cancer staging classification. AB - PURPOSE: We sought to develop prognostic models to predict disease recurrence and cancerspecific mortality in patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). MATERIALS AND METHODS: Data on 253 patients treated with RNU between 1995 and 2008 at a single high-volume tertiary referral center were analyzed. Statistically and clinically significant patient and tumor characteristics were identified in a univariate analysis and incorporated into a multivariable Cox regression model. The model was compared to the 2010 American Joint Committee on Cancer (AJCC) staging classification using the concordance index (c-index), corrected for statistical optimism using bootstrap methods. RESULTS: Five-year recurrence-free survival (RFS) and cancer specific survival (CSS) rates were 73% [95% confidence interval (CI): 66-79%)] and 78% (95% CI: 71-84%), respectively. On multivariate analysis, higher preoperative glomerular filtration rate (GFR) was associated with better CSS [hazard ratio (HR) per 1 mL/min/m2 increase in GFR for CSS: 0.74; P = .002)], while higher pathologic stage (HR for pT2: 2.99 and for >= pT3: 7.34; P < .001) and lymph node involvement (HR: 3.75; P < .001) were associated with worse CSS; results were similar for RFS. The ability of the final models, which included preoperative GFR, lymph node status, pathologic grade, and stage, to predict RFS and CSS (c-index 0.82 and 0.83, respectively) was similar to that of the 2010 AJCC staging classification (c-index 0.80 and 0.81, respectively). CONCLUSION: Given the data-dependent selection of variables in this single institution cohort, it is unlikely that the marginal improvement found with these prediction models would importantly impact clinical decision-making or improve patient care. The 2010 AJCC staging classification alone is very accurate and should continue to guide follow-up after RNU. PMID- 24807757 TI - Kidney sparing surgery for urothelial carcinoma of the pyelocalyceal system: is there a role for open techniques? Results from a small series. AB - PURPOSE: To evaluate individually tailored open nephron-sparing surgical techniques for urothelial carcinoma of the pyelocalyceal system (UCPCS). MATERIALS AND METHODS: Four patients underwent nephron-sparing surgery for UCPCS including, open partial resection of the pyelon with peritoneal reconstruction, partial nephrectomy, open partial resection of the pyelon with kidney autotransplantation, combined open resection and calicoscopic laser coagulation. RESULTS: Recurrence-free survival was 24 months without any impairment of kidney function in all patients. CONCLUSION: Open nephron-sparing surgery for UCPCS should be taken into consideration for selected cases. PMID- 24807758 TI - Impact of urinary incontinence on quality of life among residents living in Turkey. AB - PURPOSE: To assess the impact of urinary incontinence on the quality of life in Turkish population. MATERIALS AND METHODS: This was a cross-sectional study performed on 530 participants admitted to Sevket Yilmaz Research Hospital in Turkey. Quality of life (QoL) was assessed using Incontinence Impact Questionnaire (IIQ-7). Frequency and severity of urinary incontinence (UI) were diagnosed by answers to the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) instrument. The relationship between several demographic data and QoL was examined. RESULTS: The mean age of the attendees was 55.36 +/- 10.62 years (range 40-91). A total of 109 (44%) women and 46 (16%) men suffered involuntary urine leakage. QoL changes for all domains showed significant deteriorations. Frequency and severity of UI were negatively associated with the QoL scores. CONCLUSION: Our results have shown that, UI considerably worsens QoL. Challenge with UI should be priority of any project aiming to promote the quality of life. PMID- 24807759 TI - Percutaneous no-scalpel vasectomy via one puncture in China. AB - PURPOSE: To evaluate the efficacy and postoperative morbidity of percutaneous no scalpel vasectomy (NSV) via one puncture in China. MATERIALS AND METHODS: A total of 150 men visiting outpatient clinic of the surgery department of urology, Huashan Hospital and its Baoshan branch of Fudan University, opted for percutaneous NSV with local anesthesia. The clinical data of 150 who underwent modified NSV (MNSV) were retrospectively compared with those of 120 patients who underwent standard NSV (SNSV). The results and follow-up were recorded. RESULTS: The reviewed average operative time was 9.8 min (range 8 to 20 min). Average incisional length was 5 mm (range 4 to 8 mm). Patients reported complete recovery in an average of 8.5 days (range 4 to 14 days). The complication rates were extremely low with this modified technique. Only one case of late healed incision was observed (0.67%). CONCLUSION: Percutaneous NSV via one puncture was proved to be a painless and effective form of permanent contraception with an extremely low complication rate. PMID- 24807760 TI - Comparison of different autogenous graft materials for reconstruction of large segment vas deferens defect: experimental study in rat. AB - PURPOSE: Vasectomy is one of the most common urological operations performed, and provides permanent contraception. Many vasectomized men ultimately seek vasectomy reversal because of unforeseen changes in lifestyle. Vasovasostomy has varying rates of success. In this study, we utilize vas deferens (VD), artery, and vein grafts to reconstruct 30% and 50%defects of the total vas deferens length. MATERIALS AND METHODS: Forty two male Wistar rats were divided into three groups as VD graft, carotid artery and external jugular vein transplantations. Each group was equally divided into 2 different subgroups according to the length of transplant material as 1.0 cm (n = 7) and 1.5 cm (n = 7). To evaluate whether these materials may be used for long segment vas deferens reconstruction, the patency rate, partial or total graft occlusion, and histologic examination of all specimens were examined. RESULTS: No patency was found in any of the grafts and many of them suffered destructive changes in anatomic structure. Sperm granulomas were determined around the testicular side anastomosis due to accumulated semen fluid which was in our belief, a result of aperistaltic zone caused by the grafts. CONCLUSION: When the poor results obtained in our study are put into perspective, vasoepididymostomy is the only treatment method to date for reconstruction of large segment vas deferens defects. PMID- 24807761 TI - Vitrification of neat semen alters sperm parameters and DNA integrity. AB - PURPOSE: Our aim was to evaluate the effect of neat semen vitrification on human sperm vital parameters and DNA integrity in men with normal and abnormal sperm parameters. MATERIALS AND METHODS: Semen samples were 17 normozoospermic samples and 17 specimens with abnormal sperm parameters. Semen analysis was performed according to World Health Organization (WHO) criteria. Then, the smear was provided from each sample and fixed for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Vitrification of neat semen was done by plunging cryoloops directly into liquid nitrogen and preserved for 7 days. The samples were warmed and re-evaluated for sperm parameters as well as DNA integrity. Besides, the correlation between sperm parameters and DNA fragmentation was assessed pre- and post vitrification. RESULTS: Cryopreserved spermatozoa showed significant decrease in sperm motility, viability and normal morphology after thawing in both normal and abnormal semen. Also, the rate of sperm DNA fragmentation was significantly higher after vitrification compared to fresh samples in normal (24.76 ± 5.03 and 16.41 ± 4.53, P = .002) and abnormal (34.29 ± 10.02 and 23.5 ± 8.31, P < .0001), respectively. There was negative correlation between sperm motility and sperm DNA integrity in both groups after vitrification. CONCLUSION: Vitrification of neat ejaculates has negative impact on sperm parameters as well as DNA integrity, particularly among abnormal semen subjects. It is, therefore, recommend to process semen samples and vitrify the sperm pellets. PMID- 24807762 TI - Editorial comment on: Vitrification of neat semen alters sperm parameters and DNA integrity. PMID- 24807763 TI - Short-term survival in renal transplantation from brain-death donors: focusing on recipients with diabetes background. AB - PURPOSE: Our aim was to evaluate short term survival rates in renal transplant recipients from deceased donors, while focusing on recipients with diabetes mellitus background. MATERIALS AND METHODS: This is a longitudinal follow-up study based on national registry of recipients in Ministry of Health and Medical Education in Iran from 2010-11. Five hundred fifty-five recipients, 226 (40.8%) females and 328 (59.2%) males, were included in the study. Mean (+/- SD) age of the recipients was 39 +/- 14 years. Of donors 18.4% were females and 81.6% were males. Age of the donors was 33 +/- 14 years. All allograft recipients from deceased donors enrolled in the study. Short-term graft survival (1 year) was determined. Data regarding age, gender, background disease and cold ischemic time of recipients and donors were collected from the organ procurement units. RESULTS: Allografts were functioning in 499 (90.1%) of recipients after one year. Of recipients 38 (6.9%) died and rejection of transplanted kidney occurred in 17 (3.1%) cases. So, in 55 (9.9%) cases, allografts were not functioning. There were significant relationships between short term graft survival of donors' gender, age of recipients, cold ischemic time and level of clearance of creatinine of recipients. CONCLUSION: In addition to cold ischemic time, graft survival can be affected by recipients' age. There are some other considerations and implications regarding the short term graft survival in renal transplantation from cadaver donors which are discussed in this paper. PMID- 24807764 TI - Changes in bacterial species and antibiotic sensitivity in intensive care unit: acquired urinary tract infection during 10 years interval (2001-2011). AB - PURPOSE: Patients in the intensive care unit (ICU) are usually at greater risk for acquiring urinary tract infections (UTIs). Few studies have focused on UTIs specifically acquired within the ICU. We studied the change in bacterial species causing UTIs in ICU admitted patients in 2001 and 2011. MATERIALS AND METHODS: We reviewed the medical records of a total of 2,890 ICU patients who had undergone urine culture in 2001 and 2011 at the Yeouido and Bucheon St. Mary's hospitals. Changes in causative organisms and their antibiotic sensitivity between the years 2001 and 2011 were analyzed. RESULTS: Escherichia coli (E. coli) was the most common organism in ICU-acquired UTIs in 2001 and 2011 in our study. The pathogens that significantly increased in 2011 compared to 2001 were Pseudomonas, and Klebsiella species (P < .05). In 2011 gram-negative organisms showed relatively higher sensitivities to amikacin, imipenem, and tazocin (72.0%, 77.5% and 76.1%, respectively), whereas they showed relatively lower sensitivities to third generation cephalosporins and ciprofloxacin (55.2% and 45.0%, respectively). In 2011 gram-positive organisms showed high sensitivities to teicoplanin and vancomycin (91.1% and 87.9%, respectively), whereas they showed low sensitivities to ampicillin and ciprofloxacin (24.1% and 25.5%, respectively). The antibiotic resistance rate of Pseudomonas species was nearly doubles that of E. coli. CONCLUSION: Infections caused by Pseudomonas and Klebsiella species were found to have increased significantly in 2011. Pseudomonas species had a significantly lower susceptibility to antibiotic sensitivity than other identified organisms. PMID- 24807765 TI - Adrenal ganglioneuromas: experience from a retrospective study in a Chinese population. AB - PURPOSE: Ganglioneuromas (GNs) are benign neoplasms of combined neural crest, schwannian,and connective tissue origin, occurring rarely in the adrenal glands. The present study is to share our experience regarding diagnostic and therapeutic management of these tumors. MATERIALS AND METHODS: Adrenal GNs of 15 patients were found incidentally with ultrasonography and were evaluated subsequently with computed tomography (CT) scan. Clinical data as well as follow-up data were collected retrospectively. All the patients received operative resection. RESULTS: The mean age of the patients was 38.4 years (range, 25-52 years; male to female ratio, 2:1). Of study subjects 11 patients had unilateral GN on the right side, and the remaining 4 on the left side. All but 1 patient were asymptomatic. No hormonal secretion was apparent. Mean size of the tumors in CT scan was 6.27 cm (range, 2.5-14 cm), while 10 were larger than 5 cm. Eight patients underwent open adrenalectomy and the remaining 7 underwent laparoscopic anterior adrenalectomy. Histologically, all 15 neoplasms were completely differentiated,mature GN. We had no mortality or significant morbidity. Mean duration of hospitalization was 5.5 days (range, 3-7 days). There was no recurrence, during a mean followup of 5.4 years (range, 1-10 years). CONCLUSION: Pre-operative diagnosis of adrenal GNs remains difficult merely according to physical examination. Therefore, we recommend complete operative resection once malignancy cannot be excluded by pre-operative analyses. Laparoscopic adrenalectomy is a reasonable option, at least for tumors <= 5 cm. PMID- 24807766 TI - Intra urethral human papillomavirus related warts following urinary tract instrumentation. PMID- 24807767 TI - Spinning top urethra on voiding cystourethrogram. PMID- 24807768 TI - 323 renal stones in a functional kidney. PMID- 24807769 TI - Discontinuation of the tyrosine kinase inhibitor sunitinib in patients with metastatic renal cell carcinoma: a case series. AB - PURPOSE: Tyrosine kinase inhibitors (TKI) play a pivotal role in the modern treatment of patients with metastatic renal cell carcinoma (mRCC). Depending on the course and the response, the targeted therapy may last for years. Thus the question arises, if a successful treatment leading to a complete response or at least a stable disease after a partial remission, may be discontinued. MATERIALS AND METHODS: Here we present 3 patients with mRCC treated with sunitinib for at least one year, resulting in a partial response, followed by a stable disease for several years. In these patients, the treatment was interrupted for different medical reasons. RESULTS: After a period of 20, 33 and 34 months, respectively, the metastases of the renal cell cancer showed no signs of progression, neither clinically nor in computed tomography scans, but the side effects of TKI or the medical problem leading to treatment interruption resolved in all patients within a few weeks. CONCLUSION: The discontinuation of the treatment for mRCC with TKI seems to be possible, even in those patients with a partial response only, but no complete remission has been achieved before. PMID- 24807770 TI - Non invasive management of refractory hemorrhage after renal surgery with factor VIIa: report of 3 cases. PMID- 24807771 TI - Epidermoid cyst of the urinary bladder: a rare case. PMID- 24807772 TI - Ampullary tumor caused by metastatic renal cell carcinoma and literature review. AB - We present a case of a 50-year-old man with a metastasis to the ampulla of vater that led to the discovery of renal cell carcinomas.The man was referred to us because of jaundice.Computed tomography (CT) scan of the abdomen showed irregular masses in the right kidney. Magnetic resonance imaging (MRI) revealed dilatation of the bile duct. The patient underwent right nephrectomy and pancreatoduodenectomy. Postoperative histopathologic examination revealed clear cell carcinoma in both the renal and ampullary lesions. After a 5-year follow-up ,the patient was alive with no evidence of recurrent disease. PMID- 24807773 TI - Suspected ketamine-associated lower urinary tract symptoms. PMID- 24807774 TI - Digital tomosynthesis: an innovative tool for challenging diagnoses in urology. PMID- 24807775 TI - Isolated congenital megacystis with spontaneous resolution: an exceedingly rare entity. PMID- 24807776 TI - Laparoscopic management of symptomatic giant adrenal pseudocyst: a case report. PMID- 24807777 TI - Cavernous hemangioma of the female urethra: a rare case report. PMID- 24807778 TI - Intracerebral hemorrhage after sildenafil citrate use: an incidental association? PMID- 24807779 TI - Complete supine tubeless percutaneous nephrolithotomy. PMID- 24807780 TI - Same session transureteral lithotripsy and laparoscopy: a case of ureteral stone with abdominal forgotten gauze after four years. PMID- 24807781 TI - Laparoscopic redo-pyeloplasty using vertical flap technique. PMID- 24807782 TI - Changes in opioid and other analgesic use 1995-2010: repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland. AB - BACKGROUND: Despite recent concerns about increasing rates of analgesic prescribing, detailed epidemiological studies are lacking. We identified and described changes in the pattern of community-dispensed prescriptions to the Tayside population, Scotland, between 31st March 1995 (n = 301,020) and 31st March 2010 (n = 311,881). METHODS: Repeated cross-sectional analysis of patient level population data on dispensed analgesics, stratified by sociodemographic variables; logistic regression to identify factors associated with strong opioid dispensing in 2010. RESULTS: The proportion of people currently dispensed any analgesic increased in 2010 (17.9%) compared with 1995 (15.7%). This increase was not equal across drug classes, with paracetamol, opioids and gabapentin/pregabalin showing an increase, but others showing a decrease. Weak opioids were less commonly dispensed in 2010 (8.2% vs. 8.4%) but dispensing of strong opioids increased 18-fold (3.6% vs. 0.2%), including a five-fold increase of morphine, fentanyl or oxycodone (0.75% vs. 0.15%). People receiving more non analgesic drugs (odds ratio 20.7 if dispensed >14 non-analgesic medications vs. those dispensed <4) and those living in more deprived areas (OR 1.63 most deprived vs. most affluent) were more likely to receive a strong opioid in 2010. CONCLUSIONS: Analgesic use rose modestly between 1995 and 2010, but with larger changes within individual classes, only partly reflecting evidence-based guidance. Dispensing of strong opioids increased dramatically, largely driven by tramadol, although other strong opioids tripled. Polypharmacy and socio-economic deprivation were strongly associated with strong opioid use. Research is needed to establish the causes, benefits and harms of the increase in analgesic, and especially strong opioid use. PMID- 24807783 TI - Chrysanthemum zawadskii extract induces hair growth by stimulating the proliferation and differentiation of hair matrix. AB - Chrysanthemum zawadskii has been proven to possess hair growth activity and has been used as treatment for hair loss. The aim of this study was to provide a novel explanation of the mechanism by which Chrysanthemum zawadskii extracts (CZe) promote hair growth and to characterize the affected hair follicle (HF) regions and the progression of growth. The n-butanol and water fractions of CZe were used for hair growth induction by topical application to the backs of C57BL/6 mice for up to 30 days. To investigate cell development during HF morphogenesis, bromodeoxyuridine-labeled skin sections were detected using immunohistochemistry. The results showed that the water fraction of CZe promoted hair shaft production and induced premature entry of telogen HFs into the anagen. Subsequently, immunohistochemical studies indicated that the water fraction of CZe stimulated the differentiation and proliferation of pluripotent epidermal matrix cells in the matrix region and epithelial stem cells in the basal layer of the epidermis. Additionally, flavonoids were identified as effective constituents. Therefore, the findings of this study suggested that the water fraction of CZe may be developed as a therapeutic agent for the prevention of hair loss. PMID- 24807784 TI - The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. AB - OBJECTIVE: The aim of the present study was to investigate the psychometric properties of the Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS P), the first specific interview for emerging bipolar disorder (BD) symptoms. METHODS: A total of 205 youth aged 12-23 years and/or their caregivers underwent BPSS-P interviews: 129 patients with mood spectrum disorders [depression spectrum disorder (n = 77), mood disorder not otherwise specified (NOS) (n = 27), BD-NOS (n = 14), bipolar I disorder (BD-I)/bipolar II disorder (BD-II)/cyclothymia (n = 11), 34 with non-mood spectrum disorders, and 42 healthy controls (HCs)]. We used Cronbach's alpha to assess internal consistency; intra-class correlation (ICC) for inter-rater reliability; Spearman's rho for convergent validity with the Young Mania Rating Scale (YMRS), General Behavior Inventory-10-item Mania Form (GBI-M-10), and Cyclothymic-Hypersensitive Temperament (CHT) scale; and analysis of variance for discriminatory power between diagnostic groups. RESULTS: Internal consistency was good to very good for the BPSS-P Mania (Cronbach's alpha = 0.87), Depression (Cronbach's alpha = 0.89), and General Symptom indices (Cronbach's alpha = 0.74). Inter-rater reliability was high for the BPSS-P Total score (ICC = 0.939), and BPSS-P Mania (ICC = 0.934), Depression (ICC = 0.985), and General (ICC = 0.981) indices. Convergent validity was large (rho >= 0.50) between the BPSS-P Mania Index and YMRS, GBI-M-10, and CHT; BPSS-P Depression Index and Montgomery-Asberg Depression Rating Scale (MADRS) and CHT; and BPSS-P General Index and GBI-M-10 and CHT. Expectedly, convergent validity was small (rho = 0.10 to < 0.30) between the BPSS-P Mania Index and MADRS, and BPSS-P Depression Index and YMRS. Furthermore, the BPSS-P and its subscales discriminated each patient group from HCs and from non-mood spectrum patients (except for the BPSS-P General Index). Moreover, the BPSS-P Total score discriminated BD-I/BD-II/cyclothymia from depression spectrum patients, and the BPSS-Mania Index differentiated all three bipolar spectrum groups from depression spectrum patients. CONCLUSIONS: The BPSS-P has good to excellent psychometric properties. Its use across multiple settings and predictive validity requires further investigation. PMID- 24807785 TI - MicroRNA-133 modulates the beta1-adrenergic receptor transduction cascade. AB - RATIONALE: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate beta-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of beta-adrenergic receptors leads to impaired cardiac function, and beta-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. OBJECTIVE: To determine whether miR-133 affects beta adrenergic receptor signaling during progression to heart failure. METHODS AND RESULTS: Based on bioinformatic analysis, beta1-adrenergic receptor (beta1AR) and other components of the beta1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective beta1AR stimulation. Furthermore, gain-of function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic beta1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR 133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice. CONCLUSIONS: miR-133 controls multiple components of the beta1AR transduction cascade and is cardioprotective during heart failure. PMID- 24807786 TI - Myostatin regulates energy homeostasis in the heart and prevents heart failure. AB - RATIONALE: Myostatin is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes, including enhanced insulin sensitivity. However, the function of myostatin in the heart is barely understood, although it is upregulated in the myocardium under several pathological conditions. OBJECTIVE: Here, we aimed to decipher the role of myostatin and myostatin dependent signaling pathways for cardiac function and cardiac metabolism in adult mice. To avoid potential counterregulatory mechanisms occurring in constitutive and germ-line-based myostatin mutants, we generated a mouse model that allows myostatin inactivation in adult cardiomyocytes. METHODS AND RESULTS: Cardiac MRI revealed that genetic inactivation of myostatin signaling in the adult murine heart caused cardiac hypertrophy and heart failure, partially recapitulating effects of the age-dependent decline of the myostatin paralog growth and differentiation factor 11. We found that myostatin represses AMP-activated kinase activation in the heart via transforming growth factor-beta-activated kinase 1, thereby preventing a metabolic switch toward glycolysis and glycogen accumulation. Furthermore, myostatin stimulated expression of regulator of G protein signaling 2, a GTPase-activating protein that restricts Gaq and Gas signaling and thereby protects against cardiac failure. Inhibition of AMP activated kinase in vivo rescued cardiac hypertrophy and prevented enhanced glycolytic flow and glycogen accumulation after inactivation of myostatin in cardiomyocytes. CONCLUSIONS: Our results uncover an important role of myostatin in the heart for maintaining cardiac energy homeostasis and preventing cardiac hypertrophy. PMID- 24807787 TI - Phenotypical and molecular distinctness of sinonasal haemangiopericytoma compared to solitary fibrous tumour of the sinonasal tract. AB - AIMS: Sinonasal haemangiopericytoma (SN-HPC) is a rare sinonasal mesenchymal neoplasm of perivascular myoid cell origin. Solitary fibrous tumour (SFT) occurs only very rarely in the sinonasal tract. SFT and soft tissue HPC have been considered a single entity. Recently, recurrent gene fusions involving NAB2-STAT6 resulting in differential expression of STAT6 were characterized as central molecular events in SFT. However, no data exist for NAB2-STAT6 status or STAT6 expression in SN-HPC. METHODS AND RESULTS: We examined six SN-HPCs and two sinonasal SFTs by immunohistochemistry and RT-PCR for NAB2-STAT6 fusions. SN-HPC affected three females and three males (mean age: 72 years). They expressed smooth muscle actin, lacked strong CD34 reactivity and were negative for nuclear STAT6 expression. RT-PCR analysis confirmed the absence of NAB2-STAT6 fusions in all cases. Conversely, both sinonasal SFTs (in males aged 39 and 52 years) displayed classical features of pleuropulmonary and soft-tissue SFTs (uniformly CD34-positive with strong nuclear expression of STAT6). RT-PCR revealed NAB2 STAT6 fusions in both cases. CONCLUSIONS: These findings confirm the molecular and phenotypical distinctness of these two entities. While SN-HPC is a site specific sinonasal neoplasm of as yet unknown molecular pathogenesis, sinonasal SFTs show phenotypical and molecular identity to their pleural/extrapleural counterparts. PMID- 24807788 TI - Ber-EP4 immunoreactivity in infundibulocystic basal cell carcinoma. PMID- 24807789 TI - Expression of microRNA-26b, an obesity-related microRNA, is regulated by free fatty acids, glucose, dexamethasone and growth hormone in human adipocytes. AB - MicroRNAs (miRNAs) are short non-coding RNAs that are involved in numerous biological processes, including obesity and insulin resistance. miR-26b is an obesity-related intronic miRNA located in the intron of the carboxy-terminal domain, RNA polymerase II, polypeptide A, small phosphatase 1 gene. miR-26b is abundantly expressed in mice and mature human adipocytes, and is associated with the expression of adipokines. In the present study, the effects of energy-source materials and hormones associated with obesity, on miR-26b expression were investigated. It was demonstrated that free fatty acids (FFAs), glucose, glucocorticoids and growth hormone (GH) downregulate the expression of miR-26b in human adipocytes. The results indicate that the expression of miR-26b is affected by a variety of factors that are correlated with obesity and insulin sensitivity. Therefore, miR-26b may be an important mediator in the development of obesity associated insulin resistance. PMID- 24807791 TI - Assessment of five screening strategies for optimal detection of carriers of third-generation cephalosporin-resistant Enterobacteriaceae in intensive care units using daily sampling. AB - There is no consensus on optimal screening procedures for multidrug-resistant Enterobacteriaceae (MDRE) in intensive care units (ICUs). Therefore, we assessed five strategies for the detection of extended-spectrum beta-lactamase (ESBL) and high-level expressed AmpC cephalosporinase (HL-CASE) producers. During a 3-month period, a rectal screening swab sample was collected daily from every ICU patient, from the first 24 h to the last day of ICU stay. Samples were plated on MDRE-selective media. Bacteria were identified using MALDI-TOF mass spectrometry and antibiograms were performed using disk diffusion. MDREs were isolated from 682/2348 (29.0%) screening samples collected from 93/269 (34.6%) patients. Incidences of patients with ESBL and HL-CASE producers were 17.8 and 19.3 per 100 admissions, respectively. In 48/93 patients, MDRE carriage was intermittent. Compared with systematic screening at admission, systematic screening at discharge did not significantly increase the rate of MDRE detection among the 93 patients (62% vs. 70%). In contrast, screening at admission and discharge, screening at admission and weekly thereafter, and screening at admission and weekly thereafter and at discharge significantly increased MDRE detection (77%, p 0.02; 76%, p 0.01; 86%, p<0.001, respectively). The difference in MDRE detection between these strategies relies essentially on the levels of detection of patients with HL-CASE producers. The most reasonable strategy would be to collect two samples, one at admission and one at discharge, which would detect 87.5% of the ESBL strains, 67.3% of the HL-CASE strains and 77.4% of all MDRE strains. This study should facilitate decision-making concerning the most suitable screening policy for MDRE detection in a given ICU setting. PMID- 24807792 TI - Adult neuropsychiatric expression and familial segregation of 2q13 duplications. AB - New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression. PMID- 24807793 TI - Efficient spin-light emitting diodes based on InGaN/GaN quantum disks at room temperature: a new self-polarized paradigm. AB - A well-behaved spin-light emitting diode (LED) composed of InGaN/GaN multiple quantum disks (MQDs), ferromagnetic contact, and Fe3O4 nanoparticles has been designed, fabricated, and characterized. The degree of circular polarization of electroluminescence (EL) can reach up to a high value of 10.9% at room temperature in a low magnetic field of 0.35 T, which overcomes a very low degree of spin polarization in nitride semiconductors due to the weak spin-orbit interaction. Several underlying mechanisms play significant roles simultaneously in this newly designed device for the achievement of such a high performance. Most of all, the vacancy between nanodisks can be filled by half-metal nanoparticles with suitable energy band alignment, which enables selective transfer of spin polarized electrons and holes and leads to the enhanced output spin polarization of LED. Unlike previously reported mechanisms, this new process leads to a weak dependence of spin relaxation on temperature. Additionally, the internal strain in planar InGaN/GaN multiple quantum wells can be relaxed in the nanodisk formation process, which leads to the disappearance of Rashba Hamiltonian and enhances the spin relaxation time. Our approach therefore opens up a new route for the further research and development of semiconductor spintronics. PMID- 24807794 TI - The relationship between ADHD symptomatology and self-harm, suicidal ideation, and suicidal behaviours in adults: a pilot study. AB - The aim of this study was to explore whether individuals with attention deficit/hyperactivity disorder (ADHD) are at risk of harm over the lifespan due to increased rates of self-harm, suicidal ideation and suicidal behaviour, and whether this association is mediated by psychosocial factors. Sixty-six adults (43 men, 23 women; 18-65 years) participated in this study involving clinical interview and retrospective self-report measures of ADHD symptoms, self harm/suicidal behaviour, mental health disorders, and coping style measures. Significant associations were found between ADHD symptom severity and self reported histories of self-harm behaviour, suicidal ideation, and suicide attempts (all p values<.05). These relationships between self-destructive behaviours and ADHD symptom severity were found to be significantly and differentially mediated by psychosocial variables (all p values<.05) including comorbidity (mood, anxiety, drug, and alcohol abuse disorders) and emotion focussed coping style. This study suggests that linkages between self-injurious behaviour and ADHD symptomatology may be due primarily to comorbid mental health disorders and emotion-focussed coping. The identification of these mediating factors and processes may potential pathways for intervention in reducing suicide and self-harm risk amongst those with ADHD symptoms. PMID- 24807795 TI - Suppression of placental metallothionein 1 and zinc transporter 1 mRNA expressions contributes to fetal heart malformations caused by maternal zinc deficiency. AB - Zinc has been implicated to have a protective role against heart malformations during fetal development. Metallothionein 1 (MT-1) and zinc transporter 1 (ZnT-1) are two major metabolic factors that are associated with zinc metabolism. The present work aimed to investigate the association of placental MT-1 and ZnT-1 expressions with fetal heart malformations resulting from maternal zinc deficiency. Sprague-Dawley female rats were randomly divided into five groups of extremely low-zinc, low-zinc, moderately low-zinc, marginally low-zinc and normal zinc (n = 9-12), and were fed diets with controlled zinc content at 1.0 +/- 0.3, 8.4 +/- 1.8, 15.4 +/- 2.8, 22.4 +/- 4.1 and 29.4 +/- 5.3 [mean +/- standard deviation (SD)] mg of zinc/kg, respectively, from day 25 of preconception until day 19 of gestation. The female rats were bred, their fetuses were harvested at day 19 of gestation after killing the dams, and fetal hearts were morphologically examined. Zinc concentration and alkaline phosphatase (ALP) activity in maternal venous blood sera were tested, and MT-1 and ZnT-1 mRNA expressions in the placenta were assayed. Zinc concentrations and ALP activities in the blood were low in all zinc-deficient diet groups in a dose-dependent fashion. The incidences of heart malformations were increased, and the levels of placental MT-1 and ZnT-1 mRNA expressions were decreased in the extremely low-zinc, low-zinc and moderately low-zinc groups compared with the normal zinc group. Specifically, mRNA levels of placental MT-1 or ZnT-1 were significantly decreased and were lower than the specific threshold values in the fetuses with heart malformations but not in the fetuses without heart malformations in all the groups. These data indicate that maternal zinc deficiency resulted in an elevated incidence of fetal heart malformations, which was associated with significant decreases in placental MT-1 and ZnT-1 mRNA expressions to the levels below the threshold values that may be a crucial factor to determine the presence of fetal heart malformations. PMID- 24807796 TI - Shady physiology revealed. PMID- 24807797 TI - Orbital histiocytic sarcoma in a 2-year-old child. AB - Histiocytic sarcoma (HS) is an exceedingly rare hematologic malignancy that typically presents in the skin, gastrointestinal tract, and lymph nodes. Few cases of HS have been reported in the head and neck. This study describes the case of a 2-year-old girl presenting with 2 weeks of left lower eyelid swelling. Diagnostic testing and biopsy revealed a large inferior orbital mass causing severe bony destruction with extension into the sinuses. Pathologic analysis revealed classic features of HS. To the best of knowledge, no previous case of HS occurring in the orbit of a child has been reported. This study presents an exceedingly rare case of HS in a young child presenting with eyelid swelling. In addition, this case report is in compliance with HIPAA regulations. PMID- 24807798 TI - Inflammatory myofibroblastic tumor of the orbit: a case report. AB - Inflammatory myofibroblastic tumor (IMT) is a neoplasm most commonly found in the abdominal-pelvic region, lung, and retroperitoneum. The tumor tends to affect soft tissues of children and young adults and can locally recur but rarely metastasizes. Histologically, the appearance is one of bland spindle cell proliferation with a prominent, chronic inflammatory infiltrate. This article describes 1 case of IMT found in the orbit that is presented with rapidly progressive painless proptosis. In the authors' review of the literature, they have only found 2 other case reports involving the orbit. PMID- 24807799 TI - Reticulohistiocytoma of the orbit. AB - Reticulohistiocytoma is a rare, benign histiocytic proliferation of the skin or soft tissue. While ocular involvement has been documented in the past, there have been no previously reported cases of reticulohistiocytoma of the orbit. In this report, the authors describe a reticulohistiocytoma of the orbit in a middle-aged woman. PMID- 24807800 TI - Anatomical characteristics and surgical treatment of bilateral congenital upper eyelid entropion in an infant with neonatal progeroid syndrome. AB - Neonatal progeroid syndrome (NPS) is a rare, autosomal recessive disorder characterized by an aged face, wrinkled skin, decreased subcutaneous fat, and neonatal teeth. The authors describe herein a 2-month-old infant with NPS who underwent eyelid surgery for bilateral upper eyelid entropion and stromal keratitis. The preoperative examination revealed thin, narrow, and soft tarsal plates. The eyelids were large and floppy, and there was no preaponeurotic fat tissue. The entropion was successfully treated by the levator muscle advancing onto the tarsus, anterior lamellar repositioning, horizontal eyelid shortening, and canthal resuspension. Upper eyelid entropion may occur relatively frequently in infants with NPS, and the special anatomical features of the eyelid should be considered while performing entropion surgery. PMID- 24807801 TI - Naphazoline as a confounder in the diagnosis of carotid artery dissection. AB - Diagnosing Horner Syndrome can be difficult in the setting of an incomplete triad. A 27-year-old man presented with unilateral eyelid droop and intermittent ipsilateral headaches, having already seen 7 physicians. Physical examination revealed unilateral ptosis but no pupillary miosis or facial anhidrosis. Inspection of his clinical photographs revealed elevation of the ipsilateral lower eyelid, suggesting sympathetic dysfunction. On further questioning, he admitted to naphazoline dependence. Reexamination after ceasing the naphazoline unveiled the anisocoria. Vascular imaging subsequently revealed carotid dissection, and the patient was started on anticoagulant and antiplatelet therapy. The ptosis persisted after conjunctival Mullerectomy. External levator resection was recommended, but patient declined. This case underscores the importance of clinical photography, meticulous medical record review, and complete medication history including over-the-counter preparations. Clinicians should meticulously inspect the lower eyelid in cases of atypical blepharoptosis and consider the effects of eye drops when inspecting pupils for miosis. PMID- 24807802 TI - Primary renal carcinoid metastatic to the orbit. AB - A 70-year-old man with a medical history of metastatic renal carcinoid tumor presented with several months of painless proptosis of the OS. The patient was receiving octreotide and everolimus chemotherapy. MRI revealed a well circumscribed mass in the left lateral rectus muscle consistent with metastasis. Because the patient was asymptomatic, he was observed and maintained a stable amount of proptosis without diplopia or change in vision. PMID- 24807803 TI - Tissue necrosis following diode laser-assisted transcanalicular dacryocystorhinostomy. AB - Advantages of transcanalicular laser-assisted dacryocystorhinostomy (TCDCR) over conventional, external, and endonasal dacryocystorhinostomy (DCR) have been purported to include decreased operating time, reduced morbidity, enhanced cosmesis, avoidance of general anesthesia, and a shorter recovery time. However, 1 case of skin necrosis has recently been reported to have occurred following diode laser-assisted TCDCR, and the authors now report 3 additional cases that were evaluated by the Ophthalmic Plastic Surgery services at the University of North Carolina, North Carolina, and the University of California, San Francisco. Three patients developed full-thickness tissue necrosis over the medial canthus following TCDCR, and 2 of these patients experienced persistent tissue breakdown at the site following reconstructive repair. PMID- 24807804 TI - Periocular Scleromyxedema. AB - Scleromyxedema is characterized by cutaneous mucinosis and rarely presents to oculoplastic surgeons with bilateral upper and lower eyelid swelling. The authors present 2 case reports with a review of the literature and discuss the ophthalmic manifestations of scleromyxedema and the management of these cases. Both patients were in their early 50s and were fit and well prior to the presentation. They both presented with eyelid swelling and underlying nodularity of the subcutaneous tissue. The skin biopsy confirmed cutaneous manifestations of scleromyxedema. The systemic manifestations responded to intravenous and oral steroids and intravenous infusions of immunoglobulin. The ophthalmic manifestations were managed conservatively. Scleromyxedema is a rare connective tissue disease characterized by cutaneous mucinosis, extracutaneous manifestations, and monoclonal gammopathy. It rarely affects the eyelids and cornea. The authors would like to present 2 cases of periocular scleromyxedema. PMID- 24807805 TI - Surgical timing and postoperative ocular motility in type B orbital blowout fractures. AB - PURPOSE: To determine whether patients with Type B orbital blowout fractures (soft-tissue distortion disproportionate to bone-fragment displacement) repaired within 7 days of injury have statistically greater postoperative vertical binocular fusion than similar patients who undergo later surgery. METHODS: Prospective and retrospective surgical case series. Inclusion criteria were orbital floor (with or without medial wall) blowout fracture repair, preoperative coronal orbital CT scans, and patient age of at least 12 years at time of postoperative binocular visual field. RESULTS: Twenty-five patients met inclusion criteria. Ten patients (group 1) had surgery within 7 days of injury, and 15 patients (group 2) had surgery more than 7 days after injury. The total cohort had a median postoperative vertical binocular fusion of 90 degrees . Group 1 had postoperative vertical binocular fusion averaging 100 degrees . Nine of 10 patients (90%) were above and 1 of 10 (10%) were below the median for the entire cohort. Group 2 had postoperative vertical binocular fusion averaging 70 degrees . Three of 15 patients (20%) were above and 12 of 15 patients (80%) were below the median for the entire cohort. The difference between the average postoperative vertical binocular fusion of the 2 groups was statistically significant by two-tailed unpaired t test with p value 0.0022. CONCLUSIONS: Patients with Type B orbital blowout fractures (soft-tissue distortion disproportionate to bone-fragment displacement) have statistically greater average postoperative vertical binocular fusion if repaired within 7 days of injury than similar patients who undergo later surgery. PMID- 24807806 TI - Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways. AB - Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6 hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons. PMID- 24807807 TI - Thymidine phosphorylase is both a therapeutic and a suicide gene in a murine model of mitochondrial neurogastrointestinal encephalomyopathy. AB - Suicide gene therapy (SGT) is a promising strategy for treating cancer. In this work, we show that thymidine phosphorylase (TP) deficiency, the underlying genetic defect in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presents an opportunity to apply SGT using capecitabine, a commonly used prodrug that is converted into 5-fluorouracil by TP. Using an immortalised B lymphoblastoid cell line from a patient with MNGIE, the tumourigenic EL-4 cell line, lentiviral vectors encoding TP and a double knockout (Tymp(-/-)Upp1(-/-)) murine model, we found that EL-4 cell-derived TP(+) tumours were exquisitely sensitive to capecitabine and generated a significant local bystander effect. In addition, we detected a spontaneous cytolytic immune response in a significant fraction of the animals surviving more than 20 days after termination of the therapy. These data indicate that, in individuals lacking TP expression, TP is a highly specific suicide gene, which can be used to treat tumours that could hypothetically arise in MNGIE patients undergoing gene therapy, as these tumours will likely originate from the gene-modified cells and will be selectively targeted by capecitabine. These observations have important implications for gene therapy for MNGIE. PMID- 24807809 TI - B18(2-): a quasi-planar bowl member of the Wankel motor family. AB - A quasi-planar member of the so-called 'Wankel motor' family, B18(2-), is found. This boron cluster is an electronically stable dianion and a concentric doubly sigma- and pi-aromatic system. The inner B6 unit in B18(2-) undergoes quasi-free rotation inside the perimeter of the B12 ring. The absence of any localized sigma bond between the inner ring and the peripheral boron atoms makes the system fluxional. PMID- 24807808 TI - CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype. AB - Mutations in CEP290 are the most common cause of Leber congenital amaurosis (LCA), a severe inherited retinal degenerative disease for which there is currently no cure. Autosomal recessive CEP290-associated LCA is a good candidate for gene replacement therapy, and cells derived from affected individuals give researchers the ability to study human disease and therapeutic gene correction in vitro. Here we report the development of lentiviral vectors carrying full-length CEP290 for the purpose of correcting the CEP290 disease-specific phenotype in human cells. A lentiviral vector containing CMV-driven human full-length CEP290 was constructed. Following transduction of patient-specific, iPSC-derived, photoreceptor precursor cells, reverse transcriptase-PCR analysis and western blotting revealed vector-derived expression. As CEP290 is important in ciliogenesis, the ability of fibroblast cultures from CEP290-associated LCA patients to form cilia was investigated. In cultures derived from these patients, fewer cells formed cilia compared with unaffected controls. Cilia that were formed were shorter in patient-derived cells than in cells from unaffected individuals. Importantly, lentiviral delivery of CEP290 rescued the ciliogenesis defect. The successful construction and viral transfer of full-length CEP290 brings us closer to the goal of providing gene- and cell-based therapies for patients affected with this common form of LCA. PMID- 24807810 TI - The risk of bacteria in foam sclerotherapy: does the condition of the air in outpatient vs. operating rooms make a difference? AB - BACKGROUND: Foam sclerotherapy has been one of the most frequently applied therapeutic methods for the treatment of varicose veins and venous malformation. Few studies have investigated the sterile condition of the air used for foam creation. OBJECTIVES: To evaluate the bacterial conditions in foam created from the air in outpatient and operating rooms used for sclerotherapy treatment, in order to provide the basis for clinical applications in foam sclerotherapy. MATERIALS AND METHODS: In this study, we measured the amount of airborne microorganisms in the air in the operating room, and in the outpatient room, the polidocanol (POL) foam created using the air in the respective rooms, and the microorganisms present in the liquid POL. We used the settle plate method for air sampling. We used the Tessari method to generate foam. The experiment was repeated three times. RESULTS: Typical bacterial colonies were formed on nutrient agar plates in both the outpatient room and operating room air groups. No colonies were cultivated in the liquid POL. Although the use of sterile or nonsterile air in sclerotherapy produces significantly different results in the counts of colony-forming units, there was no difference in the foam created using sterile or nonsterile air (i.e. no colonies were cultivated on either foam). CONCLUSIONS: There is no increased risk of infection when using foam sclerotherapy in outpatient rooms compared with using foam created under sterile operating-room conditions. PMID- 24807811 TI - gem-Difluoroolefination of diaryl ketones and enolizable aldehydes with difluoromethyl 2-pyridyl sulfone: new insights into the Julia-Kocienski reaction. AB - The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction. PMID- 24807812 TI - Incremental layer shear bond strength of low-shrinkage resin composites under different bonding conditions. AB - The purpose of this study was to determine the incremental shear bond strength of a silorane-based composite (Filtek Silorane) repaired with silorane or a methacrylate-based composite (Filtek Z250) under various aging conditions. Also, the incremental bond strength of the silorane-based composite was compared with that of another low-shrinkage methacrylate-based composite (Aelite LS Posterior) under fresh and aged conditions, with and without the use of an adhesive resin between successive layers. The two brands of low-shrinkage composites were compared with a microhybrid, Filtek Z250, which served as the control. Substrate discs were fabricated and second layers were adhered to them immediately, after two weeks of aging, or after four weeks of aging and with and without an adhesive resin. Shear bond strengths were measured and failure modes were evaluated. The incremental bond strength of silorane to the silorane-based composite was not significantly different from that of the methacrylate-based composite. However, repairing a silorane-based composite with a methacrylate-based composite significantly reduced the bond strength. Aelite showed a lower incremental bond strength than Z250 and silorane, but the use of an adhesive significantly improved the bond strength. The absence of an oxygen-inhibited layer did not affect the bond strength of the consecutive layers of the silorane-based composite. PMID- 24807813 TI - The Tucker technique: the proximal hollow grind to address a root concavity. AB - Cast gold inlays have long been used to conservatively restore compromised tooth structure. When the mesial or distal proximal surfaces are indicated for restoration and a cast gold restoration is desired, traditionally a box is prepared with an external bevel. Often a root concavity does not allow for a standard box form or the external and/or internal bevels. A proximal hollow grind can be utilized to address limits of standard inlay or onlay preparation design. PMID- 24807814 TI - The effect of simplified adhesives on the bond strength to dentin of dual-cure resin cements. AB - The purpose of this study was to compare the shear bond strengths to dentin of two dual-cure resin cements, one with a unique initiator, NX3 (Kerr Corp), and the other with a traditional redox-initiator system, Calibra (Dentsply), when used in combination with simplified or nonsimplified adhesive agents. The two dual-cure resin cements, in either self- or dual-cure activation modes, were bonded to human dentin with four dental adhesives to create 16 subgroups of 10 specimens each. After 24 hours of storage in distilled water at 37 degrees C, the specimens were tested in shear in a universal testing machine. With both NX3 and Calibra, bond strengths significantly increased when the specimens were dual cured. In addition, with either cement in either mode, the nonsimplified adhesives performed significantly better than did the simplified adhesive bonding agents. When used specifically with simplified adhesives in either cure mode, NX3 did not produce significantly higher bond strengths than did Calibra. In general, lower dentin bond strengths were found with simplified adhesives or self-cure activation with either resin cement. PMID- 24807815 TI - Effect of different surface treatments and adhesives on repair bond strength of resin composites after one and 12 months of storage using an improved microtensile test method. AB - OBJECTIVES: To evaluate the effect of surface treatments and bonding systems on the repair bond strength between composite materials after one and 12 months of storage, using an improved microtensile test method. METHODS: A total of 72 composite cylinders (Tetric Evo Ceram, Ivoclar) were fabricated, stored in distilled water for two weeks followed by thermal cycling (5000 times between 5 degrees C and 55 degrees C), and served as substrate. The cylinders were mechanically roughened using 320-grit silicon carbide sandpaper, etched with 37% phosphoric acid gel, rinsed with water, and divided equally into three experimental groups: group 1, unchanged surface; group 2, sandblasting of the surface (CoJet tribochemical silica sand, 3M ESPE; Microetcher II, Danville Engineering Inc); and group 3, surface silane coating (Bis-Silane, BISCO Inc). Eight control cylinders were prepared and underwent similar aging as the substrate. Each experimental group was divided into subgroups that received the following bonding systems: one-step self-etching adhesive (AdheSE One, Ivoclar Vivadent), two-step self-etching adhesive (Clearfil SE, Kuraray America), and three-step etch-and-rinse adhesive (Adper Scotchbond Multi-Purpose, 3M ESPE). Fresh composite (Tetric Evo Ceram, Ivoclar) was placed and cured on top of the prepared substrate cylinders. The specimens were placed in distilled water for a week and thermocycled the same way as before. Eight composite control cylinders were also stored and thermocycled for the same period of time. Half of the cylinders in each test group were tested at one month and the second half at 12 months. The cylinders were serially sectioned in an automatic cutting machine, producing 10 to 20 1.1 * 1.1-mm test specimen beam from each cylinder. Specimens were prepared for microtensile testing and the tensile strength calculated based on the force at fracture and specimen dimension. The fracture surfaces were examined under a stereomicroscope and the type of fracture noted. RESULTS: The mean tensile strength of composite control was 54.5 +/- 6.0 MPa at one month and 49.6 +/- 5.1 MPa at 12 months. The mean tensile strength for the repaired groups ranged from 26.4 +/- 6.8 MPa to 49.9 +/- 10.4 MPa at one month and 21.2 +/- 9.9 to 41.3 +/- 7.5 at 12 months. There was a statistical difference between all groups (p<0.05) at one month. This difference was less pronounced at 12 months. The highest repair strength was obtained in the group having a silane-coated surface and Clearfil, the two-step self-etching adhesive. Clearfil also had the highest repair strength within each surface treatment group. There was a tendency for lower tensile strength at 12 months compared with one month. Most fractures were of the adhesive type; the highest number of cohesive fractures, 16% at one month and 12% at 12 months, were in groups with the highest tensile strength. CONCLUSION: The best repair bond strength was achieved by using freshly mixed silane solution on the substrate in addition to an adhesive, rendering a thin bonding layer. PMID- 24807816 TI - Effects of different feeder layers on culture of bovine embryonic stem cell-like cells in vitro. AB - To find a suitable feeder layer is important for successful culture conditions of bovine embryonic stem cell-like cells. In this study, expression of pluripotency related genes OCT4, SOX2 and NANOG in bovine embryonic stem cell-like cells on mouse embryonic fibroblast feeder layers at 1-5 passages were monitored in order to identify the possible reason that bovine embryonic stem cell-like cells could not continue growth and passage. Here, we developed two novel feeder layers, mixed embryonic fibroblast feeder layers of mouse and bovine embryonic fibroblast at different ratios and sources including mouse fibroblast cell lines. The bovine embryonic stem cell-like cells generated in our study displayed typical stem cell morphology and expressed specific markers such as OCT4, stage-specific embryonic antigen 1 and 4, alkaline phosphatase, SOX2, and NANOG mRNA levels. When feeder layers and cell growth factors were removed, the bovine embryonic stem cell-like cells formed embryoid bodies in a suspension culture. Furthermore, we compared the expression of the pluripotent markers during bovine embryonic stem cell-like cell in culture on mixed embryonic fibroblast feeder layers, including mouse fibroblast cell lines feeder layers and mouse embryonic fibroblast feeder layers by real-time quantitative polymerase chain reaction. Results suggested that mixed embryonic fibroblast and sources including mouse fibroblast cell lines feeder layers were more suitable for long-term culture and growth of bovine embryonic stem cell-like cells than mouse embryonic fibroblast feeder layers. The findings may provide useful experimental data for the establishment of an appropriate culture system for bovine embryonic stem cell lines. PMID- 24807817 TI - Hippocampal 5-HT1A receptor binding is related to object-location memory in humans. AB - Animal studies suggest that serotonin, mediated by the 5-HT1A receptor, plays a key role in spatial learning and memory. The role of serotonin in spatial memory in humans has, however, been less well studied. This study examined the relationship between serotonin receptor density in the human brain and spatial learning and memory using the 5-HT1A receptor ligand (18)F-4-(2'-methoxyphenyl)-1 [2'-(N-2-pyridinyl)-p-fluorobenzamido]-ethyl-piperazine ([(18)F] MPPF) and positron emission tomography (PET). Ten neurologically healthy individuals underwent two [(18)F] MPPF PET scans, one while performing a task which involves processing of high-level spatial information ('house scan'), and one while performing a task which involves processing of low-level spatial information ('tunnel scan'). Navigation, recall of arbitrary associations between objects and their spatial location, and ability to draw a plan of the environment were tested following the house scan. 5-HT1A receptor binding did not differ significantly between processing high and low levels of spatial information. Hippocampal asymmetry in [(18)F] MPPF binding, however, was associated with memory for object location associations; lower right than left hippocampal binding potential (BPND) was related to better memory performance. We conclude that hippocampal serotonergic function plays a role in a fundamental component of human spatial memory, the ability to recall the location of encountered objects. PMID- 24807818 TI - Dietary magnesium restriction reduces amygdala-hypothalamic GluN1 receptor complex levels in mice. AB - Reduced daily intake of magnesium (Mg(2+)) is suggested to contribute to depression. Indeed, preclinical studies show dietary magnesium restriction (MgR) elicits enhanced depression-like behaviour establishing a causal relationship. Amongst other mechanisms, Mg(2+) gates the activity of N-methyl-D-asparte (NMDA) receptors; however, it is not known whether reduced dietary Mg(2+) intake can indeed affect brain NMDA receptor complexes. Thus, the aim of the current study was to reveal whether MgR induces changes in brain NMDA receptor subunit composition that would indicate altered NMDA receptor regulation. The results revealed that enhanced depression-like behaviour elicited by MgR was associated with reduced amygdala-hypothalamic protein levels of GluN1-containing NMDA complexes. No change in GluN1 mRNA levels was observed indicating posttranslational changes were induced by dietary Mg(2+) restriction. To reveal possible protein interaction partners, GluN1 immunoprecipitation and proximity ligation assays were carried out revealing the expected GluN1 subunit association with GluN2A, GluN2B, but also novel interactions with GluA1, GluA2 in addition to known downstream signalling proteins. Chronic paroxetine treatment in MgR mice normalized enhanced depression-like behaviour, but did not alter protein levels of GluN1-containing NMDA receptors, indicating targets downstream of the NMDA receptor. Collectively, present data demonstrate that dietary MgR alters brain levels of GluN1-containing NMDA receptor complexes, containing GluN2A, GluN2B, AMPA receptors GluA1, GluA2 and several protein kinases. These data indicate that the modulation of dietary Mg(2+) intake may alter the function and signalling of this receptor complex indicating its involvement in the enhanced depression-like behaviour elicited by MgR. PMID- 24807819 TI - Self-reported recurrent pain and medicine use behaviours among 15-year olds: results from the international study. AB - BACKGROUND: There is considerable variation in adolescent pain prevalence across epidemiological studies, with limited information on pain-related behaviours among adolescents, including medicine use. The aims of this study were (1) to examine the prevalence of recurrent pain among 15-year-old adolescents internationally; (2) to investigate the association between recurrent pain and medicine use behaviours among boys and girls; and (3) to evaluate the consistency of these associations across countries. METHODS: The World Health Organization (WHO) collaborative international Health Behaviour in School-aged Children 2009/2010 study collects data about self-reported aches and medicine use from 36,762 15-year-old adolescents from 22 countries/regions in Europe and the United States. Multi-level multivariate logistic regression, stratified by gender, was used to analyse the association between recurrent pain and medicine use for headache, stomachache, nervousness and difficulties in getting to sleep. RESULTS: More than 30% of adolescents reported recurrent headache, almost 30% recurrent backache and approximately 20% recurrent stomachache. Although pain prevalence and medicine use for aches were much higher for girls, the association between pain and medicine use was similarly strong for both genders. Adolescents with recurrent pain are more likely to use medicines also for non-corresponding pain, nervousness and difficulties in getting to sleep. The association between recurrent pain and medicine use was consistent across countries despite large country differences in the prevalence of recurrent pain and medicine use. CONCLUSIONS: Recurrent pain in adolescence is common cross-nationally. Adolescents with recurrent pain are more likely to use medicine in general. Recurrent pain and medicine use should be addressed in adolescent health policies. PMID- 24807820 TI - Improving health services for African migrants in China: A health diplomacy perspective. AB - Global health has become an increasingly prominent component of foreign policy in the last decade. The term health diplomacy has been used to describe this growing interface between foreign policy and global health, and it encompasses both the concept of using health to further foreign policy objectives as well as the idea that diplomatic tools can be helpful for attaining public health goals. The Chinese presence in Africa has grown in the last 15 years, generating increased interest in Sino-African relations. While much has been written in recent years about the Chinese presence in Africa, the growing numbers of Africans in China have attracted considerably less attention. Many are small-scale traders and might be expected to face many of the health challenges common among foreign migrants, but their health needs have been largely unrecognised. In this paper, we consider how a health diplomacy approach could be applied to African migrants in China, and the potential advantages and limitations of this strategy. We identify areas of overlap between public health, trade and foreign policy goals that can be emphasised to generate support for improved services for African migrants in China and to engage partners from a diversity of sectors. PMID- 24807821 TI - Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans. AB - OBJECTIVE: To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. MATERIALS AND METHODS: Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and alpha-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina(r)), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA(r)). RESULTS: The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. CONCLUSION: We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa. PMID- 24807822 TI - Multifunctional liposomes for nasal delivery of the anti-Alzheimer drug tacrine hydrochloride. AB - The purpose of this study was the development of multifunctional liposomes for nasal administration of tacrine hydrochloride. Liposomes were prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with alpha-tocopherol and/or Omega3 fatty acids. This approach was chosen in order to obtain at the same time two positive results: an enhanced drug permeation through nasal mucosa and a concomitant neuroprotective effect. Several liposome formulations were prepared using the Reverse Phase Evaporation technique followed by membrane filter extrusion. In particular, liposome capacity to enhance drug permeation was evaluated by means of membrane permeation and cellular uptake studies. Furthermore, liposome effect on neuronal viability and intracellular ROS production was evaluated as well as their cytoprotective effect against oxidative stress. All liposome formulations showed a mean diameter in the range of 175 nm to 219 nm with polydispersity index lower than 0.22, a lightly negative zeta potential and excellent encapsulation efficiency. Moreover, along with good mucoadhesive properties, multifunctional liposomes showed a markedly increase in tacrine permeability, which can be related to liposome fusion with cellular membrane, a hypothesis, which was also supported by cellular uptake studies. Finally, the addition of alpha-tocopherol without Omega3 fatty acids, was found to increase the neuroprotective activity and antioxidant properties of liposomes. PMID- 24807823 TI - Copper-catalyzed oxidative cyclization of 1,5-enynes with concomitant C-C bond cleavage: an unexpected access to 3-formyl-1-indenone derivatives. AB - A Cu(0)/Selectfluor system-mediated oxidative cyclization of 1,5-enynes with concomitant C-C bond cleavage to access 3-formyl-1-indenone derivatives is described. Preliminary mechanistic investigations disclosed that the C-C bond cleavage involved a novel water-participated oxygen-insertion beta-carbon elimination through double oxycuprations. PMID- 24807824 TI - Age and activation determines the anticonvulsant effect of ifenprodil in rats. AB - Ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, was expected to exhibit anticonvulsant action in rat pups up to the third postnatal week because of predominance of NR2B subunit at early development. Cortical epileptic afterdischarges (ADs) were used to study possible effects on threshold current intensities and duration of ADs in 12-, 15-, 18-, and 25-day-old rats. A series of 18 stimulation series with stepwise increasing current intensities (from 0.2 to 15 mA) was applied with 10-min intervals. The first experiment studied rats pretreated with ifenprodil (20 or 40 mg/kg), the second experiment studied an effect of ifenprodil on already present ADs-the dose of 20 mg/kg was administered after stimulation with the 3.5-mA current intensity. Pretreatment with ifenprodil resulted in an anticonvulsant effect in 15-day-old rats only, on the contrary, proconvulsant action was found in 18- and 25-day-old animals (decrease of thresholds especially for transition into the second, limbic type of ADs and increase in duration of ADs). Anticonvulsant effect was found in 12-, 15 , and 18-day-old rats in the second experiment-ADs were shortened. In contrast, no effect was observed in 25-day-old animals. An anticonvulsant action of ifenprodil is not only age-dependent but also activation-dependent. PMID- 24807825 TI - Palliative Sedation: An Analysis of International Guidelines and Position Statements. AB - PURPOSE: To describe the suggested clinical practice of palliative sedation as it is presented in the literature and discuss available guidelines for its use. METHODS: CINAHL, PubMed, and Web of Science were searched for publications since 1997 for recommended guidelines and position statements on palliative sedation as well as data on its provision. Keywords included palliative sedation, terminal sedation, guidelines, United States, and end of life. Inclusion criteria were palliative sedation policies, frameworks, guidelines, or discussion of its practice, general or oncology patient population, performance of the intervention in an inpatient unit, for humans, and in English. Exclusion criteria were palliative sedation in children, acute illness, procedural, or burns, and predominantly ethical discussions. RESULTS: Guidelines were published by American College of Physicians-American Society of Internal Medicine (2000), Hospice and Palliative Nurses Association (2003), American Academy of Hospice and Palliative Medicine (2006), American Medical Association (2008), Royal Dutch Medical Association (2009), European Association for Palliative Care (2009), National Hospice and Palliative Care Organization (2010), and National Comprehensive Cancer Network (2012). Variances throughout guidelines include definitions of the practice, indications for its use, continuation of life-prolonging therapies, medications used, and timing/prognosis. RECOMMENDATIONS: The development and implementation of institutional-based guidelines with clear stance on the discussed variances is necessary for consistency in practice. Data on provision of palliative sedation after implementation of guidelines needs to be collected and disseminated for a better understanding of the current practice in the United States. PMID- 24807826 TI - Automatic pseudorotaxane formation targeting on nucleic acids using a pair of reactive oligodeoxynucleotides. AB - Here we report a novel method to form a pseudorotaxane architecture using only a pair of reactive oligodeoxyribonucleotides (ODNs), which we designed and synthesized, and then performed the pseudorotaxane formation reaction with both DNA and RNA oligonucleotides. The reaction proceeded smoothly without any extra reagents at 37 degrees C and pH 7.2, leading to the formation of a stable complex on a denaturing polyacrylamide gel. Interestingly, the pseudorotaxane was formed with the cyclized ODN reversibly by the slipping process. This new pseudorotaxane formation represents a promising method for developing new DNA nanotechnologies and antisense oligonucleotides. PMID- 24807827 TI - Orexin A protects cells from apoptosis by regulating FoxO1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in hepatocytes. AB - Orexin A and B are multifunctional neuropeptides that are involved in the regulation of food intake, energy metabolism, glucose regulation and wakefulness. They signal through two G-protein-coupled receptors (GPCR): orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). Previous studies have shown that orexins interact with PI3K/AKT signaling pathways through OX1R-coupling in other cell types, but are seldom involved in hepatocytes. In the present study, reverse transcription (RT)-PCR and western blot analysis revealed that OX1R mRNA expression and activation in rat hepatocytes in vitro were upregulated by exogenous orexin A (10(-10) to 10(-6) M) in a dose-dependent manner. The result showed that orexin A affects increasing cell proliferation and protects cells from apoptosis. Additionally, inhibition studies showed that orexin A induced forkhead box O1 (FoxO1) and mammalian target of rapamycin 1 (mTORC1) phosphorylation, while OX1R antagonist (SB334867, 10(-6) M), AKT antagonist (PF 04691502, 10(-6) M), Foxo1 inhibitor (AS1842856, 10(-6) M) or mTORC1 inhibitor (everolimus, 10(-5) M) blocked these effects of orexin A. The results of the present study showed a possible effect of orexin A on cell apoptosis in regulating Foxo1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in rat hepatocytes. PMID- 24807828 TI - Determinants and short-term physiological consequences of PHA immune response in lesser kestrel nestlings. AB - Individual immune responses are likely affected by genetic, physiological, and environmental determinants. We studied the determinants and short-term consequences of Phytohaemagglutinin (PHA) induced immune response, a commonly used immune challenge eliciting both innate and acquired immunity, on lesser kestrel (Falco naumanni) nestlings in semi-captivity conditions and with a homogeneous diet composition. We conducted a repeated measures analyses of a set of blood parameters (carotenoids, triglycerides, beta-hydroxybutyrate, cholesterol, uric acid, urea, total proteins, and total antioxidant capacity), metabolic (resting metabolic rate), genotypic (MHC class II B heterozygosity), and biometric (body mass) variables. PHA challenge did not affect the studied physiological parameters on a short-term basis (<12 hr), except plasma concentrations of triglycerides and carotenoids, which decreased and increased, respectively. Uric acid was the only physiological parameter correlated with the PHA induced immune response (skin swelling), but the change of body mass, cholesterol, total antioxidant capacity, and triglycerides between sessions (i.e., post-pre treatment) were also positively correlated to PHA response. No relationships were detected between MHC gene heterozygosity or resting metabolic rate and PHA response. Our results indicate that PHA response in lesser kestrel nestlings growing in optimal conditions does not imply a severe energetic cost 12 hr after challenge, but is condition-dependent as a rapid mobilization of carotenoids and decrease of triglycerides is elicited on a short-term basis. PMID- 24807829 TI - Influence of HepG2 cell shape on nanoparticle uptake. AB - Cell mechanics provides insights in cell responses to external stress, which is an important parameter known to influence a variety of cell functions. Understanding the interdependence between mechanical stimulus, cell shape and function is essential in controlling cell culture microenvironment. In this paper, we report on the effect of cationic and anionic interfaces on cell shape and nanoparticle uptake activity of hepatocellular carcinoma cells HepG2. The shape of HepG2 cells changed from a round-like shape to a spread-like form exhibiting lamellar protrusions by incubating them on coated polystyrene well plates with polystyrene sulfonate and poly-ethylene imine (PEI), respectively. This change in shape of HepG2 cells did not influence the uptake of 49-nm particles (which entered the cells by diffusion). However, the internalization of 240-nm diameter particles was larger on cells seeded on cationic PEI. Particle uptake was measured at 4 degrees C and 37 degrees C; the optimal incubation time was 6 h. Cell shape and particle uptake were monitored by fluorescence and confocal microscopy. Quantification of particle internalization was carried out with flow cytometry. PMID- 24807831 TI - Stress from daily hassles in couples: its effects on intradyadic stress, relationship satisfaction, and physical and psychological well-being. AB - According to the systemic-transactional stress model (STM; G. Bodenmann, European Review of Applied Psychology, 1997; 47: 137), extradyadic stress from daily hassles can have a negative impact on the individual psychological and physical health and the couple's relationship. This study is the first one to test the STM propositions in a model that includes both partners' individual and relational outcomes simultaneously. The model also includes actor and partner effects as well as the interdependence between partners' processes. Cross-sectional, self report data were collected from 110 community couples in Switzerland. Consistent with STM predictions, results from the path model analysis indicate that for actor effects extradyadic stress from daily hassles relates directly to lower psychological (increase in anxiety symptoms) and physical well-being and only indirectly to lower relationship satisfaction through increased intradyadic stress from relationship problems and also through more depressive symptomatology in men. The female extradyadic stress and intradyadic stress had partner effects on the male intradyadic stress and the male relationship satisfaction, respectively. Limitations as well as research and clinical implications for marriage and family therapists are discussed. PMID- 24807830 TI - Muscarinic receptors mediate cold stress-induced detrusor overactivity in type 2 diabetes mellitus rats. AB - OBJECTIVES: This study determined if muscarinic receptors could mediate the cold stress-induced detrusor overactivity induced in type 2 diabetes mellitus rats. METHODS: Ten-week-old female Goto-Kakizaki diabetic rats (n = 12) and Wister Kyoto non-diabetic rats (n = 12) were maintained on a high-fat diet for 4 weeks. Cystometric investigations of the unanesthetized rats were carried out at room temperature (27 +/- 2 degrees C) for 20 min. They were intravenously administered imidafenacin (0.3 mg/kg, n = 6) or vehicle (n = 6). After 5 min, the rats were transferred to a low temperature (4 +/- 2 degrees C) for 40 min where the cystometry was continued. The rats were then returned to room temperature for the final cystometric measurements. Afterwards, expressions of bladder muscarinic receptor M3 and M2 messenger ribonucleic acids and proteins were assessed by reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: In non-diabetic Wister Kyoto rats, imidafenacin did not reduce cold stress-induced detrusor overactivity. In diabetic Goto-Kakizaki rats, just after transfer to a low temperature, the cold stress-induced detrusor overactivity in imidafenacin-treated rats was reduced compared with vehicle-treated rats. Within the urinary bladders, the ratio of M3 to M2 receptor messenger ribonucleic acid in the diabetic Goto-Kakizaki rats was significantly higher than that of the non diabetic Wister Kyoto rats. The proportion of muscarinic M3 receptor-positive area within the detrusor in diabetic Goto-Kakizaki rats was also significantly higher than that in non-diabetic Wister Kyoto rats. CONCLUSIONS: Imidafenacin partially inhibits cold stress-induced detrusor overactivity in diabetic Goto Kakizaki rats. In this animal model, muscarinic M3 receptors partially mediate cold stress-induced detrusor overactivity. PMID- 24807832 TI - Asthma and other recurrent wheezing disorders in children (acute). AB - INTRODUCTION: Acute childhood asthma is a common clinical emergency presenting across a range of ages and with a range of severities. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 35 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (high-dose nebulised, metered-dose inhaler plus spacer device versus nebuliser, intravenous), corticosteroids (systemic, high dose inhaled), ipratropium bromide (single- or multiple-dose inhaled), magnesium sulphate, oxygen, and theophylline or aminophylline. PMID- 24807834 TI - Incidence of lead dislodgement, malfunction and perforation during the first year following device implantation. AB - BACKGROUND: The number of cardiac rhythm device implantations has been growing fast due to expanding indications and ageing of the population. Complications of implantation were rare in the trials. However, these involved small numbers and selected patients. Prospective real-life data are necessary to assess cardiac device implantation procedure-related risks. OBJECTIVE: To determine the incidence and predictors of lead-related re-intervention in a Dutch high-volume teaching hospital. METHODS: Data from all patients who underwent cardiac rhythm device implantation between January 2010 and December 2011 were collected in a prospective registry. At least 1 year of follow-up regarding re-intervention was available for all patients. Lead-related reasons for re-intervention were categorised into lead dislodgement, malfunctioning or perforation. RESULTS: One thousand nine hundred twenty-nine devices including 3909 leads were implanted. In 595 patients (30.8 %) a CRT-D/P was implanted. Lead-related re-intervention was necessary in 86 (4.4 %) patients; it was more common in younger and male patients, and due to either lead dislodgement (66 %), malfunctioning (20 %) or perforation (18 %). Coronary sinus lead dislodgement or malfunctioning was 1.4 %. Right atrial dislodgement (1.9 %, p < 0.001) or ICD lead dislodgement (1.8 %, p = 0.002) was more common than right ventricular dislodgement (0.3 %). The incidence of lead malfunctioning was higher (0.8 %) in ICD leads. An apical position of the right ventricular lead and lateral wall position of the right atrial lead were related to cardiac perforation. CONCLUSIONS: The incidence of lead-related re intervention was comparable with the literature. The majority of re-interventions were due to lead dislodgements, particularly with right atrial and ICD leads. Re intervention due to coronary sinus lead dislodgement was rare. PMID- 24807833 TI - Genome scan for cognitive trait loci of dyslexia: Rapid naming and rapid switching of letters, numbers, and colors. AB - Dyslexia, or specific reading disability, is a common developmental disorder that affects 5-12% of school-aged children. Dyslexia and its component phenotypes, assessed categorically or quantitatively, have complex genetic bases. The ability to rapidly name letters, numbers, and colors from rows presented visually correlates strongly with reading in multiple languages and is a valid predictor of reading and spelling impairment. Performance on measures of rapid naming and switching, RAN and RAS, is stable throughout elementary school years, with slowed performance persisting in adults who still manifest dyslexia. Targeted analyses of dyslexia candidate regions have included RAN measures, but only one other genome-wide linkage study has been reported. As part of a broad effort to identify genetic contributors to dyslexia, we performed combined oligogenic segregation and linkage analyses of measures of RAN and RAS in a family-based cohort ascertained through probands with dyslexia. We obtained strong evidence for linkage of RAN letters to the DYX3 locus on chromosome 2p and RAN colors to chromosome 10q, but were unable to confirm the chromosome 6p21 linkage detected for a composite measure of RAN colors and objects in the previous genome-wide study. PMID- 24807835 TI - Do elderly patients benefit from implantable-cardioverter defibrillators? PMID- 24807836 TI - AV block after flutter ablations? PMID- 24807837 TI - Magnetic resonance imaging and devices: a mesmerising combination. PMID- 24807839 TI - Emergency embolization for the treatment of acute hemorrhage from intercostal arteries. AB - To evaluate embolotherapy for the emergency management of acute bleeding from intercostal arteries. Between October 2003 and August 2012, 19 consecutive patients with hemorrhage from intercostal arteries were scheduled for emergency embolization. The primary study endpoints were technical and clinical success, which were defined as angiographic cessation of bleeding, and cessation of clinical signs of hemorrhage. The secondary study endpoints were periprocedural complications and 30-day mortality rate. In most patients (74 %), hemorrhage was caused by iatrogenic procedures with subsequent intercostal artery laceration. One of the patients was treated twice for recurrent hemothorax caused by a new intercostal artery pseudoaneurysm 7.5 years after the initial procedure. Thus, 20 procedures were performed in these 19 patients. Overall technical success was 85 %. In six patients, no embolization of the "backdoor" was feasible, and in two of these patients additional embolization of other intercostal arteries was necessary to prevent hemorrhage via collateral vessels. Clinical signs of hemorrhage ceased after embolotherapy in 16 of 20 procedures (clinical success 80 %). The mean follow-up was 358.7 +/- 637.1 days. One minor procedure-related complication occurred. The 30-day mortality rate was 21 %, however, this was unrelated to intercostal artery hemorrhage. Embolotherapy is an effective emergency therapy for patients with acute hemorrhage from intercostal arteries. Especially if embolization of the backdoor is not feasible, collateral supply via other intercostal arteries should be either ruled out or embolized to prevent ongoing hemorrhage. Despite successful embolotherapy, a majority of patients underwent surgery during follow-up to remove the symptomatic hematoma. PMID- 24807838 TI - High responders and low responders: factors associated with individual variation in response to standardized training. AB - The response to an exercise intervention is often described in general terms, with the assumption that the group average represents a typical response for most individuals. In reality, however, it is more common for individuals to show a wide range of responses to an intervention rather than a similar response. This phenomenon of 'high responders' and 'low responders' following a standardized training intervention may provide helpful insights into mechanisms of training adaptation and methods of training prescription. Therefore, the aim of this review was to discuss factors associated with inter-individual variation in response to standardized, endurance-type training. It is well-known that genetic influences make an important contribution to individual variation in certain training responses. The association between genotype and training response has often been supported using heritability estimates; however, recent studies have been able to link variation in some training responses to specific single nucleotide polymorphisms. It would appear that hereditary influences are often expressed through hereditary influences on the pre-training phenotype, with some parameters showing a hereditary influence in the pre-training phenotype but not in the subsequent training response. In most cases, the pre-training phenotype appears to predict only a small amount of variation in the subsequent training response of that phenotype. However, the relationship between pre-training autonomic activity and subsequent maximal oxygen uptake response appears to show relatively stronger predictive potential. Individual variation in response to standardized training that cannot be explained by genetic influences may be related to the characteristics of the training program or lifestyle factors. Although standardized programs usually involve training prescribed by relative intensity and duration, some methods of relative exercise intensity prescription may be more successful in creating an equivalent homeostatic stress between individuals than other methods. Individual variation in the homeostatic stress associated with each training session would result in individuals experiencing a different exercise 'stimulus' and contribute to individual variation in the adaptive responses incurred over the course of the training program. Furthermore, recovery between the sessions of a standardized training program may vary amongst individuals due to factors such as training status, sleep, psychological stress, and habitual physical activity. If there is an imbalance between overall stress and recovery, some individuals may develop fatigue and even maladaptation, contributing to variation in pre-post training responses. There is some evidence that training response can be modulated by the timing and composition of dietary intake, and hence nutritional factors could also potentially contribute to individual variation in training responses. Finally, a certain amount of individual variation in responses may also be attributed to measurement error, a factor that should be accounted for wherever possible in future studies. In conclusion, there are several factors that could contribute to individual variation in response to standardized training. However, more studies are required to help clarify and quantify the role of these factors. Future studies addressing such topics may aid in the early prediction of high or low training responses and provide further insight into the mechanisms of training adaptation. PMID- 24807841 TI - Analysis of Mtwo rotary instrument separation during endodontic therapy: a retrospective clinical study. AB - To analyze the incidence of instrument separation (IS) and the factors influencing it, when associated with Mtwo rotary system (VDW, Munich, Germany) during endodontic therapy. A retrospective study involving a total of 24,108 root canals (11,036 endodontic treated teeth) was conducted at Nanjing Stomatology Hospital between January 2011 and March 2013. The information included were tooth type, root canal curvature, number of fractured instruments, length of the separated fragments, and the distance from broken tip to apex. The incidence of IS was observed to be 2.2 % according to the number of teeth and 1.0 % according to the number of root canals. Many of the separated fragments were 2-4 mm in length and the mean length was 3.07 +/- 1.46 mm, and 78.4 % of fractures occurred in the apex. The mean length of separated fragments in severely curved canals was maximum, while ultra-severe curved canals was observed to be minimum. Mtwo instruments demonstrated an extremely low fracture rate during endodontic therapy. Molar teeth (especially lower molars) and the degree of canal curvature had a significant effect on the incidence of IS. PMID- 24807840 TI - Analysis of serum haptoglobin fucosylation in hepatocellular carcinoma and liver cirrhosis of different etiologies. AB - We have developed herein a quantitative mass spectrometry-based approach to analyze the etiology-related alterations in fucosylation degree of serum haptoglobin in patients with liver cirrhosis and hepatocellular carcinoma (HCC). The three most common etiologies, including infection with hepatitis B virus (HBV), infection with hepatitis C virus (HCV), and heavy alcohol consumption (ALC), were investigated. Only 10 MUL of serum was used in this assay in which haptoglobin was immunoprecipitated using a monoclonal antibody. The N-glycans of haptoglobin were released with PNGase F, desialylated, and permethylated prior to MALDI-QIT-TOF MS analysis. In total, N-glycan profiles derived from 104 individual patient samples were quantified (14 healthy controls, 40 cirrhosis, and 50 HCCs). A unique pattern of bifucosylated tetra-antennary glycan, with both core and antennary fucosylation, was identified in HCC patients. Quantitative analysis indicated that the increased fucosylation degree was highly associated with HBV- and ALC-related HCC patients compared to that of the corresponding cirrhosis patients. Notably, the bifucosylation degree was distinctly increased in HCC patients versus that in cirrhosis of all etiologies. The elevated bifucosylation degree of haptoglobin can discriminate early stage HCC patients from cirrhosis in each etiologic category, which may be used to provide a potential marker for early detection and to predict HCC in patients with cirrhosis. PMID- 24807842 TI - Computational investigation of drug-resistant mutant of M2 proton channel (S31N) against rimantadine. AB - M2 proton channel is the target for treating the patients who ere suffering from influenza A infection, which facilitates the spread of virions. Amantadine and rimantadine are adamantadine-based drugs, which target M2 proton channel and inhibit the viral replication. Preferably, rimantadine drug is used more than amantadine because of its fewer side effects. However, S31N mutation in the M2 proton channel was highly resistant to the rimantadine drug. Therefore, in the present study, we focused to understand the drug-resistance mechanism of S31N mutation with the aid of molecular docking and dynamics approach. The docking analysis undoubtedly indicates that affinity for rimantadine with mutant-type M2 proton channel is significantly lesser than the native-type M2 proton channel. In addition, RMSD, RMSF, and principal component analysis suggested that the mutation shows increased flexibility. Furthermore, the intermolecular hydrogen bonds analysis showed that there is a complete loss of hydrogen bonds in the mutant complex. On the whole, we conclude that the intermolecular contact was maintained by D-44, a key residue for stable binding of rimantadine. These findings are certainly helpful for better understanding of drug-resistance mechanism and also helpful for designing new drugs for treating influenza infection against drug-resistance target. PMID- 24807844 TI - Harmful effect of detergents on lipase. AB - In order to study effects of detergents at molecular level, we have done activity measurements of wheat germ lipase in increasing concentration of some commercial detergents. Conformational changes in protein structure using circular dichroism and fluorescence spectroscopy were studied in increasing concentration of sodium dodecyl sulfate. Our study proves that detergents may lead to loss of enzymatic activity and structure of plant enzymes. Since detergents are common source of pollution in water bodies and the water from these resources can be used in fields, our study may prove helpful in creating awareness about harmful action of detergents. PMID- 24807845 TI - Effects of Qufeng Xuanfei decoction in animal model of post-infectious cough. AB - This study evaluated the effects and potential mechanisms of Qufeng Xuanfei decoction in animal model of post-infectious cough. Sixty SD rats were randomly divided into six groups (10 animals per group): control, disease model, low- (4.62 g kg(-1)), medium- (9.24 g kg(-1)), and high-dose (13.86 g kg(-1)) decoction, and positive treatment groups (dextromethorphan hydrobromide, 8 mL kg( 1)). To model post-infectious cough, all but control group animals were challenged with exposure to 50 g sawdust and 10 cigarette smokes for 30 min day( 1) for a total of 10 days, followed by subsequent exposures to lipopolysaccharide (20 ug) and capsaicin (10(-4) M) aerosols. The drugs were given by oral gavage for 15 days after which lung pathology, cell counts and cell differentials in bronchoalveolar lavage (BAL), and concentrations of neuropeptides [substance P (SP), neurokinins A (NKA) and B (NKB), and calcitonin gene-related peptide (CGRP)] in BAL (ELISA) were assessed. Compared with control group animals, significant inflammation and damage to bronchial epithelium were observed in the disease model group. A marked decrease in BAL percentages of all types of inflammatory cells was observed in the decoction-treated groups, with most changes in the medium-dose decoction group (p < 0.001 vs. disease model group). Further, airway inflammation and damage, as well as the levels of SP, NKA, NKB, and CGRP in BAL decreased the most in the medium-dose group (p < 0.001 vs. disease model group). In conclusion, medium-dose Qufeng Xuanfei decoction efficiently decreases the levels of neuropeptides, attenuates airway inflammation, and promotes recovery from disease. PMID- 24807843 TI - Autophagy of mitochondria: a promising therapeutic target for neurodegenerative disease. AB - The autophagic process is the only known mechanism for mitochondrial turnover and it has been speculated that dysfunction of autophagy may result in mitochondrial error and cellular stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is associated with cellular oxidative stress and its impact on neurodegeneration. This impaired autophagic function may be considered as a possible mechanism in the pathogenesis of several neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. It can be suggested that autophagy dysfunction along with oxidative stress is considered main events in neurodegenerative disorders. New therapeutic approaches have now begun to target mitochondria as a potential drug target. This review discusses evidence supporting the notion that oxidative stress and autophagy are intimately associated with neurodegenerative disease pathogenesis. This review also explores new approaches that can prevent mitochondrial dysfunction, improve neurodegenerative etiology, and also offer possible cures to the aforementioned neurodegenerative diseases. PMID- 24807846 TI - Sacroiliac joint involvement in systemic sclerosis. AB - AIM: One of the major problems for systemic sclerosis (SSc) patients is suggested to be articular involvement. Mostly involved joints in SSc were reported as wrist, carpometacarpal-interphalangeal, foot, knee, hip and shoulder; however, there has been little knowledge on the sacroiliac joint. Our aim was to evaluate sacroiliac joint involvement in SSc. METHODS: Fifty-seven SSc patients, 54 rheumatoid arthritis patients and 64 healthy subjects were included. Anteroposterior pelvic radiographs were obtained and graded twice by three blinded rheumatologists. One competent radiologist has re-evaluated the X-ray results. The ASAS (Assessment of Spondylo Arthritis International Society) scoring method was applied for grading sacroiliac involvement. Inflammatory back pain was also evaluated. Other clinical and laboratory data were collected as proposed by the European Study Group. RESULTS: In the SSc group sacroiliitis was found in 13 patients (23%) and was significantly different from RA patients (two patients, 4%), P = 0.003; and the healthy control group (one participant, 2%), P < 0.001. The frequency of inflammatory back pain in SSc patients with sacroiliitis (8/13 patients, 62%) was significantly higher in SSc patients without sacroiliitis (4/44 patients, 9%), P < 0.001. The SSc patients with sacroiliitis and with inflammatory back pain (8/57 patients, 14%) were regarded as axial spondyloarthritis overlap. Male gender, diffuse subtype, inflammatory back pain and high C-reactive protein levels (odds ratio: 1.069, 1.059, 1.059 and 3.698, respectively) were found to be the significant risk factors for sacroiliitis. CONCLUSION: We suggest that, sacroiliitis may be a concern to be considered in SSc practice. PMID- 24807847 TI - Charge transport in light emitting devices based on colloidal quantum dots and a solution-processed nickel oxide layer. AB - We fabricated hybrid light emitting devices based on colloidal CdSe/ZnS core/shell quantum dots and a solution-processed NiO layer. The use of a sol-gel NiO layer as a hole injection layer (HIL) resulted in overall improvement in device operation compared to a control device with a more conventional poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) HIL. In particular, luminous efficiency increased substantially because of the suppression of excessive currents and became as large as 2.45 cd/A. To manifest the origin of current reduction, temperature- and electric field-dependent variations of currents with respect to bias voltages were investigated. In a low bias voltage range below the threshold for luminance turn-on, the Poole-Frenkel (PF) emission mechanism was responsible for the current-density variation. However, the space-charge-limited current modified with PF-type mobility ruled the current-density variation in high bias voltage range above the threshold. PMID- 24807848 TI - Radical arylalkoxycarbonylation of 2-isocyanobiphenyl with carbazates: dual C-C bond formation toward phenanthridine-6-carboxylates. AB - A sequential oxidative radical alkoxycarbonylation and aromatization of 2 isocyanobiphenyl with carbazates was developed to furnish phenanthridine-6 carboxylates. Various functional groups such as methoxy, chloro, fluoro, trifluoromethoxy, and trifluoromethyl groups were tolerated well under the reaction conditions. The sequential radical addition-cyclization strategy represents a practical route to access phenanthridine-6-carboxylates. PMID- 24807849 TI - Comparative study of the efficacy of the canalith repositioning procedure versus the vertigo treatment and rehabilitation chair. AB - CONCLUSION: Vertigo treatment and rehabilitation chair (TRV) may be suggested as the first choice for patients with posterior canal benign paroxysmal positional vertigo (p-BPPV). OBJECTIVE: To investigate the short- and long-term treatment efficacy of the canalith repositioning procedure (CRP) versus TRV for patients with p-BPPV. METHODS: A total of 165 patients with unilateral p-BPPV were assigned to either the CRP group or the TRV group. Patients were assessed at 1 week, 4 weeks, 3 months, and 6 months after their first treatment. The numbers of treatment sessions required for successful repositioning in both groups at 4 weeks, 3 months, and 6 months were recorded. RESULTS: Treatment efficacy of patients in the TRV group was significantly better than that of patients in the CRP group 1 week after the first treatment. The number of treatment sessions needed for successful repositioning was significantly lower in the TRV group than in the CRP group at 4 weeks and 3 months after the first treatment. PMID- 24807850 TI - The development and evaluation of the Finnish Matrix Sentence Test for speech intelligibility assessment. AB - CONCLUSION: The Finnish Matrix Test is the first sentence test in noise for the Finnish language. It was developed according to the HearCom standards and provides reliable speech intelligibility measurements with highly comparable results with the other international matrix tests. OBJECTIVES: The aim of the study was to develop an accurate speech intelligibility test in noise for the Finnish language that is comparable across different languages. METHODS: We chose a matrix sentence test, which comprises a base matrix of 10 names, verbs, numerals, adjectives and nouns. Test lists were formed from this matrix quasi randomly, providing test sentences of the same syntactical structure. The speech material corresponds to everyday spoken language and the phoneme distribution is representative of the Finnish language. The test was optimized by determining the speech recognition thresholds of the individual words and subsequently by applying level corrections of up to +/-3 dB. Evaluation measurements were performed to check the equivalence of the different test lists with respect to speech intelligibility and to provide reference values for further clinical applications. RESULTS: After training, the mean speech recognition threshold (SRT) and the slope of the final test lists were -10.1 +/- 0.1 dB signal-to-noise ratio (SNR)and 16.7 +/- 1.2%/dB, respectively (measurements at constant level; inter-list variability). The mean SRT and the slope of the test subjects were 10.1 +/- 0.7 dB SNR and 17.5 +/- 2.2%/dB (measurements at constant level; inter subject variability). The expected SRT range for normal-hearing young adults for adaptive measurements is -9.7 +/- 0.7 dB SNR. PMID- 24807851 TI - Regulation of dopamine D2 receptors in the guinea pig cochlea. AB - CONCLUSION: Our study demonstrates that the regulation of D2 receptors may be frequency specific. The reduction in cochlear microphonics (CM) and distortion product otoacoustic emission (DPOAE) amplitudes after perfusion with a D2 antagonist suggests that this receptor plays a role in the regulation of cochlear hair cell activation. OBJECTIVES: Dopaminergic terminals are subject to negative feedback from dopamine D2 receptors. In the present study we investigated whether the regulation of dopamine D2 receptor is frequency specific and evaluated changes in CM in guinea pig cochlea. METHODS: A total of 30 male guinea pigs were randomly assigned to 3 groups and perfused with artificial perilymph (AP), AP containing ethanol (0.1%), or a D2 antagonist (L741626) for 2 h. In each group, compound action potentials (CAPs) evoked by a 1, 2, 4, 8, 16 or 24 kHz tone pip, CM evoked by 4 kHz tone bursts, and DPOAEs were measured before and 2 h after perilymphatic perfusion. RESULTS: Perfusion with the D2 antagonist resulted in increased CAP thresholds compared with the other two groups at high frequencies (4, 8, 16, 24 kHz, p < 0.05); however, no significant increase was observed at low frequencies (1, 2 kHz, p > 0.05). There was a significant reduction in DPOAEs and CM amplitudes after the 2 h perfusion with the D2 antagonist. A CM input/output (I/O) function curve plotted with the stimulating level as input and the CM relative amplitude as output indicated obvious nonlinearity after the 2 h perfusion in all three groups. PMID- 24807852 TI - Single nanowire optical correlator. AB - Integration of miniaturized elements has been a major driving force behind modern photonics. Nanowires have emerged as potential building blocks for compact photonic circuits and devices in nanophotonics. We demonstrate here a single nanowire optical correlator (SNOC) for ultrafast pulse characterization based on imaging of the second harmonic (SH) generated from a cadmium sulfide (CdS) nanowire by counterpropagating guided pulses. The SH spatial image can be readily converted to the temporal profile of the pulses, and only an overall pulse energy of 8 MUJ is needed to acquire a clear image of 200 fs pulses. Such a correlator should be easily incorporated into a photonic circuit for future use of on-chip ultrafast optical technology. PMID- 24807853 TI - Magnetic coupling between metal spins through the 7,7,8,8 tetracyanoquinodimethane (TCNQ) dianion. AB - A family of magnetic metal-organic frameworks, (Ph3PMe)2[M2(TCNQ)3] {M=Fe(2+), Co(2+), Ni(2+) and Zn(2+)} have been prepared and structurally characterized. The honeycomb-like "layers" consist of M(II) ions doubly bridged with dinitrilomethane moieties of two 7,7,8,8-tetracyanoquinodimethane (TCNQ) dianions which are further connected through phenyl rings to form a 3D dianionic framework [M2TCNQ3](2-) with Ph3PMe(+) cations filling cavities that run along the c axis. Studies of the magnetic coupling through the TCNQ dianion in these structures revealed that it can promote long-range magnetic ordering despite the long coupling pathway. PMID- 24807855 TI - #trial: Clinical research in the age of social media. PMID- 24807854 TI - Removal of transgene-expressing cells by a specific immune response induced by sustained transgene expression. AB - BACKGROUND: Induction of the immune response to transgene products is a serious concern in gene therapy, and is generally known to be influenced by the transgene expression profile, as well as the types of cells that express the transgene. However, the exact nature of the association between the transgene expression profile and immune induction following gene transfer is unclear. METHODS: In the present study, plasmids, pCpG-fLuc or pCMV-fLuc, used for driving long- or short term expression of firefly luciferase, respectively, were injected into mice by hydrodynamic injections along with a reporter plasmid expressing Gaussia luciferase (pROSA-gLuc) to evaluate the transgene expression profile in the liver. Single pROSA-gLuc administration resulted in stable gLuc activity in serum for more than 1 year; thus, gLuc activity was used for monitoring immune responses to the liver cells expressing both gLuc and fLuc after co-injection. RESULTS: A significant reduction in gLuc activity was observed 2 weeks after co injection of pROSA-gLuc with pCpG-fLuc, whereas stable gLuc activity was observed when pROSA-gLuc was co-injected with pCMV-fLuc. A high level of fLuc-specific immunoglobulin G was detectable in pCpG-fLuc-injected mice; furthermore, histological analysis of the liver sections of these mice indicated CD8(+) cell infiltration, implying that the transgene-expressing hepatocytes were removed by the infiltrating cells. CONCLUSIONS: Our results demonstrate that sustained transgene expression in hepatocytes triggers antigen-specific immune responses, although short-term expression of the same transgene product elicits little, if any, immune response. PMID- 24807856 TI - When is downstream pathway inhibition important? PMID- 24807857 TI - Adjuvant therapy after hepatectomy for colorectal metastases. PMID- 24807858 TI - Hyperthermia in cancer: is it coming of age? PMID- 24807861 TI - Adjuvant chemotherapy for rectal cancer. PMID- 24807860 TI - Adjuvant chemotherapy for rectal cancer. PMID- 24807862 TI - Adjuvant chemotherapy for rectal cancer. PMID- 24807863 TI - Adjuvant chemotherapy for rectal cancer. PMID- 24807864 TI - Adjuvant chemotherapy for rectal cancer. PMID- 24807865 TI - Adjuvant chemotherapy for rectal cancer--authors' reply. PMID- 24807867 TI - Synthesis of D-erythro-sphinganine through serine-derived alpha-amino epoxides. AB - A total synthesis of D-erythro-sphinganine [(2S,3R)-2-aminooctadecane-1,3-diol] starting from commercial N-tert-butyloxycarbonyl-L-serine methyl ester is described. The approach is based on the completely stereoselective preparation of an alpha-amino epoxide obtained by treating a protected L-serinal derivative with dimethylsulfoxonium methylide. The oxirane synthon is obtained with an anti configuration fitting the (2S,3R) stereochemistry of the 2-amino-1,3-diol polar head of D-erythro-sphinganine. The synthetic procedure afforded the target compound in a 68% overall yield based on the initial amount of the starting L serine material. PMID- 24807866 TI - Addressing overdiagnosis and overtreatment in cancer: a prescription for change. AB - A vast range of disorders--from indolent to fast-growing lesions--are labelled as cancer. Therefore, we believe that several changes should be made to the approach to cancer screening and care, such as use of new terminology for indolent and precancerous disorders. We propose the term indolent lesion of epithelial origin, or IDLE, for those lesions (currently labelled as cancers) and their precursors that are unlikely to cause harm if they are left untreated. Furthermore, precursors of cancer or high-risk disorders should not have the term cancer in them. The rationale for this change in approach is that indolent lesions with low malignant potential are common, and screening brings indolent lesions and their precursors to clinical attention, which leads to overdiagnosis and, if unrecognised, possible overtreatment. To minimise that potential, new strategies should be adopted to better define and manage IDLEs. Screening guidelines should be revised to lower the chance of detection of minimal-risk IDLEs and inconsequential cancers with the same energy traditionally used to increase the sensitivity of screening tests. Changing the terminology for some of the lesions currently referred to as cancer will allow physicians to shift medicolegal notions and perceived risk to reflect the evolving understanding of biology, be more judicious about when a biopsy should be done, and organise studies and registries that offer observation or less invasive approaches for indolent disease. Emphasis on avoidance of harm while assuring benefit will improve screening and treatment of patients and will be equally effective in the prevention of death from cancer. PMID- 24807869 TI - Plasmonic optical interference. AB - Understanding optical interference is of great importance in fundamental and analytical optical design for next-generation personal, industrial, and military applications. So far, various researches have been performed for optical interference phenomena, but there have been no reports on plasmonic optical interference. Here, we report that optical interference could be effectively coupled with surface plasmons, resulting in enhanced optical absorption. We prepared a three-dimensional (3D) plasmonic nanostructure that consists of a plasmonic layer at the top, a nanoporous dielectric layer at the center, and a mirror layer at the bottom. The plasmonic layer mediates strong plasmonic absorption when the constructive interference pattern is matched with the plasmonic component. By tailoring the thickness of the dielectric layer, the strong plasmonic absorption can facilely be controlled and covers the full visible range. The plasmonic interference in the 3D nanostructure thus creates brilliant structural colors. We develop a design equation to determine the thickness of the dielectric layer in a 3D plasmonic nanostructure that could create the maximum absorption at a given wavelength. It is further demonstrated that the 3D plasmonic nanostructure can be realized on a flexible substrate. Our 3D plasmonic nanostructures will have a huge impact on the fields of optoelectronic systems, biochemical optical sensors, and spectral imaging. PMID- 24807868 TI - Functional module search in protein networks based on semantic similarity improves the analysis of proteomics data. AB - The continuously evolving field of proteomics produces increasing amounts of data while improving the quality of protein identifications. Albeit quantitative measurements are becoming more popular, many proteomic studies are still based on non-quantitative methods for protein identification. These studies result in potentially large sets of identified proteins, where the biological interpretation of proteins can be challenging. Systems biology develops innovative network-based methods, which allow an integrated analysis of these data. Here we present a novel approach, which combines prior knowledge of protein protein interactions (PPI) with proteomics data using functional similarity measurements of interacting proteins. This integrated network analysis exactly identifies network modules with a maximal consistent functional similarity reflecting biological processes of the investigated cells. We validated our approach on small (H9N2 virus-infected gastric cells) and large (blood constituents) proteomic data sets. Using this novel algorithm, we identified characteristic functional modules in virus-infected cells, comprising key signaling proteins (e.g. the stress-related kinase RAF1) and demonstrate that this method allows a module-based functional characterization of cell types. Analysis of a large proteome data set of blood constituents resulted in clear separation of blood cells according to their developmental origin. A detailed investigation of the T-cell proteome further illustrates how the algorithm partitions large networks into functional subnetworks each representing specific cellular functions. These results demonstrate that the integrated network approach not only allows a detailed analysis of proteome networks but also yields a functional decomposition of complex proteomic data sets and thereby provides deeper insights into the underlying cellular processes of the investigated system. PMID- 24807870 TI - Large-scale organic single-crystal thin films and transistor arrays via the evaporation-controlled fluidic channel method. AB - We report a facile and versatile approach for fabricating large-area organic thin film transistor (OTFTs) arrays via a fluidic channel method. Evaporation controlled fluidic channel-containing organic semiconductors easily produce large area organic single-crystalline thin films in a quite uniform manner. The unidirectional movement of the meniscus and the subsequent film growth via solvent evaporation inside the fluidic channel correspond to the simulation based on the finite element method. Utilizing this fluidic channel method, we fabricated high-performance 6,13-bis(triisopropylsilylethynyl)pentacene OTFT arrays with average and maximal mobilities of 0.71 and 2.18 cm(2) V(-1) s(-1), respectively, while exhibiting current on:off ratios of >1 * 10(6). We claim that this scalable fluidic channel method offers a competitive way to fabricate high performance and large-area organic semiconductor devices for a variety of applications. PMID- 24807871 TI - Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor. AB - OBJECTIVE: To evaluate the efficacy of maintenance therapy with oral micronized progesterone (OMP) for prolongation of pregnancy in cases of arrested preterm labor. METHODS: Ninety women at 24-34weeks of singleton pregnancy with intact membranes and arrested preterm labor were randomly allocated to receive OMP (n=45) or placebo (n=45) daily until 37weeks or delivery, whichever was earlier. Outcome parameters were compared using Student t test, chi(2) test, Fisher exact test, and log-rank chi(2) test. RESULTS: OMP significantly prolonged the latency period (33.29+/-22.16 vs 23.07+/-15.42days; P=0.013). Log-rank analysis revealed a significant difference in mean time to delivery between the 2 groups (P=0.014). There were significantly fewer preterm births (33% vs 58%; P=0.034) and low birth weight neonates (37% vs 64%; P=0.017), and significantly higher mean birth weight (2.44+/-0.58 vs 2.14+/-0.47kg; P=0.009) in the OMP group. Perinatal outcomes and adverse effects were similar in the 2 groups. CONCLUSION: Maintenance tocolysis with OMP significantly prolonged pregnancy and decreased the number of preterm births. Clinical Trial Registry of India: CTRI/2011/10/002043. PMID- 24807872 TI - Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection. AB - BACKGROUND: Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion. METHODS AND RESULTS: A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production. CONCLUSIONS: These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection. PMID- 24807874 TI - The role of antihypertensive drug classes and statins in preventing aortic elasticity. PMID- 24807873 TI - The endothelium: paracrine mediator of aortic dissection. PMID- 24807875 TI - Time course and the recanalization rate of superficial vein thrombosis treated with low-molecular-weight heparin. AB - The aim of this study was to follow the thrombus progression and regression in superficial veins of lower limbs in patients with superficial vein thrombosis (SVT) treated with low-molecular-weight heparin. Patients (n = 68) with a first symptomatic SVT of the lower limbs received 2 different dosages of dalteparin. The primary outcome was a change in the diameter and length of thrombus in the affected veins. The regression of thrombus was not significantly different between the groups (P = .19). The reduction in the length of thrombus as well as thrombus diameter was significantly greater in females. At the end of the observation period, the length of thrombus in the distal part was more reduced than in the proximal segments. It seems that the dosage of anticoagulant drug does not have a significant impact on thrombus resolution. PMID- 24807876 TI - Non-randomized response model for sensitive survey with noncompliance. AB - Collecting representative data on sensitive issues has long been problematic and challenging in public health prevalence investigation (e.g. non-suicidal self injury), medical research (e.g. drug habits), social issue studies (e.g. history of child abuse), and their interdisciplinary studies (e.g. premarital sexual intercourse). Alternative data collection techniques that can be adopted to study sensitive questions validly become more important and necessary. As an alternative to the famous Warner randomized response model, non-randomized response triangular model has recently been developed to encourage participants to provide truthful responses in surveys involving sensitive questions. Unfortunately, both randomized and non-randomized response models could underestimate the proportion of subjects with the sensitive characteristic as some respondents do not believe that these techniques can protect their anonymity. As a result, some authors hypothesized that lack of trust and noncompliance should be highest among those who have the most to lose and the least to use for the anonymity provided by using these techniques. Some researchers noticed the existence of noncompliance and proposed new models to measure noncompliance in order to get reliable information. However, all proposed methods were based on randomized response models which require randomizing devices, restrict the survey to only face-to-face interview and are lack of reproductivity. Taking the noncompliance into consideration, we introduce new non randomized response techniques in which no covariate is required. Asymptotic properties of the proposed estimates for sensitive characteristic as well as noncompliance probabilities are developed. Our proposed techniques are empirically shown to yield accurate estimates for both sensitive and noncompliance probabilities. A real example about premarital sex among university students is used to demonstrate our methodologies. PMID- 24807877 TI - Using perceptual illusions for redirected walking. AB - Redirected walking (RDW) gives users the ability to explore a virtual world by walking in a confined physical space. It inconspicuously guides them on a physical path that might differ from the path they perceive in the virtual world. Exploiting three motion illusions-the change-blindness illusion, the four-stroke motion illusion, and the motion-without-movement illusion-can increase RDW's effectiveness. PMID- 24807878 TI - Magic cards: a new augmented-reality approach. AB - Augmented reality (AR) commonly uses markers for detection and tracking. Such multimedia applications associate each marker with a virtual 3D model stored in the memory of the camera-equipped device running the application. Application users are limited in their interactions, which require knowing how to design and program 3D objects. This generally prevents them from developing their own entertainment AR applications. The Magic Cards application solves this problem by offering an easy way to create and manage an unlimited number of virtual objects that are encoded on special markers. PMID- 24807879 TI - Generating freestyle group formations in agent-based crowd simulations. AB - Few crowd simulation algorithms take collective group features such as group formations into consideration. Recent approaches often manually specify hard constraints such as predefined keyframe agent formations and interpolate them during the simulation. A proposed interactive, scalable framework generates freestyle group formations and transitions via natural and flexible sketching interaction. It automatically computes a plausible agent distribution in the target formation and agent correspondences between keyframes. In addition, two level formation trajectory control lets users intuitively guide agents' transition paths from the initial formation to the target formation. In experiments, the framework efficiently generated formations on the fly while providing sufficiently flexible control to users. PMID- 24807880 TI - Conservative sampling of solids in image space. AB - Conservative sampling samples boundary-representation (B-rep) solid models into layered depth images (LDIs). The resulting models have a closed boundary and are guaranteed to bound the input B-rep models on the rays of LDIs. This approach can be fully implemented by shader programs supported by various graphics hardware. Experimental results demonstrate this approach's efficiency; applications of it to evaluating intersecting volumes and computing Minkowski sums show its versatility. PMID- 24807881 TI - A VR simulator for intracardiac intervention. AB - A VR simulator provides low-cost, realistic training for intracardiac techniques for determining the heart's mechanical and electrical activities. A geometric method models interaction between a catheter and the heart wall. Boundary enhanced voxelization accelerates detection of catheter-heart interaction. A tactile interface incorporates a VR catheter unit to track the catheter's movement. PMID- 24807882 TI - Spectrum-based network visualization for topology analysis. AB - Network visualization techniques have been widely used to explore social networks, which are crucial to many application domains. A proposed visual analytics approach provides functions that were previously hard to obtain. Based on recent achievements in spectrum-based analysis, it uses the features of node distribution and coordinates in the high-dimensional spectral space. Specifically, three-stage node projection and dispersion on a k-dimensional sphere in the spectral space determines the network layout. To assist interactive exploration of network topologies, network visualization and interactive analysis let users filter nodes and edges in a way that's meaningful to the global topology structure. PMID- 24807883 TI - Helping high schoolers move the (virtual) world. AB - In a workshop, high school students built a virtual world for a car-racing game. The prerequisites were math-rather than programming-skills; instructional scaffolding (OpenGL templates and tutors) aided students through their programming tasks. This workshop was an alternative to other measures (for example, Microsoft's recent campaign) to get high school students interested in computer science. PMID- 24807884 TI - Visualization of uncertainty without a mean. AB - As dataset size and complexity steadily increase, uncertainty is becoming an important data aspect. So, today's visualizations need to incorporate indications of uncertainty. However, characterizing uncertainty for visualization isn't always straightforward. Entropy, in the information-theoretic sense, can be a measure for uncertainty in categorical datasets. The authors discuss the mathematical formulation, interpretation, and use of entropy in visualizations. This research aims to demonstrate entropy as a metric and expand the vocabulary of uncertainty measures for visualization. PMID- 24807885 TI - The therapeutic lamp: treating small-animal phobias. AB - We all have an irrational fear or two. Some of us get scared by an unexpected visit from a spider in our house; others get nervous when they look down from a high building. Fear is an evolutionary and adaptive function that can promote self-preservation and help us deal with the feared object or situation. However, when this state becomes excessive, it might develop into psychological disorders such as phobias, producing high anxiety and affecting everyday life. The Therapeutic Lamp is an interactive projection-based augmented-reality system for treating small-animal phobias. It aims to increase patient-therapist communication, promote more natural interaction, and improve the patient's engagement in the therapy. PMID- 24807886 TI - Hypothyroidism (primary). AB - INTRODUCTION: Hypothyroidism is six times more common in women, affecting up to 40 in 10,000 each year (compared with 6/10,000 men). METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for clinical (overt) hypothyroidism? What are the effects of treatments for subclinical hypothyroidism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: levothyroxine, and levothyroxine plus liothyronine. PMID- 24807887 TI - Factor Structure of Hospital Anxiety and Depression Scale in Malaysian patients with coronary artery disease. AB - The Hospital Anxiety and Depression Scale (HADS) is a common screening instrument used to determine the levels of anxiety and depression experienced by a patient and has been extensively used in patients with coronary artery disease (CAD). This study aimed to establish the factor structure of HADS in a Malaysian sample of 189 patients with CAD. Factor analysis of HADS using principal component analysis with varimax rotation yielded 3 factors. Confirmatory factor analysis supported the use of HADS in assessing 3 distinct dimensions of psychological distress--namely, anxiety, anhedonia, and psychomotor retardation. The HADS showed good internal consistency and was found to be a valid measure of psychological distress among Malaysian patients with CAD. However, low mean scores on the original 2 factors--that is, anxiety and depression--and also on the 2 depression subscales--anhedonia and psychomotor retardation--suggests that the recommended cutoff score to screen for psychological distress among CAD patients be reevaluated. Further research to determine the generalizability and consistency for the tridimensional structure of the HADS in Malaysia is recommended. PMID- 24807888 TI - Nonregenerative anemia: mechanisms of decreased or ineffective erythropoiesis. AB - In veterinary medicine, anemia without an appropriate compensatory hematopoietic response is termed nonregenerative. Nonregenerative anemia is a common clinical entity, occurring as a result of diminished or ineffective erythropoiesis in association with many types of pathology. This article reviews nonregenerative anemia in domestic animals, emphasizing mechanisms of disease, and also covers other conditions associated with nonregenerative anemia in people. Many aspects of nonregenerative anemia in animals are worthy of further investigation, from molecular mechanisms of disease to epidemiologic impacts. PMID- 24807889 TI - A phase I dose-finding study of the novel Toll-like receptor 8 agonist VTX-2337 in adult subjects with advanced solid tumors or lymphoma. AB - PURPOSE: This phase I, open-label, uncontrolled, ascending-dose study explored the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacology of the TLR8 agonist VTX-2337 in subjects with advanced solid tumors or lymphoma. EXPERIMENTAL DESIGN: VTX-2337 doses (0.1-3.9 mg/m(2)) were administered subcutaneously on days 1, 8, and 15 of each 28-day cycle. Safety/tolerability assessments included adverse events (AE); physical, ophthalmologic, and laboratory evaluations; and electrocardiograms. Dose-limiting toxicities (DLT) were evaluated during the first cycle. Pharmacokinetics were evaluated after the first dose. Plasma samples were quantitatively assessed for chemokines, cytokines, and other inflammatory mediators. Antitumor activity was assessed. RESULTS: Thirty-three subjects were enrolled in 8 cohorts and received an average of 2 treatment cycles (range, 1-8 cycles). Most AEs were grades 1 to 2; the most common drug-related AEs were injection site reactions, chills, pyrexia, and influenza-like illness. One DLT was reported: grade 3 hypotension (3.9 mg/m(2)). The MTD was considered the highest dose administered. Peak drug plasma levels and total systemic exposure were generally dose proportional. At doses >=0.4 mg/m(2), increases above baseline levels were observed for plasma levels of G-CSF, monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, and TNFalpha. Eight subjects (24.2%) had a best response of stable disease (median duration, 54.5 days). CONCLUSIONS: VTX-2337 is clinically well tolerated and biologically active with a predictable pharmacokinetic profile. Suitable doses for testing in combination studies were identified. Phase II placebo-controlled studies of VTX-2337 in combination with doxorubicin in ovarian cancer, and in combination with platinum chemotherapy, 5 FU, and cetuximab in head and neck cancer have been initiated (NCT #01666444 and NCT#01836029). PMID- 24807890 TI - Retinal detachment. AB - INTRODUCTION: Rhegmatogenous retinal detachment (RRD) is the most common form of retinal detachment, where a retinal 'break' allows the ingress of fluid from the vitreous cavity to the subretinal space, resulting in retinal separation. It occurs in about 1 in 10,000 people a year. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different surgical interventions in people with rhegmatogenous retinal detachment? What are the effects of interventions to treat proliferative vitreoretinopathy occurring as a complication of retinal detachment or previous treatment for retinal detachment? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: corticosteroids, daunorubicin, fluorouracil plus low molecular weight heparin, pneumatic retinopexy, scleral buckling, short-acting or long acting gas tamponade, silicone oil tamponade, and vitrectomy. PMID- 24807891 TI - State of the science: diabetes self-management interventions led by nurse principal investigators. AB - Over the past decade, diabetes self-management (DSM) interventions have become increasingly heterogeneous to address the needs of diverse populations. The purpose of this integrative review is to summarize the state of the science regarding DSM interventions led by nurse principal investigators. The Preferred Reporting Items of Systematic Reviews and Meta-Analyses framework informed identification, selection, and appraisal of the literature. A total of 44 national and international studies (RCTs [randomized controlled trial] and quasi experimental studies) were identified for inclusion. Across national studies, diverse ethnic groups (Latinos, African Americans, Asians, and Native Americans) were most frequently sampled (67%). Review findings identified (a) DSM intervention typologies (primary DSM intervention, DSM reinforcement intervention, and primary DSM intervention plus reinforcement intervention) and selection of blended or bundled intervention components; (b) DSM intervention translation to community-based, electronic, and home settings; and (c) DSM intervention delivery (interventionists, dosages, and fidelity). PMID- 24807892 TI - The Impact of Caregiving on Caregivers' Medication Adherence and Appointment Keeping. AB - The purpose of this study was to examine the relationships between care demands and caregivers' medication adherence and health appointment keeping. A cross sectional correlational design was used to survey a convenience sample of 45 informal caregivers of persons with dementia. Pearson product-moment correlations and hierarchical multiple regressions were used to examine the relationships among study variables. Nearly one third of caregivers reported frequently or occasionally missing medication doses and nearly a half reported not being able to fully keep appointments with health care providers. Female gender, care duration, and care-recipient activities of daily living were significant predictors for medication adherence and appointment keeping. Caregivers' education and weekly caregiving hours contributed significantly to their medication adherence. Interventions are needed to help caregivers keep health appointments and adhere to their medications. PMID- 24807893 TI - Improved scatterplot design. PMID- 24807894 TI - Serial crossover. PMID- 24807895 TI - Verifying scientific simulations via comparative and quantitative visualization. AB - This article presents a visualization-assisted process that verifies scientific simulation codes. Code verification is necessary because scientists require accurate predictions to interpret data confidently. This verification process integrates iterative hypothesis verification with comparative, feature, and quantitative visualization. Following this process can help identify differences in cosmological and oceanographic simulations. PMID- 24807896 TI - Advanced volume illumination with unconstrained light source positioning. PMID- 24807897 TI - Context-preserving, dynamic word cloud visualization. AB - The proposed method uses context-preserving, dynamic word clouds to illustrate content evolution. It generates a sequence of word clouds in which related words are grouped together. This sequence is then coupled with a trend chart that summarizes content changes so that users can better explore large collections of documents. PMID- 24807898 TI - Visualizing graphs and clusters as maps. AB - Information visualization is essential in making sense of large datasets. Often, high-dimensional data are visualized as a collection of points in 2D space through dimensionality reduction techniques. However, these traditional methods often don't capture the underlying structural information, clustering, and neighborhoods well. GMap is a practical algorithmic framework for visualizing relational data with geographic-like maps. This approach is effective in various domains. PMID- 24807899 TI - Using visualization to debug visualization software. PMID- 24807900 TI - From designing products to fabricating them from planar materials. AB - A geometric-modeling system automates design and fabrication of products customized for consumers. Specifically, it maps designs onto different reference model shapes and then unfolds them into 2D pattern pieces. A map-guided algorithm automatically positions the pieces according to industrial requirements. PMID- 24807901 TI - Kinetochore-microtubule stability governs the metaphase requirement for Eg5. AB - The mitotic spindle is a bipolar, microtubule (MT)-based cellular machine that segregates the duplicated genome into two daughter cells. The kinesin-5 Eg5 establishes the bipolar geometry of the mitotic spindle, but previous work in mammalian cells suggested that this motor is unimportant for the maintenance of spindle bipolarity. Although it is known that Kif15, a second mitotic kinesin, enforces spindle bipolarity in the absence of Eg5, how Kif15 functions in this capacity and/or whether other biochemical or physical properties of the spindle promote its bipolarity have been poorly studied. Here we report that not all human cell lines can efficiently maintain bipolarity without Eg5, despite their expressing Kif15. We show that the stability of chromosome-attached kinetochore MTs (K-MTs) is important for bipolar spindle maintenance without Eg5. Cells that efficiently maintain bipolar spindles without Eg5 have more stable K-MTs than those that collapse without Eg5. Consistent with this observation, artificial destabilization of K-MTs promotes spindle collapse without Eg5, whereas stabilizing K-MTs improves bipolar spindle maintenance without Eg5. Our findings suggest that either rapid K-MT turnover pulls poles inward or slow K-MT turnover allows for greater resistance to inward-directed forces. PMID- 24807902 TI - Biochemical and biological properties of cortexillin III, a component of Dictyostelium DGAP1-cortexillin complexes. AB - Cortexillins I-III are members of the alpha-actinin/spectrin subfamily of Dictyostelium calponin homology proteins. Unlike recombinant cortexillins I and II, which form homodimers as well as heterodimers in vitro, we find that recombinant cortexillin III is an unstable monomer but forms more stable heterodimers when coexpressed in Escherichia coli with cortexillin I or II. Expressed cortexillin III also forms heterodimers with both cortexillin I and II in vivo, and the heterodimers complex in vivo with DGAP1, a Dictyostelium GAP protein. Binding of cortexillin III to DGAP1 requires the presence of either cortexillin I or II; that is, cortexillin III binds to DGAP1 only as a heterodimer, and the heterodimers form in vivo in the absence of DGAP1. Expressed cortexillin III colocalizes with cortexillins I and II in the cortex of vegetative amoebae, the leading edge of motile cells, and the cleavage furrow of dividing cells. Colocalization of cortexillin III and F-actin may require the heterodimer/DGAP1 complex. Functionally, cortexillin III may be a negative regulator of cell growth, cytokinesis, pinocytosis, and phagocytosis, as all are enhanced in cortexillin III-null cells. PMID- 24807903 TI - SNAP23, Syntaxin4, and vesicle-associated membrane protein 7 (VAMP7) mediate trafficking of membrane type 1-matrix metalloproteinase (MT1-MMP) during invadopodium formation and tumor cell invasion. AB - Movement through the extracellular matrix (ECM) requires cells to degrade ECM components, primarily through the action of matrix metalloproteinases (MMPs). Membrane type 1-matrix metalloproteinase (MT1-MMP) has an essential role in matrix degradation and cell invasion and localizes to subcellular degradative structures termed invadopodia. Trafficking of MT1-MMP to invadopodia is required for the function of these structures, and here we examine the role of N ethylmaleimide-sensitive factor-activating protein receptor (SNARE)-mediated membrane traffic in the transport of MT1-MMP to invadopodia. During invadopodium formation in MDA-MB-231 human breast cancer cells, increased association of SNAP23, Syntaxin4, and vesicle-associated membrane protein 7 (VAMP7) is detected by coimmunoprecipitation. Blocking the function of these SNAREs perturbs invadopodium-based ECM degradation and cell invasion. Increased level of SNAP23 Syntaxin4-VAMP7 interaction correlates with decreased Syntaxin4 phosphorylation. These results reveal an important role for SNARE-regulated trafficking of MT1-MMP to invadopodia during cellular invasion of ECM. PMID- 24807904 TI - Systematic spatial mapping of proteins at exocytic and endocytic structures. AB - Vesicular secretion (exocytosis) involves the release and then compensatory recycling of vesicle components through endocytosis. This fundamental cellular process is controlled by the coordinated assembly and interactions of dozens of proteins at the plasma membrane. Understanding the molecular composition of individual exocytic and endocytic structures and their organization across the plasma membrane is critical to understanding the behavior and regulation of these two cellular processes. Here we develop a high-resolution and high-throughput fluorescence imaging-based approach for the unbiased mapping of 78 proteins at single exocytic vesicles and endocytic structures in neuroendocrine PC12 cells. This analysis uses two-color single-frame images to provide a systems-level map of the steady-state distributions of proteins at individual exocytic and endocytic structures in the cell. Along with this quantitative map, we find that both calcium-regulated exocytic vesicles (dense core vesicles) and endocytic structures (clathrin-coated structures) and the proteins associated with these structures exhibit a random spatial distribution in unstimulated neuroendocrine PC12 cells. This approach is broadly applicable for quantitatively mapping the molecular composition and spatial organization of discrete cellular processes with central molecular hubs. PMID- 24807905 TI - NME7 is a functional component of the gamma-tubulin ring complex. AB - As the primary microtubule nucleator in animal cells, the gamma-tubulin ring complex (gammaTuRC) plays a crucial role in microtubule organization, but little is known about how the activity of the gammaTuRC is regulated. Recently, isolated gammaTuRC was found to contain NME7, a poorly characterized member of the NME family. Here we report that NME7 is a gammaTuRC component that regulates the microtubule-nucleating activity of the gammaTuRC. NME7 contains two putative kinase domains, A and B, and shows autophosphorylating activity. Whereas domain A is involved in the autophosphorylation, domain B is inactive. NME7 interacts with the gammaTuRC through both A and B domains, with Arg-322 in domain B being crucial to the binding. In association with the gammaTuRC, NME7 localizes to centrosomes throughout the cell cycle and to mitotic spindles during mitosis. Suppression of NME7 expression does not affect gammaTuRC assembly or localization to centrosomes, but it does impair centrosome-based microtubule nucleation. Of importance, wild-type NME7 promotes gammaTuRC-dependent nucleation of microtubules, but kinase-deficient NME7 does so only poorly. These results suggest that NME7 functions in the gammaTuRC in a kinase-dependent manner to facilitate microtubule nucleation. PMID- 24807906 TI - Gamma-tubulin controls neuronal microtubule polarity independently of Golgi outposts. AB - Neurons have highly polarized arrangements of microtubules, but it is incompletely understood how microtubule polarity is controlled in either axons or dendrites. To explore whether microtubule nucleation by gamma-tubulin might contribute to polarity, we analyzed neuronal microtubules in Drosophila containing gain- or loss-of-function alleles of gamma-tubulin. Both increased and decreased activity of gamma-tubulin, the core microtubule nucleation protein, altered microtubule polarity in axons and dendrites, suggesting a close link between regulation of nucleation and polarity. To test whether nucleation might locally regulate polarity in axons and dendrites, we examined the distribution of gamma-tubulin. Consistent with local nucleation, tagged and endogenous gamma tubulins were found in specific positions in dendrites and axons. Because the Golgi complex can house nucleation sites, we explored whether microtubule nucleation might occur at dendritic Golgi outposts. However, distinct Golgi outposts were not present in all dendrites that required regulated nucleation for polarity. Moreover, when we dragged the Golgi out of dendrites with an activated kinesin, gamma-tubulin remained in dendrites. We conclude that regulated microtubule nucleation controls neuronal microtubule polarity but that the Golgi complex is not directly involved in housing nucleation sites. PMID- 24807907 TI - MgcRacGAP interacts with cingulin and paracingulin to regulate Rac1 activation and development of the tight junction barrier during epithelial junction assembly. AB - The regulation of Rho-family GTPases is crucial to direct the formation of cell cell junctions and tissue barriers. Cingulin (CGN) and paracingulin (CGNL1) control RhoA activation in epithelial cells by interacting with RhoA guanidine exchange factors. CGNL1 depletion also inhibits Rac1 activation during junction assembly. Here we show that, unexpectedly, Madin-Darby canine kidney epithelial cells depleted of both CGN and CGNL1 (double-KD cells) display normal Rac1 activation and tight junction (TJ) formation, despite decreased junctional recruitment of the Rac1 activator Tiam1. The expression of the Rac1 inhibitor MgcRacGAP is decreased in double-KD cells, and the barrier development and Rac1 activation phenotypes are rescued by exogenous expression of MgcRacGAP. MgcRacGAP colocalizes with CGN and CGNL1 at TJs and forms a complex and interacts directly in vitro with CGN and CGNL1. Depletion of either CGN or CGNL1 in epithelial cells results in decreased junctional localization of MgcRacGAP but not of ECT2, a centralspindlin-interacting Rho GEF. These results provide new insight into coordination of Rho-family GTPase activities at junctions, since apical accumulation of CGN and CGNL1 at TJs during junction maturation provides a mechanism to spatially restrict down-regulation of Rac1 activation through the recruitment of MgcRacGAP. PMID- 24807908 TI - Evidence for a novel antioxidant function and isoform-specific regulation of the human p66Shc gene. AB - The mammalian Shc family, composed of p46, p52, and p66 isoforms, serves as an adaptor protein in cell growth and stress response. p66Shc was shown to be a negative lifespan regulator by acting as a prooxidant protein in mitochondria; however, the regulatory mechanisms of p66Shc expression and function are incompletely understood. This study provides evidence for new features of p66Shc serving as an antioxidant and critical protein in cell differentiation. Unique among the Shc family, transcription of p66Shc is activated through the antioxidant response element (ARE)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in K562 human erythroleukemia and other cell types after treatment with hemin, an iron-containing porphyrin. Phosphorylated p66Shc at Ser-36, previously reported to be prone to mitochondrial localization, is increased by hemin treatment, but p66Shc remains exclusively in the cytoplasm. p66Shc knockdown inhibits hemin-induced erythroid differentiation, in which reactive oxygen species production and apoptosis are significantly enhanced in conjunction with suppression of other ARE-dependent antioxidant genes. Conversely, p66Shc overexpression is sufficient for inducing erythroid differentiation. Collectively these results demonstrate the isoform-specific regulation of the Shc gene by the Nrf2-ARE pathway and a new antioxidant role of p66Shc in the cytoplasm. Thus p66Shc is a bifunctional protein involved in cellular oxidative stress response and differentiation. PMID- 24807909 TI - The regulator of G protein signaling (RGS) domain of G protein-coupled receptor kinase 5 (GRK5) regulates plasma membrane localization and function. AB - The G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate activated GPCRs at the plasma membrane (PM). Here GRK5/GRK4 chimeras and point mutations in GRK5 identify a short sequence within the regulator of G protein signaling (RGS) domain in GRK5 that is critical for GRK5 PM localization. This region of the RGS domain of GRK5 coincides with a region of GRK6 and GRK1 shown to form a hydrophobic dimeric interface (HDI) in crystal structures. Coimmunoprecipitation (coIP) and acceptor photobleaching fluorescence resonance energy transfer assays show that expressed GRK5 self-associates in cells, whereas GRK5-M165E/F166E (GRK5 EE), containing hydrophilic mutations in the HDI region of the RGS domain, displays greatly decreased coIP interactions. Both forcing dimerization of GRK5 EE, via fusion to leucine zipper motifs, and appending an extra C-terminal membrane-binding region to GRK5-EE (GRK5-EE-CT) recover PM localization. In addition, GRK5-EE displays a decreased ability to inhibit PAR1-induced calcium release compared with GRK5 wild type (wt). In contrast, PM-localized GRK5-EE-CaaX (appending a C-terminal prenylation and polybasic motif from K-ras) or GRK5-EE-CT shows comparable ability to GRK5 wt to inhibit PAR1-induced calcium release. The results suggest a novel model in which GRK5 dimerization is important for its plasma membrane localization and function. PMID- 24807915 TI - Discordance in hormone receptor status among primary, metastatic, and second primary breast cancers: biological difference or misclassification? AB - INTRODUCTION: Discordance in hormone receptor status has been observed between two breast tumors of the same patients; however, the degree of heterogeneity is debatable with regard to whether it reflects true biological difference or the limited accuracy of receptor assays. METHODS: A Bayesian misclassification correction method was applied to data on hormone receptor status of two primary breast cancers from the Surveillance, Epidemiology, and End Results database between 1990 and 2010 and to data on primary breast cancer and paired recurrent/metastatic disease assembled from a meta-analysis of the literature published between 1979 and 2014. RESULTS: The sensitivity and specificity of the estrogen receptor (ER) assay were estimated to be 0.971 and 0.920, respectively. After correcting for misclassification, the discordance in ER between two primary breast cancers was estimated to be 1.2% for synchronous ipsilateral pairs, 5.0% for synchronous contralateral pairs, 14.6% for metachronous ipsilateral pairs, and 25.0% for metachronous contralateral pairs. Technical misclassification accounted for 53%-83% of the ER discordance between synchronous primary cancers and 11%-25% of the ER discordance between metachronous cancers. The corrected discordance in ER between primary tumors and recurrent or metastatic lesions was 12.4%, and there were more positive-to-negative changes (10.1%) than negative-to positive changes (2.3%). Similar patterns were observed for progesterone receptor (PR), although the overall discordance in PR was higher. CONCLUSION: A considerable proportion of discordance in hormone receptor status can be attributed to misclassification in receptor assessment, although the accuracy of receptor assays was excellent. Biopsy of recurrent tumors for receptor retesting should be conducted after considering feasibility, cost, and previous ER/PR status. PMID- 24807916 TI - Diagnostic value of next-generation sequencing in an unusual sphenoid tumor. AB - Extraordinary advancements in sequencing technology have made what was once a decade-long multi-institutional endeavor into a methodology with the potential for practical use in a clinical setting. We therefore set out to examine the clinical value of next-generation sequencing by enrolling patients with incurable or ambiguous tumors into the Personalized OncoGenomics initiative at the British Columbia Cancer Agency whereby whole genome and transcriptome analyses of tumor/normal tissue pairs are completed with the ultimate goal of directing therapeutics. First, we established that the sequencing, analysis, and communication with oncologists could be completed in less than 5 weeks. Second, we found that cancer diagnostics is an area that can greatly benefit from the comprehensiveness of a whole genome analysis. Here, we present a scenario in which a metastasized sphenoid mass, which was initially thought of as an undifferentiated squamous cell carcinoma, was rediagnosed as an SMARCB1-negative rhabdoid tumor based on the newly acquired finding of homozygous SMARCB1 deletion. The new diagnosis led to a change in chemotherapy and a complete nodal response in the patient. This study also provides additional insight into the mutational landscape of an adult SMARCB1-negative tumor that has not been explored at a whole genome and transcriptome level. PMID- 24807917 TI - Distinct clinicopathological features and prognosis of emerging young-female breast cancer in an East Asian country: a nationwide cancer registry-based study. AB - BACKGROUND: A rapid surge of young-female breast cancer (YFBC) has been observed in Taiwan and other East Asian countries. We recently reported that these cases of YFBC, in contrast to their Western counterparts, are predominantly luminal A subtype. YFBC in Asia may have distinct clinicopathological features and outcomes. METHODS: Data collected prospectively by participating hospitals were retrieved from the Taiwan Cancer Database. A total of 15,881 women with newly diagnosed stage I-III breast cancer in 2002-2006 were included. The age at diagnosis was categorized into nine 5-year groups (from <30 years to >=65 years). Clinicopathological variables and patient disease-free survival (DFS) were compared by age group. RESULTS: The rates of stage I, estrogen receptor-positive (ER+), and progesterone receptor-positive breast cancer were higher in the younger patients (<50 years) than in the older patients (>=50 years). Univariate analysis showed that the 40-44 and 45-49 age groups were significantly associated with longer DFS than the other age groups. In the ER+ subgroup, multivariate analysis consistently showed that the 40-44 age group was significantly associated with longer DFS than the other age groups except for the 45-49 age group. In contrast, multivariate analysis of the ER-negative subgroup revealed no significant difference of DFS between the 40-44 age group and other age groups. CONCLUSION: Emerging YFBC in Taiwan is uniquely associated with favorable pathological features and better outcomes and should not be regarded as the mirror image of its Western counterpart. PMID- 24807920 TI - Adaptive pinning control of deteriorated nonlinear coupling networks with circuit realization. AB - This paper deals with a class of complex networks with nonideal coupling networks, and addresses the problem of asymptotic synchronization of the complex network through designing adaptive pinning control and coupling adjustment strategies. A more general coupled nonlinearity is considered as perturbations of the network, while a serious faulty network named deteriorated network is also proposed to be further study. For the sake of eliminating these adverse impacts for synchronization, indirect adaptive schemes are designed to construct controllers and adjusters on pinned nodes and nonuniform couplings of un-pinned nodes, respectively. According to Lyapunov stability theory, the proposed adaptive strategies are successful in ensuring the achievement of asymptotic synchronization of the complex network even in the presence of perturbed and deteriorated networks. The proposed schemes are physically implemented by circuitries and tested by simulation on a Chua's circuit network. PMID- 24807918 TI - Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. AB - Serine/Arginine Splicing Factor 1 (SRSF1) is the archetype member of the SR protein family of splicing regulators. Since its discovery over two decades ago, SRSF1 has been repeatedly surprising and intriguing investigators by the plethora of complex biologic pathways it regulates. These include several key aspects of mRNA metabolism, such as mRNA splicing, stability, and translation, as well as other mRNA-independent processes, such as miRNA processing, protein sumoylation, and the nucleolar stress response. In this review, the structural features of SRSF1 are discussed as they relate to the intricate mechanism of splicing and the multiplicity of functions it performs. Similarly, a list of relevant alternatively spliced transcripts and SRSF1 interacting proteins is provided. Finally, emphasis is given to the deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers, and the complex mechanisms and pathways underlying SRSF1-mediated transformation. The accumulated knowledge about SRSF1 provides critical insight into the integral role it plays in maintaining cellular homeostasis and suggests new targets for anticancer therapy. Mol Cancer Res; 12(9); 1195-204. (c)2014 AACR. PMID- 24807921 TI - Approximate solutions to ordinary differential equations using least squares support vector machines. AB - In this paper, a new approach based on least squares support vector machines (LS SVMs) is proposed for solving linear and nonlinear ordinary differential equations (ODEs). The approximate solution is presented in closed form by means of LS-SVMs, whose parameters are adjusted to minimize an appropriate error function. For the linear and nonlinear cases, these parameters are obtained by solving a system of linear and nonlinear equations, respectively. The method is well suited to solving mildly stiff, nonstiff, and singular ODEs with initial and boundary conditions. Numerical results demonstrate the efficiency of the proposed method over existing methods. PMID- 24807919 TI - Perceptions of recovery and prognosis from long-term conditions: The relevance of hope and imagined futures. AB - OBJECTIVE: Analyses of the experiences of chronic conditions demonstrate the importance of moral worth and social meaning linked to undertaking self management practices. Rather less attention has been paid to the contemplation and significance of adopting, embedding and continuing with established practices overtime. This study explored perceptions about recovery and prognosis from the point of view of people with long-term physical health conditions and compared these findings with the mental health literature. METHODS: A longitudinal qualitative study was conducted incorporating semi-structured interviews and thematic analysis. Thirty-two participants identified as having a chronic long term physical health condition such as heart disease and diabetes were included in the study. RESULTS: In line with the notions of recovery in the mental health field, respondents viewed recovery as a complex journey related to the ability to undertake things of value in everyday life. However, there were differences in relation to reflections on trajectories and imagined futures centred on physical health. DISCUSSION: These findings are discussed in the context of literature from the mental and physical health fields and recent health policies for those with long-term conditions. The study adds to existing literature by examining the similarities and differences in the experience of chronic physical and mental health conditions. PMID- 24807922 TI - Exponential synchronization of neural networks with discrete and distributed delays under time-varying sampling. AB - This paper investigates the problem of master-slave synchronization for neural networks with discrete and distributed delays under variable sampling with a known upper bound on the sampling intervals. An improved method is proposed, which captures the characteristic of sampled-data systems. Some delay-dependent criteria are derived to ensure the exponential stability of the error systems, and thus the master systems synchronize with the slave systems. The desired sampled-data controller can be achieved by solving a set of linear matrix inequalitys, which depend upon the maximum sampling interval and the decay rate. The obtained conditions not only have less conservatism but also have less decision variables than existing results. Simulation results are given to show the effectiveness and benefits of the proposed methods. PMID- 24807923 TI - In-sample and out-of-sample model selection and error estimation for support vector machines. AB - In-sample approaches to model selection and error estimation of support vector machines (SVMs) are not as widespread as out-of-sample methods, where part of the data is removed from the training set for validation and testing purposes, mainly because their practical application is not straightforward and the latter provide, in many cases, satisfactory results. In this paper, we survey some recent and not-so-recent results of the data-dependent structural risk minimization framework and propose a proper reformulation of the SVM learning algorithm, so that the in-sample approach can be effectively applied. The experiments, performed both on simulated and real-world datasets, show that our in-sample approach can be favorably compared to out-of-sample methods, especially in cases where the latter ones provide questionable results. In particular, when the number of samples is small compared to their dimensionality, like in classification of microarray data, our proposal can outperform conventional out of-sample approaches such as the cross validation, the leave-one-out, or the Bootstrap methods. PMID- 24807924 TI - Robust exponential stability of uncertain stochastic neural networks with distributed delays and reaction-diffusions. AB - This paper considers the problem of stability analysis for uncertain stochastic neural networks with distributed delays and reaction-diffusions. Two sufficient conditions for the robust exponential stability in the mean square of the given network are developed by using a Lyapunov-Krasovskii functional, an integral inequality, and some analysis techniques. The conditions, which are expressed by linear matrix inequalities, can be easily checked. Two simulation examples are given to demonstrate the reduced conservatism of the proposed conditions. PMID- 24807925 TI - Online kernel-based learning for task-space tracking robot control. AB - Task-space control of redundant robot systems based on analytical models is known to be susceptive to modeling errors. Data-driven model learning methods may present an interesting alternative approach. However, learning models for task space tracking control from sampled data is an ill-posed problem. In particular, the same input data point can yield many different output values, which can form a nonconvex solution space. Because the problem is ill-posed, models cannot be learned from such data using common regression methods. While learning of task space control mappings is globally ill-posed, it has been shown in recent work that it is locally a well-defined problem. In this paper, we use this insight to formulate a local kernel-based learning approach for online model learning for task-space tracking control. We propose a parametrization for the local model, which makes an application in task-space tracking control of redundant robots possible. The model parametrization further allows us to apply the kernel-trick and, therefore, enables a formulation within the kernel learning framework. In our evaluations, we show the ability of the method for online model learning for task-space tracking control of redundant robots. PMID- 24807926 TI - Memristor bridge synapse-based neural network and its learning. AB - Analog hardware architecture of a memristor bridge synapse-based multilayer neural network and its learning scheme is proposed. The use of memristor bridge synapse in the proposed architecture solves one of the major problems, regarding nonvolatile weight storage in analog neural network implementations. To compensate for the spatial nonuniformity and nonideal response of the memristor bridge synapse, a modified chip-in-the-loop learning scheme suitable for the proposed neural network architecture is also proposed. In the proposed method, the initial learning is conducted in software, and the behavior of the software trained network is learned by the hardware network by learning each of the single layered neurons of the network independently. The forward calculation of the single-layered neuron learning is implemented on circuit hardware, and followed by a weight updating phase assisted by a host computer. Unlike conventional chip in-the-loop learning, the need for the readout of synaptic weights for calculating weight updates in each epoch is eliminated by virtue of the memristor bridge synapse and the proposed learning scheme. The hardware architecture along with the successful implementation of proposed learning on a three-bit parity network, and on a car detection network is also presented. PMID- 24807927 TI - Efficient sparse modeling with automatic feature grouping. AB - For high-dimensional data, it is often desirable to group similar features together during the learning process. This can reduce the estimation variance and improve the stability of feature selection, leading to better generalization. Moreover, it can also help in understanding and interpreting data. Octagonal shrinkage and clustering algorithm for regression (OSCAR) is a recent sparse modeling approach that uses a l1 -regularizer and a pairwise linfinity regularizer on the feature coefficients to encourage such feature grouping. However, computationally, its optimization procedure is very expensive. In this paper, we propose an efficient solver based on the accelerated gradient method. We show that its key proximal step can be solved by a highly efficient simple iterative group merging algorithm. Given d input features, this reduces the empirical time complexity from O(d(2) ~ d(5)) for the existing solvers to just O(d). Experimental results on a number of toy and real-world datasets demonstrate that OSCAR is a competitive sparse-modeling approach, but with the added ability of automatic feature grouping. PMID- 24807928 TI - Hierarchical approach for multiscale support vector regression. AB - Support vector regression (SVR) is based on a linear combination of displaced replicas of the same function, called a kernel. When the function to be approximated is nonstationary, the single kernel approach may be ineffective, as it is not able to follow the variations in the frequency content in the different regions of the input space. The hierarchical support vector regression (HSVR) model presented here aims to provide a good solution also in these cases. HSVR consists of a set of hierarchical layers, each containing a standard SVR with Gaussian kernel at a given scale. Decreasing the scale layer by layer, details are incorporated inside the regression function. HSVR has been widely applied to noisy synthetic and real datasets and it has shown the ability in denoising the original data, obtaining an effective multiscale reconstruction of better quality than that obtained by standard SVR. Results also compare favorably with multikernel approaches. Furthermore, tuning the SVR configuration parameters is strongly simplified in the HSVR model. PMID- 24807929 TI - Discretized-Vapnik-Chervonenkis dimension for analyzing complexity of real function classes. AB - In this paper, we introduce the discretized-Vapnik-Chervonenkis (VC) dimension for studying the complexity of a real function class, and then analyze properties of real function classes and neural networks. We first prove that a countable traversal set is enough to achieve the VC dimension for a real function class, whereas its classical definition states that the traversal set is the output range of the function class. Based on this result, we propose the discretized-VC dimension defined by using a countable traversal set consisting of rational numbers in the range of a real function class. By using the discretized-VC dimension, we show that if a real function class has a finite VC dimension, only a finite traversal set is needed to achieve the VC dimension. We then point out that the real function classes, which have the infinite VC dimension, can be grouped into two categories: TYPE-A and TYPE-B. Subsequently, based on the obtained results, we discuss the relationship between the VC dimension of an indicator-output network and that of the real-output network, when both networks have the same structure except for the output activation functions. Finally, we present the risk bound based on the discretized-VC dimension for a real function class that has infinite VC dimension and is of TYPE-A. We prove that, with such a function class, the empirical risk minimization (ERM) principle for the function class is still consistent with overwhelming probability. This is a development of the existing knowledge that the ERM learning is consistent if and only if the function class has a finite VC dimension. PMID- 24807930 TI - Limit set dichotomy and multistability for a class of cooperative neural networks with delays. AB - Recent papers have pointed out the interest to study convergence in the presence of multiple equilibrium points (EPs) (multistability) for neural networks (NNs) with nonsymmetric cooperative (nonnegative) interconnections and neuron activations modeled by piecewise linear (PL) functions. One basic difficulty is that the semiflows generated by such NNs are monotone but, due to the horizontal segments in the PL functions, are not eventually strongly monotone (ESM). This notwithstanding, it has been shown that there are subclasses of irreducible interconnection matrices for which the semiflows, although they are not ESM, enjoy convergence properties similar to those of ESM semiflows. The results obtained so far concern the case of cooperative NNs without delays. The goal of this paper is to extend some of the existing results to the relevant case of NNs with delays. More specifically, this paper considers a class of NNs with PL neuron activations, concentrated delays, and a nonsymmetric cooperative interconnection matrix A and delay interconnection matrix A(tau). The main result is that when A+A(tau) satisfies a full interconnection condition, then the generated semiflows, which are monotone but not ESM, satisfy a limit set dichotomy analogous to that valid for ESM semiflows. It follows that there is an open and dense set of initial conditions, in the state space of continuous functions on a compact interval, for which the solutions converge toward an EP. The result holds in the general case where the NNs possess multiple EPs, i.e., is a result on multistability, and is valid for any constant value of the delays. PMID- 24807931 TI - Adaptive visual and auditory map alignment in barn owl superior colliculus and its neuromorphic implementation. AB - Adaptation is one of the most important phenomena in biology. A young barn owl can adapt to imposed environmental changes, such as artificial visual distortion caused by wearing a prism. This adjustment process has been modeled mathematically and the model replicates the sensory map realignment of barn owl superior colliculus (SC) through axonogenesis and synaptogenesis. This allows the biological mechanism to be transferred to an artificial computing system and thereby imbue it with a new form of adaptability to the environment. The model is demonstrated in a real-time robot environment. Results of the experiments are compared with and without prism distortion of vision, and show improved adaptability for the robot. However, the computation speed of the embedded system in the robot is slow. A digital and analog mixed signal very-large-scale integration (VLSI) circuit has been fabricated to implement adaptive sensory pathway changes derived from the SC model at higher speed. VLSI experimental results are consistent with simulation results. PMID- 24807932 TI - Bidirectional extreme learning machine for regression problem and its learning effectiveness. AB - It is clear that the learning effectiveness and learning speed of neural networks are in general far slower than required, which has been a major bottleneck for many applications. Recently, a simple and efficient learning method, referred to as extreme learning machine (ELM), was proposed by Huang , which has shown that, compared to some conventional methods, the training time of neural networks can be reduced by a thousand times. However, one of the open problems in ELM research is whether the number of hidden nodes can be further reduced without affecting learning effectiveness. This brief proposes a new learning algorithm, called bidirectional extreme learning machine (B-ELM), in which some hidden nodes are not randomly selected. In theory, this algorithm tends to reduce network output error to 0 at an extremely early learning stage. Furthermore, we find a relationship between the network output error and the network output weights in the proposed B-ELM. Simulation results demonstrate that the proposed method can be tens to hundreds of times faster than other incremental ELM algorithms. PMID- 24807933 TI - Enhancing weak signal transmission through a feedforward network. AB - The ability to transmit and amplify weak signals is fundamental to signal processing of artificial devices in engineering. Using a multilayer feedforward network of coupled double-well oscillators as well as Fitzhugh-Nagumo oscillators, we here investigate the conditions under which a weak signal received by the first layer can be transmitted through the network with or without amplitude attenuation. We find that the coupling strength and the nodes' states of the first layer act as two-state switches, which determine whether the transmission is significantly enhanced or exponentially decreased. We hope this finding is useful for designing artificial signal amplifiers. PMID- 24807934 TI - Game analytics for game user research, part 1: a workshop review and case study. AB - The emerging field of game user research (GUR) investigates interaction between players and games and the surrounding context of play. Game user researchers have explored methods from, for example, human-computer interaction, psychology, interaction design, media studies, and the social sciences. They've extended and modified these methods for different types of digital games, such as social games, casual games, and serious games. This article focuses on quantitative analytics of in-game behavioral user data and its emergent use by the GUR community. The article outlines open problems emerging from several GUR workshops. In addition, a case study of a current collaboration between researchers and a game company demonstrates game analytics' use and benefits. PMID- 24807935 TI - Information visualization courses for students with a computer science background. AB - Linnaeus University offers two master's courses in information visualization for computer science students with programming experience. This article briefly describes the syllabi, exercises, and practices developed for these courses. PMID- 24807936 TI - Data visualization on interactive surfaces: a research agenda. AB - Interactive tabletops and surfaces (ITSs) provide rich opportunities for data visualization and analysis and consequently are used increasingly in such settings. A research agenda of some of the most pressing challenges related to visualization on ITSs emerged from discussions with researchers and practitioners in human-computer interaction, computer-supported collaborative work, and a variety of visualization fields at the 2011 Workshop on Data Exploration for Interactive Surfaces (Dexis 2011). PMID- 24807937 TI - Making public displays interactive everywhere. AB - As the number of large public displays increases, the need for interaction techniques to control them is emerging. One promising way to provide such interaction is through personal mobile devices. However, although much research has covered this topic, it hasn't yet brought those technologies fully into the public that is, by allowing for interactions in a variety of public spaces. A proposed tracking technology has led to several prototype applications that employ mobile devices to interact with large public displays. In turn, these prototypes have led to an overarching interaction concept that allows for public deployment regardless of the space's characteristics (for example, layout and technologies). PMID- 24807938 TI - Beyond information and utility: Transforming public spaces with media facades. AB - Media facades (often characterized as a building's digital skin) are public displays that substitute dynamic details and information for usually static structures. SMSlingshot is a media facade system at the confluence of art, architecture, and technology design in the context of urban human-computer interaction. It represents a participative approach to public displays that enlivens public spaces and fosters civic and social dialogue as an alternative to advertising and service-oriented information displays. Observations from SMSlingshot's implementation at festival exhibitions provide insight into the roles of scale, distance, and the spatial situation of media facade contexts. The lessons learned apply to most public-display situations and will be useful for designers and developers of this new medium in urban spaces. PMID- 24807939 TI - 3D freehand gestural navigation for interactive public displays. AB - Users increasingly expect more-interactive experiences with public displays for applications including learning, gaming, urban visualization, and planning. However, user interaction with applications on public displays is challenging and often doesn't lend itself to established interaction techniques. Navigation using only freehand gestures captured with low-cost devices might often be an appropriate solution. A formal, quantitative lab experiment and an informal, qualitative field study compared freehand gestural interaction with keyboard-and mouse interaction. No significant difference in navigation performance existed between the two interaction types. However, gestural interaction provided a more natural experience in both personal and public environments. PMID- 24807940 TI - Multipurpose public displays: how shortcut menus affect usage. AB - Transitioning from bespoke, single-purpose public displays to generic, multipurpose ones entails a number of research challenges. One such challenge is understanding how to group and present available applications to users and what effect this grouping has on application use. This study of an iterative, longitudinal deployment of a multipurpose public display examines two mechanisms that help users find the available applications: a quick-launch menu and a browsable application directory. Using the measures of relative and absolute utility, the study reveals these mechanisms' complex effects on application usage. It also addresses whether a public display should promote popular or unpopular applications. PMID- 24807941 TI - Pins and posters: Paradigms for content publication on situated displays. AB - Public-display systems are still far from being a medium for meeting people's diverse communication goals. Moving toward open displays will require publication paradigms that can overcome the challenges of meaningful engagement and enable users to fully understand and control the publication process. The metaphors of pins and posters have inspired two complementary paradigms for public displays. Researchers implemented these paradigms in the Instant Places system, which they deployed on 10 displays in diverse urban locations for six months. They collected user and system data regarding the users' practices. The findings improve the understanding of what might drive user-generated content in networks of urban displays. Such knowledge can inform the design of tools and procedures for situated publication in public displays. PMID- 24807942 TI - Haptic-based training for tank gunnery using decoupled motion control. AB - For training human motor skills, haptic guidance has proven more effective than traditional visual-feedback-only approaches. However, novices might become dependent on the feedback force provided during training and become unable to adapt to real operating environments. To overcome haptic-based training's limitations, a proposed approach uses decoupled motion control, which divides a motion into individual coordinate axis movements controlled by multiple operators. Using a networked haptic interaction system, the trainee cooperates with an expert to complete a training task. Unlike previous approaches, the force or torque exerted by the trainee's device doesn't directly correct the trainee's hand action. Instead, the trainee regulates his or her manipulation to cooperate with the expert by feeling motion feedback from the expert. The Web extra at http://youtu.be/qYBsR6AOjzQ is a video that shows a test subject operating a training simulator for tank gunnery that uses haptics. PMID- 24807943 TI - Touch-based interfaces for interacting with 3D content in public exhibitions. AB - A museum exhibition on the Lascaux caves provides the opportunity to experiment with touch-based interfaces manipulating 3D virtual objects. The researchers targeted three tasks: observing rare objects, reassembling object fragments, and reproducing artwork. PMID- 24807944 TI - Dynamic uncertain causality graph for knowledge representation and probabilistic reasoning: statistics base, matrix, and application. AB - Graphical models for probabilistic reasoning are now in widespread use. Many approaches have been developed such as Bayesian network. A newly developed approach named as dynamic uncertain causality graph (DUCG) is initially presented in a previous paper, in which only the inference algorithm in terms of individual events and probabilities is addressed. In this paper, we first explain the statistic basis of DUCG. Then, we extend the algorithm to the form of matrices of events and probabilities. It is revealed that the representation of DUCG can be incomplete and the exact probabilistic inference may still be made. A real application of DUCG for fault diagnoses of a generator system of a nuclear power plant is demonstrated, which involves > 600 variables. Most inferences take < 1 s with a laptop computer. The causal logic between inference result and observations is graphically displayed to users so that they know not only the result, but also why the result obtained. PMID- 24807945 TI - T2FELA: type-2 fuzzy extreme learning algorithm for fast training of interval type-2 TSK fuzzy logic system. AB - A challenge in modeling type-2 fuzzy logic systems is the development of efficient learning algorithms to cope with the ever increasing size of real-world data sets. In this paper, the extreme learning strategy is introduced to develop a fast training algorithm for interval type-2 Takagi-Sugeno-Kang fuzzy logic systems. The proposed algorithm, called type-2 fuzzy extreme learning algorithm (T2FELA), has two distinctive characteristics. First, the parameters of the antecedents are randomly generated and parameters of the consequents are obtained by a fast learning method according to the extreme learning mechanism. In addition, because the obtained parameters are optimal in the sense of minimizing the norm, the resulting fuzzy systems exhibit better generalization performance. The experimental results clearly demonstrate that the training speed of the proposed T2FELA algorithm is superior to that of the existing state-of-the-art algorithms. The proposed algorithm also shows competitive performance in generalization abilities. PMID- 24807946 TI - Adaptive quasi-Newton algorithm for source extraction via CCA approach. AB - This paper addresses the problem of adaptive source extraction via the canonical correlation analysis (CCA) approach. Based on Liu's analysis of CCA approach, we propose a new criterion for source extraction, which is proved to be equivalent to the CCA criterion. Then, a fast and efficient online algorithm using quasi Newton iteration is developed. The stability of the algorithm is also analyzed using Lyapunov's method, which shows that the proposed algorithm asymptotically converges to the global minimum of the criterion. Simulation results are presented to prove our theoretical analysis and demonstrate the merits of the proposed algorithm in terms of convergence speed and successful rate for source extraction. PMID- 24807947 TI - Lagrange stability of memristive neural networks with discrete and distributed delays. AB - Memristive neuromorphic system is a good candidate for creating artificial brain. In this paper, a general class of memristive neural networks with discrete and distributed delays is introduced and studied. Some Lagrange stability criteria dependent on the network parameters are derived via nonsmooth analysis and control theory. In particular, several succinct criteria are provided to ascertain the Lagrange stability of memristive neural networks with and without delays. The proposed Lagrange stability criteria are the improvement and extension of the existing results in the literature. Three numerical examples are given to show the superiority of theoretical results. PMID- 24807948 TI - Attractivity analysis of memristor-based cellular neural networks with time varying delays. AB - This paper presents new theoretical results on the invariance and attractivity of memristor-based cellular neural networks (MCNNs) with time-varying delays. First, sufficient conditions to assure the boundedness and global attractivity of the networks are derived. Using state-space decomposition and some analytic techniques, it is shown that the number of equilibria located in the saturation regions of the piecewise-linear activation functions of an n-neuron MCNN with time-varying delays increases significantly from 2(n) to 2(2n2)+n) (2(2n2) times) compared with that without a memristor. In addition, sufficient conditions for the invariance and local or global attractivity of equilibria or attractive sets in any designated region are derived. Finally, two illustrative examples are given to elaborate the characteristics of the results in detail. PMID- 24807949 TI - Novel neural control for a class of uncertain pure-feedback systems. AB - This paper is concerned with the problem of adaptive neural tracking control for a class of uncertain pure-feedback nonlinear systems. Using the implicit function theorem and backstepping technique, a practical robust adaptive neural control scheme is proposed to guarantee that the tracking error converges to an adjusted neighborhood of the origin by choosing appropriate design parameters. In contrast to conventional Lyapunov-based design techniques, an alternative Lyapunov function is constructed for the development of control law and learning algorithms. Differing from the existing results in the literature, the control scheme does not need to compute the derivatives of virtual control signals at each step in backstepping design procedures. Furthermore, the scheme requires the desired trajectory and its first derivative rather than its first n derivatives. In addition, the useful property of the basis function of the radial basis function, which will be used in control design, is explored. Simulation results illustrate the effectiveness of the proposed techniques. PMID- 24807950 TI - An ordered-patch-based image classification approach on the image Grassmannian manifold. AB - This paper presents an ordered-patch-based image classification framework integrating the image Grassmannian manifold to address handwritten digit recognition, face recognition, and scene recognition problems. Typical image classification methods explore image appearances without considering the spatial causality among distinctive domains in an image. To address the issue, we introduce an ordered-patch-based image representation and use the autoregressive moving average (ARMA) model to characterize the representation. First, each image is encoded as a sequence of ordered patches, integrating both the local appearance information and spatial relationships of the image. Second, the sequence of these ordered patches is described by an ARMA model, which can be further identified as a point on the image Grassmannian manifold. Then, image classification can be conducted on such a manifold under this manifold representation. Furthermore, an appropriate Grassmannian kernel for support vector machine classification is developed based on a distance metric of the image Grassmannian manifold. Finally, the experiments are conducted on several image data sets to demonstrate that the proposed algorithm outperforms other existing image classification methods. PMID- 24807951 TI - Artificial neural networks for control of a grid-connected rectifier/inverter under disturbance, dynamic and power converter switching conditions. AB - Three-phase grid-connected converters are widely used in renewable and electric power system applications. Traditionally, grid-connected converters are controlled with standard decoupled d-q vector control mechanisms. However, recent studies indicate that such mechanisms show limitations in their applicability to dynamic systems. This paper investigates how to mitigate such restrictions using a neural network to control a grid-connected rectifier/inverter. The neural network implements a dynamic programming algorithm and is trained by using back propagation through time. To enhance performance and stability under disturbance, additional strategies are adopted, including the use of integrals of error signals to the network inputs and the introduction of grid disturbance voltage to the outputs of a well-trained network. The performance of the neural-network controller is studied under typical vector control conditions and compared against conventional vector control methods, which demonstrates that the neural vector control strategy proposed in this paper is effective. Even in dynamic and power converter switching environments, the neural vector controller shows strong ability to trace rapidly changing reference commands, tolerate system disturbances, and satisfy control requirements for a faulted power system. PMID- 24807952 TI - A stochastic mean field model for an excitatory and inhibitory synaptic drive cortical neuronal network. AB - With the advances in biochemistry, molecular biology, and neurochemistry there has been impressive progress in understanding the molecular properties of anesthetic agents. However, there has been little focus on how the molecular properties of anesthetic agents lead to the observed macroscopic property that defines the anesthetic state, that is, lack of responsiveness to noxious stimuli. In this paper, we develop a mean field synaptic drive firing rate cortical neuronal model and demonstrate how the induction of general anesthesia can be explained using multistability; the property whereby the solutions of a dynamical system exhibit multiple attracting equilibria under asymptotically slowly changing inputs or system parameters. In particular, we demonstrate multistability in the mean when the system initial conditions or the system coefficients of the neuronal connectivity matrix are random variables. Uncertainty in the system coefficients is captured by representing system uncertain parameters by a multiplicative white noise model wherein stochastic integration is interpreted in the sense of Ito. Modeling a priori system parameter uncertainty using a multiplicative white noise model is motivated by means of the maximum entropy principle of Jaynes and statistical analysis. PMID- 24807953 TI - RandomBoost: simplified multiclass boosting through randomization. AB - We propose a novel boosting approach to multiclass classification problems, in which multiple classes are distinguished by a set of random projection matrices in essence. The approach uses random projections to alleviate the proliferation of binary classifiers typically required to perform multiclass classification. The result is a multiclass classifier with a single vector-valued parameter, irrespective of the number of classes involved. Two variants of this approach are proposed. The first method randomly projects the original data into new spaces, while the second method randomly projects the outputs of learned weak classifiers. These methods are not only conceptually simple but also effective and easy to implement. A series of experiments on synthetic, machine learning, and visual recognition data sets demonstrate that our proposed methods could be compared favorably with existing multiclass boosting algorithms in terms of both the convergence rate and classification accuracy. PMID- 24807954 TI - A unified learning framework for single image super-resolution. AB - It has been widely acknowledged that learning- and reconstruction-based super resolution (SR) methods are effective to generate a high-resolution (HR) image from a single low-resolution (LR) input. However, learning-based methods are prone to introduce unexpected details into resultant HR images. Although reconstruction-based methods do not generate obvious artifacts, they tend to blur fine details and end up with unnatural results. In this paper, we propose a new SR framework that seamlessly integrates learning- and reconstruction-based methods for single image SR to: 1) avoid unexpected artifacts introduced by learning-based SR and 2) restore the missing high-frequency details smoothed by reconstruction-based SR. This integrated framework learns a single dictionary from the LR input instead of from external images to hallucinate details, embeds nonlocal means filter in the reconstruction-based SR to enhance edges and suppress artifacts, and gradually magnifies the LR input to the desired high quality SR result. We demonstrate both visually and quantitatively that the proposed framework produces better results than previous methods from the literature. PMID- 24807955 TI - L1-norm kernel discriminant analysis via Bayes error bound optimization for robust feature extraction. AB - A novel discriminant analysis criterion is derived in this paper under the theoretical framework of Bayes optimality. In contrast to the conventional Fisher's discriminant criterion, the major novelty of the proposed one is the use of L1 norm rather than L2 norm, which makes it less sensitive to the outliers. With the L1-norm discriminant criterion, we propose a new linear discriminant analysis (L1-LDA) method for linear feature extraction problem. To solve the L1 LDA optimization problem, we propose an efficient iterative algorithm, in which a novel surrogate convex function is introduced such that the optimization problem in each iteration is to simply solve a convex programming problem and a close form solution is guaranteed to this problem. Moreover, we also generalize the L1 LDA method to deal with the nonlinear robust feature extraction problems via the use of kernel trick, and hereafter proposed the L1-norm kernel discriminant analysis (L1-KDA) method. Extensive experiments on simulated and real data sets are conducted to evaluate the effectiveness of the proposed method in comparing with the state-of-the-art methods. PMID- 24807956 TI - Online motor fault detection and diagnosis using a hybrid FMM-CART model. AB - In this brief, a hybrid model combining the fuzzy min-max (FMM) neural network and the classification and regression tree (CART) for online motor detection and diagnosis tasks is described. The hybrid model, known as FMM-CART, exploits the advantages of both FMM and CART for undertaking data classification and rule extraction problems. To evaluate the applicability of the proposed FMM-CART model, an evaluation with a benchmark data set pertaining to electrical motor bearing faults is first conducted. The results obtained are equivalent to those reported in the literature. Then, a laboratory experiment for detecting and diagnosing eccentricity faults in an induction motor is performed. In addition to producing accurate results, useful rules in the form of a decision tree are extracted to provide explanation and justification for the predictions from FMM CART. The experimental outcome positively shows the potential of FMM-CART in undertaking online motor fault detection and diagnosis tasks. PMID- 24807957 TI - Feature-based ordering algorithm for data presentation of fuzzy ARTMAP ensembles. AB - This brief presents a new ordering algorithm for data presentation of fuzzy ARTMAP (FAM) ensembles. The proposed ordering algorithm manipulates the presentation order of the training data for each member of a FAM ensemble such that the categories created in each ensemble member are biased toward the vector of the chosen input feature. Diversity is created by varying the training presentation order based on the ascending order of the values from the most uncorrelated input features. Analysis shows that the categories created in two FAMs are compulsively diverse when the chosen input features used to determine the presentation order of the training data are uncorrelated. The proposed ordering algorithm was tested on 10 classification benchmark problems from the University of California, Irvine, machine learning repository and a cervical cancer problem as a case study. The experimental results show that the proposed method can produce a diverse, yet well generalized, FAM ensemble. PMID- 24807958 TI - Self-organization in autonomous, recurrent, firing-rate CrossNets with quasi Hebbian plasticity. AB - We have performed extensive numerical simulations of the autonomous evolution of memristive neuromorphic networks (CrossNets) with the recurrent InBar topology. The synaptic connections were assumed to have the quasi-Hebbian plasticity that may be naturally implemented using a stochastic multiplication technique. When somatic gain g exceeds its critical value g(t), the trivial fixed point of the system becomes unstable, and it enters a self-excitory transient process that eventually leads to a stable static state with equal magnitudes of all the action potentials x(j) and synaptic weights w(jk). However, even in the static state, the spatial distribution of the action potential signs and their correlation with the distribution of initial values x(j)(0) may be rather complicated because of the activation function's nonlinearity. We have quantified such correlation as a function of g, cell connectivity M, and plasticity rate eta, for a random distribution of initial values of x(j) and w(jk), by numerical simulation of network dynamics, using a high-performance graphical processing unit system. Most interestingly, the autocorrelation function of action potentials is a nonmonotonic function of g because of a specific competition between self excitation of the potentials and self-adaptation of synaptic weights. PMID- 24807959 TI - A recurrent neural network for solving bilevel linear programming problem. AB - In this brief, based on the method of penalty functions, a recurrent neural network (NN) modeled by means of a differential inclusion is proposed for solving the bilevel linear programming problem (BLPP). Compared with the existing NNs for BLPP, the model has the least number of state variables and simple structure. Using nonsmooth analysis, the theory of differential inclusions, and Lyapunov like method, the equilibrium point sequence of the proposed NNs can approximately converge to an optimal solution of BLPP under certain conditions. Finally, the numerical simulations of a supply chain distribution model have shown excellent performance of the proposed recurrent NNs. PMID- 24807960 TI - Local stability analysis of discrete-time, continuous-state, complex-valued recurrent neural networks with inner state feedback. AB - Recurrent neural networks (RNNs) are well known for their capability to minimize suitable cost functions without the need for a training phase. This is possible because they can be Lyapunov stable. Although the global stability analysis has attracted a lot of interest, local stability is desirable for specific applications. In this brief, we investigate the local asymptotical stability of two classes of discrete-time, continuous-state, complex-valued RNNs with parallel update and inner state feedback. We show that many already known results are special cases of the results obtained here. We also generalize some known results from the real-valued case to the complex-valued one. Finally, we investigate the stability in the presence of time-variant activation functions. Complex-valued activation functions in this brief are separable with respect to the real and imaginary parts. PMID- 24807961 TI - Sparse Bayesian extreme learning machine for multi-classification. AB - Extreme learning machine (ELM) has become a popular topic in machine learning in recent years. ELM is a new kind of single-hidden layer feedforward neural network with an extremely low computational cost. ELM, however, has two evident drawbacks: 1) the output weights solved by Moore-Penrose generalized inverse is a least squares minimization issue, which easily suffers from overfitting and 2) the accuracy of ELM is drastically sensitive to the number of hidden neurons so that a large model is usually generated. This brief presents a sparse Bayesian approach for learning the output weights of ELM in classification. The new model, called Sparse Bayesian ELM (SBELM), can resolve these two drawbacks by estimating the marginal likelihood of network outputs and automatically pruning most of the redundant hidden neurons during learning phase, which results in an accurate and compact model. The proposed SBELM is evaluated on wide types of benchmark classification problems, which verifies that the accuracy of SBELM model is relatively insensitive to the number of hidden neurons; and hence a much more compact model is always produced as compared with other state-of-the-art neural network classifiers. PMID- 24807963 TI - BET bromodomain inhibitors block growth of pancreatic cancer cells in three dimensional collagen. AB - Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis that contributes to chemoresistance, in part, through increased histone acetylation. Because bromodomain (BRD) and extra terminal domain (BET) proteins are "readers" of histone acetylation marks, we targeted BET proteins in PDAC cells grown in three-dimensional collagen. We show that treatment with BET inhibitors decreases growth of PDAC cells (AsPC1, CD18, and Panc1) in collagen. Transfection with siRNA against BRD4, which is increased in human PDAC tumors, also decreases growth of PDAC cells. BET inhibitors additionally decrease growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or have become resistant to chemotherapy. Although BET inhibitors and BRD4 siRNA repress c-MYC only in AsPC1 and CD18 cells, downregulating c-MYC decreases growth of all three PDAC cell lines in collagen. FOSL1, which is also targeted by BET inhibitors and BRD4 siRNA in AsPC1, CD18, and Panc1 cells, additionally regulates growth of all three PDAC cell lines in collagen. BET inhibitors and BRD4 siRNA repress HMGA2, an architectural protein that modulates chromatin state and also contributes to chemoresistance, in PDAC cells grown in collagen. Importantly, we show that there is a statistically significant correlation between BRD4 and HMGA2 in human PDAC tumors. Significantly, overexpression of HMGA2 partially mitigates the effect of BET inhibitors on growth and c-MYC and/or FOSL1 expression in collagen. Overall, these results demonstrate that BET inhibitors block growth of PDAC cells in collagen and that BET proteins may be potential targets for the treatment of pancreatic cancer. PMID- 24807965 TI - Characterization of the novel positive allosteric modulator, LY2119620, at the muscarinic M(2) and M(4) receptors. AB - The M(4) receptor is a compelling therapeutic target, as this receptor modulates neural circuits dysregulated in schizophrenia, and there is clinical evidence that muscarinic agonists possess both antipsychotic and procognitive efficacy. Recent efforts have shifted toward allosteric ligands to maximize receptor selectivity and manipulate endogenous cholinergic and dopaminergic signaling. In this study, we present the pharmacological characterization of LY2119620 (3-amino 5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy] thieno[2,3-b]pyridine-2-carboxamide), a M(2)/M(4) receptor-selective positive allosteric modulator (PAM), chemically evolved from hits identified through a M4 allosteric functional screen. Although unsuitable as a therapeutic due to M(2) receptor cross-reactivity and, thus, potential cardiovascular liability, LY2119620 surpassed previous congeners in potency and PAM activity and broadens research capabilities through its development into a radiotracer. Characterization of LY2119620 revealed evidence of probe dependence in both binding and functional assays. Guanosine 5'-[gamma-(35)S]-triphosphate assays displayed differential potentiation depending on the orthosteric-allosteric pairing, with the largest cooperativity observed for oxotremorine M (Oxo-M) LY2119620. Further [(3)H]Oxo-M saturation binding, including studies with guanosine-5'-[(beta,gamma)-imido]triphosphate, suggests that both the orthosteric and allosteric ligands can alter the population of receptors in the active G protein-coupled state. Additionally, this work expands the characterization of the orthosteric agonist, iperoxo, at the M(4) receptor, and demonstrates that an allosteric ligand can positively modulate the binding and functional efficacy of this high efficacy ligand. Ultimately, it was the M(2) receptor pharmacology and PAM activity with iperoxo that made LY2119620 the most suitable allosteric partner for the M(2) active-state structure recently solved (Kruse et al., 2013), a structure that provides crucial insights into the mechanisms of orthosteric activation and allosteric modulation of muscarinic receptors. PMID- 24807964 TI - Activation of liver X receptors inhibits hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma. AB - The Hedgehog (Hh) signaling pathway is aberrantly activated in a wide variety of human cancers, and recent clinical studies have demonstrated that pathway inhibitors are effective in advanced basal cell carcinoma (BCC). The majority of these agents have been designed to target SMOOTHENED (SMO), a transmembrane regulator of Hh signaling, but subsequent mutations in SMO have been found to generate drug resistance. In other cancers, oncogenic events that bypass SMO may activate canonical Hh signaling, and SMO antagonists have not demonstrated significant activity in several diseases. Therefore, alternative strategies targeting the Hh pathway downstream of SMO may have clinical utility. Liver X receptors (LXR) regulate cholesterol and fatty acid homeostasis, and LXR activation can inhibit the Hh pathway in normal mouse embryonic fibroblasts. We examined the effects of LXR activation on Hh signaling in human multiple myeloma cells and found that LXR agonists inhibited Hh pathway activity and clonogenic tumor growth in vitro. LXR activation also inhibited putative multiple myeloma cancer stem cells in vivo leading to the loss of tumor initiating and self renewal potential. Finally, Hh signaling was inhibited downstream of SMO, suggesting that LXR agonists may represent a novel strategy to target pathogenic Hh signaling as well as treat multiple myeloma. PMID- 24807966 TI - Development of a radioligand, [(3)H]LY2119620, to probe the human M(2) and M(4) muscarinic receptor allosteric binding sites. AB - In this study, we characterized a muscarinic acetylcholine receptor (mAChR) potentiator, LY2119620 (3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4 methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide) as a novel probe of the human M2 and M4 allosteric binding sites. Since the discovery of allosteric binding sites on G protein-coupled receptors, compounds targeting these novel sites have been starting to emerge. For example, LY2033298 (3-amino-5 chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamid) and a derivative of this chemical scaffold, VU152100 (3-amino-N (4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide), bind to the human M4 mAChR allosteric pocket. In the current study, we characterized LY2119620, a compound similar in structure to LY2033298 and binds to the same allosteric site on the human M4 mAChRs. However, LY2119620 also binds to an allosteric site on the human M2 subtype. [(3)H]NMS ([(3)H]N-methylscopolamine) binding experiments confirm that LY2119620 does not compete for the orthosteric binding pocket at any of the five muscarinic receptor subtypes. Dissociation kinetic studies using [(3)H]NMS further support that LY2119620 binds allosterically to the M2 and M4 mAChRs and was positively cooperative with muscarinic orthosteric agonists. To probe directly the allosteric sites on M2 and M4, we radiolabeled LY2119620. Cooperativity binding of [(3)H]LY2119620 with mAChR orthosteric agonists detects significant changes in Bmax values with little change in Kd, suggesting a G protein-dependent process. Furthermore, [(3)H]LY2119620 was displaced by compounds of similar chemical structure but not by previously described mAChR allosteric compounds such as gallamine or WIN 62,577 (17-beta-hydroxy-17-alpha-ethynyl-delta-4-androstano[3,2-b]pyrimido[1,2 a]benzimidazole). Our results therefore demonstrate the development of a radioligand, [(3)H]LY2119620 to probe specifically the human M2 and M4 muscarinic receptor allosteric binding sites. PMID- 24807967 TI - Building and using a database of one trillion natural-image patches. AB - Many example-based image processing algorithms operate on image patches (texture synthesis, resolution enhancement, image denoising, and so on). However, inaccessibility to a large, varied collection of image patches has hindered widespread adoption of these methods. The authors describe the construction of a database of one trillion image patches and demonstrate its research utility. PMID- 24807968 TI - A viewer-centric editor for 3D movies. AB - A proposed mathematical framework is the basis for a viewer-centric digital editor for 3D movies that's driven by the audience's perception of the scene. The editing tool allows both shot planning and after-the-fact digital manipulation of the perceived scene shape. PMID- 24807969 TI - Depth director: a system for adding depth to movies. AB - Depth Director is an interactive system for converting 2D footage to 3D. It integrates recent computer vision advances with specialized tools that let users accurately recreate or stylistically manipulate 3D depths. PMID- 24807970 TI - A digital gigapixel large-format tile-scan camera. AB - Although the resolution of single-lens reflex (SLR) and medium-format digital cameras has increased in recent years, applications for cultural-heritage preservation and computational photography require even higher resolutions. Addressing this issue, a large-format cameras' large image planes can achieve very high resolution without compromising pixel size and thus can provide high quality, high-resolution images.This digital large-format tile scan camera can acquire high-quality, high-resolution images of static scenes. It employs unique calibration techniques and a simple algorithm for focal-stack processing of very large images with significant magnification variations. The camera automatically collects overlapping focal stacks and processes them into a high-resolution, extended-depth-of-field image. PMID- 24807971 TI - Using focused plenoptic cameras for rich image capture. AB - This approach uses a focused plenoptic camera to capture the plenoptic function's rich "non 3D" structure. It employs two techniques. The first simultaneously captures multiple exposures (or other aspects) based on a microlens array having an interleaved set of different filters. The second places multiple filters at the main lens aperture. PMID- 24807972 TI - Social snapshot: a system for temporally coupled social photography. AB - Social Snapshot actively acquires and reconstructs temporally dynamic data. The system enables spatiotemporal 3D photography using commodity devices, assisted by their auxiliary sensors and network functionality. It engages users, making them active rather than passive participants in data acquisition. PMID- 24807973 TI - Live theater on a virtual stage: incorporating soft skills and teamwork in computer graphics education. AB - Industry has increasingly emphasized the need for "soft" or interpersonal skills development and team-building experience in the college curriculum. Here, we discuss our experiences with providing such opportunities via a collaborative project called the Virtual Theater. In this joint project between the Rochester Institute of Technology's School of Design and Department of Computer Science, the goal is to enable live performance in a virtual space with participants in different physical locales. Students work in teams, collaborating with other students in and out of their disciplines. PMID- 24807974 TI - Visualization at supercomputing centers: the tale of little big iron and the three skinny guys. AB - Supercomputing centers are unique resources that aim to enable scientific knowledge discovery by employing large computational resources-the "Big Iron." Design, acquisition, installation, and management of the Big Iron are carefully planned and monitored. Because these Big Iron systems produce a tsunami of data, it's natural to colocate the visualization and analysis infrastructure. This infrastructure consists of hardware (Little Iron) and staff (Skinny Guys). Our collective experience suggests that design, acquisition, installation, and management of the Little Iron and Skinny Guys doesn't receive the same level of treatment as that of the Big Iron. This article explores the following questions about the Little Iron: How should we size the Little Iron to adequately support visualization and analysis of data coming off the Big Iron? What sort of capabilities must it have? Related questions concern the size of visualization support staff: How big should a visualization program be-that is, how many Skinny Guys should it have? What should the staff do? How much of the visualization should be provided as a support service, and how much should applications scientists be expected to do on their own? PMID- 24807975 TI - Augmented reality for aircraft maintenance training and operations support. PMID- 24807976 TI - The impact of ethanol lock therapy on length of stay and catheter salvage in pediatric catheter-associated bloodstream infection. AB - BACKGROUND: Ethanol lock therapy (ELT) with systemic antimicrobial therapy (SAT) is a treatment for catheter-associated bloodstream infections (CABSI). However, its impact on hospital length of stay (LOS) is unknown. OBJECTIVES: Assess the impact of ELT on LOS, LOS attributable to CABSI (ALOS), and catheter salvage in pediatric hematology, oncology, stem cell transplant (HOSCT) CABSI. METHODS: Retrospective review of HOSCT CABSI from January 2009 to July 2011. RESULTS: A total of 124 CABSI episodes were reviewed in 66 patients. Mean LOS with ELT after 1 positive blood culture (BC) was 7.1 versus 12.3 days after >=2 positive BC (P = .014). Mean ALOS was 1.6 days with ELT versus 2.9 days without ELT (P = .018). Mean ALOS with ELT after 1 positive BC was 3.75 days versus 5.8 days after >=2 positive BC (P = .022). Catheter salvage rate: 41 of 48 (85%) with ELT versus 49 of 68 (72%) without ELT (P = .169). CONCLUSION: Earlier initiation of ELT may decrease ALOS. PMID- 24807977 TI - Congenital human parvovirus b19 infection with persistent viremia. PMID- 24807978 TI - Five-month-old girl with fever of unknown origin and rash. PMID- 24807979 TI - A young girl with familial Mediterranean fever and abdominal pain. PMID- 24807981 TI - Complications of vaccination with bacille Calmette-Guerin. PMID- 24807980 TI - Prevalence of sexually transmitted infections in at-risk adolescent females at a comprehensive, stand-alone adolescent health center in New York City. AB - BACKGROUND: Sexually transmitted infections (STIs) are common among adolescents, and multiple STIs over one's lifetime can increase health risks. Few studies have assessed lifetime STI prevalence. This study evaluates minority, underserved adolescents' self-reported lifetime STI history and objective STI rates. METHODS: Lifetime STI rates of female patients at an urban adolescent health center were obtained from self-administered questionnaires. Additionally, STI test results were retrieved from electronic medical records. RESULTS: Patients reported a high lifetime prevalence of STIs. By comparing self-report and objective data, underreporting was identified for chlamydia, gonorrhea, and herpes. CONCLUSIONS: STI rates in at-risk adolescent females are higher than in the general population and remain elevated over time. Lifetime STI reports could expand our understanding of sexual health and should be further studied. Underreporting, which may increase health risks and hinder health care delivery, requires further investigation. Improvements in STI screening and prevention targeting at-risk populations are warranted. PMID- 24807982 TI - Progressive rash, oral lesions, and history of antibiotic use in a 17-year-old boy: Stevens-Johnson syndrome: a case report. PMID- 24807983 TI - Sickle cell trait and renal papillary necrosis. PMID- 24807985 TI - Using GPU shaders for visualization, part 3. AB - GPU shaders aren't just for glossy special effects. Parts 1 and 2 of this discussion looked at using them for point clouds, cutting planes, line integral convolution, and terrain bump-mapping. Part 3 covers compute shaders and shader storage buffer objects-two features announced as part of OpenGL 4.3. PMID- 24807984 TI - Sensory Nerve Dysfunction and Hallux Valgus Correction: A Prospective Study. AB - BACKGROUND: Sensory nerve dysfunction in patients with hallux valgus has been described as both a symptom of the deformity and a complication of the treatment. The purpose of this study was to quantify nerve dysfunction in hallux valgus patients and to prospectively evaluate whether the trauma of surgery or the correction of the deformity had any effect on the sensory nerve function. METHODS: Fifty-seven consecutive feet undergoing operative correction for hallux valgus were prospectively enrolled. Preoperative and 3-, 6-, and 24-month postoperative clinical, radiographic, and detailed sensory examinations were completed. For the sensory examination, a Semmes-Weinstein 5.07 monofilament was used to establish, if present, a geometric area of sensory deficit about the hallux. This area was traced onto calibrated graphing paper and processed with imaging software. A total of 48/57 (84%) went on to complete 24 months of follow up. RESULTS: Preoperative sensory area deficit improved by a mean of 529 mm2 at 24-month follow-up. The mean preoperative sensory deficit area was 688 mm2 (SD 681 mm2, range: 0 to 2885 mm2) and 24-month postoperative sensory deficit area was 159 mm2 (SD 329 mm2, range: 0 to 1463 mm2). No clinically significant correlation existed between deficit and clinical outcome measures. CONCLUSIONS: This study showed that preoperative sensory deficits exist, and can improve up to 24 months after operative correction of the hallux valgus deformity. This supports the concept that sensory deficit in hallux valgus is at least partially caused by a reversible injury to the sensory nerves, not necessarily a complication of surgery. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24807986 TI - Building virtual worlds carrying on the legacy of Randy Pausch's "head fake". AB - The Carnegie Mellon Building Virtual Worlds course fosters interdisciplinary collaboration and invention. It helps provide students with a solid foundation by challenging them to create innovative, future-oriented experiences through a series of critiqued rapid prototypes. This process, combined with carefully designed peer evaluation, has led to a system that hundreds of alumni credit with setting them on the road to inventing the future of entertainment technology. PMID- 24807987 TI - Viewing Chinese art on an interactive tabletop. AB - To protect fragile paintings and calligraphy, Taiwan's National Palace Museum (NPM) has policies controlling the frequency and duration of their exposure. So, visitors might not see the works they planned to see. To address this problem, the NPM installed an interactive tabletop for viewing the works. This tabletop, the first to feature multiresolution and gigapixel photography technology, displays extremely high-quality images revealing brushwork-level detail. A user study at the NPM examined the tabletop's performance and collected visitor feedback. PMID- 24807988 TI - Mobile expressive renderings: the state of the art. AB - Mobile applications are incorporating underlying platforms' pervasiveness in many innovative ways. Performance barriers due to resource constraints are slowly vanishing, and people are increasingly using mobile devices to perform many daily tasks they previously performed on desktop computers. Although a mobile platform's ability to handle graphics-related tasks requires further investigation, researchers have already made substantial progress. One particular related research area is nonphotorealistic rendering (NPR). NPR involves inherent abstraction, and mobile platforms offer relatively less computing power. So, a convergence of these areas can help deal with producing complex renderings on resource-constrained mobile platforms. This tutorial describes the state of NPR techniques for mobile devices, especially PDAs, tablets, and mobile phones, to motivate the development of efficient mobile NPR apps. In particular, the article addresses NPR advantages, challenges, and solutions. It also discusses mobile NPR visualizations, usability concerns, and future research directions. PMID- 24807989 TI - Estimating diffusion parameters from polarized spherical-gradient illumination. AB - The proposed method acquires subsurface-scattering parameters of heterogeneous translucent materials. It directly obtains dense per-surface-point scattering parameters from observations under cross-polarized spherical-gradient illumination of curved surfaces. This method does not require explicit fitting of observed scattering profiles. A variety of heterogeneous translucent objects illustrate its validity. PMID- 24807990 TI - Adding a solar-radiance function to the Hosek-Wilkie skylight model. AB - One prerequisite for realistic renderings of outdoor scenes is the proper capturing of the sky's appearance. Currently, an explicit simulation of light scattering in the atmosphere isn't computationally feasible, and won't be in the foreseeable future. Captured luminance patterns have proven their usefulness in practice but can't meet all user needs. To fill this capability gap, computer graphics technology has employed analytical models of sky-dome luminance patterns for more than two decades. For technical reasons, such models deal with only the sky dome's appearance, though, and exclude the solar disc. The widely used model proposed by Arcot Preetham and colleagues employed a separately derived analytical formula for adding a solar emitter of suitable radiant intensity. Although this yields reasonable results, the formula is derived in a manner that doesn't exactly match the conditions in their sky-dome model. But the more sophisticated a skylight model is and the more subtly it can represent different conditions, the more the solar radiance should exactly match the skylight's conditions. Toward that end, researchers propose a solar-radiance function that exactly matches a recently published high-quality analytical skylight model. PMID- 24807991 TI - Real-time screen-space scattering in homogeneous environments. AB - The proposed screen-space algorithm approximates light scattering in homogeneous participating environments, such as water. Instead of simulating full global illumination, this method models scattering by a physically based point spread function. A discrete hierarchical convolution in a texture MIP map makes the algorithm efficient, and a custom anisotropic incremental filter prevents illumination leaking. PMID- 24807992 TI - Double- and multiple-scattering effects in translucent materials. AB - Some materials, such as coffee, milk, or marble, have a soft translucent aspect because of subsurface scattering. Light enters them and gets scattered several times before leaving in a different place. A full representation of subsurface scattering effects in illumination simulation is computationally expensive. The main difficulty comes from multiple scattering events. The high number of events increases the results' uncertainty, requiring more computation time. However, a strong correlation exists between the surface effects of multiple scattering and the effects after just two scattering events. This knowledge can help accelerate multiple-scattering effects. In particular, researchers have exploited this knowledge to provide a model and implementation for fast computation of double scattering events using a precomputed density function stored compactly. PMID- 24807993 TI - Walled gardens: apps and data as barriers to augmenting reality. AB - For augmented reality (AR) to reach its potential, AR content from multiple distinct sources must be simultaneously displayed in a more unified manner than is possible given today's application-centric environments. AR browsers and AR enabled Web browsers point toward the functionalities that OSs must incorporate to fully support AR content. Also, application developers need richer forms of content describing the physical world and the objects in it. Standards such as ARML (Augmented Reality Markup Language) 2.0 have begun providing the glue needed to bind AR content to the physical world. PMID- 24807996 TI - Pretibial Myxedema: Case Presentation and Review of Treatment Options. AB - Pretibial myxedema (PM) is a rare autoimmune manifestation of Graves' disease, which commonly presents as diffuse, nonpitting edema of shins and less often as plaques, nodules, or elephantiasis lesions mimicking lymphedema. We present a 57 year-old woman with 12-month history of PM, which occurred a year after treatment of Graves' disease and improved with topical corticosteroids, support stockings, and intralesional steroid injections until recurrence with local erythema and woody edema. A literature review was undertaken of the evidence-based treatment modalities for symptomatic PM: although commonly asymptomatic and self-limited, severe cases of PM may be treated with topical corticosteroid, compressive therapy, and intralesional corticosteroid injections. PMID- 24807994 TI - Creating widely accessible spatial interfaces: mobile VR for managing persistent pain. AB - Using widely accessible VR technologies, researchers have implemented a series of multimodal spatial interfaces and virtual environments. The results demonstrate the degree to which we can now use low-cost (for example, mobile-phone based) VR environments to create rich virtual experiences involving motion sensing, physiological inputs, stereoscopic imagery, sound, and haptic feedback. Adapting spatial interfaces to these new platforms can open up exciting application areas for VR. In this case, the application area was in-home VR therapy for patients suffering from persistent pain (for example, arthritis and cancer pain). For such therapy to be successful, a rich spatial interface and rich visual aesthetic are particularly important. So, an interdisciplinary team with expertise in technology, design, meditation, and the psychology of pain collaborated to iteratively develop and evaluate several prototype systems. The video at http://youtu.be/mMPE7itReds demonstrates how the sine wave fitting responds to walking motions, for a walking-in-place application. PMID- 24807997 TI - Management of a Patient With Faciocervical Burns and Inhalational Injury Due to Hydrofluoric Acid Exposure. AB - Hydrofluoric acid, a highly dangerous substance, can cause tissue damage and systemic toxicity by its unique mechanisms. Many cases of severe faciocervical burns due to hydrofluoric acid exposure are lethal. Herein, we present a case of 37-year-old man who suffered from hydrofluoric acid burns to his face, anterior neck, lips, and nasal cavity. On admission, this patient coughed with much sputum, and the chest auscultation detected rough breath sounds, wheezes, and very weak heart sounds, indicating possible inhalation injury. This case highlights the extreme complexity of managing this kind of injury. Timely and accurate wound treatment and respiratory tract care, as well as active systematic support treatment, played vital roles in the management of this patient. PMID- 24807998 TI - Silicon-based dynamic synapse with depressing response. AB - A compact implementation of a dynamic charge transfer synapse cell, capable of implementing synaptic depression, is presented. The cell is combined with a simple current mirror summing node to produce biologically plausible postsynaptic potentials (PSPs). A single charge packet is effectively transferred from the synapse to the summing node, whenever a presynaptic pulse is applied to one of its terminals. The charge packet is "weighted" by a voltage applied to the second terminal of the synapse. A voltage applied to the third terminal determines the charge recovery time in the synapse, which can be adjusted over several orders of magnitude. This voltage determines the paired pulse ratio for the synapse. The fall time of the PSP is also adjustable and is set by the gate voltage of a metal oxide-semiconductor field-effect transistor operating in subthreshold. Results extracted from chips fabricated in a 0.35-MUm complementary metal-oxide semiconductor process, alongside theoretical and simulation results, confirm the ability of the cell to produce PSPs that are characteristic of real synapses. The concept addresses a key requirement for scalable hardware neural networks. PMID- 24807999 TI - Self-organizing spiking neural model for learning fault-tolerant spatio-motor transformations. AB - In this paper, we present a spiking neural model that learns spatio-motor transformations. The model is in the form of a multilayered architecture consisting of integrate and fire neurons and synapses that employ spike-timing dependent plasticity learning rule to enable the learning of such transformations. We developed a simple 2-degree-of-freedom robot-based reaching task which involves the learning of a nonlinear function. Computer simulations demonstrate the capability of such a model for learning the forward and inverse kinematics for such a task and hence to learn spatio-motor transformations. The interesting aspect of the model is its capacity to be tolerant to partial absence of sensory or motor inputs at various stages of learning. We believe that such a model lays the foundation for learning other complex functions and transformations in real-world scenarios. PMID- 24808000 TI - Learning from ISS-modular adaptive NN control of nonlinear strict-feedback systems. AB - This paper studies learning from adaptive neural control (ANC) for a class of nonlinear strict-feedback systems with unknown affine terms. To achieve the purpose of learning, a simple input-to-state stability (ISS) modular ANC method is first presented to ensure the boundedness of all the signals in the closed loop system and the convergence of tracking errors in finite time. Subsequently, it is proven that learning with the proposed stable ISS-modular ANC can be achieved. The cascade structure and unknown affine terms of the considered systems make it very difficult to achieve learning using existing methods. To overcome these difficulties, the stable closed-loop system in the control process is decomposed into a series of linear time-varying (LTV) perturbed subsystems with the appropriate state transformation. Using a recursive design, the partial persistent excitation condition for the radial basis function neural network (NN) is established, which guarantees exponential stability of LTV perturbed subsystems. Consequently, accurate approximation of the closed-loop system dynamics is achieved in a local region along recurrent orbits of closed-loop signals, and learning is implemented during a closed-loop feedback control process. The learned knowledge is reused to achieve stability and an improved performance, thereby avoiding the tremendous repeated training process of NNs. Simulation studies are given to demonstrate the effectiveness of the proposed method. PMID- 24808001 TI - Synchronization error estimation and controller design for delayed Lur'e systems with parameter mismatches. AB - This paper investigates the problem of master-slave synchronization of two delayed Lur'e systems in the presence of parameter mismatches. First, by analyzing the corresponding synchronization error system, synchronization with an error level, which is referred to as quasi-synchronization, is established. Some delay-dependent quasi-synchronization criteria are derived. An estimation of the synchronization error bound is given, and an explicit expression of error levels is obtained. Second, sufficient conditions on the existence of feedback controllers under a predetermined error level are provided. The controller gains are obtained by solving a set of linear matrix inequalities. Finally, a delayed Chua's circuit is chosen to illustrate the effectiveness of the derived results. PMID- 24808002 TI - Reproducing kernel Hilbert spaces with odd kernels in price prediction. AB - For time series of futures contract prices, the expected price change is modeled conditional on past price changes. The proposed model takes the form of regression in a reproducing kernel Hilbert space with the constraint that the regression function must be odd. It is shown how the resulting constrained optimization problem can be reduced to an unconstrained one through appropriate modification of the kernel. In particular, it is shown how odd, even, and other similar kernels emerge naturally as the reproducing kernels of Hilbert subspaces induced by respective symmetry constraints. To test the validity and practical usefulness of the oddness assumption, experiments are run with large real-world datasets on four futures contracts, and it is demonstrated that using odd kernels results in a higher predictive accuracy and a reduced tendency to overfit. PMID- 24808003 TI - Neural modeling of episodic memory: encoding, retrieval, and forgetting. AB - This paper presents a neural model that learns episodic traces in response to a continuous stream of sensory input and feedback received from the environment. The proposed model, based on fusion adaptive resonance theory (ART) network, extracts key events and encodes spatio-temporal relations between events by creating cognitive nodes dynamically. The model further incorporates a novel memory search procedure, which performs a continuous parallel search of stored episodic traces. Combined with a mechanism of gradual forgetting, the model is able to achieve a high level of memory performance and robustness, while controlling memory consumption over time. We present experimental studies, where the proposed episodic memory model is evaluated based on the memory consumption for encoding events and episodes as well as recall accuracy using partial and erroneous cues. Our experimental results show that: 1) the model produces highly robust performance in encoding and recalling events and episodes even with incomplete and noisy cues; 2) the model provides enhanced performance in a noisy environment due to the process of forgetting; and 3) compared with prior models of spatio-temporal memory, our model shows a higher tolerance toward noise and errors in the retrieval cues. PMID- 24808004 TI - A discrimination analysis for unsupervised feature selection via optic diffraction principle. AB - This paper proposes an unsupervised discrimination analysis for feature selection based on a property of the Fourier transform of the probability density distribution. Each feature is evaluated on the basis of a simple observation motivated by the concept of optical diffraction, which is invariant under feature scaling. The time complexity is O(mn), where m is number of features and n is number of instances when being applied directly to the given data. This approach is also extended to deal with data orientation, which is the direction of data alignment. Therefore, the discrimination score of any transformed space can be used for evaluating the original features. The experimental results on several real-world datasets demonstrate the effectiveness of the proposed method. PMID- 24808005 TI - Nonnegative blind source separation by sparse component analysis based on determinant measure. AB - The problem of nonnegative blind source separation (NBSS) is addressed in this paper, where both the sources and the mixing matrix are nonnegative. Because many real-world signals are sparse, we deal with NBSS by sparse component analysis. First, a determinant-based sparseness measure, named D-measure, is introduced to gauge the temporal and spatial sparseness of signals. Based on this measure, a new NBSS model is derived, and an iterative sparseness maximization (ISM) approach is proposed to solve this model. In the ISM approach, the NBSS problem can be cast into row-to-row optimizations with respect to the unmixing matrix, and then the quadratic programming (QP) technique is used to optimize each row. Furthermore, we analyze the source identifiability and the computational complexity of the proposed ISM-QP method. The new method requires relatively weak conditions on the sources and the mixing matrix, has high computational efficiency, and is easy to implement. Simulation results demonstrate the effectiveness of our method. PMID- 24808006 TI - Multiclass feature selection with kernel Gram-matrix-based criteria. AB - Feature selection has been an important issue in recent decades to determine the most relevant features according to a given classification problem. Numerous methods have emerged that take into account support vector machines (SVMs) in the selection process. Such approaches are powerful but often complex and costly. In this paper, we propose new feature selection methods based on two criteria designed for the optimization of SVM: kernel target alignment and kernel class separability. We demonstrate how these two measures, when fully expressed, can build efficient and simple methods, easily applicable to multiclass problems and iteratively computable with minimal memory requirements. An extensive experimental study is conducted both on artificial and real-world datasets to compare the proposed methods to state-of-the-art feature selection algorithms. The results demonstrate the relevance of the proposed methods both in terms of performance and computational cost. PMID- 24808007 TI - Efficient online subspace learning with an indefinite kernel for visual tracking and recognition. AB - We propose an exact framework for online learning with a family of indefinite (not positive) kernels. As we study the case of nonpositive kernels, we first show how to extend kernel principal component analysis (KPCA) from a reproducing kernel Hilbert space to Krein space. We then formulate an incremental KPCA in Krein space that does not require the calculation of preimages and therefore is both efficient and exact. Our approach has been motivated by the application of visual tracking for which we wish to employ a robust gradient-based kernel. We use the proposed nonlinear appearance model learned online via KPCA in Krein space for visual tracking in many popular and difficult tracking scenarios. We also show applications of our kernel framework for the problem of face recognition. PMID- 24808008 TI - Feedback control by online learning an inverse model. AB - A model, predictor, or error estimator is often used by a feedback controller to control a plant. Creating such a model is difficult when the plant exhibits nonlinear behavior. In this paper, a novel online learning control framework is proposed that does not require explicit knowledge about the plant. This framework uses two learning modules, one for creating an inverse model, and the other for actually controlling the plant. Except for their inputs, they are identical. The inverse model learns by the exploration performed by the not yet fully trained controller, while the actual controller is based on the currently learned model. The proposed framework allows fast online learning of an accurate controller. The controller can be applied on a broad range of tasks with different dynamic characteristics. We validate this claim by applying our control framework on several control tasks: 1) the heating tank problem (slow nonlinear dynamics); 2) flight pitch control (slow linear dynamics); and 3) the balancing problem of a double inverted pendulum (fast linear and nonlinear dynamics). The results of these experiments show that fast learning and accurate control can be achieved. Furthermore, a comparison is made with some classical control approaches, and observations concerning convergence and stability are made. PMID- 24808009 TI - Symbolic representation of recurrent neural network dynamics. AB - Simple recurrent error backpropagation networks have been widely used to learn temporal sequence data, including regular and context-free languages. However, the production of relatively large and opaque weight matrices during learning has inspired substantial research on how to extract symbolic human-readable interpretations from trained networks. Unlike feedforward networks, where research has focused mainly on rule extraction, most past work with recurrent networks has viewed them as dynamical systems that can be approximated symbolically by finite-state machine (FSMs). With this approach, the network's hidden layer activation space is typically divided into a finite number of regions. Past research has mainly focused on better techniques for dividing up this activation space. In contrast, very little work has tried to influence the network training process to produce a better representation in hidden layer activation space, and that which has been done has had only limited success. Here we propose a powerful general technique to bias the error backpropagation training process so that it learns an activation space representation from which it is easier to extract FSMs. Using four publicly available data sets that are based on regular and context-free languages, we show via computational experiments that the modified learning method helps to extract FSMs with substantially fewer states and less variance than unmodified backpropagation learning, without decreasing the neural networks' accuracy. We conclude that modifying error backpropagation so that it more effectively separates learned pattern encodings in the hidden layer is an effective way to improve contemporary FSM extraction methods. PMID- 24808010 TI - Inphase and antiphase synchronization in a delay-coupled system with applications to a delay-coupled FitzHugh-Nagumo system. AB - A time delay is inevitable in the coupled system and is an essential property of the coupling, which cannot be neglected in many realistic coupled systems. In this paper, we first study the existence of a Hopf bifurcation induced by coupling time delay and then investigate the influence of coupling time delay on the patterns of Hopf-bifurcating periodic oscillations. How the coupling time delay leads to complex scenarios of synchronized inphase or antiphase oscillations is analytically investigated. As an example, we study the delay coupled FitzHugh-Nagumo system. We find conditional stability, absolute stability, and stability switches of the steady state provoked by the coupling time delay. Then we investigate the inphase and antiphase synchronized periodic solutions induced by delay, and determine the direction and stability of these bifurcating periodic orbits by employing the center manifold reduction and normal form theory. We find that in the region where stability switches occur, there exist synchronization transitions, i.e., synchronized dynamics can be switched from inphase (antiphase) to antiphase (inphase) and back to inphase (antiphase) and so on just by progressive increase of the coupling time delay. PMID- 24808011 TI - Simple and fast calculation of the second-order gradients for globalized dual heuristic dynamic programming in neural networks. AB - We derive an algorithm to exactly calculate the mixed second-order derivatives of a neural network's output with respect to its input vector and weight vector. This is necessary for the adaptive dynamic programming (ADP) algorithms globalized dual heuristic programming (GDHP) and value-gradient learning. The algorithm calculates the inner product of this second-order matrix with a given fixed vector in a time that is linear in the number of weights in the neural network. We use a "forward accumulation" of the derivative calculations which produces a much more elegant and easy-to-implement solution than has previously been published for this task. In doing so, the algorithm makes GDHP simple to implement and efficient, bridging the gap between the widely used DHP and GDHP ADP methods. PMID- 24808012 TI - Diversity of limb-bone safety factors for locomotion in terrestrial vertebrates: evolution and mixed chains. AB - During locomotion over land, vertebrates' limb bones are exposed to loads. Like most biological structures, limb bones have a capacity to withstand greater loads than they usually experience, termed a safety factor (SF). How diverse are limb bone SFs, and what factors correlate with such variation? We have examined these questions from two perspectives. First, we evaluated locomotor SF for the femur in diverse lineages, including salamanders, frogs, turtles, lizards, crocodilians, and marsupials (opossums). Comparisons with values for hind-limb elements in running birds and eutherian mammals indicate phylogenetic diversity in limb-bone SF. A high SF (~7) is primitive for tetrapods, but low magnitudes of load and elevated strength of bones contribute to different degrees across lineages; moreover, birds and eutherians appear to have evolved lower SFs independently. Second, we tested the hypothesis that SFs would be similar across limb bones within a taxon by comparing data from the humerus and femur of alligators. Both in bending and in torsion, we found a higher SF for the humerus than for the femur. Such a "mixed chain" of different SFs across elements has been predicted if bones have differing variabilities in load, different costs to maintain, or high SF values in general. Although variability in load is similar for the humerus and femur, a high SF may be less costly for the humerus because it is smaller than the femur. The high SFs of alligators also might facilitate differences in SF among their limb bones. Beyond these specific findings, however, a more general implication of our results is that evaluations of the diversity of limb-bone SFs can provide important perspective to direct future research. In particular, more complete understanding of variation in SF could provide insight into factors that promoted the evolutionary radiation of terrestrial locomotor function in vertebrates. PMID- 24808014 TI - Multimorbidity and the risk of restless legs syndrome in 2 prospective cohort studies. AB - OBJECTIVE: Our aim was to evaluate the association between the cumulative effect of comorbidity and the risk of restless legs syndrome (RLS) in 2 population-based German cohort studies. METHODS: The Dortmund Health Study (DHS) (n = 1,312; median follow-up time: 2.1 years) and the Study of Health in Pomerania (SHIP) (n = 4,308; median follow-up time: 5.0 years) were used for the analyses. RLS was assessed at baseline and follow-up according to the RLS minimal criteria. A comorbidity index was calculated as a sum of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. The relationship between comorbidity and incident RLS was analyzed with multivariate logistic regression models. RESULTS: An increase in the number of comorbid conditions at baseline predicted prevalent RLS (DHS: trend odds ratio [OR] = 1.24, 95% confidence interval [CI] 0.99-1.56; SHIP: trend OR = 1.34, 95% CI 1.18-1.52) and incident RLS (DHS: trend OR = 1.32, 95% CI 1.04-1.68; SHIP: trend OR = 1.59, 95% CI 1.37 1.85) after adjustment for several covariates. The ORs for incident RLS associated with 3 or more comorbid diseases (DHS: OR = 2.51, 95% CI 1.18-5.34; SHIP: OR = 4.30, 95% CI 2.60-7.11) were higher than the ORs for any single disease. CONCLUSIONS: Multimorbidity was a strong risk factor for RLS in these 2 population-based cohort studies. The results support the hypothesis that cumulative disease burden is more important than the presence of a specific single disease in the pathophysiology of RLS. PMID- 24808013 TI - Mechanisms underlying epigenetic regulation in Arabidopsis thaliana. AB - In plants, epigenetic regulation mediates both the proper development of the plant and responses to environmental cues. Changes in epigenetic states employ DNA methylation, histone modification, and regulatory RNAs. In Arabidopsis thaliana, DNA methylation as a repressive mark is often associated with constitutively silenced loci, such as repetitive sequences, transposons, and heterochromatin. These sequences regularly give rise to small interfering RNAs, which direct DNA methylation through the RNA-directed DNA methylation (RdDM) pathway. For example, FWA locus is silenced in sporophytes and enriched with DNA methylation. Its methylated state is stable and passes to the next generation. This is an example of meiotically inherited epigenetic states. There are also epigenetic changes that can be inherited mitotically and are subsequently erased in the next generation. In this review, we use the vernalization-mediated epigenetic silencing of FLOWERING LOCUS C (FLC) as an example for this type of mitotically stable epigenetic state. Here, we discuss mechanisms of epigenetic changes that can result in meiotically or mitotically stable states with an emphasis on FWA and FLC as two examples. PMID- 24808015 TI - Lower motor neuron disease with respiratory failure caused by a novel MAPT mutation. AB - OBJECTIVE: To investigate the molecular defect underlying a large Italian kindred with progressive adult-onset respiratory failure, proximal weakness of the upper limbs, and evidence of lower motor neuron degeneration. METHODS: We describe the clinical features of 5 patients presenting with prominent respiratory insufficiency, proximal weakness of the upper limbs, and no signs of frontotemporal lobar degeneration or semantic dementia. Molecular analysis was performed combining linkage and exome sequencing analyses. Further investigations included transcript analysis and immunocytochemical and protein studies on established cell models. RESULTS: Genome-wide linkage analysis showed an association with chromosome 17q21. Exome analysis disclosed a missense change in MAPT segregating dominantly with the disease and resulting in D348G-mutated tau protein. Motor neuron cell lines overexpressing mutated D348G tau isoforms displayed a consistent reduction in neurite length and arborization. The mutation does not seem to modify tau interactions with microtubules. Neuropathologic studies were performed in one affected subject, which exhibited alpha-motoneuron loss and atrophy of the spinal anterior horns with accumulation of phosphorylated tau within the surviving motor neurons. Staining for 3R- and 4R-tau revealed pathology similar to that observed in familial cases harboring MAPT mutations. CONCLUSION: Our study broadens the phenotype of tauopathies to include lower motor neuron disease and implicate tau degradation pathway defects in motor neuron degeneration. PMID- 24808016 TI - Congenital mirror movements: mutational analysis of RAD51 and DCC in 26 cases. AB - OBJECTIVE: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51. METHODS: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. RESULTS: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC). CONCLUSION: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered. PMID- 24808017 TI - Motor protein mutations cause a new form of hereditary spastic paraplegia. AB - OBJECTIVE: To identify a novel disease gene in 2 families with autosomal recessive hereditary spastic paraplegia (HSP). METHODS: We used whole-exome sequencing to identify the underlying genetic disease cause in 2 families with apparently autosomal recessive spastic paraplegia. Endogenous expression as well as subcellular localization of wild-type and mutant protein were studied to support the pathogenicity of the identified mutations. RESULTS: In 2 families, we identified compound heterozygous or homozygous mutations in the kinesin gene KIF1C to cause hereditary spastic paraplegia type 58 (SPG58). SPG58 can be complicated by cervical dystonia and cerebellar ataxia. The same mutations in a heterozygous state result in a mild or subclinical phenotype. KIF1C mutations in SPG58 affect the domains involved in adenosine triphosphate hydrolysis and microtubule binding, key functions for this microtubule-based motor protein. CONCLUSIONS: KIF1C is the third kinesin gene involved in the pathogenesis of HSPs and is characterized by a mild dominant and a more severe recessive disease phenotype. The identification of KIF1C as an HSP disease gene further supports the key role of intracellular trafficking processes in the pathogenesis of hereditary axonopathies. PMID- 24808018 TI - Initial cognitive decline is associated with cortical thinning in early Parkinson disease. AB - OBJECTIVES: Our aim was to assess cortical thickness in a large multicenter cohort of drug-naive patients with early Parkinson disease (PD), with and without mild cognitive impairment (MCI), and explore the cognitive correlates of regional cortical thinning. METHODS: One hundred twenty-three newly diagnosed patients with PD and 56 healthy controls with 3-tesla structural MRI scans and complete neuropsychological assessment from the Parkinson's Progression Markers Initiative were included. Modified Movement Disorders Society Task Force level II criteria were applied to diagnose MCI in PD. FreeSurfer image processing and analysis software was used to measure cortical thickness across groups and the association with cognitive domains and tests. RESULTS: In patients with MCI, atrophy was found in temporal, parietal, frontal, and occipital areas compared with controls. Specific regional thinning in the right inferior temporal cortex was also found in cognitively normal patients. Memory, executive, and visuospatial performance was associated with temporoparietal and superior frontal thinning, suggesting a relationship between cognitive impairment and both anterior and posterior cortical atrophy in the whole patient sample. CONCLUSIONS: These findings confirm that MCI is associated with widespread cortical atrophy. In addition, they suggest that regional cortical thinning is already present at the time of diagnosis in patients with early, untreated PD who do not meet the criteria for MCI. Together, the results indicate that cortical thinning can serve as a marker for initial cognitive decline in early PD. PMID- 24808020 TI - Expanding sialidosis spectrum by genome-wide screening: NEU1 mutations in adult onset myoclonus. AB - OBJECTIVE: To identify the genetic cause of a familial form of late-onset action myoclonus in 2 unrelated patients. Both probands had 2 siblings displaying a similar disorder. Extensive laboratory examinations, including biochemical assessment for urine sialic acid in the 2 probands, were negative. METHODS: Exome sequencing was performed in the probands using an Illumina platform. Segregation analysis of putative mutations was performed in all family members by standard Sanger sequencing protocols. RESULTS: NEU1 mutations were detected in 3 siblings of each family with prominent cortical myoclonus presenting in the third decade of life and having a mild and slowly progressive course. They did not have macular cherry-red spot and their urinary sialic acid excretion was within normal values. Genetic analysis demonstrated a homozygous mutation in family 1 (c.200G>T, p.S67I) and 2 compound heterozygous mutations in family 2 (c.679G>A, p.G227R; c.913C>T, p.R305C). CONCLUSIONS: Our observation indicates that sialidosis should be suspected and the NEU1 gene analyzed in patients with isolated action myoclonus presenting in adulthood in the absence of other typical clinical and laboratory findings. PMID- 24808019 TI - Intensive care unit admission in multiple sclerosis: increased incidence and increased mortality. AB - OBJECTIVE: To compare the incidence of, and mortality after, intensive care unit (ICU) admission as well as the characteristics of critical illness in the multiple sclerosis (MS) population vs the general population. METHODS: We used population-based administrative data from the Canadian province of Manitoba for the period 1984 to 2010 and clinical data from 93% of admissions to provincial high-intensity adult ICUs. We identified 5,035 prevalent cases of MS and a cohort from the general population matched 5:1 on age, sex, and region of residence. We compared these populations using incidence rates and multivariable regression models adjusting for age, sex, comorbidity, and socioeconomic status. RESULTS: From January 2000 to October 2009, the age- and sex-standardized annual incidence of ICU admission among prevalent cohorts was 0.51% to 1.07% in the MS population and 0.34% to 0.51% in matched controls. The adjusted risk of ICU admission was higher for the MS population (hazard ratio 1.45; 95% confidence interval [CI] 1.19-1.75) than for matched controls. The MS population was more likely to be admitted for infection than the matched controls (odds ratio 1.82; 95% CI 1.10 1.32). Compared with the matched controls admitted to ICUs, 1-year mortality was higher in the MS population (relative risk 2.06; 95% CI 1.32-3.07) and was particularly elevated in patients with MS who were younger than 40 years (relative risk 3.77; 95% CI 1.45-8.11). Causes of death were MS (9.3%), infections (37.0%), and other causes (52.9%). CONCLUSIONS: Compared with the general population, the risk of ICU admission is higher in MS, and 1-year mortality after admission is higher. Greater attention to preventing infection and managing comorbidity is needed in the MS population. PMID- 24808021 TI - Paraparetic Guillain-Barre syndrome. AB - OBJECTIVE: To define the clinical and diagnostic characteristics of paraparetic Guillain-Barre syndrome (GBS) with weakness restricted to the legs, compared with the classic quadriparetic GBS. METHODS: Prospectively collected data from a cohort of 490 patients with GBS, previously involved in therapeutic or clinical studies, were used to define the demography, clinical presentation, diagnostic investigations, and clinical course in patients with paraparesis during a 6-month follow-up. RESULTS: Forty patients (8%) presented with a paraparesis without weakness of arms and hands. In 29 patients (73%), normal strength of upper extremities persisted during the follow-up period. Patients with paraparesis compared to patients with quadriparesis had a milder form of GBS, with less frequent cranial nerve involvement and less severe leg weakness, despite the fact that the majority of these patients were unable to walk unaided. Median time between onset of weakness and study entry was 6 days (interquartile range 4-11 days) for patients with paraparesis compared with 5 days (interquartile range 3-8 days) for patients with quadriparesis (p = 0.031). Fifty percent of patients with paraparesis presented with arm sensory deficits and 73% had reduced or absent arm reflexes. Nerve conduction studies demonstrated arm nerve involvement in 89% of these patients. At 6 months of follow-up, 98% of patients with paraparesis were able to walk unaided compared with 81% of the patients with quadriparesis (p = 0.008). There was no association between paraparesis and age, sex, or preceding infections. CONCLUSIONS: Paraparesis is an atypical clinical presentation or subform of GBS in which the diagnosis is usually supported by the presence of sensory deficits, reduced reflexes, or abnormal nerve conduction of the arms. PMID- 24808022 TI - PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. AB - OBJECTIVE: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). METHODS: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. RESULTS: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. CONCLUSIONS: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. PMID- 24808024 TI - Teaching a shader-based introduction to computer graphics. PMID- 24808025 TI - Efficient simplification of large vector maps rendered onto 3D landscapes. AB - Real-time rendering of large scale vector maps over terrain surfaces requires displaying substantial numbers of polylines and polygons. The proposed approach simplifies such maps, permitting more efficient rendering and reducing latency in the display and manipulation of a virtual environment. PMID- 24808023 TI - Novel (ovario) leukodystrophy related to AARS2 mutations. AB - OBJECTIVES: The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to identify the causal genetic defect shared by patients with this phenotype. METHODS: Independent next generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected. Clinical and MRI findings were investigated. RESULTS: Next-generation sequencing revealed compound heterozygous mutations in AARS2 encoding mitochondrial alanyl-tRNA synthetase in both patients. Functional studies in yeast confirmed the pathogenicity of the mutations in one patient. Sanger sequencing revealed AARS2 mutations in 4 of the 11 selected patients. The 6 patients with AARS2 mutations had childhood- to adulthood-onset signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. MRIs showed a leukoencephalopathy with striking involvement of left-right connections, descending tracts, and cerebellar atrophy. All female patients had ovarian failure. None of the patients had signs of a cardiomyopathy. CONCLUSIONS: Mutations in AARS2 have been found in a severe form of infantile cardiomyopathy in 2 families. We present 6 patients with a new phenotype caused by AARS2 mutations, characterized by leukoencephalopathy and, in female patients, ovarian failure, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported. PMID- 24808026 TI - Colorization using the rotation-invariant feature space. AB - Current colorization based on image segmentation makes it difficult to add or update color reliably and requires considerable user intervention A new approach gives similar colors to pixels with similar texture features. To do this, it uses rotation-invariant Gabor filter banks and applies optimization in the feature space. PMID- 24808027 TI - A virtual reality simulator for ultrasound-guided biopsy training. AB - A VR-based training system for practicing biopsies simulates ultrasound imagery by stitching multiple ultrasound volumes on the basis of a 3D scale-invariant feature transform algorithm. In addition, a six-degree-of-freedom force model delivers a realistic haptic rendering of needle insertion. PMID- 24808028 TI - EasyToy: plush toy design using editable sketching curves. AB - EasyToy is an industrial plush toy design system for novices. Editable sketching curves combine the advantages of free-form strokes and the controllability of B spline curves. Users can continuously edit each curve to refine designs. EasyToy provides a small set of simple tools with which users can easily construct sophisticated toy models comparable to those that professional systems produce. PMID- 24808029 TI - Linear algorithms in sublinear time a tutorial on statistical estimation. AB - This tutorial presents probability theory techniques for boosting linear algorithms. The approach is based on statistics and uses educated guesses instead of comprehensive calculations. Because estimates can be calculated in sublinear time, many algorithms can benefit from statistical estimation. PMID- 24808030 TI - Using GPU shaders for visualization, part 2. AB - GPU shaders aren't just for special effects. Previously, I looked at some uses for them in visualization. Here, the idea continues. Because visualization relies so much on high speed interaction, we use shaders for the same reason we use them in effects programming: appearance and performance. In the drive to understand large, complex data sets, no method should be overlooked. This article describes two additional visualization applications: line integral convolution (LIC) and terrain bump-mapping. I also comment on the recent (and rapid) changes to OpenGL and what these mean to educators. PMID- 24808031 TI - Computer-aided design and manufacturing of customized insoles. PMID- 24808032 TI - Generative storytelling for information visualization. PMID- 24808033 TI - Classification in the presence of label noise: a survey. AB - Label noise is an important issue in classification, with many potential negative consequences. For example, the accuracy of predictions may decrease, whereas the complexity of inferred models and the number of necessary training samples may increase. Many works in the literature have been devoted to the study of label noise and the development of techniques to deal with label noise. However, the field lacks a comprehensive survey on the different types of label noise, their consequences and the algorithms that consider label noise. This paper proposes to fill this gap. First, the definitions and sources of label noise are considered and a taxonomy of the types of label noise is proposed. Second, the potential consequences of label noise are discussed. Third, label noise-robust, label noise cleansing, and label noise-tolerant algorithms are reviewed. For each category of approaches, a short discussion is proposed to help the practitioner to choose the most suitable technique in its own particular field of application. Eventually, the design of experiments is also discussed, what may interest the researchers who would like to test their own algorithms. In this paper, label noise consists of mislabeled instances: no additional information is assumed to be available like e.g., confidences on labels. PMID- 24808034 TI - Efficient algorithms for exact inference in sequence labeling SVMs. AB - The task of structured output prediction deals with learning general functional dependencies between arbitrary input and output spaces. In this context, two loss sensitive formulations for maximum-margin training have been proposed in the literature, which are referred to as margin and slack rescaling, respectively. The latter is believed to be more accurate and easier to handle. Nevertheless, it is not popular due to the lack of known efficient inference algorithms; therefore, margin rescaling--which requires a similar type of inference as normal structured prediction--is the most often used approach. Focusing on the task of label sequence learning, we here define a general framework that can handle a large class of inference problems based on Hamming-like loss functions and the concept of decomposability for the underlying joint feature map. In particular, we present an efficient generic algorithm that can handle both rescaling approaches and is guaranteed to find an optimal solution in polynomial time. PMID- 24808035 TI - Robust adaptive dynamic programming and feedback stabilization of nonlinear systems. AB - This paper studies the robust optimal control design for a class of uncertain nonlinear systems from a perspective of robust adaptive dynamic programming (RADP). The objective is to fill up a gap in the past literature of adaptive dynamic programming (ADP) where dynamic uncertainties or unmodeled dynamics are not addressed. A key strategy is to integrate tools from modern nonlinear control theory, such as the robust redesign and the backstepping techniques as well as the nonlinear small-gain theorem, with the theory of ADP. The proposed RADP methodology can be viewed as an extension of ADP to uncertain nonlinear systems. Practical learning algorithms are developed in this paper, and have been applied to the controller design problems for a jet engine and a one-machine power system. PMID- 24808036 TI - A spiking self-organizing map combining STDP, oscillations, and continuous learning. AB - The self-organizing map (SOM) is a neural network algorithm to create topographically ordered spatial representations of an input data set using unsupervised learning. The SOM algorithm is inspired by the feature maps found in mammalian cortices but lacks some important functional properties of its biological equivalents. Neurons have no direct access to global information, transmit information through spikes and may be using phasic coding of spike times within synchronized oscillations, receive continuous input from the environment, do not necessarily alter network properties such as learning rate and lateral connectivity throughout training, and learn through relative timing of action potentials across a synaptic connection. In this paper, a network of integrate and-fire neurons is presented that incorporates solutions to each of these issues through the neuron model and network structure. Results of the simulated experiments assessing map formation using artificial data as well as the Iris and Wisconsin Breast Cancer datasets show that this novel implementation maintains fundamental properties of the conventional SOM, thereby representing a significant step toward further understanding of the self-organizational properties of the brain while providing an additional method for implementing SOMs that can be utilized for future modeling in software or special purpose spiking neuron hardware. PMID- 24808037 TI - An online outlier identification and removal scheme for improving fault detection performance. AB - Measured data or states for a nonlinear dynamic system is usually contaminated by outliers. Identifying and removing outliers will make the data (or system states) more trustworthy and reliable since outliers in the measured data (or states) can cause missed or false alarms during fault diagnosis. In addition, faults can make the system states nonstationary needing a novel analytical model-based fault detection (FD) framework. In this paper, an online outlier identification and removal (OIR) scheme is proposed for a nonlinear dynamic system. Since the dynamics of the system can experience unknown changes due to faults, traditional observer-based techniques cannot be used to remove the outliers. The OIR scheme uses a neural network (NN) to estimate the actual system states from measured system states involving outliers. With this method, the outlier detection is performed online at each time instant by finding the difference between the estimated and the measured states and comparing its median with its standard deviation over a moving time window. The NN weight update law in OIR is designed such that the detected outliers will have no effect on the state estimation, which is subsequently used for model-based fault diagnosis. In addition, since the OIR estimator cannot distinguish between the faulty or healthy operating conditions, a separate model-based observer is designed for fault diagnosis, which uses the OIR scheme as a preprocessing unit to improve the FD performance. The stability analysis of both OIR and fault diagnosis schemes are introduced. Finally, a three-tank benchmarking system and a simple linear system are used to verify the proposed scheme in simulations, and then the scheme is applied on an axial piston pump testbed. The scheme can be applied to nonlinear systems whose dynamics and underlying distribution of states are subjected to change due to both unknown faults and operating conditions. PMID- 24808038 TI - Fidelity-based probabilistic Q-learning for control of quantum systems. AB - The balance between exploration and exploitation is a key problem for reinforcement learning methods, especially for Q-learning. In this paper, a fidelity-based probabilistic Q-learning (FPQL) approach is presented to naturally solve this problem and applied for learning control of quantum systems. In this approach, fidelity is adopted to help direct the learning process and the probability of each action to be selected at a certain state is updated iteratively along with the learning process, which leads to a natural exploration strategy instead of a pointed one with configured parameters. A probabilistic Q learning (PQL) algorithm is first presented to demonstrate the basic idea of probabilistic action selection. Then the FPQL algorithm is presented for learning control of quantum systems. Two examples (a spin-1/2 system and a Lambda-type atomic system) are demonstrated to test the performance of the FPQL algorithm. The results show that FPQL algorithms attain a better balance between exploration and exploitation, and can also avoid local optimal policies and accelerate the learning process. PMID- 24808039 TI - On the impact of approximate computation in an analog DeSTIN architecture. AB - Deep machine learning (DML) holds the potential to revolutionize machine learning by automating rich feature extraction, which has become the primary bottleneck of human engineering in pattern recognition systems. However, the heavy computational burden renders DML systems implemented on conventional digital processors impractical for large-scale problems. The highly parallel computations required to implement large-scale deep learning systems are well suited to custom hardware. Analog computation has demonstrated power efficiency advantages of multiple orders of magnitude relative to digital systems while performing nonideal computations. In this paper, we investigate typical error sources introduced by analog computational elements and their impact on system-level performance in DeSTIN--a compositional deep learning architecture. These inaccuracies are evaluated on a pattern classification benchmark, clearly demonstrating the robustness of the underlying algorithm to the errors introduced by analog computational elements. A clear understanding of the impacts of nonideal computations is necessary to fully exploit the efficiency of analog circuits. PMID- 24808040 TI - Adaptive neural tracking control for a class of nonstrict-feedback stochastic nonlinear systems with unknown backlash-like hysteresis. AB - This paper considers the problem of adaptive neural control of stochastic nonlinear systems in nonstrict-feedback form with unknown backlash-like hysteresis nonlinearities. To overcome the design difficulty of nonstrict feedback structure, variable separation technique is used to decompose the unknown functions of all state variables into a sum of smooth functions of each error dynamic. By combining radial basis function neural networks' universal approximation capability with an adaptive backstepping technique, an adaptive neural control algorithm is proposed. It is shown that the proposed controller guarantees that all the signals in the closed-loop system are four-moment semiglobally uniformly ultimately bounded, and the tracking error eventually converges to a small neighborhood of the origin in the sense of mean quartic value. Simulation results further show the effectiveness of the presented control scheme. PMID- 24808041 TI - Simplified interval type-2 fuzzy neural networks. AB - This paper describes a self-evolving interval type-2 fuzzy neural network (FNN) for various applications. As type-1 fuzzy systems cannot effectively handle uncertainties in information within the knowledge base, we propose a simple interval type-2 FNN, which uses interval type-2 fuzzy sets in the premise and the Takagi-Sugeno-Kang (TSK) type in the consequent of the fuzzy rule. The TSK-type consequent of fuzzy rule is a linear combination of exogenous input variables. Given an initially empty the rule-base, all rules are generated with on-line type 2 fuzzy clustering. Instead of the time-consuming K-M iterative procedure, the design factors ql and qr are learned to adaptively adjust the upper and lower positions on the left and right limit outputs, using the parameter update rule based on a gradient descent algorithm. Simulation results demonstrate that our approach yields fewer test errors and less computational complexity than other type-2 FNNs. PMID- 24808042 TI - Modeling of batch processes using explicitly time-dependent artificial neural networks. AB - A neural network architecture incorporating time dependency explicitly, proposed recently, for modeling nonlinear nonstationary dynamic systems is further developed in this paper, and three alternate configurations are proposed to represent the dynamics of batch chemical processes. The first configuration consists of L subnets, each having M inputs representing the past samples of process inputs and output; each subnet has a hidden layer with polynomial activation function; the outputs of the hidden layer are combined and acted upon by an explicitly time-dependent modulation function. The outputs of all the subnets are summed to obtain the output prediction. In the second configuration, additional weights are incorporated to obtain a more generalized model. In the third configuration, the subnets are eliminated by incorporating an additional hidden layer consisting of L nodes. Backpropagation learning algorithm is formulated for each of the proposed neural network configuration to determine the weights, the polynomial coefficients, and the modulation function parameters. The modeling capability of the proposed neural network configuration is evaluated by employing it to represent the dynamics of a batch reactor in which a consecutive reaction takes place. The results show that all the three time-varying neural networks configurations are able to represent the batch reactor dynamics accurately, and it is found that the third configuration is exhibiting comparable or better performance over the other two configurations while requiring much smaller number of parameters. The modeling ability of the third configuration is further validated by applying to modeling a semibatch polymerization reactor challenge problem. This paper illustrates that the proposed approach can be applied to represent dynamics of any batch/semibatch process. PMID- 24808043 TI - Storing sparse messages in networks of neural cliques. AB - An extension to a recently introduced binary neural network is proposed to allow the storage of sparse messages, in large numbers and with high memory efficiency. This new network is justified both in biological and informational terms. The storage and retrieval rules are detailed and illustrated by various simulation results. PMID- 24808044 TI - Incipient interturn fault diagnosis in induction machines using an analytic wavelet-based optimized Bayesian inference. AB - Interturn fault diagnosis of induction machines has been discussed using various neural network-based techniques. The main challenge in such methods is the computational complexity due to the huge size of the network, and in pruning a large number of parameters. In this paper, a nearly shift insensitive complex wavelet-based probabilistic neural network (PNN) model, which has only a single parameter to be optimized, is proposed for interturn fault detection. The algorithm constitutes two parts and runs in an iterative way. In the first part, the PNN structure determination has been discussed, which finds out the optimum size of the network using an orthogonal least squares regression algorithm, thereby reducing its size. In the second part, a Bayesian classifier fusion has been recommended as an effective solution for deciding the machine condition. The testing accuracy, sensitivity, and specificity values are highest for the product rule-based fusion scheme, which is obtained under load, supply, and frequency variations. The point of overfitting of PNN is determined, which reduces the size, without compromising the performance. Moreover, a comparative evaluation with traditional discrete wavelet transform-based method is demonstrated for performance evaluation and to appreciate the obtained results. PMID- 24808045 TI - A scalable stagewise approach to large-margin multiclass loss-based boosting. AB - We present a scalable and effective classification model to train multiclass boosting for multiclass classification problems. A direct formulation of multiclass boosting had been introduced in the past in the sense that it directly maximized the multiclass margin. The major problem of that approach is its high computational complexity during training, which hampers its application to real world problems. In this paper, we propose a scalable and simple stagewise multiclass boosting method which also directly maximizes the multiclass margin. Our approach offers the following advantages: 1) it is simple and computationally efficient to train. The approach can speed up the training time by more than two orders of magnitude without sacrificing the classification accuracy and 2) like traditional AdaBoost, it is less sensitive to the choice of parameters and empirically demonstrates excellent generalization performance. Experimental results on challenging multiclass machine learning and vision tasks demonstrate that the proposed approach substantially improves the convergence rate and accuracy of the final visual detector at no additional computational cost compared to existing multiclass boosting. PMID- 24808046 TI - Data-driven MFAC for a class of discrete-time nonlinear systems with RBFNN. AB - A novel model-free adaptive control method is proposed for a class of discrete time single input single output (SISO) nonlinear systems, where the equivalent dynamic linearization technique is used on the ideal nonlinear controller. With radial basis function neural network, the controller parameters are tuned on-line directly using the measured input and output data of the plant, when the plant model is unavailable. The stability of the proposed method is guaranteed by rigorous theoretical analysis, and the effectiveness and applicability are verified by numerical simulation and further demonstrated by the experiment on three tanks water level control process. PMID- 24808047 TI - Is road safety being driven in the wrong direction? AB - BACKGROUND: Road traffic crashes are a major cause of death and injury worldwide and are set to increase as low- and middle-income countries motorize. United Nations (UN)and World Health Organization (WHO) road traffic injury prevention efforts depend on support from external organizations, many of which have commercial interests in increasing car use. Because of concerns about conflict of interest, this study objectively assessed the activities of a key WHO collaborator, the Global Road Safety Partnership (GRSP). METHODS: We conducted a quantitative content analysis comparing GRSP publications and the 2004 WHO World Report on Road Traffic Injury Prevention. Dictionaries of terms were constructed for each of the evidence-based interventions detailed in the World REPORT. Text analysis software was used to generate word frequency counts of those terms to compare the World Report and GRSP documents. RESULTS: Education, information and publicity featured far more commonly in the GRSP publications than in the WHO World Report [word frequency ratios and 95% confidence intervals: GRSP Newsletter 3.09, 2.53 to 3.78; Around GRSPs World 4.69, 3.76 to 5.87;GRSP Project summaries 3.42, 2.59 to 4.51] On the other hand, compared with the World Report, reducing car use [GRSP Newsletter 0.36, 0.27 to 0.48], minimizing exposure to high-risk scenarios [GRSP Newsletter 0.04, 0.02 to 0.09] and encouraging the use of safer modes of travel [GRSP Newsletter 0.02, 0.01 to 0.08] rarely featured in GRSP publications. CONCLUSIONS: The GRSP focuses on educational interventions, for which there is no evidence of effectiveness. Furthermore, the GRSP does not appear to consider the full range of WHO interventions. As motorization growth has serious negative implications for health, including those associated from physical inactivity, climate change and air and noise pollution, it is imperative that the UN and WHO do not allow business interests to dominate public health interests. PMID- 24808048 TI - Substance use and crime: identifying and treating those in need. PMID- 24808049 TI - Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress. AB - Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nomega-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8 Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO. PMID- 24808050 TI - Spatiotemporal Production of Reactive Oxygen Species by NADPH Oxidase Is Critical for Tapetal Programmed Cell Death and Pollen Development in Arabidopsis. AB - Male sterility in angiosperms has wide applications in agriculture, particularly in hybrid crop breeding and gene flow control. Microspores develop adjacent to the tapetum, a layer of cells that provides nutrients for pollen development and materials for pollen wall formation. Proper pollen development requires programmed cell death (PCD) of the tapetum, which requires transcriptional cascades and proteolytic enzymes. Reactive oxygen species (ROS) also affect tapetal PCD, and failures in ROS scavenging cause male sterility. However, many aspects of tapetal PCD remain unclear, including what sources generate ROS, whether ROS production has a temporal pattern, and how the ROS-producing system interacts with the tapetal transcriptional network. We report here that stage specific expression of NADPH oxidases in the Arabidopsis thaliana tapetum contributes to a temporal peak of ROS production. Genetic interference with the temporal ROS pattern, by manipulating RESPIRATORY-BURST OXIDASE HOMOLOG (RBOH) genes, affected the timing of tapetal PCD and resulted in aborted male gametophytes. We further show that the tapetal transcriptional network regulates RBOH expression, indicating that the temporal pattern of ROS production intimately connects to other signaling pathways regulated by the tapetal transcriptional network to ensure the proper timing of tapetal PCD. PMID- 24808051 TI - Tools and Strategies to Match Peptide-Ligand Receptor Pairs. AB - Peptide signals have emerged as an important class of regulators in cell-to-cell communication in plants. Several families of small, secreted proteins with a conserved C-terminal Pro-rich motif have been identified as functional peptide signals in Arabidopsis thaliana. These proteins are presumed to be trimmed proteolytically and undergo posttranslational modifications, such as hydroxylation of Pro residues and glycosylation, to form mature, bioactive signals. Identification and matching of such ligands with their respective receptors remains a major challenge since the genes encoding them often show redundancy and low expression restricted to a few cells or particular developmental stages. To overcome these difficulties, we propose the use of ectopic expression of receptor genes in suitable plant cells like Nicotiana benthamiana for testing ligand candidates in receptor output assays and in binding studies. As an example, we used the IDA peptide HAE/HSL2 receptor signaling system known to regulate floral organ abscission. We demonstrate that the oxidative burst response can be employed as readout for receptor activation by synthetic peptides and that a new, highly sensitive, nonradioactive labeling approach can be used to reveal a direct correlation between peptide activity and receptor affinity. We suggest that these approaches will be of broad value for the field of ligand-receptor studies in plants. PMID- 24808054 TI - Beyond control panels: direct manipulation for visual analytics. AB - To tackle the onset of big data, visual analytics seeks to marry the human intuition of visualization with mathematical models' analytical horsepower. A critical question is, how will humans interact with and steer these complex models? Initially, users applied direct manipulation to such models the same way they applied it to simpler visualizations in the premodel era--using control panels to directly manipulate model parameters. However, opportunities are arising for direct manipulation of the model outputs, where the users' thought processes take place, rather than the inputs. This article presents this new agenda for direct manipulation for visual analytics. PMID- 24808053 TI - Stitching together the Multiple Dimensions of Autophagy Using Metabolomics and Transcriptomics Reveals Impacts on Metabolism, Development, and Plant Responses to the Environment in Arabidopsis. AB - Autophagy is a fundamental process in the plant life story, playing a key role in immunity, senescence, nutrient recycling, and adaptation to the environment. Transcriptomics and metabolomics of the rosette leaves of Arabidopsis thaliana autophagy mutants (atg) show that autophagy is essential for cell homeostasis and stress responses and that several metabolic pathways are affected. Depletion of hexoses, quercetins, and anthocyanins parallel the overaccumulation of several amino acids and related compounds, such as glutamate, methionine, glutathione, pipecolate, and 2-aminoadipate. Transcriptomic data show that the pathways for glutathione, methionine, raffinose, galacturonate, and anthocyanin are perturbed. Anthocyanin depletion in atg mutants, which was previously reported as a possible defect in flavonoid trafficking to the vacuole, appears due to the downregulation of the master genes encoding the enzymes and regulatory proteins involved in flavonoid biosynthesis. Overexpression of the PRODUCTION OF ANTHOCYANIN PIGMENT1 transcription factor restores anthocyanin accumulation in vacuoles of atg mutants. Transcriptome analyses reveal connections between autophagy and (1) salicylic acid biosynthesis and response, (2) cytokinin perception, (3) oxidative stress and plant defense, and possible interactions between autophagy and the COP9 signalosome machinery. The metabolic and transcriptomic signatures identified for the autophagy mutants are discussed and show consistencies with the observed phenotypes. PMID- 24808052 TI - Growth Control: A Saga of Cell Walls, ROS, and Peptide Receptors. AB - Despite an increasingly detailed understanding of endogenous and environmental growth-controlling signals and their signaling networks, little is known on how these networks are integrated with the cell expansion machinery. Members of the CrRLK1L family control cell wall properties and cell expansion in a variety of developmental and environmental contexts. Two recent reports provide exciting new insights into the mode of action of these RLKs. One study shows that one family member, FERONIA (FER), is required for the production of hydroxyl radicals in the female gametophyte, which causes pollen tube rupture and sperm cell release during fertilization. Another study shows that FER is a receptor for a signaling peptide (Rapid Alkalinization Factor 1 [RALF1]) that triggers cell wall alkalinization and growth arrest, possibly through the inhibition of plasma membrane H+-ATPase activity. RALF1 belongs to a large gene family, with a wide range of expression patterns. Other CrRLK1L family members therefore may also be receptors for RALF-like peptides. These findings have important implications for our understanding of the control of cell wall integrity during growth and raise new intriguing questions. PMID- 24808056 TI - Customizing computational methods for visual analytics with big data. AB - The volume of available data has been growing exponentially, increasing data problem's complexity and obscurity. In response, visual analytics (VA) has gained attention, yet its solutions haven't scaled well for big data. Computational methods can improve VA's scalability by giving users compact, meaningful information about the input data. However, the significant computation time these methods require hinders real-time interactive visualization of big data. By addressing crucial discrepancies between these methods and VA regarding precision and convergence, researchers have proposed ways to customize them for VA. These approaches, which include low-precision computation and iteration-level interactive visualization, ensure real-time interactive VA for big data. PMID- 24808055 TI - How visualization courses have changed over the past 10 years. AB - The past 10 years have seen profound changes in visualization algorithms, techniques, methodologies, and applications. These changes are forcing alterations to visualization courses. Unfortunately, outdated course content recommendations, together with profound changes in the underlying technology and methodology, are producing an unstable ground for educators at a time when visual representations are becoming increasingly important. To address this issue, educators held meetings or workshops at Siggraph 2011 and 2012 and a panel and workshop at Eurographics 2012. This article presents the insights gathered at these events. PMID- 24808057 TI - Feature tracking and visualization of the Madden-Julian oscillation in climate simulation. AB - The Madden-Julian oscillation (MJO) is one of the less understood aspects of tropical meteorology. It plays a significant role in tropical intraseasonal variations in rain, temperature, and winds over the Indian and Pacific Oceans. Researchers have developed an integrated analysis and visualization tool for MJO episodes simulated by a high-resolution regional model. To distinguish the MJO from other weather phenomena, the tool uses domain knowledge to track the MJO and find the globally optimized properties in the data. To visualize large-scale events in space and time, the tool integrates different visualization components such as a Hovmoller diagram and virtual globe. By linking the visualization components on a Web-based interface, the tool lets scientists more easily identify cloud and environmental processes associated with the MJO's onset and eastward propagation. PMID- 24808058 TI - Visualizing large, heterogeneous data in hybrid-reality environments. AB - Constructing integrative visualizations that simultaneously cater to a variety of data types is challenging. Hybrid-reality environments blur the line between virtual environments and tiled display walls. They incorporate high-resolution, stereoscopic displays, which can be used to juxtapose large, heterogeneous datasets while providing a range of naturalistic interaction schemes. They thus empower designers to construct integrative visualizations that more effectively mash up 2D, 3D, temporal, and multivariate datasets. PMID- 24808059 TI - Exploring the connectome: petascale volume visualization of microscopy data streams. AB - Recent advances in high-resolution microscopy let neuroscientists acquire neural tissue volume data of extremely large sizes. However, the tremendous resolution and the high complexity of neural structures present big challenges to storage, processing, and visualization at interactive rates. A proposed system provides interactive exploration of petascale (petavoxel) volumes resulting from high throughput electron microscopy data streams. The system can concurrently handle multiple volumes and can support the simultaneous visualization of high resolution voxel segmentation data. Its visualization-driven design restricts most computations to a small subset of the data. It employs a multiresolution virtual-memory architecture for better scalability than previous approaches and for handling incomplete data. Researchers have employed it for a 1-teravoxel mouse cortex volume, of which several hundred axons and dendrites as well as synapses have been segmented and labeled. PMID- 24808060 TI - Garment personalization via identity transfer. AB - A new system provides a virtual experience akin to trying on clothing. It clones the user's photographic image into a catalog of images of models wearing the desired garments. Simple offline training extracts the user's head. Segmentation accurately separates the face, hair, and background, employing both a three kernel statistical model and graph cuts. The system adjusts the resulting image's skin color according to a statistical model and relights the head via spherical harmonics. Finally, using a parametric model, the system warps the clone's body dimensions to fit the user's dimensions. This creates high-quality compositions of the user's image and the given garment. PMID- 24808061 TI - Extracting valley-ridge lines from point-cloud-based 3D fingerprint models. AB - 3D fingerprinting is an emerging technology with the distinct advantage of touchless operation. More important, 3D fingerprint models contain more biometric information than traditional 2D fingerprint images. However, current approaches to fingerprint feature detection usually must transform the 3D models to a 2D space through unwrapping or other methods, which might introduce distortions. A new approach directly extracts valley-ridge features from point-cloud-based 3D fingerprint models. It first applies the moving least-squares method to fit a local paraboloid surface and represent the local point cloud area. It then computes the local surface's curvatures and curvature tensors to facilitate detection of the potential valley and ridge points. The approach projects those points to the most likely valley-ridge lines, using statistical means such as covariance analysis and cross correlation. To finally extract the valley-ridge lines, it grows the polylines that approximate the projected feature points and removes the perturbations between the sampled points. Experiments with different 3D fingerprint models demonstrate this approach's feasibility and performance. PMID- 24808062 TI - Methods for game user research: studying player behavior to enhance game design. AB - The emerging field of game user research (GUR) investigates interaction between players and games and the surrounding context of play. Game user researchers have explored methods from, for example, human-computer interaction, psychology, interaction design, media studies, and the social sciences. They've extended and modified these methods for different types of digital games, such as social games, casual games, and serious games. This article describes several current GUR methods. A case study illustrates two specific methods: think-aloud and heuristics. PMID- 24808063 TI - Visual matrix clustering of social networks. AB - The prevailing choices to graphically represent a social network are a node-link graph and an adjacency matrix. Both techniques have unique strengths and weaknesses for different domain applications. This article focuses on how to change adjacency matrices from merely showing pairwise associations among network actors (or graph nodes) to depicting clusters of a social network. Node-link graphs supplement the discussion. PMID- 24808064 TI - Decirculation process in neural network dynamics. AB - We describe a decirculation process which marks perturbations of network structure and neural updating that are necessary for evolutionary neural networks to proceed from one circulating state to another. Two aspects of control parameters, screen updating and flow diagrams, are developed to quantify such perturbations, and hence to manage the dynamics of evolutionary neural networks. A dynamic state-shifting algorithm is derived from the decirculation process. This algorithm is used to build models of evolutionary content-addressable memory (ECAM) networks endowed with many dynamic relaxation processes. By the training of ECAM networks based on the dynamic state-shifting algorithm, we obtain the classification of training samples and the construction of recognition mappings, both of which perform adaptive computations essential to CAM. PMID- 24808065 TI - Robust support vector regression for uncertain input and output data. AB - In this paper, a robust support vector regression (RSVR) method with uncertain input and output data is studied. First, the data uncertainties are investigated under a stochastic framework and two linear robust formulations are derived. Linear formulations robust to ellipsoidal uncertainties are also considered from a geometric perspective. Second, kernelized RSVR formulations are established for nonlinear regression problems. Both linear and nonlinear formulations are converted to second-order cone programming problems, which can be solved efficiently by the interior point method. Simulation demonstrates that the proposed method outperforms existing RSVRs in the presence of both input and output data uncertainties. PMID- 24808066 TI - Neural-fitted TD-leaf learning for playing Othello with structured neural networks. AB - This paper describes a methodology for quickly learning to play games at a strong level. The methodology consists of a novel combination of three techniques, and a variety of experiments on the game of Othello demonstrates their usefulness. First, structures or topologies in neural network connectivity patterns are used to decrease the number of learning parameters and to deal more effectively with the structural credit assignment problem, which is to change individual network weights based on the obtained feedback. Furthermore, the structured neural networks are trained with the novel neural-fitted temporal difference (TD) learning algorithm to create a system that can exploit most of the training experiences and enhance learning speed and performance. Finally, we use the neural-fitted TD-leaf algorithm to learn more effectively when look-ahead search is performed by the game-playing program. Our extensive experimental study clearly indicates that the proposed method outperforms linear networks and fully connected neural networks or evaluation functions evolved with evolutionary algorithms. PMID- 24808067 TI - Global tracking control of strict-feedback systems using neural networks. AB - Most existing adaptive neural controllers ensure semiglobally uniform ultimately bounded stability on the condition that the neural approximation remains valid for all time. However, such a condition is difficult to verify beforehand. As a result, deterioration of tracking performance or even instability may occur in real applications. A common recourse is to activate an extra robust controller outside the neural active region to pull back the transient. Such an approach, however, has been restricted to dynamic systems with matched uncertainty. We extend it to strict-feedback systems with mismatched uncertainties via multiswitching-based backstepping methodology. Each virtual and actual controller of the proposed design switches between an adaptive neural controller and a robust controller, with the switching algorithm being sufficiently smooth and, hence, able to be incorporated with the backstepping tool. The overall controller ensures globally uniform ultimate boundedness while simultaneously avoiding the possible control singularity. Simulation results demonstrate the validity of the proposed designs. PMID- 24808068 TI - Unsupervised learning of categorical data with competing models. AB - This paper considers the unsupervised learning of high-dimensional binary feature vectors representing categorical information. A cognitively inspired framework, referred to as modeling fields theory (MFT), is utilized as the basic methodology. A new MFT-based algorithm, referred to as accelerated maximum a posteriori (MAP), is proposed. Accelerated MAP allows simultaneous learning and selection of the number of models. The key feature of accelerated MAP is a steady increase of the regularization penalty resulting in competition among models. The differences between this approach and other mixture learning and model selection methodologies are described. The operation of this algorithm and its parameter selection are discussed. Numerical experiments aimed at finding performance limits are conducted. The performance with real-world data is tested by applying the algorithm to a text categorization problem and to the clustering Congressional voting data. PMID- 24808069 TI - Discriminative least squares regression for multiclass classification and feature selection. AB - This paper presents a framework of discriminative least squares regression (LSR) for multiclass classification and feature selection. The core idea is to enlarge the distance between different classes under the conceptual framework of LSR. First, a technique called epsilon-dragging is introduced to force the regression targets of different classes moving along opposite directions such that the distances between classes can be enlarged. Then, the epsilon-draggings are integrated into the LSR model for multiclass classification. Our learning framework, referred to as discriminative LSR, has a compact model form, where there is no need to train two-class machines that are independent of each other. With its compact form, this model can be naturally extended for feature selection. This goal is achieved in terms of L2,1 norm of matrix, generating a sparse learning model for feature selection. The model for multiclass classification and its extension for feature selection are finally solved elegantly and efficiently. Experimental evaluation over a range of benchmark datasets indicates the validity of our method. PMID- 24808070 TI - Decentralized asynchronous learning in cellular neural networks. AB - Cellular neural networks (CNNs), as previously described, consist of identical units called cells that are connected to their adjacent neighbors. These cells interact with each other in order to fulfill a common goal. The current methods involved in learning of CNNs are usually centralized (cells are trained in one location) and synchronous (all cells are trained simultaneously either sequentially or in parallel depending on the available hardware/software platform). In this paper, a generic architecture of CNNs is presented and a special case of supervised learning is demonstrated explaining the internal components of a cell. A decentralized asynchronous learning (DAL) framework for CNNs is developed in which each cell of the CNN learns in a spatially and temporally distributed environment. An application of DAL framework is demonstrated by developing a CNN-based wide-area monitoring system for power systems. The results obtained are compared against equivalent traditional methods and shown to be better in terms of accuracy and speed. PMID- 24808071 TI - Boosted network classifiers for local feature selection. AB - Like all models, network feature selection models require that assumptions be made on the size and structure of the desired features. The most common assumption is sparsity, where only a small section of the entire network is thought to produce a specific phenomenon. The sparsity assumption is enforced through regularized models, such as the lasso. However, assuming sparsity may be inappropriate for many real-world networks, which possess highly correlated modules. In this paper, we illustrate two novel optimization strategies, namely, boosted expectation propagation (BEP) and boosted message passing (BMP), which directly use the network structure to estimate the parameters of a network classifier. BEP and BMP are ensemble methods that seek to optimize classification performance by combining individual models built upon local network features. Neither BEP nor BMP assumes a sparse solution, but instead they seek a weighted average of all network features where the weights are used to emphasize all features that are useful for classification. In this paper, we compare BEP and BMP with network-regularized logistic regression models on simulated and real biological networks. The results show that, where highly correlated network structure exists, assuming sparsity adversely effects the accuracy and feature selection power of the network classifier. PMID- 24808072 TI - Semisupervised classification with cluster regularization. AB - Semisupervised classification (SSC) learns, from cheap unlabeled data and labeled data, to predict the labels of test instances. In order to make use of the information from unlabeled data, there should be an assumed relationship between the true class structure and the data distribution. One assumption is that data points clustered together are likely to have the same class label. In this paper, we propose a new algorithm, namely, cluster-based regularization (ClusterReg) for SSC, that takes the partition given by a clustering algorithm as a regularization term in the loss function of an SSC classifier. ClusterReg makes predictions according to the cluster structure together with limited labeled data. The experiments confirmed that ClusterReg has a good generalization ability for real world problems. Its performance is excellent when data follows this cluster assumption. Even when these clusters have misleading overlaps, it still outperforms other state-of-the-art algorithms. PMID- 24808073 TI - Latent feature kernels for link prediction on sparse graphs. AB - Predicting new links in a network is a problem of interest in many application domains. Most of the prediction methods utilize information on the network's entities, such as nodes, to build a model of links. Network structures are usually not used except for networks with similarity or relatedness semantics. In this paper, we use network structures for link prediction with a more general network type with latent feature models. The problem with these models is the computational cost to train the models directly for large data. We propose a method to solve this problem using kernels and cast the link prediction problem into a binary classification problem. The key idea is not to infer latent features explicitly, but to represent these features implicitly in the kernels, making the method scalable to large networks. In contrast to the other methods for latent feature models, our method inherits all the advantages of the kernel framework: optimality, efficiency, and nonlinearity. On sparse graphs, we show that our proposed kernels are close enough to the ideal kernels defined directly on latent features. We apply our method to real data of protein-protein interaction and gene regulatory networks to show the merits of our method. PMID- 24808074 TI - Innovative second-generation wavelets construction with recurrent neural networks for solar radiation forecasting. AB - Solar radiation prediction is an important challenge for the electrical engineer because it is used to estimate the power developed by commercial photovoltaic modules. This paper deals with the problem of solar radiation prediction based on observed meteorological data. A 2-day forecast is obtained by using novel wavelet recurrent neural networks (WRNNs). In fact, these WRNNS are used to exploit the correlation between solar radiation and timescale-related variations of wind speed, humidity, and temperature. The input to the selected WRNN is provided by timescale-related bands of wavelet coefficients obtained from meteorological time series. The experimental setup available at the University of Catania, Italy, provided this information. The novelty of this approach is that the proposed WRNN performs the prediction in the wavelet domain and, in addition, also performs the inverse wavelet transform, giving the predicted signal as output. The obtained simulation results show a very low root-mean-square error compared to the results of the solar radiation prediction approaches obtained by hybrid neural networks reported in the recent literature. PMID- 24808075 TI - Multistability of neural networks with Mexican-hat-type activation functions. AB - In this paper, we are concerned with a class of neural networks with Mexican-hat type activation functions. Due to the different structure from neural networks with saturated activation functions, a set of new sufficient conditions are presented to study the multistability, including the total number of equilibrium points, their locations, and stability. Furthermore, the attraction basins of stable equilibrium points are investigated for two-neuron neural networks. The investigation shows that the stable manifolds of unstable equilibrium points constitute the boundaries of attraction basins of stable equilibrium points. Several illustrative examples are given to verify the effectiveness of our results. PMID- 24808076 TI - Convergence analyses on on-line weight noise injection-based training algorithms for MLPs. AB - Injecting weight noise during training is a simple technique that has been proposed for almost two decades. However, little is known about its convergence behavior. This paper studies the convergence of two weight noise injection-based training algorithms, multiplicative weight noise injection with weight decay and additive weight noise injection with weight decay. We consider that they are applied to multilayer perceptrons either with linear or sigmoid output nodes. Let w(t) be the weight vector, let V(w) be the corresponding objective function of the training algorithm, let alpha >; 0 be the weight decay constant, and let MU(t) be the step size. We show that if MU(t)-> 0, then with probability one E[||w(t)||2(2)] is bound and lim(t) -> infinity ||w(t)||2 exists. Based on these two properties, we show that if MU(t)-> 0, SigmatMU(t)=infinity, and SigmatMU(t)(2) <; infinity, then with probability one these algorithms converge. Moreover, w(t) converges with probability one to a point where ?wV(w)=0. PMID- 24808077 TI - Time series modeling and forecasting using memetic algorithms for regime switching models. AB - In this brief, we present a novel model fitting procedure for the neuro coefficient smooth transition autoregressive model (NCSTAR), as presented by Medeiros and Veiga. The model is endowed with a statistically founded iterative building procedure and can be interpreted in terms of fuzzy rule-based systems. The interpretability of the generated models and a mathematically sound building procedure are two very important properties of forecasting models. The model fitting procedure employed by the original NCSTAR is a combination of initial parameter estimation by a grid search procedure with a traditional local search algorithm. We propose a different fitting procedure, using a memetic algorithm, in order to obtain more accurate models. An empirical evaluation of the method is performed, applying it to various real-world time series originating from three forecasting competitions. The results indicate that we can significantly enhance the accuracy of the models, making them competitive to models commonly used in the field. PMID- 24808078 TI - Toward adaptive VR simulators combining visual, haptic, and brain-computer interfaces. AB - The next generation of VR simulators could take into account a novel input: the user's mental state, as measured with electrodes and a brain-computer interface. One illustration of this promising path is a project that adapted a guidance system's force feedback to the user's mental workload in real time. A first application of this approach is a medical training simulator that provides virtual assistance that adapts to the trainee's mental activity. Such results pave the way to VR systems that will automatically reconfigure and adapt to their users' mental states and cognitive processes. PMID- 24808079 TI - Fast, progressive loading of binary-encoded declarative-3D Web content. AB - Until recently, a major drawback of declarative-3D approaches for the Web was the encoding of scene-graph-related structured data along with a text-based description of unstructured vertex data. Loading times were long, and 3D Web content wasn't available until the full page had completely loaded. To overcome this limitation requires external mesh data containers that are referenced in the scene description. In particular, sequential image geometry containers and explicit binary containers align well with GPU buffer structures, thus enabling fast decoding and GPU uploads. Furthermore, progressive binary geometry enables simple, yet highly progressive transmission of arbitrary mesh data on the Web. PMID- 24808080 TI - XML3D and Xflow: combining declarative 3D for the Web with generic data flows. AB - Researchers have combined XML3D, which provides declarative, interactive 3D scene descriptions based on HTML5, with Xflow, a language for declarative, high performance data processing. The result lets Web developers combine a 3D scene graph with data flows for dynamic meshes, animations, image processing, and postprocessing. PMID- 24808081 TI - The LiverAnatomyExplorer: a WebGL-based surgical teaching tool. AB - The LiverAnatomyExplorer is a real-time surgical teaching tool based on state-of the-art Web technologies such as SVG (Scalable Vector Graphics), X3D (Extensible3D), and WebGL (Web Graphics Library). Unlike other medical e-learning systems, the LiverAnatomyExplorer combines traditional clinical 2D imagery with interactive Web-based 3D models derived from patient-specific image data. The tool is enhanced by surgical videos, a self-assessment tool, and an online authoring tool with which instructors can manage the presented case studies and create multiple-choice quizzes. PMID- 24808082 TI - DPFrag: trainable stroke fragmentation based on dynamic programming. AB - Many computer graphics applications must fragment freehand curves into sets of prespecified geometric primitives. For example, sketch recognition typically converts hand-drawn strokes into line and arc segments and then combines these primitives into meaningful symbols for recognizing drawings. However, current fragmentation methods' shortcomings make them impractical. For example, they require manual tuning, require excessive computational resources, or produce suboptimal solutions that rely on local decisions. DPFrag is an efficient, globally optimal fragmentation method that learns segmentation parameters from data and produces fragmentations by combining primitive recognizers in a dynamic programming framework. The fragmentation is fast and doesn't require laborious and tedious parameter tuning. In experiments, it beat state-of-the-art methods on standard databases with only a handful of labeled examples. PMID- 24808084 TI - Vehicle teleoperation using 3D maps and GPS time synchronization. AB - In conventional vehicle teleoperation systems, using low-bandwidth, high-delay transmission links causes a serious problem for remote control of the vehicles. To solve this problem, a proposed teleoperation system employs 3D maps and GPS time synchronization. Two GPS receivers measure the transmission delay, which the system uses to estimate the vehicle's location and orientation. Field experiments show that the 3D-map-based interface lets users easily comprehend the remote environment while navigating a vehicle. The experiments also show that taking communication delays into account improves maneuverability. PMID- 24808083 TI - Optimal-scaling-factor assignment for patch-wise image retargeting. AB - Image retargeting adjusts images to arbitrary sizes such that they can be viewed on different displays. Content-aware image retargeting has been receiving increased attention. In particular, researchers have improved a patch-wise scaling method for image retargeting at the object level. The scaling partitions the image into rectangular patches of adaptive sizes, which are comparable to the sizes of the salient objects in the image. This partitioning is based on a visual saliency map; accordingly, the method labels the patches as important or unimportant. Then, the method scales the important patches as uniformly as possible and stretches or squeezes the unimportant patches to fit the target size. A patch-based image-similarity measure finds the optimal set of scaling factors. In experiments, the improved method performed well for three image types: lines and edges, foreground objects, and geometric structures. PMID- 24808085 TI - When work becomes bliss. PMID- 24808087 TI - Bold, italic, emphatic-possibilities for interactive type. PMID- 24808086 TI - Exploring visualization theory. PMID- 24808088 TI - Can computers master the art of communication? A focus on visual analytics. PMID- 24808089 TI - How the Ocean personality model affects the perception of crowds. AB - This approach extends the HiDAC (High-Density Autonomous Crowds) system by providing each agent with a personality model based on the Ocean (openness, conscientiousness, extroversion, agreeableness, and neuroticism) personality model. Each personality trait has an associated nominal behavior. Specifying an agent's personality leads to an automation of low-level parameter tuning. PMID- 24808090 TI - Bringing sketch recognition into your hands. AB - The paper mentions that a flexible method of sketch recognition works consistently across a variety of software and hardware platforms, including mobile devices such as the Nintendo DS and iPhone. An example application employs this method to drive facial expressions. PMID- 24808091 TI - Combining building and behavior models for evacuation planning. AB - To help users find optimal rescue and evacuation routes, this approach uses the extended hierarchical node relation model (EHI-NRM) to represent a building's internal structure. The approach also employs the improved cellular-automata model (ICA) to consider route-choice behavior, such as spatial reasoning and communication among evacuees. PMID- 24808092 TI - Real-time camera pose estimation for wide-area augmented reality applications. AB - Achieving accurate registration between real and synthetic worlds is one of augmented reality's biggest challenges. A real-time camera-pose estimation method, based on multiple maps and local bundle adjustment, enables the registration to work without prior knowledge of natural scenes. This method can significantly enhance AR systems' usability. PMID- 24808093 TI - Natural character posing from a large motion database. AB - An interactive inverse kinematics approach robustly generates natural poses in a large human-reachable space. It employs adaptive kd clustering to select a representative frame set from a large motion database and employs sparse approximation to accelerate training and posing. Model training is required only once. PMID- 24808095 TI - Practical game design and development pedagogy. PMID- 24808094 TI - How to read a visualization research paper: extracting the essentials. PMID- 24808096 TI - Affecticon: emotion-based icons for music retrieval. PMID- 24808097 TI - Advanced graphics technology. PMID- 24808098 TI - The Arabidopsis ZINC FINGER PROTEIN3 Interferes with Abscisic Acid and Light Signaling in Seed Germination and Plant Development. AB - Seed germination is controlled by environmental signals, including light and endogenous phytohormones. Abscisic acid (ABA) inhibits, whereas gibberellin promotes, germination and early seedling development, respectively. Here, we report that ZFP3, a nuclear C2H2 zinc finger protein, acts as a negative regulator of ABA suppression of seed germination in Arabidopsis (Arabidopsis thaliana). Accordingly, regulated overexpression of ZFP3 and the closely related ZFP1, ZFP4, ZFP6, and ZFP7 zinc finger factors confers ABA insensitivity to seed germination, while the zfp3 zfp4 double mutant displays enhanced ABA susceptibility. Reduced expression of several ABA-induced genes, such as RESPONSIVE TO ABSCISIC ACID18 and transcription factor ABSCISIC ACID-INSENSITIVE4 (ABI4), in ZFP3 overexpression seedlings suggests that ZFP3 negatively regulates ABA signaling. Analysis of ZFP3 overexpression plants revealed multiple phenotypic alterations, such as semidwarf growth habit, defects in fertility, and enhanced sensitivity of hypocotyl elongation to red but not to far-red or blue light. Analysis of genetic interactions with phytochrome and abi mutants indicates that ZFP3 enhances red light signaling by photoreceptors other than phytochrome A and additively increases ABA insensitivity conferred by the abi2, abi4, and abi5 mutations. These data support the conclusion that ZFP3 and the related ZFP subfamily of zinc finger factors regulate light and ABA responses during germination and early seedling development. PMID- 24808099 TI - CYTOKININ OXIDASE/DEHYDROGENASE4 Integrates Cytokinin and Auxin Signaling to Control Rice Crown Root Formation. AB - Crown roots constitute the majority of the rice (Oryza sativa) root system and play an important role in rice growth and development. However, the molecular mechanism of crown root formation in rice is not well understood. Here, we characterized a rice dominant mutant, root enhancer1 (ren1-D), which was observed to exhibit a more robust root system, increased crown root number, and reduced plant height. Molecular and genetic analyses revealed that these phenotypes are caused by the activation of a cytokinin oxidase/dehydrogenase (CKX) family gene, OsCKX4. Subcellular localization demonstrated that OsCKX4 is a cytosolic isoform of CKX. OsCKX4 is predominantly expressed in leaf blades and roots. It is the dominant CKX, preferentially expressed in the shoot base where crown root primordia are produced, underlining its role in root initiation. OsCKX4 is induced by exogenous auxin and cytokinin in the roots. Furthermore, one-hybrid assays revealed that OsCKX4 is a direct binding target of both the auxin response factor OsARF25 and the cytokinin response regulators OsRR2 and OsRR3. Overexpression and RNA interference of OsCKX4 confirmed that OsCKX4 plays a positive role in crown root formation. Moreover, expression analysis revealed a significant alteration in the expression of auxin-related genes in the ren1-D mutants, indicating that the OsCKX4 mediates crown root development by integrating the interaction between cytokinin and auxin. Transgenic plants harboring OsCKX4 under the control of the root-specific promoter RCc3 displayed enhanced root development without affecting their shoot parts, suggesting that this strategy could be a powerful tool in rice root engineering. PMID- 24808100 TI - Strigolactone Hormones and Their Stereoisomers Signal through Two Related Receptor Proteins to Induce Different Physiological Responses in Arabidopsis. AB - Two alpha/beta-fold hydrolases, KARRIKIN INSENSITIVE2 (KAI2) and Arabidopsis thaliana DWARF14 (AtD14), are necessary for responses to karrikins (KARs) and strigolactones (SLs) in Arabidopsis (Arabidopsis thaliana). Although KAI2 mediates responses to KARs and some SL analogs, AtD14 mediates SL but not KAR responses. To further determine the specificity of these proteins, we assessed the ability of naturally occurring deoxystrigolactones to inhibit Arabidopsis hypocotyl elongation, regulate seedling gene expression, suppress outgrowth of secondary inflorescences, and promote seed germination. Neither 5-deoxystrigol nor 4-deoxyorobanchol was active in KAI2-dependent seed germination or hypocotyl elongation, but both were active in AtD14-dependent hypocotyl elongation and secondary shoot growth. However, the nonnatural enantiomer of 5-deoxystrigol was active through KAI2 in growth and gene expression assays. We found that the four stereoisomers of the SL analog GR24 had similar activities to their deoxystrigolactone counterparts. The results suggest that AtD14 and KAI2 exhibit selectivity to the butenolide D ring in the 2'R and 2'S configurations, respectively. However, we found, for nitrile-debranone (CN-debranone, a simple SL analog), that the 2'R configuration is inactive but that the 2'S configuration is active through both AtD14 and KAI2. Our results support the conclusion that KAI2 dependent signaling does not respond to canonical SLs. Furthermore, racemic mixtures of chemically synthesized SLs and their analogs, such as GR24, should be used with caution because they can activate responses that are not specific to naturally occurring SLs. In contrast, the use of specific stereoisomers might provide valuable information about the specific perception systems operating in different plant tissues, parasitic weed seeds, and arbuscular mycorrhizae. PMID- 24808101 TI - Phosphoproteomic Analyses Reveal Early Signaling Events in the Osmotic Stress Response. AB - Elucidating how plants sense and respond to water loss is important for identifying genetic and chemical interventions that may help sustain crop yields in water-limiting environments. Currently, the molecular mechanisms involved in the initial perception and response to dehydration are not well understood. Modern mass spectrometric methods for quantifying changes in the phosphoproteome provide an opportunity to identify key phosphorylation events involved in this process. Here, we have used both untargeted and targeted isotope-assisted mass spectrometric methods of phosphopeptide quantitation to characterize proteins in Arabidopsis (Arabidopsis thaliana) whose degree of phosphorylation is rapidly altered by hyperosmotic treatment. Thus, protein phosphorylation events responsive to 5 min of 0.3 m mannitol treatment were first identified using 15N metabolic labeling and untargeted mass spectrometry with a high-resolution ion trap instrument. The results from these discovery experiments were then validated using targeted Selected Reaction Monitoring mass spectrometry with a triple quadrupole. Targeted Selected Reaction Monitoring experiments were conducted with plants treated under nine different environmental perturbations to determine whether the phosphorylation changes were specific for osmosignaling or involved cross talk with other signaling pathways. The results indicate that regulatory proteins such as members of the mitogen-activated protein kinase family are specifically phosphorylated in response to osmotic stress. Proteins involved in 5' messenger RNA decapping and phosphatidylinositol 3,5-bisphosphate synthesis were also identified as targets of dehydration-induced phosphoregulation. The results of these experiments demonstrate the utility of targeted phosphoproteomic analysis in understanding protein regulation networks and provide new insight into cellular processes involved in the osmotic stress response. PMID- 24808102 TI - Bottom-up Metabolic Reconstruction of Arabidopsis and Its Application to Determining the Metabolic Costs of Enzyme Production. AB - Large-scale modeling of plant metabolism provides the possibility to compare and contrast different cellular and environmental scenarios with the ultimate aim of identifying the components underlying the respective plant behavior. The existing models of Arabidopsis (Arabidopsis thaliana) are top-down assembled, whereby the starting point is the annotated genome, in particular, the metabolic genes. Hence, dead-end metabolites and blocked reactions can arise that are subsequently addressed by using gap-filling algorithms in combination with species-unspecific genes. Here, we present a bottom-up-assembled, large-scale model that relies solely on Arabidopsis-specific annotations and results in the inclusion of only manually curated reactions. While the existing models are largely condition unspecific by employing a single biomass reaction, we provide three biomass compositions that pertain to realistic and frequently examined scenarios: carbon limiting, nitrogen-limiting, and optimal growth conditions. The comparative analysis indicates that the proposed Arabidopsis core model exhibits comparable efficiency in carbon utilization and flexibility to the existing network alternatives. Moreover, the model is utilized to quantify the energy demand of amino acid and enzyme de novo synthesis in photoautotrophic growth conditions. Illustrated by the case of the most abundant protein in the world, Rubisco, we determine its synthesis cost in terms of ATP requirements. This, in turn, allows us to explore the tradeoff between protein synthesis and growth in Arabidopsis. Altogether, the model provides a solid basis for completely species-specific integration of high-throughput data, such as gene expression levels, and for condition-specific investigations of in silico metabolic engineering strategies. PMID- 24808103 TI - SALT-OVERLY SENSITIVE5 Mediates Arabidopsis Seed Coat Mucilage Adherence and Organization through Pectins. AB - Interactions between cell wall polymers are critical for establishing cell wall integrity and cell-cell adhesion. Here, we exploit the Arabidopsis (Arabidopsis thaliana) seed coat mucilage system to examine cell wall polymer interactions. On hydration, seeds release an adherent mucilage layer strongly attached to the seed in addition to a nonadherent layer that can be removed by gentle agitation. Rhamnogalacturonan I (RG I) is the primary component of adherent mucilage, with homogalacturonan, cellulose, and xyloglucan constituting minor components. Adherent mucilage contains rays composed of cellulose and pectin that extend above the center of each epidermal cell. CELLULOSE SYNTHASE5 (CESA5) and the arabinogalactan protein SALT-OVERLY SENSITIVE5 (SOS5) are required for mucilage adherence through unknown mechanisms. SOS5 has been suggested to mediate adherence by influencing cellulose biosynthesis. We, therefore, investigated the relationship between SOS5 and CESA5. cesa5-1 seeds show reduced cellulose, RG I, and ray size in adherent mucilage. In contrast, sos5-2 seeds have wild-type levels of cellulose but completely lack adherent RG I and rays. Thus, relative to each other, cesa5-1 has a greater effect on cellulose, whereas sos5-2 mainly affects pectin. The double mutant cesa5-1 sos5-2 has a much more severe loss of mucilage adherence, suggesting that SOS5 and CESA5 function independently. Double mutant analyses with mutations in MUCILAGE MODIFIED2 and FLYING SAUCER1 that reduce mucilage release through pectin modification suggest that only SOS5 influences pectin-mediated adherence. Together, these findings suggest that SOS5 mediates adherence through pectins and does so independently of but in concert with cellulose synthesized by CESA5. PMID- 24808105 TI - A panoply of information for the practice of family medicine. AB - The majority of articles in this issue report on clinical conditions, adding to our knowledge base with which we practice family medicine. Topics range from childhood obesity to tobacco abuse treatment for patients with psychiatric disorders. We also have clinical papers on testing for group A streptococcus pharyngitis, incidentalomas identified in chest computed tomography exams, and a case of migraines associated with an ovarian teratoma. Others include long-term use of opioids (with information that could be surprising), and hand washing and face touching in the office. Enjoy the panoply of clinical information! We also have useful information on implementing medication reconciliation, 3 articles that relate to the integration of behavioral health into family medicine, and another 2 articles about recertification. PMID- 24808104 TI - The Plant Membrane-Associated REMORIN1.3 Accumulates in Discrete Perihaustorial Domains and Enhances Susceptibility to Phytophthora infestans. AB - Filamentous pathogens such as the oomycete Phytophthora infestans infect plants by developing specialized structures termed haustoria inside the host cells. Haustoria are thought to enable the secretion of effector proteins into the plant cells. Haustorium biogenesis, therefore, is critical for pathogen accommodation in the host tissue. Haustoria are enveloped by a specialized host-derived membrane, the extrahaustorial membrane (EHM), which is distinct from the plant plasma membrane. The mechanisms underlying the biogenesis of the EHM are unknown. Remarkably, several plasma membrane-localized proteins are excluded from the EHM, but the remorin REM1.3 accumulates around P. infestans haustoria. Here, we used overexpression, colocalization with reporter proteins, and superresolution microscopy in cells infected by P. infestans to reveal discrete EHM domains labeled by REM1.3 and the P. infestans effector AVRblb2. Moreover, SYNAPTOTAGMIN1, another previously identified perihaustorial protein, localized to subdomains that are mainly not labeled by REM1.3 and AVRblb2. Functional characterization of REM1.3 revealed that it is a susceptibility factor that promotes infection by P. infestans. This activity, and REM1.3 recruitment to the EHM, require the REM1.3 membrane-binding domain. Our results implicate REM1.3 membrane microdomains in plant susceptibility to an oomycete pathogen. PMID- 24808106 TI - Content usage and the most frequently read articles by issue in 2013. PMID- 24808107 TI - Patient-centered medical home (PCMH) recognition: a time for promoting innovation, not measuring standards. PMID- 24808108 TI - National Committee for Quality Assurance (NCQA) patient-centered medical home (PCMH) recognition is suboptimal even among innovative primary care practices. AB - The National Committee for Quality Assurance (NCQA) has promoted patient-centered medical home (PCMH) recognition among primary care practices since 2008 as a standard indicator of which practices have transformed into medical homes. A 40% PCMH adoption rate among a large national cohort of identified practices with innovative staffing (n = 131) calls into question whether the NCQA recognition process is truly transformative and patient-centered or simply another certificate to hang on the wall. PMID- 24808109 TI - Incidental computer tomography radiologic findings through research participation in the North Texas Healthy Heart Study. AB - BACKGROUND: Although variation exists in the classification and practice of managing clinical findings in research, emerging views suggest that researchers bear some responsibility in the management of incidental findings. This study contributes to the documentation of the population characteristics and prevalence of medical findings incidental to research participation, specifically findings related to coronary calcium scores and computed tomography (CT) scans that investigated cardiovascular disparities in an asymptomatic population. METHODS: A total of 571 asymptomatic adult participants were recruited in the North Texas Healthy Heart Study. Participants completed a 16-slice CT scan of the heart and abdomen. Findings of radiology reports and 3 years of follow-up documentation were reviewed. RESULTS: A total of 246 clinically apparent findings were identified in 169 asymptomatic participants (32.9% of participants who completed a CT scan). Another 245 participants (48%) had findings of unknown significance, a total of 307 findings. At least 4 cases in this study led to a clinically significant intervention. CONCLUSION: Although CT scans were completed for research purposes, study procedures resulted in the diagnosis and treatment of individuals who were previously asymptomatic. Potential clinical benefits in imaging research are moderated by considerations regarding possible harm and costs resulting from uncertain findings and the use of CT scans for nonclinical purposes. The continued development of protocols for the handling of incidental findings in research and the establishment of guidelines are needed to ensure that research procedures mirror the best interests of participants. PMID- 24808110 TI - An intensive family intervention clinic for reducing childhood obesity. AB - BACKGROUND: Childhood and adolescent obesity constitute a significant public health concern. Family health care settings with multidisciplinary teams provide an opportunity for weight loss treatment. The objective of this study was to examine the effect of intensive treatment designed to reduce weight using a parent-child lifestyle modification intervention in a family health care clinic for obese and overweight children who had failed previous treatment attempts. METHODS: This was a practice-based 6-month intervention at Maccabi Health Care Services, an Israeli health maintenance organization, consisting of parental education, individual child consultation, and physical activity classes. We included in the intervention 100 obese or overweight children aged 5 to 14 years and their parents and 943 comparison children and their parents. Changes in body mass index z-scores, adjusted for socioeconomic status, were analyzed, with a follow-up at 14 months and a delayed follow-up at an average of 46.7 months. RESULTS: The mean z-score after the intervention was lower in the intervention group compared to the comparison group (1.74 and 1.95, respectively; P = .019). The intervention group sustained the reduction in z-score after an average of 46.7 months (P < .001). Of the overweight or obese children, 13% became normal weight after the intervention, compared with 4% of the comparison children. CONCLUSION: This multidisciplinary team treatment of children and their parents in family health care clinics positively affected measures of childhood obesity. Additional randomized trials are required to verify these findings. PMID- 24808111 TI - Risk of adverse health outcomes with increasing duration and regularity of opioid therapy. AB - PURPOSE: The purpose of this study was to examine trends in frequency and daily dosage of opioid use and related adverse health outcomes in a commercially insured population. METHODS: We examined medical claims from the Truven Health MarketScan commercial claims database for 789,457 continuously enrolled patients ages 18 to 64 years to whom opioids were dispensed during the first half of 2008. We tracked them every 6 months until either opioid use was discontinued or the end of 2010. We compared outcomes among all opioid users with those for patients who used opioids with only limited interruptions during the index period, referred to as "daily users." We contrasted the experience of daily users, other users, and nonusers for various outcomes. RESULTS: Of all claimants, 10.7% had at least one opioid prescription during the first 6 months of 2008. Of these, 39.9% continued through a second 6-month period, and 18.0% continued through the end of 2010. Only 9.0% of all users qualified as daily users, but 87.1% of them continued some use of opioids through the end of 2010. Only 43.8% of all users who continued use through 2010 initially qualified as daily users. Among all users who continued use through 2010, days of use and daily dosage increased with duration of use. Among daily users, only dosage increased, rising from 101 to 114 morphine milligram equivalents/day over the 3 years. The prevalence of benzodiazepine use was greater for daily than all users, exceeding 40% among daily users who continued opioid use for 3 years. Drug abuse and overdose rates increased with longer use. Daily users accounted for 25.0%, other users for 43.6%, and nonusers for 31.4% of opioid analgesic overdoses. CONCLUSIONS: Adverse health outcomes can increase with accumulating opioid use and increasing dosage. Existing guidelines developed by specialty societies for managing patients using opioids daily or nearly daily do not address the larger number of patients who use opioids intermittently over periods of years. Practitioners should consider applying such guidelines to patients who use opioids less frequently. PMID- 24808112 TI - Hand hygiene and face touching in family medicine offices: a Cincinnati Area Research and Improvement Group (CARInG) network study. AB - BACKGROUND: Family medicine offices may play an important role in the transmission of common illnesses such as upper respiratory tract infections (URTIs). There has, however, been little study of whether physicians teach patients about URTI transmission and what their own actions are to prevent infection. The purpose of this study was to assess the quality of hand hygiene and the frequency with which family physicians and staff touch their eyes, nose, and mouth (the T-zone) as well as physician and staff self-reported behaviors and recommendations given to patients regarding URTI prevention. METHODS: We observed family physicians and staff at 7 offices of the Cincinnati Area Research and Improvement Group (CARInG) practice-based research network for the quality of hand hygiene and number of T-zone touches. After observations, participants completed surveys about personal habits and recommendations given to patients to prevent URTIs. RESULTS: A total of 31 clinicians and 48 staff participated. They touched their T-zones a mean of 19 times in 2 hours (range, 0-105 times); clinicians did so significantly less often than staff (P < .001). We observed 123 episodes of hand washing and 288 uses of alcohol-based cleanser. Only 11 hand washings (9%) met Centers for Disease Control and Prevention criteria for effective hand washing. Alcohol cleansers were used more appropriately, with 243 (84%) meeting ideal use. Participants who were observed using better hand hygiene and who touched their T-zone less report the same personal habits and recommendations to patients as those with poorer URTI prevention hygiene. CONCLUSIONS: Clinicians and staff in family medicine offices frequently touch their T-zone and demonstrate mixed quality of hand cleansing. Participants' self rated URTI prevention behaviors were not associated with how well they actually perform hand hygiene and how often they touch their T-zone. The relationship between self-reported and observed behaviors and URTIs in family medicine office settings needs further study. PMID- 24808113 TI - A randomized controlled trial of two interventions to improve medication reconciliation. AB - OBJECTIVE: Medication errors can be caused by lack of agreement between what physicians believe patients are taking and what patients actually take. There has been little systematic research to find the best way to reconcile medication lists in primary care. The objective of this study was to assess the impact of 2 interventions on agreement between electronic medical record medication lists and what patients report actually taking. METHODS: This study was a factorial randomized trial that randomized 440 eligible patients (English-speaking, age 18 and older, taking at least 2 prescriptions) visiting 20 primary care physicians; 367 completed the study. Interventions included (1) providing patients a printed copy of their current medication list at check-in and (2) beginning the medication review with an open-ended question. Patients were randomized to receive no intervention, one or the other intervention, or both interventions. The outcome measure was agreement on all prescription and nonprescription medications, vitamins, and supplements between the list from the electronic medical record after the visit and a list based on patient report generated during a phone interview within a week of the office visit. RESULTS: Agreement rates between medication lists and patient report for the 4 study groups were: 67.4% in the no intervention group, 66.7% in the printed list only group, 58.1% in the open-ended question only group, and 75.6% in the combined intervention group. Both a printed list and beginning a medication discussion with an open ended question were required before any significant increase in agreement was observed. CONCLUSIONS: While neither intervention alone improved medication list agreement, these interventions may have value in a multistep protocol to improve the agreement of medication lists in primary care offices. Baseline agreement was much higher than expected, possibly reflecting a Hawthorne effect. PMID- 24808114 TI - Real-world implementation and outcomes of health behavior and mental health assessment. AB - BACKGROUND: Assessing patient-reported health behaviors is a critical first step in prioritizing prevention in primary care. We assessed the feasibility of point of-care behavioral health assessment in 9 diverse primary care practices, including 4 federally qualified health centers (FQHCs), 4 practice-based research network practices, and a Department of Veterans Affairs practice. METHODS: In this prospective mixed-methods study, practices were asked to integrate a standardized paper-based health behavior and mental health assessment into their workflow for >=50 patients. We used 3 data sources to examine the implementation process: (1) patient responses to the health assessment, (2) patient feedback surveys about how assessments were used during encounters, and (3) postimplementation interviews. RESULTS: Most nonurgent patients (71%) visiting the participating practices during the implementation period completed the health assessment, but reach varied by practice (range, 59% to 88%). Unhealthy diet, sedentary lifestyle, and stress were the most common patient problems, with similar frequencies observed across practices. The median number of "positive screens" per patient was similar among FQHCs (3.7 positives; standard deviation [SD], 1.8), practice-based research network practices (3.8 positives; SD, 1.9), and the Veterans Affairs clinic (4.1 positives; SD, 2.0). Primary care clinicians discussed assessment results with patients about half of the time (54%), with considerable variation between practices (range, 13% to 66%; lowest use among FQHC clinicians). Although clinicians were interested in routinely implementing assessments, many reported not feeling confident of having resources or support to address all patients' behavioral health needs. CONCLUSIONS: Primary care practices will need to revamp their patient-reported data collection processes to integrate routine health behavior assessments. Implementation support will be required if health assessments are to be actively used as part of routine primary care. PMID- 24808115 TI - Primary care, behavioral health, provider colocation, and rurality. AB - PURPOSE: The purpose of this study was to characterize the proximity of primary care and behavioral health service delivery sites in the United States and factors influencing their colocation. METHODS: We geocoded the practice addresses of primary care and behavioral health providers found in the Centers for Medicare & Medicaid Services' National Plan and Provider Enumeration System Downloadable File to report where colocation is occurring throughout the country. RESULTS: The extent to which primary care physicians are colocated with behavioral health providers is strongly associated with rurality. Specifically, 40.2% of primary care physicians in urban areas are colocated with behavioral health providers compared with 22.8% in isolated rural areas and 26.5% in frontier areas. However, when controlling for number of primary care physicians at a location, the odds of colocation actually are greater for physicians in a frontier area than those in urban areas (odds ratio, 1.289; P < .01). CONCLUSIONS: Our findings offer new insights into the overlap of the behavioral health and primary care workforce, where opportunities for integration may be limited because of practice size and the proximity of providers, and where new possibilities for integration exist. PMID- 24808116 TI - Provider perspectives on integrating primary and behavioral health: a report from the High Plains Research Network. AB - BACKGROUND: Integrated primary care, a health care delivery model that combines medical and behavioral health services, provides better patient access to care at a lower cost, with better outcomes compared with usual nonintegrated care models. The perspectives of primary care providers (PCPs) and behavioral health care providers (BHPs) toward integration are especially valuable because their input and endorsement are key to successful and sustained integration. However, there is little research assessing or comparing PCP and BHP perspectives on integration, especially in rural areas. The objective of this study was to identify rural PCP and BHP perspectives on integration. METHODS: Written and electronic surveys were distributed to PCPs and BHPs in the High Plains Research Network in rural eastern Colorado. Items included perspectives on improving behavioral health care, barriers to integration, and confidence in the ability to integrate primary and behavioral care. RESULTS: Surveys were completed by 88 PCPs (60%), and 49 BHPs (63%), for an overall response rate of 61%. PCPs were significantly more likely than BHPs to prefer improving referral methods (odds ratio [OR], 2.2; P = .03) and significantly less likely to prefer colocation (OR, 0.2; P < .0001), warm hand-offs (OR, 0.3; P < .01), improved behavioral health training for PCPs (OR, 0.4; P < .01), and shared visits (OR, 0.4; P =.03) as ways to improve health care. Lack of sufficient methods of payment for behavioral health care services was the most commonly selected barrier to integration by both groups. PCPs were significantly more likely than BHPs to select recruitment (OR, 3.8; P < .001) and retention (OR, 2.7; P < .01) of behavioral health care staff as a major barrier. BHPs were slightly more optimistic than PCPs about the achievability of integration. CONCLUSIONS: Important differences of perspective exist between rural PCPs and BHPs regarding the best ways to improve behavioral health care, barriers to integration, and the achievability of integration. These differences may have important implications for rural communities and health care systems considering a transition to an integrated primary care model. PMID- 24808117 TI - Community size and organization of practice predict family physician recertification success. AB - OBJECTIVE: Health disparities exist between rural and urban areas. Rural physicians may lack sufficient medical knowledge, which may lead to poor quality of care. Therefore, we sought to determine whether medical knowledge differed between family physicians (FPs) practicing in rural areas compared with those practicing in metropolitan areas. METHODS: We studied 8361 FPs who took the American Board of Family Medicine maintenance of certification (MOC) examination in 2009. Data sources were examination results and data from a demographic survey of practice structure and activities, completed as part of the examination application process. FPs' location of practice was categorized as either rural or metropolitan using a moderate and conservative definition based on reported community size. Univariate statistics assessed differences in FP characteristics between rural and metropolitan areas. Logistic regression analyses determined the adjusted relationship between rural status and the odds of passing the MOC examination. RESULTS: Metropolitan FPs were less likely than their rural counterparts to pass the MOC examination using both the moderate (odds ratio, 0.67; 95% confidence interval, 0.54-0.83) and conservative (odds ratio, 0.56; 95% confidence interval, 0.42-0.74) definitions. Physicians in solo practice were less likely to pass the examination than physicians in group practice. CONCLUSION: Rural physicians were more likely to pass the MOC examination, suggesting that rural health disparities do not result from a lack of provider knowledge. PMID- 24808118 TI - Improving quality of care and guideline adherence for asthma through a group self assessment module. AB - BACKGROUND: The quality of care for asthma remains suboptimal. Compliance with guidelines remains low, but improved adherence to guidelines may increase the quality of care. but. We conducted a trial to determine whether group Self Assessment Module (SAM) activities led by a facilitator and conducted as part of Maintenance of Certification for Family Physicians (MC-FP) would increase knowledge of and adherence to asthma guidelines. METHODS: Participating physicians completed audits of the charts of patients with asthma before and 6 months after a group SAM. Surveys of physicians' knowledge of asthma guidelines were administered immediately before, immediately after, and 6 months after the group SAM. We tested for differences in knowledge of and adherence to guidelines before and after the SAM using chi(2) and t tests. RESULTS: Thirty-eight physicians in Virginia completed the SAM and had complete data. Participants completed more MC-FP activities than other physicians but were comparable in other characteristics. Except for prescribing controller medications for persistent asthma, all other quality measures significantly improved 6 months after the group SAM. Diagnosis by severity improved from 48.3% to 80.2%, and the use of action plans increased from 8.1% to 54.1%. Physicians' knowledge of guidelines improved immediately after the SAM and was sustained at 6 months. Increased knowledge translated into clinical skills: 30% of participants reported comfort with assessing control after the SAM, which increased to 97.5% 6 months after the SAM. CONCLUSIONS: Group SAMs may be an effective method to increase physicians' knowledge of and adherence to clinical guidelines. PMID- 24808120 TI - Advanced therapy for inflammatory bowel disease: a guide for the primary care physician. AB - Primary care physicians care for patients with inflammatory bowel disease (IBD) who are receiving advanced therapies that include immunomodulator drugs (eg, azathioprine and methotrexate) and biologic therapy. These agents have significantly improved remission rates and the quality of life for patients suffering from IBD. However, patients taking these drugs need special care and counseling with regard to adverse effects, infection risk, cancer risk, and pregnancy. Newer treatment paradigms incorporate earlier use of biologic therapy, often in combination with immunomodulator drugs, to alter the natural course of the disease. Comprehensive care for these patients, including health maintenance, requires collaboration between primary care physicians and gastroenterologists. Despite their high cost, advanced therapies are likely to be cost-effective. This article discusses general concepts about azathioprine, 6-mercaptopurine, methotrexate, and common biologic drugs used in IBD. PMID- 24808121 TI - Multisystem manifestations of benign ovarian teratomas. AB - A 26-year-old woman presented with acute onset of right-sided pelvic pain and had a medical history significant for migraine headaches and polycystic ovarian disease. Ultrasonography demonstrated bilateral ovarian tumors, and the patient underwent laparoscopic removal of bilateral cystic teratomas. A literature review focused on similar presentations of teratomas revealed isolated cases of migraines and polycystic ovarian disease associated with teratomas and an increased risk for ovarian torsion. Our patient experienced complete resolution of her acute abdominal pain, as well as her long-standing headaches and hormonal symptoms, after removal of the teratomas. PMID- 24808122 TI - Association between C-reactive protein rapid test and group A streptococcus infection in acute pharyngitis. AB - INTRODUCTION: The diagnosis of streptococcal infection is usually made with the use of Centor criteria, but some family doctors also rely on the determination of C-reactive protein (CRP) to guide antibiotic therapy. METHODS: This was an observational study conducted in a health center. Adults with acute pharyngitis and the presence of the 4 Centor criteria (tonsillar exudates, tender cervical glands, history of fever, and absence of cough) were recruited. The patients underwent a pharyngotonsillar swab for microbiologic study and a CRP rapid test during the consultation. RESULTS: A total of 149 patients were enrolled. The most frequent etiology was group A streptococcus, present in 83 cases (55.7%). The highest CRP concentration was observed among patients with group C streptococcus infection, with a mean of 56.3 mg/L (95% confidence interval, 25.7-86.5 mg/L). For patients with group A streptococcus infection, the mean CRP value was 34.4 (95% confidence interval, 25.6-43.3 mg/L). CONCLUSION: CRP concentrations are not associated with group A streptococcus infection in patients with acute pharyngitis. The use of this point of care test is therefore not useful for distinguishing patients who require antibiotic therapy. PMID- 24808119 TI - Tobacco use treatment in primary care patients with psychiatric illness. AB - The prevalence of smoking is higher in patients with psychiatric illness compared with the general population. Smoking causes chronic illnesses, which lead to premature mortality in those with psychiatric illness, is associated with greater burden of psychiatric symptoms, and contributes to the social isolation experienced by individuals with psychiatric disorders. Most patients with a psychiatric illness present initially to primary care rather than specialty care settings, and some patients receive care exclusively in the primary care setting. Therefore, family physicians and other primary care clinicians have an important role in the recognition and treatment of tobacco use disorders in patients with psychiatric illnesses. In this article we review common myths associated with smoking and psychiatric illness, techniques for implementing evidence-based tobacco use treatments, the evidence base for tobacco use treatment for patients with specific psychiatric diagnoses, and factors to consider when treating tobacco use disorders in patients with psychiatric illness. PMID- 24808124 TI - From code to art. AB - This issue's article examines the digital artwork of Siebren Versteeg, whose proprietary code emulates characteristics of analog abstract paintings. PMID- 24808123 TI - Use of ovulation predictor kits as adjuncts when using fertility awareness methods (FAMs): a pilot study. AB - PURPOSE: Difficult clinical signs such as confusing cervical mucus or erratic basal body temperature can make the use of fertility awareness methods (FAMs) difficult in some cases. The goal of this study was to assess the feasibility of using a cheap urinary luteinizing hormone (LH)-surge identification kit as an adjunct to identify the infertile phase after ovulation when facing these scenarios. METHODS: The study used a block-allocation, crossover, 2-arm methodology (LH kit/FAM vs FAM only). Comparison of the 2 arms was done with regard to the accuracy of identification (yes/no) of the luteal phase in each cycle as confirmed by serum progesterone concentrations. RESULTS: We recruited 23 Canadian women currently using FAM, aged 18 to 48 years, who have had menstrual cycles 25 to 35 days long for the past 3 months and perceive themselves to have difficulty with identifying the infertile phase after ovulation. LH kits identified 100% of the luteal phases, whereas FAM indentified 87% (statistically significant). In those identified cycles, LH kits provided a mean of 10.3 days of infertility, and FAM only provided 10 days of infertility (not statistically significant). CONCLUSIONS: Among this population, LH kits may offer an adjunct for women who may wish to have an additional double-check. However, there are still clinical circumstances when even an LH kit does not provide confirmation. More research in this area is encouraged. PMID- 24808125 TI - Animatronics Workshop: a theater + engineering collaboration at a high school. AB - The Animatronics Workshop is a learning experience in which kids conceive and construct a robotic show. They write the story, build the robotic mechanisms and the set, perform voice acting, and create the motion tracks. This provides a deep cross-disciplinary experience, teaching participants how to think creatively across traditional areas of expertise. In an intensive three-day prototype workshop in summer 2013, 14 high school students created a three-character show. PMID- 24808126 TI - Spatial interaction in a multiuser immersive instrument. AB - The AlloSphere provides multiuser spatial interaction through a curved surround screen and surround sound. Two projects illustrate how researchers employed the AlloSphere to investigate the combined use of personal-device displays and the shared display. Another two projects combined multiuser interaction with multiagent systems. These projects point to directions for future ensemble-style collaborative interaction. PMID- 24808127 TI - Beautiful math--aesthetic patterns based on logarithmic spirals. AB - A simple, fast method generates various visually appealing spiral patterns. The method is based on the concept that spiral patterns comprise a symmetry group of tilings. It employs invariant mappings and a dynamical system to create seamless colored patterns. PMID- 24808128 TI - Design-to-fabricate: maker hardware requires maker software. AB - As a result of consumer-level 3D printers' increasing availability and affordability, the audience for 3D-design tools has grown considerably. However, current tools are ill-suited for these users. They have steep learning curves and don't take into account that the end goal is a physical object, not a digital model. A new class of "maker"-level design tools is needed to accompany this new commodity hardware. However, recent examples of such tools achieve accessibility primarily by constraining functionality. In contrast, the meshmixer project is building tools that provide accessibility and expressive power by leveraging recent computer graphics research in geometry processing. The project members have had positive experiences with several 3D-design-to-print workshops and are exploring several design-to-fabricate problems. This article is part of a special issue on 3D printing. PMID- 24808129 TI - Fabricating 3D figurines with personalized faces. AB - We present a semi-automated system for fabricating figurines with faces that are personalised to the individual likeness of the customer. The efficacy of the system has been demonstrated by commercial deployments at Walt Disney World Resort and Star Wars Celebration VI in Orlando Florida. Although the system is semi automated, human intervention is limited to a few simple tasks to maintain the high throughput and consistent quality required for commercial application. In contrast to existing systems that fabricate custom heads that are assembled to pre-fabricated plastic bodies, our system seamlessly integrates 3D facial data with a predefined figurine body into a unique and continuous object that is fabricated as a single piece. The combination of state-of-the-art 3D capture, modelling, and printing that are the core of our system provide the flexibility to fabricate figurines whose complexity is only limited by the creativity of the designer. PMID- 24808130 TI - 3D-printing spatially varying BRDFs. AB - A new method fabricates custom surface reflectance and spatially varying bidirectional reflectance distribution functions (svBRDFs). Researchers optimize a microgeometry for a range of normal distribution functions and simulate the resulting surface's effective reflectance. Using the simulation's results, they reproduce an input svBRDF's appearance by distributing the microgeometry on the printed material's surface. This method lets people print svBRDFs on planar samples with current 3D printing technology, even with a limited set of printing materials. It extends naturally to printing svBRDFs on arbitrary shapes. PMID- 24808131 TI - Evaluating progressive-rendering algorithms in appearance design tasks. AB - Progressive rendering is becoming a popular alternative to precomputational approaches to appearance design. However, progressive algorithms create images exhibiting visual artifacts at early stages. A user study investigated these artifacts' effects on user performance in appearance design tasks. Novice and expert subjects performed lighting and material editing tasks with four algorithms: random path tracing, quasirandom path tracing, progressive photon mapping, and virtual-point-light rendering. Both the novices and experts strongly preferred path tracing to progressive photon mapping and virtual-point-light rendering. None of the participants preferred random path tracing to quasirandom path tracing or vice versa; the same situation held between progressive photon mapping and virtual-point-light rendering. The user workflow didn’t differ significantly with the four algorithms. The Web Extras include a video showing how four progressive-rendering algorithms converged (at http://youtu.be/ck Gevl1e9s), the source code used, and other supplementary materials. PMID- 24808132 TI - A video-based system for hand-driven stop-motion animation. AB - Stop-motion is a well-established animation technique but is often laborious and requires craft skills. A new video-based system can animate the vast majority of everyday objects in stop-motion style, more flexibly and intuitively. Animators can perform and capture motions continuously instead of breaking them into increments and shooting one still picture per increment. More important, the system permits direct hand manipulation without resorting to rigs, achieving more natural object control for beginners. The system's key component is two-phase keyframe-based capturing and processing, assisted by computer vision techniques. With this system, even amateurs can generate high-quality stop-motion animations. PMID- 24808133 TI - Visualization collaborations: what works and why. AB - For over 25 years, the visualization community has grown and evolved as a function of collaboration with other areas. It's now commonplace for visualization scientists to engage with other researchers in scientific teams. Commonplace, however, doesn't mean easy. Two visualization researchers' years of experience have led to a set of observations and recommendations on what works (and what doesn't) and why in visualization collaborations. These insights can help guide the visualization community as it moves forward. PMID- 24808134 TI - Evolution of the primate trypanolytic factor APOL1. AB - ApolipoproteinL1 (APOL1) protects humans and some primates against several African trypanosomes. APOL1 genetic variants strongly associated with kidney disease in African Americans have additional trypanolytic activity against Trypanosoma brucei rhodesiense, the cause of acute African sleeping sickness. We combined genetic, physiological, and biochemical studies to explore coevolution between the APOL1 gene and trypanosomes. We analyzed the APOL1 sequence in modern and archaic humans and baboons along with geographic distribution in present day Africa to understand how the kidney risk variants evolved. Then, we tested Old World monkey, human, and engineered APOL1 variants for their ability to kill human infective trypanosomes in vivo to identify the molecular mechanism whereby human trypanolytic APOL1 variants evade T. brucei rhodesiense virulence factor serum resistance-associated protein (SRA). For one APOL1 kidney risk variant, a two-residue deletion of amino acids 388 and 389 causes a shift in a single lysine residue that mimics the Old World monkey sequence, which augments trypanolytic activity by preventing SRA binding. A second human APOL1 kidney risk allele, with an amino acid substitution that also restores sequence alignment with Old World monkeys, protected against T. brucei rhodesiense due in part to reduced SRA binding. Both APOL1 risk variants induced tissue injury in murine livers, the site of transgenic gene expression. Our study shows that both genetic variants of human APOL1 that protect against T. brucei rhodesiense have recapitulated molecular signatures found in Old World monkeys and raises the possibility that APOL1 variants have broader innate immune activity that extends beyond trypanosomes. PMID- 24808135 TI - High-throughput platform for the discovery of elicitors of silent bacterial gene clusters. AB - Over the past decade, bacterial genome sequences have revealed an immense reservoir of biosynthetic gene clusters, sets of contiguous genes that have the potential to produce drugs or drug-like molecules. However, the majority of these gene clusters appear to be inactive for unknown reasons prompting terms such as "cryptic" or "silent" to describe them. Because natural products have been a major source of therapeutic molecules, methods that rationally activate these silent clusters would have a profound impact on drug discovery. Herein, a new strategy is outlined for awakening silent gene clusters using small molecule elicitors. In this method, a genetic reporter construct affords a facile read-out for activation of the silent cluster of interest, while high-throughput screening of small molecule libraries provides potential inducers. This approach was applied to two cryptic gene clusters in the pathogenic model Burkholderia thailandensis. The results not only demonstrate a prominent activation of these two clusters, but also reveal that the majority of elicitors are themselves antibiotics, most in common clinical use. Antibiotics, which kill B. thailandensis at high concentrations, act as inducers of secondary metabolism at low concentrations. One of these antibiotics, trimethoprim, served as a global activator of secondary metabolism by inducing at least five biosynthetic pathways. Further application of this strategy promises to uncover the regulatory networks that activate silent gene clusters while at the same time providing access to the vast array of cryptic molecules found in bacteria. PMID- 24808137 TI - Tracing the paths of modern humans from Africa. PMID- 24808138 TI - Smad1 transcription factor integrates BMP2 and Wnt3a signals in migrating cardiac progenitor cells. AB - In vertebrate embryos, cardiac progenitor cells (CPCs) undergo long-range migration after emerging from the primitive streak during gastrulation. Together with other mesoderm progenitors, they migrate laterally and then toward the ventral midline, where they form the heart. Signals controlling the migration of different progenitor cell populations during gastrulation are poorly understood. Several pathways are involved in the epithelial-to-mesenchymal transition and ingression of mesoderm cells through the primitive streak, including fibroblast growth factors and wingless-type family members (Wnt). Here we focus on early CPC migration and use live video microscopy in chicken embryos to demonstrate a role for bone morphogenetic protein (BMP)/SMA and MAD related (Smad) signaling. We identify an interaction of BMP and Wnt/glycogen synthase kinase 3 beta (GSK3beta) pathways via the differential phosphorylation of Smad1. Increased BMP2 activity altered migration trajectories of prospective cardiac cells and resulted in their lateral displacement and ectopic differentiation, as they failed to reach the ventral midline. Constitutively active BMP receptors or constitutively active Smad1 mimicked this phenotype, suggesting a cell autonomous response. Expression of GSK3beta, which promotes the turnover of active Smad1, rescued the BMP-induced migration phenotype. Conversely, expression of GSK3beta-resistant Smad1 resulted in aberrant CPC migration trajectories. De-repression of GSK3beta by dominant negative Wnt3a restored normal migration patterns in the presence of high BMP activity. The data indicate the convergence of BMP and Wnt pathways on Smad1 during the early migration of prospective cardiac cells. Overall, we reveal molecular mechanisms that contribute to the emerging paradigm of signaling pathway integration in embryo development. PMID- 24808141 TI - Unsupervised learning by minimal entropy encoding. AB - Following basic principles of information-theoretic learning, in this paper, we propose a novel approach to data clustering, referred to as minimal entropy encoding (MEE), which is based on a set of functions (features) projecting each input onto a minimum entropy configuration (code). Inspired by traditional parsimony principles, we seek solutions in reproducing kernel Hilbert spaces and then we prove that the encoding functions are expressed in terms of kernel expansion. In order to avoid trivial solutions, the developed features must be as different as possible by means of a soft constraint on the empirical estimation of the entropy associated with the encoding functions. This leads to an unconstrained optimization problem that can be efficiently solved by conjugate gradient. We also investigate an optimization strategy based on concave-convex algorithms. The relationships with maximum margin clustering are studied, showing that MEE overcomes some of its critical issues, such as the lack of a multiclass extension and the need to face problems with a large number of constraints. A massive evaluation on several benchmarks of the proposed approach shows improvements over state-of-the-art techniques, both in terms of accuracy and computational complexity. PMID- 24808140 TI - Phosphatases reverse p53-mediated cell cycle checkpoints. PMID- 24808142 TI - Nonparametric mixtures of gaussian processes with power-law behavior. AB - Gaussian processes (GPs) constitute one of the most important Bayesian machine learning approaches, based on a particularly effective method for placing a prior distribution over the space of regression functions. Several researchers have considered postulating mixtures of GPs as a means of dealing with nonstationary covariance functions, discontinuities, multimodality, and overlapping output signals. In existing works, mixtures of GPs are based on the introduction of a gating function defined over the space of model input variables. This way, each postulated mixture component GP is effectively restricted in a limited subset of the input space. In this paper, we follow a different approach. We consider a fully generative nonparametric Bayesian model with power-law behavior, generating GPs over the whole input space of the learned task. We provide an efficient algorithm for model inference, based on the variational Bayesian framework, and prove its efficacy using benchmark and real-world datasets. PMID- 24808139 TI - Stress-induced glucocorticoid signaling remodels neurovascular coupling through impairment of cerebrovascular inwardly rectifying K+ channel function. AB - Studies of stress effects on the brain have traditionally focused on neurons, without considering the cerebral microcirculation. Here we report that stress impairs neurovascular coupling (NVC), the process that matches neuronal activity with increased local blood flow. A stressed phenotype was induced in male rats by administering a 7-d heterotypical stress paradigm. NVC was modeled by measuring parenchymal arteriole (PA) vasodilation in response to neuronal stimulation in amygdala brain slices. After stress, vasodilation of PAs to neuronal stimulation was greatly reduced, and dilation of isolated PAs to external K(+) was diminished, suggesting a defect in smooth muscle inwardly rectifying K(+) (KIR) channel function. Consistent with these observations, stress caused a reduction in PA KIR2.1 mRNA and smooth muscle KIR current density, and blocking KIR channels significantly inhibited NVC in control, but not in stressed, slices. Delivery of corticosterone for 7 d (without stressors) or RU486 (before stressors) mimicked and abrogated NVC impairment by stress, respectively. We conclude that stress causes a glucocorticoid-mediated decrease in functional KIR channels in amygdala PA myocytes. This renders arterioles less responsive to K(+) released from astrocytic endfeet during NVC, leading to impairment of this process. Because the fidelity of NVC is essential for neuronal health, the impairment characterized here may contribute to the pathophysiology of brain disorders with a stress component. PMID- 24808143 TI - Generalization bounds of ERM-based learning processes for continuous-time Markov chains. AB - Many existing results on statistical learning theory are based on the assumption that samples are independently and identically distributed (i.i.d.). However, the assumption of i.i.d. samples is not suitable for practical application to problems in which samples are time dependent. In this paper, we are mainly concerned with the empirical risk minimization (ERM) based learning process for time-dependent samples drawn from a continuous-time Markov chain. This learning process covers many kinds of practical applications, e.g., the prediction for a time series and the estimation of channel state information. Thus, it is significant to study its theoretical properties including the generalization bound, the asymptotic convergence, and the rate of convergence. It is noteworthy that, since samples are time dependent in this learning process, the concerns of this paper cannot (at least straightforwardly) be addressed by existing methods developed under the sample i.i.d. assumption. We first develop a deviation inequality for a sequence of time-dependent samples drawn from a continuous-time Markov chain and present a symmetrization inequality for such a sequence. By using the resultant deviation inequality and symmetrization inequality, we then obtain the generalization bounds of the ERM-based learning process for time dependent samples drawn from a continuous-time Markov chain. Finally, based on the resultant generalization bounds, we analyze the asymptotic convergence and the rate of convergence of the learning process. PMID- 24808144 TI - Neural network based online simultaneous policy update algorithm for solving the HJI equation in nonlinear Hinfinity control. AB - It is well known that the nonlinear Hinfinity state feedback control problem relies on the solution of the Hamilton-Jacobi-Isaacs (HJI) equation, which is a nonlinear partial differential equation that has proven to be impossible to solve analytically. In this paper, a neural network (NN)-based online simultaneous policy update algorithm (SPUA) is developed to solve the HJI equation, in which knowledge of internal system dynamics is not required. First, we propose an online SPUA which can be viewed as a reinforcement learning technique for two players to learn their optimal actions in an unknown environment. The proposed online SPUA updates control and disturbance policies simultaneously; thus, only one iterative loop is needed. Second, the convergence of the online SPUA is established by proving that it is mathematically equivalent to Newton's method for finding a fixed point in a Banach space. Third, we develop an actor-critic structure for the implementation of the online SPUA, in which only one critic NN is needed for approximating the cost function, and a least-square method is given for estimating the NN weight parameters. Finally, simulation studies are provided to demonstrate the effectiveness of the proposed algorithm. PMID- 24808145 TI - Cost-sensitive sequences of Bregman divergences. AB - The minimization of the empirical risk based on an arbitrary Bregman divergence is known to provide posterior class probability estimates in classification problems, but the accuracy of the estimate for a given value of the true posterior depends on the specific choice of the divergence. Ad hoc Bregman divergences can be designed to get a higher estimation accuracy for the posterior probability values that are most critical for a particular cost-sensitive classification scenario. Moreover, some sequences of Bregman loss functions can be constructed in such a way that their minimization guarantees, asymptotically, minimum number of errors in nonseparable cases, and maximum margin classifiers in separable problems. In this paper, we analyze general conditions on the Bregman generator to satisfy this property, and generalize the result for cost-sensitive classification. PMID- 24808136 TI - Simultaneous assessment of the macrobiome and microbiome in a bulk sample of tropical arthropods through DNA metasystematics. AB - Conventional assessments of ecosystem sample composition are based on morphology based or DNA barcode identification of individuals. Both approaches are costly and time-consuming, especially when applied to the large number of specimens and taxa commonly included in ecological investigations. Next-generation sequencing approaches can overcome the bottleneck of individual specimen isolation and identification by simultaneously sequencing specimens of all taxa in a bulk mixture. Here we apply multiple parallel amplification primers, multiple DNA barcode markers, 454-pyrosequencing, and Illumina MiSeq sequencing to the same sample to maximize recovery of the arthropod macrobiome and the bacterial and other microbial microbiome of a bulk arthropod sample. We validate this method with a complex sample containing 1,066 morphologically distinguishable arthropods from a tropical terrestrial ecosystem with high taxonomic diversity. Multiamplicon next-generation DNA barcoding was able to recover sequences corresponding to 91% of the distinguishable individuals in a bulk environmental sample, as well as many species present as undistinguishable tissue. 454 pyrosequencing was able to recover 10 more families of arthropods and 30 more species than did conventional Sanger sequencing of each individual specimen. The use of other loci (16S and 18S ribosomal DNA gene regions) also added the detection of species of microbes associated with these terrestrial arthropods. This method greatly decreases the time and money necessary to perform DNA-based comparisons of biodiversity among ecosystem samples. This methodology opens the door to much cheaper and increased capacity for ecological and evolutionary studies applicable to a wide range of socio-economic issues, as well as a basic understanding of how the world works. PMID- 24808146 TI - Noise-tuning-based hysteretic noisy chaotic neural network for broadcast scheduling problem in wireless multihop networks. AB - Compared with noisy chaotic neural networks (NCNNs), hysteretic noisy chaotic neural networks (HNCNNs) are more likely to exhibit better optimization performance at higher noise levels, but behave worse at lower noise levels. In order to improve the optimization performance of HNCNNs, this paper presents a novel noise-tuning-based hysteretic noisy chaotic neural network (NHNCNN). Using a noise tuning factor to modulate the level of stochastic noises, the proposed NHNCNN not only balances stochastic wandering and chaotic searching, but also exhibits stronger hysteretic dynamics, thereby improving the optimization performance at both lower and higher noise levels. The aim of the broadcast scheduling problem (BSP) in wireless multihop networks (WMNs) is to design an optimal time-division multiple-access frame structure with minimal frame length and maximal channel utilization. A gradual NHNCNN (G-NHNCNN), which combines the NHNCNN with the gradual expansion scheme, is applied to solve BSP in WMNs to demonstrate the performance of the NHNCNN. Simulation results show that the proposed NHNCNN has a larger probability of finding better solutions compared to both the NCNN and the HNCNN regardless of whether noise amplitudes are lower or higher. PMID- 24808147 TI - Exponential stabilization of memristive neural networks with time delays. AB - In this paper, a general class of memristive neural networks with time delays is formulated and studied. Some sufficient conditions in terms of linear matrix inequalities are obtained, in order to achieve exponential stabilization. The result can be applied to the closed-loop control of memristive systems. In particular, several succinct criteria are given to ascertain the exponential stabilization of memristive cellular neural networks. In addition, a simplified and effective algorithm is considered for design of the optimal controller. These conditions are the improvement and extension of the existing results in the literature. Two numerical examples are given to illustrate the theoretical results via computer simulations. PMID- 24808148 TI - Descent algorithms on oblique manifold for source-adaptive ICA contrast. AB - A Riemannian manifold optimization strategy is proposed to facilitate the relaxation of the orthonormality constraint in a more natural way in the course of performing independent component analysis (ICA) that employs a mutual information-based source-adaptive contrast function. Despite the extensive development of manifold techniques catering to the orthonormality constraint, only a limited number of works have been dedicated to oblique manifold (OB) algorithms to intrinsically handle the normality constraint, which has been empirically shown to be superior to other Riemannian and Euclidean approaches. Imposing the normality constraint implicitly, in line with the ICA definition, essentially guarantees a substantial improvement in the solution accuracy, by way of increased degrees of freedom while searching for an optimal unmixing ICA matrix, in contrast with the orthonormality constraint. Designs of the steepest descent, conjugate gradient with Hager-Zhang or a hybrid update parameter, quasi Newton, and cost-effective quasi-Newton methods intended for OB are presented in this paper. Their performance is validated using natural images and systematically compared with the popular state-of-the-art approaches in order to assess the performance effects of the choice of algorithm and the use of a Riemannian rather than Euclidean framework. We surmount the computational challenge associated with the direct estimation of the source densities using the improved fast Gauss transform in the evaluation of the contrast function and its gradient. The proposed OB schemes may find applications in the offline image/signal analysis, wherein, on one hand, the computational overhead can be tolerated, and, on the other, the solution quality holds paramount interest. PMID- 24808149 TI - Sparse approximation to the eigensubspace for discrimination. AB - Two-dimensional (2-D) image-matrix-based projection methods for feature extraction are widely used in many fields of computer vision and pattern recognition. In this paper, we propose a novel framework called sparse 2-D projections (S2DP) for image feature extraction. Different from the existing 2-D feature extraction methods, S2DP iteratively learns the sparse projection matrix by using elastic net regression and singular value decomposition. Theoretical analysis shows that the optimal sparse subspace approximates the eigensubspace obtained by solving the corresponding generalized eigenequation. With the S2DP framework, many 2-D projection methods can be easily extended to sparse cases. Moreover, when each row/column of the image matrix is regarded as an independent high-dimensional vector (1-D vector), it is proven that the vector-based eigensubspace is also approximated by the sparse subspace obtained by the same method used in this paper. Theoretical analysis shows that, when compared with the vector-based sparse projection learning methods, S2DP greatly saves both computation and memory costs. This property makes S2DP more tractable for real world applications. Experiments on well-known face databases indicate the competitive performance of the proposed S2DP over some 2-D projection methods when facial expressions, lighting conditions, and time vary. PMID- 24808150 TI - Adaptive subset kernel principal component analysis for time-varying patterns. AB - Kernel principal component analysis (KPCA) and its online learning algorithms have been proposed and widely used. Since KPCA uses training samples for bases of the operator, its online learning algorithms require the preparation of all training samples beforehand. Subset KPCA (SubKPCA), which uses a subset of samples for the basis set, has been proposed and has demonstrated better performance with less computational complexity. In this paper, we extend SubKPCA to an online version and propose methods to add and exchange a sample in the basis set. Since the proposed method uses the basis set, we do not need to prepare all training samples beforehand. Therefore, the proposed method can be applied to time-varying patterns, in contrast to existing online KPCA algorithms. Experimental results demonstrate the advantages of the proposed method. PMID- 24808151 TI - Robust single-hidden layer feedforward network-based pattern classifier. AB - In this paper, a new robust single-hidden layer feedforward network (SLFN)-based pattern classifier is developed. It is shown that the frequency spectrums of the desired feature vectors can be specified in terms of the discrete Fourier transform (DFT) technique. The input weights of the SLFN are then optimized with the regularization theory such that the error between the frequency components of the desired feature vectors and the ones of the feature vectors extracted from the outputs of the hidden layer is minimized. For the linearly separable input patterns, the hidden layer of the SLFN plays the role of removing the effects of the disturbance from the noisy input data and providing the linearly separable feature vectors for the accurate classification. However, for the nonlinearly separable input patterns, the hidden layer is capable of assigning the DFTs of all feature vectors to the desired positions in the frequency-domain such that the separability of all nonlinearly separable patterns are maximized. In addition, the output weights of the SLFN are also optimally designed so that both the empirical and the structural risks are well balanced and minimized in a noisy environment. Two simulation examples are presented to show the excellent performance and effectiveness of the proposed classification scheme. PMID- 24808152 TI - Compositional generative mapping for tree-structured data--part I: bottom-up probabilistic modeling of trees. AB - We introduce a novel compositional (recursive) probabilistic model for trees that defines an approximated bottom-up generative process from the leaves to the root of a tree. The proposed model defines contextual state transitions from the joint configuration of the children to the parent nodes. We argue that the bottom-up context postulates different probabilistic assumptions with respect to a top-down approach, leading to different representational capabilities. We discuss classes of applications that are best suited to a bottom-up approach. In particular, the bottom-up context is shown to better correlate and model the co-occurrence of substructures among the child subtrees of internal nodes. A mixed memory approximation is introduced to factorize the joint children-to-parent state transition matrix as a mixture of pairwise transitions. The proposed approach is the first practical bottom-up generative model for tree-structured data that maintains the same computational class of its top-down counterpart. Comparative experimental analyses exploiting synthetic and real-world datasets show that the proposed model can deal with deep structures better than a top-down generative model. The model is also shown to better capture structural information from real world data comprising trees with a large out-degree. The proposed bottom-up model can be used as a fundamental building block for the development of other new powerful models. PMID- 24808153 TI - Real AdaBoost with gate controlled fusion. AB - In this brief, we propose to increase the capabilities of standard real AdaBoost (RAB) architectures by replacing their linear combinations with a fusion controlled by a gate with fixed kernels. Experimental results in a series of well known benchmark problems support the effectiveness of this approach in improving classification performance. Although the need for cross-validation processes obviously leads to higher training requirements and more computational effort, the operation load is never much higher; in many cases it is even lower than that of competitive RAB schemes. PMID- 24808154 TI - Collaboration-specific color-map design. PMID- 24808155 TI - Digitally interpreting traditional folk crafts. PMID- 24808156 TI - Simulating 2D gaits with a phase-indexed tracking controller. PMID- 24808157 TI - Stable proportional-derivative controllers. PMID- 24808158 TI - Practical character physics for animators. PMID- 24808159 TI - Direct control of simulated nonhuman characters. PMID- 24808160 TI - Realistic placement of plants for virtual environments. PMID- 24808162 TI - The third wave in computer graphics and interactive techniques. PMID- 24808161 TI - Intuitive interactive human-character posing with millions of example poses. PMID- 24808163 TI - Visual embedding: a model for visualization. AB - The authors propose visual embedding as a model for automatically generating and evaluating visualizations. A visual embedding is a function from data points to a space of visual primitives that measurably preserves structures in the data (domain) within the mapped perceptual space (range). The authors demonstrate its use with three examples: coloring of neural tracts, scatterplots with icons, and evaluation of alternative diffusion tensor glyphs. They discuss several techniques for generating visual-embedding functions, including probabilistic graphical models for embedding in discrete visual spaces. They also describe two complementary approaches--crowdsourcing and visual product spaces--for building visual spaces with associated perceptual--distance measures. In addition, they recommend several research directions for further developing the visual-embedding model. PMID- 24808164 TI - Investigating landfill contamination by visualizing geophysical data. AB - Geophysical experts aimed to establish a method to identify contamination by landfill leakage without chemically analyzing subsoil samples, which is time consuming and expensive. To that end, researchers developed a software package that let the experts create 3D visualizations of geophysical data acquired around the landfill and apply statistical analysis to detect anomalous values. The data used, electrical resistivity, are typically sparse. So, the application employs kriging to interpolate the data and provide a volumetric representation of the subsoil resistivity. To avoid invalid conclusions, the visualization also represents uncertainty. The application enabled the experts to better understand the phenomenon and to develop and validate their method. Their evaluation of the application indicated that it helped them throughout the method's development and significantly eased their workload. PMID- 24808165 TI - GPU-accelerated interactive visualization and planning of neurosurgical interventions. AB - Advances in computational methods and hardware platforms provide efficient processing of medical-imaging datasets for surgical planning. For neurosurgical interventions employing a straight access path, planning entails selecting a path from the scalp to the target area that's of minimal risk to the patient. A proposed GPU-accelerated method enables interactive quantitative estimation of the risk for a particular path. It exploits acceleration spatial data structures and efficient implementation of algorithms on GPUs. In evaluations of its computational efficiency and scalability, it achieved interactive rates even for high-resolution meshes. A user study and feedback from neurosurgeons identified this methods' potential benefits for preoperative planning and intraoperative replanning. PMID- 24808166 TI - Head-pose-based attention recognition on large public displays. AB - Estimating peoples' attention to regions of large public displays has been a problem since those displays' advent. Unlike with traditional interaction with a Web browser, you can't calculate a clickstream. A method for estimating where users are looking could partly overcome this issue. Researchers evaluated how several factors (head movement, individual users, the users' locations, and the amount of training data) affected the accuracy of attention recognition based on only the head pose. The results revealed three things. First, head movement in both the yaw and pitch directions insignificantly decreased the accuracy, compared to limited vertical or horizontal movement. Second, differences in accuracy of up to 16 percent suggest that you should train such systems on individual persons to achieve optimum recognition performance. Finally, calibration on multiple positions didn't significantly enhance recognition, compared to training on a single position. PMID- 24808167 TI - Visual analytics for power grid contingency analysis. AB - Contingency analysis employs different measures to model scenarios, analyze them, and then derive the best response to any threats. A proposed visual-analytics pipeline for power grid management can transform approximately 100 million contingency scenarios to a manageable size and form. Grid operators can examine individual scenarios and devise preventive or mitigation strategies in a timely manner. Power grid engineers have applied the pipeline to a Western Electricity Coordinating Council power grid model. PMID- 24808168 TI - Highly parallel algorithms for visual-perception-guided surface remeshing. AB - A proposed framework for remeshing polygonal models employs mesh-free techniques for processing surface sample points. It's robust to input models with problematic connectivity, and the geometric processing of points runs easily in parallel on a GPU. The framework extracts visual-perception information in the image space and maps it back to the Euclidean space. On the basis of these visual cues, the framework generates a saliency field to resample the input model. A new projection operator further optimizes the distribution of resampled points. Because the downsampled points control the number of vertices on the resulting model, this framework also works for model simplification. All the algorithms in the framework can be easily parallelized to run on GPUs. In experiments, the framework remeshed diverse polygonal models to well-shaped triangular meshes with high visual fidelity. PMID- 24808169 TI - A summer blender camp: modeling, rendering, and animation for high school students. AB - At Camp Blender, high-school students of varying backgrounds learned how to use the Blender software package to create computer graphics content. In a postclass survey, most of them indicated that the camp affected how they thought about their career path. PMID- 24808170 TI - Beautiful math, part 2: aesthetic patterns based on fractal tilings. AB - A fractal tiling (f-tiling) is a tiling whose boundary is fractal. This article presents two families of rare, infinitely many f-tilings. Each f-tiling is constructed by reducing tiles by a fixed scaling factor, using a single prototile, which is a segment of a regular polygon. The authors designed invariant mappings to automatically produce appealing seamless, colored patterns from such tilings. PMID- 24808171 TI - Hands in space: gesture interaction with augmented-reality interfaces. AB - Researchers at the Human Interface Technology Laboratory New Zealand (HIT Lab NZ) are investigating free-hand gestures for natural interaction with augmented reality interfaces. They've applied the results to systems for desktop computers and mobile devices. PMID- 24808172 TI - Proteolytic degradation of topoisomerase II (Top2) enables the processing of Top2.DNA and Top2.RNA covalent complexes by tyrosyl-DNA-phosphodiesterase 2 (TDP2). AB - Eukaryotic type II topoisomerases (Top2alpha and Top2beta) are homodimeric enzymes; they are essential for altering DNA topology by the formation of normally transient double strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2.DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet Top2cc can also generate recombination, translocations, and apoptosis in normal cells. The Top2 protein-DNA covalent complexes are excised (in part) by tyrosyl-DNA-phosphodiesterase 2 (TDP2/TTRAP/EAP2/VPg unlinkase). In this study, we show that irreversible Top2cc induced in suicidal substrates are not processed by TDP2 unless they first undergo proteolytic processing or denaturation. We also demonstrate that TDP2 is most efficient when the DNA attached to the tyrosyl is in a single-stranded configuration and that TDP2 can efficiently remove a tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides, which expands the TDP2 catalytic profile with RNA substrates. The 1.6-A resolution crystal structure of TDP2 bound to a substrate bearing a 5'-ribonucleotide defines a mechanism through which RNA can be accommodated in the TDP2 active site, albeit in a strained conformation. PMID- 24808173 TI - Tenascin-C-derived peptide TNIIIA2 highly enhances cell survival and platelet derived growth factor (PDGF)-dependent cell proliferation through potentiated and sustained activation of integrin alpha5beta1. AB - Tenascin-C is an adhesion modulatory matrix protein that is highly expressed in tumors; however, its biochemical activity involved in tumorigenesis is not fully understood. On the other hand, increasing evidence indicates the importance of integrin alpha5beta1 in cancer development. We previously demonstrated that tenascin-C harbors a functional site that can be released as a proadhesive peptide such as TNIIIA2. Peptide TNIIIA2 is capable of inducing activation of beta1-integrins including alpha5beta1 via syndecan-4. In this study the proadhesive effect of TNIIIA2 was characterized by potentiated and sustained activation of integrin alpha5beta1. Based on this effect, TNIIIA2 rendered nontransformed fibroblasts (NIH3T3) resistant to serum deprivation-elicited anoikis through activation of the Akt/Bcl-2 pathway. Moreover, TNIIIA2 hyperstimulated PDGF-dependent proliferation of NIH3T3 by activating integrin alpha5beta1. Tenascin-C, a parental protein of TNIIIA2, also stimulated PDGF dependent proliferation, which was blocked by a matrix metalloproteinase-2/9 inhibitor and an anti-TNIIIA2 function-blocking antibody, suggesting proteolytic exposure of the proadhesive effect of TNIIIA2. Mechanistic analyses revealed that TNIIIA2 induced a lateral association of PDGF receptor beta with the molecular complex of activated integrin alpha5beta1 and syndecan-4 in the membrane microdomains enriched with cholesterol/caveolin-1, resulting in prolonged activation of PDGF receptor beta and the subsequent Ras/mitogen-activated protein kinase pathway in a PDGF-dependent manner. Of note, TNIIIA2 induced continuous proliferation in NIH3T3 in an integrin alpha5beta1-dependent manner even after they formed a confluent monolayer. Thus, it was proposed that tenascin-C might be involved in deregulated cell growth through potentiated and sustained activation of integrin alpha5beta1 after exposure of the proadhesive effect of TNIIIA2. PMID- 24808174 TI - The formylpeptide receptor 2 (Fpr2) and its endogenous ligand cathelin-related antimicrobial peptide (CRAMP) promote dendritic cell maturation. AB - Mouse formylpeptide receptor 2 (Fpr2) is a homologue of the human G-protein coupled chemoattractant receptor FPR2, which interacts with pathogen and host derived chemotactic agonists. Our previous studies revealed reduced allergic airway inflammation and immune responses in Fpr2-deficient (Fpr2(-/-)) mice in association with diminished dendritic cell (DC) recruitment into the airway and draining lymph nodes. These defects prompted us to investigate the potential changes in the differentiation and maturation of DCs caused by Fpr2 deficiency. Bone marrow monocytes from Fpr2(-/-) mouse mice incubated with GM-CSF and IL-4 in vitro showed normal expression of markers of immature DCs. However, upon stimulation with the TLR4 agonist LPS, Fpr2(-/-) mouse DCs failed to express normal levels of maturation markers with reduced production of IL-12 and diminished chemotaxis in response to the DC homing chemokine CCL21. Fpr2(-/-) DCs also failed to induce allogeneic T-cell proliferation in vitro, and their recruitment into the T-cell zones of the spleen was reduced after antigen immunization. The capacity of Fpr2 to sustain normal DC maturation was dependent on its interaction with an endogenous ligand CRAMP expressed by DCs, because neutralization of either Fpr2 or CRAMP inhibited DC maturation in response to LPS. We additionally observed that the presence of exogenous CRAMP in culture increased the sensitivity of WT mouse DCs to LPS stimulation. The importance of CRAMP for DC maturation was further demonstrated by the observations that DCs from CRAMP(-/-) mice expressed lower levels of costimulatory molecules and MHC II and exhibited poor chemotaxis in response to CCL21 after LPS stimulation. Our observations indicate a nonredundant role for Fpr2 and its agonist CRAMP in DC maturation in immune responses. PMID- 24808175 TI - Signal recognition particle-ribosome binding is sensitive to nascent chain length. AB - The signal recognition particle (SRP) directs ribosome-nascent chain complexes (RNCs) displaying signal sequences to protein translocation channels in the plasma membrane of prokaryotes and endoplasmic reticulum of eukaryotes. It was initially proposed that SRP binds the signal sequence when it emerges from an RNC and that successful binding becomes impaired as translation extends the nascent chain, moving the signal sequence away from SRP on the ribosomal surface. Later studies drew this simple model into question, proposing that SRP binding is unaffected by nascent chain length. Here, we reinvestigate this issue using two novel and independent fluorescence resonance energy transfer assays. We show that the arrival and dissociation rates of SRP binding to RNCs vary according to nascent chain length, resulting in the highest affinity shortly after a functional signal sequence emerges from the ribosome. Moreover, we show that SRP binds RNCs in multiple and interconverting conformations, and that conversely, RNCs exist in two conformations distinguished by SRP interaction kinetics. PMID- 24808176 TI - Insight into the role of substrate-binding residues in conferring substrate specificity for the multifunctional polysaccharide lyase Smlt1473. AB - Anionic polysaccharides are of growing interest in the biotechnology industry due to their potential pharmaceutical applications in drug delivery and wound treatment. Chemical composition and polymer length strongly influence the physical and biological properties of the polysaccharide and thus its potential industrial and medical applications. One promising approach to determining monomer composition and controlling the degree of polymerization involves the use of polysaccharide lyases, which catalyze the depolymerization of anionic polysaccharides via a beta-elimination mechanism. Utilization of these enzymes for the production of custom-made oligosaccharides requires a high degree of control over substrate specificity. Previously, we characterized a polysaccharide lyase (Smlt1473) from Stenotrophomonas maltophilia k279a, which exhibited significant activity against hyaluronan (HA), poly-beta-d-glucuronic acid (poly GlcUA), and poly-beta-d-mannuronic acid (poly-ManA) in a pH-regulated manner. Here, we utilize a sequence structure guided approach based on a homology model of Smlt1473 to identify nine putative substrate-binding residues and examine their effect on substrate specificity via site-directed mutagenesis. Interestingly, single point mutations H221F and R312L resulted in increased activity and specificity toward poly-ManA and poly-GlcUA, respectively. Furthermore, a W171A mutant nearly eliminated HA activity, while increasing poly ManA and poly-GlcUA activity by at least 35%. The effect of these mutations was analyzed by comparison with the high resolution structure of Sphingomonas sp. A1 III alginate lyase in complex with poly-ManA tetrasaccharide and by taking into account the structural differences between HA, poly-GlcUA, and poly-ManA. Overall, our results demonstrate that even minor changes in active site architecture have a significant effect on the substrate specificity of Smlt1473, whose structural plasticity could be applied to the design of highly active and specific polysaccharide lyases. PMID- 24808177 TI - Structural insights into the lipoprotein outer membrane regulator of penicillin binding protein 1B. AB - In bacteria, the synthesis of the protective peptidoglycan sacculus is a dynamic process that is tightly regulated at multiple levels. Recently, the lipoprotein co-factor LpoB has been found essential for the in vivo function of the major peptidoglycan synthase PBP1b in Enterobacteriaceae. Here, we reveal the crystal structures of Salmonella enterica and Escherichia coli LpoB. The LpoB protein can be modeled as a ball and tether, consisting of a disordered N-terminal region followed by a compact globular C-terminal domain. Taken together, our structural data allow us to propose new insights into LpoB-mediated regulation of peptidoglycan synthesis. PMID- 24808178 TI - Expression of adipocyte biomarkers in a primary cell culture models reflects preweaning adipobiology. AB - A cohort of genes was selected to characterize the adipogenic phenotype in primary cell cultures from three tissue sources. We compared the quantitative expression of biomarkers in culture relative to their expression in vivo because the mere presence or absence of expression is minimally informative. Although all biomarkers analyzed have biochemical functions in adipocytes, the expression of some of the biomarkers varied enormously in culture relative to their expression in the adult fat tissues in vivo, i.e. inguinal fat for white adipocytes and brite cells, interscapular brown adipose tissue for brown adipocytes, and ear mesenchymal stem cells for white adipocytes from adult mice. We propose that the pattern of expression in vitro does not reflect gene expression in the adult mouse; rather it is predominantly the expression pattern of adipose tissue of the developing mouse between birth and weaning. The variation in gene expression among fat depots in both human and rodent has been an extensively studied phenomenon, and as recently reviewed, it is related to subphenotypes associated with immune function, the inflammatory response, fat depot blood flow, and insulin sensitivity. We suggest that adipose tissue biology in the period from birth to weaning is not just a staging platform for the emergence of adult white fat but that it has properties to serve the unique needs of energy metabolism in the newborn. A case in point is the differentiation of brite cells that occurs during this period followed by their involution immediately following weaning. PMID- 24808179 TI - Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9. AB - Annexin A2 (AnxA2) was reported to be an extracellular endogenous inhibitor of proprotein convertase subtilisin kexin type 9 (PCSK9) activity on cell-surface LDL receptor degradation. In this study, we investigated the effect of silencing the expression of AnxA2 and PCSK9 in HepG2 and Huh7 cells to better define the role of AnxA2 in PCSK9 regulation. AnxA2 knockdown in Huh7 cells significantly increased PCSK9 protein levels as opposed to AnxA2 knockdown in HepG2 cells. However, HepG2 cells overexpressing AnxA2 had lower levels of PCSK9 protein. Overall, our data revealed a plausible new role of AnxA2 in the reduction of PCSK9 protein levels via a translational mechanism. Moreover, the C-terminal Cys/His-rich domain of PCSK9 is crucial in the regulation of PCSK9 activity, and we demonstrated by far-Western blot assay that the M1 and M2 domains are necessary for the specific interaction of PCSK9's C-terminal Cys/His-rich domain and AnxA2. Finally, we produced and purified recombinant PCSK9 from humans and mice, which was characterized and used to perform 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate LDL cell-based assays on the stable knockdown HepG2 and Huh7 cells. We also demonstrated for the first time the equipotency of human and mouse PCSK9 R218S on human cells. PMID- 24808180 TI - Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein. AB - Progressive accumulation of the amyloid beta protein in extracellular plaques is a neuropathological hallmark of Alzheimer disease. Amyloid beta is generated during sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. In addition to the proteolytic processing by secretases, APP is also metabolized by lysosomal proteases. Here, we show that accumulation of intracellular sphingosine-1-phosphate (S1P) impairs the metabolism of APP. Cells lacking functional S1P-lyase, which degrades intracellular S1P, strongly accumulate full-length APP and its potentially amyloidogenic C-terminal fragments (CTFs) as compared with cells expressing the functional enzyme. By cell biological and biochemical methods, we demonstrate that intracellular inhibition of S1P-lyase impairs the degradation of APP and CTFs in lysosomal compartments and also decreases the activity of gamma-secretase. Interestingly, the strong accumulation of APP and CTFs in S1P-lyase-deficient cells was reversed by selective mobilization of Ca(2+) from the endoplasmic reticulum or lysosomes. Intracellular accumulation of S1P also impairs maturation of cathepsin D and degradation of Lamp-2, indicating a general impairment of lysosomal activity. Together, these data demonstrate that S1P-lyase plays a critical role in the regulation of lysosomal activity and the metabolism of APP. PMID- 24808181 TI - Na+ interactions with the neutral amino acid transporter ASCT1. AB - The alanine, serine, cysteine transporters (ASCTs) belong to the solute carrier family 1A (SLC1A), which also includes the excitatory amino acid transporters (EAATs) and the prokaryotic aspartate transporter GltPh. Acidic amino acid transport by the EAATs is coupled to the co-transport of three Na(+) ions and one proton, and the counter-transport of one K(+) ion. In contrast, neutral amino acid exchange by the ASCTs does not require protons or the counter-transport of K(+) ions and the number of Na(+) ions required is not well established. One property common to SLC1A family members is a substrate-activated anion conductance. We have investigated the number and location of Na(+) ions required by ASCT1 by mutating residues in ASCT1 that correspond to residues in the EAATs and GltPh that are involved in Na(+) binding. Mutations to all three proposed Na(+) sites influence the binding of substrate and/or Na(+), or the rate of substrate exchange. A G422S mutation near the Na2 site reduced Na(+) affinity, without affecting the rate of exchange. D467T and D467A mutations in the Na1 site reduce Na(+) and substrate affinity and also the rate of substrate exchange. T124A and D380A mutations in the Na3 site selectively reduce the affinity for Na(+) and the rate of substrate exchange without affecting substrate affinity. In many of the mutants that reduce the rate of substrate transport the amplitudes of the substrate-activated anion conductances are not substantially affected indicating altered ion dependence for channel activation compared with substrate exchange. PMID- 24808183 TI - A chemical biology approach demonstrates G protein betagamma subunits are sufficient to mediate directional neutrophil chemotaxis. AB - Our laboratory has identified a number of small molecules that bind to G protein betagamma subunits (Gbetagamma) by competing for peptide binding to the Gbetagamma "hot spot." M119/Gallein were identified as inhibitors of Gbetagamma subunit signaling. Here we examine the activity of another molecule identified in this screen, 12155, which we show that in contrast to M119/Gallein had no effect on Gbetagamma-mediated phospholipase C or phosphoinositide 3-kinase (PI3K) gamma activation in vitro. Also in direct contrast to M119/Gallein, 12155 caused receptor-independent Ca(2+) release, and activated other downstream targets of Gbetagamma including extracellular signal regulated kinase (ERK), protein kinase B (Akt) in HL60 cells differentiated to neutrophils. We show that 12155 releases Gbetagamma in vitro from Galphai1beta1gamma2 heterotrimers by causing its dissociation from GalphaGDP without inducing nucleotide exchange in the Galpha subunit. We used this novel probe to examine the hypothesis that Gbetagamma release is sufficient to direct chemotaxis of neutrophils in the absence of receptor or G protein alpha subunit activation. 12155 directed chemotaxis of HL60 cells and primary neutrophils in a transwell migration assay with responses similar to those seen for the natural chemotactic peptide n-formyl-Met-Leu-Phe. These data indicate that release of free Gbetagamma is sufficient to drive directional chemotaxis in a G protein-coupled receptor signaling-independent manner. PMID- 24808182 TI - Lipocalin-2 protein deficiency ameliorates experimental autoimmune encephalomyelitis: the pathogenic role of lipocalin-2 in the central nervous system and peripheral lymphoid tissues. AB - Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system. The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE) and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild type animals. Myelin oligodendrocyte glycoprotein-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of proinflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis. PMID- 24808184 TI - Targeting the transient receptor potential vanilloid type 1 (TRPV1) assembly domain attenuates inflammation-induced hypersensitivity. AB - The transient receptor potential channel vanilloid type 1 (TRPV1) is a non selective cation channel expressed in sensory neurons of the dorsal root and trigeminal ganglia. TRPV1 is a polymodal channel activated by noxious heat, capsaicin, and protons. As a sensor for noxious stimuli, TRPV1 channel has been described as a key contributor to pain signaling. To form a functional channel, TRPV1 subunits must assemble into tetramers, and several studies have identified the TRPV1 C terminus as an essential element in subunit association. Here we combined biochemical assays with electrophysiology and imaging-based bimolecular fluorescence complementation (BiFC) and bioluminescence resonance energy transfer (BRET) in live cells to identify a short motif in the C-terminal tail of the TRPV1 subunit that governs channel assembly. Removing this region through early truncation or targeted deletion results in loss of subunit association and channel function. Importantly, we found that interfering with TRPV1 subunit association using a plasma membrane-tethered peptide attenuated mechanical and thermal hypersensitivity in two mouse models of inflammatory hyperalgesia. This represents a novel mechanism to disrupt TRPV1 subunit assembly and hence may offer a new analgesic tool for pain relief. PMID- 24808186 TI - The power of tutorials. PMID- 24808185 TI - Determinants of substrate and cation transport in the human Na+/dicarboxylate cotransporter NaDC3. AB - Metabolic intermediates, such as succinate and citrate, regulate important processes ranging from energy metabolism to fatty acid synthesis. Cytosolic concentrations of these metabolites are controlled, in part, by members of the SLC13 gene family. The molecular mechanism underlying Na(+)-coupled di- and tricarboxylate transport by this family is understood poorly. The human Na(+)/dicarboxylate cotransporter NaDC3 (SLC13A3) is found in various tissues, including the kidney, liver, and brain. In addition to citric acid cycle intermediates such as alpha-ketoglutarate and succinate, NaDC3 transports other compounds into cells, including N-acetyl aspartate, mercaptosuccinate, and glutathione, in keeping with its dual roles in cell nutrition and detoxification. In this study, we construct a homology structural model of NaDC3 on the basis of the structure of the Vibrio cholerae homolog vcINDY. Our computations are followed by experimental testing of the predicted NaDC3 structure and mode of interaction with various substrates. The results of this study show that the substrate and cation binding domains of NaDC3 are composed of residues in the opposing hairpin loops and unwound portions of adjacent helices. Furthermore, these results provide a possible explanation for the differential substrate specificity among dicarboxylate transporters that underpin their diverse biological roles in metabolism and detoxification. The structural model of NaDC3 provides a framework for understanding substrate selectivity and the Na(+) coupled anion transport mechanism by the human SLC13 family and other key solute carrier transporters. PMID- 24808187 TI - Integrating user studies into computer graphics-related courses. AB - This paper presents computer graphics. Computer graphics and visualization are essentially about producing images for a target audience, be it the millions watching a new CG-animated movie or the small group of researchers trying to gain insight into the large amount of numerical data resulting from a scientific experiment. To ascertain the final images' effectiveness for their intended audience or the designed visualizations' accuracy and expressiveness, formal user studies are often essential. In human-computer interaction (HCI), such user studies play a similar fundamental role in evaluating the usability and applicability of interaction methods and metaphors for the various devices and software systems we use. PMID- 24808189 TI - Virtual prototyping of shoes. PMID- 24808188 TI - Graph analytics-lessons learned and challenges ahead. AB - Lessons learned from developing four graph analytics applications reveal good research practices and grand challenges for future research. The application domains include electric-power-grid analytics, social-network and citation analytics, text and document analytics, and knowledge domain analytics. PMID- 24808190 TI - A responsive finite element method to aid interactive geometric modeling. AB - Current computer-aided engineering systems use numerical-simulation methods mainly as offline verification tools to reject designs that don't satisfy the required constraints, rather than as tools to guide users toward better designs. However, integrating real-time finite element method (FEM) into interactive geometric modeling can provide user guidance. During interactive editing, real time feedback from numerical simulation guides users toward an improved design without tedious trial-and-error iterations. Careful reuse of previous computation results, such as meshes and matrices, on the basis of speed and accuracy trade offs, have helped produce fast FEM analysis during interactive editing. Several 2D example applications and informal user studies show this approach's effectiveness. Such tools could help nonexpert users design objects that satisfy physical constraints and help those users understand the underlying physical properties. PMID- 24808191 TI - Context-aware motion diversification for crowd simulation. PMID- 24808192 TI - Wait-free shared-memory irradiance caching. PMID- 24808194 TI - Deco: a design editor for rhinestone decorations. PMID- 24808193 TI - Carnival-combining speech technology and computer animation. PMID- 24808195 TI - Ontologies in biological data visualization. AB - In computer science, an ontology is essentially a graph-based knowledge representation in which each node corresponds to a concept and each edge specifies a relation between two concepts. Ontological development in biology can serve as a focus to discuss the challenges and possible research directions for ontologies in visualization. The principle challenges are the dynamic and evolving nature of ontologies, the ever-present issue of scale, the diversity and richness of the relationships in ontologies, and the need to better understand the relationship between ontologies and the data analysis tasks scientists wish to support. Research directions include visualizing ontologies; visualizing semantically or ontologically annotated texts, documents, and corpora; automated generation of visualizations using ontologies; and visualizing ontological context to support search. Although this discussion uses issues of ontologies in biological data visualization as a springboard, these topics are of general relevance to visualization. PMID- 24808196 TI - Designing emergency-medical-service helicopter interiors using virtual manikins. AB - Researchers employed digital manikins to determine the space necessary in an emergency-medical-service helicopter to effectively and efficiently conduct life saving medical procedures. To simulate resuscitation with appropriate digital human models, they used Anthropos ErgoMAX modeling software in the 3D Studio Max environment. PMID- 24808197 TI - DIVE: a graph-based visual-analytics framework for big data. AB - The need for data-centric scientific tools is growing; domains such as biology, chemistry, and physics are increasingly adopting computational approaches. So, scientists must deal with the challenges of big data. To address these challenges, researchers built a visual-analytics platform named DIVE (Data Intensive Visualization Engine). DIVE is a data-agnostic, ontologically expressive software framework that can stream large datasets at interactive speeds. In particular, DIVE makes novel contributions to structured-data-model manipulation and high-throughput streaming of large, structured datasets. PMID- 24808198 TI - Characterizing cancer subtypes using dual analysis in Caleydo StratomeX. AB - Dual analysis uses statistics to describe both the dimensions and rows of a high dimensional dataset. Researchers have integrated it into StratomeX, a Caleydo view for cancer subtype analysis. In addition, significant-difference plots show the elements of a candidate subtype that differ significantly from other subtypes, thus letting analysts characterize subtypes. Analysts can also investigate how data samples relate to their assigned subtype and other groups. This approach lets them create well-defined subtypes based on statistical properties. Three case studies demonstrate the approach's utility, showing how it reproduced findings from a published subtype characterization. PMID- 24808199 TI - Visual exploration of parameter influence on phylogenetic trees. AB - Evolutionary relationships between organisms are frequently derived as phylogenetic trees inferred from multiple sequence alignments (MSAs). The MSA parameter space is exponentially large, so tens of thousands of potential trees can emerge for each dataset. A proposed visual-analytics approach can reveal the parameters' impact on the trees. Given input trees created with different parameter settings, it hierarchically clusters the trees according to their structural similarity. The most important clusters of similar trees are shown together with their parameters. This view offers interactive parameter exploration and automatic identification of relevant parameters. Biologists applied this approach to real data of 16S ribosomal RNA and protein sequences of ion channels. It revealed which parameters affected the tree structures. This led to a more reliable selection of the best trees. PMID- 24808200 TI - Ring discretization of the wave spectrum for sea surface simulation. AB - Although interactive computer-generated ocean scenes based on real wave spectra are impressively realistic, they usually don't exhibit the original sea state's statistical properties. This might be unacceptable for applications in which the sea surface height field's correctness is important, such as 3D ship simulators for training professionals. Researchers have developed a discretization of the wave spectrum that obtains a sea state statistically more equivalent to the original. This method can also improve the scene's visual realism and real-time performance. PMID- 24808201 TI - Beautiful math, part 3: hyperbolic aesthetic patterns based on conformal mappings. AB - This third installment of the Beautiful Math articles considers the visualization of aesthetic patterns with hyperbolic-triangle-group symmetries. A flexible form of invariant mappings contributes to a simple, efficient way to generate hyperbolic patterns. Combined with conformal mappings, this method can yield an abundance of exotic patterns. PMID- 24808202 TI - Student projects involving novel interaction with large displays. AB - DETI-Interact is an interactive system that offers information relevant to students in the lobby of the University of Aveiro's Department of Electronics, Telecommunications and Informatics (DETI). The project started in 2009 with a master's thesis addressing interaction with public displays through Android smartphones. Since then, it has evolved considerably; it currently allows gesture interaction based on a Kinect sensor. Meanwhile, it has involved third-year students, master's students, and undergraduate students participating in a research initiation program. PMID- 24808203 TI - Mixture subclass discriminant analysis link to restricted Gaussian model and other generalizations. AB - In this paper, a theoretical link between mixture subclass discriminant analysis (MSDA) and a restricted Gaussian model is first presented. Then, two further discriminant analysis (DA) methods, i.e., fractional step MSDA (FSMSDA) and kernel MSDA (KMSDA) are proposed. Linking MSDA to an appropriate Gaussian model allows the derivation of a new DA method under the expectation maximization (EM) framework (EM-MSDA), which simultaneously derives the discriminant subspace and the maximum likelihood estimates. The two other proposed methods generalize MSDA in order to solve problems inherited from conventional DA. FSMSDA solves the subclass separation problem, that is, the situation in which the dimensionality of the discriminant subspace is strictly smaller than the rank of the inter between-subclass scatter matrix. This is done by an appropriate weighting scheme and the utilization of an iterative algorithm for preserving useful discriminant directions. On the other hand, KMSDA uses the kernel trick to separate data with nonlinearly separable subclass structure. Extensive experimentation shows that the proposed methods outperform conventional MSDA and other linear discriminant analysis variants. PMID- 24808204 TI - Density-preserving sampling: robust and efficient alternative to cross-validation for error estimation. AB - Estimation of the generalization ability of a classification or regression model is an important issue, as it indicates the expected performance on previously unseen data and is also used for model selection. Currently used generalization error estimation procedures, such as cross-validation (CV) or bootstrap, are stochastic and, thus, require multiple repetitions in order to produce reliable results, which can be computationally expensive, if not prohibitive. The correntropy-inspired density-preserving sampling (DPS) procedure proposed in this paper eliminates the need for repeating the error estimation procedure by dividing the available data into subsets that are guaranteed to be representative of the input dataset. This allows the production of low-variance error estimates with an accuracy comparable to 10 times repeated CV at a fraction of the computations required by CV. This method can also be used for model ranking and selection. This paper derives the DPS procedure and investigates its usability and performance using a set of public benchmark datasets and standard classifiers. PMID- 24808205 TI - Two-stage nonnegative sparse representation for large-scale face recognition. AB - This paper proposes a novel nonnegative sparse representation approach, called two-stage sparse representation (TSR), for robust face recognition on a large scale database. Based on the divide and conquer strategy, TSR decomposes the procedure of robust face recognition into outlier detection stage and recognition stage. In the first stage, we propose a general multisubspace framework to learn a robust metric in which noise and outliers in image pixels are detected. Potential loss functions, including L1 , L2,1, and correntropy are studied. In the second stage, based on the learned metric and collaborative representation, we propose an efficient nonnegative sparse representation algorithm to find an approximation solution of sparse representation. According to the L1 ball theory in sparse representation, the approximated solution is unique and can be optimized efficiently. Then a filtering strategy is developed to avoid the computation of the sparse representation on the whole large-scale dataset. Moreover, theoretical analysis also gives the necessary condition for nonnegative least squares technique to find a sparse solution. Extensive experiments on several public databases have demonstrated that the proposed TSR approach, in general, achieves better classification accuracy than the state-of-the-art sparse representation methods. More importantly, a significant reduction of computational costs is reached in comparison with sparse representation classifier; this enables the TSR to be more suitable for robust face recognition on a large-scale dataset. PMID- 24808206 TI - Projection-pursuit-based method for blind separation of nonnegative sources. AB - This paper presents a projection pursuit (PP) based method for blind separation of nonnegative sources. First, the available observation matrix is mapped to construct a new mixing model, in which the inaccessible source matrix is normalized to be column-sum-to-1. Then, the PP method is proposed to solve this new model, where the mixing matrix is estimated column by column through tracing the projections to the mapped observations in specified directions, which leads to the recovery of the sources. The proposed method is much faster than Chan's method, which has similar assumptions to ours, due to the usage of optimal projection. It is also more advantageous in separating cross-correlated sources than the independence- and uncorrelation-based methods, as it does not employ any statistical information of the sources. Furthermore, the new method does not require the mixing matrix to be nonnegative. Simulation results demonstrate the superior performance of our method. PMID- 24808207 TI - Synchronization for coupled neural networks with interval delay: a novel augmented Lyapunov-Krasovskii functional method. AB - This paper is concerned with the synchronization problems for an array of neural networks with hybrid coupling and interval time-varying delay. First, a novel augmented Lyapunov-Krasovskii functional (LKF) method is proposed to develop delay-dependent synchronization criteria for the networks, which makes use of more relaxed conditions by employing the new type of augmented matrices with Kronecker product operation. The proposed method can handle a multitude of Kronecker product operations in the LKF and alleviates the requirements of the positive definiteness of some conditional matrices which are usually considered in the existing methods for complex networks. This leads to a significant improvement in the performance of the synchronization criteria, i.e., less conservative synchronization results can be obtained. Meanwhile, the case of fast time-varying delay can also be handled by the proposed method. Furthermore, based on the derived criteria, a robust synchronization criterion is obtained for the system with uncertainties both in coefficient and coupling matrix terms. Since an expression based on linear matrix inequality is used, the proposed criteria can be easily checked in practice. Finally, numerical examples are provided to show the effectiveness of the proposed method. PMID- 24808208 TI - Observer-based adaptive neural network control for nonlinear stochastic systems with time delay. AB - This paper considers the problem of observer-based adaptive neural network (NN) control for a class of single-input single-output strict-feedback nonlinear stochastic systems with unknown time delays. Dynamic surface control is used to avoid the so-called explosion of complexity in the backstepping design process. Radial basis function NNs are directly utilized to approximate the unknown and desired control input signals instead of the unknown nonlinear functions. The proposed adaptive NN output feedback controller can guarantee all the signals in the closed-loop system to be mean square semi-globally uniformly ultimately bounded. Simulation results are provided to demonstrate the effectiveness of the proposed methods. PMID- 24808209 TI - Qualitative adaptive reward learning with success failure maps: applied to humanoid robot walking. AB - In the human brain, rewards are encoded in a flexible and adaptive way after each novel stimulus. Neurons of the orbitofrontal cortex are the key reward structure of the brain. Neurobiological studies show that the anterior cingulate cortex of the brain is primarily responsible for avoiding repeated mistakes. According to vigilance threshold, which denotes the tolerance to risks, we can differentiate between a learning mechanism that takes risks and one that averts risks. The tolerance to risk plays an important role in such a learning mechanism. Results have shown the differences in learning capacity between risk-taking and risk avert behaviors. These neurological properties provide promising inspirations for robot learning based on rewards. In this paper, we propose a learning mechanism that is able to learn from negative and positive feedback with reward coding adaptively. It is composed of two phases: evaluation and decision making. In the evaluation phase, we use a Kohonen self-organizing map technique to represent success and failure. Decision making is based on an early warning mechanism that enables avoiding repeating past mistakes. The behavior to risk is modulated in order to gain experiences for success and for failure. Success map is learned with adaptive reward that qualifies the learned task in order to optimize the efficiency. Our approach is presented with an implementation on the NAO humanoid robot, controlled by a bioinspired neural controller based on a central pattern generator. The learning system adapts the oscillation frequency and the motor neuron gain in pitch and roll in order to walk on flat and sloped terrain, and to switch between them. PMID- 24808210 TI - Novel z-domain precoding method for blind separation of spatially correlated signals. AB - In this paper, we address the problem of blind separation of spatially correlated signals, which is encountered in some emerging applications, e.g., distributed wireless sensor networks and wireless surveillance systems. We preprocess the source signals in transmitters prior to transmission. Specifically, the source signals are first filtered by a set of properly designed precoders and then the coded signals are transmitted. On the receiving side, the Z-domain features of the precoders are exploited to separate the coded signals, from which the source signals are recovered. Based on the proposed precoders, a closed-form algorithm is derived to estimate the coded signals and the source signals. Unlike traditional blind source separation approaches, the proposed method does not require the source signals to be uncorrelated, sparse, or nonnegative. Compared with the existing precoder-based approach, the new method uses precoders with much lower order, which reduces the delay in data transmission and is easier to implement in practice. PMID- 24808211 TI - Local coordinates alignment with global preservation for dimensionality reduction. AB - Dimensionality reduction is vital in many fields, and alignment-based methods for nonlinear dimensionality reduction have become popular recently because they can map the high-dimensional data into a low-dimensional subspace with the property of local isometry. However, the relationships between patches in original high dimensional space cannot be ensured to be fully preserved during the alignment process. In this paper, we propose a novel method for nonlinear dimensionality reduction called local coordinates alignment with global preservation. We first introduce a reasonable definition of topology-preserving landmarks (TPLs), which not only contribute to preserving the global structure of datasets and constructing a collection of overlapping linear patches, but they also ensure that the right landmark is allocated to the new test point. Then, an existing method for dimensionality reduction that has good performance in preserving the global structure is used to derive the low-dimensional coordinates of TPLs. Local coordinates of each patch are derived using tangent space of the manifold at the corresponding landmark, and then these local coordinates are aligned into a global coordinate space with the set of landmarks in low-dimensional space as reference points. The proposed alignment method, called landmarks-based alignment, can produce a closed-form solution without any constraints, while most previous alignment-based methods impose the unit covariance constraint, which will result in the deficiency of global metrics and undesired rescaling of the manifold. Experiments on both synthetic and real-world datasets demonstrate the effectiveness of the proposed algorithm. PMID- 24808212 TI - Hopf bifurcation of an (n + 1) -neuron bidirectional associative memory neural network model with delays. AB - Recent studies on Hopf bifurcations of neural networks with delays are confined to simplified neural network models consisting of only two, three, four, five, or six neurons. It is well known that neural networks are complex and large-scale nonlinear dynamical systems, so the dynamics of the delayed neural networks are very rich and complicated. Although discussing the dynamics of networks with a few neurons may help us to understand large-scale networks, there are inevitably some complicated problems that may be overlooked if simplified networks are carried over to large-scale networks. In this paper, a general delayed bidirectional associative memory neural network model with n + 1 neurons is considered. By analyzing the associated characteristic equation, the local stability of the trivial steady state is examined, and then the existence of the Hopf bifurcation at the trivial steady state is established. By applying the normal form theory and the center manifold reduction, explicit formulae are derived to determine the direction and stability of the bifurcating periodic solution. Furthermore, the paper highlights situations where the Hopf bifurcations are particularly critical, in the sense that the amplitude and the period of oscillations are very sensitive to errors due to tolerances in the implementation of neuron interconnections. It is shown that the sensitivity is crucially dependent on the delay and also significantly influenced by the feature of the number of neurons. Numerical simulations are carried out to illustrate the main results. PMID- 24808213 TI - Prime discriminant simplicial complex. AB - The structure representation of data distribution plays an important role in understanding the underlying mechanism of generating data. In this paper, we propose the prime discriminant simplicial complex (PDSC) by utilizing persistent homology to capture such structures. Assuming that each class is represented with a prime simplicial complex, we classify unlabeled samples based on the nearest projection distances from the samples to the simplicial complexes. We also extend the extrapolation ability of these complexes with a projection constraint term. Experiments in simulated and practical datasets indicate that, compared with several published algorithms, the proposed PDSC approaches achieve promising performance without losing structure representation. PMID- 24808214 TI - Finite-horizon control-constrained nonlinear optimal control using single network adaptive critics. AB - To synthesize fixed-final-time control-constrained optimal controllers for discrete-time nonlinear control-affine systems, a single neural network (NN) based controller called the Finite-horizon Single Network Adaptive Critic is developed in this paper. Inputs to the NN are the current system states and the time-to-go, and the network outputs are the costates that are used to compute optimal feedback control. Control constraints are handled through a nonquadratic cost function. Convergence proofs of: 1) the reinforcement learning-based training method to the optimal solution; 2) the training error; and 3) the network weights are provided. The resulting controller is shown to solve the associated time-varying Hamilton-Jacobi-Bellman equation and provide the fixed final-time optimal solution. Performance of the new synthesis technique is demonstrated through different examples including an attitude control problem wherein a rigid spacecraft performs a finite-time attitude maneuver subject to control bounds. The new formulation has great potential for implementation since it consists of only one NN with single set of weights and it provides comprehensive feedback solutions online, though it is trained offline. PMID- 24808215 TI - Feature combiners with gate-generated weights for classification. AB - Using functional weights in a conventional linear combination architecture is a way of obtaining expressive power and represents an alternative to classical trainable and implicit nonlinear transformations. In this brief, we explore this way of constructing binary classifiers, taking advantage of the possibility of generating functional weights by means of a gate with fixed radial basis functions. This particular form of the gate permits training the machine directly with maximal margin algorithms. We call the resulting scheme "feature combiners with gate generated weights for classification." Experimental results show that these architectures outperform support vector machines (SVMs) and Real AdaBoost ensembles in most considered benchmark examples. An increase in the computational design effort due to cross-validation demands is the price to be paid to obtain this advantage. Nevertheless, the operational effort is usually lower than that needed by SVMs. PMID- 24808216 TI - Competitive learning with pairwise constraints. AB - Constrained clustering has been an active research topic since the last decade. Most studies focus on batch-mode algorithms. This brief introduces two algorithms for on-line constrained learning, named on-line linear constrained vector quantization error (O-LCVQE) and constrained rival penalized competitive learning (C-RPCL). The former is a variant of the LCVQE algorithm for on-line settings, whereas the latter is an adaptation of the (on-line) RPCL algorithm to deal with constrained clustering. The accuracy results--in terms of the normalized mutual information (NMI)--from experiments with nine datasets show that the partitions induced by O-LCVQE are competitive with those found by the (batch-mode) LCVQE. Compared with this formidable baseline algorithm, it is surprising that C-RPCL can provide better partitions (in terms of the NMI) for most of the datasets. Also, experiments on a large dataset show that on-line algorithms for constrained clustering can significantly reduce the computational time. PMID- 24808217 TI - Infinite hidden conditional random fields for human behavior analysis. AB - Hidden conditional random fields (HCRFs) are discriminative latent variable models that have been shown to successfully learn the hidden structure of a given classification problem (provided an appropriate validation of the number of hidden states). In this brief, we present the infinite HCRF (iHCRF), which is a nonparametric model based on hierarchical Dirichlet processes and is capable of automatically learning the optimal number of hidden states for a classification task. We show how we learn the model hyperparameters with an effective Markov chain Monte Carlo sampling technique, and we explain the process that underlines our iHCRF model with the Restaurant Franchise Rating Agencies analogy. We show that the iHCRF is able to converge to a correct number of represented hidden states, and outperforms the best finite HCRFs--chosen via cross-validation--for the difficult tasks of recognizing instances of agreement, disagreement, and pain. Moreover, the iHCRF manages to achieve this performance in significantly less total training, validation, and testing time. PMID- 24808218 TI - Predictive monitoring of mobile patients by combining clinical observations with data from wearable sensors. AB - The majority of patients in the hospital are ambulatory and would benefit significantly from predictive and personalized monitoring systems. Such patients are well suited to having their physiological condition monitored using low power, minimally intrusive wearable sensors. Despite data-collection systems now being manufactured commercially, allowing physiological data to be acquired from mobile patients, little work has been undertaken on the use of the resultant data in a principled manner for robust patient care, including predictive monitoring. Most current devices generate so many false-positive alerts that devices cannot be used for routine clinical practice. This paper explores principled machine learning approaches to interpreting large quantities of continuously acquired, multivariate physiological data, using wearable patient monitors, where the goal is to provide early warning of serious physiological determination, such that a degree of predictive care may be provided. We adopt a one-class support vector machine formulation, proposing a formulation for determining the free parameters of the model using partial area under the ROC curve, a method arising from the unique requirements of performing online analysis with data from patient-worn sensors. There are few clinical evaluations of machine learning techniques in the literature, so we present results from a study at the Oxford University Hospitals NHS Trust devised to investigate the large-scale clinical use of patient-worn sensors for predictive monitoring in a ward with a high incidence of patient mortality. We show that our system can combine routine manual observations made by clinical staff with the continuous data acquired from wearable sensors. Practical considerations and recommendations based on our experiences of this clinical study are discussed, in the context of a framework for personalized monitoring. PMID- 24808219 TI - Identification of COPD patients' health status using an intelligent system in the CHRONIOUS wearable platform. AB - The CHRONIOUS system offers an integrated platform aiming at the effective management and real-time assessment of the health status of the patient suffering from chronic obstructive pulmonary disease (COPD). An intelligent system is developed for the analysis and the real-time evaluation of patient's condition. A hybrid classifier has been implemented on a personal digital assistant, combining a support vector machine, a random forest, and a rule-based system to provide a more advanced categorization scheme for the early and in real-time characterization of a COPD episode. This is followed by a severity estimation algorithm which classifies the identified pathological situation in different levels and triggers an alerting mechanism to provide an informative and instructive message/advice to the patient and the clinical supervisor. The system has been validated using data collected from 30 patients that have been annotated by experts indicating 1) the severity level of the current patient's health status, and 2) the COPD disease level of the recruited patients according to the GOLD guidelines. The achieved characterization accuracy has been found 94%. PMID- 24808220 TI - Removing batch effects from histopathological images for enhanced cancer diagnosis. AB - Researchers have developed computer-aided decision support systems for translational medicine that aim to objectively and efficiently diagnose cancer using histopathological images. However, the performance of such systems is confounded by nonbiological experimental variations or "batch effects" that can commonly occur in histopathological data, especially when images are acquired using different imaging devices and patient samples. This is even more problematic in large-scale studies in which cross-laboratory sharing of large volumes of data is necessary. Batch effects can change quantitative morphological image features and decrease the prediction performance. Using four batches of renal tumor images, we compare one image-level and five feature-level batch effect removal methods. Principal component variation analysis shows that batch is a large source of variance in image features. Results show that feature-level normalization methods reduce batch-contributed variance to almost zero. Moreover, feature-level normalization, especially ComBatN, improves cross-batch and combined-batch prediction performance. Compared to no normalization, ComBatN improves performance in 83% and 90% of cross-batch and combined-batch prediction models, respectively. PMID- 24808221 TI - On the identification of circulating tumor cells in breast cancer. AB - Breast cancer is a highly heterogeneous disease and very common among western women. The main cause of death is not the primary tumor but its metastases at distant sites, such as lymph nodes and other organs (preferentially lung, liver, and bones). The study of circulating tumor cells (CTCs) in peripheral blood resulting from tumor cell invasion and intravascular filtration highlights their crucial role concerning tumor aggressiveness and metastasis. Genomic research regarding CTCs monitoring for breast cancer is limited due to the lack of indicative genes for their detection and isolation. Instead of direct CTC detection, in our study, we focus on the identification of factors in peripheral blood that can indirectly reveal the presence of such cells. Using selected publicly available breast cancer and peripheral blood microarray datasets, we follow a two-step elimination procedure for the identification of several discriminant factors. Our procedure facilitates the identification of major genes involved in breast cancer pathology, which are also indicative of CTCs presence. PMID- 24808222 TI - Impact of head rotation on the individualized common carotid flow and carotid bifurcation hemodynamics. AB - This paper aims at evaluating the changes that head rotation poses on morphological and flow characteristics of the carotid bifurcation (CB) and on the distribution of parameters that are regarded as important in atherosclerosis development, such as relative particle residence time (RRT), normalized oscillatory shear index (nOSI), and helicity (HL). Using a subject-specific approach, six healthy volunteers were MR-scanned in two head postures: supine neutral and prone with rightward head rotation. Cross-sectional flow velocity distribution was obtained using phase-contrast MRI at the common carotid artery (CCA). Our results indicate that peak systolic flow rate is reduced at the prone position in most cases for both CCAs. Morphological MR images are used to segment and construct the CB models. Numerical simulations are performed and areas exposed to high helicity or unfavorable hemodynamics are calculated. Head rotation affects the instantaneous spatial extent of high helicity regions. Posture-related observed differences in the distribution of nOSI and RRT suggest that inlet flow waveform tends to moderate geometry-induced changes in the qualitative and quantitative distribution of atherosclerosis-susceptible wall regions. Overall, presented results indicate that an individualized approach is required to fully assess the postural role in atherosclerosis development and in complications arising in stenotic and stented vessels. PMID- 24808223 TI - Temporal and spatial patterns of gene profiles during chondrogenic differentiation. AB - Clustering analysis based on temporal profile of genes may provide new insights in particular biological processes or conditions. We report such an integrative clustering analysis which is based on the expression patterns but is also influenced by temporal changes. The proposed platform is illustrated with a temporal gene expression dataset comprised of pellet culture-conditioned human primary chondrocytes and human bone marrow-derived mesenchymal stem cells (MSCs). We derived three clusters in each cell type and compared the content of these classes in terms of temporal changes. We further considered the induced biological processes and the gene-interaction networks formed within each cluster and discuss their biological significance. Our proposed methodology provides a consistent tool that facilitates both the statistical and biological validation of temporal profiles through spatial gene network profiles. PMID- 24808224 TI - A composite framework for the statistical analysis of epidemiological DNA methylation data with the Infinium Human Methylation 450K BeadChip. AB - High-throughput DNA methylation profiling exploits microarray technologies thus providing a wealth of data, which however solicits rigorous, generic, and analytical pipelines for an efficient systems level analysis and interpretation. In this study, we utilize the Illumina's Infinium Human Methylation 450K BeadChip platform in an epidemiological cohort, targeting to associate interesting methylation patterns with breast cancer predisposition. The computational framework proposed here extends the--established in transcriptomic microarrays- logarithmic ratio of the methylated versus the unmethylated signal intensities, quoted as M-value. Moreover, intensity-based correction of the M-signal distribution is introduced in order to correct for batch effects and probe specific errors in intensity measurements. This is accomplished through the estimation of intensity-related error measures from quality control samples included in each chip. Moreover, robust statistical measures exploiting the coefficient variation of DNA methylation measurements between control and case samples alleviate the impact of technical variation. The results presented here are juxtaposed to those derived by applying classical preprocessing and statistical selection methodologies. Overall, in comparison to traditional approaches, the superior performance of the proposed framework in terms of technical bias correction, along with its generic character, support its suitability for various microarray technologies. PMID- 24808225 TI - Web-based workflow planning platform supporting the design and execution of complex multiscale cancer models. AB - Significant Virtual Physiological Human efforts and projects have been concerned with cancer modeling, especially in the European Commission Seventh Framework research program, with the ambitious goal to approach personalized cancer simulation based on patient-specific data and thereby optimize therapy decisions in the clinical setting. However, building realistic in silico predictive models targeting the clinical practice requires interactive, synergetic approaches to integrate the currently fragmented efforts emanating from the systems biology and computational oncology communities all around the globe. To further this goal, we propose an intelligent graphical workflow planning system that exploits the multiscale and modular nature of cancer and allows building complex cancer models by intuitively linking/interchanging highly specialized models. The system adopts and extends current standardization efforts, key tools, and infrastructure in view of building a pool of reliable and reproducible models capable of improving current therapies and demonstrating the potential for clinical translation of these technologies. PMID- 24808226 TI - Modeling biological pathway dynamics with timed automata. AB - Living cells are constantly subjected to a plethora of environmental stimuli that require integration into an appropriate cellular response. This integration takes place through signal transduction events that form tightly interconnected networks. The understanding of these networks requires capturing their dynamics through computational support and models. ANIMO (analysis of Networks with Interactive Modeling) is a tool that enables the construction and exploration of executable models of biological networks, helping to derive hypotheses and to plan wet-lab experiments. The tool is based on the formalism of Timed Automata, which can be analyzed via the UPPAAL model checker. Thanks to Timed Automata, we can provide a formal semantics for the domain-specific language used to represent signaling networks. This enforces precision and uniformity in the definition of signaling pathways, contributing to the integration of isolated signaling events into complex network models. We propose an approach to discretization of reaction kinetics that allows us to efficiently use UPPAAL as the computational engine to explore the dynamic behavior of the network of interest. A user-friendly interface hides the use of Timed Automata from the user, while keeping the expressive power intact. Abstraction to single-parameter kinetics speeds up construction of models that remain faithful enough to provide meaningful insight. The resulting dynamic behavior of the network components is displayed graphically, allowing for an intuitive and interactive modeling experience. PMID- 24808227 TI - Non-calcified coronary atherosclerotic plaque characterization by dual energy computed tomography. AB - Coronary heart disease (CHD) is the most prevalent cause of death worldwide. Atherosclerosis which is the condition of plaque buildup on the inside of the coronary artery wall is the main cause of CHD. Rupture of unstable atherosclerotic coronary plaque is known to be the cause of acute coronary syndrome. Vulnerability of atherosclerotic plaque has been related to a large lipid core covered by a fibrous cap. Non-invasive assessment of plaque characterization is necessary due to prognostic importance of early stage identification. The purpose of this study is to use the additional attenuation data provided by dual energy computed tomography (DECT) for plaque characterization. We propose to train supervised learners on pixel values recorded from DECT monochromatic X-ray and material basis pairs images, for more precise classification of fibrous and lipid plaques. The interaction of the pixel values from different image types is taken into consideration, as single pixel value might not be informative enough to separate fibrous from lipid. Organic phantom plaques scanned in a fabricated beating heart phantom were used as ground truth to train the learners. Our results show that support vector machines, artificial neural networks and random forests provide accurate results both on phantom and patient data. PMID- 24808228 TI - Efficient acceleration of mutual information computation for nonrigid registration using CUDA. AB - In this paper, we propose an efficient acceleration method for the nonrigid registration of multimodal images that uses a graphics processing unit. The key contribution of our method is efficient utilization of on-chip memory for both normalized mutual information (NMI) computation and hierarchical B-spline deformation, which compose a well-known registration algorithm. We implement this registration algorithm as a compute unified device architecture program with an efficient parallel scheme and several optimization techniques such as hierarchical data organization, data reuse, and multiresolution representation. We experimentally evaluate our method with four clinical datasets consisting of up to 512 * 512 * 296 voxels. We find that exploitation of on-chip memory achieves a 12-fold increase in speed over an off-chip memory version and, therefore, it increases the efficiency of parallel execution from 4% to 46%. We also find that our method running on a GeForce GTX 580 card is approximately 14 times faster than a fully optimized CPU-based implementation running on four cores. Some multimodal registration results are also provided to understand the limitation of our method. We believe that our highly efficient method, which completes an alignment task within a few tens of seconds, will be useful to realize rapid nonrigid registration. PMID- 24808229 TI - A novel MRI tracer-based method for measuring water diffusion in the extracellular space of the rat brain. AB - We proposed a novel MRI tracer-based method for the determination of water diffusion in the brain extracellular space (ECS). The measuring system was validated in 32 Sprague Dawley rats. The rats were randomly divided into four groups with different injection sites: 1) caudate nucleus (Cn.); 2) thalamus (T.); 3) cortex (Cor.); and 4) substantia nigra (Sn.). The spin-lattice relaxation time of hydrogen nuclei in water molecules were shortened, which presented as high signal on MRI after the injection of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) into the rat brain ECS. The enhancement on MRI decreased over time due to the water diffusion and clearance process within the brain ECS. The process was dynamically recorded on a series of magnetic resonance (MR) images. As the increment in signal intensity (DeltaSI) could be converted to local Gd-DTPA concentration, the water diffusion parameters were further calculated voxel by voxel based on a modified diffusion model. The most tortuous ECS (lambda = 1.77 +/- 0.71) was found in Sn. with D*(Sn) of (2.06 +/- 1.01) * 10(-4) mm(2).s(-1) ( P < 0.05). No statistical difference was demonstrated among D*(Cn), D*(T.), and D*(Cor). with an average D* values of (3.28 +/- 0.88) * 10(-4) mm(2).s(-1)( F = 0.18, P > 0.05). By using the tracer based MRI method, the local diffusion parameters of the brain ECS can be quantitatively measured. The different distribution territories and clearance rates of the tracer in four brain areas indicated that the brain ECS is a physiologically partitioned system. PMID- 24808230 TI - Exploring early glaucoma and the visual field test: classification and clustering using Bayesian networks. AB - Bayesian networks (BNs) are probabilistic models used for classification and clustering in several fields. Their ability to deal with unobserved variables and to integrate data and expert knowledge make them an appropriate technique for modeling eye functionality measurements in glaucoma. In this study, a set of BNs is used to simultaneously perform classification of early glaucoma and cluster data into different stages of disease. A novel learning algorithm that combines clustering and quasi-greedy search is also proposed. The classification performances of the models are evaluated on an independent dataset, while the clusters are compared to K-means, previous publications, and direct knowledge. The use of clustering and structure learning enabled the exploration of the visual field patterns of the disease while obtaining good results both on pre- (50% sensitivity at 90% specificity) and post- (85% sensitivity at 90% specificity) diagnosis data. Clusters obtained were insightful and in conformity with consolidated knowledge in the field. PMID- 24808231 TI - Walking-age analyzer for healthcare applications. AB - This paper describes a walking-age pattern analysis and identification system using a 3-D accelerometer and a gyroscope. First, a walking pattern database from 79 volunteers of ages ranging from 10 to 83 years is constructed. Second, using feature extraction and clustering, three distinct walking-age groups, children of ages 10 and below, adults in 20-60s, and elders in 70s and 80s, were identified. For this study, low-pass filtering, empirical mode decomposition, and K-means were used to process and analyze the experimental results. Analysis shows that volunteers' walking-ages can be categorized into distinct groups based on simple walking pattern signals. This grouping can then be used to detect persons with walking patterns outside their age groups. If the walking pattern puts an individual in a higher "walking age" grouping, then this could be an indicator of potential health/walking problems, such as weak joints, poor musculoskeletal support system or a tendency to fall. PMID- 24808232 TI - Single-trial EEG classification using logistic regression based on ensemble synchronization. AB - In this paper, we propose an ensemble synchronization measure across all EEG channel pairs of a cluster based on Frobenius norm of the phase synchronization matrix, in a 0-1 scale enabling a direct comparison between clusters with different number of channels. Using this metric, we studied the intrahemispheric EEG synchronization in the lower gamma band (30-40 Hz) during 1229 single trials of an audio-visual integration cross modal task (CMT) recorded from five patients with schizophrenia and five healthy control subjects. Using ensemble synchronization measure and response latency of single trials recorded during the CMT as features for logistic regression, we could classify each single trial of EEG as belonging to a patient with schizophrenia or a healthy control subject with 73% accuracy, with an area under receiver operating characteristics curve of 0.83. We also propose a likelihood rating to denote the possibility of a subject belonging to the schizophrenia group. PMID- 24808234 TI - Expansion and evolution of a virulent, extensively drug-resistant (polymyxin B resistant), QnrS1-, CTX-M-2-, and KPC-2-producing Klebsiella pneumoniae ST11 international high-risk clone. AB - In this study, we report the early expansion, evolution, and characterization of a multiresistant Klebsiella pneumoniae clone that was isolated with increasing frequency from inpatients in a tertiary-care university hospital in Brazil. Seven carbapenem- and quinolone-resistant and polymyxin B-susceptible or -resistant K. pneumoniae isolates isolated between December 2012 and February 2013 were investigated. Beta-lactamase- and plasmid-mediated quinolone resistance (PMQR) encoding genes and the genetic environment were investigated using PCR, sequencing, and restriction fragment length polymorphism (RFLP). Clonal relatedness was established using XbaI-pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and phylogenetic group characterization. Plasmid analyses included PCR-based replicon typing (PBRT) and hybridization of the S1-PFGE product, plasmid MLST, and conjugation experiments. Virulence potential was assessed by PCR by searching for 10 virulence factor-encoding genes (ureA, fimH, kfuBC, uge, wabG, magA, mrkD, allS, rmpA, and cf29a) and by phenotypic tests to analyze the hypermucoviscous phenotype. The genetic context of a multidrug-resistant and extensively drug-resistant K. pneumoniae ST11-KpI clone harboring IncFIIk-Tn4401a-blaKPC-2, qnrS1, and blaCTX-M-2 was found. Moreover, three isolates displayed high resistance to polymyxin B (MICs = 32, 32, and 128 mg/liter) as well as mucous and hypermucoviscous phenotypes. These bacteria also harbored ureA, fimH, uge, wabG, and mrkD, which code for virulence factors associated with binding, biofilm formation, and the ability to colonize and escape from phagocytosis. Our study describes the association of important coresistance and virulence factors in the K. pneumoniae ST11 international high risk clone, which makes this pathogen successful at infections and points to the quick expansion and evolution of this multiresistant and virulent clone, leading to a pandrug-resistant phenotype and persistent bacteria in a Brazilian hospital. PMID- 24808235 TI - Evaluation of three rapid diagnostic methods for direct identification of microorganisms in positive blood cultures. AB - The identification of organisms from positive blood cultures generally takes several days. However, recently developed rapid diagnostic methods offer the potential for organism identification within only a few hours of blood culture positivity. In this study, we evaluated the performance of three commercial methods to rapidly identify organisms directly from positive blood cultures: QuickFISH (AdvanDx, Wolburn, MA), Verigene Gram-Positive Blood Culture (BC-GP; Nanosphere, Northbrook, IL), and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) with Sepsityper processing (Bruker Daltonics, Billerica, MA). A total of 159 blood cultures (VersaTREK Trek Diagnostic Systems, Cleveland, OH) positive for Gram-positive and Gram-negative bacteria as well as yeast were analyzed with QuickFISH and MALDI-TOF MS. In all, 102 blood cultures were analyzed using the BC-GP assay. For monomicrobial cultures, we observed 98.0% concordance with routine methods for both QuickFISH (143/146) and the BC-GP assay (93/95). MALDI-TOF MS demonstrated 80.1% (117/146) and 87.7% (128/146) concordance with routine methods to the genus and species levels, respectively. None of the methods tested were capable of consistently identifying polymicrobial cultures in their entirety or reliably differentiating Streptococcus pneumoniae from viridans streptococci. Nevertheless, the methods evaluated in this study are convenient and accurate for the most commonly encountered pathogens and have the potential to dramatically reduce turnaround time for the provision of results to the treating physician. PMID- 24808236 TI - Prospective cross-sectional evaluation of the small membrane filtration method for diagnosis of pulmonary tuberculosis. AB - Smear microscopy has suboptimal sensitivity, and there is a need to improve its performance since it is commonly used to diagnose tuberculosis (TB). We prospectively evaluated the diagnostic accuracy of the small membrane filtration (SMF) method, an approach that uses a vacuum manifold and is designed to concentrate bacilli onto a filter that can be examined microscopically. We enrolled hospitalized adults suspected to have pulmonary TB in Kampala, Uganda. We obtained a clinical history and three spontaneously expectorated sputum specimens for smear microscopy (direct, concentrated, and SMF), MGIT (mycobacterial growth indicator tube) 960 and Lowenstein-Jensen (LJ) cultures, and Xpert MTB/RIF testing. We performed per-specimen (primary) and per-patient analyses. From October 2012 to June 2013, we enrolled 212 patients (579 sputum specimens). The participants were mostly female (63.2%), and 81.6% were HIV infected; their median CD4 cell count was 47 cells/MUl. Overall, 19.0%, 20.4%, 27.1%, 25.2%, and 25.9% of specimens tested positive by direct smear, concentrated smear, MGIT culture, LJ culture, and Xpert test, respectively. In the per-specimen analysis, the sensitivity of the SMF method (48.5%; 95% confidence interval [CI], 37.4 to 59.6) was lower than those of direct smear (60.9%; 51.4 to 70.5 [P = 0.0001]) and concentrated smear (63.3%; 53.6 to 73.1 [P < 0.0001]). Subgroup analyses showed that SMF performed poorly in specimens having a low volume or low bacterial load. The SMF method performed poorly compared to standard smear techniques and was sensitive to sample preparation techniques. The optimal laboratory SMF protocol may require striking a fine balance between sample dilution and filtration failure rate. PMID- 24808237 TI - Detection and measurement of staphylococcal enterotoxin-like K (SEl-K) secretion by Staphylococcus aureus clinical isolates. AB - Staphylococcal enterotoxin-like K (SEl-K) is a potent mitogen that elicits T-cell proliferation and cytokine production at very low concentrations. However, unlike the classical enterotoxins SEB and toxic shock syndrome toxin 1 (TSST-1), the gene for SEl-K is commonly present in more than half of all Staphylococcus aureus clinical isolates and is present in almost all USA300 community-acquired methicillin-resistant S. aureus (CA-MRSA) isolates. Sequencing of the sel-k gene in over 20 clinical isolates and comparative analysis with all 14 published sel-k sequences indicate that there are at least 6 variants of the sel-k gene, including one that is conserved among all examined USA300 strains. Additionally, we have developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) that specifically detects and measures SEl-K protein in culture supernatants and biological fluids. Quantification of in vitro SEl-K secretion by various S. aureus isolates using this novel capture ELISA revealed detectable amounts of SEl K secretion by all isolates, with the highest secretion levels being exhibited by MRSA strains that coexpress SEB. In vivo secretion was measured in a murine thigh abscess model, where similar levels of SEl-K accumulation were noted regardless of whether the infecting strain exhibited high or low secretion of SEl-K in vitro. We conclude that SEl-K is commonly expressed in the setting of staphylococcal infection, in significant amounts. SEl-K should be further explored as a target for passive immunotherapy against complicated S. aureus infection. PMID- 24808238 TI - Utility of rpoB gene sequencing for identification of nontuberculous mycobacteria in the Netherlands. AB - In the Netherlands, clinical isolation of nontuberculous mycobacteria (NTM) has increased over the past decade. Proper identification of isolates is important, as NTM species differ strongly in clinical relevance. Most of the currently applied identification methods cannot distinguish between all different Mycobacterium species and complexes within species. rpoB gene sequencing exhibits a promising level of discrimination among rapidly and slowly growing mycobacteria, including the Mycobacterium avium complex. In this study, we prospectively compared rpoB gene sequencing with our routine algorithm of reverse line blot identification combined with partial 16S rRNA gene sequencing of 455 NTM isolates. rpoB gene sequencing identified 403 isolates to species level as 45 different known species and identified 44 isolates to complex level, and eight isolates remained unidentifiable to species level. In contrast, our reference reverse line blot assay with adjunctive 16S rRNA gene sequencing identified 390 isolates to species level (30 distinct species) and identified 56 isolates to complex level, and nine isolates remained unidentified. The higher discriminatory power of rpoB gene sequencing results largely from the distinction of separate species within complexes and subspecies. Also, Mycobacterium gordonae, Mycobacterium kansasii, and Mycobacterium interjectum were separated into multiple groupings with relatively low sequence similarity (98 to 94%), suggesting that these are complexes of closely related species. We conclude that rpoB gene sequencing is a more discriminative identification technique than the combination of reverse line blot and 16S rRNA gene sequencing and could introduce a major improvement in clinical care of NTM disease and the research on the epidemiology and clinical relevance of NTM. PMID- 24808240 TI - The Capnocytophaga canimorsus isolate that caused sepsis in an immunosufficient man was transmitted by the large pine weevil Hylobius abietis. AB - The first vector-borne Capnocytophaga canimorsus sepsis case is presented. An immunocompetent male who denied any contact with canines and who worked in a sawmill was bitten on his neck by a large pine weevil (Hylobius abietis L.; Coleoptera: Curculionidae). Bacteriological diagnosis was confirmed by 16S rRNA gene sequence analysis. PMID- 24808239 TI - Comparative evaluation of 11 commercialized rapid diagnostic tests for detecting Trypanosoma cruzi antibodies in serum banks in areas of endemicity and nonendemicity. AB - Chagas disease is one of the main public health issues in Latin America. Increasingly during the past few decades, Trypanosoma cruzi infection has been detected in North America, Europe, and the Western Pacific, mainly as a result of population movement. The limited availability of rapid serological diagnostic tests hinders rapid diagnosis and early treatment in areas of endemicity and nonendemicity. In collaboration with 11 national reference laboratories (NRLs) from different geographical areas, we evaluated the performances of commercialized serological rapid diagnostic tests (RDT) for T. cruzi infection. Eleven commercialized T. cruzi infection RDTs were evaluated on a total of 474 samples extensively tested with at least three different techniques for Chagas disease, maintained at controlled low temperatures, and stored in the serum banks of the 11 NRLs. We measured the sensitivity, specificity, and concordance of each RDT and provided an additional questionnaire to evaluate its ease of use. The selected RDTs in this study were performed under controlled laboratory conditions. Out of the 11 RDTs, we found 8 of them to be useful, with the cassette format favored over the strip. We did not observe significant differences in RDT performances in the different regions. Overall, the performance results were lower than those disclosed by the manufacturers. The results of this evaluation validate the possibility of using RDTs to diagnose Chagas disease, thereby decreasing the time to treatment at a primary health care facility for patients who are willing to be treated. Further studies should be conducted in the laboratory and in the field to confirm these data, expressly to evaluate reproducibility in resource-limited settings, or using whole blood in clinical settings in areas of endemicity and nonendemicity. PMID- 24808241 TI - Varicella-zoster virus (VZV) infection as a possible cause of Ogilvie's syndrome in an immunocompromised host. AB - We describe an immunodeficient adult with Ogilvie's syndrome preceding a disseminated papulovesicular skin rash in whom varicella-zoster virus infection was demonstrated by PCR assay in cutaneous and colonic biopsy specimens. In view of the significant morbidity and mortality that this condition carries, early and accurate molecular diagnosis and timely treatment are strongly recommended. PMID- 24808242 TI - Description of Dientamoeba fragilis cyst and precystic forms from human samples. AB - Dientamoeba fragilis is a common enteropathogen of humans. Recently a cyst stage of the parasite was described in an animal model; however, no cyst stage has been described in detail from clinical samples. We describe both cyst and precystic forms from human clinical samples. PMID- 24808243 TI - Neglected parasitic infections in the United States: needs and opportunities. PMID- 24808244 TI - A 41-year-old woman with migratory panniculitis. AB - A 41-year-old woman had two months of intermittent migratory swellings in the trunk, face, and limbs associated with erythema, pruritus, and pain. Laboratory analysis showed moderate eosinophilia. The triad of eosinophilia, migratory lesions (nodular panniculitis), and raw fish consumption was highly suggestive of cutaneous gnathostomiasis. She was successfully treated with albendazole (400 mg twice a day for 21 days) and showed complete and permanent resolution of the lesions. PMID- 24808245 TI - An unusual cause of breast lump: isolated tuberculosis of the breast. AB - A 60-year-old woman presented with a painful lump of 4 months duration in her right breast. She denied any history of breast trauma or family history of breast cancer. Physical examination detected a firm, tender mass in the upper inner quadrant of her right breast without an associated sinus tract. Cytology from fine-needle aspiration of the swelling showed epithelioid cells, lymphohistocytic aggregates, and necrosis. Diagnosis was confirmed by the identification of acid fast bacilli in tissue sections using Ziehl-Neelsen staining. PMID- 24808246 TI - Neglected parasitic infections in the United States: toxoplasmosis. AB - Toxoplasma gondii is a leading cause of severe foodborne illness in the United States. Population-based studies have found T. gondii infection to be more prevalent in racial/ethnic minority and socioeconomically disadvantaged groups. Soil contaminated with cat feces, undercooked meat, and congenital transmission are the principal sources of infection. Toxoplasmosis-associated illnesses include congenital neurologic and ocular disease; acquired illness in immunocompetent persons, most notably ocular disease; and encephalitis or disseminated disease in immunosuppressed persons. The association of T. gondii infection with risk for mental illness is intriguing and requires further research. Reduction of T. gondii in meat, improvements in hygiene and food preparation practices, and reduction of environmental contamination can prevent toxoplasmosis, but more research is needed on how to implement these measures. In addition, screening and treatment may help prevent toxoplasmosis or reduce the severity of disease in some settings. PMID- 24808247 TI - Neglected parasitic infections in the United States: trichomoniasis. AB - Trichomonas vaginalis is one of the most common human parasitic infections in the United States, as well as the most prevalent non-viral sexually transmitted infection. However, it has long received much less consideration than other parasitic and sexually transmitted diseases. Much of this inattention can be attributed to a poor understanding of the public health impact of trichomoniasis. Increasing recognition of the sequelae of infection, including increased risk of infection with human immunodeficiency virus and adverse outcomes of pregnancy, has led to increased interest in T. vaginalis. Recent innovations include development of diagnostic tests that could improve detection of the parasite. A number of important questions, such as the epidemiology among men and women, the true public health burden of symptomatic and asymptomatic T. vaginalis infections, and whether current treatments will be adequate to reduce the substantial health disparities and costs associated with trichomoniasis, need consideration to remedy neglect of this important disease. PMID- 24808249 TI - Neglected parasitic infections in the United States: toxocariasis. AB - Toxocariasis is a preventable parasitic disease that is caused by the dog and cat roundworms Toxocara cani and T. cati, respectively. Humans become infected when they accidently ingest infectious Toxocara eggs commonly found in contaminated soil; children are most often affected. Clinical manifestations of Toxocara infection in humans include ocular toxocariasis and visceral toxocariasis. Although infection with Toxocara can cause devastating disease, the burden of toxocariasis in the United States population remains unknown. In addition, risk factors for acquiring infection need to be better defined, and research needs to be conducted to better understand the pathophysiology and clinical course of toxocariasis. Development of diagnostic tests would enable clinicians to detect active infection, and determination of optimal drug regiments would ensure patients were appropriately treated. Addressing these public health gaps is necessary to understand and address the impact of toxocariasis in the United States. PMID- 24808248 TI - Neglected parasitic infections in the United States: cysticercosis. AB - Cysticercosis is a potentially fatal and preventable neglected parasitic infection caused by the larval form of Taenia solium. Patients with symptomatic disease usually have signs and symptoms of neurocysticercosis, which commonly manifest as seizures or increased intracranial pressure. Although there are many persons living in the United States who emigrated from highly disease-endemic countries and there are foci of autochthonous transmission of the parasite in the United States, little is known about burden and epidemiology of the disease in this country. In addition, despite advances in the diagnosis and management of neurocysticercosis, there remain many unanswered questions. Improving our understanding and management of neurocysticercosis in the United States will require improved surveillance or focused prospective studies in appropriate areas and allocation of resources towards answering some of the key questions discussed in this report. PMID- 24808252 TI - Her own virtual gallery of art. PMID- 24808250 TI - Neglected parasitic infections in the United States: Chagas disease. AB - Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi, can lead to severe cardiac and gastrointestinal disease. Most persons acquire this infection through contact with vector bugs carrying T. cruzi in endemic areas of Latin America. Infection can also be acquired by congenital, transfusion, transplantation, and foodborne transmission. Although an estimated 300,000 persons with Chagas disease live in the United States, little is known about the burden of chagasic heart disease. It is not known how often congenital or vector borne transmission of T. cruzi occurs in the United States, although it is known that infected mothers and infected vector bugs are found in this country. Better diagnostic tests and treatment drugs are needed to improve patient care, and research is needed to define transmission risks and develop strategies to prevent new infections and reduce the burden of disease. PMID- 24808253 TI - Toward a general I/O layer for parallel-visualization applications. PMID- 24808255 TI - Curve-based shape modeling a tutorial. PMID- 24808254 TI - Treevis.net: a tree visualization reference. PMID- 24808256 TI - NaturaSketch: modeling from images and natural sketches. PMID- 24808257 TI - Large-scale physics-based terrain editing. PMID- 24808258 TI - A behavior-authoring framework for multiactor simulations. PMID- 24808259 TI - Photosketcher: interactive sketch-based image synthesis. PMID- 24808261 TI - 3D rotations. PMID- 24808260 TI - Nonpinhole approximations for interactive rendering. PMID- 24808262 TI - Modeling neck and brain injuries in infants. PMID- 24808263 TI - A task-specific analysis of the benefit of haptic shared control during telemanipulation. AB - Telemanipulation allows human to perform operations in a remote environment, but performance and required time of tasks is negatively influenced when (haptic) feedback is limited. Improvement of transparency (reflected forces) is an important focus in literature, but despite significant progress, it is still imperfect, with many unresolved issues. An alternative approach to improve teleoperated tasks is presented in this study: Offering haptic shared control in which the operator is assisted by guiding forces applied at the master device. It is hypothesized that continuous intuitive interaction between operator and support system will improve required time and accuracy with less control effort, even for imperfect transparency. An experimental study was performed in a hard contact task environment. The subjects were aided by the designed shared control to perform a simple bolt-spanner task using a planar three degree of freedom (DOF) teleoperator. Haptic shared control was compared to normal operation for three levels of transparency. The experimental results showed that haptic shared control improves task performance, control effort and operator cognitive workload for the overall bolt-spanner task, for all three transparency levels. Analyses per subtask showed that free air movement (FAM) benefits most from shared control in terms of time performance, and also shows improved accuracy. PMID- 24808264 TI - Comparison of visual and vibrotactile feedback methods for seated posture guidance. AB - We introduce a novel posture guidance office chair and evaluate the effectiveness of vibrotactile and visual feedback methods for guiding seated postures. For visually dominant office work such as typing on the computer, it is possible that delivering posture feedback visually may overload the visual sense while haptic feedback may be a viable alternative. We performed two experiments to compare vibrotactile and visual feedback--posture compliance and dual-task cognitive workload assessment. In the first experiment, our results showed no statistically significant difference in effectiveness between using vibrotactile and visual feedback to obtain postural compliance to a reference posture. In the second experiment, participants experienced typing performance and response time degradations from both types of feedback. However the differences in performance degradation were not statistically significant between the two feedback methods. We conclude that vibrotactile and visual feedback are similarly effective for guiding quasistatic postures in routine tasks such as seated office work. PMID- 24808265 TI - Haptic discrimination and matching of viscosity. AB - In three experiments, viscosity perception of liquids using the sense of touch was studied. The first two were discrimination experiments in which Weber fractions were determined for a number of viscosities spanning the range of what is encountered in daily life, and for two ways of perceiving viscosity (stirring with a spatula or with the index finger). For high viscosities, Weber fractions were around 0.3, whereas they increased for lower viscosities. For low viscosities, discrimination performance was much worse with the finger than with the spatula. In the third experiment, subjects matched liquids perceived with these two methods, which resulted in biases of around 80. Control experiments and force measurements were performed to find an explanation for these results. It was concluded that the relationship between perceived and physical viscosity is steeper for stirring liquids with a spatula than stirring with the finger. PMID- 24808266 TI - Haptic feedback for enhancing realism of walking simulations. AB - In this paper, we describe several experiments whose goal is to evaluate the role of plantar vibrotactile feedback in enhancing the realism of walking experiences in multimodal virtual environments. To achieve this goal we built an interactive and a noninteractive multimodal feedback system. While during the use of the interactive system subjects physically walked, during the use of the noninteractive system the locomotion was simulated while subjects were sitting on a chair. In both the configurations subjects were exposed to auditory and audio visual stimuli presented with and without the haptic feedback. Results of the experiments provide a clear preference toward the simulations enhanced with haptic feedback showing that the haptic channel can lead to more realistic experiences in both interactive and noninteractive configurations. The majority of subjects clearly appreciated the added feedback. However, some subjects found the added feedback unpleasant. This might be due, on one hand, to the limits of the haptic simulation and, on the other hand, to the different individual desire to be involved in the simulations. Our findings can be applied to the context of physical navigation in multimodal virtual environments as well as to enhance the user experience of watching a movie or playing a video game. PMID- 24808267 TI - Human performance measures for interactive haptic-audio-visual interfaces. AB - Virtual reality and simulation are becoming increasingly important in modern society and it is essential to improve our understanding of system usability and efficacy from the users' perspective. This paper introduces a novel evaluation method designed to assess human user capability when undertaking technical and procedural training using virtual training systems. The evaluation method falls under the user-centered design and evaluation paradigm and draws on theories of cognitive, skill-based and affective learning outcomes. The method focuses on user interaction with haptic-audio-visual interfaces and the complexities related to variability in users' performance, and the adoption and acceptance of the technologies. A large scale user study focusing on object assembly training tasks involving selecting, rotating, releasing, inserting, and manipulating three dimensional objects was performed. The study demonstrated the advantages of the method in obtaining valuable multimodal information for accurate and comprehensive evaluation of virtual training system efficacy. The study investigated how well users learn, perform, adapt to, and perceive the virtual training. The results of the study revealed valuable aspects of the design and evaluation of virtual training systems contributing to an improved understanding of more usable virtual training systems. PMID- 24808268 TI - Intention recognition for dynamic role exchange in haptic collaboration. AB - In human-computer collaboration involving haptics, a key issue that remains to be solved is to establish an intuitive communication between the partners. Even though computers are widely used to aid human operators in teleoperation, guidance, and training, because they lack the adaptability, versatility, and awareness of a human, their ability to improve efficiency and effectiveness in dynamic tasks is limited. We suggest that the communication between a human and a computer can be improved if it involves a decision-making process in which the computer is programmed to infer the intentions of the human operator and dynamically adjust the control levels of the interacting parties to facilitate a more intuitive interaction setup. In this paper, we investigate the utility of such a dynamic role exchange mechanism, where partners negotiate through the haptic channel to trade their control levels on a collaborative task. We examine the energy consumption, the work done on the manipulated object, and the joint efficiency in addition to the task performance. We show that when compared to an equal control condition, a role exchange mechanism improves task performance and the joint efficiency of the partners. We also show that augmenting the system with additional informative visual and vibrotactile cues, which are used to display the state of interaction, allows the users to become aware of the underlying role exchange mechanism and utilize it in favor of the task. These cues also improve the user's sense of interaction and reinforce his/her belief that the computer aids with the execution of the task. PMID- 24808269 TI - Lossy data compression of vibrotactile material-like textures. AB - Tactile content will be delivered over the Internet in the near future. Vibrotactile material-like textures that resemble the surfaces of wood, leather, etc., are representative of such content. We performed lossy compression of texture data for reducing the data size. We confirmed the effectiveness of two compression strategies: quantization and truncation of data beneath a shifted perceptual threshold curve. In the quantization strategy, the amplitude spectra of vibrotactile textures could be quantized in 14 steps. This reduced the data size to approximately one quarter without any noticeable quality deterioration. The method for truncating frequency components with amplitudes smaller than a shifted perceptual threshold curve was also effective, and it was preferable to the automatic deletion of subthreshold amplitudes. We reduced the data size of vibrotactile material textures to 10-20 percent of their original size by combining the lossy data compression strategy with Huffman coding, which is a lossless data compression method. Lossy compression algorithms will enhance the online delivery of vibrotactile material-like textures by decreasing their data size without significant loss of quality. PMID- 24808270 TI - Psychophysical dimensions of tactile perception of textures. AB - This paper reviews studies on the tactile dimensionality of physical properties of materials in order to determine a common structure for these dimensions. Based on the commonality found in a number of studies and known mechanisms for the perception of physical properties of textures, we conclude that tactile textures are composed of three prominent psychophysical dimensions that are perceived as roughness/smoothness, hardness/softness, and coldness/warmness. The roughness dimension may be divided into two dimensions: macro and fine roughness. Furthermore, it is reasonable to consider that a friction dimension that is related to the perception of moistness/dryness and stickiness/slipperiness exists. Thus, the five potential dimensions of tactile perception are macro and fine roughness, warmness/coldness, hardness/softness, and friction (moistness/dryness, stickiness/slipperiness). We also summarize methods such as psychological experiments and mathematical approaches for structuring tactile dimensions and their limitations. PMID- 24808271 TI - The role of haptic feedback for the integration of intentions in shared task execution. AB - Recent developments strive for realizing robotic systems that not only interact, but closely collaborate with humans in performing everyday manipulation tasks. Successful collaboration requires the integration of the individual partner's intentions into a shared action plan, which may involve continuous negotiation of intentions. We focus on collaboration in a kinesthetic task, i.e., joint object manipulation. Here, ways must be found to integrate individual motion and force inputs from the members of the human-robot team, in order to achieve the joint task goal. Before guidelines on how robots should act in this process can be formulated, clarification on whether humans use the haptic channel for communicating their intentions is needed. This paper investigates this question in an experimental setup involving two collaborating humans. We consider physical effort as well as performance as indicators of successful intention integration. Our results strongly suggest that intention integration is enhanced via the haptic channel, i.e., that haptic communication takes place, especially in the case of shared decision situations. This provides a motivation for future investigations to model the process of intention integration itself in order to realize successful haptic human-robot collaboration. PMID- 24808272 TI - Using postural synergies to animate a low-dimensional hand avatar in haptic simulation. AB - A technique to animate a realistic hand avatar with 20 DoFs based on the biomechanics of the human hand is presented. The animation does not use any sensor glove or advanced tracker with markers. The proposed approach is based on the knowledge of a set of kinematic constraints on the model of the hand, referred to as postural synergies, which allows to represent the hand posture using a number of variables lower than the number of joints of the hand model. This low-dimensional set of parameters is estimated from direct measurement of the motion of thumb and index finger tracked using two haptic devices. A kinematic inversion algorithm has been developed, which takes synergies into account and estimates the kinematic configuration of the whole hand, i.e., also of the fingers whose end tips are not directly tracked by the two haptic devices. The hand skin is deformable and its deformation is computed using a linear vertex blending technique. The proposed synergy-based animation of the hand avatar involves only algebraic computations and is suitable for real-time implementation as required in haptics. PMID- 24808273 TI - Vibrotactile rendering of splashing fluids. AB - We introduce the use of vibrotactile feedback as a rendering modality for solid fluid interaction, based on the physical processes that generate sound during such interactions. This rendering approach enables the perception of vibrotactile feedback from virtual scenarios that resemble the experience of stepping into a water puddle or plunging a hand into a volume of fluid. PMID- 24808274 TI - Stability for neural networks with time-varying delays via some new approaches. AB - This paper considers the problem of delay-dependent stability criteria for neural networks with time-varying delays. First, by constructing a newly augmented Lyapunov-Krasovskii functional, a less conservative stability criterion is established in terms of linear matrix inequalities. Second, by proposing novel activation function conditions which have not been proposed so far, further improved stability criteria are proposed. Finally, three numerical examples used in the literature are given to show the improvements over the existing criteria and the effectiveness of the proposed idea. PMID- 24808275 TI - Sequential projection-based metacognitive learning in a radial basis function network for classification problems. AB - In this paper, we present a sequential projection-based metacognitive learning algorithm in a radial basis function network (PBL-McRBFN) for classification problems. The algorithm is inspired by human metacognitive learning principles and has two components: a cognitive component and a metacognitive component. The cognitive component is a single-hidden-layer radial basis function network with evolving architecture. The metacognitive component controls the learning process in the cognitive component by choosing the best learning strategy for the current sample and adapts the learning strategies by implementing self-regulation. In addition, sample overlapping conditions and past knowledge of the samples in the form of pseudosamples are used for proper initialization of new hidden neurons to minimize the misclassification. The parameter update strategy uses projection based direct minimization of hinge loss error. The interaction of the cognitive component and the metacognitive component addresses the what-to-learn, when-to learn, and how-to-learn human learning principles efficiently. The performance of the PBL-McRBFN is evaluated using a set of benchmark classification problems from the University of California Irvine machine learning repository. The statistical performance evaluation on these problems proves the superior performance of the PBL-McRBFN classifier over results reported in the literature. Also, we evaluate the performance of the proposed algorithm on a practical Alzheimer's disease detection problem. The performance results on open access series of imaging studies and Alzheimer's disease neuroimaging initiative datasets, which are obtained from different demographic regions, clearly show that PBL-McRBFN can handle a problem with change in distribution. PMID- 24808276 TI - Developing a local least-squares support vector machines-based neuro-fuzzy model for nonlinear and chaotic time series prediction. AB - Local modeling approaches, owing to their ability to model different operating regimes of nonlinear systems and processes by independent local models, seem appealing for modeling, identification, and prediction applications. In this paper, we propose a local neuro-fuzzy (LNF) approach based on the least-squares support vector machines (LSSVMs). The proposed LNF approach employs LSSVMs, which are powerful in modeling and predicting time series, as local models and uses hierarchical binary tree (HBT) learning algorithm for fast and efficient estimation of its parameters. The HBT algorithm heuristically partitions the input space into smaller subdomains by axis-orthogonal splits. In each partitioning, the validity functions automatically form a unity partition and therefore normalization side effects, e.g., reactivation, are prevented. Integration of LSSVMs into the LNF network as local models, along with the HBT learning algorithm, yield a high-performance approach for modeling and prediction of complex nonlinear time series. The proposed approach is applied to modeling and predictions of different nonlinear and chaotic real-world and hand-designed systems and time series. Analysis of the prediction results and comparisons with recent and old studies demonstrate the promising performance of the proposed LNF approach with the HBT learning algorithm for modeling and prediction of nonlinear and chaotic systems and time series. PMID- 24808277 TI - Radial basis function network training using a nonsymmetric partition of the input space and particle swarm optimization. AB - This paper presents a novel algorithm for training radial basis function (RBF) networks, in order to produce models with increased accuracy and parsimony. The proposed methodology is based on a nonsymmetric variant of the fuzzy means (FM) algorithm, which has the ability to determine the number and locations of the hidden-node RBF centers, whereas the synaptic weights are calculated using linear regression. Taking advantage of the short computational times required by the FM algorithm, we wrap a particle swarm optimization (PSO) based engine around it, designed to optimize the fuzzy partition. The result is an integrated framework for fully determining all the parameters of an RBF network. The proposed approach is evaluated through its application on 12 real-world and synthetic benchmark datasets and is also compared with other neural network training techniques. The results show that the RBF network models produced by the PSO-based nonsymmetric FM algorithm outperform the models produced by the other techniques, exhibiting higher prediction accuracies in shorter computational times, accompanied by simpler network structures. PMID- 24808278 TI - Compositional generative mapping for tree-structured data--part II: topographic projection model. AB - We introduce GTM-SD (Generative Topographic Mapping for Structured Data), which is the first compositional generative model for topographic mapping of tree structured data. GTM-SD exploits a scalable bottom-up hidden-tree Markov model that was introduced in Part I of this paper to achieve a recursive topographic mapping of hierarchical information. The proposed model allows efficient exploitation of contextual information from shared substructures by a recursive upward propagation on the tree structure which distributes substructure information across the topographic map. Compared to its noncompositional generative counterpart, GTM-SD is shown to allow the topographic mapping of the full sample tree, which includes a projection onto the lattice of all the distinct subtrees rooted in each of its nodes. Experimental results show that the continuous projection space generated by the smooth topographic mapping of GTM-SD yields a finer grained discrimination of the sample structures with respect to the state-of-the-art recursive neural network approach. PMID- 24808279 TI - Efficient multitemplate learning for structured prediction. AB - Conditional random fields (CRF) and structural support vector machines (structural SVM) are two state-of-the-art methods for structured prediction that captures the interdependencies among output variables. The success of these methods is attributed to the fact that their discriminative models are able to account for overlapping features on all input observations. These features are usually generated by applying a given set of templates on labeled data, but improper templates may lead to degraded performance. To alleviate this issue, in this paper we propose a novel multiple template learning paradigm to learn structured prediction and the importance of each template simultaneously, so that hundreds of arbitrary templates could be added into the learning model without caution. This paradigm can be formulated as a special multiple kernel learning problem with an exponential number of constraints. Then we introduce an efficient cutting-plane algorithm to solve this problem in the primal and present its convergence. We also evaluate the proposed learning paradigm on two widely studied structured prediction tasks, i.e., sequence labeling and dependency parsing. Extensive experimental results show that the proposed method outperforms CRFs and structural SVMs because of exploiting the importance of each template. Complexity analysis and empirical results also show that the proposed method is more efficient than Online multikernel learning on very sparse and high dimensional data. We further extend this paradigm for structured prediction using generalized p-block norm regularization with p >; 1, and experiments show competitive performances when p ? [1,2). PMID- 24808280 TI - Formulating robust linear regression estimation as a one-class LDA criterion: discriminative hat matrix. AB - Linear discriminant analysis, such as Fisher's criterion, is a statistical learning tool traditionally devoted to separating a training dataset into two or even several classes by the way of linear decision boundaries. In this paper, we show that this tool can formalize the robust linear regression problem as a robust estimator will do. More precisely, we develop a one-class Fischer's criterion in which the maximization provides both the regression parameters and the separation of the data in two classes: typical data and atypical data or outliers. This new criterion is built on the statistical properties of the subspace decomposition of the hat matrix. From this angle, we improve the discriminative properties of the hat matrix which is traditionally used as outlier diagnostic measure in linear regression. Naturally, we call this new approach discriminative hat matrix. The proposed algorithm is fully nonsupervised and needs only the initialization of one parameter. Synthetic and real datasets are used to study the performance both in terms of regression and classification of the proposed approach. We also illustrate its potential application to image recognition and fundamental matrix estimation in computer vision. PMID- 24808281 TI - Fuzzy-neural-network inherited sliding-mode control for robot manipulator including actuator dynamics. AB - This paper presents the design and analysis of an intelligent control system that inherits the robust properties of sliding-mode control (SMC) for an n-link robot manipulator, including actuator dynamics in order to achieve a high-precision position tracking with a firm robustness. First, the coupled higher order dynamic model of an n-link robot manipulator is briefy introduced. Then, a conventional SMC scheme is developed for the joint position tracking of robot manipulators. Moreover, a fuzzy-neural-network inherited SMC (FNNISMC) scheme is proposed to relax the requirement of detailed system information and deal with chattering control efforts in the SMC system. In the FNNISMC strategy, the FNN framework is designed to mimic the SMC law, and adaptive tuning algorithms for network parameters are derived in the sense of projection algorithm and Lyapunov stability theorem to ensure the network convergence as well as stable control performance. Numerical simulations and experimental results of a two-link robot manipulator actuated by DC servo motors are provided to justify the claims of the proposed FNNISMC system, and the superiority of the proposed FNNISMC scheme is also evaluated by quantitative comparison with previous intelligent control schemes. PMID- 24808282 TI - Generalization performance of Fisher linear discriminant based on Markov sampling. AB - Fisher linear discriminant (FLD) is a well-known method for dimensionality reduction and classification that projects high-dimensional data onto a low dimensional space where the data achieves maximum class separability. The previous works describing the generalization ability of FLD have usually been based on the assumption of independent and identically distributed (i.i.d.) samples. In this paper, we go far beyond this classical framework by studying the generalization ability of FLD based on Markov sampling. We first establish the bounds on the generalization performance of FLD based on uniformly ergodic Markov chain (u.e.M.c.) samples, and prove that FLD based on u.e.M.c. samples is consistent. By following the enlightening idea from Markov chain Monto Carlo methods, we also introduce a Markov sampling algorithm for FLD to generate u.e.M.c. samples from a given data of finite size. Through simulation studies and numerical studies on benchmark repository using FLD, we find that FLD based on u.e.M.c. samples generated by Markov sampling can provide smaller misclassification rates compared to i.i.d. samples. PMID- 24808283 TI - Selective positive-negative feedback produces the winner-take-all competition in recurrent neural networks. AB - The winner-take-all (WTA) competition is widely observed in both inanimate and biological media and society. Many mathematical models are proposed to describe the phenomena discovered in different fields. These models are capable of demonstrating the WTA competition. However, they are often very complicated due to the compromise with experimental realities in the particular fields; it is often difficult to explain the underlying mechanism of such a competition from the perspective of feedback based on those sophisticate models. In this paper, we make steps in that direction and present a simple model, which produces the WTA competition by taking advantage of selective positive-negative feedback through the interaction of neurons via p-norm. Compared to existing models, this model has an explicit explanation of the competition mechanism. The ultimate convergence behavior of this model is proven analytically. The convergence rate is discussed and simulations are conducted in both static and dynamic competition scenarios. Both theoretical and numerical results validate the effectiveness of the dynamic equation in describing the nonlinear phenomena of WTA competition. PMID- 24808284 TI - Identification and prediction of dynamic systems using an interactively recurrent self-evolving fuzzy neural network. AB - This paper presents a novel recurrent fuzzy neural network, called an interactively recurrent self-evolving fuzzy neural network (IRSFNN), for prediction and identification of dynamic systems. The recurrent structure in an IRSFNN is formed as an external loops and internal feedback by feeding the rule firing strength of each rule to others rules and itself. The consequent part in the IRSFNN is composed of a Takagi-Sugeno-Kang (TSK) or functional-link-based type. The proposed IRSFNN employs a functional link neural network (FLNN) to the consequent part of fuzzy rules for promoting the mapping ability. Unlike a TSK type fuzzy neural network, the FLNN in the consequent part is a nonlinear function of input variables. An IRSFNNs learning starts with an empty rule base and all of the rules are generated and learned online through a simultaneous structure and parameter learning. An on-line clustering algorithm is effective in generating fuzzy rules. The consequent update parameters are derived by a variable-dimensional Kalman filter algorithm. The premise and recurrent parameters are learned through a gradient descent algorithm. We test the IRSFNN for the prediction and identification of dynamic plants and compare it to other well-known recurrent FNNs. The proposed model obtains enhanced performance results. PMID- 24808285 TI - New discrete-time recurrent neural network proposal for quadratic optimization with general linear constraints. AB - In this brief, the quadratic problem with general linear constraints is reformulated using the Wolfe dual theory, and a very simple discrete-time recurrent neural network is proved to be able to solve it. Conditions that guarantee global convergence of this network to the constrained minimum are developed. The computational complexity of the method is analyzed, and experimental work is presented that shows its high efficiency. PMID- 24808286 TI - Incorporating mean template into finite mixture model for image segmentation. AB - The well-known finite mixture model (FMM) has been regarded as a useful tool for image segmentation application. However, the pixels in FMM are considered independent of each other and the spatial relationship between neighboring pixels is not taken into account. These limitations make the FMM more sensitive to noise. In this brief, we propose a simple and effective method to make the traditional FMM more robust to noise with the help of a mean template. FMM can be considered a linear combination of prior and conditional probability from the expression of its mathematical formula. We calculate these probabilities with two mean templates: a weighted arithmetic mean template and a weighted geometric mean template. Thus, in our model, the prior probability (or conditional probability) of an image pixel is influenced by the probabilities of pixels in its immediate neighborhood to incorporate the local spatial and intensity information for eliminating the noise. Finally, our algorithm is general enough and can be extended to any other FMM-based models to achieve super performance. Experimental results demonstrate the improved robustness and effectiveness of our approach. PMID- 24808287 TI - Hyperbolic Hopfield neural networks. AB - In recent years, several neural networks using Clifford algebra have been studied. Clifford algebra is also called geometric algebra. Complex-valued Hopfield neural networks (CHNNs) are the most popular neural networks using Clifford algebra. The aim of this brief is to construct hyperbolic HNNs (HHNNs) as an analog of CHNNs. Hyperbolic algebra is a Clifford algebra based on Lorentzian geometry. In this brief, a hyperbolic neuron is defined in a manner analogous to a phasor neuron, which is a typical complex-valued neuron model. HHNNs share common concepts with CHNNs, such as the angle and energy. However, HHNNs and CHNNs are different in several aspects. The states of hyperbolic neurons do not form a circle, and, therefore, the start and end states are not identical. In the quantized version, unlike complex-valued neurons, hyperbolic neurons have an infinite number of states. PMID- 24808288 TI - Seri Rama: converting a shadow play puppet to Street Fighter. AB - Shadow puppet plays, a traditional Malaysian theater art, is slowly losing its appeal to adolescents, who prefer computer games. To help reverse this decline, the authors incorporated the traditional Seri Rama character into the Street Fighter video game. Using modeling, texturing, and animation, they developed a 3D Seri Rama prototype. Users can control Seri Rama with a PlayStation game controller. PMID- 24808289 TI - Scientific storytelling using visualization. PMID- 24808290 TI - Visual analysis of particle behaviors to understand combustion simulations. AB - A dual-space method enables effective visual analysis of particles' spatial movement and attribute evolution. Intuitive interaction tools integrate users' domain knowledge to steer classification. This method has been used to analyze combustion simulations and is applicable to other scientific simulations involving particle-data analysis. PMID- 24808291 TI - Real-time visualization of streaming text with a force-based dynamic system. AB - Streamit lets users explore visualizations of text streams without prior knowledge of the data. It incorporates incoming documents from a continuous source into an existing visualization context with automatic grouping and separation based on document similarities. A powerful user interface allows in depth data analysis. PMID- 24808292 TI - ImageHive: interactive content-aware image summarization. AB - ImageHive communicates information about an image collection by generating a summary image that preserves the relationships between images and avoids occluding their salient parts. It uses a constrained graph-layout algorithm first, to preserve image similarities and keep important parts visible, and then a constrained Voronoi tessellation algorithm to locally refine the layout and tile the image plane. PMID- 24808293 TI - Interactive density maps for moving objects. AB - Density maps show trends in objects' trajectories. Density map creation involves aggregating smoothed trajectories in a density field and visualizing the field. Using an interactive distribution map, users can define subsets and, supported by graphics hardware, get fast feedback for these computationally expensive density field calculations. PMID- 24808294 TI - Two visualization tools for analyzing agent-based simulations in political science. AB - MDSVis (Multidimensional Scaling Visualization) lets analysts explore the simulation space of agent-based models, finding similar patterns at an aggregated level and finding the dominant factors affecting agent behavior. SocialVis lets analysts narrow their analysis to a single simulation run, exploring relationships between time steps and geographic regions. PMID- 24808295 TI - Using time-varying texels to simulate withering grassland. AB - This approach employs a hybrid texel-and-points scheme, allowing the volume models to handle time-varying simulations. The modeling of grass carries out physically based calculations on the point-based structure. These calculations express the geometric deformation of each grass blade while providing a basis for further transformation of the desired texel array. PMID- 24808296 TI - Fostering collaboration and self-motivated learning: best practices in a one semester visualization course. PMID- 24808297 TI - Visual analytics for converging-business-ecosystem intelligence. PMID- 24808298 TI - A hand-centric classification of human and robot dexterous manipulation. AB - This work contributes to the development of a common framework for the discussion and analysis of dexterous manipulation across the human and robotic domains. An overview of previous work is first provided along with an analysis of the tradeoffs between arm and hand dexterity. A hand-centric and motion-centric manipulation classification is then presented and applied in four different ways. It is first discussed how the taxonomy can be used to identify a manipulation strategy. Then, applications for robot hand analysis and engineering design are explained. Finally, the classification is applied to three activities of daily living (ADLs) to distinguish the patterns of dexterous manipulation involved in each task. The same analysis method could be used to predict problem ADLs for various impairments or to produce a representative benchmark set of ADL tasks. Overall, the classification scheme proposed creates a descriptive framework that can be used to effectively describe hand movements during manipulation in a variety of contexts and might be combined with existing object centric or other taxonomies to provide a complete description of a specific manipulation task. PMID- 24808299 TI - An optoelectromechanical tactile sensor for detection of breast lumps. AB - We developed a compact tactile imaging (TI) system to guide the clinician or the self-user for noninvasive detection of breast tumors. Our system measures the force distribution based on the difference in stiffness between a palpated object and an abnormality within. The average force resolution, force range, and the spatial resolution of the device are 0.02 N, 0-4 N, and 2.8 mm, respectively. To evaluate the performance of the proposed TI system, compression experiments were performed to measure the sensitivity and specificity of the system in detecting tumor-like inclusions embedded in tissue-like cylindrical silicon samples. Based on the experiments performed with 11 inclusions, having two different sizes and two different stiffnesses located at three different depths, our TI system showed an average sensitivity of 90.8 +/- 8.1 percent and an average specificity of 89.8 +/- 12.7 percent. Finally, manual palpation experiments were performed with 12 human subjects on the same silicon samples and the results were compared to that of the TI system. The performance of the TI system was significantly better than that of the human subjects in detecting deep inclusions while the human subjects performed slightly better in detecting shallow inclusions close to the contact surface. PMID- 24808300 TI - Characterization and psychophysical studies of an air-jet lump display. AB - Development of tactile displays to enhance palpation of lumps during robot assisted minimally invasive surgery is challenging due to size and weight constraints, motivating a pneumatic actuation strategy. This work describes the quantitative and psychophysical assessment of an air-jet tactile display that creates a lump percept by directing pressurized air through an aperture onto the finger. The air pressure and aperture size are meant to control the hardness and size, respectively, of the perceived lump. Jet impingement pressure and flow rate were measured by capacitive tactile sensors and mass flow meters at varying aperture sizes and pressures. The air-jet pressure profile width evolves as jet theory predicts and is largely independent of supply pressure (and therefore jet exit velocity). The method of constant stimuli was used to determine the just noticeable differences (JNDs) for the air pressure and aperture size. Qualitative results indicate that subjects perceive the stimulus as a "lump-like" shape. Pressure JNDs ranged from 19.6-24.4 kPag and aperture size JNDs ranged from 0.50 0.66 mm. No significant correlation exists between the supply pressure and changes in perceived lump size. However, pressure JNDs show significant (p < 0.001) inverse correlation with aperture size, with improved discrimination at larger apertures, where a greater finger pad area is stimulated. PMID- 24808301 TI - Configuration-based optimization for six degree-of-freedom haptic rendering for fine manipulation. AB - Six-degree-of-freedom (6-DOF) haptic rendering for fine manipulation in narrow space is a challenging topic because of frequent constraint changes caused by small tool movement and the requirement to preserve the feel of fine-features of objects. In this paper, we introduce a configuration-based constrained optimization method for solving this rendering problem. We represent an object using a hierarchy of spheres, i.e., a sphere tree, which allows faster detection of multiple contacts/collisions among objects than polygonal mesh and facilitates contact constraint formulation. Given a moving graphic tool as the avatar of the haptic tool in the virtual environment, we compute its quasi-static motion by solving a configuration-based optimization. The constraints in the 6D configuration space of the graphic tool is obtained and updated through online mapping of the nonpenetration constraint between the spheres of the graphic tool and those of the other objects in the three-dimensional physical space, based on the result of collision detection. This problem is further modeled as a quadratic programming optimization and solved by the classic active-set methods. Our algorithm has been implemented and interfaced with a 6-DOF Phantom Premium 3.0. We demonstrate its performance in several benchmarks involving complex, multiregion contacts. The experimental results show both the high efficiency and stability of haptic rendering by our method for complex scenarios. Nonpenetration between the graphic tool and the object is maintained under frequent contact switches. Update rate of the simulation loop including optimization and constraint identification is maintained at about 1 kHz. PMID- 24808302 TI - Discrimination of real and virtual surfaces with sinusoidal and triangular gratings using the fingertip and stylus. AB - Two-interval two-alternative forced-choice discrimination experiments were conducted separately for sinusoidal and triangular textured surface gratings from which amplitude (i.e., height) discrimination thresholds were estimated. Participants (group sizes: n = 4 to 7) explored one of these texture types either by fingertip on real gratings (Finger real), by stylus on real gratings (Stylus real), or by stylus on virtual gratings (Stylus virtual). The real gratings were fabricated from stainless steel by an electrical discharge machining process while the virtual gratings were rendered via a programmable force-feedback device. All gratings had a 2.5-mm spatial period. On each trial, participants compared test gratings with 55, 60, 65, or 70 MUm amplitudes against a 50-MUm reference. The results indicate that discrimination thresholds did not differ significantly between sinusoidal and triangular gratings. With sinusoidal and triangular data combined, the average (mean + standard error) for the Stylus-real threshold (2.5 +/- 0.2 MUm) was significantly smaller (p <; 0.01) than that for the Stylus-virtual condition (4.9 +/- 0.2 MUm). Differences between the Finger real threshold (3.8 +/- 0.2 MUm) and those from the other two conditions were not statistically significant. Further studies are needed to better understand the differences in perceptual cues resulting from interactions with real and virtual gratings. PMID- 24808303 TI - Enhancing audiovisual experience with haptic feedback: a survey on HAV. AB - Haptic technology has been widely employed in applications ranging from teleoperation and medical simulation to art and design, including entertainment, flight simulation, and virtual reality. Today there is a growing interest among researchers in integrating haptic feedback into audiovisual systems. A new medium emerges from this effort: haptic-audiovisual (HAV) content. This paper presents the techniques, formalisms, and key results pertinent to this medium. We first review the three main stages of the HAV workflow: the production, distribution, and rendering of haptic effects. We then highlight the pressing necessity for evaluation techniques in this context and discuss the key challenges in the field. By building on existing technologies and tackling the specific challenges of the enhancement of audiovisual experience with haptics, we believe the field presents exciting research perspectives whose financial and societal stakes are significant. PMID- 24808304 TI - Force-sensitive detents improve user performance for linear selection tasks. AB - Haptic technology, providing force cues and creating a programmable interface, can assist users in more accurately using an interface. This paper investigates haptic assistance in combination with auditory feedback instead of visual feedback. A user test is carried out in which participants select fundamental frequencies from a continuous range to play brief musical melodies. Two control conditions are compared with two detent-based haptic assistance conditions. The detents gently guide the users toward locations of equal tempered fundamental frequencies. Results from the user test confirm improved accuracy brought about by the detents. It is further helpful to provide regulation of the strength of haptic assistance in real time, allowing the user to remain always in control. This concept motivated the force-sensitive detent condition, which enables the user to adjust the strength of the haptic assistance in real time by changing the downward force applied to the haptic device. The work implies that users of graphical user interfaces could similarly benefit from force-sensitive detents and more generally real-time regulation of the strength of haptic assistance. PMID- 24808305 TI - Integration of force reflection with tactile sensing for minimally invasive robotics-assisted tumor localization. AB - Tactile sensing and force reflection have been the subject of considerable research for tumor localization in soft-tissue palpation. The work presented in this paper investigates the relevance of force feedback (presented visually as well as directly) during tactile sensing (presented visually only) for tumor localization using an experimental setup close to one that could be applied for real robotics-assisted minimally invasive surgery. The setup is a teleoperated (master-slave) system facilitated with a state-of-the-art minimally invasive probe with a rigidly mounted tactile sensor at the tip and an externally mounted force sensor at the base of the probe. The objective is to capture the tactile information and measure the interaction forces between the probe and tissue during palpation and to explore how they can be integrated to improve the performance of tumor localization. To quantitatively explore the effect of force feedback on tactile sensing tumor localization, several experiments were conducted by human subjects to locate artificial tumors embedded in the ex vivo bovine livers. The results show that using tactile sensing in a force-controlled environment can realize, on average, 57 percent decrease in the maximum force and 55 percent decrease in the average force applied to tissue while increasing the tumor detection accuracy by up to 50 percent compared to the case of using tactile feedback alone. The results also show that while visual presentation of force feedback gives straightforward quantitative measures, improved performance of tactile sensing tumor localization is achieved at the expense of longer times for the user. Also, the quickness and intuitive data mapping of direct force feedback makes it more appealing to experienced users. PMID- 24808306 TI - Robust stability of teleoperation systems with time delay: a new approach. AB - In this paper, we propose an approach to the control of linear teleoperation systems under time delays. Unlike traditional delay-robust control systems that guarantee passive communication channel through the transmission of wave variables, the new approach uses the concept of absolute stability for the physically expressive Lawrence's four-channel structure for transmitting the standard power variables, i.e., force and position. By incorporating kinesthetic performance requirements, we derive an absolutely stable four-channel controller that is transparent when time delay is negligible. Experimentally, the study evaluates and compares the performance of the proposed controller with that of a benchmark wave variable-based controller. The results indicate contact stability for large delays, a lack of position drift, and improved position and force tracking in both the free motion and rigid contact regimes for small delays. PMID- 24808307 TI - The impact of haptic feedback quality on the performance of teleoperated assembly tasks. AB - In teleoperation, haptic feedback allows the human operator to touch the remote environment. Yet, it is only partially understood to what extent the quality of haptic feedback contributes to human-in-the-loop task performance. This paper presents a human factors experiment in which teleoperated task performance and control effort are assessed for a typical (dis-)assembly task in a hard-to-hard environment, well known to the operator. Subjects are provided with four levels of haptic feedback quality: no haptic feedback, low-frequency haptic feedback, combined low- and high-frequency haptic feedback, and the best possible-a natural spectrum of haptic feedback in a direct-controlled equivalent of the task. Four generalized fundamental subtasks are identified, namely: 1) free-space movement, 2) contact transition, 3) constrained translational, and 4) constrained rotational tasks. The results show that overall task performance and control effort are primarily improved by providing low-frequency haptic feedback (specifically by improvements in constrained translational and constrained rotational tasks), while further haptic feedback quality improvements yield only marginal performance increases and control effort decreases, even if a full natural spectrum of haptic feedback is provided. PMID- 24808309 TI - Dissipativity analysis for discrete-time stochastic neural networks with time varying delays. AB - In this paper, the problem of dissipativity analysis is discussed for discrete time stochastic neural networks with time-varying discrete and finite-distributed delays. The discretized Jensen inequality and lower bounds lemma are adopted to deal with the involved finite sum quadratic terms, and a sufficient condition is derived to ensure the considered neural networks to be globally asymptotically stable in the mean square and strictly (Q, S, R)-y-dissipative, which is delay dependent in the sense that it depends on not only the discrete delay but also the finite-distributed delay. Based on the dissipativity criterion, some special cases are also discussed. Compared with the existing ones, the merit of the proposed results in this paper lies in their reduced conservatism and less decision variables. Three examples are given to illustrate the effectiveness and benefits of our theoretical results. PMID- 24808310 TI - Model-based online learning with kernels. AB - New optimization models and algorithms for online learning with Kernels (OLK) in classification, regression, and novelty detection are proposed in a reproducing Kernel Hilbert space. Unlike the stochastic gradient descent algorithm, called the naive online Reg minimization algorithm (NORMA), OLK algorithms are obtained by solving a constrained optimization problem based on the proposed models. By exploiting the techniques of the Lagrange dual problem like Vapnik's support vector machine (SVM), the solution of the optimization problem can be obtained iteratively and the iteration process is similar to that of the NORMA. This further strengthens the foundation of OLK and enriches the research area of SVM. We also apply the obtained OLK algorithms to problems in classification, regression, and novelty detection, including real time background substraction, to show their effectiveness. It is illustrated that, based on the experimental results of both classification and regression, the accuracy of OLK algorithms is comparable with traditional SVM-based algorithms, such as SVM and least square SVM (LS-SVM), and with the state-of-the-art algorithms, such as Kernel recursive least square (KRLS) method and projectron method, while it is slightly higher than that of NORMA. On the other hand, the computational cost of the OLK algorithm is comparable with or slightly lower than existing online methods, such as above mentioned NORMA, KRLS, and projectron methods, but much lower than that of SVM-based algorithms. In addition, different from SVM and LS-SVM, it is possible for OLK algorithms to be applied to non-stationary problems. Also, the applicability of OLK in novelty detection is illustrated by simulation results. PMID- 24808311 TI - Adaptive control for nonlinear pure-feedback systems with high-order sliding mode observer. AB - Most of the available control schemes for pure-feedback systems are derived based on the backstepping technique. On the contrary, this paper presents a novel adaptive control design for nonlinear pure-feedback systems without using backstepping. By introducing a set of alternative state variables and the corresponding transform, state-feedback control of the pure-feedback system can be viewed as output-feedback control of a canonical system. Consequently, backstepping is not necessary and the previously encountered explosion of complexity and circular issue are also circumvented. To estimate unknown states of the newly derived canonical system, a high-order sliding mode observer is adopted, for which finite-time observer error convergence is guaranteed. Two adaptive neural controllers are then proposed to achieve tracking control. In the first scheme, a robust term is introduced to account for the neural approximation error. In the second scheme, a novel neural network with only a scalar weight updated online is constructed to further reduce the computational costs. The closed-loop stability and the convergence of the tracking error to a small compact set around zero are all proved. Comparative simulation and practical experiments on a servo motor system are included to verify the reliability and effectiveness. PMID- 24808312 TI - Low-rank structure learning via nonconvex heuristic recovery. AB - In this paper, we propose a nonconvex framework to learn the essential low-rank structure from corrupted data. Different from traditional approaches, which directly utilizes convex norms to measure the sparseness, our method introduces more reasonable nonconvex measurements to enhance the sparsity in both the intrinsic low-rank structure and the sparse corruptions. We will, respectively, introduce how to combine the widely used lp norm (0 < p < 1) and log-sum term into the framework of low-rank structure learning. Although the proposed optimization is no longer convex, it still can be effectively solved by a majorization-minimization (MM)-type algorithm, with which the nonconvex objective function is iteratively replaced by its convex surrogate and the nonconvex problem finally falls into the general framework of reweighed approaches. We prove that the MM-type algorithm can converge to a stationary point after successive iterations. The proposed model is applied to solve two typical problems: robust principal component analysis and low-rank representation. Experimental results on low-rank structure learning demonstrate that our nonconvex heuristic methods, especially the log-sum heuristic recovery algorithm, generally perform much better than the convex-norm-based method (0 < p < 1) for both data with higher rank and with denser corruptions. PMID- 24808313 TI - Synaptic variability in a cortical neuromorphic circuit. AB - Variable behavior has been observed in several mechanisms found in biological neurons, resulting in changes in neural behavior that might be useful to capture in neuromorphic circuits. This paper presents a neuromorphic cortical neuron with synaptic neurotransmitter-release variability, which is designed to be used in neural networks as part of the Biomimetic Real-Time Cortex project. This neuron has been designed and simulated using carbon nanotube (CNT) transistors, which is one of several nanotechnologies under consideration to meet the challenges of scale presented by the cortex. Some research results suggest that some instances of variability are stochastic, while others indicate that some instances of variability are chaotic. In this paper, both possible sources of variability are considered by embedding either Gaussian noise or a chaotic signal into the neuromorphic or synaptic circuit and observing the simulation results. In order to embed chaotic behavior into the neuromorphic circuit, a chaotic signal generator circuit is presented, implemented with CNT transistors that could be embedded in the electronic neural circuit, and simulated using CNT SPICE models. The circuit uses a chaotic piecewise linear 1-D map implemented by switched current circuits. The simulation results presented in this paper illustrate that neurotransmitter-release variability plays a beneficial role in the reliability of spike generation. In an examination of this reliability, the precision of spike timing in the CNT circuit simulations is found to be dependent on stimulus (postsynaptic potential) transients. Postsynaptic potentials with low neurotransmitter release variability or without neurotransmitter release variability produce imprecise spike trains, whereas postsynaptic potentials with high neurotransmitter-release variability produce spike trains with reproducible timing. PMID- 24808314 TI - Sampled-data synchronization of chaotic Lur'e systems with time delays. AB - This paper studies the problem of sampled-data control for master-slave synchronization schemes that consist of identical chaotic Lur'e systems with time delays. It is assumed that the sampling periods are arbitrarily varying but bounded. In order to take full advantage of the available information about the actual sampling pattern, a novel Lyapunov functional is proposed, which is positive definite at sampling times but not necessarily positive definite inside the sampling intervals. Based on the Lyapunov functional, an exponential synchronization criterion is derived by analyzing the corresponding synchronization error systems. The desired sampled-data controller is designed by a linear matrix inequality approach. The effectiveness and reduced conservatism of the developed results are demonstrated by the numerical simulations of Chua's circuit and neural network. PMID- 24808315 TI - Multiplicative update rules for concurrent nonnegative matrix factorization and maximum margin classification. AB - The state-of-the-art classification methods which employ nonnegative matrix factorization (NMF) employ two consecutive independent steps. The first one performs data transformation (dimensionality reduction) and the second one classifies the transformed data using classification methods, such as nearest neighbor/centroid or support vector machines (SVMs). In the following, we focus on using NMF factorization followed by SVM classification. Typically, the parameters of these two steps, e.g., the NMF bases/coefficients and the support vectors, are optimized independently, thus leading to suboptimal classification performance. In this paper, we merge these two steps into one by incorporating maximum margin classification constraints into the standard NMF optimization. The notion behind the proposed framework is to perform NMF, while ensuring that the margin between the projected data of the two classes is maximal. The concurrent NMF factorization and support vector optimization are performed through a set of multiplicative update rules. In the same context, the maximum margin classification constraints are imposed on the NMF problem with additional discriminant constraints and respective multiplicative update rules are extracted. The impact of the maximum margin classification constraints on the NMF factorization problem is addressed in Section VI. Experimental results in several databases indicate that the incorporation of the maximum margin classification constraints into the NMF and discriminant NMF objective functions improves the accuracy of the classification. PMID- 24808316 TI - Distributed synchronization of coupled neural networks via randomly occurring control. AB - In this paper, we study the distributed synchronization and pinning distributed synchronization of stochastic coupled neural networks via randomly occurring control. Two Bernoulli stochastic variables are used to describe the occurrences of distributed adaptive control and updating law according to certain probabilities. Both distributed adaptive control and updating law for each vertex in a network depend on state information on each vertex's neighborhood. By constructing appropriate Lyapunov functions and employing stochastic analysis techniques, we prove that the distributed synchronization and the distributed pinning synchronization of stochastic complex networks can be achieved in mean square. Additionally, randomly occurring distributed control is compared with periodically intermittent control. It is revealed that, although randomly occurring control is an intermediate method among the three types of control in terms of control costs and convergence rates, it has fewer restrictions to implement and can be more easily applied in practice than periodically intermittent control. PMID- 24808317 TI - Portfolio of automated trading systems: complexity and learning set size issues. AB - In this paper, we consider using profit/loss histories of multiple automated trading systems (ATSs) as N input variables in portfolio management. By means of multivariate statistical analysis and simulation studies, we analyze the influences of sample size (L) and input dimensionality on the accuracy of determining the portfolio weights. We find that degradation in portfolio performance due to inexact estimation of N means and N(N - 1)/2 correlations is proportional to N/L; however, estimation of N variances does not worsen the result. To reduce unhelpful sample size/dimensionality effects, we perform a clustering of N time series and split them into a small number of blocks. Each block is composed of mutually correlated ATSs. It generates an expert trading agent based on a nontrainable 1/N portfolio rule. To increase the diversity of the expert agents, we use training sets of different lengths for clustering. In the output of the portfolio management system, the regularized mean-variance framework-based fusion agent is developed in each walk-forward step of an out-of sample portfolio validation experiment. Experiments with the real financial data (2003-2012) confirm the effectiveness of the suggested approach. PMID- 24808318 TI - Regularized mixture density estimation with an analytical setting of shrinkage intensities. AB - In this paper, we propose a method for P-variate probability density estimation assuming a Gaussian mixture model (GMM). Our method exploits a regularization technique for improving the estimation accuracy of the GMM component covariance matrices. We derive an expectation maximization algorithm for fitting our regularized GMM (RGMM), which exploits an analytical Ledoit-Wolf-type shrinkage estimation of the covariance matrices. Our method is compared with recent model based and variational Bayes approximation methods using synthetic and real data sets. The obtained results show that the proposed RGMM method achieves a significant improvement in the performance of multivariate probability density estimation with respect to other methods on both the synthetic and the real data sets. PMID- 24808319 TI - Stochastic optimal controller design for uncertain nonlinear networked control system via neuro dynamic programming. AB - The stochastic optimal controller design for the nonlinear networked control system (NNCS) with uncertain system dynamics is a challenging problem due to the presence of both system nonlinearities and communication network imperfections, such as random delays and packet losses, which are not unknown a priori. In the recent literature, neuro dynamic programming (NDP) techniques, based on value and policy iterations, have been widely reported to solve the optimal control of general affine nonlinear systems. However, for realtime control, value and policy iterations-based methodology are not suitable and time-based NDP techniques are preferred. In addition, output feedback-based controller designs are preferred for implementation. Therefore, in this paper, a novel NNCS representation incorporating the system uncertainties and network imperfections is introduced first by using input and output measurements for facilitating output feedback. Then, an online neural network (NN) identifier is introduced to estimate the control coefficient matrix, which is subsequently utilized for the controller design. Subsequently, the critic and action NNs are employed along with the NN identifier to determine the forward-in-time, time-based stochastic optimal control of NNCS without using value and policy iterations. Here, the value function and control inputs are updated once a sampling instant. By using novel NN weight update laws, Lyapunov theory is used to show that all the closed-loop signals and NN weights are uniformly ultimately bounded in the mean while the approximated control input converges close to its target value with time. Simulation results are included to show the effectiveness of the proposed scheme. PMID- 24808320 TI - Simple exponential family PCA. AB - Principal component analysis (PCA) is a widely used model for dimensionality reduction. In this paper, we address the problem of determining the intrinsic dimensionality of a general type data population by selecting the number of principal components for a generalized PCA model. In particular, we propose a generalized Bayesian PCA model, which deals with general type data by employing exponential family distributions. Model selection is realized by empirical Bayesian inference of the model. We name the model as simple exponential family PCA (SePCA), since it embraces both the principal of using a simple model for data representation and the practice of using a simplified computational procedure for the inference. Our analysis shows that the empirical Bayesian inference in SePCA formally realizes an intuitive criterion for PCA model selection - a preserved principal component must sufficiently correlate to data variance that is uncorrelated to the other principal components. Experiments on synthetic and real data sets demonstrate effectiveness of SePCA and exemplify its characteristics for model selection. PMID- 24808321 TI - Dynamics analysis of a population decoding model. AB - Information processing in the nervous system involves the activity of large populations of neurons. It is difficult to extract information from these population codes because of the noise inherent in neuronal responses. We propose a divisive normalization model to read the population codes. The dynamics of the model are analyzed by continuous attractor theory. Under certain conditions, the model possesses continuous attractors. Moreover, the explicit expressions of the continuous attractors are provided. Simulations are employed to illustrate the theory. PMID- 24808322 TI - Learning with kernel smoothing models and low-discrepancy sampling. AB - This brief presents an analysis of the performance of kernel smoothing models used to estimate an unknown target function, addressing the case where the choice of the training set is part of the learning process. In particular, we consider a choice of the points at which the function is observed based on low-discrepancy sequences, which is a family of sampling methods commonly employed for efficient numerical integration. We prove that, under suitable regularity assumptions, consistency of the empirical risk minimization is guaranteed with a good rate of convergence of the estimation error, as well as the convergence of the approximation error. Simulation results confirm, in practice, the good theoretical properties given by the combination of kernel smoothing models with low-discrepancy sampling. PMID- 24808323 TI - A proxy method for real-time 3-DOF haptic rendering of streaming point cloud data. AB - This paper presents a new haptic rendering method for streaming point cloud data. It provides haptic rendering of moving physical objects using data obtained from RGB-D cameras. Thus, real-time haptic interaction with moving objects can be achieved using noncontact sensors. This method extends "virtual coupling"-based proxy methods in a way that does not require preprocessing of points and allows for spatial point cloud discontinuities. The key ideas of the algorithm are iterative motion of the proxy with respect to the points, and the use of a variable proxy step size that results in better accuracy for short proxy movements and faster convergence for longer movements. This method provides highly accurate haptic interaction for geometries in which the proxy can physically fit. Another advantage is a significant reduction in the risk of "pop through" during haptic interaction with dynamic point clouds, even in the presence of noise. This haptic rendering method is computationally efficient; it can run in real time on available personal computers without the need for downsampling of point clouds from commercially available depth cameras. PMID- 24808324 TI - Application of psychophysical techniques to haptic research. AB - Various psychophysical methods have been used to study human haptic perception, although the selection of a particular method is often based on convention, rather than an analysis of which technique is optimal for the question being addressed. In this review, classical psychophysical techniques used to measure sensory thresholds are described as well as more modern methods such as adaptive procedures and those associated with signal detection theory. Details are provided as to how these techniques should be implemented to measure absolute and difference thresholds and factors that influence subjects' responses are noted. In addition to the methods used to measure sensory thresholds, the techniques available for measuring the perception of suprathreshold stimuli are presented. These scaling methods are reviewed in the context of the various stimulus and response biases that influence how subjects respond to stimuli. The importance of understanding the factors that influence perceptual processing is highlighted throughout the review with reference to experimental studies of haptic perception. PMID- 24808325 TI - Bimanual integration of position and curvature in haptic perception. AB - For small stimuli, it has been shown that subjects are very accurate in distinguishing a cylinder with an elliptical cross section from one with a circular cross section. In such a task, both curvature and length are integrated effectively. Large cylinders are explored differently: either by one hand or by two hands sliding over the surface. However, the same cues are available. We investigated the integration of position and curvature in unimanual and bimanual explorations. In Experiment 1, curved surfaces were presented as part of a horizontal cylinder with a cross section that was either a horizontally or a vertically elongated ellipse. We found that discrimination thresholds for unimanual exploration were significantly larger than for bimanual exploration. In Experiment 2, we found that position discrimination thresholds were independent of the type of exploration (unimanual or bimanual) and surprisingly also independent of the reference length. In Experiment 3, we found that discrimination thresholds for the position of the midsagittal plane were on an average lower than the position discrimination thresholds found in Experiment 2. From these findings, we conclude that the lower thresholds in Experiment 1 for bimanual exploration compared to unimanual exploration are due to the integration of curvature, not position or uncertainty of the midsagittal plane in unimanual exploration. PMID- 24808326 TI - Grasp frequency and usage in daily household and machine shop tasks. AB - In this paper, we present results from a study of prehensile human hand use during the daily work activities of four subjects: two housekeepers and two machinists. Subjects wore a head-mounted camera that recorded their hand usage during their daily work activities in their typical place of work. For each subject, 7.45 hours of video was analyzed, recording the type of grasp being used and its duration. From this data, we extracted overall grasp frequency, duration distributions for each grasp, and common transitions between grasps. The results show that for 80 percent of the study duration the housekeepers used just five grasps and the machinists used 10. The grasping patterns for the different subjects were compared, and the overall top 10 grasps are discussed in detail. The results of this study not only lend insight into how people use their hands during daily tasks, but can also inform the design of effective robotic and prosthetic hands. PMID- 24808327 TI - Human force discrimination during active arm motion for force feedback design. AB - The goal of this study was to analyze the human ability of external force discrimination while actively moving the arm. With the approach presented here, we give an overview for the whole arm of the just-noticeable differences (JNDs) for controlled movements separately executed for the wrist, elbow, and shoulder joints. The work was originally motivated in the design phase of the actuation system of a wearable exoskeleton, which is used in a teleoperation scenario where force feedback should be provided to the subject. The amount of this force feedback has to be calibrated according to the human force discrimination abilities. In the experiments presented here, 10 subjects performed a series of movements facing an opposing force from a commercial haptic interface. Force changes had to be detected in a two-alternative forced choice task. For each of the three joints tested, perceptual thresholds were measured as absolute thresholds (no reference force) and three JNDs corresponding to three reference forces chosen. For this, we used the outcome of the QUEST procedure after 70 trials. Using these four measurements we computed the Weber fraction. Our results demonstrate that different Weber fractions can be measured with respect to the joint. These were 0.11, 0.13, and 0.08 for wrist, elbow, and shoulder, respectively. It is discussed that force perception may be affected by the number of muscles involved and the reproducibility of the movement itself. The minimum perceivable force, on average, was 0.04 N for all three joints. PMID- 24808328 TI - Mechanical and psychophysical studies of surface wave propagation during vibrotactile stimulation. AB - Tactile displays are often used to present spatial cues about the environment, although the optimal configuration of a display used for spatial cuing is not known. The objective of the present set of experiments was to characterize the properties of surface waves induced by vibrotactile stimulation and to determine if the propagation of surface waves was a factor influencing the ability to localize a point of stimulation in a tactile display. Three sites on the body were tested: the palm of the hand, the forearm, and the thigh. An accelerometer array was fabricated and used to measure the surface waves. The results indicated that there were significant differences between glabrous and hairy skin in terms of the frequency and amplitude of oscillation of the motor. Analyses of the motion of the surface waves across the skin indicated that they were markedly attenuated at 8 mm from the motor, but even at 24 mm the amplitude was still above perceptual threshold. The localization experiment indicated that subjects were much better at identifying the site of stimulation on the palm as compared to the forearm and thigh, and that the latter two sites were not significantly different. PMID- 24808329 TI - Mental rotation of tactile stimuli: using directional haptic cues in mobile devices. AB - Haptic interfaces have the potential to enrich users' interactions with mobile devices and convey information without burdening the user's visual or auditory attention. Haptic stimuli with directional content, for example, navigational cues, may be difficult to use in handheld applications; the user's hand, where the cues are delivered, may not be aligned with the world, where the cues are to be interpreted. In such a case, the user would be required to mentally transform the stimuli between different reference frames. We examine the mental rotation of directional haptic stimuli in three experiments, investigating: 1) users' intuitive interpretation of rotated stimuli, 2) mental rotation of haptic stimuli about a single axis, and 3) rotation about multiple axes and the effects of specific hand poses and joint rotations. We conclude that directional haptic stimuli are suitable for use in mobile applications, although users do not naturally interpret rotated stimuli in any one universal way. We find evidence of cognitive processes involving the rotation of analog, spatial representations and discuss how our results fit into the larger body of mental rotation research. For small angles (e.g., less than 40 degree), these mental rotations come at little cost, but rotations with larger misalignment angles impact user performance. When considering the design of a handheld haptic device, our results indicate that hand pose must be carefully considered, as certain poses increase the difficulty of stimulus interpretation. Generally, all tested joint rotations impact task difficulty, but finger flexion and wrist rotation interact to greatly increase the cost of stimulus interpretation; such hand poses should be avoided when designing a haptic interface. PMID- 24808330 TI - Real-time dual-band haptic music player for mobile devices. AB - We introduce a novel dual-band haptic music player for real-time simultaneous vibrotactile playback with music in mobile devices. Our haptic music player features a new miniature dual-mode actuator that can produce vibrations consisting of two principal frequencies and a real-time vibration generation algorithm that can extract vibration commands from a music file for dual-band playback (bass and treble). The algorithm uses a "haptic equalizer" and provides plausible sound-to-touch modality conversion based on human perceptual data. In addition, we present a user study carried out to evaluate the subjective performance (precision, harmony, fun, and preference) of the haptic music player, in comparison with the current practice of bass-band-only vibrotactile playback via a single-frequency voice-coil actuator. The evaluation results indicated that the new dual-band playback outperforms the bass-only rendering, also providing several insights for further improvements. The developed system and experimental findings have implications for improving the multimedia experience with mobile devices. PMID- 24808331 TI - Vibrotactile perceived intensity for mobile devices as a function of direction, amplitude, and frequency. AB - Vibrotactile rendering is an emerging interaction method for information transmission in mobile devices, replacing or supplementing visual and auditory displays. To design effective vibrotactile actuators or display algorithms, an understanding of the perceived intensity (strength) of their vibrations is essential. This paper aims to build a robust model for the perceived intensities of mobile device vibrations, which can be immediately used by engineers and application designers. To this end, we carried out two psychophysical experiments using absolute magnitude estimation procedures. In Experiment I, we investigated the effects of vibration direction and device weight on the perceived intensity of mobile device vibrations. The vibration directions tested (height, width, and depth), and the device weights (90-130 g) were determined considering those of contemporary mobile devices. Only the vibration direction was found to be a statistically significant factor, showing the highest perceived intensities along the height direction of a mobile device. In Experiment II, we measured the perceived intensities of vibrations with various amplitudes and frequencies along the three vibration directions. Then, for each direction, a psychophysical magnitude function and equal sensation contours were constructed based on Stevens' power law, which clearly visualize the consequences of vibration parameter changes on the resulting perceptual strength. In addition, we found a monotonic relationship between the physical power of vibration absorbed by the hand and the resulting perceived intensity. This suggests that the former, which is greatly easier to acquire in practice, is a reliable predictor of the latter. We expect that the results of this study can provide immediate knowledge about the perceptual strength of vibrations that engineers and applications developers will find useful. PMID- 24808332 TI - A passivity criterion for sampled-data bilateral teleoperation systems. AB - A teleoperation system consists of a teleoperator, a human operator, and a remote environment. Conditions involving system and controller parameters that ensure the teleoperator passivity can serve as control design guidelines to attain maximum teleoperation transparency while maintaining system stability. In this paper, sufficient conditions for teleoperator passivity are derived for when position error-based controllers are implemented in discrete-time. This new analysis is necessary because discretization causes energy leaks and does not necessarily preserve the passivity of the system. The proposed criterion for sampled-data teleoperator passivity imposes lower bounds on the teleoperator's robots dampings, an upper bound on the sampling time, and bounds on the control gains. The criterion is verified through simulations and experiments. PMID- 24808333 TI - Directional torque perception with brief, asymmetric net rotation of a flywheel. AB - This paper proposes a directional torque feedback technique for mobile devices that creates brief unbalanced torque by suddenly starting to rotate a stationary flywheel and then stopping it soon after. The experimental results show that a twisting sensation was induced effectively with angular velocity profiles that include sudden starts. PMID- 24808334 TI - Effect of dynamic vibrotactile feedback on the control of isometric finger force. AB - This study investigates how controllability of force is influenced by concurrent vibrotactile feedback that is generated proportionally to the applied force. Three different models to provide tactile feedback are introduced: amplitude and frequency modulation and granular synthesis. Then, an experiment investigating the effect of the feedback models on force control is reported. The tactile feedback conditions were compared to each other and to a condition with no feedback in a force repetition and a force hold tasks. In the force repetition task, all the feedback conditions yielded significantly better accuracy compared to no feedback condition. In the force hold task, there was no difference in the accuracy between the conditions including the no feedback condition. The results suggest that dynamic vibrotactile feedback assists the force control in force repetition tasks. PMID- 24808335 TI - Clustering-based discriminant analysis for eye detection. AB - This paper proposes three clustering-based discriminant analysis (CDA) models to address the problem that the Fisher linear discriminant may not be able to extract adequate features for satisfactory performance, especially for two class problems. The first CDA model, CDA-1, divides each class into a number of clusters by means of the k-means clustering technique. In this way, a new within cluster scatter matrix Sw(c) and a new between-cluster scatter matrix Sb(c) are defined. The second and the third CDA models, CDA-2 and CDA-3, define a nonparametric form of the between-cluster scatter matrices N-Sb(c). The nonparametric nature of the between-cluster scatter matrices inherently leads to the derived features that preserve the structure important for classification. The difference between CDA-2 and CDA-3 is that the former computes the between cluster matrix N-Sb(c) on a local basis, whereas the latter computes the between cluster matrix N-Sb(c) on a global basis. This paper then presents an accurate CDA-based eye detection method. Experiments on three widely used face databases show the feasibility of the proposed three CDA models and the improved eye detection performance over some state-of-the-art methods. PMID- 24808336 TI - Robust superpixel tracking. AB - While numerous algorithms have been proposed for object tracking with demonstrated success, it remains a challenging problem for a tracker to handle large appearance change due to factors such as scale, motion, shape deformation, and occlusion. One of the main reasons is the lack of effective image representation schemes to account for appearance variation. Most of the trackers use high-level appearance structure or low-level cues for representing and matching target objects. In this paper, we propose a tracking method from the perspective of midlevel vision with structural information captured in superpixels. We present a discriminative appearance model based on superpixels, thereby facilitating a tracker to distinguish the target and the background with midlevel cues. The tracking task is then formulated by computing a target background confidence map, and obtaining the best candidate by maximum a posterior estimate. Experimental results demonstrate that our tracker is able to handle heavy occlusion and recover from drifts. In conjunction with online update, the proposed algorithm is shown to perform favorably against existing methods for object tracking. Furthermore, the proposed algorithm facilitates foreground and background segmentation during tracking. PMID- 24808337 TI - Lossy cutset coding of bilevel images based on Markov random fields. AB - An effective, low complexity method for lossy compression of scenic bilevel images, called lossy cutset coding, is proposed based on a Markov random field model. It operates by losslessly encoding pixels in a square grid of lines, which is a cutset with respect to a Markov random field model, and preserves key structural information, such as borders between black and white regions. Relying on the Markov random field model, the decoder takes a MAP approach to reconstructing the interior of each grid block from the pixels on its boundary, thereby creating a piecewise smooth image that is consistent with the encoded grid pixels. The MAP rule, which reduces to finding the block interiors with fewest black-white transitions, is directly implementable for the most commonly occurring block boundaries, thereby avoiding the need for brute force or iterative solutions. Experimental results demonstrate that the new method is computationally simple, outperforms the current lossy compression technique most suited to scenic bilevel images, and provides substantially lower rates than lossless techniques, e.g., JBIG, with little loss in perceived image quality. PMID- 24808338 TI - Characterness: an indicator of text in the wild. AB - Text in an image provides vital information for interpreting its contents, and text in a scene can aid a variety of tasks from navigation to obstacle avoidance and odometry. Despite its value, however, detecting general text in images remains a challenging research problem. Motivated by the need to consider the widely varying forms of natural text, we propose a bottom-up approach to the problem, which reflects the characterness of an image region. In this sense, our approach mirrors the move from saliency detection methods to measures of objectness. In order to measure the characterness, we develop three novel cues that are tailored for character detection and a Bayesian method for their integration. Because text is made up of sets of characters, we then design a Markov random field model so as to exploit the inherent dependencies between characters. We experimentally demonstrate the effectiveness of our characterness cues as well as the advantage of Bayesian multicue integration. The proposed text detector outperforms state-of-the-art methods on a few benchmark scene text detection data sets. We also show that our measurement of characterness is superior than state-of-the-art saliency detection models when applied to the same task. PMID- 24808339 TI - Tensor-based formulation and nuclear norm regularization for multienergy computed tomography. AB - The development of energy selective, photon counting X-ray detectors allows for a wide range of new possibilities in the area of computed tomographic image formation. Under the assumption of perfect energy resolution, here we propose a tensor-based iterative algorithm that simultaneously reconstructs the X-ray attenuation distribution for each energy. We use a multilinear image model rather than a more standard stacked vector representation in order to develop novel tensor-based regularizers. In particular, we model the multispectral unknown as a three-way tensor where the first two dimensions are space and the third dimension is energy. This approach allows for the design of tensor nuclear norm regularizers, which like its 2D counterpart, is a convex function of the multispectral unknown. The solution to the resulting convex optimization problem is obtained using an alternating direction method of multipliers approach. Simulation results show that the generalized tensor nuclear norm can be used as a standalone regularization technique for the energy selective (spectral) computed tomography problem and when combined with total variation regularization it enhances the regularization capabilities especially at low energy images where the effects of noise are most prominent. PMID- 24808340 TI - Optimal transport for secure spread-spectrum watermarking of still images. AB - This paper studies the impact of secure watermark embedding in digital images by proposing a practical implementation of secure spread-spectrum watermarking using distortion optimization. Because strong security properties (key-security and subspace-security) can be achieved using natural watermarking (NW) since this particular embedding lets the distribution of the host and watermarked signals unchanged, we use elements of transportation theory to minimize the global distortion. Next, we apply this new modulation, called transportation NW (TNW), to design a secure watermarking scheme for grayscale images. The TNW uses a multiresolution image decomposition combined with a multiplicative embedding which is taken into account at the distribution level. We show that the distortion solely relies on the variance of the wavelet subbands used during the embedding. In order to maximize a target robustness after JPEG compression, we select different combinations of subbands offering the lowest Bit Error Rates for a target PSNR ranging from 35 to 55 dB and we propose an algorithm to select them. The use of transportation theory also provides an average PSNR gain of 3.6 dB on PSNR with respect to the previous embedding for a set of 2000 images. PMID- 24808341 TI - Robust point matching via vector field consensus. AB - In this paper, we propose an efficient algorithm, called vector field consensus, for establishing robust point correspondences between two sets of points. Our algorithm starts by creating a set of putative correspondences which can contain a very large number of false correspondences, or outliers, in addition to a limited number of true correspondences (inliers). Next, we solve for correspondence by interpolating a vector field between the two point sets, which involves estimating a consensus of inlier points whose matching follows a nonparametric geometrical constraint. We formulate this a maximum a posteriori (MAP) estimation of a Bayesian model with hidden/latent variables indicating whether matches in the putative set are outliers or inliers. We impose nonparametric geometrical constraints on the correspondence, as a prior distribution, using Tikhonov regularizers in a reproducing kernel Hilbert space. MAP estimation is performed by the EM algorithm which by also estimating the variance of the prior model (initialized to a large value) is able to obtain good estimates very quickly (e.g., avoiding many of the local minima inherent in this formulation). We illustrate this method on data sets in 2D and 3D and demonstrate that it is robust to a very large number of outliers (even up to 90%). We also show that in the special case where there is an underlying parametric geometrical model (e.g., the epipolar line constraint) that we obtain better results than standard alternatives like RANSAC if a large number of outliers are present. This suggests a two-stage strategy, where we use our nonparametric model to reduce the size of the putative set and then apply a parametric variant of our approach to estimate the geometric parameters. Our algorithm is computationally efficient and we provide code for others to use it. In addition, our approach is general and can be applied to other problems, such as learning with a badly corrupted training data set. PMID- 24808342 TI - Augmented multiple instance regression for inferring object contours in bounding boxes. AB - In this paper, we address the problem of the high annotation cost of acquiring training data for semantic segmentation. Most modern approaches to semantic segmentation are based upon graphical models, such as the conditional random fields, and rely on sufficient training data in form of object contours. To reduce the manual effort on pixel-wise annotating contours, we consider the setting in which the training data set for semantic segmentation is a mixture of a few object contours and an abundant set of bounding boxes of objects. Our idea is to borrow the knowledge derived from the object contours to infer the unknown object contours enclosed by the bounding boxes. The inferred contours can then serve as training data for semantic segmentation. To this end, we generate multiple contour hypotheses for each bounding box with the assumption that at least one hypothesis is close to the ground truth. This paper proposes an approach, called augmented multiple instance regression (AMIR), that formulates the task of hypothesis selection as the problem of multiple instance regression (MIR), and augments information derived from the object contours to guide and regularize the training process of MIR. In this way, a bounding box is treated as a bag with its contour hypotheses as instances, and the positive instances refer to the hypotheses close to the ground truth. The proposed approach has been evaluated on the Pascal VOC segmentation task. The promising results demonstrate that AMIR can precisely infer the object contours in the bounding boxes, and hence provide effective alternatives to manually labeled contours for semantic segmentation. PMID- 24808343 TI - LGE-KSVD: robust sparse representation classification. AB - The parsimonious nature of sparse representations has been successfully exploited for the development of highly accurate classifiers for various scientific applications. Despite the successes of Sparse Representation techniques, a large number of dictionary atoms as well as the high dimensionality of the data can make these classifiers computationally demanding. Furthermore, sparse classifiers are subject to the adverse effects of a phenomenon known as coefficient contamination, where, for example, variations in pose may affect identity and expression recognition. We analyze the interaction between dimensionality reduction and sparse representations, and propose a technique, called Linear extension of Graph Embedding K-means-based Singular Value Decomposition (LGE KSVD) to address both issues of computational intensity and coefficient contamination. In particular, the LGE-KSVD utilizes variants of the LGE to optimize the K-SVD, an iterative technique for small yet over complete dictionary learning. The dimensionality reduction matrix, sparse representation dictionary, sparse coefficients, and sparsity-based classifier are jointly learned through the LGE-KSVD. The atom optimization process is redefined to allow variable support using graph embedding techniques and produce a more flexible and elegant dictionary learning algorithm. Results are presented on a wide variety of facial and activity recognition problems that demonstrate the robustness of the proposed method. PMID- 24808344 TI - Analysis, evaluation, and comparison of polarimetric SAR speckle filtering techniques. AB - Speckle noise filtering on polarimetric SAR (PolSAR) images remains a challenging task due to the difficulty to reduce a scatterer-dependent noise while preserving the polarimetric information and the spatial information. This challenge is particularly acute on single look complex images, where little information about the scattering process can be derived from a rank-1 covariance matrix. This paper proposes to analyze and to evaluate the performances of a set of PolSAR speckle filters. The filter performances are measured by a set of ten different indicators, including relative errors on incoherent target decomposition parameters, coherences, polarimetric signatures, point target, and edge preservation. The result is a performance profile for each individual filter. The methodology consists of simulating a set of artificial PolSAR images on which the various filters will be evaluated. The image morphology is stochastic and determined by a Markov random field and the number of scattering classes is allowed to vary so that we can explore a large range of image configurations. Evaluation on real PolSAR images is also considered. Results show that filters performances need to be assessed using a complete set of indicators, including distributed scatterer parameters, radiometric parameters, and spatial information preservation. PMID- 24808345 TI - Data-driven hierarchical structure kernel for multiscale part-based object recognition. AB - Detecting generic object categories in images and videos are a fundamental issue in computer vision. However, it faces the challenges from inter and intraclass diversity, as well as distortions caused by viewpoints, poses, deformations, and so on. To solve object variations, this paper constructs a structure kernel and proposes a multiscale part-based model incorporating the discriminative power of kernels. The structure kernel would measure the resemblance of part-based objects in three aspects: 1) the global similarity term to measure the resemblance of the global visual appearance of relevant objects; 2) the part similarity term to measure the resemblance of the visual appearance of distinctive parts; and 3) the spatial similarity term to measure the resemblance of the spatial layout of parts. In essence, the deformation of parts in the structure kernel is penalized in a multiscale space with respect to horizontal displacement, vertical displacement, and scale difference. Part similarities are combined with different weights, which are optimized efficiently to maximize the intraclass similarities and minimize the interclass similarities by the normalized stochastic gradient ascent algorithm. In addition, the parameters of the structure kernel are learned during the training process with regard to the distribution of the data in a more discriminative way. With flexible part sizes on scale and displacement, it can be more robust to the intraclass variations, poses, and viewpoints. Theoretical analysis and experimental evaluations demonstrate that the proposed multiscale part-based representation model with structure kernel exhibits accurate and robust performance, and outperforms state-of-the-art object classification approaches. PMID- 24808346 TI - Local-prediction-based difference expansion reversible watermarking. AB - This paper investigates the use of local prediction in difference expansion reversible watermarking. For each pixel, a least square predictor is computed on a square block centered on the pixel and the corresponding prediction error is expanded. The same predictor is recovered at detection without any additional information. The proposed local prediction is general and it applies regardless of the predictor order or the prediction context. For the particular cases of least square predictors with the same context as the median edge detector, gradient-adjusted predictor or the simple rhombus neighborhood, the local prediction-based reversible watermarking clearly outperforms the state-of-the-art schemes based on the classical counterparts. Experimental results are provided. PMID- 24808347 TI - Double-layer video transmission over decode-and-forward wireless relay networks using hierarchical modulation. AB - We consider a wireless relay network with a single source, a single destination, and a multiple relay. The relays are half-duplex and use the decode-and-forward protocol. The transmit source is a layered video bitstream, which can be partitioned into two layers, a base layer (BL) and an enhancement layer (EL), where the BL is more important than the EL in terms of the source distortion. The source broadcasts both layers to the relays and the destination using hierarchical 16-QAM. Each relay detects and transmits successfully decoded layers to the destination using either hierarchical 16-QAM or QPSK. The destination can thus receive multiple signals, each of which can include either only the BL or both the BL and the EL. We derive the optimal linear combining method at the destination, where the uncoded bit error rate is minimized. We also present a suboptimal combining method with a closed-form solution, which performs very close to the optimal. We use the proposed double-layer transmission scheme with our combining methods for transmitting layered video bitstreams. Numerical results show that the double-layer scheme can gain 2-2.5 dB in channel signal-to noise ratio or 5-7 dB in video peak signal-to-noise ratio, compared with the classical single-layer scheme using conventional modulation. PMID- 24808348 TI - Context-aware discovery of visual co-occurrence patterns. AB - Once an image is decomposed into a number of visual primitives, e.g., local interest points or regions, it is of great interests to discover meaningful visual patterns from them. Conventional clustering of visual primitives, however, usually ignores the spatial and feature structure among them, thus cannot discover high-level visual patterns of complex structure. To overcome this problem, we propose to consider spatial and feature contexts among visual primitives for pattern discovery. By discovering spatial co-occurrence patterns among visual primitives and feature co-occurrence patterns among different types of features, our method can better address the ambiguities of clustering visual primitives. We formulate the pattern discovery problem as a regularized k-means clustering where spatial and feature contexts are served as constraints to improve the pattern discovery results. A novel self-learning procedure is proposed to utilize the discovered spatial or feature patterns to gradually refine the clustering result. Our self-learning procedure is guaranteed to converge and experiments on real images validate the effectiveness of our method. PMID- 24808349 TI - Maximum-likelihood based synthesis of volumetric textures from a 2D sample. AB - We propose a genuine 3D texture synthesis algorithm based on a probabilistic 2D Markov random field conceptualization, capable of capturing the visual characteristics of a texture into a unique statistical texture model. We intend to reproduce, in the volumetric texture, the interactions between pixels learned in an input 2D image. The learning is done by nonparametric Parzen-windowing. Optimization is handled voxel by a relaxation algorithm, aiming at maximizing the likelihood of each voxel in terms of its local conditional probability function. Variants are proposed regarding the relaxation algorithm and the heuristic strategies used for the simultaneous handling of the orthogonal slices containing the voxel. The procedures are materialized on various textures through a comparative study and a sensitivity analysis, highlighting the variants strengths and weaknesses. Finally, the probabilistic model is compared objectively with a nonparametric neighborhood-search-based algorithm. PMID- 24808350 TI - Speckle reduction via higher order total variation approach. AB - Multiplicative noise (also known as speckle) reduction is a prerequisite for many image-processing tasks in coherent imaging systems, such as the synthetic aperture radar. One approach extensively used in this area is based on total variation (TV) regularization, which can recover significantly sharp edges of an image, but suffers from the staircase-like artifacts. In order to overcome the undesirable deficiency, we propose two novel models for removing multiplicative noise based on total generalized variation (TGV) penalty. The TGV regularization has been mathematically proven to be able to eliminate the staircasing artifacts by being aware of higher order smoothness. Furthermore, an efficient algorithm is developed for solving the TGV-based optimization problems. Numerical experiments demonstrate that our proposed methods achieve state-of-the-art results, both visually and quantitatively. In particular, when the image has some higher order smoothness, our methods outperform the TV-based algorithms. PMID- 24808352 TI - Learning cascaded shared-boost classifiers for part-based object detection. AB - This paper focuses on the problem of detecting a number of different class objects in images. We present a novel part-based model for object detection with cascaded classifiers. The coarse root and fine part classifiers are combined into the model. Different from the existing methods which learn root and part classifiers independently, we propose a shared-Boost algorithm to jointly train multiple classifiers. This paper is distinguished by two key contributions. The first is to introduce a new definition of shared features for similar pattern representation among multiple classifiers. Based on this, a shared-Boost algorithm which jointly learns multiple classifiers by reusing the shared feature information is proposed. The second contribution is a method for constructing a discriminatively trained part-based model, which fuses the outputs of cascaded shared-Boost classifiers as high-level features. The proposed shared-Boost-based part model is applied for both rigid and deformable object detection experiments. Compared with the state-of-the-art method, the proposed model can achieve higher or comparable performance. In particular, it can lift up the detection rates in low-resolution images. Also the proposed procedure provides a systematic framework for information reusing among multiple classifiers for part-based object detection. PMID- 24808351 TI - A novel multiple hypothesis based particle tracking method for clathrin mediated endocytosis analysis using fluorescence microscopy. AB - In order to quantitatively analyze biological images and study underlying mechanisms of the cellular and subcellular processes, it is often required to track a large number of particles involved in these processes. Manual tracking can be performed by the biologists, but the workload is very heavy. In this paper, we present an automatic particle tracking method for analyzing an essential subcellular process, namely clathrin mediated endocytosis. The framework of the tracking method is an extension of the classical multiple hypothesis tracking (MHT), and it is designed to manage trajectories, solve data association problems, and handle pseudo-splitting/merging events. In the extended MHT framework, particle tracking becomes evaluating two types of hypotheses. The first one is the trajectory-related hypothesis, to test whether a recovered trajectory is correct, and the second one is the observation-related hypothesis, to test whether an observation from an image belongs to a real particle. Here, an observation refers to a detected particle and its feature vector. To detect the particles in 2D fluorescence images taken using total internal reflection microscopy, the images are segmented into regions, and the features of the particles are obtained by fitting Gaussian mixture models into each of the image regions. Specific models are developed according to the properties of the particles. The proposed tracking method is demonstrated on synthetic data under different scenarios and applied to real data. PMID- 24808353 TI - Visual tracking via discriminative sparse similarity map. AB - In this paper, we cast the tracking problem as finding the candidate that scores highest in the evaluation model based upon a matrix called discriminative sparse similarity map (DSS map). This map demonstrates the relationship between all the candidates and the templates, and it is constructed based on the solution to an innovative optimization formulation named multitask reverse sparse representation formulation, which searches multiple subsets from the whole candidate set to simultaneously reconstruct multiple templates with minimum error. A customized APG method is derived for getting the optimum solution (in matrix form) within several iterations. This formulation allows the candidates to be evaluated accurately in parallel rather than one-by-one like most sparsity-based trackers do and meanwhile considers the relationship between candidates, therefore it is more superior in terms of cost-performance ratio. The discriminative information containing in this map comes from a large template set with multiple positive target templates and hundreds of negative templates. A Laplacian term is introduced to keep the coefficients similarity level in accordance with the candidates similarities, thereby making our tracker more robust. A pooling approach is proposed to extract the discriminative information in the DSS map for easily yet effectively selecting good candidates from bad ones and finally get the optimum tracking results. Plenty experimental evaluations on challenging image sequences demonstrate that the proposed tracking algorithm performs favorably against the state-of-the-art methods. PMID- 24808354 TI - Novel example-based method for super-resolution and denoising of medical images. AB - In this paper, we propose a novel example-based method for denoising and super resolution of medical images. The objective is to estimate a high-resolution image from a single noisy low-resolution image, with the help of a given database of high and low-resolution image patch pairs. Denoising and super-resolution in this paper is performed on each image patch. For each given input low-resolution patch, its high-resolution version is estimated based on finding a nonnegative sparse linear representation of the input patch over the low-resolution patches from the database, where the coefficients of the representation strongly depend on the similarity between the input patch and the sample patches in the database. The problem of finding the nonnegative sparse linear representation is modeled as a nonnegative quadratic programming problem. The proposed method is especially useful for the case of noise-corrupted and low-resolution image. Experimental results show that the proposed method outperforms other state-of-the-art super resolution methods while effectively removing noise. PMID- 24808355 TI - Colored coded aperture design by concentration of measure in compressive spectral imaging. AB - Compressive spectral imaging (CSI) senses the spatio-spectral information of a scene by measuring 2D coded projections on a focal plane array. A l1-norm-based optimization algorithm is then used to recover the underlying discretized spectral image. The coded aperture snapshot spectral imager (CASSI) is an architecture realizing CSI where the reconstruction image quality relies on the design of a 2D set of binary coded apertures which block-unblock the light from the scene. This paper extends the compressive capabilities of CASSI by replacing the traditional blocking-unblocking coded apertures by a set of colored coded apertures. The colored coded apertures are optimized such that the number of projections is minimized while the quality of reconstruction is maximized. The optimal design of the colored coded apertures aims to better satisfy the restricted isometry property in CASSI. The optimal designs are compared with random colored coded aperture patterns and with the traditional blocking unblocking coded apertures. Extensive simulations show the improvement in reconstruction PSNR attained by the optimal colored coded apertures designs. PMID- 24808356 TI - Regularized tree partitioning and its application to unsupervised image segmentation. AB - In this paper, we propose regularized tree partitioning approaches. We study normalized cut (NCut) and average cut (ACut) criteria over a tree, forming two approaches: 1) normalized tree partitioning (NTP) and 2) average tree partitioning (ATP). We give the properties that result in an efficient algorithm for NTP and ATP. In addition, we present the relations between the solutions of NTP and ATP over the maximum weight spanning tree of a graph and NCut and ACut over this graph. To demonstrate the effectiveness of the proposed approaches, we show its application to image segmentation over the Berkeley image segmentation data set and present qualitative and quantitative comparisons with state-of-the art methods. PMID- 24808357 TI - Inverse halftoning with context driven prediction. AB - A prior work proposed by Chung-Wu considered an edge-based lookup table to obtain good inversed image quality, yet it suffers from some drawbacks in terms of image quality, memory consumption, and complexity. In this correspondence, an improved scheme is proposed to deal with these issues. PMID- 24808358 TI - Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. AB - Caspase-8, an executioner enzyme in the death receptor pathway, was shown to initiate apoptosis and suppress necroptosis. In this study, we identify a novel, cell death-independent role for caspase-8 in dendritic cells (DCs): DC-specific expression of caspase-8 prevents the onset of systemic autoimmunity. Failure to express caspase-8 has no effect on the lifespan of DCs but instead leads to an enhanced intrinsic activation and, subsequently, more mature and autoreactive lymphocytes. Uncontrolled TLR activation in a RIPK1-dependent manner is responsible for the enhanced functionality of caspase-8-deficient DCs, because deletion of the TLR-signaling mediator, MyD88, ameliorates systemic autoimmunity induced by caspase-8 deficiency. Taken together, these data demonstrate that caspase-8 functions in a cell type-specific manner and acts uniquely in DCs to maintain tolerance. PMID- 24808359 TI - Deletion of CD24 impairs development of heat shock protein gp96-driven autoimmune disease through expansion of myeloid-derived suppressor cells. AB - CD24 binds to and suppresses inflammation triggered by danger-associated molecular patterns such as heat shock proteins (HSPs) and high-mobility group box 1. Paradoxically, CD24 has been shown to enhance autoimmune disease. In this study, we attempt to reconcile this paradox by deletion of CD24 (24KO) in a lupus like disease model driven by forced expression of HSP gp96 at the cell surface (transgenic mice [tm]). As expected, tm24KO mice showed increased CD11c(+) dendritic cell activation coupled to a significant increase in dendritic cell specific IL-12 production compared with tm mice. However, tm24KO mice showed less CD4 T cell activation and peripheral inflammatory cytokine production in comparison with tm mice. We characterized an enhanced immune suppressive milieu in tm24KO mice distinguished by increased TGF-beta and greater regulatory T cell suppressive capacity. We found greater absolute numbers of myeloid-derived suppressor cells (MDSCs) in tm24KO mice and showed that the Ly6C(+) MDSC subset had greater suppressive capacity from tm24KO mice. Deletion of CD24 in tm mice led to diminished lupus-like pathology as evidenced by anti-nuclear Ab deposition and glomerulonephritis. Finally, we show that expanded MDSC populations were mediated by increased free high-mobility group box 1 in tm24KO mice. Thus, the deletion of CD24 in an HSP-driven model of autoimmunity led to the unexpected development of regulatory T cell and MDSC populations that augmented immune tolerance. Further study of these populations as possible negative regulators of inflammation in the context of autoimmunity is warranted. PMID- 24808360 TI - CD36-mediated hematoma absorption following intracerebral hemorrhage: negative regulation by TLR4 signaling. AB - Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36 deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild type mice following ICH was increased, whereas the hematoma absorption in CD36(-/ ) mice was decreased. CD36(-/-) mice also showed aggravated neurologic deficits and increased TNF-alpha and IL-1beta expression levels. The phagocytic capacity of CD36(-/-) microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4(-/-) and MyD88(-/-) mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-alpha and IL 1beta significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH. PMID- 24808361 TI - Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/alphaCD40 therapy. AB - Fas ligand expression in certain tumors has been proposed to contribute to immunosuppression and poor prognosis. However, immunotherapeutic approaches may elicit the Fas-mediated elimination of immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within tumors that represent major obstacles for cancer immunotherapy. Previously, we showed that IL-2 and agonistic CD40 Ab (alphaCD40) elicited synergistic antitumor responses coincident with the efficient removal of Tregs and MDSCs. We demonstrate in this study in two murine tumor models that Treg and MDSC loss within the tumor microenvironment after IL-2/alphaCD40 occurs through a Fas-dependent cell death pathway. Among tumor-infiltrating leukocytes, CD8(+) T cells, neutrophils, and immature myeloid cells expressed Fas ligand after treatment. Fas was expressed by tumor-associated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/alphaCD40 therapy and, in contrast with effector T cells, Tregs significantly downregulated Bcl-2 expression. In contrast, Tregs and MDSCs proliferated and expanded in the spleen after treatment. Adoptive transfer of Fas-deficient Tregs or MDSCs into wild type, Treg-, or MDSC-depleted hosts resulted in the persistence of Tregs or MDSCs and the loss of antitumor efficacy in response to IL-2/alphaCD40. These results demonstrate the importance of Fas-mediated Treg/MDSC removal for successful antitumor immunotherapy. Our results suggest that immunotherapeutic strategies that include exploiting Treg and MDSC susceptibility to Fas-mediated apoptosis hold promise for treatment of cancer. PMID- 24808362 TI - Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. AB - Chronic periodontitis is induced by a dysbiotic microbiota and leads to inflammatory destruction of tooth-supporting connective tissue and bone. The third component of complement, C3, is a point of convergence of distinct complement activation mechanisms, but its involvement in periodontitis was not previously addressed. We investigated this question using two animal species models, namely, C3-deficient or wild-type mice and nonhuman primates (NHPs) locally treated with a potent C3 inhibitor (the compstatin analog Cp40) or an inactive peptide control. In mice, C3 was required for maximal periodontal inflammation and bone loss, and for the sustenance of the dysbiotic microbiota. The effect of C3 on the microbiota was therefore different from that reported for the C5a receptor, which is required for the initial induction of dysbiosis. C3 dependent bone loss was demonstrated in distinct models, including Porphyromonas gingivalis-induced periodontitis, ligature-induced periodontitis, and aging associated periodontitis. Importantly, local treatment of NHPs with Cp40 inhibited ligature-induced periodontal inflammation and bone loss, which correlated with lower gingival crevicular fluid levels of proinflammatory mediators (e.g., IL-17 and RANKL) and decreased osteoclastogenesis in bone biopsy specimens, as compared with control treatment. To our knowledge, this is the first time, for any disease, that complement inhibition in NHPs was shown to inhibit inflammatory processes that lead to osteoclastogenesis and bone loss. These data strongly support the feasibility of C3-targeted intervention for the treatment of human periodontitis. PMID- 24808363 TI - Preemptive donor apoptotic cell infusions induce IFN-gamma-producing myeloid derived suppressor cells for cardiac allograft protection. AB - We have previously shown that preemptive infusion of apoptotic donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) induces long term allograft survival in full MHC-mismatched models of allogeneic islet and cardiac transplantation. The role of myeloid-derived suppressor cells (MDSCs) in the graft protection provided by ECDI-SPs is unclear. In this study, we demonstrate that infusions of ECDI-SPs increase two populations of CD11b(+) cells in the spleen that phenotypically resemble monocytic-like (CD11b(+)Ly6C(high)) and granulocytic-like (CD11b(+)Gr1(high)) MDSCs. Both populations suppress T cell proliferation in vitro and traffic to the cardiac allografts in vivo to mediate their protection via inhibition of local CD8 T cell accumulation and potentially also via induction and homing of regulatory T cells. Importantly, repeated treatments with ECDI-SPs induce the CD11b(+)Gr1(high) cells to produce a high level of IFN-gamma and to exhibit an enhanced responsiveness to IFN-gamma by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-gamma completely abolishes the suppressive capacity of this population. We conclude that donor ECDI-SPs induce the expansion of two populations of MDSCs important for allograft protection mediated in part by intrinsic IFN-gamma-dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction. PMID- 24808364 TI - CD8 T cell-evasive functions of human cytomegalovirus display pervasive MHC allele specificity, complementarity, and cooperativity. AB - Immunoevasive proteins ("evasins") of human CMV (HCMV) modulate stability and localization of MHC class I (MHC I) molecules, and their supply of antigenic peptides. However, it is largely unknown to what extent these evasins interfere with recognition by virus-specific CD8 T cells. We analyzed the recognition of HCMV-infected cells by a panel of CD8 T cells restricted through one of nine different MHC I allotypes. We employed a set of HCMV mutants deleted for three or all four of the MHC I modulatory genes US2, US3, US6, and US11. We found that different HCMV evasins exhibited different allotype-specific patterns of interference with CD8 T cell recognition of infected cells. In contrast, recognition of different epitopes presented by the same given MHC I allotype was uniformly reduced. For some allotypes, single evasins largely abolished T cell recognition; for others, a concerted action of evasins was required to abrogate recognition. In infected cells whose Ag presentation efficiency had been enhanced by IFN-gamma pretreatment, HCMV evasins cooperatively impared T cell recognition for several different MHC I allotypes. T cell recognition and MHC I surface expression under influence of evasins were only partially congruent, underscoring the necessity to probe HCMV immunomodulation using specific T cells. We conclude that the CD8 T cell evasins of HCMV display MHC I allotype specificity, complementarity, and cooperativity. PMID- 24808366 TI - Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages. AB - Dectin-1 is a membrane-bound pattern recognition receptor for beta-glucans, which are the main constituents of fungal cell walls. Detection of beta-glucans by dectin-1 triggers an effective innate immune response. In this study, we have used a systems biology approach to provide the first comprehensive characterization of the secretome and associated intracellular signaling pathways involved in activation of dectin-1/Syk in human macrophages. Transcriptome and secretome analysis revealed that the dectin-1 pathway induced significant gene expression changes and robust protein secretion in macrophages. The enhanced protein secretion correlated only partly with increased gene expression. Bioinformatics combined with functional studies revealed that the dectin-1/Syk pathway activates both conventional and unconventional, vesicle-mediated, protein secretion. The unconventional protein secretion triggered by the dectin-1 pathway is dependent on inflammasome activity and an active autophagic process. In conclusion, our results reveal that unconventional protein secretion has an important role in the innate immune response against fungal infections. PMID- 24808365 TI - Human dendritic cells exhibit a pronounced type I IFN signature following Leishmania major infection that is required for IL-12 induction. AB - Leishmania major-infected human dendritic cells (DCs) exhibit a marked induction of IL-12, ultimately promoting a robust Th1-mediated response associated with parasite killing and protective immunity. The host cell transcription machinery associated with the specific IL-12 induction observed during L. major infection remains to be thoroughly elucidated. In this study, we used Affymetrix GeneChip (Affymetrix) to globally assess the host cell genes and pathways associated with early L. major infection in human myeloid-derived DCs. Our data revealed 728 genes were significantly differentially expressed and molecular signaling pathway revealed that the type I IFN pathway was significantly enriched. Addition of a neutralizing type I IFN decoy receptor blocked the expression of IRF7 and IL 12p40 during DC infection, indicating the L. major-induced expression of IL-12p40 is dependent upon the type I IFN signaling pathway. In stark contrast, IL-12p40 expression is not elicited by L. donovani, the etiological agent of deadly visceral leishmaniasis. Therefore, we examined the gene expression profile for several IFN response genes in L. major versus L. donovani DC infections. Our data revealed that L. major, but not L. donovani, induces expression of IRF2, IRF7, and IFIT5, implicating the regulation of type I IFN-associated signaling pathways as mediating factors toward the production of IL-12. PMID- 24808368 TI - Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. AB - High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33-Th2 cytokine production causing upregulation of the inhibitory FcgammaRIIb, as well as by modulating IFN-gamma signaling. The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels. Strikingly, no upregulation of FcgammaRIIb expression was found, but instead a decreased expression of the activating FcgammaRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-gammaR2 subunit of the IFN-gammaR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcgammaRs and IFN-gammaR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-gamma. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment. Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcgammaRIIa and IFN-gammaR2 and not by upregulation of FcgammaRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent. PMID- 24808369 TI - Protein phosphatase 6 controls BCR-induced apoptosis of WEHI-231 cells by regulating ubiquitination of Bcl-xL. AB - Crosslinking BCR in the immature B cell line WEHI-231 causes apoptosis. We found that Bcl-xL was degraded by polyubiquitination upon BCR crosslinking and in this study explored the mechanism that controls the degradation of Bcl-xL. Ser(62) of Bcl-xL was phosphorylated by JNK to trigger polyubiquitination, and this was opposed by serine/threonine protein phosphatase 6 (PP6) that physically associated with Bcl-xL. We show BCR crosslinking decreased PP6 activity to allow Ser(62) phosphorylation of Bcl-xL. CD40 crosslinking rescues BCR-induced apoptosis, and we found PP6 associated with CD40 and PP6 activation in response to CD40. Our data suggest that PP6 activity is regulated to control apoptosis by modulating Ser(62) phosphorylation of Bcl-xL, which results in its polyubiquitination and degradation. PMID- 24808367 TI - Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair. AB - Skin-resident T cells have been shown to play important roles in tissue homeostasis and wound repair, but their role in UV radiation (UVR)-mediated skin injury and subsequent tissue regeneration is less clear. In this study, we demonstrate that acute UVR rapidly activates skin-resident T cells in humans and dendritic epidermal gammadelta T cells (DETCs) in mice through mechanisms involving the release of ATP from keratinocytes. Following UVR, extracellular ATP leads to an increase in CD69 expression, proliferation, and IL-17 production, and to changes in DETC morphology. Furthermore, we find that the purinergic receptor P2X7 and caspase-1 are necessary for UVR-induced IL-1 production in keratinocytes, which increases IL-17 secretion by DETCs. IL-17, in turn, induces epidermal TNF-related weak inducer of apoptosis and growth arrest and DNA damage associated gene 45, two molecules linked to the DNA repair response. Finally, we demonstrate that DETCs and human skin-resident T cells limit DNA damage in keratinocytes. Taken together, our findings establish a novel role for skin resident T cells in the UVR-associated DNA repair response and underscore the importance of skin-resident T cells to overall skin regeneration. PMID- 24808370 TI - GANP regulates the choice of DNA repair pathway by DNA-PKcs interaction in AID dependent IgV region diversification. AB - RNA export factor germinal center-associated nuclear protein (GANP) interacts with activation-induced cytidine deaminase (AID) and shepherds it from the cytoplasm to the nucleus and toward the IgV region loci in B cells. In this study, we demonstrate a role for GANP in the repair of AID-initiated DNA damage in chicken DT40 B cells to generate IgV region diversity by gene conversion and somatic hypermutation. GANP plays a positive role in IgV region diversification of DT40 B cells in a nonhomologous end joining-proficient state. DNA-PKcs physically interacts with GANP, and this interaction is dissociated by dsDNA breaks induced by a topoisomerase II inhibitor, etoposide, or AID overexpression. GANP affects the choice of DNA repair mechanism in B cells toward homologous recombination rather than nonhomologous end joining repair. Thus, GANP presumably plays a critical role in protection of the rearranged IgV loci by favoring homologous recombination of the DNA breaks under accelerated AID recruitment. PMID- 24808373 TI - Stability analysis for neural networks with time-varying delay based on quadratic convex combination. AB - In this paper, a novel method is developed for the stability problem of a class of neural networks with time-varying delay. New delay-dependent stability criteria in terms of linear matrix inequalities for recurrent neural networks with time-varying delay are derived by the newly proposed augmented simple Lyapunov-Krasovski functional. Different from previous results by using the first order convex combination property, our derivation applies the idea of second order convex combination and the property of quadratic convex function which is given in the form of a lemma without resorting to Jensen's inequality. A numerical example is provided to verify the effectiveness and superiority of the presented results. PMID- 24808371 TI - Carbonic anhydrase IV is expressed on IL-5-activated murine eosinophils. AB - Eosinophilia and its cellular activation are hallmark features of asthma, as well as other allergic/Th2 disorders, yet there are few, if any, reliable surface markers of eosinophil activation. We have used a FACS-based genome-wide screening system to identify transcriptional alterations in murine lung eosinophils recruited and activated by pulmonary allergen exposure. Using a relatively stringent screen with false-positive correction, we identified 82 candidate genes that could serve as eosinophil activation markers and/or pathogenic effector markers in asthma. Carbonic anhydrase IV (Car4) was a top dysregulated gene with 36-fold induction in allergen-elicited pulmonary eosinophils, which was validated by quantitative PCR, immunohistochemistry, and flow cytometry. Eosinophil CAR4 expression was kinetically regulated by IL-5, but not IL-13. IL-5 was both necessary and sufficient for induction of eosinophil CAR4. Although CAR4 deficient mice did not have a defect in eosinophil recruitment to the lung, nor a change in eosinophil pH-buffering capacity, allergen-challenged chimeric mice that contained Car4(-/-) hematopoietic cells aberrantly expressed a series of genes enriched in biological processes involved in epithelial differentiation, keratinization, and anion exchange. In conclusion, we have determined that eosinophils express CAR4 following IL-5 or allergen exposure, and that CAR4 is involved in regulating the lung transcriptome associated with allergic airway inflammation; therefore, CAR4 has potential value for diagnosing and monitoring eosinophilic responses. PMID- 24808372 TI - TLR-induced cytokines promote effective proinflammatory natural Th17 cell responses. AB - Naive CD4 lymphocytes undergo a polarization process in the periphery to become induced Th17 (iTh17) cells. Using retinoic acid-related orphan receptor gammat (RORgammat)-gfp mice, we found that RORgammat and the transcription factor promyelocytic leukemia zinc finger (PLZF) are valuable new markers to identify the recently described natural Th17 (nTh17) cell population. nTh17 cells are thymically committed to promptly produce large amounts of IL-17 and IL-22. In this study, we show that, in addition to responding to TCR cross-linking, nTh17 cells secrete IL-17 and IL-22 when stimulated with IL-23 plus IL-1beta, either in recombinant form or in supernatants from TLR4-activated dendritic cells. This innate-like ability of RORgammat(+) nTh17 cells to respond to TLR4-induced cytokines was not shared by iTh17 cells. The other distinct properties of RORgammat(+) nTh17 cells are their high expression of PLZF and their absence from lamina propria; iTh17 cells are found therein. RORgammat(+) nTh17 cells are present in the thymus of germ-free RORgammat-gfp and IL-6(-/-) RORGamma: t-gfp mice, indicating that these cells do not require symbiotic microbiota or IL-6 for their generation. Finally, we found that PLZF(+)RORgammat(+) nTh17 cells represent one of the primary IL-17-producing innate-like T cell populations in a TLR7 imiquimod model of psoriasis-like disorder, indicating their involvement in this kind of lesion. Collectively, our results reveal RORgammat and PLZF as characteristic markers for identifying nTh17 cells and demonstrate one of their novel properties: the ability to respond promptly to TLR-dependent proinflammatory stimuli without TCR engagement, placing them as members of the innate-like T cell family. PMID- 24808374 TI - Factor analysis of auto-associative neural networks with application in speaker verification. AB - Auto-associative neural network (AANN) is a fully connected feed-forward neural network, trained to reconstruct its input at its output through a hidden compression layer, which has fewer numbers of nodes than the dimensionality of input. AANNs are used to model speakers in speaker verification, where a speaker specific AANN model is obtained by adapting (or retraining) the universal background model (UBM) AANN, an AANN trained on multiple held out speakers, using corresponding speaker data. When the amount of speaker data is limited, this adaptation procedure may lead to overfitting as all the parameters of UBM-AANN are adapted. In this paper, we introduce and develop the factor analysis theory of AANNs to alleviate this problem. We hypothesize that only the weight matrix connecting the last nonlinear hidden layer and the output layer is speaker specific, and further restrict it to a common low-dimensional subspace during adaptation. The subspace is learned using large amounts of development data, and is held fixed during adaptation. Thus, only the coordinates in a subspace, also known as i-vector, need to be estimated using speaker-specific data. The update equations are derived for learning both the common low-dimensional subspace and the i-vectors corresponding to speakers in the subspace. The resultant i-vector representation is used as a feature for the probabilistic linear discriminant analysis model. The proposed system shows promising results on the NIST-08 speaker recognition evaluation (SRE), and yields a 23% relative improvement in equal error rate over the previously proposed weighted least squares-based subspace AANNs system. The experiments on NIST-10 SRE confirm that these improvements are consistent and generalize across datasets. PMID- 24808375 TI - Projection-based fast learning fully complex-valued relaxation neural network. AB - This paper presents a fully complex-valued relaxation network (FCRN) with its projection-based learning algorithm. The FCRN is a single hidden layer network with a Gaussian-like sech activation function in the hidden layer and an exponential activation function in the output layer. For a given number of hidden neurons, the input weights are assigned randomly and the output weights are estimated by minimizing a nonlinear logarithmic function (called as an energy function) which explicitly contains both the magnitude and phase errors. A projection-based learning algorithm determines the optimal output weights corresponding to the minima of the energy function by converting the nonlinear programming problem into that of solving a set of simultaneous linear algebraic equations. The resultant FCRN approximates the desired output more accurately with a lower computational effort. The classification ability of FCRN is evaluated using a set of real-valued benchmark classification problems from the University of California, Irvine machine learning repository. Here, a circular transformation is used to transform the real-valued input features to the complex domain. Next, the FCRN is used to solve three practical problems: a quadrature amplitude modulation channel equalization, an adaptive beamforming, and a mammogram classification. Performance results from this paper clearly indicate the superior classification/approximation performance of the FCRN. PMID- 24808376 TI - Granular neural networks: concepts and development schemes. AB - In this paper, we introduce a concept of a granular neural network and develop its comprehensive design process. The proposed granular network is formed on the basis of a given (numeric) neural network whose structure is augmented by the formation of granular connections (being realized as intervals) spanned over the numeric ones. Owing to its simplicity of the underlying processing, the interval connections become an appealing alternative of information granules to clarify the main idea. We introduce a concept of information granularity and its quantification (viewed as a level of information granularity). Being treated as an essential design asset, the assumed level of information granularity is distributed (allocated) among the connections of the network in several different ways so that certain performance index becomes maximized. Due to the high dimensionality nature of some protocols of allocation of information granularity and the nature of the allocation process itself, single-objective versions of particle swarm optimization is considered a suitable optimization vehicle. As we are concerned with the granular output of the network, which has to be evaluated with regard to the numeric target of data, two criteria are considered; namely, coverage of numeric data and specificity of information granules (intervals). A series of numeric studies completed for synthetic data and data coming from the machine learning and StatLib repositories provide a useful insight into the effectiveness of the proposed algorithm. PMID- 24808377 TI - Noise-shaping gradient descent-based online adaptation algorithms for digital calibration of analog circuits. AB - Analog circuits that are calibrated using digital-to-analog converters (DACs) use a digital signal processor-based algorithm for real-time adaptation and programming of system parameters. In this paper, we first show that this conventional framework for adaptation yields suboptimal calibration properties because of artifacts introduced by quantization noise. We then propose a novel online stochastic optimization algorithm called noise-shaping or SigmaDelta gradient descent, which can shape the quantization noise out of the frequency regions spanning the parameter adaptation trajectories. As a result, the proposed algorithms demonstrate superior parameter search properties compared to floating point gradient methods and better convergence properties than conventional quantized gradient-methods. In the second part of this paper, we apply the SigmaDelta gradient descent algorithm to two examples of real-time digital calibration: 1) balancing and tracking of bias currents, and 2) frequency calibration of a band-pass Gm-C biquad filter biased in weak inversion. For each of these examples, the circuits have been prototyped in a 0.5-MUm complementary metal-oxide-semiconductor process, and we demonstrate that the proposed algorithm is able to find the optimal solution even in the presence of spurious local minima, which are introduced by the nonlinear and non-monotonic response of calibration DACs. PMID- 24808378 TI - Cluster consensus in discrete-time networks of multiagents with inter-cluster nonidentical inputs. AB - In this paper, cluster consensus of multiagent systems is studied via inter cluster nonidentical inputs. Here, we consider general graph topologies, which might be time-varying. The cluster consensus is defined by two aspects: intracluster synchronization, the state at which differences between each pair of agents in the same cluster converge to zero, and inter-cluster separation, the state at which agents in different clusters are separated. For intra-cluster synchronization, the concepts and theories of consensus, including the spanning trees, scramblingness, infinite stochastic matrix product, and Hajnal inequality, are extended. As a result, it is proved that if the graph has cluster spanning trees and all vertices self-linked, then the static linear system can realize intra-cluster synchronization. For the time-varying coupling cases, it is proved that if there exists T > 0 such that the union graph across any T-length time interval has cluster spanning trees and all graphs has all vertices self-linked, then the time-varying linear system can also realize intra-cluster synchronization. Under the assumption of common inter-cluster influence, a sort of inter-cluster nonidentical inputs are utilized to realize inter-cluster separation, such that each agent in the same cluster receives the same inputs and agents in different clusters have different inputs. In addition, the boundedness of the infinite sum of the inputs can guarantee the boundedness of the trajectory. As an application, we employ a modified non-Bayesian social learning model to illustrate the effectiveness of our results. PMID- 24808379 TI - Common nature of learning between back-propagation and Hopfield-type neural networks for generalized matrix inversion with simplified models. AB - In this paper, two simple-structure neural networks based on the error back propagation (BP) algorithm (i.e., BP-type neural networks, BPNNs) are proposed, developed, and investigated for online generalized matrix inversion. Specifically, the BPNN-L and BPNN-R models are proposed and investigated for the left and right generalized matrix inversion, respectively. In addition, for the same problem-solving task, two discrete-time Hopfield-type neural networks (HNNs) are developed and investigated in this paper. Similar to the classification of the presented BPNN-L and BPNN-R models, the presented HNN-L and HNN-R models correspond to the left and right generalized matrix inversion, respectively. Comparing the BPNN weight-updating formula with the HNN state-transition equation for the specific (i.e., left or right) generalized matrix inversion, we show that such two derived learning-expressions turn out to be the same (in mathematics), although the BP and Hopfield-type neural networks are evidently different from each other a great deal, in terms of network architecture, physical meaning, and training patterns. Numerical results with different illustrative examples further demonstrate the efficacy of the presented BPNNs and HNNs for online generalized matrix inversion and, more importantly, their common natures of learning. PMID- 24808380 TI - Online support vector machine based on convex hull vertices selection. AB - The support vector machine (SVM) method, as a promising classification technique, has been widely used in various fields due to its high efficiency. However, SVM cannot effectively solve online classification problems since, when a new sample is misclassified, the classifier has to be retrained with all training samples plus the new sample, which is time consuming. According to the geometric characteristics of SVM, in this paper we propose an online SVM classifier called VS-OSVM, which is based on convex hull vertices selection within each class. The VS-OSVM algorithm has two steps: 1) the samples selection process, in which a small number of skeleton samples constituting an approximate convex hull in each class of the current training samples are selected and 2) the online updating process, in which the classifier is updated with newly arriving samples and the selected skeleton samples. From the theoretical point of view, the first d+1 (d is the dimension of the input samples) selected samples are proved to be vertices of the convex hull. This guarantees that the selected samples in our approach keep the greatest amount of information of the convex hull. From the application point of view, the new algorithm can update the classifier without reducing its classification performance. Experimental results on benchmark data sets have shown the validity and effectiveness of the VS-OSVM algorithm. PMID- 24808382 TI - Just-in-time classifiers for recurrent concepts. AB - Just-in-time (JIT) classifiers operate in evolving environments by classifying instances and reacting to concept drift. In stationary conditions, a JIT classifier improves its accuracy over time by exploiting additional supervised information coming from the field. In nonstationary conditions, however, the classifier reacts as soon as concept drift is detected; the current classification setup is discarded and a suitable one activated to keep the accuracy high. We present a novel generation of JIT classifiers able to deal with recurrent concept drift by means of a practical formalization of the concept representation and the definition of a set of operators working on such representations. The concept-drift detection activity, which is crucial in promptly reacting to changes exactly when needed, is advanced by considering change-detection tests monitoring both inputs and classes distributions. PMID- 24808381 TI - Optimizing spatial filters by minimizing within-class dissimilarities in electroencephalogram-based brain-computer interface. AB - A major challenge in electroencephalogram (EEG)-based brain-computer interfaces (BCIs) is the inherent nonstationarities in the EEG data. Variations of the signal properties from intra and inter sessions often lead to deteriorated BCI performances, as features extracted by methods such as common spatial patterns (CSP) are not invariant against the changes. To extract features that are robust and invariant, this paper proposes a novel spatial filtering algorithm called Kullback-Leibler (KL) CSP. The CSP algorithm only considers the discrimination between the means of the classes, but does not consider within-class scatters information. In contrast, the proposed KLCSP algorithm simultaneously maximizes the discrimination between the class means, and minimizes the within-class dissimilarities measured by a loss function based on the KL divergence. The performance of the proposed KLCSP algorithm is compared against two existing algorithms, CSP and stationary CSP (sCSP), using the publicly available BCI competition III dataset IVa and a large dataset from stroke patients performing neuro-rehabilitation. The results show that the proposed KLCSP algorithm significantly outperforms both the CSP and the sCSP algorithms, in terms of classification accuracy, by reducing within-class variations. This results in more compact and separable features. PMID- 24808383 TI - Least square regularized regression in sum space. AB - This paper proposes a least square regularized regression algorithm in sum space of reproducing kernel Hilbert spaces (RKHSs) for nonflat function approximation, and obtains the solution of the algorithm by solving a system of linear equations. This algorithm can approximate the low- and high-frequency component of the target function with large and small scale kernels, respectively. The convergence and learning rate are analyzed. We measure the complexity of the sum space by its covering number and demonstrate that the covering number can be bounded by the product of the covering numbers of basic RKHSs. For sum space of RKHSs with Gaussian kernels, by choosing appropriate parameters, we tradeoff the sample error and regularization error, and obtain a polynomial learning rate, which is better than that in any single RKHS. The utility of this method is illustrated with two simulated data sets and five real-life databases. PMID- 24808384 TI - Dynamic sampling approach to training neural networks for multiclass imbalance classification. AB - Class imbalance learning tackles supervised learning problems where some classes have significantly more examples than others. Most of the existing research focused only on binary-class cases. In this paper, we study multiclass imbalance problems and propose a dynamic sampling method (DyS) for multilayer perceptrons (MLP). In DyS, for each epoch of the training process, every example is fed to the current MLP and then the probability of it being selected for training the MLP is estimated. DyS dynamically selects informative data to train the MLP. In order to evaluate DyS and understand its strength and weakness, comprehensive experimental studies have been carried out. Results on 20 multiclass imbalanced data sets show that DyS can outperform the compared methods, including pre-sample methods, active learning methods, cost-sensitive methods, and boosting-type methods. PMID- 24808385 TI - New parameter-free simplified swarm optimization for artificial neural network training and its application in the prediction of time series. AB - A new soft computing method called the parameter-free simplified swarm optimization (SSO)-based artificial neural network (ANN), or improved SSO for short, is proposed to adjust the weights in ANNs. The method is a modification of the SSO, and seeks to overcome some of the drawbacks of SSO. In the experiments, the iSSO is compared with five other famous soft computing methods, including the backpropagation algorithm, the genetic algorithm, the particle swarm optimization (PSO) algorithm, cooperative random learning PSO, and the SSO, and its performance is tested on five famous time-series benchmark data to adjust the weights of two ANN models (multilayer perceptron and single multiplicative neuron model). The experimental results demonstrate that iSSO is robust and more efficient than the other five algorithms. PMID- 24808386 TI - Distributed consensus tracking for multiple uncertain nonlinear strict-feedback systems under a directed graph. AB - In this brief, we study the distributed consensus tracking control problem for multiple strict-feedback systems with unknown nonlinearities under a directed graph topology. It is assumed that the leader's output is time-varying and has been accessed by only a small fraction of followers in a group. The distributed dynamic surface design approach is proposed to design local consensus controllers in order to guarantee the consensus tracking between the followers and the leader. The function approximation technique using neural networks is employed to compensate unknown nonlinear terms induced from the controller design procedure. From the Lyapunov stability theorem, it is shown that the consensus errors are cooperatively semiglobally uniformly ultimately bounded and converge to an adjustable neighborhood of the origin. PMID- 24808387 TI - Ensemble pruning using spectral coefficients. AB - Ensemble pruning aims to increase efficiency by reducing the number of base classifiers, without sacrificing and preferably enhancing performance. In this brief, a novel pruning paradigm is proposed. Two class supervised learning problems are pruned using a combination of first- and second-order Walsh coefficients. A comparison is made with other ordered aggregation pruning methods, using multilayer perceptron base classifiers. The Walsh pruning method is analyzed with the help of a model that shows the relationship between second order coefficients and added classification error with respect to Bayes error. PMID- 24808388 TI - Reply to Korch. PMID- 24808389 TI - Clostridium botulinum toxin statement from the director of the California Department of Public Health. PMID- 24808390 TI - Clarification regarding novel Clostridium botulinum toxin. PMID- 24808391 TI - A meta-analysis of the effects of haptic interfaces on task performance with teleoperation systems. AB - Human task performance with teleoperation systems is characterized by long task completion times, handling errors, and excessive force application to objects in the remote environment. Haptic interfaces promise to address these challenges by providing the human user with sensory feedback from the remote environment that would otherwise be lacking. Until now, only few attempts have been made to present current research efforts from a broader, more integrative perspective. To address this need, several meta-analyses were conducted, which aimed at establishing the overall effectiveness of haptic interfaces in improving the critical performance aspects in teleoperation systems. In this context, the influence of potential moderator variables (i.e., virtual versus real teleoperation setup; vibrotactile versus kinaesthetic force feedback) as well as outcome-specific effects (i.e., force regulation ability; task completion time; performance errors) were investigated. PMID- 24808392 TI - Anisotropy in the haptic perception of force direction and magnitude. AB - Although force-feedback devices are already being used, the human ability to perceive forces has not been documented thoroughly. The haptic perception of force direction and magnitude has mostly been studied in discrimination tasks in the direction of gravity. In our study, the influence of physical force direction on haptic perception of force magnitude and direction was studied in the horizontal plane. Subjects estimated the direction and magnitude of a force exerted on their stationary hand. A significant anisotropy in perception of force magnitude and direction was found. Force direction data showed significant subject-dependent distortions at various physical directions. Normalized force magnitude data showed a consistent elliptical pattern, with its minor axis pointing roughly from the subject's hand to his/her shoulder. This pattern could be related to arm stiffness or manipulability patterns, which are also ellipse shaped. These ellipses have an orientation consistent with the distortion measured in our study. So, forces in the direction of highest stiffness and lowest manipulability are perceived as being smaller. It therefore seems that humans possess a "sense of effort" rather than a "sense of force," which may be more useful in everyday life. These results could be useful in the design of haptic devices. PMID- 24808393 TI - Contribution of slip cue to curvature perception through active and dynamic touch. AB - Haptic perception of curvature depends largely on the kind of touch. An active and dynamic touch is considered to be the most natural way of exploring. In this study, we have designed and evaluated a kinematic platform for curvature perception through active and dynamic touch. This platform can independently orient, elevate, and translate a flat plate; by exploring forward and backward along the flat plate with a finger, users can achieve curvature feeling of extruded objects. The mechanism of platform and the way of touch have maximally respected the cues for curvature perception, especially the slip cue. Psychophysical evaluation demonstrated that the discrimination threshold of curvature for virtual shapes is close to that for real shapes, and the virtual shape is felt equally curved as the real one. The curvature perception of mono convex surfaces was then expanded to perception of more complex surfaces: large textures, which have a sinusoidal profile. The evaluation has accessed the correspondence between the virtual and real large textures. PMID- 24808394 TI - Distributed haptic interactions with physically based 3D deformable models over lossy networks. AB - Researchers have faced great challenges when simulating complicated 3D volumetric deformable models in haptics-enabled collaborative/cooperative virtual environments (HCVEs) due to the expensive simulation cost, heavy communication load, and unstable network conditions. When general network services are applied to HCVEs, network problems such as packet loss, delay, and jitter can cause severe visual distortion, haptic instability, and system inconsistency. In this paper, we propose a novel approach to support haptic interactions with physically based 3D deformable models in a distributed virtual environment. Our objective is to achieve real-time sharing of deformable and force simulations over general networks. Combining linear modal analysis and corotational methods, we can effectively simulate physical behaviors of 3D objects, even for large rotational deformations. We analyze different factors that influence HCVEs' performance and focus on exploring solutions for streaming over lossy networks. In our system, 3D deformation can be described by a fairly small amount of data (several KB) using accelerations in the spectral domain, so that we can achieve low communication load and effective streaming. We develop a loss compensation and prediction algorithm to correct the errors/distortions caused by network problem, and a force prediction method to simulate force at users' side to ensure the haptic stability, and the visual and haptic consistency. Our system works well under both the client-server and the peer-to-peer distribution structures, and can be easily extended to other topologies. In addition to theoretical analysis, we have tested the proposed system and algorithms under various network conditions. The experimental results are remarkably good, confirming the effectiveness, robustness, and validity of our approach. PMID- 24808395 TI - Dynamics modeling for parallel haptic interfaces with force sensing and control. AB - Closed-loop force control can be used on haptic interfaces (HIs) to mitigate the effects of mechanism dynamics. A single multidimensional force-torque sensor is often employed to measure the interaction force between the haptic device and the user's hand. The parallel haptic interface at the University of Colorado (CU) instead employs smaller 1D force sensors oriented along each of the five actuating rods to build up a 5D force vector. This paper shows that a particular manipulandum/hand partition in the system dynamics is induced by the placement and type of force sensing, and discusses the implications on force and impedance control for parallel haptic interfaces. The details of a "squaring down" process are also discussed, showing how to obtain reduced degree-of-freedom models from the general six degree-of-freedom dynamics formulation. PMID- 24808396 TI - Exploring the design space of haptic assistants: the assistance policy module. AB - Haptic assistants augment user commands to facilitate manipulation and to increase task performance. The strength of assistance, also referred to as assistance level, is one of the main design factors. While existing implementations mainly realize fixed assistance levels that are selected with respect to one design objective, we introduce an assistance policy module that dynamically changes assistance levels and can incorporate multiple performance measures. The design space of this assistance policy module is systematically analyzed and three design factors, 1) performance criteria, 2) performance reference, and 3) assistance policy, are identified. Different implementations of the assistance policy module are compared for a scenario involving guiding virtual fixtures. A single-user evaluation is used to illustrate the effect of the different implementations on the determined assistance levels, and a multi user study allows for a statistical comparison of them. Results show that adaptive assistance policies can outperform constant assistance policies, switching assistance policies have advantages over continuously adapting policies, a multi-criteria performance measure should be favored if there is no single criterion that has an outstanding priority, and the selection of the performance reference is highly application dependent. PMID- 24808397 TI - Human detection and discrimination of tactile repeatability, mechanical backlash, and temporal delay in a combined tactile-kinesthetic haptic display system. AB - Many of the devices used in haptics research are over-engineered for the task and are designed with capabilities that go far beyond human perception levels. Designing devices that more closely match the limits of human perception will make them smaller, less expensive, and more useful. However, many device-centric perception thresholds have yet to be evaluated. To this end, three experiments were conducted, using one degree-of-freedom contact location feedback device in combination with a kinesthetic display, to provide a more explicit set of specifications for similar tactile-kinesthetic haptic devices. The first of these experiments evaluated the ability of humans to repeatedly localize tactile cues across the fingerpad. Subjects could localize cues to within 1.3 mm and showed bias toward the center of the fingerpad. The second experiment evaluated the minimum perceptible difference of backlash at the tactile element. Subjects were able to discriminate device backlash in excess of 0.46 mm on low-curvature models and 0.93 mm on high-curvature models. The last experiment evaluated the minimum perceptible difference of system delay between user action and device reaction. Subjects were able to discriminate delays in excess of 61 ms. The results from these studies can serve as the maximum (i.e., most demanding) device specifications for most tactile-kinesthetic haptic systems. PMID- 24808398 TI - Identifying haptic exploratory procedures by analyzing hand dynamics and contact force. AB - Haptic exploratory procedures (EPs) are prototypical hand movements that are linked to the acquisition of specific object properties. In studies of haptic perception, hand movements are often classified into these EPs. Here, we aim to investigate several EPs in a quantitative manner to understand how hand dynamics and contact forces differ between them. These dissimilarities are then used to construct an EP identification model capable of discriminating between EPs based on the index finger position and contact force. The extent to which the instructed EPs were distinct, repeatable, and similar across subjects was confirmed by showing that more than 95 percent of the analyzed trials were classified correctly. Finally, the method is employed to investigate haptic exploratory behavior during similarity judgments based on several object properties. It seems that discrimination based on material properties (hardness, roughness, and temperature) yields more consistent classification results compared to discrimination based on the acquisition of shape information. PMID- 24808399 TI - Predicting successful tactile mapping of virtual objects. AB - Improving spatial ability of blind and visually impaired people is the main target of orientation and mobility (O&M) programs. In this study, we use a minimalistic mouse-shaped haptic device to show a new approach aimed at evaluating devices providing tactile representations of virtual objects. We consider psychophysical, behavioral, and subjective parameters to clarify under which circumstances mental representations of spaces (cognitive maps) can be efficiently constructed with touch by blindfolded sighted subjects. We study two complementary processes that determine map construction: low-level perception (in a passive stimulation task) and high-level information integration (in an active exploration task). We show that jointly considering a behavioral measure of information acquisition and a subjective measure of cognitive load can give an accurate prediction and a practical interpretation of mapping performance. Our simple TActile MOuse (TAMO) uses haptics to assess spatial ability: this may help individuals who are blind or visually impaired to be better evaluated by O&M practitioners or to evaluate their own performance. PMID- 24808400 TI - Task performance evaluation of asymmetric semiautonomous teleoperation of mobile twin-arm robotic manipulators. AB - A series of human factors experiments involving maneuvering and grasping tasks are carried out to evaluate the effectiveness of a novel asymmetric semiautonomous teleoperation (AST) control design framework for teleoperation of mobile twin-arm robotic manipulators. Simplified configurations are examined first to explore control strategies for different aspects of such teleoperation tasks. These include teleoperation of a nonholonomic mobile base, telemanipulation of a dual-arm robot, and dual-arm/dual-operator teleoperation task scenarios. In two sets of experiments with a planar nonholonomic mobile base, teleoperation via a 3DOF planar haptic interface with position mapping and force reflection of the nonholonomic constraint decreases task-completion-time (TCT) and reduces unwanted collisions. In dual-arm and dual-operator teleoperation maneuverability experiments, the assignment of decoupled and nonconflicting control frames reduces TCT and unwanted contacts. The use of so called "soft" constraints via passive semiautonomous control reduces TCT and unwanted block drops in telegrasping experiments with a twin-arm manipulator. A final comprehensive experiment encompassing elements of the simplified configurations demonstrates the effectiveness of AST control framework in dual operator teleoperation of a twin-arm mobile manipulator. PMID- 24808401 TI - The physical basis of perceived roughness in virtual sinusoidal textures. AB - Using a high-fidelity haptic interface based on magnetic levitation, subjects explored virtual sinusoidal textures with a frictionless probe and reported the subjective magnitude of perceived roughness. A psychophysical function was obtained spanning 33 levels of spatial periods from 0.025 to 6.00 mm. Kinematic and dynamic variables were recorded at 1,000 Hz and used to derive a set of variables to correlate with the psychophysical outcome. These included position, velocity, kinetic energy, instantaneous force (based on acceleration), mean force, and variability of the z-axis force signal from the power spectral density. The analysis implicates power of the force signal as the physical correlate of perceived roughness of sinusoidal textures. The relationship between power and roughness held across the range of spatial periods examined. PMID- 24808402 TI - Towards wearability in fingertip haptics: a 3-DoF wearable device for cutaneous force feedback. AB - Wearability will significantly increase the use of haptics in everyday life, as has already happened for audio and video technologies. The literature on wearable haptics is mainly focused on vibrotactile stimulation, and only recently, wearable devices conveying richer stimuli, like force vectors, have been proposed. This paper introduces design guidelines for wearable haptics and presents a novel 3-DoF wearable haptic interface able to apply force vectors directly to the fingertip. It consists of two platforms: a static one, placed on the back of the finger, and a mobile one, responsible for applying forces at the finger pad. The structure of the device resembles that of parallel robots, where the fingertip is placed in between the static and the moving platforms. This work presents the design of the wearable display, along with the quasi-static modeling of the relationship between the applied forces and the platform's orientation and displacement. The device can exert up to 1.5 N, with a maximum platform inclination of 30 degree. To validate the device and verify its effectiveness, a curvature discrimination experiment was carried out: employing the wearable device together with a popular haptic interface improved the performance with respect of employing the haptic interface alone. PMID- 24808403 TI - Comparison of saltation, amplitude modulation, and a hybrid method of vibrotactile stimulation. AB - Illusory vibrotactile movement can be used to provide directional tactile information on the skin. Our research question was how the presentation method affects the perception of vibrotactile movement. Illusion of vibrotactile mediolateral movement was elicited to a left dorsal forearm to investigate cognitive and emotional experiences to vibrotactile stimulation. Eighteen participants were presented with stimuli delivered to a linearly aligned row of three vibrotactile actuators. Three presentation methods were used--saltation, amplitude modulation, and a hybrid method--to form 12 distinct patterns of movement. First, the stimuli were compared pairwise using a two-alternative forced-choice procedure (same-different judgments). Second, the stimuli were rated using three nine-point bipolar scales measuring the continuity, pleasantness, and arousal of each stimulus. The stimuli presented with the amplitude modulation method were rated significantly more continuous and pleasant, and less arousing. Strong correlations between the cognition-related scale of continuity and the emotion-related scales of pleasantness and arousal were found: More continuous stimuli were rated more pleasant and less arousing. PMID- 24808404 TI - Perceptual analysis of vibrotactile flows on a mobile device. AB - "Vibrotactile flow" refers to a continuously moving sensation of vibrotactile stimulation applied by a few actuators directly onto the skin or through a rigid medium. Research demonstrated the effectiveness of vibrotactile flow for conveying intuitive directional information on a mobile device. In this paper, we extend previous research by investigating the perceptual characteristics of vibrotactile flows rendered on a mobile device and proposing a synthesis framework for vibrotactile flows with desired perceptual properties. PMID- 24808405 TI - Three-dimensional sheaf of ultrasound planes reconstruction (SOUPR) of ablated volumes. AB - This paper presents an algorithm for 3-D reconstruction of tumor ablations using ultrasound shear wave imaging with electrode vibration elastography. Radio frequency ultrasound data frames are acquired over imaging planes that form a subset of a sheaf of planes sharing a common axis of intersection. Shear wave velocity is estimated separately on each imaging plane using a piecewise linear function fitting technique with a fast optimization routine. An interpolation algorithm then computes velocity maps on a fine grid over a set of C-planes that are perpendicular to the axis of the sheaf. A full 3-D rendering of the ablation can then be created from this stack of C-planes; hence the name "Sheaf Of Ultrasound Planes Reconstruction" or SOUPR. The algorithm is evaluated through numerical simulations and also using data acquired from a tissue mimicking phantom. Reconstruction quality is gauged using contrast and contrast-to-noise ratio measurements and changes in quality from using increasing number of planes in the sheaf are quantified. The highest contrast of 5 dB is seen between the stiffest and softest regions of the phantom. Under certain idealizing assumptions on the true shape of the ablation, good reconstruction quality while maintaining fast processing rate can be obtained with as few as six imaging planes suggesting that the method is suited for parsimonious data acquisitions with very few sparsely chosen imaging planes. PMID- 24808407 TI - Common and Innovative Visuals: A sparsity modeling framework for video. AB - Efficient video representation models are critical for many video analysis and processing tasks. In this paper, we present a framework based on the concept of finding the sparsest solution to model video frames. To model the spatio-temporal information, frames from one scene are decomposed into two components: (i) a common frame, which describes the visual information common to all the frames in the scene/segment, and (ii) a set of innovative frames, which depicts the dynamic behaviour of the scene. The proposed approach exploits and builds on recent results in the field of compressed sensing to jointly estimate the common frame and the innovative frames for each video segment. We refer to the proposed modeling framework by CIV (Common and Innovative Visuals). We show how the proposed model can be utilized to find scene change boundaries and extend CIV to videos from multiple scenes. Furthermore, the proposed model is robust to noise and can be used for various video processing applications without relying on motion estimation and detection or image segmentation. Results for object tracking, video editing (object removal, inpainting) and scene change detection are presented to demonstrate the efficiency and the performance of the proposed model. PMID- 24808406 TI - Predicting visual semantic descriptive terms from radiological image data: preliminary results with liver lesions in CT. AB - We describe a framework to model visual semantics of liver lesions in CT images in order to predict the visual semantic terms (VST) reported by radiologists in describing these lesions. Computational models of VST are learned from image data using linear combinations of high-order steerable Riesz wavelets and support vector machines (SVM). In a first step, these models are used to predict the presence of each semantic term that describes liver lesions. In a second step, the distances between all VST models are calculated to establish a nonhierarchical computationally-derived ontology of VST containing inter-term synonymy and complementarity. A preliminary evaluation of the proposed framework was carried out using 74 liver lesions annotated with a set of 18 VSTs from the RadLex ontology. A leave-one-patient-out cross-validation resulted in an average area under the ROC curve of 0.853 for predicting the presence of each VST. The proposed framework is expected to foster human-computer synergies for the interpretation of radiological images while using rotation-covariant computational models of VSTs to 1) quantify their local likelihood and 2) explicitly link them with pixel-based image content in the context of a given imaging domain. PMID- 24808408 TI - Filtering chromatic aberration for wide acceptance angle electrostatic lenses. AB - Chromatic aberration is a major issue for imaging mainly with large acceptance angle electrostatic lenses. Its correction is necessary to take advantage of the outstanding spatial and angular resolution that these lenses provide. We propose a method to eliminate the effect of chromatic aberration on the measured images by determining the impact resulting from higher and lower kinetic energies. Based on a spectral image sequence and a matrix, which describes the transmission function of the lens, a system of linear equations is solved to approximate the 2D spectral intensity distribution of the sample surface. We present the description of our method and preliminary test results, which show significant contrast and image quality improvement. The presented algorithm can also be applied as a software-based energy analyzer. PMID- 24808409 TI - A novel local pattern descriptor--local vector pattern in high-order derivative space for face recognition. AB - In this paper, a novel local pattern descriptor generated by the proposed local vector pattern (LVP) in high-order derivative space is presented for use in face recognition. Based on the vector of each pixel constructed by computing the values between the referenced pixel and the adjacent pixels with diverse distances from different directions, the vector representation of the referenced pixel is generated to provide the 1D structure of micropatterns. With the devise of pairwise direction of vector for each pixel, the LVP reduces the feature length via comparative space transform to encode various spatial surrounding relationships between the referenced pixel and its neighborhood pixels. Besides, the concatenation of LVPs is compacted to produce more distinctive features. To effectively extract more detailed discriminative information in a given subregion, the vector of LVP is refined by varying local derivative directions from the n th-order LVP in (n-1) th-order derivative space, which is a much more resilient structure of micropatterns than standard local pattern descriptors. The proposed LVP is compared with the existing local pattern descriptors including local binary pattern (LBP), local derivative pattern (LDP), and local tetra pattern (LTrP) to evaluate the performances from input grayscale face images. In addition, extensive experiments conducting on benchmark face image databases, FERET, CAS-PEAL, CMU-PIE, Extended Yale B, and LFW, demonstrate that the proposed LVP in high-order derivative space indeed performs much better than LBP, LDP, and LTrP in face recognition. PMID- 24808410 TI - QR images: optimized image embedding in QR codes. AB - This paper introduces the concept of QR images, an automatic method to embed QR codes into color images with bounded probability of detection error. These embeddings are compatible with standard decoding applications and can be applied to any color image with full area coverage. The QR information bits are encoded into the luminance values of the image, taking advantage of the immunity of QR readers against local luminance disturbances. To mitigate the visual distortion of the QR image, the algorithm utilizes halftoning masks for the selection of modified pixels and nonlinear programming techniques to locally optimize luminance levels. A tractable model for the probability of error is developed and models of the human visual system are considered in the quality metric used to optimize the luminance levels of the QR image. To minimize the processing time, the optimization techniques proposed to consider the mechanics of a common binarization method and are designed to be amenable for parallel implementations. Experimental results show the graceful degradation of the decoding rate and the perceptual quality as a function the embedding parameters. A visual comparison between the proposed and existing methods is presented. PMID- 24808411 TI - Indirect estimation of signal-dependent noise with nonadaptive heterogeneous samples. AB - We consider the estimation of signal-dependent noise from a single image. Unlike conventional algorithms that build a scatterplot of local mean-variance pairs from either small or adaptively selected homogeneous data samples, our proposed approach relies on arbitrarily large patches of heterogeneous data extracted at random from the image. We demonstrate the feasibility of our approach through an extensive theoretical analysis based on mixture of Gaussian distributions. A prototype algorithm is also developed in order to validate the approach on simulated data as well as on real camera raw images. PMID- 24808412 TI - Improving level set method for fast auroral oval segmentation. AB - Auroral oval segmentation from ultraviolet imager images is of significance in the field of spatial physics. Compared with various existing image segmentation methods, level set is a promising auroral oval segmentation method with satisfactory precision. However, the traditional level set methods are time consuming, which is not suitable for the processing of large aurora image database. For this purpose, an improving level set method is proposed for fast auroral oval segmentation. The proposed algorithm combines four strategies to solve the four problems leading to the high-time complexity. The first two strategies, including our shape knowledge-based initial evolving curve and neighbor embedded level set formulation, can not only accelerate the segmentation process but also improve the segmentation accuracy. And then, the latter two strategies, including the universal lattice Boltzmann method and sparse field method, can further reduce the time cost with an unlimited time step and narrow band computation. Experimental results illustrate that the proposed algorithm achieves satisfactory performance for auroral oval segmentation within a very short processing time. PMID- 24808413 TI - Utilizing a language model to improve online dynamic data collection in P300 spellers. AB - P300 spellers provide a means of communication for individuals with severe physical limitations, especially those with locked-in syndrome, such as amyotrophic lateral sclerosis. However, P300 speller use is still limited by relatively low communication rates due to the multiple data measurements that are required to improve the signal-to-noise ratio of event-related potentials for increased accuracy. Therefore, the amount of data collection has competing effects on accuracy and spelling speed. Adaptively varying the amount of data collection prior to character selection has been shown to improve spelling accuracy and speed. The goal of this study was to optimize a previously developed dynamic stopping algorithm that uses a Bayesian approach to control data collection by incorporating a priori knowledge via a language model. Participants ( n = 17) completed online spelling tasks using the dynamic stopping algorithm, with and without a language model. The addition of the language model resulted in improved participant performance from a mean theoretical bit rate of 46.12 bits/min at 88.89% accuracy to 54.42 bits/min ( ) at 90.36% accuracy. PMID- 24808414 TI - Implantable ultrasonic imaging assembly for automated monitoring of internal organs. AB - An implantable miniaturized imaging device can be attractive in many clinical applications. They include automated, periodic, high-resolution monitoring of susceptible organs for early detection of an anomalous growth. In this paper, we propose an implantable ultrasonic imager capable of online high-resolution imaging of a region inside the body. A feasibility analysis is presented, with respect to design of such a system and its application to online monitoring of tumor growth in deep internal organs. We use ultrasound (US) imaging technology, as it is safe, low-cost, can be easily miniaturized, and amenable for long-term, point-of-care (POC) monitoring. The design space of the proposed system has been explored including form factor, transducer specifications and power/energy requirements. We have analyzed the effectiveness of the system in timely detection of anomalous growth in a case study through software simulations using a widely-accepted ultrasonic platform (Field II). Finally, through experimental studies using medical grade phantoms and an ultrasound scanner, we have evaluated the system with respect to its major imaging characteristics. It is observed that interstitial imaging under area/power constraints would achieve significantly better imaging quality in terms of contrast sensitivity and spatial resolution than existing techniques in deep, internal body parts, while maintaining the automated monitoring advantages. PMID- 24808415 TI - A robust ISFET pH-measuring front-end for chemical reaction monitoring. AB - This paper presents a robust, low-power and compact ion-sensitive field-effect transistor (ISFET) sensing front-end for pH reaction monitoring using unmodified CMOS. Robustness is achieved by overcoming problems of DC offset due to trapped charge and transcoductance reduction due to capacitive division, which commonly exist with implementation of ISFETs in CMOS. Through direct feedback to the floating gate and a low-leakage switching scheme, all the unwanted factors are eliminated while the output is capable of tracking a pH reaction which occurs at the sensing surface. This is confirmed through measured results of multiple devices of different sensing areas, achieving a mean amplification of 1.28 over all fabricated devices and pH sensitivity of 42.1 mV/pH. The front-end is also capable of compensating for accumulated drift using the designed switching scheme by resetting the floating gate voltage. The circuit has been implemented in a commercially-available 0.35 MUm CMOS technology achieving a combined chemical and electrical output RMS noise of 3.1 mV at a power consumption of 848.1 nW which is capable of detecting pH changes as small as 0.06 pH. PMID- 24808416 TI - An interoperable system for automated diagnosis of cardiac abnormalities from electrocardiogram data. AB - Electrocardiogram (ECG) data are stored and analyzed in different formats, devices, and computer platforms. As a result, ECG data from different monitoring devices cannot be displayed unless the user has access to the proprietary software of each particular device. This research describes an ontology and encoding for representation of ECG data that allows open exchange and display of ECG data in a web browser. The ontology is based on the Health Level Seven (HL7) medical device communication standard. It integrates ECG waveform data, HL7 standard ECG data descriptions, and cardiac diagnosis rules, providing a capability to both represent ECG waveforms as well as perform automated diagnosis of 37 different cardiac abnormalities. The ECG ontology is encoded in XML, thus allowing ECG data from any digital ECG device that maps to it to be displayed in a general-purpose Internet browser. An experiment was conducted to test the interoperability of the system (ability to openly share ECG data without error in a web browser) and also to assess the accuracy of the diagnosis model. Results showed 100% interoperability using 276 ECG data files and 93% accuracy in diagnosis of abnormal cardiac conditions. PMID- 24808417 TI - "First-in-man" MitraClip via pulmonary vein access through a right mini thoracotomy in a patient with agenesis of the inferior vena cava. AB - AIMS: Transcatheter mitral valve repair has become a promising alternative treatment option for severe symptomatic mitral regurgitation in patients at high risk for open heart surgery with heart-lung bypass. METHODS AND RESULTS: We describe the first successful procedure of mitral clipping through a right lateral mini-thoracotomy via the right upper pulmonary vein in a patient with an agenesis of the inferior vena cava. The set-up of the MitraClip system on a separate table located at 70! on the right side of the patient and the fixation of the steerable sheath at the entry into the thorax with constant posterior pressure enabled clip implantation using the usual manoeuvres with marked reduction of the mitral insufficiency. CONCLUSIONS: The access through the right upper pulmonary vein using the usual right mini-thoracotomy enabled a successful mitral clipping even in the absence or occlusion of the inferior vena cava. PMID- 24808418 TI - MRI of diffuse liver disease: characteristics of acute and chronic diseases. AB - Diffuse liver disease, including chronic liver disease, affects tens of millions of people worldwide, and there is a growing need for diagnostic evaluation as treatments become more readily available, particularly for viral liver diseases. Magnetic resonance imaging (MRI) provides unique capabilities for noninvasive characterization of the liver tissue that rival or surpass the diagnostic utility of liver biopsies. There has been incremental improvement in the use of standardized MRI sequences, acquired before and after administration of a contrast agent, for the evaluation of diffuse liver disease and the study of the liver parenchyma and blood supply. More recent developments have led to methods for quantifying important liver metabolites, including lipids and iron, and liver fibrosis, the hallmark of chronic liver disease. Here, we review the MRI techniques and diagnostic features associated with acute and chronic liver disease. PMID- 24808420 TI - Nonstationary source separation using sequential and variational Bayesian learning. AB - Independent component analysis (ICA) is a popular approach for blind source separation where the mixing process is assumed to be unchanged with a fixed set of stationary source signals. However, the mixing system and source signals are nonstationary in real-world applications, e.g., the source signals may abruptly appear or disappear, the sources may be replaced by new ones or even moving by time. This paper presents an online learning algorithm for the Gaussian process (GP) and establishes a separation procedure in the presence of nonstationary and temporally correlated mixing coefficients and source signals. In this procedure, we capture the evolved statistics from sequential signals according to online Bayesian learning. The activity of nonstationary sources is reflected by an automatic relevance determination, which is incrementally estimated at each frame and continuously propagated to the next frame. We employ the GP to characterize the temporal structures of time-varying mixing coefficients and source signals. A variational Bayesian inference is developed to approximate the true posterior for estimating the nonstationary ICA parameters and for characterizing the activity of latent sources. The differences between this ICA method and the sequential Monte Carlo ICA are illustrated. In the experiments, the proposed algorithm outperforms the other ICA methods for the separation of audio signals in the presence of different nonstationary scenarios. PMID- 24808421 TI - Complex-valued filtering based on the minimization of complex-error entropy. AB - In this paper, we consider the training of complex-valued filter based on the information theoretic method. We first generalize the error entropy criterion to complex domain to present the complex error entropy criterion (CEEC). Due to the difficulty in estimating the entropy of complex-valued error directly, the entropy bound minimization (EBM) method is used to compute the upper bounds of the entropy of the complex-valued error, and the tightest bound selected by the EBM algorithm is used as the estimator of the complex-error entropy. Then, based on the minimization of complex-error entropy (MCEE) and the complex gradient descent approach, complex-valued learning algorithms for both the (linear) transverse filter and the (nonlinear) neural network are derived. The algorithms are applied to complex-valued linear filtering and complex-valued nonlinear channel equalization to demonstrate their effectiveness and advantages. PMID- 24808419 TI - MRI of hepatocellular carcinoma: an update of current practices. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and liver transplantation is the optimal treatment for selected patients with HCC and chronic liver disease (CLD). Accurate selection of patients for transplantation is essential to maximize patient outcomes and ensure optimized allocation of donor organs. Magnetic resonance imaging (MRI) is a powerful tool for the detection, characterization, and staging of HCC. In patients with CLD, the MRI findings of an arterial-enhancing mass with subsequent washout and enhancing capsule on delayed interstitial phase images are diagnostic for HCC. Major organizations with oversight for organ donor distribution, such as The Organ Procurement and Transplantation Network (OPTN), accept an imaging diagnosis of HCC, no longer requiring tissue biopsy. In patients that are awaiting transplantation, or are not candidates for liver transplantation, localized therapies such as transarterial chemoembolization and radiofrequency ablation may be offered. MRI can be used to monitor treatment response. The purpose of this review article is to describe the role of imaging methods in the diagnosis, staging, and follow-up of HCC, with particular emphasis on established and evolving MRI techniques employing nonspecific gadolinium chelates, hepatobiliary contrast agents, and diffusion weighted imaging. We also briefly review the recently developed Liver Imaging Reporting and Data System (LI-RADS) formulating a standardized terminology and reporting structure for evaluation of lesions detected in patients with CLD. PMID- 24808422 TI - Multiview vector-valued manifold regularization for multilabel image classification. AB - In computer vision, image datasets used for classification are naturally associated with multiple labels and comprised of multiple views, because each image may contain several objects (e.g., pedestrian, bicycle, and tree) and is properly characterized by multiple visual features (e.g., color, texture, and shape). Currently, available tools ignore either the label relationship or the view complementarily. Motivated by the success of the vector-valued function that constructs matrix-valued kernels to explore the multilabel structure in the output space, we introduce multiview vector-valued manifold regularization (MV(3)MR) to integrate multiple features. MV(3)MR exploits the complementary property of different features and discovers the intrinsic local geometry of the compact support shared by different features under the theme of manifold regularization. We conduct extensive experiments on two challenging, but popular, datasets, PASCAL VOC' 07 and MIR Flickr, and validate the effectiveness of the proposed MV(3)MR for image classification. PMID- 24808423 TI - Stopped object detection by learning foreground model in videos. AB - The automatic detection of objects that are abandoned or removed in a video scene is an interesting area of computer vision, with key applications in video surveillance. Forgotten or stolen luggage in train and airport stations and irregularly parked vehicles are examples that concern significant issues, such as the fight against terrorism and crime, and public safety. Both issues involve the basic task of detecting static regions in the scene. We address this problem by introducing a model-based framework to segment static foreground objects against moving foreground objects in single view sequences taken from stationary cameras. An image sequence model, obtained by learning in a self-organizing neural network image sequence variations, seen as trajectories of pixels in time, is adopted within the model-based framework. Experimental results on real video sequences and comparisons with existing approaches show the accuracy of the proposed stopped object detection approach. PMID- 24808424 TI - Asynchronous cellular automaton-based neuron: theoretical analysis and on-FPGA learning. AB - A generalized asynchronous cellular automaton-based neuron model is a special kind of cellular automaton that is designed to mimic the nonlinear dynamics of neurons. The model can be implemented as an asynchronous sequential logic circuit and its control parameter is the pattern of wires among the circuit elements that is adjustable after implementation in a field-programmable gate array (FPGA) device. In this paper, a novel theoretical analysis method for the model is presented. Using this method, stabilities of neuron-like orbits and occurrence mechanisms of neuron-like bifurcations of the model are clarified theoretically. Also, a novel learning algorithm for the model is presented. An equivalent experiment shows that an FPGA-implemented learning algorithm enables an FPGA implemented model to automatically reproduce typical nonlinear responses and occurrence mechanisms observed in biological and model neurons. PMID- 24808425 TI - Soft margin multiple kernel learning. AB - Multiple kernel learning (MKL) has been proposed for kernel methods by learning the optimal kernel from a set of predefined base kernels. However, the traditional L1MKL method often achieves worse results than the simplest method using the average of base kernels (i.e., average kernel) in some practical applications. In order to improve the effectiveness of MKL, this paper presents a novel soft margin perspective for MKL. Specifically, we introduce an additional slack variable called kernel slack variable to each quadratic constraint of MKL, which corresponds to one support vector machine model using a single base kernel. We first show that L1MKL can be deemed as hard margin MKL, and then we propose a novel soft margin framework for MKL. Three commonly used loss functions, including the hinge loss, the square hinge loss, and the square loss, can be readily incorporated into this framework, leading to the new soft margin MKL objective functions. Many existing MKL methods can be shown as special cases under our soft margin framework. For example, the hinge loss soft margin MKL leads to a new box constraint for kernel combination coefficients. Using different hyper-parameter values for this formulation, we can inherently bridge the method using average kernel, L1MKL, and the hinge loss soft margin MKL. The square hinge loss soft margin MKL unifies the family of elastic net constraint/regularizer based approaches; and the square loss soft margin MKL incorporates L2MKL naturally. Moreover, we also develop efficient algorithms for solving both the hinge loss and square hinge loss soft margin MKL. Comprehensive experimental studies for various MKL algorithms on several benchmark data sets and two real world applications, including video action recognition and event recognition demonstrate that our proposed algorithms can efficiently achieve an effective yet sparse solution for MKL. PMID- 24808426 TI - Online learning control using adaptive critic designs with sparse kernel machines. AB - In the past decade, adaptive critic designs (ACDs), including heuristic dynamic programming (HDP), dual heuristic programming (DHP), and their action-dependent ones, have been widely studied to realize online learning control of dynamical systems. However, because neural networks with manually designed features are commonly used to deal with continuous state and action spaces, the generalization capability and learning efficiency of previous ACDs still need to be improved. In this paper, a novel framework of ACDs with sparse kernel machines is presented by integrating kernel methods into the critic of ACDs. To improve the generalization capability as well as the computational efficiency of kernel machines, a sparsification method based on the approximately linear dependence analysis is used. Using the sparse kernel machines, two kernel-based ACD algorithms, that is, kernel HDP (KHDP) and kernel DHP (KDHP), are proposed and their performance is analyzed both theoretically and empirically. Because of the representation learning and generalization capability of sparse kernel machines, KHDP and KDHP can obtain much better performance than previous HDP and DHP with manually designed neural networks. Simulation and experimental results of two nonlinear control problems, that is, a continuous-action inverted pendulum problem and a ball and plate control problem, demonstrate the effectiveness of the proposed kernel ACD methods. PMID- 24808427 TI - Policy improvement by a model-free Dyna architecture. AB - The objective of this paper is to accelerate the process of policy improvement in reinforcement learning. The proposed Dyna-style system combines two learning schemes, one of which utilizes a temporal difference method for direct learning; the other uses relative values for indirect learning in planning between two successive direct learning cycles. Instead of establishing a complicated world model, the approach introduces a simple predictor of average rewards to actor critic architecture in the simulation (planning) mode. The relative value of a state, defined as the accumulated differences between immediate reward and average reward, is used to steer the improvement process in the right direction. The proposed learning scheme is applied to control a pendulum system for tracking a desired trajectory to demonstrate its adaptability and robustness. Through reinforcement signals from the environment, the system takes the appropriate action to drive an unknown dynamic to track desired outputs in few learning cycles. Comparisons are made between the proposed model-free method, a connectionist adaptive heuristic critic, and an advanced method of Dyna-Q learning in the experiments of labyrinth exploration. The proposed method outperforms its counterparts in terms of elapsed time and convergence rate. PMID- 24808428 TI - Firing rate propagation through neuronal-astrocytic network. AB - Understanding the underlying mechanism of the propagation of neuronal activities within the brain is a fundamental issue in neuroscience. Traditionally, communication and information processing have been exclusively considered as the province of synaptic coupling between neurons. Astrocytes, however, have recently been acknowledged as active partners in neuronal information processing. So, it is more reasonable and accurate to study the nature of neuronal signal propagation with the participation of astrocytes. In this paper, we first propose a feedforward neuronal-astrocytic network (FNAsN), which includes the mutual neuron-astrocyte interaction. Besides, we also consider the unreliability of both the synaptic transmission between neurons and the coupling between neurons and astrocytes. Then, the performance of firing rate propagation through the proposed FNAsN is studied through a series of simulations. Results show that the astrocytes can mediate neuronal activities, and consequently improve the performance of firing rate propagation, especially in a weak and noisy environment. From this point of view, astrocytes can be regarded as a realistic internal source of noise, which collaborates with an externally applied weak noise to prevent synchronous neuron firing within the same layer and thus to ensure reliable transmission. PMID- 24808429 TI - On stabilization of stochastic Cohen-Grossberg neural networks with mode dependent mixed time-delays and Markovian switching. AB - The globally exponential stabilization problem is investigated for a general class of stochastic Cohen-Grossberg neural networks with both Markovian jumping parameters and mixed mode-dependent time-delays. The mixed time-delays consist of both discrete and distributed delays. This paper aims to design a memoryless state feedback controller such that the closed-loop system is stochastically exponentially stable in the mean square sense. By introducing a new Lyapunov Krasovskii functional that accounts for the mode-dependent mixed delays, stochastic analysis is conducted in order to derive delay-dependent criteria for the exponential stabilization problem. Three numerical examples are carried out to demonstrate the feasibility of our delay-dependent stabilization criteria. PMID- 24808430 TI - A one-layer projection neural network for nonsmooth optimization subject to linear equalities and bound constraints. AB - This paper presents a one-layer projection neural network for solving nonsmooth optimization problems with generalized convex objective functions and subject to linear equalities and bound constraints. The proposed neural network is designed based on two projection operators: linear equality constraints, and bound constraints. The objective function in the optimization problem can be any nonsmooth function which is not restricted to be convex but is required to be convex (pseudoconvex) on a set defined by the constraints. Compared with existing recurrent neural networks for nonsmooth optimization, the proposed model does not have any design parameter, which is more convenient for design and implementation. It is proved that the output variables of the proposed neural network are globally convergent to the optimal solutions provided that the objective function is at least pseudoconvex. Simulation results of numerical examples are discussed to demonstrate the effectiveness and characteristics of the proposed neural network. PMID- 24808431 TI - Constraint verification with kernel machines. AB - Based on a recently proposed framework of learning from constraints using kernel based representations, in this brief, we naturally extend its application to the case of inferences on new constraints. We give examples for polynomials and first order logic by showing how new constraints can be checked on the basis of given premises and data samples. Interestingly, this gives rise to a perceptual logic scheme in which the inference mechanisms do not rely only on formal schemes, but also on the data probability distribution. It is claimed that when using a properly relaxed computational checking approach, the complementary role of data samples makes it possible to break the complexity barriers of related formal checking mechanisms. PMID- 24808432 TI - Energy-efficient SVM learning control system for biped walking robots. AB - An energy-efficient support vector machine (EE-SVM) learning control system considering the energy cost of each training sample of biped dynamic is proposed to realize energy-efficient biped walking. Energy costs of the biped walking samples are calculated. Then the samples are weighed with the inverses of the energy costs. An EE-SVM objective function with energy-related slack variables is proposed, which follows the principle that the sample with the lowest energy consumption is treated as the most important one in the training. That means the samples with lower energy consumption contribute more to the EE-SVM regression function learning, which highly increases the energy efficiency of the biped walking. Simulation results demonstrate the effectiveness of the proposed method. PMID- 24808433 TI - Self-tuning control with a filter and a neural compensator for a class of nonlinear systems. AB - Considering the mismatching of model-process order, in this brief, a self-tuning proportional-integral-derivative (PID)-like controller is proposed by combining a pole assignment self-tuning PID controller with a filter and a neural compensator. To design the PID controller, a reduced order model is introduced, whose linear parameters are identified by a normalized projection algorithm with a deadzone. The higher order nonlinearity is estimated by a high order neural network. The gains of the PID controller are obtained by pole assignment, which together with other parameters are tuned on-line. The bounded-input bounded output stability condition and convergence condition of the closed-loop system are presented. Simulations are conducted on the continuous stirred tank reactors system. The results show the effectiveness of the proposed method. PMID- 24808434 TI - Radiology-guided forceps biopsy and airway stenting in severe airway stenosis. AB - PURPOSE: We aimed to determine the feasibility, safety, and effectiveness of radiology-guided forceps biopsy and airway stenting in patients with severe airway stenosis. MATERIALS AND METHODS: This study involved 28 patients with severe airway stenosis who underwent forceps biopsy between October 2006 and September 2011. Chest multislice computed tomography was used to determine the location and extent of stenosis. Sixteen patients had tracheal stenosis, two patients had stenosis of the tracheal carina, six patients had stenosis of the left main bronchus, and four patients had stenosis of the right main bronchus. Forceps biopsy and stenting of the stenosed area were performed under fluoroscopic guidance in digital subtraction angiography and the biopsy specimens were analyzed histopathologically. We contacted the patients via phone call and utilized a standardized questionnaire to determine their medical condition during a postoperative three-month follow-up. RESULTS: The technical success rate of radiology-guided forceps biopsy was 100%. Biopsy specimens were obtained in all patients. Dyspnea was relieved immediately after stent placement. No serious complications, such as tracheal hemorrhage or perforation, mediastinal emphysema, or asphyxia, occurred. CONCLUSION: Radiology-guided forceps biopsy and airway stenting can be used for the emergency treatment of severe airway stenosis. This method appears to be safe and effective, and it may be an alternative therapeutic option in patients who cannot tolerate fiberoptic bronchoscopy. PMID- 24808435 TI - Natural history of small index lesions suspicious for prostate cancer on multiparametric MRI: recommendations for interval imaging follow-up. AB - PURPOSE: We aimed to determine the natural history of small index lesions identified on multiparametric-magnetic resonance imaging (MP-MRI) of the prostate by evaluating lesion-specific pathology and growth on serial MP-MRI. MATERIALS AND METHODS: We performed a retrospective review of 153 patients who underwent a minimum of two MP-MRI sessions, on an institutional review board-approved protocol. Index lesion is defined as the lesion(s) with the highest cancer suspicion score based on initial MP-MRI of a patient, irrespective of size. Two study cohorts were identified: (1) patients with no index lesion or index lesion(s) <=7 mm and (2) a subset with no index lesion or index lesion(s) <=5 mm. Pathological analysis of the index lesions was performed following magnetic resonance/ultrasound fusion-guided biopsy. Growth rate of the lesions was calculated based on MP-MRI follow-up. RESULTS: Patients with small index lesions measuring <=7 mm (n=42) or a subset with lesions <=5 mm (n=20) demonstrated either benign findings (86.2% and 87.5%, respectively) or low grade Gleason 6 prostate cancer (13.8% and 12.5%, respectively) on lesion-specific targeted biopsies. These lesions demonstrated no significant change in size (P = 0.93 and P = 0.36) over a mean imaging period of 2.31+/-1.56 years and 2.40+/-1.77 years for <=7 mm and <=5 mm index lesion thresholds, respectively. These findings held true on subset analyses of patients who had a minimum of two-year interval follow up with MP-MRI. CONCLUSION: Small index lesions of the prostate are pathologically benign lesions or occasionally low-grade cancers. Slow growth rate of these small index lesions on serial MP-MRI suggests a surveillance interval of at least two years without significant change. PMID- 24808436 TI - MRI characterization of inflammatory myofibroblastic tumors in the maxillofacial region. AB - PURPOSE: We aimed to investigate the magnetic resonance imaging (MRI) appearance of inflammatory myofibroblastic tumors (IMTs) in the maxillofacial region in order to improve diagnostic quality and resection efficacy. MATERIALS AND METHODS: Ten cases of pathologically identified IMTs were analyzed by MRI. The MRI features were examined, including tumor location, tumor shape, tumor margins, and involvement of the surrounding tissues. RESULTS: Of ten masses investigated in this study, eight masses were irregular neoplasms with unclear margins and two masses, in the parotid gland, were regular neoplasms with clear margins. Precontrast T1-weighted images of all ten masses exhibited isointense signals compared to the adjacent tissue, while contrast-enhanced T1-weighted images showed strong enhancement. Six masses were hypointense and four masses were slightly hyperintense in T2-weighted images. Involvement of the adjacent structures was observed in eight of ten cases. Meanwhile, two patients experienced intracranial involvement. CONCLUSION: IMTs are rare tumors in the maxillofacial region, displaying a number of distinct MRI characteristics. Most importantly, they display low T2 signal intensity and strong enhancement, and they frequently invade surrounding structures. Thus, MRI can improve the accuracy of IMT diagnoses and provide critical information for surgical planning. PMID- 24808437 TI - Diagnosis and management of hemoptysis. AB - Hemoptysis is the expectoration of blood that originates from the lower respiratory tract. It is usually a self-limiting event but in fewer than 5% of cases it may be massive, representing a life-threatening condition that warrants urgent investigations and treatment. This article aims to provide a comprehensive literature review on hemoptysis, analyzing its causes and pathophysiologic mechanisms, and providing details about anatomy and imaging of systemic bronchial and nonbronchial arteries responsible for hemoptysis. Strengths and limits of chest radiography, bronchoscopy, multidetector computed tomography (MDCT), MDCT angiography and digital subtraction angiography to assess the cause and lead the treatment of hemoptysis were reported, with particular emphasis on MDCT angiography. Treatment options for recurrent or massive hemoptysis were summarized, highlighting the predominant role of bronchial artery embolization. Finally, a guide was proposed for managing massive and nonmassive hemoptysis, according to the most recent medical literature. PMID- 24808438 TI - CT-guided percutaneous cryoablation of central lung tumors. AB - PURPOSE: Cryoablation has been successfully used to treat lung tumors. However, the safety and effectiveness of treating tumors adjacent to critical structures has not been fully established. We describe our experience with computed tomography (CT)-guided percutaneous cryoablation of central lung tumors and the role of ice ball monitoring. MATERIALS AND METHODS: Eight patients with 11 malignant central lung tumors (nine metastatic, two primary; mean, 2.6 cm; range, 1.0-4.5 cm) located adjacent to mediastinal or hilar structures were treated using CT-guided cryoablation in 10 procedures. Technical success and effectiveness rates were calculated, complications were tabulated and intraprocedural imaging features of ice balls were described. RESULTS: All procedures were technically successful; imaging after 24 hours demonstrated no residual tumor. Five tumors recurred, three of which were re-ablated successfully. A hypodense ice ball with well-defined margin was visible during the first (n=6, 55%) or second (n=11, 100%) freeze, encompassing the entire tumor in all patients, and abutting (n=7) or minimally involving (n=4) adjacent mediastinal and hilar structures. Pneumothorax developed following six procedures (60%); percutaneous treatment was applied in three of them. All patients developed pleural effusions, with one patient requiring percutaneous drainage. Transient hemoptysis occurred after six procedures (60%), but all cases improved within a week. No injury occurred to mediastinal or hilar structures. CONCLUSION: CT-guided percutaneous cryoablation can be used to treat central lung tumors successfully. Although complications were common, they were self-limited, treatable, and not related to tumor location. Ice ball monitoring helped maximize the amount of tumor treated, while avoiding critical mediastinal and hilar structures. PMID- 24808439 TI - Acoustic noise reduction in MRI using Silent Scan: an initial experience. AB - PURPOSE: Acoustic noise during magnetic resonance imaging (MRI) is the main source for patient discomfort and leads to verbal communication problems, difficulties in sedation, and hearing impairment. Silent Scan technology uses less changes in gradient excitation levels, which is directly related to noise levels. Here, we report our preliminary experience with this technique in neuroimaging with regard to subjective and objective noise levels and image quality. MATERIALS AND METHODS: Ten patients underwent routine brain MRI with 3 Tesla MR750w system and 12-channel head coil. T1-weighted gradient echo (BRAVO) and Silenz pulse sequence (TE=0, 3D radial center-out k-space filling and data sampling with relatively small gradient steps) were performed. Patients rated subjective sound impression for both sequences on a 6-point scale. Objective sound level measurements were performed with a dedicated device in gantry at different operation modes. Image quality was subjectively assessed in consensus by two radiologists on a 3-point scale. RESULTS: Readers rated image quality as fully diagnostic in all patients. Measured mean noise was reduced significantly with Silenz sequence (68.8 dB vs. 104.65 dB with BRAVO, P = 0.024) corresponding to 34.3% reduction in sound intensity and 99,97% reduction in sound pressure. No significant difference was observed between Silenz sound levels and ambient sounds (i.e., background noise in the scanner room, 68.8 dB vs. 68.73 dB, P = 0.5). The patients' subjective sound level score was lower for Silenz compared with conventional sequence (1.1 vs. 2.3, P = 0.003). CONCLUSION: T1-weighted Silent Scan is a promising technique for acoustic noise reduction and improved patient comfort. PMID- 24808442 TI - Enlargement of mitral valve ring in a young woman with severe prosthesis-patient mismatch. AB - Mechanical prosthesis is the first choice for valve replacement at the mitral position in children. Replacement of the original prosthesis because of prosthesis-patient mismatch (PPM) is almost inevitable when prostheses are implanted in small children. The impact of PPM on long-term mortality becomes significant when the effective orifice area (EOA) is severely reduced. In these cases prosthesis replacement can be technically difficult, and it often requires extended enlargement of the mitral valve annulus ring. We report a case of a woman who underwent a mitral valve replacement with a 19-mm St. Jude mechanical prosthetic valve at the age of 3 years. At the age of 33 years, the patient underwent a successful minimally invasive mitral annulus ring enlargement and implantation of a 23-mm St. Jude mechanical prosthetic valve via a right minithoracotomy. PMID- 24808440 TI - The effect of using different embolic agents on survival in transarterial chemoembolization of hepatocellular carcinoma: gelfoam versus polyvinyl alcohol. AB - PURPOSE: We aimed to compare the effect of using different embolic agents such as gelfoam and polyvinyl alcohol (PVA) on survival, tumor response, and complications in transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) patients. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 38 inoperable HCC patients who underwent TACE between August 1998 and April 2007. A total of 50 TACE sessions were performed using PVA (n=18) or gelfoam particles (n=20), following the application of 60 mg doxorubicin with 10-20 mL lipiodol emulsion. The PVA and gelfoam groups were compared based on clinical, laboratory and demographic variables. Survival rates were calculated starting from the first TACE session using the Kaplan-Meier analysis. RESULTS: There was no significant difference between the survival rates of PVA and gelfoam groups (P = 0.235). Overall survival rates at 12, 24, 36, 48, and 60 months were 55%, 36%, 15%, 7%, and 5%, respectively. Tumor response, age, lipiodol accumulation type, number of HCC foci, complications and serum alpha-fetoprotein level were significant factors for survival in all patients. CONCLUSION: Use of gelfoam or PVA as the embolic agent did not have a significant impact on survival. Complete tumor response, intensive lipiodol accumulation in tumor, older age (<60 years), fewer (<=3) HCC foci, low serum alpha-fetoprotein level (<=400 ng/mL) were found to improve cumulative survival significantly. PMID- 24808443 TI - Does elective or emergent operative status influence outcomes in patients undergoing implantation of left ventricular assist devices? AB - BACKGROUND: Acuity models to predict survival after left ventricular assist device (LVAD) implantation do not include operative status as one of the calculated variables. The effect of elective versus emergent LVAD implantation on outcomes has not been examined. METHODS: Patients were stratified into 2 groups based on operative status (elective versus emergent). Variables were compared to determine whether there were differences in outcomes between elective versus emergent LVAD recipients RESULTS: Of the 130 patients, 59 underwent an elective procedure, whereas 71 had their LVAD implanted as an urgent/emergent operation. Patients in the urgent/emergent cohort had significantly worse preoperative hepatic and renal function and higher central venous pressures. Survival rates at 30 days, 6 months, 1 year, and 2 years were analogous for both cohorts. Patients in the emergent cohort had a higher incidence of postoperative right ventricular failure, with the requirement for short-term right ventricular support in 9.9% versus 1.7% (P = 0.054). The incidence of other LVAD-related complications, were similar in both groups. Emergency status did not predict postoperative mortality in univariate analysis. CONCLUSIONS: Although patients who underwent emergent LVAD implantations had worse preoperative renal and liver function and a higher incidence of postoperative right ventricular failure, they exhibited similar midterm survival and a similar incidence of other postoperative complications. PMID- 24808444 TI - Surgical treatment of tetralogy of Fallot with giant pulmonary artery aneurysm in an adult. PMID- 24808445 TI - Two-vessel off-pump coronary artery bypass grafting by left thoracotomy in a complex reoperative case. AB - An 83-year-old male with a history of three prior sternotomies, including coronary artery bypass surgery (CABG), presented with unstable angina. Cardiac catheterization showed left main and triple-vessel disease. The saphenous vein graft (SVG) to the right coronary artery was diseased but patent, and the SVG to the left anterior descending artery (LAD) was occluded. Preoperative evaluation showed a heavily calcified ascending aorta and minimum disease on the descending aorta. He successfully underwent a left thoracotomy 2-vessel off-pump CABG using the descending aorta for the proximal anastomosis. The left thoracotomy approach is a useful alternative to avoid complications associated with resternotomy, especially in patients with a hostile chest, although visualization of the target vessels may be limited. PMID- 24808446 TI - Type B interrupted aorta in an adult patient. AB - INTRODUCTION: Interrupted aortic arch is a rare congenital malformation characterized by a complete loss of luminal continuity between the ascending and descending aorta. It is often diagnosed during the neonatal period. CASE PRESENTATION: We presented a 51-year-old male patient with interrupted aortic arch type B who was treated successfully with posterolateral thoracotomy without using cardiopulmonary bypass. CONCLUSION: The prognosis for interrupted aortic arch depends on the associated congenital anomalies, but the outcome is usually very poor unless there is surgical treatment. Survival into adulthood depends on the development of collateral circulation. PMID- 24808448 TI - Severe isolated tricuspid insufficiency due to tricuspid papillary muscle rupture after a fall from a horse: treatment with port access minimally invasive cardiac surgery. AB - We report on the successful treatment of tricuspid valve insufficiency due to blunt chest injury using port-access minimally invasive cardiac surgery. The optimal surgical treatment of traumatic valvular insufficiency is discussed, including a brief review of the relevant literature. PMID- 24808447 TI - Operative status and survival after coronary artery bypass grafting. AB - BACKGROUND: The effect of race on long-term survival of patients undergoing elective and nonelective coronary artery bypass grafting (CABG) is currently unknown. The purpose of this study was to compare long-term survival between black and white CABG patients by operative status. METHODS: Long-term survival of black versus white patients undergoing elective and nonelective CABG procedures between 1992 and 2011 was compared. Survival probabilities were computed using the Kaplan-Meier product-limit method and stratified by race. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS: A total of 13,774 patients were included in this study. The median follow-up time for study participants was 8.2 years. Black patients undergoing elective CABG died sooner than whites (adjusted HR = 1.4, 95% CI = 1.2-1.5). Survival was similar between blacks and whites in the nonelective population (adjusted HR = 1.0, 95% CI = 0.96-1.1). CONCLUSIONS: Black race was a statistically significant predictor of long-term survival after elective but not nonelective CABG. PMID- 24808449 TI - Long-term follow-up of minimally invasive cardiac surgery using an endoaortic occlusion system. AB - OBJECTIVES: We reviewed the initial patient series (n=116) of our institution performing minimally invasive coronary artery bypass grafting (CABG) (n=79), mitral valve surgery (n=1), or atrial septal closure (ASD) procedures (n=26) using an endoaortic occlusion system. With this technique relevant intra-aortic pressures are exerted on the aortic wall during the clamping time. This might lead to late aortic degeneration and aneurysm formation. Our study sought to evaluate postoperative aortic complications and the quality of life (modified SF 12). METHODS: One hundred sixteen patients (56% male; 54 years +/- 14.5; range 19 years to 77 years) underwent a cardiac procedure using an endoaortic clamp. The endoaortic balloon clamp catheter was used to occlude the ascending aorta at pressures >300 mmHg. Patients were rescheduled for echocardiographic examination after a mean follow-up period of 8.8 years. RESULTS: The analysis performed among 78 patients showed no incidence of any structural damage to the ascending aorta at the intraoperative position of the endoaortic balloon. The physical and mental summary scores are equal to those of comparable patient groups. CONCLUSIONS: The endoaortic occlusion system causes no damage to the aortic wall. If the system causes any problems, they occur immediately during surgery. Patients treated with this minimally invasive technique exhibited the same quality of life as those undergoing conventional surgery. PMID- 24808450 TI - Neurohormonal regulation and improvement in blood glucose control: reduction of insulin requirement in patients with a nonpulsatile ventricular assist device. AB - BACKGROUND: Heart failure is associated with prolonged stress and inflammation characterized by elevated levels of cortisol and circulating catecholamines. Persistent sympathetic stimulation secondary to the stress of heart failure causes an induced insulin resistance, which creates a need for higher doses of insulin to adequately manage hyperglycemia in this patient population. We hypothesized that cortisol and catecholamine levels would be elevated in end stage heart failure patients, however, would be reduced after the implantation of a left ventricular assist device (LVAD). Insulin requirements would therefore be reduced post LVAD implant and control of diabetes improved as compared with pre implant. METHODS: Pre- and postoperative cortisol, catecholamine, glycated hemoglobin, and blood glucose levels were evaluated retrospectively in 99 LVAD patients at a single center from January 2007 through November 2011. Serum was collected before LVAD implantation and monthly after implantation for 12 months consecutively. Results were evaluated and compared to insulin requirements, if any, before and after implant. Plasma levels were measured by ELISA. RESULTS: There were a total of 99 patients (81 men and 18 women). Two patients were implanted twice due to pump dysfunction. Mean age was 59 years, +/- 10, with a median of 63 years. Of those patients, 64 had ischemic cardiomyopathy and 35 had dilated cardiomyopathy. The total patient years of LVAD support were 92.5 years. All patients received a continuous flow left ventricular assist device. Type II diabetes mellitus was diagnosed in 28 patients. Of those patients, 24 required daily insulin with an average dose of 45 units/day. Average preoperative glycated hemoglobin (HbA1c) levels were 6.8% with fasting blood glucose measurements of 136 mg/dL. Mean cortisol levels were measured at 24.3 MUg/dL before LVAD implantation, with mean plasma catecholamine levels of 1824 MUg/mL. Post operatively, average HbA1c levels were 5.38% with fasting blood glucose measurements of 122 mg/dL. Mean cortisol levels were measured at 10.9 MUg/dL with average plasma catecholamine levels were 815 MUg/mL. There was a significant decrease in both cortisol levels post LVAD implant (P = 0.012) as well as catecholamine levels (P = 0.044). The average insulin requirements post LVAD implant were significantly reduced to 13 units/day (P = 0.001). Six patients no longer required any insulin after implant. CONCLUSION: Implantation of nonpulsatile LVADs has become a viable option for the treatment of end-stage heart failure, helping to improve patient quality of life by decreasing clinical symptoms associated with poor end-organ perfusion. Frequently, diabetes is a comorbid condition that exists among heart failure patients and with the reduction of the systemic inflammatory and stress response produced by the support of a nonpulsatile LVAD, many patients may benefit from a reduction in their blood glucose levels, as well as insulin requirements. PMID- 24808452 TI - Extended Hamiltonian learning on Riemannian manifolds: numerical aspects. AB - This paper is the second part of a study initiated with the paper S. Fiori, "Extended Hamiltonian learning on Riemannian manifolds: Theoretical aspects," IEEE Trans. Neural Netw., vol. 22, no. 5, pp. 687-700, May 2011, which aimed at introducing a general framework to develop a theory of learning on differentiable manifolds by extended Hamiltonian stationary-action principle. This paper discusses the numerical implementation of the extended Hamiltonian learning paradigm by making use of notions from geometric numerical integration to numerically solve differential equations on manifolds. The general-purpose integration schemes and the discussion of several cases of interest show that the implementation of the dynamical learning equations exhibits a rich structure. The behavior of the discussed learning paradigm is illustrated via several numerical examples and discussions of case studies. The numerical examples confirm the theoretical developments presented in this paper as well as in its first part. PMID- 24808453 TI - Quantized kernel least mean square algorithm. AB - In this paper, we propose a quantization approach, as an alternative of sparsification, to curb the growth of the radial basis function structure in kernel adaptive filtering. The basic idea behind this method is to quantize and hence compress the input (or feature) space. Different from sparsification, the new approach uses the "redundant" data to update the coefficient of the closest center. In particular, a quantized kernel least mean square (QKLMS) algorithm is developed, which is based on a simple online vector quantization method. The analytical study of the mean square convergence has been carried out. The energy conservation relation for QKLMS is established, and on this basis we arrive at a sufficient condition for mean square convergence, and a lower and upper bound on the theoretical value of the steady-state excess mean square error. Static function estimation and short-term chaotic time-series prediction examples are presented to demonstrate the excellent performance. PMID- 24808451 TI - Web-based cognitive training: patient adherence and intensity of treatment in an outpatient memory clinic. AB - BACKGROUND: Cognitive training has been playing an increasing role in the treatment of patients with cognitive deficits. This type of intervention, namely its intensity, can be optimized by incorporating information technology-based systems. OBJECTIVE: The intent of the study was to determine the treatment intensity and patient adherence to home-based cognitive training strategies (Web based cognitive training). METHODS: A cohort of 45 patients with neurologic and psychiatric diseases attending an outpatient memory clinic (average age 50.7 years, SD 17.0; average education 7.8 years, SD 4.9) was followed over 18 months. Participants were challenged to use a Web-based cognitive training system, "COGWEB", on a daily basis, and fulfilled at least four weeks of training supervised remotely. Additionally, 11 patients attended face-to-face sessions. RESULTS: The average duration of continuous cognitive training was 18.8 weeks (SD 18.9). Each patient performed on average 363.5 minutes/week (SD 136.6). At 6 month follow-up, 82.8% complied with their treatment plan. The average proportion of complete weeks was 0.75 (SD 0.22). Patients with dementia trained more intensively (444.6 minutes/week), followed by patients with static brain lesion (414.5 minutes/week; P=.01). The group that held face-to-face sessions performed more training overall (481.4 vs 366.9 minutes/week), achieving a stronger expression and statistical significance in the last week of training (652.6 versus 354.9 minutes/week, P=.027). CONCLUSIONS: Overall, the weekly training intensity was high. Patients with dementia and static lesions performed more cognitive training. Face-to-face sessions were associated with higher intensities. The combination of classical methods with information technology systems seems to ensure greater training intensity. PMID- 24808454 TI - Fast and robust object detection using asymmetric totally corrective boosting. AB - Boosting-based object detection has received significant attention recently. In this paper, we propose totally corrective asymmetric boosting algorithms for real time object detection. Our algorithms differ from Viola and Jones' detection framework in two ways. Firstly, our boosting algorithms explicitly optimize asymmetric loss of objectives, while AdaBoost used by Viola and Jones optimizes a symmetric loss. Secondly, by carefully deriving the Lagrange duals of the optimization problems, we design more efficient boosting in that the coefficients of the selected weak classifiers are updated in a totally corrective fashion, in contrast to the stagewise optimization commonly used by most boosting algorithms. Column generation is employed to solve the proposed optimization problems. Unlike conventional boosting, the proposed boosting algorithms are able to de-select those irrelevant weak classifiers in the ensemble while training a classification cascade. This results in improved detection performance as well as fewer weak classifiers in the learned strong classifier. Compared with AsymBoost of Viola and Jones, our proposed asymmetric boosting is nonheuristic and the training procedure is much simpler. Experiments on face and pedestrian detection demonstrate that our methods have superior detection performance than some of the state-of-the-art object detectors. PMID- 24808455 TI - Assessing Granger non-causality using nonparametric measure of conditional independence. AB - In recent years, Granger causality has become a popular method in a variety of research areas including engineering, neuroscience, and economics. However, despite its simplicity and wide applicability, the linear Granger causality is an insufficient tool for analyzing exotic stochastic processes such as processes involving non-linear dynamics or processes involving causality in higher order statistics. In order to analyze such processes more reliably, a different approach toward Granger causality has become increasingly popular. This new approach employs conditional independence as a tool to discover Granger non causality without any assumption on the underlying stochastic process. This paper discusses the concept of discovering Granger non-causality using measures of conditional independence, and proposes a novel measure of conditional independence. In brief, the proposed approach estimates the conditional distribution function through a kernel based least square regression approach. This paper also explores the strengths and weaknesses of the proposed method compared to other available methods, and provides a detailed comparison of these methods using a variety of synthetic data sets. PMID- 24808456 TI - Synchronization of Markovian coupled neural networks with nonidentical node delays and random coupling strengths. AB - In this paper, a general model of coupled neural networks with Markovian jumping and random coupling strengths is introduced. In the process of evolution, the proposed model switches from one mode to another according to a Markovian chain, and all the modes have different constant time-delays. The coupling strengths are characterized by mutually independent random variables. When compared with most of existing dynamical network models which share common time-delay for all modes and have constant coupling strengths, our model is more practical because different chaotic neural network models can have different time-delays and coupling strength of complex networks may randomly vary around a constant due to environmental and artificial factors. By designing a novel Lyapunov functional and using some inequalities and the properties of random variables, we derive several new sufficient synchronization criteria formulated by linear matrix inequalities. The obtained criteria depend on mode-delays and mathematical expectations and variances of the random coupling strengths as well. Numerical examples are given to demonstrate the effectiveness of the theoretical results, meanwhile right-continuous Markovian chain is also presented. PMID- 24808457 TI - Visualized analysis of mixed numeric and categorical data via extended self organizing map. AB - Many real-world datasets are of mixed types, having numeric and categorical attributes. Even though difficult, analyzing mixed-type datasets is important. In this paper, we propose an extended self-organizing map (SOM), called MixSOM, which utilizes a data structure distance hierarchy to facilitate the handling of numeric and categorical values in a direct, unified manner. Moreover, the extended model regularizes the prototype distance between neighboring neurons in proportion to their map distance so that structures of the clusters can be portrayed better on the map. Extensive experiments on several synthetic and real world datasets are conducted to demonstrate the capability of the model and to compare MixSOM with several existing models including Kohonen's SOM, the generalized SOM and visualization-induced SOM. The results show that MixSOM is superior to the other models in reflecting the structure of the mixed-type data and facilitates further analysis of the data such as exploration at various levels of granularity. PMID- 24808458 TI - Robustness analysis of global exponential stability of recurrent neural networks in the presence of time delays and random disturbances. AB - In recent years, the global stability of recurrent neural networks (RNNs) has been investigated extensively. It is well known that time delays and external disturbances can derail the stability of RNNs. In this paper, we analyze the robustness of global stability of RNNs subject to time delays and random disturbances. Given a globally exponentially stable neural network, the problem to be addressed here is how much time delay and noise the RNN can withstand to be globally exponentially stable in the presence of delay and noise. The upper bounds of the time delay and noise intensity are characterized by using transcendental equations for the RNNs to sustain global exponential stability. Moreover, we prove theoretically that, for any globally exponentially stable RNNs, if additive noises and time delays are smaller than the derived lower bounds arrived at here, then the perturbed RNNs are guaranteed to also be globally exponentially stable. Three numerical examples are provided to substantiate the theoretical results. PMID- 24808459 TI - Fault detection and diagnosis of induction motors using motor current signature analysis and a hybrid FMM-CART model. AB - In this paper, a novel approach to detect and classify comprehensive fault conditions of induction motors using a hybrid fuzzy min-max (FMM) neural network and classification and regression tree (CART) is proposed. The hybrid model, known as FMM-CART, exploits the advantages of both FMM and CART for undertaking data classification and rule extraction problems. A series of real experiments is conducted, whereby the motor current signature analysis method is applied to form a database comprising stator current signatures under different motor conditions. The signal harmonics from the power spectral density are extracted as discriminative input features for fault detection and classification with FMM CART. A comprehensive list of induction motor fault conditions, viz., broken rotor bars, unbalanced voltages, stator winding faults, and eccentricity problems, has been successfully classified using FMM-CART with good accuracy rates. The results are comparable, if not better, than those reported in the literature. Useful explanatory rules in the form of a decision tree are also elicited from FMM-CART to analyze and understand different fault conditions of induction motors. PMID- 24808460 TI - Existence and uniqueness of pseudo almost-periodic solutions of recurrent neural networks with time-varying coefficients and mixed delays. AB - This paper is concerned with the existence and uniqueness of pseudo almost periodic solutions to recurrent delayed neural networks. Several conditions guaranteeing the existence and uniqueness of such solutions are obtained in a suitable convex domain. Furthermore, several methods are applied to establish sufficient criteria for the globally exponential stability of this system. The approaches are based on constructing suitable Lyapunov functionals and the well known Banach contraction mapping principle. Moreover, the attractivity and exponential stability of the pseudo almost-periodic solution are also considered for the system. A numerical example is given to illustrate the effectiveness of our results. PMID- 24808461 TI - Variable sampling approach to mitigate instability in networked control systems with delays. AB - This paper analyzes a new alternative approach to compensate for the effects of time delays on a dynamic networked control system (NCS). The approach is based on the use of time-delay-predicted values as the sampling times of the NCS. We use a one-step-ahead prediction algorithm based on an adaptive time delay neural network. The application of pole placement and linear quadratic regulator methods to compute the feedback gains taking into account the estimated time delays is investigated. PMID- 24808462 TI - Tree-structured feature extraction using mutual information. AB - One of the most informative measures for feature extraction (FE) is mutual information (MI). In terms of MI, the optimal FE creates new features that jointly have the largest dependency on the target class. However, obtaining an accurate estimate of a high-dimensional MI as well as optimizing with respect to it is not always easy, especially when only small training sets are available. In this paper, we propose an efficient tree-based method for FE in which at each step a new feature is created by selecting and linearly combining two features such that the MI between the new feature and the class is maximized. Both the selection of the features to be combined and the estimation of the coefficients of the linear transform rely on estimating 2-D MIs. The estimation of the latter is computationally very efficient and robust. The effectiveness of our method is evaluated on several real-world data sets. The results show that the classification accuracy obtained by the proposed method is higher than that achieved by other FE methods. PMID- 24808463 TI - Adaptive dynamic output feedback neural network control of uncertain MIMO nonlinear systems with prescribed performance. AB - An adaptive dynamic output feedback neural network controller for a class of multi-input/multi-output affine in the control uncertain nonlinear systems is designed, capable of guaranteeing prescribed performance bounds on the system's output as well as boundedness of all other closed loop signals. It is proved that simply guaranteeing a boundedness property for the states of a specifically defined augmented closed loop system is necessary and sufficient to solve the problem under consideration. The proposed dynamic controller is of switching type. However, its continuity is guaranteed, thus alleviating any issues related to the existence and uniqueness of solutions. Simulations on a planar two-link articulated manipulator illustrate the approach. PMID- 24808464 TI - Compact image representation model based on both nCRF and reverse control mechanisms. AB - The aim of this paper is to construct a bio-inspired hierarchical neural network that could accurately represent visual images and facilitate follow-up processing. Our computational model adopted a ganglion cell (GC) mechanism with a receptive field that dynamically self-adjusts according to the characteristics of an input image. For each GC, a micro neural circuit and a reverse control circuit were developed to self-adaptively resize the receptive field. An array was also designed to imitate the layer of GCs that perform image representation. Results revealed that this GC array could represent images from the external environment with a low processing cost, and this nonclassical receptive field mechanism could substantially improve both segmentation and integration processing. This model enables automatic extraction of blocks from images, which makes multiscale representation feasible. Importantly, once an original pixel-level image was reorganized into a GC array, semantic-level features emerged. Because GCs, like symbols, are discrete and separable, this GC-grained compact representation is open to operations that can manipulate images partially and selectively. Thus, the GC-array model provides a basic infrastructure and allows for high-level image processing. PMID- 24808465 TI - Model selection for Gaussian kernel PCA denoising. AB - We propose kernel parallel analysis (kPA) for automatic kernel scale and model order selection in Gaussian kernel principal component analysis (KPCA). Parallel analysis is based on a permutation test for covariance and has previously been applied for model order selection in linear PCA, we here augment the procedure to also tune the Gaussian kernel scale of radial basis function based KPCA. We evaluate kPA for denoising of simulated data and the U.S. postal data set of handwritten digits. We find that kPA outperforms other heuristics to choose the model order and kernel scale in terms of signal-to-noise ratio of the denoised data. PMID- 24808466 TI - Multinomial least angle regression. AB - Keerthi and Shevade (2007) proposed an efficient algorithm for constructing an approximate least angle regression least absolute shrinkage and selection operator solution path for logistic regression as a function of the regularization parameter. In this brief, their approach is extended to multinomial regression. We show that a brute-force approach leads to a multivariate approximation problem resulting in an infeasible path tracking algorithm. Instead, we introduce a noncanonical link function thereby: 1) repeatedly reusing the univariate approximation of Keerthi and Shevade, and 2) producing an optimization objective with a block-diagonal Hessian. We carry out an empirical study that shows the computational efficiency of the proposed technique. A MATLAB implementation is available from the author upon request. PMID- 24808467 TI - Nonlinear system modeling with random matrices: echo state networks revisited. AB - Echo state networks (ESNs) are a novel form of recurrent neural networks (RNNs) that provide an efficient and powerful computational model approximating nonlinear dynamical systems. A unique feature of an ESN is that a large number of neurons (the "reservoir") are used, whose synaptic connections are generated randomly, with only the connections from the reservoir to the output modified by learning. Why a large randomly generated fixed RNN gives such excellent performance in approximating nonlinear systems is still not well understood. In this brief, we apply random matrix theory to examine the properties of random reservoirs in ESNs under different topologies (sparse or fully connected) and connection weights (Bernoulli or Gaussian). We quantify the asymptotic gap between the scaling factor bounds for the necessary and sufficient conditions previously proposed for the echo state property. We then show that the state transition mapping is contractive with high probability when only the necessary condition is satisfied, which corroborates and thus analytically explains the observation that in practice one obtains echo states when the spectral radius of the reservoir weight matrix is smaller than 1. PMID- 24808468 TI - Algorithmic survey of parametric value function approximation. AB - Reinforcement learning (RL) is a machine learning answer to the optimal control problem. It consists of learning an optimal control policy through interactions with the system to be controlled, the quality of this policy being quantified by the so-called value function. A recurrent subtopic of RL concerns computing an approximation of this value function when the system is too large for an exact representation. This survey reviews state-of-the-art methods for (parametric) value function approximation by grouping them into three main categories: bootstrapping, residual, and projected fixed-point approaches. Related algorithms are derived by considering one of the associated cost functions and a specific minimization method, generally a stochastic gradient descent or a recursive least squares approach. PMID- 24808469 TI - Impulsive control for existence, uniqueness, and global stability of periodic solutions of recurrent neural networks with discrete and continuously distributed delays. AB - In this paper, a class of recurrent neural networks with discrete and continuously distributed delays is considered. Sufficient conditions for the existence, uniqueness, and global exponential stability of a periodic solution are obtained by using contraction mapping theorem and stability theory on impulsive functional differential equations. The proposed method, which differs from the existing results in the literature, shows that network models may admit a periodic solution which is globally exponentially stable via proper impulsive control strategies even if it is originally unstable or divergent. Two numerical examples and their computer simulations are offered to show the effectiveness of our new results. PMID- 24808470 TI - Effective neural network ensemble approach for improving generalization performance. AB - This paper, with an aim at improving neural networks' generalization performance, proposes an effective neural network ensemble approach with two novel ideas. One is to apply neural networks' output sensitivity as a measure to evaluate neural networks' output diversity at the inputs near training samples so as to be able to select diverse individuals from a pool of well-trained neural networks; the other is to employ a learning mechanism to assign complementary weights for the combination of the selected individuals. Experimental results show that the proposed approach could construct a neural network ensemble with better generalization performance than that of each individual in the ensemble combining with all the other individuals, and than that of the ensembles with simply averaged weights. PMID- 24808471 TI - Novel cost-sensitive approach to improve the multilayer perceptron performance on imbalanced data. AB - Traditional learning algorithms applied to complex and highly imbalanced training sets may not give satisfactory results when distinguishing between examples of the classes. The tendency is to yield classification models that are biased towards the overrepresented (majority) class. This paper investigates this class imbalance problem in the context of multilayer perceptron (MLP) neural networks. The consequences of the equal cost (loss) assumption on imbalanced data are formally discussed from a statistical learning theory point of view. A new cost sensitive algorithm (CSMLP) is presented to improve the discrimination ability of (two-class) MLPs. The CSMLP formulation is based on a joint objective function that uses a single cost parameter to distinguish the importance of class errors. The learning rule extends the Levenberg-Marquadt's rule, ensuring the computational efficiency of the algorithm. In addition, it is theoretically demonstrated that the incorporation of prior information via the cost parameter may lead to balanced decision boundaries in the feature space. Based on the statistical analysis of results on real data, our approach shows a significant improvement of the area under the receiver operating characteristic curve and G mean measures of regular MLPs. PMID- 24808472 TI - Robust kernel representation with statistical local features for face recognition. AB - Factors such as misalignment, pose variation, and occlusion make robust face recognition a difficult problem. It is known that statistical features such as local binary pattern are effective for local feature extraction, whereas the recently proposed sparse or collaborative representation-based classification has shown interesting results in robust face recognition. In this paper, we propose a novel robust kernel representation model with statistical local features (SLF) for robust face recognition. Initially, multipartition max pooling is used to enhance the invariance of SLF to image registration error. Then, a kernel-based representation model is proposed to fully exploit the discrimination information embedded in the SLF, and robust regression is adopted to effectively handle the occlusion in face images. Extensive experiments are conducted on benchmark face databases, including extended Yale B, AR (A. Martinez and R. Benavente), multiple pose, illumination, and expression (multi-PIE), facial recognition technology (FERET), face recognition grand challenge (FRGC), and labeled faces in the wild (LFW), which have different variations of lighting, expression, pose, and occlusions, demonstrating the promising performance of the proposed method. PMID- 24808473 TI - Adaptive learning in tracking control based on the dual critic network design. AB - In this paper, we present a new adaptive dynamic programming approach by integrating a reference network that provides an internal goal representation to help the systems learning and optimization. Specifically, we build the reference network on top of the critic network to form a dual critic network design that contains the detailed internal goal representation to help approximate the value function. This internal goal signal, working as the reinforcement signal for the critic network in our design, is adaptively generated by the reference network and can also be adjusted automatically. In this way, we provide an alternative choice rather than crafting the reinforcement signal manually from prior knowledge. In this paper, we adopt the online action-dependent heuristic dynamic programming (ADHDP) design and provide the detailed design of the dual critic network structure. Detailed Lyapunov stability analysis for our proposed approach is presented to support the proposed structure from a theoretical point of view. Furthermore, we also develop a virtual reality platform to demonstrate the real time simulation of our approach under different disturbance situations. The overall adaptive learning performance has been tested on two tracking control benchmarks with a tracking filter. For comparative studies, we also present the tracking performance with the typical ADHDP, and the simulation results justify the improved performance with our approach. PMID- 24808474 TI - Sparse coding from a Bayesian perspective. AB - Sparse coding is a promising theme in computer vision. Most of the existing sparse coding methods are based on either l0 or l1 penalty, which often leads to unstable solution or biased estimation. This is because of the nonconvexity and discontinuity of the l0 penalty and the over-penalization on the true large coefficients of the l1 penalty. In this paper, sparse coding is interpreted from a novel Bayesian perspective, which results in a new objective function through maximum a posteriori estimation. The obtained solution of the objective function can generate more stable results than the l0 penalty and smaller reconstruction errors than the l1 penalty. In addition, the convergence property of the proposed algorithm for sparse coding is also established. The experiments on applications in single image super-resolution and visual tracking demonstrate that the proposed method is more effective than other state-of-the-art methods. PMID- 24808475 TI - FSMRank: feature selection algorithm for learning to rank. AB - In recent years, there has been growing interest in learning to rank. The introduction of feature selection into different learning problems has been proven effective. These facts motivate us to investigate the problem of feature selection for learning to rank. We propose a joint convex optimization formulation which minimizes ranking errors while simultaneously conducting feature selection. This optimization formulation provides a flexible framework in which we can easily incorporate various importance measures and similarity measures of the features. To solve this optimization problem, we use the Nesterov's approach to derive an accelerated gradient algorithm with a fast convergence rate O(1/T(2)). We further develop a generalization bound for the proposed optimization problem using the Rademacher complexities. Extensive experimental evaluations are conducted on the public LETOR benchmark datasets. The results demonstrate that the proposed method shows: 1) significant ranking performance gain compared to several feature selection baselines for ranking, and 2) very competitive performance compared to several state-of-the-art learning-to rank algorithms. PMID- 24808476 TI - Fractional norm regularization: learning with very few relevant features. AB - Learning in the presence of a large number of irrelevant features is an important problem in high-dimensional tasks. Previous studies have shown that L1-norm regularization can be effective in such cases while L2-norm regularization is not. Furthermore, work in compressed sensing suggests that regularization by nonconvex (e.g., fractional) semi-norms may outperform L1-regularization. However, for classification it is largely unclear when this may or may not be the case. In addition, the nonconvex problem is harder to solve than the convex L1 problem. In this paper, we provide a more in-depth analysis to elucidate the potential advantages and pitfalls of nonconvex regularization in the context of logistic regression where the regularization term employs the family of Lq semi norms. First, using results from the phenomenon of concentration of norms and distances in high dimensions, we gain intuition about the working of sparse estimation when the dimensionality is very high. Second, using the probably approximately correct (PAC)-Bayes methodology, we give a data-dependent bound on the generalization error of Lq-regularized logistic regression, which is applicable to any algorithm that implements this model, and may be used to predict its generalization behavior from the training set alone. Third, we demonstrate the usefulness of our approach by experiments and applications, where the PAC-Bayes bound is used to guide the choice of semi-norm in the regularization term. The results support the conclusion that the optimal choice of regularization depends on the relative fraction of relevant versus irrelevant features, and a fractional norm with a small exponent is most suitable when the fraction of relevant features is very small. PMID- 24808477 TI - Exponential family factors for Bayesian factor analysis. AB - Expressing data as linear functions of a small number of unknown variables is a useful approach employed by several classical data analysis methods, e.g., factor analysis, principal component analysis, or latent semantic indexing. These models represent the data using the product of two factors. In practice, one important concern is how to link the learned factors to relevant quantities in the context of the application. To this end, various specialized forms of the factors have been proposed to improve interpretability. Toward developing a unified view and clarifying the statistical significance of the specialized factors, we propose a Bayesian model family. We employ exponential family distributions to specify various types of factors, which provide a unified probabilistic formulation. A Gibbs sampling procedure is constructed as a general computation routine. We verify the model by experiments, in which the proposed model is shown to be effective in both emulating existing models and motivating new model designs for particular problem settings. PMID- 24808478 TI - Backtrackless walks on a graph. AB - The aim of this paper is to explore the use of backtrackless walks and prime cycles for characterizing both labeled and unlabeled graphs. The reason for using backtrackless walks and prime cycles is that they avoid tottering, and can increase the discriminative power of the resulting graph representation. However, the use of such methods is limited in practice because of their computational cost. In this paper, we present efficient methods for computing graph kernels, which are based on backtrackless walks in a labeled graph and whose worst case running time is the same as that of kernels based on random walks. For clustering unlabeled graphs, we construct feature vectors using Ihara coefficients, since these coefficients are related to the frequencies of prime cycles in the graph. To efficiently compute the low order coefficients, we present an O(|V|(3)) algorithm which is better than the O(|V|(6)) worst case running time of previously known algorithms. In the experimental evaluation, we apply the proposed method to clustering both labeled and unlabeled graphs. The results show that using backtrackless walks and prime cycles instead of random walks can increase the accuracy of recognition. PMID- 24808479 TI - Fast-convergent double-sigmoid Hopfield neural network as applied to optimization problems. AB - The Hopfield neural network (HNN) has been widely used in numerous different optimization problems since the early 1980s. The convergence speed of the HNN (already in high gain) eventually plays a critical role in various real-time applications. In this brief, we propose and analyze a generalized HNN which drastically improves the convergence speed of the network, and thus allows benefiting from the HNN capabilities in solving the optimization problems in real time. By examining the channel allocation optimization problem in cellular radio systems, which is NP-complete and in which fast solution is necessary due to time varying link gains, as well as the associative memory problem, computer simulations confirm the dramatic improvement in convergence speed at the expense of using a second nonlinear function in the proposed network. PMID- 24808480 TI - Synchronization design of Boolean networks via the semi-tensor product method. AB - We provide a general approach for the design of a response Boolean network (BN) to achieve complete synchronization with a given drive BN. The approach is based on the algebraic representation of BNs in terms of the semi-tensor product of matrices. Instead of designing the logical dynamic equations of a response BN directly, we first construct its algebraic representation and then convert the algebraic representation back to the logical form. The results are applied to a three-neuron network in order to illustrate the effectiveness of the proposed approach. PMID- 24808481 TI - Bogdanov-Takens singularity in tri-neuron network with time delay. AB - This brief reports a retarded functional differential equation modeling tri neuron network with time delay. The Bogdanov-Takens (B-T) bifurcation is investigated by using the center manifold reduction and the normal form method. We get the versal unfolding of the norm forms at the B-T singularity and show that the model can exhibit pitchfork, Hopf, homoclinic, and double-limit cycles bifurcations. Some numerical simulations are given to support the analytic results and explore chaotic dynamics. Finally, an algorithm is given to show that chaotic tri-neuron networks can be used for encrypting a color image. PMID- 24808482 TI - Treating moderate acute malnutrition in first-line health services: an effectiveness cluster-randomized trial in Burkina Faso. AB - BACKGROUND: Management of moderate acute malnutrition (MAM) is, currently, focused on food supplementation approaches. However, the sustainability of these strategies remains weak in low- and middle-income countries. In food-secure settings, an educational/behavioral intervention could be an alternative for improving MAM management. OBJECTIVE: This study compared the effectiveness of weekly context-appropriate child-centered counseling (CCC), with an improved corn soy blend [corn-soy blend with added micronutrients (CSB++)] or a locally produced ready-to-use supplementary food (RUSF), in treating MAM through first line rural health services. DESIGN: We used a cluster randomized controlled trial design with 3 arms, involving 18 rural health centers (6 by arm) and children aged 6-24 mo with uncomplicated MAM. In the first arm (CCC), trained health workers provided weekly personalized counseling to caretakers. In the 2 other arms, children received weekly either 455 g CSB++ or 350 g locally produced soy based RUSF. Both food supplements provided ~250 kcal/d. RESULTS: The recovery rate after 3 mo of treatment was significantly lower with CCC (57.8%) than with CSB++ (74.5%) and RUSF (74.2%) (P < 0001). Mothers' attendance at health facilities was also substantially lower in the CCC arm (P < 0001); this arm had a high defaulter rate (P < 0.003). When the analysis was adjusted for attendance, we did not find a significant difference between the 3 arms, with incidence rate ratios of 1.14 (95% CI: 0.99, 1.31) and 1.13 (95% CI: 0.98, 1.30) for the CSB++ and RUSF arms, respectively, compared with the CCC arm. CONCLUSION: Whereas supplement-based treatment of MAM was found to be more effective than the provision of CCC, we hypothesize that appropriate and specific nutrition counseling centered on children's needs, through primary health facilities, might be an alternative strategy for MAM treatment in rural food-secure areas, provided that attendance at counseling sessions by the caregiver is ensured. This trial was registered at clinicaltrials.gov as NCT01115647. PMID- 24808483 TI - Determinants of body composition in preterm infants at the time of hospital discharge. AB - BACKGROUND: Preterm infants have a higher fat mass (FM) percentage and a lower fat-free mass (FFM) than do term infants at the time of hospital discharge. OBJECTIVE: We determined perinatal and nutritional factors that affect the body composition of preterm infants at discharge. DESIGN: A total of 141 preterm infants born at <35 wk of gestation and admitted to Nantes University Hospital Neonatology Unit over a period of 2 y were enrolled. Nutritional intake and growth were monitored during hospitalization. Body composition was assessed by using air-displacement plethysmography at discharge. FFM was compared with reference data in term infants according to sex and gestational age. RESULTS: Linear regression produced an excellent model to predict absolute FFM from perinatal characteristics and nutrition (R(2) = 0.82) but not the FM percentage (R(2) = 0.24). Gestational and postnatal ages played an equal role in absolute FFM accretion, as did the initial growth (between birth and day 5) and growth between day 5 and discharge. Antenatal corticosteroid treatment slightly reduced FFM accretion. As concerns nutritional intake, a higher protein:energy ratio at days 10 and 21 was significantly associated with decreased risk of an FFM deficit when preterm infants were compared with reference values for term infants. Boys had higher risk of an FFM deficit than did girls. CONCLUSION: The initial growth and quality of nutrition were significantly associated with absolute FFM accretion during a hospital stay in preterm infants. This trial was registered at clinicaltrials.gov as NCT01450436. PMID- 24808484 TI - Vitamin B-6 vitamers in human plasma and cerebrospinal fluid. AB - BACKGROUND: Vitamin B-6 comprises a group of 6 interrelated vitamers and is essential for numerous physiologic processes, including brain functioning. Genetic disorders disrupting vitamin B-6 metabolism have severe clinical consequences. OBJECTIVE: To adequately diagnose known and novel disorders in vitamin B-6 metabolism, a reference set is required containing information on all vitamin B-6 vitamers in plasma and cerebrospinal fluid (CSF). DESIGN: Concentrations of vitamin B-6 vitamers in the plasma and CSF of 533 adult subjects were measured by ultra high-performance liquid chromatography-tandem mass spectrometry. RESULTS: The relative vitamin B-6 vitamer composition of plasma [pyridoxal phosphate (PLP) > pyridoxic acid (PA) > pyridoxal] differed from that of CSF (pyridoxal > PLP > PA > pyridoxamine). Sex influenced vitamin B 6 vitamer concentrations in plasma and CSF and should therefore be taken into account when interpreting vitamin B-6 vitamer concentrations. The strict ratios and strong correlations between vitamin B-6 vitamers point to a tight regulation of vitamin B-6 vitamer concentrations in blood and CSF. Given the unique design of this study, with simultaneously withdrawn blood and CSF from a large number of subjects, reliable CSF:plasma ratios and correlations of vitamin B-6 vitamers could be established. CONCLUSIONS: We provide an extensive reference set of vitamin B-6 vitamer concentrations in plasma and CSF. In addition to providing insight on the regulation of individual vitamers and their intercompartmental distribution, we anticipate that these data will prove to be a valuable reference set for the diagnosis and treatment of conditions associated with altered vitamin B-6 metabolism. PMID- 24808485 TI - Evidence for increased catabolism of vitamin B-6 during systemic inflammation. AB - BACKGROUND: Plasma concentrations of PL 5'-phosphate (PLP), which is the active coenzyme form of vitamin B-6, are reduced during inflammation. The underlying mechanisms may include altered tissue distribution or increased catabolism via pyridoxal (PL) to pyridoxic acid (PA). Recently, we showed that catabolic enzyme activity could be assessed by substrate product ratios measured in plasma. OBJECTIVE: We evaluated the ratios PA:PL, PA:PLP, and PA:(PL + PLP) as possible markers of vitamin B-6 catabolism. DESIGN: Cross-sectional and longitudinal data were derived from the Western Norway B-Vitamin Intervention Trial. We analyzed associations of ratios with inflammatory markers and other clinical variables by using multiple linear regression and partial correlation. In addition, intraclass correlation coefficients (ICCs) were used to assess the ability of plasma indexes to differentiate between subjects. RESULTS: PA:(PL + PLP) had the highest ICC of all vitamin B-6 metabolites and ratios tested. In regression models, the inflammatory markers C-reactive protein, white blood cell count, neopterin, and kynurenine:tryptophan collectively accounted for 28% of the total and > 90% of the explained variation in PA:(PL + PLP). For individual B-6 metabolites, corresponding numbers were 19-25% and 20-44%, respectively, with vitamin supplement intake, smoking, and kidney function (estimated glomerular filtration rate) as additional predictors. In an analysis of receiver operating characteristics, PA:(PL + PLP) discriminated high inflammatory concentrations with an area under the curve (95% CI) of 0.85 (0.81, 0.89). CONCLUSIONS: Broad specificity enzymes upregulated to reduce oxidative and aldehyde stress could explain increased catabolism of vitamin B-6 during inflammation. The ratio PA:(PL + PLP) may provide novel insights into pathologic processes and potentially predict risk of future disease. PMID- 24808486 TI - Hypotensive effects of solitary addition of conventional nonfat dairy products to the routine diet: a randomized controlled trial. AB - BACKGROUND: The high consumption of low-fat and nonfat dairy products is associated with reduced risk of high blood pressure. OBJECTIVE: We aimed to investigate whether the solitary addition of nonfat dairy products to the normal routine diet was capable of lowering blood pressure in middle-aged and older adults with elevated blood pressure. DESIGN: With the use of a randomized, crossover intervention-study design, 49 adults (56% women) with elevated blood pressure (mean +/- SEM age: 53 +/- 2 y; systolic blood pressure: 135 +/- 1; diastolic blood pressure: 80 +/- 1 mm Hg) underwent a high-dairy condition (+4 servings conventional nonfat dairy products/d) and isocaloric no-dairy condition (+4 servings fruit products/d) in which all dairy products were removed. Both dietary conditions lasted 4 wk with a 2-wk washout before crossing over into the alternate condition. RESULTS: The high-dairy condition produced reductions in systolic blood pressure (135 +/- 1 to 127 +/- 1 mm Hg) and pulse pressure (54 +/- 1 to 48 +/- 1 mm Hg) (both P < 0.05). The hypotensive effects were observed within 3 wk after the initiation of the dietary intervention and in both casual seated and ambulatory (24-h) measurements (P < 0.05). Pulse pressure was increased after the removal of all dairy products in the no-dairy condition (54 +/- 1 to 56 +/- 1 mm Hg; P < 0.05). There were no changes in diastolic blood pressure after either dietary condition. CONCLUSION: We concluded that the solitary manipulation of conventional dairy products in the normal routine diet would modulate blood pressure in middle-aged and older adults with prehypertension and hypertension. This trial was registered at clinicaltrials.gov as NCT01577030. PMID- 24808487 TI - Interindividual variability of lutein bioavailability in healthy men: characterization, genetic variants involved, and relation with fasting plasma lutein concentration. AB - BACKGROUND: Lutein accumulates in the macula and brain, where it is assumed to play physiologic roles. The bioavailability of lutein is assumed to display a high interindividual variability that has been hypothesized to be attributable, at least partly, to genetic polymorphisms. OBJECTIVES: We characterized the interindividual variability in lutein bioavailability in humans, assessed the relation between this variability and the fasting blood lutein concentration, and identified single nucleotide polymorphisms (SNPs) involved in this phenomenon. DESIGN: In a randomized, 2-way crossover study, 39 healthy men consumed a meal that contained a lutein supplement or the same meal for which lutein was provided through a tomato puree. The lutein concentration was measured in plasma chylomicrons isolated at regular time intervals over 8 h postprandially. Multivariate statistical analyses were used to identify a combination of SNPs associated with the postprandial chylomicron lutein response (0-8-h area under the curve). A total of 1785 SNPs in 51 candidate genes were selected. RESULTS: Postprandial chylomicron lutein responses to meals were very variable (CV of 75% and 137% for the lutein-supplement meal and the meal with tomato-sourced lutein, respectively). Postprandial chylomicron lutein responses measured after the 2 meals were positively correlated (r = 0.68, P < 0.0001) and positively correlated to the fasting plasma lutein concentration (r = 0.51, P < 0.005 for the lutein supplement-containing meal). A significant (P = 1.9 * 10(-4)) and validated partial least-squares regression model, which included 29 SNPs in 15 genes, explained most of the variance in the postprandial chylomicron lutein response. CONCLUSIONS: The ability to respond to lutein appears to be, at least in part, genetically determined. The ability is explained, in large part, by a combination of SNPs in 15 genes related to both lutein and chylomicron metabolism. Finally, our results suggest that the ability to respond to lutein and blood lutein status are related. This trial was registered at clinicaltrials.gov as NCT02100774. PMID- 24808488 TI - Childhood growth, schooling, and cognitive development: further evidence from the Young Lives study. AB - BACKGROUND: A growing literature has linked early childhood growth to later-life cognition and schooling outcomes in developing countries. Although existing evidence suggests that children's ability to recover from early growth delays in later childhood is limited, longitudinal studies on the persistence and risk of growth faltering beyond age 5 y remain scarce. OBJECTIVE: Using longitudinal data recently collected from 4 developing countries as part of the Young Lives study, we investigated catch-up growth in children between the ages of 8 and 15 y and the effects of growth during this late-childhood and early-adolescence period on schooling and developmental outcomes. DESIGN: We analyzed the associations between children's physical growth and development by using longitudinal data from 3327 children aged 8-15 y collected in Ethiopia, India, Peru, and Vietnam as part of the Young Lives project. RESULTS: The study yielded 2 main results. First, 36% of children stunted at age 8 y managed to catch up with their peers by age 15 y, and those who caught up had smaller deficits in cognitive scores than did children who remained stunted. Second, physical growth faltering was not restricted to early childhood but rather affected a substantial share of children in the 8-15-y age range, with large negative consequences for cognition and schooling outcomes. CONCLUSION: The results from this study suggest that child development in developing countries is a dynamic process offering continued opportunities for children to catch up during adolescence and sustained risks for children to fall behind in their developmental trajectories. PMID- 24808489 TI - Revision of Dietary Reference Intakes for energy in preschool-age children. AB - BACKGROUND: Dietary Reference Intakes (DRI) for energy aim to balance energy expenditure at a level of physical activity consistent with health and support adequate growth in children. DRIs were derived from total energy expenditure (TEE) measured by using the doubly labeled water (DLW) method; however, the database was limited in the 3-5-y-old range. OBJECTIVE: We reexamined the DRI for energy for preschool-age children. DESIGN: Ninety-seven healthy, normal-weight, preschool-age children (mean +/- SD age: 4.5 +/- 0.9 y) completed a 7-d DLW protocol while wearing accelerometer and heart rate-monitoring devices. RESULTS: Mean TEE and physical activity level (PAL) averaged 1159 +/- 171 kcal/d and 1.34 +/- 0.14, respectively. TEE predicted by DRI equations agreed with observed TEE (+34 kcal/d or 3%) if the sedentary PAL category was assumed but was overestimated by using the low active (+219 kcal/d or 19%), active (398 kcal/d or 34%), and very active (593 kcal/d or 51%) PAL categories. PAL categories were redefined on the basis of the narrower PAL range observed in preschoolers (range: 1.05-1.70) compared with older children and adults (range: 1.0-2.5). Sex-specific nonlinear regression models were newly developed to predict TEE from age, weight, height, and new PAL categories. The mean absolute error of TEE prediction equations was 0.00 +/- 35 kcal/d or 0.1 +/- 3%. Ancillary measures, such as total accelerometer counts and total daily steps, that were significantly correlated (P = 0.01-0.05) with TEE (r = 0.26-0.38), TEE per kilogram (r = 0.31-0.41), and PAL (r = 0.36-0.48) may assist in the classification of preschoolers into PAL categories. CONCLUSIONS: Current DRIs for energy overestimate energy requirements of preschool-age children because of the erroneous classification of children into PAL categories. New TEE prediction equations that are based on DLW and appropriate PAL categories are recommended for preschool-age children. This trial was registered at clinicaltrials.gov as H12067. PMID- 24808490 TI - Dietary sugars and cardiometabolic risk: systematic review and meta-analyses of randomized controlled trials of the effects on blood pressure and lipids. AB - BACKGROUND: Dietary sugars have been suggested as a cause of obesity, several chronic diseases, and a range of cardiometabolic risk factors, but there is no convincing evidence of a causal relation between sugars and risk factors other than body weight. OBJECTIVE: We conducted a systematic review and meta-analysis of randomized controlled trials that examined effects of the modification of dietary free sugars on blood pressure and lipids. DESIGN: Systematic searches were conducted in OVID Medline, Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature, and Web of Science databases (to August 2013) to identify studies that reported intakes of free sugars and at least one lipid or blood pressure outcome. The minimum trial duration was 2 wk. We pooled data by using inverse-variance methods with random-effects models. RESULTS: A total of 39 of 11,517 trials identified were included; 37 trials reported lipid outcomes, and 12 trials reported blood pressure outcomes. Higher compared with lower sugar intakes significantly raised triglyceride concentrations [mean difference (MD): 0.11 mmol/L; 95% CI: 0.07, 0.15 mmol/L; P < 0.0001], total cholesterol (MD: 0.16 mmol/L; 95% CI: 0.10, 0.24 mmol/L; P < 0.0001), low-density lipoprotein cholesterol (0.12 mmol/L; 95% CI: 0.05, 0.19 mmol/L; P = 0.0001), and high density lipoprotein cholesterol (MD: 0.02 mmol/L; 95% CI: 0.00, 0.03 mmol/L; P = 0.03). Subgroup analyses showed the most marked relation between sugar intakes and lipids in studies in which efforts were made to ensure an energy balance and when no difference in weight change was reported. Potential explanatory factors, including a weight change, in most instances explained <15% of the heterogeneity between studies (I(2) = 36-75%). The effect of sugar intake on blood pressure was greatest in trials >=8 wk in duration [MD: 6.9 mm Hg (95% CI: 3.4, 10.3 mm Hg; P < 0.001) for systolic blood pressure and 5.6 mm Hg (95% CI: 2.5, 8.8 mm Hg; P = 0.0005) for diastolic blood pressure]. CONCLUSIONS: Dietary sugars influence blood pressure and serum lipids. The relation is independent of effects of sugars on body weight. Protocols for this review were registered separately for effects of sugars on blood pressure and lipids in the PROSPERO International prospective register of systematic reviews as PROSPERO 2012: CRD42012002379 and 2012: CRD42012002437, respectively. PMID- 24808491 TI - Nut consumption in relation to cardiovascular disease risk and type 2 diabetes: a systematic review and meta-analysis of prospective studies. AB - BACKGROUND: Many prospective cohort studies have investigated the association between nut consumption and risk of coronary artery disease (CAD), stroke, hypertension, and type 2 diabetes (T2D). However, results have been inconsistent. OBJECTIVE: We aimed to investigate the association between nut consumption and risk of CAD, stroke, hypertension, and T2D. DESIGN: PubMed and EMBASE databases were searched up to October 2013. All prospective cohort studies of nut consumption and risk of CAD, stroke, hypertension, and T2D were included. Summary RRs with 95% CIs were estimated by using a fixed- or random-effects model. RESULTS: A total of 23 prospective studies (9 studies for CAD, 4 studies for stroke, 4 studies for hypertension, and 6 studies for T2D) from 19 publications were included in the meta-analysis. There were 179,885 participants and 7236 CAD cases, 182,730 participants and 5669 stroke cases, 40,102 participants and 12,814 hypertension cases, and 342,213 participants and 14,400 T2D cases. The consumption of each 1 serving of nuts/d was significantly associated with incident CAD (RR: 0.81; 95% CI: 0.72, 0.91; P < 0.001) and hypertension (RR: 0.66; 95% CI: 0.44, 1.00; P = 0.049). However, there was no association between the consumption of each 1 serving of nuts/d and risk of stroke (RR: 0.90; 95% CI: 0.71, 1.14) or T2D (RR: 0.80; 95% CI: 0.57, 1.14). CONCLUSIONS: A higher consumption of nuts was associated with reduced risk of CAD and hypertension but not stroke or T2D. Large randomized controlled trials are warranted to confirm the observed associations. PMID- 24808493 TI - Infant feeding and adiposity: scientific challenges in life-course epidemiology. PMID- 24808492 TI - The effect of breakfast composition and energy contribution on cognitive and academic performance: a systematic review. AB - BACKGROUND: Most studies that assess the effects of breakfast on subsequent mental abilities compared performance in subjects who had or had not consumed this meal. However, characteristics of breakfast itself may induce metabolic and hormonal alterations of the gastrointestinal tract and potentially modify cognitive performance. Moreover, as far as the evidence on the positive effects of having breakfast is becoming more robust, interest may shift to the specific characteristics of an adequate breakfast. OBJECTIVE: The objective was to summarize existing evidence on the role of nutrient composition or energy intake at breakfast on the accomplishment of school-related tasks and cognition. DESIGN: We conducted a systematic review of the literature through the PubMed database. RESULTS: From the literature search, we identified 102 articles, 15 of which met the inclusion criteria. Of these, 3 studies provided information on the relation between cognitive and academic performance and energy intake at breakfast, 11 provided the same information for the macronutrient composition of breakfast, and 1 investigated both the aspects. Eleven studies considered breakfast meals differing in glycemic index/load. Selected studies were generally carried out in well-nourished children and adults of both sexes from general education. They were mostly experimental studies of short duration and had a limited number of subjects. Cognitive and academic performance was investigated by looking at multiple domains, including memory, attention, reasoning, learning, and verbal and math abilities, with a variety of test batteries scheduled at different time points in the morning. Breakfast options differed in terms of included foods and place and time of administration. CONCLUSIONS: There is insufficient quantity and consistency among studies to draw firm conclusions. However, whereas the hypothesis of a better and more sustained performance with a breakfast providing >20% daily energy intake still needs substantiation, there does appear to be emerging, but still equivocal, evidence that a lower postprandial glycemic response is beneficial to cognitive performance. PMID- 24808494 TI - Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: new roles for integrin alphavbeta3. AB - Thyroid hormones L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3) have been shown to initiate short- and long-term effects via a plasma membrane receptor site located on integrin alphavbeta3. Also insulin-like growth factor type I (IGF I) activity is known to be subject to regulation by this integrin. To investigate the possible cross-talk between T4 and IGF-I in rat L6 myoblasts, we have examined integrin alphavbeta3-mediated modulatory actions of T4 on glucose uptake, measured through carrier-mediated 2-deoxy-[3H]-D-glucose uptake, and on cell proliferation stimulated by IGF-I, assessed by cell counting, [3H]-thymidine incorporation, and fluorescence-activated cell sorting analysis. IGF-I stimulated glucose transport and cell proliferation via the cell surface IGF-I receptor (IGFIR) and, downstream of the receptor, by the phosphatidylinositol 3-kinase signal transduction pathway. Addition of 0.1 nM free T4 caused little or no cell proliferation but prevented both glucose uptake and proliferative actions of IGF I. These actions of T4 were mediated by an Arg-Gly-Asp (RGD)-sensitive pathway, suggesting the existence of crosstalk between IGFIR and the T4 receptor located near the RGD recognition site on the integrin. An RGD-sequence-containing integrin inhibitor, a monoclonal antibody to alphavbeta3, and the T4 metabolite tetraiodothyroacetic acid all blocked the inhibition by T4 of IGF-I-stimulated glucose uptake and cell proliferation. Western blotting confirmed roles for activated phosphatidylinositol 3-kinase and extracellular regulated kinase 1/2 (ERK1/2) in the effects of IGF-I and also showed a role for ERK1/2 in the actions of T4 that modified the effects of IGF-I. We conclude that thyroid hormone inhibits IGF-I-stimulated glucose uptake and cell proliferation in L6 myoblasts. PMID- 24808495 TI - The medial preoptic nucleus as a site of the thermogenic and metabolic actions of melanotan II in male rats. AB - The present study was designed to investigate the role of the medial preoptic nucleus (MPO) as a site of the thermogenic and metabolic effects of the alpha melanocyte-stimulating hormone analog melanotan II (MTII). We also assessed the involvement of the dorsomedial hypothalamic nucleus (DMH) by investigating the effects of the MPO infusion of MTII in rats with DMH lesions produced by kainic acid. Infusion of MTII in the MPO led to increases in interscapular brown adipose tissue (iBAT) temperature and iBAT uptake of 14C-bromopalmitate. Both increases were blocked by DMH lesions. iBAT temperature increase (area under curve) and 14C bromopalmitate uptake emerged as two correlated variables (r = 0.63, P < 0.001). DMH lesions also blocked MTII-induced expression of mRNAs coding for proteins involved in 1) thermogenesis [type II iodothyronine deiodinase (Dio2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1alpha)], 2) lipolysis [hormone-sensitive lipase (Hsl)], and 3) lipogenesis [diacylglycerol-O-acyltransferase 2 (Dgat2), fatty acid synthase (Fas)], in iBAT of rats killed 1 h after MPO infusion of MTII. MTII also stimulated expression of genes in iWAT but only in rats with DMH lesions. These genes included glucose transporter member 4 (Glut4), glycerol-3-phosphate acyltransferase 3 (Gpat3), Dgat1, Dgat2, triglyceride lipase (Atgl), Hsl, and carnitine palmitoyltransferase 1beta (Cpt1beta). Altogether, the present results reveal the MPO as a site of the thermogenic and metabolic actions of MTII. They also contribute to establish the MPO-DMH duet as a significant target for melanocortins to modulate energy homeostasis. PMID- 24808496 TI - Low-dose B-type natriuretic peptide raises cardiac sympathetic nerve activity in sheep. AB - The reported effects of atrial natriuretic peptide (ANP) on sympathetic nerve activity (SNA) are variable, dependent on concomitant hemodynamic actions, and likely to be regionally differentiated. There are few reports of the effect of B type natriuretic peptide (BNP) on SNA and none have measured cardiac SNA (CSNA) by direct microneurography. We measured the effects of low-dose ANP and BNP (2.4 pmol.kg(-1).min(-1) infused for 120 min) on CSNA and hemodynamics in conscious sheep (n = 8). While there was a trend for mean arterial pressure and cardiac output to fall with both ANP and BNP, changes were not significant compared with vehicle control. However, BNP did significantly reduce systolic arterial (97 +/- 4.2 vs. 107 +/- 6.8 mmHg during control; P = 0.043) and pulse pressures (0.047) and increase heart rate (110 +/- 6.7 vs. 96 +/- 7.3 beats/min; P = 0.044). Trends for these hemodynamic parameters to change with ANP did not achieve statistical significance. ANP also had no significant effect on any CSNA parameters measured. In contrast, BNP induced a rise in both CSNA burst frequency (~20 bursts/min higher than control, P = 0.011) and burst area (~40% higher than control, P = 0.013). BNP-induced rises in burst incidence (bursts/100 beats), and burst area per 100 beats, however, were not significant. In conclusion, BNP infused at low doses that only had subtle effects on hemodynamics increased CSNA burst frequency and burst are per minute. This increase in CSNA may in large part be secondary to an increase in heart rate as CSNA burst incidence and burst area per 100 beats were not significantly increased. This study provides no evidence for inhibition of CSNA by natriuretic peptides. PMID- 24808497 TI - Decreased complexity of glucose dynamics in diabetes: evidence from multiscale entropy analysis of continuous glucose monitoring system data. AB - Parameters of glucose dynamics recorded by the continuous glucose monitoring system (CGMS) could help in the control of glycemic fluctuations, which is important in diabetes management. Multiscale entropy (MSE) analysis has recently been developed to measure the complexity of physical and physiological time sequences. A reduced MSE complexity index indicates the increased repetition patterns of the time sequence, and, thus, a decreased complexity in this system. No study has investigated the MSE analysis of glucose dynamics in diabetes. This study was designed to compare the complexity of glucose dynamics between the diabetic patients (n = 17) and the control subjects (n = 13), who were matched for sex, age, and body mass index via MSE analysis using the CGMS data. Compared with the control subjects, the diabetic patients revealed a significant increase (P < 0.001) in the mean (diabetic patients 166.0 +/- 10.4 vs. control subjects 93.3 +/- 1.5 mg/dl), the standard deviation (51.7 +/- 4.3 vs. 11.1 +/- 0.5 mg/dl), and the mean amplitude of glycemic excursions (127.0 +/- 9.2 vs. 27.7 +/- 1.3 mg/dl) of the glucose levels; and a significant decrease (P < 0.001) in the MSE complexity index (5.09 +/- 0.23 vs. 7.38 +/- 0.28). In conclusion, the complexity of glucose dynamics is decreased in diabetes. This finding implies the reactivity of glucoregulation is impaired in the diabetic patients. Such impairment presenting as an increased regularity of glycemic fluctuating pattern could be detected by MSE analysis. Thus, the MSE complexity index could potentially be used as a biomarker in the monitoring of diabetes. PMID- 24808498 TI - Time window-dependent effect of perinatal maternal protein restriction on insulin sensitivity and energy substrate oxidation in adult male offspring. AB - Epidemiological and experimental evidence suggests that a suboptimal environment during perinatal life programs offspring susceptibility to the development of metabolic syndrome and Type 2 diabetes. We hypothesized that the lasting impact of perinatal protein deprivation on mitochondrial fuel oxidation and insulin sensitivity would depend on the time window of exposure. To improve our understanding of underlying mechanisms, an integrative approach was used, combining the assessment of insulin sensitivity and untargeted mass spectrometry based metabolomics in the offspring. A hyperinsulinemic-euglycemic clamp was performed in adult male rats born from dams fed a low-protein diet during gestation and/or lactation, and subsequently exposed to a Western diet (WD) for 10 wk. Metabolomics was combined with targeted acylcarnitine profiling and analysis of liver gene expression to identify markers of adaptation to WD that influence the phenotype outcome evaluated by body composition analysis. At adulthood, offspring of protein-restricted dams had impaired insulin secretion when fed a standard diet. Moreover, rats who demonstrated catch-up growth at weaning displayed higher gluconeogenesis and branched-chain amino acid catabolism, and lower fatty acid beta-oxidation compared with control rats. Postweaning exposure of intrauterine growth restriction-born rats to a WD exacerbated incomplete fatty acid beta-oxidation and excess fat deposition. Control offspring nursed by protein-restricted mothers showed peculiar low-fat accretion through adulthood and preserved insulin sensitivity even after WD exposure. Altogether, our findings suggest a testable hypothesis about how maternal diet might influence metabolic outcomes (insulin sensitivity) in the next generation such as mitochondrial overload and/or substrate oxidation inflexibility dependent on the time window of perinatal dietary manipulation. PMID- 24808499 TI - A unified self-stabilizing neural network algorithm for principal and minor components extraction. AB - Recently, many unified learning algorithms have been developed for principal component analysis and minor component analysis. These unified algorithms can be used to extract principal components and, if altered simply by the sign, can also serve as a minor component extractor. This is of practical significance in the implementations of algorithms. This paper proposes a unified self-stabilizing neural network learning algorithm for principal and minor components extraction, and studies the stability of the proposed unified algorithm via the fixed-point analysis method. The proposed unified self-stabilizing algorithm for principal and minor components extraction is extended for tracking the principal subspace (PS) and minor subspace (MS). The averaging differential equation and the energy function associated with the unified algorithm for tracking PS and MS are given. It is shown that the averaging differential equation will globally asymptotically converge to an invariance set, and the corresponding energy function exhibit a unique global minimum attained if and only if its state matrices span the PS or MS of the autocorrelation matrix of a vector data stream. It is concluded that the proposed unified algorithm for tracking PS and MS can efficiently track an orthonormal basis of the PS or MS. Simulations are carried out to further illustrate the theoretical results achieved. PMID- 24808500 TI - Stability and dissipativity analysis of static neural networks with time delay. AB - This paper is concerned with the problems of stability and dissipativity analysis for static neural networks (NNs) with time delay. Some improved delay-dependent stability criteria are established for static NNs with time-varying or time invariant delay using the delay partitioning technique. Based on these criteria, several delay-dependent sufficient conditions are given to guarantee the dissipativity of static NNs with time delay. All the given results in this paper are not only dependent upon the time delay but also upon the number of delay partitions. Some examples are given to illustrate the effectiveness and reduced conservatism of the proposed results. PMID- 24808501 TI - On-line node fault injection training algorithm for MLP networks: objective function and convergence analysis. AB - Improving fault tolerance of a neural network has been studied for more than two decades. Various training algorithms have been proposed in sequel. The on-line node fault injection-based algorithm is one of these algorithms, in which hidden nodes randomly output zeros during training. While the idea is simple, theoretical analyses on this algorithm are far from complete. This paper presents its objective function and the convergence proof. We consider three cases for multilayer perceptrons (MLPs). They are: (1) MLPs with single linear output node; (2) MLPs with multiple linear output nodes; and (3) MLPs with single sigmoid output node. For the convergence proof, we show that the algorithm converges with probability one. For the objective function, we show that the corresponding objective functions of cases (1) and (2) are of the same form. They both consist of a mean square errors term, a regularizer term, and a weight decay term. For case (3), the objective function is slight different from that of cases (1) and (2). With the objective functions derived, we can compare the similarities and differences among various algorithms and various cases. PMID- 24808502 TI - Tracking control for nonaffine systems: a self-organizing approximation approach. AB - This paper considers tracking control for single-input, single-output nonaffine dynamic systems. A performance-dependent self-organizing approximation-based approach is proposed. The designer specifies a positive tracking error criterion. The self-organizing approximation-based controller then monitors the tracking performance and adds basis elements only as needed to achieve the tracking specification. Even though the system is not affine, the approach is defined such that the approximated function is independent of the control variable u. Stability is proved and the self-organization is derived in a Lyapunov-based methodology. To illustrate certain novel aspects of the proposed controller, a numerical example is included. PMID- 24808503 TI - Geometric algorithms to large margin classifier based on affine hulls. AB - The geometric framework for binary data classification problems provides an intuitive foundation for the comprehension and application of geometric optimization algorithms, leading to practical solutions of real-world classification problems. In this paper, some theoretical results on the candidate extreme points of the notion of reduced affine hull (RAH) are introduced. These results allow the existing nearest point algorithms to be directly applied to solve both separable and inseparable classification problems based on RAHs successfully and efficiently. As the practical applications of the new theoretical results, the popular Gilbert-Schlesinger-Kozinec and Mitchell Dem'yanov-Malozemov algorithms are presented to solve binary classification problems in the context of the RAH framework. The theoretical analysis and some experiments show that the proposed methods successfully achieve significant performance. PMID- 24808504 TI - Concurrent subspace width optimization method for RBF neural network modeling. AB - Radial basis function neural networks (RBFNNs) are widely used in nonlinear function approximation. One of the challenges in RBFNN modeling is determining how to effectively optimize width parameters to improve approximation accuracy. To solve this problem, a width optimization method, concurrent subspace width optimization (CSWO), is proposed based on a decomposition and coordination strategy. This method decomposes the large-scale width optimization problem into several subspace optimization (SSO) problems, each of which has a single optimization variable and smaller training and validation data sets so as to greatly simplify optimization complexity. These SSOs can be solved concurrently, thus computational time can be effectively reduced. With top-level system coordination, the optimization of SSOs can converge to a consistent optimum, which is equivalent to the optimum of the original width optimization problem. The proposed method is tested with four mathematical examples and one practical engineering approximation problem. The results demonstrate the efficiency and robustness of CSWO in optimizing width parameters over the traditional width optimization methods. PMID- 24808505 TI - Adaptive multiregression in reproducing kernel Hilbert spaces: the multiaccess MIMO channel case. AB - This paper introduces a wide framework for online, i.e., time-adaptive, supervised multiregression tasks. The problem is formulated in a general infinite dimensional reproducing kernel Hilbert space (RKHS). In this context, a fairly large number of nonlinear multiregression models fall as special cases, including the linear case. Any convex, continuous, and not necessarily differentiable function can be used as a loss function in order to quantify the disagreement between the output of the system and the desired response. The only requirement is the subgradient of the adopted loss function to be available in an analytic form. To this end, we demonstrate a way to calculate the subgradients of robust loss functions, suitable for the multiregression task. As it is by now well documented, when dealing with online schemes in RKHS, the memory keeps increasing with each iteration step. To attack this problem, a simple sparsification strategy is utilized, which leads to an algorithmic scheme of linear complexity with respect to the number of unknown parameters. A convergence analysis of the technique, based on arguments of convex analysis, is also provided. To demonstrate the capacity of the proposed method, the multiregressor is applied to the multiaccess multiple-input multiple-output channel equalization task for a setting with poor resources and nonavailable channel information. Numerical results verify the potential of the method, when its performance is compared with those of the state-of-the-art linear techniques, which, in contrast, use space time coding, more antenna elements, as well as full channel information. PMID- 24808506 TI - Modeling and monitoring of dynamic processes. AB - In this paper, a new online monitoring approach is proposed for handling the dynamic problem in industrial batch processes. Compared to conventional methods, its contributions are as follows: (1) multimodes are separated correctly since the cross-mode correlations are considered and the common information is extracted; (2) the expensive computing load is avoided since only the specific information is calculated when a mode is monitored online; and (3) after that, two different subspaces are separated, and the common and specific subspace models are built and analyzed, respectively. The monitoring is carried out in the subspace. The corresponding confidence regions are constructed according to their respective models. PMID- 24808507 TI - Synchronization control for nonlinear stochastic dynamical networks: pinning impulsive strategy. AB - In this paper, a new control strategy is proposed for the synchronization of stochastic dynamical networks with nonlinear coupling. Pinning state feedback controllers have been proved to be effective for synchronization control of state coupled dynamical networks. We will show that pinning impulsive controllers are also effective for synchronization control of the above mentioned dynamical networks. Some generic mean square stability criteria are derived in terms of algebraic conditions, which guarantee that the whole state-coupled dynamical network can be forced to some desired trajectory by placing impulsive controllers on a small fraction of nodes. An effective method is given to select the nodes which should be controlled at each impulsive constants. The proportion of the controlled nodes guaranteeing the stability is explicitly obtained, and the synchronization region is also derived and clearly plotted. Numerical simulations are exploited to demonstrate the effectiveness of the pinning impulsive strategy proposed in this paper. PMID- 24808508 TI - Multistability of neural networks with time-varying delays and concave-convex characteristics. AB - In this paper, stability of multiple equilibria of neural networks with time varying delays and concave-convex characteristics is formulated and studied. Some sufficient conditions are obtained to ensure that an n-neuron neural network with concave-convex characteristics can have a fixed point located in the appointed region. By means of an appropriate partition of the n-dimensional state space, when nonlinear activation functions of an n-neuron neural network are concave or convex in 2k+2m-1 intervals, this neural network can have (2k+2m-1)n equilibrium points. This result can be applied to the multiobjective optimal control and associative memory. In particular, several succinct criteria are given to ascertain multistability of cellular neural networks. These stability conditions are the improvement and extension of the existing stability results in the literature. A numerical example is given to illustrate the theoretical findings via computer simulations. PMID- 24808509 TI - Time-frequency approach to underdetermined blind source separation. AB - This paper presents a new time-frequency (TF) underdetermined blind source separation approach based on Wigner-Ville distribution (WVD) and Khatri-Rao product to separate N non-stationary sources from M(M <; N) mixtures. First, an improved method is proposed for estimating the mixing matrix, where the negative value of the auto WVD of the sources is fully considered. Then after extracting all the auto-term TF points, the auto WVD value of the sources at every auto-term TF point can be found out exactly with the proposed approach no matter how many active sources there are as long as N <= 2M-1. Further discussion about the extraction of auto-term TF points is made and finally the numerical simulation results are presented to show the superiority of the proposed algorithm by comparing it with the existing ones. PMID- 24808510 TI - ARPOP: an appetitive reward-based pseudo-outer-product neural fuzzy inference system inspired from the operant conditioning of feeding behavior in Aplysia. AB - Appetitive operant conditioning in Aplysia for feeding behavior via the electrical stimulation of the esophageal nerve contingently reinforces each spontaneous bite during the feeding process. This results in the acquisition of operant memory by the contingently reinforced animals. Analysis of the cellular and molecular mechanisms of the feeding motor circuitry revealed that activity dependent neuronal modulation occurs at the interneurons that mediate feeding behaviors. This provides evidence that interneurons are possible loci of plasticity and constitute another mechanism for memory storage in addition to memory storage attributed to activity-dependent synaptic plasticity. In this paper, an associative ambiguity correction-based neuro-fuzzy network, called appetitive reward-based pseudo-outer-product-compositional rule of inference [ARPOP-CRI(S)], is trained based on an appetitive reward-based learning algorithm which is biologically inspired by the appetitive operant conditioning of the feeding behavior in Aplysia. A variant of the Hebbian learning rule called Hebbian concomitant learning is proposed as the building block in the neuro-fuzzy network learning algorithm. The proposed algorithm possesses the distinguishing features of the sequential learning algorithm. In addition, the proposed ARPOP CRI(S) neuro-fuzzy system encodes fuzzy knowledge in the form of linguistic rules that satisfies the semantic criteria for low-level fuzzy model interpretability. ARPOP-CRI(S) is evaluated and compared against other modeling techniques using benchmark time-series datasets. Experimental results are encouraging and show that ARPOP-CRI(S) is a viable modeling technique for time-variant problem domains. PMID- 24808511 TI - Global convergence of online BP training with dynamic learning rate. AB - The online backpropagation (BP) training procedure has been extensively explored in scientific research and engineering applications. One of the main factors affecting the performance of the online BP training is the learning rate. This paper proposes a new dynamic learning rate which is based on the estimate of the minimum error. The global convergence theory of the online BP training procedure with the proposed learning rate is further studied. It is proved that: 1) the error sequence converges to the global minimum error; and 2) the weight sequence converges to a fixed point at which the error function attains its global minimum. The obtained global convergence theory underlies the successful applications of the online BP training procedure. Illustrative examples are provided to support the theoretical analysis. PMID- 24808512 TI - Adaptive computation algorithm for RBF neural network. AB - A novel learning algorithm is proposed for nonlinear modelling and identification using radial basis function neural networks. The proposed method simplifies neural network training through the use of an adaptive computation algorithm (ACA). In addition, the convergence of the ACA is analyzed by the Lyapunov criterion. The proposed algorithm offers two important advantages. First, the model performance can be significantly improved through ACA, and the modelling error is uniformly ultimately bounded. Secondly, the proposed ACA can reduce computational cost and accelerate the training speed. The proposed method is then employed to model classical nonlinear system with limit cycle and to identify nonlinear dynamic system, exhibiting the effectiveness of the proposed algorithm. Computational complexity analysis and simulation results demonstrate its effectiveness. PMID- 24808513 TI - Asynchronous event-based binocular stereo matching. AB - We present a novel event-based stereo matching algorithm that exploits the asynchronous visual events from a pair of silicon retinas. Unlike conventional frame-based cameras, recent artificial retinas transmit their outputs as a continuous stream of asynchronous temporal events, in a manner similar to the output cells of the biological retina. Our algorithm uses the timing information carried by this representation in addressing the stereo-matching problem on moving objects. Using the high temporal resolution of the acquired data stream for the dynamic vision sensor, we show that matching on the timing of the visual events provides a new solution to the real-time computation of 3-D objects when combined with geometric constraints using the distance to the epipolar lines. The proposed algorithm is able to filter out incorrect matches and to accurately reconstruct the depth of moving objects despite the low spatial resolution of the sensor. This brief sets up the principles for further event-based vision processing and demonstrates the importance of dynamic information and spike timing in processing asynchronous streams of visual events. PMID- 24808514 TI - Frames for exact inversion of the rank order coder. AB - Our goal is to revisit rank order coding by proposing an original exact decoding procedure for it. Rank order coding was proposed by Thorpe et al. who stated that the order in which the retina cells are activated encodes for the visual stimulus. Based on this idea, the authors proposed in [1] a rank order coder/decoder associated to a retinal model. Though, it appeared that the decoding procedure employed yields reconstruction errors that limit the model bit cost/quality performances when used as an image codec. The attempts made in the literature to overcome this issue are time consuming and alter the coding procedure, or are lacking mathematical support and feasibility for standard size images. Here we solve this problem in an original fashion by using the frames theory, where a frame of a vector space designates an extension for the notion of basis. Our contribution is twofold. First, we prove that the analyzing filter bank considered is a frame, and then we define the corresponding dual frame that is necessary for the exact image reconstruction. Second, to deal with the problem of memory overhead, we design a recursive out-of-core blockwise algorithm for the computation of this dual frame. Our work provides a mathematical formalism for the retinal model under study and defines a simple and exact reverse transform for it with over than 265 dB of increase in the peak signal-to-noise ratio quality compared to [1]. Furthermore, the framework presented here can be extended to several models of the visual cortical areas using redundant representations. PMID- 24808515 TI - A globally convergent MC algorithm with an adaptive learning rate. AB - This brief deals with the problem of minor component analysis (MCA). Artificial neural networks can be exploited to achieve the task of MCA. Recent research works show that convergence of neural networks based MCA algorithms can be guaranteed if the learning rates are less than certain thresholds. However, the computation of these thresholds needs information about the eigenvalues of the autocorrelation matrix of data set, which is unavailable in online extraction of minor component from input data stream. In this correspondence, we introduce an adaptive learning rate into the OJAn MCA algorithm, such that its convergence condition does not depend on any unobtainable information, and can be easily satisfied in practical applications. PMID- 24808516 TI - Universal approximation of extreme learning machine with adaptive growth of hidden nodes. AB - Extreme learning machines (ELMs) have been proposed for generalized single-hidden layer feedforward networks which need not be neuron-like and perform well in both regression and classification applications. In this brief, we propose an ELM with adaptive growth of hidden nodes (AG-ELM), which provides a new approach for the automated design of networks. Different from other incremental ELMs (I-ELMs) whose existing hidden nodes are frozen when the new hidden nodes are added one by one, in AG-ELM the number of hidden nodes is determined in an adaptive way in the sense that the existing networks may be replaced by newly generated networks which have fewer hidden nodes and better generalization performance. We then prove that such an AG-ELM using Lebesgue p-integrable hidden activation functions can approximate any Lebesgue p-integrable function on a compact input set. Simulation results demonstrate and verify that this new approach can achieve a more compact network architecture than the I-ELM. PMID- 24808517 TI - Enhancing synchronizability of diffusively coupled dynamical networks: a survey. AB - In this paper, we review the literature on enhancing synchronizability of diffusively coupled dynamical networks with identical nodes. The last decade has witnessed intensive investigations on the collective behavior over complex networks and synchronization of dynamical systems is the most common form of collective behavior. For many applications, it is desired that the synchronizability-the ability of networks in synchronizing activity of their individual dynamical units-is enhanced. There are a number of methods for improving the synchronization properties of dynamical networks through structural perturbation. In this paper, we survey such methods including adding/removing nodes and/or edges, rewiring the links, and graph weighting. These methods often try to enhance the synchronizability through minimizing the eigenratio of the Laplacian matrix of the connection graph-a synchronizability measure based on the master-stability-function formalism. We also assess the performance of the methods by numerical simulations on a number of real-world networks as well as those generated through models such as preferential attachment, Watts-Strogatz, and Erdos-Renyi. PMID- 24808518 TI - Sparse representation classifier steered discriminative projection with applications to face recognition. AB - A sparse representation-based classifier (SRC) is developed and shows great potential for real-world face recognition. This paper presents a dimensionality reduction method that fits SRC well. SRC adopts a class reconstruction residual based decision rule, we use it as a criterion to steer the design of a feature extraction method. The method is thus called the SRC steered discriminative projection (SRC-DP). SRC-DP maximizes the ratio of between-class reconstruction residual to within-class reconstruction residual in the projected space and thus enables SRC to achieve better performance. SRC-DP provides low-dimensional representation of human faces to make the SRC-based face recognition system more efficient. Experiments are done on the AR, the extended Yale B, and PIE face image databases, and results demonstrate the proposed method is more effective than other feature extraction methods based on the SRC. PMID- 24808519 TI - Prediction intervals for a noisy nonlinear time series based on a bootstrapping reservoir computing network ensemble. AB - Prediction intervals that provide estimated values as well as the corresponding reliability are applied to nonlinear time series forecast. However, constructing reliable prediction intervals for noisy time series is still a challenge. In this paper, a bootstrapping reservoir computing network ensemble (BRCNE) is proposed and a simultaneous training method based on Bayesian linear regression is developed. In addition, the structural parameters of the BRCNE, that is, the number of reservoir computing networks and the reservoir dimension, are determined off-line by the 0.632 bootstrap cross-validation. To verify the effectiveness of the proposed method, two kinds of time series data, including the multisuperimposed oscillator problem with additive noises and a practical gas flow in steel industry are employed here. The experimental results indicate that the proposed approach has a satisfactory performance on prediction intervals for practical applications. PMID- 24808520 TI - Bayesian learning for spatial filtering in an EEG-based brain-computer interface. AB - Spatial filtering for EEG feature extraction and classification is an important tool in brain-computer interface. However, there is generally no established theory that links spatial filtering directly to Bayes classification error. To address this issue, this paper proposes and studies a Bayesian analysis theory for spatial filtering in relation to Bayes error. Following the maximum entropy principle, we introduce a gamma probability model for describing single-trial EEG power features. We then formulate and analyze the theoretical relationship between Bayes classification error and the so-called Rayleigh quotient, which is a function of spatial filters and basically measures the ratio in power features between two classes. This paper also reports our extensive study that examines the theory and its use in classification, using three publicly available EEG data sets and state-of-the-art spatial filtering techniques and various classifiers. Specifically, we validate the positive relationship between Bayes error and Rayleigh quotient in real EEG power features. Finally, we demonstrate that the Bayes error can be practically reduced by applying a new spatial filter with lower Rayleigh quotient. PMID- 24808521 TI - Neural network-based optimal adaptive output feedback control of a helicopter UAV. AB - Helicopter unmanned aerial vehicles (UAVs) are widely used for both military and civilian operations. Because the helicopter UAVs are underactuated nonlinear mechanical systems, high-performance controller design for them presents a challenge. This paper introduces an optimal controller design via an output feedback for trajectory tracking of a helicopter UAV, using a neural network (NN). The output-feedback control system utilizes the backstepping methodology, employing kinematic and dynamic controllers and an NN observer. The online approximator-based dynamic controller learns the infinite-horizon Hamilton-Jacobi Bellman equation in continuous time and calculates the corresponding optimal control input by minimizing a cost function, forward-in-time, without using the value and policy iterations. Optimal tracking is accomplished by using a single NN utilized for the cost function approximation. The overall closed-loop system stability is demonstrated using Lyapunov analysis. Finally, simulation results are provided to demonstrate the effectiveness of the proposed control design for trajectory tracking. PMID- 24808522 TI - Random sampler M-estimator algorithm with sequential probability ratio test for robust function approximation via feed-forward neural networks. AB - This paper addresses the problem of fitting a functional model to data corrupted with outliers using a multilayered feed-forward neural network. Although it is of high importance in practical applications, this problem has not received careful attention from the neural network research community. One recent approach to solving this problem is to use a neural network training algorithm based on the random sample consensus (RANSAC) framework. This paper proposes a new algorithm that offers two enhancements over the original RANSAC algorithm. The first one improves the algorithm accuracy and robustness by employing an M-estimator cost function to decide on the best estimated model from the randomly selected samples. The other one improves the time performance of the algorithm by utilizing a statistical pretest based on Wald's sequential probability ratio test. The proposed algorithm is successfully evaluated on synthetic and real data, contaminated with varying degrees of outliers, and compared with existing neural network training algorithms. PMID- 24808523 TI - Incorporating privileged information through metric learning. AB - In some pattern analysis problems, there exists expert knowledge, in addition to the original data involved in the classification process. The vast majority of existing approaches simply ignore such auxiliary (privileged) knowledge. Recently a new paradigm-learning using privileged information-was introduced in the framework of SVM+. This approach is formulated for binary classification and, as typical for many kernel-based methods, can scale unfavorably with the number of training examples. While speeding up training methods and extensions of SVM+ to multiclass problems are possible, in this paper we present a more direct novel methodology for incorporating valuable privileged knowledge in the model construction phase, primarily formulated in the framework of generalized matrix learning vector quantization. This is done by changing the global metric in the input space, based on distance relations revealed by the privileged information. Hence, unlike in SVM+, any convenient classifier can be used after such metric modification, bringing more flexibility to the problem of incorporating privileged information during the training. Experiments demonstrate that the manipulation of an input space metric based on privileged data improves classification accuracy. Moreover, our methods can achieve competitive performance against the SVM+ formulations. PMID- 24808524 TI - Novel range-free localization based on multidimensional support vector regression trained in the primal space. AB - A novel range-free localization algorithm based on the multidimensional support vector regression (MSVR) is proposed in this paper. The range-free localization problem is formulated as a multidimensional regression problem, and a new MSVR training method is proposed to solve the regression problem. Unlike standard support vector regression, the proposed MSVR allows multiple outputs and localizes the sensors without resorting to multilateration. The training of the MSVR is formulated directly in primal space and it can be solved in two ways. First, it is formulated as a second-order cone programming and trained by convex optimization. Second, its own training method is developed based on the Newton Raphson method. A simulation is conducted for both isotropic and anisotropic networks, and the proposed method exhibits excellent and robust performance in both isotropic and anisotropic networks. PMID- 24808525 TI - Exponential Hinfinity synchronization and state estimation for chaotic systems via a unified model. AB - In this paper, Hinfinity synchronization and state estimation problems are considered for different types of chaotic systems. A unified model consisting of a linear dynamic system and a bounded static nonlinear operator is employed to describe these chaotic systems, such as Hopfield neural networks, cellular neural networks, Chua's circuits, unified chaotic systems, Qi systems, chaotic recurrent multilayer perceptrons, etc. Based on the Hinfinity performance analysis of this unified model using the linear matrix inequality approach, novel state feedback controllers are established not only to guarantee exponentially stable synchronization between two unified models with different initial conditions but also to reduce the effect of external disturbance on the synchronization error to a minimal Hinfinity norm constraint. The state estimation problem is then studied for the same unified model, where the purpose is to design a state estimator to estimate its states through available output measurements so that the exponential stability of the estimation error dynamic systems is guaranteed and the influence of noise on the estimation error is limited to the lowest level. The parameters of these controllers and filters are obtained by solving the eigenvalue problem. Most chaotic systems can be transformed into this unified model, and Hinfinity synchronization controllers and state estimators for these systems are designed in a unified way. Three numerical examples are provided to show the usefulness of the proposed Hinfinity synchronization and state estimation conditions. PMID- 24808526 TI - A quadratically constrained MAP classifier using the mixture of Gaussians models as a weight function. AB - In this paper, we propose classifiers derived from quadratically constrained maximum a posteriori (QCMAP) estimation. The QCMAP consists of the maximization of the expectation of a cost function, which is derived from the maximum a posteriori probability and a quadratic constraint. This criterion is highly general since its forms include least squares regressions and a support vector machine. Furthermore, the criterion provides a novel classifier, the "Gaussian QCMAP." The QCMAP procedure still has large theoretical interest and its full extensibility has yet to be explored. In this paper, we propose using the mixture of Gaussian distributions as the QCMAP weight function. The mixture of Gaussian distributions has wide-ranging applicability, and encompasses forms, such as a normal distribution model and a kernel density model. We propose four types of mixture of Gaussian functions for QCMAP classifiers, and conduct experiments to demonstrate their advantages. PMID- 24808527 TI - Pinning consensus in networks of multiagents via a single impulsive controller. AB - In this paper, we discuss pinning consensus in networks of multiagents via impulsive controllers. In particular, we consider the case of using only one impulsive controller. We provide a sufficient condition to pin the network to a prescribed value. It is rigorously proven that in case the underlying graph of the network has spanning trees, the network can reach consensus on the prescribed value when the impulsive controller is imposed on the root with appropriate impulsive strength and impulse intervals. Interestingly, we find that the permissible range of the impulsive strength completely depends on the left eigenvector of the graph Laplacian corresponding to the zero eigenvalue and the pinning node we choose. The impulses can be very sparse, with the impulsive intervals being lower bounded. Examples with numerical simulations are also provided to illustrate the theoretical results. PMID- 24808528 TI - Robust adaptive dynamic programming with an application to power systems. AB - This brief presents a novel framework of robust adaptive dynamic programming (robust-ADP) aimed at computing globally stabilizing and suboptimal control policies in the presence of dynamic uncertainties. A key strategy is to integrate ADP theory with techniques in modern nonlinear control with a unique objective of filling up a gap in the past literature of ADP without taking into account dynamic uncertainties. Neither the system dynamics nor the system order are required to be precisely known. As an illustrative example, the computational algorithm is applied to the controller design of a two-machine power system. PMID- 24808529 TI - Structure of indicator function classes with finite Vapnik-Chervonenkis dimensions. AB - The Vapnik-Chervonenkis (VC) dimension is used to measure the complexity of a function class and plays an important role in a variety of fields, including artificial neural networks and machine learning. One major concern is the relationship between the VC dimension and inherent characteristics of the corresponding function class. According to Sauer's lemma, if the VC dimension of an indicator function class F is equal to D, the cardinality of the set F(S1(N)) will not be larger than Sigma(d=0)(D)C(N)(d). Therefore, there naturally arises a question about the VC dimension of an indicator function class: what kinds of elements will be contained in the function class F if F has a finite VC dimension? In this brief, we answer the above question. First, we investigate the structure of the function class F when the cardinality of the set F(S1(N)) reaches the maximum value Sigma(d=0)(D)C(N)(d). Based on the derived result, we then figure out what kinds of elements will be contained in F if F has a finite VC dimension. PMID- 24808530 TI - Approximating Gaussian mixture model or radial basis function network with multilayer perceptron. AB - Gaussian mixture models (GMMs) and multilayer perceptron (MLP) are both popular pattern classification techniques. This brief shows that a multilayer perceptron with quadratic inputs (MLPQ) can accurately approximate GMMs with diagonal covariance matrices. The mapping equations between the parameters of GMM and the weights of MLPQ are presented. A similar approach is applied to radial basis function networks (RBFNs) to show that RBFNs with Gaussian basis functions and Euclidean norm can be approximated accurately with MLPQ. The mapping equations between RBFN and MLPQ weights are presented. There are well-established training procedures for GMMs, such as the expectation maximization (EM) algorithm. The GMM parameters obtained by the EM algorithm can be used to generate a set of initial weights of MLPQ. Similarly, a trained RBFN can be used to generate a set of initial weights of MLPQ. MLPQ training can be continued further with gradient descent based methods, which can lead to improvement in performance compared to the GMM or RBFN from which it is initialized. Thus, the MLPQ can always perform as well as or better than the GMM or RBFN. PMID- 24808531 TI - A novel approach to the problem of non-uniqueness of the solution in hierarchical clustering. AB - The existence of multiple solutions in clustering, and in hierarchical clustering in particular, is often ignored in practical applications. However, this is a non trivial problem, as different data orderings can result in different cluster sets that, in turns, may lead to different interpretations of the same data. The method presented here offers a solution to this issue. It is based on the definition of an equivalence relation over dendrograms that allows developing all and only the significantly different dendrograms for the same dataset, thus reducing the computational complexity to polynomial from the exponential obtained when all possible dendrograms are considered. Experimental results in the neuroimaging and bioinformatics domains show the effectiveness of the proposed method. PMID- 24808532 TI - New insights into the determinants of serum Na+ and the risk for dysnatremias. PMID- 24808533 TI - Combination of bladder ultrasonography and novel cystometry method in mice reveals rapid decrease in bladder capacity and compliance in LPS-induced cystitis. AB - Various animal models have been used in research into bladder dysfunction, and in vivo cystometry is a common method to analyze bladder function in animals. However, it is rather difficult to perform reliably in small animals. Transabdominal bladder ultrasonography combined with cystometry in urethane anesthetized mice have revealed physical inhibition of bladder wall movement by a bladder catheter conventionally placed in the bladder apex. For reliable evaluation of mouse lower urinary tract function, we established a novel cystometry method in which a catheter was placed in the bladder anterior wall, in combination with bladder ultrasonography. This new method allowed the bladder to be well distended (i.e., larger maximum bladder capacity, lower pressure threshold, higher voided volume, and higher bladder compliance compared with conventional methods), which reflected more spontaneous voiding than conventional cystometry methods. We also demonstrated the usefulness of bladder ultrasonography for analysis of mouse bladder function, especially bladder dynamics, maximum bladder capacity, and post-voiding residual volume. We analyzed bladder functional changes in lipopolysaccharide (LPS)-induced cystitis by combining bladder ultrasonography and this new cystometry method. Bladder ultrasonography revealed a rapid decrease in bladder capacity, and cystometry showed a rapid decrease in voided volume due to intravesical LPS instillation. This new cystometry method also revealed a rapid decrease in bladder compliance caused by LPS instillation, which was not detectable by conventional methods. The combination of ultrasonography and the new cystometry method may become a powerful tool for analysis of mouse bladder function and could contribute to the development of new treatments for bladder dysfunction. PMID- 24808534 TI - First D1-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring. AB - The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin angiotensin-aldosterone system. Here, we show the first in vivo measurement of D1 like receptors in the renal cortex of Sprague-Dawley rat and Papio anubis baboon using [(11)C]NNC 112, a positron emission tomography radioligand for D1-like receptors. In addition, we show a D1-like binding potential response to angiotensin II blockade in rats using losartan. Demonstration of self-saturable binding in the rat as well as specific and saturable binding in Papio anubis validate the use of [(11)C]NNC 112 in the first in vivo measurement of renal dopamine D1-like receptors. Furthermore, [(11)C]NNC 112 is a radioligand tool already validated for use in probing human central nervous system (CNS) D1-like receptors. Our work demonstrates specific and saturable non-CNS binding in higher animals and the ability to quantify physiological response to drug treatment and provides a clear path to extend use of [(11)C]NNC 112 to study renal dopamine in humans. PMID- 24808535 TI - pH-responsive, gluconeogenic renal epithelial LLC-PK1-FBPase+cells: a versatile in vitro model to study renal proximal tubule metabolism and function. AB - Ammoniagenesis and gluconeogenesis are prominent metabolic features of the renal proximal convoluted tubule that contribute to maintenance of systemic acid-base homeostasis. Molecular analysis of the mechanisms that mediate the coordinate regulation of the two pathways required development of a cell line that recapitulates these features in vitro. By adapting porcine renal epithelial LLC PK1 cells to essentially glucose-free medium, a gluconeogenic subline, termed LLC PK1-FBPase(+) cells, was isolated. LLC-PK1-FBPase(+) cells grow in the absence of hexoses and pentoses and exhibit enhanced oxidative metabolism and increased levels of phosphate-dependent glutaminase. The cells also express significant levels of the key gluconeogenic enzymes, fructose-1,6-bisphosphatase (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK). Thus the altered phenotype of LLC-PK1 FBPase(+) cells is pleiotropic. Most importantly, when transferred to medium that mimics a pronounced metabolic acidosis (9 mM HCO3 (-), pH 6.9), the LLC-PK1 FBPase(+) cells exhibit a gradual increase in NH4 (+) ion production, accompanied by increases in glutaminase and cytosolic PEPCK mRNA levels and proteins. Therefore, the LLC-PK1-FBPase(+) cells retained in culture many of the metabolic pathways and pH-responsive adaptations characteristic of renal proximal tubules. The molecular mechanisms that mediate enhanced expression of the glutaminase and PEPCK in LLC-PK1-FBPase(+) cells have been extensively reviewed. The present review describes novel properties of this unique cell line and summarizes the molecular mechanisms that have been defined more recently using LLC-PK1-FBPase(+) cells to model the renal proximal tubule. It also identifies future studies that could be performed using these cells. PMID- 24808536 TI - Class I HDAC activity is required for renal protection and regeneration after acute kidney injury. AB - Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs. PMID- 24808537 TI - Dysfunction of the PGC-1alpha-mitochondria axis confers adriamycin-induced podocyte injury. AB - Adriamycin (ADR)-induced nephropathy in animals is an experimental analog of human focal segmental glomerulosclerosis, which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. The present study was designed to test the hypothesis that the peroxisome proliferator activated receptor-gamma coactivator (PGC)-1alpha-mitochondria axis is involved in ADR-induced podocyte injury. Using MPC5 immortalized mouse podocytes, ADR dose dependently induced downregulation of nephrin and podocin, cell apoptosis, and mitochondrial dysfunction based on the increase in mitochondrial ROS production, decrease in mitochondrial DNA copy number, and reduction of mitochondrial membrane potential and ATP content. Moreover, ADR treatment also remarkably reduced the expression of PGC-1alpha, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1alpha overexpression markedly attenuated mitochondrial dysfunction, the reduction of nephrin and podocin, and the apoptotic response in podocytes after ADR treatment. Moreover, downregulation of PGC-1alpha and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1alpha mitochondria axis is relevant to in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1alpha mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1alpha may be a novel strategy for the treatment of ADR nephropathy and human focal segmental glomerulosclerosis. PMID- 24808538 TI - Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK. AB - Enhanced tubular reabsorption of salt is important in the pathogenesis of obesity related hypertension, but the mechanisms remain poorly defined. To identify changes in the regulation of salt transporters in the kidney, C57BL/6 mice were fed a 40% fat diet [high-fat diet (HFD)] or a 12% fat diet (control diet) for 14 wk. Compared with control diet-fed mice, HFD-fed mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. When we examined Na(+) transporter expression, Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) was unchanged in whole kidney and reduced in the cortex, Na(+)-Cl(-) cotransporter (NCC) and alpha-epithelial Na(+) channel (ENaC) and gamma-ENaC were unchanged, and beta-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of STE-20/SPS1-related proline-alanine-rich protein kinase (SPAK)/oxidative stress responsive 1 kinase (OSR1) was increased in kidneys from HFD-fed mice, and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic experiments. HFD fed mice had reduced activating phosphorylation of AMP-activated protein kinase (AMPK) in the renal cortex. In vitro, activation of AMPK led to a reduction in phospho-SPAK/phospho-OSR1 in AMPK(+/+) murine embryonic fibroblasts (MEFs), but no effect was seen in AMPK(-/-) MEFs, indicating an AMPK-mediated effect. Activation of the with no lysine kinase/SPAK/OSR1 pathway with low-NaCl solution invoked a greater elevation in phospho-SPAK/phospho-OSR1 in AMPK(-/-) MEFs than in AMPK(+/+) MEFs, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto-unrecognized mediator of enhanced Na(+) reabsorption in obesity and identifies a new role for AMPK in regulating the activity of SPAK/OSR1. PMID- 24808539 TI - Role of medullary progenitor cells in epithelial cell migration and proliferation. AB - This study is aimed at characterizing medullary interstitial progenitor cells and to examine their capacity to induce tubular epithelial cell migration and proliferation. We have isolated a progenitor cell side population from a primary medullary interstitial cell line. We show that the medullary progenitor cells (MPCs) express CD24, CD44, CXCR7, CXCR4, nestin, and PAX7. MPCs are CD34 negative, which indicates that they are not bone marrow-derived stem cells. MPCs survive >50 passages, and when grown in epithelial differentiation medium develop phenotypic characteristics of epithelial cells. Inner medulla collecting duct (IMCD3) cells treated with conditioned medium from MPCs show significantly accelerated cell proliferation and migration. Conditioned medium from PGE2 treated MPCs induce tubule formation in IMCD3 cells grown in 3D Matrigel. Moreover, most of the MPCs express the pericyte marker PDGFR-b. Our study shows that the medullary interstitium harbors a side population of progenitor cells that can differentiate to epithelial cells and can stimulate tubular epithelial cell migration and proliferation. The findings of this study suggest that medullary pericyte/progenitor cells may play a critical role in collecting duct cell injury repair. PMID- 24808541 TI - Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. AB - Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to an increased risk of cardiovascular death in CKD. However, the effects of Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary Pi loading on the interactions among inflammation, malnutrition, and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different Pi concentrations ranging from 0.3% to 1.2% for 8 wk. CKD rats showed dietary Pi concentration-dependent increases in serum and tissue levels of TNF-alpha and urinary and tissue levels of oxidative stress markers and developed malnutrition (decrease in body weight, serum albumin, and urinary creatinine excretion), VC, and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by Pi overload. Regression analysis showed that serum Pi levels closely correlated with the extent of inflammation, malnutrition, and VC. Also, in cultured human vascular smooth muscle cells, high-Pi medium directly increased the expression of TNF-alpha in advance of the increase in osteochondrogenic markers. Our data suggest that dietary Pi overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and that inhibition of Pi loading through dietary or pharmacological interventions or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome. PMID- 24808540 TI - Role of 2',3'-cyclic nucleotide 3'-phosphodiesterase in the renal 2',3'-cAMP adenosine pathway. AB - Energy depletion increases the renal production of 2',3'-cAMP (a positional isomer of 3',5'-cAMP that opens mitochondrial permeability transition pores) and 2',3'-cAMP is converted to 2'-AMP and 3'-AMP, which in turn are metabolized to adenosine. Because the enzymes involved in this "2',3'-cAMP-adenosine pathway" are unknown, we examined whether 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) participates in the renal metabolism of 2',3'-cAMP. Western blotting and real-time PCR demonstrated expression of CNPase in rat glomerular mesangial, preglomerular vascular smooth muscle and endothelial, proximal tubular, thick ascending limb and collecting duct cells. Real-time PCR established the expression of CNPase in human glomerular mesangial, proximal tubular and vascular smooth muscle cells; and the level of expression of CNPase was greater than that for phosphodiesterase 4 (major enzyme for the metabolism of 3',5'-cAMP). Overexpression of CNPase in rat preglomerular vascular smooth muscle cells increased the metabolism of exogenous 2',3'-cAMP to 2'-AMP. Infusions of 2',3' cAMP into isolated CNPase wild-type (+/+) kidneys increased renal venous 2'-AMP, and this response was diminished by 63% in CNPase knockout (-/-) kidneys, whereas the conversion of 3',5'-cAMP to 5'-AMP was similar in CNPase +/+ vs. -/- kidneys. In CNPase +/+ kidneys, energy depletion (metabolic poisons) increased kidney tissue levels of adenosine and its metabolites (inosine, hypoxanthine, xanthine, and uric acid) without accumulation of 2',3'-cAMP. In contrast, in CNPase -/- kidneys, energy depletion increased kidney tissue levels of 2',3'-cAMP and abolished the increase in adenosine and its metabolites. In conclusion, kidneys express CNPase, and renal CNPase mediates in part the renal 2',3'-cAMP-adenosine pathway. PMID- 24808542 TI - The effects of achene type and germination time on plant performance in the heterocarpic Anacyclus clavatus (Asteraceae). AB - * PREMISE OF THE STUDY: In heterocarpy, fruits with different morphologies have been associated with alternative strategies of dispersal, germination, dormancy, and seedling competitive ability. In heterocarpic species, it is common to find fruits with competitive or dispersal syndromes. The competitive advantage of nondispersing fruits has been frequently attributed to their larger size, but recent studies have suggested that this could also be mediated by germination time. The main objective of our study was to investigate which factor, fruit type or germination time, most affects plant performance and, consequently, competitive ability, using the heterocarpic species Anacyclus clavatus* METHODS: To explore the effects of achene type and germination time on plant performance, we followed an innovative experimental approach including two experiments: one allowing for differences in germination time, and the other evaluating the effect of achene type alone by synchronizing germination time.* KEY RESULTS: A significant effect of germination time on several postdispersal life-history traits was observed: Achenes that germinated earlier produced plants with higher biomass and reproductive effort. When germination time was controlled, no significant differences were observed in any of the traits.* CONCLUSIONS: The competitive advantage of achenes with different morphologies was mainly mediated by germination time and not by differences in size or other intrinsic traits. The consequences of these results are discussed in light of the dispersal-competition trade-off. Our experimental approach (i.e., the synchronization of germination time) revealed the importance of manipulative experiments for testing the effects of germination time on plant survival and performance. PMID- 24808543 TI - Mechanical characterization of outer epidermal middle lamella of onion under tensile loading. AB - * PREMISE OF THE STUDY: The cells in plant tissue are joined together by a distinct layer called the middle lamella (ML). Understanding the mechanical properties of the ML is crucial in studying how tissue-level mechanical properties emerge from the subcellular-level mechanical properties. However, the nanoscale size of the ML presents formidable challenges to its characterization as a separate layer. Consequently, the mechanical properties of the ML under tensile loading are as yet unknown.* METHODS: Here, we characterize the ML from a subcellular sample excised from two adjacent cells and composed of two wall fragments and a single line of ML in between. Two techniques, cryotome sectioning and milling with a focused ion beam, were used to prepare ML samples, and tensile experiments were performed using microelectromechanical system (MEMS) tensile testing devices.* KEY RESULTS: Our test results showed that even at a subcellular scale, the ML appears to be stronger than the wall fragments. There was also evidence that the ML attached at the corner of cells more strongly than at the rest of the contact area. The contribution of the additional ML contact area was estimated to be 40.6 MPa. Wall fragment samples containing an ML layer were also significantly stronger (p < 0.05) than the wall fragments without an ML layer.* CONCLUSIONS: The tensile properties of the ML might not have a major impact on the tissue-scale mechanical properties. This conclusion calls for further study of the ML, including characterization under shear loading conditions and elucidation of the contributions of other extracellular parameters, such as cell size and shape, to the overall tissue-level mechanical response. PMID- 24808545 TI - Neuromorphic control of stepping pattern generation: a dynamic model with analog circuit implementation. AB - Animals such as stick insects can adaptively walk on complex terrains by dynamically adjusting their stepping motion patterns. Inspired by the coupled Matsuoka and resonate-and-fire neuron models, we present a nonlinear oscillation model as the neuromorphic central pattern generator (CPG) for rhythmic stepping pattern generation. This dynamic model can also be used to actuate the motoneurons on a leg joint with adjustable driving frequencies and duty cycles by changing a few of the model parameters while operating such that different stepping patterns can be generated. A novel mixed-signal integrated circuit design of this dynamic model is subsequently implemented, which, although simplified, shares the equivalent output performance in terms of the adjustable frequency and duty cycle. Three identical CPG models being used to drive three joints can make an arthropod leg of three degrees of freedom. With appropriate initial circuit parameter settings, and thus suitable phase lags among joints, the leg is expected to walk on a complex terrain with adaptive steps. The adaptation is associated with the circuit parameters mediated both by the higher level nervous system and the lower level sensory signals. The model is realized using a 0.3- complementary metal-oxide-semiconductor process and the results are reported. PMID- 24808544 TI - Biogeography and phylogenomics of New World Bambusoideae (Poaceae), revisited. AB - * PREMISE OF THE STUDY: New World Bambusoideae have only recently been studied in a phylogenomic context. Plastome sequences were determined and analyzed from Arundinaria appalachiana, A. tecta, and Olyra latifolia, to refine our knowledge of their evolution and historical biogeography. A correction is noted regarding an error in an earlier report on the biogeography of Cryptochloa* METHODS: Single end DNA libraries were prepared and sequenced on the Illumina platform. Complete plastomes were assembled and analyzed with 13 other Poaceae.* KEY RESULTS: Complete sampling in Arundinaria and an additional species of Olyreae gave a more detailed picture of their evolution/historical biogeography. Phylogenomic analyses indicated that the first major divergence in Arundinaria occurred around 2.3 to 3.2 mya and that Arundinaria tecta and A appalachiana diverged from their common ancestor around 0.57 to 0.82 mya. Estimates of the divergence of Olyra latifolia from Cryptochloa strictiflora ranged from 14.6 to 20.7 mya. The age of the stem node of Olyreae ranged from an estimated 26.9 to 38.2 mya.* CONCLUSIONS: Estimates of divergences in Arundinaria can be correlated with paleoclimatic events including an early Pliocene warming, subsequent cooling, and North American glaciations. Discriminating between alternate evolutionary/biogeographic scenarios in Olyreae is challenging. PMID- 24808546 TI - Stochastic competitive learning in complex networks. AB - Competitive learning is an important machine learning approach which is widely employed in artificial neural networks. In this paper, we present a rigorous definition of a new type of competitive learning scheme realized on large-scale networks. The model consists of several particles walking within the network and competing with each other to occupy as many nodes as possible, while attempting to reject intruder particles. The particle's walking rule is composed of a stochastic combination of random and preferential movements. The model has been applied to solve community detection and data clustering problems. Computer simulations reveal that the proposed technique presents high precision of community and cluster detections, as well as low computational complexity. Moreover, we have developed an efficient method for estimating the most likely number of clusters by using an evaluator index that monitors the information generated by the competition process itself. We hope this paper will provide an alternative way to the study of competitive learning.. PMID- 24808547 TI - Smoothing neural network for constrained non-Lipschitz optimization with applications. AB - In this paper, a smoothing neural network (SNN) is proposed for a class of constrained non-Lipschitz optimization problems, where the objective function is the sum of a nonsmooth, nonconvex function, and a non-Lipschitz function, and the feasible set is a closed convex subset of . Using the smoothing approximate techniques, the proposed neural network is modeled by a differential equation, which can be implemented easily. Under the level bounded condition on the objective function in the feasible set, we prove the global existence and uniform boundedness of the solutions of the SNN with any initial point in the feasible set. The uniqueness of the solution of the SNN is provided under the Lipschitz property of smoothing functions. We show that any accumulation point of the solutions of the SNN is a stationary point of the optimization problem. Numerical results including image restoration, blind source separation, variable selection, and minimizing condition number are presented to illustrate the theoretical results and show the efficiency of the SNN. Comparisons with some existing algorithms show the advantages of the SNN. PMID- 24808548 TI - View-invariant action recognition based on artificial neural networks. AB - In this paper, a novel view invariant action recognition method based on neural network representation and recognition is proposed. The novel representation of action videos is based on learning spatially related human body posture prototypes using self organizing maps. Fuzzy distances from human body posture prototypes are used to produce a time invariant action representation. Multilayer perceptrons are used for action classification. The algorithm is trained using data from a multi-camera setup. An arbitrary number of cameras can be used in order to recognize actions using a Bayesian framework. The proposed method can also be applied to videos depicting interactions between humans, without any modification. The use of information captured from different viewing angles leads to high classification performance. The proposed method is the first one that has been tested in challenging experimental setups, a fact that denotes its effectiveness to deal with most of the open issues in action recognition. PMID- 24808549 TI - Adaptive learning in complex reproducing kernel Hilbert spaces employing Wirtinger's subgradients. AB - This paper presents a wide framework for non-linear online supervised learning tasks in the context of complex valued signal processing. The (complex) input data are mapped into a complex reproducing kernel Hilbert space (RKHS), where the learning phase is taking place. Both pure complex kernels and real kernels (via the complexification trick) can be employed. Moreover, any convex, continuous and not necessarily differentiable function can be used to measure the loss between the output of the specific system and the desired response. The only requirement is the subgradient of the adopted loss function to be available in an analytic form. In order to derive analytically the subgradients, the principles of the (recently developed) Wirtinger's calculus in complex RKHS are exploited. Furthermore, both linear and widely linear (in RKHS) estimation filters are considered. To cope with the problem of increasing memory requirements, which is present in almost all online schemes in RKHS, the sparsification scheme, based on projection onto closed balls, has been adopted. We demonstrate the effectiveness of the proposed framework in a non-linear channel identification task, a non linear channel equalization problem and a quadrature phase shift keying equalization scheme, using both circular and non circular synthetic signal sources. PMID- 24808550 TI - Hybrid neural prediction and optimized adjustment for coke oven gas system in steel industry. AB - An energy system is the one of most important parts of the steel industry, and its reasonable operation exhibits a critical impact on manufacturing cost, energy security, and natural environment. With respect to the operation optimization problem for coke oven gas, a two-phase data-driven based forecasting and optimized adjusting method is proposed, where a Gaussian process-based echo states network is established to predict the gas real-time flow and the gasholder level in the prediction phase. Then, using the predicted gas flow and gasholder level, we develop a certain heuristic to quantify the user's optimal gas adjustment. The proposed operation measure has been verified to be effective by experimenting with the real-world on-line energy data sets coming from Shanghai Baosteel Corporation, Ltd., China. At present, the scheduling software developed with the proposed model and ensuing algorithms have been applied to the production practice of Baosteel. The application effects indicate that the software system can largely improve the real-time prediction accuracy of the gas units and provide with the optimized gas balance direction for the energy optimization. PMID- 24808551 TI - Network-based stochastic semisupervised learning. AB - Semisupervised learning is a machine learning approach that is able to employ both labeled and unlabeled samples in the training process. In this paper, we propose a semisupervised data classification model based on a combined random preferential walk of particles in a network (graph) constructed from the input dataset. The particles of the same class cooperate among themselves, while the particles of different classes compete with each other to propagate class labels to the whole network. A rigorous model definition is provided via a nonlinear stochastic dynamical system and a mathematical analysis of its behavior is carried out. A numerical validation presented in this paper confirms the theoretical predictions. An interesting feature brought by the competitive cooperative mechanism is that the proposed model can achieve good classification rates while exhibiting low computational complexity order in comparison to other network-based semisupervised algorithms. Computer simulations conducted on synthetic and real-world datasets reveal the effectiveness of the model. PMID- 24808552 TI - Stability analysis of Markovian jump stochastic BAM neural networks with impulse control and mixed time delays. AB - This paper discusses the issue of stability analysis for a class of impulsive stochastic bidirectional associative memory neural networks with both Markovian jump parameters and mixed time delays. The jumping parameters are modeled as a continuous-time discrete-state Markov chain. Based on a novel Lyapunov-Krasovskii functional, the generalized Ito's formula, mathematical induction, and stochastic analysis theory, a linear matrix inequality approach is developed to derive some novel sufficient conditions that guarantee the exponential stability in the mean square of the equilibrium point. At the same time, we also investigate the robustly exponential stability in the mean square of the corresponding system with unknown parameters. It should be mentioned that our stability results are delay-dependent, which depend on not only the upper bounds of time delays but also their lower bounds. Moreover, the derivatives of time delays are not necessarily zero or smaller than one since several free matrices are introduced in our results. Consequently, the results obtained in this paper are not only less conservative but also generalize and improve many earlier results. Finally, two numerical examples and their simulations are provided to show the effectiveness of the theoretical results. PMID- 24808553 TI - Sensitivity-based adaptive learning rules for binary feedforward neural networks. AB - This paper proposes a set of adaptive learning rules for binary feedforward neural networks (BFNNs) by means of the sensitivity measure that is established to investigate the effect of a BFNN's weight variation on its output. The rules are based on three basic adaptive learning principles: the benefit principle, the minimal disturbance principle, and the burden-sharing principle. In order to follow the benefit principle and the minimal disturbance principle, a neuron selection rule and a weight adaptation rule are developed. Besides, a learning control rule is developed to follow the burden-sharing principle. The advantage of the rules is that they can effectively guide the BFNN's learning to conduct constructive adaptations and avoid destructive ones. With these rules, a sensitivity-based adaptive learning (SBALR) algorithm for BFNNs is presented. Experimental results on a number of benchmark data demonstrate that the SBALR algorithm has better learning performance than the Madaline rule II and backpropagation algorithms. PMID- 24808554 TI - Bilinear probabilistic principal component analysis. AB - Probabilistic principal component analysis (PPCA) is a popular linear latent variable model for performing dimension reduction on 1-D data in a probabilistic manner. However, when used on 2-D data such as images, PPCA suffers from the curse of dimensionality due to the subsequently large number of model parameters. To overcome this problem, we propose in this paper a novel probabilistic model on 2-D data called bilinear PPCA (BPPCA). This allows the establishment of a closer tie between BPPCA and its nonprobabilistic counterpart. Moreover, two efficient parameter estimation algorithms for fitting BPPCA are also developed. Experiments on a number of 2-D synthetic and real-world data sets show that BPPCA is more accurate than existing probabilistic and nonprobabilistic dimension reduction methods. PMID- 24808555 TI - Domain adaptation from multiple sources: a domain-dependent regularization approach. AB - In this paper, we propose a new framework called domain adaptation machine (DAM) for the multiple source domain adaption problem. Under this framework, we learn a robust decision function (referred to as target classifier) for label prediction of instances from the target domain by leveraging a set of base classifiers which are prelearned by using labeled instances either from the source domains or from the source domains and the target domain. With the base classifiers, we propose a new domain-dependent regularizer based on smoothness assumption, which enforces that the target classifier shares similar decision values with the relevant base classifiers on the unlabeled instances from the target domain. This newly proposed regularizer can be readily incorporated into many kernel methods (e.g., support vector machines (SVM), support vector regression, and least-squares SVM (LS-SVM)). For domain adaptation, we also develop two new domain adaptation methods referred to as FastDAM and UniverDAM. In FastDAM, we introduce our proposed domain-dependent regularizer into LS-SVM as well as employ a sparsity regularizer to learn a sparse target classifier with the support vectors only from the target domain, which thus makes the label prediction on any test instance very fast. In UniverDAM, we additionally make use of the instances from the source domains as Universum to further enhance the generalization ability of the target classifier. We evaluate our two methods on the challenging TRECIVD 2005 dataset for the large-scale video concept detection task as well as on the 20 newsgroups and email spam datasets for document retrieval. Comprehensive experiments demonstrate that FastDAM and UniverDAM outperform the existing multiple source domain adaptation methods for the two applications. PMID- 24808556 TI - Semi-supervised dimension reduction using trace ratio criterion. AB - In this brief, we address the trace ratio (TR) problem for semi-supervised dimension reduction. We first reformulate the objective function of the recent work semi-supervised discriminant analysis (SDA) in a TR form. We also observe that in SDA the low-dimensional data representation F is constrained to be in the linear subspace spanned by the training data matrix X (i.e., F = X(T) W). In order to relax this hard constraint, we introduce a flexible regularizer ||F - X(T) W||(2) which models the regression residual into the reformulated objective function. With such relaxation, our method referred to as TR based flexible SDA (TR-FSDA) can better cope with data sampled from a certain type of nonlinear manifold that is somewhat close to a linear subspace. In order to address the non trivial optimization problem in TR-FSDA, we further develop an iterative algorithm to simultaneously solve for the low-dimensional data representation F and the projection matrix W. Moreover, we theoretically prove that our iterative algorithm converges to the optimum based on the Newton-Raphson method. The experiments on two face databases, one shape image database and one webpage database demonstrate that TR-FSDA outperforms the existing semi-supervised dimension reduction methods. PMID- 24808557 TI - Regularized kernel discriminant analysis with a robust kernel for face recognition and verification. AB - We propose a robust approach to discriminant kernel-based feature extraction for face recognition and verification. We show, for the first time, how to perform the eigen analysis of the within-class scatter matrix directly in the feature space. This eigen analysis provides the eigenspectrum of its range space and the corresponding eigenvectors as well as the eigenvectors spanning its null space. Based on our analysis, we propose a kernel discriminant analysis (KDA) which combines eigenspectrum regularization with a feature-level scheme (ER-KDA). Finally, we combine the proposed ER-KDA with a nonlinear robust kernel particularly suitable for face recognition/verification applications which require robustness against outliers caused by occlusions and illumination changes. We applied the proposed framework to several popular databases (Yale, AR, XM2VTS) and achieved state-of-the-art performance for most of our experiments. PMID- 24808558 TI - Entropy-based incremental variational Bayes learning of Gaussian mixtures. AB - Variational approaches to density estimation and pattern recognition using Gaussian mixture models can be used to learn the model and optimize its complexity simultaneously. In this brief, we develop an incremental entropy-based variational learning scheme that does not require any kind of initialization. The key element of the proposal is to exploit the incremental learning approach to perform model selection through efficient iteration over the variational Bayes optimization step in a way that the number of splits is minimized. The method starts with just one component and adds new components iteratively by splitting the worst fitted kernel in terms of evaluating its entropy. Our experimental results, on synthetic and real data sets show the effectiveness of the approach outperforming other state-of-the-art incremental component learners. PMID- 24808559 TI - Sampled-data exponential synchronization of complex dynamical networks with time varying coupling delay. AB - This paper studies the problem of sampled-data exponential synchronization of complex dynamical networks (CDNs) with time-varying coupling delay and uncertain sampling. By combining the time-dependent Lyapunov functional approach and convex combination technique, a criterion is derived to ensure the exponential stability of the error dynamics, which fully utilizes the available information about the actual sampling pattern. Based on the derived condition, the design method of the desired sampled-data controllers is proposed to make the CDNs exponentially synchronized and obtain a lower-bound estimation of the largest sampling interval. Simulation examples demonstrate that the presented method can significantly reduce the conservatism of the existing results, and lead to wider applications. PMID- 24808560 TI - Dictionary learning-based subspace structure identification in spectral clustering. AB - In this paper, we study dictionary learning (DL) approach to identify the representation of low-dimensional subspaces from high-dimensional and nonnegative data. Such representation can be used to provide an affinity matrix among different subspaces for data clustering. The main contribution of this paper is to consider both nonnegativity and sparsity constraints together in DL such that data can be represented effectively by nonnegative and sparse coding coefficients and nonnegative dictionary bases. In the algorithm, we employ the proximal point technique for the resulting DL and sparsity optimization problem. We make use of coding coefficients to perform spectral clustering (SC) for data partitioning. Extensive experiments on real-world high-dimensional and nonnegative data sets, including text, microarray, and image data demonstrate that the proposed method can discover their subspace structures. Experimental results also show that our algorithm is computationally efficient and effective for obtaining high SC performance and interpreting the clustering results compared with the other testing methods. PMID- 24808561 TI - Knowledge-leverage-based TSK Fuzzy System modeling. AB - Classical fuzzy system modeling methods consider only the current scene where the training data are assumed to be fully collectable. However, if the data available from the current scene are insufficient, the fuzzy systems trained by using the incomplete datasets will suffer from weak generalization capability for the prediction in the scene. In order to overcome this problem, a knowledge-leverage based fuzzy system (KL-FS) is studied in this paper from the perspective of transfer learning. The KL-FS intends to not only make full use of the data from the current scene in the learning procedure, but also effectively leverage the existing knowledge from the reference scenes. Specifically, a knowledge-leverage based Takagi-Sugeno-Kang-type Fuzzy System (KL-TSK-FS) is proposed by integrating the corresponding knowledge-leverage mechanism. The new fuzzy system modeling technique is evaluated through experiments on synthetic and real-world datasets. The results demonstrate that KL-TSK-FS has better performance and adaptability than the traditional fuzzy modeling methods in scenes with insufficient data. PMID- 24808562 TI - A cognitive fault diagnosis system for distributed sensor networks. AB - This paper introduces a novel cognitive fault diagnosis system (FDS) for distributed sensor networks that takes advantage of spatial and temporal relationships among sensors. The proposed FDS relies on a suitable functional graph representation of the network and a two-layer hierarchical architecture designed to promptly detect and isolate faults. The lower processing layer exploits a novel change detection test (CDT) based on hidden Markov models (HMMs) configured to detect variations in the relationships between couples of sensors. HMMs work in the parameter space of linear time-invariant dynamic systems, approximating, over time, the relationship between two sensors; changes in the approximating model are detected by inspecting the HMM likelihood. Information provided by the CDT layer is then passed to the cognitive one, which, by exploiting the graph representation of the network, aggregates information to discriminate among faults, changes in the environment, and false positives induced by the model bias of the HMMs. PMID- 24808563 TI - Boundedness and complete stability of complex-valued neural networks with time delay. AB - In this paper, the boundedness and complete stability of complex-valued neural networks (CVNNs) with time delay are studied. Some conditions to guarantee the boundedness of the CVNNs are derived using local inhibition. Moreover, under the boundedness conditions, a compact set that globally attracts all the trajectories of the network is also given. Additionally, several conditions in terms of real valued linear matrix inequalities (LMIs) for complete stability of the CVNNs are established via the energy minimization method and the approach that converts the complex-valued LMIs to real-valued ones. Examples with simulation results are given to show the effectiveness of the theoretical analysis. PMID- 24808564 TI - Fast neuromimetic object recognition using FPGA outperforms GPU implementations. AB - Recognition of objects in still images has traditionally been regarded as a difficult computational problem. Although modern automated methods for visual object recognition have achieved steadily increasing recognition accuracy, even the most advanced computational vision approaches are unable to obtain performance equal to that of humans. This has led to the creation of many biologically inspired models of visual object recognition, among them the hierarchical model and X (HMAX) model. HMAX is traditionally known to achieve high accuracy in visual object recognition tasks at the expense of significant computational complexity. Increasing complexity, in turn, increases computation time, reducing the number of images that can be processed per unit time. In this paper we describe how the computationally intensive and biologically inspired HMAX model for visual object recognition can be modified for implementation on a commercial field-programmable aate Array, specifically the Xilinx Virtex 6 ML605 evaluation board with XC6VLX240T FPGA. We show that with minor modifications to the traditional HMAX model we can perform recognition on images of size 128 * 128 pixels at a rate of 190 images per second with a less than 1% loss in recognition accuracy in both binary and multiclass visual object recognition tasks. PMID- 24808565 TI - Improving the quality of self-organizing maps by self-intersection avoidance. AB - The quality of self-organizing maps is always a key issue to practitioners. Smooth maps convey information about input data sets in a clear manner. Here a method is presented to modify the learning algorithm of self-organizing maps to reduce the number of topology errors, hence the obtained map has better quality at the expense of increased quantization error. It is based on avoiding maps that self-intersect or nearly so, as these states are related to low quality. Our approach is tested with synthetic data and real data from visualization, pattern recognition and computer vision applications, with satisfactory results. PMID- 24808566 TI - Quantum-based algorithm for optimizing artificial neural networks. AB - This paper presents a quantum-based algorithm for evolving artificial neural networks (ANNs). The aim is to design an ANN with few connections and high classification performance by simultaneously optimizing the network structure and the connection weights. Unlike most previous studies, the proposed algorithm uses quantum bit representation to codify the network. As a result, the connectivity bits do not indicate the actual links but the probability of the existence of the connections, thus alleviating mapping problems and reducing the risk of throwing away a potential candidate. In addition, in the proposed model, each weight space is decomposed into subspaces in terms of quantum bits. Thus, the algorithm performs a region by region exploration, and evolves gradually to find promising subspaces for further exploitation. This is helpful to provide a set of appropriate weights when evolving the network structure and to alleviate the noisy fitness evaluation problem. The proposed model is tested on four benchmark problems, namely breast cancer and iris, heart, and diabetes problems. The experimental results show that the proposed algorithm can produce compact ANN structures with good generalization ability compared to other algorithms. PMID- 24808567 TI - Hinging hyperplanes for time-series segmentation. AB - Division of a time series into segments is a common technique for time-series processing, and is known as segmentation. Segmentation is traditionally done by linear interpolation in order to guarantee the continuity of the reconstructed time series. The interpolation-based segmentation methods may perform poorly for data with a level of noise because interpolation is noise sensitive. To handle the problem, this paper establishes an explicit expression for segmentation from a compact representation for piecewise linear functions using hinging hyperplanes. This expression enables the use of regression to obtain a continuous reconstructed signal and, as a consequence, application of advanced techniques in segmentation. In this paper, a least squares support vector machine with lasso using a hinging feature map is given and analyzed, based on which a segmentation algorithm and its online version are established. Numerical experiments conducted on synthetic and real-world datasets demonstrate the advantages of our methods compared to existing segmentation algorithms. PMID- 24808568 TI - Ranking graph embedding for learning to rerank. AB - Dimensionality reduction is a key step to improving the generalization ability of reranking in image search. However, existing dimensionality reduction methods are typically designed for classification, clustering, and visualization, rather than for the task of learning to rank. Without using of ranking information such as relevance degree labels, direct utilization of conventional dimensionality reduction methods in ranking tasks generally cannot achieve the best performance. In this paper, we show that introducing ranking information into dimensionality reduction significantly increases the performance of image search reranking. The proposed method transforms graph embedding, a general framework of dimensionality reduction, into ranking graph embedding (RANGE) by modeling the global structure and the local relationships in and between different relevance degree sets, respectively. The proposed method also defines three types of edge weight assignment between two nodes: binary, reconstruction, and global. In addition, a novel principal components analysis based similarity calculation method is presented in the stage of global graph construction. Extensive experimental results on the MSRA-MM database demonstrate the effectiveness and superiority of the proposed RANGE method and the image search reranking framework. PMID- 24808569 TI - Feasibility and finite convergence analysis for accurate on-line nu-support vector machine. AB - The nu-support vector machine ( nu-SVM) for classification has the advantage of using a parameter nu on controlling the number of support vectors and margin errors. Recently, an interesting accurate on-line algorithm accurate on-line nu SVM algorithm (AONSVM) is proposed for training nu-SVM. AONSVM can be viewed as a special case of parametric quadratic programming techniques. It is demonstrated that AONSVM avoids the infeasible updating path as far as possible, and successfully converges to the optimal solution based on experimental analysis. However, because of the differences between AONSVM and classical parametric quadratic programming techniques, there is no theoretical justification for these conclusions. In this paper, we prove the feasibility and finite convergence of AONSVM under two assumptions. The main results of feasibility analysis include: 1) the inverses of the two key matrices in AONSVM always exist; 2) the rules for updating the two key inverse matrices are reliable; 3) the variable zeta can control the adjustment of the sum of all the weights efficiently; and 4) a sample cannot migrate back and forth in successive adjustment steps among the set of margin support vectors, the set of error support vectors, and the set of the remaining vectors. Moreover, the analyses of AONSVM also provide the proofs of the feasibility and finite convergence for accurate on-line C-SVM learning directly. PMID- 24808570 TI - Exponential synchronization of coupled switched neural networks with mode dependent impulsive effects. AB - This paper investigates the synchronization problem of coupled switched neural networks (SNNs) with mode-dependent impulsive effects and time delays. The main feature of mode-dependent impulsive effects is that impulsive effects can exist not only at the instants coinciding with mode switching but also at the instants when there is no system switching. The impulses considered here include those that suppress synchronization or enhance synchronization. Based on switching analysis techniques and the comparison principle, the exponential synchronization criteria are derived for coupled delayed SNNs with mode-dependent impulsive effects. Finally, simulations are provided to illustrate the effectiveness of the results. PMID- 24808571 TI - Analysis of boundedness and convergence of online gradient method for two-layer feedforward neural networks. AB - This paper presents a theoretical boundedness and convergence analysis of online gradient method for the training of two-layer feedforward neural networks. The well-known linear difference equation is extended to apply to the general case of linear or nonlinear activation functions. Based on this extended difference equation, we investigate the boundedness and convergence of the parameter sequence of concern, which is trained by finite training samples with a constant learning rate. We show that the uniform upper bound of the parameter sequence, which is very important in the training procedure, is the solution of an inequality regarding the bound. It is further verified that, for the case of linear activation function, a solution always exists and, moreover, the parameter sequence can be uniformly upper bounded, while for the case of nonlinear activation function, some simple adjustment methods on the training set or the activation function can be derived to improve the boundedness property. Then, for the convergence analysis, it is shown that the parameter sequence can converge into a zone around an optimal solution at which the error function attains its global minimum, where the size of the zone is associated with the learning rate. Particularly, for the case of perfect modeling, a strong global convergence result, where the parameter sequence can always converge to an optimal solution, is proved. PMID- 24808572 TI - Phase-noise-induced resonance in arrays of coupled excitable neural models. AB - Recently, it is observed that, in a single neural model, phase noise (time varying signal phase) arising from an external stimulating signal can induce regular spiking activities even if the signal is subthreshold. In addition, it is also uncovered that there exists an optimal phase noise intensity at which the spiking rhythm coincides with the frequency of the subthreshold signal, resulting in a phase-noise-induced resonance phenomenon. However, neurons usually do not work alone, but are connected in the form of arrays or blocks. Therefore, we study the spiking activity induced by phase noise in arrays of globally and locally coupled excitable neural models. We find that there also exists an optimal phase noise intensity for generating large neural response and such an optimal value is significantly decreased compared to an isolated single neuron case, which means the detectability in response to the subthreshold signal of neurons is sharply improved because of the coupling. In addition, we reveal two new resonance behaviors in the neuron ensemble with the presence of phase noise: there exist optimal values of both coupling strength and system size, where the coupled neurons generate regular spikes under subthreshold stimulations, which are called as coupling strength and system size resonance, respectively. Finally, the dependence of phase-noise-induced resonance on signal frequency is also examined. PMID- 24808573 TI - Study of the convergence behavior of the complex kernel least mean square algorithm. AB - The complex kernel least mean square (CKLMS) algorithm is recently derived and allows for online kernel adaptive learning for complex data. Kernel adaptive methods can be used in finding solutions for neural network and machine learning applications. The derivation of CKLMS involved the development of a modified Wirtinger calculus for Hilbert spaces to obtain the cost function gradient. We analyze the convergence of the CKLMS with different kernel forms for complex data. The expressions obtained enable us to generate theory-predicted mean-square error curves considering the circularity of the complex input signals and their effect on nonlinear learning. Simulations are used for verifying the analysis results. PMID- 24808574 TI - Transductive face sketch-photo synthesis. AB - Face sketch-photo synthesis plays a critical role in many applications, such as law enforcement and digital entertainment. Recently, many face sketch-photo synthesis methods have been proposed under the framework of inductive learning, and these have obtained promising performance. However, these inductive learning based face sketch-photo synthesis methods may result in high losses for test samples, because inductive learning minimizes the empirical loss for training samples. This paper presents a novel transductive face sketch-photo synthesis method that incorporates the given test samples into the learning process and optimizes the performance on these test samples. In particular, it defines a probabilistic model to optimize both the reconstruction fidelity of the input photo (sketch) and the synthesis fidelity of the target output sketch (photo), and efficiently optimizes this probabilistic model by alternating optimization. The proposed transductive method significantly reduces the expected high loss and improves the synthesis performance for test samples. Experimental results on the Chinese University of Hong Kong face sketch data set demonstrate the effectiveness of the proposed method by comparing it with representative inductive learning-based face sketch-photo synthesis methods. PMID- 24808575 TI - Learning sparse kernel classifiers for multi-instance classification. AB - We propose a direct approach to learning sparse kernel classifiers for multi instance (MI) classification to improve efficiency while maintaining predictive accuracy. The proposed method builds on a convex formulation for MI classification by considering the average score of individual instances for bag level prediction. In contrast, existing formulations used the maximum score of individual instances in each bag, which leads to nonconvex optimization problems. Based on the convex MI framework, we formulate a sparse kernel learning algorithm by imposing additional constraints on the objective function to enforce the maximum number of expansions allowed in the prediction function. The formulated sparse learning problem for the MI classification is convex with respect to the classifier weights. Therefore, we can employ an effective optimization strategy to solve the optimization problem that involves the joint learning of both the classifier and the expansion vectors. In addition, the proposed formulation can explicitly control the complexity of the prediction model while still maintaining competitive predictive performance. Experimental results on benchmark data sets demonstrate that our proposed approach is effective in building very sparse kernel classifiers while achieving comparable performance to the state-of-the-art MI classifiers. PMID- 24808576 TI - FPGA-based distributed computing microarchitecture for complex physical dynamics investigation. AB - In this paper, we present a distributed computing system, called DCMARK, aimed at solving partial differential equations at the basis of many investigation fields, such as solid state physics, nuclear physics, and plasma physics. This distributed architecture is based on the cellular neural network paradigm, which allows us to divide the differential equation system solving into many parallel integration operations to be executed by a custom multiprocessor system. We push the number of processors to the limit of one processor for each equation. In order to test the present idea, we choose to implement DCMARK on a single FPGA, designing the single processor in order to minimize its hardware requirements and to obtain a large number of easily interconnected processors. This approach is particularly suited to study the properties of 1-, 2- and 3-D locally interconnected dynamical systems. In order to test the computing platform, we implement a 200 cells, Korteweg-de Vries (KdV) equation solver and perform a comparison between simulations conducted on a high performance PC and on our system. Since our distributed architecture takes a constant computing time to solve the equation system, independently of the number of dynamical elements (cells) of the CNN array, it allows us to reduce the elaboration time more than other similar systems in the literature. To ensure a high level of reconfigurability, we design a compact system on programmable chip managed by a softcore processor, which controls the fast data/control communication between our system and a PC Host. An intuitively graphical user interface allows us to change the calculation parameters and plot the results. PMID- 24808578 TI - Cube Kohonen self-organizing map (CKSOM) model with new equations in organizing unstructured data. AB - Surface reconstruction by using 3-D data is used to represent the surface of an object and perform important tasks. The type of data used is important and can be described as either structured or unstructured. For unstructured data, there is no connectivity information between data points. As a result, incorrect shapes will be obtained during the imaging process. Therefore, the data should be reorganized by finding the correct topology so that the correct shape can be obtained. Previous studies have shown that the Kohonen self-organizing map (KSOM) could be used to solve data organizing problems. However, 2-D Kohonen maps are limited because they are unable to cover the whole surface of closed 3-D surface data. Furthermore, the neurons inside the 3-D KSOM structure should be removed in order to create a correct wireframe model. This is because only the outside neurons are used to represent the surface of an object. The aim of this paper is to use KSOM to organize unstructured data for closed surfaces. KSOM isused in this paper by testing its ability to organize medical image data because KSOM is mostly used in constructing engineering field data. Enhancements are added to the model by introducing class number and the index vector, and new equations are created. Various grid sizes and maximum iterations are tested in the experiments. Based on the results, the number of redundancies is found to be directly proportional to the grid size. When we increase the maximum iterations, the surface of the image becomes smoother. An area formula is used and manual calculations are performed to validate the results. This model is implemented and images are created using Dev C++ and GNUPlot. PMID- 24808577 TI - Neural-adaptive control of single-master-multiple-slaves teleoperation for coordinated multiple mobile manipulators with time-varying communication delays and input uncertainties. AB - In this paper, adaptive neural network control is investigated for single-master multiple-slaves teleoperation in consideration of time delays and input dead-zone uncertainties for multiple mobile manipulators carrying a common object in a cooperative manner. Firstly, concise dynamics of teleoperation systems consisting of a single master robot, multiple coordinated slave robots, and the object are developed in the task space. To handle asymmetric time-varying delays in communication channels and unknown asymmetric input dead zones, the nonlinear dynamics of the teleoperation system are transformed into two subsystems through feedback linearization: local master or slave dynamics including the unknown input dead zones and delayed dynamics for the purpose of synchronization. Then, a model reference neural network control strategy based on linear matrix inequalities (LMI) and adaptive techniques is proposed. The developed control approach ensures that the defined tracking errors converge to zero whereas the coordination internal force errors remain bounded and can be made arbitrarily small. Throughout this paper, stability analysis is performed via explicit Lyapunov techniques under specific LMI conditions. The proposed adaptive neural network control scheme is robust against motion disturbances, parametric uncertainties, time-varying delays, and input dead zones, which is validated by simulation studies. PMID- 24808579 TI - Real-time model predictive control using a self-organizing neural network. AB - In this paper, a real-time model predictive control (RT-MPC) based on self organizing radial basis function neural network (SORBFNN) is proposed for nonlinear systems. This RT-MPC has its simplicity in parallelism to model predictive control design and efficiency to deal with computational complexity. First, a SORBFNN with concurrent structure and parameter learning is developed as the predictive model of the nonlinear systems. The model performance can be significantly improved through SORBFNN, and the modeling error is uniformly ultimately bounded. Second, a fast gradient method (GM) is enhanced for the solution of optimal control problem. This proposed GM can reduce computational cost and suboptimize the RT-MPC online. Then, the conditions of the stability analysis and steady-state performance of the closed-loop systems are presented. Finally, numerical simulations reveal that the proposed control gives satisfactory tracking and disturbance rejection performances. Experimental results demonstrate its effectiveness. PMID- 24808580 TI - Memory models of adaptive behavior. AB - Adaptive response to varying environment is a common feature of biological organisms. Reproducing such features in electronic systems and circuits is of great importance for a variety of applications. We consider memory models inspired by an intriguing ability of slime molds to both memorize the period of temperature and humidity variations and anticipate the next variations to come, when appropriately trained. Effective circuit models of such behavior are designed using: 1) a set of LC contours with memristive damping and 2) a single memcapacitive system-based adaptive contour with memristive damping. We consider these two approaches in detail by comparing their results and predictions. Finally, possible biological experiments that would discriminate between the models are discussed. In this paper, we also introduce an effective description of certain memory circuit elements. PMID- 24808581 TI - Model of an excitatory synapse based on stochastic processes. AB - We present a mathematical model of a biological synapse based on stochastic processes to establish the temporal behavior of the postsynaptic potential following a quantal synaptic transmission. This potential form is the basis of the neural code. We suppose that the release of neurotransmitters in the synaptic cleft follows a Poisson process, and that they diffuse according to integrated Ornstein-Uhlenbeck processes in 3-D with random initial positions and velocities. The diffusion occurs in an isotropic environment between two infinite parallel planes representing the pre- and postsynaptic membrane. We state that the presynaptic membrane is perfectly reflecting and that the other is perfectly absorbing. The activation of the receptors polarizes the postsynaptic membrane according to a parallel RC circuit scheme. We present the results obtained by simulations according to a Gillespie algorithm and we show that our model exhibits realistic postsynaptic behaviors from a simple quantal occurrence. PMID- 24808582 TI - Combined convex technique on delay-dependent stability for delayed neural networks. AB - In this brief, by employing an improved Lyapunov-Krasovskii functional (LKF) and combining the reciprocal convex technique with the convex one, a new sufficient condition is derived to guarantee a class of delayed neural networks (DNNs) to be globally asymptotically stable. Since some previously ignored terms can be considered during the estimation of the derivative of LKF, a less conservative stability criterion is derived in the forms of linear matrix inequalities, whose solvability heavily depends on the information of addressed DNNs. Finally, we demonstrate by two numerical examples that our results reduce the conservatism more efficiently than some currently used methods. PMID- 24808583 TI - Low-temperature fabrication of spiking soma circuits using nanocrystalline silicon TFTs. AB - Spiking neuron circuits consisting of ambipolar nanocrystalline-silicon (nc-Si) thin-film transistors (TFTs) have been fabricated using low temperature processing conditions (maximum of 250 degrees C) that allow the use of flexible substrates. These circuits display behaviors commonly observed in biological neurons such as millisecond spike duration, nonlinear frequency-current relationship, and spike frequency adaptation. The maximum drive capacity of a simple soma circuit was estimated to be approximately 9200 synapses. The effect of bias stress-induced threshold voltage degradation of component nc-Si TFTs on the spike frequency of soma circuits is explored. The measured power consumption of the circuit when spiking at 100 Hz was approximately 12 nW. Finally, the power consumption of the soma circuits at different spiking conditions and its implications on a large-scale system are discussed. The fabricated circuits can be employed as part of a compact multilayer learning network. PMID- 24808584 TI - Effect of input noise and output node stochastic on Wang's kWTA. AB - Recently, an analog neural network model, namely Wang's kWTA, was proposed. In this model, the output nodes are defined as the Heaviside function. Subsequently, its finite time convergence property and the exact convergence time are analyzed. However, the discovered characteristics of this model are based on the assumption that there are no physical defects during the operation. In this brief, we analyze the convergence behavior of the Wang's kWTA model when defects exist during the operation. Two defect conditions are considered. The first one is that there is input noise. The second one is that there is stochastic behavior in the output nodes. The convergence of the Wang's kWTA under these two defects is analyzed and the corresponding energy function is revealed. PMID- 24808585 TI - Controllability and observability of Boolean control networks with time-variant delays in states. AB - This brief investigates the controllability and observability of Boolean control networks with (not necessarily bounded) time-variant delays in states. After a brief introduction to converting a Boolean control network to an equivalent discrete-time bilinear dynamical system via the semi-tensor product of matrices, the system is split into a finite number of subsystems (constructed forest) with no time delays by using the idea of splitting time that is proposed in this brief. Then, the controllability and observability of the system are investigated by verifying any so-called controllability constructed path and any so-called observability constructed paths in the above forest, respectively, which generalize some recent relevant results. Matrix test criteria for the controllability and observability are given. The corresponding control design algorithms based on the controllability theorems are given. We also show that the computing complexity of our algorithm is much less than that of the existing algorithms. PMID- 24808586 TI - Quantized kernel recursive least squares algorithm. AB - In a recent paper, we developed a novel quantized kernel least mean square algorithm, in which the input space is quantized (partitioned into smaller regions) and the network size is upper bounded by the quantization codebook size (number of the regions). In this paper, we propose the quantized kernel least squares regression, and derive the optimal solution. By incorporating a simple online vector quantization method, we derive a recursive algorithm to update the solution, namely the quantized kernel recursive least squares algorithm. The good performance of the new algorithm is demonstrated by Monte Carlo simulations. PMID- 24808587 TI - On the optimal class representation in linear discriminant analysis. AB - Linear discriminant analysis (LDA) is a widely used technique for supervised feature extraction and dimensionality reduction. LDA determines an optimal discriminant space for linear data projection based on certain assumptions, e.g., on using normal distributions for each class and employing class representation by the mean class vectors. However, there might be other vectors that can represent each class, to increase class discrimination. In this brief, we propose an optimization scheme aiming at the optimal class representation, in terms of Fisher ratio maximization, for LDA-based data projection. Compared with the standard LDA approach, the proposed optimization scheme increases class discrimination in the reduced dimensionality space and achieves higher classification rates in publicly available data sets. PMID- 24808588 TI - Linfinity analysis and state-feedback control of Hopfield networks. AB - A nonsymmetric version of Hopfield networks subject to bounded disturbances is considered. Such networks arise in the context of visuo-motor control loops and may, therefore, be used to mimic their complex behavior. In this brief, we adopt the Lur'e-Postnikov systems approach to analyze the induced Linfinity gain of generalized Hopfield networks. A state-feedback control is then designed to accomplish the Linfinity-type performance for Hopfield networks. The results are illustrated through numerical examples. PMID- 24808589 TI - Sequential blind identification of underdetermined mixtures using a novel deflation scheme. AB - In this brief, we consider the problem of blind identification in underdetermined instantaneous mixture cases, where there are more sources than sensors. A new blind identification algorithm, which estimates the mixing matrix in a sequential fashion, is proposed. By using the rank-1 detecting device, blind identification is reformulated as a constrained optimization problem. The identification of one column of the mixing matrix hence reduces to an optimization task for which an efficient iterative algorithm is proposed. The identification of the other columns of the mixing matrix is then carried out by a generalized eigenvalue decomposition-based deflation method. The key merit of the proposed deflation method is that it does not suffer from error accumulation. The proposed sequential blind identification algorithm provides more flexibility and better robustness than its simultaneous counterpart. Comparative simulation results demonstrate the superior performance of the proposed algorithm over the simultaneous blind identification algorithm. PMID- 24808590 TI - Adaptive optimal control of unknown constrained-input systems using policy iteration and neural networks. AB - This paper presents an online policy iteration (PI) algorithm to learn the continuous-time optimal control solution for unknown constrained-input systems. The proposed PI algorithm is implemented on an actor-critic structure where two neural networks (NNs) are tuned online and simultaneously to generate the optimal bounded control policy. The requirement of complete knowledge of the system dynamics is obviated by employing a novel NN identifier in conjunction with the actor and critic NNs. It is shown how the identifier weights estimation error affects the convergence of the critic NN. A novel learning rule is developed to guarantee that the identifier weights converge to small neighborhoods of their ideal values exponentially fast. To provide an easy-to-check persistence of excitation condition, the experience replay technique is used. That is, recorded past experiences are used simultaneously with current data for the adaptation of the identifier weights. Stability of the whole system consisting of the actor, critic, system state, and system identifier is guaranteed while all three networks undergo adaptation. Convergence to a near-optimal control law is also shown. The effectiveness of the proposed method is illustrated with a simulation example. PMID- 24808591 TI - Lattice computing extension of the FAM neural classifier for human facial expression recognition. AB - This paper proposes a fundamentally novel extension, namely, flrFAM, of the fuzzy ARTMAP (FAM) neural classifier for incremental real-time learning and generalization based on fuzzy lattice reasoning techniques. FAM is enhanced first by a parameter optimization training (sub)phase, and then by a capacity to process partially ordered (non)numeric data including information granules. The interest here focuses on intervals' numbers (INs) data, where an IN represents a distribution of data samples. We describe the proposed flrFAM classifier as a fuzzy neural network that can induce descriptive as well as flexible (i.e., tunable) decision-making knowledge (rules) from the data. We demonstrate the capacity of the flrFAM classifier for human facial expression recognition on benchmark datasets. The novel feature extraction as well as knowledge representation is based on orthogonal moments. The reported experimental results compare well with the results by alternative classifiers from the literature. The far-reaching potential of fuzzy lattice reasoning in human-machine interaction applications is discussed. PMID- 24808592 TI - Rapid feedforward computation by temporal encoding and learning with spiking neurons. AB - Primates perform remarkably well in cognitive tasks such as pattern recognition. Motivated by recent findings in biological systems, a unified and consistent feedforward system network with a proper encoding scheme and supervised temporal rules is built for solving the pattern recognition task. The temporal rules used for processing precise spiking patterns have recently emerged as ways of emulating the brain's computation from its anatomy and physiology. Most of these rules could be used for recognizing different spatiotemporal patterns. However, there arises the question of whether these temporal rules could be used to recognize real-world stimuli such as images. Furthermore, how the information is represented in the brain still remains unclear. To tackle these problems, a proper encoding method and a unified computational model with consistent and efficient learning rule are proposed. Through encoding, external stimuli are converted into sparse representations, which also have properties of invariance. These temporal patterns are then learned through biologically derived algorithms in the learning layer, followed by the final decision presented through the readout layer. The performance of the model with images of digits from the MNIST database is presented. The results show that the proposed model is capable of recognizing images correctly with a performance comparable to that of current benchmark algorithms. The results also suggest a plausibility proof for a class of feedforward models of rapid and robust recognition in the brain. PMID- 24808593 TI - Mean vector component analysis for visualization and clustering of nonnegative data. AB - Mean vector component analysis (MVCA) is introduced as a new method for visualization and clustering of nonnegative data. The method is based on dimensionality reduction by preserving the squared length, and implicitly also the direction, of the mean vector of the original data. The optimal mean vector preserving basis is obtained from the spectral decomposition of the inner-product matrix, and it is shown to capture clustering structure. MVCA corresponds to certain uncentered principal component analysis (PCA) axes. Unlike traditional PCA, these axes are in general not corresponding to the top eigenvalues. MVCA is shown to produce different visualizations and sometimes considerably improved clustering results for nonnegative data, compared with PCA. PMID- 24808594 TI - RBF-based technique for statistical demodulation of pathological tremor. AB - This paper presents an innovative technique based on the joint approximation capabilities of radial basis function (RBF) networks and the estimation capability of the multivariate iterated Hilbert transform (IHT) for the statistical demodulation of pathological tremor from electromyography (EMG) signals in patients with Parkinson's disease. We define a stochastic model of the multichannel high-density surface EMG by means of the RBF networks applied to the reconstruction of the stochastic process (characterizing the disease) modeled by the multivariate relationships generated by the Karhunen-Loeve transform in Hilbert spaces. Next, we perform a demodulation of the entire random field by means of the estimation capability of the multivariate IHT in a statistical setting. The proposed method is applied to both simulated signals and data recorded from three Parkinsonian patients and the results show that the amplitude modulation components of the tremor oscillation can be estimated with signal-to noise ratio close to 30 dB with root-mean-square error for the estimates of the tremor instantaneous frequency. Additionally, the comparisons with a large number of techniques based on all the combinations of the RBF, extreme learning machine, backpropagation, support vector machine used in the first step of the algorithm; and IHT, empirical mode decomposition, multiband energy separation algorithm, periodic algebraic separation and energy demodulation used in the second step of the algorithm, clearly show the effectiveness of our technique. These results show that the proposed approach is a potential useful tool for advanced neurorehabilitation technologies that aim at tremor characterization and suppression. PMID- 24808595 TI - Automated induction of heterogeneous proximity measures for supervised spectral embedding. AB - Spectral embedding methods have played a very important role in dimensionality reduction and feature generation in machine learning. Supervised spectral embedding methods additionally improve the classification of labeled data, using proximity information that considers both features and class labels. However, these calculate the proximity information by treating all intraclass similarities homogeneously for all classes, and similarly for all interclass samples. In this paper, we propose a very novel and generic method which can treat all the intra- and interclass sample similarities heterogeneously by potentially using a different proximity function for each class and each class pair. To handle the complexity of selecting these functions, we employ evolutionary programming as an automated powerful formula induction engine. In addition, for computational efficiency and expressive power, we use a compact matrix tree representation equipped with a broad set of functions that can build most currently used similarity functions as well as new ones. Model selection is data driven, because the entire model is symbolically instantiated using only problem training data, and no user-selected functions or parameters are required. We perform thorough comparative experimentations with multiple classification datasets and many existing state-of-the-art embedding methods, which show that the proposed algorithm is very competitive in terms of classification accuracy and generalization ability. PMID- 24808596 TI - Coordination of multiagents interacting under independent position and velocity topologies. AB - We consider the coordination control for multiagent systems in a very general framework where the position and velocity interactions among agents are modeled by independent graphs. Different algorithms are proposed and analyzed for different settings, including the case without leaders and the case with a virtual leader under fixed position and velocity interaction topologies, as well as the case with a group velocity reference signal under switching velocity interaction. It is finally shown that the proposed algorithms are feasible in achieving the desired coordination behavior provided the interaction topologies satisfy the weakest possible connectivity conditions. Such conditions relate only to the structure of the interactions among agents while irrelevant to their magnitudes and thus are easy to verify. Rigorous convergence analysis is preformed based on a combined use of tools from algebraic graph theory, matrix analysis as well as the Lyapunov stability theory. PMID- 24808597 TI - Learning capability of relaxed greedy algorithms. AB - In the practice of machine learning, one often encounters problems in which noisy data are abundant while the learning targets are imprecise and elusive. To these challenges, most of the traditional learning algorithms employ hypothesis spaces of large capacity. This has inevitably led to high computational burdens and caused considerable machine sluggishness. Utilizing greedy algorithms in this kind of learning environment has greatly improved machine performance. The best existing learning rate of various greedy algorithms is proved to achieve the order of (m/log m)(-1/2), where m is the sample size. In this paper, we provide a relaxed greedy algorithm and study its learning capability. We prove that the learning rate of the new relaxed greedy algorithm is faster than the order m( 1/2). Unlike many other greedy algorithms, which are often indecisive issuing a stopping order to the iteration process, our algorithm has a clearly established stopping criteria. PMID- 24808598 TI - Minimax sparse logistic regression for very high-dimensional feature selection. AB - Because of the strong convexity and probabilistic underpinnings, logistic regression (LR) is widely used in many real-world applications. However, in many problems, such as bioinformatics, choosing a small subset of features with the most discriminative power are desirable for interpreting the prediction model, robust predictions or deeper analysis. To achieve a sparse solution with respect to input features, many sparse LR models are proposed. However, it is still challenging for them to efficiently obtain unbiased sparse solutions to very high dimensional problems (e.g., identifying the most discriminative subset from millions of features). In this paper, we propose a new minimax sparse LR model for very high-dimensional feature selections, which can be efficiently solved by a cutting plane algorithm. To solve the resultant nonsmooth minimax subproblems, a smoothing coordinate descent method is presented. Numerical issues and convergence rate of this method are carefully studied. Experimental results on several synthetic and real-world datasets show that the proposed method can obtain better prediction accuracy with the same number of selected features and has better or competitive scalability on very high-dimensional problems compared with the baseline methods, including the l1-regularized LR. PMID- 24808599 TI - Ensemble learning in fixed expansion layer networks for mitigating catastrophic forgetting. AB - Catastrophic forgetting is a well-studied attribute of most parameterized supervised learning systems. A variation of this phenomenon, in the context of feedforward neural networks, arises when nonstationary inputs lead to loss of previously learned mappings. The majority of the schemes proposed in the literature for mitigating catastrophic forgetting were not data driven and did not scale well. We introduce the fixed expansion layer (FEL) feedforward neural network, which embeds a sparsely encoding hidden layer to help mitigate forgetting of prior learned representations. In addition, we investigate a novel framework for training ensembles of FEL networks, based on exploiting an information-theoretic measure of diversity between FEL learners, to further control undesired plasticity. The proposed methodology is demonstrated on a basic classification task, clearly emphasizing its advantages over existing techniques. The architecture proposed can be enhanced to address a range of computational intelligence tasks, such as regression problems and system control. PMID- 24808600 TI - SVR learning-based spatiotemporal fuzzy logic controller for nonlinear spatially distributed dynamic systems. AB - A data-driven 3-D fuzzy-logic controller (3-D FLC) design methodology based on support vector regression (SVR) learning is developed for nonlinear spatially distributed dynamic systems. Initially, the spatial information expression and processing as well as the fuzzy linguistic expression and rule inference of a 3-D FLC are integrated into spatial fuzzy basis functions (SFBFs), and then the 3-D FLC can be depicted by a three-layer network structure. By relating SFBFs of the 3-D FLC directly to spatial kernel functions of an SVR, an equivalence relationship of the 3-D FLC and the SVR is established, which means that the 3-D FLC can be designed with the help of the SVR learning. Subsequently, for an easy implementation, a systematic SVR learning-based 3-D FLC design scheme is formulated. In addition, the universal approximation capability of the proposed 3 D FLC is presented. Finally, the control of a nonlinear catalytic packed-bed reactor is considered as an application to demonstrate the effectiveness of the proposed 3-D FLC. PMID- 24808601 TI - Single image super-resolution with multiscale similarity learning. AB - Example learning-based image super-resolution (SR) is recognized as an effective way to produce a high-resolution (HR) image with the help of an external training set. The effectiveness of learning-based SR methods, however, depends highly upon the consistency between the supporting training set and low-resolution (LR) images to be handled. To reduce the adverse effect brought by incompatible high frequency details in the training set, we propose a single image SR approach by learning multiscale self-similarities from an LR image itself. The proposed SR approach is based upon an observation that small patches in natural images tend to redundantly repeat themselves many times both within the same scale and across different scales. To synthesize the missing details, we establish the HR-LR patch pairs using the initial LR input and its down-sampled version to capture the similarities across different scales and utilize the neighbor embedding algorithm to estimate the relationship between the LR and HR image pairs. To fully exploit the similarities across various scales inside the input LR image, we accumulate the previous resultant images as training examples for the subsequent reconstruction processes and adopt a gradual magnification scheme to upscale the LR input to the desired size step by step. In addition, to preserve sharper edges and suppress aliasing artifacts, we further apply the nonlocal means method to learn the similarity within the same scale and formulate a nonlocal prior regularization term to well pose SR estimation under a reconstruction-based SR framework. Experimental results demonstrate that the proposed method can produce compelling SR recovery both quantitatively and perceptually in comparison with other state-of-the-art baselines. PMID- 24808602 TI - Tracking algorithms for multiagent systems. AB - This paper is devoted to the consensus tracking issue on multiagent systems. Instead of enabling the networked agents to reach an agreement asymptotically as the time tends to infinity, the consensus tracking between agents is considered to be derived on a finite time interval as accurately as possible. We thus propose a learning algorithm with a gain operator to be determined. If the gain operator is designed in the form of a polynomial expression, a necessary and sufficient condition is obtained for the networked agents to accomplish the consensus tracking objective, regardless of the relative degree of the system model of agents. Moreover, the Hinfinity analysis approach is introduced to help establish conditions in terms of linear matrix inequalities (LMIs) such that the resulting processes of the presented learning algorithm can be guaranteed to monotonically converge in an iterative manner. The established LMI conditions can also enable the iterative learning processes to converge with an exponentially fast speed. In addition, we extend the learning algorithm to address the relative formation problem for multiagent systems. Numerical simulations are performed to demonstrate the effectiveness of learning algorithms in achieving both consensus tracking and relative formation objectives for the networked agents. PMID- 24808603 TI - A robust elicitation algorithm for discovering DNA motifs using fuzzy self organizing maps. AB - It is important to identify DNA motifs in promoter regions to understand the mechanism of gene regulation. Computational approaches for finding DNA motifs are well recognized as useful tools to biologists, which greatly help in saving experimental time and cost in wet laboratories. Self-organizing maps (SOMs), as a powerful clustering tool, have demonstrated good potential for problem solving. However, the current SOM-based motif discovery algorithms unfairly treat data samples lying around the cluster boundaries by assigning them to one of the nodes, which may result in unreliable system performance. This paper aims to develop a robust framework for discovering DNA motifs, where fuzzy SOMs, with an integration of fuzzy c-means membership functions and a standard batch-learning scheme, are employed to extract putative motifs with varying length in a recursive manner. Experimental results on eight real datasets show that our proposed algorithm outperforms the other searching tools such as SOMBRERO, SOMEA, MEME, AlignACE, and WEEDER in terms of the F-measure and algorithm reliability. It is observed that a remarkable 24.6% improvement can be achieved compared to the state-of-the-art SOMBRERO. Furthermore, our algorithm can produce a 20% and 6.6% improvement over SOMBRERO and SOMEA, respectively, in finding multiple motifs on five artificial datasets. PMID- 24808604 TI - EEG-based learning system for online motion sickness level estimation in a dynamic vehicle environment. AB - Motion sickness is a common experience for many people. Several previous researches indicated that motion sickness has a negative effect on driving performance and sometimes leads to serious traffic accidents because of a decline in a person's ability to maintain self-control. This safety issue has motivated us to find a way to prevent vehicle accidents. Our target was to determine a set of valid motion sickness indicators that would predict the occurrence of a person's motion sickness as soon as possible. A successful method for the early detection of motion sickness will help us to construct a cognitive monitoring system. Such a monitoring system can alert people before they become sick and prevent them from being distracted by various motion sickness symptoms while driving or riding in a car. In our past researches, we investigated the physiological changes that occur during the transition of a passenger's cognitive state using electroencephalography (EEG) power spectrum analysis, and we found that the EEG power responses in the left and right motors, parietal, lateral occipital, and occipital midline brain areas were more highly correlated to subjective sickness levels than other brain areas. In this paper, we propose the use of a self-organizing neural fuzzy inference network (SONFIN) to estimate a driver's/passenger's sickness level based on EEG features that have been extracted online from five motion sickness-related brain areas, while either in real or virtual vehicle environments. The results show that our proposed learning system is capable of extracting a set of valid motion sickness indicators that originated from EEG dynamics, and through SONFIN, a neuro-fuzzy prediction model, we successfully translated the set of motion sickness indicators into motion sickness levels. The overall performance of this proposed EEG-based learning system can achieve an average prediction accuracy of ~82%. PMID- 24808605 TI - New algebraic criteria for synchronization stability of chaotic memristive neural networks with time-varying delays. AB - In this brief, we consider the exponential synchronization of chaotic memristive neural networks with time-varying delays using the Lyapunov functional method and inequality technique. The dynamic analysis here employs the theory of differential equations with discontinuous right-hand side as introduced by Filippov. The designing laws in the synchronization of neural networks are proposed via state or output coupling. In addition, the new proposed algebraic criteria are very easy to verify, and they also enrich and improve the earlier publications. Finally, an example is given to show the effectiveness of the obtained results. PMID- 24808606 TI - Error surface of recurrent neural networks. AB - We found in previous work that the error surfaces of recurrent networks have spurious valleys that can cause significant difficulties in training these networks. Our earlier work focused on single-layer networks. In this paper, we extend the previous results to general layered digital dynamic networks. We describe two types of spurious valleys that appear in the error surfaces of these networks. These valleys are not affected by the desired network output (or by the problem that the network is trying to solve). They depend only on the input sequence and the architecture of the network. The insights gained from this analysis suggest procedures for improving the training of recurrent neural networks. PMID- 24808607 TI - Single-channel blind separation using pseudo-stereo mixture and complex 2-D histogram. AB - A novel single-channel blind source separation (SCBSS) algorithm is presented. The proposed algorithm yields at least three benefits of the SCBSS solution: 1) resemblance of a stereo signal concept given by one microphone; 2) independent of initialization and a priori knowledge of the sources; and 3) it does not require iterative optimization. The separation process consists of two steps: 1) estimation of source characteristics, where the source signals are modeled by the autoregressive process and 2) construction of masks using only the single-channel mixture. A new pseudo-stereo mixture is formulated by weighting and time-shifting the original single-channel mixture. This creates an artificial mixing system whose parameters will be estimated through our proposed weighted complex 2-D histogram. In this paper, we derive the separability of the proposed mixture model. Conditions required for unique mask construction based on maximum likelihood are also identified. Finally, experimental testing on both synthetic and real-audio sources is conducted to verify that the proposed algorithm yields superior performance and is computationally very fast compared with existing methods. PMID- 24808608 TI - On the SVMpath singularity. AB - This paper proposes a novel ridge-adding-based approach for handling singularities that are frequently encountered in the powerful SVMpath algorithm. Unlike the existing method that performs linear programming as an additional step to track the optimality condition path in a multidimensional feasible space, our new approach provides a simpler and computationally more efficient implementation, which needs no extra time-consuming procedures other than introducing a random ridge term to each data point. Contrary to the existing ridge-adding method, which fails to avoid singularities as the ridge terms tend to zero, our novel approach, for any small random ridge terms, guarantees the existence of the inverse matrix by ensuring that only one index is added into or removed from the active set. The performance of the proposed algorithm, in terms of both computational complexity and the ability of singularity avoidance, is manifested by rigorous mathematical analyses as well as experimental results. PMID- 24808609 TI - Multistability of two kinds of recurrent neural networks with activation functions symmetrical about the origin on the phase plane. AB - In this paper, we investigate multistability of two kinds of recurrent neural networks with time-varying delays and activation functions symmetrical about the origin on the phase plane. One kind of activation function is with zero slope at the origin on the phase plane, while the other is with nonzero slope at the origin on the phase plane. We derive sufficient conditions under which these two kinds of n-dimensional recurrent neural networks are guaranteed to have (2m+1)(n) equilibrium points, with (m+1)(n) of them being locally exponentially stable. These new conditions improve and extend the existing multistability results for recurrent neural networks. Finally, the validity and performance of the theoretical results are demonstrated through two numerical examples. PMID- 24808610 TI - Safety-aware semi-supervised classification. AB - Though semi-supervised classification learning has attracted great attention over past decades, semi-supervised classification methods may show worse performance than their supervised counterparts in some cases, consequently reducing their confidence in real applications. Naturally, it is desired to develop a safe semi supervised classification method that never performs worse than the supervised counterparts. However, to the best of our knowledge, few researches have been devoted to safe semi-supervised classification. To address this problem, in this paper, we invent a safety-control mechanism for safe semi-supervised classification by adaptive tradeoff between semi-supervised and supervised classification in terms of unlabeled data. In implementation, based on our recent semi-supervised classification method based on class memberships (SSCCM), we develop a safety-aware SSCCM (SA-SSCCM). SA-SSCCM, on the one hand, exploits the unlabeled data to help learning (as SSCCM does) under the assumption that unlabeled data can help learning, and on the other hand, restricts its prediction to approach that of its supervised counterpart least-square support vector machine (LS-SVM) under the assumption that unlabeled data can hurt learning. Therefore, prediction by SA-SSCCM becomes a tradeoff between those by semi supervised SSCCM and supervised LS-SVM, respectively, in terms of the unlabeled data. As in SSCCM, the optimization problem in SA-SSCCM can be efficiently solved by the alternating iterative strategy, and the iteration convergence can theoretically be guaranteed. Experiments over several real datasets show the promising performance of SA-SSCCM compared with LS-SVM, SSCCM, and off-the-shelf safe semi-supervised classification methods. PMID- 24808611 TI - Neural network approaches for noisy language modeling. AB - Text entry from people is not only grammatical and distinct, but also noisy. For example, a user's typing stream contains all the information about the user's interaction with computer using a QWERTY keyboard, which may include the user's typing mistakes as well as specific vocabulary, typing habit, and typing performance. In particular, these features are obvious in disabled users' typing streams. This paper proposes a new concept called noisy language modeling by further developing information theory and applies neural networks to one of its specific application-typing stream. This paper experimentally uses a neural network approach to analyze the disabled users' typing streams both in general and specific ways to identify their typing behaviors and subsequently, to make typing predictions and typing corrections. In this paper, a focused time-delay neural network (FTDNN) language model, a time gap model, a prediction model based on time gap, and a probabilistic neural network model (PNN) are developed. A 38% first hitting rate (HR) and a 53% first three HR in symbol prediction are obtained based on the analysis of a user's typing history through the FTDNN language modeling, while the modeling results using the time gap prediction model and the PNN model demonstrate that the correction rates lie predominantly in between 65% and 90% with the current testing samples, and 70% of all test scores above basic correction rates, respectively. The modeling process demonstrates that a neural network is a suitable and robust language modeling tool to analyze the noisy language stream. The research also paves the way for practical application development in areas such as informational analysis, text prediction, and error correction by providing a theoretical basis of neural network approaches for noisy language modeling. PMID- 24808612 TI - A new discrete-continuous algorithm for radial basis function networks construction. AB - The construction of a radial basis function (RBF) network involves the determination of the model size, hidden nodes, and output weights. Least squares based subset selection methods can determine a RBF model size and its parameters simultaneously. Although these methods are robust, they may not achieve optimal results. Alternatively, gradient methods are widely used to optimize all the parameters. The drawback is that most algorithms may converge slowly as they treat hidden nodes and output weights separately and ignore their correlations. In this paper, a new discrete-continuous algorithm is proposed for the construction of a RBF model. First, the orthogonal least squares (OLS)-based forward stepwise selection constructs an initial model by selecting model terms one by one from a candidate term pool. Then a new Levenberg-Marquardt (LM)-based parameter optimization is proposed to further optimize the hidden nodes and output weights in the continuous space. To speed up the convergence, the proposed parameter optimization method considers the correlation between the hidden nodes and output weights, which is achieved by translating the output weights to dependent parameters using the OLS method. The correlation is also used by the previously proposed continuous forward algorithm (CFA). However, unlike the CFA, the new method optimizes all the parameters simultaneously. In addition, an equivalent recursive sum of squared error is derived to reduce the computation demanding for the first derivatives used in the LM method. Computational complexity is given to confirm the new method is much more computationally efficient than the CFA. Different numerical examples are presented to illustrate the effectiveness of the proposed method. Further, Friedman statistical tests on 13 classification problems are performed, and the results demonstrate that RBF networks built by the new method are very competitive in comparison with some popular classifiers. PMID- 24808613 TI - Finding potential support vectors in separable classification problems. AB - This paper considers the classification problem using support vector (SV) machines and investigates how to maximally reduce the size of the training set without losing information. Under separable data set assumptions, we derive the exact conditions stating which observations can be discarded without diminishing the overall information content. For this purpose, we introduce the concept of potential SVs, i.e., those data that can become SVs when future data become available. To complement this, we also characterize the set of discardable vectors (DVs), i.e., those data that, given the current data set, can never become SVs. Thus, these vectors are useless for future training purposes and can eventually be removed without loss of information. Then, we provide an efficient algorithm based on linear programming that returns the potential and DVs by constructing a simplex tableau. Finally, we compare it with alternative algorithms available in the literature on some synthetic data as well as on data sets from standard repositories. PMID- 24808614 TI - Nonlinear systems identification and control via dynamic multitime scales neural networks. AB - This paper deals with the adaptive nonlinear identification and trajectory tracking via dynamic multilayer neural network (NN) with different timescales. Two NN identifiers are proposed for nonlinear systems identification via dynamic NNs with different timescales including both fast and slow phenomenon. The first NN identifier uses the output signals from the actual system for the system identification. In the second NN identifier, all the output signals from nonlinear system are replaced with the state variables of the NNs. The online identification algorithms for both NN identifier parameters are proposed using Lyapunov function and singularly perturbed techniques. With the identified NN models, two indirect adaptive NN controllers for the nonlinear systems containing slow and fast dynamic processes are developed. For both developed adaptive NN controllers, the trajectory errors are analyzed and the stability of the systems is proved. Simulation results show that the controller based on the second identifier has better performance than that of the first identifier. PMID- 24808615 TI - Hierarchical similarity transformations between Gaussian mixtures. AB - In this paper, we propose a method to estimate the density of a data space represented by a geometric transformation of an initial Gaussian mixture model. The geometric transformation is hierarchical, and it is decomposed into two steps. At first, the initial model is assumed to undergo a global similarity transformation modeled by translation, rotation, and scaling of the model components. Then, to increase the degrees of freedom of the model and allow it to capture fine data structures, each individual mixture component may be transformed by another, local similarity transformation, whose parameters are distinct for each component of the mixture. In addition, to constrain the order of magnitude of the local transformation (LT) with respect to the global transformation (GT), zero-mean Gaussian priors are imposed onto the local parameters. The estimation of both GT and LT parameters is obtained through the expectation maximization framework. Experiments on artificial data are conducted to evaluate the proposed model, with varying data dimensionality, number of model components, and transformation parameters. In addition, the method is evaluated using real data from a speech recognition task. The obtained results show a high model accuracy and demonstrate the potential application of the proposed method to similar classification problems. PMID- 24808616 TI - Negative correlation ensemble learning for ordinal regression. AB - In this paper, two neural network threshold ensemble models are proposed for ordinal regression problems. For the first ensemble method, the thresholds are fixed a priori and are not modified during training. The second one considers the thresholds of each member of the ensemble as free parameters, allowing their modification during the training process. This is achieved through a reformulation of these tunable thresholds, which avoids the constraints they must fulfill for the ordinal regression problem. During training, diversity exists in different projections generated by each member is taken into account for the parameter updating. This diversity is promoted in an explicit way using a diversity-encouraging error function, extending the well-known negative correlation learning framework to the area of ordinal regression, and inheriting many of its good properties. Experimental results demonstrate that the proposed algorithms can achieve competitive generalization performance when considering four ordinal regression metrics. PMID- 24808617 TI - Online learning of a Dirichlet process mixture of Beta-Liouville distributions via variational inference. AB - A large class of problems can be formulated in terms of the clustering process. Mixture models are an increasingly important tool in statistical pattern recognition and for analyzing and clustering complex data. Two challenging aspects that should be addressed when considering mixture models are how to choose between a set of plausible models and how to estimate the model's parameters. In this paper, we address both problems simultaneously within a unified online nonparametric Bayesian framework that we develop to learn a Dirichlet process mixture of Beta-Liouville distributions (i.e., an infinite Beta Liouville mixture model). The proposed infinite model is used for the online modeling and clustering of proportional data for which the Beta-Liouville mixture has been shown to be effective. We propose a principled approach for approximating the intractable model's posterior distribution by a tractable one which we develop-such that all the involved mixture's parameters can be estimated simultaneously and effectively in a closed form. This is done through variational inference that enjoys important advantages, such as handling of unobserved attributes and preventing under or overfitting; we explain that in detail. The effectiveness of the proposed work is evaluated on three challenging real applications, namely facial expression recognition, behavior modeling and recognition, and dynamic textures clustering. PMID- 24808618 TI - Transfer ordinal label learning. AB - Designing a classifier in the absence of labeled data is becoming a common encounter as the acquisition of informative labels is often difficult or expensive, particularly on new uncharted target domains. The feasibility of attaining a reliable classifier for the task of interest is embarked by some in transfer learning, where label information from relevant source domains is considered for complimenting the design process. The core challenge arising from such endeavors, however, is the induction of source sample selection bias, such that the trained classifier has the tendency of steering toward the distribution of the source domain. In addition, this bias is deemed to become more severe on data involving multiple classes. Considering this cue, our interest in this paper is to address such a challenge in the target domain, where ordinal labeled data are unavailable. In contrast to the previous works, we propose a transfer ordinal label learning paradigm to predict the ordinal labels of target unlabeled data by spanning the feasible solution space with ensemble of ordinal classifiers from the multiple relevant source domains. Specifically, the maximum margin criterion is considered here for the construction of the target classifier from an ensemble of source ordinal classifiers. Theoretical analysis and extensive empirical studies on real-world data sets are presented to study the benefits of the proposed method. PMID- 24808619 TI - Pseudo-orthogonalization of memory patterns for associative memory. AB - A new method for improving the storage capacity of associative memory models on a neural network is proposed. The storage capacity of the network increases in proportion to the network size in the case of random patterns, but, in general, the capacity suffers from correlation among memory patterns. Numerous solutions to this problem have been proposed so far, but their high computational cost limits their scalability. In this paper, we propose a novel and simple solution that is locally computable without any iteration. Our method involves XNOR masking of the original memory patterns with random patterns, and the masked patterns and masks are concatenated. The resulting decorrelated patterns allow higher storage capacity at the cost of the pattern length. Furthermore, the increase in the pattern length can be reduced through blockwise masking, which results in a small amount of capacity loss. Movie replay and image recognition are presented as examples to demonstrate the scalability of the proposed method. PMID- 24808620 TI - Multilabel classification using error-correcting codes of hard or soft bits. AB - We formulate a framework for applying error-correcting codes (ECCs) on multilabel classification problems. The framework treats some base learners as noisy channels and uses ECC to correct the prediction errors made by the learners. The framework immediately leads to a novel ECC-based explanation of the popular random k-label sets (RAKEL) algorithm using a simple repetition ECC. With the framework, we empirically compare a broad spectrum of off-the-shelf ECC designs for multilabel classification. The results not only demonstrate that RAKEL can be improved by applying some stronger ECC, but also show that the traditional binary relevance approach can be enhanced by learning more parity-checking labels. Our research on different ECCs also helps to understand the tradeoff between the strength of ECC and the hardness of the base learning tasks. Furthermore, we extend our research to ECC with either hard (binary) or soft (real-valued) bits by designing a novel decoder. We demonstrate that the decoder improves the performance of our framework. PMID- 24808621 TI - Multiclass support vector machines with example-dependent costs applied to plankton biomass estimation. AB - In many applications, the mistakes made by an automatic classifier are not equal, they have different costs. These problems may be solved using a cost-sensitive learning approach. The main idea is not to minimize the number of errors, but the total cost produced by such mistakes. This brief presents a new multiclass cost sensitive algorithm, in which each example has attached its corresponding misclassification cost. Our proposal is theoretically well-founded and is designed to optimize cost-sensitive loss functions. This research was motivated by a real-world problem, the biomass estimation of several plankton taxonomic groups. In this particular application, our method improves the performance of traditional multiclass classification approaches that optimize the accuracy. PMID- 24808623 TI - Endogenous Group Formation via Unproductive Costs. AB - Sacrifice is widely believed to enhance cooperation in churches, communes, gangs, clans, military units, and many other groups. We find that sacrifice can also work in the lab, apart from special ideologies, identities, or interactions. Our subjects play a modified VCM game-one in which they can voluntarily join groups that provide reduced rates of return on private investment. This leads to both endogenous sorting (because free-riders tend to reject the reduced-rate option) and substitution (because reduced private productivity favours increased club involvement). Seemingly unproductive costs thus serve to screen out free-riders, attract conditional cooperators, boost club production, and increase member welfare. The sacrifice mechanism is simple and particularly useful where monitoring difficulties impede punishment, exclusion, fees, and other more standard solutions. PMID- 24808624 TI - The Migration and Development Prism: A Lens on Vulnerabilities and Capabilities. AB - The inexorable link between migration and development is paradoxically both taken for granted and a challenging puzzle. Describing interdependent dynamic processes, the study of both offers opportunities to theorize and observe social change. The body of knowledge that has come to include studies of both migration and development has enriched the individual fields of migration and development. In the development field, concerned with the processes that underlie economic growth or contribute to improved livelihoods, adding a migration focus has broadened observations about development to include those about vulnerability and security, for example. A migration lens on the development process also reveals the presence of social networks and the selectivity of behaviors and events. In both cases, such observations have enriched our understanding of development processes. The same epistemological process is at work when migration scholars consider development in relation to migration. A development lens means attention to the institutions that regulate the production of goods and services and the related distributional processes. The migration of populations and experiences of migrants elucidate both the potentialities and vulnerabilities that accompany development and globalization, while simultaneously introducing a new conceptualization of class. PMID- 24808625 TI - NEW MDS AND CLUSTERING BASED ALGORITHMS FOR PROTEIN MODEL QUALITY ASSESSMENT AND SELECTION. AB - In protein tertiary structure prediction, assessing the quality of predicted models is an essential task. Over the past years, many methods have been proposed for the protein model quality assessment (QA) and selection problem. Despite significant advances, the discerning power of current methods is still unsatisfactory. In this paper, we propose two new algorithms, CC-Select and MDS QA, based on multidimensional scaling and k-means clustering. For the model selection problem, CC-Select combines consensus with clustering techniques to select the best models from a given pool. Given a set of predicted models, CC Select first calculates a consensus score for each structure based on its average pairwise structural similarity to other models. Then, similar structures are grouped into clusters using multidimensional scaling and clustering algorithms. In each cluster, the one with the highest consensus score is selected as a candidate model. For the QA problem, MDS-QA combines single-model scoring functions with consensus to determine more accurate assessment score for every model in a given pool. Using extensive benchmark sets of a large collection of predicted models, we compare the two algorithms with existing state-of-the-art quality assessment methods and show significant improvement. PMID- 24808627 TI - FORMAL SYNTHESIS OF HAPALINDOLE O AND SYNTHETIC EFFORTS TOWARDS HAPALINDOLE K AND AMBIGUINE A. AB - The formal synthesis of D,L-hapalindole O has been accomplished intercepting Natsume's total synthesis route. The intercepted substrate was synthesized in an overall 36% yield over ten-synthetic steps compared to Natsume's overall 1% yield over eighteen-synthetic steps. In addition, advanced substrates for the continuing progress towards hapalindole K and ambiguine A has been synthesized. All routes described herein employ a novel silyl ether-based strategy accessing the 6:5:6:6 ring system, that has previously been used in our laboratory to access the total synthesis of D,L-hapalindoles J and U. PMID- 24808626 TI - Serum YKL-40 levels and chitotriosidase activity in patients with beta thalassemia major. AB - BACKGROUND: YKL-40 association with human disease has been the object of many years of investigation. beta-thalassemia patients are affected by hepatic siderosis, which determines a fibrotic process and tissue remodelling. Chitotriosidase has been found to be increased in thalassemic patients returning to normal in patients submitted to bone marrow transplantation. YKL-40 is associated with macrophage activation in liver and in other tissues. The aim of the study was to analyse the level of serum YKL-40 and plasma chitotriosidase activity of patients with beta-thalassemia to assess whether their expression correlates with liver disease and degree of liver siderosis. METHODS: Expression of YKL-40 and chitotriosidase as a marker of inflammation in 69 thalassemic patients were evaluated. We sought to investigate whether these two chitinases could be considered as a significant biomarker to evaluate therapy effectiveness. RESULTS: Surprisingly we found normal value of YKL-40. We, also, analysed chitotriosidase activity in the same patients that was slightly increased as a consequence of macrophage activation. CONCLUSIONS: These data would suggest a good treatment for these patients. PMID- 24808628 TI - Motion Artifact Reduction in Ultrasound Based Thermal Strain Imaging of Atherosclerotic Plaques Using Time Series Analysis. AB - Large lipid pools in vulnerable plaques, in principle, can be detected using US based thermal strain imaging (US-TSI). One practical challenge for in vivo cardiovascular application of US-TSI is that the thermal strain is masked by the mechanical strain caused by cardiac pulsation. ECG gating is a widely adopted method for cardiac motion compensation, but it is often susceptible to electrical and physiological noise. In this paper, we present an alternative time series analysis approach to separate thermal strain from the mechanical strain without using ECG. The performance and feasibility of the time-series analysis technique was tested via numerical simulation as well as in vitro water tank experiments using a vessel mimicking phantom and an excised human atherosclerotic artery where the cardiac pulsation is simulated by a pulsatile pump. PMID- 24808629 TI - Rotation of Electromagnetic Fields and the Nature of Optical Angular Momentum. AB - The association of spin and orbital angular momenta of light with its polarization and helical phase fronts is now well established. The problems in linking this with electromagnetic theory, as expressed in Maxwell's equations, are rather less well known. We present a simple analysis of the problems involved in defining spin and orbital angular momenta for electromagnetic fields and discuss some of the remaining challenges. Crucial to our investigation is the duplex symmetry between the electric and magnetic fields. PMID- 24808630 TI - Modeling the dissemination and uptake of clinical trials results. AB - A select set of highly cited publications from the National Institutes of Health (NIH) HIV/AIDS Clinical Trials Networks was used to illustrate the integration of time interval and citation data, modeling the progression, dissemination, and uptake of primary research findings. Following a process marker approach, the pace of initial utilization of this research was measured as the time from trial conceptualization, development and implementation, through results dissemination and uptake. Compared to earlier studies of clinical research, findings suggest that select HIV/AIDS trial results are disseminated and utilized relatively rapidly. Time-based modeling of publication results as they meet specific citation milestones enabled the observation of points at which study results were present in the literature summarizing the evidence in the field. Evaluating the pace of clinical research, results dissemination, and knowledge uptake in synthesized literature can help establish realistic expectations for the time course of clinical trials research and their relative impact toward influencing clinical practice. PMID- 24808631 TI - Piloting an approach to rapid and automated assessment of a new research initiative: Application to the National Cancer Institute's Provocative Questions initiative. AB - Funders of biomedical research are often challenged to understand how a new funding initiative fits within the agency's portfolio and the larger research community. While traditional assessment relies on retrospective review by subject matter experts, it is now feasible to design portfolio assessment and gap analysis tools leveraging administrative and grant application data that can be used for early and continued analysis. We piloted such methods on the National Cancer Institute's Provocative Questions (PQ) initiative to address key questions regarding diversity of applicants; whether applicants were proposing new avenues of research; and whether grant applications were filling portfolio gaps. For the latter two questions, we defined measurements called focus shift and relevance, respectively, based on text similarity scoring. We demonstrate that two types of applicants were attracted by the PQs at rates greater than or on par with the general National Cancer Institute applicant pool: those with clinical degrees and new investigators. Focus shift scores tended to be relatively low, with applicants not straying far from previous research, but the majority of applications were found to be relevant to the PQ the application was addressing. Sensitivity to comparison text and inability to distinguish subtle scientific nuances are the primary limitations of our automated approaches based on text similarity, potentially biasing relevance and focus shift measurements. We also discuss potential uses of the relevance and focus shift measures including the design of outcome evaluations, though further experimentation and refinement are needed for a fuller understanding of these measures before broad application. PMID- 24808632 TI - Measuring the evolution and output of cross-disciplinary collaborations within the NCI Physical Sciences-Oncology Centers Network. AB - Development of effective quantitative indicators and methodologies to assess the outcomes of cross-disciplinary collaborative initiatives has the potential to improve scientific program management and scientific output. This article highlights an example of a prospective evaluation that has been developed to monitor and improve progress of the National Cancer Institute Physical Sciences Oncology Centers (PS-OC) program. Study data, including collaboration information, was captured through progress reports and compiled using the web based analytic database: Interdisciplinary Team Reporting, Analysis, and Query Resource. Analysis of collaborations was further supported by data from the Thomson Reuters Web of Science database, MEDLINE database, and a web-based survey. Integration of novel and standard data sources was augmented by the development of automated methods to mine investigator pre-award publications, assign investigator disciplines, and distinguish cross-disciplinary publication content. The results highlight increases in cross-disciplinary authorship collaborations from pre- to post-award years among the primary investigators and confirm that a majority of cross-disciplinary collaborations have resulted in publications with cross-disciplinary content that rank in the top third of their field. With these evaluation data, PS-OC Program officials have provided ongoing feedback to participating investigators to improve center productivity and thereby facilitate a more successful initiative. Future analysis will continue to expand these methods and metrics to adapt to new advances in research evaluation and changes in the program. PMID- 24808633 TI - An Asp49 phospholipase A2 from snake venom induces cyclooxygenase-2 expression and prostaglandin E2 production via activation of NF-kappaB, p38MAPK, and PKC in macrophages. AB - Phospholipases A2 (PLA2) are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA2 named MT-III leads to prostaglandin (PG)E2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2). Herein, we explored the molecular mechanisms and signaling pathways leading to these MT-III-induced effects. Results demonstrated that MT-III induced activation of the transcription factor NF-kappaB in isolated macrophages. By using NF-kappaB selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE2 production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE2 release were attenuated by pretreatment of macrophages with SB202190, and Ly294002, and H-7 dihydro compounds, indicating the involvement of p38MAPK, PI3K, and PKC pathways, respectively. Consistent with this, MT-III triggered early phosphorylation of p38MAPK, PI3K, and PKC. Furthermore, SB202190, H-7-dihydro, but not Ly294002 treatment, abrogated activation of NF-kappaB induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE2 release, which occur via NF-kappaB activation induced by the sPLA2-MT III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins. PMID- 24808634 TI - Circulating biomarkers of immune activation distinguish viral suppression from nonsuppression in HAART-treated patients with advanced HIV-1 subtype C infection. AB - Few studies have examined immune activation profiles in patients with advanced HIV-1 subtype C infection or assessed their potential to predict responsiveness to HAART. BioPlex, ELISA, and nephelometric procedures were used to measure plasma levels of inflammatory biomarkers in HIV-1 subtype C-infected patients sampled before and after 6 months of successful HAART (n = 20); in patients failing HAART (n = 30); and in uninfected controls (n = 8). Prior to HAART, CXCL9, CXCL10, beta 2M, sTNF-R1, TGF- beta 1, IFN- gamma , IL-6, TNF, and sCD14 were significantly elevated in HIV-1-infected patients compared to controls (P < 0.01). All of these markers, with the exception of sTNF-R1, were also elevated in patients failing HAART (P < 0.05). The persistently elevated levels of CXCL9, CXCL10, and beta 2M in patients failing therapy in the setting of a marked reduction in these markers in patients on successful HAART suggest that they may be useful not only to monitor immune activation during HAART, but also to distinguish between good and poor responders. In the case of sCD14 and TGF- beta 1, the levels of these biomarkers remained persistently elevated despite HAART induced virological suppression, a finding that is consistent with ongoing monocyte-macrophage activation, underscoring a potential role for adjuvant anti inflammatory therapy. PMID- 24808635 TI - Salidroside attenuates concanavalin A-induced hepatitis via modulating cytokines secretion and lymphocyte migration in mice. AB - Salidroside, isolated from the medicinal plant Rhodiola, was reported to serve as an "adaptogen." This study was designed to explore the protective effect of salidroside on concanavalin A- (Con A-) induced hepatitis in mice and investigate potential mechanisms. C57BL/6 mice were randomly divided into control group, Con A group, and salidroside group. Salidroside (50 mg/kg) was injected intravenously followed by Con A administration. The levels of ALT, AST, inflammatory cytokines and CXCL-10 were examined. The pathological damage of livers was assessed, the amounts of phosphorylated IkappaBalpha and p65 were measured, and the numbers of CD4(+) and CD8(+) T lymphocytes in the blood, spleen and infiltrated in the liver were calculated. Our results showed that salidroside pretreatment reduced the levels of ALT, AST dramatically and suppressed the secretion of proinflammatory cytokines through downregulating the activity of NF-kappaB partly. Salidroside altered the distribution of CD4(+) and CD8(+) T lymphocyte in the liver and spleen through regulating CXCL-10 and decreased the severity of liver injuries. In conclusion, these results confirm the efficacy of salidroside in the prevention of immune mediated hepatitis in mice. PMID- 24808636 TI - Danger signals in cardiovascular disease. PMID- 24808637 TI - Low intraprostatic DHT promotes the infiltration of CD8+ T cells in BPH tissues via modulation of CCL5 secretion. AB - Clinical studies suggested thatandrogen might be associated with infiltrating T cells in prostate of benign prostatic hyperplasia (BPH) patients, but detail of T cell subset and mechanism still remained unclear. The present study tested the hypothesis that intraprostatic 5 alpha -dihydrotestosterone (DHT) exerts effects on T cells recruitment by BPH epithelial cells. Prostate tissues from 64 cases of BPH patients after transurethral resection of prostate (TURP) were divided into 2 groups: (1) no medication history; (2) administration of 5 alpha -reductase type II inhibitor-finasteride 5 mg daily for at least 6 months before surgery. Group 2 presented significantly higher CD8+ T cells infiltration than group 1, but no changes in CD4+ T cells (immunohistochemistry and flow cytometry). In vitro study more CD8+ T cell migrated to the prostate tissue lysates from group 2 and BPH-1 cells in low DHT condition. Transcription of chemokine (C-C motif) Ligand 5 (CCL5) mRNA in BPH-1 cells and chemokine (C-C motif) receptor 5 (CCR5) mRNA in CD8+ T cells were upregulated in low DHT condition (q-PCR). CCL5 expression was also identified to be higher in group 2 prostate tissues by IHC. This study suggested that intraprostatic DHT may participate in regulating inflammatory response which was induced by human prostatic epithelial cell, via modulating CCL5 secretion. PMID- 24808638 TI - The relationship between the antitumor effect of the IL-12 gene therapy and the expression of Th1 cytokines in an HPV16-positive murine tumor model. AB - OBJECTIVE: The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16 positive murine tumor model and the association with the IL-12's antitumor effect. METHODS: Mice were injected with BMK-16/myc cells to establish HPV16 positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. RESULTS: Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-beta1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-gamma cytokines and reduced expression of IL-10, IL-4, and TGF-beta1. CONCLUSIONS: The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer. PMID- 24808639 TI - C-reactive protein and coronary heart disease: all said--is not it? AB - C-reactive protein (CRP) and coronary heart disease (CHD) have been the subject of intensive investigations over the last decades. Epidemiological studies have shown an association between moderately elevated CRP levels and incident CHD whereas genetic studies have shown that polymorphisms associated with elevated CRP levels do not increase the risk of ischemic vascular disease, suggesting that CRP might be a bystander rather than a causal factor in the progress of atherosclerosis. Beside all those epidemiological and genetic studies, the experimental investigations also try to reveal the role of CRP in the progress of atherosclerosis. This review will highlight the complex results of genomic, epidemiological, and experimental studies on CRP and will show why further studies investigating the relationship between CRP and atherosclerosis might be needed. PMID- 24808640 TI - A polymorphism of ORAI1 rs7135617, is associated with susceptibility to rheumatoid arthritis. AB - Rheumatoid arthritis (RA), a chronic inflammatory disease usually occurring in synovial tissues and joints, is highly associated with genetic and environmental factors. ORAI1, a gene related to cellular immune system, has been shown to be involved in the pathogenesis of chronic inflammatory diseases and immune diseases. To identify whether ORAI1 gene contributes to RA susceptibility, we enrolled 400 patients with RA and 621 healthy individuals for a case-control genetic association study. Five tagging single nucleotides polymorphisms (tSPNs) within ORAI1 gene were selected for genotyping. An SNP, rs7135617, showed a significant correlation with the risk of RA. Our results indicated that genetic polymorphism of ORAI1 gene is involved in the susceptibility of RA in a Taiwanese population. PMID- 24808641 TI - Serum IL-4, IL-12 and TNF-alpha in malaria: a comparative study associating cytokine responses with severity of disease from the Coastal Districts of Odisha. AB - We investigated the role of IL-4, IL-12 and TNF-alpha in clinically well-defined groups of Plasmodium falciparum and vivax (Pf & Pv) infected patients belonging to Group I (++), Group II (+++) and Group III (++++). On the basis of hematological parameters, hyperparasitaemia, and evidence of neurological involvement, three different levels of severity were selected attributing a score from Group I (++) to Group III (++++). In each group 16 patients each of P. falciparum and P. vivax malaria were studied. As a control group for cytokine determination 30 healthy volunteers were included in the study. Serum samples were analyzed for IL-12, IL-4 and TNF-alpha using (ELISA) obtained commercially (Ray Biotech). Hb levels of Pf and Pv patients were 8 +/- 1.94, 7.6 +/- 1.64 g/dl and 3.6 +/- 1.23 and 10.1 +/- 1.21, 9.4 +/- 1.43 and 7.1 +/- 0.98 g/dl. Serum iron levels of Pf and Pv patients were 85.86 +/- 0.86, 81.10 +/- 0.70 and 70.1 +/ 0.73 and 99.47 +/- 0.85, 96.67 +/- 1.13 and 91.7 +/- 2.65 mg/dl. TNF-alpha levels of Pf and Pv patients were 155 +/- 23.66, 307.5 +/- 111.87 and 955 +/- 261.32 and 72 +/- 9.93, 140.88 +/- 23.11 and 469.37 +/- 416.99 pg/ml. IL-12 levels of Pf and Pv patients were 117.5 +/- 8.16, 160.63 +/- 20.81 and 293.13 +/- 94.64 and 75.7 +/- 9.25, 112.9 +/- 12.05 and 200 +/- 53.78 pg/ml. IL-4 levels of Pf and Pv patients were 3.7 +/- 0.11, 3.2 +/- 0.13 and 2.3 +/- 0.63 and 5.33 +/- 1.08, 4.8 +/- 0.16 and 3.9 +/- 0.48 pg/ml. In the control group the values of TNF alpha, IL-12 and IL-4 were 42.9 +/- 13.5, 49.8 +/- 11.59 and 6.06 +/- 1.32 pg/ml respectively. Cytokines and poor oxygen delivery should not be viewed as alternative theories of malarial disease pathophysiology instead poor oxygen delivery is one of the consequences of excessive release of inflammatory cytokines which is further augmented by the present work. PMID- 24808642 TI - Antiplasmodial activity of certain medicinal plants against chloroquine resistant Plasmodium berghei infected white albino BALB/c mice. AB - In the present study of antimalarial efficacy, aqueous extracts of leaves and unripe fruits of Psidium guajava, leaves of Ocimum sanctum and leaves of Murraya koenigii are evaluated against Plasmodium berghei (chloroquine resistant NK65 strain) infected white albino BALB/c mice. A 7 days oral administration was adopted with different dosage viz., 350 mg, 750 mg and 1,000 mg/kg body weight as treatment schedule along with parasite (Group I) and drug control with Chloroquine, 50 mg/kg body weight (Group II). All the parts were extracted based on the decoction method, which is commonly seen among the villagers/tribes as their usual method of preparation of decoction for most of the ailments. The antimalarial activities were evaluated from the giemsa stained blood smears collected from different treated groups of mice used in this experiment. The antiplasmodial effect that is percent parasitaemia and percent suppression (values in parenthesis) showed by the treated groups of mice at 350 mg/kg b. wt. by the aqueous extracts of P. guajava leaves (Group III) was 19.8 +/- 1.22 (73.7 %), P. guajava unripe fruits (Group IV) was 52.7 +/- 2.19 (30.0 %), leaves of O. sanctum (Group V) was 64.0 +/- 0.73 (15.1 %) and leaves of M. koenigii (Group VI) was 28.9 +/- 0.81 (61.6 %) whereas at 750 mg/kg b. wt., it all showed 10.3 +/- 0.7 (80.2 %), 26.3 +/- 0.52 (65.1 %), 42.0 +/- 0.47 (44.2 %) and 14.9 +/- 0.46 (71.5 %) whereas at 1,000 mg/kg b. wt. dose, it all showed 9.2 +/- 0.39 (85.8 %), 25.6 +/- 0.40 (62.0 %), 41.8 +/- 0.29 (35.5 %) and 14.0 +/- 0.42 (76.9 %) respectively. PMID- 24808643 TI - Ecological morphotaxometry of trematodes of garfish (Teleostomi: Belonidae) from Gangetic riverine ecosystem in India. III. Principal component analysis in the dynamics of Cephalogonimus yamunii (Upadhyay, Jaiswal, Malhotra and Malhotra, 2012). AB - The attributes of multivariate analyses were applied to infer peculiarity in distribution dynamics of Cephalogonimus yamunii Upadhyay et al. (J Parasit, 2012) in Xenentodon cancilla under influence of interionic interactions amongst hydrobiological factors. Non-parametric Mann-Whitney's Test chi(2) statistic was significant for the effect of Dissolved Oxygen and magnesium. The temperature optimum 23-27 degrees C was concluded for expression of peak prevalence and mean intensity during change in water temperature between autumn and winter periods. The dominant Ist component (PC1 (p) ) from Principal Component Analysis of monthwise response of infection data by C. yamunii in X. cancilla was further confirmed by Scree Plot of Eigenvalues and Factor Loadings Plot to identify the critical impact of hardness of water on infection prevalence and mean intensity. The findings of larger PC1 (p) positive coefficients comprehensively substantiated predominating hardness factor, under the influence of enhanced Dissolved Oxygen and optimum thermal effect. Therefore, the role of multifactorial etiology is a definite possibility. PMID- 24808644 TI - Subclinical anaplasmosis in camel (Camelus dromedarius) and its successful therapeutic management. AB - On the Indian sub continent, dromedarian camel -'the ship of the desert' is an important constituent of the socio economic life style of nomadic owners in the semi arid to arid ecosystems. The animal suffers from a few parasitic diseases viz. surra, coccidiosis, sarcocystis, gastro intestinal concurrent metazoan infections, mange, nasal bots and ticks infestations. However, anaplasmosis in camel has not been reported so far from the Indian subcontinent. Systematic investigations of a 7 year male Jaisalmeri camel, with a clinical history of dullness, progressive loss of condition and stamina revealed subclinical Anaplasma marginale infection. The animal had depressed haematological indices, dry and constipated bowels, pale and icteric conjunctiva suggestive of anaemia. The animal positively responded to the specific integrated therapy. Reexamination of the animal on day 21 post-therapy revealed depressed haematological indices restored to normal levels and the erythrocytes were free from the pathogen. Neglected attention, poor and/or underreporting of camel diseases vis-a-vis economic significance of the versatile animal has been discussed. This appears to be the pioneer documentation of anaplasmosis in camels from Indian subcontinent. PMID- 24808645 TI - Characterization of excretory-secretory antigens of adult Toxocara canis by western blotting. AB - Toxocara canis is one of the most common helminth worm of dogs which continues to stimulate both public health concern alongside the higher scientific interest. It may cause visceral and ocular damage in humans especially in children. The identification of specific antigens of T. canis is important so as to develop better diagnostic techniques. Excretory-secretory (ES) antigens were prepared by culturing the adult T. canis worms in RPMI 1640 medium without serum supplementation followed by ammonium sulphate precipitation. These antigens were separated using sodium dodecyl sulphate-electrophoresis (SDS-PAGE). Recovered proteins ranged from 30 to 384 kDa. The specific reactivity of the T. canis excretory-secretory (TC-ES) proteins was checked by western blotting. The immuno reactivity of the naturally infected dog sera with the TC-ES antigens showed five bands at 43, 57,105, 139 and 175 kDa. The immuno-reactivity of the hyper immune serum raised in rabbits against TC-ES antigens was observed with ten polypeptides of 21, 25, 30, 37, 45, 50, 57, 69, 77 and 105 kDa. Common antigens band were observed at 57 and 105 KDa. These antigens merit further evaluation as candidate for use in diagnosis of toxocariasis in humans and adult dogs. PMID- 24808646 TI - The evaluation of retrospective pathological lesions on spirocercosis (Spirocerca lupi) in dogs. AB - From 1998 to 2012, 42 dogs with spirocercosis referred to pathology Department of Veterinary Faculty, Tehran University. Frequency of spirocercosis was higher in October, November, December, January, February, March months. Averagely, the cases were 4.73 years old of age, so that 59.3 % of them were male. The major pathological findings were located in distal part of esophagus (57 %, n = 24), stomach (24 %, n = 10), and aorta (9.5 %, n = 4), respectively. In addition, 7 % (n = 3) were in esophagus and stomach, 2 % (n = 1) in esophagus and aorta, 42 % (n = 18) indicated pulmonary lesions with hyperemia, atelectasis, edema and pneumonia. In 35 % (n = 15) of cases were with hepatic lesions hyperemia and fatty change. However, 26 % (n = 11) cases demonstrated renal lesions with hyperemia, interstitial nephritis, and 24 % (n = 10) encompassed urinary bladder lesions with hyperemia and adhesive cystitis. Furthermore, sudden death occurred in 7 % (n = 3) as well as cachexia in 7 % (n = 3) cases. Some spirocercosis cases (12 %, n = 5) were accompanied by distemper disease, mixed mammary gland tumor (2 %, n = 1) and parasitic dermatitis due to demodicosis (9.5 %, n = 4). Presumably some of pathological findings were related or emerged by other sort of diseases such as distemper. PMID- 24808648 TI - Thiosulphate: cyanide sulphur transferase activity in some species of helminth parasites. AB - Investigation on the characteristic pattern of enzymes in various organisms may be of particular importance, as this type of information can help to understand certain physiological and biochemical processes in living organisms. Thiosulfate: cyanide sulfurtransferase (rhodanese) is a ubiquitous multifunctional enzyme, which its major function is generally believed to be in cyanide detoxification. The present study was conducted to determine the activity of this enzyme in some parasitic helminths including, cestodes (Moniezia benedeni, Helicometra giardi), trematodes (Fasciola hepatica, Fasciola gigantica, Dicrocoelium dendriticum) and nematodes (Haemonchus longistipes, Marshalagia marshalli). The data resultant from this study indicates that at least some rhodanese activity was present in all the seven investigated parasites, although its activity was much lower in comparison with previously reported values for some tissues of their vertebrate hosts. With respect to some degrees of cyanide insensitivity in parasitic helminths, it may be suggested that cyanide detoxification may not be a primary benefit of rhodanese in parasitic helminths and the true physiological and biochemical functions of the enzyme remains to be further defined in such organisms. PMID- 24808647 TI - Detection of Toxocara eggs in contaminated soil from various public places of Chennai city and detailed correlation with literature. AB - Toxocarosis is one of the most prevalent human helminthosis caused by larvae of Toxocara canis and Toxocara cati, the most widely distributed nematode parasites of dogs and cats respectively. Soil is considered as the principal source of transmission of Toxocara infection to human beings. With increasing population of dogs and cats, soil contamination with ova or eggs of Toxocara can be detected in public and private locations of city backyards, playgrounds, streets, sand pits and so on, regardless of the season of the year. In this context the present study was carried out to estimate the extent of soil contamination with Toxocara eggs in public parks, playgrounds and few kennels situated in different parts of Chennai city. A total of 105 soil samples from 40 public places and 5 kennels were screened for the presence of parasitic eggs. Toxocara eggs were recovered from 5 soil samples indicating an overall prevalence rate of 4.75 %. Out of 80 samples collected from public places, three samples, one each from Mogappair, My lady park (Periamet) and Madras Veterinary College showed the presence of Toxocara spp. eggs indicating an overall prevalence of 3.75 per cent. Out of the 25 samples from 5 kennels, two samples one each from Tambaram and Thorappakkam kennels were positive for Toxocara eggs with prevalence of 8 per cent. Low prevalence of Toxocara eggs in soil samples of these areas can be attributed to the less population of pups, the carriers of adult worms and the active source of soil contamination. The progress made in ABC (animal birth control) programme carried out by both governmental and non-governmental organizations has contributed to reduction of birth rate in dogs and thereby reduced the chances of soil contamination with Toxocara eggs to a certain extent in Chennai city. PMID- 24808650 TI - Prevalence of gastro intestinal parasites in ruminants and poultry in Telangana region of Andhra Pradesh. AB - The prevalence study was conducted on gastrointestinal parasites of cattle, buffalo, sheep, goat and poultry belongs to in and around Korutla, Karimangar district (Telangana region) of Andhra Pradesh. The prevalence of Fasciola sp., Amphistome sp., Eimeria sp. and Toxocara vitulorum in cattle and buffaloes were 5.3, 8.0, 10.0, 16.7 % respectively. The prevalence of Moniezia sp., Trichuris sp., Amphistome sp., Strongyle sp., Eimeria sp. in sheep and goat were 10.7, 8.0, 6.0, 9.3,4.7 % respectively. The prevalence of Capillaria sp. and Eimeria sp. in poultry was 7.0 and 6.0 % respectively. The overall prevalence of gastro intestinal parasites in cattle and buffaloes was 40.0 %, 38.7 % in sheep and goat and 13.0 % in poultry. Two species of Eimeria were identified in sheep viz. Eimeria granulosa and Eimeria parva. PMID- 24808649 TI - Macroscopic and microscopic examination of pulmonary Crenosoma striatum in hedgehog. AB - The aim of study was to necropsy and histopathology evaluation of lung Crenosoma striatum in hedgehog. In July 2012, 10 porcupines were collected from Urmia city and transferred to parasitology lab of the veterinary faculty where they were euthanized by ketamine (over 40-90 mg/kg) intraperitoneally. In this study the lungs were assessed through naked eyes regarding parasite presence upon washing. The lung tissue was examined under loop microscope in order to finding small worms in lung parenchyma. The worms were removed by Anse forceps and kept in AFA solution, and collected for diagnosis. In order to carrying out pathological tests, some samples prepared and placed in formalin 10 % for fixation. The counted worms frequency in high severe and moderate lungs were as 86 (50 females and 36 males) and 19 (13 females and 16 males) worms respectively. But no worms were observed in healthy lungs. The infestation severity was as; low infestation (1-7 worms), moderate infestation (8-20), severe infestation (21-50) and very severe infestation (more than 50 worms). The lung examinations of non-infested lungs indicated that the lung tissues had no parasite. In addition, no inflammation reactions as inflammatory cells presence were observed, and the air spaces with alveoles' wall in some regions were observable. On histopathological examination, the observed alteration was primarily inflammatory changes, and in some cases the proliferation was also observable. Hyperemia and inflammatory cell infiltration, somehow the alveolar space was filled, representing bronchopneumonia reaction. The bronchioles had various changes as hypertrophy and hyperplastic in different parts of respiratory system. Hyperemia and hemorrhage were very severe in some cases caused hemosiderosis in the lung. In severe inflammations the pneumonia along with increasing of bronchial cells in the lumen rose as well, leading to severe verminous infestation of the lung. In regard to the obtained results, the verminous infestation of the porcupines' lung with C. striatum indicated inflammatory and proliferative alteration which was as inflammatory changes in mild cases, and inflammatory and proliferative stances in severe cases. PMID- 24808651 TI - A six year (2006-2011) retrospective study of hemoprotozoan parasites affecting dogs in Chennai, Tamil Nadu, India. AB - With the changing global scenario there is effect not only on the human survival but also on the prevalence of existing pathogens and appearance of new infectious agents among animal population. This paper emphasises the need for prevalence studies. A retrospective study for 6 years on prevalence of hemoprotozoans in dogs in Chennai showed Babesia gibsoni the predominant parasite of dogs. Details are discussed in this paper. PMID- 24808652 TI - Cloning and expression of Neospora caninum dense-granule 7 in E. coli. AB - Neospora caninum is an obligate intracellular protozoan which induces abortion, still birth and neuromuscular disorders in cattle and is an important problem in dairy and beef industry worldwide. The dense granule protein 7 (GRA7) of N. caninum is an immune-dominant protein shared by both tachyzoite and bradyzoites. This study was conducted to produce recombinant GRA7 of N. caninum using a plasmid with high level of expression of this protein in E. coli. For this purpose, a segment of N. caninum DNA corresponding to GRA7 was amplified using PCR. After sequencing, this fragment was cloned into expression vector pMAL-c2X under the control of the lac promoter. Expression of this plasmid in E. coli strain TG1 was identified by western blotting. In this study, pMAL-c2X had a strong promoter to produce high level expression of NcGRA7. This result revealed that this recombinant protein with pMAL-c2X vector may be suitable for developing of diagnostic procedures. PMID- 24808653 TI - Dicrocoeliosis in goats in Jammu, India. AB - The prevalence of dicrocoeliosis was estimated by the examination of liver of slaughtered goats (n = 228) brought from two major goat rearing regions (Kandi and R.S. Pura) of Jammu province of India. Dicrocoelium dendriticum was found in 18.9 % of the goats, with mean fluke count (+/-SEM) of 24.9 +/- 4.4 (ranged from 0 to 478). A significant seasonal variation (p < 0.01) was recorded with maximum prevalence in winter (28.9 %), followed by post-rainy (22.2 %) and minimum in rainy season (9.4 %). The highest fluke count was observed in January (47.8 +/- 24.6) while none of the examined animals was found positive in May and June. The origin of the goats had a significant association (p < 0.0001) with prevalence rates and the goats from Kandi region (27.3 %) showed higher prevalence rates as compare to R.S. Pura (8.0 %). However, the age and sex had no significant effect on the prevalence of dicrocoeliosis in goats. The histopathological examination of infected livers revealed excessive thickening and proliferation of bile duct glandular epithelium with inflammatory exudates. Also, intense mononuclear cells infiltration with young fibroblasts was observed in the surroundings of bile ducts in portal areas along with atrophy of hepatocytes. PMID- 24808654 TI - Occurrence of isopod Nerocila phaiopleura infestation on Whitefin wolf-herring (Chirocentrus nudus) from Southeast coast of India. AB - The present study reported the first observation of isopod parasite, Nerocila phaiopleura infestation on Chirocentrus nudus an economically important fish from Cuddalore coast, Southeast coast of India. The maximum prevalence of 6.3 % and mean intensity of 3.2 were observed during pre-monsoon 2010 and monsoon 2010 respectively. The highest intensity 7 was observed in the single host during monsoon. The site of attachment leads to wound and offer the secondary infection. Two pathogenic bacteria Streptococcus aureus and E. coli were isolated from the wound. PMID- 24808655 TI - One new and two known species of Dorylaimoides Thorne and Swanger, 1936 (Nematoda: Mydonomidae) from West Bengal, India. AB - A few specimens of were collected from the soil around the roots of guava (Psidium guajava L.) and litchi (Litchi chinensis Sonn.) plantations in South 24 Parganas district of West Bengal, India. It yielded a few species of which one is new to science. Dorylaimoides (Dorylaimoides) geraldi sp. n. is characterized in having long odontostyle (9.5-11 MUm), amphidelphic genital system in females, and by short rounded tail. The male is characterized by shorter body length, shorter spicules, and three regularly spaced ventromedian supplements with an adanal pair. Although D. (D.) geraldi sp. n. comes closer to D. (D.) buccinator D. (D.) indicus, D. (D.) parateres, D. (D.) teres and D. (D.) websteri among the didelphic-amphidelphic species of the genus having short tails, it differs in having shorter body length, longer odontostyle, amphidelphic genital system in females, absence of pars dialata in oviduct, short rounded tail and by different morphometric ratios. The male differs from the closely related species in having shorter body, different number and arrangements of ventromedian supplements, shorter spicule and tail. The known species agree well with the earlier reported specimens except some morphometric variations. PMID- 24808656 TI - Seroprevalence of canine visceral leishmaniasis in southeast of Iran. AB - Visceral leishmaniasis is an endemic disease in many parts of Iran and infected dogs constitute the main domestic reservoirs that play a key role in transmission to humans. The objective of this study was to assess the seroprevalence of canine visceral leishmaniasis (CVL) by enzyme linked immunosorbent assay (ELISA) in southeast of Iran. This survey was carried out from 2009 to 2011 in Kerman, Bam and Baft districts in Kerman province and Zabol in Sistan-Baluchestan province. Blood samples were taken from 201 dogs after complete clinical examination. Following hematological evaluation; collected sera were tested by indirect ELISA method for the presence of anti Leishmania infantum antibodies. Overall seroprevalence was 15.4 %, including 6.4, 3.5, 3 and 2.4 % in Bam, Zabol, Baft and Kerman, respectively. However, seroprevalence of disease was not significantly related to age, gender, presence of clinical signs and hematological disorders. Based to the results of the present study, CVL is endemic in southeastern Iran. Delayed diagnosis and euthanasia of potentially infectious animals may occur with an increased transmission risk to sand flies and subsequently to humans. Implementation of potent screening tests with high validity is essential for rapid detection and successful dog elimination programs in endemic parts of Iran. PMID- 24808657 TI - Comparison of fatty acid contents of the neutral and phospholipids of the trematode Paramphistomum cervi and liver of its host, Capra hircus. AB - The present observation records the lipid classes and their fatty acid composition of the neutral lipid and phospholipid of the trematode Paramphistomum cervi and liver of its host Capra hircus, the common Indian goat. Thin Layer Chromatography and Gas Liquid Chromatography were used to identify different neutral lipid and phospholipid components. The results show that among the neutral lipid fractions, the amount of combined hydrocarbon, wax ester and steryl ester is more or less equal in parasite and its host, but the percent of triacylglycerol is more in host liver than the parasite and the percent of total sterol is more in parasite than that of its host liver. Among the phospholipid fractions, phosphatidylinositol and phosphatidylethanolamine in the trematode parasite P. cervi and phosphatidylcholine and cardiolipin in the host's liver are the major components. The predominant fatty acids in the neutral lipid and phospholipid fractions of both the host liver and the trematode P. cervi include C16:0, C18:0, C18:1, and C18:2. The results reveal that the parasite P. cervi take up almost all the lipid and fatty acids from their host, which is required for their life cycle. PMID- 24808658 TI - Molecular detection of Sarcocystis species in slaughtered sheep by PCR-RFLP from south-western of Iran. AB - Sarcocystis spp. are the cyst forming protozoan parasites that prevalent in livestock all around the world. In the presented work, we examined 40 macroscopic and 40 microscopic sarcocysts from Khouzestan and Lorestan provinces, south western Iran, utilizing PCR-RFLP based on amplification of 18S rRNA gene. Using AvaI, HindII, TaqI and EcoRI restriction enzymes the results represented Sarcocystis gigantea in both macroscopic and microscopic cysts. This result supports the importance of molecular investigations on characterization of Sarcocystis species when we aimed to assess the reliable control and preventive programs. PMID- 24808659 TI - Occurrence of Schistosoma nasale infection in bullocks of Puducherry. AB - Nasal schistosomiasis is caused by the blood fluke Schistosoma nasale (S. nasalis) adversely affects the health and production of domestic livestock in various parts of India. The present report describes the occurrence of S. nasale infection in two Hallikar breed bullocks of Union Territory of Puducherry. Eggs of S. nasale were noticed in nasal washings/scrapings of animals and identified as per the standard taxonomical keys. PMID- 24808660 TI - Occurrence of fatal syngamosis in emu birds of Kerala. AB - Two male and two female emu birds of 8 months to 1 year old reared in a private farm were brought dead to College of Veterinary and Animal Sciences, Pookode for postmortem examination during the period from July to September, 2010. The birds were emaciated and drooling of blood from the mouth was observed for 2 days prior to death. Postmortem examination of the dead birds revealed occurrence of large numbers of red coloured worms throughout trachea with histopathological changes. The worms were identified as Syngamus trachea based on morphology. Economic losses due to this parasitism are also described. PMID- 24808661 TI - A word from Journal of Basic and Clinical Pharmacy editor's desk. PMID- 24808662 TI - Formulation and evaluation of controlled porosity osmotic pump for oral delivery of ketorolac. AB - BACKGROUND: The osmotic drug delivery systems suitable for oral administration typically consist of a compressed tablet core that is coated with a semipermeable membrane that has an orifice drilled on it by means of a laser beam or mechanical drill. Ketorolac is a nonsteroidal agent with powerful analgesic. Oral bioavailability of ketorolac was reported to be 90% with very low hepatic first pass elimination; the biological half-life of 4-6 hours requires frequent administration to maintain the therapeutic effect. AIM: The aim of the current study was to design a controlled porosity osmotic pump (CPOP)based drug delivery system for controlled release of an NSAID agent, ketorolac tromethamine, which is expected to improve patient compliance due to reduced frequency; it also eliminates the need for complicated and expensive laser drilling and maintain continuous therapeutic concentration. DESIGN: The CPOP was designed containing pore-forming water-soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a micro porous structure. MATERIALS AND METHODS: The effect of different formulation variables, namely level of pore former (PVP), plasticizer (dibutyl phthalate) in the membrane, and membrane weight gain were studied. RESULTS AND CONCLUSION: Drug release was inversely proportional to the membrane weight but directly related to the initial concentration of pore former (PVP) in the membrane. Drug release was independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. Based on the in vitro dissolution profile, formulation F3C1 (containing 0.5 g PVP and 1 g dibutyl phthalate in coating membrane) exhibited Peppas kinetic with Fickian diffusion-controlled release mechanism with a drug release of 93.67% in 12 hours and hence it was selected as optimized formulation. SEM studies showed the formation of pores in the membrane. The formulations were stable after 3 months of accelerated stability studies. CPOP was designed for effective administration of drugs for prolonged period of time. PMID- 24808663 TI - A survey on the provision of package inserts in pediatric oral formulations by pharmaceutical manufacturers in Nigeria. AB - OBJECTIVES: The purpose of this study was to obtain data and understand how pharmaceuticals manufacturers care for safety and efficacy of the products distributed for consumption in Nigeria. The study was based on a survey of wholesale pharmacies that distribute pharmaceuticals for manufacturers. The study was carried out in Jos city, a central point in the north-central Nigeria. MATERIALS AND METHODS: Samples of pediatric formulations in pharmacies were obtained based on the product and the manufacturer. The packages were inspected for packing information leaflet and measuring devices. In addition, the manufacturing date, expiry date, storage conditions, product registration status, and the address of the manufacturer were also noted. Simple statistic was used to analyze the data. RESULTS: One hundred and twenty seven oral liquid formulations from 31 manufacturers were anayzed. The results showed that leaflet and measuring device as well as statement on storage conditions were available in 88 (69.3%), 98 (77.2%), and 114 (89.8%), respectively, in the samples studied. All products had registration numbers, suggesting that the products were authorized for distribution; this implies that some manufacturers deliberately distribute their products in forms other than the approved form. CONCLUSIONS: Manufacturers of pharmaceutical products need to be more committed to the safety and efficacy of their products at all times. Regulatory agency should increase surveillance to ensure that manufacturers consistently provide in their final packages what was declared and approved for registration. PMID- 24808664 TI - Isolation of anticancer drug TAXOL from Pestalotiopsis breviseta with apoptosis and B-Cell lymphoma protein docking studies. AB - BACKGROUND: Extraction and investigation of TAXOL from Pestalotiopsis breviseta (Sacc.) using protein docking, which is a computational technique that samples conformations of small molecules in protein-binding sites. Scoring functions are used to assess which of these conformations best complements the protein binding site and active site prediction. MATERIALS AND METHODS: Coelomycetous fungi P. breviseta (Sacc.) Steyaert was screened for the production of TAXOL, an anticancer drug. RESULTS: TAXOL PRODUCTION WAS CONFIRMED BY THE FOLLOWING METHODS: Ultraviolet (UV) spectroscopic analysis, Infrared analysis, High performance liquid chromatography analysis (HPLC), and Liquid chromatography mass spectrum (LC-MASS). TAXOL produced by the fungi was compared with authentic TAXOL, and protein docking studies were performed. CONCLUSION: The BCL2 protein of human origin showed a higher affinity toward the compound paclitaxel. It has the binding energy value of -13.0061 (KJ/Mol) with four hydrogen bonds. PMID- 24808665 TI - Study of pharmacological activities of methanol extract of Jatropha gossypifolia fruits. AB - OBJECTIVE: The present study was carried out to investigate the possible in vivo analgesic, neuropharmacological and anti-diarrheal activities of the methanol extract of Jatropha gossypifolia fruits. MATERIALS AND METHODS: The analgesic activity was measured by acetic acid induced writhing inhibition test. The neuropharmacological activities were evaluated by hole cross, hole-board, and elevated plus-maze (EPM) tests and the anti-diarrheal activity was assessed by castor oil induced diarrhea inhibition method. FINDINGS: The extract showed highly significant (P < 0.001) analgesic activity with % inhibitions of writhing response at doses 200 and 400 mg/kg body weight were 77.86% and 71.25%, respectively. The extract at both doses showed significant (P < 0.05) sedative effect in-hole cross test. In-hole board test, the extract showed highly significant (P < 0.001) anxiolytic activity at lower dose whereas this activity was observed at higher dose in EPM test. The extract also showed highly significant (P < 0.001) anti-diarrheal activity. CONCLUSION: The findings of the study clearly indicate the presence of significant analgesic, neuropharmacological and anti-diarrheal properties of the plant, which demands further investigation including, compound isolation. PMID- 24808666 TI - Prospects of iontophoresis in cardiovascular drug delivery. AB - Clinical benefits, industry interest, regulatory precedence, and strong market potential have made transdermal research the fastest growth area in drug delivery. As most drugs permeate poorly through skin, a major challenge is achieving the therapeutic level by enhancement of permeation rate. Iontophoresis, utilizing a minimal amount of current, is found to affect the skin permeation process drastically. Ideally suited for protein drugs, attempts have been made to utilize the technology for accelerating the low-molecular-weight drugs for chronic administration. However, because of the difficulty associated with the energy supply, commercialization was not feasible until recent times. Fortunately, the unprecedented growth of microelectronics has bridged this lacuna and brought the technology right into limelight. This article analyses the advantages of electrically assisted drug delivery in relation to passive permeation, with special reference to some cardiovascular drugs, for which there is already a demand in the market. PMID- 24808667 TI - Management of coronary artery disease in a Tertiary Care Hospital. AB - AIMS: The objective of the study was to study the prescribing patterns of drugs used in the coronary artery disease (CAD) and to identify, which drug is mostly prescribed at that hospital. SETTINGS AND DESIGN: This was a prospective observational survey including case series analysis of patients with CAD who met the inclusion criteria. It was conducted in the cardiology unit of multidisciplinary Tertiary Care Hospital in Kanpur. MATERIALS AND METHODS: Data of patients who met the inclusion criteria was collected in specially designed case record forms. It was designed to include the patient data such as, demographics, risk factors, clinical and biochemical characteristics, procedures and investigations performed during the hospital stay, in-hospital and discharge drug therapy. STATISTICAL ANALYSIS USED: Descriptive statistics were performed for baseline characteristics, risk factors and medication use. All the analyses were performed using Statistical Package for Social Sciences version 16.0. RESULTS: Subjects of age groups 65-74 (33.34%) were found to be more susceptible to CAD. In this study, we see that Aspirin, Clopidogrel and Statins were mostly prescribed in this hospital. CONCLUSIONS: In this study, Aspirin and Clopidogrel were mostly prescribed. According to 2009 focused updates of American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with ST-elevation Myocardial Infarction. So in this hospital prescription for CAD were according to the guideline. PMID- 24808668 TI - A conventional HPLC-MS method for the simultaneous determination of ofloxacin and cefixime in plasma: Development and validation. AB - OBJECTIVE: A simple, rapid, and sensitive high performance liquid chromatography mass spectrometry (HPLC-MS) method was developed and validated for the simultaneous determination of ofloxacin (OFL) and cefixime (CEF) in human plasma using the moxifloxacin as internal standard. METHODOLOGY: Analytes were separated using an Agilent LCMS system equipped with a Zorbax eclipse XBD C18 column (150 mm * 4.6 mm i.d., 5 MUm) and using a mobile phase consisting of a mixture of acetonitrile, methanol and 0.5% formic acid in a ratio of 23:10:67% v/v and flow rate was set at 0.6 mL/min. Plasma samples were extracted using the protein precipitation with acetonitrile and analyzed by positive ion mode. RESULTS: The linearity of the proposed method was investigated in the concentration range of 4 500 ng/mL (r = 0.9996) for OFL and 40-6000 ng/mL (r = 0.9998) for CEF. The lower limits of quantification were 4 ng/mL and 40 ng/mL for OFL and CEF respectively, which reach the level of both drugs possibly found in human plasma. Further, the reported method was validated as per the ICH guidelines and found to be well within the acceptable range. CONCLUSION: The proposed method is simple, rapid, accurate, precise, and appropriate for pharmacokinetic and therapeutic drug monitoring in the clinical laboratories. PMID- 24808669 TI - A review on proniosomal drug delivery system for targeted drug action. AB - Proniosomes are dry formulation of water soluble carrier particles that are coated with surfactant. They are rehydrated to form niosomal dispersion immediately before use on agitation in hot aqueous media within minutes. Proniosomes are physically stable during the storage and transport. Drug encapsulated in the vesicular structure of proniosomes prolong the existence of drug in the systematic circulation and enhances the penetration into target tissue and reduce toxicity. From a technical point of view, niosomes are promising drug carriers as they possess greater chemical stability and lack of many disadvantages associated with liposomes, such as high- cost and variable purity problems of phospholipids. The present review emphasizes on overall methods of preparation characterization and applicability of proniosomes in targeted drug action. PMID- 24808670 TI - Brief examination of psychopharmacology. PMID- 24808671 TI - Microbiological profile of lower respiratory tract infections in neurological intensive care unit of a tertiary care center from Central India. AB - BACKGROUND: Lower respiratory tract infections (LRTI's) are the most frequent infections among patients in intensive care units. The consequences of increased drug resistance are far reaching since bacterial infection of the lower respiratory tract (LRT) is a major cause of death from infectious disease. OBJECTIVE: The study was conducted with the aim of determining the bacterial etiology of LRTI in the neuro intensive care unit (NICU) as well as to update the clinicians with the various antimicrobial alternatives available in the treatment of LRTI. SUBJECTS AND METHODS: The study was conducted for the period of 3 years from January 2010 to December 2012 in the Microbiology Department of a Teaching Tertiary Care Hospital. The LRT specimens from 230 patients admitted in a NICU during the study period were processed. Following culture, the isolated organisms were identified and antimicrobial sensitivity was performed by standard methods. RESULTS: Out of the 230 LRT specimens evaluated, 198 (86.08%) were culture positive. A total of 254 pathogens were recovered with a predominance of Gram negative isolates (n = 243; 96.05%) Pseudomonas aeruginosa was the most dominant pathogen followed by Klebsiella pneumoniae. Alarmingly high percentage of extended spectrum beta-lactamase and methicillin resistant Staphylococcus aureus isolates were detected. The resistance to cephalosporins, aminoglycosides and carbapenem were remarkable. CONCLUSIONS: Therefore, we can conclude that for effective management of LRTI's, an ultimate and detailed bacteriological diagnosis and susceptible testing is required to overcome global problem of antibiotic resistance. PMID- 24808672 TI - Antimicrobial resistance pattern in a tertiary care hospital: An observational study. AB - CONTEXT: The number of organisms developing resistance to commonly used antibiotics is increasing among the various generations. The exact national scenario of antimicrobial resistance (AMR) is not known in India owing to the absence of a central monitoring agency. AIMS: The aim of this study is to identify the group of organisms developing resistance, to know the classes of drugs against, which resistance has emerged and to assess the possible factors that can favor the development of AMR so that antibiotic policy can be formulated for the proper and effective use of antibiotics. SETTINGS AND DESIGN: An observational study was conducted for a period of 1 year from August 2011 to July 2012 in a tertiary care hospital in Pondicherry. SUBJECTS AND METHODS: Data regarding culture and sensitivity of the organisms isolated from different sources such as urine, blood, wound swab/pus, stool, sputum and tracheal aspirations were collected from the records of the Microbiology Department. Sample processing, identification of organisms to the genus and/or species level and antimicrobial sensitivity were carried out as per the Clinical and Laboratory Standards Institute guidelines on the 999 samples received. RESULTS: Out of 999 samples, 125 (12.5%) showed significant growth of organisms exhibiting resistance to either single or multiple drugs. Out of 84 (67.2%) in-patients and 41 (32.8%) out-patient samples, Escherichia was the most common organism isolated with a total of 41 (32.8%), followed by Methicillin sensitive Staphylococcus aureus, 26 (20.8%), Klebsiella 25 (20%), Methicillin resistant Staphylococcus aureus 17 (13.6%), Pseudomonas 10 (8%), Proteus 2 (1.6%), 1 (0.8%) each of Citrobacter and Enterococci. Maximum resistance was observed with commonly used first line antimicrobials such as co-trimoxazole, ampicillin, amoxicillin, amoxyclav, fluoroquinolones, third generation cephalosporins and nalidixic acid. Least resistant or highly sensitive were amikacin, nitrofurantoin, gentamycin and doxycycline among the gram-negative bacteria. Macrolides, clindamycin, gentamycin, nitrofurantoin, vancomycin were the most sensitive antimicrobials against the gram-positive bacteria. Lack of knowledge on the consequences of inappropriate use of antibiotics was exhibited by 63% of subjects in our study. CONCLUSIONS: AMR was more with hospital acquired organisms and against commonly used antibiotics that are available since long period. Variation of resistance and sensitivity pattern with time and geographical location is identified. Periodic AMR monitoring and rotation of antibiotics are suggested to restrict further emergence of resistance. PMID- 24808673 TI - An interventional study on intensive care unit drug therapy assessment in a rural district hospital in India. AB - BACKGROUND: Intensive care unit is a potential area for drug-related problems. As many of the patients treated are complex patients, clinical pharmacy intervention could find drug therapy problems. MATERIALS AND METHODS: Drug information liaisons daily attended ward rounds with intensivists and screened the patient for drug therapy assessment using the American Society for Health-System Pharmacists clinical skills competition DTA format. This was a prospective study done for 6 months from August 2012 to January 2013. Simple statistics were used to tabulate the drug-related problems assessed. RESULTS: A total of 72 patients were screened for drug therapy problems, for which 947 drug doses were prescribed in the study period. The total number of prescriptions was 148. The average number of drugs per prescription was 6.39 and the average number of drugs per patient was 13.15. A total of 243 problems were identified; on an average, 1.67 problems were present per prescription. The total number of drug interactions identified was N = 192 (78.2%); majority of them (61.4%) were of type C (not serious). So, 55.73% of them were monitored and not stopped or substituted. The second type of problem was a correlation between drug therapy and medical problem (7.4%). Appropriate drug selection and drug regimen was the third problem, and the adverse drug reactions and therapeutic duplications accounted for approximately 2% of the drug-related problems identified. CONCLUSION: Drug interactions constituted the major problem of ICUs, but not many were serious or significant. Consensus in assessment of drug-related problems and convincing intensivists with good quality evidences are required for better acceptance of interventions. PMID- 24808674 TI - Drug utilization pattern in an Omani pediatric population. AB - OBJECTIVE: Evidence suggests that medication errors have a higher incidence in children and infants than in adults. At present, there is limited local data that investigates the drug prescription trends in pediatric populations. This study aims at understanding drug utilization patterns in pediatric patients at Sultan Qaboos University Hospital (SQUH), Oman. MATERIALS AND METHODS: A retrospective cross-sectional study was conducted in the outpatient pediatric clinics and inpatient pediatric wards at SQUH, a tertiary care hospital attached to the Sultan Qaboos University Medical College, Oman. RESULTS: The average number of drugs per prescription was 2.3 +/- 1.5, and it was almost similar in all age groups and in both males and females. About 16% of the study group received antibiotics. Paracetamol was the most prescribed drug in the patients (13%). Respiratory system drugs were the most prescribed class of drugs (22%) and salbutamol was the most prescribed drug in this class. CONCLUSIONS: This study will help in assessing rational usage and cost control of various medications used in the pediatric setting. PMID- 24808676 TI - The examination of geriatric pharmacotherapy. PMID- 24808675 TI - Optimization of liposomal encapsulation for ceftazidime for developing a potential eye drop formulation. AB - Ceftazidime is a broad spectrum third generation cephalosporin antibiotic which is effective mainly against Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter and Enterobacteriaceae, the pathogens which most often cause ophthalmological infections. Unlike other commonly used beta lactam antibiotics, ceftazidime is resistant to several types of beta lactamases (e.g., TEM, SHV and PSE-1). Because of these advantages, ceftazidime is used in the treatment of eye infections. However, ceftazidime undergoes rapid degradation in aqueous solutions therefore eye drops containing ceftazidime in aqueous solutions are not commercially manufactured. In the present study, liposomal encapsulations of ceftazidime with various lipid compositions, hydrating solutions and pH-values have been studied in order to optimize liposomal composition for a potential eye drop formulation. PMID- 24808677 TI - Drug utilization in emergency medicine department at a tertiary care teaching hospital: A prospective study. AB - BACKGROUND AND OBJECTIVES: The practice of emergency medicine has the primary mission of evaluating, managing and providing treatment to those patients with unexpected injury or illness. Instituting appropriate therapy is necessary for safety of the patients and to decrease mortality and morbidity. The objectives were to study the drug utilization pattern and direct cost of therapy in emergency medicine department of a tertiary care teaching hospital. MATERIALS AND METHODS: Data of the patients admitted to emergency medicine department was collected prospectively for 48 h from the time of admission over 2 months. The prescriptions were analyzed for drug use pattern and direct cost of therapy was calculated. RESULTS: A total of 156 patients received 1635 drugs with the mean of 9.99 +/- 2.55 drugs/patient. Most common diagnosis was acute coronary syndrome 35 (21.79%). Ondansetron 135 (86.53%) was most frequently prescribed drug followed by pantoprazole 133 (85.25%) and furosemide 68 (43.58%). Amongst antimicrobials ceftriaxone 51 (32.69%) was the most commonly prescribed drug. Direct cost of treatment per patient for the first 48 h was ? 4051 +/- 1641. CONCLUSION: Ondansetron and pantoprazole were the most commonly prescribed drugs in the emergency department. However, their use in all patients was not justified. Polypharmacy was prevalent. A closer look at the rationality of therapy would help in highlighting issues involved and would be helpful to authorities in deciding prescribing policies. PMID- 24808678 TI - Evaluation of antidiabetic prescriptions, cost and adherence to treatment guidelines: A prospective, cross-sectional study at a tertiary care teaching hospital. AB - INTRODUCTION: Diabetes mellitus is on alarming rise in India. Drug utilization studies help to identify the adherence to standard treatment guidelines and to evaluate the rational drug usage. OBJECTIVE: To study prescription pattern, calculate the cost of antidiabetic drugs and to evaluate the adherence to treatment guidelines in diabetic patients attending the medicine outpatient department in a tertiary care teaching hospital. MATERIALS AND METHODS: A prospective observational study was carried out for a period of 5 months. The diabetic patients who visited the medicine outdoor department were included. Demographic data and complete prescription details were recorded in the structured case record form. Cost of the drug therapy was calculated from the patient's bills. Indian Council for Medical research guidelines-2005 for diabetes management was used to evaluate the adherence. RESULTS: A total of 250 patients were enrolled in the study with mean age 57.91 +/- 9.37. Out of 250 patients 126 (50.4%) were male and rest were female. A total of 1,391 drugs were prescribed, with mean of 5.56 +/- 2.52 drugs and out of which 539 drugs were antidiabetics with mean of 2.18 +/- 0.96. In monotherapy, metformin was frequently 218 (40.45%) prescribed. Glimepiride and metformin was the most frequently prescribed in 119 (76.28%) out of 156 antidiabetic drug combinations. Most commonly used drugs other than antidiabetics were aspirin 146 (18.9%) and atorvastatin 119 (15.41%). Mean cost of therapy for a month for a diabetic patient was 354.60 +/- 305.72 INR. Majority 209 (83.6%) of prescriptions was in accordance to guidelines. CONCLUSION: Metformin was the most frequently prescribed drug in the diabetes patient. Metformin and glimeperide being the most frequent combination used. Majority of the prescriptions followed standard guidelines. PMID- 24808679 TI - Antidiabetic and antihyperlipidemic effects of an ethanolic extract of the whole plant of Tridax procumbens (Linn.) in streptozotocin-induced diabetic rats. AB - OBJECTIVE: To study the antidiabetic and antihyperlipidemic effects of an ethanolic extract of the whole plant of Tridax procumbens (Asteraceae) in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The whole plant of T. procumbens was collected in different regions of Madurai districts, Tamil Nadu. The air dried whole plant of T. procumbens was extracted with ethanol (95%) in a Soxhlet apparatus for 72 h. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/jk, i.p.) and nicotinamide (120 mg/kg, i.p) injection. The dry mass of the extract was used for preliminary phytochemical and pharmacological analysis. Diabetic rats were treated with glibenclamide (0.25 mg/kg, p.o.) or T. procumbens extract (250 and 500 mg/k, p.o.) for 21 consecutive days. The blood samples were collected at regular intervals to access hypoglycemic effect of an ethanolic extract of the whole plant of T. procumbens. At the end of the experiment, serum lipid profile and liver enzymes levels were analyzed for all the experimental animals and compared with diabetic control. RESULTS: The preliminary phytochemical analysis of an ethanolic extract of the whole plant of T. procumbens indicated the presence of alkaloids, tannins, flavonoids, saponins, and phenolic compounds. The ethanolic extract of the whole plant of T. procumbens at 250 and 500 mg/kg has significant antidiabetic and antihyperlipidemic activities. The diabetic control animals exhibited a significant decrease in body weight compared with control animals. T. procumbens inhibited streptozotocin-induced weight loss and significantly alter the lipid levels. CONCLUSION: The ethanolic extract of the whole plant of T. procumbens showed significant antidiabetic and antihyperlipidemic activities against streptozotocin-induced diabetes in rats. PMID- 24808680 TI - Bipolar disorder: A brief examination of lithium therapy. PMID- 24808681 TI - Drug utilization patterns in the emergency department: A retrospective study. AB - OBJECTIVES: The aim of this study was to assess the prescribing trends and costs of drugs in the emergency department (ED) at Sultan Qaboos University Hospital (SQUH), a tertiary care hospital, in Muscat, the Sultanate of Oman. MATERIALS AND METHODS: This was a retrospective cross-sectional study of all patients (n = 300) who attended the ED at SQUH in May 2012. Analyses were performed using descriptive and univariate statistics. RESULTS: The average age of patients was 34 +/- 19 years. The average number of drugs prescribed per patients was 3.2 +/- 1.9 and the majority of the patients (n = 78; 26%) received two drugs. The most common route of drug administration was the oral route (n = 481; 51%) followed by parenterally (n = 357; 38%). Non-steroidal anti-inflammatory drugs (NSAIDs) were the most commonly prescribed class of drugs (38%) followed by the gastro intestinal tract drugs (19%) and central nervous system drugs (13%). The average cost per prescription was 242 +/- 632 US$. Morphine had the highest cost (1885 US$) followed by cefuroxime (1404 US$) and filgrastim (939 US$) over the 1-month period. There was a significant positive correlation between hospital cost and age (P < 0.001), duration of stay at the ED (P = 0.008) and emergency types (P < 0.001). CONCLUSION: NSAIDs were the most frequent class of drugs administered to patients. Highest number of drugs was prescribed for cardiovascular diseases followed by respiratory and gastrointestinal diseases. Anti-infective drugs cost was the highest among all other classes. The results of the present study are attempts to highlight the importance of strategies that have to be implemented to optimize medication use at the ED. PMID- 24808682 TI - Assessment of the knowledge and attitudes of intern doctors to medication prescribing errors in a Nigeria tertiary hospital. AB - CONTEXT: Junior doctors are reported to make most of the prescribing errors in the hospital setting. AIMS: The aim of the following study is to determine the knowledge intern doctors have about prescribing errors and circumstances contributing to making them. SETTINGS AND DESIGN: A structured questionnaire was distributed to intern doctors in National Hospital Abuja Nigeria. SUBJECTS AND METHODS: Respondents gave information about their experience with prescribing medicines, the extent to which they agreed with the definition of a clinically meaningful prescribing error and events that constituted such. Their experience with prescribing certain categories of medicines was also sought. STATISTICAL ANALYSIS USED: Data was analyzed with Statistical Package for the Social Sciences (SPSS) software version 17 (SPSS Inc Chicago, Ill, USA). Chi-squared analysis contrasted differences in proportions; P < 0.05 was considered to be statistically significant. RESULTS: The response rate was 90.9% and 27 (90%) had <1 year of prescribing experience. 17 (56.7%) respondents totally agreed with the definition of a clinically meaningful prescribing error. Most common reasons for prescribing mistakes were a failure to check prescriptions with a reference source (14, 25.5%) and failure to check for adverse drug interactions (14, 25.5%). Omitting some essential information such as duration of therapy (13, 20%), patient age (14, 21.5%) and dosage errors (14, 21.5%) were the most common types of prescribing errors made. Respondents considered workload (23, 76.7%), multitasking (19, 63.3%), rushing (18, 60.0%) and tiredness/stress (16, 53.3%) as important factors contributing to prescribing errors. Interns were least confident prescribing antibiotics (12, 25.5%), opioid analgesics (12, 25.5%) cytotoxics (10, 21.3%) and antipsychotics (9, 19.1%) unsupervised. CONCLUSIONS: Respondents seemed to have a low awareness of making prescribing errors. Principles of rational prescribing and events that constitute prescribing errors should be taught in the practice setting. PMID- 24808683 TI - Assessment of medication adherence in type-2 diabetes patients on poly pharmacy and the effect of patient counseling given to them in a multispecialty hospital. AB - INTRODUCTION: The ability of physicians to recognize non-adherence is poor and interventions to improve adherence have had mixed results. Furthermore, successful interventions generally are substantially complex and costly. Poor adherence to medication regimens accounts for substantial worsening of disease; death and increased health care costs. The aim of this study is to assess the medication adherence in type-2 diabetes patients who are on polypharmacy and the effect of counseling provided for them in a multispecialty hospital. MATERIALS AND METHODS: The study was carried out at Kovai Medical Center and Hospital; Coimbatore Tamil Nadu, India. This is a 500-bedded modernized, multi-specialty tertiary care hospital with full-fledged diabetic department. It caters to the needs of both out-patients and in-patients. An assessment was made on type-2 diabetic patients who are receiving more than 5 drugs for their co-morbidities were included in this study. A medication adherence questionnaire was prepared based on the literatures. The study was approved by the Kovai Medical Center and Hospital ethics committee. RESULTS: Among 240 patients, 124 patients were adherent to medication whereas 116 patients were non-adherent. The non-adherent patients were giving verbal counseling in a private counseling room regarding medication adherence. CONCLUSIONS: Best way health professionals can tackle the adherence problem is through quality patient counseling as done in this study. With limited time most professionals have with a patient today this can be easier said than done. However, techniques such as the ask-educate-ask approach, the teach-back method and motivational interviewing can help ensure patient understanding of the counseling provided. PMID- 24808684 TI - Self-medication: A current challenge. AB - Self-medication is a global phenomenon and potential contributor to human pathogen resistance to antibiotics. The adverse consequences of such practices should always be emphasized to the community and steps to curb it. Rampant irrational use of antimicrobials without medical guidance may result in greater probability of inappropriate, incorrect, or undue therapy, missed diagnosis, delays in appropriate treatment, pathogen resistance and increased morbidity. This review focused on the self-medication of allopathic drugs, their use, its safety and reason for using it. It would be safe, if the people who are using it, have sufficient knowledge about its dose, time of intake, side effect on over dose, but due to lack of information it can cause serious effects such as antibiotic resistance, skin problem, hypersensitivity and allergy. There is need to augment awareness and implement legislations to promote judicious and safe practices. Improved knowledge and understanding about self-medication may result in rationale use and thus limit emerging microbial resistance issues. Articles which were published in peer reviewed journals, World Self-Medication Industry and World Health Organization websites relating to self-medication reviewed. PMID- 24808686 TI - Are we winning the fight? PMID- 24808685 TI - A survey on medicines safety and usage in community pharmacy. PMID- 24808687 TI - Providing all children with the quality dental care they deserve. PMID- 24808688 TI - Comparative evaluation of different forms of calcium hydroxide in apexification. AB - BACKGROUND: One out of every two children sustains a dental injury most often between 8 and 10 years of age. Majority of these teeth subsequently become non vital and most often with immature apex. Management of these teeth is an enormous challenge for lack of apical stop. Calcium hydroxide in various formulations has maximum literature support in favor of successful apexification or induced apical closure. AIM: The aim of the following study is to determine the efficacy of calcium hydroxide in a different formulation to induce apexification. MATERIALS AND METHODS: The present study was undertaken on 51 children of 8-10 years of age (both sexes) at Dr. R Ahmed Dental College and Hospital from April 2006 to March 2007. All children had one or two maxillary permanent central incisor (s), non vital and apices open. In all the cases, apexification was attempted with either calcium hydroxide mixed with sterile distilled water, or calcium hydroxide plus iodoform in methyl cellulose base, or calcium hydroxide plus iodoform in polysilicone oil base. The success of apexification was determined on the basis of clinical and radiographic criteria. RESULTS: In the pre-operative asymptomatic cases (72.55%), failure occurred in only 5.45% cases and pre-operative symptomatic cases failure rate was as high as 35.71%. Success rate was 94.6% in cases with narrow open apices, whereas 64.28% in wide open apices. In cases with pre-existing apical radiolucencies, successful apexification occurred in 63.63% and success rate was 92.5% in the cases without pre-existing apical radiolucencies. Average time consumed for apexification was minimum with calcium hydroxide plus iodoform in polysilicone oil base. CONCLUSION: The overall success rate observed to be 86.27%, which is in close proximity to the findings of most of the previous studies across the globe. PMID- 24808689 TI - Strategies to promote better research on oral health in Africa: A Delphi consensus study. AB - BACKGROUND: Research on oral health contributes to improved health outcomes; it is an indispensable tool in health policy. But how to fill the gaps in research oral health and to strengthen its capacity is the question. The main objective of the present study is to identify the current status of oral health research and potential strategies, thereby strengthening the research infrastructure and capacity. Delphi consultation, in the perspective of assisting decision-makers to identify strategies to promote better research on oral health in Africa, was initiated. DESIGN AND METHODS: The panels of 30 experts were asked to complete the questionnaire with 42 items into four groups by web survey. Each indicator statement was considered to be in consensus if the expert's opinion rating was of "A or B" for more than 75% in a scale of seven categories. Quantitative analysis was made from the answers of Delphi round. RESULTS: There was a strong consensus about three items concerning the role of oral health research, the development of research policy for oral health going through an effective governance of research institutes, migration of researchers and fund raising. CONCLUSION: This study shows strong many dispersal opinions by experts, but highlights the need for to improve the effectiveness of oral health research capacity strengthening activities. Africa's researchers, policy makers and partners will have to give special attention to ensuring that knowledge generated from oral health research is acted on to improve health for all. PMID- 24808690 TI - Zinc oxide nano-particles as sealer in endodontics and its sealing ability. AB - AIMS: The aim of this study was to evaluate the sealing ability of new experimental nano-ZOE-based sealer. SETTINGS AND DESIGN: Three types of nano-ZOE based sealer (calcined at different temperatures of 500, 600 and 700 degrees C) with two other commercially available sealers (AH26 and micro-sized zinc oxide eugenol sealer) were used. MATERIALS AND METHODS: Zinc oxide nano-particles were synthesized by a modified sol-gel method. The structure and morphology of the prepared powders were characterized using x-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. The instrumented canals of 60 single-rooted teeth were divided into five groups (n = 10), with the remaining ten used as controls. The canals were filled with gutta-percha using one of the materials mentioned above as sealer. After 3, 45 and 90 days, the samples were connected to a fluid filtration system. STATISTICAL ANALYSIS USED: The data were analyzed using Student's t-test. RESULTS: The XRD patterns and TEM images revealed that all the synthesized powders had hexagonal wurtzite structures with an average particle size of about 30-60 nm at different calcination temperatures. Microleakage in AH26 groups was significantly more than that in three groups of ZnO nano-particles at all the three evaluation intervals. Apical microleakage of ZnO micro-powders was significantly more than that of all the materials, but the sealing ability of ZnO nano-powder sealers did not differ significantly. CONCLUSION: The results of this study showed that the synthesized ZnO nano-powder sealers are suitable for use as a nano-sealer in root canal therapy to prevent leakage; however, further studies should be carried out to verify their safety. PMID- 24808691 TI - Estimation of lactoferrin levels in gingival crevicular fluid before and after periodontal therapy in patients with chronic periodontitis. AB - BACKGROUND: The lactoferrin (LF) is an iron binding protein present specifically and in abundance in the secondary granules of polymorphonuclear leukocytes (PMN's). It has been suggested that LF in crevicular fluid is a useful marker of PMN activity. Hence, this study aimed to estimate the levels of LF in gingival crevicular fluid (GCF) before and after surgical therapy in chronic periodontitis patients to assess the validity of LF in monitoring of treatment results. MATERIALS AND METHODS: A total of 30 patients with chronic periodontitis having probing depth of >=5 mm who were scheduled for periodontal surgery were included in the study. The clinical parameters were recorded and GCF samples were obtained 2 weeks after scaling and root planing and 2 weeks after conventional flap technique. The samples collected were then assayed for LF using Enzyme-linked immunosorbent assay (ELISA). RESULTS: The results showed that LF levels decreased significantly from 266.53 +/- 75.86 to 195.47 +/- 74.53 after scaling and root planing. There was further significant reduction in LF levels to 90.42 +/- 32.89 following 2 weeks of periodontal surgery, indicating decrease in inflammation. CONCLUSION: There is a significant reduction in GCF LF levels following periodontal surgery. Hence, LF levels in GCF could serve as a useful marker for monitoring of periodontal treatment results. PMID- 24808692 TI - The effects of ambient temperature and mixing time of glass ionomer cement material on the survival rate of proximal ART restorations in primary molars. AB - OBJECTIVE: Temperature fluctuations and material mixing times are likely to affect the consistency and integrity of the material mixture, and hence the restoration made out of it. The purpose of the present study was to determine the influence of the ambient temperature and the mixing time of glass ionomer cement (GIC) restorative material on the survival rate of proximal atraumatic restorative treatment (ART) restorations placed in primary molars. MATERIALS AND METHODS: A total of 804 restorations were placed in the primary molars of 6-8 year-olds using the ART approach. The restorations were then followed for a period of 2 years and evaluated at given intervals. The data collected were analyzed using SPSS computer statistical program, and the results tested and compared using the Chi-square, Kaplan Meier survival analysis and Cox Proportional hazard statistical tests. RESULTS: The cumulative survival rate of the restorations dropped from the initial 94.4% to 30.8% at the end of 2 years. The higher survival rate of the restorations was associated with the experienced operators and assistants when using the rubber dam isolation method. However, there was no statistically significant difference in the survival rate of the restorations when related to the room temperature and the mixing time of the GIC materials used in spite of the variations in the temperature recoded and the methods used in mixing the materials. CONCLUSION: The ambient temperature and mixing time of GIC did not have a significant effect on the survival of the proximal ART restorations. PMID- 24808693 TI - A Scanning electron microscopic evaluation of intracanal smear layer removal by two different final irrigation activation systems. AB - AIM: The aim of this study was to compare smear layer removal at apical 1 mm level after final irrigation activation with an EndoVac system and Max-I probe. MATERIALS AND METHODS: Fifty freshly extracted maxillary central incisors were randomly divided into two groups after completing cleaning and shaping with ProTaper rotary files. In one group, final irrigation was performed with an EndoVac system while in the other group final irrigation was performed with a 30 gauge Max-I probe. 3% sodium hypochlorite and 17% ethylenediaminetetracetic acid were used as final irrigants in all teeth. After instrumentation and irrigation, the teeth were sectioned longitudinally into buccal and palatal halves and viewed under a scanning electron microscope for evaluation of the smear layer. Statistical analysis was performed using the Kruskal Wallis and Mann-Whitney U tests. RESULTS: The EndoVac group showed significantly better smear layer removal compared with the Max-I probe at the apical 1 mm level. CONCLUSION: An apical negative pressure system (EndoVac) results in better debridement at apical 1 mm when compared with side-vented closed ended needle irrigation (Max-I probe). PMID- 24808694 TI - Impact of dental fear on oral health-related quality of life among school going and non-school going children in Udaipur city: A cross-sectional study. AB - AIM: To assess the impact of dental fear on different domains of oral health related quality of life (OHRQoL) among school going and non-school going children in the Indian scenario. MATERIALS AND METHODS: The study sample consisted of 279 school children and 257 non-school going children thus making a total sample of 536 children. The sampling frame comprised of 12-15-year-old children attending two upper primary public schools and non-school going children working at shops or not working in Udaipur city, India. Information on dental fear and OHRQoL was obtained by personal interviews by a single trained and calibrated examiner through a structured questionnaire. Intercooled STATA version 9.2 was employed to perform statistical analysis. The level of significance was set at 5%. RESULTS: Mean dental fear scores among school going (35.41 [11.79]) and non-school going (47.59 [3.80]) children revealed that dental fear was significantly (P <= 0.05) higher among non-school going than among school going children. In school going children, the likelihood of having poor oral symptoms, functional limitation and poorer social and emotional well being were significantly (P <= 0.05) lesser as compared with non-school going children. CONCLUSIONS: Fear has a significant impact on different domains of OHRQoL, except emotional well being, among non school going children. PMID- 24808695 TI - Efficacy of tranexamic acid mouthwash as an alternative for factor replacement in gingival bleeding during dental scaling in cases of hemophilia: A randomized clinical trial. AB - OBJECTIVE: The objective of the following study is to evaluate freshly prepared tranexamic acid mouth wash (FTAMW) as an alternative to factor replacement therapy (FRT) in controlling gingival bleeding in hemophiliacs during dental scaling. MATERIALS AND METHODS: Experimental treatment regime (ETR) involved saline transfusion followed by FTAMW and the control treatment regime (CTR) involved FRT followed by placebo mouthwash. A total of 22 hemophiliacs randomly received dental scaling under either CTR or ETR at two different visits, following a split mouth design. They were instructed to use the rendered mouthwash 4 times a day for 5 days and record the mouthwash usage and bleeding episodes in a logbook. The difference in the bleeding episodes was analyzed using Chi-square test with the level of significance predetermined at 0.05. RESULTS: Totally 19 patients completed the study. Seven patients reported no bleeding either in ETR or CTR; five patients noticed bleeding in CTR, but not in ETR. Three patients noticed bleeding in ETR, but not in CTR. Patients reported ease in usage and cost-effectiveness of ETR. CONCLUSION: FTAMW was found to be an effective alternative to FRT in controlling gingival hemorrhage in hemophiliacs during dental scaling. PMID- 24808696 TI - Factors affecting the placement or replacement of direct restorations in a dental school. AB - CONTEXT: The knowledge of the reasons for the placement of direct restorations makes possible to trace an epidemiological profile of a specific population and to direct the teaching of dentistry to techniques that are commonly used today and will be continued performed in the future. PURPOSE: The aim of this study was to verify the reasons for placement and replacement of direct restorations in patients treated in the Dental Clinic of the Uberaba University - Brazil. MATERIALS AND METHODS: This study evaluated 306 restorative procedures carried out on 60 patients. During the treatment planning, a form that contained information about the patient's gender, tooth number, the classification of restorations, the reasons for placement and replacement of amalgam and tooth colored restorations, the material that had to be removed and the new material used to fill the cavities was filled for each patient. Statistical analysis was carried out using Chi-square test (alpha = 0.05). RESULTS: The data showed that most of the patients were female (66.7%). Of all the restorations placed, 60.45% were 1(st)-time placements, while 39.55% were replacements. For 1(st)-time restorations, the main reason for placement was primary caries (76.76%), followed by non-carious cervical lesions (15.14%). The amalgam restorations were replaced more frequently (67.77%). The primary reason for replacements was the presence of secondary caries (for both previous amalgam (42.68%) and composite (66.67%) restorations (P < 0.05). The resin composite was the most indicated material for the new restorations (98.04%) (P < 0.05). CONCLUSIONS: The main reason for placement of direct restorations was primary caries, while secondary caries was the main reason for replacements. In almost all cases, the material used to fill the cavities was the resin composite. PMID- 24808697 TI - Phenytoin, folic acid and gingival enlargement: Breaking myths. AB - BACKGROUND: Epilepsy is described as a chronic neurological disorder characterized by recurrent seizures of cerebral origin, presenting with episodes of sensory, motor or autonomic phenomenon with or, without loss of consciousness. A recent meta-analysis of published and unpublished studies puts an overall prevalence rate of epilepsy in India at 5.59 per 1,000 populations. There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the anti-epileptic therapy in the prevention of anti-epileptic drug induced gingival enlargement. However, studies conducted in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy so as to justify the use of folic acid as a routine adjuvant to the usual anti-epileptic therapy to prevent this inevitable adverse effect without destabilizing the ongoing regimen leading to the precipitation of seizures in an otherwise stable patient (breakthrough seizures). MATERIALS AND METHODS: A total of 100 patients between the ages 18 and 50 years were clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was performed prior to the start of and after 1 year of phenytoin therapy. STATISTICAL ANALYSIS USED: The statistical analysis was carried out using t-test and the baseline serum folate levels and the serum folate levels obtained after 1 year of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula. RESULTS: The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin induced gingival enlargement. CONCLUSIONS: The results of the study suggest a higher incidence of gingival enlargement with an early onset and increased severity in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases. PMID- 24808698 TI - The effect of using different rinsing angles on the micro-tensile bond strength of the sealant to the etched enamel. AB - BACKGROUND: Attempts to enhance bond strength of the sealant have been among the most important sides of dental research. AIM: The purpose of the present study was to evaluate the effect of using different rinsing angles on the micro-tensile bond strength of the sealant to the etched enamel. SETTINGS AND DESIGN: Experimental study. MATERIALS AND METHODS: Sixty first-premolars were randomly assigned to six groups based on the rinsing angle applied (15 degrees , 30 degrees , 45 degrees , 60 degrees , 75 degrees , and 90 degrees ). Following etching and rinsing, a 4-mm height build up of sealant material was created. Bonded specimens were sectioned into sticks (1 * 1 mm), which were subjected to micro-tensile bond strength, testing at a cross-head speed of 0.5 mm/min. STATISTICAL ANALYSIS USED: The data were analyzed by Kolmogorov-Smirnov and post hoc Tukey test. RESULTS: The tensile bond strength in specimens rinsed at 90 degrees were statistically higher compared to those rinsed at 15 degrees and 30 degrees (P < 0.05), and increasing the angle from 15 degrees to 90 degrees was correlated with a reduction in the number of specimens with adhesive failures. CONCLUSIONS: Rinsing the conditioned enamel surface at 90 degrees may improve the bond strength and retention of the sealant. PMID- 24808699 TI - Lack of correlation between microbial penetration method and electro chemical technique for assessment of leakage through the root canal fillings. AB - AIMS: The purpose of this study was to compare microbial penetration method and electrochemical technique for evaluation of the apical seal. MATERIALS AND METHODS: A total of 28 teeth were prepared using the step-back technique to ISO size 40 master apical files. The specimens were randomly divided into an experimental group, two positive and two negative controls. Root canals in the experimental and negative control group were filled with gutta-percha (GP) and sealer, using lateral condensation technique. In the positive control group, canals were filled with GP without any sealer. The external surface of each tooth was coated with two layers of the nail varnish, except for the access opening and the apical foramen. In the negative control group, the teeth were completely covered with nail varnish. The apical seal was recorded with two methods, each successively used on the same teeth: An electrochemical method and a bacterial penetration method. STATISTICAL ANALYSIS USED: The correlation of the electro chemical readings with the results obtained from bacterial micro leakage test was evaluated by Pearson's correlation coefficient. RESULTS: Correlation coefficient of the measurements obtained from the two evaluation methods, was 0.23 (r = 0.23), so the correlation was not statistically significant (P = 0.275). CONCLUSIONS: This study shows that several studies by different methods are necessary before evaluation of the marginal leakage. PMID- 24808700 TI - Atomic force microscopic comparison of remineralization with casein phosphopeptide amorphous calcium phosphate paste, acidulated phosphate fluoride gel and iron supplement in primary and permanent teeth: An in-vitro study. AB - CONTEXT: Demineralization of tooth by erosion is caused by frequent contact between the tooth surface and acids present in soft drinks. AIM: The present study objective was to evaluate the remineralization potential of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste, 1.23% acidulated phosphate fluoride (APF) gel and iron supplement on dental erosion by soft drinks in human primary and permanent enamel using atomic force microscopy (AFM). MATERIALS AND METHODS: Specimens were made from extracted 15 primary and 15 permanent teeth which were randomly divided into three treatment groups: CPP-ACP paste, APF gel and iron supplement. AFM was used for baseline readings followed by demineralization and remineralization cycle. RESULTS AND STATISTICS: Almost all group of samples showed remineralization that is a reduction in surface roughness which was higher with CPP-ACP paste. Statistical analysis was performed using by one-way ANOVA and Mann-Whitney U-test with P < 0.05. CONCLUSIONS: It can be concluded that the application of CPP-ACP paste is effective on preventing dental erosion from soft drinks. PMID- 24808701 TI - Oral lesions and dental status among institutionalized orphans in Yemen: A matched case-control study. AB - OBJECTIVES: The aim of this study was to assess the prevalence of oral mucosal lesions (OMLs) and dental caries and to evaluate oral health practices among institutionalized orphan-children in Sana'a city, Yemen. SUBJECTS AND METHODS: A sample of 202 institutionalized male-orphan-children in the main orphanage in Sana'a city, were matched to 202 non-orphan schoolchildren. Clinical examination included assessment of OMLs based on standard international diagnostic criteria and evaluation of dental status using the Decayed/decayed, Missed/missed and Filled/filled (DMFT/dmft) index according to World Health Organization recommendations. Demographic data and oral hygiene practices were obtained by interviewing each subject using special questionnaire form. RESULTS: Majority of children were in the 12-15 year age group. Nine types of lesions were reported among orphans; the most common lesions were fissured tongue (24.3%), herpes labialis (7.9%) and traumatic ulcers (2.5%). The occurrence of herpes labialis was found to be significantly higher in orphans than in controls (P < 0.01). The prevalence of dental caries was insignificantly lower among the orphans (84.7%) compared with the non-orphans (89.61%; P = 0.136). The mean dmft score was significantly lower in orphans than in controls (2.28 vs. 3.82; P = 0.001). CONCLUSIONS: The institutionalized children in this orphanage had a high prevalence of OMLs but low prevalence of dental caries, though they revealed poor oral hygiene practices. Effective oral health promotion strategies need to be implemented to improve the oral health and oral health practices of children living in orphanages. PMID- 24808702 TI - Comparative evaluation of microleakage in conventional glass ionomer cements and triclosan incorporated glass ionomer cements. AB - AIM AND OBJECTIVE: The aim of the following study is to comparatively evaluate the microleakage of triclosan incorporated GIC with conventional restorative GIC. MATERIALS AND METHODS: Triclosan in powder form was added to conventional GIC to formulate a concentration of 2.5%. Class five cavities were prepared in non carious extracted molars and were respectively restored with conventional restorative GIC and triclosan incorporated GIC. Samples were kept in 10% methylene blue dye. Ground sections were obtained and were observed under a binocular microscope for dye penetration. RESULT: No significant difference was found in the microleakage of two groups. CONCLUSION: Triclosan incorporated GIC can be considered as an alternative to GIC with enhanced antibacterial property. PMID- 24808703 TI - Juvenile idiopathic arthritis. AB - Juvenile Idiopathic Arthritis (JIA) is the most chronic musculoskeletal disease of pediatric population. The chronic course of disease has a great impact on oral health. Temporomandibular joint is involved in JIA causing limited mouth opening with progressive open bite, retrognathia, microgenia and bird like appearance. Joints of upper and lower extremities are also involved. Effect on upper limb function leads to difficulty with fine motor movements required for brushing and flossing. This increases incidence of caries and periodontal disease in children. The cause of JIA is still poorly understood and none of the available drugs for JIA can cure the disease. However, prognosis has improved as a result of progress in disease classification and management. The dental practitioner should be familiar with the symptoms and oral manifestations of JIA to help manage as multidisciplinary management is essential. PMID- 24808704 TI - Benign cementoblastoma: A rare case report with review of literature. AB - We present a rare case of radiopaque lesion with radiolucent rim in the right body of mandible, with history of extraction of involved tooth, which made diagnosis confusing unless pre-extraction intraoral periapical radiography radiograph was recovered, finally diagnosed as benign cementoblastoma. It was surgically managed, with no recurrence of the lesion more than 2 years of follow up. Benign cementoblastoma is a rare, benign tumor of odontogenic ectomesenchymal origin, usually associated with roots of first mandibular molar. PMID- 24808705 TI - Cavernous hemangioma of the tongue: A rare case report. AB - Hemangiomas are developmental vascular abnormalities and more than 50% of these lesions occur in the head and neck region, with the lips, tongue, buccal mucosa, and palate most commonly involved. They are considered as hamartomas rather than true neoplasms. Here we report a case of hemangioma of the body of the tongue, discussing the diagnostic aspects and treatment modalities of such lesion and emphasizing the role of the color Doppler ultrasonography, especially in the diagnosis and treatment. Factors such as patient's age, size and site of lesion and the proximity of lesion to vital structure are paramount in the determination of the therapeutic approach and surgical excision. Even though radiotherapy, cryotherapy, laser therapy, medical treatment, injection of sclerosing substances and the selective embolization of the lingual artery seem to have some efficacy, the author conclude that surgery is the therapy of choice in the isolated vascular lesions of the body of the tongue. PMID- 24808706 TI - Extracapsular dissection of pleomorphic adenoma in the parotid gland: A case report and review of the literature. AB - Salivary gland tumors comprise of less than 3% of all tumors of the head and neck region. Pleomorphic adenoma represents 45 to 74% of all these salivary gland tumors and 65% of them occur in the parotid gland. Owing to the close proximity of this tumor to the facial nerve, there have been various techniques for surgical management of this tumor in the literature. Extracapsular dissection of pleomorphic adenoma is a conservative treatment modality which spares the handling of facial nerve. We are reporting a case of extracapsular dissection of pleomorphic adenoma in the lower pole of the superficial lobe of the parotid gland in a 22 year-old Indian male with a 1-year follow-up. PMID- 24808707 TI - Collision tumor of the palate: A rare case report. AB - This case report presents an unusual swelling of the palate in a 61-year-old-male patient. Histopathologically, it revealed features of two separate adjacent lesions, a spindle cells lesion showing diffuse immune-positivity for S-100 protein and focal positivity to glial fibrillary acid protein and an osseous lesion with numerous trabaculae of bone, adipocytes and myxoid tissue confirming the diagnosis of collision tumor of benign peripheral nerve sheath tumor and osteoma. Extensive search of English literature shows no reported cases of peripheral nerve sheath tumor with osteoma. The probable histogenesis of this collision tumor is discussed in detail. The purpose of this case report is to document this rare case in the literature so as to increase the awareness of this entity. PMID- 24808708 TI - A new approach to facilitate apexogenesis using soft tissue diode laser. AB - Traumatic injuries occur commonly in children and adolescents and the prevalence of such injuries has increased over the last decade. Such injuries may result in pulpal exposure, which can endanger tooth vitality. Therefore, the treatment for such injuries should be carefully planned so as to preserve the pulp vitality. Teeth with immature roots pose a great challenge for the clinician and procedures like pulpotomy may prove effective as a treatment strategy. Such procedure may ensure continued root development and apexogenesis. Lasers have varied applications in the dental practice such as oral surgical procedures, cavity preparation, disinfection etc. This article is a case report on the use of diode laser for pulpotomy in a young permanent tooth with traumatically exposed pulp in an 8-year-old male. PMID- 24808709 TI - Modified ridge splitting and bone expansion osteotomy for placement of dental implant in esthetic zone. AB - Ridge splitting with bone expansion is a technique of manipulation of bone to form receptor site for implant without removing any bone from the implant site. Maxillary bone has inherent quality of flexibility which can bemolded to desire location by using series of instrument namely chisels and osteotome. This further improves quality of bone all around implant, at the crest and apex both. This article describes a report of a clinical case with management of bucco-palatal ridge defect with modified ridge splitting and expansion osteotomy technique using chisel and osteotomes in an esthetic zone. PMID- 24808710 TI - Neurofibroma of the maxillary antrum: A rare case. AB - Neurofibromas are benign tumors of peripheral nerve tissue, frequently associated with neurofibromatosis type 1. Their isolated occurrence in the maxillary antrum is rare, with only 6 cases described in the English literature to the best of our knowledge. Primary neurogenic tumors in the maxillary sinus are unusual entities. The majority of the reported cases that have dealt with neurilemmomas and isolated neurofibromas are extremely rare. Here, a case of neurofibroma of the maxillary sinus. We present the case of a 60-year-old female patient with the chief complain of growth in the upper right back region of the jaw, which was preceded by exfoliation of teeth in the same region 1 month back. PMID- 24808711 TI - Lymphatic malformations: A dilemma in diagnosis and management. AB - Lymphatic malformations of the head and neck, also known as lymphangiomas or cystic hygromas, are a diverse group of lesions. Lymphangiomas represent benign hamartomatous tumors of lymphatic vessels with a marked predilection for the head, neck and oral cavity. These lesions, like most of the swellings occurring in the neck, frequently pose a dilemma in diagnosis and treatment. This is a case report of a lymphatic malformation which presented as a painless mass in the lower border of mandible. PMID- 24808712 TI - Prosthodontic rehabilitation of patient with marginal mandibular resection using attachment supported prostheses: A clinical report. AB - Marginal mandibular resection to treat neoplasms leads to loss of alveolar bone and teeth at the affected side. Consequently patient suffers with poor masticatory performance and esthetic disfigurement, which we need to restore with the help of prosthodontic rehabilitation. The success of rehabilitation of these patients depends on strategic treatment planning and choice of most suitable treatment modality. In this article, case of a patient has been presented who underwent marginal mandibular resection and reported with many limiting factors like obliterated buccal and lingual sulci, attachment of lingual frenum and lower lip at the level of alveolar ridge and Macroglossia. Impression making and fabrication of a retentive prosthesis were the main challenges. Therefore, a modified impression technique was used to fabricate mandibular cast partial denture with extracoronal semi precision attachments to enhance the retention of the prosthesis. PMID- 24808713 TI - Keratinizing dentigerous cyst. AB - Keratinizing dentigerous cyst is a rare entity. This article reports a case of keratinizing dentigerous cyst associated with an impacted mandibular canine. Clinical and radiological features, cone-beam computed tomography findings and histological features of the case are reported along with a discussion on keratinizing odontogenic cysts and the need for follow-up. PMID- 24808714 TI - Contemporary endodontic management of four rooted maxillary second molar using waveOne. AB - Knowledge of root canal morphology and variations is an essential factor to successful endodontic treatment. Presence of extra roots, canals, lateral canals, deltas etc., is commonly encountered. Maxillary second molar with two palatal roots or root canals is a rare dental anatomy. The purpose of this case report is to describe the successful endodontic management of a maxillary second molar with four root canals using a single reciprocating file system. The morphology is a typical characterized by two palatal roots with widely separated two orifices and canals. The tooth presented an individual mesiobuccal, distobuccal and two separate palatal roots. PMID- 24808715 TI - Light weight dentures: An innovative technique. AB - Retention, stability and support are the basic principles on which the success of a complete denture relies. The severely resorbed maxillary and mandibular edentulous arches that are narrow and constricted with increased interarch space provide decreased support, retention and stability. To decrease the leverage, reduction in the weight of the prosthesis was recommended and also found beneficial. This article describes a simple procedure to reduce the weight of maxillary complete denture by use of an autopolymerizing acrylic resin shell which is incorporated during the packing stage. This method has the advantage of being easy and requires very little additional time. Hollow maxillary complete denture considerably reduces the weight of the prosthesis, which in turn prevents transmission of detrimental forces by reducing leverage action. This results in increased retention and stability and up to some extent it also preserves the existing residual alveolar ridge. The technique uses a clear matrix of trial denture to facilitate shaping of dough spacer to ensure an even thickness of acrylic to resist deformation and prevent seepage of saliva into the cavity making this technique more predictable. An autopolymerizing acrylic resin shell which creates hollow space and also has strength. Technique is simple to execute, easy economical and matching the shade of autopolymerizing acrylic resin with heat cures acrylic resin enhances esthetics. Light weight hollow dentures provide healthy and comfortable living for the geriatric edentulous patient. PMID- 24808716 TI - Palatogram revisited. AB - It is the responsibility of the dentist to fabricate a denture that is fully functional and perfectly esthetic. One prime oral function that has always been overlooked in this regard is speech. It has been thought that speech will follow mere replacement of teeth and that it is the patient's duty to fine tune this function with practice. Phonetics, esthetics, function and comfort form the foundation of a successful prosthodontic treatment. Accurate approximation of palatal contours of a maxillary complete denture to a patient's tongue can improve speech intelligibility, if other factors such as tooth position, occlusal plane and occlusal vertical dimension are satisfactory. Customizing palatal contours of a maxillary complete denture can be accomplished by using tissue conditioning material, which provides sufficient working time for a patient to pronounce a series of sibilant sounds while recording dynamic impression of the tongue. This article describes a technique of obtaining palatogram and customizing palatal contours of a maxillary complete denture with autopolymerizing acrylic resin to improve the intelligibility of speech. PMID- 24808717 TI - Lip repositioning surgery: A pioneering technique for perio-esthetics. AB - In our esthetic conscious society people are now demanding all types of treatments possible to have a pleasing and attractive personality. A dazzling and beautiful smile can work wonders for anyone's personality. Our smile mirrors our persona, our unique being. However, a beautiful smile comprises of a perfect balance of the white and pink. This imbalance of excessive gingival display (EGD) can be managed by a variety of treatment modalities, depending on accurate diagnosis. This case report demonstrates the successful management of EGD with a lip-repositioning procedure in a patient with incompetent short upper lip. This was accomplished by removing a partial thickness strip of mucosa from the maxillary buccal vestibule and suturing the lip mucosa to the mucogingival line. This resulted in a narrower vestibule and restricted muscle pull, thereby resulting in competent lips and reduced gingival display during smiling. PMID- 24808718 TI - Gene-Environment Interplay in Twin Models. AB - In this article, we respond to Shultziner's critique that argues that identical twins are more alike not because of genetic similarity, but because they select into more similar environments and respond to stimuli in comparable ways, and that these effects bias twin model estimates to such an extent that they are invalid. The essay further argues that the theory and methods that undergird twin models, as well as the empirical studies which rely upon them, are unaware of these potential biases. We correct this and other misunderstandings in the essay and find that gene-environment (GE) interplay is a well-articulated concept in behavior genetics and political science, operationalized as gene-environment correlation and gene-environment interaction. Both are incorporated into interpretations of the classical twin design (CTD) and estimated in numerous empirical studies through extensions of the CTD. We then conduct simulations to quantify the influence of GE interplay on estimates from the CTD. Due to the criticism's mischaracterization of the CTD and GE interplay, combined with the absence of any empirical evidence to counter what is presented in the extant literature and this article, we conclude that the critique does not enhance our understanding of the processes that drive political traits, genetic or otherwise. PMID- 24808719 TI - Functional Geometry Alignment and Localization of Brain Areas. AB - Matching functional brain regions across individuals is a challenging task, largely due to the variability in their location and extent. It is particularly difficult, but highly relevant, for patients with pathologies such as brain tumors, which can cause substantial reorganization of functional systems. In such cases spatial registration based on anatomical data is only of limited value if the goal is to establish correspondences of functional areas among different individuals, or to localize potentially displaced active regions. Rather than rely on spatial alignment, we propose to perform registration in an alternative space whose geometry is governed by the functional interaction patterns in the brain. We first embed each brain into a functional map that reflects connectivity patterns during a fMRI experiment. The resulting functional maps are then registered, and the obtained correspondences are propagated back to the two brains. In application to a language fMRI experiment, our preliminary results suggest that the proposed method yields improved functional correspondences across subjects. This advantage is pronounced for subjects with tumors that affect the language areas and thus cause spatial reorganization of the functional regions. PMID- 24808720 TI - Climate Change Impact Assessment of Food- and Waterborne Diseases. AB - The PubMed and ScienceDirect bibliographic databases were searched for the period of 1998-2009 to evaluate the impact of climatic and environmental determinants on food- and waterborne diseases. The authors assessed 1,642 short and concise sentences (key facts), which were extracted from 722 relevant articles and stored in a climate change knowledge base. Key facts pertaining to temperature, precipitation, water, and food for 6 selected pathogens were scrutinized, evaluated, and compiled according to exposure pathways. These key facts (corresponding to approximately 50,000 words) were mapped to 275 terminology terms identified in the literature, which generated 6,341 connections. These relationships were plotted on semantic network maps to examine the interconnections between variables. The risk of campylobacteriosis is associated with mean weekly temperatures, although this link is shown more strongly in the literature relating to salmonellosis. Irregular and severe rain events are associated with Cryptosporidium sp. outbreaks, while noncholera Vibrio sp. displays increased growth rates in coastal waters during hot summers. In contrast, for Norovirus and Listeria sp. the association with climatic variables was relatively weak, but much stronger for food determinants. Electronic data mining to assess the impact of climate change on food- and waterborne diseases assured a methodical appraisal of the field. This climate change knowledge base can support national climate change vulnerability, impact, and adaptation assessments and facilitate the management of future threats from infectious diseases. In the light of diminishing resources for public health this approach can help balance different climate change adaptation options. PMID- 24808721 TI - New materials graphyne, graphdiyne, graphone, and graphane: review of properties, synthesis, and application in nanotechnology. AB - Plenty of new two-dimensional materials including graphyne, graphdiyne, graphone, and graphane have been proposed and unveiled after the discovery of the "wonder material" graphene. Graphyne and graphdiyne are two-dimensional carbon allotropes of graphene with honeycomb structures. Graphone and graphane are hydrogenated derivatives of graphene. The advanced and unique properties of these new materials make them highly promising for applications in next generation nanoelectronics. Here, we briefly review their properties, including structural, mechanical, physical, and chemical properties, as well as their synthesis and applications in nanotechnology. Graphyne is better than graphene in directional electronic properties and charge carriers. With a band gap and magnetism, graphone and graphane show important applications in nanoelectronics and spintronics. Because these materials are close to graphene and will play important roles in carbon-based electronic devices, they deserve further, careful, and thorough studies for nanotechnology applications. PMID- 24808723 TI - Problems with diagnosing Conversion Disorder in response to variable and unusual symptoms. AB - Conversion Disorder (CD) is a diagnosis offered to explain signs and symptoms that do not correspond to recognized medical conditions. Pediatric patients with variable, vague, and multisystem complaints are at increased risk for being diagnosed with CD. Little is known about the impact of such a diagnosis. In making such diagnoses, it is likely that pediatric providers hope to encourage patients to access mental health care, but no basis exists to show that these diagnoses result in such access in any useful way. This article presents the case of a child with Ehlers-Danlos Syndrome, who had been previously (incorrectly) diagnosed with CD and referred for mental health care. It offers commentary based on interviews with other pediatric patients with similar experiences - conducted in collaboration with the Ehlers-Danlos National Foundation. These cases indicate that CD diagnoses can seriously undermine patients' trust in doctors, and can create such defensiveness that it may interfere with (especially) patients' abilities to engage with mental health services. Such interference is an important problem, if the diagnosis is accurate. But, in the (more likely) event that it is not accurate, this defensiveness can interfere with both important mental health care and further ongoing necessary medical care. PMID- 24808722 TI - Patient considerations in the management of focal seizures in children and adolescents. AB - Focal epilepsy accounts for approximately one-half to two-thirds of new-onset epilepsy in children. Etiologies are diverse, and range from benign epilepsy syndromes with normal neuroimaging and almost certain remission to focal malformations of cortical development or hippocampal sclerosis with intractable seizures persisting lifelong. Other important etiologies in children include pre , peri-, or postnatal brain injury, low-grade neoplasms, vascular lesions, and neuroimmunological disorders. Cognitive, behavioral, and psychiatric comorbidities are commonly seen and must be addressed in addition to seizure control. Given the diverse nature of focal epilepsies in children and adolescents, investigations and treatments must be individualized. First-line therapy consists of prophylactic antiepileptic drugs; however, prognosis is poor after failure of two to three drugs for lack of efficacy. Refractory cases should be referred for an epilepsy surgery workup. Dietary treatments and neurostimulation may be considered in refractory cases who are not good candidates for surgery. PMID- 24808724 TI - Prevalence of CMV infection among sexually active adolescents: a matched case control study. AB - BACKGROUND: We observed previously that African American adolescents in Richmond reporting infrequent sexual activity had cytomegalovirus (CMV) seroprevalence rates one half that of their adult mothers and caregivers. We therefore sought to determine if sexually active African American adolescents have higher rates of CMV infection than sexually inactive African American adolescents. METHODS: Cases (aged 13-18 years) sought care for a sexually transmitted infection (STI) or pregnancy. Controls were sexually inactive and matched to cases for age, race, and gender and enrolled at the same clinic as cases and sought medical treatment unrelated to an STI. Subjects completed a questionnaire, provided saliva for antibody testing, and were interviewed for determination of sexual activity. RESULTS: Two groups of sexually active cases were enrolled. The first group had a diagnosis of an STI. In this group, both cases and matched controls were seropositive at a rate of 32% (7/22 for cases and 7/22 for controls). In the second group, cases self-reported an STI but objective evidence was lacking. In this group, cases were seropositive at a rate of 38% (six of 16) compared with matched controls among whom 6.3% were seropositive (one in 16). The overall rate of seropositivity in all 38 cases was 34% compared with a rate of 21% for all controls (P=0.3, odds ratio 2.0, 95% confidence interval 0.6-7.5). CONCLUSION: Our results confirm lower rates of CMV infection among the current generation of African American adolescents compared with African American adults in Richmond, and suggest that this is not associated with sexual activity. PMID- 24808725 TI - Reappraisal of the etiology of extracorpuscular non-autoimmune acquired hemolytic anemia in 2657 hospitalized patients with non-neoplastic disease. AB - INTRODUCTION: Unlike autoimmune hemolytic anemia (AIHA), literature on the etiological study of non-autoimmune hemolytic anemia (non-AIHA) is scarce. The incidence and prevalence of non-AIHA in different geographic regions are largely unknown perhaps owing to the lack of perspective investigation and different profiles of etiologies from different geographic regions. We aimed to examine the real-world etiology or mechanisms of the non-hereditary non-AIHA from a nationwide population-based administrative claim database in Taiwan. PATIENTS AND METHODS: The National Health Insurance Research Database of Taiwan was adopted for this research. The studied population was total inpatient claim records including both pediatric and adult patients, contributed by a population of 23 million insured individuals in Taiwan. From 2002 to 2008, we retrieved 3,903 patients having no pre-existing malignancy discharged after inpatient management for acquired hemolytic anemia, which was defined as coding in discharge diagnoses containing ICD-9-CM code 283. By contrast, ICD-9-CM code 282 and all of the sub codes are for hereditary hemolytic anemias. RESULTS: AIHA accounted for 32% of the total cases. Among 2,657 patients with non-AIHA, mechanical or microangiopathic mechanism accounted for 19% of cases; hemolytic-uremic syndrome (HUS) 4%, hemoglobinuria because of hemolysis from external causes such as paroxysmal nocturnal hemoglobinuria (PNH) and march hemoglobinuria 7%, and chronic idiopathic hemolytic anemia or other unspecified non-AIHA 69%. We looked further for specific etiology or mechanism for this group of patients with non hereditary extrinsic non-AIHA (n = 2,657). The explanatory disease states or conditions were splenomegaly; alcohol use disorder (spur cell hemolysis); heart valve prosthesis; malignant hypertension; disseminated intravascular coagulation; transfusion reaction; dengue fever-induced hemolytic anemia; direct parasitization; snake, lizard, or spider bite; and Wilson's disease with internal toxin mechanism. All these cases can explain up to 34.6% of all the non hereditary extrinsic non-AIHA cases. Fragmentation hemolysis (HUS, heart-valve prosthesis, malignant hypertension, and disseminated intravascular coagulation) accounted for 7.4% of non-AIHA hospitalized patients with non-neoplastic disease. CONCLUSIONS: This article is the first one to clearly demonstrate that the non neoplastic-induced HUS requiring hospitalization cases in Taiwan, which has a population of over 23 million were 110 over a span of seven years, 16 cases per year. Although the etiologies of non-AIHA are well known and described in the literature, this work added the statistical percentages of the various etiologies of non-AIHA in Taiwan. PMID- 24808726 TI - Microcyle conidiation in filamentous fungi. AB - The typical life cycle of filamentous fungi commonly involves asexual sporulation after vegetative growth in response to environmental factors. The production of asexual spores is critical in the life cycle of most filamentous fungi. Normally, conidia are produced from vegetative hyphae (termed mycelia). However, fungal species subjected to stress conditions exhibit an extremely simplified asexual life cycle, in which the conidia that germinate directly generate further conidia, without forming mycelia. This phenomenon has been termed as microcycle conidiation, and to date has been reported in more than 100 fungal species. In this review, first, we present the morphological properties of fungi during microcycle conidiation, and divide microcycle conidiation into four simple categories, even though fungal species exhibit a wide variety of morphological differences during microcycle conidiogenesis. Second, we describe the factors that influence microcycle conidiation in various fungal species, and present recent genetic studies that have identified the genes responsible for this process. Finally, we discuss the biological meaning and application of microcycle conidiation. PMID- 24808727 TI - The lichen genus sticta in South Korea. AB - Sticta (Schreber.) Ach. is one of the common lichen genera in tropical and subtropical regions, but not in the Korean Peninsula. For almost two decades, no detailed taxonomic or revisionary study has been done on this genus. This study was based on the specimens deposited in the lichen herbarium at the Korean Lichen Research Institute, and the samples were identified on the basis of recent literature. In this revisionary study, a total of eight species of Sticta, including a newly recorded one are documented. These species include Sticta fuliginosa (Dicks.) Ach., Sticta gracilis (Mull. Arg.) Zahlbr., Sticta limbata (Sm.) Ach., Sticta nylanderiana Zahlbr., Sticta sublimbata (J. Steiner) Swinscow & Krog, Sticta weigelii (Ach.) Vain., Sticta wrightii Tuck., and Sticta yatabeana Mull. Arg. Detailed descriptions of S. nylanderiana, S. sublimbata, S. weigelii, and S. yatabeana with their morphological, anatomical, and chemical characteristics are provided. A key description of all known Sticta species of the Korean Peninsula is also presented. PMID- 24808728 TI - A Novel Alternaria Species Isolated from Peucedanum japonicum in Korea. AB - We isolated and examined a new Alternaria sp., which causes leaf spots on Peucedanum japonicum in Korea, by using molecular and morphological methods. Phylogenetic analysis based on a combined internal transcribed spacer region analysis and two protein-coding genes (gpd and Alt a1) demonstrated that the causal fungus was most closely related to A. cinerariae and A. sonchi, and relevant to A. brassicae. However, conidial morphology indicated that it is a novel species within the genus Alternaria, and therefore we have assigned the fungus a new name in this study. PMID- 24808729 TI - A New Species of Graphis and New Lichen Records from Vietnam, Including a Second Worldwide Report of Sarcographina cyclospora. AB - Graphis upretii is a new lichen species discovered in Vietnam. The species is characterized by a loosely corticate, rough, whitish grey to greyish green thallus, elongate and irregularly branched lirellae with an apically thin complete thalline margin (negrosina morph), laterally carbonized, entire proper exciple, clear hymenium, hyaline, 16~20 transversely locular ascospores, and about 50~95 * 10~15 um in size. In addition, members of the taxon produce norstictic and stictic acids. Currently, the lichen flora of Vietnam include Arthonia radiata, Brigantiaea tricolor, Coenogonium implexum, Dirina paradoxa, Herpothallon sipmanii, Pertusaria pertusa, and Sarcographina cyclospora. PMID- 24808730 TI - Taxonomic Re-evaluation of Megacollybia Species in Korea. AB - The diversity of the genus Megacollybia in Korea was examined based on morphological observation and analysis of molecular data. Currently, the genus is consisted of nine species with a global distribution. However, only M. platyphylla has been reported in the floral survey of Korea. During our re evaluation of the taxonomic diversity of Megacollybia in Korea, six Megacollybia specimens collected in 2012 were identified based on internal transcribed spacer (ITS) sequences and morphology. Here, we report two Megacollybia species, M. clitocyboidea and M. marginata, as newly recorded species from Korea. The microscopic features of the two species are provided in this study. To our knowledge, this is the first phylogenetic analysis of Korean Megacollybia species. PMID- 24808731 TI - Relationship between Climatic Factors and the Distribution of Higher Fungi in Byeonsanbando National Park, Korea. AB - From April 2009 to October 2011, we surveyed the higher fungi in the Byeonsanbando National Park, Korea. In total, we identified 2 kingdoms, 3 divisions, 7 classes, 22 orders, 63 families, 149 genera, and 313 species (including 6 undocumented taxa: 2 families, 2 genera, and 2 species). Seventeen 17 orders, 49 families, 128 genera, and 286 species belonged to Basidiomycota; 7 orders, 9 families, 15 genera, and 21 species were of Ascomycota; and 4 orders, 5 families, 6 genera, and 6 species of primordial fungi. Among the Basidiomycota, Agaricomycetes were represented by 47 families, 126 genera, and 282 species. The most common fungi were Boletaceae (33 species), followed by Russulaceae (30), Agaricaceae (27), and Amanitaceae (24). Various species of most of the higher fungi occurred during periods with average temperatures of 23~24.9C, maximum temperatures of 28~31.9C, minimum temperatures of 22~23.9C, > 82% relative humidity, and > 200 mm precipitation. PMID- 24808732 TI - Three New Non-reducing Polyketide Synthase Genes from the Lichen-Forming Fungus Usnea longissima. AB - Usnea longissima has a long history of use as a traditional medicine. Several bioactive compounds, primarily belonging to the polyketide family, have been isolated from U. longissima. However, the genes for the biosynthesis of these compounds are yet to be identified. In the present study, three different types of non-reducing polyketide synthases (UlPKS2, UlPKS4, and UlPKS6) were identified from a cultured lichen-forming fungus of U. longissima. Phylogenetic analysis of product template domains showed that UlPKS2 and UlPKS4 belong to group IV, which includes the non-reducing polyketide synthases with an methyltransferase (MeT) domain that are involved in methylorcinol-based compound synthesis; UlPKS6 was found to belong to group I, which includes the non-reducing polyketide synthases that synthesize single aromatic ring polyketides, such as orsellinic acid. Reverse transcriptase-PCR analysis demonstrated that UlPKS2 and UlPKS4 were upregulated by sucrose; UlPKS6 was downregulated by asparagine, glycine, and alanine. PMID- 24808733 TI - Enhancement of beta-Glucan Content in the Cultivation of Cauliflower Mushroom (Sparassis latifolia) by Elicitation. AB - The effectiveness of three kinds of enzymes (chitinase, beta-glucuronidase, and lysing enzyme complex), employed as elicitors to enhance the beta-glucan content in the sawdust-based cultivation of cauliflower mushroom (Sparassis latifolia), was examined. The elicitors were applied to the cauliflower mushroom after primordium formation, by spraying the enzyme solutions at three different levels on the sawdust-based medium. Mycelial growth was fully accomplished by the treatments, but the metabolic process during the growth of fruiting bodies was affected. The application of a lysing enzyme resulted in an increase in the beta glucan concentration by up to 31% compared to that of the control. However, the treatment resulted in a decrease in mushroom yield, which necessitated the need to evaluate its economic efficiency. Although we still need to develop a more efficient way for using elicitors to enhance functional metabolites in mushroom cultivation, the results indicate that the elicitation technique can be applied in the cultivation of medicinal/edible mushrooms. PMID- 24808734 TI - Isolation of a Variant Strain of Pleurotus eryngii and the Development of Specific DNA Markers to Identify the Variant Strain. AB - A degenerated strain of Pleurotus eryngii KNR2312 was isolated from a commercial farm. Random amplified polymorphic DNA analysis performed on the genomic DNA of the normal and degenerated strains of this species revealed differences in the DNA banding pattern. A unique DNA fragment (1.7 kbp), which appeared only in the degenerated strain, was isolated and sequenced. Comparing this sequence with the KNR2312 genomic sequence showed that the sequence of the degenerated strain comprised three DNA regions that originated from nine distinct scaffolds of the genomic sequence, suggesting that chromosome-level changes had occurred in the degenerated strain. Using the unique sequence, three sets of PCR primers were designed that targeted the full length, the 5' half, and the 3' half of the DNA. The primer sets P2-1 and P2-2 yielded 1.76 and 0.97 kbp PCR products, respectively, only in the case of the degenerated strain, whereas P2-3 generated a 0.8 kbp product in both the normal and the degenerated strains because its target region was intact in the normal strain as well. In the case of the P2-1 and P2-2 sets, the priming regions of the forward and reverse primers were located at distinct genomic scaffolds in the normal strain. These two primer sets specifically detected the degenerate strain of KNR2312 isolated from various mushrooms including 10 different strains of P. eryngii, four strains of P. ostreatus, and 11 other wild mushrooms. PMID- 24808735 TI - A Nudix Hydrolase Protein, Ysa1, Regulates Oxidative Stress Response and Antifungal Drug Susceptibility in Cryptococcus neoformans. AB - A nucleoside diphosphate-linked moiety X (Nudix) hydrolase-like gene, YSA1, has been identified as one of the gromwell plant extract-responsive genes in Cryptococcus neoformans. Ysa1 is known to control intracellular concentrations of ADP-ribose or O-acetyl-ADP-ribose, and has diverse biological functions, including the response to oxidative stress in the ascomycete yeast, Saccharomyces cerevisiae. In this study, we characterized the role of YSA1 in the stress response and adaptation of the basidiomycete yeast, C. neoformans. We constructed three independent deletion mutants for YSA1, and analyzed their mutant phenotypes. We found that ysa1 mutants did not show increased sensitivity to reactive oxygen species-producing oxidative damage agents, such as hydrogen peroxide and menadione, but exhibited increased sensitivity to diamide, which is a thiol-specific oxidant. Ysa1 was dispensable for the response to most environmental stresses, such as genotoxic, osmotic, and endoplasmic reticulum stress. In conclusion, modulation of YSA1 may regulate the cellular response and adaptation of C. neoformans to certain oxidative stresses and contribute to the evolution of antifungal drug resistance. PMID- 24808736 TI - Enhancing the Thermotolerance of Entomopathogenic Isaria fumosorosea SFP-198 Conidial Powder by Controlling the Moisture Content Using Drying and Adjuvants. AB - Entomopathogenic fungi are promising pest-control agents but their industrial applicability is limited by their thermosusceptibility. With an aim to increase the thermotolerance of Isaria fumosorosea SFP-198, moisture absorbents were added to dried conidial powder, and the relationship between its water potential and thermotolerance was investigated. Mycotized rice grains were dried at 10C, 20C, 30C, and 40C and the drying effect of each temperature for 24, 48, 96, and 140 hr was determined. Drying for 48 hr at 10C and 20C reduced the moisture content to < 5% without any significant loss of conidial thermotolerance, but drying at 30C and 40C reduced both moisture content and conidial thermotolerance. To maintain thermotolerance during storage, moisture absorbents, such as calcium chloride, silica gel, magnesium sulfate, white carbon, and sodium sulfate were individually added to previously dried-conidial powder at 10% (w/w). These mixtures was then stored at room temperature for 30 days and subjected to 50C for 2 hr. The white carbon mixture had the highest conidial thermotolerance, followed by silica gel, magnesium sulfate, and then the other absorbents. A significant correlation between the water potential and conidial thermotolerance was observed in all conidia-absorbent mixtures tested in this study (r = -0.945). Conidial thermotolerance in wet conditions was evaluated by adding moisturized white carbon (0~20% H2O) to conidia to mimic wet conditions. Notably, the conidia still maintained their thermotolerance under these conditions. Thus, it is evident that conidial thermotolerance can be maintained by drying mycotized rice grains at low temperatures and adding a moisture absorbent, such as white carbon. PMID- 24808737 TI - Occurrence of Root Rot and Vascular Wilt Diseases in Roselle (Hibiscus sabdariffa L.) in Upper Egypt. AB - Roselle (Hibiscus sabdariffa L.) family Malvaceae is an important crop used in food, cosmetics and pharmaceutics industries. Roselle is cultivated mainly in Upper Egypt (Qena and Aswan governorates) producing 94% of total production. Root rot disease of roselle is one of the most important diseases that attack both seedlings and adult plants causing serious losses in crop productivity and quality. The main objective of the present study is to identify and characterize pathogens associated with root rot and wilt symptoms of roselle in Qena, Upper Egypt and evaluate their pathogenicity under greenhouse and field condition. Fusarium oxysporum, Macrophomina phaseolina, Fusarium solani, Fusarium equiseti and Fusarium semitectum were isolated from the natural root rot diseases in roselle. All isolated fungi were morphologically characterized and varied in their pathogenic potentialities. They could attack roselle plants causing damping off and root rot/wilt diseases in different pathogenicity tests. The highest pathogenicity was caused by F. oxysporum and M. phaseolina followed by F. solani. The least pathogenic fungi were F. equiseti followed by F. semitectum. It obviously noted that Baladi roselle cultivar was more susceptible to infection with all tested fungi than Sobhia 17 under greenhouse and field conditions. This is the first report of fungal pathogens causing root rot and vascular wilt in roselle in Upper Egypt. PMID- 24808738 TI - Molecular Epidemiology of Clinical Cryptococcus neoformans Isolates in Seoul, Korea. AB - Cryptococcal infection is primarily caused by two species, Cryptococcus neoformans and C. gattii. Between the two species, C. neoformans var. grubii is the major causative agent of cryptococcosis in Asia. We investigated the molecular characteristics of 46 isolates of C. neoformans from patients with cryptococcosis between 2008 and 2012 in Seoul, Korea. All the isolates were determined to be C. neoformans var. grubii (serotype A), mating type MATalpha, and molecular type VNI by PCR-restriction fragment length polymorphism of the URA5 gene. Multilocus sequencing type (MLST) analysis using the International Society of Human and Animal Mycoses (ISHAM) consensus MLST scheme identified two sequence types (ST). Out of the 46 strains, 44 (95.7%) were identified as ST5, and remaining 2 were identified as ST31. Our study revealed that the clinical strains of C. neoformans in Korea are genetically homogeneous with the VNI/ST5 genotypes, and new appearance of VNI/ST31 genotype may serve as an important indicator of global genetic analysis. PMID- 24808739 TI - Outbreak of Rust Caused by Coleosporium asterum on Solidago virgaurea var. gigantea in Ulleung-do. AB - From June to October 2012, severe outbreaks of rust disease on Solidago virgaurea var. gigantea were observed in 5 different regions of Ulleung-do, Korea. Typical rust symptoms appeared as yellow spots, uredinia on leaves, and massive urediniospores covering the entire plant. Severely infected plants became discolored and died. On the basis of its morphological and molecular characteristics, the causal agent was identified as Coleosporium asterum. This pathogen has been reported as rust disease on S. virgaurea in the Canada and United States. In Korea, rust disease on S. virgaurea var. gigantea was reported as Uromyces rudbeckia in 1992. To the best of our knowledge, C. asterum is a novel rust pathogen on S. virgaurea var. gigantea in Korea. PMID- 24808740 TI - Characterization of Myrothecium roridum Isolated from Imported Anthurium Plant Culture Medium. AB - During an investigation of microorganisms and pests in plant culture media from imported anthurium pots, a fungal isolate (DUCC4002) was detected. Based on its morphological characters including colony shape on potato dextrose agar, the microstructures of spores observed by light and scanning electron microscopy and the results of phylogenetic analysis using an internal transcribed spacer rDNA sequence, the fungal isolate was identified as Myrothecium roridum. Pathogenicity testing on anthurium leaves revealed that the fungus could colonize and produce sporodochia on the inoculated leaves. This is the first report of M. roridum detected in imported plant culture medium in Korea. PMID- 24808741 TI - Proliferodiscus inspersus var. magniascus and Rodwayella citrinula, Two Unrecorded Taxa of Hyaloscyphaceae (Tribe Arachnopezizeae) in Korea. AB - A fungal survey that targeted the tribe Arachnopezizeae (Hyaloscyphaceae, Helotiales) was conducted in Korea. One variety belonging to Proliferodiscus and one species belonging to Rodwayella are recorded for the first time from Korea. Proliferodiscus inspersus var. magniascus differs from P. earoleucus by its amyloid reaction in ascal apices and larger asci. Rodwayella citrinula is distinguished from other members of the genus by small ascospores and its occurrence on grasses. The descriptions, illustrations and cultural characteristics of the species are provided. PMID- 24808743 TI - Pathologic potential of variant clones of the oshima strain of far-eastern subtype tick-borne encephalitis virus. AB - Tick-borne encephalitis virus (TBEV) is a zoonotic agent that causes acute central nervous system (CNS) disease in humans. We previously suggested that immune response in addition to CNS infection contribute to mouse mortality following TBEV infection. However, we did not examine the influence of virus variants in the previous study. Therefore, in this study, we investigated the biological and pathologic potentials of the variant clones in the TBEV Oshima strain. We isolated eight variant clones from the stock virus of the Oshima 5-10. These variants exhibited different plaque morphologies in BHK cells and pathogenic potentials in mice. Full sequences of viral genomes revealed that each of the variant clones except one had specific combinations of nucleotide and amino acid changes at certain positions different from the parent strain. We also showed that an amino acid substitution of Glu122->Gly in the E protein could have affected virus infection and replication in vivo, as well as the attenuated pathogenicity in mice. These data confirm the presence of virus variants or quasispecies from the parent strain. Further elucidation of the effect of each variant clone on immune responses such as the T-cell response is an important priority in the development of an effective vaccine and treatment strategies for tick-borne encephalitis. PMID- 24808742 TI - Review of parasitic zoonoses in egypt. AB - This review presents a comprehensive picture of the zoonotic parasitic diseases in Egypt, with particular reference to their relative prevalence among humans, animal reservoirs of infection, and sources of human infection. A review of the available literature indicates that many parasitic zoonoses are endemic in Egypt. Intestinal infections of parasitic zoonoses are widespread and are the leading cause of diarrhea, particularly among children and residents of rural areas. Some parasitic zoonoses are confined to specific geographic areas in Egypt, such as cutaneous leishmaniasis and zoonotic babesiosis in the Sinai. Other areas have a past history of a certain parasitic zoonoses, such as visceral leishmaniasis in the El-Agamy area in Alexandria. As a result of the implementation of control programs, a marked decrease in the prevalence of other zoonoses, such as schistosomiasis and fascioliasis has been observed. Animal reservoirs of parasitic zoonoses have been identified in Egypt, especially in rodents, stray dogs and cats, as well as vectors, typically mosquitoes and ticks, which constitute potential risks for disease transmission. Prevention and control programs against sources and reservoirs of zoonoses should be planned by public health and veterinary officers based on reliable information from systematic surveillance. PMID- 24808744 TI - Regional differences in the growing incidence of dengue Fever in Vietnam explained by weather variability. AB - Dengue fever is a major health problem in Vietnam, but its incidence differs from province to province. To understand this at the local level, we assessed the effect of four weather components (humidity, rainfall, temperature and sunshine) on the number of dengue cases in nine provinces of Vietnam. Monthly data from 1999 to 2009 were analysed by time-series regression using negative binomial models. A test for heterogeneity was applied to assess the weather-dengue association in the provinces. Those associations were significantly heterogeneous (for temperature, humidity, and sunshine: P < 0.001 heterogeneity test; for rainfall: P = 0.018 heterogeneity test). This confirms that weather components strongly affect dengue transmission at a lag time of 0 to 3 months, with considerable variation in their influence among different areas in Vietnam. This finding may promote the strategic prevention of dengue disease by suggesting specific plans at the local level, rather than a nationally unified approach. PMID- 24808745 TI - Dynamics of Centrocestus armatus Transmission in Endemic River in Hyogo Prefecture, Japan. AB - Centrocestus armatus is an intestinal parasite belonging to the family Heterophyidae. We developed an apparatus for recovering cercariae and clarified the infection dynamics of this parasite. To clarify the circadian rhythm of cercarial shedding in the summer season, we filtrated 30 l of river water every 2 h for 24 h. Cercariae were first detected between 06:00 and 08:00 h, increased over time to reach peak at 16:00 h and decreased thereafter, thus showing a single-peak pattern. In a survey of seasonal change, approximately 200 cercariae were contained in 1 l of river water during the summer season, while none were found during the winter. This cercarial shedding pattern appeared to be related to sunrise/sunset and water/atmosphere temperature. Therefore, we examined whether cercarial shedding was affected by light or temperature changes under laboratory conditions, and confirmed that both light and temperature were important factors for cercarial shedding. Light was a stronger factor than water temperature. Cercarial shedding of C. armatus occurred in response to temperature and light. The change in the number of juvenile metacercariae detected in fish brain corresponded with monthly detection rates of cercariae; however, the incidence of new infections decreased in August. This suggests that Nipponocypris temminkii contains a defense mechanism against new infections that may have hindered the increase in parasite infectivity. These results clarified the smooth infection from the first to the second intermediate host of C. armatus in the endemic river. Throughout the study period, fecal samples were collected from 19 kites, 114 herons, and three unidentified species. However, our results using C. armatus showed a low value of 1% in herons and 5% in kites. The infection dynamics of final host to first intermediate host need to be further investigated. PMID- 24808747 TI - First Susceptibility Testing of Mycobacterium tuberculosis for Second-line Anti tuberculosis Drugs in Ghana. AB - We performed drug susceptibility testing on first- and second-line drugs in Mycobacterium tuberculosis (M. tuberculosis) for the first time in Ghana to obtain preliminary data on drug-resistant tuberculosis. Of 21 isolates (4 new cases and 17 treated cases), 5 (23.8%) were multi-drug resistant tuberculosis (MDR-TB) and 19 (90.5%) were resistant to at least one drug, but no extensively drug-resistant TB (XDR-TB) was identified. Since the target patients were Category II, IV or smear positive at follow-up microscopy, it is understandable that there were many drug-resistant TB cases. Six isolates were resistant to one or two second-line drugs, but the second-line drugs were not approved in Ghana. It is considered that the bacilli were imported from abroad. Preventing the import of drug-resistant TB bacilli is probably one of best ways to control TB in Ghana. PMID- 24808746 TI - The limits of medical interventions for the elimination of preventable blindness. AB - BACKGROUND: Health authorities are working toward the global elimination of trachoma by the year 2020 with actions focused on the World Health Organization SAFE strategy (surgery of trichiasis, antibiotics, face washing and environmental changes) with emphasis on hygienist approaches for education. OBJECTIVES: The present survey was performed to assess the sustainability of the SAFE strategy 3 years after trachoma was eliminated from 6 villages. METHODS: In February 2013 a rapid trachoma assessment was conducted in 6 villages of Kolofata's district, Extreme north Region, Cameroon, where trachoma was eliminated in 2010. A total of 300 children (1-10 years) from 6 villages were examined by trained staff. RESULTS: The prevalence of active trachoma (children aged > 1 and < 10 years) in 2013 was 15% and in at least 25% was observed absence of face washing and flies in their eyes and nose. Income level, quality of roads, hygiene, and illiteracy were similar in all the villages; they did not change between 2010 and 2013 and could not be analyzed as independent risk factors. DISCUSSION: The heterogeneity of methods described for clinical trials makes it inappropriate to conduct meta analysis for the present and for other SAFE-related trials. The results obtained after implementation the SAFE strategy (recurrence) reveal that the causes (infectious agents and dirtiness) and effects (illness) were not connected by illiterate people living under conditions of extreme poverty. So far, antibiotics, surgery and hygiene education are insufficient for the sustainability of trachoma elimination and highlight that hypothetic-deductive processes seem not operational after implementing the awareness campaigns. Trachoma recurrence detected in 2013 in sedentary populations of Kolofata receiving efficacious treatments against Chlamydia sp. suggest that the elimination goals will be delayed if strategies are limited to medical actions. Restricting efforts to repeated pharmacological and surgical interventions for people infected with susceptible bacteria could be understood as the hidden side of a passive attitude toward basic education actions. PMID- 24808748 TI - Gaussian solitary waves and compactons in Fermi-Pasta-Ulam lattices with Hertzian potentials. AB - We consider a class of fully nonlinear Fermi-Pasta-Ulam (FPU) lattices, consisting of a chain of particles coupled by fractional power nonlinearities of order alpha>1. This class of systems incorporates a classical Hertzian model describing acoustic wave propagation in chains of touching beads in the absence of precompression. We analyse the propagation of localized waves when alpha is close to unity. Solutions varying slowly in space and time are searched with an appropriate scaling, and two asymptotic models of the chain of particles are derived consistently. The first one is a logarithmic Korteweg-de Vries (KdV) equation and possesses linearly orbitally stable Gaussian solitary wave solutions. The second model consists of a generalized KdV equation with Holder continuous fractional power nonlinearity and admits compacton solutions, i.e. solitary waves with compact support. When [Formula: see text], we numerically establish the asymptotically Gaussian shape of exact FPU solitary waves with near sonic speed and analytically check the pointwise convergence of compactons towards the limiting Gaussian profile. PMID- 24808749 TI - Modification of mean wake flow behind a very slender axisymmetric body of revolution by imposed nonlinear unstable helical modes. AB - For a sufficiently slender axially symmetric body placed in a uniform stream, only convectively unstable modes are found in previous experiments. This work imposes theoretically and computationally a pair of most unstable helical modes, symmetrically and asymmetrically. The Reynolds stress modification of the developing laminar mean wake flow is modified into an elliptic-like cross section for symmetrical forcing; the consequences of unequal upstream amplitudes are also explored. Energy-transfer mechanisms between the mean flow and the relevant dominant modes and between the modes through 'triad interactions' are studied. The results from dynamical considerations provide the physical understanding of the generation of a standing wave mode at twice the azimuthal wavenumber; it is necessary that the wave envelopes of participating modes, including that of the mean flow, overlap in their spatial development, which is a necessary supplement to kinematical conditions for such interactions to take place effectively. Standing wave motions, which are otherwise only found naturally in wakes behind blunt-trailing-edge axisymmetric bodies, can be rendered present through appropriate forcing and nonlinear interactions behind very slender axisymmetric bodies. PMID- 24808750 TI - Models for elastic shells with incompatible strains. AB - The three-dimensional shapes of thin lamina, such as leaves, flowers, feathers, wings, etc., are driven by the differential strain induced by the relative growth. The growth takes place through variations in the Riemannian metric given on the thin sheet as a function of location in the central plane and also across its thickness. The shape is then a consequence of elastic energy minimization on the frustrated geometrical object. Here, we provide a rigorous derivation of the asymptotic theories for shapes of residually strained thin lamina with non trivial curvatures, i.e. growing elastic shells in both the weakly and strongly curved regimes, generalizing earlier results for the growth of nominally flat plates. The different theories are distinguished by the scaling of the mid surface curvature relative to the inverse thickness and growth strain, and also allow us to generalize the classical Foppl-von Karman energy to theories of prestrained shallow shells. PMID- 24808751 TI - Non-steady-state heat conduction in composite walls. AB - The problem of heat conduction in one-dimensional piecewise homogeneous composite materials is examined by providing an explicit solution of the one-dimensional heat equation in each domain. The location of the interfaces is known, but neither temperature nor heat flux is prescribed there. Instead, the physical assumptions of their continuity at the interfaces are the only conditions imposed. The problem of two semi-infinite domains and that of two finite-sized domains are examined in detail. We indicate also how to extend the solution method to the setting of one finite-sized domain surrounded on both sides by semi infinite domains, and on that of three finite-sized domains. PMID- 24808752 TI - Theoretical analysis of the performance of a foam fractionation column. AB - A model system for theory and experiment which is relevant to foam fractionation consists of a column of foam moving through an inverted U-tube between two pools of surfactant solution. The foam drainage equation is used for a detailed theoretical analysis of this process. In a previous paper, we focused on the case where the lengths of the two legs are large. In this work, we examine the approach to the limiting case (i.e. the effects of finite leg lengths) and how it affects the performance of the fractionation column. We also briefly discuss some alternative set-ups that are of interest in industry and experiment, with numerical and analytical results to support them. Our analysis is shown to be generally applicable to a range of fractionation columns. PMID- 24808753 TI - Dark-field hyperspectral X-ray imaging. AB - In recent times, there has been a drive to develop non-destructive X-ray imaging techniques that provide chemical or physical insight. To date, these methods have generally been limited; either requiring raster scanning of pencil beams, using narrow bandwidth radiation and/or limited to small samples. We have developed a novel full-field radiographic imaging technique that enables the entire physio chemical state of an object to be imaged in a single snapshot. The method is sensitive to emitted and scattered radiation, using a spectral imaging detector and polychromatic hard X-radiation, making it particularly useful for studying large dense samples for materials science and engineering applications. The method and its extension to three-dimensional imaging is validated with a series of test objects and demonstrated to directly image the crystallographic preferred orientation and formed precipitates across an aluminium alloy friction stir weld section. PMID- 24808754 TI - Micropolar continuum modelling of bi-dimensional tetrachiral lattices. AB - The in-plane behaviour of tetrachiral lattices should be characterized by bi dimensional orthotropic material owing to the existence of two orthogonal axes of rotational symmetry. Moreover, the constitutive model must also represent the chirality inherent in the lattices. To this end, a bi-dimensional orthotropic chiral micropolar model is developed based on the theory of irreducible orthogonal tensor decomposition. The obtained constitutive tensors display a hierarchy structure depending on the symmetry of the underlying microstructure. Eight additional material constants, in addition to five for the hemitropic case, are introduced to characterize the anisotropy under Z2 invariance. The developed continuum model is then applied to a tetrachiral lattice, and the material constants of the continuum model are analytically derived by a homogenization process. By comparing with numerical simulations for the discrete lattice, it is found that the proposed continuum model can correctly characterize the static and wave properties of the tetrachiral lattice. PMID- 24808755 TI - Integrable structure in discrete shell membrane theory. AB - We present natural discrete analogues of two integrable classes of shell membranes. By construction, these discrete shell membranes are in equilibrium with respect to suitably chosen internal stresses and external forces. The integrability of the underlying equilibrium equations is proved by relating the geometry of the discrete shell membranes to discrete O surface theory. We establish connections with generalized barycentric coordinates and nine-point centres and identify a discrete version of the classical Gauss equation of surface theory. PMID- 24808756 TI - Brittle fracture in a periodic structure with internal potential energy. AB - We consider a brittle fracture taking account of self-equilibrated distributed stresses existing at microlevel in the absence of external forces. To determine how the latter can affect the crack equilibrium and growth, a model of a structured linearly elastic body is introduced, consisting of two equal symmetrically arranged layers (or half-planes) connected by an interface as a prospective crack path. The interface comprises a discrete set of elastic bonds. In the initial state, the bonds are assumed to be stressed in such a way that tensile and compressive forces of the same value alternate. In the general considerations, the layers are assumed to be of an unspecified periodic structure, where such self-equilibrated stresses may also exist. A two-line chain and a lattice are examined as the specified structure. We consider the states of the body-with-a-crack under such microlevel stresses (MS) and under a combined action of the remote forces and MS. Analytical solutions to the considered problems are presented based on the introduction of a selective discrete transform. We demonstrate that MS can increase as well as decrease the crack resistance depending on the internal energy level. We also discuss different scenarios of the crack growth. PMID- 24808757 TI - Enhanced load-carrying capacity of hairy surfaces floating on water. AB - Water repellency of hairy surfaces depends on the geometric arrangement of these hairs and enables different applications in both nature and engineering. We investigate the mechanism and optimization of a hairy surface floating on water to obtain its maximum load-carrying capacity by the free energy and force analyses. It is demonstrated that there is an optimum cylinder spacing, as a result of the compromise between the vertical capillary force and the gravity, so that the hairy surface has both high load-carrying capacity and mechanical stability. Our analysis makes it clear that the setae on water striders' legs or some insects' wings are in such an optimized geometry. Moreover, it is shown that surface hydrophobicity can further increase the capacity of a hairy surface with thick cylinders, while the influence is negligible when the cylinders are thin. PMID- 24808758 TI - A dynamical systems view of network centrality. AB - To gain insights about dynamic networks, the dominant paradigm is to study discrete snapshots, or timeslices, as the interactions evolve. Here, we develop and test a new mathematical framework where network evolution is handled over continuous time, giving an elegant dynamical systems representation for the important concept of node centrality. The resulting system allows us to track the relative influence of each individual. This new setting is natural in many digital applications, offering both conceptual and computational advantages. The novel differential equations approach is convenient for modelling and analysis of network evolution and gives rise to an interesting application of the matrix logarithm function. From a computational perspective, it avoids the awkward up front compromises between accuracy, efficiency and redundancy required in the prevalent discrete-time setting. Instead, we can rely on state-of-the-art ODE software, where discretization takes place adaptively in response to the prevailing system dynamics. The new centrality system generalizes the widely used Katz measure, and allows us to identify and track, at any resolution, the most influential nodes in terms of broadcasting and receiving information through time dependent links. In addition to the classical static network notion of attenuation across edges, the new ODE also allows for attenuation over time, as information becomes stale. This allows 'running measures' to be computed, so that networks can be monitored in real time over arbitrarily long intervals. With regard to computational efficiency, we explain why it is cheaper to track good receivers of information than good broadcasters. An important consequence is that the overall broadcast activity in the network can also be monitored efficiently. We use two synthetic examples to validate the relevance of the new measures. We then illustrate the ideas on a large-scale voice call network, where key features are discovered that are not evident from snapshots or aggregates. PMID- 24808759 TI - Modern applications for a total sulfur reduction distillation method - what's old is new again. AB - BACKGROUND: The use of a boiling mixture of hydriodic acid, hypophosphorous acid, and hydrochloric acid to reduce any variety of sulfur compounds has been in use in various applications since the first appearance of this method in the literature in the 1920's. In the realm of sulfur geochemistry, this method remains a useful, but under-utilized technique. Presented here is a detailed description of the distillation set-up and procedure, as well as an overview of potential applications of this method for marine sulfur biogeochemistry/isotope studies. The presented applications include the sulfur isotope analysis of extremely low amounts of sulfate from saline water, the conversion of radiolabeled sulfate into sulfide, the extraction of refractory sulfur from marine sediments, and the use of this method to assess sulfur cycling in Aarhus Bay sediments. RESULTS: The STrongly Reducing hydrIodic/hypoPhosphorous/hydrochloric acid (STRIP) reagent is capable of rapidly reducing a wide range of sulfur compounds, including the most oxidized form, sulfate, to hydrogen sulfide. Conversion of as little as approximately 5 micromole sulfate is possible, with a sulfur isotope composition reproducibility of 0.3 permil. CONCLUSIONS: Although developed many decades ago, this distillation method remains relevant for many modern applications. The STRIP distillation quickly and quantitatively converts sulfur compounds to hydrogen sulfide which can be readily collected in a silver nitrate trap for further use. An application of this method to a study of sulfur cycling in Aarhus Bay demonstrates that we account for all of the sulfur compounds in pore-water, effectively closing the mass balance of sulfur cycling. PMID- 24808760 TI - The feasibility and acceptability of neuromuscular electrical stimulation to improve exercise performance in patients with advanced cancer: a pilot study. AB - BACKGROUND: To determine the feasibility and acceptability of lower limb neuromuscular electrical stimulation (NMES) as a home-based exercise therapy in patients with cancer who could not attend hospital-based exercise training. METHODS: A single-arm prospective pilot study of NMES, applied daily to both quadriceps muscles for six weeks. Participants were recruited from patients referred to a hospital-based multi-disciplinary supportive care team specializing in treatment of patients with nutritional depletion and functional decline. RESULTS: Of the 15 participants who underwent baseline testing, 10 (67%) completed the study and only one (7%) withdrew because of discomfort due to NMES treatment. 7/10 (70%) of participants used NMES at least three times a week for the duration of the study. Use of NMES did not lead to significant improvements in physical performance tests. CONCLUSIONS: NMES is a feasible and acceptable intervention for home use in patients with cancer, poor performance status and metastatic disease. However, whether NMES is an effective strategy to stabilize or improve physical performance in such patients is not proven. PMID- 24808761 TI - A case of EDTA-dependent pseudothrombocytopenia: simple recognition of an underdiagnosed and misleading phenomenon. AB - BACKGROUND: EDTA-dependent pseudothrombocytopenia (EDTA-PTCP) is a common laboratory phenomenon with a prevalence ranging from 0.1-2% in hospitalized patients to 15-17% in outpatients evaluated for isolated thrombocytopenia. Despite its harmlessness, EDTA-PTCP frequently leads to time-consuming, costly and even invasive diagnostic investigations. EDTA-PTCP is often overlooked because blood smears are not evaluated visually in routine practice and histograms as well as warning flags of hematology analyzers are not interpreted correctly. Nonetheless, EDTA-PTCP may be diagnosed easily even by general practitioners without any experiences in blood film examinations. This is the first report illustrating the typical patterns of a platelet (PLT) and white blood cell (WBC) histograms of hematology analyzers. CASE PRESENTATION: A 37-year old female patient of Caucasian origin was referred with suspected acute leukemia and the crew of the emergency unit arranged extensive investigations for work-up. However, examination of EDTA blood sample revealed atypical lymphocytes and an isolated thrombocytopenia together with typical patterns of WBC and PLT histograms: a serrated curve of the platelet histogram and a peculiar peak on the left side of the WBC histogram. EDTA-PTCP was confirmed by a normal platelet count when examining citrated blood. CONCLUSION: Awareness of typical PLT and WBC patterns may alert to the presence of EDTA-PTCP in routine laboratory practice helping to avoid unnecessary investigations and over-treatment. PMID- 24808762 TI - The association between hypoxia-inducible factor-1 alpha gene G1790A polymorphism and cancer risk: a meta-analysis of 28 case-control studies. AB - PURPOSE: Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor that regulates the cellular adaptation to hypoxia. HIF-1alpha gene single nucleotide polymorphisms (SNPs) are implicated to be associated with cancer risks. However, results from the published studies remained inconclusive. The aim of this study is to investigate the relationship of HIF-1alpha gene G1790A polymorphism with cancer using meta-analysis. METHODS: A comprehensive search in Pubmed, EMBASE and China National Knowledge Infrastructure (CNKI) was conducted to identify all publications on the association between this polymorphism and cancer until December 13, 2013. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to evaluate the strength of this association. Association between lymph node metastasis and G1790A was also investigated. RESULTS: A total of 5985 cases and 6809 controls in 28 case-control studies were included in this meta-analysis. The A allele of HIF-1alpha gene G1790A polymorphism was found to be significantly associated with increased cancer risk in four genetic models: AA + AG vs. GG (dominant model OR = 1.85, 95% CI = 1.27-2.69), AA vs. AG + GG (recessive model OR = 5.69, 95% CI = 3.87-8.37), AA vs. GG (homozygote comparison OR = 6.63, 95% CI = 4.49-9.79), and AG vs. GG (heterozygote comparison OR = 2.39, 95% CI = 1.53 3.75). This variant was also significantly associated with higher risks of pancreatic cancer, head and neck cancer, lung cancer and renal cell carcinoma. However, the A allele of G1790A was not significantly associated with increased lymph node metastasis in the dominant model by overall meta-analysis. CONCLUSIONS: Our meta-analysis suggests that the substitution of G with A of HIF 1alpha gene G1790A polymorphism is a risk factor of cancer, especially for pancreatic cancer, lung cancer, renal cell carcinoma and head and neck cancer. The association is significant in Asian, Caucasian population and public based control subgroups. However, it's not associated with risk of lymph node metastasis. PMID- 24808764 TI - Bud Frazier has pioneered mechanical circulatory support. PMID- 24808763 TI - Integration of bioinformatics to biodegradation. AB - Bioinformatics and biodegradation are two primary scientific fields in applied microbiology and biotechnology. The present review describes development of various bioinformatics tools that may be applied in the field of biodegradation. Several databases, including the University of Minnesota Biocatalysis/Biodegradation database (UM-BBD), a database of biodegradative oxygenases (OxDBase), Biodegradation Network-Molecular Biology Database (Bionemo) MetaCyc, and BioCyc have been developed to enable access to information related to biochemistry and genetics of microbial degradation. In addition, several bioinformatics tools for predicting toxicity and biodegradation of chemicals have been developed. Furthermore, the whole genomes of several potential degrading bacteria have been sequenced and annotated using bioinformatics tools. PMID- 24808765 TI - Bud Frazier's 1,000 th implantation of a ventricular assist device. PMID- 24808766 TI - The 1,000 th VAD, the great rivalry, and the grand experiment of the Texas Medical Center. PMID- 24808767 TI - State of the art of mechanical circulatory support. AB - Mechanical circulatory support of the failing heart has become an important means of treating end-stage heart disease. This rapidly growing therapeutic field has produced impressive clinical outcomes and has great potential to help thousands of otherwise terminal patients worldwide. In this review, we examine the state of the art of mechanical circulatory support: current practice, totally implantable systems of the future, evolving biventricular support mechanisms, the potential for myocardial recovery and adjunctive treatment methods, and miniaturized devices with expanded indications for therapy. PMID- 24808768 TI - Texas Heart Institute Medal and the Ray C. Fish Award for Scientific Achievement in Cardiovascular Diseases. PMID- 24808769 TI - The Odyssey of TAVR from concept to clinical reality. PMID- 24808770 TI - Telephonic terrorism. PMID- 24808771 TI - Sacrifice of a human heart. PMID- 24808772 TI - Cardiac magnetic resonance imaging for the investigation of cardiovascular disorders. Part 2: emerging applications. AB - Cardiac magnetic resonance imaging has emerged as a robust noninvasive technique for the investigation of cardiovascular disorders. The coming-of-age of cardiac magnetic resonance-and especially its widening span of applications-has generated both excitement and uncertainty in regard to its potential clinical use and its role vis-a-vis conventional imaging techniques. The purpose of this evidence based review is to discuss some of these issues by highlighting the current (Part 1, previously published) and emerging (Part 2) applications of cardiac magnetic resonance. Familiarity with the versatile uses of cardiac magnetic resonance will facilitate its wider clinical acceptance for improving the management of patients with cardiovascular disorders. PMID- 24808773 TI - Perioperative outcomes after on- and off-pump coronary artery bypass grafting. AB - Although numerous reports describe the results of off-pump coronary artery bypass grafting (CABG) at specialized centers and in select patient populations, it remains unclear how off-pump CABG affects real-world patient outcomes. We conducted a large, multicenter observational cohort study of perioperative death and morbidity in on-pump (ON) versus off-pump (OFF) CABG. We reviewed Veterans Affairs Surgical Quality Improvement Program data for all patients (N=65,097) who underwent isolated CABG from October 1997 through April 2011 (intention-to-treat data were available from 2005 onward). The primary outcome was perioperative (30 day or in-hospital) death; the secondary outcomes were perioperative stroke, dialysis dependence, reoperation for bleeding, mechanical circulatory support, myocardial infarction, ventilator support >= 48 hr, and mediastinitis. Propensity scores calculated from age, 17 preoperative risk factors, and year of surgery were used to match 8,911 OFF with 26,733 ON patients. In the complete cohort, compared with the ON patients (n=53,468), the OFF patients (n=11,629) had less perioperative death (2.02% vs 2.53%, P=0.0012) and lower incidences of all morbidities except perioperative myocardial infarction. In the matched cohort, perioperative death did not differ significantly between OFF and ON patients (1.94% vs 2.28%, P=0.06), but the OFF group had lower incidences of all morbidities except for perioperative myocardial infarction and mediastinitis. A subgroup intention-to-treat analysis yielded similar but smaller outcome differences between the ON and OFF groups. Off-pump CABG might be associated with decreased operative morbidity but did not affect operative death, compared with on-pump CABG. Future studies should examine the effect of off-pump CABG on long term outcomes. PMID- 24808774 TI - Staged balloon aortic valvuloplasty before standard aortic valve replacement in selected patients with severe aortic valve stenosis. AB - This study evaluated preoperative balloon aortic valvuloplasty (BAV) as a technique to decrease aortic valve replacement (AVR) risk in patients who have severe symptomatic aortic valve stenosis with substantial comorbidity. We report the outcomes of 18 high-risk patients who received BAV within 180 days before AVR from November 1993 through December 2011. Their median age was 78 years (range, 51-93 yr), and there were 11 men (61%). The pre-BAV median calculated Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) was 18.3% (range, 9.4% 50.7%). Preoperative left ventricular ejection fraction measured a median of 0.23 (range, 0.05-0.68), and the median aortic valve area index was 0.4 cm(2)/m(2) (range, 0.2-0.7 cm(2)/m(2)). The median interval from BAV to AVR was 28 days (range, 1-155 d). There were no strokes or deaths after BAV; however, 4 patients (22%) required mechanical circulatory support, 3 (17%) required femoral artery operation, and 1 (6%) developed severe aortic valve regurgitation. After BAV, the median STS PROM fell to 9.1% (range, 2.6%-25.7%) (compared with pre-BAV, P <0.001). Echocardiography before AVR showed that the median left ventricular ejection fraction had improved to 0.35 (range, 0.15-0.66), and the aortic valve area index to 0.5 cm(2)/m(2) (range, 0.3-0.7 cm(2)/m(2)) (compared with pre-BAV, both P <0.05). All patients received AVR. Operative death occurred in 2 patients (11%), and combined operative death and morbidity in 7 patients (39%). Staged BAV substantially reduces the operative risk associated with AVR in selected patients. PMID- 24808775 TI - Serum levels of soluble ICAM-1 in children with pulmonary artery hypertension. AB - This prospective cross-sectional study attempted to determine both the usefulness of the serum intercellular adhesion molecule-1 (ICAM-1) as a biomarker for pulmonary artery hypertension secondary to congenital heart disease and the nature of this marker's association with catheter angiographic findings. Our study included a total of 70 male and female children, comprising 30 patients with both pulmonary artery hypertension and congenital heart disease, 20 patients with congenital heart disease alone, and 20 healthy control subjects. Levels of ICAM-1 in plasma samples from all groups were measured by the enzyme-linked immunosorbent assay method. Cardiac catheterization was also performed in all patients. The mean serum ICAM-1 levels in pediatric patients who had congenital heart disease with and without pulmonary artery hypertension were 349.6 +/- 72.9 ng/mL and 312.3 +/- 69.5 ng/mL, respectively (P=0.002). In healthy control subjects, the mean serum ICAM-1 level was 231.4 +/- 60.4 ng/mL. According to the results of this study, the ICAM-1 level of the pulmonary artery hypertension group was significantly higher than those of the congenital heart disease group and the healthy control group. Correlation analysis showed that ICAM-1 level was correlated with systolic and mean pulmonary artery pressures (r=0.62, P=0.001; r=0.57, P=0.001)-which are 2 important values used in diagnosis of pulmonary artery hypertension. Moreover, receiver operating characteristic analysis yielded consistent results for the prediction of pulmonary artery hypertension. Therefore, we conclude that ICAM-1 has potential use as a biomarker for the diagnosis and follow-up of pulmonary artery hypertension. PMID- 24808776 TI - Bileaflet versus posterior-leaflet-only preservation in mitral valve replacement. AB - In the present study of mitral valve replacement, we investigated whether complete preservation of both leaflets (that is, the subvalvular apparatus) is superior to preservation of the posterior leaflet alone. Seventy patients who underwent mitral valve replacement in our clinic were divided into 2 groups: MVR B (n=16), in whom both leaflets were preserved, and MVR-P (n=54), in whom only the posterior leaflet was preserved. The preoperative and postoperative clinical and echocardiographic findings were evaluated retrospectively. No signs of left ventricular outflow tract obstruction were observed in either group. In the MVR-B group, no decrease was observed in left ventricular ejection fraction during the postoperative period, whereas a significant reduction was observed in the MVR-P group (P=0.003). No differences were found between the 2 groups in their need for inotropic agents or intra-aortic balloon pump support, or in cross-clamp time, duration of intensive care unit or hospital stays, postoperative development of new atrial fibrillation, or mortality rates. Bileaflet preservation prevented the decrease in left ventricular ejection fraction that usually followed preservation of the posterior leaflet alone. However, posterior leaflet preservation alone yielded excellent results in terms of decreased left ventricular diameter. Bileaflet preservation should be the method of choice to prevent further decreases in ejection fraction and to avoid death in patients who present with substantially impaired left ventricular function. PMID- 24808777 TI - Percutaneous retrograde transfemoral closure of mitral paravalvular leak in 3 patients without construction of an arteriovenous wire loop. AB - Percutaneous closure of paravalvular leaks has emerged as an alternative to repeated surgeries. Different percutaneous techniques and various devices have been used, off-label, for paravalvular leak closure. For mitral leaks, antegrade transseptal, retrograde transfemoral, and retrograde transapical techniques have been developed. In the antegrade transseptal approach, an arteriovenous guidewire loop is often created to advance the delivery sheath. In retrograde transfemoral closure, the wire in the left atrium is usually snared after transseptal puncture, to pull it from the femoral vein. The delivery sheath and closure device will subsequently be deployed from the left atrium. Each of these procedures takes time, is costly, and increases the risk of complications. We present the cases of 3 patients in whom we closed mitral paravalvular leaks by means of a retrograde transfemoral approach, with use of an AmplatzerTM Duct Occluder II device and without the construction of an arteriovenous wire loop. We think that this approach can be very useful in a specific group of patients reducing costs, fluoroscopy times, and complications related to transseptal puncture and construction of an arteriovenous wire loop. In our institution, this reported technique is routinely used for mitral paravalvular leak closure. PMID- 24808778 TI - Life-saving systemic thrombolysis in a patient with massive pulmonary embolism and a recent hemorrhagic cerebrovascular accident. AB - Massive pulmonary embolism is associated with mortality rates exceeding 50%. Current practice guidelines include the immediate administration of thrombolytic therapy in the absence of contraindications. However, thrombolysis for pulmonary embolism is said to be absolutely contraindicated in the presence of recent hemorrhagic stroke and other conditions. The current contraindications to thrombolytic therapy have been extrapolated from data on acute coronary syndrome and are not specific for venous thromboembolic disease. Some investigators have proposed that the current contraindications be viewed as relative, rather than absolute, in cases of high-risk pulmonary embolism. We present the case of a 60 year-old woman in whom massive pulmonary embolism led to cardiac arrest with pulseless electrical activity. Eight weeks earlier, she had sustained a hemorrhagic cerebrovascular accident-a classic absolute contraindication to thrombolytic therapy. Despite this practice guideline, we administered tissue plasminogen activator systemically in order to save the patient's life. This therapy did not evoke intracranial bleeding, and the patient was eventually discharged from the hospital. Until guidelines specific to venous thromboembolic disease are developed, we think that the current contraindications to thrombolysis should be considered on an individual basis in patients who are at high risk of death from massive pulmonary embolism. PMID- 24808779 TI - Is it ever wise to disregard absolute practice guidelines? Absolutely. PMID- 24808780 TI - Two cases of apical ballooning syndrome masking apical hypertrophic cardiomyopathy. AB - Apical akinesis and dilation in the absence of obstructive coronary artery disease is a typical feature of stress-induced (takotsubo) cardiomyopathy, whereas apical hypertrophy is seen in apical-variant hypertrophic cardiomyopathy. We report the cases of 2 patients who presented with takotsubo cardiomyopathy and were subsequently found to have apical-variant hypertrophic cardiomyopathy, after the apical ballooning from the takotsubo cardiomyopathy had resolved. The first patient, a 43-year-old woman with a history of alcohol abuse, presented with shortness of breath, electrocardiographic and echocardiographic features consistent with takotsubo cardiomyopathy, and no significant coronary artery disease. An echocardiogram 2 weeks later revealed a normal left ventricular ejection fraction and newly apparent apical hypertrophy. The 2nd patient, a 70 year-old woman with pancreatitis, presented with chest pain, apical akinesis, and a left ventricular ejection fraction of 0.39, consistent with takotsubo cardiomyopathy. One month later, her left ventricular ejection fraction was normal; however, hypertrophy of the left ventricular apex was newly noted. To our knowledge, these are the first reported cases in which apical-variant hypertrophic cardiomyopathy was masked by apical ballooning from stress-induced cardiomyopathy. PMID- 24808781 TI - Takotsubo cardiomyopathy as a sequela of elective direct-current cardioversion for atrial fibrillation. AB - In takotsubo cardiomyopathy, the clinical appearance is that of an acute myocardial infarction in the absence of obstructive coronary artery disease, with apical ballooning of the left ventricle. The condition is usually precipitated by a stressful physical or psychological experience. The mechanism is unknown but is thought to be related to catecholamine excess. We present the case of a 67-year old woman who experienced cardiogenic shock caused by takotsubo cardiomyopathy, immediately after undergoing elective direct-current cardio-version for atrial fibrillation. After a course complicated by left ventricular failure, cardiogenic shock, and ventricular tachycardia, she made a complete clinical and echocardiographic recovery. In addition to this case, we discuss the possible direct effect of cardioversion in takotsubo cardiomyopathy. PMID- 24808782 TI - Emergent surgical pulmonary embolectomy in a pregnant woman: case report and literature review. AB - Acute pulmonary embolism is a leading cause of death during pregnancy and delivery in the United States. We describe the case of a 25-year-old woman who presented in cardiogenic shock in week 38 of her first pregnancy. After the emergent cesarean delivery of a healthy male neonate, the mother underwent immediate surgical pulmonary embolectomy. We confirmed the diagnosis of pulmonary embolism intraoperatively by means of transesophageal echocardiography and removed large clots from the patient's pulmonary arteries. Mother and child were doing well, 27 months later. In addition to presenting our patient's case, we discuss the other relevant reports and the options for treating massive pulmonary embolism during pregnancy. PMID- 24808783 TI - Use of a sandwich technique to repair a left ventricular rupture after mitral valve replacement. AB - One difficulty with external repair of left ventricular rupture after mitral valve replacement is collateral bleeding in friable myocardium adjacent to the rupture. The bleeding is caused by tension on the closing sutures, whether or not pledgets have been used. We report the case of a 69-year-old woman who underwent an uneventful mitral valve replacement. After cardiopulmonary bypass was terminated, brisk bleeding started from high in the posterior left ventricular wall, typical of a type III defect. We undertook external repair, placing a plug of Teflon felt into the cavity of the rupture and sandwiching it into place with pledgeted mattress and figure-of-8 sutures. The space occupied by the plug decreased the distance needed to obliterate the defect and thereby reduced the tension on the sutures necessary to achieve hemostasis. This simple technique enabled closure of the defect and avoided collateral tears that would have compromised an otherwise successful repair. Two years postoperatively, the patient had normal mitral valve function and no left ventricular aneurysm. In addition to reporting the patient's case, we review the types of left ventricular rupture that can occur during mitral valve replacement and discuss the various repair options. PMID- 24808784 TI - Endovascular repair as a bridge to surgical repair of an aortobronchial fistula complicating chronic residual aortic dissection. AB - Endovascular and open surgical repair have been used in patients with descending thoracic aortic dissection; however, the appropriate treatment is debated. We describe the case of a 60-year-old woman who had a symptomatic, chronic, residual, descending thoracic aortic dissection that was complicated by an aortobronchial fistula. She underwent emergent thoracic endovascular stent grafting but remained symptomatic. Computed tomographic angiograms showed a contained rupture into the lower lobe of the left lung. The patient underwent definitive surgery to remove the stents, reconstruct the aorta, and resect the nonviable lung tissue. The remainder of her postoperative course was uneventful, and she was discharged from the hospital 13 days after the 2nd operation. Results of genetic testing confirmed an earlier presumptive diagnosis of Marfan syndrome. In an emergency, the best initial option for patients with a complicated descending thoracic aortic dissection might be thoracic endovascular aortic repair, which could serve as a bridge to definitive open repair. PMID- 24808785 TI - Right ventricular sarcoidosis: is it time for updated diagnostic criteria? AB - A 55-year-old woman with a history of complete heart block, atrial flutter, and progressive right ventricular failure was referred to our tertiary care center to be evaluated for cardiac transplantation. The patient's clinical course included worsening right ventricular dysfunction for 3 years before the current evaluation. Our clinical findings raised concerns about arrhythmogenic right ventricular cardiomyopathy. Noninvasive imaging, including a positron emission tomographic scan, did not reveal obvious myocardial pathologic conditions. Given the end-stage nature of the patient's right ventricular failure and her dependence on inotropic agents, she underwent urgent listing and subsequent heart transplantation. Pathologic examination of the explanted heart revealed isolated right ventricular sarcoidosis with replacement fibrosis. Biopsy samples of the cardiac allograft 6 months after transplantation showed no recurrence of sarcoidosis. This atypical presentation of isolated cardiac sarcoidosis posed a considerable diagnostic challenge. In addition to discussing the patient's case, we review the relevant medical literature and discuss the need for updated differential diagnostic criteria for end-stage right ventricular failure that mimics arrhythmogenic right ventricular cardiomyopathy. PMID- 24808786 TI - Acute coronary thrombosis and multiple coronary aneurysms in a 22-year-old man with the human immunodeficiency virus. AB - The human immunodeficiency virus (HIV) can cause diverse cardiovascular complications. In HIV patients on antiretroviral therapy, the prevalence of myocardial infarction has steadily increased over the years. Young patients who are naive to antiretroviral therapy and who experience coronary events are not well represented in the medical literature. We describe the case of a 22-year-old man, infected with HIV for 4 years and never treated with antiretroviral therapy, who emergently presented with a non-ST-segment-elevation myocardial infarction. Coronary angiograms revealed thrombosis and multiple coronary artery aneurysms; however, no areas of atherosclerotic stenosis were apparent. He was successfully treated with coronary stenting, antiplatelet therapy, and anticoagulation. Nine months after the initial presentation, he exhibited excellent exercise capacity, and no ischemia was evident. We discuss the various therapeutic approaches in this case. PMID- 24808787 TI - Sudden cardiac arrest at the finish line: in coronary ectopia, the cause of ischemia is from intramural course, not ostial location. AB - A 26-year-old woman, a well-trained runner, had a sudden cardiac arrest just before crossing the finish line of a marathon. She was rapidly resuscitated and was later found to have an ectopic origin of the left coronary artery. This anomaly was surgically repaired by translocating the ostium from the right to the left sinus of Valsalva. Her difficult postoperative course prompted further coronary evaluation, which revealed severe stenosis of the neoostium. The patient underwent a second operation: this time, the stenosis was bypassed via a left internal mammary artery-to-left anterior descending coronary artery (LAD) graft. Hypoplasia of the LAD and spasm during manipulation caused the graft to fail, necessitating double-stent angioplasty of the left main ostium and the LAD 2 months later. At the patient's 6-month follow-up examination, she had no further evidence of functional ischemia, and she resumed jogging. Because the mode and mechanism of the patient's condition and events were documented in unusual detail, this case furthers our understanding of sudden cardiac arrest in athletes who have rare coronary anomalies. We conclude that ectopia of a coronary artery does not itself cause potentially fatal ischemia. Rather, these events are due to the ectopic artery's intramural proximal course within the aortic media, which might result in critical stenosis by means of hypoplasia or lateral compression of the artery. PMID- 24808788 TI - Microvascular permeability changes might explain cardiac tamponade after alcohol septal ablation for hypertrophic cardiomyopathy. AB - Various sequelae of alcohol septal ablation for hypertrophic obstructive cardiomyopathy have been reported. Of note, some cases of cardiac tamponade after alcohol septal ablation cannot be well explained. We describe the case of a 78 year-old woman with hypertrophic obstructive cardiomyopathy in whom cardiac tamponade developed one hour after alcohol septal ablation, probably unrelated to mechanical trauma. At that time, we noted a substantial difference in the red blood cell-to-white blood cell ratio between the pericardial effusion (1,957.4) and the peripheral blood (728.3). In addition to presenting the patient's case, we speculate that a possible mechanism for acute tamponade--alcohol-induced changes in microvascular permeability--is a reasonable explanation for cases of alcohol septal ablation that are complicated by otherwise-unexplainable massive pericardial effusions. PMID- 24808789 TI - A case of survival after cardiac arrest and 31/2 hours of resuscitation. AB - Although survival rates after cardiac arrest remain low, new techniques are improving patients' outcomes. We present the case of a 40-year-old man who survived a cardiac arrest that lasted approximately 31/2 hours. Resuscitation was performed with strict adherence to American Heart Association/American College of Cardiology Advanced Cardiac Life Support guidelines until bedside extracorporeal membrane oxygenation could be placed. A hypothermia protocol was initiated immediately afterwards. The patient had a full neurologic recovery and was bridged from dual ventricular assist devices to a total artificial heart. On hospital day 160, he underwent orthotopic heart and cadaveric kidney transplantation. On day 179, he was discharged from the hospital in ambulatory condition. To our knowledge, this is the only reported case in which a patient survived with good neurologic outcomes after a resuscitation that lasted as long as 31/2 hours. Documented cases of resuscitation with good recovery after prolonged arrest give hope for improved overall outcomes in the future. PMID- 24808790 TI - Infective endocarditis caused by Neisseria elongata on a native tricuspid valve and confirmed by DNA sequencing. AB - Neisseria elongata, a common oral bacterium, has been recognized as a cause of infections such as infective endocarditis, septicemia, and osteomyelitis. Neisseria-induced infective endocarditis, although infrequently reported, typically arises after dental procedures. Without antibiotic therapy, its complications can be severe. We report the case of a 27-year-old man who presented with fever, severe dyspnea, and a leg abscess from cellulitis. An echocardiogram showed a vegetation-like echogenic structure on the septal leaflet of the patient's native tricuspid valve, and an insignificant Gerbode defect. Three blood cultures grew gram-negative, antibiotic-susceptible coccobacilli that were confirmed to be N. elongata. Subsequent DNA sequencing conclusively isolated N. elongata subsp nitroreducens as the organism responsible for the infective endocarditis. The patient recovered after 21 days of antibiotic therapy. In addition to the patient's unusual case, we discuss the nature and isolation of N. elongata and its subspecies. PMID- 24808791 TI - Large lipomatous hypertrophy of the interventricular septum. AB - We present the case of a 58-year-old woman who had large lipomatous hypertrophy of the interventricular septum, a condition that is reported very infrequently. Preoperative cardiac magnetic resonance images revealed an inhomogeneous, infiltrating mass that was suppressed in fat-suppression mode. The extensive mass was causing right ventricular dysfunction, so we excised it through a right ventricular approach. The findings on histologic analysis of the mass were consistent with lipomatous hypertrophy. The patient died of septic shock on the 28th postoperative day. In addition to the patient's case, we discuss the characteristics and diagnosis of this rare entity. PMID- 24808792 TI - ST-elevation myocardial infarction and myelodysplastic syndrome with acute myeloid leukemia transformation. AB - Acute myocardial infarction and acute myeloid leukemia are rarely reported as concomitant conditions. The management of ST-elevation myocardial infarction (STEMI) in patients who have acute myeloid leukemia is challenging: the leukemia related thrombocytopenia, platelet dysfunction, and systemic coagulopathy increase the risk of bleeding, and the administration of thrombolytic agents can be fatal. We report the case of a 76-year-old man who presented emergently with STEMI, myelodysplastic syndrome, and newly recognized acute myeloid leukemia transformation. Standard antiplatelet and anticoagulation therapy were contraindicated by the patient's thrombocytopenia and by his reported ecchymosis and gingival bleeding upon admission. He declined cardiac catheterization, was provided palliative care, and died 2 hours after hospital admission. We searched the English-language medical literature, found 8 relevant reports, and determined that the prognosis for patients with concomitant STEMI and acute myeloid leukemia is clearly worse than that for either individual condition. No guidelines exist to direct the management of STEMI and concomitant acute myeloid leukemia. In 2 reports, dual antiplatelet therapy, anticoagulation, and drug-eluting stent implantation were used without an increased risk of bleeding in the short term, even in the presence of thrombocytopenia. However, we think that a more conservative approach--balloon angioplasty with the provisional use of bare-metal stents--might be safer. Simultaneous chemotherapy for the acute myeloid leukemia is crucial. Older age seems to be a major risk factor: patients too frail for emergent treatment can die within hours or days. PMID- 24808793 TI - Evaluating patent ductus arteriosus during percutaneous closure: correlation between intravascular ultrasonography and computed tomographic angiography. PMID- 24808794 TI - Pulmonary valvular stenosis in L-transposition of the great arteries with ventricular septal defect. PMID- 24808795 TI - Intracardiac thrombus-in-transit characterized on 3-dimensional transesophageal echocardiography. PMID- 24808796 TI - Severe mitral annular calcification: insights from multimodality imaging. PMID- 24808797 TI - Novel treatment of an infiltrating cardiac fibrosarcoma. PMID- 24808798 TI - An intra-articular ganglion cyst in a patient with juvenile idiopathic arthritis. AB - We report an intra-articular ganglion cyst (IAGC) presenting as knee pain and a mass in a patient with longstanding Juvenile Idiopathic Arthritis (JIA). We could not find a similar case of an IAGC occurring in the knee of JIA patients in the literature. IAGC may need to be included as a possibility in patients with inflammatory arthritis with new-onset knee pain, especially in those with a palpable mass. MRI was useful in distinguishing IAGC from more worrisome causes of a knee mass. Orthopedic input was helpful in diagnosis and treatment. In addition, methotrexate therapy was effective in bringing about a long-lasting remission. PMID- 24808799 TI - Tunable antireflection from conformal Al-doped ZnO films on nanofaceted Si templates. AB - Photon harvesting by reducing reflection loss is the basis of photovoltaic devices. Here, we show the efficacy of Al-doped ZnO (AZO) overlayer on ion beam synthesized nanofaceted silicon for suppressing reflection loss. In particular, we demonstrate thickness-dependent tunable antireflection (AR) from conformally grown AZO layer, showing a systematic shift in the reflection minima from ultraviolet to visible to near-infrared ranges with increasing thickness. Tunable AR property is understood in light of depth-dependent refractive index of nanofaceted silicon and AZO overlayer. This improved AR property significantly increases the fill factor of such textured heterostructures, which reaches its maximum for 60-nm AZO compared to the ones based on planar silicon. This thickness matches with the one that shows the maximum reduction in surface reflectance. PACS: 81.07.-b; 42.79.Wc; 81.16.Rf; 81.15.Cd. PMID- 24808801 TI - Strong anisotropic lifetime orientation distributions of a two-level quantum emitter around a plasmonic nanorod. AB - Spontaneous emission lifetime orientation distributions of a two-level quantum emitter in metallic nanorod structures are theoretically investigated by the rigorous electromagnetic Green function method. It was found that spontaneous emission lifetime strongly depended on the transition dipole orientation and the position of the emitter. The anisotropic factor defined as the ratio between the maximum and minimum values of the lifetimes along different dipole orientations can reach up to 10(3). It is much larger than those in dielectric structures which are only several times usually. Our results show that the localized plasmonic resonance effect provides a new degree of freedom to effectively control spontaneous emission by the dipole orientation of the quantum emitters. PMID- 24808800 TI - Microwave-assisted green synthesis of Ag/reduced graphene oxide nanocomposite as a surface-enhanced Raman scattering substrate with high uniformity. AB - A nanocomposite of silver nanoparticles/reduced graphene oxide (Ag/rGO) has been fabricated as a surface-enhanced Raman scattering (SERS) substrate owing to the large surface area and two-dimensional nanosheet structure of rGO. A facile and rapid microwave-assisted green route has been used for the formation of Ag nanoparticles and the reduction of graphene oxide simultaneously with L-arginine as the reducing agent. By increasing the cycle number of microwave irradiation from 1 and 4 to 8, the mean diameters of Ag nanoparticles deposited on the surface of rGO increased from 10.3 +/- 4.6 and 21.4 +/- 10.5 to 41.1 +/- 12.6 nm. The SERS performance of Ag/rGO nanocomposite was examined using the common Raman reporter molecule 4-aminothiophenol (4-ATP). It was found that the Raman intensity of 4-ATP could be significantly enhanced by increasing the size and content of silver nanoparticles deposited on rGO. Although the Raman intensities of D-band and G-band of rGO were also enhanced simultaneously by the deposited Ag nanoparticles which limited the further improvement of SERS detection sensitivity, the detectable concentration of 4-ATP with Ag/rGO nanocomposite as the SERS substrate still could be lowered to be 10(-10) M and the enhancement factor could be increased to 1.27 * 10(10). Furthermore, it was also achievable to lower the relative standard deviation (RSD) values of the Raman intensities to below 5%. This revealed that the Ag/rGO nanocomposite obtained in this work could be used as a SERS substrate with high sensitivity and homogeneity. PMID- 24808802 TI - A novel hierarchical Pt- and FTO-free counter electrode for dye-sensitized solar cell. AB - A novel hierarchical Pt- and FTO-free counter electrode (CE) for the dye sensitized solar cell (DSSC) was prepared by spin coating the mixture of TiO2 nanoparticles and poly(3,4-ethylenedioxy-thiophene):poly(styrenesulfonate) (PEDOT:PSS) solution onto the glass substrate. Compared with traditional Pt/FTO CE, the cost of the new CE is dramatically reduced by the application of bilayer TiO2-PEDOT:PSS/PEDOT:PSS film and the glass substrate. The sheet resistance of this composite film is 35 Omega sq(-1) and is low enough to be used as an electrode. The surface morphologies of TiO2-PEDOT:PSS layer and modified PEDOT:PSS layer were characterized by scanning electron microscope, which shows that the former had larger surface areas than the latter. Electrochemical impedance spectra and Tafel polarization curves prove that the catalytic activity of TiO2-PEDOT:PSS/PEDOT:PSS/glass CE is higher than that of PEDOT:PSS/FTO CE and is similar to Pt/FTO CE's. This new fabricated device with TiO2 PEDOT:PSS/PEDOT:PSS/glass CE achieves a high power conversion efficiency (PCE) of 4.67%, reaching 91.39% of DSSC with Pt/FTO CE (5.11%). PMID- 24808803 TI - Reasons for deficiencies in health information laws in Iran. AB - INTRODUCTION: Laws, regulations, and guidelines are necessary external stimuli that influence the management of health data. They serve as external mechanisms for the reinforcement and quality improvement of health information. Despite their inevitable significance, such laws have not yet been sufficiently formulated in Iran. The current study explores reasons for inadequacies in the health information laws. METHODS: In this descriptive study, health-related laws and regulations from the United States, the United Kingdom, and Iran were first collected, using a review of the literature and available data. Then, bearing in mind the significant deficiencies in health information laws in Iran, the researchers asked a group of managers and policy makers in the healthcare field to complete a questionnaire to explore the reasons for such deficiencies. A test retest method was used to determine the reliability of the questionnaire. Descriptive statistics and tables were then used to analyze the data. FINDINGS: Experts' opinion on reasons for deficiencies in health information laws and regulations in Iran are divided into four principal groups: cultural conditions of the community, the status of the health information system, characteristics of managers and policy makers in the healthcare field, and awareness level among public beneficiaries about laws. CONCLUSIONS: The health departments or ministries in developed countries have brought about suitable changes in their affiliated organizations by developing external data enhancement mechanisms such as information-related laws and standards, and accreditation of healthcare organizations. At the same time, healthcare organizations, under obligations imposed by the external forces, try to elevate the quality of information. Therefore, this study suggests that raising healthcare managers' awareness of the importance of passing health information laws, as an effective external mechanism, is essential. PMID- 24808805 TI - Leader-member exchange relationships in health information management. AB - This article seeks to raise awareness of the leader-member exchange (LMX) theory of leadership and its potential benefit to the health information management (HIM) profession. A literature review that was conducted identified a leadership challenge for HIM practitioners. The review also provides examples of leadership definitions, and potential benefits of LMX to HIM professionals in leading people and influencing leaders in their organizations. The LMX concept may be an avenue to investigate in preparing future and current HIM professionals for leadership. PMID- 24808804 TI - Personal genomic information management and personalized medicine: challenges, current solutions, and roles of HIM professionals. AB - In recent years, the term personalized medicine has received more and more attention in the field of healthcare. The increasing use of this term is closely related to the astonishing advancement in DNA sequencing technologies and other high-throughput biotechnologies. A large amount of personal genomic data can be generated by these technologies in a short time. Consequently, the needs for managing, analyzing, and interpreting these personal genomic data to facilitate personalized care are escalated. In this article, we discuss the challenges for implementing genomics-based personalized medicine in healthcare, current solutions to these challenges, and the roles of health information management (HIM) professionals in genomics-based personalized medicine. PMID- 24808806 TI - Interactive web-based portals to improve patient navigation and connect patients with primary care and specialty services in underserved communities. AB - This article presents a case study in the redesign, development, and implementation of a web-based healthcare clinic search tool for virtual patient navigation in underserved populations in Texas. It describes the workflow, assessment of system requirements, and design and implementation of two online portals: Project Safety Net and the Breast Health Portal. The primary focus of the study was to demonstrate the use of health information technology for the purpose of bridging the gap between underserved populations and access to healthcare. A combination of interviews and focus groups was used to guide the development process. Interviewees were asked a series of questions about usage, usability, and desired features of the new system. The redeveloped system offers a multitier architecture consisting of data, business, and presentation layers. The technology used in the new portals include Microsoft .NET Framework 3.5, Microsoft SQL Server 2008, Google Maps JavaScript API v3, jQuery, Telerik RadControls (ASP.NET AJAX), and HTML. The redesigned portals have 548 registered clinics, and they have averaged 355 visits per month since their launch in late 2011, with the average user visiting five pages per visit. Usage has remained relatively constant over time, with an average of 142 new users (40 percent) each month. This study demonstrates the successful application of health information technology to improve access to healthcare and the successful adoption of the technology by targeted end users. The portals described in this study could be replicated by health information specialists in other areas of the United States to address disparities in healthcare access. PMID- 24808807 TI - Evaluation of an interactive surveillance system for monitoring acute bacterial infections in Nigeria. AB - OBJECTIVE: The objective of the study is to evaluate the usability of a stand alone, Internet-enabled interactive surveillance system designed to monitor the burden of invasive bacterial infections among children in Nigeria. METHOD: A convenience sample of 10 participants were enrolled in a training session on using the system at a hospital in Nigeria. The participants performed a series of tasks assessing their ability to use the system. System usability was assessed using a System Usability Scale (SUS) questionnaire. RESULTS: The majority of participants found the system easy to use (90 percent; n = 9) and reported confidence in using the system. The average SUS score was 77.8. A total of 30 percent (n = 3) of the study participants had exceptional usability scores, 20 percent (n = 2) showed acceptable scores, and 10 percent (n = 1) had a good score. CONCLUSION: Further evaluation of the system will help gauge additional challenges during its long-term utilization. If successful, the system could also be deployed in other resource poor-environments. PMID- 24808808 TI - Electronic prescribing: improving the efficiency and accuracy of prescribing in the ambulatory care setting. AB - Electronic prescribing (e-prescribing) is an important part of the nation's push to enhance the safety and quality of the prescribing process. E-prescribing allows providers in the ambulatory care setting to send prescriptions electronically to the pharmacy and can be a stand-alone system or part of an integrated electronic health record system. The methodology for this study followed the basic principles of a systematic review. A total of 47 sources were referenced. Results of this research study suggest that e-prescribing reduces prescribing errors, increases efficiency, and helps to save on healthcare costs. Medication errors have been reduced to as little as a seventh of their previous level, and cost savings due to improved patient outcomes and decreased patient visits are estimated to be between $140 billion and $240 billion over 10 years for practices that implement e-prescribing. However, there have been significant barriers to implementation including cost, lack of provider support, patient privacy, system errors, and legal issues. PMID- 24808809 TI - Health information exchange between jails and their communities: a bridge that is needed under healthcare reform. AB - Jails have often been compared to islands because they are thought to be cut off from the community both physically and perceptually. Few people understand that besides being places of confinement, jails function as health care providers. The separation of jails from community results in disjointed health care services and treatment for individuals cycling in and out of jail. Healthcare providers in the community have little knowledge of the care their patients have received in jail; the same can be said of jail health providers about care provided in the community. With the passage of the Affordable Care Act (ACA) and the Health Information Technology for Economic and Clinical Health Act (HITECH), the federal government took the lead respectively in expanding health insurance coverage and in spurring the adoption of electronic health records (EHRs) and the development of health information exchanges (HIEs). Taken together, these initiatives place a strong emphasis on promoting continuity of care. With the expansion of Medicaid under the ACA, many of the individuals leaving jail will have access to health insurance for the first time. Community-based providers to the newly insured will want to know about the care that was provided in the jail. The developing technological infrastructure would seem to offer the best way to access this information. However linking the community and jail information systems is not just a technological issue, but requires the cooperation of all stakeholders. THIS PAPER PRESENTS TWO CASE STUDIES: one in which a single champion made the decision to link the jail health care system to the local HIE and the other where all stakeholders were included in the process. In the first case study, the jail healthcare system reverted to its "island" status when the HIE was abandoned without protest from community stakeholders. In the second case study, the multiple stakeholder approach, while not necessarily a complete guarantee of long term success, ensured that the jail healthcare system could not so easily go back to being an island cut off from the rest of the community. PMID- 24808810 TI - At the intersection of health and justice. PMID- 24808811 TI - Giving raw data a chance to talk: a demonstration of exploratory visual analytics with a pediatric research database using Microsoft Live Labs Pivot to promote cohort discovery, research, and quality assessment. AB - Secondary use of large and open data sets provides researchers with an opportunity to address high-impact questions that would otherwise be prohibitively expensive and time consuming to study. Despite the availability of data, generating hypotheses from huge data sets is often challenging, and the lack of complex analysis of data might lead to weak hypotheses. To overcome these issues and to assist researchers in building hypotheses from raw data, we are working on a visual and analytical platform called PRD Pivot. PRD Pivot is a de identified pediatric research database designed to make secondary use of rich data sources, such as the electronic health record (EHR). The development of visual analytics using Microsoft Live Labs Pivot makes the process of data elaboration, information gathering, knowledge generation, and complex information exploration transparent to tool users and provides researchers with the ability to sort and filter by various criteria, which can lead to strong, novel hypotheses. PMID- 24808812 TI - Justice-involved health information: policy and practice advances in Connecticut. AB - Sharing health information across correctional boundaries presents many challenges. Three such projects in Connecticut may be of value in informing other jurisdictions of similar opportunities. This article describes the development and implementation of an interagency release of information (ROI) document and process, a voucher program to provide discharge medications at the time of release, and a statewide research-oriented health information network. PMID- 24808814 TI - Leveraging the cloud for electronic health record access. AB - Healthcare providers are under increasing pressure to enable widespread access to their electronic health record (EHR) systems for the patients they serve; the meaningful use incentive programs are perhaps the most significant driver encouraging this access. Elsewhere, the cloud has become extremely efficient and successful at establishing digital identities for individuals and making them interoperable across heterogeneous systems. As the healthcare industry contemplates providing patients access to their EHRs, the solution should leverage existing cloud investment, not duplicate it. Through an analysis of industry standards and similar work being performed in other industries, a trust framework has been derived for exchanging identity information. This research lays out a comprehensive structure that healthcare providers can easily use to integrate their EHRs with the cloud for identity validation, while meeting compliance guidelines for security and privacy. Further, this research has been implemented at a large regional hospital, yielding immediate and tangible improvements. PMID- 24808813 TI - Factors in medical student beliefs about electronic health record use. AB - Healthcare providers' ongoing investment in electronic health records (EHRs) necessitates an understanding of physicians' expectations about using EHRs. Such understanding may aid educators and administrators when utilizing scarce resources during EHR training and implementation activities. This study aimed to link individual medical student characteristics to their perceptions of EHRs' ease of use and usefulness. This study employed a cross-sectional survey of 126 third-year medical students at a large southeastern university. Using a questionnaire designed for this study and containing previously validated items, the study team measured and related students' expectations about EHR ease of use and usefulness to their computer self-efficacy, openness to change, personality traits, and demographic characteristics. On a seven-point scale, men reported, on average, ease-of-use scores that were 0.71 higher than women's (p < .001). Also, increased computer self-efficacy related to higher expectations of EHR ease of use (p < .01) and usefulness (p < .05). Openness-to-change scores were also associated with higher expectations of EHR ease of use (p < .01) and usefulness (p < .001). Finally, a more conscientious personality was positively associated with EHR ease of use (p < .01). Our findings suggest that medical educators and administrators may consider targeting EHR management strategies on the basis of individual differences. Enhanced training and support interventions may be helpful to women or to clinicians with lower computer self-efficacy, lower openness to change, or less conscientious personalities. Also, current and future physicians who rate higher in terms of self-efficacy, openness to change, or conscientiousness may be useful as champions of EHR use among their peers. PMID- 24808815 TI - Evaluation of inpatient clinical documentation readiness for ICD-10-CM. AB - This research study examined the gaps in documentation that occur when coding in ICD-10-CM. More than 4,000 diagnoses from all chapters were coded from 656 electronic documents obtained from a large integrated healthcare facility at the time the study was conducted (2012). After the documents were coded, areas for documentation improvement were identified for chapters that resulted in deficiencies in documentation, and a quick reference guide was developed. The overall absent documentation percentage was 15.4 percent. The 10 chapters with the highest percentage of absent documentation were chapter 7 (Diseases of Eye and Adnexa), with 67.65 percent (p < .001); chapter 8 (Diseases of Ear and Mastoid Process), with 63.64 percent (p < .001); chapter 13 (Diseases of the Musculoskeletal System and Connective Tissue), with 46.05 percent (p < .001); chapter 14 (Diseases of the Genitourinary System), with 40.29 percent (p < .001); chapter 10 (Diseases of Respiratory System), with 35.52 percent (p < .001); chapter 1 (Infectious and Parasitic Diseases), with 32.88 percent (p < .001); chapter 12 (Diseases of the Skin and Subcutaneous Tissue), with 32.35 percent (p < .001); chapter 2 (Neoplasms), with 25.45 percent (p < .001); chapter 4 (Endocrine, Nutritional and Metabolic Diseases), with 14.58 percent (p < .001); and chapter 17 (Congenital Malformations, Deformations, and Chromosomal Abnormalities), with 12.50 percent. We addressed the deficient areas in the quick reference guide developed for clinicians and technology vendors. Having complete and accurate documentation would benefit both the clinician and the patient in providing the highest quality of care. PMID- 24808817 TI - The association between senior student tobacco use rate at school and alternative tobacco product use among junior students in Canadian secondary schools. AB - BACKGROUND: The use of alternative tobacco products (ATPs) has grown in popularity among Canadian youth. This study examined the association between a school-level characteristic (the senior student tobacco use rate) and the current use of manufactured cigarettes, little cigars or cigarillos, cigars, roll-your own cigarettes, smokeless tobacco (SLT), and a hookah among junior students. METHODS: This study used nationally representative Canadian data from 29,495 students in grades 9 to 12 as part of the 2010/2011 Youth Smoking Survey. For each ATP, we described rates of senior and junior tobacco use, calculated the variance attributed to school-level factors, and examined the association between the senior student (grades 11 and 12) tobacco use rate and the current use of each ATP among junior students (grades 9 and 10) while accounting for relevant student-level characteristics. SAS 9.3 was used for all analyses. RESULTS: Over half of schools sampled had senior students that reported using each ATP. School level differences accounted for between 14.1% and 29.7% of the variability in ATP current use among junior students. Each one percent increase in the number of senior students at a school that currently use manufactured cigarettes, SLT, or a hookah was significantly independently associated with an increased likelihood that a junior student at that school currently used manufactured cigarettes (OR 1.04, 95% CI 1.01 to 1.06), SLT (OR 1.14, 95% CI 1.06 to 1.24), or a hookah (OR 1.09, 95% CI 1.03 to 1.14). CONCLUSIONS: Characteristics of the school environment a junior student attends appear to play an important role in ATP use, and tobacco control programs and policies should be designed to ensure that they include strategies to curb the use of all tobacco products. Additional evidence is needed for the impact of comprehensive school-based tobacco control approaches. PMID- 24808818 TI - Cognitive processing load during listening is reduced more by decreasing voice similarity than by increasing spatial separation between target and masker speech. AB - We investigated changes in speech recognition and cognitive processing load due to the masking release attributable to decreasing similarity between target and masker speech. This was achieved by using masker voices with either the same (female) gender as the target speech or different gender (male) and/or by spatially separating the target and masker speech using HRTFs. We assessed the relation between the signal-to-noise ratio required for 50% sentence intelligibility, the pupil response and cognitive abilities. We hypothesized that the pupil response, a measure of cognitive processing load, would be larger for co-located maskers and for same-gender compared to different-gender maskers. We further expected that better cognitive abilities would be associated with better speech perception and larger pupil responses as the allocation of larger capacity may result in more intense mental processing. In line with previous studies, the performance benefit from different-gender compared to same-gender maskers was larger for co-located masker signals. The performance benefit of spatially separated maskers was larger for same-gender maskers. The pupil response was larger for same-gender than for different-gender maskers, but was not reduced by spatial separation. We observed associations between better perception performance and better working memory, better information updating, and better executive abilities when applying no corrections for multiple comparisons. The pupil response was not associated with cognitive abilities. Thus, although both gender and location differences between target and masker facilitate speech perception, only gender differences lower cognitive processing load. Presenting a more dissimilar masker may facilitate target-masker separation at a later (cognitive) processing stage than increasing the spatial separation between the target and masker. The pupil response provides information about speech perception that complements intelligibility data. PMID- 24808816 TI - Position paper on the importance of psychosocial factors in cardiology: Update 2013. AB - BACKGROUND: The rapid progress of psychosomatic research in cardiology and also the increasing impact of psychosocial issues in the clinical daily routine have prompted the Clinical Commission of the German Heart Society (DGK) to agree to an update of the first state of the art paper on this issue which was originally released in 2008. METHODS: The circle of experts was increased, general aspects were implemented and the state of the art was updated. Particular emphasis was dedicated to coronary heart diseases (CHD), heart rhythm diseases and heart failure because to date the evidence-based clinical knowledge is most advanced in these particular areas. Differences between men and women and over the life span were considered in the recommendations as were influences of cognitive capability and the interactive and synergistic impact of classical somatic risk factors on the affective comorbidity in heart disease patients. RESULTS: A IA recommendation (recommendation grade I and evidence grade A) was given for the need to consider psychosocial risk factors in the estimation of coronary risks as etiological and prognostic risk factors. Furthermore, for the recommendation to routinely integrate psychosocial patient management into the care of heart surgery patients because in these patients, comorbid affective disorders (e.g. depression, anxiety and post-traumatic stress disorder) are highly prevalent and often have a malignant prognosis. A IB recommendation was given for the treatment of psychosocial risk factors aiming to prevent the onset of CHD, particularly if the psychosocial risk factor is harmful in itself (e.g. depression) or constrains the treatment of the somatic risk factors. Patients with acute and chronic CHD should be offered anti-depressive medication if these patients suffer from medium to severe states of depression and in this case medication with selective reuptake inhibitors should be given. In the long-term course of treatment with implanted cardioverter defibrillators (ICDs) a subjective health technology assessment is warranted. In particular, the likelihood of affective comorbidities and the onset of psychological crises should be carefully considered. CONCLUSIONS: The present state of the art paper presents an update of current empirical evidence in psychocardiology. The paper provides evidence-based recommendations for the integration of psychosocial factors into cardiological practice and highlights areas of high priority. The evidence for estimating the efficiency for psychotherapeutic and psychopharmacological interventions has increased substantially since the first release of the policy document but is, however, still weak. There remains an urgent need to establish curricula for physician competence in psychodiagnosis, communication and referral to ensure that current psychocardiac knowledge is translated into the daily routine. PMID- 24808819 TI - Lifetime benefits of musical training. PMID- 24808820 TI - Delegation to automaticity: the driving force for cognitive evolution? AB - The ability to delegate control over repetitive tasks from higher to lower neural centers may be a fundamental innovation in human cognition. Plausibly, the massive neurocomputational challenges associated with the mastery of balance during the evolution of bipedality in proto-humans provided a strong selective advantage to individuals with brains capable of efficiently transferring tasks in this way. Thus, the shift from quadrupedal to bipedal locomotion may have driven the rapid evolution of distinctive features of human neuronal functioning. We review recent studies of functional neuroanatomy that bear upon this hypothesis, and identify ways to test our ideas. PMID- 24808822 TI - The effect of stimulus context on the buildup to stream segregation. AB - Stream segregation is the process by which the auditory system disentangles the mixture of sound inputs into discrete sources that cohere across time. The length of time required for this to occur is termed the "buildup" period. In the current study, we used the buildup period as an index of how quickly sounds are segregated into constituent parts. Specifically, we tested the hypothesis that stimulus context impacts the timing of the buildup and, therefore, affects when stream segregation is detected. To measure the timing of the buildup we recorded the Mismatch Negativity component (MMN) of event-related brain potentials (ERPs), during passive listening, to determine when the streams were neurophysiologically segregated. In each condition, a pattern of repeating low (L) and high (H) tones (L-L-H) was presented in trains of stimuli separated by silence, with the H tones forming a simple intensity oddball paradigm and the L tones serving as distractors. To determine the timing of the buildup, probe tones occurred in two positions of the trains, early (within the buildup period) and late (past the buildup period). The context was manipulated by presenting roving vs. non-roving frequencies across trains in two conditions. MMNs were elicited by intensity probe tones in the Non-Roving condition (early and late positions) and the Roving condition (late position only) indicating that neurophysiologic segregation occurred faster in the Non-Roving condition. This suggests a shorter buildup period when frequency was repeated from train to train. Overall, our results demonstrate that the dynamics of the environment influence the way in which the auditory system extracts regularities from the input. The results support the hypothesis that the buildup to segregation is highly dependent upon stimulus context and that the auditory system works to maintain a consistent representation of the environment when no new information suggests that reanalyzing the scene is necessary. PMID- 24808821 TI - Neurogenic and non-neurogenic functions of endogenous neural stem cells. AB - Adult neurogenesis is a lifelong process that occurs in two main neurogenic niches of the brain, namely in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. In the 1960s, studies on adult neurogenesis have been hampered by the lack of established phenotypic markers. The precise tracing of neural stem/progenitor cells (NPCs) was therefore, not properly feasible. After the (partial) identification of those markers, it was the lack of specific tools that hindered a proper experimental elimination and tracing of those cells to demonstrate their terminal fate and commitment. Nowadays, irradiation, cytotoxic drugs as well as genetic tracing/ablation procedures have moved the field forward and increased our understanding of neurogenesis processes in both physiological and pathological conditions. Newly formed NPC progeny from the SVZ can replace granule cells in the olfactory bulbs of rodents, thus contributing to orchestrate sophisticated odor behavior. SGZ-derived new granule cells, instead, integrate within the DG where they play an essential role in memory functions. Furthermore, converging evidence claim that endogenous NPCs not only exert neurogenic functions, but might also have non-neurogenic homeostatic functions by the release of different types of neuroprotective molecules. Remarkably, these non neurogenic homeostatic functions seem to be necessary, both in healthy and diseased conditions, for example for preventing or limiting tissue damage. In this review, we will discuss the neurogenic and the non-neurogenic functions of adult NPCs both in physiological and pathological conditions. PMID- 24808823 TI - Tau-tubulin kinase. AB - Tau-tubulin kinase (TTBK) belongs to casein kinase superfamily and phosphorylates microtubule-associated protein tau and tubulin. TTBK has two isoforms, TTBK1 and TTBK2, which contain highly homologous catalytic domains but their non-catalytic domains are distinctly different. TTBK1 is expressed specifically in the central nervous system and is involved in phosphorylation and aggregation of tau. TTBK2 is ubiquitously expressed in multiple tissues and genetically linked to spinocerebellar ataxia type 11. TTBK1 directly phosphorylates tau protein, especially at Ser422, and also activates cycline-dependent kinase 5 in a unique mechanism. TTBK1 protein expression is significantly elevated in Alzheimer's disease (AD) brains, and genetic variations of the TTBK1 gene are associated with late-onset Alzheimer's disease in two cohorts of Chinese and Spanish populations. TTBK1 transgenic mice harboring the entire 55-kilobase genomic sequence of human TTBK1 show progression of tau accumulation, neuroinflammation, and neurodegeneration when crossed with tau mutant mice. Our recent study shows that there is a striking switch in mononuclear phagocyte and activation phenotypes in the anterior horn of the spinal cord from alternatively activated (M2-skewed) microglia in P301L tau mutant mice to pro-inflammatory (M1-skewed) infiltrating peripheral monocytes by crossing the tau mice with TTBK1 transgenic mice. TTBK1 is responsible for mediating M1-activated microglia-induced neurotoxicity, and its overexpression induces axonal degeneration in vitro. These studies suggest that TTBK1 is an important molecule for the inflammatory axonal degeneration, which may be relevant to the pathobiology of tauopathy including AD. PMID- 24808824 TI - Ca(2+)-modulated ROS-GC1 transduction system in testes and its presence in the spermatogenic cells. AB - ROS-GC1 belongs to the Ca(2+)-modulated sub-family of membrane guanylate cyclases. It primarily exists and is linked with signaling of the sensory neurons - sight, smell, taste, and pinealocytes. Exceptionally, it is also present and is Ca(2+)-modulated in t he non-neuronal cells, the sperm cells in the testes, where S100B protein serves as its Ca(2+) sensor. The present report demonstrates the identification of an additional Ca(2+) sensor of ROS-GC1 in the testes, neurocalcin delta. Through mouse molecular genetic models, it compares and quantifies the relative input of the S100B and neurocalcin delta in regulating the Ca(2+) signaling of ROS-GC1 transduction machinery, and via immunochemistry it demonstrates the co-presence of neurocalcin delta and ROS-GC1 in the spermatogenic cells of the testes. The suggestion is that in more ways than one the Ca(2+)-modulated ROS-GC1 transduction system is linked with the testicular function. This non-neuronal transduction system may represent an illustration of the ROS-GC1 expanding role in the trans-signaling of the neural and non-neural systems. PMID- 24808825 TI - CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles. AB - Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor-receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4. The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis, and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects. PMID- 24808826 TI - Diversity among principal and GABAergic neurons of the anterior olfactory nucleus. AB - Understanding the cellular components of neural circuits is an essential step in discerning regional function. The anterior olfactory nucleus (AON) is reciprocally connected to both the ipsi- and contralateral olfactory bulb (OB) and piriform cortex (PC), and, as a result, can broadly influence the central processing of odor information. While both the AON and PC are simple cortical structures, the regions differ in many ways including their general organization, internal wiring and synaptic connections with other brain areas. The present work used targeted whole-cell patch clamping to investigate the morphological and electrophysiological properties of the AON's two main neuronal populations: excitatory projection neurons and inhibitory interneurons. Retrograde fluorescent tracers placed into either the OB or PC identified projection neurons. Two classes were observed with different physiological signatures and locations (superficial and deep pyramidal neurons), suggesting the AON contains independent efferent channels. Transgenic mice in which GABA-containing cells expressed green fluorescent protein were used to assess inhibitory neurons. These cells were further identified as containing one or more of seven molecular markers including three calcium-binding proteins (calbindin, calretinin, parvalbumin) or four neuropeptides (somatostatin, vasoactive intestinal peptide, neuropeptide Y, cholecystokinin). The proportion of GABAergic cells containing these markers varied across subregions reinforcing notions that the AON has local functional subunits. At least five classes of inhibitory cells were observed: fast-spiking multipolar, regular-spiking multipolar, superficial neurogliaform, deep neurogliaform, and horizontal neurons. While some of these cell types are similar to those reported in the PC and other cortical regions, the AON also has unique populations. These studies provide the first examination of the cellular components of this simple cortical system. PMID- 24808827 TI - CSPalpha-chaperoning presynaptic proteins. AB - Synaptic transmission relies on precisely regulated and exceedingly fast protein protein interactions that involve voltage-gated channels, the exocytosis/endocytosis machinery as well as signaling pathways. Although we have gained an ever more detailed picture of synaptic architecture much remains to be learned about how synapses are maintained. Synaptic chaperones are "folding catalysts" that preserve proteostasis by regulating protein conformation (and therefore protein function) and prevent unwanted protein-protein interactions. Failure to maintain synapses is an early hallmark of several degenerative diseases. Cysteine string protein (CSPalpha) is a presynaptic vesicle protein and molecular chaperone that has a central role in preventing synaptic loss and neurodegeneration. Over the past few years, a number of different "client proteins" have been implicated as CSPalpha substrates including voltage-dependent ion channels, signaling proteins and proteins critical to the synaptic vesicle cycle. Here we review the ion channels and synaptic protein complexes under the influence of CSPalpha and discuss gaps in our current knowledge. PMID- 24808829 TI - Frequency-pattern functional tomography of magnetoencephalography data allows new approach to the study of human brain organization. AB - A method based on a set of new theorems for the analysis of multichannel time series is described, based on precise Fourier transform and coherence analysis of the restored signals from a detailed set of frequency components. Magnetic field recordings of spontaneous and evoked activity by means of magnetic encephalography demonstrated that multichannel precise Fourier spectrum contains a very large set of harmonics with high coherence. The inverse problem can be solved with great precision based on coherent harmonics, so the technique is a promising platform of general analysis in brain imaging. The analysis method makes it possible to reconstruct sites and timing of electrical activity generated by both spontaneous and evoked brain function at different depths in the brain in the millisecond time range. PMID- 24808828 TI - Origin and neurochemical properties of bulbospinal neurons projecting to the rat lumbar spinal cord via the medial longitudinal fasciculus and caudal ventrolateral medulla. AB - Bulbospinal systems (BS) originate from various regions of the brainstem and influence spinal neurons by classical synaptic and modulatory mechanisms. Our aim was to determine the brainstem locations of cells of origin of BS pathways passing through the medial longitudinal fasciculus (MLF) and the caudal ventrolateral medulla (CVLM). We also examined the transmitter content of spinal terminations of the CVLM pathway. Six adult rats received Fluorogold (FG) injections to the right intermediate gray matter of the lumbar cord (L1-L2) and the b-subunit of cholera toxin (CTb) was injected either into the MLF or the right CVLM (3 animals each). Double-labeled cells were identified within brainstem structures with confocal microscopy and mapped onto brainstem diagrams. An additional 3 rats were injected with CTb in the CVLM to label axon terminals in the lumbar spinal cord. Double-labeled cells projecting via the MLF or CVLM were found principally in reticular regions of the medulla and pons but small numbers of cells were also located within the midbrain. CVLM projections to the lumbar cord were almost exclusively ipsilateral and concentrated within the intermediate gray matter. Most (62%) of terminals were immunoreactive for the vesicular glutamate transporter 2 while 23% contained the vesicular GABA transporter. The inhibitory subpopulation was glycinergic, GABAergic or contained both transmitters. The proportions of excitatory and inhibitory axons projecting via the CVLM to the lumbar cord are similar to those projecting via the MLF. Unlike the MLF pathway, CVLM projections are predominantly ipsilateral and concentrated within intermediate gray but do not extend into motor nuclei or laminia VIII. Terminations of the CVLM pathway are located in a region of the gray matter that is rich in premotor interneurons; thus its primary function may be to coordinate activity of premotor networks. PMID- 24808830 TI - Histamine in the brain. PMID- 24808831 TI - Neural correlates of moderate hearing loss: time course of response changes in the primary auditory cortex of awake guinea-pigs. AB - Over the last decade, the consequences of acoustic trauma on the functional properties of auditory cortex neurons have received growing attention. Changes in spontaneous and evoked activity, shifts of characteristic frequency (CF), and map reorganizations have extensively been described in anesthetized animals (e.g., Norena and Eggermont, 2003, 2005). Here, we examined how the functional properties of cortical cells are modified after partial hearing loss in awake guinea pigs. Single unit activity was chronically recorded in awake, restrained, guinea pigs from 3 days before up to 15 days after an acoustic trauma induced by a 5 kHz 110 dB tone delivered for 1 h. Auditory brainstem responses (ABRs) audiograms indicated that these parameters produced a mean ABR threshold shift of 20 dB SPL at, and one octave above, the trauma frequency. When tested with pure tones, cortical cells showed on average a 25 dB increase in threshold at CF the day following the trauma. Over days, this increase progressively stabilized at only 10 dB above control value indicating a progressive recovery of cortical thresholds, probably reflecting a progressive shift from temporary threshold shift (TTS) to permanent threshold shift (PTS). There was an increase in response latency and in response variability the day following the trauma but these parameters returned to control values within 3 days. When tested with conspecific vocalizations, cortical neurons also displayed an increase in response latency and in response duration the day after the acoustic trauma, but there was no effect on the average firing rate elicited by the vocalization. These findings suggest that, in cases of moderate hearing loss, the temporal precision of neuronal responses to natural stimuli is impaired despite the fact the firing rate showed little or no changes. PMID- 24808832 TI - Does sleep deprivation alter functional EEG networks in children with focal epilepsy? AB - Electroencephalography (EEG) recordings after sleep deprivation increase the diagnostic yield in patients suspected of epilepsy if the routine EEG remains inconclusive. Sleep deprivation is associated with increased interictal EEG abnormalities in patients with epilepsy, but the exact mechanism is unknown. In this feasibility study, we used a network analytical approach to provide novel insights into this clinical observation. The aim was to characterize the effect of sleep deprivation on the interictal functional network organization using a unique dataset of paired routine and sleep deprivation recordings in patients and controls. We included 21 children referred to the first seizure clinic of our center with suspected new onset focal epilepsy in whom a routine interictal and a sleep deprivation EEG (SD-EEG) were performed. Seventeen children, in whom the diagnosis of epilepsy was excluded, served as controls. For both time points weighted functional networks were constructed based on interictal artifact free time-series. Routine and sleep deprivation networks were characterized at different frequency bands using minimum spanning tree (MST) measures (leaf number and diameter) and classical measures of integration (path length) and segregation (clustering coefficient). A significant interaction was found for leaf number and diameter between patients and controls after sleep deprivation: patients showed a shift toward a more path-like MST network whereas controls showed a shift toward a more star-like MST network. This shift in network organization after sleep deprivation in patients is in accordance with previous studies showing a more regular network organization in the ictal state and might relate to the increased epileptiform abnormalities found in patients after sleep deprivation. Larger studies are needed to verify these results. Finally, MST measures were more sensitive in detecting network changes as compared to the classical measures of integration and segregation. PMID- 24808834 TI - Enhancement of cognitive and neural functions through complex reasoning training: evidence from normal and clinical populations. AB - Public awareness of cognitive health is fairly recent compared to physical health. Growing evidence suggests that cognitive training offers promise in augmenting cognitive brain performance in normal and clinical populations. Targeting higher-order cognitive functions, such as reasoning in particular, may promote generalized cognitive changes necessary for supporting the complexities of daily life. This data-driven perspective highlights cognitive and brain changes measured in randomized clinical trials that trained gist reasoning strategies in populations ranging from teenagers to healthy older adults, individuals with brain injury to those at-risk for Alzheimer's disease. The evidence presented across studies support the potential for Gist reasoning training to strengthen cognitive performance in trained and untrained domains and to engage more efficient communication across widespread neural networks that support higher-order cognition. The meaningful benefits of Gist training provide compelling motivation to examine optimal dose for sustained benefits as well as to explore additive benefits of meditation, physical exercise, and/or improved sleep in future studies. PMID- 24808835 TI - Thinking caps for everyone? The role of neuro-enhancement by non-invasive brain stimulation in neuroscience and beyond. AB - Neuro-enhancement by non-invasive brain stimulation (NIBS) has recently made considerable progress, triggering discussions regarding future applications to enhance human performance. We show that neuroscientific research does not aim at improving brain functions per se. Instead, neuro-enhancement is a research tool that has great potential to reveal the neural mechanisms underlying perception, cognition, and behavior. We provide instructive examples that showcase the relevance of neuro-enhancement by NIBS in neuroscience. Importantly, we argue that the scientific value of neuro-enhancement critically depends on our understanding of why enhancing effects occur. This is in contrast to applications of neuro-enhancement in other domains, where such knowledge may not be required. We conclude that neuro-enhancement as a therapeutic tool or in healthy people outside of neuroscience should be kept conceptually distinct, as these are separate domains with entirely different motives for enhancing human performance. Consequently, the underlying principles that justify the application of NIBS will be different in each domain and arguments for or against neuro-enhancement in one domain do not necessarily generalize to other domains. PMID- 24808833 TI - What limits the performance of current invasive brain machine interfaces? AB - The concept of a brain-machine interface (BMI) or a computer-brain interface is simple: BMI creates a communication pathway for a direct control by brain of an external device. In reality BMIs are very complex devices and only recently the increase in computing power of microprocessors enabled a boom in BMI research that continues almost unabated to this date, the high point being the insertion of electrode arrays into the brains of 5 human patients in a clinical trial run by Cyberkinetics with few other clinical tests still in progress. Meanwhile several EEG-based BMI devices (non-invasive BMIs) were launched commercially. Modern electronics and dry electrode technology made possible to drive the cost of some of these devices below few hundred dollars. However, the initial excitement of the direct control by brain waves of a computer or other equipment is dampened by large efforts required for learning, high error rates and slow response speed. All these problems are directly related to low information transfer rates typical for such EEG-based BMIs. In invasive BMIs employing multiple electrodes inserted into the brain one may expect much higher information transfer rates than in EEG-based BMIs because, in theory, each electrode provides an independent information channel. However, although invasive BMIs require more expensive equipment and have ethical problems related to the need to insert electrodes in the live brain, such financial and ethical costs are often not offset by a dramatic improvement in the information transfer rate. Thus the main topic of this review is why in invasive BMIs an apparently much larger information content obtained with multiple extracellular electrodes does not translate into much higher rates of information transfer? This paper explores possible answers to this question by concluding that more research on what movement parameters are encoded by neurons in motor cortex is needed before we can enjoy the next generation BMIs. PMID- 24808836 TI - Texture-defined objects influence responses of blowfly motion-sensitive neurons under natural dynamical conditions. AB - The responses of visual interneurons of flies involved in the processing of motion information do not only depend on the velocity, but also on other stimulus parameters, such as the contrast and the spatial frequency content of the stimulus pattern. These dependencies have been known for long, but it is still an open question how they affect the neurons' performance in extracting information about the structure of the environment under the specific dynamical conditions of natural flight. Free-flight of blowflies is characterized by sequences of phases of translational movements lasting for just 30-100 ms interspersed with even shorter and extremely rapid saccade-like rotational shifts in flight and gaze direction. Previous studies already analyzed how nearby objects, leading to relative motion on the retina with respect to a more distant background, influenced the response of a class of fly motion sensitive visual interneurons, the horizontal system (HS) cells. In the present study, we focused on objects that differed from their background by discontinuities either in their brightness contrast or in their spatial frequency content. We found strong object-induced effects on the membrane potential even during the short intersaccadic intervals, if the background contrast was small and the object contrast sufficiently high. The object evoked similar response increments provided that it contained higher spatial frequencies than the background, but not under reversed conditions. This asymmetry in the response behavior is partly a consequence of the depolarization level induced by the background. Thus, our results suggest that, under the specific dynamical conditions of natural flight, i.e., on a very short timescale, the responses of HS cells represent object information depending on the polarity of the difference between object and background contrast and spatial frequency content. PMID- 24808838 TI - Context-driven activation of odor representations in the absence of olfactory stimuli in the olfactory bulb and piriform cortex. AB - Sensory neural activity is highly context dependent and shaped by experience and expectation. In the olfactory bulb (OB), the first cerebral relay of olfactory processing, responses to odorants are shaped by previous experiences including contextual information thanks to strong feedback connections. In the present experiment, mice were conditioned to associate an odorant with a visual context and were then exposed to the visual context alone. We found that the visual context alone elicited exploration of the odor port similar to that elicited by the stimulus when it was initially presented. In the OB, the visual context alone elicited a neural activation pattern, assessed by mapping the expression of the immediate early gene zif268 (egr-1) that was highly similar to that evoked by the conditioned odorant, but not other odorants. This OB activation was processed by olfactory network as it was transmitted to the piriform cortex. Interestingly, a novel context abolished neural and behavioral responses. In addition, the neural representation in response to the context was dependent on top-down inputs, suggesting that context-dependent representation is initiated in cortex. Modeling of the experimental data suggests that odor representations are stored in cortical networks, reactivated by the context and activate bulbar representations. Activation of the OB and the associated behavioral response in the absence of physical stimulus showed that mice are capable of internal representations of sensory stimuli. The similarity of activation patterns induced by imaged and the corresponding physical stimulus, triggered only by the relevant context provides evidence for an odor-specific internal representation. PMID- 24808837 TI - Contingency-based emotional resilience: effort-based reward training and flexible coping lead to adaptive responses to uncertainty in male rats. AB - Emotional resilience enhances an animal's ability to maintain physiological allostasis and adaptive responses in the midst of challenges ranging from cognitive uncertainty to chronic stress. In the current study, neurobiological factors related to strategic responses to uncertainty produced by prediction errors were investigated by initially profiling male rats as passive, active or flexible copers (n = 12 each group) and assigning to either a contingency-trained or non-contingency trained group. Animals were subsequently trained in a spatial learning task so that problem solving strategies in the final probe task, as well various biomarkers of brain activation and plasticity in brain areas associated with cognition and emotional regulation, could be assessed. Additionally, fecal samples were collected to further determine markers of stress responsivity and emotional resilience. Results indicated that contingency-trained rats exhibited more adaptive responses in the probe trial (e.g., fewer interrupted grooming sequences and more targeted search strategies) than the noncontingent-trained rats; additionally, increased DHEA/CORT ratios were observed in the contingent trained animals. Diminished activation of the habenula (i.e., fos immunoreactivity) was correlated with resilience factors such as increased levels of DHEA metabolites during cognitive training. Of the three coping profiles, flexible copers exhibited enhanced neuroplasticity (i.e., increased dentate gyrus doublecortin-immunoreactivity) compared to the more consistently responding active and passive copers. Thus, in the current study, contingency training via effort-based reward (EBR) training, enhanced by a flexible coping style, provided neurobiological resilience and adaptive responses to prediction errors in the final probe trial. These findings have implications for psychiatric illnesses that are influenced by altered stress responses and decision-making abilities (e.g., depression). PMID- 24808839 TI - A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism. AB - Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repetitive behaviors during reversal learning in mice in the automated IntelliCage system. During the reward-motivated place preference reversal learning, designed to assess cognitive abilities of mice, visits to the previously rewarded places were recorded to measure cognitive flexibility. Thereafter, emotional flexibility was assessed by measuring conditioned fear extinction. Additionally, to look for neuronal correlates of cognitive impairments, we measured CA3-CA1 hippocampal long term potentiation (LTP). To standardize the designed tests we used C57BL/6 and BALB/c mice, representing two genetic backgrounds, for induction of autism by prenatal exposure to the sodium valproate. We found impairments of place learning related to perseveration and no LTP impairments in C57BL/6 valproate-treated mice. In contrast, BALB/c valproate treated mice displayed severe deficits of place learning not associated with perseverative behaviors and accompanied by hippocampal LTP impairments. Alterations of cognitive flexibility observed in C57BL/6 valproate-treated mice were related to neither restricted exploration pattern nor to emotional flexibility. Altogether, we showed that the designed tests of cognitive performance and perseverative behaviors are efficient and highly replicable. Moreover, the results suggest that genetic background is crucial for the behavioral effects of prenatal valproate treatment. PMID- 24808841 TI - Inhibition and enhancement of contextual fear memory destabilization. AB - The reactivation of a memory can result in its destabilization, necessitating a process of memory reconsolidation to maintain its persistence. Here we show that the destabilization of a contextual fear memory is potentiated by the cannabinoid CB1 receptor agonist Arachidonyl-2-chloroethylamide (ACEA). Co-infusion of ACEA and the IkappaB kinase (IKK) inhibitor sulfasalazine (Sulf) into the dorsal hippocampus impaired contextual fear memory reconsolidation. This observation was achieved under behavioral conditions that, by themselves, did not result in a reconsolidation impairment by Sulf alone. Moreover, we show that the destabilization of a contextual fear memory is dependent upon neuronal activity in the dorsal hippocampus, but not memory expression per se. The effect on contextual fear memory destabilization of intra-hippocampal ACEA was replicated by systemic injections, allowing an amnestic effect of MK-801. These results indicate that memory expression and destabilization, while being independent from one another, are both dependent upon memory reactivation. Moreover, memory destabilization can be enhanced pharmacologically, which may be of therapeutic potential. PMID- 24808840 TI - An updated animal model capturing both the cognitive and emotional features of post-traumatic stress disorder (PTSD). AB - The new-released Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines post-traumatic stress disorder (PTSD) as a "trauma and stressor-related disorder". PTSD pathogenesis relies on paradoxical changes of emotional memory processing induced by the trauma exposure and associated with emotional dysfunction. Several animal models of PTSD have been validated and are currently used. Each one mimics a particular subset of the disorder with particular emphasis, mainly driven by the past classification of PTSD in the DSM-4, on the emotional features. In view of the recent update in the DSM-5, our aim was to develop, by using well-validated paradigms, a modified model of PTSD able to mimic at the same time both the cognitive and emotional features of the disease. We exposed male rats to either a piece of worn cat collar or to a series of inescapable footshocks paired with a PTSD risk factor, i.e., social isolation. Animals were subsequently re-exposed to the conditioned contexts at different time intervals in order to test memory retention for the stressors. In addition, footshock-exposed rats were tested in the elevated-plus-maze and social interaction tests. We found that rats exposed to a cat collar exhibited an acute fear response that did not lead to enduring memory retention. Conversely, footshock-exposed rats expressed a successful retention of the stressful experience at 1, 7, 14, 21 and 56 post-exposure days. Footshock-exposed rats displayed an anxious behavioral profile in the social interaction test and a significantly reduced locomotor activity in the elevated-plus-maze test. These dysfunctions were not observed when animals were socially housed, thus highlighting a social buffering effect in the development of the pathology. Our results underline the good validity of a footshock-based paradigm paired with social isolation as a PTSD animal model, able to mimic at the same time both some of the enduring cognitive and emotional facets of the pathology. PMID- 24808842 TI - Sparse distributed memory: understanding the speed and robustness of expert memory. AB - How can experts, sometimes in exacting detail, almost immediately and very precisely recall memory items from a vast repertoire? The problem in which we will be interested concerns models of theoretical neuroscience that could explain the speed and robustness of an expert's recollection. The approach is based on Sparse Distributed Memory, which has been shown to be plausible, both in a neuroscientific and in a psychological manner, in a number of ways. A crucial characteristic concerns the limits of human recollection, the "tip-of-tongue" memory event-which is found at a non-linearity in the model. We expand the theoretical framework, deriving an optimization formula to solve this non linearity. Numerical results demonstrate how the higher frequency of rehearsal, through work or study, immediately increases the robustness and speed associated with expert memory. PMID- 24808843 TI - Language in the brain at rest: new insights from resting state data and graph theoretical analysis. AB - In humans, the most obvious functional lateralization is the specialization of the left hemisphere for language. Therefore, the involvement of the right hemisphere in language is one of the most remarkable findings during the last two decades of fMRI research. However, the importance of this finding continues to be underestimated. We examined the interaction between the two hemispheres and also the role of the right hemisphere in language. From two seeds representing Broca's area, we conducted a seed correlation analysis (SCA) of resting state fMRI data and could identify a resting state network (RSN) overlapping to significant extent with a language network that was generated by an automated meta-analysis tool. To elucidate the relationship between the clusters of this RSN, we then performed graph theoretical analyses (GTA) using the same resting state dataset. We show that the right hemisphere is clearly involved in language. A modularity analysis revealed that the interaction between the two hemispheres is mediated by three partitions: A bilateral frontal partition consists of nodes representing the classical left sided language regions as well as two right-sided homologs. The second bilateral partition consists of nodes from the right frontal, the left inferior parietal cortex as well as of two nodes within the posterior cerebellum. The third partition is also bilateral and comprises five regions from the posterior midline parts of the brain to the temporal and frontal cortex, two of the nodes are prominent default mode nodes. The involvement of this last partition in a language relevant function is a novel finding. PMID- 24808844 TI - Decoding of four movement directions using hybrid NIRS-EEG brain-computer interface. AB - The hybrid brain-computer interface (BCI)'s multimodal technology enables precision brain-signal classification that can be used in the formulation of control commands. In the present study, an experimental hybrid near-infrared spectroscopy-electroencephalography (NIRS-EEG) technique was used to extract and decode four different types of brain signals. The NIRS setup was positioned over the prefrontal brain region, and the EEG over the left and right motor cortex regions. Twelve subjects participating in the experiment were shown four direction symbols, namely, "forward," "backward," "left," and "right." The control commands for forward and backward movement were estimated by performing arithmetic mental tasks related to oxy-hemoglobin (HbO) changes. The left and right directions commands were associated with right and left hand tapping, respectively. The high classification accuracies achieved showed that the four different control signals can be accurately estimated using the hybrid NIRS-EEG technology. PMID- 24808845 TI - Individual differences in reward prediction error: contrasting relations between feedback-related negativity and trait measures of reward sensitivity, impulsivity and extraversion. AB - Medial-frontal negativity occurring ~200-300 ms post-stimulus in response to motivationally salient stimuli, usually referred to as feedback-related negativity (FRN), appears to be at least partly modulated by dopaminergic-based reward prediction error (RPE) signaling. Previous research (e.g., Smillie et al., 2011) has shown that higher scores on a putatively dopaminergic-based personality trait, extraversion, were associated with a more pronounced difference wave contrasting unpredicted non-reward and unpredicted reward trials on an associative learning task. In the current study, we sought to extend this research by comparing how trait measures of reward sensitivity, impulsivity and extraversion related to the FRN using the same associative learning task. A sample of healthy adults (N = 38) completed a battery of personality questionnaires, before completing the associative learning task while EEG was recorded. As expected, FRN was most negative following unpredicted non-reward. A difference wave contrasting unpredicted non-reward and unpredicted reward trials was calculated. Extraversion, but not measures of impulsivity, had a significant association with this difference wave. Further, the difference wave was significantly related to a measure of anticipatory pleasure, but not consummatory pleasure. These findings provide support for the existing evidence suggesting that variation in dopaminergic functioning in brain "reward" pathways may partially underpin associations between the FRN and trait measures of extraversion and anticipatory pleasure. PMID- 24808847 TI - Conceptual mappings and neural reuse. PMID- 24808846 TI - Genetic variation of the RASGRF1 regulatory region affects human hippocampus dependent memory. AB - The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans. PMID- 24808848 TI - What contributes to individual differences in brain structure? AB - Individual differences in adult human brain structure have been found to reveal a great deal of information about variability in behaviors, cognitive abilities and mental and physical health. Driven by such evidence, what contributes to individual variation in brain structure has gained accelerated attention as a research question. Findings thus far appear to support the notion that an individual's brain architecture is determined largely by genetic and environmental influences. This review aims to evaluate the empirical literature on whether and how genes and the environment contribute to individual differences in brain structure. It first considers how genetic and environmental effects may separately contribute to brain morphology, by examining evidence from twin, genome-wide association, cross-sectional and longitudinal studies. Next, evidence for the influence of the complex interplay between genetic and environmental factors, characterized as gene-environment interactions and correlations, is reviewed. In evaluating the extant literature, this review will conclude that both genetic and environmental factors play critical roles in contributing to individual variability in brain structure. PMID- 24808849 TI - Differential neural network configuration during human path integration. AB - Path integration is a fundamental skill for navigation in both humans and animals. Despite recent advances in unraveling the neural basis of path integration in animal models, relatively little is known about how path integration operates at a neural level in humans. Previous attempts to characterize the neural mechanisms used by humans to visually path integrate have suggested a central role of the hippocampus in allowing accurate performance, broadly resembling results from animal data. However, in recent years both the central role of the hippocampus and the perspective that animals and humans share similar neural mechanisms for path integration has come into question. The present study uses a data driven analysis to investigate the neural systems engaged during visual path integration in humans, allowing for an unbiased estimate of neural activity across the entire brain. Our results suggest that humans employ common task control, attention and spatial working memory systems across a frontoparietal network during path integration. However, individuals differed in how these systems are configured into functional networks. High performing individuals were found to more broadly express spatial working memory systems in prefrontal cortex, while low performing individuals engaged an allocentric memory system based primarily in the medial occipito-temporal region. These findings suggest that visual path integration in humans over short distances can operate through a spatial working memory system engaging primarily the prefrontal cortex and that the differential configuration of memory systems recruited by task control networks may help explain individual biases in spatial learning strategies. PMID- 24808850 TI - The effects of acute aerobic activity on cognition and cross-domain transfer to eating behavior. AB - Prior studies have demonstrated that a single session of aerobic exercise can enhance cognitive functioning; specifically, the inhibition facet of executive function (EF). Additionally, previous research has demonstrated that inhibitory abilities are essential for effective dietary self-control. However, it is currently unknown whether exercise induced enhancements in EF also facilitate self-control in the dietary domain. The present study sought to determine whether a single session of aerobic exercise enhances EF, and whether there is a transfer effect to dietary self-control. Thirty four undergraduate students were randomly assigned to one of three exercise conditions: (1) minimal exercise; (2) moderate intensity exercise (30% heart rate reserve); (3) vigorous intensity exercise (50% heart rate reserve). After the exercise bout, participants completed three standardized EF tasks followed by a bogus taste test for three appetitive snack foods (milk chocolate and potato chips) and two control foods (dark chocolate and crackers). The amount of food consumed during the taste test was covertly measured. The results revealed a significant main effect of treatment condition on the Stroop task performance, but not Go-NoGo (GNG) and Stop Signal task performance. Findings with respect to food consumption revealed that EF moderated the treatment effect, such that those with larger exercise effects on Stroop performance in the moderate intensity exercise condition consumed more control foods (but not less appetitive foods). These findings support the contention that a single bout of aerobic exercise enhances EF, and may have transfer effects to the dietary domain, but that such effects may be indirect in nature. PMID- 24808851 TI - The co-occurrence of autism and attention deficit hyperactivity disorder in children - what do we know? AB - Symptoms of attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) often co-occur. The DSM-IV had specified that an ASD diagnosis is an exclusion criterion for ADHD, thereby limiting research of this common clinical co-occurrence. As neurodevelopmental disorders, both ASD and ADHD share some phenotypic similarities, but are characterized by distinct diagnostic criteria. The present review will examine the frequency and implications of this clinical co-occurrence in children, with an emphasis on the available data regarding pre-school age. The review will highlight possible etiologies explaining it, and suggest future research directions necessary to enhance our understanding of both etiology and therapeutic interventions, in light of the new DSM-V criteria, allowing for a dual diagnosis. PMID- 24808852 TI - Use of diffusion spectrum imaging in preliminary longitudinal evaluation of amyotrophic lateral sclerosis: development of an imaging biomarker. AB - Previous diffusion tensor imaging (DTI) studies have shown white matter pathology in amyotrophic lateral sclerosis (ALS), predominantly in the motor pathways. Further these studies have shown that DTI can be used longitudinally to track pathology over time, making white matter pathology a candidate as an outcome measure in future trials. DTI has demonstrated application in group studies, however its derived indices, for example fractional anisotropy, are susceptible to partial volume effects, making its role questionable in examining individual progression. We hypothesize that changes in the white matter are present in ALS beyond the motor tracts, and that the affected pathways and associated pattern of disease progression can be tracked longitudinally using automated diffusion connectometry analysis. Connectometry analysis is based on diffusion spectrum imaging and overcomes the limitations of a conventional tractography approach and DTI. The identified affected white matter tracts can then be assessed in a targeted fashion using High definition fiber tractography (a novel white matter MR imaging technique). Changes in quantitative and qualitative markers over time could then be correlated with clinical progression. We illustrate these principles toward developing an imaging biomarker for demonstrating individual progression, by presenting results for five ALS patients, including with longitudinal data in two. Preliminary analysis demonstrated a number of changes bilaterally and asymmetrically in motoric and extramotoric white matter pathways. Further the limbic system was also affected possibly explaining the cognitive symptoms in ALS. In the two longitudinal subjects, the white matter changes were less extensive at baseline, although there was evidence of disease progression in a frontal pattern with a relatively spared postcentral gyrus, consistent with the known pathology in ALS. PMID- 24808853 TI - Linking motor-related brain potentials and velocity profiles in multi-joint arm reaching movements. AB - The study of the movement related brain potentials (MRPBs) needs accurate technical approaches to disentangle the specific patterns of bran activity during the preparation and execution of movements. During the last forty years, synchronizing the electromyographic activation (EMG) of the muscle with electrophysiological recordings (EEG) has been commonly ussed for these purposes. However, new clinical approaches in the study of motor diseases and rehabilitation suggest the demand of new paradigms that might go further into the study of the brain activity associated with the kinematics of movements. As a response to this call, we have used a 3-D hand-tracking system with the aim to record continuously the position of an ultrasonic sender attached to the hand during the performance of multi-joint self-paced movements. We synchronized time series of position and velocity of the sender with the EEG recordings, obtaining specific patterns of brain activity as a function of the fluctuations of the kinematics during natural movement performance. Additionally, the distribution of the brain activity during the preparation and execution phases of movements was similar that reported previously using the EMG, suggesting the validity of our technique. We claim that this paradigm could be usable in patients because of its simplicity and the potential knowledge that can be extracted from clinical protocols. PMID- 24808854 TI - The meaning of spikes from the neuron's point of view: predictive homeostasis generates the appearance of randomness. AB - The conventional interpretation of spikes is from the perspective of an external observer with knowledge of a neuron's inputs and outputs who is ignorant of the contents of the "black box" that is the neuron. Here we consider a neuron to be an observer and we interpret spikes from the neuron's perspective. We propose both a descriptive hypothesis based on physics and logic, and a prescriptive hypothesis based on biological optimality. Our descriptive hypothesis is that a neuron's membrane excitability is "known" and the amplitude of a future excitatory postsynaptic conductance (EPSG) is "unknown". Therefore excitability is an expectation of EPSG amplitude and a spike is generated only when EPSG amplitude exceeds its expectation ("prediction error"). Our prescriptive hypothesis is that a diversity of synaptic inputs and voltage-regulated ion channels implement "predictive homeostasis", working to insure that the expectation is accurate. The homeostatic ideal and optimal expectation would be achieved when an EPSP reaches precisely to spike threshold, so that spike output is exquisitely sensitive to small variations in EPSG input. To an external observer who knows neither EPSG amplitude nor membrane excitability, spikes would appear random if the neuron is making accurate predictions. We review experimental evidence that spike probabilities are indeed maintained near an average of 0.5 under natural conditions, and we suggest that the same principles may also explain why synaptic vesicle release appears to be "stochastic". Whereas the present hypothesis accords with principles of efficient coding dating back to Barlow (1961), it contradicts decades of assertions that neural activity is substantially "random" or "noisy". The apparent randomness is by design, and like many other examples of apparent randomness, it corresponds to the ignorance of external macroscopic observers about the detailed inner workings of a microscopic system. PMID- 24808855 TI - Distributed organization of a brain microcircuit analyzed by three-dimensional modeling: the olfactory bulb. AB - The functional consequences of the laminar organization observed in cortical systems cannot be easily studied using standard experimental techniques, abstract theoretical representations, or dimensionally reduced models built from scratch. To solve this problem we have developed a full implementation of an olfactory bulb microcircuit using realistic three-dimensional (3D) inputs, cell morphologies, and network connectivity. The results provide new insights into the relations between the functional properties of individual cells and the networks in which they are embedded. To our knowledge, this is the first model of the mitral-granule cell network to include a realistic representation of the experimentally-recorded complex spatial patterns elicited in the glomerular layer (GL) by natural odor stimulation. Although the olfactory bulb, due to its organization, has unique advantages with respect to other brain systems, the method is completely general, and can be integrated with more general approaches to other systems. The model makes experimentally testable predictions on distributed processing and on the differential backpropagation of somatic action potentials in each lateral dendrite following odor learning, providing a powerful 3D framework for investigating the functions of brain microcircuits. PMID- 24808856 TI - A computational paradigm for dynamic logic-gates in neuronal activity. AB - In 1943 McCulloch and Pitts suggested that the brain is composed of reliable logic-gates similar to the logic at the core of today's computers. This framework had a limited impact on neuroscience, since neurons exhibit far richer dynamics. Here we propose a new experimentally corroborated paradigm in which the truth tables of the brain's logic-gates are time dependent, i.e., dynamic logic-gates (DLGs). The truth tables of the DLGs depend on the history of their activity and the stimulation frequencies of their input neurons. Our experimental results are based on a procedure where conditioned stimulations were enforced on circuits of neurons embedded within a large-scale network of cortical cells in-vitro. We demonstrate that the underlying biological mechanism is the unavoidable increase of neuronal response latencies to ongoing stimulations, which imposes a non uniform gradual stretching of network delays. The limited experimental results are confirmed and extended by simulations and theoretical arguments based on identical neurons with a fixed increase of the neuronal response latency per evoked spike. We anticipate our results to lead to better understanding of the suitability of this computational paradigm to account for the brain's functionalities and will require the development of new systematic mathematical methods beyond the methods developed for traditional Boolean algebra. PMID- 24808857 TI - Large-scale automated image analysis for computational profiling of brain tissue surrounding implanted neuroprosthetic devices using Python. AB - In this article, we describe the use of Python for large-scale automated server based bio-image analysis in FARSIGHT, a free and open-source toolkit of image analysis methods for quantitative studies of complex and dynamic tissue microenvironments imaged by modern optical microscopes, including confocal, multi spectral, multi-photon, and time-lapse systems. The core FARSIGHT modules for image segmentation, feature extraction, tracking, and machine learning are written in C++, leveraging widely used libraries including ITK, VTK, Boost, and Qt. For solving complex image analysis tasks, these modules must be combined into scripts using Python. As a concrete example, we consider the problem of analyzing 3-D multi-spectral images of brain tissue surrounding implanted neuroprosthetic devices, acquired using high-throughput multi-spectral spinning disk step-and repeat confocal microscopy. The resulting images typically contain 5 fluorescent channels. Each channel consists of 6000 * 10,000 * 500 voxels with 16 bits/voxel, implying image sizes exceeding 250 GB. These images must be mosaicked, pre processed to overcome imaging artifacts, and segmented to enable cellular-scale feature extraction. The features are used to identify cell types, and perform large-scale analysis for identifying spatial distributions of specific cell types relative to the device. Python was used to build a server-based script (Dell 910 PowerEdge servers with 4 sockets/server with 10 cores each, 2 threads per core and 1TB of RAM running on Red Hat Enterprise Linux linked to a RAID 5 SAN) capable of routinely handling image datasets at this scale and performing all these processing steps in a collaborative multi-user multi-platform environment. Our Python script enables efficient data storage and movement between computers and storage servers, logs all the processing steps, and performs full multi threaded execution of all codes, including open and closed-source third party libraries. PMID- 24808858 TI - NeuroElectro: a window to the world's neuron electrophysiology data. AB - The behavior of neural circuits is determined largely by the electrophysiological properties of the neurons they contain. Understanding the relationships of these properties requires the ability to first identify and catalog each property. However, information about such properties is largely locked away in decades of closed-access journal articles with heterogeneous conventions for reporting results, making it difficult to utilize the underlying data. We solve this problem through the NeuroElectro project: a Python library, RESTful API, and web application (at http://neuroelectro.org) for the extraction, visualization, and summarization of published data on neurons' electrophysiological properties. Information is organized both by neuron type (using neuron definitions provided by NeuroLex) and by electrophysiological property (using a newly developed ontology). We describe the techniques and challenges associated with the automated extraction of tabular electrophysiological data and methodological metadata from journal articles. We further discuss strategies for how to best combine, normalize and organize data across these heterogeneous sources. NeuroElectro is a valuable resource for experimental physiologists attempting to supplement their own data, for computational modelers looking to constrain their model parameters, and for theoreticians searching for undiscovered relationships among neurons and their properties. PMID- 24808859 TI - The sinusoidal probe: a new approach to improve electrode longevity. AB - Micromotion between the brain and implanted electrodes is a major contributor to the failure of invasive brain-machine interfaces. Movements of the electrode tip cause recording instabilities while spike amplitudes decline over the weeks/months post-implantation due to glial cell activation caused by sustained mechanical trauma. We have designed a sinusoidal probe in order to reduce movement of the recording tip relative to the surrounding neural tissue. The probe was microfabricated from flexible materials and incorporated a sinusoidal shaft to minimize tethering forces and a 3D spheroid tip to anchor the recording site within the brain. Compared to standard microwire electrodes, the signal-to noise ratio and local field potential power of sinusoidal probe recordings from rabbits was more stable across recording periods up to 678 days. Histological quantification of microglia and astrocytes showed reduced neuronal tissue damage especially for the tip region between 6 and 24 months post-implantation. We suggest that the micromotion-reducing measures incorporated into our design, at least partially, decreased the magnitude of gliosis, resulting in enhanced longevity of recording. PMID- 24808860 TI - Controlling neural network responsiveness: tradeoffs and constraints. AB - In recent years much effort is invested in means to control neural population responses at the whole brain level, within the context of developing advanced medical applications. The tradeoffs and constraints involved, however, remain elusive due to obvious complications entailed by studying whole brain dynamics. Here, we present effective control of response features (probability and latency) of cortical networks in vitro over many hours, and offer this approach as an experimental toy for studying controllability of neural networks in the wider context. Exercising this approach we show that enforcement of stable high activity rates by means of closed loop control may enhance alteration of underlying global input-output relations and activity dependent dispersion of neuronal pair-wise correlations across the network. PMID- 24808861 TI - Botulinum toxin in the treatment of lingual dystonia induced by speaking. AB - Primary lingual dystonia is a rare condition, especially when it is only induced by speaking. Trihexyphenidyl failed to improve the symptoms. Several case series have demonstrated the effectiveness of botulinum toxin injection for the management of focal lingual movement disorders. Only 1 case of botulinum toxin injection for primary lingual dystonia induced by speaking has been reported, but this treatment has limited effectiveness. Our patient was treated with botulinum toxin using a superficial approach for injection into the tongue with continuing excellent results. Lingual botulinum toxin injection is a fairly simple, safe and viable treatment option for lingual dystonia induced by speaking. PMID- 24808862 TI - Increased reaction times and reduced response preparation already starts at middle age. AB - Generalized slowing characterizes aging and there is some evidence to suggest that this slowing already starts at midlife. This study aims to assess reaction time changes while performing a concurrent low-force and high-force motor task in young and middle-aged subjects. The high-force motor task is designed to induce muscle fatigue and thereby progressively increase the attentional demands. Twenty five young (20-30 years, 12 males) and 16 middle-aged (35-55 years, 9 males) adults performed an auditory two-choice reaction time task (CRT) with and without a concurrent low- or high-force motor task. The CRT required subjects to respond to two different stimuli that occurred with a probability of 70 or 30%. The motor task consisted of index finger abduction, at either 10% (10%-dual-task) or 30% (30%-dual-task) of maximal voluntary force. Cognitive task performance was measured as percentage of correct responses and reaction times. Middle-aged subjects responded slower on the frequent but more accurately on the infrequent stimuli of CRT than young subjects. Both young and middle-aged subjects showed increased errors and reaction times while performing under dual-task conditions and both outcome measures increased further under fatiguing conditions. Only under 30%-dual-task demands, an age-effect on dual-task performance was present. Both single- and dual-task conditions showed that already at mid-life response preparation is seriously declined and that subjects implement different strategies to perform a CRT task. PMID- 24808864 TI - Assessing analytical methods to monitor isoAsp formation in monoclonal antibodies. AB - A ubiquitous post-translational modification observed in proteins is isomerization of aspartic acid to isoaspartic acid (isoAsp). This non-enzymatic post-translational modification occurs spontaneously in proteins and plays a role in aging, autoimmune response, cancer, neurodegeneration, and other diseases. Formation of isoAsp is also a significant issue for recombinant monoclonal antibody based protein therapeutics particularly when isomerization occurs in a complementarity-determining region due to potential impact to the clinical efficacy. Here, we present and compare three analytical methods to monitor and/or quantify isoAsp formation in a monoclonal antibody. The methods include two peptide map based technologies with quantitation from either UV integration or total ion peak areas, as well as an alternative approach using IdeS digestion to generate Fc/2 and Fab'2 regions, followed by hydrophobic interaction chromatography (HIC) to separate the population of Fab'2 containing an isoAsp. The level of isoAsp detected by the peptide map and the digested-HIC methods presented here show similar trends although sample throughput varies by method. PMID- 24808863 TI - Hepcidin antagonists for potential treatments of disorders with hepcidin excess. AB - The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes), recycling of hemoglobin iron (the macrophages) and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic iron refractory iron deficiency anemia and the common anemia of chronic disease (ACD) or anemia of inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis-stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins, and aptamers), inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA) or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulfate proteoglycans in hepcidin expression and modulation of the BMP6/SMAD pathway. PMID- 24808865 TI - An approach for exploring interaction between two proteins in vivo. AB - We describe a strategy for exploring the function of protein-protein interactions in striated muscle in vivo. We describe our experience using this strategy to study the interaction of UNC-112 (kindlin) with PAT-4 (integrin linked kinase). Random mutagenesis is used to generate a collection of mutants that are screened for lack of binding or gain of binding using a yeast 2-hybrid assay. The mutant proteins are then expressed in transgenic C. elegans to determine their ability to localize in the sarcomere. We emphasize two advantages of this strategy: (1) for studying the interaction of protein A with protein B, when protein A can interact with multiple proteins, and (2) it explores the function of an interaction rather than the absence of, or reduced level of, a protein as can be obtained with null mutants or knockdown by RNAi. We propose that this method can be generalized for studying the meaning of a protein-protein interaction in muscle for any system in which transgenic animals can be generated and their muscles can be imaged. PMID- 24808868 TI - Singing emotionally: a study of pre-production, production, and post-production facial expressions. AB - Singing involves vocal production accompanied by a dynamic and meaningful use of facial expressions, which may serve as ancillary gestures that complement, disambiguate, or reinforce the acoustic signal. In this investigation, we examined the use of facial movements to communicate emotion, focusing on movements arising in three epochs: before vocalization (pre-production), during vocalization (production), and immediately after vocalization (post-production). The stimuli were recordings of seven vocalists' facial movements as they sang short (14 syllable) melodic phrases with the intention of communicating happiness, sadness, irritation, or no emotion. Facial movements were presented as point-light displays to 16 observers who judged the emotion conveyed. Experiment 1 revealed that the accuracy of emotional judgment varied with singer, emotion, and epoch. Accuracy was highest in the production epoch, however, happiness was well communicated in the pre-production epoch. In Experiment 2, observers judged point-light displays of exaggerated movements. The ratings suggested that the extent of facial and head movements was largely perceived as a gauge of emotional arousal. In Experiment 3, observers rated point-light displays of scrambled movements. Configural information was removed in these stimuli but velocity and acceleration were retained. Exaggerated scrambled movements were likely to be associated with happiness or irritation whereas unexaggerated scrambled movements were more likely to be identified as "neutral." An analysis of singers' facial movements revealed systematic changes as a function of the emotional intentions of singers. The findings confirm the central role of facial expressions in vocal emotional communication, and highlight individual differences between singers in the amount and intelligibility of facial movements made before, during, and after vocalization. PMID- 24808867 TI - Genome-wide (over)view on the actions of vitamin D. AB - For a global understanding of the physiological impact of the nuclear hormone 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) the analysis of the genome-wide locations of its high affinity receptor, the transcription factor vitamin D receptor (VDR), is essential. Chromatin immunoprecipitation sequencing (ChIP-seq) in GM10855 and GM10861 lymphoblastoid cells, undifferentiated and lipopolysaccharide-differentiated THP-1 monocytes, LS180 colorectal cancer cells and LX2 hepatic stellate cells revealed between 1000 and 13,000 VDR-specific genomic binding sites. The harmonized analysis of these ChIP-seq datasets indicates that the mechanistic basis for the action of the VDR is independent of the cell type. Formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq) data highlight accessible chromatin regions, which are under control of 1,25(OH)2D3. In addition, public data, such as from the ENCODE project, allow to relate the genome-wide actions of VDR and 1,25(OH)2D3 to those of other proteins within the nucleus. For example, locations of the insulator protein CTCF suggest a segregation of the human genome into chromatin domains, of which more than 1000 contain at least one VDR binding site. The integration of all these genome-wide data facilitates the identification of the most important VDR binding sites and associated primary 1,25(OH)2D3 target genes. Expression changes of these key genes can serve as biomarkers for the actions of vitamin D3 and its metabolites in different tissues and cell types of human individuals. Analysis of primary tissues obtained from vitamin D3 intervention studies using such markers indicated a large inter-individual variation for the efficiency of vitamin D3 supplementation. In conclusion, a genome-wide (over)view on the genomic locations of VDR provides a broader basis for addressing vitamin D's role in health and disease. PMID- 24808866 TI - Vitamin D and the epigenome. AB - Epigenetic mechanisms play a crucial role in regulating gene expression. The main mechanisms involve methylation of DNA and covalent modifications of histones by methylation, acetylation, phosphorylation, or ubiquitination. The complex interplay of different epigenetic mechanisms is mediated by enzymes acting in the nucleus. Modifications in DNA methylation are performed mainly by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, while a plethora of enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs) regulate covalent histone modifications. In many diseases, such as cancer, the epigenetic regulatory system is often disturbed. Vitamin D interacts with the epigenome on multiple levels. Firstly, critical genes in the vitamin D signaling system, such as those coding for vitamin D receptor (VDR) and the enzymes 25 hydroxylase (CYP2R1), 1alpha-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation. Secondly, VDR protein physically interacts with coactivator and corepressor proteins, which in turn are in contact with chromatin modifiers, such as HATs, HDACs, HMTs, and with chromatin remodelers. Thirdly, a number of genes encoding for chromatin modifiers and remodelers, such as HDMs of the Jumonji C (JmjC)-domain containing proteins and lysine-specific demethylase (LSD) families are primary targets of VDR and its ligands. Finally, there is evidence that certain VDR ligands have DNA demethylating effects. In this review we will discuss regulation of the vitamin D system by epigenetic modifications and how vitamin D contributes to the maintenance of the epigenome, and evaluate its impact in health and disease. PMID- 24808869 TI - Harnessing psychoanalytical methods for a phenomenological neuroscience. AB - Psychoanalysis proffers a wealth of phenomenological tools to advance the study of consciousness. Techniques for elucidating the structures of subjective life are sorely lacking in the cognitive sciences; as such, experiential reporting techniques must rise to meet both complex theories of brain function and increasingly sophisticated neuroimaging technologies. Analysis may offer valuable methods for bridging the gap between first-person and third-person accounts of the mind. Using both systematic observational approaches alongside unstructured narrative interactions, psychoanalysts help patients articulate their experience and bring unconscious mental contents into awareness. Similar to seasoned meditators or phenomenologists, individuals who have undergone analysis are experts in discerning and describing their subjective experience, thus making them ideal candidates for neurophenomenology. Moreover, analytic techniques may provide a means of guiding untrained experimental participants to greater awareness of their mental continuum, as well as gathering subjective reports about fundamental yet elusive aspects of experience including selfhood, temporality, and inter-subjectivity. Mining psychoanalysis for its methodological innovations provides a fresh turn for the neuropsychoanalysis movement and cognitive science as a whole - showcasing the integrity of analysis alongside the irreducibility of human experience. PMID- 24808871 TI - In (visual) search for a new distraction: the efficiency of a novel attentional deployment versus semantic meaning regulation strategies. AB - Cognitive emotion regulation strategies are considered the king's highway to control affective reactions. Two broad categories of cognitive regulation are attentional deployment and semantic meaning. The basic distinctive feature between these categories is the type of conflict between regulatory and emotional processes for dominance, with an early attentional selection conflict in attentional deployment and a late appraisal selection conflict in semantic meaning. However, prior studies that tested the relative efficacy of these two regulatory categories varied the type and the degree of conflict. Our major goal was to test the relative efficacy of a novel attentional deployment strategy (visual search distraction) and a classic semantic meaning strategy (reappraisal) that have a different type of conflict but a matched degree of conflict. Specifically, visual search distraction involves a strong degree of attentional selection conflict manifested in attending subtle non-emotional features that are camouflaged within potent negative emotional stimuli. Reappraisal involves a strong degree of appraisal selection conflict manifested in construing neutral reappraisals that rely on potent negative emotional appraisals. Based on our theoretical model we hypothesized and found that visual search distraction was as effective as cognitive reappraisal in down-regulating the experience of low intensity of negative emotion (Study 1), but more effective, less effortful, and more strongly blocking emotional information processing than cognitive reappraisal when regulating high intensity (Study 2). A final study ruled out a demand characteristics explanation by showing that participants' expectations about how they should feel diverged from how they actually reported feeling following regulation (Study 3). Our findings suggest that the basic difference in the type rather than degree of conflict between attentional deployment and semantic meaning determines strategies' outcome. PMID- 24808872 TI - Instructions matter: a comparison of baseline conditions for cognitive emotion regulation paradigms. AB - The choice of a meaningful baseline condition is a crucial issue for each experimental design. In the case of cognitive emotion regulation, it is common to either let participants passively view emotional stimuli without any further specific instructions or to instruct them to actively attend to and permit any arising emotions, and to contrast one of these baseline conditions with a regulation condition. While the "view" strategy can be assumed to allow for a more spontaneous emotional response, the "permit" strategy may result in a more pronounced affective and cognitive response. As these conceptual differences may be associated with differences both in subjective emotional experience and neural activation, we compared these two common control conditions within a single functional magnetic resonance imaging (fMRI) experiment, during which participants were instructed to either passively view a set of unpleasant and neutral pictures or to actively permit any emotions arising in response to the unpleasant pictures. Trial-by-trial ratings confirmed that participants perceived the unpleasant pictures as more arousing than the neutral pictures, but also indicated higher subjective arousal during the "permit negative" as compared to the "view negative" and "view neutral" conditions. While both the "permit negative" and "view negative" conditions led to increased activation of the bilateral amygdala when contrasted with the passive viewing of neutral pictures, activation in the left amygdala was increased in response to the "permit" instruction as compared to the "view" instruction for unpleasant pictures. The increase in amygdala activation in both the "permit" and "view" conditions renders both strategies as suitable baseline conditions for studies of cognitive emotion regulation. Conceptual and activation differences, however, indicate that these two variants are not exchangeable and should be chosen depending on the experimental context. PMID- 24808873 TI - Antireductionisms with regard to mental disorders: some caveats. A commentary on Marco Stier. PMID- 24808870 TI - The consciousness state space (CSS)-a unifying model for consciousness and self. AB - Every experience, those we are aware of and those we are not, is embedded in a subjective timeline, is tinged with emotion, and inevitably evokes a certain sense of self. Here, we present a phenomenological model for consciousness and selfhood which relates time, awareness, and emotion within one framework. The consciousness state space (CSS) model is a theoretical one. It relies on a broad range of literature, hence has high explanatory and integrative strength, and helps in visualizing the relationship between different aspects of experience. Briefly, it is suggested that all phenomenological states fall into two categories of consciousness, core and extended (CC and EC, respectively). CC supports minimal selfhood that is short of temporal extension, its scope being the here and now. EC supports narrative selfhood, which involves personal identity and continuity across time, as well as memory, imagination and conceptual thought. The CSS is a phenomenological space, created by three dimensions: time, awareness and emotion. Each of the three dimensions is shown to have a dual phenomenological composition, falling within CC and EC. The neural spaces supporting each of these dimensions, as well as CC and EC, are laid out based on the neuroscientific literature. The CSS dynamics include two simultaneous trajectories, one in CC and one in EC, typically antagonistic in normal experiences. However, this characteristic behavior is altered in states in which a person experiences an altered sense of self. Two examples are laid out, flow and meditation. The CSS model creates a broad theoretical framework with explanatory and unificatory power. It constructs a detailed map of the consciousness and selfhood phenomenology, which offers constraints for the science of consciousness. We conclude by outlining several testable predictions raised by the CSS model. PMID- 24808874 TI - Creating a communication system from scratch: gesture beats vocalization hands down. AB - How does modality affect people's ability to create a communication system from scratch? The present study experimentally tests this question by having pairs of participants communicate a range of pre-specified items (emotions, actions, objects) over a series of trials to a partner using either non-linguistic vocalization, gesture or a combination of the two. Gesture-alone outperformed vocalization-alone, both in terms of successful communication and in terms of the creation of an inventory of sign-meaning mappings shared within a dyad (i.e., sign alignment). Combining vocalization with gesture did not improve performance beyond gesture-alone. In fact, for action items, gesture-alone was a more successful means of communication than the combined modalities. When people do not share a system for communication they can quickly create one, and gesture is the best means of doing so. PMID- 24808875 TI - Effect of handedness on the occurrence of semantic N400 priming effect in 18- and 24-month-old children. AB - It is frequently stated that right-handedness reflects hemispheric dominance for language. Indeed, most right-handers process phonological aspects of language with the left hemisphere (and other aspects with the right hemisphere). However, given the overwhelming majority of right-handers and of individuals showing left hemisphere language dominance, there is a high probability to be right-handed and at the same time process phonology within the left hemisphere even if there was no causal link between both. One way to understand the link between handedness and language lateralization is to observe how they co-develop. In this study, we investigated to what extent handedness is related to the occurrence of a right hemisphere lateralized N400 event related potential in a semantic priming task in children. The N400 component in a semantic priming task is more negative for unrelated than for related word pairs. We have shown earlier that N400 effect occurred in 24-month-olds over the right parietal-occipital recording sites, whereas no significant effect was obtained over the left hemisphere sites. In 18 month-olds, this effect was observed only in those children with higher word production ability. Since handedness has also been associated with the vocabulary size at these ages, we investigated the relationship between the N400 and handedness in 18- and 24-months as a function of their vocabulary. The results showed that right-handers had significantly higher vocabulary size and more pronounced N400 effect over the right hemisphere than non-lateralized children, but only in the 18-month-old group. We propose that the emergences of right handedness and right-distributed N400 effect are not causally related, but that both developmental processes reflect a general tendency to recruit the hemispheres in a lateralized manner. The lack of this relationship at 24 months further suggests that there is no direct causal relation between handedness and language lateralization. PMID- 24808876 TI - Clustering, hierarchical organization, and the topography of abstract and concrete nouns. AB - The empirical study of language has historically relied heavily upon concrete word stimuli. By definition, concrete words evoke salient perceptual associations that fit well within feature-based, sensorimotor models of word meaning. In contrast, many theorists argue that abstract words are "disembodied" in that their meaning is mediated through language. We investigated word meaning as distributed in multidimensional space using hierarchical cluster analysis. Participants (N = 365) rated target words (n = 400 English nouns) across 12 cognitive dimensions (e.g., polarity, ease of teaching, emotional valence). Factor reduction revealed three latent factors, corresponding roughly to perceptual salience, affective association, and magnitude. We plotted the original 400 words for the three latent factors. Abstract and concrete words showed overlap in their topography but also differentiated themselves in semantic space. This topographic approach to word meaning offers a unique perspective to word concreteness. PMID- 24808877 TI - Here, there and everywhere: emotion and mental state talk in different social contexts predicts empathic helping in toddlers. AB - A growing body of literature suggests that parents socialize early-emerging prosocial behavior across varied contexts and in subtle yet powerful ways. We focus on discourse about emotions and mental states as one potential socialization mechanism given its conceptual relevance to prosocial behavior and its known positive relations with emotion understanding and social-cognitive development, as well as parents' frequent use of such discourse beginning in infancy. Specifically, we ask how parents' emotion and mental state talk (EMST) with their toddlers relates to toddlers' helping and how these associations vary by context. Children aged 18- to 30-months (n = 38) interacted with a parent during book reading and joint play with toys, two everyday contexts that afford parental discussion of emotions and mental states. Children also participated in instrumental and empathic helping tasks. Results revealed that although parents discuss mental states with their children in both contexts, the nature of their talk differs: during book reading parents labeled emotions and mental states significantly more often than during joint play, especially simple affect words (e.g., happy, sad) and explanations or elaborations of emotions; whereas they used more desire talk and mental state words (e.g., think, know) in joint play. Parents' emotion and mental state discourse related to children's empathic, emotion-based helping behavior; however, it did not relate to instrumental, action-based helping. Moreover, relations between parent talk and empathic helping varied by context: children who helped more quickly had parents who labeled emotion and mental states more often during joint play and who elicited this talk more often during book reading. As EMST both varies between contexts and exhibits context-specific associations with empathic prosocial behavior early in development, we conclude that such discourse may be a key form of socialization in emerging prosociality. PMID- 24808878 TI - The use of conceptual components in language production: an ERP study. AB - According to frame-theory, concepts can be represented as structured frames that contain conceptual attributes (e.g., "color") and their values (e.g., "red"). A particular color value can be seen as a core conceptual component for (high color diagnostic; HCD) objects (e.g., bananas) which are strongly associated with a typical color, but less so for (low color-diagnostic; LCD) objects (e.g., bicycles) that exist in many different colors. To investigate whether the availability of a core conceptual component (color) affects lexical access in language production, we conducted two experiments on the naming of visually presented HCD and LCD objects. Experiment 1 showed that, when naming latencies were matched for colored HCD and LCD objects, achromatic HCD objects were named more slowly than achromatic LCD objects. In Experiment 2 we recorded ERPs while participants performed a picture-naming task, in which achromatic target pictures were either preceded by an appropriately colored box (primed condition) or a black and white checkerboard (unprimed condition). We focused on the P2 component, which has been shown to reflect difficulty of lexical access in language production. Results showed that HCD resulted in slower object-naming and a more pronounced P2. Priming also yielded a more positive P2 but did not result in an RT difference. ERP waveforms on the P1, P2 and N300 components showed a priming by color-diagnosticity interaction, the effect of color priming being stronger for HCD objects than for LCD objects. The effect of color-diagnosticity on the P2 component suggests that the slower naming of achromatic HCD objects is (at least in part) due to more difficult lexical retrieval. Hence, the color attribute seems to affect lexical retrieval in HCD words. The interaction between priming and color-diagnosticity indicates that priming with a feature hinders lexical access, especially if the feature is a core feature of the target object. PMID- 24808879 TI - Processing word prosody-behavioral and neuroimaging evidence for heterogeneous performance in a language with variable stress. AB - In the present behavioral and fMRI study, we investigated for the first time interindividual variability in word stress processing in a language with variable stress position (German) in order to identify behavioral predictors and neural correlates underlying these differences. It has been argued that speakers of languages with variable stress should perform relatively well in tasks tapping into the representation and processing of word stress, given that this is a relevant feature of their language. Nevertheless, in previous studies on word stress processing large degrees of interindividual variability have been observed but were ignored or left unexplained. Twenty-five native speakers of German performed a sequence recall task using both segmental and suprasegmental stimuli. In general, the suprasegmental condition activated a subcortico-cortico cerebellar network including, amongst others, bilateral inferior frontal gyrus, insula, precuneus, cerebellum, the basal ganglia, pre-SMA and SMA, which has been suggested to be dedicated to the processing of temporal aspects of speech. However, substantial interindividual differences were observed. In particular, main effects of group were observed in the left middle temporal gyrus (below vs. above average performance in stress processing) and in the left precuneus (above vs. below average). Moreover, condition (segmental vs. suprasegmental) and group (above vs. below average) interacted in the right hippocampus and cerebellum. At the behavioral level, differences in word stress processing could be partly explained by individual performance in basic auditory perception including duration discrimination and by working memory performance (WM). We conclude that even in a language with variable stress, interindividual differences in behavioral performance and in the neuro-cognitive foundations of stress processing can be observed which may partly be traced back to individual basic auditory processing and WM performance. PMID- 24808880 TI - Openness, neuroticism, conscientiousness, and family health and aging concerns interact in the prediction of health-related Internet searches in a representative U.S. sample. AB - Recent estimates suggest 60% of the U.S. adult population uses the Internet to find health-related information. The goal of the present study was to model health-related Internet searches as a function of an interdependent system of personality adaptation in the context of recent health and aging-related concerns. Assessments of background factors, Big Five personality traits, past month health and aging-related concerns, and the frequency of past-month health related Internet searches (via Google, Yahoo, AOL, Bing, or some other search engine) were obtained from a representative U.S. sample (N = 1,015). Controlling for background factors, regression analyses showed more frequent health-related Internet searches were predicted by a drive for exploration and investigation (high openness), as well as alarm sensitivity (high openness and high neuroticism) and an anticipatory inclination (high openness and high conscientiousness) in the context of recent problems with aging parents and recent health concerns for a family member. Consistent with interdependent models of personality adaptation, as well as prior evidence for "surrogate" health related Internet searches, the results suggest a personality process model of search behavior that is partially dependent upon dispositional levels of exploration, emotional stability, control, and health and aging concerns for family members. PMID- 24808881 TI - Considerations about rodent models of binge eating episodes. PMID- 24808882 TI - Levels and kinds of explanation: lessons from neuropsychiatry. AB - I use an example from neuropsychiatry, namely delusional misidentification, to show a distinction between levels of explanation and kinds of explanation. Building on a pragmatic view of explanation, different kinds of explanation arise because we have different kinds of explanatory concerns. One important kind of explanatory concern involves asking a certain kind of "why" question. Answering such questions provides a personal explanation, namely, renders intelligible the beliefs and actions of other persons. I use contrasting theories of delusional misidentification to highlight how different facts about the phenomenon that is being explained impose constraints on the availability of personal explanation. PMID- 24808883 TI - Parent routines, child routines, and family demographics associated with obesity in parents and preschool-aged children. AB - Many daily routines and behaviors are related to the prevalence of obesity. This study investigated the association between routines and behaviors that act as protective factors related to lower prevalence of obesity in parents (BMI >= 30 kg/m(2)) and overweight in preschool children (BMI >= 85th percentile). Socio demographic characteristics were assessed in relation to protective routines (PRs), and prevalence of obesity/overweight data from 337 preschool children and their parents. The two PRs assessed with parents included adequate sleep (>=7 h/night) and family mealtime routine (scoring higher than the median score). The four PRs assessed in children included adequate sleep (>=10 h/night), family mealtime routine, limiting screen-viewing time (<=2 h/day of TV, video, DVD), and not having a bedroom TV. Overall, 27.9% of parents were obese and 22.8% of children were overweight, and 39.8% of the parents had both parent PRs, and only 11.6% of children had all four child PRs. Results demonstrated that several demographic factors were significantly related to the use of PRs for parents and children. The lack of PRs was related to increased risk for overweight in children, but not for obesity in parents. However, in the adjusted models the overall cumulative benefits of using PRs was not significant in children either. In the multivariate adjusted logistic regression models, the only significant individual PR for children was adequate sleep. In a path analysis model, parent sleep was related to child sleep, which was in turn related to decreased obesity. Overall, findings suggest that parent and child PRs, especially sleep routines, within a family can be associated and may play an important role in the health outcomes of both parents and children. Understanding the mechanisms that influence how and when parents and children use these PRs may be promising for developing targeted family-based obesity-prevention efforts. PMID- 24808884 TI - The future and the female academic leader: advancing student engagement. PMID- 24808885 TI - The early development of executive function and its relation to social interaction: a brief review. AB - Executive function (EF) refers to the ability to execute appropriate actions and to inhibit inappropriate actions for the attainment of a specific goal. Research has shown that this ability develops rapidly during the preschool years. Recently, it has been proposed that research on EF should consider the importance of social interaction. In this article, recent evidence regarding the early development of EF and its relation to social interaction has been reviewed. Research consistently showed that social interaction can influence EF skills in young children. However, the development of EF may facilitate the cognitive skills that are important for social interaction. Taken together, there might be functional dependency between the development of EF and social interaction. PMID- 24808886 TI - Volumetric Brain Morphometry Changes in Patients with Obstructive Sleep Apnea Syndrome: Effects of CPAP Treatment and Literature Review. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a frequent breathing disorder occurring during sleep that is characterized by recurrent hypoxic episodes and sleep fragmentation. It remains unclear whether OSAS leads to structural brain changes, and if so, in which brain regions. Brain region specific gray and white matter volume (GMV and WMV) changes can be measured with voxel-based morphometry (VBM). The aims of this study were to use VBM to analyze GMV and WMV in untreated OSAS patients compared to healthy controls (HC); examine the impact of OSAS-related variables (nocturnal hypoxemia duration and sleep fragmentation index) on GMV and WMV; and assess the effects of therapeutic vs. sham continuous positive airway pressure (CPAP) treatment. We discuss our results in light of previous findings and provide a comprehensive literature review. METHODS: Twenty-seven treatment-naive male patients with moderate to severe OSAS and seven healthy age- and education-matched HC were recruited. After a baseline fMRI scan, patients randomly received either active (therapeutic, n = 14) or sham (subtherapeutic, n = 13) nasal CPAP treatment for 2 months. RESULTS: Significant negative correlations were observed between nocturnal hypoxemia duration and GMV in bilateral lateral temporal regions. No differences in GMV or WMV were found between OSAS patients and HC, and no differences between CPAP vs. sham CPAP treatment effects in OSAS patients. CONCLUSION: It appears that considering VBM GMV changes there is little difference between OSAS patients and HC. The largest VBM study to date indicates structural changes in the lateral aspect of the temporal lobe, which also showed a significant negative correlation with nocturnal hypoxemia duration in our study. This finding suggests an association between the effect of nocturnal hypoxemia and decreased GMV in OSAS patients. PMID- 24808887 TI - Clinical Outcome after Intra-Arterial Stroke Therapy in the Very Elderly: Why is it so Heterogeneous? AB - Very elderly patients (i.e., >=80 years) are disproportionally affected by acute ischemic stroke. They account for a third of hospital stroke admissions, but two thirds of overall stroke-related morbidity and mortality. There is some evidence of clinical benefit in treating selected very elderly patients with intravenous thrombolysis (IVT). For very elderly patients ineligible or non-responsive to IVT, intra-arterial therapy (IAT) may have promise in improving clinical outcome. However, its unequivocal efficacy in the general population remains to be proven in randomized trials. Small cohort studies reveal that the rate of good clinical outcome for very elderly patients after IAT is highly variable, ranging from 0 to 28%. In addition, they experience higher rates of futile reperfusion than younger patients. Thus, it is imperative to understand the factors that impact on clinical outcome in very elderly patients after IAT. The aim of this review is to examine the factors that may be responsible for the heterogeneous clinical response of the very elderly to IAT. This will allow the reader to integrate the current available evidence to individualize intra-arterial stroke therapy in very elderly patients. Placing emphasis on pre-stroke independent living, smaller infarct core size, short procedure times, and avoiding general anesthesia where feasible, will help improve rates of good clinical outcome. PMID- 24808889 TI - Surgical treatment of dyskinesia in Parkinson's disease. AB - One of the main indications for stereotactic surgery in Parkinson's disease (PD) is the control of levodopa-induced dyskinesia. This can be achieved by pallidotomy and globus pallidus internus (GPi) deep brain stimulation (DBS) or by subthalamotomy and subthalamic nucleus (STN) DBS, which usually allow for a cut down in the dosage of levodopa. DBS has assumed a pivotal role in stereotactic surgical treatment of PD and, in fact, ablative procedures are currently considered surrogates, particularly when bilateral procedures are required, as DBS does not produce a brain lesion and the stimulator can be programed to induce better therapeutic effects while minimizing adverse effects. Interventions in either the STN and the GPi seem to be similar in controlling most of the other motor aspects of PD, nonetheless, GPi surgery seems to induce a more particular and direct effect on dyskinesia, while the anti-dyskinetic effect of STN interventions is mostly dependent on a reduction of dopaminergic drug dosages. Hence, the si ne qua non-condition for a reduction of dyskinesia when STN interventions are intended is their ability to allow for a reduction of levodopa dosage. Pallidal surgery is indicated when dyskinesia is a dose-limiting factor for maintaining or introducing higher adequate levels of dopaminergic therapy. Also medications used for the treatment of PD may be useful for the improvement of several non-motor aspects of the disease, including sleep, psychiatric, and cognitive domains, therefore, dose reduction of medication withdrawal are not always a fruitful objective. PMID- 24808890 TI - Artificial balance: restoration of the vestibulo-ocular reflex in humans with a prototype vestibular neuroprosthesis. AB - The vestibular system plays a crucial role in the multisensory control of balance. When vestibular function is lost, essential tasks such as postural control, gaze stabilization, and spatial orientation are limited and the quality of life of patients is significantly impaired. Currently, there is no effective treatment for bilateral vestibular deficits. Research efforts both in animals and humans during the last decade set a solid background to the concept of using electrical stimulation to restore vestibular function. Still, the potential clinical benefit of a vestibular neuroprosthesis has to be demonstrated to pave the way for a translation into clinical trials. An important parameter for the assessment of vestibular function is the vestibulo-ocular reflex (VOR), the primary mechanism responsible for maintaining the perception of a stable visual environment while moving. Here we show that the VOR can be artificially restored in humans using motion-controlled, amplitude modulated electrical stimulation of the ampullary branches of the vestibular nerve. Three patients received a vestibular neuroprosthesis prototype, consisting of a modified cochlear implant providing vestibular electrodes. Significantly higher VOR responses were observed when the prototype was turned ON. Furthermore, VOR responses increased significantly as the intensity of the stimulation increased, reaching on average 79% of those measured in healthy volunteers in the same experimental conditions. These results constitute a fundamental milestone and allow us to envision for the first time clinically useful rehabilitation of patients with bilateral vestibular loss. PMID- 24808888 TI - Neuroactive peptides as putative mediators of antiepileptic ketogenic diets. AB - Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and gamma-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin, and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal mechanisms involved in the beneficial effects of KDs. In this review, we summarize the current evidence for altered regulation of the synthesis of neuropeptides and peripheral hormones in response to KDs, and we try to define a possible role for specific neuroactive peptides in mediating the antiepileptic properties of diet-induced ketogenesis. PMID- 24808891 TI - Thyroid hormone signaling and adult neurogenesis in mammals. AB - The vital roles of thyroid hormone in multiple aspects of perinatal brain development have been known for over a century. In the last decades, the molecular mechanisms underlying effects of thyroid hormone on proliferation, differentiation, migration, synaptogenesis, and myelination in the developing nervous system have been gradually dissected. However, recent data reveal that thyroid signaling influences neuronal development throughout life, from early embryogenesis to the neurogenesis in the adult brain. This review deals with the latter phase and analyses current knowledge on the role of T3, the active form of thyroid hormone, and its receptors in regulating neural stem cell function in the hippocampus and the subventricular zone, the two principal sites harboring neurogenesis in the adult mammalian brain. In particular, we discuss the critical roles of T3 and TRalpha1 in commitment to a neuronal phenotype, a process that entails the repression of a number of genes notably that encoding the pluripotency factor, Sox2. Furthermore, the question of the relevance of thyroid hormone control of adult neurogenesis is considered in the context of brain aging, cognitive decline, and neurodegenerative disease. PMID- 24808892 TI - DNA replication origins in archaea. AB - DNA replication initiation, which starts at specific chromosomal site (known as replication origins), is the key regulatory stage of chromosome replication. Archaea, the third domain of life, use a single or multiple origin(s) to initiate replication of their circular chromosomes. The basic structure of replication origins is conserved among archaea, typically including an AT-rich unwinding region flanked by several conserved repeats (origin recognition box, ORB) that are located adjacent to a replication initiator gene. Both the ORB sequence and the adjacent initiator gene are considerably diverse among different replication origins, while in silico and genetic analyses have indicated the specificity between the initiator genes and their cognate origins. These replicator-initiator pairings are reminiscent of the oriC-dnaA system in bacteria, and a model for the negative regulation of origin activity by a downstream cluster of ORB elements has been recently proposed in haloarchaea. Moreover, comparative genomic analyses have revealed that the mosaics of replicator-initiator pairings in archaeal chromosomes originated from the integration of extrachromosomal elements. This review summarizes the research progress in understanding of archaeal replication origins with particular focus on the utilization, control and evolution of multiple replication origins in haloarchaea. PMID- 24808894 TI - Membrane interaction of retroviral Gag proteins. AB - Assembly of an infectious retroviral particle relies on multimerization of the Gag polyprotein at the inner leaflet of the plasma membrane. The three domains of Gag common to all retroviruses - MA, CA, and NC - provide the signals for membrane binding, assembly, and viral RNA packaging, respectively. These signals do not function independently of one another. For example, Gag multimerization enhances membrane binding and is more efficient when NC is interacting with RNA. MA binding to the plasma membrane is governed by several principles, including electrostatics, recognition of specific lipid head groups, hydrophobic interactions, and membrane order. HIV-1 uses many of these principles while Rous sarcoma virus (RSV) appears to use fewer. This review describes the principles that govern Gag interactions with membranes, focusing on RSV and HIV-1 Gag. The review also defines lipid and membrane behavior, and discusses the complexities in determining how lipid and membrane behavior impact Gag membrane binding. PMID- 24808893 TI - Clostridium difficile phages: still difficult? AB - Phages that infect Clostridium difficile were first isolated for typing purposes in the 1980s, but their use was short lived. However, the rise of C. difficile epidemics over the last decade has triggered a resurgence of interest in using phages to combat this pathogen. Phage therapy is an attractive treatment option for C. difficile infection, however, developing suitable phages is challenging. In this review we summarize the difficulties faced by researchers in this field, and we discuss the solutions and strategies used for the development of C. difficile phages for use as novel therapeutics. Epidemiological data has highlighted the diversity and distribution of C. difficile, and shown that novel strains continue to emerge in clinical settings. In parallel with epidemiological studies, advances in molecular biology have bolstered our understanding of C. difficile biology, and our knowledge of phage-host interactions in other bacterial species. These three fields of biology have therefore paved the way for future work on C. difficile phages to progress and develop. Benefits of using C. difficile phages as therapeutic agents include the fact that they have highly specific interactions with their bacterial hosts. Studies also show that they can reduce bacterial numbers in both in vitro and in vivo systems. Genetic analysis has revealed the genomic diversity among these phages and provided an insight into their taxonomy and evolution. No strictly virulent C. difficile phages have been reported and this contributes to the difficulties with their therapeutic exploitation. Although treatment approaches using the phage-encoded endolysin protein have been explored, the benefits of using "whole-phages" are such that they remain a major research focus. Whilst we don't envisage working with C. difficile phages will be problem-free, sufficient study should inform future strategies to facilitate their development to combat this problematic pathogen. PMID- 24808895 TI - Combined metagenomic and phenomic approaches identify a novel salt tolerance gene from the human gut microbiome. AB - In the current study, a number of salt-tolerant clones previously isolated from a human gut metagenomic library were screened using Phenotype MicroArray (PM) technology to assess their functional capacity. PM's can be used to study gene function, pathogenicity, metabolic capacity and identify drug targets using a series of specialized microtitre plate assays, where each well of the microtitre plate contains a different set of conditions and tests a different phenotype. Cellular respiration is monitored colorimetrically by the reduction of a tetrazolium dye. One clone, SMG 9, was found to be positive for utilization/transport of L-carnitine (a well-characterized osmoprotectant) in the presence of 6% w/v sodium chloride (NaCl). Subsequent experiments revealed a significant growth advantage in minimal media containing NaCl and L-carnitine. Fosmid sequencing revealed putative candidate genes responsible for the phenotype. Subsequent cloning of two genes did not replicate the L-carnitine associated phenotype, although one of the genes, a sigma(54)-dependent transcriptional regulator, did confer salt tolerance to Escherichia coli when expressed in isolation. The original clone, SMG 9, was subsequently found to have lost the original observed phenotype upon further investigation. Nevertheless, this study demonstrates the usefulness of a phenomic approach to assign a functional role to metagenome-derived clones. PMID- 24808896 TI - Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. AB - Obesity and its associated disorders are a major public health concern. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). The establishment of gut microbiota is dependent on the type of birth. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understand these changes is important to predict diseases and develop therapies. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases. PMID- 24808898 TI - A survey of the small RNA population during far-red light-induced apical hook opening. AB - Photomorphogenesis is a mechanism employed by plants to regulate their architecture and developmental program in response to light conditions. As they emerge into light for the first time, dark-grown seedlings employ a rapid and finely-controlled photomorphogenic signaling network. Small RNAs have increasingly been revealed to play an important role in regulating multiple aspects of plant development, by modulating the stability of mRNAs. The rapid alteration of the mRNA transcriptome is a known hallmark of the de-etiolation response, thus we investigated the small RNA transcriptome during this process in specific seedling tissues. Here we describe a survey of the small RNA expression profile in four tissues of etiolated soybean seedlings, the cotyledons, hypocotyl and the convex and concave sides of the apical hook. We also investigate how this profile responds to a 1-h far-red light treatment. Our data suggests that miRNAs show a different global profile between these tissues and treatments, suggesting a possible role for tissue- and treatment-specific expression in the differential morphology of the seedling on de-etiolation. Further evidence for the role of miRNA in light-regulated development is given by the de-etiolation responses of a hypomorphic ago1 mutant, which displays reduced and delayed photomorphogenic responses in apical hook and cotyledon angle to far-red light. PMID- 24808897 TI - Transport proteins of parasitic protists and their role in nutrient salvage. AB - The loss of key biosynthetic pathways is a common feature of important parasitic protists, making them heavily dependent on scavenging nutrients from their hosts. This is often mediated by specialized transporter proteins that ensure the nutritional requirements of the parasite are met. Over the past decade, the completion of several parasite genome projects has facilitated the identification of parasite transporter proteins. This has been complemented by functional characterization of individual transporters along with investigations into their importance for parasite survival. In this review, we summarize the current knowledge on transporters from parasitic protists and highlight commonalities and differences in the transporter repertoires of different parasitic species, with particular focus on characterized transporters that act at the host-pathogen interface. PMID- 24808899 TI - A PCR-based forward genetics screening, using expression domain-specific markers, identifies mutants in endosperm transfer cell development. AB - Mutant collections are an invaluable source of material on which forward genetic approaches allow the identification of genes affecting a wide variety of biological processes. However, some particular developmental stages and morphological structures may resist analysis due to their physical inaccessibility or to deleterious effects associated to their modification. Furthermore, lethal mutations acting early in development may escape detection. We have approached the characterization of 101 maize seed mutants, selected from a collection of 27,500 visually screened Mu-insertion lines, using a molecular marker approach based on a set of genes previously ascribed to different tissue compartments within the early developing kernel. A streamlined combination of qRT PCR assays has allowed us to preliminary pinpoint the affected compartment, establish developmental comparisons to WT siblings and select mutant lines with alterations in the different compartments. Furthermore, clusters of markers co affected by the underlying mutation were identified. We have analyzed more extensively a set of lines presenting significant variation in transfer cell associated expression markers, and have performed morphological observations, and immunolocalization experiments to confirm the results, validating this approach as an efficient mutant description tool. PMID- 24808900 TI - Involvement of rRNA biosynthesis in the regulation of CUC1 gene expression and pre-meristematic cell mound formation during shoot regeneration. AB - At an early stage of shoot regeneration from calli of Arabidopsis, pre meristematic cell mounds develop in association with localized strong expression of CUP-SHAPED COTYLEDON (CUC) genes. Previous characterization of root initiation defective 3 (rid3), an Arabidopsis mutant originally isolated as being temperature-sensitive for adventitious root formation, with respect to shoot regeneration implicated RID3 in the negative regulation of CUC1 expression and the restriction of cell division in pre-meristematic cell mounds. Positional cloning has identified RID3 as a WD40 repeat protein gene whose molecular function was not investigated before. Here we performed in silico analysis of RID3 and found that RID3 is orthologous to IPI3, which mediates pre-rRNA processing in Saccharomyces cerevisiae. In the rid3 mutant, rRNA precursors accumulated to a very high level in a temperature-dependent manner. This result indicates that RID3 is required for pre-rRNA processing as is IPI3. We compared rid3 with rid2, a temperature-sensitive mutant that is mutated in a putative RNA methyltransferase gene and is impaired in pre-rRNA processing, for seedling morphology, shoot regeneration, and CUC1 expression. The rid2 and rid3 seedlings shared various developmental alterations, such as a pointed-leaf phenotype, which is often observed in ribosome-related mutants. In tissue culture for the induction of shoot regeneration, both rid2 and rid3 mutations perturbed cell mound formation and elevated CUC1 expression. Together, our findings suggest that rRNA biosynthesis may be involved in the regulation of CUC1 gene expression and pre-meristematic cell-mound formation during shoot regeneration. PMID- 24808902 TI - The intriguing plant nuclear lamina. AB - The nuclear lamina is a complex protein mesh attached to the inner nuclear membrane (INM), which is also associated with nuclear pore complexes. It provides mechanical support to the nucleus and nuclear envelope, and as well as facilitating the connection of the nucleoskeleton to the cytoskeleton, it is also involved in chromatin organization, gene regulation, and signaling. In metazoans, the nuclear lamina consists of a polymeric layer of lamins and other interacting proteins responsible for its association with the INM and chromatin. In plants, field emission scanning electron microscopy of nuclei, and thin section transmission electron microscopy of isolated nucleoskeletons, reveals the lamina to have a similar structure to that of metazoans. Moreover, although plants lack lamin genes and the genes encoding most lamin-binding proteins, the main functions of the lamina are fulfilled in plants. Hence, it would appear that the plant lamina is not based on lamins and that other proteins substitute for lamins in plant cells. The nuclear matrix constituent proteins are the best characterized structural proteins in the plant lamina. Although these proteins do not display strong sequence similarity to lamins, their predicted secondary structure and sub-nuclear distribution, as well as their influence on nuclear size and shape, and on heterochromatin organization, suggest they could be functional lamin analogs. In this review we shall summarize what is currently known about the organization and composition of the plant nuclear lamina and its interacting complexes, and we will discuss the activity of this structure in the plant cell and its nucleus. PMID- 24808901 TI - Respiratory electron transfer pathways in plant mitochondria. AB - The respiratory electron transport chain (ETC) couples electron transfer from organic substrates onto molecular oxygen with proton translocation across the inner mitochondrial membrane. The resulting proton gradient is used by the ATP synthase complex for ATP formation. In plants, the ETC is especially intricate. Besides the "classical" oxidoreductase complexes (complex I-IV) and the mobile electron transporters cytochrome c and ubiquinone, it comprises numerous "alternative oxidoreductases." Furthermore, several dehydrogenases localized in the mitochondrial matrix and the mitochondrial intermembrane space directly or indirectly provide electrons for the ETC. Entry of electrons into the system occurs via numerous pathways which are dynamically regulated in response to the metabolic state of a plant cell as well as environmental factors. This mini review aims to summarize recent findings on respiratory electron transfer pathways in plants and on the involved components and supramolecular assemblies. PMID- 24808903 TI - Callose-mediated resistance to pathogenic intruders in plant defense-related papillae. AB - Plants are exposed to a wide range of potential pathogens, which derive from diverse phyla. Therefore, plants have developed successful defense mechanisms during co-evolution with different pathogens. Besides many specialized defense mechanisms, the plant cell wall represents a first line of defense. It is actively reinforced through the deposition of cell wall appositions, so-called papillae, at sites of interaction with intruding microbial pathogens. The papilla is a complex structure that is formed between the plasma membrane and the inside of the plant cell wall. Even though the specific biochemical composition of papillae can vary between different plant species, some classes of compounds are commonly found which include phenolics, reactive oxygen species, cell wall proteins, and cell wall polymers. Among these polymers, the (1,3)-beta-glucan callose is one of the most abundant and ubiquitous components. Whereas the function of most compounds could be directly linked with cell wall reinforcement or an anti-microbial effect, the role of callose has remained unclear. An evaluation of recent studies revealed that the timing of the different papilla forming transport processes is a key factor for successful plant defense. PMID- 24808904 TI - Specific targeting of proteins to outer envelope membranes of endosymbiotic organelles, chloroplasts, and mitochondria. AB - Chloroplasts and mitochondria are endosymbiotic organelles thought to be derived from endosymbiotic bacteria. In present-day eukaryotic cells, these two organelles play pivotal roles in photosynthesis and ATP production. In addition to these major activities, numerous reactions, and cellular processes that are crucial for normal cellular functions occur in chloroplasts and mitochondria. To function properly, these organelles constantly communicate with the surrounding cellular compartments. This communication includes the import of proteins, the exchange of metabolites and ions, and interactions with other organelles, all of which heavily depend on membrane proteins localized to the outer envelope membranes. Therefore, correct and efficient targeting of these membrane proteins, which are encoded by the nuclear genome and translated in the cytosol, is critically important for organellar function. In this review, we summarize the current knowledge of the mechanisms of protein targeting to the outer membranes of mitochondria and chloroplasts in two different directions, as well as targeting signals and cytosolic factors. PMID- 24808905 TI - Using previously genotyped controls in genome-wide association studies (GWAS): application to the Stroke Genetics Network (SiGN). AB - Genome-wide association studies (GWAS) are widely applied to identify susceptibility loci for a variety of diseases using genotyping arrays that interrogate known polymorphisms throughout the genome. A particular strength of GWAS is that it is unbiased with respect to specific genomic elements (e.g., coding or regulatory regions of genes), and it has revealed important associations that would have never been suspected based on prior knowledge or assumptions. To date, the discovered SNPs associated with complex human traits tend to have small effect sizes, requiring very large sample sizes to achieve robust statistical power. To address these issues, a number of efficient strategies have emerged for conducting GWAS, including combining study results across multiple studies using meta-analysis, collecting cases through electronic health records, and using samples collected from other studies as controls that have already been genotyped and made publicly available (e.g., through deposition of de-identified data into dbGaP or EGA). In certain scenarios, it may be attractive to use already genotyped controls and divert resources to standardized collection, phenotyping, and genotyping of cases only. This strategy, however, requires that careful attention be paid to the choice of "public controls" and to the comparability of genetic data between cases and the public controls to ensure that any allele frequency differences observed between groups is attributable to locus-specific effects rather than to a systematic bias due to poor matching (population stratification) or differential genotype calling (batch effects). The goal of this paper is to describe some of the potential pitfalls in using previously genotyped control data. We focus on considerations related to the choice of control groups, the use of different genotyping platforms, and approaches to deal with population stratification when cases and controls are genotyped across different platforms. PMID- 24808906 TI - categoryCompare, an analytical tool based on feature annotations. AB - Assessment of high-throughput-omics data initially focuses on relative or raw levels of a particular feature, such as an expression value for a transcript, protein, or metabolite. At a second level, analyses of annotations including known or predicted functions and associations of each individual feature, attempt to distill biological context. Most currently available comparative- and meta analyses methods are dependent on the availability of identical features across data sets, and concentrate on determining features that are differentially expressed across experiments, some of which may be considered "biomarkers." The heterogeneity of measurement platforms and inherent variability of biological systems confounds the search for robust biomarkers indicative of a particular condition. In many instances, however, multiple data sets show involvement of common biological processes or signaling pathways, even though individual features are not commonly measured or differentially expressed between them. We developed a methodology, categoryCompare, for cross-platform and cross-sample comparison of high-throughput data at the annotation level. We assessed the utility of the approach using hypothetical data, as well as determining similarities and differences in the set of processes in two instances: (1) denervated skin vs. denervated muscle, and (2) colon from Crohn's disease vs. colon from ulcerative colitis (UC). The hypothetical data showed that in many cases comparing annotations gave superior results to comparing only at the gene level. Improved analytical results depended as well on the number of genes included in the annotation term, the amount of noise in relation to the number of genes expressing in unenriched annotation categories, and the specific method in which samples are combined. In the skin vs. muscle denervation comparison, the tissues demonstrated markedly different responses. The Crohn's vs. UC comparison showed gross similarities in inflammatory response in the two diseases, with particular processes specific to each disease. PMID- 24808907 TI - miRNA gene counts in chromosomes vary widely in a species and biogenesis of miRNA largely depends on transcription or post-transcriptional processing of coding genes. AB - MicroRNAs target specific mRNA(s) to silence its expression and thereby regulate various cellular processes. We have investigated miRNA gene counts in chromosomes for 20 different species and observed wide variation. Certain chromosomes have extremely high number of miRNA gene compared with others in all the species. For example, high number of miRNA gene in X chromosome and the least or absence of miRNA gene in Y chromosome was observed in all species. To search the criteria governing such variation of miRNA gene counts in chromosomes, we have selected three parameters- length, number of non-coding and coding genes in a chromosome. We have calculated Pearson's correlation coefficient of miRNA gene counts with length, number of non-coding and coding genes in a chromosome for all 20 species. Major number of species showed that number of miRNA gene was not correlated with chromosome length. Eighty five percent of species under study showed strong positive correlation coefficient (r >= 0.5) between the numbers of miRNA gene vs. non-coding gene in chromosomes as expected because miRNA is a sub-set of non coding genes. 55% species under study showed strong positive correlation coefficient (r >= 0.5) between numbers of miRNA gene vs. coding gene. We hypothesize biogenesis of miRNA largely depends on coding genes, an evolutionary conserved process. Chromosomes having higher number of miRNA genes will be most likely playing regulatory roles in several cellular processes including different disorders. In humans, cancer and cardiovascular disease associated miRNAs are mostly intergenic and located in Chromosome 19, X, 14, and 1. PMID- 24808908 TI - Genome-wide association study and ancestral origins of the slick-hair coat in tropically adapted cattle. AB - The slick hair coat (SLICK) is a dominantly inherited trait typically associated with tropically adapted cattle that are from Criollo descent through Spanish colonization of cattle into the New World. The trait is of interest relative to climate change, due to its association with improved thermo-tolerance and subsequent increased productivity. Previous studies localized the SLICK locus to a 4 cM region on chromosome (BTA) 20 and identified signatures of selection in this region derived from Senepol cattle. The current study compares three slick haired Criollo-derived breeds including Senepol, Carora, and Romosinuano and three additional slick-haired cross-bred lineages to non-slick ancestral breeds. Genome-wide association (GWA), haplotype analysis, signatures of selection, runs of homozygosity (ROH), and identity by state (IBS) calculations were used to identify a 0.8 Mb (37.7-38.5 Mb) consensus region for the SLICK locus on BTA20 in which contains SKP2 and SPEF2 as possible candidate genes. Three specific haplotype patterns are identified in slick individuals, all with zero frequency in non-slick individuals. Admixture analysis identified common genetic patterns between the three slick breeds at the SLICK locus. Principal component analysis (PCA) and admixture results show Senepol and Romosinuano sharing a higher degree of genetic similarity to one another with a much lesser degree of similarity to Carora. Variation in GWA, haplotype analysis, and IBS calculations with accompanying population structure information supports potentially two mutations, one common to Senepol and Romosinuano and another in Carora, effecting genes contained within our refined location for the SLICK locus. PMID- 24808910 TI - Enhancing our understanding of ways to analyze metagenomes. PMID- 24808909 TI - Assessing the functional consequence of loss of function variants using electronic medical record and large-scale genomics consortium efforts. AB - Estimates from large scale genome sequencing studies indicate that each human carries up to 20 genetic variants that are predicted to results in loss of function (LOF) of protein-coding genes. While some are known disease-causing variants or common, tolerated, LOFs in non-essential genes, the majority remain of unknown consequence. We explore the possibility of using imputed GWAS data from large biorepositories such as the electronic medical record and genomics (eMERGE) consortium to determine the effects of rare LOFs. Here, we show that two hypocholesterolemia-associated LOF mutations in the PCSK9 gene can be accurately imputed into large-scale GWAS datasets which raises the possibility of assessing LOFs through genomics-linked medical records. PMID- 24808911 TI - Tracking false-negative results in molecular diagnosis: proposal of a triplex-PCR based method for leishmaniasis diagnosis. AB - BACKGROUND: Molecular biological methods have become increasingly relevant to the diagnosis and control of infectious diseases, such as leishmaniasis. Since various factors may affect the sensitivity of PCR assays, including DNA yield and purity, an optimal extraction method is pivotal. Losses of a parasite's DNA during extraction may significantly impair its detection by PCR and lead to false negative results. This study proposes a triplex PCR assay targeting the parasite's DNA, an external control (pUC18) and an internal control (G3PD) for accurate diagnosis of leishmaniasis. RESULTS: Two primer pairs were designed to detect the plasmid pUC18 and a triplex PCR assay targeting the Leishmania braziliensis kinetoplast DNA, the external control and the internal control was standardized. The triplex PCR assay was assessed for its ability to detect the three target DNA fragments simultaneously. PCR products from pUC18 DNA resulted in bands of 368 (P1) and 316 (P2) base pairs (bp). The triplex PCR optimized with the chosen external control system (P1) allowed the simultaneous detection of the internal control (G3PD - 567 bp) as well as of small quantities (10 pg) of the target parasite's DNA, detected by amplification of a 138 bp product. CONCLUSIONS: The new tool standardized herein enables a more reliable interpretation of PCR results, mainly by contributing to quality assurance of leishmaniasis diagnosis. Furthermore, after simple standardization steps, this protocol could be applied to the diagnosis of other infectious diseases in reference laboratories. This triplex PCR enables the assessment of small losses during the DNA extraction process, problems concerning DNA degradation (sample quality) and the detection of L. braziliensis kDNA. PMID- 24808912 TI - Acute one-cigarette smoking decreases ghrelin hormone in saliva: a pilot study. AB - Cigarette smoking is commonly associated with weight loss and mechanisms for these weight changes are still elusive. Ghrelin is a peptide hormone that works in a neuroendocrine fashion to stimulate hunger and the desire for food intake. Ghrelin is also secreted in saliva, probably to enhance food taste. In the current study, we tested the direct impact of acute cigarette smoking on total ghrelin found in saliva. Methods. Blood and saliva samples were collected from 30 healthy nonsmoker male volunteers before and after one-cigarette smoke. Total ghrelin in serum and saliva was measured by ELISA based method. Results. Data showed a statistically significant reduction in salivary ghrelin after smoking (P < 0.0001). In serum, total ghrelin levels were not affected before and after smoking (P = 0.1362). Additionally, positive correlation was observed between serum and salivary ghrelin before smoking (r = 0.4143 and P = 0.0158); however, this correlation was lost after smoking (r = 0.1147 and P = 0.5461). Conclusion. Acute one-cigarette smoking can negatively affect ghrelin levels in saliva that might contribute to the dull food taste in smokers. PMID- 24808913 TI - Diabetic renal disease. PMID- 24808914 TI - Analytical performances of nanostructured gold supported on metal oxide sorbents for the determination of gaseous mercury. AB - Nanostructured gold supported TiO2, ZnO, and Al2O3 materials (1% w/w Au) were tested as sorbents for gaseous mercury (Hg) trapping and preconcentration. Their analytical performances were first compared with the one of traditional gold wool trap for the quantification of Hg standards injected into the argon flow followed by thermal desorption at 600 degrees C and CVAFS detection. Good linearity and reproducibility were obtained, especially for Au/TiO2 material (R (2) = 0.995; slope: 1.39) in the volume range of 10 to 60 uL (132-778 pg Hg). This latter even showed a better performance compared to pure Au in the volume range of 10 to 100 uL (132-1329 pg Hg) when the carrier gas flow was increased from 60 to 100 mL min(-1). The method detection limit (MDL) obtained with Au/TiO2 trap (0.10 pg Hg(0) L(-1)) was suitable for total gaseous mercury (TGM) determination. Au/TiO2 was, therefore, used in trapping and determining TGM in collected air samples. TGM values in the samples ranged from 6 to 10 ng m(-3). Similar results were obtained with the commercial gold-coated sand trap which showed an average TGM concentration of 7.8 +/- 0.9 ng m(-3). PMID- 24808915 TI - Relationship between platelet activating factor acetylhydrolase activity and apolipoprotein B levels in patients with peanut allergy. AB - BACKGROUND: Platelet-activating factor (PAF) is a highly potent phospholipid mediator responsible for the life-threatening manifestations of anaphylaxis. PAF acetylhydrolase (PAF-AH) inactivates PAF and protects against severe anaphylaxis whereas deficiency of PAF-AH predisposes to severe or fatal anaphylaxis. Determinants of PAF-AH activity have not been studied in patients with peanut allergy. OBJECTIVES: To determine whether plasma PAF-AH activity in patients with peanut allergy is related to formation of circulating complexes with apolipoprotein B (apoB) the main surface protein on low density lipoprotein particles. METHODS: Plasma PAF-AH activity and apoB concentrations were measured in 63 peanut allergic patients (35 boys, 28 girls, ages 2 - 19 years). ApoB concentration was measured immunoturbidimetrically using goat anti-human apoB. The correlation between PAF-AH activity and apoB concentration was determined. RESULTS: A positive correlation was found between PAF-AH activity and apoB concentration (r(2) = 0.59, P < 0.0001). CONCLUSION: In peanut allergic patients, PAF-AH activity strongly correlates with apoB concentration, suggesting the presence of circulating PAF-AH- lipoprotein complexes. PMID- 24808916 TI - Persea declinata (Bl.) Kosterm Bark Crude Extract Induces Apoptosis in MCF-7 Cells via G0/G1 Cell Cycle Arrest, Bcl-2/Bax/Bcl-xl Signaling Pathways, and ROS Generation. AB - Persea declinata (Bl.) Kosterm is a member of the Lauraceae family, widely distributed in Southeast Asia. It is from the same genus with avocado (Persea americana Mill), which is widely consumed as food and for medicinal purposes. In the present study, we examined the anticancer properties of Persea declinata (Bl.) Kosterm bark methanolic crude extract (PDM). PDM exhibited a potent antiproliferative effect in MCF-7 human breast cancer cells, with an IC50 value of 16.68 ug/mL after 48 h of treatment. We observed that PDM caused cell cycle arrest and subsequent apoptosis in MCF-7 cells, as exhibited by increased population at G0/G1 phase, higher lactate dehydrogenase (LDH) release, and DNA fragmentation. Mechanistic studies showed that PDM caused significant elevation in ROS production, leading to perturbation of mitochondrial membrane potential, cell permeability, and activation of caspases-3/7. On the other hand, real-time PCR and Western blot analysis showed that PDM treatment increased the expression of the proapoptotic molecule, Bax, but decreased the expression of prosurvival proteins, Bcl-2 and Bcl-xL, in a dose-dependent manner. These findings imply that PDM could inhibit proliferation in MCF-7 cells via cell cycle arrest and apoptosis induction, indicating its potential as a therapeutic agent worthy of further development. PMID- 24808917 TI - Electroacupuncture at PC6 or ST36 Influences the Effect of Tacrine on the Motility of Esophagus. AB - Aim. To investigate the mechanisms of gastrointestinal side effects of tacrine, and find treatment methods with electroacupuncture (EA). Methods. Twenty-five healthy cats were randomly divided into 5 groups: gastric-distention group (model group), tacrine group (cholinesterase inhibitor), tacrine + sham acupoint group (control group), tacrine + PC6 (neiguan) group, and tacrine + ST36 (zusanli) group, with 5 cats in each group. Saline 2 mL i.p. was given 30 min before gastric distention in model group. Tacrine 5.6 mg/kg i.p. was given 30 minutes before gastric distention in the other groups. Tacrine + sham acupoint group (control group), tacrine + PC6 group, and tacrine + ST36 group received EA at corresponding acupoints during gastric distention. The frequency of TLESRs and LESP were recorded by using a perfused sleeve assembly. Results. Compared with the model group, tacrine significantly increased the frequency of gastric distention-induced TLESR (P < 0.05) but did not influence the rate of common cavity during TLESR. Tacrine significantly increased the LESP, which could not remain during gastric distention. EA at PC6 could decrease the frequency of TLESR and maintain the increase of LESP, but EA at ST36 did not have these effects. Conclusion. Tacrine can significantly increase the gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs). Electroacupuncture (EA) at PC6 may reverse the above side effect. PMID- 24808918 TI - Comparison of the Effects of Acarbose and TZQ-F, a New Kind of Traditional Chinese Medicine to Treat Diabetes, Chinese Healthy Volunteers. AB - Ethnopharmacological Relevance. TZQ-F has been traditionally used in Traditional Chinese Medicine as a formula for the treatment of diabetes. Aim of the Study. This study aims to compare the pharmacologic effects and gastrointestinal adverse events between TZQ-F and acarbose. Methods. The double-blind randomized placebo controlled fivefold crossover study was performed in 20 healthy male volunteers. Plasma glucose, plasma IRI, and plasma C-peptide were measured to assess the pharmacologic effects. Flatus and bowel activity were measured to assess the adverse event of gastrointestinal effect. Results. 3 and 4 tablets of TZQ decreased the C max of plasma glucose compared with that of the previous day and with placebo. 3 tablets also decreased C max of plasma C-peptide compared with placebo. 4 tablets increased C max of plasma insulin after breakfast and the AUC of plasma C-peptide after breakfast and dinner. 2 tablets did not decrease plasma glucose and elevated the C max and AUC of C-peptide after breakfast and dinner, respectively. Acarbose 50 mg decreased the C max of plasma insulin and C-peptide after breakfast and the C max of plasma glucose and C-peptide after dinner. The subjects who received TZQ did not report any abdominal adverse events. Conclusions. 3 tablets of TZQ have the same effects as the acarbose. PMID- 24808919 TI - Study of factors involved in tongue color diagnosis by kampo medical practitioners using the farnsworth-munsell 100 hue test and tongue color images. AB - In traditional Japanese medicine (Kampo medicine), tongue color is important in discerning a patient's constitution and medical conditions. However, tongue color diagnosis is susceptible to the subjective factors of the observer. To investigate factors involved in tongue color diagnosis, both color discrimination and tongue color diagnosis were researched in 68 Kampo medical practitioners. Color discrimination was studied by the Farnsworth-Munsell 100 Hue test, and tongue color diagnosis was studied by 84 tongue images. We found that overall color discrimination worsened with aging. However, the color discrimination related to tongue color regions was maintained in subjects with 10 or more years of Kampo experience. On the other hand, tongue color diagnosis significantly differed between subjects with <10 years of experience and >=10 years of experience. Practitioners with >=10 years of experience could maintain a consistent diagnosis of tongue color regardless of their age. PMID- 24808920 TI - Suxiao jiuxin pill induces potent relaxation and inhibition on contraction in human artery and the mechanism. AB - Suxiao Jiuxin Pill, a compound Chinese traditional medicine with main components of tetramethylpyrazine and borneol, is widely used for antiangina treatment in China but its pharmacological effect on human blood vessels is unknown. We investigated the effect and possible mechanism of SJP in the human internal mammary artery (IMA, n = 78) taken from patients undergoing coronary surgery. SJP caused full relaxation in KCl- (99.4 +/- 10.5%, n = 6) and U46619- (99.9 +/- 5.6%, n = 6) contracted IMA. Pretreatment of IMA with plasma concentrations of SJP (1 mg/mL), calculated from the plasma concentration of its major component borneol, significantly depressed the maximal contraction to KCl (from 35.8 +/- 6.0 mN to 12.6 +/- 5.6 mN, P = 0.03) and U46619 (from 19.4 +/- 2.9 mN to 5.7 +/- 2.4 mN, P = 0.007) while SJP at 10 mg/mL abolished the subsequent contraction. Endothelium denudation and inhibition of eNOS significantly altered the SJP induced relaxation without changes of eNOS expression. We conclude that SJP has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors in human arteries. The vasorelaxation involves both endothelium dependent and -independent mechanisms. Thus, the effect of SJP on human arteries demonstrated in this study may prove to be particularly important in vasorelaxing therapy in cardiovascular disease. PMID- 24808921 TI - Radiological surveillance of formerly asbestos-exposed power industry workers: rates and risk factors of benign changes on chest X-ray and MDCT. AB - BACKGROUND: To determine the prevalence of asbestos-related changes on chest X ray (CXR) and low-dose multidetector-row CT (MDCT) of the thorax in a cohort of formerly asbestos-exposed power industry workers and to assess the importance of common risk factors associated with specific radiological changes. METHODS: To assess the influence of selected risk factors (age, time since first exposure, exposure duration, cumulative exposure and pack years) on typical asbestos related radiographic changes, we employed multiple logistic regression and receiver operating characteristic (ROC) analysis. RESULTS: On CXR, pleural changes and asbestosis were strongly associated with age, years since first exposure and exposure duration. The MDCT results showed an association between asbestosis and age and between plaques and exposure duration, years since first exposure and cumulative exposure. Parenchymal changes on CXR and MDCT, and diffuse pleural thickening on CXR were both associated with smoking. Using a cut off of 55 years for age, 17 years for exposure duration and 28 years for latency, benign radiological changes in the cohort with CXR could be predicted with a sensitivity of 82.0% for all of the three variables and a specificity of 47.4%, 39.0% and 40.6%, respectively. CONCLUSIONS: Participants aged 55 years and older and those with an asbestos exposure of at least 17 years or 28 years since first exposure should be seen as having an increased risk of abnormal radiological findings. For implementing a more focused approach the routine use of low-dose MDCT rather than CXR at least for initial examinations would be justified. PMID- 24808922 TI - Repair of diaphragmatic hernia following spinal surgery by laparoscopic mesh application: a case report and review of the literature. AB - We describe the laparoscopic management of diaphragmatic hernia (DH) caused by vertebral pedicle screw displacement. A 58-year-old woman underwent surgery for scoliosis and underwent posterior pedicle screw fixation. In the first postoperative (PO)day, she developed mild dyspnea. An anteroposterior chest radiograph revealed bilateral pleural effusion, which was more pronounced on the left side. A thoracoabdominal computed tomography (CT) scan, performed in the second PO day, revealed a solid mass in the pleural cavity that was associated with screw displacement, which had also entered into the peritoneal cavity without apparent other lesion of hollow and solid viscous. In the third PO day, after the screw was removed, explorative laparoscopy was carried out. We observed herniation of the omentum through a small diaphragmatic tear. Once the absence of visceral injury was confirmed, we reduced the omentum into the abdomen. Then, we repaired the hernia by applying a dual layer polypropylene mesh over the defect with a 3-cm overlap. The remainder of the postoperative period was uneventful. Iatrogenic DH due to a pedicle screw displacement has never been described before. In cases of pleural effusion following spinal surgery, rapid assessment and treatment are crucial. We conclude that a laparoscopic approach to iatrogenic DH could be feasible and effective in a hemodynamically stable patient with negative CT findings because it enables the completion of the diagnostic cascade and the repair of the tear, providing excellent visualization of the abdominal viscera and diaphragmatic tears. PMID- 24808923 TI - Using workshops to develop theories of change in five low and middle income countries: lessons from the programme for improving mental health care (PRIME). AB - BACKGROUND: The Theory of Change (ToC) approach has been used to develop and evaluate complex health initiatives in a participatory way in high income countries. Little is known about its use to develop mental health care plans in low and middle income countries where mental health services remain inadequate. AIMS: ToC workshops were held as part of formative phase of the Programme for Improving Mental Health Care (PRIME) in order 1) to develop a structured logical and evidence-based ToC map as a basis for a mental health care plan in each district; (2) to contextualise the plans; and (3) to obtain stakeholder buy-in in Ethiopia, India, Nepal, South Africa and Uganda. This study describes the structure and facilitator's experiences of ToC workshops. METHODS: The facilitators of the ToC workshops were interviewed and the interviews were recorded, transcribed and analysed together with process documentation from the workshops using a framework analysis approach. RESULTS: Thirteen workshops were held in the five PRIME countries at different levels of the health system. The ToC workshops achieved their stated goals with the contributions of different stakeholders. District health planners, mental health specialists, and researchers contributed the most to the development of the ToC while service providers provided detailed contextual information. Buy-in was achieved from all stakeholders but valued more from those in control of resources. CONCLUSIONS: ToC workshops are a useful approach for developing ToCs as a basis for mental health care plans because they facilitate logical, evidence based and contextualised plans, while promoting stakeholder buy in. Because of the existing hierarchies within some health systems, strategies such as limiting the types of participants and stratifying the workshops can be used to ensure productive workshops. PMID- 24808924 TI - Production of marker-free transgenic Jatropha curcas expressing hybrid Bacillus thuringiensis delta-endotoxin Cry1Ab/1Ac for resistance to larvae of tortrix moth (Archips micaceanus). AB - BACKGROUND: The potential biofuel plant Jatropha curcas L. is affected by larvae of Archips micaceanus (Walker), a moth of the family Tortricidae. The hybrid Bacillus thuringiensis (Bt) delta-endotoxin protein Cry1Ab/1Ac confers resistance to lepidopteran insects in transgenic rice. RESULTS: Here, we report the production of a marker-free transgenic line of J. curcas (L10) expressing Cry1Ab/1Ac using Agrobacterium-mediated transformation and a chemically regulated, Cre/loxP-mediated DNA recombination system. L10 carries a single copy of marker-free T-DNA that contains the Cry1Ab/1Ac gene under the control of a maize phosphoenolpyruvate carboxylase gene promoter (P Pepc :Cry1Ab/1Ac:T Nos ). The P Pepc :Cry1Ab/1Ac:T Nos gene was highly expressed in leaves of L10 plants. Insecticidal bioassays using leaf explants of L10 resulted in 80-100% mortality of larvae of A. micaceanus at 4 days after infestation. CONCLUSION: The results demonstrate that the hybrid Bt delta-endotoxin protein Cry1Ab/1Ac expressed in Jatropha curcas displays strong insecticidal activity to A. micaceanus. The marker-free transgenic J. curcas line L10 can be used for breeding of insect resistance to A. micaceanus. PMID- 24808925 TI - Acute TSH stimulation in vivo does not alter serum PCSK9 levels. AB - BACKGROUND: It is now recognized that TSH can act on targets other than the thyroid, including the liver. Elevated serum TSH levels in euthyroid subjects were recently reported to correlate with high values of serum proprotein convertase subtilisin/kexin type 9 (PCSK9). This protein, expressed and secreted by hepatocytes, promotes higher LDL-cholesterol levels. We tested whether an acute increase of TSH levels following administration of TSH in vivo would raise PCSK9 levels in patients who had previously undergone total thyroidectomy and radioablation for thyroid cancer. FINDINGS: TSH levels rose from 0.64 +/- 1.02 mU/L on day 1 to 98.66 +/- 4.83 mU/L on day 3, following injections of recombinant human TSH (on days 1 and 2). PCSK9 levels were 330 +/- 99 ng/ml on day 1, and did not change on days 3 or 5 in response to TSH stimulation. CONCLUSIONS: Although a positive correlation between TSH and PCSK9 in euthyroid subjects has raised the possibility that TSH might act on the liver to raise PCSK9 values, our data show that PCSK9 levels are not affected by acute elevations of TSH levels. Whether chronic elevations of TSH are needed to upregulate PCSK9 remains to be determined. PMID- 24808926 TI - COMT polymorphism influences decrease of ovarian follicles and emerges as a predictive factor for premature ovarian insufficiency. AB - BACKGROUND: Estrogens are important factors in the female reproductive functions and are processed by a number of enzymes along their metabolic pathway. The COMT gene constitutes a crucial element in estrogen metabolism and is assumed to be involved in the development of Premature Ovarian Insufficiency (POI). This study aimed to determine whether the presence of the COMT Val/Met polymorphism (rs4680) is associated to the risk of developing POI. FINDINGS: In this case-control study, we evaluated 96 infertile women with POI and 120 fertile women as controls, after obtaining a detailed history of the disease and follicle stimulating hormone measurements, besides karyotype determination and fragile-X premutation syndrome investigation. COMT (Val/Met) genotypes were identified by real time PCR (genotyping TaqMan assay), and the results were statistically analyzed. A statistically significant difference was found in the distribution of COMT genotypes (p = 0.003) and alleles (p = 0.015) between the POI patients and the control group. CONCLUSION: We were able to demonstrate a strong association between the COMT Val/Met polymorphism and the risk of premature ovarian insufficiency in the Brazilian women evaluated. However, further studies in larger populations are necessary to confirm these findings. PMID- 24808927 TI - Comparison of digestion procedures and methods for quantification of trace lead in breast milk by isotope dilution inductively coupled plasma mass spectrometry. AB - Measurement of lead in breast milk is an important public health consideration and can be technically quite challenging. The reliable and accurate determination of trace lead in human breast milk is difficult for several reasons including: potential for contamination during sample collection, storage, and analysis; complexities related to the high fat content of human milk; and poor analytic sensitivity at low concentrations. Breast milk lead levels from previous published studies should therefore be reviewed with caution. Due to the difficulty in identifying a method that would successfully digest samples with 100% efficiency, we evaluated three different digestion procedures including: (1) dry ashing in a muffle furnace, (2) microwave oven digestion, and (3) digestion in high pressure asher. High temperature, high pressure asher digestion was selected as the procedure of choice for the breast milk samples. Trace lead analysis was performed using isotope dilution (ID) inductively coupled plasma mass spectrometry (ICP-MS). Measured lead concentrations in breast milk samples (n = 200) from Mexico ranged from 0.2 to 6.7 ng ml-1. The precision for these measurements ranged from 0.27-7.8% RSD. Use of strict contamination control techniques and of a very powerful digestion procedure, along with an ID-ICP-MS method for lead determination, enables us to measure trace lead levels as low as 0.2 ng ml-1 in milk (instrument detection limit = 0.01 ng ml-1). PMID- 24808929 TI - Synchronization criteria of discrete-time complex networks with time-varying delays and parameter uncertainties. AB - This paper is pertained with the synchronization problem for an array of coupled discrete-time complex networks with the presence of both time-varying delays and parameter uncertainties. The time-varying delays are considered both in the network couplings and dynamical nodes. By constructing suitable Lyapunov Krasovskii functional and utilizing convex reciprocal lemma, new synchronization criteria for the complex networks are established in terms of linear matrix inequalities. Delay-partitioning technique is employed to incur less conservative results. All the results presented here not only depend upon lower and upper bounds of the time-delay, but also the number of delay partitions. Numerical simulations are rendered to exemplify the effectiveness and applicability of the proposed results. PMID- 24808928 TI - An ephaptic transmission model of CA3 pyramidal cells: an investigation into electric field effects. AB - Extracellular electric fields existing throughout the living brain affect the neural coding and information processing via ephaptic transmission, independent of synapses. A two-compartment whole field effect model (WFEM) of pyramidal neurons embedded within a resistive array which simulates the extracellular medium i.e. ephapse is developed to study the effects of electric field on neuronal behaviors. We derive the two linearized filed effect models (LFEM-1 and LFEM-2) from WFEM at the stable resting state. Through matching these simplified models to the subthreshold membrane response in experiments of the resting pyramidal cells exposed to applied electric fields, we not only verify our proposed model's validity but also found the key parameters which dominate subthreshold frequency response characteristic. Moreover, we find and give its underlying biophysical mechanism that the unsymmetrical properties of active ion channels results in the very different low-frequency response of somatic and dendritic compartments. Following, WFEM is used to investigate both direct current (DC) and alternating-current field effect on the neural firing patterns by bifurcation analyses. We present that DC electric field could modulate neuronal excitability, with the positive field improving the excitability, the modest negative field suppressing the excitability, but interestingly, the larger negative field re-exciting the neuron back into spiking behavior. The neuron exposed to the sinusoidal electric field exhibits abundant firing patterns sensitive to the input frequency and intensity. In addition, the electrical properties of ephapse can modulate the efficacy of field effect. Our simulated results are qualitatively in line with the relevant experimental results and can explain some experimental phenomena. Furthermore, they are helpful to provide the predictions which can be tested in future experiments. PMID- 24808930 TI - Synchronization and stochastic resonance of the small-world neural network based on the CPG. AB - According to biological knowledge, the central nervous system controls the central pattern generator (CPG) to drive the locomotion. The brain is a complex system consisting of different functions and different interconnections. The topological properties of the brain display features of small-world network. The synchronization and stochastic resonance have important roles in neural information transmission and processing. In order to study the synchronization and stochastic resonance of the brain based on the CPG, we establish the model which shows the relationship between the small-world neural network (SWNN) and the CPG. We analyze the synchronization of the SWNN when the amplitude and frequency of the CPG are changed and the effects on the CPG when the SWNN's parameters are changed. And we also study the stochastic resonance on the SWNN. The main findings include: (1) When the CPG is added into the SWNN, there exists parameters space of the CPG and the SWNN, which can make the synchronization of the SWNN optimum. (2) There exists an optimal noise level at which the resonance factor Q gets its peak value. And the correlation between the pacemaker frequency and the dynamical response of the network is resonantly dependent on the noise intensity. The results could have important implications for biological processes which are about interaction between the neural network and the CPG. PMID- 24808931 TI - A novel approach for pilot error detection using Dynamic Bayesian Networks. AB - In the last decade Dynamic Bayesian Networks (DBNs) have become one type of the most attractive probabilistic modelling framework extensions of Bayesian Networks (BNs) for working under uncertainties from a temporal perspective. Despite this popularity not many researchers have attempted to study the use of these networks in anomaly detection or the implications of data anomalies on the outcome of such models. An abnormal change in the modelled environment's data at a given time, will cause a trailing chain effect on data of all related environment variables in current and consecutive time slices. Albeit this effect fades with time, it still can have an ill effect on the outcome of such models. In this paper we propose an algorithm for pilot error detection, using DBNs as the modelling framework for learning and detecting anomalous data. We base our experiments on the actions of an aircraft pilot, and a flight simulator is created for running the experiments. The proposed anomaly detection algorithm has achieved good results in detecting pilot errors and effects on the whole system. PMID- 24808932 TI - Exponential synchronization of memristive Cohen-Grossberg neural networks with mixed delays. AB - This paper concerns the problem of global exponential synchronization for a class of memristor-based Cohen-Grossberg neural networks with time-varying discrete delays and unbounded distributed delays. The drive-response set is discussed. A novel controller is designed such that the response (slave) system can be controlled to synchronize with the drive (master) system. Through a nonlinear transformation, we get an alternative system from the considered memristor-based Cohen-Grossberg neural networks. By investigating the global exponential synchronization of the alternative system, we obtain the corresponding synchronization criteria of the considered memristor-based Cohen-Grossberg neural networks. Moreover, the conditions established in this paper are easy to be verified and improve the conditions derived in most of existing papers concerning stability and synchronization for memristor-based neural networks. Numerical simulations are given to show the effectiveness of the theoretical results. PMID- 24808933 TI - Evaluating influence of microRNA in reconstructing gene regulatory networks. AB - Gene regulatory network (GRN) consists of interactions between transcription factors (TFs) and target genes (TGs). Recently, it has been observed that micro RNAs (miRNAs) play a significant part in genetic interactions. However, current microarray technologies do not capture miRNA expression levels. To overcome this, we propose a new technique to reverse engineer GRN from the available partial microarray data which contains expression levels of TFs and TGs only. Using S System model, the approach is adapted to cope with the unavailability of information about the expression levels of miRNAs. The versatile Differential Evolutionary algorithm is used for optimization and parameter estimation. Experimental studies on four in silico networks, and a real network of Saccharomyces cerevisiae called IRMA network, show significant improvement compared to traditional S-System approach. PMID- 24808934 TI - Convergence analysis of fully complex backpropagation algorithm based on Wirtinger calculus. AB - This paper considers the fully complex backpropagation algorithm (FCBPA) for training the fully complex-valued neural networks. We prove both the weak convergence and strong convergence of FCBPA under mild conditions. The decreasing monotonicity of the error functions during the training process is also obtained. The derivation and analysis of the algorithm are under the framework of Wirtinger calculus, which greatly reduces the description complexity. The theoretical results are substantiated by a simulation example. PMID- 24808935 TI - Primary extra nodal Hodgkin disease: Bone presentation. AB - BACKGROUND: Extra nodal and extra lymphatic propagation of Hodgkin's disease is a characteristic of the fourth stage of disease when the organs are affected. Primary appearances of the disease outside the lymph node is a rare event. Therefore, it makes diagnostic problem. Skeletal system is possible localization of primary extra nodal Hodgkin's disease. CASE REPORT: Women, 42-years-old, was admitted to hospital because of swelling and pain in the right shoulder. After imaging and histological examination diagnosed Hodgkin's nodular sclerosing histological subtype disease has been established. The patient starts to receive chemotherapy. CONCLUSIONS: Primary extra nodal Hodgkin's disease of bone is manifested with painful swelling in geared area. Imaging method shows destruction of the affected bone, with swelling of the soft tissues. Propagation in soft tissue is not accompanied by their destruction, but rather manifested swelling of the surrounding soft tissue. PMID- 24808936 TI - Forster-Induced Energy Transfer in Functionalized Graphene. AB - Carbon nanostructures are ideal substrates for functionalization with molecules since they consist of a single atomic layer giving rise to an extraordinary sensitivity to changes in their surrounding. The functionalization opens a new research field of hybrid nanostructures with tailored properties. Here, we present a microscopic view on the substrate-molecule interaction in the exemplary hybrid material consisting of graphene functionalized with perylene molecules. First experiments on similar systems have been recently realized illustrating an extremely efficient transfer of excitation energy from adsorbed molecules to the carbon substrate, a process with a large application potential for high efficiency photovoltaic devices and biomedical imaging and sensing. So far, there has been no microscopically founded explanation for the observed energy transfer. Based on first-principle calculations, we have explicitly investigated the different transfer mechanisms revealing the crucial importance of Forster coupling. Due to the efficient Coulomb interaction in graphene, we obtain strong Forster rates in the range of 1/fs. We investigate its dependence on the substrate-molecule distance R and describe the impact of the momentum transfer q for an efficient energy transfer. Furthermore, we find that the Dexter transfer mechanism is negligibly small due to the vanishing overlap between the involved strongly localized orbital functions. The gained insights are applicable to a variety of carbon-based hybrid nanostructures. PMID- 24808937 TI - Unexpected causes of pulmonary hypertension in a previously healthy Thai rural man with right-sided heart failure. AB - Male, 52 FINAL DIAGNOSIS: Pulmonary hypertension Symptoms: Diarrhea * dyspnea * jaundice MEDICATION: - Clinical Procedure: - Specialty: Endocrinology and Metabolic. OBJECTIVE: Unusual clinical course. BACKGROUND: Hyperthyroidism is one of the important causes of high-output failure and reversible pulmonary artery hypertension. Severe pulmonary artery hypertension is rarely found in associated with hyperthyroidism due to the small number of cases reported. We present an interesting case with multiple unexpected findings of the possible causes of severe pulmonary artery hypertension: hyperthyroidism, pulmonary embolism, and ostium secundum atrial septal defect. CASE REPORT: We present the case of a previously healthy rural Thai man who progressively developed dyspnea on exertion, chronic diarrhea, and jaundice for the previous 3 months. Physical examination revealed right-sided predominate chronic heart failure with signs of pulmonary hypertension. The investigation demonstrated autoimmune hyperthyroidism, cholestatic jaundice, moderate tricuspid regurgitation, ostium secundum atrial septal defect, and severe pulmonary artery hypertension. After treatment with an anti-thyroid drug and closure of the ostium secundum atrial septal defect, his symptoms of jaundice and pulmonary artery pressure were completely resolved. CONCLUSIONS: Severe pulmonary artery hypertension may not solely be a result of hyperthyroidism. Further investigation for other causes is recommended. PMID- 24808938 TI - Personal values in soldiers after military deployment: associations with mental health and resilience. AB - BACKGROUND: After military deployment, soldiers are at an increased risk of developing posttraumatic psychiatric disorders. The correlation of personal values with symptoms, however, has not yet been examined within a military context. METHOD: Schwartz's Portrait Values Questionnaire (PVQ), the Posttraumatic Stress Diagnostic Scale (PDS), and the 11-item version of the Resilience Scale (RS-11) were completed by 117 soldiers of the German Armed Forces who had recently been deployed to Afghanistan (n=40 undergoing initial psychiatric treatment, n=77 untreated). RESULTS: Logistic regression showed that the value types of hedonism (-), power (-), tradition (+), and universalism (+) were significantly correlated with the probability and severity of PTSD and whether the participant was in treatment or not. The effects were partially mediated by the RS-11 scale values. CONCLUSIONS: Value types seem to be associated with psychiatric symptoms in soldiers after deployment. These results could contribute to the further development of therapeutic approaches. PMID- 24808939 TI - Bone regeneration of calvarial defect using marine calcareous-derived beta tricalcium phosphate macrospheres. AB - The aim of this study was to examine the bone regeneration properties of beta tricalcium phosphate hydrothermally converted from foraminifera carbonate exoskeleton in the repair of rat calvarial defect. These natural materials possess unique interconnected porous network with uniform pore size distribution, which can be potentially advantageous. In total, 20 adult male Wistar rats received full-thickness calvarial defect with a diameter of 5 mm. The rate of newly formed bone was measured radiologically by X-ray and micro-computed tomography and by histologic examination. After 2 weeks, the beta-tricalcium phosphate group exhibited full closure of the defect site, while control group remained unrestored at the end of the 6-week experimentation. It was observed that the newly regenerated bone thickened over the course of the experiment in the beta-tricalcium phosphate group. No soft tissue reaction was observed around the beta-tricalcium phosphate implant and the rats remained healthy. These results showed that repair of the calvarial defect can be achieved by biomimetic beta-tricalcium phosphate macrospheres, which hold potential for application as bone grafts for bone augmentation surgeries. PMID- 24808940 TI - Participation of National Medical Associations in quality improvement activities International comparison and the Israeli case. AB - BACKGROUND: Many countries have devoted considerable efforts in an attempt to improve the performance of their health care systems. National Medical Associations (NMAs), along with other stakeholders, play a part in the promotion of such activities. The purpose of this paper is to explore the nature and level of participation of NMAs in activities of quality improvement in medicine, with a specific emphasis on Israel. METHODS: THE AUTHORS CONDUCTED A SURVEY AMONG NMAS AROUND THE WORLD INQUIRING AS TO THEIR INVOLVEMENT IN THREE CENTRAL ASPECTS OF QUALITY IMPROVEMENT: clinical guidelines, quality measurement and continuing medical education (CME). In addition, they conducted a review of the literature in order to gather more information and complete the data collected in the survey. The findings were processed and analyzed comparatively. RESULTS: Most of the NMAs surveyed participate in quality improvement activities at least to some extent. NMAs' main involvement is in the regulation of CME and they are involved to a much lesser extent in the preparation of clinical guidelines and in quality measurement. In Israel, the Israeli Medical Association (IMA) has a dominant role in both the preparation of clinical guidelines and the regulation of CME credits. DISCUSSION: It is possible that the expertise maintained by the profession, coupled with the organizational power of the NMA as a union, is viewed as beneficial for regulating educational activities in medicine such as CME. Conversely, the issuing of clinical guidelines is usually regarded as a typical scientific activity, and therefore often rests in the hands of professional medical societies. Quality measurement is regarded as a distinctive administrative tool and is usually found in the province of governments. Based on the typology that we introduced in our previous paper, we discovered that the extent of NMAs' involvement in quality improvement coincides with the mode of governance of the health care system. CONCLUSIONS: The nature and level of participation of NMAs in activities of quality improvement varies widely. Collaboration of NMAs in this field with other stakeholders is not uncommon, and may contribute to the further development of quality improvement in medicine. PMID- 24808941 TI - Low rate of non-attenders to primary care providers in Israel - a retrospective longitudinal study. AB - BACKGROUND: A model that combines reactive and anticipatory care within routine consultations has become recognized as a cost-effective means of providing preventive health care, challenging the need of the periodic health examination. As such, opportunistic screening may be preferable to organized screening. Provision of comprehensive preventive healthcare within the primary care system depends on regular attendance of the general population to primary care physicians (PCPs). OBJECTIVES: To assess the proportion of patients who do not visit a PCP even once during a four-year period, and to describe the characteristics of this population. METHODS: An observational study, based on electronic medical records of 421,012 individuals who were members of one district of Clalit Health Services, the largest health maintenance organization in Israel. RESULTS: The average annual number of visits to PCPs was 7.6 +/- 8.7 to 8.3 +/- 9.0 (median 5, 25%-75% interval 1-11) and 9.5 +/- 10.0 to10.2 +/- 10.4 (median 6, 25%-75% interval 1-14) including visits to direct access consultants) in the four years of the study. During the first year of the study 87.2% of the population visited a PCP. During the four year study period, only 1.5% did not visit a PCP even once. In a multivariate analysis having fewer chronic diseases (for each additional chronic disease the OR, 95% CI was 0.40 (0.38!0.42)), being a new immigrant (OR, 95% CI 2.46 (2.32!2.62)), and being male (OR, 95% CI 1.66 (1.58!1.75)) were the strongest predictors of being a non-attender to a PCP for four consecutive years. CONCLUSIONS: The rate of nonattendance to PCPs in Israel is low. Other than new immigrant status, none of the characteristics identified for nonattendance suggest increased need for healthcare services. PMID- 24808942 TI - A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (Part I - Protection via specific pathways). AB - Neurocognitive deficits are a major source of morbidity in survivors of cardiac arrest. Treatment options that could be implemented either during cardiopulmonary resuscitation or after return of spontaneous circulation to improve these neurological deficits are limited. We conducted a literature review of treatment protocols designed to evaluate neurologic outcome and survival following cardiac arrest with associated global cerebral ischemia. The search was limited to investigational therapies that were utilized to treat global cerebral ischemia associated with cardiac arrest. In this review we discuss potential mechanisms of neurologic protection following cardiac arrest including actions of several medical gases such as xenon, argon, and nitric oxide. The 3 included mechanisms are: 1. Modulation of neuronal cell death; 2. Alteration of oxygen free radicals; and 3. Improving cerebral hemodynamics. Only a few approaches have been evaluated in limited fashion in cardiac arrest patients and results show inconclusive neuroprotective effects. Future research focusing on combined neuroprotective strategies that target multiple pathways are compelling in the setting of global brain ischemia resulting from cardiac arrest. PMID- 24808943 TI - Intestinal carriage of methicillin-resistant Staphylococcus aureus in nasal MRSA carriers hospitalized in the neonatal intensive care unit. AB - BACKGROUND: The current data regarding the correlation between the methicillin resistant Staphylococcus aureus (MRSA) clones carried in the nasal cavity and digestive tract are inadequate. METHODS: MRSA strains were isolated from both the feces and nasal swabs of 21 nasal-MRSA carriers ranging from 10 to 104 days of age treated at the neonatal intensive care units of two hospitals. The molecular epidemiological characteristics of the isolates were determined: multilocus sequence types, spa-types, staphylococcal cassette chromosome mec (SCCmec) types, carriage of four exotoxin genes, and genes contained in commercially available kit. RESULTS: The feces of all nasal carriers contained MRSA at levels ranging from 4.0 * 10(2) to 2.8 * 10(8) colony forming units/g feces. The MRSA clones isolated from the feces and the nasal swabs of each patient were the same. Four MRSA clones, clonal complex (CC) 8-SCCmec IVl, CC8-SCCmec IVb, CC1-SCCmec IVa and CC5-SCCmec IIa were identified from 21 patients. All CC8-SCCmec IVl strains and one of three CC5-SCCmec IIa strains carried the toxic shock syndrome toxin gene. CONCLUSIONS: The feces of tested MRSA carriers contained the same MRSA clones as the nasal isolates in considerable amounts, suggesting that more careful attention should be paid for the handling of excrement in the case of newborn babies or infants than that of adults. PMID- 24808945 TI - Estimated rate of agricultural injury: the Korean Farmers' Occupational Disease and Injury Survey. AB - OBJECTIVES: This study estimated the rate of agricultural injury using a nationwide survey and identified factors associated with these injuries. METHODS: The first Korean Farmers' Occupational Disease and Injury Survey (KFODIS) was conducted by the Rural Development Administration in 2009. Data from 9,630 adults were collected through a household survey about agricultural injuries suffered in 2008. We estimated the injury rates among those whose injury required an absence of more than 4 days. Logistic regression was performed to identify the relationship between the prevalence of agricultural injuries and the general characteristics of the study population. RESULTS: We estimated that 3.2% (+/ 0.00) of Korean farmers suffered agricultural injuries that required an absence of more than 4 days. The injury rates among orchard farmers (5.4 +/- 0.00) were higher those of all non-orchard farmers. The odds ratio (OR) for agricultural injuries was significantly lower in females (OR: 0.45, 95% CI = 0.45-0.45) compared to males. However, the odds of injury among farmers aged 50-59 (OR: 1.53, 95% CI = 1.46-1.60), 60-69 (OR: 1.45, 95% CI = 1.39-1.51), and >=70 (OR: 1.94, 95% CI = 1.86-2.02) were significantly higher compared to those younger than 50. In addition, the total number of years farmed, average number of months per year of farming, and average hours per day of farming were significantly associated with agricultural injuries. CONCLUSIONS: Agricultural injury rates in this study were higher than rates reported by the existing compensation insurance data. Males and older farmers were at a greater risk of agriculture injuries; therefore, the prevention and management of agricultural injuries in this population is required. PMID- 24808944 TI - Maternal and family factors and child eating pathology: risk and protective relationships. AB - BACKGROUND: Previous studies have found associations between maternal and family factors and child eating disorder symptoms. However, it is not clear whether family factors predict eating disorder symptoms specifically, or relate to more general child psychopathology, of which eating disorder symptoms may be one component. This study aimed to identify maternal and family factors that may predict increases or decreases in child eating disorder symptoms over time, accounting for children's body mass index z-scores and levels of general psychological distress. METHODS: Participants were 221 mother-child dyads from the Childhood Growth and Development Study, a prospective cohort study in Western Australia. Participants were assessed at baseline, 1-year follow-up and 2-year follow-up using interview and self-report measures. Children had a mean age of 10 years at baseline and 46% were male. Linear mixed models and generalised estimating equations were used to identify predictors of children's eating disorder symptoms, with outcome variables including a global index of eating disorder psychopathology, levels of dietary restraint, levels of emotional eating, and the presence of loss of control ('binge') eating. RESULTS: Children of mothers with a current or past eating disorder reported significantly higher levels of global eating disorder symptoms and emotional eating than other children, and mothers with a current or past eating disorder reported significantly more concern about their children's weight than other mothers. Maternal concern about child weight, rather than maternal eating disorder symptoms, was significant in predicting child eating disorder symptoms over time. Family exposure to stress and low maternal education were additional risk factors for eating disorder symptoms, whilst child-reported family satisfaction was a protective factor. CONCLUSIONS: After adjusting for relevant confounding variables, maternal concern about child weight, children's level of family satisfaction, family exposure to stress, and maternal education are unique predictors of child eating disorder symptoms. PMID- 24808946 TI - The surgical management of thyroid cancer. AB - Thyroid cancer has been increasing in incidence, with the number of reported cases in the US rising by 25% over the last 3 years. With growing technological advances in the field and improved contributions of diagnostics, surgical decision-making and operative planning have taken on new challenges. Herein, we review the current clinical practice recommendations and active areas of surgical controversy, reflective of the most recently published professional consensus guidelines and a systematic review of the literature. PMID- 24808947 TI - Head and neck cancers in developing countries. AB - Head and neck cancers are the most common cancers in developing countries, especially in Southeast Asia. Head and neck cancers are more common in males compared to females. This is mainly attributed to tobacco, areca nut, alcohol, etc. Oral cancers are most common amongst all head and neck squamous cell cancers (HNSCC). HNSCC in the developing world differ from those in the Western world in terms of age, site of disease, etiology, and molecular biology. Poverty, illiteracy, advanced stage at presentation, lack of access to health care, and poor treatment infrastructure pose a major challenge in management of these cancers. The annual GDP (gross domestic product) spent on health care is very low in developing countries compared to the developed countries. Cancer treatment leads to a significant financial burden on the cancer patients and their families. Several health programs have been implemented to curb this rising burden of disease. The main aims of these health programs are to increase awareness among people regarding tobacco and to improve access to health care facilities, early diagnosis, treatment, and palliative care. PMID- 24808949 TI - Transnasal Flexible Fiberoptic in-office Laryngeal Biopsies-Our Experience with 117 Patients with Suspicious Lesions. AB - OBJECTIVE: To compare pathologic results obtained via in-office transnasal fiberoptic laryngoscopy (TFL) to those of subsequent direct laryngoscopy in order to assess the accuracy of TFL as a diagnostic tool. PATIENTS: One hundred and seventeen patients with suspicious laryngeal lesions. METHODS: All patients underwent in-office biopsies. All patients with malignant diagnosis were referred to treatment. All patients with benign diagnosis or carcinoma in situ were referred to direct laryngoscopy for definitive diagnosis. The pathological results of the specimens from both procedures were compared. RESULTS: Adequate tissue for diagnostic purposes was obtained in 110 of 117 in-office transnasal fiberoptic laryngoscopy biopsies (94.0%). The biopsy results revealed invasive carcinoma in 42 patients (38.2%), carcinoma in situ (CIS) in 17 patients (15.4%), and benign lesions in 51 patients (46.4%). All patients with benign pathologies and carcinoma in situ were referred to biopsy under direct laryngoscopy (five patients refused and were removed from the statistics). The final pathologies identified from the biopsies on direct laryngoscopy revealed that there was an underestimation of the transnasal fiberoptic laryngoscopy results in 33 patients (a false negative rate of 31.4%, 33/105) and an overestimation in one patient. The sensitivity of transnasal fiberoptic laryngoscopy biopsy compared with direct laryngoscopy biopsy was 70.6% and the specificity was 96.7%. CONCLUSIONS: TFL with biopsy is easy, safe, and cost-effective but raises serious doubts about its clinical value due to its low sensitivity rate for diagnosing suspicious lesions of the larynx. As such, it is recommended that all patients with a suspicious lesion diagnosed by TFL biopsy as being benign or CIS should be referred to direct laryngoscopy for verification of the findings. PMID- 24808948 TI - Transoral Robotic Surgery in the HPV Era. AB - The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades mostly due to human papillomavirus (HPV) related infections. Cancers resulting from HPV infection bear a better prognosis than those that are smoking-related. Because HPV-positive patients are often younger, with lower rates of co-morbid illness and longer overall life expectancies, long-term sequelae of therapy have become an important issue. Treatment of oropharyngeal cancers has typically involved the use of radiation and chemotherapy to avoid the morbidity of open surgery which included mandibulotomy and composite resection. Transoral robotic surgery (TORS) is an emerging treatment option for this disease, avoiding the morbidity of open approaches while providing excellent oncologic and functional outcomes. With overall survival rate at 2 years exceeding 80%, and local failure rate of less than 3%, patients receiving TORS report relatively good health-related quality of life (QOL) scores. The aim of the current review is to provide a summary of the current literature with regard to the oncologic and functional outcomes following treatment of OPSCC with TORS. PMID- 24808950 TI - Transoral laser surgery for laryngeal cancer. AB - Transoral laser microsurgery (TLM) was pioneered in the early 1970s as an approach to treat laryngeal pathology with precision and minimal thermal damage to the vocal cords. Over the last four decades, TLM has become an integral part of the treatment paradigm for patients with laryngeal cancer. TLM is one of the primary treatment options for early-stage laryngeal tumors. However, in recent years, surgeons have begun to develop TLM into a more versatile approach which can be used to address advanced laryngeal tumors. Although functional outcomes following TLM for advanced laryngeal disease are scarce, survival outcomes appear to be comparable with those reported for organ preservation strategies employing external beam radiation therapy (EBRT) and chemotherapy. In addition, TLM plays an important role in the setting of recurrent laryngeal cancer following primary irradiation. TLM has been demonstrated to decrease the need for salvage total laryngectomy resulting in improved functionality while retaining comparable oncologic outcomes. The aim of this review is to elucidate the indications, techniques, and oncological outcomes of TLM for advanced laryngeal cancers. PMID- 24808951 TI - Robot-assisted transaxillary thyroid surgery-feasibility and safety of a novel technique. AB - Developments in technology have led to a rapid progress in robotic endocrine surgery applications. With the advent of minimally invasive techniques in thyroid surgery, robot-assisted transaxillary thyroid surgery (RATS) has emerged as one of the most promising approaches. Its main advantages are improved cosmetic outcome, avoiding cervical incisions, thereby increasing patient satisfaction, and improved visualization, arms articulations, and precision, resulting in fewer surgical complications. The main disadvantages are potential new injuries to the brachial plexus, esophagus, and trachea, longer operative time, and increased cost compared to conventional thyroidectomy. In skilled hands, RATS is a safe alternative to conservative thyroidectomy and should be presented to patients with aesthetic concerns. As with any new emerging technique, careful patient selection is crucial, and further evidence must be sought to confirm its indications over time. PMID- 24808952 TI - Robotic surgery for oropharyngeal cancer. AB - Oropharyngeal cancer represents a growing proportion of head and neck malignancies. This has been associated with the increase in infection of the oropharynx by oncogenic strains of human papillomavirus (HPV). Transoral robotic surgery (TORS) has opened the door for minimally invasive surgery for HPV-related and non-HPV-related oropharyngeal cancer. Compared to traditional open surgical approaches, TORS has been shown to improve functional outcomes in speech and swallowing, while maintaining good oncologic outcomes. PMID- 24808953 TI - Management of advanced laryngeal cancer. AB - Squamous cell carcinoma of the larynx continues to be the commonest head and neck cancer in many Western countries. The larynx plays a key role for many essential functions, including breathing, voice production, airway protection, and swallowing. The goals of laryngeal cancer treatment are thus to provide best possible oncologic control, while optimizing functional outcomes. In recent decades, the treatment paradigm for advanced laryngeal cancer has shifted from one of primary surgery (total laryngectomy) as gold standard, toward non-surgical organ-preserving treatment using radiotherapy or chemoradiotherapy. However, concerns have emerged regarding functional outcomes after chemoradiotherapy, as well as possible decreased overall survival in patients with laryngeal cancer. The purpose of the present review is to review surgical and non-surgical options for treatment of advanced laryngeal cancer, as well as the evidence supporting each of these. PMID- 24808954 TI - Assessment of margins in transoral laser and robotic surgery. AB - The growing practice of endoscopic surgery has changed the therapeutic management of selected head and neck cancers. Although a negative surgical margin in resection of neoplasm is the most important surgical principle in oncologic surgery, controversies exist regarding assessment and interpretation of the status of margin resection. The aim of this review was to summarize the literature considering the assessment and feasibility of negative margins in transoral laser microsurgery (TLM) and transoral robotic surgery (TORS). Free margin status is being approached differently in vocal cord cancer (1-2 mm) compared with other sites in the upper aerodigestive tract (2-5 mm). Exposure, orientation of the pathological specimen, and co-operation with the pathologist are crucial principles needed to be followed in transoral surgery. Piecemeal resection to better expose deep tumor involvement and biopsies taken from surgical margins surrounding site of resection can improve margin assessment. High rates of negative surgical margins can be achieved with TLM and TORS. Adjuvant treatment decision should take into consideration also the surgeon's judgment with regard to the completeness of tumor resection. PMID- 24808955 TI - The injection of air/oxygen bubble into the anterior chamber of rabbits as a treatment for hyphema in patients with sickle cell disease. AB - Purpose. To investigate the changes of partial oxygen pressure (PaO2) in aqueous humour after injecting air or oxygen bubble into the anterior chamber in sickle cell hyphema. Methods. Blood samples were taken from the same patient with sickle cell disease. Thirty-two rabbits were divided into 4 groups. In group 1 (n = 8), there was no injection. Only blood injection constituted group 2 (n = 8), both blood and air bubble injection constituted group 3 (n = 8), and both blood and oxygen bubble injection constituted group 4 (n = 8). Results. The PaO2 in the aqueous humour after 10 hours from the injections was 78.45 +/- 9.9 mmHg (Mean +/ SD) for group 1, 73.97 +/- 8.86 mmHg for group 2, 123.35 +/- 13.6 mmHg for group 3, and 306.47 +/- 16.5 mmHg for group 4. There was statistically significant difference between group 1 and group 2, when compared with group 3 and group 4. Conclusions. PaO2 in aqueous humour was increased after injecting air or oxygen bubble into the anterior chamber. We offer to leave an air bubble in the anterior chamber of patients with sickle cell hemoglobinopathies and hyphema undergoing an anterior chamber washout. PMID- 24808956 TI - Caregiver burden in epilepsy: determinants and impact. AB - Aim. Caregiver burden (CB) in epilepsy constitutes an understudied area. Here we attempt to identify the magnitude of this burden, the factors associated with it, and its impact to caregiver quality of life (QOL). Methods. 48 persons with epilepsy (PWE) underwent video-EEG monitoring and their caregivers completed questionnaires providing demographic, disease-related, psychiatric, cognitive, sleep, QOL, and burden information. Results. On regression analysis, higher number of antiepileptic drugs, poorer patient neuropsychological performance, lower patient QOL score, and lower caregiver education level were associated with higher CB. Time allocated to patient care approximated but did not attain statistical significance. A moderate inverse correlation between CB and caregiver QOL physical component summary score and a stronger inverse correlation between CB and caregiver QOL mental component summary score were seen. Conclusion. In a selected cohort of PWE undergoing video-EEG monitoring, we identified modest degree of CB, comparable to that reported in the literature for other chronic neurological conditions. It is associated with specific patient and caregiver characteristics and has a negative effect on caregiver QOL. PMID- 24808957 TI - Antimicrobial Susceptibility of Escherichia coli Isolated from Fresh-Marketed Nile Tilapia (Oreochromis niloticus). AB - The contamination of seafood by bacteria of fecal origin, especially Escherichia coli, is a widely documented sanitary problem. The objective of the present study was to isolate E. coli strains from the gills, muscle, and body surface of farmed Nile tilapias (Oreochromis niloticus) fresh-marketed in supermarkets in Fortaleza (Ceara, Brazil), to determine their susceptibility to antibiotics of different families (amikacin, gentamicin, imipenem, cephalothin, cefotaxime, ciprofloxacin, aztreonam, ampicillin, nalidixic acid, tetracycline, and sulfametoxazol trimetoprim), and to determine the nature of resistance by plasmid curing. Forty four strains (body surface = 25, gills = 15, muscle = 4) were isolated, all of which were susceptible to amikacin, aztreonam, cefotaxime, ciprofloxacin, gentamicin, and imipenem. Gill and body surface samples yielded 11 isolates resistant to ampicillin, tetracycline, and sulfametoxazol-trimetoprim, 4 of which of plasmidial nature. The multiple antibiotic resistance index was higher for strains isolated from body surface than from gills. The overall high antibiotic susceptibility of E. coli strains isolated from fresh-marketed tilapia was satisfactory, although the occasional finding of plasmidial resistance points to the need for close microbiological surveillance of the farming, handling, and marketing conditions of aquaculture products. PMID- 24808958 TI - Evaluation of novel design strategies for developing zinc finger nucleases tools for treating human diseases. AB - Zinc finger nucleases (ZFNs) are associated with cell death and apoptosis by binding at countless undesired locations. This cytotoxicity is associated with the binding ability of engineered zinc finger domains to bind dissimilar DNA sequences with high affinity. In general, binding preferences of transcription factors are associated with significant degenerated diversity and complexity which convolutes the design and engineering of precise DNA binding domains. Evolutionary success of natural zinc finger proteins, however, evinces that nature created specific evolutionary traits and strategies, such as modularity and rank-specific recognition to cope with binding complexity that are critical for creating clinical viable tools to precisely modify the human genome. Our findings indicate preservation of general modularity and significant alteration of the rank-specific binding preferences of the three-finger binding domain of transcription factor SP1 when exchanging amino acids in the 2nd finger. PMID- 24808959 TI - Application of microsatellite markers in conservation genetics and fisheries management: recent advances in population structure analysis and conservation strategies. AB - Microsatellites are the most popular and versatile genetic marker with myriads of applications in population genetics, conservation biology, and evolutionary biology. These are the arrays of DNA sequences, consisting of tandemly repeating mono-, di-, tri-, and tetranucleotide units, which are distributed throughout the genomes of most eukaryotic species. Microsatellites are codominant in nature, highly polymorphic, easily typed, and Mendelian inherited, all properties which make them very suitable for the study of population structure and pedigree analysis and capable of detecting differences among closely related species. PCR for microsatellites can be automated for identifying simple sequence repeat polymorphism. Small amount of blood samples or alcohol preserved tissue is adequate for analyzing them. Most of the microsatellites are noncoding, and therefore variations are independent of natural selection. These properties make microsatellites ideal genetic markers for conservation genetics and fisheries management. This review addresses the applications of microsatellite markers in conservation genetics and recent advances in population structure analysis in the context of fisheries management. PMID- 24808960 TI - Methods of Cell Propulsion through the Local Stroma in Breast Cancer. AB - In the normal breast, cellular structures change cyclically in response to ovarian hormones. Cell proliferation, apoptosis, invasion, and differentiation are integral processes that are precisely regulated. Normal epithelial cells depend on the formation of intercellular adhesion contacts to form a continuous sheet of stratifying cell layers that are attached to one and other horizontally and vertically. Cells migrate by extending membrane protrusions to explore the extracellular space locating their targets in a chemotactic manner. The formation of cell protrusions is driven by the assembly of actin filaments at the leading edge. Reorganisation is regulated by a highly integrated signalling cascade that transduces extracellular stimuli to the actin filaments. This signalling cascade is governed by GTPases which act as molecular switches leading to actin polymerisation and the formation of filopodia and lamellipodia. This process is linked to downstream molecules known collectively as WASP proteins, which, in the presence of cortactin, form a complex leading to nucleation and formation of branched filaments. In breast cancer, the cortactin is over expressed leading to increased cellular motility and invasiveness. This hugely complex and integrated signalling cascade transduces extracellular stimuli. There are multiple genes related to cell motility which are dysregulated in human breast cancers. PMID- 24808961 TI - Secondhand smoke exposure, restless sleep, and sleep duration in adolescents. AB - Purpose. To examine whether secondhand smoke (SHS) exposure is associated with restless sleep and/or nighttime sleep duration among adolescents. Methods. Data were analyzed from 1,592 adolescents who completed an internet-delivered survey as part of the British Columbia Adolescent Substance Use Survey cohort study. Ordinal logistic and linear regression models were used to examine associations between frequency of SHS exposure in the past month and frequency of restless sleep and nighttime sleep duration, respectively. Results. SHS exposure was significantly positively associated with restless sleep and significantly negatively associated with sleep duration. In fully adjusted models, compared with students who reported never being exposed to SHS in the past month, students who reported a low, medium, or high frequency of SHS exposure were 1.53, 1.76, and 2.51 times as likely, respectively, to report more frequent restless sleep (OR = 1.53, 95% CI 1.08-2.16; OR = 1.76, 95% CI 1.22-2.53; OR = 2.51, 95% CI 1.59 3.98). With regard to sleep duration, as frequency of SHS exposure increased by one category, nighttime sleep duration during the week and weekend decreased by 4 minutes (B = -0.06, 95% CI = -0.01- - 0.11) and 6 minutes (B = -0.09, 95% CI = 0.03- - 0.14), respectively. Conclusions. This study suggests that frequency of SHS exposure has a significant dose-response relationship with restless sleep and sleep duration in adolescents. PMID- 24808962 TI - Prevalence of deletional alpha thalassemia and sickle gene in a tribal dominated malaria endemic area of eastern India. AB - Inherited hemoglobin disorders like alpha thalassemia and sickle gene are common in the Indian subcontinent. These disorders in the heterozygous state act as malaria resistance genes and influence the susceptibility to Plasmodium falciparum malaria. There is inadequate knowledge about the epidemiology of these malaria resistance genes in the tribal dominated malaria endemic region of the state of Odisha in eastern India. A cross sectional prevalence study was undertaken in 594 subjects in five tribal populations in this region, namely, Sahara (42.4%), Kutia Kandha (30.0%), Kuda (15.8%), Gond (9.8%), and Oraon (2.0%). Sickling test, Hb electrophoresis, HPLC, and molecular studies were undertaken to diagnose the prevalence of sickle allele, beta -thalassemia allele, and deletional alpha thalassemia. Sickle and beta thalassemia alleles were found in 13.1% and 3.4% of subjects, respectively. Sickle allele was found both in heterozygous (10.1%) and homozygous state (3.03%). The prevalence of alpha thalassemia was 50.84% with an allelic frequency of 0.37. Both alpha (-3.7) and alpha (-4.2) alpha thalassemia were detected with an allele frequency of 0.33 and 0.04, respectively. The high prevalence of alpha thalassemia and sickle gene in this population is probably due to selection pressure of endemic malaria in this part of India. PMID- 24808963 TI - Transoral Robotic Surgery: Step-by-Step Radical Tonsillectomy. AB - Introduction. Transoral robotic surgery (TORS) radical tonsillectomy is an emerging minimally invasive surgical procedure for the treatment of cancer of the tonsil. The detailed surgical technique and claims for its reproducibility have been previously published. Case Presentation. We present a patient with a T2N2bM0 epidermoid carcinoma of the tonsil to illustrate step by step the surgical procedure for TORS radical tonsillectomy. Neck dissection and TORS were staged. No surgical reconstruction of the defect was required. No tracheostomy was necessary. The patient could eat without any feeding tube and was on full oral diet on the fifth postoperative day. Discussion. The transoral approach offers the benefits of minimally invasive surgery to patients with cancer of the tonsil. The excellent exposure and high precision provided by robotic instrumentation allow the surgeon to closely follow and accomplish the surgical steps, which is the best warranty for safety and effectiveness. PMID- 24808964 TI - Multiple congenital epulis in alveolar ridges of maxilla and mandible in a newborn: a rare case report. AB - Congenital granular cell lesion (CGCL) or congenital epulis is an uncommon benign of the oral cavity tumor appearing at birth with typical clinical and pathologic features. It predominately affects females, mainly on the anterior maxillary alveolar ridge, and occurs usually as a single mass, although sometimes as multiple. The left side incisor area is the most common site. The etiology and histogenesis of the lesion remain obscure. Though it is a benign lesion, the tumor may cause feeding and respiratory problems if there are too large or multiple tumors. We report a case of a three-day-old, female newborn, who was referred to our hospital with multiple congenital oral swellings arising from the maxilla and mandible. The tumors caused a feeding problem and, hence, they were resected by surgical excision under general anesthesia. PMID- 24808965 TI - Primary pleomorphic adenoma of the external auditory canal: a case report and review of the literature. AB - Background. Pleomorphic adenoma (PA) is a benign tumour that mainly arises from salivary glands, and PA of the external auditory canal (EAC) is very rare. The objective of this study was to clarify the clinical presentation and treatment of PA of the EAC. Method. The authors present a case of PA arising from the EAC together with a literature review. Results. A 40-year-old man complained of hearing loss and foreign-body sensation of the right ear. Clinical and radiological examinations revealed a well-defined tumour limited to the EAC, with no connection to the parotid gland. Preoperative fine-needle aspiration cytology findings were characteristic of PA. The tumour was removed en bloc with the overlying skin. Conclusion. PA of the EAC is very rare, and methods to rule out malignancy before treatment are lacking. Thus, long-term follow-up is necessary, because malignant tumours are common in the EAC and PA has malignant potential. PMID- 24808966 TI - Congestive Heart Failure versus Inflammatory Carcinoma in Breast. AB - Inflammatory breast cancer is a rare highly malignant form of breast cancer. Clinical signs and symptoms with histologic examination usually confirm the diagnosis. There are rare reports of breast edema of congestive heart failure which were difficult to differentiate from inflammatory carcinoma. The differential becomes more difficult when congestive heart failure is associated with unilateral breast edema. We present a case of a 70-year-old woman with congestive heart failure associated with unilateral breast edema and skin thickening simulating inflammatory breast carcinoma on mammography. PMID- 24808967 TI - A Debilitating Orthopaedic Complication following Corticosteroid Therapy for Polymyalgia Rheumatica. AB - Avascular necrosis (AVN) of the scaphoid secondary to corticosteroid use is a rare entity. Previous reports in the literature refer to chronic steroid intake. We report a case secondary to low dose, short term use. AVN has a multifactorial cellular and genetic aetiology and most frequently affects the femoral head. Diagnosis relies on a high index of suspicion and early magnetic resonance (MR) scanning. Treatment options are similar to those of traumatic scaphoid nonunions and include vascularised bone grafting and scaphoid excision. Polymyalgia Rheumatica is a common condition and its treatment is led by corticosteroid use. Mild to moderate strengths are advocated. However in our report we show that even with small doses serious adverse effects can be encountered. PMID- 24808968 TI - Posttranscriptional Suppression of Lipopolysaccharide-Stimulated Inflammatory Responses by Macrophages in Middle-Aged Mice: A Possible Role for Eukaryotic Initiation Factor 2 alpha. AB - The intensities of macrophage inflammatory responses to bacterial components gradually decrease with age. Given that a reduced rate of protein synthesis is a common age-related biochemical change, which is partially mediated by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF-2 alpha ), we investigated the mechanism responsible for the deterioration of macrophage inflammatory responses, focusing specifically on the age-related biochemical changes in middle-aged mice. Peritoneal macrophages isolated from 2-month-old (young) and 12-month-old (middle-aged) male BALB/c mice were stimulated with lipopolysaccharide (LPS). Although LPS-stimulated secretion of tumor necrosis factor- alpha (TNF- alpha ) by the macrophages from middle-aged mice was significantly lower than that from young mice, LPS caused marked increases in levels of TNF- alpha mRNA in macrophages from middle-aged as well as young mice. Moreover, LPS evoked similar levels of phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor- kappa B (NF- kappa B) in young and middle-aged mice. In contrast, the basal level of phosphorylated eIF-2 alpha in macrophages from middle-aged mice was higher than that in macrophages from young mice. Salubrinal, an inhibitor of the phosphatase activity that dephosphorylates eIF-2 alpha , suppressed the LPS-stimulated inflammatory responses in a murine macrophage cell line RAW264.7. These results suggest that posttranscriptional suppression of macrophage inflammatory responses during middle age requires phosphorylation of eIF-2 alpha . PMID- 24808969 TI - Whole body bone tissue and cardiovascular risk in rheumatoid arthritis. AB - Introduction. Atherosclerosis and osteoporosis share an age-independent bidirectional correlation. Rheumatoid arthritis (RA) represents a risk factor for both conditions. Objectives. The study aims to evaluate the connection between the estimated cardiovascular risk (CVR) and the loss of bone tissue in RA patients. Methods. The study has a prospective cross-sectional design and it includes female in-patients with RA or without autoimmune diseases; bone tissue was measured using whole body dual X-ray absorptiometry (wbDXA); CVR was estimated using SCORE charts and PROCAM applications. Results. There were 75 RA women and 66 normal women of similar age. The wbDXA bone indices correlate significantly, negatively, and age-independently with the estimated CVR. The whole body bone percent (wbBP) was a significant predictor of estimated CVR, explaining 26% of SCORE variation along with low density lipoprotein (P < 0.001) and 49.7% of PROCAM variation along with glycemia and menopause duration (P < 0.001). Although obese patients had less bone relative to body composition (wbBP), in terms of quantity their bone content was significantly higher than that of nonobese patients. Conclusions. Female patients with RA and female patients with cardiovascular morbidity have a lower whole body bone percent. Obese female individuals have higher whole body bone mass than nonobese patients. PMID- 24808970 TI - Correlation of fine needle aspiration cytology findings with thyroid function test in cases of lymphocytic thyroiditis. AB - Background. Chronic lymphocytic thyroiditis is the second most common thyroid lesion diagnosed on FNAC after goiter. FNAC is reliable tool in the diagnosis of thyroid lesion. Objective. To correlate FNAC cytologic findings with TFT in the lymphocytic thyroiditis. Methods. 175 patients with thyroid swellings were referred for FNAC as well as TFT during 2011-2013. Fine needle aspiration cytology was performed using non-aspiration or aspiration techniques and TFT performed on Beckman culter access 2. Results. Lymphoid infiltrate was seen in 55 cases. The commonest age group of lymphocytic thyroiditis was 21-30 years with male : female ratio being 1 : 10. Anti-TPO and TSH were elevated in 96.16% (25/26) of cases with grade 3 lymphoid infiltrate, 94.12% (16/17) of cases with grade 2, and 91.67% (11/12) of cases with 1 grade. Increased anti-TPO with raised TSH without any lymphoid infiltrate was seen in 5 cases and 5 cases showed only raised TSH without raised anti-TPO and without any lymphoid infiltrate. We observed that grade 3 lymphocytic infiltration has correlation with anti-TPO and TSH together or TSH alone but not with anti-TPO alone. We also observed that anti TPO and TSH together are significant even if no lymphocytic infiltration is present. Conclusion. Grade 3 lymphocytic infiltration has statistical correlation with anti-TPO and TSH together or TSH alone but not with anti-TPO alone. Anti TPO was adjunct to TSH in grade 3. The presence of Hurthle cell change, giant cells, and granulomas has no statistical correlation with lymphocytic thyroiditis. PMID- 24808971 TI - Culture versus PCR for Salmonella Species Identification in Some Dairy Products and Dairy Handlers with Special Concern to Its Zoonotic Importance. AB - A total of 200 samples of milk and dairy products as well as 120 samples of dairy handlers were randomly collected from different dairy farms and supermarkets in Dakahlia Governorate, Egypt. The conventional cultural and serotyping methods for detection of Salmonella in dairy products were applied and the results were compared with those obtained by molecular screening assay using (ttr sequence). The obtained results revealed that 21% of milk and dairy products (42/200) were positive for Salmonella species using enrichment culture-based PCR method, while 12% of different dairy samples (24/200) were found to be positive for Salmonella species by using the conventional culture methods. Two stool specimens out of 40 apparently healthy dairy handlers were positive by the PCR method. Serotyping of Salmonella isolates revealed that 58.3% (14/24) from different dairy products were contaminated with Salmonella Typhimurium. We conclude that the enrichment culture-based PCR assay has high sensitivity and specificity for detection of Salmonella species in dairy products and handlers. High incidence of Salmonella Typhimurium in the examined dairy samples highlights the important role played by milk and dairy products as a vehicle in disease prevalence. Great effort should be applied for reducing foodborne risk for consumers. PMID- 24808972 TI - Tissue residues, hematological and biochemical effects of tilmicosin in broiler chicken. AB - The aim of this study was to determine the blood and tissue concentrations profile and effect of tilmicosin on some hematological and biochemical parameters in broiler chicken. Fifty clinically healthy Hubbard chickens were orally administered 25 mg/kg BW of tilmicosin once daily for 5 consecutive days. Tissue residues of tilmicosin in slaughtered healthy chicken could not be detected by microbiological assay in all tested tissues except in lung (at 96 hours) and liver and kidneys (at 72 hours) after last administration. Tilmicosin caused temporary decrease in the RBCs and WBCs counts and has no effect on hemoglobin (Hb) and packed cell volume concentration (PCV). Also, the effect of tilmicosin on some biochemical parameters was as follows: the concentrations of creatinine, uric acid, electrolytes (sodium, potassium, and calcium), glucose, AST, ALT, ALP, and HDL-cholesterol in the serum of treated chicken did not change in response to the repeated oral administration of tilmicosin. There were only a temporary significant decrease in total protein and albumin concentrations and a significant increase in cholesterol and triglycerides concentrations. Chicken must not be slaughtered before 4 days from the stopping of tilmicosin administration. Tilmicosin makes temporary changes on hematological and biochemical parameters in broiler chicken. PMID- 24808973 TI - Electrophoretic Analysis of Indian Isolates of Mycoplasma agalactiae and Mycoplasma bovis by SDS-PAGE and Immunoblotting. AB - Mycoplasma agalactiae and Mycoplasma bovis both are responsible for respiratory conditions in sheep and goats. M. agalactiae is a major pathogen of sheep and goats and accounts for almost 90% of outbreaks of contagious agalactia syndrome in goats and almost 100% in sheep. On the basis of clinical signs and cultural, morphological, and biochemical characterization it is almost impossible to differentiate between both the species. Moreover, due to presence of genomic and proteomic similarity most of the time routine diagnostic tests fail to differentiate between them. Hence the present study was conducted to find out the protein profile of isolates of both the species by SDS-PAGE and to find out the cross-reacting as well as differentiating immunogenic proteins by Immunoblotting, which can be of immunoprophylactic as well as diagnostic values. The study revealed 6-7 major immunogenic cross-reactive proteins with the presence of two important non-cross-reacting species specific polypeptides particularly 25.50 and 24.54 kDa in M. agalactiae and M. bovis, respectively, that might be of diagnostic values. PMID- 24808975 TI - Anti-PD-1 antibodies for the treatment of B-cell lymphoma: Importance of PD-1+ T cell subsets. AB - Monoclonal antibodies specific for programmed cell death 1 (PDCD1, best known as PD-1) have been shown to mediate antineoplastic effects in follicular lymphoma patients. However, the relative proportion of intratumoral PD-1+ T-cell subsets, in particular follicular helper T cells (which exert pro-tumor functions) and effector T cells (which have anticancer activity), may impact clinical outcome, and should therefore be carefully considered for patient selection in this setting. PMID- 24808974 TI - Volatile anaesthetic depression of the carotid body chemoreflex-mediated ventilatory response to hypoxia: directions for future research. AB - In assessing whether volatile anaesthetics directly depress the carotid body response to hypoxia it is necessary to combine in meta-analysis studies of when it is "functionally isolated" (e.g., recordings are made from its afferent nerve). Key articles were retrieved (full papers in English) and subjected to quantitative analysis to yield an aggregate estimate of effect. Results from articles that did not use such methodology were assessed separately from this quantitative approach, to see what could be learned also from a nonquantitative overview. Just 7 articles met the inclusion criteria for hypoxia and just 6 articles for hypercapnia. Within these articles, the anaesthetic (mean dose 0.75, standard deviation (SD) 0.40 minimum alveolar concentration, MAC) statistically significantly depressed carotid body hypoxic response by 24% (P = 0.041), but a similar dose (mean 0.81 (0.42) MAC) did not affect the hypercapnic response. The articles not included in the quantitative analysis (31 articles), assessed qualitatively, also indicated that anaesthetics depress carotid body function. This conclusion helps direct future research on the anaesthetic effects on putative cellular/molecular processes that underlie the transduction of hypoxia in the carotid body. PMID- 24808976 TI - Evidence-based Medicine: A Framework for Emotional Regulation, Intuition, and Conscious Engagement. PMID- 24808977 TI - Nonlocal Intuition: Replication and Paired-subjects Enhancement Effects. AB - This article reports the results of a study of repeat entrepreneurs in Tehran, Iran, in which nonlocal intuition was investigated in a replication and extension of experiment using measures of heart rate variability (HRV). Nonlocal intuition is the perception of information about a distant or future event by the body's psychophysiological systems, which is not based on reason or memories of prior experience. This study follows up on the McCraty, Radin, and Bradley studies, which found evidence of nonlocal intuition. We used Radin's experimental protocol, with the addition of HRV measures as in the McCraty studies involving computer administration of a random sequence of calm and emotional pictures as the stimulus, and conducted two experiments on mutually exclusive samples-the first on a group of single participants (N=15) and the second on a group of co participant pairs (N=30)-to investigate the question of the "amplification" of intuition effects by social connection. Each experiment was conducted over 45 trials while heart rate rhythm activity was recorded continuously. Results, using random permutation analysis, a statistically conservative procedure, show significant pre-stimulus results-that is, for the period before the computer had randomly selected the picture stimulus-for both experiments. Moreover, while significant separation between the emotional and calm HRV curves was observed in the single-participant experiment, an even larger separation was apparent for the experiment on co-participant pairs; the difference between the two groups was also significant. Overall, the results of the single-participant experiment confirm previous finding: that electrophysiological measures, especially changes in the heart rhythm, can detect intuitive foreknowledge. This result is notable because it constitutes cross-cultural corroboration in a non-Western context namely, Iran. In addition, the results for co-participant pairs offer new evidence on the amplification of the nonlocal intuition signal. PMID- 24808978 TI - Electrophysiology of Intuition: Pre-stimulus Responses in Group and Individual Participants Using a Roulette Paradigm. AB - This study used electrophysiological measures of pre-stimulus effects that can occur prior to an unknown future event as an indicator of nonlocal intuition. Intuition in this context is considered as a process by which information normally outside the range of conscious awareness is detected at the cellular level by the heart, the brain, and the autonomic nervous system. This study extends the findings of previous experiments demonstrating that aspects of our physiology can respond to an emotionally engaging stimulus before it is actually experienced. The study evaluated a revised version of a roulette protocol, which included two pre-stimulus segments and included an analysis of the individual participant's data over eight separate trials in addition to a group-level analysis. We also assessed the potential effects of the moon phase on the pre stimulus response outcomes and participant winning and amount won ratios. Data were collected under controlled laboratory conditions from 13 participants in 8 separate sessions using a modified version of a gambling paradigm protocol based on roulette. Half of the experimental sessions were conducted during the full moon phase and half during the new moon phase. Within each trial a total of three segments of physiological data were assessed. There were two separate pre stimulus periods, pre-bet (4 sec) and postbet (12 sec), and a post-result period (6 sec). Participants were told that they were participating in a gambling experiment and were given an initial starting kitty and told they could keep any winnings over the course of 26 trials for each of the eight sessions. The physiological measures included the electrocardiogram (ECG), from which cardiac inter-beat-intervals (heart rate variability, HRV) were derived, and skin conductance. Before the participants participated in the first session, they completed the Cognitive Styles Index questionnaire, which assesses analytical vs intuitive styles. Overall, the results indicate that the revised protocol provides an effective objective measure for detecting a pre-stimulus response, which reflects a type of nonlocal intuition. We found significant differences between the win and loss responses in the aggregated physiological waveform data during both pre-stimulus segments, which provides important information about nonlocal intuition. On average, we detected a significant pre-stimulus response starting around 18 seconds prior to participants knowing the future outcome. Interestingly, there was not a strong overall relationship between the pre stimulus responses and the amount of money the participants won or lost. We also found a significant difference in both pre-stimulus periods during the full moon phase but not in the new moon phase. The results suggest that the protocol is a reliable means of prompting physiological detection of pre-stimulus effects and can be used in future studies investigating aspects of nonlocal intuition. The findings also suggest that if participants had been able to become more attuned to their internal physiological responses, they would have performed much better on the betting choices they made. PMID- 24808979 TI - Non-pharmacological Intervention for Chronic Pain in Veterans: A Pilot Study of Heart Rate Variability Biofeedback. AB - OBJECTIVE: Chronic pain is an emotionally and physically debilitating form of pain that activates the body's stress response and over time can result in lowered heart rate variability (HRV) power, which is associated with reduced resiliency and lower self-regulatory capacity. This pilot project was intended to determine the effectiveness of HRV coherence biofeedback (HRVCB) as a pain and stress management intervention for veterans with chronic pain and to estimate the effect sizes. It was hypothesized that HRVCB will increase parasympathetic activity resulting in higher HRV coherence measured as power and decrease self reported pain symptoms in chronic pain patients. STUDY DESIGN: Fourteen veterans receiving treatment for chronic pain were enrolled in the pre-post intervention study. They were randomly assigned, with 8 subjects enrolled in the treatment group and 6 in the control group. The treatment group received biofeedback intervention plus standard care, and the other group received standard care only. The treatment group received four HRVCB training sessions as the intervention. MEASURES: Pre-post measurements of HRV amplitude, HRV power spectrum variables, cardiac coherence, and self-ratings of perceived pain, stress, negative emotions, and physical activity limitation were made for both treatment and control groups. RESULTS: The mean pain severity for all subjects at baseline, using the self scored Brief Pain Inventory (BPI), was 26.71 (SD=4.46; range=21-35) indicating a moderate to severe perceived pain level across the study subjects. There was no significant difference between the treatment and control groups at baseline on any of the measures. Post-HRVCB, the treatment group was significantly higher on coherence (P=.01) and lower (P=.02) on pain ratings than the control group. The treatment group showed marked and statistically significant (1-tailed) increases over the baseline in coherence ratio (191%, P=.04) and marked, significant (1 tailed) reduction in pain ratings (36%, P<.001), stress perception (16%, P=.02), negative emotions (49%, P<.001), and physical activity limitation (42%, P<.001). Significant between-group effects on all measures were found when pre-training values were used as covariates. CONCLUSIONS: HRVCB intervention was effective in increasing HRV coherence measured as power in the upper range of the LF band and reduced perceived pain, stress, negative emotions, and physical activity limitation in veterans suffering from chronic pain. HRVCB shows promise as an effective non-pharmacological intervention to support standard treatments for chronic pain. PMID- 24808980 TI - A Phytochemical-rich Multivitamin-multimineral Supplement Is Bioavailable and Reduces Serum Oxidized Low-density Lipoprotein, Myeloperoxidase, and Plasminogen Activator Inhibitor-1 in a Four-week Pilot trial of Healthy Individuals. AB - BACKGROUND: A multivitamin-multimineral supplement combined with a diverse blend of bioactive phytochemicals may provide additional antioxidant capacity and anti inflammatory property for overall health. This convenient feature may be useful for individuals who want to increase their intake of phytochemicals. METHODS: We conducted a pilot study in 15 healthy individuals (8 women and 7 men, mean age 41.7+/-14.9 years, mean body mass index 28.0+/-5.6) to investigate the effects of this novel formulation on biomarkers associated with oxidative stress and inflammation. After a 2-week diet that limited intake of fruits and vegetables to 2 servings/day, participants continued with the same restricted diet but began consuming 2 tablets of the study product for the subsequent 4 weeks. Fasting blood samples collected at Week 2 and Week 6 were analyzed and compared using paired t-tests for levels of carotenoids, folate, vitamin B12, homocysteine, oxidized low-density lipoprotein cholesterol (oxLDL), high-sensitivity C-reactive protein (hs-CRP), F2-isoprostane, plasminogen activator inhibitor-1 (PAI-1), and myeloperoxidase. Noninvasive peripheral arterial tonometry (EndoPAT) was also measured. RESULTS: After 4 weeks of supplementation, plasma levels of carotenoids, folate, and vitamin B12, but not homocysteine, were significantly increased (P<.05). Serum levels of oxLDL, PAI-1 and myeloperoxidase were significantly reduced (P<.05), but F2-isoprostane, hs-CRP, and EndoPAT measures were unchanged compared with baseline. The study product was well tolerated. CONCLUSIONS: This nutritional supplement is bioavailable as indicated by the significant increase in plasma carotenoids, vitamin B12, and folate levels and may provide health benefits by significantly reducing serum levels of oxLDL, myeloperoxidase, and PAI-1 in healthy individuals. PMID- 24808982 TI - Intuitive Intelligence, Self-regulation, and Lifting Consciousness. AB - This article explores the role of the heart in emotional experience, as well as how learning to shift the rhythms of the heart into a more coherent state makes it possible to establish a new inner baseline reference that allows access to our heart's intuitive capacities and deeper wisdom. The nature and types of intuition and the connection between intuition and compassionate action are discussed. It is suggested that increased effectiveness in self-regulatory capacity and the resultant reorganization of memories sustained in the neural architecture facilitates a stable and integrated experience of self in relationship to others and to the environment, otherwise known as consciousness. The implications of meeting the increasingly complex demands of life with greater love, compassion, and kindness, thereby lifting consciousness, are considered. PMID- 24808983 TI - A summary of a cochrane review: green and black tea for the primary prevention of cardiovascular disease. PMID- 24808984 TI - An Institutional Case Study: Emotion Regulation With HeartMath at Santa Cruz County Children's Mental Health. AB - This case study from Santa Cruz County Children's Mental Health Agency (CMH), California, reviews the use of measurement of heart rate variability (HRV) to enhance emotional regulation of patients. CMH serves seriously emotionally disturbed youths, many of whom have been separated from their parents for a prolonged period or have been vulnerable without the consistent presence of their caregivers. In this study, the HRV pattern was calculated as high coherence, medium coherence, or low coherence. According to Thurber et al, heart rhythm coherence "is experienced as a calm, balanced, yet energized and responsive state that is conducive to everyday functioning and interaction, including the performance of tasks requiring mental acuity, focus, problem solving and decision making, as well as physical activity and coordination."(1(p39)) In the HeartMath program, there was a game in which high coherence was rewarded with a rainbow that dropped coins into a vessel. When coherence was low, the rainbow and coins disappeared until coherence was reached again. We measured HRV using a finger or ear sensor in individual sessions using a computer-based program from HeartMath Institute, Boulder Creek, California. After juvenile offenders overcame their initial fear of being hooked up to a potential lie detector, I instructed them in "Quick Coherence"(1) and asked them to imagine breathing into the area of their heart. The participants created a library of positive feelings, thoughts, and memories on which they could focus. After a period of positive focus and rhythmic breathing, the clients were often able to move into medium or high coherence. In this state, they noticed that they felt calmer. I explained that they could use this tool to improve their mood. I also practiced alongside the youths in order to demonstrate the technique. The detained youths learned quickly, requested repeated sessions, and learned to combine breathing with recalling the good people, places, foods, and feelings in their lives that sustained them. We could also decrease coherence through the use of negative words such as "loss of privileges" on their side or "pay cut" on mine and then move back to coherence with suggestions of positive mental images. PMID- 24808981 TI - Life rhythm as a symphony of oscillatory patterns: electromagnetic energy and sound vibration modulates gene expression for biological signaling and healing. PMID- 24808985 TI - Police department personnel stress resilience training: an institutional case study. AB - The objective of this case study was to test the impact in law enforcement personnel of an innovative self-regulation and resilience building program delivered via an iPad (Apple Inc, Cupertino, California) app and personal mentoring. The Stress Resilience Training System (SRTS) app includes training on stress and its effects, HRV coherence biofeedback, a series of HeartMath self regulation techniques (The Institute of HeartMath, Boulder Creek, California), and HRV-controlled games. The stressful nature of law enforcement work is well established, and the need for meaningful and effective stress resilience training programs is becoming better understood, as it has been in the military. Law enforcement and military service share many stress-related features including psychological stressors connected with the mission, extended duty cycles, and exposure to horrific scenes of death and injury. San Diego (California) Police Department personnel who participated in the study were 12 sworn officers and 2 dispatchers, 10 men and 4 women. The SRTS intervention comprised an introductory 2-hour training session, 6 weeks of individualized learning and practice with the SRTS app, and four 1-hour telephone mentoring sessions by experienced HeartMath mentors spread over a four week period. Outcome measures were the Personal and Organizational Quality Assessment (POQA) survey, the mentors' reports of their observations, and records of participants' comments from the mentoring sessions. The POQA results were overwhelmingly positive: All four main scales showed improvement; Emotional Vitality improved by 25% (P=.05) and Physical Stress improved by 24% (P=.01). Eight of the nine subscales showed improvement, with the Stress subscale, perhaps the key measure of the study, improving by approximately 40% (P=.06). Participant responses were also uniformly positive and enthusiastic. Individual participants praised the program and related improvements in both on the-job performance and personal and familial situations. The results support the efficacy of the program to achieve its goal of building stress resilience and improving officer wellness by providing practical self-regulation skills for better management of emotional energy. We conclude that the SRTS program for building resilience and improving psychological wellness can be as effective for law enforcement as it is for military personnel. PMID- 24808987 TI - Role of Oxidative Stress in the Pathogenesis of Pancreatitis: Effect of Antioxidant Therapy. AB - Oxidative stress plays an important role in the pathogenesis of acute pancreatitis. The exact pathogenesis of pancreatitis remains unknown but several mechanisms related to oxidative and inflammatory stress are implicated. It is reasonable to surmise that antioxidants would play a protective role in ameliorating the deleterious effects of pancreatitis. We have a wealth of data from animal models that reveal a positive correlation between antioxidant drugs and improved outcomes in experimental pancreatitis. Human clinical trials with antioxidants however, have disclosed conflicting results. We review the existing pathogenesis of pancreatitis related to oxidative stress and provide of a review of current trials with antioxidant therapy. PMID- 24808989 TI - Conformational Dynamics of DNA G-Quadruplex in Solution Studied by Kinetic Capillary Electrophoresis Coupled On-line with Mass Spectrometry. AB - Invited for this months cover is the group of Prof. Maxim V. Berezovski. The cover picture shows the two-dimensional separation of unfolded (green) and folded (red) forms of G-quadruplex (GQ) DNA. The first dimension is kinetic capillary electrophoresis (KCE) separation of unfolded and folded DNA with different K(+) concentrations in solution; the second dimension is ion mobility mass spectrometry separation of DNA conformers in the gas phase. DNA folding into a compact GQ structure is mediated by K(+) ions. For more details, see the Full Paper on p. 58 ff. PMID- 24808988 TI - Genome-wide SNP analysis of the Systemic Capillary Leak Syndrome (Clarkson disease). AB - The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare, orphan disease that resembles, and is frequently erroneously diagnosed as, systemic anaphylaxis. The disorder is characterized by repeated, transient, and seemingly unprovoked episodes of hypotensive shock and peripheral edema due to transient endothelial hyperpermeability. SCLS is often accompanied by a monoclonal gammopathy of unknown significance (MGUS). Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS, which included a region flanking CAV3 (3p25.3) as well as SNP clusters in PON1 (7q21.3), PSORS1C1 (6p21.3), and CHCHD3 (7q33). Among the most highly ranked discoveries were gene-associated SNPs in the uncharacterized LOC100130480 gene (rs6417039, rs2004296). Top case-associated SNPs were observed in BTRC (rs12355803, 3rs4436485), ARHGEF18 (rs11668246), CDH13 (rs4782779), and EDG2 (rs12552348), which encode proteins with known or suspected roles in B cell function and/or vascular integrity. 61 SNPs that were significantly associated with SCLS by microarray analysis were also detected and validated by exome deep sequencing. Functional annotation of highly ranked SNPs revealed enrichment of cell projections, cell junctions and adhesion, and molecules containing pleckstrin homology, Ras/Rho regulatory, and immunoglobulin Ig-like C2/fibronectin type III domains, all of which involve mechanistic functions that correlate with the SCLS phenotype. These results highlight SNPs with potential relevance to SCLS. PMID- 24808986 TI - Emotion: The Self-regulatory Sense. AB - While emotion is a central component of human health and well-being, traditional approaches to understanding its biological function have been wanting. A dynamic systems model, however, broadly redefines and recasts emotion as a primary sensory system-perhaps the first sensory system to have emerged, serving the ancient autopoietic function of "self-regulation." Drawing upon molecular biology and revelations from the field of epigenetics, the model suggests that human emotional perceptions provide an ongoing stream of "self-relevant" sensory information concerning optimally adaptive states between the organism and its immediate environment, along with coupled behavioral corrections that honor a universal self-regulatory logic, one still encoded within cellular signaling and immune functions. Exemplified by the fundamental molecular circuitry of sensorimotor control in the E coli bacterium, the model suggests that the hedonic (affective) categories emerge directly from positive and negative feedback processes, their good/bad binary appraisals relating to dual self-regulatory behavioral regimes-evolutionary purposes, through which organisms actively participate in natural selection, and through which humans can interpret optimal or deficit states of balanced being and becoming. The self-regulatory sensory paradigm transcends anthropomorphism, unites divergent theoretical perspectives and isolated bodies of literature, while challenging time-honored assumptions. While suppressive regulatory strategies abound, it suggests that emotions are better understood as regulating us, providing a service crucial to all semantic language, learning systems, evaluative decision-making, and fundamental to optimal physical, mental, and social health. PMID- 24808990 TI - Building Blocks for the Construction of Bioorthogonally Reactive Peptides via Solid-Phase Peptide Synthesis. AB - The need for post-synthetic modifications and reactive prosthetic groups has long been a limiting factor in the synthesis and study of peptidic and peptidomimetic imaging agents. In this regard, the application of biologically and chemically orthogonal reactions to the design and development of novel radiotracers has the potential to have far-reaching implications in both the laboratory and the clinic. Herein, we report the synthesis and development of a series of modular and versatile building blocks for inverse electron-demand Diels-Alder copper-free click chemistry: tetrazine-functionalized artificial amino acids. Following the development of a novel peptide coupling protocol for peptide synthesis in the presence of tetrazines, we successfully demonstrated its effectiveness and applicability. This versatile methodology has the potential to have a transformational impact, opening the door for the rapid, facile, and modular synthesis of bioorthogonally reactive peptide probes. PMID- 24808991 TI - Room temperature, metal-free arylation of aliphatic alcohols. AB - Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90 min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron-withdrawing substituents are transferred most efficiently, and unsymmetric iodonium salts give chemoselective arylations. The methodology has been applied to the formal synthesis of butoxycaine. PMID- 24808992 TI - Conformational Dynamics of DNA G-Quadruplex in Solution Studied by Kinetic Capillary Electrophoresis Coupled On-line with Mass Spectrometry. AB - G-quadruplex-forming DNA/RNA sequences play an important role in the regulation of biological functions and development of new anticancer and anti-aging drugs. In this work, we couple on-line kinetic capillary electrophoresis with mass spectrometry (KCE-MS) to study conformational dynamics of DNA G-quadruplexes in solution. We show that peaks shift and its widening in KCE can be used for measuring rate and equilibrium constants for DNA-metal affinity interactions and G-quadruplex formation; and ion mobility mass spectrometry (IM-MS) provides information about relative sizes, absolute molecular masses and stoichiometry of DNA complexes. KCE-MS separates a thrombin-binding aptamer d[GGTTGGTGTGGTTGG] from mutated sequences based on affinity to potassium, and reveals the apparent equilibrium folding constant (K F~150 MUm), folding rate constant (k on~1.70*10(3) s(-1) m(-1)), unfolding rate constant (k off~0.25 s(-1)), half-life time of the G-quadruplex (t 1/2~2.8 s), and relaxation time (tau~3.9 ms at physiological 150 mm [K(+)]). In addition, KCE-MS screens for a GQ-stabilizing/ destabilizing effect of DNA binding dyes and an anticancer drug, cisplatin. PMID- 24808994 TI - Local uniqueness solution of illuminated solar cell intrinsic electrical parameters. AB - Starting from an electrical dissipative illuminated one-diode solar cell with a given model data at room temperature (I sc , V oc , R s0 , R sh0 , I max ); we present under physical considerations a specific mathematical method (using the Lambert function) for unique determination of the intrinsic electrical parameters (n, I s , I ph , R s , R sh ). This work proves that for a given arbitrary fixed shunt resistance R sh , the saturation current I S and the ideality factor n are uniquely determined as a function of the photocurrent I ph , and the series resistance R s . The correspondence under the cited physical considerations: R s does not exceed ]0, 20[Omega and n is between ]0, 3[ and I ph and I s are arbitrary positive [Formula: see text] , is biunivocal. This study concludes that for both considered solar cells, the five intrinsic electrical parameters that were determined numerically are unique. PMID- 24808993 TI - N-Aryl Isoleucine Derivatives as Angiotensin II AT2 Receptor Ligands. AB - A novel series of ligands for the recombinant human AT2 receptor has been synthesized utilizing a fast and efficient palladium-catalyzed procedure for aminocarbonylation as the key reaction. Molybdenum hexacarbonyl [Mo(CO)6] was employed as the carbon monoxide source, and controlled microwave heating was applied. The prepared N-aryl isoleucine derivatives, encompassing a variety of amide groups attached to the aromatic system, exhibit binding affinities at best with K i values in the low micromolar range versus the recombinant human AT2 receptor. Some of the new nonpeptidic isoleucine derivatives may serve as starting points for further structural optimization. The presented data emphasize the importance of using human receptors in drug discovery programs. PMID- 24808995 TI - Construction of a scoring system for predicting the risk of severe gastrointestinal involvement in Henoch-Schonlein Purpura. AB - OBJECTIVE: To evaluate the parameters associated with significant gastrointestinal (GI) involvement in Henoch-Schonlein Purpura (HSP), and construct a scoring system for the identification of patients at high risk of gross blood in stools. STUDY DESIGN: Data for HSP patients hospitalized at each of seven institutes were retrospectively analyzed. Patients were divided into four groups according to the consequent severity of GI involvement. Identification of laboratory parameters at the time of admission were then used to differentiate the groups, and a scoring system to predict gross intestinal bleeding was constructed. Prognostic efficiency, correlation with the subsequent duration of abdominal pain, and association with manifestations excluding abdominal pain were also analyzed. RESULTS: An analysis of variance (ANOVA) test showed significant intergroup differences in white blood cell (WBC) count, neutrophil count, serum albumin, potassium, plasma D-dimer and coagulation factor XIII activity. A scoring system consisting of these parameters showed a good prognostic value for gross intestinal bleeding in a receiver operating characteristic (ROC) analysis, and a cut-off value of 4 points showed a sensitivity of 90.0% and specificity of 80.6%. The score was also correlated with the duration of abdominal pain after admission. A significantly higher score (s) was observed in patients presenting with nephritis, although the predictive value was poor. CONCLUSION: A scoring system consisting of generally available parameters was of use in predicting severe GI involvement in HSP patients. Although further study is needed, initial therapy in accordance with disease activity may be taken into consideration using this scoring system. PMID- 24808996 TI - Duplicate publication of articles used in meta-analysis in Korea. AB - With the increasing use of meta-analysis, duplicate publication of original research is particularly problematic. Duplicate publication can result in an inappropriate weighting of the study results. The purpose of our study was to assess the incidence and characteristics of duplicate publications in Korea, and to estimate the impact of duplicate publication on meta-analyses. The meta analysis literature written by Korean authors was searched using the online search engines PubMed, KMbase, and KoreaMed. Duplication patterns were classified into the following 4 combinations: identical samples and identical outcomes (copy), identical samples and different outcomes (fragmentation), increased samples and identical outcomes (imalas), and decreased samples and identical outcomes (disaggregation). To estimate the multiple publication bias, we performed a meta-analysis with and without duplicated data. We estimated that 6 (6.9%) of the 86 analyzed meta-analyses included duplicate publications, and 6 of the 1,194 articles (0.5%) used in the meta-analyses were duplicate publications. In this study, duplicate publications were usually due to disaggregation and overlapping (imalas) publications. Of 6 duplicated articles, 1 was considered a copy (16.6%); 1, a fragmentation (16.6%); 2, imalas (33.3%); and 2, disaggregations (33.3%). There was an increase in the mean effect size and fail safe number with duplicated data. Our study found only 6 instances of duplicate publication after analyzing 1,194 articles used in meta-analyses written by Korean authors. However, 6.9% of the meta-analyses included duplicate publications. Our findings suggest that meta-analyses should be interpreted cautiously, taking into account the possibility of duplicated studies. PMID- 24808997 TI - Rotationally inelastic dynamics of LiH (X(1)Sigma(+), v = 0) in collisions with Ar: State-to-state inelastic rotational rate coefficients. AB - A theoretical study of rotational collision of LiH(X(1)Sigma(+),v = 0, J) with Ar has been carried out. The ab initio potential energy surface (PES) describing the interaction between the Ar atom and the rotating LiH molecule has been calculated very accurately and already discussed in our previous work [Computational and Theoretical Chemistry 993 (2012) 20-25]. This PES is employed to evaluate the de excitation cross sections. The ab initio PES for the LiH(X(1)Sigma(+))-Ar((1)S) Van der waals system is calculated at the coupled-cluster [CCSD(T)] approximation for a LiH length fixed to an experimental value of 3.0139 bohrs. The basis set superposition error (BSSE) is corrected and the bond functions are placed at mid distance between the center of mass of LiH and the Ar atom. The cross sections are then derived in the close coupling (CC) approach and rate coefficients are inferred by averaging these cross sections over a Maxwell-Boltzmann distribution of kinetic energies. The 11 first rotational levels of rate coefficients are evaluated for temperatures ranging from 10 to 300 K. We notice that the de excitation rate coefficients appear large in the order 10(-10) cm(-3) s(-1) and show very low temperature dependence. The rate coefficients magnify significantly the propensity toward ? J = -1 transitions. These results confirm the same propensity already noted for the cross sections. PMID- 24808999 TI - A synergetic combination of small and large neighborhood schemes in developing an effective procedure for solving the job shop scheduling problem. AB - This paper presents an effective procedure for solving the job shop problem. Synergistically combining small and large neighborhood schemes, the procedure consists of four components, namely (i) a construction method for generating semi active schedules by a forward-backward mechanism, (ii) a local search for manipulating a small neighborhood structure guided by a tabu list, (iii) a feedback-based mechanism for perturbing the solutions generated, and (iv) a very large-neighborhood local search guided by a forward-backward shifting bottleneck method. The combination of shifting bottleneck mechanism and tabu list is used as a means of the manipulation of neighborhood structures, and the perturbation mechanism employed diversifies the search. A feedback mechanism, called repeat check, detects consequent repeats and ignites a perturbation when the total number of consecutive repeats for two identical makespan values reaches a given threshold. The results of extensive computational experiments on the benchmark instances indicate that the combination of these four components is synergetic, in the sense that they collectively make the procedure fast and robust. PMID- 24808998 TI - Carotid blood flow, cardiovascular and endocrine responses during head-up tilt in patients with acute cerebrovascular diseases. AB - The purpose of this study was to define common carotid blood flow (CBF), cardiovascular and endocrine responses during head-up tilt (HUT) in patients with acute cerebrovascular diseases (CVD). In 31 male patients with acute CVD (damage of the supratentorial area) and 21 age-matched control male subjects, we measured CBF, mean blood pressure (MBP), heart rate, stroke volume and cardiac output responses before (baseline), during and after HUT. We also measured plasma levels of antidiuretic hormone, adrenaline, noradrenaline, aldosterone and plasma renin activity. After obtaining baseline measurements during 3-minutes horizontal position, HUT was performed for 5 minutes, followed by continuation of recording for 3 more minutes in the horizontal position. During HUT, CBF decreased significantly and equally in both groups. MBP did not change during HUT in both groups. The endocrine responses were also not different between the two groups. The results suggest that damage to the supratentorial area in patients with acute CVD do not alter the CBF, cardiovascular and endocrine responses. In other words, HUT does not predispose patients with acute CVD to serious falls in MBP and CBF at upright posture. PMID- 24809000 TI - Examining the potential impacts of climate change on international security: EU Africa partnership on climate change. AB - ABSTRACT: Climate Change like many global problems nowadays is recognized as a threat to the international security and cooperation. In theoretical terms, it is being securitized and included in the traditional security studies. Climate change and its accompanying environmental degradation are perceived to be a threat that can have incalculable consequences on the international community. The consequences are said to have more effects in small island developing nations and Africa where many States are fragile and overwhelmed with mounting challenges. In recent years, the security implications of the climate change are being addressed from national, regional and multilateral level. Against this backdrop, this paper intends to contribute to the debate on climate change and international security and present a broader perspective on the discussion. The paper will draw from the EU-Africa partnership on climate change and is structured as follows: the first part introduces the background of the international climate change policy and its securitization, the second part covers the EU-Africa relations and EU-Africa partnership on climate change, and the third part discusses the Congo Basin Forest Partnership as a concrete example of EU-Africa Partnership on Climate Change. Lastly, the paper concludes by drawing some conclusions and offers some policy perspectives and recommendations. JEL CLASSIFICATION: Q54; 055; 052; 01; PMID- 24809001 TI - Improving osseointegration of Co-Cr by nanostructured titanium coatings. AB - This study reports the deposition of nanostructured Ti films on Co-Cr substrates to improve their surface characteristics and biocompatibility. The microstructure of the Ti films was controlled by application of negative substrate bias voltages. The surface roughness of Co-Cr implants was increased significantly after Ti coatings. The nanostructured Ti films are found to improve osteointergration of Co-Cr implants as indicated by enhancing cellular attachment, proliferation and differentiation, which was attributed mainly to the application of a biocompatible Ti coating, possessed a higher surface area for cell attachments and growth. PMID- 24809002 TI - Altered coronary artery calcium scores before bariatric surgery. AB - INTRODUCTION: Obesity is an important cause of cardiovascular disease, especially coronary artery disease. Severely obese patients are particularly prone to this risk. The coronary artery calcium (CAC) score is a strong predictor of coronary heart disease and provides incremental information beyond traditional risk factors. We sought to determine the prevalence of abnormally high CAC scores in the preoperative setting among patients undergoing bariatric surgery and to establish risk predictors for higher scores. METHODS: We performed an observational study of 202 patients free of known coronary artery disease who were referred for bariatric surgery. In each patient, the presence of CAC was detected with computed tomography, and coronary risk variables were either measured or determined via questionnaire. RESULTS: CAC was found in 14.4% of the overall population (26% of male and 10.5% of female patients). Participants with altered CAC scores were older (mean age, 46.8 years). The variables positively associated with an altered CAC score were older age, male sex, type 2 diabetes, hypertension, and hypercholesterolemia. Multivariate-adjusted analysis showed that age (OR, 1.11; 95% CI, 1.06-1.17; p = 0.001), male sex (OR, 4.17; 95% CI, 1.52-11.47; p = 0.006), and hypercholesterolemia (OR, 6.21; 95% CI, 1.81-21.29; p = 0.004) were most closely related to the presence of CAC. CONCLUSION: Obese patients in the preoperative bariatric surgery setting have a high prevalence of abnormal CAC scores. Traditional risk factors play a important role in this scenario. PMID- 24809003 TI - Identification of a Geranylgeranyl reductase gene for chlorophyll synthesis in rice. AB - Geranylgeranyl reductase (CHL P) catalyzes the reduction of geranylgeranyl diphosphate to phytyl diphosphate, and provides phytol for both Chlorophyll (Chl) and tocopherol synthesis. In this study, we isolated a yellow-green leaf mutant, 502ys, in rice (Oryza sativa). The mutant exhibited reduced level of Chls, arrested development of chloroplasts, and retarded growth rate. The phenotype of the 502ys mutant was controlled by by a recessive mutation in a nuclear gene on the long arm of rice chromosome 2. Map-based cloning of the mutant resulted in the identification of an OsChl P gene (LOC_Os02g51080). In the 502ys mutant, a single base pair mutation was detected at residue 1279 in DNA sequence of the gene, resulting in an amino acid change (Gly-206 to Ser) in the encoded protein. HPLC analysis of Chls indicated that the majority of Chl molecules are conjugated with an unsaturated geranylgeraniol side chain, in addition to small amount of normal Chls in the mutant. Furthermore, the mutant phenotype was complemented by transformation with the wild-type gene. Therefore, this study has confirmed the 502ys mutant resulted from a single base pair mutation in OsChl P gene. PMID- 24809004 TI - Minimal invasive management of traumatic transection of the vertebral artery. AB - Stab wounds to the neck can be potentially lethal. They are often associated with vascular injury of the carotid artery and jugular vein. Injury of the vertebral artery is rarely seen. The injury can vary from severe bleeding after transection with hemorrhage into the surrounding soft tissues of the neck to dissection and separation of the intimal lining from the subjacent media of an artery and subsequent occlusion of the vessel. We report a case of traumatic vertebral artery transection managed by minimal invasive balloon occlusion. PMID- 24809005 TI - Personal travel blogs as texts for studying intercultural interactions: a pilot test case study of an American sojourner's blogs from Zimbabwe. AB - This paper makes the argument that personal travel blogs are an important site for studying self-reports of face-to-face intercultural interaction. The guiding research question is "Are personal travel blogs good sources of intercultural communication data?" A content analysis of an American woman's travel blog, written on a sojourn to Zimbabwe, was performed using four intercultural communication constructs that served as frameworks for developing a rubric and for analysis. Those constructs are: culture shock, intercultural communication challenges, cross-cultural comparison and intercultural adaptation. Results provide evidence of written reflections by the blogger in all four coding categories. The evidence of culture shock provided in the blog was multifold, multifaceted, and congruent with many of the well-established elements of culture shock reported in the field. The evidence of cross-cultural comparison in the personal travel blog was, overwhelmingly, comprised of reflections comparing host and home cultures, both in environment and cultural practices. There was limited evidence of reflections about communication challenges or adaptation by the blogger on her sojourn. The article concludes with a discussion of the implications these findings have for the potential travel blogs might provide for analysis of intercultural communication as well as addressing the limitations of the study's findings. PMID- 24809006 TI - Evidence for simvastatin anti-inflammatory actions based on quantitative analyses of NETosis and other inflammation/oxidation markers. AB - Simvastatin (SMV) has been shown to exhibit promising anti-inflammatory properties alongside its classic cholesterol lowering action. We tested these emerging effects in a major thermal injury mouse model (3rd degree scald, ~20% TBSA) with previously documented, inflammation-mediated intestinal defects. Neutrophil extracellular traps (NETs) inflammation measurement methods were used alongside classic gut mucosa inflammation and leakiness measurements with exogenous melatonin treatment as a positive control. Our hypothesis is that simvastatin has protective therapeutic effects against early postburn gut mucosa inflammation and leakiness. To test this hypothesis, we compared untreated thermal injury (TI) adult male mice with TI littermates treated with simvastatin (0.2 mg/kg i.p., TI + SMV) immediately following burn injury and two hours before being sacrificed the day after; melatonin-treated (Mel) (1.86 mg/kg i.p., TI + Mel) mice were compared as a positive control. Mice were assessed for the following: (1) tissue oxidation and neutrophil infiltration in terminal ileum mucosa using classic carbonyl, Gr-1, and myeloperoxidase immunohistochemical or biochemical assays, (2) NETosis in terminal ileum and colon mucosa homogenates and peritoneal and fluid blood samples utilizing flow cytometric analyses of the surrogate NETosis biomarkers, picogreen and Gr-1, and (3) transepithelial gut leakiness as measured in terminal ileum and colon with FITC-dextran and transepithelial electrical resistance (TEER). Our results reveal that simvastatin and melatonin exhibit consistently comparable therapeutic protective effects against the following: (1) gut mucosa oxidative stress as revealed in the terminal ileum by markers of protein carbonylation as well as myeloperoxidase (MPO) and Gr-1 infiltration, (2) NETosis as revealed in the gut milieu, peritoneal lavage and plasma utilizing picogreen and Gr-1 flow cytometry and microscopy, and (3) transepithelial gut leakiness as assessed in the ileum and colon by FITC-dextran leakiness and TEER. Thus, simvastatin exhibits strong acute anti-inflammatory actions associated with marked decreases in gut tissue and systemic NETosis and decreased gut mucosa leakiness. PMID- 24809007 TI - Systemic cytokine response to three bouts of eccentric exercise. AB - This research examined the changes in inflammatory cytokines interleukin 6 (IL 6), IL-1beta, IL-10, as well as muscle force, muscle soreness, thigh circumference, and range of motion in response to 3 bouts of eccentric knee extension. Ten males were recruited to participate. The participants performed eccentric exercise on 3 consecutive days on the knee extensors on the right leg separated by 24??h. Participants performed 6 sets of 10 repetitions of isokinetic eccentric knee extension at 120 degrees per second. Blood was sampled before and after each exercise bout and 24?h after the final exercise bout. Muscle isometric force, delayed onset muscle soreness (DOMS), thigh circumference, and range of motion were evaluated before and after each exercise bout and 24?h after the final exercise bout. There were no statistically significant differences noted for the changes in isometric strength, thigh circumference, and range of motion, or IL-6 over the 4 days (all p > 0.05). On the second day and third day there was a significant increase noted in DOMS as compared with baseline (p < 0.05). These results suggest that 3 consecutive days of eccentric exercise results in DOMS but does not produce a sustained systemic inflammatory reaction or changes in muscle function. PMID- 24809008 TI - Invasive extramammary Paget's disease of the bladder diagnosed 18 years after noninvasive extramammary Paget's disease of the vulva. PMID- 24809009 TI - Occult tubal carcinoma found at risk reducing salpingectomy in a BRCA1 carrier. AB - *This is the first report of occult cancer diagnosed at risk-reducing salpingectomy.*We propose a two-step risk-reducing strategy for premenopausal high-risk women, to begin and expedite surgical prevention. PMID- 24809011 TI - Rare diseases and expensive drugs. PMID- 24809010 TI - Hematologic improvements in a myelodysplastic syndromes with myelofibrosis (MDS F) patient treated with azacitidine. AB - Myelodysplastic syndromes with myelofibrosis (MDS-F) is a poor prognostic hematopoietic disorder. Azacitidine was shown to prolong survival of high-risk MDS patients. However, the effects of azacitidine on MDS-F have yet to be elucidated. Azacitidine was administered to a 74-year-old man with MDS-F at a dose of 75 mg/m(2)/daily subcutaneously for 7 days every 28 days. Hematologic improvements were observed according to the International Working Group 2006 criteria after 8 cycles of the azacitidine treatment, and complete remission was achieved after 14 cycles. The grade of myelofibrosis was also improved. The therapeutic activity of azacitidine was confirmed in our MDS-F patient. PMID- 24809012 TI - Epidemiology of adult asthma in Asia: toward a better understanding. AB - Asia is the world's most dynamic area. Asthma is a major chronic disease in Asia, like other continents. However, unlike childhood asthma, the epidemiological burden of asthma in Asian adults has been unclear. Here we reviewed the currently available literatures on the epidemiology of adult asthma in the Asian community populations. Adult asthma prevalence was generally lower in Asian than in Europe, but the increasing trends suggested the disease burden to rise in the near future. However, for better understanding, it may be essential to prepare for the Asian multinational network for the standardization and collaboration of research. PMID- 24809013 TI - Pholcodine consumption and immunoglobulin E-sensitization in atopics from Australia, Korea, and Japan. AB - BACKGROUND: Accumulating data indicates that pholcodine (PHO)-consuming countries have higher sero-prevalences of immunoglobulin E (IgE)-antibodies to PHO and suxamethonium (SUX) and increased frequencies of IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBAs) than nonconsuming. Withdrawing PHO containing cough syrups resulted in a significant decrease of cases with anaphylaxis in Scandinavia. Nevertheless, the European Medicines Agency in 2011 advised to continue the unrestricted use throughout the European Union. OBJECTIVE: To extend studies on PHO consumption and prevalence of IgE sensitization to morphine (MOR), PHO, and SUX to countries representing high (Australia), and low (Korea and Japan), consumers, respectively. METHODS: IgE antibodies to SUX, MOR, and PHO in atopic subjects were determined by immunoassay and compared with official figures for PHO consumption and reported anaphylaxis to NMBA. RESULTS: The prevalences of IgE-antibodies to PHO, MOR, and SUX were 10%, 8.6%, and 4.3%, respectively, in Australia. The corresponding figures for Japan were 0.8%, 0.8%, and 1.5%, and for Korea 1.0% to PHO and 0.5% to MOR and SUX. Of the SUX-positive sera, 100% were positive to PHO or MOR in Australia and 0% in Japan and Korea. CONCLUSION: The study supports previous findings; exposure to PHO may induce IgE-antibodies to the substituted ammonium ion epitope of NMBAs, thus increasing risk of NMBA-induced anaphylaxis considerably. However, other, still unknown factors occasionally might induce IgE-antibodies to SUX. PMID- 24809014 TI - Association of airborne Aspergillus with asthma exacerbation in Southern Pakistan. AB - BACKGROUND: Exposure to airborne fungi has been related with exacerbation of asthma in adults and children leading to increased outpatient, emergency room visits, and hospitalizations. Hypersensitivity to these airborne fungi may be an important initial predisposing factor in the development and exacerbation of asthma. OBJECTIVE: This study was conducted to determine an association between fungal types and spore concentrations with the risk of asthma exacerbation in adults. METHODS: This cross-sectional study was conducted from May 2008 to August 2009 at the Aga Khan University Hospital Karachi, Pakistan. All adult (age>=16 years) patients presenting to the hospital with acute asthma exacerbation were enrolled after informed consent. A home survey was conducted for each patient to assess their environmental characteristics. Indoor air samples were also obtained from the patient's home to determine the type and spore concentration of fungi within the week of their enrollment in the study. RESULTS: Three hundred and ninety-one patients with an acute asthma exacerbation were enrolled during the study period. The mean age of participants was 46 years (standard deviation, +/ 18 years) and 247 (63.2%) were females. A trend of higher asthma enrollment associated with higher Aspergillus concentrations was found in two consecutive summers. A total of nineteen types of fungi were found in air samples. Aspergillus spp. was the most frequently isolated fungus with acute asthma exacerbation. CONCLUSION: An association of higher concentration of indoor Aspergillus spp. with asthma exacerbation in adults was observed in this study. PMID- 24809015 TI - Association of insulin resistance with bronchial hyperreactivity. AB - BACKGROUND: Several epidemiologic studies showed the significant association of insulin resistance with asthma. OBJECTIVE: The aim of this study was to evaluate the association of insulin resistance with airway hyperresponsiveness (AHR) in adult population. METHODS: 1,058 subjects who visited to the Seoul National University Hospital Gangnam Center from October 2007 to January 2009 for a routine health check-up were enrolled. All subjects completed a questionnaire, anthropometric measurements such as body mass index (BMI) and waist circumference, blood tests, pulmonary function test, and methacholine bronchial provocation test (MBPT). Insulin resistance was estimated from the homeostasis model of assessment of insulin resistance (HOMA-IR). RESULTS: Thirty-three subjects (3.1%) had AHR based on MBPT. The subjects with AHR had higher BMI, waist circumference, and HOMA-IR than those without AHR (p < 0.001, p = 0.003, and p = 0.002, respectively). In case of men, fasting insulin level and HOMA-IR had significant correlation with forced expiratory volume in 1 second (%) (r = 0.1440, p = 0.011, and r = -0.1156, p = 0.042, respectively). Fasting insulin level and HOMA-IR were higher in men with AHR than in those without (p = 0.046 and p = 0.040, respectively). In binary logistic regression analysis after adjustment for age, HOMA-IR was the significant risk factor for AHR in men (HOMA IR: odds ratio [OR], 3.21; 95% confidence interval [CI], 1.00-10.30). In case of women, fasting insulin, glucose level, or insulin resistance had no significant correlation with lung function. BMI, waist circumference, and HOMA-IR were significantly higher in women with AHR than in those without (p = 0.001, p = 0.011, and p = 0.010, respectively). In binary logistic regression analysis after adjustment for age, BMI and HOMA-IR were the significant risk factors for AHR in women (BMI: OR, 2.20; 95% CI, 1.23-3.82; insulin resistance: OR, 1.05; 95% CI, 1.00-1.09). CONCLUSION: Insulin resistance was significantly associated with bronchial hyperreactivity, which is the most characteristic feature of asthma. PMID- 24809016 TI - Penicillin allergy evaluation: experience from a drug allergy clinic in an Arabian Gulf Country, Kuwait. AB - BACKGROUND: Hypersensitivity to penicillin has been studied worldwide, but data regarding patterns of sensitization in Arabian Gulf countries are scarce. OBJECTIVE: To describe the patterns of penicillin hypersensitivity during a 6 year study in Kuwait in terms of demographics, type of the culprit drug, in vivo and in vitro allergy testing. METHODS: One hundred and twenty-four patients referred to the drug allergy clinic for penicillin allergy were fully evaluated by skin prick and intradermal testing. Drug provocation test was done on patients with negative results. RESULTS: A total of 124 patients were evaluated for penicillin allergy. Mean age was 37.8 (standard deviation, 12.7) years, range from 8 to 74 years. Thirty-nine male (31.5%) and 85 female patients (68.5%) were included. Diagnosis of penicillin allergy was confirmed in 46 patients (37.1%). Among the 44 confirmed allergic patients by skin evaluation we had 15 (34.1%) positive skin prick test, and 29 (65.9%) positive intradermal testing. Among patients with positive skin testing, 47.7% were positive to major determinant benzylpenicilloyl poly-L-lysine, 20.4% to minor determinant mixture, 50.0% to penicillin G and 40.9% to ampicillin; 13.6% of patients were positive to amoxicillin by skin prick test. One patient had a positive radioallergosorbent test and one had a positive challenge test. CONCLUSION: Penicillin allergy is a common problem with an incidence of about one third in our study subjects. PMID- 24809017 TI - Efficacy of the Precise Climate Controller on the reduction of indoor microorganisms. AB - BACKGROUND: Nowadays, there are many methods to reduce microorganisms in the air, such as dehumidifier, air purifier or humidity and temperature controller. The Precise Climate Controller is an instrument for controlling humidity and temperature, a concept that is demonstrated. OBJECTIVE: To determine the efficacy of this device, in order to reduce the quantity of the fungi and bacteria in the closed system. METHODS: This study is a perspective experimental study and is conducted as follows - the air sample in the closed system, a 42-cubic-meter room, is collected before the installation of the Precise Climate Controller. Next, the room is fumed with Aspergillus flavus and closed for 2 days. Then the instrument is in use in order to keep the relative humidity (RH) and the temperature constant at 55% RH and 25 degrees Celsius (C). The air samples are collected every 3 days for 5 times during the period of 15 days to identify the type and calculate the quantity of the microorganisms. RESULTS: Before the Precise Climate Controller has been installed. Three species of bacteria are found in the air samples, but none of the fungus exists in the testing room. Once the room has been fumed with a large amount of A. flavus and the instrument is in use for 3 days, nine colonies of A. flavus are identified, but later on when the instrument is in use for 6, 9, 12, and 15 days, the air samples contain neither fungus nor bacteria. CONCLUSION: After keeping the RH and temperature of the closed system constant at 55% RH and 25C by using the Precise Climate Controller, it is found that the efficaciousness in controlling the quantity and species of fungi and bacteria is clinically significant. PMID- 24809018 TI - Radiocontrast media hypersensitivity in the Asia Pacific region. AB - Radiocontrast media (RCM) is a major cause of drug hypersensitivity reactions as the medical application of RCM is increasing recently. RCM induced hypersensitivity reactions are considered as unpredictable type B reactions. Underlying mechanism of RCM induced hypersensitivity was previously regarded as nonimmunological mechanisms but recent studies suggest that immunological mechanisms could also be involved. As a result, the roles of skin tests and premedication are revisiting. As there has been no report that comprehensively summarized and analyzed the results of the studies on RCM hypersensitivity in the Asia Pacific region, we aimed to review the literatures on hypersensitivity reactions to RCM in terms of prevalence clinical manifestations, diagnostic approach, and preventive measures in the Asia Pacific region. PMID- 24809019 TI - Successful prevention of recurrent anaphylactic events with anti-immunoglobulin E therapy. AB - Anaphylaxis is a fatal and systemic allergic reaction, which can be prevented by avoiding exposure to a causative agent. However, the causative agent cannot be identified in all cases and may be hardly avoided. A 41-year-old man, diagnosed with idiopathic anaphylaxis, experienced 6 anaphylactic events over 7 months, requiring 4 emergency department (ER) visits and 3 epinephrine self-injections. Anti-immunoglobulin E (IgE) therapy was introduced to prevent further anaphylactic events. He experienced no anaphylactic events during 13 months of 4 monthly injections from the beginning until his most recent ER visit because of a similar anaphylactic event. We report a patient who experienced recurrent anaphylactic events that were prevented effectively by anti-IgE therapy with omalizumab. Anti-IgE therapy might be considered as an option to prevent anaphylactic events in patients for whom the causative agent(s) cannot be identified or avoided. PMID- 24809020 TI - Omalizumab in recurring larynx angioedema: a case report. AB - Angioedema with swelling of larynx is a serious allergic reaction and can be life threatening. It can occur after exposure to various triggers and usually it is very difficult for the patient and the doctor to find the trigger and maintain complete remission. In idiopathic recurring angioedema presenting with frequent attacks, prophylaxis with H1 antihistamines recommended. However, not all patients respond to antihistamines. Omalizumab is an anti-immunoglobulin (Ig)-E Ig-G antibody approved for the treatment of asthma and also effective treatment in chronic spontaneous urticaria. We report a 47-year-old male patient with severe idiopathic angioedema controlled by corticosteroid and proggressed after discontining of corticosteroid because of its side effects. Omalizumab at a dose of 300 mg every 4 weeks was administrated and omalizumab provided a rapid clinical response after first injection. During the 4 months of omalizumab therapy, he had no further attacks and any other treatment needs. After 3 months of stopping omalizumab therapy, during the 4-week period he had two mild lip swelling in his lips that resolved with antihistamines. PMID- 24809021 TI - Unveiling YKL-40, from Serum Marker to Target Therapy in Glioblastoma. AB - Glioblastoma is the most common primary brain tumor in the adult and carries a poor prognosis with a median survival of only 14 months. Patients with glioblastoma are followed with MRI scans, but this technique has several limitations including low specificity to differentiate between tumor and treatment effect. Development of serum markers could significantly improve the care of glioblastoma patients. We review the current concept of developing YKL-40 as one of the most promising serum markers for glioblastoma, the recent advances on understanding the role of YKL-40 in gliomagenesis, and the promising evidence emerging from preclinical models on using this protein as a target for anti glioma therapy. PMID- 24809024 TI - Ribonucleotide reductases: essential enzymes for bacterial life. AB - Ribonucleotide reductase (RNR) is a key enzyme that mediates the synthesis of deoxyribonucleotides, the DNA precursors, for DNA synthesis in every living cell. This enzyme converts ribonucleotides to deoxyribonucleotides, the building blocks for DNA replication, and repair. Clearly, RNR enzymes have contributed to the appearance of genetic material that exists today, being essential for the evolution of all organisms on Earth. The strict control of RNR activity and dNTP pool sizes is important, as pool imbalances increase mutation rates, replication anomalies, and genome instability. Thus, RNR activity should be finely regulated allosterically and at the transcriptional level. In this review we examine the distribution, the evolution, and the genetic regulation of bacterial RNRs. Moreover, this enzyme can be considered an ideal target for anti-proliferative compounds designed to inhibit cell replication in eukaryotic cells (cancer cells), parasites, viruses, and bacteria. PMID- 24809023 TI - The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons. AB - Interferons (IFNs) are secreted proteins of the cytokine family that regulate innate and adaptive immune responses to infection. Although the importance of IFNs in the antiviral response has long been appreciated, their role in bacterial infections is more complex and is currently a major focus of investigation. This review summarizes our current knowledge of the role of these cytokines in host defense against the bacterial pathogen Listeria monocytogenes and highlights recent discoveries on the molecular mechanisms evolved by this intracellular bacterium to subvert IFN responses. PMID- 24809025 TI - Low occurrence of Pseudomonas aeruginosa in agricultural soils with and without organic amendment. AB - The occurrence of Pseudomonas aeruginosa was monitored at a broad spatial scale in French agricultural soils, from various soil types and under various land uses to evaluate the ability of soil to be a natural habitat for that species. To appreciate the impact of agricultural practices on the potential dispersion of P. aeruginosa, we further investigated the impact of organic amendment at experimental sites in France and Burkina Faso. A real-time quantitative PCR (qPCR) approach was used to analyze a set of 380 samples selected within the French RMQS ("Reseau de Mesures de la Qualite des Sols") soil library. In parallel, a culture-dependent approach was tested on a subset of samples. The results showed that P. aeruginosa was very rarely detected suggesting a sporadic presence of this bacterium in soils from France and Burkina Faso, whatever the structural and physico-chemical characteristics or climate. When we analyzed the impact of organic amendment on the prevalence of P. aeruginosa, we found that even if it was detectable in various manures (at levels from 10(3) to 10(5) CFU or DNA targets (g drywt)(-1) of sample), it was hardly ever detected in the corresponding soils, which raises questions about its survival. The only case reports were from a vineyard soil amended with a compost of mushroom manure in Burgundy, and a few samples from two fields amended with raw urban wastes in the sub-urban area of Ouagadougou, Burkina Faso. In these soils the levels of culturable cells were below 10 CFU (g drywt)(-1). PMID- 24809022 TI - How Listeria monocytogenes organizes its surface for virulence. AB - Listeria monocytogenes is a Gram-positive pathogen responsible for the manifestation of human listeriosis, an opportunistic foodborne disease with an associated high mortality rate. The key to the pathogenesis of listeriosis is the capacity of this bacterium to trigger its internalization by non-phagocytic cells and to survive and even replicate within phagocytes. The arsenal of virulence proteins deployed by L. monocytogenes to successfully promote the invasion and infection of host cells has been progressively unveiled over the past decades. A large majority of them is located at the cell envelope, which provides an interface for the establishment of close interactions between these bacterial factors and their host targets. Along the multistep pathways carrying these virulence proteins from the inner side of the cytoplasmic membrane to their cell envelope destination, a multiplicity of auxiliary proteins must act on the immature polypeptides to ensure that they not only maturate into fully functional effectors but also are placed or guided to their correct position in the bacterial surface. As the major scaffold for surface proteins, the cell wall and its metabolism are critical elements in listerial virulence. Conversely, the crucial physical support and protection provided by this structure make it an ideal target for the host immune system. Therefore, mechanisms involving fine modifications of cell envelope components are activated by L. monocytogenes to render it less recognizable by the innate immunity sensors or more resistant to the activity of antimicrobial effectors. This review provides a state-of-the-art compilation of the mechanisms used by L. monocytogenes to organize its surface for virulence, with special focus on those proteins that work "behind the frontline", either supporting virulence effectors or ensuring the survival of the bacterium within its host. PMID- 24809026 TI - Social behavior and decision making in bacterial conjugation. AB - Bacteria frequently acquire novel genes by horizontal gene transfer (HGT). HGT through the process of bacterial conjugation is highly efficient and depends on the presence of conjugative plasmids (CPs) or integrated conjugative elements (ICEs) that provide the necessary genes for DNA transmission. This review focuses on recent advancements in our understanding of ssDNA transfer systems and regulatory networks ensuring timely and spatially controlled DNA transfer (tra) gene expression. As will become obvious by comparing different systems, by default, tra genes are shut off in cells in which conjugative elements are present. Only when conditions are optimal, donor cells-through epigenetic alleviation of negatively acting roadblocks and direct stimulation of DNA transfer genes-become transfer competent. These transfer competent cells have developmentally transformed into specialized cells capable of secreting ssDNA via a T4S (type IV secretion) complex directly into recipient cells. Intriguingly, even under optimal conditions, only a fraction of the population undergoes this transition, a finding that indicates specialization and cooperative, social behavior. Thereby, at the population level, the metabolic burden and other negative consequences of tra gene expression are greatly reduced without compromising the ability to horizontally transfer genes to novel bacterial hosts. This undoubtedly intelligent strategy may explain why conjugative elements-CPs and ICEs-have been successfully kept in and evolved with bacteria to constitute a major driving force of bacterial evolution. PMID- 24809027 TI - Immunologic changes in frail older adults. AB - Several studies have shown a heightened inflammatory state in frail older adults, marked by high serum levels of interleukin-6 and C-reactive protein and an increased number of circulating leukocytes. Activation of monocytes and macrophages, marked by increased levels of neopterin, may contribute to chronic inflammation in the frail older adult. However, the reduced mononuclear cell response to lipopolysaccharide in vitro suggests the existence of defective activation pathways within the innate immune system possibly due to desensitization. Conversely, the expansion of CD8(+) T cells, and specifically those expressing the CCR5 chemokine receptor, above and beyond the levels observed in senescence, points to the involvement of adaptive immune pathways. In line with these observations, frail older adults exhibit a reduced antibody response to pneumococcal and influenza vaccines. Collectively, these observations support the existence of a dysregulated immune system in frail older adults and highlight the need for strategies to improve its function. ABBREVIATIONS: AIDS, acquired immunodeficiency syndrome; CCL, CC-chemokine receptor ligand; CCR, CC chemokine receptor; CHS, Cardiovascular Health Study; CMV, cytomegalovirus; GTP, guanosine trisphosphate; HAART, highly active anti-retroviral therapy; HIV, human immunodeficiency virus; IDO, indoleamine-pyrrole 2,3-dioxygenase; IL, interleukin; IFN, interferon; MACS, Multicenter AIDS Cohort Study; NH2PPP, dihydro-neopterin trisphosphate; Tc, T cytotoxic; TCR, T-cell receptor; TEMRA, T effector memory cells re-expressing CD45RA; Th, T helper; TNF, tumor necrosis factor; WHAS, Women's Health and Aging Study. PMID- 24809029 TI - Genomics DNA profiling in elite professional soccer players: a pilot study. AB - Functional variants in exonic regions have been associated with development of cardiovascular disease, diabetes and cancer. Athletic performance can be considered a multi-factorial complex phenotype. Genomic DNA was extracted from buccal swabs of seven soccer players from the Fulham football team. Single nucleotide polymorphism (SNPs) genotyping was undertaken. To achieve optimal athletic performance, predictive genomics DNA profiling for sports performance can be used to aid in sport selection and elaboration of personalized training and nutrition programs. Predictive DNA profiling may be able to detect athletes with potential or frank injuries, or screening and selection of future athletes, and can help them to maximize utilization of their potential and improve performance in sports. The aim of this study is to provide a wide scenario of specific genomic variants that an athlete carries, to implement which measures should be taken to maximize the athlete's potential. PMID- 24809028 TI - Redesigning service delivery for hypertensive patients: a methodological guideline to improve the management of chronic diseases. AB - Best care is not necessarily the most expensive, but the most appropriate, and prevention is the most powerful tool to promote health. A novel approach might envision the reduction of hospital admittance (thus meeting a requirement from long term condition patients: they would rather not being hospitalized!) and the enforcement of peripheral (both on the territory and at home) assistance. In this direction, experiences of reshaping new service deliveries towards an integrated disease management, namely clinical pathways, can be observed in Europe and in different parts of the world. Aim of this paper is to provide a methodological guideline to support the management in planning clinical pathways, also outlining the main barriers limiting the process. In particular, we present the results of planning a clinical pathway at the Centre for Hypertension of the Federico II University Hospital (Naples, Italy). The case study showed that the introduction of a similar service impacts on the organisation of the structure. An analysis of organizational processes "as are" and the re-design of processes "to be" are necessary to integrate the clinical pathway into the actual activities. PMID- 24809030 TI - A low cost amplifier and acquisition system for cortical-electroncephalography in non-human applications. AB - A simple circuit is described to make an AC-amplifier and an analog-to-digital converter in a single, compact solution, for use in basic research, but not on humans. The circuit sends data to and is powered from a common USB port of modern computers; using proper firmware and driver the communication with the device is an emulated RS232 serial port. PMID- 24809031 TI - Infraspinatus strength assessment and ultrasound evaluation of posterior capsulotenodesis after arthroscopic hill-sachs remplissage in traumatic anterior glenohumeral instability: a retrospective controlled study protocol. AB - PRINCIPAL INVESTIGATOR AND PROMOTER: Giovanni Merolla Co-investigator: Giuseppe Porcellini Investigation performed at the Biomechanics Laboratory "Marco Simoncelli", D. Cervesi Hospital, Cattolica - Italy PLAN OF CLINICAL INVESTIGATION (PCI): Version 1.0 of June 12, 2012 Approved by AV/IRST Ethical Committee (Comitato Etico Area Vasta Romagna) and authorized by AUSL RN ("Determina AUSL Rimini numero 326 del 29/03/2013: Remplissage U.O Chirurgia della Spalla - Valutazione clinica ed ultrasonografica dell'infraspinato dopo capsulo-tenodesi artroscopica (remplissage) nell'instabilita anteriore traumatica di spalla con lesione di Bankart e difetto omerale di Hill-Sachs"). PMID- 24809032 TI - Functional assesment of symptomatic snapping scapula after scapulothoracic arthroscopy: a prospective study protocol. AB - PRINCIPAL INVESTIGATOR AND PROMOTER: Giovanni Merolla Co-investigator: Giuseppe Porcellini Investigation performed at Biomechanics Laboratory "Marco Simoncelli", D. Cervesi Hospital, Cattolica - Italy PLAN OF CLINICAL INVESTIGATION (PCI): Version 1.0 of December 10, 2012 Approved by AV/IRST Ethical Committee (Comitato Etico Area Vasta Romagna) Reg. Sperimentazioni 914 Prot. N degrees : 1785/2013/I.5/46. PMID- 24809033 TI - Management of atrial fibrillation in patients undergoing percutaneous coronary intervention. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia, occurring in 1-2% of overall population, involving more than 6 millions of European people. It is associated to a reduced quality of life and an increased morbidity and mortality. The Framingham study showed the link between angina and AF. The same risk factors, such as hypertension, diabetes and obesity promote both AF and coronary artery disease (CAD). About 1/4 of AF patients develop a CAD and, in this setting, about 1/5 undergoes a percutaneous coronary intervention (PCI). In patients with both AF and CAD, the optimal medical strategy is challenging and it is still debated in cardiological community, since patients treated by dual (two antiplatelets drugs ore one antiplatelets drug and an oral anticoagulant drug) or triple therapy (two antiplatelets drugs and an oral anticoagulant drug) are exposed to divergent risk of bleeding or thromboembolic and ischemic complications. Aim of this paper is to focus the attention on the different problems arising from the presence of AF in patients undergoing PCI, such as the risk of stroke, bleeding and stent thrombosis. PMID- 24809034 TI - Combined administration of oxycodone/naloxone in chronic osteo-articular diseases pain therapy. AB - The aim of this study is the analysis of the beneficial impact of using opioid receptor antagonist associated to opioid analgesic on the quality of life in patients suffering from chronic non-cancer pain. We recruited 60 patients suffering from osteo-articular diseases who were randomized into two groups of treatment. The group A was treated with the association of opioid receptor antagonist and opioid agonist, represented by Oxycodone. The group B was treated with the opioid analgesics Oxycodone, transdermal Fentanil, and Hidromorphone, without the opioid antagonist. The end-points assessed were the duration of titration, the average reached dosage, the duration of the stability of dosage and the opioid-induced constipation (OIC) using the BFI. PMID- 24809035 TI - Pre-participation musculoskeletal and cardiac screening of male athletes in the United arab emirates. AB - This study presents the results of pre-participation musculoskeletal and cardiac screening using the Lausanne recommendations, which include a personal and family history, physical examination and electrocardiography. Cross sectional study using the Lausanne screenings and the European Society of Cardiology (ESC) recommendations carried out at Al-Ahli club in Dubai, United Arab Emirates. 230 male athletes participating in organised sports were included. Exclusion criteria were those under 14 or over 35 years old, females and athletes with established cardiovascular disease. Primary outcome are the results of Lausanne screening with outline of the negative, positive and false positive results and number needed to screen. Secondary outcomes include the results of musculoskeletal and neurological screening. A total of 174 (76%) athletes had a negative screening result. Fifty-four athletes (23%) underwent additional testing. Forty-seven athletes (20.4%) had false positive screening results. Seven athletes (3%) had a positive screening result and four athletes (2%) were restricted from sport. The number of athletes needed to screen to detect one lethal cardiovascular condition was 33 athletes. The Lausanne recommendations are well suited for the United Arab Emirates. The number needed to screen to detect one athlete with serious cardiovascular disease is acceptable at 33. PMID- 24809036 TI - Hydrocephalus onset after microsurgical or endovascular treatment for acute subarachnoid hemorrhage. Retrospective italian multicenter study. AB - BACKGROUND: Chronic shunt-dependent hydrocephalus is a complication of aneurysmal subarachnoid hemorrhage (aSAH). Its incidence and risk factors have been described while the hydrocephalus onset in terms of days after treatment (microsurgical or endovascular) has not been yet analyzed. MATERIALS AND METHODS: 45 patients, treated for aSAH in 4 Italian Neurosurgical Departments, were retrospectively analyzed. It was calculated the time that elapses between treatment and hydrocephalus onset in 36 patients. RESULTS: Of the 45 shunted patients, 15 (33.3%) were included in the microsurgical group (group A) and 30 (66.6%) were in the endovascular one (group B). There was no difference of the hydrocephalus onset between the two groups (24,1 days, group A vs. 27,7 days, group B). The presence of intracerebral hematoma (ICH) caused a delay in the hydrocephalus onset after endovascular treatment in terms of 11,5 days compared to microsurgical group as well the absence of vasospasm determined a delay of 13,7 days (not statistically significant). CONCLUSION: No difference in terms of hydrocephalus onset after microsurgical or endovascular treatment has been demonstrated. Only the presence of ICH or the absence of vasospasm can cause a slight delay in the time of hydrocephalus onset in the endovascular series (not statistically significant). Long-term follow-up studies involving higher numbers of subjects are needed to better demonstrate this issue. PMID- 24809038 TI - Reverse Shoulder Arthroplasty in Patients Aged Sixty Years Old or Younger: Are we Really Doing the Best? PMID- 24809037 TI - Complementary therapy in polycystic ovary syndrome. AB - Polycystic Ovary Syndrome (PCOS) is an endocrine disease. PCOS afflicts 5 to 10 % of women of reproductive age. The symptoms are: amenorrhea, oligomenorrhea, hirsutism, obesity, infertility, chronic hyperandrogenic anovulation and acne. OTHER RISK FACTORS AGGRAVATE THIS CONDITION: insulin resistance, obesity, hypertension, dyslipidemia, inflammation and subclinical cardiovascular disease. Anxiety, depression and reduced quality of life are also common. This review highlights the mechanisms and the beneficial effects of acupuncture, exercise and resveratrol on animal models and on humans affected by PCOS. PMID- 24809039 TI - Intrarenal artery pseudoaneurysm after blunt abdominal trauma: a case report of successful superselective angioembolization. AB - Renal artery pseudoaneurysm is a very rare complication after blunt trauma injury. We report on a case of a 54-year-old man admitted to our hospital for right flank pain and gross hematuria, 5 days after blunt abdominal trauma. The diagnosis of interlobar renal pseudoaneurysm was established by a computed tomography scan and confirmed by angiography. Successful superselective angioembolization was performed. This radiographic intervention is an effective and minimally invasive technique to stop active bleeding from renal artery pseudoaneurysms, when patients are hemodynamically stable and where technically feasible. A review of the literature was carried out. PMID- 24809040 TI - New Insights into Congenital Diaphragmatic Hernia - A Surgeon's Introduction to CDH Animal Models. AB - In recent decades, new research into the developmental defects and pathophysiological basis of congenital diaphragmatic hernia (CDH) has revealed opportunities for the development of innovative therapies. Importantly, the use of animal models to represent this anomaly in the laboratory has resulted in the discovery of many important genetic, epigenetic, and other molecular contributors to this condition. In this review, the most commonly used and newly devised animal models of CDH are presented to familiarize the reader with the latest innovations in the basic sciences. PMID- 24809041 TI - Psychiatric advance directives, a possible way to overcome coercion and promote empowerment. AB - Psychiatric advance directives (ADs) allow an individual to state their preferences for future treatment at times when they may be unable to make considered decisions. There are differences in their form and legal value and the process associated with their use and completion. Several studies have now been completed to assess the impact of ADs on service use and coercion. Their results give a mixed picture but directives nevertheless have the potential to support the empowerment process, minimize experienced coercion, and improve coping strategies. These may in turn reduce the frequency of in-patient service use. Further studies on the different processes of facilitation involved and on different populations are necessary to improve our knowledge and use of these potentially powerful interventions. PMID- 24809042 TI - Diffusion and molecular interactions in a methanol/polyimide system probed by coupling time-resolved FTIR spectroscopy with gravimetric measurements. AB - In this contribution the diffusion of methanol in a commercial polyimide (PMDA ODA) is studied by coupling gravimetric measurements with in-situ, time-resolved FTIR spectroscopy. The spectroscopic data have been treated with two complementary techniques, i.e., difference spectroscopy (DS) and least-squares curve fitting (LSCF). These approaches provided information about the overall diffusivity, the nature of the molecular interactions among the system components and the dynamics of the various molecular species. Additional spectroscopic measurements on thin film samples (about 2 MUm) allowed us to identify the interaction site on the polymer backbone and to propose likely structures for the H-bonding aggregates. Molar absorptivity values from a previous literature report allowed us to estimate the population of first-shell and second-shell layers of methanol in the polymer matrix. In terms of diffusion kinetics, the gravimetric and spectroscopic estimates of the diffusion coefficients were found to be in good agreement with each other and with previous literature reports. A Fickian behavior was observed throughout, with diffusivity values markedly affected by the total concentration of sorbed methanol. PMID- 24809044 TI - Transient dynamic mechanical properties of resilin-based elastomeric hydrogels. AB - The outstanding high-frequency properties of emerging resilin-like polypeptides (RLPs) have motivated their development for vocal fold tissue regeneration and other applications. Recombinant RLP hydrogels show efficient gelation, tunable mechanical properties, and display excellent extensibility, but little has been reported about their transient mechanical properties. In this manuscript, we describe the transient mechanical behavior of new RLP hydrogels investigated via both sinusoidal oscillatory shear deformation and uniaxial tensile testing. Oscillatory stress relaxation and creep experiments confirm that RLP-based hydrogels display significantly reduced stress relaxation and improved strain recovery compared to PEG-based control hydrogels. Uniaxial tensile testing confirms the negligible hysteresis, reversible elasticity and superior resilience (up to 98%) of hydrated RLP hydrogels, with Young's modulus values that compare favorably with those previously reported for resilin and that mimic the tensile properties of the vocal fold ligament at low strain (<15%). These studies expand our understanding of the properties of these RLP materials under a variety of conditions, and confirm the unique applicability, for mechanically demanding tissue engineering applications, of a range of RLP hydrogels. PMID- 24809046 TI - Microarray Analysis of the Juvenile Hormone Response in Larval Integument of the Silkworm, Bombyx mori. AB - Juvenile hormone (JH) coordinates with 20-hydroxyecdysone (20E) to regulate larval growth and molting in insects. However, little is known about how this cooperative control is achieved during larval stages. Here, we induced silkworm superlarvae by applying the JH analogue (JHA) methoprene and used a microarray approach to survey the mRNA expression changes in response to JHA in the silkworm integument. We found that JHA application significantly increased the expression levels of most genes involved in basic metabolic processes and protein processing and decreased the expression of genes associated with oxidative phosphorylation in the integument. Several key genes involved in the pathways of insulin/insulin like growth factor signaling (IIS) and 20E signaling were also upregulated after JHA application. Taken together, we suggest that JH may mediate the nutrient dependent IIS pathway by regulating various metabolic pathways and further modulate 20E signaling. PMID- 24809043 TI - Applications of density functional theory to iron-containing molecules of bioinorganic interest. AB - The past decades have seen an explosive growth in the application of density functional theory (DFT) methods to molecular systems that are of interest in a variety of scientific fields. Owing to its balanced accuracy and efficiency, DFT plays particularly useful roles in the theoretical investigation of large molecules. Even for biological molecules such as proteins, DFT finds application in the form of, e.g., hybrid quantum mechanics and molecular mechanics (QM/MM), in which DFT may be used as a QM method to describe a higher prioritized region in the system, while a MM force field may be used to describe remaining atoms. Iron-containing molecules are particularly important targets of DFT calculations. From the viewpoint of chemistry, this is mainly because iron is abundant on earth, iron plays powerful (and often enigmatic) roles in enzyme catalysis, and iron thus has the great potential for biomimetic catalysis of chemically difficult transformations. In this paper, we present a brief overview of several recent applications of DFT to iron-containing non-heme synthetic complexes, heme type cytochrome P450 enzymes, and non-heme iron enzymes, all of which are of particular interest in the field of bioinorganic chemistry. Emphasis will be placed on our own work. PMID- 24809047 TI - Combining Haar Wavelet and Karhunen Loeve Transforms for medical images watermarking. AB - This paper presents a novel watermarking method, applied to the medical imaging domain, used to embed the patient's data into the corresponding image or set of images used for the diagnosis. The main objective behind the proposed technique is to perform the watermarking of the medical images in such a way that the three main attributes of the hidden information (i.e., imperceptibility, robustness, and integration rate) can be jointly ameliorated as much as possible. These attributes determine the effectiveness of the watermark, resistance to external attacks, and increase the integration rate. In order to improve the robustness, a combination of the characteristics of Discrete Wavelet and Karhunen Loeve Transforms is proposed. The Karhunen Loeve Transform is applied on the subblocks (sized 8 * 8) of the different wavelet coefficients (in the HL2, LH2, and HH2 subbands). In this manner, the watermark will be adapted according to the energy values of each of the Karhunen Loeve components, with the aim of ensuring a better watermark extraction under various types of attacks. For the correct identification of inserted data, the use of an Errors Correcting Code (ECC) mechanism is required for the check and, if possible, the correction of errors introduced into the inserted data. Concerning the enhancement of the imperceptibility factor, the main goal is to determine the optimal value of the visibility factor, which depends on several parameters of the DWT and the KLT transforms. As a first step, a Fuzzy Inference System (FIS) has been set up and then applied to determine an initial visibility factor value. Several features extracted from the Cooccurrence matrix are used as an input to the FIS and used to determine an initial visibility factor for each block; these values are subsequently reweighted in function of the eigenvalues extracted from each subblock. Regarding the integration rate, the previous works insert one bit per coefficient. In our proposal, the integration of the data to be hidden is 3 bits per coefficient so that we increase the integration rate by a factor of magnitude 3. PMID- 24809045 TI - Grand challenges in cellular biochemistry: the "next-gen" biochemistry. PMID- 24809048 TI - Medicinal practice of bioactive compounds (natural/synthetic): an insight into gastrointestinal disorders. PMID- 24809049 TI - Standardised models for inducing experimental peritoneal adhesions in female rats. AB - Animal models for adhesion induction are heterogeneous and often poorly described. We compare and discuss different models to induce peritoneal adhesions in a randomized, experimental in vivo animal study with 72 female Wistar rats. Six different standardized techniques for peritoneal trauma were used: brushing of peritoneal sidewall and uterine horns (group 1), brushing of parietal peritoneum only (group 2), sharp excision of parietal peritoneum closed with interrupted sutures (group 3), ischemic buttons by grasping the parietal peritoneum and ligating the base with Vicryl suture (group 4), bipolar electrocoagulation of the peritoneum (group 5), and traumatisation by electrocoagulation followed by closure of the resulting peritoneal defect using Vicryl sutures (group 6). Upon second look, there were significant differences in the adhesion incidence between the groups (P < 0.01). Analysis of the fraction of adhesions showed that groups 2 (0%) and 5 (4%) were significantly less than the other groups (P < 0.01). Furthermore, group 6 (69%) was significantly higher than group 1 (48%) (P < 0.05) and group 4 (47%) (P < 0.05). There was no difference between group 3 (60%) and group 6 (P = 0.2). From a clinical viewpoint, comparison of different electrocoagulation modes and pharmaceutical adhesion barriers is possible with standardised models. PMID- 24809050 TI - Effects of single pill-based combination therapy of amlodipine and atorvastatin on within-visit blood pressure variability and parameters of renal and vascular function in hypertensive patients with chronic kidney disease. AB - Both strict blood pressure (BP) control and improvements in BP profile such as BP variability are important for suppression of renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In the present study, we examined the beneficial effects of the single pill-based combination therapy of amlodipine and atorvastatin on achievement of the target BP and clinic BP profile, as well as markers of vascular and renal damages in twenty hypertensive CKD patients. The combination therapy with amlodipine and atorvastatin for 16 weeks significantly decreased clinic BP, and achievement of target BP control was attained in an average of 45% after the combination therapy in spite of the presence of no achievement at baseline. In addition, the combination therapy significantly decreased the within-visit BP variability. With respect to the effects on renal damage markers, combination therapy with amlodipine and atorvastatin for 16 weeks significantly decreased albuminuria (urine albumin-to-creatinine ratio, 1034 +/- 1480 versus 733 +/- 1218 mg/g-Cr, P < 0.05) without decline in estimated glomerular filtration rate. Concerning parameters of vascular function, the combination therapy significantly improved both brachial-ankle pulse wave velocity (baPWV) and central systolic BP (cSBP) (baPWV, 1903 +/- 353 versus 1786 +/- 382 cm/s, P < 0.05; cSBP, 148 +/- 19 versus 129 +/- 23 mmHg, P < 0.01). Collectively, these results suggest that the combination therapy with amlodipine and atorvastatin may exert additional beneficial effects on renal and vascular damages as well as BP profile in addition to BP lowering in hypertension with CKD. PMID- 24809051 TI - Biomedicine and biotechnology: public health impact. PMID- 24809053 TI - Solubility of two resin composites in different mouthrinses. AB - AIM: This study aimed to compare the solubility of a universal restorative resin composite (Filtek Z250; FZ250) and a silorane-based resin composite (Filtek Silorane; FS) after immersion in alcohol-containing mouthrinse, alcohol-free mouthrinse, and artificial saliva. METHODS: 30 discs (10 mm * 1 mm) were prepared from each material and desiccated until a constant mass was obtained. Specimens were immersed in the test solutions for two days and desiccated again. Solubility was calculated based on the change in weight of each specimen before and after immersion. Data was analyzed using two-way ANOVA and Tukey's Post Hoc test (P < 0.05). RESULTS: Solubility values for both resin composites were the highest in the alcohol-containing mouthrinse. FZ250 showed greater solubility than FS; the difference was only significant in artificial saliva. CONCLUSION: Both resin composite materials tested exhibited some degree of solubility in each of the test solutions. The use of an alcohol-free mouthrinse may be preferable for patients with extensive composite restorations. PMID- 24809052 TI - Kallikreins as biomarkers for prostate cancer. AB - The introduction of testing for prostate-specific antigen (PSA), a member of the fifteen-gene family of kallikrein-related peptidases and also known as kallikrein related peptidase 3 (KLK3), in blood has revolutionized both the detection and management of prostate cancer. Given the similarities between PSA and other KLK gene family members along with limitations of PSA as a biomarker for prostate cancer mainly in reference to diagnostic specificity, the potential roles of other members of this gene family as well as PSA derivatives and isoforms in the management of prostate cancer have been studied extensively. Of these, approaches to measure distinct molecular forms of PSA (free, intact, complexed PSA, and pro PSA) combined with kallikrein-related peptidase 2 (KLK2), also known as hK2, have been considered holding particular promise in enhancing the diagnosis of prostate cancer. Recently, an integrated approach of applying a panel of four kallikrein markers has been demonstrated to enhance accuracy in predicting the risk of prostate cancer at biopsy. This review presents an overview of kallikreins, starting with the past and current status of PSA, summarizing published data on the evaluations of various KLKs as biomarkers in the diagnosis, prognostication, and monitoring of prostate cancer. PMID- 24809054 TI - Synchronization by food access modifies the daily variations in expression and activity of liver GABA transaminase. AB - Daytime restricted feeding (DRF) is an experimental protocol that influences the circadian timing system and underlies the expression of a biological clock known as the food entrained oscillator (FEO). Liver is the organ that reacts most rapidly to food restriction by adjusting the functional relationship between the molecular circadian clock and the metabolic networks. gamma-Aminobutyric acid (GABA) is a signaling molecule in the liver, and able to modulate the cell cycle and apoptosis. This study was aimed at characterizing the expression and activity of the mostly mitochondrial enzyme GABA transaminase (GABA-T) during DRF/FEO expression. We found that DRF promotes a sustained increase of GABA-T in the liver homogenate and mitochondrial fraction throughout the entire day-night cycle. The higher amount of GABA-T promoted by DRF was not associated to changes in GABA-T mRNA or GABA-T activity. The GABA-T activity in the mitochondrial fraction even tended to decrease during the light period. We concluded that DRF influences the daily variations of GABA-T mRNA levels, stability, and catalytic activity of GABA-T. These data suggest that the liver GABAergic system responds to a metabolic challenge such as DRF and the concomitant appearance of the FEO. PMID- 24809055 TI - Identification of microRNA as sepsis biomarker based on miRNAs regulatory network analysis. AB - Sepsis is regarded as arising from an unusual systemic response to infection but the physiopathology of sepsis remains elusive. At present, sepsis is still a fatal condition with delayed diagnosis and a poor outcome. Many biomarkers have been reported in clinical application for patients with sepsis, and claimed to improve the diagnosis and treatment. Because of the difficulty in the interpreting of clinical features of sepsis, some biomarkers do not show high sensitivity and specificity. MicroRNAs (miRNAs) are small noncoding RNAs which pair the sites in mRNAs to regulate gene expression in eukaryotes. They play a key role in inflammatory response, and have been validated to be potential sepsis biomarker recently. In the present work, we apply a miRNA regulatory network based method to identify novel microRNA biomarkers associated with the early diagnosis of sepsis. By analyzing the miRNA expression profiles and the miRNA regulatory network, we obtained novel miRNAs associated with sepsis. Pathways analysis, disease ontology analysis, and protein-protein interaction network (PIN) analysis, as well as ROC curve, were exploited to testify the reliability of the predicted miRNAs. We finally identified 8 novel miRNAs which have the potential to be sepsis biomarkers. PMID- 24809056 TI - Current advances in molecular phylogenetics. PMID- 24809057 TI - Rational design of a triple reporter gene for multimodality molecular imaging. AB - Multimodality imaging using noncytotoxic triple fusion (TF) reporter genes is an important application for cell-based tracking, drug screening, and therapy. The firefly luciferase (fl), monomeric red fluorescence protein (mrfp), and truncated herpes simplex virus type 1 thymidine kinase SR39 mutant (ttksr39) were fused together to create TF reporter gene constructs with different order. The enzymatic activities of TF protein in vitro and in vivo were determined by luciferase reporter assay, H-FEAU cellular uptake experiment, bioluminescence imaging, and micropositron emission tomography (microPET). The TF construct expressed in H1299 cells possesses luciferase activity and red fluorescence. The tTKSR39 activity is preserved in TF protein and mediates high levels of H-FEAU accumulation and significant cell death from ganciclovir (GCV) prodrug activation. In living animals, the luciferase and tTKSR39 activities of TF protein have also been successfully validated by multimodality imaging systems. The red fluorescence signal is relatively weak for in vivo imaging but may expedite FACS-based selection of TF reporter expressing cells. We have developed an optimized triple fusion reporter construct DsRedm-fl-ttksr39 for more effective and sensitive in vivo animal imaging using fluorescence, bioluminescence, and PET imaging modalities, which may facilitate different fields of biomedical research and applications. PMID- 24809058 TI - Biological safety of fish (tilapia) collagen. AB - Marine collagen derived from fish scales, skin, and bone has been widely investigated for application as a scaffold and carrier due to its bioactive properties, including excellent biocompatibility, low antigenicity, and high biodegradability and cell growth potential. Fish type I collagen is an effective material as a biodegradable scaffold or spacer replicating the natural extracellular matrix, which serves to spatially organize cells, providing them with environmental signals and directing site-specific cellular regulation. This study was conducted to confirm the safety of fish (tilapia) atelocollagen for use in clinical application. We performed in vitro and in vivo biological studies of medical materials to investigate the safety of fish collagen. The extract of fish collagen gel was examined to clarify its sterility. All present sterility tests concerning bacteria and viruses (including endotoxin) yielded negative results, and all evaluations of cell toxicity, sensitization, chromosomal aberrations, intracutaneous reactions, acute systemic toxicity, pyrogenic reactions, and hemolysis were negative according to the criteria of the ISO and the Ministry of Health, Labour and Welfare of Japan. The present study demonstrated that atelocollagen prepared from tilapia is a promising biomaterial for use as a scaffold in regenerative medicine. PMID- 24809059 TI - Genomic and proteomic characterization of bacteriocin-producing Leuconostoc mesenteroides strains isolated from raw camel milk in two southwest Algerian arid zones. AB - Information on the microbiology of camel milk is very limited. In this work, the genetic characterization and proteomic identification of 13 putative producing bacteriocin Leuconostoc strains exhibiting antilisterial activity and isolated from camel milk were performed. DNA sequencing of the 13 selected strains revealed high homology among the 16S rRNA genes for all strains. In addition, 99% homology with Leuconostoc mesenteroides was observed when these sequences were analysed by the BLAST tool against other sequences from reference strains deposited in the Genbank. Furthermore, the isolates were characterized by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDITOF MS) which allowed for the identification of 2 mass peaks 6242 m/z and 5118 m/z that resulted to be specific to the species L. mesenteroides. Remarkably, the phyloproteomic tree provided more intraspecific information of L. mesenteroides than phylogenetic analysis. Accordingly, phyloproteomic analysis grouped L. mesenteroides strains into different subbranches, while all L. mesenteroides isolates were grouped in the same branch according to phylogenetic analysis. This study represents, to our knowledge, the first report on the use of MALDI-TOF MS on the identification of LAB isolated from camel milk. PMID- 24809060 TI - Improvement in hemodynamic responses to metaboreflex activation after one year of training in spinal cord injured humans. AB - Spinal cord injured (SCI) individuals show an altered hemodynamic response to metaboreflex activation due to a reduced capacity to vasoconstrict the venous and arterial vessels below the level of the lesion. Exercise training was found to enhance circulating catecholamines and to improve cardiac preload and venous tone in response to exercise in SCI subjects. Therefore, training would result in enhanced diastolic function and capacity to vasoconstrict circulation. The aim of this study was to test the hypothesis that one year of training improves hemodynamic response to metaboreflex activation in these subjects. Nine SCI individuals were enrolled and underwent a metaboreflex activation test at the beginning of the study (T0) and after one year of training (T1). Hemodynamics were assessed by impedance cardiography and echocardiography at both T0 and T1. Results show that there was an increment in cardiac output response due to metaboreflex activity at T1 as compared to T0 (545.4 +/- 683.9 mL . min(-1) versus 220.5 +/- 745.4 mL . min(-1), P < 0.05). Moreover, ventricular filling rate response was higher at T1 than at T0. Similarly, end-diastolic volume response was increased after training. We concluded that a period of training can successfully improve hemodynamic response to muscle metaboreflex activation in SCI subjects. PMID- 24809061 TI - Factors behind leisure-time physical activity behavior based on Finnish twin studies: the role of genetic and environmental influences and the role of motives. AB - Different approaches are being taken to clarify the role of various factors in the development of physical activity behaviors. Genetic studies are a new area of physical activity research and also the motives for physical activity have been widely studied. The purpose of this paper is to review the findings emerging from the longitudinal genetic studies on leisure-time physical activity and to evaluate the associations between motivational factors and leisure-time physical activity. The focus is to review recent findings of longitudinal Finnish twin studies. The results of the latest longitudinal Finnish twin studies point to the existence of age-specific genetic and environmental influences on leisure-time physical activity. Variations in environmental factors seem to explain the observed deterioration in leisure-time physical activity levels. A decline in genetic influences is seen first from adolescence to young adulthood and again from the age of thirty to the mid-thirties. In the Finnish twin participants, mastery, physical fitness, and psychological state were the major motivation factors associated with consistent leisure-time physical activity behavior. The results also indicate that intrinsic motivation factors may be important for engagement in leisure-time physical activity. PMID- 24809062 TI - High HPV infection prevalence in men from infertile couples and lack of relationship between seminal HPV infection and sperm quality. AB - Human papillomaviruses (HPV) are the most frequently sexually transmitted viruses and etiological agents of several human cancers. Controversial results of the role of HPV in infertile population on sperm parameters have been published. The aim of this study was to estimate the type-specific prevalence of HPV DNA infection of the external genitalia and semen in 340 Slovenian men from infertile couples and to establish the relationship between seminal HPV DNA infection and abnormal sperm parameters. Self-taken swabs of the entire penile surface and semen samples were collected, and HPV detection and genotyping were performed. HPV DNA was detected in 37.12% of external genitalia and in 13.61% of semen samples with high HPV type concordance of both sampling sites. The most prevalent HPV types in the male external genitalia were HPV-CP6108 and HPV-84. The most prevalent HPV types in semen were HPV-53 and HPV-CP6108. The prevalence of HPV infection between normozoospermic men and men with abnormal sperm parameters did not differ significantly. Sperm quality did not differ significantly between men with seminal HPV infection and uninfected men. In conclusion, the men from infertile couples are equally susceptible to HPV infection regardless of their fertile potential; seminal HPV infection does not impair sperm quality. PMID- 24809063 TI - Temporal regulation of cytokines by the circadian clock. AB - Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to "circadian rhythms." Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system "circadian clock" plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK) temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines. PMID- 24809064 TI - Measuring neutrophil speed and directionality during chemotaxis, directly from a droplet of whole blood. AB - Neutrophil chemotaxis is critical for defense against infections and its alterations could lead to chronic inflammation and tissue injury. The central role that transient alterations of neutrophil chemotaxis could have on patient outcomes calls for its quantification in the clinic. However, current methods for measuring neutrophil chemotaxis require large volumes of blood and are time consuming. To address the need for rapid and robust assays, we designed a microfluidic device that measures neutrophil chemotaxis directly from a single droplet of blood. We validated the assay by comparing neutrophil chemotaxis from finger prick, venous blood and purified neutrophil samples. We found consistent average velocity of (19 +/- 6 MUm/min) and directionality (91.1%) between the three sources. We quantified the variability in neutrophil chemotaxis between healthy donors and found no significant changes over time. We also validated the device in the clinic and documented temporary chemotaxis deficiencies after burn injuries. PMID- 24809065 TI - Maximal oxygen uptake is associated with allele -202 A of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism and (CA)n tandem repeats of insulin-like growth factor IGF1 in Caucasians from Poland. AB - Physical fitness is a trait determined by multiple genes, and its genetic basis is modified by numerous environmental factors. The present study examines the effects of the (CA)n tandem repeats polymorphism in IGFI gene and SNP Alw21I restriction site -202 A>C polymorphism in IGF1BP3 on VO2max--a physiological index of aerobic capacity of high heritability. The study sample consisted of 239 (154 male and 85 female) students of the University School of Physical Education in Poznan and athletes practicing various sports, including members of the Polish national team. An association was found between -202 A/C polymorphism of IGFBP3 gene with VO2max in men. Higher VO2max values were attained by men with CC genotype, especially male athletes practicing endurance sports and sports featuring energy metabolism of aerobic/anaerobic character. A statistically significant influence of allele 188 and genotype 188/188 of tandem repeats (CA)n polymorphism of IGF1 gene on VO2max was found in women. Also, lower values of maximal oxygen uptake were noted in individuals with allele 186 or genotype 186/186, and higher VO2max values in athletes with allele 194. PMID- 24809066 TI - Computational model of abiogenic amino acid condensation to obtain a polar amino acid profile. AB - In accordance with the second law of thermodynamics, the Universe as a whole tends to higher entropy. However, the sequence of far-from-equilibrium events that led to the emergence of life on Earth could have imposed order and complexity during the course of chemical reactions in the so-called primordial soup of life. Hence, we may expect to find characteristic profiles or biases in the prebiotic product mixtures, as for instance among the first amino acids. Seeking to shed light on this hypothesis, we have designed a high performance computer program that simulates the spontaneous formation of the amino acid monomers in closed environments. The program was designed in reference to a prebiotic scenario proposed by Sydney W. Fox. The amino acid abundances and their polarities as the two principal biases were also taken into consideration. We regarded the computational model as exhaustive since 200,000 amino acid dimers were formed by simulation, subsequently expressed in a vector and compared with the corresponding amino acid dimers that were experimentally obtained by Fox. We found a very high similarity between the experimental results and our simulations. PMID- 24809067 TI - Differential prescribing of opioid analgesics according to physician specialty for Medicaid patients with chronic noncancer pain diagnoses. AB - BACKGROUND: Despite >20 years of studies investigating the characteristics of patients seeking or receiving opioid analgesics, research characterizing factors associated with physicians' opioid prescribing practices has been inconclusive, and the role of practitioner specialty in opioid prescribing practices remains largely unknown. OBJECTIVE: To examine the relationships between physicians' and other providers' primary specialties and their opioid prescribing practices among patients with chronic noncancer pain (CNCP). METHODS: Prescriptions for opioids filled by 81,459 Medicaid patients with CNCP in North Carolina (USA), 18 to 64 years of age, enrolled at any point during a one-year study period were examined. chi2 statistics were used to examine bivariate differences in prescribing practices according to specialty. For multivariable analyses, maximum-likelihood logistic regression models were used to examine the effect of specialty on prescribing practices, controlling for patients' pain diagnoses and demographic characteristics. RESULTS: Of prescriptions filled by patients with CNCP, who constituted 6.4% of the total sample of 1.28 million individuals, 12.0% were for opioids. General practitioner/family medicine specialists and internists were least likely to prescribe opioids, and orthopedists were most likely. Across specialties, men were more likely to receive opioids than women, as were white individuals relative to other races/ethnicities. In multivariate analyses, all specialties except internal medicine had higher odds of prescribing an opioid than general practitioners: orthopedists, OR 7.1 (95% CI 6.7 to 7.5); dentists, OR 3.5 (95% CI 3.3 to 3.6); and emergency medicine physicians, OR 2.7 (95% CI 2.6 to 2.8). CONCLUSIONS: Significant differences in opioid prescribing practices across prescriber specialties may be reflective of differing norms concerning the appropriateness of opioids for the control of chronic pain. If so, sharing these norms across specialties may improve the care of patients with CNCP. PMID- 24809069 TI - Guest Editorial- special issue on '-omics' based companion diagnostics for personalized medicine. PMID- 24809068 TI - Hospitalized children continue to report undertreated and preventable pain. AB - BACKGROUND: Published reports of substantial rates of moderate to severe pediatric inpatient pain tend to overlook lower-intensity pain that may be clinically significant. OBJECTIVE: To document the prevalence of clinically significant pain in pediatric inpatients by considering the pain threshold at which each child desires intervention, and to assess sources of pain, pain assessment and intervention, and relationships among demographic and medical variables to reported pain. METHODS: Inpatients or their parents on four hospital units during four nonconsecutive days were eligible for inclusion. Interviews (76 parents; 31 patients) captured experiences of 107 inpatients (three weeks to 18 years of age) including current, worst and usual pain, pain treatment thresholds, sources of pain and help received during the previous 24 h. A chart review provided data regarding demographic and medical variables, and pain assessment and management. RESULTS: In total, 94% of patients experienced pain. The prevalence of clinically significant pain was 8% (current), 62% (worst) and 24% (usual). Current and worst pain was primarily procedural, and usual pain was primarily disease related. On average, patients had 4.03 documented pain assessments over 24 h. Caregiver responses (eg, reassurance) and nonpharmacological interventions were frequently reported (>90%) but infrequently documented (<50%); 66% of patients received pharmacological interventions. Younger patients received fewer pain assessments and opioids. Patients with clinically significant usual pain were more likely to have undergone surgery, and receive more pain assessments and interventions. CONCLUSIONS: While recent studies suggest reduced pain in pediatric inpatients, the present findings reveal a continued high frequency of undertreated pain. High rates of procedural pain are preventable and should be targeted given the underutilization of pain management strategies. PMID- 24809070 TI - A nomogram to estimate the proportion of patients at hemoglobin A1c target <7% with noninsulin antidiabetic drugs in type 2 diabetes: a systematic review of 137 randomized controlled trials with 39,845 patients. AB - We assessed the efficacy of noninsulin antidiabetic medications used in current clinical practice (metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, glinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists) to reach the HbA1c target <7% in people with type 2 diabetes. MEDLINE, EMBASE, and the Cochrane CENTRAL were searched from inception through April 2011 for randomized controlled trials (RCTs) involving noninsulin antidiabetic drugs. RCTs had to report the effect of any diabetes medication on the HbA1c levels, to include at least 30 subjects in every arm of the study, and to last at least 12 weeks. Data were summarized across studies using random effects meta-regression. We found 137 RCTs with 205 arms and 39,845 patients. The proportion of patients who achieved the HbA1c goal ranged from 25.9% (95% CI 18.5 34.9) with alpha-glucosidase inhibitors to 48.6% (95% CI, 53.6) with GLP-1 analogs. Baseline HbA1c was the major determinant of the proportion of patients at HbA1c goal. The meta-regression model with mean baseline HbA1c value, concomitant drug use, and class of drugs as covariates explained almost 67% of the between-study variability. A nomogram was developed to estimate the proportion of patients at target for each noninsulin drug class: for a baseline HbA1c level of 7.5%, all noninsulin drugs, except alpha-glucosidase inhibitors, achieved the HbA1c goal <7% in more than 50% of patients. Starting or intensifying pharmacological therapy at baseline HbA1c 8% or less was associated with more than 50% of patients at HbA1c goal for most noninsulin drugs. PMID- 24809071 TI - [Benign paroxysmal positional vertigo is the Gufoni maneuver actually effective?]. PMID- 24809072 TI - [Pharmaceutical bleeding reduction with one dose or multiple doses?]. PMID- 24809073 TI - Response to "Incidence and self-management of hand-foot syndrome in patients with colorectal cancer". PMID- 24809074 TI - Response to "Drug shortages and the burden of access to care: a critical issue affecting patients with cancer". PMID- 24809075 TI - The author responds. PMID- 24809076 TI - Reply: To PMID 23657263. PMID- 24809077 TI - Methodology and reporting of meta-analyses in the neurosurgical literature. Response. PMID- 24809078 TI - Patient-specific intracranial pressure. Response. PMID- 24809079 TI - Gamma Knife radiosurgery and arteriovenous malformations. Response. PMID- 24809080 TI - Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations. Response. PMID- 24809081 TI - Neurosurgery in obsessive-compulsive disorder. Response. PMID- 24809082 TI - Intrapelvic sciatic notch schwannoma. Response. PMID- 24809083 TI - Stem cells and the origin of different glioma subtypes. Response. PMID- 24809084 TI - Response. PMID- 24809085 TI - CD133-positive stem cells. Response. PMID- 24809086 TI - Plain packaging in Australia boosts calls to Quitline. PMID- 24809087 TI - Cervical cancer: screening and risk with age. PMID- 24809088 TI - Biomarkers in blood could help to detect pancreatic cancer. PMID- 24809090 TI - WHO resolution on access to palliative care. PMID- 24809089 TI - Idelalisib: targeting PI3Kdelta in B-cell malignancies. PMID- 24809091 TI - HPV vaccinations do not encourage risky sexual behaviour. PMID- 24809092 TI - Gene sequencing yields new leukaemia target. PMID- 24809093 TI - Fast-tracked approval of drugs and tests in Australia. PMID- 24809094 TI - Sentinel-node biopsy boosts melanoma treatment. PMID- 24809095 TI - Pathological complete response is no surrogate for survival. PMID- 24809096 TI - Smoke-free Sochi showcases Russia's tobacco control effort. PMID- 24809097 TI - 2014 Gastrointestinal Cancers Symposium. PMID- 24809098 TI - Haptoglobin testing in hemolysis: measurement and interpretation. AB - Haptoglobin is primarily produced in the liver and is functionally important for binding free hemoglobin from lysed red cells in vivo, preventing its toxic effects. Because haptoglobin levels become depleted in the presence of large amounts of free hemoglobin, decreased haptoglobin is a marker of hemolysis. Despite its ubiquity and importance, a paucity of literature makes testing difficult to interpret. This review highlights the many physiological roles that have been recently elucidated in the literature. Different methodologies have been developed for testing, including spectrophotometry, immunoreactive methods, and gel electrophoresis. These are covered along with their respective advantages and disadvantages. As there is no single gold standard for hemolysis, validation studies must rely on a combination of factors, which are reviewed in this article. Pitfalls and limitations of testing are also addressed. False positives can occur in improper specimen preparations, cirrhosis, elevated estrogen states, and hemodilution. False negatives can occur in hypersplenism and medications such as androgens and corticosteroids. Haptoglobin testing in the setting of inflammation is additionally discussed as interpretation can be difficult in this setting. Given the widespread use of haptoglobin testing, it is vital that clinicians and laboratory staff understand the principles and correct interpretation of this test. PMID- 24809099 TI - Response. PMID- 24809100 TI - Letter to the editor: On "Validity and reliability of the Nintendo Wii Balance Board for assessment of standing balance" by R.A. Clark et al. [Gait & Posture 31 (2010) 307-310]: are the conclusions stated by the authors justified? PMID- 24809101 TI - Author response to the letter: On "Validity and reliability of the Nintendo Wii Balance Board for assessment of standing balance": are the conclusions stated by the authors justified? PMID- 24809102 TI - When the WBB is useful, and when it isn't. PMID- 24809103 TI - Technology from non-traditional sources should not be immune from scientific rigor. PMID- 24809104 TI - Current limitations of the Wii's validity and what should be considered for the future. PMID- 24809105 TI - We need a balanced perspective in Wii-search. PMID- 24809106 TI - Emerging technology within the field of active gaming: towards the establishment of evidence. PMID- 24809107 TI - Editorial, letter to the editor and commentaries on the Nintendo Wii Balance Board. PMID- 24809108 TI - Case study. Bad words. Commentary. PMID- 24809109 TI - Case study. Bad words. Commentary. PMID- 24809110 TI - On bugs and bias: improving Chagas disease control assessment. PMID- 24809111 TI - Synthesis of free-standing metal sulfide nanoarrays via anion exchange reaction and their electrochemical energy storage application. AB - Metal sulfides are an emerging class of high-performance electrode materials for solar cells and electrochemical energy storage devices. Here, a facile and powerful method based on anion exchange reactions is reported to achieve metal sulfide nanoarrays through a topotactical transformation from their metal oxide and hydroxide preforms. Demonstrations are made to CoS and NiS nanowires, nanowalls, and core-branch nanotrees on carbon cloth and nickel foam substrates. The sulfide nanoarrays exhibit superior redox reactivity for electrochemical energy storage. The self-supported CoS nanowire arrays are tested as the pseudo capacitor cathode, which demonstrate enhanced high-rate specific capacities and better cycle life as compared to the powder counterparts. The outstanding electrochemical properties of the sulfide nanoarrays are a consequence of the preservation of the nanoarray architecture and rigid connection with the current collector after the anion exchange reactions. PMID- 24809112 TI - The value of quantitative analysis. PMID- 24809119 TI - Weight loss surgery: can it help control diabetes? It's promising, but there's no straightforward 'yes' or 'no' answer--yet. PMID- 24809120 TI - Nosebleeds: how serious are they? PMID- 24809121 TI - Solving a C.difficile problem. If antibiotics fail, a stool transplant can help cure a severe infection. PMID- 24809122 TI - Everything you always wanted to know about sex after a heart attack.* But were afraid to ask your cardiologist. PMID- 24809123 TI - Shouldering the burden of menopause. PMID- 24809124 TI - Dealing with dental pain. PMID- 24809126 TI - Long-term exercise works best for insomnia. PMID- 24809125 TI - Early Alzheimer's indicator? PMID- 24809127 TI - How can a caregiver get over the daily fatigue that comes with caring for a person with dementia? PMID- 24809128 TI - I will undergo heart surgery soon and have heard that the effects of the general anesthesia may last more than a month. Is this true? PMID- 24809129 TI - Chocolate: pros and cons of this sweet treat. Is chocolate really good for the heart and brain, or is it just wishful thinking? PMID- 24809130 TI - Ask the doctor. My 83-year-old mother told me recently that she fell in her bedroom. She said she feels fine, and she's refusing to see her doctor about it. Should I insist that she go? PMID- 24809131 TI - Ask the doctor. Every once in a while I get bloating and gas. It's uncomfortable and embarrassing. What can I do to get rid of it? PMID- 24809132 TI - Effective exercise for osteoporosis. Staying active can strengthen bones and preserve mobility. PMID- 24809133 TI - How to prevent colorectal cancer. Simple strategies can help you avoid this common cancer. PMID- 24809134 TI - 8 reasons why you're not sleeping. Stop these common sleep stealers before they put your health at risk. PMID- 24809135 TI - To stay healthy and live longer, go nuts. PMID- 24809136 TI - Exercise may help delay hip replacement. PMID- 24809137 TI - Could cataract surgery extend your life? PMID- 24809138 TI - Soda linked to endometrial cancer. PMID- 24809139 TI - 4 important blood tests for women--and what the results mean. Here's why every woman needs to know her numbers. PMID- 24809140 TI - Healthy eating, healthy mind. PMID- 24809141 TI - Impact of fellowship during single-incision laparoscopic cholecystectomy. AB - BACKGROUND AND OBJECTIVES: Minimally invasive surgery fellowship programs have been created in response to advancements in technology and patient's demands. Single-incision laparoscopic cholecystectomy (SILC) is a technique that has been shown to be safe and feasible, but this appears to be the case only for experienced surgeons. The purpose of this study is to evaluate the impact of minimally invasive surgery fellow participation during SILC. METHODS: We reviewed data from our experience with SILC during 3 years. The cases were divided in two groups: group 1 comprised procedures performed by the main attending without the presence of the fellow, and group 2 comprised procedures performed with the fellow present during the operation. Demographic characteristics, comorbidities, indication for surgery, total surgical time, hospital length of stay, and complications were evaluated. RESULTS: The cohort included 229 patients: 142 (62%) were included in group 1 and 87 (38%) in group 2. No differences were found in demographic characteristics, comorbidities, and indication for surgery between groups. The total surgical time was 34.4 +/- 11.4 minutes for group 1 and 46.8 +/ 16.0 minutes for group 2 (P < .001). The hospital length of stay was 0.89 0.32 days for group 1 and 1.01 +/- 0.40 days for group 2 (P = .027). No intraoperative complications were seen in either group. There were 3 postoperative complications (2.1%) in group 1 and none in group 2 (P = .172). CONCLUSION: Adoption of SILC during an established fellowship program is safe and feasible. A longer surgical time is expected during the teaching process. PMID- 24809142 TI - [Impact of target energy intake on outcomes in septic patients : a prospective randomized controlled trial]. AB - OBJECTIVE: To observe the impact of the diverse caloric energy intake on the outcomes and occurrence rate of complications in septic patients. METHODS: A prospective single-blind randomized controlled trial was conducted. 158 cases of septic patients in intensive care unit (ICU) were enrolled and randomly assigned to three groups according to their different target value of nutrition: group A [measurements of resting energy expenditure ( MREE) <90% J , B ( MREE 90%-110%) and C ( MREE > 110%). The caloric intake, mechanical ventilation duration ( MVD),nosocomial infection rate, 28-day and 60-day mortality were analyzed. RESULTS: Daily energy intake in 7 days after ICU admission was as follows: the difference in target value of nutrition ( kJ/d: 7 075.0 +/- 1 046.5, 5 667.8 +/- 1 908.8,4 428.8 +/- 1 377.8), calory intake ( k]/d: 4 671.6 +/- 1 205.6, 5 655.3 +/- 1 373.0, 6 053.0 +/- 1 557.2), enteral nutrition value ( kJ/d: 2 051.1 +/- 1 046.5, 3 980.9 +/- 1 586.5, 5 337.1 +/- 2 921.8) and average intake rate [ ( 66.0 +/- 15.8 )% ,( 100.0 +/- 5.7 )% , ( 134.0 +/- 19.7)% J, and they were statistically significant difference among A, B, C groups (all P<0.05 ). The parenteral nutrition in group C were much higher than that in group A and group B ( kJ/d: 2 055.3 +/- 273.4vs. 427.0 +/- 273.4, 473.0 +/- 332.0, both P<0.05 ). The calories provided by glucose and diprivan were similar among three groups. The MVD and ICU stay were shorter in group B than that in groups A and C [ MVD (days): 8.4 +/- 6.3 vs.11.0 +/- 8.2, 17.8 +/- 13.0, P>0.05 and P<0.05; ICU stay (days): 11.0 +/- 6.4 vs. 14.9 +/- 9.6, 17.8 +/- 13.0, respectively,P>0.05 and P<0.05]. The total hospital stay (days: 32.0 +/- 22.5, 26.8 +/- 7.0, 30.4 +/- 21.4) and nosocomial infection rate [ 91.1% ( 51156) , 84.0% ( 42/50) , 90.4% ( 4 7/52) J were similar among A, B, C groups (all P>0.05). There was no difference in survival rate at 28 days among three groups as shown by the Kaplan-Meier survival curve ( F=3.145,P=0.076 ). The survival rate at 60 days showed a tendency of lowering in groups A and C, especially in group C (F=9.284, P=0.010). CONCLUSION: Both higher and lower caloric energy intake may be associated with an adverse impact, but appropriate caloric intake would improve the outcome and reduce the complication rate in septic patients. PMID- 24809143 TI - [Changes in blood lymphocytes in sepsis patients]. AB - OBJECTIVE: To investigate the change in blood lymphocyte levels and lymphocyte percentage in critical patients, including those with non-infectious systemic inflammatory response syndrome (SIRS), sepsis and severe sepsis. METHODS: Clinical data of 423 patients admitted to intensive care unit (ICU) of Department of Emergency of Peking University Third Hospital from January 2011 to September 2013 were retrospectively analyzed. Among these patients, there were 54 with non infectious SIRS, 177 with sepsis and 192 with severe sepsis. 150 of them died, and 273 survived. The white blood count (WBC), neutrophil (N), lymphocyte count, lymphocyte percentage, lactic acid,serum high-sensitivity C-reactive protein (hs CRP) and procalcitonin (PCT) were determined at admission, and acute physiology and chronic health evaluation II (APACHE II) was estimated. The patients were divided into different groups according to diagnosis and prognosis to compare the value of the indexes, and the correlation between lymphocyte count and other markers were analyzed by Spearman relative analysis. RESULTS: The older the patients, the more severe the disease. In the non-infective SIRS, sepsis and severe sepsis groups, APACHE II scores (7.78 +/- 3.72, 13.85 +/- 7.22,24.00 +/- 9.79), time of stay in hospital (days: 6.0 (1.0, 9.0), 12.0 (8.0, 22.0), 19.5 (7.0, 29.0)], the mortality rate (0, 10.2%, 52.6%), WBC ( x 109/L: 7.59 +/- 3.27, 8.94 +/- 3.95, 10.32 +/- 5.50), N (0.685 +/- 0.132, 0.778 +/- 0.135,0.831 +/ 0.086), hs-CRP (mg/L: 4.60 (2.80, 7.52), 23.58 (13.49, 49.22), 59.77 (19.36, 110.62)] and PCT[j.Lg/L: 0.05 (0.05, 0.05), 0.09 (0.05, 0.61), 0.63 (0.10, 5.25)] showed gradually increasing tendency (all P=0.000). Serum lymphocyte count levels (X 109/L: 1.53 (0.89, 1.88), 0.90 (0.65, 1.42) and 0.80 (0.50, 1.12)], lymphocyte percentage (0.225 +/- 0.122, 0.138 +/- 0.097, 0.106 +/- 0.070) showed gradually decreasing tendency (P<0.05 or P<0.01). There was significant difference in blood lactic acid among three groups [blood lactic acid were 2.40 ( 1.30, 5.10),1.10 (0.80, 2.00) and 1.40 (1.00, 2.50) mmol/L in the non-infective SIRS, sepsis and severe sepsis groups, respectively, P=0.000). Age (years old: 76.71 +/- 12.21 vs. 73.21 +/- 14.49), APACHE ll score (24.69 +/- 9.58 vs. 13.91 +/- 8.41),time of stay in hospital [days: 12.0 (4.0, 28.0) vs. 11.0 (8.0, 22.0) J, WBC (X 109/L: 10.29 +/- 5.82 vs. 8.89 +/- 3.98), N (0.809 +/- 0.130 vs. 0. 776 +/- 0.120), lactic acid [mmol/L: 1.80 (1.10, 2.90) vs. 1.30 (0.90, 2.49) J, hs-CRP [mg/L:50.94 (19.21, 97.13) vs. 21.71 (6.39, 54.40)] and PCT [J.Lg/L: 0.74 (0.13, 5.83) vs. 0.08 (0.05, 0.59)] levels in the death group were higher than those in the survival group (P<0.05 or P<0.01), serum lymphocyte count levels [X 109/L: 0.90 (0.50, 1.29) vs. 1.05 (0.70, 1.54)], lymphocyte percentage (0.123 +/-0.098 vs. 0.143 +/-0.097) level in the death group were obviously lower than those in the survival group (P<0.01 and P<0.05). Serum lymphocyte count levels were negative correlated with N (r= -0.597, P=0.000), hs-CRP (r= -0.298, P=0.000), PCT (r=-0.304, P=0.000), APACHE ll (r=-0.124, P=0.000), and positively correlated with lymphocyte percentage (r=0.691, P=0.000), and non correlations was found with WBC (r=0.082, P=0.091) and lactic acid (r=0.073, P=0.132). CONCLUSION: The serum lymphocyte levels in the critically ill patients are related with the severity of sepsis, and monitoring the change in lymphocyte may be an indicator for evaluating the illness and effect of treatment. PMID- 24809144 TI - Stuff and nonsense: 'whole-stay doctors'. PMID- 24809145 TI - NHS Change Day: nurses driving the silent revolution. PMID- 24809146 TI - A 'symptom-triggered' approach to alcohol withdrawal management. AB - In acute hospital settings, alcohol withdrawal often causes significant management problems and complicates a wide variety of concurrent conditions, placing a huge burden on the NHS. A significant number of critical incidents around patients who were undergoing detoxification in a general hospital setting led to the need for a project to implement and evaluate an evidence-based approach to the management of alcohol detoxification-a project that included a pre-intervention case note audit, the implementation of an evidence-based symptom triggered detoxification protocol, and a post-intervention case note audit. This change in practice resulted in an average reduction of almost 60% in length of hospital stay and a 66% reduction in the amount of chlordiazepoxide used in detoxification, as well as highlighting that 10% of the sample group did not display any signs of withdrawal and did not require any medication. Even with these reductions, no patient post-intervention developed any severe signs of withdrawal phenomena, such as seizures or delirium tremens. The savings to the trust (The Pennine Acute Hospital Trust) are obvious,but the development of a consistent, quality service will lead to fewer long-term negative effects for patients that can be caused by detoxification. This work is a project evaluation of a locally implemented strategy, which, it was hypothesised,would improve care by providing an individualised treatment plan for the management of alcohol withdrawal symptoms. PMID- 24809147 TI - Cytoreductive surgery and HIPEC for peritoneal carcinomatosis in the elderly. AB - BACKGROUND: The combined treatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is a rigorous surgical treatment, most suitable for young and good performance status patients. We evaluated the outcomes of elderly patients undergoing CRS and HIPEC for peritoneal carcinomatosis with careful perioperative care. METHODS: All consecutive patients 70 years of age or older who were treated for peritoneal carcinomatosis over the past five years were included. Primary outcomes were perioperative morbidity and mortality. Secondary outcomes were disease-free survival and overall survival. RESULTS: From a pool of 100 patients, with a diagnosis of PC who underwent CRS and HIPEC in our center, we have included 30 patients at an age of 70 years or older and the results were compared to the patients younger than 70 years. The total morbidity rate was 50% versus 41.5% in the group younger than 70 years (NSS).The mortality rate was 3.3% in the elderly group versus 1.43%in the younger group (NSS). Median overall survival was 30 months in the older group versus 38 months in the younger group. CONCLUSION: Cytoreductive surgery and HIPEC for peritoneal carcinomatosis may be safely performed with acceptable morbidity in selected elderly patients. PMID- 24809148 TI - A national study of acute hospital based alcohol health workers. AB - Alcohol health workers (AHWs) have been identified as an effective means of tackling alcohol-related hospital admissions. However, there is no understanding of the national coverage, or the extent and diversity of the services provided by hospital-based AHWs. Using a cross-sectional questionnaire, this is the first study to explore the current provision and remit of AHWs in acute hospitals across England.The data was analysed using SPSS. Significant differences were found with regards to the extent and diversity of AHW provision across England. This research provides a point of comparison for current and future hospital based AHW provision.Further research is necessary to examine different 'service types', establish effective ways of working, and determine whether sources of funding could and should more accurately reflect the remit of hospital-based AHW roles. PMID- 24809149 TI - Paediatric community home nursing: a model of acute care. AB - AIMS AND OBJECTIVES: The aim of this pilot service development was to determine if the community children's nursing outreach team(CCNOT) service, as a model of care, was effective and efficient in its delivery of reducing unscheduled care and admissions to hospital, and improving patient satisfaction. BACKGROUND: CCNOT was developed to manage acutely ill children at home and to reduce the demand for unscheduled care. DESIGN: This is a pilot prospective study within a dual-site integrated care organisation. METHODS: The CCNOT service was developed with the aim of determining the effectiveness of the CCNOT model of care and service delivery inthe following outcomes: 1) reducing length of hospital stay (LOS)2) reducing A&E admissions 3) reducing non-elective admissions 4) reducing readmissions and 5) improving patient satisfaction. Data were obtained from hospital episode statistics (HES) and patient satisfaction questionnaires. RESULTS: The data indicate that, after the implementation of the CCNOT service, A&E attendances fell by 5%per month, non-elective admissions by 15.8% and readmissions by 17.3%. Overall, LOS rose by 2.3%-0.88 days compared with 0.9 days but the difference was not significant. The results of the patient satisfaction survey show high overall satisfaction with the service. CONCLUSION: A paediatric CCNOT as a model of service delivery in acute paediatric care is effective in reducing hospital admissions. It also increases patient and carer satisfaction with care provision for sick children in the home environment. PMID- 24809150 TI - Patient- and family-centred care on an acute adult cardiac ward. AB - This paper outlines a service improvement project undertaken in one acute cardiac ward within a regional NHS trust in the east of England that explored the impact of advancing patient- and family-centred care within an acute adult setting. The project was implemented and evaluated over a 9-month period between March and December 2012 and data collected via a pre and post-intervention survey. The results demonstrated that the majority of family carers wanted to be involved in patient care. The provision of flexible family visiting,facilitated and supported family carer involvement in care provision and improved partnership working between family carers and the multidisciplinary team, had a positive impact on the patient and family carer experience. This project has demonstrated the value of involving family carers in acute adult inpatient care provision and the importance of flexible family visiting to enable this to be successful. PMID- 24809151 TI - Nurse leadership in sustaining programmes of change. AB - With a dearth of literature on sustaining new programmes in the NHS, a service evaluation was undertaken following the implementation of the Productive Ward (PW) programme in an acute hospital environment. It was hoped that areas would emerge that could help to sustain the programme following disbanding of the PW facilitation team. The service evaluation gathered data from 11 wards that were part of the PW programme. Data were collected on actual sustainability results, absenteeism over the 6 months prior to the sustainability score taken, changes to ward environments, changes to senior sister roles and attendance at the PW launch day or other PW activities. Themes from the literature and analysis of the data gathered were then developed into a discussion surrounding the factors that appeared to be conducive to sustaining this programme of change.Results indicate that change is difficult to sustain in au ever-changing environment. However, there appears to be a strong link between sustainability and the leadership skills and qualities of the ward sister. PMID- 24809152 TI - 'Is elderly care affected by nurse attitudes?' A systematic review. AB - BACKGROUND: The world's population of older people is increasing,The World Health Organization (WHO) (2013 a) defines 'elderly'as those 65 years and older. Currently there are deficits in good basic care, partially resulting from the negative attitudes of some nursing staff. METHOD: This systematic review was conducted by searching the CINAHL, MEDLINE and Inter nurse databases, which produced 119 results. Three original research papers were extracted,the fourth was obtained from a reference list and the final paper was taken from the internet. RESULTS: Both student and qualified nurses can portray a negative attitude towards older people, thus negatively affecting care. The reasons for these negative attitudes are numerous, although lack of knowledge of the ageing process and gerontology prevail. CONCLUSION: Further research is required and in depth interviews to establish why some nurses portray negative attitudes. Strategies need to be implemented to address these issues,so encouraging better care provision. PMID- 24809154 TI - Reflection: from staff nurse to nurse consultant. Part 2: what is reflection? PMID- 24809153 TI - Closing the gaps in mental health care. PMID- 24809155 TI - Duty of care is underpinned by a range of obligations. AB - The courts have long established that nurses are in a duty situation and owe a duty of care to their patients (Kent v Griffiths [2001]). Traditionally, the profession set the standard of care and nurses were required to act in accordance with a practice accepted by a responsible body of their peers (Bolam v Friern HMC [1957]).The introduction of the Human Rights Act 1998 gave rise to a positive obligation on government to ensure that laws, policies and procedures are in place to protect violations of human rights. Nurses must now inform their practice with relevant statute law, common law and professional standards in order to properly discharge their duty of care. Richard Griffith considers the law that now underpins a nurse's duty of care and uses a recent report from the Health Service Ombudsman for England to illustrate the obligations that underpin the nurse-patient relationship. PMID- 24809156 TI - Preventing suicide in England: saving lives. PMID- 24809157 TI - My first months as a nurse: an exhilarating whirlwind. PMID- 24809158 TI - Accreditation: concept or reality? PMID- 24809159 TI - [Comparison on the satisfaction of public about the government's response to human avian influenza A (H7N9) though different survey methods]. PMID- 24809160 TI - [Dr. Toth Klara (1930-2013)]. PMID- 24809161 TI - [Dr. Laszlovszky Jozsef (1923-2014)]. PMID- 24809162 TI - [Investigation of the recrystallization of trehalose as a good glass-former excipient]. AB - An amorphous form of trehalose is easy to prepare by using a solvent method. The recrystallization kinetics can be followed well, which is important because of the occurrence of polymorphic forms of trehalose. This is especially significant in the case of dry powder inhalers. Spray-drying was used as a preparation method this being one of the most efficient technologies with which to obtain an amorphous form. This method can result in the required particle size and a monodisperse distribution with excellent flowability and with moreover considerable amorphization. In our work, trehalose was applied as a technological auxiliary agent, and literature data relating to the spray-drying technology of trehalose were collected. Studies were made of the influence of the spraying process on the amorphization of trehalose and on the recrystallization of amorphous trehalose during storage. Amorphous samples were investigated under 3 different conditions during 3 months. The recrystallization process was followed by differential scanning calorimetry and X-ray powder diffraction. The results demonstrated the perfect amorphization of trehalose during the spray-drying process. The glass transition temperature was well measurable in the samples and proved to be the same as the literature data. Recrystallization under normal conditions was very slow but at high relative humidity the process was accelerated greatly. Amorphous trehalose gave rise to dihydrate forms (gamma- and h-trehaloses) during recrystallization, and beta-trehalose was also identified as an anhydrous form. PMID- 24809163 TI - [New facts about the molecular background of isovanilline-type sweeteners]. AB - As a continuation of our studies on the relationship between structure and sweet taste of isovanilline-type sweeteners, (3-hydroxy-4-methoxy)benzyl-benzoate (17) and -salicylate (17c), analogues of dihydrochalcone-type sweetener analogues of (+)-phyllodulcin [(+)-5] and CH-401 (14c) have been synthesized. Surprisingly, 17c has been found to be tastless, while 17e was slightly sweet. These observations could be explained by the current hypothesis on the receptor model for isovanilline-type sweet derivatives. PMID- 24809164 TI - [Thyroid hormones and their precursors. II. Species-specific properties]. AB - This paper surveys the species-specific physico-chemical parameters (basicity and lipophilicity) and related biological functions of thyroid hormones (thyroxine, liothyronine and reverse liothyronine) and their biological precursors (tyrosine, monoiodotyrosine and diiodotyrosine). The protonation macroconstants were determined by 1H NMR-pH titrations while the microconstants were determined by a multimodal spectroscopic-deductive methodology using auxiliary derivatives of reduced complexity. Our results show that the different number and/or position of iodine are the key factors to influence the phenolate basicity. The ionization state of the phenolate site is crucial in the biosynthesis and protein binding of thyroid hormones. The role of the protonation state in the receptor binding was investigated by an in silico docking method. Microspecies of thyroid hormones were docked to the thyroid hormone receptor isoforms. Our results quantitate at the molecular level how the ionization stage and the charge distribution influence the protein binding. The anionic form of the carboxyl group is essential for the protein binding, whereas the protonated form of the amino group loosens it. The protonation state of the phenolate plays a role of secondary importance in the receptor binding. The combined results of docking and microspeciation studies show that microspecies of the highest concentration at the pH of blood are not the strongest binding ones. The site-specific lipophilicity of our investigated molecules was determined with the measurement of distribution coefficients at different pH using carboxymethyl- and O-methyl derivatives to mimic the partition of some of the individual microspecies. Correction factors were determined and introduced. Our data show that the iodinated aromatic ring system is the definitive structural element that fundamentally determines the lipophilicity of thyroid hormones, whereas the protonation state of the aliphatic part is essential in receptor binding. The membrane transport of thyroid hormones can be well interpreted in terms of the site-specific lipophilicity. At physiological pH these biomolecules are strongly amphipathic due to the lipophilic aromatic rings and hydrophilic amino acid side chains which can well be the reason why thyroid hormones cannot cross membranes by passive diffusion and they even become constituents of biological membranes. The site-specific physico-chemical characterization of the thyroid hormones is of fundamental importance to understand their (patho) physiological behavior and also, to influence the therapeutic properties of their drug candidate derivatives at the molecular level. PMID- 24809165 TI - [The receptorial responsiveness method (RRM): a new possibility to estimate the concentration of pharmacologic agonists at their receptors]. AB - Cardiovascular disease is the biggest challenge in terms of life expectancy in developed countries. Adenosine contributes to the adaptation of the heart to ischemia and hypoxia, because adenosine, in addition to its metabolite role in the nucleic acid metabolism, is the endogenous agonist of the ubiquitous adenosine receptor family. Adenosine receptor activation is beneficial in most cases, it improves the balance between energy supply and consumption, reduces injury caused by stressors and inhibits the unfavorable tissue remodeling. Pharmacological manipulation of cardioprotective effects evoked by adenosine is an important, although to date not sufficiently utilized endeavor that may have therapeutic and preventive implications in cardiovascular diseases. As the ligand binding site of adenosine receptors is accessible from the extracellular space, it is especially important to know the adenosine concentration of the interstitial fluid ([Ado](ISF)). However, in the functioning heart, [Ado](ISF) values range in an extremely wide interval, spanning from nano- to micromolar concentrations, as estimated by the commonly used methods. Our recently developed procedure, the receptorial responsiveness method (RRM), may resolve this problem in certain cases. RRM enables quantification of an acute increase in the concentration of a pharmacological agonist, uniquely in the microenvironment of the receptors of the given agonist. As a limitation, concentration of agonists with short half-life (just like adenosine) at their receptors can only be quantified with the equieffective concentration of a stable agonist exerting the same action. In a previous study using RRM, inhibition of the transmembrane nucleoside transport in the euthyroid guinea pig atrium produced an increase in [Ado](ISF) that was equieffective with 18.8 +/- 3 nM CPA (N6 cyclopentyladenosine, a stable, selective A1 adenosine receptor agonist). This finding is consistent with observations of others, i.e., in the normoxic heart, adenosine flow is directed into the cell interior, and thus transport blockade elevates the extracellular adenosine level. In turn, nucleoside transport inhibition in the hyperthyroid guinea pig atrium caused a rise in [Ado](ISF) equieffective with 46.5 +/- 13.7 nM CPA. In sum, our work team was the first to demonstrate that adenosine transport in the hyperthyroid atrium has the same direction but is more intense as/than that in the euthyroid one. PMID- 24809166 TI - Indefinitely deferred: a look at blood donation policies for gay men. PMID- 24809167 TI - Maximizing access to health care in New Jersey: the case for APNs, Part II. PMID- 24809168 TI - [Characteristics of quantal release of glutamate and GABA in synapses between retinal ganglion cells and superior colliculus neurons in coculture]. AB - We investigated features of quantal release of glutamate and GABA in synapses between retinal ganglion cells (RGC) and superior colliculus (SC) neurons in coculture using dual patch-clamp technique. The main quantal characteristics of neurotransmitters release were defined on the basic of quantal analysis. Number of released quanta distributions for both neurotransmitters were corresponded to the binomial law. It was shown that evoked postsynaptic currents (PSC) in SC neurons as response to generation of action potential (AP) in RGC were mediated by simultaneous release at least from 2 to 14 quanta of glutamate and 2 quanta of GABA. Thereby high efficacy of excitatory and inhibitory signals transmission is guaranteed in retinocollicular projections. It is supposed that multiquantal character of the neurotransmitters release can be related to simultaneous involvement of several closely adjacent excited terminals, each of which possesses one active zone, or by one terminal with several. PMID- 24809169 TI - [Morphofunctional state of reproductive system of ageing male rats in case of using nanocerium]. AB - The influence of nanocrystalline cerium dioxide (NCD, 1 and 100 mg/kg per os daily for 10 days) on morphofuctional state of reproductive system was investigated in ageing male rats. It has been established that activation of hormone-producing testicular Leydig's cells, as well as of secretory and proliferative processes in prostate, underlies the stimulating effect of NCD at a dose 1 mg/kg on hormonal function of testis and spermatogenesis of ageing male rats. NCD used at a dose 100 mg/kg had no significant effect on the assessed indices of morphofuctional state of reproductive system. PMID- 24809170 TI - [The influence of dietary omega-3 polyunsaturated fatty acids on functional parameters of myocardial mitochondria during isoproterenol-induced heart injury]. AB - We have studied the functional parameters of mitochondria from hearts after isopreterenol-induced injury (two subcutaneous injections of isopreterenol at the dose 60 mg/kg/day). We investigated the influence of dietary omega-3 polyunsaturated fatty acids (omega-3 PUFAs) administered to rats (Epadol, 0.1 mg/100 gr of weight for 4 weeks) on these parameters. Isoproterenol-induced heart injury leads to a decreased parameters of respiration of isolated mitochondria in the presence of succinate. Administration of omega-3 PUFAs significantly restored the respiration rate of mitochondria: the state 3 respiration was increased by 70.12%, the state 4 by 39.87% and the respiratory control ratio by 45.19% compared to the corresponding parameters of experimental group. Also, it was shown the ability of omega-3 PUFAs to decrease mitochondria swelling (by 60%) in nominally free calcium solution. The results of the study indicate that omega-3 PUFAs improve the altered functions of the heart mitochondria evoked by isoproterenol-induced injury. PMID- 24809171 TI - [Effects of Lys-form of plasminogen on platelet actin cytoskeleton]. AB - The effects of several forms of plasminogen on the state of actin cytoskeleton of human platelets were studied. A ratio between various actin pools, which were detected by immunoblotting, was taken as indicator of platelet cytoskeleton reorganization. It was revealed that intact platelets contain globular (G) actin and membrane cortex (MC) actin in amounts that are 56 and 40% of filamentous (F) actin level, respectively. In both thrombin- and collagen-activated platelets, actin is almost entirely presented in F-form. Incubation of resting platelets with Lys-plasminogen causes elevation of MC-actin level up to 79% in respect to F form content. In addition, Lys-plasminogen inhibits reorganization of actin cytoskeleton typical for activated platelets. In contrast to Lys-form, Glu plasminogen affects neither platelet aggregation nor redistribution of actin pools. Thus, these data indicate that cytoskeletal structures of platelets are involved in realization of anti-aggregating effects of Lys-plasminogen. PMID- 24809172 TI - [Dynamics of ischemic skeletal soleus muscle contraction in rats]. AB - The processes of change in the rate of generation of power response of artificially ischemic muscle using frequency modulated electrical efferent stimulation were investigated. A strain-gauge technique for registration of contraction process was used. Ischemia was induced by ligating main blood vessels of lower extremity. It is shown that ischemia causes a decrease in muscle performance and reduces maximum frequency of the stimulus signal, which leads to the titanic contraction level. It is shown that the lowering of ischemic muscle strength and reduction of the time that needed to establish a steady state depended on the time of discharge segment in stimulation pattern. PMID- 24809173 TI - [Exocrine function of the pancreas in rats with experimental obesity]. AB - The influence of neonatal administration of hyperosmolar sodium chloride and sodium glutamate on the exocrine function of the pancreas in rats has been investigated. It was observed the development of acute pancreatitis under experimental obesity. The cross-section area of acini reduced by 12%, the cross section area of acinocytes nuclei increased by 10%, the length between the lobes of the gland has grown by 48%. The level of amylase was increased by 43%, the levels of pancreatic amylase and lipase were increased by 68% and 24%, respectively. PMID- 24809174 TI - [Frequency of allele polymorphism of immune proteasome catalytic subunits in patients with ischemic stroke]. AB - Frequency of allelic variants of proteasome subunits genes LMP2 (Arg60 --> His) and PSMA6 were determined in patients with ischemic stroke using real-time PCR. Allelic variants of PSMA6 were disposed in the next manner: C/C - 80.2%, C/G - 19.8%, G/G--were not (in control) and C/C - 75.5%, C/G - 21.4%, G/G - 3.1% (P = 0.22) in patients with IS. It was shown that distribution of LMP2 allelic variants was the following: Arg/Arg - 53.3%, Arg/His - 43.5%, His/His - 6.7% in control and Arg/Arg - 55.9%, Arg/His - 34.3%, His/His - 9.8% in IS group (P > 0.05). The data show that LMP2 and PSMA6 gene polymorphism is not a risk factor of ischemic stroke in Ukrainian population. PMID- 24809175 TI - [Effect of hypo- and hyper- accentuated NK cell activity on embryo implantation]. AB - NK lymphocytes play an important role in implantation and during development in early pregnancy. Recently, we showed that the proportion of NK that expressed CD69 after incubation with K562 (CD69(stim)) cells reflected the NK population excitation potential. In the present study, we investigated the significance of NK activation levels in predicting the implantation outcome in 84 patients following IVF (in vitro fertilization). Remarkably, the patients with an accentuated increase or a decrease of the levels of NK activity, have unfavourable conditions for implantation (9.1%, 3/13 and 15.1%, 5/25, respectively) compared to the patients with the nominally normal levels (52.2%. 25/46). Therefore, a nominally normal level of the NK activity is an important physiological condition and predictive factor for immune readiness to embryo implantation. This study describes an easy, efficient, sensitive and informative method for measuring NK cell activity that is relevant to clinical trials. PMID- 24809176 TI - [Study of calcium channels in the mitochondrial membrane of endothelial cells]. AB - Mitochondria play a central role in the regulation of cell function. Ca2+ entry into mitochondria represents a central event in the regulation of ATP production, intracellular Ca2+ homesotasis and mitochondrial permeability transition pore opening. Until recently, our understanding of the mechanisms of mitochondria Ca2+ uptake was largely limited by the use of indirect optical methods. Utilization of patch-clamp method to isolated mitoplasts allowed characterizing single channel properties of Ca2+ permeable channels in the inner mitochondrial membrane. Here we show the presence of three types of single channel activities of Ca2+ permeable channels in mitoplasts isolated from endothelial cells. While the identity and molecular structure of these channels still remain to be identified, these findings point for complex mechanisms of Ca2+ entry in mitochondria. PMID- 24809177 TI - [Morphological changes of the vision organ among winterers in Ukrainian Antarctic station "Academician Vernadskii"]. AB - The study revealed that the Antarctic territory in the area of the Ukrainian Antarctic station "Academician Vernadsky" can be referred to the zone of the "super high", risk in developing ophthalmological pathology, caused by ultraviolet radiation. The results of the comprehensive dynamic study of 24 winterers of the XVI and XVII Ukrainian Antarctic expeditions (2011-2013) showed the developing of specific changes in the organ of vision under the exposure to the excessive natural ultraviolet radiation (UVR), such as parenchymatous endothelial keratopathy, nuclear-posteriorcapsular phacopathy, maculopathy. Morphological changes were recorded using the cornea densitometry method: a decrease of the central cornea thickness by 14.3%, a decrease of the density and the number of endothelial cells of hexagonal type by 10.1% and 16.6%, respectively (P < 0.05). Using densitometry method, we detected morphological changes in the lens. Specifically, we found an increase of the optic lens density: in median zone by 10.1%, in maximal zone by 21.6%, in posterior part by 13.1%, P < 0.05. The results of densitometry recordings point to the development of local opacity in the posterior lens parts (in the nucleus and in the capsule). The data of the computed quantitative macula perimetry showed a significant decrease of light sensitivity of retina conicalis cells by 6 times (P < 0.05). The morphological signs of the endured acute solar retinopathy were found in more than 50% winterers. The revealed pathological changes can be considered as pre-, subclinical manifestations of the cornea dystrophy, cataracts and maculodystrophy, caused by specific action of the natural UVR, thus demanding the elaboration of the combined preventive measures. PMID- 24809178 TI - [Effect of deltaran and melatonin on immune system in rats with experimental contact dermatitis]. AB - The aim of the work was investigation of both humoral and cell-mediated immunity together with leukocytes functional stability indexes in rats with the experimental contact dermatitis (ECD) in conditions of complex pharmacological correction using deltaran and melatonin. Experimental trials were performed under conditions of chronic experiment on model chrome-induced ECD. Both deltaran and melatonin either alone or in combination were used for complex pharmacological correction of humoral and cell-mediated immunity and also for stability of leukocytes. The data obtained showed the expressed disturbances of humoral and cell-mediated immunity and neutrophils' functional stability damage under conditions of chrome-induced ECD in rats. The revealed alterations in functional activity of the immune system were successfully corrected using the combined administration of deltaran and melatonin. The activity of medical complex had exponential character. PMID- 24809179 TI - [Serum levels of endothelial monocyte-activating polypeptide-II in type 2 diabetes mellitus]. AB - Endothelial dysfunction is implicated in the pathogenesis of macrovascular complications of diabetes and atherosclerosis. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide with proinflammatory and antiangiogenic activity. The aim of this study was to investigate the serum level of EMAP-II in obese and nonobese patients with type 2 diabetes. We found an increase of serum level of EMAP-II in obese diabetic patients compared to obese subjects without diabetes. Similar alterations were observed also in non-obese diabetic patients compared to control subjects. Moreover, it was significant elevation of serum EMAP-II in obese patients without diabetes compared to control subjects. In obese and non-obese patients with diabetes it was a significant correlation between HbAc1, blood glucose, body mass index and levels of EMAP-II, total cholesterol, LDL, HDL, triglycerides and EMAP-II. In obese non-diabetic patients it was significant correlation between BMI, triglycerides, total cholesterol and EMAP-II. The revealed change of EMAP-II serum level reflects an endothelial dysfunction in patients with type 2 diabetes. Hyperglycemia, dyslipidemia and obesity appear to be significant factors contributing to elevation of EMAP-II level. PMID- 24809180 TI - [The use of aluminum and its compounds for the biomedical purposes]. AB - Taking into consideration the nanodimension of functional components of living cells, the application of nanotechnology in the biomedical purposes is currently an urgent task. One of these directions is the use of aluminum nanoparticles for molecular diagnostics, targeted delivery of drugs, the development of new pharmaceuticals. The action of aluminum chloride on the regulatory mechanisms of smooth and skeletal muscle contraction and also the effect of aluminum ions on the ATPase activity and superprecipitation of actomyosin of different types of muscles is discussed. PMID- 24809181 TI - [Pathophysiological mechanisms of portal hypertension syndrome development]. AB - This review presents modern understanding of the pathophysiological mechanisms which lead to intrahepatic portal hypertension syndrome, as well as the development of main complications, such as esophageal varices, cardial bleeding, ascites, hypersplenism. PMID- 24809182 TI - [Case report: Fasciola gigantica infection treated by triclabendazole]. PMID- 24809183 TI - [Preliminary observation on the effect of mefloquine against egg granuloma formation in the liver of mice infected with Schistosoma japonicum]. AB - OBJECTIVE: To explore whether mefloquine possesses the effect on granuloma formation induced by Schistosoma japonicum eggs. METHODS: Seventeen out of twenty eight mice infected with 20 S. japonicum cercariae for 35 days were treated orally with mefloquine at a single dose of 200 mg/kg, and groups of 2-3 mice were sacrificed at various intervals post-treatment. The livers removed from each group of mice were fixed in 10% formaldehyde. While the remained 11 untreated mice divided into 6 groups (1-2 mice per group) were sacrificed at the same time periods as groups of mice treated with mefloquine, and their livers served as untreated corresponding controls. The granulomas with single egg in the center were counted and their diameters were measured using an ocular micrometer. The liver tissue sections were stained with hematoxylin and eosin (HE), Foot's or Mallory's methods for observation on histopathological alteration of egg granulomas, and on the appearance of reticular and collagen fibers within the granulomas. RESULTS: After infected mice were treated with mefloquine for 3, 7, 14, 21, 28 and 35 days, i.e., 38, 42, 49, 56, 63, and 70 days post-infection, the mean diameters of granuloma with single egg measured in the liver tissues section were (161 +/- 19), (175 +/- 13), (195 +/- 9), (171 +/- 40), (180 +/- 13), and (145 +/- 25) microm, respectively, and each of them was significantly lower than that of its corresponding control group of (189 +/- 18), (197 +/- 11), (211 +/- 12), (208 +/- 19), (203 +/- 16), and (207 +/- 36) microm (P < 0.01 or P < 0.05). Histopathological observation showed that in mice treated with mefloquine, the eosinophil-predominant inflammatory cells around the egg granuloma were sustained to 14-21 d post treatment (49-56 d post infection), which was significantly different from the corresponding control groups that all the eggs were surrounded by fibroblasts at 42 d post infection. Up to 28-35 d post treatment (63-70 d post infection), the boundary of egg granulomas distributed in the liver tissues of mefloquine treated groups was nearer in comparison to the corresponding control groups. Further observation on the reticular and collagen fibers within the egg granulomas by using specially staining methods demonstrated that in groups of mice treated with mefloquine for 2 weeks, the emergence and amount of the two kinds of fibers were delayed and less in comparison with corresponding control groups. After infected mice treated with mefloquine for 21 d (56 d post infection), the amount of the two kinds of fibers revealed in some egg granulomas was similar to the corresponding control group, but no further increase in the amount of the fibers, and seldom spread over the boundary of egg granuloma were seen 28 d and 35 d after treatment (63 d and 60 d post infection). While in corresponding control groups, the two kinds of fibers increased continuously with time post infection to become thick, and spread over the boundary of granuloma to further interconnect with the fibers stretched from the adjacent granuloma, and separate the liver tissue to form the grid-like structure. CONCLUSION: Preliminary observation demonstrates that mefloquine possesses suppressive effect on granuloma formation induced by S. japonicum eggs. PMID- 24809184 TI - [IL-10 level in allergic rats infected by Echinococcus granulosus]. AB - Forty Wistar rats were randomly divided into 4 groups with 10 in each group. Group A served as normal control. The other 3 groups were injected intraperitoneally with Echinococcus granulosus protoscoleces 5 x 10(4) each. Six months later, group D was injected intraperitoneally with antibody against IL-10 2.0 microg/time, twice a day for 2 d. Two days later, rats in groups C and D were injected intraperitoneally with cyst fluid 5 ml each to induce allergic reaction. 30 min later, all the rats were sacrificed to observe the infection status and obtain peripheral blood. The level of IL-10, IgE and histamine in the sera was detected by ELISA. The results showed that 5, 6 and 5 rats in groups B, C and D were infected successfully, respectively, with 2 deaths in group A. The rats in groups C and D appeared nasal itching, sneezing and declined activity. 30 min later, the symptoms in group C got improved, but not for group D. The levels of IL-10 and IgE in groups C and D increased significantly compared to group B (P < 0.05). The levels of IL-10 and IgE in group D were (142.61 +/- 43.58) pg/ml and (20.67 +/- 1.58) microg/ml, respectively, lower than those in group C (P < 0.05). The level of histamine was (17.69 +/- 3.90) ng/ml, higher than that in groups B and C (P < 0.05). There was no significant difference in histamine level between B and C (P > 0.05). PMID- 24809185 TI - [Expression of Smad proteins in the process of liver fibrosis in mice infected with Schistosoma japonicum]. AB - OBJECTIVE: To study the expression of Smads proteins involved in TGF-beta1 signal transduction during the process of liver fibrosis in BALB/c mice infected with Schistosoma japonicum. METHODS: Thirty-four BALB/c mice were each infected with (20 +/- 1) S. japonicum cercariae. The mice were sacrificed at 8, 12, 16 and 24 weeks postinfection. Ten healthy BALB/c mice served as normal control group. The liver tissues were fixed in 10% formaldehyde for histology and immunohistochemistry assay. The single-egg granuloma area was measured in hematoxylin-eosin stain section. The degree of liver fibrosis was determined by Sirius red staining. Immunohistochemistry was used to observe the expression of Smad protein. RESULTS: The area of single-egg granuloma peaked at 8th week post infection [(533 +/- 1.03) mm2], and with time passing, the area diminished, and the area of granuloma reduced to (2.94 +/- 1.69) mm2 at 24 weeks post-infection. The difference was significant among the 4 periods after infection in single-egg granuloma area (P < 0.05). Collagen fibers appeared around granulomas at 8 weeks (2.03 +/- 0.52) and increased gradually. At 24 weeks post-infection, the degree of liver fibrosis reached a peak (6.90 +/- 1.57), and the liver fibrosis degree was significantly different among infection groups (P < 0.05). Immunohistochemistry showed low expression level of Smad2/3 and Smad7 and inconspicuous level of Smad4 in livers of the normal mice. The expression of Smad2/3 was found mostly in the cytoplasm and nucleus of cells around granulomas at 8th week post-infection, and the positive area of Smad2/3 was (7.24 +/- 1.64)% by semi-quantity. At 12 weeks post-infection, the Smad2/3 protein expression level around granulomas and liver sinus reached the peak [(10.01 +/- l.07)%], and there was significant difference between infection groups and the control [(2.13 +/- 0.32)%]. A significant difference in the Smad2/3 protein expression level was found between 12 weeks post-infection group and 8 weeks or 16 weeks post infection groups. The expression level of Smad4 was (8.81 +/- 1.13)% at 8th week post-infection, higher than that in the control [(4.83 +/- 1.15)%] (P < 0.05). There was no difference among the infected mice at different periods in the level of Smad4 (P > 0.05). After 8 weeks post infection, Smad7 protein sparsely appeared around the granuloma [(4.15 +/- 1.26)%] while it disappeared around liver sinus. At 12 weeks post-infection, the level of Smad7 protein was higher [(6.34 +/- 1.5)%], but with prolonged infection time, no significant difference was revealed (P > 0.05). The level of Smad7 in infected mice was higher than that in the control (P < 0.05). CONCLUSION: Resylts show high expression for Smad2/3 and Smad7 and low expression level of Smad4 during the process of liver fibrosis in BALB/c mice infected with Schistosoma japonicum. PMID- 24809186 TI - [Role of CD8+ T cells in the tumor growth delay induced by Toxoplasma gondii excreted-secreted antigen in B16F10 mouse melanoma model]. AB - OBJECTIVE: To observe the role of CD8+ T cells in the tumor growth delay induced by Toxoplasma gondii excreted-secreted antigens (TgESA) in B16FI0 mouse melanoma model in the early stage. METHODS: TgESA were prepared by incubating T. gondii tachyzoites for 12 h in vitro. 15 C57BL/6 mice were randomly assigned to group A, B, and C (5 mice per group). Each mouse in group B and C was subcutaneously injected in right flank with 2 x 10(5) B16F10 cells. Mice in group C were intraperitoneally injected with TgESA (100 microl per mouse) at 7d after B16F10 cells injection. Mice of group A were only injected with PBS. On the 13th day after melanoma cell injection, the mice were sacrificed and spleen was removed. The percentage of CD8+ T cells in the spleen was analyzed by flow cytometry. CD8+ T cells were isolated from spleen cells by using immunomagnetic beads. The activity of CD8+ T cells against B16F10 melanoma cells was determined by LDH release assay at different effect-to-target cell ratios (2.5:1, 5:1, and 10:1). Other 30 C57BL/6 mice were randomly divided into group E, F, and G. Each mice were injected with 2 x 10(5) B16F10 cells. At the same time, mice in group F and G were simultaneously injected via the tail vein with CD8+ T cells isolated from mice in group B and C. Tumor growth, mortality and survival time of mice were observed and recorded during 35-d observation period. RESULTS: The percentage of CD3+CD8+T cells in the spleen cells of group C [(15.74 +/- 0.28)%] was significantly higher than that of group B [(14.18 +/- 0.27)%] and A [(13.86 +/- 0.13)%] (P < 0.05). At different effect-to-target cell ratios, the activity of CD8+ T cells against B16F10 cells in group C was significantly higher than that of group B (P < 0.05). The average time of tumor formation in group G [(14.9 +/- 1.2) d] was longer than that in group F [(11.9 +/- 0.7) d] and E [(9.4 +/- 1.2) d] (P < 0.05). The tumor size in these groups increased, but there was no obvious difference in the tumor growth rate among the three groups. The tumor size of group G was significantly smaller than the other two groups (P < 0.05). In group E, F and G, mice began to die on the 26th day, the 29th day and the 30th day after tumor inoculation, and the number of survival mice was 3, 5 and 7, respectively, at the 35th day after injection. CONCLUSIONS: TgESA may up-regulate the quantity and function of CD8+ T cell in B16F10 melanoma mouse model, which plays a role of delaying tumor growth in early stage. PMID- 24809187 TI - [Study on immune response in BALB/c mice induced by ROP2 protein of Toxoplasma gondii with cimetidine]. AB - OBJECTIVE: To observe the immune response induced by ROP2 protein of Toxoplasma gondii with cimetidine in mice. METHODS: Eighty BALB/c mice were randomly divided into 4 groups: PBS (group A), ROP2 protein (group B), ROP2 protein-Freund's adjuvant (group C) and ROP2 protein-cimetidine (group D). Mice were immunized with PBS, ROP2 protein, ROP2 protein and Freund's adjuvant, ROP2 protein and cimetidine [200 mg/(kg x d)] by subcutaneous injection three times at an interval of 2 weeks, respectively. Experimental mice were immunized with 100 microg ROP2 proteins, which were diluted to a final volume of 200 microl in PBS. On day 13, 27 and 41 after immunization, mice sera were collected for determination of antibody IgG and cytokine IFN-gamma by ELISA. Two weeks after the final immunization, T cells subpopulation was detected by flow cytometry and splenocyte proliferation activity was determined with CCK-8. Another 12 immunized mice in each group were intraperitoneally challenged with 5 x 10(4) tachyzoites of T. gondii and the survival time was observed. RESULTS: Two weeks after final immunization, compared with groups A [(659.750 +/- 239.962) pg/ml] and B [(872.750 +/- 197.011) pg/ml], the level of IFN-gamma significantly increased in groups C [(1 600.750 +/- 480.680) pg/ml] and D [(1494.375 +/- 451.655) pg/ml] (P < 0.01). Similarly, compared with groups A (0.636 +/- 0.108) and B (0.871 +/- 0.089), the level of IgG was also higher in groups C (1.068 +/- 0.111) and D (1.046 +/- 0.147) (P < 0.01). The proliferation of splenocytes rose in group C (0.831 +/- 0.130) after immunization, and similarly in group D (0.762 +/- 0.089), and were both significantly higher than that of groups A (0.504 +/- 0.078) and B (0.592 +/- 0.160) (P < 0.01). Moreover, ratio of CD4+/CD8+ in groups C (0.831 +/- 0.130) and D (0.762 +/- 0.089) were higher than that of groups A (0.504 +/- 0.078) and B (0.592 +/- 0.160) (P < 0.05). After challenge with violent virulence strain of tachyzoites, the median survival time of mice in groups A, B, C, and D were 96, 108, 132, and 132 h, respectively. The mean survival time of mice in groups C and D were longer than that of groups A and B (P < 0.05). There was no significant difference in 5 parameters between C and D: the level of IFN-gamma and IgG, CD4+/CD8+ ratio, splenocyte proliferation, and survival time of mice (P > 0.05). CONCLUSION: Cimetidine can enhance the humoral and cellular immune response induced by ROP2 protein. PMID- 24809188 TI - [Effect of Toxoplasma gondii prugniaud strain infection in pregnant mice on the learning ability of the F1 generation]. AB - OBJECTIVE: To study the effect of Toxoplasma gondii prugniaud strain infection on female reproductive toxicity in mice and learning ability of their F1 generation. METHODS: Thirteen ICR mice were each infected intragastrically with 10 T. gondii cysts on the 15th day of pregnancy (late stage pregnancy). 12 mice were treated with physiological saline as control. The time from conception to birth and the number of offspring were recorded. Three mice from each group were sacrificed when pregnant 20 d, placentas from the sacrificed and output stillbirth mice were examined by using histopathology and immunohistochemistry. DNA extraction was performed from placenta tissue, and then T. gondii B1 gene was amplified by PCR. The F1 generation mice from experiment group and control group were tested by Morris water maze test. Statistical analysis on learning and memory ability was made by SPSS 13.0 software. RESULTS: The time from conception to birth in experiment group [(19.2 +/- 1.751)d] was shorter than that in control group [(21.0 +/- 1.732)d] (P < 0.05). No significant difference was found in the number of offspring between experiment group (70) and control group (85) (P > 0.05). Microscopic examination with HE staining showed multiple T. gondii among placental villi, the increase of the number of Hofbauer cells, blood sinus expansion and hyperemia, and visible nucleated erythrocytes. Immunohistochemically, T. gondii antigen was detected in placenta tissue. T. gondii B1 gene was detected in placenta tissue (194 bp). On the third and fourth day of the Morris water maze test, the latency of experiment group [(29.92 +/- 4.28) s, (27.69 +/- 6.23) s] was longer than that of the control [(24.07 +/- 5.32) s, (22.25 +/- 7.94) s] (P < 0.05). In the spatial probe test, the distance across the platform quadrant of experiment group [(384.66 +/- 41.33) cm] was shorter than that of the control [(426.12 +/- 46.48) cm] (P < 0.05). CONCLUSION: T. gondii Prugniaud strain infection in late stage pregnancy of mice may induce reproductive toxicity and affect the learning and memory capability of the F1 generation. PMID- 24809189 TI - [Investigation on the current situation of human soil-borne nematode infection in Shapingba district of Chongqing]. AB - By stratified cluster sampling method, 2 urban and 2 rural fields were selected from Shapingha district of Chongqing for survey in December 2009 to February 2010. According to the Administrating Regulations of National Investigation on Important Human Parasitic Diseases, Kato-Katz method was used to examine human intestinal soil-borne nematode eggs, and adhesive cellophane anal swab method was applied to examine Enterobius infection for children under 12 years old. 203 cases were found positive in 2121 subjects, with an infection rate of 9.6% (203/2 121), and the infection rate of hookworms, Ascaris lumbricoides and Trichuris trichiura with mild infection mostly was 9.3% (197/2 121), 0.4% (8/2 121) and 0.1% (2/2 121), respectively. The rate among people over 50 years old was 15.5% (160/1 030), and the farmers was with 22.3%(113/506). The higher the education level, the lower the infection rate (P < 0.01), and there was a significant difference in the prevalence between urban (2.1%) and rural people (17.3%) (chi2 = 140.443 5, P < 0.01). The infection rate of soil-borne nematodes in Shapingba of Chongqing was much lower than the standard of II regions and most infected subjects were with hookworm infection. PMID- 24809190 TI - [Construction and expression of the Echinococcus granulosus recombinant BCG EgG1Y162]. AB - OBJECTIVE: To construct and express Echinococcus granulosus recombinant bacille Calmette-Guerin (BCG) strain rBCG-EgG1Y162. METHODS: The encoding gene of the antigen EgG1Y162 of E. granulosus was recombined with E. coli-Mycobacterium shuttle expression plasmid vector pMV361 by genetic engineering technique, and transformed into E. coli for amplification. The recombinant plasmid rpMV-EgG1Y162 was identified by PCR, double digestion with restriction enzymes, and sequence analysis. The confirmed rpMV-EgG1Y162 was transformed into BCG strain via electroporation technique to construct the recombinant rBCG-EgG1Y162. After identification by PCR and double digestion with restriction enzymes, the recombinant strain was cultured for about 2 weeks. In order to induce the expression of target protein, the rBCG was placed in 45 degrees C for 30 min. SDS PAGE and Western blotting were used to analyze the expressive protein. RESULTS: The product of recombinant plasmid rpMV-EgG1Y162 was approximately 360 bp by PCR amplification and double digestion with restriction enzymes, consistent with the expected fragment length. Sequencing results showed that the inserted sequence was correct. The rBCG-EgG1Y162 grew well and the identification of PCR and enzyme digestion revealed accuracy. The results of SDS-PAGE and Western blotting showed that the relative molecular weight (M(r)) of the protein was about 71 000. CONCLUSION: The E. granulosus rBCG-EgG1Y162 strain is constructed and expressed. PMID- 24809191 TI - [Taxonomic composition of metagenomic community in the larval gut of mosquito Anopheles sinensis (Diptera: Culicidae)]. AB - OBJECTIVE: To investigate the bacteria diversity in larval gut of field-collected Anopheles sinensis. METHODS: The 16S rDNA V4 region of An. sinensis larvae collected from paddy on Jiading District of Shanghai (L1/L2) and small seeping water on Wenchang City of Hainan (AS) was sequenced by high-throughput pyrosequencing. Using Qiime and Mothur softwares, the number of sequences and operational taxonomic units (OTUs) for each sample was sorted and calculated, the species abundance and distribution, Alpha diversity index and difference times of species abundance among samples were analyzed. RESULTS: The number of sequences and OTUs for each sample were 253 724/3 930 (L1), 225 203/4 312 (L2) and 73 990/2 380 (AS). The rarefaction curves showed that adequate sampling was achieved. The number of OTUs was close to actual situation. The value of richness index was 5 942.61/6 534.88 (L1), 6 328.17/7 235.89 (L2) and 4228.66/5 651.20 (AS); diversity index was 4.63/0.03 (L1), 5.10/0.02 (L2) and 0.14/3.94 (AS). The dominant species of An. sinensis larvae gut microbiota all belonged to the phylum Proteobacteria, with a percentage of 87% (AS) and 90% (L). In addition, the dominant phyla among them were Firmicutes, Bacteroidetes and Actinobacteria. The comparison of bacterial abundance between L and AS showed that there were 18 phyla with significant difference, except the Proteobacteria and Deinococcus-Thermus; only 9 phyla were different significantly between L1 and L2. CONCLUSION: Evenness and richness of bacteria flora in the An. sinensis larvae gut collected from paddy and small seeping waters were obtained. PMID- 24809193 TI - [Effect of feeding on different tissues on larva development of Lucilia sericata]. AB - OBJECTIVE: To observe the effect of feeding on different pig tissues on the development of Lucilia sericata larvae. METHODS: Under a constant temperature of 25 degrees C, about 200 larvae each were reared on four different substrates, i.e. pig's brain, liver, muscle and a mixture of minced pork muscle and fat (6:4). Length and weight of larvae and pupae were measured at 12 h interval 16 h after eclosion. The time of development, mortality, sex ratio of adults were recorded. RESULTS: Compared to the other groups, the larvae of liver and mixture groups grew slower, time of reaching maximum length and weight was delayed for 12 24 h. The duration of larva development of liver group [(284.0 +/- 12.6) h] was longer than that of brain group [(257.0 +/- 11.9) h], muscle group [(258.0 +/- 10.2) h] and mixture group [(260.0 +/- 9.8) h] (P < 0.05). The mean maximum larva length and weight in mixture group [(11.85 +/- 0.36) mm, (40.4 +/- 0.2) mg] and liver group [(12.01 +/- 0.43) mm, (42.8 +/- 0.4) mg] was statistically less than that of brain group and muscle group (P < 0.05). The pupal length and weight in mixture group [(7.81 +/- 0.60) mm, (38.4 +/- 2.4) mg] was less than that of other three groups (P < 0.05). The larval and pupal mortality of mixture group [(9.8 +/ 2.4)% and (10.3 +/- 1.8)%] was statistically higher than that of other three groups (P < 0.05). There was no significant difference in the sex ratio among the four groups (P > 0.05). CONCLUSION: The development duration of the larvae fed on liver tissue is longer than other groups, and the larvae body length and weight of liver group are less than other groups. The body length and weight of larvae and pupae fed on mixture diet are less than other groups with higher mortality. PMID- 24809192 TI - [Cloning and expression of the mucin-related protein1 (Aamucin1) from salivary gland of Aedes albopictus]. AB - OBJECTIVE: To clone the mucin-related protein (Aamucin1) gene from salivary gland of Aedes albopictus Guangzhou isolate, and analyze the expression difference due to blood-feeding. METHODS: Total RNA was extracted from the salivary gland. The coding region of Aamucin1 was amplified with a pair of specific primers by RT PCR. The product was sequenced and analyzed by bioinformatics. Expression analysis was conducted by real-time RT-PCR. RESULTS: The product of RT-PCR was 849 bp with encoding 283 amino acids. To compare with that from Ae. albopictus Rome strain, 13 amino acids were deleted at the C end, and Aamucin1 in Guangzhou isolate shared 58% identity in amino acids with that of Rome isolate. In addition, an alternative splicing was found in Aamucin1 and located in a proline enrich area by Protscan. To compare with that of non-blood-feeding (group SG), Aamucin1 was significantly down-regulated with 0.39 fold expression at zero time after engorged (group BSG_0, mosquitoes with abdominal distention from the first 2 hours after blood-feeding, P < 0.01) and 0.61 fold expression at the 24th hour after engorged (group BSG_24,mosquitoes from the 24th hours after blood-feeding, P > 005). CONCLUSION: The full length of Aamucin1 gene of Ae. albopictus is cloned and it can be modulated by blood-feeding. PMID- 24809194 TI - [Laboratory detection on two cases with imported Plasmodium ovale infection]. AB - OBJECTIVE: To compare the laboratory tests of the imported Plasmodium ovale infection and analyse the genetic character. METHODS: After Giemsa staining and microscopy, CareStart rapid detection and nested PCR were used to detect two cases with P. ovale infection returning from Congo (Brazzaville) in Henan Province. Sequencing was performed after PCR amplification using the 18S rRNA genus-specific primers. Their genetic characteristics were analyzed and the sequence homology analysis was performed in the NCBI. RESULTS: The two cases were confirmed as P. ovale infection by morphological examination microscopically. Amplified bands were produced by 18S rRNA nested PCR, which was the same with P. ovale in size, whereas the results of CareStart rapid detection test were all negative. A sequence of 906 bp in length was obtained by sequencing their 18S rRNA genes in which GC accounted for 35.4%, and the sequence showed 99% homology to the corresponding part of the known P. ovale 18S rRNA gene (GenBank accession No. AB182492). CONCLUSION: Both the nested PCR and microscopy confirm the infection of P. ovale. A negative result of CareStart rapid detection can not ruled out the Plasmodium infection. PMID- 24809195 TI - [Analysis report of the national technique competition for diagnosis of parasitic diseases in 2012: I. Capability analysis of Plasmodium detection]. AB - OBJECTIVE: To analyze the result of the national technique competition for diagnosis of parasitic diseases in 2012, so as to understand the capability of detection on Plasmodium parasites among professionals from institutes for disease control and prevention at different levels. METHODS: Four professionals from institution were selected as contestants (age < or = 45 and at least two contestants from county-level institution). The content of the competition included making thick and thin blood slides of Plasmodium (3 slides in 30 min, 10 scores as full marks and 6 as passing score) and identification of species and number with microscopy (5 slides, 8 min per slide, 30 scores as full marks and 18 as passing score). All contestants were grouped by gender, age, professional title, level of institution, classification according to malaria endemicity, geographical location and economic development of the province. Their scores were statistically analyzed by SPSS 16.0 software. RESULTS: The average score of blood smear making test in 120 contestants from 30 provinces was 8.7, the highest was 10 and the lowest was 5.8, 118 (98.3%) contestants passed the test. The average score of blood smear reading was 16.0, the highest was 29 and the lowest was 0, 52 (43.3%) contestants passed the test. There were no significant differences for the scores among genders, ages (< or = 30, 31-40, > 40), professional titles (junior, intermediate and senior), institution levels (provincial, municipal or county level) (P > 0.05). However, there was a significant difference among provinces with different malaria endemicity, geographical location and development status (P < 0.05). For the blood slide-making and film-reading, scores of contestants from malaria endemic provinces including Class I (9.29 +/- 0.41, 18.17 +/- 6.42), Class II (8.92 +/- 0.79, 18.31 +/- 6.94) and Class III (8.61 +/- 0.89, 15.63 +/- 7.52) were higher than those from non-endemic provinces (7.95 +/- 1.00, 10.19 +/- 7.01) (P < 0.01). Scores of contestants from southern provinces (9.16 +/- 0.61, 18.82 +/- 6.78) were significantly higher than that from northern ones (8.30 +/- 0.99, 13.23 +/- 7.45) (P < 0.01). The film-reading scores were significantly higher in those from eastern provinces (18.20 +/- 6.88) than those from western (13.39 +/- 7.60) (P < 0.05), while no significant difference was found in blood slide-making (P > 0.05). CONCLUSION: The capability of malaria parasite detection is imbalanced. PMID- 24809196 TI - [Clinical analysis of 137 patients with visceral leishmaniasis]. AB - OBJECTIVE: To analyze the clinical and epidemiological characteristics of visceral leishmaniasis cases in Sichuan. METHODS: The medical records of 137 patients with visceral leishmaniasis were reviewed between January 2000 and April 2012 in West China Hospital. The epidemiological data, clinical manifestations, laboratory features, diagnosis, therapeutic procedures and outcome of the patients were retrospectively analyzed. RESULTS: Eighty-eight (64.2%) out of 137 cases were the residents in the endemic area of Sichuan Province and adjacent areas, and 49 (35.8%) were non-endemic area residents with a history of visiting endemic area. Patients living in rural areas accounted for 84.7% (116/137), in town for 15.3% (21/137). Visceral leishmaniasis should be strongly suspected in a patient with prolonged fever, marked hepatosplenomegaly, lymphadenectasis, cytopenia and hypergammaglobulinemia. All patients showed positive in rk39 dipstick test, and were treated with antimony sodium gluconate. Among these patients, 86.1% (118/137) were cured by drug, 2.9% (4/137) received splenectomy, and 6.6% (9/137) relapsed. The misdiagnosis rate was 23.4% (32/137). CONCLUSION: Bone marrow smear staining and biopsy, combined with rk39 antibody detection and epidemiological history are crucial for early diagnosis and treatment of visceral leishmaniasis. Antimonials is still an effective therapeutic choice. PMID- 24809197 TI - [Relationship between morphology and pathogenicity of Blastocystis hominis trophozoites]. AB - Six hundred and eighty-six fresh fecal specimens were collected from outpatients (663 well-formed feces and 23 watery feces) during March 2011 to March 2012. All specimens were examined microscopically by direct smear and iodine stained method. B. hominis obtained from the human positive fecal specimens were cultured in LES medium, and inoculated into the abdominal cavity of 10 female mice of 6-8 week old. The abdominal fluid was examined with same methods. 103 of 686 patients were positive (80 well-formed feces and 23 watery feces). Micro-scopically, the granular form and vacuolated form of B. hominis trophozoites could be easily identified by direct smear and iodine staining in well-formed fecal specimens, showing ovoid in shape and about (13.2 +/- 0.2) microm in size. The trophozoites cultured in LES medium showed similar feature. But in the watery fecal specimens and mice ascites specimen, they were amorphous containing more granules. And their average size was (28.0 +/- 0.3) microm which was larger than the former. Moreover, the ameba form of B. hominis trophozoites was also detected in the 23 watery fecal specimen and mice ascites specimen. The trophozoites of B. hominis were varying in shape and size depending on their living environment. PMID- 24809198 TI - [Report on 55 cases of small intestine hookworm disease diagnosed by capsule endoscopy]. AB - OBJECTIVE: To demonstrate the diagnostic value of capsule endoscopy for small intestine hookworm disease. METHODS: A retrospective study was carried out to analyze the clinical data and capsule endoscope image of 55 patients with small intestine hookworm disease in the hospital from June 2006 to June 2012. RESULTS: Among these patients, 40 cases manifested as gastrointestinal bleeding, 7 had iron deficiency anemia, 6 had chronic abdominal pain, and 2 showed abdominal distension or discomfort. Hookworm eggs were found in stool specimens of 2 cases, 6 cases showed peripheral eosinophilia, 46 cases were found to be fecal occult blood positive. Out of the 55 cases investigated, 44 showed anemia (11 severe, 26 moderate, and 7 mild). All patients were definitely diagnosed by capsule endoscopy. The hookworms were translucent and about 5-10 mm in length. Hookworms in most cases were diffusely distributed, but 12 patients suffered massive and severe hookworm infection. In most cases, hookworms were found in the proximal small intestine, and 6 in the distal intestine. Erosion and injury in intestinal mucosa around the hookworm were observed in several cases. CONCLUSION: Capsule endoscopy is an effective and safe diagnostic technique for hookworm disease in small intestine. PMID- 24809199 TI - [Progress on the epidemiology of echinococcosis]. AB - Echinococcosis is a zoonotic parasitic disease caused by the larval stages belonging to the genus Echinococcus. Echinococcosis is a major public health problem in many countries and regions. The epidemiological study of echinococcosis would contribute to the control and elimination of this disease. This paper summarizes the research status and progress on epidemiology of echinococcosis. PMID- 24809200 TI - [Sequence homology analysis on lactate dehydrogenase (LDH) of Plasmodium vivax Anhui isolates]. AB - DNA in dried blood spots of 39 vivax malaria patients (2009-2010) from Anhui (Bengbu urban district and counties of Wuhe, Huaiyuan, Mengcheng and Lixin) was extracted. The Plasmodium vivax LDH (PvLDH) gene was amplified, cloned and sequenced. The sequences were subjected to NCBI Blast program. The results showed that the targeted DNA fragment size was 951 bp without difference among the 39 samples (accession No. GU078391), and was more than 99% homologous to the PvLDH sequences in other strains from GenBank. There was only one different amino acid in the protein sequences between the isolates from Anhui and EJEU60134 or MIA061251 strains. PMID- 24809201 TI - [Research progress on the mechanism of host immune response regulated by Trichinella spiralis]. AB - Trichinosis caused by Trichinella spiralis is a parasitic zoonosis with world wide distribution, which impacts on the development of animal husbandry and food safety, and thus threatens human health. T. spiralis has the ability to evade the host immune response, which results in forming a long-term infection in the host. The previous studies indicated that a changed host immune state due to T. spiralis was an important reason for the evasion. Among the factors, cytokines, dendritic cells and regulatory T cells played an important role in the regulation of the host immune process. PMID- 24809202 TI - [Research priorities for the control and elimination of major helminthiases]. AB - In 2009, the Disease Reference Group on Helminth Infections (DRG4) was established by the Special Programme for Research and Training in Tropical Diseases (TDR) to comprehensively review recent advances, identify gaps and rank priorities in helminthiases research towards control and elimination. Six major human helminthiases are targeted, namely onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiasis and cysticercosis/taeniasis. Systematic reports made by the DRG4 from such aspects as the impact of helminthiases, control and elimination, interventions, diagnostics, social-ecology and health systems, modeling, basic research and capacity building in research was published in PLoS Neglected Tropical Diseases in 2012. Generalized introduction is presented here and further analysis of its influence on the research of the major helminthiases in China is done. PMID- 24809203 TI - [Field evaluation of SD(BIOLINE) malaria antigen Plasmodium falciparum/Plasmodium vivax rapid test kit]. AB - Four hundred and seventy-five patients with fever within 48 h were detected for Plasmodium using double blind field trials in China-Myanmar border from June to December 2011. The result showed that 202 of 475 were positive by SD(BIOLINE) kits, with 98 positive of Plasmodium falciparum and 104 positive of Plasmodium vivax. By microscope examination, 206 were positive. Taking the result of microscope examination as the reference standard, the general sensitivity and specificity were 98.1% (202/206) and 97.8% (263/269) respectively, and the general coincidence rate of SD(BIOLINE) kits with microscopy was 97.9% (465/475). The sensitivity and specificity of P. falciparum were 99.0% (98/99) and 97.8% (263/269) respectively, and the coincidence rate of SD(BIOLINE) with microscopy was 98.1% (361/368). The sensitivity and specificity of P. vivax were 97.2% (104/107) and 100% (269/269), and the coincidence rate of SD(BIOLINE) with microscopy was 99.2% (373/376). Therefore, the test results of SD(BIOLINE) are stable with a high specificity and sensitivity. PMID- 24809204 TI - [Candida catheter related-blood stream infection]. AB - Candida catheter-related bloodstream infection (CRBSI) is a biofilm-related disease, which is usually refractory because antifungals show limited effect. With medical development and increase in number of compromised hosts, CRBSI became more frequent. Candida, which is one of the opportunistic pathogens, ranks the fourth causative organism of bacteremia. The onset of bacteremia is greatly associated with the presence of catheter. Repeated blood cultures and the central venous catheter (CVC) tip culture are done for the definitive diagnosis of Candida CRBSI. Additionally serological examinations such as (1 --> 3)-beta-D glucan and mannan antigen are also useful for early diagnosis. It is important for the appropriate treatment to remove CVC, which is an artificial contaminated material, and administer antifungals promptly. As to the choice of antifungals, we should also take into account the ability of antibiofilm effect of antifungals as well as immunological state of host including neutropenia, prior administration of azoles, isolated or estimated Candida species, sensitivity against antifungals, administration route, pharmacokinetics (bioavailability, metabolic and excretion pathway, distribution) and drug interaction. As to complication of Candida bacteremia, first we should check endophthalmitis, which occurs frequently and leads to the loss of eyesight, as well as infective endocarditis, arthritis, metastatic infections such as embolic pneumonia and suppurative thrombotic phlebitis of catheter insertion site. Lastly we emphasize that the appropriate treatment based on the character of Candida bacteremia and biofilm leads to favorable prognosis. PMID- 24809205 TI - [Studies on the distribution of doripenem in pancreatic tissues, especially on the importance of the ratio in pancreatic tissue concentration of doripenem/serum concentration of doripenem]. AB - Doripenem (DRPM) which is injectable carbapenem antimicrobial agent is a compound with high antimicrobial activity against severe acute pancreatitis in carbapenem agents. It does not have a report of the distribution in human pancreatic tissue until now. This time, we performed examination about the distribution in pancreatic tissue of DRPM. Blood and pancreatic tissues were collected from six patients who were administered DRPM intravenously at a dose of 0.5 g after 1 hour from the start of injection. The concentration of DRPM in the serum and pancreatic tissues were measured. The concentrations of DRPM in the pancreatic tissues and serum were 0.58-5.39 microg/g and 0.02-0.24 microg/mL, respectively. DRPM distributed in pancreatic tissues sufficiently, and we could expect that DRPM was useful agent of pancreas infection in acute pancreatitis. PMID- 24809206 TI - [Efficacy and safety of levofloxacin in patients with nursing and healthcare associated pneumonia]. AB - Levofloxacin (LVFX) is one of respiratory quinolones with wide spectrum of antimicrobial efficacy for Gram-positive and -negative bacteria and also atypical bacteria, and 500 mg of intravenous LVFX infusion has recently been able to use once daily based on pharmacokinetics-pharmacodynamics in Japan. So far, there had been no reports of the prospective studies evaluating efficacy and safety of LVFX in patients with nursing and healthcare-associated pneumonia (NHCAP). This study was conducted to evaluate prospectively the efficacy and safety of LVFX in patients with NHCAP categories B and C (other antibacterial agents were allowed to use with LVFX) according to Japanese guideline for NHCAP by the Japanese Respiratory Society (JRS). LVFX 500 mg was intravenously administered once daily, and the clinical efficacy and safety were evaluated by clinical symptoms, peripheral blood laboratory findings and chest X-rays. Sixty-two patients (average age was 81.2 years old, female/male was 22/40) were firstly registered and evaluated for the safety of LVFX, and eventually 54 patients were enrolled for the evaluation of clinical efficacy of LVFX. The percentage of these 54 patients aged over 65 years old was 96.3%, NHCAP category B/C was 33/21. The efficacy of LVFX in all 54 patients evaluated was 85.2% (categories B/C of NHCAP was 81.8/90.5%). In addition, the efficacies of LVFX in each pneumonia severity category by A-DROP system by JRS in NHCAP patients were 100% in mild, 86.7% in moderate, 77.8% in severe/very severe. Nine patients (2 with liver dysfunction, 6 with renal dysfunction and 1 with thrombocytopenia) out of 62 patients were reported to have possible adverse effects of LVFX. All of the patients with liver and renal dysfunctions after starting LVFX administration demonstrated mild dysfunctions and continued LVFX treatment, and these dysfunctions normalized soon after cessation of LVFX. LVFX was changed to other antibacterial agent in one patient with thrombocytopenia, and also thrombocytopenia was normalized thereafter. In conclusion, LVFX is effective and relatively safe for categories B and C in patients with NHCAP. PMID- 24809207 TI - Prediction of clinical bacteriological efficacy of oral antibiotics using a mechanism-based pharmacokinetic-pharmacodynamics modeling. AB - The objective of this study was to predict the clinical bacteriological efficacy of antibiotics and to examine the pharmacodynamics (PD) characteristics of antibiotics against bacterial strains using a mechanism-based pharmacokinetic pharmacodynamics (PK-PD) modeling developed on the basis of interaction between drug concentrations and antibacterial activities. Dynamic PD parameters (epsilon, gamma, EC50) and growth rate of organisms (lambda) were obtained from in vitro time-kill profile data of oral antibiotics, tebipenem pivoxil (TBPM-PI) and cefditoren pivoxil (CDTR-PI) against Streptococcus pneumoniae or Haemophilus influenzae. PD characteristics of both drugs against S. pneumoniae or H. influenzae were examined, which indicated TBPM was concentration-dependent as well as time-dependent, and CDTR was mainly time-dependent to exhibit their bactericidal activities. Next, we simulated TBPM and CDTR concentrations in plasma after oral administration according to the dosage regimen of each drug specified in package insert, using population pharmacokinetic parameters of both drugs in pediatric patients with infections. In addition, changes in viable in vivo bacterial counts in humans were simulated using dynamic PD parameters and mean plasma concentrations of each drug. As a result, simulated profile of viable counts of S. pneumoniae and H. influenzae were well corresponding to the bacteriological efficacy results in clinical double-blinded comparative study of TBPM-PI and CDTR-PI in oral administration to pediatric patients with acute otitis media. As mentioned in the above, it was considered to be possible to clarify the PD characteristics of TBPM and CDTR against each bacterial strain using the mechanism-based PK-PD model developed on the basis of interaction between drug concentrations and antibacterial activities, and to estimate the clinical bacteriological efficacy of those drugs. PMID- 24809208 TI - Population pharmacokinetics of cefditoren pivoxil in non-infected adults. AB - Population pharmacokinetic analysis was conducted on cefditoren pivoxil (CDTR PI), a third generation oral antibiotic to evaluate the effect of covariates on pharmacokinetic parameters. Plasma concentrations of cefditoren (CDTR, total number of sampling points: 2864) obtained from healthy adult subjects, elderlies, and subjects with renal dysfunction (287 subjects) after CDTR-PI administration as well as demographic data of those subjects were used for analysis. We conducted the population pharmacokinetic analysis of CDTR-PI using a nonlinear mixed effects modeling (NONMEM) method. A one-compartment model with a first order absorption and lag time fitted well to plasma concentration-time curve for CDTR. The subject covariate significantly affecting pharmacokinetic parameters of CDTR-PI was demonstrated by population pharmacokinetic analysis. The absorption rate constant (ka: hr(-1)) of CDTR-PI decreased with age, total clearance adjusted by bioavailability (CL/F: L/hr/kg) increased with increasing creatinine clearance adjusted by body weight (Ccr: mL/min/kg) and volume of distribution adjusted by bioavailability (Vd/F: L/kg) decreased with increasing body weight (WT: kg). In addition, the lag time (Tlag: hr) depends on formulation (tablet or granule) of CDTR-PI and the absorption lag time of the tablet was longer than that of the granule. We could obtain the population mean parameters of CDTR-PI together with interindividual variability and intraindividual residual variability after oral administration of CDTR-PI to adult subjects. In the future, this information will enable us to simulate the plasma concentrations of CDTR in subjects with various demographic backgrounds, which contributes to future examination of the efficacy and safety of CDTR-PI. PMID- 24809209 TI - Computational analysis of methyl transfer reactions in dengue virus methyltransferase. AB - S-Adenosyl-L-methionine (SAM) dependent methyltransferases (MTases) play crucial roles in many biological processes. The MTase of the dengue virus is of particular interest for the development of antiviral drugs against flaviviruses. It catalyzes two distinct methylation reactions at the N7 and the 2'O position of the viral RNA cap structure. Based on density functional theory (DFT) electronic structure calculations, the molecular basis of the underlying chemical reactions involved in the N7 and the 2'O methyl transfer reactions of this enzyme were investigated using model systems. Calculations in the condensed phase show that both reactions are exergonic with significant activation barriers of 13.7 and 17.6 kcal/mol and stable product states, stabilized by 23.5 and 16.9 kcal/mol compared to the reactant states for the N7 and the 2'O reaction, respectively. We find that the reaction rate for the 2'O reaction is significantly enhanced in the presence of the native proton acceptor group, which lowers the activation barrier in the catalyzed reaction by 3.8 kcal/mol compared to the uncatalyzed reaction in aqueous solution. Furthermore, the 2'O reaction involves a methyl and a proton transfer reaction. Our results suggest that these two reactions occur in a concerted fashion in which the methyl group and the proton are transferred simultaneously. From a therapeutic viewpoint, SAM analogues stable under physiological conditions are particularly relevant. One such compound in MeAzaSAM, an isostructural mimic of SAM, for which the present calculations suggest that the methyl transfer reaction is unlikely to occur under biologically relevant conditions. PMID- 24809210 TI - Digallane with redox-active diimine ligand: dualism of electron-transfer reactions. AB - The reactivity of digallane (dpp-Bian)Ga-Ga(dpp-Bian) (1), which consists of redox-active ligand 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (dpp-Bian), has been studied. The reaction of 1 with I2 proceeds via one-electron oxidation of each of two dpp-Bian ligands to a radical-anionic state and affords complex (dpp-Bian)IGa-GaI(dpp-Bian) (2). Dissolution of complex 2 in pyridine (Py) gives monomeric compound (dpp-Bian)GaI(Py) (3) as a result of a solvent-induced intramolecular electron transfer from the metal-metal bond to the dpp-Bian ligands. Treatment of compound 3 with B(C6F5)3 leads to removal of pyridine and restores compound 2. The reaction of compound 1 with 3,6-di-tert-butyl-ortho benzoquinone (3,6-Q) proceeds with oxidation of all the redox-active centers in 1 (the Ga-Ga bond and two dpp-Bian dianions) and results in mononuclear catecholate (dpp-Bian)Ga(Cat) (4) (Cat = [3,6-Q](2-)). Treatment of 4 with AgBF4 gives a mixture of [(dpp-Bian)2Ag][BF4] (5) and (dpp-Bian)GaF(Cat) (6), which both consist of neutral dpp-Bian ligands. The reduction of benzylideneacetone (BA) with 1 generates the BA radical-anions, which dimerize, affording (dpp-Bian)Ga (BA-BA)-Ga(dpp-Bian) (7). In this case the Ga-Ga bond remains unchanged. Within 10 min at 95 degrees C in solution compound 7 undergoes transformation to paramagnetic complex (dpp-Bian)Ga(BA-BA) (8) and metal-free compound C36H40N2 (9). The latter is a product of intramolecular addition of the C-H bond of one of the iPr groups to the C?N bond in dpp-Bian. Diamagnetic compounds 3, 5, 6, and 9 have been characterized by NMR spectroscopy, and paramagnetic complexes 2, 4, 7, and 8 by ESR spectroscopy. Molecular structures of 2-7 and 9 have been established by single-crystal X-ray analysis. PMID- 24809211 TI - Limiting antenatal weight gain improves maternal health outcomes in severely obese pregnant women: findings of a pragmatic evaluation of a midwife-led intervention. AB - BACKGROUND: Antenatal obesity in pregnancy is associated with complications of pregnancy and poor obstetric outcomes. Although most guidance on pregnancy weight is focused on the prepregnancy period, pregnancy is widely viewed as a period where women are open to lifestyle change to optimise their health. METHODS: The hospital-based Bumps and Beyond intervention invited all pregnant women with a body mass index (BMI) >35 kg m(-2) to take part in a programme of health education around diet and exercise, accompanied by one-to-one guidance and monitoring of dietary change. This service evaluation compares 89 women who completed at a programme of seven sessions with healthy lifestyle midwives and advisors (intervention) versus a group of 89 women who chose not to attend (non intervention). RESULTS: Mean (SD) weight gain in the intervention group [4.5 (4.6) kg] was less than in the non-intervention group [10.3 (4.4) kg] between antenatal booking and 36 weeks of gestation (< 0.001). This was associated with a 95% reduction in the risk of gestational hypertension during pregnancy and a general reduction in pregnancy complications. There was no effect of the intervention upon gestational diabetes or complications in labour other than post partum haemorrhage (reduced by 55%). The impact of the intervention on gestational weight gain was greater in women with BMI >40 kg m(-2) at booking. There were no adverse effects of the intervention, even though 21% of the intervention group lost weight during their pregnancy. CONCLUSIONS: Intensive, personalised weight management intervention may be an effective strategy for the prevention of hypertensive disorders during pregnancy. PMID- 24809220 TI - High-throughput sulfide sensing with colorimetric analysis of single Au-Ag core shell nanoparticles. AB - We present a high-throughput strategy for sensitive detection of H2S by using individual spherical Au-Ag core-shell plasmonic nanoparticles (PNPs) as molecular probes. This method is based on quantification of color variation of the single PNPs resulting from formation of Ag2S on the particle surface. The spectral response range of the 51 nm PNP was specifically designed to match the most sensitive region of color cameras. A high density of immobilized PNPs and rapid color RGB (red/green/blue) analysis allow a large number of individual PNPs to be monitored simultaneously, leading to reliable quantification of color change of the PNPs. A linear logarithmic dependence on sulfide concentrations from 50 nM to 100 MUM was demonstrated by using this colorimetric assay. By designing PNPs with various surface chemistries, similar strategies could be developed to detect other chemically or biologically important molecules. PMID- 24809222 TI - Pregnancy complications in the mothers who delivered boys with isolated hypospadias - a population-based case-control study. AB - OBJECTIVE: The evaluation of pregnancy complications of mothers who delivered boys with isolated hypospadias (IHS) to estimate their roles in the higher rate of low birthweight and preterm birth in cases with IHS. METHODS: The incidence of prospectively and medically recorded pregnancy complications in the prenatal maternity logbook was compared in the mothers of 3038 cases with IHS and their 4981 matched controls, in addition, 24 814 population male controls without any defects in the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. RESULTS: The well-known higher rate of preterm birth and mainly of low birthweight was confirmed in cases with IHS. The incidence of preeclampsia/eclampsia (OR with 95% CI: 1.92, 1.62-2.27) and gestational diabetes (1.94, 1.34-2.81) was higher, while severe nausea and vomiting in pregnancy (0.77, 0.66-0.88) showed a lower incidence in the mothers of cases. CONCLUSION: The higher rate of preeclampsia/eclampsia may have a role in the intrauterine growth restriction of fetuses affected with IHS while the lower rate of nausea and vomiting in pregnancy may associate with the higher risk of preterm birth. PMID- 24809221 TI - A systematic review of pediatric obesity and family communication through the lens of addiction literature. AB - BACKGROUND: Both treatment of addiction and treatment of pediatric obesity often integrate the family unit. Thus, addiction therapies may provide a model to guide treatment of pediatric obesity, particularly issues of family communication, weight, and weight-related behaviors. The aim of this systematic review is to assess what knowledge in the field of addiction treatment can be translated to pediatric weight management, particularly in relation to family-based approaches and communication. METHODS: A systematic review of family communication and food addiction in obese children was conducted using MEDLINE and other databases, including all English-language studies published after 1990 meeting search criteria and related to family factors or family communication, and addiction treatment strategies used in obesity interventions. RESULTS: Three reviews, two survey studies, and two observational studies were included. Most focused on family communication; less-healthy communication patterns and parental restriction were related to maladaptive eating behaviors in children and attrition from weight management programs. A few studies suggested family communication interventions to improve unhealthy eating patterns in children, using therapies common in family treatment of addiction (e.g., motivational interviewing and cognitive behavioral therapy). No studies presented concrete suggestions to aid family communication around issues of food and weight management. Potential contributions of addiction therapies are discussed. CONCLUSIONS: Though the addictive properties of food have not been fully delineated and obesity is not classified as a disease of addiction, the field of addiction offers many approaches that may prove useful in the treatment of obesity. PMID- 24809223 TI - Selective uterine fundal pressure maneuver during the second stage of the first twin delivery at near term. AB - OBJECTIVE: We examined the perinatal outcomes of twin deliveries following selective uterine fundal pressure maneuver (UFPM) during the second stage of the first twin delivery. METHODS: At our institute, if non-reassuring fetal heart rate and/or maternal exhaustion were observed during the second stage of the first twin, selective UFPM was performed following making sure of the position of the first twin's buttocks by ultrasonography. We reviewed the obstetric records of all cases of trial of vaginal delivery of twins between 2002 and 2012. RESULTS: A total of 64 cases were evaluated for the statistical analyses. Of these, selective UFPM for the first twin was performed in 15 cases (24%). Although the cases requiring selective UFPM for the first twin was associated with an increased postpartum hemorrhage, there were no significant differences in neonatal outcomes between the two groups. CONCLUSION: There was no evidence that the selective UFPM is unsafe for both mother and two babies during the second stage of the first twin delivery. PMID- 24809224 TI - Expression of three different ATP-binding cassette transporters and correlation to chemoresistance in acute myeloid leukemia. PMID- 24809225 TI - Mitochondrial routing of glucose and sucrose polymers after pinocytotic uptake: avenues for drug delivery. AB - Mitochondria are key organelles organizing cellular metabolic flux. Therefore, a targeted drug delivery to mitochondria promises the advancement of medicine in fields that are associated with mitochondrial dysfunction. However, successful mitochondrial drug delivery is limited by complex transport steps across organelle membranes and fast drug efflux in cases of multidrug resistance. Strategies to deliver small-molecular-weight drugs to mitochondria are very limited, while the use of complex polymeric carriers is limited by a lack of clinical feasibility. We show here that clinically established macromolecules such as a sucrose copolymer (Ficoll 70/400 kDa) and polyglucose (dextran 70/500 kDa) are micropinocytosed swiftly by mesenchymal stem cells and subsequently routed to mitochondria. The intracellular level of Ficoll appears to decrease over time, suggesting that it does not persist within cells. After coupling to polysucrose, the low-molecular-weight photodynamic drug Rose Bengal reached mitochondria and thus exhibited an increased destructive potential after laser excitation. These findings support new opportunities to deliver already clinically approved drugs to mitochondria. PMID- 24809226 TI - Asymmetrical generalized paroxysmal fast activities in children with intractable localization-related epilepsy. AB - BACKGROUND: Generalized paroxysmal fast activity (GPFA) consists of burst of generalized rhythmic discharges; 100-200 MUV; 1-9s; 8-26 Hz; with frontal predominance; appearing during NREM sleep. GPFA was originally described as an electrographic feature of Lennox-Gastaut Syndrome (LGS). We analyzed GPFA on scalp video EEG (VEEG) in children to evaluate that GPFA presents in patients with intractable localization-related epilepsy. METHODS: We collected cases with GPFA with intractable localization-related epilepsy who underwent scalp VEEG, MRI, and magnetoencephalography (MEG) prior to intracranial video EEG (IVEEG) and surgical resection. We collected 50 epochs of GPFA per patient during the first night during scalp VEEG. We analyzed amplitude, duration and frequency of GPFA over the bilateral frontal region between surgical resection side with grid placement and non-resection side. RESULTS: We identified 14 (14%) patients with GPFA on scalp VEEG. The mean amplitude ranged from 145 to 589 MUV (mean 293 MUV). The mean duration ranged from 1.18 to 2.31s (mean 1.6s). The mean frequencies ranged from 9.3 to 14.7 Hz (mean 11.1 Hz). The amplitude (307 +/- 156 MUV) and duration (1.62 +/- 0.8s) of GPFAs in all the patients over the resection side were significantly higher than those (279 +/- 141 MUV, 1.58 +/- 0.8s) of the non resection side (p<0.001). All nine patients who showed significant duration differences between two hemispheres (p<0.05) had longer duration of GPFA over the resection side. Eight of 12 patients who showed significant amplitude differences between two hemispheres (p<0.05) had higher amplitude of GPFA over the resection side. Four of six patients who showed significant frequency differences between two hemispheres (p<0.05) had higher frequency of GPFA over the resection side. Nine (64%) patients became seizure free after surgical resection including multilobar resections in eight patients. CONCLUSIONS: GPFA can exist in localization-related epilepsy with secondary bilateral synchrony. Although EEG shows GPFA on scalp VEEG, the precise localization of the epileptogenic zone using IVEEG could achieve the successful surgical resection. PMID- 24809227 TI - Role of tartaric and malic acids in wine oxidation. AB - Tartaric acid determines the reduction potential of the Fe(III)/Fe(II) redox couple. Therefore, it is proposed that it determines the ability of Fe to catalyze wine oxidation. The importance of tartaric acid was demonstrated by comparing the aerial oxidation of 4-methylcatechol (4-MeC) in model wine made up with tartaric and acetic acids at pH 3.6. Acetic acid, as a weaker Fe(III) ligand, should raise the reduction potential of the Fe couple. 4-MeC was oxidized in both systems, but the mechanisms were found to differ. Fe(II) readily reduced oxygen in tartrate model wine, but Fe(III) alone failed to oxidize the catechol, requiring sulfite assistance. In acetate model wine the reverse was found to operate. These observations should have broad application to model systems designed to study the oxidative process in foods and other beverages. Consideration should be given to the reduction potential of metal couples by the inclusion of appropriate ligands. PMID- 24809228 TI - Applications of biosensing atomic force microscopy in monitoring drug and nanoparticle delivery. AB - INTRODUCTION: The therapeutic effects of medicinal drugs not only depend on their properties, but also on effective transport to the target receptor. Here we highlight recent developments in this discipline and show applications of atomic force microscopy (AFM) that enable us to track the effects of drugs and the effectiveness of nanoparticle delivery at the single molecule level. AREAS COVERED: Physiological AFM imaging enables visualization of topographical changes to cells as a result of drug exposure and allows observation of cellular responses that yield morphological changes. When we upgrade the regular measuring tip to a molecular biosensor, it enables investigation of functional changes at the molecular level via single molecule force spectroscopy. EXPERT OPINION: Biosensing AFM techniques have generated powerful tools to monitor drug delivery in (living) cells. While technical developments in actual AFM methods have simplified measurements at relevant physiological conditions, understanding both the biological and technical background is still a crucial factor. However, due to its potential impact, we expect the number of application-based biosensing AFM techniques to further increase in the near future. PMID- 24809230 TI - Adolescent experiences of HIV and sexual health communication with parents and caregivers in Soweto, South Africa. AB - Communication about sexual health between parents and adolescents has been shown to have a protective influence on behaviours that reduce the risk of HIV transmission. This study explored experiences of HIV and sexual health (HSH) communication between parents and/or caregivers and adolescents in an urban HIV endemic community in Southern Africa. Adolescents (aged 14-19 years) were recruited from the Kganya Motsha Adolescent Centre and the Kliptown community between June and August 2009. Qualitative data were collected through focus group discussions (n=10 adolescents) and semi-structured interviews (n=31 adolescents). In total, 41 adolescents (56% female, 44% male, mean age=17.2) participated in the study. Adolescent participants identified emotional, physical and sociocultural barriers to initiating HSH communication with parents and caregivers including fear of verbal warnings, threats and physical assault. Adolescents also expressed a desire for mentorship around HSH communication beyond abstinence and peer-based information. Public health interventions need to support adolescents' access to bi-directional HSH information from adult mentors that address the lived realities of adolescents beyond expectations of abstinence. PMID- 24809229 TI - Co-occurring prescription opioid use problems and posttraumatic stress disorder symptom severity. AB - BACKGROUND: Prescription opioids are the most rapidly growing category of abused substances, and result in significant morbidity, mortality and healthcare costs. Co-occurring with psychiatric disorders, persons with prescription opioid problems have negative treatment outcomes. Data are needed on the prevalence of co-occurring prescription opioid abuse and specific disorders, such as posttraumatic stress disorder (PTSD), to better inform clinical practice. OBJECTIVE: To determine prevalence rates of current co-occurring prescription opioid use problems and PTSD symptom severity among patients in community addiction treatment settings. METHODS: We abstracted administrative and chart information on 573 new admissions to three addictive treatment agencies during 2011. Systematic data were collected on PTSD symptoms, substance use, and patient demographics. RESULTS: Prescription opioid use was significantly associated with co-occurring PTSD symptom severity (OR: 1.42, p < 0.05). Use of prescription opioids in combination with sedatives (OR: 3.81, p < 0.01) or cocaine (OR: 2.24, p < 0.001) also were associated with PTSD severity. The odds of having co occurring PTSD symptoms and prescription opioid use problem were nearly three times greater among females versus males (OR: 2.63, p < 0.001). Younger patients (18-34 years old) also were at higher risk (OR: 1.86, p < 0.01). CONCLUSIONS: Prescription opioid use problems are a risk factor for co-occurring PTSD symptom severity. Being female or younger increase the likelihood of this co-morbidity. Further research is needed to confirm these finding, particularly using more rigorous diagnostic procedures. These data suggest that patients with prescription opioid use problems should be carefully evaluated for PTSD symptoms. PMID- 24809231 TI - The past and future of CD33 as therapeutic target in acute myeloid leukemia. AB - CD33 is a myeloid differentiation antigen with endocytic properties. It is broadly expressed on acute myeloid leukemia (AML) blasts and, possibly, some leukemic stem cells and has therefore been exploited as target for therapeutic antibodies for many years. The improved survival seen in many patients when the antibody-drug conjugate, gemtuzumab ozogamicin, is added to conventional chemotherapy validates this approach. However, many attempts with unconjugated or conjugated antibodies have been unsuccessful, highlighting the challenges of targeting CD33 in AML. With the development of improved immunoconjugates and CD33 directed strategies that harness immune effector cells, therapeutics with enhanced efficacy may soon become available. Toxic effects on normal hematopoietic cells may increase in parallel with this increased efficacy and demand new supportive care measures, including possibly rescue with donor cells, to minimize morbidity and mortality from drug-induced cytopenias and to optimize treatment outcomes with these agents in patients with AML. PMID- 24809232 TI - Distribution and molecular profiling of class 1 integrons in MDR Acinetobacter baumannii isolates and whole genome-based analysis of antibiotic resistance mechanisms in a representative strain. AB - The class 1 integron is an important driver of the nosocomial dissemination of multidrug-resistant (MDR) bacteria, such as Acinetobacters. In this study, we characterized the gene cassette arrays of class 1 integrons in Acinetobacter baumannii, where the detailed structure of these integrons for 38 clinical strains was analyzed. The results showed that there are three types of gene cassette arrays that are carried by different class 1 integrons, among them the aac(6')-IId-catB8-aadA1 array was the most prevalent. For detailed analysis of the integron structure, whole genome sequencing was carried out on strain AB16, and it was found that a single integron on its chromosome has a partial Tn21 transposon in its 5' flanking region and two complete copies of the insertion element IS26 in both the 5' and 3' flanking regions, indicating that the integron could be acquired by horizontal gene transfer. Furthermore, there is one resistance island AbaR22, one bla gene containing a transposon, four intrinsic resistant genes and one efflux pump that together confer six types of antibiotic resistance. PMID- 24809234 TI - Management of inflammatory bowel disease in France: a nationwide survey among private gastroenterologists. AB - BACKGROUND: Data on the current management of inflammatory bowel disease are scarce. METHODS: This was a nationwide survey among 65 private gastroenterologists treating patients with inflammatory bowel disease in France in 2012. RESULTS: A total of 375 inflammatory bowel disease patients were analysed: 48% had ulcerative colitis. One third of inflammatory bowel disease patients had a history of hospitalisation, and 40% of Crohn's disease patients had prior surgery. Two thirds of inflammatory bowel disease patients had active disease. Significantly fewer ulcerative colitis patients were treated with anti tumour necrosis factor therapy than Crohn's disease patients (18.9% vs. 38.9%; p<0.0001). Among patients treated with anti-tumour necrosis factor, only 4.5% were receiving concomitant immunomodulators. Half of inflammatory bowel disease patients had undergone a colonoscopy within the past year. For colorectal cancer screening, random biopsies and chromoendoscopy were performed in 75% and 40% of cases, respectively. An endoscopic score was used for only 10% of inflammatory bowel disease patients. About one third of inflammatory bowel disease patients had imaging studies within the past year (magnetic resonance enterography in 65%). An abdominal computed tomography scan was prescribed for 12% of inflammatory bowel disease patients. CONCLUSIONS: Many patients still have active disease in the biologics era, and the number of patients receiving combination therapy is low in private practice. Chromoendoscopy and endoscopy scores are not often used. PMID- 24809233 TI - Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers. AB - AIMS: The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. METHODS: Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. RESULTS: Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. CONCLUSIONS: Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. PMID- 24809236 TI - A nine carbon homologating system for skip-conjugated polyenes. AB - Ozonolysis of Z,Z,Z-cylonona-1,4,7-triene leads to a 1,9-difunctionalised Z,Z-3,6 nonadiene which is readily converted into a range of polyunsaturated pheromones and fatty acids. PMID- 24809237 TI - Capacity building - a challenge for nurse managers. PMID- 24809235 TI - Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms. AB - This report contains clinically oriented guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms in patients fit for treatment. The statements were elaborated by working groups of experts by searching and analysing the literature, and then underwent a consensus process using a modified Delphi procedure. The statements report recommendations regarding the most appropriate use and timing of various imaging techniques and of endoscopic ultrasound, the role of circulating and intracystic markers and the pathologic evaluation for the diagnosis and follow-up of cystic pancreatic neoplasms. PMID- 24809238 TI - Policy-makers' views on impact of specialist and advanced practitioner roles in Ireland: the SCAPE study. AB - AIM: To ascertain and explore the views held by key healthcare policy-makers on the impact of clinical specialist and advanced practice nursing and midwifery roles. BACKGROUND: Specialist and advanced practice roles are common world-wide and were introduced in Ireland in 2000. After experiencing these roles for a decade, the views of healthcare policy-makers were sought as part of a national evaluation. METHODS: A qualitative, descriptive design was used. Following ethical approval, 12 policy-makers were interviewed in 2010, using a six-part interview schedule. RESULTS: Policy-makers believed that specialist and advanced practice roles resulted in better continuity of care, improved patient/client outcomes and a more holistic approach. These clinicians were also said to be leading guideline development, new initiatives in care, education of staff, audit and policy development. They lacked administrative support and research time. Budget cuts and a government-applied recruitment moratorium were said to hamper the development of specialist/advanced practice roles. CONCLUSION: Healthcare policy-makers believe that specialists and advanced practitioners contribute to higher quality patient/client care, particularly at a strategic level. IMPLICATIONS FOR NURSING MANAGEMENT: These roles could make an important contribution to future health service developments, particularly in relation to chronic-disease management and community care, where more advanced practitioner posts are required. PMID- 24809239 TI - Staffing and job satisfaction: nurses and nursing assistants. AB - AIM: The aim of this study was to examine the relationship between staffing and job satisfaction of registered nurses (RNs) and nursing assistants (NAs). BACKGROUND: Although a number of previous studies have demonstrated the link between the numbers of patients cared for on the last shift and/or perceptions of staffing adequacy, we could find only one study that utilized a measure of actual staffing (opposed to perceptions of staffing adequacy) and correlated it with job satisfaction of registered nurses. METHODS: This cross-sectional study included 3523 RNs and 1012 NAs in 131 patient care units. Staff were surveyed to determine job satisfaction and demographic variables. In addition, actual staffing data were collected from each of the study units. RESULTS: Hours per patient day was a significant positive predictor for registered nurse job satisfaction after controlling for covariates. For NAs, a lower skill mix was marginally significant with higher job satisfaction. In addition, the more work experience the NAs reported, the lower their job satisfaction. CONCLUSION: Adequate staffing levels are essential for RN job satisfaction whereas NA job satisfaction depends on the number of assistive personnel in the mix of nursing staff. IMPLICATIONS FOR NURSING MANAGEMENT: Two implications are (1) providing adequate staffing is critical to maintain RN job satisfaction and (2) the NA job needs to be re engineered to make it a more attractive and satisfying career. PMID- 24809240 TI - Organisational values and organisational commitment: do nurses' ethno-cultural differences matter? AB - AIM: To examine the association between perceived organisational values and organisational commitment among Israeli nurses in relation to their ethno cultural background. BACKGROUND: Differences and the discrepancy between individuals' organisational values and those of their organisational culture are a potential source of adjustment difficulties. Organisational values are considered to be the bond of the individual to their organisation. In multicultural societies, such as Israel, the differences in perception of organisational values and organisational commitment may be reflected within workgroups. METHOD: Data were collected using a questionnaire among 106 hospital nurses. About 59.8% of the sample were Israeli-born. RESULTS: A positive correlation was found between organisational values and organisational commitment. Significant differences were found in organisational values and organisational commitment between Israeli-born-, USSR-born- and Ethiopian-born nurses. The socio-demographic profile modified the effect of organisational values on organisational commitment: when the nurse was male, Muslim, religiously orthodox and without academic education, the effect of organisational values on organisational commitment was higher. CONCLUSION: Findings confirm the role of culture and ethnicity in the perception of organisational values and the level of organisational commitment among nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Assessing ethno-cultural differences in organisational values and organisational commitment provides a fuller understanding of nurses' ability to adjust to their work environment and helps nurse managers devise means to increase nurses' commitment. PMID- 24809241 TI - Opening clinical encounters in an adult musculoskeletal setting. AB - Effective communication between healthcare professionals and their patients is crucial for successful consultations, and can profoundly affect patients' adherence to treatment. Despite this evidence, communication within the physiotherapy profession is still underexplored, in particular, how 'best' to open clinical encounters. This study explores the issue by seeking the preferences of physiotherapists for opening encounters in the adult musculoskeletal outpatient setting. Initially, 42 consultations and 17 first follow-up encounters were observed between qualified physiotherapists and patients with back pain. These encounters were audio-recorded, analysed and used to develop a questionnaire to determine clinicians' preferences for opening encounters. From these findings, a synopsis of the questionnaire was posted on the four most-relevant professional networks of the national, interactive Chartered Society of Physiotherapy (iCSP) website, to canvass opinion more widely. Among the 43 physiotherapists who responded, the preferred 'key clinical question' for an initial encounter was: "Do you want to just tell me a little bit about [your 'problem presentation'] first of all?"; and for follow-up encounters: 'How have you been since I last saw you?' These results provide an important and novel contribution to the profession, as debate on this issue has not previously been published. Although the sample size in this study is small, the aim of this paper is to generate reflection and debate among clinicians on their preferences for opening patient encounters and optimising the non-specific treatment effects. PMID- 24809242 TI - Reliability, validity and ability to detect change of the PANSS negative symptom factor score in outpatients with schizophrenia on select antipsychotics and with prominent negative or disorganized thought symptoms. AB - The PANSS is a valid instrument assessing schizophrenia symptom severity. Analyses have identified a five-factor solution. The negative symptom factor (NSFS) is robust, having been replicated in multiple analyses. The score has superior content validity versus the negative subscale. Aspects of validity in patients with predominant negative symptoms have yet to be established. The present data are from a Phase IIb study of add-on bitopertin therapy in schizophrenia outpatients with prominent negative or disorganized thought symptoms treated with antipsychotics. Analyses were conducted to evaluate reliability, validity and sensitivity to change. Test-retest screening to baseline was high (ICC=0.93). This was maintained in-study, for patients with no change in CGI negative symptom severity (CGI-S-N). Internal consistency at baseline was adequate (alpha=0.71) and increased at later assessments. Pearson correlation at baseline showed a good association between NSFS and CGI-S-N (0.63), but not overall CGI-S (0.31). Association with PSP at baseline was moderate (-0.39) and for change at Week eight good (-0.65). NSFS responders (>=20% improvement) at Week eight showed a significant improvement in function. The analyses demonstrated reliability, validity and ability to detect change of the NSFS, in schizophrenia patients with prominent negative or disorganized thought symptoms. PMID- 24809243 TI - Facial emotion recognition in borderline personality: an association, with childhood experience. AB - We investigated the relationship between borderline personality disorder (BPD) and childhood adversity using photographs of emotional faces. We found that those with BPD were less able to correctly identify emotional facial expressions, particularly disgust, and that this deficit in BPD correlated significantly with a measure of childhood trauma (CTQ). PMID- 24809244 TI - White and gray matter contrast enhancement in MR images of the mouse brain in vivo using IR UTE with a cryo-coil at 9.4 T. AB - BACKGROUND: The aim of this work was to assess the capability of high field MRI to image brain micro-structures containing various amount of myelin. NEW METHOD: A cryogenic RF receiver coil (Bruker 'CryoProbe') and an ultra-short echo (UTE) 2D pulse sequence with and without inversion pulse were used for coronal brain MR imaging of a healthy C57BL/6J mouse. A 9.4 T magnet system was used. Signal-to noise ratio (SNR) within the selected regions was measured. A room temperature volume RF coil was also used for SNR comparison. The inversion recovery IR-UTE 2D pulse sequence was optimized for maximum white matter (WM) and gray matter (GM) contrast-to-noise ratio (CNR). RESULTS: The results showed 3- to 12-fold improvement in SNR for the cryo-coil compared to the volume coil depending on the area. The inversion times providing optimum CNR for WM and GM were found to be 500 ms (negative CNR) and 1000 ms (positive CNR) for the echo time of 350 MUs. COMPARISON WITH EXISTING METHODS: Presented method provide better SNR and CNR for the brain structures with short T2 than the current techniques. CONCLUSION: The results indicate that the optimized IR-UTE pulse sequence when used with the cryo coil allows for over 10-fold enhancement of the CNR for WM and GM as compared to the standard UTE without inversion pulse. PMID- 24809245 TI - Using the readiness potential of button-press and verbal response within spoken language processing. AB - BACKGROUND: Even though research in turn-taking in spoken dialogues is now abundant, a typical EEG-signature associated with the anticipation of turn-ends has not yet been identified until now. NEW METHOD: The purpose of this study was to examine if readiness potentials (RP) can be used to study the anticipation of turn-ends by using it in a motoric finger movement and articulatory movement task. The goal was to determine the preconscious onset of turn-end anticipation in early, preconscious turn-end anticipation processes by the simultaneous registration of EEG measures (RP) and behavioural measures (anticipation timing accuracy, ATA). For our behavioural measures, we used both button-press and verbal response ("yes"). In the experiment, 30 subjects were asked to listen to auditorily presented utterances and press a button or utter a brief verbal response when they expected the end of the turn. During the task, a 32-channel EEG signal was recorded. RESULTS: The results showed that the RPs during verbal- and button-press-responses developed similarly and had an almost identical time course: the RP signals started to develop 1170 vs. 1190 ms before the behavioural responses. COMPARISON WITH EXISTING METHODS: Until now, turn-end anticipation is usually studied using behavioural methods, for instance by measuring the anticipation timing accuracy, which is a measurement that reflects conscious behavioural processes and is insensitive to preconscious anticipation processes. CONCLUSION: The similar time course of the recorded RP signals for both verbal- and button-press responses provide evidence for the validity of using RPs as an online marker for response preparation in turn-taking and spoken dialogue research. PMID- 24809246 TI - Post-partum spontaneous coronary artery dissection and the use of veno-arterial extra-corporeal membrane oxygenation. AB - AIMS: To present a rare case of a post-partum spontaneous coronary artery dissection (SCAD), a rarely seen condition which does not yet have a universally agreed treatment method and the role of the intensive care unit (ICU) nurse when caring for the adult ECMO patient. BACKGROUND: The use of extra-corporeal membrane oxygenation (ECMO) for the adult patient has increased slowly since the first reported successful treatment in 1972 (Hill et al., 1972) and is seen increasingly as a successful therapy when conventional medical treatment has failed. In this case, a young lady 2 weeks post-partum presented with acute coronary syndrome secondary to a SCAD. ECMO was used successfully as a bridge to myocardial recovery following coronary artery bypass grafts and cardiogenic shock. DESIGN AND METHOD: A case study underpinned by a review of existing literature relating to spontaneous coronary artery dissection and extra-corporeal membrane oxygenation. RESULTS AND CONCLUSIONS: ECMO is still a relatively new and invasive technology but continues to improve survival rates in critically ill patients where conventional medical treatment has failed. This article highlights requirement for further research into several aspects of care for the adult ECMO patient. Questions to be answered raised in this case study include recommendations for the weaning of inotropes and vasoconstrictors, frequency of blood gas sampling and whether it remains essential to have two nurses caring for the ECMO patient. RELEVANCE TO CLINICAL PRACTICE: As medical treatment progresses, there is an increasing demand for therapies such as ECMO to become more readily available for the care of the critically ill adult patient. This article highlights challenges that may be faced and what changes could be made to further improve standards of care and survival rates for ECMO patients. PMID- 24809247 TI - Dr. Boullosa's forgotten pieces don't fit the puzzle. PMID- 24809248 TI - What are the main risk factors for running-related injuries? AB - BACKGROUND: Despite several studies that have been conducted on running injuries, the risk factors for running-related injuries are still not clear in the literature. OBJECTIVE: The aim of this study was to systematically review prospective cohort studies that investigated the risk factors for running injuries in general. DATA SOURCES: We conducted electronic searches without restriction of language on EMBASE (1980 to Dec 2012), PUBMED (1946 to Dec 2012), CINAHL (1988 to Dec 2012) SPORTDiscus (1977 to Dec 2012), Latin American and Caribbean Centre on Health Sciences Information (1985 to Dec 2012) and Scientific Electronic Library Online (1998 to Dec 2012) databases, using subject headings, synonyms, relevant terms and variant spellings for each database. STUDY SELECTION: Only prospective cohort studies investigating the risk factors for running-related musculoskeletal injuries were included in this review. Two independent reviewers screened each article and, if they did not reach a consensus, a third reviewer decided whether or not the article should be included. STUDY APPRAISAL AND SYNTHESIS METHODS: Year of publication, type of runners, sample size, definition of running-related musculoskeletal injury, baseline characteristics, reported risk factors and the statistical measurement of risk or protection association were extracted from the articles. A scale adapted by the authors evaluated the risk of bias of the articles. RESULTS: A total of 11 articles were considered eligible in this systematic review. A total of 4,671 pooled participants were analysed and 60 different predictive factors were investigated. The main risk factor reported was previous injury (last 12 months), reported in 5 of the 8 studies that investigated previous injuries as a risk factor. Only one article met the criteria for random selection of the sample and only six articles included a follow-up of 6 months or more. There was no association between gender and running injuries in most of the studies. LIMITATIONS: It is possible that eligible articles for this review were published in journals that were not indexed in any of the searched databases. We found a great heterogeneity of statistical methods between studies, which prevented us from performing a meta-analysis. CONCLUSIONS: The main risk factor identified in this review was previous injury in the last 12 months, although many risk factors had been investigated in the literature. Relatively few prospective studies were identified in this review, reducing the overall ability to detect risk factors. This highlights the need for more, well designed prospective studies in order to fully appreciate the risk factors associated with running. PMID- 24809249 TI - The psychobiological model of endurance performance: an effort-based decision making theory to explain self-paced endurance performance. PMID- 24809252 TI - Continuous loudness response to acoustic intensity dynamics in melodies: effects of melodic contour, tempo, and tonality. AB - The aim of this work was to investigate perceived loudness change in response to melodies that increase (up-ramp) or decrease (down-ramp) in acoustic intensity, and the interaction with other musical factors such as melodic contour, tempo, and tonality (tonal/atonal). A within-subjects design manipulated direction of linear intensity change (up-ramp, down-ramp), melodic contour (ascending, descending), tempo, and tonality, using single ramp trials and paired ramp trials, where single up-ramps and down-ramps were assembled to create continuous up-ramp/down-ramp or down-ramp/up-ramp pairs. Twenty-nine (Exp 1) and thirty-six (Exp 2) participants rated loudness continuously in response to trials with monophonic 13-note piano melodies lasting either 6.4s or 12s. Linear correlation coefficients >.89 between loudness and time show that time-series loudness responses to dynamic up-ramp and down-ramp melodies are essentially linear across all melodies. Therefore, 'indirect' loudness change derived from the difference in loudness at the beginning and end points of the continuous response was calculated. Down-ramps were perceived to change significantly more in loudness than up-ramps in both tonalities and at a relatively slow tempo. Loudness change was also greater for down-ramps presented with a congruent descending melodic contour, relative to an incongruent pairing (down-ramp and ascending melodic contour). No differential effect of intensity ramp/melodic contour congruency was observed for up-ramps. In paired ramp trials assessing the possible impact of ramp context, loudness change in response to up-ramps was significantly greater when preceded by down-ramps, than when not preceded by another ramp. Ramp context did not affect down-ramp perception. The contribution to the fields of music perception and psychoacoustics are discussed in the context of real-time perception of music, principles of music composition, and performance of musical dynamics. PMID- 24809253 TI - Cultural, ethical, and humanitarian affairs: an interview with Dr K.M. Cherian, MS, FRACS, Dsc, cardiac surgeon, chairman and CEO, frontier lifeline hospital, Chennai, India. PMID- 24809254 TI - [Role and mechanism of signal pathway mediated by Toll-like receptor 9-myeloid differentiation factor 88 in alveolar macrophages in ventilator-induced lung injury in rats]. AB - OBJECTIVE: To investigate the role of Toll-like receptor 9 (TLR9)-myeloid differentiation factor 88 (MyD88) signal pathway in alveolar macrophages in ventilator-induced lung injury (VILI). METHODS: 30 adult male Sprague-Dawley (SD) rats were randomly assigned to three groups (with 10 rats in each group). Group A was the control group, with spontaneous respiration after tracheostomy. Rats in group B received mechanical ventilation for 4 hours with normal tidal volume (VT) 7 ml/kg after tracheostomy, and group C rats received mechanical ventilation with VT 40 ml/kg for 4 hours. After termination of ventilation, examination with transmission electron microscopy was performed to observe the ultrastructure changes in alveolar epithelial cell type II (AECII) of the lung. Lung wet/dry ratios (W/D) and total protein concentration, the concentration of interleukins (IL-6 and IL-1beta) in bronchoalveolar lavage fluid (BALF) were determined. The protein and mRNA expressions of TLR9, MyD88 and nuclear factor-KappaB (NF-KappaB) in alveolar macrophages were assayed by Western Blot and real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The ultrastructure of AECII in the group A and group B was almost normal, whereas the chromatin of the nuclei, the lamellar corpuscles in the cytoplasm, the cell membrane and the microvilli of the AECII in the group C showed injurious changes in various degrees. When the group C was compared with the group A and the group B, it was shown that the W/D ratios (5.54+/-0.17 vs. 4.58+/-0.17, 4.69+/-0.16) and total protein concentration (6.33+/-0.61 g/L vs. 0.45+/-0.05 g/L, 0.47+/-0.04 g/L), IL 6 (1.989+/-0.103 MUg/L vs. 1.033+/-0.061 MUg/L, 1.010+/-0.069 MUg/L) and IL-1beta (2.79+/-0.25 ng/L vs. 1.05+/-0.15 ng/L, 1.23+/-0.22 ng/L) in BALF, the protein expressions of TLR9, MyD88 and NF-KappaB [TLR9 (A value): 0.770+/-0.042 vs. 0.300+/-0.027, 0.310+/-0.037; MyD88 (A value): 0.950+/-0.091 vs. 0.560+/-0.082, 0.580+/-0.084; NF-KappaB(A value): 1.020+/-0.076 vs. 0.740+/-0.052, 0.700+/ 0.076] in alveolar macrophages were all increased significantly, and all of which showed significant difference (P<0.05 or P<0.01). The mRNA levels of TLR9, MyD88 and NF-KappaB in alveolar macrophages in the group B were (1.13+/-0.32), (1.18+/ 0.33), and (1.11+/-0.22) folds of those of the group A, respectively, but there were no significant differences (all P>0.05). While the mRNA levels of TLR9, MyD88 and NF-KappaB of alveolar macrophages in the group C were (8.66+/-0.69), (6.41+/-0.53) and (5.29+/-0.71) folds of those of the group A, respectively, and all of them showed significant difference (all P<0.01). CONCLUSIONS: TLR9-MyD88 signaling in alveolar macrophages plays a role in pathogenesis of VILI. PMID- 24809255 TI - [The use of 16S rDNA sequencing in species diversity analysis for sputum of patients with ventilator-associated pneumonia]. AB - OBJECTIVE: To study the species and amount of bacteria in sputum of patients with ventilator-associated pneumonia (VAP) by using 16S rDNA sequencing analysis, and to explore the new method for etiologic diagnosis of VAP. METHODS: Bronchoalveolar lavage sputum samples were collected from 31 patients with VAP. Bacterial DNA of the samples were extracted and identified by polymerase chain reaction (PCR). At the same time, sputum specimens were processed for routine bacterial culture. The high flux sequencing experiment was conducted on PCR positive samples with 16S rDNA macro genome sequencing technology, and sequencing results were analyzed using bioinformatics, then the results between the sequencing and bacteria culture were compared. RESULTS: (1) 550 bp of specific DNA sequences were amplified in sputum specimens from 27 cases of the 31 patients with VAP, and they were used for sequencing analysis. 103 856 sequences were obtained from those sputum specimens using 16S rDNA sequencing, yielding approximately 39 Mb of raw data. Tag sequencing was able to inform genus level in all 27 samples. (2) Alpha-diversity analysis showed that sputum samples of patients with VAP had significantly higher variability and richness in bacterial species (Shannon index values 1.20, Simpson index values 0.48). Rarefaction curve analysis showed that there were more species that were not detected by sequencing from some VAP sputum samples. (3) Analysis of 27 sputum samples with VAP by using 16S rDNA sequences yielded four phyla: namely Acitinobacteria, Bacteroidetes, Firmicutes, Proteobacteria. With genus as a classification, it was found that the dominant species included Streptococcus 88.9% (24/27), Limnohabitans 77.8% (21/27), Acinetobacter 70.4% (19/27), Sphingomonas 63.0% (17/27), Prevotella 63.0% (17/27), Klebsiella 55.6% (15/27), Pseudomonas 55.6% (15/27), Aquabacterium 55.6% (15/27), and Corynebacterium 55.6% (15/27). (4) Pyrophosphate sequencing discovered that Prevotella, Limnohabitans, Aquabacterium, Sphingomonas might not be detected by routine bacteria culture. Among seven species which were identified by both methods, pyrophosphate sequencing yielded higher positive rate than that of ordinary bacteria culture [Streptococcus: 88.9% (24/27) vs. 18.5% (5/27), Klebsiella: 55.6% (15/27) vs. 18.5% (5/27), Acinetobacter: 70.4% (19/27) vs. 37.0% (10/27), Corynebacterium: 55.6% (15/27) vs. 7.4% (2/27), P<0.05 or P<0.01]. Sequencing positive rate was found to increase positive rate for culture of Pseudomonas [55.6% (15/27) vs. 25.9% (7/27), P=0.050]. No significant differences were observed between sequencing and ordinary bacteria culture for detection Staphylococcus [7.4% (2/27) vs. 11.1% (3/27)] and Neisseria bacteria genera [18.5% (5/27) vs. 3.7% (1/27), both P>0.05]. CONCLUSIONS: 16S rDNA sequencing analysis confirmed that pathogenic bacteria in sputum of VAP were complicated with multiple drug resistant strains. Compared with routine bacterial culture, pyrophosphate sequencing had higher positive rate in detecting pathogens. 16S rDNA gene sequencing technology may become a new method for etiological diagnosis of VAP. PMID- 24809256 TI - [The effect of transfected microRNA-146a on expression of interleukin-1 receptor associated kinase 1 and tumor necrosis factor receptor-associated factor 6 in alveolar macrophages]. AB - OBJECTIVE: To observe the effect of transfected microRNA-146a (miR-146a) on expression of interleukin-1 receptor-associated kinase 1 (IRAK-1) and tumor necrosis factor receptor-associated factor 6 (TRAF-6) in alveolar macrophages, and to explore the regulatory mechanism of miR-146a in the inflammatory response of alveolar macrophages. METHODS: Alveolar macrophages NR8383 were cultured and divided into two groups: transfected miR-146a mimic group was transfected 50 nmol/L Pre-miR miR-146a precursors and the negative control group was transfected Cy3-labeled Pre-miR negative control. Cells were collected at 24 hours after transfection. The miR-146a and the mRNA expression of IRAK-1 and TRAF-6 were detected by real-time fluorescent quantitation reverse transcription-polymerase chain reaction (RT-qPCR), and the protein expression of IRAK-1 and TRAF-6 was assayed by Western Blot. RESULTS: Compared with negative control group, the expression of miR-146a was upregulated by (24.55+/-6.14) fold compared with miR 146a mimic group (t=-9.353, P=0.001). The mRNA expressions of IRAK-1 and TRAF-6 in miR-146a mimic group were upregulated by (1.16+/-0.10) fold (t=2.701, P=0.054) and (1.19+/-0.16) fold (t=2.032, P=0.112) , respectively, compared with that of negative control group, but the protein levels of IRAK-1 and TRAF-6 were decreased by 73.0% (t=-9.353, P=0.001) and 64.1% (t=-6.839, P=0.002), respectively . CONCLUSIONS: miR-146a mimic was successfully transfected into the alveolar macrophage NR8383. The overexpression of miR-146a in alveolar macrophages can down-regulate the expression of IRAK-1 and TRAF-6 in protein translation levels, and its mechanism may be related with inhibition of protein translation. PMID- 24809257 TI - [A meta analysis of the effect of enhanced hand hygiene on the morbidity of ventilator-associated pneumonia]. AB - OBJECTIVE: To determine the effect of enhanced hand hygiene on the morbidity of ventilator-associated pneumonia (VAP). METHODS: Clinical studies which were related to enhanced hand cleansing to the risk of VAP, which were published between July 1992 and June 2013 in English or Chinese were retrieved via computer and manual screening. Data were extracted according to appropriate inclusion and exclusion criteria and analyzed with RevMan 5.0 software. RESULTS: A total of 6 studies, all of which were performed with well controlled protocol, involving 28 461 mechanical ventilator days and 32 428 mechanical ventilator days were analyzed. The morbidity of VAP was 39.5 days per 1 000 mechanical ventilator days and 19.5 days per 1 000 mechanical ventilator days before and after enhanced hand cleaning, respectively. The methods of enhancing hand hygiene included feasible hand hygiene apparatus, long-term education, supervision and feedback, as well as increased hand cleaning compliance. All 6 eligible studies reported that enhanced hand washing lowered the risk of VAP, with risk reduction ranging from 29.8% to 65.5% with a mean reduction value of 50.6%. Meta analysis showed that enhanced hand cleaning could protect patients from VAP with odds ratio (OR) varying from 1.43 to 5.82 [pooled OR=2.23, 95% confidence interval (95%CI) 1.62-3.07, P<0.000 01]. It was showed in funnel chart that bias in the published articles was not significant. CONCLUSIONS: Enhanced hand hygiene has an effect of prevention of VAP morbidity and is associated with lowered morbidity of VAP. However, the reliability of this conclusion is questionable because of poor quality of these studies. PMID- 24809258 TI - [The role of thromboxane A2 receptor gene promoter polymorphism in acute cerebral infarction]. AB - OBJECTIVE: To investigate the association between thromboxane A2 receptor (TXA2R) gene promoter rs2271875, rs768963 polymorphism and acute cerebral infarction in Chinese Han population. METHODS: A prospective study was conducted. From October 2009 to May 2013, 223 patients with cerebral infarction (cerebral infarction group) and 142 cohorts with normal physical examination results (control group) from Taizhou City Central Hospital in Zhejiang Province were enrolled. Triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were determined by enzymatic colorimetry, whereas blood glucose was determined with hexokinase. The genotypes of rs2271875 and rs768963 polymorphism in TXA2R gene were detected by the polymerase chain reaction-ligase detection reaction (PCR-LDR) technique. Differences in gender, age, serum TG, TC, HDL-C, LDL-C, concentration of blood glucose, and blood pressure (systolic pressure, diastolic pressure) between cerebral infarction group and control group were compared as well as TXA2R promoter rs2271875, rs768963 genotype and allele frequencies distribution. RESULTS: The significant differences in males (147 cases vs. 57 cases, chi(2)=23.385, P=0.000), serum TG (2.02+/-1.14 mmol/L vs. 1.56+/-0.79 mmol/L, t=4.663, P=0.000), blood glucose (6.40+/-2.50 mmol/L vs. 5.28+/-0.92 mmol/L, t=6.084, P=0.000), systolic pressure (146.64+/-21.34 mmHg vs. 135.73+/-18.09 mmHg, t=5.234, P=0.000), diastolic blood pressure (86.29+/-11.79 mmHg vs. 80.74+/ 11.23 mmHg, t=4.468, P=0.000) between cerebral infarction patients and controls were found. The results from multi-logistic regression analysis suggested that male was an independent risk factor for cerebral infarction [odds ratio (OR) 3.300, 95% confidence interval (95%CI) 1.905-5.175, P=0.000]. There were statistically significant differences between infarction group and the control group both in aspects of genotype (TT: 0.112 vs. 0.183, TC: 0.498 vs. 0.535, CC: 0.390 vs. 0.282, chi(2)=6.298, P=0.043) and the allele frequency distribution (T: 0.361 vs. 0.451, C: 0.639 vs. 0.549, chi(2)=5.839, P=0.016) of TXA2R gene rs768963. No statistical significant difference was found in rs2271875 in respect of genotype (GG: 0.336 vs. 0.352, GA: 0.480 vs. 0.451, AA: 0.184 vs. 0.197, chi (2)=0.302, P=0.859) and the allele frequency distribution (G: 0.576 vs. 0.577, A: 0.424 vs. 0.423, chi(2)=0.001, P=0.974). Coefficient of both linkage disequilibrium (D') of rs2271875 and rs768963 was 0.684. When the pair was haplotype AT, the frequency in the infarction group was significantly lower than that in the control group (0.034 vs. 0.081, chi(2)=7.883, P=0.005). CONCLUSIONS: rs768963 gene mutation, but not that of the rs2271875, showed significant correlation with the occurrence of cerebral infarction. There was a loose linkage disequilibrium between rs2271875 and rs768963 of TXA2R. Haplotype AT reduces the risk of cerebral infarction. PMID- 24809259 TI - [Influences and mechanisms of somatostatin on inflammation in endotoxin-induced acute lung injury mice]. AB - OBJECTIVE: To investigate the effects of somatostatin on inflammation in endotoxin-induced acute lung injury mice and its underlying mechanisms. METHODS: 72 ICR male mice of specific pathogen free (SPF) were randomly divided into four groups: control group, SST control group, model group and SST intervention group, each group included 18 mice. The ALI model was reproduced by intraperitoneal injection of 40 mL/kg endotoxin, and the mice in control group was given intraperitoneal injection of equivalent normal saline. The mice in SST intervention group was given the subcutaneous injection of SST (20 MUg, 20 mL/kg) at 0.5, 2, 6 and 12 hours after model reproduction. Six mice were sacrificed at 3, 8 and 16 hours after the first injection of LPS or NS. The lung wet/dry ratio (W/D) was calculated with oven drying method. Pathological changes in lung tissues were observed by light microscope. Serum SST, tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-6, IL-10) levels were determined by enzyme linked immunosorbent assay (ELISA). The mRNA and protein expressions of Toll like receptor 4 (TLR4) and nuclear factor-KappaBp65 (NF-KappaBp65) were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western Blot. RESULTS: There were no significant differences in above indexes between control group and SST control group. Compared with control group, lung W/D ratio, serum SST, TNF-alpha, IL-6, IL-10, and the mRNA and protein expressions of TLR4 and NF KappaBp65 in model group were significantly increased. The W/D ratio, IL-6, IL 10, and the mRNA and protein expressions of TLR4 all peaked at 16 hours (W/D ratio: 6.32+/-0.18 vs. 4.14+/-0.14, IL-6: 673.78+/-56.13 ng/L vs. 50.17+/-7.06 ng/L, IL-10: 481.13+/-40.78 ng/L vs. 61.71+/-10.05 ng/L, TLR4 mRNA: 0.740+/-0.099 vs. 0.180+/-0.028, TLR4 protein: 0.935+/-0.067 vs. 0.222+/-0.019, all P<0.05), and SST, TNF-alpha, the mRNA and protein expressions of NF-KappaBp65 peaked at 8 hours (SST: 254.97+/-38.75 ng/L vs. 95.87+/-13.95 ng/L, TNF-alpha: 139.69+/-19.06 ng/L vs. 21.90+/-4.52 ng/L, NF-KappaBp65 mRNA: 0.753+/-0.065 vs. 0.190+/-0.026, NF-KappaBp65 protein: 1.214+/-0.079 vs. 0.303+/-0.067, all P<0.05). Compared with model group, the lung injury in SST intervention group was significantly improved, and the indexes were significantly decreased except for serum SST which was gradually increased (16-hour W/D ratio: 5.21+/-0.14 vs. 6.32+/-0.18, 8-hour TNF-alpha: 80.48+/-8.52 ng/L vs. 139.69+/-19.06 ng/L, 16-hour IL-6: 394.99+/ 37.17 ng/L vs. 673.78+/-56.13 ng/L, 16-h IL-10: 326.95+/-36.41 ng/L vs. 481.13+/ 40.78 ng/L, 16-hour TLR4 mRNA: 0.240+/-0.028 vs. 0.740+/-0.099, 16-hour TLR4 protein: 0.618+/-0.066 vs. 0.935+/-0.067, 8-hour NF-KappaBp65 mRNA: 0.240+/-0.045 vs. 0.753+/-0.065, 8-hour NF-KappaBp65 protein: 0.784+/-0.041 vs. 1.214+/-0.079, all P<0.05). CONCLUSIONS: SST has significant protective effects on endotoxin induced ALI via direct suppression of the TLR4-NF-KappaB cytokine pathway, thus alleviate lung tissue inflammation. PMID- 24809260 TI - [A research on the influence of two herbal concoctions on Toll-like receptor signal pathways of influenza virus induced pneumonia in mice]. AB - OBJECTIVE: To investigate the effect of Shufeng Xuanfei and Jiebiao Qingli concoctions on Toll-like receptor (TLR) signal pathway of pneumonia infected with influenza virus in mice. METHODS: The pneumonia model was reproduced by nasal dropping of influenza virus A in mice. The mice were randomly divided into nine groups: normal group (C), model group (M), tamiflu group (D), Shufeng Xuanfei low dose (SL), medium-dose (SM) and high-dose (SH) groups, Jiebiao Qingli low-dose (JL), medium-dose (JM) and high-dose (JH) groups, each n=12. Two hours after model-reproduction, the mice in C group and M group received distilled water by gavage. The mice in D group received 2.5 g*mL(-1)*d(-1) oseltamivir phosphate. Shufeng Xuanfei formula in doses of 3.76, 1.88, 0.94 g*kg(-1)*d(-1) were respectively administered to SH, SM and SL groups by gavage, Jiebiao Qingli formula in doses of 4.37, 2.18, 1.09 g*kg(-1)*d(-1) was given to JH, JM and JL groups by gavage, respectively. Each group was in equal dose of 0.2 mL daily over a 4-day period. Total RNA was extracted in each group. Then gene chips were used to screen these RNA samples. Some genes that were involved in TLR signal pathways were selected. These candidate genes were verified by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: TLR7, MYD88, CCL5, IFNB1, IL6, IL12a, NFKBIA and IKBKB were up-regulated in model group compared with control group. Compared with model group, down-regulated genes in medium dose, low-dose Shufeng Xuanfei formula and medium-dose Jiebiao Qingli formula included TLR3, TLR7, MYD88, CCL5, IFNB1, IL6, IL12a, NFKBIA and IKBKB (log2 signal intensity of SM/M in medium-dose Shufeng Xuanfei formula group were -1.24, -2.02, -1.36, -1.95, -0.63, -1.33, -3.50, -1.33, -1.33, log2 signal intensity of SL/M in low-dose Shufeng Xuanfei group were -1.07, -2.43, -2.63, -2.30, -5.09, 3.19, -3.53, -1.95, -1.95, log2 signal intensity of JM/M in medium-dose Jiebiao Qingli formula group were -1.78, -0.55, -1.35, -1.47, -1.65, -2.03, -3.02, -1.57, -1.57, respectively). The results suggested that the effect of Shufeng Xuanfei formula was better than that of Jiebiao Qingli formula. By RT-PCR, compared with model group, low-dose, medium-dose and high-dose groups of Shufeng Xuanfei formula, medium-dose and high-dose groups of Jiebiao Qingli formula, and tamiflu group, significant decrease in TLR7, nuclear factor-KappaB (NF-KappaB), myeloid differential protein-88 (MyD88) mRNA expression were found. Medium-dose and low dose Shufeng Xuanfei formula group (TLR7 mRNA: 3.6+/-0.3, 3.5+/-1.2 vs. 7.4+/ 1.6, NF-KappaB mRNA: 1.1+/-0.2, 1.0+/-0.2 vs. 2.2+/-0.4; MyD88 mRNA: 1.4+/-0.4, 1.0+/-0.3 vs. 3.4+/-0.9, all P<0.01) and medium-dose Jiebiao Qingli formula group (TLR7 mRNA: 4.9+/-0.3 vs. 7.4+/-1.6, NF-KappaB mRNA: 1.3+/-0.7 vs. 2.2+/-0.4, MyD88 mRNA: 1.6+/-0.8 vs. 3.4+/-0.9, P<0.05 or P<0.01) were shown statistically significant decreases compared with the model group. CONCLUSIONS: Medium-dose and low-dose Shufeng Xuanfei formula and medium-dose Jiebiao Qingli formula can inhibit the inflammatory reaction induced by influenza virus by down-regulating the NF-KappaB through TLR signal pathways dependent on MyD88. The regulation of Shufeng Xuanfei formula in TLR signal pathways was superior to that of Jiebiao Qingli formula. PMID- 24809261 TI - [Clinical study of early use of neuromuscular blocking agents in patients with severe sepsis and acute respiratory distress syndrome]. AB - OBJECTIVE: To observe the clinical effects of early use of neuromuscular blocking agents (NMBA) in patients with severe sepsis and acute respiratory distress syndrome (ARDS). METHODS: A prospective study was conducted. 96 patients with severe sepsis and ARDS admitted from July 2012 to September 2013 to intensive care unit (ICU) of Liuzhou People's Hospital in Guangxi Zhuang Autonomous Region were enrolled and divided into severe ARDS group (n=48) and moderate ARDS group (n=48) according to the Berlin definition of ARDS. Then patients in each group were randomly divided into treatment group (n=24) and control group (n=24). All patients with diagnosis in accordance with the 2008 international septic shock and severe sepsis treatment guidelines were provided with comprehensive treatment and mechanical ventilation on the basis of analgesia and sedation. The patients in treatment group were given a loading dose of vecuronium during mechanical ventilation, started with 0.1 mg/kg up to 0.05 mg*kg(-1)*h(-1) for continuous intravenous infusion for 24-48 hours. The acute physiology and chronic health evaluation II (APACHEII) score, sequential organ failure assessment (SOFA), arterial oxygenation index (PaO2/FiO2), central venous oxygen saturation (ScvO2), arterial blood lactate (Lac), C-reactive protein (CRP) levels of two groups were compared before treatment and 48 hours after treatment, and 21-day mortality rate was finally compared. RESULTS: In moderate or severe ARDS group, there were no statistically significant difference in APACHEII score, SOFA score, PaO2/FiO2, ScvO2, Lac and CRP before treatment between two groups. APACHEII score, SOFA score, PaO2/FiO2, ScvO2, and Lac 48 hours after treatment were significantly improved in severe ARDS group compared with control group (APACHEII score: 16.58+/-2.41 vs. 19.79+/-3.52, t=3.679, P=0.010; SOFA score: 12.04+/-2.17 vs. 14.75+/-3.26, t=3.385, P=0.010; PaO2/FiO2: 159.31+/-22.57 mmHg vs. 131.81+/-34.93 mmHg, t=3.239, P=0.020; ScvO2: 0.673+/-0.068 vs. 0.572+/-0.142, t=3.137, P=0.030; Lac: 3.10+/-1.01 mmol/L vs. 4.39+/-1.72 mmol/L, t=3.161, P=0.030), while the value of CRP showed no significant difference (180.91+/-37.14 mg/L vs. 174.66+/ 38.46 mg/L, t=0.572, P=0.570). 21-day mortality in treatment group was significantly lower than that in control group [20.8% (5/24) vs. 50.0% (12/24), chi(2)=4.463, P=0.035]. In moderate ARDS group, each of the above clinical parameters were improved in both groups expect for CRP at 48 hours after treatment, but the indexes showed no statistically significant difference between two groups (all P>0.05). 21-day mortality rate in the treatment group was slightly lower than that in the control group which showed no statistically significant difference [16.7% (4/24) vs. 25.0% (6/24), chi(2)=0.505, P=0.477]. CONCLUSIONS: The early use of NMBA treatment of patients with severe sepsis and severe ARDS cannot only improve the severity but also reduce 21-day mortality. PMID- 24809262 TI - [Study of timing of invasive and noninvasive sequential ventilation in patients with acute respiratory distress syndrome]. AB - OBJECTIVE: To investigate the timing and value of noninvasive ventilation (NIV) as a weaning tool immediately after early extubation in patients with acute respiratory distress syndrome (ARDS). METHODS: A prospective randomized controlled trial was conducted. The ARDS patients with surgical diseases admitted to Department of Respiratory Intensive Care Unit (RICU) of the First Affiliated Hospital of Xinjiang Medical University were enrolled. The patients were randomly divided into sequential group and control group. All patients underwent endotracheal intubation and were mechanically ventilated. Every 12 hours during the first 3 days, the lung recruitment maneuver was performed during pressure control ventilation (PCV). After lung recruitment, all patients were ventilated with synchronized intermittent mandatory ventilation (SIMV) + pressure support ventilation (PSV) + positive end-expiratory pressure (PEEP) or assistant/control ventilation (A/C). The objects in sequential group who met the following criteria including those with oxygen index (PaO2/FiO2) reaching 200-250 mmHg (1 mmHg=0.133 kPa) under PEEP of 8 cmH2O (1 cmH2O=0.098 kPa), and pressure support of 12 cmH2O, and most acute infiltrating lesions having resolved on chest imaging, received noninvasive ventilation (NIV) immediately after extubation, and patients in control group continued to have invasive mechanical ventilation via intubation or tracheostomy with an endotracheal tube. The baseline data in both groups and the number of re-intubation in the sequential group were recorded. The duration of invasive mechanical ventilation and total duration of mechanical ventilation, ICU length of stay, the incidence of ventilator-associated pneumonia (VAP), and mortality rate were compared between the two groups. RESULTS: 53 consecutive adult patients were enrolled, including 26 in sequential group and 27 cases in control group. The period of endotracheal intubation was 7.0 (6.8, 9.5) days, and 7.7% (2/26) patients underwent re-intubation in sequential group. There were significant difference in respiratory and circulatory indicators before extubation spontaneous breathing trial (SBT) <=10 minutes in sequential group, indicating that the patients were still in the early stage of extubation sequential NIV. There was no significant difference in indices reflecting respiratory function and circulation between the two groups, except that respiratory rate at 1 hour was slightly increased in sequential group as compared with that of control group, indicating that sequential NIV could maintain invasive ventilation function. There was significant difference in duration of invasive mechanical ventilation [7.0 (6.8, 9.5) days vs. 21.0 (17.0, 25.0) days, Z=-6.048, P=0.000], duration of total mechanical ventilation (18.0+/-4.1 days vs. 22.0+/-7.3 days, t=-2.805, P=0.008), and length of ICU stay (21.0+/-4.1 days vs. 28.0+/-8.1 days, t=-4.012, P=0.000) between sequential group and control group, but there was no significant differences in the incidence of VAP [15.4% (4/26) vs. 29.6 (8/27), chi(2)=1.535, P=0.215] and mortality rate [7.7% (2/26) vs. 18.5% (5/27), P=0.420]. CONCLUSIONS: When PaO2/FiO2 reached 200-250 mmHg under the condition of low ventilation, sequential NIV facilitates the early discontinuation of mechanical ventilation in ARDS patients with surgical diseases, with shortening of duration of invasive mechanical ventilation, total mechanical ventilation, and the length of ICU stay. PMID- 24809263 TI - [The influence of positive end-expiratory pressure on cerebral blood flow and cerebrovascular autoregulation in patients with acute respiratory distress syndrome]. AB - OBJECTIVE: To explore the influence of different positive end-expiratory pressure (PEEP) levels on cerebral blood flow (CBF) and cerebrovascular autoregulation in patients with acute respiratory distress syndrome(ARDS). METHODS: A prospective study was conducted. Moderate or severe ARDS patients admitted to Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from January 1st, 2013 to October 1st, 2013 were enrolled. The changes in hemodynamics, respiratory mechanics and gas exchange under different levels of PEEP were observed. CBF velocity of middle cerebral artery (MCA) was measured using transcranial Doppler (TCD), and breath-holding index (BHI) was also calculated. RESULTS: 35 patients with ARDS were included. The oxygenation index (OI), peak inspiratory pressure (PIP), plat pressure (Pplat) and central venous pressure (CVP) were markedly elevated (OI: 324.7+/-117.2 mmHg vs. 173.4+/-95.8 mmHg, t=5.913, P=0.000; PIP: 34.7+/-9.1 cmH2O vs. 26.1+/-7.9 cmH2O,t=4.222, P=0.000; Pplat: 30.5+/-8.4 cmH2O vs. 22.2+/-7.1 cmH2O, t=4.465, P=0.000; CVP: 12.1+/-3.5 mmHg vs. 8.8+/-2.2 mmHg, t=4.723, P=0.000) when PEEP was increased from (6.4+/-1.0) cmH2O to (14.5+/-2.0) cmH2O (1 cmH2O=0.098 kPa). But no significant difference in the heart rate (85.5+/-19.1 beats/min vs. 82.7+/-17.3 beats/min, t=0.643, P=0.523), mean arterial pressure (73.5+/-12.4 mmHg vs. 76.4+/-15.1 mmHg, t=0.878, P=0.383) and CBF velocity of MCA [peak systolic flow velocity (Vmax): 91.26+/-17.57 cm/s vs. 96.64+/-18.71 cm/s, t=1.240, P=0.219; diastolic flow velocity (Vmin): 31.54+/ 7.71 cm/s vs. 33.87+/-8.53 cm/s, t=1.199, P=0.235; mean velocity (Vmean): 51.19+/ 12.05 cm/s vs. 54.27+/-13.36 cm/s, t=1.013, P=0.315] was found. 18 patients with BHI<0.1 at baseline demonstrated that cerebral vasomotor reactivity was poor. BHI was slightly decreased with increase in PEEP (0.78+/-0.16 vs. 0.86+/-0.19, t=1.905, P=0.061). CONCLUSIONS: Some of moderate or severe ARDS patients without central nervous system disease have independent of preexisting cerebral autoregulation impairment. However, independent of preexisting cerebral autoregulation may not further be impaired when a high PEEP was chosen. PMID- 24809264 TI - [Effect of high positive end-expiratory pressure for mechanical ventilation in the treatment of neurological pulmonary edema]. AB - OBJECTIVE: To explore the effect of high positive end-expiratory pressure (PEEP) for the treatment of neurological pulmonary edema (NPE) in patients undergoing mechanical ventilation, and to look for the best mechanical ventilation strategy to improve the prognosis. METHODS: A prospective study was conducted, and 120 patients with NEP admitted to Department of Critical Care Medicine of the First Affiliated Hospital of Guangxi Traditional Chinese Medical University from January 2010 to August 2013 were enrolled and divided into two groups according to random number table (n=60 in each group). The patients in two groups were given empiric treatment for the disease, and they underwent mechanical ventilation. In the normal PEEP group PEEP was 3-10 cmH2O (1 cmH2O=0.098 kPa), and in the high PEEP group PEEP was 11-30 cmH2O, and all the rest parameters were the same. Clinical indices before and 7 days after treatment, and 28-day morality rate were compared between two groups. RESULTS: The 28-day morality rate in high PEEP group was obviously lower than that in the normal PEEP group [25.0% (15/60) vs. 65.0% (39/60), chi(2)=6.465, P=0.011]. The clinical signs in both groups were improved after treatment. Compared with the normal PEEP group, the clinical indices in high PEEP group were more significantly improved. There were significant differences in body temperature (37.4+/-0.5 centigrade vs. 38.5+/-0.6 centigrade), respiratory rate (18.3+/-3.1 times/min vs. 23.3+/-3.5 times/min), heart rate (94.7+/-8.5 beats/min vs. 113.5+/-8.0 beats/min), white blood cell count (WBC: 12.5+/-2.1 *10(9)/L vs. 17.1+/-1.7 *10(9)/L), acute physiology and chronic health evaluation II (APACHEII) score (15.6+/-3.2 vs. 19.8+/-3.7), Glasgow coma score (GCS: 12.5+/-2.1 vs. 8.5+/-2.9), gastrointestinal dysfunction score (3.9+/-3.0 vs. 3.6+/-2.4), oxygenation index (PaO2/FiO2: 196.5+/-45.1 mmHg vs. 134.1+/-22.3 mmHg), serum creatinine (SCr: 86.5+/-35.6 MUmol/L vs. 98.5+/ 37.7 MUmol/L), total bilirubin (TBil: 39.7+/-23.5 MUmol/L vs. 41.5+/-16.2 MUmol/L), C-reacting protein (CRP: 53.7+/-21.4 mmol/L vs. 108.4+/-26.3 mmol/L), prothrombin time (PT: 15.0+/-2.1 s vs. 20.4+/-2.2 s), activated partial thromboplastin time (APTT: 37.3+/-4.9 s vs. 56.7+/-13.6 s), international normalized ratio (INR: 2.52+/-0.64 vs. 4.01+/-0.77), extra vascular lung water index (EVLWI: 7.53+/-1.21 mL/kg vs. 15.85+/-3.41 mL/kg), pulmonary vascular permeability index (PVPI: 6.07+/-0.89 vs. 9.47+/-1.26), mean arterial pressure (MAP: 87.3+/-10.9 mmHg vs. 98.7+/-13.6 mmHg), cardiac output (CO: 7.15+/-1.42 L/min vs. 5.65+/-1.82 L/min), systemic vascular resistance index (SVRI: 112.4+/ 9.5 KP vs. 136.5+/-11.9 KP), and blood lactate (2.53+/-1.23 mmol/L vs. 5.81+/ 2.17 mmol/L) between high PEEP group and normal PEEP group (P<0.05 or P<0.01). CONCLUSIONS: Prognosis can be improved in NPE patients with the use of high PEEP in mechanical ventilation. PMID- 24809265 TI - [Study on antibacterial property of silver loaded titanium dioxide antibacterial coated endotracheal intubation tube]. AB - OBJECTIVE: To study the antibacterial property of silver loaded titanium dioxide (TiO2) antibacterial coated endotracheal intubation tube, and to determine the minimum effective antibacterial concentration. METHODS: Intubation tubes coated with different concentrations of antibacterial agents were prepared with sol gel method. Polyethylene endotracheal intubation tubes were used as substrate, and silver loaded TiO2 was used as the antibacterial agent. According to the different antibacterial concentrations of the antibacterial agent, the tubes were divided into nine groups: 10.0% group, 5.0% group, 2.0% group, 1.5% group, 1.0% group, 0.8% group, 0.6% group, 0.2% group, and control group. They were respectively immersed in three standard bacteria suspensions with 1.0*10(5) cfu/mL: Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. Together with standard bacteria liquid group, there were 10 experimental groups. They were kept overnight for 24 hours. 10 MUL of respective culture medium was smeared on blood agar culture medium. After being cultured overnight in 35 centigrade, the number of bacteria colonies was respectively counted. RESULTS: In 1.0*10(5) cfu/mL of three standard bacteria liquids with antibacterial agent concentration >=1.0%, three bacterial colonies had un-obviously growth rate. Almost the same strong antibacterial effects to achieve sterilizing rates of more than 98% was shown in each group of the antibacterial coating endotracheal intubation tubes (all P>0.05). As the antibacterial agent concentration decreased, three bacterial colonies were increasing gradually. Intermediate antibacterial effects were shown in tubes of 0.8% group, with significant statistic difference as compared with 1.0% and 0.6% groups [Pseudomonas aeruginosa: 7.300 (4.050, 8.350) vs. 0.200 (0.050, 1.200), 9.700(9.000, 10.000); Staphylococcus aureus: 4.100 (3.300, 4.650) vs. 0.000 (0.000, 0.150), 5.800 (5.350, 7.650); Escherichia coli: 1.400 (0.750, 3.750) vs. 0.050 (0.025, 0.050), 9.500 (8.500, 9.800), all P<0.01]. CONCLUSIONS: Silver loaded TiO2 antibacterial coated endotracheal intubation tube had definite antibacterial properties, which were related to the antibacterial concentration. Strong antibacterial effects were shown when antibacterial concentration was above 1.0%, with bacteria almost completely killed in the immersing liquid. PMID- 24809266 TI - [Experimental study of the monitoring bias of pressure in intubation balloon using handheld pressure gauge]. AB - OBJECTIVE: To explore the bias between the real pressure and the measured values when handheld pressure gauge (HPG) was used to monitor intermittently the pressure in the intubation balloon, so as to provide some measures for the correct use of HPG. METHODS: In the first part of the study, HPG was used to measure the pressure with the balloon connected with a three-way tube with which to control the inflation and deflation in a laboratory to measure the pressure in the air bag. After gaining the deviation in this in vitro experiment, it was tested and verified in vivo in adult patients undergoing endotracheal intubation. RESULTS: After 132 times of measurements, it was found that measurement with a HPG might result in an "inherent loss" (3.928+/-0.291) cmH2O (1 cmH2O=0.098 kPa, t=155.273, P=0.000) between inflation value [(30.000+/-0.000) cmH2O] and measured value [(26.072+/-0.291) cmH2O]. In addition, after 214 times repeated measurements, the pressure "loss" during disconnection of the gauge was as high as (1.196+/-0.954) cmH2O (t=18.348, P=0.000) between filled values [(30.000+/ 0.000) cmH2O] and measured values [(28.804+/-0.954) cmH2O] and it was named as "error loss". At last, the total error was verified by clinical test, and it was (5.270+/-2.583) cmH2O (t=29.632, P=0.000) between pressure of filled value [(30.000+/-0.000) cmH2O] and measured value [(24.730+/-2.583) cmH2O]. CONCLUSIONS: When the balloon pressure was monitored intermittently with HPG, the real value should be the measured value plus the "error". In addition, subglottic aspiration should be done before the connection of the balloon to the gauge to prevent the secretions on the cuff falls into the deeper airway, and to maintain the cuff pressure at 30 cmH2O. PMID- 24809267 TI - [The clinical study of the optimal aeration quantity of artificial airway gasbag]. PMID- 24809268 TI - [Multistepped sealed tube in patients undergoing trachea incision]. PMID- 24809269 TI - [Application of dexmedetomidine on mechanical ventilation weaning in delirium patients]. PMID- 24809270 TI - [Preliminary investigation of the critical value discussion system applied in patients in emergency observation room]. PMID- 24809271 TI - [Research progress of carbon monoxide in acute lung injury]. PMID- 24809272 TI - [The role of neutrophil elastase and its inhibitors in acute respiratory distress syndrome: an update]. PMID- 24809273 TI - Is cavotricuspid isthmus block present? PMID- 24809275 TI - Evaluation of erlotinib treatment response in non-small cell lung cancer using metabolic and anatomic criteria. AB - AIM: In this paper the clinical value of PET for early prediction of tumor response to Erlotinib in patients with advanced or metastatic nonsmall cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen is evaluated. The aim was to compare the early metabolic treatment response using European Organization for Research and Treatment of Cancer (EORTC) 1999 recommendations and PET Response Criteria in Solid Tumors (PERCIST), and the standard treatment response using Response Evaluation Criteria in Solid Tumors (RECIST). METHODS: Twenty patients with stage IV NSCLC were enrolled prospectively. PET/CT studies were performed before, then 48 h, and 45 days after the initiation of Erlotinib treatment. The lesion with the highest uptake in each patient was evaluated according to EORTC 1999 recommendations, PERCIST and RECIST to assess metabolic and anatomic response. Response classifications were compared statistically using Wilcoxon signedrank test. Disease-Free Survival (DFS) and Overall Survival (OS) were calculated by the KaplanMeier test. RESULTS: At 48 h, the KaplanMeier analysis showed that EORTC proved to be a significant prognostic factor for predicting DFS and OS. At 45 days, there was a significant difference in response evaluation between RECIST and metabolic classifications. RECIST and PERCIST were significant prognostic factors for predicting DFS and OS. EORTC was not able to discriminate responder from non-responder patients. CONCLUSION: This study shows that, according to the EORTC protocol, the PET exam is able to provide early identification of patients who benefit from Erlotinib treatment. Used at the end of therapy, PERCIST could be considered an appropriate metabolic evaluation method to discriminate responders from nonresponders. PMID- 24809274 TI - Pathogen-host reorganization during Chlamydia invasion revealed by cryo-electron tomography. AB - Invasion of host cells is a key early event during bacterial infection, but the underlying pathogen-host interactions are yet to be fully visualized in three dimensional detail. We have captured snapshots of the early stages of bacterial mediated endocytosis in situ by exploiting the small size of chlamydial elementary bodies (EBs) for whole-cell cryo-electron tomography. Chlamydiae are obligate intracellular bacteria that infect eukaryotic cells and cause sexually transmitted infections and trachoma, the leading cause of preventable blindness. We demonstrate that Chlamydia trachomatis LGV2 EBs are intrinsically polarized. One pole is characterized by a tubular inner membrane invagination, while the other exhibits asymmetric periplasmic expansion to accommodate an array of type III secretion systems (T3SSs). Strikingly, EBs orient with their T3SS-containing pole facing target cells, enabling the T3SSs to directly contact the cellular plasma membrane. This contact induces enveloping macropinosomes, actin-rich filopodia and phagocytic cups to zipper tightly around the internalizing bacteria. Once encapsulated into tight early vacuoles, EB polarity and the T3SSs are lost. Our findings reveal previously undescribed structural transitions in both pathogen and host during the initial steps of chlamydial invasion. PMID- 24809276 TI - Imaging B lymphocytes in autoimmune inflammatory diseases. AB - B cells arise from stem cells precursor and develop through a tightly regulated and selective process that lead to the generation of different B cell populations such as transitional, mature, memory and plasmacells. These B cell subsets can be identified using flow cytometry by the expression of specific surface antigens. The growing knowledge of the pivotal role played by B cells in the development and progression of autoimmune diseases combined with the advances in monoclonal antibody technology, led in the last years to the generation of different biological agents targeting B cells. In this context, nuclear medicine can offer the possibility to use a panel of biologic radiopharmaceuticals for molecular imaging of inflammatory diseases. Radiopharmaceuticals bind to their targets with high affinity and specificity and have an excellent imaging diagnostic potential for the evaluation of disease activity, selection and monitoring of immune therapies. Several molecules have been radiolabelled for the imaging of T lymphocytes whereas, by now, the anti CD20 Rituximab is the only biological therapy targeting B cells that demonstrated to be efficiently radiolabelled and used to detect inflammation in autoimmune patients. PMID- 24809277 TI - PET imaging of inflammation. AB - Inflammatory diseases are common place and often chronic. Most inflammatory cells have increased uptake of glucose which is enhanced in the presence of local cytokines. Therefore, imaging glucose metabolism by the means of [18] F-fluro-de oxy glucose (FDG) positron emission tomography (PET) holds significant promise in imaging focal inflammation. Most of the work published involved small series of patients with either vasculitis, sarcoid or rheumatoid arthritis. It would appear that FDG PET is a simple and effective technique to identify inflammatory tissue in these conditions. There is even some work to suggest that by comparing baseline and early post therapy scans clinical outcome can be predicted. This would appear to be true with vasculitis as well as retroperitoneal fibrosis. The number of patients in each study is small but the evidence is compelling enough to recommend FDG PET imaging in the routine care of these patients. PMID- 24809278 TI - Improved selectivity of an engineered multi-product terpene synthase. AB - Mutation of the sesquiterpene synthase Cop2 was conducted with a high-throughput screen for the cyclization activity using a non-natural substrate. A mutant of Cop2 was identified that contained three amino acid substitutions. This mutant, 17H2, converted the natural substrate FPP into germacrene D-4-ol with 77% selectivity. This selectivity is in contrast to that of the parent enzyme in which germacrene D-4-ol is produced as 29% and alpha-cadinol is produced as 46% of the product mixture. The mutations were shown to each contribute to this selectivity, and a homology model suggested that the mutations lie near to the active site though would be unlikely to be targeted for mutation by rational methods. Kinetic comparisons show that 17H2 maintains a kcat/KM of 0.62 mM(-1) s( 1), which is nearly identical to that of the parent Cop2, which had a kcat/KM of 0.58 mM(-1) s(-1). PMID- 24809279 TI - Implant losses for the bone-anchored hearing devices are more frequent in some patients. AB - INTRODUCTION: Our knowledge of implant losses for bone-anchored hearing devices (BAHD) is still limited. This study examined the long-term survival rate, the reasons for implant loss, and the need for implant replacement in a large cohort with a long follow-up. METHOD: Retrospective study of patients who received a BAHD between January 1977 and December 2011 as identified from records of operations performed. All data were retrieved from patient records. RESULTS: A total of 571 patients were found in the surgical records. Seven patients were excluded because of incomplete data. The follow-up period was up to 32 years, with a median follow-up of 6.6 years. Implant failures were identified in 46 (8.2%) of the patients. A total of 763 implants were inserted. Of these, 141 (18%) implants were lost: 109 (14%) due to lost osseointegration, 21 (3%) due to trauma, while 11 were electively removed. Twenty-seven patients had 1 implant reinstallation, whereas 5 patients had 2 reinstallations. Nine patients were reinstalled three times and five patients were reinstalled 4 to 6 times. Of 141 implants lost, 78 (55%) were lost in 19 patients with 2 or more implant losses. CONCLUSION/IMPLICATIONS: Implant failures were identified in 8.2% of the patients with a median follow-up time of 6.6 years. A total of 141 (18%) of 763 implants were lost; the majority of losses took place in patients with multiple implant failures. PMID- 24809280 TI - The use of cone-beam computed tomography to determine cochlear implant electrode position in human temporal bones. AB - OBJECTIVE: To assess the utility of cone-beam computed tomography (CBCT) imaging in the estimation of cochlear implant (CI) electrode position in implanted temporal bones. STUDY DESIGN: Eight fresh frozen temporal bones were mounted and oriented as for standard surgery and were implanted with Cochlear Slim-Straight (SS) or Contour Advance electrode arrays by 2 CI surgeons. The bones were then imaged using an Accuitomo F170 CBCT scanner (isometric 250 MUm voxel size) and were then processed for histologic sectioning (500 MUm sections). MAIN OUTCOME MEASURES: The CBCT images and the histologic micrographs (providing the "gold standard") were examined independently by several observers who assessed the scalar position (tympani or vestibuli) of each electrode in each temporal bone specimen. RESULTS: Examination of the histologic micrographs confirmed that all electrodes were positioned within the scala tympani in all 8 bones. Similar judgments were made by the observers rating the CBCT images, except that one of the 2 observers estimated some of the apical electrodes to be located in the scala vestibuli in two of the bones implanted with the SS electrode. CONCLUSION: Cone-beam CT imaging is able to provide a good indication of the scalar position of implanted electrodes, although estimation may be slightly less reliable for apical electrodes and for straight electrode designs. Additional advantages of using CBCT for this purpose are shorter acquisition time and reduction of radiation dose as compared with conventional CT. PMID- 24809281 TI - Brachio-Oto-Renal Syndrome: CT Imaging and Intraoperative Diagnostic Findings. PMID- 24809282 TI - Pulsatile Tinnitus Secondary to a Dural Arteriovenous Fistula. PMID- 24809283 TI - Management of postoperative Crohn's disease. AB - Surgical treatment does not cure Crohn's disease, and postoperative recurrence is a feature of the clinical course of the disease. Ileocolonoscopy remains the gold standard for the surveillance of recurrent Crohn's disease and should be performed 6-12 months after an operation. Many other non-invasive techniques are also useful and complement endoscopy for the early diagnosis of postoperative recurrence. Anti-TNF agents show great efficacy for the prevention of postoperative recurrence, and long-term use can maintain remission. It remains undetermined whether early treatment after postoperative endoscopic recurrence is ultimately as efficacious as prophylactic therapy. PMID- 24809286 TI - A shift toward building with nature in the dredging and port development industries: managerial implications for projects in or near Natura 2000 areas. AB - Building with Nature is a new approach to designing water infrastructure, one that seeks to realize socioeconomic project goals in harmony with the environment. The Dutch dredging industry is promoting its application in the Netherlands, but similar concepts are emerging internationally. The Working with Nature concept has been developed under the auspices of the World Association for Waterborne Transport Infrastructure, Engineering with Nature by the US Army Corps of Engineers, and Flanders Bays 2100 by a group of Belgian dredging companies and international consultants. The research discussed in this article focuses on the feasibility of implementing the Building with Nature approach in the context of EU Natura 2000 governance. The initial expectation of the industry was that Natura 2000 regulations would obstruct innovative Building with Nature attempts. The empirical evidence points to a shift toward Building with Nature have taken place on the governance and project levels, and the goals of Natura 2000 and Building with Nature converging in practice. Using specific project-level variables identified by researchers, guidance for project development in Natura 2000 areas was proposed. We conclude by discussing the implications of the research results for the dredging industry dealing with Natura 2000 regulations in Europe and similar overarching nature regulations elsewhere. PMID- 24809287 TI - Anti-diarrhoeal activity of methanol extract of Santalum album L. in mice and gastrointestinal effect on the contraction of isolated jejunum in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Santalum album L., namely Sandalwood, honored as "Green Gold", is a traditional Chinese herb which has the effects of anti diarrhoeal and antibacterial activity. But there is limit scientific study on its activity and mechanism in gastrointestinal disorders. MATERIALS AND METHODS: in vivo, after intragastric administration, the methanol extract of Sandalwood (SE) (200, 400 and 800 mg/kg) were studied in castor oil-induced diarrhoea mice. By the test of small intestinal hyperfunction induced by neostigmine, SE was studied on gastrointestinal transit including gastric emptying and small intestinal motility. Meanwhile, in vitro, the effects of SE (0.02, 0.05, 0.1, 0.2, 0.3, 0.4 mg/mL) on the isolated tissue preparations of rat jejunum were also investigated. The rat jejunum strips were pre-contracted with acetylcholine (Ach; 10(-6)M), 5 hydroxytryptamine (5-HT, 200 MUM) or potassium chloride (KCl; 60 mM) and tested in the presence of SE. In addition, the possible myogenic effect was analyzed in the pretreatment of the jejunum preparations with SE or verapamil in Ca(2+)-free high-K(+) (60 mM) solution containing EDTA. RESULTS: At doses of 200, 400 and 800 mg/kg, SE showed significant anti-diarrhoeal activity against castor oil-induced diarrhoea as compared with the control. At the same doses, it also inhibited the gastric emptying and small intestinal motility in the mice of which small intestinal hyperfunction induced by neostigmine. It caused inhibitory effects on the spontaneous contraction of rat-isolated jejunum in dose-dependent manner ranging from 0.02 to 0.4 mg/mL, and it also relaxed the Ach-induced, 5-HT-induced and K(+)-induced contractions. SE shifted the Ca(2+) concentration-response curves to right, similar to that caused by verapamil (0.025 mM). CONCLUSIONS: These findings indicated that SE played a spasmolytic role in gastrointestinal motility which was probably mediated through inhibition of muscarinic receptors, 5-HT receptors and calcium influx. All these results provide pharmacological basis for its clinical use in gastrointestinal tract. PMID- 24809289 TI - WITHDRAWN:A New Therapy for Intestinal Flora Imbalance Using Ampicillin-Resistant Probiotics. AB - Ahead of Print article withdrawn by publisher. PMID- 24809288 TI - Anti-tumor effect of Shu-Gan-Liang-Xue decoction in breast cancer is related to the inhibition of aromatase and steroid sulfatase expression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shu-Gan-Liang-Xue Decoction (SGLXD), a traditional Chinese herbal formula used to ameliorate the hot flushes in breast cancer patients, was reported to have anti-tumor effect on breast cancer. Estrogen plays a critical role in the genesis and evolution of breast cancer. Aromatase and steroid sulfatase (STS) are key estrogen synthesis enzymes that predominantly contribute to the high local hormone concentrations. The present study was to evaluate the anti-tumor effect of SGLXD on estrogen receptor (ER) positive breast cancer cell line ZR-75-1, and to investigate its underlying mechanisms both in vitro and in vivo. MATERIALS AND METHODS: The anti-tumor activity of SGLXD in vitro was investigated using the MTT assay. The in vivo anti tumor effect of SGLXD was evaluated in non-ovariectomized and ovariectomized athymic nude mice. The effect of SGLXD on enzymatic activity of aromatase and STS was examined using the dual-luciferase reporter (DLR) based on bioluminescent measurements. Aromatase and STS protein level were assessed using Western blot assay. RESULTS: SGLXD showed dose-dependent inhibitory effect on the proliferation of ZR-75-1 cells with IC50 value of 3.40 mg/mL. It also suppressed the stimulating effect on cell proliferation of testosterone and estrogen sulfates (E1S). Oral administration of 6 g/kg of SGLXD for 25 days resulted in a reduction in tumor volume in non-ovariectomized and ovariectomized nude mice. The bioluminescent measurements confirmed that SGLXD has a dual-inhibitory effect on the activity of aromatase and STS. Western blot assay demonstrated that the treatment of SGLXD resulted in a decrease in aromatase and STS protein levels both in vitro and in vivo. CONCLUSION: Our results suggested that SGLXD showed anti-tumor effect on breast cancer cells both in vitro and in vivo. The anti tumor activity of SGLXD is related to inhibition of aromatase and STS via decreasing their expression. SGLXD may be considered as a novel treatment for ER positive breast cancer. PMID- 24809290 TI - Kinetic characterization and molecular modeling of NAD(P)(+)-dependent succinic semialdehyde dehydrogenase from Bacillus subtilis as an ortholog YneI. AB - Succinic semialdehyde dehydrogenase (SSADH) catalyzes the oxidation of succinic semialdehyde (SSA) into succinic acid in the final step of gamma-aminobutyric acid degradation. Here, we characterized Bacillus subtilis SSADH (BsSSADH) regarding its cofactor discrimination and substrate inhibition. BsSSADH showed similar values of the catalytic efficiency (kcat/Km) in both NAD(+) and NADP(+) as cofactors, and exhibited complete uncompetitive substrate inhibition at higher SSA concentrations. Further analyses of the sequence alignment and homology modeling indicated that the residues of catalytic and cofactor-binding sites in other SSADHs were highly conserved in BsSSADH. PMID- 24809291 TI - Identification and characterization of an anaerobic ethanol-producing cellulolytic bacterial consortium from Great Basin hot springs with agricultural residues and energy crops. AB - In order to obtain the cellulolytic bacterial consortia, sediments from Great Basin hot springs (Nevada, USA) were sampled and enriched with cellulosic biomass as the sole carbon source. The bacterial composition of the resulting anaerobic ethanol-producing celluloytic bacterial consortium, named SV79, was analyzed. With methods of the full-length 16S rRNA librarybased analysis and denaturing gradient gel electrophoresis, 21 bacteria belonging to eight genera were detected from this consortium. Clones with closest relation to the genera Acetivibrio, Clostridium, Cellulosilyticum, Ruminococcus, and Sporomusa were predominant. The cellulase activities and ethanol productions of consortium SV79 using different agricultural residues (sugarcane bagasse and spent mushroom substrate) and energy crops (Spartina anglica, Miscanthus floridulus, and Pennisetum sinese Roxb) were studied. During cultivation, consortium SV79 produced the maximum filter paper activity (FPase, 9.41 U/ml), carboxymethylcellulase activity (CMCase, 6.35 U/ml), and xylanase activity (4.28 U/ml) with sugarcane bagasse, spent mushroom substrate, and S. anglica, respectively. The ethanol production using M. floridulus as substrate was up to 2.63 mM ethanol/g using gas chromatography analysis. It has high potential to be a new candidate for producing ethanol with cellulosic biomass under anoxic conditions in natural environments. PMID- 24809292 TI - PCR-DGGE analysis of the microbial communities in three different Chinese "Baiyunbian" liquor fermentation starters. AB - A systematic investigation was performed on the bacterial, Bacillus, fungal, and yeast communities of the three types of Daqu (mechanically prepared, manually prepared, and mixed prepared) used in Baiyunbian Company by reconditioning PCR denaturing gradient gel electrophoresis (PCR-DGGE). The DGGE results showed that the microbes in the three types of Daqu were mainly thermotolerant and thermophilic microbes, and the most dominant bacterial species were Bacillus and Virgibacillus, followed by Lactobacillus and Trichococcus. Furthermore, the dominant fungi were found to be molds, such as Rasamsonia, Penicillium, Aspergillus, and Monascus, and the dominant yeasts were Saccharomyces cerevisiae, Saccharomycopsis fibuligera, Pichia anomala, and Debaryomyces hansenii. In general, the three types of Daqu showed slight differences in microbial communities, and the Shannon indexes (H') of the manually prepared and mechanically prepared Daqu were similar. The results suggest that mechanically prepared Daqu can replace manually prepared Daqu in liquor production, and this research provides useful information for liquor production and process improvement. PMID- 24809293 TI - Waist-to-height ratio distinguish obstructive sleep apnea from primary snoring in obese children. AB - BACKGROUND: Sleep-disordered breathing is caused by the interaction of multiple factors, including tonsillar hypertrophy, retrognathia, maxillary atresia, neuromuscular abnormalities, activation of inflammatory mediator cascades, and obesity. The prevalence and severity of obesity among children and adolescents increased worldwide during recent decades and has thus become a public health concern. The aim of this study is to assess the metabolic and anthropometric changes associated with sleep-disordered breathing in obese children. METHODS: Prospective assessment of prepubertal obese children followed at a pediatric endocrinology outpatient clinic that had history of frequent snoring. Children were submitted to polysomnography, measurements of body weight, height, blood pressure, neck circumference, and waist circumference. BMI, neck-to-height, and waist-to-height ratios were calculated. Laboratory tests included a complete blood count, liver function tests, lipid profile, and glucose metabolism assessment. Additionally, the presence of metabolic syndrome was assessed. Differences between obstructive sleep apnea and primary snoring groups were calculated using unpaired t-test, Fisher's exact test or Mann-Whitney test (p < 0.05). RESULTS: The sample included 20 children with primary snoring and nine with obstructive sleep apnea. The two groups did not differ with regard to age, gender, BMI, or BMI z-score, serum lipids, glucose metabolism, cell count, liver function, or arterial blood pressure. Anthropometric data did not differ between groups. The waist-to-height ratio was greater among children with obstructive sleep apnea, compared to those with primary snoring. CONCLUSION: In the present study, the waist-to-height ratio was greater in children with obstructive sleep apnea and, thus, could distinguish these children from those with primary snoring. PMID- 24809294 TI - Utility of extended cardiac monitoring to detect atrial fibrillation in patients with severe obstructive sleep apnea. AB - BACKGROUND: The relationship between obstructive sleep apnea (OSA) and increased risk for atrial fibrillation (AF) has been well established in previous studies. The relationship between OSA and silent AF is unknown. We hypothesized that patients with OSA but no known history of AF are at an increased risk for the arrhythmia and may be detectable by prolonged electrocardiogram (ECG) monitoring. In this study, we examined whether 7 days of extended cardiac monitoring with an ECG event recorder is an effective screening tool to detect intermittent, silent AF in patients with severe OSA. METHODS: The study was a prospective observational study. Randomly chosen patients with newly diagnosed severe OSA, apnea-hypopnea index (AHI) >= 30, were included. Demographic, medical history, and sleep data were collected. Patients with a history of AF or symptoms of palpitations were excluded from participating. Seven consecutive days of ambulatory ECG event recording (with Model ER920W, eCardio, Houston, TX) were performed prior to the initiation of CPAP treatment. RESULTS: A total of 20 subjects, with a BMI of 38.8 +/- 12.2, successfully completed the study. The mean age group was 52.6 +/- 12.6 years and mean AHI 63.5 +/- 29.2. The majority of subjects (70 %) had no abnormal cardiac rhythms detected. AF lasting for 7 s was seen in one subject, and paroxysmal atrial tachycardia lasting for 3.6 s was seen in another. Clinically relevant AF was not detected in any of the subjects. CONCLUSION: In patients with severe OSA without a known history of AF, 7 days of extended cardiac monitoring with an ECG event recorder did not detect clinically meaningful, silent AF. PMID- 24809295 TI - Response to letter on "Validation study on sleep parameters by actigraphy for normal subjects". PMID- 24809297 TI - Seaweed-derived heteroatom-doped highly porous carbon as an electrocatalyst for the oxygen reduction reaction. AB - We report the template-free pyrolysis of easily available natural seaweed, Undaria pinnatifida, as a single precursor, which results in "seaweed carbon" (SCup). Interestingly, thus-obtained SCup not only contains heteroatoms such as nitrogen and sulfur in its framework, but it also possesses a well-developed porous structure with high surface area. The heteroatoms in SCup originate from the nitrogen- and sulfur-containing ingredients in seaweed, whereas the porosity is created by removal of salts inherently present in the seaweed. These essential and fundamental properties make seaweed a prime choice as a precursor for heteroatom-containing highly porous carbon as a metal-free efficient electrocatalyst. As-synthesized SCup showed excellent electrocatalytic activity in the oxygen reduction reaction (ORR) in alkaline medium, which can be addressed in terms of the presence of the nitrogen and sulfur heteroatoms, the well developed porosity, and the electrical conductivity in the carbon framework. The pyrolysis temperature was a key controlling parameter that determined the trade off between heteroatom doping, surface properties, and electrical conductivity. In particular, SCup prepared at 1000 degrees C showed the best ORR performance. Additionally, SCup exhibited enhanced durability and methanol tolerance relative to the state of the art commercial Pt catalyst, which demonstrates that SCup is a promising alternative to costly Pt-based catalysts for the ORR. PMID- 24809296 TI - Reduced BAFF-R and increased TACI expression in common variable immunodeficiency. AB - PURPOSE: B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL. Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL. Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood. METHODS AND RESULTS: We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls. BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects. We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels. On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels. Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID. CONCLUSIONS: Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding. Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets. PMID- 24809298 TI - Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis. AB - We scrutinized the effect of insulin receptor (INSR) in addition to IGF1R in PCa using in vitro and in vivo models. In-vitro overexpression of IGF1R and INSRA, but not INSRB increased cell proliferation, colony formation, migration, invasion and resistance to apoptosis in prostate cancer cells (DU145, LNCaP, PC3). Opposite effects were induced by downregulation of IGF1R and total INSR, but not INSRB. In contrast to tumor cells, non-cancerous epithelial cells of the prostate (EP156T, RWPE-1) were inhibited on overexpression and stimulated by knockdown of receptors. In-vivo analyses using the chicken allantoic membrane assay confirmed the tumorigenic effects of IGF1R and INSR. Apart of promoting tumor growth, IGF1R and INSR overexpression also enhanced angiogenesis indicated by higher vessel density and increased number of desmin-immunoreactive pericytes. Our study underscores the oncogenic impact of IGF1R including significant effects on tumor growth, cell migration, sensitivity to apoptotic/chemotherapeutic agents and angiogenesis, and characterizes the INSR, in particular the isoform INSRA, as additional cancer-promoting receptor in prostate cancer. Both, the insulin-like growth factor receptor 1 and the insulin receptor exert oncogenic functions, thus proposing that both receptors need to be considered in therapeutic settings. PMID- 24809299 TI - A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy. AB - DNA repair is critical to resolve extrinsic or intrinsic DNA damage to ensure regulated gene transcription and DNA replication. These pathways control repair of double strand breaks, interstrand crosslinks, and nucleotide lesions occurring on single strands. Distinct DNA repair pathways are highly inter-linked for the fast and optimal DNA repair. A deregulation of DNA repair pathways may maintain and promote genetic instability and drug resistance to genotoxic agents in tumor cells by specific mechanisms that tolerate or rapidly bypass lesions to drive proliferation and abrogate cell death. Multiple Myeloma (MM) is a plasma cell disorder characterized by genetic instability and poor outcome for some patients, in which the compendium of DNA repair pathways has as yet not been assessed for a disease-specific prognostic relevance. We design a DNA repair risk score based on the expression of genes coding for proteins involved in DNA repair in MM cells. From a consensus list of 84 DNA repair genes, 17 had a bad prognostic value and 5 a good prognostic value for both event-free and overall survival of previously untreated MM patients. The prognostic information provided by these 22 prognostic genes was summed within a global DNA repair score (DRScore) to take into account the tight linkage of repair pathways. DRscore was strongly predictive for both patients' event free and overall survivals. Also, DRscore has the potential to identify MM patients whose tumor cells are dependent on specific DNA repair pathways to design treatments that induce synthetic lethality by exploiting addiction to deregulated DNA repair pathways. PMID- 24809300 TI - Decreased expression of FOXJ1 is a potential prognostic predictor for progression and poor survival of gastric cancer. AB - BACKGROUND: FOXJ1 is a member of the forkhead transcription factor family, which has been mostly studied for its role in the development of ciliated epithelium and immunology. However, the role of FOXJ1 in tumorigenesis remains largely unknown or even conflicting. We thus investigated FOXJ1 expression in gastric cancer and analyzed its correlations with tumor progression and prognosis. METHODS: The expression of FOXJ1 was detected by immunohistochemistry in 105 gastric cancer samples and adjacent noncancerous tissues. Staining evaluation was conducted to assess clinicopathological parameters and the survival rate. In addition, the relation between FOXJ1 and metastasis was investigated in another 40 pairs of primary lesions and corresponding lymph node metastases. Furthermore, cell proliferation, migration, and invasion were confirmed in vitro. RESULTS: Decreased FOXJ1 expression was significantly correlated with clinic stage, lymph node metastasis, and distant metastasis, and lower FOXJ1 expression independently predicted shorter survival time in gastric carcinoma. Moreover, the positive incidence of FOXJ1 decreased significantly in metastatic lymph nodes compared with that in the primary lesions. Consistently, FOXJ1 overexpression significantly weakened cell proliferation, motility, migration, and invasion, while FOXJ1 knockdown induced the opposite effects. CONCLUSIONS: Decreased expression of FOXJ1 is an independent prognostic predictor for gastric cancer and is critical to disease progression. FOXJ1 may be an attractive therapeutic target for the treatment of gastric cancer. PMID- 24809301 TI - Cost of contralateral prophylactic mastectomy. AB - PURPOSE: To compare the healthcare costs of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) with those of women who did not. METHODS: We conducted a retrospective study of 904 women treated for stage I-III breast cancer with or without CPM. Women were matched according to age, year at diagnosis, stage, and receipt of chemotherapy. We included healthcare costs starting from the date of surgery to 24 months. We identified whether care was immediate or delayed (CPM within 6 months or 6-24 months after initial surgery, respectively). Costs were converted to approximate Medicare reimbursement values and adjusted for inflation. Multivariable regression analysis was performed to evaluate the effect of CPM on total breast cancer care costs adjusting for patient characteristics and accounting for matched pairs. RESULTS: The mean difference between the CPM and no-CPM matched groups was $3,573 (standard error [SE] $455) for professional costs, $4,176 (SE $1,724) for technical costs, and $7,749 (SE $2,069) for total costs. For immediate and delayed CPM, the mean difference for total costs was $6,528 (SE $2,243) and $16,744 (SE $5,017), respectively. In multivariable analysis, the CPM group had a statistically significant increase of 16.9 % in mean total costs compared with the no-CPM group (p < 0.0001). Human epidermal growth factor receptor 2/neu positive status, receipt of radiation, and reconstruction were associated with increases in total costs. CONCLUSIONS: CPM significantly increases short-term healthcare costs for women with unilateral breast cancer. These patient-level cost results can be used for future studies that evaluate the influence of costs of CPM on decision making. PMID- 24809302 TI - Proactive approach to lymphedema risk reduction: a prospective study. AB - BACKGROUND: Advances in cancer treatments continue to reduce the incidence of lymphedema. Yet, many breast cancer survivors still face long-term postoperative challenges as a result of developing lymphedema. The purpose of this study was to preliminarily evaluate The Optimal Lymph Flow program, a patient-centered education and behavioral program focusing on self-care strategies to enhance lymphedema risk reduction by promoting lymph flow and optimize body mass index (BMI). METHODS: A prospective, longitudinal, quasi-experimental design with repeated-measures was used. The study outcomes included lymph volume changes by infrared perometer, and BMI by a bioimpedance device at pre-surgery baseline, 2-4 weeks after surgery, 6-month and 12-month follow-up. A total of 140 patients were recruited and participated in The Optimal Lymph Flow program; 134 patients completed the study with 4 % attrition rate. RESULTS: Fifty-eight percent of patients had axillary node dissection and 42 % had sentinel lymph node biopsy (SLNB). The majority (97 %) of patients maintained and improved their preoperative limb volume (LV) and BMI at the study endpoint of 12 months following cancer surgery. Cumulatively, two patients with SLNB and two patients with axillary lymph node dissection had measurable lymphedema (>10 % LV change). At the 12-month follow-up, among the four patients with measurable lymphedema, two patients' LV returned to preoperative level without compression therapy but by maintaining The Optimal Lymph Flow exercises to promote daily lymph flow. CONCLUSIONS: This educational and behavioral program is effective in enhancing lymphedema risk reduction. The study provided initial evidence for emerging change in lymphedema care from treatment-focus to proactive risk reduction. PMID- 24809305 TI - Moderate intensity exercise is associated with decreased angiotensin-converting enzyme, increased beta2-adrenergic receptor gene expression, and lower blood pressure in middle-aged men. AB - PURPOSE: The purpose of the current study was to characterize the role of aerobic exercise in the gene expression of the angiotensin-converting enzyme (ACE) and the beta2-adrenergic receptor (ADRB2) in untrained men. METHODS: Twenty untrained middle-aged men were randomly assigned to exercise (Exe) and control (Con) groups. The Exe group performed aerobic exercises for eight weeks. ACE mRNA and ADRB2 mRNA were determined by PCR. RESULTS: The expression of ACE in week 4 and in the Exe group decreased significantly (p < .001). ADRB2 in the Exe group, in week 4 and in week 8, was markedly higher, and blood pressure was significantly lower than in the Con group (p < .001). In the Con group ADRB2 mRNA decreased. CONCLUSION: These results suggest that moderate intensity exercise promotes the leukocyte expression of gene markers that may affect blood pressure by improving cardiovascular fitness levels in middle-aged men. PMID- 24809306 TI - Enhanced photocatalytic CO2-reduction activity of electrospun mesoporous TiO2 nanofibers by solvothermal treatment. AB - Photocatalytic reduction of CO2 into renewable hydrocarbon fuels using semiconductor photocatalysts is considered as a potential solution to the energy deficiency and greenhouse effect. In this work, mesoporous TiO2 nanofibers with high specific surface areas and abundant surface hydroxyl groups are prepared using an electrospinning strategy combined with a subsequent calcination process, followed by a solvothermal treatment. The solvothermally treated mesoporous TiO2 nanofibers exhibit excellent photocatalytic performance on CO2 reduction into hydrocarbon fuels. The significantly improved photocatalytic activity can be attributed to the enhanced CO2 adsorption capacity and the improved charge separation after solvothermal treatment. The highest activity is achieved for the sample with a 2-h solvothermal treatment, showing 6- and 25-fold higher CH4 production rate than those of TiO2 nanofibers without solvothermal treatment and P25, respectively. This work may also provide a prototype for studying the effect of solvothermal treatment on the structure and photocatalytic activity of semiconductor photocatalysts. PMID- 24809307 TI - k-t acceleration in pure phase encode MRI to monitor dynamic flooding processes in rock core plugs. AB - Monitoring the pore system in sedimentary rocks with MRI when fluids are introduced is very important in the study of petroleum reservoirs and enhanced oil recovery. However, the lengthy acquisition time of each image, with pure phase encode MRI, limits the temporal resolution. Spatiotemporal correlations can be exploited to undersample the k-t space data. The stacked frames/profiles can be well approximated by an image matrix with rank deficiency, which can be recovered by nonlinear nuclear norm minimization. Sparsity of the x-t image can also be exploited for nonlinear reconstruction. In this work the results of a low rank matrix completion technique were compared with k-t sparse compressed sensing. These methods are demonstrated with one dimensional SPRITE imaging of a Bentheimer rock core plug and SESPI imaging of a Berea rock core plug, but can be easily extended to higher dimensionality and/or other pure phase encode measurements. These ideas will enable higher dimensionality pure phase encode MRI studies of dynamic flooding processes in low magnetic field systems. PMID- 24809308 TI - Factors affecting DSAEK graft lenticle adhesion: an in vitro experimental study. AB - PURPOSE: The aim of this study was to evaluate different factors that affect Descemet stripping automated endothelial keratoplasty (DSAEK) donor graft lenticle adhesion to the recipient cornea. METHODS: This experimental study included 10 eye bank recipient corneas and 10 donor DSAEK lenticles. Recipient corneas were mounted on an artificial anterior chamber (AC), whereas donor lenticles were placed beneath the host cornea. Using optical coherence tomography and imaging software, the interface gap (IG) between the donor and recipient cornea was quantified to evaluate the effect of variations in AC air fill pressure, AC air fill duration, corneal massage, and corneal venting incisions on DSAEK donor graft lenticle adhesion. RESULTS: Different intraocular pressures (IOP) under air for the same time intervals, do not significantly correlate with the IG; nevertheless, it was noticed that the IG decreases as the IOP increases. With respect to the magnitude of AC IOP, there was no statistically significant difference when comparing 10 mm Hg with 30 mm Hg and assessing IG (P = 0.4). Complete air-fluid exchange resulted in significantly higher IG when compared with AC air bubble of 10 and 30 mm Hg that was sustained for 1 hour (P < 0.05). Furthermore, corneal surface massage did not facilitate DSAEK graft adhesion (P = 0.59). Finally, paracentral venting incisions followed by interface fluid aspiration seemed to significantly decrease the IG (P = 0.014). CONCLUSIONS: Corneal venting incisions and higher AC IOP values seem to facilitate DSAEK donor graft lenticle adhesion to the recipient cornea. PMID- 24809309 TI - Comparison of endothelial cell density of organ cultured corneas with cornea donor study. AB - PURPOSE: Determination of the endothelial cell density (ECD) by eye banks is paramount in donor cornea qualification. Unbiased measurement avoids wastage and grafts with an increased risk of premature failure. Internal calibration of the counting method is essential, but external validation would add an extra stage in the assessment of reliability. In this respect, data published by the multicenter Cornea Donor Study (CDS) in 2005 is a reference. The aim of the study was to compare ECD determined within a single eye bank, which uses calibrated image analysis software designed for transmitted light microscopy images of organ cultured corneas, with the CDS data determined on specular microscopy images of corneas stored at 4 degrees C. METHODS: ECD of consecutive corneas retrieved between 2005 and 2013 was determined after exposure to 0.9% NaCl. More than 300 ECs were counted on 3 fields of the central 8 mm. Endothelial cell boundaries were automatically drawn and verified by a skilled technician who performed all necessary corrections. RESULTS: Three thousand fifty-two corneas were analyzed, of which 48.5% donors were >75 years (CDS upper age limit). Between 10 and 75 years, the ECD varied according to donor age exactly in the same manner as in the CDS, but were consistently higher of 100 +/- 25 cells per square millimeter (P < 0.001). CONCLUSIONS: ECD determined by a computer-aided method from transmitted light microscopy images compares favorably with the American CDS reference series. The slight systematic difference on either side of the Atlantic Ocean could be due to (1) differences in counting principles and/or (2) higher shrinkage of the cornea caused by stromal edema in organ culture. PMID- 24809310 TI - Association of monocyte chemoattractant protein-1 (MCP-1)2518A/G polymorphism with proliferative diabetic retinopathy in northern Chinese type 2 diabetes. AB - BACKGROUND: The pathogenesis of proliferative diabetic retinopathy (PDR) remains poorly understood. Recent studies have implicated that monocyte chemoattractant protein-1 (MCP-1) is associated with diabetic microvascular or macrovascular complications. However, the relationship between single nucleotide polymorphism(SNP)c.2518A/G -rs1024611 in the MCP-1 gene with diabetic retinopathy remains controversial. In the present study, we evaluated the association of SNP in the MCP-1 gene with diabetic retinopathy (DR) and diabetic macular edema (DME) in a Chinese population from Northern China with type 2 diabetes. METHODS: We conducted a case-control study, which enrolled 1,043 subjects with type 2 diabetes (528 with DR, including 277PDR; 515 without DR), and SNP genotyping of c.2518A/G in the MCP-1 gene was performed using the polymerase chain reaction. Genomic DNA was isolated from 3 ml samples of whole blood using a modified conventional DNA extraction method. The genotype and allele frequencies of 2518A/G were studied by using an automated DNA sequencer (ABI PRISM 3730 DNA Sequencer). RESULTS: The demographic and clinical characteristics did not differ among genotype subgroups. The MCP-1(-2518) GG genotype was significantly associated with DR susceptibility with OR of 1.481 (95 % CI, 1.019-2.153) (P = 0.046). There were no significant differences in the MCP-1(-2518) G allele frequencies in DR compared to non-diabetic retinopathy (DNR) (P > 0.05, OR = 0.841, 95 % CI, 0.705-1.002). The MCP-1(-2518) GG genotype was significantly associated with high-risk PDR susceptibility with OR of 2.656 (95 % CI, 1.222 5.775) (P = 0.014). The MCP-1(-2518) G allele was significantly increased in high risk PDR patients (P = 0.020, OR = 1.481, 95 % CI, 1.070-2.051) compared with A allele. Genotype and allele frequencies of various DME of the DR patients were compared, but there were no significant associations established (P > 0.05). CONCLUSIONS: It is likely that the MCP-1 c.2518G/G genotype is a susceptibility gene for DR in Chinese type 2 diabetic patients, especially the high-risk PDR. There is no association with DME and c.2518G/G. PMID- 24809312 TI - Preoperative pulmonary vascular morphology and its relationship to postpneumonectomy hemodynamics. AB - RATIONALE AND OBJECTIVES: Pulmonary edema and pulmonary hypertension are postsurgical complications of pneumonectomy that may represent the remaining pulmonary vasculature's inability to accommodate the entirety of the cardiac output. Quantification of the aggregate pulmonary vascular cross-sectional area (CSA) has been used to study the development of pulmonary vascular disease in smokers. In this study, we applied this technique to demonstrate the potential utility of pulmonary vascular quantification in surgical risk assessment. Our hypothesis was that those subjects with the lowest aggregate vascular CSA in the nonoperative lung would be most likely to have elevated pulmonary vascular pressures in the postoperative period. MATERIALS AND METHODS: A total of 61 subjects with postoperative hemodynamics and adequate imaging were identified from 159 patients undergoing pneumonectomies for mesothelioma. The total CSA of blood vessels perpendicular to the plane of computed tomographic (CT) scan slices was computed for blood vessels <5 mm(2) (CSA 5 mm). This measurement expressed as a percentage of lung parenchyma area (CSA 5%) was compared to postoperative hemodynamic measurements obtained by right heart catheterization. RESULTS: In patients where a contrasted CT scan was used (n = 26), CSA 5% was correlated with postoperative day 0 minimum cardiac index (R = 0.37, P = .03) but not with the maximum pulmonary arterial pressures. In patients with noncontrast CT scans (n = 35), CSA 5% was inversely correlated with postoperative day 0 maximum pulmonary arterial pressures (R = 0.43, P = .03) but not with the minimum cardiac index. The preoperative perfusion fraction of the nonsurgical lung did not correlate with postoperative hemodynamics. CONCLUSIONS: CSA of pulmonary vasculature with an area <=5 mm(2) has potential in estimating the ability of pulmonary vascular bed to accommodate postsurgical changes in pneumonectomy. PMID- 24809311 TI - Work stress, sleep deficiency, and predicted 10-year cardiometabolic risk in a female patient care worker population. AB - OBJECTIVES: The aim of this study was to investigate the longitudinal effect of work-related stress, sleep deficiency, and physical activity on 10-year cardiometabolic risk among an all-female worker population. METHODS: Data on patient care workers (n=99) was collected 2 years apart. Baseline measures included: job stress, physical activity, night work, and sleep deficiency. Biomarkers and objective measurements were used to estimate 10-year cardiometabolic risk at follow-up. Significant associations (P<0.05) from baseline analyses were used to build a multivariable linear regression model. RESULTS: The participants were mostly white nurses with a mean age of 41 years. Adjusted linear regression showed that having sleep maintenance problems, a different occupation than nurse, and/or not exercising at recommended levels at baseline increased the 10-year cardiometabolic risk at follow-up. CONCLUSIONS: In female workers prone to work-related stress and sleep deficiency, maintaining sleep and exercise patterns had a strong impact on modifiable 10-year cardiometabolic risk. PMID- 24809313 TI - Mass and fat infiltration of intercostal muscles measured by CT histogram analysis and their correlations with COPD severity. AB - RATIONALE AND OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is characterized by progressive respiratory function impairment and respiratory muscle dysfunction. We hypothesized that the mass and fat infiltration of respiratory muscles correlates with COPD severity and emphysema extent. MATERIALS AND METHODS: Ninety-eight male patients with COPD underwent chest computed tomography (CT) and spirometry. The mass and fat infiltrations of intercostal and latissimus muscles were quantified as the cross-sectional area (CSA) and attenuation of these muscles using CT histogram analysis. Intercostal index and latissimus index were defined as intercostal CSAs and latissimus CSAs divided by body mass index. The emphysema extent was measured as the ratio of the emphysematous lung volume to the total lung volume using a density-mask technique. Pearson correlation analyses were performed to evaluate the relationships between these parameters. Multiple regression analysis was performed using forced expiratory volume in 1 second (FEV1) as the dependent parameter and the clinical and CT data as the independent parameters. RESULTS: FEV1 was significantly correlated with intercostal index (r = 0.57), latissimus index (r = 0.34), intercostal attenuation (r = 0.62), and latissimus attenuation (r = 0.38). Emphysema extent was significantly correlated with intercostal index (r = -0.36) and intercostal attenuation (r = -0.50). Multiple regression analysis showed that FEV1 was predicted by intercostal attenuation (B = 0.40), intercostal CSA (B = 0.23), emphysema extent (B = -0.23), and age (B = -0.21, R(2) = 0.64, P < .001). CONCLUSIONS: A decrease in intercostal mass and an increase in intercostal fat are associated with worsening of COPD severity. PMID- 24809314 TI - The incidence of pulmonary embolism and associated FDG-PET findings in IV contrast-enhanced PET/CT. AB - RATIONALE AND OBJECTIVES: Most fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography with computed tomography (PET/CT) studies are performed on cancer patients. These patients are at increased risk of pulmonary embolism (PE). In this retrospective review, we determined the rate of PE, and the prevalence of associated FDG-PET findings on intravenous (IV) contrast-enhanced PET/CT. MATERIALS AND METHODS: We identified all PET/CT studies performed at our institution with a reported finding of PE between January 2005 and October 2012. The medical record was reviewed for symptoms, which were identified after the diagnosis of PE, and whether the patients received treatment. The prevalence of associated FDG-PET findings was determined. RESULTS: A total of 65 total cases of PE (of 182,72 total PET/CT examinations) were identified of which 59 were previously unknown. This gives an incidental PE (IPE) rate of 0.32%. Of the patients where sufficient clinical information was available, 34 of 36 (94%) were treated either with therapeutic anticoagulation or inferior vena cava filter, and 30 of 36 (83%) were asymptomatic in retrospect. Of the patients with IPE, we found nine (15.2%) with associated focal pulmonary artery hypermetabolism, three (5.1%) with hypermetabolic pulmonary infarction, and one with increased isolated right ventricular FDG uptake (1.7%). One case of chronic PE demonstrated a focal hypometabolic filling defect in a pulmonary artery on PET. CONCLUSIONS: We found IPE in 0.32% of PET/CT scans. Focal pulmonary artery hypermetabolism or hypometabolism, and hypermetabolic pulmonary artery infarction with the "rim sign" were uncommonly associated with PE. These findings could raise the possibility of IPE in non-IV contrast-enhanced PET/CT studies. PMID- 24809315 TI - Thymic measurements in pathologically proven normal thymus and thymic hyperplasia: intraobserver and interobserver variabilities. AB - RATIONALE AND OBJECTIVES: To determine the intraobserver and interobserver variabilities of thymic measurements on computed tomography (CT) in patients with pathologic diagnosis of thymic hyperplasia or normal thymus. MATERIALS AND METHODS: Thirty-three patients with pathologic diagnosis of thymic hyperplasia (n = 25) or normal thymus (n = 8) who had identifiable thymus gland on CT were retrospectively studied. Two radiologists independently measured thymic size and CT attenuation. Concordance correlation coefficients (CCCs) and Bland-Altman plots were used to assess intraobserver and interobserver agreements. RESULTS: The intraobserver and interobserver agreements of thymic diameters and the lobe length were moderate, with CCCs ranging from 0.73 to 0.89 and from 0.72 to 0.81, respectively. Higher agreement was noted among patients whose measurements were performed on the same CT image in two independent measurements, with intraobserver CCC >= 0.95 for diameters and length. After providing readers with an instruction for consistent selection of CT image for measurements, the intraobserver and interobserver agreements improved, resulting in CCCs ranging from 0.81 to 0.92 and from 0.77 to 0.85 for diameters and length, respectively. Thymic lobe thickness had the least agreement. CT attenuation measurements were highly reproducible, with CCCs ranging from 0.88 to 0.97. In patients with thymic CT attenuation >30 HU (Hounsfield unit), the attenuation measurements were more reproducible with narrower 95% limits of agreement. CONCLUSIONS: Thymic size measurements had moderate-to-high intraobserver and interobserver agreements, when the instruction for consistent selection of images was provided to the readers. CT attenuation was highly reproducible, with higher reproducibility for thymic glands with >30 HU. Awareness of thymic measurement variability is necessary when interpreting measured values of normal thymus and thymic pathology on CT. PMID- 24809316 TI - Contrast-enhanced magnetic resonance angiography for the preoperative evaluation of hepatic vascular anatomy in living liver donors: a meta-analysis. AB - RATIONALE AND OBJECTIVES: The objective of this study was to determine the diagnostic accuracy of contrast-enhanced magnetic resonance angiography (MRA) when used in the preoperative evaluation of hepatic vascular anatomy in living liver donors. MATERIALS AND METHODS: A computer-assisted literature searching of EMBASE, PubMed (MEDLINE), and the Cochrane library databases was conducted to identify potentially relevant articles which primarily examined the utility of contrast-enhanced MRA in the preoperative evaluation of hepatic vascular anatomy in living liver donors. We used the Q statistic of chi-squared value test and inconsistency index (I-squared, I(2)) to estimate the heterogeneity of the data extracted from all selected studies. Meta-Disc software (version 1.4) (ftp://ftp.hrc.es/pub/programas/metadisc/Metadisc_update.htm) was used to perform our analysis. RESULTS: Eight studies were included in the present meta-analysis. A total of 289 living liver donor candidates and 198 patients who underwent liver harvesting were included in the present study. The pooled sensitivities of hepatic artery (HA), portal vein (PV), and hepatic vein (HV) in this meta analysis were 0.84, 0.97, and 0.94, respectively. The pooled specificities of HA, PV, and HV were 1.00, 1.00, and 1.00, respectively. The pooled diagnostic odds ratios of HA, PV, and HV were 127.28, 302.80, and 256.59, respectively. The area under the summary receiver-operating characteristic curves of HA, PV, and HV were 0.9917, 0.9960, and 0.9813, respectively. CONCLUSIONS: The high sensitivity and specificity demonstrated in this meta-analysis suggest that contrast-enhanced MRA was a promising test for the preoperative evaluation of hepatic vascular anatomy in living liver donors. PMID- 24809317 TI - Assessment of tumor grade and angiogenesis in colorectal cancer: whole-volume perfusion CT. AB - RATIONALE AND OBJECTIVES: The preoperative evaluation of tumor grading and angiogenesis has important clinical implications in the treatment and prognosis of patients with colorectal cancers (CRCs). The aim of the present study was to assess tumor perfusion with 256-slice computed tomography (CT) using whole-volume perfusion technology before surgery, and to investigate the differences in the perfusion parameters among tumor grades and the correlation between perfusion parameters and pathologic results in CRC. MATERIALS AND METHODS: Thirty-seven patients with CRC confirmed by endoscopic pathology underwent whole-volume perfusion CT assessments with a 256-slice CT and surgery. Quantitative values for blood flow, blood volume, and time to peak were determined using commercial software. After surgery, resected specimens were analyzed immunohistochemically with CD105 antibodies for the quantification of microvessel density (MVD). The difference in CT perfusion parameters and MVD among different tumor differentiation grades was evaluated by the Student-Newman-Keuls test. The correlations between CT perfusion parameters and MVD were evaluated using the Pearson correlation analysis. RESULTS: The mean blood flow was significantly different among well, moderately, and poorly differentiated groups (61.17 +/- 17.97, 34.80 +/- 13.06, and 22.24 +/- 9.31 mL/minute/100 g, respectively; P < .05). The blood volume in the well-differentiated group was significantly higher than that in the moderately differentiated group (33.96 +/- 24.81 vs. 16.93 +/- 5.73 mL/100 g; P = .002) and that in the poorly differentiated group (33.96 +/- 24.81 vs. 18.05 +/- 6.01 mL/100 g; P = .009). The time to peak in the poorly differentiated group was significantly longer than that in the well differentiated group (27.81 +/- 11.95 vs. 17.60 +/- 8.53 seconds; P = .016) and that in the moderately differentiated group (27.81 +/- 11.95 vs. 18.94 +/- 7.47 seconds; P = .028). There was no significant difference in the MVD among well, moderately, and poorly differentiated groups (33.47 +/- 14.69, 28.89 +/- 11.82, and 29.89 +/- 11.02, respectively; P > .05). There was no significant correlation between CT perfusion parameters and MVD (r = 0.201, 0.295, and -0.178, respectively; P = .233, .076, and .292, respectively). CONCLUSIONS: CT whole volume perfusion technology has the potential to evaluate pathologic differentiation grade of CRC before surgery. However, preoperative perfusion CT parameters do not reflect the MVD of CRC. PMID- 24809318 TI - Model-based iterative reconstruction compared to adaptive statistical iterative reconstruction and filtered back-projection in CT of the kidneys and the adjacent retroperitoneum. AB - RATIONALE AND OBJECTIVES: To prospectively evaluate the perceived image quality of model-based iterative reconstruction (MBIR) compared to adaptive statistical iterative reconstruction (ASIR) and filtered back-projection (FBP) in computed tomography (CT) of the kidneys and retroperitoneum. MATERIALS AND METHODS: With investigational review board and Health Insurance Portability and Accountability Act compliance, 17 adults underwent 31 contrast-enhanced CT acquisitions at constant tube potential and current (range 30-300 mA). Each was reconstructed with MBIR, ASIR (50%), and FBP. Four reviewers scored each reconstruction's perceived image quality overall and the perceived image quality of seven imaging features that were selected by the authors as being relevant to imaging in the region and pertinent to the evaluation of high-quality diagnostic CT. RESULTS: MBIR perceived image quality scored superior to ASIR and FBP both overall (P < .001) and for observations of the retroperitoneal fascia (99.2%), corticomedullary differentiation (94.4%), renal hilar structures (96.8%), focal renal lesions (92.5%), and mitigation of streak artifact (100.0%; all, P < .001). MBIR achieved diagnostic overall perceived image quality with approximately half the radiation dose required by ASIR and FBP. The noise curve of MBIR was significantly lower and flatter (P < .001). CONCLUSIONS: Compared to ASIR and FBP, MBIR provides superior perceived image quality, both overall and for several specific imaging features, across a broad range of tube current levels, and requires approximately half the radiation dose to achieve diagnostic overall perceived image quality. Accordingly, MBIR should enable CT scanning with improved perceived image quality and/or reduced radiation exposure. PMID- 24809319 TI - Preferences for structured reporting of measurement data: an institutional survey of medical oncologists, oncology registrars, and radiologists. AB - RATIONALE AND OBJECTIVES: The aim of this study was to determine whether key radiology report "consumers" in our institution prefer structured measurement reporting in a dedicated report section over the current practice of embedding measurements throughout the "Findings" section, given the availability of new tools for quantitative imaging interpretation that enable automated structured reporting of measurement data. MATERIALS AND METHODS: Oncologic clinicians and radiologists at our institution were surveyed regarding their preferences for a standard report versus three reports each having uniquely formatted dedicated "Measurements" sections and regarding their impressions of various characteristics of report quality demonstrated by these reports. The online survey was completed by 25 radiologists, 16 oncologists, and 17 oncology nurses and research assistants (registrars). RESULTS: Aggregation of respondents' preferences by group into single orderings using the Kemeny-Young method revealed that both oncology groups preferred all proposed reports to the standard report but that radiologists only preferred two of the proposed reports to the standard report. All preferences for proposed reports in the two oncology groups were statistically significant based on Wilcoxon tests, but the preference for only one of the proposed reports was significant for radiologists. Additional results suggest that these preferences are driven by respondent favor for the readability of and confidence conveyed by the proposed reports compared to the standard report. CONCLUSIONS: Oncologic clinicians responding to our survey preferred communication of lesion measurements in a separate report section to the current practice of embedding measurements throughout the "Findings" section, based on their assessments of reports containing simulated measurement sections assembled from a single sample report using standardized formatting. PMID- 24809320 TI - Optimizing image contrast display improves quantitative stenosis measurement in heavily calcified coronary arterial segments on coronary CT angiography: A proof of-concept and comparison to quantitative invasive coronary angiography. AB - RATIONALE AND OBJECTIVES: Blooming artifact from calcified plaques often renders measurement of stenosis impossible on coronary computed tomographic angiography (CTA). We sought to evaluate the impact of modifying window level on reducing blooming artifact, and its impact on stenosis quantification. MATERIALS AND METHODS: We analyzed 125 calcified segments from 53 patients who underwent CTA and invasive coronary angiography (ICA). Segmental stenosis on CTA was measured using three window settings: width of 1000 Hounsfield units (HU) and level of 200 HU ("default"), 1500/200 HU ("widened"), and width and level based on the mean HU of the calcified plaque and pericoronary fat ("calcium-specific"). Segmental stenosis on ICA was quantified by a blinded experienced reader. RESULTS: ICA found >=50% stenosis in 30 segments. Displaying segments with widened and calcium specific settings improved overall accuracy of detecting >=50% stenosis (P's < 0.001) by increasing the rate of accurately quantifying <50% stenosis (P's < 0.001), and improved correlation of stenosis quantification to ICA (P's < 0.05). There was no difference in stenosis quantification accuracy between widened and calcium-specific window settings. Limits of agreement between CTA stenosis quantification and ICA narrowed with widened and calcium-specific settings. CONCLUSIONS: We showed for the first time that in calcified segments, widening display window width significantly improved CTA quantification of stenosis compared to ICA. PMID- 24809321 TI - Evaluation of coronary artery image quality with knowledge-based iterative model reconstruction. AB - RATIONALE AND OBJECTIVES: To evaluate knowledge-based iterative model reconstruction (IMR) to improve image quality and reduce radiation dose in coronary computed tomography angiography (cCTA). MATERIALS AND METHODS: We evaluated 45 consecutive cCTA studies, including 25 studies performed with an 80% systolic dose reduction using tube current modulation (TCM). Each study was reconstructed with filtered back projection (FBP), hybrid iterative reconstruction (iDose(4)), and IMR in a diastolic phase. Additional systolic phase reconstructions were obtained for TCM studies. Mean pixel attenuation value and standard deviation (SD) were measured in the left ventricle and left main coronary artery. Subjective scores were obtained by two independent reviewers on a 5-point scale for definitions of contours of small coronary arteries (<3 mm), coronary calcifications, noncalcified plaque, and overall diagnostic confidence for the presence/absence of stenosis. RESULTS: There was no significant difference in pixel intensity among FBP, iDose(4), and IMR (P > .8). For diastolic phase images, noise amplitude in the left main coronary artery was reduced by a factor of 1.3 from FBP to iDose(4) (SD = 99 vs. 74; P = .005) and by a factor of 2.6 from iDose(4) to IMR (SD = 74 vs. 28; P < .001). For systolic phase TCM images, noise amplitude in the left main coronary artery was reduced by a factor of 2.3 from FBP to iDose(4) (SD = 322 vs. 142; P < .001) and by a factor of 3.0 from iDose(4) to IMR (SD = 142 vs. 48; P < .001). All four subjective image quality scores were significantly better with IMR compared to iDose(4) and FBP (P < .001). The reduction in image noise amplitude and improvement in image quality scores were greatest among obese patients. CONCLUSIONS: IMR reduces intravascular noise on cCTA by 86%-88% compared to FBP, and improves image quality at radiation exposure levels 80% below our standard technique. PMID- 24809322 TI - Visualization of lenticulostriate arteries at 3T: Optimization of slice-selective off-resonance sinc pulse-prepared TOF-MRA and its comparison with flow-sensitive black-blood MRA. AB - RATIONALE AND OBJECTIVES: To optimize visualization of lenticulostriate artery (LSA) by time-of-flight (TOF) magnetic resonance angiography (MRA) with slice selective off-resonance sinc (SORS) saturation transfer contrast pulses and to compare capability of optimal TOF-MRA and flow-sensitive black-blood (FSBB) MRA to visualize the LSA at 3T. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all the subjects. TOF-MRA was optimized in 20 subjects by comparing SORS pulses of different flip angles: 0, 400 degrees , and 750 degrees . Numbers of LSAs were counted. The optimal TOF-MRA was compared to FSBB-MRA in 21 subjects. Images were evaluated by the numbers and length of visualized LSAs. RESULTS: LSAs were significantly more visualized in TOF-MRA with SORS pulses of 400 degrees than others (P < .003). When the optimal TOF-MRA was compared to FSBB-MRA, the visualization of LSA using FSBB (mean branch numbers 11.1, 95% confidence interval (CI) 10.0-12.1; mean total length 236 mm, 95% CI 210-263 mm) was significantly better than using TOF (4.7, 95% CI 4.1-5.3; 78 mm, 95% CI 67-89 mm) for both numbers and length of the LSA (P < .0001). CONCLUSIONS: LSA visualization was best with 400 degrees SORS pulses for TOF-MRA but FSBB-MRA was better than TOF-MRA, which indicates its clinical potential to investigate the LSA on a 3T magnetic resonance imaging. PMID- 24809323 TI - Learner confidence: friend or foe? PMID- 24809324 TI - Alfacalcidol enhances collagen quality in ovariectomized rat bones. AB - The aim of this study was to investigate the effects of alfacalcidol (1alpha(OH)D3 : ALF) on bone collagen employing an ovariectomized rat model. Thirty-five 16-week-old female Sprague-Dawley rats were divided into five groups: SHAM (sham-operated + vehicle), OVX (ovariectomy + vehicle), and three ALF treated groups, that is, ovariectomy + 0.022 ug/kg/day ALF, ovariectomy + 0.067 ug/kg/day ALF, and ovariectomy + 0.2 ug/kg/day ALF. After 12 weeks of treatment, tibiae were subjected to histological, biochemical and immunohistochemical analyses. Collagen matrices in OVX bone appeared as immature and poorly organized; however, with the ALF treatment, it was improved in a dose-dependent manner. Contents of collagen and pyridinoline cross-link were decreased in OVX compared with SHAM, but they increased to the level comparable to SHAM in ALF treated groups. The total aldehyde, that is, a sum of free and those involved cross-links, in the highest dose of ALF was significantly higher than the rest of the groups (p < 0.05). In addition, the expression of lysyl oxidase was increased in the all ALF-treated groups compared with OVX (p < 0.05). In conclusion, ALF increases not only the amount of collagen but also enhances the maturation of collagen in ovariectomy-induced osteoporotic bones, which likely contributes to the improvement of bone quality. PMID- 24809326 TI - Pharmacological treatment of the basic defect in cystic fibrosis. AB - Cystic fibrosis (CF) is a genetic disease due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel in epithelial cells. There are about 1900 mutations, divided in several groups, for example, stop mutations, mutations affecting the permeability of the channel, and mutations in which the mutated CFTR is recognized as abnormal and destroyed. Pharmacological treatment has become possible for stop mutations (about 10% of the patients), and for a rare mutation affecting channel permeability. For the majority of patients, however, that have a mutation in which the mutated CFTR is destroyed on its way to the cell membrane, research is still in progress, although a number of compounds have been identified that (at least partly) corrects the error in chloride transport. PMID- 24809325 TI - Nitro-oleic acid downregulates lipoprotein-associated phospholipase A2 expression via the p42/p44 MAPK and NFkappaB pathways. AB - Nitro-oleic acid (OA-NO2), acting as anti-inflammatory signaling mediators, are involved in multiple signaling pathways. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is well known as a cardiovascular risk biomarker. Our results showed that OA-NO2 downregulated the expression of Lp-PLA2 in a time- and dose-dependent manner, whereas native OA had no such effect. Furthermore, OA-NO2 could repress Lp-PLA2 expression in the peripheral blood mononuclear cells of apo CIII transgenic (apo CIII TG) pigs, which exhibited higher Lp-PLA2 expression and activity than did wild-type (WT) pigs. OA-NO2 inhibited Lp-PLA2 expression in macrophages, independent of nitric oxide formation and PPARgamma-activation. However, OA-NO2 downregulates Lp-PLA2 by inhibiting the p42/p44 mitogen-activated protein kinase (MAPK) and the nuclear factor kappaB (NFkappaB) pathways. When used to mediate anti-inflammatory signaling, the regulation of inflammatory cytokines and SOD by OA-NO2 might be associated with the reduction of Lp-PLA2. These results suggested that OA-NO2 might exert a vascular-protective effect partially via Lp-PLA2 inhibition. PMID- 24809327 TI - Computational identification of significant missense mutations in AKT1 gene. AB - The AKT1 gene is of supreme importance in cell signaling and human cancer. In the present study, we aim to understand the phenotype variations that were believed to have the highest impact in AKT1 gene by different computational approaches. The analysis was initiated with SIFT tool followed by PolyPhen 2.0, I-Mutant 2.0, and SNPs&GO tools with the aid of 22 nonsynonymous (nsSNPs) retrieved from dbSNP. A total of five AKT1 variants such as E17K, E17S, E319G, L357P, and P388T are found to exert deleterious effects on the protein structure and function. Furthermore, the molecular docking study indicates the lesser binding affinity of inhibitor with the mutant structure than the native type. In addition, root mean square deviation and hydrogen bond details were also analyzed in the 10 ns molecular dynamics simulation study. These computational evidences suggested that E17K, E17S, E319G, L357P, and P388T variants of AKT1 could destabilize the protein networks, thus causing functional deviations of protein to some extent. Moreover, the findings strongly indicate that screening for AKT1, E17K, E17S, E319G, L357P, and P388T variants may be useful for disease molecular diagnosis and also to design the potential AKT inhibitors. PMID- 24809328 TI - Understanding the molecular dynamics of type-2 diabetes drug target DPP-4 and its interaction with Sitagliptin and inhibitor Diprotin-A. AB - The occurrence of type 2 diabetes (T2D) accounts for 90-95 % of all diabetes. Intestine hormone glucagon-like peptide-1 (GLP-1) has an antidiabetic role that enhances insulin secretion and pancreatic beta-cell proliferation. GLP-1 is degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) rapidly. Hence, the DPP-4 inhibition has been preferred not only for the treatment but also as a major drug target. Sitagliptin and Diprotin-A are antihyperglycemic agents for the treatment of T2D. However, little is known on the molecular dynamics of DPP-4 and the interaction properties with its ligands, namely Sitagliptin and Diprotin-A. This study has used the latest bioinformatic tools to understand the molecular dynamics and its interaction properties of DPP-4. This study has explored the number of alpha helices, beta strands, beta hairpins, Psi loop, beta bulges, beta turns, and Upsilon turns and they were 19, 46, 25, 1, 14, 70, and 4, respectively. The highest number of H-bonds was recorded in alpha helix of domain 1, and the lowest number H-bonds were noted in alpha helix of domain-2. During interaction between residues, in A- and B-chain, 47 and 48 residues are involved for interaction, and interaction interface area was more in A-Chain (2176 A(2)). From DPP-4 and Sitagliptin interaction, three residues in active sites such as Try226, Glu205, and Glu206 were involved in three H-bond formation, while 10 other amino acids (Try547, Try667, Asn710, Val711, His740, Ser630, Ser209, Arg358, Phe357, and Val207) were involved in hydrophobic interactions. In this review, we have shown the importance of bioinformatics as an excellent tool for a rapid method to assess the molecular dynamics and its interaction properties of DPP-4. Our predictions highlighted in this review will help researchers to understand the interaction properties and recognition of interactive sites to design more DPP-4 inhibitors for the treatment of T2D and drug discovery. PMID- 24809329 TI - Cognitive impairment and electroencephalographic alterations before and after liver transplantation: what is reversible? AB - The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function remained slightly worse; in contrast, EEGs normalized in both groups. PMID- 24809330 TI - Identification of helicity-dependent photocurrents from topological surface states in Bi2Se3 gated by ionic liquid. AB - Dirac-like surface states on surfaces of topological insulators have a chiral spin structure with spin locked to momentum, which is interesting in physics and may also have important applications in spintronics. In this work, by measuring the tunable helicity-dependent photocurrent (HDP), we present an identification of the HDP from the Dirac-like surface states at room temperature. It turns out that the total HDP has two components, one from the Dirac-like surface states, and the other from the surface accumulation layer. These two components have opposite directions. The clear gate tuning of the electron density as well as the HDP signal indicates that the surface band bending and resulted surface accumulation are successfully modulated by the applied ionic liquid gate, which provides a promising way to the study of the Dirac-like surface states and also potential applications in spintronic devices. PMID- 24809331 TI - Nitric oxide donors for treating preterm labour. AB - BACKGROUND: A number of tocolytics have been advocated for the treatment of threatened preterm labour in order to delay birth. The rationale is that a delay in birth may be associated with improved neonatal morbidity or mortality. Nitric oxide donors, such as nitroglycerin, have been used to relax the uterus. This review addresses their efficacy, adverse effects and influence on neonatal outcome. OBJECTIVES: To determine whether nitric oxide donors administered in threatened preterm labour are associated with a delay in birth, adverse effects or improved neonatal outcome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013). SELECTION CRITERIA: Randomised controlled trials of nitric oxide donors administered for tocolysis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Twelve trials, including a total of 1227 women at risk of preterm labour, contributed data to this updated review. The methodological quality of trials was mixed; trials comparing nitric oxide donors with other types of tocolytics were not blinded and this may have had an impact on findings.Three studies compared nitric oxide donors (glyceryl trinitrate (GTN)) with placebo. There was no significant evidence that nitric oxide donors prolonged pregnancy beyond 48 hours (average risk ratio (RR) 1.19, 95% confidence interval (CI) 0.74 to 1.90, two studies, 186 women), and although for most adverse effects there was no significant difference between groups, women in the active treatment group in one study were at higher risk of experiencing a headache. For infant outcomes there was no significant evidence that nitric oxide donors reduced the risk of neonatal death or serious morbidity (stillbirth RR 0.36, 95% CI 0.01 to 8.59, one study, 153 infants; neonatal death RR 0.43, 95% CI 0.06 to 2.89, two studies, 186 infants). One study, using a composite outcome, reported a reduced risk of serious adverse outcomes for infants in the GTN group which approached statistical significance (RR 0.29, 95% CI 0.08 to 1.00, 153 infants). Overall, these studies were underpowered to identify differences between groups for most outcomes.When nitric oxide donors were compared with other tocolytic drugs there was no significant evidence that nitric oxide donors performed better than other tocolytics (betamimetics, magnesium sulphate, a calcium channel blocker or a combination of tocolytics) in terms of pregnancy prolongation, although nitric oxide donors appeared to be associated with a reduction in most adverse effects, apart from headache. There was no significant difference between groups for infant morbidity or mortality outcomes. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to support the routine administration of nitric oxide donors in the treatment of threatened preterm labour. PMID- 24809332 TI - A comparison of arterial spin labeling perfusion MRI and DCE-MRI in human prostate cancer. AB - Perfusion MRI has the potential to provide pathophysiological biomarkers for the evaluating, staging and therapy monitoring of prostate cancer. The objective of this study was to explore the feasibility of noninvasive arterial spin labeling (ASL) to detect prostate cancer in the peripheral zone and to investigate the correlation between the blood flow (BF) measured by ASL and the pharmacokinetic parameters K(trans) (forward volume transfer constant), kep (reverse reflux rate constant between extracellular space and plasma) and ve (the fractional volume of extracellular space per unit volume of tissue) measured by dynamic contrast enhanced (DCE) MRI in patients with prostate cancer. Forty-three consecutive patients (ages ranging from 49 to 86 years, with a median age of 74 years) with pathologically confirmed prostate cancer were recruited. An ASL scan with four different inversion times (TI = 1000, 1200, 1400 and 1600 ms) and a DCE-MRI scan were performed on a clinical 3.0 T GE scanner. BF, K(trans), kep and ve maps were calculated. In order to determine whether the BF values in the cancerous area were statistically different from those in the noncancerous area, an independent t-test was performed. Spearman's bivariate correlation was used to assess the relationship between BF and the pharmacokinetic parameters K(trans), kep and ve. The mean BF values in the cancerous areas (97.1 +/- 30.7, 114.7 +/- 28.7, 102.3 +/- 22.5, 91.2 +/- 24.2 ml/100 g/min, respectively, for TI = 1000, 1200, 1400, 1600 ms) were significantly higher (p < 0.01 for all cases) than those in the noncancerous regions (35.8 +/- 12.5, 42.2 +/- 13.7, 53.5 +/- 19.1, 48.5 +/- 13.5 ml/100 g/min, respectively). Significant positive correlations (p < 0.01 for all cases) between BF and the pharmacokinetic parameters K(trans), kep and ve were also observed for all four TI values (r = 0.671, 0.407, 0.666 for TI = 1000 ms; 0.713, 0.424, 0.698 for TI = 1200 ms; 0.604, 0.402, 0.595 for TI = 1400 ms; 0.605, 0.422, 0.548 for TI = 1600 ms). It can be seen that the quantitative ASL measurements show significant differences between cancerous and benign tissues, and exhibit strong to moderate correlations with the parameters obtained using DCE-MRI. These results show the promise of ASL as a noninvasive alternative to DCE-MRI. PMID- 24809333 TI - Nasal osteotomies: a cadaveric study of fracture lines. AB - IMPORTANCE: The different nasal osteotomy patterns used to perform rhinoplasty are poorly described in the literature, and there is a continuous debate between surgeons on the ideal sequence and technique to obtain desired results. OBJECTIVES: (1) To evaluate the necessity of a paramedian osteotomy when performing a high-low-high (HLH) osteotomy, (2) to study the fracture pattern of a high-low-low (HLL) osteotomy when combined with a paramedian osteotomy in the presence and in the absence of a transverse osteotomy, and (3) to evaluate the mobility of the central segment (located between the paramedian osteotomies) after digital pressure and the ideal osteotomy to mobilize it if needed. DESIGN AND SETTING: This was a prospective cadaveric study performed in the dissection laboratory in our tertiary referral center. EXPOSURE: Twenty cadavers were divided in 2 groups of 10. Group A had a paramedian osteotomy combined with an HLH osteotomy on 1 side and an HLH osteotomy alone on the other side. Group B had a paramedian combined with a transverse osteotomy followed by HLL osteotomy on 1 side. On the other side, we performed a paramedian combined with an HLL osteotomy. Finally, we evaluated the mobility of the central segment in group B, first with digital manipulation and then with a transverse osteotomy. MAIN OUTCOME AND MEASURE: The 3 authors evaluated individually the different fracture patterns. A result was considered successful when (1) the fracture followed the desired pattern, (2) a continuous line was obtained, and (3) a complete mobilization of the nasal segment was visualized. RESULTS: In group A, the side without a paramedian osteotomy had more unstable and greenstick fractures than the other side (P < .001). In group B, the side with a transverse osteotomy had more reliable and stable fractures than the other side (P < .05). Digital manipulation alone was not enough to mobilize the central segment in 8 of the 10 cadavers studied. CONCLUSIONS AND RELEVANCE: Following this study we make the following suggestions: (1) to perform a paramedian osteotomy when an HLH osteotomy is needed, (2) to perform a transverse osteotomy before an HLL osteotomy when combined with paramedian osteotomy, and (3) to manipulate the central segment with a transverse osteotomy in order to mobilize it in a safe and predictable manner. LEVEL OF EVIDENCE: NA. PMID- 24809335 TI - Zero frequency of internal hernias after laparoscopic double loop gastric bypass without closure of mesenteric defects. AB - PURPOSE: Laparoscopic Roux-en-Y gastric bypass is among the most effective surgical procedures for morbid obesity; however, one of its most common long-term complications is internal hernia. The purpose of this study was to evaluate the incidence of internal hernia in patients undergoing a new gastric bypass surgical technique known as "double loop" without closure of the mesenteric defects. METHODS: We reviewed 44 patients with morbid obesity, who underwent laparoscopic double loop gastric bypass. There were 34 women and 10 men, followed up for a mean period of 18 +/- 3 months, mainly by periodic medical examinations and blood tests. RESULTS: The initial body mass index (BMI) was 44.23 +/- 4.7 and the mean % excess weight (%EW) was 105.83 +/- 24.41. After 18 postoperative months, the mean BMI was 29.68 +/- 3.7 kg/m(2), representing a mean loss of 14.5 BMI units, with the mean % excess weight loss (%EWL) of 64.33 +/- 13.47. No cases of internal hernia were recorded. CONCLUSIONS: Laparoscopic double loop gastric bypass without closure of the mesenteric defects is a safe and feasible procedure. A longer observational follow-up and a large number of patients are required to confirm significant results. PMID- 24809336 TI - Inner gorges cut by subglacial meltwater during Fennoscandian ice sheet decay. AB - The century-long debate over the origins of inner gorges that were repeatedly covered by Quaternary glaciers hinges upon whether the gorges are fluvial forms eroded by subaerial rivers, or subglacial forms cut beneath ice. Here we apply cosmogenic nuclide exposure dating to seven inner gorges along ~500 km of the former Fennoscandian ice sheet margin in combination with a new deglaciation map. We show that the timing of exposure matches the advent of ice-free conditions, strongly suggesting that gorges were cut by channelized subglacial meltwater while simultaneously being shielded from cosmic rays by overlying ice. Given the exceptional hydraulic efficiency required for meltwater channels to erode bedrock and evacuate debris, we deduce that inner gorges are the product of ice sheets undergoing intense surface melting. The lack of postglacial river erosion in our seven gorges implicates subglacial meltwater as a key driver of valley deepening on the Baltic Shield over multiple glacial cycles. PMID- 24809334 TI - Negative regulators of brown adipose tissue (BAT)-mediated thermogenesis. AB - Brown adipose tissue (BAT) is specialized for energy expenditure, a process called adaptive thermogenesis. PET-CT scans recently demonstrated the existence of metabolically active BAT in adult humans, which revitalized our interest in BAT. Increasing the amount and/or activity of BAT holds tremendous promise for the treatment of obesity and its associated diseases. PGC1alpha is the master regulator of UCP1-mediated thermogenesis in BAT. A number of proteins have been identified to influence thermogenesis either positively or negatively through regulating the expression or transcriptional activity of PGC1alpha. Therefore, BAT activation can be achieved by either inducing the expression of positive regulators of PGC1alpha or by inhibiting the repressors of the PGC1alpha/UCP1 pathway. Here, we review the most important negative regulators of PGC1alpha/UCP1 signaling and their mechanism of action in BAT-mediated thermogenesis. PMID- 24809337 TI - ?Nalmefene for alcohol dependence. AB - The burden of morbidity and mortality resulting from alcohol dependence is high. World Health Organization (WHO) figures suggest that in the UK the prevalence of alcohol use disorders in those aged 15 years and older is around 6.4% for men and 1.5% for women.1 Reduction of harm resulting from alcohol dependence remains a high priority in all four devolved health services in the UK.2-5 Several medicines are licensed for the maintenance of abstinence in alcohol-dependent patients. However, until recently no drug was licensed for the management of alcohol dependence in people who are still drinking. ?Nalmefene (Selincro, Lundbeck), an opioid modulator licensed for the reduction of alcohol consumption, was launched in the UK in May 2013.6,7 Here we discuss the evidence for its effectiveness and safety and consider its place in therapy. PMID- 24809338 TI - The screening research of anti-inflammatory bioactive markers from different flowering phases of Flos Lonicerae Japonicae. AB - Flos Lonicerae Japonicae (FLJ) is an important cash crop in eastern Asia, and it is an anti-inflammatory Traditional Chinese Medicine. There are large variations in the quality of the marketed FLJ products. To find marker ingredients useful for quality control, a tandem technology integrating ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF), principal component analysis (PCA), heat map analysis and hierarchical cluster analysis coupled with a NF-kappaB luciferase reporter gene assay were used to identify the different ingredients from the green bud, white bud, flowering stage and leaf stages, as well as to screen the anti-inflammatory activity of FLJ compositions. As flowering progressed, the anti-inflammatory effects of FLJ gradually decreased; however, chlorogenic acid, swertiamarin and sweroside should be used to evaluate the quality of FLJ products. PMID- 24809339 TI - A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension. AB - Adult patients who present with papilloedema and symptoms of raised intracranial pressure need urgent multidisciplinary assessment including neuroimaging, to exclude life-threatening causes. Where there is no apparent underlying cause for the raised intracranial pressure, patients are considered to have idiopathic intracranial hypertension (IIH). The incidence of IIH is increasing in line with the global epidemic of obesity. There are controversial issues in its diagnosis and management. This paper gives a practical approach to assessing patients with papilloedema, its investigation and the subsequent management of patients with IIH. PMID- 24809340 TI - Leukocyte mitochondrial DNA copy number in blood is not associated with major depressive disorder in young adults. AB - BACKGROUND: Major depressive disorder (MDD) is the leading cause of disability worldwide, and has significant genetic predisposition. Mitochondria may have a role in MDD and so mitochondrial DNA (mtDNA) has been suggested as a possible biomarker for this disease. We aimed to test whether the mtDNA copy number of peripheral blood leukocytes is related to MDD in young adults. METHODS: A case control study was conducted with 210 MDD patients and 217 healthy controls (HC). The mtDNA copy number was measured by quantitative polymerase chain reaction (qPCR) method. Depression severity was assessed by the Hamilton-17 Depression Rating Scale (HDRS-17). RESULTS: We found no significant differences in mtDNA copy number between MDD patients and HC, though the power analysis showed that our sample size has enough power to detect the difference. There were also no significant correlations between mtDNA copy number and the clinical characteristics (such as age, age of onset, episodes, Hamilton Depression Rating Scale (HDRS) score and Global Assessment of Function Scale (GAF) score) in MDD patients. CONCLUSION: Our study suggests that leukocyte mtDNA copy number is unlikely to contribute to MDD, but it doesn't mean that we can exclude the possibility of involvement of mitochondria in the disease. Further studies are required to elucidate whether mtDNA can be a biomarker of MDD. PMID- 24809341 TI - Fast k-NNG construction with GPU-based quick multi-select. AB - In this paper, we describe a new brute force algorithm for building the k-Nearest Neighbor Graph (k-NNG). The k-NNG algorithm has many applications in areas such as machine learning, bio-informatics, and clustering analysis. While there are very efficient algorithms for data of low dimensions, for high dimensional data the brute force search is the best algorithm. There are two main parts to the algorithm: the first part is finding the distances between the input vectors, which may be formulated as a matrix multiplication problem; the second is the selection of the k-NNs for each of the query vectors. For the second part, we describe a novel graphics processing unit (GPU)-based multi-select algorithm based on quick sort. Our optimization makes clever use of warp voting functions available on the latest GPUs along with user-controlled cache. Benchmarks show significant improvement over state-of-the-art implementations of the k-NN search on GPUs. PMID- 24809342 TI - Horizontal hostility among non-meat eaters. AB - The present study examined intergroup judgments made between four groups of non meat eaters: health vegetarians; ethical vegetarians; health vegans, and ethical vegans. Consistent with hypotheses based on horizontal hostility and the need to maintain ingroup distinctiveness, ethical vegetarians gave unfavorable evaluations to health vegetarians relative to vegans, especially when the mainstream omnivore group was made salient. Contrary to expectations, vegans gave relatively more favorable evaluations to ethical vegetarians than health vegetarians when mainstream salience was low. This was especially true for vegans who were motivated primarily by ethical concerns. When mainstream salience was high, vegans did not distinguish between the vegetarian subgroups. Results suggest that one's motives for abstaining from meat often play a larger role in this type of intergroup perceptions than one's dietary practices. PMID- 24809345 TI - Fine tuning of the UPR by the ubiquitin ligases Siah1/2. AB - The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions. PMID- 24809346 TI - Fabrication of an electrochemical sensor based on gold nanoparticles/carbon nanotubes as nanocomposite materials: determination of myricetin in some drinks. AB - In this paper, the electrochemical behavior of myricetin on a gold nanoparticle/ethylenediamine/multi-walled carbon-nanotube modified glassy carbon electrode (AuNPs/en/MWCNTs/GCE) has been investigated. Myricetin effectively accumulated on the AuNPs/en/MWCNTs/GCE and caused a pair of irreversible redox peaks at around 0.408 V and 0.191 V (vs. Ag/AgCl) in 0.1 mol L-1 phosphate buffer solution (pH 3.5) for oxidation and reduction reactions respectively. The heights of the redox peaks were significantly higher on AuNPs/en/MWNTs/GCE compare with MWCNTs/GC and there was no peak on bare GC. The electron-transfer reaction for myricetin on the surface of electrochemical sensor was controlled by adsorption. Some parameters including pH, accumulation potential, accumulation time and scan rate have been optimized. Under the optimum conditions, anodic peak current was proportional to myricetin concentration in the dynamic range of 5.0*10-8 to 4.0*10-5 mol L-1 with the detection limit of 1.2*10-8 mol L-1. The proposed method was successfully used for the determination of myricetin content in tea and fruit juices. PMID- 24809347 TI - Skeletal anomaly monitoring in rainbow trout (Oncorhynchus mykiss, Walbaum 1792) reared under different conditions. AB - The incidence of skeletal anomalies could be used as an indicator of the "quality" of rearing conditions as these anomalies are thought to result from the inability of homeostatic mechanisms to compensate for environmentally-induced stress and/or altered genetic factors. Identification of rearing conditions that lower the rate of anomalies can be an important step toward profitable aquaculture as malformed market-size fish have to be discarded, thus reducing fish farmers' profits. In this study, the occurrence of skeletal anomalies in adult rainbow trout grown under intensive and organic conditions was monitored. As organic aquaculture animal production is in its early stages, organic broodstock is not available in sufficient quantities. Non-organic juveniles could, therefore, be used for on-growing purposes in organic aquaculture production cycle. Thus, the adult fish analysed in this study experienced intensive conditions during juvenile rearing. Significant differences in the pattern of anomalies were detected between organically and intensively-ongrown specimens, although the occurrence of severe, commercially important anomalies, affecting 2-12.5% of individuals, was comparable in the two systems. Thus, organic aquaculture needs to be improved in order to significantly reduce the incidence of severe anomalies in rainbow trout. PMID- 24809348 TI - Traditional cattle grazing in a mosaic alkali landscape: effects on grassland biodiversity along a moisture gradient. AB - Extensively managed pastures are of crucial importance in sustaining biodiversity both in local- and landscape-level. Thus, re-introduction of traditional grazing management is a crucial issue in grassland conservation actions worldwide. Traditional grazing with robust cattle breeds in low stocking rates is considered to be especially useful to mimic natural grazing regimes, but well documented case-studies are surprisingly rare on this topic. Our goal was to evaluate the effectiveness of traditional Hungarian Grey cattle grazing as a conservation action in a mosaic alkali landscape. We asked the following questions: (i) How does cattle grazing affect species composition and diversity of the grasslands? (ii) What are the effects of grazing on short-lived and perennial noxious species? (iii) Are there distinct effects of grazing in dry-, mesophilous- and wet grassland types? Vegetation of fenced and grazed plots in a 200-ha sized habitat complex (secondary dry grasslands and pristine mesophilous- and wet alkali grasslands) was sampled from 2006-2009 in East-Hungary. We found higher diversity scores in grazed plots compared to fenced ones in mesophilous- and wet grasslands. Higher cover of noxious species was typical in fenced plots compared to their grazed counterparts in the last year in every studied grassland type. We found an increasing effect of grazing from the dry- towards the wet grassland types. The year-to-year differences also followed similar pattern: the site dependent effects were the lowest in the dry grassland and an increasing effect was detected along the moisture gradient. We found that extensive Hungarian Grey cattle grazing is an effective tool to suppress noxious species and to create a mosaic vegetation structure, which enables to maintain high species richness in the landscape. Hungarian Grey cattle can feed in open habitats along long moisture gradient, thus in highly mosaic landscapes this breed can be the most suitable livestock type. PMID- 24809349 TI - Timed action of IL-27 protects from immunopathology while preserving defense in influenza. AB - Infection with influenza virus can result in massive pulmonary infiltration and potentially fatal immunopathology. Understanding the endogenous mechanisms that control immunopathology could provide a key to novel adjunct therapies for this disease. Here we show that the cytokine IL-27 plays a crucial role in protection from exaggerated inflammation during influenza virus infection. Using Il-27ra-/- mice, IL-27 was found to limit immunopathology, neutrophil accumulation, and dampened TH1 or TH17 responses via IL-10-dependent and -independent pathways. Accordingly, the absence of IL-27 signals resulted in a more severe disease course and in diminished survival without impacting viral loads. Consistent with the delayed expression of endogenous Il-27p28 during influenza, systemic treatment with recombinant IL-27 starting at the peak of virus load resulted in a major amelioration of lung pathology, strongly reduced leukocyte infiltration and improved survival without affecting viral clearance. In contrast, early application of IL-27 impaired virus clearance and worsened disease. These findings demonstrate the importance of IL-27 for the physiological control of immunopathology and the potential value of well-timed IL-27 application to treat life-threatening inflammation during lung infection. PMID- 24809351 TI - Spreading depolarization in the ischemic brain: does aging have an impact? AB - Recurrent waves of spreading depolarization (SD) spontaneously occur minutes after the onset of focal ischemia in the brain and keep generating for a number of days to follow. It has become widely accepted that ischemia-related SDs are part of the pathophysiology of cerebrovascular diseases and predict worse outcome. SDs may exacerbate ischemic injury via related atypical hemodynamic responses. The incidence of ischemic stroke is known to increase markedly with age; yet, very few studies investigated whether age alters SD evolution and whether a potential age-specific pattern of SD would contribute to the age related intensification of infarct development. Experimental data demonstrate that aging has a marked impact on SD evolution and corresponding changes in cerebral blood flow. We hypothesize that an age-specific pattern of the SD associated hemodynamic response must be involved in augmenting the expansion of ischemic brain damage in the elderly patients and that structural and functional (mal)adaptation of the cerebrovascular system with aging serves as a potential basis for compromised vascular reactivity and subsequent tissue damage. The concept put forward is expected to stimulate further investigation to achieve a comprehensive overview of the implication of SD in injury progression in the aged brain. PMID- 24809350 TI - Linear superposition and prediction of bacterial promoter activity dynamics in complex conditions. AB - Bacteria often face complex environments. We asked how gene expression in complex conditions relates to expression in simpler conditions. To address this, we obtained accurate promoter activity dynamical measurements on 94 genes in E. coli in environments made up of all possible combinations of four nutrients and stresses. We find that the dynamics across conditions is well described by two principal component curves specific to each promoter. As a result, the promoter activity dynamics in a combination of conditions is a weighted average of the dynamics in each condition alone. The weights tend to sum up to approximately one. This weighted-average property, called linear superposition, allows predicting the promoter activity dynamics in a combination of conditions based on measurements of pairs of conditions. If these findings apply more generally, they can vastly reduce the number of experiments needed to understand how E. coli responds to the combinatorially huge space of possible environments. PMID- 24809352 TI - Neuronal vesicular trafficking and release in age-related cognitive impairment. AB - Aging is a common major risk factor for many neurological disorders resulting in cognitive impairment and neurodegeneration including Parkinson's and Alzheimer's diseases. Novel results from the fields of molecular neuroscience and aging research provide evidence for a link between decline of various cognitive, executive functions and changes in neuronal mechanisms of intracellular trafficking and regulated vesicle release processes in the aging nervous system. In this Perspective, we review these recent findings and formulate a hypothesis on how cargo delivery to the synapses and the release of neurotrophic factors may be involved in maintaining learning and memory capabilities during healthy aging and present examples on how defects of those disrupt normal cognition. We provide an overview of emerging new concepts and approaches that will significantly advance our understanding of the aging brain and pathophysiology of dementia. This knowledge will be instrumental in defining drug targets and designing novel therapeutic strategies. PMID- 24809354 TI - Profiling of Nutrient Transporter Expression in Human Stem Cell-Derived Cardiomyocytes Exposed to Tyrosine Kinase Inhibitor Anticancer Drugs Using RBD Ligands. AB - We applied a novel profiling approach using receptor binding domain (RBD) ligands to cell surface domains of a panel of nutrient transporters to characterize the impact of a number of tyrosine kinase inhibitor anticancer drugs on human stem cell-derived cardiomyocytes. High-content screening and flow cytometry analysis showed diagnostic changes in nutrient transporter expression correlating with glycolysis and oxidative phosphorylation-based cell metabolism in glucose and galactose media. Cluster analysis of RBD binding signatures of drug-treated cells cultured in glucose medium showed good correlation with sensitization of mitochondrial toxicity in cells undergoing oxidative phosphorylation in galactose medium. These data demonstrate the potential for RBD ligands as profiling tools to improve the clinical predictivity of in vitro cell assays for drug toxicity. PMID- 24809355 TI - Endovascular Therapy And Controversies In The Management Of Vascular Trauma. AB - AIM: To review the advent of endovascular treatment of vascular injuries and its controversies. METHODS: Literature review over the past 13 years using the PubMed search engine. RESULTS: The management of vascular trauma has changed dramatically over the last decade. This is mainly due to the advent of advanced endovascular techniques and technologies. There are, however, a limited number of publications with a correspondingly small number of patients and lack of long term follow-up. In this article, we discuss the injuries to different vessel groups and their respective endovascular approaches. Of the literature available, the endovascular management of aortic injuries still holds the most experience and has shown favorable results. CONCLUSION: Endovascular management of vascular injuries is a new addition to the armamentarium of the surgeon. The fact that it is minimally invasive is a major advantage and the published data are encouraging. However, in order to determine which anatomical sites and circumstances are most appropriate for this method versus open surgery, more reports are necessary. PMID- 24809353 TI - Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737. AB - One approach currently being developed in anticancer drug discovery is to search for small compounds capable of occupying and blocking the hydrophobic pocket of anti-apoptotic Bcl-2 family members necessary for interacting with pro-apoptotic proteins. Such an approach led to the discovery of several compounds, such as ABT 737 (which interacts with Bcl-2, Bcl-xl, and Bcl-w) or the latest one, ABT-199, that selectively targets Bcl-2 protein. The efficacy of those compounds is, however, limited by the expression of two other anti-apoptotic Bcl-2 members, Mcl 1 and Bfl-1. Based on the role of Bfl-1 in cancer, especially in chemoresistance associated with its overexpression in B-cell malignancies, we searched for modulators of protein-protein interaction through a high-throughput screening of a designed chemical library with relaxed drug-like properties to identify small molecules targeting Bfl-1 anti-apoptotic protein. We found two compounds that display electrophilic functions, interact with Bfl-1, inhibit Bfl-1 protective activity, and promote cell death of malignant B cells. Of particular interest, we observed a synergistic effect of those compounds with ABT-737 in Bfl-1 overexpressing lymphoma cell lines. Our results provide the basis for the development of Bfl-1 specific antagonists for antitumor therapies. PMID- 24809356 TI - Reduction mammaplasty as an outpatient procedure: a retrospective analysis of outcome and success rate. AB - BACKGROUND AND AIMS: Reduction mammaplasty is an increasingly common plastic surgical procedure. In the United States, majority of breast reductions are performed as outpatient surgery. In European public health care, outpatient breast reductions have still been rare. Our aim was to retrospectively determine clinical outcome and the success rate of outpatient reduction mammaplasty. MATERIAL AND METHODS: A total of 110 consecutive patients underwent bilateral reduction mammaplasty with a minimum resection of 200 g per breast in an outpatient unit between 2006 and 2009. A comparison group consisted of 28 inpatients. Demographic data and pre-, intra-, and postoperative events as well as complications were recorded. RESULTS: A total of 83 outpatients (75%) were successfully discharged on the day of operation. Reasons for unexpected overnight admission were lack of adult company for the first postoperative night (13 patients, 12%), surgeon's wish (4 patients, 4%), hematoma requiring evacuation (5 patients, 5%), nausea (3 patients, 3%), and pain (2 patients, 2%). Minor complications, especially delayed healing, were common (45 patients, 41%), but major complications were rare (18 patients, 16%). Complication rate was not increased in the outpatient group. Increased duration of operation correlated with increasing complications. CONCLUSION: Reduction mammaplasty can be successfully and safely performed as an outpatient procedure in European public health care. PMID- 24809357 TI - Epidemiology of electrical injury: Differences between low- and high-voltage electrical injuries during a 7-year study period in South Korea. AB - BACKGROUND AND AIMS: Electrical burns are uncommon, but they result in high morbidity and mortality due to severe tissue damage. The purpose of this study is to analyze epidemiological variables of electrical injuries and identify preventable measures through them. MATERIAL AND METHODS: We retrospectively analyzed the clinical records of 625 patients admitted to Hangang Sacred Heart Hospital's Department of Plastic Surgery from January 2005 to December 2011. We divided the patients into two groups: (1) low-voltage injury (under 1000 V) and (2) high-voltage injury (over 1000 V). We reviewed the following variables: age, sex, total burn surface area, injury type and mode, and surgical modalities. RESULTS AND CONCLUSIONS: The mean age of all patients was 33.4 +/- 18.2 years. The ratio of males to females was 13.5 in the whole group. The mean total body surface are burned was 14.0% +/- 13.8% in total. The majority of electrical burns in the low-tension group and high-tension group occurred in patients under 20 years and in patients aged 40-59 years, respectively. Steel chopstick insertions and high-voltage electrical work/repair were the most common injury modes in the low-tension group and the high-tension group, respectively. Groin and abdominal distant flap surgeries were commonly performed in both groups. It is recommended that these risks be prevented through education and safety measures to reduce the incidence of electrical injuries. PMID- 24809358 TI - Prevalence of Body Dysmorphic Disorder Among Patients Seeking Breast Reconstruction. AB - BACKGROUND: Body dysmorphic disorder (BDD) is characterized by a preoccupation with a slight or imagined defect in physical appearance. It has significant implications for patients who desire breast reconstruction, because patient satisfaction with the aesthetic outcome is a substantial contributor to the success of the procedure. OBJECTIVES: The authors estimated the prevalence of BDD among women seeking breast reconstruction by surveying patients with the previously validated Dysmorphic Concerns Questionnaire (DCQ). METHODS: One hundred eighty-eight women who presented for immediate or delayed breast reconstruction completed the DCQ anonymously, during initial consultation with a plastic surgeon. Two groups of respondents were identified: those who desired immediate reconstruction and those who planned to undergo delayed reconstruction. The prevalence of BDD among breast reconstruction patients was compared between the 2 groups, and the overall prevalence was compared with published rates for the general public. RESULTS: Body dysmorphic disorder was significantly more prevalent in breast reconstruction patients than in the general population (17% vs 2%; P < .001). It also was much more common among patients who planned to undergo delayed (vs immediate) reconstruction (34% vs 13%; P = .004). CONCLUSIONS: Relative to the general public, significantly more women who sought breast reconstruction were diagnosed as having BDD. Awareness of the potential for BDD will enable clinicians to better understand their patients' perspectives and discuss realistic expectations at the initial consultation. Future studies are warranted to examine the implications of BDD on patient satisfaction with reconstructive surgery. LEVEL OF EVIDENCE: 3. PMID- 24809359 TI - Pathologic Findings in Primary Capsulectomy Specimens: Analysis of 2531 Patients. AB - BACKGROUND: After breast augmentation, additional operations are often needed for revision or explantation. Although the surgeon may elect to leave the capsule in situ during these procedures, excised capsule tissue may be examined histopathologically for cancer cells. OBJECTIVES: The authors assessed pathologic findings from breast implant capsules submitted for histopathologic examination and evaluated whether it is oncologically safe to leave capsule tissue in situ. METHODS: The authors searched PALGA, the nationwide histopathology and cytopathology data network and registry in the Netherlands, for primary capsulectomy specimens excised between 2003 and 2012. The authors applied a sensitive search strategy with low specificity that included female and breast as the sex and anatomic location keywords, and wildcards were used to detect different spellings. Cases were excluded if previous examinations showed compatibility with a history of breast cancer, prophylactic mastectomy, or prophylactic oophorectomy. The pathologic reports were manually reviewed for relevance, and each case's diagnosis was registered. A total of 6803 reports were available, representing 4948 patients; 2574 reports from 2531 patients were included in this study. The median age of patients was 51.2 +/- 12.0 years (range, 15-88 years). RESULTS: Invasive carcinoma was detected in 4 patients (0.16%). Four patients (0.16%) had ductal carcinoma in situ, and 1 patient (0.04%) had lobular carcinoma in situ. Metaplasia was noted in 51 patients (2.0%), calcifications in 375 (14.6%), and silicone in 701 (27.2%). CONCLUSIONS: The incidence of occult invasive or in situ carcinoma in capsulectomy specimens of patients with no previous breast pathology is low. Therefore, it appears oncologically safe to leave capsule tissue in situ. LEVEL OF EVIDENCE: 3. PMID- 24809360 TI - Comparison of Limited-Undermining Lipoabdominoplasty and Traditional Abdominoplasty Using Laser Fluorescence Imaging. AB - BACKGROUND: Body contouring that involves abdominoplasty and/or liposuction is a common cosmetic surgery procedure. Although single-staged lipoabdominoplasty has gained popularity, safety concerns remain. OBJECTIVES: The authors compared abdominal flap perfusion and overall complication rates for traditional abdominoplasty and limited-undermining lipoabdominoplasty. METHODS: Eighteen abdominoplasty patients were evaluated in a prospective study. All patients were nonsmokers and lacked major comorbidities. The control group (n = 9) underwent traditional abdominoplasty with wide undermining. The study group (n = 9) underwent abdominoplasty with limited undermining as well as liposuction of the abdominal flap. The groups were similar with respect to age and body mass index. Patients received follow-up for an average of 97 days. Fluorescence imaging was utilized for perfusion studies. Results and complications were documented, and statistical significance was ascertained via the Student t test. RESULTS: Neither group had major complications or revisions. Minor complications included an exposed suture, resulting in delayed wound healing, in the control group. A patient in the study group had a small area of fat necrosis and a small seroma, neither of which required further treatment. No significant difference in abdominal flap perfusion was found between the control (57%) and study (50%) groups based on fluorescence levels relative to a designated baseline reference marker. CONCLUSIONS: Results of the study indicate that no significant differences exist between the 2 operations with respect to the rates of abdominal flap perfusion or complications. LEVEL OF EVIDENCE: 3. PMID- 24809361 TI - Findings and implications of the Global Burden of Disease 2010 Study for the Pacific Islands. AB - The Global Burden of Disease 2010 Study is the largest study of its kind. It provides a large volume of information about the global burden of disease and associated risk factors. It estimates that lower respiratory infections, diabetes, diarrhea, and tuberculosis cause the greatest burden in the Pacific, and noncommunicable diseases caused a substantially greater burden in 2010 compared with 1990. Although the Pacific is considered to be a region rich in data, very little of these data has been analyzed, synthesized, and made publically available. Consequently, burden estimates for the Pacific are derived from models built with very limited data, and it is difficult to know how accurate they are. Health information in the Pacific needs strengthening, particularly in relation to data collection, analysis, use, and sharing. This will improve the reliability and comparability of burden of disease estimates. PMID- 24809362 TI - Perceived benefits and challenges of coordinated approaches to chronic disease prevention in state health departments. AB - INTRODUCTION: Chronic disease prevention efforts have historically been funded categorically according to disease or risk factor. Federal agencies are now progressively starting to fund combined programs to address common risk. The purpose of this study was to inform transitions to coordinated chronic disease prevention by learning views on perceived benefits and challenges of a coordinated approach to funding. METHODS: A national survey on evidence-based public health was conducted from March through May 2013 among state health department employees working in chronic disease prevention (N = 865). Participants were asked to rank the top 3 benefits and top 3 challenges in coordinating chronic disease approaches from provided lists and could provide additional responses. Descriptive analyses, chi(2) tests, and analysis of variance were conducted. RESULTS: The most common perceived benefits of coordinated approaches to chronic disease prevention were improved health outcomes, common risk factors better addressed, and reduced duplication of program efforts. The most common perceived challenges were funding restrictions, such as disease-specific performance measures; competing priorities; lack of communication across programs; funding might be reduced; agency not structured for program coordination; and loss of disease-specific partner support. Rankings of benefits and challenges were similar across states and participant roles; the perceived challenges "lack of communication across programs" (P = .02) and "funding might be reduced" differed by program area (P < .001). CONCLUSION: Findings can be used by funding agencies and state health departments for planning, training, and technical assistance. The information on perceived challenges demonstrates the need to improve communication across programs, enhance organizational support for coordinated approaches, and create benefits for organizational partners. PMID- 24809363 TI - Adapting and implementing an evidence-based sun-safety education program in rural Idaho, 2012. AB - BACKGROUND: Melanoma incidence and mortality rates in Idaho are higher than national averages. The importance of increased awareness of skin cancer has been cited by state and local organizations. St. Luke's Mountain States Tumor Institute (MSTI) prioritized educational outreach efforts to focus on the implementation of a skin cancer prevention program in rural Idaho. COMMUNITY CONTEXT: As a community cancer center, MSTI expanded cancer education services to include dedicated support to rural communities. Through this expansion, an MSTI educator sought to partner with a community organization to provide sun-safety education. MSTI selected, adapted, and implemented an evidence-based program, Pool Cool. METHODS: The education program was implemented in 5 phases. In Phase I, we identified and recruited a community partner; in Phase 2, after thorough research, we selected a program, Pool Cool; in Phase 3, we planned the details of the program, including identification of desired short- and long-term outcomes and adaptation of existing program materials; in Phase 4, we implemented the program in summer 2012; in Phase 5, we assessed program sustainability and expansion. OUTCOME: MSTI developed a sustainable partnership with Payette Municipal Pool, and in summer 2012, we implemented Pool Cool. Sun-safety education was provided to more than 700 young people aged 2 to 17 years, and educational signage and sunscreen benefitted hundreds of additional pool patrons. INTERPRETATION: Community cancer centers are increasingly being asked to assess community needs and implement evidence-based prevention and screening programs. Clinical staff may become facilitators of evidence-based public health programs. Challenges of implementing evidence-based programs in the context of a community cancer centers are staffing, leveraging of resources, and ongoing training and support. PMID- 24809364 TI - Research to reality: moving evidence into practice through an online community of practice. AB - How can a community of practice help further the practical application of cancer control research? In 2011, the National Cancer Institute (NCI) launched an online community of practice, Research to Reality (R2R). R2R aims to infuse evidence based strategies into communities by engaging researchers and practitioners in a joint approach to research dissemination. To measure community growth and engagement, NCI measures data across 3 program domains: content, interaction, and activity. NCI uses Web analytics, usability testing, and content analyses to manage and evaluate R2R. As of December 2013, R2R had more than 1,700 registered members. More than 500 researchers and practitioners register for the monthly cyber-seminars, and 40% return each month. R2R hosts more than 15,500 page views and 5,000 site visits in an average month. This article describes the process of convening this online community and quantifies our experiences to date. PMID- 24809365 TI - Atypical atrioventricular nodal reentry tachycardia in a child with polyvalvular dysplasia. AB - A 10-year-old boy with polyvalvular dysplasia and severe involvement of both atrioventricular valves presented with palpitations. Concern was raised for atrial tachyarrhythmia due to biatrial enlargement; however, ambulatory monitoring discovered a reentrant mechanism. Electrophysiology study revealed atypical atrioventricular nodal reentrant tachycardia involving two components of the slow pathway, with inputs in the posterior septum around his dysplastic tricuspid valve. He underwent successful modification of the slow pathway using cryoablation. PMID- 24809366 TI - Poor multi-rater reliability in TCM pattern diagnoses and variation in the use of symptoms to obtain a diagnosis. AB - BACKGROUND: Pattern differentiation and diagnosis are fundamental principles of Traditional Chinese Medicine (TCM). Studies have shown low inter-rater reliability in TCM pattern diagnoses. This variability may originate from both the identification and the interpretation of symptoms and signs. OBJECTIVE: To examine the inter-rater reliability in TCM pattern diagnoses made in the style of Maciocia for 25 case histories by eight acupuncturists and to explore the impact of demographic factors on the diagnostic conclusion. Further, the association between the diagnosis and the presence of symptoms was examined for a single TCM diagnosis. METHODS: Eight acupuncturists independently diagnosed 25 women (15 fertile, 10 infertile) based on written case histories. Descriptive statistics, logistic regression and inter-rater reliability (kappa) were used. RESULTS: Poor inter-rater reliability on TCM patterns (kappa<0.20) and large variation in the number of TCM pattern diagnoses were found. Sex, duration of practice and education had a highly significant effect (p<0.001) on the use of TCM patterns and working hours had a significant effect (p=0.029). There was considerable intra- and inter-rater variation in the use of symptoms to make a diagnosis. Symptoms occurring frequently as well as infrequently were inconsistently used to diagnose Liver Qi Stagnation. The study was limited by a small sample size. CONCLUSIONS: The results showed extensive variation and poor inter-rater reliability in TCM diagnoses. Demographic variables influenced the frequency of diagnoses and symptoms were used inconsistently to set a diagnosis. The variability shown could impede individually tailored treatment. PMID- 24809367 TI - Wet needling of myofascial trigger points in abdominal muscles for treatment of primary dysmenorrhoea. AB - OBJECTIVES: To evaluate the effect of wet needling (related to acupuncture) and home stretching exercises on myofascial trigger points (MTrPs) in abdominal muscles for the treatment of dysmenorrhoea. METHODS: The effect of wet needing of MTrPs in abdominal muscles, supplemented by home stretching exercises, was observed in 65 patients with moderate and severe primary dysmenorrhoea. The MTrPs in the abdominal region were localised and repeatedly needled with lidocaine injection. Menstrual pain was evaluated with a Visual Analogue Scale (VAS) score after every treatment, with the final evaluation made at a 1-year follow-up. Treatment was stopped when the VAS pain score reduced to <=3. Symptoms scores were analysed with one-way analysis of variance. RESULTS: The mean VAS pain score before treatment was 7.49+/-1.16. After a single wet needling session, 41 patients had a reduction in their VAS pain score to <3 during their following menstrual cycle, with a mean of 1.63+/-0.49. Twenty-four patients who needed two treatments showed a reduction in menstrual pain scores to 0.58+/-0.50. After 1 year, the mean VAS pain score among all patients was 0.28+/-0.45, with a response rate of 100%. CONCLUSIONS: Primary dysmenorrhoea was significantly reduced 1 year after wet needling to MTrPs in the abdominal region and home stretching exercises, justifying further research with controlled trials. PMID- 24809368 TI - Acupuncture as part of multimodal analgesia after caesarean section. PMID- 24809369 TI - Prevalence of binge drinking and associated co-factors among medical students in a U.S. Jesuit University. AB - BACKGROUND: Alcohol consumption is the third leading cause of preventable death in the U.S. Limited research has been conducted examining drinking habits of medical students. OBJECTIVE: This study was designed to measure the prevalence and associated risk factors of binge drinking among a sample of medical students. METHODS: A total of 485 medical students at a private, Jesuit medical school in the US participated in a confidential web-based survey in April 2011. Univariate and multivariate generalized linear regressions with robust error variance were performed for estimated prevalence ratio (PR) of binge drinking. RESULTS: The prevalence of binge drinking was 58.1% among the sampled medical students with the majority being white (67.0%) and between 18 and 25 years old (60.0%). After adjusting for age, gender, race/ethnicity, and year in medical school, there were statistically significant (p < 0.05) associations of drinking during an after exam party (PR = 2.82), protective behavioral strategy (PR = 0.97 per 1-score increase), self-reported diagnosis of depression (PR = 1.19), tobacco use (PR = 1.21 for previous use, 1.39 for current use), and previous illicit drug use (PR = 1.24) with binge drinking. In addition, the prevalence of binge drinking decreased among this sample of the medical students with older age (PR = 0.80 for 26-28, 0.60 for >28, p < 0.01) compared to those of 18-25 years old. CONCLUSION: Binge drinking was highly prevalent among the sampled medical students, especially during an after-exam party. Identifying healthy coping strategies among medical students is warranted to reduce binge drinking. PMID- 24809370 TI - Innate-type and acquired-type allergy regulated by IL-33. AB - We propose two types of allergic response: IgE-dependent and IgE-independent, and designate these as 'acquired-type allergy' and 'innate-type allergy', respectively. IL-33 stimulates both innate (basophils, mast cells, or group 2 innate lymphoid cells) and acquired (Th2 cells) allergy-related cells to induce and/or augment Th2 cytokine production, which leads to eosinophilic inflammation in vivo. Thus, IL-33 is an essential regulator for both 'innate-type allergy' and 'acquired-type allergy', and might be an attractive therapeutic target for allergic diseases. PMID- 24809371 TI - Dual role of interleukin-23 in epicutaneously-sensitized asthma in mice. AB - BACKGROUND: Interleukin (IL)-23/Th17 axis plays an important role in the pathophysiology of asthma and eczema, however, there are some conflicting data about the effects of this system on allergic airway inflammation. In the present study, we aim to dissect the spatiotemporal differences in the roles of IL-23 in an epicutaneously-sensitized asthma model of mice. METHODS: C57BL/6 mice were sensitized to ovalbumin (OVA) by patch application on the skin, followed by airway exposure to aerosolized OVA. During sensitization and/or challenge phase, either a specific neutralizing antibody (Ab) against IL-23 or control IgG was injected intraperitoneally. On days 1 and 8 after the final OVA exposure, airway inflammation and responsiveness to methacholine, immunoglobulin levels in serum, and cytokine release from splenocytes were evaluated. Skin Il23a mRNA levels were evaluated with quantitative RT-PCR. RESULTS: Patch application time-dependently increased the expression of Il23a mRNA expression in the skin. Treatment with the anti-IL-23 Ab during sensitization phase alone significantly reduced the number of eosinophils in bronchoalveolar lavage fluids and peribronchial spaces after allergen challenge compared with treatment with control IgG. Anti-IL-23 Ab also reduced serum levels of OVA-specific IgG1. In contrast, treatment with the anti IL-23 Ab during the challenge phase alone rather exacerbated airway hyperresponsiveness to methacholine with little effects on airway eosinophilia or serum IgG1 levels. CONCLUSIONS: IL-23 expressed in the skin during the sensitization phase plays an essential role in the development of allergic phenotypes, whereas IL-23 in the airways during the challenge phase suppresses airway hyperresponsiveness. PMID- 24809372 TI - Age at onset of asthma and allergen sensitization early in life. AB - BACKGROUND: Epidemiological evidence indicates that the age at onset of asthma and allergen sensitization in early life is decreasing in people from Western countries. To explore latent trends, we conducted a retrospective examination of the age at onset of asthma and specific IgE antibodies against inhalant allergens in Japanese asthmatic children. METHODS: We conducted a case series study of 103 consecutive children with atopic type of asthma (aged 2 years to 16 years, mean age 9.4 +/- 3.4 years). Diagnoses of asthma and allergic rhinitis were defined according to Japanese guidelines. The onset of asthma and allergic rhinitis was also defined as any report of asthma and allergic rhinitis confirmed by a physician. Allergen sensitization was evaluated as specific serum IgE levels for 9 common inhalant allergens in peripheral blood. Atopic type of asthma was defined as a being positive for at least one aeroallergen. RESULTS: Mean age at asthma onset was 2.3 +/- 1.9 years, which is slightly lower than that of previous reports, including those published in Japan. A high prevalence rate of up to 80% was found for perennial antigens including Dermatophagoides spp. and house dust, as reported previously. Notably, some of the children aged at 1 year tested positive for these allergens. CONCLUSIONS: The age at onset of asthma seems to be decreasing in comparison with previous reports. Furthermore, the age at onset of allergen sensitization against inhalant allergens appears to follow this trend. PMID- 24809373 TI - Selective suppression of Th2 cell-mediated lung eosinophilic inflammation by anti major facilitator super family domain containing 10 monoclonal antibody. AB - BACKGROUND: The eosinophil is deeply associated with the pathogenesis of bronchial asthma and other allergic diseases. We recently identified a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10 (Mfsd10). A monoclonal antibody (mAb) against Mfsd10 (M2) showed selective binding and neutralizing activities for eosinophils. However, the relative potency of the blockage of Mfsd10 and other eosinophil-specific molecules for the treatment of allergic diseases has not been evaluated. Therefore, in this study, the effects of M2 and an anti-Siglec-F mAb on antigen immunized and antigen-specific Th2 cell-transferred murine eosinophilic inflammation models were comparatively investigated. METHODS: Ovalbumin (OVA) specific Th2 cells were differentiated from naive CD4+ T cells of DO11.10/RAG-2-/ mice in vitro and cytokine producing activity of the Th2 cells was examined. OVA immunized and Th2 cell-transferred BALB/c mice were treated with M2 or anti Siglec-F and challenged with OVA. Then the number of inflammatory cells and the concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) were determined. RESULTS: Antigen-specific Th2 cells produced large amounts of IL-4, IL-5 and IL 13 but not IL-17A or IFN-gamma. Administration of M2 significantly suppressed antigen-induced lung eosinophil infiltration both in OVA-immunized and Th2 cell transferred mice. The potency as well as selectivity of M2 for down-regulating eosinophils was quite similar to that of anti-Siglec-F. Both mAbs did not affect antigen-induced IL-5 production in the lungs. CONCLUSIONS: Mfsd10 as well as Siglec-F could be an effective target to treat eosinophil-related disorders including bronchial asthma. PMID- 24809374 TI - Development of assay for determining free IgE levels in serum from patients treated with omalizumab. AB - BACKGROUND: Omalizumab, a monoclonal anti-IgE antibody, is currently indicated for the treatment of moderate-to-severe allergic asthma. To measure active IgE levels in sera from patients treated with omalizumab, the IgE subfraction in complex with omalizumab should be eliminated from total IgE, and free IgE levels can then be determined. With the aim of therapeutic monitoring for anti-IgE therapy, we developed a new ELISA for free IgE. METHODS: We used recombinant human soluble FcepsilonRIalpha as a capture antigen and a biotinylated polyclonal anti-IgE antibody for detection. Using the newly developed ELISA, we measured the serum free IgE levels weekly in four asthmatic patients after their first omalizumab injection. We also measured the serum free IgE levels in 54 patients treated with omalizumab for over 4 weeks. RESULTS: This assay was technically robust, the mean recovery rate in serum was 93.16% +/- 5.34%. For all patients, omalizumab treatment significantly reduced serum free IgE levels prior to the second omalizumab injection. To maintain the benefit of omalizumab, serum free IgE concentrations should be <50 ng/ml. However, in 14 of 54 patients treated with omalizumab for over 4 weeks, serum free IgE concentrations measured by our ELISA were >50 ng/ml. CONCLUSIONS: Our data suggest that the measurement of free IgE levels using our newly developed ELISA would be useful for monitoring serum free IgE levels during omalizumab therapy. PMID- 24809375 TI - Modulation of human basophil degranulation by geranylgeranyl compounds. PMID- 24809376 TI - Eosinophilic gastroenteritis treated with a multiple-food elimination diet. PMID- 24809377 TI - Examination of patients whose eosinophilic ratio in sputum was more than 3% with wheeze or cough symptoms. PMID- 24809378 TI - Antigen-induced mixed and separated inflammation in murine upper and lower airways. PMID- 24809379 TI - Theophylline attenuates the adhesiveness of endothelial cells augmented with interferon-gamma in the presence of TNF-alpha for blood eosinophils. PMID- 24809380 TI - Eliciting eosinophil CCR3 expression by synthetic retinoids. PMID- 24809383 TI - Expanding indications for transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) has emerged as an accepted indication for non-operable patients with severe symptomatic native aortic valve stenosis (AS) and as a reasonable alternative for high-risk surgical AS patients. Nonetheless, the safety and efficacy of performing TAVR in several other potential indications are yet unclear. In the present manuscript the authors review the current evidence supporting TAVR for other potential indications than the typical high-risk/non-operable AS patients, providing updated results of the main clinical trials and registries exploring these particular indications. Finally, the authors provide practical recommendations for TAVR in each of these conditions. PMID- 24809382 TI - Serum coenzyme Q10, alpha-tocopherol, gamma-tocopherol, and C-reactive protein levels and body mass index in adolescent and premenopausal females. AB - OBJECTIVE: Lipid-soluble antioxidants are associated with a lower incidence for many chronic diseases of aging, possibly by preventing damage from chronic inflammation. In the current study, we compared serum levels of coenzyme Q10 (CoQ10), alpha-tocopherol, gamma-tocopherol, and C-reactive protein (CRP) between adolescent girls and premenopausal women to assess changes from childhood to midlife. METHODS: Baseline serum CoQ10, alpha-tocopherol, gamma-tocopherol, and CRP levels were measured in 207 girls (13-19 years) and 183 premenopausal women (34-47 years) using standard methods and the 2 age groups were compared by t test. The influence of age, body mass index (BMI), and race/ethnicity and interaction effects on serum values were assessed using analysis of covariance. Pearson correlation coefficients were used to assess associations between pairs of lipid micronutrients. RESULTS: Overall, adolescent girls had significantly lower mean serum CoQ10, alpha-tocopherol, gamma-tocopherol, and CRP levels relative to premenopausal women (CoQ10: 376 vs 544 ng/mL, p < 0.0001; alpha tocopherol: 6.9 vs 13.5 MUg/mL, p < 0.0001; gamma-tocopherol: 1.3 vs 1.7 MUg/mL, p < 0.0001; CRP: 1.29 vs 2.13 mg/L, p < 0.0001). The differences in CoQ10 and tocopherols remained significant after adjustment for BMI and race/ethnicity. CoQ10 was significantly and positively correlated to alpha- and gamma-tocopherol, and BMI was positively associated with CRP and gamma-tocopherol in both groups. CONCLUSIONS: Lower serum CoQ10, alpha-tocopherol, gamma-tocopherol, and CRP levels in adolescent girls compared to women suggests that adolescents may have a reduced need for antioxidants possibly due to their lower BMI and inflammatory status as indicated by CRP. PMID- 24809385 TI - Variations in the Staphylococcus aureus-specific nuc gene can potentially lead to misidentification of meticillin-susceptible and -resistant S. aureus. PMID- 24809384 TI - Characterization of 17 chaperone-usher fimbriae encoded by Proteus mirabilis reveals strong conservation. AB - Proteus mirabilis is a Gram-negative enteric bacterium that causes complicated urinary tract infections, particularly in patients with indwelling catheters. Sequencing of clinical isolate P. mirabilis HI4320 revealed the presence of 17 predicted chaperone-usher fimbrial operons. We classified these fimbriae into three groups by their genetic relationship to other chaperone-usher fimbriae. Sixteen of these fimbriae are encoded by all seven currently sequenced P. mirabilis genomes. The predicted protein sequence of the major structural subunit for 14 of these fimbriae was highly conserved (>= 95% identity), whereas three other structural subunits (Fim3A, UcaA and Fim6A) were variable. Further examination of 58 clinical isolates showed that 14 of the 17 predicted major structural subunit genes of the fimbriae were present in most strains (>85%). Transcription of the predicted major structural subunit genes for all 17 fimbriae was measured under different culture conditions designed to mimic conditions in the urinary tract. The majority of the fimbrial genes were induced during stationary phase, static culture or colony growth when compared to exponential phase aerated culture. Major structural subunit proteins for six of these fimbriae were detected using MS of proteins sheared from the surface of broth cultured P. mirabilis, demonstrating that this organism may produce multiple fimbriae within a single culture. The high degree of conservation of P. mirabilis fimbriae stands in contrast to uropathogenic Escherichia coli and Salmonella enterica, which exhibit greater variability in their fimbrial repertoires. These findings suggest there may be evolutionary pressure for P. mirabilis to maintain a large fimbrial arsenal. PMID- 24809386 TI - Synergistic effect of fluconazole and doxycycline against Candida albicans biofilms resulting from calcium fluctuation and downregulation of fluconazole inducible efflux pump gene overexpression. AB - Candida albicans biofilms are intrinsically resistant to antimicrobial agents. Previous work demonstrated that the antifungal activity of fluconazole against C. albicans biofilms is notably enhanced by doxycycline. In order to explore the synergistic mechanism of fluconazole and doxycycline, we investigated the changes of efflux pump gene expression, intracellular calcium concentration and cell cycle distribution after drug intervention in this study. The expression levels of CDR1, CDR2 and MDR1 were determined by real-time PCR, and the results showed that fluconazole alone could stimulate the high expression of CDR1, CDR2 and MDR1, and the combination of doxycycline and fluconazole downregulated the gene overexpression induced by fluconazole. Intracellular calcium concentration was determined using Fluo-3/AM by observing the fluorescence with flow cytometry. A calcium fluctuation, which started 4 h and peaked 8 h after the treatment with fluconazole, was observed. The combined drugs also initiated a calcium fluctuation after 4 h treatment and showed a peak at 16 h, and the peak was higher than that stimulated by fluconazole alone. The cell cycle was measured using flow cytometry. Fluconazole alone and the combined drugs both induced a reduction in the percentages of S-phase cells and an elevation in the percentages of cells in the G2/M phase. The results of this research showed that the synergism of fluconazole and doxycycline against C. albicans biofilms is associated with blockade of the efflux pump genes CDR1, CDR2 and MDR1, and stimulation of high intracellular calcium concentration. The findings of this study are of great significance in the search for new antifungal mechanisms. PMID- 24809387 TI - Impact of the London 2012 Olympic and Paralympic Games on demand for microbiology gastrointestinal diagnostic services at the Public Health Laboratory London. AB - Planning for the London 2012 Olympic and Paralympic Games at the Public Health Laboratory London was based on the requirement to meet potential increased demand with scalable capacity. The aim of this study was to determine the impact on demand for microbiology gastrointestinal diagnostic services during the Games period. Retrospective cross-sectional time-series data analysis was used to assess the number of gastrointestinal specimens received in the laboratory and the number of positive results. There was no increase in the number of gastrointestinal specimens received during the Games period, thus the Games had no impact on demand for microbiology gastrointestinal diagnostic services at the laboratory. There was a decrease in the number of public health specimens received for culture [incidence rate ratio = 0.34, 95% confidence interval (CI) = 0.13-0.86, P = 0.02] and a decrease in the number of culture positive community specimens (odds ratio = 0.59, 95 % CI = 0.40-0.85, P = 0.005), suggesting a decrease in gastrointestinal illness during the Games period. As previous planning assumptions were not based on actual specimen activity, the results of this study may modify the extent of additional planning for microbiological services required for mass gatherings. PMID- 24809388 TI - Systemic thromboembolic adverse events in patients treated with intravitreal anti VEGF drugs for neovascular age-related macular degeneration: an overview. AB - INTRODUCTION: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events. AREAS COVERED: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs. EXPERT OPINION: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium. PMID- 24809389 TI - Prevalence and characterization of Listeria monocytogenes, Salmonella and Shiga toxin-producing Escherichia coli isolated from small Mexican retail markets of queso fresco. AB - Queso fresco (QF) is a handmade cheese consumed and produced in Latin America. In Mexico, QF production is associated with a microbiological risk. The aim of the study was to determine the incidence and characterization of Listeria monocytogenes, Salmonella spp., and Shiga toxin-producing Escherichia coli (STEC) in QF from retail markets of the north-western State of Sinaloa, Mexico, and to assess the effect of physicochemical parameters on Listeria presence. A total of 75 QF samples were obtained. L. monocytogenes, E. coli, and coliforms were detected in 9.3, 94, and 100%, respectively. Salmonella was not detected. STEC isolates showed virulence genes. Microbial loads were above the maximum values recommended by the Official Mexican Standards. Physicochemical parameters such as water activity (aw), moisture content, pH, and salinity played a role in Listeria prevalence in QF. Rigorous control in QF made in Culiacan, Mexico is needed to reduce the risk of foodborne pathogens. PMID- 24809390 TI - Piero Periti review article award 2013. PMID- 24809391 TI - Elevated hydrostatic pressures induce apoptosis and oxidative stress through mitochondrial membrane depolarization in PC12 neuronal cells: A cell culture model of glaucoma. AB - BACKGROUND: Despite the importance of oxidative stress and apoptosis through mitochondrial depolarization in neurodegenerative diseases, their roles in etiology of glaucoma are poorly understood. We aimed to investigate whether oxidative stress and apoptosis formation are altered in rat pheochromocytoma derived cell line-12 (PC12) neuronal cell cultures exposed to elevated different hydrostatic pressures as a cell culture model of glaucoma. MATERIALS: Cultured PC12 cells were subjected to 0, 15 and 70 mmHg hydrostatic pressure for 1 and 24 h. Then, the following values were analyzed: (a) cell viability; (b) lipid peroxidation and intracellular reactive oxygen species production; (c) mitochondrial membrane depolarization; (d) cell apoptosis; (e) caspase-3 and caspase-9 activities; (f) reduced glutathione (GSH) and glutathione peroxidase (GSH-Px). RESULTS: The hydrostatic pressures (15 and 70 mmHg) increased oxidative cell damage through a decrease of GSH and GSH-Px values, and increasing mitochondrial membrane potential. Additionally, 70 mmHg hydrostatic pressure for 24 h indicated highest apoptotic effects, as demonstrated by plate reader analyses of apoptosis, caspase-3 and -9 values. CONCLUSION: The present data indicated oxidative stress, apoptosis and mitochondrial changes in PC12 cell line during different hydrostatic pressure as a cell culture model of glaucoma. This findings support the view that mitochondrial oxidative injury contributes early to glaucomatous optic neuropathy. PMID- 24809392 TI - Effects of Prolonged Hypertrophic Resistance Training on Acute Endocrine Responses in Young and Older Men. AB - The present study investigated changes in acute serum hormone responses to a resistance exercise bout following a prolonged period of hypertrophic resistance training in young (YM) and older men (OM). Subjects performed a 5 * 10RM leg press exercise protocol before and after 20 weeks of hypertrophic resistance training. In YM, the acute responses in growth hormone were greater compared to before training (P < 0.05), and cortisol concentration did not increase after training. Endocrine responses in OM were similar before and after training. Greater acute growth hormone responses after training were associated with larger gains in lean mass in the entire subject group (r = 0.596, P = 0.019). These findings suggest that, in general, YM demonstrate greater adaptability within the endocrine system compared to OM. However, adaptability in growth hormone response was associated with larger training-induced gains independent of age. PMID- 24809393 TI - Neurotrophic factors for retinal ganglion cell neuropathy - with a special reference to diabetic neuropathy in the retina. AB - Diabetes mellitus is a disease with a devastating impact on population. Recent data revealed that early retinal neuropathy in patients with diabetic retinopathy involved a reduced expression of brain-derived neurotrophic factor. Retinal ganglion cells (RGC) neuropathy is a progressive optic nerve neuropathy with RGC death and axonal degeneration, and it leads to blindness in the elderly population worldwide. Thus, neuroprotective therapies that rescue damaged RGCs and inhibit the progression of RGC loss and axonal degeneration are needed. This review introduces potential neuroprotective therapies using different neurotrophic factors for damaged RGC in eyes with RGC neuropathy associated diseases. PMID- 24809395 TI - Quantum speed limit for arbitrary initial states. AB - The minimal time a system needs to evolve from an initial state to its one orthogonal state is defined as the quantum speed limit time, which can be used to characterize the maximal speed of evolution of a quantum system. This is a fundamental question of quantum physics. We investigate the generic bound on the minimal evolution time of the open dynamical quantum system. This quantum speed limit time is applicable to both mixed and pure initial states. We then apply this result to the damped Jaynes-Cummings model and the Ohimc-like dephasing model starting from a general time-evolution state. The bound of this time dependent state at any point in time can be found. For the damped Jaynes-Cummings model, when the system starts from the excited state, the corresponding bound first decreases and then increases in the Markovian dynamics. While in the non Markovian regime, the speed limit time shows an interesting periodic oscillatory behavior. For the case of Ohimc-like dephasing model, this bound would be gradually trapped to a fixed value. In addition, the roles of the relativistic effects on the speed limit time for the observer in non-inertial frames are discussed. PMID- 24809396 TI - Activity-dependent synaptic plasticity of a chalcogenide electronic synapse for neuromorphic systems. AB - Nanoscale inorganic electronic synapses or synaptic devices, which are capable of emulating the functions of biological synapses of brain neuronal systems, are regarded as the basic building blocks for beyond-Von Neumann computing architecture, combining information storage and processing. Here, we demonstrate a Ag/AgInSbTe/Ag structure for chalcogenide memristor-based electronic synapses. The memristive characteristics with reproducible gradual resistance tuning are utilised to mimic the activity-dependent synaptic plasticity that serves as the basis of memory and learning. Bidirectional long-term Hebbian plasticity modulation is implemented by the coactivity of pre- and postsynaptic spikes, and the sign and degree are affected by assorted factors including the temporal difference, spike rate and voltage. Moreover, synaptic saturation is observed to be an adjustment of Hebbian rules to stabilise the growth of synaptic weights. Our results may contribute to the development of highly functional plastic electronic synapses and the further construction of next-generation parallel neuromorphic computing architecture. PMID- 24809397 TI - Effects of a mindfulness-based psychoeducation programme for Chinese patients with schizophrenia: 2-year follow-up. AB - BACKGROUND: Psychoeducation programmes for people with schizophrenia are shown to reduce relapses but few studies have indicated significant improvements in patients' illness awareness and insight, functioning, symptom severity or rates of readmission to hospital. AIMS: To examine the effects of a mindfulness-based psychoeducation programme for Chinese people with schizophrenia. METHOD: A multisite randomised controlled trial was conducted with 107 out-patients with schizophrenia: 36 and 35 received a 6-month mindfulness-based psychoeducation and a conventional psychoeducation programme, respectively, and 35 received routine care alone. Patient outcome measures were psychiatric symptom severity, psychosocial functioning, social support, insight into illness/treatment, and frequency and duration of readmissions to hospital (ClinicalTrials.gov: trial registration NCT01667601). RESULTS: The mindfulness-based psychoeducation group reported significantly greater improvements in psychiatric symptoms, psychosocial functioning, insight into illness/treatment and duration of readmissions to hospital over 24 months when compared with the other two groups. CONCLUSIONS: Mindfulness-based psychoeducation appears to be a promising approach to treatment for Chinese patients with schizophrenia. PMID- 24809394 TI - Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. AB - Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management. PMID- 24809398 TI - Developmental model of suicide trajectories. AB - BACKGROUND: Most developmental studies on suicide do not take into account individual variations in suicide trajectories. AIMS: Using a life course approach, this study explores developmental models of suicide trajectories. METHOD: Two hundred and fourteen suicides were assessed with mixed methods. Statistical analysis using combined discrete-time survival (DTS) and growth mixture modelling (GMM) generated various trajectories, and path analysis (Mplus) identified exogenous and mediating variables associated with these trajectories. RESULTS: Two groups share common risk factors, and independently of these major risk factors, they have different developmental trajectories: the first group experienced a high burden of adversity and died by suicide in their early 20s; and the second group experienced a somewhat moderate or low burden of adversity before they took their own life. Structural equation modelling identified variables specific to the early suicide trajectory: conduct and behavioural difficulties, social isolation/conflicts mediated by school-related difficulties, the end of a love relationship, and previous suicide attempts. CONCLUSIONS: Psychosocial adversity between 10 and 20 years of age may warrant key periods of intervention. PMID- 24809399 TI - ANK3 gene expression in bipolar disorder and schizophrenia. AB - ANK3 gene variants have consistently been associated with bipolar spectrum disorder and schizophrenia spectrum disorder. However, the relevance of its encoded protein, ankyrin-3, in these disorders remains elusive. Here, we show that ANK3 gene expression in blood is significantly increased in bipolar disorder and schizophrenia compared with healthy controls. Additionally, we identified potential cis-acting expression quantitative trait loci located close to the transcription start site of one of the isoforms of the gene. These findings suggest that ANK3 mRNA is an interesting marker for further investigation of the underlying mechanisms in psychotic disorders. PMID- 24809400 TI - Impact of the diagnostic changes to post-traumatic stress disorder for DSM-5 and the proposed changes to ICD-11. AB - BACKGROUND: There have been changes to the criteria for diagnosing post-traumatic stress disorder (PTSD) in DSM-5 and changes are proposed for ICD-11. AIMS: To investigate the impact of the changes to diagnostic criteria for PTSD in DSM-5 and the proposed changes in ICD-11 using a large multisite trauma-exposed sample and structured clinical interviews. METHOD: Randomly selected injury patients admitted to four hospitals were assessed 72 months post trauma (n = 510). Structured clinical interviews for PTSD and major depressive episode, as well as self-report measures of disability and quality of life were administered. RESULTS: Current prevalence of PTSD under DSM-5 scoring was not significantly different from DSM-IV (6.7% v. 5.9%, z = 0.53, P = 0.59). However, the ICD-11 prevalence was significantly lower than ICD-10 (3.3% v. 9.0%, z = -3.8, P<0.001). The PTSD current prevalence was significantly higher for DSM-5 than ICD-11 (6.7% v. 3.3%, z = 2.5, P = 0.01). Using ICD-11 tended to show lower rates of comorbidity with depression and a slightly lower association with disability. CONCLUSIONS: The diagnostic systems performed in different ways in terms of current prevalence rates and levels of comorbidity with depression, but on other broad key indicators they were relatively similar. There was overlap between those with PTSD diagnosed by ICD-11 and DSM-5 but a substantial portion met one but not the other set of criteria. This represents a challenge for research because the phenotype that is studied may be markedly different according to the diagnostic system used. PMID- 24809401 TI - Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study. AB - BACKGROUND: Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue. AIMS: To investigate whether higher BMI increases the risk of major depression. METHOD: Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case-control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI. RESULTS: Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient -0.03, 95% CI -0.18 to 0.13, P = 0.73; GRS: coefficient -0.02, 95% CI -0.11 to 0.07, P = 0.62). CONCLUSIONS: Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding. PMID- 24809402 TI - Quantitative NMR metabolite profiling of methicillin-resistant and methicillin susceptible Staphylococcus aureus discriminates between biofilm and planktonic phenotypes. AB - Wound bioburden in the form of colonizing biofilms is a major contributor to nonhealing wounds. Staphylococcus aureus is a Gram-positive, facultative anaerobe commonly found in chronic wounds; however, much remains unknown about the basic physiology of this opportunistic pathogen, especially with regard to the biofilm phenotype. Transcriptomic and proteomic analysis of S. aureus biofilms have suggested that S. aureus biofilms exhibit an altered metabolic state relative to the planktonic phenotype. Herein, comparisons of extracellular and intracellular metabolite profiles detected by (1)H NMR were conducted for methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) S. aureus strains grown as biofilm and planktonic cultures. Principal component analysis distinguished the biofilm phenotype from the planktonic phenotype, and factor loadings analysis identified metabolites that contributed to the statistical separation of the biofilm from the planktonic phenotype, suggesting that key features distinguishing biofilm from planktonic growth include selective amino acid uptake, lipid catabolism, butanediol fermentation, and a shift in metabolism from energy production to assembly of cell-wall components and matrix deposition. These metabolite profiles provide a basis for the development of metabolite biomarkers that distinguish between biofilm and planktonic phenotypes in S. aureus and have the potential for improved diagnostic and therapeutic use in chronic wounds. PMID- 24809408 TI - Effect of oral glutamine supplementation on gut permeability and endotoxemia in patients with severe acute pancreatitis: a randomized controlled trial. AB - OBJECTIVE: The aim of this study is to evaluate the effect of oral glutamine (GL) supplementation on gut permeability and endotoxemia (surrogate end point) in patients with severe acute pancreatitis. METHODS: In a randomized controlled trial, patients were randomized to be given placebo or GL for 7 days. The primary outcome measures include the effect on gut permeability (assessed by lactulose/mannitol excretion in urine and endotoxemia assessed by endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM). The secondary outcome measures include infectious complications, mortality, total hospital/intensive care unit stay, C-reactive protein, and prealbumin levels. RESULTS: Patients were assigned to GL (n = 41) and placebo (n = 39) groups. There was no change in gut permeability after the intervention. However, the EndoCab IgM levels increased significantly (33 [4, 175] to 40 [8, 350] GMU/mL; P = 0.0164) and the C-reactive protein levels decreased significantly (133 [1, 287] to 88 [1, 267] ng/mL; P = 0.0236) in the GL group. No difference was observed in infectious complication, prealbumin value, hospital/intensive care unit stay, and mortality in both groups. CONCLUSIONS: No significant trend was identified for an effect of GL on gut permeability. Decreased inflammation and endotoxemia did not translate into reduced infectious complications in severe acute pancreatitis. However, the study was underpowered to detect the aforementioned difference (trial registration: CTRI/2009/000945). PMID- 24809409 TI - Effects of hydroxyethyl starch and cell-free hemoglobin on microcirculation, tissue oxygenation, and survival in severe acute porcine pancreatitis: results of a randomized experimental trial. AB - OBJECTIVE: Severe acute pancreatitis is a life-threatening disease with a high mortality; so far, no causal treatment is known. The aim of this study was to evaluate the therapeutic potential of hydroxyethyl starch (HES) and cell-free hemoglobin in an experimental model. METHODS: Thirty-nine pigs were randomly assigned into 3 groups. Severe acute pancreatitis was induced by intraductal injection of glycodeoxycholic acid in combination with intravenous administration of cerulein. All animals were kept in isovolemic conditions by application of Ringer solution, 10% HES, or cell-free hemoglobin. The pancreatic microcirculation was evaluated over 8 hours. Thereafter, the animals were observed for 6 days followed by killing of the animals and histopathologic examination. RESULTS: The administration of HES and cell-free hemoglobin led to improved microcirculation and tissue oxygenation compared with the Ringer's group. Consequently, the histopathologic damage was reduced (5.5 [3-8.5] vs 9.5 [7.5-11]; P < 0.001). In addition, the mean survival was significantly longer at 121 hours (95% confidence interval, 102-139) versus the Ringer group's 57 hours (95% confidence interval, 32-82; P < 0.001). CONCLUSIONS: The administration of HES and cell-free hemoglobin can improve microcirculation in severe acute porcine pancreatitis, with consequent reduction in histopathologic damage and mortality. Therefore, this might represent an interesting therapeutic option in the treatment of severe acute pancreatitis. PMID- 24809410 TI - Site-selective photoemission from delocalized valence shells induced by molecular rotation. AB - Due to the generally delocalized nature of molecular valence orbitals, valence shell spectroscopies do not usually allow to specifically target a selected atom in a molecule. However, in X-ray electron spectroscopy, the photoelectron momentum is large and the recoil angular momentum transferred to the molecule is larger when the photoelectron is ejected from a light atom compared with a heavy one. This confers an extreme sensitivity of the rotational excitation to the ionization site. Here we show that, indeed, the use of high-energy photons to photoionize valence-shell electrons of hydrogen chloride offers an unexpected way to decrypt the atomic composition of the molecular orbitals due to the rotational dependence of the photoionization profiles. The analysis of the site-specific rotational envelopes allows us to disentangle the effects of the two main mechanisms of rotational excitation, based on angular momentum exchange between the molecule and either the incoming photon or the emitted electron. PMID- 24809411 TI - OAB symptoms: assessment and discriminator for etiopathology. AB - PURPOSE OF REVIEW: Overactive bladder (OAB) is a highly common condition defined by characteristic symptoms and absence of obvious diseases. OAB symptoms are reviewed with special relevance to its etiopathlogy. RECENT FINDINGS: Numerous validated assessment tools are available for OAB symptoms. They are variable in question items and response scale, but most of them are highly responsive to quality of life impairment and treatment outcomes. It should be kept in mind whether the tool addresses symptoms including OAB symptoms, OAB symptoms alone, or symptom bother. The cardinal symptom of OAB is urgency, a strong desire to void of sudden onset. Suddenness of urgency is associated with symptom severity and its all-or-none nature is indicative of a disorder in bladder afferent signal processing. SUMMARY: Etiopathology of OAB or urgency is highly heterogeneous and may be found in detrusor muscle, bladder nervous system, and the brain. OAB is reflective of a condition of sensory dysfunction of the bladder, wherein the patients feel a strong desire to void at a smaller bladder volume (sensory hyperactivity) and notice desire to void too late (impaired perception). This ambivalent condition could be named as 'sensory hyperactivity with impaired perception'. PMID- 24809412 TI - Urethral strictures and the cancer survivor. AB - PURPOSE OF REVIEW: Urethral stricture disease is poorly understood in prostate cancer survivors who have undergone radiation or ablative treatments. We review the cause and incidence of urethral strictures (excluding bladder neck contracture) in this setting, as well as risk factors and treatment options. RECENT FINDINGS: Stricture rates differ for various modalities of radiation therapy, with the highest rate in high-dose-rate brachytherapy. Risk factors include higher dose of radiation delivered to prostate apex, radiation delivered per treatment, and prior transurethral resection of prostate. Cryoablation and high-intensity focused ultrasound of the prostate also carry high risk of urethral stricture formation, particularly in the salvage setting. Dilation or direct vision incision of the urethra can be utilized as a temporizing technique, with frequent recurrence. Urethral stenting is also an option; however, this is associated with a high rate of incontinence. Urethroplasty has durable outcomes for radiation-induced strictures, with a preference for excision and primary anastomosis because of the bulbomembranous location and relatively short length of these strictures. Salvage radical prostatectomy has been described in a small series as treatment for posterior urethral strictures and bladder neck contractures resulting from ablative therapies. SUMMARY: Prostate cancer survivors treated with radiation or ablative therapies are at risk for urethral stricture formation. Urethroplasty is a feasible and durable treatment option and should be considered in the appropriate patient. PMID- 24809414 TI - Nocturia causes vary with each decade. AB - PURPOSE OF REVIEW: To review the published literature within the last 18 months that comment on the causes of nocturia, varying with age. The causes are categorized into organized subsets: nocturnal polyuria, storage or reduced bladder capacity, 24-h polyuria, and sleep-associated nocturia. RECENT FINDINGS: Prevalence of nocturia is high, but has been reported at varying rates in the epidemiologic studies. Similarly, reported incidence has a high rate of variability. Nocturia causes were associated with nocturnal polyuria, bladder storage issues, metabolic syndrome, abnormal bowel habits, obesity, Parkinson's disease, global polyuria, insomnia, sleep disturbances, heart failure, anxiety, and depression. Although age was commented on in many articles, it was never the primary examined variable. SUMMARY: There is a lack of standardization in definition and classification of the causes of nocturia. Confounding variables included a lack of use of a standard definition of nocturia, identifying nocturia at its true onset, and a fundamental underutilization of frequency volume charts to identify patients with nocturia. The confounding variables make it difficult to compare studies. Thus, the strength of conclusion on cause will be better defined when standards are set controlling definition, identification, and diagnosis. PMID- 24809413 TI - Current management of erectile dysfunction in prostate cancer survivors. AB - PURPOSE OF REVIEW: Although no standard management of erectile dysfunction in prostate cancer (CaP) survivors exists, many treatment options are available. This review summarizes the current understanding of the cause and management of erectile dysfunction in CaP survivors. RECENT FINDINGS: Erectile dysfunction after radical therapy for CaP may be more common than previously thought. Genetics and vascular comorbidities may have a significant impact on erectile dysfunction after CaP treatment. Although penile rehabilitation with medical modalities show good efficacy in motivated patients, the return of erectile function is never guaranteed with nonsurgical management. Penile prosthesis placement results in early return to sexual function after CaP treatment with high patient satisfaction rates. Various techniques allow safe placement of a three-piece penile prosthesis in patients with a history of pelvic surgery. SUMMARY: To optimize recovery of erectile function and prevent loss of penile length, penile rehabilitation should be initiated expeditiously after prostatectomy or radiation. In patients with refractory erectile dysfunction, dexterous and motivated patients remain excellent candidates for first and second line medical therapies. However, early placement of a penile prosthesis following radical prostatectomy is now a proven and viable option. PMID- 24809415 TI - Ophthalmologic examinations in areas of Miyagi Prefecture affected by the Great East Japan Earthquake. AB - IMPORTANCE: One month after the Great East Japan Earthquake on March 11, 2011, our clinic was granted free use of the Mission Vision Van, a customized bus airlifted to Japan. This mobile eye clinic made it possible for us to provide ophthalmologic examinations anywhere in the disaster zone in Miyagi Prefecture. OBSERVATIONS: This study included 731 patients who received treatment in the eye care van in Miyagi Prefecture between April 15 and May 29, 2011. We examined and cared for patients during 25 visits to 11 emergency districts during 15 clinic days. Of the 914 diagnoses we identified, 358 were refractive disorders (39.2%), which were the most common ocular diseases we observed; others included 155 (17.0%) cataracts, 106 (11.6%) dry eye, and 73 (8.0%) infectious diseases, such as conjunctivitis. Overall, we provided emergency prescriptions for 871 bottles of eyedrops comprising 222 prescriptions (25.5%) for dry eye, 189 (21.7%) for cataracts, and 107 (12.3%) for glaucoma. CONCLUSIONS AND RELEVANCE: A substantial number of patients in the earthquake-damaged areas needed replacements for eyeglasses, contact lenses, and eyedrops. The mobile clinic appears to be a useful way to provide ophthalmologic examinations and support after a disaster. PMID- 24809418 TI - A serendipitous mentor. PMID- 24809416 TI - Three-dimensional patient-specific cardiac model for surgical planning in Nikaidoh procedure. AB - PURPOSE: To explore the use of three-dimensional patient-specific cardiovascular models using rapid prototyping techniques (fused deposition modelling) to improve surgical planning in patients with complex congenital heart disease. DESCRIPTION: Rapid prototyping techniques are used to print accurate three-dimensional replicas of patients' cardiovascular anatomy based on magnetic resonance images using computer-aided design systems. Models are printed using a translucent polylactic acid polymer. EVALUATION: As a proof of concept, a model of the heart of a 1.5-year-old boy with transposition of the great arteries, ventricular septal defect and pulmonary stenosis was constructed to help planning the surgical correction. The cardiac model allowed the surgeon to evaluate the location and dimensions of the ventricular septal defect as well as its relationship with the aorta and pulmonary artery. CONCLUSIONS: Cardiovascular models constructed by rapid prototyping techniques are extremely helpful for planning corrective surgery in patients with complex congenital malformations. Therefore they may potentially reduce operative time and morbi-mortality. PMID- 24809419 TI - Rekindling the spirit: staff engagement 2.1. PMID- 24809420 TI - Leadership profile: HealthAchieve 2013 Nursing Leadership Award Winner, Tiziana Rivera. AB - Tiziana Rivera, the winner of the 2013 Nursing Leadership Award at the November HealthAchieve conference, is chief nursing executive and chief practice officer at Mackenzie Health. As such, she provides strategic leadership for the development and implementation of a shared vision for professional practice, nursing and all disciplines to promote innovative care and the development of care delivery models that will improve quality of care and population health.Prior to assuming her position at Mackenzie Health, Rivera provided strategic leadership for the Seniors' Health Program at Trillium Health Centre, where her role focused on the development of seniors' health services across the continuum of care. She has published numerous articles in refereed journals, conducted several research studies and presented her papers provincially, nationally and internationally. Rivera has a clinical appointment at the University of Toronto Faculty of Nursing, a faculty adviser position at Ryerson and an adjunct faculty position at the School of Health Sciences, York University and at the School of Health Sciences, Humber Institute of Technology and Advanced Learning.In the following Q and A, Rivera shares her thoughts on leadership in nursing and perspectives on several critical issues. PMID- 24809421 TI - From me to we and back again: creating health system transformation through authentic collaboration within and beyond nursing. PMID- 24809422 TI - An interview with Dr. Judith Shamian, president, International Council of Nurses. AB - Judith Shamian, RN, PhD, LLD (hon), D.Sci (hon), FAAN, is the president of the International Council of Nurses (ICN). Previous positions include immediate past president and CEO of the Victorian Order of Nurses, immediate past President of the Canadian Nurses Association (CNA), executive director of the Office of Nursing Policy at Health Canada and vice-president of nursing at Mount Sinai Hospital. She is the recipient of numerous awards including the Canada's Most Powerful Women: Top 100 award; the Golden Jubilee Medal from the Governor General of Canada; and CNA's 2008 Centennial Award. From my mentor, colleague and friend here are some insights shared with CJNL about her current work and challenges PMID- 24809423 TI - The value of registered nurses in collaborative family practice: enhancing primary healthcare in Canada. AB - With the current focus on improving efficiencies and quality of care within the Canadian healthcare system, primary healthcare (PHC) is receiving renewed attention. The time is right for highlighting the value that registered nurses (RNs) can bring to collaborative practice in primary care settings. This paper discusses the untapped utilization of RNs in primary care in Canada, arguing for a strong leadership role for nurses and citing examples of RN services that could enhance care and improve population health and cost-effectiveness. Internationally, other countries with strong PHC strategies in place offer potential lessons regarding features that could be adapted in Canada. PMID- 24809424 TI - Exploring managers' views on span of control: more than a headcount. AB - The purpose of this qualitative study was to explore front-line managers' (FLMs') perceptions of their span of control (SOC) and how they manage it. As part of a larger quantitative study examining relationships between FLMs' SOC and performance outcomes, 10 manager focus groups were conducted by teleconference, involving 48 managers from 14 academic healthcare organizations. Themes and subthemes were identified according to (a) perceptions of the size and scope of SOC; (b) factors influencing the complexity of SOC; (c) supports needed to manage SOC; (d) changing leadership style; and (e) ways of coping with role overload. Participants described system demands as a significant contributor to their work responsibilities and a sense of role overload. About half of managers stated their SOC was unreasonable and that they lacked the necessary supports to manage it. Many managers who described their SOC as reasonable still expressed concerns about internal and external workload pressures that contributed to changing leadership style and role overload. Findings reinforce the importance of organizational strategies to create regular dialogue with FLMs regarding the size, complexity and appropriateness of current spans and to provide the resource supports necessary to ensure they can manage their SOC effectively. PMID- 24809425 TI - Clinical nurse specialists in Canada: why are some not working in the role? AB - Clinical nurse specialists (CNSs) are advanced practice nurses. They contribute to the quality and safety of patient care by providing an advanced level of clinical care to patients and families and by supporting healthcare team members to deliver evidence-based care. CNSs help to reduce healthcare costs when the roles are fully deployed and all the dimensions of the CNS role are implemented. The dimensions of the CNS role include clinical care, organizational leadership, research, education, professional development and consultation to provide patient care. There is a paucity of research on CNSs in Canada. We conducted the first Canada-wide survey of CNSs and asked each nursing regulatory body to identify the CNSs in their registration database. One-quarter (n=196/776) of the regulator identified CNS respondents whom we contacted for the study were no longer or had never been a CNS. Currently, adequate mechanisms are lacking to identify and track CNSs in Canada, and little is known about the factors that influence CNSs' decisions to leave their role. The non-employed CNS respondents in our survey highlighted that the lack of role clarity, their inability to find employment as a CNS and the inability to implement all the dimensions of the CNS role were key factors in their decision not to work as a CNS. These findings have important implications, given that these factors are potentially modifiable and amenable to decisions made by nursing leaders in organizations and regulatory bodies. Mechanisms to identify and track CNSs in Canada are needed to develop an effective workforce plan and maximize the integration of CNSs in the workforce. PMID- 24809426 TI - Ethics and safety in home care: perspectives on home support workers. AB - Home support workers (HSWs) encounter unique safety issues in their provision of home care. These issues raise ethical concerns, affecting the care workers provide to seniors and other recipients. This paper is derived from a subproject of a larger Canada-wide study, Safety at Home: A Pan-Canadian Home Care Safety Study, released in June 2013 by the Canadian Patient Safety Institute. Semi structured, face-to-face, audiotaped interviews were conducted with providers, clients and informal caregivers in British Columbia, Manitoba and New Brunswick to better understand their perceptions of patient safety in home care. Using the BC data only, we then compared our findings to findings of other BC studies focusing on safety in home care that were conducted over the past decade. Through our interviews and comparative analyses it became clear that HSWs experienced significant inequities in providing home care. Utilizing a model depicting concerns of and for HSWs developed by Craven and colleagues (2012), we were able to illustrate the physical, spatial, interpersonal and temporal concerns set in the context of system design that emphasized the ethical dilemmas of HSWs in home care. Our data suggested the necessity of adding a fifth domain, organizational (system design). In this paper, we issue a call for stronger advocacy for home care and improved collaboration and resource equity between institutional care and community care. PMID- 24809428 TI - The changing role of the pathologist in the management of Barrett's oesophagus. AB - Pathological specimens from columnar-lined oesophagus (CLO) comprise a considerable proportion of the workload of gastrointestinal pathologists in Western countries. There remain controversies concerning the diagnostic role of pathology. More recently, in the UK at least, the diagnosis has been regarded as primarily an endoscopic endeavour, with pathology being corroborative and only diagnostic when endoscopic features are equivocal or when there are additional features that make the endoscopic diagnosis unclear. There is also recognition that demonstration of intestinalisation or 'goblet cells' is not paramount, and should not be required for the diagnosis. There have been notable changes in the management of CLO neoplasia: pathologists are centrally involved in its management. Pathological assessment of endoscopic mucosal resection (EMR) specimens provides the most useful means of determining the management of early neoplasia and of determining indications for surgery. This represents an extraordinarily rapid change in management, in that, <10 years ago, laborious Seattle-type biopsy protocols were recommended, and high grade dysplasia was an indication for resectional surgery. Now, individual patient management is paramount: multi-professional meetings determine management after biopsy and EMR assessment. One significant change is that major resections are undertaken less often, in Western countries, for CLO neoplasia. PMID- 24809429 TI - Effects of oral nutritional supplementation in the management of malnutrition in hospital and post-hospital discharged patients in India: a randomised, open label, controlled trial. AB - BACKGROUND: Hospital malnutrition is a significant problem that still remains under-recognised and under-treated in India. The present study assessed the effects of oral nutritional supplementation (ONS) in conjunction with dietary counselling versus dietary counselling (control) alone in malnourished patients when given in hospital and post-hospital discharge. METHODS: The present study was conducted in nine private and four public hospitals. Patients from various medical wards were screened for malnutrition using modified Subjective Global Assessment (mSGA) and randomised to control (n = 106) or ONS (n = 106) for 12 weeks. Two servings (460 mL) of ONS were prescribed daily, providing 432 kcal, 16 g of protein and 28 micronutrients. The primary outcome was weight gain over 12 weeks. Other outcomes included change in body mass index (BMI), serum pre albumin, albumin and C-reactive protein levels, energy and nutrient intakes, and handgrip strength at weeks 4, 8 and 12, as well as mSGA score at week 12. RESULTS: The mean age of patients was 39 years. Fifty-five percent were males and 90.3% were moderately malnourished (mSGA score B) at baseline. At week 12, ONS significantly improved certain parameters compared to control: weight (2.0 versus 0.9 kg; P < 0.001), BMI (0.76 versus 0.37 kg m(-2) ; P < 0.001) and energy intake per day (560 versus 230 kcal; P < 0.05). There were no differences in biochemical parameters and mSGA score between groups. Additionally, patients on ONS who were more functionally impaired at baseline had significantly greater weight gain and improved handgrip strength scores than controls. CONCLUSIONS: ONS use throughout hospital stay and post-hospital discharge significantly improved energy intake and weight in malnourished Indian patients. Those patients with poorer functional status at baseline demonstrated the most benefit. PMID- 24809430 TI - The role of inflammation for a successful implantation. AB - Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate-limiting step for the success of the in vitro fertilization (IVF) treatments. We, as well as others, have demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies, and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury-derived inflammation in the biopsy-treated patients generates a focus for uterine DCs and Mac accumulation that, in turn, enhance the endometrial expression of essential molecules that facilitate the interaction between the embryo and the uterine epithelium. PMID- 24809431 TI - Biofabrication of customized bone grafts by combination of additive manufacturing and bioreactor knowhow. AB - This study reports on an original concept of additive manufacturing for the fabrication of tissue engineered constructs (TEC), offering the possibility of concomitantly manufacturing a customized scaffold and a bioreactor chamber to any size and shape. As a proof of concept towards the development of anatomically relevant TECs, this concept was utilized for the design and fabrication of a highly porous sheep tibia scaffold around which a bioreactor chamber of similar shape was simultaneously built. The morphology of the bioreactor/scaffold device was investigated by micro-computed tomography and scanning electron microscopy confirming the porous architecture of the sheep tibiae as opposed to the non porous nature of the bioreactor chamber. Additionally, this study demonstrates that both the shape, as well as the inner architecture of the device can significantly impact the perfusion of fluid within the scaffold architecture. Indeed, fluid flow modelling revealed that this was of significant importance for controlling the nutrition flow pattern within the scaffold and the bioreactor chamber, avoiding the formation of stagnant flow regions detrimental for in vitro tissue development. The bioreactor/scaffold device was dynamically seeded with human primary osteoblasts and cultured under bi-directional perfusion for two and six weeks. Primary human osteoblasts were observed homogenously distributed throughout the scaffold, and were viable for the six week culture period. This work demonstrates a novel application for additive manufacturing in the development of scaffolds and bioreactors. Given the intrinsic flexibility of the additive manufacturing technology platform developed, more complex culture systems can be fabricated which would contribute to the advances in customized and patient-specific tissue engineering strategies for a wide range of applications. PMID- 24809432 TI - Effects of expiratory ribcage compression before endotracheal suctioning on arterial blood gases in patients receiving mechanical ventilation. AB - AIM AND OBJECTIVES: To investigate the effects of expiratory ribcage compression (ERCC) before endotracheal suctioning on the arterial blood gases (ABG) in patients receiving mechanical ventilation. BACKGROUND: Endotracheal suctioning is one of the most frequently used methods for airway clearance in patients receiving mechanical ventilation. Chest physiotherapy techniques such as ERCC before endotracheal suctioning can be used as a means to facilitate mobilizing and removing airway secretions and improving alveolar ventilation. DESIGN: A prospective, randomized, controlled cross-over design. METHODS: A randomized controlled cross-over trial with a convenience sample of 70 mechanically ventilated patients was conducted from 2006 to 2007. The patients received endotracheal suctioning with (experiment-period) or without (control-period) an antecedent 5-min expiratory ribcage. All the patients experienced both periods with at least a 3-h washed-out interval between the two periods. ABG were measured 5 min before and 25 min after endotracheal suctioning. RESULTS: The statistical tests showed that the levels of partial pressure of oxygen (PaO2 )/fraction of inspired oxygen (FiO2 ), partial pressure of carbon dioxide (PaCO2 ) and arterial oxygen saturation (SaO2 ) in the experimental period at 25 min after the intervention were significantly different from the control period. The tests also revealed that the levels of these variables at 25 min after suctioning were also significantly different from baseline values. However, these differences were clinically significant only for PaO2 /FiO2 . CONCLUSION: By improving the levels of PaO2 /FiO2 , ERCC can reduce the patients' need for oxygen and hence it can at least reduce the side effects of oxygen therapy. RELEVANCE TO CLINICAL PRACTICE: Improving PaO2 /FiO2 levels means less need for oxygen therapy. Hence, by applying ERCC we can at least minimize the side effects of oxygen therapy. PMID- 24809433 TI - Atypical Alzheimer's disease in an elderly United States resident with amyotrophic lateral sclerosis and pathological tau in spinal motor neurons. PMID- 24809434 TI - Pre-analytical heat treatment and a FVIII ELISA improve Factor VIII antibody detection in acquired haemophilia A. PMID- 24809435 TI - Dysregulated expression of dickkopfs for potential detection of hepatocellular carcinoma. AB - The prognosis for hepatocellular carcinoma (HCC) remains dismal due to the lack of diagnostic markers for early detection. This review will discuss the clinical potential of the dickkopf (DKK) family members as diagnostic and/or prognostic markers for HCC. In comparison to serum alpha-fetoprotein (AFP) level, which remains the gold standard for HCC diagnosis, high serum DKK1 levels have higher diagnostic value for HCC, especially for AFP-negative HCC, and can distinguish HCC from non-malignant chronic liver diseases. Additionally, the combination of serum DKK1 and AFP levels enhances diagnostic accuracy for HCC compared to serum DKK1 or AFP levels alone. Although DKK1 offers potential for its use in HCC diagnosis this review will discuss the challenges facing DKK1 and also shed some light on recent developments on the remaining DKK family members: DKK2, DKK3 and DKK4. PMID- 24809436 TI - Programmed stimulation for risk stratification for postinfarction sudden cardiac arrest: why and how? PMID- 24809437 TI - Morning meal more efficient for fat loss in a 3-month lifestyle intervention. AB - OBJECTIVE: To evaluate the effects of 2 low-calorie diets but with different distributions of calories throughout the day on weight loss and other major obesity-related metabolic parameters. METHODS: We randomly assigned 42 nonsmoking homemakers (age = 46.3 +/- 2.3 years, body mass index [BMI] = 35.7 +/- 0.8 kg/m(2), mean +/- SD) in 2 groups of 21 subjects (G1 and G2). The participants underwent a 3 month individualized Mediterranean-style diet (55% carbohydrate, 30% fat, 15% protein and fiber > 30 g), calorie (600 kcal daily deficit compared to the total energy expenditure measured by a metabolic Holter). Diets consisted of the same food and complied with cardiovascular disease prevention guidelines but differed in the distribution of calories throughout the day (G1: 70% breakfast, morning snack, lunch and 30% afternoon snack and dinner; G2: 55 breakfast, morning snack, lunch and 45% afternoon snack and dinner). Dual-energy X-ray absorptiometry was used for pre- and postintervention body composition assessment. RESULTS: Thirty-six subjects completed the study (G1 = 18, G2 = 18). Both groups had significant improvements in body composition and metabolic parameters but G1 had enhanced results for weight loss (G1: -8.2 +/- 3.0 kg; G2: 6.5 +/- 3.4 kg; p = 0.028), waist circumference reduction (G1: -7 +/- 0.6 cm; G2: -5 +/- 0.3 cm; p = 0.033), and fat mass loss (G1: -6.8 +/- 2.1 kg, G2: -4.5 +/- 2.9 kg, p = 0.031; mean +/- SD). Improvements were detected in both groups for blood pressure and blood and lipid parameters. G1 subjects showed a greater improvement in insulin sensitivity measured by homeostasis model assessment estimated insulin resistance (G1: -1.37 +/- 0.27, G2: -0.74 +/- 0.12, p = 0.017). CONCLUSIONS: These data suggest that a low-calorie Mediterranean diet with a higher amount of calories in the first part of the day could establish a greater reduction in fat mass and improved insulin sensitivity than a typical daily diet. PMID- 24809440 TI - Increasing specificity of correlate research: exploring correlates of children's lunchtime and after-school physical activity. AB - BACKGROUND: The lunchtime and after-school contexts are critical windows in a school day for children to be physically active. While numerous studies have investigated correlates of children's habitual physical activity, few have explored correlates of physical activity occurring at lunchtime and after-school from a social-ecological perspective. Exploring correlates that influence physical activity occurring in specific contexts can potentially improve the prediction and understanding of physical activity. Using a context-specific approach, this study investigated correlates of children's lunchtime and after school physical activity. METHODS: Cross-sectional data were collected from 423 South Australian children aged 10.0-13.9 years (200 boys; 223 girls) attending 10 different schools. Lunchtime and after-school physical activity was assessed using accelerometers. Correlates were assessed using purposely developed context specific questionnaires. Correlated Component Regression analysis was conducted to derive correlates of context-specific physical activity and determine the variance explained by prediction equations. RESULTS: The model of boys' lunchtime physical activity contained 6 correlates and explained 25% of the variance. For girls, the model explained 17% variance from 9 correlates. Enjoyment of walking during lunchtime was the strongest correlate for both boys and girls. Boys' and girls' after-school physical activity models explained 20% variance from 14 correlates and 7% variance from the single item correlate, "I do an organised sport or activity after-school because it gets you fit", respectively. CONCLUSIONS: Increasing specificity of correlate research has enabled the identification of unique features of, and a more in-depth interpretation of, lunchtime and after-school physical activity behaviour and is a potential strategy for advancing the physical activity correlate research field. The findings of this study could be used to inform and tailor gender-specific public health messages and interventions for promoting lunchtime and after-school physical activity in children. PMID- 24809442 TI - Constructing bis(porphyrinato) rare earth double-decker complexes involving N confused porphyrin. AB - Reaction of metal-free N-confused 5,10,15,20-tetrakis(4-chlorophenyl)porphyrin (H2NTClPP) with metal-free 5,10,15,20-tetrakis[(4-tert-butyl)phenyl]porphyrin (H2TBPP) in the presence of M(III)(acac)3.nH2O (acac = acetylacetonate) in refluxing 1,2,4-trichlorobenzene (TCB) led to the isolation of heteroleptic bis(porphyrinato) rare earth compounds M(III)(HNTClPP)(TBPP) (M = La, Pr) (1, 2) in 6.7-10% yield. These represent the first examples of sandwich-type porphyrin rare earth double-decker complexes that involve N-confused porphyrin ligand. Different from their homoleptic bis(porphyrinato) rare earth double-decker counterparts HM(III)(TBPP)2 (M = La, Pr) (3, 4), the acidic proton in the heteroleptic analogues was revealed to localize at the inverted pyrrole nitrogen atom of the N-confused porphyrin ligand on the basis of NMR spectroscopic studies. Nevertheless, their heteroleptic bis(porphyrinato) sandwich molecular nature was confirmed on the basis of single crystal X-ray diffraction analysis over the praseodymium double-decker complex. PMID- 24809441 TI - The case for junk DNA. PMID- 24809443 TI - Addressing passive smoking in children. AB - BACKGROUND: A significant number of parents are unaware or unconvinced of the health consequences of passive smoking (PS) in children. Physicians could increase parental awareness by giving personal advice. AIM: To evaluate the current practices of three Dutch health professions (paediatricians, youth health care physicians, and family physicians) regarding parental counselling for passive smoking (PS) in children. METHODS: All physicians (n = 720) representing the three health professions in Limburg, The Netherlands, received an invitation to complete a self-administered electronic questionnaire including questions on their: sex, work experience, personal smoking habits, counselling practices and education regarding PS in children. RESULTS: The response rate was 34%. One tenth (11%) of the responding physicians always addressed PS in children, 32% often, 54% occasionally and 4% reported to never attend to it. The three health professions appeared comparable regarding their frequency of parental counselling for PS in children. Addressing PS was more likely when children had respiratory problems. Lack of time was the most frequently mentioned barrier, being very and somewhat applicable for respectively 14% and 43% of the physicians. One fourth of the responders had received postgraduate education about PS. Additionally, 49% of the responders who did not have any education about PS were interested in receiving it. CONCLUSIONS: Physicians working in the paediatric field in Limburg, The Netherlands, could more frequently address PS in children with parents. Lack of time appeared to be the most mentioned barrier and physicians were more likely to counsel parents for PS in children with respiratory complaints/diseases. Finally, a need for more education on parental counselling for PS was expressed. PMID- 24809444 TI - Origin and evolution of the sodium -pumping NADH: ubiquinone oxidoreductase. AB - The sodium -pumping NADH: ubiquinone oxidoreductase (Na+-NQR) is the main ion pump and the primary entry site for electrons into the respiratory chain of many different types of pathogenic bacteria. This enzymatic complex creates a transmembrane gradient of sodium that is used by the cell to sustain ionic homeostasis, nutrient transport, ATP synthesis, flagellum rotation and other essential processes. Comparative genomics data demonstrate that the nqr operon, which encodes all Na+-NQR subunits, is found in a large variety of bacterial lineages with different habitats and metabolic strategies. Here we studied the distribution, origin and evolution of this enzymatic complex. The molecular phylogenetic analyses and the organizations of the nqr operon indicate that Na+ NQR evolved within the Chlorobi/Bacteroidetes group, after the duplication and subsequent neofunctionalization of the operon that encodes the homolog RNF complex. Subsequently, the nqr operon dispersed through multiple horizontal transfer events to other bacterial lineages such as Chlamydiae, Planctomyces and alpha, beta, gamma and delta -proteobacteria. Considering the biochemical properties of the Na+-NQR complex and its physiological role in different bacteria, we propose a detailed scenario to explain the molecular mechanisms that gave rise to its novel redox- dependent sodium -pumping activity. Our model postulates that the evolution of the Na+-NQR complex involved a functional divergence from its RNF homolog, following the duplication of the rnf operon, the loss of the rnfB gene and the recruitment of the reductase subunit of an aromatic monooxygenase. PMID- 24809445 TI - Intravitreal docosahexaenoic acid in a rabbit model: preclinical safety assessment. AB - PURPOSE: The purpose of the present study was to evaluate the retinal toxicity of a single dose of intravitreal docosahexaenoic acid (DHA) in rabbit eyes over a short-term period. METHODS: Sixteen New Zealand albino rabbits were selected for this pre-clinical study. Six concentrations of DHA (Brudy Laboratories, Barcelona, Spain) were prepared: 10 mg/50 ul, 5 mg/50 ul, 2'5 mg/50 ul, 50 ug/50 ul, 25 ug/50 ul, and 5 ug/50 ul. Each concentration was injected intravitreally in the right eye of two rabbits. As a control, the vehicle solution was injected in one eye of four animals. Retinal safety was studied by slit-lamp examination, and electroretinography. All the rabbits were euthanized one week after the intravitreal injection of DHA and the eyeballs were processed to morphologic and morphometric histological examination by light microscopy. At the same time aqueous and vitreous humor samples were taken to quantify the concentration of omega-3 acids by gas chromatography. Statistical analysis was performed by SPSS 21.0. RESULTS: Slit-lamp examination revealed an important inflammatory reaction on the anterior chamber of the rabbits injected with the higher concentrations of DHA (10 mg/50 ul, 5 mg/50 ul, 2'5 mg/50 u) Lower concentrations showed no inflammation. Electroretinography and histological studies showed no significant difference between control and DHA-injected groups except for the group injected with 50 ug/50 ul. CONCLUSIONS: Our results indicate that administration of intravitreal DHA is safe in the albino rabbit model up to the maximum tolerated dose of 25 ug/50 ul. Further studies should be performed in order to evaluate the effect of intravitreal injection of DHA as a treatment, alone or in combination, of different retinal diseases. PMID- 24809446 TI - MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome. AB - Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30 50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (~ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.-19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort. PMID- 24809448 TI - The influence of dopamine beta-hydroxylase gene polymorphism rs1611115 on levodopa/carbidopa treatment for cocaine dependence: a preliminary study. AB - Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine dependent patients responding better to dopamine-enhancement pharmacotherapy. Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine beta-hydroxylase (DbetaH). Seventy-one cocaine dependent patients who participated in a 12-week randomized double-blind placebo controlled trial of levodopa/carbidopa were genotyped for the DbetaH gene (DBH) polymorphism rs1611115. Our results showed that for patients with the low DbetaH activity genotypes (CT/TT) who received levodopa, the odds of having cocaine positive urine decreased significantly over treatment compared with placebo treated patients with the CT/TT genotypes (P=0.004). Individuals with the normal DbetaH activity genotype (CC) showed no differential response to levodopa. These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism. PMID- 24809449 TI - Calculating Kolmogorov complexity from the output frequency distributions of small Turing machines. AB - Drawing on various notions from theoretical computer science, we present a novel numerical approach, motivated by the notion of algorithmic probability, to the problem of approximating the Kolmogorov-Chaitin complexity of short strings. The method is an alternative to the traditional lossless compression algorithms, which it may complement, the two being serviceable for different string lengths. We provide a thorough analysis for all Sigma(n=1)(11) 2(n) binary strings of length n<12 and for most strings of length 12<=n<=16 by running all ~2.5 x 10(13) Turing machines with 5 states and 2 symbols (8 x 22(9) with reduction techniques) using the most standard formalism of Turing machines, used in for example the Busy Beaver problem. We address the question of stability and error estimation, the sensitivity of the continued application of the method for wider coverage and better accuracy, and provide statistical evidence suggesting robustness. As with compression algorithms, this work promises to deliver a range of applications, and to provide insight into the question of complexity calculation of finite (and short) strings. Additional material can be found at the Algorithmic Nature Group website at http://www.algorithmicnature.org. An Online Algorithmic Complexity Calculator implementing this technique and making the data available to the research community is accessible at http://www.complexitycalculator.com. PMID- 24809450 TI - "How Hard Could it Be?" A Descriptive Analysis of Errors Made on a Validated Lifetime Physical Activity Questionnaire. AB - BACKGROUND: Measuring historical physical activity in epidemiologic research depends on self-report. We aimed to describe data reporting errors women made in completing 2 validated questionnaires: Lifetime Physical Activity Questionnaire (LPAQ) and Occupational Questionnaire (OQ). METHODS: Participants--229 women aged 38 to 65 years--completed questionnaires on paper (n = 160) or by web interface (n = 69). One research assistant collected questionnaire data, identified potential errors and contacted participants to trouble-shoot errors. RESULTS: Women made mean 9.7 (SD 11.2) errors on paper and 7.1 (SD 6.2) errors on electronic versions of the LPAQ and 2.6 (SD 3.8) and 1.1 (SD 1.4) errors on paper and electronic versions of the OQ, respectively. Fewer mistakes were made on electronic versions of both questionnaires combined (8.5 +/- 6.1) when compared with the paper versions (12.7 +/- 13.1). Only ~2% of the sample completed all questionnaires without detectable errors. The most common errors were reporting activities or frequencies inconsistently between past year survey and the current age epoch, reporting more years than allowed by age epoch and missing information. CONCLUSIONS: Despite the implications of "self-report" questionnaires, we recommend researchers provide participants with additional instructions, either verbally or as written tip sheet or both, and follow-up after questionnaire completion to correct mistakes as needed. PMID- 24809452 TI - Protein tyrosine phosphatases PTP-1B, SHP-2, and PTEN facilitate Rb/E2F associated apoptotic signaling. AB - To maintain tissue homeostasis, apoptosis is functionally linked to the cell cycle through the retinoblastoma (Rb)/E2F pathway. When the Rb tumor suppressor protein is functionally inactivated, E2F1 elicits an apoptotic response through both intrinsic (caspase-9 mediated) and extrinsic (caspase-8 mediated) apoptotic pathways in order to eliminate hyperproliferative cells. Rb/E2F-associated apoptosis has been demonstrated to be associated with the loss of constitutive transcriptional repression by Rb/E2F complexes and mediated by caspase-8. Protein tyrosine phosphatases (PTPs) PTP-1B and SHP-2 have been previously shown to be directly activated by loss of Rb/E2F repression during Rb/E2F-associated apoptosis. In this current study, we demonstrate that the PTEN tumor suppressor is also directly activated by loss of Rb/E2F repression. We also demonstrate that PTP-1B, SHP-2, and PTEN play a functional role in Rb/E2F-associated apoptosis. Knockdown of PTP1B, SHP2, or PTEN expression with small interfering RNA (siRNA) in apoptotic cells increases cell viability and rescues cells from the Rb/E2F associated apoptotic response. Furthermore, rescue from apoptosis coincides with inhibition of caspase-8 and caspase-3 cleavage (activation). Our results indicate PTP-1B, SHP-2, and PTEN all play a functional role in Rb/E2F-associated apoptotic signal transduction and provide further evidence that PTP-1B, SHP-2, and PTEN can contribute to tumor suppression through an Rb/E2F-associated mechanism. PMID- 24809453 TI - Ten years of pharmacovigilance in Italy: the experience of Emilia-Romagna region in the monitoring of drug's safety profile. AB - OBJECTIVE: To describe the evolution of adverse drug reactions (ADRs) spontaneously reporting in the Emilia-Romagna region (ERR) in the period 2001 - 2010 through qualitative and quantitative indicators following local educational and editorial initiatives. METHODS: Data of regional spontaneous reporting from 1 January 2001 to 31 December 2010 were obtained from the Pharmacovigilance National Network of the Italian Medicines Agency. Drugs were classified according to the Anatomical Therapeutic Chemical classification. ADRs were coded using the Medical Dictionary for Regulatory Activities Terminology. RESULTS: The overall contribution of the ERR was 9.7% of the total national number of reports (9631 out of 99,319) with a rate of 8 reports per 100 physicians and 230 per million inhabitants. Reports concerned more females and more patients aged 0 - 2 and 60 - 80 years. Differences between the individual local health authorities were identified in rate of ADR reporting. Hospital doctors were the main source of reports followed by general physicians. Out of 2555 serious reports, 124 cases were lethal (4.9% of serious ADRs and 1.3% of all regional reports). CONCLUSION: The results represent a useful trend analysis of the post-marketing surveillance and suggest that, although the pharmacovigilance system has succeeded in reaching a stable and lasting flow of information in ERR, there is considerable place for improvement. PMID- 24809454 TI - Rapid control of phase growth by nanoparticles. AB - Effective control of phase growth under harsh conditions (such as high temperature, highly conductive liquids or high growth rate), where surfactants are unstable or ineffective, is still a long-standing challenge. Here we show a general approach for rapid control of diffusional growth through nanoparticle self-assembly on the fast-growing phase during cooling. After phase nucleation, the nanoparticles spontaneously assemble, within a few milliseconds, as a thin coating on the growing phase to block/limit diffusion, resulting in a uniformly dispersed phase orders of magnitude smaller than samples without nanoparticles. The effectiveness of this approach is demonstrated in both inorganic (immiscible alloy and eutectic alloy) and organic materials. Our approach overcomes the microstructure refinement limit set by the fast phase growth during cooling and breaks the inherent limitations of surfactants for growth control. Considering the growing availability of numerous types and sizes of nanoparticles, the nanoparticle-enabled growth control will find broad applications. PMID- 24809455 TI - Understanding the undelaying mechanism of HA-subtyping in the level of physic chemical characteristics of protein. AB - The evolution of the influenza A virus to increase its host range is a major concern worldwide. Molecular mechanisms of increasing host range are largely unknown. Influenza surface proteins play determining roles in reorganization of host-sialic acid receptors and host range. In an attempt to uncover the physic chemical attributes which govern HA subtyping, we performed a large scale functional analysis of over 7000 sequences of 16 different HA subtypes. Large number (896) of physic-chemical protein characteristics were calculated for each HA sequence. Then, 10 different attribute weighting algorithms were used to find the key characteristics distinguishing HA subtypes. Furthermore, to discover machine leaning models which can predict HA subtypes, various Decision Tree, Support Vector Machine, Naive Bayes, and Neural Network models were trained on calculated protein characteristics dataset as well as 10 trimmed datasets generated by attribute weighting algorithms. The prediction accuracies of the machine learning methods were evaluated by 10-fold cross validation. The results highlighted the frequency of Gln (selected by 80% of attribute weighting algorithms), percentage/frequency of Tyr, percentage of Cys, and frequencies of Try and Glu (selected by 70% of attribute weighting algorithms) as the key features that are associated with HA subtyping. Random Forest tree induction algorithm and RBF kernel function of SVM (scaled by grid search) showed high accuracy of 98% in clustering and predicting HA subtypes based on protein attributes. Decision tree models were successful in monitoring the short mutation/reassortment paths by which influenza virus can gain the key protein structure of another HA subtype and increase its host range in a short period of time with less energy consumption. Extracting and mining a large number of amino acid attributes of HA subtypes of influenza A virus through supervised algorithms represent a new avenue for understanding and predicting possible future structure of influenza pandemics. PMID- 24809456 TI - Coupling of two non-processive myosin 5c dimers enables processive stepping along actin filaments. AB - Myosin 5c (Myo5c) is a low duty ratio, non-processive motor unable to move continuously along actin filaments though it is believed to participate in secretory vesicle trafficking in vertebrate cells. Here, we measured the ATPase kinetics of Myo5c dimers and tested the possibility that the coupling of two Myo5c molecules enables processive movement. Steady-state ATPase activity and ADP dissociation kinetics demonstrated that a dimer of Myo5c-HMM (double-headed heavy meromyosin 5c) has a 6-fold lower Km for actin filaments than Myo5c-S1 (single headed myosin 5c subfragment-1), indicating that the two heads of Myo5c-HMM increase F-actin-binding affinity. Nanometer-precision tracking analyses showed that two Myo5c-HMM dimers linked with each other via a DNA scaffold and moved processively along actin filaments. Moreover, the distance between the Myo5c molecules on the DNA scaffold is an important factor for the processive movement. Individual Myo5c molecules in two-dimer complexes move stochastically in 30-36 nm steps. These results demonstrate that two dimers of Myo5c molecules on a DNA scaffold increased the probability of rebinding to F-actin and enabled processive steps along actin filaments, which could be used for collective cargo transport in cells. PMID- 24809457 TI - Galectin-3 induces cell migration via a calcium-sensitive MAPK/ERK1/2 pathway. AB - The presence and level of circulating galectin-3 (Gal-3), a member of the galectin family, is associated with diverse diseases ranging from heart failure, immune disorders to cancer metastasis and serves as a biomarker of diagnosis and treatment response. However, the mechanisms by which exogenous Gal-3 affects pathobiology events remain elusive. In the current study, we found that exogenous Gal-3 slightly delays, while prolonging tyrosine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in HeLa cells through a calcium-sensitive and PKC-dependent signaling pathway. The activation was dependent on the sugar binding properties of Gal-3, since the antagonist lactose could inhibit it. The sugar-binding motif of Gal-3 was required for the activation of ERK1/2. The activation of ERK1/2 was necessary for the initiation and induction of cell migration associated with the phosphorylation of paxillin. All the results presented in this study suggest a novel calcium-sensitive and PKC-dependent pathway through which circulating Gal-3 promotes cell migration and activating the ERK1/2. Taken together, the data depicted here propose a biological function and a target for the diseases' associated circulating Gal-3. PMID- 24809458 TI - Thin-film and bulk investigations of LiCoBO3 as a Li-ion battery cathode. AB - The compound LiCoBO3 is an appealing candidate for next-generation Li-ion batteries based on its high theoretical specific capacity of 215 mAh/g and high expected discharge voltage (more than 4 V vs Li(+)/Li). However, this level of performance has not yet been realized in experimental cells, even with nanosized particles. Reactive magnetron sputtering was therefore used to prepare thin films of LiCoBO3, allowing the influence of the particle thickness on the electrochemical performance to be explicitly tested. Even when ultrathin films (~15 nm) were prepared, there was a negligible electrochemical response from LiCoBO3. Impedance spectroscopy measurements suggest that the conductivity of LiCoBO3 is many orders of magnitude worse than that of LiFeBO3 and may severely limit the performance. The unusual blue color of LiCoBO3 was investigated by spectroscopic techniques, which allowed the determination of a charge-transfer optical gap of 4.2 eV and the attribution of the visible light absorption peak at 2.2 eV to spin-allowed d -> d transitions (assigned as overlapping (4)A2' to (4)A2" and (4)E" final states based on ligand-field modeling). PMID- 24809459 TI - Phosphorylation of KasB regulates virulence and acid-fastness in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis bacilli display two signature features: acid-fast staining and the capacity to induce long-term latent infections in humans. However, the mechanisms governing these two important processes remain largely unknown. Ser/Thr phosphorylation has recently emerged as an important regulatory mechanism allowing mycobacteria to adapt their cell wall structure/composition in response to their environment. Herein, we evaluated whether phosphorylation of KasB, a crucial mycolic acid biosynthetic enzyme, could modulate acid-fast staining and virulence. Tandem mass spectrometry and site-directed mutagenesis revealed that phosphorylation of KasB occurred at Thr334 and Thr336 both in vitro and in mycobacteria. Isogenic strains of M. tuberculosis with either a deletion of the kasB gene or a kasB_T334D/T336D allele, mimicking constitutive phosphorylation of KasB, were constructed by specialized linkage transduction. Biochemical and structural analyses comparing these mutants to the parental strain revealed that both mutant strains had mycolic acids that were shortened by 4-6 carbon atoms and lacked trans-cyclopropanation. Together, these results suggested that in M. tuberculosis, phosphorylation profoundly decreases the condensing activity of KasB. Structural/modeling analyses reveal that Thr334 and Thr336 are located in the vicinity of the catalytic triad, which indicates that phosphorylation of these amino acids would result in loss of enzyme activity. Importantly, the kasB_T334D/T336D phosphomimetic and deletion alleles, in contrast to the kasB_T334A/T336A phosphoablative allele, completely lost acid fast staining. Moreover, assessing the virulence of these strains indicated that the KasB phosphomimetic mutant was attenuated in both immunodeficient and immunocompetent mice following aerosol infection. This attenuation was characterized by the absence of lung pathology. Overall, these results highlight for the first time the role of Ser/Thr kinase-dependent KasB phosphorylation in regulating the later stages of mycolic acid elongation, with important consequences in terms of acid-fast staining and pathogenicity. PMID- 24809461 TI - Gap states assisted MoO3 nanobelt photodetector with wide spectrum response. AB - Molybdenum oxides have been widely investigated for their broad applications ranging from electronics to energy storage. Photodetectors based on molybdenum trioxide (MoO3), however, were seldom reported owing to their low conductivity and weak photoresponse. Herein we report a photodetector based on single MoO3 nanobelt with wide visible spectrum response by introducing substantial gap states via H2 annealing. The pristine MoO3 nanobelt possessed low electrical conductance and no photoresponse for nearly all visible lights. The H2 annealing can significantly improve the conductance of MoO3 nanobelt, and result in a good photodetector with wide visible spectrum response. Under illumination of 680 nm light, the photodetector exhibited high responsivity of ~56 A/W and external quantum efficiency of ~10200%. As corroborated by in situ ultraviolet photoelectron spectroscopy and X-ray photoelectron spectroscopy investigations, such strong wide spectrum photoresponse arises from the largely enriched gap states in the MoO3 nanobelt after H2 annealing. PMID- 24809462 TI - The AmpliChip: A Review of its Analytic and Clinical Validity and Clinical Utility. AB - BACKGROUND: In 2005, the FDA approved the Roche AmpliChipTM for clinical application. The AmpliChip is a microarray chip that has the capability to play an important role in clinical pharmacogenetics. OBJECTIVE: Because of the possible influence the AmpliChip may have on patient medication management, the purpose of the review is to address the available evidence for the AmpliChip's overall performance at three key levels: analytic validity (genotyping accuracy, and prediction of the phenotype from the genotype) and clinical utility. DATA SOURCES: We searched Medline, Embase and PubMed for studies of the AmpliChip. Limits were English language and 2005 (the year of FDA approval) and onwards, and we corresponded with authors for further papers of interest. RESULTS: 17 articles provided data for analysis in this review: 4 involving genotype accuracy, 7 involving genotype to phenotype prediction and 9 involving clinical utility. CONCLUSION: There is limited literature comparing AmpliChip results to gold standard tests and test-retest reliability when assessing genotype accuracy. Also, there is limited literature on the accuracy of AmpliChip predictions of phenotypes from genotypes and minimal evidence with appropriately powered studies whether the AmpliChip genotype to phenotype predictions result in clinical benefit. At all three levels there is significant evidence that the AmpliChip has the potential to be a robust clinical tool. However, more and adequately powered studies are required to determine fully whether the AmpliChip is a clinically effective tool. PMID- 24809460 TI - A simulated intermediate state for folding and aggregation provides insights into DeltaN6 beta2-microglobulin amyloidogenic behavior. AB - A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of beta2-microglobulin (DeltaN6) lacking the first six N-terminal residues. Here we perform a computational study on DeltaN6, which provides clues to understand the amyloidogenicity of the full length beta2-microglobulin. Contrary to the wild-type form, DeltaN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in DeltaN6 amyloidogenesis. PMID- 24809463 TI - Clozapine safety, 40 years later. AB - Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review. PMID- 24809465 TI - Is there a "right way" to provide pediatric palliative care? PMID- 24809466 TI - Palliative sedation therapy: a systematic literature review and critical appraisal of available guidance on indication and decision making. AB - BACKGROUND: Palliative sedation therapy (PST) is increasingly used in end-of-life care. However, consensus about definitions, indications, and treatment decision making is lacking. OBJECTIVE: The objective is to review and critically appraise published guidelines on indication and decision making for PST. METHODS: Data sources are CINAHL, Cochrane Library, EMBASE, PsycINFO, PubMed, and references of included papers through February 2013. Selection criteria were that papers included a PST guideline and were written in English or German. The term "guideline" was defined according to MEDLINE. Two investigators extracted information on the guidelines' recommendations on indication and decision making. RESULTS: The nine eligible guidelines differ in their definitions of PST. In addition key terms such as "refractory symptom" or "intolerable suffering" are used differently. These criteria are also weighed differently in their relevance for indication and decision making. PST for psychological distress is regarded as exceptional by eight guidelines, but only two guidelines provide reasons for this exceptionalism in comparison with PST for somatic suffering. In the majority of guidelines the role of different stakeholders involved in decision making is not specified. With regards to the limitation of life-sustaining measures, e.g., intravenous hydration, in the context of PST the analyzed guidelines differ in their recommendations. CONCLUSIONS: PST guidelines differ considerably on aspects of indication and decision making about PST which are relevant from a clinical as well as ethical perspective. The comparison and critical appraisal can serve as a starting point for the improvement of future PST policies. PMID- 24809467 TI - Kayser-Fleischer ring and sunflower cataract in Wilson disease. PMID- 24809469 TI - Iterative genome correction largely improves proteomic analysis of nonmodel organisms. AB - The current application and development of proteomic studies typically depend on the availability of sequenced genomes. Protein identification based on the detected peptides with liquid chromatography tandem mass spectrometry is limited by the absence of sequenced genomes in many nonmodel organisms. In this study, we demonstrated a new strategy based on our stable, accurate, and error-tolerant FANSe (Fast and Accurate mapping tool for Nucleotide Sequencing datasets) mapping algorithm to correct genome sequences in an iterative manner. To evaluate the efficiency of the corrected genome databases in proteomic study, MS/MS spectra of whole proteome extracted from a Bacillus pumilus strain without complete genome sequence were searched against the protein sequence databases derived from the complete reference genome sequence of a homologous bacterium and from the corrected genome sequence. The results indicated that the corrected protein sequence database could significantly facilitate peptide/protein identification. Importantly, this strategy can help to detect novel peptide variants. This strategy of genome correction will promote the development of functional proteomics in nonmodel organisms. PMID- 24809468 TI - The characterization of a novel monoclonal antibody against CD93 unveils a new antiangiogenic target. AB - The inhibition of tumor angiogenesis is one of the main challenges in cancer therapy. With the aim of developing monoclonal antibodies able to inhibit angiogenesis, we immunized mice with proliferating human umbilical vein endothelial cells. We generated a library of monoclonal antibodies able to recognize antigens expressed on endothelial cells and screened the antibodies for their ability to inhibit endothelial cell proliferation, migration, and sprouting in vitro. Here, we show that the antibody, designated as 4E1, is able to neutralize the formation of new vessels both in vitro and in vivo without affecting endothelial cell survival. By mass spectrometry we identified CD93 as the antigen bound by 4E1 and mapped the recognized epitope. CD93 is a transmembrane protein heavily glycosylated preferentially expressed in the vascular endothelium. CD93 silencing by lentiviral-mediated small hairpin RNA expression impairs human endothelial cell proliferation, migration, and sprouting. Altogether these findings reveal 4E1 as a novel antiangiogenic antibody and identify CD93 as a new target suitable for antiangiogenic therapy. PMID- 24809470 TI - New synthetic pathways to the preparation of near-blue emitting heteroleptic Ir(III)N6 coordinated compounds with microsecond lifetimes. AB - A high yield synthetic route for the preparation of N6 coordinated heteroleptic Ir(III) complexes using bidentate polypyridyl type ligands is described. The complexes are near-blue emitters and show microsecond emission lifetimes, high emission quantum yields and have two quasi-reversible reduction processes between -1.0 and -1.3 V vs. Ag/AgCl. PMID- 24809471 TI - Lifecourse social position and D-dimer; findings from the 1958 British birth cohort. AB - The aim is to examine the association of lifecourse socioeconomic position (SEP) on circulating levels of D-dimer. Data from the 1958 British birth cohort were used, social class was determined at three stages of respondents' life: at birth, at 23 and at 42 years. A cumulative indicator score of SEP (CIS) was calculated ranging from 0 (always in the highest social class) to 9 (always in the lowest social class). In men and women, associations were observed between CIS and D dimer (P<0.05). Thus, the respondents in more disadvantaged social classes had elevated levels of D-dimer compared to respondents in less disadvantaged social class. In multivariate analyses, the association of disadvantaged social position with D-dimer was largely explained by fibrinogen, C-reactive protein and von Willebrand Factor in women, and additionally by smoking, alcohol consumption and physical activity in men. Socioeconomic circumstances across the lifecourse at various stages also contribute independently to raised levels of D-dimer in middle age in women only. Risk exposure related to SEP accumulates across life and contributes to raised levels of D-dimer. The association of haemostatic markers and social differences in health may be mediated by inflammatory and other markers. PMID- 24809472 TI - The deficiency of tumor suppressor prep1 accelerates the onset of meis1- hoxa9 leukemogenesis. AB - Prep1 and Meis1 ortholog TALE transcription factors have opposing roles in tumorigenesis: Meis1 serves as an oncogene, Prep1 as a tumor suppressor. We now report that, Meis1 overexpression in primary Prep1-deficient (Prep1i/i) embryonic hematopoietic cells increases self-renewal potential of cells in vitro but not in vivo, whereas leukemia is instead obtained when Meis1 is combined with another oncogene, HoxA9. Prep1i/i Meis1-HoxA9-generated leukemic cells are less differentiated and grow more aggressively after the second passage in the mouse. These data indicate that Prep1 represents a barrier to the transforming activity of Meis1 in vitro, but its absence is not sufficient to induce early leukemogenesis. On the other hand, the Prep1i/i background appears to favor the insurgence of mutations that cause a more aggressive Meis1-HoxA9-generated leukemia. Indeed, the Prep1i/i leukemic cells upregulate the Polycomb protein Bmi 1 and expectedly down-regulate the Ink4a/Arf locus products. Finally, an important feature contributed by the Prep1i/i background is the post transcriptional increase in Meis1 protein level. PMID- 24809473 TI - Strengths and limitations of period estimation methods for circadian data. AB - A key step in the analysis of circadian data is to make an accurate estimate of the underlying period. There are many different techniques and algorithms for determining period, all with different assumptions and with differing levels of complexity. Choosing which algorithm, which implementation and which measures of accuracy to use can offer many pitfalls, especially for the non-expert. We have developed the BioDare system, an online service allowing data-sharing (including public dissemination), data-processing and analysis. Circadian experiments are the main focus of BioDare hence performing period analysis is a major feature of the system. Six methods have been incorporated into BioDare: Enright and Lomb Scargle periodograms, FFT-NLLS, mFourfit, MESA and Spectrum Resampling. Here we review those six techniques, explain the principles behind each algorithm and evaluate their performance. In order to quantify the methods' accuracy, we examine the algorithms against artificial mathematical test signals and model generated mRNA data. Our re-implementation of each method in Java allows meaningful comparisons of the computational complexity and computing time associated with each algorithm. Finally, we provide guidelines on which algorithms are most appropriate for which data types, and recommendations on experimental design to extract optimal data for analysis. PMID- 24809474 TI - Relative importance of current and past landscape structure and local habitat conditions for plant species richness in dry grassland-like forest openings. AB - In fragmented landscapes, plant species richness may depend not only on local habitat conditions but also on landscape structure. In addition, both present and past landscape structure may be important for species richness. There are, however, only a few studies that have investigated the relative importance of all of these factors. The aim of this study was to examine the effect of current and past landscape structures and habitat conditions on species richness at dry grassland-like forest openings in a forested landscape and to assess their relative importance for species richness. We analyzed information on past and present landscape structures using aerial photographs from 1938, 1973, 1988, 2000 and 2007. We calculated the area of each locality and its isolation in the present and in the past and the continuity of localities in GIS. At each locality, we recorded all vascular plant species (296 species in 110 forest openings) and information on abiotic conditions of the localities. We found that the current species richness of the forest openings was significantly determined by local habitat conditions as well as by landscape structure in the present and in the past. The highest species richness was observed on larger and more heterogeneous localities with rocks and shallow soils, which were already large and well connected to other localities in 1938. The changes in the landscape structure in the past can thus have strong effects on current species richness. Future studies attempting to understand determinants of species diversity in fragmented landscapes should also include data on past landscape structure, as it may in fact be more important than the present structure. PMID- 24809475 TI - How does NAADP release lysosomal Ca2+? PMID- 24809476 TI - Population genomic analysis of ancient and modern genomes yields new insights into the genetic ancestry of the Tyrolean Iceman and the genetic structure of Europe. AB - Genome sequencing of the 5,300-year-old mummy of the Tyrolean Iceman, found in 1991 on a glacier near the border of Italy and Austria, has yielded new insights into his origin and relationship to modern European populations. A key finding of that study was an apparent recent common ancestry with individuals from Sardinia, based largely on the Y chromosome haplogroup and common autosomal SNP variation. Here, we compiled and analyzed genomic datasets from both modern and ancient Europeans, including genome sequence data from over 400 Sardinians and two ancient Thracians from Bulgaria, to investigate this result in greater detail and determine its implications for the genetic structure of Neolithic Europe. Using whole-genome sequencing data, we confirm that the Iceman is, indeed, most closely related to Sardinians. Furthermore, we show that this relationship extends to other individuals from cultural contexts associated with the spread of agriculture during the Neolithic transition, in contrast to individuals from a hunter-gatherer context. We hypothesize that this genetic affinity of ancient samples from different parts of Europe with Sardinians represents a common genetic component that was geographically widespread across Europe during the Neolithic, likely related to migrations and population expansions associated with the spread of agriculture. PMID- 24809477 TI - Developmental changes in the role of different metalinguistic awareness skills in Chinese reading acquisition from preschool to third grade. AB - The present study investigated the relationship between Chinese reading skills and metalinguistic awareness skills such as phonological, morphological, and orthographic awareness for 101 Preschool, 94 Grade-1, 98 Grade-2, and 98 Grade-3 children from two primary schools in Mainland China. The aim of the study was to examine how each of these metalinguistic awareness skills would exert their influence on the success of reading in Chinese with age. The results showed that all three metalinguistic awareness skills significantly predicted reading success. It further revealed that orthographic awareness played a dominant role in the early stages of reading acquisition, and its influence decreased with age, while the opposite was true for the contribution of morphological awareness. The results were in stark contrast with studies in English, where phonological awareness is typically shown as the single most potent metalinguistic awareness factor in literacy acquisition. In order to account for the current data, a three stage model of reading acquisition in Chinese is discussed. PMID- 24809479 TI - The return of halothane anaesthesia? PMID- 24809478 TI - Implications of the admixture process in skin color molecular assessment. AB - The understanding of the complex genotype-phenotype architecture of human pigmentation has clear implications for the evolutionary history of humans, as well as for medical and forensic practices. Although dozens of genes have previously been associated with human skin color, knowledge about this trait remains incomplete. In particular, studies focusing on populations outside the European-North American axis are rare, and, until now, admixed populations have seldom been considered. The present study was designed to help fill this gap. Our objective was to evaluate possible associations of 18 single nucleotide polymorphisms (SNPs), located within nine genes, and one pseudogene with the Melanin Index (MI) in two admixed Brazilian populations (Gaucho, N = 352; Baiano, N = 148) with different histories of geographic and ethnic colonization. Of the total sample, four markers were found to be significantly associated with skin color, but only two (SLC24A5 rs1426654, and SLC45A2 rs16891982) were consistently associated with MI in both samples (Gaucho and Baiano). Therefore, only these 2 SNPs should be preliminarily considered to have forensic significance because they consistently showed the association independently of the admixture level of the populations studied. We do not discard that the other two markers (HERC2 rs1129038 and TYR rs1126809) might be also relevant to admixed samples, but additional studies are necessary to confirm the real importance of these markers for skin pigmentation. Finally, our study shows associations of some SNPs with MI in a modern Brazilian admixed sample, with possible applications in forensic genetics. Some classical genetic markers in Euro-North American populations are not associated with MI in our sample. Our results point out the relevance of considering population differences in selecting an appropriate set of SNPs as phenotype predictors in forensic practice. PMID- 24809480 TI - Complications associated with 27 031 ultrasound-guided axillary brachial plexus blocks: a web-based survey of 36 French centres. AB - BACKGROUND: Ultrasound guidance improves the efficacy of peripheral nerve blocks, reducing performance time and local anaesthetic doses. It should also reduce the risk of systemic toxicity of local anaesthetic and nerve injuries. OBJECTIVE: The primary objective of this prospective study was to estimate the incidence of immediate complications related to ultrasound-guided axillary brachial plexus blocks in a multicentre observational cohort. DESIGN: Prospective multicentre observational study. SETTING: Thirty-six French centres participated in the study between 2009 and 2012. PATIENTS: A total of 27 031 axillary brachial plexus blocks were recorded. INTERVENTIONS: The study objective, the incidence of immediate complications related to ultrasound-guided axillary brachial plexus blocks (intravascular injection of local anaesthetic and neurological deficit at hospital discharge), was based on data collected by anaesthesiologists through a web-based case report form. MAIN OUTCOME MEASURE: Incidence of immediate complications related to ultrasound-guided axillary brachial plexus blocks. RESULTS: Of 27 031 blocks performed, the incidence of systemic toxicity of local anaesthetic was very low at 1.5 per 10 000, and the overall incidence of postoperative neurological symptoms was 0.37 per 10 000. CONCLUSION: We have reported a large series of ultrasound-guided axillary brachial plexus blocks in a multicentre study. Our results confirm the low incidence of local anaesthetic systemic toxicity and postoperative neurological complications as previously described. PMID- 24809481 TI - Transversus abdominis plane block in inguinal hernia repair. PMID- 24809482 TI - Deep neuromuscular block improves surgical conditions during laparoscopic hysterectomy: a randomised controlled trial. AB - BACKGROUND: The benefit of inducing deep neuromuscular block to improve laparoscopic surgical conditions is controversial. OBJECTIVE: The goal of this study was to determine the depth of neuromuscular block needed to guarantee excellent operating conditions during laparoscopic hysterectomy. DESIGN: A randomised controlled trial. SETTING: A single-centre study performed between February 2011 and May 2012. PATIENTS: One hundred and two women of ASA physical status 1 or 2 gave consent to participate and were allocated randomly to one of two groups. INTERVENTION: Under desflurane general anaesthesia, patients in Group S (shallow block), neuromuscular blockade was induced by administration of rocuronium 0.45 mg kg-1 followed by spontaneous recovery or a rescue bolus dose of 5 mg if surgical conditions were unacceptable. In Group D (deep block), neuromuscular block was induced by administration of rocuronium 0.6 mg kg-1 and maintained by bolus doses of 5 mg if the train-of-four count exceeded two, using adductor pollicis electromyography. MAIN OUTCOME MEASURES: With a stable pneumoperitoneum (13 mmHg), the surgeon scored the quality of the surgical field every 10 min as excellent (1), good but not optimal (2), poor but acceptable (3) or unacceptable (4). The groups were compared using the Cochran-Armitage trend test. The level of neuromuscular blockade was recorded each time the surgical field score exceeded 1. RESULTS: For groups S and D, respectively, the maximum surgical field scores were 1 in 21 and 34 patients, 2 in 11 and 11 patients, 3 in 4 and 5 patients and 4 in 14 and 0 patients. A trend towards higher scores was demonstrated in group S (P < 0.001). Surgical field scores of 2, 3 and 4 occurred only when the train-of-four count was at least 1, 2 and 3, respectively. CONCLUSION: Inducing deep neuromuscular block (train-of-four count <1) significantly improved surgical field scores and made it possible to completely prevent unacceptable surgical conditions. PMID- 24809483 TI - Simulation-based training in flexible fibreoptic intubation: A randomised study. AB - BACKGROUND: Flexible fibreoptic intubation (FOI) is a key element in difficult airway management. Training of FOI skills is an important part of the anaesthesiology curriculum. Simulation-based training has been shown to be effective when learning FOI, but the optimal structure of the training is debated. The aspect of dividing the training into segments (part-task training) or assembling into one piece (whole-task training) has not been studied. OBJECTIVE: The aims of this study were to compare the effect of training the motor skills of FOI as part-task training or as whole-task training and to relate the performance levels achieved by the novices to the standard of performance of experienced FOI practitioners. DESIGN: A randomised controlled study. SETTING: Centre for Clinical Education, University of Copenhagen and the Capital Region of Denmark, between January and April 2013. PARTICIPANTS: Twenty-three anaesthesia residents in their first year of training in anaesthesiology with no experience in FOI, and 10 anaesthesia consultants experienced in FOI. INTERVENTIONS: The novices to FOI were allocated randomly to receive either part-task or whole-task training of FOI on virtual reality simulators. Procedures were subsequently trained on a manikin and assessed by an experienced anaesthesiologist. The experienced group was assessed in the same manner with no prior simulation-based training. MAIN OUTCOME MEASURES: The primary outcome measure was the score of performance on testing FOI skills on a manikin. RESULTS: A positive learning effect was observed in both the part-task training group and the whole-task training group. There was no statistically significant difference in final performance scores of the two novice groups (P = 0.61). Furthermore, both groups of novices were able to improve their skill level significantly by the end of manikin training to levels comparable to the experienced anaesthesiologists. CONCLUSION: Part-task training did not prove more effective than whole-task training when training novices in FOI skills. FOI is very suitable for simulation based training and segmentation of the procedure during training is not necessary. PMID- 24809485 TI - Exploring codon optimization and response surface methodology to express biologically active transmembrane RANKL in E. coli. AB - Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL), a master cytokine that drives osteoclast differentiation, activation and survival, exists in both transmembrane and extracellular forms. To date, studies on physiological role of RANKL have been mainly carried out with extracellular RANKL probably due to difficulties in achieving high level expression of functional transmembrane RANKL (mRANKL). In the present study, we took advantage of codon optimization and response surface methodology to optimize the soluble expression of mRANKL in E. coli. We optimized the codon usage of mRANKL sequence to a preferred set of codons for E. coli changing its codon adaptation index from 0.64 to 0.76, tending to increase its expression level in E. coli. Further, we utilized central composite design to predict the optimum combination of variables (cell density before induction, lactose concentration, post-induction temperature and post induction time) for the expression of mRANKL. Finally, we investigated the effects of various experimental parameters using response surface methodology. The best combination of response variables was 0.6 OD600, 7.5 mM lactose, 26 degrees C post-induction temperature and 5 h post-induction time that produced 52.4 mg/L of fusion mRANKL. Prior to functional analysis of the protein, we purified mRANKL to homogeneity and confirmed the existence of trimeric form of mRANKL by native gel electrophoresis and gel filtration chromatography. Further, the biological activity of mRANKL to induce osteoclast formation on RAW264.7 cells was confirmed by tartrate resistant acid phosphatase assay and quantitative real-time polymerase chain reaction assays. Importantly, a new finding from this study was that the biological activity of mRANKL is higher than its extracellular counterpart. To the best of our knowledge, this is the first time to report heterologous expression of mRANKL in soluble form and to perform a comparative study of functional properties of both forms of RANKL. PMID- 24809486 TI - Multi-contrast multi-atlas parcellation of diffusion tensor imaging of the human brain. AB - In this paper, we propose a novel method for parcellating the human brain into 193 anatomical structures based on diffusion tensor images (DTIs). This was accomplished in the setting of multi-contrast diffeomorphic likelihood fusion using multiple DTI atlases. DTI images are modeled as high dimensional fields, with each voxel exhibiting a vector valued feature comprising of mean diffusivity (MD), fractional anisotropy (FA), and fiber angle. For each structure, the probability distribution of each element in the feature vector is modeled as a mixture of Gaussians, the parameters of which are estimated from the labeled atlases. The structure-specific feature vector is then used to parcellate the test image. For each atlas, a likelihood is iteratively computed based on the structure-specific vector feature. The likelihoods from multiple atlases are then fused. The updating and fusing of the likelihoods is achieved based on the expectation-maximization (EM) algorithm for maximum a posteriori (MAP) estimation problems. We first demonstrate the performance of the algorithm by examining the parcellation accuracy of 18 structures from 25 subjects with a varying degree of structural abnormality. Dice values ranging 0.8-0.9 were obtained. In addition, strong correlation was found between the volume size of the automated and the manual parcellation. Then, we present scan-rescan reproducibility based on another dataset of 16 DTI images - an average of 3.73%, 1.91%, and 1.79% for volume, mean FA, and mean MD respectively. Finally, the range of anatomical variability in the normal population was quantified for each structure. PMID- 24809487 TI - Does preoperative neutrophil lymphocyte ratio predict risk of recurrence and occult central nodal metastasis in papillary thyroid carcinoma? AB - BACKGROUND: Preoperative neutrophil to lymphocyte ratio (NLR) might be prognostic in papillary thyroid carcinoma (PTC). Given the controversy of prophylactic central neck dissection (pCND) in clinically nodal-negative (cN0) PTC, our study evaluated whether preoperative NLR predicted disease-free survival (DFS) and occult central nodal metastasis (CNM) in cN0 PTC. METHODS: A total of 191 patients who underwent pCND were analyzed. Complete blood counts with differential counts were taken before operation. NLR was calculated by dividing preoperative neutrophil count with lymphocyte count. Patients were categorized into NLR tertiles: first (NLR < 1.93; n = 63), second (NLR = 1.93-2.79; n = 64), and third tertile (NLR > 2.79; n = 64). Four other patient types, namely, benign nodular goiter, clinically nodal-positive (cN1) PTC, poorly differentiated thyroid carcinoma, and anaplastic thyroid carcinoma (ATC), were used as references. RESULTS: Age at operation (p < 0.001) and tumor size (p = 0.037) significantly increased with higher NLR. First tertile had significantly more TNM stage I tumors (p = 0.01) and lowest MACIS score (p = 0.002). Tumor size [hazard ratio (HR) 1.422, 95% confidence interval (CI) 1.119-1.809, p = 0.004] and multicentricity (HR = 2.545, 95% CI 1.073-6.024, p = 0.034) independently predicted DFS, whereas old age [odds ratio (OR) 1.026, 95% CI 1.006-1.046, p = 0.009), male (OR 2.882, 95% CI 1.348-6.172, p = 0.006), and large tumor (OR 1.567, 95% CI 1.209-2.032, p = 0.001) independently predicted occult CNM. NLR was not significantly associated with DFS or occult CNM. ATC had significantly higher NLR than cN1 PTC (7.28 vs. 2.74, p < 0.001). CONCLUSIONS: Although a higher NLR may imply a poorer tumor profile, it was not significantly associated with a worse DFS or higher risk of occult CNM in cN0 PTC. Perhaps, future research should focus on the prognostic value in other thyroid cancer types with a poorer prognosis. PMID- 24809488 TI - Modeling and forecasting daily movement of ambient air mean PM2.5 concentration based on the elliptic orbit model with weekly quasi-periodic extension: a case study. AB - Nowadays, the issue of air pollution has continuously been a global public health concern. Modeling and forecasting daily movement of ambient air mean PM2.5 concentration is an increasingly important task as it is intimately associated with human health that the air pollution has unignorable negative effects in reducing air quality, damaging environment, even causing serious harm to health. It is demonstrated that daily movement of mean PM2.5 concentration approximately exhibits weekly cyclical variations as daily particle pollution in the air is largely influenced by human daily activities. Then, based on weekly quasi periodic extension for daily movement of mean PM2.5 concentration, the called elliptic orbit model is proposed to describe its movement. By mapping daily movement of mean PM2.5 concentration as one time series into the polar coordinates, each 7-day movement is depicted as one elliptic orbit. Experimental result and analysis indicate workability and effectiveness of the proposed method. Here we show that with the weekly quasi-periodic extension, daily movements of mean PM2.5 concentration at the given monitoring stations in Xiangtan of China are well described by the elliptic orbit model, which provides a vivid description for modeling and prediction daily movement of mean PM2.5 concentration in a concise and intuitive way. PMID- 24809489 TI - Antimicrobial potential of the ionophore monensin on freshwater biofilm bacteria. AB - Microorganisms play key roles in stream ecosystems, but comparatively little is known about the resilience of freshwater bacterial communities and their susceptibility to the chemical by-products of agricultural land use. Antibiotics used in the agricultural sector are of particular concern and have been detected in waterways associated with agricultural land. Despite widespread agricultural intensification globally and the sector's high antibiotic use, the effects of agricultural antibiotic by-products on stream microbial communities have yet to be characterised. We investigated the impacts of the antibiotic monensin on microbial biofilm communities in a simulated contamination event using streamside replicated channels. A 24-h pulse experiment in flow channels precolonised by stream biofilm microbial communities contrasted the effects of monensin concentrations ranging from realistic to extreme toxicity levels (1-550 ug L( 1)). Biofilm community composition was characterised immediately before and after the pulse for several weeks using automated ribosomal intergenic spacer analysis. Despite applying acutely toxic levels of monensin, only limited effects to biofilm community composition were detected immediately after antibiotic application, and these disappeared within 4 days. Rather, temporal factors drove biofilm differences, highlighting the overriding importance of wider, catchment level, physiochemical hydrological influences on structuring freshwater biofilm communities, as opposed to localised and sporadic agricultural surface runoff contamination events containing antibiotics. PMID- 24809490 TI - Reactions of Cl atoms with alkyl esters: kinetic, mechanism and atmospheric implications. AB - Rate coefficients have been measured for the reaction of Cl atoms with a series of alkyl esters at 298 +/- 2 K and atmospheric pressure in a large volume photoreactor using the relative kinetic technique. The kinetic data have been used in conjunction with other literature studies on the reactions of Cl atoms with esters to revise the existing values for ester substituent factors in a structure activity relationship (SAR) for Cl reactions. Product studies are reported for the reactions of Cl atoms with isopropyl ethanoate and methyl-2 methyl-propanoate under NO x -free conditions. These studies highlight the types of products that can be expected when oxidation occurs at R groups on the acyl ( C(O)OR) and oxy (RC(O)O-) sides of the ester functionality where R is a straight or branched chain alkyl entity. Possible atmospheric repercussions of the atmospheric chemistry of esters are considered. PMID- 24809491 TI - Andra Environmental Specimen Bank: archiving the environmental chemical quality for long-term monitoring. AB - Andra Environmental Specimen Bank (ESB) was established in 2010 as a part of the Perennial Observatory of the Environment (OPE), ongoing Long-Term Environmental Research Monitoring and Testing System located next to the Underground Research Laboratory (URL) at Bure, Meuse/Haute-Marne, France. The URL is used to study the deep geological disposal of high and intermediate level radioactive waste. Andra ESB is designed to archive during at least 100 years samples collected to define the initial state of environmental quality of the local area before the construction of industrial facilities and to ensure the traceability of long-term series of samples collected by the OPE ( http://www.andra.fr/ope ), using safe long-term conservation practices. Samples archived in the bank include some local food chain products (milk, cheese, honey, cereals, grass, cherry plum...) and specimen usually archived internationally to monitor the environmental quality (soil, sediment, water, fish, tree leaves, wild life, etc.). Regarding the different samples and analytical issues, three conservation modalities and facilities were designed: dry conservation under controlled temperature and humidity, cryopreservation in liquid nitrogen (LN2) vapor phase freezers (-150 degrees C) and in deep-freezing at -80 degrees C for temporary storage and raw samples before preparation. Andra ESB is equipped with a sample preparation clean room, certified ISO Class 5, dedicated to cryopreservation. This paper describes this first French experiment of long-term chemical quality monitoring and samples cryopreservation of different ecosystems and environmental compartments. PMID- 24809492 TI - Mobility and phytoavailability of Cu, Cr, Zn, and As in a contaminated soil at a wood preservation site after 4 years of aided phytostabilization. AB - The remediation of copper-contaminated soils by aided phytostabilisation in 16 field plots at a wood preservation site was investigated. The mobility and bioavailability of four potentially toxic trace elements (PTTE), i.e., Cu, Zn, Cr, and As, were investigated in these soils 4 years after the incorporation of compost (OM, 5 % w/w) and dolomite limestone (DL, 0.2 % w/w), singly and in combination (OMDL), and the transplantation of mycorrhizal poplar and willows. Topsoil samples were collected in all field plots and potted in the laboratory. Total PTTE concentrations were determined in soil pore water (SPW) collected by Rhizon soil moisture samplers. Soil exposure intensity was assessed by Chelex100 DGT (diffusive gradient in thin films) probes. The PTTE phytoavailability was characterized by growing dwarf beans on potted soils and analyzing their foliar PTTE concentrations. OM and DL, singly and in combination (OMDL), were effective to decrease foliar Cu, Cr, Zn, and As concentrations of beans, the lowest values being numerically for the OM plants. The soil treatments did not reduce the Cu and Zn mineral masses of the bean primary leaves, but those of Cr and As decreased for the OM and DL plants. The Cu concentration in SPW was increased in the OM soil and remained unchanged in the DL and OMDL soils. The available Cu measured by DGT used to assess the soil exposure intensity correlated with the foliar Cu concentration. The Zn concentrations in SPW were reduced in the DL soil. All amendments increased As in the SPW. Based on DGT data, Cu availability was reduced in both OM and OMDL soils, while DL was the most effective to decrease soil Zn availability. PMID- 24809493 TI - Cyprodinil retention on mixtures of soil and solid wastes from wineries. Effects of waste dose and ageing. AB - In spite of its wide-world economic relevance, wine production generates a huge amount of waste that threatens the environment. A batch experiment was designed to assess the effect of the amendment of an agricultural soil with two winery wastes (perlite and bentonite wastes) in the immobilization of cyprodinil. Waste addition (0, 10, 20, 40, and 80 Mg ha(-1)) and different times of incubation of soil-waste mixtures (1, 30, and 120 days) were tested. The addition of wastes improved the soil's ability to immobilize cyprodinil, which was significantly correlated to total C content in soil-waste mixtures. Longer incubation times decreased the cyprodinil sorption possibly due to the mineralization of organic matter but also as a consequence of the high pH values reached after bentonite waste addition (up to 10.0). Cyprodinil desorption increased as the amount of waste added to soil, and the incubation time increased. The use of these winery wastes contributes to a more sustainable agriculture preventing fungicide mobilization to groundwater. PMID- 24809494 TI - Solar photocatalytic gas-phase degradation of n-decane--a comparative study using cellulose acetate monoliths coated with P25 or sol-gel TiO2 films. AB - Cellulose acetate monoliths (CAM) were used as the substrate for the deposition of TiO2 films to produce honeycombed photoactive structures to fill a tubular photoreactor equipped with a compound parabolic collector. By using such a setup, an efficient single-pass gas-phase conversion was achieved in the degradation of n-decane, a model volatile organic compound. The CAM three-dimensional, gas permeable transparent structure with a rugged surface enables a good adhesion of the catalytic coating. It also provides a rigid structure for packing the tubular photoreactor, and maximizing the illuminated catalyst surface. The efficiency of the photocatalytic oxidation (PCO) process on n-decane degradation was evaluated under different operating conditions, such as feeding concentration (73 and 146 ppm), gas stream flow rate (73, 150, and 300 mL min(-1)), relative humidity (3 and 25 %), and UV irradiance (18.9, 29.1, and 38.4 WUV m(-2)). The results show that n-decane degradation by neat photolysis is negligible, but mineralization efficiencies of 86 and 82 % were achieved with P25-CAM and SG-CAM, respectively, for parent pollutant conversions above 95 %, under steady-state conditions. A mass transfer model, considering the mass balance to the plug-flow packed photoreactor, and PCO reaction given by a Langmuir-Hinshelwood bimolecular non competitive two types of sites equation, was able to predict well the PCO kinetics under steady-state conditions, considering all the operational parameters tested. Overall, the performance of P25-CAM was superior taking into account mineralization efficiency, cost of preparation, surface roughness, and robustness of the deposited film. PMID- 24809495 TI - Dynamic modelling for cork boiling wastewater treatment at pilot plant scale. AB - Solar photo-Fenton process has been extensively reported to be highly efficient in the remediation of complex industrial wastewater containing several families of pollutants such as pharmaceuticals, dyes, pesticides, derivatives of wine, etc. Moreover, solar photo-Fenton mathematical modelling regarded as a powerful tool for scaling-up and process control purposes is hindered by the complexity and variability of its reaction mechanism which depends on the particular wastewater under study. In this work, non-biodegradable cork boiling wastewater has been selected as a case study for solar photo-Fenton dynamic modelling by using MATLAB(r) software. First of all physic-chemical pretreatment was applied attaining chemical oxygen demand (COD) reductions between 43 and 70 % and total suspended solid (TSS) reductions between 23 % and 59 %. After solar photo-Fenton treatment, COD decreased between 45 and 90 % after consumptions of H2O2 varying around 1.9 and 2.4 g/L. Individual calibration of the semi-empirical model by using experimental results made it possible to perfectly predict hydrogen peroxide variations throughout the treatment. It must be highlighted that slight deviations between predictions and experimental data must be attributed to important changes in wastewater characteristics. PMID- 24809496 TI - Fenton-like processes and adsorption using iron oxide-pillared clay with magnetic properties for organic compound mitigation. AB - In this work, a new step was added to the classic route of iron-pillared clay obtention, resulting in a material with both magnetic and oxidative properties. The saturation of the material surface intercalated with trinuclear acetate hydroxo iron (III) nitrate in glacial acetic acid atmosphere before heat treatment promoted magnetic phase formation (FePMAG). The material was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), nitrogen adsorption/desorption isotherms, scanning electron microscopy coupled with energy dispersive spectroscopy (SEM/EDS), and X-ray photoelectron spectroscopy (XPS). FePMAG showed an increase of 0.57 nm in basal spacing which contributed to the specific surface area increase from 39.1 to 139.2 m(2)/g. The iron phase identified by XRD and XPS was maghemite, with a little presence of hematite formed by the trinuclear acetate-hydroxo iron (III) nitrate decomposition during heat treatment. In the adsorption tests, FePMAG displayed a good capacity for organic dye methylene blue (MB) removal, reaching 41 % at 150 min. Under photo-Fenton conditions, the material showed an excellent MB oxidation capacity, completely removing the color of the solution within 90 min. Identification of the oxidation products with lower molecular (m/z = 160, 220, and 369) mass was performed by electrospray ionization mass spectroscopy (ESI-MS). PMID- 24809497 TI - Polychlorinated biphenyl contamination of paints containing polycyclic- and Naphthol AS-type pigments. AB - This study reports the concentrations and congener partners of polychlorinated biphenyls (PCBs) in commercially available paints. Polycyclic-type pigments containing dioxazine violet (pigment violet (PV) 23, PV37) and diketopyrrolopyrrole (PR254, PR255) were found to contain PCB-56, PCB-77, PCB-40, PCB-5, and PCB-12, and PCB-6, PCB-13, and PCB-15, respectively, as major congeners. Dioxazine violet is contaminated with by-products during synthesis from o-dichlorobenzene, which is used as a solvent during synthesis, and diketopyrrolopyrrole is contaminated with by-products during synthesis from p chlorobenzonitrile. The concentration of PCBs in paint containing PV23 or PV37 was 0.050-29 mg/kg, and toxic equivalency (TEQ) values ranged 1.1-160 pg-TEQ/g. The concentration of PCBs in paint containing PR254 or PR255 was 0.0019-2.4 mg/kg. Naphthol AS is an azo-type pigment, and PCB-52 was detected in paint containing pigment red (PR) 9 with 2,5-dichloroaniline as its source. PCB-146, PCB-149, and PCB-153 were identified from paint containing PR112 produced from 2,4,5-trichloroaniline, as major congeners. These congeners have chlorine positions similar to aniline, indicating that these congeners are by-products obtained during the synthesis of pigments. The concentrations of PCBs in paints containing PR9 and PR112 were 0.0042-0.43 and 0.0044-3.8 mg/kg, respectively. The corresponding TEQ for PR112 was 0.0039-8.6 pg-TEQ/g. PMID- 24809498 TI - Enhancement of nitrogen and phosphorus removal from eutrophic water by economic plant annual ryegrass (Lolium multiflorum) with ion implantation. AB - Severe eutrophication of surface water has been a major problem of increasing environmental concern worldwide. In the present study, economic plant annual ryegrass (Lolium multiflorum) was grown in floating mats as an economic plant based treatment system to evaluate its potential after ion implantation for removing nutrients in simulated eutrophic water. The specific weight growth rate of L. multiflorum with ion implantation was significantly greater than that of the control, and the peroxidase, nitrate reductase, and acid phosphatase activities of the irradiated L. multiflorum were found to be greater than those plants without ion implantation. Higher total nitrogen (TN) and total phosphorus (TP) removal efficiencies were obtained for the L. multiflorum irradiated with 25 keV 5.2 * 10(16) N(+) ions/cm(2) and 30 keV 4.16 * 10(16) N(+) ions/cm(2), respectively (p < 0.05). Furthermore, the nitrogen and phosphorus contents in the plant biomass with ion implantation were also greater than those in the control and were positively correlated with TN and TP supplied. L. multiflorum itself was directly responsible for 39-49 and 47-58 % of the overall N and P removal in the experiment, respectively. The research results suggested that ion implantation could become a promising approach for increasing phytoremediation efficiency of nutrients from eutrophic water by L. multiflorum. PMID- 24809499 TI - Phragmites sp. physiological changes in a constructed wetland treating an effluent contaminated with a diazo dye (DR81). AB - The role of Phragmites sp. in phytoremediation of wastewaters containing azo dyes is still, in many ways, at its initial stage of investigation. This plant response to the long-term exposure to a highly conjugated di-azo dye (Direct Red 81, DR81) was assessed using a vertical flow constructed wetland, at pilot scale. A reed bed fed with water was used as control. Changes in photosynthetic pigment content in response to the plant contact with synthetic DR81 effluent highlight Phragmites plasticity. Phragmites leaf enzymatic system responded rapidly to the stress imposed; in general, within 1 day, the up-regulation of foliar reactive oxygen species-scavenging enzymes (especially superoxide dismutase, ascorbate peroxidase (APX), glutathione peroxidase (GPX) and peroxidase) was noticed as plants entered in contact with synthetic DR81 effluent. This prompt activation decreased the endogenous levels of H2O2 and the malonyldialdehyde content beyond reference values. Glutathione S-transferase (GST) activity intensification was not enough to cope with stress imposed by DR81. GPX activity was pivotal for the detoxification pathways after a 24-h exposure. Carotenoid pool was depleted during this shock. After the imposed DR81 stress, plants were harvested. In the next vegetative cycle, Phragmites had already recovered from the chemical stress. Principal component analysis (PCA) highlights the role of GPX, GST, APX, and carotenoids along catalase (CAT) in the detoxification process. PMID- 24809500 TI - Concentration and distribution of antibiotics in water-sediment system of Bosten Lake, Xinjiang. AB - This study investigated the residues of four sulfonamides, four quinolones, and four tetracyclines in surface water as well as surficial sediment samples, of Bosten Lake, in Xinjiang, China. The results showed the presence of 10 out of the 12 selected antibiotics in both water and sediment. Lomefloxacin was not detected in any of the samples. Among the 12 antibiotics considered, ciprofloxacin, with median concentrations of 39.22 ng L(-1) in surface water and 76.51 MUg kg(-1) in surficial sediment, was the dominant antibiotic in all samples. The sorption coefficient values presented higher sorption capacities of tetracycline and chlortetracycline than the other antibiotics. The cluster analysis revealed elevated levels of pollution in sampling sites 1, 2, and 3, which were situated in a nearby urban area and in the estuary of Kaidu River. This study demonstrates the necessity of regulating the use of antibiotics and improving the management and treatment of their release. PMID- 24809502 TI - Incentivizing fruit and vegetable purchases among participants in the Special Supplemental Nutrition Program for Women, Infants, and Children. AB - OBJECTIVE: In 2009, the US Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) began to provide participants with cash-value vouchers to purchase fruits and vegetables ($US 10 for women and $US 6 for children per month). The present paper assesses the potential effects of the new WIC incentives on fruit and vegetable purchases among WIC households in two New England states. DESIGN: A pre-post assessment of changes in fruit and vegetable purchases after the WIC revisions in generalized estimating equation models. SETTING: Scanner data on grocery purchases from a regional supermarket chain in New England, USA. SUBJECTS: WIC-participating households (n 2137) that regularly shopped at the chain during January-September 2009 and January-September 2010. RESULTS: After the WIC revisions, purchases of fresh and frozen vegetables increased in volume by 17.5 % and 27.8 %, respectively. The biggest improvements were observed for fresh fruit, an increase of 28.6 %, adding almost a kilogram of fresh fruits per household per month. WIC households spent three times more of their WIC vouchers on purchasing fresh fruits than fresh vegetables. The magnitudes of substitution effects were relatively small: between 4 % (fresh fruit) and 13 % (canned vegetables) of the amounts purchased in 2009 with non-WIC funds were replaced by purchases made using WIC vouchers in 2010. CONCLUSIONS: The provision of fruit and vegetable benefits in the revised WIC food packages increased overall purchases of fruits and vegetables among WIC-participating households in New England. Efforts to encourage consumption of fruits and vegetables by people receiving federal food assistance are paying off. PMID- 24809501 TI - Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential. AB - Circulating tumor cells (CTCs) have emerged as a viable solution to the lack of tumor tissue availability for patients with a variety of solid tumors, including prostate cancer. Different approaches have been used to capture this tumor cell population and several of these techniques have been used to assess the potential role of CTCs as a biological marker to predict treatment efficacy and clinical outcome. CTCs are now considered a strong tool to understand the molecular characteristics of prostate cancer, and to be used and analyzed as a 'liquid biopsy' in the attempt to grasp the biological portrait of the disease in the individual patient. PMID- 24809503 TI - Synonymous constraint elements show a tendency to encode intrinsically disordered protein segments. AB - Synonymous constraint elements (SCEs) are protein-coding genomic regions with very low synonymous mutation rates believed to carry additional, overlapping functions. Thousands of such potentially multi-functional elements were recently discovered by analyzing the levels and patterns of evolutionary conservation in human coding exons. These elements provide a good opportunity to improve our understanding of how the redundant nature of the genetic code is exploited in the cell. Our premise is that the protein segments encoded by such elements might better comply with the increased functional demands if they are structurally less constrained (i.e. intrinsically disordered). To test this idea, we investigated the protein segments encoded by SCEs with computational tools to describe the underlying structural properties. In addition to SCEs, we examined the level of disorder, secondary structure, and sequence complexity of protein regions overlapping with experimentally validated splice regulatory sites. We show that multi-functional gene regions translate into protein segments that are significantly enriched in structural disorder and compositional bias, while they are depleted in secondary structure and domain annotations compared to reference segments of similar lengths. This tendency suggests that relaxed protein structural constraints provide an advantage when accommodating multiple overlapping functions in coding regions. PMID- 24809504 TI - Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis. AB - Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs), SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC) inhibitors (NaB or TSA) produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139 treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development. PMID- 24809505 TI - Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat. AB - PURPOSE: Chemokines are major promoters of repair and may regulate nerve ingrowth that is essential in tendon healing. The purpose of this study was to assess the temporal occurrence of different chemokines during Achilles tendon healing in relation to sensory nerve regeneration. Chemokine presence in tendon healing has not been studied previously. METHODS: Chemokine expression, nerve regeneration, angiogenesis and inflammatory cell occurrence during healing of Achilles tendon rupture in the rat were studied by immunohistochemistry and histology including semiquantitative assessment. Markers for chemokines (CCL5, CCL2, CCL3, CXCL10), nerves (PGP-9.5) and sensory neuropeptide substance P (SP) were analysed at different time points (1 day-16 weeks) post-rupture. RESULTS: In intact tendons (controls) immunoreactivity to all chemokines, PGP-9.5 and SP were confined to the tendon surroundings. After rupture, there was rapid increase in the tendon proper of the chemokines studied, all exhibiting their peak expression at week 1. Subsequently, at weeks 2-6, emerging inflammatory cells and maximum sprouting of PGP-/SP-positive nerves were observed close to newly formed blood vessels within the tendon proper, while chemokine expression already decreased. During weeks 6 8, PGP-/SP-positive nerves withdrew from the rupture site and relocated together with the chemokines in the surrounding tendon. CONCLUSIONS: Early chemokine expression in the healing tendon precedes ingrowth of new nerves, angiogenesis and emergence of inflammatory cells. The fine-tuned temporal and spatial appearance of chemokines suggests a chemoattractant role for inflammatory cell migration and possibly also a role in angiogenesis and neurogenesis. Chemokines may thus exhibit vital targets for biological modulation of tendon repair. PMID- 24809506 TI - Nerve injury induces a Gem-GTPase-dependent downregulation of P/Q-type Ca2+ channels contributing to neurite plasticity in dorsal root ganglion neurons. AB - Small RGK GTPases, Rad, Gem, Rem1, and Rem2, are potent inhibitors of high voltage-activated (HVA) Ca(2+) channels expressed in heterologous expression systems. However, the role of this regulation has never been clearly demonstrated in the nervous system. Using transcriptional analysis, we show that peripheral nerve injury specifically upregulates Gem in mice dorsal root ganglia. Following nerve injury, protein expression was increased in ganglia and peripheral nerve, mostly under its phosphorylated form. This was confirmed in situ and in vitro in dorsal root ganglia sensory neurons. Knockdown of endogenous Gem, using specific small-interfering RNA (siRNA), increased the HVA Ca(2+) current only in the large somatic-sized neurons. Combining pharmacological analysis of the HVA Ca(2+) currents together with Gem siRNA-transfection of larger sensory neurons, we demonstrate that only the P/Q-type Ca(2+) channels were enhanced. In vitro analysis of Gem affinity to various CaVbetax-CaV2.x complexes and immunocytochemical studies of Gem and CaVbeta expression in sensory neurons suggest that the specific inhibition of the P/Q channels relies on both the regionalized upregulation of Gem and the higher sensitivity of the endogenous CaV2.1-CaVbeta4 pair in a subset of sensory neurons including the proprioceptors. Finally, pharmacological inhibition of P/Q-type Ca(2+) current reduces neurite branching of regenerating axotomized neurons. Taken together, the present results indicate that a Gem-dependent P/Q-type Ca(2+) current inhibition may contribute to general homeostatic mechanisms following a peripheral nerve injury. PMID- 24809508 TI - An additional Baurusuchid from the cretaceous of Brazil with evidence of interspecific predation among crocodyliformes. AB - A new Baurusuchidae (Crocodyliformes, Mesoeucrocodylia), Aplestosuchus sordidus, is described based on a nearly complete skeleton collected in deposits of the Adamantina Formation (Bauru Group, Late Cretaceous) of Brazil. The nesting of the new taxon within Baurusuchidae can be ensured based on several exclusive skull features of this clade, such as the quadrate depression, medial approximation of the prefrontals, rostral extension of palatines (not reaching the level of the rostral margin of suborbital fenestrae), cylindrical dorsal portion of palatine bar, ridge on the ectopterygoid-jugal articulation, and supraoccipital with restricted thin transversal exposure in the caudalmost part of the skull roof. A newly proposed phylogeny of Baurusuchidae encompasses A. sordidus and recently described forms, suggesting its sixter-taxon relationship to Baurusuchus albertoi, within Baurusuchinae. Additionally, the remains of a sphagesaurid crocodyliform were preserved in the abdominal cavity of the new baurusuchid. Direct fossil evidence of behavioral interaction among fossil crocodyliforms is rare and mostly restricted to bite marks resulting from predation, as well as possible conspecific male-to-male aggression. This is the first time that a direct and unmistaken evidence of predation between different taxa of this group is recorded as fossils. This discovery confirms that baurusuchids were top predators of their time, with sphagesaurids occupying a lower trophic position, possibly with a more generalist diet. PMID- 24809507 TI - Multi-faceted proteomic characterization of host protein complement of Rift Valley fever virus virions and identification of specific heat shock proteins, including HSP90, as important viral host factors. AB - Rift Valley fever is a potentially fatal disease of humans and domestic animals caused by Rift Valley fever virus (RVFV). Infection with RVFV in ruminants can cause near 100% abortion rates and recent outbreaks in naive human populations have suggested case fatality rates of greater than thirty percent. To elucidate the roles that host proteins play during RVFV infection, proteomic analysis of RVFV virions was conducted using complementary analytical approaches, followed by functional validation studies of select identified host factors. Coupling the more traditional Gel LC/MS/MS approach (SDS PAGE followed by liquid chromatography tandem mass spectrometry) with an alternative technique that preserves protein complexes allowed the protein complement of these viral particles to be thoroughly examined. In addition to viral proteins present within the virions and virion-associated host proteins, multiple macromolecular complexes were identified. Bioinformatic analysis showed that host chaperones were among over-represented protein families associated with virions, and functional experiments using siRNA gene silencing and small molecule inhibitors identified several of these heat shock proteins, including heat shock protein 90 (HSP90), as important viral host factors. Further analysis indicated that HSP inhibition effects occur during the replication/transcription phase of the virus life cycle, leading to significant lowering of viral titers without compromising the functional capacity of released virions. Overall, these studies provide much needed further insight into interactions between RVFV and host cells, increasing our understanding of the infection process and suggesting novel strategies for anti-viral development. In particular, considering that several HSP90 inhibitors have been advancing through clinical trials for cancer treatment, these results also highlight the exciting potential of repurposing HSP90 inhibitors to treat RVF. PMID- 24809509 TI - Interprofessional education for whom? --challenges and lessons learned from its implementation in developed countries and their application to developing countries: a systematic review. AB - BACKGROUND: Evidence is available on the potential efficacy of interprofessional education (IPE) to foster interprofessional cooperation, improve professional satisfaction, and improve patient care. While the intention of the World Health Organization (WHO) is to implement IPE in all countries, evidence comes from developed countries about its efficiency, challenges, and barriers to planning and implementing IPE. We therefore conducted this review to examine challenges of implementing IPE to suggest possible pathways to overcome the anticipated challenges in developing countries. METHODS: We searched for literatures on IPE in PubMed/MEDLINE, CINAHL, PsycINFO, and ERIC databases. We examined challenges or barriers and initiatives to overcome them so as to suggest methods to solve the anticipated challenges in developing countries. We could not conduct a meta analysis because of the qualitative nature of the research question and the data; instead we conducted a meta-narrative of evidence. RESULTS: A total of 40 out of 2,146 articles were eligible for analyses in the current review. Only two articles were available from developing countries. Despite the known benefits of IPE, a total of ten challenges or barriers were common based on the retrieved evidence. They included curriculum, leadership, resources, stereotypes and attitudes, variety of students, IPE concept, teaching, enthusiasm, professional jargons, and accreditation. Out of ten, three had already been reported in developing countries: IPE curriculum, resource limitations, and stereotypes. CONCLUSION: This study found ten important challenges on implementing IPE. They are curriculum, leadership, resources, stereotypes, students' diversity, IPE concept, teaching, enthusiasm, professional jargons, and accreditation. Although only three of them are already experienced in developing countries, the remaining seven are potentially important for developing countries, too. By knowing these challenges and barriers in advance, those who implement IPE programs in developing countries will be much more prepared, and can enhance the program's potential success. PMID- 24809510 TI - An automated procedure for evaluating song imitation. AB - Songbirds have emerged as an excellent model system to understand the neural basis of vocal and motor learning. Like humans, songbirds learn to imitate the vocalizations of their parents or other conspecific "tutors." Young songbirds learn by comparing their own vocalizations to the memory of their tutor song, slowly improving until over the course of several weeks they can achieve an excellent imitation of the tutor. Because of the slow progression of vocal learning, and the large amounts of singing generated, automated algorithms for quantifying vocal imitation have become increasingly important for studying the mechanisms underlying this process. However, methodologies for quantifying song imitation are complicated by the highly variable songs of either juvenile birds or those that learn poorly because of experimental manipulations. Here we present a method for the evaluation of song imitation that incorporates two innovations: First, an automated procedure for selecting pupil song segments, and, second, a new algorithm, implemented in Matlab, for computing both song acoustic and sequence similarity. We tested our procedure using zebra finch song and determined a set of acoustic features for which the algorithm optimally differentiates between similar and non-similar songs. PMID- 24809511 TI - A lack of parasitic reduction in the obligate parasitic green alga Helicosporidium. AB - The evolution of an obligate parasitic lifestyle is often associated with genomic reduction, in particular with the loss of functions associated with increasing host-dependence. This is evident in many parasites, but perhaps the most extreme transitions are from free-living autotrophic algae to obligate parasites. The best-known examples of this are the apicomplexans such as Plasmodium, which evolved from algae with red secondary plastids. However, an analogous transition also took place independently in the Helicosporidia, where an obligate parasite of animals with an intracellular infection mechanism evolved from algae with green primary plastids. We characterised the nuclear genome of Helicosporidium to compare its transition to parasitism with that of apicomplexans. The Helicosporidium genome is small and compact, even by comparison with the relatively small genomes of the closely related green algae Chlorella and Coccomyxa, but at the functional level we find almost no evidence for reduction. Nearly all ancestral metabolic functions are retained, with the single major exception of photosynthesis, and even here reduction is not complete. The great majority of genes for light-harvesting complexes, photosystems, and pigment biosynthesis have been lost, but those for other photosynthesis-related functions, such as Calvin cycle, are retained. Rather than loss of whole function categories, the predominant reductive force in the Helicosporidium genome is a contraction of gene family complexity, but even here most losses affect families associated with genome maintenance and expression, not functions associated with host-dependence. Other gene families appear to have expanded in response to parasitism, in particular chitinases, including those predicted to digest the chitinous barriers of the insect host or remodel the cell wall of Helicosporidium. Overall, the Helicosporidium genome presents a fascinating picture of the early stages of a transition from free-living autotroph to parasitic heterotroph where host-independence has been unexpectedly preserved. PMID- 24809513 TI - [Interpretation of the diagnosis and assessment of acute pancreatitis: determinant-based the consensus of the revised Atlanta classification]. PMID- 24809512 TI - Exercise protects against chronic beta-adrenergic remodeling of the heart by activation of endothelial nitric oxide synthase. AB - Extensive data have shown that exercise training can provide cardio-protection against pathological cardiac hypertrophy. However, how long the heart can retain cardio-protective phenotype after the cessation of exercise is currently unknown. In this study, we investigated the time course of the loss of cardio-protection after cessation of exercise and the signaling molecules that are responsible for the possible sustained protection. Mice were made to run on a treadmill six times a week for 4 weeks and then rested for a period of 0, 1, 2 and 4 weeks followed by isoproterenol injection for 8 days. Morphological, echocardiographic and hemodynamic changes were measured, gene reactivation was determined by real-time PCR, and the expression and phosphorylation status of several cardio-protective signaling molecules were analyzed by Western-blot. HW/BW, HW/TL and LW/BW decreased significantly in exercise training (ER) mice. The less necrosis and lower fetal gene reactivation induced by isoproterenol injection were also found in ER mice. The echocardiographic and hemodynamic changes induced by beta adrenergic overload were also attenuated in ER mice. The protective effects can be sustained for at least 2 weeks after the cessation of the training. Western blot analysis showed that the alterations in the phosphorylation status of endothelial nitric oxide synthase (eNOS) (increase in serine 1177 and decrease in threonine 495) continued for 2 weeks after the cessation of the training whereas increases of the phosphorylation of Akt and mTOR disappeared. Further study showed that L-NG-Nitroarginine methyl ester (L-NAME) treatment abolished the cardio-protective effects of ER. Our findings demonstrate that stimulation of eNOS in mice through exercise training provides acute and sustained cardioprotection against cardiac hypertrophy. PMID- 24809514 TI - [Current status and prospects of risk models for heart valve surgery]. PMID- 24809515 TI - [Operative and long term results after diseased bowel resection for chronic radiation enteritis complicated with intestinal obstruction]. AB - OBJECTIVE: To report operative and long-term results after surgery for chronic radiation enteritis and to evaluate the therapeutic efficacy of surgery and investigate the risk factors of postoperative survival rate. METHODS: The 120 CRE patients performed with diseased bowel resection from June 2001 to March 2011 were analyzed retrospectively and followed up by telephone. There were 22 male and 98 female patients and their age were 23-82 years (median 52 years). Their demographic data, the cancer history, the characteristics of radiotherapy received (total dose, defined as the cumulative dose of external and endocavity radiation), the time interval between the first symptoms and the first surgical procedure, postoperative complications, length of residual small bowel, postoperative survival rate were recorded. Evaluate the therapeutic efficacy of surgery and investigate the risk factors of postoperative survival rate. RESULTS: The postoperative overall complications and the incidence of moderate to severe complications (Clavien-Dindo Grade III-V) were 61.7% and 33.3%, respectively. The postopertive mortality was 2.5%. The survival probabilities were 96%, 60% and 37% at 1-, 5- and 10-years, respectively. At the end of follow up, the mean of body mass index (BMI) increased compared with the BMI of preoperatiive ((17.6 +/- 3.0) kg/m(2) vs. (20.2 +/- 3.0) kg/m(2), t = 6.01, P < 0.01). The 93% of patients can stop PN and regain full oral diet after operation (chi(2) = 164.1, P < 0.01). On multivariate analysis, survival was significantly decreased with residual neoplastic disease (HR = 4.082, 95%CI: 1.318-12.648), an American Society of Anesthesiologists score>3 (HR = 3.495, 95%CI: 1.131-10.800) and an age of chronic radiation enteritis diagnosis >70 years (HR = 2.800, 95%CI: 0.853-9.189). CONCLUSIONS: The survival of patients with chronic radiation enteritis complicated with intestinal obstruction after intestinal resection was good and was mainly influenced by underlying comorbidities. Majority of the patients can stop PN and regain full oral diet after operation. PMID- 24809516 TI - [Postoperative pathological staging correlates the prognosis of rectal cancer after neoadjuvant chemoradiotherapy]. AB - OBJECTIVE: The present study assessed the pathological staging features of rectal cancer after neoadjuvant chemoradiotherapy, and its relation to prognosis. METHODS: Pathologic data related to TNM classification were analyzed on the surgical specimens of 135 patients with mid-low rectal cancer after neoadjuvant themoradiotherapy from 2005 to 2012. Tumor invasion, nodal status, local invasive factors (including cancer deposit, radial margin, perivascular or perineural invasion) were investigated with patients' 3-year disease-free survival (DFS). RESULTS: The overall 3-year DFS was 85.2%, with a pathological complete response (pCR) rate of 19.26%. Three out of 29 patients (10.4%) with ypT0 were found to have positive lymph nodes. There was a trend towards decreased survival as the ypT category and ypTNM staging increased (chi(2) = 14.296 and 52.643, P = 0.006 and 0.000). ypT0-T2 in T category and yp0-I in TNM staging showed a favorable survival above 92%, while the patients with ypT3, or ypIIIB had a comparable lower DFS of 70.2% and 46.7%. DFS in patients with negative lymph node were significantly improved than those with positive nodes (93.5% vs. 66.7%, chi(2) = 34.125, P = 0.000). Patients with or without local invasive factor significantly differed in DFS (42.9% vs. 90.1%, chi(2) = 32.666, P = 0.000) . Cox regression analyze showed that the nodal status (RR = 12.312, 95%CI: 2.828-39.258, P = 0.000) and local invasive factors (RR = 5.422, 95%CI: 1.202-8.493, P = 0.020) were independent risk factors to 3-year survival. As the concept of clinical complete response (cCR) is obscure, there were 27.6% of patients with ypT0 had normal mucosa or no evidence of tumor by EUS or MRI tests before surgery. CONCLUSION: Postoperative pathologic staging features were closely associated with patient's prognosis. The increasing of ypT or ypTNM staging was correlated to decreasing of DFS. Nodal status, positive radial margin, perivascular and perineural invasion were independent risk factors to DFS. Since cCR did not correlate and could not predict pCR, the ongoing radical surgery could not be avoided even there was no evidence of tumor existing before operation. PMID- 24809517 TI - [Predictors of local recurrence and survival in primary retroperitoneal leiomyosarcoma]. AB - OBJECTIVE: To investigate the predictors of local recurrence and survival in primary retroperitoneal leiomyosarcoma (PRLS). METHODS: A retrospective analysis was conducted on 46 cases of PRLS between August 2006 and April 2012. There were 9 male and 37 female patients, and they were 30-79 year old (median 49 year old). Kaplan-Meier estimations and Cox regression analyses were performed. RESULTS: The tumor size were 5-36 cm, and 29 cases (63.1%) of this group was more than 10 cm. Local 3- and 5-year control rates after complete resection were 47% and 30%. FNCLCC (Federation Nationale des Centres de Lutte Contre le Cancer) grading (RR = 3.10, 95%CI: 1.59-6.04), gender (RR = 5.30, 95%CI: 1.64-17.13) and blood loss (RR = 3.12, 95%CI: 1.28-7.60) were independent prognostic factor of local recurrence in multivariable analysis (P < 0.05). The 5-year disease-free survival rates after complete resection of PRLS was 26%; and the 5-year disease-specific survival (DSS) rates after complete resection was 48%. The median DSS was 60 months in negative margin of resection and 50 months in positive margin. However, by multivariate analysis, only FNCLCC grading was significant independent predictors of DSS (RR = 2.01, 95%CI: 1.16-3.49, P = 0.013). CONCLUSIONS: Gender, FNCLCC grading and blood loss were independent prognostic factor of local recurrence. The disease-specific survival in PRLS varied significantly according to FNCLCC grading. PMID- 24809518 TI - [Research of conjugated bile acids in gallbladder bile of patients with polypoid lesions of gallbladder]. AB - OBJECTIVE: To investigate the difference in conjugated bile acids in the gallbladder bile between gallbladder cholesterol polyps and adenomatous polyps patients, and screen the differential diagnosis-markers for polypoid lesions of gallbladder (PLG). METHODS: From January to June 2013, the 20 cholesterol polyps patients, 10 adenomatous polyps patients and 10 patients without gallbladder diseases were enrolled. High performance liquid chromatography assay with ultraviolet detection was used to test 8 conjugated bile acids in gallbladder bile. RESULTS: The 8 conjugated bile acids were completely analyzed in 10 minutes, and the assay was liner in the range 8-500 ug/ml. The correlation coeffients for linear regression was from 0.9996-0.9999 and the detection limits ranged from 3.90-7.81 ug/ml. The level of taurocholic acid (TCA) in adenomatous polyps group ((75 +/- 51) ug/ml) was significantly lower than that in the cholesterol polyps ((228 +/- 206) ug/ml, q = 3.120, P = 0.014) and control groups ((104 +/- 40) ug/ml, q = 2.950, P = 0.027). The level of taurochenodeoxycholic acid (TCDCA) in cholesterol polyps group ((604 +/- 444) ug/ml) was significantly higher than that in the adenomatous polyps ((310 +/- 182) ug/ml, q = 2.560, P = 0.048) and control groups ((308 +/- 21) ug/ml, q = 2.970, P = 0.023). CONCLUSIONS: The levels of TCA and TCDCA in the gallbladder biles in cholesterol polyps patients were higher than those in adenomatous polyps patients, which may be the differential diagnosis-markers for PLG. PMID- 24809519 TI - [Study on clinicopathological classification and clinical and pathological characteristics in breast cancer]. AB - OBJECTIVE: To explored the relationship of clinicopathological classification and clinical and pathological characteristics of breast cancer and analyze the value in treatment. METHODS: The patients with invasive breast carcinoma had been treated between January 2011 and December 2012. The breast cancer have been divided into luminal A, luminal B, HER2-positive and triple-negative subtypes according to criteria of St. Gallen International Expert Consensus report 2011. The Mann-Whitney test and Kruskal-Wallis test were used to analyze the relationships between four subtypes and TNM staging, histopathological grading. RESULTS: The 530 cases of invasive breast cancer patients were included in this study. The luminal A was 94 cases (17.7%), the luminal B was of 285 cases (53.8%), the HER2-positive was 59 cases (11.1%), and the triple-negative subtype was 92 cases (17.4%). In luminal B subtype, the HER2-positive was 56 (19.6%) and negative was 229 (80.4%). Most of luminal B was later in grade (71.7% of cases were more than II grade) and stage (66.7% were more than stage II). CONCLUSIONS: Clinical pathological classification is important in the individualized treatments of breast cancer, and the Luminal types (A+B) are more than 71.5% of all breast cancer patients, and they should be paid more attention to the endocrine therapy; Luminal B type accounted for 53.8% of all breast cancer and it needs further study to improve the precision of the diagnosis and treatment. PMID- 24809520 TI - [Applied rigid choledochoscope and pneumatic lithotripsy in targeting treatment of hepatolithiasis guided by three-dimensional visualization technology]. AB - OBJECTIVE: To study the value of rigid choledochoscope and pneumatic lithotripsy in targeting treatment of hepatolithiasis under the guidance of three-dimensional visualization technology. METHODS: The 26 patients with hepatolithiasis from February 2012 to June 2013 were analyzed. There were 11 male and 15 female patients with a median age of 55.2 years (range 31-75 years old). The image data of CT scanning of hepatolithiasis were introduced into medical image three dimensional visualization system (MI-3DVS) for three-dimensional reconstruction, 3D classifications of hepatolithiasis were obtained based on it. Applied rigid choledochoscope and pneumatic lithotripsy in targeting treatment of hepatolithiasis guided by three-dimensional visualization technology. RESULTS: The 26 patients (29 times) experienced targeting treatment of rigid choledochoscope and pneumatic lithotripsy under the guidance of three-dimensional visualization technology, including:19 cases (4 cases of type IIc) through percutaneous biliary tract sinus, laparoscopic surgery 3 cases, laparotomy 4 cases. Three patients underwent surgery twice. The final stone clearance rate was 100%.One case confirmed combined with cholangiocarcinoma and transfer to radical resection.Intraoperative blood loss was (41.7 +/- 8.5) ml, operating time was (100.8 +/- 7.6) minutes, and postoperative hospital stay was (7.0 +/- 0.6) days. A patient suffered postoperative biliary tract bleeding.Without bile duct injury, bleeding, bile leakage and other complications were occurred. CONCLUSION: Rigid choledochoscope and pneumatic lithotripsy in the treatment of hepatolithiasis under the guidance of three-dimensional visualization technology achieved digital minimally invasive treatment of hepatolithiasis, which can be a new approach to hepatobiliary surgery. PMID- 24809521 TI - [Correlation between the 4th lumbar degenerative spondylolisthesis and radiographic parameters]. AB - OBJECTIVE: To investigate the relationship between radiographic parameters and the 4th lumbar(L4) degenerative spondylolisthesis. METHODS: From April 2010 to April 2012, 60 patients with the L 4 degenerative spondylolisthesis (DLS) were enrolled in DLS group, 56 healthy volunteers were recruited in control group. A series of radiographic parameters were measured in the two groups, including disc height (DH), disc degeneration index(DDI), L4 vertebral inclination angle(L4-VA), pelvic incidence (PI), L4 vertebral size (L4-VS), lumbar lordosis angle (LLA), facet joint angulation (FJA) of cephalad and caudad portions, delta FJA of cephlad and caudad portions, asymmetry variation of FJA, bone mineral density(BMD). Student's test was used to compare difference of parameters between two groups. Multivariate logistic regression analysis was used to reveal risk factors of the development of DLS. RESULTS: Fifty-three cases of L4 spondylolisthesis in DLS group were classified into grade I, 7 cases of L4 spondylolisthesis were classified into grade II. The average Boxall index was 0.17 +/- 0.05. There were significant difference of DH, DDI, L4-VS, L4-VA, LLA, PI, FJA, BMD between DLS group and control group (t = 2.28-9.33, P = 0.021-0.043) . There were significant differences of delta FJA of cephlad and caudad portions in L3-4, L4-5 between DLS group and control group (t = 3.398 and 28.122, P = 0.000 and 0.039). There was no significant difference of asymmetry variation of FJA in L3-4, L4-5 between DLS group and control group (t = 0.209-0.465, P = 0.295 0.858). Multivariate logistic regression analysis showed that LDS was more frequent among patients with smaller L4-VS(OR = 1.01, 95%CI = 1.000-1.024, P = 0.048), larger L4-VA (OR = 1.88, 95%CI = 14.000-14.600, P = 0.037), larger LLA (OR = 1.90, 95%CI = 1.600-15.800, P = 0.040), larger PI (OR = 2.58, 95%CI = 18.000-19.600, P = 0.029) and the more sagittal FJA (OR = 2.46, 95%CI = 1.400 16.400, P = 0.035) than those in control group. CONCLUSIONS: DLS is signifantly correlated with L4-VS, L4-VA, LLA, PI, FJA . They may be risk factors of the development of DLS. PMID- 24809522 TI - [Surgical treatment of congenital heart diseases with tracheal stenosis]. AB - OBJECTIVE: To retrospectively analyze the experience of one-stage surgical correction for children with congenital heart diseases and tracheal stenosis and further to clear the principle of treatment for these patients. METHODS: From January 2006 to June 2013, 48 patients with congenital heart diseases and tracheal stenosis underwent surgical correction. There were 36 male and 12 female patients. The mean age at operation was (23 +/- 27)months (range: 3-72 months) and the mean weight was (12 +/- 8) kg (range: 3.4-46.0 kg). The underlying diagnoses were pulmonary sling in 33 patients, double aortic arch in 3, tetrology of Fallot in 6, ventricular septal defect in 4, double outlet right ventricle in 1, and pulmonary atresia in 1 patient. Among them, short tracheal stenosis was present in 15, long tracheal stenosis in 25 and bridging bronchus in 8 patients. Repairs with autogenous tracheal tissue were performed in 6, and end-to-end anastomosis in 11 and slide tracheoplasty in 31 patients. Two patients had granulation tissue growing in the airway postoperatively and were re-operated by autogenous rib tissue. All of patients were followed up after operation 1, 3, 6, 12 months and if the patient had symptoms that should be examined by bronchoscopy. The patients should be examined by CT post-operation one year. RESULTS: There were 7 deaths in all 48 cases and the early mortality was 14.6%. Two deaths were not related to tracheal stenosis, and other 5 were associated with long segment tracheal stenosis. Forty-one patients were followed for 2 months to 6 years, and no patients required re-operations. Clinical symptoms of tracheal stenosis disappeared and the results of CT scan were satisfied. CONCLUSIONS: One stage surgical repair of the patients with congenital heart diseases and tracheal stenosis have a good effect. Slide tracheoplasty is the effective surgical method for long segment tracheal stenosis. Postoperative granulation tissue growing in the airway is the leading cause of death. PMID- 24809523 TI - [Clinical research of aortic valve replacement in small aortic annulus]. AB - OBJECTIVE: To compare the effect aortic valve replacement(AVR) combined with aortic root enlargement and simple St.Jude Regent AVR in small aortic annulus patients. METHODS: From June 2008 to June 2012, 62 severe aortic valvular stenosis patients with small aortic annulus (annulus diameter of 15-21 mm) entered the study. Twenty-seven cases received AVR combined with aortic root enlargement (enlargement group) and 35 cases received simple St.Jude Regent AVR(non-enlargement group), 17 mm St.Jude Regent in 15 cases(17 mm group) and 19 mm in 20 cases (19 mm group). Aortic root enlargement techniques included Nicks in 2, modified Nicks in 6 cases, modified Manouguian in 19 cases. Patients were followed up and received ultrasonic cardiogram (UCG) 3, 12 months postoperatively and t-test was used for statistical comparison. RESULTS: In enlargement group, 1 Nicks patient received reoperation due to aortic root hemorrhage, and died of mediastinal infection, 1 Manouguian patient received permanent pacemaker. In non enlargement group, low cardiac output syndrome in 1 case. Three months and 12 months postoperative UCG showed, comparing to preoperation, effective orifice area (EOAI) increased significantly, postoperative transvalular pressure gradient and flow rate decreased significantly in each group (P = 0.000). Left ventricular diastolic diameter (LVDd) decreased significantly in both enlargement group and 19 mm group(P = 0.000), but no significant change in 17 mm group (P > 0.05). In non-enlargement group, 19 mm compared to 17 mm group, 3 months and 12 months postoperative EOAI increased significantly, pressure gradient, flow rate and LVDd decreased significantly(t = 2.449-12.291, P = 0.000-0.029). Comparing to enlargement group, there were significant differences in EOAI, pressure gradient, flow rate and LVDd in 17 mm group (t = 2.278-17.860, P = 0.000-0.028), but no significant differences in 19 mm group(t = 0.118-1.630, P = 0.110-0.907). CONCLUSIONS: For small aortic annulus AVR patient, 19 mm and larger St.Jude Regent prosthetic valves may produce satisfied hemodynamic, otherwise, aortic root enlargement is recommended. PMID- 24809524 TI - [Comparation of the transperitoneal and extraperitoneal laparoscopic radical prostatectomy]. AB - OBJECTIVE: To compare the transperitoneal laparoscopic radical prostatectomy procedures with extraperitoneal laparoscopic radical prostatectomy procedures to assess for differences in outcomes and complications. METHODS: A retrospective review 190 patients who had received laparoscopic radical prostatectomy for prostate cancer from June 2002 to January 2013. The results were compared between 116 transperitoneal laparoscopic radical prostatectomy procedures and 74 extraperitoneal laparoscopic radical prostatectomy procedures. RESULTS: The cohorts were similar in terms of mean patient age, height, weight, body mass index, Gleason score from biopsy, and clinical stage. Patients receiced extraperitoneal laparoscopic radical prostatectomy had shorter operation time (146 minutes vs. 224 minutes, Z = -7.220, P = 0.000), less postoperative drainage time (3 days vs. 7 days, Z = -7.115, P = 0.000) and shorter postoperative length of hospital stay (5 days vs. 10 days, Z = -7.250, P = 0.000) than patients receiced transperitoneal procedures. However, the Gleason score, pathological stage, positive margin rate, intraoperative and early postoperative complications has no differences between the 2 groups (P > 0.05). CONCLUSIONS: The patients who received extraperitoneal laparoscopic radical prostatectomy had shorter operative time and revovered faster recovery and the effect of surgery was similar. PMID- 24809525 TI - [Significance of the R.E.N. A.L. nephrometry scoring system in renal tumour of T1 stage]. AB - OBJECTIVE: To evaluate the application value of R.E.N. A.L. nephrometry score for surgery type decisions of T1 stage renal tumor. METHODS: Clinical data including image data, surgery type and prognosis etc were collected retrospectively for 122 cases from January 2010 to December 2012. There were 76 male and 46 female patients and they were 29-82 years (mean 51 years). The body mass index was (22.8 +/- 3.9) kg/m(2). The patients were undergoing surgical excision with renal tumor of T1 stage. The R.E.N. A.L. nephrometry score was analyzed to evaluate their relationships to surgery type (RN or NSS) and the approach of NSS (ONSS or LNSS) using chi-square tests, Fisher's exact tests, and logistic regressions analysis. RESULTS: All surgery had been completed. The surgery included RN of 45 patients, LNSS of 45 patients and ONSS of 32 patients. The R.E.N. A.L. nephrometry score was significantly associated with the type of surgery (chi(2) = 27.89, P < 0.05), and the NSS approach (chi(2) = 12.87, P < 0.05). When the scores less than 7 points, it is majorly treated by nephron sparing surgery (92.9%), and when the scores more than 9 points, it is majorly treated by radical nephrectomy (69.4%). Individual component scores were analyzed to evaluate that they were all related to surgery type (chi(2) = 7.00-14.57, P < 0.05), and the individual component N associated the surgery type mostly. Furthermore, individual component R,E,N and L were statistically significant predictors of the NSS approach (chi(2) = 4.92 15.07, P < 0.05). CONCLUSION: The R.E.N. A.L. nephrometry scoring system provides a simple, useful, and stable system to character the salient renal anatomy of T1 stage, and can provide the best surgery approach. PMID- 24809526 TI - Factors associated with post-intensive care unit adverse events: a clinical validation study. AB - BACKGROUND: Many patients discharged from intensive care units (ICU) have complex care needs, placing them at risk of an adverse event in a ward environment. Currently, there is limited understanding of factors associated with these events in the post-intensive care population. A recent study explored intensive care liaison nurses' opinions on factors associated with these events; 25 factors were identified, highlighting the multifaceted nature of post-intensive care adverse events. AIM: This study aimed to clinically validate 25 factors intensive care liaison nurses believe are associated with post-intensive care adverse events, to determine the factors' relevance and importance to clinical practice. DESIGN: Prospective, clinical validation study. METHOD: Data were prospectively collected on a convenience sample of 52 patients at 4 tertiary referral hospitals in an Australian capital city. All patients had experienced an adverse event after intensive care discharge. RESULTS: Each of the 25 factors contributed to adverse events in at least 6 patients. The factors associated with the most adverse events were those that related to the patient such as illness severity and co morbidities. CONCLUSION: Clinical care and research should focus on modifiable factors in care processes to reduce the risk of future adverse events in post intensive care patients. RELEVANCE TO CLINICAL PRACTICE: Many patients are at risk of post-ICU adverse events due to the contribution of non-modifiable factors. However, by focusing on modifiable factors in care processes, the risk of post-ICU adverse events may be reduced. PMID- 24809527 TI - Non steroidal anti-inflammatory drug induced damage on lower gastro-intestinal tract: is there an involvement of microbiota? AB - Intestinal microbiota is composed by a community of microorganisms, which regulate intestinal functions and affect the global health. It is presumable that the well-known intestinal damages induced by Non Steroidal Antiinflammatory Drugs (NSAIDs) mirror on the homeostasis of microbiota, as confirmed by studies investigating this aspect. This review reports the evolving knowledge in this field taking into account both intestinal damage and microbiota involvement. In addition, we analyze a recent study reporting how NSAIDs change intestinal bacterial composition and, on this basis, hypothesize further possible interactions. Indeed, NSAIDs are responsible for a marked reduction of Lactobacilli, which act in the maintenance of luminal pH, mucosal permeability, enterocyte adhesion, mucus production, and immune system modulation. Moreover, Bifidobacteria are involved in the modulation of intestinal motility and local immunity and the demonstrated dangerous effect of NSAIDs could operate through an interference with these functions. A participation of microbiota in mesalazine and salycilate prevention of intestinal cancer may be supposed through their ability to stimulate bacterial production of molecules interfering with cell cycle on the basis of scanty available data. Finally, a supplementation with probiotics in chronic users of NSAIDs may help microbiota remodeling in a damaged intestine, but the poor current knowledge does not allow setting a clear indication for their use despite few evidences of a beneficial effect. In conclusion, it is presumable that the multiple effects of NSAIDs on the lower gastro-intestinal tract may involve microbiota alterations and this consideration suggests further investigations. PMID- 24809528 TI - Cognitive deficits in patients with trigeminal neuralgia: opportunities to improve care and quality of life. PMID- 24809529 TI - Intraoperative indocyanine green angiography during microvascular decompression surgery: report of 30 cases. AB - BACKGROUND: The purpose of this study was to evaluate the use of intraoperative indocyanine green (ICG) angiography during microvascular decompression (MVD) surgery. METHODS: The surgical outcomes of 19 patients with hemifacial spasm, nine patients with trigeminal neuralgia, and two patients with glossopharyngeal neuralgia who were treated with MVD surgery, using the posterior approach and routine craniotomy, via procedures in which ICG angiography was used were analyzed retrospectively. RESULTS: ICG angiography clearly displayed the nerves and blood vessels. Among the 30 patients, 25 were cured, four showed improvements, and one had a worsened outcome. There were no significant complications. Outcome was not associated with age, gender, or diagnosis. CONCLUSION: Intraoperative ICG angiography used during MVD surgery provided a clear display of the nerves and arteries. All but one patient was cured or had improvement. The findings suggest that intraoperative ICG angiography may be an effective supplemental technique for use during MVD surgery. PMID- 24809530 TI - Suboptimal interventional conditions for the occlusion of ruptured intracranial aneurysms do not increase periprocedural complications and poor clinical outcomes. AB - BACKGROUND AND OBJECTIVE: Occluding a ruptured intracranial aneurysm as early as possible may entail certain periprocedural conditions that compromise the outcome. The aim of the present study was to evaluate the effectiveness, safety, and clinical outcome of endovascular coiling procedures performed on an emergency basis under potentially suboptimal conditions, and to compare results with those from scheduled procedures under potentially optimal conditions. METHODS: Interventions performed on 66 SAH patients were retrospectively analysed by classifying them into two groups: under emergency (within three hours from diagnosis or during non-standard working hours) or scheduled conditions. A binary logistic regression analysis was also performed to identify characteristics associated with poor outcomes. RESULTS: No differences in effectiveness, periprocedural complications, or clinical outcomes were found between the two groups. Rebleeding was detected in 4.8 % of the emergency interventions and 2.2 % of the scheduled interventions. Multivariate analysis identified age and Hunt and Hess grade, but no conditions of treatment, as the factors associated to poor outcome. CONCLUSION: Suboptimal interventional conditions for occluding ruptured intracranial aneurysms, such as performing procedures outside of standard working hours or within three hours of diagnosis, do not result in increased periprocedural complications and poor clinical outcomes compared with scheduled procedures under potentially optimal conditions. These results suggest the need for treatment to be provided as soon as possible. PMID- 24809531 TI - Avoidance of postoperative epistaxis and anosmia in endonasal endoscopic skull base surgery: a technical note. AB - BACKGROUND: Most endoscopic transsphenoidal approaches jeopardize the sphenopalatine artery and septal olfactory strip (SOS), increasing the risk of postoperative anosmia and epistaxis while precluding the ability to raise pedicled nasoseptal flaps (NSF). We describe a bilateral "rescue flap" technique that preserves the mucosa containing the nasal-septal vascular pedicles and the SOS. This approach can reduce the risk of postoperative complications, including epistaxis and anosmia. METHODS: A retrospective analysis was conducted of all patients who underwent endoscopic transsphenoidal surgery with preservation of both sphenopalatine vascular pedicles and SOS. In a recent subset of patients, olfactory assessment was performed. RESULTS: Of 174 consecutive operations performed in 161 patients, bilateral preservation of the sphenopalatine vascular pedicle and SOS was achieved in 139 (80 %) operations, including 31 (22 %) with prior transsphenoidal surgery. Of the remaining 35 operations, 18 had a planned formal NSF and 17 had prior surgery or extensive lesions precluding use of this technique. Of pituitary adenomas, RCCs or sellar arachnoid cysts, 118 (94 %) underwent this approach, including 91 % of patients who had prior surgery. Preoperative olfaction function was maintained in 97 % of patients that were tested. None of the patients had postoperative arterial epistaxis. CONCLUSION: Preservation of bilateral sphenopalatine vascular pedicles and the SOS is feasible in over 90 % of patients undergoing endonasal endoscopic surgery for pituitary adenomas and RCCs. This approach, while not hindering exposure or limiting instrument maneuverability, preserves the nasoseptal vasculature for future NSF use if needed and appears to minimize the risks of postoperative arterial epistaxis and anosmia. PMID- 24809532 TI - The ventricular system and choroid plexus as a primary site for renal cell carcinoma metastasis. AB - BACKGROUND: Brain metastases (BM) are the most common intracranial tumours amongst adults. Ten to 40 % of patients with cancer will develop BM. In this study, we observed a high affinity of renal cell carcinoma (RCC) to the ventricular system, with close association to the choroid plexus. METHODS: This is a retrospective study evaluating data of our prospectively maintained brain tumour database, focusing on consecutive BM patients, who were treated at our center between March 2003 and December 2011. Data collected included primary pathologies, anatomical distribution of the brain metastasis according to neuroimaging, and treatment modalities. RESULTS: We identified 614 patients with BM, of whom 24 (3.9 %) were diagnosed with RCC, harboring 33 lesions. Nine of the 24 patients (37.5 %) presented with an intraventricular location (10 of 33 RCC BM lesions). Of the remaining 590 patients with non-RCC pathologies, five patients (0.8 %) were diagnosed with intraventricular lesions (p < 0.0001). CONCLUSION: In this unselected, consecutive treated BM patient cohort we observed a high affinity of RCC BM to the ventricular system with close association to the choroid plexus. The reason for this affinity is unknown. Surgical approaches for resection of these lesions should be planned to include early control on the vascular supply from the choroidal vessels. PMID- 24809533 TI - Specific polyphenols and tannins are associated with defense against insect herbivores in the tropical oak Quercus oleoides. AB - The role of plant polyphenols as defenses against insect herbivores is controversial. We combined correlative field studies across three geographic regions (Northern Mexico, Southern Mexico, and Costa Rica) with induction experiments under controlled conditions to search for candidate compounds that might play a defensive role in the foliage of the tropical oak, Quercus oleoides. We quantified leaf damage caused by four herbivore guilds (chewers, skeletonizers, leaf miners, and gall forming insects) and analyzed the content of 18 polyphenols (including hydrolyzable tannins, flavan-3-ols, and flavonol glycosides) in the same set of leaves using high performance liquid chromatography and mass spectrometry. Foliar damage ranged from two to eight percent per region, and nearly 90% of all the damage was caused by chewing herbivores. Damage due to chewing herbivores was positively correlated with acutissimin B, catechin, and catechin dimer, and damage by mining herbivores was positively correlated with mongolinin A. By contrast, gall presence was negatively correlated with vescalagin and acutissimin B. By using redundancy analysis, we searched for the combinations of polyphenols that were associated to natural herbivory: the combination of mongolinin A and acutissimin B had the highest association to herbivory. In a common garden experiment with oak saplings, artificial damage increased the content of acutissimin B, mongolinin A, and vescalagin, whereas the content of catechin decreased. Specific polyphenols, either individually or in combination, rather than total polyphenols, were associated with standing leaf damage in this tropical oak. Future studies aimed at understanding the ecological role of polyphenols can use similar correlative studies to identify candidate compounds that could be used individually and in biologically meaningful combinations in tests with herbivores and pathogens. PMID- 24809534 TI - Extrahepatic autoimmune conditions associated with primary biliary cirrhosis. AB - There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8 +/- 6.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991 2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p = 0.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival. PMID- 24809535 TI - The role of the microenvironment in human immunodeficiency virus-associated classical Hodgkin lymphoma. AB - AIMS: To characterize the microenvironment of classical Hodgkin lymphoma (cHL) in people living with human immunodeficiency virus (PLWH). The objective was to identify and then quantify the immune cells present in the microenvironment. METHODS AND RESULTS: Ten samples of cHL from PLWH were compared with 10 samples of cHL from the general population using tissue microarray technology and immunohistochemistry. Sections were immunostained with antibodies for CD30, CD3, CD4, CD8, CD20, CD68R, CD56, CD57, CD123, FoxP3 and granzyme B. A statistically significant reduction of CD4(+) T cells, CD56(+) cells, CD57(+) cells, CD123(+) cells and B cells and an increase in numbers in FoxP3(+) CD8(+) cells was observed in cHL diagnosed in PLWH. No significant differences were seen in the number of CD8(+) T cells, CD4(+) FoxP3(+) T cells and macrophages. CONCLUSION: There are considerable differences in the microenvironment of cHL occurring with and without HIV. PMID- 24809536 TI - Syntheses, structures and properties of 5-azotetrazolyl salicylic acid and its dilanthanide complexes. AB - Two hydrated 5-azotetrazolyl salicylic acid (H3ASA) of [(H3ASA).H2O] (1) and [(H3ASA).4H2O] (2) and five H3ASA based dinuclear Ln(3+) complexes of {[Ln2(H1.5ASA)4(H2O)8].6H2O} [Ln = Dy (3), Tb(4)], {[Gd2(H1.5ASA)4 (H2O)8].5H2O} (5), {[Sm2(H1.5ASA)4(H2O)8].6H2O} (6) and {[Eu4(H1.5ASA)8(H2O)18].10H2O} (7) have been synthesized and characterized by single crystal X-ray diffraction analysis. In 1 and 2, the neutral H3ASA molecules show a trans-enol-E isomer but display two different dihedral angles. Complexes 3-7 exhibit three types of dinuclear structures in which the anionic ligands show two trans-enol-E/Z isomers. The photochromic and photoluminescent properties of 1, 3-7 and the magnetic properties for 3-7 were investigated. PMID- 24809537 TI - Non-linear analysis indicates chaotic dynamics and reduced resilience in model based Daphnia populations exposed to environmental stress. AB - In this study we present evidence that anthropogenic stressors can reduce the resilience of age-structured populations. Enhancement of disturbance in a model based Daphnia population lead to a repression of chaotic population dynamics at the same time increasing the degree of synchrony between the population's age classes. Based on the theory of chaos-mediated survival an increased risk of extinction was revealed for this population exposed to high concentrations of a chemical stressor. The Lyapunov coefficient was supposed to be a useful indicator to detect disturbance thresholds leading to alterations in population dynamics. One possible explanation could be a discrete change in attractor orientation due to external disturbance. The statistical analysis of Lyapunov coefficient distribution is proposed as a methodology to test for significant non-linear effects of general disturbance on populations. Although many new questions arose, this study forms a theoretical basis for a dynamical definition of population recovery. PMID- 24809538 TI - Influence of light intensity on surface free energy and dentin bond strength of core build-up resins. AB - OBJECTIVE: We examined the influence of light intensity on surface free energy characteristics and dentin bond strength of dual-cure direct core build-up resin systems. METHODS: Two commercially available dual-cure direct core build-up resin systems, Clearfil DC Core Automix with Clearfil Bond SE One and UniFil Core EM with Self-Etching Bond, were studied. Bovine mandibular incisors were mounted in acrylic resin and the facial dentin surfaces were wet ground on 600-grit silicon carbide paper. Adhesives were applied to dentin surfaces and cured with light intensities of 0 (no irradiation), 200, 400, and 600 mW/cm(2). The surface free energy of the adhesives (five samples per group) was determined by measuring the contact angles of three test liquids placed on the cured adhesives. To determine the strength of the dentin bond, the core build-up resin pastes were condensed into the mold on the adhesive-treated dentin surfaces according to the methods described for the surface free energy measurement. The resin pastes were cured with the same light intensities as those used for the adhesives. Ten specimens per group were stored in water maintained at 37 degrees C for 24 hours, after which they were shear tested at a crosshead speed of 1.0 mm/minute in a universal testing machine. Two-way analysis of variance (ANOVA) and a Tukey-Kramer test were performed, with the significance level set at 0.05. RESULTS: The surface free energies of the adhesive-treated dentin surfaces decreased with an increase in the light intensity of the curing unit. Two-way ANOVA revealed that the type of core build-up system and the light intensity significantly influence the bond strength, although there was no significant interaction between the two factors. The highest bond strengths were achieved when the resin pastes were cured with the strongest light intensity for all the core build-up systems. When polymerized with a light intensity of 200 mW/cm(2) or less, significantly lower bond strengths were observed. CONClUSIONS: The data suggest that the dentin bond strength of core build-up systems are still affected by the light intensity of the curing unit, which is based on the surface free energy of the adhesives. On the basis of the results and limitations of the test conditions used in this study, it appears that a light intensity of >400 mW/cm(2) may be required for achieving the optimal dentin bond strength. PMID- 24809539 TI - Seven-year clinical performance of resin composite versus resin-modified glass ionomer restorations in noncarious cervical lesions. AB - PURPOSE: The purpose of this study was to comparatively assess the seven-year clinical performance of a one-bottle etch-and-rinse adhesive with resin composite (RC) and resin-modified glass ionomer (RMGI) restorations in noncarious cervical lesions. METHODS AND MATERIALS: One operator placed 70 restorations (35 restorations in each group) in 30 patients under rubber dam isolation without mechanical preparation. The restorations were directly assessed by two independent examiners, using modified US Public Health Service criteria at baseline and 6, 12, 24, 60, and 84 months. The obtained data were tabulated and statistically analyzed using the Fisher and McNemar tests. A difference was significant if p<0.05. RESULTS: Twenty patients were available for recall after seven years (66.6%), and 25 RC and 26 RMGI restorations out of 70 restorations were evaluated. Excellent agreement was registered for all criteria between examiners (kappa>=0.85). Alfa and bravo scores were classified as clinically acceptable. The McNemar test detected significant differences within RC restorations between baseline and seven-year evaluations for anatomic form, marginal integrity, and retention (p<0.05). For RMGI restorations, a significant difference was identified for marginal integrity (p<0.05). As to material comparison, the Fisher exact showed a better retention performance for RMGI restorations than for RC restorations (p<0.05). Twelve composite restorations were dislodged (52.0% retention) and three ionomer restorations were lost (88.5% retention). The cumulative success rate for RC and RMGI was 30% and 58.1%, respectively. CONCLUSIONS: After seven years of service, the clinical performance of RMGI restorations was superior to that of the adhesive system/resin composite restorations in this study. PMID- 24809541 TI - Effects of heat treating silane and different etching techniques on glass fiber post push-out bond strength. AB - The aims of this study were to compare two pretreatment methods of a fiber post and to evaluate the effect of heat treatment to applied silane on the push-out bond strength for different levels of root. In this in vitro study, 40 glass fiber posts were divided into five groups (n=8) according to the kind of surface treatment applied. They were then inserted into extracted and endodontically treated human canines using a self-etch resin cement (Panavia F2.0, Kuraray, Japan). Group HF+S = hydrofluoric acid (HF) etching and silane (S) application; group HF+S+WP = HF etching and heat-treated silane application and warmed posts (WP); group H2O2+S = hydrogen peroxide etching and silane application; group H2O2+S+WP = hydrogen peroxide and heat-treated-silane application and warmed post; and group C, the control group, received no pretreatment. After completion of thermal cycling (1000 cycles, 5-55 degrees C), all specimens were cut horizontally to obtain three sections. Each section was subjected to a push-out test, and the test results were analyzed using two-way analysis of variance, post hoc Tukey honestly significant difference test, and a paired sample t-test (alpha=0.05). It was found that bond strength was not statistically influenced by the kind of etching material used (p=0.224), but was significantly affected by heat treatment of applied silane (p<0.001). The interaction between these two factors was not statistically significant (p=0.142). Group HF+S+WP showed the highest bond strength (12.56+/-1.73 MPa) (p<0.05). Scanning electron microscopy revealed the effect of the different treatments on the surface characteristics of posts. In the four pretreated groups, the bond strength decreased significantly from the coronal to the apical root canal sections (p<=0.05). The results of this study show that the use of heat-treated silane significantly enhances the push out bond strength of the fiber posts to root. HF acid etching with heat-treated silane application led to the highest bond strength. PMID- 24809540 TI - Patient age and dentists' decisions about occlusal caries treatment thresholds. AB - OBJECTIVES: This study was performed to 1) quantify dentists' treatment thresholds for occlusal primary caries; 2) determine if the patient's age affects dentists' decisions to surgically treat these carious lesions; and 3) test the hypothesis that patients', dentists', and practices' characteristics are significantly associated with surgical enamel intervention. METHODS: The study used a cross-sectional design consisting of a questionnaire survey in Japan. This study queried dentists working in outpatient dental practices who were affiliated with the Dental Practice-Based Research Network Japan (JDPBRN), which aims to allow dentists to investigate research questions and share experiences and expertise (n=282). Participants were asked whether they would surgically intervene in a series of cases depicting occlusal caries. Each case included a photograph of an occlusal surface displaying typical characteristics of caries penetration and written descriptions of adult and pediatric patients at high caries risk. RESULTS: In a case of a carious lesion within inner enamel, the proportion of dentists who indicated surgical intervention was significantly higher in adult patients (48%) when compared with pediatric patients (34%; p<0.01). Logistic regression analysis showed that using a dental explorer for the diagnosis of primary occlusal caries, type of practice, practice busyness, and percentage of patients who self-pay were significantly associated with dentists' decisions to intervene surgically into the inner enamel carious lesion. CONCLUSIONS: These findings demonstrate that more than one-third of participants chose to intervene surgically into inner enamel carious lesions, and patients' age affects dentists' decisions about when to intervene surgically (clinicaltrials.gov registration number NCT01680848). PMID- 24809542 TI - Evaluation of tensile retention of Y-TZP crowns after long-term aging: effect of the core substrate and crown surface conditioning. AB - This study evaluated the effect of the core substrate type (dentin and composite resin) on the retention of crowns made of yttrium oxide stabilized tetragonal zirconia polycrystal (Y-TZP), submitted to three inner surface conditionings. For this purpose, 72 freshly extracted molars were embedded in acrylic resin, perpendicular to the long axis, and prepared for full crowns: 36 specimens had crown preparations in dentin; the remaining 36 teeth had the crowns removed, and crown preparations were reconstructed with composite resin plus fiber posts with dimensions identical to the prepared dentin. The preparations were impressed using addition silicone, and 72 Y-TZP copings for the tensile test were produced. Cementation was performed with a dual-cured cement containing phosphate monomers. For cementation, the crown preparation (dentin or resin) was conditioned with the adhesive system, and the ceramic was subjected to one of three surface treatments: isopropyl alcohol, tribochemical silica coating, or thin low-fusing glassy porcelain layer application plus silanization. After 24 hours, all specimens were submitted to thermocycling (6000 cycles) and placed in a special tensile testing device in a universal testing machine to determine failure loads. The failure modes of all samples were analyzed under a stereomicroscope. Two-way analysis of variance showed that the surface treatment and substrate type (alpha=0.05) affected the tensile retention results. The dentin substrate presented the highest tensile retention values, regardless of the surface treatment. When the substrate was resin, the tribochemical silica coating and low fusing glaze application plus silanization groups showed the higher retention values. PMID- 24809544 TI - Long-term decoding stability of local field potentials from silicon arrays in primate motor cortex during a 2D center out task. AB - OBJECTIVE: Many serious concerns exist in the long-term stability of brain machine interfaces (BMIs) based on spike signals (single unit activity, SUA; multi unit activity, MUA). Some studies showed local field potentials (LFPs) could offer a stable decoding performance. However, the decoding stability of LFPs was examined only when high quality spike signals were recorded. Here we aim to examine the long-term decoding stability of LFPs over a larger time scale when the quality of spike signals was from good to poor or even no spike was recorded. APPROACH: Neural signals were collected from motor cortex of three monkeys via silicon arrays over 230, 290 and 690 days post-implantation when they performed 2D center out task. To compare long-term stability between LFPs and spike signals, we examined them in neural signals characteristics, directional tuning properties and offline decoding performance, respectively. MAIN RESULTS: We observed slow decreasing trends in the number of LFP channels recorded and mean LFP power in different frequency bands when spike signals quality decayed over time. The number of significantly directional tuning LFP channels decreased more slowly than that of tuning SUA and MUA. The variable preferred directions for the same signal features across sessions indicated non-stationarity of neural activity. We also found that LFPs achieved better decoding performance than SUA and MUA in retrained decoder when the quality of spike signals seriously decayed. Especially, when no spike was recorded in one monkey after 671 days post implantation, LFPs still provided some kinematic information. In addition, LFPs outperformed MUA in long-term decoding stability in a static decoder. SIGNIFICANCE: Our results suggested that LFPs were more durable and could provide better decoding performance when spike signals quality seriously decayed. It might be due to their resistance to recording degradation and their high redundancy among channels. PMID- 24809543 TI - Brain remodelling following endothelin-1 induced stroke in conscious rats. AB - The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76-77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis. PMID- 24809545 TI - Chronic non-communicable diseases. PMID- 24809546 TI - Medical emergencies: essential piece of kit. PMID- 24809547 TI - Oral surgery: ARONJ masterclass. PMID- 24809548 TI - Pharmacology: prolonged meds use. PMID- 24809549 TI - Erroneous abscess. PMID- 24809550 TI - Draft oral health guidance published. PMID- 24809551 TI - A patient's view: third molar surgery. PMID- 24809553 TI - Dental art: dentistry through art. Part 5. PMID- 24809556 TI - A dentist's life: I am known as Dr Hitman. PMID- 24809562 TI - Pandas love sweeties too. PMID- 24809563 TI - Professionalism, then and now. AB - For centuries only three professions were recognised as such: medicine, law and theology. Now that the word 'professional' is applied to all occupations it can be difficult to understand the meaning of professionalism within dentistry and healthcare. We simply cannot treat dentistry as a commodity or business when it is a highly specialised personal service. Now more than ever, dentistry is a team game and all dental professionals must maintain the values and codes that distinguish what we do from most other vocations. PMID- 24809564 TI - Minimal intervention dentistry II: part 6. Microscope and microsurgical techniques in periodontics. AB - Different aspects of treatment for periodontal diseases or gingival problems require rigorous diagnostics. Magnification tools and microsurgical instruments, combined with minimally invasive techniques can provide the best solutions in such cases. Relevance of treatments, duration of healing, reduction of pain and post-operative scarring have the potential to be improved for patients through such techniques. This article presents an overview of the use of microscopy in periodontics, still in the early stages of development. PMID- 24809565 TI - Clinical guide to periodontology: reconstructive periodontal treatment. AB - Regeneration of the lost tissues of the periodontium is an ideal therapeutic goal and has been the subject of much research and ingenious clinical techniques. Reconstructive or regenerative techniques are used either singly or in combination for three main purposes: (1) to regain lost periodontal ligament attachment, (2) to provide a wider zone of attached gingiva, and (3) to cover previously exposed root surfaces. PMID- 24809566 TI - Onychophagia and subgingival foreign body embedment: a case report. AB - This paper describes a case of subgingival foreign body embedment in the form of a finger nail fragment, as a consequence of onychophagia (fingernail biting). The result was periodontal infection that was concurrent with apical pathology on an adjacent non-vital tooth. This finding complicated the diagnosis and management of this case. Although foreign body impactions are relatively rare, they should be considered in a differential diagnosis, especially when the clinician is presented with an unusual clinical picture. PMID- 24809571 TI - Summary of: dental triage Hydebank Wood Prison and young offenders centre, Belfast. AB - OBJECTIVE: The aim of this study was to devise and test a triage protocol to prioritise patients' dental needs in a prison environment. Secondary aims were to include in the triage process oral health promotion and information about accessing prison dental services. Also to work collaboratively with the prison staff to improve referrals to the dental services. METHOD: The triage system was devised to have three strands: (1) an oral health assessment conducted by the dental nurse during the induction process for each new prisoner; (2) a simple oral health examination conducted in monthly screening clinics; (3) the prioritisation of referrals from prison landing staff using the prisons computer system PRISM. The triage was evaluated by assessing the first 100 patients' records with regard to the prioritisation of the triage category at the time of the clinical dental examination. RESULTS: Of the 100 patients triaged 95% were prioritised into the correct triage category. Seventy-two percent of patients were seen in the appropriate timeframe. Referral patterns from prison landing staff were improved along with interdisciplinary working in the prison. All new prisoners were seen within 72 hours of committal and received oral health advice and information on accessing dental services. CONCLUSION: This is the first triage system to be introduced into Hydebank Wood Prison, facilitating a targeted approach to dental care. It has improved access to the prison dental services; introduced oral health advice and information into the regular prison healthcare structure; and improved the efficiency of the clinical dental sessions. It is hoped to strategically address problems with waiting times and inequity in service utilisation. PMID- 24809572 TI - Summary of: continuing development of an oral health score for clinical audit. AB - AIM: To compare the outcomes of a contemporary oral health status (OHS) scoring system with national oral health data from the 2009 Adult Dental Health Survey, and to explore the utility of the OHS in audit and service development. METHODS: An OHS scoring system was developed as part of a previously reported comprehensive on-line patient assessment tool. The assessment tool also measured future disease risk and indicative capitation fee grading. The modified OHS score component was developed over 20 years of research and experience from the original Oral Health Index (Burke and Wilson 1995). The online tool was piloted by 25 volunteer dentists on 640 recall patients and qualitative and quantitative feedback provided. Anonymised data from the inputs and scores generated were collected centrally and analysed using descriptive statistics. RESULTS: The modified OHS was reported to have good validity by the pilot group. Submitted data confirmed a mean age for the recall patients examined as 53 +/- 15.8 years and an average oral health status score of 79.5 +/- 10.8 where a score of 100 equates to perfect oral health. A breakdown of the scores into the eight principal components provided evidence of cross validation with the Adult Dental Health Survey (2009). CONCLUSIONS: Scoring oral health status electronically offers valuable opportunities for clinical audit. The reported benchmark oral health score of 79.5 for recall patients can be updated as increased numbers of patients enter the centralised data recording system. Audit can be facilitated by this move from a paper-based system to an on-line tool with central data collection. PMID- 24809573 TI - Dental indicators of ancient dietary patterns: dental analysis in archaeology. AB - What can the study of ancient teeth tell us about the dietary habits of our ancestors? Diet plays a prominent role in the organisation and evolution of human cultures and an increasingly diverse array of analytical techniques are available to help reconstruct diet in ancient populations. Dental palaeopathology is particularly important as it can provide direct evidence of the type of diet an individual consumed during life. Heavy occlusal tooth wear is the most frequent condition recognisable and an examination of both macro and microscopic patterns of wear can establish the differences between the hard fibrous diet typical of a hunter-gatherer, and a diet primarily consisting of softer plant foods consumed by an agriculturist. The distributions of trace elements and stable isotopes in food webs make it possible to use them as natural tracers of foodstuffs. Through a consideration of photosynthetic pathways, the ratios of the different stable isotopes of carbon and nitrogen can determine which specific groups of plants and animals were dominant in the food chains of various populations - a fact that has been used to trace the spread of agriculture in ancient civilisations. PMID- 24809588 TI - Dental triage Hydebank Wood Prison and young offenders centre, Belfast. AB - OBJECTIVE: The aim of this study was to devise and test a triage protocol to prioritise patients' dental needs in a prison environment. Secondary aims were to include in the triage process oral health promotion and information about accessing prison dental services. Also to work collaboratively with the prison staff to improve referrals to the dental services. METHOD: The triage system was devised to have three strands: (1) an oral health assessment conducted by the dental nurse during the induction process for each new prisoner; (2) a simple oral health examination conducted in monthly screening clinics; (3) the prioritisation of referrals from prison landing staff using the prisons computer system PRISM. The triage was evaluated by assessing the first 100 patients' records with regard to the prioritisation of the triage category at the time of the clinical dental examination. RESULTS: Of the 100 patients triaged 95% were prioritised into the correct triage category. Seventy-two percent of patients were seen in the appropriate timeframe. Referral patterns from prison landing staff were improved along with interdisciplinary working in the prison. All new prisoners were seen within 72 hours of committal and received oral health advice and information on accessing dental services. CONCLUSION: This is the first triage system to be introduced into Hydebank Wood Prison, facilitating a targeted approach to dental care. It has improved access to the prison dental services; introduced oral health advice and information into the regular prison healthcare structure; and improved the efficiency of the clinical dental sessions. It is hoped to strategically address problems with waiting times and inequity in service utilisation. PMID- 24809589 TI - Continuing development of an oral health score for clinical audit. AB - AIM: To compare the outcomes of a contemporary oral health status (OHS) scoring system with national oral health data from the 2009 Adult Dental Health Survey, and to explore the utility of the OHS in audit and service development. METHODS: An OHS scoring system was developed as part of a previously reported comprehensive on-line patient assessment tool. The assessment tool also measured future disease risk and indicative capitation fee grading. The modified OHS score component was developed over 20 years of research and experience from the original Oral Health Index (Burke and Wilson 1995). The online tool was piloted by 25 volunteer dentists on 640 recall patients and qualitative and quantitative feedback provided. Anonymised data from the inputs and scores generated were collected centrally and analysed using descriptive statistics. RESULTS: The modified OHS was reported to have good validity by the pilot group. Submitted data confirmed a mean age for the recall patients examined as 53 +/- 15.8 years and an average oral health status score of 79.5 +/- 10.8 where a score of 100 equates to perfect oral health. A breakdown of the scores into the eight principal components provided evidence of cross validation with the Adult Dental Health Survey (2009). CONCLUSIONS: Scoring oral health status electronically offers valuable opportunities for clinical audit. The reported benchmark oral health score of 79.5 for recall patients can be updated as increased numbers of patients enter the centralised data recording system. Audit can be facilitated by this move from a paper-based system to an on-line tool with central data collection. PMID- 24809591 TI - Safety and outcomes of magnetic resonance imaging in patients with abandoned pacemaker and defibrillator leads. AB - INTRODUCTION: Abandoned cardiovascular implantable electronic device (CIED) leads remain a contraindication to magnetic resonance imaging (MRI) studies, largely due to in vitro data showing endocardial heating secondary to the radiofrequency field. We tested the hypothesis that abandoned CIED leads do not pose an increased risk of clinical harm for patients undergoing MRI. METHODS: This single center retrospective study examined the outcomes of patients who had device generators removed before MRI, rendering the device leads abandoned. Information was gathered through chart review. Data collected included lead model, pacing threshold before MRI, anatomic region examined, threshold data after generator reimplantation, and clinical patient outcome. RESULTS: Patients (n = 19, 11 men and eight women) ranged in age from 19 to 85 at the time of MRI. There was a mean of 1.63 abandoned leads at the time of imaging; none of the leads were MRI conditional. Of the three implantable cardioverter defibrillator (ICD) leads, two of three were dual coil. Most (31/35) of the scans performed were of the central nervous system, including head and spinal imaging. There were no adverse events associated with MRI in any of these patients with abandoned leads within 7 days of the scan. No lead malfunctions or clinically significant change in pacing thresholds were noted with generator reimplantation. CONCLUSION: The use of MRI in patients with abandoned cardiac device leads appears feasible when performed under careful monitoring, with no adverse events, although the experience is small. MRI did not affect the function of leads that were subsequently reconnected to a cardiac device. PMID- 24809592 TI - Risk factors and surgical management of anastomotic biliary complications after pediatric liver transplantation. AB - Biliary complications (BCs) still remain the Achilles heel of liver transplantation (LT) with an overall incidence of 10% to 35% in pediatric series. We hypothesized that (1) the use of alternative techniques (reduced size, split, and living donor grafts) in pediatric LT may contribute to an increased incidence of BCs, and (2) surgery as a first treatment option for anastomotic BCs could allow a definitive cure for the majority of these patients. Four hundred twenty nine primary pediatric LT procedures, including 88, 91, 47, and 203 whole, reduced size, split, and living donor grafts, respectively, that were performed between July 1993 and November 2010 were retrospectively reviewed. Demographic and surgical variables were analyzed, and their respective impact on BCs was studied with univariate and multivariate analyses. The modalities of BC management were also reviewed. The 1- and 5-year patient survival rates were 94% and 90%, 89% and 85%, 94% and 89%, and 98% and 94% for whole, reduced size, split, and living donor liver grafts, respectively. The overall incidence of BCs was 23% (n = 98). Sixty were anastomotic complications [47 strictures (78%) and 13 fistulas (22%)]. The graft type was not found to be an independent risk factor for the development of BCs. According to a multivariate analysis, only hepatic artery thrombosis and acute rejection increased the risk of anastomotic BCs (P < 0.001 and P = 0.003, respectively). Anastomotic BCs were managed primarily with surgical repair in 59 of 60 cases with a primary patency rate of 80% (n = 47). These results suggest that (1) most of the BCs were anastomotic complications not influenced by the type of graft, and (2) the surgical management of anastomotic BCs may constitute the first and best therapeutic option. PMID- 24809593 TI - Vigorous physical activity may be important for the insulin sensitivity in immigrants from the Middle East and native Swedes. AB - PURPOSE: To compare physical activity measures and their associations with insulin sensitivity, beta-cell function and body mass index (BMI) between Iraqi immigrants and native Swedes. METHODS: A cross-sectional study of 493 Iraqis (58% men) and 469 Swedes (54% men) aged 30 to 75 years living in the city of Malmo, Sweden. Accelerometry was used for physical activity measures (sedentary time, breaks in sedentary time, moderate and vigorous physical activity, total counts). Insulin sensitivity index and oral disposal index were determined from an oral glucose tolerance test and BMI by body weight and height. RESULTS: Iraqi men were less physically active than Swedish men, while the physical activity was more similar in the women. BMI was a strong predictor of insulin sensitivity and beta cell function and frequently associated with the physical activity measures. BMI modified the associations of insulin sensitivity and beta-cell function with the physical activity measures to such extent that only VPA and total counts show direct associations with insulin sensitivity in addition to the indirect associations via BMI. Iraqi women demonstrated weaker associations compared with Swedish women. CONCLUSIONS: Physical activity and performed at vigorous intensity may be important mainly for the insulin sensitivity in Iraqi immigrants and native Swedes. PMID- 24809594 TI - Occupational handling of nickel nanoparticles: a case report. AB - A 26-year-old female chemist formulated polymers and coatings usually using silver ink particles. When she later began working with nickel nanoparticle powder weighed out and handled on a lab bench with no protective measures, she developed throat irritation, nasal congestion, "post nasal drip," facial flushing, and new skin reactions to her earrings and belt buckle which were temporally related to working with the nanoparticles. Subsequently she was found to have a positive reaction to nickel on the T.R.U.E. patch test, and a normal range FEV1 that increased by 16% post bronchodilator. It was difficult returning her to work even in other parts of the building due to recurrence of symptoms. This incident triggered the company to make plans for better control measures for working with nickel nanoparticles. In conclusion, a worker developed nickel sensitization when working with nanoparticle nickel powder in a setting without any special respiratory protection or control measures. PMID- 24809595 TI - Increased iron level in motor cortex of amyotrophic lateral sclerosis patients: an in vivo MR study. AB - Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative disorders, but no definite mechanism has been defined on the loss of motor neurons in ALS and currently no therapy can block its progression. Many lines of evidence indicate that there is a disorder of iron homeostasis in ALS, and thus we sought to test the iron level in ALS patients by susceptibility weighted imaging (SWI). Sixteen ALS patients and 16 healthy persons underwent brain scans using SWI with a 3T Siemens MR scanner. The red nucleus, substantia nigra, globus pallidus, putamen, the head of caudate nucleus, and motor cortex were measured in the filtered phase images and analysed for their SWI phase values as relative marker for iron content. We found that phase shift values were significantly higher in the motor cortex of ALS patients by SWI, indicating increased iron level in this area. In contrast, we found that there were no differences of phase shift values between ALS patients and healthy controls in the other nuclei including the red nucleus, substantia nigra, globus pallidus, putamen and the head of the caudate nucleus. Furthermore, we found that there were no relationships between SWI signal and some clinical features of ALS. In conclusion, these results demonstrate that iron level increases in the motor cortex of ALS and that SWI is a reliable method to test iron in the brain. PMID- 24809596 TI - Evaluation of the serum free light chain (sFLC) analysis in prediction of response in symptomatic multiple myeloma patients: rapid profound reduction in involved FLC predicts achievement of VGPR. AB - BACKGROUND: Observational data from clinical studies indicate that the goal of first-line therapy in newly diagnosed patients with symptomatic multiple myeloma (MM) should be very good partial response (VGPR) or better, preferably before high-dose treatment. We evaluated the value of early measurements of involved free light chains (iFLC) in prediction of high-quality responses. Measuring iFLC has a potential advantage due to a short half-life compared to the half-life of the M-protein. METHODS: In 36 multiple myeloma (MM) patients, we measured serial changes in iFLC and M-protein after start of treatment. iFLC and M-protein were measured before treatment, the following 5 wk days, 2, 3 and 6 wks after start of treatment. RESULTS: Median iFLC and M-protein half-life was 2.75 and 11.9 d, respectively. All patients with an iFLC >75 mg/L had an initial significant reduction (>20%) in iFLC, even patients with no response to treatment. The mean per cent reduction in iFLC 3 d after start of treatment was 52.3% and 23.6% (P = 0.021) in patients achieving >=VGPR and PR, respectively. The mean per cent reduction in M-protein in patients achieving >=VGPR and PR was not significantly different in the 6-wk study period. As a predictor of VGPR, an 80% reduction in iFLC at day 21 resulted in a sensitivity of 87.5% and a specificity of 100%. CONCLUSION: Changes in iFLC could be a tool for early identification of responders to anti-myeloma therapy. Early, sequential measurements of iFLC within the first week after start of treatment are not meaningful. PMID- 24809597 TI - Health intuitions inform patient-centered care. PMID- 24809599 TI - Patient and public participation in health care: can we do it better? PMID- 24809598 TI - Patient and citizen participation in health: the need for improved ethical support. AB - Patient and citizen participation is now regarded as central to the promotion of sustainable health and health care. Involvement efforts create and encounter many diverse ethical challenges that have the potential to enhance or undermine their success. This article examines different expressions of patient and citizen participation and the support health ethics offers. It is contended that despite its prominence and the link between patient empowerment and autonomy, traditional bioethics is insufficient to guide participation efforts. In addition, the turn to a "social paradigm" of ethics in examinations of biotechnologies and public health does not provide an account of values that is commensurable with the pervasive autonomy paradigm. This exacerbates rather than eases tensions for patients and citizens endeavoring to engage with health. Citizen and patient participation must have a significant influence on the way we do health ethics if its potential is to be fulfilled. PMID- 24809600 TI - Ensuring that we promote participation in health for everyone. PMID- 24809601 TI - Managing disease, or managing the self?: Philosophical challenges to patient participation in (mental) health care and the need for self-management training. PMID- 24809602 TI - Community engagement: an important addition to the medical curriculum. PMID- 24809603 TI - PPI: understanding the difference between patient and public involvement. PMID- 24809604 TI - Dialogical ethics and responsive evaluation as a framework for patient participation. PMID- 24809605 TI - From subjects to experts--on the current transition of patient participation in research. PMID- 24809606 TI - Which public to involve? More reflection on collective agency and sufficient representativeness is needed. PMID- 24809607 TI - Exploring accountability of clinical ethics consultants: practice and training implications. AB - Clinical ethics consultants represent a multidisciplinary group of scholars and practitioners with varied training backgrounds, who are integrated into a medical environment to assist in the provision of ethically supportable care. Little has been written about the degree to which such consultants are accountable for the patient care outcome of the advice given. We propose a model for examining degrees of internally motivated accountability that range from restricted to unbounded accountability, and support balanced accountability as a goal for practice. Finally, we explore implications of this model for training of clinical ethics consultants from diverse academic backgrounds, including those disciplines that do not have a formal code of ethics relating to clinical practice. PMID- 24809608 TI - Clinical ethics consultation: accountability or shared responsibility? PMID- 24809609 TI - On internal accountability in clinical ethics consultation. PMID- 24809610 TI - Incorporating balanced accountability in a clinical ethics fellowship program. PMID- 24809611 TI - Collaboration in clinical ethics consultation: a method for achieving "balanced accountability". PMID- 24809612 TI - Ethics consultations should mirror other clinical consultations in accountability. PMID- 24809613 TI - Moral and professional accountability for clinical ethics consultants. PMID- 24809614 TI - Accountability and the clinical practice of ethics consultation: roles, activities, and the experience of doing. PMID- 24809616 TI - Cost-effectiveness of novel therapies for overactive bladder. AB - Overactive bladder is a difficult to treat condition affecting a large proportion of adults resulting in considerable economic impact to society. First-line treatments such as behavioral therapy or antimuscarinic medication are frequently not effective in adequately controlling symptoms or have intolerable side effects. Patients subsequently require second-line therapy including, sacral neuromodulation through either posterior tibial nerve stimulation or sacral nerve stimulation or intra-detrusor injection of Onabotulinumtoxin-A. Mirabegron, a relatively new drug in a separate class, is also employed in the treatment of overactive bladder. The question of which novel therapy to initiate depends on several factors including patient preference, effectiveness and cost. The purpose of this review is to present and discuss the most recent studies pertaining to the cost-effectiveness of novel therapies for overactive bladder. PMID- 24809617 TI - Multicenter cross-sectional study of asymptomatic peripheral arterial disease among patients with a single previous coronary or cerebrovascular event in the Arabian Gulf. AB - OBJECTIVE: To evaluate the epidemiology and predictors of asymptomatic peripheral artery disease (PAD) in patients with a single previous coronary or cerebrovascular event in the Arabian Gulf. METHODS: This was a cross-sectional, multicenter, observational survey in consecutive patients (>=18 years) with documented previous coronary and/or cerebrovascular atherothrombotic event in the United Arab Emirates (UAE), Kuwait and Qatar (64 centers), from October 2008 to December 2010. PAD was defined as an ankle brachial index <0.9 in at least one leg. RESULTS: The overall mean age of the cohort (n = 2110) was 54 +/- 11 years with only 14% being female (n = 303). The prevalence of asymptomatic PAD was 13.7%, with the highest prevalence seen in Kuwait (16.3%) and the UAE (14.7%) and the lowest in Qatar (5.3%). There were significant differences in the prevalence of asymptomatic PAD among the ethnic groups (p < 0.001): it was highest among the local Arabs and Caucasians at 19% and lowest among South East Asians (6%). The multivariate logistic model demonstrated that the most significant predictors of PAD were old age (adjusted odds ratio [OR], 1.04; 95% CI: 1.02-1.05; p < 0.001), female gender (OR, 1.56; 95% CI: 1.06-2.29; p = 0.024), ethnicity (OR, 0.39; 95% CI: 0.19-0.79; p = 0.009), smoking (OR, 1.70; 95% CI: 1.22-2.37: p = 0.002) and diabetes mellitus (OR, 1.49; 95% CI: 1.14-1.94; p = 0.004). CONCLUSIONS: PAD is prevalent in the Arabian Gulf and is more likely to be associated with old age, females, ethnicity, smokers and those with diabetes mellitus. PMID- 24809618 TI - Spontaneous cyclization of polypeptides with a penultimate Asp, Asn or isoAsp at the N-terminus and implications for cleavage by aminopeptidase. AB - A cyclic product that forms spontaneously from peptides that contain a penultimate Asp, Asn or isoAsp residue at the N-terminus has been characterized. This 2,5-diketopiperazine derivative forms under physiological conditions and is stable, showing little degradation even following heating at 60 degrees C. A mechanism for its formation from Asn and Asp peptides is proposed that involves a succinimide or isoaspartate intermediate. A diketopiperazine-modified peptide was also detected in human lens extracts. Since peptides that contain the diketopiperazine moiety are not readily hydrolysed by leucine aminopeptidase, it is hypothesized that proteins and peptides modified in this way in the body may not readily be digested by the normal proteolytic machinery of cells. PMID- 24809619 TI - Functions of gamma-band synchronization in cognition: from single circuits to functional diversity across cortical and subcortical systems. AB - Gamma-band activity (30-90 Hz) and the synchronization of neural activity in the gamma-frequency range have been observed in different cortical and subcortical structures and have been associated with different cognitive functions. However, it is still unknown whether gamma-band synchronization subserves a single universal function or a diversity of functions across the full spectrum of cognitive processes. Here, we address this question reviewing the mechanisms of gamma-band oscillation generation and the functions associated with gamma-band activity across several cortical and subcortical structures. Additionally, we raise a plausible explanation of why gamma rhythms are found so ubiquitously across brain structures. Gamma band activity originates from the interplay between inhibition and excitation. We stress that gamma oscillations, associated with this interplay, originate from basic functional motifs that conferred advantages for low-level system processing and multiple cognitive functions throughout evolution. We illustrate the multifunctionality of gamma-band activity by considering its role in neural systems for perception, selective attention, memory, motivation and behavioral control. We conclude that gamma-band oscillations support multiple cognitive processes, rather than a single one, which, however, can be traced back to a limited set of circuit motifs which are found universally across species and brain structures. PMID- 24809620 TI - Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. AB - Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44(+) /CD24(-/low) cancer stem cells (CSCs), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an antimalarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44(+) /CD24(-/low) CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus, the objectives of this study were to examine the potential enhanced efficacy arising from addition of CQ to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44(+) /CD24(-/low) CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2)-signal transducer and activator of transcription 3 signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1. PMID- 24809622 TI - China type 2 diabetes treatment status survey of treatment pattern of oral drugs users AB - BACKGROUND: The aim of the present study was to investigate the current status of oral anti-diabetic drug (OAD) therapy in patients with type 2 diabetes and influencing factors in a real-world setting in China. METHODS: A total of 9872 outpatients with type 2 diabetes, who had received OADs (monotherapy or combination therapy) for at least 3 months were recruited in this study. Current antidiabetic treatment regimen and related clinical data were collected from medical records and analyzed. RESULTS: The most common OADs in use were insulin secretagogues (70.2%) such as sulfonylureas (SUs; 42.7%) or glinides (27.5%), followed by metformin (53.7%), alpha-glucosidase inhibitors (35.9%), thiazolidinediones (17.2%), and dipeptidyl peptidase-4 (DPP-4) inhibitors (0.8%). Dual-drug combination therapy was more common (45.4%) than monotherapy (35.8%) and combination therapy with at least three drugs (17.0%). Patients on SU or glinide monotherapy were more likely to alter their treatment frequently (odds ratio [OR], 1.7; 95% CI, 1.38-2.08; P < 0.001). CONCLUSIONS: The status of OAD use in China is varied with a majority of the patients altering their treatment regimen citing poor effectiveness. These observations from a real-world setting may serve as guidance for improving diabetes management in China. PMID- 24809621 TI - SslE elicits functional antibodies that impair in vitro mucinase activity and in vivo colonization by both intestinal and extraintestinal Escherichia coli strains. AB - SslE, the Secreted and surface-associated lipoprotein from Escherichia coli, has recently been associated to the M60-like extracellular zinc-metalloprotease sub family which is implicated in glycan recognition and processing. SslE can be divided into two main variants and we recently proposed it as a potential vaccine candidate. By applying a number of in vitro bioassays and comparing wild type, knockout mutant and complemented strains, we have now demonstrated that SslE specifically contributes to degradation of mucin substrates, typically present in the intestine and bladder. Mutation of the zinc metallopeptidase motif of SslE dramatically impaired E. coli mucinase activity, confirming the specificity of the phenotype observed. Moreover, antibodies raised against variant I SslE, cloned from strain IHE3034 (SslEIHE3034), are able to inhibit translocation of E. coli strains expressing different variants through a mucin-based matrix, suggesting that SslE induces cross-reactive functional antibodies that affect the metallopeptidase activity. To test this hypothesis, we used well-established animal models and demonstrated that immunization with SslEIHE3034 significantly reduced gut, kidney and spleen colonization by strains producing variant II SslE and belonging to different pathotypes. Taken together, these data strongly support the importance of SslE in E. coli colonization of mucosal surfaces and reinforce the use of this antigen as a component of a broadly protective vaccine against pathogenic E. coli species. PMID- 24809623 TI - The impact of negative affect on reality discrimination. AB - BACKGROUND AND OBJECTIVES: People who experience auditory hallucinations tend to show weak reality discrimination skills, so that they misattribute internal, self generated events to an external, non-self source. We examined whether inducing negative affect in healthy young adults would increase their tendency to make external misattributions on a reality discrimination task. METHODS: Participants (N = 54) received one of three mood inductions (one positive, two negative) and then performed an auditory signal detection task to assess reality discrimination. RESULTS: Participants who received either of the two negative inductions made more false alarms, but not more hits, than participants who received the neutral induction, indicating that negative affect makes participants more likely to misattribute internal, self-generated events to an external, non-self source. LIMITATIONS: These findings are drawn from an analogue sample, and research that examines whether negative affect also impairs reality discrimination in patients who experience auditory hallucinations is required. CONCLUSIONS: These findings show that negative affect disrupts reality discrimination and suggest one way in which negative affect may lead to hallucinatory experiences. PMID- 24809625 TI - Negative pressure wound therapy is associated with up-regulation of bFGF and ERK1/2 in human diabetic foot wounds. AB - Chronic foot wounds are a leading cause of morbidity and hospitalization for patients with diabetes. Negative pressure wound therapy (NPWT) is known to promote healing of diabetic foot wounds, but the underlying molecular mechanisms remain elusive. We propose to gain molecular insights into the wound healing promoting signals underlying the effects of NPWT on diabetic foot wounds in humans. We assessed 30 patients with diabetic foot ulcers. Of these cases, 15 were treated with NPWT, while 15 patients were treated with traditional gauze therapy. Granulated tissue was harvested before and after treatment in both patient groups and histologically analyzed with hematoxylin & eosin as well as Masson's trichrome staining methods. Immunohistochemistry and Western blot analysis was performed to evaluate expression of basic fibroblast growth factor (bFGF) and extracellular signal-regulated kinase (ERK)1/2, previously associated with promoting cellular growth and/or wound healing. Unlike controls, the wounds in the NPWT-treated diabetic patients developed characteristic features of granulated tissue with increased collagen deposition. Immunohistochemical analysis also revealed an increase in bFGF levels in NPWT-treated patients. Western blot analysis further showed a significant up-regulation of bFGF and phosphorylated ERK1/2 protein levels in the NPWT-treated diabetic patients vs. controls. Our studies reveal that NPWT is associated with an up-regulation of bFGF and ERK1/2 signaling, which may be involved in promoting the NPWT-mediated wound healing response. PMID- 24809624 TI - Xylem hydraulic evolution, I. W. Bailey, and Nardini & Jansen (2013): pattern and process. PMID- 24809626 TI - In vitro development of engineered muscle using a scaffold based on the pressure activated microsyringe (PAM) technique. AB - The development of new human skeletal muscle tissue is an alternative approach to the replacement of tissue after severe damage, for example in the case of traumatic injury, where surgical reconstruction is often needed following major loss of natural tissue. Treatment to date has involved the transfer of muscle tissue from other sites, resulting in a functional loss and volume deficiency of donor sites. Approaches that seek to eliminate these problems include the relatively new solution of skeletal muscle engineering. Here there are two main components to consider: (a) the cells with their regenerative potential; and (b) the polymeric structure onto which cells are seeded and where they must perform their activities. In this paper we describe well-defined two- and three dimensional polymeric structures able to drive the myoblast process of adhesion, proliferation and differentiation. We examine a series of polymers and protein adhesions with which to functionalize the structures, and cell-seeding methods, with a view to defining the optimal protocol for engineering skeletal muscle tissue. All polymer samples were tested for their mechanical and biological properties, to support the validity of our results in the real context of muscle tissue engineering. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24809628 TI - Comprehensive analysis of RNA-protein interactions by high-throughput sequencing RNA affinity profiling. AB - RNA-protein interactions play critical roles in gene regulation, but methods to quantitatively analyze these interactions at a large scale are lacking. We have developed a high-throughput sequencing-RNA affinity profiling (HiTS-RAP) assay by adapting a high-throughput DNA sequencer to quantify the binding of fluorescently labeled protein to millions of RNAs anchored to sequenced cDNA templates. Using HiTS-RAP, we measured the affinity of mutagenized libraries of GFP-binding and NELF-E-binding aptamers to their respective targets and identified critical regions of interaction. Mutations additively affected the affinity of the NELF-E binding aptamer, whose interaction depended mainly on a single-stranded RNA motif, but not that of the GFP aptamer, whose interaction depended primarily on secondary structure. PMID- 24809630 TI - A combined stretching-tilting mechanism produces negative, zero and positive linear thermal expansion in a semi-flexible Cd(II)-MOF. AB - A novel semi-flexible Cd(II)-MOF has been synthesized and characterized by variable temperature powder and single-crystal X-ray diffraction. The material displays an unusual combination of thermal expansion (TE) i.e. negative, zero and positive, which is an extremely rare finding, especially for metal-organic frameworks as a result of a combined stretching-tilting mechanism. PMID- 24809629 TI - Estimating per-act HIV transmission risk: a systematic review. AB - BACKGROUND: Effective HIV prevention programs rely on accurate estimates of the per-act risk of HIV acquisition from sexual and parenteral exposures. We updated the previous risk estimates of HIV acquisition from parenteral, vertical, and sexual exposures, and assessed the modifying effects of factors including condom use, male circumcision, and antiretroviral therapy. METHODS: We conducted literature searches to identify new studies reporting data regarding per-act HIV transmission risk and modifying factors. Of the 7339 abstracts potentially related to per-act HIV transmission risk, three meta-analyses provided pooled per act transmission risk probabilities and two studies provided data on modifying factors. Of the 8119 abstracts related to modifying factors, 15 relevant articles, including three meta-analyses, were included. We used fixed-effects inverse-variance models on the logarithmic scale to obtain updated estimates of certain transmission risks using data from primary studies, and employed Poisson regression to calculate relative risks with exact 95% confidence intervals for certain modifying factors. RESULTS: Risk of HIV transmission was greatest for blood transfusion, followed by vertical exposure, sexual exposures, and other parenteral exposures. Sexual exposure risks ranged from low for oral sex to 138 infections per 10,000 exposures for receptive anal intercourse. Estimated risks of HIV acquisition from sexual exposure were attenuated by 99.2% with the dual use of condoms and antiretroviral treatment of the HIV-infected partner. CONCLUSION: The risk of HIV acquisition varied widely, and the estimates for receptive anal intercourse increased compared with previous estimates. The risk associated with sexual intercourse was reduced most substantially by the combined use of condoms and antiretroviral treatment of HIV-infected partners. PMID- 24809631 TI - Precipitating factors of delirium: stress response to multiple triggers among patients with and without dementia. AB - BACKGROUND AND AIM: Delirium is common and serious acute syndrome among older people precipitated by multiple external factors such as acute illnesses, trauma, surgery, and drugs. The aim of this study was to find possible stressors and causative triggers for acute delirium and compare patients with or without dementia in this respect. METHODS: 193 delirious patients from two separate delirium studies including settings of nursing homes and geriatric wards were thoroughly assessed for precipitating factors of delirium. Patients with and without dementia were compared for their clinical status, symptoms and signs, prognosis, and the profile of precipitating factors of delirium. RESULTS: The patients with dementia (n=98) and without dementia (n=95) did not differ in their demographic factors, mean number of drugs, or their psychiatric symptoms. The patients with dementia had higher number of comorbidities, poorer cognition, and they were more often restrained than those without dementia. The mean number of precipitators for delirium was 2.6 among those without dementia and 2.0 among those with dementia (p=0.0019). Infections, metabolic conditions, trauma, and surgery were more common precipitating factors for delirium in those without than those with dementia. There was no difference in mortality between the groups. CONCLUSION: Most patients had multiple precipitating factors for delirium irrespective of prior dementia. Those with dementia and decreased cognitive reserves needed lower number of etiologies to develop delirium. The profile of causative agents differed among patients with and without dementia. PMID- 24809633 TI - Gender-specific cold responses induce a similar body-cooling rate but different neuroendocrine and immune responses. AB - This study investigated whether there are any gender differences in body-heating strategies during cold stress and whether the immune and neuroendocrine responses to physiological stress differ between men and women. Thirty-two participants (18 men and 14 women) were exposed to acute cold stress by immersion to the manubrium level in 14 degrees C water. The cold stress continued until rectal temperature (TRE) reached 35.5 degrees C or for a maximum of 170 min. The responses to cold stress of various indicators of body temperature, insulation, metabolism, shivering, stress, and endocrine and immune function were compared between men and women. During cold stress, TRE and muscle and mean skin temperatures decreased in all subjects (P<0.001). These variables and the TRE cooling rate did not differ between men and women. The insulative response was greater in women (P<0.05), whereas metabolic heat production and shivering were greater (P<0.05) in men. Indicators of cold strain did not differ between men and women, but men exhibited larger changes in the indicators of neuroendocrine (epinephrine level) and in immune (tumor necrosis factor-alpha level) responses (both P<0.05). The results of the present study indicated that men exhibited a greater metabolic response and shivering thermogenesis during acute cold stress, whereas women exhibited a greater insulative response. Despite the similar experience of cold strain in men and women, the neuroendocrine and immune responses were larger in men. Contrary to our expectations, the cooling rate was similar in men and women. PMID- 24809632 TI - Birth cohort differences in the prevalence of longevity-associated variants in APOE and FOXO3A in Danish long-lived individuals. AB - Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE epsilon4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915. Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE epsilon4 allele (P=0.026) or for the FOXO3A rs7762395 minor allele (P=0.048). For the APOE epsilon4 allele, the significance is further strengthened when restricting to women (P=0.006). Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100years. Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity. PMID- 24809634 TI - Effects of type III antifreeze protein on sperm and embryo cryopreservation in rabbit. AB - We investigated the effects of antifreeze protein (AFP) III supplementation on the cryopreservation of rabbit sperm cells and embryos. Ejaculated semen was collected from male Japanese white (JW) rabbits and divided into four AFP supplemented groups (0.1 MUg/ml, 1 MUg/ml, 10 MUg/ml, 100 MUg/ml) and one control group with no AFP-supplementation. The semen samples were treated with egg-yolk HEPES extender containing 6% acetamide before the sperm was cooled from room temperature to 5 degrees C, then packed into sperm straws. The straws were frozen in steam of liquid nitrogen (LN2) and then preserved in the LN2. The motility of the sperm after thawing in 37 degrees C water was analyzed. The percentage of rapidly motile sperm in the 1 MUg/ml AFP group was significantly higher than in the control group. Morulae were collected from female JW rabbits and divided into three AFP-supplemented groups (100 ng/ml, 500 ng/ml, 1000 ng/ml) and one control group. The morulae, immersed in an embryo-freezing solution (M199 HEPES containing 20% ethylene glycol, 20% dimethylsulfoxide, 10% fetal bovine serum and 0.25 M sucrose), were packed into open pulled embryo straws and vitrified in LN2. The frozen embryos were thawed in the embryo-freezing solution, and the rates of embryo survival and development to blastocyte stage were analyzed after incubation for 72 h. The development rate of the embryos in the 500 ng/ml AFP group was significantly higher than in the control group, but that in the 1000 ng/ml AFP group was significantly lower. In conclusion, the appropriate dose of AFP III increased the number of rapidly motile sperm and embryo survival following freezing and thawing. The results suggest that supplementation with AFP III can increase the efficiency of cryopreservation of rabbit sperm cells and embryos. PMID- 24809635 TI - Molecular epidemiology of Japanese encephalitis virus in mosquitoes during an outbreak in China, 2013. AB - Japanese encephalitis virus (JEV) can cause serious encephalitis and Culex mosquitoes are the primary vector. In 2013, a JE outbreak occurred in Shandong Province, China with 407 confirmed cases, including 11 deaths. An investigation on JEV in mosquitoes during the outbreak was conducted. A total of 14,719 mosquitoes were collected at 3 sites. For the 12,695 Culex tritaeniorhynchus mosquitoes, 88/201 pooled samples were positive by RT-PCR for the presence of the pre-membrane or envelope protein coding genes. The maximum likelihood estimates of JEV positive individuals per 1,000 vectors were 12.0, 7.2, and 6.0 in the 3 sites respectively with an overall estimate of 9.1. Phylogenetic analysis on these pre-membrane (n = 72) and envelope (n = 26) sequences with those of reference strains revealed they belonged to genotype I. This study describes the molecular epidemiology of JEV and suggests the high infection rate in mosquitoes is an important factor for the outbreak. PMID- 24809636 TI - Predicting the responses of repetitively firing neurons to current noise. AB - We used phase resetting methods to predict firing patterns of rat subthalamic nucleus (STN) neurons when their rhythmic firing was densely perturbed by noise. We applied sequences of contiguous brief (0.5-2 ms) current pulses with amplitudes drawn from a Gaussian distribution (10-100 pA standard deviation) to autonomously firing STN neurons in slices. Current noise sequences increased the variability of spike times with little or no effect on the average firing rate. We measured the infinitesimal phase resetting curve (PRC) for each neuron using a noise-based method. A phase model consisting of only a firing rate and PRC was very accurate at predicting spike timing, accounting for more than 80% of spike time variance and reliably reproducing the spike-to-spike pattern of irregular firing. An approximation for the evolution of phase was used to predict the effect of firing rate and noise parameters on spike timing variability. It quantitatively predicted changes in variability of interspike intervals with variation in noise amplitude, pulse duration and firing rate over the normal range of STN spontaneous rates. When constant current was used to drive the cells to higher rates, the PRC was altered in size and shape and accurate predictions of the effects of noise relied on incorporating these changes into the prediction. Application of rate-neutral changes in conductance showed that changes in PRC shape arise from conductance changes known to accompany rate increases in STN neurons, rather than the rate increases themselves. Our results show that firing patterns of densely perturbed oscillators cannot readily be distinguished from those of neurons randomly excited to fire from the rest state. The spike timing of repetitively firing neurons may be quantitatively predicted from the input and their PRCs, even when they are so densely perturbed that they no longer fire rhythmically. PMID- 24809637 TI - Differentiation between vasogenic-edema versus tumor-infiltrative area in patients with glioblastoma during bevacizumab therapy: a longitudinal MRI study. AB - BACKGROUND: Treatment with bevacizumab is associated with substantial radiologic response in patients with glioblastoma (GB). However, following this initial response, changes in T2-weighted MRI signal may develop, suggesting an infiltrative pattern of tumor progression. The aim of this study was to differentiate between vasogenic-edema versus tumor-infiltrative area in GB patients. METHODS AND MATERIALS: Fourteen patients with GB were longitudinally scanned, before and during intravenous bevacizumab therapy (5/10mg/kg every 2 weeks). A total of 40 MR scans including conventional, diffusion, dynamic susceptibility contrast, dynamic contrast enhancement imaging, and MR spectroscopy (MRS) were analyzed. Classification of non-enhancing fluid attenuation-inversion-recovery (FLAIR) area was performed based on mean diffusivity, cerebral blood volume and flow maps, and further characterized using multiple MRI parameters. RESULTS: The non-enhancing FLAIR lesion area was classified into: vasogenic-edema, characterized by reduced perfusion and increased FLAIR values; or tumor-infiltrative area, characterized by increased perfusion. Tumor-infiltrative area demonstrated a higher malignant pattern on MRS compared to areas of vasogenic-edema. Substantial reductions of the enhanced T1 weighted (58 +/- 10%) and hyperintense FLAIR (53 +/- 9%) lesion volumes were detected mainly during the first weeks of therapy, with a shift to an infiltrative pattern of tumor progression thereafter, as detected by an increase in tumor-infiltrative area in the majority of patients, which correlated with progression-free survival (week 8: r=-0.86, p=0.003, week 16: r=-0.99, p=0.001). CONCLUSION: Characterization of non-enhancing hyperintense FLAIR lesion area in GB patients can provide an MR-based biomarker, indicating a shift to an infiltrative progression pattern, and may improve therapy response assessment in patients following bevacizumab therapy. PMID- 24809638 TI - Ultrasound of the paediatric urogenital tract. AB - Pathology in the urinary tract is one of the most frequent queries when children are referred for an ultrasound examination. Comprehensive ultrasound examinations can answer most clinical questions of the urogenital tract with minimal patient preparation and without the use of ionising radiation. Therefore, optimised imaging protocols should be available in all radiology departments where children are examined. This review suggests a preferred imaging protocol for urogenital imaging in children and gives an overview of the different structures of the urogenital tract, the normal age-related sonographic anatomy, and gives examples of the most commonly encountered diseases of the urogenital system in children. PMID- 24809639 TI - Direct writing of graphene patterns on insulating substrates under ambient conditions. AB - To unleash the full potential of graphene in electronics and optoelectronics, high-quality graphene patterns on insulating substrates are required. However, existing methods generally follow a "synthesis + patterning" strategy, which are time consuming and costly for fabricating high-quality graphene patterns on desired substrates. We developed a nanofabrication process to deposit high quality graphene patterns directly on insulating substrates via a solid-phase laser direct writing (LDW) process. Open-air and room-temperature fabrication of graphene patterns on insulating substrates has been achieved via a femtosecond LDW process without graphene transfer and patterning. Various graphene patterns, including texts, spirals, line arrays, and integrated circuit patterns, with a feature line width of 800 nm and a low sheet resistance of 205 ohm/sq, were fabricated. The LDW method provides a facile and cost-effective way to fabricate complex and high-quality graphene patterns directly on target substrates, which opens a door for fabricating various advanced functional devices. PMID- 24809640 TI - Changes observed in the thymus and lymph nodes 14 days after exposure to BVDV field strains of enhanced or typical virulence in neonatal calves. AB - Clinical presentation following uncomplicated acute infection with bovine viral diarrhea viruses (BVDV) ranges from clinically unapparent to severe (including hemorrhagic disease and death) depending on the strain virulence. Regardless of clinical presentation, BVDV infection of cattle results in a generalized immunosuppression. BVDV immunosuppression is characterized by a reduction of circulating white blood cells (WBC) that is typically evident by day 3 post infection (PI). In infections with typical BVDV field strains WBC counts decrease until days 6-9 PI and then return to baseline values. In infections with enhanced virulence BVDV, WBC counts may continue to decline through day 14. In this study, the lymph nodes and thymus of non-infected neonatal calves and neonatal calves infected 14 days previously with either a BVDV of typical virulence or one of enhanced virulence were compared. It was found that while calves, infected with the typical virulence BVDV, had cleared BVDV, and WBC counts had returned to near baseline, the number of B-B7(+) cells in lymph nodes were reduced whereas numbers of CD4(+) cells were increased as compared to control calves. In contrast, calves infected with the high virulence strain, had not cleared the virus by day 14 and WBC counts had not returned to pre-exposure levels. Furthermore, these calves had more substantial deficits of B-B7(+) and CD4(+) cell subpopulations, compared to calves infected with a typical virulence strain. There were also an increased number of macrophages observed in both lymphoid tissues examined. The thymuses from both groups of BVDV-infected calves were significantly smaller than non infected age matched calves. The reduction in size was accompanied by a significant depletion of the thymic cortex. These results indicate that regardless of the virulence of the infecting BVDV, infection leaves neonatal calves with deficits in specific lymphocyte subsets and lymphoid tissues that could have long-term immunosuppressive implications. PMID- 24809641 TI - Sealing effect of external diathermy on leaking sclerotomies after small-gauge vitrectomy: a clinicopathological report. PMID- 24809654 TI - Bisphenol-A induces podocytopathy with proteinuria in mice. AB - Bisphenol-A, a chemical used in the production of the plastic lining of food and beverage containers, can be found in significant levels in human fluids. Recently, bisphenol-A has been associated with low-grade albuminuria in adults as well as in children. Since glomerular epithelial cells (podocytes) are commonly affected in proteinuric conditions, herein we explored the effects of bisphenol-A on podocytes in vitro and in vivo. On cultured podocytes we first observed that bisphenol-A-at low or high concentrations-(10 nM and 100 nM, respectively) was able to induce hypertrophy, diminish viability, and promote apoptosis. We also found an increase in the protein expression of TGF-beta1 and its receptor, the cyclin-dependent kinase inhibitor p27Kip1, as well as collagen-IV, while observing a diminished expression of the slit diaphragm proteins nephrin and podocin. Furthermore, mice intraperitoneally injected with bisphenol-A (50 mg/Kg for 5 weeks) displayed an increase in urinary albumin excretion and endogenous creatinine clearance. Renal histology showed mesangial expansion. At ultrastructural level, podocytes displayed an enlargement of both cytoplasm and foot processes as well as the presence of condensed chromatin, suggesting apoptosis. Furthermore, immunohistochemistry for WT-1 (specific podocyte marker) and the TUNEL technique showed podocytopenia as well as the presence of apoptosis, respectively. In conclusion, our data demonstrate that Bisphenol-A exposure promotes a podocytopathy with proteinuria, glomerular hyperfiltration and podocytopenia. Further studies are needed to clarify the potential role of bisphenol-A in the pathogenesis as well as in the progression of renal diseases. PMID- 24809655 TI - Effect of type 2 diabetes mellitus on the risk for hepatocellular carcinoma in chronic liver diseases: a meta-analysis of cohort studies. AB - Questions remain about the relationship between type 2 diabetes mellitus (type 2 DM) and the risk of hepatocellular carcinoma (HCC), especially in patients with chronic liver diseases. We carried out a meta-analysis of cohort studies to explore these issues. We searched PubMed and EMBASE for studies on the association between type 2 DM and the risk of HCC through 30 September 2013. We included patients with chronic liver diseases. Summary relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a random effects model. A total of 21 cohort studies with 24 reports were included in our analysis. After a median duration of follow-up of 6.4 years, a total of 2528 HCC cases were identified in 35 202 participants. The summary relative risk of HCC with type 2 DM was 1.86 (95% CI 1.49-2.31) for patients with chronic liver disease, 1.90 (95% CI 1.37-2.63) for patients with hepatitis C virus infection, 1.93 (95% CI 1.35-2.76) for patients with cirrhosis, and 1.69 (95% CI 0.97-2.92) for patients with hepatitis B virus infection. Subgroup analyses indicated that the positive associations were independent of geographic location, duration of follow-up, and confounding factors such as smoking, alcohol use, and body mass index (BMI). Hepatitis C virus-infected or cirrhotic patients with the concomitant presence of type 2 DM would have a higher risk of developing HCC than those without DM. Therefore, these patients require more active monitoring of the development of HCC. PMID- 24809656 TI - Comparison between the effects of 4 different electrical stimulation current waveforms on isometric knee extension torque and perceived discomfort in healthy women. AB - INTRODUCTION: We studied the effects of different neuromuscular electrical stimulation (NMES) currents, 2 kHz-frequency alternating currents (KACs, Russian and Aussie) and 2 pulsed currents (PCs), on isometric knee extension torque and discomfort level, both in isolation and combined, with maximum voluntary contraction (MVC). METHODS: Twenty-one women (age 21.6 +/- 2.5 years) were studied. We evaluated torque evoked by NMES or NMES combined with maximum voluntary contraction of the quadriceps muscle of healthy women. Discomfort level was measured using a visual analog pain scale. RESULTS: Despite comparable levels of discomfort, evoked torque was lower for Russian current compared with the other modalities (Russian 50.8%, Aussie 71.7%, PC500 76.9%, and PC200 70.1%; P < 0.001). There was no advantage in combining NMES with MVC compared with isolated NMES. CONCLUSIONS: The Aussie and PC approaches proved superior to Russian current for inducing isometric knee extension torque. This information is important in guiding decision making with regard to NMES protocols for muscle strengthening. PMID- 24809657 TI - Single dose oral etoricoxib for acute postoperative pain in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review first published in Issue 2, 2009, and updated in Issue 4, 2012.Etoricoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor licensed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis, and acute pain in some jurisdictions. This class of drugs is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti inflammatory drugs (NSAIDs). OBJECTIVES: To assess the efficacy and adverse effects of single dose etoricoxib for acute postoperative pain using methods that permit accurate comparison with other analgesics evaluated in the same way, using criteria of efficacy recommended by in-depth studies at the individual patient level. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, www.clinicaltrials.gov, and reference lists of articles. The date of the most recent search was 31 January 2014. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled clinical trials of single dose, oral etoricoxib for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered studies for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed etoricoxib or placebo with at least 50% pain relief over six hours, using validated equations. We calculated relative risk (RR) and number needed to treat to benefit (NNT). We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse events. MAIN RESULTS: We identified no new studies for this updated review, which includes six studies with 1214 participants in comparisons of etoricoxib with placebo. All six studies reported on the 120 mg dose (798 participants in a comparison with placebo). Sixty-six per cent of participants with etoricoxib 120 mg and 12% with placebo reported at least 50% pain relief (NNT 1.8 (1.7 to 2.0); high-quality evidence). For dental studies only, the NNT was 1.6 (1.5 to 1.8). A single dose of 90 mg produced similar results in one large trial. Other doses (60, 180, and 240 mg) were each studied in only one treatment arm.Significantly fewer participants used rescue medication over 24 hours when taking etoricoxib 120 mg than placebo (NNT to prevent remedication 2.2 (1.9 to 2.8)), and the median time to use of rescue medication was 20 hours for etoricoxib and two hours for placebo. Adverse events were reported at a similar rate to placebo (moderate-quality evidence), with no serious events. AUTHORS' CONCLUSIONS: Single-dose oral etoricoxib produces high levels of good quality pain relief after surgery, and adverse events did not differ from placebo in these studies. The 120 mg dose is as effective as, or better than, other commonly used analgesics. PMID- 24809658 TI - Assisted outpatient treatment: we can do better. PMID- 24809659 TI - Experimental and Computational Thermochemistry of 3- and 4-Nitrophthalic Anhydride. AB - In order to understand the influence that the position of the nitro group on the aromatic ring has on the relative stability of two isomers, the standard enthalpies of formation of 3- and 4-nitrophthalic anhydride in the gaseous phase, at T = 298.15 K, were obtained by experimental thermochemistry and theoretical studies. The standard enthalpies of formation in the crystalline phase, at T = 298.15 K, were obtained by combustion calorimetry and the enthalpies of sublimation by the Knudsen method. For the theoretical calculations, a standard ab initio molecular orbital method at the G3 level was used. The enthalpies of formation in the gaseous phase were obtained from atomization and isodesmic reactions. A theoretical study of the molecular and electronic structures of these compounds was also performed. Differences of -9.7 kJ.mol-1, for 3 nitrophthalic anhydride, and -2.6 kJ.mol-1 for 4-nitrophthalic anhydride, were found from a comparison between our theoretical and experimental results. PMID- 24809661 TI - Effect of cellulose nanocrystals (CNC) particle morphology on dispersion and rheological and mechanical properties of polypropylene/CNC nanocomposites. AB - Polypropylene (PP) nanocomposites containing spray-dried cellulose nanocrystals (CNC), freeze-dried CNC, and spray-freeze-dried CNC (CNCSFD) were prepared via melt mixing in an internal batch mixer. Polarized light, scanning electron, and atomic force microscopy showed significantly better dispersion of CNCSFD in PP/CNC nanocomposites compared with the spray-dried and freeze-dried CNCs. Rheological measurements, including linear and nonlinear viscoelastic tests, were performed on PP/CNC samples. The microscopy results were supported by small amplitude oscillatory shear tests, which showed substantial rises in the magnitudes of key rheological parameters of PP samples containing CNCSFD. Steady shear results revealed a strong shear thinning behavior of PP samples containing CNCSFD. Moreover, PP melts containing CNCSFD exhibited a yield stress. The magnitude of the yield stress and the degree of shear thinning behavior increased with CNCSFD concentration. It was found that CNCSFD agglomerates with a weblike structure were more effective in modifying the rheological properties. This effect was attributed to better dispersion of the agglomerates with the weblike structure. Dynamic mechanical analysis showed considerable improvement in the modulus of samples containing CNCSFD agglomerates. The percolation mechanical model with modified volume percolation threshold and filler network strength values and the Halpin-Kardos model were used to fit the experimental results. PMID- 24809660 TI - Periostin secreted by mesenchymal stem cells supports tendon formation in an ectopic mouse model. AB - True tendon regeneration in human patients remains a vision of musculoskeletal therapies. In comparison to other mesenchymal lineages the biology of tenogenic differentiation is barely understood. Specifically, easy and efficient protocols are lacking that might enable tendon cell and tissue differentiation based on adult (stem) cell sources. In the murine mesenchymal progenitor cell line C3H10T1/2, overexpression of the growth factor bone morphogenetic protein 2 (BMP2) and a constitutively active transcription factor, Smad8 L+MH2, mediates tendon cell differentiation in vitro and the formation of tendon-like tissue in vivo. We hypothesized that during this differentiation secreted factors involved in extracellular matrix formation exert a major impact on tendon development. Gene expression analyses revealed four genes encoding secreted factors that are notably upregulated: periostin, C-type lectin domain family 3 (member b), RNase A4, and follistatin-like 1. These factors have not previously been implicated in tendon biology. Among these, periostin showed a specific expression in tenocytes of adult mouse Achilles tendon and in chondrocytes within the nonmineralized fibrocartilage zone of the enthesis with the calcaneus. Overexpression of periostin alone or in combination with constitutively active BMP receptor type in human mesenchymal stem cells and subsequent implantation into ectopic sites in mice demonstrated a reproducible moderate tenogenic capacity that has not been described before. Therefore, periostin may belong to the factors contributing to the development of tenogenic tissue. PMID- 24809662 TI - Does concomitant anterior/apical repair during midurethral sling improve the overactive bladder component of mixed incontinence? AB - INTRODUCTION AND HYPOTHESIS: Midurethral sling (MUS) can improve overactive bladder (OAB) symptoms. It is unclear if anterior/apical prolapse (AA) repair provides additional benefit. We hypothesized that women with mixed urinary incontinence (MUI) experience greater improvement in the OAB component of their symptoms after concomitant MUS and AA repair compared with MUS alone. METHODS: This is a retrospective cohort study of women with bothersome MUI (defined by objective stress test and validated questionnaire) undergoing MUS alone ("MUS only") or concomitant MUS and AA repair ("MUS + AA"). Our primary outcome was the Overactive Bladder Questionnaire Symptom Severity (OAB-q SS) change score 6 weeks after surgery. RESULTS: Of 151 women, 67 (44 %) underwent MUS-only and 84 (56 %) underwent MUS + AA. The MUS-only cohort was younger and had less severe baseline prolapse (p < 0.05 for both). Postoperative complications (predominantly UTI) occurred in 35 (23 %) patients and were similar between cohorts. For all subjects mean OAB-q SS scores significantly improved postoperatively (p < 0.05). Our primary outcome, OAB-q SS change score, showed no significant differences between cohorts (30 +/- 26 MUS-only vs 25 +/- 25 MUS + AA, p = 0.20), indicating similar improvements in OAB symptoms. Multivariate linear regression analysis revealed no difference in OAB-q SS change score between cohorts; however, OAB-q SS change scores were lower for women with a postoperative complication (beta = -19, 95 % CI -31 to -6; p < 0.01). CONCLUSIONS: In women with bothersome MUI, concomitant AA repair does not result in additional improvement in OAB symptoms over MUS alone. Patients with postoperative complications exhibit less improvement in OAB symptoms. PMID- 24809663 TI - Comment on: Prolapse of a single-system ureterocele causing urinary retention in an adult woman. PMID- 24809664 TI - Fate of platinum metals in the environment. AB - For many years now automotive exhaust catalysts have been used to reduce the significant amounts of harmful chemical substances generated by car engines, such as carbon monoxide, nitrogen oxides, and aromatic hydrocarbons. Although they considerably decrease environmental contamination with the above-mentioned compounds, it is known that catalysts contribute to the environmental load of platinum metals (essential components of catalysts), which are released with exhaust fumes. Contamination with platinum metals stems mainly from automotive exhaust converters, but other major sources also exist. Since platinum group elements (PGEs): platinum (Pt), palladium (Pd), rhodium (Rh), ruthenium (Ru) and iridium (Ir) seem to spread in the environment and accumulate in living organisms, they may pose a threat to animals and humans. This paper discusses the modes and forms of PGE emission as well as their impact on the environment and living organisms. PMID- 24809665 TI - Technical considerations on the validity of blood oxygenation level-dependent based MR assessment of vascular deoxygenation. AB - A blood oxygenation level-dependent (BOLD)-based apparent relative oxygen extraction fraction (rOEF) as a semi-quantitative marker of vascular deoxygenation has recently been introduced in clinical studies of patients with glioma and stroke, yielding promising results. These rOEF measurements are based on independent quantification of the transverse relaxation times T2 and T2* and relative cerebral blood volume (rCBV). Simulations demonstrate that small errors in any of the underlying measures may result in a large deviation of the calculated rOEF. Therefore, we investigated the validity of such measurements. For this, we evaluated the quantitative measurements of T2 and T2* at 3 T in a gel phantom, in healthy subjects and in healthy tissue of patients with brain tumors. We calculated rOEF maps covering large portions of the brain from T2, T2* and rCBV [routinely measured in patients using dynamic susceptibility contrast (DSC)], and obtained rOEF values of 0.63 +/- 0.16 and 0.90 +/- 0.21 in healthy appearing gray matter (GM) and white matter (WM), respectively; values of about 0.4 are usually reported. Quantitative T2 mapping using the fast, clinically feasible, multi-echo gradient spin echo (GRASE) approach yields significantly higher values than much slower multiple single spin echo (SE) experiments. Although T2* mapping is reliable in magnetically homogeneous tissues, uncorrectable macroscopic background gradients and other effects (e.g. iron deposition) shorten T2*. Cerebral blood volume (CBV) measurement using DSC and normalization to WM yields robust estimates of rCBV in healthy-appearing brain tissue; absolute quantification of the venous fraction of CBV, however, is difficult to achieve. Our study demonstrates that quantitative measurements of rOEF are currently biased by inherent difficulties in T2 and CBV quantification, but also by inadequacies of the underlying model. We argue, however, that standardized, reproducible measurements of apparent T2, T2* and rCBV may still allow the estimation of a meaningful apparent rOEF, which requires further validation in clinical studies. PMID- 24809666 TI - The importance of predation risk and missed opportunity costs for context dependent foraging patterns. AB - Correct assessment of risks and costs of foraging is vital for the fitness of foragers. Foragers should avoid predation risk and balance missed opportunities. In risk-heterogeneous landscapes animals prefer safer locations over riskier, constituting a landscape of fear. Risk-uniform landscapes do not offer this choice, all locations are equally risky. Here we investigate the effects of predation risk in patches, travelling risk between patches, and missed social opportunities on foraging decisions in risk-uniform and risk-heterogeous landscapes. We investigated patch leaving decisions of 20 common voles (M. arvalis) in three experimental landscapes: safe risk-uniform, risky risk-uniform and risk-heterogeneous. We varied both the predation risk level and the predation risk distribution between two patches experimentally and in steps, assuming that our manipulation consequently yield different distributions and levels of risk while foraging, risk while travelling, and costs of missed, social opportunities (MSOCs). We measured mean GUDs (giving-up density of food left in the patch) for both patches as a measure of foraging gain, and delta GUD, the differences among patches, as a measure of the spatial distribution of foraging effort over a period of six hours. Distribution of foraging effort was most even in the safe risk-uniform landscapes and least even in the risk-heterogeneous landscape, with risky risk-uniform landscapes in between. Foraging gain was higher in the safe than in the two riskier landscapes (both uniform and heterogeneous). Results supported predictions for the effects of risk in foraging patches and while travelling between patches, however predictions for the effects of missed social opportunities were not met in this short term experiment. Thus, both travelling and foraging risk contribute to distinct patterns observable high risk, risk uniform landscapes. PMID- 24809667 TI - Comprehensive evaluation and optimization of amplicon library preparation methods for high-throughput antibody sequencing. AB - High-throughput sequencing (HTS) of antibody repertoire libraries has become a powerful tool in the field of systems immunology. However, numerous sources of bias in HTS workflows may affect the obtained antibody repertoire data. A crucial step in antibody library preparation is the addition of short platform-specific nucleotide adapter sequences. As of yet, the impact of the method of adapter addition on experimental library preparation and the resulting antibody repertoire HTS datasets has not been thoroughly investigated. Therefore, we compared three standard library preparation methods by performing Illumina HTS on antibody variable heavy genes from murine antibody-secreting cells. Clonal overlap and rank statistics demonstrated that the investigated methods produced equivalent HTS datasets. PCR-based methods were experimentally superior to ligation with respect to speed, efficiency, and practicality. Finally, using a two-step PCR based method we established a protocol for antibody repertoire library generation, beginning from inputs as low as 1 ng of total RNA. In summary, this study represents a major advance towards a standardized experimental framework for antibody HTS, thus opening up the potential for systems-based, cross-experiment meta-analyses of antibody repertoires. PMID- 24809669 TI - Spontaneous isolated posterior inferior cerebellar artery dissection: rare but underdiagnosed cause of ischemic stroke. AB - BACKGROUND: Spontaneous isolated posterior inferior cerebellar artery dissection (PICAD) is a very rare cause of ischemic stroke. Clinical and radiologic features of ischemic type of isolated spontaneous PICAD are not well established. METHODS: We consecutively enrolled patients who had spontaneous isolated PICAD confirmed by digital subtraction cerebral angiography. Clinical manifestation, magnetic resonance imaging (MRI), and angiography were analyzed. RESULTS: Seven patients were diagnosed as ischemic type of spontaneous isolated PICAD. Patients experienced an occipital headache, followed by vertigo, postural imbalance, or Wallenberg syndrome. Six showed medullar, unilateral, or bilateral cerebellar infarctions on diffusion-weighted imaging (DWI). One presented with transient cerebellar ischemia and negative on DWI. T1-weighted imaging showed high signal intensity in posterior inferior cerebellar artery in only 1 patient. Susceptibility-weighted imaging (SWI) revealed hypointense signal with blooming effect in posterior inferior cerebellar artery in 5 patients. The modified Rankin Scale score at 3 months was 0 or 1 in all patients. CONCLUSIONS: Clinical manifestations in ischemic type of spontaneous isolated PICAD were similar to those of intracranial vertebral artery dissection. Clinical course was relatively stable and benign. SWI was more helpful to suspect abnormality of posterior inferior cerebellar artery than conventional MRI or magnetic resonance angiography in our small series. Cerebral angiography is recommended in patients with clinically suspected spontaneous isolated PICAD for definite diagnosis. PMID- 24809668 TI - Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities. AB - Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor. PMID- 24809670 TI - Predictors of functional and gait outcomes for persons poststroke undergoing home based rehabilitation. AB - BACKGROUND: The literature on the impact of home-based rehabilitation on functional outcomes for patients after stroke is limited. The purpose of this study was to describe the outcomes of home-based rehabilitation (HBR) on functional and gait performance for patients after stroke and associated factors that contribute to better outcomes after an episode of care. METHODS: The nature of the study design was retrospective and the settings used were home care services. The total number of subjects receiving home care services after stroke was 213 (mean age 76.5 +/- 9 years, 51% female). Treatment records for patients receiving HBR in 2010 were reviewed at the start of care and discharge. The primary outcome measure was a change in a gait speed and activities of daily living (ADL) performance between admission and discharge from home health care services. The composite score to calculate overall functional status (Outcome Information and Assessment Set-version C [OASIS-C]) was used. Mean change in ADL and gait scores and factors predictive of improvement were identified using an analysis of covariance and multivariate linear models. The main outcome measures were change in the OASIS-C composite scores and gait speed. RESULTS: After adjustment for age and ADL score at the start of care, discharge from skilled nursing or long-term facilities, presence of confusion most of the times, cognitive impairment, and memory deficits were negatively associated with an improvement in functional scores (ADL). Living in congregate facilities was also negatively associated with an improvement in gait speed. The best multivariate model included age, baseline ADL composite scores, confusion status, and gait speed at the start of care, which predicted 41% of the variance in ADL score changes over the course of intervention. CONCLUSIONS: Gait speed and ADL scores at the start of care had largest influence on functional and gait improvement. Type of discharge facility, confusion status, and living arrangement had effects on HBR outcomes for stroke survivors. PMID- 24809671 TI - Factors related to knowledge of stroke symptoms and risk factors in a norwegian stroke population. AB - BACKGROUND: Previous studies have identified insufficient knowledge of stroke symptoms and risk factors both among survivors of stroke and in the general population. The purpose of this study was to investigate knowledge of stroke symptoms and risk factors in a Norwegian stroke population and to identify factors associated with good knowledge. METHODS: This prospective study included patients with acute transient ischemic attack, ischemic stroke, and intracerebral hemorrhage. Knowledge of stroke symptoms and risk factors was explored by asking open-ended questions. Bivariate and multivariate regression analyses were performed to identify factors related to good knowledge. RESULTS: In total, 287 patients (mean age +/- standard deviation, 70.0 +/- 12.9 years) answered the open ended questionnaire of which 71% knew at least 1 symptom of stroke whereas 43% knew at least 1 risk factor. Knowledge of both numbness/weakness and speech difficulties as symptoms of stroke (43% of the patients) was associated with lower age (odds ratio [OR], .96; 95% confidence interval [CI], .94-.99), higher education (OR, 2.25; 95% CI, 1.17-4.30), and having previously received information regarding stroke (OR, 7.74; 95% CI, 3.82-15.67). Knowing at least 2 of the 3 risk factors of stroke "smoking", "hypertension", and "diabetes" (14% of the patients) was associated with lower age (OR, .94; 95% CI, .92-.97). CONCLUSIONS: Knowledge of stroke symptoms and risk factors in patients with acute cerebrovascular disease seems to be insufficient. Further educational efforts are needed, as better knowledge may improve prevention of stroke and increase the number of patients who can receive thrombolysis. PMID- 24809672 TI - "Invisible" brain stem infarction at the first day. AB - BACKGROUND: In specific stroke cases, serial diffusion-weighted magnetic resonance imaging (DW MRI) on day 1 was unable to show a lesion, whereas that on day 4 and later clearly revealed a lesion. However, clinical features of this phenomenon ("invisible" brain stem infarction [IBI] at the first day) have not been fully delineated. METHODS: We retrospectively recruited 212 stroke patients in the Emergency Unit and Neurology Department. Among these, we studied patients with IBI. Definition of IBI is that acute and clear brain stem symptoms/signs on arrival were ameliorated at discharge and appearance of high signal intensity on serial DW images with low apparent diffusion coefficient (ADC) by 1.5 T MRI with 2-mm slices. RESULTS: IBI were found in only 6 patients. Day 1 invisible stroke was found only in the brain stem (17%, 6 of 35) but none (0 of 177) in the hemispheric infarction (P < .05). In most patients with IBI, DW MRI turned out visible at the third/fourth day. Before the fourth day, DW/ADC signal changes in patients with IBI were minimal. In IBI, lesion size (mean 2.7 mm(2)) was smaller than that of visible cases (mean 7.3 mm(2)). In IBI, lesion location was mostly at the dorsolateral medulla. In IBI, sensory disturbance was significantly more common (67%) than visible cases (24%; P < .05), whereas dysarthria was less common (0%; P < .01) than visible cases (66%; P < .01). CONCLUSIONS: It is likely that patients with smaller stroke volume, sensory disturbance, and medullary location are prone to develop IBI. When evaluating stroke using MRI criteria, recognition of IBI is important to start early management. PMID- 24809673 TI - In breast cancer patients sentinel lymph node metastasis characteristics predict further axillary involvement. AB - The aim of the study was to correlate various primary tumor characteristics with lymph node status, to examine sentinel lymph node (SLN) metastasis size and non SLN axillary involvement, to look for a cut-off size/number value possibly predicting additional axillary involvement with more accuracy and to examine the relationship of SLN metastasis size to overall survival. Of 301 patients who underwent SLN biopsy, 75 had positive SLNs. The size of the metastases was measured. For different size categories, association with the prevalence of non SLN metastases was assessed. Associations between metastasis size and tumor characteristics and overall survival (OS) were studied. The prevalence of axillary lymph node (ALN) involvement was not significantly different between cases with micrometastasis or macrometastasis in SLNs (p = 0.124). However, for metastases larger than 6, 7, and 8 mm, the prevalence of ALN involvement was significantly higher (p = 0.046, 0.022, and 0.025). OS was significantly lower in SLN-positive than in SLN-negative cases (p = 0.0375). Primary tumor size larger than 20 mm was associated with a significantly higher incidence of SLN metastasis (p < 0.001), and primary tumor size over 26 mm was associated with additional positive non-SLN (p < 0.001). Higher mitotic index (>= 7) in primary tumors was significantly (p < 0.001) associated with ALN involvement in SLN-positive cases, whereas higher Ki67 labeling index was not significantly correlated with SLN or ALN involvement. Lymphovascular invasion (LVI) in primary tumors was significantly correlated with SLN positivity (p < 0.001) but not with further ALN involvement or OS. Tumor size and LVI are predictive for SLN metastasis. Mitotic index, primary tumor size, and larger volume SLN involvement are determinants of further ALN involvement. SLN metastasis size over 6 mm is a strong predictor of further axillary involvement. OS is shorter in the presence of positive SLN. PMID- 24809674 TI - Clinical associations of hepatic stellate cell (HSC) hyperplasia. AB - Hepatic stellate cell (HSC) hyperplasia has been principally attributed to hypervitaminosis A. There are sporadic reports of HSC hyperplasia in other conditions such as chronic biliary disease and hepatitis C, but clinical associations of this entity have not been studied in detail. We aimed to investigate the clinical associations of HSC hyperplasia aside from hypervitaminosis A. We identified 34 patients whose liver histology showed HSC hyperplasia. We reviewed the liver samples; additional histologic findings in addition to HSC hyperplasia were consolidated into a histologic diagnosis. We collected clinical, laboratory, and radiologic data; the histologic diagnosis was combined with this data to reach an "overall diagnosis." Four patients had hypervitaminosis A (all native livers). In native livers (n = 24), HSC hyperplasia also occurred in association with drug-induced hepatitis [n = 6, niacin was the most common inducing agent (n = 3)], reactive hepatitis (n = 4), chronic hepatitis C (n = 4), autoimmune hepatitis (n = 3), steatohepatitis (n = 1), chronic biliary disease (n = 1), and portal venopathy (n = 1). In liver allografts (n = 10), HSC hyperplasia was seen in protocol biopsies without other significant abnormalities (n = 5), chronic biliary disease (n = 4), and acute cellular rejection (n = 1). All patients used medications (total of 99) and 82 % were on multiple medications. HSC hyperplasia is an uncommon and relatively nonspecific finding that most commonly occurs in multimedicated patients, often in the absence of hypervitaminosis A. Associated conditions include drug toxicity (such as niacin), post-liver transplant setting, reactive hepatitis (due to systemic illness or inflammatory disorders of the gastrointestinal tract), and chronic liver disease. PMID- 24809675 TI - Impact of peer counselling breast-feeding support programme protocols on any and exclusive breast-feeding discontinuation in low-income women. AB - OBJECTIVE: Peer counselling (PC) programmes have been shown to improve breast feeding outcomes in populations at risk for early discontinuation. Our objective was to describe associations between programme components (individual and combinations) and breast-feeding outcomes (duration and exclusivity) in a PC programme for low-income women. DESIGN: Secondary analysis of programme data. Multivariable-adjusted Cox proportional hazards models were used to examine associations between type and quantity of peer contacts with breast-feeding outcomes. Types of contacts included in-person (hospital or home), phone or other (e.g. mail, text). Quantities of contacts were considered 'optimal' if they adhered to standard programme guidelines. SETTING: Programme data collected from 2005 to 2011 in Michigan's Breastfeeding Initiative Peer Counseling Program. SUBJECTS: Low-income (n 5886) women enrolled prenatally. RESULTS: For each additional home, phone and other PC contact there was a significant reduction in the hazard of discontinuing any breast-feeding by 6 months (hazard ratio (HR)=0.90 (95% CI 0.88, 0.92); HR=0.89 (95% CI 0.87, 0.90); and HR=0.93 (95% CI 0.90, 0.96), respectively) and exclusive breast-feeding by 3 months (HR=0.92 (95% CI 0.89, 0.95); HR=0.90 (95% CI 0.88, 0.91); and HR=0.93 (95% CI 0.89, 0.97), respectively). Participants receiving greater than optimal in-person and less than optimal phone contacts had a reduced hazard of any and exclusive breast feeding discontinuation compared with those who were considered to have optimum quantities of contacts (HR=0.17 (95% CI 0.14, 0.20) and HR=0.28 (95% CI 0.23, 0.35), respectively). CONCLUSIONS: Specific components of a large PC programme appeared to have an appreciable impact on breast-feeding outcomes. In-person contacts were essential to improving breast-feeding outcomes, but defining optimal programme components is complex. PMID- 24809676 TI - The cost and impact of the interim federal health program cuts on child refugees in Canada. AB - INTRODUCTION: On June 30, 2012, Interim Federal Health Program (IFHP) funding was cut for refugee claimant healthcare. The potential financial and healthcare impacts of these cuts on refugee claimants are unknown. METHODS: We conducted a one-year retrospective chart review spanning 6 months before and after IFHP funding cuts at The Hospital for Sick Children, a tertiary care children's hospital in Toronto. We analyzed emergency room visits characteristics, admission rates, reasons for admission, and financial records including billing from Medavie Blue Cross. RESULTS: There were 173 refugee children visits to the emergency room in the six months before and 142 visits in the six months after funding cuts. The total amount billed to the IFHP program during the one-year of this study was $131,615. Prior to the IFHP cuts, 46% of the total emergency room bills were paid by IFHP compared to 7% after the cuts (p<0.001). INTERPRETATION: After the cuts to the IFHP, The Hospital for Sick Children was unable to obtain federal health coverage for the vast majority of refugee claimant children registered under the IFHP. This preliminary analysis showed that post-IFHP cuts healthcare costs at the largest tertiary pediatric institution in the country increased. PMID- 24809677 TI - Autocatalytic formation of an iron(IV)-oxo complex via scandium ion-promoted radical chain autoxidation of an iron(II) complex with dioxygen and tetraphenylborate. AB - A non-heme iron(IV)-oxo complex, [(TMC)Fe(IV)(O)](2+) (TMC = 1,4,8,11-tetramethyl 1,4,8,11-tetraazacyclotetradecane), was formed by oxidation of an iron(II) complex ([(TMC)Fe(II)](2+)) with dioxygen (O2) and tetraphenylborate (BPh4(-)) in the presence of scandium triflate (Sc(OTf)3) in acetonitrile at 298 K via autocatalytic radical chain reactions rather than by a direct O2 activation pathway. The autocatalytic radical chain reaction is initiated by scandium ion promoted electron transfer from BPh4(-) to [(TMC)Fe(IV)(O)](2+) to produce phenyl radical (Ph(*)). The chain propagation step is composed of the addition of O2 to Ph(*) and the reduction of the resulting phenylperoxyl radical (PhOO(*)) by scandium ion-promoted electron transfer from BPh4(-) to PhOO(*) to produce phenyl hydroperoxide (PhOOH), accompanied by regeneration of phenyl radical. PhOOH reacts with [(TMC)Fe(II)](2+) to yield phenol (PhOH) and [(TMC)Fe(IV)(O)](2+). Biphenyl (Ph-Ph) was formed via the radical chain autoxidation of BPh3 by O2. The induction period of the autocatalytic radical chain reactions was shortened by addition of a catalytic amount of [(TMC)Fe(IV)(O)](2+), whereas addition of a catalytic amount of ferrocene that can reduce [(TMC)Fe(IV)(O)](2+) resulted in elongation of the induction period. Radical chain autoxidation of BPh4(-) by O2 also occurred in the presence of Sc(OTf)3 without [(TMC)Fe(IV)(O)](2+), initiating the autocatalytic oxidation of [(TMC)Fe(II)](2+) with O2 and BPh4(-) to yield [(TMC)Fe(IV)(O)](2+). Thus, the general view for formation of non-heme iron(IV)-oxo complexes via O2-binding iron species (e.g., Fe(III)(O2(*-))) without contribution of autocatalytic radical chain reactions should be viewed with caution. PMID- 24809678 TI - Adherence with national guidelines in hospitalized patients with community acquired pneumonia: results from the CAPO study in Venezuela. AB - INTRODUCTION: The Community-Acquired Pneumonia Organization (CAPO) is an international observational study in 130 hospitals, with a total of 31 countries, to assess the current management of hospitalized patients with community-acquired pneumonia (CAP). 2 Using the centralized database of CAPO was decided to conduct this study with the aim of evaluate the level of adherence with national guidelines in Venezuela, to define in which areas an intervention may be necessary to improve the quality of care of hospitalized patients with CAP. METHODS: In this observational retrospective study quality indicators were used to evaluate the management of hospitalized patients with CAP in 8 Venezuelan's centers. The care of the patients was evaluated in the areas of: hospitalization, oxygen therapy, empiric antibiotic therapy, switch therapy, etiological studies, blood cultures indication, and prevention. The compliance was rated as good (>90%), intermediate (60% to 90%), or low (<60%). RESULTS: A total of 454 patients with CAP were enrolled. The empiric treatment administered within 8 hours of the patient arrival to the hospital was good (96%), but the rest of the indicators showed a low level of adherence (<60%). CONCLUSION: We can say that there are many areas in the management of CAP in Venezuela that are not performed according to the national guidelines of SOVETHORAX.1 In any quality improvement process the first step is to evaluate the difference between what is recommended and what is done in clinical practice. While this study meets this first step, the challenge for the future is to implement the processes necessary to improve the management of CAP in Venezuela. PMID- 24809679 TI - Elevated carboxyhemoglobin: sources of carbon monoxide exposure. AB - INTRODUCTION: Inhalation of carbon monoxide (CO) can result in poisoning, with symptoms ranging from mild and nonspecific to severe, or even death. CO poisoning is often underdiagnosed because exposure to low concentrations goes unnoticed, and threshold values for normal carboxyhemoglobin vary according to different authors. The aim of our study was to analyze carboxyhemoglobin (COHb) levels in an unselected population and detect sources of CO exposure METHODS: In a cross sectional descriptive study, we analyzed consecutive arterial blood gas levels processed in our laboratory. We selected those with COHb>=2.5% in nonsmokers and >=5% in smokers. In these cases a structured telephone interview was conducted. RESULTS: Elevated levels of COHb were found in 64 (20%) of 306 initial determinations. Of these, data from 51 subjects aged 65+/-12 years, 31 (60%) of which were men, were obtained. Mean COHb was 4.0%. Forty patients (78%) were non smokers with mean COHb of 3.2%, and 11 were smokers with COHb of 6.7%. In 45 patients (88.2%) we detected exposure to at least one source of ambient CO other than cigarette smoke. CONCLUSIONS: A significant proportion of individuals from an unselected sample had elevated levels of COHb. The main sources of CO exposure were probably the home, so this possibility should be explored. The population should be warned about the risks and encouraged to take preventive measures. PMID- 24809680 TI - Interspinous spacer versus traditional decompressive surgery for lumbar spinal stenosis: a systematic review and meta-analysis. AB - BACKGROUND: Dynamic interspinous spacers, such as X-stop, Coflex, DIAM, and Aperius, are widely used for the treatment of lumbar spinal stenosis. However, controversy remains as to whether dynamic interspinous spacer use is superior to traditional decompressive surgery. METHODS: Medline, Embase, Cochrane Library, and the Cochrane Controlled Trials Register were searched during August 2013. A track search was performed on February 27, 2014. Study was included in this review if it was: (1) a randomized controlled trial (RCT) or non-randomized prospective comparison study, (2) comparing the clinical outcomes for interspinous spacer use versus traditional decompressive surgery, (3) in a minimum of 30 patients, (4) with a follow-up duration of at least 12 months. RESULTS: Two RCTs and three non-randomized prospective studies were included, with 204 patients in the interspinous spacer (IS) group and 217 patients in the traditional decompressive surgery (TDS) group. Pooled analysis showed no significant difference between the IS and TDS groups for low back pain (WMD: 1.2; 95% CI: -10.12, 12.53; P = 0.03; I2 = 66%), leg pain (WMD: 7.12; 95% CI: -3.88, 18.12; P = 0.02; I2 = 70%), ODI (WMD: 6.88; 95% CI: -14.92, 28.68; P = 0.03; I2 = 79%), RDQ (WMD: -1.30, 95% CI: -3.07, 0.47; P = 0.00; I2 = 0%), or complications (RR: 1.39; 95% CI: 0.61, 3.14; P = 0.23; I2 = 28%). The TDS group had a significantly lower incidence of reoperation (RR: 3.34; 95% CI: 1.77, 6.31; P = 0.60; I2 = 0%). CONCLUSION: Although patients may obtain some benefits from interspinous spacers implanted through a minimally invasive technique, interspinous spacer use is associated with a higher incidence of reoperation and higher cost. The indications, risks, and benefits of using an interspinous process device should be carefully considered before surgery. PMID- 24809683 TI - Critical care nurses management of prolonged weaning: an interview study. AB - BACKGROUND: For most critically ill patients requiring mechanical ventilation in the intensive care unit (ICU) weaning is uncomplicated. For the remainder, weaning is a challenge and may result in further complications and increased risk of mortality. Critical care nurses (CCNs) require substantial knowledge and experience to manage patients experiencing prolonged weaning. AIM: The aim of this study was to explore CCNs approach for management of patients experiencing prolonged weaning in the ICU. DESIGN: A descriptive qualitative design. METHODS: Semi-structured interviews with 19 experienced CCNs were conducted. Data were analysed using content analysis. RESULTS: Participants used various strategies for weaning that were grouped into four categories: individualized planning for the weaning process, assessing patient's capacity, managing the process and team interaction. The overall theme that emerged was: CCNs drive the weaning process using both a patient centred and targeted approach. CONCLUSION: CCNs in these ICUs performed weaning using a patient centred approach to plan, initiate, assess and establish a holistic weaning process. Team collaboration among all health care practitioners was important. CCNs have a key role in prioritizing weaning and driving the process forward. RELEVANCE TO CLINICAL PRACTICE: Closeness to the patient and a key role in management of the mechanical ventilated patient in ICU gives the CCN unique potential to develop and create models and tools for prolonged weaning. These tools, specially designed for patients undergoing prolonged weaning, would give focus on continuous planning, collaborating, managing and evaluation in the process of liberating patients from mechanical ventilation. PMID- 24809681 TI - A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya. AB - BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ. PMID- 24809684 TI - Mismatch negativity-like potential (MMN-like) in the subthalamic nuclei in Parkinson's disease patients. AB - An infrequent change to an otherwise repetitive sequence of stimuli leads to the generation of mismatch negativity (MMN), even in the absence of attention. This evoked negative response occurs in the scalp-recorded electroencephalogram (EEG) over the temporal and frontal cortices, 100-250 ms after onset of the deviant stimulus. The MMN is used to detect sensory information processing. The aim of our study was to investigate whether MMN can be recorded in the subthalamic nuclei (STN) as evidence of auditory information processing on an unconscious level within this structure. To our knowledge, MMN has never been recorded in the human STN. We recorded intracerebral EEG using a MMN paradigm in five patients with Parkinson's disease (PD) who were implanted with depth electrodes in the subthalamic nuclei (STN). We found far-field MMN when intracerebral contacts were connected to an extracranial reference electrode. In all five PD patients (and nine of ten intracerebral electrodes), we also found near-field MMN-like potentials when intracerebral contacts were referenced to one another, and in some electrodes, we observed phase reversals in these potentials. The mean time to-peak latency of the intracerebral MMN-like potentials was 214 +/- 38 ms (median 219 ms). We reveal MMN-like potentials in bilateral STN. This finding provides evidence that STN receives sensory (auditory) information from other structures. The question for further research is whether STN receives such signals through a previously described hyperdirect pathway between STN and frontal cortex (a known generator of the MMN potential) and if the STN contributes to sensorimotor integration. PMID- 24809685 TI - Pharmacoepigenetics of depression: no major influence of MAO-A DNA methylation on treatment response. AB - The monoamine oxidase A (MAO-A) gene has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of major depressive disorder. In the present analysis, for the first time a pharmacoepigenetic approach was applied investigating the influence of DNA methylation patterns in the MAO-A regulatory and exon1/intron1 region on antidepressant treatment response. 94 patients of Caucasian descent with major depressive disorder (f = 61; DSM-IV) were analyzed for DNA methylation status at 43 MAO-A CpG sites via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional MAO-A VNTR. Clinical response to antidepressant treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 weeks of treatment. Apart from two CpG sites, male subjects showed no or only very minor methylation. In female patients, lower methylation at two individual CpG sites in the MAO-A promoter region was nominally associated with impaired response to antidepressant treatment after 6 weeks (GRCh37/hg19: CpG 43.514.063, p = 0.04; CpG 43.514.684, p = 0.009), not, however, withstanding correction for multiple testing. MAO-A VNTR genotypes did not influence MAO-A methylation status. The present pilot data do not suggest a major influence of MAO-A DNA methylation on antidepressant treatment response. However, the presently observed trend towards CpG-specific MAO-A gene hypomethylation-possibly via increased gene expression and consecutively decreased serotonin and/or norepinephrine availability-to potentially drive impaired antidepressant treatment response in female patients might be worthwhile to be followed up in larger pharmacoepigenetic studies. PMID- 24809686 TI - Characteristics and occurrence of speech impairment in Huntington's disease: possible influence of antipsychotic medication. AB - Although motor speech impairment is a common manifestation of Huntington's disease (HD), its description remains limited. The aim of the current study was therefore to estimate the occurrence and characteristics of speech disorder in HD and to explore the influence of antipsychotic medication on speech performance. Speech samples, including reading passage and monologue, were acquired from 40 individuals diagnosed with HD and 40 age- and sex-matched healthy controls. Objective acoustic analyses were used to evaluate key aspects of speech including vowel articulation, intensity, pitch and timing. A predictive model was constructed to detect the occurrence and most prominent patterns of speech dysfunction in HD. We revealed that 93% of HD patients manifest some degree of speech impairment. Decreased number of pauses, slower articulation rate, imprecise vowel articulation and excess intensity variations were found to be the most salient patterns of speech dysfunction in HD. We further demonstrated that antipsychotic medication may induce excessive loudness and pitch variations perceptually resembling excess patterns of word stress, and may also accentuate general problems with speech timing. Additionally, antipsychotics induced a slight improvement of vowel articulation. Specific speech alterations observed in HD patients indicate that speech production may reflect the pathophysiology of the disease as well as treatment effects, and may therefore be considered a valuable marker of functional disability in HD. PMID- 24809687 TI - An Evolving Identity: How Chronic Care Is Transforming What it Means to Be a Physician. AB - Physician identity and the professional role physicians play in health care is rapidly evolving. Over 130 million adults and children in the USA have complex and chronic diseases, each of which is shaped by aspects of the patient's social, psychological, and economic status. These patients have lifelong health care needs that require the ongoing care of multiple health care providers, access to community services, and the involvement of patients' family support networks. To date, physician professional identity formation has centered on autonomy, authority, and the ability to "heal." These notions of identity may be counterproductive in chronic disease care, which demands interdependency between physicians, their patients, and teams of multidisciplinary health care providers. Medical educators can prepare trainees for practice in the current health care environment by providing training that legitimizes and reinforces a professional identity that emphasizes this interdependency. This commentary outlines the important challenges related to this change and suggests potential strategies to reframe professional identity to better match the evolving role of physicians today. PMID- 24809688 TI - A Call to Restructure Psychiatry General and Subspecialty Training. AB - Dire shortages of psychiatrists with special expertise in geriatrics, substance abuse, forensics, and psychosomatics create barriers to care for populations with complex mental disorders and pose a significant public health concern. To address these disparities in access to care, we propose streamlining graduate medical education to increase efficiency and enhance cost-effectiveness while simultaneously increasing the number of psychiatric subspecialists in these key areas. We propose that trainees interested in subspecialties complete their general training in 3 years, while meeting ACGME required milestones, and then utilize their 4th year to complete subspecialty fellowship training. Eligible trainees would then qualify for psychiatry subspecialty certification and general psychiatry ABPN certification at the end of 4 years. PMID- 24809689 TI - Epstein-Barr virus down-regulates tumor suppressor DOK1 expression. AB - The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2'-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis. PMID- 24809690 TI - Characteristic CSF prion seeding efficiency in humans with prion diseases. AB - The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrP(Sc)) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrP(Sc) type, and other disease-related factors on the real-time quaking-induced conversion (RT-QuIC) response. We analyzed times to 10,000 relative fluorescence units, areas under the curve and the signal maximum of RT QuIC response as seeding parameters of interest. Interestingly, type of prion disease (sporadic vs. genetic) and the PRNP mutation (E200K vs. V210I and FFI), codon 129 genotype, and PrP(Sc) type affected RT-QuIC response. In genetic forms, type of mutation showed the strongest effect on the observed outcome variables. In sporadic CJD, MM1 patients displayed a higher RT-QuIC signal maximum compared to MV1 and VV1. Age and gender were not associated with RT-QuIC signal, but patients with a short disease course showed a higher seeding efficiency of the RT QuIC response. This study demonstrated that PrP(Sc) characteristics in the CSF of human prion disease patients are associated with disease subtypes and rate of decline as defined by disease duration. PMID- 24809691 TI - Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases. AB - Motor neuron disorders, and particularly amyotrophic lateral sclerosis (ALS), are fatal diseases that are due to the loss of motor neurons in the brain and spinal cord, with progressive paralysis and premature death. It has been recently shown that the most frequent genetic cause of ALS, frontotemporal dementia (FTD), and other neurological diseases is the expansion of a hexanucleotide repeat (GGGGCC) in the non-coding region of the C9ORF72 gene. The pathogenic mechanisms that produce cell death in the presence of this expansion are still unclear. One of the most likely hypotheses seems to be the gain-of-function that is achieved through the production of toxic RNA (able to sequester RNA-binding protein) and/or toxic proteins. In recent works, different authors have reported that antisense oligonucleotides complementary to the C9ORF72 RNA transcript sequence were able to significantly reduce RNA foci generated by the expanded RNA, in affected cells. Here, we summarize the recent findings that support the idea that the buildup of "toxic" RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS and also suggest that the use of antisense oligonucleotides targeting this transcript is a promising strategy for treating ALS/frontotemporal lobe dementia (FTLD) patients with the C9ORF72 repeat expansion. These data are particularly important, given the state of the art antisense technology, and they allow researchers to believe that a clinical application of these discoveries will be possible soon. PMID- 24809692 TI - Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke. AB - Accumulating evidence suggests that ischemic preconditioning (IPC) increases cerebral tolerance to the subsequent ischemic exposure. However, the underlying mechanisms are still not fully understood. In the present study, we tested the hypothesis that AMP-activated protein kinase (AMPK)-dependent autophagy contributed to the neuroprotection of IPC in rats with permanent cerebral ischemia. Male Sprague-Dawley rats were pretreated with vehicle, compound C (an AMPK inhibitor), or 3-methyladenine (3-MA, an autophagy inhibitor) and then were subjected to IPC induced by a 10-min middle cerebral artery occlusion. Afterward, the brain AMPK activity and autophagy biomarkers were measured. At 24 h after IPC, permanent cerebral ischemia was induced in these rats, and infarct volume, neurological deficits as well as cell apoptosis were evaluated 24 h later. We demonstrated that IPC activated AMPK and induced autophagy in the brain, which was accompanied by a reduction of infract volume, neurological deficits, and cell apoptosis after cerebral ischemia. Meanwhile, the IPC-induced autophagy was inhibited by compound C while the neuroprotection of IPC was abolished by compound C or 3-MA. These findings suggest that AMPK-mediated autophagy contributes to the neuroprotection of IPC, highlighting AMPK as a therapeutic target for stroke prevention and treatment. PMID- 24809693 TI - Gearing up chromatin: A role for chromatin remodeling during the transcriptional restart upon DNA damage. AB - During transcription, RNA polymerase may encounter DNA lesions, which causes stalling of transcription. To overcome the RNA polymerase blocking lesions, the transcribed strand is repaired by a dedicated repair mechanism, called transcription coupled nucleotide excision repair (TC-NER). After repair is completed, it is essential that transcription restarts. So far, the regulation and exact molecular mechanism of this transcriptional restart upon genotoxic damage has remained elusive. Recently, three different chromatin remodeling factors, HIRA, FACT, and Dot1L, were identified to stimulate transcription restart after DNA damage. These factors either incorporate new histones or establish specific chromatin marks that will gear up the chromatin to subsequently promote transcription recovery. This adds a new layer to the current model of chromatin remodeling necessary for repair and indicates that this specific form of transcription, i.e., the transcriptional restart upon DNA damage, needs specific chromatin remodeling events. PMID- 24809694 TI - Characteristics of attempted suicide by patients with schizophrenia compared with those with mood disorders: a case-controlled study in northern Japan. AB - Recent reports suggest a lifetime suicide risk for schizophrenia patients of approximately 5%. This figure is significantly higher than the general population suicide risk consequently, detection of those at risk is clinically important. This study was undertaken to define the characteristics of suicide attempts by schizophrenia patients compared with attempts by patients with mood disorders. All patients were diagnosed using the ICD-10 criteria. The study population comprised 65 patients with F2 disorders (schizophrenia, schizotypal and delusional disorders), i.e., "the F2 group", and 94 patients with F3 disorders (mood disorders), i.e., "the F3 group", who presented in the clinical setting of consultation-liaison psychiatry. The F2 group had a significantly younger mean age and significantly higher ratios of 'past/present psychiatric treatment' and 'more than 3 months interruption of psychiatric treatment'. In contrast, the ratios of 'physical disorder comorbidity', 'alcohol intake at suicide attempt' and 'suicide note left behind' were significantly higher in the F3 group. The F2 group attempted suicide by significantly more serious methods. Furthermore, 'hallucination-delusion' was the most prevalent motive in the F2 group and was the only factor that showed a significant association with the seriousness of the method of suicide attempt (OR = 3.36, 95% CI: 1.05-11.33). PMID- 24809696 TI - Comparing population attributable risks for heart disease across the adult lifespan in women. AB - BACKGROUND: Recent estimates suggest that high body mass index (BMI), smoking, high blood pressure (BP) and physical inactivity are leading risk factors for the overall burden of disease in Australia. The aim was to examine the population attributable risk (PAR) of heart disease for each of these risk factors, across the adult lifespan in Australian women. METHODS: PARs were estimated using relative risks (RRs) for each of the four risk factors, as used in the Global Burden of Disease Study, and prevalence estimates from the Australian Longitudinal Study on Women's Health, in 15 age groups from 22-27 (N=9608) to 85 90 (N=3901). RESULTS: RRs and prevalence estimates varied across the lifespan. RRs ranged from 6.15 for smoking in the younger women to 1.20 for high BMI and high BP in the older women. Prevalence of risk exposure ranged from 2% for high BP in the younger women to 79% for high BMI in mid-age women. In young adult women up to age 30, the highest population risk was attributed to smoking. From age 31 to 90, PARs were highest for physical inactivity. CONCLUSIONS: From about age 30, the population risk of heart disease attributable to inactivity outweighs that of other risk factors, including high BMI. Programmes for the promotion and maintenance of physical activity deserve to be a much higher public health priority for women than they are now, across the adult lifespan. PMID- 24809695 TI - Toward discovering new anti-cancer agents targeting topoisomerase IIalpha: a facile screening strategy adaptable to high throughput platform. AB - Topoisomerases are a family of vital enzymes capable of resolving topological problems in DNA during various genetic processes. Topoisomerase poisons, blocking reunion of cleaved DNA strands and stabilizing enzyme-mediated DNA cleavage complex, are clinically important antineoplastic and anti-microbial agents. However, the rapid rise of drug resistance that impedes the therapeutic efficacy of these life-saving drugs makes the discovering of new lead compounds ever more urgent. We report here a facile high throughput screening system for agents targeting human topoisomerase IIalpha (Top2alpha). The assay is based on the measurement of fluorescence anisotropy of a 29 bp fluorophore-labeled oligonucleotide duplex. Since drug-stabilized Top2alpha-bound DNA has a higher anisotropy compared with free DNA, this assay can work if one can use a dissociating agent to specifically disrupt the enzyme/DNA binary complexes but not the drug-stabilized ternary complexes. Here we demonstrate that NaClO4, a chaotropic agent, serves a critical role in our screening method to differentiate the drug-stabilized enzyme/DNA complexes from those that are not. With this strategy we screened a chemical library of 100,000 compounds and obtained 54 positive hits. We characterized three of them on this list and demonstrated their effects on the Top2alpha-mediated reactions. Our results suggest that this new screening strategy can be useful in discovering additional candidates of anti cancer agents. PMID- 24809697 TI - Predicting birth weight with conditionally linear transformation models. AB - Low and high birth weight (BW) are important risk factors for neonatal morbidity and mortality. Gynecologists must therefore accurately predict BW before delivery. Most prediction formulas for BW are based on prenatal ultrasound measurements carried out within one week prior to birth. Although successfully used in clinical practice, these formulas focus on point predictions of BW but do not systematically quantify uncertainty of the predictions, i.e. they result in estimates of the conditional mean of BW but do not deliver prediction intervals. To overcome this problem, we introduce conditionally linear transformation models (CLTMs) to predict BW. Instead of focusing only on the conditional mean, CLTMs model the whole conditional distribution function of BW given prenatal ultrasound parameters. Consequently, the CLTM approach delivers both point predictions of BW and fetus-specific prediction intervals. Prediction intervals constitute an easy to-interpret measure of prediction accuracy and allow identification of fetuses subject to high prediction uncertainty. Using a data set of 8712 deliveries at the Perinatal Centre at the University Clinic Erlangen (Germany), we analyzed variants of CLTMs and compared them to standard linear regression estimation techniques used in the past and to quantile regression approaches. The best performing CLTM variant was competitive with quantile regression and linear regression approaches in terms of conditional coverage and average length of the prediction intervals. We propose that CLTMs be used because they are able to account for possible heteroscedasticity, kurtosis, and skewness of the distribution of BWs. PMID- 24809698 TI - A dominant-negative mutation of mouse Lmx1b causes glaucoma and is semi-lethal via LDB1-mediated dimerization [corrected]. AB - Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice. PMID- 24809699 TI - Reciprocal regulation as a source of ultrasensitivity in two-component systems with a bifunctional sensor kinase. AB - Two-component signal transduction systems, where the phosphorylation state of a regulator protein is modulated by a sensor kinase, are common in bacteria and other microbes. In many of these systems, the sensor kinase is bifunctional catalyzing both, the phosphorylation and the dephosphorylation of the regulator protein in response to input signals. Previous studies have shown that systems with a bifunctional enzyme can adjust the phosphorylation level of the regulator protein independently of the total protein concentrations--a property known as concentration robustness. Here, I argue that two-component systems with a bifunctional enzyme may also exhibit ultrasensitivity if the input signal reciprocally affects multiple activities of the sensor kinase. To this end, I consider the case where an allosteric effector inhibits autophosphorylation and, concomitantly, activates the enzyme's phosphatase activity, as observed experimentally in the PhoQ/PhoP and NRII/NRI systems. A theoretical analysis reveals two operating regimes under steady state conditions depending on the effector affinity: If the affinity is low the system produces a graded response with respect to input signals and exhibits stimulus-dependent concentration robustness--consistent with previous experiments. In contrast, a high-affinity effector may generate ultrasensitivity by a similar mechanism as phosphorylation dephosphorylation cycles with distinct converter enzymes. The occurrence of ultrasensitivity requires saturation of the sensor kinase's phosphatase activity, but is restricted to low effector concentrations, which suggests that this mode of operation might be employed for the detection and amplification of low abundant input signals. Interestingly, the same mechanism also applies to covalent modification cycles with a bifunctional converter enzyme, which suggests that reciprocal regulation, as a mechanism to generate ultrasensitivity, is not restricted to two-component systems, but may apply more generally to bifunctional enzyme systems. PMID- 24809701 TI - Long-range integration of repressive and patterning inputs. PMID- 24809702 TI - Targeting insulin-like growth factor 1 receptor inhibits pancreatic cancer growth and metastasis. AB - Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor beta. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer. PMID- 24809703 TI - DWT-based segmentation method for coronary arteries. AB - This work presents a new method for segmenting coronary arteries automatically in computed tomography angiography (CTA) data sets. The method automatically isolates heart and coronary arteries from surrounding structures and search for the probable location of coronary arteries by 3D region growing. Based on the dilation of the probable location, discrete wavelet transformation (DWT) and lambda - mean operation complete accurate detection of coronary arties. Finally, the proposed method is tested on clinical CTA data-sets. The results on clinical datasets show that the proposed method is able to extract each branch of arteries when comparing to commercial software GE Healthcare and delineated ground truth. PMID- 24809705 TI - [Lung cancer screening:review and prospect]. PMID- 24809704 TI - Predicting smoking cessation and its relapse in HIV-infected patients: the Swiss HIV Cohort Study. AB - OBJECTIVES: The aim of the study was to assess whether prospective follow-up data within the Swiss HIV Cohort Study can be used to predict patients who stop smoking; or among smokers who stop, those who start smoking again. METHODS: We built prediction models first using clinical reasoning ('clinical models') and then by selecting from numerous candidate predictors using advanced statistical methods ('statistical models'). Our clinical models were based on literature that suggests that motivation drives smoking cessation, while dependence drives relapse in those attempting to stop. Our statistical models were based on automatic variable selection using additive logistic regression with component wise gradient boosting. RESULTS: Of 4833 smokers, 26% stopped smoking, at least temporarily; because among those who stopped, 48% started smoking again. The predictive performance of our clinical and statistical models was modest. A basic clinical model for cessation, with patients classified into three motivational groups, was nearly as discriminatory as a constrained statistical model with just the most important predictors (the ratio of nonsmoking visits to total visits, alcohol or drug dependence, psychiatric comorbidities, recent hospitalization and age). A basic clinical model for relapse, based on the maximum number of cigarettes per day prior to stopping, was not as discriminatory as a constrained statistical model with just the ratio of nonsmoking visits to total visits. CONCLUSIONS: Predicting smoking cessation and relapse is difficult, so that simple models are nearly as discriminatory as complex ones. Patients with a history of attempting to stop and those known to have stopped recently are the best candidates for an intervention. PMID- 24809706 TI - [Molecular testing clinical progress for EGFR mutation and ALK rearrangement of lung cancer based on the guideline from IASLC/CAP/AMP]. PMID- 24809707 TI - [Hotspot issues about epidermal growth factor receptor tyrosine kinase inhibitor in treatment of non-small cell lung cancer central nervous system metastasis]. PMID- 24809708 TI - [Combination of narrow band imaging (NBI) and autofluorescence bronchoscopy (AFB) in the assessment of central lung cancer]. AB - OBJECTIVE: To assess the diagnostic value of narrow-band imaging(NBI) in the diagnosis of central lung cancer. METHODS: Patients (n = 153) suspected of having lung cancer underwent white light bronchoscopy(WLB), NBI and autofluorescence bronchoscopy(AFB) in turn. At least 3 biopsies in each case were taken from sites visualized as lesions. The sensitivity and specificity of NBI, AFB and combination of NBI and AFB were compared. RESULTS: There were 106 male (69.3%) and 47 female patients (30.7%). By NBI, 91 and 62 cases were positive and negative respectively. The sensitivity and specificity of NBI were 63.5% (87/137) and 75.0% (12/16) respectively. By AFB, 140 and 13 cases were positive and negative respectively. The sensitivity and specificity of AFB were 94.2% (129/137) and 87.5% (5/16) respectively. By NBI combined with AFB, 133 and 20 cases were positive and negative respectively, the sensitivity and specificity being 95.6% (131/137) and 87.5% (14/16) respectively. The difference of specificity between NBI plus AFB and AFB alone was significant (P < 0.01), but the difference of sensitivity between NBI plus AFB and AFB alone(P > 0.05) was not. The difference of specificity between NBI plus AFB and NBI alone was significant (P < 0.01), but the P value of specificity between NBI plus AFB and NBI was 0.03. CONCLUSION: Combination of NBI and AFB could increase the specificity of lung cancer diagnosis compared to AFB alone. PMID- 24809709 TI - [A cohort study on the outcome of multidrug-resistant tuberculosis in elderly patients]. AB - OBJECTIVE: To investigate the clinical curative effect and outcomes of multidrug resistant tuberculosis (MDR-TB) in elderly patients. METHODS: Fifty-nine elderly patients with MDR-TB were enrolled from Shanghai Pulmonary Hospital from January 2007 to January 2010, and 80 younger patients with MDR-TB during the same period served as the control group. Clinical characteristics, outcomes and adverse effects of treatment were reviewed, and the data of the 2 groups were compared using cohort analysis. Comparisons of categorical variables were performed using the Pearson Chi-square tests, and differences between groups were compared by Fisher's exact test. RESULTS: Compared with those of the younger patients, the clinical symptoms of the elderly patients showed no significant differences except shortness of breath. The proportion of retreated patients in the elderly patients (96.6%, 57/59) was significantly higher than that in the younger group (86.3%, 69/80) (chi2 = 4.299, P < 0.05). The proportion of the patients with lesions involving 5-6 lung fields in the elderly group was 57.6% (34/59), higher than that in the younger group (22.5%, 18/80) (chi2 = 17.894, P < 0.01). The treatment success rate in the elderly MDR-TB group was 28.2% (17/59), lower than that in the younger group (51.3%, 41/80) (chi2 = 7.029, P < 0.01). The death rate in the elderly group was 17.0% (10/59), significantly higher than that in the younger group (3.4%, 3/80) (chi2 = 6.837-17.894, P < 0.05). The incidence of liver injury in the elderly group was higher than that in the younger group (23.7%, 14/59 vs 10.0%, 8/80,chi2 = 4.804, P < 0.05), and so was that of kidney dysfunction (10.2%, 6/59 vs 1.3%, 1/80, chi2 = 5.649, P < 0.05). CONCLUSIONS: In elderly patients with MDR-TB, the pulmonary lesions were extensive, the number of retreated cases was higher, and the incidence of adverse drug reactions was also higher. The treatment success rate was lower while the mortality rate was higher for elderly patients with MDR-TB. PMID- 24809710 TI - [Clinical evaluation of T-SPOT. TB assay in 1 084 tuberculosis suspects]. AB - OBJECTIVE: To evaluate the T-SPOT. TB assay for the diagnosis of tuberculosis in a large clinical samples. METHODS: We analyzed the T-SPOT. TB results of 1 084 tuberculosis (TB) suspects who were admitted to the First Affiliated Hospital of Zhengzhou University from February 2011 to October 2011. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio of T-SPOT. TB were analyzed according to the final diagnosis. Among these patients, 60 were retested by T-SPOT. TB after 2-4 week anti-tuberculosis treatment, and spot forming cells (SFCs) were compared before and after treatment. Paired t-test was used for comparison between groups. RESULTS: Three hundred and eighty-four patients were eventually diagnosed to have TB. Among 54 patients with laboratory diagnosis of TB, 42 were T-SPOT. TB positive, and the sensitivity was 77.8% (42/54). In 330 cases clinically diagnosed as tuberculosis, 289 were T-SPOT. TB positive, and the sensitivity was 87.6% (289/330). The total sensitivity of T-SPOT. TB was 86.2% (331/384). In 700 non-TB patients, 638 cases were T-SPOT. TB negative, and the specificity was 91.1% (638/700). The positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio were 84.2% (331/393), 92.3% (638/691), 9.69 and 0.15, respectively. Sixty patients were retested by the T-SPOT. TB after anti-TB treatment (2-4 weeks), and the results showed that both ESAT-6 and CFP-10 specific SFCs (47 and 18, respectively) decreased significantly compared with those before anti-TB treatment (99 and 49, respectively). CONCLUSION: in this large scale study indicate that T-SPOT. TB is a promising test for the diagnosis of tuberculosis due to its high sensitivity and specificity. PMID- 24809711 TI - [Prognostic significance of early lactate clearance rate for severe acute respiratory failure patients on extracorporeal membrane oxygenation]. AB - OBJECTIVE: To investigate the prognostic significance of early lactate clearance rate for severe acute respiratory failure patients on extracorporeal membrane oxygenation (ECMO). METHODS: Forty-three patients with severe acute respiratory failure supported by venous-venous (v-v) ECMO were enrolled from January 2007 to January 2013. Arterial blood lactate at pre-ECMO support(0 h) and at post-ECMO 6 hours (6 h) were measured and then 6 h lactate clearance rate was calculated. The acute physiology and chronic health evaluation II (APACHEII) score was evaluated on the first day of ECMO support. Survival at 90 d after admission was the study endpoint. Patients were divided into the survival group (n = 24) and the death group (n = 19) . The 0 h blood lactate, 6 h lactate clearance rate and APACHE II score were compared between groups. The value of 0 h blood lactate, 6 h lactate clearance rate and APACHE II score for predicting death was evaluated by receiver operating characteristic (ROC) curves. The surviving curve was drawn using the Kaplan-Meier method, and the survival of the patients was analyzed by the Log rank test. Factors influencing the prognosis were analyzed by the multiple logistic regression analysis. RESULTS: (1) The 0 h blood lactate and APACHE II score were lower in survivors than in nonsurvivors [(3.8 +/- 2.1) mmol/L vs. (5.9 +/- 2.3) mmol/L, (18 +/- 7) vs. (25 +/- 7) , t = 7.924, 8.446, respectively, both P < 0.05], while the 6 h lactate clearance rate was higher in survivors than in nonsurvivors [(35.7 +/- 20.4) % vs. (10.7 +/- 18.2) %, t = 8.607, P < 0.05]. (2) The areas under the ROC curve of 0 h blood lactate, 6 h lactate clearance rate and APACHE II score for predicting death were 0.699 +/- 0.083 (95%CI:0.567~0.892, P < 0.05) , 0.871 +/- 0.119 (95%CI:0.724~0.980, P < 0.05) and 0.836 +/- 0.063 (95%CI: 0.713~0.958, P < 0.05) . The best cutoff point was 17.5% for 6 h lactate clearance with a sensitivity of 87.5% and specificity of 84.2%. (3) Kaplan-Meier survival analysis showed that 90 d survival rate of the high lactate clearance rate group and the low lactate clearance rate group were 78.3% and 30%, with significant difference between the two groups (chi2 = 10.103, P < 0.05). (4) Multivariate logistic regression analysis showed that 0 h blood lactate (OR = 1.318, 95%CI:1.159~6.882, P < 0.05) , 6 h lactate clearance rate (OR = 6.921, 95%CI:4.469~15.036, P < 0.05) and APACHEII score (OR = 4.417, 95%CI:3.058~10.356, P < 0.05) were independent risk factors associated with mortality of patients on ECMO. CONCLUSION: Early lactate clearance rate could be used as an important variable for evaluating the prognosis of severe acute respiratory failure patients on ECMO. PMID- 24809712 TI - [Management of pulmonary nodules: introduction of ACCP guildlines]. PMID- 24809713 TI - [Research progress of microRNA in infectious diseases and tuberculosis]. PMID- 24809714 TI - [Advances in the research on etiology of local inflamation in obstructive sleep apnea syndrome]. PMID- 24809715 TI - Genomic prediction for tuberculosis resistance in dairy cattle. AB - BACKGROUND: The increasing prevalence of bovine tuberculosis (bTB) in the UK and the limitations of the currently available diagnostic and control methods require the development of complementary approaches to assist in the sustainable control of the disease. One potential approach is the identification of animals that are genetically more resistant to bTB, to enable breeding of animals with enhanced resistance. This paper focuses on prediction of resistance to bTB. We explore estimation of direct genomic estimated breeding values (DGVs) for bTB resistance in UK dairy cattle, using dense SNP chip data, and test these genomic predictions for situations when disease phenotypes are not available on selection candidates. METHODOLOGY/PRINCIPAL FINDINGS: We estimated DGVs using genomic best linear unbiased prediction methodology, and assessed their predictive accuracies with a cross validation procedure and receiver operator characteristic (ROC) curves. Furthermore, these results were compared with theoretical expectations for prediction accuracy and area-under-the-ROC-curve (AUC). The dataset comprised 1151 Holstein-Friesian cows (bTB cases or controls). All individuals (592 cases and 559 controls) were genotyped for 727,252 loci (Illumina Bead Chip). The estimated observed heritability of bTB resistance was 0.23+/-0.06 (0.34 on the liability scale) and five-fold cross validation, replicated six times, provided a prediction accuracy of 0.33 (95% C.I.: 0.26, 0.40). ROC curves, and the resulting AUC, gave a probability of 0.58, averaged across six replicates, of correctly classifying cows as diseased or as healthy based on SNP chip genotype alone using these data. CONCLUSIONS/SIGNIFICANCE: These results provide a first step in the investigation of the potential feasibility of genomic selection for bTB resistance using SNP data. Specifically, they demonstrate that genomic selection is possible, even in populations with no pedigree data and on animals lacking bTB phenotypes. However, a larger training population will be required to improve prediction accuracies. PMID- 24809716 TI - Inhibitors of bacterial transcription are compounds for potent antimicrobial drugs. AB - The increasing resistance of microorganisms against antibiotics available on the pharmaceutical market is now a global problem. There is an incessant necessity to search for new, effective treatments against resistant strains of microorganisms, for new potent classes of antibiotics with novel modes of action targeted at important components of microbial cells. Such a critical, essential system for cell functioning is a RNA polymerase (RNAP), an enzyme that catalyses one of the stages of gene expression: transcription. RNAP is a proven target for a number of antibiotics, and it still remains an attractive drug target for new potent antimicrobial compounds. In this review several examples of inhibitors for transcription and RNAP are presented. PMID- 24809717 TI - Nanoparticle enabled drug delivery across the blood brain barrier: in vivo and in vitro models, opportunities and challenges. AB - The blood brain barrier (BBB) maintains homeostasis by regulating the transport of chemicals at the brain interface. However, it is also one of the largest obstacles for drug delivery to the central nervous system (CNS). The utilization of nanoparticles as drug delivery vehicles is one potential solution to overcome this barrier. This review highlights the characteristics of the BBB that inhibit the passage of drugs to the brain, evaluates the efficiency of current in vitro models to mimic the BBB, and discusses the use of nanoparticles in both in vivo and in vitro models to enhance drug permeability across the barrier. In addition, this review describes factors that influence the passage of nanoparticles (type of polymers and surfactant coating, nanoparticle size) across the barrier. Protein opsonization and phagocytic activity of the reticuloendothelial system limits the amount of drug delivered to the brain, and this article summarizes methods to circumvent these issues. This paper also reviews literature covering opportunities and challenges provided with current applications of nanoparticle drug delivery systems for diseases of the brain, including cancer, HIV, and Alzheimer's disease. PMID- 24809718 TI - The role of neighbours selection on cohesion and order of swarms. AB - We introduce a multi-agent model for exploring how selection of neighbours determines some aspects of order and cohesion in swarms. The model algorithm states that every agents' motion seeks for an optimal distance from the nearest topological neighbour encompassed in a limited attention field. Despite the great simplicity of the implementation, varying the amplitude of the attention landscape, swarms pass from cohesive and regular structures towards fragmented and irregular configurations. Interestingly, this movement rule is an ideal candidate for implementing the selfish herd hypothesis which explains aggregation of alarmed group of social animals. PMID- 24809719 TI - Cellular activation and intracellular HCV load in peripheral blood monocytes isolated from HCV monoinfected and HIV-HCV coinfected patients. AB - BACKGROUND: During HCV infection, the activation status of peripheral blood monocytes and its impact on HCV replication are poorly understood. We hypothesized that a modified activation of peripheral blood monocytes in HIV-HCV coinfected compared to HCV monoinfected patients may contribute to different monocytes reservoirs of HCV replication. METHODS: We performed a case-control analysis involving HCV-infected patients with and without HIV coinfection. In peripheral blood mononuclear cells (PBMCs), peripheral blood lymphocytes (PBLs) and peripheral blood monocytes isolated from HCV monoinfected and HIV-HCV coinfected patients, intracellular HCV load and a marker of cellular activation, nuclear factor-kappaB (NF-kappaB) activation, were quantified using intracellular detection of HCV-core protein and electrophoretic mobility shift assay, respectively. RESULTS: Intracellular HCV loads were higher in monocytes isolated from HIV-HCV coinfected patients than in those of monoinfected patients. Among PBMCs isolated from HIV-HCV coinfected patients, intracellular HCV loads were higher in monocytes compared to PBLs. Cellular activation as measured by NF kappaB activation was higher in monocytes isolated from HIV-HCV coinfected patients than in those of monoinfected patients. CONCLUSIONS: Our results reveal the peripheral blood monocytes as an important extrahepatic reservoir for HCV in HIV-HCV coinfected patients and indicate a potential association between the activation state of monocytes and the size of the HCV reservoir in HIV-HCV coinfected patients. PMID- 24809720 TI - Dinuclear magnesium, zinc and aluminum complexes supported by bis(iminopyrrolide) ligands: synthesis, structures, and catalysis toward the ring-opening polymerization of epsilon-caprolactone and rac-lactide. AB - Synthesis and characterization of novel dinuclear magnesium, zinc and aluminum complexes supported by bis(iminopyrrolide) ligands and their catalysis toward the ring-opening polymerization (ROP) of epsilon-caprolactone (epsilon-CL) and rac lactide (rac-LA) were carried out. The ligand precursors [(5-Bu(t)-2 C4H2NH)CH=N(CH2)2]2NH (H2L(Bu), 1) and [(2-C4H3NH)CH=N(CH2)2]2NH (H2L(H), 2) were prepared by condensation of diethylene triamine with 5-tert-butyl-1H-pyrrole-2 carbaldehyde and 1H-pyrrole-2-carbaldehyde, respectively. Treatment of 1 with 2 equiv. of Bu(n)MgOBn in toluene at 70 degrees C produced dinuclear magnesium complex [(MU-OBn)2Mg2L(Bu)] (3). Similar treatment of 1 with EtZnOBn generated [(MU-OBn)2Zn2L(Bu)] (4). Reaction of 2 with 2 equiv. of Me2AlOBn in toluene at 70 degrees C afforded aluminum complex [Me2Al(MU-OBn)2AlL(H)] (5). Complexes 3-5 were characterized by (1)H and (13)C NMR spectroscopy, elemental analyses, and single crystal X-ray diffraction techniques. Each of complexes 3-5 is active for the ROP of epsilon-CL and rac-LA. Kinetic studies of the polymerization reactions were performed. PMID- 24809721 TI - Study of motor asymmetry in ALS indicates an effect of limb dominance on onset and spread of weakness, and an important role for upper motor neurons. AB - In amyotrophic lateral sclerosis (ALS), onset and spread of upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction is typically asymmetric. Our aim was to investigate the relationship between limb dominance and the onset and spread of clinical UMN and LMN dysfunction in ALS. We studied 138 ALS subjects with unilateral and concordant limb dominance, from two tertiary centres. A questionnaire was used to determine the pattern of disease onset and spread. The clinical severity of UMN and LMN signs in each limb was quantified using a validated scoring system. Results showed that onset of weakness was more likely to occur in the dominant upper limb (p = 0.02). In subjects with initial weakness in a non-dominant limb, spread of weakness was more likely to be to the other limb on that side (p = 0.008). The relative distribution of upper limb UMN signs was affected by whether weakness first occurred on the dominant or non-dominant side (p = 0.03). These findings support limb dominance as a significant factor underlying onset and spread of ALS, with UMN processes playing an important role. The effect of limb dominance on the presentation of ALS may reflect underlying neuronal vulnerabilities, which become exposed by the disease. PMID- 24809722 TI - EEG classification in a single-trial basis for vowel speech perception using multivariate empirical mode decomposition. AB - OBJECTIVE: The objective of this study is to find components that might be related to phoneme representation in the brain and to discriminate EEG responses for each speech sound on a trial basis. APPROACH: We used multivariate empirical mode decomposition (MEMD) and common spatial pattern for feature extraction. We chose three vowel stimuli, /a/, /i/ and /u/, based on previous findings, such that the brain can detect change in formant frequency (F2) of vowels. EEG activity was recorded from seven native Korean speakers at Gwangju Institute of Science and Technology. We applied MEMD over EEG channels to extract speech related brain signal sources, and looked for the intrinsic mode functions which were dominant in the alpha bands. After the MEMD procedure, we applied the common spatial pattern algorithm for enhancing the classification performance, and used linear discriminant analysis (LDA) as a classifier. MAIN RESULTS: The brain responses to the three vowels could be classified as one of the learned phonemes on a single-trial basis with our approach. SIGNIFICANCE: The results of our study show that brain responses to vowels can be classified for single trials using MEMD and LDA. This approach may not only become a useful tool for the brain computer interface but it could also be used for discriminating the neural correlates of categorical speech perception. PMID- 24809723 TI - From in vitro to in situ tissue engineering. AB - In vitro tissue engineering enables the fabrication of functional tissues for tissue replacement. In addition, it allows us to build useful physiological and pathological models for mechanistic studies. However, the translation of in vitro tissue engineering into clinical therapies presents a number of technical and regulatory challenges. It is possible to circumvent the complexity of developing functional tissues in vitro by taking an in situ tissue engineering approach that uses the body as a native bioreactor to regenerate tissues. This approach harnesses the innate regenerative potential of the body and directs the appropriate cells to the site of injury. This review surveys the biomaterial-, cell-, and chemical factor-based strategies to engineer tissue in vitro and in situ. PMID- 24809724 TI - Ex vivo lymphatic perfusion system for independently controlling pressure gradient and transmural pressure in isolated vessels. AB - In addition to external forces, collecting lymphatic vessels intrinsically contract to transport lymph from the extremities to the venous circulation. As a result, the lymphatic endothelium is routinely exposed to a wide range of dynamic mechanical forces, primarily fluid shear stress and circumferential stress, which have both been shown to affect lymphatic pumping activity. Although various ex vivo perfusion systems exist to study this innate pumping activity in response to mechanical stimuli, none are capable of independently controlling the two primary mechanical forces affecting lymphatic contractility: transaxial pressure gradient, [Formula: see text], which governs fluid shear stress; and average transmural pressure, [Formula: see text], which governs circumferential stress. Hence, the authors describe a novel ex vivo lymphatic perfusion system (ELPS) capable of independently controlling these two outputs using a linear, explicit model predictive control (MPC) algorithm. The ELPS is capable of reproducing arbitrary waveforms within the frequency range observed in the lymphatics in vivo, including a time-varying [Formula: see text] with a constant [Formula: see text], time-varying [Formula: see text] and [Formula: see text], and a constant [Formula: see text] with a time-varying [Formula: see text]. In addition, due to its implementation of syringes to actuate the working fluid, a post-hoc method of estimating both the flow rate through the vessel and fluid wall shear stress over multiple, long (5 s) time windows is also described. PMID- 24809725 TI - Method for high accuracy differential pressure measurements using fluid-filled catheters. AB - The advantage of measuring differential pressure using fluid-filled catheters is that the system is relatively inexpensive, but the readings are not accurate and affected by the common mode pressure (CMP) distortion. High accuracy differential pressure measurements are required in various biomedical applications, such as in fluid-dynamic test rigs, or in the cath-lab, from cardiac valves efficacy to functional assessment of arterial stenoses. We have designed and built a unique system in which the pressure difference was measured along the fluid flow inside a rigid circular tube using a fluid-filled double-lumen catheter. The differential pressure measurements were taken across two side-holes near the catheter distal tip, spaced apart by 3 cm. The goal was to overcome the CMP error, which significantly distorted the output differential pressure signal and to formulate a restoration factor. A restoration formula was developed based on simultaneous gauge pressure measurements, and was tested in several different cases. Several representative cases are presented and show that the common mode artifact was reduced by factors of 12-27. The restored pressure gradient signal was validated using direct pressure drop measurements, and showed very good agreement. PMID- 24809726 TI - The association between HIV infection, antiretroviral therapy and cervical squamous intraepithelial lesions in South Western Nigerian women. AB - INTRODUCTION: Findings from studies that evaluated the effect of antiretroviral drug use on the development of cervical squamous intraepithelial lesion differed in their conclusions. This study investigated the association between HIV infection, antiretroviral drug use and cervical squamous intraepithelial lesion in a high HIV and cervical cancer burden setting- Nigeria. METHODS: A cross sectional study among 1140 women of known HIV status enrolled in a randomised study to determine the test characteristics of visual inspection in detecting cytology diagnosed squamous intraepithelial lesion. Multivariate analysis was used to determine the association between HIV infection, antiretroviral drug use and the twin outcome variables of cervical squamous intraepithelial lesion (SIL) and High grade squamous intraepithelial lesion (HSIL) while controlling for confounders. RESULTS: Prevalence of cervical squamous intraepithelial lesion was 8.5%, with a higher prevalence of 14.3% in HIV positive compared to 3.3% in HIV negative women (aOR: 5.4; 95% CI: 2.9-8.8). Not using antiretroviral drugs was found to be associated with an increased risk of SIL (aOR: 2.1; 95% CI: 1.4-3.5) and HSIL (aOR: 2.6; 95% CI: 1.1-6.4). Participants who had a CD4 cell count <200 cells/mm3, were also found to be at increased risk for SIL (aOR: 1.9; 95% CI: 1.1 5.9) and HSIL (aOR: 5.7; 95% CI: 1.1-7.2). CONCLUSION: HIV infection and severe immunosuppression were found to be associated with increased risk of cervical squamous intraepithelial lesion but not viral load. For the first time, in the West African sub-region with specific HIV type and strains, we established the protective effect of antiretroviral drug use against the development of SIL. Integration of cervical cancer screening programme into HIV services and early initiation of antiretroviral drug in HIV positive women especially those with severe immune-suppression could therefore prove to be useful in preventing and controlling cervical cancer development in HIV positive women. PMID- 24809727 TI - Posttreatment with Ma-Xing-Shi-Gan-Tang, a Chinese medicine formula, ameliorates lipopolysaccharide-induced lung microvessel hyperpermeability and inflammatory reaction in rat. AB - OBJECTIVE: The aim of present study was to investigate the efficacy of MXSGT, a traditional Chinese medicine formula used for treatment of respiratory system diseases, in the LPS-induced rat ALI particularly with a focus on its effect on lung microvascular hyperpermeability and inflammatory reaction. METHODS: Male Sprague-Dawley rats were injected with LPS (7.5 mg/kg, 1.5 mg/mL) intraperitoneally. MXSGT (0.52 g or 2.61 g/kg) was given by gavage six hours after LPS injection. RESULTS: LPS stimulation resulted in a reduced survival rate, deteriorated vital signs, an increase in the number of leukocytes adhering to lung venules, the albumin leakage, the activity of MPO in lung tissues, the production of pro-inflammatory cytokines and lung perivascular edema. After LPS stimulation, western blot analysis revealed an increase in the expression of ICAM 1 and toll-like receptor 4, a decrease in tight junction proteins and an activation of cav-1, Src, and NF-kappaB. All the LPS-induced alterations were significantly attenuated by posttreatment with MXSGT. CONCLUSIONS: This study demonstrated MXSGT as a potential strategy for lung microvascular hyperpermeability and inflammatory reaction in ALI, and suggested that the beneficial role of MXSGT was correlated with toll-like receptor 4, Src, and NF kappaB. PMID- 24809728 TI - Rethinking the role of opioids in the outpatient management of chronic nonmalignant pain. AB - OBJECTIVE: Opioid analgesics are commonly and increasingly prescribed by physicians for the management of chronic pain. However, strong evidence supports the need for strategies that reduce opioid use. The objective of this review is to outline limitations associated with opioid use and discuss therapeutic techniques that can be adopted to optimize the use of opioids in the management of chronic nonmalignant pain. SCOPE: Literature searches through MEDLINE and Cochrane databases were used to identify relevant journal articles. The search was limited to articles published from January 1980 to January 2014. Additional references were obtained from articles extracted during the database search. Relevant search terms included opioid, opioid abuse, chronic pain management, written care agreements, urine drug testing, and multimodal therapy. FINDINGS: Opioids exhibit a well established abuse potential and evidence supporting the efficacy of opioids in chronic pain management is limited. In addition, opioid exposure is associated with adverse effects on multiple organ systems. Effective strategies designed to mitigate opioid abuse and diversion and optimize clinical outcomes should be employed. CONCLUSIONS: Appropriate patient selection through identification of risk factors, urine drug testing, and access to prescription monitoring programs has been shown to effectively improve care. Structured opioid therapy in a multimodal platform, including use of a low initial dose, prescription of alternative non-opioid analgesics including non-steroidal anti inflammatory drugs and acetaminophen, as well as development of written care agreements to individualize and guide therapy has also been shown to improve patient outcomes. Implementation of opioid allocation strategies has the potential to encourage appropriate opioid use and improve patient care. PMID- 24809729 TI - Development of an efficient qRT-PCR assay for quality control and cellular quantification of respiratory samples. AB - BACKGROUND: Sample quality is a fundamental parameter for the successful diagnosis of respiratory viruses. This parameter depends upon the concentration of epithelial cells. Respiratory samples are usually heterogeneous, which makes relative quantification of the viral load, against the quantity of cells, the most suitable measurement. The quantification of viral load in the field of respiratory viruses is a vital piece of information. Quantification is required from RNA or DNA viral genomes extracted. OBJECTIVES: To design (RT-)PCR assays for reference genes, which show stable expression during viral infection, to be used as cellular controls and cellular quantification tools. STUDY DESIGN: Assays were designed for two reference genes: hypoxanthine phosphoribosyltransferase 1 (HPRT1) and ubiquitin C (UBC). The glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) was used as a reference for this study. The transcriptional activity of the three genes was studied during infection with respiratory syncytial virus and adenovirus. The HPRT1 q(RT-)PCR assay was used on clinical samples. RESULTS: All the analysis methods concluded that the three reference genes were stably expressed during viral infection. The HPRT1 q(RT-)PCR assay indicated that the majority of clinical samples (n=301, 69%) had a cellular load of between 100 and 10,000 cells/PCR. The data showed that the concentration decreased as the age of patient increased. CONCLUSIONS: A new tool has been developed and commercialized for quality control and evaluation of cellular concentration in respiratory samples. PMID- 24809730 TI - Comparison of the Abbott RealTime HBV assay with the Roche Cobas AmpliPrep/Cobas TaqMan HBV assay for HBV DNA detection and quantification. AB - BACKGROUND: Measurement of hepatitis B virus (HBV) DNA levels is essential in the clinical management of patients with chronic HBV infection. Performance and accuracy of quantitation for HBV DNA are therefore critical in clinical practice. OBJECTIVES: We aimed to compare and evaluate the performance characteristics of two HBV DNA quantitative assays: Abbott RealTime HBV (RealTime assay) and Cobas AmpliPrep/Cobas TaqMan HBV assays 2.0 (TaqMan assay). STUDY DESIGN: Serum samples from 220 HBV-infected patients were collected. Performance characteristics of the HBV DNA quantitative assays, including sensitivity, linearity, and reproducibility were measured. The assays were compared based on the viral status, including HBeAg, genotype, core promoter and pre-core region mutations. RESULTS: The RealTime assay had a sensitivity and specificity of 98.2% and 100%, respectively. The intra-assay coefficients of variation of serum samples ranged from 0.00% to 11.25% for the RealTime assay and 1.22% to 8.22% for TaqMan assay. Paired quantitative results showed excellent correlation by linear regression analysis (R(2)=0.961), good level of agreement with a mean difference of 0.31log10IU/mL, and limits of agreement of -0.62 to 1.24log10IU/mL, irrespective of HBeAg, genotype, core promoter and pre-core region mutation-specific differences. In this study, a difference of >=1log10IU/mL between the two assays was observed in 8.6% of the samples. Genotype B and average HBV DNA levels of <3log10IU/mL were significant associated factors of this discordance. CONCLUSIONS: The Abbott assay delivered high performance for HBV DNA quantification and correlated extremely well with the TaqMan assay, irrespective of viral status. PMID- 24809731 TI - Role of dynamin and clathrin in the cellular trafficking of flotillins. AB - Flotillin-1 and flotillin-2 are highly conserved, membrane-microdomain-associated proteins that have been shown to be involved in signal transduction, membrane trafficking and cell adhesion. Upon growth factor stimulation, flotillins are tyrosine phosphorylated and become endocytosed from the plasma membrane into endosomes from which they are recycled back to the plasma membrane. Although a role for flotillin-1 in the endocytosis of certain cargo proteins has been suggested, it is not known how the growth-factor-induced endocytosis of flotillins is regulated and which endocytosis pathway is used. However, this is likely to be different from the pathway used by flotillin-dependent cargo. In this study, we have addressed the mechanistic details of flotillin trafficking during growth factor signaling. We show that dynamin-2 activity is required for the uptake of flotillins from the plasma membrane upon epidermal growth factor stimulation, and inhibition of dynamin-2 GTPase activity impairs flotillin endocytosis. Surprisingly, recycling of flotillins from endosomes to the plasma membrane appears to require both dynamin-2 and clathrin. Upon overexpression of dynamin-2 mutants or depletion of clathrin heavy chain, flotillins are permanently trapped in endosomes. These data show that clathrin and dynamin are required for the endosomal sorting of flotillins, and the study provides a mechanistic dissection of the thus far poorly characterized endosomal trafficking of flotillins. PMID- 24809732 TI - Epicardial fat is associated with duration of antiretroviral therapy and coronary atherosclerosis. AB - OBJECTIVE: Cytokines released by epicardial fat are implicated in the pathogenesis of atherosclerosis. HIV infection and antiretroviral therapy have been associated with changes in body fat distribution and coronary artery disease. We sought to determine whether HIV infection is associated with greater epicardial fat and whether epicardial fat is associated with subclinical coronary atherosclerosis. DESIGN: We studied 579 HIV-infected and 353 HIV-uninfected men aged 40-70 years with noncontrast computed tomography to measure epicardial adipose tissue (EAT) volume and coronary artery calcium (CAC). Total plaque score (TPS) and plaque subtypes (noncalcified, calcified, and mixed) were measured by coronary computed tomography angiography in 706 men. METHODS: We evaluated the association between EAT and HIV serostatus, and the association of EAT with subclinical atherosclerosis, adjusting for age, race, and serostatus and with additional cardiovascular risk factors and tested for modifying effects of HIV serostatus. RESULTS: HIV-infected men had greater EAT than HIV-uninfected men (P=0.001). EAT was positively associated with duration of antiretroviral therapy (P=0.02), specifically azidothymidine (P<0.05). EAT was associated with presence of any coronary artery plaque (P=0.006) and noncalcified plaque (P=0.001), adjusting for age, race, serostatus, and cardiovascular risk factors. Among men with CAC, EAT was associated with CAC extent (P=0.006). HIV serostatus did not modify associations between EAT and either CAC extent or presence of plaque. CONCLUSION: Greater epicardial fat volume in HIV-infected men and its association with coronary plaque and antiretroviral therapy duration suggest potential mechanisms that might lead to increased risk for cardiovascular disease in HIV. PMID- 24809733 TI - Enrichment of denitrifying methanotrophic bacteria from municipal wastewater sludge in a membrane bioreactor at 20 degrees C. AB - Simultaneous nitrogen and methane removal by the slow growing denitrifying methanotrophic bacterium 'Candidatus Methylomirabilis oxyfera' offers opportunities for a new approach to wastewater treatment. However, volumetric nitrite consumption rates should be increased by an order of magnitude before application in wastewater treatment becomes possible. A maximum volumetric nitrite consumption rate of 36 mg NO2(-)-N/L d was achieved in a membrane bioreactor inoculated with wastewater sludge and operated at 20 degrees C. This rate is similar to maximum rates reported in literature, though it was thought that by strict biomass retention using membranes, higher rates would be achieved. In experiments lasting several years, growth was not stable: every experiment showed a decrease in activity after 1-2 years. The cause remains unknown. Rates increased after addition of copper and operating a membrane bioreactor at shorter hydraulic retention times. Further research should focus on long-term effects of copper addition and operation at hydraulic retention times in the order of hours using membrane bioreactors. PMID- 24809735 TI - Career satisfaction and burnout in the reconstructive microsurgeon in the United States. PMID- 24809734 TI - Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes. AB - The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2+MMP9+ monocytic cells were consistently detected in the invasive tumor edge upon anti-VEGF therapies. Our results suggest the presence of a specific myeloid/monocytic subpopulation that plays a pivotal role in the mechanism of escape of malignant gliomas from anti-VEGF therapies and therefore constitutes a new cellular target for combination therapies in patients selected for anti-angiogenesis treatment. PMID- 24809736 TI - Totally drug-resistant tuberculosis and adjunct therapies. AB - The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options. PMID- 24809738 TI - Do educators need educating? PMID- 24809737 TI - Association of quality of life, anxiety, and depression with left atrial ablation outcomes. AB - BACKGROUND: Atrial fibrillation (AF) is associated with significant impairment of quality of life (QoL). Anxiety and depression are common in AF patients and might predispose to AF. We sought to investigate associations of preablative QoL and stress parameters with AF ablation outcomes, as well as possible changes in QoL, anxiety, and depression parameters after ablation. METHODS: A total of 57 consecutive patients with paroxysmal AF underwent pulmonary vein (PV) antral isolation. The Short-Form Life Survey-36 items (SF-36), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) were assessed before and at 6 months after ablation. RESULTS: After a mean follow-up of 8.0 +/- 2.5 months, 41 patients (71.9%) remained free from arrhythmia. Baseline mental health summary QoL SF-36 score was significantly lower in patients with AF recurrence (53.2 +/- 10.3 vs 69.7 +/- 17.9; P = 0.001), while the physical health summary score did not differ significantly between patients with and without recurrence. Patients with recurrence had higher baseline STAI-trait (41.9 +/- 1.5 vs 34.7 +/- 4.9) and BDI (17.3 +/- 9.7 vs 5.4 +/- 3.0) scores (P < 0.001 for both). In multivariable analysis, SF-36 mental health summary, STAI-trait, and BDI scores remained significant predictors of recurrence after adjustment for age, gender, body mass index, diabetes, and hypertension. Mental and physical domain SF-36 summary scores were significantly improved 6 months after ablation (P = 0.001) and a significant reduction in symptoms of depression (P = 0.001) and anxiety (P = 0.001) was observed. CONCLUSIONS: Baseline QoL, anxiety, and depression metrics were associated with AF recurrence following PV antral isolation. Furthermore, there was a significant improvement in QoL, anxiety, and depression after left atrial ablation. PMID- 24809739 TI - Botulinum Toxin as an Alternative to Treat the Spasm of the Near Reflex. AB - We describe the case of an eight-year-old girl with complaints of headaches and blurred vision (uncorrected visual acuity: 0.1 decimal) that showed on examination miotic pupils, pseudomyopia, no ocular motility restrictions, and no associated neurological disease. After initial treatment with cyclopentolate for two months, pseudomyopia persisted with an intermittent and variable esotropia. Spectacles of +1 both eyes and atropine 1% one drop daily were then prescribed. The situation improved and remained stable for several weeks, with pseudomyopia and esotropia reappearing later. Finally, botulinum toxin (2.5 iu Botox) was injected in the medial rectus muscle on two occasions and a visual therapy program based on the stimulation of fusional divergence, diplopia, and stereopsis consciousness was recommended. This prescription was combined with the use of atropine during the first few weeks. Orthotropia and corrected distance visual acuity of 1.0 were found three months after treatment. The evolution and clinical results of this case report suggest that botulinum toxin in combination with other therapeutic alternatives may be useful in the treatment of spasm of the near reflex. PMID- 24809740 TI - Ten-Year Results of Home Vision-Screening Test in Children Aged 3-6 Years in Seoul, Korea. AB - PURPOSE: To characterize the prevalence of refractive error and amblyopia among three- to six-year-old children during the period from 2002 to 2011. METHODS: About 31,400 children annually (from 16,592 to 40,816) during the period from 2002 to 2011 were enrolled. The preschool vision screening was performed by the Korean Foundation for the Prevention of Blindness (KFPB) annually during a period that extended from March to September. We reviewed the KFPB annual report about the home vision-screening test as performed during the period from 2002 to 2011. Changes in the prevalence and types of refractive error, strabismus, and amblyopia that manifested throughout this period were analyzed. RESULTS: The prevalence of refractive errors ranged from 1.10% in 2002 to 0.42% in 2011. The prevalence of hyperopia and myopia changed little throughout the 10-year study period. Myopia and hyperopia were equally common among the population examined (chi(2)-test, p = 0.137). The prevalence of anisometropia decreased over time. The annual prevalence of amblyopia ranged from 0.39% to 0.06%, while the overall prevalence of amblyopia dropped from 0.25% in 2002 to 0.06% in 2011. The prevalence of strabismus was highest in 2006 (0.30%) and had decreased by 0.06% in 2011. The type of strabismus showed no significant difference over time (chi(2)-test, p = 0.579). CONCLUSIONS: The prevalence of amblyopia, refractive error, anisometropia, and strabismus was lower in 2011 than in early 2000. The prevalence of hyperopia and myopia as well as strabismus remained similar throughout the study period. PMID- 24809742 TI - A hierarchy of cortical responses to sequence violations in three-month-old infants. AB - The adult human brain quickly adapts to regular temporal sequences, and emits a sequence of novelty responses when these regularities are violated. These novelty responses have been interpreted as error signals that reflect the difference between the incoming signal and predictions generated at multiple cortical levels. Do infants already possess such a hierarchy of violation-detection mechanisms? Using high-density recordings of event-related potentials during an auditory local-global violation paradigm, we show that three-month-old infants process novelty in temporal sequences at two distinct levels. Violations of local expectancies, such as perceiving a deviant vowel "a" after repeated presentation of another vowel i-i-i, elicited an early auditory mismatch response. Conversely, violations of global expectancies, such as hearing the rare sequence a-a-a-a instead of the frequent sequence a-a-a-i, modulated this early mismatch response and led to a late frontal negative slow wave, whose cortical sources included the left inferior frontal region. These results suggest that the infant brain already possesses two dissociable systems for temporal sequence learning. PMID- 24809741 TI - Topographical Analysis of Non-Glaucomatous Myopic Optic Discs Using a Confocal Scanning Laser Ophthalmoscope (TopSS). AB - OBJECTIVES: To show normative data of optic discs and the mechanism of glaucoma in people with myopia. DESIGN: Cross-sectional study. PARTICIPANTS: This study investigated 89 Korean adults with myopia but without glaucoma. METHODS: Patients were divided into three groups according to the refractive error: low, moderate, and high; and axial length: normal or below normal length, moderately long, and extremely long. Optic disc variables were obtained by confocal scanning laser ophthalmoscope and compared among groups. RESULTS: The optic disc parameters have a correlation between the refractive error and the optic disc parameters such as average depth, volume below, and half-depth volume. Those parameters also decreased as the axial length increased. The thickness of the volume above decreased significantly as the axial length increased, but a similar relationship was not evident with the refractive error change. In addition, the optic disc parameters were analyzed with respect to the 12 clockwise directions. CONCLUSIONS: Analyses of optic disc parameters provided by TopSSTM revealed the height of the disc decreased as the myopic refractive error and/or axial length increased. The RNFL bundle became compacted in the thinner disc of the myopic population. This could be an explanation for the fragility of the RNFL in the myopic population. The 12 radial section analyses revealed the shallow cupping at the temporal side in the high-myopic, very-long-axis group. The neuroretinal rim (NRR) height significantly decreased at the superior and inferior sides. These findings suggest that the RNFL bundle should be under high mechanical strain in these sectors. PMID- 24809743 TI - Object labeling influences infant phonetic learning and generalization. AB - Different kinds of speech sounds are used to signify possible word forms in every language. For example, lexical stress is used in Spanish (/'be.be/, 'he/she drinks' versus /be.'be/, 'baby'), but not in French (/'be.be/ and /be.'be/ both mean 'baby'). Infants learn many such native language phonetic contrasts in their first year of life, likely using a number of cues from parental speech input. One such cue could be parents' object labeling, which can explicitly highlight relevant contrasts. Here we ask whether phonetic learning from object labeling is abstract-that is, if learning can generalize to new phonetic contexts. We investigate this issue in the prosodic domain, as the abstraction of prosodic cues (like lexical stress) has been shown to be particularly difficult. One group of 10-month-old French-learners was given consistent word labels that contrasted on lexical stress (e.g., Object A was labeled /'ma.bu/, and Object B was labeled /ma.'bu/). Another group of 10-month-olds was given inconsistent word labels (i.e., mixed pairings), and stress discrimination in both groups was measured in a test phase with words made up of new syllables. Infants trained with consistently contrastive labels showed an earlier effect of discrimination compared to infants trained with inconsistent labels. Results indicate that phonetic learning from object labeling can indeed generalize, and suggest one way infants may learn the sound properties of their native language(s). PMID- 24809744 TI - Touching words is not enough: how visual experience influences haptic-auditory associations in the "Bouba-Kiki" effect. AB - Since Kohler's experiments in the 1920s, researchers have demonstrated a correspondence between words and shapes. Dubbed the "Bouba-Kiki" effect, these auditory-visual associations extend across cultures and are thought to be universal. More recently the effect has been shown in other modalities including taste, suggesting the effect is independent of vision. The study presented here tested the "Bouba-Kiki" effect in the auditory-haptic modalities, using 2D cut outs and 3D models based on Kohler's original drawings. Presented with shapes they could feel but not see, sighted participants showed a robust "Bouba-Kiki" effect. However, in a sample of people with a range of visual impairments, from congenital total blindness to partial sight, the effect was significantly less pronounced. The findings suggest that, in the absence of a direct visual stimulus, visual imagery plays a role in crossmodal integration. PMID- 24809747 TI - Magnetic separation techniques in sample preparation for biological analysis: a review. AB - Sample preparation is a fundamental and essential step in almost all the analytical procedures, especially for the analysis of complex samples like biological and environmental samples. In past decades, with advantages of superparamagnetic property, good biocompatibility and high binding capacity, functionalized magnetic materials have been widely applied in various processes of sample preparation for biological analysis. In this paper, the recent advancements of magnetic separation techniques based on magnetic materials in the field of sample preparation for biological analysis were reviewed. The strategy of magnetic separation techniques was summarized. The synthesis, stabilization and bio-functionalization of magnetic nanoparticles were reviewed in detail. Characterization of magnetic materials was also summarized. Moreover, the applications of magnetic separation techniques for the enrichment of protein, nucleic acid, cell, bioactive compound and immobilization of enzyme were described. Finally, the existed problems and possible trends of magnetic separation techniques for biological analysis in the future were proposed. PMID- 24809746 TI - The Longissimus and Semimembranosus muscles display marked differences in their gene expression profiles in pig. AB - BACKGROUND: Meat quality depends on skeletal muscle structure and metabolic properties. While most studies carried on pigs focus on the Longissimus muscle (LM) for fresh meat consumption, Semimembranosus (SM) is also of interest because of its importance for cooked ham production. Even if both muscles are classified as glycolytic muscles, they exhibit dissimilar myofiber composition and metabolic characteristics. The comparison of LM and SM transcriptome profiles undertaken in this study may thus clarify the biological events underlying their phenotypic differences which might influence several meat quality traits. METHODOLOGY/PRINCIPAL FINDINGS: Muscular transcriptome analyses were performed using a custom pig muscle microarray: the 15 K Genmascqchip. A total of 3823 genes were differentially expressed between the two muscles (Benjamini-Hochberg adjusted P value <=0.05), out of which 1690 and 2133 were overrepresented in LM and SM respectively. The microarray data were validated using the expression level of seven differentially expressed genes quantified by real-time RT-PCR. A set of 1047 differentially expressed genes with a muscle fold change ratio above 1.5 was used for functional characterization. Functional annotation emphasized five main clusters associated to transcriptome muscle differences. These five clusters were related to energy metabolism, cell cycle, gene expression, anatomical structure development and signal transduction/immune response. CONCLUSIONS/SIGNIFICANCE: This study revealed strong transcriptome differences between LM and SM. These results suggest that skeletal muscle discrepancies might arise essentially from different post-natal myogenic activities. PMID- 24809748 TI - Data processing of vibrational chemical imaging for pharmaceutical applications. AB - Vibrational spectroscopy (MIR, NIR and Raman) based hyperspectral imaging is one of the most powerful tools to analyze pharmaceutical preparation. Indeed, it combines the advantages of vibrational spectroscopy to imaging techniques and allows therefore the visualization of distribution of compounds or crystallization processes. However, these techniques provide a huge amount of data that must be processed to extract the relevant information. This review presents fundamental concepts of hyperspectral imaging, the basic theory of the most used chemometric tools used to pre-process, process and post-process the generated data. The last part of the present paper focuses on pharmaceutical applications of hyperspectral imaging and highlights the data processing approaches to enable the reader making the best choice among the different tools available. PMID- 24809750 TI - Kidney transplantation and the intensity of poverty in the contiguous United States. AB - BACKGROUND: Geographic variation in kidney transplantation rates in the United States has been described previously but remains unexplained by age, race, sex, or socioeconomic status differences. Geographic variations in the concentration of poverty appear to impact end-stage renal disease care and potentially access to transplantation. METHODS: We studied the impact of how spatial topography of poverty across geographical regions in the contiguous United States is associated with kidney transplantation in the 48 contiguous U.S. states. RESULTS: We found considerable geographic variation in transplantation rates across the country that persisted across quartiles of county-level median household income and percentage minority population. Higher transplant rates were seen with increasing median household income and decreasing minority populations but were not influenced by education level. Transplantation rates in counties with poverty rates above the national average had low transplant rates, but these rates were influenced by the poverty level in the surrounding counties. Similarly, wealthy counties had higher transplant rates but were lowered in counties of relative wealth that were surrounded by less wealthy counties. CONCLUSIONS: Our results underline the geographical heterogeneity of kidney transplantation in the United States and identify regions of the country most likely to benefit from interventions that may reduce disparities in transplantation. PMID- 24809751 TI - Lysyl oxidase-like 1 gene in the reversal of promoter risk allele in pseudoexfoliation syndrome. AB - IMPORTANCE: This study was necessary to establish the association between common genetic variants in the lysyl oxidase-like 1 (LOXL1) gene with pseudoexfoliation (PEX) syndrome and emphasize the reversal of promoter risk allele in a South Indian population. OBJECTIVE: To investigate the potential association of genetic variants across the LOXL1 gene in South Indian patients with PEX syndrome and glaucoma. DESIGN, SETTING, AND PARTICIPANTS: A case-control study of individuals from Madurai, India, with PEX syndrome and glaucoma as well as healthy people serving as controls. Three hundred unrelated people with PEX syndrome and 225 age and ethnically matched controls were recruited for genetic analysis. MAIN OUTCOMES AND MEASURES: Four single-nucleotide polymorphisms in LOXL1 (rs16958477, rs1048661, rs3825942, and rs2165241) were genotyped by direct sequencing in all participants. Regulatory regions and 7 coding exons of LOXL1 were directly sequenced in 50 patients and 50 controls. A case-control association analysis was performed using the Golden Helix SVS suite. RESULTS: An association between 4 LOXL1 single-nucleotide polymorphisms with PEX syndrome and glaucoma was observed (rs16958477, P = 4.77 * 10-6 [odds ratio, 0.50]; rs1048661, P = 4.28 * 10-5 [1.79]; rs3825942, P = 4.68 * 10-30 [9.19]; and rs2165241, P = 1.98 * 10-15 [2.88]). Sequencing of 7 exons and regulatory regions of LOXL1 identified 11 additional sequence variants; only rs41435250 showed an association (P = 3.80 * 10-5 [0.49]) with PEX syndrome and glaucoma. CONCLUSIONS AND RELEVANCE: Genetic variants in LOXL1 are associated with PEX syndrome and glaucoma in the South Indian population. To our knowledge, this is the first study to demonstrate the association of rs41435250 with PEX as well as reversal of the promoter risk allele. Understanding the role of the LOXL1 gene in PEX pathogenesis will facilitate early detection in individuals at risk for this condition. PMID- 24809749 TI - Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection. AB - Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity. PMID- 24809753 TI - Three-year follow-up of an early childhood intervention: what about physical activity and weight status? AB - BACKGROUND: Fundamental movement skills are a correlate of physical activity and weight status. Children who participated in a preschool intervention had greater movement skill proficiency and improved anthropometric measures (waist circumference and BMI z scores) post intervention. Three years later, intervention girls had retained their object control skill advantage. The study purpose was to assess whether at 3-year follow up a) intervention children were more physically active than controls and b) the intervention effect on anthropometrics was still present. METHODS: Children were assessed at ages 4, 5, and 8 years for anthropometric measures and locomotor and object control proficiency (Test of Gross Motor Development-2). At age 8, children were also assessed for moderate to vigorous physical activity (MVPA) (using accelerometry). Several general linear models were run, the first with MVPA as the outcome, intervention/control, anthropometrics, object control and locomotor scores as predictors, and age and sex as covariates. The second and third models were similar, except baseline to follow-up anthropometric differences were the outcome. RESULTS: Overall follow-up rate was 29% (163/560), with 111 children having complete data. There were no intervention control differences in either MVPA or anthropometrics. CONCLUSION: Increased skill competence did not translate to increased physical activity. PMID- 24809754 TI - Microwave ablation in combination with chemotherapy for the treatment of advanced non-small cell lung cancer. AB - PURPOSE: To verify whether microwave ablation (MWA) used as a local control treatment had an improved outcome regarding advanced non-small cell lung cancer (NSCLC) when combined with chemotherapy. METHODS: Thirty-nine patients with histologically verified advanced NSCLC and at least one measurable site other than the ablative sites were enrolled. Primary tumors underwent MWA followed by platinum-based doublet chemotherapy. Modified response evaluation criteria in solid tumors (mRECIST) and RECIST were used to evaluate therapeutic response. Complications were assessed using the National Cancer Institute Common Toxicity Criteria (version 3.0). RESULTS: MWA was administered to 39 tumors in 39 patients. The mean and median diameters of the primary tumor were 3.84 cm and 3.30 cm, respectively, with a range of 1.00-9.00 cm. Thirty-three (84.6 %) patients achieved a partial response. No correlation was found between MWA efficacy and clinicopathologic characteristics. For chemotherapy, 11 patients (28.2 %) achieved a partial response, 18 (46.2 %) showed stable disease, and 10 (25.6 %) had progressive disease. The overall objective response rate and disease control rate were 28.2 and 74.4 %, respectively. The median progression-free survival time was 8.7 months (95 % CI 5.5-11.9). The median overall survival time was 21.3 months (95 % CI 17.0-25.4). Complications were observed in 22 (56.4 %) patients, and grade 3 adverse events were observed in 3 (7.9 %) patients. CONCLUSIONS: Patients with advanced NSCLC could benefit from MWA in combination with chemotherapy. Complications associated with MWA were common but tolerable. PMID- 24809755 TI - Can early computed tomography angiography after endovascular aortic aneurysm repair predict the need for reintervention in patients with type II endoleak? AB - PURPOSE: This study was designed to identify parameters on CT angiography (CTA) of type II endoleaks following endovascular aortic aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA), which can be used to predict the subsequent need for reinterventions. METHODS: We retrospectively identified 62 patients with type II endoleak who underwent early CTA in mean 3.7 +/- 1.9 days after EVAR. On the basis of follow-up examinations (mean follow-up period 911 days; range, 373-1,987 days), patients were stratified into two groups: those who did (n = 18) and those who did not (n = 44) require reintervention. CTA characteristics, such as AAA, endoleak, as well as nidus dimensions, patency of the inferior mesenteric artery, number of aortic branch vessels, and the pattern of endoleak appearance, were recorded and correlated with the clinical outcome. RESULTS: Univariate and receiver operating characteristic curve regression analyses revealed significant differences between the two groups for the endoleak volume (surveillance group: 1391.6 +/- 1427.9 mm(3); reintervention group: 3227.7 +/- 2693.8 mm(3); cutoff value of 2,386 mm(3); p = 0.002), the endoleak diameter (13.6 +/- 4.3 mm compared with 25.9 +/- 9.6 mm; cutoff value of 19 mm; p < 0.0001), the number of aortic branch vessels (2.9 +/- 1.2 compared with 4.2 +/- 1.4 vessels; p = 0.001), as well as a "complex type" endoleak pattern (13.6 %, n = 6 compared with 44.4 %, n = 8; p = 0.02). CONCLUSIONS: Early CTA can predict the future need for reintervention in patients with type II endoleak. Therefore, treatment decision should be based not only on aneurysm enlargement alone but also on other imaging characteristics. PMID- 24809756 TI - Specialty status for interventional radiology: the time is now. PMID- 24809757 TI - New American Heart Association/American College of Cardiology guidelines on cardiovascular risk: when will fitness get the recognition it deserves? PMID- 24809758 TI - Association of multiple adiposity exposures and cardiorespiratory fitness with all-cause mortality in men: the Cooper Center Longitudinal Study. AB - OBJECTIVE: To examine the additive effects of an increased number of positive adiposity exposures on all-cause mortality in men before and after stratification by cardiorespiratory fitness (CRF) level. PATIENTS AND METHODS: A total of 36,836 men underwent a physical examination at the Cooper Clinic from January 1, 1971, through December 31, 2006. Exposures included body mass index, waist circumference, percentage of body fat, and CRF as determined by duration of a maximal exercise test. Participants were identified as being either obese (positive) or nonobese (negative) for each adiposity exposure and then grouped into 4 categories: group 1, negative for all adiposity exposures; group 2, positive for any 1 exposure; group 3, positive for any 2 exposures; and group 4, positive for all exposures. Then CRF was grouped as fit or unfit on the basis of the upper 80% and lower 20% of the age-standardized CRF distribution as previously reported in the Cooper Center Longitudinal Study. Hazard ratios were computed with Cox regression analysis. RESULTS: A total of 2294 deaths occurred during a mean +/- SD of 15.5 +/- 8.1 years of follow-up. Adjusted hazard ratios across adiposity groups were 1.0 (referent), 1.05, 1.37, and 1.87 for groups 1 through 4, respectively (P for trend <.001). Mortality rates were significantly lower within each of the first 3 adiposity groups in fit compared with unfit men (P<.009 for all comparisons). CONCLUSION: An increasing number of positive adiposity exposures were associated with increased mortality in men. Because moderate to high CRF attenuated mortality rates in all adiposity groups, measurement of CRF should be included for identifying men at increased risk for all-cause mortality. PMID- 24809759 TI - Comparing the Asthma APGAR system and the Asthma Control TestTM in a multicenter primary care sample. AB - OBJECTIVE: To compare asthma control assessment using the Asthma APGAR system, a tool developed by primary care clinicians, in a multicenter primary care sample with the Asthma Control Test (ACTTM)/Childhood Asthma Control Test (CACTTM), a tool developed by asthma specialists. PATIENTS AND METHODS: This is a substudy of a multicenter, randomized, controlled pragmatic trial that tests the effectiveness of the Asthma APGAR system in primary care practices. As part of the study, enrolled patients completed both the ACTTM/CACTTM and the Asthma APGAR system between March 1, 2011, and December 31, 2011. Kappa and McNemar statistics were used to compare the results of questionnaires. RESULTS: Of the 468 patients in our sample, 306 (65%) were classified as not controlled by the ACTTM/CACTTM or the Asthma APGAR system. The overall agreement was 84.4%, with a kappa value of .68 (substantial agreement) and a McNemar test P value of .35 (suggesting no significant difference in the direction of disagreement). Of those with poor control as defined by the Asthma APGAR system, 23.8% (73) had no controller medications and 76.5% (234) were seldom or sometimes able to avoid identified triggers for their asthma. Of those who stated that they had been prescribed controller medications, 116 of 332 (35%) stated that they did not use the controller medication on a daily basis. CONCLUSION: The Asthma APGAR system and the ACTTM/CACTTM similarly assess asthma control in a multicenter primary care based sample. The Asthma APGAR system identified an "actionable item" in more than 75% (234) of the individuals with poor asthma control, thus linking an assessment of poor asthma control with a management strategy. PMID- 24809760 TI - Osteoporosis and fractures after solid organ transplantation: a nationwide population-based cohort study. AB - OBJECTIVE: To investigate the incidence of bone disorders after solid organ transplantation (SOT). PARTICIPANTS AND METHODS: We used Taiwan's National Health Insurance Research Database to identify 9428 recipients of SOT and 38,140 sex- and age- matched control subjects between January 1, 1997, and December 31, 2010, to compare the incidence and risk of bone disorders between groups. RESULTS: Recipients of SOT had a significantly higher incidence of osteoporosis and related fractures compared with the non-SOT group. The overall hazard ratio (HR) of osteoporosis after SOT was 5.14 (95% CI, 3.13-8.43), and the HR of related fractures was 5.76 (95% CI, 3.80-8.74). The highest HRs were observed in male patients (HR, 7.09; 95% CI, 3.09-16.3) and in those aged 50 years or younger (HR, 7.38; 95% CI, 2.46-22.1). In addition, SOT patients without any comorbidities had a 9.03-fold higher risk of osteoporosis than non-SOT participants (HR, 9.03; 95% CI, 5.29-15.4). To compare the risk of osteoporosis and related fractures in different recipients of SOT, the highest risk of osteoporosis and fractures was noted in patients receiving lung transplantation, followed by other types of SOT. CONCLUSION: We report high rates of metabolic bone disorders after SOT in chronic transplant patients over a long follow-up. Both underlying bone disorders before transplantation and use of immunosuppressant agents may contribute to bone disorders after transplantation. PMID- 24809761 TI - Moderate cardiorespiratory fitness is positively associated with resting metabolic rate in young adults. AB - OBJECTIVE: To determine whether moderate cardiorespiratory fitness (CRF) or moderate to vigorous physical activity (MVPA) is associated with elevations in resting metabolic rate (RMR) similar to findings previously observed in endurance athletes. PARTICIPANTS AND METHODS: Using a cross-sectional design, we measured CRF, RMR, body composition, energy expenditure, and time in MVPA via an arm-based activity monitor in 423 young adults (mean age, 27.6 years). Based on the results of a fitness test, participants were classified into CRF tertiles (low, moderate, or high) by sex. RESULTS: There were significant differences among the low-, moderate-, and high-CRF groups for mean +/- SD body mass index (calculated as the weight in kilograms divided by the height in meters squared) (28.1 +/- 4.1, 25.1 +/- 3.4, and 23.6 +/- 2.5, respectively; P<.001) and fat mass (28.8 +/- 9.7, 20.5 +/- 8.2, and 14.8 +/- 6.5 kg, respectively; P<.001) but not fat-free mass (53.1 +/- 11.5, 53.5 +/- 12.4, and 54.7 +/- 12.1 kg, respectively; P=.49). There were no differences in mean +/- SD unadjusted RMR among the groups (1533.2 +/- 266.2, 1519.7 +/- 267.6, and 1521.9 +/- 253.9 kcal/d, respectively). However, after statistical adjustment for differences in body composition, the moderate- and high-CRF groups had a higher RMR compared with low-CRF individuals by 39.7 and 59.9 kcal/d, respectively (P<.05). After further adjustment for MVPA, RMR was higher in the high-CRF group compared with the low-CRF group by 51.2 kcal/d (P<.05). CONCLUSION: In this large sample of young adults representing a range of CRF, there was a positive stepwise gradient in RMR across tertiles of CRF independent of body composition. Also, MVPA was independently associated with RMR, although this relationship was modest. These findings underscore the multidimensional role of CRF and MVPA on health. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01746186. PMID- 24809762 TI - Intramolecular hydrogen bonding motifs in deprotonated glycine peptides by cryogenic ion infrared spectroscopy. AB - The infrared spectra of deprotonated glycine peptides, (Gn-H)(-) with n = 1-4, in the 1200-3500 cm(-1) spectral region are presented. Comparisons between the experimental and calculated spectra reveal the chain length dependent hydrogen bonding motifs that define the geometries of these species. First, an interaction between the terminal carboxylate and the neighboring amide N-H is present in all the peptide structures. This interaction is strong enough to align this amide group in the same plane as the carboxylate. However, we found that the vibrational frequency shift of this hydrogen bonded N-H group is not well reproduced in the calculations. Second, in the longer (G3-H)(-) and (G4-H)(-) species, the peptide chain folds such that the terminal NH2 group also interacts with the carboxylate. Both of these folded structures display an interaction between the terminal NH2 and the neighboring N-H as well. Lastly, an amide-amide interaction is observed in the longest (G4-H)(-) structure. Analysis of the N-H peak positions reveals the interplay among the different hydrogen bonds, especially around the negatively charged carboxylate moiety. PMID- 24809763 TI - Authors' reply to Davis. PMID- 24809764 TI - Temperament subtypes in treatment seeking obese individuals: a latent profile analysis. AB - OBJECTIVE: This study aimed to investigate temperament subtypes in obese patients. METHODS: Ninety-three bariatric surgery candidates and 63 obese inpatients from a psychotherapy unit answered the Behavioral Inhibition System/Behavioral Activation System Scale (BIS/BAS), the Effortful Control subscale of the Adult Temperament Questionnaire-Short Form (ATQ-EC), and questionnaires for eating disorder, depressive and attention deficit hyperactivity disorder (ADHD) symptoms and completed neurocognitive testing for executive functions. Binge eating disorder and impulse control disorders were diagnosed using interviews. RESULTS: A latent profile analysis using BIS/BAS and ATQ-EC scores revealed a 'resilient/high functioning' cluster (n = 88) showing high ATQ-EC and low BIS/BAS scores and an 'emotionally dysregulated/undercontrolled' cluster (n = 68) with low ATQ-EC and high BIS/BAS scores. Patients from the 'emotionally dysregulated/undercontrolled' cluster showed more eating disorder, depressive and ADHD symptoms, and poorer performance in the labyrinth task. CONCLUSION: The findings support the assumptions regarding the heterogeneity of obesity and the association between temperament subtypes and psychopathology. PMID- 24809766 TI - Intraocular surgery in a large diabetes patient population: risk factors and surgical results. AB - The prevalence of diabetes is on the increase in developed countries. Accordingly, the prevention and treatment of vision-threatening diabetic eye complications is assuming greater importance. The overall aim of this thesis is to analyse risk factors for intraocular surgery in a large diabetes population and to report surgical results. The specific objectives are to (1) estimate the incidence of diabetic vitrectomy and analyse risk factors (Study I), (2) report long-term results, prognostic factors and incidence of cataract surgery after diabetic vitrectomy (Study II), (3) report results and prognostic factors after cataract surgery in diabetes patients (Study III) and (4) analyse risk factors for diabetic papillopathy with emphasis on metabolic control variability (Study IV). All studies are based on a close-to-complete national surgery register and a large, closely followed diabetic retinopathy screening population. Study I (cohort study, 3980 type 1 diabetes patients) illustrates that diabetic vitrectomy is rarely required in a diabetes patient population with varying degrees of diabetic retinopathy. The risk of reaching diabetic vitrectomy increases fourfold with poor metabolic control, defined as glycosylated haemoglobin A1c > 75 mmol/mol (~9%), which points to good metabolic control as an important preventive measure. Study II (cohort study, 167 diabetes patients) shows that most diabetic vitrectomy patients stand to gain visual acuity >=0.3 after surgery. Visual acuity is stable after 1 year, and the stability is maintained through 10 years of follow-up. The use of silicone oil for endotamponade is a consistent long-term predictor of low vision after surgery. The risk of requiring cataract surgery after diabetic vitrectomy is substantial, and the risk increases if silicone oil is used. Study III (cohort study, 285 diabetes patients) shows, on the other hand, that diabetes patients can expect a significant improvement in visual acuity after cataract surgery, regardless of the degree of diabetic retinopathy. Poor preoperative visual acuity, a high degree of diabetic retinopathy and advanced age are predictors of a poor visual acuity after surgery. The risk of diabetic macular oedema after surgery is 4%. Finally, Study IV (case-control study, 2066 type 1 diabetes patients) demonstrates that diabetic papillopathy shares characteristics with diabetic retinopathy. The risk of experiencing diabetic papillopathy increases markedly with a drastic, recent reduction in glycosylated haemoglobin A1c and a small optic disc. This lends support to the theory that diabetic eye complications may occur in anatomically predisposed patients in response to metabolic control variability. Overall, results after intraocular surgery in diabetes patients are favourable. Surgery, however, is associated with costs to society, patient discomfort and risk of complications. This thesis provides an analysis of risk factors for intraocular surgery and identifies prognostic factors for visual acuity after surgery, which can be used for preventive purposes, surgical decision-making and patient counselling. PMID- 24809765 TI - Understanding and manipulating plant lipid composition: Metabolic engineering leads the way. AB - The manipulation of plant seed oil composition so as to deliver enhanced fatty acid compositions suitable for feed or fuel has long been a goal of metabolic engineers. Recent advances in our understanding of the flux of acyl-changes through different key metabolic pools such as phosphatidylcholine and diacylglycerol have allowed for more targeted interventions. When combined in iterative fashion with further lipidomic analyses, significant breakthroughs in our capacity to generate plants with novel oils have been achieved. Collectively these studies, working at the interface between metabolic engineering and synthetic biology, demonstrate the positive fundamental and applied outcomes derived from such research. PMID- 24809767 TI - Early complications following cochlear implantation in children and their management. AB - OBJECTIVES: To report the early postoperative complications of cochlear implantation (CI) in the pediatric population and discuss the intervention measures. METHODS: We retrospectively analyzed 260 consecutive pediatric cochlear implantations performed at the First Affiliated Hospital of Zhengzhou University between March 2010 and July 2013. All patients were younger than 12 years old at the time of implantation, with a mean age of 4.3 years, and 47 cases had inner ear malformations. Complications correlated to age at CI and inner ear malformations were analyzed using the chi(2) test. RESULTS: Of the 260 patients, early postoperative complications were observed in 17 (6.54%) cases, of which 16 (6.15%) were minor and one (0.38%) was major, none required surgical device removal or reimplantation. Among the 16 minor complications, transient vertigo was the most common (nine cases, 3.46%), three (1.15%) of them with severe CSF gusher during the surgery; followed by transient facial nerve palsy (two cases, 0.77%, both were reversible); external auditory canal injury, subcutaneous hematoma each in two cases (0.77%), and minor dural injury in one case (0.38%). One major complication included an epidural hematoma in a 7-year-old boy who recovered completely without any neurologic deficits following immediate evacuation. Inner ear malformations were significantly associated with the surgical complications, especially vertigo and gusher (P<0.05). CONCLUSIONS: Cochlear implantation in children is fairly a safe procedure with a relatively low complication rate. The most common early postoperative complications are minor, but serious and life threatening complications rarely may occur. Awareness of complications helps clinicians to adopt the specific preventive measures and immediate interventions so that the outcome will be successful. PMID- 24809768 TI - Maxillofacial extramedullary hematopoiesis in a child with sickle cell presenting as bilateral periorbital cellulitis. AB - Review of a case of paraosseous extramedullary hematopoiesis (EMH) affecting the maxillary sinuses and retro-orbital spaces imitating bilateral orbital cellulitis. Maxillofacial EMH causes diagnostic/therapeutic challenges. This case report describes a 4-year-old African American male with sickle cell disease (HbSS) who presented with bilateral orbitofacial swelling. Diagnosis was made with imaging and confirmed with tissue sampling. Partial exchange transfusion was utilized to stop the progression of maxillofacial EMH and to treat the patient's chronic anemia. Follow-up MRI showed regression of orbital and retro-orbital involvement. Early treatment with conservative modalities and close observation may prevent need for more invasive treatments. PMID- 24809769 TI - Resection of recurrent branchial cleft deformity using selective neck dissection technique. AB - OBJECTIVES: This study explores application of selective neck dissection technique in recurrent second, third, and fourth branchial cleft deformities. METHODS: A total of 19 cases of recurrent second, third, and fourth branchial cleft deformities were treated using the selective neck dissection technique, during which the sternocleidomastoid muscle, cervical anterior muscle, and carotid sheath were contoured. The lesion above the prevertebral fascia was then resected en bloc. Finally, the opening of the internal fistula was ligated and sutured using the purse-string approach. RESULTS: Patients in this study had no injures to their internal carotid artery, jugular vein, vagus nerve, accessory nerve, hypoglossal nerve, or recurrent laryngeal nerve. There were also no complications such as poor wound healing. The patients were monitored for 7-73 months and showed no recurrences. CONCLUSIONS: Using selective neck dissection to treat second, third, and fourth branchial cleft deformities resulted in en bloc lesion resections and reduced the chance of recurrence. Contouring the sternocleidomastoid muscle, strap muscle, and carotid sheath is key to the surgical procedure, as it leads to en bloc lesion resection while retaining the recurrent laryngeal nerve and carotid sheath. PMID- 24809770 TI - The effectiveness of nasal saline irrigation (seawater) in treatment of allergic rhinitis in children. AB - OBJECTIVE: To evaluate the effect of nasal saline irrigation in the treatment of allergic rhinitis (AR) in children and to assess whether nasal saline irrigation could be used as a complementary therapy for AR in children in combination with the intranasal corticosteroids (INS). METHOD: In total, 61 children with AR were divided into three groups: the nasal irrigation, intranasal corticosteroid, and combined treatment groups. Symptoms and signs of AR and eosinophils (EOS) in the nasal secretions were evaluated after 4 weeks, 8 weeks, and 12 weeks of treatment. RESULTS: In AR children treated with nasal irrigation and a decreased the INS dose, a significant improvement in symptoms and signs and a significant decrease in the mean EOS count in nasal secretions were observed at week 12. CONCLUSION: Nasal saline irrigation with physiological seawater is well tolerated and benefits the patients with AR, and can thus be considered a good adjunctive treatment option to maintain the effectiveness of the INS at a lower dose, thus resulting in reduced side effects and a decreased economic burden. PMID- 24809771 TI - Obstructive sleep apnea in younger school children with Down syndrome. AB - OBJECTIVE: We aimed to assess the prevalence of obstructive sleep apnea (OSA) in 8 year old school children with Down syndrome (DS). While the prevalence in otherwise healthy children is below 5%, the prevalence estimates in children with DS are uncertain (30-80%). OSA directly affects cognitive development and school performance. STUDY DESIGN: Population based cross sectional study in a limited geographical area. METHODS: Polysomnography (PSG) with video and audio recordings was performed in 8-year-old children with DS in a pediatric sleep unit according to the guidelines of American Academy of Sleep Medicine. Twenty-nine of all 32 children with DS within a restricted area comprising >50% of the Norwegian population and 54% of the children with DS born in Norway in 2002 were enrolled. RESULTS: This study reports an apnea hypopnea index AHI>1.5 in 28 of 29 children and an obstructive apnea index (OAI)>1 in 24 of 29 children. 19 children (66%) had an AHI>5 and 17 children (59%) had an OAI>5 which indicated moderate to severe OSA. No correlation was found between OSA and obesity or gender. CONCLUSION: The high prevalence of disease found in these previously undiagnosed 8-year-old children underlines the importance of performing OSA diagnostics in children with DS throughout childhood. These findings suggest that the prevalence of OSA remains high up to early school years. In contrast to earlier publications, this current study has the advantage of being population based, the study is performed on children of a narrow age band to estimate prevalence of disease and the diagnostic gold standard of PSG is applied. PMID- 24809772 TI - Parental role in the diagnostics of otitis media: can parents be taught to use tympanometry reliably? AB - OBJECTIVE: Tympanometry can be used to detect middle ear effusion (MEE). As the need for rearrangement of clinical resources at the primary care level increases, it is important to determine whether layman parents could be taught to use the tympanometer reliably, aiming to reduce unnecessary physician visits during respiratory tract infections. METHODS: From our AOM treatment trial we enrolled 78 children (age 6-35 months) who had persistent MEE, parents were voluntary and willing to use a tympanometer at home, the child was sufficiently co-operative, and parents learned technically the use of the tympanometer. At home, parents were asked to perform daily bilateral tympanometry on their child. We included those parental tympanometric examinations, to which the corresponding tympanometric examination, within one day by a study physician was available. Parental tympanometric examinations were compared to the pneumatic otoscopy by a study physician which served as the diagnostic standard. RESULTS: This study involved 78 children and a total of 432 parental tympanometric examinations. From these 432 examinations, parents obtained an interpretable tympanogram in 83% (359/432) and physicians in 91% (393/432) (absolute rate difference 8%, 95% CI 3 12%). Both obtained an interpretable tympanogram from the same ear in 75% (326/432) of the tympanometric examinations. Of these 326 interpretable examinations, parents and physicians were in accordance with either a peaked or a flat tympanogram in 88% of examinations (288/326) (kappa-value 0.77). When the tympanogram was peaked, pneumatic otoscopy indicated healthy middle ear in 72% (122/169) of parental and in 69% (149/217) of study physicians' tympanometric examinations (absolute rate difference 4%, 95% CI -6% to 13%). When the tympanogram was flat, pneumatic otoscopy indicated any MEE in 92% of parental (174/190) and in 96% (169/176) of study physicians' tympanometric examinations (absolute rate difference 4%, 95% CI -9% to 1%). CONCLUSION: This study showed that layman parents are able to use tympanometry technically successfully, and that the parental tympanometric examinations are as reliable as those obtained by study physicians. PMID- 24809773 TI - Fully endoscopic resection of juvenile nasopharyngeal angiofibroma - own experience and clinical outcomes. AB - OBJECTIVES: The treatment of choice in juvenile nasopharyngeal angiofibroma (JNA) is surgery - nowadays endoscopic techniques. The aim of the study was to present the results of endoscopic treatment in patients diagnosed with juvenile angiofibroma. MATERIALS AND METHODS: In this retrospective case series, 10 patients with a diagnosis of JNA treated at the Department of Otolaryngology of the Medical University in Poznan from 2006 to June 2013 were included. The age of patients were between 11 and 19 years old (14.6 on average). In 9 out of 10 patients the treatment was preceded by embolization. The surgery used the endoscopic approach through one nostril and the four-handed technique. RESULTS: Total resection was possible in all cases. Blood loss ranged from 100 to 250 ml. Post-operative hospitalization lasted from 3 to 5 days (3.3 days on average). Recurrence was reported in one patient. The observation lasted from six months to seven years (3.55 on average). CONCLUSIONS: Endoscopic resection of juvenile angiofibroma is safe for the patient. Moreover, if the evaluation of the tumour size and staging is correct, the ability of total removal of the tumour is very high. It is also connected with small blood loss, short hospital stay and good cosmetic effects. PMID- 24809774 TI - Tunable band gaps in silicene-MoS2 heterobilayers. AB - The geometric and electronic properties of silicene paired with a MoS2 substrate are studied systematically by using density functional theory with van der Waals corrections. It is found that the nearly linear band dispersions can be preserved in the heterobilayers due to the weak interface interactions. Meanwhile, the band gap is opened because of the sublattice symmetry broken by the intrinsic interface dipole. Moreover, the band gap values could be effectively modulated under an external electric field. Therefore, a way is paved for silicene-MoS2 heterobilayers to be candidate materials for logic circuits and photonic devices. PMID- 24809775 TI - Anterior tongue cancer with no history of tobacco and alcohol use may be a distinct molecular and clinical entity. AB - BACKGROUND: A small, albeit significant, number of head and neck squamous cell carcinoma (HNSCC) patients has no history of tobacco and alcohol use. Such non habits associated HNSCCs may represent a distinct clinical entity and exhibit increased aggressiveness. The objective of the study was to understand differences in molecular etiology of habits, and non-habits associated tongue carcinomas. MATERIALS AND METHODS: High-throughput gene expression profiling of 22 tumor samples was carried out. This was followed by quantitative real-time PCR validation of four of the identified differentially expressed genes. RESULTS AND CONCLUSION: Eighteen genes were identified that correlate strongly with the habits- and non-habits distinction. Among the genes significantly overexpressed in the non-habits group are CCND1, a key cell-cycle regulator, DACT3, a modulator of the Wnt/beta-catenin pathway, and three genes associated with the Notch signaling pathway. CCND1 and DACT3 overexpression in non-habits associated tongue carcinomas were subsequently validated by quantitative real-time PCR in an independent cohort (n = 18) of patient samples. Gene expression data were integrated with publicly available protein interaction data to build a small protein interaction network containing five of 18 differentially expressed genes. This suggested that a functional 'network module' can be implicated in the subgroup distinction. All the tumors analyzed here were human papillomavirus (HPV) negative samples. An association between CCND1 overexpression in oral tumors and poor prognosis has previously been reported. Thus, CCND1 overexpression in non-habits associated anterior tongue carcinomas may contribute to their increased clinical aggressiveness. PMID- 24809776 TI - A clue towards improving the European Society of Medical Oncology risk group classification in apparent early stage endometrial cancer? Impact of lymphovascular space invasion. AB - BACKGROUND: Lymphovascular space invasion (LVSI) is one of the most important predictors of nodal involvement and recurrence in early stage endometrial cancer (EC). Despite its demonstrated prognostic value, LVSI has not been incorporated into the European Society of Medical Oncology (ESMO) classification. The aim of this prospective multicentre database study is to investigate whether it may improve the accuracy of the ESMO classification in predicting the recurrence risk. METHODS: Data of 496 patients with apparent early-stage EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from prospective multicentre database. A modified ESMO classification including six risk groups was created after inclusion of the LVSI status in the ESMO classification. The primary end point was the recurrence accuracy comparison between the ESMO and the modified ESMO classifications with respect to the area under the receiver operating characteristic curve (AUC). RESULTS: The recurrence rate in the whole population was 16.1%. The median follow-up and recurrence time were 31 (range: 1-152) and 27 (range: 1-134) months, respectively. Considering the ESMO modified classification, the recurrence rates were 8.2% (8 out of 98), 23.1% (15 out of 65), 25.9% (15 out of 58), and 45.1% (28 out of 62) for intermediate risk/LVSI-, intermediate risk/LVSI+, high risk/LVSI-, and high risk/LVSI+, respectively (P<0.001). In the low risk group, LVSI status was not discriminant as only 7.0% (14 out of 213) had LVSI+. The staging accuracy according to AUC criteria for ESMO and ESMO modified classifications were of 0.71 (95% CI: 0.68-0.74) and 0.74 (95% CI: 0.71-0.77), respectively. CONCLUSIONS: The current modified classification could be helpful to better define indications for nodal staging and adjuvant therapy, especially for patients with intermediate risk EC. PMID- 24809777 TI - Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas. AB - BACKGROUND: c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas. METHODS: In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ?3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ?2. RESULTS: We observed c MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS). CONCLUSIONS: c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death. PMID- 24809779 TI - Differential effect of MMSET mRNA levels on survival to first-line FOLFOX and second-line docetaxel in gastric cancer. AB - BACKGROUND: Breast cancer susceptibility gene 1 (BRCA1) expression differentially affects outcome to platinum- and taxane-based chemotherapy. Mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1 (53BP1), multiple myeloma SET domain (MMSET) and ubiquitin-conjugating enzyme 9 (UBC9) are involved in DNA repair and could modify the BRCA1 predictive model. METHODS: Mediator of DNA damage checkpoint protein 1, 53BP1, MMSET and UBC9 mRNA were assessed in gastric tumours from patients in whom BRCA1 levels had previously been determined. RESULTS: In vitro chemosensitivity assay, MMSET levels were higher in docetaxel-sensitive samples. In a separate cohort, survival was longer in those with low MMSET (12.3 vs 8.8 months; P=0.04) or UBC9 (12.4 vs 8.8 months; P=0.01) in patients receiving only folinic acid, fluorouracil (5-FU) and oxaliplatin (FOLFOX). Conversely, among patients receiving second-line docetaxel, longer survival was associated with high MMSET (19.1 vs 13.9 months; P=0.003). Patients with high MMSET and BRCA1 attained a median survival of 36.6 months, compared with 13.9 months for those with high BRCA1 and low MMSET (P=0.003). In the multivariate analyses, low MMSET (hazard ratio (HR), 0.59; P=0.04) and low UBC9 (HR, 0.52; P=0.01) levels were markers of longer survival to first-line FOLFOX, whereas palliative surgery (HR, 2.47; P=0.005), low BRCA1 (HR, 3.17; P=0.001) and low MMSET (HR, 2.52; P=0.004) levels were markers of shorter survival to second line docetaxel. CONCLUSIONS: Breast cancer susceptibility gene 1, MMSET and UBC9 can be useful for customising chemotherapy in gastric cancer patients. PMID- 24809780 TI - Comparison of radiological and clinical features of temporal lobe necrosis in nasopharyngeal carcinoma patients treated with 2D radiotherapy or intensity modulated radiotherapy. AB - BACKGROUND: To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT). METHODS: We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, 128 temporal lobes) or IMRT (36 patients, 50 lobes) and developed radiation-induced, MRI-confirmed TLN. RESULTS: White-matter lesions (WMLs), contrast-enhanced lesions, cysts and local mass effects were present in 128 out of 128 vs 48 out of 50 (P=0.078), 123 out of 128 vs 47 out of 50 (P=0.688), 10 out of 128 vs 1 out of 50 (P=0.185) and 57 out of 128 vs 13 out of 50 (P=0.023) temporal lobes, respectively, in the 2D-RT and IMRT groups. The WMLs were more extensive in the 2D-RT group (P<0.001). The maximum diameter of contrast-enhanced lesions was greater in the 2D-RT group (P<0.001), and these lesions tended to extend far away from the nasopharynx. The WMLs and enhancement had no impact on cyst development (both P=1). Local mass effects were always accompanied with contrast-enhanced lesions (P=0.024) but were not correlated with WMLs or cysts (P=0.523 and 0.341, respectively). There were no between-group differences in clinical features (all P-values>0.05), whereas the difference in the incidence of severe debility was of marginal significance (18.1% vs 5.6%, P=0.077). CONCLUSIONS: The IMRT-induced TLN was less extensive and milder than 2D-RT induced TLN, but both had similar clinical features. PMID- 24809781 TI - Comment on 'Interventions to improve exercise behaviour in sedentary people living with and beyond cancer: a systematic review'. PMID- 24809778 TI - Direct T cell-tumour interaction triggers TH1 phenotype activation through the modification of the mesenchymal stromal cells transcriptional programme. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are heterogeneous cells with immunoregulatory and wound-healing properties. In cancer, they are known to be an essential part of the tumour microenvironment. However, their role in tumour growth and rejection remains unclear. To investigate this, we co-cultured human MSCs, tumour infiltrating lymphocytes (TIL), and melanoma cells to investigate the role of MSCs in the tumour environment. METHODS: Mesenchymal stromal cells were co-cultured with melanoma antigen-specific TIL that were stimulated either with HLA-A*0201(+) melanoma cells or with a corresponding clone that had lost HLA A*0201 expression. RESULTS: Activated TIL induced profound pro-inflammatory gene expression signature in MSCs. Analysis of culture supernatant found that MSCs secreted pro-inflammatory cytokines, including TH1 cytokines that have been previously associated with immune-mediated antitumor responses. In addition, immunohistochemical analysis on selected markers revealed that the same activated MSCs secreted both the TH1 cytokine (interleukin-12) and indoleamine 2,3 dioxygenase (IDO), a classical immunosuppressive factor. CONCLUSIONS: This study reflected that the plasticity of MSCs is highly dependent upon microenvironment conditions. Tumour-activated TIL induced TH1 phenotype change in MSCs that is qualitatively similar to the previously described immunologic constant of rejection signature observed during immune-mediated, tissue-specific destruction. This response may be responsible for the in loco amplification of antigen specific anti-cancer immune response. PMID- 24809784 TI - Laparoscopic versus endoscopic management of choledocholithiasis in patients undergoing laparoscopic cholecystectomy: a meta-analysis. AB - AIM: To compare the clinical effectiveness of the treatment of choledocholithiasis by laparoscopic common bile duct (CBD) exploration and by endoscopic sphincterotomy (EST). MATERIALS AND METHODS: A meta-analysis of studies about CBD stones was performed to analyze EST in comparison with laparoscopic CBD exploration procedures. Trials were identified by searching the Medline, EMBASE, PubMed, CBM, and CNKI databases from January 1990 to December 2012 for laparoscopic CBD exploration or EST for CBD stones. RESULTS: Fifteen studies were identified in the meta-analysis. The incidence of bleeding or pancreatitis in the EST group was higher than that in the laparoscopic group. However, the incidence of bile leakage in the EST group was lower than that in the laparoscopic group. The differences in cases of retained stones or total complications were not statistically significant between the laparoscopic and EST groups (P>.05). There were more successful cases in the laparoscopic group than in the EST group (P<.05). Hospital cost was less in the laparoscopic group than in the EST group (P<.05). Mean operation time and hospital stay in the laparoscopic group were shorter than those in the EST group (P<.05). CONCLUSIONS: To some degree, laparoscopic treatment of the CBD may be a better way of removing stones than EST. PMID- 24809783 TI - Mammary gland-specific ablation of focal adhesion kinase reduces the incidence of p53-mediated mammary tumour formation. AB - BACKGROUND: Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneous mammary tumour development caused by loss of tumour suppressor genes such as p53 is lacking. Alterations in the tumour suppressor gene p53 have been implicated in over 50% of human breast cancers. Given that elevated FAK expression highly correlates with p53 mutation status in human breast cancer, we set out to investigate the importance of FAK in p53-mediated spontaneous mammary tumour development. METHODS: To directly assess the role of FAK, we generated mice with conditional inactivation of FAK and p53. We generated female p53(lox/lox)/FAK(+/+)/WapCre, p53(lox/lox)/FAK(flox/+)/WapCre and p53(lox/lox)/FAK(flox/-)/WapCre mice, and mice with WapCre-mediated conditional expression of p53(R270H), the mouse equivalent of human p53(R273H) hot spot mutation, together with conditional deletion of FAK, P53(R270H/+)/FAK(lox/+)/WapCre and p53(R270H/+)/FAK(flox/-)/WapCre mice. All mice were subjected to one pregnancy to induce WapCre-mediated deletion of p53 or expression of p53 R270H, and Fak genes flanked by two loxP sites, and subsequently followed the development of mammary tumours. RESULTS: Using this approach, we show that FAK is important for p53-induced mammary tumour development. In addition, mice with the mammary gland-specific conditional expression of p53 point mutation R270H, the mouse equivalent to human R273H, in combination with conditional deletion of Fak showed reduced incidence of p53(R270H)-induced mammary tumours. In both models these effects of FAK were related to reduced proliferation in preneoplastic lesions in the mammary gland ductal structures. CONCLUSIONS: Mammary gland-specific ablation of FAK hampers p53-regulated spontaneous mammary tumour formation. Focal adhesion kinase deletion reduced proliferative capacity of p53 null and p53(R270H) mammary epithelial cells but did not lead to increased apoptosis in vivo. Our data identify FAK as an important regulator in mammary epithelial cell proliferation in p53-mediated and p53(R270H)-induced mammary tumour development. PMID- 24809782 TI - SERPINB3 is associated with TGF-beta1 and cytoplasmic beta-catenin expression in hepatocellular carcinomas with poor prognosis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome. METHODS: Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-beta and beta-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out. RESULTS: High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-beta at transcription and protein level was observed, whereas for beta catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis. CONCLUSIONS: SERPINB3 is overexpressed in the subset of the most aggressive HCCs. PMID- 24809785 TI - Minimally invasive thoracic sympathectomy for palmar hyperhidrosis via a single unilateral incision approach by the pleura videoscope. AB - OBJECTIVE: Palmar hyperhidrosis is a common disease that causes intense significant embarassment for patients. Bilateral single-port thoracoscopic sympathectomy is an effective surgical treatment with high success rates and improvement in quality of life. In order to reduce surgical invasion and to seek better cosmetic results, we describe a novel protocol for thoracic sympathectomy in the treatment of palmar hyperhidrosis. MATERIALS AND METHODS: Between January 2012 and September 2012, bilateral thoracic sympathectomy was performed through the anterior mediastinal pleura using the pleural videoscope with a single unilateral skin incision in 10 men and 6 women. RESULTS: In total, 16 patients were cured, and the skin temperature increased by a mean of 2.7+/-0.6 degrees C. The average operation time was 67.9+/-15.8 minutes, with a postoperative hospital stay of 1.9+/-0.6 days and operative bleeding of less than 20 mL. All operations were successful, with no severe complications or perioperative mortality. Follow up of 9.8+/-2.3 months (range, 7-14 months) showed that palmar sweating improved in all patients, and the effective rate was 100%. CONCLUSIONS: A single unilateral incision for two-sided thoracic sympathectomy through the anterior mediastinal pleura is an effective, feasible, safe, and minimally invasive procedure with excellent cosmetic results. PMID- 24809786 TI - Endoscope-assisted transoral thyroidectomy using a frenotomy incision. AB - OBJECTIVE: Natural orifice translumenal endoscopic surgery (NOTES((r)); American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and Society of American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) has generated excitement among surgeons as potentially scar-free surgery. We developed this technique while taking into consideration that it could also be applied to transoral thyroid surgery. PATIENT AND METHODS: We report the case of a 35-year old woman with a 0.5*0.5-cm papillary thyroid microcarcinoma. We implemented a modified approach for the removal of the thyroid by using a frenotomy incision of the mouth, accompanied by an endoscope system. RESULTS: A modified approach for the removal of the thyroid was used on the patient. The total operating time was 120 minutes, and there were no specific complications. The patient continues to be free of any diseases 12 months after the excision. CONCLUSIONS: Thyroidectomy can be performed by a transoral endoscope-assisted approach through a frenotomy incision of the mouth. We describe the detailed procedures for an endoscope assisted transoral thyroidectomy using a frenotomy incision. PMID- 24809787 TI - Comparison of the Airtraq and McCoy laryngoscopes using a rigid neck collar in patients with simulated difficult laryngoscopy. AB - STUDY OBJECTIVE: To determine the efficacy of the Airtraq versus the McCoy laryngoscope as intubation devices with the neck stabilized by a rigid cervical collar. DESIGN: Prospective, randomized, double-blinded study. SETTING: Jawaharlal Nehru Medical College. PATIENTS: 60 ASA physical status 1, 2, and 3 patients, aged 18-70 years, scheduled for various surgical procedures requiring tracheal intubation for surgical anesthesia. INTERVENTIONS: Patients were randomly allocated to undergo intubation with the McCoy (n = 30) or Airtraq (n = 30) laryngoscope. MEASUREMENTS AND MAIN RESULTS: Differences in intubation times between the Airtraq and the McCoy laryngoscope, modified Cormack-Lehane score, percentage of glottic opening (POGO) score, and airway trauma were compared. Overall intubation success rates were 100% with both devices and a similar number of intubation attempts were required. However, the mean (SD) time required for successful intubation was shorter with the Airtraq (28.73 +/- 6.39 sec) than the McCoy laryngoscope (39.11 +/- 14.01 sec; P < 0.0001). The frequencies of intubation complications were similar. Esophageal intubation occurred in 4 cases but only with the McCoy laryngoscope. CONCLUSION: Intubation time was shorter with the Airtraq than the McCoy laryngoscope, even though the overall success rates between the two devices were similar. PMID- 24809788 TI - Airway sealing pressure behavior of the Laryngeal Mask Airway Supreme in patients undergoing surgery with general anesthesia: a pilot study. PMID- 24809789 TI - Increased recombinant activated factor VII use and need for surgical reexploration following a switch from aprotinin to epsilon-aminocaproic acid in infant cardiac surgery. AB - STUDY OBJECTIVE: To evaluate whether conversion from aprotinin to epsilon aminocaproic acid (EACA) during infant cardiac surgery was associated with increased perioperative bleeding. DESIGN: Structured retrospective chart review. SETTING: University-affiliated large congenital cardiac surgery program. MEASUREMENTS: Records from 145 infants (age < 1 yr) receiving aprotinin as antifibrinolytic therapy for cardiac surgery between 6/1/2006 and 12/31/2006 were compared with a cohort of infants receiving EACA for cardiac surgery between 6/1/2008 and 12/31/2008. Sixty-eight infants received aprotinin and 77 infants received EACA. Measured indicators of perioperative bleeding included transfusion volumes, recombinant activated clotting factor VIIa (rFVIIa) administration, need for reexploration, and perioperative chest tube output. MAIN RESULTS: EACA treated patients received significantly more rFVIIa for uncontrolled bleeding (19/77 [25%] vs 3/68 [4%]; P < 0.001) and required surgical reexploration more frequently (21/77 [27%] vs 7/68 [10%]; P = 0.01]. Median (25th-75th percentiles) intraoperative platelet transfusion requirements were also increased after the switch to EACA (28 mL [0-58 mL] vs 0 mL [0 mL - 34.5 mL]), but this difference did not reach statistical significance (P = 0.06). CONCLUSIONS: Bleeding in infant cardiac surgery increased following the change in antifibrinolytic therapy from aprotinin to EACA. Given the potential for major harm, especially thrombotic complications, from rFVIIa use, prospective studies examining the safety of postcardiopulmonary bypass rFVIIa administration in infants are necessary before the routine off-label use may be recommended. PMID- 24809790 TI - Quantitative and qualitative research across cultures and languages: cultural metrics and their application. AB - Growing globalisation of the world draws attention to cultural differences between people from different countries or from different cultures within the countries. Notwithstanding the diversity of people's worldviews, current cross cultural research still faces the challenge of how to avoid ethnocentrism; comparing Western-driven phenomena with like variables across countries without checking their conceptual equivalence clearly is highly problematic. In the present article we argue that simple comparison of measurements (in the quantitative domain) or of semantic interpretations (in the qualitative domain) across cultures easily leads to inadequate results. Questionnaire items or text produced in interviews or via open-ended questions have culturally laden meanings and cannot be mapped onto the same semantic metric. We call the culture-specific space and relationship between variables or meanings a 'cultural metric', that is a set of notions that are inter-related and that mutually specify each other's meaning. We illustrate the problems and their possible solutions with examples from quantitative and qualitative research. The suggested methods allow to respect the semantic space of notions in cultures and language groups and the resulting similarities or differences between cultures can be better understood and interpreted. PMID- 24809791 TI - From the analysis of verbal data to the analysis of organizations: organizing as a dialogical process. AB - The analysis of conversational turn-taking and its implications on time (the speaker cannot completely anticipate the future effects of her/his speech) and sociality (the speech is co-produced by the various speakers rather than by the speaking individual) can provide a useful basis to analyze complex organizing processes and collective action: the actor cannot completely anticipate the future effects of her/his acts and the act is co-produced by multiple actors. This translation from verbal to broader classes of interaction stresses the performativity of speeches, the importance of the situation, the role of semiotic mediations to make temporally and spatially distant "ghosts" present in the dialog, and the dissymmetrical relationship between successive conversational turns, due to temporal irreversibility. PMID- 24809792 TI - High-efficiency aqueous-processed hybrid solar cells with an enormous Herschel infrared contribution. AB - Aqueous-processed solar cells have evolved into a new generation of promising and renewable energy materials due to their excellent optical, electrical, and low cost properties. In this work, Cd0.75Hg0.25Te colloid quantum dots (CQDs) were incorporated into a water-soluble conjugated polymer with broad absorption and high charge-carrier-mobility (5 * 10(-4) cm(2) V(-1) s(-1)) to obtain a composite with an absorption spectrum ranging from 300 to 1200 nm. The matched energy level between polymer and CQDs ensured the effective electron transfer, while the interpenetrating network structure formed via heat treatment guaranteed the quick electron transport. Moreover, the formation process of the interpenetrating network was systematically monitored by using AFM and TEM instruments and further confirmed through the measurement of charge-carrier-mobility of the active layers. In combination with the surface modification of a single Cd0.75Hg0.25Te layer, this aqueous-processed solar cell showed excellent photovoltaic response and the power conversion efficiency (PCE) reached 2.7% under AM 1.5 G illumination (100 mW cm(-2)). Especially, the contribution of the Herschel infrared region (780-1100 nm) to the photocurrent was as high as 15.04%. This device showed the highest PCE among organic-inorganic hybrid solar cells (HSCs) based on CdxHg1-xTe CQDs and the highest near infrared (NIR) contribution among aqueous-processed HSCs, indicating the enormous potential of taking advantage of NIR energy in a solar spectrum and a promising application in solar cells especially used in cloudy weather. PMID- 24809793 TI - Histamine induces human lung fibroblast-mediated collagen gel contraction via histamine H1 receptor. AB - BACKGROUND: Airway remodeling is implicated in irreversible airflow limitation of refractory asthma, which includes increased smooth muscle mass and subepithelial fibrosis. Activated fibroblasts acquire contractile phenotype to participate in tissue contraction and structural alteration of extracellular matrices. Histamine is a potent mediator of allergic inflammation, substantially involved in asthmatic pathophysiology. OBJECTIVE: We hypothesized that histamine might play a role in airway remodeling, and investigated its effect on fibroblast-mediated collagen gel contraction. METHODS: Fibroblast-mediated collagen gel contraction was studied. Histamine's regulation of collagen gel contraction was characterized by using specific histamine-receptor antagonists, an IP3 receptor antagonist and a PKC inhibitor. RESULTS: Histamine induced contraction of collagen gels embedded with human lung fibroblasts, in a time-dependent manner, and at the concentration more than 10(-6) M, both in four primary cultured adult lung fibroblasts and three fetal lung fibroblast cell lines. This effect was attenuated by H1 receptor antagonist, whereas those for H2 to H4 receptors failed to show an inhibitory effect. Furthermore, IP3 receptor-mediated Ca(2+) mobilization was implicated in histamine's action on collagen gel contraction. CONCLUSIONS: Our results suggest that histamine is involved in airway remodeling through its action on lung fibroblasts, and antihistamine drugs, especially H1 receptor antagonists, might be potentially beneficial for a subset of asthmatic patients. PMID- 24809794 TI - Activation of AMPK inhibits pulmonary arterial smooth muscle cells proliferation. AB - The aims of the present study were to examine the effect of AMPK activation on pulmonary arterial smooth muscle cells (PASMCs) proliferation and to address its potential mechanisms. ET-1 dose and time-dependently induced PASMCs proliferation, and this effect was suppressed by a selective AMPK activator metformin. The results of the study further indicated that the proliferation of PASMCs stimulated by ET-1 was associated with the increase of Skp2 and decrease of p27, and metformin reversed ET-1-induced Skp2 elevation and raised p27 protein level. Our study suggests that activation of AMPK suppresses PASMCs proliferation and has potential value in negatively modulating pulmonary vascular remodeling and therefore could prevent or treat the development of pulmonary arterial hypertension (PAH). PMID- 24809795 TI - Salt as a public health challenge in continental European convenience and ready meals. AB - OBJECTIVE: To assess the salt content of continental European convenience and ready meals. DESIGN: A multistage study in which, after laboratory analysis of the products' salt contents (n 32), new salt-reduced meals were developed through food reformulation. Additionally, a comprehensive survey of convenience meals from the Austrian market (n 572) was conducted to evaluate the salt contents of a wider product range. SETTING: Six continental European countries participated. SUBJECTS: No subjects enrolled. RESULTS: The salt contents of continental European convenience and ready meals mostly exceeded 1.8 g/100 g, which is 30 % of the targeted daily intake level; some contained even more than the recommended daily intake of 6 g. The highest salt contents were found in pizzas and pasta dishes, the lowest ones in sweet meals. Large variations in salt levels were found not only between and within meal type categories, but also between similar meals from different producers. In addition, our approach to develop new salt reduced meals showed that a stepwise reduction of the ready meals' salt contents is possible without compromising the sensory quality. CONCLUSIONS: To address the problem of hypertension and increased risk for CVD through high salt intake, a reduction of the salt levels in continental European convenience and ready meals is urgently needed, since they are providing a major part of the daily salt intake. Successful national-wide salt reduction strategies in the UK or Finland have already demonstrated the public health impact of this setting. PMID- 24809796 TI - The value of certification in HIV/AIDS nursing revisited. PMID- 24809798 TI - Polyspermy block in jellyfish eggs: collaborative controls by Ca(2+) and MAPK. AB - Jellyfish eggs neither undergo apparent cortical reaction nor show any significant change in the membrane potential at fertilization, but nevertheless show monospermy. Utilizing the perfectly transparent eggs of the hydrozoan jellyfish Cytaeis uchidae, here we show that the polyspermy block is accomplished via a novel mechanism: a collaboration between Ca(2+) and mitogen-activated protein kinase (MAPK). In Cytaeis, adhesion of a sperm to the animal pole surface of an egg was immediately followed by sperm-egg fusion and initiation of an intracellular Ca(2+) rise from this site. The elevated Ca(2+) levels lasted for several minutes following the sperm-egg fusion. The Ca(2+) rise proved to be necessary and sufficient for a polyspermy block, as inhibiting a Ca(2+) rise with EGTA promoted polyspermy, and conversely, triggering a Ca(2+) rise by inositol 1,4,5-trisphosphate (IP3) or excess K(+) immediately abolished the egg's capacity for sperm-egg fusion. A Ca(2+) rise at fertilization or by artificial stimulations evoked dephosphorylation of MAPK in eggs. The eggs in which phosphorylated MAPK was maintained by injection of mRNA for MAPK kinase kinase (Mos), like intact eggs, exhibited a Ca(2+) rise at fertilization or by IP3 injection, and shut down the subsequent sperm-egg fusion. However, the Mos expressing eggs became capable of accepting sperm following the arrest of Ca(2+) rise. In contrast, addition of inhibitors of MAPK kinase (MEK) to unfertilized eggs caused MAPK dephosphorylation without elevating Ca(2+) levels, and prevented sperm-egg fusion. Rephosphorylation of MAPK by injecting Mos mRNA after fertilization recovered sperm attraction, which is known to be another MAPK dependent event, but did not permit subsequent sperm-egg fusion. Thus, it is possible that MAPK dephosphorylation irreversibly blocks sperm-egg fusion and reversibly suppresses sperm attraction. Collectively, our data suggest that both the fast and late mechanisms dependent on Ca(2+) and MAPK, respectively, ensure a polyspermy block in jellyfish eggs. PMID- 24809797 TI - Sema3A maintains corneal avascularity during development by inhibiting Vegf induced angioblast migration. AB - Corneal avascularity is important for optical clarity and normal vision. However, the molecular mechanisms that prevent angioblast migration and vascularization of the developing cornea are not clear. Previously we showed that periocular angioblasts and forming ocular blood vessels avoid the presumptive cornea despite dynamic ingression of neural crest cells. In the current study, we investigate the role of Semaphorin3A (Sema3A), a cell guidance chemorepellent, on angioblast migration and corneal avascularity during development. We show that Sema3A, Vegf, and Nrp1 are expressed in the anterior eye during cornea development. Sema3A mRNA transcripts are expressed at significantly higher levels than Vegf in the lens that is positioned adjacent to the presumptive cornea. Blockade of Sema3A signaling via lens removal or injection of a synthetic Sema3A inhibitor causes ectopic migration of angioblasts into the cornea and results in its subsequent vascularization. In addition, using bead implantation, we demonstrate that exogenous Sema3A protein inhibits Vegf-induced vascularization of the cornea. In agreement with these findings, loss of Sema/Nrp1 signaling in Nrp1(Sema-) mutant mice results in ectopic angioblasts and vascularization of the embryonic mouse corneas. Altogether, our results reveal Sema3A signaling as an important cue during the establishment of corneal avascularity in both chick and mouse embryos. Our study introduces cornea development as a new model for studying the mechanisms involved in vascular patterning during embryogenesis and it also provides new insights into therapeutic potential for Sema3A in neovascular diseases. PMID- 24809799 TI - Sorafenib use in the transplant setting. AB - Liver transplantation (LT) is an established treatment for hepatocellular carcinoma (HCC), and sorafenib (SFN) is a validated treatment for patients harboring advanced tumors. It is still not clear whether the combination of the 2 treatments, with SFN used in the neoadjuvant, adjuvant, or recurrence setting, is useful and cost-effective. This article summarizes the present evidence in favor of and against the use of SFN in the setting of LT for HCC, and it also includes the problem of toxicity, particularly when mammalian target of rapamycin inhibitors, which play a central role in regulating cellular growth and proliferation, are used as immunosuppressants. Overall, the data do not support the use of SFN in the pre- or post-LT setting as adjuvant therapy, and additional studies are needed to reach sound conclusions on the topic. PMID- 24809800 TI - A rapid assay for measuring nucleotide excision repair by oligonucleotide retrieval. AB - Nucleotide excision repair (NER) excises bulky DNA lesions induced by mutagens and carcinogens. The repair process includes recognition of DNA damage, excision of a short patch of nucleotides containing the damaged base, re-synthesis of a new DNA strand and ligation of the nicks to restore the sequence integrity. Mutation or aberrant transcription of NER genes reduces repair efficiency and results in the accumulation of mutations that is associated with the development of cancer. Here we present a rapid, sensitive and quantitative assay to measure NER activity in human cells, which we term the Oligonucleotide Retrieval Assay (ORA). We used oligonucleotide constructs containing the UV-damaged adduct, cyclobutane pyrimidine dimer (CPD), to transfect human cells, and retrieved the oligonucleotides for quantification of the repaired, CPD-free DNA by real-time quantitative PCR. We demonstrate that ORA can quantify the extent of NER in diverse cell types, including immortalized, primary and stem-like cells. PMID- 24809801 TI - Category-specific processing of scale-invariant sounds in infancy. AB - Increasing evidence suggests that the natural world has a special status for our sensory and cognitive functioning. The mammalian sensory system is hypothesized to have evolved to encode natural signals in an efficient manner. Exposure to natural stimuli, but not to artificial ones, improves learning and cognitive function. Scale-invariance, the property of exhibiting the same statistical structure at different spatial or temporal scales, is common to naturally occurring sounds. We recently developed a 3-parameter model to capture the essential characteristics of water sounds, and from this generated both scale invariant and variable-scale sounds. In a previous study, we found that adults perceived a wide range of the artificial scale-invariant, but not the variable scale, sounds as instances of natural sounds. Here, we explored the ontogenetic origins of these effects by investigating how young infants perceive and categorize scale-invariant acoustic stimuli. Even though they have several months of experience with natural water sounds, infants aged 5 months did not show a preference, in the first experiment, for the instances of the scale-invariant sounds rated as typical water-like sounds by adults over non-prototypical, but still scale-invariant instances. Scale-invariance might thus be a more relevant factor for the perception of natural signals than simple familiarity. In a second experiment, we thus directly compared infants' perception of scale-invariant and variable-scale sounds. When habituated to scale-invariant sounds, infants looked significantly longer to a change in sound category from scale-invariant to variable-scale sounds, whereas infants habituated to variable-scale sounds showed no such difference. These results suggest that infants were able to form a perceptual category of the scale-invariant, but not variable-scale sounds. These findings advance the efficient coding hypothesis, and suggest that the advantage for perceiving and learning about the natural world is evident from the first months of life. PMID- 24809803 TI - Rational design and bioimaging applications of highly selective fluorescence probes for hydrogen polysulfides. AB - Reactive sulfur species have received considerable attention due to their various biological functions. Among these molecules, hydrogen polysulfides (H2S(n), n > 1) are recently suggested to be the actual signaling molecules derived from hydrogen sulfide (H2S). Hydrogen polysulfides may also have their own biosynthetic pathways. The research on H2S(n) is rapidly growing. However, the detection of H2S(n) is still challenging. In this work we report a H2S(n) mediated benzodithiolone formation under mild conditions. Based on this reaction, specific fluorescent probes for H2S(n) are prepared and evaluated. The probe DSP 3 shows good selectivity and sensitivity for H2S(n). PMID- 24809804 TI - Carbon related defects in irradiated silicon revisited. AB - Electronic structure calculations employing hybrid functionals are used to gain insight into the interaction of carbon (C) atoms, oxygen (O) interstitials, and self-interstitials in silicon (Si). We calculate the formation energies of the C related defects Ci(SiI), CiOi, CiCs, and CiOi(SiI) with respect to the Fermi energy for all possible charge states. The Ci(SiI)(2+) state dominates in almost the whole Fermi energy range. The unpaired electron in the CiOi(+) state is mainly localized on the C interstitial so that spin polarization is able to lower the total energy. The three known atomic configurations of the CiCs pair are reproduced and it is demonstrated that hybrid functionals yield an improved energetic order for both the A and B-types as compared to previous theoretical studies. Different structures of the CiOi(SiI) cluster result for positive charge states in dramatically distinct electronic states around the Fermi energy and formation energies. PMID- 24809802 TI - High-mobility group box 1 (HMGB1) in childhood: from bench to bedside. AB - High-mobility group box protein 1 (HMGB1) is a nonhistone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 activates the innate system and mediates a wide range of physiological and pathological responses. HMGB1 exerts these actions through differential engagement of multiple surface receptors, including Toll-like receptor (TLR)2, TLR4, and receptor for advanced glycation end products (RAGE). HMGB1 is implicated as a late mediator of sepsis and is also involved in inflammatory and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Interestingly, HMGB1 was associated with tumor progression, becoming a potential therapeutic target, due to its involvement in the resistance to chemotherapy. Its implication on the pathogenesis of systemic vasculitis and inflammatory bowel diseases has also been evaluated. Moreover, it regulates neuroinflammation after traumatic brain injuries or cerebral infectious diseases. The aim of this review is to analyze these different roles of HMGB1, both in physiological and pathological conditions, discussing clinical and scientific implications in the field of pediatrics. CONCLUSION: HMGB1 plays a key role in several pediatric diseases, opening new scenarios for diagnostic biomarkers and therapeutic strategies development. PMID- 24809805 TI - Partner approval and intention to use contraception among Zanzibari women presenting for post-abortion care. AB - OBJECTIVE: We examined the effect of partner approval of contraception on intention to use contraception among women obtaining post-abortion care in Zanzibar. STUDY DESIGN: Our data source was a 2010 survey of 193 women obtaining post-abortion care at a large public hospital in Zanzibar. We used multivariable logistic regression analysis to assess associations between partner approval and intention to use contraception. RESULTS: Overall, 23% of participants had used a contraceptive method in the past, and 66% reported intending to use contraception in the future. We found that partner approval of contraception and ever having used contraception in the past were each associated with intending to use contraception in the future. In the multivariable model, adjusting for past contraception use, partner approval of contraception was associated with 20 times the odds of intending to use contraception (odds ratio, 20.25; 95% confidence interval, 8.45-48.56). CONCLUSIONS: We found a strong association between partner approval and intention to use contraception. Efforts to support contraceptive use must include both male and female partners. IMPLICATIONS: Public health and educational efforts to increase contraceptive use must include men and be targeted to both male and female partners. Given that male partners are often not present when women obtain health care, creative efforts will be required to meet men in community settings. PMID- 24809806 TI - Calcitonin pump improves nerve regeneration after transection injury and repair. AB - INTRODUCTION: After nerve injury, excessive calcium impedes nerve regeneration. We previously showed that calcitonin improved nerve regeneration in crush injury. We aimed to validate the direct effect of calcitonin on transected and repaired nerve. METHODS: Two rat groups (n = 8) underwent sciatic nerve transection followed by direct repair. In the calcitonin group, a calcitonin-filled mini osmotic pump was implanted subcutaneously, with a catheter parallel to the repaired nerve. The control group underwent repair only, without a pump. Evaluation and comparison between the groups included: (1) compound muscle action potential recording of the extensor digitorum longus (EDL) muscle; (2) tetanic muscle force test of EDL; (3) nerve calcium concentration; and (4) nerve fiber count and calcified spot count. RESULTS: The calcitonin pump group showed superior recovery. CONCLUSIONS: Calcitonin affects injured and repaired peripheral nerve directly. The calcitonin-filled mini-osmotic pump improved nerve functional recovery by accelerating calcium absorption from the repaired nerve. This finding has potential clinical applications. PMID- 24809807 TI - Waning predictive value of serum adiponectin for fracture risk in elderly men: MrOS Sweden. AB - Serum adiponectin is a risk factor for fracture. The predictive value attenuates with time in elderly men so that its use for the risk assessment in the long term is questionable. The study underlines the importance of testing the long-term stability of potential risk factors. INTRODUCTION: High serum adiponectin is associated with an increased risk of fracture in elderly men. The aim of the present study was to determine the impact of adiponectin on the probability of fracture as a function of time. METHODS: The probability of osteoporotic fracture was computed in 989 elderly men from the MrOS study in Sweden. Baseline data included clinical risk factors for fracture, femoral neck BMD and serum adiponectin. Men were followed for up to 7.4 years with a mean follow up of 5.3 years (range 0.0-7.4 years). Poisson regression was used to model the hazard function for osteoporotic fracture and death to determine the 10 year probability of fracture. RESULTS: During follow up, 124 men sustained one or more osteoporotic fracture. There was a significant interaction between adiponectin and time since baseline (p = 0.026) such that the longer time since baseline, the lower the gradient of fracture risk. When using this interaction in the calculation of 10-year probability of fracture, the probabilities of osteoporotic fracture varied little over the range of adiponectin values. CONCLUSION: Serum adiponectin is a risk factor for fracture. Nevertheless, the predictive value attenuates with time so that its use for the risk assessment in the long term is questionable. This study underlines the importance of testing the long-term stability of potential risk factors that might be used in fracture risk assessment. PMID- 24809808 TI - Overuse of short-interval bone densitometry: assessing rates of low-value care. AB - We evaluated the prevalence and geographic variation of short-interval (repeated in under 2 years) dual-energy X-ray absorptiometry tests (DXAs) among Medicare beneficiaries. Short-interval DXA use varied across regions (coefficient of variation = 0.64), and unlike other DXAs, rates decreased with payment cuts. INTRODUCTION: The American College of Rheumatology, through the Choosing Wisely initiative, identified measuring bone density more often than every 2 years as care "physicians and patients should question." We measured the prevalence and described the geographic variation of short-interval (repeated in under 2 years) DXAs among Medicare beneficiaries and estimated the cost of this testing and its responsiveness to payment change. METHODS: Using 100 % Medicare claims data, 2006 2011, we identified DXAs and short-interval DXAs for female Medicare beneficiaries over age 66. We determined the population rate of DXAs and short interval DXAs, as well as Medicare spending on short-interval DXAs, nationally and by hospital referral region (HRR). RESULTS: DXA use was stable 2008-2011 (12.4 to 11.5 DXAs per 100 women). DXA use varied across HRRs: in 2011, overall DXA use ranged from 6.3 to 23.0 per 100 women (coefficient of variation = 0.18), and short-interval DXAs ranged from 0.3 to 8.0 per 100 women (coefficient of variation = 0.64). Short-interval DXA use fluctuated substantially with payment changes; other DXAs did not. Short-interval DXAs, which represented 10.1 % of all DXAs, cost Medicare approximately US$16 million in 2011. CONCLUSIONS: One out of ten DXAs was administered in a time frame shorter than recommended and at a substantial cost to Medicare. DXA use varied across regions. Short-interval DXA use was responsive to reimbursement changes, suggesting carefully designed policy and payment reform may reduce this care identified by rheumatologists as low value. PMID- 24809809 TI - Influence of physical activity and skeleton geometry on bone mass at the proximal femur in 10- to 12-year-old children--a longitudinal study. AB - Physical activity (PA) have long been identified as a determining factor of the mineralization of the skeleton, particularly in children. Our research supports the hypothesis that the geometry of the pelvis and proximal femur (PF) might moderate the effect of PA in the relative mineralization of the PF subregions. INTRODUCTION: Using a longitudinal observational study with two evaluations and a 1-year follow-up interval, we investigated the influence of PA and skeletal geometry in bone mineral density (BMD) and bone mass distribution at the PF in 96 girls and 81 boys (10-12 years). It is plausible that the geometry of the pelvis PF structure moderates mechanical forces exerted at the hip and therefore creates different degrees of mineralization among PF subregions. METHODS: Whole body and left hip dual X-ray absorptiometry scans were used to derive geometric measures of the pelvis-inter-acetabular distance (IAD) and PF abductor lever arm (ALA). BMD was measured at the integral, superolateral (SL), and inferomedial (IM) femoral neck (FN), and at the trochanter (TR). These subregions were used to represent bone mass distribution via three BMD ratios: FN/PF, IM/SL, and TR/PF. PA was measured using accelerometry and a bone-specific PA questionnaire (BPAQ). RESULTS: A longitudinal data approach revealed BPAQ as a positive predictor for all BMD variables (p < 0.05) except TR BMD in girls and FN BMD in boys. Comparing the most active with the less-active participants, the greatest benefits of PA were observed at the FN of the girls with the lowest IAD (p < 0.001), at the FN of the boys with the highest IAD (p < 0.001) and at the TR of the boys with the lowest ALA (p < 0.01). CONCLUSIONS: Geometric measures of IAD and ALA seem to moderate the effect of PA role in the relative mineralization of the PF regions. On the other hand, absolute BMD levels appear to be determined by mechanical loading. PMID- 24809811 TI - Dosing of antibacterial agents in obese adults: does one size fit all? AB - Obesity is a global pandemic affecting 33% of adults in the United States. Obese persons receiving cefazolin or fluconazole have been shown to have worse outcomes with suboptimal dosing. Studies evaluating the safety of colistin, daptomycin, and vancomycin have shown increased weight or obesity may potentially increase toxicity. Many antimicrobials lack pharmacokinetic data to support dose individuation in obese persons, due in part to the lack of obese patients in drug development studies. A one size fits all approach to dose optimization for obese patients is not likely. Current expert opinion suggests some antimicrobials (i.e. vancomycin) be dosed according to total body weight, whereas others (i.e. aminoglycosides) require adjusted body weight for dose calculations. Yet other antimicrobials are reported to need no dose adjustment, largely based on studies using body mass index groups. Therefore, each drug should be individually evaluated to determine the proper dose for obese persons. PMID- 24809810 TI - PET imaging in multiple sclerosis. AB - Positron emission tomography (PET) is a non-invasive technique for quantitative imaging of biochemical and physiological processes in animals and humans. PET uses probes labeled with a radioactive isotope, called PET tracers, which can bind to or be converted by a specific biological target and thus can be applied to detect and monitor different aspects of diseases. The number of applications of PET imaging in multiple sclerosis is still limited. Clinical studies using PET are basically focused on monitoring changes in glucose metabolism and the presence of activated microglia/macrophages in sclerotic lesions. In preclinical studies, PET imaging of targets for other processes, like demyelination and remyelination, has been investigated and may soon be translated to clinical applications. Moreover, more PET tracers that could be relevant for MS are available now, but have not been studied in this context yet. In this review, we summarize the PET imaging studies performed in multiple sclerosis up to now. In addition, we will identify potential applications of PET imaging of processes or targets that are of interest to MS research, but have yet remained largely unexplored. PMID- 24809812 TI - Novel evidence of ghrelin and growth hormone segretagogue receptor expression by human ocular tissues. AB - AIM OF THE STUDY: The gastrointestinal peptide hormone ghrelin (Ghr) was discovered in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). It is a pleiotropic peptide that modulates a wide spectrum of biological activities, such as growth hormone (GH) release, feeding stimulation, adiposity and cardiovascular actions. The presence of Ghr mRNA in the iris and ciliary body (CB) epithelium was recently demonstrated in animal models, where a possible myorelaxing effect on the iris muscles has been suggested. Based on these observations, the aim of our study was to investigate the Ghr and GHSR-1a expression and localization in the normal human eye. MATERIAL: Five different ciliary body/iris samples from normal eyes were subjected to Western blot analysis. Immunohistochemical detection was performed on three enucleated eyes. Twenty aqueous humor (AqH) samples obtained from patients submitted to cataract surgery were analyzed with an ELISA for the presence of Ghr. RESULTS: Ghr and GHSR-1a were co-expressed by the pigmented epithelium (PE) of the CB, by the retinal pigmented epithelium (RPE) and by the anterior limiting layer (ALL) of the iris. No reaction was detected at the subepithelial level in the ciliary or pupillae smooth muscle cells. The AqH samples were positive for the presence of Ghr. CONCLUSION: This study provides the first evidence that Ghr and GHSR-1a are expressed in the human eye by specific cells. The understanding of the functional role of Ghr at the human eye level needs more efforts and investigation, but a hypothetical action on the GH retinal synthesis and/or on the circadian clock system could be suggested. PMID- 24809814 TI - Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-methylpiperazin-1 yl]nicotinonitriles as active-site inhibitors of sphingosine 1-phosphate lyase for the treatment of multiple sclerosis. AB - Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2 methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases. PMID- 24809813 TI - Skin cancer in kidney transplant recipients. AB - Morbidity and mortality due to skin cancer is excessively high in renal transplant recipients compared to the general population. This epidemiologic difference is mainly due to the severe immunosuppression that enhances ultraviolet-induced DNA damage and leads to reactivation of potential oncogenic viruses. The most common skin cancer in transplant recipients is squamous cell carcinoma followed by basal cell carcinoma, while in the general population this ratio is reversed. Melanoma and cutaneous lymphoma are relatively rare although they occur more frequently in transplant patients than in the general population. Notably some tumors, such as Kaposi's sarcoma, are seldom encountered in the general population while they are frequently observed in transplant recipients. Local recurrences and visceral spreading are not so uncommon and pose a major issue for quality of life and overall prognosis of these patients. Timely diagnosis is essential and may be challenging, since the accuracy of clinical diagnosis is modest; thus skin biopsy is an essential tool for appropriate management. In this review, we describe the most common types of skin cancer in renal transplant recipients, with a focus on pathogenic issues that account for the different epidemiology and clinical expression of these neoplasms in this population. PMID- 24809815 TI - Jehovah's Witnesses and cardiac surgery: a single institution's experience. AB - BACKGROUND: Based on biblical doctrines, patients of the Jehovah's Witness faith refuse allogeneic blood transfusion. Cardiac surgery carries a high risk of blood transfusion, but has been performed in Jehovah's Witnesses for many years. The literature contains information on the outcomes of this cohort, but does not detail the perioperative care of these patients. This article describes a single institution's experience in perioperative care of Jehovah's Witnesses undergoing cardiac surgery. STUDY DESIGN AND METHODS: A chart review of adult Jehovah's Witness patients undergoing cardiac surgery at Duke University between January 2005 and June 2012 was completed. Institutional protocols regarding preoperative erythropoietin (EPO) therapy and intraoperative isovolemic hemodilution are detailed. Patient demographics and use of various blood conservation techniques are described. Hemoglobin (Hb) at various points throughout the perioperative management, hospital length of stay, and mortality are reviewed as indicators of outcome. RESULTS: Forty-five Jehovah's Witness patients underwent cardiac surgery at Duke University Medical Center. Preoperative EPO increased the mean Hb by 1.2 g/dL before surgery. Intraoperative normovolemic hemodilution was used in 37 patients with intraoperative mean nadir Hb of 10.3 g/dL. Antifibrinolytics and desmopressin were commonly used as coagulation adjuncts. Mean cardiopulmonary bypass time was 137 minutes, with mean nadir temperature of 30.5 degrees C. The mean length of hospital stay was 6.2 days, with mean intensive care unit stay of 1.7 days. This cohort had zero 90-day mortality in the perioperative period. CONCLUSIONS: This case series demonstrates that bloodless cardiac surgery can be performed in select patients refusing allogeneic blood transfusion. PMID- 24809816 TI - Audio-visual presentation of information for informed consent for participation in clinical trials. AB - BACKGROUND: Informed consent is a critical component of clinical research. Different methods of presenting information to potential participants of clinical trials may improve the informed consent process. Audio-visual interventions (presented, for example, on the Internet or on DVD) are one such method. We updated a 2008 review of the effects of these interventions for informed consent for trial participation. OBJECTIVES: To assess the effects of audio-visual information interventions regarding informed consent compared with standard information or placebo audio-visual interventions regarding informed consent for potential clinical trial participants, in terms of their understanding, satisfaction, willingness to participate, and anxiety or other psychological distress. SEARCH METHODS: We searched: the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, issue 6, 2012; MEDLINE (OvidSP) (1946 to 13 June 2012); EMBASE (OvidSP) (1947 to 12 June 2012); PsycINFO (OvidSP) (1806 to June week 1 2012); CINAHL (EbscoHOST) (1981 to 27 June 2012); Current Contents (OvidSP) (1993 Week 27 to 2012 Week 26); and ERIC (Proquest) (searched 27 June 2012). We also searched reference lists of included studies and relevant review articles, and contacted study authors and experts. There were no language restrictions. SELECTION CRITERIA: We included randomised and quasi randomised controlled trials comparing audio-visual information alone, or in conjunction with standard forms of information provision (such as written or verbal information), with standard forms of information provision or placebo audio-visual information, in the informed consent process for clinical trials. Trials involved individuals or their guardians asked to consider participating in a real or hypothetical clinical study. (In the earlier version of this review we only included studies evaluating informed consent interventions for real studies). DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and extracted data. We synthesised the findings using meta analysis, where possible, and narrative synthesis of results. We assessed the risk of bias of individual studies and considered the impact of the quality of the overall evidence on the strength of the results. MAIN RESULTS: We included 16 studies involving data from 1884 participants. Nine studies included participants considering real clinical trials, and eight included participants considering hypothetical clinical trials, with one including both. All studies were conducted in high-income countries.There is still much uncertainty about the effect of audio-visual informed consent interventions on a range of patient outcomes. However, when considered across comparisons, we found low to very low quality evidence that such interventions may slightly improve knowledge or understanding of the parent trial, but may make little or no difference to rate of participation or willingness to participate. Audio-visual presentation of informed consent may improve participant satisfaction with the consent information provided. However its effect on satisfaction with other aspects of the process is not clear. There is insufficient evidence to draw conclusions about anxiety arising from audio-visual informed consent. We found conflicting, very low quality evidence about whether audio-visual interventions took more or less time to administer. No study measured researcher satisfaction with the informed consent process, nor ease of use.The evidence from real clinical trials was rated as low quality for most outcomes, and for hypothetical studies, very low. We note, however, that this was in large part due to poor study reporting, the hypothetical nature of some studies and low participant numbers, rather than inconsistent results between studies or confirmed poor trial quality. We do not believe that any studies were funded by organisations with a vested interest in the results. AUTHORS' CONCLUSIONS: The value of audio-visual interventions as a tool for helping to enhance the informed consent process for people considering participating in clinical trials remains largely unclear, although trends are emerging with regard to improvements in knowledge and satisfaction. Many relevant outcomes have not been evaluated in randomised trials. Triallists should continue to explore innovative methods of providing information to potential trial participants during the informed consent process, mindful of the range of outcomes that the intervention should be designed to achieve, and balancing the resource implications of intervention development and delivery against the purported benefits of any intervention.More trials, adhering to CONSORT standards, and conducted in settings and populations underserved in this review, i.e. low- and middle-income countries and people with low literacy, would strengthen the results of this review and broaden its applicability. Assessing process measures, such as time taken to administer the intervention and researcher satisfaction, would inform the implementation of audio-visual consent materials. PMID- 24809817 TI - Emergency dispatch process and patient outcome in bystander-witnessed out-of hospital cardiac arrest with a shockable rhythm. AB - OBJECTIVE: To describe the dispatch process for out-of-hospital cardiac arrest (OHCA) in bystander-witnessed patients with initial shockable rhythm, and to evaluate whether recognition of OHCA by the emergency medical dispatcher (EMD) has an effect on the outcome. METHODS: This study was part of the FINNRESUSCI study focusing on the epidemiology and outcome of OHCA in Finland. Witnessed [not by Emergency Medical Service (EMS)] OHCA patients with initial shockable rhythm in the southern and the eastern parts of Finland during a 6-month period from March 1 to August 31 2010, were electronically collected from eight dispatch centres and from paper case reports filled out by EMS crews. RESULTS: Of the 164 patients, 82.3% (n=135) were correctly recognized by the EMD as cardiac arrests. The majority of all calls (90.7%) were dispatched within 2 min. Patients were more likely to survive and be discharged from the hospital if the EMS response time was within 8 min (P<0.001). Telephone-guided cardiopulmonary resuscitation (T-CPR) was given in 53 cases (32.3%). Overall survival to hospital discharge was 43.4% (n=71). Survival to hospital discharge was 44.4% (n=60) when the EMD recognized OHCA and 37.9% (n=11) when OHCA was not recognized. The difference was not statistically significant (P=0.521). CONCLUSION: The rate of recognition of cardiac arrest by EMD was high, but EMD recognition did not affect the outcome. The survival rate was high in both groups. Recognized cardiac arrest patients received bystander CPR more frequently than those for whom OHCA remained unrecognized. PMID- 24809821 TI - Protein flexibility and cysteine reactivity: influence of mobility on the H-bond network and effects on pKa prediction. AB - Thanks to its chemical plasticity, cysteine (Cys) is a very versatile player in proteins. A major determinant of Cys reactivity is pKa: the ability to predict it is deemed critical in redox bioinformatics. I considered different computational methods for pKa predictions and ultimately applied one (propka, ppka1) to various datasets; for all residues I assessed the effect of (1) hydrogen bonding, electrostatics and solvation on predictions and (2) protein mobility on pKa variability. Particularly for Cys, exposure and H-bond contributions heavily dictated propka predictions. The prominence of H-bond contributions was previously reported: this may explain the effectiveness of ppka1 (with Cys, tested in a benchmark). However ppka1 was also very sensitive to protein mobility; I assessed the effects of mobility on particularly large (compared to previous studies) datasets of structural ensembles; I found that exposed Cys presented the highest pKa variability, ascribable to correspondingly high H-bond fluctuations associated with protein flexibility. The benefit of including protein dynamics in pKa predictions was previously proposed, but empirical methods were never tested in this sense; instead, giving their outstanding speed, they could lend particularly well to this purpose. I devised a strategy combining short range molecular dynamics with ppka1; the protocol aimed to mitigate high ppka1 variability by including a "statistical view" of fast conformational changes. Tested in a benchmark, the strategy lead to improved performances. These results provide new insights on Cys bioinformatics (pKa prediction protocols) and Cys biology (effect of mobility on exposed Cys properties). PMID- 24809822 TI - The eunuch phenomenon: adaptive evolution of genital emasculation in sexually dimorphic spiders. AB - Under natural and sexual selection traits often evolve that secure paternity or maternity through self-sacrifice to predators, rivals, offspring, or partners. Emasculation-males removing their genitals-is an unusual example of such behaviours. Known only in insects and spiders, the phenomenon's adaptiveness is difficult to explain, yet its repeated origins and association with sexual size dimorphism (SSD) and sexual cannibalism suggest an adaptive significance. In spiders, emasculation of paired male sperm-transferring organs - secondary genitals - (hereafter, palps), results in 'eunuchs'. This behaviour has been hypothesized to be adaptive because (i) males plug female genitals with their severed palps (plugging hypothesis), (ii) males remove their palps to become better fighters in male-male contests (better-fighter hypothesis), perhaps reaching higher agility due to reduced total body mass (gloves-off hypothesis), and (iii) males achieve prolonged sperm transfer through severed genitals (remote copulation hypothesis). Prior research has provided evidence in support of these hypotheses in some orb-weaving spiders but these explanations are far from general. Seeking broad macroevolutionary patterns of spider emasculation, we review the known occurrences, weigh the evidence in support of the hypotheses in each known case, and redefine more precisely the particular cases of emasculation depending on its timing in relation to maturation and mating: 'pre-maturation', 'mating', and 'post-mating'. We use a genus-level spider phylogeny to explore emasculation evolution and to investigate potential evolutionary linkage between emasculation, SSD, lesser genital damage (embolic breakage), and sexual cannibalism (females consuming their mates). We find a complex pattern of spider emasculation evolution, all cases confined to Araneoidea: emasculation evolved at least five and up to 11 times, was lost at least four times, and became further modified at least once. We also find emasculation, as well as lesser genital damage and sexual cannibalism, to be significantly associated with SSD. These behavioural and morphological traits thus likely co-evolve in spiders. Emasculation can be seen as an extreme form of genital mutilation, or even a terminal investment strategy linked to the evolution of monogyny. However, as different emasculation cases in araneoid spiders are neither homologous nor biologically identical, and may or may not serve as paternity protection, the direct link to monogyny is not clear cut. Understanding better the phylogenetic patterns of emasculation and its constituent morphologies and behaviours, a clearer picture of the intricate interplay of natural and sexual selection may arise. With the here improved evolutionary resolution of spider eunuch behaviour, we can more specifically tie the evidence from adaptive hypotheses to independent cases, and propose promising avenues for further research of spider eunuchs, and of the evolution of monogyny. PMID- 24809820 TI - Predicting the minimal translation apparatus: lessons from the reductive evolution of mollicutes. AB - Mollicutes is a class of parasitic bacteria that have evolved from a common Firmicutes ancestor mostly by massive genome reduction. With genomes under 1 Mbp in size, most Mollicutes species retain the capacity to replicate and grow autonomously. The major goal of this work was to identify the minimal set of proteins that can sustain ribosome biogenesis and translation of the genetic code in these bacteria. Using the experimentally validated genes from the model bacteria Escherichia coli and Bacillus subtilis as input, genes encoding proteins of the core translation machinery were predicted in 39 distinct Mollicutes species, 33 of which are culturable. The set of 260 input genes encodes proteins involved in ribosome biogenesis, tRNA maturation and aminoacylation, as well as proteins cofactors required for mRNA translation and RNA decay. A core set of 104 of these proteins is found in all species analyzed. Genes encoding proteins involved in post-translational modifications of ribosomal proteins and translation cofactors, post-transcriptional modifications of t+rRNA, in ribosome assembly and RNA degradation are the most frequently lost. As expected, genes coding for aminoacyl-tRNA synthetases, ribosomal proteins and initiation, elongation and termination factors are the most persistent (i.e. conserved in a majority of genomes). Enzymes introducing nucleotides modifications in the anticodon loop of tRNA, in helix 44 of 16S rRNA and in helices 69 and 80 of 23S rRNA, all essential for decoding and facilitating peptidyl transfer, are maintained in all species. Reconstruction of genome evolution in Mollicutes revealed that, beside many gene losses, occasional gains by horizontal gene transfer also occurred. This analysis not only showed that slightly different solutions for preserving a functional, albeit minimal, protein synthetizing machinery have emerged in these successive rounds of reductive evolution but also has broad implications in guiding the reconstruction of a minimal cell by synthetic biology approaches. PMID- 24809824 TI - Morphological characteristics of the temporomandibular joint in the pouch young of the Tasmanian devil. AB - We recently reported the absence of the articular disc, which is a constant structure in mammals, in the temporomandibular joint of the adult Tasmanian devil. However, whether the articular disc disappears with growth of the animal was unknown. The aim of this study was to determine whether a pouch young of the Tasmanian devil has the articular disc. The temporomandibular joint of a fresh carcass of the pouch young, whose crown-rump length was 43 mm, was examined microscopically and by microcomputed tomography. The absence of the articular disc in the pouch young temporomandibular joint was histologically confirmed. It is suggested that the articular disc of the Tasmanian devil is naturally absent. PMID- 24809823 TI - Axonal noise as a source of synaptic variability. AB - Post-synaptic potential (PSP) variability is typically attributed to mechanisms inside synapses, yet recent advances in experimental methods and biophysical understanding have led us to reconsider the role of axons as highly reliable transmission channels. We show that in many thin axons of our brain, the action potential (AP) waveform and thus the Ca++ signal controlling vesicle release at synapses will be significantly affected by the inherent variability of ion channel gating. We investigate how and to what extent fluctuations in the AP waveform explain observed PSP variability. Using both biophysical theory and stochastic simulations of central and peripheral nervous system axons from vertebrates and invertebrates, we show that channel noise in thin axons (<1 um diameter) causes random fluctuations in AP waveforms. AP height and width, both experimentally characterised parameters of post-synaptic response amplitude, vary e.g. by up to 20 mV and 0.5 ms while a single AP propagates in C-fibre axons. We show how AP height and width variabilities increase with a 3/4 power-law as diameter decreases and translate these fluctuations into post-synaptic response variability using biophysical data and models of synaptic transmission. We find for example that for mammalian unmyelinated axons with 0.2 um diameter (matching cerebellar parallel fibres) axonal noise alone can explain half of the PSP variability in cerebellar synapses. We conclude that axonal variability may have considerable impact on synaptic response variability. Thus, in many experimental frameworks investigating synaptic transmission through paired-cell recordings or extracellular stimulation of presynaptic neurons, causes of variability may have been confounded. We thereby show how bottom-up aggregation of molecular noise sources contributes to our understanding of variability observed at higher levels of biological organisation. PMID- 24809825 TI - Ab initio structure determination of interlayer expanded zeolites by single crystal rotation electron diffraction. AB - Layered solids often form thin plate-like crystals that are too small to be studied by single-crystal X-ray diffraction. Although powder X-ray diffraction (PXRD) is the conventional method for studying such solids, it has limitations because of peak broadening and peak overlapping. We have recently developed a software-based rotation electron diffraction (RED) method for automated collection and processing of 3D electron diffraction data. Here we demonstrate the ab initio structure determination of two interlayer expanded zeolites, the microporous silicates COE-3 and COE-4 (COE-n stands for International Network of Centers of Excellence-n), from submicron-sized crystals by the RED method. COE-3 and COE-4 are built of ferrierite-type layers pillared by (-O-Si(CH3)2-O-) and ( O-Si(OH)2-O-) linker groups, respectively. The structures contain 2D intersecting 10-ring channels running parallel to the ferrierite layers. Because both COE-3 and COE-4 are electron-beam sensitive, a combination of RED datasets from 2 to 3 different crystals was needed for the structure solution and subsequent structure refinement. The structures were further refined by Rietveld refinement against the PXRD data. The structure models obtained from RED and PXRD were compared. PMID- 24809826 TI - Nuclear localization of SMN and FUS is not altered in fibroblasts from patients with sporadic ALS. AB - Abstract Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no established biological marker. Recent observation of a reduced number of gems (survival motor neuron protein (SMN) positive nuclear bodies) in cells from patients with familial ALS and the mouse models suggests an involvement of SMN in ALS pathology. At a molecular level, fused in sarcoma (FUS), one of the familial ALS-linked proteins, has been demonstrated to directly interact with SMN, while impaired nuclear localization of mutated FUS causes defective gem formation. Our objective was to determine whether gems and/or nuclear FUS levels in skin derived fibroblasts from sporadic ALS patients are consistently reduced and thus could constitute a novel and readily available biomarker of the disease. Fibroblasts from 20 patients and 17 age-matched healthy controls were cultured and co-immunostained for SMN and FUS. Results showed that no difference was detected between the two groups in the number of gems and in expression pattern of FUS. The number of gems negatively correlated with the age at biopsy in both ALS and control subjects. In conclusion, the expression pattern of SMN and FUS in fibroblasts cannot serve as a biomarker for sporadic ALS. Donor age-dependent gem reduction is a novel observation that links SMN with cellular senescence. PMID- 24809827 TI - Visual function assessment in simulated real-life situations in HIV-infected subjects. AB - Visual function abnormalities are common in people living with HIV disease (PLWH) without retinitis, even after improvement in immune status. Abnormalities such as reduced contrast sensitivity, altered color vision, peripheral visual field loss, and electrophysiological changes are related to a combination of retinal dysfunctions, involving inner and outer retinal structures. The standard protocol for testing vision performance in clinical practice is the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. However, this method poorly correlates with activities of daily living that require patients to assess visual stimuli in multiple light/contrast conditions, and with limited time. We utilized a novel interactive computer program (Central Vision Analyzer) to analyze vision performance in PLWH under a variety of light/contrast conditions that simulate stressful and real-world environments. The program tests vision in a time dependent way that we believe better correlates with daily living activities than the non-timed ETDRS chart. We also aimed to correlate visual scores with retinal neuro-fiber layer thickness on optical coherence tomography. Here we show that visual acuity is more affected in PLWH in comparison to HIV-seronegative controls in varying contrast and luminance, especially if the nadir CD4+ T-cell count was lower than 100 cells/mm3. Visual impairment reflects the loss of retinal nerve fiber layer thickness especially of the temporal-inferior sector. In PLWH the ETDRS chart test led to better visual acuity compared to the Central Vision Analyzer equivalent test, likely because patients had indefinite time to guess the letters. This study confirms and strengthens the finding that visual function is affected in PLWH even in absence of retinitis, since we found that the HIV serostatus is the best predictor of visual loss. The Central Vision Analyzer may be useful in the diagnosis of subclinical HIV-associated visual loss in multiple light/contrast conditions, and may offer better understanding of this entity called "neuroretinal disorder". PMID- 24809828 TI - Ornithinibacillus heyuanensis sp. nov., isolated from South China. AB - A novel Gram-stain-positive, motile, hemolytic, endospore-forming and rod-shaped bacterium was isolated and designated as strain GIESS003(T). The strain grew optimally at 35 degrees C, at pH 7.0-7.5, and with 3.0-3.5 % (w/v) NaCl. The 16S rRNA gene sequence analysis indicated that strain GIESS003(T) was associated with the genus Ornithinibacillus and was most closely related to the type strain of Ornithinibacillus contaminans (96.5 % similarity). The major cellular fatty acids were iso-C15:0 and anteiso-C15:0. The polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The major respiratory quinone was menaquinone-7. Strain GIESS003(T) contained a peptidoglycan of type A4beta L-Orn-D-Asp. The G+C content of genomic DNA was 40.1 mol%. On the basis of polyphasic evidence from this study, a new species of the genus Ornithinibacillus, Ornithinibacillus heyuanensis sp. nov., is proposed, with strain GIESS003(T) (=KCTC 33159(T)=CCTCC 2013106(T)) as the type strain. PMID- 24809829 TI - Brain potentials reflecting spontaneous retrieval of emotional long-term memories. AB - Recent ERP studies using immediate recognition suggest better recollection for emotional, relative to neutral, scenes when retrieved in tasks where memory is not explicitly probed. In the present study we examined ERPs associated with explicit and spontaneous retrieval using a long retention interval. In a between group design, one week after incidental encoding of emotional and neutral scenes, participants performed either an explicit recognition task or a categorization task whilst viewing old and new pictures. Enhanced ERP old/new differences were found for emotional and neutral stimuli over frontal regions and selectively for emotional pictures over centro-parietal regions during explicit recognition, but not during categorization. During categorization, old/new differences were only present for emotional scenes over frontal regions. Taken together, spontaneous retrieval of emotional memories occurs even after long retention intervals and is probably based on familiarity. PMID- 24809830 TI - [Type 1 Diabetes Mellitus: brief review of the main associated psychological factors]. AB - Type 1 Diabetes Mellitus (T1DM) is a widespread chronic disease among children and adolescents. Diagnosis and evolution usually involves a significant burden on the patient, and their families must change various aspects of their lifestyle to fulfill the demands of treatment. This study aims to identify the main psychological, family, and adjustment to illness features of children and adolescents diagnosed with DM1 and, in particular to highlight the associated psychopathological factors. The methodology involved a systematic literature search in the main scientific databases. Due to the biopsychosocial impact of DM1 usually assumed in the life of the child and family, and how it may compromise the quality of life and emotional well-being of both, different studies have agreed on the importance of identifying the set of psychological factors involved in healthy adjustment to illness in the child and adolescent with DM1. PMID- 24809831 TI - Lessons learned from setting up the Nahuche Health and Demographic Surveillance System in the resource-constrained context of northern Nigeria. AB - BACKGROUND: The present time reflects a period of intense effort to get the most out of public health interventions, with an emphasis on health systems reform and implementation research. Population health approaches to determine which combinations are better at achieving the goals of improved health and well-being are needed to provide a ready response to the need for timely and real-world piloting of promising interventions. OBJECTIVE: This paper describes the steps needed to establish a population health surveillance site in order to share the lessons learned from our experience launching the Nahuche Health and Demographic Surveillance System (HDSS) in a relatively isolated, rural district in Zamfara, northern Nigeria, where strict Muslim observance of gender separation and seclusion of women must be respected by any survey operation. DISCUSSION: Key to the successful launch of the Nahuche HDSS was the leadership's determination, stakeholder participation, support from state and local government areas authorities, technical support from the INDEPTH Network, and international academic partners. Solid funding from our partner health systems development programme during the launch period was also essential, and provided a base from which to secure long-term sustainable funding. Perhaps the most difficult challenges were the adaptations needed in order to conduct the requisite routine population surveillance in the communities, where strict Muslim observance of gender separation and seclusion of women, especially young women, required recruitment of female interviewers, which was in turn difficult due to low female literacy levels. Local community leaders were key in overcoming the population's apprehension of the fieldwork and modern medicine, in general. Continuous engagement and sensitisation of all stakeholders was a critical step in ensuring sustainability. While the experiences of setting up a new HDSS site may vary globally, the experiences in northern Nigeria offer some strategies that may be replicated in other settings with similar challenges. PMID- 24809832 TI - Blood pressure control with selective vagal nerve stimulation and minimal side effects. AB - OBJECTIVE: Hypertension is the largest threat to patient health and a burden to health care systems. Despite various options, 30% of patients do not respond sufficiently to medical treatment. Mechanoreceptors in the aortic arch relay blood pressure (BP) levels through vagal nerve (VN) fibers to the brainstem and trigger the baroreflex, lowering the BP. Selective electrical stimulation of these nerve fibers reduced BP in rats. However, there is no technique described to localize and stimulate these fibers inside the VN without inadvertent stimulation of non-baroreceptive fibers causing side effects like bradycardia and bradypnea. APPROACH: We present a novel method for selective VN stimulation to reduce BP without the aforementioned side effects. Baroreceptor compound activity of rat VN (n = 5) was localized using a multichannel cuff electrode, true tripolar recording and a coherent averaging algorithm triggered by BP or electrocardiogram. MAIN RESULTS: Tripolar stimulation over electrodes near the barofibers reduced the BP without triggering significant bradycardia and bradypnea. The BP drop was adjusted to 60% of the initial value by varying the stimulation pulse width and duration, and lasted up to five times longer than the stimulation. SIGNIFICANCE: The presented method is robust to impedance changes, independent of the electrode's relative position, does not compromise the nerve and can run on implantable, ultra-low power signal processors. PMID- 24809835 TI - Unani treatment and leech therapy saved the diabetic foot of a patient from amputation. AB - Every 30 seconds, a lower limb amputation is carried out due to diabetes throughout the world. The mortality rate due to diabetic foot gangrene is just next to that of cancer. As tissue death cannot be reversed, surgical removal of the affected tissue (debridement) or amputation of the limb is the only treatment option left when gangrene has advanced. The present case study illustrates an option to treat poorly healing diabetic wounds with Unani medicine (blood purifier and deobstruent) besides hirudotherapy. The study was performed on a 60 year-old woman suffering from diabetic foot (on the left) grade 5 and facing the prospect of imminent amputation. The patient was having severe pain (80 mm on a 100 mm visual analogue scale) in the gangrenous foot and foul-smelling with necrosed areas. Wound dressing was done with unripe papaya as it has a very good role in clearing necrotising area and hirudotherapy was also used in poorly healing wounds. The pain score decreased to 0-10 mm on a 100 mm visual analogue scale within 20 days and no further pain relieving medication was required. Over a time interval of nearly 3.5 months, necrotic areas disappeared and the wound was completely healed. PMID- 24809834 TI - Evaluation of practice patterns in the treatment of atrial fibrillation among the commercially insured. AB - OBJECTIVE: The management of atrial fibrillation (AF) involves two choices: (1) rate control versus rhythm control, and (2) anticoagulation treatment based upon risk of stroke. The objective of the study was to describe practice patterns in both of these treatment areas in patients with newly diagnosed AF among a commercially insured population. METHODS: This retrospective administrative claims analysis included patients with >=2 AF claims between 1 January 2008 and 30 September 2010. Patients with AF claims within a year prior to the index date (i.e., the first AF diagnosis date) were excluded. The primary outcome was the proportion of patients treated with rate control (i.e., beta blockers, calcium channel blockers, digoxin) versus rhythm control (i.e., electrical cardioversion, left atrial catheter ablation [LACA], and/or surgical ablation) and the use of anticoagulants stratified by risk of stroke based on CHADS2 score. RESULTS: Of 48,814 patients with a diagnosis of AF, 38,502 (78.9%) received treatment. Of those treated, the majority received only pharmacologic treatment (73.4%), of which beta blockers were predominantly used in the initial regimen (66.7%). Antiarrhythmic drugs were used in 23.9% of patients, but within the initial regimen in only 11.7% of patients. Direct current cardioversion occurred in 18.2% of patients, with the majority being either first-line (8.5%) or second-line (9.1%) therapy. LACA was used in only 5.2% of patients and was typically reserved for use after pharmacologic treatment or direct current cardioversion. Of 1924 patients who received LACA, 14.6% received a repeat procedure and 53.4% of the repeat procedures occurred within 6 months of the initial one. A little more than half of all patients (57.0%) received anticoagulant therapy (predominantly warfarin); of those at high risk for stroke, 63.8% with a CHADS2 score >=2 received anticoagulants. KEY LIMITATIONS: It is a retrospective analysis using administrative claims data from a commercially insured population only. Identification of the first episode of AF may be inaccurate, and we cannot differentiate between paroxysmal and persistent AF. CONCLUSIONS: Debate continues regarding whether the preferred management of most patients with AF is through rate control or restoration of normal sinus rhythm. Our retrospective study found that treatments to restore normal heart rhythm, including LACA, which could be considered aggressive initial treatment, were typically reserved as second- or third-line alternatives. Initial standard of care for the majority patients was beta blockers. Though use of anticoagulation may be higher than other observational studies, opportunities exist to increase treatment in high risk patients. PMID- 24809836 TI - We need to confirm, not relearn old information. PMID- 24809833 TI - Rho GTPases, oxidation, and cell redox control. AB - While numerous studies support regulation of Ras GTPases by reactive oxygen and nitrogen species, the Rho subfamily has received considerably less attention. Over the last few years, increasing evidence is emerging that supports the redox sensitivity of Rho GTPases. Moreover, as Rho GTPases regulate the cellular redox state by controlling enzymes that generate and convert reactive oxygen and nitrogen species, redox feedback loops likely exist. Here, we provide an overview of cellular oxidants, Rho GTPases, and their inter-dependence. PMID- 24809837 TI - Strategies for preventing side effects of systemic opioid in postoperative pediatric patients. AB - BACKGROUND AND OBJECTIVES: Opioid is the gold standard for treating moderate-to severe pain in pediatric patients. However, its undesirable side effects lead to unsatisfied postoperative pain management outcome (Pediatr Anesth, 17, 2007, 756). The most commonly reported opioid-related side effects are vomiting (40%), pruritus (20-60%) (Anesthesiology, 77, 1992, 162; Drugs, 67, 2007, 2323), and constipation (15-90%) (Int J Clin Pract, 61, 2007, 1181). The potential life threatening adverse event, respiratory depression, is less common (0.0013%) (Pediatr Anesth, 20, 2010, 119). The aim of this review was to evaluate prevention strategies that have been shown to decrease opioid side effects in pediatric patients during the postoperative period. METHODS: Literature searches were conducted from 1984 to February 2013. Meta-analysis, systematic review, and randomized, placebo-controlled studies were obtained from PubMed and the Cochrane Library. The medical subject heading (MeSH) terms were opioid analgesics, adverse effects, pediatrics, children, side effects, and postoperative pain. RESULTS AND CONCLUSION: Data from 62 studies were reviewed. The strategies that could effectively prevent and reduce opioid side effects in pediatric patients during the postoperative period included minimizing the amount of opioid consumption by a multimodal approach, opioid titration, using local anesthetic techniques and providing the specific prophylaxis for each side effect. PMID- 24809838 TI - Prolonged perioperative infusion of low-dose ketamine does not alter opioid use after pediatric scoliosis surgery. AB - BACKGROUND: Opioid consumption after posterior spinal fusion is known to be high and often exceeds those reported in other major surgical procedures. A number of clinical trials provide evidence that the perioperative use of subanesthetic doses of ketamine reduces pain and opioid requirements in some surgical procedures, but the effect of prolonged perioperative low-dose ketamine infusion in patients undergoing posterior spinal fusion for pediatric scoliosis surgery is unknown. OBJECTIVE: To test the hypothesis that a 72-h perioperative low-dose ketamine infusion would decrease opioid use in pediatric patients undergoing posterior spinal fusion. METHODS: In a double-blind prospective controlled trial, patients undergoing posterior spinal fusion for scoliosis were randomized to receive perioperative low-dose ketamine or placebo control. Patients received general anesthesia, intraoperative remifentanil, and morphine patient-controlled analgesia postoperatively. Daily opioid consumption, self-reported pain scores, and sedation scores were measured. RESULTS: Fifty-four patients were enrolled and 50 completed the study. Contrary to our hypothesis, ketamine- and control-treated patients had similar postoperative opioid use, pain scores, and sedation scores measurements. In contrast, ketamine-treated patients required less intraoperative remifentanil compared with control (mean 2.9 mg vs. 4 mg, P = 0.0415). Number of vertebrae instrumented, time between end-of-surgery and 24 h assessment, or remifentanil doses did not impact on postoperative opioid use. Over 96-h postoperatively, morphine-equivalent consumption was lower (-0.40, P = 0.006) and sedation score was higher (0.47, P = 0.0211) in male patients, compared with female patients. CONCLUSIONS: These findings do not support the use of perioperative low-dose ketamine to decrease opioid use in children with scoliosis undergoing posterior spinal fusion. PMID- 24809839 TI - The origins and development of pediatric outpatient surgery. PMID- 24809840 TI - Response to Voepel-Lewis and Malviya's comment 'pain score guided morphine titration is risky and inappropriate'. PMID- 24809841 TI - A simple formula to calculate the length of peripherally inserted central catheters in children. PMID- 24809842 TI - Gastric perforation caused by oxygen insufflations through a nasopharyngeal Nelaton catheter. PMID- 24809843 TI - Multiplex quantitative measurement of mRNAs from fixed tissue microarray sections. AB - The development of prognostic and diagnostic biomarkers, such as those from gene expression studies, requires independent validation in clinical specimens. Immunohistochemical analysis on tissue microarrays (TMAs) of formalin-fixed paraffin-embedded tissue is often used to increase the statistical power, and it is used more often than in situ hybridization, which can be technically limiting. Herein, we introduce a method for performing quantitative gene expression analysis across a TMA using an adaptation of 2D-RT-qPCR, a recently developed technology for measuring transcript levels in a histologic section while maintaining 2-dimensional positional information of the tissue sample. As a demonstration of utility, a TMA with tumor and normal human prostate samples was used to validate expression profiles from previous array-based gene discovery studies of prostate cancer. The results show that 2D-RT-qPCR expands the utility of TMAs to include sensitive and accurate gene expression measurements. PMID- 24809844 TI - Role of glutathione S transferase polymorphism in COPD with special reference to peoples living in the vicinity of the open cast coal mine of Assam. AB - BACKGROUND: COPD may develop due to variation in the functioning of antioxidants along with smoking and environmental factors in genetically susceptible individuals. Since there are different views about the antioxidants responsible for detoxifying xenobiotic compound in the human body whose functional variation may lead to obstructive disease, this associative study has been taken up between GST gene polymorphism and COPD in populations exposed to coal dusts. METHODS: Genotypes of the 70 COPD patients and 85 non COPD patients were determined by PCR based methods followed by multiplex PCR of GSTT1 and GSTM1 genes taking albumin gene as a control. Suspended particulate analyses were determined through the Respirable Dust sampler along with the FTIR analysis of the dust samples from the glass microfiber filters. RESULTS: Dust sampling analysis reveals higher level of respirable suspended particulate matter, non respirable particulate matter, SO2 and NO2 present in air of the study site. FTIR analysis also suggests a higher concentration of organic silicone and aliphatic C-F compounds present in air of the study site and when spirometry was done, low lung function was observed among most of the subjects. GSTM1 null type was significantly associated with low lung function in smoker groups and the presence of at least one active allele (either GSTM1/GSTT1) seemed to have a protective role in the development of COPD. CONCLUSIONS: GSTM1 (null genotype) appeared to be a risk factor for lower lung function in smokers living in the vicinity of coal mines. Apart from polluted environment and genetic susceptibility, mixed coal dust exposure rich in organic silicone and aliphatic C-F compounds also appears to be a factor for the low lung function. PMID- 24809846 TI - Antifungal treatment in allergic bronchopulmonary aspergillosis with and without cystic fibrosis: a systematic review. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a rare disease that affects patients with asthma or cystic fibrosis. Its debilitating course has led to the search for new treatments, including antifungals and monoclonal antibodies. To evaluate the efficacy and safety of antifungal treatments in patients with ABPA and either asthma or cystic fibrosis, we performed a systematic review of the literature on the effects of antifungal agents in ABPA using three biomedical databases. Quality assessment was performed using the GRADE methodology and, where appropriate, studies with comparable outcomes were pooled for meta analysis. Thirty-eight studies - four randomized controlled trials and 34 observational studies - met the eligibility criteria. The antifungal interventions described were itraconazole, voriconazole, posaconazole, ketoconazole, natamycin, nystatin and amphotericin B. An improvement in symptoms, frequency of exacerbations and lung function was reported in most of the studies and was more common with oral azoles. Antifungals also had a positive impact on biomarkers and radiological pulmonary infiltrates, but adverse effects were also common. The quality of the evidence supporting these results was low or very low due to a shortage of controlled studies, heterogeneity between studies and potential bias. Antifungal interventions in ABPA improved patient and disease outcomes in both asthma and cystic fibrosis. However, the recommendation for their use is weak and clinicians should therefore weigh up desirable and undesirable effects on a case-by-case basis. More studies with a better methodology are needed, especially in cystic fibrosis, to increase confidence in the effects of antifungal treatments in ABPA. PMID- 24809845 TI - Effects of cortisol on the intestinal mucosal immune response during cohabitant challenge with IPNV in Atlantic salmon (Salmo salar). AB - Infectious pancreatic necrosis virus (IPNV) causes high incidence of disease in salmonids during the first period after SW transfer. During this period as well as during periods of stress, cortisol levels increase and indications of a relationship between IPNV susceptibility and cortisol have been suggested. The intestine is an entry route and a target tissue for IPNV displaying severe enteritis and sloughing of the mucosa in infected fish. The mechanisms behind effects of the virus on the intestinal tissue and the impact of cortisol on the effect remain unclear. In the present study, Atlantic salmon post smolts treated with or without slow release cortisol implants were subjected to a cohabitant IPNV challenge. Analysis of genes and proteins related to the innate and acquired immune responses against virus was performed 6 days post-challenge using qPCR and immunohistochemistry. An increased mRNA expression of anti-viral cytokine interferon type I was observed in the proximal intestine and head kidney as a response to the viral challenge and this effect was suppressed by cortisol. No effect was seen in the distal intestine. T-cell marker CD3 as well as MHC-I in both intestinal regions and in the head kidney was down regulated at the mRNA level. Number of CD8alpha lymphocytes decreased in the proximal intestine in response to cortisol. On the other hand, mRNA expression of Mx and IL-1beta increased in the proximal intestine and head kidney in IPNV challenged fish in the presence of cortisol suggesting that the immune activation shifts in timing and response pathway during simulated stress. The present study clearly demonstrates that IPNV infection results in a differentiated epithelial immune response in the different intestinal regions of the Atlantic salmon. It also reveals that the epithelial immune response differs from the systemic, but that both are modulated by the stress hormone cortisol. PMID- 24809847 TI - Multi-modality imaging to determine the cellular heterogeneity of nasopharyngeal carcinoma components. AB - Nasopharyngeal carcinoma (NPC) is an endemic public health problem in South and Southeast Asian countries. The disease components at the molecular level are unclear and need exploration for the development of future individualized molecular medicine. The purpose of this study was to test the feasibility of target-specific agents to detect different components of NPC. The binding capability of human NPC cell lines was determined by incubation with either agents that specifically target the metabolic status, host cytokines, and stroma. Mice bearing human NPC xenografts were injected with the same test agents plus a clinical molecular imaging agent (18F-fluorodeoxyglucose) and computer tomography (CT) contrast agent. In vitro cell studies have demonstrated that target-specific agents bind to NPC cells with significantly higher signal intensities. Those agents not only bound to the cell membrane but also penetrated into the cytosol and cell nuclei. In vivo imaging demonstrated that the human NPC xenografts revealed high glucose uptake and a profound vasculature in the tumor. All agents were bound to the tumor regions with a high tumor-to-muscle ratio. Finally, all imaging data were validated by histopathological results. Multiple, target specific agents determine the dynamic and heterogeneous components of NPC at the molecular level. PMID- 24809848 TI - Considering the role of time budgets on copy-error rates in material culture traditions: an experimental assessment. AB - Ethnographic research highlights that there are constraints placed on the time available to produce cultural artefacts in differing circumstances. Given that copying error, or cultural 'mutation', can have important implications for the evolutionary processes involved in material culture change, it is essential to explore empirically how such 'time constraints' affect patterns of artefactual variation. Here, we report an experiment that systematically tests whether, and how, varying time constraints affect shape copying error rates. A total of 90 participants copied the shape of a 3D 'target handaxe form' using a standardized foam block and a plastic knife. Three distinct 'time conditions' were examined, whereupon participants had either 20, 15, or 10 minutes to complete the task. One aim of this study was to determine whether reducing production time produced a proportional increase in copy error rates across all conditions, or whether the concept of a task specific 'threshold' might be a more appropriate manner to model the effect of time budgets on copy-error rates. We found that mean levels of shape copying error increased when production time was reduced. However, there were no statistically significant differences between the 20 minute and 15 minute conditions. Significant differences were only obtained between conditions when production time was reduced to 10 minutes. Hence, our results more strongly support the hypothesis that the effects of time constraints on copying error are best modelled according to a 'threshold' effect, below which mutation rates increase more markedly. Our results also suggest that 'time budgets' available in the past will have generated varying patterns of shape variation, potentially affecting spatial and temporal trends seen in the archaeological record. Hence, 'time-budgeting' factors need to be given greater consideration in evolutionary models of material culture change. PMID- 24809849 TI - Self-navigated isotropic three-dimensional cardiac T2 mapping. AB - PURPOSE: To implement and characterize an isotropic three-dimensional cardiac T2 mapping technique. METHODS: A self-navigated three-dimensional radial segmented balanced steady-state free precession pulse sequence with an isotropic 1.7-mm spatial resolution was implemented at 3T with a variable T2 preparation module. Bloch equation and Monte Carlo simulations were performed to determine the influence of the heart rate, B1 inhomogeneity and noise on the T2 fitting accuracy. In a phantom study, the accuracy of the pulse sequence was studied through comparison with a gold-standard spin-echo T2 mapping method. The robustness and homogeneity of the technique were ascertained in a study of 10 healthy adult human volunteers, while first results obtained in patients are reported. RESULTS: The numerical simulations demonstrated that the heart rate and B1 inhomogeneity cause only minor deviations in the T2 fitting, whereas the phantom study showed good agreement of the technique with the gold standard. The volunteer study demonstrated an average myocardial T2 of 40.5 +/- 3.3 ms and a <15% T2 gradient in the base-apex and anterior-inferior direction. In three patients, elevated T2 values were measured in regions with expected edema. CONCLUSION: This respiratory self-navigated isotropic three-dimensional technique allows for accurate and robust in vitro and in vivo T2 quantification. PMID- 24809851 TI - Implantable cardioverter defibrillator system with floating atrial sensing dipole: a single-center experience. AB - BACKGROUND: The concept of a single-lead dual-chamber implantable cardioverter defibrillator (ICD) with floating sensing atrial dipole has been proven safe and functional. We report a single-center experience with this ICD system; the major focus of the work is on the recorded atrial activation and its stability on a medium term follow-up. METHODS: Thirteen patients received a DX ICD (BIOTRONIK SE & Co, Berlin, Germany) with the Linox Smart S DX(ProMRI) ICD lead; the implantation data were reported. Daily P- and R-wave sensing amplitude was collected and followed up during 200 days; their coefficient of variance (CV) was calculated. In addition, all the atrial and ventricular high-rate episodes were analyzed. RESULTS: The total x-ray exposure time was 3.9 +/- 1.8 minutes. The overall mean sensing was 4.2 +/- 1.9 mV for P wave and 12.9 +/- 4.5 mV for R wave. The CV was significantly higher for the P-wave amplitude than for the R wave one (0.25 +/- 0.11 vs 0.08 +/- 0.06; P < 0.001). A total of 27 high ventricular rate episodes were recorded and correctly discriminated by the device. Fifty-six high atrial rate episodes were recorded, 49 were true arrhythmic events. CONCLUSIONS: The single-lead ICD system with floating atrial dipole provides reliable atrial sensing amplitude over time. The physician, without the implantation of an additional lead, has the atrial information that may be used for the discrimination of supraventricular tachyarrhythmia/ventricular tachycardia, for the early detection of atrial fibrillation episodes and for the evaluation of changes in the patient's heart status. PMID- 24809850 TI - Identification of miRNA-mediated core gene module for glioma patient prediction by integrating high-throughput miRNA, mRNA expression and pathway structure. AB - The prognosis of glioma patients is usually poor, especially in patients with glioblastoma (World Health Organization (WHO) grade IV). The regulatory functions of microRNA (miRNA) on genes have important implications in glioma cell survival. However, there are not many studies that have investigated glioma survival by integrating miRNAs and genes while also considering pathway structure. In this study, we performed sample-matched miRNA and mRNA expression profilings to systematically analyze glioma patient survival. During this analytical process, we developed pathway-based random walk to identify a glioma core miRNA-gene module, simultaneously considering pathway structure information and multi-level involvement of miRNAs and genes. The core miRNA-gene module we identified was comprised of four apparent sub-modules; all four sub-modules displayed a significant correlation with patient survival in the testing set (P values<=0.001). Notably, one sub-module that consisted of 6 miRNAs and 26 genes also correlated with survival time in the high-grade subgroup (WHO grade III and IV), P-value = 0.0062. Furthermore, the 26-gene expression signature from this sub-module had robust predictive power in four independent, publicly available glioma datasets. Our findings suggested that the expression signatures, which were identified by integration of miRNA and gene level, were closely associated with overall survival among the glioma patients with various grades. PMID- 24809852 TI - Social and personal information use by squirrel monkeys in assessing predation risk. AB - The threat of predation can significantly influence prey behaviors through altered perceptions of risk. Prey risk perception is constantly updated via collection of personal and social information about predators. Better understanding of the links between information availability, its use, and prey species' perception of risk will aid in explaining how animals adapt to predation. The goal of this study was to determine the environmental and social cues-available to prey via personal and social information, respectively-that influence wild squirrel monkey (Saimiri sciureus) reactivity to potential predators, treated here as a proxy for risk perception. We followed squirrel monkey troops for 3 years in Suriname, South America, and accounted for environmental and social variables associated with potential predator encounters. We utilized logistic regression models applied to a robust and long-term data set to reveal relationships among factors affecting squirrel monkey anti-predator responses. Our analyses revealed that height, season, type of predator stimulus, and mixed-species associations with capuchin monkeys (Sapajus apella) were highly related to intensity of squirrel monkey anti-predator responses. Moreover, our analyses revealed that squirrel monkeys overestimate the immediate threat of predation when individuals have incomplete information regarding the potential predator. PMID- 24809853 TI - The intergenerational relationships of gay men and lesbian women. AB - OBJECTIVES: Despite the demonstrated importance of intergenerational ties across the life course, few studies examine relationships between gay men and lesbians and their later life parents and parents-in-law. The present study examines how midlife to later life gay men and lesbians in intimate partnerships conceptualize these intergenerational ties. METHOD: Qualitative analysis of 50 in-depth interviews collected with midlife to later life gay men and lesbians (ages 40-72) in long-term intimate partnerships. RESULTS: Findings reveal 4 central ways respondents describe supportive parent-child and parent-child in-law relationships: integration, inclusion through language, social support, and affirmations. Findings reveal 3 central ways individuals distinguish strained parent-child and parent-child in-law relationships: rejection in everyday life, traumatic events, and the threat of being usurped. Findings further articulate how intergenerational ambivalence is distinguished through descriptions of a parent as simultaneously supportive (via subthemes of solidarity) and rejecting (via subthemes of strain). DISCUSSION: Findings from this study provide empirical evidence of how support, strain, and ambivalence in intergenerational ties are identified and experienced by gay men and lesbian women. This study reveals a new lens to view relationships between midlife to later life adults and their aging parents and parents-in-law and further identifies linkages between solidarity conflict and ambivalence paradigms. PMID- 24809854 TI - Missing data in Wave 2 of NSHAP: prevalence, predictors, and recommended treatment. AB - OBJECTIVES: This report seeks to inform National Social Life, Health, and Aging Project (NSHAP) data users of the prevalence and predictors of missing data in the in-person interview (CAPI) and leave-behind questionnaire (LBQ) in Wave 2 of NSHAP, and methods to handle missingness. METHOD: Missingness is quantified at the unit and item levels separately for CAPI and LBQ data, and at the item level is assessed within domains of conceptually related variables. Logistic and negative binomial regression analyses are used to model predictors of unit- and item-level nonresponse, respectively. RESULTS: Unit-level nonresponse on the CAPI was 10.6% of those who responded at Wave 1, and LBQ nonresponse was 11.37% of those who completed the Wave 2 CAPI component. CAPI item-level missingness was less than 1% of items for most domains but 7.1% in the Employment and Finances domain. LBQ item-level missingness was 5% across domains but 8.3% in the Attitudes domain. Missingness was predicted by characteristics of the sample and features of the study design. DISCUSSION: Multiple imputation is recommended to handle unit- and item-level missingness and can be readily and flexibly conducted with multiple imputation by chained equations, inverse probability weighting, and in some instances, full-information maximum-likelihood methods. PMID- 24809855 TI - Socioeconomic disparities in health among older adults and the implications for the retirement age debate: a brief report. AB - OBJECTIVE: Policy debates about raising the full retirement age often neglect socioeconomic health disparities among U.S. workers. In response to this gap, we analyzed educational differentials in health among middle-age and older adults and translated the findings into age equivalents. METHOD: We used the nationally representative 1997-2010 National Health Interview Surveys data on white and black adults aged 40-74 (N = 341,060). Using nonparametric regression (locally weighted scatterplot smoother) stratified by sex, race, and three educational levels, we determined age-specific prevalence of fair or poor self-rated health and any activity limitation, and compared the ages at which different demographic groups experienced a specific level of these two outcomes. RESULTS: Results varied slightly across health outcomes and demographic groups but generally showed that college-educated white men reported a level of limitations at age 70 that is equivalent to the levels reported by high school graduates at age 40-55. High school dropouts reported worse health at age 40 than the college educated at age 70, a gap of more than 30 years. CONCLUSIONS: Our findings revealed enormous health inequalities in self-reported health, using a powerful and intuitive age equivalence formulation. They highlighted the importance of considering health disparities in discussions about raising the retirement age, both in terms of fairness and feasibility. PMID- 24809856 TI - Spinal cord development in marsupials in relation to birthing strategies and in comparison with monotremes and the laboratory rat. AB - Marsupials are born in an immature state, followed by prolonged nurturing of pouch young by maternal lactation. Spinal cord sections held in the collections at the Museum fur Naturkunde, Berlin were used to test the relationship between structural maturity of the spinal cord and the locomotor challenges that face young marsupials and monotremes. Analysis of variance indicated that body length is a much stronger determinant of variation in anatomical measures of spinal cord maturation than mammal type. PMID- 24809857 TI - Staphylococcal superantigens and toxins are detectable in the serum of adult burn patients. AB - Bacterial infection in burn patients is still a devastating contributor to morbidity and mortality. Little is known regarding the presence of staphylococcal toxins in the burn-injured patient. The aim of this study was to characterize the prevalence of several of these toxins and their relationship to clinical metrics and mortality in burn patients. Levels of exotoxins staphylococcal enterotoxin A (SEA), staphylococcal enterotoxin B, toxic shock syndrome toxin 1 (TSST-1), and alpha-hemolysin were assayed from the serum of 207 adult burn patients aged 16-92 years. Clinical, demographic, and microbiological data from these patients were then compared to toxin levels. Staphylococcal exotoxins alpha-hemolysin and SEA were present in 45% and 25% of the population, respectively. Bacterial cultures concomitantly showed a high prevalence of Staphylococcus aureus in 48% of patients, of which 59% were methicillin resistant. Several metrics may be predictive of high toxin concentrations of alpha-hemolysin and TSST-1 and SEA including burn size, length of stay, and bacteremia. Mortality associations indicated that burn size, bacteremia, age, and the presence of alpha-hemolysin and SEA may be predictors of mortality. A high prevalence of staphylococcal toxin alpha-hemolysin and superantigens TSST-1 and SEA can be found in the circulation of the adult burn population. The presence of these toxins may contribute to the morbidity and mortality of the burn patient. PMID- 24809858 TI - Comparative evaluation of the new ARCHITECT EBV assays considering different testing algorithms. AB - In the current evaluation, Epstein-Barr virus (EBV) serology was performed on 1113 routine serum samples. Although the initial request for all samples from the general practitioner was EBV IgM testing, 80.9% were classified as past infections. The ARCHITECT((r)) viral capsid antigen (VCA) IgM, VCA IgG, and EBV nuclear antigen (EBNA) 1 IgG assays showed good results for sensitivity and specificity, being 100.0%, 98.3%, and 100.0% and 99.9%, 95.4%, and 99.6%, respectively. Using an algorithm based on initial EBNA-1 IgG testing, followed by VCA IgG and IgM for samples that were not EBNA-1 IgG reactive, the number of tests per sample could be reduced to nearly 50% compared to parallel testing. The high sensitivity and specificity of the ARCHITECT((r)) EBNA-1 IgG assay in combination with a low number of grayzone results are a precondition for the chosen test algorithm. Thus, the newly developed ARCHITECT((r)) EBV panel is suitable for accurate and cost-efficient EBV serology in a routine clinical laboratory. PMID- 24809859 TI - Rapid identification of strains belonging to the Mycobacterium abscessus group through erm(41) gene pyrosequencing. AB - Mycobacterium abscessus and Mycobacterium massiliense lung infections have different clarithromycin susceptibilities, making proper identification important; however, standard multi-gene sequencing in clinical laboratories is laborious and time consuming. We developed a pyrosequencing-based method for rapid identification of strains belonging to the M. abscessus group by targeting erm(41). We examined 55 isolates from new pulmonary M. abscessus infections and identified 28 M. abscessus, 25 M. massiliense, and 2 Mycobacterium bolletii isolates. Multi-gene sequencing of 16S rRNA, hsp65, rpoB, and the 16S-23S ITS region was concordant with the results of erm(41) pyrosequencing; thus, the M. abscessus group can be identified by single-nucleotide polymorphisms in erm(41). The method also enables rapid identification of polymorphic, inducible clarithromycin-resistant sequevars (T28 or C28). Pyrosequencing of erm(41) is a rapid, reliable, high-throughput alternative method for identifying and characterizing M. abscessus species. Further testing of a diverse collection of isolates is necessary to demonstrate the discriminatory power of erm(41) sequencing to differentiating species with this highly divergent group. PMID- 24809860 TI - Use of avibactam to detect Ambler class A carbapenemases and OXA-48 beta lactamases in Enterobacteriaceae. PMID- 24809861 TI - In vivo emergence of colistin resistance in Acinetobacter baumannii clinical isolates of sequence type 357 during colistin treatment. AB - This study was performed to investigate the mechanisms of in vivo acquisition of colistin resistance in A. baumannii during colistin treatment. Three colistin susceptible/resistant pairs of A. baumannii were recovered from patients who underwent colistin treatment. All of the 6 isolates included in this study shared an identical sequence type (ST), ST375, and they showed identical SmaI macrorestriction patterns by pulsed-field gel electrophoresis. The individual colistin-resistant isolates harbored distinct mutations in the pmrB gene. Mutations detected in the pmrB gene were Ala227Val, Pro233Ser, and frame shift from Phe26. In matrix-assisted laser desorption ionization-time of flight analysis, colistin-resistant isolates were different from their colistin susceptible counterparts, and they showed additional distinct peaks at 1852 m/z, 1937 m/z, 1954 m/z, 1975 m/z, 2034 m/z, and 2157 m/z. In vivo selection of colistin-resistant A. baumannii occurred independently in strains of ST357 during colistin treatment, and the strains acquired colistin resistance via mutations in the pmrB gene resulting in modification of lipid A components. PMID- 24809862 TI - Local delivery of linezolid from poly-D,L-lactide (PDLLA)-linezolid-coated orthopaedic implants to prevent MRSA mediated post-arthroplasty infections. AB - The present study focuses on the use of linezolid as local delivery agent for direct administration of the drug at the orthopaedic implant site. Local drug delivery system with linezolid added to the Poly D, L-(Lactide) polymer solution was used to coat the orthopaedic grade K-wires. Bacterial adherence on K-wires was then determined to evaluate the effect of the coated drug on the adherence of MRSA. A significant decrease in bacterial adherence as compared to naked wires was observed on all the coated K-wires (2.5, 5 and 10% w/w linezolid coated) with maximum decrease of 60%. This represents an aggressive early approach to prevent initial adherence of bacterial population. With the rise in MRSA mediated orthopaedic device related infections, the use of linezolid loaded polymer coated implants is definitely an attractive strategy against drug resistant strains of S. aureus. PMID- 24809863 TI - The balancing act. PMID- 24809864 TI - Creating the perfect little eater. PMID- 24809865 TI - Adolescent consumption of sports and energy drinks: linkages to higher physical activity, unhealthy beverage patterns, cigarette smoking, and screen media use. AB - OBJECTIVE: To examine patterns of adolescent sports and energy drink (SED) consumption and identify behavioral correlates. DESIGN: Data were drawn from Eating and Activity in Teens, a population-based study. SETTING: Adolescents from 20 middle and high schools in Minneapolis/St Paul, MN completed classroom administered surveys. PARTICIPANTS: A total of 2,793 adolescents (53.2% girls) in grades 6-12. VARIABLES MEASURED: Beverage patterns; breakfast frequency; moderate to vigorous physical activity (MVPA); media use; sleep; and cigarette smoking. ANALYSIS: Linear and logistic regression models were used to estimate associations between health behaviors and SED consumption, adjusting for demographics. RESULTS: Over a third of adolescents consumed sports drinks and 14.7% consumed energy drinks at least once a week. Among boys and girls, both sports and energy drink consumption were related to higher video game use; sugar sweetened beverage and fruit juice intake; and smoking (P < .05). Sports drink consumption was also significantly related to higher MVPA and organized sport participation for both genders (P < .01). CONCLUSIONS AND IMPLICATIONS: Although sports drink consumption was associated with higher MVPA, adolescents should be reminded of recommendations to consume these beverages only after vigorous, prolonged activity. There is also a need for future interventions designed to reduce SED consumption, to address the clustering of unhealthy behaviors. PMID- 24809866 TI - The influence of home food environments on eating behaviors of overweight and obese women. AB - OBJECTIVE: To describe home food environments and examine which aspects are associated with fruit and vegetable intake and percent calories from fat among overweight and obese women. DESIGN: Baseline data from a weight gain prevention trial collected through telephone interviews. SETTING: Participants were recruited from 3 federally qualified health centers in rural Georgia. PARTICIPANTS: Overweight and obese patients (n = 319) were referred by their providers if they had a body mass index (BMI) > 25 and lived with at least 1 other person. Participants were primarily African American (83.7%), with a mean BMI of 38.4. MAIN OUTCOME MEASURES: Fruit and vegetable intake and percent calories from fat. ANALYSIS: Descriptive statistics and multiple regression. RESULTS: Participants reported a large variety of both fruits and vegetables and unhealthy foods in their homes, and an average of 2.6 family meals from non-home sources per week. Eating family meals with the television on was common. Availability of fruits and vegetables in the home (P < .001) and frequency of fruit shopping (P = .01) were associated with fruit and vegetable intake. The number of unhealthy foods in the home (P = .01) and food preparation methods (P = .01) were associated with percent calories from fat. CONCLUSIONS AND IMPLICATIONS: Home food environments may be effective intervention targets for nutrition programs designed for overweight and obese women. PMID- 24809868 TI - Ratiometric fluorescent/colorimetric cyanide-selective sensor based on excited state intramolecular charge transfer-excited-state intramolecular proton transfer switching. AB - A novel salicylideneaniline-based fluorescent sensor, SB1, with a unique excited state intramolecular charge transfer-excited-state intramolecular proton transfer (ESICT-ESIPT) coupled system was synthesized and demonstrated to fluorescently sense CN(-) with specific selectivity and high sensitivity in aqueous media based on ESICT-ESIPT switching. A large blue shift (96 nm) was also observed in the absorption spectra in response to CN(-). The bleaching of the color could be clearly observed by the naked eye. Moreover, SB1-based test strips were easily fabricated and low-cost, and could be used in practical and efficient CN(-) test kits. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations further support the cyanide-induced ESICT-ESIPT switching mechanism. The results provide the proof of concept that the colorimetric and ratiometric fluorescent cyanide-selective chemodosimeter can be created based on an ESICT ESIPT coupled system. PMID- 24809869 TI - Sex- and age-specific prevalence and incidence rates of sight-threatening diabetic retinopathy in Taiwan. AB - IMPORTANCE: The prevalence of diabetic retinopathy (DR) is high in individuals with diabetes mellitus. Published estimates for sight-threatening DR (STDR) prevalence range widely. There is a need for precise contemporary estimates of the prevalence and incidence of STDR for providing optimal strategies of clinical management in Taiwan. OBJECTIVE: To determine the precise contemporary estimates of the prevalence and incidence of STDR in patients with type 2 diabetes mellitus in Taiwan. DESIGN, SETTING, AND PARTICIPANTS: Data were collected from a representative database, the Longitudinal Health Insurance Database 2005, from 2005 to 2011, on a total of 2926 incident cases of patients with STDR among 63,582 patients with type 2 diabetes. Sight-threatening DR was defined as clinically significant macular edema, severe nonproliferative DR, or proliferative DR according to the classification of the Early Treatment Diabetic Retinopathy Study research group. Sex-specific and age-adjusted incidence and prevalence rates of STDR were analyzed for patients with type 2 diabetes and STDR identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and procedure codes. MAIN OUTCOMES AND MEASURES: Procedure codes were used to determine the diagnosis of STDR. RESULTS: The number of incident cases of STDR increased in line with the increasing diabetic population during 2005-2011. Sex differences in the age-adjusted incidence rates were observed, showing a declining trend from 10.84 (95% CI, 10.69%-10.99%) to 6.00 (95% CI, 5.86%-6.14%) per 1000 person-years for women (P < .001) contrasting with an increasing trend in men, from 14.86 (95% CI, 14.71%-15.01%) to 21.89 (95% CI, 21.76%-22.02%) per 1000 person-years (P < .001). The age-adjusted prevalence rates of STDR were in decreasing trends for both sexes, with a mean of 2.75% for women and 2.87% for men. Apart from apparent sex differences in prevalence rates of STDR, increasing trends were observed among younger patients (aged <60 years). CONCLUSIONS AND RELEVANCE: We found considerable variation in the incidence trends between sexes. Our findings provide evidence that the incident cases of STDR have increased among patients with type 2 diabetes, but the overall prevalence of STDR is in a declining trend in Taiwan, suggesting that decreased mortality rate, better diabetes management, and early detection of treatable DR might contribute to the prevalence patterns. PMID- 24809870 TI - A systematic review of interventions aiming to improve involvement in physical activity among adults with intellectual disability. AB - BACKGROUND: Evidence suggests that most adults with intellectual disability do not participate in sufficient amounts of physical activity (PA). A systematic review of peer-reviewed studies that reported an intervention aiming to improve PA levels of adults with intellectual disability was conducted. METHODS: Keywords related to intellectual disability and physical activity were used to search relevant databases. Studies were excluded if they did not measure PA as an outcome for adults with intellectual disability, were non-English, and were not peer-reviewed. All relevant studies were included in the review regardless of methodological quality and design. RESULTS: Six articles met the inclusion criteria. These included health education or health promotion programs with PA, nutrition, and weight loss components. The quality of studies included in this review was generally poor. Most studies used a prepost design, sample sizes were small, and measurement tools were used that are not valid and reliable for the population assessed. CONCLUSIONS: PA interventions have the potential to improve the health and wellbeing of people with intellectual disability, a vulnerable group who require attention from public health practitioners and researchers. Given the health inequities that exist, public health researchers should target efforts to improve PA levels among this group. PMID- 24809872 TI - Heads up for scalp melanoma. PMID- 24809873 TI - Defining locally advanced Basal cell carcinoma. PMID- 24809874 TI - Two recent JDD articles highlight genome and proteome protection and repair strategies. PMID- 24809875 TI - A retrospective comparison between preoperative and postoperative Breslow depth in primary cutaneous melanoma: how preoperative shave biopsies affect surgical management. AB - BACKGROUND: Accurate histopathologic staging of preoperative biopsy specimens is critical for determining optimal surgical management for patients with primary cutaneous melanoma. The American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN) currently list narrow excisional biopsy (fusiform excision) as the preferred technique for biopsying lesions suspicious for melanoma. However, preoperative shave biopsies are routinely performed on lesions concerning for melanoma in many medical centers out of convenience. OBJECTIVE: The current retrospective chart review was performed to determine whether preoperative shave biopsies are acceptable for evaluating lesions suspicious for melanoma and whether shave biopsies lead to underestimation of Breslow depth great enough to require additional surgeries. METHODS: A consecutive sample of 242 primary cutaneous melanoma cases surgically excised between January 1, 2004 and December 31, 2010 in a private practice setting was analyzed for this study. RESULTS: Breslow depth underestimation occurred in 8 of 226 shave biopsy cases (3.5%). Differences in preoperative and postoperative Breslow depths in shave biopsy cases were not statistically significant (P=0.48). Underestimation of Breslow depth, melanoma transection, positive deep biopsy margins, and tumor upstaging did not lead to statistically significant changes in surgical management. CONCLUSIONS: Based on the results from the current study and available literature, the authors posit that preoperative deep excisional shave biopsies performed by dermatologists are accurate for determining Breslow depth and for planning surgical management of melanomas. PMID- 24809876 TI - Review of the use of a semisynthetic bilaminar skin substitute in dermatology and a case series report of its utility in Mohs surgery. AB - Biobrane is a biosynthetic wound dressing that has been widely used in burn treatment and as a skin graft donor site dressing. Our aim for this review was to establish whether Biobrane serves as a useful tool for the field of Dermatology and Dermatologic surgery. It has been frequently used in the field of Dermatology for the management of burns, erosive skin diseases, laser procedures, and surgical procedures. From the past experiences evident in the literature and in our cases series, it has been shown to improve patient's quality of life by reducing pain, healing time, and length of hospital stay. Our case series further demonstrate its use in temporary closures, delayed reconstructions, and secondary intention healing in Mohs surgery. Reports of successful use of Biobrane in the literature and in our case series support the fact that it is an effective therapeutic option to facilitate the healing process in the field of Dermatology and Dermatologic surgery. PMID- 24809877 TI - Trends in the outpatient medication management of lupus erythematosus in the United States. AB - BACKGROUND: Systemic lupus erythematosus (SLE) and chronic cutaneous lupus (CCLE) therapy has changed little over the past 50 years. In March 2011, the US Food and Drug Administration (FDA) approved belimumab, complementing the three preexisting approved therapies: low dose aspirin, prednisone, and hydroxychloroquine. OBJECTIVE: The objectives for this study were to evaluate trends in the medications prescribed for the management of lupus erythematosus (LE) and to assess how treatment varies among different specialists. METHODS: Outpatient visits for treatment of lupus and its comorbidities were identified in the National Ambulatory Medical Care Survey (NAMCS), a representative survey of visits to physician offices in the United States. Data was evaluated to determine patient demographics, treatments prescribed by each specialty, and comorbidities encountered during the study period of 1993-2010. RESULTS: From 1993-2004, prednisone was the most frequently prescribed medication; however, prednisone became the second most frequently prescribed medication in 2005-2010, as hydroxychloroquine became the leading medication prescribed for LE. In primary care physicians and other non-dermatology specialists, the most frequently prescribed medications for lupus were prednisone and hydroxychloroquine; whereas, hydroxychloroquine and triamcinolone were the top two medications preferred by dermatologists. LIMITATIONS: The NAMCS collects cross-sectional data, such that individual patients cannot be followed over time. Hence, it does not provide data regarding the incidence of disease, patient age at the time of diagnosis, change in individual patient's medication regimens over time, or prognosis related to patient demographics. In addition, it is possible that the physician did not always record nonprescription medication use, such as NSAIDS, since these are typically used first line. CONCLUSION: First-line treatment of LE changed minimally from 1993 to 2010, with prednisone and hydroxychloroquine serving as the primary medications utilized by most physicians for the management of LE. PMID- 24809878 TI - Analysis of body regions and components of PASI scores during adalimumab or methotrexate treatment for patients with moderate-to-severe psoriasis. AB - BACKGROUND: The PASI score, the most common outcome measure in clinical trials of psoriasis treatment, is a non-linear scale that does not allow reliable assessment of subtle variations of its components (erythema, induration, and desquamation). OBJECTIVE: Highlight treatment response patterns potentially hidden by PASI score's compounded weighted-average calculation. METHODS: Patients with moderate-to-severe psoriasis enrolled in the phase-3, 16-week, randomized CHAMPION study, and received adalimumab, methotrexate, or placebo. PASI scores were assessed post hoc for improvement, by body region and component. RESULTS: At Week 16, a significantly greater percentage of adalimumab-treated patients vs methotrexate- and placebo-treated patients, achieved PASI 75, PASI 90 and PASI 100 response in each body region and component. 55.7% of adalimumab-treated patients reached PASI 100 response in the head and neck region vs 16.7% overall. Two key components of PASI, induration and desquamation, were affected by treatment more than erythema, the third component. Adalimumab was particularly effective in complete resolution of induration (44.9% of patients) vs methotrexate (10.9%). For all PASI body regions and components, mean percent improvement in score at Weeks 2, 4, 8, 12, and 16 was significantly greater (P<0.05) for adalimumab treatment vs methotrexate or placebo. CONCLUSION: Adalimumab therapy resulted in complete resolution of individual body regions in at least 30.6% up to 55.7% of patients in CHAMPION. This was more than twice that of methotrexate and placebo. PASI improvement by body region is a novel and an important patient-relevant outcome worthy of reporting in future studies. PMID- 24809879 TI - Update on the immunological mechanism of action behind phototherapy. AB - Phototherapy is often used to treat inflammatory skin conditions such as psoriasis and eczema. Much progress has recently been made in understanding the mechanisms underlying the local, cutaneous immune effects induced by phototherapy. Unlike many immunosuppressive drugs used in the management of inflammatory skin disease, phototherapy not only targets effector immune cells but also appears to up-regulate regulatory T cells (Tregs). Additionally, phototherapy reverses epidermal barrier abnormalities common in these diseases, allowing for restoration of cutaneous homeostasis. PMID- 24809880 TI - Effect of prophylactic antibiotics on polyacrylamide gel safety in facial augmentation. AB - BACKGROUND: Polyacrylamide hydrogel has in the last decade gained popularity as an injectable filler for facial augmentation due to its features of non-toxicity, biocompatibility, safety profile, and immediate effect. However, as all types of injections carry the risk of infection and since the polyacrylamide hydrogel is a non-degradable implant, the possibility of bacterial biofilm formation exists. Theoretically, the risk of infection and subsequent biofilm formation can be avoided by using prophylactic antibiotic treatment prior to the time of injection. METHOD: This retrospective study of outcomes following polyacrylamide hydrogel injections includes 657 subjects from one centre, which had facial injections from 2001 and 2011. Until 2007 prophylactic antibiotics were not given prior to treatment, but in September 2007 a single oral dose of azithromycin (Zitromax) and moxifloxacin (Avelox) was introduced as prophylactic antibiotics. A total of 496 subjects were injected before 2007 without antibiotic prophylactic treatment, and 161 subjects received these two antibiotics prior to treatment from September 2007. RESULTS: The prophylactic antibiotics (azithromycin and moxifloxacin) significantly reduced the incidence of clinical signs of inflammation/infections from 7 to 2% (P=0.03). CONCLUSION: Even though the incidence of inflammation/infections following injection of polyacrylamide hydrogel is relatively low, it may be reduced further by using prophylactic antibiotic treatment. Based on our experience, we recommend prophylactic antibiotics to patients who have facial augmentation with polyacrylamide hydrogel in order to avoid infection and risk of biofilm formation due to contamination during injection with naturally occurring micro flora from skin and lips. PMID- 24809881 TI - An immunohistochemical panel to assess ultraviolet radiation-associated oxidative skin injury. AB - Ultraviolet (UV) radiation results in a significant loss in years of healthy life, approximately 1.5 million disability-adjusted life years (DALYs), and is associated with greater than 60,000 deaths annually worldwide that are attributed to melanoma and other skin cancers. Currently, there are no standardized biomarkers or assay panels to assess oxidative stress skin injury patterns in human skin exposed to ionizing radiation. Using biopsy specimens from chronic solar UV-exposed and UV-protected skin, we demonstrate that UV radiation-induced oxidative skin injury can be evaluated by an immunohistochemical panel that stains 8-hydroxydeoxyguanosine (8-OH-dG) to assess DNA adducts, 4-hydroxy-2 nonenal (HNE) to assess lipid peroxidation, and advanced glycation end products (AGEs) to assess protein damage. We believe this panel contains the necessary cellular biomarkers to evaluate topical agents, such as sunscreens and anti oxidants that are designed to prevent oxidative skin damage and may reduce UV associated skin aging, carcinogenesis, and inflammatory skin diseases. We envision that this panel will become an important tool for researchers developing topical agents to protect against UV radiation and other oxidants and ultimately lead to reductions in lost years of healthy life, DALYs, and annual deaths associated with UV radiation. PMID- 24809882 TI - A study to assess the occlusivity and moisturization potential of three topical corticosteroid products using the skin trauma after razor shaving (STARS) bioassay. AB - Dysfunction of the epidermal barrier is generally considered a precursor of cutaneous inflammation that can directly contribute to the pathogenesis of skin diseases, notably atopic dermatitis (AD). We also know that topical corticosteroids may actually impair the epidermal barrier by interfering with epidermal lipid synthesis. Therefore, it is important to utilize topical corticosteroids in vehicles that will help at least to enhance the already disrupted epidermal barrier in atopic dermatitis patients. Two studies of identical design were conducted to determine and compare the occlusivity and moisturizing potential of three topical corticosteroid products when applied to skin whose barrier integrity has been disrupted by dry shaving. Findings in both studies showed the clocortolone pivalate cream decreased TEWL better than non treatment or treatment with hydrocortisone butyrate lotion. Skin surface hydration increased significantly (P<0.001) in all three treated sites, compared to the non-treated damaged control and non-treated normal skin. Clocortolone pivalate cream increased skin surface hydration significantly (P<0.001) better than hydrocortisone butyrate lipocream or hydrocortisone butyrate lotion. These studies showed that clocortolone pivalate cream enhances barrier function by providing occlusion. While understanding of the structure and function of the stratum corneum (SC) and epidermal barrier function has evolved tremendously over the last several decades, and especially over the last 15 years,1 confusion and misinformation still persist. Dysfunction of the epidermal barrier is generally considered a precursor of cutaneous inflammation that can directly contribute to the pathogenesis of skin diseases, notably atopic dermatitis (AD).2,3 Topical steroids are standard of care in treatment of atopic dermatitis. However, we also know that topical corticosteroids may actually impair epidermal barrier by interfering with epidermal lipid synthesis.4,5 In addition to that, various penetration enhancers in the topical steroid formulations also contribute to the impairment of the epidermal barrier.4 Therefore, it is important to utilize topical corticosteroids in vehicles that will help at least to enhance the already disrupted epidermal barrier in atopic dermatitis patients. In this regard, these studies were designed to determine the hydrating effects of clocortolone pivalate cream 0.1% (Cloderm Cream, Promius Pharma). PMID- 24809883 TI - Vemurafenib-related cutaneous side effects ameliorated by acitretin. AB - BACKGROUND: Vemurafenib is a BRAF kinase inhibitor that improves the survival of patients with metastatic melanoma, who have the V600E BRAF mutation. The development of cutaneous neoplasms, including squamous cell carcinomas (SCCs), keratoacanthomas (KAs), and hyperkeratotic papules is one of the most common adverse effects of this therapy. Systemic retinoids, such as isotretinoin and acitretin, have been used for chemoprophylaxis in individuals at high risk of developing many non-melanoma skin cancers, such as immunosuppressed solid organ transplant recipients. These agents may reduce and delay the growth of skin cancers by exerting their effects during the promotion and progression stages of carcinogenesis. OBSERVATIONS: We report a series of two patients with stage IV metastatic melanoma who presented to our Dermatology clinic for evaluation of a florid eruption of hyperkeratotic neoplasms (verrucae, actinic keratoses, and SCCs) within one month of initiating vemurafenib. After one month of acitretin, substantially fewer new neoplasms were observed in both patients. CONCLUSIONS: Although not definitive, these cases suggest that acitretin may have a role in chemoprevention of a subset of patients with rapidly developing vemurafenib associated neoplasms and slowing the progression of more aggressive SCCs and KAs. Future studies to evaluate acitretin may substantially improve the morbidity associated with vemurafenib. PMID- 24809884 TI - Steroid-free emollient formulations reduce symptoms of eczema and improve quality of life. AB - Two over-the-counter products have been clinically tested for efficacy and tolerability in the treatment of atopic dermatitis. Study 1 evaluated a daily maintenance Body Cream (Eucerin Eczema Relief Body Creme) applied twice daily for 14 days, followed by treatment withdrawal for 5 days (regression period) in subjects with a history of atopic dermatitis. Study 2 evaluated an acute treatment (Eucerin Eczema Relief Instant Therapy [Instant Therapy]) for active atopic dermatitis lesions administered for 14 days. Skin barrier function, hydration, tolerability, and relief of symptoms were assessed at baseline, day 7, and day 14. Study 2 also measured itch relief and treatment impact on work, social activities, and sleep. Body Cream significantly improved skin hydration and barrier function (P<.001) at 14 days, with improvements persisting through the 5-day regression phase. Itching was significantly improved in 93.8% of subjects (P<.001). Instant Therapy treatment of atopic dermatitis lesions significantly improved skin hydration and barrier function, as well as symptoms of erythema, pruritus, excoriation, and lichenification, with rapid improvement of itch reported within minutes of the first treatment application. Instant Therapy significantly reduced itch intensity and frequency, and demonstrated beneficial improvements in subjects' quality of life. Body Cream and Instant Therapy were both safe and well tolerated. PMID- 24809885 TI - Modified instrument tie for surgical wound closure. PMID- 24809886 TI - Solitary necrobiotic xanthogranuloma of an upper extremity in association with multiple myeloma. AB - Necrobiotic xanthogranuloma (NXG) is an uncommon granulomatous disorder of unknown pathogenesis that often presents with yellowish plaques in a periorbital distribution. While a majority of cases are associated with an underlying paraproteinemia of the IgG kappa type, a much smaller number are found to be associated with an underlying multiple myeloma. We present a case of a 78-year old male with an isolated lesion of NXG on his right upper extremity. Following his diagnosis of NXG, further investigation for underlying systemic disorders with serum immunofixation revealed a monoclonal IgG kappa immunoglobulin with an M-spike of 1.2 g/dL. A PET-CT demonstrated bone destruction in the left proximal fifth rib, left scapula, the anterior lumbar I (L1) vertebrae, the left lumbar III (L3) vertebrae posterior elements and possibly left sacrum. A bone marrow biopsy revealed 18 % plasma cells. With these findings he was diagnosed with stage I multiple myeloma. Though clinically unimpressive and atypical in location for NXG, early biopsy and diagnosis of this solitary lesion led to the discovery of his hematopoietic disorder. PMID- 24809887 TI - Multidisciplinary management of advanced basal cell carcinoma: report of four cases. AB - BACKGROUND: Advanced basal cell carcinomas (BCC) are neoplasms with high-risk clinical characteristics that can develop as locally advanced disease or metastasis. Treatment of advanced BCC may result in significant morbidity due to the technical challenges of size and/or location or in which surgery and radiation therapy may be contraindicated. No standard of care exists for the management of advanced BCC. As such, the difficulty in managing these tumors necessitates a multidisciplinary approach to patient care. METHODS: We report four cases of advanced BCC that benefited from a multidisciplinary approach, as well as highlight treatment considerations and factors in the development of advanced BCC. RESULTS: All four complex cases of advanced BCC presented to a multidisciplinary non-melanoma skin cancer tumor board with extensive tumor involvement. Treatment of disease was effective in preventing recurrence while optimizing aesthetic outcomes. CONCLUSIONS: The multidisciplinary tumor board has a central and important role in the evaluation and management of advanced BCC. PMID- 24809888 TI - Paraneoplastic pityriasis rubra pilaris as the presenting manifestation of metastatic squamous cell carcinoma. AB - Pityriasis rubra pilaris (PRP) is a rare idiopathic papulosquamous eruption. Few cases of PRP have been reported in association with malignancies. We report a case of an 83-year-old Caucasian male who presented with recalcitrant paraneoplastic PRP as the presenting manifestation of metastatic squamous cell carcinoma with unknown primary. Treatment with chemotherapy and radiation led to temporary radiologic and symptomatic regression of the cancer as well as resolution of cutaneous findings. This suggests a direct relationship between the PRP and the underlying malignancy in this patient. This case highlights a rare, but important phenomenon in which PRP may act as a harbinger for underlying malignancy. PMID- 24809889 TI - Superior vena cava obstruction associated with nephrogenic systemic fibrosis. AB - A 56-year-old woman with hypertension-induced end stage renal disease presented with skin thickening and mottled discoloration. Cutaneous biopsy showed increased dermal fibroblasts embedded in fibromyxoid stroma with scattered perivascular and interstitial mononuclear cells. Immunohistochemistry revealed prominent CD34+ dendritic cells in septal spaces, consistent with Nephrogenic Systemic Fibrosis (NSF). Seven years and two years prior she had received a gadolinium-based contrast agent (GBCA). She died due to NSF. Gross autopsy revealed a thickened and stenotic superior vena cava (SVC). Extensive fibrosis of the SVC, dermis, and subcutaneous tissue was noted, together with hyalinized collagen fibers within the muscular wall of the intestines and dura mater. These findings support the importance of skin changes in the recognition of life threatening extracutaneous tissue involvement in NSF. PMID- 24809890 TI - Papulonodular mucinosis in a patient with systemic lupus erythematosus and antiphospholipid syndrome. AB - The skin is one of the target organs most commonly affected in lupus erythematosus (LE) and a wide range of cutaneous changes have been described in LE patients. Papulonodular mucinosis (PNM) in particular is an uncommon cutaneous manifestation of LE. We discuss the case of a 26-year-old Senegalese woman with systemic LE and antiphospholipid syndrome (APS) who presented with pruritic papules on her back and extremities that appeared when she was on vacation in Africa and non-compliant with medications. Histopathologic examination was consistent with PNM. The patient was treated with mycophenolate mofetil and hydroxychloroquine, with subjective relief in pruritis at 6-week follow-up. To our knowledge, this is the first case of PNM presenting in a patient with both SLE and APS. Whether APS contributes to the pathogenesis of PNM is currently unknown. PMID- 24809891 TI - Resident Rounds part III: scleromyxedema: a rare disorder associated with a monoclonal gammopathy. AB - Scleromyxedema is a rare primary cutaneous mucinosis affecting middle-aged adults. It is characterized by dermal mucin deposition with increased collagen in the skin and internal organs. We report a case of a 72-year-old man with classic skin findings of scleromyxedema as well as a monoclonal gammopathy. PMID- 24809892 TI - Comparative effects between electronic and cigarette smoke in human keratinocytes and epithelial lung cells. AB - Information about the harmful effects of vaping is sparse and inconsistent, therefore, since the use of electronic cigarettes (e-CIGs) has become increasingly popular as a tool to limit tobacco smoking, it is urgent to establish the toxicity of the commercial e-CIGs. Skin (HaCaT) and lung (A549) cells, the main targets of cigarette smoke (CS), were exposed to e-CIG vapor and CS using an in vitro system. The cytotoxic effect of the exposure was analyzed in both cell types by ultrastructural morphology, Trypan Blue exclusion test and LDH assay. In addition, pro-inflammatory cytokines were measured by the Bio-Plex assay. The cytotoxic components of e-CIG were restrained to the flavoring compound and, to a lesser extent, to nicotine although their effects were less harmful to that of CS. Humectants alone exhibited no cytotoxicity but induced the release of cytokines and pro-inflammatory mediators. Based on our results, we can state that exposure to e-CIG vapors results in far less toxic than exposure to CS. In fact, besides the deleterious effect of flavor and nicotine, even the humectants alone are able to evocate cytokines release. This study will hopefully promote the development of safer e-CIGs to help people quit smoking. PMID- 24809893 TI - GSSG/GSH ratios in cryopreserved rat and human hepatocytes as a biomarker for drug induced oxidative stress. AB - The formation of reactive oxygen species (ROS) could cause cellular damage and eventually lead to apoptosis and necrosis. The ratio between oxidized glutathione and reduced glutathione (GSSG-to-GSH ratio) has been used as an important in vitro and in vivo biomarker of the redox balance in the cell and consequently of cellular oxidative stress. This paper optimizes a LC-MS/MS method for the simultaneous determination of GSH and GSSG. The proposed method is based on the derivatization of reduced GSH using iodoacetic acid (IAA) in order to prevent its rapid oxidation to GSSG during sample preparation. The optimized analytical method was applied to evaluate the effect of different pharmaceutical agents on GSSG-to-GSH ratio in cryopreserved rat and human hepatocytes in culture. Hepatocyte viabilities were also determined at the same time by using the WST-1 assay as a direct measurement of cell mitochondrial respiration. The results obtained demonstrate that cryopreserved rat and human hepatocytes in culture are reliable in vitro models for the evaluation of cellular oxidative stress. In addition, the GSSG-to-GSH ratio measurements could be a biomarker of hepatotoxicity providing similar results to those of cytotoxicity assay. PMID- 24809894 TI - Formation of a new benzene-ethane co-crystalline structure under cryogenic conditions. AB - We report the first experimental finding of a solid molecular complex between benzene and ethane, two small apolar hydrocarbons, at atmospheric pressure and cryogenic temperatures. Considerable amounts of ethane are found to be incorporated inside the benzene lattice upon the addition of liquid ethane onto solid benzene at 90-150 K, resulting in formation of a distinctive co-crystalline structure that can be detected via micro-Raman spectroscopy. Two new features characteristic of these co-crystals are observed in the Raman spectra at 2873 and 1455 cm(-1), which are red-shifted by 12 cm(-1) from the upsilon1 (a1g) and upsilon11 (eg) stretching modes of liquid ethane, respectively. Analysis of benzene and ethane vibrational bands combined with quantum mechanical modeling of isolated molecular dimers reveal an interaction between the aromatic ring of benzene and the hydrogen atoms of ethane in a C-H...pi fashion. The most favored configuration for the benzene-ethane dimer is the monodentate-contact structure, with a calculated interaction energy of 9.33 kJ/mol and an equilibrium bonding distance of 2.66 A. These parameters are comparable to those for a T-shaped co crystalline complex between benzene and acetylene that has been previously reported in the literature. These results are relevant for understanding the hydrocarbon cycle of Titan, where benzene and similar organics may act as potential hydrocarbon reservoirs due to this incorporation mechanism. PMID- 24809895 TI - Desorption/ionization efficiencies of triacylglycerols and phospholipids via EASI MS. AB - Knowledge of the major effects governing desorption/ionization efficiency is required for the development and application of ambient mass spectrometry. Although all triacylglycerols (TAG) have the same favorable protonation and cationization sites, their desorption/ionization efficiencies can vary dramatically during easy ambient sonic-spray ionization because of structural differences in the carbon chain. To quantify this somewhat surprising and drastic effect, we have performed a systematic investigation of desorption/ionization efficiencies as a function of unsaturation and length for TAG as well as for diacylglycerols, monoacylglycerols and several phospholipids (PL). Affinities for Na(+) as a function of unsaturation level have also been assayed via comprehensive metadynamics calculations to understand the influence of this phenomenon on the ionization efficiency. The results suggest that dipole-dipole interactions within a carbon chain tuned by unsaturation sites govern ionization efficiency of TAG and PL. PMID- 24809896 TI - Surface effects on the diagnostic of carbon/nitrogen low-pressure plasmas studied by differentially pumped mass spectrometry. AB - In this work, the characterization of the species produced in reactive plasmas by differentially pumped mass spectrometry is addressed. A H2/CH4/N2 mixture (90 : 5 : 5) was fed into a direct current glow discharge and analysed by conventional and cryo-trap assisted mass spectrometry. The gaseous mixture was chosen because of its particular relevance in the inhibition of tritium-rich carbon film deposition in fusion plasmas (scavenger technique) and in the deposition of amorphous hydrogenated carbon films by plasma-assisted chemical vapour deposition. Important changes in the composition of the detected species upon surface modification of the reactor walls (stainless steel or covered by an amorphous hydrogenated carbon layer) or in the way they are sampled (length and spatial configuration of the stainless steel duct) were detected. They are analysed in terms of radical formation and recombination on the reactor walls or into the sampling duct, thus providing some insight into the underlying chemistry. In general, when the reactor walls are covered by an amorphous hydrogenated carbon layer, more hydrocarbons are produced, but the radical production is lower and seem to be less reactive than in stainless steel. Also, two sources of oxygen contamination in the plasma have been identified, from the native oxide layer in stainless steel and from unintended water contamination in the chamber, which modify considerably the detected species. PMID- 24809897 TI - Nontargeted GC-MS approach for volatile profile of toasting in cherry, chestnut, false acacia, and ash wood. AB - By using a nontargeted GC-MS approach, 153 individual volatile compounds were found in extracts from untoasted, light toasted and medium-toasted cherry, chestnut, false acacia, as well as European and American ash wood, used in cooperage for aging wines, spirits and other beverages. In all wood types, the toasting provoked a progressive increase in carbohydrate derivatives, lactones and lignin constituents, along with a variety of other components, thus increasing the quantitative differences among species with the toasting intensity. The qualitative differences in the volatile profiles allow for identifying woods from cherry (being p-anisylalcohol, p-anisylaldehyde, p anisylacetone, methyl benzoate and benzyl salicylate detected only in this wood), chestnut (cis and trans whisky lactone) and false acacia (resorcinol, 3,4 dimethoxyphenol, 2,4-dihydroxy benzaldehyde, 2,4-dihydroxyacetophenone, 2,4 dihydroxypropiophenone and 2,4-dihydroxy-3-methoxyacetophenone), but not those from ash, because of the fact that all compounds present in this wood are detected in at least one other. However, the quantitative differences can be clearly used to identify toasted ash wood, with tyrosol being most prominent, but 2-furanmethanol, 3- and 4-ethylcyclotene, alpha-methylcrotonolactone, solerone, catechol, 3-methylcatechol and 3-hydroxybenzaldehyde as well. Regarding oak wood, its qualitative volatile profile could be enough to distinguish it from cherry and acacia woods, and the quantitative differences from chestnut (vanillyl ethyl ether, isoacetovanillone, butirovanillone, 1-(5-methyl-2-furyl)-2-propanone and 4 hydroxy-5,6-dihydro-(2H)-pyran-2-one) and ash toasted woods. PMID- 24809898 TI - Imidazole and imidazolium porphyrins: gas-phase chemistry of multicharged ions. AB - Electrospray ionization mass spectrometry/mass spectrometry in the positive ion mode was used to investigate the gas-phase chemistry of multicharged ions from solutions of porphyrins with 1,3-dimethylimidazolium-2-yl (DMIM) and 1 methylimidazol-2-yl (MIm) meso-substituents. The studied compounds include two free bases and 12 complexes with transition metals (Cu(II), Zn(II), Mn(III), and Fe(III)). The observed multicharged ions are either preformed or formed during the electrospraying process by reduction or protonation and comprise closed-shell and hypervalent mono-radical and bi-radical ions. The observed extensive and abundant fragmentation of the DMIM and MIm meso-substituents is a characteristic feature of these porphyrins. Fragments with the same mass values can be lost from the meso-substituents either as charged or neutral species and from closed-shell and hypervalent radical ions. Reduction processes are observed for both the free bases and the metallated DMIM porphyrins and occur predominantly by formation of hypervalent radicals that fragment, at low energy collisions, by loss of methyl radicals with formation of the corresponding MIm functionalities. These findings confirm that, when using electrospray ionization, reduction is an important characteristic of cationic meso-substituted tetrapyrrolic macrocycles, always occurring when delocalization of the formed hypervalent radicals is possible. For the Fe(III) and Mn(III) complexes, reduction of the metal centers is also observed as the predominant fragmentation of the corresponding reduced ions through losses of charged fragments testifies. The fragmentation of the closed shell ions formed by protonation of the MIm porphyrins mirrors the fragmentation of the closed-shell ions of their DMIM counterparts. PMID- 24809899 TI - Characterization of forced degradation products of ketorolac tromethamine using LC/ESI/Q/TOF/MS/MS and in silico toxicity prediction. AB - Ketorolac, a nonsteroidal anti-inflammatory drug, was subjected to forced degradation studies as per International Conference on Harmonization guidelines. A simple, rapid, precise, and accurate high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (LC/ESI/Q/TOF/MS/MS) method has been developed for the identification and structural characterization of stressed degradation products of ketorolac. The drug was found to degrade in hydrolytic (acidic, basic, and neutral), photolytic (acidic, basic, and neutral solution), and thermal conditions, whereas the solid form of the drug was found to be stable under photolytic conditions. The method has shown adequate separation of ketorolac tromethamine and its degradation products on a Grace Smart C-18 (250 mm * 4.6 mm i.d., 5 um) column using 20 mM ammonium formate (pH = 3.2): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 1.0 ml/min. A total of nine degradation products were identified and characterized by LC/ESI/MS/MS. The most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the [M + H](+) ions of ketorolac and its degradation products. In silico toxicity of the drug and degradation products was investigated by using topkat and derek softwares. The method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization guidelines. PMID- 24809900 TI - Assessment of the various ionization methods in the analysis of metal salen complexes by mass spectrometry. AB - Metal salen complexes are one of the most frequently used catalysts in enantioselective organic synthesis. In the present work, we compare a series of ionization methods that can be used for the mass spectral analysis of two types of metalosalens: ionic complexes (abbreviated as Com(+)X(-)) and neutral complexes (NCom). These methods include electron ionization and field desorption (FD) which can be applied to pure samples and atmospheric pressure ionization techniques: electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric pressure photoionization (APPI) which are suitable for solutions. We found that FD is a method of choice for recording molecular ions of the complexes containing even loosely bonded ligands. The results obtained using atmospheric pressure ionization methods show that the results depend mainly on the structure of metal salen complex and the ionization method. In ESI spectra, Com(+) ions were observed, while in APCI and APPI spectra both Com(+) and [Com + H](+) ions are observed in the ratio depending on the structure of the metal salen complex and the solvent used in the analysis. For complexes with tetrafluoroborate counterion, an elimination of BF3 took place, and ions corresponding to complexes with fluoride counterion were observed. Experiments comparing the relative sensitivity of ESI, APCI and APPI (with and without a dopant) methods showed that for the majority of the studied complexes ESI is the most sensitive one; however, the sensitivity of APCI is usually less than two times lower and for some compounds is even higher than the sensitivity of ESI. Both methods show very high linearity of the calibration curve in a range of about 3 orders of magnitude of the sample concentration. PMID- 24809901 TI - A method combining SPITC and 18O labeling for simultaneous protein identification and relative quantification. AB - The relative quantification and identification of proteins by matrix-assisted laser desorption ionization time-of-flight MS is very important in /MS is very important in protein research and is usually conducted separately. Chemical N terminal derivatization with 4-sulphophenyl isothiocyanate facilitates de novo sequencing analysis and accurate protein identification, while (18)O labeling is simple, specific and widely applicable among the isotopic labeling methods used for relative quantification. In the present study, a method combining 4 sulphophenyl isothiocyanate derivatization with (18)O isotopic labeling was established to identify and quantify proteins simultaneously in one experiment. Reaction conditions were first optimized using a standard peptide (fibrin peptide) and tryptic peptides from the model protein (bovine serum albumin). Under the optimized conditions, these two independent labeling steps show good compatibility, and the linear relativity of quantification within the ten times dynamic range was stable as revealed by correlation coefficient analysis (R(2) value = 0.998); moreover, precursor peaks in MS/MS spectrum could provide accurate quantitative information, which is usually acquired from MS spectrum, enabling protein identification and quantification in a single MS/MS spectrum. Next, this method was applied to native peptides isolated from spider venoms. As expected, the de novo sequencing results of each peptide matched with the known sequence precisely, and the measured quantitative ratio of each peptide corresponded well with the theoretical ratio. Finally, complex protein mixtures of spider venoms from male and female species with unknown genome information were analyzed. Differentially expressed proteins were successfully identified, and their quantitative information was also accessed. Taken together, this protein identification and quantification method is simple, reliable and efficient, which has a good potential in the exploration of peptides/proteins from species with unknown genome. PMID- 24809904 TI - Use of transition metals to improve the diastereomers differentiation by ion mobility and mass spectrometry. PMID- 24809903 TI - Matrix pre-coated targets for high throughput MALDI imaging of proteins. AB - We have developed matrix pre-coated targets for imaging proteins in thin tissue sections by matrix-assisted laser desorption/ionization mass spectrometry. Gold covered microscope slides were coated with sinapinic acid (SA) in batches in advance and were shown to be stable for over 6 months when kept in the dark. The sample preparation protocol using these SA pre-coated targets involves treatment with diisopropylethylamine (DIEA)-H2 O vapor, transforming the matrix layer to a viscous ionic liquid. This SA-DIEA ionic liquid layer extracts proteins and other analytes from tissue sections that are thaw mounted to this target. DIEA is removed by the immersion of the target into diluted acetic acid, allowing SA to co-crystallize with extracted analytes directly on the target. Ion images (3-70 kDa) of sections of mouse brain and rat kidney at spatial resolution down to 10 um were obtained. Use of pre-coated slides greatly reduces sample preparation time for matrix-assisted laser desorption/ionization imaging while providing high throughput, low cost and high spatial resolution images. PMID- 24809902 TI - Low C24-OH and C22-OH sulfatides in human renal cell carcinoma. AB - Histopathologic diagnosis of renal cell carcinoma (RCC) may sometimes be difficult with small biopsy samples. We applied histology-directed matrix assisted laser desorption/ionization mass spectrometry to RCC samples to evaluate whether and how lipid profiles are different between RCC and normal tissue. We evaluated 59 RCC samples and 24 adjacent normal tissue samples collected from patients who underwent surgery. Five peaks were significantly differently expressed (p < 10(-7)) between RCCs and adjacent normal tissue samples. C24-OH sulfatide (ST-OH {18:1/24:0}[M-H](-); m/z 906.7 in the negative ion mode) and C22 OH sulfatide (ST-OH {18:1/22:0}[M-H](-); m/z 878.6 in the negative ion mode) were most significantly underexpressed in RCC samples, compared with adjacent normal tissue samples. With 100 random training-to-test partitions within these samples, the median prediction accuracy (RCC vs. normal) ranged from 96.3% to 100% at p cutoff values for feature selection ranging from 0.001 to 10(-7). Two oncocytoma samples were predicted as normal tissue by five lipids that were differentially expressed between RCC and normal tissue at p < 10(-7). Clear-cell, papillary, and chromophobe RCCs were different in lipid profiles. Permutation p- values for 0.632+ bootstrap cross-validated misclassification rates were less than 0.05 for all the classifiers. Thus, lipid profiles differentiate RCC from normal tissue and may possibly classify the histology of RCC. PMID- 24809905 TI - Analysis of a caffeic acid derivative by ESI-MS/MS: unexpected product ions formed by 'internal residue loss'. PMID- 24809906 TI - Droplet-based electrospray ionization mass spectrometry for qualitative and quantitative analysis. PMID- 24809909 TI - G-protein-coupled receptor heteromers as key players in the molecular architecture of the central nervous system. AB - The overall architecture of the nervous system, especially the CNS, is remarkable. The anatomy of the nervous system is constituted not only by macroscopic and microscopy identifiable regions and neuronal cell types, but also by protein complexes whose identification and localization require sophisticated techniques. G-protein-coupled receptors (GPCRs) constitute an example of proteins that are the key factors in the framework needed to sustain brain and nerve structure and function. The versatility underlying nervous system anatomy takes advantage of a recently discovered feature of GPCRs, the possibility to form heteromers that, placed at specific neuronal subsets and at specific locations (pre-, post-, or peri-synaptic), contribute to attain unique neural functions. PMID- 24809910 TI - Mechanistic and kinetic implications on the ORR on a Au(100) electrode: pH, temperature and H-D kinetic isotope effects. AB - pH, temperature and H-D kinetic isotope effects (KIEs) on the ORR on Au(100) have been examined systematically using a hanging meniscus rotating disk electrode system. We found that for the cases with pH > 7, the ORR mainly goes through a 4 electron reduction to OH(-) at E > pzc (potential of zero charge) without any pH and H-D KIEs. When the pH at the electrode/electrolyte interface (pH(s)) is below 7, O2 only reduces to H2O2, its activity increases with pH(s), and a H-D KIE of above 2 is observed in 0.1 M HClO4. According to the experimental results in acid solution, a mechanism with O2 + H(+) + e -> HO(2,ad) as the rate determining step followed by decoupled electron and proton transfer steps is proposed. The high activation barrier for O-O bond breaking and the fast oxidation of H2O2 or HO2(-) to O2 render the ORR observable only at potentials negative of the equilibrium potential (Eeq) of the redox of H2O2/O2 in acidic media or of HO2(-)/O2 in an alkaline environment. The apparent activation energy (E(a,app)) for O2 reduction to H2O2 is ca. 35 +/- 3 kJ mol(-1) and to OH(-) is 60 +/- 6 kJ mol(-1), while the pre-exponential factor (A) for the former is ca. 3-6 orders of magnitude smaller than that of the latter. The lower activity for O2 reduction to H2O2 on Au(100) is attributed to the small pre-exponential factor. PMID- 24809911 TI - Determination of 17 organophosphate pesticide residues in mango by modified QuEChERS extraction method using GC-NPD/GC-MS and hazard index estimation in Lucknow, India. AB - A total of 162 samples of different varieties of mango: Deshehari, Langra, Safeda in three growing stages (Pre-mature, Unripe and Ripe) were collected from Lucknow, India, and analyzed for the presence of seventeen organophosphate pesticide residues. The QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method of extraction coupled with gas chromatography was validated for pesticides and qualitatively confirmed by gas chromatography-mass spectrometry. The method was validated with different concentrations of mixture of seventeen organophosphate pesticides (0.05, 0.10, 0.50 mg kg(-1)) in mango. The average recovery varied from 70.20% to 95.25% with less than 10% relative standard deviation. The limit of quantification of different pesticides ranged from 0.007 to 0.033 mg kg(-1). Out of seventeen organophosphate pesticides only malathion and chlorpyriphos were detected. Approximately 20% of the mango samples have shown the presence of these two pesticides. The malathion residues ranged from ND 1.407 mg kg(-1) and chlorpyriphos ND-0.313 mg kg(-1) which is well below the maximum residues limit (PFA-1954). In three varieties of mango at different stages from unpeeled to peeled sample reduction of malathion and chlorpyriphos ranged from 35.48%-100% and 46.66%-100% respectively. The estimated daily intake of malathion ranged from 0.032 to 0.121 ug kg(-1) and chlorpyriphos ranged from zero to 0.022 ug kg(-1) body weight from three different stages of mango. The hazard indices ranged from 0.0015 to 0.0060 for malathion and zero to 0.0022 for chlorpyriphos. It is therefore indicated that seasonal consumption of these three varieties of mango may not pose any health hazards for the population of Lucknow, city, India because the hazard indices for malathion and chlorpyriphos residues were below to one. PMID- 24809913 TI - Differential gene expression of C-type natriuretic peptide and its related molecules in dilated and ischemic cardiomyopathy. A new option for the management of heart failure. PMID- 24809912 TI - Pharmacological stimulation of the brain serotonin receptor 7 as a novel therapeutic approach for Rett syndrome. AB - Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2-308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability. PMID- 24809914 TI - Recent prevalence of hypertension among Chinese children and adolescents based on 2010 China national blood pressure references. PMID- 24809915 TI - Mitral valve anatomy predicts outcome of MitraClip implantation. PMID- 24809916 TI - Thyroid stimulating hormone levels and risk of coronary heart disease in patients with type 2 diabetes mellitus. PMID- 24809917 TI - Circulating angiogenic cells from obese children do not display leptin resistance. PMID- 24809918 TI - Association of virtual histology characteristics of the culprit plaque with post fibrinolysis flow restoration in ST-elevation myocardial infarction. AB - OBJECTIVES: We sought to test the hypothesis that virtual histology characteristics of the culprit lesion in patients with ST-elevation myocardial infarction are associated with blood flow restoration after thrombolysis. METHODS: Consecutive patients referred for coronary angiography after successful thrombolysis were included in this correlational cross-sectional study. Evaluation with intravascular ultrasound (IVUS) and virtual histology of the culprit arterial segment was performed in all cases. RESULTS: Forty-eight patients (60.5 +/- 10.7 years) were included. TIMI flow grade 3 was found in 24 (50%). Diabetes was strongly associated with lower TIMI flow 3 rate (26.7% vs 60.6%; p = 0.029) and there was a significant difference in the time to thrombolysis (2.0 +/- 0.8 hours in those with TIMI flow 3 vs 3.0 +/- 0.7 hours in TIMI flow grades 1-2; p < 0.001). Patients with TIMI flow grades 3 and 1-2 had similar absolute total plaque volume (152.8 +/- 59.3mm(3) vs 147.5 +/- 92.3mm(3); p = 0.817) and absolute necrotic core (NC) volume (31.2 +/- 13.9 mm(3) vs 33.6 +/ 23.2mm(3); p = 0.671). However, there were significant differences in the relative NC content, both in proportion to the whole plaque volume (26.3% vs 29.9%; p = 0.016) and as an area fraction at the largest NC site (31.5% vs 40.3%; p < 0.001). CONCLUSION: The NC content of atherosclerotic plaques is meaningful for flow restoration after the occurrence of a coronary event. This finding highlights the importance of plaque composition, as studied with virtual histology, not only for the sequence of processes leading to an acute plaque related event, but also for thrombus formation and lysis, following the occurrence of such an event. PMID- 24809919 TI - Subclinical infections of cardiac implantable electronic devices: insights into the host-bacteria dialog from blood and pocket tissue with pyrosequencing. AB - While bacteria exist in CIED patients without clinical signs of infection, the underlying bacterial community structure and diversity in the bloodstream and pocket tissue of asymptomatic CIED patients remain unknown. In this study, we performed high-throughput 454 pyrosequencing of bacterial 16S rDNA of blood and pocket tissue from 54 asymptomatic CIED patients as well as blood from 30 normal individuals (normal controls). Firstly, we observed a significant increase of blood bacterial diversity in patients as compared with blood of normal subjects or patient tissues. We also found significant differences in 13 blood-associated bacterial genera between patients and normal subjects, and 14 bacteria genera between blood and tissues within patients. Secondly, we found that the serum levels of four inflammatory markers (CRP, IL-1beta, IL-6, and MCP-1) in CIED patients were significantly higher than those in normal subjects. Thirdly, we found that there were significant correlations between 43 bacterial species and these inflammatory markers. Taken together, our results reveal a high diversity in the microbial community in CIED patients, and suggest the potential roles of multiple bacteria co-occurrence in the CIED subclinical infections. PMID- 24809920 TI - Orthostatic intolerance is common in chronic disease--a clinical cohort study. PMID- 24809921 TI - Chronic treatment with trimetazidine after discharge reduces the incidence of restenosis in patients who received coronary stent implantation: a 1-year prospective follow-up study. AB - BACKGROUND: The incidence of stent restenosis (SR) has risen with as more patients are being treated with drug-eluting stents (DESs). Trimetazidine has multiple favorable effects on the cardiovascular system. Here, we aimed to evaluate whether chronic treatment with trimetazidine reduced the incidence of SR. METHODS: From January 2009 to December 2011 at Chinese PLA General Hospital, 768 patients were enrolled and randomized into the trimetazidine treatment group (TG, n = 384) and control group (CG, n = 384). After DES implantation, all patients were treated with regular medication. In the TG, trimetazidine was administrated at 20mg tid for at least 30days. All patients received follow-up angiography 9-13 months after discharge. Major adverse cardiac and cerebrovascular events (MACCEs) were recorded. RESULTS: Six hundred thirty-five patients were included in the final analysis (TG, n = 312; CG, n = 323). SR occurred in 49 (7.7%) patients. The TG had a lower incidence of SR compared to the CG (4.2% vs. 11.1%, p = 0.001). At the 30-day follow-up, the TG exhibited a higher left ventricular ejection fraction than the CG (65.4 +/- 10.7 vs. 63.1 +/- 10.4, p = 0.006). The incidence of MACCEs was also lower in the TG at the 1-year follow-up (6.1% vs. 10.8%, p = 0.032). Further multivariate analysis revealed that trimetazidine treatment was a predictor for SR (OR: 0.376; 95% CI: 0.196 0.721; p = 0.003). CONCLUSIONS: Trimetazidine treatment effectively reduced the incidence of SR and MACCEs after DES implantation at the 1-year follow-up. PMID- 24809922 TI - SAT-TAVI (single antiplatelet therapy for TAVI) study: a pilot randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation. AB - BACKGROUND: Common clinical practice recommends dual antiplatelet therapy (DAPT) for transcatheter aortic valve implantation (TAVI). The aim of the study was to evaluate, in a double blind randomized study, the safety of TAVI, with adjunctive pharmacotherapy consisting of single antiplatelet therapy. METHODS AND RESULTS: From April 2010 to April 2011, 120 consecutive patients, undergoing TAVI, have been enrolled in the study. Patients were randomly assigned to DAPT group (aspirin and clopidogrel 75 mg/qd or ticlopidine 500 mg/bid) or ASA group (aspirin only). TAVI device was the Sapien XT-Novaflex Delivery System (Edwards Lifesciences, Inc.). All patients were followed up to 6 months. Device success was achieved in 100% of patients. No difference in the VARC combined 30 day safety endpoint, all cause and cardiovascular mortality was observed. At 30 days vascular complications were reduced in the ASA group (p<0.05). No differences in the clinical status were detected between the groups up to 6 months. CONCLUSIONS: This study suggests that TAVI procedures can be performed without DAPT without increasing the morbidity and mortality. These findings, if confirmed in a larger multicenter randomized trial, will no longer support the use of DAPT for TAVI. PMID- 24809923 TI - Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy. AB - AIM: Takotsubo cardiomyopathy (TTC) is a disorder of myocardial inflammation induced by high catecholamine levels and is associated with acute complications. In the long-term TTC is associated with a risk of single or multiple recurrences, but risk of such occurrences is not clear. We performed a systematic review and meta-analysis to identify and consolidate the evidence on the incidence and clinical correlates of cases of TTC recurrence. METHODS: A comprehensive search of four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to first week of Jan 2014. We included original research studies, recruiting >= 5 participants, with >= 3 months follow-up, published in English language that reported data on recurrence in patients with TTC. RESULTS: Out of 298 studies searched, 31 cohorts (1664 TTC patients) were included in the analyses. Out of 74 cases of recurrence, with a mean follow-up of 24.5 months (95% CI, 19.3 to 33 months), extensive recurrence data were available for 23 cases. Cumulative incidence of recurrence was approximately 5% at 6 years. Annual rate of recurrence was approximately 1.5%. Furthermore, 14% of cases had recurrent chest pain and 11% reported dyspnea without definite evidence of recurrent TTC. Discharge medications at index admission included beta adrenoceptor antagonists (BB) in 66.8% and ACE inhibitors (ACEi) and ARB in 67.4%. Recurrence rate was independent of clinic utilization of BB prescription, but inversely correlated (r=-0.45, p=0.016) with ACEi/ARB prescription. Patients with severe TTC at index admission were noted to have more recurrences. CONCLUSIONS: (1) TTC is associated with only 1-2% annual recurrence rate but substantially greater frequency of ongoing symptoms. (2) ACEi/ARB rather than BB may reduce risk of recurrence. PMID- 24809924 TI - Evaluation of the indoor air quality minimum ventilation rate procedure for use in California retail buildings. AB - This research assesses benefits of adding to California Title-24 ventilation rate (VR) standards a performance-based option, similar to the American Society of Heating, Refrigerating, and Air Conditioning Engineers 'Indoor Air Quality Procedure' (IAQP) for retail spaces. Ventilation rates and concentrations of contaminants of concern (CoC) were measured in 13 stores. Mass balance models were used to estimate 'IAQP-based' VRs that would maintain concentrations of all CoCs below health- or odor-based reference concentration limits. An intervention study in a 'big box' store assessed how the current VR, the Title 24-prescribed VR, and the IAQP-based VR (0.24, 0.69, and 1.51 air changes per hour) influenced measured IAQ and perceived of IAQ. Neither current VRs nor Title 24-prescribed VRs would maintain all CoCs below reference limits in 12 of 13 stores. In the big box store, the IAQP-based VR kept all CoCs below limits. More than 80% of subjects reported acceptable air quality at all three VRs. In 11 of 13 buildings, saving energy through lower VRs while maintaining acceptable IAQ would require source reduction or gas-phase air cleaning for CoCs. In only one of the 13 retail stores surveyed, application of the IAQP would have allowed reduced VRs without additional contaminant-reduction strategies. PMID- 24809925 TI - p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells. AB - The p53 family members p73 and p63 have been implicated in various aspects of stem cell regulation. Here, we have asked whether they work together to regulate stem cell biology, focusing upon neural precursor cells (NPCs) in the adult murine brain. By studying mice that are haploinsufficient for p63 and/or p73, we show that these two proteins cooperate to ensure appropriate NPC self-renewal and long-term maintenance in the hippocampus and forebrain, and that when both are haploinsufficient, the NPC deficits are significantly greater than haploinsufficiency for either alone. We show that, in the case of p63(+/-) mice, this decrease in adult NPCs is caused by enhanced apoptosis. However, when p73 is coincidently haploinsufficient, this rescues the enhanced apoptosis of p63(+/-) NPCs under both basal conditions and following genotoxic stress, instead causing increased cellular senescence. This increase in cellular senescence is likely due, at least in part, to increased levels of basal DNA damage and p53 activation, as genetic ablation of p53 completely rescues the senescence phenotype observed in p63(+/-); p73(+/-) mice. Thus, the presence of p73 determines whether p63(+/-) NPCs exhibit increased p53-dependent apoptosis or senescence. Together, these studies demonstrate that p63 and p73 cooperate to maintain adult NPC pools through regulation of p53 function; p63 antagonizes p53 to promote cellular survival, whereas p73 regulates self-renewal and p53-mediated apoptosis versus senescence. PMID- 24809926 TI - Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi. AB - Mucorales, Scedosporium and Fusarium species are rarely considered as cause for bone and joint infections. However, these moulds are emerging as important fungal pathogens in immunocompromised and immunocompetent patients. Typical pre disposing host conditions are immunosuppression and diabetes. Most common causative pathogens are Mucorales followed by Scedosporium and Fusarium. Acremonium and Phialemonium species are rare but some case reports exist. MRI is the gold standard imaging technique. Tissue specimens obtained as aspirates, imaging guided biopsy or open surgery need mycological and histopathological work up for genus and species identification. Multimodal treatment strategies combine surgical debridement, drainage of joints or abscesses, removal of infected prosthetic joints and systemic antifungals. The treatment of mucormycosis is polyene based and may be combined with either posaconazole or - in rare cases - caspofungin. As Scedosporium species are intrinsically resistant to polyenes and azoles show absence of in vitro activity, voriconazole plus synergistic treatment regimens become the therapeutic standard. In fusariosis, fungal susceptibility is virtually impossible to predict, so that combination treatment of voriconazole and lipid-based amphotericin B should be the first-line strategy while susceptibility results are pending. In the absence of randomized controlled trials, infections due to the above moulds should be registered, e.g. in the registries of the European Confederation of Medical Mycology (ECMM). PMID- 24809928 TI - Mn-doped TiO2 nanosheet-based spheres as anode materials for lithium-ion batteries with high performance at elevated temperatures. AB - Novel Mn(2+)-doped TiO2 nanosheet-based spheres have been successfully prepared via a simple hydrothermal and ion-exchange process. After hydrothermal growth, flowerlike nanosheet-based spheres of protonated dititanate were confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The hierarchical nanostructure was obtained via a dissolution-recrystallization process starting from a precursor of homogenous TiO2 nanospheres. Moreover, as prepared protonated dititanate was converted to Mn-doped nanosheet-based spheres via the ion-exchange method. Then, both the doped and undoped protonated dititanate were calcined and tested as anode materials for lithium-ion battery applications at elevated temperatures. The undoped sample showed an initial capacity of 201 mAh g(-1) but only had 44.1% of the initial capacity retained after 50 cycles at mixed current densities of 30, 150, and 500 mA g(-1) at 55 degrees C, while the Mn-doped one exhibited an initial capacity of 190 mAh g(-1) and 91.4% capacity retention with superior reversible capacity under the same test conditions. Comparisons between different samples suggest that manganese ions on the surface of TiO2 nanosheet-based spheres are responsible for the enhanced electrochemical performance. PMID- 24809927 TI - A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias. AB - Acute porphyrias are a heterogeneous group of metabolic disorders resulting from a variable catalytic defect of four enzymes out of the eight involved in the haem biosynthesis pathway; they are rare and mostly inherited diseases, but in some circumstances, the metabolic disturbance may be acquired. Many different environmental factors or pathological conditions (such as drugs, calorie restriction, hormones, infections, or alcohol abuse) often play a key role in triggering the clinical exacerbation (acute porphyric attack) of these diseases that may often mimic many other more common acute medical and neuropsychiatric conditions and whose delayed diagnosis and treatment may be fatal. In order to obtain an accurate diagnosis of acute porphyria, the knowledge and the use of appropriate diagnostic tools are mandatory, even in order to provide as soon as possible the more effective treatment and to prevent the use of potentially unsafe drugs, which can severely precipitate these diseases, especially in the presence of life-threatening symptoms. In this paper, we provide some recommendations for the diagnostic steps of acute porphyrias by reviewing literature and referring to clinical experience of the board members of the Gruppo Italiano Porfiria (GrIP). PMID- 24809929 TI - Differences in breast-feeding initiation and continuation by maternal diabetes status. AB - OBJECTIVE: To examine (i) the prevalence of and associations between breast feeding initiation and continuation by maternal diabetes status and (ii) the reasons for not initiating and/or continuing breast-feeding by maternal diabetes status. DESIGN: Secondary data analyses of a population-based cross-sectional study were conducting using data from the US Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System (PRAMS), 2009-2011. Multivariable logistic regression was used to investigate the associations between breast-feeding initiation and continuation by diabetes status. SETTING: Thirty states and New York City, USA. SUBJECTS: Mothers of recently live-born infants, selected by birth certificate sampling. RESULTS: Among 72755 women, 8.8 % had gestational diabetes mellitus (GDM) and 1.7 % had pregestational diabetes mellitus (PDM). Breast-feeding initiation was similar among GDM and no diabetes mellitus (NDM) women (80.8 % v. 82.2 %, respectively, P=0.2), but continuation was lower among GDM (65.7 % v. 68.8 %, respectively, P=0.01). PDM women had lower initiation and continuation compared with NDM (78.2 %, P=0.03 and 60.4 %, P<0.01, respectively). In adjusted analyses, current smoking status was a significant effect modifier for initiation, but not for continuation. CONCLUSIONS: Differences in breast-feeding initiation and continuation prevalence by maternal diabetes status may reflect differences in prenatal education, indicating the need for increased efforts among PDM women. Additionally, non-smoking women with PDM or GDM would benefit from additional breast-feeding education. PMID- 24809930 TI - Pharmacokinetics considerations for gout treatments. AB - INTRODUCTION: Patients with gout often have comorbid conditions such as renal failure, cardiovascular disease and metabolic syndrome. The presence and required treatment of these conditions can make the treatment of gout challenging. Knowledge of the pharmacokinetics of the available drugs for the management of gout is mandatory. AREAS COVERED: A MEDLINE PubMed search for articles published in English from January 1990 to January 2014 was completed using the terms: pharmacokinetics, colchicine, canakinumab, allopurinol, febuxostat, pegloticase, gout, toxicity, drug interaction. EXPERT OPINION: Colchicine is a drug with a narrow therapeutic-toxicity window. Co-prescription with strong CYP3A4 or P glycoprotein inhibitors can greatly modify its pharmacokinetics and is to be avoided. Elimination of canakinumab mainly occurs via intracellular catabolism, following receptor mediator endocytosis. Canakinumab appears to be a good alternative for patients with contraindications to colchicine, NSAIDs and corticosteroids. For patients with renal impairment, some authors recommend that the allopurinol maximum dosage should be adjusted to creatinine clearance. If the urate target cannot be achieved, the therapy should be switched to febuxostat, which is appropriate with mild-to-moderate renal failure. Anti-pegloticase antibodies affect the pharmacokinetics of the drug because they increase its clearance, with loss of pegloticase activity. PMID- 24809932 TI - Astragaloside IV ameliorates diabetic nephropathy involving protection of podocytes in streptozotocin induced diabetic rats. AB - Podocyte loss and dysfunction play key role during the development of diabetic nephropathy (DN). The aim of this study was to observe the protective effects of astragaloside IV on podocyte in diabetic rats and explore its mechanisms preliminary. Healthy male Sprague-Dawley (SD) rats were randomized into normal control group, diabetic nephropathy group and diabetic nephropathy with AS-IV treatment group. DN was induced by intraperitoneal injection of streptozotocin (STZ). AS-IV treatment started 2 weeks before STZ injection and lasted 14 weeks. 24h Urinary proteins were measured 4, 8 and 12 weeks after STZ injection. Body weight, blood glucose, blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured 12 weeks after STZ injection. Renal pathology, podocyte morphological changes, podocyte density, protein and mRNA expression of integrin alpha3, integrin beta1 and integrin-linked kinase (ILK) were detected by histopathology, electron microscopy, immunohistochemistry, western blot and real-time PCR, respectively. Hyperglycemia, proteinuria, mesangial expansion and podocyte loss, increased protein expression of ILK and decreased protein expression of integrin alpha3 and integrin beta1 were detected in diabetic rats. AS-IV treatment ameliorated podocyte loss, renal histopathology and podocyte foot process effacement, decreased proteinuria, partially restored protein expression of integrin alpha3, integrin beta1 and ILK. These findings suggested that AS-IV may protect podocyte and ameliorate diabetic nephropathy by inhibiting the expression of ILK and restoring the expression of integrin alpha3beta1 in diabetic rats. PMID- 24809933 TI - Ultrastructural localization of adiponectin protein in vasculature of normal and atherosclerotic mice. AB - Adiponectin, adipose-specific secretory protein, abundantly circulates in bloodstream and its concentration is around 1000-fold higher than that of other cytokines and hormones. Hypoadiponectinemia is a risk factor for atherosclerosis. There is little or no information on ultrastructural localization of adiponectin in the vasculature. Herein we investigated the localization of vascular adiponectin in the aorta using the immunoelectron microscopic technique. In wild type (WT) mice, adiponectin was mainly detected on the luminal surface membrane of endothelial cells (ECs) and also found intracellularly in the endocytic vesicles of ECs. In the atherosclerotic lesions of apolipoprotein E-knockout (ApoE-KO) mice, adiponectin was detected in ECs, on the cell surface membrane of synthetic smooth muscle cells, and on the surface of monocytes adherent to ECs. Changes in adiponectin localization within the wall of the aorta may provide novel insight into the pathogenesis of atherosclerosis. PMID- 24809934 TI - Improved oncologic outcomes with image-guided intensity-modulated radiation therapy using helical tomotherapy in locally advanced hepatocellular carcinoma. AB - AIM: To investigate whether image-guided intensity-modulated radiation therapy (IG-IMRT) improves survival in hepatocellular carcinoma (HCC) relative to 3 dimensional conformal radiotherapy (3D-CRT). METHODS: Between 2006 and 2011, 187 HCC patients treated with definitive RT were reviewed. Median age was 53(range 51 83). All patients were stage III or IV-A. Concurrent chemoradiation was received by 178 patients (95.2 %). Overall actuarial survival (OS), progression-free survival (PFS), and infield-failure-free survival (IFFS) analyses were performed by Kaplan-Meier method. A Cox proportional hazards model was used for univariate and multivariate analysis. Pearson's chi-square test or Fisher's exact test was used to compare patient characteristics and treatment-related toxicity between the groups. RESULTS: Sixty-five patients were treated with IG-IMRT and 122 patients with 3D-CRT. No significant differences were seen between the groups for all patient characteristics. IG-IMRT delivered higher doses than 3D-CRT (median biological effective dose 62.5 vs 53.1 Gy, P < 0.001). IG-IMRT showed significantly higher 3-year OS (33.4 vs 13.5 %, P < 0.001), PFS (11.1 vs 6.0 %, P = 0.004), and IFFS (46.8 vs 28.2 %, P = 0.007) than 3D-CRT. On univariate and multivariate analysis, RT modality was significant prognostic factor for OS (HR 2.18; 95 % CI 1.45-3.25; P < 0.001), PFS (HR 1.64; 95 % CI 1.17-2.29; P = 0.004). There was no significant difference between the two modalities for radiation induced liver disease (P = 0.716). CONCLUSION: Our findings suggest that IG-IMRT could be an effective treatment that provides survival benefit without increasing severe toxicity in locally advanced HCC. PMID- 24809931 TI - BMI and waist circumference are associated with impaired glucose metabolism and type 2 diabetes in normal weight Chinese adults. AB - AIMS: To examine the associations of BMI and waist circumference with glucose metabolism and (pre)diabetes among adults with BMI < 25 kg/m2. METHODS: We conducted a cross-sectional study in a nationally representative sample (10,098 men and 17,454 women) of Chinese adults aged >= 20 years with BMI < 25 kg/m2. Glucose levels after at least 10 hours of overnight fasting, at 30 minutes and at 120 minutes after a standard 75-g oral glucose load were measured. Associations of BMI and waist circumference with outcomes were examined by general linear models for continuous outcomes and by logistic regression models for dichotomous outcomes. RESULTS: Among those with BMI < 25 kg/m2, 18.8% of men and 17.1% of women had abnormal glucose metabolism, including 4.9% of men and 3.8% of women with undiagnosed type 2 diabetes. For each SD increase in BMI (2.1 kg/m2) and waist circumference (8.3 cm), fasting glucose levels increased by 0.128 and 0.170 mmol/L in men, and by 0.112 and 0.167 mmol/L in women, respectively; the corresponding increases for 2-hour post-load glucose levels were 0.121 and 0.217 mmol/L in men, and 0.241 and 0.362 mmol/L in women. When simultaneously included in the same model, these associations with waist circumference were stronger than with BMI. CONCLUSION: Obesity measures are associated with abnormal glucose metabolism and diabetes, with central obesity playing a more prominent role than general obesity in Chinese population with BMI < 25 kg/m2. Chinese diabetes prevention and treatment programs should incorporate targeting of normal weight adults with central obesity. PMID- 24809935 TI - Can a treatment be licenced on the basis of post-treatment predictive biomarkers? AB - In recent years, there has been a great deal of literature published concerning the identification of predictive biomarkers and indeed, an increasing number of therapies have been licenced on this basis. However, this progress has been made almost exclusively on the basis of biomarkers measured prior to exposure to treatment. There are quite different challenges when the responding population can only be identified on the basis of outcomes observed following exposure to treatment, especially if it represents only a small proportion of patients. The purpose of this paper is to explore whether or when a treatment could be licenced on the basis of post-treatment predictive biomarkers (PTPB), the focus is on oncology but the concepts should apply to all therapeutic areas. We review the potential pitfalls in hypothesising the presence of a PTPB. We also present challenges in trial design required to confirm and licence on the basis of a PTPB: what's the control population?, could there be a detriment to non responders by exposure to the new treatment?, can responders be identified rapidly?, could prior exposure to the new treatment adversely affect performance of the control in responders? Nevertheless, if the patients to be treated could be rapidly identified after prior exposure to treatment, and without harm to non responders, in appropriately designed and analysed trials, may be more targeted therapies could be made available to patients. PMID- 24809936 TI - Chemoselective N-heterocyclic carbene-catalyzed cross-benzoin reactions: importance of the fused ring in triazolium salts. AB - Morpholinone- and piperidinone-derived triazolium salts are shown to catalyze highly chemoselective cross-benzoin reactions between aliphatic and aromatic aldehydes. The reaction scope includes ortho-, meta-, and para-substituted benzaldehyde derivatives with a range of electron-donating and -withdrawing groups as well as branched and unbranched aliphatic aldehydes. Catalytic loadings as low as 5 mol % give excellent yields in these reactions (up to 99%). PMID- 24809937 TI - Biomimetic cloning of quantum observables. AB - We propose a bio-inspired sequential quantum protocol for the cloning and preservation of the statistics associated to quantum observables of a given system. It combines the cloning of a set of commuting observables, permitted by the no-cloning and no-broadcasting theorems, with a controllable propagation of the initial state coherences to the subsequent generations. The protocol mimics the scenario in which an individual in an unknown quantum state copies and propagates its quantum information into an environment of blank qubits. Finally, we propose a realistic experimental implementation of this protocol in trapped ions. PMID- 24809938 TI - Diabetes risk increased between spouses. PMID- 24809939 TI - Sexual dysfunction common in people with coronary heart disease, but few cardiovascular changes actually occur during sexual activity. PMID- 24809940 TI - Small-for-gestational-age pregnancies are at cumulative increased risk of stillbirth for each week pregnancy continues beyond 37 weeks. PMID- 24809941 TI - Emotional intelligence: enhancing value-based practice and compassionate care in nursing. PMID- 24809943 TI - Optimizing measures of HIV-associated neuropathy. AB - INTRODUCTION: Distal symmetric polyneuropathy (DSP) is common in HIV and is associated with autonomic impairment. However tools to measure HIV-DSP do not include autonomic indices. We sought to optimize the Total Neuropathy Score (TNS) and the Composite Autonomic Severity Score (CASS) for use in HIV. METHODS: HIV infected adults (n = 102) underwent neurologic examination, quantitative sensory testing (QST), nerve conduction studies, and autonomic testing. Modifications of the TNS and CASS were assessed for validity based on correlation with the original measure and internal consistency. RESULTS: The TNS version commonly used in HIV-DSP is valid, but it is improved by elimination of QST and addition of autonomic indices. A modified version of the CASS (M-CASS) which was designed for sensitivity to milder impairment was also valid. CONCLUSIONS: A modified TNS that excludes QST and includes autonomic indices is optimal for HIV-DSP. The M-CASS is a valid measure of autonomic impairment in HIV. PMID- 24809944 TI - Modulation of the cAMP response by Galphai and Gbetagamma: a computational study of G protein signaling in immune cells. AB - Cyclic AMP is important for the resolution of inflammation, as it promotes anti inflammatory signaling in several immune cell lines. In this paper, we present an immune cell specific model of the cAMP signaling cascade, paying close attention to the specific isoforms of adenylyl cyclase (AC) and phosphodiesterase that control cAMP production and degradation, respectively, in these cells. The model describes the role that G protein subunits, including Galphas, Galphai, and Gbetagamma, have in regulating cAMP production. Previously, Galphai activation has been shown to increase the level of cAMP in certain immune cell types. This increase in cAMP is thought to be mediated by betagamma subunits which are released upon Galpha activation and can directly stimulate specific isoforms of AC. We conduct numerical experiments in order to explore the mechanisms through which Galphai activation can increase cAMP production. An important conclusion of our analysis is that the relative abundance of different G protein subunits is an essential determinant of the cAMP profile in immune cells. In particular, our model predicts that limited availability of betagamma subunits may both (i) enable immune cells to link inflammatory Galphai signaling to anti-inflammatory cAMP production thereby creating a balanced immune response to stimulation with low concentrations of PGE2, and (ii) prohibit robust anti-inflammatory cAMP signaling in response to stimulation with high concentrations of PGE2. PMID- 24809945 TI - Fold-change detection in a whole-pathway model of Escherichia coli chemotaxis. AB - There has been recent interest in sensory systems that are able to display a response which is proportional to a fold change in stimulus concentration, a feature referred to as fold-change detection (FCD). Here, we demonstrate FCD in a recent whole-pathway mathematical model of Escherichia coli chemotaxis. FCD is shown to hold for each protein in the signalling cascade and to be robust to kinetic rate and protein concentration variation. Using a sensitivity analysis, we find that only variations in the number of receptors within a signalling team lead to the model not exhibiting FCD. We also discuss the ability of a cell with multiple receptor types to display FCD and explain how a particular receptor configuration may be used to elucidate the two experimentally determined regimes of FCD behaviour. All findings are discussed in respect of the experimental literature. PMID- 24809946 TI - Tropomyosin receptor kinase inhibitors: a patent update 2009 - 2013. AB - INTRODUCTION: Tropomyosin receptor kinases (Trks) are a family of three similar tyrosine kinases activated by peptide hormones of the neurotrophin family. The nerve growth factor antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA pathway in pain. As an alternative modality, small molecule inhibitors of the Trks have been pursued in recent years to probe the role of these neurotrophin pathways in pain, cancer and other indications. AREAS COVERED: This paper reviews the patent literature between mid-2009 and 2013, claiming inhibitors of Trk family members as the primary biological targets. Additional patents have been reviewed where Trk is not the main kinase of interest but in which high Trk potency is observed and the chemical matter is particularly noteworthy. Patents pre-dating this period have been reviewed previously. Scifinder and Google were used to find relevant patents and clinical information using Trk or Tropomyosin as the search term. EXPERT OPINION: Considerable recent progress has been made in the identification of selective pan Trk inhibitors with pharmacodynamic and pharmacokinetic properties appropriate for clinical evaluation. Inhibitors of both active and inactive conformations of the Trks as well as peripherally restricted molecules have been identified. Furthermore, TrkA-selective allosteric inhibitors have recently been disclosed, which enables the biology of this isoform to be probed. The recent identification of a TrkA gene fusion in a subset of lung cancer patients will increase further the attraction of Trk inhibition to the pharmaceutical industry. PMID- 24809947 TI - Antigenic characteristics of glycosylated protein 3 of highly pathogenic porcine reproductive and respiratory syndrome virus. AB - Highly pathogenic (HP)-porcine reproductive and respiratory syndrome virus (PRRSV) emerged in 2006 and has now become a global threat to pig farms. Despite extensive characterization of HP-PRRSV proteins by direct analysis and comparison with typical PRRSV, immune recognition remain poorly understood. Glycosylated protein 3 (GP3) has an important function in inducing protective immune response. To analyze the antigenic character of HP-PRRSV GP3, a total of 217 peptides were printed on a chip and used to react with HP-PRRSV specific serum. The reactions of these peptides to HP-PRRSV specific pig serum were scanned and quantified using the software PepSlide Analyzer by fluorescence intensity. The intensity plots showed various reactions in different parts of GP3. The highest reaction intensity value reached 29,184.5 with the peptide sequence of CSENDHDELGFMVPP. Conversely, 88 peptides showed no reaction with 0 florescence intensity. A further analysis based on the result of the peptide microarray revealed an antigen reaction active region (AR) from Y(51) to S(106) in GP3. The AR had four parts of variation that may be a significant mutation of the typical PRRSV to HP PRRSV. Acquired data may be useful for understanding HP-PRRSV variation and its GP3 immune recognition. PMID- 24809948 TI - First molecular analysis of West Nile virus during the 2013 outbreak in Croatia. AB - This is the second subsequent year of West Nile neuroinvasive disease (WNND) outbreak in Croatia. Between July and October 2013, 22 patients presented with symptoms of WNND: all with meningitis and 18 additionally with encephalitis. In contrast to 2012, where six autochthonous infections were confirmed in eastern Croatia, the majority of this year's cases occurred in and around the city of Zagreb, where no West Nile virus infections have been observed before. Viral RNA was recovered from two patients and phylogenetic analyses revealed West Nile virus lineage 2. This represents the first molecular characterization and phylogenetic analysis of the circulating West Nile virus strain in Croatia. PMID- 24809949 TI - Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma. AB - Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy. PMID- 24809951 TI - [Iron deficiency anemia and anemia of chronic disease (ACD)]. PMID- 24809950 TI - Analysis of the prevalence, secretion and function of a cell cycle-inhibiting factor in the melioidosis pathogen Burkholderia pseudomallei. AB - Enteropathogenic and enterohaemorrhagic Escherichia coli express a cell cycle inhibiting factor (Cif), that is injected into host cells via a Type III secretion system (T3SS) leading to arrest of cell division, delayed apoptosis and cytoskeletal rearrangements. A homologue of Cif has been identified in Burkholderia pseudomallei (CHBP; Cif homologue in B. pseudomallei; BPSS1385), which shares catalytic activity, but its prevalence, secretion and function are ill-defined. Among 43 available B. pseudomallei genome sequences, 33 genomes (76.7%) harbor the gene encoding CHBP. Western blot analysis using antiserum raised to a synthetic CHBP peptide detected CHBP in 46.6% (7/15) of clinical B. pseudomallei isolates from the endemic area. Secretion of CHBP into bacterial culture supernatant could not be detected under conditions where a known effector (BopE) was secreted in a manner dependent on the Bsa T3SS. In contrast, CHBP could be detected in U937 cells infected with B. pseudomallei by immunofluorescence microscopy and Western blotting in a manner dependent on bsaQ. Unlike E. coli Cif, CHBP was localized within the cytoplasm of B. pseudomallei infected cells. A B. pseudomallei chbP insertion mutant showed a significant reduction in cytotoxicity and plaque formation compared to the wild-type strain that could be restored by plasmid-mediated trans-complementation. However, there was no defect in actin-based motility or multinucleated giant cell formation by the chbP mutant. The data suggest that the level or timing of CHBP secretion differs from a known Bsa-secreted effector and that CHBP is required for selected virulence-associated phenotypes in vitro. PMID- 24809952 TI - Learning histology - dental and medical students' study strategies. AB - PURPOSE: Histology, the science of cells and tissues at the microscopic level, is an integral component of most dental and medical curricula and is often taught using both traditional and novel computer-based didactic approaches. The purpose of this study was to analyse the strategies used by dental and medical students when studying this very visual and challenging subject. METHODS: Data were collected from 75 dental and 143 medical students, who had almost identical histology learning resources at their disposal. RESULTS: When compared with their medical counterparts, dental students view histology as a more difficult subject and as less relevant for their future career. Whereas dental students, who are required to attend class unlike medical students, made more use of in-classroom learning opportunities, they did not take as much advantage of out-of-classroom resources. In addition, dental students reported a significantly higher tendency than medical students to work together, rather than to study alone. DISCUSSION: Small differences in the dental versus the medical learning environment associate with several observed differences in learning strategies that are adopted by dental and medical students. CONCLUSIONS: These differences should be considered when teaching the subject of histology to dental or to medical students. PMID- 24809954 TI - Validating the Western Neuro Sensory Stimulation Profile for patients with severe traumatic brain injury who are slow-to-recover. AB - BACKGROUND/AIM: The Western Neuro Sensory Stimulation Profile (WNSSP) is designed to measure disorders of consciousness in people with severe traumatic brain injury who are slow-to-recover. This study explores internal consistency reliability and concurrent validity of the WNSSP with function and two other consciousness measures. METHOD: Retrospective chart audit of all severe traumatic brain injury patients admitted to a specialist neurological rehabilitation centre from January 2001 to December 2006 in a vegetative or minimally conscious state. Medical record of demographical, clinical and Glasgow Coma Scale (GCS) data were recorded. To be included in the study, patients needed admission and discharge WNSSP results; plus Functional Independence MeasureTM (FIMTM) and Rancho Los Amigos Scale (RLAS) scores. RESULTS: Of 37 potential participants, 33 had required WNSSP results (mean age 28 years; 27 male participants). Internal consistency reliability was very high (alpha = 0.933). Concurrent validity in relation to function was significant but weak at admission for FIMTM Total-scale but not subscales (rs = -0.146, P = 0.0424). At discharge, there was a modest relationship with FIMTM Motor-subscale (rs = 0.374; P = 0.045), and FIMTM Cognition-subscale (rs = 0.412; P = 0.026) scores, but not the FIMTM Total scale. Concurrent validity in relation to the RLAS was strong at admission (rs = 0.693, P = 0.01) and discharge (rs = 0.788, P = 0.01). The WNSSP and GCS scores were not associated. CONCLUSION: The WNSSP is sensitive to behavioural change in slow-to-recover patients with severe traumatic brain injury. It demonstrates very high internal consistency reliability, and positive evidence of concurrent validity with FIMTM and the RLAS providing detailed description of cognitive sensory behaviour within RLAS-levels. PMID- 24809953 TI - Novel N-linked aminopiperidine-based gyrase inhibitors with improved hERG and in vivo efficacy against Mycobacterium tuberculosis. AB - DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis. PMID- 24809955 TI - Throwing out the baby with the bathwater?: Comparing 2 approaches to implausible values of change in body size. AB - BACKGROUND: In childhood obesity research, the appearance of height loss, or "shrinkage," indicates measurement error. It is unclear whether a common response -excluding "shrinkers" from analysis--reduces bias. METHODS: Using data from the National Longitudinal Study of Adolescent Health, we sampled 816 female adolescents (>=17 years) who had attained adult height by 1996 and for whom adult height was consistently measured in 2001 and 2008 ("gold-standard" height). We estimated adolescent obesity prevalence and the association of maternal education with adolescent obesity under 3 conditions: excluding shrinkers (for whom gold standard height was less than recorded height in 1996), retaining shrinkers, and retaining shrinkers but substituting their gold-standard height. RESULTS: When we estimated obesity prevalence, excluding shrinkers decreased precision without improving validity. When we regressed obesity on maternal education, excluding shrinkers produced less valid and less precise estimates. CONCLUSION: In some circumstances, ignoring shrinkage is a better strategy than excluding shrinkers. PMID- 24809959 TI - Processing Conventional Conceptual Metaphors in Persian: A Corpus-Based Psycholinguistic Study. AB - Research on the psycholinguistic processing of conceptual metaphors has produced contrasting results in recent years. There have also been criticisms that in experimental studies of metaphor processing, linguistic stimuli are mostly intuition-based and not designed objectively based on the original language use data. To address these issues, we studied the processing of conventional metaphoric expressions in Persian language using corpus data. A reading time experiment was designed to test whether conventional metaphoric expressions activated conceptual metaphors. A corpus of 50 million word tokens was used to study the conventional patterns of metaphoric expressions usages and construct experimental items. Fifty five Persian speakers read a set of scenarios containing non-conventional metaphor, conventional metaphor and non-metaphor expressions on computer and the reading times of the following novel target sentence in each condition were recorded by DMDX stimulus presenter program. Comparing mean reading times using one-way ANOVA revealed that reading target sentence after conventional metaphor scenarios had been significantly faster than non-metaphor scenarios, but slower than non-conventional scenarios. The results show that conventionality has a weakening effect on the strength of metaphoric expressions to activate conceptual metaphors. PMID- 24809956 TI - Effects of temperature and relative humidity on DNA methylation. AB - BACKGROUND: Previous studies have found relationships between DNA methylation and various environmental contaminant exposures. Associations with weather have not been examined. Because temperature and humidity are related to mortality even on non-extreme days, we hypothesized that temperature and relative humidity may affect methylation. METHODS: We repeatedly measured methylation on long interspersed nuclear elements (LINE-1), Alu, and 9 candidate genes in blood samples from 777 elderly men participating in the Normative Aging Study (1999 2009). We assessed whether ambient temperature and relative humidity are related to methylation on LINE-1 and Alu, as well as on genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. We examined intermediate-term associations of temperature, relative humidity, and their interaction with methylation, using distributed lag models. RESULTS: Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5 degrees C increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (-8% to -1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days. CONCLUSIONS: DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may also interact to produce stronger effects. PMID- 24809960 TI - How do we communicate health risks clearly? PMID- 24809962 TI - Gill reaction to pollutants from the Tamis River in three freshwater fish species, Esox lucius L. 1758, Sander lucioperca (L. 1758) and Silurus glanis L. 1758: a comparative study. AB - The study evaluated the effects of waterborne pollutants from the Tamis River on gill histology and possible differences in gill reaction patterns between three freshwater fish species, pike Esox lucius L. 1758, pike-perch Sander lucioperca (L. 1758) and wels catfish Silurus glanis L. 1758 from the Tamis River. Gills from analysed fish species showed moderate to intense histopathological alterations. The most frequent progressive alteration was hyperplasia of epithelium, whereas the most frequent regressive alteration was epithelial lifting. Circulatory disturbances were most often manifested in the form of hyperaemia. During comparative analysis, differences in gill indices, reaction and alteration indices, as well as in gill and filament prevalence between analysed species, were observed. Although all analysed fish species did show both progressive and regressive alterations, there was a significant difference in the level of expression of these reaction patterns. Gill index obtained for pike clearly stands out as the lowest. Wels catfish showed the highest progressive reaction index, significantly higher in comparison with the other two species (P < 0.05), while pike-perch showed the highest regressive reaction index, also significantly higher in comparison with the other species (P < 0.001). These results may implicate species-specific gill reactions and thus present a useful tool for better understanding toxic mechanisms of various pollutants. PMID- 24809963 TI - Single-nucleotide polymorphisms and activity analysis of the promoter and enhancer of the pig lactase gene. AB - Lactose intolerance in northern Europeans is strongly associated with a single nucleotide polymorphism (SNP) located 14 kb upstream of the human lactase gene: 13,910 C/T. We examined whether SNPs in the 5' flanking region of the pig lactase gene are similar to those in the human gene and whether these polymorphisms play a functional role in regulating pig lactase gene expression. The 5' flanking region of the lactase gene from several different breeds of pigs was cloned and analyzed for gene regulatory activity of a luciferase reporter gene. One SNP was found in the enhancer region (-797 G/A) and two were found in the promoter region (-308G/C and -301 A/G). The promoter C-308,G-301(Pro-CG) strongly promotes the expression of the lactase gene, but the promoter G-308,A-301(Pro-GA) does not. The enhancer A-797(Enh-A) genotype for Pro-GA can significantly enhance promoter activity, but has an inhibitory effect on Pro-CG. The Enhancer G-797(Enh-G) has a significant inhibitory effect on both promoters. In conclusion, the order of effectiveness on the pig lactase gene is Enh-A+Pro-GA>Enh-A/G+Pro-CG>Enh-G+Pro GA. PMID- 24809961 TI - Genomic landscape of human, bat, and ex vivo DNA transposon integrations. AB - The integration and fixation preferences of DNA transposons, one of the major classes of eukaryotic transposable elements, have never been evaluated comprehensively on a genome-wide scale. Here, we present a detailed study of the distribution of DNA transposons in the human and bat genomes. We studied three groups of DNA transposons that integrated at different evolutionary times: 1) ancient (>40 My) and currently inactive human elements, 2) younger (<40 My) bat elements, and 3) ex vivo integrations of piggyBat and Sleeping Beauty elements in HeLa cells. Although the distribution of ex vivo elements reflected integration preferences, the distribution of human and (to a lesser extent) bat elements was also affected by selection. We used regression techniques (linear, negative binomial, and logistic regression models with multiple predictors) applied to 20 kb and 1-Mb windows to investigate how the genomic landscape in the vicinity of DNA transposons contributes to their integration and fixation. Our models indicate that genomic landscape explains 16-79% of variability in DNA transposon genome-wide distribution. Importantly, we not only confirmed previously identified predictors (e.g., DNA conformation and recombination hotspots) but also identified several novel predictors (e.g., signatures of double-strand breaks and telomere hexamer). Ex vivo integrations showed a bias toward actively transcribed regions. Older DNA transposons were located in genomic regions scarce in most conserved elements-likely reflecting purifying selection. Our study highlights how DNA transposons are integral to the evolution of bat and human genomes, and has implications for the development of DNA transposon assays for gene therapy and mutagenesis applications. PMID- 24809964 TI - Molecular cloning of two tropomyosin family genes and expression analysis during development in oriental river prawn, Macrobrachium nipponense. AB - This paper reports that Slow-tonic S2 tropomyosin (Sst) and Slow tropomyosin isoform (Sti) was highly expressed in androgenic gland transcriptome of Macrobrachium nipponense, which may play crucial roles in sexual differentiation to maleness. In this study, two Sst and Sti gene homologues designated as Mnsst and Mnsti were cloned and characterized from a freshwater prawn M. nipponense. The full-length cDNA of Mnsst and Mnsti consists of 997 bp and 1926 bp, respectively, with an ORF of 852 bp encoding 284 amino acids, and the similarity in ORF reached to 95.82%. The deduced amino acid sequences of Mnsst and Mnsti shared the highest identity with Slow-tonic S2 tropomyosin and Slow tropomyosin isoform of Homarus americanus. Real-time quantitative RT-PCR showed that the Mnsst and Mnsti genes were expressed in different tissues with the highest level of expression in the androgenic gland, implying that these two genes may be related to sex-determination in M. nipponense. Real-time quantitative RT-PCR revealed that in addition, Mnsst and Mnsti were speculated to be related with embryonic organogenesis of M. nipponense, especially for the formation of complete mouthpart and digestive organ and stimulating larval changes of morphology and initiate metamorphosis, the results of present study implied that the two genes may play complex and important roles in sex differentiation of M. nipponense. Thus, we isolated two candidate genes that may advance the studies of sex-determination mechanism in M. nipponense and even the whole crustacean species, as well as promoting the all-male population culture of M. nipponense. PMID- 24809966 TI - Octanuclear [Ni(II)4Ln(III)4] complexes. Synthesis, crystal structures and magnetocaloric properties. AB - Two original heterooctanuclear [Ni(II)4Ln(III)4] complexes (Ln(III) = Sm(III), Gd(III)) have been obtained starting from the [Ni(II)(valpn)(H2O)2] mononuclear precursor [H2valpn = 1,3-propanediylbis(2-iminomethylene-6-methoxy-phenol)] and the corresponding lanthanide nitrates, in the presence of azide anions, through slow capture of atmospheric CO2. Three weak and competitive exchange interactions, J(GdGd), J(GdNi), J(NiNi), make the ground state of this magnetic system degenerate at cryogenic temperature and zero field. This, along with the high spin of Gd(III), lead to a significant magnetocaloric effect spread in the temperature range 1 to 20 K (DeltaSm[0-7 T, 3.5 K] = 19 J kg(-1) K(-1)). PMID- 24809965 TI - In silico analysis of expression pattern of a Wnt/beta-catenin responsive gene ANLN in gastric cancer. AB - Actin-binding protein anillin (ANLN) is primarily involved in the cytokinesis and known to be dysregulated in many cancers including gastric cancer (GC). However, the regulation and clinical significance of ANLN in GC are far less clear. In the present study, we aimed to investigate the clinical significance and possible regulators of ANLN in GC. We have identified the Wnt/beta-catenin associated regulation of ANLN by analyzing the in vitro perturbed beta-catenin mRNA expression profiles. Investigating the gastric tumors from publicly available genome-wide mRNA expression profiles, we have identified the over expression of ANLN in gastric tumors. Association between ANLN expression and clinical characteristics of GC showed elevated expression in intestinal type GC. Performing a single sample prediction method across GC mRNA expression profiles, we have identified the over expression of ANLN in proliferative type gastric tumors compared to the invasive and metabolic type gastric tumors. In silico pathway prediction analysis revealed the association between Wnt/beta-catenin signaling and ANLN expression in gastric tumors. Our results highlight that expression of a Wnt/beta-catenin responsive gene ANLN in GC is a molecular predictor of intestinal and proliferative type gastric tumors. PMID- 24809967 TI - Theodore Leon 'Ted' Munsat MD (1930-2013). PMID- 24809968 TI - Hydrogels for lung tissue engineering: Biomechanical properties of thin collagen elastin constructs. AB - In this study, collagen-elastin constructs were prepared with the aim of producing a material capable of mimicking the mechanical properties of a single alveolar wall. Collagen has been used in a wide range of tissue engineering applications; however, due to its low mechanical properties its use is limited to non load-bearing applications without further manipulation using methods such as cross-linking or mechanical compression. Here, it was hypothesised that the addition of soluble elastin to a collagen hydrogel could improve its mechanical properties. Hydrogels made from collagen only and collagen plus varying amounts elastin were prepared. Young's modulus of each membrane was measured using the combination of a non-destructive indentation and a theoretical model previously described. An increase in Young's modulus was observed with increasing concentration of elastin. The use of non-destructive indentation allowed for online monitoring of the elastic moduli of cell-seeded constructs over 8 days. The addition of lung fibroblasts into the membrane increased the stiffness of the hydrogels further and cell-seeded collagen hydrogels were found to have a stiffness equal to the theoretical value for a single alveolar wall (~5kPa). Through provision of some of the native extracellular matrix components of the lung parenchyma these scaffolds may be able to provide an initial building block toward the regeneration of new functional lung tissue. PMID- 24809969 TI - TVAR modeling of EEG to detect audio distraction during simulated driving. AB - OBJECTIVE: The objective of our current study was to look for the EEG correlates that can reveal the engaged state of the brain while undertaking cognitive tasks. Specifically, we aimed to identify EEG features that could detect audio distraction during simulated driving. APPROACH: Time varying autoregressive (TVAR) analysis using Kalman smoother was carried out on short time epochs of EEG data collected from participants as they undertook two simulated driving tasks. TVAR coefficients were then used to construct all pole model enabling the identification of EEG features that could differentiate normal driving from audio distracted driving. MAIN RESULTS: Pole analysis of the TVAR model led to the visualization of event related synchronization/desynchronization (ERS/ERD) patterns in the form of pole displacements in pole plots of the temporal EEG channels in the z plane enabling the differentiation of the two driving conditions. ERS in the EEG data has been demonstrated during audio distraction as an associated phenomenon. SIGNIFICANCE: Visualizing the ERD/ERS phenomenon in terms of pole displacement is a novel approach. Although ERS/ERD has previously been demonstrated as reliable when applied to motor related tasks, it is believed to be the first time that it has been applied to investigate human cognitive phenomena such as attention and distraction. Results confirmed that distracted/non-distracted driving states can be identified using this approach supporting its applicability to cognition research. PMID- 24809970 TI - Review and analysis of differing regulatory indications and expert panel guidelines for the treatment of hyponatremia. AB - INTRODUCTION AND OBJECTIVE: As evidence grows about the management of hyponatremia, a number of different international and national recommendations/guidelines from professional organizations have recently been published that offer guidance on decision-making. However, they include several important differences that could confuse practising physicians. This article summarizes the key differences in guideline recommendations by various independent groups, taking the marketing authorizations granted by different regulatory agencies into account. It proposes a synthesis of implications for practising physicians as a practical method for resolving these differences as they relate to everyday clinical practice. METHODS: The authors reviewed all recent guidelines and consensus documents worldwide to assess differences and similarities. They also reviewed licensed indications for therapeutic agents in hyponatremia. RESULTS: The actual indications for the only pharmacological therapy approved across three continents for the treatment of hyponatremia--the vaptans--differ substantially around the world. The numerous treatment guidelines published to date also fail to achieve agreement on hyponatremia management. The possible reasons for these differences are explored in this paper. The authors emphasize the crucial role that clinical judgment must continue to play in decision-making about the management of hyponatremia in individual patients. Such judgments should take into account appropriate appraisals of evidence by authoritative experts in the field, as well as the decisions of regulatory agencies that have based their approvals on a critical review of the efficacy and safety data for approved treatments for hyponatremia. CONCLUSION: It is clinical judgment rather than guidelines that should dictate the ultimate choices physicians make for their patients, not only in hyponatremia, but in all aspects of medicine. PMID- 24809972 TI - Pulmonary haemorrhage from therapeutic rivaroxaban use: chest radiograph consolidation is not always infection! PMID- 24809971 TI - From Haiti to the Amazon: public health issues related to the recent immigration of Haitians to Brazil. PMID- 24809974 TI - A special issue on infections in solid organ transplant recipients. PMID- 24809975 TI - Barriers to cooperation aid ideological rigidity and threaten societal collapse. AB - Understanding the factors that promote, disrupt, or shape the nature of cooperation is one of the main tasks of evolutionary biology. Here, we focus on attitudes and beliefs supportive of in-group favoritism and strict adherence to moral consensus, collectively known as ideological rigidity, that have been linked with both ends of the political spectrum. The presence among the political right and the left is likely to make ideological rigidity a major determinant of the political discourse with an important social function. To better understand this function, we equip the indirect reciprocity framework--widely used to explain evaluation-mediated social cooperation--with multiple stylized value systems, each corresponding to the different degree of ideological rigidity. By running game theoretical simulations, we observe the competitive evolution of these systems, map conditions that lead to more ideologically rigid societies, and identify potentially disastrous outcomes. In particular, we uncover that barriers to cooperation aid ideological rigidity. The society may even polarize to the extent where social parasites overrun the population and cause the complete collapse of the social structure. These results have implications for lawmakers globally, warning against restrictive or protectionist policies. PMID- 24809977 TI - Neurosteroids allopregnanolone sulfate and pregnanolone sulfate have diverse effect on the alpha subunit of the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 expressed in xenopus oocytes. AB - BACKGROUND: The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of gamma-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels. METHODS: Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 alpha subunits. RESULTS: APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 +/ 4 (n = 6), 41 +/- 2 (n = 7), and 131 +/- 15 (n = 5) MUmol/l (mean +/- SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all alpha subunits, while they showed different actions on activation of each alpha subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7. CONCLUSION: APAS and PAS have diverse effects on sodium currents in oocytes expressing four alpha subunits. APAS inhibited the sodium currents of Nav1.2 most strongly. PMID- 24809976 TI - Early effect of tidal volume on lung injury biomarkers in surgical patients with healthy lungs. AB - BACKGROUND: The early biological impact of short-term mechanical ventilation on healthy lungs is unknown. The authors aimed to characterize the immediate tidal volume (VT)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications. METHODS: Twenty-eight healthy patients for knee replacement surgery were prospectively randomized to volume controlled ventilation with VT 6 (VT6) or 10 (VT10) ml/kg predicted body weight. General anesthesia and other ventilatory parameters (positive end-expiratory pressure, 5 cm H2O, FIO2, 0.5, respiratory rate titrated for normocapnia) were managed similarly in the two groups. Exhaled breath condensate and blood samples were collected for nitrite, nitrate, tumor necrosis factor-alpha, interleukins 1beta, -6, -8, -10, -11, neutrophil elastase, and Clara Cell protein 16 measurements, at the onset of ventilation and 60 min later. RESULTS: No significant differences in biomarkers were detected between the VT groups at any time. The coefficient of variation of exhaled breath condensate nitrite and nitrate decreased in the VT6 but increased in the VT10 group after 60-min ventilation. Sixty-minute ventilation significantly increased plasma neutrophil elastase levels in the VT6 (35.2 +/- 30.4 vs. 56.4 +/- 51.7 ng/ml, P = 0.008) and Clara Cell protein 16 levels in the VT10 group (16.4 +/- 8.8 vs. 18.7 +/- 9.5 ng/ml, P = 0.015). Exhaled breath condensate nitrite correlated with plateau pressure (r = 0.27, P = 0.042) and plasma neutrophil elastase (r = 0.44, P = 0.001). Plasma Clara Cell protein 16 correlated with compliance (r = 0.34, P = 0.014). CONCLUSIONS: No tidal volume-related changes were observed in the selected lung injury biomarkers of patients with healthy lungs after 60-min ventilation. Plasma neutrophil elastase and plasma Clara Cell protein 16 might indicate atelectrauma and lung distention, respectively. PMID- 24809978 TI - The bacteriocin sublancin attenuates intestinal injury in young mice infected with Staphylococcus aureus. AB - Sublancin, a bacteriocin, has bactericidal activity against a broad spectrum of gram-positive bacteria. However, studies have not been conducted to determine its in vivo efficacy against potential pathogens. The objective of this study was to investigate the effects of sublancin in a Staphylococcus aureus (S. aureus) infected mouse model which induced intestinal injury. A total of 160, 4-week-old mice were randomly assigned to one of eight treatments. Mice in the control group were injected intraperitoneally with 0.5 mL of 0.9% saline. Mice in the other seven groups were given an intraperitoneal injection of 0.5 mL saline containing 1.0 * 10(10) colony-forming units (CFU)/mL S. aureus. Six hours after inoculation, mice in the control group were again injected with 0.5 mL of 0.9% saline. Mice in the other seven groups were injected intraperitoneally with 0.5 mL of 0.9% saline containing 0, 0.5, 1.0, 2.0, or 4.0 mg/kg body weight (BW) sublancin or 1.0 or 2.0 mg/kg BW ampicillin. The results showed that 4.0 mg/kg sublancin and 2.0 mg/kg ampicillin significantly reduced mice mortality from 55 to 10%. The height and the number of proliferated cells from the intestinal villi in the sublancin and ampicillin treated mice were higher than in the control. We conclude that sublancin has potent antibacterial activity against S. aureus. Therefore, sublancin could find use as an alternative antimicrobial agent for the treatment of gram-positive bacterial infections. PMID- 24809980 TI - Methodology or method? A critical review of qualitative case study reports. AB - Despite on-going debate about credibility, and reported limitations in comparison to other approaches, case study is an increasingly popular approach among qualitative researchers. We critically analysed the methodological descriptions of published case studies. Three high-impact qualitative methods journals were searched to locate case studies published in the past 5 years; 34 were selected for analysis. Articles were categorized as health and health services (n=12), social sciences and anthropology (n=7), or methods (n=15) case studies. The articles were reviewed using an adapted version of established criteria to determine whether adequate methodological justification was present, and if study aims, methods, and reported findings were consistent with a qualitative case study approach. Findings were grouped into five themes outlining key methodological issues: case study methodology or method, case of something particular and case selection, contextually bound case study, researcher and case interactions and triangulation, and study design inconsistent with methodology reported. Improved reporting of case studies by qualitative researchers will advance the methodology for the benefit of researchers and practitioners. PMID- 24809979 TI - Proteomic analysis of mesenchymal stem cells from normal and deep carious dental pulp. AB - Dental pulp stem cells (DPSCs), precursor cells of odontoblasts, are ideal seed cells for tooth tissue engineering and regeneration. Our previous study has demonstrated that stem cells exist in dental pulp with deep caries and are called carious dental pulp stem cells (CDPSCs). The results indicated that CDPSCs had a higher proliferative and stronger osteogenic differentiation potential than DPSCs. However, the molecular mechanisms responsible for the biological differences between DPSCs and CDPSCs are poorly understood. The aim of this study was to define the molecular features of DPSCs and CDPSCs by comparing the proteomic profiles using two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) in combination with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Our results revealed that there were 18 protein spots differentially expressed between DPSCs and CDPSCs in a narrow pH range of 4 to 7. These differently expressed proteins are mostly involved in the regulation of cell proliferation, differentiation, cell cytoskeleton and motility. In addition, our results suggested that CDPSCs had a higher expression of antioxidative proteins that might protect CDPSCs from oxidative stress. This study explores some potential proteins responsible for the biological differences between DPSCs and CDPSCs and expands our understanding on the molecular mechanisms of mineralization of DPSCs in the formation of the dentin-pulp complex. PMID- 24809981 TI - Subcutaneous bortezomib is highly effective for pure red cell aplasia after ABO incompatible haematopoietic stem cell transplantation. PMID- 24809982 TI - A long non-coding RNA signature to improve prognosis prediction of colorectal cancer. AB - Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-mining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this six-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC. PMID- 24809983 TI - p21 and p27 a shared senescence history. PMID- 24809984 TI - Robust phase unwrapping for MR temperature imaging using a magnitude-sorted list, multi-clustering algorithm. AB - PURPOSE: Several methods in MRI use the phase information of the complex signal and require phase unwrapping (e.g., B0 field mapping, chemical shift imaging, and velocity measurements). In this work, an algorithm was developed focusing on the needs and requirements of MR temperature imaging applications. METHODS: The proposed method performs fully automatic unwrapping using a list of all pixels sorted by magnitude in descending order and creates and merges clusters of unwrapped pixels until the entire image is unwrapped. The algorithm was evaluated using simulated phantom data and in vivo clinical temperature imaging data. RESULTS: The evaluation of the phantom data demonstrated no errors in regions with signal-to-noise ratios of at least 4.5. For the in vivo data, the algorithm did not fail at an average of more than one pixel for signal-to-noise ratios greater than 6.3. Processing times less than 30 ms per image were achieved by unwrapping pixels inside a region of interest (53 * 53 pixels) used for referenceless MR temperature imaging. CONCLUSIONS: The algorithm has been demonstrated to operate robustly with clinical in vivo data in this study. The processing time for common regions of interest in referenceless MR temperature imaging allows for online updates of temperature maps without noticeable delay. PMID- 24809985 TI - Multiple-Family Group Intervention for Incarcerated Male Adolescents Who Sexually Offend and Their Families: Change in Maladaptive Emotion Regulation Predicts Adaptive Change in Adolescent Behaviors. AB - The multiple-family group intervention is an effective, yet affordable, 8-week treatment that is conducted in a juvenile correctional institution in Alabama with adolescents who sexually offend and their families. Data from 115 incarcerated male adolescents and their male and female caregivers collected at pre-, post-, and 1-year follow-up were used to determine that problem behaviors (internalizing, externalizing) decreased over pre- and posttest and the significant decreases in maladaptive emotion regulation predicted those changes. Adolescent-reported anxiety over abandonment and attachment dependence on parents increased significantly; these changes were predicted by decreases in maladaptive emotion regulation. Linear growth models were also fit over the 3 time points and indicate decreases in adolescent problem behavior and maladaptive emotion regulation. PMID- 24809986 TI - Management of thoracic endometriosis: single institution experience. AB - OBJECTIVE: Thoracic endometriosis is a relatively rare type of endometriosis and includes catamenial pneumothorax, hemothorax and hemoptysis, and presence of intrathoracic endometriotic nodules. We want to clarify and resume the most appropriate management of this pathology. STUDY DESIGN: We retrospectively reviewed all the cases of thoracic endometriosis diagnosed and followed up in our Unit from 2005 to 2013. This search revealed five women, with a mean age of 34.5 (26-44). Four had previous history of endometriosis or severe dysmenorrhea. One patient complained of chronic shoulder pain with diaphragmatic implants, another one presented catamenial hemoptysis, and three women suffered from catamenial pneumothorax, with right-side preference. RESULTS: Three patients underwent surgery and all of them were treated with GnRH agonists at least during 6 month referring improvement in symptoms. After 1-8 years follow-up, all these patients remain asymptomatic. CONCLUSION: The optimal management of thoracic endometriosis needs further evaluation but the combined approach by hormonal therapy and surgery could be the best option. PMID- 24809987 TI - Hysterectomy rates for benign conditions are declining in Lombardy, Italy: 1996 2010. AB - OBJECTIVE: To analyse the hysterectomy rates (HR) temporal trends for gynecological benign conditions in Lombardy, Northern Italy. STUDY DESIGN: Since 1991, discharges from public or private hospitals have been registered in a standard form (Lombardy Region registry). Women aged >=20 years, residing in Lombardy, who underwent hysterectomy for benign conditions, were included in the study. Admissions were codified according to the ICD-9 and ICD-10. HRs per 1000 women residing in Lombardy, of the same age class, were computed. RESULTS: In 1996-2010, 143,045 hysterectomies were performed for benign indications. HR showed a declining trend (average annual percent change (AAPC) -2.9), mainly due to the falling number of total abdominal hysterectomies (AAPC -5.3). The most remarkable decrease was seen in women aged 45-54 years (HR 8.05 in 1996 and 4.83 in 2010). Leiomyoma was the most frequent indication in women aged <55 years, whereas in older patients it was uterine prolapse. CONCLUSIONS: In 1996-2010, the frequency of hysterectomy in Lombardy fell markedly. This study confirms the declining trend in abdominal hysterectomies observed in most developed countries, though the surgical approaches to hysterectomy differ in different countries. In particular, in Lombardy the proportion of laparoscopically assisted vaginal hysterectomies, though increasing, is low. PMID- 24809988 TI - Influence of an oral contraceptive containing drospirenone on insulin sensitivity of healthy women. AB - OBJECTIVES: Oral contraceptives (OCs) containing androgenic second and third generation progestins decrease insulin sensitivity (SI). In this study we investigated whether an oral contraceptive containing the anti-androgenic progestin drospirenone (DRSP) still alters SI. Lipid modifications were investigated as well. STUDY DESIGN: Eleven young healthy women were allocated to receive for 6 months ethinyl-estradiol (EE) 30MUg plus DRSP (3mg). SI and glucose utilization independent of insulin (Sg) was investigated by the minimal model method. Lipid modifications were also analyzed. RESULTS: SI did not vary during EE/DRSP (from 3.72+/-2.62 to 3.29+/-2.93; p=0.73). Similarly, values of Sg did not vary (from 0.03+/-0.02 to 0.032+/-0.014; p=0.87). An increase was observed in HDL cholesterol (9.4+/-9.8mg/dl; p=0.05) and triglycerides (46.9+/-75.1mg/dl; p=0.046), with no modification in LDL cholesterol (-4.64+/-1.704mg/dl; p=0.6). CONCLUSIONS: EE/DRSP does not deteriorate SI. These results are reassuring for the long-term use of this association. PMID- 24809989 TI - Long-term data on reproductive output and longevity in captive female common marmosets (Callithrix jacchus). AB - The common marmoset (Callithrix jacchus) is widely used in biomedical research, with many housed for breeding purposes world-wide. Significant variation in reproductive output among females has been found compared to other anthropoid primates. The present study explores this reproductive variation, focusing on potential predictors of dam longevity and litter size, as well as changes over time. Back-record analysis was conducted, yielding litter information and reproductive summaries of 360 dams housed at three UK marmoset colonies over four decades (1970s-2000s). Results revealed differences among the colonies, as well as within colonies over decades, suggesting environment may play an important role. Cox proportional hazards regression analyses revealed significant effects of mean litter size and yearly production on dam longevity. Decade, mean inter birth interval and mean dam weight were found to be significant factors explaining dam longevity when looking at colonies individually. The most commonly recorded cause of death was "poor condition." Linear regression models found that no reproductive variable was useful in explaining mean litter size, except dam weight at conception, data which was only consistently recorded at one colony. While triplets were common at all three colonies, these larger litters were consistently associated with higher infant mortality, despite human intervention to improve survival. This study increases our understanding of marmoset reproduction, and possible improvements to practical aspects of colony management to enhance survival and welfare are discussed. PMID- 24809990 TI - Factors associated with early deterioration after spontaneous intracerebral hemorrhage: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke with a poor prognosis overall. We conducted a systematic review and meta-analysis to identify and describe factors associated with early neurologic deterioration (END) after ICH. METHODS: We sought to identify any factor which could be prognostic in the absence of an intervention. The Cochrane Library, EMBASE, the Global Health Library, and PubMed were searched for primary studies from the years 1966 to 2012 with no restrictions on language or study design. Studies of patients who received a surgical intervention or specific experimental therapies were excluded. END was defined as death, or worsening on a reliable outcome scale within seven days after onset. RESULTS: 7,172 abstracts were reviewed, 1,579 full-text papers were obtained and screened. 14 studies were identified; including 2088 patients. Indices of ICH severity such as ICH volume (univariate combined OR per ml:1.37, 95%CI: 1.12-1.68), presence of intraventricular hemorrhage (2.95, 95%CI: 1.57-5.55), glucose concentration (per mmol/l: 2.14, 95%CI: 1.03-4.47), fibrinogen concentration (per g/l: 1.83, 95%CI: 1.03-3.25), and d-dimer concentration at hospital admission (per mg/l: 4.19, 95%CI: 1.88-9.34) were significantly associated with END after random-effects analyses. Whereas commonly described risk factors for ICH progression such as blood pressure, history of hypertension, and ICH growth were not. CONCLUSIONS: This study summarizes the evidence to date on early ICH prognosis and highlights that the amount and distribution of the initial bleed at hospital admission may be the most important factors to consider when predicting early clinical outcomes. PMID- 24809991 TI - Multi-scale analysis of the European airspace using network community detection. AB - We show that the European airspace can be represented as a multi-scale traffic network whose nodes are airports, sectors, or navigation points and links are defined and weighted according to the traffic of flights between the nodes. By using a unique database of the air traffic in the European airspace, we investigate the architecture of these networks with a special emphasis on their community structure. We propose that unsupervised network community detection algorithms can be used to monitor the current use of the airspace and improve it by guiding the design of new ones. Specifically, we compare the performance of several community detection algorithms, both with fixed and variable resolution, and also by using a null model which takes into account the spatial distance between nodes, and we discuss their ability to find communities that could be used to define new control units of the airspace. PMID- 24809992 TI - Drop-in access to specialist services for eating disorders: a qualitative study of patient experiences. AB - Lack of patient motivation and dropout are common problems in the treatment of eating disorders. The present study explored patient experiences with open access to specialist eating disorder services through a drop-in program aiming to enable early identification of eating disorders, address motivational problems, and strengthen the therapeutic alliance. Semi-structured qualitative interviews were used to explore the experiences of 11 individuals attending the program. Results suggest that drop-in access may strengthen the therapeutic alliance, motivate engagement in treatment, and reduce dropout. Strengths and weaknesses of the program are discussed and the need for more systematic research is elaborated. PMID- 24809993 TI - WIC supplement. PMID- 24809994 TI - Infant feeding practices and food consumption patterns of children participating in WIC. AB - OBJECTIVE: To describe feeding practices and food consumption of infants and children participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). DESIGN: National, cross-sectional analysis of 24 hour dietary recall data from the 2008 Feeding Infants and Toddlers Study. PARTICIPANTS: Random sample of infants (6-11 months of age), toddlers (12-23 months of age), and preschoolers (24-47 months of age); WIC participants (n = 794) and nonparticipants (n = 2,477). MAIN OUTCOME MEASURES: Breastfeeding rates, introduction to solids, food consumption. ANALYSIS: Used weighted descriptive statistics, chi-square tests, and t tests to identify dietary outcomes unique to WIC participants vs nonparticipants. RESULTS: Compared with nonparticipants, fewer WIC infants were breastfed (P < .01) and consumed any vegetable (P < .05) but more consumed 100% juice (P < .05). Fewer WIC toddlers and preschoolers consumed any fruit vs nonparticipants (P < .01). The WIC toddlers were more likely to consume any sweet vs nonparticipants (P < .05), especially sugar sweetened beverages (P < .01). Over 80% of all preschoolers consumed any sweet, and nearly half consumed sugar-sweetened beverages on an average day. CONCLUSIONS AND IMPLICATIONS: Findings identify feeding and dietary issues that begin during infancy and are also present in toddler and preschool stages. These findings are useful for WIC nutritionists and health care practitioners to encourage the early development of healthful eating patterns. PMID- 24809995 TI - The influence of the WIC food package changes on the retail food environment in New Orleans. AB - OBJECTIVE: To examine the effect of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) food package changes on availability of healthy foods in small stores. DESIGN: Pre-post comparison group design with repeat in-store observations. SETTING: New Orleans. PARTICIPANTS: Small stores (n = 102; 77% of total) were visited in 2009. Of these, 91% were observed again in 2010, including both WIC (n = 27) and non-WIC (n = 66) stores. INTERVENTION: The 2009 WIC food package changes to include healthier foods. MAIN OUTCOME MEASURES: Change in store availability of fruits, vegetables, lower-fat milks, whole wheat bread, and brown rice. Change in number of varieties and shelf length of fruits and vegetables. ANALYSIS: Difference-in-differences analysis using logit models for change in availability and regression models for change in number of varieties or shelf length. RESULTS: The WIC stores were more likely to improve availability of lower-fat milks than non-WIC stores (adjusted odds ratio, 5.0, 95% confidence interval, 1.2-21.0). An even greater relative improvement was seen with whole grains. The WIC stores showed a relative increase in number of varieties of fresh fruits (0.9 +/- 0.3; P < .01) and shelf length of vegetables (1.2 +/- 0.4 meters; P < .01). CONCLUSIONS AND IMPLICATIONS: Results suggest that WIC changes improved the availability of healthy foods in small stores in New Orleans. Similar changes throughout the country could have a significant impact on neighborhood food environments. PMID- 24809996 TI - Comparison of WIC benefit redemptions in Michigan indicates higher utilization among Arab American families. AB - OBJECTIVE: To assess Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) benefit use across Arab American, Hispanic, and non-Arab/non Hispanic families participating in the Michigan WIC program using point-of-sale Electronic Benefits Transfer data. DESIGN: Cross-sectional analysis using administrative data obtained from the Michigan WIC program, which collects Arab American ethnicity in addition to Hispanic ethnicity and race. SETTING: Michigan. PARTICIPANTS: Families participating in the Michigan WIC program in March, 2012 (n = 152,989). MAIN OUTCOME MEASURE: Families redeeming all WIC benefits. ANALYSIS: Bivariate frequencies and multivariate logistic regression model identified characteristics of families associated with full redemption of WIC food benefits. RESULTS: About 12% of WIC families fully redeemed their benefits in March, 2012. Compared with non-Arab/non-Hispanic families, Arab American WIC families were significantly more likely to use all of their monthly WIC benefits, even after controlling for family characteristics (adjusted odds ratio, 3.6; 95% confidence interval, 3.4-3.8). Rates of redemption for Hispanic families, however, were the same as for non-Arab/non-Hispanic families (adjusted odds ratio, 1.0; 95% confidence interval, 0.9-1.0). CONCLUSIONS AND IMPLICATIONS: State WIC programs moving toward implementation of Electronic Benefits Transfer should consider ways to enhance systems that would allow for more opportunities to conduct targeted analyses of benefit use across participant subpopulations. Findings point to low overall WIC benefit use. Additional research is needed to explore methods to increase benefit use among all WIC populations, including whether specific factors may contribute to higher redemptions among ethnic minorities, and whether they can be translated to other subpopulations. PMID- 24809997 TI - Women, infants, and children cash value voucher (CVV) use in Arizona: a qualitative exploration of barriers and strategies related to fruit and vegetable purchases. AB - OBJECTIVE: Women, Infants, and Children (WIC) cash value vouchers (CVV) have been inconsistently redeemed in Arizona. The objective of this study was to explore perceived barriers to use of CVV as well as strategies participants use to overcome them. DESIGN: Eight focus groups were conducted to explore attitudes and behaviors related to CVV use. SETTING: Focus groups were conducted at 2 WIC clinics in metro-Phoenix, AZ. PARTICIPANTS: Participants in WIC who were at least 18 years of age and primarily responsible for buying and preparing food for their households. PHENOMENON OF INTEREST: Perceived barriers to CVV use and strategies used to maximize their purchasing value. ANALYSIS: Transcripts were analyzed using a general inductive approach to identify emergent themes. RESULTS: Among 41 participants, multiple perceived barriers emerged, such as negative interactions in stores or confusion over WIC rules. Among experienced shoppers, WIC strategies also emerged to deal with barriers and maximize CVV value, including strategic choice of times and locations at which to shop and use of price-matching, rewards points, and other ways to increase purchasing power. CONCLUSIONS AND IMPLICATIONS: Arizona WIC participants perceived barriers that limit easy redemption of CVV. Useful strategies were also identified that could be important to explore further to improve WIC CVV purchasing experiences. PMID- 24809998 TI - A comparison of beverage intakes in US children based on WIC participation and eligibility. AB - OBJECTIVE: To compare beverage intakes for 2- to 4-year-olds based on Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) participation. METHODS: Data from National Health and Nutrition Examination Survey, 2005-2010 were analyzed to assess beverage intakes for 2- to 4-year-olds. Children were classified as WIC participants, low-income nonparticipants, and higher-income nonparticipants. All beverages were manually coded into 6 categories: water, milk, 100% juice, fruit drinks, soda, and low-calorie/diet drinks. Grams, calories, and percent consumers of each beverage were compared across groups. RESULTS: Special Supplemental Nutrition Program for Women, Infants, and Children participants had the highest 100% juice consumption (P = .001) and their milk consumption was similar to higher-income children. Higher income nonparticipants drank significantly less fruit drink (P < .001) and soda (P = .001) than both the WIC participants and low-income nonparticipants. CONCLUSIONS AND IMPLICATIONS: Participation in WIC was related to higher intakes of the beverages provided in food packages for 2- to 4-year-olds. Intakes of fruit juice and sugar-sweetened beverages should be addressed during the WIC nutrition education counseling sessions. PMID- 24809999 TI - Farmers' markets: costs compared with supermarkets, use among WIC clients, and relationship to fruit and vegetable intake and related psychosocial variables. AB - OBJECTIVE: To determine fruit and vegetable (FV) costs at farmers' markets (FMs) and grocery stores, determine Special Supplemental Nutrition Program for Women, Infants, and Children participants' FV intake and psychosocial predictors, and compare FM users and nonusers. METHODS: Prices were collected biweekly from grocery stores and FM vendors. Participants were recruited from Special Supplemental Nutrition Program for Women, Infants, and Children clinic to complete a survey of FV intake, psychosocial variables, and FM usage. RESULTS: The FM cost was greater. A total of 377 participants (51%) used FMs. The FM users more often ate vegetables as snacks and > 1 vegetable per day (P < .05). CONCLUSIONS AND IMPLICATIONS: Despite higher costs, FMs were often used. The FM users had a better vegetable intake pattern. PMID- 24810000 TI - Satisfaction of California WIC participants with food package changes. AB - OBJECTIVE: Assess California Women, Infants, and Children (WIC) participant satisfaction with the 2009 food package revisions and compare satisfaction based on language preference and timing of WIC enrollment relative to the revisions. METHODS: Computer-assisted telephone interviews of 2,996 WIC participants in 2010. RESULTS: Most participants (91.3%) were satisfied with checks for new WIC foods (fruits/vegetables, whole grains, and lower-fat milk) and 82.7% of participants were satisfied with amounts of foods that were reduced in the revised food package (milk, cheese, eggs, and juice). Difficulty using new checks was reported by 13.7% of participants. Compared with English-speaking participants, a higher percentage of Spanish speakers reported satisfaction (P < .01) and a lower percentage reported difficulties using checks (P < .001). A higher percentage of newer enrollees reported satisfaction compared with those participating in WIC before the revisions (P < .01). CONCLUSIONS AND IMPLICATIONS: This research suggests that recent policy change to the WIC food package improves WIC participant access to healthful food options without decreasing satisfaction. PMID- 24810001 TI - Differences in energy and micronutrient intakes among Central Texas WIC infants and toddlers after the package change. AB - OBJECTIVE: To assess nutrient intakes after the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) package changes within an at-risk, majority Hispanic population of WIC infants and toddlers in Central Texas. METHODS: For this cross-sectional observational study, Nutrition Data System for Research was used to collect 24-hour recalls of infants and toddlers from a sample of caregivers in 2009 and 2011. Usual nutrient intakes were estimated and compared with Dietary Reference Intakes using the National Cancer Institute method. Mean single-day nutrient intakes were compared using Mann-Whitney tests. RESULTS: Subjects were children ages 4-24 months (2009, n = 84; 2011, n = 120). After the package change, usual energy intakes exceeded recommended levels for infants (79% in excess of Estimated Energy Requirement), but fell below recommended levels for toddlers (88% below Estimated Energy Requirement). Also after the package change, mean usual intake of vitamin D was below the Estimated Average Requirement for toddlers (6.54 vs 10 MUg), and mean usual intakes of vitamin A and zinc exceeded the Tolerable Upper Intake Level for all groups. CONCLUSIONS AND IMPLICATIONS: Whereas lower energy intake may reduce obesity risk, in toddlers, lower energy intake increases risk for micronutrient deficiencies. Recommendations include culturally appropriate education and reinstatement of previous milk allotment in the toddler package. PMID- 24810002 TI - Accessibility and preferred use of online Web applications among WIC participants with Internet access. AB - OBJECTIVE: This study examined the current technology use of clients in the western Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) region and the preferences these current clients have for using new technologies to interact with WIC. METHODS: Cross-sectional convenience sample for online survey of WIC clients over 2 months in 2011. RESULTS: A weighted sample of 8,144 participants showed that the majority of WIC clients have access to the Internet using a computer or mobile phone. E-mail, texting, and Facebook were technologies most often used for communication. Significant differences (P < .05) existed between age groups and Facebook use, education level and technology use for education delivery, and education level and use of video chat. CONCLUSIONS AND IMPLICATIONS: Technologies should be considered for addressing WIC clients' needs, including use of text messaging and smartphone apps for appointments, education, and other WIC services; online scheduling and nutrition education; and a stronger Facebook presence for connecting with WIC clients and breastfeeding support. PMID- 24810003 TI - Special Supplemental Nutrition Program for Women, Infants, and Children participants perceive that Zobey's Jungle Jive promotes healthy eating and physical activity for their preschool-aged children. PMID- 24810004 TI - Quantification of each serogroup polysaccharide of Neisseria meningitidis in A/C/Y/W-135-DT conjugate vaccine by high-performance anion-exchange chromatography-pulsed amperometric detection analysis. AB - Invasive bacterial meningitis caused by Neisseria meningitidis can be prevented by active immunization with meningococcal polysaccharide or polysaccharide protein conjugate vaccines. In a tetravalent A/C/Y/W-135-DT meningococcal conjugate vaccine vial, or in a final formulated bulk, accurate identification and quantification of each polysaccharide are critical in product release. Determination of sialic acid serogroups (C, W-135, and Y) unambiguously is complex since all these serogroups contribute to the sialic acid monosaccharide peaks that overlap in the high-performance anion-exchange chromatography-pulsed amperometric detection (HPAEC-PAD). We report a quantification method that involves generation of monosaccharide standard plots for respective sugars mannosamine-6-phosphate, sialic acid, galactose- and glucose-derived from hydrolysis of mixtures of the four serogroups A, C, W, and Y reference polysaccharides. These plots were then used to obtain the unknown polysaccharide concentrations of A/C/Y/W-135 in vialed vaccine or from formulated final bulks. We also present our results of the HPAEC-PAD profiles on groups C, W-135, and Y polysaccharides when hydrolyzed individually and/or in mixtures to discuss the individual sialic acid peak contributions. PMID- 24810005 TI - Detection of retinitis pigmentosa by differential interference contrast microscopy. AB - Differential interference contrast microscopy is designed to image unstained and transparent specimens by enhancing the contrast resulting from the Nomarski prism effected optical path difference. Retinitis pigmentosa, one of the most common inherited retinal diseases, is characterized by progressive loss of photoreceptors. In this study, Differential interference contrast microscopy was evaluated as a new and simple application for observation of the retinal photoreceptor layer and retinitis pigmentosa diagnostics and monitoring. Retinal tissues of Royal College of Surgeons rats and retinal-degeneration mice, both well-established animal models for the disease, were prepared as flatmounts and histological sections representing different elapsed times since the occurrence of the disease. Under the microscopy, the retinal flatmounts showed that the mosaic pattern of the photoreceptor layer was irregular and partly collapsed at the early stage of retinitis pigmentosa, and, by the advanced stage, amorphous. The histological sections, similarly, showed thinning of the photoreceptor layer at the early stage and loss of the outer nuclear layer by the advanced stage. To count and compare the number of photoreceptors in the normal and early-retinitis pigmentosa-stage tissues, an automated cell-counting program designed with MATLAB, a numerical computing language, using a morphological reconstruction method, was applied to the differential interference contrast microscopic images. The number of cells significantly decreased, on average, from 282 to 143 cells for the Royal College of Surgeons rats and from 255 to 170 for the retinal degeneration mouse. We successfully demonstrated the potential of the differential interference contrast microscopy technique's application to the diagnosis and monitoring of RP. PMID- 24810006 TI - Congenital cataract surgery during the early enlightenment period and the Stepkins oculists. AB - From antiquity through the Renaissance, congenital blindness was generally regarded as incurable, as noted in both medical and lay publications. The earliest reference to congenital cataract surgery that we identified, reported in 1663, referred to an 18-year-old female treated by English oculist John Stepkins (d. 1652). An examination of the literature related to the Stepkins family reveals the presence of male and female oculists during that period, including his daughter, Lady Theodosia Ivy. Eye waters attributed to Stepkins contained tutty (an oxide of zinc), roses, sugar candy, and other ingredients. Interestingly, John Thomas Woolhouse, the author of the next identified report of congenital cataract surgery in 1706, stated that he was related to Stepkins. Woolhouse reported by 1721 that he had performed 36 congenital cataract surgeries, with the youngest patient being 18 months of age. PMID- 24810007 TI - A care pathway analysis of tuberculosis patients in benin: Highlights on direct costs and critical stages for an evidence-based decision-making. AB - BACKGROUND: Free tuberculosis control fail to protect patients from substantial medical and non-medical expenditure, thus a greater degree of disaggregation of patient cost is needed to fully capture their context and inform policymaking. METHODS: A retrospective cross-sectional study was conducted on a convenience sample of six health districts of Southern Benin. From August 2008 to February 2009, we recruited all smear-positive pulmonary tuberculosis patients treated under the national strategy in the selected districts. Direct out-of-pocket costs associated with tuberculosis, time delays, and care-seeking pattern were collected from symptom onset to end of treatment. RESULTS: Population description and outcome data were reported for 245 patients of whom 153 completed their care pathway. For them, the median overall direct cost was USD 183 per patient. Payments to traditional healers, self-medication drugs, travel, and food expenditures contributed largely to this cost burden. Patient, provider, and treatment delays were also reported. Pre-diagnosis and intensive treatment stages were the most critical stages, with median expenditure of USD 43 per patient and accounting for 38% and 29% of the overall direct cost, respectively. However, financial barriers differed depending on whether the patient lived in urban or rural areas. CONCLUSIONS: This study delivers new evidence about bottlenecks encountered during the TB care pathway. Financial barriers to accessing the free of-charge tuberculosis control strategy in Benin remain substantial for low income households. Irregular time delays and hidden costs, often generated by multiple visits to various care providers, impair appropriate patient pathways. Particular attention should be paid to pre-diagnosis and intensive treatment. Cost assessment and combined targeted interventions embodied by a patient centered approach on the specific critical stages would likely deliver better program outcomes. PMID- 24810008 TI - The effect of health insurance status on the treatment and outcomes of patients with colorectal cancer. AB - BACKGROUND AND OBJECTIVES: Uninsured and underinsured cancer patients often have delayed diagnosis and inferior outcomes. As healthcare reform proceeds in the US, this disparity may gain increasing importance. Our objective was to investigate the impact of health insurance status on the presentation, treatment, and survival among colorectal cancer (CRC) patients. METHODS: A total of 10,692 patients diagnosed with CRC between 2004 and 2008 identified from the Tennessee Cancer Registry were stratified into five groups: Private, Medicare, Military, Medicaid, and uninsured. Multivariable regression models were constructed to test the association of insurance with receipt of recommended adjuvant therapy and overall survival (OS). RESULTS: Uninsured and Medicaid patients were more often African American (AA) and presented with higher stage tumors (P < 0.001). Medicare patients were less likely to receive recommended adjuvant therapy (OR 0.54). Lack of insurance, Medicaid, and failure to receive recommended adjuvant therapy were independently associated with worse OS. CONCLUSIONS: Although uninsured and Medicaid patients receive recommended adjuvant therapy comparable to other patients, they present with later stage disease and have a worse OS. Future studies are needed to better explain these disparities especially in the light of changing healthcare climate in the US. PMID- 24810009 TI - Exercise and food compensation: exploring diet-related beliefs and behaviors of regular exercisers. AB - BACKGROUND: The goal of this qualitative study is to identify common beliefs and behaviors related to exercise and diet. METHODS: Data were collected in focus group discussions with regular exercisers who were physically active between 1 and 5 h per week. Exercise objectives, beliefs and behaviors regarding food intake before, during, and after exercise, consumption of sport supplements, and dietary patterns on sedentary days were explored. All focus groups were audio taped and transcribed verbatim. Transcripts were analyzed using a grounded theory approach. RESULTS: Participants reported that they reward themselves for being active by consuming food. Other exercisers had specific beliefs about dietary needs and how to compensate for exercise-induced losses along with exercise related food likes and dislikes. The participants' food intake also depended on their personal exercise objectives, such as the goal of performing well in competitions. External and physiological factors also played a role in determining participants' dietary patterns. CONCLUSIONS: Results of this study show that exercising and dietary patterns are closely intertwined. In addition, we articulate new hypotheses and outline a research agenda that can help improve how regular exercisers eat. PMID- 24810010 TI - [Sao Paulo residents known as "Southern Yankees" and the "modern disease," namely neurasthenia, in the early decades of the twentieth century]. AB - In a brief period of time the coffee boom, European immigration and the "atlanticization" of various sectors of life saw Sao Paulo transform from a small village into a thriving Atlantic metropolis. In the early decades of the twentieth century, observers described the city as Yankee City, due to its progress and activity. To what extent does neurasthenia, namely "the most modern and American of disorders", tally with that image? After analysis of advertisements, scientific books and texts for the dissemination of science, as well as articles in journals, it can be stated that neurasthenia was prevalent and widespread. This work emphasizes the socio-cultural familiarity of Sao Paulo with the phenomenon of neurasthenia. PMID- 24810011 TI - [From the deposit to the reception accommodation for immigrants: the genesis of an "inspection gateway center" on the path to emigration to Brazil]. AB - The scope of this paper is to reflect upon the emergence and organization of territorial and administrative arrangements, qualified here as inspection gateway centers, for the control and screening of migrants at the moment of entry into Brazil. Between the reuse of existing forms (deposits, warehouses) in the first half of the nineteenth century and the invention of a new form (the inspection gateway center), in the late nineteenth century, long debates mobilizing various actors (in the political, economic, and medical world) revolved around various questions. What is the most appropriate spatial and architectural form for temporary shelter? How to enhance the waiting time to carry out administrative and health controls, making it possible to define the desirable immigrant? PMID- 24810012 TI - [Germany and Brazil, 1870-1945: a relationship between spaces]. AB - Relations between Germany and Brazil were influenced by different spatial orders which co-existed and influenced each other between 1870 and 1945. The article discusses the idea of living in different worlds, and being worlds apart. It argues that the concept of distance changed slowly, but surely, with the rise of modern communication technologies. Hierarchically structured spatial orders of centers and peripheries dominated the relationship in this period. Not only the Germans considered their own space superior, and on a higher level than the Brazilian, many Brazilians of the time agreed with this point of view, but also, since the First World War, were not willing to accept this allegedly natural order of the globe any longer. PMID- 24810013 TI - Biological evaluation of secondary metabolites from the roots of Myrica adenophora. AB - Bioassay-guided fractionation of the roots of Myrica adenophora led to isolation of 24 known compounds and hitherto unknown compounds, including three A-type proanthocyanidins [adenodimerins A-C], two esters of sucrose [myricadenins A and B ], and the phenolic glycoside 6'-O-galloyl orbicularin. Spectroscopic analyses were used to determine their structures. Adenodimerin A, myricananin C, and myricetin showed strong 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities, with SC50 values of 7.9, 16.3, and 15.9 MUM, respectively. Adenodimerin A, myricanone, myricananin C, (-)-myricanol, myricanol 11-O-beta-D glucopyranoside, and myricetin showed stronger 2,2'-azino-bis-3 ethylbenzthiazoline-6-sulphonic acid (ABTS) radical scavenging activities than the positive control, with SC50 values of 7.5, 19.6, 12.0, 22.3, 19.6, and 15.6 MUM, respectively. 5-Deoxymyricanone, porson, 12-hydroxymyricanone (-)-myricanol, and (+)-galeon exhibited anti-tubercular activity against Mycobacterium tuberculosis H37Rv in vitro and MICs values of 25.8, 40.0, 35.8, 30.0, and 15.0 MUg/mL, respectively. Myricadenin A, myricanone, myricananin C, and (-)-myricanol exhibited anti-inflammatory activities in the iNOS assay with EC50 values of 18.1, 1.00, 13.0, and 7.5 MUM, respectively. PMID- 24810014 TI - Biochemical characterization of the castor bean ent-kaurene synthase(-like) family supports quantum chemical view of diterpene cyclization. AB - It has become apparent that plants have extensively diversified their arsenal of labdane-related diterpenoids (LRDs), in part via gene duplication and neo functionalization of the ancestral ent-kaurene synthase (KS) required for gibberellin metabolism. For example, castor bean (Ricinus communis) was previously shown to produce an interesting set of biosynthetically related diterpenes, specifically ent-sandracopimaradiene, ent-beyerene, and ent trachylobane, in addition to ent-kaurene, using four separate diterpene synthases, albeit these remain unidentified. Notably, despite mechanistic similarity of the underlying reaction to that catalyzed by KSs, ent-beyerene and ent-trachylobane synthases have not yet been identified. Given our interest in LRD biosynthesis, and the recent availability of the castor bean genome sequence, a synthetic biology approach was applied to biochemically characterize the four KS(-like) enzymes [KS(L)s] found in Ricinus communis [i.e., the RcKS(L)s]. In particular, using bacteria engineered to produce the relevant ent-copalyl diphosphate precursor and synthetic genes based on the predicted RcKS(L)s, although this ultimately required correction of a "splicing" error in one of the predicted genes, highlighting the dependence of such a synthetic biology approach on accurate gene sequences. Nevertheless, it is possible to assign each of the four RcKS(L)s to one of the previously observed diterpene synthase activities, providing access to functionally enzymes. Intriguingly, the product distribution of the RcKS(L)s seems to support the distinct diterpene synthase reaction mechanism proposed by quantum chemical calculations, rather than the classically proposed pathway. PMID- 24810015 TI - Cellular localization of 5alpha-reductase in the rat cerebellum. AB - The enzyme 5alpha-reductase catalyzes the transformation of progesterone, testosterone, and deoxycorticosterone into 5alpha-reduced metabolites, which are recognized as neurosteroids in the brain with variable potential neuroactivity. Two isoforms of 5alpha-reductase were identified in rodents, and, of these, 5alpha-reductase type 1 (5alpha-R1) is abundantly expressed in the brain. To understand the multiple influences of neurosteroids in the central nervous system, we need to know their region-specific synthesis. The present study reports the detailed localization of 5alpha-R1 in the adult rat cerebellum. The occurrence of 5alpha-R1 was detected by reverse transcription-polymerase chain reaction. The enzyme activity was also detected by thin layer chromatography. Immunocytochemistry showed 5alpha-R1 immunoreactive cells in all cerebellar layers. Multiple immunolabeling revealed that 5alpha-R1 was mainly localized in glia, such as astrocytes and oligodendrocytes. The most intense immunoreactivity for 5alpha-R1 was found in Bergmann glia, and the processes of these glia were associated with dendrites of both Purkinje cells and interneurons in the molecular layer. The 5alpha-R1 in the cerebellum was expressed consistently throughout different ages and sexes, in both gonadectomized and hypophysectomized rats. Thus, 5alpha-R1 may contribute to the formation and maintenance of the cerebellar neurons through 5alpha-reduced metabolites, which are synthesized through a complex interaction between neurons and glia. PMID- 24810016 TI - Light-Induced Structural Change in Iridium Complexes Studied by Electron Spin Resonance. AB - Iridium-based compounds are materials of great interest in the production of highly efficient organic light emitting diodes and several other applications. However, these organometallic compounds present relative low stability due to photodegradation processes still not well understood. In this work we investigated paramagnetic states induced by UV photoexcitation on iridium(III) bis[(4,6-fluorophenyl)-pyridinato-N,C2']picolinate (FIrpic) and iridium(III) tris(2-phenylpyridine) (Ir(ppy)3) complexes dispersed in different polymeric matrices by electron spin resonance (ESR). Photogenerated charged states with relatively strong hyperfine interactions were observed and attributed to matrix/complex charge-transfer processes. Measurements of the signal amplitude decay after photoexcitation interruption were performed as a function of temperature. The photoinduced centers are thermally activated with energy barrier between 0.3 and 0.6 eV. Electronic structure calculations suggest that the signals observed by ESR are associated with metastable negatively charged Ir complexes distorted structures. PMID- 24810018 TI - Conformational changes of globular proteins upon adsorption on a hydrophobic surface. AB - This paper presents a study of protein adsorption and denaturation using coarse grained Monte Carlo simulations with simulated annealing. Intermolecular interactions are modeled using the Miyazawa-Jernigan (MJ) knowledge-based potential for an implicit solvent. Three different hydrophobicity scales are tested for adsorption of fibronectin on a hydrophobic surface. The hydrophobic scale BULDG was chosen for further analysis due to its greater stability during heating and its partial regenerative ability upon slow cooling. Differences between helical and sheet structures are observed upon denaturation -alpha helices undergo spreading of their native helical order to an elliptical perturbed shape, while beta-sheets transform into random coils and other more structured conformations. Electronic calculations carried out on rebuilt all-atom coordinates of adsorbed lysozymes revealed consistent destabilization of helices, while beta sheets show a greater variety of trends. PMID- 24810017 TI - BASI, a potent small molecular inhibitor, inhibits glioblastoma progression by targeting microRNA-mediated beta-catenin signaling. AB - BACKGROUND AND AIMS: The nuclear localization of beta-catenin, a mediator of canonical Wnt signaling, has been indicated in a variety of cancers and is frequently related to tumor progression and metastasis. Therefore, targeting beta catenin is an attractive therapeutic strategy for cancers. METHODS: Herein, we identified a natural, small molecule inhibitor of beta-catenin signaling, BASI, and evaluated its therapeutic efficacy both in vitro and in orthotopic mouse models of glioma. RESULTS: BASI significantly suppressed proliferation and invasion and induced apoptosis in glioblastoma cells and resulted in the remarkable attenuation of orthotopic tumor growth in vivo. Furthermore, we found that BASI altered the expression of several microRNAs, which mediated the posttranscriptional silencing of beta-catenin expression either directly or indirectly through a von Hippel-Lindau (VHL)-mediated beta-catenin degradation pattern. CONCLUSIONS: Taken together, our findings offer preclinical validation of BASI as a promising new type of beta-catenin inhibitor with a mechanism of inhibition that has broad potential for the improved treatment of glioblastoma. PMID- 24810019 TI - 'The Other Side': abuse and maltreatment of children and young people with disabilities. PMID- 24810020 TI - Imperfect physician assistant and physical therapist admissions processes in the United States. AB - We compared and contrasted physician assistant and physical therapy profession admissions processes based on the similar number of accredited programs in the United States and the co-existence of many programs in the same school of health professions, because both professions conduct similar centralized application procedures administered by the same organization. Many studies are critical of the fallibility and inadequate scientific rigor of the high-stakes nature of health professions admissions decisions, yet typical admission processes remain very similar. Cognitive variables, most notably undergraduate grade point averages, have been shown to be the best predictors of academic achievement in the health professions. The variability of non-cognitive attributes assessed and the methods used to measure them have come under increasing scrutiny in the literature. The variance in health professions students' performance in the classroom and on certifying examinations remains unexplained, and cognitive considerations vary considerably between and among programs that describe them. One uncertainty resulting from this review is whether or not desired candidate attributes highly sought after by individual programs are more student-centered or graduate-centered. Based on the findings from the literature, we suggest that student success in the classroom versus the clinic is based on a different set of variables. Given the range of positions and general lack of reliability and validity in studies of non-cognitive admissions attributes, we think that health professions admissions processes remain imperfect works in progress. PMID- 24810021 TI - Molecular structure, quantum mechanical calculation and radical scavenging activities of (E)-4,6-dibromo-2-[(3,5-dimethylphenylimino)methyl]-3-methoxyphenol and (E)-4,6-dibromo-2-[(2,6-dimethylphenylimino)methyl]-3-methoxyphenol compounds. AB - In this study, (E)-4,6-dibromo-2-[(3,5-dimethylphenylimino)methyl]-3 methoxyphenol and (E)-4,6-dibromo-2-[(2,6-dimethylphenylimino)methyl]-3 methoxyphenol compounds have been synthesized and characterized by using X-ray crystallographic method, FT-IR and Density functional method. The molecular geometry, vibrational frequencies of the title compounds in the ground state have been calculated by using B3LYP with the 6-31G(d,p) basis set. The tautomeric form of the compounds has been demonstrated by using single crystal X-ray method, FT IR spectrometer and DFT method. In addition, HOMO-LUMO energy gap, molecular electrostatic potential map and NBO analysis of the compounds are performed at B3LYP/6-31G(d,p) level. It may be remarked that the free radical scavenging activities of the title compounds were assessed using DPPH, DMPD+, and ABTS+ assays. The obtained results show that especially compound 2 has effective DPPH (SC50 1.52+/-0.14 MUg/mL), DMPD+ (SC50 1.22+/-0.21 MUg/mL), and ABTS+ (SC50 3.32+/-0.17 MUg/mL) scavenging activities compared with standards (BHA, rutin, and trolox). PMID- 24810022 TI - Conformational stability, spectroscopic (FT-IR & FT-Raman), HOMO-LUMO, NBO and thermodynamic function of 4-(trifloromethoxy) phenol. AB - FT-IR and FT-Raman spectra of 4-(trifloromethoxy) phenol (4TFMP) have been recorded in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. The total energy calculations of 4TFMP were tried for the possible conformers. The molecular structure, geometry optimization, vibrational frequencies were obtained by the DFT level of theory (B3LYP) with the standard basis sets 6-31+G(d) and 6 311++G(d,p). The harmonic frequencies were calculated and the scaled values were compared with experimental FT-IR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The chemical parameters were calculated from the HOMO and LUMO values. Molecular electrostatic potential (MEP) were calculated and analyzed. The thermodynamic functions (heat capacity, entropy, enthalpy) from spectroscopic data by statistical methods were obtained for the range of temperature 100-1000 K. PMID- 24810023 TI - Raman spectroscopic evaluation of DNA adducts of a platinum containing anticancer drug. AB - Mechanistic understanding of the interaction of drugs with their target molecules is important for better understanding of their mode of action and to improve their efficacy. Carboplatin is a platinum containing anticancer drug, used to treat different type of tumors. In the present work, we applied Raman spectroscopy to study the interaction of carboplatin with DNA at molecular level using different carboplatin-DNA molar ratios. These Raman spectroscopic results provide comprehensive understanding on the carboplatin-DNA interactions and indicate that DNA cross-linked adducts formed by carboplatin are similar to cisplatin adducts. The results indicate that guanine N7 and adenine N7 are the putative sites for carboplatin interaction. It is observed that carboplatin has some affinity toward cytosine in DNA. Phosphate sugar backbone of DNA showed conformation perturbation in DNA which were easily sensible at higher concentrations of carboplatin. Most importantly, carboplatin interaction induces intermediate A- and B-DNA conformations at the cross-linking sites. PMID- 24810024 TI - Synthesis, characterization, and biological activities of two Cu(II) and Zn(II) complexes with one polyquinoline ligand. AB - Two new complexes, [CuLCl]ClO4 (1) and [Zn2L2SO4(H2O)2](ClO4)2 (2) [L=N,N bis(quinolin-2-ylmethyl)quinolin-8-amine], have been synthesized and structurally characterized. The interactions of two complexes with CT-DNA have been investigated by UV absorption, fluorescence spectroscopy, viscosity measurements and gel electrophoresis under physiological conditions. Results show that the complexes bind to CT-DNA with a moderate intercalative mode and exhibit efficient DNA cleavage activity on UV-A light of 365 nm. Furthermore, two complexes could quench the intrinsic fluorescence of BSA in a static quenching process based on BSA binding experiments. Notably, in vitro cytotoxicity study of two complexes on four human tumor cells lines (7404, HeLa, MCF-7, and HepG-2) indicate that both of them have the potential to act as effective anticancer drugs with low IC50 values. PMID- 24810025 TI - Vibrational spectra, theoretical calculations, and structure of 4 silaspiro(3,3)heptane. AB - Theoretical computations have been carried out for 4-silaspiro(3,3)heptane (SSH) in order to calculate its structure and vibrational spectra. SSH was found to have two puckered four-membered rings with dihedral angles of 34.2 degrees and a tilt angle of 9.4 degrees between the two rings. The puckering and tilting reduce the D2d symmetry to C2. Nonetheless, the vibrational assignments can be done quite well on the basis of D2d symmetry. This is confirmed by the fact that all but the lowest E vibrations show insignificant splitting into A and B modes of C2 symmetry. However, the observed splittings of the lowest frequency modes do confirm the lower conformational symmetry. The calculated infrared and Raman spectra were compared to the experimental spectra collected for the vapor, liquid, and solid states, and the agreement is excellent. PMID- 24810026 TI - Development of morin-conjugated Au nanoparticles: exploring the interaction efficiency with BSA using spectroscopic methods. AB - In order to enhance its interaction efficiency with biomacromolecules for the usage as a therapeutic agent, we have conjugated morin, an antioxidant activity and anti-tumor drug, with citrate-coated Au nanoparticles (M-C-AuNPs). M-C-AuNPs were prepared by reducing chloroauric acid using trisodium citrate in the boiling condition, and the resulted M-C-AuNPs were characterized by UV-vis absorption spectroscopy, Transmission Electron Microscopy (TEM), X-ray diffraction (XRD) and FTIR analysis. In this article, UV-vis absorption spectroscopy in combination with fluorescence spectroscopy, and circular dichroism (CD) spectroscopy were employed to investigate the interactions between M-C-AuNPs and bovine serum albumin (BSA), C-AuNPs and BSA in a phosphate buffer at pH 7.4. By comparing the quenching constant KSV, effective quenching constant Ka, binding constant Kb and the number of binding sites n, it is clearly suggested that M-C-AuNPs could enhance the binding force of morin with BSA, which would pave the way for the design of nanotherapeutic agents with improved functionality. PMID- 24810027 TI - Three-dimensional fluorescence characteristics of white chrysanthemum flowers. AB - White chrysanthemum flower is one of the most popular plants found everywhere in China and used as herbs. In the present work, three-dimensional fluorescence technique was used to discriminate species of white chrysanthemum flowers. Parameters affecting extraction efficiency were investigated. Under the optimal conditions, the three-dimensional fluorescence characteristics of three types of white chrysanthemum flowers were obtained. It was found that there were two main fluorescence peaks with remarkable difference in fluorescence intensity, one was corresponding to flavonoids and another was attributed to chlorophyll-like compounds. There were remarkable differences among the contours of the three white chrysanthemum flowers. Further studies showed that the fluorescence intensity ratios of chlorophyll-like compounds to flavonoids had a certain relationship with the species; those for Huai, Hang and Huangshan white chrysanthemum flowers were 6.9-7.4, 18.9-21.4 and 73.6-84.5, respectively. All of the results suggest that three-dimensional fluorescence spectra can be used for the discrimination of white chrysanthemum flowers with the advantages of low cost, ease for operation and intuition. PMID- 24810028 TI - Synthesis, growth, crystal structure and characterization of a new organic NLO crystal: L-lysine 4-nitrophenolate monohydrate (LLPNP). AB - L-lysine 4-nitrophenolate monohydrate (LLPNP) has been synthesized and grown by solution growth method at room temperature using deionised water as a solvent. The crystal structure of the materials was solved by single crystal X-ray diffraction analysis and it was found that the material has orthorhombic system. The crystallinity of the grown crystals was studied by the powder X-ray diffraction analysis. Molecular structure of the grown crystal was investigated by 1H NMR spectroscopy. The various functional groups of the sample were identified by Fourier transform infrared and Fourier transform-Raman spectroscopic analyses. Thermal stability of the grown crystal has been studied by Thermogravimetric and Differential thermal (TG&DTA) analysis. The optical absorption of the grown crystals has been ascertained by UV-Vis-NIR absorption studies. Second harmonic generation (SHG) efficiency of the material has been determined by Kurtz and Perry technique and the efficiency was found to be 4.45 and 1.4 times greater than that of standard KDP and urea samples, respectively. PMID- 24810029 TI - Analysis of solvation and structural contributions in spectral characteristics of dipyrrin Zn(II) complexes. AB - Photophysical characteristics of several alkylated dipyrrin Zn(II) complexes in organic solvents were analyzed. Relations between spectral properties of complexes and physical-chemical parameters of solvents were determined with the use of linear regression analysis method. Each solvent parameter contribution in investigated spectral characteristics was estimated. Spectral properties of complexes under study depend on the specific interactions of zinc with the solvent molecules by specific axial coordination. Increasing of alkyl substitution lead to the bathochromic shifts in spectra due to the positive induction effect of alkyl groups. PMID- 24810030 TI - Spectral characterization, molecular modeling and antimicrobial studies on hydrazone metal complexes of 5-acetyl-4-hydroxy-2H-1,3-thiazine-2,6(3H)dione and S-methyl dithiocarbazate. AB - Metal complexes of copper(II), nickel(II), cobalt(II), oxovanadium(IV), chromium(III) and cadmium(II) with a new bridged ONS dibasic tridentate hydrazone (H2L) derived from 5-acetyl-4-hydroxy-2H-1,3-thiazine-2,6(3H)-dione with S-methyl dithiocarbazate have been synthesized and characterized by elemental analysis, molar conductance, magnetic susceptibility measurements, spectral (infrared, electronic, mass, 1H NMR and ESR) studies as well as thermal gravimetric analysis (TGA). The synthesized complexes have dimeric structures with the general formula [ML(NO3)m(H2O)x]2.nH2O.zMeOH, L=dianion of the hydrazone, m=0-1, x=0-2, n=0-4 and z=0-1. The metal complexes exhibited square planar, tetrahedral and octahedral geometrical arrangements, the molar conductivity data indicates that all complexes are neutral. The Coats-Redfern equation was used to calculate the kinetic and thermodynamic parameters for the different thermal decomposition stages of some complexes. Structural parameters of the ligand and its metal complexes have been theoretically computed on the basis of semiempirical PM3 level and the results were correlated with their experimental data. Antibacterial activities of the free ligand and its metal complexes were screened against various organisms. PMID- 24810035 TI - Barium dibenzopentalenide as a main-group metal eta8 complex: facile synthesis from 1,4-dilithio-1,3-butadienes and Ba[N(SiMe3)2]2, structural characterization, and reaction chemistry. PMID- 24810036 TI - Using TRIP for genome-wide position effect analysis in cultured cells. AB - The influence of local chromatin context on gene expression can be explored by integrating a transcription reporter at different locations in the genome as a sensor. Here we provide a detailed protocol for analyzing thousands of reporters integrated in parallel (TRIP) at a genome-wide level. TRIP is based on tagging each reporter with a unique barcode, which is used for independent reporter expression analysis and integration site mapping. Compared with previous methods for studying position effects, TRIP offers a 100-1,000-fold higher throughput in a faster and less-labor-intensive manner. The entire experimental protocol takes ~42 d to complete, with high-throughput sequencing and data analysis requiring an additional ~11 d. TRIP was developed by using transcription reporters in mouse embryonic stem (mES) cells, but because of its flexibility the method can be used to probe the influence of chromatin context on a variety of molecular processes in any transfectable cell line. PMID- 24810037 TI - Cell type-specific mRNA purification by translating ribosome affinity purification (TRAP). AB - Cellular diversity and architectural complexity create barriers to understanding the function of the mammalian CNS at a molecular level. To address this problem, we have recently developed a methodology that provides the ability to profile the entire translated mRNA complement of any genetically defined cell population. This methodology, which we termed translating ribosome affinity purification, or TRAP, combines cell type-specific transgene expression with affinity purification of translating ribosomes. TRAP can be used to study the cell type-specific mRNA profiles of any genetically defined cell type, and it has been used in organisms ranging from Drosophila melanogaster to mice and human cultured cells. Unlike other methodologies that rely on microdissection, cell panning or cell sorting, the TRAP methodology bypasses the need for tissue fixation or single-cell suspensions (and the potential artifacts that these treatments introduce) and reports on mRNAs in the entire cell body. This protocol provides a step-by-step guide to implement the TRAP methodology, which takes 2 d to complete once all materials are in hand. PMID- 24810038 TI - Engineering genetic circuits that compute and remember. AB - Memory and logic are central to complex state-dependent computing, and state dependent behaviors are a feature of natural biological systems. Recently, we created a platform for integrated logic and memory by using synthetic gene circuits, and we demonstrated the implementation of all two-input logic gates with memory in living cells. Here we provide a detailed protocol for the construction of two-input Boolean logic functions with concomitant DNA-based memory. This technology platform allows for straightforward assembly of integrated logic-and-memory circuits that implement desired behaviors within a couple of weeks. It should enable the encoding of advanced computational operations in living cells, including sequential-logic and biological-state machines, for a broad range of applications in biotechnology, basic science and biosensing. PMID- 24810040 TI - Rethinking production of Taxol(r) (paclitaxel) using endophyte biotechnology. AB - Taxol(r) (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol(r)-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol(r) production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol(r) biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol(r) using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol(r) are discussed. PMID- 24810039 TI - Monitoring protein conformational changes and dynamics using stable-isotope labeling and mass spectrometry. AB - An understanding of the mechanism accompanying functional conformational changes associated with protein activation has important implications for drug design. Here we describe a powerful method, conformational changes and dynamics using stable-isotope labeling and mass spectrometry (CDSiL-MS), which involves chemical labeling by isotope-coded forms of N-ethylmaleimide or succinic anhydride to site specifically label the side chains of cysteines or lysines, respectively, in native proteins. Subsequent MS analysis allows the quantitative monitoring of reactivity of residues as a function of time, providing a measurement of the labeling kinetics and thereby enabling elucidation of conformational changes of proteins. We demonstrate the utility of this method using a model G protein coupled receptor, the beta2-adrenergic receptor, including experiments that characterize the functional conformational changes associated with activation of distinct signaling pathways induced by different beta-adrenoceptor ligands. The procedure requires 5 d, and it can easily be adapted to systems in which soluble and detergent-solubilized membrane protein targets, which undergo function dependent conformational changes, can be interrogated structurally to allow drug screening. PMID- 24810041 TI - Editorial: vitamin D therapy: an update available experimental and clinical evidences to select " which D for which patient". PMID- 24810042 TI - Isothiazolone emissions from building products. AB - Adding biocides to dispersion products is a well-known practice to control microbial deterioration. Isothiazolones are among the most commonly used preservatives, in particular a mixture of 2-methyl-2H-isothiazol-3-one (MIT) and 5-chloro-2-methyl-2H-isothiazol-3-one (CIT). In recent years, for health reasons, due to its strong sensitizing effect, CIT has been replaced by 1,2-benzisothiazol 3-one (BIT). Furthermore, numerous products are now available for interiors containing the fungicidal active substance 2-octyl-2H-isothiazol-3-one (OIT). So far nearly nothing is known of the emission behavior of BIT and OIT. An analytical method was developed for these two isothiazolones and interior products containing BIT respectively OIT have been investigated in an emission chamber and in test rooms. The chamber tests revealed maximum concentrations of 6.7 MUg OIT/m3, 1.9 MUg BIT/m3, and 187 MUg MIT/m3. Concentrations obtained in the test rooms were at levels up to 1.4 MUg OIT/m3 and 29 MUg MIT/m3. A noticeable finding was the very slight subsidence of OIT and BIT levels over several weeks. While MIT outgassed quickly, OIT in particular showed low concentrations, but prolonged evaporation. PMID- 24810043 TI - EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury. AB - Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, have a variety of roles in the developing and adult central nervous system that require direct cell-cell interactions; including regulating axon path finding, cell proliferation, migration and synaptic plasticity. Recently, we identified a novel pro-survival role for ephrins in the adult subventricular zone, where ephrinB3 blocks Eph-mediated cell death during adult neurogenesis. Here, we examined whether EphB3 mediates cell death in the adult forebrain following traumatic brain injury and whether ephrinB3 infusion could limit this effect. We show that EphB3 co-labels with microtubule-associated protein 2-positive neurons in the adult cortex and is closely associated with ephrinB3 ligand, which is reduced following controlled cortical impact (CCI) injury. In the complete absence of EphB3 (EphB3(-/-)), we observed reduced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and functional improvements in motor deficits after CCI injury as compared with wild-type and ephrinB3(-/-) mice. We also demonstrated that EphB3 exhibits dependence receptor characteristics as it is cleaved by caspases and induces cell death, which is not observed in the presence of ephrinB3. Following trauma, infusion of pre-clustered ephrinB3-Fc molecules (eB3-Fc) into the contralateral ventricle reduced cortical infarct volume and TUNEL staining in the cortex, dentate gyrus and CA3 hippocampus of wild-type and ephrinB3(-/-) mice, but not EphB3(-/-) mice. Similarly, application of eB3-Fc improved motor functions after CCI injury. We conclude that EphB3 mediates cell death in the adult cortex through a novel dependence receptor-mediated cell death mechanism in the injured adult cortex and is attenuated following ephrinB3 stimulation. PMID- 24810044 TI - Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice. AB - Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNFalpha), interleukin 6 (IL6) and interferon-gamma were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFalpha. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFalpha and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages. PMID- 24810045 TI - Metformin lowers Ser-129 phosphorylated alpha-synuclein levels via mTOR-dependent protein phosphatase 2A activation. AB - Phospho-Ser129 alpha-synuclein is the modified form of alpha-synuclein that occurs most frequently within Parkinson's disease pathological inclusions. Here we demonstrate that the antidiabetic drug metformin significantly reduces levels of phospho-Ser129 alpha-synuclein and the ratio of phospho-Ser129 alpha-synuclein to total alpha-synuclein. This effect was documented in vitro in SH-SY5Y and HeLa cells as well as in primary cultures of hippocampal neurons. In vitro work also elucidated the mechanisms underlying metformin's action. Following metformin exposure, decreased phospho-Ser129 alpha-synuclein was not strictly dependent on induction of AMP-activated protein kinase, a primary target of the drug. On the other hand, metformin-induced phospho-Ser129 alpha-synuclein reduction was consistently associated with inhibition of mammalian target of rapamycin (mTOR) and activation of protein phosphatase 2A (PP2A). Evidence supporting a key role of mTOR/PP2A signaling included the finding that, similar to metformin, the canonical mTOR inhibitor rapamycin was capable of lowering the ratio of phospho Ser129 alpha-synuclein to total alpha-synuclein. Furthermore, no decrease in phosphorylated alpha-synuclein occurred with either metformin or rapamycin when phosphatase activity was inhibited, supporting a direct relationship between mTOR inhibition, PP2A activation and protein dephosphorylation. A final set of experiments confirmed the effectiveness of metformin in vivo in wild-type C57BL/6 mice. Addition of the drug to food or drinking water lowered levels of phospho Ser129 alpha-synuclein in the brain of treated animals. These data reveal a new mechanism leading to alpha-synuclein dephosphorylation that could be targeted for therapeutic intervention by drugs like metformin and rapamycin. PMID- 24810046 TI - Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer. AB - There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here the anti-tumor effect of the angio-inhibitory pigment epithelium-derived factor (PEDF) in the metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy in combination with low-dose chemotherapy. Androgen sensitive LNCaP and CRPC PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that PEDF limited the proliferation of all prostatic cell lines tested; an effect attributed to interleukin 8 (IL8) CXCR1/IL8RA inhibition. PEDF also reduced the number and size of 3D tumor spheroids in vitro, but only induced cell differentiation in CRPC spheroids. Similarly, PEDF inhibited the migration of CRPC cells suggesting both anti proliferative and anti-migratory functions. In vivo, PEDF decreased by 85% and 65% the growth of subcutaneous (s.c.) PC3 and CL1 tumors, respectively. In the CL1 orthotopic model, tumor intake with lethal metastases was found in all animals; nevertheless, PEDF prolonged the median survival of tumor-bearing mice (95% confidence interval: 53 +/- 0.001 to 57 +/- 1 days). Accordingly, PEDF delayed the emergence of skeletal-related event in intra-tibial xenografts. Next, we evaluated low-dose docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10-20 mg/kg) on established s.c. PC3 tumors that conditionally express PEDF anti tumoral epitope/NT3. Although NT3-DTX-5 mg/kg combination was inefficient, NT3 DTX-1 mg/kg and -0.5 mg/kg inhibited by 95% and 87.8%, respectively, tumor growth compared with control and induced tumor stasis. Both NT3-CTX combinations were advantageous. Inversely, PEDF-DTX-5 mg/kg and PEDF-CTX-10 mg/kg delayed the most CL1 tumor growth (15, 11 and 5 days for PEDF-DTX-5 mg/kg, PEDF-CTX-10 mg/kg and single treatments, respectively) with elevated apoptosis and serum thrombospondin 1 as possible mechanism and marker, respectively. As well, both PEDF-CTX-10 mg/kg and PEDF-DTX-5 mg/kg prolonged significantly the survival of tumor-bearing mice compared with single treatments. Metastases were reduced in PEDF-DTX-5 mg/kg compared with other treatments, suggesting that PEDF-DTX delayed metastases formation. Our results advocate that PEDF/low-dose chemotherapy may represent a new therapeutic alternative for CRPC. PMID- 24810047 TI - Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth. AB - ErbB2, an important membrane-bound receptor tyrosine kinase, was discovered nearly 30 years ago, but a natural ligand has never been found previously. ErbB2 is also an important oncogene and anticancer target, and its overexpression in cancer is associated with poor disease prognosis. Here, we report that human prolidase (PEPD) is a high affinity ligand of ErbB2 and binds as a homodimer to subdomain 3 in the extracellular domain of this receptor. In ErbB2-overexpressing cells, both ErbB2 monomers and activated dimers exist. PEPD bound to ErbB2 monomers relatively slowly but caused ErbB2 dimerization, ErbB2 phosphorylation and downstream signaling. In contrast, PEPD bound rapidly to ErbB2 homodimers and rapidly silenced ErbB2 dimer-Src signaling, a key oncogenic pathway of ErbB2, by disrupting the association of Src with ErbB2. PEPD also caused pronounced ErbB2 depletion, resulting from ErbB2 internalization and degradation. Moreover, PEPD strongly inhibited the DNA synthesis, anchorage-independent growth and invasion and migration of cells that overexpressed ErbB2 but had no effect on cells without ErbB2 overexpression. Cells became sensitized to PEPD upon achieving stable ErbB2 overexpression. Thus, the impact of PEPD on ErbB2 is predominantly inhibitory, and PEPD targets cells addicted to ErbB2. PEPD is also a dipeptidase, but its enzymatic function is not involved in ErbB2 modulation. These findings revise our understanding of ErbB2 and PEPD and may be especially important for combating ErbB2-positive cancers. PMID- 24810048 TI - Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. AB - Oxidative stress serves as an important regulator of both apoptosis and metabolic reprogramming in tumor cells. Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation. As elevating basal ROS level sensitizes glioma cells to apoptosis, the ability of Chaetocin in regulating apoptotic and metabolic adaptive responses in glioma was investigated. Chaetocin induced glioma cell apoptosis in a ROS-dependent manner. Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation. Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner. Chaetocin induced JNK modulated several metabolic parameters like glucose uptake, lactate production, ATP generation, and activity of glycolytic enzymes hexokinase and pyruvate kinase. However, JNK had no effect on ATM or YAP1 expression. Coherent with the in vitro findings, Chaetocin reduced tumor burden in heterotypic xenograft glioma mouse model. Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels. Our study highlights the coordinated control of glioma cell proliferation and metabolism by ROS through (i) ATM-YAP1-driven apoptotic pathway and (ii) JNK-regulated metabolic adaptation. The elucidation of these newfound connections and the roles played by ROS to simultaneously shift metabolic program and induce apoptosis could provide insights toward the development of new anti-glioma strategies. PMID- 24810049 TI - Fas-associated factor (Faf1) is a novel CD40 interactor that regulates CD40 induced NF-kappaB activation via a negative feedback loop. AB - CD40-induced signalling through ligation with its natural ligand (CD40L/CD154) is dependent on recruitment of TRAF molecules to the cytoplasmic domain of the receptor. Here, we applied the yeast two-hybrid system to examine whether other proteins can interact with CD40. Fas-Associated Factor 1(FAF1) was isolated from a HeLa cDNA library using the CD40 cytoplasmic tail (216-278 aa) as a bait construct. FAF1 was able to interact with CD40 both in vitro and in vivo. The FAF1 N-terminal domain was sufficient to bind CD40 and required the TRAF6-binding domain within the cytoplasmic tail of CD40 for binding. CD40 ligation induced FAF1 expression in an NFkappaB-dependent manner. Knockdown of FAF1 prolonged CD40 induced NFkappaB, whereas overexpression of FAF1 suppressed CD40-induced NFkappaB activity and this required interaction of FAF1 with the CD40 receptor via its FID domain. Thus, we report a novel role for FAF1in regulating CD40-induced NFkappaB activation via a negative feedback loop. Loss of FAF1 function in certain human malignancies may contribute to oncogenesis through unchecked NFkappaB activation, and further understanding of this process may provide a biomarker of NFkappaB targeted therapies for such malignancies. PMID- 24810050 TI - Rapamycin reverses insulin resistance (IR) in high-glucose medium without causing IR in normoglycemic medium. AB - Mammalian target of rapamycin (mTOR) is involved in insulin resistance (IR) and diabetic retinopathy. In retinal pigment epithelial (RPE) cells, insulin activates the mTOR pathway, inducing hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-dependent transcription in serum-free minimum essential medium Eagle (MEM). Serendipitously, we found that insulin failed to induce the HIF-1alpha dependent response, when RPE cells were cultured in Dulbecco's modification of Eagle's medium (DMEM). Whereas concentration of glucose in MEM corresponds to normal glucose levels in blood (5.5 mM), its concentration in DMEM corresponds to severe diabetic hyperglycemia (25 mM). Addition of glucose to MEM also caused IR. Glucose-mediated IR was characterized by basal activation of mTORC1 and its poor inducibility by insulin. Basal levels of phosphorylated S6 kinase (S6K), S6 and insulin receptor substrate 1 (IRS1) S635/639 were high, whereas their inducibilities were decreased. Insulin-induced Akt phosphorylation was decreased and restored by rapamycin and an inhibitor of S6K. IR was associated with de phosphorylation of IRS1 at S1011, which was reversed by rapamycin. Both short (16 40 h) and chronic (2 weeks) treatment with rapamycin reversed IR. Furthermore, rapamycin did not impair Akt activation in RPE cells cultured in normoglycemic media. In contrast, Torin 1 blocked Akt activation by insulin. We conclude that by activating mTOR/S6K glucose causes feedback IR, preventable by rapamycin. Rapamycin does not cause IR in RPE cells regardless of the duration of treatment. We confirmed that rapamycin also did not impair phosphorylation of Akt at T308 and S473 in normal myoblast C2C12 cells. Our work provides insights in glucose induced IR and suggests therapeutic approaches to treat patients with IR and severe hyperglycemia and to prevent diabetic complications such as retinopathy. Also our results prompt to reconsider physiological relevance of numerous data and paradigms on IR given that most cell lines are cultured with grossly super physiological levels of glucose. PMID- 24810051 TI - Simultaneous loss of phospholipase Cdelta1 and phospholipase Cdelta3 causes cardiomyocyte apoptosis and cardiomyopathy. AB - Phospholipase C (PLC) is a key enzyme in phosphoinositide turnover. Among 13 PLC isozymes, PLCdelta1 and PLCdelta3 share high sequence homology and similar tissue distribution, and are expected to have functional redundancy in many tissues. We previously reported that the simultaneous loss of PLCdelta1 and PLCdelta3 caused embryonic lethality because of excessive apoptosis and impaired vascularization of the placenta. Prenatal death of PLCdelta1/PLCdelta3 double-knockout mice hampered our investigation of the roles of these genes in adult animals. Here, we generated PLCdelta1/PLCdelta3 double-knockout mice that expressed PLCdelta1 in extra-embryonic tissues (cDKO mice) to escape embryonic lethality. The cDKO mice were born at the expected Mendelian ratio, which indicated that the simultaneous loss of PLCdelta1 and PLCdelta3 in the embryo proper did not impair embryonic development. However, half of the cDKO mice died prematurely. In addition, the surviving cDKO mice spontaneously showed cardiac abnormalities, such as increased heart weight/tibial length ratios, impaired cardiac function, cardiac fibrosis, dilation, and hypertrophy. Predating these abnormalities, excessive apoptosis of their cardiomyocytes was observed. In addition, siRNA-mediated simultaneous silencing of PLCdelta1 and PLCdelta3 increased apoptosis in differentiated-H9c2 cardiomyoblasts. Activation of Akt and protein kinase C (PKC) theta was impaired in the hearts of the cDKO mice. siRNA-mediated simultaneous silencing of PLCdelta1 and PLCdelta3 also decreased activated Akt and PKCtheta in differentiated-H9c2 cardiomyoblasts. These results indicate that PLCdelta1 and PLCdelta3 are required for cardiomyocyte survival and normal cardiac function. PMID- 24810052 TI - Celastrol targets proteostasis and acts synergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells. AB - Glioblastoma multiforme is a devastating disease of the central nervous system and, at present, no effective therapeutic interventions have been identified. Celastrol, a natural occurring triterpene, exhibits potent anti-tumor activity against gliomas in xenograft mouse models. In this study, we describe the cell death mechanism employed by celastrol and identify secondary targets for effective combination therapy against glioblastoma cell survival. In contrast to the previously proposed reactive oxygen species (ROS)-dependent mechanism, cell death in human glioblastoma cells is shown here to be mediated by alternate signal transduction pathways involving, but not fully dependent on, poly(ADP ribose) polymerase-1 and caspase-3. Our studies indicate that celastrol promotes proteotoxic stress, supported by two feedback mechanisms: (i) impairment of protein quality control as revealed by accumulation of polyubiquitinated aggregates and the canonical autophagy substrate, p62, and (ii) the induction of heat-shock proteins, HSP72 and HSP90. The Michael adduct of celastrol and N acetylcysteine, 6-N-acetylcysteinyldihydrocelastrol, had no effect on p62, nor on HSP72 expression, confirming a thiol-dependent mechanism. Restriction of protein folding stress with cycloheximide was protective, while combination with autophagy inhibitors did not sensitize cells to celastrol-mediated cytotoxicity. Collectively, these findings imply that celastrol targets proteostasis by disrupting sulfyhydryl homeostasis, independently of ROS, in human glioblastoma cells. This study further emphasizes that targeting proteotoxic stress responses by inhibiting HSP90 with 17-N-Allylamino-17-demethoxygeldanamycin sensitizes human glioblastoma to celastrol treatment, thereby serving as a novel synergism to overcome drug resistance. PMID- 24810053 TI - Mitochondrial dysfunction driven by the LRRK2-mediated pathway is associated with loss of Purkinje cells and motor coordination deficits in diabetic rat model. AB - Diabetic neuropathy develops on a background of hyperglycemia and an entangled metabolic imbalance. There is increasing evidence of central nervous system involvement in diabetic neuropathy and no satisfactory treatment except maintenance of good glycemic control, thereby highlighting the importance of identifying novel therapeutic targets. Purkinje cells are a class of metabolically specialized active neurons, and degeneration of Purkinje cells is a common feature of inherited ataxias in humans and mice. However, whether Purkinje cells are implicated in diabetic neuropathy development under metabolic stress remains poorly defined. Here, we revealed a novel leucine-rich repeat kinase 2 (LRRK2)-mediated pathway in Purkinje cells that is involved in the pathogenesis of diabetic neuropathy from a 24-week long study of streptozotocin (STZ)-diabetic rats. We found that hyperglycemia, cerebellum proinflammatory cytokines, and chemokines increased markedly in 24-week STZ-diabetic rats. Furthermore, we demonstrated that degeneration of Purkinje cells is characterized by progressive swellings of axon terminals, no autophagosome formation, the reduction of LC3II/LC3I and Lamp2, and accumulation of p62 puncta in 24-week STZ-diabetic rats. Importantly, a higher expression level of LRRK2-mediated hyperphosphorylation of tau along with increased mitochondrial dynamin-like protein (mito-DLP1) was demonstrated in 24-week STZ-diabetic rats. This effect of LRRK2 overexpression induced mitochondrial fragmentation, and reduced mitochondrial protein degradation rates were confirmed in vitro. As a consequence, 24-week STZ-diabetic rats showed mitochondrial dysfunction in cerebellar Purkinje neurons and coordinated motor deficits evaluated by rotarod test. Our findings are to our knowledge the first to suggest that the LRRK2 mediated pathway induces mitochondrial dysfunction and loss of cerebellar Purkinje neurons and, subsequently, may be associated with motor coordination deficits in STZ-diabetic rats. These data may indicate a novel cellular therapeutic target for diabetic neuropathy. PMID- 24810054 TI - Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death. AB - Zeaxanthin (Zea) is a major carotenoid pigment contained in human retina, and its daily supplementation associated with lower risk of age-related macular degeneration. Despite known property of Zea as an antioxidant, its underlying molecular mechanisms of action remain poorly understood. In this study, we aim to study the regulation mechanism of Zea on phase II detoxification enzymes. In normal human retinal pigment epithelium cells, Zea promoted the nuclear translocation of NF-E2-related factor 2 (Nrf2) and induced mRNA and protein expression of phase II enzymes, the induction was suppressed by specific knockdown of Nrf2. Zea also effectively protected against tert-butyl hydroperoxide-induced mitochondrial dysfunction and apoptosis. Glutathione (GSH) as the most important antioxidant was also induced by Zea through Nrf2 activation in a time- and dose-dependent manner, whereas the protective effects of Zea were decimated by inhibition of GSH synthesis. Finally, Zea activated the PI3K/Akt and MAPK/ERK pathway, whereas only PI3K/Akt activation correlated with phase II enzymes induction and Zea protection. In further in vivo analyses, Zea showed effects of inducing phase II enzymes and increased GSH content, which contributed to the reduced lipid and protein peroxidation in the retina as well as the liver, heart, and serum of the Sprague-Dawley rats. For the first time, Zea is presented as a phase II enzymes inducer instead of being an antioxidant. By activating Nrf2 mediated phase II enzymes, Zea could enhance anti-oxidative capacity and prevent cell death both in vivo and in vitro. PMID- 24810055 TI - Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP. AB - Disturbance of endoplasmic reticulum (ER) homeostasis causes ER stress and leads to activation of the unfolded protein response, which reduces the stress and promotes cell survival at the early stage of stress, or triggers cell death and apoptosis when homeostasis is not restored under prolonged ER stress. Here, we report that Cab45S, a member of the CREC family, inhibits ER stress-induced apoptosis. Depletion of Cab45S increases inositol-requiring kinase 1 (IRE1) activity, thus producing more spliced forms of X-box-binding protein 1 mRNA at the early stage of stress and leads to phosphorylation of c-Jun N-terminal kinase, which finally induces apoptosis. Furthermore, we find that Cab45S specifically interacts with 78-kDa glucose-regulated protein/immunoglobulin heavy chain binding protein (GRP78/BiP) on its nucleotide-binding domain. Cab45S enhances GRP78/BiP protein level and stabilizes the interaction of GRP78/BiP with IRE1 to inhibit ER stress-induced IRE1 activation and apoptosis. Together, Cab45S, a novel regulator of GRP78/BiP, suppresses ER stress-induced IRE1 activation and apoptosis by binding to and elevating GRP78/BiP, and has a role in the inhibition of ER stress-induced apoptosis. PMID- 24810056 TI - The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer. AB - The survival of prostate cancer (PrCa) patients is associated with the transition to hormone-independent tumor growth and metastasis. Clinically, the dysregulation of androgen action has been associated with the formation of PrCa and the outcome of androgen deprivation therapy in PrCa. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor that has been reported to act as an oncogene or tumor suppressor, depending on the extra- and intracellular environments following tumorigenesis. We found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to the CEBPD promoter region. Increases of suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2) attenuated the androgen-induced transcription of CEBPD. Importantly, the increases in E2F1, SUZ12 and EZH2 as well as the inactivation of CEBPD were associated with the clinicopathological variables and survival of PrCa patients. We revealed that caspase 8 (CASP8), an apoptotic initiator, is responsive to CEBPD induction. Reporter and in vivo DNA-binding assays revealed that CEBPD directly binds to and activates CASP8 reporter activity. A prodrug system was developed for therapeutic application in AR-independent or androgen-insensitive PrCa to avoid the epigenetic effects on the suppression of CEBPD expression. Our results showed that the combination of a perforin (PF)-CEBPD prodrug (which increases the level of procaspase-8) and a PF-granzyme B prodrug (which activates CASP8 and caspase 3 (CASP3)) showed an additive effect in triggering the apoptotic pathway and enhancing apoptosis in PrCa cells. PMID- 24810057 TI - Palmdelphin, a novel target of p53 with Ser46 phosphorylation, controls cell death in response to DNA damage. AB - The tumor suppressor gene p53 regulates apoptosis in response to DNA damage. Promoter selectivity of p53 depends on mainly its phosphorylation. Particularly, the phosphorylation at serine-46 of p53 is indispensable in promoting pro apoptotic genes that are, however, poorly determined. In the current study, we identified palmdelphin as a pro-apoptotic gene induced by p53 in a phosphorylated serine-46-specific manner. Upregulation of palmdelphin was observed in wild-type p53-transfected cells, but not in serine-46-mutated cells. Expression of palmdelphin was induced by p53 in response to DNA damage. In turn, palmdelphin induced apoptosis. Intriguingly, downregulation of palmdelphin resulted in necroptosis-like cell death via ATP depletion. Upon DNA damage, palmdelphin dominantly accumulated in the nucleus to induce apoptosis. These findings define palmdelphin as a target of serine-46-phosphorylated p53 that controls cell death in response to DNA damage. PMID- 24810060 TI - Stigma as a public health tool: implications for health promotion and citizen involvement. PMID- 24810058 TI - Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). AB - Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4 phenylpyridinium (MPP(+)) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP(+) (5 MUM). At 18-24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP(+). Thus, combined 'Omics' analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate. PMID- 24810061 TI - The complete mitochondrial genome of the Culter recurviceps (Teleostei, Cyprinidae). AB - We present the complete mitochondrial genome of the Culter recurviceps in this study. The mitochondrial genome is 16,622 bp long and consists of 13 protein coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The gene order and composition of C. recurviceps mitochondrial genome was similar to that of most other vertebrates. The nucleotide compositions of the light strand are 31.36% of A, 24.77% of T, 27.77% of C and 16.09% of G. With the exception of ND6 and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. Two copies of tandem repeat sequence (24 bp) was observed in the end of the 123 bp in control region. PMID- 24810059 TI - Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo. AB - Glioblastoma (GBM) is the most common and deadly adult brain tumor. Despite aggressive surgery, radiation, and chemotherapy, the life expectancy of patients diagnosed with GBM is ~14 months. The extremely aggressive nature of GBM results from glioblastoma stem-like cells (GSCs) that sustain GBM growth, survive intensive chemotherapy, and give rise to tumor recurrence. There is accumulating evidence revealing that GSC resilience is because of concomitant activation of multiple survival pathways. In order to decode the signal transduction networks responsible for the malignant properties of GSCs, we analyzed a collection of GSC lines using a dual, but complementary, experimental approach, that is, reverse phase protein microarrays (RPPMs) and kinase inhibitor library screening. We treated GSCs in vitro with clinically relevant concentrations of temozolomide (TMZ) and performed RPPM to detect changes in phosphorylation patterns that could be associated with resistance. In addition, we screened GSCs in vitro with a library of protein and lipid kinase inhibitors to identify specific targets involved in GSC survival and proliferation. We show that GSCs are relatively insensitive to TMZ treatment in terms of pathway activation and, although displaying heterogeneous individual phospho-proteomic profiles, most GSCs are resistant to specific inhibition of the major signaling pathways involved in cell survival and proliferation. However, simultaneous multipathway inhibition by the staurosporin derivative UCN-01 results in remarkable inhibition of GSC growth in vitro. The activity of UCN-01 on GSCs was confirmed in two in vivo models of GBM growth. Finally, we used RPPM to study the molecular and functional effects of UCN-01 and demonstrated that the sensitivity to UCN-01 correlates with activation of survival signals mediated by PDK1 and the DNA damage response initiated by CHK1. Taken together, our results suggest that a combined inhibition of PDK1 and CHK1 represents a potentially effective therapeutic approach to reduce the growth of human GBM. PMID- 24810062 TI - The complete chloroplast genome sequence of desert poplar (Populus euphratica). AB - The complete chloroplast sequence of the desert poplar (Populus euphratica), a plant well-adapted to salt stress, was determined in this study. The genome consists of 156,766 bp containing a pair of inverted repeats (IRs) of 16,591 bp separated by a large single-copy region and a small single-copy region of 84,888 bp and 27,646 bp, respectively. The chloroplast genome contains 130 known genes, including 89 protein-coding genes, 8 ribosomal RNA genes, and 37 tRNA genes; 18 of these are located in the inverted repeat region. PMID- 24810063 TI - The complete mitochondrial DNA of the bull shark (Carcharhinus leucas). AB - The bull shark mitochondrial structure is similar to that of other elasmobranchs; it has a total length of 16,100 bp, the base composition of the genomes was as follows: A (31.35%), T (31.35%), C (24.38%) and G (12.90%). It contains 13 protein-coding genes and 23 tRNA genes. The tRNA genes range from 70-72 bp. Gene order is the same as in other vertebrates and teleosts. PMID- 24810064 TI - Detecting mitochondrial signatures of selection in wild Tibetan pigs and domesticated pigs. AB - Selection in genomic regions is prevalent in mammals; however, the effects of selection on the mitogenome are not clearly understood. We determined the complete mitochondrial DNA (mtDNA) sequences from six wild Tibetan pigs from the Tibetan plateau and four domestic pig breeds from the lowland of neighboring southwest China. Nucleotide diversity analysis using the sliding window method showed that the nucleotide diversity of wild Tibetan pigs in most regions of the mitogenome was higher than that of domestic pigs. The 12 s ribosomal RNA showed relatively lower nucleotide diversity in Tibetan pigs, suggesting purifying selection of these genes during high-altitude adaptation. More non-synonymous nucleotide substitutions in the ATP6 were found in wild Tibetan pigs, indicating adaptive selection in Tibetan pigs. The results suggested distinct impacts of natural selection and artificial selection upon the mitogenome, especially the mitochondrial signatures of adaptive evolution in wild Tibetan pigs under natural selection. PMID- 24810065 TI - The complete mitochondrial genome of Poratrioza sinica (Insecta: Hemiptera: Psyllidae). AB - The complete mitochondrial genome (mitogenome) of Poratrioza sinica (Hemiptera: Psyllidae) has been sequenced and annotated in this study. This mitogenome is 14,863 bp in length with an A + T content of 72.0%, and contains 37 typical animal mitochondrial genes that are arranged in the same order as that of the putative ancestral insect mitogenome. All protein-coding genes start with ATN codons except for nad5, which uses TTG as the initial codon. All the transfer RNA genes have the typical cloverleaf structure, except for trnS1 (AGN) which lacks the dihydrouridine (DHU) arm. The control region is 700 bp in length with 82.4% A + T content. This is the second completely sequenced mitogenome from the family Psyllidae of Hemiptera. PMID- 24810066 TI - The complete mitochondrial DNA of endemic Eastern Pacific coral (Porites panamensis). AB - The mitogenome of the endemic coral Porites panamensis (Genbank accession number KJ546638) has a total length of 18,628 bp, and the arrangement consist of 13 protein-coding genes, 2 ribosomal RNA (rRNA) genes and 2 transfer RNA (tRNA) genes. Gene order was equal to other scleractinian coral mitogenomes. PMID- 24810067 TI - Complete mitochondrial genome of Amolops mantzorum (Anura: Ranidae). AB - Sichuan torrent frog, Amolops mantzorum (family Ranidae, suborder Neobatrachia), possesses heteromorphic sex chromosomes unusual characteristics among amphibians. We determined the complete nucleotide sequence of the A. mantzorum mitogenome. This genome is 17,744 bp in length and contains 37 genes, 1 control region, and 1 light strand replication origin typically found in vertebrate mtDNAs. In the A. mantzorum mitogenome, a novel gene arrangement is observed within the WANCY tRNA gene cluster region. This mt gene arrangement seems to be usable as a molecular maker to distinguish to this species from other species in the genus Amolops. PMID- 24810068 TI - The complete mitochondrial genome of the Megalobrama skolkovii (Cyprinidae: Cultrinae). AB - The complete mitochondrial DNA (mtDNA) sequence of Megalobrama skolkovii was first presented in this study. The mitochondrial genome is 16,620 bp in length, including 13 protein-coding genes, 2 ribosomal RNA gens (12S rRNA and 16S rRNA), 22 transfer RNA genes (tRNA) and a control region (D-loop), with the gene identical to that of typical vertebrates. The overall base composition of the light strand are 31.23% A, 24.73% T, 16.16% G and 27.88% C. Two copies of tandem repeat sequence was found in the control region. PMID- 24810069 TI - The complete mitochondrial genome of the Hemibagrus guttatus (Teleostei, Bagridae). AB - The complete mitochondrial genome of the Hemibagrus guttatus was presented in this study. The mitochondrial genome is 16,523 bp long and consists of 13 protein coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The gene order and composition of H. guttatus mitochondrial genome was similar to that of most other vertebrates. The nucleotide compositions of the light strand are 31.73% of A, 25.42% of C, 28.02% of T and 14.83% of G. With the exception of the NADH dehydrogenase subunit 6 (ND6) and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. PMID- 24810070 TI - The complete mitochondrial genome of the subspecies, Phrynocephalus erythrurus parva (Reptilia, Squamata, Agamidae), a toad-headed lizard dwell at highest elevations of any reptile in the world. AB - The complete mitochondrial genome was sequenced from the toad-headed viviparous lizard subspecies, Phrynocephalus erythrurus parva, which occupies the highest regions of any reptile on the earth. The mitogenome sequence was 16,431 bp in size, with the overall base composition of H-strand is T: 26.06%, C: 25.14%, A: 36.45%, G: 12.35%. It consists of 13 protein coding, 22 tRNA, 2 rRNA genes and 3 control regions, and its gene order and gene content were identical with the published congeneric mitogenomes of other Phrynocephalus, except for the small protion between tRNA-Pro and tRNA-Phe. PMID- 24810071 TI - The complete chloroplast genome sequence of American bird pepper (Capsicum annuum var. glabriusculum). AB - The complete chloroplast genome sequence of American bird pepper (Capsicum annuum var. glabriusculum) is reported and characterized in this study. The genome size is 156,612 bp, containing a pair of inverted repeats (IRs) of 25,776 bp separated by a large single-copy region of 87,213 bp and a small single-copy region of 17,851 bp. The chloroplast genome harbors 130 known genes, including 89 protein coding genes, 8 ribosomal RNA genes, and 37 tRNA genes. A total of 18 of these genes are duplicated in the inverted repeat regions, 16 genes contain 1 intron, and 2 genes and one ycf have 2 introns. PMID- 24810072 TI - Determination and analysis of complete mitochondrial genome sequence of Peking duck (Anas platyrhychos). AB - The complete mitochondrial genome (mtDNA) of Peking duck (Anas platyrhychos) was determined. The entire genome was 16,604 bp in length. Similar to the typical mtDNA of vertebrates, it contained 37 genes (13 protein-coding genes, 2 rRNA genes, 22 tRNA genes) and a non-coding region (D-loop). The characteristics of the mitochondrial genome was analyzed and discussed in detail. PMID- 24810073 TI - Characterization of the complete mitochondrial genome of Collared Finchbill, Spizixos semitorques (Passeriformes: Pycnonotidae). AB - The complete mitochondrial genome of Spizixos semitorques is 17,045 bp long with an A+T content of 55.52%, which composed of 13 typical protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and 2 extensive heteroplasmic control regions (CR1 and CR2). Genome organization of S. semitorques is similar to that of other birds. All of the PCGs started with ATG, except for cox1, which began with GTG. Six types of termination codons were used, canonical TAA and TAG termination codons are found in seven protein-coding genes, while AGA for nad1 and nad5, AGG for cox1, and the remaining genes (nad2, cox3, nad4) have incomplete termination codons (TA- or T- -). All tRNA genes have a typical clover-leaf structure. Furthermore, a minisatellite of 24 nucleotides (5' CACAAAAATCAAACAAAAATACAA-3') with 2.9 tandem repeats at the end of CR2 were detected. PMID- 24810074 TI - Complete mitochondrial genome of Aeolesthes oenochrous (Fairmaire) (Coleoptera: Cerambycidae): an endangered and colorful longhorn beetle. AB - Aeolesthes oenochrous (Fairmaire), a large and colorful longhorn beetle, is an endangered species in Taiwan. Its complete mitogenome, 15,747 bp, shows a typical coleopteran organization, containing 13 protein coding genes, 22 tRNA genes, 2 rRNA genes and one A + T rich region. Two protein coding genes, i.e. COI and ND1, have the atypical start codon of AAT and TTG, respectively. The third nucleotide position of codons shows extremely low guanine content. In the A + T rich region, there were two poly-T stretches with 14 and 13 thymine each. These two poly-T stretches were clarified by the cloning method. PMID- 24810075 TI - The complete mitochondrial genome of the ratmouth barbell, Ptychidio jordani (Cypriniformes Cyprnidae). AB - The complete mitochondrial genome of an endemic fish Ptychidio jordani is a circular molecular of 16,602 bp in size, containing 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and a non coding control region. Most of the genes are encoded on the heavy strand, expect for ND6 and eight tRNAs. The control region is 940 bp in length and is located between the tRNA(Pro) and tRNA(Phe) genes. Of 13 PCGs, 7 genes (ND2, COII, ATPase 6, COIII, ND3, ND4, Cytb) had an incomplete stop codon. The complete mtDNA genome sequence obtained in this study would be useful for studying genetic diversity and phylogenetics in Ptychidio jordani and related taxa in future. PMID- 24810076 TI - Acceptor-donor-acceptor small molecules based on indacenodithiophene for efficient organic solar cells. AB - Four A-D-A type small molecules using 4,4,9,9-tetrakis(4-hexylphenyl)- indaceno[1,2-b:5,6-b']dithiophene as central building block, bithiophene or terthiophene as pi-bridges, alkyl cyanoacetate or rhodanine as end acceptor groups were synthesized and investigated as electron donors in solution-processed organic solar cells (OSCs). These molecules showed excellent thermal stability with decomposition temperatures over 360 degrees C, relatively low HOMO levels of -5.18 to -5.22 eV, and strong optical absorption from 350 to 670 nm with high molar extinction coefficient of 1.1 * 10(5) to 1.6 * 10(5) M(-1) cm(-1) in chloroform solution. OSCs based on blends of these molecules and PC71BM achieved average power conversion efficiencies of 2.32 to 5.09% (the best 5.32%) after thermal annealing. The effects of thiophene bridge length and end acceptor groups on absorption, energy level, charge transport, morphology, and photovoltaic properties of the molecules were investigated. PMID- 24810077 TI - Toxicological perspectives of inhaled therapeutics and nanoparticles. AB - INTRODUCTION: The human respiratory system is an important route for the entry of inhaled therapeutics into the body to treat diseases. Inhaled materials may consist of gases, vapours, aerosols and particulates. In all cases, assessing the toxicological effect of inhaled therapeutics has many challenges. AREAS COVERED: This article provides an overview of in vivo and in vitro models for testing the toxicity of inhaled therapeutics and nanoparticles implemented in drug delivery. Traditionally, inhalation toxicity has been performed on test animals to identify the median lethal concentration of airborne materials. Later maximum tolerable concentration denoted by LC0 has been introduced as a more ethically acceptable end point. More recently, in vitro methods have been developed, allowing the direct exposure of airborne material to cultured human target cells on permeable porous membranes at the air-liquid interface. EXPERT OPINION: Modifications of current inhalation therapies, new pulmonary medications for respiratory diseases and implementation of the respiratory tract for systemic drug delivery are providing new challenges when conducting well-designed inhalation toxicology studies. In particular, the area of nanoparticles and nanocarriers is of critical toxicological concern. There is a need to develop toxicological test models, which characterise the toxic response and cellular interaction between inhaled particles and the respiratory system. PMID- 24810078 TI - Adherence to the Mediterranean diet and consumption of functional foods among the Balearic Islands' adolescent population. AB - OBJECTIVE: To assess differences in adherence to the Mediterranean diet (MD) between consumers and non-consumers of functional foods among the Balearic Islands' adolescent population. DESIGN: Cross-sectional nutritional survey carried out (2007-2008) in the Balearic Islands, a Mediterranean region. Dietary assessment was based on a semi-quantitative FFQ and two non-consecutive 24 h recalls. Anthropometric measurements and questions related to socio-economic status, physical activity and adherence to the MD were assessed. SETTING: Data obtained from a representative sample of all inhabitants living in the Balearic Islands aged 12-17 years. SUBJECTS: A random sample (n 1961) of the adolescent population was interviewed. RESULTS: The mean adherence to the MD among consumers of functional foods was 56.42 (sd 6.05) % and 55.76 (sd 5.41) % among non consumers. Consumption of fruit juice, fibre-rich bread/cookies, cereal bars, fish and soya milk was higher among adolescents with high MD adherence, and consumption of modified milk, probiotics, breakfast cereals and infusions was higher among adolescents with low MD adherence. Daily intakes of functional dietary components from plant foods (dietary fibre, vitamins C and E, carotene, folic acid) were higher among adolescents with high MD adherence. CONCLUSIONS: The Balearic Islands' adolescent population had moderate adherence to the MD; higher adherence was observed among consumers of functional foods. Average daily intakes of functional foods and functional dietary components were higher among adolescents with high adherence to the MD. Gender, age and low parental education were risk factors for low adherence to the MD, mainly among non-consumers of functional foods. PMID- 24810079 TI - Stainless steel wire versus FiberWire suture cerclage fixation to stabilize the humerus in total shoulder arthroplasty. AB - HYPOTHESIS: No. 5 FiberWire (Arthrex, Naples, FL, USA) cerclage (FWC) and 1.25-mm stainless steel wire cerclage (SSWC) are biomechanically similar in resistance to prosthetic subsidence in shoulder arthroplasty. METHODS: In this laboratory bench study, 3 different surgical knot configurations (4-throw knot, cow hitch, and simple hitch) using a No. 5 FWC were evaluated and compared with a 1.25-mm SSWC. First, distraction tests were performed using bovine femoral cortical half shells mounted on a testing jig. Cerclage tightening, load to a 3-mm gap opening, and load to total failure were measured. Second, uncemented humeral prosthetic stems were inserted into an experimentally split humeral medullary canal, secured by the cerclage. After 100 N of preloading, the prosthesis was advanced into the humerus at a speed of 0.2 mm/s, and resistance during subsidence up to a penetration depth of 10 mm, as well as gap opening, was measured. RESULTS: Tightening force showed higher values for SSWC (618 N) than FWC (131-137 N) (P < .001). Load to total failure was comparable among the 3 different FWC knots (2,642-2,804 N), which were significantly stronger than SSWC (1,775 N, P < .001). At 3 mm of distraction, SSWC (1,820 N), cow hitch (1,803 N), and single-throw hitch (1,709 N) performed significantly better than a 4-throw knot (1,289 N) (P < .01). Subsidence testing showed no difference in force restraint or gap opening between the best FWC and SSWC. CONCLUSIONS: FWCs appear, in vitro, equally suitable to steel wires to stabilize nondisplaced periprosthetic humeral fractures. To actively reduce a displaced fracture, steel wires may still be the first choice. PMID- 24810080 TI - Biomechanical comparison of two techniques for arthroscopic suprapectoral biceps tenodesis: interference screw versus implant-free intraosseous tendon fixation. AB - BACKGROUND: A novel arthroscopic technique allows for intraosseous tendon placement in biceps tenodesis using bone tunnels and suture while avoiding the expense of an implant. No biomechanical characterization exists for this construct. METHODS: Tensile tests were used to compare a suture-only biceps tenodesis technique (arthroscopic biceps intraosseous tenodesis [ABIT]) with interference screws in 7 pairs of cadaveric shoulders. The ABIT used a modified finger-trap suture method to secure the tendon to itself through an intraosseous bone tunnel. Interference screw placement followed the manufacturer's protocol for implantation. An open technique was used to provide consistency during laboratory preparation. RESULTS: During cyclic loading, the screws were significantly stiffer (P = .040) but dissipated more energy (P = .002). During failure loading, suture-only specimens showed significantly greater failure loads (P < .001) and deformation (P = .046). The failure mechanism for the ABIT method was tendon elongation with progressive tensioning and slippage of the tendon through the suture mass. No complete tendon failure occurred for the ABIT. Gross tendon failure occurred in all interference screw tests at the bone-tendon-screw interface. No screw or suture failed in any biceps tendon test. CONCLUSION: The ABIT construct showed significantly higher failure loads and deformation compared with interference screws. The comparable stiffness after cycling of both constructs suggests that micromotion at the bone-tendon interface is similar, which-in addition to the intraosseous fixation-may be important in promoting healing. The ABIT construct was found to absorb and restore more energy (hysteresis), suggesting potential for greater tendon preservation, which may translate into improved construct longevity. The suture-only method can eliminate the expense of an implant. PMID- 24810081 TI - Strategic approach to O'Driscoll type 2 anteromedial coronoid facet fracture. AB - BACKGROUND: The purpose of this study was to suggest a strategic approach to the management of anteromedial coronoid facet (AMCF) fracture that is related to posteromedial rotational instability of the elbow through investigation of the surgical outcome of diverse combinations, including internal fixation of AMCF fractures and repair of collateral ligament injury. METHODS: The study enrolled 18 patients. On the basis of the size of the coronoid fracture and the degree of the soft tissue injuries that were evaluated with computed tomography, magnetic resonance imaging, and varus stress test under anesthesia, these fractures were managed differently. Functional outcomes were evaluated with the visual analog scale score, modified Mayo Elbow Performance Score, and Disabilities of the Arm, Shoulder and Hand score. Plain radiographs were used to evaluate the degree of arthrosis. RESULTS: There were 2 cases of O'Driscoll type 2, subtype 1 fractures; 14 cases of type 2, subtype 2 fractures; and 2 cases of type 2, subtype 3 fractures. Seven cases were managed with only AMCF fracture fixation, 4 cases with only lateral ulnar collateral ligament (LUCL) repair, 6 cases with concomitant repair of the LUCL and AMCF fracture, and 1 case with a conservative method. There were no significant differences among O'Driscoll types and among the subgroups of type 2-2 (P > .05). When the elbow showed instability on the varus stress test after AMCF fracture fixation, the soft tissue injuries of the lateral elbow were more severe (P =. 015). Arthrosis was not correlated with the patient's symptoms (P > .05). CONCLUSION: AMCF fracture can be treated by only AMCF fracture fixation, only LUCL repair, or a combination of these techniques, depending on the size of the AMCF fracture fragment and the degree of the lateral soft tissue injuries. PMID- 24810082 TI - Overview of pediatric peripheral facial nerve paralysis: analysis of 40 patients. AB - Peripheral facial nerve paralysis in children might be an alarming sign of serious disease such as malignancy, systemic disease, congenital anomalies, trauma, infection, middle ear surgery, and hypertension. The cases of 40 consecutive children and adolescents who were diagnosed with peripheral facial nerve paralysis at Baskent University Adana Hospital Pediatrics and Pediatric Neurology Unit between January 2010 and January 2013 were retrospectively evaluated. We determined that the most common cause was Bell palsy, followed by infection, tumor lesion, and suspected chemotherapy toxicity. We noted that younger patients had generally poorer outcome than older patients regardless of disease etiology. Peripheral facial nerve paralysis has been reported in many countries in America and Europe; however, knowledge about its clinical features, microbiology, neuroimaging, and treatment in Turkey is incomplete. The present study demonstrated that Bell palsy and infection were the most common etiologies of peripheral facial nerve paralysis. PMID- 24810083 TI - Classification in childhood disability: focusing on function in the 21st century. AB - Classification systems in health care are usually based on current understanding of the condition. They are often derived empirically and adopted applying sound principles of measurement science to assess whether they are reliable (consistent) and valid (true) for the purposes to which they are applied. In the past 15 years, the authors have developed and validated classification systems for specific aspects of everyday function in people with cerebral palsy--gross motor function, manual abilities, and communicative function. This article describes the approaches used to conceptualize each aspect of function, develop the tools, and assess their reliability and validity. We report on the utility of each system with respect to clinical applicability, use of these tools for research, and the uptake and impact that they have had around the world. We hope that readers will find these accounts interesting, relevant, and applicable to their daily work with children and youth with disabilities. PMID- 24810084 TI - Family-centered care for children with cerebral palsy: conceptual and practical considerations to advance care and practice. AB - This article focuses on conceptual and practical considerations in family centered care for children with cerebral palsy and their families. In the last 5 years, there have been important advances in our understanding of the components of family-centered care, and initial attempts to understand the client change processes at play. Recent research elaborates on family-centered care by delving into aspects of family-provider partnership, and applying family-centered principles to organizational service delivery to bring about organizational cultures of family-centered care. Recent research has also begun to consider mediators of client change, and new practice models have been proposed that embrace family-centered principles and illustrate the "art" of practice. Future research directions are discussed, including explorations of causal relationships between family-centered care principles, elements of caregiving practice, client change processes, and child and family outcomes. The meaning of the recent literature for pediatric neurology practice is considered. PMID- 24810085 TI - Relevant areas of functioning in children with cerebral palsy based on the international classification of functioning, disability and health coding system: a clinical perspective. AB - In the context of the development of the International Classification of Functioning, Disability and Health Core Sets for children and youth with cerebral palsy, an evidence-based methodology was implemented to select the most relevant categories out of the entire classification. The aim of this study was to describe the contribution of the clinical perspective to select categories of functioning in children and youth with cerebral palsy. We conducted a chart review of clinical assessments of children and youth with cerebral palsy aged 0 to 18 years in a tertiary level center. In total, 129 International Classification of Functioning categories were covered in clinical encounters: representing 19% body structures, 33% body functions, 37% activity and participation, and 11% environmental factors. Our findings can guide clinical assessments and goal-setting of this population. This important perspective will inform the development of the International Classification of Functioning, Disability and Health Core Sets for children and youth with cerebral palsy. PMID- 24810086 TI - Emerging therapy approaches: an emphasis on function. AB - Children and youth with cerebral palsy receive ongoing physical and occupational therapy services to improve their functional performance and participation in activities at home, school, and in the community. Over the past 2 decades, rehabilitation interventions have become more functional and goal oriented. In this article, we discuss factors that have influenced emerging intervention approaches. These factors include greater involvement of families in decision making, changing conceptual frameworks and theories underlying skill development and improved outcome measures. New research findings indicate that rehabilitation interventions embracing family-centered services and focusing on functional improvement can be more effective in promoting participation. This knowledge can serve as the platform for further examination of the most effective rehabilitation interventions for children and youth with cerebral palsy. PMID- 24810087 TI - Symptomatic neonatal seizures followed by febrile status epilepticus: the two-hit hypothesis for the subsequent development of epilepsy. AB - Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has been demonstrated in animal models. We describe 2 cases of preterm babies sustaining recurrent neonatal seizures in the context of a severe perinatal brain damage who presented with symptomatic epilepsy only after the occurrence of an episode of febrile status epilepticus. In the context of preexisting perinatal brain damage, febrile status epilepticus acted as a second hit for developing epilepsy, confirming animal evidence. PMID- 24810088 TI - Fixation-off sensitivity in idiopathic childhood occipital epilepsy of Gastaut. AB - A 7-year-old boy presented with episodic blindness for the last 2 months with occipital paroxysms and fixation-off sensitivity on electroencephalography (EEG). The clinico-EEG features were suggestive of idiopathic childhood occipital epilepsy of Gastaut. The interesting phenomenon of fixation-off sensitivity is discussed. PMID- 24810089 TI - The Ethics Writings of Roger A. Brumback, MD. AB - Roger A. Brumback, MD (1953-2013), a renaissance man, shared with the world his knowledge and opinions on many subjects. Thus, it should come as no surprise that ethics did not escape Dr Brumback's consideration. Reading Dr Brumback's vitae, I came across several publications that afford insights into topics that tugged at his moral fabric. Dr Brumback was a steadfast defender of the scientific method. Reading his commentaries, one gets the sense that Dr Brumback felt personally attacked when quackery challenged science. In addition, and as long-time Editor in-Chief of the Journal of Child Neurology, Dr Brumback considered it a personal affront every time a paper he published, or for that matter published by any scientific journal, had to be retracted or corrected. In the following paragraphs, I review a selection of Dr Brumback's ethics writings. PMID- 24810090 TI - Induction of pancreatic cancer cell migration by an autocrine epidermal growth factor receptor activation. AB - Pancreatic cancer is characterized by aggressive local invasion and early metastasis formation. Active migration of the pancreatic cancer cells is essential for these processes. We have shown previously that the pancreatic cancer cells lines CFPAC1 and IMIM-PC2 show high migratory activity, and we have investigated herein the reason for this observation. Cell migration was assessed using a three-dimensional, collagen-based assay and computer-assisted cell tracking. The expression of receptor tyrosine kinases was determined by flow cytometry and cytokine release was measured by an enzyme-linked immunoassay. Receptor function was blocked by antibodies or pharmacological enzyme inhibitors. Both cells lines express the epidermal growth factor receptor (EGFR) as well as its family-member ErbB2 and the platelet-derived growth factor receptor (PDGFR)alpha, whereas only weak expression was detected for ErbB3 and no expression of PDGFRbeta. Pharmacological inhibition of the EGFR or ErbB2 significantly reduced the migratory activity in both cell lines, as did an anti EGFR antibody. Interestingly, combination of the latter with an anti-PDGFR antibody led to an even more pronounced reduction. Both cell lines release detectable amounts of EGF. Thus, the high migratory activity of the investigated pancreatic cancer cell lines is due to autocrine EGFR activation and possibly of other receptor tyrosine kinases. PMID- 24810091 TI - Health impact of fasting in Saudi Arabia during Ramadan: association with disturbed circadian rhythm and metabolic and sleeping patterns. AB - BACKGROUND: Muslims go through strict Ramadan fasting from dawn till sunset for one month yearly. These practices are associated with disturbed feeding and sleep patterns. We recently demonstrated that, during Ramadan, circadian cortisol rhythm of Saudis is abolished, exposing these subjects to continuously increased cortisol levels. HYPOTHESIS: Secretory patterns of other hormones and metabolic parameters associated with cortisol, and insulin resistance, might be affected during Ramadan. PROTOCOL: Ramadan practitioners (18 males, 5 females; mean age +/ SEM = 23.16+/-1.2 years) were evaluated before and two weeks into Ramadan. Blood was collected for measurements of endocrine and metabolic parameters at 9 am (+/ 1 hour) and again twelve hours later. RESULTS: In Ramadan, glucose concentration was kept within normal range, with a significant increase in the morning. Mean morning concentration of leptin was significantly higher than pre-Ramadan values (p = 0.001), in contrast to that of adiponectin, which was significantly lower (p<0.001). These changes were associated with increased insulin resistance in morning and evening. Concentrations of hsCRP were lower during Ramadan than those during regular living conditions, however, normal circadian fluctuation was abolished (p = 0.49). Even though means of liver enzymes, total bilirubin, total protein and albumin were all decreased during Ramadan, statistically lower means were only noted for GGT, total protein, and albumin (p = 0.018, 0.002 and 0.001 respectively). DISCUSSION: Saudi Ramadan practitioners have altered adipokine patterns, typical of insulin resistance. The noted decreases of hsCRP, liver enzymes, total protein, and albumin, are most likely a result of fasting, while loss of circadian rhythmicity of hsCRP is probably due to loss of circadian cortisol rhythm. CONCLUSIONS: Modern Ramadan practices in Saudi Arabia, which are associated with evening hypercortisolism, are also characterized by altered adipokines patterns, and an abolished hsCRP circadian rhythm, all likely to increase cardiometabolic risk. PMID- 24810092 TI - CDPKs of Cryptosporidium parvum--stage-specific expression in vitro. AB - Cryptosporidium parvum is a zoonotic agent that bears a high risk for the health of particularly immunocompromised humans and animals. As currently available drugs and therapies against cryptosporidiosis do not turn out satisfactory, more intensive research on the control of this parasite is necessary. The genus Cryptosporidium is unique within the phylum Apicomplexa as its localisation is intracellular but extracytoplasmatic. Infection of host cells is initially a parasite-driven process, but the signalling events and their downstream actions within Cryptosporidium are poorly understood. Calcium-dependent protein kinases (CDPKs) are probably involved in the regulation of invasion and egress. Previously described in plants, algae and other Apicomplexa, CDPKs are not found in vertebrates. They are thus promising targets for pharmaceutical intervention. While CDPK1 is well characterised in Toxoplasma gondii (TgCDPK1) and Plasmodium falciparum (PfCDPK1), only little information exists about the expression and function of CDPK in C. parvum. Here, we describe results of the in silico analysis of seven CpCDPKs. Five CpCDPKs contain potential sites for N myristoylation and N-palmitoylation. In a nested 3' rapid amplification of cDNA ends (RACE)-PCR, expression of six CpCDPKs resulted in distinct bands in infected cell cultures and extracts of freshly excysted sporozoites. The length of the 3' untranslated region (3' UTR) is described as well. Our results indicate CDPK expression to be stage specific on the mRNA level. PMID- 24810095 TI - Quantum dot-based multidonor concentric FRET system and its application to biosensing using an excitation ratio. AB - A plethora of semiconductor quantum dot (QD)-based probes that rely on Forster resonance energy transfer (FRET) have been developed for the optical detection of a wide array of biological targets. To date, the vast majority of these probes have utilized one-step energy transfer between individual donor-acceptor pairs. Here, we report a new multidonor concentric FRET configuration that comprised two fluorescent dyes assembled around a central CdSeS/ZnS QD through peptide linkers. One of these dyes, either Alexa Fluor 555 (A555) or Alexa Fluor 647 (A647), served as an acceptor for both the central QD and the other coassembled dye, Alexa Fluor 488 (A488). The unresolved emission between the A488 and the QD precluded a standard analysis of FRET efficiency from quenching of donor emission intensity or decay time, instead necessitating an analysis of the two energy transfer pathways from deconvolved excitation spectra. When A647 was the terminal acceptor, both the QD-to-A647 and A488-to-A647 energy transfer pathways could be interrogated with blue light, but only the former could be interrogated with violet light. The different degrees of A647 sensitization between these two excitation wavelengths was a predictable function of the above energy transfer efficiencies and dye stoichiometry, and was exploited for quantitative bioanalysis through an excitation ratio, which is in contrast to the conventional use of an emission ratio with FRET-based probes. Detection of the activity of nanomolar concentrations of trypsin, a model protease that hydrolyzed the A488 labeled peptide linker, was demonstrated using both a fluorescence plate reader and a low-cost, compact device that used two low-power light-emitting diodes (LEDs) as excitation sources and a silicon photodiode to detect A647 emission. This multidonor concentric FRET configuration represents a new modality for ratiometric biosensing with QDs and is potentially useful for portable in vitro diagnostics. PMID- 24810096 TI - Ketyl-type radicals from cyclic and acyclic esters are stabilized by SmI2(H2O)n: the role of SmI2(H2O)n in post-electron transfer steps. AB - Mechanistic details pertaining to the SmI2-H2O-mediated reduction and reductive coupling of 6-membered lactones, the first class of simple unactivated carboxylic acid derivatives that had long been thought to lie outside the reducing range of SmI2, have been elucidated. Our results provide new experimental evidence that water enables the productive electron transfer from Sm(II) by stabilization of the radical anion intermediate rather than by solely promoting the first electron transfer as originally proposed. Notably, these studies suggest that all reactions involving the generation of ketyl-type radicals with SmI2 occur under a unified mechanism based on the thermodynamic control of the second electron transfer step, thus providing a blueprint for the development of a broad range of novel chemoselective transformations via open-shell electron pathways. PMID- 24810097 TI - Full counting statistics of quantum dot resonance fluorescence. AB - The electronic energy levels and optical transitions of a semiconductor quantum dot are subject to dynamics within the solid-state environment. In particular, fluctuating electric fields due to nearby charge traps or other quantum dots shift the transition frequencies via the Stark effect. The environment dynamics are mapped directly onto the fluorescence under resonant excitation and diminish the prospects of quantum dots as sources of indistinguishable photons in optical quantum computing. Here, we present an analysis of resonance fluorescence fluctuations based on photon counting statistics which captures the underlying time-averaged electric field fluctuations of the local environment. The measurement protocol avoids dynamic feedback on the electric environment and the dynamics of the quantum dot's nuclear spin bath by virtue of its resonant nature and by keeping experimental control parameters such as excitation frequency and external fields constant throughout. The method introduced here is experimentally undemanding. PMID- 24810093 TI - Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer. AB - ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells. PMID- 24810098 TI - Identification of four genotypes of H3N2 swine influenza virus in pigs from southern China. AB - In 2011, four H3N2 swine influenza viruses (SIVs) were isolated from nasal swabs of four pigs (800 nasal swabs were collected from pigs showing influenza-like symptoms) in Guangdong province, China. Four different genotypes of H3N2 appeared among pigs in southern China, including wholly human-like H3N2 viruses, intermediate (1975) double-reassortant human H3N2 viruses (resulting from reassortment between an early human lineage and a recent human lineage), recent double-reassortant human H3N2 viruses, and avian-like H3N2 viruses. Because pigs can support the reassortment of human and avian influenza viruses, our surveillance should be enhanced as a part of an overall pandemic preparedness plan. PMID- 24810099 TI - Peroxisome-localized hepatitis Bx protein increases the invasion property of hepatocellular carcinoma cells. AB - HBx acts as a multifunctional regulator that modulates various cellular responses, which can lead to development and progression of hepatocellular carcinoma (HCC). Here, we show that the HBx protein is also localized to peroxisomes, and this increases cellular reactive oxygen species (ROS) to levels that are higher than when HBx is localized to other organelles. The elevated ROS strongly activated nuclear factor (NF)-kappaB. In addition, the peroxisome localized HBx increased the expressions of matrix metalloproteinases and decreased the expression of E-cadherin, which increased the invasive ability of HCC cells. Thus, a specific distribution of HBx to peroxisomes may contribute to HCC progression by increasing the invasive ability of HCC cells through elevation of the cellular ROS level. PMID- 24810100 TI - Association of a distinct strain of hollyhock yellow vein mosaic virus and Ludwigia leaf distortion betasatellite with yellow vein mosaic disease of hollyhock (Alcea rosea) in India. AB - A distinct strain of hollyhock yellow vein mosaic virus (HoYVMV) and Ludwigia leaf distortion betasatellite (LuLDB) were associated with yellow vein mosaic of hollyhock. The viral DNA genome (JQ911766) and betasatellite (JQ408216) shared highest nucleotide sequence identity (89.2 %) with HoYVMV (the only available sequence in GenBank) and 92 % identity with LuLDB. Agroinfiltration of HoYVMV and LuLDB induced yellow vein mosaic symptoms on hollyhock, thereby demonstrating causality of the disease. PMID- 24810105 TI - Electromembrane extraction--three-phase electrophoresis for future preparative applications. AB - The purpose of this article is to discuss the principle and the future potential for electromembrane extraction (EME). EME was presented in 2006 as a totally new sample preparation technique for ionized target analytes, based on electrokinetic migration across a supported liquid membrane under the influence of an external electrical field. The principle of EME is presented, and typical performance data for EME are discussed. Most work with EME up to date has been performed with low molecular weight pharmaceutical substances as model analytes, but the principles of EME should be developed in other directions in the future to fully explore the potential. Recent research in new directions is critically reviewed, with focus on extraction of different types of chemical and biochemical substances, new separation possibilities, new approaches, and challenges related to mass transfer and background current. The intention of this critical review is to give a flavor of EME and to stimulate into more research in the area of EME. Unlike other review articles, the current one is less comprehensive, but put more emphasis on new directions for EME. PMID- 24810107 TI - The novel alpha7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. AB - BACKGROUND: Alpha7 and alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer's disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and gamma-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition. RESULTS: Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3 yl)benzo[b]thiophene-2-carboxamide], a high-affinity alpha7 nAChR partial agonist, at 0.1 mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3 mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1 mg/kg, but not 0.03 and 0.3 mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other alpha7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective alpha7 nAChR antagonist, methyllycaconitine (MLA, 1.0 mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1 mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to alpha7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC. CONCLUSION: These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the alpha7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology. PMID- 24810106 TI - The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. AB - RATIONALE: Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, there by curtailing the elevation of extracellular 5 hydroxytryptamine (5-HTExt), and hence anti-depressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition here of. OBJECTIVES: Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5 HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. METHODS: Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). RESULTS: We generated mice expressing either the wild-type human SERT (hSERT(WT)) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERT(ALI/VFL+SI/TT)). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration. CONCLUSIONS: We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram. PMID- 24810111 TI - Mandible reconstruction using patient-specific pre-bent reconstruction plates: comparison of standard and transfer key methods. AB - PURPOSE: Mandible reconstruction with reconstruction plates requires bending the plates during the operation and fixation using the "standard method" (ST-method). The ST-method is limited when a pathological process has perforated the mandibular outer cortex. A transfer key method (TK-method) was developed where plates are pre-bent using a patient-specific mandible model and positioned on the mandible with the help of transfer keys. The ST-method and TK-method were compared in a clinical trial. METHODS: Mandibular reconstruction was performed on 42 patients in this study: 22 were performed using the TK-method and 20 using the ST-method. Pre- and postoperative CT scans were evaluated by measuring the distances between six corresponding landmarks on the mandibular condyles and rami. The difference between pre- and postoperative distances was used to evaluate reconstruction accuracy. RESULTS: The median deviation of the unsigned/ absolute values of all six distances was 1.07 mm for the TK-method and 1.67 mm for the ST-method. The TK-method showed significantly better results. For the signed values, the median deviation of the six distances was -0.6 mm for the TK method and -1.47 mm for the ST-method, indicating that the mandibles became narrower with both methods. This width difference was not statistically significant. CONCLUSION: The TK-method was more accurate than the ST-method in a clinical trial. The TK-method was effective and accurate for mandible reconstruction using pre-bent fixation plates. PMID- 24810112 TI - Patented pulsatile drug delivery technologies for chronotherapy. AB - INTRODUCTION: Oral-controlled and modified-release drug delivery systems with zero-order sustained-release kinetics have been developed and proven suitable for meeting increasingly sophisticated therapeutic needs. Nevertheless, the impact of basic chronobiology concepts on the practice of medicine is still ongoing and to address chronotherapy needs, various types of pulsatile drug delivery systems have been innovated. The purpose of this review is to highlight these innovations in the field of chronotherapy. AREAS COVERED: The present review discusses in depth on recent patents and developments related to pulsatile drug delivery systems with eroding, soluble or rupturable barrier coatings, and systems with capsular structures. Besides focusing on all recent innovations, the review addresses the novelty and feasibility of all upcoming technologies being exploited considering pulsatile drug delivery systems. EXPERT OPINION: There has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable and well-defined lag phase from the time of administration. From 1981 until the present date, patent publications related to pulsatile drug delivery have shown more promising systems with numerous developments in arena of drug delivery. Future development of chronotherapeutic medications requires proper assessment and integration with other emerging disciplines such as hydrogel and transdermal delivery systems. The selection of the appropriate chronopharmaceutical technology should take into considerations with the ease of manufacturing and the cost-effectiveness. PMID- 24810108 TI - Effects of the neuroactive steroid allopregnanolone on intracranial self stimulation in C57BL/6J mice. AB - RATIONALE: The neuroactive steroid (3alpha,5alpha)-3-hydroxy-pregnan-20-one (3alpha,5alpha-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration. OBJECTIVE: To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine. METHODS: Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward (BSR)). Mice received cocaine (n = 11, 3.0-30.0 mg/kg, intraperitoneal (i.p.)) or the neuroactive steroid allopregnanolone (n = 11, 3.0 17.0 mg/kg, i.p.). BSR thresholds (theta 0) and maximum (MAX) operant response rates after drug treatments were compared to those after vehicle injections. RESULTS: Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 min following the 30 mg/kg dose, while allopregnanolone was maximally effective (30 % reduction) 15-45 min after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates. CONCLUSIONS: The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol, suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice. PMID- 24810113 TI - IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma. AB - Insulin-like growth factor (IGF) signaling is involved in oral squamous cell carcinoma (OSCC), but IGF-1 receptor (IGF-1R)-mediated intricate regulatory networks among molecular interactions and signalling path ways in OSCC remain unclear. Here, we found that overexpression of IGF-1R and insulin receptor substrate-2 (IRS-2) was negatively associated with histological differentiation. IGF signaling stimulated OSCC cell growth. Conversely, overexpression of let-7b inhibited proliferation and colony formation and triggered S/G2 cell cycle arrest by targeting IGF-1R and IRS-2 through the Akt pathway. Also, the inverse relationship between expression of let-7b and IGF-1R/IRS-2 was confirmed in OSCC tumor xenografts and clinical specimens. Furthermore, by activating ERK1/2, IGF 1R transcriptionally upregulated IRS-2. Our results indicate that let-7b/IGF-1R mediated crosstalk between IRS-2/Akt and MAPK is involved in OSCC and is a potential therapeutic target for therapy. PMID- 24810115 TI - In vivo near-infrared fluorescence imaging of FAP-expressing tumors with activatable FAP-targeted, single-chain Fv-immunoliposomes. AB - Molecular and cellular changes that precede the invasive growth of solid tumors include the release of proteolytic enzymes and peptides in the tumor stroma, the recruitment of phagocytic and lymphoid infiltrates and alteration of the extracellular matrix. The reactive tumor stroma consists of a large number of myofibroblasts, characterized by high expression of fibroblast activation protein alpha (FAP). FAP, a type-II transmembrane sialoglycoprotein is an attractive target in diagnosis and therapy of several pathologic disorders especially cancer. In the underlying work, a fluorescence-activatable liposome (fluorescence quenched during circulation and fluorescence activation upon cellular uptake), bearing specific single-chain Fv fragments directed against FAP (scFv'FAP) was developed, and its potential for use in fluorescence diagnostic imaging of FAP expressing tumor cells was evaluated by whole body fluorescence imaging. The liposomes termed anti-FAP-IL were prepared via post-insertion of ligand phospholipid-conjugates into preformed DY-676-COOH-containing liposomes. The anti FAP-IL revealed a homogeneous size distribution and showed specific interaction and binding with FAP-expressing cells in vitro. The high level of fluorescence quenching of the near-infrared fluorescent dye sequestered in the aqueous interior of the liposomes enables fluorescence imaging exclusively upon uptake and degradation by cells, which results in fluorescence activation. Only FAP expressing cells were able to take up and activate fluorescence of anti-FAP-IL in vitro. Furthermore, anti-FAP-IL accumulated selectively in FAP-expressing xenograft models in vivo, as demonstrated by blocking experiments using free scFv'FAP. The local tumor fluorescence intensities were in agreement with the intrinsic degree of FAP-expression in different xenograft models. Thus, anti-FAP IL can serve as a suitable in vivo diagnostic tool for pathological disorders accompanied by high FAP-expression. PMID- 24810116 TI - Developing clinical reasoning in the classroom - analysis of the 4C/ID-model. AB - OBJECTIVES: The purpose of this study is to provide a theoretical rationale for the implementation of the four-component instructional design model for complex learning (4C/ID-model) at the University of Pretoria with the aim of systematically developing the clinical reasoning of undergraduate dental students in a classroom setting. METHODS: Recent literature provides a rationale for the use of the 4C/ID-model to teach clinical reasoning in terms of four strategic teaching and learning needs: (i) the need for authenticity in the learning process; (ii) the need to manage cognitive load during the learning process; (iii) the need for repeated practice; (iv) a need for valid assessment, feedback and reflection. RESULTS AND DISCUSSION: The literature review indicated that the 4C/ID-model makes provision for teaching and learning in an authentic context and proposes systematically structured methods that could be practically applied to manage cognitive load during repetitive exercises. The model also makes provision for cognitive feedback following assessment in order to eliminate misconceptions about content and to develop the cognitive strategies of the learner. CONCLUSIONS: On the basis of the literature review above, it is recommended that the 4C/ID-model be considered as a basis for classroom teaching and learning to develop competence in clinical reasoning in undergraduate dental students, even at pre-clinical level. The model may also have an application in medical education. PMID- 24810117 TI - Phosphine-catalyzed asymmetric synthesis of beta-lactones from disubstituted ketenes and aldehydes. AB - In this article we describe a general catalytic procedure for the formation of beta-lactones bearing two stereogenic centers, from disubstituted ketenes and achiral aldehydes. BINAPHANE was found to display excellent enantioselectivity (>=90% ee for eight examples) and good diastereoselectivity (>=90:10 for 13 examples) in catalyzing the formation of beta-lactones bearing two stereogenic centers from achiral aldehydes (both aromatic and aliphatic) and alkylarylketenes or dialkylketenes. A preference for formation of the trans diastereomer was observed in these reactions. For those reactions where BINAPHANE failed as a catalyst, tri-n-butylphosphine was found to be an effective achiral nucleophilic catalyst, effecting good yield and diastereoselectivity in racemic beta-lactone formation. Evidence for the involvement of phosphonium enolate intermediates in the reaction mechanism was obtained through reaction monitoring by (31)P NMR spectroscopy and by comparison with previously characterized intermediates observed in the phosphine-catalyzed ketene homodimerization reaction. PMID- 24810114 TI - Fab'-bearing siRNA TNFalpha-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis. AB - Patients suffering from inflammatory bowel disease (IBD) are currently treated by systemic drugs that can have significant side effects. Thus, it would be highly desirable to target TNFalpha siRNA (a therapeutic molecule) to the inflamed tissue. Here, we demonstrate that TNFalpha siRNA can be efficiently loaded into nanoparticles (NPs) made of poly (lactic acid) poly (ethylene glycol) block copolymer (PLA-PEG), and that grafting of the Fab' portion of the F4/80 Ab (Fab' bearing) onto the NP surface via maleimide/thiol group-mediated covalent bonding improves the macrophage (MP)-targeting kinetics of the NPs to RAW264.7 cells in vitro. Direct binding was shown between MPs and the Fab'-bearing NPs. Next, we orally administered hydrogel (chitosan/alginate)-encapsulated Fab'-bearing TNFalpha-siRNA-loaded NPs to 3% dextran sodium sulfate (DSS)-treated mice and investigated the therapeutic effect on colitis. In vivo, the release of TNFalpha siRNA-loaded NPs into the mouse colon attenuated colitis more efficiently when the NPs were covered with Fab'-bearing, compared to uncovered NPs. All DSS induced parameters of colonic inflammation (e.g., weight loss, myeloperoxidase activity, and Ikappabalpha accumulation) were more attenuated Fab'-bearing NPs loaded with TNFalpha siRNA than without the Fab'-bearing. Grafting the Fab' bearing onto the NPs improved the kinetics of endocytosis as well as the MP targeting ability, as indicated by flow cytometry. Collectively, our results show that Fab'-bearing PLA-PEG NPs are powerful and efficient nanosized tools for delivering siRNAs into colonic macrophages. PMID- 24810118 TI - 11th International Symposium of Facial Plastic Surgery. Preface. PMID- 24810119 TI - Global facial beauty: approaching a unified aesthetic ideal. AB - Recognition of facial beauty is both inborn and learned through social discourses and exposures. Demographic shifts across the globe, in addition to cross-cultural interactions that typify 21st century globalization in virtually all industries, comprise major active evolutionary forces that reshape our individual notions of facial beauty. This article highlights the changing perceptions of beauty, while defining and distinguishing natural beauty and artificial beauty. PMID- 24810120 TI - Future of cosmetic surgery. AB - Changes in cosmetic surgery will be driven by several key forces. The patient's self-image, and perceived place in society, will continue to drive patients to the cosmetic surgeon as well as to demand newer and better treatments. Technological advances, especially those based on an enhanced understanding of cellular and tissue physiology, promise enhanced tools other than the scalpel for the surgeon. Conceptual advances in our understanding of beauty and patient psychology will lead to a more integrative approach to cosmetic surgery. PMID- 24810121 TI - Dichotomy of rhinoplasty practice: from the conference floor to the operating room. AB - Advancements in surgical techniques and improvements in clinical practice inevitably lag behind scientific progress and peer-led opinion. The rapid rise and fall in the popularity of rhinoplasty techniques makes scientific evidence gathering and education a daunting task. Students of rhinoplasty face a long and steep learning curve, and need to acquire sound analytical tools to critically evaluate both literature contributions and operative reports shown in conferences. Such a complex learning process requires continuous self examination, and must account for the increasingly sophisticated and intricate wishes of rhinoplasty patients whose desires do not always coincide with what surgeons have been taught and practiced. In contemporary practice, the developing rhinoplasty surgeon must be also familiar with the range of racial features, as the broad variety of nasal anatomies and beauty canons are truly staggering, and one formula does not fit all cases.The complex set of circumstances that lead to disharmony between scientific progress and clinical practice is addressed, and a utilitarian plan to remedy this awkward dichotomy is suggested. PMID- 24810122 TI - Refining the nasal tip-an anatomical approach. AB - Surgical strategies to refine the nasal tip should be conceived to address the lobule rather than just the domal extremity of this aesthetic region. The goal should be to create normal, stable anatomy. The anatomy of the tip cartilages is complex. Surgical strategies must consider the size, shape, position, and orientation of each crus including their relationships with the ipsilateral and contralateral crura of both lower lateral cartilage rings. Every surgical step has the potential for unintended as well as intended change. We favor as a first step fixation of the medial and lobular segments of the middle crura. The domes and lateral crura can then be addressed on a stable base. Suture placement must be precise with excess tightening avoided to prevent nonanatomical twists of the tip cartilage ring in part or whole. Consideration must be given to structural grafts to brace the crura and to correct convex lateral crura. These grafts should be incorporated within or deep to the tip cartilage framework to minimize visibility. It is the, contour, position, and orientation of the caudal margins of the middle and lateral crura which we think are a key component in achieving natural tip refinement. PMID- 24810123 TI - Perspectives in asian rhinoplasty. AB - Asian patients present with relatively poorly developed dorsal and tip height and thicker skin, so augmentation rhinoplasty is the most commonly performed rhinoplasty procedure. Tip surgery using autologous cartilage followed by dorsal augmentation using an alloplastic implant material is the most widely performed surgical procedure for augmentation rhinoplasty on Asian patients. Cartilage tip grafting procedures, including shield grafting, multilayer tip grafting, onlay grafting, and modified vertical dome division, are key maneuvers for building up and providing better definition on a relatively poorly developed Asian tip. When performing primary cosmetic dorsal augmentation using alloplastic implants, the implant material should be selected according to the surgeon's experience, the pros and cons of available dorsal implant materials, and host factors such as skin thickness, associated deformities, and aesthetic goals. The costal cartilage is best reserved for difficult revisions, except in a limited number of primary cases who present with a very poorly developed nasal skeleton and thick skin. PMID- 24810124 TI - Forehead flap: master techniques in otolaryngology-head and neck surgery. AB - When the nose is missing, most patients would like to have their normal appearance and function restored. Unfortunately, the wound does not reflect the true tissue loss and the available donor tissues are not similar to nasal tissues. So subunit principles are applied and donor tissues modified to achieve a satisfactory result. All major reconstructions will require a late revision to revise scars, improve asymmetry, or open the airway. However, when cover and lining are grossly deficient, the repair must be totally redone with a second regional flap. Success requires a thoughtful preoperative analysis and careful reconstructive plan. Small nasal defects may be resurfaced in two stages with a forehead flap but large deep defects are best repaired in three stages with an intermediate operation which allows the placement of primary and delayed primary cartilage grafts, soft tissue sculpting, and folded flap lining replacements with safety. PMID- 24810125 TI - Contemporary facial reanimation. AB - The facial nerve is the most commonly paralyzed nerve in the human body. Facial paralysis affects aesthetic appearance, and it has a profound effect on function and quality of life. Management of patients with facial paralysis requires a multidisciplinary approach, including otolaryngologists, plastic surgeons, ophthalmologists, and physical therapists. Regardless of etiology, patients with facial paralysis should be evaluated systematically, with initial efforts focused upon establishing proper diagnosis. Management should proceed with attention to facial zones, including the brow and periocular region, the midface and oral commissure, the lower lip and chin, and the neck. To effectively compare contemporary facial reanimation strategies, it is essential to employ objective intake assessment methods, and standard reassessment schemas during the entire management period. PMID- 24810126 TI - The pain truth: recognizing the influence of pain on cosmetic outcomes. AB - Anxiety is an under recognized and major obstacle among patients seeking cosmetic procedures. The ability to alleviate it may be essential for achieving high patient satisfaction and better outcomes. Key initiators leading to anxiety include the fear of appearing unnatural and the fear of pain. Pain perception can be mitigated or augmented by psychological factors. Based on patient expectations, they may experience diminished pain perception through the placebo effect or catastrophized pain due to previous painful experiences. It is also important to recognize the influence of religion, cultural, ethnic, and gender bias on pain perception. In recent years, the aesthetic medical community has responded to patient demand for more minimally invasive procedures with more natural appearing result, resulting in a dramatic increase in the number of cosmetic procedures performed each year. Achieving pain and anxiety-free aesthetic medicine will likely result in a pronounced increase in the demand for cosmetic treatments. PMID- 24810127 TI - The potential of topical and injectable growth factors and cytokines for skin rejuvenation. AB - Growth factors and cytokines (referred to collectively hereafter as GFs) control cell growth, proliferation, and differentiation via a network of inter and intracellular signaling pathways. There are striking parallels between the pathways involved in skin wound healing and those implicated in photoaging of the skin. In recent years, topical and injectable GFs have emerged as an intriguing therapeutic modality that can be harnessed for aesthetic and medical purposes. This article provides a review of available evidence for the role in skin regeneration of topical GFs, and of injectable GFs contained in autologous platelet-rich plasma (PRP). It presents data from recent studies of GFs, offers a discussion of their potential to serve as antiaging actives, and includes safety considerations. As studies of injectable GFs typically assume preexisting familiarity with PRP protocols and the theory behind them, explanatory notes are provided. An assessment is provided of the evidence gaps that exist currently between experimental observations regarding GFs and their proven clinical benefits. Data of evidence levels II and III support the use for skin rejuvenation of topical GFs derived from sources including secretions or lysate of human dermal fibroblasts, and secretions of the snail Cryptomphalus aspersa. GFs with associated stem cell proteins, secreted by human dermal fibroblasts under hypoxic stress, can accelerate skin healing after laser resurfacing. In vitro and animal studies, small case series of PRP-treated patients and one prospective clinical study of its variant, platelet-rich fibrin matrix (PRFM), suggest the value of injectable GFs for skin rejuvenation. However, data of higher power are required to expand this proof of concept into an evidence-based paradigm. The clinical applications of topical and injectable GFs are promising, and remain to be fully defined. With continued study, data of higher evidence level can be accrued and formulations can be developed that offer optimal clinical efficacy, safety, tolerability, and stability. Better understanding of the mechanism of action of GFs can potentially advance our general understanding of dermal signaling pathways, and hence of hyaluronic acid and other alloplastic fillers; and allow the development of protocols for synergistic combination of GFs with other skin rejuvenation modalities. PMID- 24810128 TI - Key principles in running a successful business in facial plastics. AB - The ultimate goal for most facial plastic surgeons is to develop a successful practice. For those currently owning a practice and those planning on developing a practice, the skills and training necessary to establish and manage a facial plastic practice are not taught in medical school, residency, or most fellowships. The goal of this article is to underline the key principles of running a successful business. This article does not replace an MBA, but it allows you to be aware of potential challenges that all businesses encounter. PMID- 24810129 TI - My personal evolution of caring for patients with congenital cleft malformations: a joyous, but humbling career. AB - The evaluation and treatment of patients with congenital orofacial clefting is a challenging task. Successful treatment requires a concerted effort by the cleft surgeon and cleft team to maximize the appearance and function of the cleft patient. To become a competent cleft surgeon, a facial plastic surgeon must be dedicated to a lifelong pursuit of technical excellence through continual evaluation, self-criticism, and improvement of surgical techniques and approaches. The contemporary cleft surgeon must integrate the knowledge gained by mentors that have years of expert experience and evidence-based information demonstrated by careful study. This information should help guide the young cleft surgeon as experience is gained and expertise developed through years of careful observation and evaluation of patients. This article is a discussion of the art and science of cleft surgery. It outlines the timetable associated with cleft repairs, the resources necessary to provide superior cleft care, and exposes the weaknesses and frailties of all cleft surgeons. It is designed to aid cleft surgeons in their pursuit of perfection. PMID- 24810130 TI - Auricular reconstruction: surgical innovations, training methods, and an attempt for a look forward. AB - The construction of an auricle from autologous tissue is highly complex and demanding for a reconstructive surgeon. Depending on the characteristics of the underlying malformation, there are various surgical techniques available, which in specialized hands, promise regularly achievable attractive and stable results. To achieve this goal, a long-term training in super specialized centers is required. Training models available today, can partially systematize this training. The future of auricular reconstruction lies probably in the tissue engineering of organ complexes, including their nerve and vascular supply. PMID- 24810131 TI - Extracorporeal septoplasty: variations of the technique. AB - Complex deviation of the nasal septum is one of the most challenging situations for the nasal surgeon. Standard septoplasty fails to obtain a good outcome when multiple planes of deviation are present. We describe three different techniques for extracorporeal nasal septum reconstruction suitable for any possible situation of the septal framework. Normal nasal patency and a good aesthetic result were achieved in every case. No important complications or sequelae appeared in any of the patients. Complete external reconstruction of the septal framework is the technique of choice in complex deviations of the nasal septum. PMID- 24810132 TI - Management of the middle vault in endonasal rhinoplasty. AB - The management of the middle vault has become a crucial consideration in esthetic and functional rhinoplasty. Central to this management is an acknowledgment of the importance of the anatomic features and functional integrity of this nasal region. The diagnosis of middle vault insufficiency and techniques to prevent and repair such collapse have been widely reported. Many of these descriptions are based on the management of the middle vault using an open rhinoplasty approach. The purpose of this article is to describe various options for the management of the middle vault using an endonasal approach that have been used by a single surgeon in a university hospital-based setting. PMID- 24810133 TI - Restoration of the eyebrows by hair transplantation. AB - Partial loss of the eyebrows can be the result of epilation, scars, and inflammatory diseases. Facial hair and eyebrows play a major role in our mimetic expression and interaction. Therefore, facial hair restoration of the eyebrows can improve the appearance and psychological well-being of patients. We report the use of partial longitudinal follicular unit transplantation (PLFUT) to restore eyebrows. A total of 10 patients (age between 18 and 59 years; mean, 39 years) have been treated with PLFUT to restore the eyebrows. The grafts were harvested from the occipital area of the scalp. Suitable grafts were impregnated with a preservative solution and implanted into the eyebrows areas. Hair growth in the donor area as well as the eyebrows was observed before treatment and at intervals of 1 week, 3 months, and 1 year after treatment. Evaluation of the donor area reveals no visible scars with almost all hair follicles in the donor site reproducing hairs after 1 year. All treated patients were satisfied or very satisfied with their cosmetic results. PLFUT is a reliable, patient friendly method suitable for hair restoration of eyebrows in healthy persons as well as in burn scar tissue. PMID- 24810134 TI - Platelet-rich fibrin matrix (PRFM) for androgenetic alopecia. AB - The objective of this study was to determine the effect of platelet-rich fibrin matrix (PRFM) treatment on androgenetic alopecia. Prospective cohort study of 15 (9 male and 6 female) subjects with androgenetic alopecia for at least 1 year who were treated with intradermal injections of autologous PRFM three times on a monthly basis. Hair density indices were measured in triplicate in the same area of the scalp before the treatment and 1, 2, 3 and 6 months after initial treatment. Hair density index (HDI) measurements were obtained and compared with pretreatment values for each subject. After a series of three intradermal PRFM injections, hair density indices increased significantly at 2 (47.4 +/- 22.7%, p = 0.0031) and 3 (106.4 +/- 56.9%, p = 0.0277, paired t-test) months after the initial treatment, and approached statistical significance at 6 months (75.1 +/- 46.82%, p = 0.0606) after the initial treatment. Patients who achieved greater than 25% increase in HDI by 2 months after the initial treatment were more likely to have greater than 25% improvement at 6 months after the initial treatment (100 vs. 16.7%, p = 0.0476). Androgenetic alopecia affects a significant number of both men and women. A series of intradermal injections of autologous PRFM increased the HDI in patients with androgenetic alopecia at 2 and 3 months after initial treatment; this improvement approached statistical significance at 6 months after initiating treatment. Autologous PRFM injections may be a valuable treatment for androgenetic alopecia, particularly in cases with mild hair loss. The level of evidence is level 2. PMID- 24810135 TI - Contextual influences on employment of people with dual diagnosis: spinal cord injury and traumatic brain injury. AB - BACKGROUND/AIM: Research into the paid employment of people with spinal cord injury or traumatic brain injury is prevalent; however, little research has examined the factors that may support employment for adults with a concomitant spinal cord injury and traumatic brain injury (dual diagnosis). This study aimed to determine the level of paid employment reported by people with dual diagnosis and to explore contextual factors that supported paid employment. METHODS: This cross-sectional cohort study recruited 30 participants with dual diagnosis from a specialist spinal rehabilitation unit. Interviews were conducted during the first five years post-rehabilitation discharge to determine level of paid employment and contextual factors that supported employment. RESULTS: At interview, 47% of participants were in paid employment. Employment type at interview indicated a shift away from more physically intensive jobs. Employed and unemployed participants reported a high level of social support and reported experiencing few physical or attitudinal barriers in their day to day lives. These environmental factors did not differentiate between employed and unemployed participants (z range = -0.98 to -0.17; P value range = 0.33-0.86). The most common facilitator of employment identified by participants was the personal factor - motivation (93% of employed participants). CONCLUSION: When considering the impact of contextual factors on paid employment for people with a dual diagnosis of spinal cord injury/traumatic brain injury, personal factors may be of greater influence than environmental factors. Study participants experienced few physical or attitudinal barriers and reported highly supportive interpersonal relationships. PMID- 24810136 TI - Dietary variation and food hardness in sooty mangabeys (Cercocebus atys): implications for fallback foods and dental adaptation. AB - We present information on food hardness and monthly dietary changes in female sooty mangabeys (Cercocebus atys) in Tai Forest, Ivory Coast to reassess the hypothesis that thick molar enamel is parsimoniously interpreted as a response to consumption of hard foods during fallback periods. We demonstrate that the diet of sooty mangabeys varies seasonally, but that one food--Sacoglottis gabonensis- is the most frequently consumed food every month and year round. This food is the hardest item in the sooty diet. Given that this species has among the thickest enamel within the primate order, a plausible conclusion is that thick enamel in this taxon evolved not in response to seasonally critical function or fallback foods, but rather to the habitual, year round processing of a mechanically protected foodstuff. These data serve as a caution against de rigueur interpretations that reliance on fallback foods during lean periods primarily explains the evolution of thick enamel in primates. PMID- 24810137 TI - Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure. AB - BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) have been associated with increased risks of adverse birth outcomes. Disease activity and drug exposure may contribute to the association. METHODS: A cohort from the Swedish health registers including 470,110 singleton births in Sweden from July 2006 to December 2010; 1833 to women with UC and 1220 to women with CD. Birth outcomes for women with UC and CD were compared with outcomes among those without disease. Diseased women were categorized by drug exposure, need of surgery, and hospital admissions as (1) no disease activity and (2) stable or (3) flaring disease. Logistic regression was used to calculate odds ratios with adjustments (aOR) for maternal age, parity, smoking status, body mass index, and comorbidity. RESULTS: There were increased risks of preterm birth for both UC (aOR, 1.78; 95% confidence interval [CI], 1.49-2.13) and CD (aOR, 1.65; 95% CI, 1.33-2.06). Risks were more pronounced in women with flaring disease during pregnancy. Risks of small for gestational age, low Apgar score, and hypoglycemia were also increased. The risk of stillbirth was elevated in women with CD, particularly among those with flaring disease (aOR, 4.48; 95% CI, 1.67-11.90). Thiopurine exposure increased risks for preterm birth, both in women with stable (aOR, 2.41; 95% CI, 1.05-5.51) and with flaring disease (aOR, 4.90; 95% CI, 2.76-8.69). CONCLUSIONS: Women with UC and CD are at increased risk of adverse birth outcomes, such as stillbirth, growth restriction, and preterm birth, particularly when they suffer from flares throughout pregnancy. Thiopurine exposure seems to further increase risks, independently of disease activity. PMID- 24810138 TI - An optimized patient-reported ulcerative colitis disease activity measure derived from the Mayo score and the simple clinical colitis activity index. AB - BACKGROUND: There is a need for simple, noninvasive patient-driven disease assessment instruments in ulcerative colitis (UC). We sought to further assess and refine the previous described 6-point Mayo score. METHODS: A cross-sectional study of 282 UC patients was conducted assessing the correlation of the 2 patient reported Mayo score components (6-point Mayo score) with the simple clinical colitis activity index (SCCAI) and a single Likert scale of patient-reported disease activity. Spearman's correlation, sensitivity, specificity, and area under the receiver operating curves (AUC) were calculated. A separate validation study in 59 UC patients was also conducted. RESULTS: Participants predominantly had long-standing disease (83%) and were in self-reported remission (63%). The 6 point Mayo score correlated well with the SCCAI (rho = 0.71; P < 0.0001) and patient-reported disease activity (rho = 0.65; P < 0.0001). Using a cutpoint of 1.5, the 6-point Mayo score had 83% sensitivity and 72% specificity for patient defined remission, and 89% sensitivity and 67% specificity for SCCAI-defined remission (score, <2.5). The 6-point Mayo score and SCCAI had similar accuracy of predicting patient-defined remission (AUC = 0.84 and 0.87, respectively). Addition of the SCCAI general well-being question to the 6-point Mayo improved the predictive ability for patient-defined remission; and a new weighted score had an AUC of 0.89 in the development cohort and 0.93 in the validation cohort. The optimal cutpoint was 1.6. CONCLUSIONS: The patient-reported UC severity index that includes stool frequency, bleeding, and general well-being accurately measures clinical disease activity without requiring direct physician contact. PMID- 24810139 TI - Influence of Holy Month Ramadan on Alcohol Consumption in Turkey. AB - This study utilizes a balanced panel data set covering 50 monthly observations regarding the brewery products to examine the impact of holy month Ramadan on alcohol consumption in Turkey. In addition to the Ramadan, temperature, prices of the products and disposable income are other demand factors which are taken into account in this study. As expected, the Ramadan has been found to be associated with lower alcohol usage. As price of alcoholic drinks increases, the alcohol consumption decreases significantly. In addition, alcohol consumption rises with the enhancements in the disposable income. However, surprisingly, the temperature has not any significant effect on alcohol consumption in Turkey. PMID- 24810140 TI - Economic evaluation of robot-assisted hysterectomy: a cost-minimisation analysis. AB - OBJECTIVE: The aim of this study was to carry out an economic evaluation of robot assisted hysterectomy compared with the current standard of care in Ireland. DESIGN: Cost-minimisation analysis of robot-assisted hysterectomy compared with a combination of traditional open and conventional laparoscopic surgery. SETTING: The publicly funded healthcare system in Ireland. POPULATION: The target population was women requiring hysterectomy that could be completed using robot assisted surgery. METHODS: A simulation-based economic evaluation model including data derived from a systematic review and local databases was used to estimate surgical costs. MAIN OUTCOME MEASURES: Incremental cost of robot-assisted surgery compared to current routine care. RESULTS: The incremental cost of robot-assisted hysterectomy is an estimated ?3291 (95% confidence interval ?2509-?4183) more than the existing mix of open and traditional laparoscopic surgery. The additional cost of robot-assisted surgery is primarily driven by the increased cost of surgical equipment, the robot, maintenance of the robot, and the cost of theatre staff due to longer operative times. The only significant factor reducing the cost of surgery is a shorter hospital stay relative to open surgery. CONCLUSIONS: Robot-assisted hysterectomy is more costly than the current mix of open and traditional laparoscopic surgery. Without longer-term or functional outcome data, the additional expense associated with robot-assisted hysterectomy may not be justified in a budget-constrained health system. PMID- 24810141 TI - Theoretical investigation of the charge-transfer properties in different meso linked zinc porphyrins for highly efficient dye-sensitized solar cells. AB - The charge transfer effect of different meso-substituted linkages on porphyrin analogue 1 (A1, B1 and C1) was theoretically investigated using density functional theory (DFT) and time-dependent DFT (TDDFT) calculations. The calculated geometry parameters and natural bond orbital analysis reveal that the twisted conformation between porphyrin macrocycle and meso-substituted linkages leads to blocking of the conjugation of the conjugated backbone, and the frontier molecular orbital plot shows that the intramolecular charge transfer of A1, B1 and C1 hardly takes place. In an attempt to improve the photoinduced intramolecular charge transfer ability of the meso-linked zinc porphyrin sensitizer, a strong electron-withdrawing group (CN) was introduced into the anchoring group of analogue 1 forming analogue 2 (A2, B2 and C2). The density difference plot of A2, B2 and C2 shows that the charge transfer properties dramatically improved. The electron injection process has been performed using TDDFT; the direct charge-transfer transition in the A2-(TiO2)38 interacting system takes place; our results strongly indicated that introducing electron withdrawing groups into the acceptor part of porphyrin dyes can fine-tune the effective conjugation length of the pi-spacer and improve intramolecular charge transfer properties, consequently inducing the electron injection process from the anchoring group of the porphyrin dye to the (TiO2)38 surface which may improve the conversion efficiency of the DSSCs. Our calculated results can provide valuable information and a promising outlook for computation-aided sensitizer design with anticipated good properties in further experimental synthesis. PMID- 24810142 TI - Histology and ultrastructure of the lymph nodes of the buffalo (Bos bubalus). AB - Pre-scapular, femoral and mesenteric lymph nodes from five buffalo calves and five buffalo bulls were studied using light and transmission electron microscopy. The nodes were surrounded with a thin capsule of dense connective tissue and smooth muscles. Subcapsular and trabecular lymphatic sinuses were lined with endothelial cells resting on a basement membrane. The cortex was formed by lymphoid follicles and inter-follicular lymphocytes. Primary and secondary follicles were observed. The medulla was made up of medullary cords of lymphocytes separated by lymphatic sinuses. These sinuses were lined with a discontinuous epithelium and interestingly crossed by reticular fibres. High endothelial venules were found in the paracortical area. Several lymphocytes were observed infiltrating the wall of these venules. The lymph nodes of the Egyptian water buffalo showed a typical structure compared with the majority of mammals, with no age-related structural variation. PMID- 24810143 TI - A comparison of peak callers used for DNase-Seq data. AB - Genome-wide profiling of open chromatin regions using DNase I and high-throughput sequencing (DNase-seq) is an increasingly popular approach for finding and studying regulatory elements. A variety of algorithms have been developed to identify regions of open chromatin from raw sequence-tag data, which has motivated us to assess and compare their performance. In this study, four published, publicly available peak calling algorithms used for DNase-seq data analysis (F-seq, Hotspot, MACS and ZINBA) are assessed at a range of signal thresholds on two published DNase-seq datasets for three cell types. The results were benchmarked against an independent dataset of regulatory regions derived from ENCODE in vivo transcription factor binding data for each particular cell type. The level of overlap between peak regions reported by each algorithm and this ENCODE-derived reference set was used to assess sensitivity and specificity of the algorithms. Our study suggests that F-seq has a slightly higher sensitivity than the next best algorithms. Hotspot and the ChIP-seq oriented method, MACS, both perform competitively when used with their default parameters. However the generic peak finder ZINBA appears to be less sensitive than the other three. We also assess accuracy of each algorithm over a range of signal thresholds. In particular, we show that the accuracy of F-Seq can be considerably improved by using a threshold setting that is different from the default value. PMID- 24810145 TI - Limitations of log-rank tests for analysing longevity data in biogerontology. AB - Log-rank tests are sometimes used to analyse longevity data when other tests should be preferred. When the experimental design involves more than one factor, some authors perform several log-rank tests with the same data, which increases the risk to wrongly conclude that a difference among groups does exist and does not allow to test interactions. When analysing the effect of a single factor with more than two groups, some authors also perform several tests (e.g. comparing a control group to each of the experimental groups), because post hoc analysis is not available with log-rank tests. These errors prevent to fully appreciate the longevity results of these articles and it would be easy to overcome this problem by using statistical methods devoted to one-way or multi-way designs, such as Cox's models, analysis of variance, and generalised linear models. PMID- 24810144 TI - Role of growth arrest-specific gene 6 in the development of fungal allergic airway disease in mice. AB - Growth arrest-specific gene (Gas)6 is a secreted vitamin K-dependent protein with pleiotropic effects via activation of receptor tyrosine kinase Tyro3, Axl, and Mertk receptors, but little is known about its role in allergic airway disease. We investigated the role of Gas6 in the development of fungal allergic airway disease in mice. The immune response was evaluated in Gas6-deficient (Gas6-/-) and wild-type (WT) mice and in recombinant Gas6-treated WT mice during Aspergillus fumigatus-induced allergic airway disease. Gas6 plasma levels were significantly elevated in adult clinical asthma of all severities compared with subjects without asthma. In a murine model of fungal allergic airway disease, increased protein expression of Axl and Mertk were observed in the lung. Airway hyperresponsiveness (AHR), whole lung Th2 cytokine levels, goblet cell metaplasia, and peribronchial fibrosis were ameliorated in Gas6-/- mice compared with WT mice with fungal allergic airway disease. Intranasal Gas6 administration into WT mice had a divergent effect on airway inflammation and AHR. Specifically, a total dose of 2 MUg of exogenous Gas6 (i.e., low dose) significantly increased whole lung Th2 cytokine levels and subsequent AHR, whereas a total dose of 7 MUg of exogenous Gas6 (i.e., high dose) significantly suppressed Th1 and Th2 cytokines and AHR compared with appropriate control groups. Mechanistically, Gas6 promoted Th2 activation via its highest affinity receptor Axl expressed by myeloid DCs. Intranasal administration of Gas6 consistently exacerbated airway remodeling compared with control WT groups. These results demonstrate that Gas6 enhances several features of fungal allergic airway disease. PMID- 24810146 TI - Meta-analysis of Atherogenic Index of Plasma and other lipid parameters in relation to risk of type 2 diabetes mellitus. AB - AIMS: Diabetic dyslipidemia is one of important complication of type 2 diabetes mellitus (T2DM). Blood lipid parameters (e.g., triglyceride, TG; total cholesterol, TC; high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; Atherogenic Index of Plasma defined as lg(TG/HDL C), AIP), are important indexes in predicting risk of T2DM. This study performed comprehensive meta-analyses to evaluate the powers of these indexes, especially for AIP, on predicting risk of T2DM. METHODS: We searched PubMed Database, China National Knowledge Infrastructure (CNKI) and Wanfang Database in February 2014 to identify eligible studies. Case-control studies that have mean baseline values of AIP were included. Random-effect models were used to pool the summary standardized mean difference (SMD) in meta-analysis. RESULTS: Fifteen eligible studies, with a total sample size of 4010, were included in meta-analysis. All these studies reported positive associations between AIP and T2DM. Moreover, the SMD for the AIP is 1.78 (95% confidence interval (CI): 1.04-2.52), which is higher than for other parameters (TG: 0.93, 95% CI: 0.78-1.09; TC: 0.46, 95% CI: 0.21-0.71; HDL-C: -0.89, 95% CI: -1.18 to -0.60; and LDL-C: 0.44, 95% CI: 0.11 0.77). Meta-analysis of association between BMI and T2DM gave a SMD of 0.85 (95% CI: 0.38 to 1.32). CONCLUSIONS: The results suggest that lipid parameters have ability to reflect the risk of T2DM, but AIP may be more closely associated with the risk of T2DM. The current results suggest AIP may be used as a simple, easily calculated parameter in assessing the risk of T2DM. PMID- 24810148 TI - Delivering group treatment via videoconference to individuals with traumatic brain injury: a feasibility study. AB - The objective was to assess the feasibility of delivering a group treatment to improve emotional regulation via videoconferencing to individuals with traumatic brain injury (TBI). A pre-post feasibility study was undertaken. Seven individuals with TBI were recruited at a brain injury research centre in an urban medical centre. The main measures were therapist assessment of session-by-session progress and feasibility, Difficulties in Emotion Regulation Scale (DERS), Brain Injury Rehabilitation Trust Regulation of Emotions Questionnaire (BREQ), Satisfaction with Therapy and Therapist Scale (STTS), and exit interview. Attendance across sessions and participants was over 90%. Adequate skill acquisition and ease of use of the technology were demonstrated. Self-reported satisfaction with treatment was high. Participants noted several benefits in terms of the treatment delivery modality. There was no change is self-reported emotional dysregulation. This is the first study to report the use of videoconferencing for the delivery of group treatment to individuals with TBI. The exceptional compliance and self-reported satisfaction suggest that this treatment delivery option could be a viable alternative for increasing access to healthcare in this population. The findings of the study supported the development of a large clinical trial to assess treatment effectiveness. PMID- 24810147 TI - Initiation of treatment for incident diabetes: evidence from the electronic health records in an ambulatory care setting. AB - OBJECTIVE: We examined patterns and predictors of initiation of treatment for incident diabetes in an ambulatory care setting in the US. METHODS: Data were extracted from electronic health records (EHR) for active patients >= 35 years in a multispecialty, multiclinic ambulatory care organization with 1000 providers. New onset type 2 diabetes and subsequent treatment were identified using lab, diagnosis, medication prescription, and service use data. Time from the first evidence of diabetes until initial treatment, either medication or education/counseling, was examined using a Kaplan-Meier hazards curve. Potential predictors of initial treatment were examined using multinomial logistic models accounting for physician random effects. RESULTS: Of 2258 patients with incident diabetes, 55% received either medication or education/counseling (20% received both) during the first year. Of the treated patients, 68% received a treatment within the first four weeks, and 13% after initial 16 weeks. Strong positive predictors (P < 0.01) of combined treatment were younger age, higher fasting glucose at diagnosis, obesity, and visits with an endocrinologist. CONCLUSIONS: Among insured patients who have a primary care provider in a multispecialty health care system, incident diabetes is treated only half the time. Improved algorithms for identifying incident diabetes from the EHR and team approach for monitoring may help treatment initiation. PMID- 24810149 TI - Growth of primary motor neurons on horizontally aligned carbon nanotube thin films and striped patterns. AB - OBJECTIVE: Carbon nanotubes (CNTs) are attractive for use in peripheral nerve interfaces because of their unique combination of strength, flexibility, electrical conductivity and nanoscale surface texture. Here we investigated the growth of motor neurons on thin films of horizontally aligned CNTs (HACNTs). APPROACH: We cultured primary embryonic rat motor neurons on HACNTs and performed statistical analysis of the length and orientation of neurites. We next presented motor neurons with substrates of alternating stripes of HACNTs and SiO2. MAIN RESULTS: The neurons survived on HACNT substrates for up to eight days, which was the full duration of our experiments. Statistical analysis of the length and orientation of neurites indicated that the longest neurites on HACNTs tended to align with the CNT direction, although the average neurite length was similar between HACNTs and glass control substrates. We observed that when motor neurons were presented with alternating stripes of HACNTs and SiO2, the proportion of neurons on HACNTs increases over time, suggesting that neurons selectively migrate toward and adhere to the HACNT surface. SIGNIFICANCE: The behavior of motor neurons on CNTs has not been previously investigated, and we show that aligned CNTs could provide a viable interface material to motor neurons. Combined with emerging techniques to build complex hierarchical structures of CNTs, our results suggest that organised CNTs could be incorporated into nerve grafts that use physical and electrical cues to guide regenerating axons. PMID- 24810150 TI - Identifying factors associated with hypoglycemia-related hospitalizations among elderly patients with T2DM in the US: a novel approach using influential variable analysis. AB - OBJECTIVE: Healthcare providers managing older patients with type 2 diabetes mellitus (T2DM) face a complex milieu of medical conditions and comorbidities, which increase the risk of unintended treatment consequences. The objective of this study was to understand factors associated with hypoglycemia-related hospitalizations among adults with T2DM with an emphasis on older patients. RESEARCH DESIGN AND METHODS: A large retrospective cohort study using claims data from the United States was undertaken identifying actively registered patients diagnosed with T2DM and at least one diabetes medication prescription. MAIN OUTCOME MEASURES: The main outcomes included hypoglycemia-related hospitalization and frequency of comorbidities. RESULTS: Of patients with T2DM and hospitalization records (n = 887,182), 52.3% were male and 30.7% were aged >=65 years. At baseline, the proportion of patients taking metformin was 52.4%, insulin 7.3%, and sulfonylurea 26.4%. Among those with diabetes-related hospitalizations, the incidence of hospitalization-related hypoglycemia in patients >=65 years of age was greater than in patients <65 years of age (0.59 compared to 0.16 per 1000 person years). Using boosted regression tree modeling, age (older vs. younger), sulfonylurea use, insulin use, and renal disease were variables most associated with predicting hospitalizations associated with hypoglycemia. Elderly patients prescribed both insulin and sulfonylurea were most likely to experience hypoglycemia-related hospitalizations (odds ratio = 4.7; 95% CI 3.7-6.1). CONCLUSIONS: Older patients using both insulin and sulfonylurea were most likely to experience a hypoglycemia-related hospitalization. Age, sulfonylurea use, insulin use, renal disease, a history of hypoglycemia-related hospitalization and general hospitalization were the leading variables associated with hypoglycemia-related hospitalization. Glucagon-like peptide and dipeptidyl peptidase-4 medication use was not significantly associated with hypoglycemia related hospitalizations. The strength of this analysis, compared to similar studies, lies in the large and generalizable sample size and statistical methodology, which control for the interdependence of predictive variables. Limitations include lack of information, such as dietary intake and exercise habits, which are known to influence the rate of hypoglycemia in certain patients. Given the frequency of use of insulin and sulfonylurea in a population at risk for hypoglycemia (older patients with diabetes), care should be taken when balancing cost and efficacy against safety and increased risk of hospitalization due to hypoglycemia. PMID- 24810151 TI - Traumatic orbital compartment syndrome: importance of the lateral canthomy and cantholysis. AB - BACKGROUND: Orbital compartment syndrome (OCS) is an ophthalmic emergency that requires urgent surgical decompression to preserve vision. OBJECTIVE: To describe the clinical presentation, management and outcomes for patients with traumatic OCS. METHODS: Retrospective case series of eight patients with OCS secondary to blunt trauma presenting to the Royal Adelaide Hospital between 2004 and 2013. RESULTS: All patients had acute, painful decrease in visual acuity and proptosis. Common examination findings included a relative afferent pupillary defect, periorbital oedema, ophthalmoparesis and chemosis. All patients underwent surgical decompression in the form of a lateral canthotomy or cantholysis. Three patients who were decompressed within 2 h after injury recovered fully. One patient who sustained a macular hole at the time of injury recovered four lines of Snellen acuity after being decompressed within 1 h. Another patient recovered three lines of Snellen acuity after undergoing decompression at 2.5 h post injury. The remaining patients had minimal visual recovery, with postoperative visual acuities ranging from hand movements to no perception to light. Of these patients, one was decompressed at 2 h, while the remaining underwent decompression at 4 and 6 h post-injury. CONCLUSIONS: Prompt decompression is essential for visual recovery in OCS, which appears maximal if performed within 2 h of injury. All patients presenting with history and examination findings suggestive of OCS should undergo emergency canthotomy and cantholysis prior to any additional investigations to minimise visual loss. PMID- 24810152 TI - Invasive fungal infections in solid organ transplant recipients. AB - Solid organ transplant (SOT) recipients have a significant risk of invasive fungal diseases (IFD) caused mainly by Candida spp. and Aspergillus spp. Candida spp. is the most frequent agent of IFD in the transplant recipient. The absence of clinical trials and the epidemiological differences in IFD in different transplant programmes mean that there are no definitive recommendations for the diagnosis, treatment and prevention of IFD in SOT, so most of the evidence must be based on clinical experience. PMID- 24810153 TI - Giardia and Vilem Dusan Lambl. PMID- 24810155 TI - How many 'statuses' should the paediatrician be aware of? PMID- 24810156 TI - Autism: the management and support of children and young people on the autism spectrum (NICE Clinical Guideline 170). PMID- 24810158 TI - Technical review: In situ hybridization. AB - In situ hybridization is a technique that is used to detect nucleotide sequences in cells, tissue sections, and even whole tissue. This method is based on the complementary binding of a nucleotide probe to a specific target sequence of DNA or RNA. These probes can be labeled with either radio-, fluorescent-, or antigen labeled bases. Depending on the probe used, autoradiography, fluorescence microscopy, or immunohistochemistry, respectively, are used for visualization. In situ hybridization is extensively used in research, as well as clinical applications, especially for diagnostic purposes. This review discusses the basic technique of in situ hybridization. The standard in situ hybridization process is reviewed, and different types of in situ hybridization, their applications, and advantages and disadvantages are discussed. PMID- 24810159 TI - A clip in time--selecting interventions for severe mitral valve regurgitation. PMID- 24810160 TI - Aurora-A signaling is activated in advanced stage of squamous cell carcinoma of head and neck cancer and requires osteopontin to stimulate invasive behavior. AB - The clinical significances, cellular effects, and molecular mechanisms by which Aurora-A mediate its invasive effects in HNSCC are still unclear. Here, we found that Aurora-A expression is significantly higher in tumor tissues on 14 microarray of HNSCC in Oncomine-databases. The activity of Aurora-A was not only found in HNSCC specimens, but also significantly correlated with advanced-T classification, positive-N-classification, TNM-stage and the poor 5-year survival rate. HNSCC-microarray profile showed that osteopontin and Aurora-A exhibited positive correlation. Stimulation of HNC cells with osteopontin results in an increase in Aurora-A expression where localized at the centrosome. Functionally, Aurora-A had the abilities to stimulate cell motility in HNC cells through increase ERK1/2 activity under osteopontin stimulation. Conversely, depletion of Aurora-A expression by siRNAs suppressed ERK1/2 activity as well as inhibition of cell invasiveness. Treatment with anti-CD44 antibodies in HNC cells not only caused a decrease of mRNA/protein of Aurora-A and ERK1/2 activity upon osteopontin stimulation, but also affected the abilities of Aurora-A-elicited cell motility. Finally, immunohistochemical/Western-blotting analysis of human aggressive HNSCC specimens showed a significant positively correlation between osteopontin-Aurora-A and ERK1/2. These findings suggest that Aurora-A is not only an important prognostic factor but also a new therapeutic target in the osteopontin/CD44/ERK pathway for HNSCC treatment. PMID- 24810161 TI - Root interactions in a maize/soybean intercropping system control soybean soil borne disease, red crown rot. AB - BACKGROUND: Within-field multiple crop species intercropping is well documented and used for disease control, but the underlying mechanisms are still unclear. As roots are the primary organ for perceiving signals in the soil from neighboring plants, root behavior may play an important role in soil-borne disease control. PRINCIPAL FINDINGS: In two years of field experiments, maize/soybean intercropping suppressed the occurrence of soybean red crown rot, a severe soil borne disease caused by Cylindrocladium parasiticum (C. parasiticum). The suppressive effects decreased with increasing distance between intercropped plants under both low P and high P supply, suggesting that root interactions play a significant role independent of nutrient status. Further detailed quantitative studies revealed that the diversity and intensity of root interactions altered the expression of important soybean PR genes, as well as, the activity of corresponding enzymes in both P treatments. Furthermore, 5 phenolic acids were detected in root exudates of maize/soybean intercropped plants. Among these phenolic acids, cinnamic acid was released in significantly greater concentrations when intercropped maize with soybean compared to either crop grown in monoculture, and this spike in cinnamic acid was found dramatically constrain C. parasiticum growth in vitro. CONCLUSIONS: To the best of our knowledge, this study is the first report to demonstrate that intercropping with maize can promote resistance in soybean to red crown rot in a root-dependent manner. This supports the point that intercropping may be an efficient ecological strategy to control soil-borne plant disease and should be incorporated in sustainable agricultural management practices. PMID- 24810162 TI - Deconstructing alcohol use on a night out in England: promotions, preloading and consumption. AB - INTRODUCTION AND AIMS: To examine alcohol consumed during a drinking event (a single drinking occasion) by those attending public house/on-trade establishments on nights with standard pricing and nights with promotional prices. DESIGN AND METHODS: Data (n = 425) were collected in an ecological momentary assessment over eight nights in two locations (Midlands and London) on both promotional and standard (Saturday) nights. Multiple regression was used to predict event alcohol consumption by sex, age, type of night, alcohol preloading behaviour, marital and employment status, education, Alcohol Use Disorders Identification Test alcohol consumption questions separately or total AUDIT-C and social group size. RESULTS: Mean (UK) units consumed were 11.8 (London) and 14.4 (Midlands). In London, consumption was similar on promotional and standard nights, but in the Midlands, standard night consumption was three units higher. Preloading was reported by 30%; more common on standard nights. Regression analyses revealed being male, preloading and past-year total AUDIT-C were associated with higher event consumption. However, when AUDIT-C questions were added separately, being a standard night was associated with increased event consumption and different AUDIT-C questions were significantly associated with event consumption in each location. DISCUSSION AND CONCLUSIONS: Event consumption reflected heavy episodic drinking and was influenced by price. Promotional night consumption either matched standard Saturday night consumption or was slightly lower. In London, there was a significant preference for drinking at least one promotional beverage on promotional nights. On standard nights, consumption was over a wider range of venues, and preloading with off-trade alcohol was more likely. PMID- 24810163 TI - Atypical presentations of spontaneous spinal epidural hematomas. PMID- 24810164 TI - Myxococcus xanthus gliding motors are elastically coupled to the substrate as predicted by the focal adhesion model of gliding motility. AB - Myxococcus xanthus is a model organism for studying bacterial social behaviors due to its ability to form complex multi-cellular structures. Knowledge of M. xanthus surface gliding motility and the mechanisms that coordinated it are critically important to our understanding of collective cell behaviors. Although the mechanism of gliding motility is still under investigation, recent experiments suggest that there are two possible mechanisms underlying force production for cell motility: the focal adhesion mechanism and the helical rotor mechanism, which differ in the biophysics of the cell-substrate interactions. Whereas the focal adhesion model predicts an elastic coupling, the helical rotor model predicts a viscous coupling. Using a combination of computational modeling, imaging, and force microscopy, we find evidence for elastic coupling in support of the focal adhesion model. Using a biophysical model of the M. xanthus cell, we investigated how the mechanical interactions between cells are affected by interactions with the substrate. Comparison of modeling results with experimental data for cell-cell collision events pointed to a strong, elastic attachment between the cell and substrate. These results are robust to variations in the mechanical and geometrical parameters of the model. We then directly measured the motor-substrate coupling by monitoring the motion of optically trapped beads and find that motor velocity decreases exponentially with opposing load. At high loads, motor velocity approaches zero velocity asymptotically and motors remain bound to beads indicating a strong, elastic attachment. PMID- 24810165 TI - Structure and inhibition of mouse leukotriene C4 synthase. AB - Leukotriene (LT) C4 synthase (LTC4S) is an integral membrane protein that catalyzes the conjugation reaction between the fatty acid LTA4 and GSH to form the pro-inflammatory LTC4, an important mediator of asthma. Mouse models of inflammatory disorders such as asthma are key to improve our understanding of pathogenesis and potential therapeutic targets. Here, we solved the crystal structure of mouse LTC4S in complex with GSH and a product analog, S-hexyl-GSH. Furthermore, we synthesized a nM inhibitor and compared its efficiency and binding mode against the purified mouse and human isoenzymes, along with the enzymes' steady-state kinetics. Although structural differences near the active site and along the C-terminal alpha-helix V suggest that the mouse and human LTC4S may function differently in vivo, our data indicate that mouse LTC4S will be a useful tool in future pharmacological research and drug development. PMID- 24810166 TI - Identification of coagulase-negative staphylococci in daily disposable contact lens wearers. AB - This study aimed to identify and quantify the number of contaminating organisms on daily disposable (DD) soft contact lenses, which may be responsible for mild cases of keratitis that occur with this lens wear modality. Ten participants wore DD lenses, and 10 participants wore planned replacement (PR) lenses. Lenses were collected aseptically and analysed for microbial contamination. Colony-forming units (CFU) were recorded, and representative colonies were used for identification using the API identification system. The DD lenses evaluated in this study were contaminated with coagulase-negative staphylococcus (CNS), ranging from 1 to 653 CFU. PR lenses showed more diversity in the types of contaminating micro-organisms and consisted of CNS, Gram-negative bacteria (Pseudomonas), a yeast (Candida) and a mould (Aspergillus), ranging from 1 to 230 CFU. CNS was the only type of micro-organism found on DD contact lenses and therefore may be the cause of any form of keratitis observed in DD lens wearers. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to determine the frequency and identify the contaminating organisms found on daily disposable (DD) soft contact lenses. The contaminating organisms identified on DD contact lenses were solely coagulase-negative staphylococcus (CNS), suggesting that CNS may be the causative organism associated with infectious keratitis that occurs with DD contact lens wear. PMID- 24810167 TI - FokI polymorphism in the vitamin D receptor gene (VDR) and its association with lumbar spine pathologies in the Italian population: a case-control study. AB - Alterations in vitamin D homeostasis, mainly involving its nuclear receptor (VDR), could have a role in the pathophysiology of the spine. The association between VDR polymorphisms and spine disorders has been analyzed in different ethnic groups, focusing on the functional FokI polymorphism. However, so far, inconsistent findings were reported. The aims of this study were to evaluate, in the Italian white population, the VDR FokI polymorphism frequencies distribution in subjects with clearly defined lumbar spinal pathologies compared to asymptomatic controls and to analyze the interplay of genetic and conventional risk factors. Using a case-control design, 267 patients with spinal disorders and 220 asymptomatic controls were enrolled, evaluating their exposition to putative risk factors. Patients' clinical assessment was performed by Magnetic Resonance Imaging. FokI polymorphism (rs2228570) was detected by PCR-RFLP. Genotypes were designated by a lowercase letter (f allele, T nucleotide) for the presence of the restriction site and by a capital letter (F allele, C nucleotide) for its absence. Family history, higher age and BMI, exposure to vibration, physical job demand, smoking habit and lower practice of leisure physical activity were associated with spinal disorders. The FF genotype and F allele represented approximately 2-fold risk factors to develop discopathies and/or osteochondrosis concomitant with disc herniation, while f allele was protective. In conclusion, the link we observed between VDR FokI variants and specific lumbar spine pathologies suggests that spinal tissue degeneration is influenced by the genetic background. Future studies should evaluate the signaling pathways involving alterations in VDR and influencing the development and/or progression of spine disorders. PMID- 24810168 TI - Associations of suPAR with lifestyle and cardiometabolic risk factors. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR), a novel indicator of low-grade inflammation, is associated with cardiovascular disease and mortality in the general population, while an unhealthy lifestyle influences inflammatory status. We aimed to explore the relationship of suPAR with lifestyle and cardiometabolic risk factors in a black South African population. DESIGN: This cross-sectional study includes 1068 men and women (56.4 +/- 10.1 years) from the North West province who took part in the South African leg of the Prospective Urban and Rural Epidemiology (PURE) study in 2010. Captured data included a detailed lifestyle profile (tobacco use, alcohol consumption, physical activity, psychological and dietary intake status), biochemical analyses (suPAR, C-reactive protein (CRP), glucose and lipids), as well as cardiovascular and anthropometric measurements. RESULTS: In exploratory analyses, we observed positive relationships between suPAR and lifestyle factors, such as tobacco use (P-trend < 0.001), both alcohol consumption (P-trend = 0.001) and gamma-glutamyl transferase (GGT) (P-trend < 0.001) and unemployment (P-trend = 0.002). suPAR and CRP correlated significantly (r = 0.23; P < 0.001). These relationships were confirmed in multiple regression analyses as suPAR independently associated with tobacco use (beta = 0.13; P < 0.001), GGT (beta = 0.24; P < 0.001) and unemployment (beta = 0.07; P = 0.039). suPAR did not associate with the cardiometabolic factors glucose, lipids, blood pressure or measures of adiposity. CONCLUSION: suPAR was independently associated with unhealthy lifestyle behaviours, but not with cardiometabolic risk factors suggesting that suPAR, as known predictor of cardiovascular disease and mortality, is augmented by modifiable cardiovascular risk factors. These findings emphasise the need for a healthy lifestyle to decrease the burden of cardiovascular disease in Africans. PMID- 24810169 TI - Relaxed open mouth as a playful signal in wild ring-tailed lemurs. AB - Play signals are commonly used by animals to communicate their playful motivation and to limit the risk that rough acts are misunderstood by playmates. The relaxed open mouth is the most common facial expression performed during play in many mammals and represents the ritualized version of the movement anticipating a play bite. The signaling nature of this expression has been proven in many haplorrhine species but never demonstrated in strepsirrhines. Our purpose was assessing whether, also in strepsirrhines, the relaxed open mouth has an actual communicative function. We studied wild ring-tailed lemurs (Lemur catta), characterized by highly social habits including intense playful interactions. They largely use playful signals, mostly performed with the black and white tail. The signaling function of the tail (tail play) has been widely demonstrated. We analyzed both tail play and the relaxed open mouth to verify how their distribution is affected by different play variables (e.g., play session symmetry, number of play mates, previous use of the same pattern). Indeed, ring tailed lemurs use the relaxed open mouth as a communicative signal during play. Relaxed open mouth was more frequent during unbalanced interactions showing the highest asymmetry in the patterns performed by the two players (offensive/neutral). Compared to tail play, relaxed open mouth was more frequent during dyadic than polyadic interactions and, as a highly directional signal, it was more frequently replicated by the play mate. Therefore, the relaxed open mouth needs to be performed face-to-face so that signal detection can be optimized. Similar to previous findings in monkeys and apes, the relaxed open mouth in lemurs seems to be a ritualized signal used to engage and, perhaps, sustain playful interaction. PMID- 24810170 TI - Synthesis of RpoS is dependent on a putative enhancer binding protein Rrp2 in Borrelia burgdorferi. AB - The RpoN-RpoS regulatory pathway plays a central role in governing adaptive changes by B. burgdorferi when the pathogen shuttles between its tick vector and mammalian hosts. In general, transcriptional activation of bacterial RpoN (sigma54)-dependent genes requires an enhancer binding protein. B. burgdorferi encodes the putative enhancer binding protein Rrp2. Previous studies have revealed that the expression of sigma54-dependent rpoS was abolished in an rrp2 point mutant. However, direct evidence linking the production of Rrp2 in B. burgdorferi and the expression of rpoS has been lacking, primarily due to the inability to inactivate rrp2 via deletion or insertion mutagenesis. Herein we introduced a regulatable (IPTG-inducible) rrp2 expression shuttle plasmid into B. burgdorferi, and found that the controlled up-regulation of Rrp2 resulted in the induction of sigma54-dependent rpoS expression. Moreover, we created an rrp2 conditional lethal mutant in virulent B. burgdorferi. By exploiting this conditional mutant, we were able to experimentally manipulate the temporal level of Rrp2 expression in B. burgdorferi, and examine its direct impact on activation of the RpoN-RpoS regulatory pathway. Our data revealed that the synthesis of RpoS was coincident with the IPTG-induced Rrp2 levels in B. burgdorferi. In addition, the synthesis of OspC, a lipoprotein required by B. burgdorferi to establish mammalian infection, was rescued in the rrp2 point mutant when RpoS production was restored, suggesting that Rrp2 influences ospC expression indirectly via its control over RpoS. These data demonstrate that Rrp2 is required for the synthesis of RpoS, presumably via its action as an enhancer binding protein for the activation of RpoN and subsequent transcription of rpoS in B. burgdorferi. PMID- 24810171 TI - Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2-ARE signaling pathway as a potential mechanism. AB - The goal of this study was to evaluate the potential involvement of melatonin in the activation of the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling pathway and the modulation of antioxidant enzyme activity in an experimental model of traumatic brain injury (TBI). In experiment 1, ICR mice were divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + melatonin group (n = 38 per group). Melatonin (10mg/kg) was administered via an intraperitoneal (ip) injection at 0, 1, 2, 3, and 4h post-TBI. In experiment 2, Nrf2 wild-type (Nrf2(+/+) group) and Nrf2 knockout (Nrf2(-/-) group) mice received a TBI insult followed by melatonin administration (10mg/kg, ip) at the corresponding time points (n = 35 per group). The administration of melatonin after TBI significantly ameliorated the effects of the brain injury, such as oxidative stress, brain edema, and cortical neuronal degeneration. Melatonin markedly promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus; increased the expression of Nrf2-ARE pathway related downstream factors, including heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1; and prevented the decline of antioxidant enzyme activities, including superoxide dismutase and glutathione peroxidase. Furthermore, knockout of Nrf2 partly reversed the neuroprotection of melatonin after TBI. In conclusion, melatonin administration may increase the activity of antioxidant enzymes and attenuate brain injury in a TBI model, potentially via mediation of the Nrf2-ARE pathway. PMID- 24810172 TI - Haemoproteus iwa in Great Frigatebirds (Fregata minor) in the Islands of the Western Indian Ocean. AB - Blood parasites of the sub-genus Haemoproteus have been reported in seabirds, in particular in species in the Suliformes order. These parasites are transmitted by hippoboscid flies of the genus Olfersia; strong specificity has been suggested between the vector and its vertebrate host. We investigated the prevalence of Haemoproteus infection in Suliformes and hippoboscid flies in two oceanic islands of the Western Indian Ocean: Europa and Tromelin. In total, 209 blood samples were collected from great frigatebirds (Fregata minor), masked boobies (Sula dactylatra) and red-footed boobies (Sula sula). Forty-one hippoboscid flies were also collected from birds. Seventeen frigatebirds and one fly collected on Europa tested positive for the presence of Haemoproteus parasites by polymerase chain reaction. Phylogenetic analyses based on partial sequences of the Cytochrome b gene showed that parasites were closely related to Haemoproteus iwa reported from frigatebirds in the Pacific Ocean and in the Caribbean. Plasmodium was also detected in a frigatebird on Europa; however, its placement on the phylogenetic tree could not be resolved. We provide strong support for transmission of blood parasites in seabirds in the Western Indian Ocean and suggest that migrations between the Pacific and the Indian oceans could favor the large-scale distribution of Haemoproteus iwa in frigatebird populations. PMID- 24810173 TI - Genomics, phylogeny and in silico analysis of mitochondrial glutathione S transferase-kappa from the camel Camelus dromedarius. AB - The domesticated one-humped camel, Camelus dromedarius, is one of the most important animals in the Arabian Peninsula. For most of its life, this species is exposed to both intrinsic and extrinsic genotoxic factors that cause gross DNA alterations in many organisms. GST enzymes constitute an important supergene family involved in protection against the deleterious effects of oxidative stress and xenobiotics. Cloning the camel mitochondrial GST kappa (GSTK) gene and comparing its structural similarities with different species may aid in understanding its evolutionary relics. We cloned the camel GSTK using RT-PCR. This yielded an open reading frame of 678 nucleotides, encoding a protein of 226 amino acid residues. In a comparative analysis, the cloned GSTK was used to screen orthologues from different organisms. Phylogenetic analysis demonstrated that the camel GSTK apparently evolved from an ancestral GSTK gene that predated the appearance of vertebrates, and it grouped with pig, cattle, dog, horse, human and monkey GSTKs. The calculated molecular weight of the translated ORF was 25.52 kDa and the isoelectric point was 8.4. The deduced cGSTK sequence exhibited high identity with many mammals, such as Bactrian camel (99.55%), pig, cattle and human (>74%), and lower identity with other unrelated organisms, such as frog (Xenopus tropicalis, 61%), chicken (Gallus gallus, 57%), salmon (Salmo salar, 49%), sponge (Amphimedon queenslandica, 46%), tick (Amblyomma maculatum, 45%) and roundworm (Caenorhabditis elegans, 33%). A 3D structure was built based on the crystal structure of the human and rat enzymes. The levels of cGSTK expression in five camel tissues were examined via real-time PCR. The highest level of cGSTK transcripts was found in the camel liver, followed by the testis, spleen, kidney and lung. PMID- 24810174 TI - A new scoring system for upper airway pediatric sleep endoscopy. AB - IMPORTANCE: Sleep-associated upper-airway obstruction in children is a significant cause of morbidity. Development of a simple, standardized, quantitative technique to assess anatomic causes of sleep-related breathing disorder is important for surgical planning, clinical communication, and research. OBJECTIVE: To design, implement, and evaluate a scoring system to quantify airway obstruction in pediatric drug-induced sleep endoscopy. DESIGN, SETTING, AND PARTICIPANTS: This study was a retrospective case series conducted at a tertiary pediatric hospital. The patients were children with sleep-related breathing disorder who underwent polysomnography and drug-induced sleep endoscopy. INTERVENTIONS: Flexible fiber-optic laryngoscopy was performed. Endoscopic examinations were recorded on video and assessed by 4 independent raters based on a scoring template. MAIN OUTCOMES AND MEASURES: Five locations in the upper aerodigestive tract (adenoid, velum, lateral pharyngeal wall, tongue base, and supraglottis) were evaluated on a 4-point scale for minimum and maximum obstruction. Internal reliability was assessed by calculating interrater and intrarater intraclass correlation coefficients (ICCs). For external validation, aggregate and site-specific scores were correlated with preoperative polysomnographic indices. RESULTS: Videos recorded of sleep endoscopies from 23 children (mean age, 2.2 years) were reviewed and rated. Children had an average apnea-hypopnea index of 24.8. Seventy percent of interrater and intrarater ICC values (7 of 10 for each set) were above 0.6, demonstrating substantial agreement. Higher total obstructive scores were associated with lower oxygen saturation nadir (P = .04). The scoring system was also used to quantitatively identify children with multilevel airway obstruction, who were found to have significantly worse polysomnographic indices compared with children with single level obstruction (P = .02). CONCLUSIONS AND RELEVANCE: The proposed scoring system, which is designed to be easy to use and allow for subjectivity in evaluating obstruction at multiple levels, nonetheless achieves good internal reliability and external validity. Implementing this system will allow for standardization of reporting for sleep endoscopy outcomes, as well as aid the practicing clinician in the interpretation of sleep endoscopy findings to inform site-directed surgical intervention in cases of complicated obstructive sleep apnea. PMID- 24810175 TI - Virulence variation among epidemic and non-epidemic strains of Saint Louis encephalitis virus circulating in Argentina. AB - Saint Louis encephalitis virus caused an outbreak of febrile illness and encephalitis cases in Cordoba, Argentina, in 2005. During this outbreak, the strain CbaAr-4005 was isolated from Culex quinquefasciatus mosquitoes. We hypothesised that this epidemic variant would be more virulent in a mouse model than two other non-epidemic strains (78V-6507 and CorAn-9275) isolated under different epidemiological conditions. To test this hypothesis, we performed a biological characterisation in a murine model, including mortality, morbidity and infection percentages and lethal infection indices using the three strains. Mice were separated into age groups (7, 10 and 21-day-old mice) and analysed after infection. The strain CbaAr-4005 was the most infective and lethal of the three variants, whereas the other two strains exhibited a decreasing mortality percentage with increasing animal age. The strain CbaAr-4005 produced the highest morbidity percentages and no significant differences among age groups were observed. The epidemic strain caused signs of illness in all inoculated animals and showed narrower ranges from the onset of symptoms than the other strains. CbaAr-4005 was the most virulent for Swiss albino mice. Our results highlight the importance of performing biological characterisations of arbovirus strains likely to be responsible for emerging or reemerging human diseases. PMID- 24810176 TI - Acute dacryocystitis: another clinical manifestation of sporotrichosis. AB - Sporotrichosis associated with exposure to domestic cats is hyperendemic in Rio de Janeiro, Brazil. A review of the clinical records at our institute revealed four patients with clinical signs of dacryocystitis and a positive conjunctival culture for Sporothrix who were diagnosed with Sporothrix dacryocystitis. Three patients were children (< 13 years of age) and one patient was an adult. Two patients reported contact with a cat that had sporotrichosis. Dacryocystitis was associated with nodular, ulcerated lesions on the face of one patient and with granulomatous conjunctivitis in two patients; however, this condition manifested as an isolated disease in another patient. All of the patients were cured of the fungal infections, but three patients had chronic dacryocystitis and one patient developed a cutaneous fistula. Sporotrichosis is usually a benign disease, but may cause severe complications when the eye and the adnexa are affected. Physicians, especially ophthalmologists in endemic areas, should be aware of the ophthalmological manifestations and complications of sporotrichosis. PMID- 24810177 TI - Haplomyxa saranae gen. nov. et sp. nov., a new naked freshwater foraminifer. AB - A new naked foraminifer, Haplomyxa saranae gen. nov. sp. nov., is described from an established cell line made from a single cell isolated from a freshwater garden pond. The new species was morphologically close to Reticulomyxa filosa, the only valid naked freshwater foraminifer species. However the two species differed when it came to the morphology of the cell body, the number of cysts, and the nutrition. The 18S rRNA gene had one of the longest sequences to date (4863 nucleotides), and it contained many insertions that are typical of Foraminifera. The size of this gene was 45% longer than the one of R. filosa due to the elongation of A+T rich regions, but molecular phylogeny based on conserved regions of the 3'-end placed the new species in the same morphological clade K. This report includes both morphological and genetic data which undoubtedly show that the new species is a new naked freshwater foraminifer and the second species of the clade K. PMID- 24810178 TI - The dinoflagellate Lingulodinium has predicted casein kinase 2 sites in many RNA binding proteins. AB - Many cellular processes in the dinoflagellate Lingulodinium polyedrum are controlled by a circadian (daily) clock. Since the activity of proteins involved in various metabolic pathways or in regulating gene expression can be affected by phosphorylation, we established a generalized phosphoproteome catalog using LC MS/MS to analyze a phosphoprotein-enriched fraction. Over 11,000 peptides were identified by comparison to a Lingulodinium transcriptome, and 527 of these had at least one identified phosphosite. Gene ontology analysis revealed that RNA binding and translation were one of the major categories among these proteins identified by these peptides. Since casein kinase 2 (CK2) is known to be important in eukaryotic circadian biology substrates, we next tried to identify specific substrates for this kinase. To achieve this we first classified and catalogued the kinases in the Lingulodinium transcriptome then assigned the different phosphosites to the different kinase classes. Interestingly, potential CK2 targets include a substantial proportion of RNA binding proteins. Phosphosite identification thus provides a promising new approach to investigate the Lingulodinium circadian system. PMID- 24810179 TI - Interplay between the ionic and electronic transport and its effects on the reaction pattern during the electrochemical conversion in an FeF2 nanoparticle. AB - Using a charge dependent embedded atom method potential in conjunction with a dynamically adaptive multibody force field, the conversion reaction in an iron difluoride nanoparticle exposed to lithium ions is investigated. The reactions take advantage of the multiple valence states of the cations. A subtle interplay between the ionic and electronic transport, which is not accessible in conventional fixed-charge simulations, has been revealed. The simulated reaction pattern is in close agreement with that observed experimentally at the nanoscale, while providing detailed atomistic mechanisms. Due to difference in the ionic and electronic transport, different stages of reaction are observed and the corresponding phase growth mechanisms have been identified. Initially local Li concentration plays a key role in driving the reaction through amorphous reaction products to the crystalline phases that inhibit Li transport. However, electronic transport and interfacial ion diffusion are shown to be important in creating further transport pathways that allow continued conversion reactions, providing the mechanism that enables the use of these materials in advanced high capacity lithium ion batteries. Such interplay between the ionic and electronic transport will also be important in other materials and devices for energy conversion and storage. PMID- 24810180 TI - Amperometric biosensor system for simultaneous determination of adenosine-5' triphosphate and glucose. AB - The majority of biosensors for adenosine-5'-triphosphate (ATP) determination are based on cascades of enzymatic reactions; therefore, they are sensitive to glucose or glycerol (depending on the enzymatic system) as well as to ATP. The presence of unknown concentrations of these substances in the sample greatly complicates the determination of ATP. To overcome this disadvantage of known biosensors, we developed a biosensor system consisting of two biosensors: the first one is based on glucose oxidase and is intended for measuring glucose concentration, and the second one is based on glucose oxidase and hexokinase and is sensitive toward both glucose and ATP. Using glucose concentration measured by the first biosensor, we can analyze the total response to glucose and ATP obtained by the second biosensor. Platinum disc electrodes were used as amperometric transducers. The polyphenilenediamine membrane was deposited onto the surface of platinum electrodes to avoid the response to electroactive substances. The effect of glucose concentration on biosensor determination of ATP was studied. The reproducibility of biosensor responses to glucose and ATP during a day was tested (relative standard deviation, RSD, of responses to glucose was 3 6% and to ATP was 8-12%) as well as storage stability of the biosensors (no decrease of glucose responses and 43% drop of ATP responses during 50 days). The measurements of ATP and glucose in pharmaceutical vials (including mixtures of ATP and glucose) were carried out. It was shown that the developed biosensor system can be used for simultaneous analysis of glucose and ATP concentrations in water solutions. PMID- 24810181 TI - Results of a phase 1, randomized study evaluating the effects of food and diurnal variation on the pharmacokinetics of linifanib. AB - PURPOSE: The primary objectives of this study were to evaluate the effect of food on the oral bioavailability and to evaluate the effect of diurnal variation on the pharmacokinetics of linifanib, a novel tyrosine kinase (TK) inhibitor selective for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, in patients with advanced solid tumors. Adverse events were monitored. METHODS: This was a phase 1, open-label, randomized, crossover study. Thirty-four patients received dosing regimens to evaluate linifanib pharmacokinetic parameters under fasting and non-fasting conditions and with morning or evening dosing. Adverse events (AEs) were assessed according to National Cancer Institute Common Terminology Criteria for AEs (Version 3.0). RESULTS: The administration with food had a negligible effect on the AUCinfinity of linifanib, but the Cmax of linifanib was decreased by 40 % compared to the fasting condition. Evening dosing after a 2-h fast had a negligible effect on AUC24; however, the dose-normalized Cmax of linifanib after evening dosing was 64 % of that after morning dosing following a 10-h fast. Common Grade 3/4 AEs were fatigue (24 %), hypertension (21 %), and palmar-plantar erythrodysaesthesia syndrome (15 %). CONCLUSIONS: Dosing with food or in the evening has a significant effect on the oral bioavailability of linifanib that should be taken into consideration when designing future clinical studies. The pattern of adverse advents reported in this study is similar to that seen in other studies of linifanib and other agents in the VEGF/PDGF TK receptor inhibitor class. PMID- 24810182 TI - Do male and female patients with chronic neck pain really have different health related physical fitness, depression, anxiety and quality of life parameters? AB - AIM: The purpose of this study was to investigate whole body physical fitness parameters such as maximal aerobic capacity (VO2 max), muscle strength, trunk flexibility, daily physical activity, pulmonary function, body composition, anxiety and depression, as well as other disease-related changes in patients with chronic neck pain (CNP), and to compare them with healthy controls. METHOD: Eighty patients (40 male, 40 female) with CNP and 80 (40 male, 40 female) controls were included in this study. VO2 max, handgrip and back-leg strengths, trunk flexibility, daily physical activity, pulmonary function test (PFT), body composition and pressure pain threshold (PPT) measurements were carried out. Neck disability index (NDI), Beck anxiety inventory (BAI), Beck depression inventory (BDI), Pittsburg sleep quality index (PSQI), and Short-Form health survey (SF-36) questionnaires were applied to all participants. RESULTS: Handgrip and back-leg strengths and suboccipital and paraspinal-C7 PPTs and health-related quality of life (HRQoL) were lower, and PSQI, BAI and BDI were higher, in female patients with CNP, compared to healthy controls; whereas, VO2 max and HRQoL were lower, and body fat percantage and PSQI were higher, in male patients with CNP, compared to healthy controls. Trunk flexibility and PFT values were not significantly different between the patients and the controls in both genders. CONCLUSION: We suggest that, on the basis of gender, consideration of not only the neck region but also whole body physical fitness, anxiety and depression parameters in patients with CNP might be helpful to the development of more benefical strategies for illness management. PMID- 24810183 TI - Everything you always wanted to know about ethical issues in gastroenterology... PMID- 24810184 TI - 'Please, sir, can I have some more?' Food, lifestyle, diets: respect and moral responsibility. AB - This article is about respect for food, responsibility for lifestyle and diet and responsibility for those who suffer from lack of food. After some general reflections on food, feasts, flatulence, taboos and waste, I argue that we have a responsibility to live a healthy lifestyle, but that there are also morally good reasons for taking risks with our health as we cherish other goals and values. Then I discuss situations, using the example of obesity, in which people are not free to choose their lifestyle. Governments and doctors have responsibilities in enabling people to chose healthy eating habits, e.g. by facilitating access to healthy foods and by criticizing scientifically unfounded weight loss diets. I continue to defend that we need to respect food and those who prepare it, and that we have a moral responsibility to contribute to the solution of the food gap in the world. PMID- 24810185 TI - Artificial nutrition at the end of life: ethical issues. AB - Artificial nutrition is a medical treatment that first of all needs a sound scientific base before prescribing it. This base is absent for dying patients and patients in the end stage of dementia. Because feeding is a very emotional and symbolical issue, patient and family may request this treatment despite the lack of evidence. These issues should be addressed in good communication with patient and relatives. For comatose patients and patients in a persistent vegetative state artificial nutrition is a necessary support to bridge the time until either recovery is imminent or improbable. At that moment artificial nutrition no longer contributes to the life of the patient and should be ceased. Artificial nutrition has no place in patients that voluntary decide to stop eating and drinking in order to die. PMID- 24810186 TI - Letter to the Editor/Case report: why should we not tube-feed patients with severe Alzheimer dementia? PMID- 24810187 TI - Human stem-cell research in gastroenterology: experimental treatment, tourism and biobanking. AB - The growing interest in the possibility of applying stem-cell therapies to gastroenterological diseases is outlined. Some promising results have been reported, but more research is needed in view of the uncertainties and knowledge gaps that still exist. The ethical issues raised by this kind of research are then indicated and classified. Three problematic kinds of situation are outlined: experimental treatments, stem-cell tourism and biobanking. A four-question approach - which is not to be confused with the well-known four-principle approach introduced by Beauchamp and Childress - is described and applied to these three challenging situations. In conclusion, it is pointed out that the analysis of these situations illustrates the interplay between definitions, empirical research and ethics. They are interrelated and need to be integrated. PMID- 24810188 TI - Ethical issues raised by whole genome sequencing. AB - While there is ongoing discussion about the details of implementation of whole genome sequencing (WGS) and whole exome sequencing (WES), there appears to be a consensus amongst geneticists that the widespread use of these approaches is not only inevitable, but will also be beneficial [1]. However, at the present time, we are unable to anticipate the full range of uses, consequences and impact of implementing WGS and WES. Nevertheless, the already known ethical issues, both in research and in clinical practice are diverse and complex and should be addressed properly presently. Herein, we discuss the ethical aspects of WGS and WES by particularly focussing on three overlapping themes: (1) informed consent, (2) data handling, and (3) the return of results. PMID- 24810189 TI - Liver, pancreas and small bowel transplantation: current ethical issues. AB - We describe the medical state of the art in liver, pancreas and small bowel transplantation, and portray the ethical issues. Although most ethical questions related to these transplantations are not specific for liver, pancreas and small bowel, they do challenge ethical analysis as well as new policies and clinical procedures. Firstly, outcomes continue to be of utmost concern, as information is only limited available, is developing over time and is surrounded by many uncertainties. Secondly, characteristics of donors and recipients should be carefully evaluated. The question of what qualifies a donor and a recipient should be considered against the background of a quest for extended criteria, embracing marginal cases, and a judgment with regard to what counts as a good enough outcome. Thirdly, ethical principles of autonomy and fairness are pushed, given the circumstance of severe scarcity, towards limits that can easily be crossed. PMID- 24810190 TI - Competence assessment in minors, illustrated by the case of bariatric surgery for morbidly obese children. AB - Clinicians have to assess children's competence frequently. In order to do justice to children who are competent to make decisions and to protect incompetent children, valid assessment is essential. We address this issue by using bariatric surgery for morbidly obese minors as a case study. Our previous research indicated that opponents of bariatric surgery tend to be sceptical of the competence of adolescents to consent and inclined to set more stringent standards than proponents. Furthermore, there is the concern that minors wanting surgery are less able to make an autonomous decision than minors who do not wish to undergo surgery. Hence, few patients may be qualified as eligible. We argue for a risk-related standard, so that concerns are met, while at the same time preventing to set the bar too high, excluding paediatric patients who are most likely to benefit from surgery. This standard is also applicable in gastroenterology practice. PMID- 24810191 TI - Ethical aspects of obesity prevention. AB - Programs to prevent overweight and obesity are needed in order to improve individual and public health, to support informed choice and to diminish the societal costs associated with overweight. However, lifestyle interventions frequently evoke ethical debate. The potential ethical pitfalls that arise with respect to the prevention of overweight regard consequences for physical health, psychosocial well-being, equality, informed choice, social and cultural values, privacy, the attributions of responsibilities and liberty. For doctors in gastroenterology, it is important to be aware of these ethical pitfalls, either because they apply directly to questions in the consulting-room, or because they help to create awareness of the societal context a patient lives in. An ethical framework is being presented to show which ethical issues play a role in obesity prevention and how they can be prevented, followed by reflection on the ethical issues in interventions and in policy and media debate. PMID- 24810192 TI - Ethical issues in colorectal cancer screening. AB - In many countries, colorectal cancer screening is currently an established population screening program due to the evidence on its reduction of colorectal cancer mortality. There is general consensus that colorectal cancer screening meets the screening criteria as proposed by Wilson and Jungner. However, as for all population screening programs, colorectal cancer screening also has disadvantages and thereby entails ethical issues. There are the general issues concerning the introduction of screening programs (e.g. medicalization, overdiagnosis and overtreatment, information provision to screenees), evaluation of cancer screening programs (e.g. lead time and length bias), chosen screening method (e.g. false-positive and false-negative test results, reduction of all cause mortality, choice between different screening methods). The different colorectal cancer screening methods and the ethical issues concerning colorectal cancer screening will be discussed in this review. PMID- 24810193 TI - Expensive cancer drugs and just health care. AB - Extremely expensive drugs which cost more than 100.000 $ per year for the treatment of one patient are increasingly common. The benefit of these drugs may either be not accessible to many patients or the overall costs could lead to a heavy burden on the health care system and public resources. This article describes the overall background of this trend and addresses the problem of expensive drugs from a perspective of just health care and just health outcomes. Therefore, basic aspects of just health care are outlined such as goods and principles relevant from a perspective of justice. This framework is applied to the allocation of expensive drugs on three levels. These reflections will demonstrate that there is no simple solution to this problem, and that the decisions cannot be taken by experts, but should be the result of an open, transparent, and fair public dialogue on health priorities. PMID- 24810194 TI - The integrity of science - lost in translation? AB - This paper presents some selected issues currently discussed about the integrity of science, and it argues that there exist serious challenges to integrity in the various sciences. Due to the involved conceptual complexities, even core definitions of scientific integrity have been disputed, and core cases of scientific misconduct influenced the public discussion about them. It is claimed that ethics and law may not always go well together in matters of scientific integrity. Explanations of the causes of scientific misconduct vary, and defining good scientific practices is not a straightforward task. Even though the efficacy of ethics courses to improve scientific integrity can be doubted, and universities probably need to come up with more innovative formats to improve ethics in scientific training, ethics talk may be the only practical remedy. PMID- 24810195 TI - Ordinary tales from endoscopic odysseys: fiction, ethics, and the gastroenterological journey. AB - Fiction (i.e. novels, short stories, and movies) provides an opportunity for imaginative moral reflection and can serve as a basis for moral argument. Narratives play a role in moral reasoning because they are exemplars as well as tests. Those who care for sick people, should be interested in patient's and literary stories. Exploring the representation of gastroenterological ailments in fiction gives insight in the experience of undergoing colonoscopy, farting, pain, the borders of intimacy, hygiene and the lack of it, taboos and the doctor patient-relationship. Included authors are, among others: Michel Faber, Alan Bennett, Charles Bukowski, Charlotte Roche and James Joyce. Several movies are discussed as well. Though in general gastroenterological problems don't seem often at foreground in fiction, in some cases they are represented in a more symbolic way, and touch upon some fundamental aspects of the human condition. PMID- 24810196 TI - Does building a greenway promote physical activity among proximate residents? AB - BACKGROUND: Previous research has observed a positive correlation between having greenways or trails proximate to homes and the physical activity behaviors among residents. Few studies using a pre-post research design have been conducted, and each has pointed to the need for more rigorous studies which incorporate an appropriate control group. METHODS: Residents from households living within 1 mile of a proposed greenway and those from a control neighborhood located between 2 and 3 miles of the proposed greenway were randomly selected to participate in the study. Participants were mailed a survey before the onset of construction and again 1 year after the trail was opened. Outcomes were the number of days during the previous week that respondents reported participating in walking, moderate activity, and vigorous activity. RESULTS: Repeated measures analyses of variance indicated no significant differences between the experimental and control groups in days of walking, moderate activity, or vigorous activity before and after the greenway was constructed. CONCLUSIONS: Findings suggest that building a greenway did not affect the physical activity behaviors of proximate residents. Other studies should consider different trail types from a variety of settings to determine whether physical activity behavior changes may be context specific. PMID- 24810197 TI - Detection and quantification of Vibrio parahaemolyticus in shellfish from Italian production areas. AB - Vibrio parahaemolyticus is a marine microorganism, recognized as an important cause of foodborne illness particularly in Asia, South America and United States. Outbreaks are rarely reported in Europe, but they can occur unexpectedly in relation, among other reasons, to the spread of highly virulent strains. It is known that the risk is proportional to exposure levels to pathogenic V. parahaemolyticus (i.e. carrying the tdh and/or the trh genes) but currently there is a lack of occurrence data for pathogenic V. parahaemolyticus in shellfish production areas of the Member States. In this study a total of 147 samples of bivalve molluscs, from harvesting areas of two Italian regions (Sardinia and Veneto) were analyzed for Escherichia coli and salmonella, according to Reg 2073/2005, and for detection and enumeration of total and toxigenic V. parahaemolyticus strains using a new DNA colony hybridization method. Environmental parameters (water temperature and salinity) were also recorded. Results of E. coli were consistently in agreement with the legislation limits for the harvesting class of origin and Salmonella was detected only in one sample. The average contamination levels for total V. parahaemolyticus were 84 and 73 CFU/g respectively for Sardinia and Veneto, with the highest value reaching 8.7 * 10(3)CFU/g. Nineteen samples (12.9%) resulted positive for the presence of potentially pathogenic V. parahaemolyticus strains, with levels ranging between 10 and 120 CFU/g and most of the positive samples (n=17) showing values equal or below 20 CFU/g. A significant correlation (r=0.41) was found between water temperature and V. parahaemolyticus levels, as well as with isolation frequency. The data provided in this study on contamination levels of total and potentially pathogenic V. parahaemolyticus, seasonal distribution and correlation with water temperature, will help in defining appropriate monitoring programs and post harvest policies for this hazard, improving the management of the harvesting areas and the safety of bivalve molluscs. PMID- 24810198 TI - Innate immunity: A wee protection. PMID- 24810199 TI - T cell signalling: p53 controls the crowd. PMID- 24810200 TI - Performance evaluation of a novel personalized ventilation-personalized exhaust system for airborne infection control. AB - In the context of airborne infection control, it is critical that the ventilation system is able to extract the contaminated exhaled air within the shortest possible time. To minimize the spread of contaminated air exhaled by occupants efficiently, a novel personalized ventilation (PV)-personalized exhaust (PE) system has been developed, which aims to exhaust the exhaled air as much as possible from around the infected person (IP). The PV-PE system was studied experimentally for a particular healthcare setting based on a typical consultation room geometry and four different medical consultation positions of an IP and a healthy person (HP). Experiments using two types of tracer gases were conducted to evaluate two types of PE: Top-PE and Shoulder-PE under two different background ventilation systems: Mixing Ventilation and Displacement Ventilation. Personalized exposure effectiveness, intake fraction (iF) and exposure reduction (epsilon) were used as indices to evaluate the PV-PE system. The results show that the combined PV-PE system for the HP achieves the lowest intake fraction; and the use of PE system for the IP alone shows much better performance than using PV system for the HP alone. PMID- 24810201 TI - Transformation of phosphorus during drying and roasting of sewage sludge. AB - Sewage sludge (SS), a by-product of wastewater treatment, consists of highly concentrated organic and inorganic pollutants, including phosphorus (P). In this study, P with different chemical fractions in SS under different drying and roasting temperatures was investigated with the use of appropriate standards, measurements, and testing protocol. The drying and roasting treatment of SS was conducted in a laboratory-scale furnace. Two types of SS samples under different treatment temperatures were analyzed by (31)P NMR spectroscopy. These samples were dried by a vacuum freeze dryer at -50 degrees C and a thermoelectric thermostat drying box at 105 degrees C. Results show that the inorganic P (IP) content increased as the organic P content decreased, and the bio-availability of P increased because IP is a form of phosphorousthat can be directly absorbed by plants. (31)P NMR analysis results indicate the change in P fractions at different temperatures. Non-apatite P was the dominant form of P under low temperature drying and roasting, whereas apatite P was the major one under high temperature drying and roasting. Results indicate that temperature affects the transformation of P. PMID- 24810202 TI - Application of compost of two-phase olive mill waste on olive grove: effects on soil, olive fruit and olive oil quality. AB - Composting is a method for preparing organic fertilizers that represents a suitable management option for the recycling of two-phase olive mill waste (TPOMW) in agriculture. Four different composts were prepared by mixing TPOMW with different agro-industrial by-products (olive pruning, sheep manure and horse manure), which were used either as bulking agents or as N sources. The mature composts were added during six consecutive years to a typical "Picual" olive tree grove in the Jaen province (Spain). The effects of compost addition on soil characteristics, crop yield and nutritional status and also the quality of the olive oil were evaluated at the end of the experiment and compared to a control treated only with mineral fertilization. The most important effects on soil characteristics included a significant increase in the availability of N, P, K and an increase of soil organic matter content. The application of TPOMW compost produced a significant increase in olive oil content in the fruit. The compost amended plots had a 15% higher olive oil content than those treatment with inorganic fertilization. These organics amendments maintained the composition and quality of the olive oil. PMID- 24810203 TI - Co-pyrolysis of swine manure with agricultural plastic waste: laboratory-scale study. AB - Manure-derived biochar is the solid product resulting from pyrolysis of animal manures. It has considerable potential both to improve soil quality with high levels of nutrients and to reduce contaminants in water and soil. However, the combustible gas produced from manure pyrolysis generally does not provide enough energy to sustain the pyrolysis process. Supplementing this process may be achieved with spent agricultural plastic films; these feedstocks have large amounts of available energy. Plastic films are often used in soil fumigation. They are usually disposed in landfills, which is wasteful, expensive, and environmentally unsustainable. The objective of this work was to investigate both the energetics of co-pyrolyzing swine solids with spent plastic mulch films (SPM) and the characteristics of its gas, liquid, and solid byproducts. The heating value of the product gas from co-pyrolysis was found to be much higher than that of natural gas; furthermore, the gas had no detectable toxic fumigants. Energetically, sustaining pyrolysis of the swine solids through the energy of the product gas could be achieved by co-pyrolyzing dewatered swine solids (25%m/m) with just 10% SPM. If more than 10% SPM is used, the co-pyrolysis would generate surplus energy which could be used for power generation. Biochars produced from co-pyrolyzing SPM and swine solid were similar to swine solid alone based on the surface area and the (1)H NMR spectra. The results of this study demonstrated the potential of using pyrolysis technology to manage two prominent agricultural waste streams (SPM and swine solids) while producing value-added biochar and a power source that could be used for local farm operations. PMID- 24810204 TI - Conductive upconversion Er,Yb-FTO nanoparticle coating to replace Pt as a low cost and high-performance counter electrode for dye-sensitized solar cells. AB - F-doped SnO2 (FTO) nanocrystals modified by Er and Yb with upconversion capability and excellent catalytic properties have been designed and fabricated as an economic replacement for Pt for use as the counter electrode (CE) in dye sensitized solar cells. The cost of the UC-FTO counter electrode is only ~(1)/20th of that for Pt. The upconverted luminescence-mediated energy transfer and the superior catalytic property for I3(-)/I(-) circulation overpowered the slight degradation caused by increased CE/electrolyte interface resistance. A 23.9% enhancement in photocurrent was achieved with little degradation in photovoltage, resulting in a 9.12% increase in solar-to-electric power conversion efficiency. Near-infrared (NIR) light-to-electricity has been directly observed by SPS and IPCE characterizations, showing the effect of the upconversion counter electrode. PMID- 24810205 TI - Lack of drug dosing guidelines for critically ill patients receiving continuous renal replacement therapy. AB - Acute kidney injury requiring continuous renal replacement therapy is common, costly, and associated with mortality rates of up to 60%. Accurate pharmacokinetic data are essential to developing rational individualized dosing strategies and providing optimal care to these patients, yet few such data exist, probably due in part to an absence of regulatory guidance on the issue. The Kidney Health Initiative is working with stakeholders to propose strategies to address this in a standardized manner. PMID- 24810206 TI - Reading comprehension of health checkup reports and health literacy in Japanese people. AB - OBJECTIVES: To determine the reading comprehension of health checkup reports in the context of health literacy (HL) in Japanese people. METHODS: A web-based survey was conducted among 424 Japanese adults aged 35-59 years. Participants were asked to read specifically designed health checkup reports and then answer a series of questions to examine whether they accomplished the fundamental purposes of health checkup reports (recognition of the problems, recognition of the risk of illness, recognition of the need for preventive action, and motivation for preventive action). HL was simultaneously measured using the 14-item health literacy scale (HLS-14), the 11-item Lipkus scale (Lipkus-J), and the Newest Vital Sign (NVS-J). RESULTS: About 70 % of the study subjects misread the normal/abnormal classification for at least one items. Those with lower HLS-14 scores were significantly less likely to recognize the problems, the risk of illness, and the need for preventive action for the examinee, and also less likely to express their willingness to take preventive action in compliance with the doctor's advice after having received the health checkup report. Compared with the HLS-14 scores, the Lipkus-J and NVS-J scores showed hardly any association with the reading comprehension of health checkup reports. CONCLUSION: All examinees do not always have an adequate level of HL. HL may be the major determinant of reading comprehension of health checkup reports. For more effective health checkups, health promotion service providers should become aware of the existence of examinees with inadequate HL and address the problem of misreading health checkup results. PMID- 24810208 TI - Nonconvulsive status epilepticus in patients with brain tumors. AB - PURPOSE: The prevalence of nonconvulsive status epilepticus (NCSE) in brain tumor patients is unknown. Since NCSE has been associated with significant mortality and morbidity, early identification is essential. This study describes the clinical and EEG characteristics, treatment, and outcome in brain tumor patients with NCSE. METHOD: All patients admitted to Mount Sinai Hospital from 2009 to 2012 with an ICD-9 brain tumor code were cross-referenced with the epilepsy department's database. EEGs from matching patients were reviewed for NCSE. Relevant information from the medical records of the patients with NCSE was extracted. RESULTS: 1101 brain tumor patients were identified, of which 259 (24%) had an EEG and 24 (2%) had NCSE. The vast majority of seizures captured were subclinical with 13 patients (54%) having only subclinical seizures. Treatment resolved the NCSE in 22 patients (92%) with accompanying clinical improvement in 18 (75%) of those patients. Tumor recurrence or progression on MRI was associated with decreased 2-month survival (75% mortality, p=0.035) compared to stable tumors (20% mortality). Patients with metastatic disease had median survival from tumor diagnosis of 1.2 months. CONCLUSION: NCSE in brain tumor patients may be under diagnosed due to the frequent lack of outward manifestations and highly treatable with improvement in the majority of patients. NCSE patients with progressing brain lesions, tumor recurrence, or metastatic disease are at serious risk of mortality within 2 months. Continuous EEG monitoring in brain tumor patients with recent clinical seizures and/or a depressed level of consciousness may be critical in providing appropriate care. PMID- 24810207 TI - Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet in relation to obesity among Iranian female nurses. AB - OBJECTIVE: Limited observational studies have considered habitual consumption of the general population to examine the relationship between the Dietary Approaches to Stop Hypertension (DASH) diet and obesity. The aim of the present study was to investigate adherence to the DASH diet in relation to general and central obesity among female nurses in Isfahan, Iran. DESIGN: Cross-sectional study carried out among 293 female nurses aged >30 years who were selected by a multistage, cluster random sampling method. Usual dietary intakes were assessed using a validated FFQ. We constructed the DASH score based on foods and nutrients emphasized or minimized in the DASH diet, focusing on eight components: high intake of fruits, vegetables, nuts and legumes, low-fat dairy products and whole grains and low intakes of sodium, sweetened beverages, and red and processed meats. General and abdominal obesity were defined as BMI >= 25 kg/m2 and waist circumference >= 88 cm, respectively. SETTING: Isfahan, Iran. SUBJECTS: Female nurses (n 293) aged >30 years. RESULTS: Increased adherence to the DASH diet was associated with older age (P<0.01) and lower waist circumference (P=0.04). There was no statistically significant difference in the prevalence of general obesity between extreme quartiles of the DASH diet score. After adjustment for age, energy intake and other confounding factors, DASH diet score was not significantly associated with obesity. However, with further controlling for other dietary factors, those in the highest quartile of DASH diet score were 71 % less likely to have general obesity compared with those in the lowest quartile. In addition, following a DASH diet was inversely associated with central obesity after adjustment for potential confounders (OR=0.37; 95 % CI 0.14, 0.96). CONCLUSIONS: We found that adherence to the DASH diet was inversely related to central obesity among Iranian adult females. This association remained significant even after adjustment for potential confounders. PMID- 24810209 TI - Changes in current-source density of interictal spikes in benign epilepsy of childhood with centrotemporal spikes following treatment with oxcarbazepine. AB - PURPOSE: The aim of this study was to detect clinical variables associated with the extent of change of the irritative zone in benign epilepsy of childhood with centrotemporal spikes (BECTS) after oxcarbazepine monotherapy. METHOD: BECTS patients receiving oxcarbazepine monotherapy were retrospectively reviewed. Changes in current-source density (CSD) of the maximum negative points of interictal spikes prior to the start of oxcarbazepine treatment were compared with CSD following oxcarbazepine treatment for 6-12 months. CSD was measured using low-resolution brain electromagnetic tomography (LORETA). Patients were divided into two groups based on the change in CSD: increased-extent or decreased extent. Comparisons were made between the groups based on the age of onset, seizure frequency before treatment, time interval between seizure onset and treatment start, time interval between the two EEGs, oxcarbazepine dosage at the follow-up electroencephalography, occurrence of daytime seizures, and seizure control. RESULTS: Fourteen patients were enrolled. Seven patients were in the decreased-extent group and six in the increased-extent group; one patient was excluded because she did not demonstrate any change in CSD. We found that seizure control differed significantly between the two groups: seizures were well controlled in six out of seven patients in the decreased-extent group (85.7%), but in only one of six patients (16.7%) in the increased-extent group (p=0.03). The other variables did not differ between the groups. CONCLUSION: Seizure control may be associated with the extent of changes in the neuronal irritative zones of BECTS patients. We suggest that changes of CSD extent may be used as an imaging modality to evaluate clinical improvement in BECTS patients. PMID- 24810210 TI - Honokiol suppresses renal cancer cells' metastasis via dual-blocking epithelial mesenchymal transition and cancer stem cell properties through modulating miR 141/ZEB2 signaling. AB - Renal cell carcinoma (RCC) is associated with a high frequency of metastasis and only few therapies substantially prolong survival. Honokiol, isolated from Magnolia spp. bark, has been shown to exhibit pleiotropic anticancer effects in many cancer types. However, whether honokiol could suppress RCC metastasis has not been fully elucidated. In the present study, we found that honokiol suppressed renal cancer cells' metastasis via dual-blocking epithelial mesenchymal transition (EMT) and cancer stem cell (CSC) properties. In addition, honokiol inhibited tumor growth in vivo. It was found that honokiol could upregulate miR-141, which targeted ZEB2 and modulated ZEB2 expression. Honokiol reversed EMT and suppressed CSC properties partly through the miR-141/ZEB2 axis. Our study suggested that honokiol may be a suitable therapeutic strategy for RCC treatment. PMID- 24810211 TI - Value of repeat testing using Cepheid GeneXpert CT/NG for indeterminate PCR results when diagnosing Chlamydia trachomatis and Neisseria gonorrhoeae. AB - Nucleic acid amplification tests (NAATs) are the most sensitive method for diagnosing chlamydia and gonorrhoea. We use the COBAS 4800 CT/NG combined assay (Roche Molecular Diagnostics, CA, USA), and whilst the majority of samples yield definitive results, a small proportion are reported as indeterminate. In these instances, it is usual practice to request repeat samples which delays diagnosis. This audit was twofold: first to establish the proportion of indeterminate results with current NAAT testing requiring re-sampling. Second, to determine whether a second NAAT such as Cepheid GeneXpert CT/NG assay (Cepheid, CA, USA) could be used on initial indeterminate samples to resolve indeterminate results, therefore reducing need for repeat sampling. During 2012, 144/21,931 (0.66%) samples were indeterminate for Neisseria gonorrhoeae, Chlamydia trachomatis or both, and a repeat sample was received in only 51.77% of patients with final results being delayed for more than 24 h. Over the next six months, there were 77/9472 (0.81%) indeterminate results. After an evaluation and introduction of the Cepheid assay, the number of indeterminate results fell to 9 (0.10%). Thus, use of the Cepheid assay significantly reduced indeterminate results, reduced reliance on a repeat sampling and significantly improved turnaround time, laboratory workflow and patient experience. PMID- 24810212 TI - Response letter to T Fowler and co-authors - estimating the positive predictive value of opportunistic population testing for gonorrhoea as part of the English Chlamydia Screening Programme. PMID- 24810213 TI - Can an asymptomatic screening pathway for men who have sex with men be introduced safely at a level 3 sexual health service in the UK? AB - To manage the rising demand on sexual health services in the UK, many clinics have introduced asymptomatic screening pathways for heterosexuals, which omit examination. In men who have sex with men however the screening of extragenital sites poses additional challenges. This study aimed to establish whether omitting examination of asymptomatic men who have sex with men would lead to clinically significant diagnoses being missed. The notes of all men who have sex with men who attended a UK level 3 sexual health clinic between 1 July 2011 and 30 June 2012 were retrospectively reviewed. Exclusion criteria included HIV-positive patients attending for HIV-related care, attendances for follow-up consultations not requiring a full sexual health screen, symptomatic patients, contacts of sexually transmitted infections and patients requesting an examination or a repeat prescription of a regularly used medication. In all, 920 consultations occurred during 12 months, of which 893 were reviewed; 476 (53.3%) consultations would have been eligible for screening on an asymptomatic pathway and, of these, 21 (4.4%) had abnormalities found at examination. Findings included genital warts, minor dermatological conditions and three cases of minor asymptomatic urological conditions. There were no clinically significant findings on examination of asymptomatic men who have sex with men requiring treatment, indicating that examination in this cohort may be of little benefit. PMID- 24810214 TI - Etravirine: a good option for concomitant use with chemotherapy for Hodgkin's lymphoma. AB - The treatment of malignancies in HIV patients is challenged by the issue of drug drug interactions between antiretroviral therapy and antineoplastic agents. While protease inhibitors have been shown to increase the incidence and severity of cancer therapy-related side effects, the impact of other antiretroviral agents on the tolerability and response to chemotherapy is less well documented. We report the successful use of an etravirine-based regimen in a patient treated with BEACOPP chemotherapy for advanced Hodgkin's lymphoma. Etravirine constitutes a valuable option for concomitant use with chemotherapy due to its moderate inducing effect on drug metabolising enzymes. PMID- 24810215 TI - Latinos in the United States on the HIV/AIDS care continuum by birth country/region: a systematic review of the literature. AB - Twenty percent of Latinos with HIV in the US are unaware of their HIV status, 33% are linked to care late, and 74% do not reach viral suppression. Disparities along this HIV/AIDS care continuum may be present between various ethnic groups historically categorised as Latino. To identify differences along the HIV/AIDS care continuum between US Latinos of varying birth countries/regions a systematic review of articles published in English between 2002 and 2013 was conducted using MEDLINE, PsycINFO, and Web of Science. Studies that reported on one or more steps of the HIV/AIDS care continuum and reported results by birth country/region for Latinos were included. Latinos born in Mexico and Central America were found to be at increased risk of late diagnosis compared with US-born Latinos. No studies were found that reported on linkage to HIV care or viral load suppression by country/region of birth. Lower survival was found among Latinos born in Puerto Rico compared with Latinos born in mainland US. Inconsistent differences in survival were found among Latinos born in Mexico, Cuba, and Central America. Socio/cultural context, immigration factors, and documentation status are discussed as partial explanations for disparities along the HIV/AIDS care continuum. PMID- 24810216 TI - Do genitourinary physicians report notifiable diseases? A survey in South East England. AB - Genitourinary medicine work requires public health actions. Notifiable infections may be seen in genitourinary medicine, but concerns over confidentiality could delay public health actions and outbreak management. To assess genitourinary medicine clinicians' awareness of notification of infectious disease, reporting practices and liaison with Health Protection Units, we sent postal surveys to 140 genitourinary medicine clinicians (SE HPA region) that explored prior public health training, Health Protection Unit liaison and management of possible clinical scenarios. Fifty-seven respondents reported median genitourinary medicine experience of 12 years; 29% had prior public health training, nine on the British Association for Sexual Health and HIV course. A total of 90% had heard of Health Protection Units and understood their role. Approximately one third would not report key diseases at all, most reporting only on laboratory confirmation. In all, 83% would only notify acute hepatitis on lab confirmation; 50% would report suspected measles immediately (44% awaiting lab confirmation) and 40% would not pass on any patient details without consent. Clinicians have good knowledge of notification of infectious disease conditions but responses suggest it is not always used in clinical context. Reporting delays occur waiting for lab confirmation and liaison with local Health Protection Units may be hindered by confidentiality concerns, potentially delaying public health action. Doctors with prior public health training are more likely to report appropriately. PMID- 24810217 TI - Effects of rapid versus standard HIV voluntary counselling and testing on receipt rate of HIV test results: a meta-analysis. AB - Rapid HIV voluntary counselling and testing (RVCT) is an alternative method of standard HIV voluntary counselling and testing (SVCT). Less is known about whether RVCT improves the receipt rate of HIV test results among clients who seek HIV counselling and testing. We aimed to evaluate effectiveness of RVCT on result receipt rate. We conducted a comprehensive search of databases containing Medline, EBSCO, Web of science, and Cochrane library to identify studies published up to August 2012. Reviewers extracted information independently. Risk of bias was evaluated with Cochrane Collaboration's tool for assessing study quality. Five randomised controlled trials were included and analysed for the result receipt rate using a random-effects model. The pooled receipt rate of HIV test results in the RVCT was significantly higher than in the SVCT (RR = 1.74, 95% CI = 1.47-2.07). Our results suggest RVCT as a favourable method to increase the receipt of HIV test results. Only two included studies assessed the modification of risk behaviour after HIV-CT in a different manner; also, the sample size was small in the current meta-analysis. In future research, it is necessary to confirm the effect of RVCT on disinhibition of post-test risk behaviour. PMID- 24810219 TI - Douching practices among female sex workers in Phnom Penh, Cambodia. AB - Several studies indicate that douching has few benefits but numerous adverse health outcomes, including increased risk for sexually transmitted infections and HIV. No published study explores douching practices among Cambodian female sex workers. This report provides preliminary data about the prevalence and frequency of douching among female sex workers in Phnom Penh, Cambodia. Survey data were obtained from 81 female sex workers who were taken into custody due to engagement in commercial sex from March to June 2011. Results showed that 91% of participants douched. The mean numbers of times douched before sex and after sex per 10 sex episodes were 4.43 (SD = 3.87) and 4.63 (SD = 3.94), respectively. Half of the participants thought that douching could help to prevent sexually transmitted infections including HIV; 24% were unsure about this. Usually, douching after sex was associated with ever obtaining an HIV test (p = .012) and was marginally associated (although not statistically significant) with a higher average number of clients per week (p =. 063) and consistent condom use with clients (p = .053). This suggests that these practices may be related to individual perceptions of sexually transmitted infections/HIV risk or susceptibility. Given the commonness of douching and related misperceptions among Cambodian female sex workers, future studies and interventions are needed to prevent adverse health problems. PMID- 24810218 TI - Correlates of prevalent sexually transmitted infections among participants screened for an HIV incidence cohort study in Kisumu, Kenya. AB - We determined the prevalence of four sexually transmitted infections and the demographic and behavioural correlates associated with having one or more sexually transmitted infections among participants in an HIV incidence cohort study in Kisumu, western Kenya. Participants were enrolled from a convenience sample and underwent aetiologic sexually transmitted infection investigation. Demographic and behavioural information were collected and basic clinical evaluation performed. Multiple regression analysis was done to determine variables associated with having one or more sexually transmitted infections. We screened 846, 18- to 34-year-olds. One-third had at least one sexually transmitted infection with specific prevalence being: syphilis, 1.6%; gonorrhoea, 2.4%; herpes simplex virus type-2, 29.1%; chlamydia, 2.8%; and HIV, 14.8%. Odds of having any sexually transmitted infection were higher among participants who were women, were aged 20-24 or 30-34 years compared to 18-19 years, had secondary or lower education compared to tertiary education, were divorced, widowed or separated compared to singles, reported having unprotected sex compared to those who did not, reported previous sexually transmitted infection treatment, and tested HIV-positive. Multiple strategies are needed to address the overall high prevalence of sexually transmitted infections as well as the gender disparity found in this Kenyan population. Structural interventions may be beneficial in addressing educational and socio-economic barriers, and increasing the uptake of health-promoting practices. PMID- 24810220 TI - Prevalence and predictors of anaemia in patients with HIV infection at the initiation of combined antiretroviral therapy in Xinjiang, China. AB - We retrospectively analysed routinely collected baseline data of 2252 patients with HIV infection registered in the National Free Antiretroviral Treatment Program in Xinjiang province, China, from 2006 to 2011 to estimate the prevalence and predictors of anaemia at the initiation of combined antiretroviral therapy. Anaemia was diagnosed using the criteria set forth by the World Health Organisation, and univariate and multivariate logistic regression analyses were performed to determine its predictors. The prevalences of mild, moderate, and severe anaemia at the initiation of combined antiretroviral therapy were 19.2%, 17.1%, and 2.6%, respectively. Overall, 38.9% of the patients were anaemic at the initiation of combined antiretroviral therapy. The multivariate logistic regression analysis indicated that Uyghur ethnicity, female gender, lower CD4 count, lower body mass index value, self-reported tuberculosis infection, and oral candidiasis were associated with a higher prevalence of anaemia, whereas higher serum alanine aminotransferase level was associated with a lower prevalence of anaemia. The results suggest that the overall prevalence of anaemia at the initiation of combined antiretroviral therapy in patients with HIV infection is high in Xinjiang, China, but severe anaemia is uncommon. Patients in China should be routinely checked for anaemia prior to combined antiretroviral therapy initiation, and healthcare providers should carefully select the appropriate first-line combined antiretroviral therapy regimens for anaemic patients. PMID- 24810221 TI - Bleomycin and pulmonary screening: many questions, few answers. PMID- 24810223 TI - Genetic testing in Tunisian families with heritable retinoblastoma using a low cost approach permits accurate risk prediction in relatives and reveals incomplete penetrance in adults. AB - Heritable retinoblastoma is caused by oncogenic mutations in the RB1 tumor suppressor gene. Identification of these mutations in patients is important for genetic counseling and clinical management of relatives at risk. In order to lower analytical efforts, we designed a stepwise mutation detection strategy that was adapted to the spectrum of oncogenic RB1 gene mutations. We applied this strategy on 20 unrelated patients with familial and/or de novo bilateral retinoblastoma from Tunisia. In 19 (95%) patients, we detected oncogenic mutations including base substitutions, small length mutations, and large deletions. Further analyses on the origin of the mutations showed mutational mosaicism in one unilaterally affected father of a bilateral proband and incomplete penetrance in two mothers. In a large family with several retinoblastoma patients, the mutation identified in the index patient was also detected in several non-penetrant relatives. RNA analyses showed that this mutation results in an in-frame loss of exon 9. In summary, our strategy can serve as a model for RB1 mutation identification with high analytical sensitivity. Our results point out that genetic testing is needed to reveal or exclude incomplete penetrance specifically in parents of patients with sporadic disease. PMID- 24810224 TI - Direct growth of self-crystallized graphene and graphite nanoballs with Ni vapor assisted growth: from controllable growth to material characterization. AB - A directly self-crystallized graphene layer with transfer-free process on arbitrary insulator by Ni vapor-assisted growth at growth temperatures between 950 to 1100 degrees C via conventional chemical vapor deposition (CVD) system was developed and demonstrated. Domain sizes of graphene were confirmed by Raman spectra from ~12 nm at growth temperature of 1000 degrees C to ~32 nm at growth temperature of 1100 degrees C, respectively. Furthermore, the thickness of the graphene is controllable, depending on deposition time and growth temperature. By increasing growth pressure, the growth of graphite nano-balls was preferred rather than graphene growth. The detailed formation mechanisms of graphene and graphite nanoballs were proposed and investigated in detail. Optical and electrical properties of graphene layer were measured. The direct growth of the carbon-based materials with free of the transfer process provides a promising application at nanoelectronics. PMID- 24810222 TI - Autophagy in the eye: implications for ocular cell health. AB - Autophagy, a catabolic process by which a cell "eats" itself, turning over its own cellular constituents, plays a key role in cellular homeostasis. In an effort to maintain normal cellular function, autophagy is often up-regulated in response to environmental stresses and excessive organelle damage to facilitate aggregated protein removal. In the eye, virtually all cell types from those comprising the cornea in the front of the eye to the retinal pigment epithelium (RPE) providing a protective barrier for the retina at the back of the eye, rely on one or more aspects of autophagy to maintain structure and/or normal physiological function. In the lens autophagy plays a critical role in lens fiber cell maturation and the formation of the organelle free zone. Numerous studies delineating the role of Atg5, Vsp34 as well as FYCO1 in maintenance of lens transparency are discussed. Corneal endothelial dystrophies are also characterized as having elevated levels of autophagic proteins. Therefore, novel modulators of autophagy such as lithium and melatonin are proposed as new therapeutic strategies for this group of dystrophies. In addition, we summarize how corneal Herpes Simplex Virus (HSV-1) infection subverts the cornea's response to infection by inhibiting the normal autophagic response. Using glaucoma models we analyze the relative contribution of autophagy to cell death and cell survival. The cytoprotective role of autophagy is further discussed in an analysis of photoreceptor cell heath and function. We focus our analysis on the current understanding of autophagy in photoreceptor and RPE health, specifically on the diverse role of autophagy in rods and cones as well as its protective role in light induced degeneration. Lastly, in the RPE we highlight hybrid phagocytosis-autophagy pathways. This comprehensive review allows us to speculate on how alterations in various stages of autophagy contribute to glaucoma and retinal degenerations. PMID- 24810225 TI - Interaction of poly(N-isopropylacrylamide) with sodium dodecyl sulfate below the critical aggregation concentration. AB - Interaction between the thermoresponsive polymer poly(N-isopropylacrylamide) (P NIP) and sodium dodecyl sulfate (SDS) both above and below its phase transition temperature was examined under dilute conditions. Above the lower critical solution temperature (LCST) of P-NIP (32 degrees C), 0.01 wt % P-NIP specifically interacted with 1.0 * 10(-5) mol/L SDS to form a precipitate. However, when SDS was added at concentrations above or below 1.0 * 10(-5) mol/L, the P-NIP solution remained clear above the LCST. A fluorometric probe, N-phenyl naphthalene, indicated that the hydrophobicity of the aggregates composed of P NIP and SDS changed at an SDS concentration of 1.0 * 10(-5) mol/L. Although the hydrophobicity of the precipitate was similar to that of P-NIP alone at less than 1.0 * 10(-5) mol/L, it approached that of SDS homomicelles as the SDS concentration increased above 1.0 * 10(-5) mol/L. Dynamic light scattering and turbidimetry studies showed no P-NIP phase transition above an SDS concentration of 1.0 * 10(-5) mol/L, which is much lower than the reported critical association concentration (CAC) of SDS with P-NIP. This indicates that P-NIP interacted with SDS above the LSCT at much lower SDS concentration than the reported CAC. PMID- 24810226 TI - N-terminal microdomain peptide from human dihydroorotate dehydrogenase: structure and model membrane interactions. AB - The N-terminus of the human dihydroorotate dehydrogenase (HsDHODH) has been described as important for the enzyme attachment in the inner mitochondrial membrane and possibly to regulate enzymatic activity. In this study, we synthesized the peptide acetyl-GDERFYAEHLMPTLQGLLDPESAHRL AVRFTSLGamide, comprising the residues 33-66 of HsDHODH N-terminal conserved microdomain. Langmuir monolayers and circular dichroism (CD) were employed to investigate the interactions between the peptide and membrane model, as micelles and monolayers of the lipids phosphatidylcholine (PC), 3-phosphatidylethanolamine (PE) and cardiolipin (CL). These lipids represent the major constituents of inner mitochondrial membranes. According to CD data, the peptide adopted a random structure in water, whereas it acquired alpha-helical structures in the presence of micelles. The pi-A isotherms and polarization- modulated infrared reflection absorption spectroscopy on monolayers showed that the peptide interacted with all lipids, but in different ways. In DPPC monolayers, the peptide penetrated into the hydrophobic region. The strongest initial interaction occurred with DPPE, but the peptide was expelled from this monolayer at high surface pressures. In CL, the peptide could induce a partial dissolution of the monolayer, leading to shorter areas at the monolayer collapse. These results corroborate the literature, where the HsDHODH microdomain is anchored into the inner mitochondrial membrane. Moreover, the existence of distinct conformations and interactions with the different membrane lipids indicates that the access to the enzyme active site may be controlled not only by conformational changes occurring at the microdomain of the protein, but also by some lipid-protein synergetic mechanism, where the HsDHODH peptide would be able to recognize lipid domains in the membrane. PMID- 24810227 TI - Arylboration of alkenes by cooperative palladium/copper catalysis. AB - Arylboration of vinylarenes and methyl crotonate with aryl halides and bis(pinacolato)diboron by cooperative Pd/Cu catalysis has been developed, giving 2-boryl-1,1-diarylethanes and an alpha-aryl-beta-boryl ester in a regioselective manner. The reaction is compatible with a variety of functionalities and amenable to be scaled-up to a gram scale with no detriment to the yield. A short synthesis of the biologically active compound CDP840 was performed using the present reaction as a key step. PMID- 24810228 TI - Apparent strength conceals instability in a model for the collapse of historical states. AB - An explanation for the political processes leading to the sudden collapse of empires and states would be useful for understanding both historical and contemporary political events. We examine political disintegration across eras, cultures and geographical scale to form a simple hypothesis that can be expressed verbally yet formulated mathematically. Factions within a state make choices described by game-theory about whether to accept the political status quo, or to attempt to better their circumstances through costly rebellion. In lieu of precise data we verify our model using sensitivity analysis. We find that a small amount of dissatisfaction is typically harmless to the state, but can trigger sudden collapse when there is a sufficient buildup of political inequality. Contrary to intuition, a state is predicted to be least stable when its leadership is at the height of its political power and thus most able to exert its influence through external warfare, lavish expense or autocratic decree. PMID- 24810229 TI - Morphological, anatomical, and ultrastructural changes (visualized through scanning electron microscopy) induced in Triticum aestivum by Pb2+ treatment. AB - Lead (Pb) causes severe damage to crops, ecosystems, and humans, and alters the physiology and biochemistry of various plant species. It is hypothesized that Pb induced metabolic alterations could manifest as structural variations in the roots of plants. In light of this, the morphological, anatomical, and ultrastructural variations (through scanning electron microscopy, SEM) were studied in 4-day-old seedlings of Triticum aestivum grown under Pb stress (0, 8, 16, 40, and 80 mg Pb(2+) l(-1); mild to highly toxic). The toxic effect was more pronounced in radicle growth than on the plumule growth. The SEM of the root of T. aestivum depicted morphological alterations and surface ultrastructural changes. Compared to intact and uniform surface cells in the control roots, cells were irregular and desiccated in Pb(2+)-treated roots. In Pb(2+)-treated roots, the number of root hairs increased manifold, showing dense growth, and these were apparently longer. Apart from the deformity in surface morphology and anatomy of the roots in response to Pb(2+) toxicity, considerable anatomical alterations were also observed. Pb(2+)-treated root exhibited signs of injury in the form of cell distortion, particularly in the cortical cells. The endodermis and pericycle region showed loss of uniformity post Pb(2+) exposure (at 80 mg l(-1) Pb(2+)). The cells appeared to be squeezed with greater depositions observed all over the tissue. The study concludes that Pb(2+) treatment caused structural anomalies and induced anatomical and surface ultrastructural changes in T. aestivum. PMID- 24810230 TI - Establishment and application of a loop-mediated isothermal amplification (LAMP) system for detection of cry1Ac transgenic sugarcane. AB - To meet the demand for detection of foreign genes in genetically modified (GM) sugarcane necessary for regulation of gene technology, an efficient method with high specificity and rapidity was developed for the cry1Ac gene, based on loop mediated isothermal amplification (LAMP). A set of four primers was designed using the sequence of cry1Ac along with optimized reaction conditions: 5.25 mM of Mg(2+), 4:1 ratio of inner primer to outer primer, 2.0 U of Bst DNA polymerase in a reaction volume of 25.0 MUL. Three post-LAMP detection methods (precipitation, calcein (0.60 mM) with Mn(2+) (0.05 mM) complex and SYBR Green I visualization), were shown to be effective. The sensitivity of the LAMP method was tenfold higher than that of conventional PCR when using templates of the recombinant cry1Ac plasmid or genomic DNA from cry1Ac transgenic sugarcane plants. More importantly, this system allowed detection of the foreign gene on-site when screening GM sugarcane without complex and expensive instruments, using the naked eye. This method can not only provide technological support for detection of cry1Ac, but can also further facilitate the use of this detection technique for other transgenes in GM sugarcane. PMID- 24810231 TI - Dynamic computer simulation of electrophoretic enantiomer migration order and separation in presence of a neutral cyclodextrin. AB - One-dimensional dynamic computer simulation was employed to investigate the separation and migration order change of ketoconazole enantiomers at low pH in presence of increasing amounts of (2-hydroxypropyl)-beta-cyclodextrin (OHP-beta CD). The 1:1 interaction of ketoconazole with the neutral cyclodextrin was simulated under real experimental conditions and by varying input parameters for complex mobilities and complexation constants. Simulation results obtained with experimentally determined apparent ionic mobilities, complex mobilities, and complexation constants were found to compare well with the calculated separation selectivity and experimental data. Simulation data revealed that the migration order of the ketoconazole enantiomers at low (OHP-beta-CD) concentrations (i.e. below migration order inversion) is essentially determined by the difference in complexation constants and at high (OHP-beta-CD) concentrations (i.e. above migration order inversion) by the difference in complex mobilities. Furthermore, simulations with complex mobilities set to zero provided data that mimic migration order and separation with the chiral selector being immobilized. For the studied CEC configuration, no migration order inversion is predicted and separations are shown to be quicker and electrophoretic transport reduced in comparison to migration in free solution. The presented data illustrate that dynamic computer simulation is a valuable tool to study electrokinetic migration and separations of enantiomers in presence of a complexing agent. PMID- 24810232 TI - Is the pathway of energy metabolism modified in advanced cirrhosis? PMID- 24810233 TI - Analytical strategies for controlling polysorbate-based nanomicelles in fruit juice. AB - This study focused on the detection and quantification of organic micelle-type nanoparticles (NPs) with polysorbate components (polysorbate 20 and polysorbate 80) in their micelle shells that could be used to load biologically active compounds into fruit juice. Several advanced analytical techniques were applied in the stepwise method development strategy used. In the first phase, a system consisting of ultrahigh-performance liquid chromatography employing a size exclusion column coupled with an evaporative light scattering detector (UHPLC-SEC ELSD) was used for the fractionation of micelle assemblies from other, lower molecular weight sample components. The limit of detection (LoD) of these polysorbate micelles in spiked apple juice was 500 MUg mL(-1). After this screening step, mass spectrometric (MS) detection was utilized to confirm the presence of polysorbates in the detected micelles. Two alternative MS techniques were tested: (i) ambient high-resolution mass spectrometry employing a direct analysis in real time ion source coupled with an Orbitrap MS analyzer (DART Orbitrap MS) enabled fast and simple detection of the polysorbates present in the samples, with a lowest calibration level (LCL) of 1000 MUg mL(-1); (ii) ultrahigh performance reversed-phase liquid chromatography coupled with high-resolution time-of-flight mass spectrometry (UHPLC-HRTOF-MS) provided highly selective and sensitive detection and quantification of polysorbates with an LCL of 0.5 MUg mL( 1). PMID- 24810235 TI - [Analysis of workplace health promotion and its effect on work ability and health related quality of life in a medium-sized business]. AB - This study analyses the effect of workplace health promotion on work ability and health-related quality of life in white-collar and blue-collar workers in a medium-sized business. The intervention group contains 75 subjects with a mean age of 36.6+/-10.63 years (55 men, 20 women). The participation rate is 47%. White-collar workers show improvement in their health-related quality of life regarding physical and psychological aspects and work ability. Physically inactive employees show improvement in their health-related quality of life regarding physical and psychological aspects as well as context. Active employees only show significant improvement in terms of work ability. In conclusion, the promotion of exercise in the context of occupational health promotion has a positive effect on quality of life and work ability of employees and, thus, is a benefit for both the individual as well as the business itself. PMID- 24810236 TI - [Associations with Muslim patients in general practice surgeries--a survey among German general practicioners]. AB - INTRODUCTION: Due to the increasing numbers of Muslims in Germany(1)--about 4.3 million at the moment--more Muslim patients are medicated in the practices of family doctors. Their heterogeneous cultural and religious backgrounds are nontheless unknown and unfamiliar for the treating general practitioner. Based on the daily experiences of the latter and in order to capture their development of intercultural competence, in the present study a brainwriting with general practitioners was conducted to record their spontaneous associations with Muslim patients. METHODOLOGY: Individually and without exchange 90 general practitioners (66 male, 24 female) listed subjective thoughts regarding "Muslim patients" on a prepared sheet of paper. Additionally, sex, age, number of years as physician in a private practice and the frequency of treatment of Muslim patients in their own practice were requested. The content of the notes were evaluated using MAXQDA and were clustered in the categories of "language", "company", "violence", "men"/"women", "psychosomatic medicine", "compliance", "understanding of illness", "physical examination" and "head scarf". RESULTS: The ideas listed show that the majority of interviewed general practitioners regarded the treatment of Muslim patients as difficult. They associate Muslim patients with communication problems, a different type of disease understanding and a fear of contact, which hampers the examination situation. Less frequently, positive associations and unproblematic examination situations were noted. CONCLUSIONS: Due to a lack of knowledge about cultural and religious contexts Muslim patients are often described by using stereotypes. This underlines the necessity to foster intercultural competences and self-reflection in daily practice and its systematic inclusion in medical education. PMID- 24810237 TI - The influence of practice educators on occupational therapy students' understanding of the practical applications of theoretical knowledge: a phenomenological study into student experiences of practice education. AB - BACKGROUND/AIM: Practice education is a compulsory component of all entry-level programmes in the health professions. It is used as a teaching strategy to connect theoretical knowledge, such as occupation-focussed models with practice. The study aimed to explore students' perceptions about the influence of practice educators on their understanding of the use of occupation-focussed models in practice. METHODS: Using a phenomenological approach, semi-structured interviews gained an understanding of six participants' experiences of their practice education. Interview transcripts were analysed thematically. FINDINGS: Three themes emerged from participants' experiences of practice education. 'Explaining the theory-practice nexus' referred to participants' difficulties in distinguishing between different forms of theoretical knowledge, it described educators struggle to fulfil the dual roles of educator and practitioner' when articulating the theoretical knowledge underpinning practice. This often led participants taking an active role in their own learning. 'Experiencing dissonance between university-based studies and the real-world' described the difference between the importance university studies placed on theory in comparison to practice. 'Creating a positive mindset for the use of theoretical knowledge in practice for future practice' illustrated strategies used by some practice educators to articulate the use of theoretical knowledge. CONCLUSIONS: The study highlighted practice educators role in shaping students' perceptions of theoretical knowledge use in professional reasoning. The increased recognition of practice educators on the implicit curricula creates an onus on the university sector to provide discussion and information exchanges to increase educators' opportunities to develop, update and increase their skills in describing and using theoretical knowledge to underpin practice. PMID- 24810238 TI - Surgical and endoscopic management of remnant cystic duct lithiasis after cholecystectomy--a case series. AB - INTRODUCTION: Postcholecystectomy syndrome (PCS) as a result of remnant cystic duct lithiasis (RCDL), or gallstones within the cystic duct after cholecystectomy, can cause persistent or recurrent symptoms after cholecystectomy. STUDY DESIGN: A retrospective descriptive analysis was performed for all patients with RDCL at a single institution between 2001 and 2012. Details of presentation, diagnosis, and surgical and endoscopic treatments, and outcomes were collected and analyzed. RESULTS: Twelve patients with RCDL were identified. The interval between cholecystectomy to RCDL discovery was 34.2 months (range 0.5 168 months). On a standard liver enzyme panel, 75% of patients had derangements in >=1 indices, with the most common single laboratory test abnormality occurring in gamma-glutamyl transferase (GGT) (80%). Eight operative reports noted that the cystic duct was noticeably dilated at the time of cholecystectomy. Two patients developed a cystic duct leak (Strasberg type A bile duct injury) postoperatively, which was managed nonoperatively. Six cases of RCDL required surgery, and six were managed endoscopically. CONCLUSION: RCDL is a potential cause of postcholecystectomy syndrome, but the true incidence is unknown. Laboratory analysis and imaging are helpful in establishing the diagnosis of RCDL. Endoscopic therapy has a role in the treatment of RCDL, but surgical excision of the remnant cystic duct lithiasis may be required. PMID- 24810239 TI - Synthesis, characterization and mechanistic-insight into the anti-proliferative potential of PLGA-gemcitabine conjugate. AB - Gemcitabine, a nucleoside analogue, is used in the treatment of various solid tumors, however, its efficacy is limited by rapid metabolism by cytidine deaminase and fast kidney excretion. In this study, a polymeric conjugate of gemcitabine was prepared by covalent coupling with poly(lactic-co-glycolic) acid (PLGA), in order to improve anticancer efficacy of the drug. The prepared conjugate was characterized by various analytical techniques including FTIR, NMR and mass spectroscopic analysis. The stability study indicated that the polymeric conjugate was more stable in plasma as compared to native gemcitabine. Further, in vitro cytotoxicity determined in a panel of cell lines including pancreatic cancer (MIAPaCa-2), breast cancer (MCF-7) and colon cancer (HCT-116), indicated that the cytotoxic activity of gemcitabine was retained following conjugation with polymeric carrier. In the nucleoside transportation inhibition assay, it was found that the prepared conjugate was not dependent on nucleoside transporter for entering into the cells and this, in turn, reflecting potential implication of this conjugate in the therapy of transporter- deficient resistance cancer. Further, the cell cycle analysis showed that the sub-G1 (G0) apoptotic population was 46.6% and 60.6% for gemcitabine and PLGA gemcitabine conjugate, respectively. The conjugate produced remarkable decrease in mitochondrial membrane potential, a marker of apoptosis. In addition, there was a marked increase in PARP cleavage and P-H2AX expression with PLGA gemcitabine conjugate as compared to native gemcitabine indicating improved apoptotic activity. The findings demonstrated the potential of PLGA gemcitabine conjugate to improve clinical outcome of gemcitabine based chemotherapy of cancer. PMID- 24810240 TI - Lecithin-linker formulations for self-emulsifying delivery of nutraceuticals. AB - Lecithin-linker microemulsions are formulations produced with soybean lecithin in combination with a highly lipophilic (lipophilic linker) and highly hydrophilic (hydrophilic linkers) surfactant-like additives. In this work, lecithin-linker systems were formulated to produce self-emulsifying delivery systems for beta carotene and beta-sitosterol. The concentration of the lipophilic linker, sorbitan monooleate, was adjusted to minimize the formation of liquid crystals. The concentration of hydrophilic linkers, decaglyceryl caprylate/caprate and PEG 6-caprylic/capric glycerides, was gradually increased (scanned) until single phase clear microemulsions were obtained. For these scans, the oil (ethyl caprate) to water ratio was set to 1. The single phase, clear microemulsions were diluted with fed-state simulated intestinal fluid (FeSSIF) and produced stable emulsions, with drop sizes close to 200 nm. Using pseudo-ternary phase diagrams to evaluate the process of dilution of microemulsion preconcentrates (mixtures of oil, lecithin and linkers with little or no water) with FeSSIF, it was determined that self-emulsifying systems are obtained when the early stages of the dilution produce single phase microemulsions. If liquid crystals or multiple phase systems are obtained during those early stages, then the emulsification yields unstable emulsions with large drop sizes. An in vitro permeability study conducted using a Flow-Thru Dialyzer revealed that stable emulsions with drop sizes of 150-300 nm produce large and irreversible permeation of beta-carotene to sheep intestine. On the other hand, unstable emulsions produced without the linker combination separated in the dialyzer chamber. PMID- 24810241 TI - Pharmacoscintigraphic evaluation of potential of lipid nanocarriers for nose-to brain delivery of antidepressant drug. AB - Efficacy of antidepressants relies upon their continued presence at the site of action (brain) over a prolonged period of time. The BBB restricts the access of antidepressants to the brain on oral as well as intravenous administration. Direct delivery (by-passing the BBB) of antidepressant drugs can increase the CSF concentration with concomitant reduction in dose and side effects. Intranasal administration of nanostructured lipid carriers (NLC) containing antidepressant drug circumvent the BBB and maintain the prolonged release at the site of action. The aim of the present study was to evaluate the enhancement in brain uptake of NLC containing duloxetine (DLX) after intranasal administration. Duloxetine loaded NLC (DLX-NLC) was evaluated pharmacoscintigraphically for drug targeting potential (DTP), drug targeting efficiency (DTE) and biodistribution studies in different organs including brain. The radiolabeling efficiency of DLX and DLX-NLC was found to be 98.41 +/- 0.96 and 98.87 +/- 0.82 after 30 min, respectively. The biodistribution studies exhibited higher percentage of radioactivity/g for DLX NLC formulations in brain as compared with the DLX. The higher DTP (86.80%) and DTE (757.74%) suggested that DLX-NLC formulation has a better brain targeting efficiency than DLX solution (DTP=65.12%; DTE=287.34%) when administered intranasally. Moreover, the intranasal administration exhibited about 8-times higher concentration of DLX in brain when compared with the intravenous administration of DLX solution. The intranasal NLC containing DLX can be employed as an effective method for the treatment of depression. PMID- 24810242 TI - Comparison of different failure tests for pharmaceutical tablets: applicability of the Drucker-Prager failure criterion. AB - Several tests can be used to study the strength of pharmaceutical tablets. Equations exist in the literature to transform the failure force measured into a failure stress which can be considered as a characteristic of the strength of the material. For each failure test, the stress state at failure is different, and as a consequence, the failure stresses obtained are also different. It would thus be interesting to find a failure criterion to unify the different results. In this study four different tests were performed on pharmaceutical compacts of various densities: diametral compression, three-point flexure, biaxial flexure and uniaxial compressive tests. The Drucker-Prager criterion was tested as a possible fracture envelope. The results showed that this criterion is well suited to explain the failures obtained by diametral compression, three-point flexure and biaxial flexure. Nevertheless, for the uniaxial compressive test, the use of this criterion led to a significative underestimation of the experimental value of the failure stress. As a consequence, the Drucker-Prager criterion must be used with caution and is not able to explain all the failures that can occur in a pharmaceutical compact. PMID- 24810244 TI - Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study. AB - BACKGROUND: Clostridium difficile is a major cause of nosocomial diarrhea. The incidence and prognosis of C. difficile-associated diarrhea (CDAD) has not yet been assessed in adult patients after unrelated cord blood transplantation (uCBT). METHODS: The medical records of 135 adult unrelated cord blood transplant recipients were reviewed retrospectively to investigate the clinical features of CDAD after uCBT. These data were compared to medical records of 39 unrelated bone marrow transplant recipients and 27 related peripheral blood stem cell transplant recipients as controls. RESULTS: A total of 17 recipients developed CDAD, with onset occurring at a median of 22 days (range, 0-56 days) after transplantation. Among the unrelated cord blood transplant recipients, 11 (9%) developed CDAD. These results were comparable with those of CDAD after unrelated bone marrow transplantation (uBMT) (2/39, 6%) and related peripheral blood stem cell transplantation (rPBSCT) (4/27, 16%) (P=0.37). Fifteen of the infected recipients were successfully treated with oral metronidazole, vancomycin, or cessation of antibiotics. The remaining 2 recipients who developed CDAD after uCBT died of other causes. The development of CDAD did not negatively affect overall survival after uCBT. CONCLUSIONS: These data indicate that the incidence and prognosis of CDAD after uCBT are comparable with those after uBMT and rPBSCT. PMID- 24810243 TI - Tuneable resolution as a systems biology approach for multi-scale, multi compartment computational models. AB - The use of multi-scale mathematical and computational models to study complex biological processes is becoming increasingly productive. Multi-scale models span a range of spatial and/or temporal scales and can encompass multi-compartment (e.g., multi-organ) models. Modeling advances are enabling virtual experiments to explore and answer questions that are problematic to address in the wet-lab. Wet lab experimental technologies now allow scientists to observe, measure, record, and analyze experiments focusing on different system aspects at a variety of biological scales. We need the technical ability to mirror that same flexibility in virtual experiments using multi-scale models. Here we present a new approach, tuneable resolution, which can begin providing that flexibility. Tuneable resolution involves fine- or coarse-graining existing multi-scale models at the user's discretion, allowing adjustment of the level of resolution specific to a question, an experiment, or a scale of interest. Tuneable resolution expands options for revising and validating mechanistic multi-scale models, can extend the longevity of multi-scale models, and may increase computational efficiency. The tuneable resolution approach can be applied to many model types, including differential equation, agent-based, and hybrid models. We demonstrate our tuneable resolution ideas with examples relevant to infectious disease modeling, illustrating key principles at work. PMID- 24810246 TI - Polyoxometalate complexes for oxidative kinetic resolution of secondary alcohols: unique effects of chiral environment, immobilization and aggregation. AB - In this paper, the chiral surfactants bearing two long alkyl chains with hydroxyl groups at their terminals were synthesized and employed to encapsulate a catalytically efficient polyoxometalate through electrostatic interaction. The obtained chiral surfactant-encapsulated polyoxometalate complexes, in which a defined chiral microenvironment surrounds the inorganic cluster, were covalently immobilized into the silica matrix via a sol-gel process. Kinetic resolution of racemic aromatic alcohols was selected as the model reaction to evaluate the chiral supramolecular hybrid catalysts. Up to 89% enantiomeric excess was obtained by varying the reaction conditions. Importantly, the change of loading values of the chiral surfactant-encapsulated polyoxometalates leads to mutative inner microstructures ranging from uniform dispersion to subsequent formation of nanocrystalline domains in the silica matrix. Such a structural evolution differentiates the density and stability of the chiral microenvironment, resulting in a regular change of enantioselectivity of the prepared asymmetric catalysts. Moreover, the fixation of the chiral microenvironment surrounding the polyoxometalates by covalent immobilization was proved to have a promoting effect on enantioselectivity. The present research uncovers the unique effect of immobilization on the kinetic resolution. The strategy helps to understand the influencing factors of enantioselectivity, and provides a convenient and efficient approach for the construction of supramolecular asymmetric catalysts based on chiral surfactant-encapsulated polyoxometalate complexes. PMID- 24810245 TI - Tumor acquisition for biomarker research in lung cancer. AB - The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N = 30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing. PMID- 24810247 TI - Climate policy decisions require policy-based lifecycle analysis. AB - Lifecycle analysis (LCA) metrics of greenhouse gas emissions are increasingly being used to select technologies supported by climate policy. However, LCAs typically evaluate the emissions associated with a technology or product, not the impacts of policies. Here, we show that policies supporting the same technology can lead to dramatically different emissions impacts per unit of technology added, due to multimarket responses to the policy. Using a policy-based consequential LCA, we find that the lifecycle emissions impacts of four US biofuel policies range from a reduction of 16.1 gCO2e to an increase of 24.0 gCO2e per MJ corn ethanol added by the policy. The differences between these results and representative technology-based LCA measures, which do not account for the policy instrument driving the expansion in the technology, illustrate the need for policy-based LCA measures when informing policy decision making. PMID- 24810248 TI - Intralipid therapy does not improve level of consciousness in overdoses with sedating drugs: a case series. AB - OBJECTIVE: To assess the effect of intralipid emulsion therapy (ILE) in sedating drugs presenting to an urban emergency department. METHODS: Following the introduction of a clinical protocol for the use of ILE a retrospective chart review was undertaken, which describes the use of ILE in treating sedating drug overdose in a facility with a tertiary referral level clinical toxicology unit. Demographic data as well as details of drug ingested, physiological parameters and disposition were extracted from the medical record. RESULTS: Over a 7 month period nine cases were treated with intralipid, of which two were male and the median age was 33 years (17-52 years). Endotracheal intubation was required in seven cases and of the other two, one required a nasopharyngeal airway for several hours while being observed in a critical care area. One patient was managed in the intensive care unit without intubation. The median duration of ventilation in the seven patients was 31 h (22-82 h), and median length of stay for all nine cases was 63 h (24-133 h). CONCLUSION: This study does not support any clinically significant effect of intralipid in sedating drug overdose. PMID- 24810250 TI - The beneficial effect of escitalopram on obsessive-compulsive-related musical hallucinations in elderly patients with hearing impairment: a case series. AB - Musical hallucinations (MHs), characterized by the hearing of tunes, melodies, or songs, is a relatively under-recognized phenomenon among elderly individuals with hearing impairment. In some patients, MHs represent a complex psychopathological phenomenon, hallucinatory in content and obsessive-compulsive (OC) in form, justifying trial with an antiobsessive agent. In the present case series, we describe our clinical experience with escitalopram in six (two men, four women; age 74-85 years) elderly individuals with OC-related MH and hearing impairment who did not respond to previous antipsychotic treatment. Switch to escitalopram (mean 12.5 mg) led to a substantial improvement in the MH symptom severity, as reflected in a decrease in the global score of the Yale-Brown Obsessive Compulsive Scale adapted to OC-related MH (scores before escitalopram, 13.2+/ 0.9; after 12 weeks of treatment, 7.8+/-2.8; P<0.01). Escitalopram was well tolerated, and the only detected side effects, nausea and headache, were mild and transient. If confirmed in controlled trials, escitalopram and probably other selective serotonin reuptake inhibitors may be a therapeutic option in elderly individuals with OC-related MH. PMID- 24810249 TI - Partial agonist, telmisartan, maintains PPARgamma serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass. AB - Peroxisome proliferator activated receptor gamma (PPARgamma) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARgamma protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARgamma full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARgamma agonist with insulin-sensitizing and a weak pro adipocytic activity. TEL decreased S273pPPARgamma and did not affect S112pPPARgamma levels in a model of marrow MSC differentiation, U-33/gamma2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARgamma. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARgamma acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARgamma agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARgamma fat "browning" activity and a lack of anti osteoblastic activity. PMID- 24810251 TI - Alterations of bronchial epithelial metabolome by cigarette smoke are reversible by an antioxidant, O-methyl-L-tyrosinyl-gamma-L-glutamyl-L-cysteinylglycine. AB - Human bronchial epithelial cells (HBECs) have first-line contact with harmful substances during smoking, and changes in their metabolism most likely represent a defining factor in coping with the stress and development of airway diseases. This study was designed to determine the dynamics of metabolome changes in HBECs treated with cigarette smoke condensate (CSC), and to test whether normal metabolism can be restored by synthetic antioxidants. Principal component analysis, based on untargeted mass spectra, indicated that treatment of CSC exposed HBECs with O-methyl-L-tyrosinyl-gamma-L-glutamyl-L-cysteinylglycine (UPF1) acted faster than did N-acetylcysteine to revert the effect of CSC. The maximum effect of 10 MUg/ml CSC itself on HBEC cell line, BEAS-2B, metabolism was seen at 2 hours after treatment, with return to the baseline level by 7 hours. In primary HBECs, the initial maximum effect was seen at 1 hour after CSC exposure. Certain metabolites associated with redox pathways and energy production were affected by CSC. Subsequent restoration of their content by UPF1 supports the hypothetical protective capacity of UPF1 against the oxidative stress and increased energy demand, respectively. Furthermore, UPF1 up-regulated the contents of phospholipid species identified as phosphatidylcholines and phosphatidylethanolamines in the CSC-exposed HBECs, indicating possible suppression of inflammatory processes along with an increase in spermidine as an endogenous cytoprotector. In conclusion, with this dynamic metabolomics study, we characterize the durability of the CSC-induced metabolic changes in BEAS-2B line cells and primary HBECs, and demonstrate the ability of UPF1 to significantly accelerate the recovery of HBECs from CSC insult. PMID- 24810252 TI - Effect of lace-up ankle braces on electromyography measures during walking in adults with chronic ankle instability. AB - BACKGROUND: Lace-up ankle braces reduce the incidence of ankle sprains and have been hypothesized to do so through both mechanical and neuromuscular mechanisms. OBJECTIVE: To determine the effect of lace-up ankle braces on surface electromyography (sEMG) measures during walking in adults with chronic ankle instability (CAI). DESIGN: Randomized crossover. SETTING: Laboratory. PARTICIPANTS: Fifteen adults with CAI. MAIN OUTCOME MEASURES: Surface EMG activity was recorded from the anterior tibialis, peroneus longus, lateral gastrocnemius, rectus femoris, biceps femoris and gluteus medius during treadmill walking with and without lace-up ankle braces. The dependent variables were sEMG amplitude 100 ms pre- and 200 ms post-initial contact, time of activation relative to initial contact, and percent of activation across the stride cycle. RESULTS: When compared to no brace, ankle bracing resulted in lower pre-contact amplitude of the peroneus longus (p = 0.02). The anterior tibialis, peroneus longus, rectus femoris, and gluteus medius were activated later relative to initial contact (p < 0.03). The peroneus longus and rectus femoris were activated for a shorter percentage of the stride cycle (p < 0.05). CONCLUSION: Braces cause a change in neuromuscular activity during walking. Clinicians should be aware of these changes when prescribing braces, as it may relate to the mechanism in which braces decrease sprains. PMID- 24810253 TI - Impact of chronic pain on primary care across Europe. AB - The results of a survey conducted by the pan-European Opioids and Pain European Network of Minds (OPENMinds) Primary Care Group (OMPC) on pain assessment, opioid therapy, and educational needs are presented. PMID- 24810254 TI - Haemorrhoids and anal fissures during pregnancy and after childbirth: a prospective cohort study. AB - OBJECTIVE: To identify the incidence and risk factors of haemorrhoids and fissures during pregnancy and after childbirth. DESIGN: Prospective observational cohort study. SETTING: University hospital and outpatient clinics in Lithuania. POPULATION: A total of 280 pregnant women followed up until 1 month after delivery. METHODS: Women were examined four times through pregnancy and after delivery; those that developed peri-anal diseases were compared with those that did not. MAIN OUTCOME MEASURES: Incidence, time and risk factors of haemorrhoids and fissures. RESULTS: In all, 123 (43.9%) women developed peri-anal disease: 1.6% in the first trimester, 61% during the third trimester, 34.1% after delivery and 3.3% 1 month after delivery; 114 (40.7%) women were diagnosed with haemorrhoids, seven (2.5%) with haemorrhoids and anal fissure and two (0.71%) with anal fissure. Ninety-nine (80.5%) women had vaginal delivery and 24 (19.5%) women had undergone caesarean section. Multivariate analysis identified personal history of peri-anal diseases (odds ratio [OR] 11.93; 95% confidence interval [95% CI] 2.18-65.30), constipation (OR 18.98; 95% CI 7.13-50.54), straining during delivery for more than 20 minutes (OR 29.75; 95% CI 4.00-221.23) and birthweight of newborn>3800 g (OR 17.99; 95% CI 3.29-98.49) as significant predictors of haemorrhoids and anal fissures during pregnancy and perinatal period. CONCLUSIONS: Haemorrhoids and fissures are common during the last trimester of pregnancy and 1 month after delivery, with constipation, personal history of haemorrhoids or fissures, birthweight of newborn>3800 g, straining during delivery for more than 20 minutes being independently associated risk factors. PMID- 24810255 TI - Combinatorial inhibition of Plk1 and PKCbeta in cancer cells with different p53 status. AB - PKCbeta and Plk1 are fascinating targets in cancer therapy. Therefore, we combined Enzastaurin targeting PKCbeta and SBE13 targeting Plk1 to test synergistic effects in cells with different p53 status. We analyzed cell proliferation and apoptosis induction, and did Western blot and FACScan analyses to examine the combined PKCbeta and Plk1 inhibition. p53-wild-type cells are more resistant to the combinatorial treatment than p53-deficient cells, which displayed a synergistic reduction of cell proliferation after the combination. HeLa, MCF-7 and HCT116(p53wt) and HCT116(p53-/-) cells differed in their cell cycle distribution after combinatorial treatment in dependence on a functional p53-dependent G1/S checkpoint (p53-deficient cells showed an enrichment in S and G2/M, p53-wild-type cells in G0/G1 phase). hTERT-RPE1 cells did not show the synergistic effects of cancer cells. Thus, we demonstrate for the first time that Plk1 inhibition using SBE13 enhances the effects of Enzastaurin in cancer cells. HCT116(p53wt) and HCT116(p53-/-) cells confirmed the p53-dependence of different effects after Plk1 and PKCbeta inhibition observed in HeLa and MCF-7 cells. Obviously, p53 protects cells from the cytotoxicity of Enzastaurin in combination with SBE13. For that reason this combination can be useful to treat p53-deficient cancers, without displaying toxicity to normal cells, which all have functional p53. PMID- 24810257 TI - Posttraumatic stress symptoms seen in children within the 3-month period after the Van earthquake in Turkey. AB - The research was conducted to determine the posttraumatic stress symptoms seen in children within the 3 month period after the Van earthquake in Turkey. The research was conducted between December 2011 and January 2012 with the earthquake survivor children in the 7-12 age group living in the tent city built in the central area of Van. The research data were collected by the researcher using the Childhood Post-Traumatic Stress Reaction Index (CPTS-RI) and a questionnaire prepared by the researchers that contained questions on some information about the earthquake and on sociodemographic characteristics.It was found out that 8.6% (26) of the children had mild symptoms of posttraumatic stress disorder (PTSD), 19.7% (60) of the children had moderate symptoms of PTSD, 47.7% (145) of the children had severe symptoms of PTSD and 24.0% (73) of the children had very severe symptoms of PTSD. Furthermore, a significant difference (P < 0.001) was found between mean CPTS-RI scores and the economic losses experienced in the families of the children. In the study, PTSD was identified in the majority of children in the 7-12 age group who experienced the Van earthquake. PMID- 24810256 TI - Concordance study and population frequencies for 16 autosomal STRs analyzed with PowerPlex(r) ESI 17 and AmpFlSTR(r) NGM SElectTM in Somalis, Danes and Greenlanders. AB - A concordance study of the results of PowerPlex((r)) ESI 17 and AmpFlSTR((r)) NGM SElectTM kits obtained from 591 individuals from Somalia (N=198), Denmark (N=199) and Greenland (N=194) was performed. Among 9456 STR types, seven discordant results were found with the two kits: one observed in the D19S433 system in an individual from Denmark and six in the SE33 system in six individuals from Somalia. Sequencing of SE33 in the six samples with discordant results showed G>A transition 15bp downstream of the repeat unit in three of the individuals, and G>A transition 68bp downstream of the repeat unit in the other three individuals. Population data for 16 autosomal STR systems analyzed in 989 individuals from Somalia, Denmark and Greenland are also presented. The highest mean heterozygosity was observed in Danes (82.5%). With the exception of D8S1179 in Danes, no significant deviations from Hardy-Weinberg expectations were observed. Only one pair of systems (D12S391 and D18S51) showed significant allelic association in Greenlanders (after Holm-Sidak correction). A MDS plot drawn from pairwise FST values calculated between 21 populations showed a clear displacement of the Greenlandic population versus the other ones included in the analyses. The highest combined chance of exclusion and power of discrimination was observed for Danes reaching values of 99.9999987% and 1 in 1.8*10(21), respectively. PMID- 24810258 TI - An autoinhibitory conformation of the Bacillus subtilis spore coat protein SpoIVA prevents its premature ATP-independent aggregation. AB - Spores of Bacillus subtilis are dormant cell types that are formed when the bacterium encounters starvation conditions. Spores are encased in a shell, termed the coat, which is composed of approximately seventy different proteins and protects the spore's genetic material from environmental insults. The structural component of the basement layer of the coat is an exceptional cytoskeletal protein, termed SpoIVA, which binds and hydrolyzes ATP. ATP hydrolysis is utilized to drive a conformational change in SpoIVA that leads to its irreversible self-assembly into a static polymer in vitro. Here, we characterize the middle domain of SpoIVA, the predicted secondary structure of which resembles the chemotaxis protein CheX but, unlike CheX, does not harbor residues required for phosphatase activity. Disruptions in this domain did not abolish ATP hydrolysis, but resulted in mislocalization of the protein and reduction in sporulation efficiency in vivo. In vitro, disruptions in this domain prevented the ATP hydrolysis-driven conformational change in SpoIVA required for polymerization and led to the aggregation of SpoIVA into particles that did not form filaments. We propose a model in which SpoIVA initially assumes a conformation in which it inhibits its own aggregation into particles, and that ATP hydrolysis remodels the protein so that it assumes a polymerization-competent conformation. PMID- 24810259 TI - Optical coherence tomography microangiography for monitoring the response of vascular perfusion to external pressure on human skin tissue. AB - Characterization of the relationship between external pressure and blood flow is important in the examination of pressure-induced disturbance in tissue microcirculation. Optical coherence tomography (OCT)-based microangiography is a promising imaging technique, capable of providing the noninvasive extraction of functional vessels within the skin tissue with capillary-scale resolution. Here, we present a feasibility study of OCT microangiography (OMAG) to evaluate changes in blood perfusion in response to externally applied pressure on human skin tissue in vivo. External force is loaded normal to the tissue surface at the nailfold region of a healthy human volunteer. An incremental force is applied step by step and then followed by an immediate release. Skin perfusion events including baseline are continuously imaged by OMAG, allowing for visualization and quantification of the capillary perfusion in the nailfold tissue. The tissue strain maps are simultaneously evaluated through the available OCT structural images to assess the relationship of the microcirculation response to the applied pressure. The results indicate that the perfusion progressively decreases with the constant increase of pressure. Reactive hyperemia occurs right after the removal of the pressure. The perfusion returns to the baseline level after a few minutes. These findings suggest that OMAG may have great potential for quantitatively assessing tissue microcirculation in the locally pressed tissue in vivo. PMID- 24810260 TI - Recent advances in and limitations of cardiac output monitoring by means of electrical impedance tomography. AB - BACKGROUND: Currently, the monitoring of cardiac output (CO) and stroke volume (SV) is mainly performed using invasive techniques. Therefore, performing CO monitoring noninvasively by means of electrical impedance tomography (EIT) would be advantageous for intensive care. Our hypothesis was that, by means of EIT, it is possible to assess heart rate (HR) and to quantify changes in SV due to changes in ventilator settings. METHODS: CO (HR and SV) of 14 pigs (32-40 kg body weight) was changed by incremental increases in positive end-expiratory pressure levels (0, 5, 10, 15, and 20 cm.H2O; ramp maneuver). This ramp maneuver was applied 4 times in each animal, yielding 43 evaluable single experiments. At each positive end-expiratory pressure level, SV was assessed by transpulmonary thermodilution using a PiCCO device. EIT data were acquired using a Drager EIT Evaluation Kit 2. RESULTS: The EIT-based SV-related signal, Z(SV) (in [AU]), showed only a weak correlation (after excluding 2 measurements) with SV(TTD) of r = 0.58 (95% confidence interval, 0.43-0.71). If Z(SV) is calibrated by the reference 1 time for each experiment (defined as SVEIT), the correlation is approximately 0.85 (95% confidence interval, 0.78-0.90). A possible reason for the moderate correlation is the unexpected scaling pattern, leading to amplification of the cardiac impedance signal, found in some animals. The scaling is probably due to the imperfect reconstruction (i.e., a change of sensitivity) of the EIT images or to a change in the position of the heart. CONCLUSIONS: The hypothesis that EIT can be used to monitor CO and SV was confirmed, but further studies are required before this technique can be applied in clinical practice. HR was determined robustly and accurately. For SV monitoring, promising results were obtained in 80% of the experiments. However, unexpected scaling of the cardiac EIT signal causing inaccurate estimation of SV remains an issue. Before robust assessment of SV by EIT is suitable for clinical practice, the cause of and compensation for undesired scaling effects need to be investigated. PMID- 24810261 TI - The use of a novel technology to study dynamics of pathogen transmission in the operating room. AB - Pathogenic organisms have been found in the intraoperative environment, potentially posing a risk of infection that could cause morbidity and mortality. In an effort to understand how a patient's bacteria can be spread throughout the operating room with the anesthesia provider as a vector, we conducted a study using recently developed experimental technology in a simulated operating room environment with a high-fidelity human patient simulator. PMID- 24810262 TI - Intraoperative dexamethasone and delirium after cardiac surgery: a randomized clinical trial. AB - BACKGROUND: Delirium is common after cardiac surgery and may be partly related to the systemic inflammatory response triggered by the surgery and the use of cardiopulmonary bypass. We hypothesized that intraoperative administration of high-dose dexamethasone, a drug with potent anti-inflammatory effects, would reduce the incidence of delirium at any time point during the first 4 postoperative days after cardiac surgery. METHODS: This was a single-center substudy within a larger, multicenter placebo-controlled randomized clinical trial, the Dexamethasone for Cardiac Surgery (DECS) trial that randomized patients >=18 years, undergoing cardiac surgery with cardiopulmonary bypass, to receive, in a double-blind fashion, either dexamethasone 1 mg/kg or placebo at the induction of anesthesia. Over the first 4 postoperative days, we compared between groups the incidence of delirium (based on the Confusion Assessment Method adapted for the intensive care unit, or after intensive care unit discharge, by the Confusion Assessment Method, accompanied by chart review), restraint use, and administered haloperidol, benzodiazepines, and opioids. Data were analyzed according to the intention-to-treat principle. The proportion of patients with delirium in the dexamethasone versus the placebo group was compared using the odds ratio (OR) with a 95% confidence interval (CI). The proportion also was compared using logistic regression to adjust for common baseline variables that might confound the presence of delirium between the 2 groups. RESULTS: Of 768 eligible patients, 737 subjects (96.0%) had complete data. The incidence of delirium was similar between the dexamethasone (14.2%) and placebo (14.9%) groups (crude OR = 0.95, 95% CI, 0.63-1.43; adjusted OR = 0.85, 95% CI, 0.55-1.31). Among patients who developed delirium, the median (interquartile range) duration of delirium was similar between the dexamethasone and placebo groups (2 [1-3] vs 2 [1-2] days, respectively, P = 0.45; WMWodds 0.98, 95% CI, 0.83-1.17). Restraint use and the administration of haloperidol, benzodiazepines, and opioids were also similar between the 2 groups. CONCLUSIONS: The intraoperative administration of dexamethasone did not reduce the incidence or duration of delirium in the first 4 days after cardiac surgery. PMID- 24810263 TI - Matrix metalloproteinase-27 is expressed in CD163+/CD206+ M2 macrophages in the cycling human endometrium and in superficial endometriotic lesions. AB - Matrix metalloproteinases (MMPs) are key enzymes involved in extracellular matrix remodelling. In the human endometrium, the expression and activity of several MMPs are maximal during the menstrual phase. Moreover, MMPs are thought to be involved in the pathogenesis of endometriosis and cancers, in particular with invasion and metastasis. We recently reported that MMP-27 is a unique MMP with an intracellular retention motif. We investigated the expression and cellular localization of MMP-27 in the cycling human endometrium and in endometriotic lesions. MMP-27 mRNA was detected throughout the menstrual cycle. Despite large interpatient variations, mRNA levels increased from the proliferative to the secretory phase, to peak during the menstrual phase. MMP-27 was immunolocalized in large isolated cells scattered throughout the stroma and around blood vessels: these cells were most abundant at menstruation and were identified by immunofluorescence as CD45(+), CD163(+) and CD206(+) macrophages. CD163(+) macrophages were also abundant in endometriotic lesions, but showed different patterns in ovarian or peritoneal endometriotic lesions (co-labelling for CD206 and MMP-27) and rectovaginal lesions (no co-labelling). In conclusion, MMP-27 is expressed in a subset of endometrial macrophages related to menstruation and in ovarian and peritoneal endometriotic lesions. PMID- 24810264 TI - Effects of plasmon energetics on light emission induced by scanning tunneling microscopy. AB - A theoretical model of plasmon and molecular luminescence induced by scanning tunneling microscopy using a molecule-covered tip on clean metal surfaces is developed. The effects of coupling between molecular exciton and interface plasmon on the luminescence spectra are investigated for variable energy of plasmon modes by means of the nonequilibrium Green's function method. It is found that spectral features arising from interference between the processes of energy absorption by the molecule and interface plasmons appear near the energy of the excitonic mode. For the energy of plasmon above (below) the energy of excitonic mode, an additional peak structure appears in the energy range slightly below (above) the energy of the excitonic mode. Prominent peak and dip structures observed in recent luminescence experiments are interpreted by the developed theory whereby its utility in the fields of plasmonics and nanophotonics is demonstrated. PMID- 24810265 TI - Glucose oxidase from Penicillium amagasakiense: characterization of the transition state of its denaturation from molecular dynamics simulations. AB - Glucose oxidase (GOx) is a flavoenzyme having applications in food and medical industries. However, GOx, as many other enzymes when extracted from the cells, has relatively short operational lifetimes. Several recent studies (both experimental and theoretical), carried out on small proteins (or small fractions of large proteins), show that a detailed knowledge of how the breakdown process starts and proceeds on molecular level could be of significant help to artificially improve the stability of fragile proteins. We have performed extended molecular dynamics (MD) simulations to study the denaturation of GOx (a protein dimer containing nearly 1200 amino acids) to identify weak points in its structure and in this way gather information to later make it more stable, for example, by mutations. A denaturation of a protein can be simulated by increasing the temperature far above physiological temperature. We have performed a series of MD simulations at different temperatures (300, 400, 500, and 600 K). The exit from the protein's native state has been successfully identified with the clustering method and supported by other methods used to analyze the simulation data. A common set of amino acids is regularly found to initiate the denaturation, suggesting a moiety where the enzyme could be strengthened by a suitable amino acid based modification. PMID- 24810266 TI - Outcome of endovascular reintervention for significant stenosis at infrainguinal bypass anastomoses. AB - OBJECTIVE: The durability of an infrainguinal bypass may be hampered by development of stenosis at the anastomoses. We describe the patency of percutaneous transluminal angioplasty (PTA) of these anastomotic stenoses. METHODS: Any venous or prosthetic infrainguinal bypass with a hemodynamically significant anastomotic stenosis, symptomatic or asymptomatic, was considered a bypass at risk (BAR) for occlusion. All BARs undergoing PTA in two large vascular referral centers between January 2005 and December 2010 were retrospectively reviewed. Procedural success was defined as <30% residual stenosis. Primary end points were primary, assisted primary, and secondary patency rates. RESULTS: Included were 43 patients with 43 BARs (31 venous, 11 prosthetic, and 1 unknown conduit; 19 supragenicular and 24 infragenicular). Mean follow-up was 17 months (range, 0-57 months). Procedures constituted 48 interventions for proximal (n = 13), distal (n = 25), or combined (n = 5) anastomotic stenoses. Procedural success was 96%. The primary, assisted primary, and secondary patency rates were 58%, 85%, and 88%, respectively, at 2 years. CONCLUSIONS: PTA for infrainguinal BAR due to anastomotic stenosis is technically feasible with acceptable durability. PTA for these anastomotic stenoses may be considered a safe option as the first-line treatment. PMID- 24810268 TI - Association of a single-nucleotide polymorphism in myosin-binding protein C, slow type (MYBPC1) gene with marbling in Japanese Black beef cattle. PMID- 24810269 TI - Epidemiologic features and environmental risk factors of severe fever with thrombocytopenia syndrome, Xinyang, China. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in rural areas of Central China in 2009, caused by a novel bunyavirus, SFTS virus (SFTSV). The disease usually presents as fever, thrombocytopenia, and leukocytopenia, with case-fatality rates ranging from 2.5% to 30%. Haemaphysalis longicornis was suspected to be the most likely vector of SFTSV. By the end of 2012, the disease had expanded to 13 provinces of China. SFTS patients have been reported in Japan and South Korea, and a disease similar to SFTS has been reported in the United States. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the epidemiologic features of 504 confirmed SFTS cases in Xinyang Region, the most severely SFTS-afflicted region in China from 2011 to 2012, and assessed the environmental risk factors. All cases occurred during March to November, with the epidemic peaking from May to July. The patients' ages ranged from 7 to 87 years (median 61 years), and the annual incidence increased with age (chi2 test for trend, P<0.001). The female-to-male ratio of cases was 1.58, and 97.0% of the cases were farmers who resided in the southern and western parts of the region. The Poisson regression analysis revealed that the spatial variations of SFTS incidence were significantly associated with the shrub, forest, and rain-fed cropland areas. CONCLUSIONS: The distribution of SFTS showed highly significant temporal and spatial heterogeneity in Xinyang Region, with the majority of SFTS cases being elderly farmers who resided in the southern and western parts of the region, mostly acquiring infection between May and July when H. longicornis is highly active. The shrub, rain-fed, and rain-fed cropland areas were associated with high risk for this disease. PMID- 24810270 TI - Age-related concerns of male veteran callers to a suicide crisis line. AB - In July 2007, the United States Department of Veterans Affairs (VA) partnered with the Department of Health and Human Services' Substance Abuse and Mental Health Service Administration (SAMHSA) to create the Veterans Crisis Line (VCL) in order to meet the unique needs of Veterans in distress. The current study utilized a mixed methods design to examine characteristics of male callers to the VCL. Results from qualitative analyses demonstrated that the majority of callers between April 1 and August 31, 2008 contacted the VCL with concerns related to mental health issues, suicide ideation, and substance abuse issues. Quantitative analyses demonstrated age differences associated with concerns presented by callers such that middle-aged and older callers were more likely to present with loneliness and younger callers were more likely to present with mental health concerns. The results of this study will help to inform future research designed to optimize the effectiveness of the VCL for suicide prevention in Veterans. PMID- 24810271 TI - Imaging the eye in idiopathic intracranial hypertension. PMID- 24810272 TI - The hidden price of repeated traumatic exposure. AB - Neuroimaging studies have demonstrated reduced hippocampal volume in trauma exposed individuals without posttraumatic stress disorder (PTSD). However, the implications of such a deficit in this non-clinical population are still unclear. Animal and human models of PTSD suggest that hippocampal deficit may result in impaired learning and use of associations between contextual information and aversive events. Previous study has shown that individuals with PTSD have a selective impairment in reversing the negative outcome of context-related information. The aim of this study was to test whether non-PTSD individuals who are repeatedly exposed to traumatic events display similar impairment. To that end, we compared the performance of active-duty firefighters who are frequently exposed to traumatic events as part of their occupational routine and civilian matched-controls with no history of trauma-exposure. We used a novel cue-context reversal paradigm, which separately evaluates reversal of negative and positive outcomes of cue and context-related information. As predicted, we found that while both trauma-exposed firefighters and unexposed matched-controls were able to acquire and retain stimulus-outcome associations, firefighters struggled to learn that a previously negative context is later associated with a positive outcome. This impairment did not correlate with levels of PTSD, anxiety or depressive symptoms. The results suggest that similar to individuals with PTSD, highly exposed individuals fail to associate traumatic outcomes with their appropriate context. This impairment may reflect a possible hidden price of repeated traumatic exposure, which is not necessarily associated with PTSD diagnosis, and may affect the way highly exposed individuals interpret and react to their environment. PMID- 24810273 TI - Patterns of nucleotide diversity at photoperiod related genes in Norway spruce [Picea abies (L.) Karst]. AB - The ability of plants to track seasonal changes is largely dependent on genes assigned to the photoperiod pathway, and variation in those genes is thereby important for adaptation to local day length conditions. Extensive physiological data in several temperate conifer species suggest that populations are adapted to local light conditions, but data on the genes underlying this adaptation are more limited. Here we present nucleotide diversity data from 19 genes putatively involved in photoperiodic response in Norway spruce (Picea abies). Based on similarity to model plants the genes were grouped into three categories according to their presumed position in the photoperiod pathway: photoreceptors, circadian clock genes, and downstream targets. An HKA (Hudson, Kreitman and Aquade) test showed a significant excess of diversity at photoreceptor genes, but no departure from neutrality at circadian genes and downstream targets. Departures from neutrality were also tested with Tajima's D and Fay and Wu's H statistics under three demographic scenarios: the standard neutral model, a population expansion model, and a more complex population split model. Only one gene, the circadian clock gene PaPRR3 with a highly positive Tajima's D value, deviates significantly from all tested demographic scenarios. As the PaPRR3 gene harbours multiple non synonymous variants it appears as an excellent candidate gene for control of photoperiod response in Norway spruce. PMID- 24810274 TI - Genetic Association of MPPED2 and ACTN2 with Dental Caries. AB - The first genome-wide association study of dental caries focused on primary teeth in children aged 3 to 12 yr and nominated several novel genes: ACTN2, EDARADD, EPHA7, LPO, MPPED2, MTR, and ZMPSTE24. Here we interrogated 156 single-nucleotide polymorphisms (SNPs) within these candidate genes for evidence of association with dental caries experience in 13 race- and age-stratified samples from 6 independent studies (n = 3600). Analysis was performed separately for each sample, and results were combined across samples via meta-analysis. MPPED2 was significantly associated with caries via meta-analysis across the 5 childhood samples, with 4 SNPs showing significant associations after gene-wise adjustment for multiple comparisons (p < .0026). These results corroborate the previous genome-wide association study, although the functional role of MPPED2 in caries etiology remains unknown. ACTN2 also showed significant association via meta analysis across childhood samples (p = .0014). Moreover, in adults, genetic association was observed for ACTN2 SNPs in individual samples (p < .0025), but no single SNP was significant via meta-analysis across all 8 adult samples. Given its compelling biological role in organizing ameloblasts during amelogenesis, this study strengthens the hypothesis that ACTN2 influences caries risk. Results for the other candidate genes neither proved nor precluded their associations with dental caries. PMID- 24810275 TI - Whole Body Vibration Reduces Inflammatory Bone Loss in a Lipopolysaccharide Murine Model. AB - Whole body vibration (WBV) stimulation has a beneficial effect on the recovery of osteoporotic bone. We aimed to investigate the immediate effect of WBV on lipopolysaccharide (LPS)-mediated inflammatory bone loss by varying the exposure timing. Balb/C mice were divided into the following groups: control, LPS (L), and LPS with vibration (LV). The L and LV groups received LPS (5 mg/kg) by 2 intraperitoneal injections on days 0 and 4. The LV group was exposed to WBV (0.4 g, 45 Hz) either during LPS treatment (LV1) or after cessation of LPS injection (LV2) and then continued WBV treatment for 10 min/d for 3 d. Evaluation based on micro-computed tomography was performed 7 d after the first injection, when the L group showed a significant decrease in bone volume (-25.8%) and bone mineral density (-33.5%) compared with the control group. The LV2 group recovered bone volume (35%) and bone mineral density (19.9%) compared with the L group, whereas the LV1 group showed no improvement. This vibratory signal showed a suppressive effect on the LPS-mediated induction of inflammatory cytokines such as IL-1beta or TNF-alpha in human mesenchymal stem cells in vitro. These findings suggest that immediate exposure to WBV after the conclusion of LPS treatment efficiently reduces trabecular bone loss, but WBV might be less effective during the course of treatment with inflammatory factor. PMID- 24810276 TI - Genome sequencing and comparative genomics of the broad host-range pathogen Rhizoctonia solani AG8. AB - Rhizoctonia solani is a soil-borne basidiomycete fungus with a necrotrophic lifestyle which is classified into fourteen reproductively incompatible anastomosis groups (AGs). One of these, AG8, is a devastating pathogen causing bare patch of cereals, brassicas and legumes. R. solani is a multinucleate heterokaryon containing significant heterozygosity within a single cell. This complexity posed significant challenges for the assembly of its genome. We present a high quality genome assembly of R. solani AG8 and a manually curated set of 13,964 genes supported by RNA-seq. The AG8 genome assembly used novel methods to produce a haploid representation of its heterokaryotic state. The whole-genomes of AG8, the rice pathogen AG1-IA and the potato pathogen AG3 were observed to be syntenic and co-linear. Genes and functions putatively relevant to pathogenicity were highlighted by comparing AG8 to known pathogenicity genes, orthology databases spanning 197 phytopathogenic taxa and AG1-IA. We also observed SNP-level "hypermutation" of CpG dinucleotides to TpG between AG8 nuclei, with similarities to repeat-induced point mutation (RIP). Interestingly, gene-coding regions were widely affected along with repetitive DNA, which has not been previously observed for RIP in mononuclear fungi of the Pezizomycotina. The rate of heterozygous SNP mutations within this single isolate of AG8 was observed to be higher than SNP mutation rates observed across populations of most fungal species compared. Comparative analyses were combined to predict biological processes relevant to AG8 and 308 proteins with effector-like characteristics, forming a valuable resource for further study of this pathosystem. Predicted effector-like proteins had elevated levels of non-synonymous point mutations relative to synonymous mutations (dN/dS), suggesting that they may be under diversifying selection pressures. In addition, the distant relationship to sequenced necrotrophs of the Ascomycota suggests the R. solani genome sequence may prove to be a useful resource in future comparative analysis of plant pathogens. PMID- 24810278 TI - Diversity and molecular phylogeny of mitochondrial DNA of rhesus macaques (Macaca mulatta) in Bangladesh. AB - While studies of rhesus macaques (Macaca mulatta) in the eastern (e.g., China) and western (e.g., India) parts of their geographic range have revealed major genetic differences that warrant the recognition of two different subspecies, little is known about genetic characteristics of rhesus macaques in the transitional zone extending from eastern India and Bangladesh through the northern part of Indo-China, the probable original homeland of the species. We analyzed genetic variation of 762 base pairs of mitochondrial DNA from 86 fecal swab samples and 19 blood samples from 25 local populations of rhesus macaque in Bangladesh collected from January 2010 to August 2012. These sequences were compared with those of rhesus macaques from India, China, and Myanmar. Forty-six haplotypes defined by 200 (26%) polymorphic nucleotide sites were detected. Estimates of gene diversity, expected heterozygosity, and nucleotide diversity for the total population were 0.9599 +/- 0.0097, 0.0193 +/- 0.0582, and 0.0196 +/ 0.0098, respectively. A mismatch distribution of paired nucleotide differences yielded a statistically significantly negative value of Tajima's D, reflecting a population that rapidly expanded after the terminal Pleistocene. Most haplotypes throughout regions of Bangladesh, including an isolated region in the southwestern area (Sundarbans), clustered with haplotypes assigned to the minor haplogroup Ind-2 from India reflecting an east to west dispersal of rhesus macaques to India. Haplotypes from the southeast region of Bangladesh formed a cluster with those from Myanmar, and represent the oldest rhesus macaque haplotypes of Bangladesh. These results are consistent with the hypothesis that rhesus macaques first entered Bangladesh from the southeast, probably from Indo China, then dispersed westward throughout eastern and central India. PMID- 24810277 TI - Role of autophagy in metabolic syndrome-associated heart disease. AB - Metabolic syndrome is a constellation of multiple metabolic risk factors including abdominal obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. Over the past decades, the prevalence of metabolic syndrome has increased dramatically, imposing a devastating, pandemic health threat. More importantly, individuals with metabolic syndrome are at an increased risk of diabetes mellitus and overall cardiovascular diseases. One of the common comorbidities of metabolic syndrome is heart anomalies leading to the loss of cardiomyocytes, cardiac dysfunction and ultimately heart failure. Up-to-date, a plethora of cell signaling pathways have been postulated for the pathogenesis of cardiac complications in obesity including lipotoxicity, inflammation, oxidative stress, apoptosis and sympathetic overactivation although the precise mechanism of action underscoring obesity-associated heart dysfunction remains elusive. Recent evidence has indicated a potential role of protein quality control in components of metabolic syndrome. Within the protein quality control system, the autophagy-lysosome pathway is an evolutionarily conserved pathway responsible for bulk degradation of large intracellular organelles and protein aggregates. Autophagy has been demonstrated to play an indispensible role in the maintenance of cardiac geometry and function under both physiological and pathological conditions. Accumulating studies have demonstrated that autophagy plays a pivotal role in the etiology of cardiac anomalies under obesity and metabolic syndrome. In this minireview, we will discuss on how autophagy is involved in the regulation of cardiac function in obesity and metabolic syndrome. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. PMID- 24810279 TI - Mitochondrial disorders and epilepsy. AB - INTRODUCTION: Mitochondrial respiratory chain defects (RCD) often exhibit multiorgan involvement, affecting mainly tissues with high-energy requirements such as the brain. Epilepsy is frequent during the evolution of mitochondrial disorders (30%) with different presentation in childhood and adulthood in term of type of epilepsy, of efficacy of treatment and also in term of prognosis. STATE OF ART: Mitochondrial disorders can begin at any age but the diseases with early onset during childhood have generally severe or fatal outcome in few years. Four age-related epileptic phenotypes could be identified in infancy: infantile spasms, refractory or recurrent status epilepticus, epilepsia partialis continua and myoclonic epilepsy. Except for infantile spasms, epilepsy is difficult to control in most cases (95%). In pediatric patients, mitochondrial epilepsy is more frequent due to mutations in nDNA-located than mtDNA-located genes and vice versa in adults. Ketogenic diet could be an interesting alternative treatment in case of recurrent status epilepticus or pharmacoresistant epilepsy. CONCLUSION: Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. PMID- 24810281 TI - Primary Presentations of Laryngomalacia. AB - IMPORTANCE: Laryngomalacia (LM) classically presents with stridor in early infancy but can present atypically with snoring and/or sleep-disordered breathing (S-SDB) or swallowing dysfunction (SwD). The epidemiology of these atypical presentations has not been established in the literature. OBJECTIVE: To document the primary modes of presentation for LM in a consecutive series of children and to compare the characteristics of each subgroup. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series in a single tertiary pediatric otolaryngology practice. Outpatient and surgical records were searched for patients diagnosed as having LM from 2002 to 2009. We included all children with endoscopically confirmed LM without prior documentation of the diagnosis (n = 88). INTERVENTIONS: Patients were investigated and managed according to the routine practice pattern of the senior author. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the proportion of the various primary presentations of LM. Age, sex, type of LM, management, and secondary diagnoses were also collected. Subgroup analysis was performed. RESULTS: Of 117 potentially eligible patients identified, 88 children had a confirmed diagnosis of LM and were thus included (1.9:1 male to female sex ratio; mean [SD] age, 14.5 [23.0] months; age range, 0.2-96.0 months). Fifty-six children (64%) presented primarily with awake stridor and variable respiratory distress; 22 (25%) with S-SDB; and 10 (11%) with SWD. The difference in mean (SD) age for each group was statistically significant by analysis of variance: stridor, 3.5 (2.8) months; S-SDB, 46.0 (27.2) months; and SwD, 4.8 (4.6) months (P < .001). By chi2 analysis, sex distribution was not significantly different between subgroups (P = .29), nor was the proportion of children who underwent supraglottoplasty (P = .07). The difference in proportion of types of LM between the stridor and atypical presentations was statistically significant (chi2P < .05), with type 1 LM predominating in children presenting with S-SDB. CONCLUSIONS AND RELEVANCE: Because LM may present primarily with S SDB and SwD in a significant proportion of children, the diagnosis must be considered in patients presenting with these upper airway complaints. The morphologic type of LM may vary by presentation. PMID- 24810280 TI - The significance of Exo1 K589E polymorphism on cancer susceptibility: evidence based on a meta-analysis. AB - The exonuclease1 (Exo1) gene is a key component of mismatch repair (MMR) by resecting the damaged strand, which is the only exonuclease involved in the human MMR system. The gene product is a member of the RAD2 nuclease family and functions in DNA replication, repair and recombination. However, whether Exo1 is required to activate MMR-dependent DNA damage response (DDR) remains unknown, the conclusions of the Exo1 polymorphisms on cancer susceptibility studies were not consistent. We carried out a meta-analysis of 7 case-control studies to clarify the association between the Exo1 K589E polymorphism and cancer risk. Overall,a significant association of the Exo1 K589E polymorphism with cancer risk in all genetic models (Lys vs Glu: OR = 1.51, 95%CI:1.39-1.99, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.43, 95%CI:1.28-1.60, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.45, 95%CI:1.90-3.17, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.53, 95%CI:1.38-1.71, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.27, 95%CI:1.79-2.89, P<0.01). In the stratified analysis by ethnicity, significantly increased risk was observed in Asian population (Lys vs Glu: OR = 1.53, 95%CI:1.39-1.69, P<0.01; Glu/Lys vs Glu/Glu: OR = 1.50, 95%CI:1.34-1.69, P<0.01; Lys/Lys vs Glu/Glu: OR = 2.48, 95%CI:1.84-3.34, P<0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR = 1.58, 95%CI:1.41-1.78, P<0.01; Glu/Glu vs Glu/Lys+Lys/Lys: OR = 2.18, 95%CI:1.62-2.93, P<0.01). Subgroup analysis based on smoking suggested Exo1 K589E polymorphism conferred significant risk among smokers (Lys/Lys+Glu/Lys vs Glu/Glu: OR = 2.16, 95%CI:1.77-2.63, P<0.01), but not in non-smokers (Lys/Lys+Glu/Lys vs Glu/Glu: OR = 0.89, 95%CI:0.64-1.24, P = 0.50). In conclusion, Exo1 K589E Lys allele may be used as a novel biomarker for cancer susceptibility, particularly in smokers. PMID- 24810283 TI - The H + HeH(+) -> He + H2(+) reaction from the ultra-cold regime to the three body breakup: exact quantum mechanical integral cross sections and rate constants. AB - In this work, we present a quantum mechanical scattering study of the title reaction from 1 mK to 2000 K. Total integral cross sections and thermal rate constants are compared with previous theoretical and experimental data and with simpler theoretical models to understand the range of validity of the approximations used in the previous studies. The obtained quantum reactive observables have been found to be nearly insensitive to the roto-vibrational energy of the reactants at high temperatures. More sensitive to the reactant's roto-vibrational energy are the data in the cold and ultra-cold regimes. The implications of the new data presented here in the early universe scenario are also discussed and analyzed. PMID- 24810282 TI - The efficacy of a brief motivational enhancement education program on CPAP adherence in OSA: a randomized controlled trial. AB - BACKGROUND: Poor adherence to CPAP treatment in OSA adversely affects the effectiveness of this therapy. This randomized controlled trial (RCT) examined the efficacy of a brief motivational enhancement education program in improving adherence to CPAP treatment in subjects with OSA. METHODS: Subjects with newly diagnosed OSA were recruited into this RCT. The control group received usual advice on the importance of CPAP therapy and its care. The intervention group received usual care plus a brief motivational enhancement education program directed at enhancing the subjects' knowledge, motivation, and self-efficacy to use CPAP through the use of a 25-min video, a 20-min patient-centered interview, and a 10-min telephone follow-up. Self-reported daytime sleepiness adherence related cognitions and quality of life were assessed at 1 month and 3 months. CPAP usage data were downloaded at the completion of this 3-month study. RESULTS: One hundred subjects with OSA (mean +/- SD, age 52 +/- 10 years; Epworth Sleepiness Scales [ESS], 9 +/- 5; median [interquartile range] apnea-hypopnea index, 29 [20, 53] events/h) prescribed CPAP treatment were recruited. The intervention group had better CPAP use (higher daily CPAP usage by 2 h/d [Cohen d = 1.33, P < .001], a fourfold increase in the number using CPAP for >= 70% of days with >= 4 h/d [P < .001]), and greater improvements in daytime sleepiness (ESS) by 2.2 units (P = .001) and treatment self-efficacy by 0.2 units (P = .012) compared with the control group. CONCLUSIONS: Subjects with OSA who received motivational enhancement education in addition to usual care were more likely to show better adherence to CPAP treatment, with greater improvements in treatment self-efficacy and daytime sleepiness. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01173406; URL: www.clinicaltrials.gov. PMID- 24810284 TI - Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs? AB - PURPOSE OF REVIEW: Respiratory syncytial virus (RSV) represents the most common respiratory pathogen observed worldwide in infants and young children and may play a role in the inception of recurrent wheezing and asthma in childhood. We discuss herein the recent hypothesis that RSV vertically transmitted from the mother to the fetus in utero causes persistent structural and functional changes in the developing lungs of the offspring, thereby predisposing to postnatal airway obstruction. RECENT FINDINGS: A number of observations in humans support the notion that extrapulmonary tissues may be infected hematogenously by RSV and harbor this virus allowing the persistence of latent infection. More recent data from animal models suggest that RSV can be transmitted across the placenta from the respiratory tract of the mother to that of the fetus, and persist in the lungs both during development, as well as during adulthood. Vertical RSV infection is associated with dysregulation of crucial neurotrophic pathways during ontogenesis, leading to aberrant parasympathetic innervation and airway hyperreactivity after postnatal reinfection. SUMMARY: These new data challenge the current paradigm that acquisition of RSV infection occurs only after birth and shift attention to the prenatal effects of the virus, with the potential to result in more severe and lasting consequences by interfering with crucial developmental processes. The most immediate implication is that prophylactic strategies targeted to the mother-fetus dyad may reduce the incidence of postviral sequelae like childhood wheezing and asthma. PMID- 24810285 TI - Cyclic nucleotide-based therapeutics for chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) defines a group of chronic inflammatory disorders of the airways that are characterised by a progressive and largely irreversible decline in expiratory airflow. Drugs used to treat COPD through actions mediated by cyclic AMP (cAMP) are restricted to long-acting and short-acting beta2-adrenoceptor agonists and, in a subset of patients with chronic bronchitis, a phosphodiesterase 4 inhibitor, roflumilast. These agents relax airway smooth muscle and suppress inflammation. At the molecular level, these effects in the airways are mediated by two cAMP effectors, cAMP-dependent protein kinase and exchange proteins activated by cAMP. The pharmacology of newer agents, acting through these systems, is discussed here with an emphasis on their potential to interact and increase therapeutic effectiveness. PMID- 24810286 TI - Urbanization impacts on mammals across urban-forest edges and a predictive model of edge effects. AB - With accelerating rates of urbanization worldwide, a better understanding of ecological processes at the wildland-urban interface is critical to conserve biodiversity. We explored the effects of high and low-density housing developments on forest-dwelling mammals. Based on habitat characteristics, we expected a gradual decline in species abundance across forest-urban edges and an increased decline rate in higher contrast edges. We surveyed arboreal mammals in sites of high and low housing density along 600 m transects that spanned urban areas and areas turn on adjacent native forest. We also surveyed forest controls to test whether edge effects extended beyond our edge transects. We fitted models describing richness, total abundance and individual species abundance. Low density housing developments provided suitable habitat for most arboreal mammals. In contrast, high-density housing developments had lower species richness, total abundance and individual species abundance, but supported the highest abundances of an urban adapter (Trichosurus vulpecula). We did not find the predicted gradual decline in species abundance. Of four species analysed, three exhibited no response to the proximity of urban boundaries, but spilled over into adjacent urban habitat to differing extents. One species (Petaurus australis) had an extended negative response to urban boundaries, suggesting that urban development has impacts beyond 300 m into adjacent forest. Our empirical work demonstrates that high-density housing developments have negative effects on both community and species level responses, except for one urban adapter. We developed a new predictive model of edge effects based on our results and the literature. To predict animal responses across edges, our framework integrates for first time: (1) habitat quality/preference, (2) species response with the proximity to the adjacent habitat, and (3) spillover extent/sensitivity to adjacent habitat boundaries. This framework will allow scientists, managers and planners better understand and predict both species responses across edges and impacts of development in mosaic landscapes. PMID- 24810287 TI - Determination of the 14C content in activated steel components from a neutron spallation source and a nuclear power plant. AB - The (14)C content in activated steel components from the Swiss Nuclear Power Plant (NPP) Gosgen and the Spallation Neutron Source SINQ at the Paul Scherrer Institute is determined using a wet chemistry digestion technique and liquid scintillation counting for (14)C activity measurements. The (14)C activity of an activated fuel assembly steel nut from the NPP is further compared with theoretical predictions made on the basis of a Monte Carlo reactor model for this NPP. Knowledge of the (14)C inventory in these activated steel materials is important in conjunction with future corrosion studies on these materials aimed at identifying the (14)C containing organic compounds possibly formed in the cement-based near field of a repository for radioactive waste. PMID- 24810288 TI - Effects of heat stress on the quality of Trichogrammatoidea bactrae Nagaraja (Hymenoptera: Trichogrammatidae). AB - Trichogrammatoidea bactrae Nagaraja (Hymenoptera: Trichogrammatidae) is an important natural enemy of many species of lepidopterous pests. The effects of heat stress temperature (33, 36, and 39 degrees C), duration of exposure (2, 4, 6, and 8 h), and developmental stage during exposure (embryo-first instar larvae, second instar larvae, prepupae, and pupae) on the development and reproduction of parasitoid T. bactrae were investigated in the laboratory. When exposed to 39 degrees C for 8 h during pupal stage, only 19.90% adults emerged from host eggs, and more than 14% were deformed (wings were folded or incomplete). Parasitoid females exposed to 39 degrees C for 8 h as prepupae only lived for 1.45 days and parasitized about 23.5 host eggs. Moreover, life-table parameters of T. bactrae were also influenced by exposure to heat stress temperatures during each preimaginal developmental stage. Based on these results, we propose that T. bactrae is susceptible to high temperatures, especially at 39 degrees C. Thus, this parasitoid may be more effectively controlling lepidopterous pests during cooler weather conditions. PMID- 24810289 TI - Expanding the RpoS/sigmaS-network by RNA sequencing and identification of sigmaS controlled small RNAs in Salmonella. AB - The RpoS/sigmaS sigma subunit of RNA polymerase (RNAP) controls a global adaptive response that allows many Gram-negative bacteria to survive starvation and various stresses. sigmaS also contributes to biofilm formation and virulence of the food-borne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). In this study, we used directional RNA-sequencing and complementary assays to explore the sigmaS-dependent transcriptome of S. Typhimurium during late stationary phase in rich medium. This study confirms the large regulatory scope of sigmaS and provides insights into the physiological functions of sigmaS in Salmonella. Extensive regulation by sigmaS of genes involved in metabolism and membrane composition, and down-regulation of the respiratory chain functions, were important features of the sigmaS effects on gene transcription that might confer fitness advantages to bacterial cells and/or populations under starving conditions. As an example, we show that arginine catabolism confers a competitive fitness advantage in stationary phase. This study also provides a firm basis for future studies to address molecular mechanisms of indirect regulation of gene expression by sigmaS. Importantly, the sigmaS-controlled downstream network includes small RNAs that might endow sigmaS with post-transcriptional regulatory functions. Of these, four (RyhB-1/RyhB-2, SdsR, SraL) were known to be controlled by sigmaS and deletion of the sdsR locus had a competitive fitness cost in stationary phase. The sigmaS-dependent control of seven additional sRNAs was confirmed in Northern experiments. These findings will inspire future studies to investigate molecular mechanisms and the physiological impact of post transcriptional regulation by sigmaS. PMID- 24810290 TI - Obstructive Sleep Apnea Syndrome (OSAS), metabolic syndrome and mental health in small enterprise workers. feasibility of an Action for Health. AB - OBJECTIVE: To determine the frequency of obstructive sleep apnea syndrome (OSAS), metabolic syndrome and common mental disorders in the working population of 11 small enterprises and the feasibility of a program of action for health. METHOD: The clinical risk of OSAS, the prevalence of metabolic syndrome, and the level of psychological disorders were assessed during routine medical examination at the workplace in 2012. The response to medical advice was assessed in 2013. RESULTS: 12.3% of the workers were suspected of being affected by OSAS. One or more components of metabolic syndrome were present in 24.5% of cases. OSAS in "healthy" workers was significantly associated with the presence of one or more components of metabolic syndrome (OR = 3.83; 95%CI 1.45-10.13) and with a psychological disorders score in the highest quartile (OR = 4.67; 95%CI = 1.72 12.64). Workers with suspected OSAS were reluctant to follow advice about undergoing further tests under the NHS. However, in some cases, confirmation of the OSAS diagnosis and subsequent treatment led to an improvement in metabolic condition. CONCLUSION: Although participation in treatment was limited, anecdotal cases support the idea that prevention of obstructive sleep apnea in the workplace might be useful for workers' health. PMID- 24810291 TI - Gibberella moniliformis AH13 with antitumor activity, an endophytic fungus strain producing triolein isolated from Adlay (Coix lacryma-jobi: poaceae). AB - In this study, the isolation of an endophytic fungus from the leaves of the medicinal herb adlay (Coix lacryma-jobi L. var. ma-yuen Stapf) is reported for the first time. The fungus produced Triolein (trioleoylglycerol), a major constituent of triacylglycerols (TAGs) of adlay, in rice medium under shake-flask and bench-scale fermentation conditions. The fungus was identified as Gibberella moniliformis (Fusarium verticillioides) by its morphology and authenticated by ITS analysis (ITS1 and ITS2 regions and the intervening 5.8S rDNA region). Triolein was identified by HPLC-ELSD coupled with APCI-MS and confirmed through comparison with authentic standard. The concentration of triolein produced by G. moniliformis AH13 reached 2.536 +/- 0.006 mg/g dry weight of mycelium. Moreover, the EtOAc extract of G. moniliformis AH13 showed strong antitumor activity against four types of tumor cells (A549, HCT116, MDA-MB-231, and SW1990). These results suggest that G. moniliformis AH13 in adlay has significant scientific and industrial potential to meet the pharmaceutical demands and sustainable energy requirements for TAGs in a cost-effective, easily accessible, and reproducible way and is also a potential novel source of natural antitumor bioactive agents. PMID- 24810292 TI - Cell envelope phospholipid composition of Burkholderia multivorans. AB - Burkholderia multivorans causes opportunistic pulmonary infections in cystic fibrosis and immunocompromised patients. The purpose of the present study was to determine the nature of the phospholipids and their fatty acid constituents comprising the cell envelope membranes of strains isolated from three disparate sources. A conventional method for obtaining the readily extractable lipids fraction from bacteria was employed to obtain membrane lipids for thin-layer chromatographic and gas chromatography-mass spectrophotometric analyses. Major fatty acid components of the B. multivorans readily extractable lipid fractions included C(16:0) (palmitic acid), C(16:1) (palmitoleic acid), and C(18:1) (oleic acid), while C(14:0) (myristic acid), DeltaC(17:0) (methylene hexadecanoic acid), C(18:0) (stearic acid), and DeltaC(19:0) (methylene octadecanoic acid) were present in lesser amounts. Fatty acid composition differed quantitatively among strains with regard to C(16:0), C(16:1), DeltaC(17:0), C(18:1), and DeltaC(19:0) with the unsaturated:saturated fatty acid ratios being significantly less in a cystic fibrosis type strain than either environmental or chronic granulomatous disease strains. Phospholipids identified in all B. multivorans strains included lyso-phosphatidylethanolamine, phosphatidylglycerol, phosphatidylethanolamine, and diphosphatidylglycerol in similar ratios. These data support the conclusion that the cell envelope phospholipid profiles of disparate B. multivorans strains are similar, while their respective fatty acyl substituent profiles differ quantitatively under identical cultivation conditions. PMID- 24810293 TI - The effectiveness of autologous conditioned serum in the treatment of knee osteoarthritis. AB - CLINICAL SCENARIO: Osteoarthritis (OA) is a debilitating degenerative disease affecting an estimated 27 million Americans. A systematic review found that patients with a previous history of traumatic knee injury are at increased risk of developing knee OA, regardless of specific injury. It is vital for the maintenance of quality of life for individuals affected with OA that the treatment options available be able to reduce symptoms and restore quality of living. The pain-relief benefits of traditional injection treatments are small to moderate and have a limited duration. It was found that at 2 wk postinjection that corticosteroids were more effective than hyaluronic acid (HA) injections. Autologous conditioned serum (ACS) injection is a novel treatment that has shown favorable results. However, many clinicians continue to use HA injections for reduction of symptoms in patients with osteoarthritis when the use of ACS may be more beneficial. FOCUSED CLINICAL QUESTION: For patients with knee OA, is an ACS injection more efficient at producing a reduction in symptoms than HA or a saline injection? PMID- 24810294 TI - Ion channels: regulating cell volume. PMID- 24810295 TI - Pre- and postnatal exposure to tobacco smoke and respiratory outcomes during the first year. AB - The different role of prenatal and postnatal exposure to tobacco smoke in respiratory outcomes in infants has not yet been clearly established. Our objective is to assess the effects of these exposures on the risk of respiratory outcomes during the first year of life of infants from a Spanish multicenter cohort study. A total of 2506 women were monitored until delivery. About 2039 infants made up the final population. The outcomes were caused by the occurrence of the following: otitis, cough persisting for more than 3 weeks, lower respiratory tract symptoms (wheezing or chestiness), and lower respiratory tract infections (bronchitis, bronchiolitis, or pneumonia). The relationship between prenatal and postnatal exposure and health outcomes was explored using logistic regression analysis. Maternal smoking during pregnancy increased the odds for wheezing (OR: 1.41, 95% CI: 0.99-2.01) and chestiness (OR: 1.46, 95% CI: 1.03 2.01). Postnatal exposure from fathers was associated with otitis (OR: 1.25, 95% CI: 1.01-1.54). Passive exposure at work of non-smoking mothers during pregnancy was related to cough (OR: 1.62, 95% CI: 1.05-2.51). Exposure to tobacco smoke was related to a higher risk of experiencing respiratory outcomes in young infants. Prenatal exposure was that most clearly associated with the respiratory outcomes analyzed. PMID- 24810296 TI - Verrucous carcinoma of the foot, not your typical plantar wart: a case study. AB - STATEMENT OF PURPOSE: Verrucous carcinoma of the foot is often misdiagnosed initially as plantar warts. Delayed diagnostic treatments with the use of optimal biopsy techniques may result in significant hindrances for patient care and may often result in detrimental outcomes to the patient. With the use of various epidermal biopsy methods, early diagnostic treatment can be implemented to a slow growing lesion unresponsive to topical agents preventing unfavorable pedal amputations. DESIGN: A case study of verrucous carcinoma of the foot with surgical resection was conducted along with a literature review. BACKGROUND: Verrucous carcinoma (VC) of the foot is known to be a rare, locally invasive, well-differentiated low-grade squamous cell carcinoma that may evolve from the human papilloma virus. This localized tumor of the foot often has low metastatic potential, however can be quite invasive. It is therefore pertinent to obtain adequate radiological studies when planning for surgical resection of this tumor. When localized to the foot, it often involves deep structures such as tendons, muscle & bone. Complete wide local excision of the tumor is essential to avoid recurrence. We present a case of verrucous carcinoma of the foot in a 46-year-old African American male with a past medical history of Human immunodeficiency virus (HIV) and Human papilloma virus (HPV). The patient refused a Transmetatarsal amputation. The loss of the third digit was a result of tissue loss following resection and an attempt to relocate a severely laterally dislocated 3rd digit, not PVD. PMID- 24810297 TI - Effect of mycotoxin-containing diets on epigenetic modifications of mouse oocytes by fluorescence microscopy analysis. AB - Mycotoxins, such as aflatoxin (AF), fumonisin B1, zearalenone (ZEA), and deoxynivalenol (DON), are commonly found in many food commodities. Mycotoxins have been shown to increase DNA methylation levels in a human intestinal cell line. We previously showed that the developmental competence of oocytes was affected in mice that had been fed a mycotoxin-containing diet. In this study, we explored possible mechanisms of low mouse oocyte developmental competence after mycotoxin treatment in an epigenetic modification perspective. Mycotoxin contaminated maize (DON at 3,875 MUg/kg, ZEA at 1,897 MUg/kg, and AF at 806 MUg/kg) was included in diets at three different doses (mass percentage: 0, 15, and 30%) and fed to mice for 4 weeks. The fluorescence intensity analysis showed that the general DNA methylation levels increased in oocytes from high dose mycotoxin-fed mice. Mouse oocyte histone methylation was also altered. H3K9me3 and H4K20me3 level increased in oocytes from mycotoxin-fed mice, whereas H3K27me3 and H4K20me2 level decreased in oocytes from mycotoxin-fed mice. Thus, our results indicate that naturally occurring mycotoxins have effects on epigenetic modifications in mouse oocytes, which may be one of the reasons for reduced oocyte developmental competence. PMID- 24810298 TI - Redefining the modular organization of the core Mediator complex. AB - The Mediator complex plays an essential role in the regulation of eukaryotic transcription. The Saccharomyces cerevisiae core Mediator comprises 21 subunits, which are organized into Head, Middle and Tail modules. Previously, the Head module was assigned to a distinct dense domain at the base, and the Middle and Tail modules were identified to form a tight structure above the Head module, which apparently contradicted findings from many biochemical and functional studies. Here, we compared the structures of the core Mediator and its subcomplexes, especially the first 3D structure of the Head + Middle modules, which permitted an unambiguous assignment of the three modules. Furthermore, nanogold labeling pinpointing four Mediator subunits from different modules conclusively validated the modular assignment, in which the Head and Middle modules fold back on one another and form the upper portion of the core Mediator, while the Tail module forms a distinct dense domain at the base. The new modular model of the core Mediator has reconciled the previous inconsistencies between the structurally and functionally defined Mediator modules. Collectively, these analyses completely redefine the modular organization of the core Mediator, which allow us to integrate the structural and functional information into a coherent mechanism for the Mediator's modularity and regulation in transcription initiation. PMID- 24810299 TI - Manipulation of a VEGF-Notch signaling circuit drives formation of functional vascular endothelial progenitors from human pluripotent stem cells. AB - Human pluripotent stem cell (hPSC)-derived endothelial lineage cells constitutes a promising source for therapeutic revascularization, but progress in this arena has been hampered by a lack of clinically-scalable differentiation protocols and inefficient formation of a functional vessel network integrating with the host circulation upon transplantation. Using a human embryonic stem cell reporter cell line, where green fluorescent protein expression is driven by an endothelial cell specific VE-cadherin (VEC) promoter, we screened for > 60 bioactive small molecules that would promote endothelial differentiation, and found that administration of BMP4 and a GSK-3beta inhibitor in an early phase and treatment with VEGF-A and inhibition of the Notch signaling pathway in a later phase led to efficient differentiation of hPSCs to the endothelial lineage within six days. This sequential approach generated > 50% conversion of hPSCs to endothelial cells (ECs), specifically VEC(+)CD31(+)CD34(+)CD14(-)KDR(high) endothelial progenitors (EPs) that exhibited higher angiogenic and clonogenic proliferation potential among endothelial lineage cells. Pharmaceutical inhibition or genetical knockdown of Notch signaling, in combination with VEGF-A treatment, resulted in efficient formation of EPs via KDR(+) mesodermal precursors and blockade of the conversion of EPs to mature ECs. The generated EPs successfully formed functional capillary vessels in vivo with anastomosis to the host vessels when transplanted into immunocompromised mice. Manipulation of this VEGF-A-Notch signaling circuit in our protocol leads to rapid large-scale production of the hPSC-derived EPs by 12- to 20-fold vs current methods, which may serve as an attractive cell population for regenerative vascularization with superior vessel forming capability compared to mature ECs. PMID- 24810300 TI - Structure and domain organization of Drosophila Tudor. PMID- 24810302 TI - Keeping 53BP1 out of focus in mitosis. AB - A recent study published in Science reveals the mechanism and biological importance of DNA damage response abrogation in mitotic cells. PMID- 24810301 TI - Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity. AB - Subtelomeres consist of sequences adjacent to telomeres and contain genes involved in important cellular functions, as subtelomere instability is associated with several human diseases. Balancing between subtelomere stability and plasticity is particularly important for Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis. T. brucei regularly switches its major variant surface antigen, variant surface glycoprotein (VSG), to evade the host immune response, and VSGs are expressed exclusively from subtelomeres in a strictly monoallelic fashion. Telomere proteins are important for protecting chromosome ends from illegitimate DNA processes. However, whether they contribute to subtelomere integrity and stability has not been well studied. We have identified a novel T. brucei telomere protein, T. brucei TRF-Interacting Factor 2 (TbTIF2), as a functional homolog of mammalian TIN2. A transient depletion of TbTIF2 led to an elevated VSG switching frequency and an increased amount of DNA double-strand breaks (DSBs) in both active and silent subtelomeric bloodstream form expression sites (BESs). Therefore, TbTIF2 plays an important role in VSG switching regulation and is important for subtelomere integrity and stability. TbTIF2 depletion increased the association of TbRAD51 with the telomeric and subtelomeric chromatin, and TbRAD51 deletion further increased subtelomeric DSBs in TbTIF2-depleted cells, suggesting that TbRAD51-mediated DSB repair is the underlying mechanism of subsequent VSG switching. Surprisingly, significantly more TbRAD51 associated with the active BES than with the silent BESs upon TbTIF2 depletion, and TbRAD51 deletion induced much more DSBs in the active BES than in the silent BESs in TbTIF2-depleted cells, suggesting that TbRAD51 preferentially repairs DSBs in the active BES. PMID- 24810304 TI - A Spanish May. PMID- 24810303 TI - Hallmarks of triple negative breast cancer emerging at last? AB - Triple negative breast cancers (TNBC) are clinically heterogeneous but mostly aggressive malignancies devoid of expression of the estrogen, progesterone and HER2 (ERBB2 or NEU) receptors. Recent evidence shows that basal endoplasmic reticulum stress (ERS) is typically activated in TNBC and cooperates with hypoxia signaling to promote tumor progression and relapse; ERS and hypoxia response may therefore be among the long-searched hallmarks of TNBC. PMID- 24810305 TI - Evaluation of a pilot Pressure Ulcer Prevention Initiative (PUPI) for patients with traumatic spinal cord injury. AB - OBJECTIVE: The purpose of this study was to determine whether implementation of a Pressure Ulcer Prevention Initiative (PUPI) changed the assessment and treatment of patients with a traumatic spinal cord injury (SCI) in an acute care setting, and improved patient outcomes. METHOD: The success of implementation was evaluated by examining the percentage of patients with completed occupational therapist (OT) skin care assessments and prescriptions for therapeutic support surfaces (TSS; i.e., mattresses) before implementation (historical, cohort 1) and after implementation (experimental, cohort 2). Patient outcomes were evaluated by examining changes in PU incidence, severity, timing and recurrence, as well as PU prevalence and satisfaction with life in the community. RESULTS: Final analysis included 70 patients in cohort 1 and 73 in cohort 2. OT skin care assessment documentation (31% to 60%; p<0.001) and TSS prescriptions (31% to 60%; p=0.02) significantly increased following the implementation. The PU incidence based on patient charts (both nursing and OT assessments) did not increase significantly (26% to 36%; p=0.2). However, documented PU incidence according to OT assessments showed a substantial increase (14% to 33%; p=0.002). No effect of the PUPI was seen on immediate or long-term patient outcomes during the study period. CONCLUSION: PUPI was successful in changing clinical practice in PU prevention but no statistically significant improvements in PU-related patient outcomes were demonstrated. Results from this study identified facilitators and barriers to implementation and highlighted the complexity and difficulty of instituting effective preventative or therapeutic interventions for this population in an acute care setting. This information will assist with refinements of the PUPI and inform similar future initiatives. PMID- 24810306 TI - Treatment for wound pruritus following burns. AB - OBJECTIVE: To review the current literature on the treatment of itching, or pruritus, in people with burn wounds. METHOD: A literature search using the databases PubMed, MEDLINE and Google Scholar was undertaken. Studies were included in the review if they discussed or evaluated different treatment options for pruritus in patients with burn wounds. RESULTS: A variety of treatments are available for the relief of pruritus in patients with burns wounds, ranging from antihistamines and topical emollients to psychological therapies, massage and dermatological treatments. Oral antihistamines are used most commonly, yet research indicates that these are not always effective. Few studies are methodologically robust. In recent years, there has been an attempt to design and implement treatment strategies and algorithms, however, there is currently no agreed and consistent management plan for the treatment of pruritus due to burn injury. CONCLUSION: Simple single therapies should be the first line therapy for the treatment of pruritus due to burns, however, if these are unsuccessful, combination therapy should be introduced early to try to reduce the onset of chronic itch. Current algorithms and treatment plans based on the stage of healing show promise but need further modification and testing before they can be recommended for common use. PMID- 24810307 TI - The production and measurement of sub-bandage pressure: Laplace's Law revisited. AB - OBJECTIVE: The present study was undertaken to demonstrate that the pressures produced by multiple layers of compression bandages applied to artificial limbs of known circumference with predetermined levels of tension can be predicted accurately using the modified Laplace equation. METHOD: Up to four layers of different bandage types were applied in a carefully controlled fashion to cylinders of known circumference, with tensions ranging from around 200-2000 grams/10cm width. The pressures generated were measured using pneumatic pressure sensors previously shown to possess the required degree of accuracy for this type of experimental system. RESULTS: Good correlation was observed between the mean and standard deviation of each pair of experimental and calculated pressure values for all combinations of bandage type, application tension and cylinder circumference. Over the clinically relevant range of pressures, the difference between data sets was generally less than 1.0mmHg. CONCLUSION: The results of this experimental study unequivocally prove that provided accurate values for all the relevant variables are known, it is possible to predict the pressure that will be developed by a compression bandage on a limb of known size. However, it is important to recognise that other factors such as the elastomeric properties of the fabric will have a major effect upon the ability of a bandage system to sustain initial compression values. Furthermore, the variation in radius of curvature around a limb will mean that point pressures readings recorded at individual locations around the circumference may vary dramatically from the average value predicted by the modified Laplace equation, calling into question the value of sub-bandage pressure measuring devices for this application. PMID- 24810308 TI - Knowledge and practice of foot self-care among Jordanians with diabetes: an interview-based survey study. AB - OBJECTIVE: To examine knowledge and practice of foot care among Jordanian patients with diabetes. METHOD: An ethically-approved Arabic language questionnaire was used to interview participants recruited from five Jordanian governorates. Data was analysed using the Statistical Package for Social Sciences (SPSS version 16). Total scores for knowledge and practice were computed, and were classified as poor (<50%), satisfactory (50-70%) or good (>70%). RESULTS: Out of 1085 participants, 51.1% were males and 48.8% were females. The average age was 53.3 years (SD=13.3 years), with over half (54.0%) were between 41-60 years of age. More than half of knowledge scores were within the range 'good', in which there was around 6% of the practice scores. Those classified as having poor knowledge amounted to 7.2%, whilst those classified as exercising poor practice amounted to 42%. Statistically significant associations were established between level of education and knowledge (p<0.001) as well as practice (p<0.006). CONCLUSION: The study demonstrated discrepancies between knowledge and practice in relation to foot care. Efforts are required to reduce these discrepancies between knowledge and the real practice of foot self-care, taking into account the patients' levels of education and the cultural context. PMID- 24810309 TI - A novel use of amniotic membrane for fingertip injuries. AB - OBJECTIVE: Fingertip injuries, which are the most common hand injury, represent management challenges for hand surgeons. Full thickness skin grafts are routinely used to cover the fingertip site, but has significant donor site morbidity. As amniotic membranes (AM) are used as a dressing substitute in burns, we decided to evaluate the efficacy of AM as a biologic wound dressing material for coverage of these injuries. METHOD: In this clinical study, 30 patients with full-thickness zone 1 fingertip skin loss were included. The patients were divided into 2 groups using the block randomisation method. In the first group, a skin graft was used for coverage and in the second group, AM was used. All patients were operated on by the same hand surgeon between February 2012 to October 2012. The minimum follow-up period was 6 months. Two point discrimination (T.P.D), light touch, healing time, days lost from work and infection rate were evaluated and recorded. RESULTS: This study recruited 30 patients with full-thickness zone 1 fingertip skin loss (age range 13-47 years). Fingertips in both groups were assessed. T.P.D, light touch and days lost from work were significantly lower in the AM group than in the skin graft group. Healing time was lower in the skin graft group. In the both groups, no infection was detected. Patients of both groups were satisfied of their treatment and healing progress. CONCLUSION: Our results showed the effectiveness and safety of AM for the treatment of fingertip amputation, which can produce better sensation and functional outcomes than skin graft transplantations. PMID- 24810310 TI - The use of a specialised amino acid mixture for pressure ulcers: a placebo controlled trial. AB - OBJECTIVE: To compare pressure ulcer healing rates in patients supplemented with a specialised amino acid mixture containing (beta)-hydroxy (beta)-methylbutyrate (HMB), arginine and glutamine, and standard oral nutritional supplements versus patients supplemented with oral nutritional supplements and a placebo mixture. METHOD: Twenty-three inpatients with stage II, III or IV pressure ulcers in an acute care hospital were randomised to recieve (A) a HMB, arginine and glutamine mixture twice daily alongside oral nutritional supplements (n=11) or (B) standard nutritional care alongside oral nutritional supplements (n=12) for 2 weeks. Pressure ulcers were measured weekly for area, depth and Pressure Ulcer Scale for Healing (PUSH) scores. The proportion of viable tissue was determined based on area of wound tracing. Weekly laboratory tests were performed to measure C reactive protein and pre-albumin levels. This trial is registered at http://ClinicalTrials.gov under NCT01090076. RESULTS: There was no difference between anthropometrical measurements, biochemical parameters and nutritional intake pre- and post- study. Wound area did not decrease significantly in the short term for both groups. The proportion of viable tissues increased within 2 weeks on HMB, arginine and glutamine supplementation (p=0.02). PUSH scores showed significant improvement within 1 week of supplementation for the experimental group (p=0.013). CONCLUSION: The use of specialised amino acid does not appear to reduce wound size and PUSH scores but may improve tissue viability after 2 weeks. Further confirmation on a larger scale is required to determine the benefits of supplementing additional HMB, arginine and glutamine in patients with pressure ulcers. PMID- 24810311 TI - Neonatal necrotising fasciitis managed conservatively: an experience from a tertiary centre. AB - OBJECTIVE: Conventional therapy for neonatal necrotising fasciitis (NF) involves resuscitation and aggressive surgical debridement of necrotic tissue. This approach adds surgical stress in septicaemic neonates with low reserves. The present study reports a more conservative approach to the management of neonatal NF. METHOD: A prospective study was conducted between July 2010 and June 2013 and included 11 cases of neonatal NF. Demographic characteristics of patients were noted. No debridement was performed. Dressings were applied after cleaning with normal saline every 24 hours. The necrotic slough was allowed to separate spontaneously. A record was made of type and duration of supportive modalities and complications. The primary outcome was recorded as final recovery, need of surgical intervention or need of grafting. RESULTS: Out of 11 neonates, 6 were males and 5 were females. Age ranged from 13 to 24 days (mean age 18.45+/-3.24 days), and weight varied from 1.8 to 2.6 kg (mean weight 2.12+/-0.24kg) at presentation. Duration of illness before admission to hospital ranged from 3 to 9 days (mean 4.84+/-2.13 days). The most common site of the initial involvement was the neck and upper thoracic region (n=4), scalp (n=3), lower back (n=2), face (n=1) and extremities (n=1). In all cases, the wound was cleaned with normal saline, dressed, necrotic slough was allowed to separate spontaneously and granulation tissue was allowed to develop; this took approximately 14 to 28 days (mean 20.45+/-5.78 days). CONCLUSION: As opposed to the conventional approach of aggressive debridement in neonatal NF, these cases can be managed conservatively without increase in morbidity or mortality. This approach also minimises the surgical risk and requirement of blood transfusion. Antifungal drugs have a definitive role in management of these immunologically deficient babies. PMID- 24810312 TI - Bacterial colonisation of the burn wound: a UK experience. AB - OBJECTIVE: Bacterial colonisation of the burn wound remains a major source of morbidity and mortality in burns patients. This study aimed to determine the presence of different micro-organisms in a UK regional burns centre and to examine the relationships between bacterial colonisation, burn size, length of hospital stay and delayed referral. METHOD: A retrospective review of microbiology surveillance swab results on all adult patients admitted to a regional burns centre over a 12-month period was performed. RESULTS: 139 adult patients were included in the study. Approximately 68% of patients showed evidence of burn wound colonisation at some point during their inpatient stay. The remaining 32% had negative microbiology swabs throughout their hospital stay. A total of 202 micro-organisms were isolated. Staphylococcus aureus was found to be the most common micro-organism, found in 79% of patients with positive swab results. A direct link was found between an increased incidence of bacterial colonisation and delay in referral of >24 hours, larger burn size and length of hospital stay. CONCLUSION: By understanding the potential sources of bacteria and the effect of patient factors on their susceptibility to bacterial colonisation, we can form better management and treatment strategies to reduce morbidity and mortality from burns wound sepsis. PMID- 24810313 TI - The direct inhibition of MMP-2 and MMP-9 by an enzyme alginogel: a possible mechanism of healing support for venous leg ulcers. AB - Flaminal Forte is an enzyme alginogel,whose activity depends on the absorption and binding of matrix metalloproteinases (MMPs), which are known to play a crucial role in delayed wound healing. The aim of the study was to evaluate the influence of Flaminal on MMP-2/-9 activity in ulcer exudate, ex vivo. Eight patients with bilateral venous leg ulcers were treated for 4 weeks with Flaminal Forte covered by hydrocolloid ('F' wounds), or with hydrocolloid alone ('H' wounds) as a reference control. Clinical assessment did not reveal any differences between F and H wounds regarding surface reduction and general wound condition. Nevertheless, although non-significant, there was a visible difference in peri-wound skin appearance in F wounds, as compared to H wounds. The wound exudate contained high MMP-2/-9 levels, which gradually decreased as wounds healed. The attenuation of MMPs was stronger in F than in H exudate, however, in standard zymography this difference appeared non-significant. Real-time zymography revealed that Flaminal mediated a powerful direct inhibition of gelatinolytic activity of wound exudate and of recombinant MMP-2/-9 in vitro. PMID- 24810314 TI - Structure-function relationship of thiazolide-induced apoptosis in colorectal tumor cells. AB - Thiazolides are a novel class of anti-infectious agents against intestinal intracellular and extracellular protozoan parasites, bacteria, and viruses. While the parent compound nitazoxanide (NTZ; 2-(acetolyloxy)-N-(5-nitro-2 thiazolyl)benzamide) has potent antimicrobial activity, the bromo-thiazolide RM4819 (N-(5-bromothiazol-2-yl)-2-hydroxy-3-methylbenzamide) shows only reduced activity. Interestingly, both molecules are able to induce cell death in colon carcinoma cell lines, indicating that the molecular target in intestinal pathogens and in colon cancer cells is different. The detoxification enzyme glutathione S-transferase of class Pi 1 (GSTP1) is frequently overexpressed in various tumors, including colon carcinomas, and limits the efficacy of antitumor chemotherapeutic drugs due to its detoxifying activities. In colorectal tumor cells RM4819 has been shown to interact with GSTP1, and GSTP1 enzymatic activity is required for thiazolide-induced apoptosis. At present it is unclear which molecular structures of RM4819 are required to interact with GSTP1 and to induce cell death in colon carcinoma cell lines. Here, we demonstrate that novel thiazolide derivatives with variation in their substituents of the benzene ring do not significantly affect apoptosis induction in Caco-2 cells, whereas removal of the bromide atom on the thiazole ring leads to a strong reduction of cell death induction in colon cancer cells. We further show that active thiazolides require caspase activation and GSTP1 expression in order to induce apoptosis. We demonstrate that increased glutathione (GSH) levels sensitize colon cancer cells to thiazolides, indicating that both GSTP1 enzymatic activity as well as GSH levels are critical factors in thiazolide-induced cell death. PMID- 24810315 TI - Surface reconstruction-induced coincidence lattice formation between two dimensionally bonded materials and a three-dimensionally bonded substrate. AB - Sb2Te3 films are used for studying the epitaxial registry between two dimensionally bonded (2D) materials and three-dimensional bonded (3D) substrates. In contrast to the growth of 3D materials, it is found that the formation of coincidence lattices between Sb2Te3 and Si(111) depends on the geometry and dangling bonds of the reconstructed substrate surface. Furthermore, we show that the epitaxial registry can be influenced by controlling the Si(111) surface reconstruction and confirm the results for ultrathin films. PMID- 24810316 TI - Dyella jejuensis sp. nov., isolated from soil of Hallasan Mountain in Jeju Island. AB - A novel bacterium, designated JP1(T), was isolated from soil of Hallasan Mountain in Jeju Island. The isolate was a Gramnegative, aerobic, motile and rod-shaped (0.2-0.4 * 1.2-2.0 MUm) bacterium. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain JP1(T) was closely related to Dyella koreensis with 97.6% similarity. Growth of strain JP1(T) occurred at 10-37 degrees C, pH 5 7 and 0-1% (w/v) NaCl. The genomic DNA G+C content of strain JP1(T) was 62.1 mol%. The major fatty acids were iso-C16:0, iso-C17:1 omega9c, and iso-C15:0. The predominant quinone was ubiquinone-8. The major polar lipids of strain JP1(T) were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, unidentified aminolipids and unidentified aminophospholipids. The DNA-DNA relatedness values between strain JP1(T) and previously reported Dyella species were <10%. Based on phenotypic, genotypic, and phylogenetic distinctness, strain JP1(T) represents a novel species in the genus Dyella, for which the name Dyella jejuensis sp. nov. is proposed. The type strain is JP1(T) (=KACC 17701(T) =JCM 19615(T)). PMID- 24810317 TI - Massilia kyonggiensis sp. nov., isolated from forest soil in Korea. AB - A Gram-negative, short, rod-shaped bacterium, TSA1(T), was isolated from forest soil collected at Kyonggi University, South Korea. Assessment of 16S rRNA gene sequence similarity indicated that the strain is related to Massilia niastensis 5516S-1(T) (98.3%), M. haematophila CCUG 38318(T) (97.9%), M. aerilata 5516S 11(T) (97.9%), M. tieshanensis TS3(T) (97.6%), and M. varians CCUG 3529(T) (97.1%). Colonies grown on Reasoner's 2A agar at 30 degrees C for 2 days were transparent, white, round, smooth, and glossy. The cells grew at 10-42 degrees C (optimum: 25-37 degrees C) and pH 5-9 (optimum: 5-9) and in 0-2% NaCl (optimum: 0 1%). TSA1(T) was able to grow on trypticase soy and nutrient agar, but not on Luria-Bertani or MacConkey agar. The strain was catalase- and oxidasepositive and able to degrade starch and casein, but not carboxymethyl cellulose. The predominant quinone of TSA1(T) was Q-8, the major fatty acids were summed feature 3 and C16:0, and the DNA G+C content was 66.7 mol%. Given these findings, we propose that this strain is a novel species of the genus Massilia. We suggest the name Massilia kyonggiensis sp. nov. (type strain, KACC 17471(T) =KEMB 9005-031(T) =JCM 19189(T)). PMID- 24810318 TI - Production of an endoinulinase from Aspergillus niger AUMC 9375, by solid state fermentation of agricultural wastes, with purification and characterization of the free and immobilized enzyme. AB - Two different substrates, sunflower (Helianthus annuus L.) tubers and lettuce (Lactuca sativa) roots, were tested. Using a mixture of both wastes resulted in higher production of endoinulinase than either waste alone. Also, ten fungal species grown on these substrates as inexpensive, carbon sources were screened for the best production of endoinulinase activities. Of these, Aspergillus niger AUMC 9375 was the most productive, when grown on the mixture using a 6:1 w/w ratio of sun flower: lettuce, and yielded the highest levels of inulinase at 50% moisture, 30 degrees C, pH 5.0, with seven days of incubation, and with yeast extract as the best nitrogen source. Inulinase was purified to homogeneity by ion exchange chromatography and gel-filtration giving a 51.11 fold purification. The mixture of sunflower tubers and lettuce roots has potential to be an effective and economical substrate for inulinase production. Inulinase was successfully immobilized with an immobilization yield of 71.28%. After incubation for 2 h at 60 degrees C, the free enzyme activity decreased markedly to 10%, whereas that of the immobilized form decreased only to 87%. A reusability test demonstrated the durability of the immobilized inulinase for 10 cycles and in addition, that it could be stored for 32 days at 4 degrees C. These results indicate that this inulinase, in the immobilized form, is a potential candidate for large-scale production of high purity fructose syrups. PMID- 24810319 TI - Characterization of recombinant beta-glucosidase from Arthrobacter chlorophenolicus and biotransformation of ginsenosides Rb1, Rb 2, Rc, and Rd. AB - The focus of this study was the cloning, expression, and characterization of recombinant ginsenoside hydrolyzing beta-glucosidase from Arthrobacter chlorophenolicus with an ultimate objective to more efficiently bio-transform ginsenosides. The gene bglAch, consisting of 1,260 bp (419 amino acid residues) was cloned and the recombinant enzyme, overexpressed in Escherichia coli BL21 (DE3), was characterized. The GST-fused BglAch was purified using GST.Bind agarose resin and characterized. Under optimal conditions (pH 6.0 and 37 degrees C) BglAch hydrolyzed the outer glucose and arabinopyranose moieties of ginsenosides Rb1 and Rb2 at the C20 position of the aglycone into ginsenoside Rd. This was followed by hydrolysis into F2 of the outer glucose moiety of ginsenoside Rd at the C3 position of the aglycone. Additionally, BglAch more slowly transformed Rc to F2 via C-Mc1 (compared to hydrolysis of Rb1 or Rb2). These results indicate that the recombinant BglAch could be useful for the production of ginsenoside F2 for use in the pharmaceutical and cosmetic industries. PMID- 24810320 TI - Biodegradation of C5-C 8 fatty acids and production of aroma volatiles by Myroides sp. ZB35 isolated from activated sludge. AB - In the effluents of a biologically treated wastewater from a heavy oil-refining plant, C5-C8 fatty acids including pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, and 2-methylbutanoic acid are often detected. As these residual fatty acids can cause further air and water pollution, a new Myroides isolate ZB35 from activated sludge was explored to degrade these C5-C8 fatty acids in this study. It was found that the biodegradation process involved a lag phase that became prolonged with increasing acyl chain length when the fatty acids were individually fed to this strain. However, when fed as a mixture, the ones with longer acyl chains were found to become more quickly assimilated. The branched 2 methylbutanoic acid was always the last one to be depleted among the five fatty acids under both conditions. Metabolite analysis revealed one possible origin of short chain fatty acids in the biologically treated wastewater. Aroma volatiles including 2-methylbutyl isovalerate, isoamyl 2-methylbutanoate, isoamyl isovalerate, and 2-methylbutyl 2-methylbutanoate were subsequently identified from ZB35 extracts, linking the source of the fruity odor to these esters excreted by Myroides species. To our best knowledge, this is the first finding of these aroma esters in bacteria. From a biotechnological viewpoint, this study has revealed the potential of Myroides species as a promising source of aroma esters attractive for food and fragrance industries. PMID- 24810321 TI - Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats. AB - Obstructive sleep apnea hypopnea syndrome (OSAHS) in children is associated with multiple system morbidities. Cognitive dysfunction as a result of central nervous system complication has been reported in children with OSAHS. However, the underlying mechanisms are poorly understood. Endoplasmic reticulum stress (ERS) related apoptosis plays an important role in various diseases of the central nervous system, but very little is known about the role of ERS in mediating pathophysiological reactions to cognitive dysfunction in OSAHS. Chronic intermittent hypoxia (CIH) exposures, modeling OSAHS, across 2 and 4weeks in growing rats made more reference memory errors, working memory errors and total memory errors in the 8-Arm radial maze task, increased significantly TUNEL positive cells, upregulated the unfolded protein response in the hippocampus and prefrontal cortex as evidenced by increased phosphorylation of PKR-like endoplasmic reticulum kinase, inositol-requiring enzyme l and some downstream products. A selective inhibitor of eukaryotic initiation factor-2a dephosphorylation, salubrinal, prevented C/EBP-homologous protein activation in the hippocampus and prefrontal cortex throughout hypoxia/reoxygenation exposure. Our findings suggest that ERS mediated cell apoptosis may be one of the underlying mechanisms of cognitive dysfunction in OSAHS children. Further, a specific ERS inhibitor Salubrinal should be tested for neuroprotection against CIH-induced injury. PMID- 24810322 TI - Sustained complete molecular remission after imatinib discontinuation in children with chronic myeloid leukemia. AB - Approximately 40% of adults with chronic myeloid leukemia (CML) in prolonged complete molecular response (CMR) remain in CMR after imatinib discontinuation. Corresponding information in children is lacking. Two children with CML in CMR for 48 and 19 months after imatinib discontinuation showed low-level fluctuating disease at RNA transcript and genomic DNA levels. Both patients were low risk according to adult criteria. Since adults with molecular relapse responded to re introduction of imatinib, we postulated that treatment discontinuation in low risk children might be justified within clinical trials with close monitoring. This may help to minimize exposure to imatinib and its potential side effects. PMID- 24810324 TI - Management intensity at field and landscape levels affects the structure of generalist predator communities. AB - Agricultural intensification is recognised as a major driver of biodiversity loss in human-modified landscapes. Several agro-environmental measures at different spatial scales have been suggested to mitigate the negative impact of intensification on biodiversity and ecosystem services. The effect of these measures on the functional structure of service-providing communities remains, however, largely unexplored. Using two distinct landscape designs, we examined how the management options of organic farming at the field scale and crop diversification at the landscape level affect the taxonomic and functional structure of generalist predator communities and how these effects vary along a landscape complexity gradient. Organic farming as well as landscapes with longer and more diversified crop rotations enhanced the activity-density of spiders and rove beetles, but not the species richness or evenness. Our results indicate that the two management options affected the functional composition of communities, as they primarily enhanced the activity-density of functionally similar species. The two management options increased the functional similarity between spider species in regards to hunting mode and habitat preference. Organic farming enhanced the functional similarity of rove beetles. Management options at field and landscape levels were generally more important predictors of community structure when compared to landscape complexity. Our study highlights the importance of considering the functional composition of generalist predators in order to understand how agro-environmental measures at various scales shape community assemblages and ecosystem functioning in agricultural landscapes. PMID- 24810323 TI - Circulating tumor cell identification by functionalized silver-gold nanorods with multicolor, super-enhanced SERS and photothermal resonances. AB - Nanotechnology has been extensively explored for cancer diagnostics. However, the specificity of current methods to identify simultaneously several cancer biomarkers is limited due to color overlapping of bio-conjugated nanoparticles. Here, we present a technique to increase both the molecular and spectral specificity of cancer diagnosis by using tunable silver-gold nanorods with narrow surface-enhanced Raman scattering (SERS) and high photothermal contrast. The silver-gold nanorods were functionalized with four Raman-active molecules and four antibodies specific to breast cancer markers and with leukocyte-specific CD45 marker. More than two orders of magnitude of SERS signal enhancement was observed from these hybrid nanosystems compared to conventional gold nanorods. Using an antibody rainbow cocktail, we demonstrated highly specific detection of single breast cancer cells in unprocessed human blood. By integrating multiplex targeting, multicolor coding, and multimodal detection, our approach has the potential to improve multispectral imaging of individual tumor cells in complex biological environments. PMID- 24810325 TI - Small-scale spatial variability in phylogenetic community structure during early plant succession depends on soil properties. AB - During early plant succession, the phylogenetic structure of a community changes in response to important environmental filters and emerging species interactions. We traced the development of temperate-zone plant communities during the first 7 years of primary succession on catchment soils to explore patterns of initial species assembly. We found pronounced small-scale differences in the phylogenetic composition of neighbouring plant assemblages and a large-scale trend towards phylogenetic evenness. This small-scale variability appears to be mediated by soil properties, particularly carbonate content. Therefore, abiotic environmental conditions might counteract or even supersede the effects of interspecific competition among closely related species, which are usually predicted to exhibit patterns of phylogenetic evenness. We conclude that theories on phylogenetic community composition need to incorporate effects of small-scale variability of environmental factors. PMID- 24810326 TI - To dare or not to dare? Risk management by owls in a predator-prey foraging game. AB - In a foraging game, predators must catch elusive prey while avoiding injury. Predators manage their hunting success with behavioral tools such as habitat selection, time allocation, and perhaps daring-the willingness to risk injury to increase hunting success. A predator's level of daring should be state dependent: the hungrier it is, the more it should be willing to risk injury to better capture prey. We ask, in a foraging game, will a hungry predator be more willing to risk injury while hunting? We performed an experiment in an outdoor vivarium in which barn owls (Tyto alba) were allowed to hunt Allenby's gerbils (Gerbillus andersoni allenbyi) from a choice of safe and risky patches. Owls were either well fed or hungry, representing the high and low state, respectively. We quantified the owls' patch use behavior. We predicted that hungry owls would be more daring and allocate more time to the risky patches. Owls preferred to hunt in the safe patches. This indicates that owls manage risk of injury by avoiding the risky patches. Hungry owls doubled their attacks on gerbils, but directed the added effort mostly toward the safe patch and the safer, open areas in the risky patch. Thus, owls dared by performing a risky action-the attack maneuver-more times, but only in the safest places-the open areas. We conclude that daring can be used to manage risk of injury and owls implement it strategically, in ways we did not foresee, to minimize risk of injury while maximizing hunting success. PMID- 24810327 TI - Multiphase water-in-oil emulsion droplets for cell-free transcription translation. AB - The construction of genetically encoded cellular mimics in compartments containing organized synthetic cytosols is desirable for the development of artificial cells. Phase separated aqueous domains were placed within water-in-oil emulsion droplets in a manner compatible with transcription and translation machinery. Aqueous two-phase and three-phase systems (ATPS and A3PS) were assembled with dextran, poly(ethylene glycol), and Ficoll. Aqueous two-phase systems were capable of supporting the cell-free expression of protein within water droplets, whereas the aqueous three-phase-based system did not give rise to detectable protein synthesis. The expressed protein preferentially partitioned to the dextran-enriched phase. The system could serve as a foundation for building cellular mimics with liquid organelles. PMID- 24810328 TI - Role of IscX in iron-sulfur cluster biogenesis in Escherichia coli. AB - The Escherichia coli isc operon encodes key proteins involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Whereas extensive studies of most ISC proteins have revealed their functional properties, the role of IscX (also dubbed YfhJ), a small acidic protein encoded by the last gene in the operon, has remained in question. Previous studies showed that IscX binds iron ions and interacts with the cysteine desulfurase (IscS) and the scaffold protein for cluster assembly (IscU), and it has been proposed that IscX functions either as an iron supplier or a regulator of Fe-S cluster biogenesis. We have used a combination of NMR spectroscopy, small-angle X-ray scattering (SAXS), chemical cross-linking, and enzymatic assays to enlarge our understanding of the interactions of IscX with iron ions, IscU, and IscS. We used chemical shift perturbation to identify the binding interfaces of IscX and IscU in their complex. NMR studies showed that Fe(2+) from added ferrous ammonium sulfate binds IscX much more avidly than does Fe(3+) from added ferric ammonium citrate and that Fe(2+) strengthens the interaction between IscX and IscU. We found that the addition of IscX to the IscU IscS binary complex led to the formation of a ternary complex with reduced cysteine desulfurase activity, and we determined a low-resolution model for that complex from a combination of NMR and SAXS data. We postulate that the inhibition of cysteine desulfurase activity by IscX serves to reduce unproductive conversion of cysteine to alanine. By incorporating these new findings with results from prior studies, we propose a detailed mechanism for Fe-S cluster assembly in which IscX serves both as a donor of Fe(2+) and as a regulator of cysteine desulfurase activity. PMID- 24810330 TI - Compounds from multilayer plastic bags cause reproductive failures in artificial insemination. AB - High levels of reproductive failure were detected in some Spanish sow farms in the Spring of 2010. Regular returns to estrus and variable reductions in litter size were observed. The problem started suddenly and did not appear to be related to the quality of the ejaculates, disease, alterations of body condition or any other apparent reasons. Subsequent studies determined that the problem was the origin of the plastic bags used for semen storage. Chemical analysis of the suspicious bags identified unexpected compounds such as BADGE, a cyclic lactone and an unknown phthalate that leached into the semen at concentrations of 0.2 to 2.5 mg/L. Spermatozoa preserved in these bags passed all of the routine quality control tests, and no differences were observed between storage in the control and suspicious bags (p > 0.05). In vitro fecundation tests and endocrine profiler panel analysis (EPP) did not show any alterations, whereas the in vivo tests confirmed the described failure. This is the first described relationship between reproductive failure and toxic compounds released from plastic bags. PMID- 24810329 TI - Effects of L-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol. AB - Not much is known about effects of gestational alcohol exposure on maternal and fetal cardiovascular adaptations. This study determined whether maternal binge alcohol exposure and L-glutamine supplementation could affect maternal-fetal hemodynamics and fetal regional brain blood flow during the brain growth spurt period. Pregnant sheep were randomly assigned to one of four groups: saline control, alcohol (1.75-2.5 g/kg body weight), glutamine (100 mg/kg body weight) or alcohol + glutamine. A chronic weekend binge drinking paradigm between gestational days (GD) 99 and 115 was utilized. Fetuses were surgically instrumented on GD 117 +/- 1 and studied on GD 120 +/- 1. Binge alcohol exposure caused maternal acidemia, hypercapnea, and hypoxemia. Fetuses were acidemic and hypercapnic, but not hypoxemic. Alcohol exposure increased fetal mean arterial pressure, whereas fetal heart rate was unaltered. Alcohol exposure resulted in ~40 % reduction in maternal uterine artery blood flow. Labeled microsphere analyses showed that alcohol induced >2-fold increases in fetal whole brain blood flow. The elevation in fetal brain blood flow was region-specific, particularly affecting the developing cerebellum, brain stem, and olfactory bulb. Maternal L glutamine supplementation attenuated alcohol-induced maternal hypercapnea, fetal acidemia and increases in fetal brain blood flow. L-Glutamine supplementation did not affect uterine blood flow. Collectively, alcohol exposure alters maternal and fetal acid-base balance, decreases uterine blood flow, and alters fetal regional brain blood flow. Importantly, L-glutamine supplementation mitigates alcohol induced acid-base imbalances and alterations in fetal regional brain blood flow. Further studies are warranted to elucidate mechanisms responsible for alcohol induced programming of maternal uterine artery and fetal circulation adaptations in pregnancy. PMID- 24810333 TI - Nucleus accumbens core and shell inactivation differentially affects impulsive behaviours in rats. AB - Impulsivity is a multifactorial phenomenon, determined by deficits in decision making (impulsive choice) and impulse control (impulsive action). Recent findings indicate that impulsive behaviour is not only top-down controlled by cortical areas, but also modulated at subcortical level. The nucleus accumbens (NAc) might be a key substrate in cortico-limbic-striatal circuits involved in impulsive behaviour. Dissociable effects of the NAc subregions in various behavioural paradigms point to a potential functional distinction between NAc core and shell concerning different types of impulsivity. The present study used reversible inactivation of the rats' NAc core and shell via bilateral microinfusion of the GABAA receptor agonist muscimol (0.05MUg/0.3MUl) and fluorophore-conjugated muscimol (FCM, 0.27MUg/0.3MUl) in order to study their contribution to different aspects of impulse control in a 5-choice serial reaction time task (5-CSRTT) and impulsive choice in a delay-based decision-making T-maze task. Acute inactivation of NAc core as well as shell by muscimol increased impulsive choice, with higher impairments of the rats' waiting capacity in the T-maze following core injections compared to shell. Intra-NAc shell infusion of muscimol also induced specific impulse control deficits in the 5-CSRTT, while deactivation of the core caused severe general impairments in task performance. FCM did not affect animal behaviour. Our findings reveal clear involvement of NAc shell in both forms of impulsivity. Both subareas play a key role in the regulation of impulsive decision-making, but show functional dichotomy regarding impulse control with the core being more implicated in motivational and motor aspects. PMID- 24810334 TI - A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing. AB - BACKGROUND: Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described. METHODS AND FINDINGS: We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3-20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation. CONCLUSION: The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis. PMID- 24810335 TI - [Text mining, a method for computer-assisted analysis of scientific texts, demonstrated by an analysis of author networks]. AB - Searching for relevant publications is becoming more difficult with the increasing number of scientific articles. Text mining as a specific form of computer-based data analysis may be helpful in this context. Highlighting relations between authors and finding relevant publications concerning a specific subject using text analysis programs are illustrated graphically by 2 performed examples. PMID- 24810336 TI - miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma. AB - Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC. PMID- 24810338 TI - Development and validation of a fast and simple multi-analyte procedure for quantification of 40 drugs relevant to emergency toxicology using GC-MS and one point calibration. AB - Diagnosis and prognosis of poisonings should be confirmed by comprehensive screening and reliable quantification of xenobiotics, for example by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS). The turnaround time should be short enough to have an impact on clinical decisions. In emergency toxicology, quantification using full scan acquisition is preferable because this allows screening and quantification of expected and unexpected drugs in one run. Therefore, a multi-analyte full-scan GC-MS approach was developed and validated with liquid-liquid extraction and one point calibration for quantification of 40 drugs relevant to emergency toxicology. Validation showed that 36 drugs could be determined quickly, accurately, and reliably in the range of upper therapeutic to toxic concentrations. Daily one-point calibration with calibrators stored for up to four weeks reduced workload and turn-around time to less than 1 h. In summary, the multi-analyte approach with simple liquid-liquid extraction, GC-MS identification, and quantification over fast one-point calibration could successfully be applied to proficiency tests and real case samples. PMID- 24810337 TI - DNA vaccination by intradermal electroporation induces long-lasting immune responses in rhesus macaques. AB - BACKGROUND: A desirable HIV vaccine should induce protective long-lasting humoral and cellular immune responses. METHODS: Macaques were immunized by env DNA, selected from a panel of recently transmitted SIVmac251 Env using intradermal electroporation as vaccine delivery method and magnitude, breadth and longevity of humoral and cellular immune responses. RESULTS: The macaques developed high, long-lasting humoral immune responses with neutralizing capacity against homologous and heterologous Env. The avidity of the antibody responses was also preserved over 1-year follow-up. Analysis of cellular immune responses demonstrated induction of Env-specific memory T cells harboring granzyme B, albeit their overall levels were low. Similar to the humoral responses, the cellular immunity was persistent over the ~1-year follow-up. CONCLUSION: These data show that vaccination by this intradermal DNA delivery regimen is able to induce potent and durable immune responses in macaques. PMID- 24810340 TI - Predatory prokaryotes wage war against eye infections. PMID- 24810341 TI - Is inherited human herpesvirus 6 the perpetrator behind some cases of chronic fatigue syndrome? PMID- 24810343 TI - Latest developments on Streptococcus suis: an emerging zoonotic pathogen: part 1. AB - First International Workshop on Streptococcus suis, Beijing, China, 12-13 August 2013 The first international workshop on Streptococcus suis, which is an important swine pathogen and emerging zoonotic agent, took place in Beijing, jointly organized by the Faculty of Veterinary Medicine, University of Montreal, Canada and the National Institute for Communicable Disease Control and Prevention, China CDC. The aim of the meeting was to gather together, for the first time, more than 80 researchers working on S. suis, from countries including China, Canada, Japan, The Netherlands, Germany, Thailand, the UK and Vietnam. This article, the first of a two-part report on this First International Workshop, reviews current aspects of the epidemiology and population genomics of S. suis, covers public health concerns and discusses questions about S. suis serotyping and molecular diagnostics. PMID- 24810344 TI - Honey flavonoids inhibit Candida albicans morphogenesis by affecting DNA behavior and mitochondrial function. AB - AIM: Candida albicans is a pathogenic yeast, which forms a range of polarized and expanded cell shapes. We aimed to determine the correlation between honey extract (HFE) activity and changes in C. albicans cell cycle, morphology and subcellular organelles. MATERIALS & METHODS: HFE anticandidal properties were investigated using flow cytometry and scanning electron microscopy. RESULTS: Flow cytometry and scanning electron microscopy analyses indicated that HFE may inhibit the growth of the three phenotypes displayed by C. albicans and reduce infection by affecting membrane integrity. HFE affects hyphal transition by reducing the G0/G1 phase and increasing the G2/M phase. Conversely, yeast and pseudohyphae do not appear to be affected. Modifications of vacuolization and mitochondrial activity, during yeast-hypha transition establish the involvement of vacuole and mitochondria. CONCLUSION: HFE improved mitochondrial functionality and reduced the vacuolization, modifying the branching process associated with virulence. It is hypothesized that HFE induces changes in cell cycle progress, membrane integrity, mitochondrial function and biogenesis. PMID- 24810345 TI - Vaccine development and passive immunization for Pseudomonas aeruginosa in critically ill patients: a clinical update. AB - Pseudomonas aeruginosa is one of the most common causes of nosocomial infection in intensive care unit patients and is independently associated with worse outcomes. Resistance of P. aeruginosa to antimicrobial agents is increasingly common and treatment of these infections is a growing challenge for intensivists. The development of methods to prevent infection, such as vaccines, is thus of considerable interest. Three agents currently show promise in this population of patients and are undergoing clinical evaluation; however, further vaccine targets are being discovered and more potential agents will likely be developed in the near future. PMID- 24810346 TI - Antibiotic-resistant Pseudomonas aeruginosa: focus on care in patients receiving assisted ventilation. AB - This article discusses ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Ventilator-associated pneumonia caused by P. aeruginosa is one of the leading causes of morbidity and mortality in the intensive care unit, and nowadays it represents a major concern due to the increasing resistance rate of the pathogen to different classes of antibiotics. Here, the choice between a combination therapy and a monotherapy in the empirical setting is analyzed and discussed, by focusing on the recommendations of different published guidelines. Pros and cons of the different possible associations are analyzed and suggestions are given in light of the emergence of multidrug-resistant strains. Route of administration is also discussed, with an emphasis on the use of nebulized antibiotics. Optimal duration of treatment is an additional point of discussion, and explanations are provided for the suggested longer course compared with that of other etiologies. PMID- 24810347 TI - Clostridium difficile spores: a major threat to the hospital environment. AB - Clostridium difficile is a Gram-positive, anaerobic spore former and is an important nosocomial and community-acquired pathogenic bacterium. C. difficile infections (CDI) are a leading cause of infections worldwide with elevated rates of morbidity. Despite the fact that two major virulence factors, the enterotoxin TcdA and the cytotoxin TcdB, are essential in the development of CDI, C. difficile spores are the main vehicle of infection, and persistence and transmission of CDI and are thought to play an essential role in episodes of CDI recurrence and horizontal transmission. Recent research has unmasked several properties of C. difficile's unique strategy to form highly transmissible spores and to persist in the colonic environment. Therefore, the aim of this article is to summarize recent advances in the biological properties of C. difficile spores, which might be clinically relevant to improve the management of CDI in hospital environments. PMID- 24810348 TI - Device-related infections in long-term healthcare facilities: the challenge of prevention. AB - The world is aging and the number of elderly multimorbid patients is steadily increasing. The limited numbers of acute care beds in hospitals, in addition to the need to reduce costs, has led to the introduction of efficient discharge policies, which in turn have increased demand for beds in nursing homes and long term care facilities (LTCFs). As a consequence, the number of postacute LTCF residents is rising, as is the number of residents requiring complex medical care delivered by use of indwelling medical devices. These devices place patients at a heightened risk for infection. Furthermore, infection control resources in LTCFs are often limited. This article reviews the preventive measures that should be taken in LTCFs to reduce the risk of device-related infections. PMID- 24810349 TI - Elucidating the function of the RpoS regulon. AB - Bacterial adaptation to suboptimal nutrient environments, including host and/or extreme environments, is subject to complex, coordinated control involving many proteins and RNAs. Among the gamma-proteobacteria, which includes many pathogens, the RpoS regulon has been a key focus for many years. Although the RpoS regulator was first identified as a growth phase-dependent regulator, our current understanding of RpoS is now more nuanced as this central regulator also has roles in exponential phase, biofilm development, bacterial virulence and bacterial persistence, as well as in stress adaptation. Induction of RpoS can also exert substantial metabolic effects by negatively regulating key systems including flagella biosynthesis, cryptic phage gene expression and the tricarboxylic acid cycle. Although core RpoS-controlled metabolic functions are conserved, there are substantial differences in RpoS regulation even among closely related bacteria, indicating that regulatory plasticity may be an important aspect of RpoS regulation, which is important in evolutionary adaptation to specialized environments. PMID- 24810350 TI - Imaging of Chlamydia and host cell metabolism. AB - Chlamydial infections cause a wide range of acute and chronic diseases. Chlamydia trachomatis is the most common sexually transmitted bacterium while Chlamydia pneumoniae causes infections of the upper and lower respiratory tract. Chlamydia are obligate, intracellular bacteria with a biphasic developmental cycle that involves unique metabolic changes. Aside from entering an actively replicating state, Chlamydia may also implement persistent infections depending on different microenvironmental factors. In addition, changes in local oxygen availability and the composition of surrounding host microbiota are suggested to affect chlamydial growth and metabolism. Both bacteria and host cells endure characteristic metabolic changes during infection. Technical developments in recent years enable us to separately characterize chlamydial and host cell metabolism in living cells. This article focuses on novel approaches to analyze chlamydial metabolism such as NAD(P)H fluorescence lifetime imaging by two-photon microscopy. In addition, we provide an overview regarding promising future possibilities to further elucidate host-pathogen metabolic interactions. PMID- 24810351 TI - Elucidating drug resistance in human fungal pathogens. AB - Fungal pathogens cause life-threatening infections in immunocompetent and immunocompromised individuals. Millions of people die each year due to fungal infections, comparable to the mortality attributable to tuberculosis or malaria. The three most prevalent fungal pathogens are Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Fungi are eukaryotes like their human host, making it challenging to identify fungal-specific therapeutics. There is a limited repertoire of antifungals in clinical use, and drug resistance and host toxicity compromise the clinical utility. The three classes of antifungals for treatment of invasive infections are the polyenes, azoles and echinocandins. Understanding mechanisms of resistance to these antifungals has been accelerated by global and targeted approaches, which have revealed that antifungal drug resistance is a complex phenomenon involving multiple mechanisms. Development of novel strategies to block the emergence of drug resistance and render resistant pathogens responsive to antifungals will be critical to treating life-threatening fungal infections. PMID- 24810352 TI - Nonculture techniques for the detection of bacteremia and fungemia. AB - Bacteremia and fungemia account for a substantial proportion of all cases of severe sepsis. Antibiotic resistance is a contributing factor in many hospital acquired infection deaths. Traditional phenotypic methods for the identification of bacteria and yeasts from positive blood cultures and determining antimicrobial susceptibility require 48-72 h, delaying optimal therapy and negatively impacting patient outcomes. Molecular methods, including nonamplified DNA probe panels and peptide nucleic acid probes, and nucleic acid amplification methods such as PCR, proteomic methods (matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry) and direct biochemical tests provide more rapid identification of bacteria and fungi, and in some cases antimicrobial resistance markers, from positive blood cultures, as well as directly from whole blood. These methods vary in the breadth of organisms that they detect, and equally important, their ease of use. This article examines the principles, performance and practicality of the various rapid, nonculture techniques for the detection of bacteremia and fungemia. PMID- 24810353 TI - Towards improved shRNA and miRNA reagents as inhibitors of HIV-1 replication. AB - miRNAs are the key players of the RNAi mechanism, which regulates the expression of a large number of mRNAs in human cells. shRNAs are man-made synthetic miRNA mimics that exploit similar intracellular RNA processing routes. Massive amounts of data derived from next-generation sequencing have revealed miRNA species that are derived from alternative biosynthesis pathways. Here, we review recent progress in our understanding of these noncanonical routes of miRNA and shRNA biosynthesis. We focus on ways to use these novel insights for the design of more potent and specific RNAi reagents for therapeutic applications, including the AgoshRNA design, which is processed differently than regular shRNAs. We will also discuss the development of a durable gene therapy against HIV1. PMID- 24810354 TI - 9-fluorenemethanol: an internal electron donor to fine tune olefin polymerization activity. AB - A new MgCl2 based molecular adduct has been synthesized with 9-fluorenemethanol (9FM) as a novel internal electron donor (IED), along with ethanol (EtOH) (MgCl2.n9FM.xEtOH). The above molecular adduct has been subjected to a variety of structural, spectroscopic and morphological characterization techniques. The results of the solid state (13)C CPMAS NMR technique suggests the coordination of 9FM to MgCl2. Observation of a low angle diffraction peak at 2theta = 5.7 degrees (d = 15.5 A) underscores the coordination of 9FM along the z-axis, and ethanol in the molecular adduct. Active Ziegler-Natta catalysts were prepared by two different synthesis methods; the conventional method to obtain a high surface area active catalyst, and other one with 9FM as an integral part of the active catalyst in order to study the influence of 9FM as an IED over the active sites. The active catalysts were also characterized thoroughly with different analytical tools. The XRD results show (003) facets of delta-MgCl2 (alpha-MgCl2) for the conventional (non-conventional) titanated catalyst. Results of the ethylene polymerization activity study reveals that the conventionally prepared highly porous active catalyst shows 1.7-2.5 times higher activity than the non conventional prepared catalyst; however, the latter shows a low molecular weight distribution and confirms the role of the Lewis base as an IED. PMID- 24810355 TI - Cytomegalovirus infection after acute rejection therapy in seropositive kidney transplant recipients. AB - BACKGROUND: Acute rejection (AR) after solid organ transplantation has been known to be a risk factor for cytomegalovirus (CMV) infection. However, data regarding the risk for CMV infection during and after anti-rejection therapy are limited. This study investigated whether the risk of CMV infection and disease within 6 months of kidney transplantation (KT) increases in CMV-seropositive KT recipients who develop AR. METHODS: A total of 992 seropositive KT recipients, including 75 patients (8%) who developed AR within 6 months after KT and 917 patients (92%) who did not, were recruited between May 2007 and April 2012. RESULTS: No significant difference was found in the incidence of CMV infection between the groups (AR group, 13% [10/75] vs. non-AR group, 10% [92/917], P = 0.37). The number of KT recipients in each group receiving preemptive therapy for CMV was similar (5% [4/75] vs. 6% [53/917], P > 0.99). While the incidence of CMV syndrome was comparable (0% [0/75] vs. 1% [12/917], P > 0.99), the incidence of tissue-invasive CMV disease (8% [6/75] vs. 3% [27/917], P = 0.04), particularly gastrointestinal CMV disease, was significantly greater in patients who experienced AR. No CMV-related mortality occurred in either group. AR (odds ratio, 2.81; 95% confidence interval, 1.08-7.29; P = 0.03) was an independent risk factor for tissue-invasive CMV disease within 6 months of KT. CONCLUSIONS: A high index of suspicion and active evaluation for tissue-invasive CMV disease in KT recipients suffering AR may be necessary to ensure appropriate treatment. PMID- 24810356 TI - To bind or not to bind: the taxonomic scope of nuclear receptor mediated endocrine disruption in invertebrate phyla. PMID- 24810357 TI - Adverse drug reactions causing hospital admissions in childhood: a prospective, observational, single-centre study. AB - Adverse drug reactions (ADRs) are common problems in both paediatric and adult medicine. The aim of this study was to prospectively identify the ADRs causing hospital admission of children and identification of the risk factors and involved drugs. The study was performed at the University Hospital in Olomouc, Czech Republic. All patients aged 19 years or under admitted to hospital were included in the study, and all admissions for ADRs were prospectively screened for a period of 9 months. Suspected ADRs were subsequently evaluated in detail, and causality assessment was undertaken to determine whether each suspected reaction was possible, probable or definite. The assessment of ADR causality was performed using the Naranjo algorithm, the Liverpool ADR Causality Assessment Tool and the Edwards and Aronson causality assessment method. During the study period, 2903 admissions were identified; of these, there were 143 admissions of patients with an oncological disease. Sixty-four admissions (2.2%) were caused by an ADR. Anticancer chemotherapy accounted for 35% of the cases, followed by antibiotics (18%), immunosuppressants and vaccines (9% each). The use of different scoring systems does not lead to the differences in the numbers of ADR diagnosed patient but may result in differences in the determination of the level of certainty. ADRs cause a substantial proportion of children's hospital admissions. The majority of the ADR-diagnosed patient affected the hematopoietic and gastrointestinal systems; the drugs most frequently involved were cytotoxic agents and antibiotics. The most important risk factors identified were female sex and oncological disease. PMID- 24810358 TI - Characterization of oxygen transfer in vertical microbubble columns for aerobic biotechnological processes. AB - This paper presents the applicability of a microtechnologically fabricated microbubble column as a screening tool for submerged aerobic cultivation. Bubbles in the range of a few hundred micrometers in diameter were generated at the bottom of an upright-positioned microdevice. The rising bubbles induced the circulation of the liquid and thus enhanced mixing by reducing the diffusion distances and preventing cells from sedimentation. Two differently sized nozzles (21 * 40 um(2) and 53 * 40 um(2) in cross-section) were tested. The gas flow rates were adjustable, and the resulting bubble sizes and gas holdups were investigated by image analysis. The microdevice features sensor elements for the real-time online monitoring of optical density and dissolved oxygen. The active aeration of the microdevice allowed for a flexible oxygen supply with mass transfer rates of up to 0.14 s(-1). Slightly higher oxygen mass transfer rates and a better degassing were found for the microbubble column equipped with the smaller nozzle. To validate the applicability of the microbubble column for aerobic submerged cultivation processes, batch cultivations of the model organism Saccharomyces cerevisiae were performed, and the specific growth rate, oxygen uptake rate, and yield coefficient were investigated. PMID- 24810359 TI - Carboxyl-terminal and Arg38 are essential for activity of the 7alpha hydroxysteroid dehydrogenase from Clostridium absonum. AB - 7alpha-hydroxysteroid dehydrogenase (7alpha-HSDH, EC 1.1.1.159), one of the short chain dehydrogenase/reductase superfamily, catalyzes the dehydrogenation of C7 hydroxyl group of the steroid skeleton of bile acids. Clostridium absonum 7alpha HSDH (Ca 7alpha-HSDH) was cloned and heterologously expressed in Escherichia coli. The function of carboxyterminal (C-terminal) and Arg38 of Ca 7alpha-HSDH was investigated through truncations and site-directed mutagenesis, respectively. When 2 and 6 amino acids of C-terminal were removed, the catalytic efficiency (k(cat)/K(m)) of Ca 7alpha-HSDH remained 19.1% and 2.5%, respectively. Furthermore, the activity could not be detected after 8, 14 and 17 amino acids were deleted. No activity could be detected with coenzyme either NADP(+) or NAD(+) after replacement of arginine at position 38 by aspartic acid. The metal ions Mg(2+) (50 mM), Na(+) (200 mM) and K(+) (500 mM) could maximally improve the activity of Ca 7alpha-HSDH by 61.4%, 64.7% and 105.7%, respectively. The activity had no significant change after incubation at 4 or 25 degrees C for 108 h, but decreased dramatically at 37 degrees C. Our study confirmed that C-terminal and Arg38 were essential for the catalytic function of Ca 7alpha-HSDH and the enzyme activity can be improved by metal ions. PMID- 24810360 TI - Synthesis of calcium phosphate-zirconia scaffold and human endometrial adult stem cells for bone tissue engineering. AB - To address the hypothesis that using a zirconia (ZrO2)/ beta-tricalcium phosphate (beta-TCP) composite might improve both the mechanical properties and cellular compatibility of the porous material, we fabricated ZrO2/beta-TCP composite scaffolds with different ZrO2/beta-TCP ratios, and evaluated their physical and mechanical characteristics, also the effect of three-dimensional (3D) culture (ZrO2/beta-TCP scaffold) on the behavior of human endometrial stem cells. Results showed the porosity of a ZrO2/beta-TCP scaffold can be adjusted from 65% to 84%, and the compressive strength of the scaffold increased from 4.95 to 6.25 MPa when the ZrO2 content increased from 30 to 50 wt%. The cell adhesion and proliferation in the ZrO2/beta-TCP scaffold was greatly improved when ZrO2 decreased. Moreover, in vitro study showed that an osteoblasts-loaded ZrO2/beta-TCP scaffold provided a suitable 3D environment for osteoblast survival and enhanced bone regeneration. We thus showed that a porous ZrO2/beta-TCP composite scaffold has excellent mechanical properties, and cellular/tissue compatibility, and would be a promising substrate to achieve both bone reconstruction and regeneration needed during in vivo study for treatment of large bone defects. PMID- 24810362 TI - Pelvis, posture and protrusion: evolution and haemorrhoids. PMID- 24810361 TI - HIV counseling and testing for the prevention of mother-to-child transmission of HIV in Swaziland: a multilevel analysis. AB - HIV counseling and voluntary testing during antenatal care have been proven to reduce the risk of HIV transmission from mother to child, through increasing knowledge about safe behaviors, ascertaining HIV status and increasing coverage of effective antiretroviral regimens. However, it remains that, in developing countries where 95 % of mother-to-child HIV transmissions (MTCT) take place, such interventions are not widely accessible or available. Using a nationally representative cross-sectional household survey, the present study aimed to examine individual- and contextual-level influences on the receipt of HIV pre test counseling and uptake of HIV testing during the antenatal care period in Swaziland, a country highly burdened by HIV/AIDS. The study sample was restricted to women aged 15-49 years with a live birth in the past five years preceding the survey and who received antenatal care for the most recent birth. The findings of this study indicated that only 62 % of women received pre-test counseling for the prevention of MTCT and no more than 56 % of women consented to be tested for HIV during antenatal care. The multilevel regression analysis revealed that the likelihood of receiving HIV pre-test counseling increases significantly with higher parity, education level, household wealth and antenatal visits while it is lower in areas where poverty is pervasive (OR = 0.474) and in rural regions (OR = 0.598) as well. Beyond all the significant predictors, undergoing pre-test counseling has emerged as an important determinant of HIV testing. Receiving pre test counseling increases the odds of accepting an HIV test by 77 %. Evidence from this analysis underscores bottlenecks and challenges that persist in increasing the need for and uptake of HIV preventive and treatment services to stop new HIV infections among children. PMID- 24810363 TI - Interspecific communication between pinewood nematode, its insect vector, and associated microbes. AB - Pine wilt disease (PWD) is perhaps the most serious threat to pine forests worldwide. The causative agent of PWD, the pinewood nematode (PWN), engages in a symbiotic partnership with its insect vector, the Monochamus beetle, as well as associated bacteria and ophiostomatoid fungi, in order to successfully infect and kill its host pine tree. This review focuses on the interspecific communication between PWN and its associated partners, and the potential role of this communication in promoting pathogenicity and invasiveness of PWN. We describe the chemical and molecular signals positively influencing the survival, reproduction, and spread of PWN. Knowledge of these signals could potentially be used to interfere with the proliferation and dispersal of PWN. PMID- 24810365 TI - The 'caring experience': Testing the psychometric properties of the Caring Efficacy Scale. AB - The purpose of the study was to undertake rigorous psychometric testing of the Caring Efficacy Scale in a sample of Registered Nurses. A cross-sectional survey of 2000 registered nurses was undertaken. The Caring Efficacy Scale was utilized to inform the psychometric properties of the selected items of the Caring Efficacy Scale. Cronbach's Alpha identified reliability of the data. Exploratory Factor Analysis and Confirmatory Factor Analysis were undertaken to validate the factors. Confirmatory factor analysis confirmed the development of two factors; Confidence to Care and Doubts and Concerns. The Caring Efficacy Scale has undergone rigorous psychometric testing, affording evidence of internal consistency and goodness-of-fit indices within satisfactory ranges. The Caring Efficacy Scale is valid for use in an Australian population of registered nurses. The scale can be used as a subscale or total score reflective of self-efficacy in nursing. This scale may assist nursing educators to predict levels of caring efficacy. PMID- 24810364 TI - Long noncoding RNA ANRIL indicates a poor prognosis of gastric cancer and promotes tumor growth by epigenetically silencing of miR-99a/miR-449a. AB - Long noncoding RNAs are involved in diseases including cancer. Here, we reported that ANRIL (CDKN2B-AS1), a 3.8-kb long noncoding RNA, recruiting and binding to PRC2, was generally upregulated in human gastric cancer (GC) tissues. In a cohort of 120 GC patients, the higher expression of ANRIL was significantly correlated with a higher TNM stage (P=0.041) and tumor size (P=0.001). Multivariate analyses revealed that ANRIL expression served as an independent predictor for overall survival (P=0.036). Further experiments revealed that ANRIL knockdown significantly repressed the proliferation both in vitro and in vivo. We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is in part due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets--mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation. To our knowledge, this is the first report showed that the role of ANRIL in the progression of GC and ANRIL could crosstalk with microRNAs in epigenetic level. Our results suggest that ANRIL, as a growth regulator, may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer. PMID- 24810366 TI - Congo virus 2013: another public health failure in Pakistan? PMID- 24810367 TI - Analysis of the defence-related mechanism in cucumber seedlings in relation to root colonization by nonpathogenic Fusarium oxysporum CS-20. AB - A defence response can be induced by nonpathogenic Fusarium oxysporum CS-20 in several crops, but the molecular mechanism has not been clearly demonstrated. In the present study, we analysed the defence mechanism of a susceptible cucumber cultivar (Cucumis sativus L. 9930) against a pathogen (F. oxysporum f. sp. cucumerinum) through the root precolonization of CS-20. A challenge inoculation assay indicated that the disease severity index (DSI) was reduced, ranging from 18.83 to 61.67 in comparison with the pathogen control. Root colonization analysis indicated that CS-20 clearly did not appear to influence the growth of cucumber seedlings. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) revealed that CS-20-mediated defence response was activated by PR3, LOX1 and PAL1 and the pathogen-mediated resistance response was regulated by PR1 and PR3. Moreover, both nonpathogenic and pathogenic F. oxysporum were able to upregulate NPR1 expression. In contrast to a pathogen, CS-20 can activate the Ca(2+) /CaM signal transduction pathway, and the gene expression of both CsCam7 and CsCam12 increased significantly. The gene expression analysis indicated that CS-20 strongly enhanced the expression of PR3, LOX1, PAL1, NPR1, CsCam7 and CsCam12 after inoculation. Overall, the defence response induced by CS-20 can be controlled by multiple genes in the cucumber plant. PMID- 24810368 TI - Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models-a cohort study in 180 patients. AB - BACKGROUND: Glutaric aciduria type I (GA-I) is a cerebral organic aciduria caused by inherited deficiency of glutaryl-CoA dehydrogenase and is characterized biochemically by an accumulation of putatively neurotoxic dicarboxylic metabolites. The majority of untreated patients develops a complex movement disorder with predominant dystonia during age 3-36 months. Magnetic resonance imaging (MRI) studies have demonstrated striatal and extrastriatal abnormalities. AIMS/METHODS: The major aim of this study was to elucidate the complex neuroradiological pattern of patients with GA-I and to associate the MRI findings with the severity of predominant neurological symptoms. In 180 patients, detailed information about the neurological presentation and brain region-specific MRI abnormalities were obtained via a standardized questionnaire. RESULTS: Patients with a movement disorder had more often MRI abnormalities in putamen, caudate, cortex, ventricles and external CSF spaces than patients without or with minor neurological symptoms. Putaminal MRI changes and strongly dilated ventricles were identified as the most reliable predictors of a movement disorder. In contrast, abnormalities in globus pallidus were not clearly associated with a movement disorder. Caudate and putamen as well as cortex, ventricles and external CSF spaces clearly collocalized on a two-dimensional map demonstrating statistical similarity and suggesting the same underlying pathomechanism. CONCLUSIONS: This study demonstrates that complex statistical methods are useful to decipher the age-dependent and region-specific MRI patterns of rare neurometabolic diseases and that these methods are helpful to elucidate the clinical relevance of specific MRI findings. PMID- 24810369 TI - Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo controlled study. AB - OBJECTIVE: To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS: Patients with Morquio A aged >=5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6 min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated. RESULTS: At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI 17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation. CONCLUSIONS: Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile. PMID- 24810371 TI - Implementation of evidence-based policies and practices. PMID- 24810370 TI - Changes in the expression of the Toll-like receptor system in the aging rat kidneys. AB - BACKGROUND: The mechanisms of kidney aging are not yet clear. Studies have shown that immunological inflammation is related to kidney aging. Toll-like receptors (TLRs) are one of the receptor types of the body's innate immune system. The function of the TLR system and the mechanisms by which it functions in renal aging remain unclear. In the present study, we, for the first time, systematically investigated the role of the TLR system and the inflammation responses activated by TLRs during kidney aging. METHODS: We used western blot and immunohistochemistry to systematically analyze the changes in the expression and activation of the endogenous TLR ligands HSP70 and HMGB1, the TLRs (TLR1 TLR11), their downstream signaling pathway molecules MyD88 and Phospho-IRF-3, and the NF-kappaB signaling pathway molecules Phospho-IKKbeta, Phospho-IkappaBalpha (NF-kappaB inhibition factor alpha), NF-kappaBp65, and Phospho-NF-kappaBp65 (activated NF-kappaB p65) in the kidneys of 3 months old (youth group), 12 months old (middle age group), and 24 months old (elderly group) rats. We used RT-qPCR to detect the mRNA expression changes of the proinflammatory cytokines CCL3, CCL4, CCL5, CD80, TNF-alpha, and IL-12b in the rat renal tissues of the various age groups. RESULTS: We found that during kidney aging, the HSP70 and HMGB1 expression levels were significantly increased, and the expression levels of TLR1, 2, 3, 4, 5, and 11 and their downstream signaling pathway molecules MyD88 and Phospho-IRF-3 were markedly elevated. Further studies have shown that in the aging kidneys, the expression levels of the NF-kappaB signaling pathway molecules Phospho-IKKbeta, Phospho-IkappaBalpha, NF-kappaBp65, and Phospho-NF-kappaBp65 were obviously increased, and those of the proinflammatory cytokines CCL3, CCL4, CCL5, CD80, TNF-alpha, and IL-12b were significantly upregulated. CONCLUSIONS: These results showed that the TLR system might play an important role during the kidney aging process maybe by activating the NF-kappaB signaling pathway and promoting the high expression of inflammation factors. PMID- 24810372 TI - Interaction of 3D dewetting nanodroplets on homogeneous and chemically heterogeneous substrates. AB - Long-time interaction of dewetting nanodroplets is investigated using a long-wave approximation method. Although three-dimensional (3D) droplets evolution dynamics exhibits qualitative behavior analogous to two-dimensional (2D) dynamics, there is an extensive quantitative difference between them. 3D dynamics is substantially faster than 2D dynamics. This can be related to the larger curvature and, as a consequence, the larger Laplace pressure difference between the droplets in 3D systems. The influence of various chemical heterogeneities on the behavior of droplets has also been studied. In the case of gradient surfaces, it is shown how the gradient direction could change the dynamics. For a chemical step located between the droplets, the dynamics is enhanced or weakened depending on the initial configuration of the system. PMID- 24810373 TI - Crystal structure of a Chlamydomonas reinhardtii flagellar RabGAP TBC-domain at 1.8 A resolution. AB - Rab GTPases play a crucial role in the regulation of many intracellular membrane trafficking pathways including endocytosis and ciliogenesis. Rab GTPase activating proteins (RabGAPs) increase the GTP hydrolysis rate of Rab GTPases and turn them into guanine nucleotide diphosphate (GDP) bound inactive form. Here, we determined the crystal structure of the putative catalytic domain of a RabGAP (which we name CrfRabGAP) that is found in the flagellar proteome of the unicellular green alga Chlamydomonas reinhardtii. BLAST searches revealed potential human orthologues of CrfRabGAP as TBC1D3 and TBC1D26. Sequence and structural comparison with other canonical RabGAPs revealed that the CrfRabGAP does not contain the canonical catalytic residues required for the activation of Rab GTPases. The function of noncanonical RabGAPs-like CrfRabGAP might be to serve as Rab effectors rather than activators. PMID- 24810374 TI - Dirofilaria immitis: an emerging parasite in dogs, red foxes and golden jackals in Hungary. AB - Hungary was not considered to be a heartworm (Dirofilaria immitis) endemic country until 2007, when the first autochthonous canine infection was described. Herein we report additional autochthonous heartworm infections in two dogs (Canis familiaris), twenty red foxes (Vulpes vulpes) (n=534; prevalence: 3.7%; 95% CI=2.4-5.7%) and two golden jackals (Canis aureus) (n=27; prevalence: 7.4%; 95% CI=2.1-23.4%) coming from eight counties. The identification of the parasite was based on morphology, morphometrics and amplification of 12S rDNA followed by sequencing in all cases. Our results indicate that Hungary became a D. immitis endemic country in the past decade. The prevalence and intensity of heartworm infection in wild canids is similar to or lower than that observed in the Mediterranean countries of Europe (3.7-7.4% vs. 0.4-12.7% and 1.5 vs. 2.9-4.4 worms/animal). These findings are in line with the results of the recently developed climate based forecast model to predict the establishment of D. immitis in Hungary. PMID- 24810375 TI - Epidemiology of the eye worm Thelazia callipaeda in cats from southern Switzerland. AB - Thelazia callipaeda is a spiruroid nematode of dogs, cats and wild carnivores transmitted by zoophilic drosophilid Phortica flies and found in an increasing number of European countries. In cats the disease is diagnosed sporadically. This study presents an epidemiological investigation of feline thelaziosis, performed in southern Ticino, Switzerland, an endemic area for T. callipaeda. Between January 2009 and July 2011 2171 cats, having outdoor access and presenting for various reasons, were examined by in-depth eye examinations, and clinical and anamnestic data were collected. The overall prevalence of T. callipaeda in the study area was 0.8% (17/2171 cats, 95% confidence interval: 0.5-1.3%). Among cats showing ocular illness, the prevalence was 9.2% (11/120, CI: 4.7-15.8%). Cats with eye worms had no international travel history and were significantly more often diagnosed between June and December than during other months. With one exception, one single eye per cat was infested, each harboring between 1 and 10 eye worms (arithmetic mean: 2.8 per cat). One cat presented with conjunctivitis and ulcers, seven with conjunctivitis only and 3 with a mildly increased lacrimation, while 6 cats were asymptomatic. Significantly more male than female cats had eye worms and cats older than one year were overrepresented. No pure bred cats were infested. This study confirms the establishment of this potentially zoonotic parasite in cats from the study area. Due to the clinical relevance and pain caused by the infestations, increased disease awareness and in depth eye examination for the detection of T. callipaeda in cats are recommended, even in absence of obvious clinical signs, in order to initiate appropriate anthelmintic treatment. PMID- 24810377 TI - A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults. PMID- 24810379 TI - [French national survey on difficult intubation in intensive care units]. AB - OBJECTIVES: Assessing the theoretical knowledge, practical experience of French intensivists, and their compliance with French Anesthesiology and Critical Care Society's difficult airway algorithms of the expert's SFAR conference of 2006. STUDY DESIGN: Prospective and descriptive national survey. MATERIAL AND METHODS: An anonymous questionnaire with 40 questions was emailed to physicians working in intensive care units in France. RESULTS: Five hundred and eight intensivists answered the survey. Ninety-seven percent of physicians reported having a portable storage unit for difficult intubation. As for practical experience, 421 physicians (83 %) have set up less than 10 laryngeal mask airway, 257 (51 %) have performed less than 10 intubations under fibroscopy and 269 (53 %) have never performed a cricothyroidotomy on mannequin, and 331 (65 %) on a patient. In case of emergency intubation, 29 % of them do not use a rapid sequence induction. Three hundred physicians (59 %) use capnography as monitoring of the endotracheal position. Two hundred and nine (42 %) consider they have not been trained to difficult intubation and 443 (87 %) would like to participate in high fidelity simulations mannequin. CONCLUSIONS: National airway management algorithm was insufficiently followed. Alternative techniques do not seem to be mastered by all physicians. French intensivists expect more training on difficult intubation, including high fidelity simulation. PMID- 24810381 TI - Three new species of fleas belonging to the genus Macrostylophora from the three striped ground squirrel, Lariscus insignis, in Java. AB - Three new species of fleas belonging to the genus Macrostylophora (Siphonaptera, Ceratophyllidae) are described from the three-striped ground squirrel, Lariscus insignis, from Tjibodas, West Java (Jawa Barat), Indonesia at an elevation of 1500 m. Macrostylophora larisci sp. n. is described from three male specimens, Macrostylophora debilitata sp. n. is described from one male and Macrostylophora wilsoni sp. n. is described from one female. Non-genital morphological characters of the female specimen, including ctenidial spine shapes and lengths, show that it is not the corresponding female for either M. larisci sp. n. or M. debilitata sp. n. It is unusual for three different species of congeneric fleas to parasitize the same host species in the same geographical location. These three new species represent the first known records of Macrostylophora from Java and they could be enzootic vectors between rodents of flea-borne zoonotic pathogens such as Rickettsia typhi and Yersinia pestis, both of which are established on Java. A list is provided of the 43 known species and 12 subspecies of Macrostylophora together with their known geographical distributions and hosts. A map depicting the distributions of known Indonesian (and Bornean) species of Macrostylophora is also included. PMID- 24810382 TI - The DAN family: modulators of TGF-beta signaling and beyond. AB - Extracellular binding proteins or antagonists are important factors that modulate ligands in the transforming growth factor (TGF-beta) family. While the interplay between antagonists and ligands are essential for developmental and normal cellular processes, their imbalance can lead to the pathology of several disease states. In particular, recent studies have implicated members of the differential screening-selected gene in neuroblastoma (DAN) family in disease such as renal fibrosis, pulmonary arterial hypertension, and reactivation of metastatic cancer stem cells. DAN family members are known to inhibit the bone morphogenetic proteins (BMP) of the TGF-beta family. However, unlike other TGF-beta antagonist families, DAN family members have roles beyond ligand inhibition and can modulate Wnt and vascular endothelial growth factor (VEGF) signaling pathways. This review describes recent structural and functional advances that have expanded our understanding of DAN family proteins with regards to BMP inhibition and also highlights their emerging roles in the modulation of Wnt and VEGF signaling pathways. PMID- 24810383 TI - Factors associated with hospitalization after suicide spectrum behaviors: results from a multicenter study in Spain. AB - The objective of this study was to identify factors associated with hospital admission after suicide spectrum behaviors. Patients' characteristics, the nature of the suicidal behavior, admission rates between centers, and factors associated with admission have been examined in suicide spectrum presentations to emergency departments in 3 Spanish cities. The intent of the suicidal behavior had the greatest impact on hospitalization. Older age, living alone, self-harm method not involving drug overdose, previous history of suicide spectrum behaviors, and psychiatric diagnosis of schizophrenia, mood, or personality disorder were independently associated with being admitted. There was a 3-fold between-center difference in the rate of hospitalization. Widespread differences in the rate of hospitalization were primarily accounted for by characteristics of the individual patients and their suicidal behavior. PMID- 24810385 TI - Can progression to permanent atrial fibrillation be prevented by pacing? PMID- 24810384 TI - Specialization for aggression in sexually dimorphic skeletal morphology in grey wolves (Canis lupus). AB - Aggressive behaviour is important in the life history of many animals. In grey wolves (Canis lupus), territory defence through direct competition with conspecifics is severe and often lethal. Thus, performance in aggressive encounters may be under strong selection. Additionally, grey wolves frequently kill large dangerous prey species. Because both sexes actively participate in aggressive activities and prey capture, wolves are expected to exhibit a low level of musculoskeletal sexual dimorphism. However, male wolves more often lead in agonistic encounters with conspecifics and must provision the nursing female during the pup-rearing period of the breeding season. These behaviours may select for males that exhibit a higher degree of morphological adaptation associated with aggression and prey capture performance. To test this prediction, we assessed skeletal sexual dimorphism in three subspecies of grey wolves using functional indices reflecting morphological specialization for aggression. As expected, sexual dimorphism in skeletal shape was limited. However, in two of three subspecies, we found sexually dimorphic traits in the skull, forelimbs and hindlimbs that are consistent with the hypothesis that males are more specialized for aggression. These characters may also be associated with selection for improved prey capture performance by males. Thus, the sexually dimorphic functional traits identified by our analysis may be adaptive in the contexts of both natural and sexual selection. Several of these traits may conflict with locomotor economy, indicating the importance of aggression in the life history of male grey wolves. The presence of functional specialization for aggression in a generally monogamous species indicates that sexual dimorphism in specific musculoskeletal traits may be widespread among mammals. PMID- 24810386 TI - Vascular signs of Takayasu's arteritis: porcelain aorta and the 'macaroni sign'. PMID- 24810387 TI - Ruptured aneurysm of non-coronary sinus of valsalva as a rare cause of chest pain. PMID- 24810388 TI - Edoxaban: a focused review of its clinical pharmacology. AB - Long-term anticoagulation treatment with warfarin has been associated with a number of limitations in clinical practice and there is a need for more convenient long-term anticoagulation treatment. One of the non-vitamin K oral anticoagulants in development is edoxaban, a factor Xa inhibitor that is administered once daily. The pharmacological properties of edoxaban have various advantages in anticoagulant therapy. Edoxaban quickly reaches peak plasma concentrations in 1.5 h, has a half-life of 10-14 h, has relatively high bioavailability of 62% and exhibits highly selective, competitive, concentration dependent inhibition of human factor Xa. The plasma concentrations of edoxaban are also closely correlated with suppression of thrombin generation and a range of platelet activation parameters (fragment 1+2, thrombin-antithrombin complex, and beta-thromboglobulin), which edoxaban has been shown to rapidly inhibit. The anticoagulant activity of edoxaban is not affected by food intake or ethnicity and a number of drug-drug interaction studies have been performed. Co administration of edoxaban with strong P-glycoprotein inhibitors, such as dronedarone, quinidine, and verapamil requires edoxaban dose-reduction by 50% to avoid the risk of over-exposure. The exposure of edoxaban may also increase in patients with a body weight <=60 kg and moderate renal impairment. This meant a dose-reduction strategy in patients at risk of over-exposure was utilized in Phase III clinical studies. In conclusion, the pharmacological properties of edoxaban provide rapid and specific inhibition of factor Xa, which is closely related to plasma concentrations. Given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients. PMID- 24810389 TI - Significance of left ventricular apical-basal muscle bundle identified by cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy. AB - AIMS: Cardiovascular magnetic resonance (CMR) has improved diagnostic and management strategies in hypertrophic cardiomyopathy (HCM) by expanding our appreciation for the diverse phenotypic expression. We sought to characterize the prevalence and clinical significance of a recently identified accessory left ventricular (LV) muscle bundle extending from the apex to the basal septum or anterior wall (i.e. apical-basal). METHODS AND RESULTS: CMR was performed in 230 genotyped HCM patients (48 +/- 15 years, 69% male), 30 genotype positive/phenotype-negative (G+/P-) family members (32 +/- 15 years, 30% male), and 126 controls. Left ventricular apical-basal muscle bundle was identified in 145 of 230 (63%) HCM patients, 18 of 30 (60%) G+/P- family members, and 12 of 126 (10%) controls (G+/P- vs. controls; P < 0.01). In HCM patients, the prevalence of an apical-basal muscle bundle was similar among those with disease-causing sarcomere mutations compared with patients without mutation (64 vs. 62%; P = 0.88). The presence of an LV apical-basal muscle bundle was not associated with LV outflow tract obstruction (P = 0.61). In follow-up, 33 patients underwent surgical myectomy of whom 22 (67%) were identified to have an accessory LV apical basal muscle bundle, which was resected in all patients. CONCLUSION: Apical-basal muscle bundles are a unique myocardial structure commonly present in HCM patients as well as in G+/P- family members and may represent an additional morphologic marker for HCM diagnosis in genotype-positive status. PMID- 24810390 TI - Benzodiazepines consumption: does dependence vary with age? AB - We have compared two groups of chronic benzodiazepines (or zolpidem/zopiclone) users: "Seniors," aged 65 years or more, and "Adults," aged less than 65 years. The study took place in the Pays de Loire region. The questionnaire assesses dependence based on items from the DSM-IV. The analysis was based on 176 Senior questionnaires and 212 Adult questionnaires. Whereas Senior patients take benzodiazepines routinely with little negative consequences, Adults suffer from underlying psychological trouble, mention a higher consumption than planned, which causes negative consequences. 35.2% of Seniors are dependent on benzodiazepines versus 49.8% of Adults. PMID- 24810391 TI - Dose-related association between urinary cotinine-verified smoking status and dyslipidemia among Korean men: the 2008-2010 Korea National Health and Nutrition Examination Survey. AB - This cross-sectionally designed study was based on data collected during the 2008 2010 Korea National Health and Nutrition Examination Survey. A total 3231 South Korean men aged more than 19 years were included. Urinary cotinine concentrations were measured. Smoking status was defined using questionnaire responses and urinary cotinine concentrations. Hierarchical multivariate logistic regression analyses were used to assess the association of urinary cotinine concentrations with the prevalence of dyslipidemia and various parameters of dyslipidemia. There is a significant dose-related association between smoking as assessed by urinary cotinine concentration and dyslipidemia and various parameters of dyslipidemia among South Korean men. PMID- 24810392 TI - Volume and type of alcohol during early pregnancy and the risk of miscarriage. AB - BACKGROUND: Research on alcohol consumption during pregnancy and miscarriage spans over three decades, yet the relationship is still not well-understood. OBJECTIVES: To assess the relationship between volume and type of alcohol consumed during pregnancy in relation to miscarriage. METHODS: We utilized data from a population-based cohort study of pregnant women (n = 1061) of which 172 (16%) women had a miscarriage. Upon study entry, participants were asked about their alcohol consumption during pregnancy. Based on the average number of drinks per week, women were categorized into one of three categories: four or more drinks per week (n = 32, 3%), less than four drinks per week (n = 403, 38%), and no alcohol intake (n = 626, 59%). In addition, women were categorized by the type of alcohol beverage they consumed: beer only (n = 47, 4%), spirits only (n = 56, 5%), wine only (n = 160, 15%), or a combination of two or more types of alcohol (n = 172, 16%). RESULTS: A significant increased risk of miscarriage (adjusted hazard ratio (aHR): 2.65; 95% confidence interval (CI): 1.38, 5.10) was found for women who drank four or more drinks a week. Our findings also suggest the relationship between alcohol intake during pregnancy and miscarriage is strongest for miscarriage occurring prior to 10 weeks of gestation. In addition, women who drank only spirits had more than a two-fold increased risk of miscarriage compared to women who abstained (aHR: 2.24; 95% CI: 1.32, 3.81). Conclusions/Importance: Future research assessing the factors that may contribute to an increased risk of miscarriage should consider the type of alcohol consumed. PMID- 24810393 TI - Topical drug delivery to retinal pigment epithelium with microfluidizer produced small liposomes. AB - Drug delivery from topically instilled eye drops to the posterior segment of the eye has long been one of the greatest challenges of ocular drug development. We developed methods of liposome preparation utilizing a microfluidizer to achieve adjustable nanoparticle size (even less than 80 nm) and high loading capacity of plasmid DNA. The microfluidizing process parameters were shown to affect the size of the liposomes. Higher operating pressures and passage for at least 10 times through the microfluidizer produced small liposomes with narrow size distribution. The liposomes were physically stable for several months at +4 degrees C. In vivo distribution of the optimized liposome formulations in the rat eyes was investigated with confocal microscopy of the histological specimens. Transferrin was used as a targeting ligand directed to retinal pigment epithelium. Size dependent distribution of liposomes to different posterior segment tissues was seen. Liposomes with the diameter less than 80 nm permeated to the retinal pigment epithelium whereas liposomes with the diameter of 100 nm or more were distributed to the choroidal endothelium. Active targeting was shown to be necessary for liposome retention to the target tissue. In conclusion, these microfluidizer produced small liposomes in eye drops are an attractive option for drug delivery to the posterior segment tissues of the eye. PMID- 24810394 TI - Enhanced bioavailability and intestinal uptake of Gemcitabine HCl loaded PLGA nanoparticles after oral delivery. AB - The aim of study was to formulate PLGA nanoparticles (NPs) of Gemcitabine HCl for enhanced oral bioavailability via absorption through M cells of Peyer's patches. Commercially, the drug is available as i.v. infusion due to its short half life (8-17 min), rapid metabolism and limited tumor uptake. The NPs were prepared by multiple solvent emulsification method. Optimized formulation had particle size of 166.4+/-2.42 nm, and entrapment of 56.48+/-3.63%. TEM image revealed discrete spherical structures of NPs. DSC and FTIR studies confirmed absence of interaction between drug and polymer. In vitro and ex vivo studies demonstrated sustained release from the NPs. The enhanced absorption and uptake of NPs in Caco 2 cells and in vivo absorption in intestinal tissue after oral delivery in rats was confirmed by confocal microscopy. Transport studies in Caco-2 cells confirmed 6.37-fold permeability for NPs. In vitro antiproliferative studies confirmed marked cytotoxicity of NPs on K562 leukemia cell lines. In vivo pharmacokinetic studies in rats showed 21.47-folds bioavailability enhancement from NPs. Hence, orally delivered Gemcitabine HCl loaded NPs have the potential for improving its bioavailability and avoiding side effects associated with iv infusions as well as enhancing patient compliance through "Chemotherapy at Home". PMID- 24810395 TI - Sleeping site selection by proboscis monkeys (Nasalis larvatus) in West Kalimantan, Indonesia. AB - Primates spend at least half their lives sleeping; hence, sleeping site selection can have important effects on behavior and fitness. As proboscis monkeys (Nasalis larvatus) often sleep along rivers and form bands (aggregations of one male groups) at their sleeping sites, understanding sleeping site selection may shed light on two unusual aspects of this species' socioecology: their close association with rivers and their multilevel social organization. We studied sleeping site selection by proboscis monkeys for twelve months at Sungai Tolak, West Kalimantan, Indonesia to test two main hypotheses regarding the drivers of sleeping site selection: reduction of molestation by mosquitoes and anti-predator behavior. We identified to genus and collected data on the physical structure (diameter at breast height, relative height, branch structure, and leaf coverage) of sleeping trees and available trees in three forest types. We used resource selection function models to test specific predictions derived from our two hypotheses. The monkeys preferred to sleep in large trees with few canopy connections located along rivers. The selection of large emergent trees was consistent with both of our main hypotheses: decreased molestation by mosquitoes and reduced potential entry routes for terrestrial predators. Although we are only beginning to understand how sleeping sites might influence behavior, grouping, and potential survival of this species, our study has shown that proboscis monkeys (at Sungai Tolak) have a very strong preference for large trees located near the river. As these trees are often the first to be logged by local villagers, this may exacerbate the problems of forest loss for these endangered monkeys. PMID- 24810396 TI - Otalgia, Facial Nerve Paralysis, and Hearing Loss. PMID- 24810397 TI - Stroke/thromboembolism and intracranial hemorrhage in a real-world atrial fibrillation population: the Complications of Atrial Fibrillation in the Bologna Area (CAFBO) study. AB - BACKGROUND: Ischemic events (IEs) and intracranial hemorrhages (ICHs) are feared complications of atrial fibrillation (AF) and of antithrombotic treatment in patients with these conditions. METHODS: Patients with AF admitted to the EDs of the Bologna, Italy, area with acute IE or ICH were prospectively recorded over 6 months. RESULTS: A total of 178 patients (60 male patients; median age: 85 years) presented with acute IE. Antithrombotic therapy was as follows: (1) vitamin K antagonists (VKAs) in 31 patients (17.4%), with international normalized ratio (INR) at admission of < 2.0 in 16 patients, 2.0 to 3.0 in 13 patients, and > 3.0 in two patients; (2) aspirin (acetylsalicylic acid) (ASA) in 107 patients (60.1%); and (3) no treatment in 40 patients (22.5%), mainly because AF was not diagnosed. Twenty patients (eight male patients; median age: 82 years) presented with acute ICH: 13 (65%) received VKAs (INR, 2.0-3.0 in 11 patients and > 3.0 in two patients), while six (30%) received ASA. Most IEs (88%) and ICHs (95%) occurred in patients aged > 70 years. A modeling analysis of patients aged > 70 years was used to estimate annual incidence in subjects anticoagulated with VKAs in our Network of Anticoagulation Centers (NACs), or those expected to have AF but not included in NACs. The expected incidence of IE was 12.0%/y (95% CI, 10.7 13.3) in non-NACs and 0.57%/y (95% CI, 0.42-0.76) in NACs (absolute risk reduction [ARR], 11.4%/y; relative risk reduction [RRR], 95%; P < .0001). The incidence of ICH was 0.63%/y (95% CI, 0.34-1.04) and 0.30%/y (95% CI, 0.19-0.44), respectively (ARR, 0.33%/y; RRR, 52.4%/y; P = .04). CONCLUSIONS: IEs occurred mainly in elderly patients who received ASA or no treatment. One-half of patients with IEs receiving anticoagulant treatment had subtherapeutic INRs. Therapeutic approaches to elderly subjects with AF require an effective anticoagulant treatment strategy. PMID- 24810398 TI - Generation of guanine-amino acid cross-links by a free radical combination mechanism. AB - A direct method has been developed for the in vitro synthesis of stable DNA protein cross-links (DPC's) between guanine and amino acids (lysine and arginine). This method employs the combination of guanine neutral radicals, G( H), and side-chain C-centered amino acid radicals. The latter were generated indirectly after first causing the selective photoionization of 2-aminopurine (2AP) embedded in the oligonucleotide, 5'-d(CC[2AP]TCGCTACC), by intense nanosecond 308 nm excimer laser pulses. The 2AP radical cation deprotonates rapidly to form the 2AP(-H) neutral radical which, in turn, oxidizes the nearby guanine to form the neutral guanine G(-H) radical, as described previously (Shafirovich et al., J. Phys. Chem. B, 2001, 105, 8431). In parallel, the hydrated electrons, generated by the photoionization of 2AP, are scavenged by nitrous oxide to generate hydroxyl radicals. In the presence of a large excess of the amino acids, the hydroxyl radicals oxidize the latter to produce C-centered amino acid radicals that combine with the G(-H) radicals to form the guanine amino acid cross-linked oligonucleotide product. Analogous products were generated by photoionizing the free nucleoside, 2',3',5'-tri-O-acetylguanosine, (tri-O-Ac-Guo), using intense nanosecond 266 nm Nd:YAG laser pulse irradiation. The guanine-amino acid cross-links thus produced site-specifically positioned either in oligonucleotides, or in the free nucleoside tri-O-Ac-Guo were isolated by HPLC methods and identified by high resolution LC-TOF/MS and LC-MS/MS methods. The possibility that analogous guanine-amino acid cross-linked products could be formed in vivo using single hit radical generation mechanisms during oxidative stress is discussed. PMID- 24810399 TI - Fitness impact and stability of a transgene conferring resistance to dengue-2 virus following introgression into a genetically diverse Aedes aegypti strain. AB - In 2006, we reported a mariner (Mos1)-transformed Aedes aegypti line, Carb77, which was highly resistant to dengue-2 virus (DENV2). Carb77 mosquitoes expressed a DENV2-specific inverted-repeat (IR) RNA in midgut epithelial cells after ingesting an infectious bloodmeal. The IR-RNA formed double-stranded DENV2 derived RNA, initiating an intracellular antiviral RNA interference (RNAi) response. However, Carb77 mosquitoes stopped expressing the IR-RNA after 17 generations in culture and lost their DENV2-refractory phenotype. In the current study, we generated new transgenic lines having the identical transgene as Carb77. One of these lines, Carb109M, has been genetically stable and refractory to DENV2 for >33 generations. Southern blot analysis identified two transgene integration sites in Carb109M. Northern blot analysis detected abundant, transient expression of the IR-RNA 24 h after a bloodmeal. Carb109M mosquitoes were refractory to different DENV2 genotypes but not to other DENV serotypes. To further test fitness and stability, we introgressed the Carb109M transgene into a genetically diverse laboratory strain (GDLS) by backcrossing for five generations and selecting individuals expressing the transgene's EGFP marker in each generation. Comparison of transgene stability in replicate backcross 5 (BC5) lines versus BC1 control lines demonstrated that backcrossing dramatically increased transgene stability. We subjected six BC5 lines to five generations of selection based on EGFP marker expression to increase the frequency of the transgene prior to final family selection. Comparison of the observed transgene frequencies in the six replicate lines relative to expectations from Fisher's selection model demonstrated lingering fitness costs associated with either the transgene or linked deleterious genes. Although minimal fitness loss (relative to GDLS) was manifest in the final family selection stage, we were able to select homozygotes for the transgene in one family, Carb109M/GDLS.BC5.HZ. This family has been genetically stable and DENV2 refractory for multiple generations. Carb109M/GDLS.BC5.HZ represents an important line for testing proof-of-principle vector population replacement. PMID- 24810400 TI - Launching Hsp70 neuroprotection: two drugs better than one. PMID- 24810401 TI - Alteration of functional connectivity within visuospatial working memory-related brain network in patients with right temporal lobe epilepsy: a resting-state fMRI study. AB - PURPOSE: This study aimed to investigate the resting-state brain network related to visuospatial working memory (VSWM) in patients with right temporal lobe epilepsy (rTLE). The functional mechanism underlying the cognitive impairment in VSWM was also determined. METHOD: Fifteen patients with rTLE and 16 healthy controls matched for age, gender, and handedness underwent a 6-min resting-state functional MRI session and a neuropsychological test using VSWM_Nback. The VSWM related brain network at rest was extracted using multiple independent component analysis; the spatial distribution and the functional connectivity (FC) parameters of the cerebral network were compared between groups. Behavioral data were subsequently correlated with the mean Z-value in voxels showing significant FC difference during intergroup comparison. RESULTS: The distribution of the VSWM related resting-state network (RSN) in the group with rTLE was virtually consistent with that in the healthy controls. The distribution involved the dorsolateral prefrontal lobe and parietal lobe in the right hemisphere and the partial inferior parietal lobe and posterior lobe of the cerebellum in the left hemisphere (p<0.05, AlphaSim corrected). Between-group differences suggest that the group with rTLE had a decreased FC within the right superior frontal lobe (BA8), right middle frontal lobe, and right ventromedial prefrontal lobe compared with the controls (p<0.05, AlphaSim corrected). The regions of increased FC in rTLE were localized within the right superior frontal lobe (BA11), right superior parietal lobe, and left posterior lobe of the cerebellum (p<0.05, AlphaSim corrected). Moreover, patients with rTLE performed worse than controls in the VSWM_Nback test, and there were negative correlations between ACCmeanRT (2-back) and the mean Z-value in the voxels showing decreased or increased FC in rTLE (p<0.05). CONCLUSION: The results suggest that the alteration of the VSWM-related RSN might underpin the VSWM impairment in patients with rTLE and possibly implies a functional compensation by enlarging the FC within the ipsilateral cerebral network. PMID- 24810403 TI - Does short-term placebo response predict the long-term observation? Meta-analysis on forced expiratory volume in 1 second from asthma trials. AB - The objectives of this work were: (1) to characterize the placebo FEV1 response in asthma; (2) to identify the potential factors with strong influence on FEV1; (3) to determine the predictability of the early (week 2) placebo FEV1 response to the longer term (week 12) FEV1 response. Placebo FEV1 data of about 800 subjects from 11 randomized 12-week clinical trials in mild-to-moderate asthmatics were collected. Stepwise logistic regression methods using SAS were used to model the week 12 trough FEV1 change from baseline greater than a clinically relevant value (150 mL) and to select the predictive covariates. The study effect was assessed using hierarchical logistic regression models implemented in WinBUGS. The results indicated that the early (week 2) placebo response was significantly predictive of the FEV1 response at week 12. Age, baseline predicted FEV1, and season showed statistical significance in the model. The final model showed satisfactory predictability with the area under the receiver operating characteristic curve (ROC) of 80%. The late (week 12) FEV1 response with placebo was positively related to the early (week 2) FEV1 change. The use of the predictive modeling approach proposed in this article presents a valuable method to increase the efficiency of clinical trial design in asthma population. PMID- 24810404 TI - Male flight phenology of the European grapevine moth Lobesia botrana (Lepidoptera: Tortricidae) in different wine-growing regions in Spain. AB - Lobesia botrana is the most significant pest of grape berries in Spain. Further knowledge of its phenology would enable wine growers to decide on an optimal treatment schedule. The aim of this study is, therefore, to predict the flight peaks of L. botrana in seven wine-growing regions of Spain. The main goal is to provide a prediction model based on meteorological data records. A logistic function model, based on temperature and humidity records, together with an exhaustive statistical analysis, were used to compare the wine-growing regions in which the male flight phenology of L. botrana displays similar patterns and to sort them into groups. By doing so, a joint study of the dynamics of the moth is possible in the regions within each group. A comparison of the prediction errors before and after applying the Touzeau model confirmed that the fit of the latter model is not sufficiently accurate for the regions under study. Moth flight predictions with the logistic function model are good, but accuracy may still be improved by evaluating other non-biotic and biotic factors. PMID- 24810405 TI - Augmented osteogenic responses in human aortic valve cells exposed to oxLDL and TLR4 agonist: a mechanistic role of Notch1 and NF-kappaB interaction. AB - Aortic valve calcification causes the progression of calcific aortic valve disease (CAVD). Stimulation of aortic valve interstitial cells (AVICs) with lipopolysaccharide (LPS) up-regulates the expression of osteogenic mediators, and NF-kappaB plays a central role in mediating AVIC osteogenic responses to Toll like receptor 4 (TLR4) stimulation. Diseased aortic valves exhibit greater levels of oxidized low-density lipoprotein (oxLDL). This study tested the hypothesis that oxLDL augments the osteogenic responses in human AVICs through modulation of NF-kappaB and Notch1 activation. AVICs isolated from normal human aortic valves were treated with LPS (0.1 ug/ml), oxLDL (20 ug/ml) or LPS plus oxLDL for 48 h. OxLDL alone increased cellular bone morphogenetic protein-2 (BMP-2) levels while it had no effect on alkaline phosphatase (ALP) levels. Cells exposed to LPS plus oxLDL produced higher levels of BMP-2 and ALP than cells exposed to LPS alone. Further, LPS plus oxLDL induced greater NF-kappaB activation, and inhibition of NF-kappaB markedly reduced the expression of BMP-2 and ALP in cells treated with LPS plus oxLDL. OxLDL also induced Notch1 activation and resulted in augmented Notch1 activation when it was combined with LPS. Inhibition of Notch1 cleavage attenuated NF-kappaB activation induced by LPS plus oxLDL, and inhibition of NF kappaB suppressed the expression of BMP-2 and ALP induced by the synergistic effect of Jagged1 and LPS. These findings demonstrate that oxLDL up-regulates BMP 2 expression in human AVICs and synergizes with LPS to elicit augmented AVIC osteogenic responses. OxLDL exerts its effect through modulation of the Notch1-NF kappaB signaling cascade. Thus, oxLDL may play a role in the mechanism underlying CAVD progression. PMID- 24810407 TI - Spatial pattern formation in the lung. AB - Clustered ventilation defects are a hallmark of asthma, typically seen via imaging studies during asthma attacks. The mechanisms underlying the formation of these clusters is of great interest in understanding asthma. Because the clusters vary from event to event, many researchers believe they occur due to dynamic, rather than structural, causes. To study the formation of these clusters, we formulate and analyze a lattice-based model of the lung, considering both the role of airway bistability and a mechanism for organizing the spatial structure. Within this model we show how and why the homogeneous ventilation solution becomes unstable, and under what circumstances the resulting heterogeneous solution is a clustered solution. The size of the resulting clusters is shown to arise from structure of the eigenvalues and eigenvectors of the system, admitting not only clustered solutions but also (aphysical) checkerboard solutions. We also consider the breathing efficiency of clustered solutions in severely constricted lungs, showing that stabilizing the homogeneous solution may be advantageous in some circumstances. Extensions to hexagonal and cubic lattices are also studied. PMID- 24810408 TI - Current problems in pediatric and adolescent health care. Foreword. PMID- 24810406 TI - RPM-1 uses both ubiquitin ligase and phosphatase-based mechanisms to regulate DLK 1 during neuronal development. AB - The Pam/Highwire/RPM-1 (PHR) proteins are key regulators of neuronal development that function in axon extension and guidance, termination of axon outgrowth, and synapse formation. Outside of development, the PHR proteins also regulate axon regeneration and Wallerian degeneration. The PHR proteins function in part by acting as ubiquitin ligases that degrade the Dual Leucine zipper-bearing Kinase (DLK). Here, we show that the Caenorhabditis elegans PHR protein, Regulator of Presynaptic Morphology 1 (RPM-1), also utilizes a phosphatase-based mechanism to regulate DLK-1. Using mass spectrometry, we identified Protein Phosphatase Magnesium/Manganese dependent 2 (PPM-2) as a novel RPM-1 binding protein. Genetic, transgenic, and biochemical studies indicated that PPM-2 functions coordinately with the ubiquitin ligase activity of RPM-1 and the F-box protein FSN-1 to negatively regulate DLK-1. PPM-2 acts on S874 of DLK-1, a residue implicated in regulation of DLK-1 binding to a short, inhibitory isoform of DLK-1 (DLK-1S). Our study demonstrates that PHR proteins function through both phosphatase and ubiquitin ligase mechanisms to inhibit DLK. Thus, PHR proteins are potentially more accurate and sensitive regulators of DLK than originally thought. Our results also highlight an important and expanding role for the PP2C phosphatase family in neuronal development. PMID- 24810409 TI - Fetal alcohol spectrum disorders: an overview for pediatric and adolescent care providers. AB - Fetal alcohol spectrum disorder (FASD) is a term used to describe the spectrum of conditions associated with prenatal alcohol exposure. These are characterized by facial dysmorphia, growth deficits and central nervous system abnormalities. FASDs are the most common preventable cause of intellectual disability in the United States and have high financial costs. Therefore, efforts at prevention are paramount. When an individual with an FASD goes undiagnosed and when appropriate interventions are not instituted, secondary disabilities such as substance abuse, school dropout, and criminal involvement are common with corresponding suffering endured by both the affected individual and the family. The diagnostic process opens up access to existing tools and resources, including the new American Academy of Pediatrics (AAP) FASD algorithm for the evaluation of FASDs, the new AAP FASD toolkit and evidence-based interventions specific to FASDs. Pediatric and adolescent clinicians are challenged to participate in the continuum of care from FASD prevention to identification, diagnosis, and management, including provision of supportive services for families in order for clinicians to make a difference in this 100% preventable disorder. PMID- 24810410 TI - Screening and brief intervention for risky alcohol use. AB - Alcohol screening and brief intervention are effective evidence-based methods recommended by multiple major medical societies. Primary care providers are uniquely positioned to recognize patients with alcohol use problems when they utilize screening in their practices. SBI has the potential to improve patients' overall health, reduce the risk of alcohol dependence, and prevent future alcohol exposed pregnancies. PMID- 24810411 TI - Fetal alcohol spectrum disorders: guidance for recognition, diagnosis, differential diagnosis and referral. AB - FASDs are the most common preventable cause of developmental and intellectual disabilities in the United States and yet can easily be overlooked in pediatric and adolescent practices. Early diagnosis, presence of developmental and educational services, and a nurturing home environment have been associated with decreased occurrence of secondary disabilities such as substance use and criminal involvement.23 Therefore, it is important for providers to know how to go about the identification, diagnostic, and evaluation process. Pediatric care clinicians should be knowledgeable about the diagnostic criteria for fetal alcohol syndrome and know common differentiating conditions. Furthermore, they should be able to recognize other disorders on the spectrum, and in doing so, they should facilitate appropriate referral, initial management, and coordination of care. PMID- 24810412 TI - Managing children and adolescents with fetal alcohol spectrum disorders in the medical home. PMID- 24810413 TI - Fetal spectrum disorders: an overview of ethical and legal issues for healthcare providers. PMID- 24810414 TI - Commentary. Fetal alcohol exposure and complications. PMID- 24810415 TI - How does a coordinated radical ligand affect the spin crossover properties in an octahedral iron(II) complex? AB - The influence of a coordinated pi-radical on the spin crossover properties of an octahedral iron(II) complex was investigated by preparing and isolating the iron(II) complex containing the tetradentate N,N'-dimethyl-2,11 diaza[3.3](2,6)pyridinophane and the radical anion of N,N'-diphenyl-acenaphtene 1,2-diimine as ligands. This spin crossover complex was obtained by a reduction of the corresponding low-spin iron(II) complex with the neutral diimine ligand, demonstrating that the reduction of the strong pi-acceptor ligand is accompanied by a decrease in the ligand field strength. Characterization of the iron(II) radical complex by structural, magnetochemical, and spectroscopic methods revealed that spin crossover equilibrium occurs above 240 K between an S=1/2 ground state and an S=3/2 excited spin state. The possible origins of the fast spin interconversion observed for this complex are discussed. PMID- 24810416 TI - Quality of obstetric referral services in India's JSY cash transfer programme for institutional births: a study from Madhya Pradesh province. AB - BACKGROUND: India launched JSY cash transfer programme to increase access to emergency obstetric and neonatal care (EmONC) by incentivising in-facility births. This increased in-facility births from 30%in 2005 to 73% in 2012 however, decline in maternal mortality follows a secular trend. Dysfunctional referral services can contribute to poor programme impact on outcomes. We hence describe inter- facility referrals and study quality of referral services in JSY. METHODS AND RESULTS: Women accessing intra natal care (n = 1182) at facilities (reporting >10 deliveries/month, n = 96) were interviewed in a 5 day cross sectional survey in 3 districts of Madhya Pradesh province. A nested matched case control study (n = 68 pairs) was performed to study association between maternal referral and adverse birth outcomes. There were 111 (9.4%) in referrals and 69 (5.8%) out referrals. Secondary level facilities sent most referrals and 40% were for conditions expected to be treated at this level. There were 36 adverse birth outcomes (intra partum and in-facility deaths). After matching for type of complication and place of delivery, conditional logistic regression model showed maternal referral at term delivery was associated with higher odds of adverse birth outcomes (OR- 2.6, 95% CI: 1.0-6.6 p = 0.04). Maternal death record review (April 10-March 12) was conducted at the CEmOC facility in one district. Spatial analysis of transfer time from sending to the receiving CEmOC facility among in facility maternal deaths was conducted in ArcGIS10 applying two hours (equated to 100 Km) as desired transfer time. There were 124 maternal deaths, 55 of which were among mothers referred in. Buffer analysis revealed 98% mothers were referred from <2 hours. Median time between arrival and death was 6.75 hours. CONCLUSIONS: High odds of adverse birth outcomes associated with maternal referral and high maternal deaths despite spatial access to referral care indicate poor quality of referral services. PMID- 24810417 TI - Changes in muscle thickness after exercise and biofeedback in people with low back pain. AB - CONTEXT: Individuals with low back pain (LBP) have reduced function of the transversus abdominis (TrA) and lumbar multifidus (LM) muscles. Biofeedback during exercise may increase the ability to contract the TrA and LM muscles compared with exercise alone. OBJECTIVE: To compare TrA preferential activation ratio (PAR) and the percent change in LM-muscle thickness in patients with LBP history before and after exercise with or without biofeedback. DESIGN: Controlled laboratory study. SETTING: University research laboratory. PATIENTS: 20 LBP individuals, 10 exercise alone and 10 exercise with biofeedback. INTERVENTIONS: Patients were allotted to tabletop exercises in isolation or tabletop exercises with visual, auditory, and tactile biofeedback. MAIN OUTCOME MEASURES: TrA PAR and percent change in LM-muscle thickness. RESULTS: There were no differences between groups at baseline (all P > .05). Nonparametric statistics showed decreased resting muscle thickness for total lateral abdominal-wall muscles (P = .007) but not TrA (P = .410) or LM (P = .173). Percent TrA thickness increased from table to standing positions before (P = .006) and after exercise (P = .009). TrA PAR increased after exercise (pre 0.01 +/- 0.02, post 0.03 +/- 0.04, P = .033) for all patients and for exercise with biofeedback (pre 0.02 +/- 0.01, post 0.03 +/- 0.01, P = .037) but not for exercise alone (pre 0.01 +/- 0.02, post 0.02 +/- 0.05, P = .241). No group differences were observed for TrA PAR before (exercise 0.01 +/- 0.02, exercise with biofeedback 0.02 +/- 0.01, P = .290) or after exercise (exercise 0.02 +/- 0.05, exercise with biofeedback 0.03 +/- 0.01, P = .174). There were no group differences in LM percent change before exercise (P = .999) or after exercise (P = .597). In addition, no changes were observed in LM percent change as a result of exercise among all participants (P = .391) or for each group (exercise P = .508, exercise with biofeedback P = .575). CONCLUSION: TrA PAR increased after a single session of exercises, whereas no thickness changes occurred in LM. PMID- 24810418 TI - Myelination: A not so even distribution. PMID- 24810419 TI - Olfaction: Critical timing in mapping olfaction. PMID- 24810420 TI - Body weight, meat quality and blood metabolite responses to carbohydrate administration in the drinking water during pre-slaughter feed withdrawal in broilers. AB - This study was conducted to determine weights of body (BW), carcass (CW), gastrointestinal tract (GTW), meat quality and some blood metabolite responses to corn starch, saccharose or glucose administration in the drinking water during pre-slaughter feed withdrawal (FW) in broilers. On day 42 of age, 200 broilers (Ross 308) were allocated randomly to five treatments with four replicates. During a 10-h FW, control broilers (C) were provided with non-treated water and the standard finisher diet ad libitum, whereas fasted broilers provided with non treated (NFW) or treated water, 3 g glucose (G), saccharose (S) or corn starch (CS)/L. Eight birds (four males and four females) per treatment were slaughtered. Birds receiving non-treated or treated water had lower BW and higher carcass yield than the full-fed broilers. The full-fed broilers had higher absolute and relative GTW than the fasted birds. Broilers consumed more readily treated water compared with non-treated water. While the a* value of breast meat from CS birds was higher than that from NFW, the b* value of that was higher than S and C birds. The c* values of breast meat from S birds were lower compared with that from the CS treatment. The thigh meat from NFW broilers had higher h* value than that from C and G broilers. The thigh meats of C and CS broilers had higher c* value than that of G birds. The full-fed broilers had higher plasma triglyceride concentration than NFW, S and G birds. The full-fed broilers had higher plasma uric acid and uric acid nitrogen concentrations than S birds. These results show that carbohydrate administration in the drinking water cannot be a good alternative for the FW period before slaughter due to the fact that the carbohydrates do not reduce BW losses and do not lead to increases in meat quality. PMID- 24810421 TI - Sequencing and validation of reference genes to analyze endogenous gene expression and quantify yellow dwarf viruses using RT-qPCR in viruliferous Rhopalosiphum padi. AB - The bird cherry-oat aphid (Rhopalosiphum padi), an important pest of cereal crops, not only directly sucks sap from plants, but also transmits a number of plant viruses, collectively the yellow dwarf viruses (YDVs). For quantifying changes in gene expression in vector aphids, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is a touchstone method, but the selection and validation of housekeeping genes (HKGs) as reference genes to normalize the expression level of endogenous genes of the vector and for exogenous genes of the virus in the aphids is critical to obtaining valid results. Such an assessment has not been done, however, for R. padi and YDVs. Here, we tested three algorithms (GeNorm, NormFinder and BestKeeper) to assess the suitability of candidate reference genes (EF-1alpha, ACT1, GAPDH, 18S rRNA) in 6 combinations of YDV and vector aphid morph. EF-1alpha and ACT1 together or in combination with GAPDH or with GAPDH and 18S rRNA could confidently be used to normalize virus titre and expression levels of endogenous genes in winged or wingless R. padi infected with Barley yellow dwarf virus isolates (BYDV)-PAV and BYDV-GAV. The use of only one reference gene, whether the most stably expressed (EF-1alpha) or the least stably expressed (18S rRNA), was not adequate for obtaining valid relative expression data from the RT-qPCR. Because of discrepancies among values for changes in relative expression obtained using 3 regions of the same gene, different regions of an endogenous aphid gene, including each terminus and the middle, should be analyzed at the same time with RT-qPCR. Our results highlight the necessity of choosing the best reference genes to obtain valid experimental data and provide several HKGs for relative quantification of virus titre in YDV viruliferous aphids. PMID- 24810422 TI - Cumulative effects of the ApoE genotype and gender on the synaptic proteome and oxidative stress in the mouse brain. AB - Elderly females, particularly those carrying the apolipoprotein E (ApoE)-epsilon4 allele, have a higher risk of developing Alzheimer's disease (AD). However, the underlying mechanism for this increased susceptibility remains unclear. In this study, we investigated the effects of the ApoE genotype and gender on the proteome of synaptosomes. We isolated synaptosomes and used label-free quantitative proteomics, to report, for the first time, that the synaptosomal proteomic profiles in the cortex of female human-ApoE4 mice exhibited significantly reduced expression of proteins related to energy metabolism, which was accompanied by increased levels of oxidative stress. In addition, we also first demonstrated that the proteomic response in synaptic termini was more susceptible than that in the soma to the adverse effects induced by genders and genotypes. This suggests that synaptic mitochondria might be 'older' than mitochondria in the soma of neurons; therefore, they might contain increased cumulative damage from oxidative stress. Furthermore, female human-ApoE4 mice had much lower oestrogen levels in the cortex and treatment with oestrogen protected ApoE3 stable transfected C6 neurons from oxidative stress. Overall, this study reveals complex ApoE- and gender-dependent effects on synaptic function and also provides a basis for future studies of candidates based on specific pathways involved in the pathogenesis of AD. The lack of oestrogen-mediated protection regulated by the ApoE genotype led to synaptic mitochondrial dysfunction and increased oxidative stress, which might make older females more susceptible to AD. PMID- 24810424 TI - Efficient and accurate fragmentation methods. AB - Conspectus Three novel fragmentation methods that are available in the electronic structure program GAMESS (general atomic and molecular electronic structure system) are discussed in this Account. The fragment molecular orbital (FMO) method can be combined with any electronic structure method to perform accurate calculations on large molecular species with no reliance on capping atoms or empirical parameters. The FMO method is highly scalable and can take advantage of massively parallel computer systems. For example, the method has been shown to scale nearly linearly on up to 131 000 processor cores for calculations on large water clusters. There have been many applications of the FMO method to large molecular clusters, to biomolecules (e.g., proteins), and to materials that are used as heterogeneous catalysts. The effective fragment potential (EFP) method is a model potential approach that is fully derived from first principles and has no empirically fitted parameters. Consequently, an EFP can be generated for any molecule by a simple preparatory GAMESS calculation. The EFP method provides accurate descriptions of all types of intermolecular interactions, including Coulombic interactions, polarization/induction, exchange repulsion, dispersion, and charge transfer. The EFP method has been applied successfully to the study of liquid water, pi-stacking in substituted benzenes and in DNA base pairs, solvent effects on positive and negative ions, electronic spectra and dynamics, non adiabatic phenomena in electronic excited states, and nonlinear excited state properties. The effective fragment molecular orbital (EFMO) method is a merger of the FMO and EFP methods, in which interfragment interactions are described by the EFP potential, rather than the less accurate electrostatic potential. The use of EFP in this manner facilitates the use of a smaller value for the distance cut off (Rcut). Rcut determines the distance at which EFP interactions replace fully quantum mechanical calculations on fragment-fragment (dimer) interactions. The EFMO method is both more accurate and more computationally efficient than the most commonly used FMO implementation (FMO2), in which all dimers are explicitly included in the calculation. While the FMO2 method itself does not incorporate three-body interactions, such interactions are included in the EFMO method via the EFP self-consistent induction term. Several applications (ranging from clusters to proteins) of the three methods are discussed to demonstrate their efficacy. The EFMO method will be especially exciting once the analytic gradients have been completed, because this will allow geometry optimizations, the prediction of vibrational spectra, reaction path following, and molecular dynamics simulations using the method. PMID- 24810423 TI - Role of histone deacetylase activity in the developing lateral line neuromast of zebrafish larvae. AB - Histone deacetylases are involved in many biological processes and have roles in regulating cell behaviors such as cell cycle entry, cell proliferation and apoptosis. However, the effect of histone deacetylases on the development of hair cells (HCs) has not been fully elucidated. In this study, we examined the influence of histone deacetylases on the early development of neuromasts in the lateral line of zebrafish. Hair cell development was evaluated by fluorescent immunostaining in the absence or presence of histone deacetylase inhibitors. Our results suggested that pharmacological inhibition of histone deacetylases with inhibitors, including trichostatin A, valproic acid and MS-275, reduced the numbers of both HCs and supporting cells in neuromasts. We also found that the treatment of zebrafish larvae with inhibitors caused accumulation of histone acetylation and suppressed proliferation of neuromast cells. Real-time PCR results showed that the expression of both p21 and p27 mRNA was increased following trichostatin A treatment and the increase in p53 mRNA was modest under the same conditions. However, the expression of p53 mRNA was significantly increased by treatment with a high concentration of trichostatin A. A high concentration of trichostatin A also led to increased cell death in neuromasts as detected in a TUNEL assay. Moreover, the nuclei of most of these pyknotic cells were immunohistochemically positive for cleaved caspase-3. These results suggest that histone deacetylase activity is involved in lateral line development in the zebrafish and might have a role in neuromast formation by altering cell proliferation through the expression of cell cycle regulatory proteins. PMID- 24810426 TI - Observation of multiple, identical binding sites in the exchange of carboxylic acid ligands with CdS nanocrystals. AB - We study ligand exchange between the carboxylic acid group and 5.0 nm oleic-acid capped CdS nanocrystals (NCs) using fluorescence resonance energy transfer (FRET). This is the first measurement of the initial binding events between cadmium chalcogenide NCs and carboxylic acid groups. The binding behavior can be described as an interaction between a ligand with single binding group and a substrate with multiple, identical binding sites. Assuming Poissonian binding statistics, our model fits both steady-state and time-resolved photoluminescence (SSPL and TRPL, respectively) data well. A modified Langmuir isotherm reveals that a CdS nanoparticle has an average of 3.0 new carboxylic acid ligands and binding constant, Ka, of 3.4 * 10(5) M(-1). PMID- 24810425 TI - CCL21 Cancer Immunotherapy. AB - Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer. PMID- 24810427 TI - A prospective stratified case-cohort study on statins and multiple adverse events in Japan. AB - PURPOSE: To assess the association between statins and diverse adverse events in Japanese population. METHODS: New users of statin who started statin after 6 month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009. RESULTS: A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009). CONCLUSIONS: Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies. PMID- 24810428 TI - The "gray zone" for the heart to mediastinum MIBG uptake ratio. PMID- 24810430 TI - Limitations of parametric modeling of the left ventricle using first harmonic analysis: possible role for gaussian modeling. AB - BACKGROUND: Fourier (cosine) analysis of time activity curves (TAC) of radionuclide ventriculography (RVG) may oversimplify the TAC and has limitations. METHODS: We identified 21 patients who had undergone 24 frame planar RVG with ejection fractions ranging from 8% to 76% (43% +/- 19%). The TAC for each pixel was fitted to both a cosine and gaussian function then analyzed on a pixel-by pixel basis then over the entire LV. Second, mathematical simulations were performed to analyze the stability of each fit in the presence of low amplitude and noise. RESULTS: The fit was slightly but significantly better for the gaussian compared to the cosine function (RMS gaussian 13.0% +/- 2.5% vs 13.5% +/ 2.1% cosine; P = .016). There was near exact correlation with amplitude and between gaussian mu and cosine phase. The SD of phase from the cosine fit correlated strongly with the SD of the mu from the gaussian fit. The proposed new measure of dyssynchrony, the sigma parameter of the gaussian fit, correlated with the SD of the cosine phase (r = 0.520, P = .016). Simulations showed gradual but modest deviation of the sigma parameter from the gaussian fit with lower amplitudes whereas the deviation of the calculated SD of phase increased exponentially with decreasing amplitude. CONCLUSIONS: First harmonic (cosine) fitting has significant limitations. Gaussian fitting is an alternative way to model the LV TAC. The sigma from the gaussian may provide additional information LV dyssynchrony and is less influenced by image noise. Gaussian fitting merits further evaluation for modeling LV function. PMID- 24810429 TI - Segmental and global left ventricular function assessment using gated SPECT with a semiconductor Cadmium Zinc Telluride (CZT) camera: phantom study and clinical validation vs cardiac magnetic resonance. AB - BACKGROUND: We evaluated gated-SPECT using a Cadmium-Zinc-Telluride (CZT) camera for assessing global and regional left ventricular (LV) function. METHODS: A phantom study evaluated the accuracy of wall thickening assessment using systolic count increase on both Anger and CZT (Discovery 530NMc) cameras. The refillable phantom simulated variable myocardial wall thicknesses. The apparent count increase (%CI) was compared to the thickness increase (%Th). CZT gated-SPECT was compared to cardiac magnetic resonance (CMR) in 27 patients. Global and regional LV function (wall thickening and motion) were quantified and compared between SPECT and CMR data. RESULTS: In the phantom study using a 5-mm object, the regression between %CI and %Th was significantly closer to the line of identity (y = x) with the CZT (R (2) = 0.9955) than the Anger (R (2) = 0.9995, P = .03). There was a weaker correlation for larger objects (P = .003). In patients, there was a high concordance between CZT and CMR for ESV, EDV, and LVEF (all CCC >0.80, P < .001). CZT underestimated %CI and wall motion (WM) compared to CMR (P < .001). The agreement to CMR was better for WM than wall thickening. CONCLUSION: The Discovery 530NMc provided accurate measurements of global LV function but underestimated regional wall thickening, especially in patients with increased wall thickness. PMID- 24810431 TI - Survival analysis and regression models. AB - Time-to-event outcomes are common in medical research as they offer more information than simply whether or not an event occurred. To handle these outcomes, as well as censored observations where the event was not observed during follow-up, survival analysis methods should be used. Kaplan-Meier estimation can be used to create graphs of the observed survival curves, while the log-rank test can be used to compare curves from different groups. If it is desired to test continuous predictors or to test multiple covariates at once, survival regression models such as the Cox model or the accelerated failure time model (AFT) should be used. The choice of model should depend on whether or not the assumption of the model (proportional hazards for the Cox model, a parametric distribution of the event times for the AFT model) is met. The goal of this paper is to review basic concepts of survival analysis. Discussions relating the Cox model and the AFT model will be provided. The use and interpretation of the survival methods model are illustrated using an artificially simulated dataset. PMID- 24810432 TI - Analysis of transposable elements in the genome of Asparagus officinalis from high coverage sequence data. AB - Asparagus officinalis is an economically and nutritionally important vegetable crop that is widely cultivated and is used as a model dioecious species to study plant sex determination and sex chromosome evolution. To improve our understanding of its genome composition, especially with respect to transposable elements (TEs), which make up the majority of the genome, we performed Illumina HiSeq2000 sequencing of both male and female asparagus genomes followed by bioinformatics analysis. We generated 17 Gb of sequence (12*coverage) and assembled them into 163,406 scaffolds with a total cumulated length of 400 Mbp, which represent about 30% of asparagus genome. Overall, TEs masked about 53% of the A. officinalis assembly. Majority of the identified TEs belonged to LTR retrotransposons, which constitute about 28% of genomic DNA, with Ty1/copia elements being more diverse and accumulated to higher copy numbers than Ty3/gypsy. Compared with LTR retrotransposons, non-LTR retrotransposons and DNA transposons were relatively rare. In addition, comparison of the abundance of the TE groups between male and female genomes showed that the overall TE composition was highly similar, with only slight differences in the abundance of several TE groups, which is consistent with the relatively recent origin of asparagus sex chromosomes. This study greatly improves our knowledge of the repetitive sequence construction of asparagus, which facilitates the identification of TEs responsible for the early evolution of plant sex chromosomes and is helpful for further studies on this dioecious plant. PMID- 24810433 TI - In vitro and in vivo antileishmania activity of sesquiterpene lactone-rich dichloromethane fraction obtained from Tanacetum parthenium (L.) Schultz-Bip. AB - The discovery of new treatments for neglected diseases, including leishmaniasis, is a substantial challenge for scientific research. Plant extracts have shown potential in the selective treatment of tropical diseases. The present study evaluated the in vitro and in vivo antileishmania effects of a sesquiterpene lactone-rich dichloromethane fraction (DF) obtained from the aerial parts of Tanacetum parthenium (L.) Schultz-Bip. In vitro studies of the DF indicated an IC50 of 2.40+/-0.76 MUg mL(-1) against the promastigote form and 1.76+/-0.25 MUg mL(-1) against the axenic amastigote form of Leishmania amazonensis. In vivo intramuscular treatment with DF decreased the growth and size of footpad lesions in mice. The DF also significantly decreased the parasite population compared with animals that were treated with the reference drug. Plasma malondialdehyde levels were increased slightly by the DF, attributable to its parthenolide-rich composition that causes cellular apoptosis, compared with the control group, demonstrating treatment efficacy without toxicity or genotoxicity. Because the isolation and purification of plant compounds are costly and time-consuming and generate low yields, extract fractions, such as the DF studied herein, represent a promising alternative for the treatment of leishmaniasis. PMID- 24810434 TI - Vapor-deposited amorphous metamaterials as visible near-perfect absorbers with random non-prefabricated metal nanoparticles. AB - Spatial order or periodicity is usually required and constructed with tens of nanometers in the feature size, which makes it difficult to process the near perfect metamaterial absorbers (PMAs) working in the visible range in large-area and mass-production scale. Although many established technologies and theoretical modeling methods used for order-based metamaterials, aperiodic or disordered structures have been gradually recognized to achieve similar functionalities for which the ordered structures are overwhelmingly used. Here, we demonstrated the vapor-deposited 'amorphous' metamaterials as controlled-reflectance surfaces and tunable PMAs without the use of the lithographically ordered arrays, the prefabricated colloidal metal nanoparticles (MNPs) or the multilayer of nanoparticles. The flexible construction, the control of the monolayer of MNPs and the atomic-layer-deposited (ALD) dielectric spacer layer provide more insight for understanding the controlled-reflectance surfaces. Such processes have a few key advantages of CMOS-compatible simple processing, low cost and large-area plating, allowing the PMAs to be flexibly constructed in mass-production scale. PMID- 24810435 TI - Biodegradation of Methyl Orange by alginate-immobilized Aeromonas sp. in a packed bed reactor: external mass transfer modeling. AB - Azo dyes are recalcitrant and xenobiotic nature makes these compounds a challenging task for continuous biodegradation up to satisfactorily levels in large-scale. In the present report, the biodegradation efficiency of alginate immobilized indigenous Aeromonas sp. MNK1 on Methyl Orange (MO) in a packed bed reactor was explored. The experimental results were used to determine the external mass transfer model. Complete MO degradation and COD removal were observed at 0.20 cm bead size and 120 ml/h flow rate at 300 mg/l of initial dye concentration. The degradation of MO decreased with increasing bead sizes and flow rates, which may be attributed to the decrease in surface of the beads and higher flux of MO, respectively. The experimental rate constants (k ps) for various beads sizes and flow rates were calculated and compared with theoretically obtained rate constants using external film diffusion models. From the experimental data, the external mass transfer effect was correlated with a model J D = K Re (-(1 - n)). The model was tested with K value (5.7) and the Colburn factor correlation model for 0.20, 0.40 and 0.60 bead sizes were J D = 5.7 Re (-0.15), J D = 5.7 Re (-0.36) and J D = 5.7 Re (-0.48), respectively. Based on the results, the Colburn factor correlation models were found to predict the experimental data accurately. The proposed model was constructive to design and direct industrial applications in packed bed reactors within acceptable limits. PMID- 24810436 TI - Adenomatoid odontogenic tumour in a 20-year-old woman. AB - Adenomatoid odontogenic tumour is a relatively rare and distinct odontogenic tumour that is exclusively odontogenic epithelium in origin. It comprises 3% of all odontogenic tumours. This report describes the surgical therapy, clinical course and morphological characteristics of an adenomatoid odontogenic tumour that developed in the left maxilla of a 20-year-old patient. PMID- 24810437 TI - Isolated suppurative submandibular sialadenitis in a preterm neonate. AB - Neonatal isolated suppurative submandibular sialadenitis (NISSS) is rare, with only 21 cases described in the English literature. All cases, with the exception of one, were caused by Staphylococcus aureus. In this case report, we describe a preterm neonate with NISSS due to infection by S aureus and Klebsiella pneumonia presenting on day 11 of life with submandibular swelling and low-grade fever. Possible contributors for the development of the infection include prematurity, neutropenia, prolonged orogastric feed and bacterial virulence. Antibiotic treatment was effective. To the best of our knowledge, this is the first case report of NISSS caused by a mixed flora. PMID- 24810438 TI - Paratesticular fibrous pseudotumour. AB - A 38-year-old man presented with a 2-year history of an enlarging scrotal nodule. Scrotal ultrasound revealed two soft tissue masses separate from the testicle in the right scrotum measuring 1.7 and 0.8 cm. The patient underwent excision of the scrotal nodules, revealing firm, white tissue with a smooth, nodular surface. On histology, the lesions appeared fibrous with scattered capillaries and areas of inflammatory infiltrate consistent with paratesticular fibrous pseudotumour. On a follow-up ultrasound at 6 months, he had no evidence of recurrence. PMID- 24810439 TI - Lumbar hernia: a diagnostic dilemma. AB - Lumbar hernia is one of the rare cases that most surgeons are not exposed to. Hence the diagnosis can be easily missed. This leads to delay in the treatment causing increased morbidity. We report a case of lumbar hernia in a middle-aged woman. It was misdiagnosed as lipoma by another surgeon. It was a case of primary acquired lumbar hernia in the superior lumbar triangle. Clinical and MRI findings were correlated to reach the diagnosis. We also highlight the types, the process of diagnosis and the surgical repair of lumbar hernias. We wish to alert our fellow surgeons to keep the differential diagnosis of the lumbar hernia in mind before diagnosing any lumbar swelling as lipoma. PMID- 24810440 TI - Orbital trauma and its impact on the heart. AB - We present the case of a 16-year-old boy, who was hit in the right orbital region during a soccer match. Immediately after the blow, the patient felt nauseous and fell to the ground. The otherwise healthy patient presented with headache, nausea and sinus bradycardia (38 bpm). Clinically there were no obvious signs of fracture of facial bones. There was no sign of injury to the eyes, only the right globe was slightly restricted in movement. With suspicion of head injury, a CT scan was performed revealing a trapdoor fracture of the medial orbital wall. The medial rectus muscle was entrapped within the fracture inducing the oculocardiac reflex. The trapped rectus muscle was released endoscopically on the same day and the heart rate normalised. Early surgical intervention is recommended to avoid prolonged muscle ischaemia and to shorten the vagal symptoms. PMID- 24810441 TI - Breast carcinoma in a prepubertal girl. AB - Breast carcinoma is a very rare disease in children. We present a rare case of breast cancer in an 11-year-old prepubertal girl. Clinically, it was a case of locally advanced breast cancer (T4bN1M0). The core biopsy report showed adenocarcinoma of the not otherwise specified (NOS) variety (oestrogen receptor negative, progesterone receptor-negative and human epidermal growth factor receptor 2-negative). Diagnosis was late in this case due to lack of suspicion. A modified radical mastectomy was considered to be adequate treatment. Histologically, it was adenocarcinoma NOS, which is rare in young girls (the secretory type being more common). Incidence, differential diagnoses, investigation and management of breast carcinoma in young girls are discussed. The purpose of reporting this case is to highlight that prevention and early detection of breast carcinoma in children is very important. PMID- 24810442 TI - Delayed torrential haemorrhage after firearm injury. AB - A 30-year-old man was referred to us after 48 days of gunshot injury to left groin, with torrential bleeding from a pseudoaneurysm of the left external iliac artery. He was successfully managed with a team of specialists involving trauma surgeon, vascular and plastic surgeon, general surgeons and intervention radiologist with the help of critical care specialists. He required judicious debridement, a transverse rectus abdominis musculocutaneous flap, stenting of the external iliac artery, repair of the external iliac vein and ligation of the bilateral internal iliac artery. He had prolonged intensive care unit stay with open abdomen requiring specialised care. Errors in regular assessment of patient by clinical and radiological examination along with failure in early adequate debridement were responsible for trauma suffered by him. Though it is a rare injury, these devastating complications can occur after any gunshot injury and proper management guidelines must be established. PMID- 24810443 TI - Reversal of TTTS after fetoscopic laser photocoagulation for communicating vessels. AB - We report a case of reversal of twin-to-twin transfusion syndrome (Stage IV TTTS) at 24 weeks of gestation after fetoscopic laser photocoagulation (FLP) for communicating vessels. The pathology of reversal of TTTS found that the 'initial' donor developed polyhydramnios whereas the 'initial' recipient developed oligohydramnios. With careful follow-up, the hydrops fetalis of the 'initial' recipient improved at 31 weeks of gestation. Because of the onset of labour pain at 34 weeks of gestation, two live and healthy babies were delivered by emergency caesarean section. PMID- 24810444 TI - Concurrent meningococcal and herpes simplex infection in a non-immunocompromised child. AB - A previously well 11-month-old infant presented with lethargy, a blanching rash, vomiting and diarrhoea. She was diagnosed with suspected gastroenteritis and discharged. The patient deteriorated and re-presented 24 h later with lumbar puncture (LP) confirming Neisseria meningitidis. Following an initial good response to ceftriaxone, the patient then developed a blistering facial rash on day 3 for which topical aciclovir was started with no improvement. She subsequently developed fever and redeveloped a rising C reactive protein (CRP). A CT of the head on day 6 was normal, however a repeat LP on day 7 showed persistently raised cerebrospinal fluid (CSF), white cell count (WCC), high proteins and low CSF glucose. A CSF viral PCR confirmed concurrent herpes simplex virus (HSV) type 1 for which parenteral aciclovir was started. The patient responded well to bacterial and viral anti-infective treatments and was subsequently discharged on day 16 with no neurological sequelae. PMID- 24810445 TI - Symptomatic hepatitis secondary to disseminated coccidioidomycosis in an immunocompetent patient. AB - A young man from California presented with acute onset of cough, fevers, night sweats and pruritus with dark urine. Laboratory studies were notable for moderate transaminitis with elevated bilirubin and eosinophilia. Hepatitis panel, HIV screen and heterophile antibodies were negative. CT scan showed multiple bilateral focal opacities with hilar and mediastinal lymphadenopathy with no ductal dilation or gallbladder stones. The patient had positive coccidioidomycosis serologies and he was started on fluconazole with resolution of symptoms and improvement in transaminitis over the next month. This article highlights a rare manifestation of disseminated coccidioidomycosis with symptomatic hepatitis. Although an increasingly prevalent infection found in southwest USA, dissemination is rare in immunocompetent hosts. Postmortem studies suggest hepatic involvement is common in disseminated infection. However symptomatic hepatitis is rare, with only three cases of symptomatic hepatitis found in the literature. PMID- 24810446 TI - Encephalopathy in an infant with infantile spasms: possible role of valproate toxicity. AB - An infant presented with global developmental delay and infantile spasms. EEG was suggestive of hypsarrhythmia. She was started on sodium valproate, clonazepam and adrenocorticotropic hormone injection. After an initial improvement the child developed vomiting, altered sensorium and increase in frequency of seizures suggestive of encephalopathy. Valproate-induced hyperammonaemia or hepatic encephalopathy was considered and the drug was withheld following which there was a dramatic improvement. Paradoxically, the liver function tests and serum ammonia were normal. However, a complete reversal of encephalopathy, on withdrawal of the drug, strongly suggested an adverse drug reaction (ADR) due to valproic acid. Marginal elevation of serum valproic acid prompted us to use the Naranjo ADR probability score to confirm the diagnosis. This case highlights the fact that valproate toxicity can manifest with normal liver function and serum ammonia levels. This is the youngest reported case with this rare form of valproate induced encephalopathy. PMID- 24810447 TI - Juvenile xanthogranuloma presenting as a large neck mass and ocular complications: a diagnostic and therapeutic dilemma. AB - Juvenile xanthogranuloma is a non-Langerhans cell histiocytosis that originates from dendritic cells. Dendritic cells can accumulate in the skin of the head, neck, trunk, arms and legs. They may also involve other tissues such as the bones, lung, liver, heart, bone marrow, central nervous system, spleen and large intestine in rare cases. We report a rare case of juvenile xanthogranuloma in a 16-year-old girl who presented with a neck mass and left-sided ptosis 2.5 months previously. Excisional biopsy of the neck lesion revealed proliferated histiocytes admixed with numerous eosinophils and multinucleated giant cells that simulate eosinophilic granuloma; however, the histiocytes were negative for CD1a, CD123 and S-100 protein and positive for CD68 and CD14. The course of the disease led to treatment of the patient with chemotherapy, followed by low-dose radiotherapy. PMID- 24810448 TI - Ventricular tachycardia with regular capture beats. PMID- 24810449 TI - Mucosal and cutaneous lesions in mandibular zoster. PMID- 24810450 TI - Two iniencephaly cases born the same day in the same hospital of Cali, Colombia. Iniencephaly cluster? AB - Two patients with short and hyperextended neck, cervical meningocele and other birth defects, were born the same day at the same hospital, both died. The autopsy report and X-rays show iniencephaly's classic findings. Revision of clinical histories did not show consanguinity between the parents, or exposure to environmental factors. PMID- 24810451 TI - Dasatinib-induced pulmonary hypertension in chronic myelogenous leukaemia. PMID- 24810452 TI - Extensive subdural spinal enhancement mimicking leptomeningeal disease in a young child with posterior fossa tumour following lumbar puncture and surgery. PMID- 24810453 TI - Echinococcus multilocularis infection of the liver presenting as abdominal wall fistula. AB - Echinococcus multilocularis causes infection where the most commonly affected organ is the liver, followed by the lung, kidney, bone and the brain. Other sites such as the heart, spleen, pancreas and soft tissues are very rarely affected. Surgical treatment combined with chemotherapy using various technical approaches remains the main therapeutic modality for echinococcal liver disease. To the best of our knowledge there are less than five clinical cases of cutaneous presentation of liver alveolar echinococcosis described. We present a unique case of liver echinococcosis presenting as recurrent abdominal wall fistula and abscess in a 29-year-old man. Diagnosis was based on CT imaging, serological analysis and histological findings from the fistula. Medical treatment with albendazole was initiated and liver resection was performed. The patient has no symptoms and signs of recurrence 1 year after operation, while still on albendazole therapy. This case description highlights the importance of early suspicion and treatment of unusual echinococcosis clinical presentations. PMID- 24810454 TI - Anti-M antibodies as a cause of intrauterine fetal death and neonatal hyperbilirubinaemia. AB - A preterm male infant (35 weeks), appropriate for gestational age with birth weight of 2.20 kg was born to a 28-year G2 P0 mother. The mother's blood group was A positive and the father's was B positive. Her first pregnancy was an intrauterine fetal death due to immune hydrops. The mother's blood was positive for indirect Coomb's test with 1:32 dilution and anti-M antibodies. This pregnancy was induced at 35 weeks of gestation. Investigations from the cord blood revealed A positive blood group, positive direct Coomb's test, haematocrit of 41.4%, cord reticulocyte count of 5.3% and total serum bilirubin (TSB) of 2.7 mg/dL. Phototherapy was started at 27 h of life for visible jaundice. In view of progressive pallor and a sudden rise of bilirubin, the infant was subjected to exchange transfusion on day 5 of life. The transfusion was given with O negative and anti-M antibodies negative donor blood. Total serum bilirubin (TSB) prior to exchange transfusion was 28 mg/dL and packed cell volume (PCV) was 21%. Phototherapy was continued for a total duration of 8 days. PMID- 24810455 TI - Giant spinal exostosis. PMID- 24810456 TI - Tuberculosis of the patella imitating chronic knee synovitis. AB - Tuberculosis of patella is a rare occurrence with incidence of less than 0.15% in the literature. Owing to its rarity the diagnosis is usually missed. Here we present a case of tuberculosis of the patella, being treated as chronic synovitis elsewhere. An 11-year-old boy presented to us with chronic knee swelling and a draining sinus of 5 months duration. He was being treated with broad spectrum antibiotics and incision and drainage. Standard X-rays revealed a lytic area with surrounding coke such as sequestrum in patella. MRI was suggestive of osteomyelitis of the patella with soft tissue oedema. Diagnosis was confirmed on biopsy. The patient was managed by curettage and excision of the sinus tract along with antitubercular treatment. The patient responded well to antitubercular therapy and gained excellent functional range of movement. In today's era of potent antituberculous drugs and decreasing tuberculosis incidence the rare and unusual locations of tuberculosis such as patella should be borne in mind while dealing with chronic lesions of the knee especially in tubercular endemic areas. A timely diagnosis helps in regaining good range of motion and a satisfactory outcome. PMID- 24810457 TI - Xanthoma of the urinary bladder: a rare benign condition which may be mistaken for malignancy. AB - A 77-year-old man was referred with a history of recurrent urinary tract infections and a raised prostate-specific antigen. He was found to have an atypical lesion of the urinary bladder on cystoscopic examination. A preoperative MRI study suggested no evidence of malignancy and histology was consistent with urinary bladder xanthoma. This is a benign and exceedingly rare condition which requires no further treatment or follow-up. Patients should, however, have a lipid profile measured. Our case illustrates the use of MRI as an adjunct to aid operative planning. Although not essential, it may help to avoid an over aggressive initial resection in more precarious areas of the urinary bladder. PMID- 24810458 TI - Acute disseminated encephalomyelitis presenting as optic neuritis in a case of idiopathic thrombocytopaenic purpura. PMID- 24810459 TI - Gastric autonomic nerve tumour: a rare gastric tumour. PMID- 24810460 TI - Hydrostatic pressure effect on micro air bubbles deposited on surfaces with a retreating tip. AB - The effect of hydrostatic pressure on 6 MUL air bubbles formed on micropillar structured PDMS and silicone surfaces using a 2 mm diameter stainless steel tip retreated at 1 mm/s was investigated. Dimensional analysis of the tip retraction process showed the experiments to be conducted in the condition where fluid inertial forces are comparable in magnitude with surface tension forces, while viscous forces were lower. Larger bubbles could be left behind on the structured PDMS surface. For hydrostatic pressures in excess of 20 mm H2O (196 Pa), the volume of bubble deposited was found to decrease progressively with pressure increase. The differences in width of the deposited bubbles (in contact with the substrate) were significant at any particular pressure but marginal in height. The attainable height before rupture reduced with pressure increase, thereby accounting for the reducing dispensed volume characteristic. On structured PDMS, the gaseous bridge width (in contact with the substrate) was invariant with tip retraction, while on silicone it was initially reducing before becoming invariant in the lead up to rupture. With silicone, hence, reductions in the contact width and height were both responsible for reduced volumes with pressure increase. Increased hydrostatic pressure was also found to restrict the growth in contact width on silicone during the stage when air was injected in through the tip. The ability to effect bubble size in such a simple manner may already be harnessed in nature and suggests possibilities in technological applications. PMID- 24810461 TI - Thermal gating in lipid membranes using thermoresponsive cyclic peptide-polymer conjugates. AB - The partition and self-assembly of a new generation of cyclic peptide-polymer conjugates into well-defined phospholipid trans-bilayer channels is presented. By varying the structural parameters of the cyclic peptide-polymer conjugates through the ligation of hydrophobic and hydrophilic polymers, both the structure of the artificial channels using large unilamellar vesicle assays and the structural parameters required for phospholipid bilayer partitioning are elucidated. In addition, temperature was used as an external stimulus for the modulation of transbilayer channel formation without requiring the redesign and synthesis of the cyclic peptide core. The thermoresponsive character of the cyclic peptide-polymer conjugates lays the foundation for on-demand control over phospholipid transmembrane transport, which could lead to viable alternatives to current transport systems that traditionally rely on endocytic pathways. PMID- 24810462 TI - Modeling proton-induced damage on 2-deoxy-D-ribose. Conformational analysis. AB - Modeling proton-induced damage in biological systems, in particular in DNA building blocks, is of major concern in studies on cancer proton therapy. This is indeed an extremely complex process and analysis of the mechanism at the molecular level is of crucial interest. Such collision reactions of protons on biological targets induce different reactions: excitation and ionization of the biomolecule, fragmentation of the ionized species, and charge transfer from the projectile ion toward the biomolecular target. In order to have an insight into such mechanisms, we have performed a theoretical approach of two of the most important steps, the fragmentation and the charge transfer processes. For that purpose, we have considered collision of protons with isolated 2-deoxy-D-ribose by means of ab-initio molecular dynamics and quantum chemistry molecular methods. The conformation of the sugar moiety has been analyzed and appears to induce important effects, in particular different fragmentation patterns have been pointed out with regard to the conformation, and significant variations of the charge transfer cross sections have been exhibited. PMID- 24810463 TI - Probing the global and local dynamics of aminoacyl-tRNA synthetases using all atom and coarse-grained simulations. AB - Coarse-grained simulations have emerged as invaluable tools for studying conformational changes in biomolecules. To evaluate the effectiveness of computationally inexpensive coarse-grained models in studying global and local dynamics of large protein systems like aminoacyl-tRNA synthetases, we have performed coarse-grained normal mode analysis, as well as principle component analysis on trajectories of all-atom and coarse-grained molecular dynamics simulations for three aminoacyl-tRNA synthetases--Escherichia coli methionyl-tRNA synthetase, Thermus thermophilus leucyl-tRNA synthetase, and Enterococcus faecium prolyl-tRNA synthetase. In the present study, comparison of predicted dynamics based on B-factor and overlap calculations revealed that coarse-grained methods are comparable to the all-atom simulations in depicting the intrinsic global dynamics of the three enzymes. However, the principal component analyses of the motions obtained from the all-atom molecular dynamics simulations provide a superior description of the local fluctuations of these enzymes. In particular, the all-atom model was able to capture the functionally relevant substrate induced dynamical changes in prolyl-tRNA synthetase. The alteration in the coupled dynamics between the catalytically important proline-binding loop and its neighboring structural elements due to substrate binding has been characterized and reported for the first time. Taken together, the study portrays comparable and contrasting situations in studying the functional dynamics of large multi domain aminoacyl-tRNA synthetases using coarse-grained and all-atom simulation methods. PMID- 24810464 TI - Theoretical mechanistic study of the formic acid decomposition assisted by a Ru(II)-phosphine catalyst. AB - A density functional theory (DFT) study of formic acid decomposition, catalyzed by a model of the trans-[Ru(TPPTS)2(H2O)4]2+ complex, has been performed. A mechanism comprising two competitive catalytic cycles, which have as a common intermediate a monohydride ruthenium complex, has been hypothesized in literature on the basis of high pressure NMR experiments. To explain the observed increase in H2 production rate during the process, it has been suggested by the same authors that the reaction occurs entering the second proposed cycle (Cycle 2), although none of the complexes assumed to be formed have been experimentally observed. To gain more insights into the reaction mechanism, a detailed investigation of both the proposed catalytic cycles has been carried out. To describe the energy profiles, different accurate computational protocols have been employed. Our computations reveal that molecular hydrogen cannot be produced more rapidly following cycle 2, since it requires a larger amount of energy to occur. Moreover, the release of molecular hydrogen has been found to be the step that limits the reaction rate in both cycles, instead of the CO2 dissociation as hypothesized by the authors. PMID- 24810465 TI - Sperm proteomics: fertility diagnostic testing beyond the semen analysis? PMID- 24810467 TI - Synthesis of beta-C-galactosyl ceramide and its new aza variant via the Horner Wadsworth-Emmons reaction. AB - A simple strategy for the synthesis of beta-C-galactosyl ceramide and its new aza variant analogue is described using the Horner-Wadsworth-Emmons reaction as the key step in combining the sugar and aglycone portions. PMID- 24810466 TI - Berberine exposure triggers developmental effects on planarian regeneration. AB - The mechanisms of action underlying the pharmacological properties of the natural alkaloid berberine still need investigation. Planarian regeneration is instrumental in deciphering developmental responses following drug exposure. Here we report the effects of berberine on regeneration in the planarian Dugesia japonica. Our findings demonstrate that this compound perturbs the regenerative pattern. By real-time PCR screening for the effects of berberine exposure on gene expression, we identified alterations in the transcriptional profile of genes representative of different tissues, as well as of genes involved in extracellular matrix (ECM) remodeling. Although berberine does not influence cell proliferation/apoptosis, our experiments prove that this compound causes abnormal regeneration of the planarian visual system. Potential berberine-induced cytotoxic effects were noticed in the intestine. Although we were unable to detect abnormalities in other structures, our findings, sustained by RNAi-based investigations, support the possibility that berberine effects are critically linked to anomalous ECM remodeling in treated planarians. PMID- 24810468 TI - First trimester screening can predict adverse pregnancy outcomes. AB - There has been an increasing drive over the last two decades to push the detection of women at risk of adverse pregnancy outcomes into the first trimester. This has led to a plethora of techniques, risk assessments and biomarkers, both fascinating and bewildering in its breadth. Despite the vast amount of knowledge available, it is often difficult to determine what is practicable and valuable for clinical practice. This is especially true as earlier diagnosis does not necessarily equate to improved outcomes for mother and child. We suggest that, at least for preeclampsia, fetal growth restriction, spontaneous preterm birth and gestational diabetes, there are effective first trimester tests available to identify the women at risk of subsequently developing complications. Unfortunately, there are no currently reliable first trimester tests available for identifying women at risk of stillbirth. It is likely that this field will continue to develop over time, and we hope that new and better strategies will continue to emerge to target these clinically important pathologies. PMID- 24810469 TI - Evaluation of the toxicological safety of erinacine A-enriched Hericium erinaceus in a 28-day oral feeding study in Sprague-Dawley rats. AB - Natural products have attained great importance as they are believed to be the new alternative medicines for conventional therapy. As numerous studies have proved the tremendous medicinal values of Hericium erinaceus, it is necessary to take into account its safety as well as its risk for the recipient. However, mushroom mycelium has an identity distinct from mushrooms, as two specific classes of compounds, hericenones and erinacines, can only be extracted from both the fruit body and the cultured mycelium, respectively. Therefore, this is the first report on the evaluation of the toxicity of H.erinaceus mycelium, enriched with 5mg/g erinacine A, by a 28-day repeated oral administration study in Sprague Dawley rats. Three doses of 1 (Low), 2 (Mid) and 3 (High) g/kg body weight/day were selected for the study while distilled water served as control. All animals survived to the end of the study. No abnormal changes were observed in clinical signs. No adverse or test article-related differences were found in urinalysis, haematology and serum biochemistry parameters, between the treatment and control groups. No gross pathological findings and histopathological differences were seen. Therefore, the no-observed-adverse-effect level of erinacine A-enriched H.erinaceus is greater than 3g/kgbody weight/day. PMID- 24810470 TI - The role of urinary aldosterone for the diagnosis of primary aldosteronism. AB - When diagnosing primary aldosteronism, the measurement of urinary aldosterone after oral sodium loading is one of the currently recommended confirmatory tests. The aim of the study was to assess the repeatability and interpretation of urinary aldosterone in patients examined for suspected primary aldosteronism. Sixty-four hypertensive patients with suspected primary aldosteronism were prospectively enrolled and examined according to the study protocol. After antihypertensive medications interfering with renin-angiotensin-aldosterone system were withdrawn for at least 2 weeks, the confirmatory testing was performed: oral sodium loading preceded the collection of 24-h urine sample and subsequent saline infusion test. The identical procedures were repeated after 2 weeks. The concordant results of both saline infusion tests served for confirmation/exclusion of primary aldosteronism. Forty-nine patients were included in data analysis. Primary aldosteronism was excluded in 16, and confirmed in 33 individuals. The repeatability of urinary aldosterone was evaluated in 44 patients: the difference of urinary aldosterone levels ranged between 1 and 88% (median 31%). Ninety-three urine samples from 49 patients were used to validate the interpretation of urinary aldosterone in respect to the diagnosis of primary aldosteronism made by saline infusion testing; 96% sensitivity was characterized by urinary aldosterone >=19 nmol/day, and 96% specificity was associated with urinary aldosterone >=92 nmol/day. In 22 (45%) patients, urinary aldosterone remained in the "gray" zone between 19 and 92 nmol/day in all provided samples. The estimation of urinary aldosterone excretion after oral sodium loading is associated with marked intraindividual variability, and significant number of inconclusive results. PMID- 24810471 TI - Osteoprotegerin is secreted into the coronary circulation: a possible association with the renin-angiotensin system and cardiac hypertrophy. AB - The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67+/-10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7+/-4.1 vs. 6.7+/-3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (>=116 for males, or >= 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system. PMID- 24810472 TI - Insulin polymers in the plasma of obese subjects are associated with elevated levels of carbonyl groups and are decreased by (-)-epicatechin. AB - We investigated whether oxidative damage and insulin polymerization at a systemic level are associated with the insulin resistance (IR) observed in obese subjects. We evaluated 3 groups (n=16/each) divided according to body mass index (BMI): Normal weight (NW) with a BMI of 18.5-24.9, obese 1 (O1) 30-34.9, and obese 3 (O3)>40 kg/m(2). IR and oxidative damage status of the groups were established by HOMA value and the analysis of biomarkers of oxidative stress in plasma. Insulin polymers in systemic circulation were detected using an antibody specific coupled to magnetic beads, which were incubated in plasma from the study groups. Analysis of magnetic beads by electrophoresis on polyacrylamide gel and silver stain assessed the presence of insulin polymers. The inhibition of polymers formation was studied by the presence of (-)-epicatechin. We demonstrated that O1 and O3 subjects with IR showed higher oxidative damage to their plasma lipids and proteins than NW subjects. This oxidative damage was associated with the presence of insulin polymers in the plasma of the O1 and O3 subjects. This polymer showed a high concentration of carbonyl groups by Western blot, suggesting the participation of oxidative damage in the generation of the polymer. The antioxidant (-)-epicatechin decreased the formation of the insulin polymer, indicating that the prevention of oxidative damage can inhibit insulin polymerization. Our study revealed an association between the presence of carbonyl stress, IR, and insulin polymer formation in obese subjects. This study also demonstrates that the antioxidant (-)-epicatechin inhibits insulin polymerization. PMID- 24810473 TI - Gene expression of androgen metabolising enzymes in benign and malignant prostatic tissues. AB - Benign prostatic hyperplasia (BPH) as well as prostate cancer (CaP) are prevalent in the aging male population, and both the diseases display androgen-dependence when the circulating testosterone from the gonads decreases. This suggests that the local or intracrine production of androgens may drive these diseases. Both diseases are dependent on the conversion of androgen by the epithelial compartment to the ligand with higher affinity and can be treated by blocking synthesis of this androgen metabolite. For this approach to be effective, a detailed knowledge of androgen biosynthesis in both disease states is required. The aim of the present study was to investigate the gene expression levels of androgen metabolising enzymes in BPH compared to normal adjacent prostate tissues and CaP. Expression of the genes HSD3B1, HSD17B3, and SRD5A2 was significantly increased in BPH tissues compared to normal adjacent prostate tissues. In contrast to BPH, CaP demonstrated significant decrease in the expression of HSD17B3, AKR1C2, and SRD5A2 compared to normal adjacent prostate tissues. HSD17B2 expression was significantly decreased in all samples. Moreover, HSD3B1 and SRD5A2 mRNA levels were upregulated in BPH compared with CaP. These results suggest that a change in androgen metabolism may be an important step in the pathogenesis of BPH, leading to increased cell proliferation due to in situ androgen synthesis. These features can be used to develop differential treatment strategies for BPH. HSD3B1 and SRD5A2 could be used as therapeutic target for BPH. PMID- 24810474 TI - ATRX mRNA expression combined with IDH1/2 mutational status and Ki-67 expression refines the molecular classification of astrocytic tumors: evidence from the whole transcriptome sequencing of 169 samples samples. AB - Astrocytic tumors are the most common primary brain tumors in adults. ATRX mutations have been identified in gliomas and are correlated with its loss of expression, which causes alternative lengthening of telomeres (ALT) leading to genomic instability. In this study, we aimed to explore the role of ATRX mRNA expression alteration in the progression and subclassification of astrocytic tumors and examine its impact on clinical outcome. We investigated ATRX mRNA expression and its association with IDH1 and IDH2 mutations in 169 adult astrocytic tumors using whole transcriptome sequencing. In our cohort, low ATRX mRNA expression was detected in 68% of astrocytomas, 50% of anaplastic astrocytomas and 41.6% of glioblastomas. Low ATRX expression closely overlapped with mutations in IDH1/2 (P<0.0001) in astrocytic tumors across WHO grades II-IV. Significant association between low ATRX expression and longer overall survival was identified in our cohort (P<0.01). ATRX combined with IDH1/2 and Ki-67 was used to re-classify patients with astrocytic tumors: group A1 containing IDH1/2 mutations and low ATRX expression predicted a better prognostic outcome, whereas group A3 carrying wild-type IDH1/2 and high Ki-67 expression had the shortest overall survival; IDH-mutant tumors with low ATRX expression and IDH-wild-type tumors with high Ki-67 expression were grouped into group A2. In summary, our results showed that ATRX in cooperation with IDH1/2 and Ki-67 defines three subgroups of astrocytic tumors regardless of the conventional WHO grades consensus. The molecular stratification in astrocytic tumors may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation. PMID- 24810475 TI - Assessment and improvement of Indian-origin rhesus macaque and Mauritian-origin cynomolgus macaque genome annotations using deep transcriptome sequencing data. AB - BACKGROUND: The genome annotations of rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques, two of the most common non-human primate animal models, are limited. METHODS: We analyzed large-scale macaque RNA-based next generation sequencing (RNAseq) data to identify un-annotated macaque transcripts. RESULTS: For both macaque species, we uncovered thousands of novel isoforms for annotated genes and thousands of un-annotated intergenic transcripts enriched with non-coding RNAs. We also identified thousands of transcript sequences which are partially or completely 'missing' from current macaque genome assemblies. We showed that many newly identified transcripts were differentially expressed during SIV infection of rhesus macaques or during Ebola virus infection of cynomolgus macaques. CONCLUSIONS: For two important macaque species, we uncovered thousands of novel isoforms and un-annotated intergenic transcripts including coding and non-coding RNAs, polyadenylated and non-polyadenylated transcripts. This resource will greatly improve future macaque studies, as demonstrated by their applications in infectious disease studies. PMID- 24810476 TI - Impact of 60 days of 6 degrees head down bed rest on cardiopulmonary function, and the effects of Taikong Yangxin Prescription as a countermeasure. AB - OBJECTIVE: To study the changes in cardiopulmonary function induced by mid/long term simulated microgravity with 6 degrees head down bed rest (HDBR), and the effects of Taikong Yangxin Prescription (, TYP) as a countermeasure. METHODS: Fourteen healthy male volunteers were randomly divided into a control group and a Chinese medicine (CM) group (7 in each group) by a random digital table based on their body weight. Both groups underwent 6 degrees HDBR for 60 days. Subjects in the CM group received daily TYP pills and subjects in the control group received daily placebo pills. Cardiac systolic and pumping functions were measured by echocardiography before HDBR; on days 20, 42, and 57 of HDBR; and on day 3 of recovery after HDBR (R+3). Cardiopulmonary functional reserve and exercise capacity were evaluated before HDBR, on day 29, and on day R+3 by exercise testing. RESULTS: The heart rate (HR) increased gradually during HDBR. The HR was significantly higher on day 57 than before HDBR in the control group (P<0.05), but did not increase significantly in the CM group. The stroke volume/stroke volume index, ejection fraction, and left ventricular fractional shortening tended to decrease over time in the control group, but not in the CM group. These parameters were significantly higher in the CM group than in the control group on day 42 (P<0.05 or <0.01). Exercise testing showed that maximum O2 consumption (VO2max), metabolic equivalents, relative O2 consumption (VO2), O2 pulse, and exercise duration were significantly lower on day 29 than before HDBR in the control group, but not in the CM group. CONCLUSIONS: Sixty days of 6 degrees HDBR induced a reduction in cardiac systolic and pumping functions, and reduced cardiopulmonary functional reserve and exercise capacity. Administration of TYP significantly improved cardiac systolic and pumping functions, and maintained cardiopulmonary functional reserve and exercise capacity. PMID- 24810477 TI - U-251 revisited: genetic drift and phenotypic consequences of long-term cultures of glioblastoma cells. AB - It is well known that in vitro subculture represents a selection pressure on cell lines, and over time this may result in a genetic drift in the cancer cells. In addition, long-term cultures harbor the risk of cross-contamination with other cell lines. The consequences may have major impact on experimental results obtained in various laboratories, where the cell lines no longer reflect the original tumors that they are supposed to represent. Much neglected in the scientific community is a close monitoring of cell cultures by regular phenotypic and genetic characterization. In this report, we present a thorough characterization of the commonly used glioblastoma (GBM) model U-251, which in numerous publications has been wrongly identified as U-373, due to an earlier cross-contamination. In this work, the original U-251 and three subclones of U 251, commonly referred to as U-251 or U-373, were analyzed with regard to their DNA profile, morphology, phenotypic expression, and growth pattern. By array comparative genomic hybridization (aCGH), we show that only the original low passaged U-251 cells, established in the 1960s, maintain a DNA copy number resembling a typical GBM profile, whereas all long-term subclones lost the typical GBM profile. Also the long-term passaged subclones displayed variations in phenotypic marker expression and showed an increased growth rate in vitro and a more aggressive growth in vivo. Taken together, the variations in genotype and phenotype as well as differences in growth characteristics may explain different results reported in various laboratories related to the U-251 cell line. PMID- 24810478 TI - The estimation of the rates of lead exchange between body compartments of smelter employees. AB - The overwhelming proportion of the mass of lead (Pb) is stored in bone and the residence time of Pb in bone is much longer than that in other tissues. Hence, in a metabolic model that we used to solve the differential equations governing the transfer of lead between body compartments, three main compartments are involved: blood (as a transfer compartment), cortical bone (tibia), and trabecular bone (calcaneus). There is a bidirectional connection between blood and the other two compartments. A grid search chi-squared minimization method was used to estimate the initial values of lead transfer rate values from tibia (lambdaTB) and calcaneus (lambdaCB) to blood of 209 smelter employees whose bone lead measurements are available from 1994, 1999, and 2008, and their blood lead level from 1967 onwards (depending on exposure history from once per month to once per year), and then the initial values of kinematic parameters were used to develop multivariate models in order to express lambdaTB and lambdaCB as a function of employment time, age, body lead contents and their interaction. We observed a significant decrease in the transfer rate of lead from bone to blood with increasing body lead contents. The model was tested by calculating the bone lead concentration in 1999 and 2008, and by comparing those values with the measured ones. A good agreement was found between the calculated and measured tibia/calcaneus lead values. Also, we found that the transfer rate of lead from tibia to blood can be expressed solely as a function of cumulative blood lead index. PMID- 24810479 TI - Spoiling and sustainability: technology, water insecurity, and visibility in Arctic Alaska. AB - One third of households in Alaska Native villages lack running water and sewer services. Historically, this public health need drove policies to improve access to treated water and sanitation. However, despite public health being a stated priority of water infrastructure development, current policies require demonstrated economic sustainability in ways that render suffering from water insecurity invisible. In this article, I situate the introduction of water treatment technologies within the history of domination coproduced with vulnerability. These processes are reflected in local narratives describing the relationships between technology, tradition, and suffering. By drawing attention to the role of the state in creating vulnerability, village leaders are trying to historicize and insert their health concerns into the sustainability conversation using narratives that both fit within and challenge the ideology of sustainability. These narratives are thus central to Inupiat struggles for visibility. PMID- 24810480 TI - Clinical features and outcomes of influenza infections in lung transplant recipients: a single-season cohort study. AB - BACKGROUND: For lung transplant recipients (LTRs) influenza infections pose a considerable risk for complications. These infections have mainly been described in hospitalized patients. The aim of this study was to describe characteristics of predominantly outpatient-treated influenza infections. METHODS: We conducted a single-season (2010/2011) retrospective observational study using database information of our cohort. Patients with evidence for respiratory tract infection received empirical oseltamivir and an oral antibiotic, pending results from nasopharyngeal swab analysis. In laboratory-confirmed influenza infection, treatment was continued and serial weekly swabs were performed until virologic results were negative. RESULTS: We identified 22 infections in 21 of 173 patients followed up; influenza A virus was diagnosed in 13 and influenza B virus in 9 infections. Leading presenting symptoms were cough and rhinorrhea. Oseltamivir was given within 48 h of symptom onset in 13 infections and within 72 h in 21 infections. Prolonged viral shedding (PVS) for >= 7 days was detected in 15 infections; median shedding duration for influenza A was 21 days. In univariable analysis, viral load (VL) at diagnosis was associated with extended duration of shedding (P = 0.006). Multivariable analysis confirmed this association. Bronchiolitis obliterans syndrome stage increased in 3 patients at 6-month follow up. CONCLUSION: In this study, PVS of influenza virus was detected in the majority of LTRs and high VL at diagnosis was predictive for prolonged shedding, which occurred despite extended antiviral therapy. PMID- 24810481 TI - Conditions associated with circulating tumor-associated folate receptor 1 protein in healthy men and women. AB - BACKGROUND: Serum concentrations of the tumor-associated folate receptor 1 (FOLR1) protein may be a marker for early cancer detection, yet concentrations have also been detected in cancer-free women. We investigated the conditions associated with circulating FOLR1 protein in healthy individuals and sought to clarify the range of normal serum values. METHODS: Sera of cancer-free men and women (N = 60) enrolled in a population-based cohort study in Alberta, Canada were analyzed for FOLR1 protein using an electrochemical luminescence immunoassay. Dietary, lifestyle, medical and reproductive history information was collected by questionnaires. Differences in serum FOLR1 concentrations between groups were assessed by non-parametric tests, and predictors of serum FOLR1 concentrations were estimated using multivariable linear regression. RESULTS: Median serum FOLR1 concentration was higher in women (491 pg/ml, range = 327-693 pg/ml) than in men (404 pg/ml, range = 340-682 pg/ml), P = 0.001. FOLR1 concentration was also positively associated with vitamin A intake (P = 0.02), and showed positive trends with age and with oral contraceptive hormone use among women and an inverse trend with body mass index. All variables examined explained almost half of the variation in serum FOLR1 (model R2 = 0.44, P = 0.04); however, the retention of gender (P = 0.003) and vitamin A intake (P = 0.03) together explained 20% (P = 0.001) of serum FOLR1 variation. No other predictor was significant at P<0.05. CONCLUSIONS: The positive association between serum FOLR1 concentration and female gender independent of an age effect suggests caution against statements to exploit serum FOLR1 for early cancer detection without further understanding the biological underpinnings of these observations. Serum FOLR1 concentrations may be influenced by the steroid retinoic acid (vitamin A) but do not appear to be associated with folate nutritional status. These findings require confirmation in larger independent studies. PMID- 24810483 TI - Evidence for involvement of spinal RANTES in the antinociceptive effects of triptolide, a diterpene triepoxide, in a rat model of bone cancer pain. AB - It has been shown that triptolide has beneficial effects in the treatment of neuropathic pain, but its effects on bone cancer pain (BCP) remain unclear. In this study, we aimed to explore the potential role of spinal regulated activation of normal T cell expressed and secreted (RANTES) in the antinociceptive effects of triptolide on BCP. A BCP model was induced by injecting Walker 256 mammary gland carcinoma cells into the intramedullary space of rat tibia. Intrathecal administration of triptolide (0.5, 1, 2 MUg) could dose-dependently alleviate mechanical hyperalgesia and spontaneous pain. In addition, there were also concomitant decreases in RANTES mRNA and protein expression levels in spinal dorsal horn. These results suggest that the antinociceptive effects of triptolide are related with inhibition of spinal RANTES expression in BCP rats. The findings of this study may provide a promising drug for the treatment of BCP. PMID- 24810484 TI - Longitudinal study of growth of children with unilateral cleft lip and palate: 2 to 10 years of age. AB - Objective : To study the growth of children with complete unilateral cleft lip and palate (UCLP) from 2 to 10 years of age and to assess whether growth varied from that of children without UCLP (typical children). Design : Physical growth was one of the outcome measures of a National Institutes of Health-sponsored longitudinal, prospective clinical trial conducted by the University of Florida and the University of Sao Paulo. Setting : Hospital of Rehabilitation of Craniofacial Anomalies, University of Sao Paulo (HRAC-USP), Bauru, Brazil. Main Outcome Measures : Height and weight were prospectively measured for 360 healthy children with UCLP who were nonsyndromic, belonged to median socioeconomic status, and received health care at HRAC-USP. To compare growth of children with UCLP to that of typical children, growth curves for UCLP were developed and compared with World Health Organization curves for 2006 and 2007, which were used as reference for typical children. Third-degree polynomials were used to explain the relationship of length and weight with age. Confidence limits of 95% were used for the mean curve using the statistic Z ~ N (0,1). Results : Children with UCLP from 2 to 10 years old presented height and weight growth curves similar to those of typical children for both genders. Conclusion : Children with UCLP from 2 to 10 years old presented physical growth similar to that of typical children. PMID- 24810485 TI - A peculiar case of recombination at HLA-A locus. PMID- 24810487 TI - Population estimates of undocumented incident traumatic brain injuries among combat-deployed US military personnel. AB - OBJECTIVE: To estimate the number of undocumented incident traumatic brain injuries (TBIs) among active component US military personnel serving in Iraq and Afghanistan prior to policy changes implemented in late 2006 and 2010 that improved TBI documentation. METHODS: Negative binomial regression was used to model monthly incident TBI counts between December 2010 and June 2012 (N = 19) and then estimate expected monthly counts of incident TBIs during 2 periods: January 2003-October 2006 and November 2006-November 2010. Monthly amputation counts from Department of Defense surveillance data were used as a proxy for changing injury rates. Monthly active component deployment estimates derived from the Congressional Research Service, Brookings Institution, and Defense Manpower Data Center were used to estimate the size of the at-risk population each month. The difference between expected monthly incident TBI counts and reported counts is presented as the estimated number of undocumented incident TBIs. RESULTS: The full model estimates that 21 257 active component military personnel experienced undocumented incident TBIs while deployed in Iraq or Afghanistan between January 2003 and October 2006, more than 4 times the 5272 incident TBIs documented during that period. CONCLUSIONS: A sizeable majority of Iraq and Afghanistan combat veterans who experienced incident TBI while deployed prior to November 2006 are likely to have had their injuries undocumented, creating challenges for clinical care, disability evaluation, and future research. PMID- 24810486 TI - Dendritic cell development requires histone deacetylase activity. AB - DCs develop from multipotent progenitors (MPPs), which commit into DC-restricted common dendritic cell progenitors (CDPs). CDPs further differentiate into classical DCs (cDCs) and plasmacytoid DCs (pDCs). Here, we studied the impact of histone acetylation on DC development in C57BL/6 mice by interfering with histone acetylation and deacetylation, employing histone deacetylase (HDAC) inhibitors. We observed that commitment of MPPs into CDPs was attenuated by HDAC inhibition and that pDC development was specifically blocked. Gene expression profiling revealed that HDAC inhibition prevents establishment of a DC-specific gene expression repertoire. Importantly, protein levels of the core DC transcription factor PU.1 were reduced in HDAC inhibitor-treated cells and consequently PU.1 recruitment at PU.1 target genes Fms-like tyrosine kinase 3 (Flt3), interferon regulatory factor 8 (IRF8), and PU.1 itself was impaired. Thus, our results demonstrate that attenuation of PU.1 expression by HDAC inhibition causes reduced expression of key DC regulators, which results in attenuation of DC development. We propose that chromatin modifiers, such as HDACs, are required for establishing a DC gene network, where Flt3/STAT3 signaling drives PU.1 and IRF8 expression and DC development. Taken together, our study identifies HDACs as critical regulators of DC lineage commitment and development. PMID- 24810489 TI - Functional role of mechanosensitive ion channel Piezo1 in human periodontal ligament cells. AB - OBJECTIVE: To evaluate the function of Piezo1, an evolutionarily conserved mechanically activated channel, in periodontal ligament (PDL) tissue homeostasis under compressive loading. MATERIALS AND METHODS: Primary human PDL cells (hPDLCs) were isolated, cultured, and then subjected to 2.0 g/cm(2) static compressive loading for 0.5, 3, 6, and 12 hours, respectively. The expressions of Piezo1 and osteoclastogenesis marker gene were assessed by semiquantitative reverse transcription-polymerase chain reaction. In addition, Piezo1 inhibitor, GsMTx4, was used to block the function of Piezo1, and tumor necrosis factor-alpha was also used as a positive control. After 12 hours of compressive loading the PDLCs were co-cultured with murine monocytic cell line RAW264.7. Immunofluorescence, western blot, enzyme-linked immunosorbent assay, and tartrate resistant acid phosphatase staining were also used to test the potency of PDLCs to induce osteoclastogenesis and the activation of nuclear factor (NF)-kappaB. RESULTS: Piezo1, cyclooxygenase-2, receptor activator of NF-kappaB ligand, and prostaglandin E2 were significantly upregulated under static compressive stimuli. GsMTx4 repressed osteoclastogenesis in the mechanical stress-pretreated PDLCs RAW264.7 co-culture system. Furthermore, NF-kappaB signaling pathway was involved in the mechanical stress-induced osteoclastogenesis. CONCLUSIONS: Piezo1 exerts a transduction role in mechanical stress-induced osteoclastogenesis in hPDLCs. PMID- 24810490 TI - Assessment of the upper body contribution to multiple-sprint cycling in men and women. AB - The aim of this study was to investigate the effect of repeated cycling sprints on power profiles while assessing upper body muscle contraction. Eighteen physically active participants performed 8 * 10 s repeated sprints while muscle activity was recorded via surface electromyography (sEMG) from the brachioradialis (BR), biceps brachii (BB), triceps brachii (TB) and upper trapezius (UT). Measurements were obtained at rest, during a functional maximum contraction (FMC) while participants were positioned in a seated position on the cycle ergometer and during the repeated sprint protocol. Results suggest that mainly type I muscle fibres (MFs) are being recruited within the upper body musculature due to the submaximal and intermittent nature of the contractions. Subsequently, there is no evidence of upper body fatigue across the sprints, which is reflected in the lack of changes in the median frequency of the power spectrum (P<0.05). PMID- 24810492 TI - HIV treatment strategies that can weather future challenges. PMID- 24810491 TI - Early versus delayed initiation of highly active antiretroviral therapy for HIV positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. AB - BACKGROUND: WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV positive patients with CD4 counts of 220 cells per MUL or more. METHODS: We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per MUL vs >=350 cells per MUL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). FINDINGS: We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8.5%) of 767 patients in the early ART group versus 71 (9.2%) of 771 in the delayed ART group (relative risk [RR] 0.91, 95% CI 0.64-1.30; p=0.9). Of patients with a CD4 cell count of 220-349 cells per MUL, 26 (7.9%) of 331 patients versus 33 (9.6%) of 342 reached the primary endpoint (RR 0.80, 95% CI 0.46-1.39; p=0.6). For those with 350 cells per MUL or more, 39 (8.9%) of 436 versus 38 (8.9%) of 429 reached the primary endpoint (RR 1.01, 95% CI 0.63-1.62; p=0.4). Mortality did not differ significantly between treatment groups (RR 1.4, 95% CI 0.8-2.3; p=0.23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0.37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0.56). INTERPRETATION: ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per MUL. WHO guidelines should be updated accordingly. FUNDING: USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR. PMID- 24810494 TI - Prevalence of 'being at risk of malnutrition' and associated factors in adult patients receiving nursing care at home in Belgium. AB - Malnutrition is a known problem in hospitals and nursing homes. This study aims to evaluate the prevalence of being at risk of malnutrition in community living adults receiving homecare nursing and to determine factors independently associated with this risk of malnutrition. Furthermore, it also aimed to describe aspects of current nutritional nursing care. Patients (n = 100) are screened with the Malnutrition Universal Screening Tool to evaluate their risk of malnutrition. A patient survey was used to analyse associated factors. In this population, 29% are at risk for malnutrition. Following a multivariate logistic regression analysis, 'loss of appetite' proved the most important factor. A survey for nurses (n = 61) revealed low awareness, poor knowledge, poor communication between stakeholders and a moderate approach of malnutrition. These findings should encourage homecare nurses to use a recommended screening tool for malnutrition and to actively observe and report loss of appetite to initiate the prescription of individual tailored interventions. Belgian homecare nurses' management does not yet fully comply with international recommendations. Additional training in nutritional nursing care and screening methods for malnutrition is needed. Systematic screening should be further developed and evaluated in this at-risk population. PMID- 24810493 TI - Multiplex genomic profiling of non-small cell lung cancers from the LETS phase III trial of first-line S-1/carboplatin versus paclitaxel/carboplatin: results of a West Japan Oncology Group study. AB - Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from advanced NSCLC patients enrolled in LETS phase III trial comparing first line S-1/carboplatin with paclitaxel/carboplatin and subjected to multiplex genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel) with the Sequenom MassARRAY platform. MET amplification was evaluated by fluorescence in situ hybridization. A somatic mutation in at least one gene was identified in 48% of non-squamous cell carcinoma and 45% of squamous cell carcinoma specimens, with EGFR (17%), TP53 (11%), STK11 (9.8%), MET (7.6%), and KRAS (6.2%). Mutations in EGFR or KRAS were associated with a longer or shorter median overall survival, respectively. The LungFusion Panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and a RET fusion in one case (0.4%), with these three types of rearrangement being mutually exclusive. Nine (3.9%) of 229 patients were found to be positive for de novo MET amplification. This first multiplex genotyping of NSCLC associated with a phase III trial shows that MassARRAY-based genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE specimens of NSCLC tissue. PMID- 24810495 TI - Complete traumatic backout of the blade of proximal femoral nail antirotation: a case report. AB - This article presents a rare case of traumatic complete expulsion of the helical blade after successful treatment of an intertrochanteric fracture with proximal femoral nail antirotation (PFNA). A 94-year-old woman sustained an intertrochanteric fracture of the left femur. Fracture fixation was performed by using PFNA-II. At six months FU, the patient presented with pain at the proximal lateral left thigh after she had fallen. A protrusion was noted. Radiographs showed a complete expulsion of the helical blade with a healed intertrochanteric fracture. The PFNA-II was removed and a cemented bipolar hemiarthroplasty was performed. At 5 months after surgery, the patient was able to walk with a walker without pain. Traumatic complete expulsion of the blade should be considered as a possible complication of PFNA/PFNA-II. PMID- 24810496 TI - Ada response - a strategy for repair of alkylated DNA in bacteria. AB - Alkylating agents are widespread in the environment and also occur endogenously. They can be cytotoxic or mutagenic to the cells introducing alkylated bases to DNA or RNA. All organisms have evolved multiple DNA repair mechanisms to counteract the effects of DNA alkylation: the most cytotoxic lesion, N(3) methyladenine (3meA), is excised by AlkA glycosylase initiating base excision repair (BER); toxic N(1)-methyladenine (1meA) and N(3)-methylcytosine (3meC), induced in DNA and RNA, are removed by AlkB dioxygenase; and mutagenic and cytotoxic O(6)-methylguanine (O(6) meG) is repaired by Ada methyltransferase. In Escherichia coli, Ada response involves the expression of four genes, ada, alkA, alkB, and aidB, encoding respective proteins Ada, AlkA, AlkB, and AidB. The Ada response is conserved among many bacterial species; however, it can be organized differently, with diverse substrate specificity of the particular proteins. Here, an overview of the organization of the Ada regulon and function of individual proteins is presented. We put special effort into the characterization of AlkB dioxygenases, their substrate specificity, and function in the repair of alkylation lesions in DNA/RNA. PMID- 24810498 TI - That was a great catch! PMID- 24810499 TI - In praise of.... PMID- 24810497 TI - Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators. AB - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. The epithelial-to-mesenchymal transition (EMT) is a key contributor in the metastatic process. We previously showed the pan-deacetylase inhibitor LBH589 induces CDH1 expression in TNBC cells, suggesting regulation of EMT. The purpose of this study was to examine the effects of LBH589 on the metastatic qualities of TNBC cells and the role of EMT in this process. A panel of breast cancer cell lines (MCF-7, MDA-MB-231, and BT 549), drugged with LBH589, was examined for changes in cell morphology, migration, and invasion in vitro. The effect on in vivo metastasis was examined using immunofluorescent staining of lung sections. EMT gene expression profiling was used to determine LBH589-induced changes in TNBC cells. ZEB overexpression studies were conducted to validate requirement of ZEB in LBH589-mediated proliferation and tumorigenesis. Our results indicate a reversal of EMT by LBH589 as demonstrated by altered morphology and altered gene expression in TNBC. LBH589 was shown to be a more potent inhibitor of EMT than other HDAC inhibitors, SAHA and TMP269. Additionally, we found that LBH589 inhibits metastasis of MDA-MB-231 cells in vivo. These effects of LBH589 were mediated in part by inhibition of ZEB, as overexpression of ZEB1 or ZEB2 mitigated the effects of LBH589 on MDA-MB 231 EMT-associated gene expression, migration, invasion, CDH1 expression, and tumorigenesis. These data indicate therapeutic potential of LBH589 in targeting EMT and metastasis of TNBC. PMID- 24810500 TI - Propofol: sedation with or without analgesia? PMID- 24810501 TI - Response. PMID- 24810502 TI - Using telemedicine in stroke care. PMID- 24810503 TI - Relieving anxiety in the emergency department for our patient population. PMID- 24810504 TI - Emergency department nurse empowerment: research lacking. PMID- 24810505 TI - Treating pain in patients with a history of substance addiction: case studies and review. PMID- 24810507 TI - Rescue on two wheels. PMID- 24810508 TI - Preemies to preschoolers: tubing tiny tots and trauma FAQs, part 1. PMID- 24810509 TI - Statistics for emergency nurses. PMID- 24810510 TI - Triage: the sorting of patients. PMID- 24810511 TI - Reprint of: Caring for critical care boarders in the emergency department. PMID- 24810514 TI - Zinc and Vitamin Supplementation in an Under-5 Indigenous Population of Guatemala: Influence of Lay Health Promoters in Decreasing Incidence of Diarrhea. AB - BACKGROUND: Malnutrition is an urgent problem in the developing world, especially for children under 5 years of age. The article describes the utilization of a standard of practice designed to prevent illness in a malnourished, under-5 indigenous population and reinforced by weekly basic health messages taught by lay community health promoters. METHOD: The two villages were chosen for observation after administration of the standard of care among the Maya-Kiche, the most numerous Mayan group in Guatemala. The standard of practice, 20 mg of daily oral zinc, was administered for 10 days in the home and followed by daily vitamin supplementation that continued throughout the 3 months of the project. All patients received four monthly clinic visits, with one of the village groups receiving weekly health promoter visits. RESULTS: Data evaluated after the quality improvement project showed significant differences in adherence to the zinc regimen (chi(2) = 3.677, p <= .05) as well as lower rates of diarrheal illnesses (chi(2) = 5.850, p <= .05), with both of these improved in the health promoter group. DISCUSSION: This study suggests that the training and implementation of para-health professionals from the lay community in response to specific health care needs could be considered a best practice in developing countries. IMPLICATIONS: Public health professionals are key to health promoter training and direction, and their importance in the global setting cannot be understated. PMID- 24810513 TI - beta-Carboxysomal proteins assemble into highly organized structures in Nicotiana chloroplasts. AB - The photosynthetic efficiency of C3 plants suffers from the reaction of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) with O2 instead of CO2 , leading to the costly process of photorespiration. Increasing the concentration of CO2 around Rubisco is a strategy used by photosynthetic prokaryotes such as cyanobacteria for more efficient incorporation of inorganic carbon. Engineering the cyanobacterial CO2 -concentrating mechanism, the carboxysome, into chloroplasts is an approach to enhance photosynthesis or to compartmentalize other biochemical reactions to confer new capabilities on transgenic plants. We have chosen to explore the possibility of producing beta-carboxysomes from Synechococcus elongatus PCC7942, a model freshwater cyanobacterium. Using the agroinfiltration technique, we have transiently expressed multiple beta carboxysomal proteins (CcmK2, CcmM, CcmL, CcmO and CcmN) in Nicotiana benthamiana with fusions that target these proteins into chloroplasts, and that provide fluorescent labels for visualizing the resultant structures. By confocal and electron microscopic analysis, we have observed that the shell proteins of the beta-carboxysome are able to assemble in plant chloroplasts into highly organized assemblies resembling empty microcompartments. We demonstrate that a foreign protein can be targeted with a 17-amino-acid CcmN peptide to the shell proteins inside chloroplasts. Our experiments establish the feasibility of introducing carboxysomes into chloroplasts for the potential compartmentalization of Rubisco or other proteins. PMID- 24810515 TI - Cultural Awareness: Nursing Care of Iraqi Patients. AB - PURPOSE: The aim of this study was to describe the cultural factors that have an impact on military nursing care for Iraqi patients. The results were part of a larger study in which the purpose was to understand nurses' experiences of delivery of care for Iraqi patients. METHOD: Three focus groups, consisting of military registered nurses and licensed practical nurses, were used to generate rich descriptions of experiences in a military combat support hospital in Iraq. Data were analyzed using thematic analysis methods. FINDINGS: Culturally, the differences between the Iraqi patients and the nurses included variations in communication, diet, and beliefs and values in reference to gender and patient dependency. CONCLUSION: The findings indicated that the nurses need language skills and cultural customs and beliefs training to provide care to culturally diverse patients. In addition, support services, such as dieticians, need to be involved in the plan of care to address applicable cultural issues. IMPLICATIONS: Implementation of learning to provide nurses language skills and cultural awareness of the diet, customs and beliefs of Iraqi people as well as the economic, political, and social factors that have an impact on their lives will promote quality nursing care and optimal health outcomes. PMID- 24810516 TI - Acculturation, Health Literacy, and Illness Perceptions of Hypertension among Hispanic Adults. AB - PURPOSE: Hypertension treatment rates are disproportionately lower among Hispanics compared to non-Hispanic Whites and non-Hispanic Blacks. The purpose of this study was to examine the relationship among acculturation, health literacy, and illness perceptions of hypertension among Hispanics. DESIGN: A cross sectional correlational design was used, including 144 Hispanic adults with a self-reported diagnosis of hypertension. METHOD: The instruments used included the Short Acculturation Scale for Hispanics, the Newest Vital Sign instrument to measure health literacy, and the Brief Illness Perception Questionnaire. RESULTS: Significant relationships were found among acculturation, health literacy, and several illness perceptions (consequences, control, symptoms, and emotions). CONCLUSION: Acculturation and health literacy play an important role in illness perceptions of hypertension among Hispanics. IMPLICATIONS: Findings could be helpful in the development of tailored health promotion interventions to improve hypertension management among Hispanic adults. PMID- 24810517 TI - Psychometric evaluation of the Tilburg Pregnancy Distress Scale-Turkish version (TPDS-T). AB - PURPOSE: The purpose of this study was to determine the validity and reliability of the Tilburg Pregnancy Distress Scale-Turkish version (TPDS-T). METHODS: The sample consisted of 214 healthy pregnant women in maternity clinics in an urban center in western Turkey. The instruments included a demographic questionnaire and TPDS-T. RESULTS: The internal consistency reliability coefficient of the TPDS T was .70. The correlation coefficients between the lower dimension item scores and lower dimension total scores were .20 to .73. According to the confirmatory factor analysis, the model fit indexes of the scale were determined as root mean square error of approximation = .051, goodness-of-fit index = .91, comparative fit index = .92, and nonnormed fit index = .90. CONCLUSION: The TPDS-T is a valid and reliable scale that can be used to determine distress of pregnant women in Turkey. IMPLICATIONS FOR PRACTICE: This scale can be used as a guide by Turkish midwives and obstetric nurses planning pregnancy follow-up care. PMID- 24810518 TI - Infant-feeding practices among African American women: social-ecological analysis and implications for practice. AB - Despite extensive evidence supporting the health benefits of breastfeeding, significant disparities exist between rates of breastfeeding among African American women and women of other races. Increasing rates of breastfeeding among African American women can contribute to the improved health of the African American population by decreasing rates of infant mortality and disease and by enhancing cognitive development. Additionally, higher rates of breastfeeding among African American women could foster maternal-child bonding and could contribute to stronger families, healthier relationships, and emotionally healthier adults. The purpose of this article is twofold: (a) to use the social ecological model to explore the personal, socioeconomic, psychosocial, and cultural factors that affect the infant feeding decision-making processes of African American women and (b) to discuss the implications of these findings for clinical practice and research to eliminate current disparities in rates of breastfeeding. PMID- 24810519 TI - The Environment and Support Needs of Japanese Families on Temporary Work Assignments in the United States. AB - PURPOSE: This study aimed to describe the environment and the family support needs of families of Japanese nationals rearing children who are temporarily working in the Southwestern United States. DESIGN: Mixed methods were utilized based on the Concentric Sphere Family Environment Model. Data collection occurred over 132 days, with 25 families participating in formal interviews and 40 families completing a written questionnaire survey. FINDINGS/RESULTS: "Mutual support from relatives and friends in Japan, and with local Japanese peers," and other themes, six in all, were extracted. Japanese families require intervention for measures related to the global environment in their daily lives. DISCUSSION AND CONCLUSIONS: The common factor for those families with high intervention needs was the inability to access family external resources that were usually available in Japan. IMPLICATION FOR PRACTICE: The building of peer support and intervention to promote their participation in the community are necessary. PMID- 24810520 TI - A modified Raman multidimensional spectroscopic signature of blood to account for the effect of laser power. AB - Raman spectroscopy has been used for the development of a universal method for the identification of traces of all major body fluids. Multidimensional spectroscopic signatures, which account for the intrinsic sample heterogeneity and variations between donors, have been described for blood, semen, saliva, vaginal fluid and sweat. Here, we report on a shortcoming of the existing spectroscopic signature of blood due to the effect of laser power. The issue is the result of the previously discovered phenomenon of photoinduced hemoglobin aggregation. An investigation of this effect on the performance of the Raman signature is reported along with a remediating modification. This adjustment is demonstrated to extend the application of the multidimensional signatures to spectra obtained under low laser power conditions while preserving the signature's specificity. PMID- 24810521 TI - Scattering of charge carriers by Cr impurities in magnetotransport on a Bi(1 1 1) ultra-thin film. AB - In this investigation we tested the role of Cr impurities on the strongly spin polarized surface states of ultra-thin epitaxially grown Bi(1 1 1) films by measuring surface magnetoconductance and the Hall effect in conjunction with low energy electron diffraction at a low temperature (10 K). Compared with Fe and Co, investigated recently, Cr atoms turned out to have scattering cross-sections that are about a factor of three higher than the former atoms. Nevertheless, only a small electron donation (0.03 e/atom) was found for Cr. It also exhibits strong spin-orbit scattering, as judged from quantitative analysis of weak localization effects. As a result, all spin-dependent selection rules are gradually relaxed with increasing Cr concentration, so that the initially observed weak anti localization shifts towards weak localization. The non-monotonic decrease of conductance as a function of Cr concentration, even at 10 K, indicates high diffusivity and activated adsorption into its final optimal adsorption site. PMID- 24810522 TI - Prevalence and test characteristics of national health safety network ventilator associated events. AB - OBJECTIVES: The primary aim of the study was to measure the test characteristics of the National Health Safety Network ventilator-associated event/ventilator associated condition constructs for detecting ventilator-associated pneumonia. Its secondary aims were to report the clinical features of patients with National Health Safety Network ventilator-associated event/ventilator-associated condition, measure costs of surveillance, and its susceptibility to manipulation. DESIGN: Prospective cohort study. SETTING: Two inpatient campuses of an academic medical center. PATIENTS: Eight thousand four hundred eight mechanically ventilated adults discharged from an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The National Health Safety Network ventilator-associated event/ventilator-associated condition constructs detected less than a third of ventilator-associated pneumonia cases with a sensitivity of 0.325 and a positive predictive value of 0.07. Most National Health Safety Network ventilator associated event/ventilator-associated condition cases (93%) did not have ventilator-associated pneumonia or other hospital-acquired complications; 71% met the definition for acute respiratory distress syndrome. Similarly, most patients with National Health Safety Network probable ventilator-associated pneumonia did not have ventilator-associated pneumonia because radiographic criteria were not met. National Health Safety Network ventilator-associated event/ventilator associated condition rates were reduced 93% by an unsophisticated manipulation of ventilator management protocols. CONCLUSIONS: The National Health Safety Network ventilator-associated event/ventilator-associated condition constructs failed to detect many patients who had ventilator-associated pneumonia, detected many cases that did not have a hospital complication, and were susceptible to manipulation. National Health Safety Network ventilator-associated event/ventilator-associated condition surveillance did not perform as well as ventilator-associated pneumonia surveillance and had several undesirable characteristics. PMID- 24810523 TI - Minocycline but not tigecycline is neuroprotective and reduces the neuroinflammatory response induced by the superimposition of sepsis upon traumatic brain injury. AB - OBJECTIVE: The development of sepsis in patients with traumatic brain injury increases mortality, exacerbates morphological and functional cerebral damage, and causes persistent neuroinflammation, including microglial activation. The administration of antibiotics possessing both antimicrobial and immunomodulatory activity might attenuate both sepsis and posttraumatic cerebral inflammation. We compared the potential therapeutic efficacy of two tetracyclines, minocycline and the newer generation tigecycline, on functional neurobehavioral impairment and regional histopathological damage in an experimental model of combined traumatic brain injury and sepsis. DESIGN: Prospective, experimental animal study. SETTING: University Research Laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Controlled cortical impact was used to induce traumatic brain injury and cecal ligation and puncture for sepsis. Immediately following injury, animals were treated with minocycline (45 mg/kg intraperitoneal), tigecycline (7.5 mg/kg intraperitoneal), or saline every 12 hours for 3 days. MEASUREMENTS AND MAIN RESULTS: The development of sepsis and cerebral inflammatory response were evaluated, respectively, by 1) growth of peritoneal microorganisms and clinical variables and 2) tumor necrosis factor-alpha expression in the perilesional cortex. To assess posttraumatic outcome, vestibulomotor and cognitive function were evaluated at different time points for 14 days post injury whereupon animals were killed and cerebral tissue analyzed for lesion volume, regional hippocampal (CA1/CA3) cell death, and microglial activation in the perilesional cortex, lesion core zone, and choroid plexus. Treatment with both antibiotics reduced microorganism growth, body weight loss, and mortality but had no effect on vestibulomotor or cognitive function. Minocycline alone attenuated postinjury cortical lesion volume, hippocampal CA3 neuronal cell loss, tumor necrosis factor-alpha expression, and the extent of microglial activation and infiltration. CONCLUSIONS: The significantly heightened mortality caused by the superimposition of sepsis upon traumatic brain injury can be reduced by administration of both antibiotics but only minocycline can decrease the extent of cell death in selectively cortical and hippocampal brain regions, via, in part, a reduction in cerebral inflammation. PMID- 24810524 TI - Factors associated with two different protocols of do-not-resuscitate orders in a medical ICU*. AB - OBJECTIVE: The State of Ohio in the United States has the legislation for two different protocols of do-not-resuscitate orders. The objective of this study was to examine the clinical/demographic factors and outcomes associated with the two different do-not-resuscitate orders. DESIGN: Data were concurrently and retrospectively collected from August 2002 to December 2005. The clinical/demographic factors of do-not-resuscitate patients were compared with those of non-do-not-resuscitate patients, and the clinical/demographic factors of do-not-resuscitate comfort care-arrest patients were compared with those of do not-resuscitate comfort care patients. SETTING: An ICU in a university-affiliated hospital located at Northeast Ohio in the United States. PATIENTS: A sample of 2,440 patients was collected: 389 patients were do-not-resuscitate; and 2,051 patients were non-do-not-resuscitate. Among the 389 do-not-resuscitate patients, 194 were do-not-resuscitate comfort care-arrest patients and 91 were do-not resuscitate comfort care patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The factors associated with do-not-resuscitate were older age, race and ethnicity with white race, more severe clinical illness at admission to the ICU, and longer stay before admission to the ICU. Comparing do-not-resuscitate comfort care-arrest patients with do-not-resuscitate comfort care patients, those with more severe clinical illness, longer ICU stay before making a do-not-resuscitate decision, and being cared for by only one intensivist during ICU stay were significantly associated with do-not-resuscitate comfort care decisions. For 149 do-not-resuscitate patients who eventually survived to hospital discharge and 86 do-not-resuscitate patients who eventually did not, only eight (5.4%) and 23 (26.7%) had the order written within 48 hours before the end of ICU stay, respectively. CONCLUSIONS: Our study showed that some clinical/demographic factors predicted do-not-resuscitate comfort care orders. This study also suggested that Ohio's Do-Not-Resuscitate Law, clearly indicating two different protocols of do-not-resuscitate orders, facilitated early do-not-resuscitate decision. PMID- 24810525 TI - Propofol ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction via heme oxygenase-1/signal transducer and activator of transcription 3 signaling pathway in rats. AB - OBJECTIVES: Heme oxygenase-1 is inducible in cardiomyocytes in response to stimuli such as oxidative stress and plays critical roles in combating cardiac hypertrophy and injury. Signal transducer and activator of transcription 3 plays a pivotal role in heme oxygenase-1-mediated protection against liver and lung injuries under oxidative stress. We hypothesized that propofol, an anesthetic with antioxidant capacity, may attenuate hyperglycemia-induced oxidative stress in cardiomyocytes via enhancing heme oxygenase-1 activation and ameliorate hyperglycemia-induced cardiac hypertrophy and apoptosis via heme oxygenase 1/signal transducer and activator of transcription 3 signaling and improve cardiac function in diabetes. DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: In vivo and in vitro treatments. MEASUREMENTS AND MAIN RESULTS: At 8 weeks of streptozotocin-induced type 1 diabetes in rats, myocardial 15-F2t-isoprostane was significantly increased, accompanied by cardiomyocyte hypertrophy and apoptosis and impaired left ventricular function that was coincident with reduced heme oxygenase-1 activity and signal transducer and activator of transcription 3 activation despite an increase in heme oxygenase-1 protein expression as compared to control. Propofol infusion (900 MUg/kg/min) for 45 minutes significantly improved cardiac function with concomitantly enhanced heme oxygenase-1 activity and signal transducer and activator of transcription activation. Similar to the changes seen in diabetic rat hearts, high glucose (25 mmol/L) exposure for 48 hours led to cardiomyocyte hypertrophy and apoptosis, both in primary cultured neonatal rat cardiomyocytes and in H9c2 cells compared to normal glucose (5.5 mmol/L). Hypertrophy was accompanied by increased reactive oxygen species and malondialdehyde production and caspase-3 activity. Propofol, similar to the heme oxygenase-1 inducer cobalt protoporphyrin, significantly increased cardiomyocyte heme oxygenase-1 and p-signal transducer and activator of transcription protein expression and heme oxygenase-1 activity and attenuated high-glucose-mediated cardiomyocyte hypertrophy and apoptosis and reduced reactive oxygen species and malondialdehyde production (p < 0.05). These protective effects of propofol were abolished by heme oxygenase-1 inhibition with zinc protoporphyrin and by heme oxygenase-1 or signal transducer and activator of transcription 3 gene knockdown. CONCLUSIONS: Heme oxygenase-1/signal transducer and activator of transcription 3 signaling plays a critical role in propofol-mediated amelioration of hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis, whereby propofol improves cardiac function in diabetic rats. PMID- 24810526 TI - Mannose-binding lectin is expressed after clinical and experimental traumatic brain injury and its deletion is protective. AB - OBJECTIVE: Mannose-binding lectin protein is the activator of the lectin complement pathway. Goals were (1) to investigate mannose-binding lectin expression after human and experimental traumatic brain injury induced by controlled cortical impact and (2) to evaluate whether mannose-binding lectin deletion is associated with reduced sequelae after controlled cortical impact. DESIGN: Translational research, combining a human/experimental observational study and a prospective experimental study. SETTING: University hospital/research laboratory. PATIENTS AND SUBJECTS: Brain-injured patients, C57Bl/6 mice, and mannose-binding lectin-A and mannose-binding lectin-C double-knockout (-/-) mice. INTERVENTIONS: Using anti-human mannose-binding lectin antibody, we evaluated mannose-binding lectin expression in tissue samples from six patients who underwent surgery for a cerebral contusion. Immunohistochemistry was also performed on tissues obtained from mice at 30 minutes; 6, 12, 24, 48, and 96 hours; and 1 week after controlled cortical impact using anti-mouse mannose binding lectin-A and mannose-binding lectin-C antibodies. We evaluated the effects of mannose-binding lectin deletion in wild-type and mannose-binding lectin-A and mannose-binding lectin-C double-knockout mice. Functional outcome was evaluated using the neuroscore and beam walk tests for 4 weeks postinjury (n = 11). Histological injury was evaluated by comparing neuronal cell counts in the cortex adjacent to the contusion (n = 11). MEASUREMENTS AND MAIN RESULTS: Following human traumatic brain injury, we observed mannose-binding lectin positive immunostaining in the injured cortex as early as few hours and up to 5 days postinjury. Similarly in mice, we observed mannose-binding lectin-C-positive immunoreactivity in the injured cortex beginning 30 minutes and persisting up to 1 week postinjury. The extent of mannose-binding lectin-A expression was lower when compared with that of mannose-binding lectin-C. We observed attenuated sensorimotor deficits in mannose-binding lectin (-/-) mice compared with wild type mice at 2-4 weeks postinjury. Furthermore, we observed reduced cortical cell loss at 5 weeks postinjury in mannose-binding lectin (-/-) mice compared with wild-type mice. CONCLUSIONS: Mannose-binding lectin expression was documented after traumatic brain injury. The reduced sequelae associated with mannose binding lectin absence suggest that mannose-binding lectin modulation might be a potential target after traumatic brain injury. PMID- 24810527 TI - The opportunity cost of futile treatment in the ICU*. AB - OBJECTIVE: When used to prolong life without achieving a benefit meaningful to the patient, critical care is often considered "futile." Although futile treatment is acknowledged as a misuse of resources by many, no study has evaluated its opportunity cost, that is, how it affects care for others. Our objective was to evaluate delays in care when futile treatment is provided. DESIGN: For 3 months, we surveyed critical care physicians in five ICUs to identify patients that clinicians identified as receiving futile treatment. We identified days when an ICU was full and contained at least one patient who was receiving futile treatment. For those days, we evaluated the number of patients waiting for ICU admission more than 4 hours in the emergency department or more than 1 day at an outside hospital. SETTING: One health system that included a quaternary care medical center and an affiliated community hospital. PATIENTS: Critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Boarding time in the emergency department and waiting time on the transfer list. Thirty-six critical care specialists made 6,916 assessments on 1,136 patients of whom 123 were assessed to receive futile treatment. A full ICU was less likely to contain a patient receiving futile treatment compared with an ICU with available beds (38% vs 68%, p < 0.001). On 72 (16%) days, an ICU was full and contained at least one patient receiving futile treatment. During these days, 33 patients boarded in the emergency department for more than 4 hours after admitted to the ICU team, nine patients waited more than 1 day to be transferred from an outside hospital, and 15 patients canceled the transfer request after waiting more than 1 day. Two patients died while waiting to be transferred. CONCLUSIONS: Futile critical care was associated with delays in care to other patients. PMID- 24810529 TI - The effect of acute kidney injury and discharge creatinine level on mortality following cardiac surgery*. AB - OBJECTIVES: Acute kidney injury after cardiac surgery is associated with increased operative and late mortality. The objective was to determine if short and long term mortality are systematically improved with completeness of postoperative acute kidney injury reversal or with amount of residual renal function. DESIGN: Retrospective, single center study. SETTING: Tertiary care hospital. PATIENTS: One thousand five hundred and forty-three cardiac surgery patients divided into acute kidney injury groups based on Kidney Disease International Group Outcome criteria. MEASUREMENTS AND MAIN RESULTS: Operative mortality was 3.1% overall and was progressively worse with increasing acute kidney injury: none (0.8%), minimal (1.6%), Kidney Disease International Group Outcome stage 1 (4.3%), stage 2 (17%), and stage 3 (29%). Similar to the operative outcomes, late outcomes were progressively worse with rising amounts of acute kidney injury. The risk of late death was related to amount of acute kidney injury and remaining renal function at discharge. CONCLUSIONS: Acute kidney injury was associated with higher operative and late mortality. Lesser amounts of residual renal function were associated with increased late mortality. PMID- 24810528 TI - Statins and delirium during critical illness: a multicenter, prospective cohort study. AB - OBJECTIVE: Since statins have pleiotropic effects on inflammation and coagulation that may interrupt delirium pathogenesis, we tested the hypotheses that statin exposure is associated with reduced delirium during critical illness, whereas discontinuation of statin therapy is associated with increased delirium. DESIGN: Multicenter, prospective cohort study. SETTING: Medical and surgical ICUs in two large tertiary care hospitals in the United States. PATIENTS: Patients with acute respiratory failure or shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured statin exposure prior to hospitalization and daily during the ICU stay, and we assessed patients for delirium twice daily using the Confusion Assessment Method for the ICU. Of 763 patients included, whose median (interquartile range) age was 61 years (51-70 yr) and Acute Physiology and Chronic Health Evaluation II was 25 (19-31), 257 (34%) were prehospital statin users and 197 (26%) were ICU statin users. Overall, delirium developed in 588 patients (77%). After adjusting for covariates, ICU statin use was associated with reduced delirium (p < 0.01). This association was modified by sepsis and study day; for example, statin use was associated with reduced delirium among patients with sepsis on study day 1 (odds ratio, 0.22; 95% CI, 0.10-0.49) but not among patients without sepsis on day 1 (odds ratio, 0.92; 95% CI, 0.46-1.84) or among those with sepsis later, for example, on day 13 (odds ratio, 0.70; 95% CI, 0.35-1.41). Prehospital statin use was not associated with delirium (odds ratio, 0.86; 95% CI, 0.44-1.66; p = 0.18), yet the longer a prehospital statin user's statin was held in the ICU, the higher the odds of delirium (overall p < 0.001 with the odds ratio depending on sepsis status and study day due to significant interactions). CONCLUSIONS: In critically ill patients, ICU statin use was associated with reduced delirium, especially early during sepsis; discontinuation of a previously used statin was associated with increased delirium. PMID- 24810530 TI - Intra-aortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation*. AB - OBJECTIVES: This study was designed to assess the effects on macrocirculation and microcirculation of adding an intra-aortic balloon pump to peripheral venoarterial extracorporeal membrane oxygenation in patients with severe cardiogenic shock and little/no residual left ventricular ejection. DESIGN: A prospective, single-center, observational study where macrocirculation and microcirculation were assessed with clinical-, Doppler echocardiography-, and pulmonary artery-derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation and side-stream dark-field imaging of sublingual microcirculation. SETTING: A 26-bed tertiary ICU in a university hospital. PATIENTS: We evaluated 12 consecutive patients before and 30 minutes after interrupting and restarting intra-aortic balloon pump. INTERVENTIONS: Measurements were performed before, and 30 minutes after interrupting and restarting intra-aortic balloon pump. MEASUREMENTS AND MAIN RESULTS: Stopping intra-aortic balloon pump was associated with higher pulmonary artery-occlusion pressure (19 +/- 10 vs 15 +/- 8 mm Hg, p = 0.01), increased left ventricular end systolic (51 +/- 13 vs 50 +/- 14 mm, p = 0.05) and end-diastolic (55 +/- 13 vs 52 +/- 14 mm, p = 0.003) dimensions, and decreased pulse pressure (15 +/- 13 vs 29 +/- 22 mm Hg, p = 0.02). Maximum pulmonary artery-occlusion pressure reduction when the intra-aortic balloon pump was restarted was observed in the seven patients whose pulmonary artery-occlusion pressure was more than 15 mm Hg when intra-aortic balloon pump was off (-6.6 +/- 4.3 vs -0.6 +/- 3.4 mm Hg, respectively). Thenar eminence and brain tissue oxygenation and side-stream dark field-assessed sublingual microcirculation were unchanged by stopping and restarting intra-aortic balloon pump. CONCLUSIONS: Restoring pulsatility and decreasing left ventricular afterload with intra-aortic balloon pump was associated with smaller left ventricular dimensions and lower pulmonary artery pressures but did not affect microcirculation variables in cardiogenic shock patients with little/no residual left ventricular ejection while on peripheral venoarterial extracorporeal membrane oxygenation. PMID- 24810531 TI - When cardiac failure, kidney dysfunction, and kidney injury intersect in acute conditions: the case of cardiorenal syndrome. AB - OBJECTIVE: To review and describe diagnostic and prognostic value of biomarkers of renal function and renal injury in the cardiorenal syndrome complicating acutely decompensated heart failure. DATA SOURCES: PubMed search and review of relevant medical literature. STUDY SELECTION: Two reviewers screened and selected studies in English with diagnostic or prognostic assessment of biomarkers of renal injury. DATA EXTRACTION: Narrative review of the medical literature. DATA SYNTHESIS: Cardiorenal syndrome has a complex pathophysiology and has a generally poor prognosis in patients with acutely decompensated heart failure. Among the methods to recognize risk for cardiorenal syndrome may be the use of circulating or urinary biomarkers, which may allow for more accurate early diagnosis and risk stratification; use of biomarkers may provide important pathophysiologic understanding beyond risk prediction. However, different phenotypes of patients with acute renal dysfunction may be present, which has ramifications with respect to response to treatment strategies. Addition of biomarkers of renal injury may provide additional prognostic value to biomarkers of renal or cardiac function, but more data are needed. CONCLUSIONS: Biomarkers reflecting renal function and injury are likely to better phenotype subgroups of patients with cardiorenal syndrome and to provide unique prognostic information. Future studies are needed relative to strategies using such biomarkers to guide care of affected patients. PMID- 24810532 TI - Do-not-resuscitate status and observational comparative effectiveness research in patients with septic shock*. AB - OBJECTIVES: To assess the importance of including do-not-resuscitate status in critical care observational comparative effectiveness research. DESIGN: Retrospective analysis. SETTING: All California hospitals participating in the 2007 California State Inpatient Database, which provides do-not-resuscitate status within the first 24 hours of admission. PATIENTS: Septic shock present at admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We investigated the association of early do-not-resuscitate status with in-hospital mortality among patients with septic shock. We also examined the strength of confounding of do-not-resuscitate status on the association between activated protein C therapy and mortality, an association with conflicting results between observational and randomized studies. We identified 24,408 patients with septic shock; 19.6% had a do-not-resuscitate order. Compared with patients without a do-not-resuscitate order, those with a do-not-resuscitate order were significantly more likely to be older (75 +/- 14 vs 67 +/- 16 yr) and white (62% vs 53%), with more acute organ failures (1.44 +/- 1.15 vs 1.38 +/- 1.15), but fewer inpatient interventions (1.0 +/- 1.0 vs 1.4 +/- 1.1). Adding do-not-resuscitate status to a model with 47 covariates improved mortality discrimination (c-statistic, 0.73-0.76; p < 0.001). Addition of do-not-resuscitate status to a multivariable model assessing the association between activated protein C and mortality resulted in a 9% shift in the activated protein C effect estimate toward the null (odds ratio from 0.78 [95% CI, 0.62-0.99], p = 0.04, to 0.85 [0.67-1.08], p = 0.18). CONCLUSIONS: Among patients with septic shock, do-not-resuscitate status acts as a strong confounder that may inform past discrepancies between observational and randomized studies of activated protein C. Inclusion of early do-not-resuscitate status into more administrative databases may improve observational comparative effectiveness methodology. PMID- 24810533 TI - Vital signs after cardiac arrest following withdrawal of life-sustaining therapy: a multicenter prospective observational study. AB - OBJECTIVE: Controversies regarding the process and timing of the determination of death for controlled organ donation after circulatory death persist. This study assessed the feasibility of conducting a prospective, observational study of continuous monitoring of vital signs for 30 minutes after the clinical determination of death in five Canadian ICUs. Waveform data were analyzed. DESIGN: Prospective observational cohort study. SETTING: One pediatric and four adult Canadian ICUs. PATIENTS: One month of age or older, admitted to the ICU, and for whom a consensual decision to withdraw life-sustaining therapies had been made, with an anticipation of imminent death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive arterial blood pressure, electrocardiogram, and oxygen saturation plethysmography activity were recorded and reviewed for 30 minutes after declaration of death. Feasibility was assessed (recruitment, consent rate, protocol compliance, and staff satisfaction). Of 188 subjects screened over 16 months, 41 subjects were enrolled (87% consent rate). Data collection was complete for 30 subjects (73% protocol compliance). In four subjects, arterial blood pressure resumed following cessation of activity. The longest period of cessation of arterial blood pressure before resumption was 89 seconds. The duration of resumed activity ranged from 1 to 172 seconds. No cases of sustained resumption of arterial blood pressure activity were recorded, and no instances of clinical autoresuscitation were reported. In nearly all patients (27 of 30), electrocardiogram activity continued after the disappearance of arterial blood pressure. CONCLUSIONS: This is the first observational study to prospectively collect waveform data for 30 minutes after the declaration of death. A future larger study may support initial data suggesting that circulatory function does not resume after more than 89 seconds of absence. Furthermore, persistence of cardiac electrical activity with the documented absence of circulation may not be relevant to declaration of death. PMID- 24810534 TI - The solution structure of full-length dodecameric MCM by SANS and molecular modeling. AB - The solution structure of the full-length DNA helicase minichromosome maintenance protein from Methanothermobacter thermautotrophicus was determined by small-angle neutron scattering (SANS) data together with all-atom molecular modeling. The data were fit best with a dodecamer (dimer of hexamers). The 12 monomers were linked together by the B/C domains, and the adenosine triphosphatase (AAA+) catalytic regions were found to be freely movable in the full-length dodecamer both in the presence and absence of Mg(2+) and 50-meric single-stranded DNA (ssDNA). In particular, the SANS data and molecular modeling indicate that all 12 AAA+ domains in the dodecamer lie approximately the same distance from the axis of the molecule, but the positions of the helix-turn-helix region at the C terminus of each monomer differ. In addition, the A domain at the N-terminus of each monomer is tucked up next to the AAA+ domain for all 12 monomers of the dodecamer. Finally, binding of ssDNA does not lock the AAA+ domains in any specific position, which leaves them with the flexibility to move both for helicase function and for binding along the ssDNA. PMID- 24810535 TI - Response to letter to the editor: 'Skin substitutes: which one do we know, which one do we use?'. PMID- 24810536 TI - Insulin and wound healing. AB - Skin is a dynamic and complex organ that relies on the interaction of different cell types, biomacromolecules and signaling molecules. Injury triggers a cascade of events designed to quickly restore skin integrity. Depending on the size and severity of the wound, extensive physiological and metabolic changes can occur, resulting in impaired wound healing and increased morbidity resulting in higher rates of death. While wound dressings provide a temporary barrier, they are inherently incapable of significantly restoring metabolic upsets, post-burn insulin resistance, and impaired wound healing in patients with extensive burns. Exogenous insulin application has therefore been investigated as a potential therapeutic intervention for nearly a century to improve wound recovery. This review will highlight the important achievements that demonstrate insulin's ability to stimulate cellular migration and burn wound recovery, as well as providing a perspective on future therapeutic applications and research directions. PMID- 24810537 TI - Estimating Culicoides sonorensis biting midge abundance using digital image analysis. AB - ImageJ is an open-source software tool used for a variety of scientific objectives including cell counting, shape analysis and image correction. This technology has previously been used to estimate mosquito abundance in surveillance efforts. However, the utility of this application for estimating abundance or parity in the surveillance of Culicoides spp. (Diptera: Ceratopogonidae) has not yet been tested. Culicoides sonorensis (Wirth and Jones), a biting midge often measuring 2.0-2.5 mm in length, is an economically important vector of ruminant arboviruses in California. Current surveillance methods use visual sorting for the characteristics of midges and are very time intensive for large studies. This project tested the utility of ImageJ as a tool to assist in gross trap enumeration as well as in parity analysis of C. sonorensis in comparison with traditional visual methods of enumeration using a dissecting microscope. Results confirmed that automated counting of midges is a reliable means of approximating midge numbers under certain conditions. Further evaluation confirmed accurate and time-efficient parity analysis in comparison with hand sorting. The ImageJ software shows promise as a tool that can assist and expedite C. sonorensis surveillance. Further, these methods may be useful in other insect surveillance activities. PMID- 24810539 TI - Patient specific instrumentation. AB - Patient specific instrumentation (PSI) has recently been developed as a replacement for traditional instrumentation in total knee arthroplasty (TKA). The study aim was to assess efficiency via the mean total OR time using the PSI versus computer-assisted (CAS) TKAs with accuracy as a secondary endpoint. Sixty patients were randomized to CAS or PSI. A formula was developed to derive a profit ratio (PR) that incorporated costs, revenue, and total OR time. The PSI cases were 1.45 times more profitable than CAS allowing for approximately 3 PSI cases versus 2 CAS cases in one 8 hour OR day. Results from this series show that PSI improves OR efficiency, but does not improve accuracy. PMID- 24810541 TI - Basic need satisfaction and suicidal ideation: a self-determination perspective on interpersonal suicide risk and suicidal thinking. AB - This study investigated the relationship between the basic psychological needs, as outlined by self-determination theory, and the interpersonal predictors of suicidal desire, as outlined by the interpersonal-psychological theory of suicidal behavior. It was hypothesized that basic need satisfaction (collective feeling of autonomy, relatedness, and competence) would be related to suicidal ideation through thwarted belongingness and perceived burdensomeness. Mediation analyses demonstrated that thwarted belongingness and perceived burdensomeness both individually mediated the relationship between basic need satisfaction and suicidal ideation. Relatedness also predicted variance of the interaction of thwarted belongingness by perceived burdensomeness while controlling for depression. The clinical utility of assessing need satisfaction as an indication of suicide risk is discussed. Future research to investigate the temporal relationship of the study variables is recommended. PMID- 24810540 TI - The high-molecular-weight kininogen domain 5 is an intrinsically unstructured protein and its interaction with ferritin is metal mediated. AB - High-molecular-weight kininogen domain 5 (HK5) is an angiogenic modulator that is capable of inhibiting endothelial cell proliferation, migration, adhesion, and tube formation. Ferritin can bind to a histidine-glycine-lysine-rich region within HK5 and block its antiangiogenic effects. However, the molecular intricacies of this interaction are not well understood. Analysis of the structure of HK5 using circular dichroism and nuclear magnetic resonance [(1) H, (15) N]-heteronuclear single quantum coherence determined that HK5 is an intrinsically unstructured protein, consistent with secondary structure predictions. Equilibrium binding studies using fluorescence anisotropy were used to study the interaction between ferritin and HK5. The interaction between the two proteins is mediated by metal ions such as Co(2+) , Cd(2+) , and Fe(2+) . This metal-mediated interaction works independently of the loaded ferrihydrite core of ferritin and is demonstrated to be a surface interaction. Ferritin H and L bind to HK5 with similar affinity in the presence of metals. The ferritin interaction with HK5 is the first biological function shown to occur on the surface of ferritin using its surface-bound metals. PMID- 24810542 TI - The hinge region of type VII collagen is intrinsically disordered. AB - Type VII collagen (Col7) is important for skin integrity. As a major component of the anchoring fibrils, Col7 is essential for linking different skin layers together. The central collagenous domain of Col7 contains several interruptions of the collagen triple helix. The longest interruption is 39 amino acids long and referred to as the hinge region. The hinge region is highly conserved between species. This region was predicted to adopt a coiled coil structure and to serve as the trimerization domain of Col7. To gain insight into the potential function of the hinge region we investigated a heterologous expressed peptide by CD and NMR spectroscopy. CD spectroscopy implies that the hinge region is intrinsically disordered. Resonance assignment was performed and allowed secondary structure analysis based on the chemical shift values. Seven amino acids in the N-terminal moiety show residual alpha-helical conformation. Subsequent investigation of temperature dependency of amide chemical shifts indicated participation in hydrogen bonding of amino acid residues in the C-terminal moiety of the hinge region. Therefore, the hinge region does not form a coiled coil structure under the employed experimental conditions. The intrinsic disorder of the hinge region might be desired for flexibility to serve as a "hinge" or the hinge region is an important interaction site as typically observed for intrinsically disordered proteins. PMID- 24810543 TI - Infectious endocarditis associated with a permanent pacemaker lead. PMID- 24810544 TI - The role of anthropic, ecological, and social factors in sleeping site choice by long-tailed macaques (Macaca fascicularis). AB - When choosing their sleeping sites, primates make adaptive trade-offs between various biotic and abiotic constraints. In human-modified environments, anthropic factors may play a role. We assessed the influence of ecological (predation), social (intergroup competition), and anthropic (proximity to human settlements) factors in sleeping site choice by long-tailed macaques (Macaca fascicularis) occupying a habitat at the interface of natural forests and human-modified zones in Bali Barat National Park, Indonesia. Over the course of 56 nights, we collected data relating to physical features of sleeping trees, patterns of the use of sleeping sites within the home range, pre-sleep behavior, diurnal ranging patterns and availability of natural and human food. Overall, the macaques used 17 sleeping sites with 37 sleeping trees. When the monkeys slept in forest zones, they selected sleeping trees that had larger trunks but were not significantly taller than surrounding trees. Though the macaques rarely re-used sleeping sites on consecutive nights, they frequently re-used four sites over the study period. The group favored sleeping within the core area of its home range, despite the occurrence of frequent agonistic intergroup encounters there. Macaques preferentially selected sleeping trees located within or near human-modified zones, especially when human food was abundant and natural food was scarce. These results partially support the hypothesis that long-tailed macaques choose their sleeping sites to avoid predation; proximity to human settlements appears to be the primary factor influencing sleeping site choice in this primate species. Our results reflect the strong influence that anthropic factors have on primates, which subsist in increasingly human-dominated landscapes. PMID- 24810545 TI - Mass originating from the maxillary alveolar crest in an infant. PMID- 24810546 TI - Comparative effectiveness of robotic-assisted vs thoracoscopic lobectomy. AB - BACKGROUND: Robotic-assisted lobectomy is being offered increasingly to patients. However, little is known about its safety, complication profile, or effectiveness. METHODS: Patients undergoing lobectomy in in the United States from 2008 to 2011 were identified in the Nationwide Inpatient Sample. In-hospital mortality, complications, length of stay, and cost for patients undergoing robotic-assisted lobectomy were compared with those for patients undergoing thoracoscopic lobectomy. RESULTS: We identified 2,498 robotic-assisted and 37,595 thoracoscopic lobectomies performed from 2008 to 2011. The unadjusted rate for any complication was higher for those undergoing robotic-assisted lobectomy than for those undergoing thoracoscopic lobectomy (50.1% vs 45.2%, P < .05). Specific complications that were higher included cardiovascular complications (23.3% vs 20.0%, P < .05) and iatrogenic bleeding complications (5.0% vs 2.0%, P < .05). The higher risk of iatrogenic bleeding complications persisted in multivariable analyses (adjusted OR, 2.64; 95% CI, 1.58-4.43). Robotic-assisted lobectomy costs significantly more than thoracoscopic lobectomy ($22,582 vs $17,874, P < .05). CONCLUSIONS: In this early experience with robotic surgery, robotic-assisted lobectomy was associated with a higher rate of intraoperative injury and bleeding than was thoracoscopic lobectomy, at a significantly higher cost. PMID- 24810547 TI - Frequent hepatocyte growth factor overexpression and low frequency of c-Met gene amplification in human papillomavirus-negative tonsillar squamous cell carcinoma and their prognostic significances. AB - Human papillomavirus (HPV) is an important prognostic factor for tonsillar squamous cell carcinoma (TSCC). HPV-positive and HPV-negative TSCCs are considered distinct in terms of prognosis and sensitivity to chemo/radiotherapy. However, to date, no study has thoroughly evaluated the individual prognostic factors for these 2 disease subgroups. Hepatocyte growth factor (HGF)-Met signaling pathway can be a predictive marker for prognosis or therapy response, especially in HPV-negative TSCC. We therefore investigated the prognostic values of HGF and c-Met expression in TSCC according to HPV status. Immunohistochemical analyses of HGF and c-Met protein expression and silver in situ hybridization of c-Met gene copy number were performed in 79 formalin-fixed, paraffin-embedded specimens. In HPV-negative TSCC, HGF overexpression, regional lymph node category, and ipsilateral cervical nodal metastasis predicted decreased overall survival (OS) (P = .017, P = .024, and P = .003, respectively). The latter 2 were also independent prognostic factors for progression-free survival (P = .023 and P = .002, respectively). In HPV-positive TSCC, heavy alcohol consumption and advanced primary tumor category were predictive of progression-free survival, whereas no independent prognostic factor for OS was identified. HGF overexpression had a significant effect on OS in HPV-negative TSCC but not in HPV positive TSCC. HPV-negative/HGF-high expression tumors exhibited the worst survival outcomes, whereas HPV-positive/HGF-low expression tumors had the most favorable prognosis. c-Met expression and c-Met gene amplification were not associated with survival outcomes in TSCC patients. In conclusion, HGF may be a potential prognostic marker in HPV-negative TSCC, whereas c-Met exhibited limited clinical significance in TSCC. PMID- 24810549 TI - Excited state deactivation pathways of neutral/protonated anisole and p fluoroanisole: a theoretical study. AB - The potential energy profiles of neutral and protonated anisole and p fluoroanisole at different electronic states have been investigated extensively by the RI-MP2 and RI-CC2 methods. The calculations reveal that the relaxation dynamics in protonated anisole and p-fluoroanisole are essentially different from those of the neutral analogues. In neutral anisole/p-fluoroanisole, the (1)pisigma* state plays a vital relaxation role along the O-CH3 coordinate, yielding the CH3 radical. For both of these molecules, the calculations indicate conical intersections (CIs) between the ground and excited state potential energy (PE) curves, hindered by a small barrier, and providing non-adiabatic gates for radiation-less deactivation to the ground state. Nevertheless, for the protonated cases, besides the prefulvenic deformation of the benzene ring, it has been predicted that the lowest (1)(sigma,n)pi* state along the C-O-C bond angle plays an important role in photochemistry and the relaxation dynamics. The S1, S0 PE profiles of protonated anisole along with the former reaction coordinate (out-of plane deformation) show a barrierless relaxation pathway, which can be responsible for the ultrafast deactivation of excited systems to the ground state via the low-lying S1/S0 conical intersection. Moreover, the later reaction coordinate in protonated species (C-O-C angle from 120 degrees -180 degrees ) is consequently accompanied with the bond cleavage of C-OCH3 at the (1)(sigma,n)pi* state, hindered by a barrier of ~0.51 eV, and can be responsible for the relaxation of excited systems with significant excess energy (hnu>= 5 eV). Furthermore, according to the RI-CC2 calculated results, different effects on the S1-S0 electronic transition energy of anisole and p-fluoroanisole upon protonation have been predicted. The first electronic transitions of anisole and p-fluoroanisole shift by ~0.3 and 1.3 eV to the red respectively due to protonation. PMID- 24810548 TI - A meta-analysis of P2X7 gene-762T/C polymorphism and pulmonary tuberculosis susceptibility. AB - AIM: We performed a comprehensive meta-analysis to determine the association between P2X7 -762T/C polymorphism and pulmonary tuberculosis susceptibility. METHODOLOGY: Based on comprehensive searches of the PubMed, SCI, Elsevier, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between P2X7 -762T/C polymorphism and pulmonary tuberculosis risk. Pooled odds ratio (ORs) and 95% confidence intervals (95%CIs) were calculated in random-effects model. RESULTS: A total of 2207 tuberculosis cases and 2220 controls in 8 case-control studies were included in this meta-analysis. Allele model (C vs. T: p = 0.15; OR = 0.83, 95% CI = 0.65 1.07), homozygous model (CC vs. TT: p = 0.23; OR = 0.73, 95% CI = 0.44 to 1.22), and heterozygous model (CT vs. TT: p = 0.57; OR = 0.92, 95% CI = 0.68 to 1.24) did not show increased risk of developing pulmonary tuberculosis. Similarly, dominant model (CC+CT vs. TT: p = 0.32; OR = 0.84, 95% CI = 0.59 to 1.19) and recessive model (CC vs. CT+TT: p = 0.08; OR = 0.77, 95% CI = 0.57 to 1.04) failed to show increased risk of developing pulmonary tuberculosis. Subgroup analysis by ethnicity did not detect any significant association between P2X7-762T/C polymorphism and pulmonary tuberculosis susceptibility. CONCLUSIONS: P2X7 -762T/C gene polymorphism is not associated with pulmonary tuberculosis susceptibility. PMID- 24810550 TI - Biomarkers of healthy ageing: expectations and validation. AB - The challenge of devising a set of biomarkers capable of measuring the ageing rate in human subjects was articulated long ago. In recent years, progress in the basic biology of ageing suggests the realistic possibility of preventive or restaurative interventions that may extend healthy lifespan in mammals including human subjects. Specifically, frailty is being increasingly recognised as a clinically relevant syndrome that may be therapeutically addressed. This greatly enhances the need for sensitive and specific biomarkers of healthy ageing that are validated in both experimental animals and, importantly, in human subjects over the whole age range. Here, we will discuss the present challenges and requirements for biomarker validation in human subjects. We propose the central requirements for a validated biomarker of healthy ageing as: (i) better predictive power than chronological age for multiple dimensions of ageing; (ii) identification of the age range in which the marker is informative; (iii) establishment of sensitivity/specificity as indicators of its predictive power at the level of the individual; (iv) minimisation of methodological variation between laboratories. PMID- 24810551 TI - The molecular structure of Alzheimer beta-amyloid fibrils formed in the presence of phospholipid vesicles. AB - beta-amyloid (Abeta) fibrils are the major species involved in Alzheimer's disease (AD). An atomic-resolution molecular structure of Abeta40 fibrils formed in the presence of lipid vesicles was obtained by using magic angle spinning (MAS) solid-state NMR spectroscopy. The fibril structures formed in the presence of the lipid vesicles are remarkably different from those formed in solution. These results provide insights into the molecular mechanism of Abeta aggregation in the presence of lipid vesicles. PMID- 24810552 TI - Ramadan fasting and pregnancy: implications for fetal development in summer season. AB - AIMS: In the Islamic religion, Ramadan is a month in the year that is passed by fasting. Healthy adult individuals are prohibited to eat, drink, and smoke from sunrise to sunset. In the present study, our aim was to assess the relation of Ramadan fasting with fetal development and maternal-fetal Doppler indices in pregnant women. METHODS: This is a prospective case-control study carried out in the month of Ramadan in 2013 (9 July-7 August). One hundred and six pregnant women at the second and third trimesters of pregnancy were enrolled into the study. The sample size of the fasting group was 83 and the non-fasting group sample size was also 83. Fetal biometric measurements, such as biparietal diameter, head circumference, abdominal circumference, femur length, estimated fetal weight, amniotic fluid index, and Doppler indices of both uterine and umbilical arteries were evaluated by gray scala and color Doppler ultrasound at the beginning and end of Ramadan. RESULTS: At the end of the Ramadan, increase in biparietal diameter, head circumference, and femur length showed a statistically significant difference from initial measurements (P<0.05). When fasting and non fasting groups were compared separately, an increase in amniotic fluid index was statistically significant in the non-fasting group (P<0.05). CONCLUSION: We demonstrated some adverse effects of Ramadan fasting on fetal development. In the Islamic religion, pregnant individuals have the privilege of not fasting; therefore, they should consider postponing fasting to the postpartum period, especially in the summer season. If they are willing to do so, an appropriate nutritional program should be recommended. PMID- 24810553 TI - Individual consultant practice does not affect the overall intervention rate: a 6 year study. AB - BACKGROUND: Differences exist in obstetric intervention rates between hospitals but it is not known if the individual consultant governs the decision to intervene or whether intervention is a product of agreed protocols and working practices. The purpose of this study is to analyse the differences in obstetric intervention rates amongst individual consultants working in a large maternity unit. METHODS: Each consultant was responsible for all deliveries occurring in successive 24-h periods. Over a 6-year period all deliveries resulting from a spontaneous onset of labour were matched to the consultant in charge at the time of the delivery and analysed. RESULTS: There were no differences seen in normal delivery rates (chi2=4.478, P=0.812) and vacuum (chi2=12.232, P=0.141) rates for the consultants. Significant differences were found in both forceps rate (chi2=21.462, P=0.006) and caesarean rate (chi2=24.535, P=0.002) between consultants. When the forceps rate was combined with vacuum rate there were no significant differences. CONCLUSIONS: Within the hospital, individual consultants demonstrated no significant variations in overall intervention rates. However, when intervention occurred, different consultants showed preferences for forceps and caesarean section. PMID- 24810554 TI - Controversial clinical practices for patients with preeclampsia or HELLP syndrome: a survey. AB - BACKGROUND: Considerable controversy continues to surround the management of severe preeclampsia and HELLP syndrome. Experts, researchers, and those published in the field were surveyed about their specific practices. MATERIALS AND METHODS: An extensive literature search was undertaken to identify the cohort of authors with recent publications on the subjects of preeclampsia (2009-2012) and HELLP syndrome (2005-2012). Online surveys were sent to all authors using the email addresses found in their publications. RESULTS: Surveys were delivered by email to 363 authors of preeclampsia publications and 91 authors of HELLP syndrome publications. Completed surveys were received from 61 (13.4%) of the group. Except for consensus about the indication of corticosteroids for the enhancement of fetal lung maturation, there was considerable variation in corticosteroid practice and anesthesia techniques. CONCLUSIONS: A marked diversity in practice characterized the clinical care rendered by experts in the field of preeclampsia and HELLP syndrome. Thus, there is an urgent need for well-designed and executed prospective clinical trials to improve the evidence for best consensus practice in this area of obstetrical medicine. PMID- 24810555 TI - An assessment of basic nutrition knowledge of adolescents with eating disorders and their parents. AB - Objective: This study aims to determine and compare the level of basic nutrition knowledge of adolescents with eating disorders and their parents to adolescents without eating disorders and their parents. MATERIALS AND METHODS: This six-month convenience based survey recruited a total of 182 adolescents with and without an eating disorder and their parents. The surveys were conducted in a suburban adolescent medicine office. Main outcome measures were based on the 18 basic nutrition questions, while means, standard deviations, Wilcoxon Rank Sum Test, and chi2 were all employed for the analysis. RESULTS: None of the groups correctly answered more than half of the questions. In terms of the percentage of correct responses, there was a statistically significant difference between adolescents with eating disorders and their parents compared with adolescents without an eating disorder and their parents. Fewer than 16% of respondents in each group correctly answered the recommended daily caloric balance of fats, carbohydrates, and proteins. CONCLUSIONS: There is a deficiency in basic nutrition knowledge among adolescents with and without eating disorders and their parents. A significant increase in basic nutrition education needs to occur in order to increase the understanding of what is a "healthy" diet. PMID- 24810556 TI - Effect of external classroom noise on schoolchildren's reading and mathematics performance: correlation of noise levels and gender. AB - The present study investigated the effect of low, medium, and high traffic road noise as well as irrelevant background speech noise on primary school children's reading and mathematical performance. A total of 676 participants (324 boys, 47.9% and 352 girls, 52.1%) of the 4th and 5th elementary classes participated in the project. The participants were enrolled in public primary schools from urban areas and had ages ranging from 9 to 10 years and from. Schools were selected on the basis of increasing levels of exposure to road traffic noise and then classified into three categories (Low noise: 55-66 dB, Medium noise: 67-77 dB, and High noise: 72-80 dB). We measured reading comprehension and mathematical skills in accordance with the national guidelines for elementary education, using a test designed specifically for the purpose of this study. On the one hand, children in low-level noise schools showed statistically significant differences from children in medium- and high-level noise schools in reading performance (p<0.001). On the other hand, children in low-level noise schools differed significantly from children in high-level noise schools but only in mathematics performance (p=0.001). Girls in general did better in reading score than boys, especially in schools with medium- and high-level noise. Finally the levels of noise and gender were found to be two independent factors. PMID- 24810557 TI - More than a break: the impact of a social-pedagogical intervention during young persons' long-term hospital admission--a qualitative study. AB - BACKGROUND: Critical illness and long-term or repeated hospitalization can affect normal adolescent development. As a result, adolescents may feel isolated and "misplaced" on both pediatric and adult departments. The mission of the Center of Adolescent Medicine is to improve conditions for adolescent patients. To achieve this, the social educator offers an individualized social-pedagogical intervention for young people during long-term or repeated hospitalization. OBJECTIVE: The aim of this study was to identify the impact of the social pedagogical intervention using a qualitative approach. MATERIALS AND METHODS: A trained anthropologist interviewed seven adolescents who had individual sessions with a social educator during their hospital stay. The interviews were recorded and transcribed verbatim, and the transcripts were coded and thematized continuously. RESULTS: Through qualitative analysis, the following themes emerged: Recreation; Structure, participation, and motivation; and Friends and social network. The social-pedagogical approach is a combination of interpersonal relationships and individually tailored recreational activities. Even small entertaining activities changed the focus from patient identity and contributed to the feeling of being "normal." All young patients reported that the increased opportunities for decision-making and influence on the daily structure supported the feeling of being recognized and respected as an individual person as well as increased their motivation to go through their treatment. The interviewees emphasized the importance of experiencing something that was worth telling their friends about to help them stay in touch. CONCLUSION: Although the young patients emphasized the recreational aspects, the time spent with the social educator facilitated training in social competencies as well as conversations about emotional and sensitive topics. PMID- 24810558 TI - The effect of growth hormone treatment on height in children with idiopathic short stature. AB - BACKGROUND: Idiopathic short stature (ISS) is short stature of unknown cause. In 2003, the Food and Drug Administration (FDA) approved the use of growth hormone (GH) for ISS. Several studies have evaluated the effect of GH in children with ISS, in whom improved growth velocities and height standard deviation scores (SDS) have been reported. However, clinical variables influence the height improvement. OBJECTIVE: This study aimed to evaluate the effects of GH treatment on ISS and to analyze clinical factors associated with growth velocity. MATERIALS AND METHODS: This study was conducted retrospectively. Subjects diagnosed with ISS at Ajou University Hospital were divided into two groups, an ISS with GH treatment group (n=34) and an ISS control group (n=36). All children were prepubertal, and aged <10 years. We reviewed their auxological data, laboratory findings, and bone age. RESULTS: Growth velocity of the GH-treatment group exceeded that of controls by 3.37 cm/year (95% CI, 2.78-3.95). At baseline, the mean SDS for height in the treatment and control groups were equivalent (-2.25 +/ 0.29 and -2.22 +/- 0.31, respectively). However, after 1 year, the height of the GH-treated group exceeded that of the control group by 0.73 SDS (95% CI, 0.57 0.88). A negative correlation was found between age and growth velocity in the GH treatment group. CONCLUSION: GH treatment increased short-term growth velocity and height SDS of Korean children with ISS. Age was identified as the single most important factor correlated with growth velocity in GH treatment. PMID- 24810559 TI - Common approach to childhood obesity in Japan. AB - Although the prevalence of childhood obesity is plateauing, it remains a social concern. The Japan Society for the Study of Obesity devised criteria for obesity disease as a morbid state that requires medical treatment in 2002. Moreover, the Japanese Ministry of Health, Labour and Welfare announced diagnostic criteria for childhood metabolic syndrome in 2010 because of the increasing number of children with lifestyle-related diseases. The treatment of obesity needs to be prioritized, and three principles, other than behavioral therapy, have been introduced in this study for the general medical treatment of obesity without underlying diseases: (1) diet therapy, (2) exercise, and (3) no pharmacotherapy. However, preventing obesity is more important than its treatment. A previous study reported the tracking of an overweight status from infancy; therefore, it is important to prevent infants from becoming overweight. The concept of the developmental origins of health and disease has been attracting more attention in recent years; however, preventative measures prior to birth should also be considered to reduce the incidence of obesity. Although the methods used to approach the treatment of childhood obesity change with differences in race or lifestyle, those who are engaged in the medical treatment of childhood obesity worldwide can contribute to its treatment and prevention by a mutual exchange of information. PMID- 24810560 TI - Involvement of opioidergic and serotonergic systems in the analgesic activity of Cissus quadrangularis L. stem extract in mice. AB - BACKGROUND: Cissus quadrangularis L. (Vitaceae) is used as a bonesetter and as an analgesic. However, the bioactive fractions and the pharmacological mechanism of analgesic activity are not clearly known. Hence, this study aimed to characterize the analgesic activity profile of successively extracted fractions of C. quadrangularis and the pharmacological mechanism of analgesic activity in mice. METHODS: Dried C. quadrangularis stem was extracted successively with chloroform and methanol. The dried extracts were separately administered to mice intraperitoneally at the doses of 75, 150 and 300 mg/kg. The mice were tested separately in hot plate and tail flick tests. The mechanism of analgesic activity of chloroform extract was explored in the hot plate test at the dose of 300 mg/kg after pretreatment with naloxone, p-chlorophenylalanine methyl ester (pCPA) and phentolamine. The data were analyzed by one-way analysis of variance followed by Dunnett's test. RESULTS: Chloroform extract showed significant (p<0.05) analgesic effect at the doses of 75, 150 and 300 mg/kg in hot plate and tail flick tests. Methanol extract showed significant (p<0.05) analgesic effect at the dose of 300 mg/kg in hot plate and tail flick tests. Analgesic activity was not blocked (p<0.05) in the group pretreated with phentolamine but blocked in the groups pretreated with naloxone and pCPA. CONCLUSIONS: The chloroform extract was found to be more potent than methanol extract in inducing analgesic effect in mice, and the analgesic activity may be mediated through opioidergic and serotonergic pathways. PMID- 24810561 TI - Interference of therapeutic monoclonal immunoglobulins in the investigation of M proteins. PMID- 24810562 TI - Practical experience using galectin-3 in heart failure. AB - Heart failure is a complex mechanical and neurohormonal syndrome where the left ventricle fails as a pump, resulting in stasis of blood in the lungs and the periphery resulting in the cardial features of effort intolerance, fatigue, and peripheral edema. As part of the neurohormonal and local mechanical strain, tissue macrophages resident in the myocardium secrete galectin-3 which is a paracrine and endocrine factor which stimulates additional macrophages, pericytes, myofibroblasts, and fibroblasts to proliferate and secrete procollagen I which is irreversibly crosslinked resulting in myocardial fibrosis. In the general population, normal plasma concentrations of galectin-3 are <11.0 ng/mL. Galectin-3 measured in blood has been shown to: 1) identify increased risk for new onset heart failure in healthy middle-aged adults; 2) predict cardiac failure in patients after acute coronary syndromes; 3) help establish the diagnosis of heart failure with preserved ejection fraction in patients presenting with exercise intolerance; and 4) aid in the prognosis of heart failure with preserved and reduced left ventricular ejection fraction. This manuscript will present practical real case management in these applications to highlight the importance of this new in vitro diagnostic test. PMID- 24810563 TI - Optical cell separation from three-dimensional environment in photodegradable hydrogels for pure culture techniques. AB - Cell sorting is an essential and efficient experimental tool for the isolation and characterization of target cells. A three-dimensional environment is crucial in determining cell behavior and cell fate in biological analysis. Herein, we have applied photodegradable hydrogels to optical cell separation from a 3D environment using a computer-controlled light irradiation system. The hydrogel is composed of photocleavable tetra-arm polyethylene glycol and gelatin, which optimized cytocompatibility to adjust a composition of crosslinker and gelatin. Local light irradiation could degrade the hydrogel corresponding to the micropattern image designed on a laptop; minimum resolution of photodegradation was estimated at 20 um. Light irradiation separated an encapsulated fluorescent microbead without any contamination of neighbor beads, even at multiple targets. Upon selective separation of target cells in the hydrogels, the separated cells have grown on another dish, resulting in pure culture. Cell encapsulation, light irradiation and degradation products exhibited negligible cytotoxicity in overall process. PMID- 24810564 TI - Defining hospital's internal boundaries. An organisational complexity criterion. AB - The aim of this paper is to provide empirical evidences supporting the definition of hospital wards' boundaries in organisational designing processes, by suggesting services aggregation criteria that are focused on organisational complexity. In order to test the research hypotheses, a panel data analysis was conducted on Lombardy hospitals in Italy. Information was gathered both from administrative records - aggregated at in-patient ward level - and general registry offices. The results highlight that the wards offering integrated services perform better than those that are more specialised. However, for growing levels of within-complexity, the positive effects of formal integration between wards tend to reduce. Some guidelines for practitioners engaged in defining hospitals' organisational structures can be drawn from the empirical analysis. PMID- 24810566 TI - DNA loops specify p53 network responses. PMID- 24810565 TI - Antileishmanial activity of the estrogen receptor modulator raloxifene. AB - BACKGROUND: The treatment of leishmaniasis relies mostly on parenteral drugs with potentially serious adverse effects. Additionally, parasite resistance in the treatment of leishmaniasis has been demonstrated for the majority of drugs available, making the search for more effective and less toxic drugs and treatment regimens a priority for the control of leishmaniasis. The aims of this study were to evaluate the antileishmanial activity of raloxifene in vitro and in vivo and to investigate its mechanism of action against Leishmania amazonensis. METHODOLOGY/PRINCIPAL FINDINGS: Raloxifene was shown to possess antileishmanial activity in vitro against several species with EC50 values ranging from 30.2 to 38.0 uM against promastigotes and from 8.8 to 16.2 uM against intracellular amastigotes. Raloxifene's mechanism of action was investigated through transmission electron microscopy and labeling with propidium iodide, DiSBAC2(3), rhodamine 123 and monodansylcadaverine. Microscopic examinations showed that raloxifene treated parasites displayed autophagosomes and mitochondrial damage while the plasma membrane remained continuous. Nonetheless, plasma membrane potential was rapidly altered upon raloxifene treatment with initial hyperpolarization followed by depolarization. Loss of mitochondrial membrane potential was also verified. Treatment of L. amazonensis-infected BALB/c mice with raloxifene led to significant decrease in lesion size and parasite burden. CONCLUSIONS/SIGNIFICANCE: The results of this work extend the investigation of selective estrogen receptor modulators as potential candidates for leishmaniasis treatment. The antileishmanial activity of raloxifene was demonstrated in vitro and in vivo. Raloxifene produces functional disorder on the plasma membrane of L. amazonensis promastigotes and leads to functional and morphological disruption of mitochondria, which culminate in cell death. PMID- 24810567 TI - Impacts of UVB provision and dietary calcium content on serum vitamin D3 , growth rates, skeletal structure and coloration in captive oriental fire-bellied toads (Bombina orientalis). AB - Many amphibian species are dependent on ex situ conservation interventions for their long-term persistence. However, projects have been jeopardised by husbandry issues involving poor calcium metabolism and nutritional metabolic bone disease (NMBD). Healthy calcium metabolism requires appropriate dietary calcium content and access to vitamin D3 . In many animals, vitamin D3 can be photobiosynthesised in skin exposed to UVB radiation, as well as extracted from the diet, but the extent of vitamin D3 photobiosynthesis in amphibians is poorly known. Additionally, prey insects for captive amphibians are deficient in calcium and calcium content must be artificially increased, but the effects of different levels of augmentation and their interaction with UVB exposure are also little understood. We fed captive fire-bellied toads (Bombina orientalis) with crickets augmented to contain 5% and 10% calcium and housed them with and without UVB exposure. Despite additional dietary vitamin D3 supplementation, we found that toads exposed to UVB radiation exhibited significantly higher serum vitamin D3 levels, indicating that this species may partly rely on photobiosynthesis sources of vitamin D3 . These data are the first to show a direct link between UVB exposure and serum vitamin D3 in an amphibian. We found significant positive effects of UVB exposure and 10% dietary calcium content on skeletal structure, as well as complex interactions between treatments. We also found UVB radiation exposure resulted in more rapid natural coloration acquisition. Together, this indicates that standard calcium plus vitamin D3 supplementation methods may not fully substitute for UVB exposure and for increased feeder insect calcium content. This may have implications for the success of ex situ amphibian conservation, as well as for the welfare of captive amphibians in general. Our data lend support for the provision of UVB radiation for captive, basking amphibians. PMID- 24810568 TI - Histological changes induced by Polyglycolic-Acid (PGA) scaffolds seeded with autologous adipose or muscle-derived stem cells when implanted on rabbit bladder. AB - PURPOSE: To evaluate the morphological and histological changes induced by PGA scaffold seeded with autologous adipose or muscle derived stem cells implanted on rabbit bladder wall. MATERIAL AND METHODS: Adipose derived stem cells (ADSCs) were obtained from the inguinal fat of eight rabbits and muscle derived stem cells (MDSCs) from the anterior tibial muscle of other eight rabbits. After culture and isolation, the cells were stained with Vybrant Red CM DiI and then implanted at third passage. Two PGA scaffolds were implanted on the bladder submucosa of each animal. On the right bladder side was implanted unseeded PGA scaffold while on the left side was implanted ADSCs or skeletal MDSCs seeded PGA scaffold. ADSCs were implanted in eight animals and MDSC in other eight animals. The animals were sacrificed at four and eight weeks. Histological evaluation was performed with Hematoxylin and Eosin, Masson's Trichrome and smooth muscle alpha actin. RESULTS: We observed a mild inflammatory response in all the three groups. Seeded scaffolds induced higher lymphocytes and lower polimorphonuclear migration than controls. Fibrosis was more pronounced in the control groups. Smooth muscle alpha-actin was positive only in ADSC and MDSC seeded scaffolds. At four and eight weeks ADCSs and skeletal MDSCs labeled cells were found at the implant sites. CONCLUSIONS: The implantation of PGA scaffolds seeded with ADSC and MDSC induced less fibrosis than control and smooth muscle regeneration. PMID- 24810569 TI - Synthesis and insecticidal activity of novel hydrazone compounds derived from a naturally occurring lignan podophyllotoxin against Mythimna separata (Walker). AB - In continuation of our program aimed at the discovery and development of natural product-based insecticidal agents, a series of novel hydrazone derivatives of podophyllotoxin, which is a naturally occurring aryltetralin lignan and isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum species, were synthesized and evaluated as insecticidal agents against the pre third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. Especially compounds 8i, 8j, 8t, and 8u showed the more potent insecticidal activity with the final mortality rates greater than 60%. PMID- 24810571 TI - Indentation and needle insertion properties of the human eye. AB - PURPOSE: Characterization of the biomechanical properties of the human eye has a number of potential utilities. One novel purpose is to provide the basis for development of suitable tissue-mimicking material. The purpose of this study was to determine the indentation and needle insertion characteristics on human eye globes and tissue strips. METHODS: An indenter assessed the elastic response of human eye globes and tissue strips under increasing compressive loads. Needle insertion determined the force (N) needed to penetrate various areas of the eye wall. RESULTS: The results demonstrated that globes underwent slightly greater indentation at the midline than at the central cornea, and corneal strips indented twofold more than scleral strips, although neither difference was significant (P=0.400 and P=0.100, respectively). Significant differences were observed among various areas of needle insertion (P<0.001). Needle insertion through the anterior sclera (adjacent to the limbus) and posterior sclera (adjacent to the optic nerve) required the greatest amount of force (0.954 and 1.005 N, respectively). The force required to penetrate the central cornea (0.518 N) was significantly lower than all other areas except the midline sclera (0.700 N) CONCLUSION: These data form the basis for further research into the development of a tissue-mimicking human eye construct with potential utility as a model for use in ophthalmology research and surgical teaching. PMID- 24810572 TI - RE: Long-term outcomes and risk factors for failure with the EX-press glaucoma drainage device. PMID- 24810573 TI - Response to: RE: Long-term outcomes and risk factors for failure with the EX press glaucoma drainage device. PMID- 24810570 TI - Adipose-derived stromal cells for osteoarticular repair: trophic function versus stem cell activity. AB - The identification of multipotent adipose-derived stromal cells (ASC) has raised hope that tissue regeneration approaches established with bone-marrow-derived stromal cells (BMSC) can be reproduced with a cell-type that is far more accessible in large quantities. Recent detailed comparisons, however, revealed subtle functional differences between ASC and BMSC, stressing the concept of a common mesenchymal progenitor existing in a perivascular niche across all tissues. Focussing on bone and cartilage repair, this review summarises recent in vitro and in vivo studies aiming towards tissue regeneration with ASC. Advantages of good accessibility, high yield and superior growth properties are counterbalanced by an inferiority of ASC to form ectopic bone and stimulate long bone healing along with their less pronounced osteogenic and angiogenic gene expression signature. Hence, particular emphasis is placed on establishing whether stem cell activity of ASC is so far proven and relevant for successful osteochondral regeneration, or whether trophic activity may largely determine therapeutic outcome. PMID- 24810574 TI - Relapsed T-cell acute lymphoblastic leukaemia in the vitreous of an adult: a case report. PMID- 24810575 TI - Probing the orbital origin of conductance oscillations in atomic chains. AB - We investigate periodical oscillations in the conductance of suspended Au and Pt atomic chains during elongation under mechanical stress. Analysis of conductance and shot noise measurements reveals that the oscillations are mainly related to variations in a specific conduction channel as the chain undergoes transitions between zigzag and linear atomic configurations. The calculated local electronic structure shows that the oscillations originate from varying degrees of hybridization between the atomic orbitals along the chain as a function of the zigzag angle. These variations are highly dependent on the directionally and symmetry of the relevant orbitals, in agreement with the order-of-magnitude difference between the Pt and Au oscillation amplitudes observed in experiment. Our results demonstrate that the sensitivity of conductance to structural variations can be controlled by designing atomic-scale conductors in view of the directional interactions between atomic orbitals. PMID- 24810577 TI - Integrating social capital theory, social cognitive theory, and the technology acceptance model to explore a behavioral model of telehealth systems. AB - Telehealth has become an increasingly applied solution to delivering health care to rural and underserved areas by remote health care professionals. This study integrated social capital theory, social cognitive theory, and the technology acceptance model (TAM) to develop a comprehensive behavioral model for analyzing the relationships among social capital factors (social capital theory), technological factors (TAM), and system self-efficacy (social cognitive theory) in telehealth. The proposed framework was validated with 365 respondents from Nantou County, located in Central Taiwan. Structural equation modeling (SEM) was used to assess the causal relationships that were hypothesized in the proposed model. The finding indicates that elderly residents generally reported positive perceptions toward the telehealth system. Generally, the findings show that social capital factors (social trust, institutional trust, and social participation) significantly positively affect the technological factors (perceived ease of use and perceived usefulness respectively), which influenced usage intention. This study also confirmed that system self-efficacy was the salient antecedent of perceived ease of use. In addition, regarding the samples, the proposed model fitted considerably well. The proposed integrative psychosocial-technological model may serve as a theoretical basis for future research and can also offer empirical foresight to practitioners and researchers in the health departments of governments, hospitals, and rural communities. PMID- 24810576 TI - Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson's disease. AB - Alpha-synuclein (aSyn) is the main component of proteinaceous inclusions known as Lewy bodies (LBs), the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Although aSyn is phosphorylated at low levels under physiological conditions, it is estimated that ~ 90% of aSyn in LBs is phosphorylated at S129 (pS129). Nevertheless, the significance of pS129 in the biology of aSyn and in PD pathogenesis is still controversial. Here, we harnessed the power of budding yeast in order to assess the implications of phosphorylation on aSyn cytotoxicity, aggregation and sub-cellular distribution. We found that aSyn is phosphorylated on S129 by endogenous kinases. Interestingly, phosphorylation reduced aSyn toxicity and the percentage of cells with cytosolic inclusions, in comparison to cells expressing mutant forms of aSyn (S129A or S129G) that mimic the unphosphorylated form of aSyn. Using high-resolution 4D imaging and fluorescence recovery after photobleaching (FRAP) in live cells, we compared the dynamics of WT and S129A mutant aSyn. While WT aSyn inclusions were very homogeneous, inclusions formed by S129A aSyn were larger and showed FRAP heterogeneity. Upon blockade of aSyn expression, cells were able to clear the inclusions formed by WT aSyn. However, this process was much slower for the inclusions formed by S129A aSyn. Interestingly, whereas the accumulation of WT aSyn led to a marked induction of autophagy, cells expressing the S129A mutant failed to activate this protein quality control pathway. The finding that the phosphorylation state of aSyn on S129 can alter the ability of cells to clear aSyn inclusions provides important insight into the role that this posttranslational modification may have in the pathogenesis of PD and other synucleinopathies, opening novel avenues for investigating the molecular basis of these disorders and for the development of therapeutic strategies. PMID- 24810578 TI - Perchlorate exposure and thyroid function in ammonium perchlorate workers in Yicheng, China. AB - The impact of low level dust on the thyroid function of workers chronically exposed to ammonium perchlorate (AP) is uncertain and controversial. The aim of this study was to examine whether workers in China with long-term (>3 years) occupational exposure to low levels of AP dust had affected thyroid homeostasis. Mean occupational exposures to AP dust ranged from 0.43 to 1.17 mg/m3. Geometric means of post-shift urinary perchlorate levels were 20.5 ug/L for those exposed and 12.8 ug/L for the controls. No significant differences were found for thyroid function parameters of FT3, FT4, or log TSH or for TPO prevalence or thyroglobulin levels. Additionally, no differences in findings were observed for complete blood count (CBC), serum biochemical profile, or pulmonary function test. Median urinary iodine levels of 172 and 184 ug/L showed that the workers had sufficient iodine intake. This study found no effect on thyroid function from long term, low-level documented exposure to ammonium perchlorate. It is the first study to report both thyroid status parameters and urinary perchlorate, a biomarker of internal perchlorate exposure, in occupationally exposed workers in China. PMID- 24810579 TI - Health utilities of type 2 diabetes-related complications: a cross-sectional study in Sweden. AB - This study estimates health utilities (HU) in Sweden for a range of type 2 diabetes-related complications using EQ-5D and two alternative tariffs (UK and Swedish) from 1757 patients with type 2 diabetes from the Swedish National Diabetes Register (NDR). Ordinary least squares were used for statistical analysis. Lower HU was found for female gender, younger age at diagnosis, higher BMI, and history of complications. Microvascular and macrovascular complications had the most negative effect on HU among women and men, respectively. The greatest decline in HU was associated with kidney disorders (-0.114) using the UK tariff and stroke (-0.059) using the Swedish tariff. Multiple stroke and non acute ischaemic heart disease had higher negative effect than a single event. With the UK tariff, each year elapsed since the last microvascular/macrovascular complication was associated with 0.013 and 0.007 units higher HU, respectively. We found important heterogeneities in effects of complications on HU in terms of gender, multiple event, and time. The Swedish tariff gave smaller estimates and so may result in less cost-effective interventions than the UK tariff. These results suggest that incorporating subgroup-specific HU in cost-utility analyses might provide more insight for informed decision-making. PMID- 24810580 TI - De novo microdeletion of BCL11A is associated with severe speech sound disorder. AB - In 10 cases of 2p15p16.1 microdeletions reported worldwide to date, shared phenotypes included growth retardation, craniofacial and skeletal dysmorphic traits, internal organ defects, intellectual disability, nonverbal or low verbal status, abnormal muscle tone, and gross motor delays. The size of the deletions ranged from 0.3 to 5.7 Mb, where the smallest deletion involved the BCL11A, PAPOLG, and REL genes. Here we report on an 11-year-old male with a heterozygous de novo 0.2 Mb deletion containing a single gene, BCL11A, and a phenotype characterized by childhood apraxia of speech and dysarthria in the presence of general oral and gross motor dyspraxia and hypotonia as well as expressive language and mild intellectual delays. BCL11A is situated within the dyslexia susceptibility candidate region 3 (DYX3) candidate region on chromosome 2. The present case is the first to involve a single gene within the microdeletion region and a phenotype restricted to a subset of the traits observed in other cases with more extensive deletions. PMID- 24810581 TI - Validation of potential reference genes for qPCR in maize across abiotic stresses, hormone treatments, and tissue types. AB - The reverse transcription quantitative polymerase chain reaction (RT-qPCR) is a powerful and widely used technique for the measurement of gene expression. Reference genes, which serve as endogenous controls ensure that the results are accurate and reproducible, are vital for data normalization. To bolster the literature on reference gene selection in maize, ten candidate reference genes, including eight traditionally used internal control genes and two potential candidate genes from our microarray datasets, were evaluated for expression level in maize across abiotic stresses (cold, heat, salinity, and PEG), phytohormone treatments (abscisic acid, salicylic acid, jasmonic acid, ethylene, and gibberellins), and different tissue types. Three analytical software packages, geNorm, NormFinder, and Bestkeeper, were used to assess the stability of reference gene expression. The results revealed that elongation factor 1 alpha (EF1alpha), tubulin beta (beta-TUB), cyclophilin (CYP), and eukaryotic initiation factor 4A (EIF4A) were the most reliable reference genes for overall gene expression normalization in maize, while GRP (Glycine-rich RNA-binding protein), GLU1(beta-glucosidase), and UBQ9 (ubiquitin 9) were the least stable and most unsuitable genes. In addition, the suitability of EF1alpha, beta-TUB, and their combination as reference genes was confirmed by validating the expression of WRKY50 in various samples. The current study indicates the appropriate reference genes for the urgent requirement of gene expression normalization in maize across certain abiotic stresses, hormones, and tissue types. PMID- 24810583 TI - Towards the development of a surface plasmon resonance assay to evaluate the glycosylation pattern of monoclonal antibodies using the extracellular domains of CD16a and CD64. AB - We here report the production and purification of the extracellular domains of two Fcgamma receptors, namely CD16a and CD64, by transient transfection in mammalian cells. The use of these two receptor ectodomains for the development of quantitative assays aiming at controlling the quality of monoclonal antibody production lots is then discussed. More specifically, the development of surface plasmon resonance-based biosensor assays for the evaluation of the glycosylation pattern and the aggregation state of monoclonal antibodies is presented. Our biosensor approach allows discriminating between antibodies harboring different galactosylation profiles as well as to detect low levels (i.e., less than 2%) of monoclonal antibody aggregates. PMID- 24810582 TI - Maternal cypermethrin exposure during the perinatal period impairs testicular development in C57BL male offspring. AB - Numerous studies have demonstrated that endocrine-disrupting compounds (EDC) are a possible cause of male reproductive organ malfunction and malformation. Cypermethrin (CYP) is a widely used synthetic pyrethroid and a potential EDC. This study aimed to examine the effects of perinatal exposure to low-dose CYP on the development and function of the offspring testes. Pregnant mice were intragastrically administered 0.12 to 12 mg/kg/day CYP from embryonic day 0.5 (E0.5) to weaning (PD21.5, postnatal day 21.5). Maternal exposure to 0.12, 1.2, and 12 mg/kg/day CYP affected the body and organ weight of the offspring. Exposure of CYP led to a dose-dependent decrease in the male-to-female sex ratio. A histopathological analysis revealed a thinner seminiferous epithelium layer at PD21.5, interstitial hyperplasia at PD45.5, and germ cell vacuolization at PD90.5 in the 12 mg/kg/day CYP group. The TUNEL assay results revealed increased germ cell apoptosis in the 12 mg/kg/day CYP group. The serum testosterone (T) level decreased, whereas the estradiol level increased with age in the 1.2 and 12 mg/kg/day CYP groups. The RT-PCR analysis demonstrated decreased expression of T production-related, mitosis-related, and meiosis-related genes in the 1.2 and 12 mg/kg/day CYP groups. The in vitro experimental results demonstrated reduced expression of steroidogenesis genes and decreased T levels. It is concluded that perinatal exposure to low-dose CYP affects testes development and function in adults. PMID- 24810584 TI - Meta-analysis of the association between dietary lycopene intake and ovarian cancer risk in postmenopausal women. AB - Accumulating evidence suggests the protective role of dietary lycopene against the risk of ovarian cancer due to its antioxidant activity, but not all relevant studies have deduced positive results. The aim of the present study was to investigate the exact relationship between dietary lycopene intake and ovarian cancer risk by conducting a meta-analysis. The 10 studies included in our meta analysis were selected from the PubMed database, and final risk estimates were calculated by using a random-effects model. Our study demonstrated an insignificant reverse association between dietary lycopene and ovarian cancer risk (OR, 0.963; 95% CI, 0.859-1.080), and subgroup analysis stratified by study design, location, histological type of ovarian cancer, and length of dietary recall showed no statistically significant results. No heterogeneity was observed (p = 0.336, I(2) = 11.6%). Our present meta-analysis suggests the potential role of dietary lycopene against the risk of ovarian cancer among postmenopausal women, which provides opportunity for developments in the prevention of ovarian cancer. PMID- 24810585 TI - Effect of hydrophilic defects on water transport in MFI zeolites. AB - The subnanometer pore structure of zeolites and other microporous materials has been proposed to act as a molecular sieve for various water separation technologies. However, due to the increased interaction between the solid and water in these nanoconfined spaces, it is unclear which type of interface, be it hydrophilic or hydrophobic, offers an advantageous medium for enhancing transport properties. In this work, we probe the role of hydrophilic defects on the transport of water inside the microporous hydrophobic MFI zeolite pore structure via combined sorption and high-pressure infiltration experiments. While the inclusion of defects was observed to increase the amount of water within the zeolite pore network by up to 7 times at the saturation pressure, the diffusivity of this infiltrated water was lowered by up to 2 orders of magnitude in comparison to that of water within the nearly defect-free hydrophobic MFI zeolite. Subsequently, the permeability of water within the more defective MFI zeolite was an order of magnitude lower than that of the nearly defect-free zeolite. The results from these experiments suggest that the intrinsic hydrophobic pore structure of MFI zeolites can facilitate faster water transport due to the decreased attraction between the water and the defect-free surface. While the strong attraction of water to the defects allows for water to infiltrate the porous network at lower pressures, the results suggest that this strong attraction decreases the mobility of the infiltrated water. The insights gained from this study can be utilized to improve the design of future membranes for water desalination and other separation techniques. PMID- 24810586 TI - Identification and validation of reference genes for quantitative real-time PCR normalization and its applications in lycium. AB - Lycium barbarum and L. ruthenicum are extensively used as traditional Chinese medicinal plants. Next generation sequencing technology provides a powerful tool for analyzing transcriptomic profiles of gene expression in non-model species. Such gene expression can then be confirmed with quantitative real-time polymerase chain reaction (qRT-PCR). Therefore, use of systematically identified suitable reference genes is a prerequisite for obtaining reliable gene expression data. Here, we calculated the expression stability of 18 candidate reference genes across samples from different tissues and grown under salt stress using geNorm and NormFinder procedures. The geNorm-determined rank of reference genes was similar to those defined by NormFinder with some differences. Both procedures confirmed that the single most stable reference gene was ACNTIN1 for L. barbarum fruits, H2B1 for L. barbarum roots, and EF1alpha for L. ruthenicum fruits. PGK3, H2B2, and PGK3 were identified as the best stable reference genes for salt treated L. ruthenicum leaves, roots, and stems, respectively. H2B1 and GAPDH1+PGK1 for L. ruthenicum and SAMDC2+H2B1 for L. barbarum were the best single and/or combined reference genes across all samples. Finally, expression of salt-responsive gene NAC, fruit ripening candidate gene LrPG, and anthocyanin genes were investigated to confirm the validity of the selected reference genes. Suitable reference genes identified in this study provide a foundation for accurately assessing gene expression and further better understanding of novel gene function to elucidate molecular mechanisms behind particular biological/physiological processes in Lycium. PMID- 24810587 TI - Combined deacetylation and PFI refining pretreatment of corn cob for the improvement of a two-stage enzymatic hydrolysis. AB - A combined deacetylation and PFI refining pretreatment was applied to corn cob for the improvement of a two-stage enzymatic hydrolysis. In stage 1, the pretreated corn cob was first hydrolyzed by xylanase to produce xylo oligosaccharides (XOS). In stage 2, the solid residue isolated from stage 1 was further hydrolyzed by cellulase and beta-glucosidase. NaOH, Na2CO3, and Ca(OH)2 were tested to remove acetyl groups in the process of deacetylation, and it was found that Ca(OH)2 could be the most suitable alkali for deacetylation in this work. After deacetylation using 0.8 mmol of Ca(OH)2/g of substrate and PFI refining, 50.5% xylan in the raw material could be hydrolyzed into XOS. The corresponding xylan yield of stage 1, the glucan yield of stage 2, and the total sugar yield (all sugars released in the hydrolyzate) after the two-stage enzymatic hydrolysis were 0.306, 0.305, and 0.661 g/g of corn cob, respectively. PMID- 24810588 TI - Involvement of microtubular network and its motors in productive endocytic trafficking of mouse polyomavirus. AB - Infection of non-enveloped polyomaviruses depends on an intact microtubular network. Here we focus on mouse polyomavirus (MPyV). We show that the dynamics of MPyV cytoplasmic transport reflects the characteristics of microtubular motor driven transport with bi-directional saltatory movements. In cells treated with microtubule-disrupting agents, localization of MPyV was significantly perturbed, the virus was retained at the cell periphery, mostly within membrane structures resembling multicaveolar complexes, and at later times post-infection, only a fraction of the virus was found in Rab7-positive endosomes and multivesicular bodies. Inhibition of cytoplasmic dynein-based motility by overexpression of dynamitin affected perinuclear translocation of the virus, delivery of virions to the ER and substantially reduced the numbers of infected cells, while overexpression of dominant-negative form of kinesin-1 or kinesin-2 had no significant impact on virus localization and infectivity. We also found that transport along microtubules was important for MPyV-containing endosome sequential acquisition of Rab5, Rab7 and Rab11 GTPases. However, in contrast to dominant-negative mutant of Rab7 (T22N), overexpression of dominant-negative mutant Rab11 (S25N) did not affect the virus infectivity. Altogether, our study revealed that MPyV cytoplasmic trafficking leading to productive infection bypasses recycling endosomes, does not require the function of kinesin-1 and kinesin-2, but depends on functional dynein-mediated transport along microtubules for translocation of the virions from peripheral, often caveolin-positive compartments to late endosomes and ER - a prerequisite for efficient delivery of the viral genome to the nucleus. PMID- 24810589 TI - Slc26a7 chloride channel activity and localization in mouse Reissner's membrane epithelium. AB - Several members of the SLC26 gene family have highly-restricted expression patterns in the auditory and vestibular periphery and mutations in mice of at least two of these (SLC26A4 and SLC26A5) lead to deficits in hearing and/or balance. A previous report pointed to SLC26A7 as a candidate gene important for cochlear function. In the present study, inner ears were assayed by immunostaining for Slc26a7 in neonatal and adult mice. Slc26a7 was detected in the basolateral membrane of Reissner's membrane epithelial cells but not neighboring cells, with an onset of expression at P5; gene knockout resulted in the absence of protein expression in Reissner's membrane. Whole-cell patch clamp recordings revealed anion currents and conductances that were elevated for NO3- over Cl- and inhibited by I- and NPPB. Elevated NO3- currents were absent in Slc26a7 knockout mice. There were, however, no major changes to hearing (auditory brainstem response) of knockout mice during early adult life under constitutive and noise exposure conditions. The lack of Slc26a7 protein expression found in the wild-type vestibular labyrinth was consistent with the observation of normal balance. We conclude that SLC26A7 participates in Cl- transport in Reissner's membrane epithelial cells, but that either other anion pathways, such as ClC-2, possibly substitute satisfactorily under the conditions tested or that Cl- conductance in these cells is not critical to cochlear function. The involvement of SLC26A7 in cellular pH regulation in other epithelial cells leaves open the possibility that SLC26A7 is needed in Reissner's membrane cells during local perturbations of pH. PMID- 24810591 TI - Design principles for single standing nanowire solar cells: going beyond the planar efficiency limits. AB - Semiconductor nanowires (NWs) have long been used in photovoltaic applications but restricted to approaching the fundamental efficiency limits of the planar devices with less material. However, recent researches on standing NWs have started to reveal their potential of surpassing these limits when their unique optical property is utilized in novel manners. Here, we present a theoretical guideline for maximizing the conversion efficiency of a single standing NW cell based on a detailed study of its optical absorption mechanism. Under normal incidence, a standing NW behaves as a dielectric resonator antenna, and its optical cross-section shows its maximum when the lowest hybrid mode (HE11delta) is excited along with the presence of a back-reflector. The promotion of the cell efficiency beyond the planar limits is attributed to two effects: the built-in concentration caused by the enlarged optical cross-section, and the shifting of the absorption front resulted from the excited mode profile. By choosing an optimal NW radius to support the HE11delta mode within the main absorption spectrum, we demonstrate a relative conversion-efficiency enhancement of 33% above the planar cell limit on the exemplary a-Si solar cells. This work has provided a new basis for designing and analyzing standing NW based solar cells. PMID- 24810590 TI - A novel TetR-regulating peptide turns off rtTA-mediated activation of gene expression. AB - Conditional regulation of gene expression is a powerful and indispensable method for analyzing gene function. The "Tet-On" system is a tool widely used for that purpose. Here, the transregulator rtTA mediates expression of a gene of interest after addition of the small molecule effector doxycycline. Although very effective in rapidly turning on gene expression, the system is hampered by the long half-life of doxycycline which makes shutting down gene expression rapidly very difficult to achieve. We isolated an rtTA-binding peptide by in vivo selection that acts as a doxycycline antagonist and leads to rapid and efficient shut down of rtTA-mediated reporter gene expression in a human cell line. This peptide represents the basis for novel effector molecules which complement the "Tet-system" by enabling the investigator to rapidly turn gene expression not just on at will, but now also off. PMID- 24810592 TI - Functional outcome of patients treated for radiation-induced complete esophageal obstruction after successful endoscopic recanalization (with video). PMID- 24810593 TI - Diagnostic accuracy and cost-effectiveness of alternative methods for detection of soil-transmitted helminths in a post-treatment setting in western Kenya. AB - OBJECTIVES: This study evaluates the diagnostic accuracy and cost-effectiveness of the Kato-Katz and Mini-FLOTAC methods for detection of soil-transmitted helminths (STH) in a post-treatment setting in western Kenya. A cost analysis also explores the cost implications of collecting samples during school surveys when compared to household surveys. METHODS: Stool samples were collected from children (n = 652) attending 18 schools in Bungoma County and diagnosed by the Kato-Katz and Mini-FLOTAC coprological methods. Sensitivity and additional diagnostic performance measures were analyzed using Bayesian latent class modeling. Financial and economic costs were calculated for all survey and diagnostic activities, and cost per child tested, cost per case detected and cost per STH infection correctly classified were estimated. A sensitivity analysis was conducted to assess the impact of various survey parameters on cost estimates. RESULTS: Both diagnostic methods exhibited comparable sensitivity for detection of any STH species over single and consecutive day sampling: 52.0% for single day Kato-Katz; 49.1% for single-day Mini-FLOTAC; 76.9% for consecutive day Kato-Katz; and 74.1% for consecutive day Mini-FLOTAC. Diagnostic performance did not differ significantly between methods for the different STH species. Use of Kato-Katz with school-based sampling was the lowest cost scenario for cost per child tested ($10.14) and cost per case correctly classified ($12.84). Cost per case detected was lowest for Kato-Katz used in community-based sampling ($128.24). Sensitivity analysis revealed the cost of case detection for any STH decreased non-linearly as prevalence rates increased and was influenced by the number of samples collected. CONCLUSIONS: The Kato-Katz method was comparable in diagnostic sensitivity to the Mini-FLOTAC method, but afforded greater cost-effectiveness. Future work is required to evaluate the cost-effectiveness of STH surveillance in different settings. PMID- 24810594 TI - Determinants and improvement of electrocardiographic diagnosis of left ventricular hypertrophy in a black African population. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a major cardiovascular risk factor. The electrocardiogram (ECG) has been shown to be a poor tool in detecting LVH due to cardiac and extracardiac factors. We studied the determinants and possibility of improving the test performance of the ECG in a group of Black Africans. METHODS: We studied echocardiograms and electrocardiograms of 182 Cameroonian patients among whom 113 (62.1%) were having an echocardiographic LVH. Echocardiographic LVH was defined as Left Ventricular Mass Indexed to height 2.7(LVMI)>48 g/m2.7 in men, and >44 g/m 2.7 in women or Body Surface Area >=116 g/m2 in men, and >=96 g/m2 in women. Test performances were calculated for 6 classic ECG criteria Sokolow-Lyon, Cornell, Cornell product, Gubner-Ungerleiger, amplitudes of R in aVL, V5 and V6. RESULTS: The most sensitive criteria were Cornell (37.2%) and Sokolow-Lyon index (26.5%). The most specific criteria were Gubner (98.6%), RaVL (97.1%), RV5/V6 (95.7%) and Cornell product (94.2%). The performance of the ECG in diagnosing LVH significantly increased with the severity of LVH for Cornell index (r = 0.420, p<0.0001) and Sokolow index (r = 0.212, p = 0.002). It decreased with body habitus (r = -0.248, p = 0.001) for Sokolow-Lyon index. Cornell index was less affected (age p = 0.766; body habitus: p = 0.209). After sex-specific adjustment for BMI, Cornell BMI sensitivity increased from 37.2% to 69% (r = 0.472, p<0.0001), and Sokolow-Lyon BMI sensitivity increased from 26.5% to 58.4% (r = 0.270, p<0.001). CONCLUSION: The test performance of the ECG in diagnosing LVH is low in this Black African population, due to extracardiac factors such as age, sex, body habitus, and cardiac factors such as LVH severity and geometry. However, this performance is improved after adjustment for extracardiac factors. PMID- 24810595 TI - Time delay and long-range connection induced synchronization transitions in Newman-Watts small-world neuronal networks. AB - The synchronization transitions in Newman-Watts small-world neuronal networks (SWNNs) induced by time delay tau and long-range connection (LRC) probability P have been investigated by synchronization parameter and space-time plots. Four distinct parameter regions, that is, asynchronous region, transition region, synchronous region, and oscillatory region have been discovered at certain LRC probability P = 1.0 as time delay is increased. Interestingly, desynchronization is observed in oscillatory region. More importantly, we consider the spatiotemporal patterns obtained in delayed Newman-Watts SWNNs are the competition results between long-range drivings (LRDs) and neighboring interactions. In addition, for moderate time delay, the synchronization of neuronal network can be enhanced remarkably by increasing LRC probability. Furthermore, lag synchronization has been found between weak synchronization and complete synchronization as LRC probability P is a little less than 1.0. Finally, the two necessary conditions, moderate time delay and large numbers of LRCs, are exposed explicitly for synchronization in delayed Newman-Watts SWNNs. PMID- 24810596 TI - NIAM's tangled web of growth control. PMID- 24810598 TI - Palladium-catalyzed one-pot synthesis of quinazolinones via tert-butyl isocyanide insertion. AB - A novel palladium-catalyzed three-component reaction for the synthesis of quinazolin-4(3H)-ones from readily available 2-aminobenzamides and aryl halides via a palladium-catalyzed isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of operational simplicity. PMID- 24810599 TI - Field-evaluation of a new lateral flow assay for detection of cellular and humoral immunity against Mycobacterium leprae. AB - BACKGROUND: Field-applicable tests detecting asymptomatic Mycobacterium leprae (M. leprae) infection or predicting progression to leprosy, are urgently required. Since the outcome of M. leprae infection is determined by cellular- and humoral immunity, we aim to develop diagnostic tests detecting pro-/anti inflammatory and regulatory cytokines as well as antibodies against M. leprae. Previously, we developed lateral flow assays (LFA) for detection of cytokines and anti-PGL-I antibodies. Here we evaluate progress of newly developed LFAs for applications in resource-poor settings. METHODS: The combined diagnostic value of IP-10, IL-10 and anti-PGL-I antibodies was tested using M. leprae-stimulated blood of leprosy patients and endemic controls (EC). For reduction of the overall test-to-result time the minimal whole blood assay time required to detect distinctive responses was investigated. To accommodate LFAs for field settings, dry-format LFAs for IP-10 and anti-PGL-I antibodies were developed allowing storage and shipment at ambient temperatures. Additionally, a multiplex LFA format was applied for simultaneous detection of anti-PGL-I antibodies and IP-10. For improved sensitivity and quantitation upconverting phosphor (UCP) reporter technology was applied in all LFAs. RESULTS: Single and multiplex UCP-LFAs correlated well with ELISAs. The performance of dry reagent assays and portable, lightweight UCP-LF strip readers indicated excellent field-robustness. Notably, detection of IP-10 levels in stimulated samples allowed a reduction of the whole blood assay time from 24 h to 6 h. Moreover, IP-10/IL-10 ratios in unstimulated plasma differed significantly between patients and EC, indicating the feasibility to identify M. leprae infection in endemic areas. CONCLUSIONS: Dry-format UCP LFAs are low-tech, robust assays allowing detection of relevant cytokines and antibodies in response to M. leprae in the field. The high levels of IP-10 and the required shorter whole blood assay time, render this cytokine useful to discriminate between leprosy patients and EC. PMID- 24810600 TI - dGTP starvation in Escherichia coli provides new insights into the thymineless death phenomenon. AB - Starvation of cells for the DNA building block dTTP is strikingly lethal (thymineless death, TLD), and this effect is observed in all organisms. The phenomenon, discovered some 60 years ago, is widely used to kill cells in anticancer therapies, but many questions regarding the precise underlying mechanisms have remained. Here, we show for the first time that starvation for the DNA precursor dGTP can kill E. coli cells in a manner sharing many features with TLD. dGTP starvation is accomplished by combining up-regulation of a cellular dGTPase with a deficiency of the guanine salvage enzyme guanine (hypoxanthine)-phosphoribosyltransferase. These cells, when grown in medium without an exogenous purine source like hypoxanthine or adenine, display a specific collapse of the dGTP pool, slow-down of chromosomal replication, the generation of multi-branched nucleoids, induction of the SOS system, and cell death. We conclude that starvation for a single DNA building block is sufficient to bring about cell death. PMID- 24810601 TI - Study on the interaction of beta-cyclodextrin and berberine hydrochloride and its analytical application. AB - The fluorescence enhancement of berberine hydrochloride (BBH) as a result of complex with beta-cyclodextrin (beta-CD) is investigated. The mechanism of the inclusion was studied and discussed by spectrofluoremetry and infrared spectrograms. The results showed that a 1?1 (beta-CD: BBH) complex was formed with an apparent association constant of 4.23*10(2) L/mol. Based on the enhancement of the fluorescent intensity of berberine hydrochloride, a new spectrofluorimetric method for the determination of BBH in the presence of beta CD was developed. The linear range was 1.00~4.00 ug/mL with the detection limit of 5.54 ng/mL. The proposed method was successfully applied to the determination of BBH in tablets. PMID- 24810603 TI - Rhythms and community dynamics of a hydrothermal tubeworm assemblage at main endeavour field - a multidisciplinary deep-sea observatory approach. AB - The NEPTUNE cabled observatory network hosts an ecological module called TEMPO mini that focuses on hydrothermal vent ecology and time series, granting us real time access to data originating from the deep sea. In 2011-2012, during TEMPO mini's first deployment on the NEPTUNE network, the module recorded high resolution imagery, temperature, iron (Fe) and oxygen on a hydrothermal assemblage at 2186 m depth at Main Endeavour Field (North East Pacific). 23 days of continuous imagery were analysed with an hourly frequency. Community dynamics were analysed in detail for Ridgeia piscesae tubeworms, Polynoidae, Pycnogonida and Buccinidae, documenting faunal variations, natural change and biotic interactions in the filmed tubeworm assemblage as well as links with the local environment. Semi-diurnal and diurnal periods were identified both in fauna and environment, revealing the influence of tidal cycles. Species interactions were described and distribution patterns were indicative of possible microhabitat preference. The importance of high-resolution frequencies (<1 h) to fully comprehend rhythms in fauna and environment was emphasised, as well as the need for the development of automated or semi-automated imagery analysis tools. PMID- 24810602 TI - Exome-wide association study of endometrial cancer in a multiethnic population. AB - Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC. PMID- 24810604 TI - Emotion regulation moderates the association between empathy and prosocial behavior. AB - Theory and evidence suggest that empathy is an important motivating factor for prosocial behaviour and that emotion regulation, i.e. the capacity to exert control over an emotional response, may moderate the degree to which empathy is associated with prosocial behaviour. However, studies to date have not simultaneously explored the associations between different empathic processes and prosocial behaviour, nor whether different types of emotion regulation strategies (e.g. cognitive reappraisal and expressive suppression) moderate associations between empathy and prosocial behaviour. One hundred-and-ten healthy adults completed questionnaire measures of empathy, emotion regulation and prosocial tendencies. In this sample, both affective and cognitive empathy predicted self reported prosocial tendencies. In addition, cognitive reappraisal moderated the association between affective empathy and prosocial tendencies. Specifically, there was a significant positive association between empathy and prosocial tendencies for individuals with a low or average tendency to reappraise but not for those with a high tendency to reappraise. Our findings suggest that, in general, empathy is positively associated with prosocial behaviour. However, this association is not significant for individuals with a high tendency for cognitive reappraisal. PMID- 24810605 TI - Composition and structure of Pinus koraiensis mixed forest respond to spatial climatic changes. AB - BACKGROUND: Although some studies have indicated that climate changes can affect Pinus koraiensis mixed forest, the responses of composition and structure of Pinus koraiensis mixed forests to climatic changes are unknown and the key climatic factors controlling the composition and structure of Pinus koraiensis mixed forest are uncertain. METHODOLOGY/PRINCIPAL FINDINGS: Field survey was conducted in the natural Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. In order to build the mathematical models for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non climatic factors, stepwise linear regression analyses were performed, incorporating 14 dependent variables and the linear and quadratic components of 9 factors. All the selected new models were computed under the +2 degrees C and +10% precipitation and +4 degrees C and +10% precipitation scenarios. The Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month were observed to be key climatic factors controlling the stand densities and total basal areas of Pinus koraiensis mixed forest. Increased summer temperatures and precipitations strongly enhanced the stand densities and total basal areas of broadleaf trees but had little effect on Pinus koraiensis under the +2 degrees C and +10% precipitation scenario and +4 degrees C and +10% precipitation scenario. CONCLUSIONS/SIGNIFICANCE: These results show that the Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month are key climatic factors which shape the composition and structure of Pinus koraiensis mixed forest. Although the Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitation. PMID- 24810606 TI - Protective effect of indole-3-pyruvate against ultraviolet b-induced damage to cultured HaCaT keratinocytes and the skin of hairless mice. AB - Previous investigations demonstrated that pyruvate protects human keratinocytes against cell damage stemming from exposure to ultraviolet B (UVB) radiation. This study endeavoured to elucidate the protective capacity of aromatic pyruvates (e.g., phenylpyruvate (PPyr), 4-hydroxyphenylpyruvate (HPPyr), and indole-3 pyruvate (IPyr)) against UVB-induced injury to skin cells, both in vitro and in vivo. Cultured human HaCaT keratinocytes were irradiated with UVB light (60 mJ/cm2) and maintained with or without test compounds (1-25 mM).In addition, the dorsal skin of hairless mice (HR-1) was treated with test compounds (10 MUmol) and exposed to UVB light (1 J/cm2) twice [corrected]. The ability of the test compounds to ameliorate UVB-induced cytotoxicity and inflammation was then assessed. Aromatic pyruvates reduced cytotoxicity in UVB-irradiated HaCaT keratinocytes, and also diminished the expression of interleukin 1beta (IL-1beta) and interleukin 6 (IL-6). IPyr was more efficacious than either PPyr or HPPyr. Furthermore, only IPyr inhibited cyclooxygenase-2 (Cox-2) expression at both the mRNA and the protein level in UVB-treated keratinocytes. Topical application of IPyr to the dorsal skin of hairless mice reduced the severity of UVB-induced skin lesions, the augmentation of dermal thickness, and transepithelial water loss. Overproduction of IL-1beta and IL-6 in response to UVB radiation was also suppressed in vivo by the topical administration of IPyr. These data strongly suggest that IPyr might find utility as a UVB-blocking reagent in therapeutic strategies to lessen UVB-induced inflammatory skin damage. PMID- 24810608 TI - Add-on effect of probucol in atherosclerotic, cholesterol-fed rabbits treated with atorvastatin. AB - OBJECTIVE: Lowering the blood concentration of low-density lipoprotein (LDL) cholesterol is the primary strategy employed in treating atherosclerotic disorders; however, most commonly prescribed statins prevent cardiovascular events in just 30% to 40% of treated patients. Therefore, additional treatment is required for patients in whom statins have been ineffective. In this study of atherosclerosis in rabbits, we examined the effect of probucol, a lipid-lowering drug with potent antioxidative effects, added to treatment with atorvastatin. METHODS AND RESULTS: Atherosclerosis was induced by feeding rabbits chow containing 0.5% cholesterol for 8 weeks. Probucol 0.1%, atorvastatin 0.001%, and atorvastatin 0.003% were administered solely or in combination for 6 weeks, beginning 2 weeks after the start of atherosclerosis induction. Atorvastatin decreased the plasma concentration of non-high-density lipoprotein cholesterol (non-HDLC) dose-dependently; atorvastatin 0.003% decreased the plasma concentration of non-HDLC by 25% and the area of atherosclerotic lesions by 21%. Probucol decreased the plasma concentration of non-HDLC to the same extent as atorvastatin (i.e., by 22%) and the area of atherosclerotic lesions by 41%. Probucol with 0.003% atorvastatin decreased the plasma concentration of non-HDLC by 38% and the area of atherosclerotic lesions by 61%. Co-administration of probucol with atorvastatin did not affect the antioxidative effects of probucol, which were not evident on treatment with atorvastatin alone, such as prevention of in vitro LDL-oxidation, increase in paraoxonase-1 activity of HDL, and decreases in plasma and plaque levels of oxidized-LDL in vivo. CONCLUSIONS: Probucol has significant add-on anti-atherosclerotic effects when combined with atorvastatin treatment; suggesting that this combination might be beneficial for treatment of atherosclerosis. PMID- 24810609 TI - Determinants of institutional delivery among childbearing age women in Western Ethiopia, 2013: unmatched case control study. AB - BACKGROUND: Place of delivery is a crucial factor which affects the health and wellbeing of the mother and newborn. Institutional delivery helps the women to access skilled assistance, drugs, equipment, and referral transport. Even though 34% of pregnant women received at least one antenatal care from a skilled provider in Ethiopia by 2013, institutional delivery was 10%. The main objective of the study was to assess determinants of institutional delivery in Western Ethiopia. METHODS: Retrospective unmatched case control study design was used to assess determinants of institutional delivery in Western Ethiopia from September to October 2013. A total of 320 respondents from six districts of East Wollega zone, West Ethiopia were included. Data were collected using pretested and structured questionnaires. Data were entered and cleaned by Epi-info then exported and analyzed using SPSS software. Statistical significance was determined through a 95% confidence level. RESULTS: Education [Adjusted Odds Ratio (AOR) (95% Confidence Interval (CI)) = 2.754(1.510-8.911)], family size [AOR (95% CI) = .454(.209-.984)], residence [AOR (95% CI) = 3.822 (1.766-8.272)] were important predictors of place of delivery. Four or more antenatal care [(ANC) (AOR (95% CI) = 2.914(1.105-7.682)], birth order [(AOR (95% CI) = .136(.054-.344), age at last delivery [(AOR (95% CI) = 9.995(2.101-47.556)], birth preparedness [AOR (95% CI) = 6.957(2.422-19.987)], duration of labour [AOR (95% CI) = 3.541(1.732-7.239)] were significantly associated with institutional delivery. Moreover service related factors such as distance from health institutions [AOR (95% CI) = .665(.173-.954)], respondents' awareness of skill of health care professionals [AOR (95% CI) = 2.454 (1.663-6.255)], mode of transportations [AOR (95% CI) = .258(.122-.549)] were significantly associated with institutional delivery. CONCLUSIONS AND RECOMMENDATIONS: Policy makers, health service organizations, community leaders and other concerned bodies have to consider the predictors of institutional delivery like education, birth order, antenatal care utilization and residence to improve institutional delivery in the area. PMID- 24810610 TI - Renal function in children suffering from sickle cell disease: challenge of early detection in highly resource-scarce settings. AB - BACKGROUND: The prevalence of Sickle cell disease is extremely high in Democratic Republic of Congo. Despite this high prevalence of the disease, data on renal abnormalities in children are rare. METHOD: The study proposed to assess blood pressure, glomerular function, urea and uric acid levels in 65 steady state Congolese children with homozygous sickle cell disease and 67 normal controls. RESULTS: In Hb-SS group, blood pressure level tended to be lower than Hb-AA groups but there was no statistically significant difference (p>0.05) between the two groups. The absolute values for GFR corrected for BSA were significantly higher in Hb-SS group compared to Hb-AA group (130.5+/-34.1 ml/min/1.73 m2 vs 113.7+/-24.5 ml/min/1.73 m2; p = 0.004). Children with Hb-SS were more likely to hyperfiltrate (30.8% of subjects) than children with Hb-AA (6.1% of subjects). Proteinuria was found in 4 (6.2%) children with Hb-SS. Uric acid level was significantly increased in children with Hb-SS compared to corresponding values in control group (4.4+/-1.3 mg/dl vs 3.5+/-1.1 mg/dl; p<0.001). Urea level was significantly decreased compared to corresponding values in Hb-AA group (15.3+/ 8.3 mg/dl vs 22.9+/-10.1 mg/dl; p<0.001). CONCLUSION: Hyperfiltration, low creatinine, lower urea and high uric acid are more common in children with sickle cell disease than in normal controls. PMID- 24810611 TI - Effects of individual polychlorinated naphthalene (PCN) components of Halowax 1051 and two defined, artificial PCN mixtures on AHR and CYP1A1 protein expression, steroid secretion and expression of enzymes involved in steroidogenesis (CYP17, 17beta-HSD and CYP19) in porcine ovarian follicles. AB - In this study we tried to answer a question which component of Halowax 1051 is responsible for, observed in previously published study, androgenic effects of the mixture, and whether it is possible to draw conclusions about the action of mixtures by examining the effect of an indicator congener. Ovarian follicles were incubated with individual congeners of an artificial mixture for 6-24h. At the end of the incubation period, media were collected for determination of progesterone (P4), androstenedione (A4), testosterone (T) and estradiol (E2) levels by enzyme immunoassay, and follicles were retained for an examination of aryl hydrocarbon receptor (AHR), cytochrome p450 enzymes (CYP1A1, CYP17, CYP19), and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) protein expression by Western blotting. CN73 in dose 50pg/ml after 6h had no effect and decreased AHR expression after 24h, while at dose 400pg/ml increased AHR protein expression after 6h of exposure which remained elevated after 24h. CN74 and CN75 at both concentrations tested (25 and 50pg/ml) stimulated AHR protein expression after 6h and decreased it after 24h of exposure. Individual congeners induced a rapid increase in CYP1A1 protein expression, with a rank order of efficacy of CN73>CN74=CN75. All congeners increased P4/A4 and T/E2 secretion ratios in association with a decrease in the A4/T ratio, pointing to androgenic and anti estrogenic properties of PCNs in ovarian follicles. The most potent congener in this context was CN73. The effects of mixtures were comparable to those of CN74 and CN75, and were not as strong as those observed for CN73. Collectively, these data suggest antagonistic actions of single congeners in a mixture, indicating that the actions of a mixture cannot be predicted based on the actions of individual congeners. PMID- 24810612 TI - Risk of hip fracture among older people using anxiolytic and hypnotic drugs: a nationwide prospective cohort study. AB - PURPOSE: Anxiolytics and hypnotics are widely used and may cause injurious falls. We aimed to examine associations between exposure to anxiolytics and hypnotics and the risk of hip fracture among all older people in Norway. Further, we wanted to examine associations between exposure to hypnotics and time of fracture. METHODS: A nationwide prospective cohort study of people in Norway born before 1945 (n=906,422) was conducted. We obtained information on all prescriptions of anxiolytics and hypnotics dispensed in 2004-2010 (the Norwegian Prescription Database) and all primary hip fractures in 2005-2010 (the Norwegian Hip Fracture Registry). We compared the incidence rates of hip fracture during drug exposure and non-exposure by calculating the standardized incidence ratio (SIR). RESULTS: Altogether, 39,938 people (4.4%) experienced a primary hip fracture. The risk of hip fracture was increased for people exposed to anxiolytics (SIR 1.4, 95% confidence interval (CI) 1.4-1.5) and hypnotics (SIR 1.2, 95% CI 1.1-1.2); the excess risk was highest regarding short-acting benzodiazepine anxiolytics (SIR 1.5, 95% CI 1.4-1.6). Benzodiazepine-like hypnotics (z-hypnotics) were associated with higher excess risk of hip fracture at night (SIR 1.3, 95% CI 1.2-1.4) than during the day (SIR 1.1, 95% CI 1.1-1.2). CONCLUSIONS: Older people had an increased risk of hip fracture during anxiolytic or hypnotic drug use, including short-acting benzodiazepine anxiolytics and z-hypnotics that were previously considered less harmful; cautious prescribing is therefore needed. People using z hypnotics were at greatest excess risk at night; this association deserves further investigation. PMID- 24810613 TI - Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM(r) model to optimize dosing. AB - PURPOSE: We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data. METHODS: PopPK analyses were done with NONMEM(r) 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation). RESULTS: The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]=target AUC[mg*h/L]*3.04L/h*(ABW/16.1)0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients. CONCLUSIONS: We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed. PMID- 24810614 TI - Heterogeneity of host TLR2 stimulation by Staphylocoocus aureus isolates. AB - High lipoprotein expression and potent activation of host Toll-like receptor-2 (TLR2) are characteristic features of the staphylococcal species. Expression of TLR2 in the host is important for clearance of Staphylococcus aureus infection and host survival. Thus, we hypothesized that bacterial regulation of its intrinsic TLR2-stimulatory capacity could represent a means for immune evasion or host adaptation. We, therefore, compared clinical S. aureus isolates in regards to their TLR2 activation potential and assessed the bacterial factors that modulate TLR2-mediated recognition. S. aureus isolates displayed considerable variability in TLR2-activity with low to absent TLR2-activity in 64% of the isolates tested (68/106). Notably, strain-specific TLR2-activity was independent of the strain origin, e.g. no differences were found between strains isolated from respiratory specimen from cystic fibrosis patients or those isolated from invasive disease specimen. TLR2-activity correlated with protein A expression but not with the agr status. Capsule expression and small colony variant formation had a negative impact on TLR2-activity but any disruption of cell wall integrity enhanced TLR2 activation. Altogether, heterogeneity in host TLR2-activity reflects differences in metabolic activity and cell wall synthesis and/or remodeling. PMID- 24810615 TI - Cytokine responses to the anti-schistosome vaccine candidate antigen glutathione S-transferase vary with host age and are boosted by praziquantel treatment. AB - BACKGROUND: Improved helminth control is required to alleviate the global burden of schistosomiasis and schistosome-associated pathologies. Current control efforts rely on the anti-helminthic drug praziquantel (PZQ), which enhances immune responses to crude schistosome antigens but does not prevent re-infection. An anti-schistosome vaccine based on Schistosoma haematobium glutathione-S transferase (GST) is currently in Phase III clinical trials, but little is known about the immune responses directed against this antigen in humans naturally exposed to schistosomes or how these responses change following PZQ treatment. METHODOLOGY: Blood samples from inhabitants of a Schistosoma haematobium-endemic area were incubated for 48 hours with or without GST before (n = 195) and six weeks after PZQ treatment (n = 107). Concentrations of cytokines associated with innate inflammatory (TNFalpha, IL-6, IL-8), type 1 (Th1; IFNgamma, IL-2, IL 12p70), type 2 (IL-4, IL-5, IL-13), type 17 (IL-17A, IL-21, IL-23p19) and regulatory (IL-10) responses were quantified in culture supernatants via enzyme linked immunosorbent assay (ELISA). Factor analysis and multidimensional scaling were used to analyse multiple cytokines simultaneously. PRINCIPAL FINDINGS: A combination of GST-specific type 2 (IL-5 and IL-13) and regulatory (IL-10) cytokines was significantly lower in 10-12 year olds, the age group at which S. haematobium infection intensity and prevalence peak, than in 4-9 or 13+ year olds. Following PZQ treatment there was an increase in the number of participants producing detectable levels of GST-specific cytokines (TNFalpha, IL-6, IL-8, IFNgamma, IL-12p70, IL-13 and IL-23p19) and also a shift in the GST-specific cytokine response towards a more pro-inflammatory phenotype than that observed before treatment. Participant age and pre-treatment infection status significantly influenced post-treatment cytokine profiles. CONCLUSIONS/SIGNIFICANCE: In areas where schistosomiasis is endemic host age, schistosome infection status and PZQ treatment affect the cellular cytokine response to GST. Thus the efficacy of a GST-based vaccine may also be shaped by the demographic and epidemiological characteristics of targeted populations. PMID- 24810616 TI - Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression. AB - To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. PMID- 24810617 TI - Identification of HIV-1 Vif regions required for CBF-beta interaction and APOBEC3 suppression. AB - Human immunodeficiency virus type 1 (HIV-1) Vif requires core binding factor beta (CBF-beta) to degrade the host APOBEC3 restriction factors. Although a minimum domain and certain amino acids of HIV-1 Vif, including hydrophobic residues at the N-terminal, have been identified as critical sites for binding with CBF-beta, other regions that potentially mediate this interaction need to be further investigated. Here, we mapped two new regions of HIV-1 Vif that are required for interaction with CBF-beta by generating a series of single-site or multiple-site Vif mutants and testing their effect on the suppression of APOBEC3G (A3G) and APOBEC3F (A3F). A number of the mutants, including G84A/SIEW86-89AAAA (84/86-89), E88A/W89A (88/89), G84A, W89A, L106S and I107S in the 84GxSIEW89 and L102ADQLI107 regions, affected Vif function by disrupting CBF-beta binding. These Vif mutants also had altered interactions with CUL5, since CBF-beta is known to facilitate the binding of Vif to CUL5. We further showed that this effect was not due to misfolding or conformational changes in Vif, as the mutants still maintained their interactions with other factors such as ElonginB, A3G and A3F. Notably, G84D and D104A had stronger effects on the Vif-CUL5 interaction than on the Vif CBF-beta interaction, indicating that they mainly influenced the CUL5 interaction and implying that the interaction of Vif with CUL5 contributes to the binding of Vif to CBF-beta. These new binding interfaces with CBF-beta in HIV-1 Vif provide novel targets for the development of HIV-1 inhibitors. PMID- 24810619 TI - Isolation and partial characterization of bacteriophages infecting Pseudomonas syringae pv. actinidiae, causal agent of kiwifruit bacterial canker. AB - The phytopathogen Pseudomonas syringae pv. actinidiae (Psa) is the causal agent of bacterial canker of kiwifruit. In the last years, it has caused severe economic losses to Actinidia spp. cultivations, mainly in Italy and New Zealand. Conventional strategies adopted did not provide adequate control of infection. Phage therapy may be a realistic and safe answer to the urgent need for novel antibacterial agents aiming to control this bacterial pathogen. In this study, we described the isolation and characterization of two bacteriophages able to specifically infect Psa. phiPSA1, a member of the Siphoviridae family, is a temperate phage with a narrow host range, a long latency, and a burst size of 178; phiPSA2 is a lytic phage of Podoviridae family with a broader host range, a short latency, a burst size of 92 and a higher bactericidal activity as determined by the TOD value. The genomic sequence of phiPSA1 has a length of 51,090 bp and a low sequence homology with the other siphophages, whereas phiPSA2 has a length of 40 472 bp with a 98% homology with Pseudomonas putida bacteriophage gh-1. Of the two phages examined, phiPSA2 may be considered as a candidate for phage therapy of kiwifruit disease, while phiPSA1 seems specific toward the recent outbreak's isolates and could be useful for Psa typing. PMID- 24810618 TI - Inter-species cross-seeding: stability and assembly of rat-human amylin aggregates. AB - Diseases such as type 2 diabetes, Alzheimer's and Parkinson's share as common feature the accumulation of mis-folded disease-specific protein aggregates into fibrillar structures, or plaques. These fibrils may either be toxic by themselves, or act as reservoirs for smaller cytotoxic oligomers. This suggests to investigate molecules as potential therapeutics that either reduce fibril formation or increase fibril stability. One example is rat amylin, which can inhibit aggregation of human amylin, a hallmark of type 2 diabetes. In the present paper, we use molecular dynamics to compare the stability of various preformed aggregates, built out of either human amylin, rat amylin, or mixtures of both. We considered two types of fibril-like oligomers: a single-layer in register conformation, and a double-layer conformation in which the first U shaped layer consists of rat amylin and the second layer of human amylin. Our results explain the weak amyloid-inhibiting properties of rat amylin and suggest that membrane leakage due to pore formation is responsible for the toxicity of rat amylin observed in a recent experiment. Together, our results put in question the use of rat amylin or the similar FDA approved drug pramlintide as an inhibitor of human amylin aggregation. They also point to mixed human-rat amylin fibril-like oligomers as possible model-systems for studies of amyloid formation that involve cross-species transmission. PMID- 24810620 TI - [Firework-related eye trauma from 2005 to 2013]. AB - PURPOSE: Fireworks combusted during New Year's Eve festivities can cause different eye traumas which often need complex reconstructive surgery. It was our aim to systematically analyse these eye trauma cases which were treated at our clinic during the last eight years. MATERIALS AND METHODS: Age, gender, side, trauma mechanism, treatment methods and outcome were analysed for all eye trauma cases caused by fireworks during the New Year's Eve celebrations from 2006 to 2013. For statistical analysis all trauma cases were divided into two groups of major and non-major eye trauma. RESULTS: The total number of patients treated was 122 (28 women, 94 men, mean age 26.2+/-13.0 years) with 137 traumatised eyes (77 right, 60 left). 24.6% of patients were <=18 years of age. 76.2% were bystanders. 50 eyes from 46 patients (37.7%) suffered from major eye trauma. 26 patients (21.3%) were hospitalised. 8 eyes (5.8%) suffered from a penetrating injury or globe rupture and underwent primary reconstructive surgery. Further 16 eyes (11.7%) suffered from major eye trauma without open globe injury. In the aftermath 11 eyes (8.0%) went blind (visual acuity<1/50). Gender, side and role of the patient were not significantly different between the two groups. Mean age was significantly higher in the major eye trauma group (p=0.01). CONCLUSION: Young male bystanders have a high risk for suffering from eye trauma caused by fireworks. However older patients suffer from major eye trauma more often. More education and prophylaxis of eye trauma caused by fireworks is desirable. PMID- 24810621 TI - New regulatory role for SRF in neutrophils. PMID- 24810622 TI - Indolent and mantle cell NHL: the future is BRIGHT. PMID- 24810623 TI - Abnl(17p) in AML: who will guard the guardian? PMID- 24810624 TI - The right "Job" for STAT3 mutant mice! PMID- 24810625 TI - Cellular origin of T-cell lymphomas. PMID- 24810626 TI - Bortezomib resistance and MUC1 in myeloma. PMID- 24810627 TI - Cardiac sensitivity in children: sex differences and its relationship to parameters of emotional processing. AB - In adults, the level of ability to perceive one's own body signals plays an important role for many concepts of emotional experience as demonstrated for emotion processing or emotion regulation. Representative data on perception of body signals and its emotional correlates in children is lacking. Therefore, the present study investigated the cardiac sensitivity of 1,350 children between 6 and 11 years of age in a heartbeat perception task. Our main findings demonstrated the distribution of cardiac sensitivity in children as well as associations with interpersonal emotional intelligence and adaptability. Furthermore, independent of body mass index, boys showed a significantly higher cardiac sensitivity than girls. We conclude that cardiac sensitivity in children appears to show weaker but similar characteristics and relations to emotional parameters as found in adults, so that a dynamic developmental process can be assumed. PMID- 24810628 TI - miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. AB - MicroRNAs (miRNAs) are small non-coding RNAs, which inhibit the stability and/or translation of a mRNA. miRNAs have been found to play a powerful role in various cardiovascular diseases. Recently, we have demonstrated that a microRNA (miR 181c) can be encoded in the nucleus, processed to the mature form in the cytosol, translocated into the mitochondria, and ultimately can regulate mitochondrial gene expression. However the in vivo impact of miR-181c is unknown. Here we report an in-vivo method for administration of miR-181c in rats, which leads to reduced exercise capacity and signs of heart failure, by targeting the 3'-end of mt-COX1 (cytochrome c oxidase subunit 1). We cloned miR-181c and packaged it in lipid-based nanoparticles for systemic delivery. The plasmid DNA complexed nanovector shows no apparent toxicity. We find that the mRNA levels of mitochondrial complex IV genes in the heart, but not any other mitochondrial genes, are significantly altered with miR-181c overexpression, suggesting selective mitochondrial complex IV remodeling due to miR-181c targeting mt-COX1. Isolated heart mitochondrial studies showed significantly altered O2-consumption, ROS production, matrix calcium, and mitochondrial membrane potential in miR-181c treated animals. For the first time, this study shows that miRNA delivered to the heart in-vivo can lead to cardiac dysfunction by regulating mitochondrial genes. PMID- 24810629 TI - Identification of 9alpha-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrost-6-en-5-oic acid and beta-oxidation products of the C-17 side chain in cholic acid degradation by Comamonas testosteroni TA441. AB - Comamonas testosteroni degrades testosterone into 9,17-dioxo-1,2,3,4,10,19 hexanorandrostan-5-oic acid and 2-hydroxyhexa-2,4-dienoic acid via aromatization of the A-ring. The former compound is suggested to be degraded further by beta oxidation, but the details of the process remain unclear. In this study, we identified 9alpha-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrost-6-en-5-oic acid as an intermediate compound in the beta-oxidation of this compound. ORF32, located in one of the two main steroid degradation gene clusters, was shown to be indispensable for the conversion of this compound. A homology search indicated that ORF32 encodes a hydratase for the CoA-ester, suggesting that ORF32 encodes a hydratase that adds a water molecule to a double bond at C-6 of the CoA-ester of 9alpha-hydroxy-17-oxo-1,2,3,4,10,19-hexanorandrost-6-en-5-oic acid. From the culture of an ORF32-disrupted mutant incubated with cholic acid for a short period (around two days, when a considerable number of intermediate compounds were detected by HPLC), 7alpha,12alpha-dihydroxy-3-oxochola-1,4-dien-24-oic acid, 7alpha,12alpha-dihydroxy-3-oxochol-4-en-24-oic acid, 12alpha-hydroxy-3-oxochola 4,6-dien-24-oic acid, 7alpha,12alpha-dihydroxy-3-oxopregna-1,4-diene-20 carboxylic acid, 12alpha-hydroxy-3-oxopregna-4,6-diene-20-carboxylic acid, 7alpha,12alpha-dihydroxy-3-oxopregn-4-ene-20-carboxylic acid, 12alpha-hydroxy-3 oxopregna-4,6-diene-20-carboxylic acid, 7alpha-hydroxy-3-oxopregna-4,17(20)-diene 20-carboxylic acid, and 3-oxopregna-4,6,17(20)-triene-20-carboxylic acid were isolated as intermediate compounds of C-17 side-chain degradation. The presence of these compounds implies that the process of degradation of the C-17 side chain in C. testosteroni will be similar to the process in Pseudomonas. The final two compounds, which have a double bond at the C-17(20) position, are here identified for the first time, to the best of our knowledge, as intermediate compounds in bacterial steroid degradation; their composition suggests that the remaining three carbons at the C-17 position would be removed oxidatively as a propionic acid derivative. PMID- 24810630 TI - Incidence of the urological tumours in patients suffering from multiple sclerosis. AB - OBJECTIVES: The goal of this study was to evaluate the incidence of urological malignancies in MS patients using active screening. MATERIAL AND METHODS: A total of 495 MS patients (141 men, 354 women, age of 42+/-13.4) were included in the study. The duration of disease was 12.3+/-11 years, and the EDSS score was 4.3 (+/-2.5). Patients, regardless of specific urological symptoms, were referred for urological evaluation. The outcomes of these evaluations were compared with data from the 2009 National Oncology Register of the Czech Republic. RESULTS: The standardized incidence ratio (SIR) for the whole MS study population was 38.8 (95% CI 12.6-90.6). This incidence of urological malignancies in the MS study population was higher (statistically significant) than that of the general population. The SIR for females was 66.0 (95% CI 18.0-169.1) in the MS study population, representing a statistically significant increase over that of the general female population. The increase in incidence of urological malignancies in men with MS did not reach statistical significance over that of the general male population (SIR 14.7, 95% CI 0.4-81.7). CONCLUSIONS: The incidence of urological cancer in MS patients as determined by active screening is significantly higher than that found in general population. PMID- 24810631 TI - Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelination and axonal damage of the central nervous system. The pathogenesis of MS has also been linked to vascular inflammation and local activation of the coagulation system, resulting in perivascular fibrin deposition. Treatment of experimental autoimmune encephalomyelitis (EAE), a model of human MS, with antithrombotic and antiinflammatory activated protein C (APC) reduces disease severity. Since recombinant APC (Drotecogin alfa), originally approved for the treatment of severe sepsis, is not available for human MS studies, we tested the hypothesis that pharmacologic activation of endogenous protein C could likewise improve the outcome of EAE. Mice were immunized with murine myelin oligodendrocyte glycoprotein (MOG) peptides and at the onset of EAE symptoms, were treated every other day with either WE thrombin (25 MUg/kg; i.v.), a selective recombinant protein C activator thrombin analog, or saline control. Mice were monitored for changes in disease score until euthanized for ex vivo analysis of inflammation. Administration of WE thrombin significantly ameliorated clinical severity of EAE, reduced inflammatory cell infiltration and demyelination, suppressed the activation of macrophages comprising the CD11b + population and reduced accumulation of fibrin (ogen) in the spinal cord. These data suggest that symptomatic MS may respond to a treatment strategy that involves temporal pharmacological enhancement of endogenous APC generation. PMID- 24810633 TI - QPEEG analysis of the effects of sodium valproate on adult Chinese patients with generalized tonic-clonic seizures. AB - Objectives EEG effects of the sustained-release form of sodium valproate (SR-VPA) are unknown, although it is widely used in Chinese patients with generalized tonicclonic seizures (GTCS). Methods Fourteen newly diagnosed, untreated GTCS patients were recruited and treated with SR-VPA. Waking EEG was recorded and analyzed by way of quantitative pharmaco-electroencephalogram (QPEEG) analysis during the three-month follow-up. Results There was a statistically significant decrease in the absolute power of the delta band (P < 0.05), theta band (P < 0.03) and partial alpha-1 band (p < 0.05) with treatment compared to before treatment, while there was no significantly different absolute power between one month and three-months after treatment. There was a strong correlation between the decrease in absolute power and the degree of the initial abnormality in all frequency bands. Two of 14 patients experienced seizures during the second month after initiation of SR-VPA therapy. Conclusions SR-VPA selectively decreased the activity of the abnormal EEG synchronization in a use-dependent manner. The reduced theta, delta, and partial alpha-1 absolute power may reflect or confirm the efficacy of SR-VPA on patients with GTCS. PMID- 24810632 TI - Intracerebral hemorrhage in mouse models: therapeutic interventions and functional recovery. AB - There has been strong pre-clinical research on mechanisms of initial cell death and tissue injury in intracerebral hemorrhage (ICH). This data has led to the evaluation of several therapeutics for neuroprotection or the mitigation of early tissue damage. Most of these studies have been done in the rat. Also, there has been little study of the mechanisms of tissue repair and recovery. This review examines the testing of candidate therapeutics in mouse models of ICH for their effect on tissue protection and repair. This review will help the readers compare it to the extensively researched rat model of ICH and thus enhance work that are pending in mouse model. PMID- 24810634 TI - Reflections on glycogen and beta-amyloid: why does glycogenolytic beta2 adrenoceptor stimulation not rescue memory after beta-amyloid? AB - Normally noradrenaline release ~30 min after training in the day-old chick is essential for memory consolidation by simultaneously increasing both glycogenolysis, by its stimulation of beta2-adrenergic (AR) receptors, and glycogen synthesis, by its stimulation of alpha2-AR receptors in astrocytes. At the same time noradrenaline stimulation of beta3-AR receptors increases glucose uptake solely in astrocytes. Intracerebral injection of small oligomeric beta amyloid protein (Abeta1-42) (Abeta) 45 min before one-trial bead discrimination learning in day-old chicks abolishes consolidation of memory 30 min post learning. The ensuing memory loss can be rescued by injection of selective beta3- and beta(2-AR agonists (CL316243 and zinterol), which also have the ability to consolidate weakly-reinforced learning into long-term memory. However, although CL316243 rescues Abeta-induced memory loss over a similar time period to when it consolidates weak learning (up to 25 min post training), zinterol is effective over a more limited time period and unexpectedly it does not rescue at the time it promotes glycogenolysis. Injection of Abeta into the hippocampus and the locus coeruleus (LoC) also produces similar memory deficits and injection of both AR agonists into a cortical area can rescue memory from LoC Abeta. We have previously shown that beta3-AR stimulation increases astrocytic glucose uptake and have suggested there may be sensitization or upregulation of the receptor. Since beta2-AR stimulation does not rescue memory at the time it promotes glycogenolysis, but the receptor does not appear to be impaired, it is suggested that Abeta may be causing an impairment in the synthesis of readily available glycogen. PMID- 24810635 TI - Effect of physical exercise on changes in activities of creatine kinase, cytochrome c oxidase and ATP levels caused by ovariectomy. AB - The reduction in the secretion of ovarian hormones, principally estrogen, is a consequence of menopause. Estrogens act primarily as female sex hormones, but also exert effects on different physiological systems including the central nervous system. The treatment normally used to reduce the symptoms of menopause is the hormone therapy, which seems to be effective in treating symptoms, but it may be responsible for adverse effects. Based on this, there is an increasing demand for alternative therapies that minimize signs and symptoms of menopause. In the present study we investigated the effect of ovariectomy and/or physical exercise on the activities of energy metabolism enzymes, such as creatine kinase (cytosolic and mitochondrial fractions), pyruvate kinase, succinate dehydrogenase, complex II, cytochrome c oxidase, as well as on ATP levels in the hippocampus of adult rats. Adult female Wistar rats with 90 days of age were subjected to ovariectomy (an animal model widely used to mimic the postmenopausal changes). Thirty days after the procedure, the rats were submitted to the exercise protocol, which was performed three times a week for 30 days. Twelve hours after the last training session, the rats were decapitated for subsequent biochemical analyzes. Results showed that ovariectomy did not affect the activities of pyruvate kinase, succinate dehydrogenase and complex II, but decreased the activities of creatine kinase (cytosolic and mitochondrial fractions) and cytochrome c oxidase. ATP levels were also reduced. Exercise did not produce the expected results since it was only able to partially reverse the activity of creatine kinase cytosolic fraction. The results of this study suggest that estrogen deficiency, which occurs as a result of ovariectomy, affects generation systems and energy homeostasis, reducing ATP levels in hippocampus of adult female rats. PMID- 24810636 TI - IFN-gamma regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1. AB - Myeloid derived suppressor cells (MDSCs) play a critical role in suppression of immune responses in cancer and inflammation. Here, we describe how regulation of Bcl2a1 by cytokines controls the suppressor function of CD11b(+) Gr-1(high) granulocytic MDSCs. Coculture of CD11b(+) Gr-1(high) granulocytic MDSCs with antigen-stimulated T cells and simultaneous blockade of IFN-gamma by the use of anti-IFN-gamma blocking antibody, IFN-gamma(-/-) effector T cells, IFN-gammaR(-/ ) MDSCs or STAT1(-/-) MDSCs led to upregulation of Bcl2a1 in CD11b(+) Gr-1(high) cells, improved survival, and enhanced their suppressor function. Molecular studies revealed that GM-CSF released by antigen-stimulated CD8(+) T cells induced Bcl2a1 upregulation, which was repressed in the presence of IFN-gamma by a direct interaction of phosphorylated STAT-1 with the Bcl2a1 promotor. Bcl2a1 overexpressing granulocytic MDSCs demonstrated prolonged survival and enhanced suppressor function in vitro. Our data suggest that IFN-gamma/ STAT1-dependent regulation of Bcl2a1 regulates survival and thereby suppressor function of granulocytic MDSCs. PMID- 24810637 TI - Treatment with a fusion protein of the extracellular domains of NKG2D to IL-15 retards colon cancer growth in mice. AB - Tumor-targeted cytokines are a new class of pharmaceutical anticancer agents often considered superior to the corresponding unconjugated cytokines for therapeutic purposes. We generated a new fusion protein, dsNKG2D-IL-15, in which double NKG2D extracellular domains were fused to IL-15, in Escherichia coli. This fusion protein promoted the activation, proliferation, and cytotoxicity of NK cells, and bound to NKG2D ligand-positive tumor cells. These tumor cells were also more susceptible to NK-cell attack when decorated with dsNKG2D-IL-15. The administration of mouse dsNKG2D-IL-15 protein in vivo significantly retarded the growth of transplanted colon cancers and prolonged the survival of tumor-bearing mice. Treatment with dsNKG2D-IL-15 increased the frequencies of NK and CD8 T cells in spleen and tumor tissues. The antitumor effect mediated by dsNKG2D-IL-15 was significantly decreased with in vivo depletion of NK cells or CD8 T cells. Recombinant dsNKG2D-IL-15 thus inhibited NKG2D ligand-positive tumor growth effectively by activating lymphocytes. This new biological fusion protein could potentially be used to elicit immunity in tumor-targeting treatments. PMID- 24810638 TI - Ex vivo generation of interstitial and Langerhans cell-like dendritic cell subset based vaccines for hematological malignancies. AB - Autologous, patient-specific, monocyte-derived dendritic cell (MoDC) vaccines have been successfully applied in the clinical studies so far. However, the routine application of this strategy has been hampered by the difficulties in generating sufficient numbers of DC and the poor DC vaccine quality because of pathology or prior treatment received by the patients. The immunotherapeutic potential of other subsets of DC has not been thoroughly investigated because of their rarity in tissues and difficulties associated with their ex vivo generation. The high expansion and differentiation potential of CD34 hematopoietic progenitor cells (HPC), isolated from umbilical cord blood (UCB), into different DC subsets make them an attractive alternative DC source for cancer immunotherapy. Therefore, the aim of this study was to generate a large number of different DC subsets from CD34 HPC and evaluate their functionality in comparison with MoDC. Our culture protocol generated a clinically relevant number of mature CD1a myeloid DC and CD207 Langerhans cells (LC)-like DC subsets from CD34 HPC with >95% purity. Both DC subsets exhibited a cytokine profile that favors cytotoxic T-cell responses. Furthermore, UCB-DC and UCB-LC demonstrated superior induction of proliferation of both allogeneic as well as viral antigen specific CD8 T cells, both in vitro and in vivo. Additional studies revealed that UCC-DC and UCB-LC can efficiently expand minor histocompatibility antigen (MiHA) HA-1-specific cytotoxic T cells in the peripheral blood of leukemia patients and prime MiHA HA-1-specific and HA-2-specific cytotoxic T cells in vitro. These preclinical findings support the pharmaceutical development of the described culture protocol for clinical evaluation. PMID- 24810639 TI - Enhanced cytotoxic activity of ex vivo-differentiated human natural killer cells in the presence of HOXB4. AB - We have previously shown that human umbilical cord blood CD34 progenitor cells undergo in vitro differentiation into functional natural killer (NK) cells and that their coculture in the presence of HOXB4-transduced stromal MS-5 cells resulted in an increase in differentiated NK number. The present study was conducted to compare the stromal effect on NK lytic potential in the presence and absence of HOXB4. Our results provide evidence that HOXB4-transduced MS-5 cells as compared with transduced GFP (+) MS-5 cells induced highly differentiated cytotoxic NK cells. Importantly, this difference was not because of the expression of activating NK receptors but was associated with an increased induction of granzyme B degranulation in response to stimulation with NK cell susceptible targets. DNA microarray-based global transcriptional profiling confirmed the upregulation of granzyme B. These findings provide further evidence that HOXB4 is a crucial regulator of NK function and that its use in generating functional NK cells with increased lytic potential may be significant for cancer immunotherapy. PMID- 24810640 TI - Adenoviral-based immunotherapy provides local disease control in an orthotopic murine model of esophageal cancer. AB - Despite recent advances in the development of novel therapies, esophageal carcinoma remains an aggressive cancer associated with a poor prognosis. The lack of a high throughput, reproducible syngeneic animal model that replicates human disease is partly responsible for the paucity of novel therapeutic approaches. In this report, we present the first successful syngeneic, orthotopic model for esophageal cancer. This model was used to test an established adenoviral-based tumor vaccine. We utilized a murine esophageal cancer cell line established from the ED-L2-cyclin D1;p53 mouse that was transduced to express a viral tumor antigen, the Human Papilloma Virus (HPV) E7 protein. The tumor was established in its natural microenvironment at the gastroesophageal junction. Tumor growth was consistent and reproducible. An adenoviral vaccine to E7 (Ad.E7) induced an E7 specific population of functionally active CD8 T cells that trafficked into the tumors and retained cytotoxicity. Ad.E7 vaccination reduced local tumor growth and prolonged overall survival. These findings suggest that orthotopic tumor growth is a reasonable preclinical model to validate novel therapies. PMID- 24810641 TI - Enhancement of DNA vaccine potency against legumain. AB - The asparaginyl endopeptidase legumain that is overexpressed in M2-polarized tumor-associated macrophages has been identified as a suitable target for elimination of these cells supporting tumor progression. To enhance the efficacy of DNA immunization against legumain, we performed several modifications in this protein that could improve induction of immune responses. First, we mutated the RGD motif into GGD or RGG sequences. This alteration resulted in diminished maturation of legumain and impaired cellular localization. Then, as tolerance to self-antigens can be broken by the activation of CD4 T-cell help, we tried to enhance the immunogenicity of legumain by the insertion of a foreign helper epitope, namely the p30 epitope from the tetanus toxin. Finally, the 2 modifications were combined. After gene gun DNA immunization of C57BL/6 mice with these constructs, we identified the Lgmn111-119 CD8 T-cell epitope that binds to H-2D molecules. Furthermore, we showed that mutagenesis in the RGD motif significantly enhanced the immune response against legumain. The addition of the p30 helper epitope induced the specific production of IFN-gamma by T cells, but did not significantly increase legumain-specific immunity activated after mutagenesis in the RGD motif which might be caused by simultaneous activation of a Th2 response demonstrated by the production of IL-4. However, the beneficial effect of the helper epitope on legumain-specific response was proved after the depletion of regulatory T cells by antibody against CD25 that preferentially stimulated Th1 immunity. The antitumor effect of the modified legumain gene was shown in the immunization against tumors induced by MK16 cells. PMID- 24810642 TI - High-dose interleukin 2-induced myocarditis: can myocardial damage reversibility be assessed by cardiac MRI? AB - High-dose interleukin 2 (HD-IL2) is one of the therapeutic options for patients with metastatic renal cell carcinoma. In well-selected patients with favorable clinical and pathologic features, it offers impressive response and potential long-term remission. It also has a place for treatment for metastatic malignant melanoma and in adoptive cell therapy. However, it is known for its intensive course and toxicities. Myocarditis is one of the known complications of this treatment and can pose a diagnostic challenge to treating oncologists because of its nonspecific and similar presentation to acute coronary syndrome (ACS). We report 3 short cases of HD-IL2-related myocarditis, which were either missed or misdiagnosed as ACS using conventional assessment but subsequently accurately diagnosed by cardiac magnetic resonant imaging (CMR). We discussed the clinical presentation of these cases and demonstrated the diagnostic advantage of CMR compared with standard investigations including its superior capability to assess myocardial reversibility, which has important short-term and long-term implications. The use of CMR also avoided unnecessary invasive intervention such as coronary angiogram in all 3 patients. These example cases call for effort to conduct prospective research to assess and confirm the utility of CMR, thus informing a more effective management pathway for immune-related myocarditis in HD-IL2 and other cancer immunotherapy. PMID- 24810644 TI - Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with non muscle invasive bladder cancer? An update and cumulative meta-analysis. AB - Approximately 70% of newly diagnosed bladder tumors are non-muscle invasive bladder cancer (NMIBC). NMIBC accounts for approximately 80% of total bladder cancer cases. Bacillus Calmette-Guerin (BCG) instillation and maintenance is considered as the standard adjuvant treatment for superficial bladder cancer. A number of randomized studies have focused on the benefit of maintenance therapy following initial BCG induction. To provide further insights into the effect of intravesical instillation on recurrence in patients with NMIBC, we analyzed this relationship by conducting an updated detailed meta-analysis. Evidence suggested that adjuvant intravesical BCG with maintenance treatment is significantly effective for the prophylaxis of tumor recurrence in patients with NMIBC. PMID- 24810645 TI - Chronic hepatitis B virus infection: epidemiology, prevention, and treatment in China. AB - Chronic hepatitis B is a major health problem in China. The universal vaccination program since 1992 has changed the epidemiology of hepatitis B virus infection in China from highly to moderately endemic. The most prevalent hepatitis B virus strains in China are genotypes B and C, whereas those in western provinces are genotypes D and C/D hybrid. Chronic hepatitis B poses a heavy burden to the society in China. Different treatment strategies have been explored to improve patient outcomes in a cost-effective manner. However, antiviral drugs with a low genetic barrier to resistance are still extensively used because of the generally low income and limited resources in China. Individualized antiviral therapy is closely associated with translational medicine, which utilizes information from studies on genomics, immune biomarkers, and fibrosis. The results of these studies are crucial in further improving treatment outcomes. PMID- 24810647 TI - Comprehensive treatment of acute-on-chronic liver failure in a patient with hepatitis B: a case report. AB - The clinical data of a patient with acute-on-chronic liver failure were analyzed retrospectively. The patient has suffered from hepatitis B for 30 years. His liver function deteriorated, yielding Child-Pugh grade C and reaching a model for end-stage liver disease score of 33 points within a short period; this condition was complicated with highly active variceal bleeding and coagulation system failure (PT > 100 s). The patient also presented hepatocellular carcinoma. Comprehensive treatments included effective inhibition of hepatitis B virus replication and intensive care support. Piggyback orthotopic liver transplantation was performed as the final treatment. The patient recovered uneventfully and was discharged after surgery. PMID- 24810648 TI - Pain assessment in children: validity of facial expression items in observational pain scales. AB - OBJECTIVES: Assessing pain in young children requires astute judgment by observers. Multidimensional observational scales for pediatric pain contribute by providing behavioral cues believed to characterize pain in children; yet, few measurement items have undergone rigorous psychometric evaluation. This is the case with facial expression, which has been widely recognized as the most sensitive and specific nonverbal indicator of pain. The criteria for identifying facial expressions of pain differ substantially across scales and are frequently inconsistent with empirical descriptions. MATERIALS AND METHODS: The present study compared observer ratings of children's (aged 1 to 6 y, inclusive) videotaped postoperative pain reactions using the facial activity items from 6 widely used pediatric pain assessment scales and an anatomically based and empirically validated measure, the Child Facial Coding System. We hypothesized that facial expression items that did not correspond to empirical descriptions would lead to less reliable and divergent pain estimates. Intercoder reliability, criterion validity (empirical and convergent), content validity, and face validity were examined. RESULTS: Findings supported hypotheses and indicated that variation in cues proposed for assessing facial expression led to widely ranging scores that could be insensitive to differences in children's pain intensity. DISCUSSION: The facial items varied considerably in coder judgment reliability as well as criterion (empirical and convergent), content, and face validity. Observational scales should provide behavioral cues that correspond to empirical descriptions of the facial expression of pain. PMID- 24810649 TI - Are prevalent self-reported cardiovascular disorders associated with delayed recovery from whiplash-associated disorders: a population-based cohort study. AB - OBJECTIVES: The aim of this cohort study was to investigate the association between self-reported cardiovascular disorders (CVD) and recovery from whiplash associated disorder (WAD) after a traffic collision. MATERIALS AND METHODS: This study was based on the Saskatchewan Government Insurance cohort, including individuals over 18 years of age, who made a traffic-injury claim or received health care after a traffic injury, between 1997 and 1999. Participants completed a baseline questionnaire and were followed up by telephone interviews at 6 weeks, 3 months, 6 months, 9 months, and 12 months after injury. Our sample includes a subcohort of 6011 participants who reported WAD (defined as answering "yes" to the question "Did the accident cause neck or shoulder pain") at baseline. The outcome, self-perceived recovery, was measured at all follow-up interviews. The presence of CVD and its effect on health was classified into 3 exposure categories: (1) CVD absent, (2) CVD present with no or mild effect on health, and (3) CVD present with moderate or severe effect on health. The association between CVD and recovery from WAD was assessed with Cox regression, and adjusted for potential confounders. RESULTS: We found a crude association between comorbid CVD with moderate or severe effect on health in women. However, the adjusted association was weak and potentially affected by residual confounding. We found no association in men. DISCUSSION: Our results suggest that CVD does not have an impact on the recovery of individuals with WAD. PMID- 24810646 TI - Advances in managing hepatocellular carcinoma. AB - Multiple modalities for treatment of hepatocellular carcinoma are available, depending on tumor size and number. Surgical resection remains the gold standard, so long as the residual liver function reserve is sufficient. In patients with advanced cirrhosis, liver transplantation is the preferred option, as these patients may not have adequate hepatic reserve after resection. Salvage liver transplantation has also become an option for a select few patients who recur after surgical resection. Ablative techniques have been used for palliation as well as to either completely destroy the tumor, act as an adjunct to resection, or downstage the tumor to meet Milan criteria such that a patient may be a candidate for liver transplantation. Radiofrequency ablation, microwave ablation, chemoembolization, radioembolization, and irreversible electroporation have all been used in this capacity. Currently, sorafenib is the only US Food and Drug Administration-approved chemotherapeutic for hepatocellular carcinoma. The efficacy of sorafenib, in combination with other agents, transarterial chemoembolization, and surgical resection is currently being investigated. Sunitinib and brivanib, tyrosine kinase inhibitors, have failed as potential first- or second-line options for chemotherapy. Bevacizumab in combination with erlotinib is also currently being studied. Final analysis for ramucirumab and axitinib are pending. Tivantinib, a selective mesenchymal-epithelial transition factor (MET) inhibitor, is also undergoing clinical trials for efficacy in MET high tumors. This review serves to emphasize the current and new technologies emerging in the treatment of hepatocellular carcinoma. PMID- 24810650 TI - Opioid-related adverse drug events: do parents recognize the signals? AB - OBJECTIVES: Evidence of unrelieved childhood pain, adverse drug events (ADE), and deaths suggest that parents may inadequately respond to pain and opioid-related ADE signals. This study examined parents' recognition and response to pain and ADE signals using both dynamic hypothetical scenarios and real at-home opioid decisions. MATERIALS AND METHODS: A total of 514 parents whose children required prescription opioids after discharge were surveyed. Parents made analgesic decisions for 4 hypothetical scenarios wherein the child's pain level and ADE symptoms were altered. After discharge, parents recorded their child's real pain levels, ADEs, and their analgesic decisions. Mixed-effects logistic regression examined the influence of pain and ADE signals on parents' opioid decisions. RESULTS: Pain intensity had a main effect on parents' hypothetical and real decisions to give opioids (P<=0.001). Nausea/vomiting influenced the decision to give the prescribed opioid dose (beta=-1.48 [95% confidence interval (CI): -1.78, -1.19], P<0.001) as did oversedation (beta=-1.02 [95% CI: -1.30, -0.75], P<0.001); however, parents were more likely to give the prescribed dose for oversedation than nausea/vomiting (odds ratio (OR) =1.53 [95% CI: 1.14, 2.05], P=0.005). Gastrointestinal effects were more likely to motivate a change in postdischarge opioid administration compared with other ADEs (OR=4.41 [95% CI: 1.91, 10.18], P<0.001), whereas sedation symptoms did not (OR=0.46 [95% CI: 0.21, 1.04], P=0.06). DISCUSSION: Findings demonstrated that many parents failed to withhold a prescribed opioid dose for oversedation, suggesting a lack of awareness regarding this potentially serious ADE. Strategies to improve parents' recognition of oversedation and its potential consequences are warranted to improve opioid safety. PMID- 24810651 TI - Nociceptive processing in women with premenstrual dysphoric disorder (PMDD): the role of menstrual phase and sex hormones. AB - OBJECTIVE: Premenstrual dysphoric disorder (PMDD) is associated with increased pain, but there has been a lack of well-controlled research assessing pain responsivity, sex hormones, and their relationships in this group. This study was designed to address this gap in the literature. MATERIALS AND METHODS: Healthy, regularly cycling participants (14 PMDD, 14 non-PMDD) attended pain testing sessions during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (order counterbalanced) and salivary estradiol, progesterone, and testosterone were assessed at each testing session. Pain sensitivity was measured from electrocutaneous threshold/tolerance, ischemic threshold/tolerance, sensory and affective ratings of electrocutaneous and ischemic stimuli, and the nociceptive flexion reflex threshold (NFR, a measure of spinal nociception). RESULTS: Women with PMDD had higher sensory pain ratings of electrocutaneous stimuli and trends for lower ischemic thresholds and higher affective pain ratings of electrocutaneous stimuli. However, there were no group differences observed in NFR threshold. Testosterone levels were also lower during the mid follicular and ovulatory phases in PMDD. Correlations between pain outcomes and estradiol and testosterone indicated that these hormones are hypoalgesic, with estradiol having a greater hypoalgesic effect within the PMDD group. DISCUSSION: Overall, women with PMDD may have a phase-independent hyperalgesia, with pain amplification likely occurring at the supraspinal level rather than the spinal level, given the lack of group differences in NFR threshold. Because testosterone was hypoalgesic and lower in women with PMDD, and there were strong associations between pain and estradiol in PMDD, sex hormones may play a role in PMDD-related hyperalgesia. PMID- 24810652 TI - Emotion work, ethnography, and survival strategies on the streets of Yogyakarta. AB - Anthropological research with street-related children, adolescents, and young adults raises epistemological, methodical, and ethical predicaments. In this article, I illustrate the advantages of an anthropology that acknowledges the ethnographer's emotions as valuable data when conducting research with marginalized communities. By drawing on my own experiences when conducting long term fieldwork, I argue that systematic self-reflexivity and an emotionally aware epistemology enhance both the anthropologist's emotional literacy and his or her understanding of informants and interlocutors. The integration of the ethnographer's emotions in the analysis and interpretation of ethnographic data can assist in formulating anthropological theory, challenging the limits of traditional empiricism, and raising emotions to a category of epistemic value. PMID- 24810654 TI - Body mass index and weight change in men with prostate cancer: progression and mortality. AB - PURPOSE: Body mass index (BMI) is a modifiable lifestyle factor that has been associated with an increased risk of fatal prostate cancer and biochemical recurrence. The main purpose of the present study was to investigate the association between the exposure BMI at the time of a prostate cancer diagnosis and weight change after diagnosis, and the outcomes of prostate cancer progression and mortality in a large cohort study. METHODS: Data from 4,376 men diagnosed with clinically localized prostate cancer between 1997 and 2002 were analyzed. BMI and weight change were self-reported in 2007. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated in complete-case analysis (n = 3,214) using Cox proportional hazards models. RESULTS: Progression was experienced among 639 (14.6 %) of the study participants, and in total, 450 (10.3 %) deaths of any cause and 134 (3.1 %) prostate cancer-specific deaths were recorded during follow-up. Obese men had a 47 % increased rate of overall mortality compared to normal weight men (HR 1.47, 95 % CI 1.03-2.10). No statistically significant associations were found for BMI and prostate cancer progression or prostate cancer-specific mortality. A weight loss >5 % after diagnosis almost doubled the rate of overall mortality compared to maintaining a stable weight (HR 1.94, 95 % CI 1.41-2.66), while a weight gain >5 % was associated with an almost doubled increased rate of prostate cancer-specific mortality (HR 1.93, 95 % CI 1.18-3.16). CONCLUSIONS: Being obese was associated with an increased rate of overall mortality, and gaining weight after a prostate cancer diagnosis was associated with an increased rate of prostate cancer specific mortality. PMID- 24810653 TI - Breast cancer risk in older women: results from the NIH-AARP Diet and Health Study. AB - BACKGROUND: Divergent risk factors exist for premenopausal and postmenopausal breast cancers, but it is unclear whether differences by age exist among postmenopausal women. METHODS: We examined relationships among 190,872 postmenopausal women, ages 50-71 years recruited during 1995-1996 for the NIH AARP Diet and Health Study, in whom 7,384 incident invasive breast carcinomas were identified through 2006. Multivariable Cox regression hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for breast cancer risk factors by age (50-59, 60-69, >=70 years). RESULTS: The only factor showing significant statistical heterogeneity by age (p(het) = 0.001) was menopausal hormone therapy duration, but trends were apparent across all ages and the strongest association prevailed among women 60-69 years. Although other risk factors did not show statistically significant heterogeneity by age, we did observe attenuated relations for parity and late age at first birth among older women [e.g., HR for age at first birth >=30 vs. 20-24 = 1.62 (95% CI 1.23-2.14) for women 50-59 years vs. 1.12 (0.96-1.31) for >=70 years]. In contrast, risk estimates associated with alcohol consumption and BMI tended to be slightly stronger among the oldest subjects [e.g., HR for BMI >=35 vs. 18.5-24.9 = 1.24 (95% CI 0.97-1.58) for 50-59 years vs. 1.46 (1.26-1.70) for >=70 years]. These differences were somewhat more pronounced for estrogen receptor positive and ductal cancers, tumors predominating among older women. Breast cancer family history, physical activity, and previous breast biopsies did not show divergent associations by age. CONCLUSION: Although breast cancer risk factor differences among older women were not large, they may merit further consideration with respect to individualized risk prediction. PMID- 24810655 TI - Study on chemical, bioactive and food preserving properties of Laetiporus sulphureus (Bull.: Fr.) Murr. AB - Laetiporus sulphureus (Bull.: Fr.) Murr. was studied to determine the nutritional value, bioactive compounds, in vitro antioxidants, and antimicrobial and antitumor activities. The studied mushroom is a rich source of carbohydrates and proteins. Mannitol and trehalose were the main free sugars. In addition, the polyunsaturated fatty acids alpha-, gamma- and delta-tocopherols were found. Oxalic and citric acids were the most abundant organic acids; cinnamic and p hydroxybenzoic acids were quantified in the methanolic extract and could be related to the antioxidant properties. It was the polysaccharidic extract that exhibited higher antioxidant and antimicrobial activities, indicating that the compounds present in this extract possess stronger bioactivity. Only the polysaccharidic extract revealed antiproliferative activity in human tumor cell lines. In addition, a suitable model system with chicken pate was developed to test the antimicrobial preserving properties of L. sulphureus. The methanolic extract was used to examine in situ preserving properties against Aspergillus flavus and demonstrated excellent preserving potential. PMID- 24810656 TI - Human herpesvirus 6 reactivation on the 30th day after allogeneic hematopoietic stem cell transplantation can predict grade 2-4 acute graft-versus-host disease. AB - BACKGROUND: Viral infections and their occult reactivation occasionally cause not only organ damage, but also exacerbation of acute graft-versus-host disease (aGVHD), which may increase transplantation-related mortality synergistically. To determine correlations between viral reactivation and transplantation-related complications, we performed various viral screening tests on the 30th day after allogeneic hematopoietic stem cell transplantation (HSCT), and assessed the clinical implications. PATIENTS AND METHODS: Between August 2007 and January 2013, 49 patients (37 men, 12 women) underwent HSCT in our hospital. The stem cell sources were bone marrow (n = 21), peripheral blood (n = 13), and cord blood (n = 15). The presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpesvirus (HHV) 6, and HHV7 in plasma samples prospectively collected from HSCT recipients on day 30 after HSCT was assayed by quantitative polymerase chain reaction, and the correlations with transplantation-related complications were evaluated. RESULTS: The positivities of CMV, EBV, HHV6, and HHV7 were 44.9%, 22.4%, 53.1%, and 18.3%, respectively. We analyzed transplantation-related complications, and a significant correlation was found only between HHV6 and grade 2-4 aGVHD from day 30 to day 100 (P < 0.001). Using a receiver operating characteristic curve, the area under the curve was calculated as 0.86 (95% confidence interval [CI], 0.74-0.98) between the viral load (VL) of HHV6 and grade 2-4 aGVHD. The sensitivity and specificity were 79% and 93%, respectively, when a cutoff value of 87 copies/mL was used. In multivariate analysis using the Fine and Gray proportional hazards model, the clinically determined high-risk patients (P = 0.004; hazard ratio [HR], 3.69; 95% CI, 1.52-9.00) and the positivity of HHV6 (P < 0.001; HR, 9.957; 95% CI, 2.68-37.06) were extracted as independent risk factors for the cumulative incidence of grade 2-4 aGVHD on or after post-HSCT day 30. The only risk factor extracted for the elevation of HHV6 VL >87 copies/mL was cord blood transplantation (P = 0.0032; odds ratio, 7.10; 95% CI, 1.98-30.00). CONCLUSION: All of the risk factors previously reported to predict severe aGVHD were obtained only during, but not after, HSCT. Our study suggests that the reactivation of HHV6 (>= 87 copies/mL) at 30 days after HSCT is a possible predictive marker for grade 2-4 aGVHD on or after post-HSCT day 30. PMID- 24810657 TI - Influence of preoperative factors on the oncologic outcome for upper urinary tract urothelial carcinoma after radical nephroureterectomy. AB - PURPOSE: To evaluate the influence of preoperative factors on the survival of patients diagnosed with upper tract urothelial carcinoma (UTUC) who underwent a radical nephroureterectomy (RNU). METHODS: A multicentre retrospective study was performed on all patients with UTUC who underwent a RNU. Multiple preoperative criteria were tested as prognostic factors for cancer-specific survival (CSS) using univariate and multivariable Cox regression analyses. RESULTS: Overall, 476 patients with a median age of 69.2 (IQR 60.8-76.5) years were included. The median follow-up was 27.8 months (IQR 10.5-49.3). At the time of diagnosis, 400 (84.1 %) patients presented with symptoms and 76 patients (15.9 %) were asymptomatic. Renal failure, altered general health, a preoperative locally advanced tumour and multifocal disease appeared to be preoperative prognostic factors for CSS (p = 0.01, 0.03, 0.001 and 0.03, respectively) in the univariate analysis. Only renal failure (p = 0.03), a preoperative locally advanced tumour (0.004), and multifocal locations (p = 0.01) were confirmed as independent factors of CSS in the multivariate analysis. The independent prognosticators of definitive muscle-invasive stage and non-organ-confined disease were preoperative renal failure (p = 0.02, 0.027, respectively), locally advanced stage (p < 0.001, <0.001, respectively) and positive cytology (p = 0.006, 0.003 respectively). Female gender was independent factor only for prediction of final non-organ confined disease (p = 0.007). The addition of these parameters in our preoperative complex model permitted the prediction of muscle-invasive or locally advanced disease in 65.3 and 67.2 % of patients, respectively. CONCLUSIONS: Patients with preoperative impaired renal function, locally advanced stage and multifocal tumours before RNU had worse survival outcomes compared to other patients. PMID- 24810658 TI - Graphene/MoS2 hybrid technology for large-scale two-dimensional electronics. AB - Two-dimensional (2D) materials have generated great interest in the past few years as a new toolbox for electronics. This family of materials includes, among others, metallic graphene, semiconducting transition metal dichalcogenides (such as MoS2), and insulating boron nitride. These materials and their heterostructures offer excellent mechanical flexibility, optical transparency, and favorable transport properties for realizing electronic, sensing, and optical systems on arbitrary surfaces. In this paper, we demonstrate a novel technology for constructing large-scale electronic systems based on graphene/molybdenum disulfide (MoS2) heterostructures grown by chemical vapor deposition. We have fabricated high-performance devices and circuits based on this heterostructure, where MoS2 is used as the transistor channel and graphene as contact electrodes and circuit interconnects. We provide a systematic comparison of the graphene/MoS2 heterojunction contact to more traditional MoS2-metal junctions, as well as a theoretical investigation, using density functional theory, of the origin of the Schottky barrier height. The tunability of the graphene work function with electrostatic doping significantly improves the ohmic contact to MoS2. These high-performance large-scale devices and circuits based on this 2D heterostructure pave the way for practical flexible transparent electronics. PMID- 24810659 TI - Physicochemical properties of pentaglyme-sodium bis(trifluoromethanesulfonyl)amide solvate ionic liquid. AB - The physicochemical properties of pentaglyme (G5) and sodium bis(trifluoromethanesulfonyl)amide (Na[TFSA]) binary mixtures were investigated with respect to salt concentration and temperature. The density, viscosity, ionic conductivity, self-diffusion coefficient, and oxidative stability of a series of binary mixtures were measured, and the mixtures were examined as electrolytes for Na secondary batteries. An equimolar mixture of G5 and Na[TFSA] formed a low melting solvate, [Na(G5)1][TFSA], which exhibited an ionic conductivity of 0.61 mS cm(-1) at 30 degrees C. The ionicity (Lambdaimp/Lambdaideal) of the glyme Na[TFSA] mixture was estimated from the molar conductivity of electrochemical impedance measurements (Lambdaimp) and the Walden plot (Lambdaideal). [Na(G5)1][TFSA] possessed a high ionicity of 0.63 at 30 degrees C, suggesting that [Na(G5)1][TFSA] is highly dissociated into a [Na(G5)1](+) cation and a [TFSA](-) anion, regardless of the extreme salt concentration in the liquid. The oxidative stabilities of G5-Na[TFSA] mixtures were investigated by linear sweep voltammetry, and the higher concentration resulted in higher oxidative stability due to the lowering of the HOMO energy level of G5 by complexation with the Na(+) ion. In addition, battery tests were performed using the mixtures as electrolytes. The [Na|[Na(G5)1][TFSA]|Na0.44MnO2] cell showed good charge discharge cycle stability, with a discharge capacity of ca. 100 mA h g(-1), while the [Na(G5)1.25][TFSA] system, containing excess G5, showed poor stability. PMID- 24810660 TI - Erythema multiforme after orf virus infection: a report of two cases and literature review. AB - Orf virus has a worldwide distribution among sheep and goats. The hypersensitivity reaction erythema multiforme (EM) is a known complication of orf infection in humans; however, its occurrence is poorly understood and has not been extensively reviewed. We present two unrelated cases of orf-associated EM, and a review of the literature, highlighting important clinical, epidemiological and immunological aspects of this condition. Orf and its associated complications can occur in rural areas, as well as urban settings, where it is less well-known, through religious or cultural practices involving animal slaughter. Obtaining a history of animal exposures from patients with lesions suspicious for orf and secondary skin eruptions can guide diagnosis and identification of the inciting immune stimulus. Determining the pathophysiology and relative contribution of host and viral factors contributing to EM and other orf-associated hypersensitivity reactions could facilitate the identification of risk factors and inform treatment decisions. PMID- 24810661 TI - A 'lost life': coming to terms with haemodialysis. AB - AIMS AND OBJECTIVES: To describe the essence of the lived experience of patients and families in the early phase of long-term haemodialysis therapy. BACKGROUND: Past qualitative research has taken a long-term view describing established haemodialysis therapy as it impacts on physical limitations and changes in self concept, psychosocial well-being and sense of dignity with subsequent consequences for family roles and financial status. DESIGN: This study used the qualitative approach of Heideggerian phenomenology. METHODS: Eleven patients with end-stage kidney disease who had recently initiated haemodialysis and five family carers engaged in semi-structured interviews. These were recorded and transcribed verbatim and analysed using an hermeneutic framework. RESULTS: The essence of the early dialysis experience was a 'lost life', and participants were overwhelmed by shock and grief. This appeared to result from a lack of mental and physical preparation for dialysis as a long-term management strategy. A loss of sense of self, loss of spontaneity and personal freedom and loss of social connectedness challenged the participants' ability to contribute to family and community. Changed body sensations ranged from improved wellness to a sense of depletion and fatigue. Family caregivers found the caring role was unremitting and required intense vigilance. CONCLUSIONS: Patients and family members in the early phase of dialysis may have difficulty perceiving a positive future. RELEVANCE TO CLINICAL PRACTICE: A greater focus on preparation for the possibility of dialysis and frameworks of care that support adjustment to this new way of life are of vital importance. Family presence during haemodialysis and support groups for patients and family should be actively facilitated. PMID- 24810662 TI - Long-term abstinence from developmental cocaine exposure alters Arc/Arg3.1 modulation in the rat medial prefrontal cortex. AB - Cocaine is a psychostimulant whose abuse causes a social and economic burden for our society. Most of the published literature deals with acute effects of cocaine or short-term abstinence in adult animals but much less information exists on neuroplastic changes following long-term abstinence. We have recently shown that the long-term abstinence following developmental exposure to cocaine results in increased Activity-Regulated Cytoskeletal-associated protein (Arc/Arg3.1) expression in the crude synaptosomal fraction (Giannotti et al. Int J Neuropsychopharmacology 7(4):625-634, 2014). Given that Arc/Arg3.1 localizes not only at active synapse but also in the nucleus (Okuno et al. Cell 149:886-898, 2012; Korb et al. Nat Neurosci 16:874-883 2013; Bloomer et al. Brain Res 1153:20 33 2007), we investigated Arc/Arg3.1 protein levels in the whole homogenate and the nuclear fraction of animals exposed to cocaine during adolescence. We observed the increased expression of Arc/Arg3.1 in both the fractions, suggesting that up-regulation of Arc/Arg3.1 protein may be partly due to the increased nuclear expression of Arc/Arg3.1 in the medial prefrontal cortex (mPFC) of rats sacrificed at postnatal day 90, following 48 days of abstinence. This effect seems to cause reduced Gria1 transcription. We also found reduced expression of fragile X mental retardation gene (FMR1) which normally inhibits Arc/Arg3.1 translation together with reduced expression of Ubiquitin-protein ligase E3A (Ube3a) that normally causes Arc/Arg3.1 protein degradation via ubiquitination. Further, we found increased expression of metabotropic glutamate receptor 5 (GRM5) which is also involved in the regulation of Arc/Arg3.1 expression. Taken together, our findings show that abstinence from developmental exposure to cocaine is associated with alterations in the finely tuned mechanisms that regulate Arc/Arg3.1 expression. PMID- 24810663 TI - Quantum and classical magnetoresistance in ambipolar topological insulator transistors with gate-tunable bulk and surface conduction. AB - Weak antilocalization (WAL) and linear magnetoresistance (LMR) are two most commonly observed magnetoresistance (MR) phenomena in topological insulators (TIs) and often attributed to the Dirac topological surface states (TSS). However, ambiguities exist because these phenomena could also come from bulk states (often carrying significant conduction in many TIs) and are observable even in non-TI materials. Here, we demonstrate back-gated ambipolar TI field effect transistors in (Bi0.04Sb0.96)2Te3 thin films grown by molecular beam epitaxy on SrTiO3(111), exhibiting a large carrier density tunability (by nearly 2 orders of magnitude) and a metal-insulator transition in the bulk (allowing switching off the bulk conduction). Tuning the Fermi level from bulk band to TSS strongly enhances both the WAL (increasing the number of quantum coherent channels from one to peak around two) and LMR (increasing its slope by up to 10 times). The SS-enhanced LMR is accompanied by a strongly nonlinear Hall effect, suggesting important roles of charge inhomogeneity (and a related classical LMR), although existing models of LMR cannot capture all aspects of our data. Our systematic gate and temperature dependent magnetotransport studies provide deeper insights into the nature of both MR phenomena and reveal differences between bulk and TSS transport in TI related materials. PMID- 24810664 TI - The need for pelvic angiographic embolisation in stable pelvic fracture patients with a "blush" on computed tomography. PMID- 24810665 TI - Enhanced casualty care from a Global Military Orthopaedic Teleconsultation Program. AB - BACKGROUND: Since its advent, telemedicine has facilitated access to subspecialty medical care for the treatment of patients in remote and austere settings. The United States military introduced a formal orthopaedic teleconsultation system in 2007, but few reports have explored its scope of practice and efficacy, particularly in a deployed environment during a time of conflict. METHODS: All teleconsultations placed to the orthopaedic service between April 2009 and December 2012 were obtained and retrospectively reviewed. Case files were abstracted and anatomical location of injury, type of injury, origin of consult (country or Navy Afloat), branch of service, and treatment recommendations, were recorded for descriptive analysis. The final result of the consult was also determined, with service members transported from the combat theatre or deployment location defined as medically evacuated. Instances where teleconsultations averted a medical evacuation were also documented as a separate outcome. RESULTS: Over a 32-month period, 597 orthopaedic teleconsultations were placed, with the majority derived from Army (46%) and Navy (32%) personnel deployed in Afghanistan, Iraq, or with Navy Afloat. Approximately 51% of consults involved the upper extremity, including 197 hand injuries, followed by lower extremity (37%) and spine (7.8%) complaints. Fractures comprised over half of all injuries, with the hand and foot most commonly affected. The average response time for teleconsultations was 7.54h. A total of 56 service members required immediate evacuation for further orthopaedic management, while at least 26 medical evacuations were prevented due to the teleconsultation system. CONCLUSIONS: The teleconsultation system promotes early access to orthopaedic subspecialty care in a resource-limited, deployed military setting. The telemedicine network also appears to mitigate unnecessary aeromedical evacuations, reducing healthcare costs, lost duty time, and treatment delays. These findings have important meaning for the future of telemedicine in both the military and civilian setting. LEVEL OF EVIDENCE: IV. PMID- 24810666 TI - Influence of bearing devices on the dose effect and image quality of trauma whole body CT scans. PMID- 24810667 TI - The ideal target blood pressure for resuscitation during uncontrolled haemorrhagic shock. PMID- 24810668 TI - Experimental analyses of the retinal and subretinal haemorrhages accompanied by shaken baby syndrome/abusive head trauma using a dummy doll. AB - INTRODUCTION: We explored several modes of violent shaking using a dummy doll with an eyeball model to reproduce abusive events that lead to retinal haemorrhages (RH) seen in shaken baby syndrome or abusive head trauma (SBS/AHT). MATERIALS AND METHODS: A dummy doll equipped with an eyeball model was prepared. The eyeball model was filled with a model of vitreous body, i.e. agar gel or water, and was with a pressure sensor to measure normal stress. RESULTS: The modes of shaking were classified into three patterns, i.e. fast shaking with the fore arms, fast shaking with the whole arms and synchronized shaking with the whole arms. The frequency of the cyclic acceleration-deceleration history experienced by the head of the dummy doll was 5.0, 4.0 and 2.2 Hz, respectively, with the maximum acceleration of 20, 20 and 60 m/s(2), respectively. We considered the last of these three modes of shaking as possibly corresponding to the worst case of violent shaking. This mode of shaking could be instructed to volunteers who acted as imitate perpetrators, and resulted in both increased peak intensities of the acceleration experienced by the head of the dummy doll and increased stresses on the retina at the posterior pole of the eyeball model. DISCUSSION: The time integral of the stress through a single cycle of shaking was 107 Pa.s, much larger than that of a single event of fall, which resulted in 60 73 Pa.s. Taking into account that abusive shaking is likely to include multiple cycles, the time integral of the stress due to abusive shaking can be even larger. This clear difference may explain why RH in SBS/AHT is frequent, while RH in accidental falls is rare. PMID- 24810669 TI - Necessity of monitoring after negative head CT in acute head injury. AB - OBJECTIVE: The main objective of this study was to evaluate the incidence of delayed complications in acute head injury (HI) patients with an initial normal head computed tomography (CT). MATERIALS AND METHODS: This retrospective study included 3023 consecutive patients who underwent head CT due to an acute HI at the Emergency Department (ED) of Tampere University Hospital (August 2010-July 2012). Regardless of clinical injury severity, the patients with a normal head CT were selected (n=2444, 80.9%). The medical records of these patients were reviewed to identify the individuals with a serious clinically significant complication related to the primary HI. The time window considered was the following 72h after the primary head CT. A repeated head CT in the hospital ward, death, or return to the ED were indicative of a possible complication. RESULTS: The majority (n=1811, 74.1%) of the patients with a negative head CT were discharged home and 1.1% (n=27) of these patients returned to ED within 72h post CT. A repeated head CT was performed on 12 (44.4%) of the returned patients and none of the scans revealed an acute lesion. Of the 632 (25.9%) CT-negative patients admitted to the hospital ward from the ED, a head CT was repeated in 46 (7.3%) patients within 72h as part of routine practice. In the repeated CT sample, only one (0.2%) patient had a traumatic intracranial lesion. This lesion did not need neurosurgical intervention. The overall complication rate was 0.04%. CONCLUSION: In the present study, which includes head injuries of all severity, the probability of delayed life-threatening complications was negligible when the primary CT scan revealed no acute traumatic lesions. PMID- 24810670 TI - Who makes use of Internet-delivered health information? The role of gender role self-concept in young men and women. AB - This study examined the contribution of gender role self-concept (expressiveness and instrumentality) on active interest in and use of Internet-delivered health information among young men and women. Four hundred and twenty university students reported health behaviours and perceived personal vulnerability regarding five diseases. We analysed active interest in receiving health-related information concerning these diseases (providing email address to receive a link to health-related websites) and actual use of provided websites two weeks afterwards. Usage of health-related information via the Internet was objectively assessed by recording log-ins on the website and obtaining individual click counts. In both sexes, higher expressiveness was independently associated with being more likely to show active interest in health-related information. Additionally, expressiveness was positively associated with website use in men independent of age, personal vulnerability and reported health behaviours. Thus, an expressive self-concept facilitates the use of health-related information, especially among men. PMID- 24810671 TI - Image analysis of platelet derived growth factor receptor-beta (PDGFRbeta) expression to determine the grade and dynamics of myelofibrosis in bone marrow biopsy samples. AB - BACKGROUND: Myelofibrosis (MF) is characterized by accumulation of stromal cells and extracellular matrix. Progression of fibrosis is an important clinical issue and monitoring is required for new therapeutic approaches. Currently, the quantification is based on semiquantitative evaluation of reticulin silver stained slides. We recently reported that platelet derived growth factor receptor beta (PDGFRbeta) expression in fibroblasts is a useful marker of stromal activation. PDGFRbeta expression based scores represent significant differences in different MF grade which provides optimal source of quantification. In this study, slide-based measurements were performed to support correlations of PDGFRbeta expression with MF grade. METHODS: Scanned image tiles from 79 bone marrow samples (BM) with different MF grades were evaluated for PDGFRbeta-related IHC parameters. Following the determination of immunopositive (brown component) and total area (region of interest) of the BM, PDGFRbeta related image parameters were defined and evaluated in comparison with the classical reticulin based grading. RESULTS: Eight PDGFRbeta expression related image parameters showed excellent correlation with the MF grade (correlation coefficient ranging between 0.79 and 0.83) and with PDGFRbeta score (0.76-0.87). Despite the significant sample heterogeneity, the parameters showed significant differences between fibrotic and nonfibrotic cases and between mild and advanced fibrosis. Distribution of values within a particular specimen emphasizes the heterogeneity of bone marrow involvement which may cause difficulties in semiquantitative methods. CONCLUSIONS: Our results clearly demonstrated the correlation between MF and PDGFRbeta expression considering all relevant areas in BM samples. This method provides good basis for follow-up comparison of the fibrotic samples. PMID- 24810672 TI - The use and correlates of illicit silicone or "fillers" in a population-based sample of transwomen, San Francisco, 2013. AB - INTRODUCTION: There is a dearth of studies to quantify the use of illicit fillers by transwomen. Case studies of illicit filler injections have pointed to an array of serious health complications, including death. AIMS: The aims of this study were to determine the population prevalence and identify correlates of filler use among transwomen in San Francisco, CA. METHODS: An analysis of data collected in 2013 with a population-based sample of 233 transwomen recruited using respondent driven sampling (RDS). We used RDS weights to conduct bivariate and multivariate analyses of correlates of filler use. MAIN OUTCOME MEASURES: Main outcome measures were an RDS-weighted population prevalence of filler use among transwomen and differences in demographic characteristics, transition-related care factors, and self-esteem related to appearance. RESULTS: Weighted filler prevalence among transwomen was 16.7%. Being a transwoman between 30 and 49 years of age, owning/renting or living with a partner/family/friend, having had and planning to have surgery in the future, and having used nonprescribed hormones were all significantly associated with filler use. HIV was not associated with filler use. CONCLUSIONS: This study provides the first known estimate to date of the prevalence of filler use in a population-based sample of transwomen in San Francisco. Accessing illicit fillers may be the only choice available for many transwomen to make changes to their appearance due to the high cost of legal surgeries and other cosmetic procedures. An important next step in this research is to determine the overall prevalence and long-term consequences of filler use among transwomen, to explore how the use of fillers is protective to the safety and well-being of transwomen, and to find safe and affordable alternatives to this method that meet important gender-related appearance needs. PMID- 24810673 TI - Vesicles formed in aqueous mixtures of cholesterol and imidazolium surface active ionic liquid: a comparison with common cationic surfactant by water dynamics. AB - The formation of stable unilamellar vesicles which hold great potential for biological as well as biomedical applications has been reported in the aqueous mixed solution of a surface active ionic liquid (SAIL), 1-hexadecyl-3 methylimidazolium chloride ([C16mim]Cl) and cholesterol. To make a comparison we have also shown the formation of such stable vesicles using a common cationic surfactant, benzyldimethylhexadecylammonium chloride (BHDC) which has a similar alkyl chain length but different headgroup region to that of [C16mim]Cl. It has been revealed from dynamic light scattering (DLS), transmission electron microscopy (TEM), nuclear magnetic resonance (NMR), and other optical spectroscopic techniques that the micelles of [C16mim]Cl and BHDC in aqueous solutions transform into stable unilamellar vesicles upon increasing concentration of cholesterol. We find that, as the concentration of cholesterol increases, the solvation and rotational relaxation time of C153 in [C16mim]Cl/cholesterol solution as well as in BHDC/cholesterol solution gradually increases indicating a significant decrease in the hydration behavior around the self-assemblies upon micelle-vesicle transition. However, the extent of increase in solvation and rotational relaxation time is more prominent in the case of [C16mim]Cl/cholesterol solutions than in the BHDC/cholesterol system. This indicates that [C16mim]Cl/cholesterol vesicular membranes are comparatively less hydrated and more rigid than the BHDC/cholesterol vesicular bilayer. PMID- 24810674 TI - Combination of monoclonal antibodies and DPP-IV inhibitors in the treatment of type 1 diabetes: a plausible treatment modality? AB - Regulatory T cells (Tregs) are crucial for the maintenance of immunological tolerance. Type 1 diabetes (T1D) occurs when the immune-regulatory mechanism fails. In fact, T1D is reversed by islet transplantation but is associated with hostile effects of persistent immune suppression. T1D is believed to be dependent on the activation of type-1 helper T (Th1) cells. Immune tolerance is liable for the activation of the Th1 cells. The important role of Th1 cells in pathology of T1D entails the depletion of CD4(+) T cells, which initiated the use of monoclonal antibodies (mAbs) against CD4(+) T cells to interfere with induction of T1D. Prevention of autoimmunity is not only a step forward for the treatment of T1D, but could also restore the beta-cell mass. Glucagon-like peptide (GLP)-1 stimulates beta-cell proliferation and also has anti-apoptotic effects on them. However, the potential use of GLP-1 as a possible method to restore pancreatic beta-cells is limited due to rapid degradation by dipeptidyl peptidase (DPP)-IV. We hypothesize that treatment with combination of CD4 mAbs and DPP-IV inhibitors could prevent/reverse T1D. CD4 mAbs have the ability to induce immune tolerance, thereby arresting further progression of T1D; DPP-IV inhibitors have the capability to regenerate the beta-cell mass. Consequently, the combination of CD4 mAbs and DPP-IV inhibitor could avoid or at least minimize the constraints of intensive subcutaneous insulin therapy. We presume that if this hypothesis proves correct, it may become one of the plausible therapeutic options for T1D. PMID- 24810675 TI - Fibromuscular dysplasia unraveled: the pulsation-induced microtrauma and reactive hyperplasia theory. AB - INTRODUCTION: Fibromuscular dysplasia (FMD) is a relatively uncommon, non inflammatory, non-atherosclerotic vascular condition of unknown etiology. There have been no major advancements in understanding FMD in the past 30-40yrs. We hypothesize that the vascular changes seen in FMD are a direct result of recurrent mechanical trauma in susceptible vessels and reflect a compensatory response to recurrent pulsation-induced mechanical trauma. METHODS: Radiology records at a large tertiary care medical center were queried for cases of cervical carotid FMD. Cases with viewable sequential angiographic evidence of FMD were selected and analyzed for degree of vessel tortuosity, FMD type, degree of vessel movement, and association with the FMD lesion. Images were independently analyzed by 1 neurologist and 2 neuroradiologists. RESULTS: Twenty-four carotid vessels in fourteen patients were identified to have FMD, 100% of patients were female, average age was 58.43+/-8.72yrs (range 45-73), 35.7% were black, 35.7% had HTN, 7.14% had CKD and 7.14% used tobacco in the past year. Associated findings included aneurysms and dissections. All but 1 patient had at least mild vessel tortuosity, and 28.6% were moderate or severe. All but 1 patient had at least "some" pulsation-like vessel movement, 16.7% had "significant" movement, and all movement was focally associated with the FMD abnormality. CONCLUSION: Pulsatile vascular movements were observed in high frequency and in high association with FMD. We propose a theoretical connection between the pulsation induced movement and a process of reactive vascular hyperplasia and fibrosis responsible for the FMD phenotype and is consistent with previous findings. PMID- 24810676 TI - Muscle as a molecular machine for protecting joints and bones by absorbing mechanical impacts. AB - We hypothesize that dissipation of mechanical energy of external impact to absorb mechanical shock is a fundamental function of skeletal muscle in addition to its primary function to convert chemical energy into mechanical energy. In physical systems, the common mechanism for absorbing mechanical shock is achieved with the use of both elastic and viscous elements and we hypothesize that the viscosity of the skeletal muscle is a variable parameter which can be voluntarily controlled by changing the tension of the contracting muscle. We further hypothesize that an ability of muscle to absorb shock has been an important factor in biological evolution, allowing the life to move from the ocean to land, from hydrodynamic to aerodynamic environment with dramatically different loading conditions for musculoskeletal system. The ability of muscle to redistribute the energy of mechanical shock in time and space and unload skeletal joints is of key importance in physical activities. We developed a mathematical model explaining the absorption of mechanical shock energy due to the increased viscosity of contracting skeletal muscles. The developed model, based on the classical theory of sliding filaments, demonstrates that the increased muscle viscosity is a result of the time delay (or phase shift) between the mechanical impact and the attachment/detachment of myosin heads to binding sites on the actin filaments. The increase in the contracted muscle's viscosity is time dependent. Since the forward and backward rate constants for binding the myosin heads to the actin filaments are on the order of 100s(-1), the viscosity of the contracted muscle starts to significantly increase with an impact time greater than 0.01s. The impact time is one of the key parameters in generating destructive stress in the colliding objects. In order to successfully dampen a short high power impact, muscles must first slow it down to engage the molecular mechanism of muscle viscosity. Muscle carries out two functions, acting first as a nonlinear spring to slow down impact and second as a viscous damper to absorb the impact. Exploring the ability of muscle to absorb mechanical shock may shed light to many problems of medical biomechanics and sports medicine. Currently there are no clinical devices for real-time quantitative assessment of viscoelastic properties of contracting muscles in vivo. Such assessment may be important for diagnosis and monitoring of treatment of various muscle disorders such as muscle dystrophy, motor neuron diseases, inflammatory and metabolic myopathies and many more. PMID- 24810677 TI - Personalized prediction of chronic wound healing: an exponential mixed effects model using stereophotogrammetric measurement. AB - STUDY AIM: Stereophotogrammetric digital imaging enables rapid and accurate detailed 3D wound monitoring. This rich data source was used to develop a statistically validated model to provide personalized predictive healing information for chronic wounds. MATERIALS: 147 valid wound images were obtained from a sample of 13 category III/IV pressure ulcers from 10 individuals with spinal cord injury. METHODS: Statistical comparison of several models indicated the best fit for the clinical data was a personalized mixed-effects exponential model (pMEE), with initial wound size and time as predictors and observed wound size as the response variable. Random effects capture personalized differences. RESULTS: Other models are only valid when wound size constantly decreases. This is often not achieved for clinical wounds. Our model accommodates this reality. Two criteria to determine effective healing time outcomes are proposed: r-fold wound size reduction time, t(r-fold), is defined as the time when wound size reduces to 1/r of initial size. t(delta) is defined as the time when the rate of the wound healing/size change reduces to a predetermined threshold delta < 0. Healing rate differs from patient to patient. Model development and validation indicates that accurate monitoring of wound geometry can adaptively predict healing progression and that larger wounds heal more rapidly. Accuracy of the prediction curve in the current model improves with each additional evaluation. CONCLUSION: Routine assessment of wounds using detailed stereophotogrammetric imaging can provide personalized predictions of wound healing time. Application of a valid model will help the clinical team to determine wound management care pathways. PMID- 24810678 TI - Determination of ketamine, norketamine and dehydronorketamine in urine by hollow fiber liquid-phase microextraction using an essential oil as supported liquid membrane. AB - Here, we present a method for the determination of ketamine (KT) and its main metabolites, norketamine (NK) and dehydronorketamine (DHNK) in urine samples by using hollow-fiber liquid-phase microextraction (HF-LPME) in the three-phase mode. The fiber pores were filled with eucalyptus essential oil and a solution of 1.0mol/L of HCl was introduced into the lumen of the fiber (acceptor phase). The fiber was submersed in the alkalinized urine containing 10% NaCl, and the system was submitted to lateral shaking (2400rpm) during 30min. Acceptor phase was withdrawn from the fiber, dried and the residue was then derivatized with trifluoroacetic anhydride (TFAA) for further determination by gas chromatography mass spectrometry (GC-MS). The calibration curves were linear over the specified range and limits of detection (LoDs) obtained for KT, NK and DHNK were below the cut-off value (1.0ng/mL) recommended by the United Nations Office on Drugs and Crime (UNODC). A totally "green chemistry" approach of the sample extraction was obtained by using essential oil as a supported liquid membrane in HF-LPME. The developed method was successfully validated and applied to urine samples collected from two clinical cases in which KT was suspected to be involved. PMID- 24810679 TI - A 3-year review of new psychoactive substances in casework. AB - Following the initial popularity of mephedrone (4-methylmethcathinone) there has been a stream of new "recreational drugs" entering the global market. The lack of clinical studies on the effects and toxicity of these drugs has made interpretation of toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and the fatalities that have been linked to these compounds we present our collated findings in post-mortem and criminal casework where these have been detected and/or implicated. Between January 2010 and December 2012 we have detected new psychoactive substances (NPS) in 203 cases, with 120 cases in 2012 alone. The drugs detected in in life or post mortem blood and urine are, in order of decreasing frequency; mephedrone, 4 methylethcathinone, BZP, MDPV, TFMPP, methoxetamine, 4-fluoromethcathinone, 4 methylamphetamine, PMA, methylone, PMMA, naphyrone, alpha-methyltryptamine, butylone, MDAI, desoxypipradrol, D2PM, MPA, synthetic cannabinoids, 2-AI, 5-IAI, 5-MeODALT, MDPBP, 5/6-APB, pentedrone and pentylone. Other drugs or alcohol were detected in 84% of the cases including other NPS and in fatalities it should be noted that alternative causes of death (including mechanical suicide, accidental death and non-psychoactive drug overdose) accounted for the majority. Related to this was that of all fatalities involving cathinones, 41% of these were hangings or other mechanical suicides, this was a higher proportion than seen with other drugs found in such cases. The presence of multiple NPS and/or other stimulants was a particular feature in various cases, however, of the drug deaths only 7% solely involved NPS. Across all case types and including some cases investigated in 2013, NPS concentrations showed a wide range but these and selected cases are presented to assist toxicological interpretation in future cases. PMID- 24810680 TI - Biosimilars 101: considerations for U.S. oncologists in clinical practice. AB - Biosimilars of biologics used for cancer treatment and supportive care are expected to enter the U.S. market soon. Biosimilars will be highly similar to their reference products, but unlike generic drugs, not identical. Differences between a biosimilar and its reference product may arise because of the complexity of biologics, and differences in the cell lines and processes used during manufacturing. Biosimilars will be approved in the United States through a regulatory pathway based on comparative analytical and clinical studies for their characterization and demonstration of no clinically meaningful differences from their reference products. Unlike generics, initial approval may not include interchangeability, as additional evidence may be required before a biosimilar could be approved as interchangeable with its reference product; interchangeable designation could allow pharmacy-level substitution without prescriber intervention. In some cases, the U.S. Food and Drug Administration (FDA) may extrapolate an indication that has not been formally investigated for the biosimilar but that is approved for the reference product. Robust safety monitoring of all biologics is important to track and accurately attribute adverse events, particularly because their inherent complexity and manufacturing differences make them susceptible to structural changes that can affect safety (e.g., immunogenicity). Accuracy of postapproval safety reports will partly depend on the biosimilar naming approach. Potential cost savings should be evaluated in the context of differences in manufacturers' patient-assistance programs, copayments, and institutional costs. A manufacturer's ability to ensure reliable supply of high-quality biosimilars should also be considered. Broad understanding of these issues is critical for oncologists preparing for their use in clinical practice. PMID- 24810681 TI - Pressure effects on the vibrational properties of alpha-Bi(2)O(3): an experimental and theoretical study. AB - We report an experimental and theoretical high-pressure study of the vibrational properties of synthetic monoclinic bismuth oxide (alpha-Bi(2)O(3): ), also known as mineral bismite. The comparison of Raman scattering measurements and theoretical lattice-dynamics ab initio calculations is key to understanding the complex vibrational properties of bismite. On one hand, calculations help in the symmetry assignment of phonons and to discover the phonon interactions taking place in this low-symmetry compound, which shows considerable phonon anticrossings; and, on the other hand, measurements help to validate the accuracy of first-principles calculations relating to this compound. We have also studied the pressure-induced amorphization (PIA) of synthetic bismite occurring around 20 GPa and showed that it is reversible below 25 GPa. Furthermore, a partial temperature-induced recrystallization (TIR) of the amorphous sample can be observed above 20 GPa upon heating to 200 degrees C, thus evidencing that PIA at room temperature occurs because of the inability of the alpha phase to undergo a phase transition to a high-pressure phase. Raman scattering measurements of the TIR sample at room temperature during pressure release have been performed. The interpretation of these results in the light of ab initio calculations of the candidate phases at high pressures has allowed us to tentatively attribute the TIR phase to the recently found high-pressure hexagonal HPC phase and to discuss its lattice dynamics. PMID- 24810683 TI - Isolated abdominal wall actinomycosis after hysterectomy. PMID- 24810684 TI - Resistance training enhances muscular performance in patients with anorexia nervosa: a randomized controlled trial. AB - OBJECTIVE: Low-intensity exercise applied in anorexia nervosa patients has been shown to have a harmless effect on body composition and to effect short-term improvements in muscular strength and agility. The aim of this study was to determine the effects of a high-intensity resistance training program designed for adolescents to improve strength and agility in anorexia nervosa restricting type patients (AN-R). METHODS: From a total of 36 female patients with AN-R, one group (intervention, n = 18) underwent a supervised high-intensity resistance training program lasting 8 weeks, and the other group with no exercise (control, n = 18). Body weight, body mass index, whole-body muscular strength, and agility were assessed before, after, and 4 weeks after training (detraining). RESULTS: Leg-press, bench-press, and lateral row tests improved significantly (p < 0.001) after 8 weeks of training compared with controls. Improvements were maintained after the detraining period. The training program also showed beneficial effects on agility. DISCUSSION: A high-intensity resistance training program adapted to the recommendations for adolescents in AN-R patients was effective and safe, improving muscular strength in the whole body and the ability to perform daily tasks. However, long-term maintenance of gains seems to be linked to the continuance of training or the use of a maintenance program. PMID- 24810685 TI - Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review. AB - Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1. PMID- 24810686 TI - Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations. AB - PURPOSE: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined. METHODS: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced. RESULTS: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR. CONCLUSION: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects. PMID- 24810687 TI - Genome-wide karyomapping accurately identifies the inheritance of single-gene defects in human preimplantation embryos in vitro. AB - PURPOSE: Our aim was to compare the accuracy of family- or disease-specific targeted haplotyping and direct mutation-detection strategies with the accuracy of genome-wide mapping of the parental origin of each chromosome, or karyomapping, by single-nucleotide polymorphism genotyping of the parents, a close relative of known disease status, and the embryo cell(s) used for preimplantation genetic diagnosis of single-gene defects in a single cell or small numbers of cells biopsied from human embryos following in vitro fertilization. METHODS: Genomic DNA and whole-genome amplification products from embryo samples, which were previously diagnosed by targeted haplotyping, were genotyped for single-nucleotide polymorphisms genome-wide detection and retrospectively analyzed blind by karyomapping. RESULTS: Single-nucleotide polymorphism genotyping and karyomapping were successful in 213/218 (97.7%) samples from 44 preimplantation genetic diagnosis cycles for 25 single-gene defects with various modes of inheritance distributed widely across the genome. Karyomapping was concordant with targeted haplotyping in 208 (97.7%) samples, and the five nonconcordant samples were all in consanguineous regions with limited or inconsistent haplotyping results. CONCLUSION: Genome-wide karyomapping is highly accurate and facilitates analysis of the inheritance of almost any single-gene defect, or any combination of loci, at the single-cell level, greatly expanding the range of conditions for which preimplantation genetic diagnosis can be offered clinically without the need for customized test development. PMID- 24810688 TI - Mucin 1 gene (MUC1) and gastric-cancer susceptibility. AB - Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia. It is classified into intestinal and diffuse types. While the intestinal type GC (IGC) is almost certainly caused by Helicobacter pylori (HP) infection, its role in the diffuse-type GC (DGC) appears limited. Recently, genome-wide association studies (GWAS) on Japanese and Chinese populations identified chromosome 1q22 as a GC susceptibility locus which harbors mucin 1 gene (MUC1) encoding a cell membrane-bound mucin protein. MUC1 has been known as an oncogene with an anti-apoptotic function in cancer cells; however, in normal gastric mucosa, it is anticipated that the mucin 1 protein has a role in protecting gastric epithelial cells from a variety of external insults which cause inflammation and carcinogenesis. HP infection is the most definite insult leading to GC, and a protective function of mucin 1 protein has been suggested by studies on Muc1 knocked-out mice. PMID- 24810689 TI - Human papillomavirus 16 E6 contributes HIF-1alpha induced Warburg effect by attenuating the VHL-HIF-1alpha interaction. AB - Cervical cancer is still one of the leading causes of cancer deaths in women worldwide, especially in the developing countries. It is a major metabolic character of cancer cells to consume large quantities of glucose and derive more energy by glycolysis even in the presence of adequate oxygen, which is called Warburg effect that can be exaggerated by hypoxia. The high risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. Hypoxia-inducible factor 1alpha (HIF-1alpha), a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth, is highly increased by HPV E6. HIF-1alpha is a best-known target of the von Hippel Lindau tumor suppressor (VHL) as an E3 ligase for degradation. In the present work, we found that HPV16 E6 promotes hypoxia induced Warburg effect through hindering the association of HIF-1alpha and VHL. This disassociation attenuates VHL-mediated HIF-1alpha ubiquitination and causes HIF-1alpha accumulation. These results suggest that oncoprotein E6 plays a major role in the regulation of Warburg effect and can be a valuable therapeutic target for HPV-related cancer. PMID- 24810690 TI - Endothelial nitric oxide synthase (eNOS) 4b/a gene polymorphisms and coronary artery disease: evidence from a meta-analysis. AB - A variety of studies have suggested that the 4b/a polymorphism in the endothelial nitric oxide synthase (eNOS) was associated with coronary artery disease (CAD) risk. However, the data remain conflicting. The aim of the present meta-analysis was to estimate the overall association between risk of CAD and eNOS 4b/a polymorphism. Case-control, cohort or cross-sectional studies evaluating the association between eNOS 4b/a polymorphism and CAD susceptibility were systematically identified in PubMed up to 31 October 2013. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the association in overall and subgroup analyses. A total of 10,617 cases and 8302 controls from 37 studies were included in the study. The results of overall analysis revealed significant positive associations between CAD risk and eNOS 4b/a polymorphism in homozygote comparisons (OR = 1.47, 95% CI = 1.16-1.87), heterozygote comparisons (OR = 1.14, 95% CI = 1.02-1.27) and dominant models (OR = 1.18, 95% CI = 1.06-1.33). In subgroup analyses, similar associations were identified in African individuals, as determined using population-based source subgroups and noted in small-and-moderate sample size subgroups (case sample size or control sample size <500). The current meta-analysis revealed that eNOS 4b/a polymorphisms could be a risk factor for developing CAD, particularly in African populations and population-based subgroups. PMID- 24810691 TI - Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease. AB - BACKGROUND: Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks). METHODS: Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation. RESULTS: Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation. CONCLUSION: Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation. PMID- 24810692 TI - Docosahexaenoic acid supplementation during pregnancy: a potential tool to prevent membrane rupture and preterm labor. AB - Polyunsaturated fatty acids (PUFAs) are required to maintain the fluidity, permeability and integrity of cell membranes. Maternal dietary supplementation with omega-3 PUFAs during pregnancy has beneficial effects, including increased gestational length and reduced risk of pregnancy complications. Significant amounts of omega-3 docosahexaenoic acid (DHA) are transferred from maternal to fetal blood, hence ensuring high levels of DHA in the placenta and fetal bloodstream and tissues. Fetal DHA demand increases exponentially with gestational age, especially in the third trimester, due to fetal development. According to the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), a daily intake of DHA is recommended during pregnancy. Omega-3 PUFAs are involved in several anti-inflammatory, pro resolving and anti-oxidative pathways. Several placental disorders, such as intrauterine growth restriction, premature rupture of membranes (PROM) and preterm-PROM (pPROM), are associated with placental inflammation and oxidative stress. This pilot study reports on a preliminary evaluation of the significance of the daily DHA administration on PROM and pPROM events in healthy pregnant women. Further extensive clinical trials will be necessary to fully elucidate the correlation between DHA administration during pregnancy and PROM/pPROM occurrence, which is related in turn to gestational duration and overall fetal health. PMID- 24810695 TI - A complicated case of sarcoidosis. Neurosyphilis. PMID- 24810696 TI - Neuroendocrine tumor of the eyelid: a clinicopathological case report. PMID- 24810697 TI - Blue toe syndrome: a complication of intra-arterial technique, not intra-arterial chemotherapy for retinoblastoma. PMID- 24810698 TI - Blue toe syndrome--reply. PMID- 24810699 TI - Detection of dynamic frequencies of Th17 cells and their associations with clinical parameters in patients with systemic lupus erythematosus receiving standard therapy. AB - Recent evidence implicated an important role of Th17 cells in the pathogenesis of systemic lupus erythematosus (SLE). However, the association between dynamic changes of Th17 cell frequency and clinical parameters in SLE patients receiving clinical managements remains unknown. Here, we sought to evaluate their correlation in Chinese new-onset SLE patients with standard therapy. We found that the frequency of Th17 cells was higher in SLE patients than that in healthy controls and could be decreased by standard care. In consistent, the level of serum IL-6, IL-1beta, IL-23, and Stat3 activity was elevated in SLE patients and down-regulated by disease treatment. Of note, the frequency of Th17 cells was correlated with SLEDAI and serum C3 in SLE patients. The changes of Th17 cell frequency were associated with those of SLEDAI and serum C3 in SLE patients between pretreatment and posttreatment. Further, the Th17 cell frequency was positively correlated with serum anti-dsDNA antibody in SLE patients. The changes of Th17 cell frequency were associated with those of serum anti-dsDNA antibody in SLE patients. Our findings showed that dynamic frequencies of Th17 cells were closely correlated with clinical parameters in SLE patients receiving standard treatment, which could facilitate the efficient management and development of novel therapeutics for SLE. PMID- 24810701 TI - Introduction to the eleventh Spondyloarthritis Research and Therapy Network (SPARTAN) annual research and education meeting. PMID- 24810700 TI - Rheumatoid myositis leading to acute lower extremity compartment syndrome: a case based review. AB - Muscle pain and weakness in a rheumatoid arthritis (RA) patient has a broad differential, and myositis should be considered early in the disease course as serious limb and life-threatening sequelae may occur. A 55-year-old woman with a past medical history of methotrexate-controlled RA presented with right leg pain for 4 days. The patient suffered sensory loss in the right foot and decreased strength in the toes. Lab tests revealed elevated creatine kinase, ESR, and anti rheumatoid factor antibody titers. CT scan revealed myositis of posterior compartment muscles. Progressive edema, pain, and neuromuscular deficits persisted despite steroid and antibiotic therapy, so the patient was taken for urgent fasciotomy for acute compartment syndrome. The muscle biopsy showed diffuse mononuclear cell infiltration as well as perivascular and perineural involvement consistent with rheumatoid myositis (RM). The patient did well post op on a prednisone taper. This case underlines the systemic nature of RA and exemplifies the severity of inflammation that may lead to grave consequences such as compartment syndrome. The histopathology is diagnostic when there is evidence of mononuclear cell infiltration; however, this is not entirely specific. Early, aggressive therapy with immunosuppressives is warranted in such patients. RM has not, to our knowledge, been recorded to cause acute compartment syndrome. Clinicians should be aware of this uncommon manifestation of RA keeping the various presentations of rheumatoid disease in mind when faced with these patients. PMID- 24810702 TI - Update on the American College of Rheumatology/Spondyloarthritis Research and Treatment Network/Spondylitis Association of America axial spondyloarhtritis treatment guidelines project. AB - The American College of Rheumatology, the Spondyloarthritis Research and Treatment Network, and the Spondylitis Association of America have begun collaborating on a project to develop treatment guidelines for axial spondyloarthritis. The project will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method, which is based on systematic literature reviews and quantitative evidence summaries, to develop treatment recommendations for the use of pharmacological interventions, rehabilitation, surgery, preventive care, and disease monitoring in patients with ankylosing spondylitis and axial spondyloarthritis. PMID- 24810703 TI - Does the microbiome play a causal role in spondyloarthritis? AB - The purpose of this study is to review the potential causal role of the microbiome in the pathogenesis of spondyloarthritis. The method used for the study is literature review. The microbiome plays a major role in educating the immune response. The microbiome is strongly implicated in inflammatory bowel disease which has clinical and genetic overlap with spondyloarthritis. The microbiome also plays a causal role in bowel and joint disease in HLA B27/human beta 2 microglobulin transgenic rats. The mechanism(s) by which HLA B27 could influence the microbiome is unknown but theories include an immune response gene selectivity, an effect on dendritic cell function, or a mucosal immunodeficiency. Bacteria are strongly implicated in the pathogenesis of spondyloarthritis. Studies to understand how HLA B27 affects bacterial ecosystems should be encouraged. PMID- 24810704 TI - Development of a new lingual range-of-motion assessment scale: normative data in surgically treated oral cancer patients. AB - Surgical resection in oral cancer patients can result in altered speech, swallowing, and patient perception of quality of life (QOL). Oral surgery can result in reduced lingual range of motion (ROM). However, few studies have quantified the degree of lingual restriction after surgery. This pilot study describes a new measurement system to define tongue ROM in surgically treated tongue cancer patients. This measurement system was validated by comparing results in these treated surgical patients versus healthy individuals. This scale was further validated by correlating ROM with performance status, oral outcomes, and patient-rated QOL. Thirty-six patients who underwent oral tongue surgery and 31 healthy individuals were included. Tongue ROM was assessed using a novel ROM assessment system. This novel system was examined in these patients versus healthy subjects. This measurement tool was further validated by correlating tongue ROM in treated patients with performance status, oral outcomes, and patient-rated QOL. Tongue ROM was found to be significantly lower in the surgically treated patients than in the healthy individuals (p = 0.0001). Tongue ROM correlated with performance status, oral outcomes, and all QOL measures. This new tongue ROM measurement system defined tongue deficits in surgically treated oral cancer patients. This tool was validated by comparing results to those in healthy individuals, as well as by correlating tongue ROM to performance status, oral outcomes, and QOL. This measurement tool can be used to define baseline and postsurgery tongue ROM in oral cancer patients, as well as track change over time with recovery and therapy. Future studies should examine use of this measurement tool with other populations demonstrating tongue deficits. PMID- 24810705 TI - How the folding rates of two- and multistate proteins depend on the amino acid properties. AB - Proteins fold by either two-state or multistate kinetic mechanism. We observe that amino acids play different roles in different mechanism. Many residues that are easy to form regular secondary structures (alpha helices, beta sheets and turns) can promote the two-state folding reactions of small proteins. Most of hydrophilic residues can speed up the multistate folding reactions of large proteins. Folding rates of large proteins are equally responsive to the flexibility of partial amino acids. Other properties of amino acids (including volume, polarity, accessible surface, exposure degree, isoelectric point, and phase transfer energy) have contributed little to folding kinetics of the proteins. Cysteine is a special residue, it triggers two-state folding reaction and but inhibits multistate folding reaction. These findings not only provide a new insight into protein structure prediction, but also could be used to direct the point mutations that can change folding rate. PMID- 24810706 TI - Microbial engineering of floc Fe and trace element geochemistry in a circumneutral, remote lake. AB - Evaluation of lacustrine floc Fe, Pb, and Cd biogeochemistry over seasonal (summer, winter) and water column depth (metalimnetic, hypolimnetic) scales reveals depth-independent seasonally significant differences in floc Fe biominerals and trace element (TE: Pb, Cd) sequestration, driven by floc microbial community shifts. Winter floc [TE] were significantly lower than summer [TE], driven by declining abundance and reactivity of floc amorphous Fe((III)) (oxy)hydroxide (FeOOH) phases under ice ([FeOOH](summer) = 37-77 mgg(-1) vs [FeOOH](winter) = 0.3-7 mgg(-1)). Further, while high summer floc [FeOOH] was observed at both water column depths, winter floc was dominated by Fe((II)) phases. However, the observed seasonal change in the nature and concentrations of floc Fe-phases was independent of water column [Fe], O2, and pH and, instead, significantly correlated to floc bacterial community membership. Bioinformatic modeling (Unifrac, PCA analyses) of in situ and experimental microcosm results identified a temperature-driven seasonal turnover of floc microbial communities, shifting from dominantly putative Fe metabolisms within summer floc to wintertime ancillary Fe reducing and S metabolizing bacteria. This seasonal shift of floc microbial community functioning, significantly the wintertime loss of microbial Fe((II))-oxidizing capability and concomitant increases of sulfur-reducing bacteria, alters dominant floc Fe minerals from Fe((III)) to Fe((II)) phases. This resulted in decreased winter floc [TE], not predicted by water column geochemistry. PMID- 24810708 TI - In situ study of CO2 and H2O partitioning between Na-montmorillonite and variably wet supercritical carbon dioxide. AB - Shale formations play fundamental roles in large-scale geologic carbon sequestration (GCS) aimed primarily to mitigate climate change and in smaller scale GCS targeted mainly for CO2-enhanced gas recovery operations. Reactive components of shales include expandable clays, such as montmorillonites and mixed layer illite/smectite clays. In this study, in situ X-ray diffraction (XRD) and in situ infrared (IR) spectroscopy were used to investigate the swelling/shrinkage and H2O/CO2 sorption of Na(+)-exchanged montmorillonite, Na SWy-2, as the clay is exposed to variably hydrated supercritical CO2 (scCO2) at 50 degrees C and 90 bar. Measured d001 values increased in stepwise fashion and sorbed H2O concentrations increased continuously with increasing percent H2O saturation in scCO2, closely following previously reported values measured in air at ambient pressure over a range of relative humidities. IR spectra show H2O and CO2 intercalation, and variations in peak shapes and positions suggest multiple sorbed types of H2O and CO2 with distinct chemical environments. Based on the absorbance of the asymmetric CO stretching band of the CO2 associated with the Na SWy-2, the sorbed CO2 concentration increases dramatically at sorbed H2O concentrations from 0 to 4 mmol/g. Sorbed CO2 then sharply decreases as sorbed H2O increases from 4 to 10 mmol/g. With even higher sorbed H2O concentrations as saturation of H2O in scCO2 was approached, the concentration of sorbed CO2 decreased asymptotically. Two models, one involving space filling and the other a heterogeneous distribution of integral hydration states, are discussed as possible mechanisms for H2O and CO2 intercalations in montmorillonite. The swelling/shrinkage of montmorillonite could affect solid volume, porosity, and permeability of shales. Consequently, the results may aid predictions of shale caprock integrity in large-scale GCS as well as methane transmissivity in enhanced gas recovery operations. PMID- 24810707 TI - SuSPect: enhanced prediction of single amino acid variant (SAV) phenotype using network features. AB - Whole-genome and exome sequencing studies reveal many genetic variants between individuals, some of which are linked to disease. Many of these variants lead to single amino acid variants (SAVs), and accurate prediction of their phenotypic impact is important. Incorporating sequence conservation and network-level features, we have developed a method, SuSPect (Disease-Susceptibility-based SAV Phenotype Prediction), for predicting how likely SAVs are to be associated with disease. SuSPect performs significantly better than other available batch methods on the VariBench benchmarking dataset, with a balanced accuracy of 82%. SuSPect is available at www.sbg.bio.ic.ac.uk/suspect. The Web site has been implemented in Perl and SQLite and is compatible with modern browsers. An SQLite database of possible missense variants in the human proteome is available to download at www.sbg.bio.ic.ac.uk/suspect/download.html. PMID- 24810709 TI - Genetic comparisons yield insight into the evolution of enamel thickness during human evolution. AB - Enamel thickness varies substantially among extant hominoids and is a key trait with significance for interpreting dietary adaptation, life history trajectory, and phylogenetic relationships. There is a strong link in humans between enamel formation and mutations in the exons of the four genes that code for the enamel matrix proteins and the associated protease. The evolution of thick enamel in humans may have included changes in the regulation of these genes during tooth development. The cis-regulatory region in the 5' flank (upstream non-coding region) of MMP20, which codes for enamelysin, the predominant protease active during enamel secretion, has previously been shown to be under strong positive selection in the lineages leading to both humans and chimpanzees. Here we examine evidence for positive selection in the 5' flank and 3' flank of AMELX, AMBN, ENAM, and MMP20. We contrast the human sequence changes with other hominoids (chimpanzees, gorillas, orangutans, gibbons) and rhesus macaques (outgroup), a sample comprising a range of enamel thickness. We find no evidence for positive selection in the protein-coding regions of any of these genes. In contrast, we find strong evidence for positive selection in the 5' flank region of MMP20 and ENAM along the lineage leading to humans, and in both the 5' flank and 3' flank regions of MMP20 along the lineage leading to chimpanzees. We also identify putative transcription factor binding sites overlapping some of the species specific nucleotide sites and we refine which sections of the up- and downstream putative regulatory regions are most likely to harbor important changes. These non-coding changes and their potential for differential regulation by transcription factors known to regulate tooth development may offer insight into the mechanisms that allow for rapid evolutionary changes in enamel thickness across closely-related species, and contribute to our understanding of the enamel phenotype in hominoids. PMID- 24810710 TI - Twenty-eight years after the complete ban on the physical punishment of children in Finland: trends and psychosocial concomitants. AB - In 1983 Finland became the second country in the world, after Sweden, to adopt a law prohibiting all kinds of physical punishment towards children, also by parents. The present investigation was carried out in 2011, 28 years after the law was adopted. Changes in exposure to various types of physical punishment towards respondents born between 1931 and 1996 are presented. A representative sample from Western Finland, consisting of 4,609 respondents (2,632 females, 1,977 males) between 15 and 80 years, filled in a paper-and-pencil questionnaire. A number of psychosocial concomitants were measured. The results showed a significant drop in reports of being slapped and beaten with an object among respondents who were born after the law was adopted. The decline in physical punishment was associated with a similar decline in the number of murdered children. Respondents who had been exposed to higher amounts of physical punishment than average scored significantly higher on alcohol abuse, depression, mental health problems, and schizotypal personality. Divorced respondents had been significantly more physically punished than others. Respondents who had attempted suicide during the last 12 months had been exposed to physical punishment during childhood significantly more often than those who had not attempted suicide. PMID- 24810711 TI - Multiparous mothers: Breastfeeding support provided by nurses. AB - The study aimed to identify the informational, practical and emotional support that multiparous mothers had received from nurses in the early postpartum period.This is a descriptive and cross-sectional study on 278 multiparous mothers who took part in the research prior to their discharge from a maternity hospital in Ankara, Turkey. The instrument used was a 38-item questionnaire. Experiencing breastfeeding problems was the only statistically significant predictor of in hospital supplementation (P < 0.01, OR 0.028, 95% CI 0.005-0.159). There were no statistically significant association between some predictor variables with regard to breastfeeding support and breastfeeding outcomes including in-hospital formula supplementation and breastfeeding problems. No significant associations are indicative for the need of more effective implementation of informational, practical and emotional breastfeeding support for multiparous mothers in easing their adjustment to breastfeeding. Nurses can encourage multiparous mothers to maintain breastfeeding through individual teaching, giving mothers a sense of security, providing understanding care and telling about what to do with regard to breastfeeding problems. Antenatal education and support could be more likely to make a difference. PMID- 24810712 TI - Non-hepatic gastrointestinal surgery in patients with cirrhosis. AB - Gastrointestinal surgery is feasible in patients with Child A cirrhosis, but is associated with higher morbidity and mortality. Hernia repair, biliary and colonic surgery are the most frequently performed interventions in this context. Esophageal and pancreatic surgery are more controversial and less frequently performed. For patients with decompensated liver function (Child B or C patients), the indications for surgery should be discussed by a multi-specialty team including the hepatologist, anesthesiologist, surgeon; liver function should be optimized if possible. During emergency surgery, histologic diagnosis of cirrhosis should be confirmed by liver biopsy because the histologic diagnosis has therapeutic and prognostic implications. The management of patients with Child A cirrhosis without portal hypertension is little different from the management of patients without cirrhosis. However, the management of patients with Child B or C cirrhosis or with portal hypertension is more complex and requires an accurate assessment of the balance of benefit vs. risk for surgical intervention on a case-by-case basis. PMID- 24810713 TI - Risk management to decrease bile duct injury associated with cholecystectomy: measures to improve patient safety. PMID- 24810715 TI - Chemical strategies for development of ATR inhibitors. AB - ATR protein kinase is one of the key players in maintaining genome integrity and coordinating of the DNA damage response and repair signalling pathways. Inhibition of ATR prevents signalling from stalled replication forks and enhances the formation of DNA damage, particularly under conditions of replication stress present in cancers. For this reason ATR/CHK1 checkpoint inhibitors can potentiate the effect of DNA cross-linking agents, as evidenced by ATR inhibitors recently entering human clinical trials. This review aims to compile the existing literature on small molecule inhibitors of ATR, both from academia and the pharmaceutical industry, and will provide the reader with a comprehensive summary of this promising oncology target. PMID- 24810714 TI - SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I. AB - SERPINB3 (SB3) is a serine protease inhibitor overexpressed in several malignancies of epithelial origin, including primary liver cancer, where it inhibits apoptosis through poorly defined mechanisms. In the present study we analyze the effect of SB3 on hepatoma cell death elicited by a panel of chemotherapeutic agents. We report that SB3 shields cells from the toxicity of drugs with a pro-oxidant action such as doxorubicin, cisplatin and EM20-25. The rapid rise in ROS levels prompted by these compounds causes opening of the mitochondrial permeability transition pore (PTP), irreversibly committing cells to death. We find that a fraction of SB3 locates in mitochondrial inner compartments, and that this mitochondrial fraction increases under conditions of oxidative stress. Mitochondrial SB3 inhibits ROS generation and the ensuing PTP induction and cell death through an inhibitory interaction with respiratory Complex I. These findings identify a novel mechanism of action of SB3 that contributes to tumor cell resistance to anti-neoplastic drugs. PMID- 24810716 TI - Report on carcinogens monograph on 1-bromopropane. AB - The National Toxicology Program conducted a cancer evaluation on 1 bromopropane for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for 1 bromopropane in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to 1-bromopropane. This monograph provides an assessment of the available scientific information on 1 bromopropane, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that 1 bromopropane be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found inhalation exposure to 1-bromopropane caused skin tumors in male rats, large intestine tumors in female and male rats, and lung tumors in female mice. Also noted was that 1 bromopropane, either directly or via reactive metabolites, caused molecular alterations that typically are associated with carcinogenesis, including genotoxicity, oxidative stress, and glutathione depletion. These alterations, observed in mainly in vitro and toxicity studies in rodents, are relevant to possible mechanisms of human carcinogenicity and support the relevance of the cancer studies in experimental animals to humans. PMID- 24810718 TI - Individual reference values for 2D echocardiographic measurements. The Stockholm Umea Study. AB - OBJECTIVES: Improved reference values for 2D echocardiographic measurements are required, even when more recent echocardiographic technology is employed. In addition, it may be preferable to individualize reference values from age, gender and body characteristics of any subject. DESIGN: A material of 180 healthy subjects was collected and investigated, aiming for an even distribution of sex and age (from 20 to 80 years of age; the Stockholm material). For atrial areas, material from another 216 healthy subjects with similar sex and age distribution was added (the Umea material). The 2D measures determined were the left and right ventricular diameters in diastole, the left ventricular diameter in systole, the thickness of septum and posterior wall, the diameters of the aortic root (sinotubular junction) and the left atrium (all in parasternal view), together with the left and right ventricular diameters in diastole and left and right atrial areas in end-systole (apical four-chamber view). The width of the inferior vena cava (from subcostal view) was also determined. RESULTS: Confidence intervals for females and males are presented for each of these measures. Multiple linear regression analyses with age, sex and measures of body characteristics as predictors were also performed, and for eight of the 12 measurements, such equations are presented. CONCLUSIONS: It is possible to obtain more highly individualized reference values for these cardiac dimensions, which may clinically be a better way of distinguishing pathological states from normal states. PMID- 24810717 TI - Caspase-3 and caspase-6 cleave STAT1 in leukemic cells. AB - Signal Transducer and Activator of Transcription-1 (STAT1) is phosphorylated upon interferon (IFN) stimulation, which can restrict cell proliferation and survival. Nevertheless, in some cancers STAT1 can act in an anti-apoptotic manner. Moreover, certain malignancies are characterized by the overexpression and constitutive activation of STAT1. Here, we demonstrate that the treatment of transformed hematopoietic cells with epigenetic drugs belonging to the class of histone deacetylase inhibitors (HDACi) leads to the cleavage of STAT1 at multiple sites by caspase-3 and caspase-6. This process does not occur in solid tumor cells, normal hematopoietic cells, and leukemic cells that underwent granulocytic or monocytic differentiation. STAT1 cleavage was studied under cell free conditions with purified STAT1 and a set of candidate caspases as well as with mass spectrometry. These assays indicate that unmodified STAT1 is cleaved at multiple sites by caspase-3 and caspase-6. Our study shows that STAT1 is targeted by caspases in malignant undifferentiated hematopoietic cells. This observation may provide an explanation for the selective toxicity of HDACi against rapidly proliferating leukemic cells. PMID- 24810719 TI - Structural basis of chitin oligosaccharide deacetylation. AB - Cell signaling and other biological activities of chitooligosaccharides (COSs) seem to be dependent not only on the degree of polymerization, but markedly on the specific de-N-acetylation pattern. Chitin de-N-acetylases (CDAs) catalyze the hydrolysis of the acetamido group in GlcNAc residues of chitin, chitosan, and COS. A major challenge is to understand how CDAs specifically define the distribution of GlcNAc and GlcNH2 moieties in the oligomeric chain. We report the crystal structure of the Vibrio cholerae CDA in four relevant states of its catalytic cycle. The two enzyme complexes with chitobiose and chitotriose represent the first 3D structures of a CDA with its natural substrates in a productive mode for catalysis, thereby unraveling an induced-fit mechanism with a significant conformational change of a loop closing the active site. We propose that the deacetylation pattern exhibited by different CDAs is governed by critical loops that shape and differentially block accessible subsites in the binding cleft of CE4 enzymes. PMID- 24810720 TI - Transcriptional repressor domain of MBD1 is intrinsically disordered and interacts with its binding partners in a selective manner. AB - Methylation of DNA CpG sites is a major mechanism of epigenetic gene silencing and plays important roles in cell division, development and carcinogenesis. One of its regulators is the 64-residue C-terminal Transcriptional Repressor Domain (the TRD) of MBD1, which recruits several repressor proteins such as MCAF1, HDAC3 and MPG that are essential for the gene silencing. Using NMR spectroscopy, we have characterized the solution structure of the C-terminus of MBD1 (MBD1-c, residues D507 to Q605), which included the TRD (A529 to P592). Surprisingly, the MBD1-c is intrinsically disordered. Despite its lack of a tertiary folding, MBD1 c could still bind to different partner proteins in a selective manner. MPG and MCAF1Delta8 showed binding to both the N-terminal and C-terminal residues of MBD1 c but HDAC3 preferably bound to the C-terminal region. This study reveals how MBD1-c discriminates different binding partners, and thus, expands our understanding of the mechanisms of gene regulation by MBD1. PMID- 24810721 TI - Maternal prepregnancy body mass index and risk of spontaneous preterm birth. AB - BACKGROUND: Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent. METHODS: Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989,687 singleton births in California, 2007-09. Preterm birth was grouped as 20-23, 24 27, 28-31, or 32-36 weeks gestation (compared with 37-41 weeks). BMI was categorised as <18.5 (underweight); 18.5-24.9 (normal); 25.0-29.9 (overweight); 30.0-34.9 (obese I); 35.0-39.9 (obese II); and >= 40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women. RESULTS: Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I-III to be associated with increased risk of spontaneous preterm birth at 20-23 and 24-27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20-23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity >= 2 and preterm birth at 20-23 weeks. Underweight was associated with modest risks for preterm birth at >= 24 weeks among women in each racial/ethnic group regardless of parity. CONCLUSIONS: The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity. PMID- 24810722 TI - Severe pulmonary exacerbation in cystic fibrosis caused by cat allergy. AB - This paper describes a preschool child who had persistent symptoms suggestive of significant cystic fibrosis lung disease over a period of eighteen months following first isolation of Pseudomonas aeruginosa. Despite vigorous anti infective treatment and extensive investigations seeking undetected infection, improvement only occurred once severe cat allergy was diagnosed and cats were removed from the household. Whilst infection is the most common cause of respiratory exacerbations in cystic fibrosis, this article serves as a reminder that it is important to consider non-infective pathologies when the response to anti-infective treatment is unexpectedly poor. PMID- 24810723 TI - Ethics and regulatory complexities for pragmatic clinical trials. PMID- 24810724 TI - Analysing the diffusion and adoption of mobile IT across social worlds. AB - The diffusion and adoption of information technology innovations (e.g. mobile information technology) in healthcare organizations involves a dynamic process of change with multiple stakeholders with competing interests, varying commitments, and conflicting values. Nevertheless, the extant literature on mobile information technology diffusion and adoption has predominantly focused on organizations and individuals as the unit of analysis, with little emphasis on the environment in which healthcare organizations are embedded. We propose the social worlds approach as a promising theoretical lens for dealing with this limitation together with reports from a case study of a mobile information technology innovation in elderly home care in Denmark including both the sociopolitical and organizational levels in the analysis. Using the notions of social worlds, trajectories, and boundary objects enables us to show how mobile information technology innovation in Danish home care can facilitate negotiation and collaboration across different social worlds in one setting while becoming a source of tension and conflicts in others. The trajectory of mobile information technology adoption was shaped by influential stakeholders in the Danish home care sector. Boundary objects across multiple social worlds legitimized the adoption, but the use arrangement afforded by the new technology interfered with important aspects of home care practices, creating resistance among the healthcare personnel. PMID- 24810725 TI - Health-oriented electronic oral health record: development and evaluation. AB - This study aims to develop and evaluate a new Health-oriented Electronic Oral Health Record that implements the health-oriented status and intervention index. The index takes the principles of holistic oral healthcare and applies them to the design and implementation of the Health-oriented Electronic Oral Health Record. We designed an experiment using focus groups and a consensus (Delphi process) method to develop a new health-oriented status and intervention index and graphical user interface. A comparative intervention study with qualitative and quantitative methods was used to compare an existing Electronic Oral Health Record to the Health-oriented Electronic Oral Health Record, focusing on dentist satisfaction, accuracy, and completeness of oral health status recording. The study was conducted by the dental staff of the Inter-country Center for Oral Health collaborative hospitals in Thailand. Overall, the user satisfaction questionnaire had a positive response to the Health-oriented Electronic Oral Health Record. The dentists found it easy to use and were generally satisfied with the impact on their work, oral health services, and surveillance. The dentists were significantly satisfied with the Health-oriented Electronic Oral Health Record compared to the existing Electronic Oral Health Record (p < 0.001). The accuracy and completeness values of the oral health information recorded using the Health-oriented Electronic Oral Health Record were 97.15 and 93.74 percent, respectively. This research concludes that the Health-oriented Electronic Oral Health Record satisfied many dentists, provided benefits to holistic oral healthcare, and facilitated the planning, managing, and evaluation of the healthcare delivery system. PMID- 24810726 TI - Cyborg practices: call-handlers and computerised decision support systems in urgent and emergency care. AB - This article draws on data collected during a 2-year project examining the deployment of a computerised decision support system. This computerised decision support system was designed to be used by non-clinical staff for dealing with calls to emergency (999) and urgent care (out-of-hours) services. One of the promises of computerised decisions support technologies is that they can 'hold' vast amounts of sophisticated clinical knowledge and combine it with decision algorithms to enable standardised decision-making by non-clinical (clerical) staff. This article draws on our ethnographic study of this computerised decision support system in use, and we use our analysis to question the 'automated' vision of decision-making in healthcare call-handling. We show that embodied and experiential (human) expertise remains central and highly salient in this work, and we propose that the deployment of the computerised decision support system creates something new, that this conjunction of computer and human creates a cyborg practice. PMID- 24810728 TI - Novel water-based antiseptic lotion demonstrates rapid, broad-spectrum kill compared with alcohol antiseptic. AB - A novel alcohol-based antiseptic and a novel water-based antiseptic lotion, both with a synergistic combination of antimicrobial ingredients containing 0.2% benzethonium chloride, were evaluated using the standard time-kill method against 25 FDA-specified challenge microorganisms. The purpose of the testing was to determine whether a non-alcohol product could have equivalent rapid and broad spectrum kill to a traditional alcohol sanitizer. Both the alcohol- and water based products showed rapid and broad-spectrum antimicrobial activity. The average 15-s kill was 99.999% of the challenge organism for the alcohol-based antiseptic and 99.971% for the water-based antiseptic. The alcohol-based product demonstrated 100% of peak efficacy (60s) within the first 15s, whereas the water based product showed 99.97%. The novel alcohol-based antiseptic reduced concentrations of 100% of organisms by 99.999%, whereas the water-based antiseptic lotion showed the same reduction for 96% of organisms. A novel water based antiseptic product demonstrated equivalent rapid, broad-spectrum antimicrobial activity to an alcohol-based sanitizer and provided additional benefits of reduced irritation, persistent effect, and greater efficacy against common viruses. The combination of rapid, broad-spectrum immediate kill and persistent efficacy against pathogens may have significant clinical benefit in limiting the spread of disease. PMID- 24810727 TI - Endovascular treatment for superior cerebellar artery aneurysms: morphological features, technique, and outcome. AB - INTRODUCTION: Superior cerebellar artery (SCA) aneurysms have distinctive morphologic configurations and vascular origins. Herein, we have analyzed the angioarchitectural characteristics of SCA aneurysms and outcomes achieved through endovascular treatment. METHODS: Data accruing prospectively from January, 2002 to September, 2013 yielded 53 SCA aneurysms in 53 patients. Each lesion was classified as either basilar artery (BA), BA-SCA, or SCA type, according to the nature of incorporated vasculature. Clinical and morphologic outcomes were assessed, with emphasis on technical aspects of treatment. RESULTS: Angles formed by SCA and posterior cerebral artery were obtuse (124.8 +/- 29.1 degrees ) on sides ipsilateral to aneurysms, differing significantly from contralateral counterparts (44.8 +/- 22.0 degrees ) (p<0.001). The most common type of aneurysm was BA-SCA (54.7 %), followed by SCA (28.3 %) and BA (17.0 %), and BA type aneurysms were the largest in size. Steam-shaped S-configured microcatheters (n=19, 67.9 %) facilitated aneurysm selection for approach via contralateral vertebral artery (n=28), whereas pre-shaped 45/90/J microcatheters (n=21, 84.0 %) primarily were used for ipsilateral vertebral artery approach (n=25). Single microcatheter technique (52.8 %) was most often applied, followed by double microcatheter (34.0 %), stent-assisted (9.4 %), and microcatheter-protection techniques (3.8 %). Aneurysmal occlusion was satisfactorily achieved in 45 lesions (82.1 %), with no procedure-related morbidity and mortality. In follow-up monitoring of 46 patients for a mean period of 25.8 +/- 24.4 months, only a single instance of major recanalization (2.2 %) occurred. CONCLUSION: Coil embolization of SCA aneurysms is a safe and effective treatment modality, enabling individualized procedural strategies to accommodate distinctive angio anatomic configurations. PMID- 24810729 TI - Group B streptococcal infective endocarditis. AB - Streptococcus agalactiae (S. agalactiae), also referred as group B streptococcus (GBS), is an important pathogen in neonates and a rare cause of invasive infection in adults. It is well known that GBS endocarditis is a virulent infection that can cause serious complications. The overall mortality rate remains high despite surgical treatment. We describe a case of native mitral valve endocarditis caused by GBS in an 86-year-old woman treated medically. PMID- 24810730 TI - Women are more than twice as likely to die from burns as men in Australia and New Zealand: an unexpected finding of the Burns Evaluation And Mortality (BEAM) Study. AB - While the risk of death after nonthermal trauma and sepsis may be higher for men, sex differences in outcome after burns are inconsistently reported. The Burns Evaluation And Mortality Study examined the outcomes of all patients admitted after thermal injury to the intensive care unit (ICU) at 8 of 9 burn referral centers in Australia and New Zealand between January 1, 2005, and December 31, 2011. There were 348 women and 1367 men treated for acute burns. Women were older, had more extensive burns, and higher severity of illness scores. Women spent longer in hospital and in ICU than men. Mortality among women was higher than in men (21% vs 8.3%, P<.001). Trends toward a survival disadvantage for women were seen across all ages, at all levels of severity of illness, at every proportion of body surface area burnt, and across all centers. After adjusting for confounding factors, women had more than double the risk of death compared with men (odds ratio, 2.35; 95% confidence interval, 1.38-4.01; P=.002). Our study conclusively shows worse outcomes for women with burns admitted to ICUs in Australia and New Zealand. Further research is required to determine why this is happening. PMID- 24810731 TI - Neurally adjusted ventilatory assist: first indications of clinical outcomes. PMID- 24810732 TI - Variation in abundance of nectarivorous birds: does a competitive despot interfere with flower tracking? AB - Adaptive resource tracking in space and time may be disrupted by the modification of resources and competitors. Major global change drivers (e.g. land-use change) have induced declines in many native species, while facilitating only a few. Given that many resources are predicted to become increasingly scarce under the joint effects of climate and land-use change, disturbance-tolerant species that are able to defend high-value resources may further limit the persistence of disturbance-sensitive species. We sought to determine which nectarivorous birds track variation in flowering and if relationships between nectarivores and flowering are affected by on-transect vegetation structure or the occurrence of a native, hyper-aggressive species, the noisy miner Manorina melanocephala, which has become more prevalent. We measured eucalypt flowering and abundances of nectarivorous birds over the course of a year; we measured vegetation structure on the same forest transects. Nectarivores tracked spatial and some temporal variation in flowering, but this relationship was disrupted by noisy miners. Where present in sufficient numbers, the noisy miner excluded small-bodied nectarivores (<63 g) from fragments, limiting the ability of this numerically dominant component of the avifauna to gain access to flowering resources. Altered patterns of interspecific competition due to vegetation fragmentation and climate induced degradation may have led to changes in the distribution of small nectarivore species that is a departure from the 'ideal free distribution' model. Interactions between noisy miners and small-bodied nectarivores appear to be best described by the 'ideal despotic distribution' model in which noisy miners exclude smaller competitors and monopolize local resources. Increases in the severity and frequency of extreme climatic events (e.g. long droughts) predicted under climate change may create a boom-bust pattern of availabilities of resources. The apparent insensitivity of noisy miners to such variation in flowering resource availability and the miners' influence on the ability of small nectarivores to access resources may lead to disproportionate declines in smaller bodied nectarivorous species. Reduced tracking of flowering by nectarivores has the potential to disrupt ecosystem services (e.g. pollination, seed dispersal) and may have long-term consequences for the persistence of fragmented vegetation, adding further pressure on forest-dependent biota. PMID- 24810733 TI - p53, DNA damage, and NAD+ homeostasis. PMID- 24810734 TI - Casuarine stereoisomers from achiral substrates: chemoenzymatic synthesis and inhibitory properties. AB - A straightforward chemoenzymatic synthesis of four uncovered casuarine stereoisomers is described. The strategy consists of L-fuculose-1-phosphate aldolase F131A-variant-catalyzed aldol addition of dihydroxyacetone phosphate to aldehyde derivatives of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and its enantiomer (LAB) and subsequent one-pot catalytic deprotection-reductive amination. DAB and LAB were obtained from dihydroxyacetone and aminoethanol using D-fructose-6-phosphate aldolase and L-rhamnulose-1-phosphate aldolase catalysts, respectively. The new ent-3-epi-casuarine is a strong inhibitor of alpha-d glucosidase from rice and of rat intestinal sucrase. PMID- 24810735 TI - Solvent-free fabrication of polyHIPE microspheres for controlled release of growth factors. AB - The growth factor bone morphogenetic protein 2 (BMP-2) is utilized in surgical procedures to improve bone regeneration; however, current treatments deliver BMP 2 at amounts greater than 100,000 fold of physiological levels, which increases treatment costs and risk of side effects. Drug-eluting microcarriers developed to improve these therapies have faced significant commercialization challenges including particle size distributions, solvent removal, low encapsulation efficiency, and bioactivity loss. In this study, a solvent-free method is presented for fabrication of uniform polyHIPE microspheres for controlled growth factor release. Emulsion templating principles and fluid dynamics were used to fabricate uniform particles with tunable particle size (200-800 MUm) and pore size (10-30 MUm). The ability to independently tune particle and pore size is expected to provide excellent control of release kinetics. Overall, this solvent free method for making porous microspheres displays strong promise for the controlled release of BMP-2 and other growth factors. PMID- 24810736 TI - Automatic detection of the carotid lumen axis in B-mode ultrasound images. AB - A new approach is introduced for the automatic detection of the lumen axis of the common carotid artery in B-mode ultrasound images. The image is smoothed using a Gaussian filter and then a dynamic programming scheme extracts the dominant paths of local minima of the intensity and the dominant paths of local maxima of the gradient magnitude with the gradient pointing downwards. Since these paths are possible estimates of the lumen axis and the far wall of a blood vessel, respectively, they are grouped together into pairs. Then, a pattern of two features is computed from each pair of paths and used as input to a linear discriminant classifier in order to select the pair of paths that correspond to the common carotid artery. The estimated lumen axis is the path of local minima of the intensity that belongs to the selected pair of paths. The proposed method is suited to real time processing, no user interaction is required and the number of parameters is minimal and easy to determine. The validation was performed using two datasets, with a total of 199 images, and has shown a success rate of 99.5% (100% if only the carotid regions for which a ground truth is available are considered). The datasets have a large diversity of images, including cases of arteries with plaque and images with heavy noise, text or other graphical markings inside the artery region. PMID- 24810737 TI - A new approach for treatment of refractory ventricular fibrillation allowed by extra corporeal life support (ECLS)? PMID- 24810738 TI - Pleural plaques and their effect on lung function in Libby vermiculite miners. AB - BACKGROUND: Multiple studies have investigated the relationship between asbestos related pleural plaques (PPs) and lung function, with disparate and inconsistent results. Most use chest radiographs to identify PPs and simple spirometry to measure lung function. High-resolution CT (HRCT) scanning improves the accuracy of PP identification. Complete pulmonary function tests (PFTs), including spirometry, lung volumes, and diffusing capacity of the lung for carbon monoxide, provide a more definitive assessment of lung function. The goal of this study was to determine, using HRCT scanning and complete PFTs, the effect of PPs on lung function in Libby vermiculite miners. METHODS: The results of HRCT scanning and complete PFTs performed between January 2000 and August 2012 were obtained from the medical records of 166 Libby vermiculite miners. Multivariate regression analyses with Tukey multivariate adjustment were used to assess statistical associations between the presence of PPs and lung function. Adjustments were made for age, BMI, smoking history, duration of employment, and years since last occupational asbestos exposure. RESULTS: Nearly 90% of miners (n = 149) had evidence of PPs on HRCT scan. No significant differences in spirometry results, lung volumes, or diffusing capacity of the lung for carbon monoxide were found between miners with PPs alone and miners with normal HRCT scans. Miners with both interstitial fibrosis and the presence of PPs had a significantly decreased total lung capacity in comparison with miners with normal HRCT scans (P = .02). Age, cumulative smoking history, and BMI were significant covariates that contributed to abnormal lung function. CONCLUSIONS: Asbestos-related PPs alone have no significant effect on lung function in Libby vermiculite miners. PMID- 24810739 TI - A rapid, non-destructive methodology to monitor activity of sulfide-induced corrosion of concrete based on H2S uptake rate. AB - Many existing methods to monitor the corrosion of concrete in sewers are either very slow or destructive measurements. To overcome these limitations, a rapid, non-invasive methodology was developed to monitor the sulfide-induced corrosion process on concrete through the measurement of the H2S uptake rates of concrete at various corrosion stages. The H2S uptake rate for a concrete coupon was determined by measuring the gaseous H2S concentrations over time in a temperature and humidity-controlled gas-tight reactor. The reliability of this method was evaluated by carrying out repeated tests on different concrete coupons previously exposed to 50 ppm of H2S, at 30 degrees C and 100% relative humidity for over 32 months. The H2S uptake measurements showed good reproducibility. It was also shown that a severely corroded coupon exhibited higher sulfide uptake rates than a less corroded coupon. This could be explained by the corrosion layer in the more corroded coupon having a higher biological sulfide oxidation activity than the less corroded coupon. Additionally, temperature changes had a stronger effect on the uptake rate of the heavily corroded coupon compared to the less corroded coupon. A corrosion rate of 8.9 +/- 0.5 mm/year, estimated from the H2S uptake results, agreed well with the corrosion rate observed in real sewers under similar conditions. The method could be applied to investigate important factors affecting sulfide-induced concrete corrosion, particularly temperature, fluctuating gaseous H2S concentrations, oxygen concentrations, surface pH and relative humidity. PMID- 24810740 TI - Mechanism of red mud combined with Fenton's reagent in sewage sludge conditioning. AB - Red mud was evaluated as an alternative skeleton builder combined with Fenton's reagent in sewage sludge conditioning. The results show that red mud combined with Fenton's reagent showed good conditioning capability with the pH of the filtrate close to neutrality, indicating that red mud acted as a neutralizer as well as a skeleton builder when jointly used with Fenton's reagent. Through response surface methodology (RSM), the optimal dosages of Fe(2+), H2O2 and red mud were proposed as 31.9, 33.7 and 275.1 mg/g DS (dry solids), respectively. The mechanism of the composite conditioner could be illuminated as follows: (1) extracellular polymeric substances (EPS), including loosely bound EPS and tightly bound EPS, were degraded into dissolved organics, e.g., proteins and polysaccharides; (2) bound water was released and converted into free water due to the degradation of EPS; and (3) morphology of the conditioned sludge exhibited a porous structure in contrast with the compact structure of raw sludge, and the addition of red mud formed new mineral phases and a rigid lattice structure in sludge, allowing the outflow of free water. Thus, sludge dewatering performance was effectively improved. The economic assessment for a wastewater treatment plant of 370,000 equivalent inhabitants confirms that using red mud conditioning, combined with Fenton's reagent, leads to a saving of approximately 411,000 USD/y or 50.8 USD/t DS comparing with using lime and ordinary Portland cement combined with Fenton's reagent, and approximately 612,000 USD/y or 75.5 USD/t DS comparing with the traditional treatment. PMID- 24810741 TI - Polyphasic identification of cyanobacterial isolates from Australia. AB - Reliable identification of cyanobacterial isolates has significant socio-economic implications as many bloom-forming species affect the aesthetics and safety of drinking water, through the production of taste and odour compounds or toxic metabolites. The limitations of morphological identification have promoted the application of molecular tools, and encouraged the adoption of combined (polyphasic) approaches that include both microscopy- and DNA-based analyses. In this context, the rapid expansion of available sequence data is expected to allow increasingly reliable identification of cyanobacteria, and ultimately resolve current discrepancies between the two approaches. In the present study morphological and molecular characterisations of cyanobacterial isolates (n = 39), collected from various freshwater sites in Australia, were compared. Sequences were obtained for the small ribosomal subunit RNA gene (16S rDNA) (n = 36), the DNA-dependent RNA polymerase gene (rpoC1) (n = 22), and the phycocyanin operon, with its intergenic spacer region (cpcBA-IGS) (n = 19). Phylogenetic analyses identified three cyanobacterial orders: the Chroococcales (n = 8), Oscillatoriales (n = 6), and Nostocales (n = 25). Interestingly, multiple novel genotypes were identified, with 22% of the strains (17/77) having <95% similarity to available sequences in GenBank. Morphological and molecular data were in agreement at the species level for only 26% of the isolates obtained (10/39), while agreement at the genus level was obtained for 31% (12/39). Confident identification of the remaining 44% of the strains (17/39) beyond the order level was not possible. The present study demonstrates that, despite the taxonomic revisions, and advances in molecular-, and bioinformatics-tools, the lack of reliable morphological features, culture-induced pleomorphism, and proportion of misidentified or poorly described sequences in GenBank, still represent significant factors, impeding the confident identification of cyanobacteria species. PMID- 24810742 TI - Static and dynamic removal of aquatic natural organic matter by carbon nanotubes. AB - Carbon nanotubes (CNTs) were investigated for their capability and mechanisms to simultaneously remove colloidal natural organic matter (NOM) and humic substances from natural surface water. Static removal testing was conducted via adsorption experiments while dynamic removal was evaluated by layering CNTs onto substrate membranes and filtering natural water through the CNT-layered membranes. Analyses of treated water samples showed that removal of humic substances occurred via adsorption under both static and dynamic conditions. Removal of colloidal NOM occurred at a moderate level of 36-66% in static conditions, independent of the specific surface area (SSA) of CNTs. Dynamic removal of colloidal NOM increased from approximately 15% with the unmodified membrane to 80-100% with the CNT modified membranes. Depth filtration played an important role in colloidal NOM removal. A comparison of the static and dynamic removal of humic substances showed that equilibrium static removal was higher than dynamic (p < 0.01), but there was also a significant linear relationship between static and dynamic removal (p < 0.05). Accounting for contact time of CNTs with NOM during filtration, it appeared that CNT mat structure was an important determinant of removal efficiencies for colloidal NOM and humic substances during CNT membrane filtration. PMID- 24810743 TI - How different is the composition of the fouling layer of wastewater reuse and seawater desalination RO membranes? AB - To study the effect of water quality and operating parameters on membrane fouling, a comparative analysis of wastewater (WW) and seawater (SW) fouled reverse osmosis (RO) membranes was conducted. Membranes were harvested from SWRO and WWRO pilot plants located in Vilaseca (East Spain), both using ultrafiltration as pretreatment. The SWRO unit was fed with Mediterranean seawater and the WWRO unit was operated using secondary effluent collected from the municipal wastewater treatment plant. Lead and terminal SWRO and WWRO modules were autopsied after five months and three months of operation, respectively. Ultrastructural, chemical, and microbiological analyses of the fouling layers were performed. Results showed that the WWRO train had mainly bio/organic fouling at the lead position element and inorganic fouling at terminal position element, whereas SWRO train had bio/organic fouling at both end position elements. In the case of WWRO membranes, Betaproteobacteria was the major colonizing species; while Ca, S, and P were the major present inorganic elements. The microbial population of SWRO membranes was mainly represented by Alpha and Gammaproteobacteria. Ca, Fe, and S were the main identified inorganic elements of the fouling layer of SWRO membranes. These results confirmed that the RO fouling layer composition is strongly impacted by the source water quality. PMID- 24810744 TI - Effect of coagulation on fouling potential and removal of algal organic matter in ultrafiltration pretreatment to seawater reverse osmosis. AB - This paper investigated the effect of coagulation on fouling potential and removal of algal organic matter (AOM) in seawater ultrafiltration (UF) systems. AOM harvested from a strain of bloom forming marine diatom, Chaetoceros affinis, was coagulated with ferric chloride under different coagulation modes and conditions. The effect of coagulation on fouling potential was determined with the Modified Fouling Index-Ultrafiltration (MFI-UF). Removal of AOM was studied for three different modes of coagulation, namely, coagulation followed by sedimentation, coagulation followed by sedimentation and filtration through 0.45 MUm, and inline coagulation followed by filtration through 150 kDa UF membranes. Liquid chromatography - organic carbon detection was used to determine the removal of AOM with particular emphasis on biopolymers. AOM (as biopolymers) had a high fouling potential as measured by MFI-UF, which strongly depended on filtration flux. Moreover, the developed cake/gel layer on the membrane was fairly compressible during filtration; manifested as higher fouling potential at higher filtration flux and non-linear development of pressure in filtration tests. Coagulation substantially reduced fouling potential and compressibility of the AOM cake/gel layer. The impact of coagulation was particularly significant at coagulant doses >1 mg Fe/L. Coagulation also substantially reduced the flux dependency of AOM fouling potential, resulting in linear development of pressure in filtration tests at constant flux. This was attributed to adsorption of biopolymers on precipitated iron hydroxide and formation of Fe-biopolymer aggregates, such that the fouling characteristics of iron hydroxide precipitates prevailed and AOM fouling characteristics diminished. At low coagulant dose, inline coagulation/UF was more effective in removing AOM than the other two coagulation modes tested. At high coagulant dose where sweep floc conditions prevailed, AOM removal was considerably higher and controlled by coagulant dose rather than coagulation mode. PMID- 24810745 TI - Resistance to beta-lactam antibiotics conferred by point mutations in penicillin binding proteins PBP3, PBP4 and PBP6 in Salmonella enterica. AB - Penicillin-binding proteins (PBPs) are enzymes responsible for the polymerization of the glycan strand and the cross-linking between glycan chains as well as the target proteins for beta-lactam antibiotics. Mutational alterations in PBPs can confer resistance either by reducing binding of the antibiotic to the active site or by evolving a beta-lactamase activity that degrades the antibiotic. As no systematic studies have been performed to examine the potential of all PBPs present in one bacterial species to evolve increased resistance against beta lactam antibiotics, we explored the ability of fifteen different defined or putative PBPs in Salmonella enterica to acquire increased resistance against penicillin G. We could after mutagenesis and selection in presence of penicillin G isolate mutants with amino-acid substitutions in the PBPs, FtsI, DacB and DacC (corresponding to PBP3, PBP4 and PBP6) with increased resistance against beta lactam antibiotics. Our results suggest that: (i) most evolved PBPs became 'generalists" with increased resistance against several different classes of beta lactam antibiotics, (ii) synergistic interactions between mutations conferring antibiotic resistance are common and (iii) the mechanism of resistance of these mutants could be to make the active site more accessible for water allowing hydrolysis or less binding to beta-lactam antibiotics. PMID- 24810746 TI - Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells. AB - The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors. PMID- 24810747 TI - Directed evolution of improved zinc finger methyltransferases. AB - The ability to target DNA methylation toward a single, user-designated CpG site in vivo may have wide applicability for basic biological and biomedical research. A tool for targeting methylation toward single sites could be used to study the effects of individual methylation events on transcription, protein recruitment to DNA, and the dynamics of such epigenetic alterations. Although various tools for directing methylation to promoters exist, none offers the ability to localize methylation solely to a single CpG site. In our ongoing research to create such a tool, we have pursued a strategy employing artificially bifurcated DNA methyltransferases; each methyltransferase fragment is fused to zinc finger proteins with affinity for sequences flanking a targeted CpG site for methylation. We sought to improve the targeting of these enzymes by reducing the methyltransferase activity at non-targeted sites while maintaining high levels of activity at a targeted site. Here we demonstrate an in vitro directed evolution selection strategy to improve methyltransferase specificity and use it to optimize an engineered zinc finger methyltransferase derived from M.SssI. The unusual restriction enzyme McrBC is a key component of this strategy and is used to select against methyltransferases that methylate multiple sites on a plasmid. This strategy allowed us to quickly identify mutants with high levels of methylation at the target site (up to ~80%) and nearly unobservable levels of methylation at a off-target sites (<1%), as assessed in E. coli. We also demonstrate that replacing the zinc finger domains with new zinc fingers redirects the methylation to a new target CpG site flanked by the corresponding zinc finger binding sequences. PMID- 24810748 TI - Bacterial communities in the collection and chlorinated distribution sections of a drinking water system in Budapest, Hungary. AB - Bacterial communities of a bank-filtered drinking water system were investigated by aerobic cultivation and clone library analysis. Moreover, bacterial communities were compared using sequence-aided terminal restriction fragment length polymorphism (T-RFLP) fingerprinting at ten characteristic points located at both the collecting and the distributing part of the water supply system. Chemical characteristics of the samples were similar, except for the presence of chlorine residuals in the distribution system and increased total iron concentration in two of the samples. Assimilable organic carbon (AOC) concentration increased within the collection system, it was reduced by chlorination and it increased again in the distribution system. Neither fecal indicators nor pathogens were detected by standard cultivation techniques. Chlorination reduced bacterial diversity and heterotrophic plate counts. Community structures were found to be significantly different before and after chlorination: the diverse communities in wells and the collection system were dominated by chemolithotrophic (e.g., Gallionella and Nitrospira) and oligocarbophilic-heterotrophic bacteria (e.g., Sphingomonas, Sphingopyxis, and Bradyrhizobium). After chlorination in the distribution system, the most characteristic bacterium was related to the facultative methylotrophic Methylocella spp. Communities changed within the distribution system too, Mycobacterium spp. or Sphingopyxis spp. became predominant in certain samples. PMID- 24810749 TI - Fatal non-accidental alpha-lipoic acid intoxication in an adolescent girl. AB - The aim of our report is to increase awareness that the antioxidant alpha-lipoic acid, which is marketed primarily as weight loss and energy supplement, has potentially lethal effects. A 14-year-old girl ingested in suicidal intention a large amount of alpha-lipoic acid, which led to multiorgan failure and subsequent death within 24 h. Multiorgan failure consisted of decreased myocardial contractility, seizures, anuria, thrombocytopenia, and coagulopathy. Therapy consisted of ventilation, anticonvulsive treatment and circulatory support with high-dose catecholamines. According to alpha-lipoic acid serum levels following ingestion the girl must have ingested a minimum of 10 alpha-lipoic acid tablets of 600 mg each. This is the first report on a fatal case of alpha-lipoic acid ingestion, which is intended to inform physicians, pharmacists and patients about critical side effects of this allegedly innocuous drug. PMID- 24810750 TI - Laryngomalacia and complicated, life-threatening mTOR-positive Kaposiform hemangioendothelioma cured by Supraglottoplasty and sirolimus. AB - The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE. PMID- 24810751 TI - Perianal streptococcal dermatitis is not a major cause of constipation in pediatric patients with cerebral palsy. PMID- 24810752 TI - White sponge nevus - a rare autosomal dominant keratinopathy. PMID- 24810753 TI - In vitro and in vivo trypanocidal activity of H2bdtc-loaded solid lipid nanoparticles. AB - The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activity of 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyl dithiocarbazate) (H2bdtc) as a free compound or encapsulated into solid lipid nanoparticles (SLN); we compared the results with those achieved by using the currently employed drug, benznidazole. H2bdtc encapsulated into solid lipid nanoparticles (a) effectively reduced parasitemia in mice at concentrations 100 times lower than that normally employed for benznidazole (clinically applied at a concentration of 400 umol kg( 1) day(-1)); (b) diminished inflammation and lesions of the liver and heart; and (c) resulted in 100% survival of mice infected with T. cruzi. Therefore, H2bdtc is a potent trypanocidal agent. PMID- 24810754 TI - Association mapping for epistasis and environmental interaction of yield traits in 323 cotton cultivars under 9 different environments. AB - Improving yield is a major objective for cotton breeding schemes, and lint yield and its three component traits (boll number, boll weight and lint percentage) are complex traits controlled by multiple genes and various environments. Association mapping was performed to detect markers associated with these four traits using 651 simple sequence repeats (SSRs). A mixed linear model including epistasis and environmental interaction was used to screen the loci associated with these four yield traits by 323 accessions of Gossypium hirsutum L. evaluated in nine different environments. 251 significant loci were detected to be associated with lint yield and its three components, including 69 loci with individual effects and all involved in epistasis interactions. These significant loci explain ~ 62.05% of the phenotypic variance (ranging from 49.06% ~ 72.29% for these four traits). It was indicated by high contribution of environmental interaction to the phenotypic variance for lint yield and boll numbers, that genetic effects of SSR loci were susceptible to environment factors. Shared loci were also observed among these four traits, which may be used for simultaneous improvement in cotton breeding for yield traits. Furthermore, consistent and elite loci were screened with -Log10 (P-value) >8.0 based on predicted effects of loci detected in different environments. There was one locus and 6 pairs of epistasis for lint yield, 4 loci and 10 epistasis for boll number, 15 loci and 2 epistasis for boll weight, and 2 loci and 5 epistasis for lint percentage, respectively. These results provided insights into the genetic basis of lint yield and its components and may be useful for marker-assisted breeding to improve cotton production. PMID- 24810755 TI - Results of minimally invasive, video-assisted mitral valve repair in advanced Barlow's disease with bileaflet prolapse. AB - OBJECTIVES: Minimally invasive mitral valve (MV) surgery has recently gained popularity as the standard approach for MV repair, albeit there could be potential concerns about the feasibility of complex repair in the presence of extreme Barlow's disease via a minimally invasive route. METHODS: Fifty consecutive patients with advanced Barlow's disease and bileaflet prolapse underwent minimally invasive, video-assisted MV repair via a 5 cm right antero lateral thoracotomy with peripheral cannulation and external aortic clamping. Mean age, left ventricular ejection fraction and New York Heart Association class were 53+/-11 years, 62+/-7% and 3.1+/-0.8, respectively. Logistic EuroSCORE (mean) was 3.1. Either Custodiol (36 patients; 72%) or crystalloid (14 patients; 28%) cardioplegia were utilized. Complete rings (CE Classic or Physio) were implanted. Chordal reimplantation was carried out by means of polytetrafluoroethylene (PTFE) chordae. RESULTS: All procedures were successfully performed with null/mild residual mitral regurgitation (MR) intraoperatively. A repair strategy of posterior leaflet resection and PTFE chordae implant (for anterior leaflet) or no-resect approach (only PTFE chordae on both leaflets) was performed in 62% (31 patients) and 38% (19 patients) of cases, respectively. Mean aortic cross-clamp and cardiopulmonary bypass times were 98+/-23 and 131+/-41 min, respectively. Hospital mortality was 0%. At a median follow-up of 761 days, 2 patients (4%) required reoperation (infective endocarditis: 1 patient; partial ring detachment: 1 patient) and valve rerepair was achieved in both. All patients are alive with a freedom from >=2+ degree of MR of 100% at the latest echocardiographic evaluation. CONCLUSIONS: Minimally invasive approach for complex MV repair is feasible and safe and provided excellent early and mid-term results. PMID- 24810756 TI - Preoperative liver dysfunction influences blood product administration and alterations in circulating haemostatic markers following ventricular assist device implantation. AB - OBJECTIVES: Preoperative liver dysfunction may influence haemostasis following ventricular assist device (VAD) implantation. The Model for End-stage Liver Disease (MELD) score was assessed as a predictor of bleeding and levels of haemostatic markers in patients with currently utilized VADs. METHODS: Sixty three patients (31 HeartMate II, 15 HeartWare, 17 Thoratec paracorporeal ventricular assist device) implanted 2001-11 were analysed for preoperative liver dysfunction (MELD) and blood product administration. Of these patients, 21 had additional blood drawn to measure haemostatic marker levels. Cohorts were defined based on high (>=18.0, n = 7) and low (<18.0, n = 14) preoperative MELD scores. RESULTS: MELD score was positively correlated with postoperative administration of red blood cell (RBC), platelet, plasma and total blood product units (TBPU) , as well as chest tube drainage and cardiopulmonary bypass time. Age and MELD were preoperative predictors of TBPU by multivariate analysis. The high-MELD cohort had higher administration of TBPU, RBC and platelet units and chest tube drainage postimplant. Similarly, patients who experienced at least one bleeding adverse event were more likely to have had a high preoperative MELD. The high-MELD group exhibited different temporal trends in F1 + 2 levels and platelet counts to postoperative day (POD) 55. D-dimer levels in high-MELD patients became elevated versus those for low-MELD patients on POD 55. CONCLUSIONS: Preoperative MELD score predicts postoperative bleeding in contemporary VADs. Preoperative liver dysfunction may also alter postoperative subclinical haemostasis through different temporal trends of thrombin generation and platelet counts, as well as protracted fibrinolysis. PMID- 24810757 TI - Influence of intraoperative cerebral oximetry monitoring on neurocognitive function after coronary artery bypass surgery: a randomized, prospective study. AB - OBJECTIVES: Postoperative cognitive decline is common after cardiac surgery, but it is often unrecognized at the time of hospital discharge. However, it has a great impact on patient's quality of life. Cerebral oximetry with the INVOS (IN Vivo Optical Spectroscopy) system provides the possibility of non-invasive, continuous measurement of regional cerebral oxygen saturation (rSO2), which can improve patients' outcome. The aim of this study was to examine whether cerebral oximetry can decrease the incidence of cognitive decline after coronary artery bypass grafting. METHODS: We have performed a prospective, randomized study with 200 patients enrolled. Patients were divided into INVOS interventional group and CONTROL group without monitoring of cerebral oximetry. A standardized interventional protocol was performed in the INVOS group to maintain rSO2 above 80% of the patient's baseline value or above 50% of the absolute value. Cognitive evaluation was performed in all patients before and 7 days after surgery. Logistic regression was used to reveal predictors of cognitive decline. RESULTS: The incidence of cognitive decline 7 days after surgery was significantly lower (P = 0.002) in the INVOS interventional group (28%) than in the CONTROL group (52%). Intraoperative use of INVOS monitoring was associated with lower incidence of cognitive decline (odds ratio 0.21). In addition, predictors of cognitive decline revealed by multivariate logistic regression were older age, higher EuroSCORE and SAPS II (Simplified Acute Physiology Score) values, lower educational level and persistence of preoperative atrial fibrillation. Patients with prolonged rSO2 desaturation, defined as rSO2 area under the curve (AUC) of more than 150 min% for desaturation below 20% of baseline or AUC of more than 50 min% for desaturation below 50% absolute value, had an increased risk of cognitive decline. CONCLUSION: Postoperative cognitive outcome was significantly better in patients with intraoperative cerebral oximetry monitoring. Prolonged rSO2 desaturation is a predictor of cognitive decline and has to be avoided. PMID- 24810759 TI - Endograft connector technique to treat popliteal artery aneurysm in a morbid obese patient. AB - Surgical repair of popliteal artery aneurysm in morbid obese patients poses additional challenges. We report a morbid obese patient who had a 59 mm right popliteal artery aneurysm which was successfully treated with the endograft connector technique. This technique was used to perform the distal anastomosis of the below-knee femoro-popliteal bypass. A 10 mm Dacron graft was used as a main graft bypass and an 11 mm/10 cm stentgraft as endograft connector. Following the respective tunnel of the Dacron graft, an end-to-side proximal anastomosis was performed at distal femoral artery. The aneurysm exclusion was obtained through a proximal and a distal ligation. Postoperative duplex showed adequate bypass patency. Knee x-rays demonstrated no signs of stent kinking/fractures. The postoperative course was uneventful and the patient was discharged home on fourth day post operative. The six-month computed tomography scan and the 12-month duplex control showed a patent bypass with no signs of stenosis. PMID- 24810758 TI - ROS-mediated autophagy induced by dysregulation of lipid metabolism plays a protective role in colorectal cancer cells treated with gambogic acid. AB - Gambogic acid (GA), the main active component of gamboge resin, has potent antitumor activity both in vivo and in vitro. However, the underlying molecular mechanisms remain unclear. In this study, we found that GA could initiate autophagy in colorectal cancer cells, and inhibition of the autophagy process accelerated the effect of proliferative inhibition and apoptotic cell death induced by GA, implying a protective role of autophagy. Two-dimensional electrophoresis-based proteomics showed that GA treatment altered the expression of multiple proteins involved in redox signaling and lipid metabolism. Functional studies revealed that GA-induced dysregulation of lipid metabolism could activate 5-lipoxygenase (5-LOX), resulting in intracellular ROS accumulation, followed by inhibition of Akt-mTOR signaling and autophagy initiation. Finally, results using a xenograft model suggested ROS-induced autophagy protect against the antitumor effect of GA. Taken together, these data showed new biological activities of GA against colorectal cancer underlying the protective role of ROS-induced autophagy. This study will provide valuable insights for future studies regarding the anticancer mechanisms of GA. PMID- 24810760 TI - Retinoid-X-receptors (alpha/beta) in melanocytes modulate innate immune responses and differentially regulate cell survival following UV irradiation. AB - Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor alpha (RXRalpha) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte specific ablation of RXRalpha and RXRbeta, melanocytes attract fewer IFN-gamma secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-gamma in the microenvironment alters UVR induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRalpha/beta. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRalpha/beta. Loss of RXRs alpha/beta specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a "non-cell autonomous" manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a "cell autonomous" manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma. PMID- 24810761 TI - Direct anthelmintic effects of condensed tannins from diverse plant sources against Ascaris suum. AB - Ascaris suum is one of the most prevalent nematode parasites in pigs and causes significant economic losses, and also serves as a good model for A. lumbricoides, the large roundworm of humans that is ubiquitous in developing countries and causes malnutrition, stunted growth and compromises immunity to other pathogens. New treatment options for Ascaris infections are urgently needed, to reduce reliance on the limited number of synthetic anthelmintic drugs. In areas where Ascaris infections are common, ethno-pharmacological practices such as treatment with natural plant extracts are still widely employed. However, scientific validation of these practices and identification of the active compounds are lacking, although observed effects are often ascribed to plant secondary metabolites such as tannins. Here, we extracted, purified and characterised a wide range of condensed tannins from diverse plant sources and investigated anthelmintic effects against A. suum in vitro. We show that condensed tannins can have potent, direct anthelmintic effects against A. suum, as evidenced by reduced migratory ability of newly hatched third-stage larvae and reduced motility and survival of fourth-stage larvae recovered from pigs. Transmission electron microscopy showed that CT caused significant damage to the cuticle and digestive tissues of the larvae. Furthermore, we provide evidence that the strength of the anthelmintic effect is related to the polymer size of the tannin molecule. Moreover, the identity of the monomeric structural units of tannin polymers may also have an influence as gallocatechin and epigallocatechin monomers exerted significant anthelmintic activity whereas catechin and epicatechin monomers did not. Therefore, our results clearly document direct anthelmintic effects of condensed tannins against Ascaris and encourage further in vivo investigation to determine optimal strategies for the use of these plant compounds for the prevention and/or treatment of ascariosis. PMID- 24810762 TI - Oxysterol-EBI2 signaling in immune regulation and viral infection. AB - The seven transmembrane G protein-coupled receptor Epstein-Barr virus (EBV) induced gene 2 (EBI2; also known as GPR183) was identified in 1993 on the basis of its substantial upregulation in EBV-infected cells. It is primarily expressed in lymphoid cells; most abundantly in B cells. EBI2 is central for the positioning of B cells within the lymphoid organs, a process that is regulated in part by a chemotactic gradient formed by the endogenous lipid agonists, and in part by a fine-tuned regulation of EBI2 cell surface expression. The most potent endogenous EBI2 agonist is 7alpha, 25-dihydroxyxcholesterol (7alpha,25-OHC), yet many structurally related oxysterols can bind to an EBI2 pocket that is defined by the upper parts of the transmembrane helices and extracellular receptor regions. EBI2 signals via Galphai, as well as via G protein-independent pathways like beta-arrestin recruitment. The concerted action of these pathways leads to cell migration. By genetically interfering with its up- and downregulation, EBI2 was also recently shown to induce cell proliferation, an action that could be inhibited by small molecule antagonists. Here, we focus on the oxysterol-EBI2 axis in immune control, including its role in the EBV life cycle. We also summarize the structural and functional properties of EBI2 interaction with oxysterol agonists and small molecule antagonists and discuss EBI2 as therapeutic target for diseases of the immune system. PMID- 24810763 TI - Pediatric blood sample collection from a pre-existing peripheral intravenous (PIV) catheter. AB - Aiming to minimize pain in a hospitalized child, the purpose of this observational study was to describe characteristics of blood samples collected from pre-existing peripheral intravenous (PIV) catheters in pediatric patients. One hundred and fifty blood samples were reviewed for number of unusable samples requiring a specimen to be re-drawn. Success of the blood draw and prevalence of the loss of the PIV following blood collection was also measured. Findings included one clotted specimen, success rate of 91.3%, and 1.3% of PIVs becoming non-functional after collection. Obtaining blood specimens from a pre-existing PIV should be considered in a pediatric patient. PMID- 24810764 TI - Short-term outcomes of sleeve gastrectomy for morbid obesity: does staple line reinforcement matter? AB - BACKGROUND: Stand-alone laparoscopic sleeve gastrectomy (LSG) has been found to be effective in producing weight loss but few large, one-center LSG series have been reported. Gastric leakage from the staple line is a life-threatening complication of LSG, but there is controversy about whether buttressing the staple line with a reinforcement material will reduce leaks. We describe a single center, 518-patient series of LSG procedures in which a synthetic buttressing material (GORE(r) SEAMGUARD(r) Bioabsorbable Staple Line Reinforcement) was used in the most recently treated patients. METHODS: We retrospectively reviewed the medical records of all patients who underwent LSG in our unit between September 2007 and December 2011. Patients treated before August 2009 did not receive the staple line reinforcement material (n = 186), whereas all patients treated afterward did (n = 332). RESULTS: The percentages of excess weight loss in the 518 patients (mean age, 41 years; 82% female; mean preoperative body mass index, 44 kg/m(2)) were 67% (79% follow-up rate) at 6 months postoperatively, 81% (64%) at 1 year, and 84% (30%) at 2 years. Type 2 diabetes resolved in 71 % of patients (91/128). Patients given reinforcement material had baseline characteristics similar to those in the no-reinforcement-material group, but had no postoperative staple line leaks or bleeding. The no-reinforcement group had three leaks (p = 0.045) and one case of bleeding. CONCLUSIONS: LSG resulted in substantial short term weight loss. Use of the bioabsorbable staple line reinforcement material may decrease leaks after LSG. PMID- 24810765 TI - An analysis of patient safety incidents associated with medications reported from critical care units in the North West of England between 2009 and 2012. AB - Incident reporting is promoted as a key tool for improving patient safety in healthcare. We analysed 2238 patient safety incidents involving medications submitted from up to 29 critical care units each year in the North West of England between 2009 and 2012; 452 (20%) of these incidents led to harm to patients. Although 1461 (65%) incidents were judged to have been preventable, there was no reduction in the rate of incidents per 1000 days between 2009 and 2012 (5.9 in 2009, 6.6 in 2012). Furthermore, in the 2012 data, there were wide variations in the incident rates between units, the median (IQR [range]) rate per 1000 patient days for individual units being 6.8 (3.8-11.0 [1.3-37.1]). The variation in the percentage that could have been avoided was narrower, with a median (IQR [range]) of 70% (61-80% [38-100%]). The most commonly reported drugs were noradrenaline (161 incidents, 92 with harm), heparins (153 incidents, 29 with harm), morphine (131 incidents, 14 with harm) and insulin (111 incidents, 54 with harm). The administration of drugs was the stage in the process where incidents were most commonly reported; it was also the stage most likely to harm patients. We conclude that the wide range in reported rates between units, and the scope for preventing many incidents, suggest that quality improvement initiatives could improve medication safety in the units studied. PMID- 24810766 TI - Soy isoflavone antagonizes the oxidative cerebrovascular injury induced by beta amyloid peptides 1-42 in rats. AB - Numerous evidences have shown that the antioxidative properties of soy isoflavone (SIF) have beneficial effects on prophylaxis of neurodegeneration, however, the mechanism is still not fully illustrated. As cerebrovascular dysfunction could initiate a cascade of events leading to pathogenesis of Alzheimer's disease, we tried to investigate whether SIF could protect the cerebrovascular system due to antagonizing oxidative damage induced by Abeta1-42 in present study. In addition, NF-E2-related factor 2 (Nrf2) signaling pathways in the cerebrovascular tissue of Wistar rats were investigated to identify the potential cerebrovascular protective targets of SIF. Research results showed that SIF reduced the excessive production of nitrotyrosine in cerebrovascular tissue induced by Abeta1-42, and maintained redox homeostasis by increasing the level of GSH and GSH/GSSG. Moreover, SIF could alleviate the down-regulation of Nrf2, gamma-glutamylcysteine synthetase, Heme oxygenase-1 expressions in cerebrovascular tissue induced by Abeta1-42 and suppress the increase of Kelch like ECH protein-1 (Keap1). These data suggested that SIF might reduce the cerebrovascular oxidative damage induced by Abeta1-42 through regulating the Nrf2 signaling pathway. The mechanisms of SIF modulating the potential target Nrf2 might be associated with Keap1 expression. PMID- 24810767 TI - K+ uptake in plant roots. The systems involved, their regulation and parallels in other organisms. AB - Potassium (K(+)) is an essential macronutrient for plants. It is taken into the plant by the transport systems present in the plasma membranes of root epidermal and cortical cells. The identity of these systems and their regulation is beginning to be understood and the systems of K(+) transport in the model species Arabidopsis thaliana remain far better characterized than in any other plant species. Roots can activate different K(+) uptake systems to adapt to their environment, important to a sessile organism that needs to cope with a highly variable environment. The mechanisms of K(+) acquisition in the model species A. thaliana are the best characterized at the molecular level so far. According to the current model, non-selective channels are probably the main pathways for K(+) uptake at high concentrations (>10mM), while at intermediate concentrations (1mM), the inward rectifying channel AKT1 dominates K(+) uptake. Under lower concentrations of external K(+) (100MUM), AKT1 channels, together with the high affinity K(+) uptake system HAK5 contribute to K(+) acquisition, and at extremely low concentrations (<10MUM) the only system capable of taking up K(+) is HAK5. Depending on the species the high-affinity system has been named HAK5 or HAK1, but in all cases it fulfills the same functions. The activation of these systems as a function of the K(+) availability is achieved by different mechanisms that include phosphorylation of AKT1 or induction of HAK5 transcription. Some of the characteristics of the systems for root K(+) uptake are shared by other organisms, whilst others are specific to plants. This indicates that some crucial properties of the ancestral of K(+) transport systems have been conserved through evolution while others have diverged among different kingdoms. PMID- 24810768 TI - Cellular and tissue distribution of potassium: physiological relevance, mechanisms and regulation. AB - Potassium (K(+)) is the most important cationic nutrient for all living organisms. Its cellular levels are significant (typically around 100mM) and are highly regulated. In plants K(+) affects multiple aspects such as growth, tolerance to biotic and abiotic stress and movement of plant organs. These processes occur at the cell, organ and whole plant level and not surprisingly, plants have evolved sophisticated mechanisms for the uptake, efflux and distribution of K(+) both within cells and between organs. Great progress has been made in the last decades regarding the molecular mechanisms of K(+) uptake and efflux, particularly at the cellular level. For long distance K(+) transport our knowledge is less complete but the principles behind the overall processes are largely understood. In this chapter we will discuss how both long distance transport between different organs and intracellular transport between organelles works in general and in particular for K(+). Where possible, we will provide examples of specific genes and proteins that are responsible for these phenomena. PMID- 24810769 TI - The twins K+ and Na+ in plants. AB - In the earth's crust and in seawater, K(+) and Na(+) are by far the most available monovalent inorganic cations. Physico-chemically, K(+) and Na(+) are very similar, but K(+) is widely used by plants whereas Na(+) can easily reach toxic levels. Indeed, salinity is one of the major and growing threats to agricultural production. In this article, we outline the fundamental bases for the differences between Na(+) and K(+). We present the foundation of transporter selectivity and summarize findings on transporters of the HKT type, which are reported to transport Na(+) and/or Na(+) and K(+), and may play a central role in Na(+) utilization and detoxification in plants. Based on the structural differences in the hydration shells of K(+) and Na(+), and by comparison with sodium channels, we present an ad hoc mechanistic model that can account for ion permeation through HKTs. PMID- 24810770 TI - Organelle-localized potassium transport systems in plants. AB - Some intracellular organelles found in eukaryotes such as plants have arisen through the endocytotic engulfment of prokaryotic cells. This accounts for the presence of plant membrane intrinsic proteins that have homologs in prokaryotic cells. Other organelles, such as those of the endomembrane system, are thought to have evolved through infolding of the plasma membrane. Acquisition of intracellular components (organelles) in the cells supplied additional functions for survival in various natural environments. The organelles are surrounded by biological membranes, which contain membrane-embedded K(+) transport systems allowing K(+) to move across the membrane. K(+) transport systems in plant organelles act coordinately with the plasma membrane intrinsic K(+) transport systems to maintain cytosolic K(+) concentrations. Since it is sometimes difficult to perform direct studies of organellar membrane proteins in plant cells, heterologous expression in yeast and Escherichia coli has been used to elucidate the function of plant vacuole K(+) channels and other membrane transporters. The vacuole is the largest organelle in plant cells; it has an important task in the K(+) homeostasis of the cytoplasm. The initial electrophysiological measurements of K(+) transport have categorized three classes of plant vacuolar cation channels, and since then molecular cloning approaches have led to the isolation of genes for a number of K(+) transport systems. Plants contain chloroplasts, derived from photoautotrophic cyanobacteria. A novel K(+) transport system has been isolated from cyanobacteria, which may add to our understanding of K(+) flux across the thylakoid membrane and the inner membrane of the chloroplast. This chapter will provide an overview of recent findings regarding plant organellar K(+) transport proteins. PMID- 24810771 TI - Lobar lung transplantation--is it comparable with standard lung transplantation? AB - Lobar lung transplantation is used mainly for urgent small recipients who are less likely to obtain size matched lungs in due time. Only limited numbers have been published, and we herewith report the largest series of lobar-LuTX. We analyzed our LuTX database from 1/2001 to 12/2012 and compared the outcome of lobar-LuTX recipients with those receiving standard LuTX. Seven hundred and seventy-eighty LuTX (group 1) were performed either in standard technique by implanting the whole lungs (n = 539) or with downsizing by wedge resection of the right middle lobe and/or the left lingula (n = 239). One hundred and thirty-eight LuTX were performed in lobar technique (group 2) to overcome more pronounced size discrepancies. Patients in group 1 had a different spectrum of diagnoses and were less frequently bridged to LuTX (P < 0.001). Intubation time, ICU stay, and hospital stay were shorter in group 1 (P < 0.001). One-year survival was 84.8% vs. 65.1%, and 5-years survival 69.9% vs. 54.9% (P < 0.001). In multivariate analyzes, procedure, diagnosis, and pre-operative bridging were shown to be significant prognostic factors in survival. Early postoperative outcome in Lobar LuTX was significantly inferior to standard LuTX recipients. However, survival rates of successfully dismissed patients were comparable with standard LuTX (P = 0.168); thereby, Lobar-LuTX remains an important option in the management of urgent small recipients. PMID- 24810772 TI - ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity. AB - BACKGROUND: Since the past 2 decades, new evidence for brain plasticity has caused a shift in both preclinical and clinical ECT research from falsifying the "brain damage hypothesis" toward exploring ECT's enabling brain (neuro)plasticity effects. METHODS: By reviewing the available animal and human literature, we examined the theory that seizure-induced structural changes are crucial for the therapeutic efficacy of ECT. RESULTS: Both animal and human studies suggest electroconvulsive stimulation/electroconvulsive therapy (ECT)-related neuroplasticity (neurogenesis, synaptogenesis, angiogenesis, or gliogenesis). CONCLUSION: It remains unclear whether structural changes might explain the therapeutic efficacy and/or be related to the (transient) learning and memory impairment after ECT. Methods to assess in vivo brain plasticity of patients treated with ECT will be of particular importance for future longitudinal studies to give support to the currently available correlational data. PMID- 24810773 TI - Epigenetic effects of electroconvulsive seizures. AB - Electroconvulsive therapy (ECT) is one of the most effective methods for managing treatment-resistant depression. Although the proposed mechanisms of action have thus far mainly been investigated at the cellular level, recent observations and developments in the field of molecular biology and genomics have provided novel insights in the actual molecular underpinnings of dynamic alterations in gene expression, particularly in response to environmental exposures, and experience dependent plasticity, both of which are highly relevant to ECT. Here, we provided a brief background on epigenetics and we reviewed the current state of knowledge on epigenetic mediation of ECT-related therapeutic effects. We performed a systematic search on the effects of ECT on epigenetics and found only a limited number on animal studies relevant to our search. These studies, however, support the notion of a robust impact of ECT on epigenetic mechanisms and set the stage for human ECT studies on the epigenetic machinery. PMID- 24810774 TI - What does the electroencephalogram tell us about the mechanisms of action of ECT in major depressive disorders? AB - Electroconvulsive therapy (ECT) remains to be one of the most effective treatment options in treatment-resistant major depressive disorder (MDD). From the early days, researchers have embarked on extracting information from electroencephalography (EEG) recordings before, during, and after ECT to identify neurophysiological targets of ECT and discover EEG predictors of response to ECT in patients with MDD. In this article, we provide an overview of visually detected and quantitative EEG features that could help in furthering our understanding of the mechanisms of action of ECT in MDD. We further discuss the EEG findings in the context of postulated hypotheses of ECT therapeutic pathways. We introduce an alternative and unifying hypothesis suggesting that ECT may exert its therapeutic efficacy through resetting the aberrant functional connectivity and promoting the generation of new and healthy connections in brain regions implicated in MDD pathophysiology, a mechanism that may be in part mediated by the ECT-induced activation of inhibitory and neuroplasticity mechanisms. We further discuss the added value of EEG markers in the larger context of ECT research and as complementary to neuroimaging and genetic markers. We conclude by drawing attention to the need for longitudinal studies in large cohort of patients and the need for standardization and validation of EEG algorithms of functional connectivity across studies to facilitate the translation of EEG correlates of ECT response in routine clinical practice. PMID- 24810775 TI - Electroconvulsive therapy (ECT) in Parkinson's disease: ECS and dopamine enhancement. AB - INTRODUCTION: In addition to its effects in major psychiatric illness, electroconvulsive therapy (ECT) is known to have a beneficial effect on the core motor symptoms of Parkinson's disease (PD). This effect is believed to be mediated via dopamine in the striatum. Electroconvulsive shock (ECS), the animal analogue of ECT, is the model in which investigators have sought to elucidate the specific dopaminergic mechanisms by which ECT exerts its therapeutic effect in PD. Electroconvulsive shock has been given to intact animals as well as to animals with neurotoxic lesions that create parkinsonism. METHODS: In this paper, we selectively review the electroconvulsive shock literature on dopamine in the striatum. RESULTS: Electroconvulsive shock, and by extension, ECT, is associated with increased dopamine release and modulation of dopamine receptors. CONCLUSION: Better understanding of how ECT works to enhance dopaminergic systems in the brain could help to make it a more accepted treatment for PD. PMID- 24810776 TI - The antipsychotic effects of ECT: a review of possible mechanisms. AB - OBJECTIVES: Electroconvulsive therapy (ECT) exhibits demonstrable effectiveness for psychotic symptoms associated with a broad range of neuropsychiatric conditions. However, the mechanism remains poorly understood particularly with regard to antipsychotic effects. METHODS: We examined studies of ECT in schizophrenia and mood disorders, as well as from animal models of psychotic disorders, and compared the results to those of antipsychotic medications. This review focuses on 3 potential domains of exploration of ECT's antipsychotic effects: dopamine and serotonin neurotransmitter activity, neurotrophic effects, and immune system modulation. RESULTS: Preliminary results support a putative role for all three of these domains but are limited by a lack of replicated findings, including negative studies. CONCLUSIONS: A comparison of the neurophysiologic and molecular properties of antipsychotic drugs and ECT reveals some overlap, but there are also distinctive differences; and the significance of these findings remains uncertain. PMID- 24810777 TI - A mechanism of seizure induction by electricity and its clinical implications. AB - A model of ECT seizure induction by rapid kindling is described. The electrical stimulus as a series of pulses progressively disrupts neuronal cell membranes, with corresponding progressive increases in intracellular concentrations of sodium, calcium, and voltage. Eventually, the intracellular voltage rises to trigger neuronal firing in waves from seizure foci. The quantity of seizure foci produced is expressed by the stimulus charge multiplied by the current cubed. Differences in implications are described between this model and the traditional model that extrapolates from an isolated single neuron undergoing immediate electrical depolarization by a single pulse. Total brain exposure to seizure neurotransmitter release in ECT is analogous to body exposure to medication in drug therapy and may be expressed by a physiological measurement such as electroencephalographic postictal suppression or peak seizure heart rate. PMID- 24810778 TI - HOXC8 promotes breast tumorigenesis by transcriptionally facilitating cadherin-11 expression. AB - Cell-cell adhesion molecule cadherin-11(CDH11) is preferentially expressed in basal-like breast cancer cells and facilitates breast cancer cell migration by promoting small GTPase Rac activity. However, how the expression of CDH11 is regulated in breast cancer cells is not understood. Here, we show that CDH11 is transcriptionally controlled by homeobox C8 (HOXC8) in human breast cancer cells. HOXC8 serves as a CDH11-specific transcription factor and binds to the site of nucleotides -196 to -191 in the CDH11 promoter. Depletion of HOXC8 leads to the decrease in anchorage-independent cell growth, cell migration/invasion and spontaneous metastasis of breast cancer cells; however, suppressed tumorigenic events were fully rescued by ectopic CDH11 expression in HOXC8-knockdown cells. These results indicate that HOXC8 impacts breast tumorigenesis through CDH11. The analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression ( = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) show that both high HOXC8 and CDH11 expression correlate with poor recurrence-free survival rate of patients. Together, our study suggests that HOXC8 promotes breast tumorigenesis by maintaining high level of CDH11 expression in breast cancer cells. PMID- 24810779 TI - Gene expression signature of tolerance and lymphocyte subsets in stable renal transplants: results of a cross-sectional study. AB - BACKGROUND: In kidney transplants operational tolerance has been associated with up-regulation of B cell differentiation genes and an increased number of total, naive and transitional peripheral B cells. The aim is to evaluate tolerance biomarkers in different cohorts of stable renal transplants under immunosuppression. METHODS: This is a cross-sectional study conducted in renal transplants. We evaluate genetic tolerance signature and lymphocyte subsets in stable transplants treated with calcineurin inhibitors (CNI) at 1 (n=15), 5 (n=14) and 10 (n=16) years, and azathioprine-treated transplants followed 30 years (n=8). Healthy volunteers (n=10) and patients with chronic rejection (n=15) served as controls. RESULTS: We confirm that peripheral expression of IGKV1D-13 and IGKV4-1 genes by RT-PCR distinguish tolerant (n=10) from stable transplants (n=10) provided by the International Tolerance Network. Tolerance signature was defined as the lowest expression for both genes in tolerant patients. In CNI treated patients, genetic signature of tolerance and B cells showed a time dependent increase not observed in azathioprine-treated patients (p<0.01). Genetic tolerance signature was observed in 0% at 1, 7% at 5 and 25% at 10-years while it was not observed in azathioprine-treated and chronic rejection patients. Fifteen out of 16 CNI-treated transplants at 10 years were revaluated 3 months apart. Nine did not show the tolerance signature in any determination, 4 in one and 2 in both determinations. Genetic signature of tolerance was associated with an increase of total, naive and transitional B cells (p<0.05). CONCLUSIONS: IGKV1D-13 and IGKV4-1 gene expression and its linked B cell populations increase during follow up in CNI-treated patients. At 10 years, 2 out of 15 CNI treated patients consistently express biomarkers associated with true tolerance. In azathioprine-treated patients these biomarkers were down-regulated. PMID- 24810782 TI - Diagnosis of squamous cell carcinoma metastasis with 18F-FDG PET/CT in stoma after percutaneous endoscopic gastrostomy: a rare and poorly known iatrogenic cause of spread of head and neck cancer. AB - Patients undergoing percutaneous endoscopic gastrostomy (PEG) for pharyngoesophageal malignancies are subject to develop malignant seeding at the PEG stoma. Risk factors include an untreated or recurrent advanced stage squamous cell carcinoma at the time of the PEG procedure and an endoscopic pull-string gastrostomy. Diagnosis is frequently late because this rare complication is poorly known. Prognosis remains poor despite aggressive treatment. Physicians should be aware of this complication in the event of hypermetabolic uptake around or close to a PEG stoma in patients monitored for a pharyngoesophageal squamous cell carcinoma. PMID- 24810781 TI - Non-linear blending of dual-energy CT data improves depiction of late iodine enhancement in chronic myocardial infarction. AB - To compare non-linear and linear blending of cardiac dual-energy computed tomography (DECT) for optimal visualization of late iodine enhancement (LIE) in patients with chronic myocardial infarction (CMI). LIE-DECT data from 20 patients with known CMI were retrospectively analyzed. Images were reconstructed using non linear blending center and width settings in the range of 0-500. Linear blending was performed with weighting factors 0.8 (80% 100 kV, 20% 140 kV), 0.6 and 0.3. 100-/140-kV data and blended images were analyzed. Contrast and percentage signal differences between infarcted and healthy myocardium and the left ventricle blood pool were computed. Statistical analysis was performed using repeated-measures analysis of variance and post hoc t tests. Non-linear blending showed the highest signal differences for all contrasts and analyses. Repeated-measures ANOVA tests confirmed the statistical differences between the investigated blending techniques (P < 0.01). Paired-samples post hoc t tests confirmed the significance of these results (P < 0.04). The ideal non-linear blending settings for best demarcation of CMI from healthy myocardium were a center of 65.8 +/- 23.2 and a width of 0.0 +/- 0.0. Non-linear blending of LIE-DECT improves display of LIE in patients with CMI in comparison with linear blending and non-post-processed image data from 100-/140-kV. PMID- 24810783 TI - PET/CT findings in acute gastric anisakiasis. AB - Acute gastric anisakiasis is caused by the consumption of raw or undercooked fish containing Anisakis larvae. Although several reports have demonstrated the CT features of acute gastric anisakiasis, little is known about the FDG PET/CT findings. We report a 59-year-old woman who underwent FDG PET/CT and was finally diagnosed as having acute gastric anisakiasis. The PET/CT demonstrated focal FDG accumulation in the fornix of the gastric wall and lymph nodes in the lesser curvature and paraaortic regions. PMID- 24810784 TI - Walking Drosophila align with the e-vector of linearly polarized light through directed modulation of angular acceleration. AB - Understanding the mechanisms that link sensory stimuli to animal behavior is a central challenge in neuroscience. The quantitative description of behavioral responses to defined stimuli has led to a rich understanding of different behavioral strategies in many species. One important navigational cue perceived by many vertebrates and insects is the e-vector orientation of linearly polarized light. Drosophila manifests an innate orientation response to this cue ('polarotaxis'), aligning its body axis with the e-vector field. We have established a population-based behavioral paradigm for the genetic dissection of neural circuits guiding polarotaxis to both celestial as well as reflected polarized stimuli. However, the behavioral mechanisms by which flies align with a linearly polarized stimulus remain unknown. Here, we present a detailed quantitative description of Drosophila polarotaxis, systematically measuring behavioral parameters that are modulated by the stimulus. We show that angular acceleration is modulated during alignment, and this single parameter may be sufficient for alignment. Furthermore, using monocular deprivation, we show that each eye is necessary for modulating turns in the ipsilateral direction. This analysis lays the foundation for understanding how neural circuits guide these important visual behaviors. PMID- 24810785 TI - Water and membrane dynamics in suspensions of lipid vesicles functionalized with poly(ethylene glycol)s. AB - The present work was aimed at studying the molecular dynamics at different levels of model membranes having a simulated glycoclix, with focus on the molecular crowding conditions at the lipid-water interfacial region. Thus, binary mixtures of dipalmitoylphosphatidylcholine (dpPC) and a poly(ethylene glycol) (PEG(n)) derivative of dipalmitoylphosphatidylethanolamine (PE) (where n = 350, 1000, and 5000, respectively, refer to PEG molecular masses) were submitted to (1)H spin lattice relaxation time (T1) and (31)P NMR spectra analysis. (1)H NMR relaxation times revealed two contributing components in each proton system (PEG, phospholipids, and water), for all the mixtures studied, exhibiting values of T1 with very different orders of magnitude. This allowed identifying confined and bulk water populations as well as PEG moieties becoming more disordered and independent from the phospholipid moiety as n increased. (31)P spectra showed a typical broad bilayer signal for n = 350 and 1000, and an isotropic signal characteristic of micelles for n = 5000. Surface pressure (pi)-molecular area isotherms and compressional modulus measurements provided further structural information. Moreover, epifluorescence microscopy data from monolayers at pi ~ 30 mN/m, the expected equilibrium pi in lipid bilayers, allowed us to postulate that both (1)H populations resolved through NMR in phospholipids and lipopolymers corresponded to different phase domains. PMID- 24810786 TI - Antioxidant activity in cooked and simulated digested eggs. AB - The avian egg is an excellent source of nutrients consisting of components with beneficial properties but there is limited knowledge on the effect of cooking methods and gastrointestinal digestion on the antioxidant activity of eggs. The present study was focused on the effect of cooking and simulated gastrointestinal digestion on antioxidant activity of eggs using ORAC, ABTS and DPPH assays. The results suggest that fresh egg yolk has higher antioxidant activity than fresh egg white and whole eggs. Cooking reduced whereas simulated gastrointestinal digestion increased the antioxidant activity of eggs. Boiled egg white hydrolysate showed the highest antioxidant activity; a total of 63 peptides were identified, indicative of the formation of novel antioxidant peptides upon simulated gastrointestinal digestion. This study suggests the potential role of eggs as a dietary source of antioxidants. PMID- 24810787 TI - Shiga toxin-producing E. coli (STEC) in swine: prevalence over the finishing period and characteristics of the STEC isolates. AB - This descriptive longitudinal study was conducted to investigate the faecal shedding of Shiga toxin-producing E. coli (STEC) in finishing swine and to characterize the swine STEC isolates that were recovered. Three cohorts of finishing swine (n = 50/cohort; total 150 pigs) were included in the longitudinal study. Individual faecal samples were collected every 2 weeks (8 collections/pig) from the beginning (pig age 10 weeks) to the end (pig age 24 weeks) of the finishing period. STEC isolates were recovered in at least one sample from 65.3% (98/150) of the pigs, and the frequency distribution of first-time STEC detection during the finishing period resembled a point-source outbreak curve. Nineteen O:H serotypes were identified among the STEC isolates. Most STEC isolates (n = 148) belonged to serotype O59:H21 and carried the stx 2e gene. One O49:H21 STEC isolate carried the stx 2e and eae genes. High prevalence rates of STEC during the finishing period were observed, and STEC isolates in various non-O157 serogroups were recovered. These data enhance understanding of swine STEC epidemiology, and future research is needed to confirm whether or not swine STEC are of public health concern. PMID- 24810789 TI - Development of echinocandin-resistant Candida albicans candidemia following brief prophylactic exposure to micafungin therapy. AB - Empiric antifungal coverage is indicated in patients with graft-versus-host disease (GVHD) following a stem cell transplant (SCT) who are febrile and neutropenic for extended periods of time. Empiric antifungal coverage is indicated for patients with hematologic malignancies who have persistent fever and neutropenia as well as patients who have GVHD following SCT. Although the prophylactic use of antifungals is a cornerstone of the care for such patients, the selection of the particular antifungal is at the discretion of the clinician. We report a patient case whose surveillance blood cultures obtained 14 days after the switch from voriconazole to micafungin were positive for the growth of Candida albicans. Clinicians prescribing echinocandin therapy for antifungal prophylaxis must be aware of the risks of echinocandin resistance and possible breakthrough candidemia with C. albicans. PMID- 24810790 TI - Limitations of predicting in vivo biostability of multiphase polyurethane elastomers using temperature-accelerated degradation testing. AB - Polyurethane biostability has been the subject of intense research since the failure of polyether polyurethane pacemaker leads in the 1980s. Accelerated in vitro testing has been used to isolate degradation mechanisms and predict clinical performance of biomaterials. However, validation that in vitro methods reproduce in vivo degradation is critical to the selection of appropriate tests. High temperature has been proposed as a method to accelerate degradation. However, correlation of such data to in vivo performance is poor for polyurethanes due to the impact of temperature on microstructure. In this study, we characterize the lack of correlation between hydrolytic degradation predicted using a high temperature aging model of a polydimethylsiloxane-based polyurethane and its in vivo performance. Most notably, the predicted molecular weight and tensile property changes from the accelerated aging study did not correlate with clinical explants subjected to human biological stresses in real time through 5 years. Further, DMTA, ATR-FTIR, and SAXS experiments on samples aged for 2 weeks in PBS indicated greater phase separation in samples aged at 85 degrees C compared to those aged at 37 degrees C and unaged controls. These results confirm that microstructural changes occur at high temperatures that do not occur at in vivo temperatures. In addition, water absorption studies demonstrated that water saturation levels increased significantly with temperature. This study highlights that the multiphase morphology of polyurethane precludes the use of temperature accelerated biodegradation for the prediction of clinical performance and provides critical information in designing appropriate in vitro tests for this class of materials. PMID- 24810788 TI - The diagnostic value of DNA methylation in leukemia: a systematic review and meta analysis. AB - BACKGROUND: Accumulating evidence supports a role of DNA methylation in the pathogenesis of leukemia. The aim of our study was to evaluate the potential genes with aberrant DNA methylation in the prediction of leukemia risk by a comprehensive meta-analysis of the published data. METHODS: A series of meta analyses were done among the eligible studies that were harvested after a careful filtration of the searching results from PubMed literature database. Mantel Haenszel odds ratios and 95% confidence intervals were computed for each methylation event assuming the appropriate model. RESULTS: A total of 535 publications were initially retrieved from PubMed literature database. After a three-step filtration, we harvested 41 case-control articles that studied the role of gene methylation in the prediction of leukemia risk. Among the involving 30 genes, 20 genes were shown to be aberrantly methylated in the leukemia patients. A further subgroup meta-analysis by subtype of leukemia showed that CDKN2A, CDKN2B, ID4 genes were significantly hypermethylated in acute myeloid leukemia. CONCLUSIONS: Our meta-analyses identified strong associations between a number of genes with aberrant DNA methylation and leukemia. Further studies should be required to confirm the results in the future. PMID- 24810791 TI - Nanowire antenna absorption probed with time-reversed fourier microscopy. AB - Understanding light absorption in individual nanostructures is crucial for optimizing the light-matter interaction at the nanoscale. Here, we introduce a technique named time-reversed Fourier microscopy that enables the measurement of the angle-dependent light absorption in dilute arrays of uncoupled semiconductor nanowires. Because of their large separation, the nanowires have a response that can be described in terms of individual nanostructures. The geometry of individual nanowires makes them behave as nanoantennas that show a strong interaction with the incident light. The angle-dependent absorption measurements, which are compared to numerical simulations and Mie scattering calculations, show the transition from guided-mode to Mie-resonance absorption in individual nanowires and the relative efficiency of these two absorption mechanisms in the same nanostructures. Mie theory fails to describe the absorption in finite-length vertical nanowires illuminated at small angles with respect to their axis. At these angles, the incident light is efficiently absorbed after being coupled to guided modes. Our findings are relevant for the design of nanowire-based photodetectors and solar cells with an optimum efficiency. PMID- 24810792 TI - Treatment plan complexity metrics for predicting IMRT pre-treatment quality assurance results. AB - The planning of IMRT treatments requires a compromise between dose conformity (complexity) and deliverability. This study investigates established and novel treatment complexity metrics for 122 IMRT beams from prostate treatment plans. The Treatment and Dose Assessor software was used to extract the necessary data from exported treatment plan files and calculate the metrics. For most of the metrics, there was strong overlap between the calculated values for plans that passed and failed their quality assurance (QA) tests. However, statistically significant variation between plans that passed and failed QA measurements was found for the established modulation index and for a novel metric describing the proportion of small apertures in each beam. The 'small aperture score' provided threshold values which successfully distinguished deliverable treatment plans from plans that did not pass QA, with a low false negative rate. PMID- 24810793 TI - The relationship between photoluminescence (PL) decay and crystal growth kinetics in thioglycolic acid (TGA) capped CdTe quantum dots (QDs). AB - The PL lifetime optimization of CdTe QDs capped with TGA has yet to be understood from a perspective of growth kinetics. In this work, the growth kinetics and PL properties of CdTe QDs growing in aqueous solutions of two TGA concentrations, 0 mM and 57 mM, were systematically investigated using UV, TEM, and PL methods. CdTe QDs in 0 mM TGA solution were found to follow the mixed OA (Oriented Attachment)-OR (Ostwald Ripening) growth kinetics. The PL peaks experienced a red shift with almost unchanged intensity and the PL lifetimes increased gradually. In 57 mM TGA solution, the QDs followed the OA dominated growth mechanism. The PL peak broadened greatly with a red-shift and its intensity decreased significantly. The PL lifetime increased much higher than that in 0 mM TGA solution. Based on the different growth kinetic models of the two systems, we suggest that in the low (0 mM) TGA solution, the increased surface defects induced by TGA desorption and the existence of partial internal defects caused by OA growth were the main reasons for the gradual increase of PL lifetime, while in high (57 mM) TGA solution, the increase of PL lifetime was ascribed to the abundant internal defects produced by OA collision. Finally, kinetic data showed the effect of the TGA concentration on crystal growth and PL lifetime of CdTe QDs. The results might provide guidance for understanding the mechanism behind the phenomena of ligand-related PL properties. PMID- 24810794 TI - Level of confidence in venepuncture and knowledge in determining causes of blood sample haemolysis among clinical staff and phlebotomists. AB - AIMS AND OBJECTIVES: To investigate the association between confidence level in venepuncture and knowledge in determining causes of blood sample haemolysis among clinical staff and phlebotomists. BACKGROUND: Various collection methods are used to perform venepuncture, also called phlebotomy, the act of drawing blood from a patient using a needle. The collection method used has an impact on preanalytical blood sample haemolysis. Haemolysis is the breakdown of red blood cells, which makes the sample unsuitable. Despite available evidence on the common causes, extensive literature search showed a lack of published evidence on the association of haemolysis with staff confidence and knowledge. DESIGN: A quantitative primary research design using survey method. METHODS: A purposive sample of 290 clinical staff and phlebotomists conducting venepuncture in one North England hospital participated in this quantitative survey. A three-section web-based questionnaire comprising demographic profile, confidence and competence levels, and knowledge sections was used to collect data in 2012. The chi-squared test for independence was used to compare the distribution of responses for categorical data. anova was used to determine mean difference in the knowledge scores of staff with different confidence levels. RESULTS: Almost 25% clinical staff and phlebotomists participated in the survey. There was an increase in confidence at the last venepuncture among staff of all categories. While doctors' scores were higher compared with healthcare assistants', p <= 0.001, nurses' were of wide range and lowest. There was no statistically significant difference (at the 5% level) in the total knowledge scores and confidence level at the last venepuncture F(2,4.690) = 1.67, p = 0.31 among staff of all categories. CONCLUSION: Evidence-based measures are required to boost staff knowledge base of preanalytical blood sample haemolysis for standardised and quality service. Monitoring and evaluation of the training, conducting and monitoring haemolysis rate are equally crucial. RELEVANCE TO CLINICAL PRACTICE: Although the hospital is succeeding in providing regular training in venepuncture, this is only one aspect of quality. The process and outcome also need interventions. PMID- 24810795 TI - Monitoring the performance of "screen-and-treat" cervical cancer prevention programs. PMID- 24810797 TI - Starting small: using microbiology to foster scientific literacy. AB - In order to achieve scientific literacy for all students, Bard College recently implemented Citizen Science, a common January course for all first-year students. Structured around the question 'how do we reduce the global burden of disease?', this course uses microbiological tools to develop an understanding of potential answers. PMID- 24810796 TI - Is oxygen required before atropine administration in organophosphorus or carbamate pesticide poisoning? - A cohort study. AB - BACKGROUND: Early and adequate atropine administration in organophosphorus (OP) or carbamate insecticide poisoning improves outcome. However, some authors advise that oxygen must be given before atropine due to the risk of inducing ventricular dysrhythmias in hypoxic patients. Because oxygen is frequently unavailable in district hospitals of rural Asia, where the majority of patients with insecticide poisoning present, this guidance has significant implications for patient care. The published evidence for this advice is weak. We therefore performed a patient cohort analysis to look for early cardiac deaths in patients poisoned by anticholinesterase pesticides. METHODS: We analysed a prospective Sri Lankan cohort of OP or carbamate-poisoned patients treated with early atropine without the benefit of oxygen for evidence of early deaths. The incidence of fatal primary cardiac arrests within 3 h of admission was used as a sensitive (but non specific) marker of possible ventricular dysrhythmias. RESULTS: The cohort consisted of 1957 patients. The incidence of a primary cardiac death within 3 h of atropine administration was 4 (0.2%) of 1957 patients. The majority of deaths occurred at a later time point from respiratory complications of poisoning. CONCLUSION: We found no evidence of a high number of early deaths in an observational study of 1957 patients routinely given atropine before oxygen that might support guidance that oxygen must be given before atropine. The published literature indicates that early and rapid administration of atropine during resuscitation is life-saving. Therefore, whether oxygen is available or not, early atropinisation of OP- and carbamate-poisoned patients should be performed. PMID- 24810798 TI - Notch3 signaling is associated with MUC5AC expression and favorable prognosis in patients with small intestinal adenocarcinomas. AB - BACKGROUND: Notch signaling plays diverse roles not only in physiologic processes, including development and differentiation but also in tumorigenesis, either as a tumor promoter or suppressor depending on the cellular context, level of expression and cross-talk with other signaling pathways. In this study we investigated the expression of Notch3 and MUC proteins and their clinicopathological significance in small intestinal adenocarcinoma (SIAC). METHODS: Surgically resected 191 SIACs and their clinical data were collected. Immunohistochemistry for Notch3, MUC2, MUC5AC, and MUC6 using tissue microarrays from formalin-fixed paraffin-embedded normal and matched tumor tissues was performed. RESULTS: Notch3 expression was found in 52 (29.9%) cases of the tumors. MUC2, MUC5AC, and MUC6 were expressed in 52 (27.5%), 51 (31.9%), and 42 (22.0%) cases of the tumor, respectively. Notch3 expression was correlated with the absence of lymphovascular invasion (p=0.009), lower T stage (p=0.038), and histological subtype of tubular adenocarcinoma (p=0.01), respectively. MUC2 was correlated with large tumor size (p=0.013) and mucinous and signet ring cell adenocarcinomas (p=0.01). MUC5A was correlated with proximal tumor location (p<0.0001) and tumor differentiation (p=0.027). MUC6 was correlated with proximal tumor location (p<0.0001) and lower pT stage (p=0.009), and absence of lymphovascular invasion, respectively. A significant correlation was noted between Notch3 and MUC5AC expression (p=0.019). Notch3 expression was a relatively favorable prognostic factor in SIACs by univariate (p=0.05) and multivariate analysis (p=0.08, Cox Hazard ratio 0.841). CONCLUSION: Our findings indicate that Notch3 signaling, associated with MUC5AC expression, could be a more favorable prognostic factor in SIACs. PMID- 24810799 TI - Sexual dysfunction induced by intrathecal baclofen administration: is this the price to pay for severe spasticity management? AB - INTRODUCTION: Intrathecal administration of baclofen (ITB) is widely recognized as an effective treatment for severe spasticity of both spinal and supraspinal origin with fewer side effects. The lower drug dosages used for spinal intrathecal administration, acting directly on the receptor sites, result in greater therapeutic efficacy with less systemic toxicity than with oral preparations. AIM: This study aims to prospectively evaluate the effects of ITB on erectile function in male patients affected by severe spasticity. METHODS: Twenty adult male patients, with a 34.85 +/- 10.27 mean age, affected by severe spasticity mainly due to spinal cord lesions (10 traumatic, three vascular, six degenerative, and one congenital in origin) and treated with ITB, were enrolled in the study. All participants underwent specific clinical scales to evaluate force, muscle tone, cognition and mood, and specific sexual questionnaires, including an accurate semi-structured interview. MAIN OUTCOME MEASURE: The International Index of Erectile Function (IIEF) was used to evaluate sexual function before and after pump implantation. RESULTS: A comparative analysis of the neurological scales and psychometric scores at T1 (baseline) and T2 (follow up) showed statistically significant differences before and after pump implantation. In particular, we noted a significant decrease in the IIEF median scores (from 0.42 +/- 0.07 to 0.14 +/- 0.02, P value < 0.0001) and a correlation between ITB dosage and IIEF scores (rho = -0.60; P < 0.05). CONCLUSIONS: This study supports previous findings on a possible negative effect of ITB on sexual function, with regard to erection. Patients who are considering ITB for treatment of severe spasticity should be informed about possible but reversible sexual side effects, especially at higher dosage. Future studies with larger samples should be fostered to confirm these findings for a better management of these, often young, patients. PMID- 24810800 TI - Driving forces of researchers mobility. AB - Starting from the dataset of the publication corpus of the APS during the period 1955-2009, we reconstruct the individual researchers trajectories, namely the list of the consecutive affiliations for each scholar. Crossing this information with different geographic datasets we embed these trajectories in a spatial framework. Using methods from network theory and complex systems analysis we characterise these patterns in terms of topological network properties and we analyse the dependence of an academic path across different dimensions: the distance between two subsequent positions, the relative importance of the institutions (in terms of number of publications) and some socio-cultural traits. We show that distance is not always a good predictor for the next affiliation while other factors like "the previous steps" of the career of the researchers (in particular the first position) or the linguistic and historical similarity between two countries can have an important impact. Finally we show that the dataset exhibit a memory effect, hence the fate of a career strongly depends from the first two affiliations. PMID- 24810802 TI - Temperature dependence of clusters with attracting vortices in superconducting niobium studied by neutron scattering. AB - We investigated the intermediate mixed state of a superconducting niobium sample using very small angle neutron scattering. We show that this state is stabilized through a sequence where a regular vortex lattice appears, which then coexists with vortex clusters before vanishing at low temperature. Vortices in clusters have a constant periodicity regardless of the applied field and exhibit a temperature dependence close to the one of the penetration depth. The clusters disappear in the high temperature limit. All the results agree with an explanation in terms of vortex attraction due to non-local effects and indicate a negligible role for pinning. Phase coexistence between the Abrikosov vortex lattice and vortex clusters is reported, showing the first-order nature of the boundary line. PMID- 24810801 TI - Identification and expression of troponin T, a new marker on the surface of cultured tumor endothelial cells by aptamer ligand. AB - The identification of a specific biomarker involves the development of new clinical diagnostic tools, and an in-depth understanding of the disease at the molecular level. When new blood vessels form in tumor cells, endothelial cell production is induced, a process that plays a key role in disease progression and metastasis to distinct organs for solid tumor types. The present study reports on the identification of a new biomarker on primary cultured mouse tumor endothelial cells (mTECs) using our recently developed high-affinity DNA aptamer AraHH001 (Kd = 43 nmol/L) assisted proteomics approach. We applied a strategy involving aptamer-facilitated biomarker discovery. Biotin-tagged AraHH001 was incubated with lysates of mTECs and the aptamer-proteins were then conjugated with streptavidin magnetic beads. Finally, the bound proteins were separated by sodiumdodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with silver staining. We identified troponin T via matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, the molecular target of aptamer AraHH001, and its presence was confirmed by measuring mRNA, protein levels, western blot, immunostaining, a gel shift assay of AraHH001 with troponin T. We first report here on the discovery of troponin T on mTECs, a promising and interesting diagnostic tool in the development of antiangiogenic therapy techniques the involves the targeting of the tumor vasculature. PMID- 24810803 TI - "I'm concerned - What Do I Do?" recognition and management of disordered eating in fitness center settings. AB - OBJECTIVE: To examine group fitness instructors' knowledge and attitudes toward identification and management of disordered eating (DE). METHOD: Group fitness instructors representing the three largest fitness center companies in Norway (n = 837, response rate: 57%) completed a questionnaire through Questback (www.questback.com). The questionnaire contained items regarding gender, age, educational background, exercise behavior, and knowledge of recognition and response to DE. RESULTS: Eighty-nine percent of the respondents reported knowledge about symptoms of DE, 29% was classified with adequate DE knowledge skills. Forty-nine percent of the instructors reported current concern about DE among one or more members, 47% reported knowledge about how to recognize and respond to DE, and 37% reported knowledge about their fitness center's guidelines for approaching DE concerns. The level of formal education in sports and exercise, and a history of self-reported eating disorder, but not fitness instructor experience, were explanatory factors for knowledge about DE symptoms. Both exercise specific educational level and instructor experience were explanatory variables for knowledge about recognition of and response to DE concerns. DISCUSSION: Implications of the findings include a need for increased confidence among group fitness instructors regarding how to approach DE concerns, increased awareness of excessive/compulsive exercise as a symptom of DE, and enhanced dissemination of existing guidelines for managing DE concerns among members and/or staff. PMID- 24810804 TI - Risk factors for surgical site infection in emergency colorectal surgery: a retrospective analysis. AB - BACKGROUND: Since 2005, we have been conducting prospective surgical site infection (SSI) surveillance and infection control according to the U.S. Centers for Disease Control and Prevention guidelines for patients who undergo gastrointestinal surgery at our institution. Surgical site infection occurs with greater frequency in emergency than in elective surgery because of factors such as ill-conceived preoperative preparation and "dirty" operations. A large number of studies have been reported on risk factors for SSI in elective colorectal surgery; however, there are few papers on such factors in emergency colorectal surgery. The aim of this study was to identify risk factors for incisional SSI in emergency colorectal surgery. METHODS: Using our SSI surveillance database, we analyzed retrospectively 78 patients who underwent emergency colorectal surgery between 2005 and 2010. Univariable and multivariable analyses were used to identify risk factors for incisional SSI. Moreover, we subclassified dirty infected operations (class IV) by the extent of contamination according to our own definition to study the incidence of incisional SSI at each degree. RESULTS: The incidence of incisional SSI was 32.1% (25/78 patients). By univariable analysis, seven parameters correlated with a higher risk of incisional SSI: Surgical incision class III-IV, obesity (body mass index >=25 kg/m(2)), American Society of Anesthesiologists score 3 or 4 points, chronic kidney disease (serum creatinine concentration >1.2 mg/dL), blood loss >=200 mL, blood transfusion, and ventilator support. Multivariable analyses showed that surgical incision class III-IV (odds ratio [OR] 5.9; 95% confidence interval [CI] 1.7, 25.2) and obesity (OR 11.9; 95% CI 2.1, 87.8) were independent risk factors for incisional SSI. The incidence of incisional SSI in colon perforation with generalized contamination was statistically higher than that in prepared colon perforation and colon perforation with localized contamination (82.4% vs. 25.0%; p<0.001). CONCLUSIONS: The risk factors for incisional SSI in emergency colorectal surgery were incision contamination and obesity. Moreover, the incidence of incisional SSI among the incision class IV operations increased significantly with increasing extents of contamination. As a tactic for management of dirty abdominal wounds, we suggest that primary skin closure is suitable in cases of perforation of a prepared colon or colon perforation with localized contamination. On the other hand, in cases of colon perforation with generalized contamination, delayed primary skin closure or leaving an incision open to heal by secondary intention should be considered. PMID- 24810805 TI - Comparative study on the antioxidant and anti-Toxoplasma activities of vanillin and its resorcinarene derivative. AB - A resorcinarene derivative of vanillin, resvan, was synthesized and characterized by spectroscopic techniques. We measured the cytotoxicity (in vivo and in vitro), antioxidant and anti-Toxoplasma activities of vanillin and the resorcinarene compound. Here we show that vanillin has a dose-dependent behavior with IC50 of 645 ug/mL through an in vitro cytotoxicity assay. However, we could not observe any cytotoxic response at higher concentrations of resvan (IC50 > 2,000 ug/mL). The in vivo acute toxicity assays of vanillin and resvan exhibited a significant safety margin indicated by a lack of systemic and behavioral toxicity up to 300 mg/kg during the first 30 min, 24 h or 14 days after administration. The obtained derivative showed greater antioxidative activity (84.9%) when comparing to vanillin (19.4%) at 1,000 MUg/mL. In addition, vanillin presents anti-Toxoplasma activity, while resvan does not show that feature. Our findings suggest that this particular derivative has an efficient antioxidant activity and a negligible cytotoxic effect, making it a potential target for further biological investigations. PMID- 24810806 TI - Use of a new retrograde filling material (Biodentine) for endodontic surgery: two case reports. AB - Mineral trioxide aggregate (MTA) is considered at the present time as the gold standard for root-end filling in endodontic surgery. However, this biocompatible material presents several drawbacks such as a long setting time and handling difficulties. The aim of this article is to present a new commercialized calcium silicate-based material named Biodentine with physical improved properties compared to MTA in a clinical application. Two endodontic microsurgeries were performed by using specific armamentarium (microsurgical instrumentation, ultrasonic tips) under high-power magnification with an operatory microscope. Biodentine was used as a root-end filling in order to seal the root canal system. The two cases were considered completely healed at 1 year and were followed for one more year. The 2-year follow-up consolidated the previous observation with absence of clinical symptoms and radiographic evidence of regeneration of the periapical tissues. PMID- 24810807 TI - Anti-proteolytic capacity and bonding durability of proanthocyanidin-biomodified demineralized dentin matrix. AB - Our previous studies showed that biomodification of demineralized dentin collagen with proanthocyanidin (PA) for a clinically practical duration improves the mechanical properties of the dentin matrix and the immediate resin-dentin bond strength. The present study sought to evaluate the ability of PA biomodification to reduce collagenase-induced biodegradation of demineralized dentin matrix and dentin/adhesive interfaces in a clinically relevant manner. The effects of collagenolytic and gelatinolytic activity on PA-biomodified demineralized dentin matrix were analysed by hydroxyproline assay and gelatin zymography. Then, resin /dentin-bonded specimens were prepared and challenged with bacterial collagenases. Dentin treated with 2% chlorhexidine and untreated dentin were used as a positive and negative control, respectively. Collagen biodegradation, the microtensile bond strengths of bonded specimens and the micromorphologies of the fractured interfaces were assessed. The results revealed that both collagenolytic and gelatinolytic activity on demineralized dentin were notably inhibited in the PA-biomodified groups, irrespective of PA concentration and biomodification duration. When challenged with exogenous collagenases, PA-biomodified bonded specimens exhibited significantly less biodegradation and maintained higher bond strengths than the untreated control. These results suggest that PA biomodification was effective at inhibiting proteolytic activity on demineralized dentin matrix and at stabilizing the adhesive/dentin interface against enzymatic degradation, is a new concept that has the potential to improve bonding durability. PMID- 24810809 TI - Pseudarthrosis of the clavicle. AB - A 21-year-old active duty soldier presented with right shoulder pain and prominence over his right clavicle, with no history of trauma. He recalled that the deformity had been present for a long time, but only recently became painful. The onset of shoulder pain coincided with the beginning of his military service and the requirement to wear over-the-shoulder equipment such as back packs and load-bearing equipment. Physical examination revealed a prominence over the right midshaft clavicle with tenderness to palpation, full active range of motion of the shoulder, and that he was neurovascularly intact. PMID- 24810808 TI - Bone marrow-derived mesenchymal stem cells migrate to healthy and damaged salivary glands following stem cell infusion. AB - Xerostomia is a severe side effect of radiation therapy in head and neck cancer patients. To date, no satisfactory treatment option has been established. Because mesenchymal stem cells (MSCs) have been identified as a potential treatment modality, we aimed to evaluate stem cell distribution following intravenous and intraglandular injections using a surgical model of salivary gland damage and to analyse the effects of MSC injections on the recruitment of immune cells. The submandibular gland ducts of rats were surgically ligated. Syngeneic adult MSCs were isolated, immortalised by simian virus 40 (SV40) large T antigen and characterized by flow cytometry. MSCs were injected intravenously and intraglandularly. After 1, 3 and 7 days, the organs of interest were analysed for stem cell recruitment. Inflammation was analysed by immunohistochemical staining. We were able to demonstrate that, after intravenous injection, MSCs were recruited to normal and damaged submandibular glands on days 1, 3 and 7. Unexpectedly, stem cells were recruited to ligated and non-ligated glands in a comparable manner. After intraglandular injection of MSCs into ligated glands, the presence of MSCs, leucocytes and macrophages was enhanced, compared to intravenous injection of stem cells. Our data suggest that injected MSCs were retained within the inflamed glands, could become activated and subsequently recruited leucocytes to the sites of tissue damage. PMID- 24810810 TI - Prediction of prognosis in patients with cervical spinal cord injury without radiologic evidence of trauma using MRI. PMID- 24810811 TI - What do we (not) know about antibiotic-loaded hip spacers? PMID- 24810812 TI - Elbow arthrodesis: a novel technique and review of the literature. AB - The elbow is a complex joint that is the mechanical link in the upper extremity between the hand and the shoulder. Loss of elbow function can severely affect activities of daily living. Arthrodesis of the elbow results in greater functional disability than arthrodesis of the ankle, hip, or knee joints. Arthrodesis is mainly performed for severe joint destruction most commonly due to posttraumatic arthrosis, instability, or infection. The authors describe a new technique of elbow arthrodesis using a step-cut osteotomy that has not been previously reported. They believe that this can increase the surface area for healing with the outcome of a higher fusion rate. It is most important, however, to achieve good compression with lag screws across the fusion site after the desired angled has been achieved. Elbow arthrodesis is not a common orthopedic procedure, but the authors believe that their novel technique provides a reproducible and reliable way to achieve a high fusion rate and desired fusion angle. PMID- 24810813 TI - Arthrometric stability of horizontal versus vertical single-bundle arthroscopic anterior cruciate ligament reconstruction. AB - The anteroposterior (AP) stability of standard anterior cruciate ligament (ACL) reconstruction, referred to as "vertical," was compared with that of a modified femoral position, referred to as "horizontal," which is lower than and anterior to an operative knee at 90 degrees flexion. Two consecutive series of 50 patients underwent vertical and horizontal arthroscopic single-bundle ACL reconstruction, respectively. For vertical reconstruction, the clock position was chosen, placing the graft at 10:30 in right knees and 1:30 in left knees, 1 to 2 mm anterior to the posterior femoral cortical cortex and at the back of the resident ridge. In the horizontal reconstruction, the transplant replaced the original ligament insertion at approximately the 9:30 o'clock position in right knees and the 2:30 o'clock position in left knees, approximately 2 mm in front of the posterior femoral cortical cortex. One year after surgery, the results of stabilometric evaluation revealed good performance after horizontal transplant. The mean clinical results changed from 1.0 (+/-1.3) mm for vertical to 0.7 (+/ 1.3) mm for horizontal reconstruction. PMID- 24810814 TI - Pediatric anterior cruciate ligament reconstruction using low-profile hybrid tibial fixation. AB - The authors introduce the application of a low-profile hybrid fixation technique for pediatric anterior cruciate ligament graft fixation into the tibia using both an interference screw and knotless anchors. This technique allows for physeal avoidance while maintaining fixation strength. PMID- 24810815 TI - Evaluation of the cellular origins of heterotopic ossification. AB - Heterotopic ossification (HO), acquired or hereditary, is featured by the formation of bone outside of the normal skeleton. Typical acquired HO is a common, debilitating condition associated with traumatic events. Cardiovascular calcification, an atypical form of acquired HO, is prevalent and associated with high rates of cardiovascular mortality. Hereditary HO syndromes, such as fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, are rare, progressive, life-threatening disorders. The cellular origins of HO remain elusive. Some bona fide contributing cell populations have been found through genetic lineage tracing and other experiments in vivo, and various other candidate populations have been proposed. Nevertheless, because of the difficulties in establishing cellular phenotypes in vivo and other confounding factors, the true identities of these populations are still uncertain. This review critically evaluates the accumulating data in the field. The major focus is on the candidate populations that may give rise to osteochondrogenic lineage cells directly, not the populations that may contribute to HO indirectly. This issue is important not solely because of the clinical implications, but also because it highlights the basic biological processes that govern bone formation. PMID- 24810816 TI - Operative versus nonoperative treatment in complex proximal humeral fractures. AB - This updated meta-analysis investigated whether operative treatment is superior to nonoperative treatment in complex proximal humeral fractures. The authors searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. Randomized controlled trials that evaluated operative vs nonoperative treatment for exclusively 3- or 4-part proximal humeral fractures were considered. Six studies with a total of 287 patients who had proximal humeral fractures were included. According to the meta-analysis, no statistically significant differences were found between operative and nonoperative treatment in Constant Murley shoulder scores (Constant scores); Disabilities of the Arm, Shoulder, and Hand scores; total complication events; mortality; infection; nonunion; avascular necrosis; osteoarthritis; redisplacement of fractures; or dislocation or resorption of tuberosity. For health-related quality of life, EuroQol-5D (EQ-5D) favored operative treatment, but 15D scores showed no significant difference. Compared with nonoperative treatment, open reduction and internal fixation required significantly more additional surgeries (risk ratio, 6.50; 95% confidence interval, 1.54-27.50; P=.01), and more penetrations into joint space occurred (risk ratio, 9.56; 95% confidence interval, 2.27-40.13; P=.002). The limited evidence suggests that no convincing findings support the use of either open reduction and internal fixation or hemiarthroplasty for the treatment of complex proximal humeral fractures. The findings of the current study should be interpreted cautiously because of the modest sample size and the short follow-up period. PMID- 24810817 TI - Deviation analysis of atlantoaxial pedicle screws assisted by a drill template. AB - Although C1-C2 pedicle screw fixation provides an excellent fusion rate and rigid fixation, this technique has a potential risk. It is essential to develop an accurate screwing method to avoid this neurovascular injury. To develop and validate the accuracy of a novel navigational template for C1-C2 pedicle screw placement in cadaveric specimens, computed tomography scans with 1-mm-wide cuts were obtained of 32 cadaveric cervical specimens. The authors developed 64 three dimensional full-scale templates that were created by computer modeling with a rapid prototyping technique from the computed tomography data. Drill templates were constructed with a custom trajectory for each level and side. The drill templates were used to guide the establishment of a pilot hole for screw placement. The average distances between ideal and actual entry points of the C1 pedicle screws in the x, y, and z axes were 0.16+/-0.46 mm, 0.11+/-0.52 mm, and 0.01+/-0.54 mm, respectively, on the left side and 0.11+/-0.49 mm, 0.01+/-0.56 mm, and -0.09+/-0.59 mm, respectively, on the right side. The average distances between ideal and actual entry points of the C2 pedicle screws in the x, y, and z axes were 0.05+/-0.54 mm, 0.20+/-0.59 mm, and -0.06+/-0.58 mm, respectively, on the left side and 0.17+/-0.55 mm, 0.1+/-0.58 mm, and -0.01+/-0.49 mm, respectively, on the right side. Factors related to human error and imprecision are responsible for most malpositioning of instrumentation. The rapid prototyping drill template for C1-C2 screw placement is described to minimize human error, although it introduces error related to computer software and variation in manufacturing. PMID- 24810818 TI - Bupivacaine for pain reduction after iliac crest bone graft harvest. AB - Iliac crest bone graft remains the gold standard in achieving spinal arthrodesis, but chronic pain from graft harvest occurs in up to 39% of patients. Studies have shown that a single administration of local anesthetic reduces short-term pain, but they have not adequately investigated possible longer-term benefits. The goal of this study was to determine whether local administration of bupivacaine after iliac crest bone graft harvesting reduces pain and improves patient-reported outcomes. In this prospective, randomized, controlled, and blinded clinical study, 40 patients were identified who underwent posterior spine fusion with iliac crest bone graft and were randomized to receive either bupivacaine (treatment group, n=20) or saline (control group, n=20) at the iliac crest bone graft site. Pain at the harvest site was determined by a series of 12 visual and numeric pain scale assessments. Short Form-12 mental and physical component scores, EuroQol-5D, and Oswestry Disability Index assessments were made, along with determination of patient satisfaction and self-reported outcome of surgery. Baseline pain and outcome assessments were statistically similar (P>.05). Average pain scores were lower for all 12 assessments in the treatment group at mean follow-up of 5 weeks (significant differences in 6 assessments) and 20 weeks (significant differences in 2 assessments). No significant differences were found in Short Form-12 and EuroQol-5D scores. For patients who underwent lumbar fusion, the treatment group had significantly improved Oswestry Disability Index scores (mean+/-SD=10.8+/-7.1 vs 18.7+/-5.9, P=.012). Significantly more patients in the treatment group reported that surgery met all expectations (90% vs 50%, P=.016). This study is the 1st to show that a single administration of bupivacaine at the iliac crest bone graft harvest site during posterior spine fusion surgery can result in improved outcomes and reduced pain far beyond the anesthetic duration of activity. PMID- 24810819 TI - Posterior iliac crescent fracture-dislocation: is it only rotationally unstable? AB - Posterior iliac crescent fracture-dislocation is generally considered rotationally unstable and vertically stable. The current study (1) investigated whether vertical instability may occur in posterior iliac crescent fracture dislocation and (2) analyzed the clinical features of vertically unstable iliac crescent fracture-dislocation as well as treatment strategies. Patients with pelvic fracture who were treated in the authors' department from June 2009 to June 2012 were retrospectively reviewed. This study analyzed the clinical features, including incidence, hemodynamic state, associated injuries, injury severity score, and treatment methods for vertically unstable iliac crescent fracture-dislocation. Four patients had vertically unstable fracture-dislocation, accounting for 12.9% of all iliac crescent fracture-dislocations. All 4 patients were hemodynamically unstable on admission and had complications of associated injuries with a higher injury severity score. In 3 of the 4 patients, iliac crescent fracture-dislocations were reduced via the posterior approach at the initial stage and these patients underwent fixation with a plate. The remaining patient was initially given transcondylar traction because of severe complications and underwent open reduction and internal fixation (ORIF) via a posterior approach at a later stage. The outcomes of all 4 patients were rated as good or excellent by the Kobbe rating system at the last follow-up. Vertical instability may occur in iliac crescent fracture-dislocation. The authors propose ORIF of the fracture-dislocation via a posterior approach. When initial surgery is not possible because of severe associated organ injuries, the authors propose transcondylar traction to allow reduction of the sacroiliac joint and ORIF at a later stage. PMID- 24810820 TI - Finite element analysis of 3 posterior fixation techniques in the lumbar spine. AB - This study compared the biomechanics of 3 fixation techniques: bilateral pedicle screw (BPS) fixation, unilateral pedicle screw (UPS) fixation, and UPS supplemented with translaminar facet screw (UPS+TLFS) fixation. The study was conducted in an L3-L5 finite element model. Three different finite element models were created by adopting different fixation techniques after removal of the left L3-L4 and L4-L5 facet joints. A 500-N compressive preload combined with 8-NM moment were applied in 3 finite element models with 3 fixation techniques during different movements. Angular displacement and stress distribution were recorded. As described in this article, the UPS model had the most variation in angular displacement, the BPS model was intermediate, and the UPS+TLFS model had the least mobility. Most of the stress accumulated on the body and tail of the pedicle screws and the connecting rods in the UPS and BPS models, but stress accumulated on the rods and the part of the facet joint pierced by the TLFS in the UPS+TLFS model. The middle part of the pedicle screw endured little stress compared with the upper and lower parts. The maximum stress on the fixation devices was highest in the UPS model. The maximum stress in the UPS+TLFS model was the lowest among the 3 models. Biomechanically, UPS+TLFS fixation is superior to either UPS fixation or BPS fixation in improving stability and reducing stress. Bilateral pedicle screw fixation is intermediate, and UPS fixation is inferior. PMID- 24810821 TI - Relationship among radiographic ankle medial clear space, sex, and height. AB - The ankle medial clear space (MCS) is frequently measured to evaluate ankle stability after an injury. However, controversy exists regarding a threshold size that distinguishes a normal MCS from an abnormal MCS. A retrospective radiographic review of mortise ankle radiographs in the uninjured ankle was performed, with the goal of defining the relationship among patient height, sex, and radiographic ankle MCS. Forty-nine patients with normal mortise radiographs and with information on patient height available in the electronic medical chart were identified for inclusion. For men, mean+/-standard deviation (in millimeters) was 3.3+/-0.8 for MCS perpendicular (MCSp), 3.8+/-0.7 for MCS oblique (MCSo), and 3.8+/-0.5 for superior clear space (SCS). For women, mean+/ standard deviation was 2.3+/-0.6 for MCSp, 2.9+/-0.5 for MCSo, and 3+/-0.4 for SCS. Univariate analysis showed that all 3 variables (MCSp, MCSo, and SCS) were statistically different when men were compared with women (P<.0001). Bivariate regression models showed statistically significant (P<.001) positive relationships between each of the measures of clear space and height. In multivariate analysis, female sex alone was associated with a decrease in clear space. When evaluating isolated lateral malleolus fractures, clinicians should consider the patient's height and sex when measuring MCS and SCS to determine deltoid ligament competence. These data suggest that men and people of tall stature are at risk for a false-positive diagnosis of deltoid ligament rupture when previously published threshold MCS and SCS values, such as 4 mm or 5 mm, are used for diagnosis and operative indication. PMID- 24810822 TI - Exposure of the distal humerus using a triceps hemi-peel approach. AB - This study evaluates the exposure of the distal humerus articular surface obtained using a triceps hemi-peel approach versus the triceps-flexor carpi ulnaris (TRIFCU) approach. Twelve cadaveric upper extremity specimens were dissected using a lateral-to-medial hemi-peel modification of the TRIFCU approach to the elbow. After completing the hemi-peel exposure, the visible border of the articular surface was marked with a permanent ink pen. The dissection was continued to complete a standard TRIFCU approach, and the visible border of the exposure was again marked. The elbow was disarticulated, and calibrated digital images were taken to quantify the humeral surface area exposed through each approach. During both approaches, the surgeon's ability to visualize the intertrochlear groove, medial crista anterior crest, medial crista posterior crest, anterior capitulum, and posterior capitulum was recorded. No difference was found in the surgeons' ability to identify the 5 designated anatomic landmarks using the hemi-peel versus the TRIFCU approach. The TRIFCU exposed an average of 6.68 cm(2) of the trochlear articular surface, whereas the hemi-peel approach exposed an average of 5.93 cm(2). The average difference between the exposures was 0.75 cm(2) (P<.001), or 12.5%. The hemi-peel and TRIFCU approaches to the elbow both allow excellent visualization of the distal humerus articular surface. The hemi-peel exposure is a useful approach for the accurate reduction and fixation of displaced intra-articular distal humerus fractures. PMID- 24810823 TI - Tissue levels of leukemia inhibitory factor vary by osteoarthritis grade. AB - The objective of this study was to observe the expression of leukemia inhibitory factor (LIF) in animals and in different clinical grades of patient osteoarthritic tissues. Thirty-five rabbits were used in a Colombo model of experimental osteoarthritis (OA). Five rabbits each were sacrificed on postoperative days 3, 7, 14, 28, 42, 56, and 84. Immunohistochemistry analysis for LIF expression and distribution in the cartilage and synovium of animals was performed at these times. Sixty-seven samples of human articular tissue were obtained from patients with different grades of OA according to symptoms and radiographic inspection. The mRNA expression of LIF was determined by reverse transcription polymerase chain reaction, and LIF protein was determined by enzyme linked immunosorbent assay (ELISA). The results showed a slight expression of LIF in normal cartilage tissue but less in synovium tissue; however, the expression of LIF was marked in synovial lining cells and superficial and middle-layer cartilage in animal OA (P<.05). Leukemia inhibitory factor mRNA was expressed at the highest level in moderate degrading subchondral bone, and LIF was expressed at the highest level in seriously degrading articular cartilage tissue. These results were similar to those found with ELISA. This study suggests that LIF in OA articular tissues varies by clinical symptoms and grade. It plays an important role in the pathogenesis of OA. PMID- 24810824 TI - Anterior longitudinal decompression in the management of severe ossification of the posterior longitudinal ligament in the cervical spine. AB - The advantages of anterior surgery for severe ossification of the posterior longitudinal ligament in the cervical spine have been reported. However, it is more technically demanding and associated with a high risk of surgery-related complications. The purpose of this study was to evaluate the feasibility of longitudinal decompression techniques in anterior surgery for severe ossification of the posterior longitudinal ligament in the cervical spine. Between June 2008 and December 2011, twenty-two patients (16 men and 6 women; average age, 58 years [range, 45-72 years]) who underwent anterior corpectomy and fusion for severe ossification of the posterior longitudinal ligament were studied retrospectively. The clinical efficacy, canal narrowing ratio, fused segment height, and complications were investigated. After a mean 25.4-month follow-up, mean Japanese Orthopaedic Association score increased from 8.8+/-1.4 preoperatively to 14.0+/ 1.2 at final follow-up (P<.05), an improvement rate of 63.5%+/-12.5%. Mean canal narrowing ratio decreased from 62.0%+/-6.0% preoperatively to 8.2%+/-4.9% postoperatively (P<.05). Mean fused segment height increased 2.3+/-0.5 mm from pre- to postoperatively and decreased 2.8+/-0.4 mm from postoperatively to final follow-up (P>.05). Five patients developed cerebrospinal fluid leakage, and 1 patient experienced hematoma. No instrument failure was observed, and all patients had successful fusion. Anterior longitudinal decompression is a relatively effective procedure in the management of severe ossification of the posterior longitudinal ligament in the cervical spine. It can be applied to treat closed-base ossification of the posterior longitudinal ligament (defined as no space between the lateral margin of the ossified base and the spinal canal lateral wall), but it is associated with a high risk of cerebrospinal fluid leakage. PMID- 24810825 TI - Use of a bipolar sealer in total hip arthroplasty: medical resource use and costs using a hospital administrative database. AB - Perioperative blood loss during total hip arthroplasty (THA) increases patient morbidity, length of stay (LOS), medical resource use (MRU), and costs. Minimizing blood loss may reduce postoperative anemia, the need for blood transfusions, and the increased risk of infections and longer hospital stays associated with blood transfusions. Pharmacologic agents and bipolar sealer devices can minimize perioperative bleeding. A retrospective, comparative cohort study in the US hospital setting was conducted to assess MRU and associated costs and the incidence of transfusion and complications among patients undergoing THA with or without the use of a bipolar sealer. Using a nationwide all-payer hospital administrative database, THA procedures from January 1, 2008, to March 31, 2011, were identified using International Classification of Diseases, Ninth Revision, Clinical Modification procedure code 81.51. The bipolar sealer cohort (n=2683) and matched control cohort (n=2683) had a mean age of 65 years from 38 hospitals. The 2 groups had similar incidences of pre-operative anemia and medical comorbidities. Patients in the bipolar sealer group required significantly fewer blood transfusions (21.3% vs 23.8%; P=.0286) and had significantly lower incidence of hematomas (0.2% vs 0.9%; P=.0015) and significantly shorter LOS (2.90 vs 3.31 days; P<.0001) overall. The bipolar sealer group had higher supply costs, which were offset by reduced hospital inpatient room and board and operating room costs; there was no significant difference in total hospital costs between the 2 groups ($18,937 vs $18,734; P=.56). A bipolar sealer decreases postoperative blood transfusions and LOS during primary THA without increasing total hospital costs. PMID- 24810826 TI - Arthroscopic lysis of adhesions for the stiff total knee: results after failed manipulation. AB - Arthrofibrosis after total knee arthroplasty (TKA) is a potentially devastating complication, resulting in loss of motion and function and residual pain. For patients in whom aggressive physical therapy and manipulation under anesthesia fail, lysis of adhesions may be the only option to rescue the stiff TKA. The purpose of this study is to report the results of arthroscopic lysis of adhesions after failed manipulation for a stiff, cruciate-substituting TKA. This retrospective study evaluated patients who had undergone arthroscopic lysis of adhesions for arthrofibrosis after TKA between 2007 and 2011. Minimum follow-up was 12 months (average, 31 months). Average total range of motion of patients in this series was 62.3 degrees . Average preoperative flexion contracture was 16 degrees and average flexion was 78.6 degrees . Statistical analysis was performed using Student's t test. Pre- to postoperative increase in range of motion was significant (P<.001) (average, 62 degrees preoperatively to 98 degrees postoperatively). Average preoperative extension deficit was 16 degrees , which was reduced to 4 degrees at final follow-up. This value was also found to be statistically significant (P<.0001). With regard to ultimate flexion attained, average preoperative flexion was 79 degrees , which was improved to 103 degrees at final follow-up. This improvement in flexion was statistically significant (P<.0001). Patients can reliably expect an improvement after arthroscopic lysis of adhesions for a stiff TKA using a standardized arthroscopic approach; however, patients achieved approximately half of the improvement that was obtained at the time of surgery. PMID- 24810827 TI - Three intraoperative methods to determine limb-length discrepancy in THA. AB - Limb-length discrepancy (LLD) is a common concern for both surgeon and patient in the setting of elective total hip arthroplasty (THA). There is a paucity of evidence guiding surgeons to an optimal method for measuring intraoperative LLD and minimizing postoperative LLD. The primary objective of this prospective, randomized, double-blinded study was to determine which of 3 intraoperative methods used at the authors' institution was best correlated to postoperative radiographic LLD. From 2011 to 2012, 81 patients undergoing either primary (75) or revision (6) THA with an anterolateral (Watson-Jones) approach were prospectively randomized and received intraoperative measurement of LLD via 1 of 3 methods: abductor shuck (AS), tranosseous pins with calibrated caliper (TP), or patella electrocardiogram (EKG) leads (PL). Intraoperative measurements of LLD were compared to clinical and radiographic postoperative measurements of LLD, and absolute differences and correlation coefficients were calculated for each method. Overall, the mean LLD preoperatively was 8.09 mm, and mean radiographic LLD postoperatively was 4.20 mm. The AS method was associated with the highest correlation to postoperative radiographic LLD (R=0.360; P<.05), whereas the other methods had mildly positive but statistically insignificant correlations (TP R=0.275; P>.05; PL R=0.301; P>.05). The AS method best correlates to postoperative radiographic LLD among the 3 techniques, although all methods were positively correlated. Clinical measurements of LLD correlate poorly with radiographic measurements and may be of limited utility. PMID- 24810828 TI - Arthroscopic treatment of femoral nerve paresthesia caused by an acetabular paralabral cyst. AB - This report describes a rare case of femoral nerve paresthesia caused by an acetabular paralabral cyst of the hip joint. A 68-year-old woman presented with a 6-month history of right hip pain and paresthesia along the anterior thigh and radiating down to the anterior aspect of the knee. Radiography showed osteoarthritis with a narrowed joint space in the right hip joint. Magnetic resonance imaging showed a cyst with low T1- and high T2-weighted signal intensity arising from a labral tear at the anterior aspect of the acetabulum. The cyst was connected to the joint space and displaced the femoral nerve to the anteromedial side. The lesion was diagnosed as an acetabular paralabral cyst causing femoral neuropathy. Because the main symptom was femoral nerve paresthesia and the patient desired a less invasive procedure, arthroscopic labral repair was performed to stop synovial fluid flow to the paralabral cyst that was causing the femoral nerve paresthesia. After surgery, the cyst and femoral nerve paresthesia disappeared. At the 18-month follow-up, the patient had no recurrence. There have been several reports of neurovascular compression caused by the cyst around the hip joint. To the authors' knowledge, only 3 cases of acetabular paralabral cysts causing sciatica have been reported. The current patient appears to represent a rare case of an acetabular paralabral cyst causing femoral nerve paresthesia. The authors suggest that arthroscopic labral repair for an acetabular paralabral cyst causing neuropathy can be an option for patients who desire a less invasive procedure. PMID- 24810829 TI - Chondroblastoma with secondary aneurysmal bone cyst of the capitate. AB - Chondroblastoma is a benign tumor that typically arises in the epiphysis of a long bone. There have been only 2 reported cases of chondroblastoma involving the capitate. This is the first report of chondroblastoma with secondary aneurysmal bone cyst involving the capitate. A 33-year-old man presented with a 3-year history of pain and swelling of the right wrist. Radiography as well as computed tomography showed a radiolucent area and no matrix calcification within the capitate. Magnetic resonance imaging revealed a homogeneous signal that was low on T1-weighted images and high on T2-weighted images and showed only slight enhancement. On the basis of imaging findings, the authors chose excisional biopsy. The bone tumor in the capitate was explored through a dorsal approach by dividing the extensor tendons. After repeated curettages, bone graft substitute using allograft bone was packed into the capitate. Histologically, the authors diagnosed this tumor as a chondroblastoma with a secondary aneurysmal bone cyst. At the final 2-year follow-up, there was evidence of bone union, full range of motion, and recovery and no evidence of recurrence. Although the recurrence of chondroblastoma is occasionally reported, the principal treatment is intralesional curettage and bone graft. High-speed burring, phenol, bone cement, and cryosurgery have been reported to reduce local recurrence. Complete excision of the carpal bone seems to be overtreatment. PMID- 24810830 TI - Chondroblastoma of the distal phalanx. AB - Chondroblastoma is a rare, benign primary bone tumor that usually occurs at the epiphysis of long bones. The authors present an example of the diagnosis and successful treatment of this neoplasm in an exceedingly rare location in the distal phalanx. Clinical and radiographic outcomes after 68 months of follow-up are presented. A 15-year-old, right hand-dominant, boy developed painful swelling of the right ring finger. Radiographs revealed a radiolucent lesion of the distal phalanx with expansile remodeling of the bone. An excisional biopsy was performed with curettage and bone grafting of the lesion. The diagnosis of chondroblastoma was made based on pathologic evaluation of the biopsy specimen. Sixty-six months after surgical treatment, the patient was free of recurrence and metastatic disease with excellent clinical and functional outcomes. To the authors' knowledge, this represents only the second reported case of chondroblastoma of the distal phalanx. The diagnosis of chondroblastoma in this rare location was made by pathologic review of the resection specimen. It is imperative to confirm the diagnosis of any resected bone specimen even when the concern for an aggressive or malignant lesion is low. A tumor presenting in an unusual location may require a change in treatment or surveillance. PMID- 24810831 TI - Unilateral adrenal hemorrhage after total knee arthroplasty. AB - Adrenal hemorrhage (AH) is a rare but serious condition that is often diagnosed at autopsy. Unilateral adrenal hemorrhage (UAH) in adults is extremely rare and is often due to trauma or anticoagulation or is associated with systemic illness. The case of a 73-year-old man who was diagnosed with UAH several days after an elective total knee replacement is presented. The patient had an uncomplicated procedure and he was treated postoperatively with a prophylactic dose of subcutaneous low-molecular- weight heparin and compression sleeves. On postoperative day 8, he reported sustained epigastric and midback pain at the lower thoracic level. He had a temperature of 38.5 degrees C. On clinical examination, the patient expressed only mild tenderness at the lumbar area. Abdominal ultrasound and computed tomography (CT) scan were inconclusive. On postoperative day 13, the patient experienced no pain but remained febrile. An abdominal CT scan revealed a high-density mass on the left adrenal gland suggestive of hemorrhage. The subcutaneous heparin as well as the antimicrobial therapy was discontinued and a serum cortisol examination was done. Serum levels were within normal values in the evening and the morning. On postoperative day 16, all laboratory values returned to normal and the patient was discharged in excellent condition. Patients who have abdominal pain, hypotension, or both soon after initiation of anticoagulation or patients who experience abdominal pain, fever, nausea, or confusion postoperatively should be screened for AH. PMID- 24810832 TI - Fibrosarcoma development 15 years after curettage and bone grafting of giant cell tumor of bone. AB - Malignant transformation of conventional giant cell tumor of bone is rare and usually occurs with irradiation. This article describes a case of malignant transformation of a giant cell tumor 15 years after initial curettage and bone graft. A 35-year-old man was admitted to the hospital with a recurrent giant cell tumor of the distal femur. On presentation, the patient reported the insidious onset of a dull aching pain in the distal part of the left thigh 4 months prior to admission. Radiographs revealed a destructive lesion in the left distal femur. Needle biopsy revealed recurrence of giant cell tumor with suspected malignant transformation. The patient underwent en bloc resection of the distal femur with adequately wide margins and reconstruction of the knee joint with a prosthesis. Pathological findings showed malignant transformation of a giant cell tumor to high-grade spindle cell sarcoma. Immunohistochemistry showed diffuse and strong p53 expression. A diagnosis of secondary fibrosarcoma was made after discussion. Unfortunately, the tumor proved to be highly resistant to the chemotherapy, and the patient died of multiple lung metastases 14 months after the diagnosis of malignant transformation. What has to be stressed in this case is that any late recurrence must be approached considering the possibility of a secondary induced primary tumor. Because of the rarity of this disease, the effective therapeutic strategy for fibrosarcoma secondary to giant cell tumor is lacking. In addition, identification of the p53 mutation may help in diagnosing cases of potential malignant transformation of giant cell tumor. PMID- 24810833 TI - Occupational asbestos exposure and risk of oral cavity and pharyngeal cancer in the prospective Netherlands Cohort Study. AB - OBJECTIVES: The evidence for an association between occupational asbestos exposure and pharyngeal cancer (PhC) is limited, while for oral cavity cancer (OCC) the literature is even sparser. We studied OCC and PhC risk both separately and combined (OCPC) in relation to occupational asbestos exposure, specifically addressing the influence of potential confounders, the existence of an exposure response relation, and the presence of interaction between asbestos and smoking. METHODS: Using the prospective Netherlands Cohort Study (N=58 279 men, aged 55-69 years), we estimated asbestos exposure by linkage to a general population job exposure matrix (DOMJEM) and a Finnish job exposure matrix (FINJEM). After 17.3 years of follow-up, 58 OCC and 53 PhC cases were available for analysis. RESULTS: No association between asbestos and risk of OCC was observed for either JEM. Hazard ratios (HR) of PhC and OCPC increased after adjusting for confounders, particularly alcohol consumption and socioeconomic status. For PhC, a multivariable-adjusted increased HR was observed for "ever" versus "never" exposed to asbestos [HR 2.20, 95% confidence interval (95% CI) 1.08-4.49] when using FINJEM, but a trend of increased risks with higher cumulative exposure could not be demonstrated for either JEM. Results for OCPC showed patterns similar to those observed for PhC. None of the cancers showed a significant interaction between asbestos and smoking. CONCLUSIONS: This prospective population-based study showed no convincing evidence of an association between asbestos and risk of OCC, PhC, and OCPC as an exposure-response relation was lacking, and results were not robust against the use of different JEM. However, the potentially increased HR of PhC and OCPC observed in this and previous studies warrant further research. PMID- 24810834 TI - University presidents' perceptions and practice regarding the carrying of concealed handguns on college campuses. AB - OBJECTIVE: To assess the perceptions and practices of a national sample of college and university presidents regarding their support for concealed handguns being carried on college campuses. PARTICIPANTS: The sample for this study consisted of a national random sample of 900 college or university presidents. METHODS: In the spring of 2013, a 3-wave mailing procedure was used to ensure an adequate response rate to a valid and reliable questionnaire. RESULTS: The response rate was 46%, more than what was needed based on the power analysis. The vast majority (95%) of respondents were not supportive of carrying concealed handguns on campuses. They perceived there to be more disadvantages than advantages to handguns on campus. However, college administrators were not focused enough on the primary prevention of campus firearm trauma. CONCLUSIONS: The findings of this study suggest a number of activities that could be implemented to enhance safety on college and university campuses. PMID- 24810835 TI - Primary meningeal NK/T cell lymphoma masquerading as tuberculous meningitis. PMID- 24810836 TI - Downregulation of dopamine D1 receptors and increased neuronal apoptosis upon ethanol and PTZ exposure in prenatal rat cortical and hippocampal neurons. AB - The objective of this study was to evaluate the effect of ethanol and pentylenetetrazol (PTZ) on the expression of dopamine receptors (D1R) and to observe the apoptotic neurodegeneration in prenatal rat cortical and hippocampal neurons at gestational days (GD) 17.5. In the present study, ethanol (100 mM) and PTZ (15 mM) were exposed to the prenatal rat cortical and hippocampal neuronal cell cultures for 1 h. For mRNA RT-PCR and for protein Western blot analysis was done to elucidate D1R, Bax, Bak, Bcl-2 and cleaved caspase-3 expression upon ethanol and PTZ exposure in neuronal cell cultures. Furthermore, ethanol and PTZ induced apoptotic neurodegeneration was also observed using TUNEL staining and propidium iodide (PI) used as counter stain under confocal microscopy. The results of present study showed that ethanol and PTZ exposure significantly decreased D1R expression and induced neuronal death by significantly increasing the expression of pro-apoptotic Bax, Bak and decreasing anti-apoptotic protein Bcl-2 leading to the apoptosis by increasing cleaved caspase-3 expression in cortical and hippocampal primary neuronal cell cultures. Our findings indicated that ethanol and PTZ exposure to the prenatal neurons showed not only downregulation of D1R but also causes neuronal apoptosis in the developing rat brain. Further, this explains the possibility of higher risk of developmental disturbances and malformations during early developmental stage. PMID- 24810837 TI - The diagnostic challenge of bilateral vision loss: a case of chiasmal optic neuritis. PMID- 24810838 TI - Parameterization of thermal properties of aging secondary organic aerosol produced by photo-oxidation of selected terpene mixtures. AB - Formation and evolution of secondary organic aerosols (SOA) from biogenic VOCs influences the Earth's radiative balance. We have examined the photo-oxidation and aging of boreal terpene mixtures in the SAPHIR simulation chamber. Changes in thermal properties and chemical composition, deduced from mass spectrometric measurements, were providing information on the aging of biogenic SOA produced under ambient solar conditions. Effects of precursor mixture, concentration, and photochemical oxidation levels (OH exposure) were evaluated. OH exposure was found to be the major driver in the long term photochemical transformations, i.e., reaction times of several hours up to days, of SOA and its thermal properties, whereas the initial concentrations and terpenoid mixtures had only minor influence. The volatility distributions were parametrized using a sigmoidal function to determine TVFR0.5 (the temperature yielding a 50% particle volume fraction remaining) and the steepness of the volatility distribution. TVFR0.5 increased by 0.3+/-0.1% (ca. 1 K), while the steepness increased by 0.9+/-0.3% per hour of 1*10(6) cm(-3) OH exposure. Thus, aging reduces volatility and increases homogeneity of the vapor pressure distribution, presumably because highly volatile fractions become increasingly susceptible to gas phase oxidation, while less volatile fractions are less reactive with gas phase OH. PMID- 24810840 TI - Modeling oncolytic virotherapy: is complete tumor-tropism too much of a good thing? AB - The specific targeting of tumor cells by replication-competent oncolytic viruses is considered indispensable for realizing the potential of oncolytic virotherapy. Yet off-target infections by oncolytic viruses may increase virus production, further reducing tumor load. This ability may be critical when tumor-cell scarcity or the onset of an adaptive immune response constrain viral anti-tumoral efficacy. Here we develop a mathematical framework for assessing whether oncolytic viruses with reduced tumor-specificity can more effectively eliminate tumors while keeping losses to normal cell populations low. We find viruses that infect some normal cells can potentially balance the competing goals of tumor elimination and minimizing the effects on normal cell populations. Particularly when infected tissues can be regenerated, moderating rather than completely eliminating the ability of oncolytic viruses to infect and lyse normal cells could improve cancer treatment, with potentially fewer side-effects than conventional treatments such as chemotherapy. PMID- 24810841 TI - Bayesian inference of whole-organ deformation dynamics from limited space-time point data. AB - To understand the morphogenetic mechanisms of organ development and regeneration, it is essential to clarify the inter-hierarchical relationship between microscopic, molecular/cellular activities and organ-level tissue deformation dynamics. While the former have been studied for several decades, the latter - macroscopic geometrical information about physical tissue deformation - is often missing, especially for many vertebrates. This is mainly because live recording of detailed cell behaviors in whole tissues during vertebrate organogenesis is technically difficult. In this study, we have developed a novel method that combines snapshot lineage tracing with Bayesian statistical estimation to construct whole-organ deformation maps from landmark data on limited numbers of space-time points. Following the validation of the method using artificially generated data sets, we applied it to the analysis of tissue deformation dynamics in chick limb development. A quantitative tissue deformation map for St.23-St.24 has been constructed, and its precision has been proven by evaluating its predictive performance. Geometrical analyses of the map have revealed a spatially heterogeneous volume growth pattern that is consistent with the expression pattern of a major morphogen and anisotropic tissue deformation along an axis. Thus, our method enables deformation dynamics analysis in organogenesis using practical lineage marking techniques. PMID- 24810842 TI - Mathematical model of macrophage-facilitated breast cancer cells invasion. AB - Mortality from breast cancer stems from its tendency to invade into surrounding tissues and organs. Experiments have shown that this metastatic process is facilitated by macrophages in a short-ranged chemical signalling loop. Macrophages secrete epidermal growth factor, EGF, and respond to the colony stimulating factor 1, CSF-1. Tumor cells secrete CSF-1 and respond to EGF. In this way, the cells coordinate aggregation and cooperative migration. Here we investigate this process in a model for in vitro interactions using two distinct but related mathematical approaches. In the first, we analyze and simulate a set of partial differential equations to determine conditions for aggregation. In the second, we use a cell-based discrete 3D simulation to follow the fates and motion of individual cells during aggregation. Linear stability analysis of the PDE model reveals that decreasing the chemical secretion, chemotaxis coefficients or density of cells or increasing the chemical degradation in the model could eliminate the spontaneous aggregation of cells. Simulations with the discrete model show that the ratio between tumor cells and macrophages in aggregates increases when the EGF secretion parameter is increased. The results also show how CSF-1/CSF-1R autocrine signalling in tumor cells affects the ratio between the two cell types. Comparing the continuum results with simulations of a discrete cell-based model, we find good qualitative agreement. PMID- 24810843 TI - Improving the orientation-dependent statistical potential using a reference state. AB - Statistical potentials are frequently engaged in the protein structural prediction and protein folding for conformational evaluation. Theoretically, to describe the many-body effect, pairwise interaction between two atom groups should be corrected by their relative geometric orientation. The potential functions developed by this means are called orientation-dependent statistical potentials and have exhibited substantially improved performance. However, none of the currently available orientation-dependent statistical potentials use any reference state, which has been proven to greatly enhance the power of distance dependent statistical potentials in numerous previous studies. In this work, we designed a reasonable reference state for the orientation-dependent statistical potentials: using the average geometric relationship between atom pairs in known structures by neglecting their residue identities. The statistical potential developed using this reference state (called ORDER_AVE) prevails most available rival potentials in a series of tests on the decoy sets, although the information of side chain atoms (except the beta-carbon) is absent in its construction. PMID- 24810844 TI - Robotic implantation of biodegradable regenerative urinary conduit: experimental study. AB - PURPOSE: To determine the feasibility and develop a robotic technique for intracorporeal implantation of a biodegradable tubular scaffold seeded with adipose-sourced smooth muscle cells (Neo-Urinary-Conduit) that, when implanted as a conduit for urinary diversion, facilitates regeneration of native-like neourinary tissue. MATERIALS AND METHODS: Robotic NUC implantation was performed in two fresh male cadavers. The greater omentum was widely detached from the greater curvature of the stomach, in preparation for final wrapping of the conduit. Bilateral ureters were mobilized for implantation. The NUC, with two precreated ureteral openings, was inserted into the abdomen. Bilateral, stented uretero-NUC anastomoses were created. The NUC was circumferentially wrapped with the predissected omentum, exteriorized through the abdominal wall, and maturated. RESULTS: Both procedures were successfully completed intracorporeally. Operative time for NUC implantation was 90 and 100 minutes, respectively. Examination of gross anatomy showed no injury to other organs. There was no omental kinking, rotation, eversion, or stripping from the NUC. Bilateral stents were confirmed to be in situ with the proximal coil in the kidney. Uretero-NUC anastomoses and omentum were tension free. The entire NUC, including its distal edge and posterior aspect, was circumferentially wrapped 360 degrees. CONCLUSION: We demonstrated the feasibility and developed a robotic technique for intracorporeal implantation of a biodegradable regenerative urinary conduit. This study serves as the foundation for the robotic surgical technique before the clinical application. PMID- 24810845 TI - Experimental confirmation of transformation pathways between inverse double diamond and gyroid cubic phases. AB - A macroscopically oriented double diamond inverse bicontinuous cubic phase (QII(D)) of the lipid glycerol monooleate is reversibly converted into a gyroid phase (QII(G)). The initial QII(D) phase is prepared in the form of a film coating the inside of a capillary, deposited under flow, which produces a sample uniaxially oriented with a ?110? axis parallel to the symmetry axis of the sample. A transformation is induced by replacing the water within the capillary tube with a solution of poly(ethylene glycol), which draws water out of the QII(D) sample by osmotic stress. This converts the QII(D) phase into a QII(G) phase with two coexisting orientations, with the ?100? and ?111? axes parallel to the symmetry axis, as demonstrated by small-angle X-ray scattering. The process can then be reversed, to recover the initial orientation of QII(D) phase. The epitaxial relation between the two oriented mesophases is consistent with topology-preserving geometric pathways that have previously been hypothesized for the transformation. Furthermore, this has implications for the production of macroscopically oriented QII(G) phases, in particular with applications as nanomaterial templates. PMID- 24810846 TI - Siglec-7 is an inhibitory receptor on human mast cells and basophils. PMID- 24810848 TI - Management of pain in advanced disease. AB - BACKGROUND: Pain is common in advanced malignancy but also prevalent in other non malignant life-limiting diseases such as advanced heart disease; end stage renal failure and multiple sclerosis. Patients with renal or liver impairment need specific consideration, as most analgesics rely on either or both for their metabolism and excretion. SOURCES OF DATA: Recent evidence-based guidelines and the systematic reviews that have informed their recommendations. AREAS OF AGREEMENT: The principles of the WHO (World Health Organisation) analgesic ladder are commonly endorsed as a structured approach to the management of pain. For neuropathic pain, the efficacy of different agents is similar and choice of drug more guided by side effects, drug interactions and cost. AREAS OF CONTROVERSY: Evidence supporting the WHO analgesic ladder is disputed and alternatives suggested, but no overwhelming evidence for an alternative approach exists to date. GROWING POINTS: Alternative approaches to the WHO analgesic ladder, new analgesic agents, e.g. rapid onset oral/intranasal fentanyl. PMID- 24810847 TI - Expression of 11beta-hydroxysteroid dehydrogenase 1 and 2 in patients with chronic rhinosinusitis and their possible contribution to local glucocorticoid activation in sinus mucosa. AB - BACKGROUND: It has been suggested that glucocorticoids might act in target tissues to increase their own intracellular availability in response to inflammatory stimuli. These mechanisms depend on the local metabolism of glucocorticoids catalyzed by 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). OBJECTIVE: This study is to investigate the effect of chronic rhinosinusitis (CRS) on expression of 11beta HSD1, 11beta-HSD2, steroidogenic enzymes (cytochrome P450, family 11, subfamily B, polypeptide 1 [CYP11B1] and cytochrome P450, family 11, subfamily A, polypeptide 1 [CYP11A1]), and endogenous cortisol levels in human sinus mucosa. Expression levels were compared with those of healthy control subjects. METHODS: The expression levels of 11beta-HSD1, 11beta-HSD2, CYP11B1, CYP11A1, and cortisol were measured in healthy control subjects, patients with CRS with nasal polyps, and patients with CRS without nasal polyps by using real-time PCR, Western blotting, immunohistochemistry, and ELISA. Expression levels of 11beta-HSD1, 11beta-HSD2, CYP11B1, CYP11A1, and cortisol were determined in cultured epithelial cells treated with CRS-relevant cytokines. The conversion ratio of cortisone to cortisol was evaluated by using the small interfering RNA technique, 11beta-HSD1 inhibitor, and measurement of 11beta-HSD1 activity. RESULTS: 11beta HSD1, CYP11B1, and cortisol levels increased in patients with CRS with nasal polyps and those with CRS without nasal polyps, but 11beta-HSD2 expression decreased. In cultured epithelial cells treated with IL-4, IL-5, IL-13, IL-1beta, TNF-alpha, and TGF-beta1, 11beta-HSD1 expression and activity increased in parallel with expression levels of CYP11B1 and cortisol, but the production of 11beta-HSD2 decreased. The small interfering RNA technique or the measurement of 11beta-HSD1 activity showed that the sinus epithelium activates cortisone to cortisol in an 11beta-HSD-dependent manner. CONCLUSION: These results indicate that CRS-relevant cytokines can modulate the expression of 11beta-HSD1, 11beta HSD2, and CYP11B1 in the sinus mucosa, resulting in increasing intracellular concentrations of bioactive glucocorticoids. PMID- 24810849 TI - Novel diagnostics and therapeutics for drug-resistant tuberculosis. AB - INTRODUCTION: Drug-resistant tuberculosis (DR-TB) is associated with increased mortality and morbidity. This is at least partly due to late diagnosis and ineffective treatment of drug-resistant status. SOURCES OF DATA: Selective search of the literature on DR-TB supplemented by recent guidelines from the World Health Organization. AREAS OF AGREEMENT: Better and more rapid diagnosis of DR-TB by new techniques such as Xpert Mtb/RIF are likely to make a substantial impact on the disease. New therapeutics for DR-TB are entering, or about to enter the market for the first time in decades. AREAS OF CONTROVERSY: It is not clear whether new treatments should be restricted for DR-TB or also used for drug susceptible tuberculosis. GROWING POINTS: With several new agents on the horizon, there is the real possibility of an entirely new regimen for tuberculosis. AREAS TIMELY FOR DEVELOPING RESEARCH: An inexpensive 'near-patient' diagnostic test is still needed. Optimizing new drug combination regimens in a timely manner is urgently required. PMID- 24810850 TI - mrsFAST-Ultra: a compact, SNP-aware mapper for high performance sequencing applications. AB - High throughput sequencing (HTS) platforms generate unprecedented amounts of data that introduce challenges for processing and downstream analysis. While tools that report the 'best' mapping location of each read provide a fast way to process HTS data, they are not suitable for many types of downstream analysis such as structural variation detection, where it is important to report multiple mapping loci for each read. For this purpose we introduce mrsFAST-Ultra, a fast, cache oblivious, SNP-aware aligner that can handle the multi-mapping of HTS reads very efficiently. mrsFAST-Ultra improves mrsFAST, our first cache oblivious read aligner capable of handling multi-mapping reads, through new and compact index structures that reduce not only the overall memory usage but also the number of CPU operations per alignment. In fact the size of the index generated by mrsFAST Ultra is 10 times smaller than that of mrsFAST. As importantly, mrsFAST-Ultra introduces new features such as being able to (i) obtain the best mapping loci for each read, and (ii) return all reads that have at most n mapping loci (within an error threshold), together with these loci, for any user specified n. Furthermore, mrsFAST-Ultra is SNP-aware, i.e. it can map reads to reference genome while discounting the mismatches that occur at common SNP locations provided by db-SNP; this significantly increases the number of reads that can be mapped to the reference genome. Notice that all of the above features are implemented within the index structure and are not simple post-processing steps and thus are performed highly efficiently. Finally, mrsFAST-Ultra utilizes multiple available cores and processors and can be tuned for various memory settings. Our results show that mrsFAST-Ultra is roughly five times faster than its predecessor mrsFAST. In comparison to newly enhanced popular tools such as Bowtie2, it is more sensitive (it can report 10 times or more mappings per read) and much faster (six times or more) in the multi-mapping mode. Furthermore, mrsFAST-Ultra has an index size of 2GB for the entire human reference genome, which is roughly half of that of Bowtie2. mrsFAST-Ultra is open source and it can be accessed at http://mrsfast.sourceforge.net. PMID- 24810851 TI - e-RNA: a collection of web servers for comparative RNA structure prediction and visualisation. AB - e-RNA offers a free and open-access collection of five published RNA sequence analysis tools, each solving specific problems not readily addressed by other available tools. Given multiple sequence alignments, Transat detects all conserved helices, including those expected in a final structure, but also transient, alternative and pseudo-knotted helices. RNA-Decoder uses unique evolutionary models to detect conserved RNA secondary structure in alignments which may be partly protein-coding. SimulFold simultaneously co-estimates the potentially pseudo-knotted conserved structure, alignment and phylogenetic tree for a set of homologous input sequences. CoFold predicts the minimum-free energy structure for an input sequence while taking the effects of co-transcriptional folding into account, thereby greatly improving the prediction accuracy for long sequences. R-chie is a program to visualise RNA secondary structures as arc diagrams, allowing for easy comparison and analysis of conserved base-pairs and quantitative features. The web site server dispatches user jobs to a cluster, where up to 100 jobs can be processed in parallel. Upon job completion, users can retrieve their results via a bookmarked or emailed link. e-RNA is located at http://www.e-rna.org. PMID- 24810852 TI - Theoretical and experimental assessment of degenerate primer tagging in ultra deep applications of next-generation sequencing. AB - Primer IDs (pIDs) are random oligonucleotide tags used in next-generation sequencing to identify sequences that originate from the same template. These tags are produced by degenerate primers during the reverse transcription of RNA molecules into cDNA. The use of pIDs helps to track the number of RNA molecules carried through amplification and sequencing, and allows resolution of inconsistencies between reads sharing a pID. Three potential issues complicate the above applications. First, multiple cDNAs may share a pID by chance; we found that while preventing any cDNAs from sharing a pID may be unfeasible, it is still practical to limit the number of these collisions. Secondly, a pID must be observed in at least three sequences to allow error correction; as such, pIDs observed only one or two times must be rejected. If the sequencing product contains copies from a high number of RT templates but produces few reads, our findings indicate that rejecting such pIDs will discard a great deal of data. Thirdly, the use of pIDs could influence amplification and sequencing. We examined the effects of several intrinsic and extrinsic factors on sequencing reads at both the individual and ensemble level. PMID- 24810854 TI - Multimodality systematic approach to mediastinal lymph node staging in non-small cell lung cancer. AB - Establishing an accurate diagnosis and stage for non-small cell lung cancer has important implications for treatment and prognosis. Ideally, the process should be performed in a way that maximizes the information from each procedure while minimizing the risk to the patient. The concepts of decision analysis and Bayes' theorem form a basis to develop the strategy. In this framework, the pre-test probability of malignancy is estimated in the lung nodule or mass, the regional lymph nodes and in distant sites. Invasive diagnostic tests are performed in sites with a pre-test probability greater than the testing threshold, beginning with those sites that would yield the highest stage, if positive. Modalities are chosen that are able to biopsy the suspicious sites and present the least amount of risk to the patient. Following each test, the post-test probability of malignancy is calculated to determine if it crosses the testing or test-treatment thresholds. The process continues with further tests until a diagnosis and stage are established. PMID- 24810853 TI - Non-inhibited miRNAs shape the cellular response to anti-miR. AB - Identification of primary microRNA (miRNA) gene targets is critical for developing miRNA-based therapeutics and understanding their mechanisms of action. However, disentangling primary target derepression induced by miRNA inhibition from secondary effects on the transcriptome remains a technical challenge. Here, we utilized RNA immunoprecipitation (RIP) combined with competitive binding assays to identify novel primary targets of miR-122. These transcripts physically dissociate from AGO2-miRNA complexes when anti-miR is spiked into liver lysates. mRNA target displacement strongly correlated with expression changes in these genes following in vivo anti-miR dosing, suggesting that derepression of these targets directly reflects changes in AGO2 target occupancy. Importantly, using a metric based on weighted miRNA expression, we found that the most responsive mRNA target candidates in both RIP competition assays and expression profiling experiments were those with fewer alternative seed sites for highly expressed non inhibited miRNAs. These data strongly suggest that miRNA co-regulation modulates the transcriptomic response to anti-miR. We demonstrate the practical utility of this 'miR-target impact' model, and encourage its incorporation, together with the RIP competition assay, into existing target prediction and validation pipelines. PMID- 24810855 TI - Potential applications for antiviral therapy and prophylaxis in bovine medicine. AB - Viral disease is one of the major causes of financial loss and animal suffering in today's cattle industry. Increases in global commerce and average herd size, urbanization, vertical integration within the industry and alterations in global climate patterns have allowed the spread of pathogenic viruses, or the introduction of new viral species, into regions previously free of such pathogens, creating the potential for widespread morbidity and mortality in naive cattle populations. Despite this, no antiviral products are currently commercially licensed for use in bovine medicine, although significant progress has been made in the development of antivirals for use against bovine viral diarrhea virus (BVDV), foot and mouth disease virus (FMDV) and bovine herpesvirus (BHV). BVDV is extensively studied as a model virus for human antiviral studies. Consequently, many compounds with efficacy have been identified and a few have been successfully used to prevent infection in vivo although commercial development is still lacking. FMDV is also the subject of extensive antiviral testing due to the importance of outbreak containment for maintenance of export markets. Thirdly, BHV presents an attractive target for antiviral development due to its worldwide presence. Antiviral studies for other bovine viral pathogens are largely limited to preliminary studies. This review summarizes the current state of knowledge of antiviral compounds against several key bovine pathogens and the potential for commercial antiviral applications in the prevention and control of several selected bovine diseases. PMID- 24810856 TI - Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases. AB - gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER) associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. The E4-like activity of gp78 was illustrated by an in vitro polyubiquitylation assay using Ub-DHFR as a model substrate. We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady state level of gp78. This study uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation. PMID- 24810857 TI - Understanding surgical residents' postoperative practices and barriers and enablers to the implementation of an Enhanced Recovery After Surgery (ERAS) Guideline. AB - INTRODUCTION: An Enhanced Recovery after Surgery (ERAS) Clinical Practice Guideline (CPG) was developed at the University of Toronto. Before implementation, general surgery residents were surveyed to assess their current stated practices and their perceived barriers and enablers to early discharge. METHODS: The survey, which consisted of 33 questions related to the postoperative management of patients undergoing laparoscopic colectomy (LAC), open colectomy (OC) and open low anterior resection (LAR), was distributed to all residents. Chi square and Fisher exact tests were used to test differences. Open-ended questions were analyzed using content analysis. RESULTS: Of 77 residents surveyed, 58 (75%) responded. Residents stated that a fluid diet would be ordered on POD#0 and regular diet on POD#1 by 67.9% and 49.1%, respectively, following LAC, and 50.0% and 25.9%, respectively, following OC. On POD#1, 89.3% expected patients to ambulate following LAC compared with 67.9% following OC. Residents indicated that urinary catheters would be removed on POD#1 by 87% following LAC and by 81.3% following OC, and by POD#3 by 89.1% following LAR. However, in patients with an epidural, approximately 50% of residents stated that they would wait until it was removed. Overall, 76.4% of residents agreed that an ERAS CPG should be adopted. Residents cited setting expectations, encouragement of early ambulation and feeding, and good pain control as enablers to early discharge. However, patient and family expectations, surgeon preferences, and beliefs of the health care team were mentioned as barriers to early discharge. CONCLUSION: Residents have a reasonable approach to the management of patients who underwent LAC, but there are gaps that exist in their management, especially following OC and LAR. Although most residents agreed with the implementation of an ERAS CPG, barriers exist, and strategies aimed at ensuring adherence with the recommendations are required. PMID- 24810858 TI - Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. AB - Long non-coding RNAs (lncRNAs) play key roles in the progression and metastasis of some carcinomas. We previously showed that the expression of lncRNA H19 (H19) was higher in gastric cancer (GC) tissues than that in paired noncanerous tissues. However, the underlying mechanisms remain unclear. In this study, H19/miR-675 knockdown models in the MKN45 cell line and ectopic expression models in the SGC7901 cell line were established, and a co-expression network of H19 was generated to identify target genes by RIP and DLR. The results showed that overexpression of H19 promoted the features of GC including proliferation, migration, invasion and metastasis. An H19 co-expression network identified ISM1 as a binding protein of H19, and its expression was positively correlated with that of H19. CALN1 was identified as a target gene of miR-675 and its expression was negatively correlated with that of miR-675. H19 and MiR-675 function in a similar manner. However, H19 RNA actively binds to ISM1 and miR-675 targets CALN1. These differences suggest that H19 plays other roles besides encoding miR 675 in GC. Our results suggest that the effect of H19 in GC is mediated by the direct upregulation of ISM1 and the indirect suppression of CALN1 expression via miR-675. PMID- 24810859 TI - A study to determine the contribution to right ventricle stroke volume from pulmonary and tricuspid valve displacement volumes. AB - BACKGROUND: Describing the systolic function of the right ventricle (RV) is a difficult task due to the complex shape and orientation of the RV. The purpose of this study was to investigate the extent to which the volumes encompassed by the pulmonary and tricuspid valve displacements contribute to the total right ventricle stroke volume (RVSV). METHODS: Twelve healthy volunteers were examined using cardiac magnetic resonance (CMR). Two series of time-resolved axially rotated MR images were acquired that encompassed the tricuspid valve and the pulmonary valve, respectively. The volume related to each valve movement, the tricuspid plane displacement (TPD) and the pulmonary plane displacement (PPD), was determined by delineation in diastole and systole. These volumes, RVSV(TPD) and RVSV(PPD) , were compared to the stroke volume to determine the contributions to the total stroke volume from the TPD and the PPD. The remaining volume of the total RVSV was referred to as RVSV(Other) . An initial in vitro study was carried out to validate the accuracy of volume measurements using axially rotated images. RESULTS: In vitro measurements indicated that the method for volumetric measurements using axially rotated images was a very accurate one, with a mean difference of 0.04 +/- 0.10 ml. The in vivo measurements of RVSV(TPD) , RVSV(PPD) and RVSVOther were 45 +/- 10%, 13 +/- 2% and 42 +/- 11%, respectively. CONCLUSIONS: Right ventricle stroke volume is determined by different individual volume changes as follows: RVSV(TPD) together with RVSVOther contributes to almost the entire RVSV in nearly equal proportions, while RVSV(PPD) contributes only a small amount and is approximately 30% of either RVSV(TPD) or RVSV(Other) . PMID- 24810860 TI - Report on carcinogens monograph on cumene. AB - The National Toxicology Program conducted a cancer evaluation on cumene for possible listing in the Report on Carcinogens (RoC). The cancer evaluation is captured in the RoC monograph, which was peer reviewed in a public forum. The monograph consists of two components: (Part 1) the cancer evaluation, which reviews the relevant scientific information, assesses its quality, applies the RoC listing criteria to the scientific information, and provides the NTP recommendation for listing status for cumene in the RoC, and (Part 2) the substance profile proposed for the RoC, containing the NTP's listing status recommendation, a summary of the scientific evidence considered key to reaching that decision, and data on properties, use, production, exposure, and Federal regulations and guidelines to reduce exposure to cumene. This monograph provides an assessment of the available scientific information on cumene, including human exposure and properties, disposition and toxicokinetics, cancer studies in experimental animals, and studies of mechanisms and other related effects, including relevant toxicological effects, genetic toxicology, and mechanisms of carcinogenicity. From this assessment, the NTP recommended that cumene be listed as reasonably anticipated to be a human carcinogen in the RoC based on sufficient evidence from studies in experimental animals, which found that cumene exposure caused lung tumors in male and female mice and liver tumors in female mice. Several proposed mechanisms of carcinogenesis support the relevance to humans of the lung and liver tumors observed in experimental animals. Specifically, there is evidence that humans and experimental animals metabolize cumene through similar metabolic pathways. In addition, mutations of the K-ras oncogene and p53 tumor-suppressor gene observed in cumene-induced lung tumors in mice, along with altered expression of many other genes, resemble molecular alterations found in human lung and other cancers. PMID- 24810861 TI - Multidisciplinary consensus guideline for managing trigger finger: results from the European HANDGUIDE Study. AB - BACKGROUND: Trigger finger is characterized by sometimes painful snapping or locking when flexing the finger. Although trigger finger is frequently seen in clinical practice, no standard treatment protocol has been established as "best practice." OBJECTIVE: The aim of this study was to achieve consensus on a multidisciplinary treatment guideline for trigger finger. DESIGN: A European Delphi consensus strategy was initiated. Systematic reviews reporting on the effectiveness of surgical and nonsurgical interventions were conducted and used as an evidence-based starting point for this study. SETTING: In total, 35 experts (hand therapists and hand surgeons selected by the national member associations of their European federations and physical medicine and rehabilitation physicians) participated in the Delphi consensus strategy. MEASUREMENTS: Each Delphi round consisted of a questionnaire, an analysis, and a feedback report. RESULTS: After 4 Delphi rounds, consensus was achieved on the description, symptoms, and diagnosis of trigger finger. The experts agreed that use of orthoses (splinting), corticosteroid injections, corticosteroid injections plus use of orthoses, and surgery are suitable treatment options. Relevant details for the use of orthoses, corticosteroid injections, and surgery were described. Main factors for selecting one of these treatment options were identified as severity and duration of the disease and previous treatments received. A relationship between the severity and duration of the disorder and the choice of therapy was indicated by the experts and reported on in the guideline. LIMITATIONS: The results represent a group's opinion at a given point in time. When the evidence for the effectiveness of interventions increases, experts' opinions will change, and the guideline should be re-evaluated and adjusted in view of these new insights. CONCLUSIONS: This multidisciplinary treatment guideline may help involved therapists and physicians in the treatment of trigger finger and indicate areas needing additional research. PMID- 24810862 TI - Cross-sectional study to examine evidence-based practice skills and behaviors of physical therapy graduates: is there a knowledge-to-practice gap? AB - BACKGROUND: Curricula changes in physical therapist education programs in Canada emphasize evidence-based practice skills, including literature retrieval and evaluation. Do graduates use these skills in practice? OBJECTIVES: The aim of this study was to evaluate the use of research information in the clinical decision making of therapists with different years of experience and evidence based practice preparation. Perceptions about evidence-based practice were explored qualitatively. DESIGN: A cross-sectional study with 4 graduating cohorts was conducted. METHODS: Eighty physical therapists representing 4 different graduating cohorts participated in interviews focused on 2 clinical scenarios. Participants had varying years of clinical experience (range=1-15 years) and academic knowledge of evidence-based practice skills. Therapists discussed the effectiveness of interventions related to the scenarios and identified the sources of information used to reach decisions. Participants also answered general questions related to evidence-based practice knowledge. RESULTS: Recent graduates demonstrated better knowledge of evidence-based practice skills compared with therapists with 6 to 15 years of clinical experience. However, all groups used clinical experience most frequently as their source of information for clinical decisions. Research evidence was infrequently included in decision making. LIMITATIONS: This study used a convenience sample of therapists who agreed to volunteer for the study. CONCLUSIONS: The results suggest a knowledge to-practice gap; graduates are not using the new skills to inform their practice. Tailoring academic evidence-based activities more to the time constraints of clinical practice may help students to be more successful in applying evidence in practice. Academic programs need to do more to create and nurture environments in both academic and clinical settings to ensure students practice using evidence based practice skills across settings. PMID- 24810863 TI - The physical function intensive care test: implementation in survivors of critical illness. AB - BACKGROUND: Recent studies have demonstrated safety, feasibility, and decreased hospital length of stay for patients with weakness acquired in the intensive care unit (ICU) who receive early physical rehabilitation. The scored Physical Function in Intensive Care Test (PFIT-s) was specifically designed for this population and demonstrated excellent psychometrics in an Australian ICU population. OBJECTIVE: The purpose of this study was to determine the responsiveness and predictive capabilities of the PFIT-s in patients in the United States admitted to the ICU who required mechanical ventilation (MV) for 4 days or longer. METHODS: This nested study within a randomized trial administered the PFIT-s, Medical Research Council (MRC) sum score, and grip strength test at ICU recruitment and then weekly until hospital discharge, including at ICU discharge. Spearman rho was used to determine validity. The effect size index was used to calculate measurement responsiveness for the PFIT-s. The receiver operating characteristic curve was used in predicting participants' ability to perform functional components of the PFIT-s. RESULTS: From August 2009 to July 2012, 51 patients were recruited from 4 ICUs in the Denver, Colorado, metro area. At ICU discharge, PFIT-s scores were highly correlated to MRC sum scores (rho=.923) and grip strength (rho=.763) (P<.0005). Using baseline test with ICU discharge (26 pairs), test responsiveness was large (1.14). At ICU discharge, an MRC sum score cut-point of 41.5 predicted participants' ability to perform the standing components of the PFIT-s. LIMITATIONS: The small sample size was a limitation. However, the findings are consistent with those in a larger sample from Australia. CONCLUSIONS: The PFIT-s is a feasible and valid measure of function for individuals who require MV for 4 days or longer and who are alert, able to follow commands, and have sufficient strength to participate. PMID- 24810864 TI - Responsive supramolecular polymers based on the bis[alkynylplatinum(II)] terpyridine molecular tweezer/arene recognition motif. AB - Supramolecular polymers are constructed based on the novel bis[alkynylplatinum(II)] terpyridine molecular tweezer/pyrene recognition motif. Successive addition of anthracene as the diene and cyano-functionalized dienophile triggers the reversible supramolecular polymerization process, thus advancing the concept of utilizing Diels-Alder chemistry to access stimuli responsive materials in compartmentalized systems. PMID- 24810865 TI - C@SiNW/TiO2 core-shell nanoarrays with sandwiched carbon passivation layer as high efficiency photoelectrode for water splitting. AB - One-dimensional heterostructure nanoarrays are efficiently promising as high performance electrodes for photo electrochemical (PEC) water splitting applications, wherein it is highly desirable for the electrode to have a broad light absorption, efficient charge separation and redox properties as well as defect free surface with high area suitable for fast interfacial charge transfer. We present highly active and unique photoelectrode for solar H2 production, consisting of silicon nanowires (SiNWs)/TiO2 core-shell structures. SiNWs are passivated to reduce defect sites and protected against oxidation in air or water by forming very thin carbon layer sandwiched between SiNW and TiO2 surfaces. This carbon layer decreases recombination rates and also enhances the interfacial charge transfer between the silicon and TiO2. A systematic investigation of the role of SiNW length and TiO2 thickness on photocurrent reveals enhanced photocurrent density up to 5.97 mA/cm(2) at 1.0 V vs.NHE by using C@SiNW/TiO2 nanoarrays with photo electrochemical efficiency of 1.17%. PMID- 24810866 TI - Use of the implicit association test for the measurement of tinnitus-related distress. AB - PURPOSE: A priming stimulus activates and increases an association with the target stimulus. The goal of this research was to investigate whether current tinnitus measures are susceptible to increased error due to priming and, if so, to examine the feasibility of using the Implicit Association Test (IAT; Greenwald, McGhee, & Schwartz, 1998) for an alternative measurement of tinnitus related distress. METHOD: Participants completed 2 tinnitus-related questionnaires and the IAT online. RESULTS: Although participants with tinnitus did not view sound-related words as significantly more negative and IAT scores did not predict scores on the Tinnitus Handicap Inventory (Newman, Jacobson, & Spitzer, 1996), priming did affect negative implicit attitudes toward sound related words. CONCLUSIONS: On the basis of these results, it is suggested that current tinnitus measures may be susceptible to priming error and that future studies should continue to pursue how the IAT can be utilized in the measure of tinnitus-related distress. Moreover, researchers should develop overt-behavioral measurements that can assess the validity of a tinnitus IAT. PMID- 24810867 TI - Enoxaparin: pharmacokinetics and treatment schedule for cats. AB - Detailed pharmacokinetic data are not available for subcutaneously (SC) administered enoxaparin in cats and this causes difficulties in establishing treatment protocols. The aims of this study were (1) to establish pharmacokinetic data of SC administered enoxaparin and (2) to establish a treatment schedule. Six healthy cats received a single SC injection of 1 mg enoxaparin/kg and blood samples were collected before and 1, 2, 3, 4, 6, 8, 10 and 12 h after the injection. Six further healthy cats received 0.75 mg/kg every 6 h for four consecutive days and blood samples were collected before and 2 h after the first and second injection on day 1, and the first injection on days 2 and 4. Anti factor Xa (FXa) activity, coagulation tests and thromboelastometry assays were performed. Enoxaparin injection was well tolerated. Following the single SC injection Cmax was 0.83 +/- 0.08 anti-Xa IU/mL and in 5/6 cats was detected after 2 h (Tmax = 110 +/- 25 min). The total clearance was 23.4 +/- 4.8 mL/h/kg and the terminal half-life was 2.27 +/- 0.4 h. All cats receiving repeated injections reached the defined target peak range of 0.5-1.0 IU/mL by 2 h after the second injection (0.54 [0.50-0.61]; median, [minimum - maximum]) and there was no considerable accumulation subsequently. With the exception of thromboelastometry (especially non-activated), ratio values of coagulation times increased significantly although only slightly (e.g., the maximal value of median activated partial thromboplastin time ratio was 1.27). Significant, although only moderately close relationships with Spearman rank correlation coefficients between 0.424 and 0.558 were calculated between anti-FXa activities and ratios of different coagulation times. A dosage schedule of 0.75 mg/kg four times a day seems suitable for therapeutic use of enoxaparin in cats as it leads to reproducible peak anti-FXa activities within the target range for the treatment of thrombosis in humans. The low inter-individual variation may indicate that monitoring based on anti-FXa activities is not necessary. PMID- 24810868 TI - Evaluating binding avidities of populations of heterogeneous multivalent ligand functionalized nanoparticles. AB - Ligand-functionalized, multivalent nanoparticles have been extensively studied as targeted carriers in biomedical applications for drug delivery and imaging. The chemical synthesis method used, however, generates nanoparticles that are heterogeneous with respect to the number of ligands on each nanoparticle. This article examines the role this heterogeneity in ligand number plays in multivalent interactions between nanoparticle ligands and targeted receptors. We designed and synthesized a model heterogeneous multivalent nanoparticle system and developed a unique kinetic analysis to quantify the avidity interactions. This system used mono-dispersed poly(amidoamine) (PAMAM) dendrimers that were then chemically functionalized with ssDNA oligonucleotides as to yield the heterogeneous nanoparticle platform (ligand valencies n = 1.7, 3.1, 6), and employed complementary oligonucleotides as targeted receptors on a surface plasmon resonance (SPR) biosensor to evaluate the multivalent binding of the nanoparticle population. Kinetic analysis of both parallel initial rate and dual Langmuir analyses of SPR binding curves was performed to assess avidity distributions. We found that batches of multivalent nanoparticles contain both fast- and slow-dissociation subpopulations, which can be characterized as having "weak" and "strong" surface interactions ("binding"), respectively. Furthermore, we found that the proportion of "strong" binders increased as a function of the mean oligonucleotide valence of the nanoparticle population. These analyses allowed an assessment of how avidity distributions are modulated by the number of functionalized ligands and suggested that there are threshold valences that differentiated fast- and slow-dissociation nanoparticles. PMID- 24810869 TI - A beneficial effect of purse-string skin closure after ileostomy takedown: a retrospective cohort study. AB - OBJECTIVES: The aim of this study was to investigate the clinical benefits of purse-string skin closure (PS) in daily practice compared with conventional linear skin closure (CL) after ileostomy takedown in Korean population. METHODS: These retrospectively collected data were based on 157 consecutive patients who underwent ileostomy takedown between November 2010 and September 2011. Before March, 2011, CL was performed in 79 patients. Thereafter, PS was performed in 78 patients. The medical records including pain score recorded daily were reviewed and the postoperative outcomes, including SSI, were analyzed. RESULTS: PS group had a significantly lower overall complication rate than the CL group (8.97% vs. 25.32%, p = 0.010). Among complications, PS group had a significantly lower SSI rate than the CL group (0% vs. 11.39%, p = 0.003). After adjusted for other risk factors (smoking, body mass index, anastomosis method), PS method was associated significantly and independently with a lower SSI rate than CL method (adjusted odds ratio: 26.63, 95% confidence interval: 3.02-267.70, p = 0.001). And the two groups did not differ in terms of postoperative pain (p = 0.323) or pain pattern (p = 0.548). CONCLUSION: In daily practice, PS had a beneficial effect on SSI in patients who underwent ileostomy takedown in the Korean population. PMID- 24810870 TI - The impact of 5-HTTLPR on acute serotonin transporter blockade by escitalopram on emotion processing: preliminary findings from a randomised, crossover fMRI study. AB - OBJECTIVE: Benefit from antidepressant treatment such as selective serotonin reuptake inhibitors (SSRIs) may depend on individual differences in acute effects on neural emotion processing. The short ('S') allele of the serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) is associated with both negative emotion processing biases and poorer treatment outcomes. Therefore, the aim of the present study was to explore the effects of 5-HTTLPR on the impact of the SSRI escitalopram during processing of positive and negative emotional images, as well as neutral stimuli. METHODS: The study employed a double-blind, randomised, placebo-controlled crossover design on 36 healthy Caucasian female participants who underwent functional magnetic resonance imaging (fMRI) scanning following placebo or escitalopram treatment, separated by a 7-day washout period. RESULTS: Changes in the left amygdala signal with escitalopram treatment during processing of emotional stimuli were linearly related to the 5-HTTLPR 'S' allele load such that the signal to positive stimuli decreased and the signal to negative stimuli increased with an increasing number of low-expressing 'S' alleles. While 5-HTTLPR subgroups were small in size, individual subject changes with treatment and task condition increase confidence in the findings. CONCLUSIONS: While preliminary, our findings comprise the first pharmacogenetic study demonstrating an effect of the 5-HTTLPR 'S' allele load on escitalopram-induced changes in amygdala activity during emotional processing, consistent with a 5-HTT expression dosage model. The present findings have implications for the impact of this polymorphism on antidepressant efficacy in patients with mood and anxiety disorders. PMID- 24810871 TI - Metacognitive therapy versus cognitive behavioural therapy for depression: a randomized pilot study. AB - OBJECTIVE: Metacognitive therapy (MCT) is one of the newer developments within cognitive therapy. This randomized controlled pilot study compared independently applied MCT with cognitive behavioural therapy (CBT) in outpatients with depression to explore the relative speed and efficacy of MCT, ahead of a planned randomized controlled trial. METHOD: A total of 48 participants referred for outpatient therapy were randomized to up to 12 weeks of MCT or CBT. Key outcomes were reduction in depressive symptoms at week 4 and week 12, measured using the independent-clinician-rated Quick Inventory of Depressive Symptomatology16. Intention-to-treat and completer analyses as well as additional methods of reporting outcome of depression are presented. RESULTS: Both therapies were effective in producing clinically significant change in depressive symptoms, with moderate-to-large effect sizes obtained. No differences were detected between therapies in overall outcome or early change on clinician-rated or self-reported measures. Post-hoc analyses suggest that MCT may have been adversely affected by greater comorbidity. CONCLUSIONS: In this large pilot study conducted independently of MCT's developers, MCT was an effective treatment for outpatients with depression, with similar results overall to CBT. Insufficient power and imbalanced comorbidity limit conclusions regarding comparative efficacy so further studies of MCT and CBT are required. PMID- 24810872 TI - Understanding service demand for mental health among Australians aged 16 to 64 years according to their possible need for treatment. AB - BACKGROUND: To inform decisions about mental health resource allocation, planners require reliable estimates of people who report service demand (i.e. people who use or want mental health services) according to their level of possible need. METHODS: Using data on 6915 adults aged 16-64 years in Australia's 2007 National Survey of Mental Health and Wellbeing, we examined past-year service demand among respondents grouped into four levels of possible need: (a) 12-month mental disorder; (b) lifetime but no 12-month mental disorder; (c) any other indicator of possible need (12-month symptoms or reaction to stressful event, or lifetime hospitalisation); (d) no indicator of possible need. Multivariate logistic regression analyses examined correlates of service demand, separately for respondents in each of levels 1-3. RESULTS: Sixteen per cent of Australian adults reported service demand, of whom one-third did not meet criteria for a 12-month mental disorder (equivalent to 5.7% of the adult population). Treatment patterns tended to follow a gradient defined by level of possible need. For example, service users with a 12-month disorder received, on average, 1.6-3.9 times more consultations than their counterparts in other levels of possible need, and had 1.9-2.2 times higher rates of psychologist consultation. Service users with a lifetime but not 12-month disorder or any other indicator of need consumed a similar average number of services to people with mild 12-month mental disorders, but received relatively fewer services involving the mental health sector. Service demand was associated with increased suicidality and psychological distress in all levels of possible need examined, and with poorer clinical and functional status for those with 12-month or lifetime disorders. CONCLUSIONS: Many Australians reporting service demand do not meet criteria for a current mental disorder, but may require services to maintain recovery following a past episode or because they are experiencing symptoms and significant psychological distress. PMID- 24810873 TI - Improving the physical health of long-term psychiatric inpatients. AB - BACKGROUND: Patients with psychiatric illness have increased somatic morbidity and increased mortality. Knowledge of how to integrate the prevention and care of somatic illness into the treatment of psychiatric patients is required. The aims of this study were to investigate whether an intervention programme to improve physical health is effective. METHODS: An extension of the European Network for Promoting the Health of Residents in Psychiatric and Social Care Institutions (HELPS) project further developed as a 12-month controlled cluster-randomized intervention study in the Danish centre. Waist circumference was a proxy of unhealthy body fat in view of the increased risk of cardiovascular diseases and type 2 diabetes. RESULTS: Waist circumference was 108 cm for men and 108 cm for women. Controlled for cluster randomization, sex, age, and body fat, the intervention group showed a small, but not significant, reduction in waist circumference, while participants in the control group showed a significant increase in waist circumference. CONCLUSIONS: The intervention had a positive effect on the physical health of the patients measured by a reduction in the increase of waist circumference. PMID- 24810874 TI - Therapeutic hypothermia in neonates and selective hippocampal injury on diffusion weighted magnetic resonance imaging. AB - BACKGROUND: Hippocampal injury is most often observed in conjunction with basal ganglia injury after hypoxia-ischemia in term newborns. Objective was to determine perinatal characteristics leading to selective hippocampal injury vs basal ganglia injury on diffusion-weighted imaging in term encephalopathic infants following intrapartum hypoxia-ischemia treated with selective head cooling and to correlate specific injury to subsequent neurodevelopmental outcome. METHODS: Retrospective chart review of obstetric and/or perinatal risk factors and patient characteristics in term infants treated with selective head cooling. All infants met standard enrollment criteria for cooling. MRI was obtained at a median of 7 days of life. Abnormal outcome was defined as spastic quadriplegia, cognitive delay, both, or death. RESULTS: Fifty-seven infants were included for analysis. Diffusion-weighted imaging findings included normal (n = 31), basal ganglia injury (n = 16), and selective hippocampal injury (n = 10). No differences in gestational age, birth weight, sex, or labor complications between groups. More infants in the basal ganglia vs hippocampal group required delivery room cardiopulmonary resuscitation (P = 0.05), exhibited persistent severe acidosis, severe amplitude electroencephalography suppression, and encephalopathy at birth (P < 0.05). Abnormal neurodevelopmental outcome or death was observed in 88% vs 10% of infants in the basal ganglia vs the hippocampal group, respectively (P = 0.0001). CONCLUSIONS: Infants with hippocampal injury on diffusion-weighted imaging recovered from an intrapartum asphyxial insult more rapidly as reflected by an earlier correction of acid-base status, were less likely to need cardiopulmonary resuscitation, and were less severely encephalopathic. These findings highlight the exquisite vulnerability of the hippocampus to acute hypoxia unaffected by selective head cooling, whereas the normal appearance of the basal ganglia in these infants suggests a neuroprotective effect of cooling. PMID- 24810875 TI - Topical everolimus for facial angiofibromas in the tuberous sclerosis complex. A first case report. AB - BACKGROUND: Facial angiofibromas are present in most of the patients with the tuberous sclerosis complex and may cause severe disfiguration of the face. The tumor growth in tuberous sclerosis complex is promoted by the disinhibition of the mammalian target of rapamycin pathway. Thus, the systemic treatment with mammalian target of rapamycin inhibitors such as sirolimus and everolimus has recently been established to treat specific tuberous sclerosis complex-associated lesions. For patients who suffer from disfiguring facial angiofibromas only, there is a need for a topical use of mammalian target of rapamycin inhibitors. Sirolimus has been shown to be beneficial in treating facial angiofibromas. But the topical use of everolimus, which has the approval to treat tuberous sclerosis complex-associated tumors, namely giant cell astrocytomas and renal angiofibromas, has not been reported. PATIENTS AND RESULTS: We present a 10-year old girl whose facial angiofibromas were successfully treated with an everolimus ointment without relevant side effects. In addition, we provide a short pharmacological overview of sirolimus and everolimus with focus on the topical use. CONCLUSIONS: Topical everolimus seems to be a favorable and safe option for patients with facial angiofibromas who do not require systemic treatment. PMID- 24810876 TI - The diagnosis of band heterotopia. PMID- 24810877 TI - Two infants with infantile spasms associated with vitamin B12 deficiency. AB - BACKGROUND: In developing countries, nutritional vitamin B12 deficiency in infants because of maternal deficiency often causes hematological and neurological disorders. However, epilepsy is a rare manifestation of vitamin B12 deficiency. The biological basis for the observed neurological symptoms of infantile vitamin B12 deficiency remains uncertain. There are only a few reports in the English literature regarding the relationship between infantile spasms and vitamin B12 deficiency. PATIENTS: We report two unrelated infants having infantile spasms associated with vitamin B12 deficiency related to maternal nutritional deficiency. RESULTS: During the first month of adrenocorticotropic hormone (ACTH), phenobarbital, and vitamin B12 treatments, both infants' abnormalities resolved. After 3 months, electroencephaography was completely normal. ACTH and phenobarbital treatments were ended. The children are disease free 9 months after the treatment. CONCLUSIONS: We suggest that vitamin B12 deficiency should be considered in the differential diagnosis of infantile spasms as a treatable cause, especially with a history of maternal nutritional deficiency. PMID- 24810878 TI - Prevalence and beta diversity in avian malaria communities: host species is a better predictor than geography. AB - Patterns of diversity and turnover in macroorganism communities can often be predicted from differences in habitat, phylogenetic relationships among species and the geographical scale of comparisons. In this study, we asked whether these factors also predict diversity and turnover in parasite communities. We studied communities of avian malaria in two sympatric, ecologically similar, congeneric host species at three different sites. We asked whether parasite prevalence and community structure varied with host population, host phylogeography or geographical distance. We used PCR to screen birds for infections and then used Bayesian methods to determine phylogenetic relationships among malaria strains. Metrics of both community and phylogenetic beta diversity were used to examine patterns of malaria strain turnover between host populations, and partial Mantel tests were used determine the correlation between malaria beta diversity and geographical distance. Finally, we developed microsatellite markers to describe the genetic structure of host populations and assess the relationship between host phylogeography and parasite beta diversity. We found that different genera of malaria parasites infect the two hosts at different rates. Within hosts, parasite communities in one population were phylogenetically clustered, but there was otherwise no correlation between metrics of parasite beta diversity and geographical or genetic distance between host populations. Patterns of parasite turnover among host populations are consistent with malaria transmission occurring in the winter rather than on the breeding grounds. Our results indicate greater turnover in parasite communities between different hosts than between different study sites. Differences in host species, as well as transmission location and vector ecology, seem to be more important in structuring malaria communities than the distance-decay relationships frequently found in macroorganisms. Determining the factors affecting parasite community diversity and turnover has wide-ranging implications for understanding the selective pressures shaping host ecology and ecosystem structure. This study shows that metrics of community and phylogenetic beta diversity can be useful tools for disentangling the ecological and evolutionary processes that underlie geographical variation in parasite communities. PMID- 24810879 TI - Synthesis and folding propensity of aliphatic oligoureas containing repeats of proline-type units. AB - The synthesis and conformational analysis of aliphatic oligoureas containing multiple adjacent N-alkylated units derived from proline (i.e., Pro(u)) are reported. The insertion of trisubstituted ureas in the main chain of N,N'-linked oligourea foldamers locally impairs the characteristic three centered-hydrogen bonding pattern associated with the formation of 2.5-helical structures. Three series of oligomers have been studied: one series in which the Pro(u) repeat is flanked on both sides by canonical urea residues (e.g., oligomers 2-6), one series with canonical residues on either side of the Pro(u) repeat (oligomers 12 and 23), and one series consisting exclusively of Pro(u) residues (oligomers 25 and 26). Spectroscopic (NMR and electronic circular dichroism) and X-ray diffraction studies reveal that the 2.5-helix formed by oligomers of N,N' disubstituted ureas is robust enough to accommodate short oligopyrrolidine segments (Pro(u))n (n < 7) that alone display no intrinsic folding propensity. PMID- 24810880 TI - Role of histone acetyltransferases and histone deacetylases in adipocyte differentiation and adipogenesis. AB - Adipogenesis is a complex process strictly regulated by a well-established cascade that has been thoroughly studied in the last two decades. This process is governed by complex regulatory networks that involve the activation/inhibition of multiple functional genes, and is controlled by histone-modifying enzymes. Among such modification enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the transcriptional regulation and post-translational modification of protein acetylation. HATs and HDACs have been shown to respond to signals that regulate cell differentiation, participate in the regulation of protein acetylation, mediate transcription and post-translation modifications, and directly acetylate/deacetylate various transcription factors and regulatory proteins. In this paper, we review the role of HATs and HDACs in white and brown adipocyte differentiation and adipogenesis, to expand our knowledge on fat formation and adipose tissue biology. PMID- 24810881 TI - Vimentin intermediate filament and plectin provide a scaffold for invadopodia, facilitating cancer cell invasion and extravasation for metastasis. AB - To investigate the molecular mechanisms of cancer metastasis, we have isolated a high-metastatic bladder cancer cell subpopulation from a low-metastatic cell line by using an in vivo selection system. Cells in the subpopulation showed a high ability to form invadopodia, the filamentous actin (F-actin)-based membrane protrusions that play an essential role in cancer cell invasion. Analysis of the gene expression profile revealed that the expression of an intermediate filament (IF) protein, vimentin and a cytoskeletal linker protein, plectin was up regulated in the high-metastatic subpopulation compared with the low metastatic cell line. Here we report a novel role of vimentin IF and plectin in metastasis. In invasive bladder cancer cells, the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of extracellular matrix degradation, transendothelial migration and metastasis. In addition, the vimentin assembly into the filaments was required for invadopodia formation. Our results suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular process for cancer cell invasion and extravasation for metastasis. PMID- 24810882 TI - MiR-134 blockade prevents status epilepticus like-activity and is neuroprotective in cultured hippocampal neurons. AB - Status epilepticus (SE) is a life-threatening neurological disorder associated with significant morbidity and mortality. MicroRNAs (miRNAs) are small, non coding RNAs that act post-transcriptionally modulating messenger RNA (mRNA) translation or stability which may have important roles in the pathogenesis of epilepsy. It has been reported that silencing microRNA-134 in vivo has significant neuroprotective and prolonged seizure-suppressive effects. However, the mechanism by which miR-134 inhibition suppressed seizures and whether miR-134 inhibition works in an in vitro model of SE, is unknown. Compared to a complex in vivo system, in vitro models of SE-like electrographic activity can be powerful tools to study this miRNA. Using a cell culture model of low Mg(2+) treatment of rat hippocampal neurons, we found SE-like electrographic activity increased expression of miR-134. Inhibiting expression of miR-134 using an inhibitor lentivirus with two miR-134 binding sites reduced SE-like electrographic activity in the hippocampal neurons and reduced neuronal death. This study provides direct evidence that inhibition of miR-134 can block status epilepticus-like discharges and is neuroprotective in hippocampal neuronal cultures and implies that inhibiting miR-134 may be a potential candidate for the clinical treatment of SE. PMID- 24810883 TI - Xanthoceraside rescues learning and memory deficits through attenuating beta amyloid deposition and tau hyperphosphorylation in APP mice. AB - Xanthoceraside, a triterpenoid saponin, has been shown to reverse cognitive deficits in several Alzheimer's disease (AD) animal models. However, the effects of xanthoceraside on the Abeta deposition pathology and the APP processing in AD are unclear. Here, we show that xanthoceraside at doses of 0.08 and 0.32 mg/kg/d for 6 months significantly improved learning and memory impairment in APP transgenic mice assessed by the Y maze and novel object recognition tests. Immunohistochemical analyses revealed that xanthoceraside strongly attenuated beta-amyloid deposition in the brains of APP transgenic mice. Western blotting revealed that xanthoceraside decreased tau phosphorylation protein levels at Ser396 and Ser404 in the hippocampus; xanthoceraside also decreased APP protein levels and GSK-3beta phosphorylation. These results suggest that xanthoceraside could be a promising novel candidate for the therapy of AD. PMID- 24810884 TI - Somatostatin 4 receptor activation modulates TRPV1[correction of TPRV1] currents in dorsal root ganglion neurons. AB - Somatostatin (sst) is a cyclic neuropeptide known to have inhibitory roles in the central nervous system. It exerts its biological effects via the activation of the 5 sst receptor subtypes, which belong to the family of G-protein coupled receptors (GPCR). This peptide has analgesic properties, specifically via the activation of the sst4 receptor subtype. Although this is established, the precise molecular mechanisms causing this have not yet been fully elucidated. This research aimed to identify a possible anti-nociceptive mechanism, showing functional links to the transient receptor potential vanilloid type 1 (TRPV1) within the pain processing pathway. Calcium imaging and whole cell voltage clamp experiments were conducted on DRG neurons prepared from adult rats, utilizing capsaicin stimulations and the sst4 receptor specific agonist J-2156. The complete Freund's adjuvant (CFA) inflammatory pain model was used to examine if effects are augmented in pain conditions. The sst4 receptor agonist J-2156 was able significantly to inhibit capsaicin induced calcium and sodium influx, where the effect was more potent after CFA treatment. This inhibition identifies a contributory molecular mechanism to the analgesic properties of sst4 receptor activation. PMID- 24810885 TI - Increased serum brain-derived neurotrophic factor levels during opiate withdrawal. AB - Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of opiate addiction. Both increased and decreased serum BDNF levels have been reported in heroin addicts. Moreover, the role of BDNF in heroin dependent patients during withdrawal has not been studied. This study aimed to explore the differences in serum BDNF levels of heroin addicts and healthy controls, and investigate the changes of serum BDNF levels in heroin addicts at baseline and at one month after heroin cessation. Seventy-two heroin-dependent patients and ninety age- and gender-matched healthy controls were enrolled in this study. We measured serum BDNF levels at baseline (both heroin addicts and healthy controls) and one month after heroin cessation (heroin addicts only). A total of 37 (51.4%) heroin addicts completed the one-month study. We found that baseline serum BDNF levels were significantly higher in heroin addicts compared to controls (F=36.5, p=0.001). There was no difference in serum BDNF levels among heroin addicts at baseline and one month after heroin cessation (F=1.101, p=0.301). These results indicate that BDNF may play a critical role in the course of opiate addiction and withdrawal. PMID- 24810886 TI - Assisted reproductive technology results: why are live-birth percentages so low? AB - The present bioessay aims to analyze the impact of parental age, cause of infertility, embryo chromosomal anomalies, assisted reproduction technology (ART) treatments, and environmental and occupational exposures to xenobiotics on ART results, particularly on live-birth percentages per transfer. Special attention is paid to analyzing the effects of these factors on the mitochondrial, genetic, and epigenetic traits of gametes and embryos to ascertain the molecular/cellular mechanisms responsible for the relatively low percentages of live births reported year after year in ART cycles. The bias of age distribution of women attending fertility clinics toward the late thirties and beyond and the high incidence of mosaicism found in pre-implantation embryos emerge as the two biggest players in this scenario. Parental reproductive aging and some causes of infertility are associated with mitochondrial, genetic, and epigenetic alterations to gametes. ART treatments such as ovarian stimulation, gamete/embryo cryopreservation, oocyte in vitro maturation, intracytoplasmic sperm injection, in vitro culture system, and embryo biopsy may also induce epigenetic changes in gametes and/or pre-implantation embryos. Finally, exposure to numerous environmental chemicals is linked to sperm genetic and epigenetic defects. Whereas the selective transfer of euploid blastocysts may improve implantation and pregnancy percentages, especially in reproductively older women, it does not guarantee the total absence of mitochondrial and/or epigenetic defects in embryos. The presence of induced and/or inherited DNA epigenetic disturbances in ART offspring is unlikely to be prevented, even by replacing the whole cytoplasm of oocytes using nuclear-genome transfer technology. PMID- 24810887 TI - Forced oscillation technique in spinal muscular atrophy. AB - BACKGROUND: Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. METHODS: Children with SMA aged < 10 years were recruited. FOT was performed every 3 months for 12 months (five visits). Spirometry and assisted and unassisted peak cough flow (PCF) were performed where possible. Polysomnography was performed on children with type 2 SMA. Clinical information included SMA type, chest infections, Cobb angle, medications, and mobility. Regression analysis assessed relationships between FOT and FVC, PCF, and apnea/hypopnea index (AHI). Analysis of variance sought relationships to clinical characteristics. RESULTS: Twelve children (seven male) were recruited; mean age was 6.26 (+/- 2.59) years. Respiratory reactance at 8 Hz (Xrs8) (mean z score, +1.41; SD, 1.90; P < .03) and respiratory resistance at 8 Hz (Rrs8) (mean z score, +0.66; SD, 1.34; P = .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8z score worsened (rate of change of +1.08, P < .001) and Rrs8z score worsened (rate of change +0.51, P < .001). No relationship (P > .05) was found between clinical characteristics and FOT values. CONCLUSIONS: FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted. PMID- 24810888 TI - European type-approval test procedure for evaporative emissions from passenger cars against real-world mobility data from two Italian provinces. AB - This paper presents an evaluation of the European type-approval test procedure for evaporative emissions from passenger cars based on real-world mobility data. The study relies on two large databases of driving patterns from conventional fuel vehicles collected by means of on-board GPS systems in the Italian provinces of Modena and Firenze. Approximately 28,000 vehicles were monitored, corresponding to approximately 36 million kilometres over a period of one month. The driving pattern of each vehicle was processed to derive the relation between trip length and parking duration, and the rate of occurrence of parking events against multiple evaporative cycles, defined on the basis of the type-approval test procedure as 12-hour diurnal time windows. These results are used as input for an emission simulation model, which calculates the total evaporative emissions given the characteristics of the evaporative emission control system of the vehicle and the ambient temperature conditions. The results suggest that the evaporative emission control system, fitted to the vehicles from Euro 3 step and optimised for the current type-approval test procedure, could not efficiently work under real-world conditions, resulting in evaporative emissions well above the type-approval limit, especially for small size vehicles and warm climate conditions. This calls for a revision of the type-approval test procedure in order to address real-world evaporative emissions. PMID- 24810889 TI - PM2.5 emissions from light-duty gasoline vehicles in Beijing, China. AB - As stricter standards for diesel vehicles are implemented in China, and the use of diesel trucks is forbidden in urban areas, determining the contribution of light-duty gasoline vehicles (LDGVs) to on-road PM2.5 emissions in cities is important. Additionally, in terms of particle number and size, particulates emitted from LDGVs have a greater health impact than particulates emitted from diesel vehicles. In this work, we measured PM2.5 emissions from 20 LDGVs in Beijing, using an improved combined on-board emission measurement system. We compared these measurements with those reported in previous studies, and estimated the contribution of LDGVs to on-road PM2.5 emissions in Beijing. The results show that the PM2.5 emission factors for LDGVs, complying with European Emission Standards Euro-0 through Euro-4 were: 117.4 +/- 142, 24.1 +/- 20.4, 4.85 +/- 7.86, 0.99 +/- 1.32, 0.17 +/- 0.15 mg/km, respectively. Our results show a significant decline in emissions with improving vehicle technology. However, this trend is not reflected in recent emission inventory studies. The daytime contributions of LDGVs to PM2.5 emissions on highways, arterials, residential roads, and within urban areas of Beijing were 44%, 62%, 57%, and 57%, respectively. The contribution of LDGVs to PM2.5 emissions varied both for different road types and for different times. PMID- 24810890 TI - Purification and biochemical characterization of a novel protease from Penicillium digitatum - Use in bioactive peptides production. AB - This work reports the production of a novel serine protease enzyme (P. dig protease) from the fungus Penicillium digitatum. The protease was purified from the culture supernatant to homogeneity using ammonium sulfate precipitation, Sephadex G-150 gel filtration and carboxymethyl-sepharose ion exchange chromatography with a 13-fold increase in specific activity. The apparent molecular weight of P.dig-protease was estimated to be 120 kDa by native high performance liquid chromatography (HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a single polypeptide at about 30 kDa that indicates a tetrameric protein. The proteolytic activity was inhibited by phenylmethylsulfonyl fluoride suggesting a serine-protease enzyme. P.dig-protease stability was investigated over broad range of pH, temperature, salt concentrations, surfactants and metal ions. The purified P.dig-protease was used for the production of bioactive peptides. Red scorpionfish (Scorpaena notata) muscle was hydrolyzed with P.dig-protease in order to obtain peptides with biological activities. Interestingly, the hydrolysate revealed the presence of antioxidant and angiotensin-I converting enzyme inhibitor peptides. PMID- 24810891 TI - [Two-year results of a prospective randomised controlled multicenter trial to compare open operative therapy vs. endoluminal venous laser therapy with and without high ligation for the therapy of varicose greater saphenous veins]. AB - INTRODUCTION: Therapeutic options for the treatment of varicosis of the great saphenous vein (gsv) include endoluminal laser therapy, crossectomy/stripping and a combination of both. In this paper we present data for clinical and sonographic inguinal recurrencies up to two years post operation. MATERIAL AND METHODS: In an open multicentre, randomised three-arm trial, sonographic and clinical parameters were compared perioperatively, after 2, 6, 12 and 24 months between endoluminal venous laser therapy, high ligation and invaginating stripping and a combination of both (laser: 980 nm, continuous mode, 30 W, Biolitec(r), Jena, Germany). Data of 449 patients were available for the perioperative and 2 months examination. 388 patients were followed up until 6, 380 patients for 12 and 332 patients for 24 months. We compared clinical recurrences, sonographic reflux findings, and reflux side branches in the inguinal region at the saphenofemoral junction. RESULTS: We found significantly more inguinal reflux and reflux side branches in the laser groups (p < 0.0001), however, there was no statistically significant relation between clinical recurrences and sonographic reflux. Over time, there were no intraindividual constant refluxes. Regarding the secondary endpoints oedema, lymphatic oedema, local disturbances of sensibility and irritations of the saphenous nerve, lymphatic oedema and irritations of the saphenous nerve were significantly more present in the two laser groups. After two years pain and restrictions in professional life were no longer relevant in all groups. DISCUSSION: Clinical recurrences developed both in the C/S and in the laser group but reflux into the gsv and into proximal side branches developed significantly more often in the laser group. In a long-term follow-up we have to investigate the importance of reflux side branches for the development of clinical recurrences to reveal differences between the three therapeutic strategies. PMID- 24810892 TI - [Oligometastatic non-small cell lung cancer--surgical options and therapy strategies]. AB - OBJECTIVE: The therapeutic strategies for oligometastatic non-small cell lung cancer have changed over the last decade from palliative to curative intent. The role of surgery in this multimodal treatment in selected patients remains a subject for open discussion. METHODS: Data of 34 patients with one or two metastases treated from January 1998 to January 2013 were retrospectively analysed. RESULTS: The mean age was 59.7 (+/- 10.1) years. The male vs. female ratio was 20 vs. 14. Adenocarcinoma was the most common histological type (58.8 %). The synchronous metastases were present in 15 patients, the metachronous in 19 patients. Single metastases were present in 27 patients, two metastases in 7 patients. The most frequently involved organs were brain (58.8 %) and the lungs (23.6 %). The primary tumour resection was achievable in 20 patients as R0 and in 2 patients as R1. The median overall survival, the local and the systemic disease free survivals in the entire group were 40, 38 and 25 months, respectively. The 5 year overall survival, the 5 year local and systemic disease-free survivals were 29.2, 26.9 and 16.5 %, respectively. The treatment strategies including surgery for primary tumour as well as for pulmonary metastases site, combined with the lymph node dissection and the resection of the extracerebral and cerebral metastases, were identified as independent prognostic factors for long-term survival. CONCLUSION: Surgery in oligometastatic non-small cell lung carcinoma is feasible for primary tumour and for metastases. It is an effective option in the multimodal treatment in highly selected patients. The lymph node dissection should remain an important integral part of the surgical treatment. PMID- 24810893 TI - Integrin receptors on tumor cells facilitate NK cell-mediated antibody-dependent cytotoxicity. AB - NK cells that mediate ADCC play an important role in tumor-specific immunity. We have examined factors limiting specific lysis of tumor cells by CD16.NK-92 cells induced by CNTO 95LF antibodies recognizing alphaV integrins that are overexpressed on many tumor cells. Although all tested tumor cells were killed by CD16.NK-92 effectors in the presence of the antibodies, the killing of target cells with a low level of ICAM-1 expression revealed a dramatic decrease in their specific lysis at high antibody concentration, revealing a dose limiting effect. A similar effect was also observed with primary human NK cells. The effect was erased after IFN-gamma treatment of tumor cells resulting in upregulation of ICAM 1. Furthermore, killing of the same tumor cells induced by Herceptin antibody was significantly impaired in the presence of CNTO 95Ala-Ala antibody variant that blocks alphaV integrins but is incapable of binding to CD16. These data suggest that alphaV integrins on tumor cells could compensate for the loss of ICAM-1 molecules, thereby facilitating ADCC by NK cells. Thus, NK cells could exercise cytolytic activity against ICAM-1 deficient tumor cells in the absence of proinflammatory cytokines, emphasizing the importance of NK cells in tumor specific immunity at early stages of cancer. PMID- 24810894 TI - Epigenetic regulation of sox30 is associated with testis development in mice. AB - DNA methylation is involved in tissue-specific and developmentally regulated gene expression. Here, we screened a novel methylation gene Sox30, whose methylation might contribute to its regulation and testis development in mice. Sox30 is a member of Sox transcription factors, and is considered to be involved in spermatogonial differentiation and spermatogenesis. However, the precise function and regulatory expression pattern remain unclear. In the present study, we found that Sox30 is highly expressed in adult testes but not in ovaries. Sox30 expression begins in early development, and in the testes, it is specifically increased coincidentally with development until adulthood. Moreover, Sox30 is expressed not only in testis germ cells, but also in sertoli cells. Sox30 is hypo methylated in testis, epididymis and lung of adult mice, in which Sox30 is expressed. By contrast, Sox30 is hypermethylated in ovary, heart, brain, liver, kidney, spleen, pancreas, muscle, intestine, pituitary gland, blood and hippocampus of adult mice, in which the Sox30 is absent. Importantly, decreased methylation at CpG islands of Sox30 is observed in mouse developmental testes after birth, which is associated with enhanced Sox30 expression. However, the hypermethylated status of Sox30 is maintained in ovaries that does not express Sox30 during this period. Further, following demethylation treatment using 5-aza dC, Sox30 expression is restored in GC2, TM3 and TM4 cell lines. This observation convincingly confirms that methylation really contributes to Sox30 silencing. In summary, we show that Sox30 expression is under the control of DNA methylation status, and this expression pattern is associated with testis development in mice. PMID- 24810895 TI - A tracer bolus method for investigating glutamine kinetics in humans. AB - Glutamine transport between tissues is important for the outcome of critically ill patients. Investigation of glutamine kinetics is, therefore, necessary to understand glutamine metabolism in these patients in order to improve future intervention studies. Endogenous glutamine production can be measured by continuous infusion of a glutamine tracer, which necessitates a minimum measurement time period. In order to reduce this problem, we used and validated a tracer bolus injection method. Furthermore, this method was used to measure the glutamine production in healthy volunteers in the post-absorptive state, with extra alanine and with glutamine supplementation and parenteral nutrition. Healthy volunteers received a bolus injection of [1-13C] glutamine, and blood was collected from the radial artery to measure tracer enrichment over 90 minutes. Endogenous rate of appearance (endoRa) of glutamine was calculated from the enrichment decay curve and corrected for the extra glutamine supplementation. The glutamine endoRa of healthy volunteers was 6.1+/-0.9 umol/kg/min in the post absorptive state, 6.9+/-1.0 umol/kg/min with extra alanyl-glutamine (p = 0.29 versus control), 6.1+/-0.4 umol/kg/min with extra alanine only (p = 0.32 versus control), and 7.5+/-0.9 umol/kg/min with extra alanyl-glutamine and parenteral nutrition (p = 0.049 versus control). In conclusion, a tracer bolus injection method to measure glutamine endoRa showed good reproducibility and small variation at baseline as well as during parenteral nutrition. Additionally, we showed that parenteral nutrition including alanyl-glutamine increased glutamine endoRa in healthy volunteers, which was not attributable to the alanine part of the dipeptide. PMID- 24810896 TI - A reassessment of the role of sucrose synthase in the hypoxic sucrose-ethanol transition in Arabidopsis. AB - Plants under low-oxygen availability adapt their metabolism to compensate for the lower ATP production that arises from the limited respiratory activity in mitochondria. Anaerobic glycolysis requires continuous fuelling of carbon units, also provided from sucrose. The anaerobic catabolism of sucrose is thought to require the activity of sucrose synthase, being this enzymatic reaction more energetically favourable than that of invertase. The role of sucrose synthases (SUS) for aerobic sucrose catabolism in Arabidopsis has been recently questioned since SUS mutants fail to show altered phenotype or metabolic profile. In the present paper, we analysed the role of SUS1 and SUS4, both induced by low oxygen, in plant survival and ethanol production. The results showed that mutants lacking both SUS were as tolerant to low oxygen as the wild type in most of the experimental conditions tested. Only under conditions of limiting sugar availability the requirement of SUS1 and SUS4 for ethanol production was evident, although partly compensated by invertase activities, as revealed by the use of a double mutant lacking the two major cytosolic invertases. We conclude that, contrary to general belief, the sucrose synthase pathway is not the preferential route for sucrose metabolism under hypoxia. PMID- 24810897 TI - Clinical relevance of decreased oxygen saturation during 6-min walk test in preoperative physiologic assessment for lung cancer surgery. AB - OBJECTIVE: The Japanese Association for Chest Surgery (JACS) has released guidelines on preoperative physiologic assessment for lung cancer surgery. However, cardiopulmonary exercise testing (CPET), which is recommended for patients with poor pulmonary function, is available only in limited institutions. We investigated the possibility of 6-min walk test (6MWT) as a substitute of maximum oxygen consumption test (VO(2)max) on preoperative physiologic assessment for lung cancer surgery. METHODS: The relationship between VO(2)max and 6MWT was retrospectively analyzed in 51 subjects other than lung cancer patients. Following the preliminary analysis, we modified the risk assessment in the JACS guidelines by substituting 6MWT for VO(2)max, and patients who underwent lung cancer surgery were retrospectively assessed using the modified assessment. RESULTS: Analysis of the correlation between VO(2)max and 6MWT revealed VO(2)max to be significantly correlated to minimum SpO(2) (SpO(2)min) and maximum decrease in SpO(2) (DeltaSpO(2)) during 6MWT. Receiver operating characteristic analysis revealed that SpO(2)min and DeltaSpO(2) were predictable for a VO(2)max of 15 mL/kg/min, which is the borderline between the average- and increased-risk groups in the JACS guidelines. A total of 1,066 patients were assigned to the average- or increased-risk group according to the modified JACS guidelines using the criteria of SpO(2)min < 91 % and DeltaSpO(2) > 4 %. The increased-risk group was significantly inferior to the average-risk group in Home Oxygen Therapy induction rate, cardiopulmonary-related 30- and 90-day mortality (p < 0.001). CONCLUSIONS: In clinical practice, decreased saturation during 6MWT may be simple and substitutive for CPET in risk assessment for lung cancer surgery using the JACS guidelines. PMID- 24810898 TI - Coronary endarterectomy for the diffusely diseased coronary artery. AB - The diffusely diseased coronary artery is challenging for cardiac surgeons because diffuse atheromatous lesions frequently render it unsuitable for conventional distal grafting. Coronary endarterectomy was introduced in the 1950s as a treatment option for diffusely diseased coronary arteries. However, initial studies demonstrated high operative mortality and morbidity associated with coronary endarterectomy; therefore, many cardiac surgeons have been reluctant to perform this procedure. With percutaneous coronary interventions increasingly being applied to coronary artery disease, the incidence of complex and diffuse coronary artery disease in patients referred for coronary artery bypass surgery has been increasing, and recent advances in the surgical technique and perioperative management have improved the surgical outcomes of coronary endarterectomy. In this review article, we sought to discuss coronary endarterectomy for the diffusely diseased coronary artery. PMID- 24810899 TI - Efficacy of cardiopulmonary resuscitation in the supine position with manual displacement of the uterus vs lateral tilt using a firm wedge: a manikin study. AB - Prevention of aortocaval compression is essential for effective cardiopulmonary resuscitation in late pregnancy. This can be achieved by either lateral maternal tilt or lateral uterine displacement. Results from a previous manikin study show that a firm foam-rubber wedge allowed successful chest compressions whilst providing stable and reliable lateral tilt. However, it did not investigate resuscitation in the supine position with manual uterine displacement. The aim of this study was to compare the effectiveness of chest compressions in a manikin in the supine position vs lateral tilt using a foam-rubber wedge, both on the floor and on a typical patient bed. Overall, we found that compressions were easier to perform in the supine position (p = 0.007 (bed) and 0.048 (floor)), and with greater stability in the supine position on the floor (p = 0.011). The effectiveness of chest compressions was similar in both the supine/uterine displacement and the lateral tilt positions, suggesting that either method may be suitable for CPR. PMID- 24810900 TI - Effects of low dose versus high dose human growth hormone on body composition and lipids in adults with GH deficiency: a meta-analysis of placebo-controlled randomized trials. AB - PURPOSE: Doses of growth hormone in adults with growth hormone deficiency are now lower than previously. However, it is not clear they are as effective as higher doses. The objective of this meta-analysis was to assess efficacy of low to moderate dose (LD) GH replacement on standard endpoints of GH compared to higher doses. METHODS: A meta-analysis was carried out using PubMed, Cochrane and Embase databases from 1960 to 9/23/12. Three reviewers identified randomized double blind, placebo-controlled trials of 6 months duration. Of 173 publications, 28 representing 22 trials (591 GH-treated patients and 562 placebo) were included. Data were independently extracted by three reviewers. Endpoints were analyzed if >=4 studies per dose group reported baseline and 6 month data. RESULTS: Mean lean body mass (LBM) increased by 2.61 kg in GH-treated subjects versus 0.04 in the placebo group (P < 0.0001). Fat mass (FM) was reduced by -2.19 kg versus 0.31 (GH vs. placebo) (P = 0.0002). Changes in LBM and FM were dose-related (P = 0.02 and 0.007, respectively), high dose (HD) being more effective than low dose (LBM P = 0.03 and FM P = 0.04). In contrast, treatment with GH reduced total cholesterol 0.38 mmol/L versus. 0.01 (placebo) (P < 0.0001), and low density lipoprotein cholesterol (LDL-C) -0.42 mmol/L versus -0.1 (P = 0.0009), but there were no differences between LD and HD GH. CONCLUSIONS: LDs of hGH improve total- and LDL C, and body composition. Higher doses are more effective on body composition, but not lipids. PMID- 24810901 TI - Assessing the relationship between vector indices and dengue transmission: a systematic review of the evidence. AB - BACKGROUND: Despite doubts about methods used and the association between vector density and dengue transmission, routine sampling of mosquito vector populations is common in dengue-endemic countries worldwide. This study examined the evidence from published studies for the existence of any quantitative relationship between vector indices and dengue cases. METHODOLOGY/PRINCIPAL FINDINGS: From a total of 1205 papers identified in database searches following Cochrane and PRISMA Group guidelines, 18 were included for review. Eligibility criteria included 3-month study duration and dengue case confirmation by WHO case definition and/or serology. A range of designs were seen, particularly in spatial sampling and analyses, and all but 3 were classed as weak study designs. Eleven of eighteen studies generated Stegomyia indices from combined larval and pupal data. Adult vector data were reported in only three studies. Of thirteen studies that investigated associations between vector indices and dengue cases, 4 reported positive correlations, 4 found no correlation and 5 reported ambiguous or inconclusive associations. Six out of 7 studies that measured Breteau Indices reported dengue transmission at levels below the currently accepted threshold of 5. CONCLUSIONS/SIGNIFICANCE: There was little evidence of quantifiable associations between vector indices and dengue transmission that could reliably be used for outbreak prediction. This review highlighted the need for standardized sampling protocols that adequately consider dengue spatial heterogeneity. Recommendations for more appropriately designed studies include: standardized study design to elucidate the relationship between vector abundance and dengue transmission; adult mosquito sampling should be routine; single values of Breteau or other indices are not reliable universal dengue transmission thresholds; better knowledge of vector ecology is required. PMID- 24810902 TI - Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity. AB - Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1 benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 uM, in agreement with its DNMT3A inhibitory potency. PMID- 24810903 TI - Distinction of salvaged and infarcted myocardium within the ischaemic area-at risk with T2 mapping. AB - AIM: Area-at-risk (AAR) measurements often rely on T2-weighted images, but subtle differences in T2 may be overlooked with this method. To determine the differences in oedema between salvaged and infarcted myocardium, we performed quantitative T2 mapping of the AAR. We also aimed to determine the impact of reperfusion time on T2 in the AAR. METHODS: Twenty-two dogs underwent 2 h of coronary occlusion followed by 4 or 48 h of reperfusion before cardiac magnetic resonance imaging at 1.5 T. Late gadolinium enhancement images were used to define the infarcted, salvaged, and remote myocardium. T2 values from T2 maps and signal intensities on T2-weighted images were measured in the corresponding areas. RESULTS: At both imaging time points, the T2 of the salvaged myocardium was longer than of remote (66.0 +/- 6.9 vs. 51.4 +/- 3.5 ms, P < 0.001 at 4 h, and 56.7 +/- 7.3 vs. 48.1 +/- 3.5 ms, P < 0.001 at 48 h). The T2 was also longer in the infarcted myocardium compared with remote at both 4 and 48 h (71.4 +/- 7.6 ms, P < 0.01 vs. salvage and 64.0 +/- 6.9 ms, P = 0.03 vs. salvage, both P < 0.001 vs. remote). The increase in T2 in the salvaged myocardium compared with remote was greater after 4 h than after 48 h (14.7 +/- 5.6 vs. 8.7 +/- 5.1 ms, P = 0.02). CONCLUSIONS: T2 relaxation parameters are different in the infarcted and salvaged myocardium, and both are significantly longer than remote. Furthermore, the magnitude of increase in T2 was less in the salvaged myocardium after longer reperfusion, indicating partial resolution of oedema in the first 48 h after reperfusion. PMID- 24810904 TI - Necrostatin-1 inhibits Hmgb1-IL-23/IL-17 pathway and attenuates cardiac ischemia reperfusion injury. AB - Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Necrostatin-1 (Nec-1) is a small molecule capable of inhibiting RIP1 kinase activity and attenuates inflammation-mediated tissue injury. In our study, hearts of C57Bl/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipients. We found that Nec-1 decreased cardiomyocyte necrosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by Nec-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with Nec-1 administration and the cardiac allograft survival in Nec-1-treated animals was significantly prolonged (MST = 90 days in IR + Nec-1 group, P < 0.05 as compared with IR group, MST = 83.5 days). Nec-1 treatment attenuated ROS generation and increased expression of NOS2 and COX-2. The expression of Hmgb1, IL-23, and IL-17A were also decreased with Nec-1 administration. Furthermore, the decreased TnT expression induced by Nec-1 was abrogated with exogenous Hmgb1 administration. In conclusion, Nec-1 played a protective role in cardiomyocyte IR injury, and this was associated with inhibited Hmgb1-IL-23/IL-17 pathway. PMID- 24810907 TI - Every second counts: innovations to increase timely defibrillation rates. AB - Early defibrillation is an essential step in the "chain of survival" for patients with in-hospital cardiac arrest. To increase the rate of early defibrillation by nurse first responders in noncritical care areas, our institution employed a quality resuscitation consultant, implemented nursing education programs, and standardized equipment and practices. Automated external defibrillator application by nurse first responders prior to advanced cardiac life support team arrival has improved from 15% in 2011 to 76% in 2013 (P < .001). PMID- 24810906 TI - Epigenetic silencing of EYA2 in pancreatic adenocarcinomas promotes tumor growth. AB - To identify potentially important genes dysregulated in pancreatic cancer, we analyzed genome-wide transcriptional analysis of pancreatic cancers and normal pancreatic duct samples and identified the transcriptional coactivator, EYA2 (Drosophila Eyes Absent Homologue-2) as silenced in the majority of pancreatic cancers. We investigated the role of epigenetic mechanisms of EYA2 gene silencing in pancreatic cancers, performed in vitro and in vivo proliferation and migration assays to assess the effect of EYA2 silencing on tumor cell growth and metastasis formation, and expression analysis to identify genes transcriptionally regulated by EYA2. We found loss of tumoral Eya2 expression in 63% of pancreatic cancers (120/189 cases). Silencing of EYA2 expression in pancreatic cancer cell lines correlated with promoter methylation and histone deacetylation and was reversible with DNA methyltransferase and HDAC inhibitors. EYA2 knockdown in pancreatic cancer cell lines increased cell proliferation. Compared to parental pancreatic cancer cells, pancreatic cancers stably-expressing EYA2 grew more slowly and had fewer metastases in orthotopic models. The transcriptional changes after stable expression of EYA2 in pancreatic cancer cells included induction of genes in the TGFbeta pathway. Epigenetic silencing of EYA2 is a common event in pancreatic cancers and stable expression EYA2 limits the growth and metastases of pancreatic adenocarcinoma. PMID- 24810908 TI - Sustainability of improvements in perinatal teamwork and safety climate. AB - The purposes of this study were to describe changes in perinatal nurse (n = 70) and physician (n = 88) perceptions of teamwork and safety climate after implementing a 6-month Crew Resource Management training program and compare responses between nurses and physicians. The Teamwork and Safety Climate Survey was administered prior to and 1 year after the intervention. There were significant improvements in nurse and physician perceptions of teamwork and safety climate; however, physicians perceived teamwork more positive than nurses. PMID- 24810909 TI - Pathologic and cardiovascular characterization of pheochromocytoma-associated cardiomyopathy in dogs. AB - Pheochromocytoma-associated catecholamine-induced cardiomyopathy is a well-known entity in man, nonhuman primates, and mice but has not been described in dogs. In this retrospective study, 9 dogs were identified with pheochromocytomas and concurrent cardiovascular pathology observed histologically (n = 6), echocardiographically (n = 4), and/or electrocardiographically (n = 5). Cardiac lesions included multifocal cardiomyocyte necrosis with contraction bands, cardiomyocyte degeneration, myocardial hemorrhage, lymphohistiocytic myocarditis, and interstitial fibrosis. Clinical procedures, including electrocardiographic and echocardiographic examinations, Doppler blood pressure measurement, and auscultation, were available for 5 dogs and consistently revealed concentric or mixed (eccentric and concentric) ventricular hypertrophy. Additional changes observed included arrhythmias, systemic hypertension, and heart murmurs. The myocardial lesions observed in this series of dogs are similar to those observed in humans with pheochromocytoma-associated catecholamine-induced cardiomyopathy. Since the clinical manifestations of catecholamine-induced cardiac disease are amenable to medical treatment, recognition of this cardiomyopathy has the potential to reduce morbidity and mortality in dogs with pheochromocytoma. PMID- 24810910 TI - Expression and purification of soluble recombinant full length HIV-1 Pr55(Gag) protein in Escherichia coli. AB - The HIV-1 Gag precursor protein, Pr55(Gag), is a multi-domain polyprotein that drives HIV-1 assembly. The morphological features of HIV-1 suggested Pr55(Gag) assumes a variety of different conformations during virion assembly and maturation, yet structural determination of HIV-1 Pr55(Gag) has not been possible due to an inability to express and to isolate large amounts of full-length recombinant Pr55(Gag) for biophysical and biochemical analyses. This challenge is further complicated by HIV-1 Gag's natural propensity to multimerize for the formation of viral particle (with ~2500 Gag molecules per virion), and this has led Pr55(Gag) to aggregate and be expressed as inclusion bodies in a number of in vitro protein expression systems. This study reported the production of a recombinant form of HIV-1 Pr55(Gag) using a bacterial heterologous expression system. Recombinant HIV-1 Pr55(Gag) was expressed with a C-terminal His*6 tag, and purified using a combination of immobilized metal affinity chromatography and size exclusion chromatography. This procedure resulted in the production of milligram quantities of high purity HIV-1 Pr55(Gag) that has a mobility that resembles a trimer in solution using size exclusion chromatography analysis. The high quantity and purity of the full length HIV Gag will be suitable for structural and functional studies to further understand the process of viral assembly, maturation and the development of inhibitors to interfere with the process. PMID- 24810911 TI - Purification and characterization of the acyltransferase involved in biosynthesis of the major mycobacterial cell envelope glycolipid--monoacylated phosphatidylinositol dimannoside. AB - Phosphatidylinositol mannosides are essential structural components of the mycobacterial cell envelope. They are implicated in host-pathogen interactions during infection and serve as a basis for biosynthesis of other unique molecules with immunomodulatory properties - mycobacterial lipopolysaccharides lipoarabinomannan and lipomannan. Acyltransferase Rv2611 is involved in one of the initial steps in the assembly of these molecules in Mycobacterium tuberculosis - the attachment of an acyl group to position-6 of the 2-linked mannosyl residue of the phosphatidylinositol mannoside anchor. Although the function of this enzyme was annotated 10 years ago, it has never been completely biochemically characterized due to lack of the pure protein. We have successfully overexpressed and purified MSMEG_2934, the ortholog of Rv2611c from the non pathogenic model organism Mycobacteriumsmegmatis mc(2)155 using mycobacterial pJAM2 expression system, which allowed confirmation of its in vitro acyltransferase activity, and establishment of its substrate specificity. PMID- 24810913 TI - Quantification of dynamic morphological drug responses in 3D organotypic cell cultures by automated image analysis. AB - Glandular epithelial cells differentiate into complex multicellular or acinar structures, when embedded in three-dimensional (3D) extracellular matrix. The spectrum of different multicellular morphologies formed in 3D is a sensitive indicator for the differentiation potential of normal, non-transformed cells compared to different stages of malignant progression. In addition, single cells or cell aggregates may actively invade the matrix, utilizing epithelial, mesenchymal or mixed modes of motility. Dynamic phenotypic changes involved in 3D tumor cell invasion are sensitive to specific small-molecule inhibitors that target the actin cytoskeleton. We have used a panel of inhibitors to demonstrate the power of automated image analysis as a phenotypic or morphometric readout in cell-based assays. We introduce a streamlined stand-alone software solution that supports large-scale high-content screens, based on complex and organotypic cultures. AMIDA (Automated Morphometric Image Data Analysis) allows quantitative measurements of large numbers of images and structures, with a multitude of different spheroid shapes, sizes, and textures. AMIDA supports an automated workflow, and can be combined with quality control and statistical tools for data interpretation and visualization. We have used a representative panel of 12 prostate and breast cancer lines that display a broad spectrum of different spheroid morphologies and modes of invasion, challenged by a library of 19 direct or indirect modulators of the actin cytoskeleton which induce systematic changes in spheroid morphology and differentiation versus invasion. These results were independently validated by 2D proliferation, apoptosis and cell motility assays. We identified three drugs that primarily attenuated the invasion and formation of invasive processes in 3D, without affecting proliferation or apoptosis. Two of these compounds block Rac signalling, one affects cellular cAMP/cGMP accumulation. Our approach supports the growing needs for user-friendly, straightforward solutions that facilitate large-scale, cell-based 3D assays in basic research, drug discovery, and target validation. PMID- 24810914 TI - Validation of an alternative microbiological method for tissue products. AB - According to the European Pharmacopoeia sterility testing of products includes an incubation time of 14 days in thioglycollate medium and soya-bean casein medium. In this case a large period of time is needed for product testing. So we designed a study to evaluate an alternative method for sterility testing. The aim of this study was to reduce the incubation time for the routinely produced products in our tissue bank (cornea and amnion grafts) by obtaining the same detection limit, accurateness and recovery rates as the reference method described in the European Pharmacopoeia. The study included two steps of validation. Primary validation compared the reference method with the alternative method. Therefore eight bacterial and two fungi test strains were tested at their preferred milieu. A geometric dilution series from 10 to 0.625 colony forming unit per 10 ml culture media was used. Subsequent to the evaluation the second part of the study started including the validation of the fertility of the culture media and the parallel testing of the two methods by investigating products. For this purpose two product batches were tested in three independent runs. Concerning the validation we could not find any aberration between the alternative and the reference method. In addition, the recovery rate of each microorganism was between 83.33 and 100 %. The alternative method showed non-inferiority regarding accuracy to the reference method. Due to this study we reduced the sterility testing for cornea and amniotic grafts to 9 days. PMID- 24810916 TI - Circadian rhythms, insulin action, and glucose homeostasis. AB - PURPOSE OF REVIEW: Accumulating evidence supports a role for the circadian clock in the development of metabolic disease. We discuss the influence of the circadian clock on glucose homeostasis, intermediary factors in this relationship, and potential therapies for the prevention or attenuation of metabolic disease associated with circadian misalignment. RECENT FINDINGS: Murine studies with tissue-specific deletion of core clock genes in key metabolic tissues confirm a mechanistic relationship between the circadian clock and the development of metabolic disease. Circadian misalignment increases insulin resistance and decreases pancreatic function. Clock gene polymorphisms or altered expression of clock genes induced by circadian misalignment appear to play a role in the development of obesity and diabetes in humans. Circadian disruption caused by exposure to light at night is associated with lower nocturnal melatonin, which in turn seems to affect glucose metabolism. Potential therapies for circadian misalignment include entraining the central pacemaker with timed light exposure and/or melatonin and restricting food intake to the biological day. SUMMARY: Completing the understanding of how genetic and environmental factors influence the circadian clock and the effect these have on human circadian metabolic physiology and disease will allow us to develop therapies for treating and preventing associated metabolic disease. PMID- 24810915 TI - Genetic dissection of the Drosophila melanogaster female head transcriptome reveals widespread allelic heterogeneity. AB - Modern genetic mapping is plagued by the "missing heritability" problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies. PMID- 24810919 TI - A Quick Test of Cognitive Speed: norm-referenced criteria for 121 Italian adults aged 45 to 90 years. AB - ABSTRACT Background: A Quick Test of Cognitive Speed (AQT) is a brief test that can identify cognitive impairment. AQT has been validated in Arabic, English, Greek, Japanese, Norwegian, Spanish, and Swedish. The aim of this study was to develop Italian criterion-referenced norms for AQT. Methods: AQT consists of three test plates where the patient shall rapidly name (1) the color of 40 blue, red, yellow, or black squares (AQT color), (2) the form of 40 black figures (circles, squares, triangles, or rectangles; AQT form), (3) the color and form of 40 figures (consisting of previous colors and forms; AQT color-form). The AQT test was administered to 121 Italian cognitively healthy primary care patients (age range: 45-90 years). Their mean Mini-Mental State Examination (MMSE) score was 28.8 +/- 0.9 points (range 26-30 points). AQT naming times in seconds were used for developing preliminary criterion cut-off times for different age groups. Results: Age was found to have a significant moderate positive correlation with AQT naming times color (r = 0.65, p < 0.001), form (r = 0.53, p < 0.001), color form (r = 0.63, p < 0.001) and a moderate negative correlation with MMSE score (r = -0.44, p < 0.001) and AQT naming times differed significantly between younger (45-55 years old), older (56-70 years old), and the oldest (71-90 years old) participants. Years of education correlated positively but weakly with MMSE score (r = 0.27, p = 0.003) and negatively but weakly with AQT color (r = -0.16, p = ns), form (r = -0.24, p = 0.007), and color-form (r = -0.19, p = 0.005). We established preliminary cut-off times for the AQT test based on +1 and +2 standard deviations according to the approach in other languages and settings. Conclusions: This is the first Italian normative AQT study. Future studies of AQT - a test useful for dementia screening in primary care - will eventually refine cut-off times for normality balancing sensitivity and specificity in cognitive diagnostics. PMID- 24810917 TI - Protein-protein interactions in dilute to concentrated solutions: alpha chymotrypsinogen in acidic conditions. AB - Protein-protein interactions were investigated for alpha-chymotrypsinogen by static and dynamic light scattering (SLS and DLS, respectively), as well as small angle neutron scattering (SANS), as a function of protein and salt concentration at acidic conditions. Net protein-protein interactions were probed via the Kirkwood-Buff integral G22 and the static structure factor S(q) from SLS and SANS data. G22 was obtained by regressing the Rayleigh ratio versus protein concentration with a local Taylor series approach, which does not require one to assume the underlying form or nature of intermolecular interactions. In addition, G22 and S(q) were further analyzed by traditional methods involving fits to effective interaction potentials. Although the fitted model parameters were not always physically realistic, the numerical values for G22 and S(q -> 0) were in good agreement from SLS and SANS as a function of protein concentration. In the dilute regime, fitted G22 values agreed with those obtained via the osmotic second virial coefficient B22 and showed that electrostatic interactions are the dominant contribution for colloidal interactions in alpha-chymotrypsinogen solutions. However, as protein concentration increases, the strength of protein protein interactions decreases, with a more pronounced decrease at low salt concentrations. The results are consistent with an effective "crowding" or excluded volume contribution to G22 due to the long-ranged electrostatic repulsions that are prominent even at the moderate range of protein concentrations used here (<40 g/L). These apparent crowding effects were confirmed and quantified by assessing the hydrodynamic factor H(q -> 0), which is obtained by combining measurements of the collective diffusion coefficient from DLS data with measurements of S(q -> 0). H(q -> 0) was significantly less than that for a corresponding hard-sphere system and showed that hydrodynamic nonidealities can lead to qualitatively incorrect conclusions regarding B22, G22, and static protein-protein interactions if one uses only DLS to assess protein interactions. PMID- 24810918 TI - The effects of spatial scale on breakdown of leaves in a tropical watershed. AB - The objective was to assess the effects of natural variation in the physical structure of the environment on biological communities and on the processing of Eucalyptus cloeziana and Inga laurina and to identify the controlling factors at different scales along stream order gradients. The study area consisted of 14 sampling sites distributed within a tropical watershed (1st, 2nd, 3rd and 4th order streams replicated in 4 sub-basins). Our samples consisted of 3 g of leaves of E. cloeziana (high-quality) and I. laurina (low-quality) placed in 252 bags with 10mm mesh (measured by the chemical composition of the detritus). Four samples of each leaf type were collected periodically (three times) over a period of 75-125 days and washed on a sieve to separate the invertebrates. A series of leaf disks were cut to determine ash-free dry mass, polyphenol, lignin, cellulose, total microbial biomass and fungal biomass, and the remaining material was oven-dried to determine the dry weight. We performed analyses within and between spatial scales (regional and local) to assess which watershed scale was the more import determinant of the leaf breakdown rate (k). The microbial and shredder were most influenced at the local scale (stream order). Shredders were influenced by microorganisms, with stronger interactions between them than were found to drive the k at the local scale. Moreover, differences in the overall k and abiotic variables were more strongly influenced at the regional scale (sub basin), showing that the study scale alters the response of the studied variables. We found higher k values at higher values of water velocity, dissolved oxygen and temperature, all of which accelerate biological metabolism in response to variations on the regional scale. Watersheds with warmer microclimates and streams with higher nutrient levels and oxygen could be accelerating the ecosystem metabolism, independent of the detritus quality. PMID- 24810920 TI - A simple strategy for in situ fabrication of a smart hydrogel microvalve within microchannels for thermostatic control. AB - Self-regulation of temperature in microchip systems is crucial for their applications in biomedical fields such as cell culture and biomolecule synthesis as well as those cases that require constant temperature conditions. Here we report on a simple and versatile approach for in situ fabrication of a smart hydrogel microvalve within a microchip for thermostatic control. The thermo responsive hydrogel microvalve enables the "on-off" switch by sensing temperature fluctuations to control the fluid flux as well as the fluid heat exchange for self-regulation of the temperature at a constant range. Such temperature self regulation is demonstrated by integrating the microvalve-incorporated microchip into the flow circulation loop of a micro-heat-exchanging system for thermostatic control. Moreover, the microvalve-incorporated microchip is employed for culturing cells under temperature self-regulation. The smart microvalve shows great potential as a temperature controller for applications that require thermostatic conditions. This approach offers a facile and flexible strategy for in situ fabricating hydrogel microvalves within microchips as chemostats and microreactors for biomedical applications. PMID- 24810921 TI - Psychological distress, depression, anxiety, stress, and exercise in Australian and New Zealand mothers: A cross-sectional survey. AB - Postnatal psychological well-being is a complex issue characterized by major changes in physical, social, and emotional health. In response to addressing limitations of previous research this study aimed to: (i) quantify psychological distress, depression, anxiety, and stress in a large sample of Australian and New Zealand mothers and to compare to Australian norm data; and (ii) identify any significant differences in psychological distress, depression, anxiety, and stress of the mothers when grouped according to their self-reported exercise incidence. Self-reported short-form version Depression Anxiety Stress Scale data were collected from 3601 Australia and New Zealand mothers with at least one child under the age of 5 years. Results demonstrated that this sample of mothers had significantly poorer psychological well-being than the general Australian population. Furthermore, with the exception of anxiety, psychological well-being of mothers who reported exercising three to four times per week was significantly and meaningfully more positive compared to those mothers that reported not to exercise. PMID- 24810922 TI - History and performance of implant materials applied as peritendinous antiadhesives. AB - Peritendinous fibrotic adhesions after tendon surgery are still a problem up-to date. Approaches to overcome or at least minimize adhesion formation include implantation of barrier materials, application of lubricants or combinations of materials and functionalized drugs that are controllably released and support the healing tendon to glide and achieve the full range of motion after regeneration. Although a huge amount of different materials have been experimentally tested, the optimal strategy with respect to material and method has not yet been determined. In this review, we present a historical overview of physical barriers as well as liquid agents that have been used in order to prevent peritendinous adhesion formation. The materials are divided according to their first publication into two time frames; before and after 1980. There is no claim to include all materials tested neither will the "best" material be chosen; however, we present several materials that were experimentally tested in different animal trials as well as in clinical trials in contrast to other materials that were only tested once and disappeared from the assortment of anti-adhesives; which as such is a valuable information about its applicability for this purpose. PMID- 24810923 TI - CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. AB - CXCR4 and its ligand CXCL12 can promote the proliferation, survival, and invasion of cancer cells. They have been shown to play an important role in regulating metastasis of breast cancer to specific organs. High CXCR4 expression was also correlated to poor clinical outcome. Previous study also showed that tumor cells express a high level of CXCR4 and that tumor metastasis target tissues (lung, liver, and bone) express high levels of the ligand CXCL12, allowing tumor cells to directionally migrate to target organs via a CXCL12-CXCR4 chemotactic gradient. However, the exact mechanisms of how CXCR4 and CXCL12 enhance metastasis and/or tumor growth and their full implications on breast cancer progression are unknown. Yet it is likely that chemokine receptor signaling may provide more than just a migrational advantage by also helping the metastasized cells establish and survive in secondary environments. In this study, we investigated CXCR4 and CXCL12 expression in breast cancer and analyzed its association with clinicopathological factors by immunohistochemistry first. Then, we detected the mRNA and protein expression of CXCR4 and CXCL12 in breast cancer cell lines by Western blot and RT-PCR. The MDA-MB-231 has CXCR4 expression and very weak CXCL12 expression. So, we constructed the functional CXCL12 expression in MDA-MB-231 using a gene transfection technique. Further experiments were conducted to evaluate the effect of CXCL12 transfection on the biological behaviors of MDA-MB-231. The cell proliferation of MDA-MB-231-CXCL12 was accessed by MTT assay; the apoptosis was analyzed by an AnnexinV-FITC/propidium iodide double staining of flow cytometry method; and the cell invasive ability was examined by Matrigel invasion assay. Immunohistochemical analysis showed the co expression of CXCR4 and CXCL12 correlated with lymph node metastasis and TNM stage (p < 0.01). It suggested that the chemokine CXCL12 and its sole ligand CXCR4 play important role in the malignance of breast cancer. To gain a deeper insight into it, we picked CXCR4-expressing cells MDA-MB-231 to be transfected with CXCL12 stably. The decreased cellular proliferation, increased apoptosis, and invasive ability were found in MDA-MB-231 with successful CXCL12 transfection (p < 0.05). Our findings underlined the CXCL12-CXCR4 axis correlated tightly with breast cancer metastasis. CXCL12-CXCR4 axis can increase the invasion and apoptosis of MDA-MB-231 simultaneously. These data strongly support the hypothesis that CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. Our findings could have significant implications in terms of breast cancer aggressiveness and the effectiveness of targeting the receptors and downstream signaling pathways for the treatment of breast cancer. PMID- 24810924 TI - Expression of CD34 and maspin in ameloblastoma from a West African subpopulation. AB - Ameloblastoma is a locally invasive odontogenic tumor with a high recurrence rate. Its local invasiveness is aided by angiogenesis, which can be correctly estimated by CD34. On the other hand, maspin decreases the local invasive and metastatic capability of cancer cells and functions as an angiogenesis inhibitor. We aim to assess the association between maspin expression and microvessel density in ameloblastoma. Twenty-five formalin-fixed paraffin-embedded (FFPE) blocks of ameloblastoma cases were prepared for antibody processing to CD34 and maspin. Positive immunohistochemical staining was marked by brown cytoplasmic/membrane coloration for CD34 and by nuclear/cytoplasmic coloration for maspin. At the *40 magnification, we counted blood vessels in two areas of dimension; 300 * 400 MUm (area A) and 150 * 200 MUm (area B) adjacent to the tumor region to assess relative dispersion of the vessels bordering the tumor. The overall approximate microvessel density (MVD) for area A = 11 (minimum 2, maximum 21) and that for area B = 5 (minimum 1, maximum 10). The MVD in the area A of plexiform ameloblastoma was similar to that of the unicystic, while the hemangiomatous variant had the highest MVD for area A. Maspin positivity was present only in the cytoplasm of ameloblast, stellate reticulum, and the fibrous connective tissue in varying proportions. There was no evidence of the anti angiogenesis effect of maspin in ameloblastoma from this study. The significance of cytoplasmic localization of maspin in the ameloblasts and stellate reticulum cells needs further investigation. PMID- 24810925 TI - Long noncoding RNA SPRY4-IT1 is upregulated in esophageal squamous cell carcinoma and associated with poor prognosis. AB - LncRNA SPRY4-IT1 has been shown to promote the progression of melanoma. However, the role of lncRNA SPRY4-IT1 in human esophageal squamous cell carcinoma (ESCC) remains unclear. The purpose of this study is to investigate the clinical significance and biological functions of SPRY4-IT1 in ESCC. The expression levels of lncRNA SPRY4-IT in 92 ESCC patients and 8 ESCC cell lines were evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The prognostic significance was evaluated using Kaplan-Meier and Cox regression analyses. Small interfering RNA (siRNA) was used to suppress SPRY4-IT1 expression in ESCC cell lines. Both in vitro and in vivo assays were performed to further explore its role in tumor progression. SPRY4-IT1 levels were significantly higher in ESCC tissues and cells than in corresponding adjacent noncancerous tissues and nontumorigenic esophageal epithelial cells, and the ESCC patients with higher SPRY4-IT1 expression had an advanced clinical stage and poorer prognosis than those with lower SPRY4-IT1 expression. The multivariate analysis revealed that SPRY4-IT1 expression level is an independent prognostic factor in ESCC patients. In vitro assays demonstrated that knockdown of SPRY4-IT1 reduced cell proliferation, invasiveness, and migration. In vivo assays demonstrated that knockdown of SPRY4-IT1 decreases cell growth. SPRY4-IT1 is a novel molecule involved in ESCC progression, which may provide a potential prognostic biomarker and a potential target for therapeutic intervention. PMID- 24810926 TI - Triple-negative and luminal A breast tumors: differential expression of miR-18a 5p, miR-17-5p, and miR-20a-5p. AB - New concepts in epigenetics, microRNAs, and gene expression analysis have significantly enhanced knowledge of cancer pathogenesis over the last decade. MicroRNAs (miRNAs) are a class of non-coding RNAs that regulate gene expression by base pairing with target messenger RNAs (mRNAs), resulting in the repression of translation or the degradation of mRNA. To compare the carcinogenic process in tumors with different prognoses, we used real-time RT-PCR to evaluate the miRNA expression profiles of 24 triple-negative breast invasive ductal carcinoma, 20 luminal A breast invasive ductal carcinoma, and 13 normal breast parenchyma controls. We extracted total RNA from tissues fixed in formol and embedded in paraffin (FFPE). Results revealed the upregulation of miR-96-5p (9.35-fold; p = 0.000115), miR-182-5p (7.75-fold; p = 0.000033), miR-7-5p (6.71-fold; p = 0.015626), and miR-21-5p (6.10-fold; p = 0.000000) in tumors group. In addition, the expression of miR-125b-5p (4.49-fold; p = 0.000000) and miR-205-5p (4.36 fold; p = 0.006098) was downregulated. When the expression profiles of triple negative and luminal A tumors were compared, there was enhanced expression of miR 17-5p (4.27-fold; p = 0.000664), miR-18a-5p (9.68-fold; p = 0.000545), and miR 20a-5 (4.07-fold; p = 0.001487) in the triple-negative tumors compared with luminal A. These data suggest that there is a similar regulation of certain miRNAs in triple-negative and luminal A tumors. However, it is possible that differences in the expression of miR-17-92 cluster will explain the phenotypic differences between these molecular tumor subtypes. PMID- 24810927 TI - Overexpression of ANXA1 confers independent negative prognostic impact in rectal cancers receiving concurrent chemoradiotherapy. AB - Neoadjuvant concurrent chemoradiation therapy (CCRT) is an increasingly common therapeutic strategy for rectal cancer. Clinically, it remains a major challenge to predict therapeutic response and patient outcomes after CCRT. Annexin I (ANXA1), encoded by ANXA1, is a Ca(2+)/phospholipid-binding protein that mediates actin dynamics and cellular proliferation, as well as suggesting tumor aggressiveness and predicting therapeutic response in certain malignancies. However, expression of ANXA1 has never been reported in rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of ANXA1 expression in patients with rectal cancer following neoadjuvant CCRT. We identified ANXA1 as associated with resistance to CCRT through data mining from a published transcriptomic dataset. Its immunoexpression was retrospectively assessed using H scores on pre-treatment biopsies from 172 rectal cancer patients treated with neoadjuvant CCRT followed by curative surgery. Results were correlated with clinicopathological features, therapeutic response, tumor regression grade (TRG), and metastasis-free survival (MeFS), as well as local recurrent-free survival (LRFS) and disease-specific survival (DSS). High expression of ANXA1 was associated with advanced pre-treatment tumor status (T3, T4, p = 0.022), advanced pre-treatment nodal status (N1, N2, p = 0.004), advanced post-treatment tumor status (T3, T4, p < 0.001), advanced post-treatment nodal status (N1, N2, p = 0.001) and inferior TRG (p = 0.009). In addition, high expression of ANXA1 emerged as an adverse prognosticator for DSS (p < 0.0001), LRFS (p = 0.0001) and MeFS (p = 0.0004). Moreover, high expression of ANXA1 also remained independently prognostic of worse DSS (hazard ratio [HR] = 3.998; p = 0.007), LRFS (HR = 3.206; p = 0.028) and MeFS (HR = 3.075; p = 0.017). This study concludes that high expression of ANXA1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients treated with neoadjuvant CCRT. PMID- 24810928 TI - Visible-light photoredox-catalyzed synthesis of nitrones: unexpected rate acceleration by water in the synthesis of isoxazolidines. AB - A new oxidative [3 + 2] cycloaddition of N-substituted hydroxylamines with alkenes was established under visible light photoredox catalysis. This novel protocol provides a rapid, mild, and efficient access to valuable five-membered ring isoxazolidine heterocycles in a concise fashion. PMID- 24810929 TI - Effects of unit empowerment and perceived support for professional nursing practice on unit effectiveness and individual nurse well-being: a time-lagged study. AB - BACKGROUND: Recruitment and retention strategies have emphasized the importance of positive work environments that support professional nursing practice for sustaining the nursing workforce. Unit leadership that creates empowering workplace conditions plays a key role in establishing supportive practice environments that increase work effectiveness, and, ultimately, improves job satisfaction. OBJECTIVES: To test a multi-level model examining the effect of both contextual and individual factors on individual nurse job satisfaction. At the unit level, structural empowerment and support for professional nursing practice (organizational resources) were hypothesized to be predictors of unit level effectiveness. At the individual level, core self-evaluation, and psychological empowerment (intrapersonal resources) were modeled as predictors of nurse job satisfaction one year later. Cross-level unit effects on individual nurses' job satisfaction were also examined. DESIGN: This study employed a longitudinal survey design with 545 staff nurses from 49 hospital units in Ontario, Canada. Participants completed a survey at two points in time (response rate of 40%) with standardized measures of the major study variables in the hypothesized model. Multilevel structural equation modeling was used to test the model. RESULTS: Nurses shared perceptions of structural empowerment on their units indirectly influenced their shared perceptions of unit effectiveness (Level 2) through perceived unit support for professional nursing practice, which in turn, had a significant positive direct effect on unit effectiveness (Level 2). Unit effectiveness was also strongly related to individual nurse job satisfaction one year later. At Level 1, higher core self-evaluation had a direct and indirect effect on job satisfaction through increased psychological empowerment. CONCLUSIONS: The results suggest that nurses' job satisfaction is influenced by a combination of individual and contextual factors demonstrating utility in considering both sources of nurses' satisfaction with their work in creating effective nursing work environments. PMID- 24810930 TI - UPBEAT study patients' perceptions of the effect of coronary heart disease on their lives: a cross-sectional sub-study. AB - BACKGROUND: Patients can report positive effects of myocardial infarction. It is unknown whether these effects are sustained or what factors influence adaptation. OBJECTIVES: To explore primary care patients' perceptions of the effect of coronary heart disease and to identify possible modifiable predictors of adaptation. DESIGN AND SETTING: Cross-sectional, sub-study of UPBEAT cohort participants. Patients were recruited from coronary heart disease Registers in South London General Practices. METHOD: 548 participants were asked "Has having heart disease changed your life? If so, was that change for the better, worse, both or neither?" Participants were asked to explain their response; explanations were subjected to content analysis. Associations between response and lifestyle, demographic, mood and coronary heart disease variables were tested. RESULTS: Respondents (394 male, 72%) were aged 27-98 years and had had heart disease for a mean of 12.4 SD +/- 8.4 years. 120 (22%) reported that life was better and 200 (37%) said it was worse. The explanations of those who said 'better' were categorised as 'Healthier Living', 'Recognised Mortality' and 'Stress Reduction'. For those saying 'worse', categories were 'Restricted Lifestyle', 'Recognised Mortality', 'Loss and Burden'. More anxiety symptoms (RRR 1.56, 95% CI 1.12, 2.17), lower functional status (RRR 2.46, 95% CI 1.21, 4.98) and self-reported chest pain (RRR 2.24, 95% CI 1.34, 3.77) were associated with saying 'worse'. CONCLUSIONS: Many primary care patients are ambivalent to the effects of coronary heart disease, but some report positive effects. Negative perceptions are associated with reported functional impairment, chest pain and anxiety, but not illness severity or patient characteristics. Future work will track the implications of these perceptions, but nurses managing patients with coronary heart disease should consider these effects as they may be modifiable predictors of adaptation. PMID- 24810931 TI - Looking like a proper baby: nurses' experiences of caring for extremely premature infants. AB - AIMS AND OBJECTIVES: To explore the ways in which neonatal nurses draw meaning and deal with the challenges associated with caring for extremely premature babies. BACKGROUND: Current literature suggests that nurses face challenges providing care to certain patients because of their appearance. This article will focus on those difficulties in relation to neonatal nurses caring for infants <=24 weeks of gestation in the neonatal intensive care unit. Extremely premature babies often have more the appearance of a foetus than the appearance of a baby, and this presented challenges for the neonatal nurses. DESIGN: This paper has used interviews and drew insights from interpretative phenomenology. METHODS: This paper used a series of interviews in a qualitative study informed by phenomenology. The analysis of the interview data involved the discovery of thematic statements and the analysis of the emerging themes. RESULTS: This paper outlines the difficulties experienced by neonatal nurses when caring for a baby that resembles a foetus more than it does a full-term infant. The theme the challenges of caregiving was captured by three subthemes: A foetus or a viable baby?; protective strategies and attributing personality. CONCLUSION: This study identified that neonatal nurses experience a range of difficulties when providing care for an infant who resembled a foetus rather than a full-term baby. They employed strategies that minimised the foetal appearance and maximised the appearance and attributes associated with a newborn baby. RELEVANCE TO CLINICAL PRACTICE: Increasing survival of extremely premature infants will see nurses caring for more babies <=24 weeks of gestation. Caring for extremely premature babies has been reported as being stressful. It is important to understand the nature of stress facing this highly specialised neonatal nursing workforce. Supportive work environments could help to ameliorate stress, facilitate better care of tiny babies and decrease staff turnover. PMID- 24810932 TI - Near room temperature reduction of graphene oxide Langmuir-Blodgett monolayers by hydrogen plasma. AB - Langmuir-Blodgett monolayer sheets of graphene oxide (GO) were transferred onto Si and SiO2/Si, and subjected to hydrogen plasma treatment near room temperature. GO monolayers were morphologically stable at low power (15 W) plasma treatment, for durations up to 2 min and temperatures up to 120 degrees C. GO monolayers reduced under optimized plasma treatment conditions (30 s duration at 50 degrees C) exhibit a sheet thickness of (0.5-0.6) nm, high sp(2)-C content (75%), a low O/C ratio (0.16) and a significant red-shift of Raman G-mode to 1588 cm(-1), indicating efficient de-oxygenation and a substantial decrease of defects. A study of the valence band electronic structure of hydrogen plasma reduced GO monolayers shows an increase of DOS in the vicinity of the Fermi level, due to the increase of C 2p-pi states, and a substantial decrease of work function. These results, along with conductivity measurements and transfer characteristics, reveal the p-type nature of hydrogen plasma reduced GO monolayers, displaying a conductivity of (0.2-31) S cm(-1) and a field effect mobility of (0.1-6) cm(2) V( 1) s(-1). Plasma treatment at higher temperatures results in a substantial increase in sp(3)-C/damaged alternant hydrocarbon content and incorporation of defects related to the hydrogenation of the graphitic network, as evidenced by multiple Raman features, including a large red-shift of D-mode to 1331 cm(-1) and a high I(D)/I(G) ratio, and supported by the appearance of mid-gap states in the vicinity of the Fermi level. PMID- 24810933 TI - Game-based digital interventions for depression therapy: a systematic review and meta-analysis. AB - The aim of this study was to review the existing literature on game-based digital interventions for depression systematically and examine their effectiveness through a meta-analysis of randomized controlled trials (RCTs). Database searching was conducted using specific search terms and inclusion criteria. A standard meta-analysis was also conducted of available RCT studies with a random effects model. The standard mean difference (Cohen's d) was used to calculate the effect size of each study. Nineteen studies were included in the review, and 10 RCTs (eight studies) were included in the meta-analysis. Four types of game interventions-psycho-education and training, virtual reality exposure therapy, exercising, and entertainment-were identified, with various types of support delivered and populations targeted. The meta-analysis revealed a moderate effect size of the game interventions for depression therapy at posttreatment (d=-0.47 [95% CI -0.69 to -0.24]). A subgroup analysis showed that interventions based on psycho-education and training had a smaller effect than those based on the other forms, and that self-help interventions yielded better outcomes than supported interventions. A higher effect was achieved when a waiting list was used as the control. The review and meta-analysis support the effectiveness of game-based digital interventions for depression. More large-scale, high-quality RCT studies with sufficient long-term data for treatment evaluation are needed. PMID- 24810934 TI - Endoscopic endonasal resection of sinonasal and anterior skull base schwannomas. AB - Sinonasal and anterior skull base (ASB) schwannomas are rare entities. The majority of these lesions are found within the sinonasal tract, although some have intracranial extension via invasion of the ASB. Often, these tumors can be confused for other entities, especially olfactory groove meningiomas and esthesioneuroblastomas in the olfactory groove region, and juvenile nasopharyngeal angiofibromas in the infratemporal fossa. We present a single institutional series of four patients with sinonasal and ASB schwannomas that were resected purely via an endoscopic endonasal approach. A retrospective chart review was performed to identify individuals with sinonasal and/or ASB schwannomas. Demographic data, presenting symptoms, imaging, treatment, and follow-up were recorded. Two male and two female patients were included in this study. The average age was 53.5 years (range, 21 to 71). The most common presenting symptoms were facial pain and hyposmia. All tumors were treated with endoscopic endonasal resection. One patient had intradural intracranial extension and required an extended endoscopic endonasal transcribriform approach with ASB resection, while another case involving the infratemporal fossa was treated with an extended endoscopic endonasal transpterygoid approach to this region. There were no major complications at an average follow-up of 9 months (range, 0 to 16). Sinonasal and ASB schwannomas are rare entities, with often nondescript symptoms and can often mimic other types of skull base tumors. Total resection via a purely endoscopic endonasal approach can be considered for these rare neoplasms. PMID- 24810935 TI - Complications after volar plating of distal radius fractures. PMID- 24810936 TI - Osteosarcoma of the distal radius treated with segmental forearm resection, hand replantation, and subsequent limb lengthening: case report. AB - A 9-year-old girl with osteosarcoma of the radius was treated with segmental forearm resection and replantation followed by forearm lengthening of 11 cm. At 9 year follow-up, she had recovered sensory function, and her pinch and grasp were sufficient for performing daily activities. Functional outcomes evaluated by the Disabilities of the Arm, Shoulder, and Hand questionnaire and International Society of Limb Salvage functional score system were 4/100 and 23/30, respectively. PMID- 24810937 TI - Measurement of ulnar variance from the lateral radiograph: a comparison of techniques. AB - PURPOSE: To determine the reliability of measuring ulnar variance on lateral wrist radiographs and to compare this technique with previously described methods. METHODS: Ulnar variance was measured in 100 normal wrist radiographs using the methods of perpendiculars, central reference point, and the lateral radiograph by 3 surgeons on 2 occasions. Intraobserver repeatability and agreement between raters and methods were assessed and compared. RESULTS: Intra- and interobserver reliability and agreement were both excellent using all 3 methods within a +/- 1.0-mm cutoff. However, there was substantial pairwise disagreement in measures of ulnar variance between all 3 methods. CONCLUSIONS: This study demonstrates that, for measurement of ulnar variance, the methods of perpendiculars, central reference point, and lateral radiographic measurement each have clinically acceptable intraobserver repeatability and interobserver agreement. Despite their independent reliability, each method of radiographic determination of ulnar variance had considerable disagreement with the other methods, indicative of inherent inaccuracies in the techniques. The lateral radiograph uniquely allows for visualization of the amount of ulnar head protruding proximal or distal to the concave lunate facet and allows for a rapid estimation of pronosupination, which is known to affect ulnar variance. CLINICAL RELEVANCE: Determination of ulnar variance can be an important component of surgical decision making in various pathological conditions of the hand and wrist. Traditionally, it has been measured through methods using the posteroanterior wrist radiograph, but there are potential shortcomings with these methods, and use of the lateral radiograph may provide a more clinically relevant picture of ulnar variance. This study shows that measurement from the lateral radiograph provides similar reliability to previously accepted techniques. PMID- 24810938 TI - Radial longitudinal deficiency. PMID- 24810939 TI - Comparison of the anatomical dimensions and mechanical properties of the dorsoradial and anterior oblique ligaments of the trapeziometacarpal joint. AB - PURPOSE: The respective roles of the dorsoradial (DRL) and anterior oblique (AOL) ligaments in stability of the highly mobile trapeziometacarpal (TMC) joint remain disputed. Earlier publications have pointed to the AOL as the key stabilizing structure; yet, more recent publications have challenged the stabilizing role of the AOL, favoring the DRL as the main TMC joint stabilizer. We executed an anatomical study of the ligaments, including detailed dissection to quantify the length, width, and thickness of the AOL and DRL and tested the material properties of these ligaments. METHODS: Thirteen fresh frozen cadaveric thumbs from 9 specimens were used. Length, width, and thickness of the AOL and DRL were measured on magnetic resonance imaging and/or after dissection. Next, the first metacarpal and trapezium were isolated together with both ligaments, and both bones were cut sagittally to isolate a first metacarpal-AOL-trapezium and first metacarpal-DRL-trapezium complex from each thumb. These samples were subjected to cyclic loading in displacement-controlled tests. The obtained force-displacement curves were used to calculate stiffness and hysteresis of each sample. RESULTS: Our results showed that the DRL is significantly shorter and thicker than the AOL, which is thin and ill-defined. Our results also indicate that the DRL has a higher stiffness than the AOL, making it a more likely candidate to provide joint stability. CONCLUSIONS: Although the AOL has been asserted to be the primary restraint to dorsoradial subluxation, this view has been challenged over the past 10 years by several studies. These studies have shown the AOL to be relatively weak and compliant compared with the intermetacarpal and dorsoradial ligaments and have demonstrated that the DRL is the strongest and stiffest ligament of the TMC joint. Our studies confirm these findings. CLINICAL RELEVANCE: This study indicates that the DRL is relatively stiff and thick, suggesting it should be repaired or reconstructed when disrupted to restore stability of the TMC joint. PMID- 24810940 TI - Efficacy and safety of sorafenib in combination with gemcitabine in patients with advanced hepatocellular carcinoma: a multicenter, open-label, single-arm phase II study. AB - AIMS: Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. METHODS: Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4 week cycle of gemcitabine (1000 mg/m(2) days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progression-free survival. RESULTS: Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5-3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4-15.9). The median time to progression was 3.6 months (95% CI 3.4-3.7). The most frequently reported grade 3/4 treatment-related adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. CONCLUSION: The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding. PMID- 24810941 TI - A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3beta and serotonin 1B receptor. AB - The cellular prion protein, PrP(C), is a glycosylphosphatidylinositol-anchored protein, abundant in lipid rafts and highly expressed in the brain. While PrP(C) is much studied for its involvement under its abnormal PrP(Sc) isoform in Transmissible Spongiform Encephalopathies, its physiological role remains unclear. Here, we report that GSK3beta, a multifunctional kinase whose inhibition is neuroprotective, is a downstream target of PrP(C) signalling in serotonergic neuronal cells. We show that the PrP(C)-dependent inactivation of GSK3beta is relayed by a caveolin-Lyn platform located on neuronal cell bodies. Furthermore, the coupling of PrP(C) to GSK3beta potentiates serotonergic signalling by altering the distribution and activity of the serotonin 1B receptor (5-HT1BR), a receptor that limits neurotransmitter release. In vivo, our data reveal an increased GSK3beta kinase activity in PrP-deficient mouse brain, as well as sustained 5-HT1BR activity, whose inhibition promotes an anxiogenic behavioural response. Collectively, our data unveil a new facet of PrP(C) signalling that strengthens neurotransmission. PMID- 24810942 TI - Years of life lost due to external causes of death in the lodz province, poland. AB - BACKGROUND: The aim of the study is the analysis of years of life lost due to external causes of death, particularly due to traffic accidents and suicides. MATERIALS AND METHODS: The study material includes a database containing information gathered from 376,281 death certificates of inhabitants of the Lodz province who died between 1999 and 2010. The Lodz province is characterized by the highest mortality rates in Poland. The SEYLLp (Standard Expected Years of Life Lost per living person) and the SEYLLd (per death) indices were used to determine years of life lost. Joinpoint models were used to analyze time trends. RESULTS: In 2010, deaths due to external causes constituted 6.0% of the total number of deaths. The standardized death rate (SDR) due to external causes was 110.0 per 100,000 males and was five times higher than for females (22.0 per 100,000 females). In 2010, the SEYLLp due to external causes was 3746 per 100,000 males and 721 per 100,000 females. Among males, suicides and traffic accidents were the most common causes of death (the values of the SEYLLp were: 1098 years and 887 years per 100,000 people, respectively). Among females, the SEYLLp values were 183 years due to traffic accidents and 143 years due to suicides (per 100,000 people). CONCLUSIONS: A decrease in the number of years of life lost due to external causes is much higher among females. The authors observe that a growing number of suicides contribute to an increase in the value of the SEYLLp index. This directly contributes to over-mortality of males due to external causes. The analysis of the years of life lost focuses on the social and economic aspects of premature mortality due to external causes. PMID- 24810943 TI - Vacuum-assisted closure versus closure without vacuum assistance for preventing surgical site infections and infections of chronic wounds: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: We sought to examine whether vacuum-assisted closure (VAC) is associated with fewer surgical site infections (SSIs) or infections of chronic wounds than other management procedures for surgical wounds. METHODS: The PubMed and Scopus databases were searched systematically. Randomized controlled trials (RCTs) comparing the development of SSIs or infections of chronic wounds between patients treated with VAC for acute or chronic wounds and those whose wounds were treated without VAC were considered eligible for inclusion in the study. RESULTS: Eight RCTs met the inclusion criteria for the study. Four of the studies included chronic or diabetic lower extremity wounds and four included fractures. In three of four studies reporting on fractures, the wounds were not closed post operatively, whereas in one study primary closure of the wound was performed. With regard to wounds left open after the stabilization of fractures, patients whose wounds were treated with VAC developed fewer SSIs than those whose wounds were treated without VAC ([367 patients (196 with VAC; 171 without VAC) relative risk [RR], 0.47; 95% CI 0.28-0.81]). On the contrary, no difference in the development of SSIs occurred among patients with chronic or diabetic lower extremity wounds treated with VAC and those whose wounds were treated without VAC ([638 patients (320 with VAC; 318 without VAC) RR 1.67; 95% CI: 0.71-3.94]). CONCLUSION: The available evidence suggests that the development of infections in wounds treated with VAC depends on the type of wound being treated. PMID- 24810944 TI - Path-integral simulation of solids. AB - The path-integral formulation of the statistical mechanics of quantum many-body systems is described, with the purpose of introducing practical techniques for the simulation of solids. Monte Carlo and molecular dynamics methods for distinguishable quantum particles are presented, with particular attention to the isothermal-isobaric ensemble. Applications of these computational techniques to different types of solids are reviewed, including noble-gas solids (helium and heavier elements), group-IV materials (diamond and elemental semiconductors), and molecular solids (with emphasis on hydrogen and ice). Structural, vibrational, and thermodynamic properties of these materials are discussed. Applications also include point defects in solids (structure and diffusion), as well as nuclear quantum effects in solid surfaces and adsorbates. Different phenomena are discussed, as solid-to-solid and orientational phase transitions, rates of quantum processes, classical-to-quantum crossover, and various finite-temperature anharmonic effects (thermal expansion, isotopic effects, electron-phonon interactions). Nuclear quantum effects are most remarkable in the presence of light atoms, so that especial emphasis is laid on solids containing hydrogen as a constituent element or as an impurity. PMID- 24810945 TI - The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. AB - Surgical extent-of-resection has been shown to have an impact on high-grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult-to-access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA-HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA-HGGs. We retrospectively reviewed 34 consecutive DTA-HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011 December 2012) using the NeuroBlate((r)) System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43 degrees C for 2 min) and blue TDT line (43 degrees C for 10 min). Volumetric analysis was performed to determine the extent-of-coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1-year estimate of OS was 68 +/- 9%. Median progression-free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria-(1) <0.05 cm(3) tumor volume not covered by the yellow TDT line and (2) <1.5 cm(3) additional tumor volume not covered by the blue TDT line-had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA-HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery. PMID- 24810946 TI - A note on implementation of decaying product correlation structures for quasi least squares. AB - This note implements an unstructured decaying product matrix via the quasi-least squares approach for estimation of the correlation parameters in the framework of generalized estimating equations. The structure we consider is fairly general without requiring the large number of parameters that are involved in a fully unstructured matrix. It is straightforward to show that the quasi-least squares estimators of the correlation parameters yield feasible values for the unstructured decaying product structure. Furthermore, subject to conditions that are easily checked, the quasi-least squares estimators are valid for longitudinal Bernoulli data. We demonstrate implementation of the structure in a longitudinal clinical trial with both a continuous and binary outcome variable. PMID- 24810947 TI - Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey. AB - Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia. PMID- 24810951 TI - PEG-protein interaction induced contraction of NalD chains. AB - In a recent attempt to crystallize a regulator of MexAB-OprM multi-drug efflux systems in Pseudomonas aeruginosa (NalD), we found that adding polyethylene glycol (PEG3350, Mw = 3,350 g/mol) into the protein solution increases the speed of NalD migration in gel electrophoresis, signaling a smaller hydrodynamic size. At first we conjectured that NalD was degraded unexpectedly by PEG; however, we found that there was no change in its molar mass by MALDI-TOF characterization. Moreover, we found that adding polyacrylic acid (PAA) into the solution mixture returned the NalD migration to its normal speed. Furthermore, our analytic ultracentrifugation and dynamic laser light scattering results directly reveal that NalD interacts with PEG so that individual NalD chains gradually shrink as more PEG chains are added in the range of 10-50 mg/mL. Size exclusion chromatography also confirms that the NalD chain shrinks in the presence of PEG. A combination of these results indicates that PEG3350 chains can complex with NalD to induce an intra-protein chain contraction, presumably via the formation of hydrogen bond between -C-O-C- on PEG and -COOH on NalD, resulting in a smaller hydrodynamic size (faster migration) and a higher apparent molar mass. Note that because the presence of PEG affects osmotic pressure, it is considered to be a precipitator of protein crystallization. Our current finding reveals that the interaction of PEG/protein may play a significant role in protein crystallization. The complexation potentially makes the protein chain segments less flexible, and consequently makes crystallization easier. Hopefully, our current results will stimulate further studies in this direction. PMID- 24810948 TI - Slow feature analysis on retinal waves leads to V1 complex cells. AB - The developing visual system of many mammalian species is partially structured and organized even before the onset of vision. Spontaneous neural activity, which spreads in waves across the retina, has been suggested to play a major role in these prenatal structuring processes. Recently, it has been shown that when employing an efficient coding strategy, such as sparse coding, these retinal activity patterns lead to basis functions that resemble optimal stimuli of simple cells in primary visual cortex (V1). Here we present the results of applying a coding strategy that optimizes for temporal slowness, namely Slow Feature Analysis (SFA), to a biologically plausible model of retinal waves. Previously, SFA has been successfully applied to model parts of the visual system, most notably in reproducing a rich set of complex-cell features by training SFA with quasi-natural image sequences. In the present work, we obtain SFA units that share a number of properties with cortical complex-cells by training on simulated retinal waves. The emergence of two distinct properties of the SFA units (phase invariance and orientation tuning) is thoroughly investigated via control experiments and mathematical analysis of the input-output functions found by SFA. The results support the idea that retinal waves share relevant temporal and spatial properties with natural visual input. Hence, retinal waves seem suitable training stimuli to learn invariances and thereby shape the developing early visual system such that it is best prepared for coding input from the natural world. PMID- 24810952 TI - Expanding the phenotype of proteinuria in Dent disease. A case series. AB - BACKGROUND: Dent disease is an X-linked recessive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure (MIM 300009). A recent case series identified four patients with CLCN5 mutations who presented with nephrotic-range proteinuria, histologic evidence of focal segmental and/or global sclerosis, and low molecular weight proteinuria. CASE-DIAGNOSIS/TREATMENT: We characterize the clinical, genetic, and histopathological features of seven unrelated adolescent males with nephrotic-range proteinuria and CLCN5 mutations. Six patients underwent renal biopsy prior to assessing tubular proteinuria. All biopsied patients had either segmental sclerosis (3/6) or segmental increase in mesangial matrix (3/6). Five patients revealed some degree of foot process effacement, but only one patient biopsy revealed >50 % foot process effacement. The attenuated foot process effacement suggests the glomerulosclerosis is not due to a primary podocytopathy. CONCLUSIONS: These data suggest that clinicians should consider a diagnostic evaluation for Dent disease in young males presenting with high-grade proteinuria. PMID- 24810953 TI - Daytime sleepiness, poor sleep quality, eveningness chronotype, and common mental disorders among Chilean college students. AB - OBJECTIVES: To evaluate whether daytime sleepiness, poor sleep quality, and morningness and eveningness preferences are associated with common mental disorders (CMDs) among college students. METHODS: A total of 963 college students completed self-administered questionnaires that collected information about sociodemographic characteristics, sleep quality characteristics, CMDs, and other lifestyle behaviors. RESULTS: The prevalence of CMDs was 24.3% (95% confidence interval [CI] [21.5%, 27.1%]) among all students. Prevalence estimates of both excessive daytime sleepiness and poor sleep quality were higher among females (35.4% and 54.4%) than males (22.0% and 45.8%). Cigarette smoking was statistically significantly and positively associated with having CMDs (p = .034). Excessive daytime sleepiness (odds ratio [OR] = 3.65; 95% CI [2.56, 4.91]) and poor sleep quality (OR = 4.76; 95% CI [3.11, 7.29]) were associated with increased odds of CMDs. CONCLUSION: Given the adverse health consequences associated with both sleep disorders and CMDs, improving sleep hygiene among college students is imperative to public health. PMID- 24810954 TI - Central neural versus peripheral muscular origin of vagus somatosensory - evoked potentials. PMID- 24810955 TI - It's all in your head: reinforcing the placebo response with tDCS. PMID- 24810956 TI - Effects of different electrical brain stimulation protocols on subcomponents of motor skill learning. AB - BACKGROUND: Noninvasive electrical brain stimulation (NEBS) with transcranial direct current (tDCS) or random noise stimulation (tRNS) applied to the primary motor cortex (M1) can augment motor learning. OBJECTIVE: We tested whether different types of stimulation alter particular aspects of learning a tracing task over three consecutive days, namely skill acquisition (online/within session effects) or consolidation (offline/between session effects). METHODS: Motor training on a tracing task over three consecutive days was combined with different types and montages of stimulation (tDCS, tRNS). RESULTS: Unilateral M1 stimulation using tRNS as well as unilateral and bilateral M1 tDCS all enhanced motor skill learning compared to sham stimulation. In all groups, this appeared to be driven by online effects without an additional offline effect. Unilateral tDCS resulted in large skill gains immediately following the onset of stimulation, while tRNS exerted more gradual effects. Control stimulation of the right temporal lobe did not enhance skill learning relative to sham. CONCLUSIONS: The mechanisms of action of tDCS and tRNS are likely different. Hence, the time course of skill improvement within sessions could point to specific and temporally distinct interactions with the physiological process of motor skill learning. Exploring the parameters of NEBS on different tasks and in patients with brain injury will allow us to maximize the benefits of NEBS for neurorehabilitation. PMID- 24810957 TI - The sonic hedgehog signaling pathway induces myopic development by activating matrix metalloproteinase (MMP)-2 in Guinea pigs. AB - PURPOSE: To investigate whether the Sonic hedgehog (Shh) signaling induces myopic development by increasing the expression of matrix metalloproteinase (MMP)-2 in guinea pigs. METHODS: A translucent diffuser was glued onto the right eye to induce form-deprivation myopia (FDM) in 10 guinea pigs. Four guinea pigs were served as a control group. The other 100 guinea pigs were subdivided into 5 groups (20 per group) and received a 10 ul intravitreal injection every 2 days for 4 times. Two groups were injected with 20 or 50 ug/ml Shh amino-terminal peptide (Shh-N) into the right eye and 0.1% bovine serum albumin into the other. FDM was induced in the right eyes of the three cyclopamine-treated groups and both eyes were injected with 50, 100, or 200 ug/ml cyclopamine. Retinoscopic refraction and eye dimensions were assessed on Day 14 of treatment. MMP-2 protein expression was determined in both scleras by western blotting. RESULTS: Both concentrations of Shh-N stimulated myopic development and axial growth as compared with control eyes. Myopia and axial elongation were significantly greater in the 50 ug/ml than in the 20 ug/ml Shh-N group (P<0.001 and P = 0.0019, respectively). All three doses of cyclopamine significantly attenuated myopic development compared with the FDM group (P<0.0001). Cyclopamine at 100 or 200 ug/ml significantly reduced axial elongation compared with the FDM group (P = 0.044 and P = 0.001, respectively). FDM-induced myopia and axial elongation were significantly greater in the 50 ug/ml than in the 200 ug/ml cyclopamine group (P<0.0001 and P = 0.008, respectively). MMP-2 expression was significantly greater in Shh-N-treated eyes than in the control eyes, and was lower in the cyclopamine plus FDM groups than in the FDM group. CONCLUSIONS: The Shh signaling pathway induces myopic development by activating MMP-2 in guinea pigs. PMID- 24810958 TI - Reduction patterns of acute schistosomiasis in the People's Republic of China. AB - BACKGROUND: Despite significant, steady progress in schistosomiasis control in the People's Republic of China over the past 50 years, available data suggest that the disease has re-emerged with several outbreaks of acute infections in the early new century. In response, a new integrated strategy was introduced. METHODS: This retrospective study was conducted between Jan 2005 and Dec 2012, to explore the effectiveness of a new integrated control strategy that was implemented by the national control program since 2004. RESULTS: A total of 1,047 acute cases were recorded between 2005 and 2012, with an annual reduction in prevalence of 97.7%. The proportion of imported cases of schistosomiasis was higher in 2011 and 2012. Nine clusters of acute infections were detected by spatio-temporal analysis between June and November, indicating that the high risk areas located in the lake and marshland regions. CONCLUSION: This study shows that the new integrated strategy has played a key role in reducing the morbidity of schistosomiasis in the People's Republic of China. PMID- 24810960 TI - Does variation in the intensity and duration of predation drive evolutionary changes in senescence? AB - The evolutionary theory of senescence predicts that increased rates of extrinsic mortality select for faster declines in fertility and survival with age. One predicted mechanism is that increased mortality favours alleles that enhance fitness early in life at the expense of survival or reproduction later in life (antagonistic pleiotropy). We tested these predictions in natural populations of Daphnia ambigua from lakes that vary in the severity and duration of fish predation. Daphnia are found in lakes with (i) anadromous alewife (Alosa pseudoharengus) that migrate between marine and freshwater, (ii) permanent landlocked alewife and (iii) no alewife. Daphnia are rare year-round in 'landlocked lakes' and are seasonally eliminated from the water column in 'anadromous lakes' due to the very strong predatory impact of anadromous alewife on populations of zooplankton. Previous work has also shown that intense seasonal bouts of predation by anadromous alewife has selected for increased allocation towards growth and reproduction in Daphnia found in lakes with anadromous alewife. Such variation in the risk of mortality and the expression of life history traits early in life provides the raw materials to test the evolutionary theory of ageing. We reared replicate populations of Daphnia from all three lake types and quantified lifetime rates of offspring production and intrinsic survival. We found no differences in age-related declines in fertility or survival. Daphnia from anadromous lakes produced significantly more offspring throughout their lifetime despite no differences in life span or in the number of reproductive bouts compared with Daphnia from lakes with landlocked and no alewife. The lack of divergence in ageing contradicts the prediction that elevated mortality rates drive evolutionary shifts in ageing. We reconcile these results by considering the predictions of theoretical frameworks that incorporate feedbacks associated with increased mortality such as density- and condition dependent processes. Our results, which are better explained by a consideration of these processes, thus call for a greater consideration of models that more explicitly consider the ecology of focal organisms. PMID- 24810959 TI - WT1 regulates angiogenesis in Ewing Sarcoma. AB - Angiogenesis is required for tumor growth. WT1, a protein that affects both mRNA transcription and splicing, has recently been shown to regulate expression of vascular endothelial growth factor (VEGF), one of the major mediators of angiogenesis. In the present study, we tested the hypothesis that WT1 is a key regulator of tumor angiogenesis in Ewing sarcoma. We expressed exogenous WT1 in the WT1-null Ewing sarcoma cell line, SK-ES-1, and we suppressed WT1 expression using shRNA in the WT1-positive Ewing sarcoma cell line, MHH-ES. Suppression of WT1 in MHH-ES cells impairs angiogenesis, while expression of WT1 in SK-ES-1 cells causes increased angiogenesis. Different WT1 isoforms result in vessels with distinct morphologies, and this correlates with preferential upregulation of particular VEGF isoforms. WT1-expressing tumors show increased expression of pro angiogenic molecules such as VEGF, MMP9, Ang-1, and Tie-2, supporting the hypothesis that WT1 is a global regulator of angiogenesis. We also demonstrate that WT1 regulates the expression of a panel of pro-angiogenic molecules in Ewing sarcoma cell lines. Finally, we found that WT1 expression is correlated with VEGF expression, MMP9 expression, and microvessel density in samples of primary Ewing sarcoma. Thus, our results demonstrate that WT1 expression directly regulates tumor angiogenesis by controlling the expression of a panel of pro-angiogenic genes. PMID- 24810961 TI - Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid. AB - Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection. PMID- 24810962 TI - MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways. AB - While MDM2 inhibitors hold great promise as cancer therapeutics, drug resistance will likely limit their efficacy as single agents. To identify drug combinations that might circumvent resistance, we screened for agents that could synergize with MDM2 inhibition in the suppression of cell viability. We observed broad and robust synergy when combining MDM2 antagonists with either MEK or PI3K inhibitors. Synergy was not limited to cell lines harboring MAPK or PI3K pathway mutations, nor did it depend on which node of the PI3K axis was targeted. MDM2 inhibitors also synergized strongly with BH3 mimetics, BCR-ABL antagonists, and HDAC inhibitors. MDM2 inhibitor-mediated synergy with agents targeting these mechanisms was much more prevalent than previously appreciated, implying that clinical translation of these combinations could have far-reaching implications for public health. These findings highlight the importance of combinatorial drug targeting and provide a framework for the rational design of MDM2 inhibitor clinical trials. PMID- 24810963 TI - Novel high-molecular weight fucosylated milk oligosaccharides identified in dairy streams. AB - Oligosaccharides are the third largest component in human milk. This abundance is remarkable because oligosaccharides are not digestible by the newborn, and yet they have been conserved and amplified during evolution. In addition to encouraging the growth of a protective microbiota dominated by bifidobacteria, oligosaccharides have anti-infective activity, preventing pathogens from binding to intestinal cells. Although it would be advantageous adding these valuable molecules to infant milk formula, the technologies to reproduce the variety and complexity of human milk oligosaccharides by enzymatic/organic synthesis are not yet mature. Consequently, there is an enormous interest in alternative sources of these valuable oligosaccharides. Recent research has demonstrated that bovine milk and whey permeate also contain oligosaccharides. Thus, a thorough characterization of oligosaccharides in bovine dairy streams is an important step towards fully assessing their specific functionalities. In this study, bovine milk oligosaccharides (BMOs) were concentrated by membrane filtration from a readily available dairy stream called "mother liquor", and analyzed by high accuracy MALDI FT-ICR mass spectrometry. The combination of HPLC and accurate mass spectrometry allowed the identification of ideal processing conditions leading to the production of Kg amount of BMO enriched powders. Among the BMOs identified, 18 have high-molecular weight and corresponded in size to the most abundant oligosaccharides present in human milk. Notably 6 oligosaccharides contained fucose, a sugar monomer that is highly abundant in human milk, but is rarely observed in bovine milk. This work shows that dairy streams represent a potential source of complex milk oligosaccharides for commercial development of unique dairy ingredients in functional foods that reproduce the benefits of human milk. PMID- 24810964 TI - FibroTest (FT) has similar accuracy for cirrhosis in 'intention-to-diagnose' which is superior to transient elastography (TE) in chronic hepatitis B. PMID- 24810965 TI - Elevated plasma sphingomyelin (d18:1/22:0) is closely related to hepatic steatosis in patients with chronic hepatitis C virus infection. AB - Hepatic steatosis affects disease progression in patients with chronic hepatitis C virus (HCV) infection. We investigated the plasma sphingolipid profile in patients with chronic hepatitis C (CHC) and whether there was an association between HCV-related steatosis and plasma sphingolipids. We used high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze plasma sphingolipids in 120 interferon-naive, non-diabetic, and non-obese CHC patients. Hepatic steatosis was defined as >=5 % hepatocytes with fat based on histopathological analysis. Blood biochemical indicators and HCV load and genotype were also determined. Thirty-six (30.0 %) of 120 patients presented with hepatic steatosis Grades 1-3. Forty-four plasma sphingolipids were detected. Plasma sphingomyelin (SM) (d18:1/22:0) and ceramide (Cer) (d18:1/24:0)-1-P correlated with steatosis grade (r = 0.22, p = 0.015; r = -0.23, p = 0.012, respectively). SM (d18:1/22:0) [odds ratio (OR) = 1.12] and Cer (d18:1/24:0)-1-P (OR = 0.88) were independent factors for the presence of hepatic steatosis in CHC patients. The area under the curve (AUC) of SM (d18:1/22:0) and Cer (d18:1/24:0) 1-P was 0.637 and 0.638, respectively, to identify the presence of steatosis. Further analysis for genotype 2 CHC showed that only SM (d18:1/22:0) was independently linked to steatosis (OR = 1.21). The AUC of SM (d18:1/22:0) to identify hepatic steatosis in genotype 2 CHC was 0.726. Its sensitivity and negative predictive value reached 0.813 and 0.886, respectively. This study suggested that altered plasma SM (d18:1/22:0) was closely related to hepatic steatosis in chronic HCV infection, especially with genotype 2. Experimental studies are needed to determine further the underlying mechanisms responsible for these associations. PMID- 24810966 TI - Antibody development to Fusobacterium necrophorum in patients with peritonsillar abscess. AB - A polymicrobial mixture of aerobic and anaerobic bacteria is commonly recovered from peritonsillar abscess (PTA) aspirates. Previous studies have suggested a role for Fusobacterium necrophorum (FN) in the development of PTA. The purpose of the current study was to explore whether anti-FN antibodies were produced in patients with PTA. We developed a novel immunofluorescence-based method to measure anti-FN antibody levels in acute and convalescent sera from 15 patients with PTA and 47 patients with chronic tonsillar conditions (controls) undergoing acute or elective tonsillectomy, respectively. Bacterial cultures were performed on tonsillar cores and surfaces, pus aspirates, and blood. An increase in anti-FN antibody levels (of at least doubling of the previous level) was observed in 8 of 11 (73 %) PTA patients with FN-positive pus aspirate cultures (FN-positive patients). In contrast, the four FN-negative PTA patients did not have an increase in anti-FN antibody levels (p = 0.026). The change in anti-FN antibody levels in FN-positive PTA patients was also significantly greater than that for FN-positive electively tonsillectomized patients (p = 0.0014) and all electively tonsillectomized patients (p < 0.001). Our results validate FN as a significant and prevalent pathogen in PTA. This finding has implications for the diagnostic work-up of PTA and may also have implications for the treatment of acute tonsillitis. PMID- 24810968 TI - Does microchimerism mediate kin conflicts? AB - Fetal microchimerism (FMc) is predicted to promote the fitness of the fetus and maternal microchimerism (MMc) to promote the fitness of the mother. Offspring and mothers benefit from each other's health. Therefore, microchimeric cells should usually not be harmful to their host. However, the evolutionary interests of mothers and offspring diverge when there is competition among siblings for maternal investment. Fetal cells in mothers' bodies could benefit their own offspring at the expense of its sibs by promoting lactogenesis or by extending the interbirth interval. Maternal cells in fetal bodies could benefit from the suppression of sibling rivalry. Non-inherited haplotypes in MMc or sibling microchimerism (SMc) gain no direct benefit from their hosts' health and could be associated with substantial detrimental effects. PMID- 24810967 TI - Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology. AB - We aimed to determine the incidence of Clostridium difficile infection (CDI), the molecular epidemiology of circulating C. difficile strains and risk factors for CDI among hospitalised children in the Auckland region. A cross-sectional study was undertaken of hospitalised children <15 years of age in two hospitals investigated for healthcare-associated diarrhoea between November 2011 and June 2012. Stool specimens were analysed for the presence of C. difficile using a two step testing algorithm including polymerase chain reaction (PCR). C. difficile was cultured and PCR ribotyping performed. Demographic data, illness characteristics and risk factors were compared between children with and without CDI. Non-duplicate stool specimens were collected from 320 children with a median age of 1.2 years (range 3 days to 15 years). Forty-six patients (14 %) tested met the definition for CDI. The overall incidence of CDI was 2.0 per 10,000 bed days. The percentage of positive tests among neonates was only 2.6 %. PCR ribotyping showed a range of strains, with ribotype 014 being the most common. Significant risk factors for CDI were treatment with proton pump inhibitors [risk ratio (RR) 1.74, 95 % confidence interval (CI) 1.09-5.59; p = 0.002], presence of underlying malignancy (RR 2.71, 95 % CI 1.65-4.62; p = 0.001), receiving chemotherapy (RR 2.70, 95 % CI 1.41-4.83; p = 0.003) and exposure to antibiotics (RR 1.17, 95 % CI 0.99-1.17; p = 0.03). C. difficile is an important cause of healthcare-associated diarrhoea in this paediatric population. The notion that neonatal populations will always have high rates of colonisation with C. difficile may not be correct. Several risk factors associated with CDI among adults were also found to be significant. PMID- 24810969 TI - Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors. AB - FTY720 is a sphingosine 1-phosphate receptor (S1PR) modulator used as a daily therapy to reduce disease activity in the relapsing form of multiple sclerosis (MS). FTY720 readily accesses the CNS. Previous studies have shown that phosphorylated FTY720 (FTY720-p) enhances oligodendrocyte progenitor cell (OPC) survival, differentiation, and remyelination following experimentally induced demyelination in rodents. To elucidate the underlying mechanism, human fetal OPCs alone or in co-culture with rat dorsal root ganglia neurons (DRGN) were treated daily with FTY720-p, a condition that desensitizes cellular responses to S1P, the natural ligand of S1PR. In co-cultures, FTY720-p and S1P given daily or every three days increased the number of O1/MBP double positive cells and axonal ensheathment. In cultures composed of PDGFRalpha-antibody selected cells alone, daily application of FTY720-p also increased the number of O4/GC double positive cells. At an early time point (day 2), FTY720-p activated ERK1/2, CREB and p38MAPK in O4-positive cells, as well as in beta-III Tubulin positive neurons and GFAP positive astrocytes. In later cultures (day 6), FTY720-p activated p38MAPK in O4 positive cells, p38MAPK and ERK1/2 in neurons, and p38MAPK, ERK1/2 and CREB in astrocytes. A MEK inhibitor (U0126) prevented the differentiation of OPCs into O4-positive cells, while a p38MAPK inhibitor (PD169316) blocked progression into O4-positive and into GC-positive stages of differentiation. Our results demonstrate that FTY720-p, under conditions that model daily clinical use, can act directly on OPCs to impact differentiation, and also indirectly via neurons and astrocytes by activating ERK1/2 and p38MAPK. PMID- 24810970 TI - Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial. AB - INTRODUCTION: The minimal clinically important difference (MCID) is the smallest outcome change that has clinical significance. Its use has not been established in the study of myasthenia gravis (MG). METHODS: Patients from a published intravenous immunoglobulin (IVIg) vs. placebo study were studied. One anchor based and 3 distribution-based techniques were used to identify quantitative myasthenia gravis score (QMGS), repetitive nerve stimulation (RNS), and single fiber electromyography (SFEMG) MCID cut-offs. Patients with a change-score exceeding MCID cut-offs were compared. RESULTS: MCID cut-offs were below a QMGS change of 3.0. Anchor-based and 1 * SEM cut-offs showed 58.3% vs. 30.7% responders (P = 0.017), 1/2 SD 54.2% vs. 19.2% responders (P = 0.018), and effect size 0.519 vs. 0.164 (P = 0.011) in IVIg vs. placebo. Anchor-based (P = 0.73) and effect-size (P = 0.41) MCID cut-offs did not show a difference between IVIg and placebo. MCID methods did not produce meaningful RNS cut-offs. CONCLUSIONS: QMGS MCID values provide clinically relevant information and are recommended in MG trials. MCID analysis shows that improvement in MG patients treated with IVIg reflects clinically meaningful changes. PMID- 24810971 TI - Epidemiology of asthma hospitalizations among American Indian and Alaska Native people and the general United States population. AB - BACKGROUND: Asthma, a common chronic disease among adults and children in the United States, results in nearly one-half million hospitalizations annually. There has been no evaluation of asthma hospitalizations for American Indian and Alaska Native (AI/AN) people since a previous study using data for 1988-2002. In this study, we describe the epidemiology and trends for asthma hospitalizations among AI/AN people and the general US population for 2003-2011. METHODS: Hospital discharge records with a first-listed diagnosis of asthma for 2003-2011 were examined for AI/AN people, using Indian Health Service (IHS) data, and for the general US population, using the Nationwide Inpatient Sample. Average annual crude and age-adjusted hospitalization rates were calculated. RESULTS: The average annual asthma hospitalization rates for AI/AN people and the general US population decreased from 2003-2005 to 2009-2011 (32% and 11% [SE, 3%], respectively). The average annual age-adjusted rate for 2009-2011 was lower for AI/AN people (7.6 per 10,000 population) compared with the general US population (13.2 per 10,000; 95% CI, 12.8-13.6). Age-specific AI/AN rates were highest among infants and children 1 to 4 years of age. IHS regional rates declined in all regions except Alaska. CONCLUSIONS: Asthma hospitalization rates are decreasing for AI/AN people and the general US population despite increasing prevalence rates. AI/AN people experienced a substantially lower age-adjusted asthma hospitalization rate compared with the general US population. Although the rates for AI/AN infants and children 1 to 4 years of age have declined substantially, they remain higher compared with other age groups. Improved disease management and awareness should help to further decrease asthma hospitalizations, particularly among young children. PMID- 24810972 TI - Photoreceptor outer segment layer thickness measured manually on images from spectral domain optical coherence tomography in healthy volunteers. AB - BACKGROUND AND OBJECTIVE: To investigate photoreceptor outer segment layer thickness measured with a manual technique on images from spectral domain optical coherence tomography (OCT) in healthy volunteers. MATERIALS AND METHODS: In 60 eyes of 30 healthy volunteers, a spectral domain OCT device (Spectralis, Heidelberg Engineering) was used to obtain cross-sectional images of the retina. For each volunteer, two images of each eye were obtained in one sitting. Images were digitally enlarged and the manual calipers feature of the device's software was used to measure, at the lowest point in the fovea, the thickness of the photoreceptor outer segment layer. All measurements were performed by the same investigator. Repeatability was evaluated with the Bland-Altman repeatability coefficient, and intersubject variability with Pearson's coefficient of variation. RESULTS: The mean values of measurements across all the volunteers were as follows: right eye first image 38.1 micrometers, right eye second image 37.9 micrometers, left eye first image 37.9 micrometers, left eye second image 37.9 micrometers. The repeatability coefficient, i.e. the difference between repeated measurements which would be exceeded in only 5% of cases, was 1.6 micrometers. Coefficients of variation for the right eye were 3.4% for the first images and 3.4% for the second images, and for the left eye they were 3.2 and 4.0% respectively. CONCLUSION: With a manual method based on spectral domain OCT, the thickness of the photoreceptor outer segment layer at the central fovea can be measured within a useful range of repeatability and appears to be relatively constant across healthy volunteers. PMID- 24810973 TI - Continuous positive airway pressure is associated with a decrease in pulmonary artery pressure in patients with obstructive sleep apnoea: a meta-analysis. AB - Pulmonary hypertension has been recognized as being associated with obstructive sleep apnoea (OSA). Continuous positive airway pressure (CPAP) might reduce pulmonary artery pressure in OSA patients; however, evidence from clinical studies is limited and inconsistent. This meta-analysis aims to assess whether CPAP is associated with a decrease in pulmonary artery pressure in patients with OSA. This systematic review was performed in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. Published studies were identified through a search in MEDLINE, EMBASE and the Cochrane library through to May 2013. Two reviewers sorted papers and extracted data. A random-effects model was used to combine results across studies comparing pulmonary artery pressure in OSA patients before and after CPAP treatment. Six articles with 181 patients were included in this meta-analysis, including five before-after studies and one matched-control study. The meta-analysis showed that CPAP was associated with a statistically significant reduction in pulmonary artery pressure in OSA patients (standardized mean difference -1.34, 95% confidence interval: -2.33 to 0.34, P = 0.009). Although this meta-analysis has some limitations, it indicates that CPAP is associated with a decrease in pulmonary artery pressure in patients with OSA. PMID- 24810974 TI - Antioxidant and anti-inflammatory effects of N-acetylcysteine against malathion induced liver damages and immunotoxicity in rats. AB - AIMS: Occupational exposure to organophosphate pesticides is becoming a common and increasingly alarming world-wide phenomenon. The present study is designed to investigate the preventive effect of N-acetylcysteine on malathion-induced hepatic injury and inflammation in rats. MAIN METHODS: Adult male Wistar rats of body weight 200-230 g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation and N-acetylcysteine (2g/l) in drinking water for 28 days. Rats were sacrificed on the 28th day, 2h after the last administration. Markers of liver injury (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate desyhdogenase), inflammation (leukocyte counts, myeloperoxidase, immunophenotyping of CD4(+) and CD8(+), interleukin-1beta, interleukin-6 and interferon-gamma expression) and oxidative stress (lipid peroxidation, reduced glutathione and antioxidant status) were assessed. KEY FINDINGS: Malathion induced an increase in activities of hepatocellular enzymes in plasma, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) percent and pro-inflammatory cytokines, when decreased antioxidant status in liver was noted. When malathion-treated rats were compared to NAC supplemented rats, leukocytosis, T cell count and IL-1beta, IL-6, INF-gamma expression were reduced. Furthermore, NAC restored liver enzyme activities and oxidative stress markers. SIGNIFICANCE: Malathion induces hepatotoxicity, oxidative stress and liver inflammation. N-acetylcysteine showed therapeutic effects against malathion toxicity. PMID- 24810975 TI - Influence of bioselector processes on 17alpha-ethinylestradiol biodegradation in activated sludge wastewater treatment systems. AB - The removal of the potent endocrine-disrupting estrogen hormone, 17alpha ethinylestradiol (EE2), in municipal wastewater treatment plant (WWTP) activated sludge (AS) processes can occur through biodegradation by heterotrophic bacteria growing on other organic wastewater substrates. Different kinetic and metabolic substrate utilization conditions created with AS bioselector processes can affect the heterotrophic population composition in AS. The primary goal of this research was to determine if these changes also affect specific EE2 biodegradation kinetics. A series of experiments were conducted with parallel bench-scale AS reactors treating municipal wastewater with estrogens at 100-300 ng/L concentrations to evaluate the effect of bioselector designs on pseudo first order EE2 biodegradation kinetics normalized to mixed liquor volatile suspended solids (VSS). Kinetic rate coefficient (kb) values for EE2 biodegradation ranged from 5.0 to 18.9 L/g VSS/d at temperatures of 18 degrees C to 24 degrees C. EE2 kb values for aerobic biomass growth at low initial food to mass ratio feeding conditions (F/Mf) were 1.4 to 2.2 times greater than that from growth at high initial F/Mf. Anoxic/aerobic and anaerobic/aerobic metabolic bioselector reactors achieving biological nutrient removal had similar EE2 kb values, which were lower than that in aerobic AS reactors with biomass growth at low initial F/Mf. These results provide evidence that population selection with growth at low organic substrate concentrations can lead to improved EE2 biodegradation kinetics in AS treatment. PMID- 24810976 TI - Protein phosphatases PP2A, PP4 and PP6: mediators and regulators in development and responses to environmental cues. AB - The three closely related groups of serine/threonine protein phosphatases PP2A, PP4 and PP6 are conserved throughout eukaryotes. The catalytic subunits are present in trimeric and dimeric complexes with scaffolding and regulatory subunits that control activity and confer substrate specificity to the protein phosphatases. In Arabidopsis, three scaffolding (A subunits) and 17 regulatory (B subunits) proteins form complexes with five PP2A catalytic subunits giving up to 255 possible combinations. Three SAP-domain proteins act as regulatory subunits of PP6. Based on sequence similarities with proteins in yeast and mammals, two putative PP4 regulatory subunits are recognized in Arabidopsis. Recent breakthroughs have been made concerning the functions of some of the PP2A and PP6 regulatory subunits, for example the FASS/TON2 in regulation of the cellular skeleton, B' subunits in brassinosteroid signalling and SAL proteins in regulation of auxin transport. Reverse genetics is starting to reveal also many more physiological functions of other subunits. A system with key regulatory proteins (TAP46, TIP41, PTPA, LCMT1, PME-1) is present in all eukaryotes to stabilize, activate and inactivate the catalytic subunits. In this review, we present the status of knowledge concerning physiological functions of PP2A, PP4 and PP6 in Arabidopsis, and relate these to yeast and mammals. PMID- 24810977 TI - The acylated (AG) to unacylated (UAG) ghrelin ratio in esterase inhibitor-treated blood is higher than previously described. AB - CONTEXT: The acylated/unacylated ghrelin (AG/UAG) ratio has been reported to range from 0.02 to 0.3, suggesting biologically relevant independent regulation of each ghrelin isoform. However, AG is deacylated to UAG by esterases in blood samples, and esterase inhibition is critical for their accurate measurement. Our hypothesis is that at least part of the variation in reported AG and UAG values is due to inconsistent sample preparation. DESIGN: A non-interventional study. Quantification with two different, commercially available, ELISA formats of AG and UAG in venous plasma stabilized or not with 4-(2-aminoethyl) benzenesulphonyl fluoride (AEBSF) and stored for 0-6 months at -20 or -80 degrees C. PARTICIPANTS: Healthy, non-obese, adults (n = 8; 4 women), age 26-42 yrs, after an overnight fast. MEASUREMENTS: AG and UAG stability following different methods of sample treatment and storage. RESULTS: Non-AEBSF plasma contained low AG and high UAG (>270 pg/ml) indicating rapid conversion of AG to UAG. However, AEBSF plasma, stored at -80 degrees C and measured at 0, 1, 3 and 6 months contained AG and UAG ranges of 12-350 and 17-170 pg/ml, respectively. Mean (SEM) AG/UAG ratios were 1.7(0.3), 1.2(0.2), 1.5(0.3) and 1.8(0.5) at each time point with no significant effect of storage period. CONCLUSIONS: AG and UAG levels measured in AEBSF-stabilized plasma indicate that the AG/UAG ratio is markedly higher than previously described and that UAG is a physiological component of the circulation. This highlights the importance of immediately stabilizing blood samples on collection for determination of both AG and UAG concentrations and provides a valuable tool for their measurement in physiological and interventional studies. PMID- 24810978 TI - Effects of policy changes to universal newborn hearing screening follow-up in a university clinic. AB - PURPOSE: The purpose of this study was to evaluate the effects of policy changes on loss to follow-up rates and the ability to achieve the goals of the American Academy of Pediatrics Joint Committee on Infant Hearing Screening (2007) for diagnosis of hearing loss by 3 months, amplification within 1 month of diagnosis, and start of intervention by 6 months. METHOD: From the files of 111 infants, data were extracted on the following: date of birth, birth hospital, hometown, parents' ages, ethnicity, nursery status, medical history, age at initial evaluation and diagnosis, results of evaluation(s), and age at hearing aid fitting and start of early intervention. Data were compared with previously published data from the clinic (Krishnan, 2009). RESULTS: Policy changes led to a decrease in loss to follow-up and a younger age at diagnosis of hearing loss. Infants identified with hearing loss were fit with amplification at younger ages but not within 1 month of diagnosis of hearing loss. Policy changes had positive outcomes on loss to follow-up and age of diagnosis and amplification. CONCLUSIONS: Challenges remain in meeting the goals of amplification within 1 month of diagnosis and documenting the start of early intervention. Improved communication between and education of all parties involved in the care of infants is needed. PMID- 24810979 TI - Single cell tracking assay reveals an opposite effect of selective small non peptidic alpha5beta1 or alphavbeta3/beta5 integrin antagonists in U87MG glioma cells. AB - BACKGROUND: Integrins are extracellular matrix receptors involved in several pathologies. Despite homologies between the RGD-binding alpha5beta1 and alphavbeta3 integrins, selective small antagonists for each heterodimer have been proposed. Herein, we evaluated the effects of such small antagonists in a cellular context, the U87MG cell line, which express both integrins. The aim of the study was to determine if fibronectin-binding integrin antagonists are able to impact on cell adhesion and migration in relationships with their defined affinity and selectivity for alpha5beta1 and alphavbeta3/beta5 purified integrins. METHODS: Small antagonists were either selective for alpha5beta1 integrin, for alphavbeta3/beta5 integrin or non-selective. U87MG cell adhesion was evaluated on fibronectin or vitronectin. Migration assays included wound healing recovery and single cell tracking experiments. U87MG cells stably manipulated for the expression of alpha5 integrin subunit were used to explore the impact of alpha5beta1 integrin in the biological assays. RESULTS: U87MG cell adhesion on fibronectin or vitronectin was respectively dependent on alpha5beta1 or alphavbeta3/beta5 integrin. Wound healing migration was dependent on both integrins. However U87MG single cell migration was highly dependent on alpha5beta1 integrin and was inhibited selectively by alpha5beta1 integrin antagonists but increased by alphavbeta3/beta5 integrin antagonists. CONCLUSIONS: We provide a rationale for testing new integrin ligands in a cell-based assay to characterize more directly their potential inhibitory effects on integrin cellular functions. GENERAL SIGNIFICANCE: Our data highlight a single cell tracking assay as a powerful cell-based test which may help to characterize true functional integrin antagonists that block alpha5beta1 integrin-dependent cell migration. PMID- 24810980 TI - Anti-Mullerian hormone screening to assess ovarian reserve among female survivors of childhood cancer. AB - PURPOSE: Anti-Mullerian hormone (AMH) is an indicator of oocyte reserve in healthy females. The role of AMH testing in oncology remains investigational, although its sensitivity and stability over the menstrual cycle make it an attractive screening test for fertility assessment among female cancer survivors. We measured AMH level in survivors of childhood cancer and evaluated its association with treatment and patient factors. METHODS: Participants were adult female survivors of childhood malignancy treated with chemotherapy. Serum AMH was measured at a random day of the menstrual cycle. Multivariate analysis was used to evaluate the association between AMH level, alkylating agent exposure using the cyclophosphamide equivalent dose (CED), and other covariates. RESULTS: Sixty six females with a median attained age of 23.3 years were eligible for analysis. Median AMH was 25.5 pM (range 0.5-108.0), at a median time of 11.5 years (range 1.4-25.1) since cancer diagnosis. Twenty-three patients (34.8%) had low AMH, including a significant proportion that reported normal menstrual cycles. Compared to ALL survivors, sarcoma survivors had significantly lower AMH levels. Among alkylating agents evaluated, procarbazine had the greatest adverse effect on AMH. In multivariate analysis, higher CED (p = 0.001), older age at diagnosis (p < 0.001), and use of oral contraceptive pills (p = 0.04) remained significantly associated with lower AMH. CONCLUSIONS: Random AMH can reveal evidence of oocyte depletion among female survivors reporting normal cycles, although low AMH should be interpreted cautiously among those taking oral contraception. Age at exposure and CED can aid identification of those more likely to have low AMH, although CED may underestimate the effect of procarbazine on oocyte reserve. IMPLICATIONS FOR CANCER SURVIVORS: Measurement of AMH can reveal apparent depletion of ovarian reserve in female childhood cancer survivors reporting normal menstrual cycles. Sarcoma survivors and those exposed to procarbazine may benefit from targeted AMH evaluation in an outpatient setting, and thereby allow appropriate fertility counseling before the onset of premature ovarian failure. The cyclophosphamide equivalent dose may facilitate comparison of the potential effect of different regimens on fertility. PMID- 24810981 TI - Reactions and attitudes to postpartal mental symptoms in a rural community. AB - We examined the reactions of population, social and health care professionals and local politicians in the context of a narrative case of a newborn and her mother evincing postpartal mental symptoms. The results of this postal questionnaire study indicated that in assessing the urgent need for support, a significant positive association prevailed in the resident cohort with female gender, age over 50 years or being a parent. Professionals and politicians estimated that appropriate care and access to care would be obtained in the maternity and child health clinic in the local health centre. Residents would contact relatives rather than social and health care professionals. A future challenge is to promote the knowledge and sensitivity of the general population in recognizing mental symptoms in mothers with small children. Adequate information is also called for regarding local services and means of access to care. PMID- 24810982 TI - Flexibility and structure may enhance implementation of family-focused therapy in community mental health settings. AB - This study elicited provider and administrator preferences in implementing an evidence-based practice (EBP) for bipolar disorder or psychosis, family-focused therapy (FFT). Providers (n = 35) and administrators (n = 5) from three community mental health centers took part in FFT training and participated in pre- and post training focus groups. Transcripts were examined using conventional content analysis. Providers and administrators discussed barriers to implementing EBPs. Successful EBPs were described as incorporating flexibility and close supervision to maximize provider adherence. Providers expressed preferences for structured EBPs like FFT that have both explicit implementation steps and built-in flexibility. PMID- 24810983 TI - Iatrogenic vertebral artery injury secondary to vessel tortuosity in a grossly degenerate cervical spine. AB - Iatrogenic vertebral artery (VA) injury is a rare but significant complication of anterior cervical spine surgery. In the grossly degenerate cervical spine the VA may adopt a tortuous pathway thus predisposing to inadvertent injury during surgery. Here we illustrate such a case and discuss potential management strategies. PMID- 24810984 TI - History of neurosurgery at the Royal Free Hospital in London. AB - The recent move of the neurosurgical services from The Royal Free London NHS Foundation Trust in Hampstead to The National Hospital for Neurology and Neurosurgery at Queen Square signified the end of an era of neurosurgery in North London. It also represents also another chapter in the history of the remarkable North London hospital that is The Royal Free Hospital. This short article looks at the history of the Department of Neurosurgery at The Royal Free Hospital and the factors contributing to the reorganisation of neurosurgical services in North London. PMID- 24810985 TI - Medical negligence. Legal theory and neurosurgical practice: informed consent. AB - This article discusses the principles of the law in relation to informed consent as applied to neurosurgical practice. Patient autonomy, forms of consent, capacity to consent, the nature of information that should be given to patients, the level of information given, alternatives to treatment, which doctor should consent and when, consenting children, differing opinions, euthanasia and respect for the state of scientific knowledge are discussed. PMID- 24810986 TI - Ventriculostomy associated haemorrhage: a complication of anti-platelet therapy during coiling. AB - A young man with Fisher grade IV subarachnoid haemorrhage (SAH) underwent aneurysm coiling following external ventriculostomy. Coiling was complicated by thrombus formation and parent vessel occlusion necessitating anti-platelet therapy. Several hours after anti-platelet therapy, catastrophic haemorrhage associated with the ventriculostomy tract occurred. Timing and location of haemorrhage suggest combined anti-platelet therapy and ventriculostomy may have been causal. The literature on ventriculostomy haemorrhage rates and risks with concomitant anti-platelet therapy are reviewed. Where endovascular coiling is being considered, the possibility of ventriculostomy-related haemorrhage should be considered and should influence subsequent treatment decisions. PMID- 24810987 TI - Medical negligence. An overview of legal theory and neurosurgical practice: causation. AB - This article discusses the principles of the law in relation to legal causation as applied to neurosurgical practice. Causation is a causal link between a breach of duty of care and the final harm. The fundamental "but-for" test for causation will be discussed, together with Chester v Afshar modified causation, prospective and retrospective probabilities of harm, loss of a chance, causation following breach of duty of care by omission, breaking the chain of causation, material contribution and the law in relation to multiple defendants, with neurosurgical examples. PMID- 24810988 TI - Ligand-assisted dual-site click labeling of EGFR on living cells. AB - We have developed a dual-site click labeling strategy for the simultaneous installation of a FRET donor-acceptor pair onto the extracellular domains of epidermal growth factor receptor (EGFR) on living cells. Our method integrates the genetic code expansion strategy, enzyme-mediated protein labeling, and ligand assisted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) into a tri-step labeling procedure. This enabled cis-membrane FRET imaging of EGFR under living conditions. This procedure might be generally applicable for dual-site labeling and cis-membrane FRET analysis of the domain-domain dynamics of important mammalian cell-surface receptors. PMID- 24810989 TI - YAP1 acts as oncogenic target of 11q22 amplification in multiple cancer subtypes. AB - The transcriptional coactivator YAP1 is a critical effector of the human Salvador Warts-Hippo pathway. Literature data report apparently discrepant results on the carcinogenic role of YAP1, which acts either as oncogene or as tumor suppressor in different in vitro and in vivo models. Furthermore, genomic amplification events of 11q22 locus encompassing YAP1 gene have been detected in multiple tumor types but there is limited direct evidence about the oncogenic role of endogenous YAP1 within in the amplicon. We screened a panel of human tumor samples and cancer cell lines and identified that the YAP1 amplification event is actually present in up to 23% of the cases. We exploited EKVX (lung cancer), CaSki (cervical cancer) and RO82 (thyroid cancer) cell lines harboring both genomic YAP1 amplification and YAP1 protein overexpression, in order to study the effects of downregulation of endogenous YAP1 by RNA-interference strategies. Class comparison analysis of gene expression profiling data identified 707 statistically significantly modulated genes (multivariable global test p-value = 0.002) that were functionally annotated for cell proliferation and cellular movement ontologies. Mechanistic studies of the identified perturbed pathways revealed that YAP1 silencing significantly decreased cell proliferation and cell cycle perturbation associated with upregulation of p21 and p27 cell-cycle inhibitors, reduced cell migration (p<0.048) and anchorage-independent growth (p<0.02). In CaSki cell line, YAP1 silencing induced significantly increased sensitivity and cell-death response to cisplatin treatment (p=0.011) as well as reduction of in-vivo tumorigenic potential (p=0.027). Overall, these results establish that YAP1 is a direct oncogenic target of the 11q22 amplicon in previously unreported cancer types and support the relevance of such genetic aberration in carcinogenesis in a fraction of multiple tumor types. PMID- 24810990 TI - Dexamethasone PONV prophylaxis alters the hypothalamic-pituitary-adrenal axis after transsphenoidal pituitary surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is common after general anesthesia and are reported by approximately 20% to 25% of all patients and up to 39% of patients undergoing neurosurgical procedures. The most common standard prophylaxis is a single application of 4 mg of dexamethasone before initiating anesthesia. Dexamethasone is known to suppress adreno-corticotroph hormone and cortisol levels. The objective was to find out whether this prophylaxis has an effect on the postoperative levels of cortisol in patients undergoing transsphenoidal pituitary surgery, and therefore simulates pituitary deficiency. PATIENTS AND METHODS: A retrospective analysis of the files of 136 consecutive patients who were operated during a course of 6 months were included. Nineteen patients with a known history of PONV received a standard dose of 4 mg of dexamethasone perioperatively. Blood tests were drawn at the first postoperative day and were compared with blood tests of patients who had no history of PONV and therefore received no prophylaxis. RESULTS: Patients who were treated with a dexamethasone PONV prophylaxis showed no significant changes in cortisol levels; preoperative median of 93 MUg/L (range, 39 to 427) and a postoperative median of 87 MUg/L (range, 10 to 733; P=0.798) opposed to patients who did not receive such treatment; preoperative cortisol 114 MUg/L (range, 10 to 387) and postoperative levels of 273 MUg/L (range, 10 to 1352; P<0.001). CONCLUSIONS: As early postoperative blood checks of the cortisol levels yield important information about potential pituitary sufficiency after transsphenoidal surgery, the probability that dexamethasone PONV prophylaxis suppresses postoperative cortisol levels should be considered. PMID- 24810992 TI - Photochemical preparation of silver nanoparticles supported on zeolite crystals. AB - A facile and rapid photochemical method for preparing supported silver nanoparticles (Ag-NPs) in a suspension of faujasite type (FAU) zeolite nanocrystals is described. Silver cations are introduced by ion exchange into the zeolite and subsequently irradiated with a Xe-Hg lamp (200 W) in the presence of a photoactive reducing agent (2-hydroxy-2-methylpropiophenone). UV-vis characterization indicates that irradiation time and intensity (I0) influence significantly the amount of silver cations reduced. The full reduction of silver cations takes place after 60 s of a polychromatic irradiation, and a plasmon band of Ag-NPs appears at 380 nm. Transmission electron microscopy combined with theoretical calculation of the plasmon absorbance band using Mie theory shows that the Ag-NPs, stabilized in the micropores and on the external surface of the FAU zeolite nanocrystals, have an almost spheroidal shape with diameters of 0.75 and 1.12 nm, respectively. Ag-NPs, with a homogeneous distribution of size and morphology, embedded in a suspension of FAU zeolites are very stable (~8 months), even without stabilizers or capping agents. PMID- 24810991 TI - Mechanisms of motor adaptation in reactive balance control. AB - Balance control must be rapidly modified to provide stability in the face of environmental challenges. Although changes in reactive balance over repeated perturbations have been observed previously, only anticipatory postural adjustments preceding voluntary movements have been studied in the framework of motor adaptation and learning theory. Here, we hypothesized that adaptation occurs in task-level balance control during responses to perturbations due to central changes in the control of both anticipatory and reactive components of balance. Our adaptation paradigm consisted of a Training set of forward support surface perturbations, a Reversal set of novel countermanding perturbations that reversed direction, and a Washout set identical to the Training set. Adaptation was characterized by a change in a motor variable from the beginning to the end of each set, the presence of aftereffects at the beginning of the Washout set when the novel perturbations were removed, and a return of the variable at the end of the Washout to a level comparable to the end of the Training set. Task level balance performance was characterized by peak center of mass (CoM) excursion and velocity, which showed adaptive changes with repetitive trials. Only small changes in anticipatory postural control, characterized by body lean and background muscle activity were observed. Adaptation was found in the evoked long-latency muscular response, and also in the sensorimotor transformation mediating that response. Finally, in each set, temporal patterns of muscle activity converged towards an optimum predicted by a trade-off between maximizing motor performance and minimizing muscle activity. Our results suggest that adaptation in balance, as well as other motor tasks, is mediated by altering central sensitivity to perturbations and may be driven by energetic considerations. PMID- 24810993 TI - High R.E.N.A.L. Nephrometry scores are associated with pathologic upstaging of clinical T1 renal-cell carcinomas in radical nephrectomy specimens: implications for nephron-sparing surgery. AB - BACKGROUND AND PURPOSE: The R.E.N.A.L. Nephrometry Score (RNS) was developed to standardize the reporting of anatomic information of a renal mass. This study aimed to identify the association of preoperative clinical and tumor features assessed by the RNS with pathologic upstaging of clinical T1 renal-cell carcinomas (RCCs) in complete en bloc radical nephrectomy (RN) specimens. PATIENTS AND METHODS: A review was performed for 65 consecutive patients (2005 2013) who underwent RNs for a unilateral clinical T1N0M0 RCC. The RNS was measured in all patients based on preoperative CT scans. Pathologic review was performed to identify patients with final pathologic upstaging. Associations were assessed with the Fisher exact test, Student t test, and Wilcoxon rank sum test. RESULTS: Of the 65 patients (41 male, mean age 59 years), 4 (6%) patients were upstaged to pT2 and 16 (25%) were upstaged to pT3a and above in the final histologic evaluation. Upstaged patients were not significantly different from those without in terms of age, sex, race, surgical approach, side of surgery, Fuhrman grade, and histologic cell type. Independent tumor features associated with pathologic upstaging were (R) tumor diameter (P=0.021), and (L) central location within polar lines (P=0.010). Tumors that were upstaged had a higher median total RNS than those without (10 vs 9, P=0.010). Complex tumors, with RNS>=10, were associated with significantly increased risk of upstaging compared with low and intermediate complexity categories (RNS<10) (relative risk=2.56, 95% confidence interval 1.22-5.37, P=0.014). CONCLUSIONS: A higher RNS was associated with an increased risk of upstaging in clinical T1 cancers, predominantly from perinephric or sinus fat invasion in RN pathologic specimens. This may have implications on the selection of surgical option for the clinical T1 renal mass. PMID- 24810994 TI - Scombroid fishes provide novel insights into the trait/rate associations of molecular evolution. AB - The study of which life history traits primarily affect molecular evolutionary rates is often confounded by the covariance of these traits. Scombroid fishes (billfishes, tunas, barracudas, and their relatives) are unusual in that their mass-specific metabolic rate is positively associated with body size. This study exploits this atypical pattern of trait variation, which allows for direct tests of whether mass-specific metabolic rate or body size is the more important factor of molecular evolutionary rates. We inferred a phylogeny for scombroids from a supermatrix of molecular and morphological characters and used new phylogenetic comparative approaches to assess the associations of body size and mass-specific metabolic rate with substitution rate. As predicted by the body size hypothesis, there is a negative correlation between body size and substitution rate. However, unexpectedly, we also find a negative association between mass-specific metabolic and substitution rates. These relationships are supported by analyses of the total molecular data, separate mitochondrial and nuclear genes, and individual loci, and they are robust to phylogenetic uncertainty. The molecular evolutionary rates of scombroids are primarily tied to body size. This study demonstrates that groups with novel patterns of trait variation can be particularly informative for identifying which life history traits are the primary factors of molecular evolutionary rates. PMID- 24810995 TI - Synthesis and biological activity of the C'D'E'F' ring system of maitotoxin. AB - Stereoselective synthesis of the C'D'E'F' ring system of maitotoxin was achieved starting from the E' ring through successive formation of the D' and C' rings based on SmI2-mediated reductive cyclization. Construction of the F' ring was accomplished via Suzuki-Miyaura cross-coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol. The C'D'E'F' ring system inhibited maitotoxin-induced Ca(2+) influx in rat glioma C6 cells with an IC50 value of 59 MUM. PMID- 24810996 TI - Vascularization of broad ligament of uterus and its relationship with fetal and placental development in gilts. AB - The objective of this study was to evaluate the influence of vascular architecture of broad ligament of the uterus on fetal and placental development in gilts. Fifteen gilts DB-90 (DanBred) were divided into three groups according to gestational age at slaughter (50, 80, and 106 days). After slaughter, fetuses and placentas were collected, weighed, and measured. The uterine arterial system was detached by latex repletion for quantification of the number and diameter of the terminal vessels in different regions of the uterine horns (apex, middle region, and base). Fetal and placental measurements were statistically analyzed and correlated with the number and diameter of arteries in each uterine segment. No correlation was observed (P > 0.10) between the number and diameter of arteries destined to the uterus with the number or weight of fetuses or placental weight in any gestational group. It was observed (P < 0.05) that more vessels destined to the medium region of the uterine horns, independent of the gestational age or uterus side. At the 80th day of gestation, fetuses located at the base of the uterus have (P < 0.05) smaller cephalic and thoracic perimeters. It was concluded that there were differences in vascularization of broad ligament that irrigates the different uterine segments, but this was not sufficient to influence the development of fetuses in gilts. The middle region of the uterine horns was the segment with a greater number of vessels, regardless of gestational age. PMID- 24810997 TI - Nanosilver incurs an adaptive shunt of energy metabolism mode to glycolysis in tumor and nontumor cells. AB - Due to its significant antimicrobial properties, nanosilver (nAg) has been substantially used in a wide spectrum of areas. This has raised the concerns on the detrimental effects on environment and human health. Although numerous studies have documented nAg-mediated toxicity to cells or organisms, little attempt has been made to study the biological impacts of nAg on cells at nontoxic concentrations, namely, the distinct biological effects that can be separated from direct cytotoxicity. Here, we studied nAg-mediated effects on energy metabolism in cells under sublethal exposure. Treatment of nAg at nontoxic concentrations resulted in a decline of ATP synthesis and attenuation of respiratory chain function in nontumor HEK293T cells and tumor cells with differential respiration rate, including HepG2, HeLa, A498, and PC3 cells. Cellular energy homeostasis was switched from oxidative phosphorylation-based aerobic metabolism to anaerobic glycolysis, which is an adaption process to satisfy the energy demand for cell survival. Nanospheres with smaller size showed greater capability to alter cellular energy metabolism than those with larger size or nanoplates. Mechanistic investigation manifested that inhibition of PGC 1alpha by nAg was, at least partially, accountable for the transition from oxidative phosphorylation to glycolysis. Additionally, altered expression of a few energy metabolism-related genes (such as PFKFB3 and PDHA1) was also involved in the transition process. We further showed nAg-induced depolarization of mitochondrial membrane potential and reduction of respiratory chain complex activity. Together, our combined results uncovered the mechanisms by which nAg induced energy metabolism reprogramming in both tumor and nontumor cells under sublethal dosage. PMID- 24810998 TI - Vocal tract shapes in different singing functions used in musical theater singing a pilot study. AB - OBJECTIVE: Singing styles in Musical Theater singing might differ in many ways from Western Classical singing. However, vocal tract adjustments are not understood in detail. MATERIAL AND METHODS: Vocal tract shapes of a single professional Music Theater female subject were analyzed concerning different aspects of singing styles using dynamic real-time magnetic resonance imaging technology with a frame rate of 8 fps. The different tasks include register differences, belting, and vibrato strategies. RESULTS: Articulatory differences were found between head register, modal register, and belting. Also, some vibrato strategies ("jazzy" vibrato) do involve vocal tract adjustments, whereas others (classical vibrato) do not. CONCLUSIONS: Vocal tract shaping might contribute to the establishment of different singing functions in Musical Theater singing. PMID- 24810999 TI - Fitting anxious emotion-focused intervention into the ecology of schools: results from a test anxiety program evaluation. AB - Emotion-focused prevention and intervention efforts in schools have been promoted as a significant developmental and public health priority. This paper reports the results of a longitudinal study testing central premises of a school-based prevention model aimed at promoting positive emotional development through targeting test anxiety. Test anxiety interventions may be a practical strategy for conducting emotion-focused prevention and intervention efforts because of a natural fit within the ecology of the school setting. At-risk youth (n = 1,048) from urban public schools were screened and 325 with elevated test anxiety were offered the intervention in one of two waves (immediate intervention vs. waitlist). The intervention was associated with decreases in test anxiety, anxiety disorder, and depression symptoms. Critically, results suggest high participant satisfaction and growth curve analysis of follow-up assessments (end of the year, the next school year, and a subsequent school year) demonstrated positive developmental trajectories consistent with predictions (e.g., initial change in test anxiety predicted change in other symptoms). Findings provide evidence for the ecological validity of targeting test anxiety in school-based, emotion-focused prevention efforts. PMID- 24811000 TI - A heartbreaking case of Wilson's disease: Takotsubo cardiomyopathy complicating fulminant hepatic failure. PMID- 24811001 TI - A high-performance liquid chromatography-tandem mass spectrometry method coupled with protein precipitation for determination of granisetron in human plasma and its application to a comparative pharmacokinetic study. AB - A rapid, simple and validated method based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has been developed for the determination of granisetron in human plasma. Plasma samples were pre-purified by protein precipitation procedure. The chromatographic separation was achieved with Synergi Polar-RP (75 * 2 mm, 4 um) column using a mixture of 5 mm pH4.0 ammonium formate and methanol (300:316, v/v) under isocratic conditions at a flow rate of 0.3 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode using positive electrospray ionization. The analysis time was about 2.5 min. The method was fully validated over the concentration range 0.1-10 ng/mL. The lower limit of quantification was 0.1 ng/mL. Inter- and intra-batch precision was <6.1% and the accuracy was within 95.6-100.0%. The mean extraction recovery was 96.3%. Selectivity, matrix effect and stability were also validated. The method was applied to the comparative pharmacokinetic study of granisetron in Chinese healthy subjects. PMID- 24811002 TI - Antimuscle atrophy effect of nicotine targets muscle satellite cells partly through an alpha7 nicotinic receptor in a murine hindlimb ischemia model. AB - We have recently identified that donepezil, an anti-Alzheimer drug, accelerates angiogenesis in a murine hindlimb ischemia (HLI) model. However, the precise mechanisms are yet to be fully elucidated, particularly whether the effects are derived from endothelial cells alone or from other nonvascular cells. Further investigation of the HLI model revealed that nicotine accelerated angiogenesis by activation of vascular endothelial cell growth factor (VEGF) synthesis through nicotinic receptors in myogenic cells, that is, satellite cells, in vivo and upregulated the expression of angiogenic factors, for example, VEGF and fibroblast growth factor 2, in vitro. As a result, nicotine prevented skeletal muscle from ischemia-induced muscle atrophy and upregulated myosin heavy chain expression in vitro. The in vivo anti-atrophy effect of nicotine on muscle was also observed in galantamine, another anti-Alzheimer drug, playing as an allosteric potentiating ligand. Such effects of nicotine were attenuated in alpha7 nicotinic receptor knockout mice. In contrast, PNU282987, an alpha7 nicotinic receptor agonist, comparably salvaged skeletal muscle, which was affected by HLI. These results suggest that cholinergic signals also target myogenic cells and have inhibiting roles in muscle loss by ischemia-induced muscle atrophy. PMID- 24811004 TI - An interpretative phenomenological analysis exploring the lived experience of individuals dying from terminal cancer in Ireland. AB - OBJECTIVE: The experience of living with dying has attracted limited research. We utilized interpretive phenomenological analysis to explore the lived experience of individuals with terminal cancer receiving palliative care in Ireland. METHOD: Participants were purposely selected from public interviews that had been conducted between 2006 and 2011. The study included the accounts of eight participants (N = 8; six females and two males) with a diagnosis of terminal cancer. Participant ages ranged from 36 to 68 years. RESULTS: Three master themes emerged from the analysis: the personal impact of diagnosis, the struggle in adjusting to change, and dying in context. The results revealed that participants were still living while simultaneously dying. Interestingly, participants did not ascribe new meaning to their lives. The terminal illness was understood within the framework of the life that had existed before diagnosis. They strove to maintain their normal routines and continued to undertake meaningful activities. Management of unfinished business and creation of a legacy were salient tasks. Social withdrawal was not present; rather, participants engaged in emotional labor to sustain valued roles. However, we found that within the public domain there is a paucity of education and discourse supporting individuals at the end of life. The hospice was noted as an important external resource. Each participant experienced a unique dying process that reflected their context. SIGNIFICANCE OF RESULTS: Healthcare professionals need to recognize the subjectivity of the dying process. Dying individuals require support and options to maintain their personhood. PMID- 24811003 TI - Adiposity distribution influences circulating adiponectin levels. AB - Thirty percent of obese individuals are metabolically healthy and were noted to have increased peripheral obesity. Adipose tissue is the primary source of adiponectin, an adipokine with insulin-sensitizing and anti-inflammatory properties. Lower adiponectin levels are observed in individuals with obesity and those at risk for cardiovascular disease. Conversely, higher levels are noted in some obese individuals who are metabolically healthy. Our objective was to determine whether abdominal adiposity distribution, rather than body mass index (BMI) status, influences plasma adiponectin level. A total of 424 subjects (female, 255) of Northern European ancestry were recruited from "Take Off Pounds Sensibly" weight loss club members. Demographics, anthropometrics, and dual emission x-ray absorptiometry of the whole body, and computed tomography scan of the abdomen were performed to obtain total body fat content and to quantify subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), respectively. Laboratory measurements included fasting plasma glucose, insulin, lipid panel, and adiponectin. Age- and gender-adjusted correlation analyses showed that adiponectin levels were negatively correlated with BMI, waist circumference, triglycerides, total fat mass, and VAT. A positive correlation was noted with high-density lipoprotein cholesterol and fat-free mass (P < 0.05). SAT to-VAT ratios were also significantly associated with adiponectin (r = 0.13, P = 0.001). Further, the best positive predictors for plasma adiponectin were found to be SAT-to-VAT ratios and gender by regression analyses (P < 0.01). Abdominal adiposity distribution is an important predictor of plasma adiponectin and obese individuals with higher SAT-to-VAT ratios may have higher adiponectin levels. PMID- 24811005 TI - Phospholipase D1 mediates lymphocyte adhesion and migration in experimental autoimmune encephalomyelitis. AB - Lymphocyte adhesion and subsequent trafficking across endothelial barriers are essential steps in various immune-mediated disorders of the CNS, including MS. The molecular mechanisms underlying these processes, however, are still unknown. Phospholipase D1 (PLD1), an enzyme that generates phosphatidic acid through hydrolysis of phosphatidylcholine and additionally yields choline as a product, has been described as regulator of the cell mobility. By using PLD1-deficient mice, we investigated the functional significance of PLD1 for lymphocyte adhesion and migration in vitro and after myelin oligodendrocyte glycoprotein (MOG)35-55 induced EAE, a model of human MS. The lack of PLD1 reduced chemokine-mediated static adhesion of lymphocytes to the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in vitro, and was accompanied by a decreased migratory capacity in both blood brain barrier and cell migration models. Importantly, PLD1 is also relevant for the recruitment of immune cells into the CNS in vivo since disease severity after EAE was significantly attenuated in PLD1-deficient mice. Furthermore, PLD1 expression could be detected on lymphocytes in MS patients. Our findings suggest a critical function of PLD1-dependent intracellular signaling cascades in regulating lymphocyte trafficking during autoimmune CNS inflammation. PMID- 24811006 TI - P-glycoprotein expression in Perna viridis after exposure to Prorocentrum lima, a dinoflagellate producing DSP toxins. AB - Bivalves naturally exposed to toxic algae have mechanisms to prevent from harmful effects of diarrhetic shellfish poisoning (DSP) toxins. However, quite few studies have examined the mechanisms associated, and the information currently available is still insufficient. Multixenobiotic resistance (MXR) is ubiquitous in aquatic invertebrates and plays an important role in defense against xenobiotics. Here, to explore the roles of P-glycoprotein (P-gp) in the DSP toxins resistance in shellfish, complete cDNA of P-gp gene in the mussel Perna viridis was cloned and analyzed. The accumulation of okadaic acid (OA), a main component of DSP toxins, MXR activity and expression of P-gp in gills of P. viridis were detected after exposure to Prorocentrum lima, a dinoflagellate producing DSP toxins in the presence or absence of P-gp inhibitors PGP-4008, verapamil (VER) and cyclosporin A (CsA). The mussel P. viridis P-gp closely matches MDR/P-gp/ABCB protein from various organisms, having a typical sequence organization as full transporters from the ABCB family. After exposure to P. lima, OA accumulation, MXR activity and P-gp expression significantly increased in gills of P. viridis. The addition of P-gp-specific inhibitors PGP-4008 and VER decreased MXR activity induced by P. lima, but had no effect on the OA accumulation in gills of P. viridis. However, CsA, a broad-spectrum inhibitor of ABC transporter not only decreased MXR activity, but also increased OA accumulation in gills of P. viridis. Together with the ubiquitous presence of other ABC transporters such as MRP/ABCC in bivalves and potential compensatory mechanism in P-gp and MRP-mediated resistance, we speculated that besides P-gp, other ABC transporters, especially MRP might be involved in the resistance mechanisms to DSP toxins. PMID- 24811007 TI - Identification of a novel molluscan short-type peptidoglycan recognition protein in disk abalone (Haliotis discus discus) involved in host antibacterial defense. AB - Peptidoglycan recognition proteins (PGRPs) are a widely studied group of pattern recognition receptors found in invertebrate as well as vertebrate lineages, and are involved in bacterial pathogen sensing. However, in addition to this principal role, they can also function in multiple host defense processes, including cell phagocytosis and hydrolysis of peptidoglycans (PGNs). In this study, a novel invertebrate short-type PGRP was identified in disk abalone (Haliotis discus discus) designated as AbPGRP. The complete coding sequence of AbPGRP was 534 bp, encoding a 178-amino acid protein with a predicted molecular mass of 20 kDa. The AbPGRP gene had a bipartite arrangement consisting of two exons separated by a single intron. Homology analysis revealed that AbPGRP shares conserved features, including amino acid residues critical for substrate and ion binding as well as for its amidase activity, with homologs of other species. Phylogenetic analysis of AbPGRP revealed that it likely evolved from a common ancestor of invertebrates, having significant homology with other molluscan PGRPs. Recombinant AbPGRP exhibited detectable, dose-dependent PGN-hydrolyzing activity with the presence of Zn(2+), and strong antibacterial activity against Vibrio tapetis, consistent with the functional properties previously reported for PGRPs in other mollusks. Moreover, AbPGRP transcription was induced upon treatment of healthy abalones with bacterial peptidoglycan and lipopolysaccharide, although the expression profiles differed with treatment, suggesting a capacity for discriminating between bacterial pathogens through molecular pattern recognition. Collectively, the findings of this study indicate that AbPGRP is a true homolog of invertebrate PGRPs and likely plays an indispensable role in host immunity. PMID- 24811008 TI - Isolation and characterization of tumor necrosis factor receptor-associated factor 6 (TRAF6) from grouper, Epinephelus tauvina. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the key adapter molecules in Toll-like receptor signal transduction that triggers downstream cascades involved in innate immunity. In the present study, a TRAF6 (named as Et-TRAF6) was identified from the marine fish grouper, Epinephelus tauvina by RACE PCR. The full-length cDNA of Et-TRAF6 comprised 1949 bp with a 1713 bp open reading frame (ORF) that encodes a putative protein of 570 amino acids. Similar to most TRAF6s, Et-TRAF6 includes one N-terminal RING domain (78aa 116aa), two zinc fingers of TRAF-type (159aa-210aa and 212aa-269aa), one coiled coil region (370aa-394aa), and one conserved C-terminal meprin and TRAF homology (MATH) domain (401aa-526aa). Quantitative real-time PCR analysis revealed that Et TRAF6 mRNA is expressed in all tested tissues, with the predominant expression in the stomach and intestine. The expression of Et-TRAF6 was up-regulated in the liver after challenge with Lipoteichoic acid (LTA), Peptidoglycan (PGN), Zymosan, polyinosine-polycytidylic acid [Poly(I:C)] and Polydeoxyadenylic acid . Polythymidylic acid sodium salt [Poly(dA:dT)]. The expression of Et-TRAF6 was also up-regulated in the liver after infection with Vibrio alginolyticus, Singapore grouper iridovirus (SGIV) and grouper nervous necrosis virus (GNNV). Recombinant Et-TRAF6 (rEt-TRAF6) was expressed in Escherichia BL21 (DE3) and purified for mouse anti-Et-TRAF6 serum preparation. Intracellular localization revealed that Et-TRAF6 is distributed in both cytoplasm and nucleus, and predominantly in the cytoplasm. These results together indicated that Et-TRAF6 might be involved in immune responses toward bacterial and virus challenges. PMID- 24811009 TI - Transgenic expression of salmon delta-5 and delta-6 desaturase in zebrafish muscle inhibits the growth of Vibrio alginolyticus and affects fish immunomodulatory activity. AB - Marine fish are an important nutritional source for highly polyunsaturated fatty acids (PUFAs). PUFA biosynthesis requires the following key enzymes: delta-4 (Delta-4) desaturase, delta-5 (Delta-5) desaturase, delta-6 (Delta-6) desaturase, delta-5 (Delta-5) elongase, and delta-6 (Delta-6) elongase. The effect of overexpressing delta-5 desaturase and/or delta-6 desaturase in zebrafish muscle has not previously been reported. Herein, we investigated the effects of these proteins on antibacterial and immunomodulatory activity in transgenic zebrafish infected with Vibrio alginolyticus. Overexpression of delta-5 and delta-6 desaturase enhanced antibacterial activity at 4 and 12 h after injection of bacteria into muscle, as compared to controls. Furthermore, expression of immune related genes (IL-1beta, IL-22, and TNF-alpha) was observed to be altered in transgenic fish after 4 h of bacterial infection, resulting in a significant decrease in the inflammatory response, as compared to control fish. These results demonstrate that muscle-specific expression of transgenic desaturases in zebrafish not only enhance PUFA production, but also enhance antibacterial and anti-inflammatory activity. Overall, these results identify delta-5 and delta-6 desaturase as novel candidate genes for use in aquaculture, to enhance both disease resistance and fish oil production. PMID- 24811010 TI - Vascular lesions and functional limitations among older adults: does depression make a difference? AB - ABSTRACT Background: The association between disability and depression is complex, with disability well established as a correlate and consequence of late life depression. Studies in community samples report that greater volumes of cerebral white matter hyperintensities (WMHs) seen on brain imaging are linked with functional impairment. These vascular changes are also associated with late life depression, but it is not known if depression is a modifier in the relationship between cerebrovascular changes and functional impairment. Methods: The study sample was 237 older adults diagnosed with major depression and 140 never depressed comparison adults, with both groups assessed at study enrollment. The dependent variable was the number of limitations in basic activities of daily living (ADL), instrumental ADLs, and mobility tasks. The independent variable was the total volume of cerebral white matter lesions or hyperintensities assessed though magnetic resonance imaging. Results: In analyses controlling for age, sex, race, high blood pressure, and cognitive status, a greater volume of WMH was positively associated with the total number of functional limitations as well as the number of mobility limitations among those older adults with late life depression but not among those never depressed, suggesting the association between WMH volume and functional status differs in the presence of late life depression. Conclusions: These findings suggest older patients with both depression and vascular risk factors may be at an increased risk for functional decline, and may benefit from management of both cerebrovascular risk factors and depression. PMID- 24811011 TI - President's page: CV workforce projections are not what they seem. PMID- 24811012 TI - Idiopathic anaphylaxis. AB - Idiopathic anaphylaxis is a perplexing problem that accounts for approximately 30% to 60% of cases of anaphylaxis in ambulatory adults and perhaps 10% of cases in children. Advances in our knowledge of idiopathic anaphylaxis have occurred over the past decade with the elucidation of mast cell activating disorders and the discovery of episodes of anaphylaxis caused by galactose-alpha-1,3-galactose. Most patients do well because fatalities can usually be prevented with proper therapy, and many individuals, for reasons not understood, undergo spontaneous remission. PMID- 24811013 TI - Mast cell activation disorders. AB - Disorders associated with mast cell activation range from relatively common IgE mediated disease and chronic urticaria to rarer conditions such as mastocytosis or monoclonal mast cell activation disorder. Mast cell activation disorders can be mechanistically classified into primary (associated with abnormal production of mast cells that carry pathologic markers of clonality), secondary (normal mast cells activated in reaction to a microenvironmental trigger), and idiopathic (no etiology is found). Clinical presentations, diagnostic criteria as well as general principles of a stepwise therapy approach are discussed. PMID- 24811014 TI - Delayed anaphylaxis to red meat masquerading as idiopathic anaphylaxis. AB - Anaphylaxis is traditionally recognized as a rapidly developing combination of symptoms that often includes hives and hypotension or respiratory symptoms. Furthermore, when a specific cause is identified, exposure to this cause is usually noted to have occurred within minutes to 2 hours before the onset of symptoms. This case is of a 79-year-old woman who developed a severe episode of anaphylaxis 3 hours after eating pork. Before 2012, she had not experienced any symptoms after ingestion of meat products. Delayed anaphylaxis to mammalian meat has many contrasting features to immediate food-induced anaphylaxis. The relevant IgE antibody is specific for the oligosaccharide galactose-alpha-1,3-galactose, a blood group substance of nonprimate mammals. There is evidence from Australia, Sweden, and the United States that the primary cause of this IgE antibody response is tick bites. These bites characteristically itch for 10 days or more. Diagnosis can be made by the presence of specific IgE to beef, pork, lamb, and milk, and the lack of IgE to chicken, turkey, and fish. Skin prick tests (but not intradermal tests) generally are negative. Management of these cases, now common across the southeastern United States, consists of education combined with avoidance of both ingestion of red meat and further tick bites. PMID- 24811015 TI - Omalizumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report. AB - Patients with all forms of mastocytosis can experience urticaria, abdominal cramps, nausea, diarrhea, or hypotension due to release of mediators by mast cells. Patients with mastocytosis and Hymenoptera venom allergy can develop severe adverse reactions to Hymenoptera stings. In addition, patients with mastocytosis and on venom immunotherapy are at high risk for incomplete protection and fatal reactions. Recent literature has reported the use of omalizumab as an adjunctive treatment in patients with mastocytosis, used for both symptom improvement and to dampen adverse effects caused by venom immunotherapy. This article reviews the literature regarding omalizumab use in the treatment of mastocytosis and for protection against the adverse effects during venom immunotherapy. In addition, we report the case of a patient at high risk and with cutaneous mastocytosis, whose symptoms improved with concomitant administration of omalizumab and venom immunotherapy. PMID- 24811016 TI - Are you comfortable with over-the-counter intranasal steroids for children? A call to action. AB - The early expression of allergic rhinitis in children is a potential red flag for lifelong problems and comorbid conditions. However, treating pediatric allergic rhinitis in the United States is trending toward a self-management or parental management model with little clinical supervision, which reflects changes in the delivery of health care. Of particular concern are the recent approval of an over the-counter intranasal steroid to treat nasal allergy symptoms in adults and children as young as age 2 years and the push for a retail model of health care as exists in some other countries. For children with allergic rhinitis, treating nasal symptoms alone with over-the-counter products may further delay a diagnosis that is often already ignored due to its "annoyance factor" as opposed to being considered a serious health issue. How to ensure an appropriate diagnosis and management for these children remains a challenge, regardless of who is doing the treating. The call to action is for allergists and allergy medical organizations to drive the effort to ensure awareness of the why and how for appropriately diagnosing and treating allergic rhinitis in children. Starting points for the discussion are provided. PMID- 24811017 TI - Improving screening and diagnosis of exercise-induced bronchoconstriction: a call to action. AB - This article summarizes the findings of an expert panel of nationally recognized allergists and pulmonologists who met to discuss how to improve detection and diagnosis of exercise-induced bronchoconstriction (EIB), a transient airway narrowing that occurs during and most often after exercise in people with and without underlying asthma. EIB is both commonly underdiagnosed and overdiagnosed. EIB underdiagnosis may result in habitual avoidance of sports and physical activity, chronic deconditioning, weight gain, poor asthma control, low self esteem, and reduced quality of life. Routine use of a reliable and valid self administered EIB screening questionnaire by professionals best positioned to screen large numbers of people could substantially improve the detection of EIB. The authors conducted a systematic review of the literature that evaluated the accuracy of EIB screening questionnaires that might be adopted for widespread EIB screening in the general population. Results of this review indicated that no existing EIB screening questionnaire had adequate sensitivity and specificity for this purpose. The authors present a call to action to develop a new EIB screening questionnaire, and discuss the rigorous qualitative and quantitative research necessary to develop and validate such an instrument, including key methodological pitfalls that must be avoided. PMID- 24811018 TI - Predictors of biphasic reactions in the emergency department for patients with anaphylaxis. AB - BACKGROUND: A biphasic reaction is the recurrence of anaphylaxis symptoms within 72 hours of the initial anaphylactic event, without re-exposure to the trigger. Biphasic reactions are uncommon and unpredictable, and risk factors for biphasic reactions are poorly understood. OBJECTIVE: To identify predictors of biphasic anaphylactic reactions in patients with anaphylaxis in the emergency department (ED). METHODS: Patients of all ages who presented to the ED and met diagnostic criteria for anaphylaxis from April 2008 to January 2013 at an academic medical center with 73,000 annual patient visits were consecutively included. We collected data on patient characteristics, suspected triggers, signs and symptoms, ED management, and disposition. Univariate analyses were performed to estimate the association between potential predictor variables and biphasic reactions. We report associations as odds ratios (OR) and corresponding 95% CIs. RESULTS: Among 541 patients with anaphylaxis, median age was 34.6 years (interquartile range, 18-52 years), and 320 (59%) were female patients. Twenty one patients (4%) had biphasic reactions. Two pediatric patients, ages of 5 years old and 16 years old, developed a biphasic reaction. The median time between the resolution of initial symptoms and onset of the biphasic reaction was 7 hours (range, 1-72 hours). Biphasic reactions were associated with a history of prior anaphylaxis (OR 2.6 [95% CI, 1.1-6.4]; P = .029), unknown precipitant (OR 2.6 [95% CI, 1.1-6.2]; P = .03), symptoms of diarrhea (OR 4.5 [95% CI, 1.4-14.0]; P = .024), and wheezing (OR 2.6 [95% CI, 1.4-8.9]; P = .029). CONCLUSIONS: Patients with a history of prior anaphylaxis, an unknown precipitant, or who present with symptoms of diarrhea or wheezing may be at increased risk for a biphasic reaction. PMID- 24811019 TI - Disparity in the availability of injectable epinephrine in a large, diverse US school district. AB - BACKGROUND: Food allergies affect 2.5% of the US population. Results of studies show that minorities have the highest prevalence of food allergies. The Houston Independent School District (HISD) has an urban, socioeconomically diverse population and the role of ethnicity and socioeconomic status (SES) with availability of epinephrine has not been explored in this population. OBJECTIVE: This study sought to understand the association of SES and the presence of epinephrine in urban schools. METHODS: A 6-item questionnaire about food allergy characteristics was sent by e-mail to one nurse per elementary school in the HISD to identify the number, characteristics and treatment of food allergic reactions, and the presence of epinephrine injectors. The reactions and presence of injectors were assessed for the previous school year. Schools were categorized by socioeconomic variables as "low" or "non-low" based on National School Lunch Program student participation. Poisson, logistic, and linear regression analyses were used for group comparisons. RESULTS: One or more children with food allergies were reported in 97% of responding schools, but only 43% of schools reported having epinephrine injectors. A larger number of injectors in schools were associated with students of higher SES (r(2) = 0.701; P < .001). There were 6 times more injectors in non-low SES schools than in low SES schools (P < .03). Low SES and limited English proficiency were associated with decreased epinephrine injectors in schools. CONCLUSION: In the HISD, epinephrine injectors were more likely to be found in non-low SES schools versus low SES schools. Because minority students are disproportionately highly represented in low SES schools, there appears to be a disparity in the availability of injectable epinephrine for minority students in HISD schools. PMID- 24811021 TI - Predicting outcomes of oral food challenges by using the allergen-specific IgE total IgE ratio. AB - BACKGROUND: Although allergists typically use allergen-specific IgE (sIgE) levels or skin prick test wheal sizes to identify food allergens that may provoke IgE mediated food-induced allergic reactions, both tests have high rates of false positivity and mislabel patients who are tolerant as allergic to the food allergen. OBJECTIVE: To examine the accuracy of the ratio of sIgE to total IgE ("Ratio") in predicting the outcome of challenges performed to confirm the development of tolerance. METHODS: Medical records of children diagnosed with food allergy who participated in oral food challenge at an allergy outpatient clinic (2009-2013) were reviewed for IgE antifood serology and concomitant oral food challenge outcomes, which were analyzed for associations by using logistic regression models and receiver operator characteristics curves. RESULTS: The Ratio for participants who failed their challenge was higher than the Ratio of those who passed their challenge (failed 1.48% vs passed 0.49%; n = 195). Receiver operator characteristic curves showed that the Ratio was significantly more accurate than sIgE alone in predicting challenge outcome (Ratio 0.69 vs sIgE alone 0.55; P = .03). These trends were mostly associated with more persistent food allergens, such as peanut, tree nuts, shellfish, and seeds (failed 2.18% vs passed 0.41%; n = 93) (Ratio 0.81 vs sIgE alone 0.54; P < .01). CONCLUSION: Our findings suggest that the Ratio is more accurate than sIgE alone in predicting outcomes of challenges performed to confirm the development of tolerance to select food allergens, especially to peanut and tree nuts. The Ratio may be useful in identifying patients most likely to pass oral food challenge. PMID- 24811020 TI - A multifaceted intervention for patients with anaphylaxis increases epinephrine use in adult emergency department. AB - BACKGROUND: Studies have documented inconsistent emergency anaphylaxis care and low compliance with published guidelines. OBJECTIVE: To evaluate anaphylaxis management before and after implementation of an emergency department (ED) anaphylaxis order set and introduction of epinephrine autoinjectors, and to measure the effect on anaphylaxis guideline adherence. METHODS: A cohort study was conducted from April 29, 2008, to August 9, 2012. Adult patients in the ED who were diagnosed with anaphylaxis were included. ED management, disposition, self-injectable epinephrine prescriptions, allergy follow-up, and incidence of biphasic reactions were evaluated. RESULTS: The study included 202 patients. The median age of the patients was 45.3 years (interquartile range, 31.3-56.4 years); 139 (69%) were women. Patients who presented after order set implementation were more likely to be treated with epinephrine (51% vs 33%; odds ratio [OR] 2.05 [95% CI, 1.04-4.04]) and admitted to the ED observation unit (65% vs 44%; OR 2.38 [95% CI, 1.23-4.60]), and less likely to be dismissed home directly from ED (16% vs 29%, OR 0.47 [95% CI, 0.22-1.00]). Eleven patients (5%) had a biphasic reaction. Of these, 5 (46%) had the biphasic reaction in the ED observation unit; 1 patient was admitted to the intensive care unit. Six patients (55%) had reactions within 6 hours of initial symptom resolution, of whom 2 were admitted to the intensive care unit. CONCLUSIONS: Significantly higher proportions of patients with anaphylaxis received epinephrine and were admitted to the ED observation unit after introduction of epinephrine autoinjectors and order set implementation. Slightly more than half of the biphasic reactions occurred within the recommended observation time of 4 to 6 hours. Analysis of these data suggests that the multifaceted approach to changing anaphylaxis management described here improved guideline adherence. PMID- 24811022 TI - Physician specialty influences important aspects of pediatric asthma management. AB - BACKGROUND: Physician training influences patient care. OBJECTIVE: To compare asthma management and change in the percentage predicted FEV1 among pediatric physician specialties. METHODS: A retrospective cohort of children 6 years of age or older, seen in a multidisciplinary asthma clinic between 2009 and 2010, and followed to 2012, was completed to examine differences in asthma outcomes by specialty (2 pediatricians, 3 pediatric allergists, 5 pediatric respirologists). Univariate analyses compared investigation, including allergy testing (skin prick or RAST), comorbid conditions, and prescription by specialty. Multivariate regression, which controlled for random effect of the individual physician, examined specialty differences for prescribed inhaled corticosteroids (ICS) and changes in percentage predicted FEV1. RESULTS: More than 56% of the patients (309/548) were seen by pediatric respirologists, 26% by pediatric allergists, and 18% by pediatricians. Physician specialty influences investigation requested, comorbid diagnoses, treatment, and improvement in FEV1. Pediatric allergists' patients had more allergy tests, were more likely to be diagnosed with allergic rhinitis and, consequently, were more likely to be prescribed nasal steroids than pediatricians and pediatric respirologists. Pediatricians were less likely to prescribe ICS (odds ratio 0.39 [95% CI, 0.15-0.96]; P < .05) than pediatric allergists, with the greatest difference in ICS prescription among children with a percentage predicted FEV1 >= 80%. Improvement in FEV1 among children who received care with pediatric allergists was higher than those seen by pediatricians (13%; P < .001) and pediatric respirologists (8%; P = .005). CONCLUSIONS: Patient management domains with the greatest room for discretion (investigations, comorbid diagnoses, and treatment with ICS among children with normal lung function) are most heavily influenced by physician specialty. These results have implications for asthma management at the patient level and in future practice guidelines. PMID- 24811023 TI - Self-medication in persistent rhinitis: overuse of decongestants in half of the patients. AB - BACKGROUND: Patients with rhinitis often self-medicate with over-the-counter drugs, however this self-treating population has remained largely unstudied. OBJECTIVE: To characterize individuals self-medicating persistent rhinitis and to determine the prevalence of and risk factors for intranasal decongestant overuse within this population. METHODS: A cross-sectional observational study of individuals self-medicating persistent rhinitis (defined according to the Allergic Rhinitis and its Impact on Asthma guidelines). Participants (n = 895) completed a self-administered questionnaire to assess current symptoms, rhinitis medication, and previous physician diagnosis. Intranasal decongestant overuse was defined as daily use for at least 1 year. RESULTS: The vast majority of subjects (95%) had moderate-to-severe rhinitis. Nasal congestion was the predominant symptom (median visual analog scale, 6.6 cm; interquartile range, 3.4 cm). Sixty five percent had had their current nasal problems for more than 5 years. Approximately 80% had a physician diagnosis (mainly allergic rhinitis or rhinosinusitis). The prevalence of intranasal decongestant overuse was high (49%), despite the fact that most of the patients (80%) were educated about the limit on duration of use. Use of intranasal glucocorticosteroids was inversely related to being an overuser (odds ratio 0.24 [95% CI, 0.17-0.35]). The risk of intranasal decongestant overuse also was reduced by use of other medications (oral H1 antihistamines and decongestants), use of nasal saline solution, and more symptoms of itchy and/or runny eyes or colored mucus. Risk was increased by a more severely blocked nose, longer duration of symptoms, the presence of sleep disturbance, higher body mass index, and previous advice to limit the duration of intranasal decongestant use. CONCLUSION: Half of the individuals self-medicating persistent rhinitis overused intranasal decongestants, despite the fact that they were educated about the limit on duration of use. PMID- 24811024 TI - Racial differences in the clinical presentation of pediatric eosinophilic esophagitis. AB - BACKGROUND: Analysis of current data suggests that 80% to 90% of children diagnosed with eosinophilic esophagitis are white. Little data exist regarding the presentation of eosinophilic esophagitis and potential clinical differences in minority children. OBJECTIVE: This study compared the clinical presentation of eosinophilic esophagitis in African American children with white children treated at an urban allergy referral center. METHODS: At an urban allergy clinic, a 2 year retrospective chart review was performed of 50 consecutive pediatric patients diagnosed with eosinophilic esophagitis. Presenting symptoms, age at diagnosis, coexisting atopic disease, and laboratory parameters were compared between races. RESULTS: Most of the 50 children identified were boys (74%), as previously described. However, unlike prior literature, most were nonwhite (42% white, 42% African American, 4% Asian, and 12% other). African American children compared with white children had (1) a significantly higher frequency of failure to thrive (P < .01) and vomiting (P < .01) as presenting symptoms, (2) a higher frequency of comorbid atopic dermatitis (P < .01), (3) a younger mean age of symptom presentation and formal diagnosis (3.7 vs 9.1 years; P < .01), and (4) a trend toward a longer interval between symptom onset and formal diagnosis. However, after adjusting for confounding variables of age and insurance type, several of these racial differences were no longer significant. CONCLUSION: African American children in this series had a larger burden of eosinophilic esophagitis than previously described as well as differences in clinical presentation compared with white patients. Analysis of these findings suggests that providers be aware of this potential diagnosis in young, atopic African American children with symptoms of esophageal dysfunction. PMID- 24811026 TI - Omalizumab for the treatment of inadequately controlled allergic rhinitis: a systematic review and meta-analysis of randomized clinical trials. AB - BACKGROUND: Patients with moderate-to-severe allergic rhinitis who are inadequately controlled despite treatment according to current rhinitis management guidelines have a significant unmet medical need. Such patients have a negative impact on daily functioning and are at risk of developing serious comorbidities, such as asthma and chronic rhinosinusitis. OBJECTIVE: To assess the efficacy and safety of omalizumab in poorly controlled allergic rhinitis under a meta-analysis framework. METHODS: MEDLINE and the Cochrane Central Register of Controlled Trials were searched through September 2013. Studies on the efficacy of omalizumab in allergic rhinitis that assessed clinical outcomes were selected. Descriptive and quantitative information was extracted; mean differences and relative risk estimates were synthesized under a fixed or random effects model. Heterogeneity was assessed by using the Q statistic and the I(2) metric. Subgroup analyses were performed for the presence of specific immunotherapy treatment. RESULTS: Of the 352 citations retrieved, 11 studies of 2870 patients were finally included. A statistically significant reduction in the daily nasal symptom severity score (standardized mean difference -0.67 [95% CI, 1.3 to -0.31]; P < .0001; I(2), 92%) and a statistically significant reduction in daily nasal rescue medication score (-0.22 [95% CI, -0.39 to -0.05; P = .01; I(2), 58%) were observed. There was not a statistically significant difference in the occurrence of any adverse event (relative risk 1.06 [95% CI, 0.94-1.19; I(2), 55%). CONCLUSIONS: Omalizumab is statistically significantly associated with symptom relief, decreased rescue medication use, and improvement of quality of life in patients with inadequately controlled allergic rhinosinusitis. PMID- 24811025 TI - Validation of the Spanish version of the Test for Respiratory and Asthma Control in Kids (TRACK) in a population of Hispanic preschoolers. AB - BACKGROUND: There is a critical need for validation studies of questionnaires designed to assess the level of control of asthma in children younger than 5 years old. OBJECTIVE: To validate the Spanish version of the Test for Respiratory and Asthma Control in Kids (TRACK) questionnaire in children younger than age 5 years with symptoms consistent with asthma. METHODS: In a prospective cohort validation study, parents and/or caregivers of children younger than age 5 years and with symptoms consistent with asthma, during a baseline and a follow-up visit 2 to 6 weeks later, completed the information required to assess the content validity, criterion validity, construct validity, test-retest reliability, sensitivity to change, internal consistency reliability, and usability of the TRACK questionnaire. RESULTS: Median (interquartile range) of the TRACK scores were significantly different between patients with well-controlled asthma, patients with not well-controlled asthma, and patients with very poorly controlled asthma (90.0 [75.0-95.0], 75.0 [55.0-85.0], and 35.0 [25.0-55.0], respectively, P < .001). TRACK scores were significantly different between patients classified as currently symptomatic and symptomatic in the recent past (42.5 [25.0-55.0] vs 85.0 [75.0-90.0]; P < .001). The intraclass correlation coefficient of the measurements was 0.755 (95% CI, 0.503-1.00). All patients whose clinical status changed showed an increase of 10 or more points in TRACK score between baseline and follow-up visits. The Cronbach alpha was 0.77 for the questionnaire as a whole. CONCLUSION: The Spanish version of the TRACK questionnaire has excellent sensitivity to change and usability; adequate criterion validity, construct validity, and test-retest reliability; and an acceptable internal consistency, when used in children younger than age 5 years with symptoms consistent with asthma. PMID- 24811027 TI - Diffuse cutaneous mastocytosis, bullous variant, presenting in a six-month-old infant. PMID- 24811028 TI - Selective hypersensitivity reactions to acetaminophen: a 13-case series. PMID- 24811029 TI - Successful rapid desensitization to methylprednisolone sodium hemisuccinate: a case report. PMID- 24811030 TI - Chronic rhinosinusitis: potential new use for topical sulfasalazine. PMID- 24811031 TI - Molecular diagnosis in cannabis allergy. PMID- 24811033 TI - Non-IgE-mediated gastrointestinal food hypersensitivity syndrome in adults. PMID- 24811032 TI - Macrogol hypersensitivity reactions during cleansing preparation for colon endoscopy. PMID- 24811034 TI - Catamenial anaphylaxis. PMID- 24811036 TI - Origami paper-based fluidic batteries for portable electrophoretic devices. AB - A manufacturing approach for paper-based fluidic batteries was developed based on the origami principle (three-dimension paper folding). Microfluidic channels were first created on a filter paper by a wax-printing method. Copper and aluminium sheets were then glued onto the paper as electrodes for the redox reaction. After the addition of copper sulphate and aluminium chloride, commonly available cellophane paper was attached as a membrane to separate the two electrodes. The resulting planar paper sheets were then folded into three-dimensional structures and compiled as a single battery with glue. The two half reactions (Al/Al(3+) and Cu/Cu(2+)) in the folded batteries provided an open-circuit potential from 0.82 V (one cell) to 5.0 V (eight cells in series) depending on the origami design. The prepared battery can provide a stable current of 500 MUA and can light a regular LED for more than 65 min. These paper-based fluidic batteries in a set can also be compiled into a portable power bank to provide electric power for many electric or biomedical applications, such as LED lights and electrophoretic devices, as we report here. PMID- 24811038 TI - Exogenous spatial precuing reliably modulates object processing but not object substitution masking. AB - Object substitution masking (OSM) is used in behavioral and imaging studies to investigate processes associated with the formation of a conscious percept. Reportedly, OSM occurs only when visual attention is diffusely spread over a search display or focused away from the target location. Indeed, the presumed role of spatial attention is central to theoretical accounts of OSM and of visual processing more generally (Di Lollo, Enns, & Rensink, Journal of Experimental Psychology: General 129:481-507, 2000). We report a series of five experiments in which valid spatial precuing is shown to enhance the ability of participants to accurately report a target but, in most cases, without affecting OSM. In only one experiment (Experiment 5) was a significant effect of precuing observed on masking. This is in contrast to the reliable effect shown across all five experiments in which precuing improved overall performance. The results are convergent with recent findings from Argyropoulos, Gellatly, and Pilling (Journal of Experimental Psychology: Human Perception and Performance 39:646-661, 2013), which show that OSM is independent of the number of distractor items in a display. Our results demonstrate that OSM can operate independently of focal attention. Previous claims of the strong interrelationship between OSM and spatial attention are likely to have arisen from ceiling or floor artifacts that restricted measurable performance. PMID- 24811037 TI - Enhanced interaction between pseudokinase and kinase domains in Gcn2 stimulates eIF2alpha phosphorylation in starved cells. AB - The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2alpha, from yeast to mammals. The Gcn2 kinase domain (KD) is inherently inactive and requires allosteric stimulation by adjoining regulatory domains. Gcn2 contains a pseudokinase domain (YKD) required for high-level eIF2alpha phosphorylation in amino acid starved yeast cells; however, the role of the YKD in KD activation was unknown. We isolated substitutions of evolutionarily conserved YKD amino acids that impair Gcn2 activation without reducing binding of the activating ligand, uncharged tRNA, to the histidyl-tRNA synthetase-related domain of Gcn2. Several such Gcn- substitutions cluster in predicted helices E and I (alphaE and alphaI) of the YKD. We also identified Gcd- substitutions, evoking constitutive activation of Gcn2, mapping in alphaI of the YKD. Interestingly, alphaI Gcd- substitutions enhance YKD-KD interactions in vitro, whereas Gcn- substitutions in alphaE and alphaI suppress both this effect and the constitutive activation of Gcn2 conferred by YKD Gcd- substitutions. These findings indicate that the YKD interacts directly with the KD for activation of kinase function and identify likely sites of direct YKD-KD contact. We propose that tRNA binding to the HisRS domain evokes a conformational change that increases access of the YKD to sites of allosteric activation in the adjoining KD. PMID- 24811040 TI - Facilitation by exogenous attention for static and dynamic gestalt groups. AB - Attentional mechanisms allow the brain to selectively allocate its resources to stimuli of interest within the huge amount of information reaching its sensory systems. The voluntary component of attention, endogenous attention, can be allocated in a flexible manner depending on the goals and strategies of the observer. On the other hand, the reflexive component, exogenous attention, is driven by the stimulus. Here, we investigated how exogenous attention is deployed to moving stimuli that form distinct perceptual groups. We showed that exogenous attention is deployed according to a reference frame that moves along with the stimulus. Moreover, in addition to the cued stimulus, exogenous attention is deployed to all elements forming a perceptual group. These properties provide a basis for the efficient deployment of exogenous attention under ecological viewing conditions. PMID- 24811039 TI - The bisection point across variants of the task. AB - Bisection tasks are used in research on normal space and time perception and to assess the perceptual distortions accompanying neurological disorders. Several variants of the bisection task are used, which often yield inconsistent results, prompting the question of which variant is most dependable and which results are to be trusted. We addressed this question using theoretical and experimental approaches. Theoretical performance in bisection tasks is derived from a general model of psychophysical performance that includes sensory components and decisional processes. The model predicts how performance should differ across variants of the task, even when the sensory component is fixed. To test these predictions, data were collected in a within-subjects study with several variants of a spatial bisection task, including a two-response variant in which observers indicated whether a line was transected to the right or left of the midpoint, a three-response variant (which included the additional option to respond "midpoint"), and a paired-comparison variant of the three-response format. The data supported the model predictions, revealing that estimated bisection points were least dependable with the two-response variant, because this format confounds perceptual and decisional influences. Only the three-response paired comparison format can separate out these influences. Implications for research in basic and clinical fields are discussed. PMID- 24811041 TI - Threatening scenes but not threatening faces shorten time-to-contact estimates. AB - We previously reported that time-to-contact (TTC) judgments of threatening scene pictures (e.g., frontal attacks) resulted in shortened estimations and were mediated by cognitive processes, and that judgments of threatening (e.g., angry) face pictures resulted in a smaller effect and did not seem cognitively mediated. In the present study, the effects of threatening scenes and faces were compared in two different tasks. An effect of threatening scene pictures occurred in a prediction-motion task, which putatively requires cognitive motion extrapolation, but not in a relative TTC judgment task, which was designed to be less reliant on cognitive processes. An effect of threatening face pictures did not occur in either task. We propose that an object's explicit potential of threat per se, and not only emotional valence, underlies the effect of threatening scenes on TTC judgments and that such an effect occurs only when the task allows sufficient cognitive processing. Results are consistent with distinctions between predator and social fear systems and different underlying physiological mechanisms. Not all threatening information elicits the same responses, and whether an effect occurs at all may depend on the task and the degree to which the task involves cognitive processes. PMID- 24811042 TI - Effect on perceived duration and sensitivity to time when observing disgusted faces and disgusting mutilation pictures. AB - The aim of this study was to compare the effect on interval discrimination of the presentation of disgusting mutilation images and the presentation of faces expressing disgust. In Experiments 1 and 2, participants had to say whether the second of two images was presented for a shorter or a longer duration than the first (intervals = 400 ms vs. 482 ms). Although the overall probability of responding "long" was not exactly the same in these two experiments, participants reported that duration was longer more often when disgusting mutilation images were presented than when neutral or disgusted faces were presented. In Experiment 3, in which a single-stimulus method was employed, mutilation images were once again reported to be presented for a longer duration than neutral or disgusted faces. The investigation also reveals that discrimination levels are not higher when mutilation images are presented. It is argued that the effect of mutilation images on perceived duration is not due to attention; it is rather attributed to the increased arousal caused by these images. PMID- 24811043 TI - Hitting ability and perception of object's size: evidence for a negative relation. AB - We examined the relation between motor performance and perception of object's size in near space. The general task was to repeatedly hit a target by means of pointing movements and to estimate target's size. In contrast to the results of previous studies, Experiment 1 and Experiment 2 revealed a negative relation between action ability and perceived target size: Participants who hit the target relatively often and whose motor variability was relatively low judged targets to be smaller than did participants whose motor performance was relatively poor. In Experiment 3, the size judgments were made in the presence of the target before, as well as after, pointing movements. The target was judged as smaller when it was easy, rather than difficult, to hit before as well as after the movement. Altogether, these results indicate that under certain conditions, an increased action ability reduces the apparent size of the actions' target objects. PMID- 24811044 TI - Modelling and simulation of porcine liver tissue indentation using finite element method and uniaxial stress-strain data. AB - We hypothesize that both compression and elongation stress-strain data should be considered for modeling and simulation of soft tissue indentation. Uniaxial stress-strain data were obtained from in vitro loading experiments of porcine liver tissue. An axisymmetric finite element model was used to simulate liver tissue indentation with tissue material represented by hyperelastic models. The material parameters were derived from uniaxial stress-strain data of compressions, elongations, and combined compression and elongation of porcine liver samples. in vitro indentation tests were used to validate the finite element simulation. Stress-strain data from the simulation with material parameters derived from the combined compression and elongation data match the experimental data best. This is due to its better ability in modeling 3D deformation since the behavior of biological soft tissue under indentation is affected by both its compressive and tensile characteristics. The combined logarithmic and polynomial model is somewhat better than the 5-constant Mooney Rivlin model as the constitutive model for this indentation simulation. PMID- 24811045 TI - Simulation of uphill/downhill running on a level treadmill using additional horizontal force. AB - Tilting treadmills allow a convenient study of biomechanics during uphill/downhill running, but they are not commonly available and there is even fewer tilting force-measuring treadmill. The aim of the present study was to compare uphill/downhill running on a treadmill (inclination of +/- 8%) with running on a level treadmill using additional backward or forward pulling forces to simulate the effect of gravity. This comparison specifically focused on the energy cost of running, stride frequency (SF), electromyographic activity (EMG), leg and foot angles at foot strike, and ground impact shock. The main results are that SF, impact shock, and leg and foot angle parameters determined were very similar and significantly correlated between the two methods, the intercept and slope of the linear regression not differing significantly from zero and unity, respectively. The correlation of oxygen uptake (VO2) data between both methods was not significant during uphill running (r=0.42; P>0.05). VO2 data were correlated during downhill running (r=0.74; P<0.01) but there was a significant difference between the methods (bias=-2.51 +/- 1.94 ml min(-1) kg(-1)). Linear regressions for EMG of vastus lateralis, biceps femoris, gastrocnemius lateralis, soleus and tibialis anterior were not different from the identity line but the systematic bias was elevated for this parameter. In conclusion, this method seems appropriate for the study of SF, leg and foot angle, impact shock parameters but is less applicable for physiological variables (EMG and energy cost) during uphill/downhill running when using a tilting force-measuring treadmill is not possible. PMID- 24811046 TI - Hydrogel coated and dexamethasone releasing cochlear implants: quantification of fibrosis in guinea pigs and evaluation of insertion forces in a human cochlea model. AB - The insertion of cochlear implants (CIs) often causes fibrous tissue growth around the electrode, which leads to attenuation of function of CIs. Inhibition of fibrosis in vivo using dexamethasone (Dex) released from the implant base material (polydimethylsiloxane [PDMS]) coated with a protein repelling hydrogel (star-shaped polyethylene glycol prepolymer, sPEG) was, therefore, the aim of the study. PDMS filaments with Dex or sPEG were implanted into guinea pigs. The hearing status after implantation did not differ significantly in the treated groups. Using confocal laser scanning microscopy in transparent whole mount preparations, Dex, Dex/sPEG, as well as sPEG showed a tendency toward reduced formation of connective tissue around the implant. To apply such coatings for glass fibers for optical stimulation of the inner ear, insertion forces were measured into a human scala tympani model using fibers with sPEG coating. The results show that the hydrogel did not reduce insertion forces compared to the uncoated samples. However, PDMS-embedded fibers provide comparable insertion forces and depth to those measured with conventional CI electrodes, demonstrating the suitability of laser fibers for a minimal traumatic cochlear implantation. PMID- 24811047 TI - Role of Red-Ox Cycle in Structural Oscillations and Solvation Dynamics in the Mitochondria of a Live Cell. AB - Structural oscillations and solvation dynamics in the mitochondria of a live cell are studied by time-resolved microscopy using a covalent fluorescence probe. We compared the dynamics in a human breast cancer cell (MCF-7) with that in a normal breast cell MCF-10A. The probe, CPM (7-diethylamino-3-(4-maleimido-phenyl)-4 methylcoumarin), binds with the free thiol groups. In MCF-10A cell, CPM binds with the discrete mitochondria. In MCF-7, CPM labels the clustered mitochondria in the peri-nuclear region. Location of the CPM in the mitochondria is confirmed by colocalization with a mitochondria-tracker dye. The red-ox cycle in the mitochondria causes periodic fluctuation in the microenvironment in the discrete mitochondria. This is manifested in fluctuations in fluorescence intensity of CPM bound to mitochondria. The magnitude of oscillation is much less for CPM bound to the clustered mitochondria (in which the red-ox cycle is inefficient) in the cancer cell (MCF-7). In both of the cells (MCF-10A and MCF-7) CPM bound to thiol containing proteins in mitochondria exhibits ultraslow response with average solvation time (?taus?) of 850 and 1400 ps in MCF-10A and MCF-7, respectively. PMID- 24811048 TI - Demographic disparities of children presenting with symptomatic Meckel's diverticulum in children's hospitals. AB - PURPOSE: Most of the literature about Meckel's diverticulum (MD) consists of single institutional longitudinal case series. We queried the pediatric hospital information system (PHIS) database to obtain information about the epidemiology of MD from a large number of children at geographically diverse locations. METHODS: After IRB approval, the PHIS database was queried over a 9-year period for de-identified patients with both ICD-9 diagnoses of MD and a procedure code for Meckel's diverticulectomy. Data from five hospitals were excluded due to incomplete information. RESULTS: 4,338,396 were children admitted during the study interval; 945 had a symptomatic MD. The incidence decreased with age: 56.4% were under 5 years old, 26.8% were between the ages of 6-12 years, and 16.8% were older than 12 years. 74% were male, which was significantly higher than the PHIS population (53.8% male, P < 0.0001). Caucasians are over-represented in the symptomatic MD group (63.4%) compared to the rest of the PHIS population (48.1%, P < 0.0001). CONCLUSIONS: According to the PHIS data, there appears to be significant gender and race influence on symptomatic MD. Males present more commonly, as do non-Hispanic White patients, while it is less common among non Hispanic Black patients. PMID- 24811049 TI - Improving the efficacy of appearance-based sun exposure interventions with the terror management health model. AB - The terror management health model (TMHM) suggests that when thoughts of death are accessible people become increasingly motivated to bolster their self-esteem relative to their health, because doing so offers psychological protection against mortality concerns. Two studies examined sun protection intentions as a function of mortality reminders and an appearance-based intervention. In Study 1, participants given a sun protection message that primed mortality and shown a UV filtered photo of their face reported greater intentions to use sun protection on their face, and took more sunscreen samples than participants shown a regular photo of their face. In Study 2, reminders of mortality increased participants' intentions to use facial sun protection when the UV photo was specifically framed as revealing appearance consequences of tanning, compared to when the photo was framed as revealing health consequences or when no photo was shown. These findings extend the TMHM, and provide preliminary evidence that appearance-based tanning interventions have a greater influence on sun protection intentions under conditions that prime thoughts of death. We discuss implications of the findings, and highlight the need for additional research examining the applicability to long-term tanning behaviour. PMID- 24811050 TI - Micropulse versus continuous wave transscleral diode cyclophotocoagulation in refractory glaucoma: a randomized exploratory study. AB - BACKGROUND: The aim of this study was to compare the efficacy and safety of micropulse and continuous wave diode transscleral cyclophotocoagulation in refractory glaucoma. DESIGN: Randomized, comparative, exploratory study in a tertiary hospital setting. PARTICIPANTS: Patients with refractory, end-stage glaucoma. METHODS: Forty-eight patients were randomized to either treatment. The intraocular pressure, visual acuity, number of medicines and repeat treatment were monitored for 18 months. Complications that include visual acuity decline, prolonged anterior chamber inflammation, phthisis bulbi, scleral thinning and ocular pain were noted. MAIN OUTCOME MEASURE: Intraocular pressure between 6 and 21 mmHg and at least a 30% reduction with or without anti-glaucoma medications after 18 months. RESULTS: A successful primary outcome was achieved in 75% of patients who underwent micropulse cyclophotocoagulation and 29% of patients who received continuous wave cyclophotocoagulation after 12 months (P < 0.01). At 18 months, successful outcome was 52% and 30% (P = 0.13), respectively. The mean intraocular pressure was reduced by 45% in both groups (P = 0.70) from a baseline of 36.5 mmHg and 35.0 mmHg (P = 0.50) after 17.5 +/- 1.6 months (range 16-19) follow up. No significant difference in retreatment rates or number of intraocular pressure lowering medications was noted. The ocular complication rate was higher in continuous wave treated eyes (P = 0.01). CONCLUSION: Diode transscleral cyclophotocoagulation in both micropulse and continuous modes was effective in lowering intraocular pressure. The micropulse mode provided a more consistent and predictable effect in lowering intraocular pressure with minimal ocular complications. PMID- 24811051 TI - Asymmetric catalytic conjugate addition of acetaldehyde to nitrodienynes/nitroenynes: applications to the syntheses of (+)-alpha-lycorane and chiral beta-alkynyl acids. AB - The catalytic enantioselective conjugate addition of acetaldehyde to polyconjugated substrates, nitrodienynes and nitroenynes, has been accomplished using organocatalysis. Various functionalized 1,3-enynes and propargylic compounds were obtained in moderate to good yields with high enantioselectivity. The synthetic utilities of the conjugate addition reactions have been highlighted in the concise total synthesis of (+)-alpha-lycorane and the metal-free synthesis of chiral beta-alkynyl acids. PMID- 24811052 TI - Serological studies in inflammatory bowel disease: how important are they? AB - PURPOSE OF REVIEW: Serum antibodies have the potential role to assist in the diagnosis, disease stratification and prognostication of inflammatory bowel disease (IBD). Understanding antibody formation might provide insight into the dysregulated immunological response to the gut microbiota in IBD. This review summarizes recent evidence regarding the role of serology in IBD. RECENT FINDINGS: There is accumulating evidence from cross-sectional and longitudinal studies and from recent meta-analyses that supports the value of serological markers in identifying patients with complicated disease phenotype and increased risk of surgery in patients with Crohn's disease. Anti-Saccharomyces cerevisiae antibody remains the most accurate single marker, and recently identified exocrine pancreas antibodies (GP2 and CUZD1) have been suggested as evidence for a role of antibodies in the pathogenesis of Crohn's disease. SUMMARY: Despite these various developments, the use of the serum antibodies remains complementary in clinical practice. New markers are being currently evaluated that may reflect events relevant to the pathogenesis of IBD. PMID- 24811053 TI - The meaning of low-grade inflammation in clinically quiescent inflammatory bowel disease. AB - PURPOSE OF REVIEW: Low-grade inflammation can persist in many patients with inflammatory bowel disease (IBD) who have otherwise obtained clinical remission. This review will summarize the prognostic implications of this finding for patients. RECENT FINDINGS: At least 40% of patients with IBD in clinical remission have ongoing histological evidence of inflammation, despite continued use of maintenance therapy. Follow-up endoscopy and biopsy is the current gold standard for identifying these patients. Recent studies have suggested that an elevated C-reactive protein is associated with underlying histological abnormalities in this setting. Patients with histological inflammation at baseline are at increased risk of clinical relapse, hospitalization, surgery, and colon cancer in observational longitudinal studies. Even when endoscopic healing has been achieved, the presence of underlying architectural changes on biopsies can identify patients at a higher risk of complications. Prospective studies to determine if 'histological healing' provides additional outcome benefits beyond endoscopic or clinical remission alone have not been performed to date, but warrant inclusion in future trials. SUMMARY: Chronic low-grade inflammation is common in patients with IBD in clinical remission. Clinicians should actively try to identify these patients and consider a lower threshold for intervention to reduce their higher risk of adverse outcomes over time. PMID- 24811054 TI - Inflammatory bowel disease and irritable bowel syndrome: similarities and differences. AB - PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are classically viewed as dichotomous conditions. The former is perceived as a typical organic disease, and the latter is regarded as a disorder of gut function driven by mood. Recent research identified some shared contributing factors, which will be discussed here. RECENT FINDINGS: Mounting evidence shows the importance in both IBD and IBS of genetic, microbiological, epithelial, and immunological factors. In some instances, these factors overlap in the two conditions as shown by: involvement of brain-gut axis dysfunction in IBD, implication of TNFSF gene in Crohn's disease and IBS, evidence of abnormal microbiota and its impact on host functions, identification of low-grade inflammation in subsets of IBS patients, and development of IBS symptoms in patients with IBD in remission. SUMMARY: IBD and IBS remain separate conditions although there are some overlapping mechanisms. Both research and clinical management would benefit from considering a functional approach for certain manifestations of IBD and accepting an organic view in subsets of IBS patients. PMID- 24811055 TI - Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis. AB - A series of co-engineered macrolide-mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital(TM) inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ: mannitol had 57.6% +/- 7.6% delivery efficiency with a fine particle fraction (<=6.8 um) of the emitted aerosol cloud being 80.4% +/- 1.1%, with minimal throat deposition (5.3 +/- 0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide-mannitol therapy may provide a means of treating bronchiectasis. PMID- 24811056 TI - Silver nanoparticles linked by a Pt-containing organometallic dithiol bridge: study of local structure and interface by XAFS and SR-XPS. AB - Silver nanoparticles (AgNPs) functionalized with an organometallic bifunctional thiol containing Pt(ii) centers, generated in situ from trans-trans-[thioacetyl bistributylphosphine-diethynylbiphenyl-diplatinum(ii)], were synthesized with different sulphur/metal molar ratios (i.e. AgNPs-1 and AgNPs-2) with the aim to obtain nanosystems of different mean size and self-organization behaviour. AgNPs spontaneously self-assemble, giving rise to 2D networks, as previously assessed. In this work a deeper insight into the chemico-physical properties of these AgNPs is proposed by means of synchrotron radiation induced X-ray photoelectron spectroscopy (SR-XPS) and X-ray absorption fine structure spectroscopy (XAFS) techniques. The results are discussed in order to probe the interaction at the interface between a noble metal and a thiol ligand at the atomic level and the aim of this study is to shed light on the chemical structure and self organization details of nanosystems. The nature of the chemical interaction between the dithiol ligand and the Ag atoms on the nanoparticle surface was investigated by combining SR-XPS (S2p, Ag3d core levels) and XAS (S and Ag K edges) analysis. UV-visible absorption and emission measurements were also carried out on all samples and compared with TD-DFT calculations so as to get a better understanding of their optical behavior and establish the nature of the excitation and emission processes. PMID- 24811057 TI - A global coupling index of multivariate neural series with application to the evaluation of mild cognitive impairment. AB - Recently, the synchronization between neural signals has been widely used as a key indicator of brain function. To understand comprehensively the effect of synchronization on the brain function, accurate computation of the synchronization strength among multivariate neural series from the whole brain is necessary. In this study, we proposed a method named global coupling index (GCI) to estimate the synchronization strength of multiple neural signals. First of all, performance of the GCI method was evaluated by analyzing simulated EEG signals from a multi-channel neural mass model, including the effects of the frequency band, the coupling coefficient, and the signal noise ratio. Then, the GCI method was applied to analyze the EEG signals from 12 mild cognitive impairment (MCI) subjects and 12 normal controls (NC). The results showed that GCI method had two major advantages over the global synchronization index (GSI) or S-estimator. Firstly, simulation data showed that the GCI method provided both a more robust result on the frequency band and a better performance on the coupling coefficients. Secondly, the actual EEG data demonstrated that GCI method was more sensitive in differentiating the MCI from control subjects, in terms of the global synchronization strength of neural series of specific alpha, beta1 and beta2 frequency bands. Hence, it is suggested that GCI is a better method over GSI and S-estimator to estimate the synchronization strength of multivariate neural series for predicting the MCI from the whole brain EEG recordings. PMID- 24811058 TI - Home recovery following day surgery: a patient perspective. AB - AIMS AND OBJECTIVES: To investigate aspects of care potentially most influencing home recovery following day surgery. BACKGROUND: Elective surgery undertaken on a day-case basis is expanding. Many medical aspects of recovery have been investigated although less is known about the psychosocial view of postdischarge recovery. Greater insight into such issues is required for the development of a more coordinated nurse-led approach. DESIGN: Cross-sectional questionnaire. METHOD: As part of a larger study, questionnaires were distributed to 2401 adult patients on the day of operation (September 2010-October 2011) to examine patients' experiences of psychosocial recovery. Participants were requested to complete and return the questionnaire by mail one week after surgery with 684 returned. RESULTS: Eighty-five per cent were fully prepared for all events during home recovery. Satisfaction with pre- and postoperative surgical information was high although less so anaesthetic information. Using factor analysis, preoperative information, pain management, postdischarge information, anxiety management, postoperative nausea and vomiting, help and rest once home were central features. Multiple regression analysis demonstrated pre- and postoperative information provision to have a statistically significant positive association with patients' being 'fully prepared for all events during home recover'. Unsatisfactory pain management, increased anxiety and reduced help once home had a statistically significant negative association with patients' being 'fully prepared for all events during home recovery'. CONCLUSION: Focusing on the delivery of surgical and anaesthetic information, managing pain and anxiety and ensuring support once home may help to enhance recovery. A more comprehensive plan embracing such aspects could help enhance the day surgery patients' experience. RELEVANCE TO CLINICAL PRACTICE: Increased satisfaction and surgical/anaesthetic information are central to the continued success of minimal stay surgery. A broader hospital/home strategy is required as too frequently nursing care can become fragmented between the preoperative outpatient visit, preassessment, day of surgery and postoperative outpatient visit. PMID- 24811059 TI - Suppression of Akt-mTOR pathway-a novel component of oncogene induced DNA damage response barrier in breast tumorigenesis. AB - DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized 'normal-like' breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis. PMID- 24811060 TI - PRDM14: a unique regulator for pluripotency and epigenetic reprogramming. AB - PRDM14 belongs to the PR domain-containing (PRDM) transcriptional regulators. Among the PRDM family members, PRDM14 shows specific expression in preimplantation embryos, primordial germ cells (PGCs), and embryonic stem cells (ESCs) in vitro, and accordingly plays a key role in the regulation of their pluripotency and epigenetic reprogramming, most notably, genome-wide DNA demethylation. The function of PRDM14 appears to be conserved between mice and humans, but it shows several characteristic differences between the two species. A precise understanding of the function of PRDM14 in mice and humans would shed new light on the regulation of pluripotency and the epigenome in these two species, providing a foundation for better control of stem cell fates in a broader context. PMID- 24811061 TI - A high-throughput method to examine protein-nucleotide interactions identifies targets of the bacterial transcriptional regulatory protein fur. AB - The Ferric uptake regulatory protein (Fur) is a transcriptional regulatory protein that functions to control gene transcription in response to iron in a number of pathogenic bacteria. In this study, we applied a label-free, quantitative and high-throughput analysis method, Interferometric Reflectance Imaging Sensor (IRIS), to rapidly characterize Fur-DNA interactions in vitro with predicted Fur binding sequences in the genome of Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea. IRIS can easily be applied to examine multiple protein-protein, protein-nucleotide and nucleotide nucleotide complexes simultaneously and demonstrated here that seventy percent of the predicted Fur boxes in promoter regions of iron-induced genes bound to Fur in vitro with a range of affinities as observed using this microarray screening technology. Combining binding data with mRNA expression levels in a gonococcal fur mutant strain allowed us to identify five new gonococcal genes under Fur mediated direct regulation. PMID- 24811063 TI - Evidence for different expression profiles for c-Met, EGFR, PTEN and the mTOR pathway in low and high grade endometrial carcinomas in a cohort of consecutive women. Occurrence of PIK3CA and K-Ras mutations and microsatellite instability. AB - Molecular and genetic investigations in endometrial carcinogenesis may have prognostic and therapeutic implications. We studied the expression of EGFR, c Met, PTEN and the mTOR signalling pathway (phospho-AKT/phospho-mTOR/phospho-RPS6) in 69 consecutive tumours and 16 tissue microarrays. We also analysed PIK3CA, K Ras mutations and microsatellite instability (MSI). We distinguished two groups: group 1 (grade 1 and 2 endometrioid cancers) and group 2 (grade 3 endometrioid and type II clear and serous cell cancers). We hypothesised that these histological groups might have different features. We found that a) survival was higher in group 1 with less aggressive tumours (P?0.03); b) EGFR (P=0.01), PTEN and the AKT/mTOR/RPS6 signalling pathway were increased in group 1 versus group 2 (P=0.05 for phospho-mTOR); c) conversely, c-Met was higher (P?0.03) in group 2 than in group 1; d) In group 1, EGFR was correlated with c-Met, phospho-mTOR, phospho-RPS6 and the global activity of the phospho-AKT/phospho-mTOR/phospho-RPS6 pathway. In group 2, EGFR was correlated only with the phospho-AKT/phospho mTOR/phospho-RPS6 pathway, whereas c-Met was correlated with PTEN; e) survival was higher for tumours with more than 50% PTEN-positive cells; f) K-RAS and PIK3CA mutations occurred in 10-12% of the available tumours and MSI in 40.4%, with a loss of MLH1 and PMS2 expression. Our results for endometrial cancers provide the first evidence for a difference in status between groups 1 and 2. The patients may benefit from different targeted treatments, anti-EGFR agents and rapamycin derivatives (anti-mTOR) for group 1 and an anti c-MET/ligand complex for group 2. PMID- 24811064 TI - Usefulness of circulating microRNAs for the prediction of early preeclampsia at first-trimester of pregnancy. AB - To assess the usefulness of circulating microRNAs (miRNAs) as non-invasive molecular biomarkers for early prediction of preeclampsia, a differential miRNA profiling analysis was performed in first-trimester pooled sera from 31 early preeclampsia patients, requiring delivery before 34 weeks of gestation, and 44 uncomplicated pregnancies using microfluidic arrays. Among a total of 754 miRNAs analyzed, the presence of 63 miRNAs (8%) was consistently documented in the sera from preeclampsia and control samples. Nevertheless, only 15 amplified miRNAs (2%) seemed to be differentially, although modestly, represented (fold change range: 0.4-1.4). After stem loop RT-qPCR from individual samples, the statistical analysis confirmed that none of the most consistent and differentially represented miRNAs (3 overrepresented and 4 underrepresented) were differentially abundant in serum from preeclamptic pregnancies compared with serum from normal pregnancies. Therefore, maternal serum miRNA assessment at first-trimester of pregnancy does not appear to have any predictive value for early preeclampsia. PMID- 24811065 TI - G673 could be a novel mutational hot spot for intragenic suppressors of pheS5 lesion in Escherichia coli. AB - The pheS5 Ts mutant of Escherichia coli defined by a G293 -> A293 transition, which is responsible for thermosensitive Phenylalanyl-tRNA synthetase has been well studied at both biochemical and molecular level but genetic analyses pertaining to suppressors of pheS5 were hard to come by. Here we have systematically analyzed a spectrum of Temperature-insensitive derivatives isolated from pheS5 Ts mutant and identified two intragenic suppressors affecting the same base pair coordinate G673 (pheS19 defines G673 -> T673 ; Gly225 -> Cys225 and pheS28 defines G673 -> C673 ; Gly225 -> Arg225). In fact in the third derivative, the intragenic suppressor originally named pheS43 (G673 -> C673 transversion) is virtually same as pheS28. In the fourth case, the very pheS5 lesion itself has got changed from A293 -> T293 (named pheS40). Cloning of pheS(+), pheS5, pheS5-pheS19, pheS5-pheS28 alleles into pBR322 and introduction of these clones into pheS5 mutant revealed that excess of double mutant protein is not at all good for the survival of cells at 42 degrees C. These results clearly indicate a pivotal role for Gly225 in the structural/functional integrity of alpha subunit of E. coli PheRS enzyme and it is proposed that G673 might define a hot spot for intragenic suppressors of pheS5. PMID- 24811066 TI - Survival and reproduction of Myxobolus cerebralis-resistant rainbow trout introduced to the Colorado river and increased resistance of age-0 progeny. AB - Myxobolus cerebralis caused severe declines in rainbow trout populations across Colorado following its introduction in the 1980s. One promising approach for the recovery of Colorado's rainbow trout populations has been the production of rainbow trout that are genetically resistant to the parasite. We introduced one of these resistant crosses, known as the GR*CRR (cross between the German Rainbow [GR] and Colorado River Rainbow [CRR] trout strains), to the upper Colorado River. The abundance, survival, and growth of the stocked GR*CRR population was examined to determine if GR*CRRs had contributed offspring to the age-0 population, and determine whether these offspring displayed increased resistance and survival characteristics compared to their wild CRR counterparts. Apparent survival of the introduced GR*CRR over the entire study period was estimated to be 0.007 (+/-0.001). Despite low survival of the GR*CRRs, age-0 progeny of the GR*CRR were encountered in years 2008 through 2011. Genetic assignments revealed a shift in the genetic composition of the rainbow trout fry population over time, with CRR fish comprising the entirety of the fry population in 2007, and GR-cross fish comprising nearly 80% of the fry population in 2011. A decrease in average infection severity (myxospores fish-1) was observed concurrent with the shift in the genetic composition of the rainbow trout fry population, decreasing from an average of 47,708 (+/-8,950) myxospores fish-1 in 2009 to 2,672 (+/-4,379) myxospores fish-1 in 2011. Results from this experiment suggest that the GR*CRR can survive and reproduce in rivers with a high prevalence of M. cerebralis. In addition, reduced myxospore burdens in age-0 fish indicated that stocking this cross may ultimately lead to an overall reduction in infection prevalence and severity in the salmonid populations of the upper Colorado River. PMID- 24811068 TI - Anti-p16 autoantibodies may be a useful biomarker for early diagnosis of esophageal cancer. AB - AIM: Our recent work suggested that circulating IgG antibodies to a linear peptide derived from p16 protein were significantly increased in patients with lung cancer. The present study was then designed to test whether such autoantibodies were also altered in esophageal cancer. METHODS: An enzyme-linked immunosorbent assay was developed in-house to determine circulating IgA and IgG antibodies against p16 protein-derived antigens in 97 patients with esophageal squamous cell carcinoma (ESCC) and 226 healthy subjects. RESULTS: The levels of anti-p16 IgG but not IgA antibodies were significantly higher in the patient group than the control group (t = 2.81, P = 0.0052); circulating anti-p16 IgG levels were inversely correlated with stages of ESCC (r = -0.30, df = 81, P = 0.0058) and patients with stage I of ESCC had the highest IgG level among all four stages (t = 5.25, P <= 0.0001, compared with control subjects). There was no correlation between the levels of IgA and IgG either in the patient group (r = 0.05, df = 86, P = 0.627) or in the control group (r = -0.1, df = 205, P = 0.146). CONCLUSION: Circulating IgG autoantibody to p16 protein may be a potential biomarker for early diagnosis of esophageal cancer. PMID- 24811069 TI - Effects of specular highlights on perceived surface convexity. AB - Shading is known to produce vivid perceptions of depth. However, the influence of specular highlights on perceived shape is unclear: some studies have shown that highlights improve quantitative shape perception while others have shown no effect. Here we ask how specular highlights combine with Lambertian shading cues to determine perceived surface curvature, and to what degree this is based upon a coherent model of the scene geometry. Observers viewed ambiguous convex/concave shaded surfaces, with or without highlights. We show that the presence/absence of specular highlights has an effect on qualitative shape, their presence biasing perception toward convex interpretations of ambiguous shaded objects. We also find that the alignment of a highlight with the Lambertian shading modulates its effect on perceived shape; misaligned highlights are less likely to be perceived as specularities, and thus have less effect on shape perception. Increasing the depth of the surface or the slant of the illuminant also modulated the effect of the highlight, increasing the bias toward convexity. The effect of highlights on perceived shape can be understood probabilistically in terms of scene geometry: for deeper objects and/or highly slanted illuminants, highlights will occur on convex but not concave surfaces, due to occlusion of the illuminant. Given uncertainty about the exact object depth and illuminant direction, the presence of a highlight increases the probability that the surface is convex. PMID- 24811070 TI - Microembolism induces anhedonia but no detectable changes in white matter integrity in aged rats. AB - Microvascular disease leads to alterations of cerebral vasculature including the formation of microembolic (ME) strokes. Though ME are associated with changes in mood and the severity and progression of cognitive decline, the effect of ME strokes on cerebral microstructure and its relationship to behavioral endpoints is unknown. Here, we used adult and aged male rats to test the hypotheses that ME lesions result in subtle changes to white and gray matter integrity as detected by high-throughput diffusion tensor imaging (DTI) and that these structural disruptions correspond to behavioral deficits. Two weeks post-surgery, aged animals showed depressive-like behaviors in the sucrose consumption test in the absence of altered cerebral diffusivity as assessed by ex-vivo DTI. Furthermore, DTI indices did not correlate with the degree of behavioral disruption in aged animals or in a subset of animals with observed tissue cavitation and subtle DTI alterations. Together, data suggest that behavioral deficits are not the result of damage to brain regions or white matter tracts, rather the activity of other systems may underlie functional disruption and recovery. PMID- 24811071 TI - Broad-spectrum transgenic resistance against distinct tospovirus species at the genus level. AB - Thrips-borne tospoviruses cause severe damage to crops worldwide. In this investigation, tobacco lines transgenic for individual WLm constructs containing the conserved motifs of the L RNA-encoded RNA-dependent RNA polymerase (L) gene of Watermelon silver mottle virus (WSMoV) were generated by Agrobacterium mediated transformation. The WLm constructs included: (i) translatable WLm in a sense orientation; (ii) untranslatable WLmt with two stop codons; (iii) untranslatable WLmts with stop codons and a frame-shift; (iv) untranslatable antisense WLmA; and (v) WLmhp with an untranslatable inverted repeat of WLm containing the tospoviral S RNA 3'-terminal consensus sequence (5'-ATTGCTCT-3') and an NcoI site as a linker to generate a double-stranded hairpin transcript. A total of 46.7-70.0% transgenic tobacco lines derived from individual constructs showed resistance to the homologous WSMoV; 35.7-100% plants of these different WSMoV-resistant lines exhibited broad-spectrum resistance against four other serologically unrelated tospoviruses Tomato spotted wilt virus, Groundnut yellow spot virus, Impatiens necrotic spot virus and Groundnut chlorotic fan-spot virus. The selected transgenic tobacco lines also exhibited broad-spectrum resistance against five additional tospoviruses from WSMoV and Iris yellow spot virus clades, but not against RNA viruses from other genera. Northern analyses indicated that the broad-spectrum resistance is mediated by RNA silencing. To validate the L conserved region resistance in vegetable crops, the constructs were also used to generate transgenic tomato lines, which also showed effective resistance against WSMoV and other tospoviruses. Thus, our approach of using the conserved motifs of tospoviral L gene as a transgene generates broad-spectrum resistance against tospoviruses at the genus level. PMID- 24811073 TI - Perceived need for information among patients with a haematological malignancy: associations with information satisfaction and treatment decision-making preferences. AB - For patients with haematological malignancies, information on disease, prognosis, treatment and impact on quality of life is of the utmost importance. To gain insight into the perceived need for information in relation to sociodemographic and clinical parameters, comorbidity, quality of life (QoL) and information satisfaction, we compiled a questionnaire based on existing validated questionnaires. A total of 458 patients diagnosed with a haematological malignancy participated. The perceived need for information was moderate to high (40-70%). Multivariate regression analyses showed that a higher need for information was related to younger age, worse QoL, being member of a patient society and moderate comorbidity. The need for disease and treatment-related information was higher than the need for psychosocial information. A higher need for disease and treatment-related information was associated to being diagnosed with multiple myeloma. A higher need for psychosocial information was related to a lower educational level. The information provision could be improved according to 41% of the patients. Higher satisfaction with provided information was associated with better QoL. Most patients (62%) reported that they wanted to be fully informed about their illness and actively involved in treatment decision making. The results contribute to improving patient-tailored information provision and shared decision-making in clinical practice. PMID- 24811072 TI - Transcriptional and proteomic responses to carbon starvation in Paracoccidioides. AB - BACKGROUND: The genus Paracoccidioides comprises human thermal dimorphic fungi, which cause paracoccidioidomycosis (PCM), an important mycosis in Latin America. Adaptation to environmental conditions is key to fungal survival during human host infection. The adaptability of carbon metabolism is a vital fitness attribute during pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: The fungal pathogen Paracoccidioides spp. is exposed to numerous adverse conditions, such as nutrient deprivation, in the human host. In this study, a comprehensive response of Paracoccidioides, Pb01, under carbon starvation was investigated using high resolution transcriptomic (RNAseq) and proteomic (NanoUPLC-MSE) approaches. A total of 1,063 transcripts and 421 proteins were differentially regulated, providing a global view of metabolic reprogramming during carbon starvation. The main changes were those related to cells shifting to gluconeogenesis and ethanol production, supported by the degradation of amino acids and fatty acids and by the modulation of the glyoxylate and tricarboxylic cycles. This proposed carbon flow hypothesis was supported by gene and protein expression profiles assessed using qRT-PCR and western blot analysis, respectively, as well as using enzymatic, cell dry weight and fungus-macrophage interaction assays. The carbon source provides a survival advantage to Paracoccidioides inside macrophages. CONCLUSIONS/SIGNIFICANCE: For a complete understanding of the physiological processes in an organism, the integration of approaches addressing different levels of regulation is important. To the best of our knowledge, this report presents the first description of the responses of Paracoccidioides spp. to host like conditions using large-scale expression approaches. The alternative metabolic pathways that could be adopted by the organism during carbon starvation can be important for a better understanding of the fungal adaptation to the host, because systems for detecting and responding to carbon sources play a major role in adaptation and persistence in the host niche. PMID- 24811074 TI - Can we define surgical site infection accurately in colorectal surgery? AB - BACKGROUND: Increasingly, surgical site infection (SSI) is being tied to quality of care. The incidence of SSI after colorectal surgery differs widely. We hypothesize that it is difficult to define SSI reliably and reproducibly when adhering to the U.S. Centers for Disease Control and Prevention (CDC) definitions. METHODS: Elective intra-abdominal colorectal procedures via a clean contaminated incision performed at a single institution between January 1 and May 1, 2011 were queried. Three attending surgeons examined all patients' records retrospectively for documentation of SSI. These data were compared with the institutional National Surgeon Quality Improvement Program (NSQIP) data with regard to deep and superficial incisional SSI. RESULTS: Seventy-one cases met the inclusion criteria. There were six SSIs identified by NSQIP, representing 8.4% of cases. Review of the three attending surgeons demonstrated a significantly higher incidence of SSI, at 27%, 38%, and 23% (p=0.002). The percent of overall agreement between all reviewers was 82.16 with a kappa of 0.64, indicating only modest inter-rater agreement. Lack of attending surgeon documentation and subjective differences in chart interpretation accounted for most discrepancies between the surgeon and NSQIP SSI capture rates. CONCLUSIONS: This study highlights the difficulty in defining SSI in colon and rectal surgery, which oftentimes is subjective and difficult to discern from the medical record. According to these preliminary data from our institution, there is poor reliability between clinical reviewers in defining SSI on the basis of the CDC criteria, which has serious implications. The interpretation of clinical trials may be jeopardized if we cannot define SSI accurately. Furthermore, according to current CDC definitions and infection tracking strategies, these data suggest that the institutional incidence of SSI may not be a reliable measure by which to compare institutions. Better methods for defining SSI should be implemented if these data are made publicly available and tied to performance measures. PMID- 24811075 TI - Bundle block adjustment of airborne three-line array imagery based on rotation angles. AB - In the midst of the rapid developments in electronic instruments and remote sensing technologies, airborne three-line array sensors and their applications are being widely promoted and plentiful research related to data processing and high precision geo-referencing technologies is under way. The exterior orientation parameters (EOPs), which are measured by the integrated positioning and orientation system (POS) of airborne three-line sensors, however, have inevitable systematic errors, so the level of precision of direct geo-referencing is not sufficiently accurate for surveying and mapping applications. Consequently, a few ground control points are necessary to refine the exterior orientation parameters, and this paper will discuss bundle block adjustment models based on the systematic error compensation and the orientation image, considering the principle of an image sensor and the characteristics of the integrated POS. Unlike the models available in the literature, which mainly use a quaternion to represent the rotation matrix of exterior orientation, three rotation angles are directly used in order to effectively model and eliminate the systematic errors of the POS observations. Very good experimental results have been achieved with several real datasets that verify the correctness and effectiveness of the proposed adjustment models. PMID- 24811076 TI - Acetylcholinesterase inhibition-based biosensor for aluminum(III) chronoamperometric determination in aqueous media. AB - A novel amperometric biosensor for the determination of Al(III) based on the inhibition of the enzyme acetylcholinesterase has been developed. The immobilization of the enzyme was performed on screen-printed carbon electrodes modified with gold nanoparticles. The oxidation signal of acetylthiocholine iodide enzyme substrate was affected by the presence of Al(III) ions leading to a decrease in the amperometric current. The developed system has a detection limit of 2.1 +/- 0.1 MUM for Al(III). The reproducibility of the method is 8.1% (n = 4). Main interferences include Mo(VI), W(VI) and Hg(II) ions. The developed method was successfully applied to the determination of Al(III) in spiked tap water . The analysis of a certified standard reference material was also carried out. Both results agree with the certified values considering the respective associated uncertainties. PMID- 24811077 TI - Smartphone sensors for stone lithography authentication. AB - Nowadays mobile phones include quality photo and video cameras, access to wireless networks and the internet, GPS assistance and other innovative systems. These facilities open them to innovative uses, other than the classical telephonic communication one. Smartphones are a more sophisticated version of classic mobile phones, which have advanced computing power, memory and connectivity. Because fake lithographs are flooding the art market, in this work, we propose a smartphone as simple, robust and efficient sensor for lithograph authentication. When we buy an artwork object, the seller issues a certificate of authenticity, which contains specific details about the artwork itself. Unscrupulous sellers can duplicate the classic certificates of authenticity, and then use them to "authenticate" non-genuine works of art. In this way, the buyer will have a copy of an original certificate to attest that the "not original artwork" is an original one. A solution for this problem would be to insert a system that links together the certificate and the related specific artwork. To do this it is necessary, for a single artwork, to find unique, unrepeatable, and unchangeable characteristics. In this article we propose an innovative method for the authentication of stone lithographs. We use the color spots distribution captured by means of a smartphone camera as a non-cloneable texture of the specific artworks and an information management system for verifying it in mobility stone lithography. PMID- 24811078 TI - Design, development and testing of a low-cost sEMG system and its use in recording muscle activity in human gait. AB - Surface electromyography (sEMG) is an important measurement technique used in biomechanical, rehabilitation and sport environments. In this article the design, development and testing of a low-cost wearable sEMG system are described. The hardware architecture consists of a two-cascade small-sized bioamplifier with a total gain of 2,000 and band-pass of 3 to 500 Hz. The sampling frequency of the system is 1,000 Hz. Since real measured EMG signals are usually corrupted by various types of noises (motion artifacts, white noise and electromagnetic noise present at 50 Hz and higher harmonics), we have tested several denoising techniques, both on artificial and measured EMG signals. Results showed that a wavelet-based technique implementing Daubechies5 wavelet and soft sqtwolog thresholding is the most appropriate for EMG signals denoising. To test the system performance, EMG activities of six dominant muscles of ten healthy subjects during gait were measured (gluteus maximus, biceps femoris, sartorius, rectus femoris, tibialis anterior and medial gastrocnemius). The obtained EMG envelopes presented against the duration of gait cycle were compared favourably with the EMG data available in the literature, suggesting that the proposed system is suitable for a wide range of applications in biomechanics. PMID- 24811079 TI - Capability of integrated MODIS imagery and ALOS for oil palm, rubber and forest areas mapping in tropical forest regions. AB - Various classification methods have been applied for low resolution of the entire Earth's surface from recorded satellite images, but insufficient study has determined which method, for which satellite data, is economically viable for tropical forest land use mapping. This study employed Iterative Self Organizing Data Analysis Techniques (ISODATA) and K-Means classification techniques to classified Moderate Resolution Imaging Spectroradiometer (MODIS) Surface Reflectance satellite image into forests, oil palm groves, rubber plantations, mixed horticulture, mixed oil palm and rubber and mixed forest and rubber. Even though frequent cloud cover has been a challenge for mapping tropical forests, our MODIS land use classification map found that 2008 ISODATA-1 performed well with overall accuracy of 94%, with the highest Producer's Accuracy of Forest with 86%, and were consistent with MODIS Land Cover 2008 (MOD12Q1), respectively. The MODIS land use classification was able to distinguish young oil palm groves from open areas, rubber and mature oil palm plantations, on the Advanced Land Observing Satellite (ALOS) map, whereas rubber was more easily distinguished from an open area than from mixed rubber and forest. This study provides insight on the potential for integrating regional databases and temporal MODIS data, in order to map land use in tropical forest regions. PMID- 24811080 TI - Cystoid macular edema associated with juvenile idiopathic arthritis resolved by a dexamethasone intravitreal implant. AB - Uveitis, glaucoma, and cystoid macular edema frequently develop in patients with juvenile idiopathic arthritis. The authors describe a case of cystoid macular edema associated with juvenile idiopathic arthritis that had not responded to intravitreal triamcinolone acetonide and bevacizumab but improved significantly following intravitreal injection with a dexamethasone 0.7 mg implant. PMID- 24811081 TI - Genetic interactions with sex make a relatively small contribution to the heritability of complex traits in mice. AB - The extent to which sex-specific genetic effects contribute to phenotypic variation is largely unknown. We applied a novel Bayesian method, sparse partitioning, to detect gene by sex (GxS) and gene by gene (GxG) quantitative loci (QTLs) in 1,900 outbred heterogeneous stock mice. In an analysis of 55 phenotypes, we detected 16 GxS and 6 GxG QTLs. The increase in the amount of phenotypic variance explained by models including GxS was small, ranging from 0.14% to 4.30%. We conclude that GxS rarely make a large overall contribution to the heritability of phenotypes, however there are cases where these will be individually important. PMID- 24811083 TI - Terahertz optoelectronics with surface plasmon polariton diode. AB - The field of plasmonics has experience a renaissance in recent years by providing a large variety of new physical effects and applications. Surface plasmon polaritons, i.e. the collective electron oscillations at the interface of a metal/semiconductor and a dielectric, may bridge the gap between electronic and photonic devices, provided a fast switching mechanism is identified. Here, we demonstrate a surface plasmon-polariton diode (SPPD) an optoelectronic switch that can operate at exceedingly large signal modulation rates. The SPPD uses heavily doped p-n junction where surface plasmon polaritons propagate at the interface between n and p-type GaAs and can be switched by an external voltage. The devices can operate at transmission modulation higher than 98% and depending on the doping and applied voltage can achieve switching rates of up to 1 THz. The proposed switch is compatible with the current semiconductor fabrication techniques and could lead to nanoscale semiconductor-based optoelectronics. PMID- 24811082 TI - Bak and Mcl-1 are essential for Temozolomide induced cell death in human glioma. AB - Temozolomide (TMZ) is an alkylating agent used for the treatment of glioblastoma multiforme (GBM), the main form of human brain tumours in adults. It has been reported that TMZ induced DNA lesions that subsequently trigger cell death but the actual mechanisms involved in the process are still unclear. We investigated the implication of major proteins of the Bcl-2 family in TMZ-induced cell death in GBM cell lines at concentrations closed to that reached in the brain during the treatments. We did not observe modulation of autophagy at these concentrations but we found an induction of apoptosis. Using RNA interference, we showed that TMZ induced apoptosis is dependent on the pro-apoptotic protein Bak but independent of the pro-apoptotic protein Bax. Apoptosis was not enhanced by ABT-737, an inhibitor of Bcl-2/Bcl-Xl/Bcl-W but not Mcl-1. The knock-down of Mcl 1 expression increased TMZ induced apoptosis. Our results identify a Mcl-1/Bak axis for TMZ induced apoptosis in GBM and thus unravel a target to overcome therapeutic resistance toward TMZ. PMID- 24811084 TI - Effects of extremely low-frequency electric fields at different intensities and exposure durations on mismatch negativity. AB - The effects of extremely low-frequency electric fields (ELF-EFs, 3-300Hz) on lipid peroxidation levels and antioxidant enzyme activities have been shown in many tissues and plasma after exposure to 50-Hz alternating current (AC) electric fields. However, similar studies investigating brain lipid peroxidation status are limited. Moreover and as far as we know, no study has been conducted to examine mismatch negativity (MMN) response in rats following exposure to a 50-Hz AC electric field. Therefore, the purpose of the study was to investigate different intensities and exposure durations of ELF-EFs on MMN component of event related potentials (ERPs) as well as apoptosis and oxidative brain damage in rats. Ninety male rats, aged 3months were used in our study. A total of six groups, composed of 15 animals each, was formed as follows: sham-exposed rats for 2weeks (C2), sham-exposed rats for 4weeks (C4), rats exposed to 12-kV/m and 18 kV/m electric fields for 2weeks (E12-2 and E18-2), rats exposed to 12- and 18 kV/m electric fields for 4weeks (E12-4 and E18-4). At the end of the experimental period, MMN responses were recorded in urethane-anesthetized rats by electrodes positioned stereotaxically to the surface of the dura. After MMN recordings, animals were killed by exsanguination and their brain tissues were removed for 4 hydroxy-2-nonenal (4-HNE), protein carbonyl and TUNEL analysis. In the current study, different change patterns in ERP parameters were observed dependent on the intensity and exposure duration of ELF-EFs. There were differences in the amplitudes of ERP between the responses to the standard and the deviant tones in all groups. When peak-to-peak amplitude of the difference curves was evaluated, MMN amplitude was significantly decreased in the E18-4 group compared with the C4 group. Additionally, the amount of 4-HNE was increased in all experimental groups compared with the control group. Consequently, it could be concluded that electric field decreased MMN amplitudes possibly induced by lipid peroxidation. PMID- 24811085 TI - A randomized clinical trial of the effect of low-level laser therapy before composite placement on postoperative sensitivity in class V restorations. AB - This study aimed to investigate the efficacy of low-level laser irradiation when applied just before placement of resin composite on reducing postoperative sensitivity of class V lesions. In this randomized clinical trial, 31 patients with 62 class V cavities were included (two teeth in each participant). The teeth were randomly assigned into laser and placebo groups. After cavity preparation, the teeth in the experimental group were subjected to irradiation from a low power red laser (630 nm, 28 mW, continuous wave, 60 s, 1.68 J), which was applied for 1 min on the axial wall of the cavity. In the control group, the same procedure was performed but with laser simulation. Then, a self-etch adhesive was applied and the cavities were restored with a microhybrid resin composite. Before treatment and on days 1, 14, and 30 after treatment, tooth sensitivity to a cold stimulus was recorded using a visual analogue scale. Data were analyzed by Friedman and Wilcoxon signed-rank tests (p < 0.05). Pain scores after restorative procedures were significantly lower in the laser group compared to the placebo application (p < 0.05). Although both groups experienced a significant improvement in pain and discomfort throughout the follow-up periods (p < 0.001), the changes in visual analogue scale (VAS) scores between baseline and each follow-up examination were significantly greater in the laser than the placebo group (p < 0.05). Low-level laser therapy (LLLT) before placement of resin composite could be suggested as a suitable approach to reduce postoperative sensitivity in class V restorations. PMID- 24811086 TI - Radial neck fractures in children: experience from two level-1 trauma centers. AB - The aim of this study was to compare different treatment modalities for different severities of pediatric radial neck fractures in a large cohort of patients and determine prognostic factors. A retrospective, comparative study was conducted of all children treated for different severities of radial neck fractures at two level-1 pediatric trauma centers between 1990 and 2007. Pertinent data were collected, and the outcome was measured by the Tibone criteria. Several variables were compared to determine the prognostic value. Seventy-eight children were identified, 35 male and 43 female, at an average age of 7.8 years (range 3-15 years). Twenty-nine of the 78 (37%) children had associated injuries. Fracture patterns varied in their severity. Nineteen patients needed casting alone; 16 required closed reduction; of the children requiring surgery, 26 responded to percutaneous reduction and 17 were severe enough to need open reduction. Complications occurred in 28/78 (36%) children, 24 of which were related to stiffness. Seventeen of the 19 (89%) fractures that were amenable to casting alone had excellent or good outcomes, as did 11/16 (69%) in the closed reduction group. Among children treated operatively, 19/26 (73%) patients who underwent percutaneous reduction had an excellent or good outcome. Only 6/17 (35%) of the severe cases who underwent open reduction had an excellent or good outcome. The treatment method, essentially dictated by the severity of the cases, did correlate with the outcome (P=0.001). Compared with more severe fractures that required operative treatment, patients treated nonoperatively had a higher rate of excellent to good outcome (P=0.018). In particular, patients who underwent percutaneous reduction alone had improved outcomes versus open reduction (P=0.008). The outcome was not related to the presence of an associated injury (P=0.302). Initial fracture severity, as graded by the Judet classification, correlated with the outcome (P=0.004). Furthermore, age also expressed significance, as patients younger than 10 years of age tended to do better than those above 10 years of age (P=0.025). Children with less severe radial neck fractures amenable to nonoperative treatment fare well. Operative treatment of these fractures, particularly in severe cases when an open (not percutaneous) reduction is needed, is associated with a higher risk of poor outcome. Children over 10 years of age, especially those with more severe initial angulation, tend to fare worse. The presence of associated injuries does not appear to increase the risk of a poor outcome after treatment. There is a high rate of complications (36%), stiffness being the most common (24). This large bi-center retrospective study from two level-1 pediatric trauma centers emphasizes that in severe cases of radial neck fractures, open treatment does not necessarily decrease the risk of a poor outcome. PMID- 24811087 TI - The quality of life of mothers of children with spina bifida. AB - Spina bifida (SB) is a common birth defect associated with significant lifelong morbidity. The objective of this study was to assess the quality of life and psychological status of mothers of children with SB. In this study, we included 30 mothers with children with SB and 30 mothers of healthy children. The groups were similar for background variables (child's age, sex, and number of siblings; mother's age, marital status; economic status of the families, and presence of health insurance). The 36-item short-form health survey (SF-36), State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) were administered to all mothers. Except for social functioning and mental health, all SF-36 subscale scores were significantly lower and the mean STAI and BDI scores were higher for mothers of children with SB (P<0.001). SF-36, STAI, and BDI scores were not associated significantly with the child's age, sex, number of siblings, and mother's age. This study shows that the quality of life is affected negatively for mothers of children with SB. The clinician should pay close attention to the psychosocial status of mothers of these children within the scope of disease management. PMID- 24811088 TI - The efficacy of semirigid hip orthosis in the delayed treatment of developmental dysplasia of the hip. AB - This study assessed the use of semirigid hip orthosis to stabilize the femoral head into the acetabulum in the delayed treatment of developmental dysplasia of the hip (DDH; Graf type IIb or more severe) under the age of 6 months. Ninety eight hips from 75 patients (four boys, 71 girls) were evaluated retrospectively. The mean age at treatment initiation was 3.2+/-1.3 months (1-6 months). As the dysplastic hip matured into a type I hip, we applied the weaning regimen for 1 month. Seventy-two patients (96%) were treated successfully in 4.2+/-1.1 months (2-8 months). All of the failures were type IV hips. We did not detect any acetabular or femoral head pathology in the later follow-up. Semirigid hip orthosis is safe and effective as the first-line treatment method for delayed DDH except in type IV hips in patients under 6 months of age. LEVEL OF EVIDENCE: Level IV. Case series. PMID- 24811089 TI - JAK2 V617F mutation status of 232 patients diagnosed with chronic myeloproliferative neoplasms. AB - INTRODUCTION/BACKGROUND: The aim of this study was to investigate the presence of Janus kinase 2 (JAK2) V617F mutation in patients with break point cluster region abelson negative chronic myeloproliferative neoplasms (CMPNs) in our center. PATIENTS AND METHODS: We compared patients with and without the mutation, and also patients with the homozygous and heterozygous mutation, in terms of different clinical and laboratory features. RESULTS: The JAK2 V617F mutation was detected in 77 (95%), 88 (68%), and 17 (77%) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) patients, respectively. Among JAK2 V617F-positive patients, the homozygous genotype was found in 39 (50.6%) of the 77 PV, 23 (26.1%) of the 88 ET, and 11 (64.7%) of the 17 PMF patients. Bleeding was seen in 14 (6%) of all patients. Upper gastrointestinal bleeds were the most common, seen in 11 patients. Out of 232 CMPN patients, 44 (19%) had thrombosis. The most common thrombotic event was transient ischemic attack (52%). Progression to myelofibrosis was seen in 1 (1.2%) PV and 3 (2.3%) ET patients, and progression to acute leukemia was seen in 2 (2.5%) PV and 3 (2.3%) ET patients. Three patients with PV (3.7%), 3 with ET (2.7%), and 5 with PMF (2.7%) died during follow-up. CONCLUSION: JAK2 V617F mutation frequencies in our PV and ET patients were similar to those reported previously. JAK2 V617F mutation frequency in our PMF patients was greater than in previous reports. All of our PV patients with thrombosis and most of our ET patients with thrombosis (76.1%) were JAK2 V617F mutation-positive. This mutation seems to be correlated with thrombosis risk. PMID- 24811090 TI - Living donor liver transplantation in HCV-infected patients: improvement of the donor risk-recipient benefit ratio is around the corner. PMID- 24811091 TI - A molecular phylogeny of Raddia and its allies within the tribe Olyreae (Poaceae, Bambusoideae) based on noncoding plastid and nuclear spacers. AB - The plastid spacer trnD-trnT and the nuclear ribosomal internal transcribed spacer (ITS) were sequenced for 37 samples of herbaceous bamboos (Poaceae: Olyreae), including all Raddia species and allied genera, as well as two members of the woody bamboos (tribes Bambuseae and Arundinarieae), in order to examine their relationships. The sequences were analyzed using maximum parsimony and Bayesian inference. Both the individual and combined analyses of ITS and trnD trnT supported Olyreae as a monophyletic group. All species of Raddia also formed a well-supported monophyletic group, and combined datasets allowed us to outline some relationships within this group. Individual analyses indicated incongruence regarding the sister group of Raddia, with ITS data weakly indicating Raddiella malmeana whereas trnD-trnT data supported Sucrea maculata in this position. However, the combined analysis supported Sucrea as sister to Raddia, although the monophyly of Sucrea is not well supported. Parodiolyra is paraphyletic to Raddiella in all analyses; Olyra is also paraphyletic, with species of Lithachne, Arberella and Cryptochloa nested within it. Eremitis and Pariana appeared as an isolated clade within Olyreae, and the position of the New Guinean Buergersiochloa remains uncertain within this tribe. PMID- 24811093 TI - Prediction of the therapeutic effect of dienogest in ovarian endometrial cysts using the apparent diffusion coefficient. AB - The purpose of this study was to investigate whether apparent diffusion coefficient (ADC) mean values can be used for predicting the treatment response in ovarian endometrial cyst patients with dienogest (DNG) administration. Eighteen patients received DNG (2 mg/day, orally) for 60 days, among whom 26 ovarian endometrial cysts were retrospectively identified. Mean ADC values of individual ovarian endometrial cysts were obtained by ADC maps inside the tumor. There was a significant correlation between ADC values and reduction ratio. When calculating the mean ADC values for three groups; more than 50%, 50-25% and less than 25%, ADC values significantly increased with increasing reduction ratio; 2.05 * 10(-3)mm(2)/s, 1.28 * 10(-3)mm(2)/s and 0.94 * 10(-3)mm(2)/s, respectively (p = 0.0180). Multiple regression analysis by reduction ratio (%), ADC mean values (* 10(-3)mm(2)/s), tumor longest diameter (cm) and CA125 (U/ml) revealed that tumor reduction ratio by DNG administration could be predicted by the following equation; R = 19.3 + 24.0x - 0.4y + 0.1z (R: Reduction ratio, x: ADC mean, y: Longest diameter, z: CA125). In conclusion, the ADC mean value is useful for the prediction of the treatment response in ovarian endometrial cyst patients with DNG administration. PMID- 24811092 TI - Mlh2 is an accessory factor for DNA mismatch repair in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, the essential mismatch repair (MMR) endonuclease Mlh1-Pms1 forms foci promoted by Msh2-Msh6 or Msh2-Msh3 in response to mispaired bases. Here we analyzed the Mlh1-Mlh2 complex, whose role in MMR has been unclear. Mlh1-Mlh2 formed foci that often colocalized with and had a longer lifetime than Mlh1-Pms1 foci. Mlh1-Mlh2 foci were similar to Mlh1-Pms1 foci: they required mispair recognition by Msh2-Msh6, increased in response to increased mispairs or downstream defects in MMR, and formed after induction of DNA damage by phleomycin but not double-stranded breaks by I-SceI. Mlh1-Mlh2 could be recruited to mispair-containing DNA in vitro by either Msh2-Msh6 or Msh2-Msh3. Deletion of MLH2 caused a synergistic increase in mutation rate in combination with deletion of MSH6 or reduced expression of Pms1. Phylogenetic analysis demonstrated that the S. cerevisiae Mlh2 protein and the mammalian PMS1 protein are homologs. These results support a hypothesis that Mlh1-Mlh2 is a non essential accessory factor that acts to enhance the activity of Mlh1-Pms1. PMID- 24811094 TI - SPRY4-mediated ERK1/2 signaling inhibition abolishes 17beta-estradiol-induced cell growth in endometrial adenocarcinoma cell. AB - OBJECTIVE: Basic fibroblast growth factor (FGF2)-mediated Extracellular signal regulated kinases1/2 (ERK1/2) signaling is a critical modulator in angiogenesis. SPRY4 has been reported to be a feedback negative regulator of FGFs-induced ERK1/2 signaling. The aim of this study was to explore the role of SPRY4 in endometrial adenocarcinoma cell. MATERIALS AND METHODS: The effect of SPRY4 expression on FGF2-mediated ERK1/2 signaling was detected by luciferase assay and Western blot analysis. The growth of Ishikawa cells was detected using colony formation assay and cell number counting experiment. RESULTS: We found that plasmid-driven SPRY4 expression efficiently blocked the activity of FGF2-induced ERK1/2 signaling in Ishikawa cells. SPRY4 expression significantly reduced the proliferation and 17beta-estradiol-induced proliferation of Ishikawa cells. CONCLUSION: SPRY4 may function as a tumor suppressor in endometrial adenocarcinoma. PMID- 24811095 TI - Adding serum estradiol measurements to ultrasound monitoring does not change the yield of mature oocytes in IVF/ICSI. AB - In a non-randomized, comparative prospective study (416 patients) we compared the outcome of IVF/ICSI in two parallel control groups: one in which patients were followed up using combined monitoring (ultrasound plus serum estradiol monitoring, the UHM group) and one in which only ultrasound monitoring was used (the UM group). This study has taken the number of mature oocytes at the moment of egg retrieval as its primary end variable. After adjustment for age, gravidity, antagonist protocol, AMH and infertility diagnosis, the average difference in number of mature oocytes between the UHM group and the UM group was -0.4 (95% CI: -1.7 to 1.0), which met our definition of clinical equivalence (95% CI for the adjusted mean difference between -2 and 2). Larger studies are still needed to evaluate the differences in the live birth rates per cycle and to further confirm that blood sampling definitively has no added value in monitoring ovarian stimulation for IVF/ICSI. PMID- 24811096 TI - Total fertilization failure in intra-cytoplasmic sperm injection cycles- classification and management. AB - In this retrospective cohort study we intended to propose a classification and preliminary management strategy for couples exhibiting total fertilization failure (TFF) in intra-cytoplasmic sperm injection (ICSI) cycles. Sixteen couples with a total of 27 cycles exhibiting TFF, age <40 and/or more than four M2 oocytes aspirated were enrolled. While TFF occurred in 4.3% of all 3723 ICSI cycles, in women younger than 40 with at least 5 M2 oocytes the TFF rate was 0.7%. Indications for ICSI were severe male factor and unexplained infertility. Of the 16 couples with TFF, 4 demonstrated a single episode of TFF, with either subsequent or former normal fertilizations, thus implying possible sporadic faulty laboratory conditions. Ten couples demonstrated repeated total or very low fertilization rates, hinting at a gamete defect not overcome by ICSI. Two couples experienced TFF in the first and only cycle performed at our unit. We conclude that initial and repeated TFF hints at severe gamete defects for which only donor gametes may prove successful while sporadic TFF events could simply imply a technical modifiable condition. PMID- 24811097 TI - Mast cells in chronic inflammation, pelvic pain and depression in women. AB - Inflammatory and neuroinflammatory processes are increasingly recognized as critical pathophysiologic steps in the development of multiple chronic diseases and in the etiology of persistent pain and depression. Mast cells are immune cells now viewed as cellular sensors in inflammation and immunity. When stimulated, mast cells release an array of mediators to orchestrate an inflammatory response. These mediators can directly initiate tissue responses on resident cells, and may also regulate the activity of other immune cells, including central microglia. New evidence supports the involvement of peripheral and central mast cells in the development of pain processes as well as in the transition from acute, to chronic and neuropathic pain. That behavioral and endocrine states can increase the number and activation of peripheral and brain mast cells suggests that mast cells represent the immune cells that peripherally and centrally coordinate inflammatory processes in neuropsychiatric diseases such as depression and anxiety which are associated with chronic pelvic pain. Given that increasing evidence supports the activated mast cell as a director of common inflammatory pathways/mechanisms contributing to chronic and neuropathic pelvic pain and comorbid neuropsychiatric diseases, mast cells may be considered a viable target for the multifactorial management of both pain and depression. PMID- 24811098 TI - Tobacco smoking increases the risk for death from pneumococcal pneumonia. AB - BACKGROUND: Active smoking increases the risk of developing community-acquired pneumonia (CAP) and invasive pneumococcal disease, although its impact on mortality in pneumococcal CAP outcomes remains unclear. The aim of this study was to investigate the influence of current smoking status on pneumococcal CAP mortality. METHODS: We performed a multicenter, prospective, observational cohort study in 4,288 hospitalized patients with CAP. The study group consisted of 892 patients with pneumococcal CAP: 204 current smokers (22.8%), 387 nonsmokers (43.4%), and 301 exsmokers (33.7%). RESULTS: Mortality at 30 days was 3.9%: 4.9% in current smokers vs 4.3% in nonsmokers and 2.6% in exsmokers. Current smokers with CAP were younger (51 years vs 74 years), with more alcohol abuse and fewer cardiac, renal, and asthma diseases. Current smokers had lower CURB-65 (confusion, uremia, respiratory rate, BP, age >= 65 years) scores, although 40% had severe sepsis at diagnosis. Current smoking was an independent risk factor (OR, 5.0; 95% CI, 1.8-13.5; P = .001) for 30-day mortality of pneumococcal CAP after adjusting for age (OR, 1.06; P = .001), liver disease (OR, 4.5), sepsis (OR, 2.3), antibiotic adherence to guidelines, and first antibiotic dose given < 6 h. The independent risk effect of current smokers remained when compared only with nonsmokers (OR, 4.0; 95% CI, 1.3-12.6; P = .015) or to exsmokers (OR, 3.9; 95% CI, 1.09-4.95; P = .02). CONCLUSIONS: Current smokers with pneumococcal CAP often develop severe sepsis and require hospitalization at a younger age, despite fewer comorbid conditions. Smoking increases the risk of 30-day mortality independently of tobacco-related comorbidity, age, and comorbid conditions. Current smokers should be actively targeted for preventive strategies. PMID- 24811099 TI - Child labor in a rural Egyptian community: an epidemiological study. AB - OBJECTIVES: Estimating the burden of child labor in a rural community of El-Minia governorate, Egypt and exploring its determinants and health impact. METHODS: One hundred and ninety nine children randomly participated from a randomly selected village; 147 (73.9%) males and 52 (26.1%) females, whose ages ranged from 6 to 17 years (mean age 12.1 +/- 2.9). All children were subjected to interview questionnaire, and medical examination. RESULTS: Ninety (45.2%) of the children reported that they are engaged in a work. The working children belonged to 65.6 and 85.6% of illiterate fathers and mothers, respectively. The majority of the working children were engaged in jobs at quarries (58.9%), followed by farming (21.1%), then small proportions of children were working in other jobs. Poverty, big families and insufficient family's income were the most frequently reported reasons for starting to work (80%). There was a significant higher prevalence of the reported health complaints among working children. CONCLUSIONS: Working children are at high risk of many health problems. Poverty, parents' illiteracy, large family size and fathers' absence are the driving force for child labor in the rural community of Eastern Minia. PMID- 24811103 TI - Gas gangrene presenting with back pain. AB - A 61-year-old Caucasian man (previously fit and well) presented to the emergency department with 2 days of non-traumatic, non-radiating lower back pain. He was admitted to our department having been provisionally diagnosed with discitis. Later that night, while being reassessed, a skin lesion on his thigh appeared and gas could be palpated. The patient was then taken immediately to theatre and a radical surgical debridement was performed. The organism that grew from tissue samples was Clostridium septicum, which when identified is an indication to exclude colonic neoplasms. The patient managed to preserve his limb on this occasion, however, he underwent a right hemicolectomy for what proved to be a colonic tumour at a later date. PMID- 24811104 TI - A rare differential diagnosis of a groin lump: lymphangioma. PMID- 24811105 TI - Is that lumbar disc symptomatic? Herniated lumbar disc associated with contralateral radiculopathy. AB - Herniated lumbar disc may be asymptomatic or associated with lower limb radiculopathy. Most spinal surgeons would offer surgery following a period of conservative measures if the radiological and clinical findings correlate. However, the existing dictum that lumbar radiculopathy should correlate with ipsilateral lumbar disc herniation may not be accurate as it can rarely present with contralateral sciatica. Literature regarding this phenomenon is scarce. Therefore, we report a patient with herniated lumbar disc presenting with predominantly contralateral motor weakness radiculopathy, which resolved after discectomy. PMID- 24811106 TI - Mild meningococcaemia, pyrexia protocols and a problematic public health response. AB - Meningococcal septicaemia was masked by an acute tonsillitis in a university student presenting to the emergency department. The diagnosis was made as a result of routine blood culture and resulted in the patient being recalled for appropriate treatment. Although the patient was relatively well, public health contact tracing and prophylaxis ensued as per any other case of meningococcal disease. This case highlights the protean manifestations of meningococcaemia and the importance of evidence-based protocols. Blood culture guidelines led to the diagnosis in the absence of clinical suspicion and in sharp contrast to the paucity of evidence informing the public health response in this area. PMID- 24811107 TI - An unusual cause of a fall: an unusual presentation of lung carcinoma. AB - An 80-year-old gentleman presented with a fall and subtle symptoms suggestive of a cerebellar lesion, on a background of hemiparesis due to a previous cerebral vascular accident. On admission it was thought that changes on a chest radiograph were consistent with a community-acquired pneumonia. A CT of the head showed a space-occupying lesion in the right cerebellum with surrounding oedema. A previous MRI of the brain performed 8 months earlier for investigation of dementia showed evidence of this lesion although it was significantly smaller and without midline shift; however, this had not been discussed on the MRI report. A subsequent CT of the thorax confirmed a thick-walled cavitating mass in the left upper lobe, with biopsy of this lesion and bronchial washings showing metaplastic and atypical cells suggestive of adenocarcinoma. This report highlights both the importance of accurate imaging reporting, even of incidental findings, and the insidious nature of lung malignancy and its broad clinical presentation. PMID- 24811108 TI - Impetigo contagiosa: an interesting and a very rare finding in a newborn. PMID- 24811109 TI - Giant coronaries: coronary ectasia as an isolated cause of exertional angina and positive stress test. PMID- 24811111 TI - Diffusive fractionation of BTEX and chlorinated ethenes in aqueous solution: quantification of spatial isotope gradients. AB - Laboratory experiments were performed to investigate and quantify the extent of diffusive isotope fractionation of organic contaminants in aqueous solution. We selected petroleum hydrocarbons (toluene and ethylbenzene, in 1:2 mixtures of labeled (perdeuterated) and nonlabeled isotopologues) and chlorinated solvents (trichloroethene, TCE, and cis-dichloroethene, cis-DCE, at their natural isotopic abundance) as model compounds. The experimental approach using gel diffusion tubes allowed us to resolve concentration and isotopic gradients induced by isotopologue-specific diffusion and to determine aqueous diffusion coefficients in agreement with the values calculated using published empirical correlations. The experimental results were quantitatively evaluated with numerical simulations to determine the aqueous diffusion coefficients, D, and the exponent of the inverse power-law relation between D and the molecular mass of the isotopologues. The results show remarkable diffusive isotope fractionation for all the investigated organic compounds; however, the extent of fractionation was found to be smaller for the chlorinated ethenes and remarkably deviating from an inverse square root relationship between the isotopologues diffusion coefficients and their molecular mass. The outcomes of this study are relevant for the interpretation of isotopic signatures of organic contaminants in environmental systems and for the quantitative application of compound specific isotope analysis (CSIA) that needs to take into account the fractionation effects of both physical and transformation processes. PMID- 24811110 TI - A nanoparticle carrying the p53 gene targets tumors including cancer stem cells, sensitizes glioblastoma to chemotherapy and improves survival. AB - Temozolomide (TMZ)-resistance in glioblastoma multiforme (GBM) has been linked to upregulation of O(6)-methylguanine-DNA methyltransferase (MGMT). Wild-type (wt) p53 was previously shown to down-modulate MGMT. However, p53 therapy for GBM is limited by lack of efficient delivery across the blood brain barrier (BBB). We have developed a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic), which is currently in multiple clinical trials. This self-assembling nanocomplex is formed by simple mixing of the components in a defined order and a specific ratio. Here, we demonstrate that scL crosses the BBB and efficiently targets GBM, as well as cancer stem cells (CSCs), which have been implicated in recurrence and treatment resistance in many human cancers. Moreover, systemic delivery of scL-p53 down-modulates MGMT and induces apoptosis in intracranial GBM xenografts. The combination of scL-p53 and TMZ increased the antitumor efficacy of TMZ with enhanced survival benefit in a mouse model of highly TMZ-resistant GBM. scL-p53 also sensitized both CSCs and bulk tumor cells to TMZ, increasing apoptosis. These results suggest that combining scL-p53 with standard TMZ treatment could be a more effective therapy for GBM. PMID- 24811112 TI - Mobilizing victim services: the role of reporting to the police. AB - Victim assistance programs have grown dramatically in response to the victim's rights movement and concern over difficulty navigating victim services. Evidence, however, indicates that very few victims seek assistance. The present study examined factors associated with victim service use including reporting to the police, the victim's demographic characteristics, the victim's injury, offender's use of a weapon, the victim's relationship to the offender, and the victim's mental and physical distress. Data came from a subset of the National Crime Victimization Survey 2008-2011 (N = 4,746), a stratified multistage cluster sample survey of persons age 12 years and older in the United States. Logistic regression models indicated that fewer than 10% of victims of violent crime sought help from victim services. Reporting to the police increased the odds of seeking services by 3 times. In addition, the odds of victims attacked by an intimate partner seeking services were 4.5 times greater than victims attacked by strangers. Findings suggest that additional exploratory work is needed in uncovering the mechanism of police involvement in linking victims to services. Specifically, do police understand what services are available to victims and why are police more likely to inform some types of victims about services more than others? PMID- 24811113 TI - Rule breaking mediates the developmental association between GABRA2 and adolescent substance abuse. AB - BACKGROUND: This study's primary aim was to examine age-specific associations between GABRA2, rule breaking, problematic alcohol use, and substance abuse symptomatology. The secondary aim was to examine the extent to which rule breaking mediates the GABRA2-substance abuse relationship. METHODS: A sample (n = 518) of primarily male (70.9%) and White (88.8%) adolescents from the Michigan Longitudinal Study was assessed from ages 11-18. Age-specific effects of GABRA2 on rule breaking, problematic alcohol use, and substance abuse symptomatology were examined using nested path models. The role of rule breaking as a mediator in the association between GABRA2 and substance abuse outcomes was tested using prospective cross-lagged path models. RESULTS: GABRA2 is significantly (p < 0.05) associated with rule breaking in mid- to late-adolescence, but not substance abuse symptomatology across adolescence. GABRA2 effects on problematic alcohol use and substance abuse symptomatology operate largely (45.3% and 71.1%, respectively, p < 0.05) via rule breaking in midadolescence. CONCLUSIONS: GABRA2 represents an early risk factor for an externalizing pathway to the development of problematic alcohol and drug use. PMID- 24811114 TI - Seasonal screening for viral gastroenteritis in young children and elderly hospitalized patients: is it worthwhile? AB - BACKGROUND: Viral gastroenteritis is common, especially in young children. In adults, particularly amongst the elderly, it can lead to outbreaks at a time when demands on clinical services are at their peak. AIM: To evaluate seasonal screening of young children and elderly patients with suspected viral gastroenteritis using multiplex polymerase chain reaction (PCR) for enteric viruses within a general hospital setting. METHODS: Stool samples from 200 children aged five years and under were screened for rotavirus, adenovirus, astrovirus, sapovirus and norovirus using multiplex PCR and a combined rotavirus/adenovirus immunochromatographic test (ICT) during the winter of 2012. Diarrhoeal samples submitted to the laboratory from 195 adults aged 65 years and over attending as inpatients were also evaluated by multiplex PCR. FINDINGS: One or more enteric viruses were detected by PCR in 56% of children. Rotavirus was the most prevalent virus, found in 19% of samples. Enteric (diarrhoea-associated) adenovirus was detected in 5% of samples and non-enteric adenovirus was detected in 14% of samples. Astrovirus, norovirus and sapovirus were detected in 18%, 12% and 10% of samples, respectively. The ICT yielded a slightly lower rate for rotavirus and enteric adenovirus, but gave more rapid results. Norovirus, rotavirus and adenovirus were detected in 15%, 2.5% and 1% of elderly adults attending hospital as inpatients, respectively. CONCLUSIONS: Rapid screening of young children (for rotavirus, adenovirus and norovirus) and symptomatic, elderly adults (for norovirus) during winter months may help to limit nosocomial spread. PMID- 24811115 TI - No association between ultrasound-guided insertion of central venous catheters and bloodstream infection: a prospective observational study. AB - BACKGROUND: Ultrasound guidance for the insertion of central venous catheters (CVCs) reduces mechanical complications and shortens insertion time, but its effect on CVC-associated bloodstream infection (CABSI) remains controversial. AIM: To test the effect of ultrasound-guided CVC insertion on CABSI in a hospital wide setting. METHODS: A four-year prospective cohort study was conducted at a university-affiliated, tertiary care centre. All patients receiving a non tunnelled CVC, inserted by an anaesthetist, were enrolled. Catheter surveillance was performed by trained infection control nurses and checked by an infection control doctor. The primary outcome was CABSI as defined by the US Centers for Disease Control and Prevention. The secondary outcome was all-cause mortality up to 28 days after CVC removal. FINDINGS: In total, 2312 patients with 2483 CVCs were included and analysed. Ultrasound guidance was used for 844 CVC insertions (34.0%), with a significant increasing trend over the study period [incidence rate ratio 1.13, 95% confidence interval (CI) 01.11-1.15; P < 0.001]. Forty-seven CABSIs were identified, representing an overall incidence of 2.1 episodes per 1000 catheter-days. No association was detected between ultrasound guidance and CABSI (hazard ratio 0.69, 95% CI 0.36-1.30; P = 0.252). All-cause mortality was 11.0% (253/2312), with no significant trend and no association with ultrasound guidance. CONCLUSION: Ultrasound guidance had no effect on CABSI or mortality. In a hospital-wide setting with baseline CABSI rates at the standard level currently found in high-income countries, the use of ultrasound has no additional benefit for the prevention of CABSI. PMID- 24811116 TI - Response to P. Destrez concerning G.J. Hughes et al.: Impact of cleaning and other interventions on the reduction of hospital-acquired Clostridium difficile infections in two hospitals in England assessed using a breakpoint model. PMID- 24811117 TI - Confirmed pathogenic effect of a splice site variation in the MLH1 gene causing Lynch syndrome. PMID- 24811118 TI - Diagnosis of colorectal cancer from tissue sample passed per rectum. PMID- 24811119 TI - Synchronous ileocecal and duodenal tuberculosis: case report and review of the literature. PMID- 24811120 TI - Rad51 supports triple negative breast cancer metastasis. AB - In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months. PMID- 24811121 TI - Electrochemical formation of an ultrathin electroactive film from 1,10 phenanthroline on a glassy carbon electrode in acidic electrolyte. AB - The electrochemical reduction of 1,10-phenanthroline in aqueous acidic electrolyte at a glassy carbon electrode led to the covalent modification of the electrode. Thereafter, the deposited film can be switched to an electroactive form by electrochemical oxidation. An electroactive film can be also generated by alternate reductive and oxidative voltammetric cycling in a 1,10 phenanthroline/aqueous sulfuric acid solution. First, the electrochemical procedure for the formation of a film is presented. Second, the morphology and chemical structure of 1,10-phenanthroline coatings were investigated by atomic force microscopy, time-of-flight secondary ion mass spectrometry, X-ray photoelectron spectroscopy, and electrochemical techniques. The ultrathin (<15 nm) electrodeposited films consist of oligomeric species. The coatings deposited in alternate and/or continuous reductive and oxidative steps contain oxygen atoms incorporated into the oligomer backbone. The preliminary results point out the formation of a dione derivative that is responsible for the electroactivity of the grafted layer. PMID- 24811122 TI - Repression/depression of conjugative plasmids and their influence on the mutation selection balance in static environments. AB - We study the effect that conjugation-mediated Horizontal Gene Transfer (HGT) has on the mutation-selection balance of a population in a static environment. We consider a model whereby a population of unicellular organisms, capable of conjugation, comes to mutation-selection balance in the presence of an antibiotic, which induces a first-order death rate constant [Formula: see text] for genomes that are not resistant. We explicitly take into consideration the repression/de-repression dynamics of the conjugative plasmid, and assume that a de-repressed plasmid remains temporarily de-repressed after copying itself into another cell. We assume that both repression and de-repression are characterized by first-order rate constants [Formula: see text]and [Formula: see text], respectively. We find that conjugation has a deleterious effect on the mean fitness of the population, suggesting that HGT does not provide a selective advantage in a static environment, but is rather only useful for adapting to new environments. This effect can be ameliorated by repression, suggesting that while HGT is not necessarily advantageous for a population in a static environment, its deleterious effect on the mean fitness can be negated via repression. Therefore, it is likely that HGT is much more advantageous in a dynamic landscape. Furthermore, in the limiting case of a vanishing spontaneous de-repression rate constant, we find that the fraction of conjugators in the population undergoes a phase transition as a function of population density. Below a critical population density, the fraction of conjugators is zero, while above this critical population density the fraction of conjugators rises continuously to one. Our model for conjugation-mediated HGT is related to models of infectious disease dynamics, where the conjugators play the role of the infected (I) class, and the non-conjugators play the role of the susceptible (S) class. PMID- 24811123 TI - Determination of natural in vivo noble-gas concentrations in human blood. AB - Although the naturally occurring atmospheric noble gases He, Ne, Ar, Kr, and Xe possess great potential as tracers for studying gas exchange in living beings, no direct analytical technique exists for simultaneously determining the absolute concentrations of these noble gases in body fluids in vivo. In this study, using human blood as an example, the absolute concentrations of all stable atmospheric noble gases were measured simultaneously by combining and adapting two analytical methods recently developed for geochemical research purposes. The partition coefficients determined between blood and air, and between blood plasma and red blood cells, agree with values from the literature. While the noble-gas concentrations in the plasma agree rather well with the expected solubility equilibrium concentrations for air-saturated water, the red blood cells are characterized by a distinct supersaturation pattern, in which the gas excess increases in proportion to the atomic mass of the noble-gas species, indicating adsorption on to the red blood cells. This study shows that the absolute concentrations of noble gases in body fluids can be easily measured using geochemical techniques that rely only on standard materials and equipment, and for which the underlying concepts are already well established in the field of noble-gas geochemistry. PMID- 24811124 TI - Assessment of fetal cell chimerism in transgenic pig lines generated by Sleeping beauty transposition. AB - Human cells migrate between mother and fetus during pregnancy and persist in the respective host for long-term after birth. Fetal microchimerism occurs also in twins sharing a common placenta or chorion. Whether microchimerism occurs in multiparous mammals such as the domestic pig, where fetuses have separate placentas and chorions, is not well understood. Here, we assessed cell chimerism in litters of wild-type sows inseminated with semen of transposon transgenic boars. Segregation of three independent monomeric transposons ensured an excess of transgenic over non-transgenic offspring in every litter. Transgenic siblings (n = 35) showed robust ubiquitous expression of the reporter transposon encoding a fluorescent protein, and provided an unique resource to assess a potential cell trafficking to non-transgenic littermates (n = 7) or mothers (n = 4). Sensitive flow cytometry, fluorescence microscopy, and real-time PCR provided no evidence for microchimerism in porcine littermates, or piglets and their mothers in both blood and solid organs. These data indicate that the epitheliochorial structure of the porcine placenta effectively prevents cellular exchange during gestation. PMID- 24811125 TI - Modeling disease vector occurrence when detection is imperfect II: Drivers of site-occupancy by synanthropic Triatoma brasiliensis in the Brazilian northeast. AB - BACKGROUND: Understanding the drivers of habitat selection by insect disease vectors is instrumental to the design and operation of rational control surveillance systems. One pervasive yet often overlooked drawback of vector studies is that detection failures result in some sites being misclassified as uninfested; naive infestation indices are therefore biased, and this can confound our view of vector habitat preferences. Here, we present an initial attempt at applying methods that explicitly account for imperfect detection to investigate the ecology of Chagas disease vectors in man-made environments. METHODOLOGY: We combined triplicate-sampling of individual ecotopes (n = 203) and site-occupancy models (SOMs) to test a suite of pre-specified hypotheses about habitat selection by Triatoma brasiliensis. SOM results were compared with those of standard generalized linear models (GLMs) that assume perfect detection even with single bug-searches. PRINCIPAL FINDINGS: Triatoma brasiliensis was strongly associated with key hosts (native rodents, goats/sheep and, to a lesser extent, fowl) in peridomestic environments; ecotope structure had, in comparison, small to negligible effects, although wooden ecotopes were slightly preferred. We found evidence of dwelling-level aggregation of infestation foci; when there was one such focus, same-dwelling ecotopes, whether houses or peridomestic structures, were more likely to become infested too. GLMs yielded negatively-biased covariate effect estimates and standard errors; both were, on average, about four times smaller than those derived from SOMs. CONCLUSIONS/SIGNIFICANCE: Our results confirm substantial population-level ecological heterogeneity in T. brasiliensis. They also suggest that, at least in some sites, control of this species may benefit from peridomestic rodent control and changes in goat/sheep husbandry practices. Finally, our comparative analyses highlight the importance of accounting for the various sources of uncertainty inherent to vector studies, including imperfect detection. We anticipate that future research on infectious disease ecology will increasingly rely on approaches akin to those described here. PMID- 24811126 TI - Microarray-based analysis of the differential expression of melanin synthesis genes in dark and light-muzzle Korean cattle. AB - The coat color of mammals is determined by the melanogenesis pathway, which is responsible for maintaining the balance between black-brown eumelanin and yellow reddish pheomelanin. It is also believed that the color of the bovine muzzle is regulated in a similar manner; however, the molecular mechanism underlying pigment deposition in the dark-muzzle has yet to be elucidated. The aim of the present study was to identify melanogenesis-associated genes that are differentially expressed in the dark vs. light muzzle of native Korean cows. Using microarray clustering and real-time polymerase chain reaction techniques, we observed that the expression of genes involved in the mitogen-activated protein kinase (MAPK) and Wnt signaling pathways is distinctively regulated in the dark and light muzzle tissues. Differential expression of tyrosinase was also noticed, although the difference was not as distinct as those of MAPK and Wnt. We hypothesize that emphasis on the MAPK pathway in the dark-muzzle induces eumelanin synthesis through the activation of cAMP response element-binding protein and tyrosinase, while activation of Wnt signaling counteracts this process and raises the amount of pheomelanin in the light-muzzle. We also found 2 novel genes (GenBank No. NM-001076026 and XM-588439) with increase expression in the black nose, which may provide additional information about the mechanism of nose pigmentation. Regarding the increasing interest in the genetic diversity of cattle stocks, genes we identified for differential expression in the dark vs. light muzzle may serve as novel markers for genetic diversity among cows based on the muzzle color phenotype. PMID- 24811128 TI - HER2 directed therapy for gastric/esophageal cancers. AB - OPINION STATEMENT: The majority of patients with esophagogastric cancer present with advanced disease, which is incurable. Systemic chemotherapy can lead to a decrease in cancer-related symptoms and prolongs survival. However, even with treatment, the prognosis remains poor; most patients with advanced disease have a median overall survival less than one year. Molecularly targeted therapies, such as those targeting human epidermal growth factor receptor 2 (HER2), are anticipated to improve the current status of systemic treatment beyond conventional cytotoxic therapy. Trastuzumab in combination with chemotherapy in patients is the first molecular agent in metastatic HER2 positive gastric and gastroesophageal adenocarcinomas to result in improvements in response rates, time to progression and survival. Trastuzumab is now being investigated in the neoadjuvant and adjuvant setting. Unfortunately, as with breast cancer, many esophagogastric patients will develop resistance to trastuzumab. Several promising therapies are currently under investigation as monotherapy and in combination with chemotherapy in the first and second line setting. PMID- 24811129 TI - Preventive role of gallic acid on hepatic ischemia and reperfusion injury in rats. AB - There is little information about the hepatoprotective effects of gallic acid against ischemia-reperfusion (I/R) damage. Animals were subjected to I/R. Gallic acid at doses of 50 and 100 mg/kg body weight (bw) were injected as a single dose prior to ischemia. Liver tissue homogenates were used for the measurement of malondialdehyde (MDA), catalase (CAT) and glutathione peroxidase (GPx) levels. At the same time alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were assayed in serum samples and compared statistically. While the ALT, AST, LDH activities and MDA levels were significantly increased, CAT and GPx activities significantly decreased in only I/R-induced control rats compared to normal control rats (P < 0.05). Treatment with gallic acid at a dose of 100 mg/kg bw significantly decreased the ALT, AST, LDH activities and MDA levels, and markedly increased activities of CAT and GPx in tissue homogenates compared to I/R-induced rats with no treatment group (P < 0.05). In oxidative stress generated by hepatic ischemia-reperfusion, gallic acid contributes partially an alteration in the delicate balance between the scavenging capacity of antioxidant defense systems and free radicals in favour of the antioxidant defense systems in the body. PMID- 24811130 TI - Investigation of relationship between IL-6 gene variants and hypertension in Turkish population. AB - Hypertension (HT) is a common and life threating health problem worldwide leading to stroke, heart attack and renal failure. It is characterized by elevated blood pressure forced heart load. Human interleukin-6 (IL-6) and C- reactive protein (CRP) are known to be involved in inflammatory processes. IL-6 gene is a polymorphic gene which -174 G/C is a common and -572 G/C is a rare polymorphisms identified in promoter region. Publications on IL-6 gene polymorphisms raised the question whether this gene polymorphisms lead to susceptibility to HT or not. To investigate the effects of IL-6 gene -174 G/C (rs 1800795) and -572 G/C (rs1800796) polymorphisms on plasma IL-6 and CRP levels and their associations with hypertension disease in Turkish population we analyzed -174 G/C and -572 G/C polymorphisms and plasma IL-6 and CRP levels in 111 healthy controls and 108 hypertension patients from Adiyaman, Turkey. We determined the genotypes using polymerase chain reaction-restriction fragment length polymorphism and analyzed plasma levels of IL-6 by ELISA and CRP by automated standard biochemical methods. We have found no statistically significant differences between IL-6 gene -174 G/C and -572 G/C genotypes and allelic frequencies and IL-6 and CRP plasma levels and HT (p > 0.05). No CC genotype was found in control subjects for -572 G/C polymorphism. In conclusion, we found relation to -174 G/C and -572 G/C gene variants between neither IL-6 and CRP levels nor hypertension. The -572 G allele and GG genotype are predominant in Turkish population in Adiyaman, Turkey whereas the CC genotype is very rare. PMID- 24811131 TI - Aligning mouse models of asthma to human endotypes of disease. AB - Substantial gains in understanding the pathophysiologic mechanisms underlying asthma have been made using preclinical mouse models. However, because asthma is a complex, heterogeneous syndrome that is rarely due to a single allergen and that often presents in the absence of atopy, few of the promising therapeutics that demonstrated effectiveness in mouse models have translated into new treatments for patients. This has resulted in an urgent need to characterize T helper (Th) 2-low, non-eosinophilic subsets of asthma, to study models that are resistant to conventional treatments such as corticosteroids and to develop therapies targeting patients with severe disease. Classifying asthma based on underlying pathophysiologic mechanisms, known as endotyping, offers a stratified approach for the development of new therapies for asthma. In preclinical research, new models of asthma are being utilized that more closely resemble the clinical features of different asthma endotypes, including the presence of interleukin-17 and a Th17 response, a biomarker of severe disease. These models utilize more physiologically relevant sensitizing agents, exacerbating factors and allergens, as well as incorporate time points that better reflect the natural history and chronicity of clinical asthma. Importantly, some models better represent non-classical asthma endotypes that facilitate the study of non-Th2 driven pathology and resemble the complex nature of clinical asthma, including corticosteroid resistance. Placing mouse asthma models into the context of human asthma endotypes will afford a more relevant approach to the understanding of pathophysiological mechanisms of disease that will afford the development of new therapies for those asthmatics that remain difficult to treat. PMID- 24811132 TI - Identification of quantitative trait loci and a candidate locus for freezing tolerance in controlled and outdoor environments in the overwintering crucifer Boechera stricta. AB - Development of chilling and freezing tolerance is complex and can be affected by photoperiod, temperature and photosynthetic performance; however, there has been limited research on the interaction of these three factors. We evaluated 108 recombinant inbred lines of Boechera stricta, derived from a cross between lines originating from Montana and Colorado, under controlled long day (LD), short-day (SD) and in an outdoor environment (OE). We measured maximum quantum yield of photosystem II, lethal temperature for 50% survival and electrolyte leakage of leaves. Our results revealed significant variation for chilling and freezing tolerance and photosynthetic performance in different environments. Using both single- and multi-trait analyses, three main-effect quantitative trait loci (QTL) were identified. QTL on linkage group (LG)3 were SD specific, whereas QTL on LG4 were found under both LD and SD. Under all conditions, QTL on LG7 were identified, but were particularly predictive for the outdoor experiment. The co localization of photosynthetic performance and freezing tolerance effects supports these traits being co-regulated. Finally, the major QTL on LG7 is syntenic to the Arabidopsis C-repeat binding factor locus, known regulators of chilling and freezing responses in Arabidopsis thaliana and other species. PMID- 24811134 TI - Patterns of racial and educational assortative mating in Brazil. AB - Exchange of racial for educational status has been documented for black/white marriages in the United States. Exchange may be an idiosyncratic feature of U.S. society, resulting from unusually strong racial boundaries historically developed there. We examine status exchange across racial lines in Brazil. In contrast to the United States, Brazil features greater fluidity of racial boundaries and a middle tier of "brown" individuals. If exchange is contingent on strong racial boundaries, it should be weak or non-existent in Brazilian society. Contrary to this expectation, we find strong evidence of status exchange. However, this pattern results from a generalized penalty for darkness, which induces a negative association between higher education and marrying darker spouses ("market exchange") rather than from a direct trading of resources by partners ("dyadic exchange"). The substantive and methodological distinction between market and dyadic exchange helps clarify and integrate prior findings in the status exchange literature. PMID- 24811133 TI - Effects of GLP-1 on appetite and weight. AB - Glucagon-like peptide 1 (GLP-1) is a cleavage product of the pre-proglucagon gene which is expressed in the alpha-cells of the pancreas, the L-cells of the intestine, and neurons located in the caudal brainstem and hypothalamus. GLP-1 is of relevance to appetite and weight maintenance because it has actions on the gastrointestinal tract as well as the direct regulation of appetite. It delays gastric emptying and gut motility in humans. In addition, interventricular injections of GLP-1 inhibit food intake, independent of the presence of food in the stomach or gastric emptying. Peripherally administered GLP-1 also affects the central regulation of feeding. It is therefore the synergistic actions of GLP-1 in the gut and brain, acting on both central and peripheral receptors that seem responsible for the effects of the hormone on satiety. PMID- 24811135 TI - Who gets custody now? Dramatic changes in children's living arrangements after divorce. AB - This article reexamines the living arrangements of children following their parents' divorce, using Wisconsin Court Records, updating an analysis that showed relatively small but significant increases in shared custody in the late 1980s and early 1990s. These changes have accelerated markedly in the intervening years: between 1988 and 2008, the proportion of mothers granted sole physical custody fell substantially, the proportion of parents sharing custody increased dramatically, and father-sole custody remained relatively stable. We explore changes in the correlates of alternative custody outcomes, showing that some results from the earlier analysis still hold (for example, cases with higher total family income are more likely to have shared custody), but other differences have lessened (shared-custody cases have become less distinctive as they have become more common). Despite the considerable changes in marriage and divorce patterns over this period, we do not find strong evidence that the changes in custody are related to changes in the characteristics of families experiencing a divorce; rather, changes in custody may be the result of changes in social norms and the process by which custody is determined. PMID- 24811136 TI - Feedback control of inertial microfluidics using axial control forces. AB - Inertial microfluidics is a promising tool for many lab-on-a-chip applications. Particles in channel flows with Reynolds numbers above one undergo cross streamline migration to a discrete set of equilibrium positions in square and rectangular channel cross sections. This effect has been used extensively for particle sorting and the analysis of particle properties. Using the lattice Boltzmann method, we determined the equilibrium positions in square and rectangular cross sections and classify their types of stability for different Reynolds numbers, particle sizes, and channel aspect ratios. Our findings thereby help to design microfluidic channels for particle sorting. Furthermore, we demonstrated how an axial control force, which slows down the particles and shifts the stable equilibrium position towards the channel center. Ultimately, the particles then stay on the centerline for forces exceeding the threshold value. This effect is sensitive to the particle size and channel Reynolds number and therefore suggests an efficient method for particle separation. In combination with a hysteretic feedback scheme, we can even increase the particle throughput. PMID- 24811137 TI - All solution-processed inorganic/organic hybrid permeable metal-base transistor. AB - All solution-processed inorganic/organic hybrid permeable-base transistor (PMBT) based on nickel oxide emitter and P3HT collector is developed. Due to the high charge injection properties of nickel oxide and spontaneously formed nano pinholes in the base electrode, the devices exhibit high common-base and common emitter current gains up to 0.98 and 304, respectively with saturated output current. PMID- 24811138 TI - Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and ascites: a real-life cross-sectional study. AB - BACKGROUND & AIMS: A moderate sodium restriction diet should be indicated in patients with cirrhosis and ascites. Nevertheless, there is a lack of specific investigation on its correct application. To evaluate the adherence of patients with cirrhosis and ascites to a moderately low-salt diet and the impact on intake of total calories and serum sodium concentration. METHODS: A total of 120 outpatients with cirrhosis and ascites were interviewed with a pre-established questionnaire. A quantitative assessment of nutrient and salt intake was performed. RESULT: A moderately low-salt diet was followed by 37 patients (Group A). Of the 83 patients who did not follow the diet (Group B), 54 thought that they were following it. The mean daily sodium intake was 79.5 +/- 5.5 mmol/day (Group A) and 205.9 +/- 14.1 mmol/day (Group B), P < 0.0001. The adherence to diet was related to the severity of cirrhosis, and was higher among candidates for liver transplantation and in patients followed through the Care Management Program. Patients of Group A had reduced the mean daily calorie intake by 20% compared with Group B patients (P < 0.0005), while there was no difference on the occurrence of hyponatraemia. CONCLUSIONS: This study shows a poor adherence of patients with cirrhosis and ascites to a moderate dietary sodium restriction. Adherence to a diet seems to increase with the worsening of liver disease, probably because of the reduction of alternative therapeutic options. In addition, a deficiency in the educational process can lead the patient to follow a sodium-reduced diet by means of dangerous tools, such as reducing the overall daily food intake. PMID- 24811139 TI - Clarification of cross-linkage structure in boric acid doped poly(vinyl alcohol) and its model compound as studied by an organized combination of X-ray single crystal structure analysis, Raman spectroscopy, and density functional theoretical calculation. AB - When boric acid (BA) is added to poly(vinyl alcohol) (PVA), a chemical reaction occurs to form the cross-linkages between the amorphous PVA chains. The local structural change caused by this reaction has been clarified concretely from the microscopic level on the basis of the X-ray-analyzed crystal structure, Raman spectra, and ab initio density functional theory using a model compound produced by the reaction between pentanediol (PENT) and boric acid (PENT-BA). The PENT-BA compound was found to take the TT and TG conformations in the methylene segmental parts depending on the stereoregularity of the PENT molecule itself, meso and racemo configurations, respectively. These two conformations give the Raman bands at the different positions. By comparison of the Raman spectra between the PVA-BA and PENT-BA model compounds, the local structures of PVA chains connected to BA molecules have been derived concretely: the syndiotactic PVA parts in the amorphous region form the TG-type ring structure with the 3-coordinate boron atom, where T and G are trans and gauche conformers, respectively. On the other hand, the isotactic PVA part takes the TT conformation when it forms a ring with boron atom. The thus-created rings are hydrogen-bonded to form a dimer, which plays a role as cross-linkage between the neighboring PVA chain segments in the amorphous region. PMID- 24811140 TI - Rapid post-oral stimulation of intake and flavor conditioning in rats by glucose but not a non-metabolizable glucose analog. AB - Mice adapted to drink a flavored saccharin solution (CS-) paired with intragastric (IG) self-infusions of water rapidly increase their intake of a new flavored solution (CS+) that is paired with IG glucose self-infusions. The present study extends this method to examine post-oral glucose appetition in rats. Food-restricted rats were trained to consume a CS- flavor (e.g., grape saccharin) paired with IG water in 5 daily 1-h tests. In the next 3 tests, they drank a CS+ (e.g., cherry saccharin) paired with IG glucose. Rats infused with 8% glucose increased intake significantly on CS+ Test 1, but those infused with 16% glucose showed only a small increase in intake, which may reflect a counteracting satiating effect. Both groups further increased CS+ intakes in Tests 2 and 3, and preferred (81%) the CS+ to the CS- in a two-bottle test without infusions. A second experiment investigated rats' responses to IG alpha-methyl-d glucopyranoside (MDG), a non-metabolizable sugar analog which stimulates CS+ intake and preference in mice. The rats reduced their intake of the MDG-paired CS+ flavor over sessions, and preferred the CS- to the CS+ in the choice test. The glucose data show that rats, like mice, rapidly detect the sugar's positive post-oral effects that can stimulate intake within the first hour of exposure. The MDG avoidance may indicate a greater sensitivity to its post-oral inhibitory effects in rats than in mice, or perhaps slower clearance of MDG in rats. The test protocol described here can be used to investigate the peripheral and central processes involved in stimulation of intake by post-oral nutrients in rats. PMID- 24811142 TI - Alterations of thyroid volume and nodular size during and after pregnancy in a severe iodine-deficient area. AB - OBJECTIVE: The effects of pregnancy on thyroid nodules were investigated in a few number of studies. We aimed to evaluate the prevalence of thyroid nodules, the changes in size, volume and number of nodules during pregnancy and after delivery in pregnant women. DESIGN AND METHODS: This prospective study was performed in a severe iodine-deficient area and included 83 pregnant women (mean age 30.4 +/- 5.5 years). We evaluated thyroid hormone levels, ultrasound examination of thyroid and urine iodine concentration (UIE) at each trimester and at 3-month post-partum period (PP). All patients with thyroid nodules >1 cm underwent fine needle aspiration biopsy (FNAB) after the last visit at the PP. RESULTS: Twenty six women had thyroid nodules on thyroid ultrasonography at the first trimester. The volume of single/dominant nodule showed enlargement during pregnancy and remained at the PP; however, it was not significant (first trimester: 0.83 +/- 0.8 ml; second trimester: 0.92 +/- 1 ml; third trimester: 0.99 +/- 1.2 ml; PP: 0.92 +/- 1.2 ml). The maximum diameter of single/dominant nodule in the third trimester of pregnancy (12.6 +/- 5.4 mm) was greater than the first trimester (11.9 +/- 4.8 mm) (P = 0.002). The number of nodules did not change during pregnancy. The mean TV increased during pregnancy and remained 3 months after delivery (P < 0.001), and the maximum value of TV was reached in the third trimester (14.2 +/- 7.9 ml). FNAB results revealed a 6.6% prevalence of malignancy among the nodules. CONCLUSIONS: Thyroid nodules were present in 30.1% of pregnant women. While size of the single/dominant thyroid nodule increased significantly during pregnancy, the number of nodules did not change. PMID- 24811141 TI - The EF-hand calcium-binding protein tescalcin is a potential oncotarget in colorectal cancer. AB - Tescalcin (TESC) is an EF-hand calcium binding protein that is differentially expressed in several tissues, however it is not reported that the expression and functional roles of TESC in colorectal cancer. Levels of messenger RNA (mRNA) and protein expression of TESC in colorectal cancer tissues were assessed using RT PCR, real time PCR, immunohistochemistry, and clinicopathologic analyses. Quantitative analysis of TESC levels in serum specimens was performed using sandwich ELISA. Colorectal cancer cells transfected with TESC small interfering RNA and short hairpin RNA were examined in cell proliferation assays, phospho MAPK array, and mouse xenograft models. Here we demonstrated that TESC is overexpressed in colorectal cancer (CRC), but was not expressed in normal mucosa and premalignant dysplastic lesions. Furthermore, serum TESC levels were elevated in patients with CRC. Knockdown of TESC inhibited the Akt-dependent NF-kappaB pathway and decreased cell survival in vitro. Depletion of TESC reduced tumor growth in a CRC xenograft model. Thus, TESC is a potential diagnostic marker and oncotarget in colorectal cancer. PMID- 24811143 TI - Genetic and environmental stability of intelligence in childhood and adolescence. AB - The present study examined the genetic and environmental contributions to the temporal stability of verbal, non-verbal and general intelligence across a developmental period spanning childhood and adolescence (5-18 years). Longitudinal twin data collected in four different studies on a total of 1,748 twins, comprising 4,641 measurement points in total, were analyzed using genetic adaptations of the simplex model. The heterogeneity in the type of instrument used to assess psychometric intelligence across the different subsamples and ages allowed us to address the auxiliary question of how to optimally utilize the existing longitudinal data in the context of gene-finding studies. The results were consistent across domains (verbal, non-verbal and general intelligence), and indicated that phenotypic stability was driven primarily by the high stability of additive genetic factors, that the stability of common environment was moderate, and that the unique environment contributed primarily to change. The cross subscale stability was consistently low, indicating a small overlap between different domains of intelligence over time. The high stability of additive genetic factors justifies the use of a linear combination of scores across the different ages in the context of gene-finding studies. PMID- 24811144 TI - Evaluation of two types of swabs for sampling allograft musculoskeletal tissue. AB - BACKGROUND: Allograft musculoskeletal tissue is commonly sampled by a swab for bioburden screening. To determine if bioburden recovery could be improved at the pre-analytical stage, two swab systems were evaluated: the Amies gel swab and the ESwab. METHODS: In vitro studies were performed to determine the recovery of each swab system with <100 colony-forming unit of challenge organisms using inoculated swabs and by sampling inoculated femoral heads. The standard culture protocol used in this laboratory was also evaluated after sampling of inoculated femoral heads. A prospective study was performed with both swab systems used in parallel to sample cadaveric allograft musculoskeletal tissue. RESULTS: The challenge organisms could be recovered from the in vitro inoculated studies. The standard culture protocol in this laboratory recovered all challenge organisms from both swab systems. One hundred and six paired Amies and ESwabs were collected from eight cadaveric donors with skin commensals the predominant isolates. CONCLUSIONS: The sampling of an inoculated femoral head was included to reflect routine swab sampling practice as was the inclusion of the standard method used in this laboratory. This appears to be the first study to compare Amies gel swabs with ESwabs to sample allograft femoral heads and in a prospective study with cadaveric allograft musculoskeletal tissue. Other comparative studies of swab systems have used a much higher inoculum to mimic an infection; however, sepsis is an exclusion criterion for allograft donors. It was found that the Amies gel swab and ESwab are both suitable sampling devices for bioburden testing of allograft musculoskeletal tissue. PMID- 24811145 TI - The benefits of implementing a computerized intervention-management-system (IMS) on delivering integrated dementia care in the primary care setting. AB - BACKGROUND: A computerized Intervention-Management-System (IMS) has been developed and implemented to facilitate dementia care management. IMS is a rule based expert decision support system that matches individual patient characteristics to a computerized knowledge base. One of the most important functionalities of IMS is to support the compilation of the individual intervention plan by systematically identifying unmet needs and suggesting the corresponding specific interventions for recommendation to the general practitioner (GP). The present analysis aimed to determine if the implementation of IMS improves the identification of unmet needs and the recommendation of adequate specific interventions. In addition, the feasibility and acceptability of the IMS were evaluated. METHODS: Delphi-MV is an on-going GP-based, cluster randomized, controlled intervention trial to implement and evaluate a collaborative dementia care management program for community-dwelling PWDs and their caregivers. IMS was developed and implemented over the course of the DelpHi trial. The identified unmet needs and the interventions that were recommended to the GP before and after the implementation of IMS were compared. To evaluate the feasibility and acceptability of the IMS, a survey was conducted among the current users of IMS. RESULTS AND CONCLUSIONS: After the implementation of IMS, the number of specific interventions recommended to the GP increased by 85%. Our findings provide evidence that IMS improves the systematic identification of unmet needs and the subsequent recommendation of interventions to address these needs. The users evaluated IMS as very helpful and would like to use it for their future work. However, the usability could be further improved. PMID- 24811146 TI - Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer. AB - BACKGROUND: HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. METHODS: HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. RESULTS: The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. CONCLUSION: Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer. PMID- 24811148 TI - Supported imidazolylphosphine catalysts for highly (E)-selective alkene isomerization. AB - For fine chemical synthesis, immobilized catalysts offer little advantage if they produce a product mixture that must be separated. Selective isomerization of terminal olefins is achieved by heterogenized bifunctional catalysts. Outstanding and consistent (E)-selectivity (>99%) even in cases where (E) and (Z) isomers are of comparable stability, combined with modest catalyst loadings (1 to 2 mol %), set these catalysts apart from previously reported systems. Ease of catalyst removal and high geometric selectivity avoid tedious purifications. PMID- 24811147 TI - Artificial pancreas (AP) clinical trial participants' acceptance of future AP technology. AB - BACKGROUND: Artificial pancreas (AP) systems are currently an active field of diabetes research. This pilot study examined the attitudes of AP clinical trial participants toward future acceptance of the technology, having gained firsthand experience. SUBJECTS AND METHODS: After possible influencers of AP technology adoption were considered, a 34-question questionnaire was developed. The survey assessed current treatment satisfaction, dimensions of clinical trial participant motivation, and variables of the technology acceptance model (TAM). Forty-seven subjects were contacted to complete the survey. The reliability of the survey scales was tested using Cronbach's alpha. The relationship of the factors to the likelihood of AP technology adoption was explored using regression analysis. RESULTS: Thirty-six subjects (76.6%) completed the survey. Of the respondents, 86.1% were either highly likely or likely to adopt the technology once available. Reliability analysis of the survey dimensions revealed good internal consistency, with scores of >0.7 for current treatment satisfaction, convenience (motivation), personal health benefit (motivation), perceived ease of use (TAM), and perceived usefulness (TAM). Linear modeling showed that future acceptance of the AP was significantly associated with TAM and the motivation variables of convenience plus the individual item benefit to others (R(2)=0.26, P=0.05). When insulin pump and continuous glucose monitor use were added, the model significance improved (R(2)=0.37, P=0.02). CONCLUSIONS: This pilot study demonstrated that individuals with direct AP technology experience expressed high likelihood of future acceptance. Results support the factors of personal benefit, convenience, perceived usefulness, and perceived ease of use as reliable scales that suggest system adoption in this highly motivated patient population. PMID- 24811149 TI - Novel and simple headspace in-tube microextraction coupled with capillary electrophoresis. AB - In liquid phase microextraction, high enrichment factors can be obtained using an acceptor phase of small volume. By hanging an acceptor drop at the separation capillary tip, single drop microextraction (SDME) can be in-line coupled with capillary electrophoresis (CE). The small surface-to-volume ratio of the drop enables high enrichment factors to be obtained in a short time. One practical issue in SDME is how to keep the drop attached to the capillary stable. Here, we present novel but extremely simple in-tube microextraction (ITME) using the liquid inside the capillary as an acceptor phase, without forming a drop at the capillary tip. As a first example, ITME has been combined with headspace (HS) extraction. Simply by placing a capillary filled with a basic run buffer in the HS above an acidic donor solution, volatile acidic analytes were extracted into the acceptor phase in the capillary. After extraction, electrophoresis of the extracts in the capillary was carried out. Owing to the robust nature of the acceptor phase, the extraction temperature and time ranges of HS-ITME can be extended significantly, compared to HS-SDME. The enrichment factors for chlorophenols in a standard solution were up to 1100 under an optimal HS-ITME condition of 80 degrees C for 15min and the limits of detections (LODs) obtained by monitoring the absorbance at 214nm were about 4nM. The whole procedures of HS ITME-CE were carried out automatically using built-in programs of a commercial CE instrument. PMID- 24811150 TI - Phytochemical profile and nutraceutical potential of chia seeds (Salvia hispanica L.) by ultra high performance liquid chromatography. AB - Chia seeds (Salvia hispanica) were analyzed for total phenolic compounds, antioxidant activity, and quantification of phenolic acids and isoflavones by ultra high performance liquid chromatography (UHPLC), in order to obtain a phenolic phytochemical profile. The total phenolic concentration was 1.8-fold higher than previous reports and the antioxidant activity using DPPH (2,2 diphenyl-1-picrylhydrazyl) radical assay showed 68.83% inhibition, which was higher than the values reported previously for chia and different plant foods. Additionally, a simple, reproducible and rapid UHPLC method was proposed for the analysis of phenolic acids and isoflavones in chia. The method demonstrated to perform well with regard to linearity, limits of detection and quantification, precision, accuracy, and sensitivity. The detection limits ranged from 0.05 to 0.4ng/mL and the recovery percentage from 23.62 to 162.48%. With this method the major compounds identified and quantified were: rosmarinic acid 0.92, protocatechuic ethyl ester 0.74, caffeic acid 0.02, gallic acid 0.01, and daidzin 0.006mg/g seed. In brief, this study demonstrates that chia could be considered a seed with high antioxidant capacity and novel isoflavone source that can be incorporated in human diet. PMID- 24811151 TI - Method validation strategies involved in non-targeted metabolomics. AB - Non-targeted metabolomics is the hypothesis generating, global unbiased analysis of all the small-molecule metabolites present within a biological system, under a given set of conditions. It includes several common steps such as selection of biological samples, sample pre-treatment, analytical conditions set-up, acquiring data, data analysis by chemometrics, database search and biological interpretation. Non-targeted metabolomics offers the potential for a holistic approach in the area of biomedical research in order to improve disease diagnosis and to understand its pathological mechanisms. Various analytical methods have been developed based on nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) coupled with different separation techniques. The key points in any analytical method development are the validation of every step to get a reliable and reproducible result and non-targeted metabolomics is not beyond this criteria, although analytical challenges are completely new and different to target methods. This review paper will describe the available validation strategies that are being used and as well will recommend some steps to consider during a non-targeted metabolomics analytical method development. PMID- 24811152 TI - Hybrid molecularly imprinted polymers synthesized with 3 aminopropyltriethoxysilane-methacrylic acid monomer for miniaturized solid-phase extraction: A new and economical sample preparation strategy for determination of acyclovir in urine. AB - The miniaturized molecularly imprinted solid-phase extraction (mini-MISPE) coupled with high-performance liquid chromatography was proposed for the determination of acyclovir in urine. 1.5-mL tapered plastic centrifuge tube filled with hybrid molecularly imprinted polymers (HMIPs) was used as the cartridge of mini-MISPE, and the HMIPs synthesized with 3-aminopropyltriethoxy silane-methacrylic acid as monomer exhibited good recognition and selectivity for acyclovir. Under the optimized condition, good linear calibration was obtained in a range of 0.5-15MUgmL(-1) with the correlation coefficient of 0.9994, and the recoveries at three spiked levels were 91.6-103.3% in urine with the relative standard deviation (RSD) of <=3.5%. Excellent intra-day and inter-day repeatability were achieved with RSD of <=2.6% and 4.0% in three different concentrations. This method combined the advantages of HMIPs and mini-MISPE, and it could become an alternative tool for analyzing the residues of acyclovir in complex urine matrices. PMID- 24811153 TI - A high-performance alginate hydrogel binder for the Si/C anode of a Li-ion battery. AB - An alginate hydrogel binder is prepared through the cross linking effect of Na alginate with Ca(2+) ions, which leads to a remarkable improvement in the electrochemical performance of the Si/C anode of a Li-ion battery. PMID- 24811154 TI - Animal models of excessive alcohol consumption: recent advances and future challenges. PMID- 24811155 TI - The alcohol deprivation effect model for studying relapse behavior: a comparison between rats and mice. AB - Understanding the psychological mechanisms and underlying neurobiology of relapse behavior is essential for improving the treatment of addiction. Because the neurobiology of relapse behavior cannot be well studied in patients, we must rely on appropriate animal models. The alcohol deprivation effect (ADE) is a phenomenon in laboratory animals that models a relapse-like drinking situation, providing excellent face and predictive validity. In rodents, relapse-like behavior is largely influenced by the genetic make-up of an animal. It is not clear which other factors are responsible for variability of this behavior, but there seems to be no correlation between levels of baseline alcohol intake and the occurrence, duration, and robustness of the ADE. Rats that undergo long-term alcohol drinking for several months with repeated deprivation phases develop a compulsive drinking behavior during a relapse situation, characterized by insensitivity to taste adulteration with quinine, a loss of circadian drinking patterns during relapse-like drinking, and a shift toward drinking highly concentrated alcohol solutions to rapidly increase blood alcohol concentrations and achieve intoxication. Some mouse strains also exhibit an ADE, but this is usually of shorter duration than in rats. However, compulsive drinking in mice during a relapse situation has yet to be demonstrated. We extend our review section with original data showing that during long-term alcohol consumption, mice show a decline in alcohol intake, and the ADE fades with repeated deprivation phases. Furthermore, anti-relapse compounds that produce reliable effects on the ADE in rats produce paradoxical effects in mice. We conclude that the rat provides a better model system to study alcohol relapse and putative anti relapse compounds. PMID- 24811156 TI - Editorial comment for Molinari et al. PMID- 24811157 TI - The intellectual challenges and emotional consequences of equipoise contributed to the fragility of recruitment in six randomized controlled trials. AB - OBJECTIVE: The aim of the study was to investigate how doctors considered and experienced the concept of equipoise while recruiting patients to randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: In-depth interviews with 32 doctors in six publicly funded pragmatic RCTs explored their perceptions of equipoise as they undertook RCT recruitment. The RCTs varied in size, duration, type of complex intervention, and clinical specialties. Interview data were analyzed using qualitative content and thematic analytical methods derived from grounded theory and synthesized across six RCTs. RESULTS: All six RCTs suffered from poor recruitment. Doctors wanted to gather robust evidence but experienced considerable discomfort and emotion in relation to their clinical instincts and concerns about patient eligibility and safety. Although they relied on a sense of community equipoise to justify participation, most acknowledged having "hunches" about particular treatments and patients, some of which undermined recruitment. Surgeons experienced these issues most intensely. Training and support promoted greater confidence in equipoise and improved engagement and recruitment. CONCLUSION: Recruitment to RCTs is a fragile process and difficult for doctors intellectually and emotionally. Training and support can enable most doctors to become comfortable with key RCT concepts including equipoise, uncertainty, patient eligibility, and randomization, promoting a more resilient recruitment process in partnership with patients. PMID- 24811158 TI - Determination of crizotinib in human and mouse plasma by liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). AB - An LC-ESI-MS/MS method using high-throughput solid-phase extraction (SPE) was developed and validated to measure crizotinib in human and mouse plasma to support ongoing clinical and preclinical pharmacokinetic studies. Chromatographic separation of mouse or human plasma extracts was performed on a Supelco Discovery c18 column (50 mm * 2.1mm, 5.0 MU) with gradient elution using a combination of acidified aqueous and methanol (MeOH) mobile phases. The mass-to-charge transition monitored for detection and quantitation of crizotinib was m/z 450.2>260.2 while the stable label internal standard (ISTD) was monitored at m/z 457.2>267.3. The validation studies demonstrated that the assay is both precise and accurate with %CV<9% and accuracies within 8% of nominal target concentration across all concentrations tested for both the human and mouse plasma matrices. Sample volumes required for analysis were 50 and 25 MUL for human plasma and mouse plasma, respectively. Calibration curves were linear over a range of 5 5,000 ng/mL for human plasma and 2-2,000 ng/mL for mouse plasma. The use of a 96 well plate format enabled rapid extraction as well as compatibility with automated workflows. The method was successfully applied to analyze crizotinib concentrations in plasma samples collected from children enrolled on a phase I pediatric study investigating the use of crizotinib for treatment of pediatric brain tumors. PMID- 24811159 TI - Auditory middle latency responses differ in right- and left-handed subjects: an evaluation through topographic brain mapping. AB - PURPOSE: To investigate the association of handedness with auditory middle latency responses (AMLRs) using topographic brain mapping by comparing amplitudes and latencies in frontocentral and hemispheric regions of interest (ROIs). METHOD: The study included 44 healthy subjects with normal hearing (22 left handed and 22 right handed). AMLRs were recorded from 29 scalp electrodes in response to binaural 4-kHz tone bursts. RESULTS: Frontocentral ROI comparisons revealed that Pa and Pb amplitudes were significantly larger in the left-handed than the right-handed group. Topographic brain maps showed different distributions in AMLR components between the two groups. In hemispheric comparisons, Pa amplitude differed significantly across groups. A left-hemisphere emphasis of Pa was found in the right-handed group but not in the left-handed group. CONCLUSION: This study provides evidence that handedness is associated with AMLR components in frontocentral and hemispheric ROI. Handedness should be considered an essential factor in the clinical or experimental use of AMLRs. PMID- 24811160 TI - Near-infrared light-responsive nanomaterials in cancer therapeutics. AB - Noninvasive techniques, such as breath tests (urea breath test), blood pressure measurements using a sphygmomanometer and electrocardiography, were employed by a physician to perform classical diagnosis. The use of state-of-the-art noninvasive therapies at the organ level in modern medicine has gradually become possible. However, cancer treatment demands spatially and temporally controlled noninvasive therapy at the cell level because nonspecific toxicity often causes complicated side effects. To increase survival in cancer patients further, combination therapy and combination drugs are explored which demand high specificity to avoid combined-drug side effects. We believe that high specificity could be obtained by implementing near-infrared (NIR) light-assisted nanoparticles in photothermal therapy, chemotherapy, and photodynamic therapy. To refine this therapy and subsequently achieve high efficiency, novel nanomaterials have been designed and modified either to enhance the uptake and drug delivery to the cancer site, or control treatment to administer therapy efficiently. These modifications and developments have been demonstrated to achieve spatial and temporal control when conducting an in vivo xenograft, because the NIR light penetrated effectively the biological tissue. The nanoplatforms discussed in this review are grouped under the following subheadings: Au nanorods (NRs), Au nanoshells, other Au-related nanomaterials, graphene oxide, upconversion nanoparticles, and other related materials (including materials such as CuS, Fe3O4-related systems, and carbon nanotubes (CNTs)). PMID- 24811162 TI - Rational combination therapies targeting survival signaling in aggressive B-cell leukemia/lymphoma. AB - PURPOSE OF REVIEW: The identification of oncogenic 'driver' mutations and activated survival pathways in selected aggressive B-cell malignancies directs the development of novel adjunctive therapies using targeted small molecule inhibitors. With a focus on diffuse large B-cell lymphoma 'not otherwise specified', Hodgkin lymphoma and childhood B-cell precursor acute lymphoblastic leukemia, this review will provide an up-to-date account of the current literature on the development of new molecularly targeted treatment modalities for aggressive B-cell malignancies. RECENT FINDINGS: Subclassification of B-cell malignancies depending on their particular genetic 'driver' lesions and transcriptional and/or signaling signatures has led to the development of targeted therapeutic approaches using small molecule inhibitors to amend current combination chemotherapy. SUMMARY: Treatment outcome with current combination chemotherapy is still poor for subsets of aggressive B-cell malignancies, and demands development of targeted therapeutic approaches. Advanced gene expression profiling and genomic sequencing have revealed a more detailed landscape of recurrent alterations, allowing a better subclassification of B-cell lymphomas and leukemias. Many alterations directly or indirectly lead to activation of survival signaling pathways and expression of key oncoproteins and prosurvival molecules, including Janus kinase-signal transducer and activator of transcription (JAK-STAT), phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), avian myelocytomatosis viral oncogene homolog (MYC) and B-cell lymphoma 2 (BCLl-2). Small molecule inhibitors targeting these proteins and pathways are currently being tested in clinical trials and preclinically to improve chemotherapeutic regimes and treatment outcomes. PMID- 24811161 TI - Targeting the B-cell receptor signaling pathway in B lymphoid malignancies. AB - PURPOSE OF REVIEW: Normal B cells that have failed to productively rearrange immunoglobulin V region genes encoding a functional B-cell receptor (BCR) are destined to die. Likewise, the majority of B-cell malignancies remain dependent on functional BCR signaling, whereas in some subtypes BCR expression is missing and, apparently, counterselected. Here, we summarize the recent experimental evidence for the importance of BCR signaling and clinical concepts to target the BCR pathway in B-cell leukemia and lymphoma. RECENT FINDINGS: Although the dependency on pre-BCR signaling in pre-B acute lymphoblastic leukemia (ALL) seems to be limited to few ALL subtypes (e.g. TCF3-PBX1), most mature B-cell lymphomas rely on BCR signaling provided by different stimuli, for example tonic B-cell signaling, chronic (auto)-antigen exposure, and self-binding properties of the BCR. The finding that in chronic lymphocytic leukemia, BCRs bind to an epitope on the BCR itself unravels a novel concept for chronic lymphocytic leukemia pathogenesis. SUMMARY: Targeting of the B-cell receptor tyrosine kinases spleen tyrosine kinase, Bruton's tyrosine kinase, and phosphatidylinositol 3-kinase achieve promising clinical responses in various mature B-cell malignancies and might also be useful in defined subsets of ALL. However, further understanding of the BCR signal integration in the different disease groups is required to accurately predict which groups of patients will benefit from BCR pathway inhibition. PMID- 24811163 TI - Common progenitor cells in mature B-cell malignancies: implications for therapy. AB - PURPOSE OF REVIEW: This review summarizes the recent progress in defining the patterns of genetic evolution giving rise to relapse in follicular lymphoma and multiple myeloma, and discusses their implications with respect to 'personalized medicine'. RECENT FINDINGS: High-throughput sequencing studies have uncovered a large degree of clonal heterogeneity within tumors, and found that subclones have a variable contribution to relapse. Recent studies aimed at defining patterns of clonal evolution have revealed that serial tumors in some malignancies share their ancestry in a less evolved common progenitor cell (CPC) that bears only a subset of the mutations that are present in the fully evolved tumors that present clinically. This pattern of 'divergent evolution' means that the majority of 'actionable mutations' in tumor specimens are absent within the progenitors that give rise to relapse. SUMMARY: Follicular lymphoma and multiple myeloma are clinically, biologically and genetically distinct mature B-cell malignancies. However, recent studies have found them to share important similarities in their patterns of genetic evolution. Tumor cells that constitute subclonal populations within these tumors, or between consecutive tumors, share their origins within a genetically less evolved common progenitor cell. This pattern of evolution indicates that current therapies are unable to eradicate these less evolved populations that are at the root of relapse. This suggests that in order to obtain the best results with modern 'targeted therapies' that are directed towards 'actionable mutations', these mutations should be considered within the context of the evolutionary stage at which mutations are acquired, not simply on a presence or absence basis. PMID- 24811164 TI - RNA interference screening to detect targetable molecules in hematopoietic stem cells. AB - PURPOSE OF REVIEW: The molecular principles regulating hematopoietic stem cells (HSCs) remain incompletely defined. In this review, we will discuss how RNA interference (RNAi) screening has emerged as a new and powerful tool to molecularly dissect various functional aspects of both normal and malignant HSCs, and how this may ultimately enable the discovery of novel therapeutic targets for clinical applications. RECENT FINDINGS: Advances in RNAi technology and the creation of short hairpin RNA retroviral and lentiviral vector-libraries have provided tools to perform broad forward genetic screens in primary mammalian hematopoietic cells. Recent studies have identified novel fate determinants in murine HSCs as well as potential targets for ex-vivo expansion of human HSCs. RNAi screens have further unraveled tumor suppressor genes associated with hematopoietic neoplasms as well as candidate therapeutic targets in leukemic cells. SUMMARY: RNAi screening is a feasible tool to discover novel molecules that regulate both normal and malignant HSCs, thus increasing our general understanding of the physiology and pathophysiology of hematopoiesis. Moreover, RNAi technology holds great promise for the discovery of specific targets for therapeutic interventions. PMID- 24811165 TI - Insulin-like growth factor-2 enhances functions of antigen (Ag)-specific regulatory B cells. AB - Regulatory B cells (Bregs) are important in immune regulation. The factors that regulate Breg functions are less clear. Insulin-like growth factor 2 (IGF2) is capable of inducing hematopoietic stem cell differentiation. This study aimed to investigate the role of IGF2 in the development of Bregs and the enhancement of their function. In this study, the expression of IGF1 receptor (IGF1R) and IGF2R in ovalbumin (OVA)-specific B cells (OVAsBCs) was assessed by real time RT-PCR and Western blotting. The release of interleukin (IL)-10 from OVAsBCs and OVAsBC proliferation were assessed by enzyme-linked immunoassay and proliferation assay. The role of IGF2 in enhancing the function of OVAsBCs was tested with an intestinal allergic inflammation mouse model. The results showed that OVAsBCs expressed high levels of IGF2R. Exposure to both IGF2 and a specific antigen (Ag), OVA, markedly enhanced the expression of IL-10 in OVAsBCs as well as enhanced the IL-10(+) OVAsBC proliferation. The concurrent exposure to IGF2 and specific Ag markedly induced the IL-10 promoter DNA demethylation via activating the STAT5 pathway. IGF2 also enhanced both the OVAsBC proliferation in vivo and the effect of Ag-specific immunotherapy on inhibiting allergic inflammation in the intestine. We conclude that OVAsBCs express high levels of IGF2R and that IGF2 increases the expression of IL-10 in OVAsBCs and enhances OVAsBC proliferation and the inhibitory effect on allergic inflammation. PMID- 24811166 TI - The stoichiometry and biophysical properties of the Kv4 potassium channel complex with K+ channel-interacting protein (KChIP) subunits are variable, depending on the relative expression level. AB - Kv4 is a voltage-gated K(+) channel, which underlies somatodendritic subthreshold A-type current (ISA) and cardiac transient outward K(+) (Ito) current. Various ion channel properties of Kv4 are known to be modulated by its auxiliary subunits, such as K(+) channel-interacting protein (KChIP) or dipeptidyl peptidase-like protein. KChIP is a cytoplasmic protein and increases the current amplitude, decelerates the inactivation, and accelerates the recovery from inactivation of Kv4. Crystal structure analysis demonstrated that Kv4 and KChIP form an octameric complex with four Kv4 subunits and four KChIP subunits. However, it remains unknown whether the Kv4.KChIP complex can have a different stoichiometry other than 4:4. In this study, we expressed Kv4.2 and KChIP4 with various ratios in Xenopus oocytes and observed that the biophysical properties of Kv4.2 gradually changed with the increase in co-expressed KChIP4. The tandem repeat constructs of Kv4.2 and KChIP4 revealed that the 4:4 (Kv4.2/KChIP4) channel shows faster recovery than the 4:2 channel, suggesting that the biophysical properties of Kv4.2 change, depending on the number of bound KChIP4s. Subunit counting by single-molecule imaging revealed that the bound number of KChIP4 in each Kv4.2.KChIP4 complex was dependent on the expression level of KChIP4. Taken together, we conclude that the stoichiometry of Kv4.KChIP complex is variable, and the biophysical properties of Kv4 change depending on the number of bound KChIP subunits. PMID- 24811167 TI - The carboxyl-terminal tail of Noxa protein regulates the stability of Noxa and Mcl-1. AB - The BH3-only protein Noxa is a critical mediator of apoptosis and functions primarily by sequestering/inactivating the antiapoptotic Bcl-2 family protein Mcl 1. Although Noxa is a highly labile protein, recent studies suggested that it is degraded by the proteasome in a ubiquitylation-independent manner. In the present study, we investigated the mechanism of Noxa degradation and its ability to regulate the stability of Mcl-1. We found that the ubiquitylation-independent degradation of Noxa does not require a physical association with Mcl-1. A short stretch of amino acid residues in the C-terminal tail was found to mediate the proteasome-dependent degradation of Noxa. Ectopic placement of this degron was able to render other proteins unstable. Surprisingly, mutation of this sequence not only attenuated the rapid degradation of Noxa, but also stabilized endogenous Mcl-1 through the BH3-mediated direct interaction. Together, these results suggest that the C-terminal tail of Noxa regulates the stability of both Noxa and Mcl-1. PMID- 24811169 TI - FAD2 and FAD3 desaturases form heterodimers that facilitate metabolic channeling in vivo. AB - Plant desaturases comprise two independently evolved classes, a structurally well characterized soluble class responsible for the production of monoenes in the plastids of higher plants and the poorly structurally characterized integral membrane class that has members in the plastid and endoplasmic reticulum that are responsible for producing mono- and polyunsaturated fatty acids. Both require iron and oxygen for activity and are inhibited by azide and cyanide underscoring their common chemical imperatives. We previously showed that the Delta(9) acyl CoA integral membrane desaturase Ole1p from Saccharomyces cerevisiae exhibits dimeric organization, like the soluble plastidial acyl-ACP desaturases. Here we use two independent bimolecular complementation assays, i.e. yeast two-hybrid analysis and Arabidopsis leaf protoplast split luciferase assay, to demonstrate that members of the plant integral membrane fatty acid desaturase (FAD) family, FAD2, FAD3, FAD6, FAD7, and FAD8, self-associate. Further, the endoplasmic reticulum-localized desaturase FAD2 can associate with FAD3, as can the plastid localized FAD6 desaturase with either FAD7 or FAD8. These pairings appear to be specific because pairs such as FAD3 and FAD7 (or FAD8) and FAD2 and FAD6 do not interact despite their high amino acid similarity. These results are consistent also with their known endoplasmic reticulum and plastid subcellular localizations. Chemical cross-linking experiments confirm that FAD2 and FAD3 can form dimers like the yeast Ole1p and, when coexpressed, can form FAD2-FAD3 heterodimers. Metabolic flux analysis of yeast coexpressing FAD2 and FAD3 indicates that heterodimers can form a metabolic channel in which 18:1-PC is converted to 18:3-PC without releasing a free 18:2-PC intermediate. PMID- 24811168 TI - Cdh1, a substrate-recruiting component of anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, specifically interacts with phosphatase and tensin homolog (PTEN) and promotes its removal from chromatin. AB - A pool of PTEN localizes to the nucleus. However, the exact mechanism by which nuclear PTEN is regulated remains unclear. We have recently reported that Plk1 specifically phosphorylates PTEN on Ser-380 during mitosis. Here we report that PTEN also localized to chromatin and that chromatin PTEN was removed by a proteasome-dependent process during mitotic exit. Pulldown analysis revealed that Cdh1, but not Cdc20, was significantly associated with PTEN. Cdh1 interacted with PTEN via two separate domains, and their interaction was enhanced by MG132, a proteasome inhibitor. Cdh1 negatively controlled the stability of chromatin PTEN by polyubiquitination. Phosphorylation of PTEN on Ser-380 impaired its interaction with Cdh1, thus positively regulating PTEN stability on chromatin. Significantly, the PTEN interaction with Cdh1 was phosphatase-independent, and Cdh1 knockdown via RNAi led to significant accumulation of chromatin PTEN, delaying mitotic exit. Combined, our studies identify Cdh1 as an important regulator of nuclear/chromatin PTEN during mitosis. PMID- 24811170 TI - Steroid receptor coactivator-2 is a dual regulator of cardiac transcription factor function. AB - We have previously demonstrated the potential role of steroid receptor coactivator-2 (SRC-2) as a co-regulator in the transcription of critical molecules modulating cardiac function and metabolism in normal and stressed hearts. The present study seeks to extend the previous information by demonstrating SRC-2 fulfills this role by serving as a critical coactivator for the transcription and activity of critical transcription factors known to control cardiac growth and metabolism as well as in their downstream signaling. This knowledge broadens our understanding of the mechanism by which SRC-2 acts in normal and stressed hearts and allows further investigation of the transcriptional modifications mediating different types and degrees of cardiac stress. Moreover, the genetic manipulation of SRC-2 in this study is specific for the heart and thereby eliminating potential indirect effects of SRC-2 deletion in other organs. We have shown that SRC-2 is critical to transcriptional control modulated by MEF2, GATA-4, and Tbx5, thereby enhancing gene expression associated with cardiac growth. Additionally, we describe SRC-2 as a novel regulator of PPARalpha expression, thus controlling critical steps in metabolic gene expression. We conclude that through regulation of cardiac transcription factor expression and activity, SRC-2 is a critical transcriptional regulator of genes important for cardiac growth, structure, and metabolism, three of the main pathways altered during the cardiac stress response. PMID- 24811171 TI - Coregulator cell cycle and apoptosis regulator 1 (CCAR1) positively regulates adipocyte differentiation through the glucocorticoid signaling pathway. AB - Glucocorticoids contribute to adipocyte differentiation by cooperating with transcription factors, such as CCAAT/enhancer-binding protein beta (C/EBPbeta), to stimulate transcription of the gene encoding peroxisome proliferator-activated receptor (PPARgamma), a master regulator of adipogenesis. However, the mechanism of PPARgamma gene regulation by glucocorticoids, the glucocorticoid receptor (GR), and its coregulators is poorly understood. Here we show that two GR binding regions (GBRs) in the mouse PPARgamma gene were responsive to glucocorticoid, and treatment of 3T3-L1 preadipocytes with glucocorticoid alone induced GR occupancy and chromatin remodeling at PPARgamma GBRs, which also contain binding sites for C/EBP and PPARgamma proteins. GR recruited cell cycle and apoptosis regulator 1 (CCAR1), a transcription coregulator, to the PPARgamma gene GBRs. Notably, CCAR1 was required for GR occupancy and chromatin remodeling at one of the PPARgamma gene GBRs. Moreover, depletion of CCAR1 markedly suppressed differentiation of mouse mesenchymal stem cells and 3T3-L1 preadipocytes to mature adipocytes and decreased induction of PPARgamma, C/EBPalpha, and C/EBPdelta. Although CCAR1 was required for stimulation of several GR-regulated adipogenic genes in 3T3-L1 preadipocytes by glucocorticoid, it was not required for GR-activated transcription of certain anti-inflammatory genes in human A549 lung epithelial cells. Overall, our results highlighted the novel and specific roles of GR and CCAR1 in adipogenesis. PMID- 24811172 TI - Mutations in the X-linked intellectual disability gene, zDHHC9, alter autopalmitoylation activity by distinct mechanisms. AB - Early onset intellectual disabilities result in significant societal and economic costs and affect 1-3% of the population. The underlying genetic determinants are beginning to emerge and are interpreted in the context of years of work characterizing postsynaptic receptor and signaling functions of learning and memory. DNA sequence analysis of intellectual disability patients has revealed greater than 80 loci on the X-chromosome that are potentially linked to disease. One of the loci is zDHHC9, a gene encoding a Ras protein acyltransferase. Protein palmitoylation is a reversible modification that controls the subcellular localization and distribution of membrane receptors, scaffolds, and signaling proteins required for neuronal plasticity. Palmitoylation occurs in two steps. In the first step, autopalmitoylation, an enzyme-palmitoyl intermediate is formed. During the second step, the palmitoyl moiety is transferred to a protein substrate, or if no substrate is available, hydrolysis of the thioester linkage produces the enzyme and free palmitate. In this study, we demonstrate that two naturally occurring variants of zDHHC9, encoding R148W and P150S, affect the autopalmitoylation step of the reaction by lowering the steady state amount of the palmitoyl-zDHHC9 intermediate. PMID- 24811173 TI - Caerulomycin A enhances transforming growth factor-beta (TGF-beta)-Smad3 protein signaling by suppressing interferon-gamma (IFN-gamma)-signal transducer and activator of transcription 1 (STAT1) protein signaling to expand regulatory T cells (Tregs). AB - Cytokines play a very important role in the regulation of immune homeostasis. Regulatory T cells (Tregs) responsible for the generation of peripheral tolerance are under the tight regulation of the cytokine milieu. In this study, we report a novel role of a bipyridyl compound, Caerulomycin A (CaeA), in inducing the generation of Tregs. It was observed that CaeA substantially up-regulated the pool of Tregs, as evidenced by an increased frequency of CD4(+) Foxp3(+) cells. In addition, CaeA significantly suppressed the number of Th1 and Th17 cells, as supported by a decreased percentage of CD4(+)/IFN-gamma(+) and CD4(+)/IL-17(+) cells, respectively. Furthermore, we established the mechanism and observed that CaeA interfered with IFN-gamma-induced STAT1 signaling by augmenting SOCS1 expression. An increase in the TGF-beta-mediated Smad3 activity was also noted. Furthermore, CaeA rescued Tregs from IFN-gamma-induced inhibition. These results were corroborated by blocking Smad3 activity, which abolished the CaeA facilitated generation of Tregs. In essence, our results indicate a novel role of CaeA in inducing the generation of Tregs. This finding suggests that CaeA has enough potential to be considered as a potent future drug for the treatment of autoimmunity. PMID- 24811174 TI - A novel Ste20-related proline/alanine-rich kinase (SPAK)-independent pathway involving calcium-binding protein 39 (Cab39) and serine threonine kinase with no lysine member 4 (WNK4) in the activation of Na-K-Cl cotransporters. AB - Na(+)-dependent chloride cotransporters (NKCC1, NKCC2, and NCC) are activated by phosphorylation to play critical roles in diverse physiological responses, including renal salt balance, hearing, epithelial fluid secretion, and volume regulation. Serine threonine kinase WNK4 (With No K = lysine member 4) and members of the Ste20 kinase family, namely SPAK and OSR1 (Ste20-related proline/alanine-rich kinase, Oxidative stress-responsive kinase) govern phosphorylation. According to present understanding, WNK4 phosphorylates key residues within SPAK/OSR1 leading to kinase activation, allowing SPAK/OSR1 to bind to and phosphorylate NKCC1, NKCC2, and NCC. Recently, the calcium-binding protein 39 (Cab39) has emerged as a binding partner and enhancer of SPAK/OSR1 activity, facilitating kinase autoactivation and promoting phosphorylation of the cotransporters. In the present study, we provide evidence showing that Cab39 differentially interacts with WNK4 and SPAK/OSR1 to switch the classic two kinase cascade into a signal kinase transduction mechanism. We found that WNK4 in association with Cab39 activates NKCC1 in a SPAK/OSR1-independent manner. We discovered that WNK4 possesses a domain that bears close resemblance to the SPAK/OSR1 C-terminal CCT/PF2 domain, which is required for physical interaction between the Ste20 kinases and the Na(+)-driven chloride cotransporters. Modeling, yeast two-hybrid, and functional data reveal that this PF2-like domain located downstream of the catalytic domain in WNK4 promotes the direct interaction between the kinase and NKCC1. We conclude that in addition to SPAK and OSR1, WNK4 is able to anchor itself to the N-terminal domain of NKCC1 and to promote cotransporter activation. PMID- 24811175 TI - Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3beta to regulate aerobic glycolysis. AB - Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. To determine the contribution of Irs-2 dependent PI3K signaling to this selective regulation, we generated an Irs-2 mutant deficient in the recruitment of PI3K. We identified four tyrosine residues (Tyr-649, Tyr-671, Tyr-734, and Tyr-814) that are essential for the association of PI3K with Irs-2 and demonstrate that combined mutation of these tyrosines inhibits glucose uptake and lactate production, two measures of aerobic glycolysis. Irs-2-dependent activation of PI3K regulates the phosphorylation of specific Akt substrates, most notably glycogen synthase kinase 3beta (Gsk-3beta). Inhibition of Gsk-3beta by Irs-2-dependent PI3K signaling promotes glucose uptake and aerobic glycolysis. The regulation of unique subsets of Akt substrates by Irs 1 and Irs-2 may explain their non-redundant roles in mammary tumor biology. Taken together, our study reveals a novel mechanism by which Irs-2 signaling preferentially regulates tumor cell metabolism and adds to our understanding of how this adaptor protein contributes to breast cancer progression. PMID- 24811176 TI - A splicing variant of NME1 negatively regulates NF-kappaB signaling and inhibits cancer metastasis by interacting with IKKbeta. AB - IKKbeta functions as a principal upstream activator of the canonical NF-kappaB pathway by phosphorylating IkappaB, leading to its proteasomal degradation. Because IKKbeta is considered a therapeutic target, understanding its regulation may facilitate the design of efficient regulators of this molecule. Here, we report a novel IKKbeta-interacting molecule, NME1L, a splicing variant of the NME1 protein. NME1 has attracted attention in cancer research because of its antimetastatic activity and reduced expression in multiple aggressive types of cancer. However, the effect was just moderate but not dramatic in anti-cancer activities. We found that only NME1L interacts with IKKbeta. Exogenous expression of NME1L resulted in a potent decrease in TNFalpha-stimulated NF-kappaB activation, whereas knockdown of NME1/NME1L with shRNA enhanced activity of NF kappaB. NME1L down-regulates IKKbeta signaling by blocking IKKbeta-mediated IkappaB degradation. When NME1L was introduced into highly metastatic HT1080 cells, the mobility was efficiently inhibited. Furthermore, in a metastasis assay, NME1L-expressing cells did not colonize the lung. Based on these results, NME1L is a potent antimetastatic protein and may be a useful weapon in the fight against cancers. PMID- 24811177 TI - Serum- and glucocorticoid-induced protein kinase 1 (SGK1) increases the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells by phosphorylating Shank2E protein. AB - The glucocorticoid dexamethasone increases cystic fibrosis transmembrane conductance regulator (CFTR) abundance in human airway epithelial cells by a mechanism that requires serum- and glucocorticoid-induced protein kinase 1 (SGK1) activity. The goal of this study was to determine whether SGK1 increases CFTR abundance by phosphorylating Shank2E, a PDZ domain protein that contains two SGK1 phosphorylation consensus sites. We found that SGK1 phosphorylates Shank2E as well as a peptide containing the first SGK1 consensus motif of Shank2E. The dexamethasone-induced increase in CFTR abundance was diminished by overexpression of a dominant-negative Shank2E in which the SGK1 phosphorylation sites had been mutated. siRNA-mediated reduction of Shank2E also reduced the dexamethasone induced increase in CFTR abundance. Taken together, these data demonstrate that the glucocorticoid-induced increase in CFTR abundance requires phosphorylation of Shank2E at an SGK1 consensus site. PMID- 24811178 TI - Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation. AB - Lipin 2 is a phosphatidic acid phosphatase (PAP) responsible for the penultimate step of triglyceride synthesis and dephosphorylation of phosphatidic acid (PA) to generate diacylglycerol. The lipin family of PA phosphatases is composed of lipins 1-3, which are members of the conserved haloacid dehalogenase superfamily. Although genetic alteration of LPIN2 in humans is known to cause Majeed syndrome, little is known about the biochemical regulation of its PAP activity. Here, in an attempt to gain a better general understanding of the biochemical nature of lipin 2, we have performed kinetic and phosphorylation analyses. We provide evidence that lipin 2, like lipin 1, binds PA via the electrostatic hydrogen bond switch mechanism but has a lower rate of catalysis. Like lipin 1, lipin 2 is highly phosphorylated, and we identified 15 phosphosites. However, unlike lipin 1, the phosphorylation of lipin 2 is not induced by insulin signaling nor is it sensitive to inhibition of the mammalian target of rapamycin. Importantly, phosphorylation of lipin 2 does not negatively regulate either membrane binding or PAP activity. This suggests that lipin 2 functions as a constitutively active PA phosphatase in stark contrast to the high degree of phosphorylation-mediated regulation of lipin 1. This knowledge of lipin 2 regulation is important for a deeper understanding of how the lipin family functions with respect to lipid synthesis and, more generally, as an example of how the membrane environment around PA can influence its effector proteins. PMID- 24811179 TI - Brain-derived neurotrophic factor (BDNF) induces sustained intracellular Ca2+ elevation through the up-regulation of surface transient receptor potential 3 (TRPC3) channels in rodent microglia. AB - Microglia are immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO), and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) is important for microglial functions such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we sought to examine the underlying mechanism of BDNF-induced sustained increase in [Ca(2+)]i in rodent microglial cells. We observed that canonical transient receptor potential 3 (TRPC3) channels contribute to the maintenance of BDNF-induced sustained intracellular Ca(2+) elevation. Immunocytochemical technique and flow cytometry also revealed that BDNF rapidly up-regulated the surface expression of TRPC3 channels in rodent microglial cells. In addition, pretreatment with BDNF suppressed the production of NO induced by tumor necrosis factor alpha (TNFalpha), which was prevented by co-adiministration of a selective TRPC3 inhibitor. These suggest that BDNF induces sustained intracellular Ca(2+) elevation through the up-regulation of surface TRPC3 channels and TRPC3 channels could be important for the BDNF-induced suppression of the NO production in activated microglia. We show that TRPC3 channels could also play important roles in microglial functions, which might be important for the regulation of inflammatory responses and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders. PMID- 24811181 TI - Letter from the editor in chief. PMID- 24811180 TI - Oligomerization inhibits Legionella pneumophila PlaB phospholipase A activity. AB - The intracellularly replicating lung pathogen Legionella pneumophila consists of an extraordinary variety of phospholipases, including at least 15 different phospholipases A (PLA). Among them, PlaB, the first characterized member of a novel lipase family, is a hemolytic virulence factor that exhibits the most prominent PLA activity in L. pneumophila. We analyzed here protein oligomerization, the importance of oligomerization for activity, addressed further essential regions for activity within the PlaB C terminus, and the significance of PlaB-derived lipolytic activity for L. pneumophila intracellular replication. We determined by means of analytical ultracentrifugation and small angle x-ray scattering analysis that PlaB forms homodimers and homotetramers. The C-terminal 5, 10, or 15 amino acids, although the individual regions contributed to PLA activity, were not essential for protein tetramerization. Infection of mouse macrophages with L. pneumophila wild type, plaB knock-out mutant, and plaB complementing or various mutated plaB-harboring strains showed that catalytic activity of PlaB promotes intracellular replication. We observed that PlaB was most active in the lower nanomolar concentration range but not at or only at a low level at concentration above 0.1 MUm where it exists in a dimer/tetramer equilibrium. We therefore conclude that PlaB is a virulence factor that, on the one hand, assembles in inactive tetramers at micromolar concentrations. On the other hand, oligomer dissociation at nanomolar concentrations activates PLA activity. Our data highlight the first example of concentration-dependent phospholipase inactivation by tetramerization, which may protect the bacterium from internal PLA activity, but enzyme dissociation may allow its activation after export. PMID- 24811182 TI - Recent advances in nerve tissue engineering. AB - Nerve injury secondary to trauma, neurological disease or tumor excision presents a challenge for surgical reconstruction. Current practice for nerve repair involves autologous nerve transplantation, which is associated with significant donor-site morbidity and other complications. Previously artificial nerve conduits made from polycaprolactone, polyglycolic acid and collagen were approved by the FDA (USA) for nerve repair. More recently, there have been significant advances in nerve conduit design that better address the requirements of nerve regrowth. Innovations in materials science, nanotechnology, and biology open the way for the synthesis of new generation nerve repair conduits that address issues currently faced in nerve repair and regeneration. This review discusses recent innovations in this area, including the use of nanotechnology to improve the design of nerve conduits and to enhance nerve regeneration. PMID- 24811183 TI - The dialysis staff workload and the blood volume tracking system during the hemodialysis sessions of hypotension-prone patients. AB - PURPOSE: Intradialytic hypotension (IDH) represents a common hemodialysis (HD) complication. Blood volume tracking (BVT) is a tool regulating the relative blood volume changes and potentially reducing the occurrence of IDH. The aim of this study was to evaluate the ability of BVT to reduce the staff workload associated to IDH. METHODS: Ten hypotension-prone HD patients were treated each with 39 conventional HD (HD) sessions and then switched to 39 HD sessions with BVT (HD BVT). The staff interventions related to IDH were monitored by a trained staff. RESULTS: Dialysis sessions complicated by IDH and staff interventions were affected by BVT (HD: 102 and 127 vs. HD-BVT: 57 and 59, respectively, for both p<0.001). The time consumed by staff in IDH management was decreased by HD-BVT (1416 vs. 578 min, p<0.001). CONCLUSIONS: The effectiveness of BVT to reduce the frequency of IDH leads to a reduction of the dialysis staff workload with fewer staff interventions, allowing for major work-time saving. PMID- 24811184 TI - Endotoxin adsorption using polymyxin B immobilized fiber cartridges in severe sepsis patients following cardiac surgery. AB - INTRODUCTION: Sepsis still represents an obstacle in modern medicine. The purpose of this study was to evaluate the safety and effectiveness of selective lipopolysaccharide (LPS)-adsorption therapy using polymyxin B immobilized fiber cartridges in adult patients complicated with severe sepsis after cardiac surgery. METHODS: 65 patients received extracorporeal LPS-adsorption procedures using Toraymyxin columns (PMX; Toray, Tokyo, Japan) in addition to the standard treatment according to the Surviving Sepsis Campaign guidelines. The inclusion criteria were clinical signs of severe sepsis, endotoxin activity assay (EAA)>=0.6, and blood plasma procalcitonin (PCT)>2 ng/ml. For the control group, we selected 40 patients who were comparable with the study group but who received only the standard therapy. RESULTS: Each patient received 2 standard LPS adsorption procedures (lasting for 120 min each). After the LPS-adsorption course, we noted any indices of hemodynamic improvements, including an increase in mean arterial pressure from 73 to 89 mmHg (p<0.001), mean oxygenation index (213-265, p<0.001. We observed a decrease in LPS concentrations by the EAA (0.71 0.55, p<0.001) and by the LAL test (1.44-0.36 EU/ml, p<0.001). In the control group, there were no significant changes in any of the studied parameters. Moreover, the 28-day mortality was 42% in the study group and 65% in the control group (p=0.032). The endotoxin adsorption procedures were not associated with any adverse reactions, and specifically, no extracorporeal circuit thrombosis cases were noted. CONCLUSIONS: Selective LPS-adsorption is a safe and possibly effective adjunctive treatment method for severe sepsis patients. PMID- 24811185 TI - First impressions of cardiovascular calcification treatment in hemodialysis patients with a new dialysis fluid containing sodium thiosulphate (STS). AB - BACKGROUND: Cardiovascular calcification (CVC) in hemodialysis patients (HDP) causes cardiovascular pathology. Up until now very few drugs and therapeutic interventions have been able to reduce cardiovascular calcium deposits in hemodialysis patients and the process requires more than a year. Our idea in this study was to test 2 calcium binders--sodium thiosulfate (STS) and dinatrium ethylene diamine tetraacetic acid (DNEDTA)--for prevention and treatment of cardiovascular calcification of hemodialysis patients, using both substances not as an intravenous infusion but by adding them to the liquid bicarbonate part of the dialysis fluid. MATERIAL AND METHODS: 6 HDPs were treated with sodium thiosulphate (STS), 6 with dinatrium ethylene diamine tetraacetic acid (DNEDTA), and 6 patients served as controls. Electrolytes, liver function, markers of inflammation, oxidative stress, bone metabolism, spiral computed tomography (SCT) of coronary CVC and bone densitometry were performed twice (start and end of the study). RESULTS: Starting blood parameters were similar to the end (STS group). No toxic or side effects from STS were observed. Initially in the DNEDTA group all the patients had vomiting so we excluded DNEDTA from the study. SCT found a significant reduction of calcification in 4 patients (STS group) and retardation in 2 patients comparatively to controls. CONCLUSIONS: The first results are hopeful, but the number of the patients was small, so we are enlarging the enrollment in the expectation of corroborating our results soon. PMID- 24811186 TI - In vitro study of a standardized approach to aortic cusp extension. AB - PURPOSE: Cusp extension technique (CET) is a reparative surgical procedure for restoring aortic valve function by suturing patches to the compromised native leaflets. Its outcomes are strongly dependent on the ability of the surgeon. We proposed and tested a novel approach on an in vitro model, aimed at standardizing and simplifying the surgical procedure. METHODS: A set of standard pre-cut bovine pericardium patches, available in different sizes, was developed. The surgeon can choose the leaflet-specific patches to be implanted according to the patient anatomy, using a geometrical model of the aortic valve whose inputs are the measured intercommissural distances. The hemodynamic performance of this approach was evaluated on porcine aortic roots in a pulsatile mock loop. Hydrodynamic and kinematic evaluation of the samples was provided. RESULTS: After CET, mean and maximum pressure drops were 3.1+/-1.3 mmHg and 25.4+/-5.0 mmHg respectively, and EOA was 3.8+/-0.8 cm. CONCLUSIONS: Our approach to cusp extension proved to be reliable and effective in restoring valve functioning, without significantly altering the physiological kinematics. The use of pre-cut patches considerably simplified the surgery, increasing standardization and repeatability. PMID- 24811187 TI - In vitro study of hemodynamic treatment improvement: Hunterian ligation of a fenestrated basilar artery aneurysm after coiling. AB - Hunterian ligation affecting hemodynamics in vessels was proposed to avoid rebleeding in a case of a fenestrated basilar artery aneurysm after incomplete coil occlusion. We studied the hemodynamics in vitro to predict the hemodynamic changes near the aneurysm remnant caused by Hunterian ligation. A transparent model was fabricated based on three-dimensional rotational angiography imaging. Arteries were segmented and reconstructed. Pulsatile flow in the artery segments near the partially occluded (coiled) aneurysm was investigated by means of particle image velocimetry. The hemodynamic situation was investigated before and after Hunterian ligation of either the left or the right vertebral artery (LVA/RVA). Since post-ligation flow rate in the basilar artery was unknown, reduced and retained flow rates were simulated for both ligation options. Flow in the RVA and in the corresponding fenestra vessel is characterized by a vortex at the vertebrobasilar junction, whereas the LVA exhibits undisturbed laminar flow. Both options (RVA or LVA ligation) cause a significant flow reduction near the aneurysm remnant with a retained flow rate. The impact of RVA ligation is, however, significantly higher. This in vitro case study shows that flow reduction near the aneurysm remnant can be achieved by Hunterian ligation and that this effect depends largely on the selection of the ligated vessel. Thus the ability of the proposed in vitro pipe-line to improve hemodynamic impact of the proposed therapy was successfully proved. PMID- 24811188 TI - Knowledge of the brain death concept by personnel in Spanish and Latin-American healthcare centers. AB - BACKGROUND: The knowledge and acceptance of the concept of brain death (BD) among health care personnel is fundamental. OBJECTIVE: To analyze the level of understanding of the BD concept among personnel in Spanish and Latin American healthcare centers and to determine the factors affecting this attitude. MATERIAL AND METHODS: Data from 12 hospitals and 32 primary care centers in 4 countries within the International Collaborative Donor Project were selected (Spain, Mexico, Cuba and Costa Rica (n=4378)). RESULTS: 62% of the personnel (n=2714) understood BD and believed that this was the death of an individual. Of the rest, 30% (n=1333) did not understand it and the remaining 8% (n=331) believed it did not mean the death of a patient. 83% (n=931) of physicians understood BD, compared to 75% (n=895) of nurses, 55% (n=299) of healthcare assistants, 53% (n=108) of non-healthcare university-educated personnel and 36% (n=481) of those without a university education (p<0.001). 68% (n=1084) of Mexicans understood BD compared to 66% (n=134) of Cubans, 58% (n=1411) of Spaniards, and 52% (n=85) (p<0.001) of Costa Ricans. There were significant relationships between knowledge of the concept and the following: type of healthcare center (p<0.001), clinical service (p<0.001), having spoken about organ donation within the family (p<0.001) and one's partner's attitude to the subject (p<0.001). A direct relationship has been found between understanding the concept and attitude toward deceased donation (p<0.001). CONCLUSIONS: The understanding of BD by personnel from healthcare centers was not as good as expected. There were marked differences depending on job category. PMID- 24811189 TI - A review of conceptualisation of expressed emotion in caregivers of older adults with dementia. AB - AIMS AND OBJECTIVES: To clarify the concept of 'expressed emotion' and its application to caregivers of older adults with dementia. BACKGROUND: Expressed emotion has been a useful construct for understanding the quality of family relationships affecting patients with mental illness and their caregivers. However, this concept has been developed without precisely defining 'expressed emotion' as it pertains to dementia patients. Clarity regarding expressed emotion will enable nurses to apply knowledge of expressed emotion and provide important information for the development of new clinical interventions for this specific population. DESIGN: Integrative review. METHODS: A review of literature on expressed emotion by caregivers of older adults with dementia. The inclusion criteria were: (1) published in English or Chinese during 1970-2012; (2) included both research and theoretical review articles on expressed emotion in nursing and other disciplines such as psychology, psychiatry and sociology. Initially, 236 articles were screened, and finally, 32 articles were evaluated for this review. RESULTS: Emotional expression and expressed emotion were discussed to clarify the distinctions and address overlap between these two similar terms. In addition, expressed emotion was examined further from three different aspects: trait or state, social control and cross-cultural. Finally, the results of reviewed papers for expressed emotion on dementia patients were explored and synthesised. CONCLUSION: A conceptual definition and a theoretical framework for the concept of expressed emotion are urgently needed to further our understanding of this critical phenomenon. With increasing attention to caregiving for patients with dementia, including the concept of expressed emotion in the research of this field may accelerate understanding of the importance of the family dynamics in advanced ageing caregiving. RELEVANCE TO CLINICAL PRACTICE: The expressed emotion concept could guide much of current clinical practice and help professional nurses understand the family's experience and perspective on mental illness, especially regarding dementia within the family. PMID- 24811191 TI - Rock-salt-type lithium metal sulphides as novel positive-electrode materials. AB - One way of increasing the energy density of lithium-ion batteries is to use electrode materials that exhibit high capacities owing to multielectron processes. Here, we report two novel materials, Li2TiS3 and Li3NbS4, which were mechanochemically synthesised at room temperature. When used as positive electrode materials, Li2TiS3 and Li3NbS4 charged and discharged with high capacities of 425 mA h g(-1) and 386 mA h g(-1), respectively. These capacities correspond to those resulting from 2.5- and 3.5-electron processes. The average discharge voltage was approximately 2.2 V. It should be possible to prepare a number of high-capacity materials on the basis of the concept used to prepare Li2TiS3 and Li3NbS4. PMID- 24811190 TI - Tricompartmental resurfacing arthroplasty with a follow-up of more than 30 years. AB - BACKGROUND: Unicompartmental and patellofemoral joint replacements are proven solutions for arthritis limited to one compartment of the knee. Bicompartmental replacement has been considered lately as an alternative for combined medial and patellofemoral arthritis. The main idea behind these resurfacing solutions is tissue preservation with conservation of bone stock and both cruciate ligaments. Tricompartmental replacement with selective resurfacing of all three compartments with different modular implants is exceptional. METHODS: The authors present a case with more than thirty year follow-up both clinically and radiographically. RESULTS: Excellent function and patient satisfaction are observed at 30 year follow-up. Radiographs show no osteolysis or loosening of components. CONCLUSIONS: Conservation of both anterior and posterior cruciate ligaments seems to protect against polyethylene wear at long-term follow-up. LEVEL OF EVIDENCE: IV. PMID- 24811192 TI - Cholesterol aided etching of tomatine gold nanoparticles: a non-enzymatic blood cholesterol monitor. AB - Colloidal gold is extensively used for molecular sensing because of the wide flexibilities it offers in terms of modifications of the gold nanoparticles (GNPs) surface with a variety of functional groups. We describe a simple, enzyme free assay for the detection of cholesterol, and demonstrate its applicability by estimating cholesterol in human serum samples. To enable cholesterol detection, we functionalized GNPs with tomatine, a glycoalkaloid found in the leaves and stem of tomato plants. The binding of cholesterol onto tomatine functionalized gold nanoparticles (TGNPs) was characterized by a blue shift in the plasmon absorption spectra (SPR) followed by reduction in the particle size. The TGNPs have been core etched with increasing concentration of cholesterol and with 800 ng/mL of cholesterol particles in the size range of 10-12 nm have been obtained. This behavior was attributed to the enhanced hydrophobicity of the surface acquired by cholesterol binding resulting in the folding or shrinkage of molecule in turn leading to core etching. The method was successfully applied for the detection of cholesterol in real samples and agrees well with values obtained from the conventional method. Because of its significant plasmonic shift and simplicity, this biosensor could be used for cholesterol detection as it does not demand either any hazardous and costly chemicals or any complex synthetic routes. PMID- 24811193 TI - A highly sensitive microRNA biosensor based on hybridized microRNA-guided deposition of polyaniline. AB - On the basis of hybridized microRNA (miRNA)-guided deposition of polyaniline (PAn), a highly sensitive impedimetric miRNA biosensor is developed in this report. Briefly, a gold electrode coated with charge neutral peptide nucleic acid (PNA) capture probes (CPs) is first hybridized to a target miRNA. After a very brief rinsing the hybridized electrode is incubated in pH 3.0 of 0.10 M potassium phosphate buffer-based cocktail containing aniline, H2O2, and a G-qudraplex-hemin DNAzyme. The DNAzyme catalyzes the polymerization of aniline and the hybridized miRNA strands guide the deposition of PAn, thus resulting in the formation of a thin PAn film on the biosensor surface. Electron-transfer impeding power of the PAn film in alkaline medium is utilized to determine the concentration of the target miRNA. Under optimized experimental conditions, 0.50 fM target miRNA is successfully detected. Excellent mismatch discrimination capability of the biosensor was observed largely due to the excellent hybridization selectivity of the PNA CPs. Attempts were made in profiling miRNAs in total RNA samples extracted from cancer cells and blood. PMID- 24811194 TI - Characterization of a bacterial tyrosine kinase in Porphyromonas gingivalis involved in polymicrobial synergy. AB - Interspecies communication between Porphyromonas gingivalis and Streptococcus gordonii underlies the development of synergistic dual species communities. Contact with S. gordonii initiates signal transduction within P. gingivalis that is based on protein tyrosine (de)phosphorylation. In this study, we characterize a bacterial tyrosine (BY) kinase (designated Ptk1) of P. gingivalis and demonstrate its involvement in interspecies signaling. Ptk1 can utilize ATP for autophosphorylation and is dephosphorylated by the P. gingivalis tyrosine phosphatase, Ltp1. Community development with S. gordonii is severely abrogated in a ptk1 mutant of P. gingivalis, indicating that tyrosine kinase activity is required for maximal polymicrobial synergy. Ptk1 controls the levels of the transcriptional regulator CdhR and the fimbrial adhesin Mfa1 which mediates binding to S. gordonii. The ptk1 gene is in an operon with two genes involved in exopolysaccharide synthesis, and similar to other BY kinases, Ptk1 is necessary for exopolysaccharide production in P. gingivalis. Ptk1 can phosphorylate the capsule related proteins PGN_0224, a UDP-acetyl-mannosamine dehydrogenase, and PGN_0613, a UDP-glucose dehydrogenase, in P. gingivalis. Knockout of ptk1 in an encapsulated strain of P. gingivalis resulted in loss of capsule production. Collectively these results demonstrate that the P. gingivalis Ptk1 BY kinase regulates interspecies communication and controls heterotypic community development with S. gordonii through adjusting the levels of the Mfa1 adhesin and exopolysaccharide. PMID- 24811195 TI - The effect of practice on random number generation task: a transcranial direct current stimulation study. AB - Random number generation (RNG) is a procedurally-simple task related to specific executive functions, such as updating and monitoring of information and inhibition of automatic responses. The effect of practice on executive functions has been widely investigated, however little is known on the impact of practice on RNG. Transcranial direct current stimulation (tDCS) allows to modulate, non invasively, brain activity and to enhance the effects of training on executive functions. Hence, this study aims to investigate the effect of practice on RNG and to explore the possibility to influence it by tDCS applied over dorsolateral prefrontal cortex. Twenty-six healthy volunteers have been evaluated within single session and between different sessions of RNG using several measures of randomness, which are informative of separable cognitive components servicing random behavior. We found that repetition measures significantly change within single session, seriation measures significantly change both within and between sessions, while cycling measures are not affected by practice. tDCS does not produce any additional effect, however a sub-analysis limited to the first session revealed an increasing trend in seriation measure after anodal compared to cathodal stimulation. Our findings support the hypothesis that practice selectively and consistently influences specific cognitive components related to random behavior, while tDCS transiently affects RNG performance. PMID- 24811196 TI - Evolution of direct costs in the first years of rheumatoid arthritis: impact of early versus late biologic initiation--an economic analysis based on the ESPOIR cohort. AB - OBJECTIVES: To estimate annual direct costs of early RA by resource component in an inception cohort, with reference to four distinct treatment strategies: no disease modifying antirheumatic drugs (DMARDs), synthetic DMARDs only, biologic DMARDs in the first year ('first-year biologic', FYB), and biologic DMARDs from the second year after inclusion ('later-year biologic', LYB); to determine predictors of total and non-DMARD related costs. METHODS: The ESPOIR cohort is a French multicentric, prospective study of 813 patients with early arthritis. Data assessing RA-related resource utilisation and disease characteristics were collected at baseline, biannually during the first two years and annually thereafter. Costs predictors were determined by generalised linear mixed analyses. RESULTS: Over the 4-year follow-up, mean annual direct total costs per treatment strategy group were ?3,612 for all patients and ?998, ?1,922, ?14,791, ?8,477 respectively for no DMARDs, synthetic DMARDs only, FYB and LYB users. The main predictors of higher costs were biologic use and higher Health Assessment Questionnaire (HAQ) scores at baseline. Being a biologic user led to a higher total cost (FYB Rate Ratio (RR) 7.22, [95% CI 5.59-9.31]; LYB RR 4.39, [95% CI 3.58-5.39]) compared to non-biologic users. Only LYB increased non-DMARD related costs compared to all other patients by 60%. CONCLUSIONS: FYB users incurred the highest levels of total costs, while their non-DMARD related costs remained similar to non-biologic users, possibly reflecting better RA control. PMID- 24811198 TI - From the phenomenology to the mechanisms of consciousness: Integrated Information Theory 3.0. AB - This paper presents Integrated Information Theory (IIT) of consciousness 3.0, which incorporates several advances over previous formulations. IIT starts from phenomenological axioms: information says that each experience is specific--it is what it is by how it differs from alternative experiences; integration says that it is unified--irreducible to non-interdependent components; exclusion says that it has unique borders and a particular spatio-temporal grain. These axioms are formalized into postulates that prescribe how physical mechanisms, such as neurons or logic gates, must be configured to generate experience (phenomenology). The postulates are used to define intrinsic information as "differences that make a difference" within a system, and integrated information as information specified by a whole that cannot be reduced to that specified by its parts. By applying the postulates both at the level of individual mechanisms and at the level of systems of mechanisms, IIT arrives at an identity: an experience is a maximally irreducible conceptual structure (MICS, a constellation of concepts in qualia space), and the set of elements that generates it constitutes a complex. According to IIT, a MICS specifies the quality of an experience and integrated information PhiMax its quantity. From the theory follow several results, including: a system of mechanisms may condense into a major complex and non-overlapping minor complexes; the concepts that specify the quality of an experience are always about the complex itself and relate only indirectly to the external environment; anatomical connectivity influences complexes and associated MICS; a complex can generate a MICS even if its elements are inactive; simple systems can be minimally conscious; complicated systems can be unconscious; there can be true "zombies"--unconscious feed-forward systems that are functionally equivalent to conscious complexes. PMID- 24811199 TI - Drought-tolerance of wheat improved by rhizosphere bacteria from harsh environments: enhanced biomass production and reduced emissions of stress volatiles. AB - Water is the key resource limiting world agricultural production. Although an impressive number of research reports have been published on plant drought tolerance enhancement via genetic modifications during the last few years, progress has been slower than expected. We suggest a feasible alternative strategy by application of rhizospheric bacteria coevolved with plant roots in harsh environments over millions of years, and harboring adaptive traits improving plant fitness under biotic and abiotic stresses. We show the effect of bacterial priming on wheat drought stress tolerance enhancement, resulting in up to 78% greater plant biomass and five-fold higher survivorship under severe drought. We monitored emissions of seven stress-related volatiles from bacterially-primed drought-stressed wheat seedlings, and demonstrated that three of these volatiles are likely promising candidates for a rapid non-invasive technique to assess crop drought stress and its mitigation in early phases of stress development. We conclude that gauging stress by elicited volatiles provides an effectual platform for rapid screening of potent bacterial strains and that priming with isolates of rhizospheric bacteria from harsh environments is a promising, novel way to improve plant water use efficiency. These new advancements importantly contribute towards solving food security issues in changing climates. PMID- 24811200 TI - Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness. AB - The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G0/G1 and 70% in S/G2/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Similarly, approximately 75% of cancer cells far from (> 100 um) tumor blood vessels of an established tumor are in G0/G1. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G2/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed. PMID- 24811201 TI - Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: a randomized controlled trial. AB - BACKGROUND: A double-blind RCT on the short-term efficacy of nicotine patches compared to placebo patches among Dutch adolescents was conducted. The findings demonstrated that nicotine patches are efficacious for smoking cessation at end of-treatment; however, only in highly compliant participants. We tested whether the effects of NRT also held in 6- (T7) and 12-month (T8) follow-up assessments. METHODS: Adolescents aged 12-18 years, who smoked at least seven cigarettes a day and who were motivated to quit smoking were recruited at school yards and randomly assigned to either a nicotine patch (n=182) or a placebo patch (n=180) condition according to a computer generated list. Participants (N=257, age: 16.7 +/- 1.13 years) attended an information meeting followed by a 6- or 9-week treatment. Smoking cessation, compliance, and potential covariates were measured by means of online questionnaires. Smoking cessation at T8 was biochemically validated by saliva cotinine. RESULTS: At T7, 8.1% and 5.7% of participants were abstinent in the nicotine and placebo patch groups, respectively. At T8, abstinence was 4.4% and 6.6%, respectively. Intention-to-treat analyses showed no significant effects of NRT on abstinence rates at T7 (OR=1.54, 95% CI=0.57, 4.16) and validated abstinence rates at T8 (OR=0.64, 95% CI=0.21, 1.93) neither after considering compliance nor after adjusting for covariates. CONCLUSIONS: NRT fails in helping adolescents quit smoking at 6- and 12-month follow-ups. This finding suggests that a more intensive approach is needed to assist youngsters in their quit attempts. PMID- 24811202 TI - Pilot randomized controlled trial of an internet-based smoking cessation intervention for pregnant smokers ('MumsQuit'). AB - BACKGROUND: Internet-based Smoking Cessation Interventions could help pregnant women quit smoking, especially those who do not wish to, or cannot, access face to-face or telephone support. This study aimed to preliminarily evaluate the effectiveness and usage of a fully automated smoking cessation website targeted to pregnancy, 'MumsQuit', and obtain an initial effect-size estimate for a full scale trial. METHODS: We recruited 200 UK-based pregnant adult smokers online to a two-arm double-blind pilot RCT assessing the effectiveness of MumsQuit compared with an information-only website. MumsQuit was adapted from a generic internet smoking cessation intervention, 'StopAdvisor'. The primary outcome was self reported continuous 4-week abstinence assessed at 8 weeks post-baseline. Secondary outcomes were automatically collected data on intervention usage. RESULTS: Participants smoked 15 cigarettes per day on average, 73% were in the first trimester of their pregnancy, 48% were from lower socioeconomic backgrounds, and 43% had never used evidence-based cessation support. The point estimate of odds ratio for the primary outcome was 1.5 (95% CI=0.8-2.9; 28% vs. 21%). Compared with control participants, those in the MumsQuit group logged in more often (3.5 vs. 1.3, p<0.001), viewed more pages (67.4 vs. 5.7, p<0.001) and spent more time browsing the website (21.3min vs. 1.0min, p<0.001). CONCLUSIONS: MumsQuit is an engaging and potentially helpful form of support for pregnant women who seek cessation support online, and merits further development and evaluation in a full-scale RCT. PMID- 24811204 TI - Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle and lung of a patient with rheumatoid arthritis. AB - We report an extremely rare case of massive methotrexate-associated lymphoproliferative disorder (MTX-LPD) arising in the retromolar triangle and lung of a patient with rheumatoid arthritis. The patient was a 75-year-old woman who was referred to our department because of severe pain associated with a unilateral ulcer on the left retromolar triangle. The tumor had an extranodal location in the retromolar triangle and in the right lung. A clinicopathologic examination found a lymphocytic infiltrate with increasingly atypical histopathologic features. Atypical large cells were strongly positive in Epstein Barr virus-encoded small RNA in situ hybridization and in staining with CD20 antibodies. MTX-LPD was diagnosed based on the medical history and histopathologic results. The lesion responded well to withdrawal of MTX followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. There have been no signs of recurrence for 4 years since withdrawal of MTX. PMID- 24811203 TI - Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown. METHODS: To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post natal day 28-55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule. RESULTS: Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains. CONCLUSIONS: The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD. PMID- 24811205 TI - The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry. AB - Here we describe a structure-function analysis of the cell-penetrating peptide Xentry derived from the X-protein of the hepatitis B virus. Remarkably, the tetrapeptide core LCLR retains the cell-penetrating ability of the parental peptide LCLRPVG, as either an L- or D-enantiomer. Substitution of the cysteine with leucine revealed that the cysteine is essential for activity. In contrast, the C-terminal arginine could be substituted in the L-isomer with lysine, histidine, glutamic acid, glutamine, and asparagine, though the resulting peptides displayed distinct cell-type-specific uptake. Substitution of the leucines in the D-isomer with other hydrophobic residues revealed that leucines are optimal for activity. Surprisingly, linear di- and tetra-peptide forms of Xentry are not cell-permeable. Protease-activatable forms of Xentry were created by fusing Xentry to itself via a protease-cleavable peptide, or by attaching a heparin mimic peptide to the N-terminus. These novel activatable forms of Xentry were only taken up by MCF-7 cells after cleavage by matrix metalloproteinase 9, and could be used to deliver drugs specifically to tumours. PMID- 24811206 TI - Role of Fc in antibody-mediated protection from ricin toxin. AB - We have studied the role of the antibody (Ab) Fc region in mediating protection from ricin toxicity. We compared the in vitro and in vivo effects of intact Ig and of Fab fragments derived from two different neutralizing Ab preparations, one monoclonal, the other polyclonal. Consistent results were obtained from each, showing little difference between Ig and Fab in terms of antigen binding and in vitro neutralization, but with relatively large differences in protection of animals. We also studied whether importing Ab into the cell by Fc receptors enhanced the intracellular neutralization of ricin toxin. We found that the imported Ab was found in the ER and Golgi, a compartment traversed by ricin, as it traffics through the cell, but intracellular Ab did not contribute to the neutralization of ricin. These results indicate that the Fc region of antibody is important for in vivo protection, although the mechanism of enhanced protection by intact Ig does not appear to operate at the single cell level. When using xenogeneic antibodies, the diminished immunogenicity of Fab/F(ab')2 preparations should be balanced against possible loss of protective efficacy. PMID- 24811207 TI - Functional roles of CREB as a positive regulator in the formation and enhancement of memory. AB - cAMP response element-binding (CREB) has been known to be an essential transcription factor that activates gene expression required for the formation of long-term memory (LTM) in a wide range of animal models, from nematodes to higher animals such as Aplysia, Drosophila, and rodents. In mammals, various CREB mutant mice have been developed and analyzed. These studies have shown that gain or loss of CREB function improves and impairs, respectively, the formation of LTMs, enabling us to understand the roles of CREB in the formation and enhancement of memory. In this article, the analyses conducted on CREB mutant mice are reviewed with a particular focus on learning and memory formation. This article is part of a Special Issue entitled 'Memory enhancement'. PMID- 24811208 TI - Expression of angiotensin-converting enzyme gene in whole blood in patients with essential hypertension. AB - OBJECTIVE: The present study aims to investigate the correlation of the angiotensin-converting enzyme (ACE) gene expression and protein expression in patients with essential hypertension in whole blood. METHODS: ACE gene expression was analyzed by Real Time PCR and western blot in 52 patients with essential hypertension and 42 healthy controls. RESULTS: We observed a significant increase in Delta threshold cycle (DeltaCT) values in the circulating ACE gene and ACE protein expression in patients as compared to controls. CONCLUSIONS: The up regulation in relative expression of circulating Angiotensin converting enzyme mRNA and protein in patients with respect to controls might be correlated with high blood pressure in patients with essential hypertension. PMID- 24811209 TI - Sperm protein 17 is an oncofetal antigen: a lesson from a murine model. AB - Sperm protein 17 (Sp17) was originally identified in the flagellum of spermatozoa and subsequently included in the subfamily of tumor-associated antigens known as cancer-testes antigens (CTA). Sp17 has been associated with the motility and migratory capacity in tumor cells, representing a link between gene expression patterns in germinal and tumor cells of different histological origins. Here we review the relevance of Sp17 expression in the mouse embryo and cancerous tissues, and present additional data demonstrating Sp17 complex expression pattern in this murine model. The expression of Sp17 in embryonic as well as adult neoplastic cells, but not normal tissues, suggests this protein should be considered an "oncofetal antigen." Further investigations are necessary to elucidate the mechanisms and functional significance of Sp17 aberrant expression in human adult cells and its implication in the pathobiology of cancer. PMID- 24811210 TI - The role of human papilloma virus (HPV) infection in non-anogenital cancer and the promise of immunotherapy: a review. AB - Over the past 30 years, human papilloma virus (HPV) has been shown to play a role in the development of various cancers. Most notably, HPV has been linked to malignant progression in neoplasms of the anogenital region. However, high-risk HPV has also been suggested to play a significant role in the development of cancers in other anatomic locations, such as the head and neck, lung, breast and bladder. In 2006, the first vaccine for HPV, Gardasil, was approved for the prevention of subtypes 6, 11, 16 and 18. A few years later, Cevarix was approved for the prevention of subtypes 16 and 18, the HPV subtypes most frequently implicated in malignant progression. Although increased awareness and vaccination could drastically decrease the incidence of HPV-positive cancers, these approaches do not benefit patients who have already contracted HPV and developed cancer as a result. For this reason, researchers need to continue developing treatment modalities, such as targeted immunotherapies, for HPV-positive lesions. Here, we review the potential evidence linking HPV infection with the development of non-anogenital cancers and the potential role of immunotherapy in the prevention and eradication of HPV infection and its oncogenic sequela. PMID- 24811211 TI - The biocompatibility evaluation of mPEG-PLGA-PLL copolymer and different LA/GA ratio effects for biocompatibility. AB - Biomaterial poly(lactic-co-glycolic acid) (PLGA), a FDA-approved material for clinical application, showed broad prospects in the past, but gradually can no longer meet present clinical developments and requirements, which we synthesized monomethoxy(polyethylene glycol)-poly(D,L-lactic-co-glycolic acid)-poly(L-lysine) (mPEG-PLGA-PLL) (PEAL) and have had some relevant reports. But studies on biocompatibility and the impacts of LA and GA ratio (LA/GA=60/40, 70/30, and 80/20) in main material have not yet been reported. Hemolysis experiment indicates that the hemolysis rate of PEAL extraction medium is less than 5%. Whole blood clotting time (CT), plasma recalcification time, activated partial thromboplastin time, prothrombin time evaluations, and dynamic CT assay show that the anticoagulant time of PEAL copolymer for blood is longer than that under negative and positive control. Protein adsorption assay indicates that PEAL films adsorb less protein than PLGA films (p<0.01); but comparing with expanded polytetrafluoroethylene, the aforementioned difference is not significant (p>0.05). Complement activation test shows that PEAL surface does not induce complement activation. CCK8 measurement shows that the relative growth rates of Huh7, L02, and L929 cells co-incubated with PEAL nanoparticles (NPs) are more than 90%. PEAL NPs co-incubated with 5% foetal bovine serum or 2% bovine serum albumin, through dynamic light scattering assay, remain stable. Different concentrations of PEAL NPs co-incubated with zebrafish embryos at 6-72 h post fertilization show that comparing with negative control, 10, 100, or 500 MUM of NPs for embryos development has no significant effects (p>0.05), only 1000 or 2000 MUM of NPs has some effects (p<0.05). It is concluded that the PEAL copolymer, with excellent biocompatibility, proves to be a high-safety dose as drug carrier and implant candidate in vivo. PMID- 24811212 TI - Relationship between progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with anticancer agents after first-line treatment failure. AB - AIM: The hazard ratio of progression-free survival (PFS-HR) generally does not reflect that of overall survival (OS-HR) in advanced non-small cell lung cancer (NSCLC) patients treated with first-line therapy. Short survival post-progression (SPP) better reflects the PFS-HR and OS-HR in simulations. We aimed to evaluate whether the PFS-HR reflects the OS-HR in NSCLC clinical trials for post-first line treatments. METHOD: We reviewed clinical studies of post-first-line anticancer agents for NSCLC. We examined the sample size of the experimental arm (EA), median PFS (mPFS) or median time to progression in the EA, median overall survival (mOS) in the EA, the PFS-HR and the OS-HR. SPP was defined as the difference between mOS and mPFS. The association between mPFS and SPP, mPFS and mOS, and the PFS-HR and OS-HR was tested. We sought for the optimal point of correlation of PFS-HR and OS-HR by every 1 month of SPP. RESULTS: We identified 32 trials (34 arms). mPFS and mOS were weakly correlated (correlation coefficient [r] = 0.376; P = 0.0286). The PFS-HR and OS-HR were also moderately correlated (r = 0.415; P = 0.015). The maximum r value was 0.770 (SPP < 6 months; P < 0.0001) when we tested the associations between the PFS-HR and OS-HR for SPP using 1 month increments. The estimated regression equation at this point was OS-HR = 0.679 * (PFS-HR) + 0.349. CONCLUSION: The PFS-HR and OS-HR were strongly correlated in advanced NSCLC patients treated with post-first-line anticancer agents, with a SPP of less than 6 months. PMID- 24811213 TI - Is there a therapeutic benefit of complete lymph node dissection in melanoma patients with low tumor burden in the sentinel node? AB - In the case of a positive sentinel lymph node (SLN), melanoma patients are recommended to proceed to complete lymph node dissection (CLND). However, CLND for SLN-positive patients - especially with minimal tumor burden in SLN - is becoming more controversial. We analyzed the clinical course of 305 SLN-positive patients with a mean follow-up of 51.1 months by Kaplan-Meier analyses. Overall, 58/305 (17%) patients did not undergo CLND. These were compared with a matched selection of 58 comparable patients who underwent CLND. Moreover, 106/305 patients with minimal tumor burden in SLN (<0.1 mm diameter of the largest tumor deposit) were analyzed separately. Of these 106 patients, 34 did not undergo CLND, whereas 72/106 patients were treated by CLND. In the matched groups, the CLND group and the non-CLND group did not differ significantly with respect to clinical characteristics, characteristics of the primary melanoma, and histopathological parameters of SLN. There were no differences in recurrence-free survival (P=0.765) and overall survival (P=0.844). The total number of regional lymph node metastases and time to regional lymph node metastases were not significantly higher for non-CLND patients. The subgroup of patients with minimal tumor burden in SLN also did not benefit significantly from CLND. In our analyses from a single German center, we could not find any evidence for a therapeutic survival benefit for CLND after positive SLN. However, future prospective randomized trials should confirm these data. PMID- 24811214 TI - OSA and depression are common and independently associated with refractory angina in patients with coronary artery disease. AB - OBJECTIVE: Refractory angina is a severe form of coronary artery disease (CAD) characterized by persistent angina despite optimal medical therapy. OSA and depression are common in patients with stable CAD and may contribute to a poor prognosis. We hypothesized that OSA and depression are more common and more severe in patients with refractory angina than in patients with stable CAD. METHODS: We used standardized questionnaires and full polysomnography to compare consecutive patients with well-established refractory angina vs consecutive patients with stable CAD evaluated for coronary artery bypass graft surgery. RESULTS: Patients with refractory angina (n = 70) compared with patients with stable CAD (n = 70) were similar in sex distribution (male, 61.5% vs 75.5%; P = .07) and BMI (29.5 +/- 4 kg/m2 vs 28.5 +/- 4 kg/m2, P = .06), and were older (61 +/- 10 y vs 57 +/- 7 y, P = .013), respectively. Patients with refractory angina had significantly more symptoms of daytime sleepiness (Epworth Sleepiness Scale score, 12 +/- 6 vs 8 +/- 5; P < .001), had higher depression symptom scores (Beck Depression Inventory score, 19 +/- 8 vs 10 +/- 8; P < .001) despite greater use of antidepressants, had a higher apnea-hypopnea index (AHI) (AHI, 37 +/- 30 events/h vs 23 +/- 20 events/h; P = .001), higher proportion of oxygen saturation < 90% during sleep (8% +/- 13 vs 4% +/- 9, P = .04), and a higher proportion of severe OSA (AHI >= 30 events/h, 48% vs 27%; P = .009) than patients with stable CAD. OSA (P = .017), depression (P < .001), higher Epworth Sleepiness Scale score (P = .007), and lower sleep efficiency (P = .016) were independently associated with refractory angina in multivariate analysis. CONCLUSIONS: OSA and depression are independently associated with refractory angina and may contribute to poor cardiovascular outcome. PMID- 24811215 TI - Gene expression profiling of immune responsive and fibrosis genes in hepatitis C virus infected patients. AB - Hepatitis C virus (HCV) is a dreadful viral disease, responsible for 170 million cases worldwide, of which most are from Asia and Africa and approximately 10 million people are from Pakistan. Currently, the pegylated interferon alpha (PEG INF-alpha) has been approved as the standard of care in combination with ribavirin and Boceprevir/Telaprevir. Many studies regarding gene expression analysis of liver biopsy samples of patients with chronic HCV infection have been carried out previously. However, there are very few reports of expression analysis carried out using blood samples of HCV patients. Therefore, in this study, gene expression of human immune responsive genes (MMP-9, OAS1) and fibrogenic responsive gene (KRT19) was done in the peripheral blood mononuclear cells (PBMCs) of chronic HCV infected patients having differences in viral titers. Blood samples were collected from different hospitals in Pakistan. RNA was extracted and cDNA was synthesized according to the protocol prescribed by the EnzynomicsTM M-MLV Reverse Transcriptase((r)) Kit. The synthesized cDNA was amplified through polymerase chain reaction (PCR) using specific primers of immune responsive genes. The results were further evaluated using real-time PCR. There was a significant increase in the expression of the immune responsive genes (MMP-9, OAS1, CXCL6, CXCR3, ApoA1, and MYC) of HCV genotype 3a patients compared to controls. Similarly, the expression of the fibrosis genes was upregulated in HCV genotype 3a patients compared to controls. The information gained through this study is helpful to identify a noninvasive marker to determine liver fibrosis, and may also give useful information to understand HCV pathogenesis and develop better therapeutic regimens. PMID- 24811216 TI - Psychological distress and quality of life of palliative cancer patients and their caring relatives during home care. AB - PURPOSE: Palliative patients and their family caregivers were interviewed at the beginning of home care in personal interviews at home in regard to their psychological distress as well as their quality of life. METHODS: Quality of life was collected with the palliative module EORTC QLQ-C15-PAL (patients) and the Short Form-8 Health Survey (caregivers). The psychological distress was assessed using the Hospital Anxiety and Depression Scale, the extent of social support with the Oslo 3-items social support scale. Two multiple regression models were employed to examine factors associated with psychological distress. Data from 106 palliative patients (39.6 % female) and their family caregivers (67.9 % female) were included in the analysis. RESULTS: Every fourth patient had clinically relevant anxiety levels and half of the palliative patients had clinically symptomatic depression scores. The main symptoms of the patients were: fatigue, loss of appetite, pain, and shortness of breath. Patients' and caregivers' anxiety and depression scores were significantly correlated (anxiety r = 0.386, depression r = 0.416). Thirty-three percent of caregivers suffered from high anxiety and 28 % from depression. Spousal caregivers had higher psychological distress than other caregivers. Other relevant factors for higher distress were high financial burden and low social support. There was hardly any family member receiving professional psychological support. CONCLUSIONS: In palliative patients, depressive symptoms should not be judged as a normal attendant of the terminal illness situation. Instead, patients should be referred to appropriate support services for pharmacological or psychological treatment. Spousal caregivers and caregivers who are socially not well integrated are in particular need of support. Attention to the financial burden of family caregivers is also very important. Due to the existing correlation between the psychological situation of palliative patients and their caring relatives, couples must be considered an emotional system rather than just two individuals. PMID- 24811217 TI - Validation of the "Quality of Life in Life-Threatening Illness--Family Carer Version" (QOLLTI-F) in German-speaking carers of advanced cancer patients. AB - BACKGROUND: Palliative care is a multidisciplinary approach that focuses on the improvement of quality of life (QOL) of patients as well as their families. QOL research in palliative care has so far primarily focused on patients, but interest in the QOL of their relatives is increasing. For instruments measuring QOL in relatives, data on psychometric properties are often limited, and so far, none has been available in German. OBJECTIVE: This study translates and validates the "Quality of Life in Life-Threatening Illness-Family Carer Version" (QOLLTI-F) in German-speaking carers of advanced cancer patients. METHODS: The QOLLTI-F was translated from English into German according to the World Health Organisation's recommendations and validated in informal caregivers of terminally ill cancer patients of three Viennese hospitals. Hope was measured to assess concurrent validity; traumatic stress, anxiety, depression and subjective burden were measured to assess discriminant validity. Internal consistency, test-retest reliability and discriminative power were established. The scale's factor structure was explored using a set of factor analyses. RESULTS: Of the 308 caregivers participating in the study, 42 completed the QOLLTI-F retest after a mean of 5 days. The internal consistency was alpha = 0.85 for the overall scale, Pearson correlation between test and retest lay at r = 0.92. As expected, a significant positive correlation was found with hope (r = 0.40) and significant negative correlations with traumatic stress (r = -0.41), depression (r = -0.51), anxiety (r = -0.52) and overall subjective burden (r = -0.55). The original seven factor structure was not reproduced, but the scale showed a stable four-factor structure with factors capturing (1) feelings about carers' own life, (2) professional care, (3) interaction with the patient and others and (3) carers' outlook on life. CONCLUSION: This study provides a sound translation and validation of the first QOL assessment tool for caregivers of palliative care patients in German. It also adds to the knowledge on the scale's psychometric properties, which prove to be highly satisfactory. The QOLLTI-F may serve as an outcome measure in palliative care practice, clinical trials and epidemiological research. PMID- 24811218 TI - Evaluation of the Semmes-Weinstein filaments and a questionnaire to assess chemotherapy-induced peripheral neuropathy. AB - OBJECTIVE: This study aims to assess the use of Semmes-Weinstein monofilaments (SWMs) and of the Chemotherapy-Induced Neurotoxicity Questionnaire (CINQ) in the detection of chemotherapy-induced peripheral neuropathy (CIPN). METHOD: It is a comparative and cross-sectional study performed in a philanthropic general hospital, located in the state of Minas Gerais, Brazil. One hundred seventeen individuals have participated in this study; they were divided into two groups: patients (n = 87) treated with oxaliplatin, paclitaxel, or docetaxel and controls (n = 30) without malignant disease. RESULTS: There were statistically significant differences between groups for all symptoms assessed by means of the CINQ. Lower limbs were more severely affected. Patients had increased frequency and severity of changes in all points assessed with SWM compared with controls. In the analyses of concordance between CINQ and SWM, kappa = 0.320 (p < 0.001) was obtained, and there was a moderate and positive correlation (rho = 0.357; p < 0.001). CONCLUSION: CINQ and SWM may be valid tools for diagnosing CIPN in oncology practice. SWM may identify subclinical CIPN. PMID- 24811219 TI - Reprint of: the ciliary marginal zone (CMZ) in development and regeneration of the vertebrate eye. AB - The ciliary marginal zone (CMZ) is a circumferential ring of cells found at the extreme periphery of the maturing and mature neural retina that consists of retinal stem and progenitor cells. It functions to add retinal neurons to the periphery of the neural retina in larval and adult fish, larval frogs, and birds. Additionally, the CMZ may contribute to regeneration of the damaged retina in frogs and fish. In mammals, cells from the ciliary epithelium can be induced to express retinal stem cell-like characteristics in culture but may not comprise a classically defined CMZ. PMID- 24811220 TI - Posterior fossa arterio-venous malformations: current multimodal treatment strategies and results. AB - The present study aimed to determine the clinical presentation, the multimodal interdisciplinary treatment strategies and outcome of posterior fossa arterio venous malformations (AVMs) in our neurovascular centre. Fifty-three patients with a posterior fossa AVM were seen between 1998 and 2012 and analysed retrospectively. Patients were either managed conservatively or treated with endovascular, microsurgical or radiosurgical procedures or in combination. Thirty nine patients (74 %) presented with intracranial haemorrhage and 14 patients (26 %) with unspecific symptoms. In 22 cases with haemorrhage (56 %), an intracerebellar haematoma was found, whereas 17 patients (44 %) suffered from subarachnoid haemorrhage. AVMs were located in the cerebellum in 44 patients (83 %), in the brainstem in four patients (7.5 %) and the cerebello-pontine angle in another four individuals (7.5 %). Forty-two patients (79 %) were treated either by emboliziation (n = 12, 29 %), surgical resection (n = 16, 38 %), surgical resection with preoperative embolization (n = 12, 29 %) or radiotherapy alone (n = 2, 4 %). A total of eleven patients did not receive any treatment (21 %). Both, morbidity and mortality related to treatment were 12 %, whereas overall morbidity and mortality was 26 and 15 %, respectively. Complete AVM elimination was achieved in 81 % of the treated lesions. A multimodal treatment sequence nowadays represents the gold standard for posterior fossa AVMs. Patients are at high risk for morbidity and mortality, due to the impact of haemorrhage and treatment. Therefore, treatment has to be thoroughly indicated, especially for those patients without bleeding. The initial neurological condition seems to be crucial in terms of clinical outcome. PMID- 24811222 TI - [The 2014 Julius Springer prize for surgery awarded]. PMID- 24811221 TI - Alternative splicing of FBP-interacting repressor coordinates c-Myc, P27Kip1/cyclinE and Ku86/XRCC5 expression as a molecular sensor for bleomycin induced DNA damage pathway. AB - The far-upstream element-binding protein-interacting repressor (FIR) is a c-myc transcriptional suppressor. FIR is alternatively spliced to lack the transcriptional repression domain within exon 2 (FIRDeltaexon2) in colorectal cancers. FIR and FIRDeltaexon2 form homo- or heterodimers that complex with SAP155. SAP155, a subunit of the essential splicing factor 3b subcomplex in the spliceosome, is required for proper P27Kip1 pre-mRNA splicing, and P27Kip1 arrests cells at G1. In contrast, FIR was co-immunoprecipitated with Ku86 and DNA PKcs. siRNA against Ku86/Ku70 decreased FIR and P27Kip1 expression, whereas siRNA against FIR decreased Ku86/XRCC5 and P27Kip1 expression. Thus the mechanical interaction of FIR/FIRDeltaexon2/SAP155 bridges c-myc and P27Kip1 expression, potentially integrates cell-cycle progression and c-myc transcription in cell. Bleomycin(BLM) is an anticancer agent that introduces DNA breaks. Because DNA breaks generate the recruitment of Ku86/Ku70 to bind to the broken DNA ends, the possible involvement of FIR and Ku86/Ku70 interaction in the BLM-induced DNA damage repair response was investigated in this study. First, BLM treatment reduced SAP155 expression and increased FIR and FIRDeltaexon2 mRNA expression as well as the ratio of FIRDeltaexon2:FIR in hepatoblastoma cells (HLE and HLF). Second, FIR or FIRDeltaexon2 adenovirus vectors (Ad-FIR or Ad-FIRDeltaexon2) increased Ku86/Ku70 and P27Kip1 expression in vitro. Third, BLM decreased P27Kip1 protein expression, whereas increased P27Kip1 and gammaH2AX expression with Ad FIRDeltaexon2. Together, the interaction of FIR/SAP155 modulates FIR splicing and involves in cell-cycle control or cell fate via P27Kip1 and c-myc in BLM-induced DNA damage pathway. This novel function of FIR splicing will contribute to clinical studies of cancer management through elucidating the mechanical interaction of FIR/FIRDeltaexon2/SAP155 as a potential target for cancer treatment. PMID- 24811223 TI - [Pediatric multiple trauma]. AB - Multiple trauma in children is rare so that even large trauma centers will only treat a small number of cases. Nevertheless, accidents are the most common cause of death in childhood whereby the causes are mostly traffic accidents and falls. Head trauma is the most common form of injury and the degree of severity is mostly decisive for the prognosis. Knowledge on possible causes of injury and injury patterns as well as consideration of anatomical and physiological characteristics are of great importance for treatment. The differences compared to adults are greater the younger the child is. Decompression and stopping bleeding are the main priorities before surgical fracture stabilization. The treatment of a severely injured child should be carried out by an interdisciplinary team in an approved trauma center with expertise in pediatrics. An inadequate primary assessment involves a high risk of early mortality. On the other hand children have a better prognosis than adults with comparable injuries. PMID- 24811224 TI - Congenital heart defects and maternal fever: systematic review and meta-analysis. AB - OBJECTIVE: To systematically review and meta-analyze the relation between maternal fever in the first trimester and congenital heart defect (CHD) in offspring. STUDY DESIGN: We searched PubMed (1977-2012), Embase (1974-2012) and the Cochrane Library (2012) databases to identify relevant articles. Random effects model were performed, with the conduction of subgroup analysis. RESULT: Meta-analysis yielded a pooled odds ratio of 1.53 (95% confidence interval=1.36 to 1.73) for the magnitude of the relation between maternal fever in the first trimester and CHD in offspring. As to subgroup analysis, it is associated with ventricular septal defects (VSDs) and right obstructive defects. CONCLUSION: Our analysis suggests that maternal fever in the first trimester is the risk factor of congenital heart diseases in offspring. Through the subgroup analysis, we find that exposure to maternal fever is the risk factor of VSD and right obstructive defects. PMID- 24811225 TI - Quantitative elastography of the uterine cervix as a predictor of preterm delivery. AB - OBJECTIVE: To evaluate the correlation between preterm delivery before 37 weeks of gestation and ultrasound elastography strain measurement of cervical stiffness. STUDY DESIGN: In this prospective study, 182 pregnant women were examined vaginally by ultrasound elastography from a mid-sagittal plane. Cervical length was measured and strain was calculated in four regions of interest on the anterior cervical lip. First, the software was validated by intraobserver variability. Second, strain and strain ratios were calculated with adjusted software presets and correlated to the outcome of spontaneous preterm delivery (sPTD). RESULT: A total of 8928 regions of interest (ROIs) and 6696 ratios were evaluated. The median gestational age at examination was 26 +/- 6.1 weeks. A median maternal age of 33 +/- 5.6 and a medial parity of 1 +/- 0.9 were observed. Intra-Class-Correlation values in validation phase ranged from 0.893 to 0.967. The prevalence of sPTD was 11.9%. Strain ratio Rselective was identified as the best predictor of preterm delivery. Rselective values >0.89 were associated with preterm delivery with a sensitivity of 0.59 and a specificity of 0.86 (odds ratio=1.474 for an increase of 0.1 in Rselective; P=0.002). CONCLUSION: Ultrasound elastography strain measurement of cervical stiffness is correlated with the predictability of preterm delivery. PMID- 24811226 TI - Comparison between nitroglycerin dermal patch and nifedipine for treatment of preterm labor: a randomized clinical trial. AB - OBJECTIVE: Preterm labor and delivery are of the most important complications of pregnancy and have a major role in neonatal mortality and morbidity. Management of preterm labor and prevention from preterm delivery in order to lower these risks have always been under serious concern. The purpose of this study was to compare the effect of nifedipine and nitroglycerin (NG) dermal patch for taking control of preterm labor. STUDY DESIGN: The study was performed as a randomized clinical trial on women who had been admitted in the hospital diagnosed with preterm labor. In one group, the NG dermal patch and in the other group, nifedipine was prescribed. Then the women of the two groups were followed up to delivery and were compared according to arrest of labor for 2 h, 48 h, 7 days, gestational age at the time of delivery and their adverse effects. The primary outcome was to postpone delivery for 48 h in order to have enough time for prescribing corticosteroids RESULT: The women of the two groups did not have any significant difference according to age, body mass index, primary Bishop Score, gestational age at the time of tocolytic therapy, history of abortion, vaginal or cesarean delivery and preterm labor. In more women in the NG group, delivery was postponed for 2 h (59 (98.3%) vs 48 (80%), P=0.001), for 48 h (52 women (86.7%) vs 41(68.3%), P=0.016) and also for 7 days (47 (78.3%) vs 37 (61.7%), P=0.046), than the women in the nifedipine group. Gestational age at the time of delivery was higher in the NG group (35.6+/-1.9 vs 34.3+/-2.05 weeks, P=0.155), however, it was not statistically significant. Apgar score of minute 5, (P=0.03) and neonatal weight (P=0.04), were more and cesarean deliveries, neonatal intensive care unit (NICU) admission and duration of NICU stay were less in the NG group. Adverse effects were similar, minimal and negligible in both groups. CONCLUSION: The NG patch is a more effective method for preterm labor control than nifedipine with regard to minimal side effects. PMID- 24811227 TI - Maternal obesity and increased risk for autism and developmental delay among very preterm infants. AB - OBJECTIVE: Thirty-five percent of women of child-bearing age are obese, and there is evidence that maternal obesity may increase the risk for adverse neurodevelopmental outcome. However, research regarding obesity and neurodevelopment among children born preterm is limited. This study aimed to determine associations between maternal obesity and neurodevelopment in very preterm children at age 2 years. STUDY DESIGN: Maternal/infant dyads (n=62) born ?30 weeks gestation were enrolled in a prospective cohort study at a level-III neonatal intensive care unit. Mothers were classified as obese or non-obese based on pre-pregnancy body mass index. Infants underwent magnetic resonance imaging at term equivalent and developmental testing at age 2. Maternal obesity was investigated for associations with neurodevelopment. RESULT: Maternal obesity was associated with positive screen for autism (odds ratio=9.88, P=0.002) and lower composite language scores (beta=-9.36, (confidence interval=-15.11, -3.61), P=0.002). CONCLUSION: Maternal obesity was associated with adverse neurodevelopmental outcome at age 2 in this cohort of very preterm children. This study requires replication, but may support targeted surveillance of infants born to women with maternal obesity. PMID- 24811228 TI - Comparison of intra-procedural pain between a novel continuous arteriovenous exchange and conventional pull-push techniques of partial exchange transfusion in neonates: a randomized controlled trial. AB - OBJECTIVE: We compared intra-procedural neonatal pain, agitation and sedation scale (N-PASS) scores between a novel 'continuous arteriovenous exchange' (CAVE) and conventional pull-push (PP) techniques of partial exchange transfusion (PET) among neonates with polycythemia. STUDY DESIGN: Neonates >32-0/7 weeks gestation, requiring PET for polycythemia, were randomized to PP or CAVE techniques. The procedure was video-recorded and edited to mask the technique. Intra-procedural N PASS scores assigned by two trained and masked neonatal fellows were compared. RESULT: Twenty-two neonates were randomized to CAVE (n=12) or PP (n=10) method. The area under curve for cumulative N-PASS scores was significantly lesser in CAVE group (mean difference-11.9 (95% CI=-4.2, -19.6), P=0.005)). Decrease in hematocrit and complications of PET were comparable. Time for PET was longer with CAVE technique (16 (9, 29) min vs 10 (6, 12) min, P=0.016). CONCLUSION: CAVE technique of PET was associated with lesser procedure-related pain (N-PASS scores) as compared with PP technique among neonates >32 weeks gestation. PMID- 24811229 TI - Nickel nanoparticle-doped paper as a bioactive scaffold for targeted and robust immobilization of functional proteins. AB - Cellulose-based materials are widely used in analytical chemistry as platforms for chromatographic and immunodiagnostic techniques. Due to its countless advantages (e.g., mechanical properties, three-dimensional structure, large surface to volume area, biocompatibility and biodegradability, and high industrial availability), paper has been rediscovered as a valuable substrate for sensors. Polymeric materials such as cellulosic paper present high protein capture ability, resulting in a large increase of detection signal and improved assay sensitivity. However, cellulose is a rather nonreactive material for direct chemical coupling. Aiming at developing an efficient method for controlled conjugation of cellulose-based materials with proteins, we devised and fabricated a hybrid scaffold based on the adsorption and in situ self-assembly of surface oxidized Ni nanoparticles on filter paper, which serve as "docking sites" for the selective immobilization of proteins containing polyhistidine tags (His-tag). We demonstrate that the interaction between the nickel substrate and the His-tagged protein G is remarkably resilient toward chemicals at concentrations that quickly disrupt standard Ni-NTA and Ni-IDA complexes, so that this system can be used for applications in which a robust attachment is desired. The bioconjugation with His tagged protein G allowed the binding of anti-Salmonella antibodies that mediated the immuno-capture of live and motile Salmonella bacteria. The versatility and biocompatibility of the nickel substrate were further demonstrated by enzymatic reactions. PMID- 24811230 TI - Blood pressure, albuminuria and renal dysfunction: the 'chicken or egg' dilemma. PMID- 24811231 TI - To TDM or not to TDM in lupus nephritis patients treated with MMF? AB - Mycophenolic acid (MPA) has become the cornerstone in the treatment of lupus nephritis. However, response rates are still far from ideal in clinical trials. Uncertainty exists regarding the correct dosing of MPA, and the recommended doses vary between recently published guidelines. Side effects are an additional problem resulting in frequent dose reduction and possible suboptimal exposure.In this review, we discuss the large variability between patients in drug exposure to MPA and the evidence for a relationship between drug exposure and efficacy in lupus nephritis. Methods for drug monitoring of MPA are discussed, and based on the current literature, we suggest as potential target levels a pre-dose level of 3.0 mg/L and an area under the concentration-versus-time curve between 35 and 45 mg h/L.Therapeutic drug monitoring may improve response rates in lupus nephritis by preventing low exposure and at the same time may reduce unnecessary side effects in patients who have high drug exposure with standard dose MPA. We specifically advise assessment of MPA drug exposure early after start of treatment and before concluding that treatment with MPA has failed. PMID- 24811232 TI - Thermodynamic contributions to the stability of the insulin hexamer. AB - The insulin hexamer is resistant to degradation and fibrillation, which makes it an important quaternary structure for its in vivo storage in Zn(2+)- and Ca(2+) rich vesicles in the pancreas and for pharmaceutical formulations. In addition to the two Zn(2+) ions that are required for its formation, three other species, Zn coordinating anions (e.g., Cl(-)), Ca(2+), and phenols (e.g., resorcinol), bind to the hexamer and affect the subunit conformation and stability. The contributions of these four species to the thermodynamics of insulin unfolding have been quantified by differential scanning calorimetry and thermal unfolding measurements to determine the extent and nature of their stabilization of the insulin hexamer. Both Zn(2+) and resorcinol make a significant enthalpic contribution, while Ca(2+) primarily affects the protein heat capacity (solvation) by its interactions in the central cation-binding cavity, which is modulated by the surrounding subunit conformations. Coordinating anions have a negligible effect on the stability of the hexamer, even though subunits shift to an alternate conformation when these anions bind to the Zn(2+) ions. Finally, Zn(2+) in excess of the two that are required to form the hexamer further stabilizes the protein by additional enthalpic contributions. PMID- 24811233 TI - Air-water exchange of brominated anisoles in the northern Baltic Sea. AB - Bromophenols produced by marine algae undergo O-methylation to form bromoanisoles (BAs), which are exchanged between water and air. BAs were determined in surface water of the northern Baltic Sea (Gulf of Bothnia, consisting of Bothnian Bay and Bothnian Sea) during 2011-2013 and on a transect of the entire Baltic in September 2013. The abundance decreased in the following order: 2,4,6 tribromoanisole (2,4,6-TBA)>2,4-dibromoanisole (2,4-DBA)?2,6-dibromoanisole (2,6 DBA). Concentrations of 2,4-DBA and 2,4,6-TBA in September were higher in the southern than in the northern Baltic and correlated well with the higher salinity in the south. This suggests south-to-north advection and dilution with fresh riverine water enroute, and/or lower production in the north. The abundance in air over the northern Baltic also decreased in the following order: 2,4,6-TBA>2,4 DBA. However, 2,6-DBA was estimated as a lower limit due to breakthrough from polyurethane foam traps used for sampling. Water/air fugacity ratios ranged from 3.4 to 7.6 for 2,4-DBA and from 18 to 94 for 2,4,6-TBA, indicating net volatilization. Flux estimates using the two-film model suggested that volatilization removes 980-1360 kg of total BAs from Bothnian Bay (38000 km2) between May and September. The release of bromine from outgassing of BAs could be up to 4-6% of bromine fluxes from previously reported volatilization of bromomethanes and bromochloromethanes. PMID- 24811234 TI - Staff's perceptions of the use of evidence-based physical activity promotion strategies for promoting girls' physical activity at afterschool programs: a qualitative study. AB - There is a need to improve girls' physical activity (PA) in afterschool programs as girls' PA levels are consistently lower than boys'. An evidence-based professional development framework, the 5 Ms, has been effective in helping staff to improve PA in both girls and boys but further improvements in girls' PA are needed. Little is known about staff's perceptions of using PA promotion strategies to promote girls' PA. Therefore, the purpose of this study was to explore staff perceptions of the use of evidence-based PA promotion strategies for promoting PA in girls. Semi-structured interviews were conducted with staff from three community-based afterschool programs located within a school setting (n=18). Data were analyzed using the process of immersion/crystallization. A majority of staff had some knowledge of PA promotion strategies but few staff consistently utilized these strategies and a majority felt several strategies were unnecessary (i.e., having a PA policy). Newer staff reported depending on senior staff to promote PA in girls. Overall, findings suggest that staff's perceptions may impact their use of PA promotions strategies. The results of this study will contribute to the enhancement of an existing staff training framework (the 5 Ms) to improve girls' PA in afterschool programs. PMID- 24811235 TI - Evaluating the delivery performance of public spending programs from an efficiency perspective. AB - There is increasing recognition that performance evaluation of national as well as foreign public economic development programs should emphasize on their implementation rather than focus solely on their outcomes. This paper presents a framework for comparing the delivery or administrative efficiency of public spending programs at local level, based on a novel application of Data Envelopment Analysis (DEA). It is focused on the European Union context and specifically on the Greek LEADER operational program. The results of this application indicate that DEA, in contrast to traditional performance metrics, is an insightful tool in revealing administrative inefficiencies in program delivery by capturing the operational and scale components of performance while taking into account the complex mix of tasks and interventions carried out by its operators. The proposed technique may be easily integrated into a program evaluation scheme and may be utilized as a tool to support rational decision making and program improvement. PMID- 24811236 TI - Epistatically interacting substitutions are enriched during adaptive protein evolution. AB - Most experimental studies of epistasis in evolution have focused on adaptive changes-but adaptation accounts for only a portion of total evolutionary change. Are the patterns of epistasis during adaptation representative of evolution more broadly? We address this question by examining a pair of protein homologs, of which only one is subject to a well-defined pressure for adaptive change. Specifically, we compare the nucleoproteins from human and swine influenza. Human influenza is under continual selection to evade recognition by acquired immune memory, while swine influenza experiences less such selection due to the fact that pigs are less likely to be infected with influenza repeatedly in a lifetime. Mutations in some types of immune epitopes are therefore much more strongly adaptive to human than swine influenza--here we focus on epitopes targeted by human cytotoxic T lymphocytes. The nucleoproteins of human and swine influenza possess nearly identical numbers of such epitopes. However, mutations in these epitopes are fixed significantly more frequently in human than in swine influenza, presumably because these epitope mutations are adaptive only to human influenza. Experimentally, we find that epistatically constrained mutations are fixed only in the adaptively evolving human influenza lineage, where they occur at sites that are enriched in epitopes. Overall, our results demonstrate that epistatically interacting substitutions are enriched during adaptation, suggesting that the prevalence of epistasis is dependent on the underlying evolutionary forces at play. PMID- 24811238 TI - Adriaan van den Spiegel (1578-1625): anatomist, physician, and botanist. AB - Adriaan van den Spiegel (1578-1625) was a Flemish anatomist and physician. He was one of the most prominent anatomists at the University of Padua during the 17th century and became professor of anatomy and surgery there in 1619. He was privileged to have two of the most accomplished anatomists of that period, Fabricius ab Aquapendente and Iulius Casserius, as his teachers. His anatomical works were published after his death by his pupil Bucretius and his son-in-law Liberalis Crema, with illustrations procured from Casserius's unpublished anatomical atlas. He contributed significantly to establishing basic morphological facts about the developing embryo in his text De formato foetu liber singularis. In his book De humani corporis fabrica libri decem, Spiegel's lobe (caudate lobe) of the liver and the linea semilunaris (Spiegel's line) on the lateral side of the rectus abdominis muscle were described for the first time. Subsequently, Spigelian aponeurosis (between the lateral margin of the rectus abdominis and the linea semilunaris) and Spigelian hernia (lateral ventral hernia) were named after him. He was a renowned physician in his time and was the first to give a detailed description of malaria. He made significant contributions as a botanist: the genus Spigelia, which has six species, is named after him. PMID- 24811237 TI - Development of children at risk for adverse outcomes participating in early intervention in developing countries: a randomized controlled trial. AB - BACKGROUND: Previous research has indicated positive effects of early developmental intervention (EDI) on the development of children in developing countries. Few studies, however, have examined longitudinally when differential treatment effects may be observed and whether differential outcomes are associated with exposure to different risk factors and country of implementation. Also, birth asphyxia as a risk condition has not been well studied. To address these limitations, we conducted a randomized controlled trial to test the hypothesis that there will be differential developmental trajectories favoring those who receive EDI versus a health education intervention in children in rural areas of India, Pakistan, and Zambia. METHODS: Children with and without birth asphyxia were randomized to EDI or control intervention, which was implemented by parents who received training in biweekly home visits initiated before child age 1 month and continuing until 36 months. Development was assessed in 376 children at ages 12, 24, and 36 months using the Bayley Scales of Infant Development and Ages & Stages Questionnaire administered by evaluators blind to intervention assignment and risk condition. RESULTS: Longitudinal mixed model analysis indicated that EDI resulted in better development over 36 months in cognitive abilities, regardless of risk condition, maternal resources, child gender, or country. Psychomotor development and parent-reported general development showed similar trends as for cognitive abilities, but were not statistically different between intervention conditions. Developmental differences were observed first at 36 months of age. CONCLUSION: Early developmental intervention has promise for improving development in children across developing countries when exposed to various risk conditions. EDI should be one prominent approach used to begin to address long-term outcomes and intergenerational transmission of poverty. PMID- 24811239 TI - Interventions employed to improve intrahospital handover: a systematic review. AB - BACKGROUND: Modern medical care requires numerous patient handovers/handoffs. Handover error is recognised as a potential hazard in patient care, and the information error rate has been estimated at 13%. While accurate, reliable handover is essential to high quality care, uncertainty exists as to how intrahospital handover can be improved. This systematic review aims to evaluate the effectiveness of interventions aimed at improving the quality and/or safety of the intrahospital handover process. METHODS: We searched for articles on handover improvement interventions in EMBASE, MEDLINE, HMIC and CINAHL between January 2002 and July 2012. We considered studies of: staff knowledge and skills, staff behavioural change, process change or patient outcomes. RESULTS: 631 potentially relevant papers were identified from which 29 papers were selected for inclusion (two randomised controlled trials and 27 uncontrolled studies). Most studies addressed shift-change handover and used a median of three outcome measures, but there was no outcome measure common to all. Poor study design and inconsistent reporting methods made it difficult to reach definite conclusions. Information transfer was improved in most relevant studies, while clinical outcome improvement was reported in only two of 10 studies. No difference was noted in the likelihood of success across four types of intervention. CONCLUSIONS: The current literature does not confirm that any methodology reliably improves the outcomes of clinical handover, although information transfer may be increased. Better study designs and consistency of the terminology used to describe handover and its improvement are urgently required. PMID- 24811240 TI - Regulating and legislating safety: the case for candour. PMID- 24811241 TI - Distinct pattern of hypometabolism and atrophy in preclinical and predementia Alzheimer's disease. AB - The goal of the present study was to determine the earliest patterns of hypometabolism and atrophy in the development of Alzheimer's disease (AD). Stages of AD were defined by positron emission tomography imaging evidence of cortical amyloid pathology in addition to cognitive criteria. Subjects for the study were selected from the Alzheimer's Disease Neuroimaging Initiative database and divided into 4 groups: cognitively normal (CN) amyloid negative (Abeta-) elderly subjects (n = 36), CN amyloid-positive (Abeta+) (n = 21), early mild cognitive impairment Abeta+ (n = 65), and late mild cognitive impairment Abeta+ (n = 23) subjects. Region of interest-based (primary) and voxel-based (secondary) analyses were used to assess gray matter hypometabolism, quantified by [18F]fluorodeoxyglucose-positron emission tomography, and decrease in gray matter volume and cortical thickness was measured by magnetic resonance imaging. Region of interest- and voxel-based analyses showed significant hypometabolism but not atrophy in CN Abeta+ subjects compared with CN Abeta- subjects. The results suggest that hypometabolism exceeds atrophy in preclinical AD, supporting the notion that amyloid load may affect synaptic activity, leading to synaptic loss and subsequent neuronal loss. PMID- 24811242 TI - RNA binding protein RBM14 promotes radio-resistance in glioblastoma by regulating DNA repair and cell differentiation. AB - Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Standard treatment for GBM patients is surgery followed by radiotherapy and/or chemotherapy, but tumors always recur. Traditional therapies seem to fail because they eliminate only the bulk of the tumors and spare a population of stem like cells termed tumor-initiating cells. The stem-like state and preferential activation of DNA damage response in the GBM tumor-initiating cells contribute to their radio-resistance and recurrence. The molecular mechanisms underlying this efficient activation of damage response and maintenance of stem-like state remain elusive. Here we show that RBM14 controls DNA repair pathways and also prevents cell differentiation in GBM spheres, causing radio-resistance. Knockdown of RBM14 affects GBM sphere maintenance and sensitizes radio-resistant GBM cells at the cellular level. We demonstrate that RBM14 knockdown blocks GBM regrowth after irradiation in vivo. In addition, RBM14 stimulates DNA repair by controlling the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway. These results reveal unexpected functions of the RNA-binding protein RBM14 in control of DNA repair and maintenance of tumor-initiating cells. Targeting the RBM14-dependent pathway may prevent recurrence of tumors and eradicate the deadly disease completely. PMID- 24811243 TI - Poly(amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium. AB - Small interfering RNA (siRNA)-based therapies have great promise in the treatment of a number of prevalent pulmonary disorders including lung cancer, asthma and cystic fibrosis. However, progress in this area has been hindered due to the lack of carriers that can efficiently deliver siRNA to lung epithelial cells, and also due to challenges in developing oral inhalation (OI) formulations for the regional administration of siRNA and their carriers to the lungs. In this work we report the ability of generation four, amine-terminated poly(amidoamine) (PAMAM) dendrimer (G4NH2)-siRNA complexes (dendriplexes) to silence the enhanced green fluorescent protein (eGFP) gene on A549 lung alveolar epithelial cells stably expressing eGFP. We also report the formulation of the dendriplexes and their aerosol characteristics in propellant-based portable OI devices. The size and gene silencing ability of the dendriplexes was seen not to be a strong function of the N/P ratio. Silencing efficiencies of up to 40% are reported. Stable dispersions of the dendriplexes encapsulated in mannitol and also in a biodegradable and water-soluble co-oligomer were prepared in hydrofluoroalkane (HFA)-based pressurized metered-dose inhalers (pMDIs). Their aerosol characteristics were very favorable, and conducive to deep lung deposition, with respirable fractions of up to 77%. Importantly, siRNA formulated as dendriplexes in pMDIs was shown to keep its integrity after the particle preparation processes, and also after long-term exposures to HFA. The relevance of this study stems from the fact that this is the first work to report the formulation of inhalable siRNA with aerosol properties suitable to deep lung deposition using pMDIs devices that are the least expensive and most widely used portable inhalers. This study is relevant because, also for the first time, it shows that siRNA-G4NH2 dendriplexes can efficiently target lung alveolar epithelial A549 cells and silence genes even after siRNA has been exposed to the propellant environment. PMID- 24811245 TI - GERD symptoms in the general population: prevalence and severity versus care seeking patients. AB - BACKGROUND: Prior estimates suggest that up to 40% of the US general population (GP) report symptoms of gastroesophageal reflux disease (GERD). However, symptoms in the GP versus patients seeking care for gastrointestinal (GI) complaints have not been compared. We estimated the prevalence and severity of GERD symptoms in the GP versus GI patients, and identified predictors of GERD severity. We hypothesized that similar to functional GI disorders, psychosocial factors would predict symptom severity in GERD as much, or perhaps more, than care-seeking behavior alone. METHODS: We compared the prevalence of heartburn and regurgitation between a sample from the US GP and patients seeking GI specialty care. We compared GERD severity between groups using the NIH PROMIS((r)) GERD scale. We then performed multivariable regression to identify predictors of GERD severity. RESULTS: There was no difference in the prevalence of heartburn between the GP and patient groups (59 vs. 59%), but regurgitation was more common in patients versus GP (46 vs. 39%; p = 0.004). In multivariable regression, having high visceral anxiety (p < 0.001) and being divorced or separated (p = 0.006) were associated with higher GERD severity. CONCLUSIONS: More than half of a GP sample reports heartburn-higher than previous series and no different from GI patients. Although regurgitation was more prevalent in patients versus the GP, there was no difference in GERD severity between groups after adjusting for other factors; care seeking in GERD appears related to factors beyond symptoms, including visceral anxiety. PMID- 24811246 TI - Prognostic marker microRNA-125b inhibits tumorigenic properties of hepatocellular carcinoma cells via suppressing tumorigenic molecule eIF5A2. AB - BACKGROUND: MicroRNAs (miRNAs) belong to a group of small non-coding RNA with differential expression in tumors, including hepatocellular carcinoma (HCC). AIM: This study investigates the involvement of miR-125b in HCC. METHODS: Clinical analysis of miR-125b was performed using data derived from miRNA profiling and qPCR. Phenotypic changes of liver cell lines were examined after ectopic miR-125b expression. Lastly, bioinformatics analysis coupled with luciferase reporter assay was used to reveal the cellular target of miR-125b. RESULTS: A down regulation of miR-125b was found in HCC tumors and cultured cells. Patients having tumors with >=twofold reduction in miR-125b compared to adjacent non-tumor tissues contributed to 23 out of 49 HCC cases (46.9 %), while this down regulation was usually found in patients with tumor venous infiltration and recurrence. miR-125b expression was also negatively correlated with increased serum AFP level and poor overall survival of patients. Ectopic expression of miR 125b led to alleviated tumor phenotypes of HCC cells. Among the 110 bioinformatically predicated candidates, 31 of them negatively correlated with miR-125b in HCC tumors for which one of them named eukaryotic translation initiation factor 5A2 (eIF5A2), known also as a liver oncofetal molecule, was validated to be a direct target of miR-125b in HCC. CONCLUSIONS: This study has evidenced for the negative correlation of tumor miR-125b expression with poor prognosis of HCC patients. Expression of miR-125b can reverse the tumorigenic properties of cultured HCC cells via suppressing the tumorigenic molecule eIF5A2, thus postulating restoration of miR-125b level as a way to counteract liver tumorigenesis. PMID- 24811247 TI - Urgent monitoring of direct oral anticoagulants in patients with atrial fibrillation: a tentative approach based on routine laboratory tests. AB - The number of patients diagnosed with atrial fibrillation who will be candidates for antithrombotic therapy with direct oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban and edoxaban) is exponentially arising worldwide, thus posing substantial economic and organizational challenges for their urgent monitoring. Due to long turnaround time and inherent technical complexity, liquid chromatography techniques are unsuitable for rapid assessment of their concentration. Even the use of surrogate tests such as thrombin clotting time or anti-factor Xa activity carries some economic and technical drawbacks. Based on literature data, we have hence developed an algorithm based on first-line tests for urgent screening of the anticoagulant effect of direct oral anticoagulants, which entails activated partial thromboplastin time (aPTT) for dabigatran and prothrombin time (PT) for rivaroxaban. Although these tests also display a concentration-dependent prolongation in patients taking apixaban and edoxaban, neither of them is sufficiently sensitive for providing accurate estimation of the pharmacodynamic effect, so that the measurement of anti-factor Xa activity remains the most suitable approach in patients taking these drugs. According to literature data, this strategy appears suitable to reliably define the thrombotic or bleeding risk in an urgent setting, contextually saving precious laboratory resources. PMID- 24811248 TI - Potato plants ectopically expressing Arabidopsis thaliana CBF3 exhibit enhanced tolerance to high-temperature stress. AB - CBF3, a known cold-inducible gene that encodes a transcription factor, was isolated from Arabidopsis thaliana and introduced into the potato (Solanum tuberosum cv. 'luyin NO.1') under the control of the CaMV35S promoter or the rd29A promoter. Our results revealed that temperature of 40 degrees C or higher can significantly induce AtCBF3 expression. After heat stress, the net photosynthetic rate (Pn ), the maximal photochemical efficiency of photosystem II (PSII) (Fv /Fm ) and the accumulation of the D1 protein were higher in the transgenic lines than in the wild-type (WT) line. Moreover, compared with the WT line, O2 (?-) and H2 O2 accumulation in the transgenic lines were reduced. A Q PCR assay of a subset of the genes involved in photosynthesis and antioxidant defence further verified the above results. Interestingly, under heat stress conditions, the accumulation of heat-shock protein 70 (HSP70) increased in the WT line but decreased in the transgenic lines. These results suggest that potato plants ectopically expressing AtCBF3 exhibited enhanced tolerance to high temperature, which is associated with improved photosynthesis and antioxidant defence via induction of the expression of many stress-inducible genes. However, this mechanism may not depend upon the regulatory pathways in which HSP70 is involved. PMID- 24811249 TI - The inhibition of the dorsal paragigantocellular reticular nucleus induces waking and the activation of all adrenergic and noradrenergic neurons: a combined pharmacological and functional neuroanatomical study. AB - GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking. PMID- 24811251 TI - Event-triggered logical flow control for comprehensive process integration of multi-step assays on centrifugal microfluidic platforms. AB - The centrifugal "lab-on-a-disc" concept has proven to have great potential for process integration of bioanalytical assays, in particular where ease-of-use, ruggedness, portability, fast turn-around time and cost efficiency are of paramount importance. Yet, as all liquids residing on the disc are exposed to the same centrifugal field, an inherent challenge of these systems remains the automation of multi-step, multi-liquid sample processing and subsequent detection. In order to orchestrate the underlying bioanalytical protocols, an ample palette of rotationally and externally actuated valving schemes has been developed. While excelling with the level of flow control, externally actuated valves require interaction with peripheral instrumentation, thus compromising the conceptual simplicity of the centrifugal platform. In turn, for rotationally controlled schemes, such as common capillary burst valves, typical manufacturing tolerances tend to limit the number of consecutive laboratory unit operations (LUOs) that can be automated on a single disc. In this paper, a major advancement on recently established dissolvable film (DF) valving is presented; for the very first time, a liquid handling sequence can be controlled in response to completion of preceding liquid transfer event, i.e. completely independent of external stimulus or changes in speed of disc rotation. The basic, event triggered valve configuration is further adapted to leverage conditional, large scale process integration. First, we demonstrate a fluidic network on a disc encompassing 10 discrete valving steps including logical relationships such as an AND-conditional as well as serial and parallel flow control. Then we present a disc which is capable of implementing common laboratory unit operations such as metering and selective routing of flows. Finally, as a pilot study, these functions are integrated on a single disc to automate a common, multi-step lab protocol for the extraction of total RNA from mammalian cell homogenate. PMID- 24811250 TI - Inhibition of tumor vasculogenic mimicry and prolongation of host survival in highly aggressive gallbladder cancers by norcantharidin via blocking the ephrin type a receptor 2/focal adhesion kinase/paxillin signaling pathway. AB - Vasculogenic mimicry (VM) is a newly-defined tumor microcirculation pattern in highly aggressive malignant tumors. We recently reported tumor growth and VM formation of gallbladder cancers through the contribution of the ephrin type a receptor 2 (EphA2)/focal adhesion kinase (FAK)/Paxillin signaling pathways. In this study, we further investigated the anti-VM activity of norcantharidin (NCTD) as a VM inhibitor for gallbladder cancers and the underlying mechanisms. In vivo and in vitro experiments to determine the effects of NCTD on tumor growth, host survival, VM formation of GBC-SD nude mouse xenografts, and vasculogenic-like networks, malignant phenotypes i.e., proliferation, apoptosis, invasion and migration of GBC-SD cells. Expression of VM signaling-related markers EphA2, FAK and Paxillin in vivo and in vitro were examined by immunofluorescence, western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The results showed that after treatment with NCTD, GBC-SD cells were unable to form VM structures when injecting into nude mouse, growth of the xenograft was inhibited and these observations were confirmed by facts that VM formation by three-dimensional (3-D) matrix, proliferation, apoptosis, invasion, migration of GBC-SD cells were affected; and survival time of the xenograft mice was prolonged. Furthermore, expression of EphA2, FAK and Paxillin proteins/mRNAs of the xenografts was downregulated. Thus, we concluded that NCTD has potential anti VM activity against human gallbladder cancers; one of the underlying mechanisms may be via blocking the EphA2/FAK/Paxillin signaling pathway. PMID- 24811252 TI - Is tocilizumab safe in Kaposi sarcoma? A complex association among rheumatoid arthritis, psoriasis, and Kaposi sarcoma. PMID- 24811253 TI - Authors' reply to Verdelli et al.: there is no knowledge without experience. PMID- 24811254 TI - Predisposing risk factors for delirium in living donor liver transplantation patients in intensive care units. AB - BACKGROUND: Delirium is one of the main causes of increased length of intensive care unit (ICU) stay among patients who have undergone living donor liver transplantation (LDLT). We aimed to evaluate risk factors for delirium after LDLT as well as to investigate whether delirium impacts the length of ICU and hospital stay. METHODS: Seventy-eight patients who underwent LDLT during the period January 2010 to December 2012 at a single medical center were enrolled. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale was used to diagnose delirium. Preoperative, postoperative, and hematologic factors were included as potential risk factors for developing delirium. RESULTS: During the study period, delirium was diagnosed in 37 (47.4%) patients after LDLT. The mean onset of symptoms occurred 7.0+/-5.5 days after surgery and the mean duration of symptoms was 5.0+/-2.6 days. The length of stay in the ICU for patients with delirium (39.8+/-28.1 days) was significantly longer than that for patients without delirium (29.3+/-19.0 days) (p<0.05). Risk factors associated with delirium included history of alcohol abuse [odds ratio (OR) = 6.40, 95% confidence interval (CI): 1.85-22.06], preoperative hepatic encephalopathy (OR = 4.45, 95% CI: 1.36-14.51), APACHE II score >=16 (OR = 1.73, 95% CI: 1.71-2.56), and duration of endotracheal intubation >=5 days (OR = 1.81, 95% CI: 1.52-2.23). CONCLUSIONS: History of alcohol abuse, preoperative hepatic encephalopathy, APACHE II scores >=16 and endotracheal intubation >=5 days were predictive of developing delirium in the ICU following liver transplantation surgery and were associated with increased length of ICU and hospital stay. PMID- 24811255 TI - Application of a thiourea-containing task-specific ionic liquid for the solid phase extraction cleanup of lead ions from red lipstick, pine leaves, and water samples. AB - Here, task-specific ionic liquid solid-phase extraction is proposed for the first time. In this approach, a thiourea-functionalized ionic liquid is immobilized on the solid sorbent, multiwalled carbon nanotubes. These modified nanotubes packed into a solid-phase extraction column are used for the selective extraction and preconcentration of ultra-trace amounts of lead(II) from aqueous samples prior to electrothermal atomic absorption spectroscopy determination. The thiourea functional groups act as chelating agents for lead ions retaining them and so, give the selectivity to the sorbent. Elution of the retained ions can be performed using an acidic thiourea solution. The effects of experimental parameters including pH of the aqueous solution, type and amount of eluent, and the flow rates of sample and eluent solutions on the separation efficiency are investigated. The linear dependence of absorbance of lead on its concentration in the initial solution is in the range of 0.5-40.0 ng/mL with the detection limit of 0.13 ng/mL (3(Sb)/m, n = 10). The proposed method is applicable to the analysis of red lipstick, pine leaves, and water samples for their lead contents. PMID- 24811256 TI - Prognostic value of the lymph node ratio in stage III gastric cancer patients undergoing radical resection. AB - OBJECTIVE: The aim of this study was to investigate the prognostic value of metastatic lymph node ratio (LNR) in patients having radical resection for stage III gastric cancer. METHODS: A total of 365 patients with stage III gastric cancer who underwent radical resection between 2002 and 2008 at Tianjin Medical University Cancer Institute and Hospital were analyzed. The cut-point survival analysis was adopted to determine the appropriate cutoffs for LNR. Kaplan-Meier survival curves and log-rank tests were used for the survival analysis. RESULTS: By cut-point survival analysis, the LNR staging system was generated using 0.25 and 0.50 as the cutoff values. Pearson's correlation test revealed that the LNR was related with metastatic lymph nodes but not related with total harvested lymph nodes. Cox regression analysis showed that depth of invasion and LNR were the independent predictors of survival (p<0.05). There was a significant difference in survival between each pN stages classified by the LNR staging, however no significant difference was found in survival rate between each LNR stages classified by the pN staging. CONCLUSIONS: The LNR is an independent prognostic factor for survival in stage III gastric cancer and is superior to the pN category in TNM staging. It may be considered as a prognostic variable in future staging system. PMID- 24811257 TI - Delivery of platinum(IV) drug to subcutaneous tumor and lung metastasis using bradykinin-potentiating peptide-decorated chitosan nanoparticles. AB - Selectively activating tumor vessels to increase drug delivery and reduce interstitial fluid pressure of tumors is actively pursued. Here we developed a vasoactive peptide-decorated chitosan nanoparticles for enhancing drug accumulation and penetration in subcutaneous tumor and lung metastasis. The vasoactive peptide used here is bradykinin-potentiating peptide (BPP) containing 9 amino acid residues and the drug is bioreductively sensitive platinum(IV) compound which becomes cisplatin in intracellular reductive environments. Both peptide and drug are covalently linked with chitosan nanoparticles with a diameter of 120 nm. We demonstrate that BPP-decorated chitosan nanoparticles increase the tumorous vascular permeability and reduce the interstitial fluid pressure of tumor simultaneously, both of which improve the penetration of nanoparticles in tumor tissues. The in vivo biodistribution and tumor inhibition examinations demonstrate that the BPP-decorated nanoparticle formulation has more superior efficacy in enhancing drug accumulation in tumor, restraining tumor growth and prolonging the lifetime of tumor-bearing mice than free drug and non decorated nanoparticle formulation. Meanwhile, the drug accumulation in the lung with metastasis reaches 17% and 20% injected dose per gram of lung for the chitosan nanoparticles without and with BPP decoration, respectively, which is 10 fold larger than that of free cisplatin. The examination of lung metastasis inhibition further indicates that BPP-decorated chitosan nanoparticle formulations can more effectively inhibit lung metastasis. PMID- 24811258 TI - Engineered protein nanoparticles for in vivo tumor detection. AB - Two different protein nanoparticles that are totally different in shape and surface structure, i.e. Escherichia coli DNA-binding protein (eDPS) (spherical, 10 nm) and Thermoplasma acidophilum proteasome (tPTS) (cylindrical, 12 * 15 nm) were engineered for in vivo optical tumor detection: arginine-glycine-aspartic acid (RGD) peptide (CDCRGDCFC) was genetically inserted to the surface of each protein nanoparticle, and also near-infrared fluorescence dye was chemically linked to the surface lysine residues. The specific affinity of RGD for integrin (alphavbeta3) facilitated the uptake of RGD-presenting protein nanoparticles by integrin-expressing tumor cells, and also the protein nanoparticles neither adversely affected cell viability nor induced cell damage. After intravenously injected to tumor-bearing mice, all the protein nanoparticles successfully reached tumor with negligible renal clearance, and then the surface RGD peptides caused more prolonged retention of protein nanoparticles in tumor and accordingly higher fluorescence intensity of tumor image. In particular, the fluorescence of tumor image was more intensive with tPTS than eDPS, which is due presumably to longer in vivo half-life and circulation of tPTS that originates from thermophilic and acidophilic bacterium. Although eDPS and tPTS were used as proof of-concept in this study, it seems that other protein nanoparticles with different size, shape, and surface structure can be applied to effective in vivo tumor detection. PMID- 24811259 TI - Gadolinium-functionalized nanographene oxide for combined drug and microRNA delivery and magnetic resonance imaging. AB - The delivery of anti-cancer therapeutics to tumors at clinically effective concentrations, while avoiding nonspecific toxicity, remains a major challenge for cancer treatment. Here we present nanoparticles of poly(amidoamine) dendrimer grafted gadolinium-functionalized nanographene oxide (Gd-NGO) as effective carriers to deliver both chemotherapeutic drugs and highly specific gene targeting agents such as microRNAs (miRNAs) to cancer cells. The positively charged surface of Gd-NGO was capable of simultaneous adsorption of the anti cancer drug epirubicin (EPI) and interaction with negatively charged Let-7g miRNA. Using human glioblastoma (U87) cells as a model, we found that this conjugate of Let-7g and EPI (Gd-NGO/Let-7g/EPI) not only exhibited considerably higher transfection efficiency, but also induced better inhibition of cancer cell growth than Gd-NGO/Let-7g or Gd-NGO/EPI. The concentration of Gd-NGO/Let-7g/EPI required for 50% inhibition of cellular growth (IC50) was significantly reduced (to the equivalent of 1.3 MUg/mL EPI) compared to Gd-NGO/EPI (3.4 MUg/mL EPI). In addition, Gd-NGO/Let-7g/EPI could be used as a contrast agent for magnetic resonance imaging to identify the location and extent of blood-brain barrier opening and quantitate drug delivery to tumor tissues. These results suggest that Gd-NGO/Let-7g/EPI may be a promising non-viral vector for chemogene therapy and molecular imaging diagnosis in future clinical applications. PMID- 24811260 TI - Bone regeneration performance of surface-treated porous titanium. AB - The large surface area of highly porous titanium structures produced by additive manufacturing can be modified using biofunctionalizing surface treatments to improve the bone regeneration performance of these otherwise bioinert biomaterials. In this longitudinal study, we applied and compared three types of biofunctionalizing surface treatments, namely acid-alkali (AcAl), alkali-acid heat treatment (AlAcH), and anodizing-heat treatment (AnH). The effects of treatments on apatite forming ability, cell attachment, cell proliferation, osteogenic gene expression, bone regeneration, biomechanical stability, and bone biomaterial contact were evaluated using apatite forming ability test, cell culture assays, and animal experiments. It was found that AcAl and AnH work through completely different routes. While AcAl improved the apatite forming ability of as-manufactured (AsM) specimens, it did not have any positive effect on cell attachment, cell proliferation, and osteogenic gene expression. In contrast, AnH did not improve the apatite forming ability of AsM specimens but showed significantly better cell attachment, cell proliferation, and expression of osteogenic markers. The performance of AlAcH in terms of apatite forming ability and cell response was in between both extremes of AnH and AsM. AcAl resulted in significantly larger volumes of newly formed bone within the pores of the scaffold as compared to AnH. Interestingly, larger volumes of regenerated bone did not translate into improved biomechanical stability as AnH exhibited significantly better biomechanical stability as compared to AcAl suggesting that the beneficial effects of cell-nanotopography modulations somehow surpassed the benefits of improved apatite forming ability. In conclusion, the applied surface treatments have considerable effects on apatite forming ability, cell attachment, cell proliferation, and bone ingrowth of the studied biomaterials. The relationship between these properties and the bone-implant biomechanics is, however, not trivial. PMID- 24811261 TI - Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis. AB - Carbon monoxide (CO) has potent anti-inflammatory and anti-oxidant effects. We report herein on the preparation of a nanotechnology-based CO donor, CO-bound hemoglobin-vesicles (CO-HbV). We hypothesized that CO-HbV could have a therapeutic effect on idiopathic pulmonary fibrosis (IPF), an incurable lung fibrosis, that is thought to involve inflammation and the production of reactive oxygen species (ROS). Pulmonary fibril formation and respiratory function were quantitatively evaluated by measuring hydroxyproline levels and forced vital capacity, respectively, using a bleomycin-induced pulmonary fibrosis mice model. CO-HbV suppressed the progression of pulmonary fibril formation and improved respiratory function compared to saline and HbV. The suppressive effect of CO-HbV on pulmonary fibrosis can be attributed to a decrease in ROS generation by inflammatory cells, NADPH oxidase 4 and the production of inflammatory cells, cytokines and transforming growth factor-beta in the lung. This is the first demonstration of the inhibitory effect of CO-HbV on the progression of pulmonary fibrosis via the anti-oxidative and anti-inflammatory effects of CO in the bleomycin-induced pulmonary fibrosis mice model. CO-HbV has the potential for use in the treatment of, not only IPF, but also a variety of other ROS and inflammation-related disorders. PMID- 24811262 TI - Repair of spinal cord injury by inhibition of astrocyte growth and inflammatory factor synthesis through local delivery of flavopiridol in PLGA nanoparticles. AB - The cell-cycle inhibitor flavopiridol has been shown to improve recovery from spinal cord injury in animal models. However, the systemic dose of flavopiridol has side-effects and the mechanism of action is not clear. This study aimed to develop a strategy for the local delivery of flavopiridol and investigate its mechanisms of action. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used for the sustained delivery of flavopiridol. The spinal cord was right hemisectioned and NPs were delivered into the injury site. Transparent spinal cord technology was used for the three-dimensional observation of anterograde tracing. The results showed that flavopiridol NPs had a sustained release of up to 3 days in vitro. Flavopiridol NPs significantly decreased inflammatory factor synthesis by astrocytes, including TNF-alpha, IL-1beta, and IL-6, while the IL-10 expression was elevated. In vivo study demonstrated that flavopiridol NPs decreased cell-cycle activation, inflammatory expression and glial scarring, and facilitated neuronal survival and regeneration. The cavitation volume was decreased by ~90%. Administration of flavopiridol NPs also improved the motor recovery of injured animals. These findings demonstrated that local delivery of flavopiridol in PLGA NPs improves recovery from spinal cord injury by inhibiting astrocyte growth and inflammatory factor synthesis. PMID- 24811264 TI - Chemically tunable ionic liquids with aprotic heterocyclic anion (AHA) for CO(2) capture. AB - Ionic liquids (ILs) with aprotic heterocyclic anions, or AHAs, can bind CO2 with reaction enthalpies that are suitable for gas separations and without suffering large viscosity increases. In the present work, we have synthesized ILs bearing an alkyl-phosphonium cation with indazolide, imidazolide, pyrrolide, pyrazolide and triazolide-based anions that span a wide range of predicted reaction enthalpies with CO2. Each AHA-based IL was characterized by NMR spectroscopy and their physical properties (viscosity, glass transition, and thermal decomposition temperature) determined. In addition, the influence of substituent groups on the reaction enthalpy was investigated by measuring the CO2 solubility in each IL at pressures between 0 and 1 bar at 22 degrees C using a volumetric method. The isotherm-derived enthalpies range between -37 and -54 kJ mol(-1) of CO2, and these values are in good agreement with computed enthalpies of gas-phase IL-CO2 reaction products from molecular electronic structure calculations. The AHA ILs show no substantial increase in viscosity when fully saturated with CO2 at 1 bar. Phase splitting and compositional analysis of one of the IL/H2O and IL/H2O/CO2 systems conclude that protonation of the 2-cyanopyrrolide anion is improbable, and this result was confirmed by the equimolar CO2 absorption in the presence of water. Taking advantage of the tunable binding energy and absence of viscosity increase after the reaction with CO2, AHA ILs are promising candidates for efficient and environmental-friendly absorbents in postcombustion CO2 capture. PMID- 24811263 TI - Nanofibrous gelatin substrates for long-term expansion of human pluripotent stem cells. AB - Nanofibrous gelatin substrates are suited for long-term expansion of human pluripotent stem cells (hPSCs) under feeder- and serum-free culture conditions. A combinatorial library with different sets of processing parameters was established to assess the culture performance of hPSCs on nanofibrous substrates in terms of cell adhesion and growth rate, using Matrigel as control. Then, the optimal conditions were applied to long-term expansion of hPSCs with several cell lines, showing a maintained pluripotency over more than 20 passages without introducing any abnormal chromosome. In addition, this approach allowed us to avoid enzymatic disassociation and mechanic cutting during passages, thereby promoting a better hPSC culture and long-term expansion. PMID- 24811266 TI - Low body mass index might be a predisposing factor for varicocele recurrence: a prospective study. AB - We investigated the possible relationship between body mass index (BMI) score and varicocele recurrence in an infertile patient population. A total of 255 primary infertile male patients (138 with varicocele and 117 for control) were included in this study. Height and weight measurements, clinical examination for varicocele, determination of serum hormone levels and spermiogram were performed in all cases. The BMI score was calculated, and patients with varicocele were operated with subinguinal technique and re-examined for recurrences. The varicocele group had significantly lower weight and the BMI score than the control group (P < 0.001). Varicocele recurrences were found in 22 patients (16% of them) after the operations. The BMI score was significantly lower in the recurrent group than in the nonrecurrent and control groups (P < 0.001). 73% of the recurrent, 50% of the nonrecurrent and 25% of the control group patients' BMI scores were under 25 kg m(-2) (P < 0.001). In logistic regression analysis, the BMI score was found as a determinant for varicocele recurrence (P = 0.027; OR: 1.25). It is concluded that BMI score lower than 25 kg m(-2) significantly increases the recurrence rate after varicocele operation, and it can be used as an objective indicator for microsurgical varicocelectomy. PMID- 24811265 TI - Cytotoxic steroids from the leaves of Dysoxylum binectariferum. AB - Four new cholestane-type (1-4) and two new ergostane-type (5, 6) steroids were isolated from the leaves of Dysoxylum binectariferum. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques. The absolute configurations were established by comparison with the literature and Mo2(OAc)4-induced electronic circular dichroism (ECD) data. All the isolates were evaluated for cytotoxicity against A549 (lung carcinoma), MCF-7 (breast adenocarcinoma), and HepG2 (hepatocellular carcinoma) human cancer cell lines. Three of the new cholestane-type steroids displayed potent antiproliferative effects on the tumor cells with IC50 values ranging from 1.5 to 9.6MUM, whereas the two new ergostane-type (5, 6) steroids were deemed inactive. PMID- 24811267 TI - The importance of individual developmental variation in stage-structured population models. AB - Population stage structure is fundamental to ecology, and models of this structure have proven useful in many different systems. Many ecological variables other than stage, such as habitat type, site occupancy and metapopulation status are also modelled using transitions among discrete states. Transitions among life stages can be characterised by the distribution of time spent in each stage, including the mean and variance of each stage duration and within-individual correlations among multiple stage durations. Three modelling traditions represent stage durations differently. Matrix models can be derived as a long-run approximation from any distribution of stage durations, but they are often interpreted directly as a Markov model for stage transitions. Statistical stage duration distribution models accommodate the variation typical of cohort development data, but such realism has rarely been incorporated in population theory or statistical population models. Delay-differential equation models include lags but no variation, except in limited cases. We synthesise these models in one framework and illustrate how individual variation and correlations in development can impact population growth. Furthermore, different development models can yield the same long-term matrix transition rates but different sensitivities and elasticities. Finally, we discuss future directions for estimating realistic stage duration models from data. PMID- 24811268 TI - Experimental examination of worry among older and young adults. AB - BACKGROUND: Worry is experienced by many older adults, yet our understanding of the emotional experience of late-life worry is poor as findings regarding older adults are inferred from findings of studies conducted with young adults. In the present study, we aimed to characterize age differences in affect, self-reported arousal, and physiological arousal experienced during worry. METHODS: Fifty-three young (M = 21.4, SD = 2.6 years) and 55 older community-dwelling adults (M = 69.1, SD = 8.1 years) participated in an experimental induction of worry or pleasant/neutral recall. Measures collected included: Penn State Worry Questionnaire (PSWQ), worry intensity item, Multiple Affect Adjective Checklist Revised (MAACL-R), Self-Assessment Maniken arousal item, and heart rate. Standardized residual scores were calculated to represent change from baseline for self-report and psychophysiological measures. RESULTS: Older adults had lower trait worry and worry intensity at baseline. A significant age by induction type interaction was found for the MAACL-R subscales of anxiety, depression, hostility, and positive affect. Compared with young adults, older adults experienced smaller changes in emotions in response to the worry induction than in the recall induction. For both worry and recall inductions, older adults exhibited less change in self-reported arousal and interbeat intervals from baseline compared with young adults. CONCLUSIONS: Findings from the present study illuminate both similarities and differences in the experience of worry for older and young adults. This study provides preliminary evidence for the characterization of late-life worry as generating less anxiety than worry during young adulthood. PMID- 24811269 TI - Exercise, hypoglycemia, and type 1 diabetes. PMID- 24811270 TI - Cynomolgus and pigtail macaque IgG subclasses: characterization of IGHG genes and computational analysis of IgG/Fc receptor binding affinity. AB - Macaques are the most widely used experimental nonhuman primate (NHP) species. Rhesus (Macaca mulatta, Macmul), cynomolgus (Macaca fascicularis, Macfas), and pigtail (Macaca nemestrina, Macnem) macaques continue to be popular models for vaccine and infectious diseases research, especially HIV infection and AIDS, and for the development of antibody-based therapeutic strategies. Increased understanding of the immune system of these species is necessary for their optimal use as models of human infections and intervention. In the past few years, the antibody/Fc receptor system has been characterized in a stepwise manner in these species. We have continued this characterization by identifying the four IG heavy gamma (IGHG) genes of Macfas and Macnem in this study. Our results show that these genes share a high degree of similarity with those from other NHP species, while presenting consistent differences when compared to human IGHG genes. Furthermore, comparison of Macfas IGHG genes with those described in other studies suggests the existence of polymorphism. Using sequence- and structure-based computational tools, we performed in silico analysis on multiple polymorphic Macfas IgG and their interactions with human IgG Fc receptors (FcgammaR), thus predicting that Macfas IGHG polymorphisms influence IgG protein stability and/or binding affinity towards FcgammaR. The presence of macaque IGHG polymorphisms and macaque/human amino acid changes at locations potentially involved in antibody functional properties indicate the need for cautious design and data interpretation of studies in these models, possibly requiring the characterization of antibody/Fc receptor interactions at the individual level. PMID- 24811272 TI - Synthesis of diazo-bridged BODIPY dimer and tetramer by oxidative coupling of beta-amino-substituted BODIPYs. AB - A diazo-bridged BODIPY dimer and tetramer were prepared by the oxidative coupling reaction of beta-amino-substituted BODIPYs. The structure of the dimer was elucidated by X-ray diffraction analysis, showing its coplanar orientation of two BODIPY units. Effective extension of pi-conjugation was confirmed by optical and electrochemical investigations. PMID- 24811271 TI - Genome-wide SNP associations with rubella-specific cytokine responses in measles mumps-rubella vaccine recipients. AB - Genetic polymorphisms are known to affect responses to both viral infection and vaccination. Our previous work has described genetic polymorphisms significantly associated with variations in immune response to rubella vaccine from multiple gene families with known immune function, including HLA, cytokine and cytokine receptor genes, and in genes controlling innate and adaptive immunity. In this study, we assessed cellular immune responses (IFNgamma and IL-6) in a cohort of healthy younger individuals and performed genome-wide SNP analysis on these same individuals. Here, we report the first genome-wide association study focused on immune responses following rubella vaccination. Our results indicate that rs16928280 in protein tyrosine phosphatase delta (PTPRD) and a collection of SNPs in ACO1 (encoding an iron regulatory protein) are associated with interindividual variations in IFNgamma response to rubella virus stimulation. In contrast, we did not identify any significant genetic associations with rubella-specific IL-6 response. These genetic regions may influence rubella vaccine-induced IFNgamma responses and warrant further studies in additional cohorts in order to confirm these findings. PMID- 24811273 TI - Cytological, histological and ultrastructural nuclear features of monster cells in a canine carotid body carcinoma. AB - A 7-year-old female Shih-tzu dog was presented with severe dyspnoea. A large mass was palpated in the left cranial neck. Cytological examination of an aspirate sample revealed cells with marked anisokaryosis, giant elements and many bare nuclei. Scattered intact giant cells showed scant, granular cytoplasm and intranuclear inclusions. Histologically, neoplastic cells were subdivided into lobules by fine collagenous trabeculae. Numerous pleomorphic giant, or 'monster', cells were observed, showing a highly indented nuclear envelope, intranuclear cytoplasmic pseudoinclusions (ICPs) and 'ground-glass' nuclear appearance. Neoplastic emboli were present, but no distant metastases were detected grossly. Immunohistochemically, the neoplastic cells expressed synaptophysin and had variable expression of neuron-specific enolase and vimentin. The cells were negative for pan-cytokeratin, CAM 5.2, glial fibrillary acidic protein and S100. Nuclear abnormalities and cytoplasmic neurosecretory granules were noted ultrastructurally. These features were consistent with a diagnosis of carotid body carcinoma (chemodectoma). Monster cells with ICPs have not been documented previously in canine chemodectoma. PMID- 24811275 TI - A stable, pillar-layer metal-organic framework containing uncoordinated carboxyl groups for separation of transition metal ions. AB - A 3D pillar-layer framework (1) with uncoordinated carboxyl groups exhibits exceptional stability. It can effectively and selectively adsorb Cu(2+) ions and has been applied as a chromatographic column for separating Cu(2+)/Co(2+) ions. PMID- 24811274 TI - A collision tumour consisting of malignant trichoblastoma and melanosarcoma in a rabbit. AB - A 7-year-old mixed breed neutered female rabbit (Orytolagus cuniculus) developed a solitary black nodular mass (1 cm in diameter) in the skin of the right flank. Microscopically, the mass consisted of an admixture of neoplastic trichoblasts and melanocytes. The former were arranged as solid, trabecular, island-like and gland-like structures and the cells had oval nuclei with prominent nucleoli and lightly eosinophilic scant cytoplasm. The latter population exhibited prominent nuclear atypia and high mitotic index in the clusters of a few cells or single cells. Immunohistochemically, the neoplastic trichoblasts expressed cytokeratins and E-cadherin, while the neoplastic melanocytes expressed vimentin, S100 protein, melan-A and melanoma antigen. A diagnosis of collision tumour involving malignant trichoblastoma and melanosarcoma was made. PMID- 24811281 TI - Comparison of the efficacy and morbidity of flexible ureterorenoscopy for lower pole stones compared with other renal locations. AB - BACKGROUND AND PURPOSE: Flexible ureterorenoscopy (f-URS) for lower pole stones (LPS) compared with other renal locations can be challenging because of anatomic and technical considerations. We aimed to compare the stone-free rate (SFR) and surgical complication rate with f-URS for LPS vs other renal locations. PATIENTS AND METHODS: We performed a retrospective, single-center study including 371 f URS for renal stone retrieval performed in our institution between January 2004 and December 2010. Among the 371 procedures included in this analysis, 139 were performed for stones located in a single renal location other than the lower pole (group 1), and 232 for at least one stone located in the lower pole (group 2). We compared the efficacy (SFR) and the morbidity of f-URS between the two groups. The success of the procedure was defined as a complete SFR 6 months after f-URS. RESULTS: Age, sex, history of urolithiasis, body mass index, and preoperative stent placement did not differ between the two groups. No differences in stone characteristics were observed between both groups except stone size under 10 mm that was significantly higher in group 2 (P=0.018). Technical aspects of the procedure did not differ between the groups, except for more frequent use of an access sheath in group 2 (P=0.007). SFR was comparable between groups (P=0.774). The complication rate was similar in both groups, as was the severity of complications. By multivariate analysis, stone size >10 mm (P<0.0001) and multiple stone locations (P=0.001) were associated with f-URS failure, but lower pole location did not impact on SFR. CONCLUSION: In our study, stone location, in particular LPS, did not have any impact on efficacy and morbidity of f-URS. Only multiple locations and stone size >10 mm seemed to significantly decrease the SFR, without impacting morbidity. PMID- 24811282 TI - The peril of order? IPV, injury, and order in Mongolian families. AB - Despite its consistent and latent appearance in feminist accounts of intimate partner violence (IPV), the characterization of IPV as an elaborately ordered relationship whose norms are backed up by force is notably absent from the empirical IPV literature. Drawing on Emery's typology of IPV, we hypothesized a curvilinear relationship between order and IPV injury. We developed a measure of relationship order and implemented it in a representative, randomly selected cluster sample of 250 families from Ulaanbaatar, Mongolia. Controlling for the severity of the IPV, higher levels of order, but not lower levels, are associated with higher numbers of reported IPV injuries. Theoretical and practical implications of order as a risk factor are discussed. PMID- 24811283 TI - "Same-sex relationship in a straight world": individual and societal influences on power and control in young men's relationships. AB - Young men who have sex with men (YMSM) continue to experience higher rates of HIV infection than other populations. Recently, there have been recommendations to consider HIV prevention at the dyadic or couple level. Using a dyadic approach to HIV prevention would also address an unaddressed concern related to intimate partner violence (IPV) among YMSM. Although research on IPV among YMSM is still in its infancy, great strides have been made in the past 10 years to describe the prevalence and related correlates of IPV within older adult same-sex relationships. These studies have found rates of IPV among MSM to be similar to rates among heterosexual women, and to be on the rise. The present study is designed to provide insight into how power is conceptualized within YMSM relationships and the role it may play in relationship challenges. This study draws from qualitative data collected from 11 focus groups with 86 YMSM and 26 individual semi-structured interviews to understand relationship challenges and the experiences of YMSM involved in partner violence. YMSM described relationship power as stemming from numerous sources including sexual positioning, gender roles, education, income, prior relationship experiences, and internalized homophobia. The findings have a number of implications for service providers and program design. Interventionists and other researchers need to consider power dynamics and other contextual elements of IPV before effective interventions can be developed for YMSM and other sexual minority populations. PMID- 24811284 TI - Predicting aggression, conciliation, and concurrent rumination in escalating conflict. AB - Interactions are characterized by opposite motives according to game theory. The purpose of this study was to explore how people judge the probability and advisability of conflict reactions in an unfolding dispute within a married couple using latent growth curve modeling (LGCM). Individuals participated in a study using two videotaped scenarios depicting marital conflict in which a spouse comes home after a long day at work only to criticize his or her partner for violating expectations of a good meal. One situation involved male-initiated conflict and female reactance, whereas another illustrated female-initiated conflict and male reactance. Participants were asked to predict the future reactions based on aggressive tactics (e.g., slapping the partner, insulting the partner) or prosocial and forgiving communication (e.g., apologizing, discussing the issue calmly) as well as the use of online, imagined interaction (II) rumination in which individuals replay arguments in their mind as well as thinking about what to say next during the argument. Results of the LGCM revealed support for various hypotheses in which it was predicted that the husband would be more likely to be conciliatory than the wife, and the wife would be more aggressive than her husband. II rumination was initially expected to increase and be advised before reaching a plateau. Findings are discussed in terms of game theory and II conflict-linkage theory. PMID- 24811285 TI - Informal social reactions to college women's disclosure of intimate partner violence: associations with psychological and relational variables. AB - This researchers assessed informal (e.g., friends, family) social reactions to college women's (N = 139) disclosure of intimate partner violence (IPV) within their current romantic relationships and associated psychological (i.e., posttraumatic stress symptoms [PTSS] and global psychological distress symptoms) and relational (i.e., intentions to leave the abusive relationship) variables. Women completed confidential surveys, which assessed current partner abuse, psychological and relational variables, and three types of social reactions from informal supports to disclosure of IPV: positive (e.g., believing, validating the victim), negative (e.g., disbelieving, blaming the victim), and leaving (i.e., being told to end the relationship) reactions. At the bivariate level, negative social reactions to women's disclosure were related to increases in global psychological distress, PTSS, and leaving intentions; positive social reactions to disclosure related only to increases in PTSS; and being told to leave the relationship related to increases in PTSS and leaving intentions. In the regression analyses, after controlling for abuse severity, negative social reactions were significantly related to global psychological distress and PTSS, and being told to leave significantly related to leaving intentions and PTSS. Mechanisms for these relationships and implications are discussed. PMID- 24811287 TI - Response to "Acquaintance molestation and youth-serving organizations" by Kenneth V. Lanning and Park Dietz. PMID- 24811286 TI - Trauma, gender, and mental health symptoms in individuals with substance use disorders. AB - Individuals with substance use disorders are often plagued by psychiatric comorbidities and histories of physical and/or sexual trauma. Males and females, although different in their rates of expressed trauma and psychiatric symptomatology, experience comparable adverse consequences, including poorer substance abuse treatment outcomes, diminished psychosocial functioning, and severe employment problems. The goal of the current study was to examine the relationships between trauma history, lifetime endorsement of psychiatric symptoms, and gender in a sample of individuals participating in outpatient substance abuse treatment. Study participants (N = 625) from six psychosocial counseling and five methadone maintenance programs were recruited as part of a larger study conducted through the National Institute on Drug Abuse Clinical Trials Network (NIDA CTN). Study measures included lifetime trauma experience (yes/no), type of trauma experienced (sexual, physical, both), lifetime depression/anxiety, and lifetime suicidal thoughts/attempts (as measured by the Addiction Severity Index-Lite [ASI-Lite]). Lifetime endorsement of psychiatric symptoms was compared between individuals with and without trauma history. The role of gender was also examined. Results indicated that the experience of trauma was associated with an increase in lifetime report of psychiatric symptoms. Experience of physical and combined physical and sexual trauma consistently predicted positive report of psychiatric symptoms in both males and females, even when controlling for demographic and treatment-related variables. Employment outcomes, however, were not predicted by self-reported history of lifetime trauma. PMID- 24811288 TI - Racial disparities in age at time of homicide victimization: a test of the multiple disadvantage model. AB - This study sought the factors associated with race/ethnicity disparities in the age at which homicide deaths tend to occur. We used the multiple disadvantage model to take race into account as we evaluated associations between age at time of homicide victimization and several social structural, mental health-related, and lifestyle factors. Data were derived from the 1993 National Mortality Followback Survey, a cross-sectional interview study of spouses, next of kin, other relatives, and close friends of individuals 15 years and older who died in the United States in 1993. Our results showed age at time of homicide mortality to be related to the three types of factors; race moderated some of these relationships. In general, being employed, married, and a homeowner appeared associated with reduced victimization while young. The relationship of victimization age and employment was not uniform across racial groups, nor was the relationship of victimization age and marital status uniform across groups. Among Blacks, using mental health services was associated with longer life. Homicide by firearm proved important for our Black and Hispanic subsamples, while among Whites, alcohol's involvement in homicide exerted significant effects. Our results suggest that programs and policies serving the various racial/ethnic groups can alleviate multiple disadvantages relevant in homicide victimization at an early age. PMID- 24811290 TI - Recurrent head and neck desmoplastic melanoma with perineural spread along the nervus mandibularis revealed by 18F-FDG PET/CT. AB - This report describes a rare case of recurrent head and neck desmoplastic neurotropic melanoma with perineural spread along the nervus mandibularis. An 87 year-old male presented with a rapidly growing mass on the right side of the chin, 4 years after surgical excision of a desmoplastic non-melanotic melanoma of the tip of the chin, with lymphadenectomy of the right side submental and submandibular areas. A panoramic X-ray showed extensive widening of the mandibular canal compatible with perineural tumour growth. (18)F fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) images revealed intense pathological uptake in the recurrent tumour mass located in the right lower buccal fold, and linear pathological uptake in the mandibular canal. Although magnetic resonance imaging is considered the standard of reference, recognition of perineural spread on (18)F-FDG PET/CT is important, as it usually leads to a change in patient management from cure to palliation and may avert further diagnostic procedures. PMID- 24811289 TI - Early intra-articular injection of alendronate reduces cartilage changes and subchondral bone loss in rat temporomandibular joints after ovariectomy. AB - This study investigated the effects of intra-articular injection of alendronate on the mandibular condyle in ovariectomized rats. Sixty rats were divided into five groups: ovariectomy with vehicle treatment alone, early alendronate treatment at ovariectomy, late alendronate treatment at 4 weeks after ovariectomy, sham-operation with vehicle treatment, and normal controls. The changes in cartilage and subchondral bone were evaluated by micro-computed tomography, histology, tartrate-resistant acid phosphatase (TRAP) staining, immunohistochemistry, and real-time quantitative polymerase chain reaction. Compared with late alendronate treatment, early alendronate treatment completely inhibited cartilage thickening (727.6+/-39.3 vs. 1013.3+/-51.6; P=0.017) and improved microstructural properties of the subchondral bone, with a higher bone volume ratio (46.4+/-2.5 vs. 37.5+/-2.1; P=0.038), trabecular thickness (47.3+/ 1.7 vs. 34.6+/-1.4; P=0.029), and trabecular number (8.5+/-0.6 vs. 6.2+/-0.3; P=0.041) and lower trabecular separation (30.2+/-1.6 vs. 37.7+/-2.6; P=0.034). Fewer TRAP-positive cells (4.2+/-0.2 vs. 6.8+/-0.4; P=0.019) and a higher OPG/RANKL ratio (0.38+/-0.01 vs. 0.25+/-0.03; P=0.043) in the subchondral bone were observed in the animals with early treatment compared to late treatment or ovariectomy/vehicle treatment. In addition, early alendronate treatment blocked the up-regulation of matrix metalloproteinase (MMP)-13 expression in the chondrocytes, whereas late alendronate treatment attenuated the up-regulation of MMP-13 expression. Our results suggest the therapeutic potential of intra articular alendronate injection in the treatment of osteoporosis-associated temporomandibular disorders. PMID- 24811293 TI - Development and validation of the tinnitus primary function questionnaire. AB - PURPOSE: To create a questionnaire focused on the primary activities impaired by tinnitus and therefore more sensitive to treatments. METHOD: Questions were developed on (a) emotions, (b) hearing, (c) sleep, and (d) concentration. A 20 item questionnaire was administered to 158 patients. First, confirmatory factor analysis was used to select 3 questions per domain. Second, factor analysis was used to evaluate the appropriateness of the 12-item questionnaire. RESULTS: The analysis indicated that the selected questions successfully represented 4 independent domains. Scores were correlated with the Tinnitus Handicap Questionnaire ( r = .77, p < .01) and loudness ( r = .40, p < .01). The Sleep subscale correlated with the Pittsburgh Sleep Index ( r = .68, p < .01); the Emotion subscale correlated with the Beck Inventory ( r = .66, p < .01) and the Trait Anxiety questionnaire ( r = .67, p < .01). The average scores went from 51% to 38% following treatment. CONCLUSION: The Tinnitus Primary Function Questionnaire is valid, reliable, and sensitive and can be used to determine the efficacy of clinical trials. PMID- 24811294 TI - Learning from photobiology how to design molecular devices using a computer. AB - Biological photoreceptors and fluorescent proteins provide striking examples of how non-covalent interactions could be exploited for tuning the photochemistry and photophysics of organic chromophores. In this tutorial review we show how the construction of computer models of such natural supramolecular systems not only provides atomic-level information on the mechanisms of their function, but also principles useful for designing light-responsive components of artificial supramolecular systems. Using a few complementary case studies, the intellectual process leading to the implementation of such an engineering target is followed up to the actual construction of a working prototype of a biomimetic molecular switch. PMID- 24811296 TI - Familial combined hyperlipidemia: from molecular insights to tailored therapy. AB - PURPOSE OF REVIEW: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). RECENT FINDINGS: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. SUMMARY: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications. PMID- 24811297 TI - Clinical utility of serum markers of cholesterol absorption and synthesis. AB - PURPOSE OF REVIEW: The serum noncholesterol sterols are widely used today in clinical lipid research as surrogate markers of cholesterol absorption and synthesis. Their applicability and some aspects related to their analysis, use, and interpretations are discussed. RECENT FINDINGS: The serum markers of cholesterol metabolism have been carefully validated in several populations and during different interventions. If the homeostasis between cholesterol absorption and synthesis is lost, the markers cannot be used as surrogates. The markers have been applied in large population and cohort studies to find out how cholesterol metabolism is related to coronary artery disease. Most of the large studies suggested that increased levels of the markers of cholesterol absorption may conceivably be a risk factor for coronary artery disease. SUMMARY: Results even from large population studies vary from population to population. The large number of factors, which interfere with cholesterol metabolism, such as age, sex, BMI, diet, health status, medication, and genetic background, and differences in the analysis methods of the serum markers should be taken into consideration when interpreting the data. PMID- 24811295 TI - Recent advances in understanding the STSL locus and ABCG5/ABCG8 biology. AB - PURPOSE OF REVIEW: To provide an update on recent advances made in our mechanistic and pathophysiological understanding of the rare human disease Sitosterolemia, the role of ABCG5/ABCG8 in sterol trafficking and how newer data implicate a more wider role in the body. RECENT FINDINGS: Sitosterolemia is caused by a genetic defect of sterolins (ABCG5/ABCG8) mapped to the STSL locus. Polymorphic variations in STSL have been linked to lipid levels and gallstone disease in whites. Newer studies now link this locus to a more diverse ethnic group for gallstone disease, susceptibility to biliary cancer, and show variants that alter sterolin function. Intriguingly, carriers of a mutant allele seem to show protection against carotid wall disease. Although the 'promoter' region of the STSL is minimal, regulatory regions responsive to liver X receptor have remained elusive, but no longer; two intronic regions in ABCG8 have now been identified. Xenosterol accumulation leads to loss of abdominal fat, infertility, and premature death. Xenosterol accumulation in mouse platelet membranes leads to platelet hyperactivation, increased microparticle formation, and reduced alphaIIbbeta3 surface expression. In humans, phytosterols may promote liver injury in parenteral nutrition-associated liver disease. SUMMARY: Progress in understanding sterolin function is beginning to show that xenosterols can be toxic and are involved on pathogenesis, and the role of ABCG5/ABCG8 may extend into other metabolic processes by altering intracellular sterol metabolism. PMID- 24811298 TI - The composition and metabolism of large and small LDL. AB - PURPOSE OF REVIEW: Decreased size and increased density of LDL have been associated with increased coronary heart disease (CHD) risk. Elevated plasma concentrations of small dense LDL (sdLDL) correlate with high plasma triglycerides and low HDL cholesterol levels. This review highlights recent findings about the metabolism and composition of LDL subfractions. RECENT FINDINGS: The development of an automated assay has recently made possible the assessment of the CHD risk associated with sdLDL in large clinical trials and has demonstrated convincingly that sdLDL cholesterol levels are a more significant independent determinant of CHD risk than total LDL cholesterol. Metabolic studies have revealed that sdLDL particles originate through the delipidation of larger atherogenic VLDL and large LDL and from direct de novo production by the liver. Proteins associated with LDL, in addition to apolipoprotein (apo) B, include the C apolipoproteins, apoA-I, apoA-IV, apoD, apoE, apoF, apoH, apoJ, apoL-1, apoM, alpha-1 antitrypsin, migration inhibitory factor-related protein 8, lysosome C, prenylcysteine oxidase 1, paraoxonase 1, transthyretin, serum amyloid A4, and fibrinogen alpha chain. The role of the increasing number of LDL-associated proteins remains unclear; however, the data do indicate that LDL particles not only transport lipids but also carry proteins involved in inflammation and thrombosis. The sdLDL proteome in diabetic individuals differs significantly from that of larger LDL, being enriched in apoC-III. SUMMARY: Progress in our understanding of the composition and metabolism of LDL subfractions strengthens the association between sdLDL and CHD risk. PMID- 24811299 TI - Living with hepatitis C: a phenomenological study. AB - AIMS AND OBJECTIVES: To explore the experience of adults living with hepatitis C over time. BACKGROUND: Hepatitis C virus is a growing problem affecting thousands of people worldwide. The majority of individuals infected develop chronic liver disease, but treatment is not always successful, leaving many to live with the virus indefinitely. Experiences of living with hepatitis C are poorly understood yet essential to meet the needs of an increasing number of affected people. DESIGN: A qualitative study using a descriptive phenomenological methodology. METHODS: Unstructured interviews were conducted with 23 hepatitis C-positive individuals in the East of England; participants were interviewed twice within a year. RESULTS: Data analysis revealed six themes of the experience of living with hepatitis C: hepatitis C and self; hepatitis C, self and others; self and handling hepatitis C; self and handling hepatitis C treatment issues; living with the consequences of hepatitis C; self, hepatitis C and thoughts of the future. CONCLUSIONS: Diagnosis of hepatitis C can disrupt people's sense of identity and trigger a life transition. A complex range of factors create uncertainty for people living with hepatitis C. Many struggle to make a healthy transition to life with the condition, instead living in a state of sustained uncertainty. RELEVANCE TO CLINICAL PRACTICE: Nurses working within a chronic care framework of ongoing advice and support can improve experiences for those living with hepatitis C. Practice aimed at reducing both the disruptive effect of the diagnosis and the uncertainties it creates can help facilitate a transition to life with the disease. PMID- 24811300 TI - Biased and unbiased strategies to identify biologically active small molecules. AB - Small molecules are central players in chemical biology studies. They promote the perturbation of cellular processes underlying diseases and enable the identification of biological targets that can be validated for therapeutic intervention. Small molecules have been shown to accurately tune a single function of pluripotent proteins in a reversible manner with exceptional temporal resolution. The identification of molecular probes and drugs remains a worthy challenge that can be addressed by the use of biased and unbiased strategies. Hypothesis-driven methodologies employs a known biological target to synthesize complementary hits while discovery-driven strategies offer the additional means of identifying previously unanticipated biological targets. This review article provides a general overview of recent synthetic frameworks that gave rise to an impressive arsenal of biologically active small molecules with unprecedented cellular mechanisms. PMID- 24811301 TI - Dynamic changes in saliva after acute mental stress. AB - Stress-related variations of fluoride concentration in supernatant saliva and salivary sediment, salivary cortisol, total protein and pH after acute mental stress were assessed. The hypothesis was that stress reactions have no influence on these parameters. Thirty-four male students were distributed into two groups: first received the stress exposure followed by the same protocol two weeks later but without stress exposure, second underwent the protocol without stress exposure followed by the stress exposure two weeks later. The stressor was a public speech followed by tooth brushing. Saliva was collected before, immediately after stress induction and immediately, at 10, 30 and 120 min. after tooth brushing. Cortisol concentrations, total protein, intraoral pH, and fluoride content in saliva were measured. The data were analyzed statistically. Salivary sediment was ca 4.33% by weight of whole unstimulated saliva. Fluoride bioavailability was higher in salivary sediment than in supernatant saliva. The weight and fluoride concentration was not altered during 2 hours after stress exposure. After a public speech, the salivary cortisol concentration significantly increased after 20 minutes compared to the baseline. The salivary protein concentration and pH also increased. Public speaking influences protein concentration and salivary pH but does not alter the fluoride concentration of saliva. PMID- 24811302 TI - Alpinia oxyphylla Miquel fruit extract activates MAPK-mediated signaling of PAs and MMP2/9 to induce Schwann cell migration and nerve regeneration. AB - OBJECTIVES: This study investigates the molecular mechanisms by which Alpiniae oxyphyllae fructus (AOF) promotes neuron regeneration. METHODS: A piece of silicone rubber was guided across a 15 mm gap in the sciatic nerve of a rat. This nerve gap was then filled with different concentrations of AOF extract (0-200 mg/ml). We investigated the role of MAPK (ERK1/2, JNK and p38) pathways for AOF induced matrix-degrading proteolytic enzyme (PAs and MMP2/9) production in RSC96 Schwann cells. RESULTS: The results showed that AOF increased the expressions of uPA, tPA, MMP-9, and MAPKs in vivo. In vitro, our results show that treatment with AOF extract induces ERK1/2, JNK, and p38 phosphorylation to activate the downstream PAs and MMPs signaling expression. AOF-stimulated ERK1/2, JNK, and p38 phosphorylation attenuated by individual pretreatment with siRNAs or inhibitors (U0126, SP600125 and SB203580), resulting in migration and uPA-related signal pathway inhibition. CONCLUSIONS: Taken together our data suggests the MAPKs (ERK1/2, JNK and p38), PAs (uPA, tPA), MMP (MMP2, MMP9) regenerative and migration signaling pathway of Schwann cells regulated by AOF extract might play a major role in Schwann cell migration and damaged peripheral nerve regeneration. PMID- 24811303 TI - Elevated resistin levels are associated with inflammation in hemodialysis patients with failed renal allografts. AB - BACKGROUND: Resistin is an adipocytokine, associated with insulin resistance and inflammation. The aim of this study is to evaluate the levels of serum resistin levels and other markers of inflammation in hemodialysis (HD) patients with failed renal allografts. METHODS: Sixty-nine HD patients with failed renal allografts and 98 never transplanted (naive) HD patients and also 21 healthy controls were included in the study. Serum levels of various biochemical parameters as well as resistin, IL-6, TNF-alpha and hs-CRP as biochemical markers of inflammation, were measured. RESULTS: Serum resistin levels in patients with failed renal allografts (4.80 +/- 2.06 ng/mL) were significantly higher than those of the naive HD patients (3.44 +/- 1.48 ng/mL) and healthy controls (0.95 +/- 0.38 ng/mL; p<0.001). Patients with failed transplants were also characterized by higher TNF-alpha levels (96.8 +/- 131.3 pg/mL vs. 40.9 +/- 25.4 pg/mL; p<0.001) and IL-6 levels (83.9 +/- 150.9 pg/mL vs. 14.6 +/- 14.4 pg/mL; p<0.001) as compared to naive HD patients. Serum hs-CRP levels in patients with failed renal allografts (9.33 +/- 11.86 mg/L) were significantly higher than those of the naive HD patients (1.26 +/- 1.71 mg/L) and healthy controls (2.12 +/ 1.82 mg/L; p<0.001). Serum albumin levels in patients with failed transplants (3.84 +/- 0.47 g/dL) were lower as compared to never transplanted HD patients (4.13 +/- 0.33 g/dL) and healthy controls (4.53 +/- 0.40 g/dL; p<0.001). There was a positive correlation between serum resistin and TNF-alpha levels (r = 0.486, p<0.001). CONCLUSIONS: Serum resistin levels are increased in HD patients with failed renal allografts very probably reflecting an allograft-induced chronic inflammatory state. PMID- 24811304 TI - Chronic dialysis discontinuation: a systematic narrative review of the literature in the new millennium. AB - INTRODUCTION AND AIMS: Renal function recovery (RFR), defined as the discontinuation of dialysis after 3 months of replacement therapy, is an uncommon occurrence. At a time when the "too early" start of dialysis is in discussion, a systematic review of the literature for cases in which patients recovered renal function after starting dialysis with chronic indications, including single cases and large series, may lead to attention being focused on this interesting issue. METHODS: The search strategy was built in Medline on Pubmed, in EMBASE and in the Cochrane Collaboration (August 2013) combining Mesh, Emtree and free terms: dialysis or hemodialysis, kidney function, renal function and recovery (publication date 2000-2013). The following tasks were performed in duplicate: titles and abstracts were manually screened, the data were extracted: title, author, objective, year, journal, period of study, multi-center, country, type of study. RESULTS: The systematic review retrieved 1,894 titles; 58 full papers were retrieved and the final selection included 24 papers: 11 case series or Registry data (4 from ANZdata) and 13 case reports. In spite of the high heterogeneity of the studies, overall they suggest that RFR occurs in about 1% of patients, without differences between PD and HD. RFR appears to be more frequent in elderly patients with renal vascular disease (up to 10% RFR in cholesterol emboli or scleroderma), but is reported in all types of primary and secondary kidney diseases. CONCLUSIONS: RFR is a clinical event that should be looked for, particularly in elderly patients with vascular comorbidity. PMID- 24811305 TI - Intra-operative graft blood flow measurements for composite and sequential coronary artery bypass grafting. AB - OBJECTIVES: Intraoperative assessment of coronary artery bypass grafts (CABG) anastomotic quality can be performed using transit-time flowmetry (TTF). The aim of this study was to compare on- versus off-pump coronary graft TTF and early postoperative outcomes. MATERIALS AND METHODS: Between January 2009 and January 2010, 521 distal graft flows were assessed using TTF measurements in 253 consecutive patients undergoing primary isolated CABG surgery. Data were analyzed using multilevel models accounting for clustering among surgeons and grafts performed in the same patient. RESULTS: Mean age was 66 +/- 10 years and 22% were female (n = 55) with 34% diabetics (n = 86) and 40% preoperative myocardial infarction (MI) (n = 101). The surgeries were performed off-pump in 67% (n = 170) with sequential vein grafts in 57% (n = 144) of patients. Off-pump patients had higher pre-operative left ventricular ejection fractions (LVEF), fewer urgent surgeries, fewer distal anastomoses, and fewer sequential vein grafts (all p<0.001). Intra-operative coronary graft TTF measurements were lower in sequential vein grafts performed off-pump versus on-pump. More patients in the on pump group needed milrinone or dobutamine 24-48 h postoperatively (p = 0.005). Independent predictors of lower TTF included female gender and off-pump surgery, whereas predictors of better TTF were preoperative MI, larger coronary diameter at the site of the distal anastomosis, and sequential vein grafting. CONCLUSIONS: Lower intra-operative TTF measurements were found in sequential vein grafts in off-pump CABG. However, off-pump patients experienced similar short-term outcomes compared to on-pump patients. PMID- 24811306 TI - Influence of polysulphone-derived dialysis membranes on the interaction of circulating mononuclear cells with the endothelium. AB - PURPOSE: Cardiovascular morbidity in hemodialysis (HD) patients may be influenced by the activation of circulating mononuclear cells (MCs) with subsequently increased endothelium interaction. The use of more biocompatible membranes would reduce this monocyte activation. We compare monocyte activation after using two different high-flux polymers, polysulphone and polyethersulphone. METHODS: The first part of the study was done with 10 patients who successively received dialysis for 2 weeks with polysulphone and polyethersulphone. The second part with 30 patients dialyzed for 3 months with polysulphone or polyethersulphone. Blood samples were taken before (pre-HD) and after (post-HD) the first HD session with each membrane to evaluate the effect of a single HD session. To assess acute and chronic effects of membranes, blood samples were taken pre-HD, after 2 weeks (first part of study) and after 3 months (second part of study). MCs were isolated from blood and then incubated with cultured human endothelial cells to evaluate MC adhesion, MC-dependent endothelial toxicity, and endothelial protein expressions of nitric oxide synthase and endothelin-converting enzyme-1 (ECE-1). RESULTS: One single HD session did not induce any changes. Dialysis for 2 weeks (first part of study) with polyethersulphone reduced MC adhesion to endothelium, cellular toxicity, and ECE-1 protein expression compared to polysulphone or basal conditions. Dialysis for 3 months (second part of study) increased MC adhesion to endothelium, whereas cellular toxicity was decreased with both dialyzers compared to the basal situation. CONCLUSIONS: Although polyethersulphone HD decreased the interaction of MC with the endothelium in short-term experiments, both membranes were comparable in the long-term. PMID- 24811307 TI - Evaluation of the hemodynamic effectiveness of aortic dissection treatments via virtual stenting. AB - Aortic dissection treatment varies for each patient and stenting is one of a number of approaches that are utilized to Stabilize the condition. Information regarding the hemodynamic forces in the aorta in dissected and virtually stented cases could support clinicians in their choices of treatment prior to medical intervention. Computational fluid dynamics coupled with lumped parameter models have shown promise in providing detailed information that could be used in the clinic; for this, it is necessary to develop personalized workflows in order to produce patient-specific simulations. In the present study, a case of pre- and post-stenting (virtual stent-graft) of an aortic dissection is investigated with a particular focus on the role of personalized boundary conditions. For each virtual case, velocity, pressure, energy loss, and wall shear stress values are evaluated and compared. The simulated single stent-graft only marginally reduced the pulse pressure and systemic energy loss. The double stent-graft results showed a larger reduction in pulse pressure and a 40% reduction in energy loss as well as a more physiological wall shear stress distribution.Regions of potential risk were highlighted. The methodology applied in the present study revealed detailed information about two possible surgical outcome cases and shows promise as both a diagnostic and an interventional tool. PMID- 24811308 TI - Septic shock secondary to beta-hemolytic streptococcus-induced necrotizing fasciitis treated with a novel cytokine adsorption therapy. AB - INTRODUCTION: Numerous animal studies and preliminary data from a clinical trial in septic patients demonstrated that a decrease in blood cytokine levels using an extracorporeal cytokine filter (CytoSorb) can effectively attenuate the inflammatory response during sepsis and possibly improve outcomes. METHODS: A 60 year-old female was admitted to hospital due to a forearm fracture. After surgical wound care by osteosynthesis the patient developed surgical wound infection which progressed to necrotizing fasciitis. All diagnostic criteria for SIRS were evident with additional proven infection from beta-hemolytic streptococcus. On admission to the ICU, the patient presented a full picture of multiple organ dysfunction syndrome due to septic shock including kidney failure, lung failure as well as thrombocytopenia, metabolic acidosis, and arterial hypotension. RESULTS: After one day on mechanical ventilation and an IL-6 level of 70,000 pg/ml the patient was treated with CytoSorb therapy over a period of four days, resulting in a significant reduction of IL-6 to 66 pg/ml and an overall improvement of the patient's condition. Despite the necessity of enucleation, the patient was successfully stabilized until control of the surgical infectious source was achieved. Importantly, treatment was safe and well tolerated, without any adverse events. CONCLUSIONS: This is the first report of the clinical application of CytoSorb hemoadsorption in combination with a CRRT in a patient with septic shock. CytoSorb as described was able to significantly reduce IL-6 plasma levels and decrease vasopressor need while no adverse and device-related events occurred. CytoSorb seems to be an interesting and safe extracorporeal therapy to stabilize and bridge septic patients to surgery or recovery. PMID- 24811309 TI - A continuous veno-venous hemofiltration protocol with anticoagulant citrate dextrose formula A and a calcium-containing replacement fluid. AB - INTRODUCTION: Regional citrate anticoagulation (RCA) is used as an anticoagulant for continuous renal replacement therapy (CRRT). A systemic calcium (Ca2+) infusion is required to replace Ca2+ lost in the effluent. The shortage of intravenous Ca2+ in the United States has limited RCA use. We describe a continuous veno-venous hemofiltration (CVVH) protocol with RCA using 2.2% anticoagulant citrate dextrose formula-A (ACD-A) and a commercial dialysate containing Ca2+ 1.5 mmol/l (N * Stage) as post-filter replacement fluid (RF), without need for Ca2+ infusion. METHODS: We prospectively evaluated five patients on CRRT who had at least three episodes of filter clotting within 24 h. Patients were switched to CVVH using ACD-A infused pre-blood pump and titrated to achieve a post-filter ionized calcium (iCa2+) level <0.5 mmol/l. The Ca2+ -containing dialysate was delivered post-filter as RF. RESULTS: Steady state mean serum chemistries were: Na+: 140.8 +/- 2.3 meq/l, K+: 4.2 +/- 0.4 meq/l, HCO3-: 30.9 +/ 3.7 meq/l, pH: 7.42 +/- 0.07, CO2: 47.9 +/- 8.3 mmHg, total Ca2+: 8.08 +/- 1.09 mg/dL. Post-filter iCa2+ ranged 0.27-0.36 mmol/l, and patient iCa2+ ranged 0.81 1.24 mmol/l. Mean post-filter RF rate: 3086 +/- 164 ml/h, mean ACD-A rate: 298 +/ 21 ml/h. Mean blood flow rate: 200 +/- 17 ml/min, mean filtration fraction: 39.6 +/- 7.2%. Mean effluent flow rate: 38.6 +/- 6.7 ml/kg/h (range 28.7-55.8). Mean filter survival was 7 h without anticoagulation, compared to 42.6 h in the ACD-A group (p<0.0001). CONCLUSIONS: In this pilot study, CVVH using ACD-A for RCA and a Ca2+ -containing RF was safely and effectively used without a continuous Ca2+ infusion. This protocol is a promising solution for maintaining effective CRRT when intravenous calcium is in short supply. PMID- 24811310 TI - Evolution of renal function after partial and full mechanical support for chronic heart failure. AB - PURPOSE: Recently a minimal invasive, partial support continuous flow left ventricular assist device (LVAD) became available for treatment of chronic heart failure. The aim of this study was to analyze whether partial support is capable of improving kidney function in end-stage heart failure. METHODS: We performed a single-center retrospective analysis of patients how received a full (n = 43) or partial support LVAD (n = 18) between 2007 and 2013. Patients on dialysis or in INTERMACS class I were excluded. Renal function was assessed until 3 months after the implantation. A calculated GFR less than 60 m/min was considered to be renal failure. RESULTS: Creatinine level after LVAD implant decreased 23% in patients on full support (1.3 +/- 0.4 mg/dl vs. 1.0 +/- 0.3 mg/dl; p<0.001) and 24% in patients on partial support (1.6 +/- 0.6 mg/dl vs. 1.2 +/- 0.4 mg/dl; p = 0.17) within 3 months. In each group patients with a preoperative GFR less than 60 ml/min were selected. In this subgroup there was a 35% decrease in creatinine levels for patients on full support (1.7 +/- 0.4 mg/dl vs. 1.1 +/- 0.5 mg/dl; p<0.01) and a 32% decrease in patients on partial support (2 +/- 0.4 mg/dl vs. 1.4 +/- 0.3 mg/dl; p<0.05) at 3 months. CONCLUSIONS: We observed a significant improvement in renal function in patients supported by full or partial support devices, even if the preoperative renal function was severly impaired. The use of diuretics decreased in both groups. In chronic heart failure patients with impaired renal function, partial support is sufficient to improve renal function significantly. PMID- 24811312 TI - Roles of the sodium-translocating NADH:quinone oxidoreductase (Na+-NQR) on vibrio cholerae metabolism, motility and osmotic stress resistance. AB - The Na+ translocating NADH:quinone oxidoreductase (Na+-NQR) is a unique respiratory enzyme catalyzing the electron transfer from NADH to quinone coupled with the translocation of sodium ions across the membrane. Typically, Vibrio spp., including Vibrio cholerae, have this enzyme but lack the proton-pumping NADH:ubiquinone oxidoreductase (Complex I). Thus, Na+-NQR should significantly contribute to multiple aspects of V. cholerae physiology; however, no detailed characterization of this aspect has been reported so far. In this study, we broadly investigated the effects of loss of Na+-NQR on V. cholerae physiology by using Phenotype Microarray (Biolog), transcriptome and metabolomics analyses. We found that the V. cholerae DeltanqrA-F mutant showed multiple defects in metabolism detected by Phenotype Microarray. Transcriptome analysis revealed that the V. cholerae DeltanqrA-F mutant up-regulates 31 genes and down-regulates 55 genes in both early and mid-growth phases. The most up-regulated genes included the cadA and cadB genes, encoding a lysine decarboxylase and a lysine/cadaverine antiporter, respectively. Increased CadAB activity was further suggested by the metabolomics analysis. The down-regulated genes include sialic acid catabolism genes. Metabolomic analysis also suggested increased reductive pathway of TCA cycle and decreased purine metabolism in the V. cholerae DeltanqrA-F mutant. Lack of Na+-NQR did not affect any of the Na+ pumping-related phenotypes of V. cholerae suggesting that other secondary Na+ pump(s) can compensate for Na+ pumping activity of Na+-NQR. Overall, our study provides important insights into the contribution of Na+-NQR to V. cholerae physiology. PMID- 24811311 TI - Cellular superspreaders: an epidemiological perspective on HIV infection inside the body. PMID- 24811313 TI - Polymers fight HIV: potent (pro)drugs identified through parallel automated synthesis. AB - Macromolecular (pro)drugs interfere with the proliferation of HIV through both inhibition of viral cell entry and via intracellular delivery of antiviral drugs. Lead polymer conjugates exhibit longevity of action exceeding that of parent nucleoside analogue drug and are active in primary T cell over at least 72 h. PMID- 24811314 TI - Tumour control probability in cancer stem cells hypothesis. AB - The tumour control probability (TCP) is a formalism derived to compare various treatment regimens of radiation therapy, defined as the probability that given a prescribed dose of radiation, a tumour has been eradicated or controlled. In the traditional view of cancer, all cells share the ability to divide without limit and thus have the potential to generate a malignant tumour. However, an emerging notion is that only a sub-population of cells, the so-called cancer stem cells (CSCs), are responsible for the initiation and maintenance of the tumour. A key implication of the CSC hypothesis is that these cells must be eradicated to achieve cures, thus we define TCPS as the probability of eradicating CSCs for a given dose of radiation. A cell surface protein expression profile, such as CD44high/CD24low for breast cancer or CD133 for glioma, is often used as a biomarker to monitor CSCs enrichment. However, it is increasingly recognized that not all cells bearing this expression profile are necessarily CSCs, and in particular early generations of progenitor cells may share the same phenotype. Thus, due to the lack of a perfect biomarker for CSCs, we also define a novel measurable TCPCD+, that is the probability of eliminating or controlling biomarker positive cells. Based on these definitions, we use stochastic methods and numerical simulations parameterized for the case of gliomas, to compare the theoretical TCPS and the measurable TCPCD+. We also use the measurable TCP to compare the effect of various radiation protocols. PMID- 24811315 TI - A computational framework for analyzing stochasticity in gene expression. AB - Stochastic fluctuations in gene expression give rise to distributions of protein levels across cell populations. Despite a mounting number of theoretical models explaining stochasticity in protein expression, we lack a robust, efficient, assumption-free approach for inferring the molecular mechanisms that underlie the shape of protein distributions. Here we propose a method for inferring sets of biochemical rate constants that govern chromatin modification, transcription, translation, and RNA and protein degradation from stochasticity in protein expression. We asked whether the rates of these underlying processes can be estimated accurately from protein expression distributions, in the absence of any limiting assumptions. To do this, we (1) derived analytical solutions for the first four moments of the protein distribution, (2) found that these four moments completely capture the shape of protein distributions, and (3) developed an efficient algorithm for inferring gene expression rate constants from the moments of protein distributions. Using this algorithm we find that most protein distributions are consistent with a large number of different biochemical rate constant sets. Despite this degeneracy, the solution space of rate constants almost always informs on underlying mechanism. For example, we distinguish between regimes where transcriptional bursting occurs from regimes reflecting constitutive transcript production. Our method agrees with the current standard approach, and in the restrictive regime where the standard method operates, also identifies rate constants not previously obtainable. Even without making any assumptions we obtain estimates of individual biochemical rate constants, or meaningful ratios of rate constants, in 91% of tested cases. In some cases our method identified all of the underlying rate constants. The framework developed here will be a powerful tool for deducing the contributions of particular molecular mechanisms to specific patterns of gene expression. PMID- 24811317 TI - Reflections on cell competition. AB - Cell competition is a process by which otherwise viable cells are actively eliminated due to the presence of more competitive cells. It is a conserved phenomenon and occurs in various developmental and experimental contexts. Competitive elimination represents a safeguard mechanism that potentiates animal development. However, the process can also be hijacked, for example, by cancer cells to promote and sustain malignancy. One of the challenges facing the field is that the term "cell competition" is used to describe a variety of phenomena whose relatedness is under debate. The goals of this review are to provide an overview of the literature on cell competition-like phenomena, highlight where there are discrepancies, and, when possible, provide alternative interpretations to reconcile the dissonance. Central to this is a comparison of the various models of cell competition. With our critical examination we seek to draw attention to future prospects in the field of cell competition. We believe that the elucidation of the interplay between loser and winner cells in the process of cell competition will provide new targets for the development of cancer therapeutics. PMID- 24811318 TI - Context-dependent modulation reconfigures interactive sensory-mediated microcircuits in Caenorhabditis elegans. AB - Caenorhabditis elegans navigates sensory landscapes by integrating inputs from 14 pairs of polymodal sensory neurons. Sensory neurons interact synaptically and through gap junction networks and are modulated by complex local/humoral, nutritionally dependent, monoaminergic and peptidergic signaling cascades that dynamically reconfigure individual sensory-mediated locomotory circuits. Monoaminergic/peptidergic signaling modifies the sensory signal by providing, first, feedback loops between sensory neurons and postsynaptic partners to fine tune inputs, second, crosstalk between sensory neurons to integrate responses and third, local/humoral extrasynaptic signals to facilitate broader, long term system-wide modulation. Overall, these observations highlight the differences between an anatomical wiring diagram and 'functional connectomes' that are essential to generate the alternative circuit configurations required to choose different behavioral outcomes in the face of changing environmental inputs. PMID- 24811316 TI - Mechanism and physiological significance of programmed replication termination. AB - Replication forks in both prokaryotic and eukaryotic systems pause at random sites due to depletion of dNTP pools, DNA damage, tight binding nonhistone proteins or unusual DNA sequences and/or structures, in a mostly non-polar fashion. However, there is also physiologically programmed replication termination at sequence-specific authentic replication termini. Here, the structure and functions of programmed replication termini, their mechanism of action and their diverse physiological functions in prokaryotes and eukaryotes have been reviewed. PMID- 24811319 TI - Three types of ependymal cells with intracellular calcium oscillation are characterized by distinct cilia beating properties. AB - Ependymal cells are multiciliated epithelial cells that line the ventricles in the adult brain. Abnormal function or structure of ependymal cilia has been associated with various neurological deficits. For the first time, we report three distinct ependymal cell types, I, II, and III, based on their unique ciliary beating frequency and beating angle. These ependymal cells have specific localizations within the third ventricle of the mouse brain. Furthermore, neither ependymal cell types nor their localizations are altered by aging. Our high-speed fluorescence imaging analysis reveals that these ependymal cells have an intracellular pacing calcium oscillation property. Our study further shows that alcohol can significantly repress the amplitude of calcium oscillation and the frequency of ciliary beating, resulting in an overall decrease in volume replacement by the cilia. Furthermore, the pharmacological agent cilostazol could differentially increase cilia beating frequency in type II, but not in type I or type III, ependymal cells. In summary, we provide the first evidence of three distinct types of ependymal cells with calcium oscillation properties. PMID- 24811320 TI - Characterization of cytomegalovirus lung infection in non-HIV infected children. AB - Cytomegalovirus (CMV) is a prevalent pathogen in the immunocompromised host and invasive pneumonia is a feared complication of the virus in this population. In this pediatric case series we characterized CMV lung infection in 15 non-HIV infected children (median age 3 years; IQR 0.2-4.9 years), using current molecular and imaging diagnostic modalities, in combination with respiratory signs and symptoms. The most prominent clinical and laboratory findings included cough (100%), hypoxemia (100%), diffuse adventitious breath sounds (100%) and increased respiratory effort (93%). All patients had abnormal lung images characterized by ground glass opacity/consolidation in 80% of cases. CMV was detected in the lung either by CMV PCR in bronchoalveolar lavage (82% detection rate) or histology/immunohistochemistry in lung biopsy (100% detection rate). CMV caused respiratory failure in 47% of children infected and the overall mortality rate was 13.3%. CONCLUSION: CMV pneumonia is a potential lethal disease in non HIV infected children that requires a high-index of suspicion. Common clinical and radiological patterns such as hypoxemia, diffuse adventitious lung sounds and ground-glass pulmonary opacities may allow early identification of CMV lung infection in the pediatric population, which may lead to prompt initiation of antiviral therapy and better clinical outcomes. PMID- 24811322 TI - Exchanging Ohmic losses in metamaterial absorbers with useful optical absorption for photovoltaics. AB - Using metamaterial absorbers, we have shown that metallic layers in the absorbers do not necessarily constitute undesired resistive heating problem for photovoltaics. Tailoring the geometric skin depth of metals and employing the natural bulk absorbance characteristics of the semiconductors in those absorbers can enable the exchange of undesired resistive losses with the useful optical absorbance in the active semiconductors. Thus, Ohmic loss dominated metamaterial absorbers can be converted into photovoltaic near-perfect absorbers with the advantage of harvesting the full potential of light management offered by the metamaterial absorbers. Based on experimental permittivity data for indium gallium nitride, we have shown that between 75%-95% absorbance can be achieved in the semiconductor layers of the converted metamaterial absorbers. Besides other metamaterial and plasmonic devices, our results may also apply to photodectors and other metal or semiconductor based optical devices where resistive losses and power consumption are important pertaining to the device performance. PMID- 24811321 TI - A novel adenovirus in Chinstrap penguins (Pygoscelis antarctica) in Antarctica. AB - Adenoviruses (family Adenoviridae) infect various organ systems and cause diseases in a wide range of host species. In this study, we examined multiple tissues from Chinstrap penguins (Pygoscelis antarctica), collected in Antarctica during 2009 and 2010, for the presence of novel adenoviruses by PCR. Analysis of a 855-bp region of the hexon gene of a newly identified adenovirus, designated Chinstrap penguin adenovirus 1 (CSPAdV-1), showed nucleotide (amino acid) sequence identity of 71.8% (65.5%) with South Polar skua 1 (SPSAdV-1), 71% (70%) with raptor adenovirus 1 (RAdV-1), 71.4% (67.6%) with turkey adenovirus 3 (TAdV 3) and 61% (61.6%) with frog adenovirus 1 (FrAdV-1). Based on the genetic and phylogenetic analyses, CSPAdV-1 was classified as a member of the genus, Siadenovirus. Virus isolation attempts from kidney homogenates in the MDTC-RP19 (ATCC(r) CRL-8135TM) cell line were unsuccessful. In conclusion, this study provides the first evidence of new adenovirus species in Antarctic penguins. PMID- 24811323 TI - Analysis of elder abuse statutes across the United States, 2011-2012. AB - The purpose of this article is to describe the state elder abuse statutes in the United States and Washington DC during 2011-2012. The last review of elder abuse statutes occurred in 2001; thus, a reexamination is warranted given the increased awareness of elder abuse at the state and national level and the growing number of older adults in the United States. This descriptive study analyzed the following components of elder or dependent abuse statutes: definitions, reporting requirements, training, and consequences for failure to report. It was determined that differences remain in how states respond to elder abuse at the community based level. PMID- 24811324 TI - Hepatoprotective coumarins and secoiridoids from Hydrangea paniculata. AB - Three new coumarin glucosides (1, 3, 4), and a new secoiridoid glucoside (2), together with one known secoiridoid glucoside (5), were isolated from the stems of Hydrangea paniculata. Their structures were elucidated on the basis of spectroscopic methods, including extensive NMR, MS and CD spectra. At 10 MUM, compounds 1-5 showed hepatoprotective activities against DL-galactosamine-induced toxicity in HL-7702 cells. PMID- 24811325 TI - The Leishmania donovani chaperone cyclophilin 40 is essential for intracellular infection independent of its stage-specific phosphorylation status. AB - During its life cycle, the protozoan pathogen Leishmania donovani is exposed to contrasting environments inside insect vector and vertebrate host, to which the parasite must adapt for extra- and intracellular survival. Combining null mutant analysis with phosphorylation site-specific mutagenesis and functional complementation we genetically tested the requirement of the L. donovani chaperone cyclophilin 40 (LdCyP40) for infection. Targeted replacement of LdCyP40 had no effect on parasite viability, axenic amastigote differentiation, and resistance to various forms of environmental stress in culture, suggesting important functional redundancy to other parasite chaperones. However, ultrastructural analyses and video microscopy of cyp40-/- promastigotes uncovered important defects in cell shape, organization of the subpellicular tubulin network and motility at stationary growth phase. More importantly, cyp40-/- parasites were unable to establish intracellular infection in murine macrophages and were eliminated during the first 24 h post infection. Surprisingly, cyp40-/- infectivity was restored in complemented parasites expressing a CyP40 mutant of the unique S274 phosphorylation site. Together our data reveal non-redundant CyP40 functions in parasite cytoskeletal remodelling relevant for the development of infectious parasites in vitro independent of its phosphorylation status, and provide a framework for the genetic analysis of Leishmania-specific phosphorylation sites and their role in regulating parasite protein function. PMID- 24811326 TI - Estimating energy expenditure using heat flux measured at a single body site. AB - INTRODUCTION: The Personal Calorie Monitor (PCM) is a portable direct calorimeter that estimates energy expenditure (EE) from measured heat flux (i.e., the sum of conductive, convective, radiative, and evaporative heat). PURPOSE: The primary aim of this study was to compare EE estimated from measures of heat flux with those measured using indirect calorimetry in a thermoneutral environment (26 degrees C). A secondary aim was to determine whether exposure to ambient temperature below thermoneutral condition (19 degrees C) influences the accuracy of the PCM. METHODS: Thirty-four adults (mean +/- SD: age, 28 +/- 5 yr; body mass index, 22.9 +/- 2.6 kg . m(-2)) were studied for 5 h in a whole-room indirect calorimeter (IC) in thermoneutral and cool conditions. Participants wore the PCM on their upper arm and completed two 20-min treadmill walking bouts (0% grade, 3 mph). The remaining time was spent sedentary (e.g., watching television, using a computer). RESULTS: In thermoneutral conditions, EE values (mean (95% confidence interval)) measured by IC and PCM were 560.0 (526.5-593.5) and 623.3 (535.5 711.1) kcal, respectively. In cool conditions, EE values measured by IC and PCM were 572.5 (540.9-604.0) and 745.5 (668.1-822.8) kcal, respectively. Under thermoneutral conditions, mean PCM minute-by-minute EE tracked closely with IC, resulting in a small nonsignificant bias (63 kcal (-5.8 to 132.4)). During cool conditions, mean PCM minute-by-minute EE did not track IC, resulting in a large bias (173.0 kcal (93.9-252.1)) (P <; 0.001). CONCLUSIONS: This study demonstrated the validity of using measured heat flux to estimate EE. However, accuracy may be impaired in cool conditions possibly because of excess heat loss from the exposed limbs. PMID- 24811327 TI - Sex differences in the effects of type 2 diabetes on exercise performance. AB - PURPOSE: People with uncomplicated type 2 diabetes (T2D) have impaired peak exercise performance compared with that of their nondiabetic counterparts. This impairment may represent the earliest indication of cardiovascular (CV) abnormalities in T2D. Women with T2D are known to have worse CV outcomes than those in men with T2D. We hypothesized that women with diabetes have a greater exercise impairment than that in men with diabetes compared with that in their nondiabetic counterparts. METHODS: We studied 15 women (premenopausal) and 14 men with T2D as well as their nondiabetic counterparts (22 women and 13 men). Exercise testing was performed. Additional outcomes included measurements of insulin sensitivity, endothelial function, blood flow, and resting cardiac function. RESULTS: Men and women with T2D but not controls had impaired insulin sensitivity. Women with T2D had a lower peak oxygen consumption (VO2peak) compared with that of nondiabetic women (24%, P < 0.05) than men with diabetes compared with that in nondiabetic men (16%, P < 0.05) (P value between groups < 0.05). The time constants (phase 2) of the VO2 kinetic response tended to be slower in men and women with T2D than those in nondiabetic controls (P = 0.08). There were no differences in resting ventricular function by Doppler echocardiography techniques between groups. Women with T2D had significantly lower flow-mediated dilation and blood flow responses to hyperemia than those in nondiabetic women (both P < 0.05), whereas men with T2D had lower flow-mediated dilation but not lower blood flow than those in nondiabetic men. CONCLUSIONS: Although both men and women with uncomplicated T2D had a lower VO2peak, the abnormality in women with T2D compared with that in nondiabetic women was greater than that seen in men. Because VO2peak has a strong inverse correlation with mortality, sex disparities observed in exercise capacity among people with T2D suggest a possible rationale for the increased CV morbidity and mortality observed in women compared with those observed in men with uncomplicated T2D. PMID- 24811330 TI - KRAS mutation testing of metastatic colorectal cancer in Australia: where are we at? AB - AIM: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutation frequencies and turnaround times that might impact on patient care. METHODS: Participating laboratories contributed information on KRAS mutation frequencies, including the G13D mutation type, as well as turnaround times for tumor block retrieval and testing. RESULTS: The KRAS mutation frequency observed by nine different test sites for a total of 3688 metastatic colorectal cancers ranged from 34.4% to 40.7%, with an average across all sites of 38.8%. The average frequency of the G13D mutation type among all cases was 8.0%. The median turnaround time was 17 days (range 0-191), with 20% of cases requiring more than 4 weeks for a KRAS test result. The major contributor to long turnaround times was the time taken to retrieve archived blocks of primary tumor, particularly from sources external to the test site. CONCLUSION: The frequency of KRAS mutations in metastatic colorectal cancer reported by the major Australian test sites is very similar to that reported by other large overseas studies. More widespread introduction of routine testing at the time of initial diagnosis should eliminate the long turnaround times currently being experienced in a significant proportion of cases. Future expansion of testing to include other KRAS and NRAS mutation hotspots may spur the introduction of next generation sequencing platforms. PMID- 24811328 TI - Microbial mucosal colonic shifts associated with the development of colorectal cancer reveal the presence of different bacterial and archaeal biomarkers. AB - BACKGROUND: Epidemiological studies demonstrate a link between gastrointestinal cancers and environmental factors such as diet. It has been suggested that environmental cancer risk is determined by the interaction between diet and microbes. Thus, the purpose of this study was to examine the hypothesis that microbiota composition during colorectal cancer (CRC) progression might differ depending on the stage of the disease. METHODS: A total of 28 age-matched and sex matched subjects, seven with CRC adenocarcinoma, 11 with tubular adenomas and ten healthy subjects with intact colon, were included into the study. Microbiomes from mucosal and fecal samples were analyzed with 16S ribosomal RNA gene pyrosequencing, together with quantitative PCR of specific bacteria and archaea. RESULTS: The principal coordinates analysis clearly separated healthy tissue samples from polyps and tumors, supporting the presence of specific bacterial consortia that are associated with affected sites and that can serve as potential biomarkers of CRC progression. A higher presence of Fusobacterium nucleatum and Enterobacteriaceae was found by qPCR in samples from CRC compared to healthy controls. We observed a correlation between CRC process development and levels of Methanobacteriales (R = 0.537, P = 0.007) and Methanobrevibacterium (R = 0.574, P = 0.03) in fecal samples. CONCLUSION: Differences in microbial and archaeal composition between mucosal samples from healthy and disease tissues were observed in tubular adenoma and adenocarcinoma. In addition, microbiota from mucosal samples represented the underlying dysbiosis, whereas fecal samples seem not to be appropriate to detect shifts in microbial composition. CRC risk is influenced by microbial composition, showing differences according to disease progression step and tumor severity. PMID- 24811331 TI - Cerebral oxygenation in patients with OSA: effects of hypoxia at altitude and impact of acetazolamide. AB - BACKGROUND: Sleep-disordered breathing may impair cerebral oxygenation in patients with OSA syndrome, in particular during altitude travel. We studied cerebral tissue oxygenation (CTO) at low and moderate altitude in patients with OSA and evaluated whether acetazolamide improved CTO. METHODS: Eighteen patients with OSA living at < 600 m discontinued CPAP therapy during studies in Zurich (490 m) and during two sojourns of 3 days in the Swiss Alps (2 days at 1,860 m and 1 day at 2,590 m) separated by a 2-week washout period at < 600 m. Patients received acetazolamide (2 * 250 mg/d) or placebo at altitude in a randomized, double-blind, crossover design. Nocturnal polysomnography, including CTO monitoring by near-infrared spectroscopy (NIRS), was performed. RESULTS: At 490 m, medians of CTO, peripheral oxygen saturation as measured by pulse oximetry (Spo2), and apnea/hypopnea index were 65%, 93%, and 57.3/h, respectively. At 2,590 m, on placebo, the corresponding values were 59%, 86%, and 86.4/h, respectively (P < .05, all corresponding comparisons). Acetazolamide increased CTO and Spo2 at 2,590 m by mean values of 2% (95% CI, 0%-4%) and 2% (95% CI, 1% 3%), respectively, and reduced the apnea/hypopnea index by 23.4/h (95% CI, 14.0 32.8/h) (P < .05, all changes). Cerebral total hemoglobin concentration, a NIRS derived surrogate reflecting regional cerebral blood volume, increased by a similar degree in response to apneas at 490 m and 2,590 m and during acetazolamide and placebo treatment. CONCLUSIONS: In patients with OSA staying at altitude, nocturnal cerebral and arterial oxygenation were reduced in association with exacerbated sleep apnea. Acetazolamide partially improved CTO, Spo2, and sleep apnea without impairing the cerebral blood flow response to apneas. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00714740; URL: www.clinicaltrials.gov. PMID- 24811332 TI - Melatonin improves cerebrovascular function and decreases oxidative stress in chronically hypoxic lambs. AB - Chronic hypoxia during gestation and delivery results in oxidative stress and cerebrovascular dysfunction in the neonate. We assessed whether melatonin, a potent antioxidant and potential vasodilator, improves the cerebral vascular function in chronically hypoxic neonatal lambs gestated and born in the highlands (3600 m). Six lambs received melatonin (1 mg/kg per day oral) and six received vehicle, once a day for 8 days. During treatment, biometry and hemodynamic variables were recorded. After treatment, lambs were submitted to a graded FiO2 protocol to assess cardiovascular responses to oxygenation changes. At 12 days old, middle cerebral arteries (MCA) were collected for vascular reactivity, morphostructural, and immunostaining evaluation. Melatonin increased fractional growth at the beginning and improved carotid blood flow at all arterial PO2 levels by the end of the treatment (P < 0.05). Further, melatonin treatment improved vascular responses to potassium, serotonin, methacholine, and melatonin itself (P < 0.05). In addition, melatonin enhanced the endothelial response via nitric oxide-independent mechanisms in isolated arteries (162 +/- 26 versus 266 +/- 34 AUC, P < 0.05). Finally, nitrotyrosine staining as an oxidative stress marker decreased in the MCA media layer of melatonin-treated animals (0.01357 +/- 0.00089 versus 0.00837 +/- 0.00164 pixels/MUm2 , P < 0.05). All the melatonin induced changes were associated with no systemic cardiovascular alterations in vivo. In conclusion, oral treatment with melatonin modulates cerebral vascular function, resulting in a better cerebral perfusion and reduced oxidative stress in the neonatal period in chronically hypoxic lambs. Melatonin is a potential therapeutic agent for treating cerebrovascular dysfunction associated with oxidative stress and developmental hypoxia in neonates. PMID- 24811333 TI - Administration of chemotherapy via the median cubital vein without implantable central venous access ports: port-free chemotherapy for metastatic colorectal cancer patients. AB - BACKGROUND: Repeated venous punctures are usually required during chemotherapy administration for cancer patients. Central venous catheters and implantable port systems have substantially facilitated vascular access, and safe, easy-to-handle port systems have become an integral part of daily clinical routines in oncology. However, several serious complications are associated with central venous ports (CV-ports), and recent developments of combined oral capecitabine and oxaliplatin (XELOX) therapies allow CV-port-free administration. In this study, the safety and efficacy of CV-port-free chemotherapy administration via the median cubital vein was assessed in metastatic colorectal cancer patients. METHODS: This study included 144 patients who received XELOX + bevacizumab (BV) or XELOX therapy for metastatic colorectal cancer without CV-port implantation. RESULTS: Eighty-five patients experienced transient vascular pain. The drip infusion route was switched to the opposite side following vascular pain in only 1 patient. No patients required CV-port implantation or delayed treatment due to adverse events associated with drug administration via the peripheral vein. Grade 3 or higher hemotoxicity and grade 3 or higher non-hematological toxicity was noted in 12.5 and 17.4 % of patients, respectively. CONCLUSIONS: Port-free-chemotherapy administration via the median cubital vein is appropriate for patients with colorectal cancer, thereby avoiding complications associated with CV-ports. PMID- 24811334 TI - Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma. AB - Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies. PMID- 24811335 TI - Newer anticoagulants can be used off-label. PMID- 24811336 TI - Fruits and vegetables consumption and risk of stroke: a meta-analysis of prospective cohort studies. AB - BACKGROUND AND PURPOSE: We conducted a meta-analysis to summarize evidence from prospective cohort studies about the association of fruits and vegetables consumption with the risk of stroke. METHODS: Pertinent studies were identified by a search of Embase and PubMed databases to January 2014. Study-specific relative risks with 95% confidence intervals were pooled using a random-effects model. Dose-response relationship was assessed by restricted cubic spline. RESULTS: Twenty prospective cohort studies were included, involving 16 981 stroke events among 760 629 participants. The multivariable relative risk (95% confidence intervals) of stroke for the highest versus lowest category of total fruits and vegetables consumption was 0.79 (0.75-0.84), and the effect was 0.77 (0.71-0.84) for fruits consumption and 0.86 (0.79-0.93) for vegetables consumption. Subgroup and meta-regression showed that the inverse association of total fruits and vegetables consumption with the risk of stroke was consistent in subgroup analysis. Citrus fruits, apples/pears, and leafy vegetables might contribute to the protection. The linear dose-response relationship showed that the risk of stroke decreased by 32% (0.68 [0.56-0.82]) and 11% (0.89 [0.81-0.98]) for every 200 g per day increment in fruits consumption (P for nonlinearity=0.77) and vegetables consumption (P for nonlinearity=0.62), respectively. CONCLUSIONS: Fruits and vegetables consumption are inversely associated with the risk of stroke. PMID- 24811337 TI - Newer anticoagulants should not be used for off-label indications. PMID- 24811339 TI - Off-label use of new oral anticoagulants: a one-way ticket to nowhere. PMID- 24811338 TI - Predicting symptomatic intracerebral hemorrhage versus lacunar disease in patients with longstanding hypertension. AB - BACKGROUND AND PURPOSE: Hypertension results in a spectrum of subcortical cerebrovascular disease. It is unclear why some individuals develop ischemia and others develop hemorrhage. Risk factors may differ for each population. We identify factors that predispose an individual to subcortical symptomatic intracerebral hemorrhage (sICH) compared with ischemia. METHODS: Demographic and laboratory data were prospectively collected for hypertensive patients presenting with ischemic stroke or sICH during an 8.5-year period. Neuroimaging was retrospectively reviewed for acute (subcortical lacunes [<2.0 cm] versus subcortical sICH) and chronic (periventricular white matter disease and cerebral microbleeds) findings. We evaluated the impact of age, race, sex, serum creatinine, erythrocyte sedimentation rate, low-density lipoprotein, presence of periventricular white matter disease or cerebral microbleeds, and other factors on the risk of sICH versus acute lacune using multivariate logistic regression. RESULTS: Five hundred seventy-one patients had subcortical pathology. The presence of cerebral microbleeds (adjusted odds ratio [OR], 3.39; confidence interval [CI], 2.09-5.50) was a strong predictor of sICH, whereas severe periventricular white matter disease predicted ischemia (OR, 0.56 risk of sICH; CI, 0.32-0.98). This association was strengthened when the number of microbleeds was evaluated; subjects with >5 microbleeds had an increased risk of sICH (OR, 4.11; CI, 1.96-8.59). It remained significant when individuals with only cortical microbleeds were removed (OR, 1.77, CI, 1.13-2.76). An elevated erythrocyte sedimentation rate (OR, 1.19 per 10 mm/h increase; CI, 1.06-1.34) was significantly associated with sICH, whereas low-density lipoprotein was associated with ischemic infarct (OR, 0.93 risk of sICH per 10 mg/dL increase; CI, 0.86-0.99). CONCLUSIONS: Subclinical pathology is the strongest predictor of the nature of subsequent symptomatic event. Low-density lipoprotein and erythrocyte sedimentation rate may also have a role in risk stratification. PMID- 24811340 TI - Reperfusion therapies for wake-up stroke: systematic review. PMID- 24811341 TI - Detection of Chemlali extra-virgin olive oil adulteration mixed with soybean oil, corn oil, and sunflower oil by using GC and HPLC. AB - Fatty acid composition as an indicator of purity suggests that linolenic acid content could be used as a parameter for the detection of extra/virgin olive oil fraud with 5% of soybean oil. The adulteration could also be detected by the increase of the trans-fatty acid contents with 3% of soybean oil, 2% of corn oil, and 4% of sunflower oil. The use of the DeltaECN42 proved to be effective in Chemlali extra-virgin olive oil adulteration even at low levels: 1% of sunflower oil, 3% of soybean oil, and 3% of corn oil. The sterol profile is almost decisive in clarifying the adulteration of olive oils with other cheaper ones: 1% of sunflower oil could be detected by the increase of Delta7-stigmastenol and 4% of corn oil by the increase of campesterol. Linear discriminant analysis could represent a powerful tool for faster and cheaper evaluation of extra-virgin olive oil adulteration. PMID- 24811342 TI - [Heart failure. A medical challenge]. PMID- 24811343 TI - FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma. AB - Impaired Fas-mediated apoptosis is associated with poor clinical outcomes and cancer chemoresistance. Soluble Fas receptor (sFas), produced by skipping of exon 6, inhibits apoptosis by sequestering Fas ligand. Serum sFas is associated with poor prognosis of non-Hodgkin's lymphomas. We found that the alternative splicing of Fas in lymphomas is tightly regulated by a long-noncoding RNA corresponding to an antisense transcript of Fas (FAS-AS1). Levels of FAS-AS1 correlate inversely with production of sFas, and FAS-AS1 binding to the RBM5 inhibits RBM5-mediated exon 6 skipping. EZH2, often mutated or overexpressed in lymphomas, hyper methylates the FAS-AS1 promoter and represses the FAS-AS1 expression. EZH2 mediated repression of FAS-AS1 promoter can be released by DZNeP (3 Deazaneplanocin A) or overcome by ectopic expression of FAS-AS1, both of which increase levels of FAS-AS1 and correspondingly decrease expression of sFas. Treatment with Bruton's tyrosine kinase inhibitor or EZH2 knockdown decreases the levels of EZH2, RBM5 and sFas, thereby enhancing Fas-mediated apoptosis. This is the first report showing functional regulation of Fas repression by its antisense RNA. Our results reveal new therapeutic targets in lymphomas and provide a rationale for the use of EZH2 inhibitors or ibrutinib in combination with chemotherapeutic agents that recruit Fas for effective cell killing. PMID- 24811345 TI - Spatial extent of plasmonic enhancement of vibrational signals in the infrared. AB - Infrared vibrations of molecular species can be enhanced by several orders of magnitude with plasmonic nanoantennas. Based on the confined electromagnetic near fields of resonantly excited metal nanoparticles, this antenna-assisted surface enhanced infrared spectroscopy enables the detection of minute amounts of analytes localized in the nanometer-scale vicinity of the structure. Among other important parameters, the distance of the vibrational oscillator of the analyte to the nanoantenna surface determines the signal enhancement. For sensing applications, this is a particularly important issue since the vibrating dipoles of interest may be located far away from the antenna surface because of functional layers and the large size of biomolecules, proteins, or bacteria. The relation between distance and signal enhancement is thus of paramount importance and measured here with in situ infrared spectroscopy during the growth of a probe layer. Our results indicate a diminishing signal enhancement and the effective saturation of the plasmonic resonance shift beyond 100 nm. The experiments carried out under ultra-high-vacuum conditions are supported by numerical calculations. PMID- 24811346 TI - Differential effect of solar light in increasing the toxicity of silver and titanium dioxide nanoparticles to a fish cell line and zebrafish embryos. AB - The increasing use of silver (Ag) and titanium dioxide (TiO2) nanoparticles (NPs) in consumer products and their inevitable seepage into the environment prompted us to investigate their potential toxicity to a fish cell line (BF-2) and zebrafish embryos under dark and Simulated Solar Light (SSL) exposure conditions. Using high throughput screening (HTS) platforms, we showed that the oxidative stress-dependent cytotoxicity and embryonic toxicity of NPs were significantly increased upon exposure to SSL. While, the toxicity of TiO2 NPs under SSL exposure could be explained by hydroxyl radical generation, the enhanced toxicity of Ag NPs under SSL exposure was due to surface oxidation and physicochemical modification of Ag NPs and shedding of Ag+, leading to an increased bioavailability of silver. Our observations that solar light could induce physicochemical transformation of TiO2 and Ag NPs and enhance their toxic potential emphasizes the need for conducting future toxicity studies under environmentally relevant exposure conditions to guide decision making on the safe handling of NPs. PMID- 24811344 TI - Extensive diversity of prion strains is defined by differential chaperone interactions and distinct amyloidogenic regions. AB - Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. PMID- 24811349 TI - Food chemistry in JFS: 4 scores of innovative research and counting. PMID- 24811347 TI - The carbamoylmannose moiety of bleomycin mediates selective tumor cell targeting. AB - Recently, we reported that both bleomycin (BLM) and its disaccharide, conjugated to the cyanine dye Cy5**, bound selectively to cancer cells. Thus, the disaccharide moiety alone recapitulates the tumor cell targeting properties of BLM. Here, we demonstrate that the conjugate of the BLM carbamoylmannose moiety with Cy5** showed tumor cell selective binding and also enhanced cellular uptake in most cancer cell lines. The carbamoyl functionality was required for tumor cell targeting. A dye conjugate prepared from a trivalent cluster of carbamoylmannose exhibited levels of tumor cell binding and internalization significantly greater than those of the simple carbamoylmannose-dye conjugate, consistent with a possible multivalent receptor. PMID- 24811350 TI - Functional properties of vinegar. AB - A variety of natural vinegar products are found in civilizations around the world. A review of research on these fermented products indicates numerous reports of health benefits derived by consumption of vinegar components. Therapeutic effects of vinegar arising from consuming the inherent bioactive components including acetic acid, gallic acid, catechin, ephicatechin, chlorogenic acid, caffeic acid, p-coumaric acid, and ferulic acid cause antioxidative, antidiabetic, antimicrobial, antitumor, antiobesity, antihypertensive, and cholesterol-lowering responses. The aims of this article are to discuss vinegar history, production, varieties, acetic acid bacteria, and functional properties of vinegars. PMID- 24811351 TI - Detection of soybean proteins in fermented soybean products by using heating extraction. AB - Soybean is used in processed foods worldwide. Because soybean can cause adverse reactions in some atopic patients, appropriate labeling regarding its content in processed foods is needed to better protect consumers. In the previous study, we developed a reliable sandwich Enzyme Linked Immunosorbent Assay (ELISA) method with high sensitivity and specificity for detecting soybean proteins by using antibody to Gly m Bd 30K, which was originally characterized as a vacuolar protein with a molecular mass of 34 kDa in soybean. The ELISA displayed satisfactory repeatability and reproducibility in an interlaboratory evaluation. However, it could not detect soybean protein in fermented soybean products. We therefore developed an extraction method combined with a heating process to inhibit soybean protein degradation by microbial proteolytic enzymes in fermented soybean products. This extraction method enables the sensitive detection of soybean protein in fermented soybean products such as natto and miso. It was able to detect with high-sensitivity soybean protein present at 10 MUg/g levels in model processed foods. This method is suitable for quantifying soybean protein in processed foods without the degrading effects of microbial proteolytic enzymes. The present extraction method can be used sensitively to monitor labeling systems in a reliable manner and should be useful for the mandatory inspections required under Japanese regulations. PRACTICAL APPLICATION: The extraction and ELISA methods that we developed enable sensitive detection of soybean protein in soybean products, including fermented foods. These methods should be useful for reliable and sensitive monitoring of product labeling systems and should help to solve the problem of insensitive in soybean labeling of processed foods. PMID- 24811353 TI - Organic/hybrid nanoparticles and single-walled carbon nanotubes: preparation methods and chiral applications. AB - Nanoparticles are molecular-sized solids with at least one dimension measuring between 1-100 nm or 10-1000 nm depending on the individual discipline's perspective. They are aggregates of anywhere from a few hundreds to tens of thousands of atoms which render them larger than molecules but smaller than bulk solids. Consequently, they frequently exhibit physical and chemical properties somewhere between. On the other hand, nanocrystals are a special class of nanoparticles which have started gaining attention recently owing to their unique crystalline structures which provide a larger surface area and promising applications including chiral separations. Hybrid nanoparticles are supported by the growing interest of chemists, physicists, and biologists, who are researching to fully exploit them. These materials can be defined as molecular or nano composites with mixed (organic or bio) and inorganic components, where at least one of the component domain has a dimension ranging from a few A to several nanometers. Similarly, and due to their extraordinary physical, chemical, and electrical properties, single-walled carbon nanotubes have been the subject of intense research. In this short review, the focus is mainly on the current well established simple preparation techniques of chiral organic and hybrid nanoparticles as well as single-walled carbon nanotubes and their applications in separation science. Of particular interest, cinchonidine, chitosan, and beta-CD modified gold nanoparticles (GNPs) are discussed as model examples for organic and hybrid nanoparticles. Likewise, the chemical vapor deposition method, used in the preparation of single-walled carbon nanotubes, is discussed. The enantioseparation applications of these model nanomaterials is also presented. PMID- 24811354 TI - The challenge: understanding the molecular pathogenesis of osteoarthritis and developing innovative therapeutic concepts. PMID- 24811355 TI - [Osteological aspects]. PMID- 24811356 TI - [Metabolic bone disease osteomalacia]. AB - Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases. PMID- 24811357 TI - [Pharmaceutical therapy of bone metabolism disorders in chronic kidney disease mineral bone disorder (CKD-MBD) with special respect to antiresorptive substances]. AB - Disturbances in bone and mineral turnover are common complications in patients with impaired renal function. Besides an increased risk for cardiovascular events they promote skeletal events, such as bone pain and fractures. Evidence for the antifracture efficacy of antiresorptive and osteoanabolic treatment strategies has only been demonstrated for patients with osteoporosis. The use of osteotropic drugs in patients with impaired renal function requires large randomized placebo controlled trials. PMID- 24811358 TI - [Inflammation and bone metabolism]. AB - A finely balanced relationship between bone resorption and bone formation is characteristic for a healthy bone metabolism. Osteoblasts are responsible for bone formation and osteoclasts for bone resorption. In general inflammatory and in particular chronic inflammatory processes influence osteoblast and osteoclast function directly or via indirect mechanisms. Bone metabolism can be influenced by the interaction of cytokines, hormones and growth factors with bone cells. A central factor involved in bone metabolism is the receptor activator of nuclear factor-kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is influenced by different inflammatory processes. Usually, (chronic) inflammation results in increased bone loss. The molecular mechanisms and pathophysiological pathways of bone metabolism under the influence of inflammation are summarized in this review. PMID- 24811359 TI - [Chondrocalcinosis due to calcium pyrophosphate deposition (CPPD). From incidental radiographic findings to CPPD crystal arthritis]. AB - If acute arthritis occurs in the elderly in addition to typical degenerative, load-related joint complaints, this is often induced by crystal deposition. The crystals lead to activation of the immune system resulting in acute inflammation. In addition to gout, calcium pyrophosphate deposition (CPPD) disease in particular must also be taken into consideration. Diagnostically important are imaging techniques, e.g. early specific alterations of cartilage can be shown by joint sonography and later calcium pyrophosphate crystals can be detected as cartilage calcification (chondrocalcinosis) by radiography. Important for the diagnosis of crystal arthropathy is usually the microscopic detection of specific crystals in the synovial fluid and is supported by exclusion of septic arthritis by arthrocentesis. In contrast to gout, which can be well controlled by the pharmaceutical lowering of uric acid levels, there is no causal therapy for CPPD disease so far. As CPPD may occur as a secondary effect in metabolic disorders, such as hyperparathyroidism or hemochromatosis, it seems to be important to search for the underlying disease. The following article presents the current knowledge on clinically relevant aspects of the pathogenesis, diagnosis and therapy of CPPD disease. PMID- 24811360 TI - [50 years of rheumatology in Bad Nauheim. Presentation at the Jubilee Symposium on 29 June 2013]. PMID- 24811361 TI - Validation of the manufacturing process used to produce long-acting recombinant factor IX Fc fusion protein. AB - Recombinant factor IX Fc (rFIXFc) fusion protein is the first of a new class of bioengineered long-acting factors approved for the treatment and prevention of bleeding episodes in haemophilia B. The aim of this work was to describe the manufacturing process for rFIXFc, to assess product quality and to evaluate the capacity of the process to remove impurities and viruses. This manufacturing process utilized a transferable and scalable platform approach established for therapeutic antibody manufacturing and adapted for production of the rFIXFc molecule. rFIXFc was produced using a process free of human- and animal-derived raw materials and a host cell line derived from human embryonic kidney (HEK) 293H cells. The process employed multi-step purification and viral clearance processing, including use of a protein A affinity capture chromatography step, which binds to the Fc portion of the rFIXFc molecule with high affinity and specificity, and a 15 nm pore size virus removal nanofilter. Process validation studies were performed to evaluate identity, purity, activity and safety. The manufacturing process produced rFIXFc with consistent product quality and high purity. Impurity clearance validation studies demonstrated robust and reproducible removal of process-related impurities and adventitious viruses. The rFIXFc manufacturing process produces a highly pure product, free of non-human glycan structures. Validation studies demonstrate that this product is produced with consistent quality and purity. In addition, the scalability and transferability of this process are key attributes to ensure consistent and continuous supply of rFIXFc. PMID- 24811364 TI - Adverse drug effects and their clinical management: a personal view. AB - This paper describes the personal views of the author about diagnosis and management of an adverse drug effect. It proposes that diagnosis is complicated and is also supported by carefully observed management of changes in drug therapy. Drug-related adverse effects may be due to the drug itself, though many are due to systematic errors occurring in the process from diagnosis of the primary treated condition, through prescribing and dispensing, to the way the drug is used by the patient. Bringing awareness of such systematic errors for consideration and management is part of a health care professional's responsibilities. PMID- 24811362 TI - Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. AB - Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options. PMID- 24811363 TI - Diabetes in pregnancy: timing and mode of delivery. AB - Diabetes in pregnancy represents a risk condition for adverse maternal and feto neonatal outcomes and many of these complications might occur during labor and delivery. In this context, the obstetrician managing women with pre-existing and gestational diabetes should consider (1) how these conditions might affect labor and delivery outcomes; (2) what are the current recommendations on management; and (3) which other factors should be considered to decide about the timing and mode of delivery. The analysis of the studies considered in this review leads to the conclusion that the decision to deliver should be primarily intended to reduce the risk of stillbirth, macrosomia, and shoulder dystocia. In this context, this review provides useful information for managing specific subgroups of diabetic women that may present overlapping risk factors, such as women with insulin-requiring diabetes and/or obesity and/or prenatal suspicion of macrosomic fetus. To date, the lack of definitive evidences and the complexity of the problem suggest that the "appropriate" clinical management should be customized according with the clinical condition, the type and mode of intervention, its consequences on outcomes, and considering the woman's consent and informed decisions. PMID- 24811365 TI - Solid phase extraction of Cd, Pb, Ni, Cu, and Zn in environmental samples on multiwalled carbon nanotubes. AB - A simple and sensitive solid phase extraction (SPE) method on multiwalled carbon nanotubes (MWCNTs) is presented for the determination of cadmium, lead, nickel, copper, and zinc at trace levels combined with flame atomic absorption spectrometry. The effects of parameters like pH, sample volume, sample and eluent flow rates, eluent concentration, and volume and type of eluent on the recovery of trace elements was examined. The metals retained on the nanotube at pH 6.5 as alpha-benzoin oxime complexes were eluted by 10 mL 2 M HNO3 in acetone. The influence of matrix ions on the developed method was also evaluated. The preconcentration factor of the method was found to be 50. The detection limits for Cd(II), Pb(II), Ni(II), Cu(II), and Zn(II) were found as 1.7, 5.5, 6.0, 2.3, and 2.4 MUg L(-1), respectively. To test the accuracy of the method, the method was applied to TMDA-70 fortified lake water and Spinach 1570A standard reference materials. Addition recovery studies were applied to tap water and cracked wheat samples, and determination of the analyte elements was carried out in some food samples with good results. PMID- 24811366 TI - Update on the distribution and phylogenetics of Biomphalaria (Gastropoda: Planorbidae) populations in Guangdong Province, China. AB - In 1973 planorbid snails then identified as Biomphalaria straminea were discovered in Hong Kong, China. It was assumed that these snails had been introduced to Hong Kong via the import of tropical fish by air from South America. In 2012 Biomphalaria were found for the first time in Guangdong Province, China. In view of the renewed interest in these invasive snails, a morphological and DNA-sequence based phylogenetic study was undertaken for seven populations of Biomphalaria snails collected in Guangdong. Morphologically and phylogenetically, five of the populations clustered more closely with Biomphalaria kuhniana than with B. straminea. Levels of genetic diversity among the populations were about half those of autochthonous populations in Brazil, the phylogenetic relationships did not correlate with a radiation from any one international port in China, and different lineages appeared associated with different ports. Consequently in explaining the current distribution of the snails, multiple colonization events, each establishing a new local snail population near to maritime international container ports, were considered more likely than the spread of snails from Hong Kong to China. The displacement of B. straminea by B. kuhniana in Guangdong is considered as an explanation for the habitat changes observed among the snails between Hong Kong in the 1980s and the present. The conclusions of the study are that any risk of Schistosoma mansoni transmission in China is more likely to come from parasite importation in the intramolluscan stage, than from transmission by migrant workers from South America or Africa. In addition, although likely to be rare, sporadic outbreaks of imported schistosomiasis (caused by invading infected snails) could be a threat to public health in the vicinity of International container ports (not only in Guangdong Province). Further work is called for to investigate further the presence of B. kuhniana and its potential interactions with B. straminea (the former is thought to be incompatible with S. mansoni), and the responses of Chinese Biomphalaria to potential competitors such as Thiaridae. The current expansion of container ports in Brazil and Venezuela, and the increase in trade with China, is likely to accentuate any current risk of imported schistosomiasis, and surveillance around ports in China, together with further research, are necessary. PMID- 24811367 TI - Effects of melatonin on oxidative stress, and resistance to bacterial, parasitic, and viral infections: a review. AB - Melatonin, a hormone secreted by the pineal gland, works directly and indirectly as a free radical scavenger. Its other physiological or pharmacological activities could be dependent or independent of receptors located in different cells, organs, and tissues. In addition to its role in promoting sleep and circadian rhythms regulation, it has important immunomodulatory, antioxidant, and neuroprotective effects suggesting that this indole must be considered as a therapeutic alternative against infections. The aim of this review is to describe the effects of melatonin on oxidative stress and the resistance to bacterial (Klebsiella pneumoniae, Helicobacter pylori, Mycobacterium tuberculosis, and Clostridium perfringens), viral (Venezuelan equine encephalomyelitis virus and respiratory syncytial virus), and parasitic (Plasmodium spp., Entamoeba histolytica, Trypanosoma cruzi, Toxoplasma gondii, and Opisthorchis viverrini) infections. PMID- 24811368 TI - [Implementation of a double-check system in the dispensing of oncological drugs in a clinical trial]. PMID- 24811369 TI - [The right to die at home. Reflections of a physician]. PMID- 24811370 TI - Is nitrogen transfer among plants enhanced by contrasting nutrient-acquisition strategies? AB - Nitrogen (N) transfer among plants has been found where at least one plant can fix N2 . In nutrient-poor soils, where plants with contrasting nutrient acquisition strategies (without N2 fixation) co-occur, it is unclear if N transfer exists and what promotes it. A novel multi-species microcosm pot experiment was conducted to quantify N transfer between arbuscular mycorrhizal (AM), ectomycorrhizal (EM), dual AM/EM, and non-mycorrhizal cluster-rooted plants in nutrient-poor soils with mycorrhizal mesh barriers. We foliar-fed plants with a K(15) NO3 solution to quantify one-way N transfer from 'donor' to 'receiver' plants. We also quantified mycorrhizal colonization and root intermingling. Transfer of N between plants with contrasting nutrient-acquisition strategies occurred at both low and high soil nutrient levels with or without root intermingling. The magnitude of N transfer was relatively high (representing 4% of donor plant N) given the lack of N2 fixation. Receiver plants forming ectomycorrhizas or cluster roots were more enriched compared with AM-only plants. We demonstrate N transfer between plants of contrasting nutrient-acquisition strategies, and a preferential enrichment of cluster-rooted and EM plants compared with AM plants. Nutrient exchanges among plants are potentially important in promoting plant coexistence in nutrient-poor soils. PMID- 24811371 TI - Impact of feeding on growth performance, blood biochemical and mineral profiles of pre-pubescent camels under pastoral management in arid western Rajasthan. AB - The experiment was undertaken on 20 pre-pubescent dromedary camels of 300 +/- 7.0 kg average bodyweight (BW) and 1.5-2 years of age to determine change in body weight, blood biochemical and mineral profiles and morphometric parameters on rangeland grazing (GR) and supplementary stall feeding (GS) at arid northwestern part of Rajasthan over a period of 80 days. GR camels were maintained only on grazing, while GS camels were fed semi-intensively ad-lib groundnut haulms along with formulated concentrate and mineral mixture to meet maintenance requirement. Intake of young camels was determined using chromium(III) oxide as internal marker. The biomass yield of rangeland estimated was 0.54 t DM/ha. Dry matter intake (kg/day) by GR camels on rangeland grazing was lower than that by GS camels fed on supplementary feeding. The nutrient digestibility of dry matter and organic matter (P < 0.05) and crude protein was higher in GS camels than that in GR camels. Likewise, intake of digestible crude protein (P < 0.05) and metabolizable energy were higher in stall-fed young camels. Pre-pubescent camels fed on grazing had significantly (P < 0.01) low glucose and higher urea concentration compared to stall-fed camels. Final body weight of camels differed significantly (P < 0.05) between groups. The camels fed on supplementary stall feeding had significantly (P < 0.01) higher total gain (kg) and average daily gain (ADG) compared to camels on grazing. Among morphometric parameters, body length and body height showed more significant increase in GS compared to GR camels. Intake of digestible crude protein (DCP) by GR group was 43% low compared to the requirement for growing camel of 300 kg body weight. Despite this, GR camels were able to maintain body weight due to better recycling of urea which was significantly higher in comparison to GS camels. The findings of significantly (P < 0.01) low serum glucose and higher urea concentration and lower body weight gain of GR camels suggest the need of locally available protein and energy supplement in addition to grazing for better growth performance. PMID- 24811372 TI - Effect of the replacement of Tifton 85 with manicoba hay on the performance of Morada Nova hair sheep. AB - The use of native and adapted forages is an alternative for sustainable production systems in northeast Brazil. The goal of this study was to evaluate the substitution of Tifton 85 by manicoba hay on the performance and carcass traits of Morada Nova hair sheep. The 16 lambs that were used in this study initially weighed 19.36 +/- 1.48 kg, were housed in individual pens, and were slaughtered at 58 days of confinement. The dry matter intake (839.84 g/day and 3.81% WB) was higher (P < 0.05) in sheep fed manicoba hay. The feed conversion was 7.39 for sheep fed manicoba hay. The empty body weight (21.61 kg) and cold carcass weight (11.40 kg) did not differ (P > 0.05) between sheep fed different hay types. The replacement of Tifton 85 by manicoba hay did not influence the loin eye area (cm(2)) or carcass compactness index (kg/cm). The replacement of Tifton 85 by manicoba hay in Morada Nova sheep diet did not affect the weight gain or carcass characteristics. The manicoba hay can be considered a forage resource for feeding sheep in Brazilian semiarid tropics. PMID- 24811373 TI - The quintessence of quiescence. AB - Neurogenic niches in the adult mammalian brain are composed of heterogeneous populations of neural stem cells. In this issue of Neuron, Codega et al. (2014) isolate quiescent neural stem cells from the adult subventricular zone and demonstrate their stem cell characteristics. PMID- 24811374 TI - Interneurons scratch an itch. AB - Itch is immensely frustrating. Most studies focus on the cause of itch. In this issue of Neuron, Kardon et al. (2014) find that itch can be modulated by inhibitory neurons that produce dynorphin, an endogenous agonist of kappa-opioid receptors. PMID- 24811375 TI - On track with two gammas. AB - CA1 place cells discharge in prospective and retrospective modes, possibly reflecting memory retrieval and encoding, respectively. In this issue of Neuron, Bieri et al. (2014) report that slow and fast gamma oscillations associate with prospective and retrospective discharge, indicating that gamma oscillations organize information-processing modes. PMID- 24811376 TI - Primary cilia in the developing and mature brain. AB - Primary cilia were the largely neglected nonmotile counterparts of their better known cousin, the motile cilia. For years these nonmotile cilia were considered evolutionary remnants of little consequence to cellular function. Fast forward 10 years and we now recognize primary cilia as key integrators of extracellular ligand-based signaling and cellular polarity, which regulate neuronal cell fate, migration, differentiation, as well as a host of adult behaviors. Important future questions will focus on structure-function relationships, their roles in signaling and disease and as areas of target for treatments. PMID- 24811377 TI - Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. AB - The original formulation of Gate Control Theory (GCT) proposed that the perception of pain produced by spinal cord signaling to the brain depends on a balance of activity generated in large (nonnociceptive)- and small (nociceptive) diameter primary afferent fibers. The theory proposed that activation of the large-diameter afferent "closes" the gate by engaging a superficial dorsal horn interneuron that inhibits the firing of projection neurons. Activation of the nociceptors "opens" the gate through concomitant excitation of projection neurons and inhibition of the inhibitory interneurons. Sixty years after publication of the GCT, we are faced with an ever-growing list of morphologically and neurochemically distinct spinal cord interneurons. The present Review highlights the complexity of superficial dorsal horn circuitry and addresses the question whether the premises outlined in GCT still have relevance today. By examining the dorsal horn circuits that underlie the transmission of "pain" and "itch" messages, we also address the extent to which labeled lines can be incorporated into a contemporary view of GCT. PMID- 24811378 TI - Kruppel mediates the selective rebalancing of ion channel expression. AB - Ion channel gene expression can vary substantially among neurons of a given type, even though neuron-type-specific firing properties remain stable and reproducible. The mechanisms that modulate ion channel gene expression and stabilize neural firing properties are unknown. In Drosophila, we demonstrate that loss of the Shal potassium channel induces the compensatory rebalancing of ion channel expression including, but not limited to, the enhanced expression and function of Shaker and slowpoke. Using genomic and network modeling approaches combined with genetic and electrophysiological assays, we demonstrate that the transcription factor Kruppel is necessary for the homeostatic modulation of Shaker and slowpoke expression. Remarkably, Kruppel induction is specific to the loss of Shal, not being observed in five other potassium channel mutants that cause enhanced neuronal excitability. Thus, homeostatic signaling systems responsible for rebalancing ion channel expression can be selectively induced after the loss or impairment of a specific ion channel. PMID- 24811379 TI - Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. AB - Adult neurogenic niches harbor quiescent neural stem cells; however, their in vivo identity has been elusive. Here, we prospectively isolate GFAP(+)CD133(+) (quiescent neural stem cells [qNSCs]) and GFAP(+)CD133(+)EGFR(+) (activated neural stem cells [aNSCs]) from the adult ventricular-subventricular zone. aNSCs are rapidly cycling, highly neurogenic in vivo, and enriched in colony-forming cells in vitro. In contrast, qNSCs are largely dormant in vivo, generate olfactory bulb interneurons with slower kinetics, and only rarely form colonies in vitro. Moreover, qNSCs are Nestin negative, a marker widely used for neural stem cells. Upon activation, qNSCs upregulate Nestin and EGFR and become highly proliferative. Notably, qNSCs and aNSCs can interconvert in vitro. Transcriptome analysis reveals that qNSCs share features with quiescent stem cells from other organs. Finally, small-molecule screening identified the GPCR ligands, S1P and PGD2, as factors that actively maintain the quiescent state of qNSCs. PMID- 24811380 TI - TNF-alpha/TNFR1 signaling is required for the development and function of primary nociceptors. AB - Primary nociceptors relay painful touch information from the periphery to the spinal cord. Although it is established that signals generated by receptor tyrosine kinases TrkA and Ret coordinate the development of distinct nociceptive circuits, mechanisms modulating TrkA or Ret pathways in developing nociceptors are unknown. We have identified tumor necrosis factor (TNF) receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and nonpeptidergic nociceptors. Specifically, TrkA+ peptidergic nociceptors require TNF-alpha-TNFR1 forward signaling to suppress nerve growth factor (NGF)-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNF-alpha reverse signaling augments the neurite growth and excitability of Ret+ nonpeptidergic nociceptors. The developmental and functional nociceptive defects associated with loss of TNFR1 signaling manifest behaviorally as lower pain thresholds caused by increased sensitivity to NGF. Thus, TNFR1 exerts a dual role in nociceptor information processing by suppressing TrkA and enhancing Ret signaling in peptidergic and nonpeptidergic nociceptors, respectively. PMID- 24811381 TI - Miniature neurotransmission regulates Drosophila synaptic structural maturation. AB - Miniature neurotransmission is the transsynaptic process where single synaptic vesicles spontaneously released from presynaptic neurons induce miniature postsynaptic potentials. Since their discovery over 60 years ago, miniature events have been found at every chemical synapse studied. However, the in vivo necessity for these small-amplitude events has remained enigmatic. Here, we show that miniature neurotransmission is required for the normal structural maturation of Drosophila glutamatergic synapses in a developmental role that is not shared by evoked neurotransmission. Conversely, we find that increasing miniature events is sufficient to induce synaptic terminal growth. We show that miniature neurotransmission acts locally at terminals to regulate synapse maturation via a Trio guanine nucleotide exchange factor (GEF) and Rac1 GTPase molecular signaling pathway. Our results establish that miniature neurotransmission, a universal but often-overlooked feature of synapses, has unique and essential functions in vivo. PMID- 24811382 TI - STIM1 controls neuronal Ca2+ signaling, mGluR1-dependent synaptic transmission, and cerebellar motor behavior. AB - In central mammalian neurons, activation of metabotropic glutamate receptor type1 (mGluR1) evokes a complex synaptic response consisting of IP3 receptor-dependent Ca(2+) release from internal Ca(2+) stores and a slow depolarizing potential involving TRPC3 channels. It is largely unclear how mGluR1 is linked to its downstream effectors. Here, we explored the role of stromal interaction molecule 1 (STIM1) in regulating neuronal Ca(2+) signaling and mGluR1-dependent synaptic transmission. By analyzing mouse cerebellar Purkinje neurons, we demonstrate that STIM1 is an essential regulator of the Ca(2+) level in neuronal endoplasmic reticulum Ca(2+) stores. Both mGluR1-dependent synaptic potentials and IP3 receptor-dependent Ca(2+) signals are strongly attenuated in the absence of STIM1. Furthermore, the Purkinje neuron-specific deletion of Stim1 causes impairments in cerebellar motor behavior. Together, our results demonstrate that in the mammalian nervous system STIM1 is a key regulator of intracellular Ca(2+) signaling, metabotropic glutamate receptor-dependent synaptic transmission, and motor coordination. PMID- 24811385 TI - Incremental integration of global contours through interplay between visual cortical areas. AB - The traditional view on visual processing emphasizes a hierarchy: local line segments are first linked into global contours, which in turn are assembled into more complex forms. Distinct from this bottom-up viewpoint, here we provide evidence for a theoretical framework whereby objects and their parts are processed almost concurrently in a bidirectional cortico-cortical loop. By simultaneous recordings from V1 and V4 in awake monkeys, we found that information about global contours in a cluttered background emerged initially in V4, started ~40 ms later in V1, and continued to develop in parallel in both areas. Detailed analysis of neuronal response properties implicated contour integration to emerge from both bottom-up and reentrant processes. Our results point to an incremental integration mechanism: feedforward assembling accompanied by feedback disambiguating to define and enhance the global contours and to suppress background noise. The consequence is a parallel accumulation of contour information over multiple cortical areas. PMID- 24811383 TI - Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration. AB - Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity. PMID- 24811384 TI - Sorting nexin 27 regulation of G protein-gated inwardly rectifying K+ channels attenuates in vivo cocaine response. AB - The subcellular pathways that regulate G protein-gated inwardly rectifying potassium (GIRK or Kir3) channels are important for controlling the excitability of neurons. Sorting nexin 27 (SNX27) is a PDZ-containing protein known to bind GIRK2c/GIRK3 channels, but its function in vivo is poorly understood. Here, we investigated the role of SNX27 in regulating GIRK currents in dopamine (DA) neurons of the ventral tegmental area (VTA). Mice lacking SNX27 in DA neurons exhibited reduced GABABR-activated GIRK currents but had normal Ih currents and DA D2R-activated GIRK currents. Expression of GIRK2a, an SNX27-insensitive splice variant, restored GABABR-activated GIRK currents in SNX27-deficient DA neurons. Remarkably, mice with significantly reduced GABABR-activated GIRK currents in only DA neurons were hypersensitive to cocaine and could be restored to a normal locomotor response with GIRK2a expression. These results identify a pathway for regulating excitability of VTA DA neurons, highlighting SNX27 as a promising target for treating addiction. PMID- 24811386 TI - Decoding wakefulness levels from typical fMRI resting-state data reveals reliable drifts between wakefulness and sleep. AB - The mining of huge databases of resting-state brain activity recordings represents state of the art in the assessment of endogenous neuronal activity-and may be a promising tool in the search for functional biomarkers. However, the resting state is an uncontrolled condition and its heterogeneity is neither sufficiently understood nor accounted for. We test the hypothesis that subjects exhibit unstable wakefulness, i.e., drift into sleep during typical resting-state experiments. Analyzing 1,147 resting-state functional magnetic resonance data sets, we revealed a reliable loss of wakefulness in a third of subjects within 3 min and demonstrated the dynamic nature of the resting state, with fundamental changes in the associated functional neuroanatomy. Implications include the necessity of wakefulness monitoring and modeling, taking measures to maintain a state of wakefulness, acknowledging the possibility of sleep and exploring its consequences, and especially the critical assessment of possible false-positive or false-negative results. PMID- 24811387 TI - Neural oscillations and synchronization differentially support evidence accumulation in perceptual and value-based decision making. AB - Organisms make two types of decisions on a regular basis. Perceptual decisions are determined by objective states of the world (e.g., melons are bigger than apples), whereas value-based decisions are determined by subjective preferences (e.g., I prefer apples to melons). Theoretical accounts suggest that both types of choice involve neural computations accumulating evidence for the choice alternatives; however, little is known about the overlap or differences in the processes underlying perceptual versus value-based decisions. We analyzed EEG recordings during a paradigm where perceptual- and value-based choices were based on identical stimuli. For both types of choice, evidence accumulation was evident in parietal gamma-frequency oscillations, whereas a similar frontal signal was unique for value-based decisions. Fronto-parietal synchronization of these signals predicted value-based choice accuracy. These findings uncover how decisions emerge from topographic- and frequency-specific oscillations that accumulate distinct aspects of evidence, with large-scale synchronization as a mechanism integrating these spatially distributed signals. PMID- 24811388 TI - Heme in the marine environment: from cells to the iron cycle. AB - Hemes are iron containing heterocyclic molecules important in many cellular processes. In the marine environment, hemes participate as enzymatic cofactors in biogeochemically significant processes like photosynthesis, respiration, and nitrate assimilation. Further, hemoproteins, hemes, and their analogs appear to be iron sources for some marine bacterioplankton under certain conditions. Current oceanographic analytical methodologies allow for the extraction and measurement of heme b from marine material, and a handful of studies have begun to examine the distribution of heme b in ocean basins. The study of heme in the marine environment is still in its infancy, but some trends can be gleaned from the work that has been published so far. In this review, we summarize what is known or might be inferred about the roles of heme in marine microbes as well as the few studies on heme in the marine environment that have been conducted to date. We conclude by presenting some future questions and challenges for the field. PMID- 24811389 TI - Elucidation of the retention mechanism on a reverse-phase cyano column by modeling. AB - Partial least squares and quantitative structure-retention relationship models have been used mainly to explain and then to predict the retention mechanism on a cyanopropyl high-performance liquid chromatography column. Developing and applying the models involves studying the chromatographic behavior of 100 probes. Characterization of the probes took place under optimized isocratic conditions at variable proportions of two mobile phase mixtures. Retention time was correlated with numerous physicochemical properties and structural features of the probes. The goodness-of-fit for both models was estimated by the coefficient of multiple determinations, while the prediction of a test set was achieved by the root mean square error of prediction. The contribution of the descriptors in partial least squares is confirmed by the information derived from the variable importance in the projection and loadings plots, while a quantitative structure-retention relationship reflects the behavior model. In both cases, the descriptors determining the retention mechanism are lipophilicity, solubility in water, molecular volume and the presence of -COOH and/or condensed rings. Such techniques are proven useful tools for visualizing, exploring, and modeling the complex interactions between solutes and the mobile and stationary phase while at the same time this information can be quantified. PMID- 24811390 TI - Dequalinium induces cytotoxicity in human leukemia NB4 cells by downregulation of Raf/MEK/ERK and PI3K/Akt signaling pathways and potentiation of specific inhibitors of these pathways. AB - Delocalized lipophilic cation dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia. PMID- 24811391 TI - Association of high-sensitivity cardiac troponin T and N-terminal pro-brain-type natriuretic peptide with left ventricular structure: J-HOP study. AB - Although both high-sensitivity cardiac troponin T (Hs-cTnT) and N-terminal pro brain-type natriuretic peptide (NT-proBNP) levels are higher among patients with cardiac structural abnormalities than among those with apparently normal hearts, there is considerable overlap between the groups. The authors evaluated 1336 patients who had >=1 cardiovascular risk factors, underwent echocardiography, and had Hs-cTnT and NT-proBNP measured and excluded patients with left ventricular (LV) dysfunction. The patients in the highest Hs-cTnT category in quintiles had an increased likelihood of abnormal relative wall thickness compared with those in the lowest category (odds ratio, 1.66; 95% confidence interval, 1.17-2.36; P<.01). However, no such association was found in the category of NT-proBNP. The patients in the highest NT-proBNP category had an increased likelihood of abnormal LV diastolic dimension/body surface area compared with those in the lowest category (odds ratio, 2.11; 95% confidence interval, 1.17-3.79; P<.05). However, no such association was found in the category of Hs-cTnT. The data suggest that the measurement of Hs-cTnT and NT-proBNP might provide information on cardiac structural abnormalities. PMID- 24811393 TI - Determination and comparison of how the chain number and chain length of a lipid affects its interactions with a phospholipid at an air/water interface. AB - We determined how the number of chains in a lipid and its chain length affects its interactions with a phospholipid model membrane, and whether the number of chains or the chain length of lipids affects their interactions with the phospholipids more. This was achieved by using a Langmuir trough and a fluorescence microscope to study the interactions of mono-, di-, and triglycerides with a phospholipid monolayer at an air/water interface. The effect of the number of chains in a lipid on its interactions with phospholipids at air/water interfaces was shown by surface pressure-area per molecule isotherms and their thermodynamic analysis to worsen as the number of alkyl chains was increased to be greater than one. An increase in the packing density decreased the mixing ability of the lipids with the phospholipids, resulting in the formation of aggregates in the mixed monolayer. The aggregation was explained by the intermolecular hydrophobic and van der Waals attractions between the lipid molecules. Fluorescence microscopy revealed partial mixing without aggregation for monoglycerides, but the presence of lipid aggregation for diglycerides and triglycerides. The effect of decreasing the chain length of triglycerides from a long chain to a medium chain caused the interactions of the lipids with the phospholipid molecules at the air/water interface to significantly improve. Decreasing the chain length of monoglycerides from a long chain to a medium chain worsened their interaction with the phospholipid molecules. The effect of decreasing the triglyceride chain length on their interactions with phospholipids was much greater than the effect of decreasing the number of alkyl chains in the lipid. PMID- 24811394 TI - Antiretroviral and Medication Errors in Hospitalized HIV-Positive Patients. AB - OBJECTIVE: To summarize the literature regarding antiretroviral and other medication errors in hospitalized HIV-positive patients and to discuss potential interventions and solutions that have been studied to minimize drug error. DATA SOURCES: A systematic search of MEDLINE, PubMed, and EMBASE (2000-April 2014) was conducted. Search terms included HIV/AIDS, HAART, hospitalization, patient admission, inpatient, patient transfer, medication error, inappropriate prescribing, drug interaction, drug omission, drug toxicity, and contraindication. STUDY SELECTION AND DATA EXTRACTION: English-language research articles, case reports, conference abstracts, and letters to the editor were reviewed. DATA SYNTHESIS: A high overall medication error rate was reported in HIV-positive inpatients. Errors occurred mainly at the time of prescribing on admission but were also detected throughout hospitalization and at discharge. Errors in the antiretroviral regimen, dosing, scheduling, and drug-drug and drug food interactions were the most common. The most successful interventions involved a clinical pharmacist, who specializes in infectious diseases and/or HIV, completing medication reconciliation on admission, reviewing orders daily, and screening for errors at discharge. CONCLUSIONS: Although studies varied greatly in methodology, overall, a large number of medication errors occurred in this patient population. This underscores the important role the pharmacist has in optimizing care to hospitalized HIV-positive patients and provides further insights into the types of medication errors that occur and proposed solutions to reduce these errors. Because medication errors are multifactorial, ongoing initiatives to improve the quality of medication reconciliation processes, educate the health care team on antiretroviral medications, and improve the drug distribution system are required. PMID- 24811392 TI - Role of AKT signaling in DNA repair and clinical response to cancer therapy. AB - Effective cancer treatment has been limited by the emergence of resistant cancer cells. The results of many studies indicate that AKT activation plays an important role in the acquisition of resistance to anticancer therapy. AKT is a critical effector serine/threonine kinase in the receptor tyrosine kinase/phosphatase and tensin homolog/phospho-inositide 3-kinase pathway and controls a myriad of cellular functions. Activation of AKT not only supports tumor growth and progression but also contributes to tumor-cell evasion of the cytotoxic effects of cancer therapy through many avenues including the promotion of anti-apoptosis, proliferation, and migration and regulation of the cell cycle. Accumulating evidence has implicated AKT as a direct participant in the DNA damage response and repair induced by commonly used genotoxic agents. In this review, we discuss the molecular mechanisms by which genotoxic agents activate AKT and therefore contribute to resistance to cancer therapeutics, with particular emphasis on DNA repair. PMID- 24811395 TI - Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients. AB - BACKGROUND: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance. OBJECTIVE: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients. METHODS: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL). RESULTS: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P < 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels. CONCLUSIONS: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful. PMID- 24811396 TI - Sofosbuvir: A Nucleotide NS5B Inhibitor for the Treatment of Chronic Hepatitis C Infection. AB - OBJECTIVE: To review the use of sofosbuvir for the treatment of chronic hepatitis C virus (HCV). DATA SOURCES: Review and nonreview articles were identified through MEDLINE (1996-April 2014), citations of articles, and meeting abstracts using keywords, including NS5B polymerase inhibitor, GS-7977, sofosbuvir, direct acting antiviral (DAA), and others. STUDY SELECTION AND DATA EXTRACTION: Phase 1, 2, and 3 studies describing dose-ranging potential, pharmacokinetics, efficacy, safety, and tolerability of sofosbuvir were identified. DATA SYNTHESIS: Sofosbuvir is an NS5B polymerase inhibitor that was approved for use by the Food and Drug Administration in December 2013 for the treatment of chronic HCV in combination with pegylated interferon (peg-IFN) and ribavirin (RBV) for genotype 1. Additionally, it has been evaluated with other oral DAAs, such as simeprevir and others in the pipeline. It is not recommended as monotherapy because of lower sustained virological response (SVR) rates in clinical studies. Most of the treatment regimens are 12 weeks in duration; however, certain populations require a longer duration. Sofosbuvir has activity against all 6 genotypes, although most clinical trials evaluated genotypes 1 to 3. Sofosbuvir has a favorable safety and tolerability profile, making it a recommended first-line agent for chronic HCV infection. CONCLUSION: In clinical trials, 12 weeks of sofosbuvir with concomitant peg-IFN and RBV therapy in treatment-naive and experienced HCV genotype 1 patients resulted in SVR rates of >90%. An all-oral regimen of sofosbuvir and RBV is highly effective for genotype 2 and 3 patients. Sofosbuvir was found to be tolerable with minimal adverse effects (AEs), and no treatment discontinuations occurred secondary to drug related AEs.. PMID- 24811397 TI - Patient Failure to Seek Care for Non-ST-Elevated Myocardial Infarction Because of Symptoms Being Attributed to Dyspepsia From Dabigatran. PMID- 24811398 TI - Levomilnacipran: A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder. AB - OBJECTIVE: To provide a clinical overview of the antidepressant levomilnacipran. DATA SOURCES: Articles were identified by searching the MEDLINE, PubMed, Cochrane Library, and Clinicaltrials.gov databases through March 2014 using the keyword levomilnacipran. The manufacturer provided additional information from unpublished phase II and phase III trials. STUDY SELECTION AND DATA EXTRACTION: Any clinical trial conducted for at least 3 weeks and published in the English language was selected for review. Additional documentation, including the product dossier, package insert, pharmacokinetic studies, and poster presentations supplied by the manufacturer, was also evaluated. DATA SYNTHESIS: Levomilnacipran is the more potent enantiomer of milnacipran. It is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), dosed from 20 to 120 mg daily for the treatment of major depressive disorder (MDD). Efficacy and tolerability were established during 3 phase III randomized, double-blind placebo-controlled trials finding levomilnacipran to be significantly more efficacious than placebo in reduction of Montgomery-Asberg Depression Rating Scale scores. It is not known whether this agent is more efficacious than other antidepressants because direct comparison studies have not been conducted as of the time of this review. CONCLUSIONS: Levomilnacipran demonstrates efficacy and tolerability for short term treatment of MDD in adults. Available evidence does not strongly indicate that there is a specific subpopulation of patients who would benefit from levomilnacipran over currently available SNRIs. Full characterization of the agent's place in therapy alongside multiple other agents with similar mechanisms and efficacy requires trials with longer duration and active comparators. PMID- 24811399 TI - Rapid Oral Desensitization to Everolimus. PMID- 24811400 TI - Dornase Alfa for Non-Cystic Fibrosis Pediatric Pulmonary Atelectasis. AB - OBJECTIVE: To review the literature evaluating the efficacy of dornase alfa for non-cystic fibrosis pediatric patients with pulmonary atelectasis. DATA SOURCES: Articles were retrieved after a search of MEDLINE/PubMed (1946 to April 2014), and International Pharmaceutical Abstracts (1970-April 2014) was performed using the terms dornase alfa, recombinant human deoxyribonuclease, pulmonary, persistent, and atelectasis. Other relevant articles referenced from the MEDLINE search were also utilized. STUDY SELECTION AND DATA EXTRACTION: Data sources were limited to English language clinical trials and case studies including only children; 8 clinical trials and 12 case reports met the criteria. DATA SYNTHESIS: Dornase alfa is used as an off-label treatment option for pulmonary atelectasis because limited treatment modalities exist after conventional therapy has failed. We evaluated 8 clinical trials and 12 case reports involving this pediatric population with varying primary diagnoses. The majority of patients experienced improvement in atelectasis, suggesting benefit after receiving treatment with dornase alfa. However, the outcomes were possibly confounded by those receiving combination therapies, varying primary diagnoses, and varying end points evaluated. Dornase alfa was overall well tolerated, with only a few patients experiencing worsening atelectasis posttreatment. CONCLUSIONS: Dornase alfa may be considered as a therapeutic option in non-cystic fibrosis pediatric patients with pulmonary atelectasis, who require treatment intervention when conventional therapy is unsuccessful. PMID- 24811401 TI - Ecosystem stability in space: alpha, beta and gamma variability. AB - The past two decades have seen great progress in understanding the mechanisms of ecosystem stability in local ecological systems. There is, however, an urgent need to extend existing knowledge to larger spatial scales to match the scale of management and conservation. Here, we develop a general theoretical framework to study the stability and variability of ecosystems at multiple scales. Analogously to the partitioning of biodiversity, we propose the concepts of alpha, beta and gamma variability. Gamma variability at regional (metacommunity) scale can be partitioned into local alpha variability and spatial beta variability, either multiplicatively or additively. On average, variability decreases from local to regional scales, which creates a negative variability-area relationship. Our partitioning framework suggests that mechanisms of regional ecosystem stability can be understood by investigating the influence of ecological factors on alpha and beta variability. Diversity can provide insurance effects at the various levels of variability, thus generating alpha, beta and gamma diversity-stability relationships. As a consequence, the loss of biodiversity and habitat impairs ecosystem stability at the regional scale. Overall, our framework enables a synthetic understanding of ecosystem stability at multiple scales and has practical implications for landscape management. PMID- 24811403 TI - Effect of long-term testosterone propionate or human chorionic gonadotrophin administration on reproductive glands in adult male rabbits. AB - The study was aimed to investigate the effect of testosterone propionate (TP) or human chorionic gonadotrophin (hCG) treatment on reproductive glands in sexually mature male rabbits. A total 36 adult male rabbits were randomly distributed to six equal groups. The first control group (CON), the second treated with low-dose TP (TPL), the third treated with high-dose TP (TPH), the fourth treated with low dose hCG (CGL), the fifth treated with medium-dose hCG (CGM) and sixth treated with high-dose hCG (CGH). At the 16th post-treatment week, the animals were sacrificed, and the testes and accessory sex glands dissected, weighted and stored at -20 degrees C until assay. Testosterone propionate treatment in both doses resulted in reduction (P < 0.01) in testicular weight and increase (P < 0.01) in weight of vesicular gland, paraprostate and proprostate glands. High dose TP increased the weight of prostate and bulbouretheral gland (BUG). Testosterone propionate increased total androgen (P < 0.01) with Testosterone (T) predominating in serum, dihydrotestosterone (DHT) predominating in testes and most accessory sex glands. High dose of hCG increased the weight of proprostate and paraprostate glands. Androgen level in serum, testes and accessory sex glands increased (P < 0.01) after hCG treatment. PMID- 24811402 TI - MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis. AB - Rhabdomyosarcoma (RMS) is a childhood malignant soft tissue cancer that is derived from myogenic progenitors trapped in a permanent mode of growth. Here, we report that miR-214 is markedly down-regulated in human RMS cell lines. Although not required for embryogenesis in mice, miR-214 suppresses mouse embryonic fibroblast (MEF) proliferation. When re-introduced into RD cells, a line of human embryonal RMS cells, miR-214 showed inhibition of tumor cell growth, induction of myogenic differentiation and apoptosis, as well as suppression of colony formation and xenograft tumorigenesis. We show that in the absence of miR-214, expression of proto-oncogene N-ras is markedly elevated in miR-214(-/-) MEFs, and manipulations of miR-214 levels using microRNA mimics or inhibitor in RD cells reciprocally altered N-ras expression. We further demonstrate that forced expression of N-ras from a cDNA that lacks its 3'-untranslated region neutralized the pro-myogenic and anti-proliferative activities of miR-214. Finally, we show that N-ras is a conserved target of miR-214 in its suppression of xenograft tumor growth, and N-ras expression is up-regulated in xenograft tumor models as well as actual human RMS tissue sections. Taken together, these data indicate that miR 214 is a bona fide suppressor of human RMS tumorigensis. PMID- 24811404 TI - Telaprevir-based treatment effects on hepatitis C virus in liver and blood. AB - Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug-resistant variants in the liver is limited. We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin. Hepatic fine needle aspiration was performed before treatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. All patients completed all protocol-defined procedures that were generally well tolerated. First-phase HCV decline (baseline/treatment day 4) was significantly slower in liver than in plasma (slope plasma: -0.29; liver, -0.009; P < 0.001), whereas second-phase decline (posttreatment days 4-15) did not differ between the two body compartments (-0.11 and -0.15, respectively; P = 0.1). TVR-resistant variants were detected in plasma, but not in liver (where only wild-type virus was detected). Based upon nonstructural protein 3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower, compared to plasma, on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments. CONCLUSION: These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites. PMID- 24811405 TI - Preventing non-alcoholic fatty liver disease through Lactobacillus johnsonii BS15 by attenuating inflammation and mitochondrial injury and improving gut environment in obese mice. AB - The increasing prevalence of obesity worldwide is associated with a parallel increase in non-alcoholic fatty liver disease (NAFLD). To investigate the effect of Lactobacillus johnsonii BS15 on NAFLD, 120 male ICR mice were randomly divided into four groups and administrated with BS15 (2 * 10(7) cfu/0.2 mL or 2 * 10(8) cfu/0.2 mL) or phosphate buffered saline (PBS) throughout a 17-week experimental period. The mice were fed with normal chow diet (NCD) 5 weeks before the experimental period. Afterward, with the exception of the PBS group, NCD was changed into high-fat diet (HFD) for the remaining experimental period. Results showed that BS15-treated HFD mice were protected from hepatic steatosis and hepatocyte apoptosis. BS15 exhibited a positive effect on liver lipid peroxidation through an anti-oxidative stress activity by enhancing the liver antioxidant defense system. In addition, BS15 inhibited the insulin resistance; decreased the mRNA levels of acetyl-CoA carboxylase 1, fatty acid synthase, and peroxisome proliferator-activated receptor gamma; and increased the expression of the fasting-induced adipose factor in livers. Meanwhile, BS15 attenuated mitochondria abnormalities when the content of uncoupling protein-2 decreased and cytochrome c increased in NAFLD mice. BS15 also reduced the level of serum lipopolysaccharide in NAFLD mice by lowering the intestinal permeability and adjusting gut flora, followed by the downregulation of the TNFalpha mRNA level in liver and the serum level of C-reactive protein. These findings suggest that BS15 may be effective in preventing NAFLD induced by HFD. PMID- 24811406 TI - An extracytoplasmic function sigma factor, sigma(25), differentially regulates avermectin and oligomycin biosynthesis in Streptomyces avermitilis. AB - sigma(25) is an extracytoplasmic function (ECF) sigma factor in the bacterium Streptomyces avermitilis that plays a differential regulatory role in avermectin and oligomycin biosynthesis. Gene deletion, complementation, and overexpression experiments showed that sigma(25) inhibited avermectin production but promoted oligomycin production. sigma(25) indirectly inhibited avermectin production by affecting the transcription of the pathway-specific activator gene aveR, whereas it directly activated oligomycin production by initiating transcription of the pathway-specific activator gene olmRI. The divergently transcribed genes smrAB are located upstream of sig25 and encode a putative two-component system (TCS). sigma(25) was found to initiate its own transcription, and its expression was directly activated by SmrA. The precise SmrA-binding sites in the region upstream of sig25 were determined by DNase I footprinting assays and identified two direct repeat sequences CTGTGA-n5-CTGTGA, suggesting that SmrA regulates sig25 transcription by binding to these direct repeats. The deletion of smrAB had the similar effect on avermectin and oligomycin A production to the deletion of sig25, indicating that sigma(25) and SmrAB function similarly in the regulation of antibiotic production. These findings helpfully clarify the regulation of antibiotic biosynthesis by an ECF sigma factor-TCS signal transduction system in S. avermitilis. PMID- 24811408 TI - Tug of war for antiviral drugs data. PMID- 24811409 TI - Oseltamivir: the real world data. PMID- 24811410 TI - Tamiflu: "a nice little earner". PMID- 24811407 TI - Insect antimicrobial peptides and their applications. AB - Insects are one of the major sources of antimicrobial peptides/proteins (AMPs). Since observation of antimicrobial activity in the hemolymph of pupae from the giant silk moths Samia Cynthia and Hyalophora cecropia in 1974 and purification of first insect AMP (cecropin) from H. cecropia pupae in 1980, over 150 insect AMPs have been purified or identified. Most insect AMPs are small and cationic, and they show activities against bacteria and/or fungi, as well as some parasites and viruses. Insect AMPs can be classified into four families based on their structures or unique sequences: the alpha-helical peptides (cecropin and moricin), cysteine-rich peptides (insect defensin and drosomycin), proline-rich peptides (apidaecin, drosocin, and lebocin), and glycine-rich peptides/proteins (attacin and gloverin). Among insect AMPs, defensins, cecropins, proline-rich peptides, and attacins are common, while gloverins and moricins have been identified only in Lepidoptera. Most active AMPs are small peptides of 20-50 residues, which are generated from larger inactive precursor proteins or pro proteins, but gloverins (~14 kDa) and attacins (~20 kDa) are large antimicrobial proteins. In this mini-review, we will discuss current knowledge and recent progress in several classes of insect AMPs, including insect defensins, cecropins, attacins, lebocins and other proline-rich peptides, gloverins, and moricins, with a focus on structural-functional relationships and their potential applications. PMID- 24811411 TI - Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. AB - OBJECTIVE: To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments ("regulatory information"). DESIGN: Systematic review of regulatory information. DATA SOURCES: Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza. MAIN OUTCOME MEASURES: Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population. RESULTS: From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval -0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for "pneumonia," and no clinical study reports reported laboratory or diagnostic confirmation of "pneumonia." The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined "on-treatment" and "off-treatment" periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two "pivotal" treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, -0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116). CONCLUSIONS: In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling. PMID- 24811413 TI - Neuraminidase inhibitors for influenza. PMID- 24811412 TI - Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. AB - OBJECTIVES: To describe the potential benefits and harms of zanamivir. DESIGN: Systematic review of clinical study reports of randomised placebo controlled trials and regulatory information DATA SOURCES: Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised placebo controlled trials in adults and children who had confirmed or suspected exposure to natural influenza. MAIN OUTCOME MEASURES: Time to first alleviation of symptoms, influenza outcomes and complications, admissions to hospital, and adverse events in the intention to treat (ITT) population. RESULTS: We included 28 trials in stage 1 (judgment of appropriate study design) and 26 in stage 2 (formal analysis). For treatment of adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, P<0.001, I(2)=9%), which equates to an average 14.4 hours' reduction, or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia (risk difference 0.17%, 0.73% to 0.70%) or radiologically confirmed pneumonia (-0.06%, -6.56% to 2.11%) in adults. The effect on pneumonia in children was also not significant (0.56%, 1.64% to 1.04%). There was no significant effect on otitis media or sinusitis in both adults and children, with only a small effect noted for bronchitis in adults (1.80%, 0.65% to 2.80%), but not in children. There were no data to assess effects on admissions in adults and children. Zanamivir tended to be well tolerated. In zanamivir prophylaxis studies, symptomatic influenza in individuals was significantly reduced (1.98%, (0.98% to 2.54%); reducing event rates from 3.26% to 1.27%, which means 51 people need to be treated to prevent one influenza case (95% confidence interval, 40 to 103). In contrast, the prophylaxis effect on asymptomatic influenza cases was not significant in individuals (risk difference 0.14%, -1.10% to 1.10%) or in households (1.32%, -2.20% to 3.84%). In households treated prophylactically there was an effect on symptomatic influenza (14.84%, 12.18% to 16.55%), but this was based on only two small studies including 824 participants. Prophylaxis in adults reduced unverified pneumonia (0.32%, 0.09% to 0.41%; NNTB (number needed to treat to benefit) 311, 244 to 1086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children (risk difference 0.32%, 0.09% to 0.41%; NNTB 311, 244 to 1086). CONCLUSIONS: Based on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability. PMID- 24811414 TI - The Tamiflu trials. PMID- 24811416 TI - Absolute and relative morbidity burdens attributable to various illnesses and injuries, U.S. Armed Forces, 2013. PMID- 24811415 TI - Conceptual scoring of receptive and expressive vocabulary measures in simultaneous and sequential bilingual children. AB - PURPOSE: The authors examined the effects of conceptual scoring on the performance of simultaneous and sequential bilinguals on standardized receptive and expressive vocabulary measures in English and Spanish. METHOD: Participants included 40 English-speaking monolingual children, 39 simultaneous Spanish English bilingual children, and 19 sequential bilingual children, ages 5-7. The children completed standardized receptive and expressive vocabulary measures in English and also in Spanish for those who were bilingual. After the standardized administration, bilingual children were given the opportunity to respond to missed items in their other language to obtain a conceptual score. RESULTS: Controlling for group differences in socioeconomic status (SES), both simultaneous and sequential bilingual children scored significantly below monolingual children on single-language measures of English receptive and expressive vocabulary. Conceptual scoring removed the significant difference between monolingual and simultaneous bilingual children in the receptive modality but not in the expressive modality; differences remained between monolingual and sequential bilingual children in both modalities. However, in both bilingual groups, conceptual scoring increased the proportion of children with vocabulary scores within the average range. CONCLUSION: Conceptual scoring does not fully ameliorate the bias inherent in single-language standardized vocabulary measures for bilingual children, but the procedures employed here may assist in ruling out vocabulary deficits, particularly in typically developing simultaneous bilingual children. PMID- 24811417 TI - Hospitalizations among members of the active component, U.S. Armed Forces, 2013. PMID- 24811418 TI - Ambulatory visits among members of the active component, U.S. Armed Forces, 2013. PMID- 24811421 TI - Absolute and relative morbidity burdens attributable to various illnesses and injuries, non-service member beneficiaries of the Military Health System, 2013. PMID- 24811422 TI - Foetal supraventricular tachycardia with hydrops fetalis: a role for direct intraperitoneal amiodarone. AB - INTRODUCTION: Persistent foetal tachyarrythmias complicated by hydrops fetalis carry a poor prognosis, with foetal death reported in excess of a quarter despite treatment. We present our experience with direct intraperitoneal amiodarone administration in eight hydropic foetuses with resistant supraventricular tachycardia. METHODS: Amiodarone was injected slowly into foetal peritoneal cavity under ultrasound guidance. All mothers were loaded with oral amiodarone before the procedure and maintained on it. The procedure was repeated guided by foetal rhythm. RESULT: All eight cases had severe hydrops with a median foetal heart rate of 255 bpm (range 240-300 bpm), and the median gestational age was 27+1 weeks (range 21-33+3 weeks) at presentation. In six cases, the average time for supraventricular tachycardia to revert to sinus rhythm from the first procedure was 11.5 days. In one case, intravascular injection of amiodarone into the umbilical vein was performed before intraperitoneal injection, which resulted in conversion to sinus rhythm sustained until delivery. In the last case, supraventricular tachycardia and severe hydrops persisted and the baby was delivered 5 days later at 34 weeks' gestation. Hydrops resolved in five foetuses with a mean resolution time of 28.4 days. The mean gestational age at delivery was 34+5 days and seven of eight cases survived beyond the neonatal period with good postnatal outcomes. CONCLUSION: Intraperitoneal administration of amiodarone is a relatively simple and effective strategy in refractory supraventricular tachycardia complicated by severe hydrops. The intraperitoneal route assures delivery of the drug to the severely hydropic foetus and enables a bolus dose to be delivered for sustained absorption. PMID- 24811423 TI - The application of nanosponges to cancer drug delivery. AB - INTRODUCTION: The design of new nanocarriers as a strategy for the delivery of anti-cancer drugs offers a potential platform to overcome some limitations of current clinical treatments and to achieve targeted release into tumour tissues. Cyclodextrin-based nanosponges are a novel nanosized delivery system composed of hyper-cross-linked cyclodextrins connected in a three-dimensional network. They form porous nanoparticles with sizes lower than 500 nm, spherical shape and negative surface charge. They show a good capacity for incorporating small molecules, macromolecules, ions and gases within their structure. AREA COVERED: This review will describe some applications of cyclodextrin-based nanosponges as carriers for anticancer drugs. Recent smart nanosponges, able to be responsive to an external stimulus, will be also discussed. In vitro and in vivo experimental results, obtained with currently used molecules, such as paclitaxel, doxorubicin, 5-fluorourcil and tamoxifen, will be shown. EXPERT OPINION: Cyclodextrin-based nanosponges can be considered a challenging technology for the development of innovative formulations, suitable for various administration routes for anti cancer drugs. PMID- 24811424 TI - Aqueous processing of graphene-polymer hybrid thin film nano-composites and gels. AB - Research into the structure, properties and applications of graphene has moved at a tremendous pace over the past few years. This review describes one aspect of this research, that of the incorporation of graphene particles with a range of polymers to create novel hybrid materials with increased functionality such as improved conductance, increased strength and introduced biocompatibility or cytotoxicity. This review focuses on dispersing graphene in polymer matrices, both insulating and conducting. Additionally, a brief discussion of carbon based platelet production methods is given in order to provide context on the subsequent use of this family of materials such as graphene, graphene oxide (GO) and reduced graphene oxide (rGO) incorporated into polymeric thin films. PMID- 24811425 TI - Structuring of metal-organic frameworks at the mesoscopic/macroscopic scale. AB - The assembly of metal ions with organic ligands through the formation of coordination bonds gives crystalline framework materials, known as metal-organic frameworks (MOFs), which recently emerged as a new class of porous materials. Besides the structural designability of MOFs at the molecular length scale, the researchers in this field very recently made important advances in creating more complex architectures at the mesoscopic/macroscopic scale, in which MOF nanocrystals are used as building units to construct higher-order superstructures. The structuring of MOFs in such a hierarchical order certainly opens a new opportunity to improve the material performance via design of the physical form rather than altering the chemical component. This review highlights these superstructures and their applications by categorizing them into four dimensionalities, zero-dimensional (0D), one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) superstructures. Because the key issue for structuring of MOFs is to spatially control the nucleation process in desired locations, this review conceptually categorizes the available synthetic methodologies from the viewpoint of the reaction system. PMID- 24811426 TI - Exploring pharmacists' opinions regarding PHARMAC's interventions in promoting brand changes. AB - BACKGROUND: In New Zealand, the use of generic medicines is advocated by the Pharmaceutical Management Agency of New Zealand (PHARMAC). Among other interventions, PHARMAC uses educational awareness campaigns to educate pharmacists to promote the uptake of generic medicines. However, the opinion of pharmacists regarding these interventions has not yet been evaluated. OBJECTIVES: The objective of this study was to explore pharmacists' opinions regarding PHARMAC's interventions in promoting medicine brand changes. METHOD: A cross sectional study design was employed to explore pharmacists' opinions regarding brand changes. A questionnaire was sent to 500 randomly selected pharmacists in New Zealand. In second component of the study, five community pharmacies in the Auckland region were selected through convenience sampling, and a semi-structured interview was conducted with a pharmacist in each site. RESULTS: One-hundred and eighty seven questionnaires were returned and analyzed (response rate of 37.4%). Sixty-eight percent of pharmacists supported brand changes and 98.4% mentioned that PHARMAC is responsible for informing them of brand changes. Over half (51.3%) of pharmacists found the current interventions effective, and 39.6% were satisfied with the current brand change information provided by PHARMAC. The majority (94.7%) of pharmacists currently receive faxed information but many indicated (70.8%) that they prefer email notifications. Cilazapril was considered the least difficult medicine to substitute in the past 10 years and omeprazole the most difficult. Patient acceptance and claims about effectiveness were the main factors in determining the difficulty of brand substitution. Fewer than half of the respondents felt that interventions were implemented with enough preparation time for a brand change. The ideal lead-in time was in the range of three to six months. Pharmacists expressed a number of concerns about brand changes such as the frequency at which they occur and the lack of generic stock availability when a brand change occurs. CONCLUSION: Over one-third of respondents were satisfied with brand change information provided by PHARMAC. Cilazapril was the least difficult medicine to substitute, while omeprazole and salbutamol changes were the most difficult. Claims about effectiveness, quality and side effects were the main factors identified as barriers to generic substitution. PMID- 24811427 TI - Chilaiditi's syndrome associated with colonic volvulus and intestinal malrotation A rare case. AB - INTRODUCTION: Chilaiditi's syndrome (symptomatic hepatodiaphragmatic interposition of the colon) is an exceptionally rare cause of bowel obstruction and may present difficulty in diagnosis and management. This is the first reported case of colonic volvulus occurring in Chilaiditi's syndrome in association with intestinal malrotation and this case study describes its successful management. PRESENTATION OF CASE: An 18 year old male presented as an emergency with vague abdominal pain and a past history of gastroschisis repair with intestinal malrotation. CT scanning showed a closed loop obstruction due to a volvulus of the colon herniating under the falciform ligament. The patient was successfully treated by surgical reduction of the hernia, anatomical correction of the malrotation and caecopexy with a tube caecostomy. At six month follow up the patient was well and asymptomatic. DISCUSSION: In nine of the previously reported cases of Chilaiditi's syndrome with colonic volvulus, treatment was by partial colonic resection of which a third underwent stoma formation. One patient died as a consequence of anastomotic leak following primary anastomosis. We therefore suggest an alternative approach to management. CONCLUSION: Chilaiditi's syndrome with colonic volvulus in association with intestinal malrotation has not previously been described. As there is no consensus in the literature as to how to manage such a case we suggest that reduction of the volvulus, anatomical correction of the malrotation and fixation of the caecum by tube caecostomy results in a successful outcome. This approach avoids the need for colonic resection and possible stoma formation. PMID- 24811428 TI - Abstracts from 2014 VASA Symposium, 2-3 May 2014, Dallas, Texas - USA. PMID- 24811429 TI - Prophylactic and curative anti-ulcerative colitis activity and the possible mechanisms of action of some desert plants. AB - The aim of the present study was to evaluate both prophylactic and curative anti ulcerative colitis activity and the possible mechanism of action of seven desert plant extracts. Seven desert plants from different families; Conyza dioscoridis (L.) Desf. (Asteraceae), Euphorbia hirta L. (Euphorpiaceae), Origanum syriacum L. and Salvia lanigera L. (Lamiaceae), Sisymbrium irio L., Solanum nigrum Linn. (Solanaceae) and Solenostemma arghel (Del.) Hayne. (Asclepiadaceae) were separately evaluated at three doses (125, 250, and 500 mg/kg) using the acetic acid-induced colitis model. The investigated extracts possessed prophylactic and curative anti-ulcerative colitis activities in a dose-dependent manner, where Salvia lanigera (87.9) and Solenostemma arghel (89.2) were the most effective extracts whereas the dexamesathone produced 68%. These extracts were further investigated for estimation of their mechanism of action. The in vitro potential radical (DPPH) scavenging activities of the investigated extracts were well supported with the reduction of colonic MDA content for both extracts. Suppression of the inflammatory mediator TNF-alpha and inhibition of both PLA2 and protease enzymes may play an important role in the anti-ulcerative colitis activities. The investigated extracts were safe for use up to 5 g/kg and the total alcohol extracts of Salvia lanigera and Solenostemma arghel (400 mg/kg for 35 d) showed no alteration on liver and kidney functions. Phytochemical screening of the investigated extracts revealed the presence of flavonoids, tannins, unsaturated sterols, and proteins which could be responsible for the activities. PMID- 24811430 TI - Meanings of being a close relative of a family member treated with haemodialysis approaching end of life. AB - AIMS AND OBJECTIVES: To describe and elucidate the meanings of being a close relative of a severely ill family member treated with maintenance haemodialysis approaching the end of life. BACKGROUND: End-stage renal disease together with comorbidities, haemodialysis treatment and high mortality rates also affects the lives of close relatives, who report burdens and impaired quality of life. To improve care, more understanding is needed of close relatives' experiences during these patients' end of life. DESIGN: This study has a qualitative interpretative design. METHODS: Fourteen retrospective qualitative interviews were conducted with close relatives (aged 48-93 years) of deceased patients who had been treated with haemodialysis. The interview text was interpreted using a phenomenological hermeneutical method in three phases. RESULTS: The findings of the structural analysis were formulated as six themes: Striving to be supportive and helpful without doing harm to the ill person's self; Needing increasing strength and support; Balancing the will to help with one's own ongoing life; Increasing responsibility involving dilemmas; Striving for a good life together in the present and Living with awareness of death. CONCLUSIONS: Close relatives strive for balance and well-being accompanying their ill family member through the end of life. They are facing moral dilemmas and growing demands as their responsibility increases with the deterioration of their family member. Support from and interaction with the healthcare professionals is then of significance. RELEVANCE TO CLINICAL PRACTICE: Findings challenge healthcare professionals in haemodialysis settings to identify close relatives' individual resources and needs towards the patients' end of life. Healthcare professionals in haemodialysis settings need to offer close relatives opportunities to talk about the future and what may be expected at end of life, with or without haemodialysis. They should also contact the closest relative after the death as they may need confirmation and closure. PMID- 24811431 TI - Quantitatively estimating defects in graphene devices using discharge current analysis method. AB - Defects of graphene are the most important concern for the successful applications of graphene since they affect device performance significantly. However, once the graphene is integrated in the device structures, the quality of graphene and surrounding environment could only be assessed using indirect information such as hysteresis, mobility and drive current. Here we develop a discharge current analysis method to measure the quality of graphene integrated in a field effect transistor structure by analyzing the discharge current and examine its validity using various device structures. The density of charging sites affecting the performance of graphene field effect transistor obtained using the discharge current analysis method was on the order of 10(14)/cm(2), which closely correlates with the intensity ratio of the D to G bands in Raman spectroscopy. The graphene FETs fabricated on poly(ethylene naphthalate) (PEN) are found to have a lower density of charging sites than those on SiO2/Si substrate, mainly due to reduced interfacial interaction between the graphene and the PEN. This method can be an indispensable means to improve the stability of devices using a graphene as it provides an accurate and quantitative way to define the quality of graphene after the device fabrication. PMID- 24811432 TI - Abnormalities of the glutamine-glutamate-GABA cycle in the schizophrenia brain. PMID- 24811433 TI - Relative stability of neurocognitive deficits in early onset schizophrenia spectrum patients. AB - In contrast to the findings of progressive structural brain changes in adolescence, longitudinal studies of patients with early onset schizophrenia spectrum disorders (EOS) indicate that neurocognitive deficits are relatively stable over the first years. The aim of this study is to assess neurocognitive functions longitudinally in patients with EOS compared to healthy controls (HC) using the MATRICS Cognitive Consensus Battery (MCCB). METHODS: Twenty patients with EOS and 41 HC were tested with the MCCB at baseline (T1) and after one (T2) and two years (T3). The mean age for the EOS group was 15.6 (SD=1.8) years, while the mean duration of illness was 1.7 (SD=1.4) years at T1. RESULTS: The EOS group's neurocognitive performances indicate a stable deficit on most measures. Both the EOS and HC groups showed improved neurocognitive functioning over time on all measures except for the verbal learning domain. There was an interaction between the EOS and HC groups' performance over time on the Trail Making Test A (TMA), a subtest on the processing speed domain. CONCLUSION: The longitudinal neurocognitive performances measured by the MCCB confirm previous findings of stable deficits in patients with EOS. It is premature to conclude whether the increases in neurocognitive performance reflect developmental processes in adolescence or may be explained by learning effects, or both. As opposed to the other tests in this domain, a stagnation in processing speed as measured by the TMA suggests that the TMA is a particularly sensitive measure of neurodevelopmental deviance in EOS. PMID- 24811434 TI - Merkel cell carcinoma - recent advances in the biology, diagnostics and treatment. AB - Merkel cell carcinoma (MCC) is an uncommon primary cutaneous carcinoma with neuroendocrine differentiation. Since recent discovery of MCCs strong association with Merkel cell polyomavirus (MCPyV), there has been a rapid increase in the understanding of the carcinomas genetics, molecular biology and pathogenesis. In our study, we reviewed recent advances and controversies concerning MCC histogenesis, epidemiology, diagnostic and prognostic markers. We analyzed the association of MCPyV with MCC and the possible new targets for therapy. We also examined English-based literature regarding MCC pathogenesis published between 2008 and 2013, which lead to a deeper understanding of the topic. Our study showed that the association of MCPyV strongly influences the course of MCC. Additionally, it has been shown that a immunological response to MCPyV may in the future give hope to identify new therapeutic strategies in treatment of this fatal malignancy. This article is part of a Directed Issue entitled: Rare Cancers. PMID- 24811435 TI - Hepatocellular cancer: how to expand safely inclusion criteria for liver transplantation. AB - PURPOSE OF REVIEW: The Milan criteria are still considered to be the best ones to select patients with hepatocellular cancer (HCC) for liver transplantation. Although the Milan criteria allowed lowering the incidence of tumor recurrence to a remarkable 10%, there is growing evidence that high numbers of patients were unrightfully excluded from a curative liver transplantation when exceeding these criteria. New strategies have been advocated during recent years with the intent not only to enlarge the number of potential transplant candidates, but also to select recipients with the lowest biological risk of recurrence. RECENT FINDINGS: Different 'biological' and 'dynamic' parameters have been proposed both in western and eastern scenarios, such as alpha-fetoprotein dynamics, radiological response to locoregional treatments and several inflammatory markers, the neutrophil-to-lymphocyte ratio being the most promising one. SUMMARY: The paradigm that HCC patients should be selected according to morphological aspects (tumor numbers and diameters) only, based on the almost 20-year old success story of the Milan criteria, should be modified by combining these parameters with newer biological tumor markers in order to further refine the selection for liver transplantation. Such therapeutic algorithm will allow to further improve selection for and thus outcome after liver transplantation for HCC patients. PMID- 24811436 TI - Liver transplantation for cholangiocarcinoma: current best practice. AB - PURPOSE OF REVIEW: Cholangiocarcinoma is a rare tumour with dismal prognosis. Only radical resection offers a chance for cure with reported survivals ranging from 25 to 45% at 5 years. Considering the low rate of resectability and lack of efficacy of other treatments, liver transplantation has emerged as a reasonable approach to cure selective patients with unresectable diseases. The use of liver transplantation, however, is associated with the inherent risk of early tumour recurrence due to the need for immunosuppression and the poor survival rate. This review will focus on the role of liver transplantation in treating patients with cholangiocellular cancer. RECENT FINDINGS: The indication of liver transplantation for cholangiocarcinoma has evolved over time moving from an absolute to a relative contraindication until eventually becoming the best indication for a small group of patients presenting with unresectable perihilar cholangiocarcinoma, when associated with a neoadjuvant chemoradiotherapy. In contrast, the indication of liver transplantation for intrahepatic cholangiocarcinoma is far from being established and should be offered only under protocol, mainly for small tumours in the setting of cirrhosis. SUMMARY: The poor outcome of cholangiocarcinoma, irrespective of the therapy, justifies the search for novel approaches. Only selective patients with perihilar cholangiocarcinoma subjected to a neoadjuvant protocol may qualify for liver transplantation. PMID- 24811437 TI - Donor-specific human leukocyte antigen antibodies in intestinal transplantation. AB - PURPOSE OF REVIEW: Early outcomes following intestinal transplantation (ITx) have markedly improved in recent years. However, there has been a lack of improvement in long-term outcomes. Increasing amounts of data suggest the humoral immune system is a major contributor to rejection and late allograft loss. This review will summarize the available data on donor-specific human leukocyte antigen antibodies (DSAs) in ITx, with a focus on the clinical significance of DSAs, diagnosis of antibody-mediated rejection (AMR), and available treatment modalities. Areas requiring further investigation will also be identified. RECENT FINDINGS: Mounting evidence shows that pre- and/or posttransplant DSAs are associated with rejection and allograft loss following ITx. Preformed DSAs are present in nearly one-third of ITx recipients, and de-novo DSAs develop in up to 40% of patients. Diagnosis and treatment of AMR remains challenging, but reports indicate that when optimal induction and maintenance immunosuppressive agents are used, the impact of DSAs may be negligible. SUMMARY: Although data are limited due to center differences with regard to patient population, induction and maintenance immunosuppression protocols, and monitoring strategies, DSAs are associated with poor outcomes following ITx. A consensus to define AMR and optimal treatment strategies is needed. PMID- 24811438 TI - Thrombotic microangiopathy in renal allografts: the diagnostic challenge. AB - PURPOSE OF REVIEW: The diagnosis of thrombotic microangiopathy (TMA) is complex and often difficult. This review provides an approach to the diagnosis with emphasis on recent relevant developments. RECENT FINDINGS: There is increasing evidence that most cases of recurrent TMA in renal allografts are secondary to mutations in genes encoding complement regulatory factors and complement components, such as factor H, factor I, membrane cofactor protein, C3, and others. Genetic work-up for these potential complement abnormalities is now available and recommended. Another important cause for recurrent TMA is the presence of autoantibodies, such as antibodies to factor H and antiphospholipid antibodies. De-novo TMA is much more common than recurrent TMA in renal allografts. De-novo TMA can be secondary to calcineurin inhibitor treatment, mammalian target of rapamycin inhibitor treatment, but frequently also to antibody-mediated rejection and less commonly to infections. Systemic signs of TMA are often absent, and the gold standard for diagnosis is the renal allograft biopsy. Unfortunately, diagnostic criteria for TMA are somewhat subjective, and the biopsy provides limited information regarding the exact underlying cause. SUMMARY: TMA is a serious complication of renal transplantation, usually with poor outcome. However, with improving understanding of underlying pathogeneses, more effective disease-specific therapeutic interventions can be designed. Appropriate treatment depends on the correct diagnosis, which relies primarily on renal allograft biopsy. Standardization of pathologic criteria and introduction of new molecular testing methods in renal biopsy specimens hopefully will improve diagnostic accuracy. PMID- 24811439 TI - Chronic rejection in vascularized composite allografts. AB - PURPOSE OF REVIEW: To convey key issues surrounding chronic rejection in vascularized composite tissue allotransplantation (VCA), and to highlight pathologic features consistent with VCA chronic rejection. RECENT FINDINGS: Features consistent with chronic rejection have been reported in three VCA animal models, and have been observed in a paucity of human knee and hand transplants. These features include transplant vasculopathy with intimal hyperplasia, tertiary lymphoid follicles, graft fibrosis, and graft edema. Transplant vasculopathy has been the most consistent finding across cases, and has resulted in graft dysfunction and loss. Antibody-mediated rejection has not been conclusively reported in animal models or human subjects, although some cases have demonstrated donor-specific antibody in conjunction with C4d deposition. Multiple immunologic and non-immunologic mechanisms of VCA chronic rejection have been proposed. SUMMARY: As in solid organ transplantation, chronic rejection in VCA remains ill-defined. Transplant vasculopathy appears to be a key feature of chronic VCA rejection, whereas tertiary lymphoid follicles, graft fibrosis, and graft edema appear to be less-specific findings. Intimal hyperplasia can be detected with advanced imaging modalities. PMID- 24811440 TI - An updated Banff schema for diagnosis of antibody-mediated rejection in renal allografts. AB - PURPOSE OF REVIEW: To introduce the updated Banff schema for antibody-mediated renal allograft rejection and related revisions to definitions within this schema agreed upon during and immediately subsequent to the 2013 Banff Conference on Allograft Pathology. RECENT FINDINGS: The original Banff schema for diagnosis of acute and chronic, active antibody-mediated rejection (ABMR) in renal allografts, formulated at the 2001 and 2007 Banff Conferences, has been of great assistance to pathologists and clinicians faced with an increasing awareness of the role of donor-specific alloantibodies (DSAs) in producing graft injury. This schema requires histologic (primarily microvascular inflammation and transplant glomerulopathy), immunohistologic (C4d in peritubular capillaries), and serologic (circulating DSA) evidence for a definitive diagnosis of ABMR. Still, like other Banff classifications, the 2001/2007 schema for renal ABMR is a working classification subject to revision based on new data. Increasing evidence for C4d negative ABMR and antibody-mediated arterial lesions led to the development of a consensus at the 2013 Banff Conference for updating the schema to include these lesions. Definitions and thresholds for glomerulitis and chronic glomerulopathy were also revised to improve interobserver agreement and correlation with clinical, molecular, and serologic data. SUMMARY: From a consensus reached at the 2013 Banff Conference, an updated schema for diagnosis of acute/active and chronic, active ABMR has been developed that accounts for recent data supporting the existence of C4d-negative ABMR and antibody-mediated intimal arteritis. PMID- 24811441 TI - High magnetic field phase diagram in electron-doped manganites La(0.4)Ca(0.6)Mn(1 y)Cr(y)O3. AB - We report the charge-order to ferromagnetic phase transition induced by pulsed high magnetic field and impurity doping effects in manganites La(0.4)Ca(0.6)(Mn(1 y)Cr(y))O3 (0 <= y <= 0.2). Significant charge-order suppression and ferromagnetic tendency upon the Cr(3+)-doping are evidenced, and three different ground states are identified, namely the charge-order state, the phase separated state, and the spin-glass like state. Phase diagram in the H-y plane at 4.2 K is determined by the high magnetic field study, in which the charge-order and ferromagnetic phase boundary is clearly figured out. The critical magnetic field for melting the charge-order phase of La(0.4)Ca(0.6)MnO3 is revealed to reach up to 46 T at 4.2 K. Interestingly, distinct responses of the three states to the high magnetic field are observed, indicating the special physics regarding the charge order melting process in each state. The mechanism of the doping induced charge-order suppression and ferromagnetism promotion can be understood by the competition between the antiferromagnetic interaction of Cr-Mn and local enhancement of electron hopping by Cr(3+). PMID- 24811442 TI - Efficient process for ethanol production from Thai Mission grass (Pennisetum polystachion). AB - Mission grass (Pennisetum polystachion) obtained from Tak Province, Thailand, possesses the potential to become a lignocellulosic biomass for bioethanol production. After the grass underwent milling and alkaline pretreatments, it was subjected to acid and enzymatic hydrolysis. The glucose hydrolyzate from the grass was detoxified to remove inhibitory compounds and degradation products such as furfural and 5-hydroxymethylfurfural. Overliming at pH 10 produced the highest ethanol yield. Among various strains of baker's yeasts, Saccharomyces cerevisiae TISTR 5596 with a yeast concentration of 10% v/v produced the maximum ethanol yield at 16 g/L within 24h, which is among one of the fastest ethanol producing microorganisms compared to other strains of S. cerevisiae as well as other ethanol-producing microorganisms. PMID- 24811443 TI - Improving lactic acid productivity from wheat straw hydrolysates by membrane integrated repeated batch fermentation under non-sterilized conditions. AB - Bacillus coagulans IPE22 was used to produce lactic acid (LA) from mixed sugar and wheat straw hydrolysates, respectively. All fermentations were conducted under non-sterilized conditions and sodium hydroxide was used as neutralizing agent to avoid the production of insoluble CaSO4. In order to eliminate the sequential utilization of mixed sugar and feedback inhibition during batch fermentation, membrane integrated repeated batch fermentation (MIRB) was used to improve LA productivity. With MIRB, a high cell density was obtained and the simultaneous fermentation of glucose, xylose and arabinose was successfully realized. The separation of LA from broth by membrane in batch fermentation also decreased feedback inhibition. MIRB was carried out using wheat straw hydrolysates (29.72 g/L glucose, 24.69 g/L xylose and 5.14 g/L arabinose) as carbon source, LA productivity was increased significantly from 1.01 g/L/h (batch 1) to 2.35 g/L/h (batch 6) by the repeated batch fermentation. PMID- 24811444 TI - Selective adsorption and recovery of Au(III) from three kinds of acidic systems by persimmon residual based bio-sorbent: a method for gold recycling from e wastes. AB - A low cost bio-sorbent, named "PPF resin", was prepared by crosslinking the persimmon residual with formaldehyde. The adsorption behavior of PPF resin towards Au(III) from varied HCl and HNO3 concentration solutions was studied. PPF resin could adsorb almost complete Au(III) from high acidic systems. The influence of dilution ratio, solid-liquid ratio and time towards Au(III) from aqua regia leached PCBs liquor was censored in detail by batch and continuous adsorption methods. The PPF resin before and after adsorption was characterized by FT-IR, XRD and XPS spectra which provided evidences for the reduction of Au(III) to Au(0) with a proposed mechanism of Au(III) adsorption-reduction process. After saturated column adsorption of 0.1g PPF resin, 0.0506 g gold (purity: 99.9%) was obtained by the method of incineration. The present results provide a new approach for gold recovery from the secondary resources. PMID- 24811445 TI - Stable high-titer n-butanol production from sucrose and sugarcane juice by Clostridium acetobutylicum JB200 in repeated batch fermentations. AB - The production of n-butanol, a widely used industrial chemical and promising transportation fuel, from abundant, low-cost substrates, such as sugarcane juice, in acetone-butanol-ethanol (ABE) fermentation was studied with Clostridium acetobutylicum JB200, a mutant with high butanol tolerance and capable of producing high-titer (>20 g/L) n-butanol from glucose. Although JB200 is a favorable host for industrial bio-butanol production, its fermentation performance with sucrose and sugarcane juice as substrates has not been well studied. In this study, the long-term n-butanol production from sucrose by JB200 was evaluated with cells immobilized in a fibrous-bed bioreactor (FBB), showing stable performance with high titer (16-20 g/L), yield (~ 0.21 g/g sucrose) and productivity (~ 0.32 g/Lh) for 16 consecutive batches over 800 h. Sugarcane thick juice as low-cost substrate was then tested in 3 consecutive batches, which gave similar n-butanol production, demonstrating that JB200 is a robust and promising strain for industrial ABE fermentation. PMID- 24811446 TI - Utilization of lipid extracted algal biomass and sugar factory wastewater for algal growth and lipid enhancement of Ettlia sp. AB - The present study assessed the use of hydrolysate of lipid extracted algal biomass (LEA) combined with the sugar factory wastewater (SFW) as a low cost nutrient and a carbon source, respectively for microalgal cultivation. Microalgal strain Ettlia sp. was both mixotrophically and heterotrophically cultivated using various amounts of hydrolysate and SFW. The culture which was grown in medium containing 50% LEA hydrolysate showed highest growth, achieving 5.26 +/- 0.14 gL( 1) after 12 days of cultivation. The addition of SFW increased the lipid productivity substantially from 5.8 to 95.5 mg L(-1)d(-1) when the culture medium was fortified with 20% SFW. Gas chromatography analysis indicated a noticeable increase of 20% in C16 and C18 fraction in FAME distribution under above condition. Therefore, it can be concluded that the combination of LEA hydrolysate and sugar factory waste water can be a powerful growth medium for economical algal cultivation. PMID- 24811447 TI - In situ volatile fatty acids influence biogas generation from kitchen wastes by anaerobic digestion. AB - Anaerobic digestion is considered to be an efficient way of disposing kitchen wastes, which can not only reduce waste amounts, but also produce biogas. However, the excessive accumulation of volatile fatty acids (VFA) caused by high organic loads will inhibit anaerobic digestion intensively. Effects of the VFA composition on biogas generation and microbial community are still required for the investigation under various organic loads of kitchen wastes. Our results showed that the maximum specific methane production was 328.3 ml g TS(-1), and acetic acid was the main inhibitor in methanogenesis. With the increase of organic load, aceticlastic methanogenesis was more sensitive to acetic acid than hydrogenotrophic methanogenesis. Meanwhile, methanogenic microbial community changed significantly, and few species grew well under excessive organic loads. This study provides an attempt to reveal the mechanism of VFA inhibition in anaerobic digestion of kitchen wastes. PMID- 24811448 TI - Abdominal near-infrared spectroscopy in preterm infants: a comparison of splanchnic oxygen saturation measurements at two abdominal locations. AB - BACKGROUND: Splanchnic tissue oxygenation monitoring has been performed at both the liver and the infra-umbilical regions. It is unknown whether these measurements could be substituted one for the other when interpreting splanchnic oxygenation since they have not been measured simultaneously before. AIMS: To evaluate the feasibility and safety of liver and infra-umbilical near-infrared spectroscopy (NIRS) monitoring in preterm infants with suspected necrotizing enterocolitis (NEC) and to assess the correlation and agreement between NIRS measurements performed simultaneously at the two abdominal locations. STUDY DESIGN AND SUBJECTS: This study was part of a prospective observational cohort study. Preterm infants who were suspected of NEC or who had been diagnosed with NEC were included. OUTCOME MEASURES: Liver oxygen saturation and infra-umbilical oxygen saturation were monitored simultaneously and continuously for 48h by NIRS. RESULTS: NIRS monitoring was performed in 20 out of 24 infants for the entire 48 hour study period. No adverse effects were observed. Values of liver and infra umbilical oxygen saturation correlated weakly (Spearman's rho=0.244, P<.001). On the Bland-Altman plot liver oxygen saturation was higher than infra-umbilical oxygen saturation (mean difference 6.6%, SD 22.5%). CONCLUSIONS: Using NIRS as method for monitoring oxygen saturation simultaneously in both the liver and infra-umbilical regions is safe and feasible. Additionally, we demonstrated that values of liver and infra-umbilical oxygen saturation cannot be randomly substituted one for the other for the purpose of assessing splanchnic oxygenation. PMID- 24811449 TI - Choice and timing in pigeons under differing levels of food deprivation. AB - State-dependent valuation learning (SDVL) is a preference for stimuli associated with relative food deprivation over stimuli associated with relative satiety. Pigeons were exposed to experimental conditions designed to investigate SDVL and to test the hypothesis that obtained relative immediacy during training predicts choice during test probes. Energy states were manipulated using a procedure that has previously revealed SDVL in starlings and pigeons. In Experiment 1, pigeons preferred the stimulus associated with deprivation in the first choice probe session, but were indifferent in the second. Changes in choice were consistent with changes in obtained relative immediacy. In Experiment 2, training parameters were altered and SDVL did not occur. Obtained relative immediacy again predicted choice. Results of both experiments provide evidence that obtained relative immediacy may be an important contributing factor to the SDVL phenomenon. PMID- 24811450 TI - Frequency difference limens and auditory cue trading in CBA/CaJ mice (Mus musculus). AB - Mice are emerging as an important behavioral model for studies of auditory perception and acoustic communication. These mammals frequently produce ultrasonic vocalizations, although the details of how these vocalizations are used for communication are not entirely understood. An important step in determining how they might be differentiating their calls is to measure discrimination and identification of the dimensions of various acoustic stimuli. Here, behavioral operant conditioning methods were employed to assess frequency difference limens for pure tones. We found that their thresholds were similar to those in other rodents but higher than in humans. We also asked mice, in an identification paradigm, whether they would use frequency or duration differences to classify stimuli varying on those two dimensions. We found that the mice classified the stimuli based on frequency rather than duration. PMID- 24811451 TI - US-preexposure effects in flavor-preference and flavor-aversion learning with nonnutritive USs. AB - In two experiments, rats received exposure to either a saccharin or quinine solution followed by conditioning with a solution of almond as the conditioned stimulus (CS) and either saccharin or quinine as the unconditioned stimulus (US). In Experiment 1, rats received preexposure and conditioning using saccharin as the US; in Experiment 2 quinine was the US. In both cases the magnitude of the conditioning effect (an enhanced preference for the CS in Experiment 1; a reduced preference in Experiment 2) was reduced by preexposure to the US. The results provided confirmation of the occurrence of the US-preexposure effect in the flavor-preference procedure and demonstrate that the effect can be obtained with nonnutritive USs that lack significant post-oral consequences. The implications of these results for theories of the US-preexposure effect are discussed. PMID- 24811452 TI - Are 50-kHz calls used as play signals in the playful interactions of rats? I. Evidence from the timing and context of their use. AB - During playful interactions, rats emit increased levels of 50-kHz vocalizations. It is possible that these vocalizations are used as play signals that promote and maintain playful contact. The study investigated this possibility. It was predicted that if these vocalizations are used as play signals, they should be more prevalent (1) before an attack, (2) in attacks leading to wrestling, and (3) in males compared to females, as males play more roughly. Moreover, given that there are at least 15 different subtypes of 50-kHz calls, it is possible that different calls are used in different contexts. Therefore, our prediction (4) was that different subtypes would be used for initiating and terminating playful contact. Pairs of same-sex juveniles were tested so that video recordings of their play and audio recordings of their vocalizations were synchronized. 50-kHz vocalizations occur more often before an attack and in male pairs. Specific calls were associated with specific types of behaviors and these associations differed between male and female rats. However, calls were not more frequent in attacks leading to wrestling than in attacks leading to withdrawal. The data provide qualified support for the hypothesis that 50-kHz vocalizations function as play signals. PMID- 24811453 TI - Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling. AB - Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH induction of pulmonary hypertension. PMID- 24811455 TI - Comment on: The Portuguese Society of Rheumatology position paper on the use of biosimilars. PMID- 24811454 TI - The three major types of CRISPR-Cas systems function independently in CRISPR RNA biogenesis in Streptococcus thermophilus. AB - CRISPR-Cas systems are small RNA-based immune systems that protect prokaryotes from invaders such as viruses and plasmids. We have investigated the features and biogenesis of the CRISPR (cr)RNAs in Streptococcus thermophilus (Sth) strain DGCC7710, which possesses four different CRISPR-Cas systems including representatives from the three major types of CRISPR-Cas systems. Our results indicate that the crRNAs from each CRISPR locus are specifically processed into divergent crRNA species by Cas proteins (and non-coding RNAs) associated with the respective locus. We find that the Csm Type III-A and Cse Type I-E crRNAs are specifically processed by Cas6 and Cse3 (Cas6e), respectively, and retain an 8 nucleotide CRISPR repeat sequence tag 5' of the invader-targeting sequence. The Cse Type I-E crRNAs also retain a 21-nucleotide 3' repeat tag. The crRNAs from the two Csn Type II-A systems in Sth consist of a 5'-truncated targeting sequence and a 3' tag; however, these are distinct in size between the two. Moreover, the Csn1 (Cas9) protein associated with one Csn locus functions specifically in the production of crRNAs from that locus. Our findings indicate that multiple CRISPR Cas systems can function independently in crRNA biogenesis within a given organism - an important consideration in engineering coexisting CRISPR-Cas pathways. PMID- 24811456 TI - Revisiting rheumatic diseases and cancer. PMID- 24811457 TI - Monoclonal gammopathy and rheumatic diseases. AB - It is common to find monoclonal gammopathy in the investigation workout for an unrelated disorder. There are studies relating rheumatic diseases and therapies which show an increased risk of monoclonal gammopathy. The specific mechanisms are not well understood but chronic antigen stimulation assumes an important role. Specific rheumatic diseases have consistently been associated with lymphoproliferative disorders but less attention has been paid to the possible association between monoclonal gammopathy of undetermined significance and multiple myeloma. We reviewed previous studies regarding monoclonal gammopathy and different rheumatic diseases and treatments associated focusing on prevalence, risk factors and possible pathogenic mechanisms. The clinical approach of a monoclonal gammopathy and its follow-up are explained. PMID- 24811458 TI - Pharmacology of biosimilar candidate drugs in rheumatology: a literature review. AB - OBJECTIVE: To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. METHODS: A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. RESULTS: Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. CONCLUSION: Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis. PMID- 24811459 TI - Assessment of atrial conduction time in patients with Behcet's disease. AB - OBJECTIVE: Behcet's disease is characterized by increased inflammatory activity, and there there might be an increased risk of atrial arrhythmia in patients with this disease. Our study is aimed to evaluate a novel method of measuring atrial electromechanical features expressed as interatrial and intraatrial electromechanical delay by tissue Doppler echocardiography in patients with Behcet's disease. METHODS: We evaluated 57 patients (mean age: 36.3+/-12.1 years) with Behcet's disease and 34 sex and age matched healthy volunteers (mean age: 38.4+/-8.6 years) as control group. P-wave dispersion (PWD) was calculated from the 12-lead surface ECG, interatrial and intraatrial electromechanical delay were measured by tissue Doppler imaging and conventional echocardiography. RESULTS: Interatrial electromechanical delay and intraatrial electromechanical delay were prolonged in patients with active Behcet's disease compared with the patients with inactive disease and the controls (p<0.0001, p<0.0001, p=0.013 and p=0.001, respectively). Erythrocyte sedimentation rate and high-sensitivity C-reactive protein values of of patients with active Behcet's were significantly higher than those with inactive Behcet's disease and the controls (p<0.0001 and p<0.0001, respectively). High-sensitivity C-reactive protein and erythrocyte sedimentation rate were correlated with interatrial electromechanical delay in patients with Behcet's disease (r=0.44, p=0.001 and r=0.64, p<0.0001, respectively). CONCLUSIONS: The prolongation of atrial electromechanical conduction might be related with changes in structure and electrophysiological properties of the atrial myocardium or the conduction system in patients with active Behcet's disease. PMID- 24811460 TI - [Chronic recurrent multifocal osteomyelitis: case series of four patients treated with biphosphonates]. AB - AIM: To report and describe a series of four cases of chronic recurrent multifocal osteomyelitis (CRMO) and to discuss therapeutic options, particularly bisphosphonate therapy. METHODS: Retrospective review of four CRMO cases in two Pediatric Units in Lisbon, between 2005 and 2010. RESULTS: Median age of first CRMO symptoms was 11.3 years (range 9-13). The more affected sites were the metaphysis of the long bones, pelvis and coxofemoral joints. Median number of initial bony lesions for each patient was 2.3 (range 1-3) at onset and 3.8 (range 2-6) during the disease course. All patients failed to respond to NSAIDs therapy. Two patients received corticosteroids, with clinical disease remission in only one of them. All patients received bisphosphonates (alendronate in two and pamidronate in two), all with good clinical response and induction of clinical remission in two of them. After a median follow-up period of 4.3 years (range 4 5), three patients are clinically asymptomatic and one patient remains with chronic residual pain. CONCLUSIONS: The treatment of CRMO is not standardized. Bisphosphonate therapy can be of benefit to patients with relapsing symptoms. Randomized controlled multicentric trials are needed to provide better evidence for universal recommendation and definition of bisphosphonate therapy protocol. PMID- 24811461 TI - What affects the quality of life in patients with Behcet's disease? AB - AIM: The aim of this study was to evaluate the possible associations between quality of life (QoL) and sociodemographic features, disease characteristics and the Behcet's Disease (BD) disease activity of the patients with BD. PATIENTS AND METHODS: One hundred and seven patients with BD were included in this study. Sociodemographic features including age, gender, education level of the patients and the disease characteristics including disease duration, disease onset age, the history BD clinical involvements were recorded. In patients with BD, the BD Current Activity Form was used for the evaluation of disease activity. The short form-36 (SF-36) QoL scale was used to evaluate the QoL in patients with BD. The Student t test, analysis of variance and Spearman's correlation matrix were used for the statistical analysis. RESULTS: Men showed higher mean scores of role physical and bodily pain domains of SF-36 than women did (p <0.000 and 0.001). Patients over 41 years of age had higher mean general health scores and university graduates patients had higher mean mental health scores than the other groups (p <0,01). Patients with a disease duration more than 5 years and patients have a younger disease onset age showed lower general health score than the others (p <0,01). Also patients with an anamnesis of uveitis, genital ulceration, erythema nodosum, thrombophlebitis, joint and gastrointestinal system involvement showed lower QoL than the patients without these complaints (p <0,05 and p <0,01). In the analysis of disease activity physical subscores of SF-36 were found to be correlated with fatigue, oral ulceration and joint involvement (p <0,01). Bodily pain showed a correlation with fatigue, headache and more highly with joint involvement (p <0,01 and p <0,001 respectively). General health was correlated with GIS and eye involvement and vitality was found to be correlated with fatigue, patient's and doctor's impression of disease activity (p <0,01). Mental and emotional scores were correlated with oral- genital ulceration, eye and joint involvements (p <0,01). CONCLUSION: In addition to demografic features and clinical involvements, BD disease activity can affect QoL in patients with BD. These results highlight the importance of managing the symptoms and the disease activity effectively in order to improve QoL in BD. PMID- 24811462 TI - Prevalence of self-reported rheumatic diseases in a Portuguese population. AB - OBJECTIVES: With this study we attempted to estimate the prevalence of self reported rheumatic diseases in a Portuguese population. It was also our objective to evaluate the influence of the variables sex and age on the prevalence of these diseases. PATIENTS AND METHODS: The study population was comprised of 297 individuals from a total of 573 random telephone numbers selected from the city of Lisbon telephone book (landline/residents). Those 297 were the ones that agreed to answer the proposed questionnaire. RESULTS: The prevalence value of self-reported rheumatic diseases was 26.3%. A prevalence value of self-declared osteoarthritis of 21.2% was found, 7.7% for osteoporosis, 1.3% for rheumatoid arthritis and 0.3% each for gout, systemic lupus erythematosus, Behcet's disease and fibromyalgia. An association with the variables sex and age was achieved for the total of rheumatic diseases. The same association was obtained for osteoarthritis and osteoporosis. CONCLUSIONS: This study emphasizes the good self -judgment that the inquired population has about their rheumatic diseases, and some of the obtained results are in agreement with the national and worldwide literature. PMID- 24811463 TI - The Portuguese Society of Rheumatology position paper on the use of biosimilars. AB - Biotechnological drugs have become a fundamental resource for the treatment of rheumatic patients. Patent expiry of some of these drugs created the opportunity for biopharmaceutical manufacturers to develop biosimilar drugs intended to be as efficacious as the originator product but with a lower cost to healthcare systems. Due to the complex manufacturing process and highly intricate structure of biologicals, a biosimilar can never be an exact copy of its reference product. Consequently, regulatory authorities issued strict preclinical and clinical guidelines to ensure safety and efficacy equivalence and, in September 2013, the biosimilar of infliximab was the first biosimilar monoclonal antibody to be authorized for use in the European Union. The current document is a position statement of the "Sociedade Portuguesa de Reumatologia" (Portuguese Society of Rheumatology) on the use of biosimilar drugs in rheumatic diseases. Two systematic literature reviews were performed, one concerning clinical trials and the other one concerning international position papers on biosimilars. The results were presented and discussed in a national meeting and a final position document was discussed, written and approved by Portuguese rheumatologists. Briefly, this position statement is contrary to automatic substitution of the originator by the biosimilar, defends either a different INN or the prescription by brand name, supports that switching between biosimilars and the originator molecule should be done after at least 6 months of treatment and based on the attending physician decision and after adequate patient information, recommends the registration of all biosimilar treated patients in Reuma.pt for efficacy, safety and immunogenicity surveillance, following the strategy already ongoing for originators, and opposes to extrapolation of indications approved to the originator to completely different diseases and/or age groups without adequate pre-clinical, safety or efficacy data. PMID- 24811464 TI - Colonic perforation secondary to metastatic lung adenocarcinoma during anti-TNF treatment for ankylosing spondylitis. AB - Biological agents targeting inflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha) have emerged in recent years as effective medications for a variety of inflammatory arthropathies. Although the relationship between the use of anti-TNF drugs and an increase in the rate of infections is well established, the role of these drugs in the development of different types of cancer is unclear. Randomized clinical trials and national registries have not demonstrated a significant increase in the risk of cancer in patients treated with anti-TNF drugs, but numerous cases of the appearance of malignant tumors in patients receiving these drugs have been reported. We describe the case of a 73-year-old man, ex-smoker, who developed a lung cancer during treatment with infliximab further complicated by perforation of a metastasis in the sigmoid colon, which is a very infrequent event in the course of this malignancy. A few similar cases previously reported in the literature are reviewed. PMID- 24811465 TI - Nasal type extranodal NK/T cell lymphoma diagnosed in a patient with rheumatoid arthritis under methotrexate. AB - Rheumatoid arthritis (RA) patients have increased risk of lymphoma which seems associated mainly with high inflammatory state and disease activity, but also with immunosuppressive agents or Epstein-Barr virus (EBV) infection. Many case reports describe lymphoproliferative lesions arising during methotrexate therapy, often EBV positive with possible regression after methotrexate withdrawal. The authors report the case of an 85-year-old patient with erosive and seronegative RA, in remission under methotrexate who developed a midfacial destructive lesion with epistaxis and local inflammatory signs. The magnetic resonance imaging showed a large nasal septum defect. Anti-neutrophil cytoplasmic antibodies titres and angiotensin converting enzyme were normal. Biopsies of the lesion identified a NK/ T nasal type lymphoma. EBV latent membrane protein research on the lesion was negative. Polymerase chain reaction analysis of the bone marrow aspirate showed EBV DNA positivity. Withdrawal of methotrexate was performed without tumour regression. The authors described the single case of a patient with RA in stable remission under methotrexate who presented a rare type of lymphoma, a nasal type NK/T. EBV active replication was found in the bone marrow. PMID- 24811466 TI - Mantle cell lymphoma and systemic sclerosis. AB - Systemic sclerosis (SSc) is a rare disease with an increased incidence of cancer, but the ocorrence of Non-Hodgkin lymphoma (NHL) is a very uncommon event. We report a case of a 76-year-old female addmited to the hematology clinic with long term adenopathies and ocasional gastro-intestinal symptomatology. Progressive symmetrical swelling of hands was also noticed. Colonoscopy revealed multiple polyps and histopathology was consistent with Mantle-Cell Lymphoma (MCL)-NHL. R CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) regimen was promptly iniated with complete response. Persistent swelling of both hands was observed, with thickening of the skin of both hands with proximal extension until the forearm. Biopsy confirmed the diagnosis of scleroderma. Symptomatic and rehabilitation treatment was initiated with mild improvement of symptoms. To our knowledge this is the first case of MCL associated with SSc. PMID- 24811467 TI - Paraneoplastic sclerodermiform syndrome--case report. AB - Occasionally, auto-immune diseases may emerge as paraneoplastic syndromes. This is especially recognized in the case of polymyositis/dermatomyostis, but it is an extremely rare event in systemic sclerosis (SSc). The authors report the case of a sixty-year-old woman who presented with Raynaud's phenomenon and rapidly progressing skin thickness of the forearms, hands and lower limbs. Patient evaluation revealed a colorectal carcinoma. The patient was referred to the oncology department. This concomitance of cancer and SSc with rapid progression of the latter, suggests that the scleroderma might have a paraneoplastic origin. Such an hypothesis deserves consideration in every case as early diagnosis may be decisive to control the progression of either disease. PMID- 24811468 TI - Giant buttock lipoma with an atypical presentation as a sciatic hernia--case report. PMID- 24811469 TI - [Unifocal chronic non-bacterial osteomyielitis of mandible]. PMID- 24811470 TI - Ultrasonographic imaging of the peripheral nerves in a Wegener granulomatosis patient with multiple mononeuropathies. PMID- 24811471 TI - Fever of unknown origin and leukemoid reaction as initial presentation of adult onset Still's disease. AB - Adult Still's Disease has been reported as cause of Fever of Unknown Origin. Leukocytosis has been described as a common haematological abnormality in Adult Still's Disease. In some rare cases, leukemoid reaction has been reported associated to Still's Disease. We report the case of Adult Still's Disease presenting as Fever of Unknown Origin and leukemoid reaction in a patient with Down Syndrome. The patient needed high dosage of corticosteroids to control the disease and haematological findings. PMID- 24811472 TI - Leadership lessons from the gym. PMID- 24811473 TI - The high cost of hoarding disorder. PMID- 24811475 TI - Implications of genetic selection on yolk proportion on the dry matter content of eggs in a White Leghorn population. AB - 1. The responses to genetic selection on yolk proportion as a technique for increasing egg dry matter content, an important criterion for the egg-product industry, was investigated in a pedigree flock of White Leghorn hens. 2. Parents were preselected on high and low yolk proportion from a base population. The absolute estimated breeding value for yolk proportion of both groups differed by 3%. The realised selection difference in dry matter content of eggs between groups was more than 1% in the analysed offspring population. 3. Heritability estimates were moderate and dry matter had a lower heritability (h(2) = 0.39) than yolk proportion (h(2) = 0.44). 4. The genetic correlation between yolk proportion and dry matter content was highly positive (rg = 0.91). Genetic correlations with egg weight were negative and would have to be compensated for in a breeding programme (rg = -0.76 with yolk proportion and rg = -0.64 with dry matter content). The genetic correlation between the laying performance and yolk proportion was rg = 0.28 and close to zero (rg = -0.05) for dry matter content. 5. Easy recording and lower undesirable correlations make yolk proportion more suitable for commercial selection compared with egg dry matter content in layer breeding. PMID- 24811474 TI - Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation. AB - Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction. PMID- 24811476 TI - Process evaluation of an open architecture real-time molecular laboratory platform. AB - The needs of molecular diagnostic laboratories that perform both Food and Drug Administration-cleared as well as laboratory-developed tests are usually not met on a single analytical platform. Furthermore, little information is available about the direct impact of molecular automation on labor costs and efficiency in clinical laboratories. We performed a process impact analysis from time and motion studies of a novel molecular diagnostic robotic system designed to automate sample preparation, extraction, and analysis. All 27 preanalytical tasks were quantified for the amount of time spent preparing 24 specimens for analysis. These steps were completed in 899 s (14 min, 59 s) followed by 7887 s (131 min, 27 s) of instrument operation independent of operator control (walk-away time). Postanalytical results evaluation required 1 min per specimen. The instrument automatically extracted the nucleic acid from the specimen, added the eluted DNA to the amplification reagents, and performed the analysis. Only 12% of the total instrument operations required relatively unskilled human labor. Thus, the availability of automated molecular diagnostic instruments will facilitate the expansion of molecular testing in the clinical laboratory because they reduce operator costs with respect to time and complexity of the tasks they are asked to perform. PMID- 24811478 TI - Short peptide type I interferon mimetics: therapeutics for experimental allergic encephalomyelitis, melanoma, and viral infections. AB - The classical canonical model of interferon (IFN) signaling focuses solely on the activation of STAT transcription factors, which limits the model in terms of specific gene activation, associated epigenetic events, and IFN mimetic development. Accordingly, we have developed a noncanonical model of IFN signaling and report the development of short type I IFN peptide mimetic peptides based on the model. The mimetics, human IFNalpha1(152-189), human IFNbeta(150-187), and ovine IFNtau(156-195) are derived from the C-terminus of the parent IFNs and function intracellularly based on the noncanonical model. Vaccinia virus produces a decoy IFN receptor (B18R) that inhibits type I IFN, but the IFN mimetics bypass B18R for effective antiviral activity. By contrast, both parent IFNs and mimetics inhibited vesicular stomatitis virus. The mimetics also possessed anti-tumor activity against murine melanoma B16 tumor cells in culture and in mice, including synergizing with suppressor of cytokine signaling 1 antagonist. Finally, the mimetics were potent therapeutics against experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. The mimetics lack toxic side effects of the parent IFNs and, thus, are a potent therapeutic replacement of IFNs as therapeutics. PMID- 24811479 TI - Novel 3-substituted ocotillol-type triterpenoid derivatives as antibacterial candidates. AB - Plant-derived triterpenoid saponins are involved in the plant defense system by targeting bacterial membranes. A series of ocotillol-type triterpenoid derivatives were synthesized starting from PPD, one of the main components of Panax ginseng and their antibacterial activity against several representative bacteria were evaluated. Compounds 5 and 11 exhibited excellent antibacterial activity with MIC values of 1 MUg/mL against Staphylococcus aureus and 8 MUg/mL and 4 MUg/mL against Bacillus subtilis, respectively. Furthermore, when compounds 5 and 11 were combined with two commercial antibiotics kanamycin and chloramphenicol, they showed strong synergistic activity at sub-MIC levels against S. aureus USA300 and B. subtilis 168. Moreover, chloramphenicol turned from a bacteriostatic to a bactericidal agent when combined with compound 11 against B. subtilis 168. PMID- 24811480 TI - Characteristics and outcomes of patients hospitalized following pulmonary aspiration. AB - BACKGROUND: Pulmonary aspiration is an important recognized cause of ARDS. Better characterization of patients who aspirate may allow identification of potential risks for aspiration that could be used in future studies to mitigate the occurrence of aspiration and its devastating complications. METHODS: We conducted a secondary analysis of the Lung Injury Prediction Score cohort to better characterize patients with aspiration, including their potential risk factors and related outcomes. RESULTS: Of the 5,584 subjects at risk for ARDS and who required hospitalization, 212 (3.8%) presented with aspiration. Subjects who aspirated were likely to be male (66% vs 56%, P < .007), slightly older (59 years vs 57 years), white (73% vs 61%, P = .0004), admitted from a nursing home (15% vs 5.9%, P < .0001), have a history of alcohol abuse (21% vs 8%, P < .0001), and have lower Glasgow Coma Scale (median, 13 vs 15; P < .0001). Aspiration subjects were sicker (higher APACHE [Acute Physiology and Chronic Health Evaluation] II score), required more mechanical ventilation (54% vs 32%, P < .0001), developed more moderate to severe ARDS (12% vs 3.8%, P < .0001), and were twofold more likely to die in-hospital, even after adjustment for severity of illness (OR = 2.1; 95% CI, 1.2-3.6). Neither obesity nor gastroesophageal reflux was associated with aspiration. CONCLUSIONS: Aspiration was more common in men with alcohol abuse history and a lower Glasgow Coma Scale who were admitted from a nursing home. It is independently associated with a significant increase in the risk for ARDS as well as morbidity and mortality. Findings from this study may facilitate the design of future clinical studies of aspiration-induced lung injury. PMID- 24811481 TI - Centralized molecular testing for oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. AB - BACKGROUND: Molecular testing for oncogenic gene mutations and chromosomal rearrangements plays a growing role in the optimal management of thyroid nodules, yet lacks standardized testing modalities and systematic validation data. Our objective was to assess the performance of molecular cytology on preoperative thyroid nodule fine-needle aspirates (FNAs) across a broad range of variables, including independent collection sites, clinical practices, and anatomic pathology interpretations. METHODS: Single-pass FNAs were prospectively collected from 806 nodules 1 cm or larger by ultrasonography at five independent sites across the United States. Specimens were shipped in a nucleic acid stabilization solution and tested at a centralized clinical laboratory. Seventeen genetic alterations (BRAF, KRAS, HRAS, and NRAS mutations, PAX8-PPARG and RET-PTC rearrangements) were evaluated by multiplex polymerase chain reaction and liquid bead array cytometry in 769 FNAs that met inclusion criteria. Cytology, histology, and clinical care followed local procedures and practices. All results were double-blinded. RESULTS: Thirty-two specimens (4.2%) failed to yield sufficient nucleic acid to generate molecular data. A single genetic alteration was detected in 80% of cytology malignant cases, 21% of indeterminate, 7.8% of nondiagnostic, and 3.5% of benign cases. Among 109 nodules with surgical histology reference standard, oncogenic mutations were present in 50% of malignant nodules missed by cytology. There were 14 cancers not identified by cytology or molecular tests, including 5 carcinomas with histologic sizes less than 1 cm (3 multifocal) and 8 noninvasive follicular variants of papillary carcinoma (4 encapsulated). No mutations were detected in 89% of the nodules benign by histopathology with 6 false-positive molecular results in 5 adenomas (2 5.5 cm) and 1 cystic nodule with an incidental papillary microcarcinoma (0.15 cm). The posttest probability of thyroid cancer was 100% for nodules positive for BRAF or RET-PTC, 70% for RAS or PAX8-PPARG, and 88% for molecular cytology overall. CONCLUSIONS: Centralized and standardized molecular testing for genetic alterations associated with a high risk of malignancy efficiently complements the local cytopathologic diagnosis of thyroid nodule aspirates in the clinical setting. Actionable molecular cytology can improve the personalized surgical and medical management of patients with thyroid cancers, facilitating one-stage total thyroidectomy and reducing the number of unnecessary diagnostic surgeries. PMID- 24811482 TI - Temporal discrimination deficits as a function of lag interference in older adults. AB - A vital component of episodic memory is the ability to determine the temporal order of remembered events. Although it has been demonstrated that the hippocampus plays a crucial role in this ability, the details of its contributions are not yet fully understood. One proposed contribution of the hippocampus is the reduction of mnemonic interference through pattern separation. Prior studies have used behavioral paradigms designed to assess this function in the temporal domain by evaluating the ability to determine the order of remembered events as a function of proximity in time. Results from these paradigms in older adults (OA) have been mixed, possibly due to limitations in controlling elapsed time and narrow range of temporal lags. Here, we introduce a novel behavioral paradigm designed to overcome these limitations. We report that OAs are impaired relative to younger adults at moderate and high temporal lags but not at low lags (where performance approached floor). We evaluated OAs' ability to benefit from primacy (enhanced order judgment on the first few items of any given sequence) and found two distinct subgroups: one group was on par with young adults [aged-unimpaired (AU)] and the other group was two standard deviations below the mean of young adults [aged-impaired (AI)]. Temporal discrimination performance in AU adults was consistent with a pattern separation deficit, while performance in AI adults was consistent with a generalized temporal processing deficit. We propose that the task introduced is a sensitive marker for episodic memory deficits with age, and may have diagnostic value for early detection of age-related pathology. PMID- 24811484 TI - Minimizing errors in acute traumatic spinal cord injury trials by acknowledging the heterogeneity of spinal cord anatomy and injury severity: an observational Canadian cohort analysis. AB - Clinical trials of therapies for acute traumatic spinal cord injury (tSCI) have failed to convincingly demonstrate efficacy in improving neurologic function. Failing to acknowledge the heterogeneity of these injuries and under-appreciating the impact of the most important baseline prognostic variables likely contributes to this translational failure. Our hypothesis was that neurological level and severity of initial injury (measured by the American Spinal Injury Association Impairment Scale [AIS]) act jointly and are the major determinants of motor recovery. Our objective was to quantify the influence of these variables when considered together on early motor score recovery following acute tSCI. Eight hundred thirty-six participants from the Rick Hansen Spinal Cord Injury Registry were analyzed for motor score improvement from baseline to follow-up. In AIS A, B, and C patients, cervical and thoracic injuries displayed significantly different motor score recovery. AIS A patients with thoracic (T2-T10) and thoracolumbar (T11-L2) injuries had significantly different motor improvement. High (C1-C4) and low (C5-T1) cervical injuries demonstrated differences in upper extremity motor recovery in AIS B, C, and D. A hypothetical clinical trial example demonstrated the benefits of stratifying on neurological level and severity of injury. Clinically meaningful motor score recovery is predictably related to the neurological level of injury and the severity of the baseline neurological impairment. Stratifying clinical trial cohorts using a joint distribution of these two variables will enhance a study's chance of identifying a true treatment effect and minimize the risk of misattributed treatment effects. Clinical studies should stratify participants based on these factors and record the number of participants and their mean baseline motor scores for each category of this joint distribution as part of the reporting of participant characteristics. Improved clinical trial design is a high priority as new therapies and interventions for tSCI emerge. PMID- 24811486 TI - Gene of the month: BECN1. AB - The BECN1 gene encodes the Beclin-1 protein, which is a well-established regulator of the autophagic pathway. It is a mammalian orthologue of the ATG6 gene in yeast and was one of the first identified mammalian autophagy-associated genes. Beclin-1 interacts with a number of binding partners in the cell which can lead to either activation (eg, via PI3KC3/Vps34, Ambra 1, UV radiation resistance associated gene) or inhibition (eg, via Bcl-2, Rubicon) of the autophagic pathway. Apart from its role as a regulator of autophagy, it is also shown to effect important biological processes in the cell such as apoptosis and embryogenesis. Beclin-1 has also been implicated to play a critical role in the pathology of a variety of disease states including cancer, neurological disorders (eg, Alzheimer's disease, Parkinson's disease) and viral infections. Thus, understanding the functions of Beclin-1 and its interactions with other cellular components will aid in its development as an important therapeutic target for future drug development. PMID- 24811487 TI - A cautionary lesson on the use of targeted methods for EGFR mutation analysis: a case report. AB - Epidermal growth factor receptor (EGFR) mutation analysis is recommended for lung cancer patients prior to the prescription of first-line EGFR tyrosine kinase inhibitors in order to predict response to treatment. There are many methods available to identify mutations in the EGFR gene; a large number of clinical laboratories use the therascreen EGFR RGQ PCR kit (Qiagen). We report a case where this kit detected an exon 19 deletion, predicting sensitivity to tyrosine kinase inhibitors (TKIs), which on further analysis was found to be a 2 bp indel (c.2239_2240delinsCC, p.(Leu747Pro)). Two of four published cases with this mutation were found to be associated with resistance to EGFR TKI. The sample was also tested using two other commercial kits, one of which indicated a deletion. This is a rare mutation making the erroneous detection of a deletion unlikely; however, it is important that clinical laboratories are aware of the potential failings of two commercial kits for EGFR mutation analysis. PMID- 24811485 TI - Inhibition of the vacuolar ATPase induces Bnip3-dependent death of cancer cells and a reduction in tumor burden and metastasis. AB - The pro-apoptotic protein Bnip3 is induced by hypoxia and is present in the core regions of most solid tumors. Bnip3 induces programmed necrosis by an intrinsic caspase independent mitochondrial pathway. Many tumor cells have evolved pathways to evade Bnip3-mediated death attesting to the physiological relevance of the survival threat imposed by Bnip3. We have reported that acidosis can trigger the Bnip3 death pathway in hypoxic cells therefore we hypothesized that manipulation of intracellular pH by pharmacological inhibition of the vacuolar (v)ATPase proton pump, a significant pH control pathway, may activate Bnip3 and promote death of hypoxic cells within the tumor. Here we confirm that bafilomycin A1 (BafA1), a selective vATPase inhibitor, significantly increased death of breast cancer cells in a hypoxia and Bnip3-dependent manner and significantly reduced tumor growth in MCF7 and MDA-MB-231 mouse xenografts. Combined treatment of cells with BafA1 and the ERK1/2 inhibitor U0126 further augmented cell death. Combined treatment of mice containing MDA-MB-231 xenografts with BafA1 and the ERK1/2 inhibitor sorafenib was superior to either treatment alone and supported tumor regression. BafA1 and sorafenib treatments alone reduced MDA-MB-231 cell metastasis and again the combination was significantly more effective than either treatment alone and was without apparent side effects. These results present a novel mechanism to destroy hypoxic tumor cells that may help reverse the resistance of hypoxic tumors to radiation and chemotherapy and perhaps target tumor stem cells. PMID- 24811488 TI - Epigenetic inactivation of DAPK1, p14ARF, mir-34a and -34b/c in acute promyelocytic leukaemia. AB - AIM: TP53 mutation frequently occurs in solid cancers but not haematological cancers including acute promyelocytic leukaemia (APL) characterised by t(15;17). Both DAPK1 and p14(ARF) positively regulate p53 whereas miR-34a and -34b/c are direct transcriptional targets of p53. We studied if DNA methylation might contribute to inactivation of gene/microRNA (miRNA) in the TP53 tumour suppressor network. METHODS: Promoter methylation of DAPK1, p14(ARF), miR-34a and -34b/c were studied in 10 normal bone marrow samples, NB4 cell line and 60 APL primary samples at diagnosis by methylation-specific PCR (MSP). RESULTS: DAPK1, p14(ARF), miR-34a and -34b/c were completely unmethylated in normal bone marrow samples. DAPK1, miR-34a and -34b/c were completely methylated in NB4. Treatment of NB4 by 5'-Aza-2'-deoxyctidine resulted in promoter demethylation together with re expression of DAPK1 and both miRNAs. In primary APL samples, methylation of miR 34b/c was detected in 43% in contrast to absence of methylation of DAPK1, p14(ARF) or miR-34a. Overexpression of miR-34b in NB4 resulted in inhibition of proliferation. CONCLUSIONS: Methylation of DAPK1, miR-34a and -34b/c is tumour specific, and associated with gene/miRNAs silencing. miR-34b/c is a tumour suppressor miRNA in APL. Methylation of miR-34b/c may contribute to APL leukaemogenesis. PMID- 24811489 TI - Utility of the Singapore nomogram for predicting recurrence-free survival in Japanese women with breast phyllodes tumours. PMID- 24811490 TI - Nontargeted detection of adulteration of skim milk powder with foreign proteins using UHPLC-UV. AB - Chromatographic profiles of skim milk powder (SMP) and mixtures of SMP with soy (SPI), pea (PPI), brown rice (BRP), and hydrolyzed wheat protein (HWPI) isolates were obtained by ultrahigh-performance liquid chromatography (UHPLC) with 215 nm detection. Two data analysis approaches were compared for their utility to classify samples as authentic or adulterated. The t test approach evaluated data points exceeding the 99% confidence limit of the mean authentic SMP chromatogram and used data points from the entire chromatogram. The other approach used the multivariate Q statistic from a SIMCA model of authentic samples to determine adulteration and used a selected retention window to obtain best classifications. Q-Statistic and t test correctly classified adulteration of SMP with SPI at the 1% and 3% levels, respectively, while minimizing false classifications of authentic SMP. Detection of SMP adulterated with PPI, BRP, and HWPI was possible at higher adulteration levels. PMID- 24811492 TI - HIV immunity goes direct. PMID- 24811493 TI - Rarefied drug pricing. PMID- 24811494 TI - Genentech to salvage anti-MET antibody with subgroup analysis. PMID- 24811495 TI - Fecal transplantation poses dilemma for FDA. PMID- 24811491 TI - Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies. AB - Only approximately 10% of genetically unselected patients with chemorefractory metastatic colorectal cancer experience tumor regression when treated with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab ("primary" or "de novo" resistance). Moreover, nearly all patients whose tumors initially respond inevitably become refractory ("secondary" or "acquired" resistance). An ever-increasing number of predictors of both primary and acquired resistance to anti-EGFR antibodies have been described, and it is now evident that most of the underlying mechanisms significantly overlap. By trying to extrapolate a unifying perspective out of many idiosyncratic details, here, we discuss the molecular underpinnings of therapeutic resistance, summarize research efforts aimed to improve patient selection, and present alternative therapeutic strategies that are now under development to increase response and combat relapse. PMID- 24811496 TI - Patenting natural products just got harder. PMID- 24811498 TI - HIV treatment study clears virus, sends Sangamo stock soaring. PMID- 24811502 TI - Indiana jumps the biosimilars gun. PMID- 24811507 TI - Going it alone. PMID- 24811508 TI - Surveying the best in translation. PMID- 24811509 TI - Reducing the burden of disclosure for public biotech companies. PMID- 24811510 TI - iGEM 2.0--refoundations for engineering biology. PMID- 24811511 TI - Sex-ratio-biasing constructs for the control of invasive lower vertebrates. PMID- 24811512 TI - Biotech's wellspring: the health of private biotech in 2013. PMID- 24811513 TI - Patent office backlog adds billions to national drug expenditure. PMID- 24811515 TI - Tumor signatures in the blood. PMID- 24811516 TI - Simply better glycoproteins. PMID- 24811517 TI - SORTing out cellular proteomes in vivo. PMID- 24811519 TI - Optimizing genome-scale network reconstructions. PMID- 24811521 TI - First-quarter biotech job picture. PMID- 24811520 TI - Detecting and characterizing circular RNAs. AB - Circular RNA transcripts were first identified in the early 1990s but knowledge of these species has remained limited, as their study through traditional methods of RNA analysis has been difficult. Now, novel bioinformatic approaches coupled with biochemical enrichment strategies and deep sequencing have allowed comprehensive studies of circular RNA species. Recent studies have revealed thousands of endogenous circular RNAs in mammalian cells, some of which are highly abundant and evolutionarily conserved. Evidence is emerging that some circRNAs might regulate microRNA (miRNA) function, and roles in transcriptional control have also been suggested. Therefore, study of this class of noncoding RNAs has potential implications for therapeutic and research applications. We believe the key future challenge for the field will be to understand the regulation and function of these unusual molecules. PMID- 24811523 TI - Role of management strategies and environmental factors in determining the emissions of biogenic volatile organic compounds from urban greenspaces. AB - Biogenic volatile organic compound (BVOC) emissions from urban greenspace have recently become a global concern. To identify key factors affecting the dynamics of urban BVOC emissions, we built an estimation model and utilized the city of Hangzhou in southeastern China as an example. A series of single-factor scenarios were first developed, and then nine multifactor scenarios using a combination of different single-factor scenarios were built to quantify the effects of environmental changes and urban management strategies on urban BVOC emissions. Results of our model simulations showed that (1) annual total BVOC emissions from the metropolitan area of Hangzhou were 4.7*10(8) g of C in 2010 and were predicted to be 1.2-3.2 Gg of C (1 Gg=10(9) g) in our various scenarios in 2050, (2) urban management played a more important role in determining future urban BVOC emissions than environmental changes, and (3) a high ecosystem service value (e.g., lowest BVOC/leaf mass ratio) could be achieved through positive coping in confronting environmental changes and adopting proactive urban management strategies on a local scale, that is, to moderately increase tree density while restricting excessive greenspace expansion and optimizing the species composition of existing and newly planted trees. PMID- 24811524 TI - Quantum mechanics/molecular mechanics studies of the mechanism of falcipain-2 inhibition by the epoxysuccinate E64. AB - Because of the increasing resistance of malaria parasites to antimalarial drugs, the lack of highly effective vaccines, and an inadequate control of mosquito vectors, the problem is growing, especially in the developing world. New approaches to drug development are consequently required. One of the proteases involved in the degradation of human hemoglobin is named falcipain-2 (FP2), which has emerged as a promising target for the development of novel antimalarial drugs. However, very little is known about the inhibition of FP2. In this paper, the inhibition of FP2 by the epoxysuccinate E64 has been studied by molecular dynamics (MD) simulations using hybrid AM1d/MM and M06-2X/MM potentials to obtain a complete picture of the possible free energy reaction paths. A thorough analysis of the reaction mechanism has been conducted to understand the inhibition of FP2 by E64. According to our results, the irreversible attack of Cys42 on E64 can take place on both carbon atoms of the epoxy ring because both processes present similar barriers. While the attack on the C2 atom presents a slightly smaller barrier (12.3 vs 13.6 kcal mol(-1)), the inhibitor-protein complex derived from the attack on C3 appears to be much more stabilized. In contrast to previous hypotheses, our results suggest that residues such as Gln171, Asp170, Gln36, Trp43, Asn81, and even His174 would be anchoring the inhibitor in a proper orientation for the reaction to take place. These results may be useful for the rational design of new compounds with higher inhibitory activity. PMID- 24811525 TI - A new strategy to prevent chemotherapy and radiotherapy-induced alopecia using topically applied vasoconstrictor. AB - In a new strategy, we sought to determine whether topically applied vasoconstrictor, with its accompanying transient skin hypoxia and exclusion of systemic drug, would prevent or suppress radiotherapy or chemotherapy-induced alopecia. Topical vasoconstrictor was applied to 1-cm(2) skin patches on the backs of 10-day-old rats and minutes later they received either 7.1 gray (Gy) whole-body radiation or systemic N-nitroso-N-methylurea (MNU) or Cytoxan. The degree of alopecia was scored 10 days later by visual assessment (% coat retention) and hair follicle histologic analysis. Topical application of epinephrine or norepinephrine in an alcohol:water delivery vehicle induced clear skin blanch, and in a dose-dependent manner, topical epinephrine or norepinephrine (20-1,000 mM) applied before 7.1 Gy irradiation conferred 95% of coat retention in the treated skin patches versus 0% coat retention in vehicle controls, or in skin outside the treated patches. By histology, small numbers of dystrophic hair follicles were observed in hairless skin versus the normal density of anagen follicles in the immediately adjacent, drug-protected skin patches at day 20; protected coats were retained into adulthood. Topical epinephrine or norepinephrine before systemic MNU (30 ug/gm body weight) conferred up to 95% of coat retention in treated skin patches versus 0% coat retention elsewhere. Epinephrine-conferred % coat retention dropped to 16% in rats that received systemic Cytoxan, a drug whose plasma half-life is at least 8- to 10-fold longer than MNU. A general strategy is discussed for the use of topical epinephrine or norepinephrine in the clinic to provide an inexpensive and convenient strategy to prevent cancer therapy-induced alopecia. PMID- 24811526 TI - CT quantification of large opacities and emphysema in silicosis: correlations among clinical, functional, and radiological parameters. AB - BACKGROUND: The assessment of the extent of silicosis on chest radiographs is subjective and could be more standardized by using computed tomography (CT) quantification methods. We propose a semiautomatic method of quantifying the anatomical lung damage (LD) (the sum of the emphysema and large opacities volumes) measured by CT densitovolumetry in complicated silicosis. METHODS: Twenty-three nonsmokers with complicated silicosis were included. Large opacities were recorded as size A, B, or C according to the size of the opacities on chest radiographs. Pulmonary function tests (PFT) were assessed by spirometry and the carbon monoxide diffusion capacity. Total lung capacity (TLC) was measured by helium dilution, and total lung volume (TLV) was measured by CT quantification (TLVct). CT images were postprocessed using CT densitovolumetry to measure the TLVct, large opacities volume, emphysema volume (EV), and emphysema index (EI). RESULTS: Significant correlations were observed between the EV and the forced vital capacity (r = 0.41, p = 0.04), TLC (r = 0.44, p = 0.03), and residual volume (RV) (r = 0.49, p = 0.01). A correlation also was observed between the LD% and RV (r = 0.43, p = 0.03) and between the LD and RV (r = 0.47, p = 0.02). CONCLUSIONS: The PFT findings were correlated with the EV, EI, LD, and LD%, but they were not correlated with the large opacities volume. These results suggest that the emphysema volume, more than the large opacities volume, is responsible for functional impairment in patients with complicated silicosis. PMID- 24811527 TI - Commentary on: Johnson MM, David JA, Michelhaugh SK, Schmidt CJ, Bannon MJ. Increased heat shock protein 70 gene expression in the brains of cocaine-related fatalities may be reflective of postdrug survival and intervention rather than excited delirium. J Forensic Sci 2012;57(6):1519-23. PMID- 24811528 TI - Authors' response. PMID- 24811529 TI - What is (or will be) happening to the cognitive abilities of forensic experts in the new technological age. PMID- 24811538 TI - [Bibliometric map of research done in primary care in Spain during the period 2008-2012]. AB - OBJECTIVE: To describe the Spanish scientific production of primary care during 2008-2012. DESIGN: Observational study bibliometric. SETTING: Spanish scientific production in primary care. PARTICIPANTS: The study focused on publications indexed in Medline. MAIN MEASUREMENTS: In each record was obtained journal, year of publication, first/last author, workplace and autonomous community. Later, articles were classified according to their content or areas of research. The impact factor was obtained from the basis of bibliometric analysis Journal Citation Reports. RESULTS: Using search criteria, were selected 1,048 documents. The transiency rate was 62.6%. Production increased from 170 papers in 2008 to 291 in 2012. Most (65.7%) came from health centers, but we observed a significant increase (P=.01) of the articles from units or research institutes (5.9% in 2008, 12.0% in 2012). Of the total, 61.6% were classified as "clinical aspects", 22.5% were published in the journal Atencion Primaria, 80.5% in journals with impact factor and 33.49% in foreign journals, being higher this proportion (P<.001) in units or research institutes (70.5% vs. 29.8%). In relation to population (articles/100.000 inhab.), the most productive communities were Cataluna (4.1), Castilla-La Mancha (3.6), Aragon (3.4) and Navarra (3.4). CONCLUSIONS: In primary care publications there is great diversity in both research areas such as in journals where published. Most are from health centers, treat clinical aspects and published in Spanish journals. Differences in the volume of scientific production between regions are observed. PMID- 24811539 TI - ROS-induced epithelial-mesenchymal transition in mammary epithelial cells is mediated by NF-kB-dependent activation of Snail. AB - Epithelial-mesenchymal transition (EMT) is characterized by loss of cell-cell junctions, polarity and epithelial markers, and in turn, acquisition of mesenchymal features and motility. Changes associated with this developmental process have been extensively implicated in breast cancer progression and metastasis. Matrix metalloproteinases (MMPs) have been identified as specific inducers of EMT in mammary epithelial cells. MMP-3 induces EMT associated with malignant transformation via a pathway dependent upon production of reactive oxygen species (ROS). While the process by which exposure to MMP-3 leads to induction of ROS has been extensively studied, exactly how the MMP-3-induced ROS stimulate EMT remains unknown. Here, we used profiling methods to identify MMP-3 induced transcriptional alterations in mouse mammary epithelial cells, finding common overlap with changes mediated by nuclear factor-kappaB (NF-kappaB) and found in advanced breast cancer. In cultured cells, we found that Snail, an ROS dependent key mediator of MMP-3-induced changes, is regulated by NF-kappaB in response to MMP-3. More specifically, we found MMP-3 to cause binding of p65 and cRel NF-kappaB subunits to the Snail promoter, leading to its transcription. Our results identify a specific pathway by which MMPs induce EMT and malignant characteristics, and provide insight into potential therapeutic approaches to target MMP-associated breast cancers. PMID- 24811541 TI - Mitochondrial delivery of doxorubicin via triphenylphosphine modification for overcoming drug resistance in MDA-MB-435/DOX cells. AB - In this study, doxorubicin (DOX) was conjugated to a lipophilic triphenylphosphonium (TPP) that is selectively taken up by the mitochondrial membrane of cells. This new derivative of DOX, i.e., TPP-DOX, was characterized by infrared spectroscopy (IR), nuclear magnetic resonance ((1)H NMR, (13)C NMR), and mass spectrometry. The effect of TPP modification on DOX cell uptake, intracellular trafficking, eventual DOX induced cytotoxicity, and the level of cleaved caspase 3 and PARP in wild type MDA-MB-435/WT and DOX resistant MDA-MB 435/DOX cells was then evaluated and compared to that for free DOX. In general, free DOX cellular uptake appeared to be significantly higher in MDA-MB-435/WT than MDA-MB-435/DOX cells. Moreover, free DOX was able to enter the nucleus of MDA-MB-435/WT cells, but in MDA-MB-435/DOX cells, it was confined within the cytoplasm. The TPP-DOX, on the other hand, was localized in the cytoplasm of both cell phenotypes and showed preferential distribution to the mitochondria. Correspondingly, in MDA-MB-435/DOX cells, an enhanced cytotoxicity was observed for TPP-DOX (IC50 of 33.6 and 21.0 MUM at 48 and 72 h incubation, respectively) in comparison to free DOX (IC50 of 126.7 and 77.96 MUM at 48 and 72 h incubation, respectively). This observation was accompanied by the increased level of cleaved caspase 3 and PARP indicating enhanced apoptosis in both cell lines, particularly that of MDA-MB-435/DOX, for TPP-DOX compared to free DOX following 24 h treatment. The present study highlights promising application of TPP-DOX in reversing drug resistance in tumor cells. PMID- 24811540 TI - Biased, non-equivalent gene-proximal and -distal binding motifs of orphan nuclear receptor TR4 in primary human erythroid cells. AB - We previously reported that TR2 and TR4 orphan nuclear receptors bind to direct repeat (DR) elements in the epsilon- and gamma-globin promoters, and act as molecular anchors for the recruitment of epigenetic corepressors of the multifaceted DRED complex, thereby leading to epsilon- and gamma-globin transcriptional repression during definitive erythropoiesis. Other than the epsilon- and gamma-globin and the GATA1 genes, TR4-regulated target genes in human erythroid cells remain unknown. Here, we identified TR4 binding sites genome-wide using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) as human primary CD34(+) hematopoietic progenitors differentiated progressively to late erythroid precursors. We also performed whole transcriptome analyses by RNA-seq to identify TR4 downstream targets after lentiviral-mediated TR4 shRNA knockdown in erythroid cells. Analyses from combined ChIP-seq and RNA-seq datasets indicate that DR1 motifs are more prevalent in the proximal promoters of TR4 direct target genes, which are involved in basic biological functions (e.g., mRNA processing, ribosomal assembly, RNA splicing and primary metabolic processes). In contrast, other non DR1 repeat motifs (DR4, ER6 and IR1) are more prevalent at gene-distal TR4 binding sites. Of these, approximately 50% are also marked with epigenetic chromatin signatures (such as P300, H3K27ac, H3K4me1 and H3K27me3) associated with enhancer function. Thus, we hypothesize that TR4 regulates gene transcription via gene-proximal DR1 sites as TR4/TR2 heterodimers, while it can associate with novel nuclear receptor partners (such as RXR) to bind to distant non-DR1 consensus sites. In summary, this study reveals that the TR4 regulatory network is far more complex than previously appreciated and that TR4 regulates basic, essential biological processes during the terminal differentiation of human erythroid cells. PMID- 24811542 TI - Prevalence and patterns of depression and anxiety in hemodialysis patients: a 12 month prospective study on incident and prevalent populations. AB - OBJECTIVE: Depression is common in dialysis patients and has been shown to be associated with higher morbidity and mortality, but little is known about the course of symptoms over time. The current study set up to explore group and individual patterns of change in symptoms of anxiety and depression within the hemodialysis population and to identify socio-demographic, clinical, and psychological factors that may be associated with different trajectories of emotional distress. METHODS: A total of 159 hemodialysis patients (n = 42 incident and n = 117 prevalent) completed the Hospital Anxiety and Depression Scale and social support and symptoms subscales from the Kidney Disease Quality of Life (Short Form) on two occasions 12 months apart. Clinical cut-offs were used to identify individual patterns of change in anxiety and depression symptoms across time, and analysis of variance (ANOVA) procedures were employed to establish potential correlates of these trajectories. RESULTS: Mean levels of anxiety and depression symptoms remained unchanged over 1 year with 44.7-54.1% of patients above cut-off at both baseline and follow-up. Individual-level analyses showed that the course of symptoms does not follow a single trajectory. While most patients had either persistent symptoms of distress (39.6% and 31.8% for depression and anxiety, respectively) or no/low symptoms of distress (32.1% and 36.9% for depression and anxiety, respectively), a total of 12.7-18.5% patients either had new-onset symptoms of depression/anxiety or symptoms diminishing over time. Patients with persisting or new-onset symptoms of depression or anxiety reported reduced perceived social support and quality of social interaction compared to the subgroups with low depressive/anxious symptoms. CONCLUSION: Different patterns of symptoms reflect heterogeneity in patients' emotional reactions and adjustment. More research is needed to identify patients at risk for emotional distress and to explore social support in the context of dialysis. Statement of contribution What is already known on this subject? Depression and poor mental health are common in hemodialysis patients and are associated with higher risk of hospitalization and death. Course of depression in incident hemodialysis patients is variable, but evidence on prevalent patients and course of symptoms of anxiety is largely lacking. What does this study add? Anxiety and depression remain undifferentiated over time with most patients reporting persistently high or no symptoms of anxiety or depression. New-onset symptoms of anxiety or depression or recovery are less frequent. The lack of consistent associations between socio-demographic or clinical parameters with patterns of emotional distress makes early identification difficult. Regular screening as part of clinical care is hence essential. Persistently high or new-onset symptoms of anxiety and/or depression are associated with reduced perceived social support. More research is needed to explore the role of social resources in the context of dialysis. PMID- 24811544 TI - CORR Insights(r): High early failure rate after cementless hip replacement in the octogenarian. PMID- 24811543 TI - Task-specific fall prevention training is effective for warfighters with transtibial amputations. AB - BACKGROUND: Key factors limiting patients with lower extremity amputations to achieve maximal functional capabilities are falls and fear of falling. A task specific fall prevention training program has successfully reduced prospectively recorded trip-related falls that occur in the community by the elderly. However, this program has not been tested in amputees. QUESTIONS/PURPOSES: In a cohort of unilateral transtibial amputees, we aimed to assess effectiveness of a falls prevention training program by (1) quantifying improvements in trunk control; (2) measuring responses to a standardized perturbation; and (3) demonstrating retention at 3 and 6 months after training. Second, we collected patient-reported outcomes for balance confidence and falls control. METHODS: Fourteen male military service members (26 +/- 3 years) with unilateral transtibial amputations and who had been walking without an assistive device for a median of 10 months (range, 2-106 months) were recruited to participate in this prospective cohort study. The training program used a microprocessor-controlled treadmill designed to deliver task-specific postural perturbations that simulated a trip. The training consisted of six 30-minute sessions delivered over a 2-week period, during which task difficulty, including perturbation magnitude, increased as the patient's ability progressed. Training effectiveness was assessed using a perturbation test in an immersive virtual environment. The key outcome variables were peak trunk flexion and velocity, because trunk kinematics at the recovery step have been shown to be a determinant of fall likelihood. The patient-reported outcomes were also collected using questionnaires. The effectiveness of the rehabilitation program was also assessed by collecting data before perturbation training and comparing the key outcome parameters with those measured immediately after perturbation training (0 months) as well as both 3 and 6 months posttraining. RESULTS: Mean trunk flexion angle and velocity significantly improved after participating in the training program. The prosthetic limb trunk flexion angle improved from pretraining (42 degrees ; 95% confidence interval [CI], 38 degrees -47 degrees ) to after training (31 degrees ; 95% CI, 25 degrees -37 degrees ; p < 0.001). Likewise, the trunk flexion velocity improved from pretraining (187 degrees /sec; 95% CI, 166 degrees -209 degrees ) to after training (143 degrees /sec; 95% CI, 119 degrees -167 degrees ; p < 0.004). The results display a significant side-to-side difference for peak trunk flexion angle (p = 0.01) with perturbations of the prosthetic limb resulting in higher peak angles. Prosthetic limb trips also exhibited significantly greater peak trunk flexion velocity compared with trips of the prosthetic limb (p = 0.005). These changes were maintained up to 6 months after the training. The peak trunk flexion angle of the subjects when the prosthetic limb was perturbed had a mean of 31 degrees (95% CI, 25 degrees -37 degrees ) at 0 month, 32 degrees (95% CI, 28 degrees -37 degrees ) at 3 months, and 30 degrees (95% CI, 25 degrees -34 degrees ) at 6 months. Likewise, the peak trunk flexion velocity for the prosthetic limb was a mean of 143 degrees /sec (95% CI, 118 degrees -167 degrees ) at 0 months, 143 degrees /sec (95% CI, 126 degrees -159 degrees ) at 3 months, and 132 degrees (95% CI, 115 degrees -149 degrees ) at 6 months. The peak trunk flexion angle when the nonprosthetic limb was perturbed had a mean of 22 degrees (95% CI, 18 degrees -24 degrees ) at 0 months, a mean of 26 degrees (95% CI, 20 degrees -32 degrees ) at 3 months, and a mean of 23 degrees (95% CI, 19 degrees 28 degrees ) at 6 months. The peak trunk flexion velocity for the nonprosthetic limb had a mean of 85 degrees /sec (95% CI, 71 degrees -98 degrees ) at 0 months, a mean of 96 degrees (95% CI, 68 degrees -124 degrees ) at 3 months, and 87 degrees /sec (95% CI, 68 degrees -105 degrees ) at 6 months. There were no significant changes in the peak trunk flexion angle (p = 0.16) or peak trunk flexion velocity (p = 0.35) over time after the training ended. The skill retention was present when either the prosthetic or nonprosthetic limb was perturbed. There were side-to-side differences in the trunk flexion angle (p = 0.038) and trunk flexion velocity (p = 0.004). Perturbations of the prosthetic side resulted in larger trunk flexion and higher trunk flexion velocities. Subjects prospectively reported decreased stumbles, semicontrolled falls, and uncontrolled falls. CONCLUSIONS: These results indicate that task-specific fall prevention training is an effective rehabilitation method to reduce falls in persons with lower extremity transtibial amputations. PMID- 24811545 TI - Can an ancestral condition for milk oligosaccharides be determined? Evidence from the Tasmanian echidna (Tachyglossus aculeatus setosus). AB - The monotreme pattern of egg-incubation followed by extended lactation represents the ancestral mammalian reproductive condition, suggesting that monotreme milk may include saccharides of an ancestral type. Saccharides were characterized from milk of the Tasmanian echidna Tachyglossus aculeatus setosus. Oligosaccharides in pooled milk from late lactation were purified by gel filtration and high performance liquid chromatography using a porous graphitized carbon column and characterized by (1)H NMR spectroscopy; oligosaccharides in smaller samples from early and mid-lactation were separated by ultra-performance liquid chromatography and characterized by negative electrospray ionization mass spectrometry (ESI-MS) and tandem collision mass spectroscopy (MS/MS) product ion patterns. Eight saccharides were identified by (1)H NMR: lactose, 2'-fucosyllactose, difucosyllactose (DFL), B-tetrasaccharide, B-pentasaccharide, lacto-N fucopentaose III (LNFP3), 4-O-acetyl-3'-sialyllactose [Neu4,5Ac(alpha2 3)Gal(beta1-4)Glc] and 4-O-acetyl-3'-sialyl-3-fucosyllactose [Neu4,5Ac(alpha2 3)Gal(beta1-4)[Fuc(alpha1-3)]Glc]. Six of these (all except DFL and LNFP3) were present in early and mid-lactation per ESI-MS, although some at trace levels. Four additional oligosaccharides examined by ESI-MS and MS/MS are proposed to be 3'-sialyllactose [Neu5Ac(alpha2-3)Gal(beta1-4)Glc], di-O-acetyl-3'-sialyllactose [Neu4,5,UAc3(alpha2-3)Gal(beta1-4)Glc where U = 7, 8 or 9], 4-O-acetyl-3' sialyllactose sulfate [Neu4,5Ac(alpha2-3)Gal(beta1-4)GlcS, where position of the sulfate (S) is unknown] and an unidentified 800 Da oligosaccharide containing a 4 O-acetyl-3'-sialyllactose core. 4-O-acetyl-3'-sialyllactose was the predominant saccharide at all lactation stages. 4-O-Acetylation is known to protect sialyllactose from bacterial sialidases and may be critical to prevent microbial degradation on the mammary areolae and/or in the hatchling digestive tract so that sialyllactose can be available for enterocyte uptake. The ability to defend against microbial invasion was probably of great functional importance in the early evolution of milk saccharides. PMID- 24811547 TI - A cost sensitive inpatient bed reservation approach to reduce emergency department boarding times. AB - Emergency departments (ED) in hospitals are experiencing severe crowding and prolonged patient waiting times. A significant contributing factor is boarding delays where admitted patients are held in ED (occupying critical resources) until an inpatient bed is identified and readied in the admit wards. Recent research has suggested that if the hospital admissions of ED patients can be predicted during triage or soon after, then bed requests and preparations can be triggered early on to reduce patient boarding time. We propose a cost sensitive bed reservation policy that recommends optimal bed reservation times for patients. The policy relies on a classifier that estimates the probability that the ED patient will be admitted using the patient information collected and readily available at triage or right after. The policy is cost sensitive in that it accounts for costs associated with patient admission prediction misclassification as well as costs associated with incorrectly selecting the reservation time. Results from testing the proposed bed reservation policy using data from a VA Medical Center are very promising and suggest significant cost saving opportunities and reduced patient boarding times. PMID- 24811546 TI - Sevelamer carbonate: a review in hyperphosphataemia in adults with chronic kidney disease. AB - Sevelamer carbonate (Renvela((r))), a buffered form of sevelamer hydrochloride (Renagel((r))), is an orally administered non-absorbed phosphate-binding anion exchange resin used in the treatment of hyperphosphataemia in chronic kidney disease (CKD). In the EU, sevelamer carbonate is approved in adult CKD patients who require dialysis and in those who do not require dialysis with serum phosphate levels >= 1.78 mmol/L, whereas in the USA sevelamer carbonate is approved in adult CKD patients who require dialysis. Sevelamer carbonate and sevelamer hydrochloride achieved similar reductions in serum phosphate levels in randomized comparative trials in patients with CKD receiving haemodialysis; sevelamer carbonate also reduced serum phosphate levels in noncomparative studies in CKD patients not requiring dialysis. The most common adverse events with sevelamer carbonate are gastrointestinal in nature. Sevelamer has pleiotropic effects, such as improving the serum lipid profile and attenuating endothelial and cardiovascular risk factors in CKD. All formulations of sevelamer have markedly higher acquisition costs than calcium-based phosphate binders. Cost effectiveness analyses focusing specifically on sevelamer carbonate have not been conducted, and those based on clinical trial data with sevelamer hydrochloride have provided both favourable and unfavourable results compared with calcium based phosphate binders, reflecting heterogeneity between modelled analyses in terms of data sources, assumptions, comparators, geographical regions, type of costs included and other factors. Although well-designed studies evaluating the impact of phosphate binders on hard clinical endpoints appear to be warranted, sevelamer carbonate may be particularly useful for the treatment of patients at risk of metabolic acidosis (offering advantages over sevelamer hydrochloride in this regard) and for individuals requiring treatment with a phosphate binding agent that does not contain aluminium or calcium. PMID- 24811548 TI - Myocardial crypts: role of modified two-chamber view. PMID- 24811549 TI - Double ring sign at the macula in a patient with Valsalva retinopathy. PMID- 24811550 TI - Intramural esophageal dissection caused by upper endoscopy. PMID- 24811551 TI - The composition of anabolic steroids from the illicit market is largely unknown: implications for clinical case reports. PMID- 24811552 TI - The epidemic of the 20(th) century: coronary heart disease. AB - Heart disease was an uncommon cause of death in the US at the beginning of the 20th century. By mid-century it had become the commonest cause. After peaking in the mid-1960s, the number of heart disease deaths began a marked decline that has persisted to the present. The increase in heart disease deaths from the early 20th century until the 1960s was due to an increase in the prevalence of coronary atherosclerosis with resultant coronary heart disease, as documented by autopsy studies. This increase was associated with an increase in smoking and dietary changes leading to an increase in serum cholesterol levels. In addition, the ability to diagnose acute myocardial infarction with the aid of the electrocardiogram increased the recognition of coronary heart disease before death. The substantial decrease in coronary heart disease deaths after the mid 1960s is best explained by the decreased incidence, and case fatality rate, of acute myocardial infarction and a decrease in out-of-hospital sudden coronary heart disease deaths. These decreases are very likely explained by a decrease in coronary atherosclerosis due to primary prevention, and a decrease in the progression of nonobstructive coronary atherosclerosis to obstructive coronary heart disease due to efforts of primary and secondary prevention. In addition, more effective treatment of patients hospitalized with acute myocardial infarction has led to a substantial decrease in deaths due to acute myocardial infarction. It is very likely that the 20th century was the only century in which heart disease was the most common cause of death in America. PMID- 24811553 TI - Isolated hypoglossal nerve paralysis. PMID- 24811554 TI - Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide. AB - BACKGROUND: Chlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia. METHODS: To investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects >=18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset. RESULTS: A total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide. CONCLUSIONS: This is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose. PMID- 24811555 TI - Ocular manifestations in porphyria cutanea tarda. AB - A 24-year-old man presented with pain, sticky discharge and loss of vision in the right eye. He has had typical skin manifestations of porphyria cutanea tarda (PCT) since 6 years and ophthalmological symptom for 6 weeks. On ophthalmological examination, visual acuity was light perception in the right eye and 6/12 in the left. There were bilateral, symmetrical temporal scleromalacia along with temporal corneal melting in both eyes and perforation in the right eye. Ultrasonography B-scan (USG B-scan) revealed a retinal detachment in the right eye. Artificial tear instillation was started every hour along with topical antibiotic coverage in both eyes. Additionally, ultraviolet protective sunglasses and hat for photo-protection was advised. The vision in the right eye improved to 5/60 along with subsidence of retinal detachment on repeat USG B-scan after 3 weeks. PMID- 24811556 TI - Xanthogranulomatous cholecystitis mimicking gallbladder cancer. AB - Xanthogranulomatous cholecystitis (XGC) is a benign, uncommon variant of chronic cholecystitis characterised by focal or diffuse destructive inflammatory process of the gallbladder (GB). Macroscopically, it appears like yellowish tumour-like masses in the wall of the GB. This article reports on a 74-year-old woman with XGC mimicking GB cancer. PMID- 24811557 TI - Subclinical miliary Mycobacterium bovis following BCG immunotherapy for transitional cell carcinoma of the bladder. AB - The authors present an unusual case of a 51-year-old man who developed relatively mild non-specific symptoms following intravesical BCG instillation for superficial transitional cell carcinoma of the bladder, with radiological investigations demonstrating typical features of miliary tuberculosis (TB). Transbronchial biopsy showed small foci of poorly formed granuloma suggestive of Mycobacterium infection. The patient's respiratory symptoms only became apparent 7 days after discharge having had 4 weeks of unremarkable inpatient stay where he remained clinically well. Prompt anti-TB treatment resulted in a remarkable improvement in his symptoms and radiological appearance, supporting the diagnosis of disseminated Mycobacterium bovis infection. This case highlights the importance of recognising miliary M bovis as a potential complication in patients receiving BCG immunotherapy, and that the disease course can be subclinical with delayed onset of symptoms. PMID- 24811558 TI - The diagnosis and treatment of a symptomatic mesenteric cyst. PMID- 24811559 TI - Missing the beat: arrhythmia as a presenting feature of eosinophilic granulomatosis with polyangiitis. AB - Palpitations are a common presenting symptom in patients attending the emergency department; however, eosinophilic infiltration of the myocardium is rarely the cause. This case describes a 77-year-old woman who presents with sudden onset palpitations and is later diagnosed with eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome). Cardiac involvement does occur in 50% of cases but heart failure, myocarditis, pericarditis, constrictive pericarditis and myocardial infarction are much more commonly recognised complications. Arrhythmia is less well described. In this report, we propose eosinophilic inflammation as the precipitant for an aberrant conduction pathway. PMID- 24811560 TI - Niemann-Pick disease type C or Gaucher's disease type 3? A clinical conundrum. AB - We describe a patient who presented with a neurovisceral syndrome characterised by ataxia, bulbar dysfunction, supranuclear gaze palsy, splenomegaly and foamy histiocytes in the bone marrow. This presentation was suggestive of a lysosomal storage disorder such as Niemann-Pick disease type C or Gaucher's disease type 3. We review the presentation of these disorders, with a focus on the neurological features. In addition, we briefly discuss the disease-modifying therapeutic options which have recently become available. PMID- 24811561 TI - Acute kidney injury in a diabetic haemophiliac: one step at a time. AB - We present a young man with type 1 diabetes mellitus and haemophilia A; who presented with oliguric acute kidney injury (AKI). He is also known to have chronic hepatitis C virus infection. On presentation, he had an active urinary sediment warranting a renal biopsy for definitive diagnosis and management. Although he was at high risk for bleeding we elected for renal biopsy with appropriate factor VIII supplementation and monitoring. Ultrasound-guided percutaneous renal biopsy was successful with no immediate or long-term complications. Biopsy revealed advanced diabetic glomerulosclerosis with mild chronic interstitial inflammation. PMID- 24811562 TI - 'Doctor, treat your patient, not your monitor!' Tremor-induced ECG artefacts mimicking torsades de pointes. PMID- 24811563 TI - An unexpected cause of small bowel obstruction in an adult patient: midgut volvulus. AB - The most important complication of intestinal malrotation is midgut volvulus because it may lead to intestinal ischaemia and necrosis. A 29-year-old male patient was admitted to the emergency department with abdominal pain. Ultrasonography (US), colour Doppler ultrasonography (CDUS), CT and barium studies were carried out. On US and CDUS, twisting of intestinal segments around the superior mesenteric artery (SMA) and superior mesenteric vein (SMV) and alteration of the SMA-SMV relationship were detected. CT demonstrated that the small intestine was making a rotation around the SMA and SMV, which amounted to more than 360 degrees . The upper gastrointestinal barium series revealed a corkscrew appearance of the duodenum and proximal jejunum, which is a pathognomonic finding of midgut volvulus. Prior knowledge of characteristic imaging findings of midgut volvulus is essential in order to reach proper diagnosis and establish proper treatment before the development of intestinal ischaemia and necrosis. PMID- 24811564 TI - Evaluation of blood donors questionnaire in a developing country: The case of Gabon. AB - BACKGROUND: Blood transfusion is a life-saving therapeutic act without alternative. Each blood transfusion carries the risk of blood-borne pathogens transmission. The present study, is the first establishing the usefulness of blood donors screening questionnaire in the setting of the Gabonese National Blood Transfusion Center. STUDY DESIGN: Nine hundred and thirty-four blood donors aged between 18 and 48 years old were initially enrolled and submitted to physical examination (body-mass index and blood pressure). After physical examination 854 donors were judged fit for blood donation and were randomly distributed in two groups. The first group of donors did not take the screening questionnaire; whereas the second group went through the screening questionnaire. Both groups were then tested for human immunodeficiency virus, hepatitis B, hepatitis C and syphilis. RESULTS: Data revealed a seroprevalence among the donors of 2.5%, 2.5%, 1.1%, and 3.3% for the human immunodeficiency virus, hepatitis B, hepatitis C and syphilis markers respectively. In the Gabonese setting, blood donors' screening questionnaire reduced respectively by 0.6%, 0.35% and 1.3% the proportion of hepatitis B, hepatitis C and treponema pallidum seroreactive donors being selected for donation. The questionnaire had no positive effect on discriminating human immunodeficiency virus positive donors. CONCLUSION: Blood donors' seroprevalence of blood-borne pathogens is relatively important in our setting. Blood donors' screening questionnaire reduced the proportion of hepatitis B, hepatitis C and syphilis seropositive blood donors. The questionnaire did not effectively discriminate human immunodeficiency virus infected donor candidates. PMID- 24811565 TI - [Transfusion and sickle cell disease: axes of transfusion safety optimization]. AB - Transfusion remains a major treatment in sickle cell disease. In France, sickle cell disease patients are mainly from Sub-Saharan Africa and West Indies. The immuno-hematological characteristics of these patients of African ancestry induce a short supply of compatible packed red blood cells and an increased rate of haemolytic transfusion reactions, compared to the general transfused population. The optimization of transfusion safety relies on all steps of the transfusion chain. This article aims to describe the current situation in France and to determine the axes of optimization at all steps of the transfusion organization: promotion of donation, preparation of products, taking into account the sickle trait, qualification of packed red blood cells, supply of the blood banks concerned by transfusion of these patients, transfusion protocols and pre transfusion analysis. Research and formation play an important part. PMID- 24811566 TI - Soybean resistance to stink bugs (Nezara viridula and Piezodorus guildinii) increases with exposure to solar UV-B radiation and correlates with isoflavonoid content in pods under field conditions. AB - Solar UV-B radiation (280-315 nm) has a significant influence on trophic relationships in natural and managed ecosystems, affecting plant-insect interactions. We explored the effects of ambient UV-B radiation on the levels of herbivory by stink bugs (Nezara viridula and Piezodorus guildinii) in field-grown soybean crops. The experiments included two levels of UV-B radiation (ambient and attenuated UV-B) and four soybean cultivars known to differ in their content of soluble leaf phenolics. Ambient UV-B radiation increased the accumulation of the isoflavonoids daidzin and genistin in the pods of all cultivars. Soybean crops grown under attenuated UV-B had higher numbers of unfilled pods and damaged seeds than crops grown under ambient UV-B radiation. Binary choice experiments with soybean branches demonstrated that stink bugs preferred branches of the attenuated UV-B treatment. We found a positive correlation between percentage of undamaged seeds and the contents of daidzin and genistin in pods. Our results suggest that constitutive and UV-B-induced isoflavonoids increase plant resistance to stink bugs under field conditions. PMID- 24811567 TI - The value of respective urodynamic parameters for evaluating the occurrence of complications linked to benign prostatic enlargement. AB - PURPOSE: To assess the correlation between urodynamic parameters and urinary tract complications linked to benign prostatic enlargement (BPE), as well to assess the possible value of these parameters for predicting complications. METHODS: We retrospectively analyzed the relationship between the complications and correlative urodynamic data of 486 BPH patients. Multivariate stepwise logistic regression was used to identify major independent predictors and establish regression models. Receiver operating characteristic (ROC) curves were constructed to evaluate the models' predictive values. RESULTS: All of the individual parameters examined significantly correlated with most of the complications linked to BPE, except bladder calculus. According to ROC analysis, all of the areas under ROC curves (AUC), comparison of the individual parameters and the combined effects from the logistical regression models reached statistical significance (p < 0.05), and combining the parameters revealed a higher AUC compared to the individual parameters; however, all of the AUCs were below 0.9. CONCLUSIONS: Urodynamic parameters are significantly correlated with most of the complications linked to BPE, and these parameters have predictive value for the occurrence of these complications with limited values. PMID- 24811569 TI - Hollow manganese phosphonate microspheres with hierarchical porosity for efficient adsorption and separation. AB - Hollow manganese phosphonate microspheres of an inorganic-organic hybrid with hierarchically porous shells were prepared through a template-free hydrothermal method using ethylene diamine tetra(methylene phosphonic acid) as the coupling molecule. The hollow structures with hierarchical porosity were confirmed by SEM, TEM and N2 sorption. FT-IR, XPS and TG-DSC measurements revealed that the organophosphonate linkers were homogeneously incorporated into the hybrid framework. The hierarchical manganese phosphonates could be used as efficient adsorbents for the removal of copper ions, showing fast binding kinetics due to the well-structured porosity. The adsorption process follows pseudo-second order reaction kinetics, as well as Langmuir isotherm, indicating that Cu(2+) was monolayer adsorbed on the hybrid by chemical complexation. Furthermore, the synthesized manganese phosphonates with peculiar porosity exhibited excellent size selectivity for protein adsorption in a complex solution, presenting the promising potential as candidates for biomaterials. PMID- 24811568 TI - Cinacalcet may improve oxidative DNA damage in maintenance hemodialysis patients: an observational study. AB - BACKGROUND: Oxidative stress is accepted as a non-classical cardiovascular risk factor in patients on maintenance hemodialysis (HD). The aim of this study was to evaluate the impact of cinacalcet on oxidative stress biomarkers, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine/deoxyguanosine), endothelial function (FMD %) and carotid artery intima-media thickness (CIMT) in HD patients. METHODS: Forty two chronic HD patients with secondary hyperparathyroidism undergoing 60 mg/day cinacalcet treatment with a follow-up of 6 months and 38 age- and sex-matched healthy individuals were included in this prospective study. Plasma malondialdehyde (MDA) levels and 8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG) were determined as oxidative stress markers. Superoxide dismutase (SOD), paraoxonase (PON), catalase (CAT), carbonic anhydrase (CAN) and glutathione peroxidase (GPx) activities were measured as antioxidants. FMD % and CIMT were assessed by ultrasonography. RESULTS: MDA levels were decreased; SOD, PON, CAT, CAN and GPx activities were increased after 6 months of cinacalcet treatment in HD patients. Although CIMT remained stabile, there was a significant improvement in FMD % as well as a notable reduction trend in 8-OHdG/dG ratio after 6 months of treatment. CONCLUSION: Our data have demonstrated that cinacalcet improves oxidative stress, genomic damage, endothelial function and increases antioxidant protection in HD patients after 6 months of treatment. PMID- 24811570 TI - Tailor-made nanocontainers for combined magnetic-field-induced release and MRI. AB - The synthesis of a novel nanocapsule-based carrier system is described, possessing a triggered release in remote-controlled fashion upon application of an external magnetic field in combination with the possibility to use the capsules as contrast agents for magnetic resonance imaging (MRI). Therefore, polymeric nanocontainers containing a high amount of superparamagnetic MnFe2 O4 nanoparticles and a thermo-degradable shell are fabricated via a miniemulsion route. The process allows the facile encapsulation of hydrophilic compounds, as demonstrated for a model dye. Release of the encapsulated dye is achieved upon application of an external alternating magnetic field. While the magnetic nanoparticles here act as heat generators to stimulate the decomposition of the shell and subsequently a release of the payload, they additionally enable the use of the nanocapsules as imaging agents for MRI. Due to the encapsulated magnetic nanoparticles, the nanocapsules possess high r2 relaxivity values of 96-120 Hz mmol(-1) , which makes them suitable for MRI. In toxicity experiments, the nanocapsules show no cell toxicity up to fairly high concentrations (600 ug mL( 1) ). Due to their dual-functionality, the nanocapsules possess high potential as nanocarriers with combined magnetic-field-induced release capability and as contrast agents for MRI. PMID- 24811572 TI - Policy statement of the world hypertension league on noninvasive blood pressure measurement devices and blood pressure measurement in the clinical or community setting. PMID- 24811573 TI - Dynamical heterogeneity of the glassy state. AB - We compare dynamical heterogeneities in equilibrated supercooled liquids and in the nonequilibrium glassy state within the framework of the random first order transition theory. Fluctuating mobility generation and transport in the glass are treated by numerically solving stochastic continuum equations for mobility and fictive temperature fields that arise from an extended mode coupling theory containing activated events. Fluctuating spatiotemporal structures in aging and rejuvenating glasses lead to dynamical heterogeneity in glasses with characteristics distinct from those found in the equilibrium supercooled liquid. The non-Gaussian distribution of activation free energies, the stretching exponent beta, and the growth of characteristic lengths are studied along with the four-point dynamical correlation function. Asymmetric thermodynamic responses upon heating and cooling are predicted to be the result of the heterogeneity and the out-of-equilibrium behavior of glasses below Tg. Our numerical results agree with experimental calorimetry. We numerically confirm the prediction of Lubchenko and Wolynes in the glass that the dynamical heterogeneity can lead to noticeably bimodal distributions of local fictive temperatures during some histories of preparation which explains in a unified way recent experimental observations that have been interpreted as coming from there being two distinct equilibration mechanisms in glasses. PMID- 24811571 TI - The mediating role of self-compassion in the relationship between victimization and psychological maladjustment in a sample of adolescents. AB - The objectives of the present study were to analyze the relationship between victimization and psychological maladjustment in adolescents and the role of self compassion as a mediator in this relationship. The sample was composed of 109 adolescents aged from 15 to 18 years old with poor school performance. The participants filled out a battery of questionnaires made up of: a socio demographic data questionnaire; the Juvenile Victimization Questionnaire (JVQ); the Youth Self-Report (YSR); and the Self-Compassion Scale (SCS). Results indicated that victimization was positively associated with psychological maladjustment. Moreover, adolescents reporting poly-victimization showed significantly higher level of psychological maladjustment and different types of victimization show different effects on adolescents' psychological maladjustment. Self-compassion partially mediated the relationship between victimization and psychological maladjustment and reduced negative consequences in adolescents who reported having been victimized. Adolescence is a time of development and search for identity in which strengthening personal protective factors could help overcome any traumas experienced. Therefore, developing self-compassion in adolescence could be a good way to help young people recover from bad experiences and protect themselves against future negative experiences. As self-compassion can be improved with practice it could be included in adolescent intervention and prevention programs. PMID- 24811574 TI - The therapeutic significance of aromatase inhibitors in endometrial carcinoma. AB - OBJECTIVE: To review recent studies about the application of aromatase inhibitors in endometrial carcinoma and the benefits and challenges of aromatase inhibitors in this regard. METHODS: Relevant studies and manuscripts were searched for in Pubmed using the following terms, either alone or in combination: aromatase, aromatase inhibitors, letrozole, anastrozole, endometrial cancer, breast cancer, endocrine, therapy, and side effects. RESULTS: Endometrial carcinoma is one of the most pervasive gynecological malignancies. Type I endometrial carcinoma is estrogen-dependent. Recent studies have demonstrated that aromatase inhibitors, which interfere with estrogen biosynthesis by inhibiting the activity of aromatase, can be used to treat endometrial carcinoma and its precancerous lesions to some extent. In early-stage endometrial carcinoma or atypical hyperplasia, a precancerous lesion of endometrial carcinoma, the effects of aromatase inhibitors were promising. However, in advanced or recurrent endometrial carcinoma, the application of aromatase inhibitors cannot solve the problem evidently. In addition, these inhibitors have limitations, like side effects and drug resistance. The need for a new generation of inhibitors with higher specificity and fewer side effects should be studied further. CONCLUSIONS: Aromatase inhibitors show promise in the therapy of endometrial carcinoma, especially the early stage. Further studies should be conducted to develop next generation aromatase inhibitors with higher specificity and fewer side effects. PMID- 24811575 TI - A memory-based foraging tactic reveals an adaptive mechanism for restricted space use. AB - The restricted area of space used by most mobile animals is thought to result from fitness-rewarding decisions derived from gaining information about the environment. Yet, assessments of how animals deal with uncertainty using memory have been largely theoretical, and an empirically derived mechanism explaining restricted space use in animals is still lacking. Using a patch-to-patch movement analysis, we investigated predictions of how free-ranging bison (Bison bison) living in a meadow-forest matrix use memory to reduce uncertainty in energy intake rate. Results indicate that bison remembered pertinent information about location and quality of meadows, and they used this information to selectively move to meadows of higher profitability. Moreover, bison chose profitable meadows they had previously visited, and this choice was stronger after visiting a relatively poor quality meadow. Our work demonstrates a link between memory, energy gains and restricted space use while establishing a fitness-based integration of movement, cognitive and spatial ecology. PMID- 24811576 TI - School - a multitude of opportunities for promoting healthier eating. PMID- 24811578 TI - Combination therapy with selective serotonin reuptake inhibitors and phosphodiesterase-5 inhibitors in the treatment of premature ejaculation. AB - We aimed to evaluate the effectiveness of paroxetine and tadalafil combination in the treatment of premature ejaculation (PE). A total of 150 primary (lifelong)PE patients were randomly distributed into three groups of 50 patients each. Group 1 received 20 mg paroxetine every day for 1 month, Group 2 received 20 mg tadalafil on demand 2 h before intercourse, and Group 3 received paroxetine and tadalafil on demand 2 h before intercourse. Intravaginal ejaculatory latency times (IELT) scores were evaluated at baseline, at the end of the first month of therapy and 1 month after discontinuation of the treatment, while International Index of Erectile Function (IIEF) questionnaire scores were evaluated both prior to and after the treatment. At the end of the first month of therapy, IELT scores were compared with the basal values and statistically significant changes were detected (60.6 +/- 30.2-117.3 +/- 67.3, 68.5 +/- 21.4-110.2 +/- 37.3, 71.56 +/- 40.23-175.2 +/- 60.2)(P < 0.01). IELT scores after discontinuation of treatment were found to be close to the baseline IELT scores (P > 0.05). IIEF scores were evaluated both prior to and after the treatment, and no statistically significant difference was detected (P > 0.05). It is concluded that utilisation of selective serotonin reuptake inhibitors (SSRI) and phosphodiesterase-5 inhibitors (PDE5i) combination before intercourse seems to provide significantly longer ejaculatory latency times as compared with SSRI alone for a long time in patients with PE. PMID- 24811577 TI - Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin lymphoma. AB - PURPOSE: The presence of a bulky tumour at staging in Hodgkin lymphoma (HL) is a predictor of a poor outcome. The total metabolic tumour volume at baseline (TMTV0) computed on PET may improve the evaluation of tumour burden. To explore the clinical usefulness of TMTV0, we compared the prognostic value of TMTV0, tumour bulk and interim PET response in a retrospective single-centre study. METHODS: From 2007 to 2010, 59 consecutive patients with a first diagnosis of HL were treated in our institution. PET was done at baseline (PET0) and after two cycles of chemotherapy (PET2), and treatment was not modified according to the PET2 result. TMTV0 was measured with a semiautomatic method using a 41 % SUVmax threshold. SUVmax reduction between PET0 and PET2 (DeltaSUVmaxPET0-2) was also computed. Based on ROC analysis, patients with a DeltaSUVmaxPET0-2 >71 % were considered good responders and a TMTV0 >225 ml was considered to represent hypermetabolic bulky disease. RESULTS: Median TMTV0 was 117 ml and 17 patients (29 %) had a TMTV0 >225 ml. TMTV0 (>225 ml vs. <=225 ml) and tumour bulk (<10 cm vs. >=10 cm) were predictive of 4-year PFS: 42 % vs. 85 % (p = 0.001) and 44 % vs. 79 % (p < 0.03), respectively. In multivariate analysis, using DeltaSUVmaxPET0-2, TMTV0 and bulky tumour as covariates, only DeltaSUVmaxPET0-2 (p = 0.0005, RR 6.3) and TMTV0 (p < 0.006, RR 4.4) remained independent predictors of PFS. Three prognosis groups were thus identified: DeltaSUVmaxPET0-2 >71 % and TMTV0 <=225 ml (n = 37, 63 %), DeltaSUVmaxPET0-2 = <71 % or TMTV0 >225 ml (n = 17, 29 %), and DeltaSUVmaxPET0-2 = <71 % and TMTV0 >225 ml (n = 5, 8 %). In these three groups the 4-year PFS rates were 92 %, 49 %, and 20 % (p < 0.0001), respectively. CONCLUSION: TMTV0 is more relevant than tumour bulk for predicting the outcome in patients with HL, and adds a significant prognostic insight to interim PET response assessment. The combination of TMTV0 and DeltaSUVmaxPET0-2 made it possible to identify three subsets of HL patients with different outcomes. This may guide clinicians in their choice of therapeutic strategy. PMID- 24811579 TI - Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7. AB - Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as hepatocyte growth factor (HGF), which restrains hepatic injury and facilitates reversibility of fibrotic reaction in response to an acute insult. Chronic liver injury and sustained inflammation cause progressive fibrosis and, ultimately, organ dysfunction. The mechanisms tipping the balance from restoration to progressive liver tissue scarring are not well understood. In the present study, we identify a mechanism in which the tumor-suppressor gene, cylindromatosis (CYLD), confers protection from hepatocellular injury and fibrosis. Mice lacking CYLD (CYLD-/-) were highly susceptible to hepatocellular damage, inflammation, and fibrosis and revealed significantly lower hepatic HGF levels, compared to wild-type (WT) animals. Exogenous application of HGF rescued the liver injury phenotype of CYLD-/- mice. In the absence of CYLD, gene transcription of HGF in hepatic stellate cells was repressed through binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In WT cells, CYLD removed HDAC7 from the HGF promoter and induced HGF expression. Of note, this interaction occurred independently of the deubiquitinating activity of CYLD. CONCLUSIONS: Our findings highlight a novel link between CYLD and HDAC7, offering mechanistic insight into the contribution of these proteins to progression of liver disease. Thus, through regulation of HGF level, CYLD ameliorates hepatocellular damage and liver fibrogenesis. PMID- 24811580 TI - Effects of animation on naming and identification across two graphic symbol sets representing verbs and prepositions. AB - PURPOSE: The effects of animation on naming and identification of graphic symbols for verbs and prepositions were studied in 2 graphic symbol sets in preschoolers. METHOD: Using a 2 * 2 * 2 * 3 completely randomized block design, preschoolers across three age groups were randomly assigned to combinations of symbol set (Autism Language Program [ALP] Animated Graphics or Picture Communication Symbols [PCS]), symbol format (animated or static), and word class (verbs or prepositions). Children were asked to name symbols and to identify a target symbol from an array given the spoken label. RESULTS: Animated symbols were more readily named than static symbols, although this was more pronounced for verbs than for prepositions. ALP symbols were named more accurately than PCS in particular with prepositions. Animation did not facilitate identification. ALP symbols for prepositions were identified better than PCS, but there was no difference for verbs. Finally, older children guessed and identified symbols more effectively than younger children. CONCLUSIONS: Animation improves the naming of graphic symbols for verbs. For prepositions, ALP symbols are named more accurately and are more readily identifiable than PCS. Naming and identifying symbols are learned skills that develop over time. Limitations and future research directions are discussed. PMID- 24811581 TI - Unravelling the mysteries surrounding development of the outflow tracts. PMID- 24811582 TI - Development of a dual nanocarrier system as a potential stratagem against amyloid induced toxicity. AB - OBJECTIVE: Therapeutic formulation to reduce amyloid beta (Abeta) insult in neuronal cells remains an important focus in the treatment of Alzheimer's disease. To combat the multifactorial threats that arise during amyloid plaque formation, multi-dimensional approach is required. METHODS: Peptide sequence KLVFF derived from the core recognition motif of Abeta1 - 42 can bind to the plaques and help to reduce further accumulation. In our previous work, we have reported various self-assembling structures of KLVFF along with its surface tension lowering ability to overcome the cytotoxicity caused by Abeta1 - 42. In the present work, we have developed a novel combination of peptide-curcumin loaded liposomal formulation and characterized for its morphology, protein adsorption and colloidal stability. The therapeutic efficacy of the formulation was tested using a cholinergic neuronal cell line pre-treated with Abeta1 - 42. RESULTS: The physiochemical characterization and in vitro efficacy of peptide curcumin-loaded liposomal formulation were found to outperform well in bringing down the amyloid toxicity. CONCLUSION: This cumulative evidence indicates that the nanocarrier-based alternative treatment stratagem is an effective way to treat Alzheimer's disease. PMID- 24811583 TI - Albumin-micelles via a one-pot technology platform for the delivery of drugs. AB - A new micelle delivery platform based on albumin coated nanoparticles is able to selectively deliver the payload to cancerous cells while healthy cells remain less affected. The technology is simple and can be used in a one-pot procedure. PMID- 24811584 TI - Design and synthesis of organic-inorganic hybrid capsules for biotechnological applications. AB - Organic-inorganic hybrid capsules, which typically possess a hollow lumen and a hybrid wall, have emerged as a novel and promising class of hybrid materials and have attracted enormous attention. In comparison to polymeric capsules or inorganic capsules, the hybrid capsules combine the intrinsic physical/chemical properties of the organic and inorganic moieties, acquire more degrees of freedom to manipulate multiple interactions, create hierarchical structures and integrate multiple functionalities. Thus, the hybrid capsules exhibit superior mechanical strength (vs. polymeric capsules) and diverse functionalities (vs. inorganic capsules), which may give new opportunities to produce high-performance materials. Much effort has been devoted to exploring innovative and effective methods for the synthesis of hybrid capsules that exhibit desirable performance in target applications. This tutorial review firstly presents a brief description of the capsular structure and hybrid materials in nature, then classifies the hybrid capsules into molecule-hybrid capsules and nano-hybrid capsules based upon the size of the organic and inorganic moieties in the capsule wall, followed by a detailed discussion of the design and synthesis of the hybrid capsules. For each kind of hybrid capsule, the state-of-the-art synthesis methods are described in detail and a critical comment is embedded. The applications of these hybrid capsules in biotechnological areas (biocatalysis, drug delivery, etc.) have also been summarized. Hopefully, this review will offer a perspective and guidelines for the future research and development of hybrid capsules. PMID- 24811585 TI - Syncope risk stratification in the ED. AB - Syncope may be the final common presentation of a number of clinical conditions spanning benign (i.e. neurally-mediated syncope) to life-threatening diseases (i.e. cardiac syncope). Hospitalization rate after a syncopal episode is high. An effective risk stratification is crucial to identify patients at risk of poor prognosis in the short term period to avoid unnecessary hospital admissions. The decision to admit or discharge a syncope patient from the ED is often based on the physician's clinical judgment. In recent years, several prognostic tools (i.e. clinical prediction rules and risk scores) have been developed to provide emergency physicians with accurate guidelines for hospital admission. At present, there are no compelling evidence that prognostic tools perform better than physician's clinical judgment in assessing the short-term outcome of syncope. However, the risk factors characterizing clinical prediction rules and risk scores may be profitably used by emergency doctors in their decision making, specifically whenever a syncope patient has to be discharged from ED or admitted to hospital. Patients with syncope of undetermined etiology, who are characterized by an intermediate-high risk profile after the initial evaluation, should be monitored in the ED. Indeed, data suggest that the 48h following syncope are at the highest risk for major adverse events. A new tool for syncope management is represented by the Syncope Unit in the ED or in an outpatient setting. Syncope Unit may reduce hospitalization and length of hospital stay. However, further studies are needed to clarify whether syncope patients' prognosis can be also improved. PMID- 24811586 TI - Hunt should issue guidance on "do not resuscitate" directions, court hears. PMID- 24811587 TI - Is the pH of vancomycin an indication for central venous access? AB - All vascular access devices (VADs) have associated risks and benefits. Therefore, the decision to place a particular VAD rests on the assumption that the benefits of that device will outweigh the risks and allow for effective delivery of the treatment plan. The study by Caparas and colleagues, in the present issue of JVA, challenges the pH restrictions presented in the Standards. Caparas and her team have reconfirmed the previously reported findings that peripheral venous administration of vancomycin carries a low risk of phlebitis and extravasation and an even lower risk of catheter-related bloodstream infection. Central venous administration of vancomycin, on the other hand, carries the greater risk of central line associated bloodstream infection and deep vein thrombosis (DVT). In light of these findings and a lack of evidence to the contrary, the decision to place a central venous access device based solely on the pH of the intended therapy, vancomycin in particular, is not supported by the evidence and findings of this study. From a risk-benefit perspective, based on Caparas's study evidence, midline catheters are a safe option for patients for the administration of vancomycin, under specific concentrations, and for many other indicated medications and solutions. PMID- 24811588 TI - Validation of computational fluid dynamics-based analysis to evaluate hemodynamic significance of access stenosis. AB - PURPOSE: Stenosis in a vascular access circuit is the predominant cause of access dysfunction. Hemodynamic significance of a stenosis identified by angiography in an access circuit is uncertain. This study utilizes computational fluid dynamics (CFD) to model flow through arteriovenous fistula to predict the functional significance of stenosis in vascular access circuits. METHODS: Three-dimensional models of fistulas were created with a range of clinically relevant stenoses using SolidWorks. Stenoses diameters ranged from 1.0 to 3.0 mm and lengths from 5 to 60 mm within a fistula diameter of 7 mm. CFD analyses were performed using a blood model over a range of blood pressures. Eight patient-specific stenoses were also modeled and analyzed with CFD and the resulting blood flow calculations were validated by comparison with brachial artery flow measured by duplex ultrasound. RESULTS: Predicted flow rates were derived from CFD analysis of a range of stenoses. These stenoses were modeled by CFD and correlated with the ultrasound measured flow rate through the fistula of eight patients. The calculated flow rate using CFD correlated within 20% of ultrasound measured flow for five of eight patients. The mean difference was 17.2% (ranged from 1.3% to 30.1%). CONCLUSIONS: CFD analysis-generated flow rate tables provide valuable information to assess the functional significance of stenosis detected during imaging studies. The CFD study can help in determining the clinical relevance of a stenosis in access dysfunction and guide the need for intervention. PMID- 24811589 TI - Patterns of blood flow as a predictor of maturation of arteriovenous fistula for haemodialysis. AB - PURPOSE: A palpable "thrill" is traditionally associated with success following arteriovenous fistula (AVF) surgery. A thrill typically characterizes turbulent flow and this is a paradox as turbulence is a driver of neointimal hyperplasia. Spiral laminar flow (SLF) has been described as normal and protective pattern of flow in native arteries and is associated with superior patency in bypass grafts that generate it. The aim of this study was to define the pattern of flow within AVFs immediately post-operatively and at follow-up to assess maturation. METHODS: Doppler ultrasound was used immediately post-operatively and at follow-up (6 weeks). Blood flow was assessed as SLF or non-SLF. Two blinded qualified observers analysed the images. Patients were followed up for 6 months. Maturation was statistically analysed against the type of flow. RESULTS: Sequential patients having AVF surgery (n=56) were assessed: 46 (82%) patients had a thrill, 3 patients had no flow and 7 patients had pulsatile flow without a palpable thrill. SLF was present in 80% of those with a thrill but not in any without a thrill (p<0.0001). At follow-up (n=51) 41, patients had a matured AVF (80%), of which 76% had SLF immediately post-operatively. Only one patient with SLF failed to mature. In the non-SLF group 5 of the 15 AVFs failed to mature (66%; p<0.005). CONCLUSIONS: SLF was strongly supportive of successful fistula maturation. A "thrill" was characteristic of spiral rather than turbulence. The mechanism of this apparent beneficial effect of this pattern of flow requires further investigation. PMID- 24811590 TI - Hemodialysis tunneled central venous catheters: five-year outcome analysis. AB - BACKGROUND: Tunneled central venous catheters (tCVCs) are considered inferior to arteriovenous fistulas (AVFs) and grafts in all nephrology guidelines. However, they are being increasingly used as hemodialysis vascular access. The purpose of this study was to document the natural history of tCVCs and determine the rate and type of catheter replacement. METHODS: This was a prospective study of 141 patients who underwent hemodialysis with tCVCs between January 2008 and December 2012. The patients used 154 tCVCs. Standard protocols about management of tCVCs, according to European Renal Best Practice, were well established. All catheters were inserted in the internal jugular vein. Criteria for catheter removal were persistent bloodstream infection, detection of an outbreak of catheter-related bloodstream (CRBS) infections, or catheter dysfunction. Event rates were calculated per 1,000 catheter days; tCVC cumulative survival was estimated by Kaplan-Meier analysis. RESULTS: Catheter replacement occurred in 15 patients (0.29 per 1,000 days); catheter dysfunction was the main cause of replacement (0.18 per 1,000 days), typically within 12 months of surgical insertion. A total of 53 CRBS events in 36 patients were identified (0.82 per 1,000 days); 17 organisms, most commonly Gram-positive pathogens, were isolated; 87% of CVC infections were treated by systemic antibiotics associated with lock therapy. tCVC cumulative survival was 91% at 1 year, 88% at 2 years and 85% at 4 years. CONCLUSIONS: Our data show a high survival rate of tCVCs in hemodialysis patients, with low incidence of catheter dysfunction and CRBS events. These data justify tCVC use for hemodialysis vascular access, also as first choice, especially in patients with exhausted peripheral access and limited life expectancy. PMID- 24811591 TI - Peripherally inserted central catheter (PICC)-related thrombosis in critically ill patients. AB - BACKGROUND: Peripherally inserted central catheters (PICC) are being increasingly used in critical care setting. However, PICCs are associated with a number of complications, particularly upper extremity venous thrombosis (UEVT), leading to post-thrombotic syndrome, pulmonary embolism and increased risk of catheter related infection. OBJECTIVE: To review the literature surrounding PICCs and highlight the epidemiology, pathophysiology, diagnosis and management of PICC related thrombosis in critically ill patients. DATA SOURCES AND EXTRACTION: We performed an electronic literature search of the databases PubMed, EMBASE and Google scholar using set search terms, from their commencement date to the end of January 2014. SUMMARY OF REVIEW: It has been shown that PICCs may double the risk of deep venous thrombosis compared with centrally inserted venous catheters, in critically ill patients. However, the incidence of PICC-related thrombosis in critically ill patients has not been quantified. Ultrasonography is the preferred diagnostic imaging modality. There are no randomized controlled trials (RCTs) on the best treatment of PICC-related thrombosis in the intensive care unit (ICU) setting and in most cohort studies, anticoagulation strategies with or without PICC removal have been used. CONCLUSIONS: Decision to insert a PICC should be taken after careful risk stratification. There is lack of high-quality evidence assessing prevention strategies and management of PICC-related thrombosis in the ICU. Well-designed RCTs are required to estimate the prevalence of UEVT in ICU patients with PICCs and evaluate the efficacy and magnitude of clinical benefit and cost-effectiveness of therapeutic strategies. PMID- 24811592 TI - Thromboaspiration of arteriovenous hemodialysis graft thrombosis using Desilets Hoffman sheath: single-center experience. AB - PURPOSE: The purpose of this study was to evaluate the feasibility, efficacy and safety of percutaneous thromboaspiration with a 7F Desilets-Hoffman sheath compared with previously established percutaneous mechanical thrombectomy techniques in occluded hemodialysis grafts. MATERIALS AND METHODS: One thousand three hundred five patients (767 women, 538 men; mean age, 61.04+/-13.09 years; mean graft age, 36.64+/-30.80 mo) with 2,531 episodes of hemodialysis graft thrombosis underwent percutaneous thromboaspiration with a 7F Desilets-Hoffman sheath using criss-cross or apex puncture technique. Technical success rate, procedure time, complications and patency rates were analyzed. RESULTS: Technical success was achieved in 2,426 of 2,531 procedures (95.9%). Average procedure time of the intervention was 42.87+/-22.77 minutes. Primary patency rate was 61.9% at 3 mo, 41.2% at 6 mo and 19.6% at 1 year. Major complications occurred in 4.1% of cases (23 graft outflow rupture; 68 arterial emboli; 1 arterial dissection; 3 symptomatic pulmonary embolism; 1 stent migration) and minor complications occurred in 7.7% of cases (196 cases). These results were comparable to previously reported mechanical thrombectomy techniques in occluded hemodialysis grafts. CONCLUSIONS: Percutaneous thromboaspiration of occluded hemodialysis grafts with a Desilets-Hoffman Sheath is an effective and safe method. PMID- 24811593 TI - Penetration of arcus aorta by tunneled cuffed catheter: should fluoroscopic guidance be preferred? PMID- 24811594 TI - A new model of arteriovenous fistula to study hemodialysis access complications. AB - PURPOSE: This report presents a new animal model of arteriovenous fistula (AVF) with attention given to surgical techniques as well as hemodynamic and pathologic measurements. Of note, this model was created with a tunneled central catheter with the purpose of studying therapeutic interventions, including hemodialysis. METHODS: Side-common carotid artery to end-external jugular vein AVFs were created in eight minipigs. A tunneled central catheter was also placed in the internal jugular vein. After 28 days, hemodynamic measurements of AVF flow and stenosis were performed. The minipigs were then euthanized and the AVFs were harvested for pathologic measurements of neointimal hyperplasia and thrombus volumes. In order to account for variable size of the AVFs, percentage luminal stenosis and degree of intima-media thickening were calculated. RESULTS: After 28 days, all eight AVFs remained patent. On average, 19% of arterial blood flow that approached the AVF traveled through the anastomosis. The average luminal stenosis by angiogram was 61.1%. The average neointimal hyperplasia and thrombus volumes were 1.4*10(8) and 3.8*10(8) MUm3, respectively. The average luminal stenosis and intima-media thickening were 65.2% and 430.4 MUm, respectively. CONCLUSIONS: This AVF model is ideal because of the relative ease of surgery and husbandry, lack of complications, as well as consistent and rapid development of the neointimal lesion which underlies AVF failure. PMID- 24811595 TI - Liposuction for superficialization of deep veins after creation of arteriovenous fistulas. AB - PURPOSE: Many individuals with end-stage renal disease (ESRD) have adequate arteries and veins for construction of an arteriovenous fistula (AVF) but the fistula may be too deep to cannulate because of overlying adipose tissue. This study evaluated the safety and efficacy of liposuction to superficialize deep AVFs. METHODS: Between September 2009 and January 2011, 13 patients participated in the study. Mean body mass index (BMI) was 39.1 kg/m2. The study was limited to brachiocephalic and radiocephalic fistulas. Mean fistula depth was 8.1 mm. The primary endpoint was the date of the first successful cannulation with two 17 gauge needles. Patients were followed for 12 mo. RESULTS: Eleven subjects (85%) underwent successful two-needle cannulation a mean of 33.7 days after the procedure. One patient died of endocarditis and one developed a hematoma and wound necrosis that required surgical elevation to enable cannulation. Projection and palpability of the fistulas tended to increase over time. Mean tissue removed was 243 mL and correlated positively with the number of days to cannulation (r=0.74, p=0.01). Greater BMI correlated positively with more surgical site complications and delays in cannulation. At 12 mo, primary patency after liposuction was 50% and secondary patency was 83%. CONCLUSIONS: Most subjects had prompt, uncomplicated cannulation but a few had wound necrosis, large hematomas and prolonged time until cannulation. Liposuction is effective in enabling cannulation of deep vein fistulas but because of the substantial risk of serious surgical site complications, it may not be the ideal method. PMID- 24811596 TI - Hybrid simultaneous treatment of thrombosed prosthetic grafts for hemodialysis. AB - PURPOSE: The aim of the study was to evaluate our experience in the hybrid simultaneous treatment (open and endovascular) of acute thrombosis of prosthetic grafts for hemodialysis. METHODS: Between January 2011 and June 2013, 23 patients with acute thrombosis of a prosthetic graft for hemodialysis were urgently treated with a hybrid simultaneous treatment in order to obtain a prompt restoration of the flow. A new puncture of the graft was scheduled after 24 hours. RESULTS: Intraoperative technical success was 100% with a completion angiography showing the restored patency of the graft. As adjunctive procedures, in 6 patients (26.1%) locoregional thrombolysis was necessary and in all cases further endovascular manoeuvres (angioplasty/stenting) were immediately performed to solve a significant stenosis of the venous anastomosis/first tract of the vein. At 24 hours when the first puncture was done, three grafts were occluded resulting in a primary patency of 87%. During the follow-up (mean duration 5.6 months) four reocclusions occurred. In-stent restenosis occurred in all patients undergone stenting. At 1 year the rates of primary patency, primary assisted patency and secondary patency were 58.7%, 78.3% and 87%, respectively. CONCLUSIONS: In our series the combined simultaneous hybrid approach in urgency maximizes the use of different available techniques, which appeared to improve overall success rate to save a thrombosed graft for hemodialysis. The great difference showed between primary and primary assisted patency demonstrates the necessity of a close follow-up. PMID- 24811597 TI - Emergency vascular access via the external iliac vein for haemodialysis and subsequent renal transplantation. PMID- 24811598 TI - Flushing the central venous catheter: is heparin necessary? AB - PURPOSE: The aim of this systematic review was to assess the efficacy of heparin flushing in the lock of central venous catheters. METHODS: We searched MEDLINE and CINAHL databases. Eligible studies were randomized controlled trials evaluating the use of heparin versus normal saline or other solution in the flushing of central catheter among adult patients. No language restrictions were applied. Two reviewers independently screened titles and abstracts in order to identify relevant publications. The same two reviewers retrieved and evaluated full texts. Parameter estimates regarding catheter occlusion were pooled using network meta-analysis with Bayesian hierarchical modeling. RESULTS: We identified 462 references. Eight studies were included. There was no evidence that heparin was more effective than normal saline in reducing occlusions. It was unclear whether urokinase and lepirudin were more effective than heparin in reducing occlusions. Vitamin C solution does not appear to prolong catheter patency. CONCLUSIONS: There is no evidence of a different effectiveness between heparin flushing and normal saline or other solutions in reducing catheter occlusions. Due to the little and inconclusive evidence available in this field, further studies might be necessary. PMID- 24811599 TI - Early cannulation prosthetic graft (Acuseal) for arteriovenous access: a useful option to provide a personal vascular access solution. AB - PURPOSE: Early cannulation arteriovenous grafts (ecAVGs), such as the GORE Acuseal, have "low bleed" properties permitting cannulation within 24 hours of insertion. They may provide an alternative to tunneled central venous catheters (and associated line complications) in patients requiring urgent vascular access. METHODS: We present our early experience of 37 patients treated with the GORE Acuseal ecAVG. RESULTS: A total of 11 upper limb, 24 lower limb and 2 complex graft procedures were performed. Indications for ecAVG were as follows: bridge to transplantation (21.6%); bridge to arteriovenous fistula (AVF) maturation (8.1%); AVF salvage (8.1%); no native options (67.6%, including 17 patients with bilateral central vein stenosis); 36 AVGs (97.3%) were successfully cannulated. Mean time to first cannulation: 30.4+/-23.4 hours (range: 2-192). Primary and secondary patency rates at 3, 6 and 12 months were 64.9%, 48.6%, 32.4% and 70.2%, 59.4%, 40.5% respectively. The systemic bacteremia rate was 0.2 per 1,000 access days. There was one perioperative death. Other complications included hematoma at cannulation sites (n=9), pseudoaneurysm (n=3) and local infection at graft site (n=6). A total of 26 of 37 patients (70.6%) achieved a "personal vascular access solution": bridge to transplantation (n=8), bridge to functioning AVF/interposition AVG (n=5), maintenance hemodialysis via ecAVG (n=13); death with functioning AVG (n=1). CONCLUSIONS: Early experience with the GORE Acuseal is encouraging. Patency and bacteremia rates are at least comparable to standard polytetrafluoroethylene grafts. ecAVGs have permitted cannulation within 24 hours of insertion and line avoidance in the majority of patients. Nearly three quarters of patients achieved a definitive "personal vascular access solution" from their ecAVG. PMID- 24811600 TI - Autologous surgical reconstruction for true venous hemodialysis access aneurysms- techniques and results. AB - PURPOSE: Due to their relatively low complication rates autogenous arteriovenous fistulas (AVFs) are the preferred access for hemodialysis. In long-standing AVF, however, aneurysmatic degeneration of the fistula vein can develop. Several treatment options have been published. We evaluated our experience with autologous surgical reconstruction in patients with AVF aneurysms in order to assess complication and patency rates. METHODS: Demographics and comorbidities of all patients operated on for true AVF aneurysms in our institution, during a 7 year period, were reviewed. Access function and surgical outcomes were evaluated with pre- and postoperative Doppler ultrasonography. Patient survival, primary and secondary access patency rates are presented. RESULTS: From April 2006 through March 2013, 31 patients presented with access-associated upper extremity venous aneurysms. The mean time from AVF creation to aneurysm formation was 4.9+/ 3.6 years. The most frequent indication for surgery was aneurysm-associated stenosis (n=16) followed by high flow (n=9), complete thrombosis (n=3) and uncontrolled bleeding (n=3). All patients had autologous reconstructions: 5 resections with end-to-end anastomosis and 26 aneurysmorrhaphies. Overall patient survival at 1 and 2 years was 89% and 84%, respectively. The primary (secondary) patency rates at 6 mo, 1 and 2 years were 87%, 81% and 81% (96%, 96% and 90%), respectively. CONCLUSIONS: Autologous surgical reconstruction is feasible in the majority of AVF aneurysms. It preserves fistula function and--in contrast to graft interposition and endovascular repair--keeps the advantages of an autogenous access: low complication and high patency rates. PMID- 24811601 TI - Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kidney disease. AB - PURPOSE: To explore the safety and efficacy of PRT-201 applied to the outflow vein of a newly created arteriovenous graft (AVG). METHODS: Randomized, double blind, placebo-controlled, single-dose escalation study of PRT-201 (0.01 to 9 mg) applied to the graft-vein anastomosis and adjacent outflow vein immediately after AVG placement. The primary outcome measure was safety. The efficacy measures were intraoperative increases in outflow vein diameter and blood flow rate, primary unassisted patency, and secondary patency by dose groups (placebo, low, medium, high and All PRT-201). RESULTS: A total of 89 patients were treated (28 placebo and 61 PRT-201). There were no significant differences in the proportion of placebo and PRT-201 patients reporting adverse events. Intraoperative outflow vein diameter increased 5% (p=0.14) in the placebo group compared with 13% (p=0.01), 15% (p=0.07) and 12% (p<0.001), in the low, medium and high groups, respectively. The comparison between the high and placebo groups was marginally statistically significant (p=0.06). The intraoperative blood flow did not change in the placebo group, and increased in the low, medium and high groups by 19% (p=0.34), 36% (p=0.09) and 46% (p=0.02), respectively. The low group had the longest primary unassisted and secondary patency and the fewest procedures to restore or maintain patency; however, the differences between groups were not statistically significant. CONCLUSIONS: PRT-201 was well tolerated and increased AVG intraoperative outflow vein diameter and blood flow. Low dose tended to increase secondary patency and decrease the rate of procedures to restore or maintain patency. Larger studies with these doses will be necessary to confirm these results. PMID- 24811602 TI - Central venous catheter-related complications in acute myeloid ?leukemia patients. PMID- 24811603 TI - Safe administration of vancomycin through a novel midline catheter: a randomized, prospective clinical trial. AB - BACKGROUND: According to the 2011 Infusion Nursing Standards of Practice, the low pH of intravenous vancomycin requires that it be administered through a central line. However, a careful review of the literature and a retrospective analysis of the experience at New York Hospital Queens (NYHQ) did not support the position of the Standards. PURPOSE: A prospective, controlled, randomized clinical trial was conducted to determine if intravenous vancomycin could be safely administered through a novel midline catheter (POWERWAND(r), Access Scientific, San Diego, CA). METHODS: Patients scheduled to receive short-term (<6 days) intravenous vancomycin were randomly assigned to receive treatment through either a peripherally inserted central catheter (PICC) or the midline study device. Complications and the costs of insertion were recorded. RESULTS: The two groups did not differ significantly with respect to total complications (17.9% with PICCs vs. 19.9% with the midline), phlebitis (0% vs. 0%) or thrombosis (0% vs. 0%). One suspected catheter-associated bloodstream infection did occur in the PICC group. Insertion costs were $90.00 less per insertion in the midline group. CONCLUSIONS: Short-term intravenous vancomycin can be safely and cost-efficiently administered in the deep vessels of the upper arm using the midline study device. PMID- 24811604 TI - Variability in anesthetic considerations for arteriovenous fistula creation. AB - INTRODUCTION: Anesthetic options for arteriovenous fistula (AVF) creation include regional anesthesia (RA), general anesthesia (GA) and local anesthetic for select cases. In addition to the benefits of avoiding GA in high-risk patients, recent studies suggest that RA may increase perioperative venous dilation and improve maturation. Our objective was to assess perioperative outcomes of AVF creation with respect to anesthetic modality and identify patient-level factors associated with variation in contemporary anesthetic selection. METHODS: National Surgical Quality Improvement Project (NSQIP) data (2007-2010) were accessed to identify patients undergoing AVF creation. Univariate analysis and multivariate logistic regression were performed to assess the relationships among patient characteristics, anesthesia modality and outcome. RESULTS: Of 1,540 patients undergoing new upper extremity AVF creation, 52% were male and 81% were younger than 75 years. Anesthesia distribution was GA in 85.2%, local/monitored anesthetic care (MAC) in 2.9% and RA in 11.9% of cases. By multivariate analysis, independent predictors of RA were dyspnea at rest (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.9), age >75 (HR 1.6, 95% CI 1.1-2.3) and teaching hospital status as indicated by housestaff involvement (HR 3.7, 95% CI 2.5-5.5). RA was associated with higher total operative time, duration of anesthesia, length of time in operating room and duration of anesthesia start until surgery start (p<0.01). There were no differences between perioperative complications or mortality among anesthetic modalities, although all deaths occurred in the GA group. DISCUSSIONS: Despite recent reports highlighting potential benefits of RA for AVF creation, GA was surprisingly used in the vast majority of cases in the United States. The only comorbidities associated with preferential RA use were advanced age and dyspnea at rest. Practice environment may influence anesthetic selection for these cases, as a nonteaching environment was associated with GA use. The trend seen here toward higher mortality in GA and the potential perioperative benefits of RA for the access should encourage more widespread use of RA in practice for this high-risk patient population. PMID- 24811605 TI - Unfavorable peripheral intravenous catheter replacements can be reduced using an integrated closed intravenous catheter system. AB - PURPOSE: To evaluate the clinical usefulness of an integrated closed intravenous catheter system (CICS) with a preattached stabilization platform and extension tube (BD NexivaTM; Becton, Dickinson and Company) in Japanese patients. METHODS: In this open, single-center study, patients who required peripheral intravenous (PIV) catheterization for >=72 hours were quasi-randomized to receive a CICS or a conventional intravenous catheter. Study outcomes included adverse events during catheter insertion, catheter replacements during the initial 72 hours, catheter survival rate at 72 hours after insertion and costs of initial catheterization and catheter replacement. RESULTS: Of 359 patients enrolled, 194 received the CICS and 165 received the conventional catheter. The incidence rates of >=1 failed insertion attempts, blood leakage and blood exposure were similar in both groups. The survival rate of the CICS group (83.7%) was significantly higher than that of the conventional catheter group (62.6%) in the intention-to-treat analysis (p=0.0085). There were significantly fewer catheter replacements due to catheter-related complications (e.g., catheter failure or extravasation) in the CICS group (p=0.0056). Although the initial cost per patient was greater for the CICS group (US$17.07 vs. US$13.26), the total cost per patient over 72 hours was similar (US$21.00 vs. US$20.30) because of the cost of unplanned replacements of conventional catheters. CONCLUSIONS: Although rates of adverse events at insertion were similar for both catheters, significantly fewer patients required unplanned reinsertion with the CICS. The results suggest that the longer survival rate for the CICS can offset the higher initial catheterization costs. PMID- 24811606 TI - An update on current pharmacotherapy options in atopic dermatitis. AB - INTRODUCTION: New knowledge on the pathogenesis of atopic dermatitis (AD) gives us new treatment options. This review emphasizes long-term treatment results. AREAS COVERED: This study includes basic pathogenic factors in AD and presents present and future treatment options. Topical corticosteroids treat the inflammation effectively short term. Topical calcineurin inhibitors (TCIs) show better benefit/risk ratio in long-term treatment. For topical treatment, an effective maintenance treatment results in optimal control of the AD. Of systemic immunosuppressive treatments, efficacy has been shown with azathioprine, ciclosporin, methotrexate and mycophenolate-free sodium. With these compounds, the treatment outcome was ~ 50% improvement in clinical signs compared with baseline. New treatments under study include systemic compounds, which suppress the T helper type 2 cells. The importance of adherence to treatment is often overlooked, although it has a major impact on treatment outcome. For the present review, PubMed was used as a primary source. EXPERT OPINION: Combination of future T(H)2-specific systemic treatment with optimal topical treatment with TCI, especially tacrolimus ointment, could help to completely control the skin inflammation in AD. The ultimate goal is to control AD completely, which should help to control the atopic airway disease as well. PMID- 24811607 TI - Perturbative approach to Markovian open quantum systems. AB - The exact treatment of Markovian open quantum systems, when based on numerical diagonalization of the Liouville super-operator or averaging over quantum trajectories, is severely limited by Hilbert space size. Perturbation theory, standard in the investigation of closed quantum systems, has remained much less developed for open quantum systems where a direct application to the Lindblad master equation is desirable. We present such a perturbative treatment which will be useful for an analytical understanding of open quantum systems and for numerical calculation of system observables which would otherwise be impractical. PMID- 24811608 TI - Attenuated behavioral and brain responses to trust violations among assaulted adolescent girls. AB - Physical and sexual assault during adolescence is a potent risk factor for mental health and psychosocial problems, as well as revictimization, especially among female victims. To better understand this conferred risk, we conducted an exploratory study comparing assaulted and non-assaulted girls' behavioral and brain responses during a trust learning task. Adolescent girls (14 assaulted, 16 non-assaulted) performed a functional magnetic resonance imaging task that manipulated the percentages of which three different faces delivered positive and negative outcomes. Analyses focused on comparing unexpected to expected outcomes. We found that assaulted adolescent girls demonstrated less behavioral slowing in response to unexpected negative social outcomes, or trust violations (i.e., when a presumably trustworthy face delivered a negative outcome), relative to control girls. Trust violations were also associated with less activation in anterior insular and anterior cingulate regions among the assaulted group compared to the control group. Furthermore, we found that the severity of participants' exposure to assaultive events scaled negatively with recruitment of these regions. These preliminary results suggest that assault victims may engage differential learning processes upon unexpected negative social outcomes. These findings have implications for understanding impaired trust learning and social functioning among assault victims. PMID- 24811609 TI - Celecoxib modulates nitric oxide and reactive oxygen species in kidney ischemia/reperfusion injury and rat aorta model of hypoxia/reoxygenation. AB - OBJECTIVE: This study investigated the interaction between COX-2, NO and ROS after ischemia/reperfusion events in the kidney and vascular beds. MATERIALS AND METHODS: Kidney IRI model in male Sprague-Dawley rats was used and various biochemical and histopathological parameters were examined. The isolated rat aortic rings served as model for hypoxia/reoxygenation. RESULTS: Celecoxib reduced serum creatinine and urea and kidney malonaldehyde levels, increased kidney superoxide dismutase activity and reduced glutathione level and histopathological scores at 24 and 48 h after reperfusion compared to IRI group. This was associated with a significant increase in NO level to 0.70 +/- 0.03 nmol/mg protein compared to 0.37 +/- 0.01 nmol/mg protein for IRI group. Unexpectedly, celecoxib reduced COX-2 expression in the kidney. Celecoxib reversed the effect of hypoxia-reoxygenation on ACh and SNP-induced relaxation in aortic rings but failed to potentiate the SNP relaxations in the control rings. Hypoxia-reoxygenation significantly impaired celecoxib's relaxation of aorta (12.69 +/- 2.69% vs. 35.84 +/- 0.84%) which was significantly inhibited in presence of L-NAME. CONCLUSIONS: Celecoxib beneficially affects the outcome of renal IRI by lowering the expression of COX-2 and hence reducing oxidative stress and increasing the bioavailability of NO. Direct interaction between celecoxib and NO in associated vascular beds may also be a contributing mechanism. PMID- 24811610 TI - Long-term cardiovascular risks associated with an elevated heart rate: the Framingham Heart Study. AB - BACKGROUND: Higher heart rate has been associated with an adverse prognosis, but most prior studies focused on individuals with known cardiovascular disease or examined a limited number of outcomes. We sought to examine the association of baseline heart rate with both fatal and nonfatal outcomes during 2 decades of follow-up. METHODS AND RESULTS: Our study included 4058 Framingham Heart Study participants (mean age 55 years, 56% women). Cox models were performed with multivariable adjustment for clinical risk factors and physical activity. A total of 708 participants developed incident cardiovascular disease (303 heart failure, 343 coronary heart disease, and 216 stroke events), 48 received a permanent pacemaker, and 1186 died. Baseline heart rate was associated with incident cardiovascular disease (hazard ratio [HR] 1.15 per 1 SD [11 bpm] increase in heart rate, 95% CI 1.07 to 1.24, P=0.0002), particularly heart failure (HR 1.32, 95% CI 1.18 to 1.48, P<0.0001). Higher heart rate was also associated with higher all-cause (HR 1.17, 95% CI 1.11 to 1.24, P<0.0001) and cardiovascular mortality (HR 1.18, 95% CI 1.04 to 1.33, P=0.01). Spline analyses did not suggest a lower threshold beyond which the benefit of a lower heart rate abated or increased. In contrast, individuals with a higher heart rate had a lower risk of requiring permanent pacemaker placement (HR 0.55, 95% CI 0.38 to 0.79, P=0.001). CONCLUSIONS: Individuals with a higher heart rate are at elevated long-term risk for cardiovascular events, in particular, heart failure, and all-cause death. On the other hand, a higher heart rate is associated with a lower risk of future permanent pacemaker implantation. PMID- 24811611 TI - Temporal trends in pulse pressure and mean arterial pressure during the rise of pediatric obesity in US children. AB - BACKGROUND: Somatic growth in childhood is accompanied by substantial remodeling of the aorta. Obesity is associated with increased aortic stiffness and flow and may interfere with aortic remodeling during growth. Wide pulse pressure (PP) indicates mismatch between aortic impedance and pulsatile flow and increases risk for future systolic hypertension and cardiovascular disease (CVD). We hypothesized that the rise of pediatric obesity would be associated with a temporal trend to higher PP. METHODS AND RESULTS: We analyzed demographic, anthropometric, and blood pressure (BP) data for 8- to 17-year-old children (N=16 457) from the cross-sectional National Health and Nutrition Examination Surveys (NHANES) for 1976 through 2008. Multivariable adjusted survey regression was used to examine temporal trends in PP and mean arterial pressure (MAP) and the relation to obesity. Across this period, unadjusted PP was higher (0.29 mm Hg/y, 95% CI 0.26 to 0.33 mm Hg/y; P<0.0001), while MAP was lower (-0.24 mm Hg/y, 95% CI -0.27 to -0.20 mm Hg/y; P<0.0001) across examinations. Adjusting for body mass index partially attenuated the temporal trend for PP by 32% (P<0.0001). Obesity amplified the relation between taller height and higher PP (from 0.23 [95% CI 0.19 to 0.28] to 0.27 [95% CI 0.21 to 0.34] mm Hg/cm height in boys and from 0.08 [95% CI 0.04 to 0.13] to 0.22 [95% CI 0.13 to 0.31] mm Hg/cm height in girls; P<0.01 for both). CONCLUSIONS: PP has increased during the rise of pediatric obesity. Higher PP may indicate mismatch between aortic diameter, wall stiffness, and flow in obese children during a period of rapid somatic growth when the aorta is already under considerable remodeling stress. PMID- 24811612 TI - Identification of Hic-5 as a novel scaffold for the MKK4/p54 JNK pathway in the development of abdominal aortic aneurysms. AB - BACKGROUND: Although increased amounts of reactive oxygen species in the pathogenesis of abdominal aortic aneurysm (AAA) are well documented, the precise molecular mechanisms by which reactive oxygen species induce AAAs have not been fully elucidated. This study focused on the role of hydrogen peroxide-inducible clone 5 (Hic-5), which is induced by hydrogen peroxide and transforming growth factor-beta, in the cellular signaling of AAA pathogenesis. METHODS AND RESULTS: Using the angiotensin II-induced AAA model in Apoe(-/-) mice, we showed that Apoe(-/-)Hic-5(-/-) mice were completely protected from AAA formation and aortic rupture, whereas Apoe(-/-) mice were not. These features were similarly observed in smooth muscle cell-specific Hic-5-deficient mice. Furthermore, angiotensin II treatment induced Hic-5 expression in a reactive oxygen species-dependent manner in aortic smooth muscle cells in the early stage of AAA development. Mechanistic studies revealed that Hic-5 interacted specifically with c-Jun N-terminal kinase p54 and its upstream regulatory molecule mitogen-activated protein kinase kinase 4 as a novel scaffold protein, resulting in the expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase 2 activation in aortic smooth muscle cells. CONCLUSION: Hic-5 serves as a novel scaffold protein that specifically activates the mitogen-activated protein kinase kinase 4/p54 c-Jun N terminal kinase pathway, thereby leading to the induction and activation of matrix metalloproteinases in smooth muscle cells and subsequent AAA formation. Our study provided a novel therapeutic option aimed at inhibiting the mitogen activated protein kinase kinase 4-Hic-5-p54 c-Jun N-terminal kinase pathway in the vessel wall, particularly through Hic-5 inhibition, which may be used to produce more precise and effective therapies. PMID- 24811613 TI - Clinical features and prognosis of patients with coronary spasm-induced non-ST segment elevation acute coronary syndrome. AB - BACKGROUND: The prevalence, clinical features, and long-term outcome of patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) associated with coronary spasm are not fully investigated. METHODS AND RESULTS: This observational multicenter study enrolled 1601 consecutive patients with suspected NSTE-ACS who underwent cardiac catheterization between January 2001 and December 2010. A culprit lesion was found in 1152 (72%) patients. In patients without a culprit lesion, the acetylcholine provocation test was performed in 221 patients and was positive in 175 patients. In the other patients, coronary spasm was verified in 145 patients during spontaneous attack. Spasm-induced NSTE-ACS was diagnosed in 320 (20%) patients. Multivariable analysis identified age <70 years (odds ratio [OR] 2.19, 95% CI 1.58 to 3.04), estimated glomerular filtration rate >60 mL/min per 1.73 m(2) (OR 1.72, 95% CI 1.16 to 2.56), and lack of hypertension (OR 2.55, 95% CI 1.90 to 3.41), dyslipidemia (OR 2.76, 95% CI 2.05 to 3.73), diabetes mellitus (OR 2.49, 95% CI 1.78 to 3.48), previous myocardial infarction (OR 5.37, 95% CI 2.89 to 10.0), and elevated cardiac biomarkers (OR 2.84, 95% CI 2.11 to 3.83) as significant correlates of spasm-induced NSTE-ACS (P<0.01 for all variables). Transient ST-segment elevation during spontaneous attack (variant angina) was observed in 119 patients with spasm-induced NSTE-ACS. Variant angina was more common in nondyslipidemic men among patients with spasm-induced NSTE ACS. CONCLUSIONS: The study showed frequent involvement of coronary spasm in the pathogenesis of NSTE-ACS. Variant angina was observed in one third of patients with spasm-induced NSTE-ACS. Coronary spasm should be considered even in patients with less coronary risk factors and nonobstructive coronary arteries. PMID- 24811614 TI - Population-based incidence of sudden cardiac and unexpected death before and after the 2011 earthquake and tsunami in Iwate, northeast Japan. AB - BACKGROUND: The aim of this study was to evaluate the temporal impact of the 2011 Japan earthquake and tsunami on the incidence of sudden cardiac and unexpected death (SCUD). METHODS AND RESULTS: We surveyed the impact of the disaster on the incidence and clinical characteristics of SCUD in Iwate. To perform complete identification of SCUD for 8 weeks before and 40 weeks after the disaster, medical records and death certificates relevant to SCUD were surveyed in the study area. Compared with the previous year's rate, the incidence (per 10 000 person-year) of SCUD for the initial 4 weeks after the disaster (acute phase) was double (33.5 vs 18.9), and thereafter the rate returned to the previous level. Significant relationships were found between weekly numbers of SCUD and seismic activity (intensity, r=0.43; P<0.005: frequency, r=0.46; P<0.002). The standardized incidence ratio (SIR) of SCUD in the acute phase was significantly increased compared with that of previous years (1.71, 95% CI 1.33 to 2.16). Increased SIRs were predominantly found in female subjects (1.73, 95% CI 1.22 to 2.37), the elderly (1.73, 95% CI 1.29 to 2.27), and residents living in the tsunami-stricken area (1.83, 95% CI 1.33 to 2.46). In addition, SIRs for weekdays (1.71, 95% CI 1.28 to 2.24) and nights-mornings (2.09, 95% CI 1.48 to 2.86) were amplified. CONCLUSIONS: The present results suggest that the magnitude of a disaster, related stress, and population aging may cause a temporary increase in the incidence of SCUD with amplification of ordinary weekly and circadian variations. PMID- 24811617 TI - Communication: Quantum molecular dynamics simulation of liquid para-hydrogen by nuclear and electron wave packet approach. AB - Liquid para-hydrogen (p-H2) is a typical quantum liquid which exhibits strong nuclear quantum effects (NQEs) and thus anomalous static and dynamic properties. We propose a real-time simulation method of wave packet (WP) molecular dynamics (MD) based on non-empirical intra- and inter-molecular interactions of non spherical hydrogen molecules, and apply it to condensed-phase p-H2. The NQEs, such as WP delocalization and zero-point energy, are taken into account without perturbative expansion of prepared model potential functions but with explicit interactions between nuclear and electron WPs. The developed MD simulation for 100 ps with 1200 hydrogen molecules is realized at feasible computational cost, by which basic experimental properties of p-H2 liquid such as radial distribution functions, self-diffusion coefficients, and shear viscosities are all well reproduced. PMID- 24811615 TI - Effect of diet or diet plus physical activity versus usual care on inflammatory markers in patients with newly diagnosed type 2 diabetes: the Early ACTivity in Diabetes (ACTID) randomized, controlled trial. AB - BACKGROUND: Inflammation plays a major role in diabetes-associated cardiovascular disease (CVD). There is uncertainty whether diet and physical activity interventions can be successfully integrated into healthcare settings and reduce markers of inflammation and risk of CVD in patients with type 2 diabetes (T2D). METHODS AND RESULTS: Systemic markers of inflammation were determined in a 12 month, real-world, multicenter, randomized, controlled trial that investigated the effect of diet, diet plus physical activity, and usual care in 593 individuals with newly diagnosed T2D. During the first 6 months, serum C-reactive protein (CRP) improved by -21 (-36 to -1.4)% and -22 (-38 to -3.1)% in diet and diet plus physical activity arms versus usual care. There were also improvements in adiponectin and soluble intercellular adhesion molecule-1 (sICAM-1). Though medication-adjusted CRP was improved between 6 and 12 months for usual care, both interventions were more successful in reducing the relative risk of a high-risk CRP level of >3 mg/L (risk ratios of 0.72 [0.55 to 0.95] for diet versus usual care and 0.67 [0.50 to 0.90] for diet plus activity versus usual care). Furthermore, sICAM-1 (a marker of vascular risk), remained substantially lower than usual care in both intervention arms at 12 months. CONCLUSIONS: Motivational, unsupervised diet and/or diet plus physical activity interventions given soon after diagnosis in real-world healthcare settings improve markers of inflammation and cardiovascular risk in patients with T2D, even after accounting for the effect of adjustments to medication to try and control blood pressure, glycated hemoglobin, and lipids. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com/. Unique identifier: ISRCTN92162869. PMID- 24811616 TI - Identification of nutrient deficiency in maize and tomato plants by in vivo chlorophyll a fluorescence measurements. AB - The impact of some macro (Ca, S, Mg, K, N, P) and micro (Fe) nutrients deficiency on the functioning of the photosynthetic machinery in tomato (Solanum lycopersicum L.) and maize (Zea mays L.) plants grown in hydroponic cultures were investigated. Plants grown on a complete nutrient solution (control) were compared with those grown in a medium, which lacked one of macro- or microelements. The physiological state of the photosynthetic machinery in vivo was analysed after 14-days of deficient condition by the parameters of JIP-test based on fast chlorophyll a fluorescence records. In most of the nutrient deficient samples, the decrease of photochemical efficiency, increase in non photochemical dissipation and decrease of the number of active photosystem II (PSII) reaction centres were observed. However, lack of individual nutrients also had nutrient-specific effects on the photochemical processes. In Mg and Ca deficient plants, the most severe decrease in electron donation by oxygen evolving complex (OEC) was indicated. Sulphur deficiency caused limitation of electron transport beyond PSI, probably due to decrease in the PSI content or activity of PSI electron acceptors; in contrary, Ca deficiency had an opposite effect, where the PSII activity was affected much more than PSI. Despite the fact that clear differences in nutrient deficiency responses between tomato and maize plants were observed, our results indicate that some of presented fluorescence parameters could be used as fluorescence phenotype markers. The principal component analysis of selected JIP-test parameters was presented as a possible species-specific approach to identify/predict the nutrient deficiency using the fast chlorophyll fluorescence records. PMID- 24811618 TI - Communication: Helium nanodroplet isolation and rovibrational spectroscopy of hydroxymethylene. AB - Hydroxymethylene (HCOH) and its d1-isotopologue (HCOD) are isolated in low temperature helium nanodroplets following pyrolysis of glyoxylic acid. Transitions identified in the infrared spectrum are assigned exclusively to the trans-conformation based on previously reported anharmonic frequency computations [P. R. Schreiner, H. P. Reisenauer, F. C. Pickard, A. C. Simmonett, W. D. Allen, E. Matyus, and A. G. Csaszar, Nature 453, 906 (2008); L. Koziol, Y. M. Wang, B. J. Braams, J. M. Bowman, and A. I. Krylov, J. Chem. Phys. 128, 204310 (2008)]. For the OH(D) and CH stretches, a- and b-type transitions are observed, and when taken in conjunction with CCSD(T)/cc-pVTZ computations, lower limits to the vibrational band origins are determined. The relative intensities of the a- and b type transitions provide the orientation of the transition dipole moment in the inertial frame. The He nanodroplet data are in excellent agreement with anharmonic frequency computations reported here and elsewhere, confirming an appreciable Ar-matrix shift of the OH and OD stretches and strong anharmonic resonance interactions in the high-frequency stretch regions of the mid-infrared. PMID- 24811619 TI - A new efficient method for calculation of Frenkel exciton parameters in molecular aggregates. AB - The Frenkel exciton Hamiltonian is at the heart of many simulations of excitation energy transfer in molecular aggregates. It separates the aggregate into Coulomb coupled monomers. Here it is shown that the respective parameters, i.e., monomeric excitation energies and Coulomb couplings between transition densities can be efficiently calculated using time-dependent tight-binding-based density functional theory (TD-DFTB). Specifically, Coulomb couplings are expressed in terms of self-consistently determined Mulliken transition charges. The approach is applied to two dimer systems. First, formaldehyde oxime for which a detailed comparison with standard DFT using the B3LYP and the PBE functionals as well as with SCS-CC2 is provided. Second, the Coulomb coupling is explored in dependence on the intermolecular coordinates for a perylene bisimide dimer. This provides structural evidence for the previously observed biphasic aggregation behavior of this dye. PMID- 24811620 TI - Ionic size effects to molecular solvation energy and to ion current across a channel resulted from the nonuniform size-modified PNP equations. AB - Ionic finite size can impose considerable effects to both the equilibrium and non equilibrium properties of a solvated molecular system, such as the solvation energy, ionic concentration, and transport in a channel. As discussed in our former work [B. Lu and Y. C. Zhou, Biophys. J. 100, 2475 (2011)], a class of size modified Poisson-Boltzmann (PB)/Poisson-Nernst-Planck (PNP) models can be uniformly studied through the general nonuniform size-modified PNP (SMPNP) equations deduced from the extended free energy functional of Borukhov et al. [I. Borukhov, D. Andelman, and H. Orland, Phys. Rev. Lett. 79, 435 (1997)] This work focuses on the nonuniform size effects to molecular solvation energy and to ion current across a channel for real biomolecular systems. The main contributions are: (1) we prove that for solvation energy calculation with nonuniform size effects (through equilibrium SMPNP simulation), there exists a simplified approximation formulation which is the same as the widely used one in PB community. This approximate form avoids integration over the whole domain and makes energy calculations convenient. (2) Numerical calculations show that ionic size effects tend to negate the solvation effects, which indicates that a higher molecular solvation energy (lower absolute value) is to be predicted when ionic size effects are considered. For both calculations on a protein and a DNA fragment systems in a 0.5M 1:1 ionic solution, a difference about 10 kcal/mol in solvation energies is found between the PB and the SMPNP predictions. Moreover, it is observed that the solvation energy decreases as ionic strength increases, which behavior is similar as those predicted by the traditional PB equation (without size effect) and by the uniform size-modified Poisson-Boltzmann equation. (3) Nonequilibrium SMPNP simulations of ion permeation through a gramicidin A channel show that the ionic size effects lead to reduced ion current inside the channel compared with the results without considering size effects. As a component of the current, the drift term is the main contribution to the total current. The ionic size effects to the total current almost come through the drift term, and have little influence on the diffusion terms in SMPNP. PMID- 24811621 TI - Analytical gradients of complete active space self-consistent field energies using Cholesky decomposition: geometry optimization and spin-state energetics of a ruthenium nitrosyl complex. AB - We present a formulation of analytical energy gradients at the complete active space self-consistent field (CASSCF) level of theory employing density fitting (DF) techniques to enable efficient geometry optimizations of large systems. As an example, the ground and lowest triplet state geometries of a ruthenium nitrosyl complex are computed at the DF-CASSCF level of theory and compared with structures obtained from density functional theory (DFT) using the B3LYP, BP86, and M06L functionals. The average deviation of all bond lengths compared to the crystal structure is 0.042 A at the DF-CASSCF level of theory, which is slightly larger but still comparable with the deviations obtained by the tested DFT functionals, e.g., 0.032 A with M06L. Specifically, the root-mean-square deviation between the DF-CASSCF and best DFT coordinates, delivered by BP86, is only 0.08 A for S0 and 0.11 A for T1, indicating that the geometries are very similar. While keeping the mean energy gradient errors below 0.25%, the DF technique results in a 13-fold speedup compared to the conventional CASSCF geometry optimization algorithm. Additionally, we assess the singlet-triplet energy vertical and adiabatic differences with multiconfigurational second-order perturbation theory (CASPT2) using the DF-CASSCF and DFT optimized geometries. It is found that the vertical CASPT2 energies are relatively similar regardless of the geometry employed whereas the adiabatic singlet-triplet gaps are more sensitive to the chosen triplet geometry. PMID- 24811622 TI - Solid-state dimer method for calculating solid-solid phase transitions. AB - The dimer method is a minimum mode following algorithm for finding saddle points on a potential energy surface of atomic systems. Here, the dimer method is extended to include the cell degrees of freedom for periodic solid-state systems. Using this method, reaction pathways of solid-solid phase transitions can be determined without having to specify the final state structure or reaction mechanism. Example calculations include concerted phase transitions between CdSe polymorphs and a nucleation and growth mechanism for the A15 to BCC transition in Mo. PMID- 24811623 TI - Mixed quantum classical calculation of proton transfer reaction rates: from deep tunneling to over the barrier regimes. AB - We present mixed quantum classical calculations of the proton transfer (PT) reaction rates represented by a double well system coupled to a dissipative bath. The rate constants are calculated within the so called nontraditional view of the PT reaction, where the proton motion is quantized and the solvent polarization is used as the reaction coordinate. Quantization of the proton degree of freedom results in a problem of non-adiabatic dynamics. By employing the reactive flux formulation of the rate constant, the initial sampling starts from the transition state defined using the collective reaction coordinate. Dynamics of the collective reaction coordinate is treated classically as over damped diffusive motion, for which the equation of motion can be derived using the path integral, or the mixed quantum classical Liouville equation methods. The calculated mixed quantum classical rate constants agree well with the results from the numerically exact hierarchical equation of motion approach for a broad range of model parameters. Moreover, we are able to obtain contributions from each vibrational state to the total reaction rate, which helps to understand the reaction mechanism from the deep tunneling to over the barrier regimes. The numerical results are also compared with those from existing approximate theories based on calculations of the non-adiabatic transmission coefficients. It is found that the two-surface Landau-Zener formula works well in calculating the transmission coefficients in the deep tunneling regime, where the crossing point between the two lowest vibrational states dominates the total reaction rate. When multiple vibrational levels are involved, including additional crossing points on the free energy surfaces is important to obtain the correct reaction rate using the Landau Zener formula. PMID- 24811625 TI - Model reduction for slow-fast stochastic systems with metastable behaviour. AB - The quasi-steady-state approximation (or stochastic averaging principle) is a useful tool in the study of multiscale stochastic systems, giving a practical method by which to reduce the number of degrees of freedom in a model. The method is extended here to slow-fast systems in which the fast variables exhibit metastable behaviour. The key parameter that determines the form of the reduced model is the ratio of the timescale for the switching of the fast variables between metastable states to the timescale for the evolution of the slow variables. The method is illustrated with two examples: one from biochemistry (a fast-species-mediated chemical switch coupled to a slower varying species), and one from ecology (a predator-prey system). Numerical simulations of each model reduction are compared with those of the full system. PMID- 24811624 TI - Predicting the influence of long-range molecular interactions on macroscopic scale diffusion by homogenization of the Smoluchowski equation. AB - The macroscopic diffusion constant for a charged diffuser is in part dependent on (1) the volume excluded by solute "obstacles" and (2) long-range interactions between those obstacles and the diffuser. Increasing excluded volume reduces transport of the diffuser, while long-range interactions can either increase or decrease diffusivity, depending on the nature of the potential. We previously demonstrated [P. M. Kekenes-Huskey et al., Biophys. J. 105, 2130 (2013)] using homogenization theory that the configuration of molecular-scale obstacles can both hinder diffusion and induce diffusional anisotropy for small ions. As the density of molecular obstacles increases, van der Waals (vdW) and electrostatic interactions between obstacle and a diffuser become significant and can strongly influence the latter's diffusivity, which was neglected in our original model. Here, we extend this methodology to include a fixed (time-independent) potential of mean force, through homogenization of the Smoluchowski equation. We consider the diffusion of ions in crowded, hydrophilic environments at physiological ionic strengths and find that electrostatic and vdW interactions can enhance or depress effective diffusion rates for attractive or repulsive forces, respectively. Additionally, we show that the observed diffusion rate may be reduced independent of non-specific electrostatic and vdW interactions by treating obstacles that exhibit specific binding interactions as "buffers" that absorb free diffusers. Finally, we demonstrate that effective diffusion rates are sensitive to distribution of surface charge on a globular protein, Troponin C, suggesting that the use of molecular structures with atomistic-scale resolution can account for electrostatic influences on substrate transport. This approach offers new insight into the influence of molecular-scale, long-range interactions on transport of charged species, particularly for diffusion-influenced signaling events occurring in crowded cellular environments. PMID- 24811626 TI - Compressible generalized hybrid Monte Carlo. AB - One of the most demanding calculations is to generate random samples from a specified probability distribution (usually with an unknown normalizing prefactor) in a high-dimensional configuration space. One often has to resort to using a Markov chain Monte Carlo method, which converges only in the limit to the prescribed distribution. Such methods typically inch through configuration space step by step, with acceptance of a step based on a Metropolis(-Hastings) criterion. An acceptance rate of 100% is possible in principle by embedding configuration space in a higher dimensional phase space and using ordinary differential equations. In practice, numerical integrators must be used, lowering the acceptance rate. This is the essence of hybrid Monte Carlo methods. Presented is a general framework for constructing such methods under relaxed conditions: the only geometric property needed is (weakened) reversibility; volume preservation is not needed. The possibilities are illustrated by deriving a couple of explicit hybrid Monte Carlo methods, one based on barrier-lowering variable-metric dynamics and another based on isokinetic dynamics. PMID- 24811627 TI - Graphics processing units accelerated semiclassical initial value representation molecular dynamics. AB - This paper presents a Graphics Processing Units (GPUs) implementation of the Semiclassical Initial Value Representation (SC-IVR) propagator for vibrational molecular spectroscopy calculations. The time-averaging formulation of the SC-IVR for power spectrum calculations is employed. Details about the GPU implementation of the semiclassical code are provided. Four molecules with an increasing number of atoms are considered and the GPU-calculated vibrational frequencies perfectly match the benchmark values. The computational time scaling of two GPUs (NVIDIA Tesla C2075 and Kepler K20), respectively, versus two CPUs (Intel Core i5 and Intel Xeon E5-2687W) and the critical issues related to the GPU implementation are discussed. The resulting reduction in computational time and power consumption is significant and semiclassical GPU calculations are shown to be environment friendly. PMID- 24811628 TI - A Gibbs-ensemble based technique for Monte Carlo simulation of electric double layer capacitors (EDLC) at constant voltage. AB - Current methods for molecular simulations of Electric Double Layer Capacitors (EDLC) have both the electrodes and the electrolyte region in a single simulation box. This necessitates simulation of the electrode-electrolyte region interface. Typical capacitors have macroscopic dimensions where the fraction of the molecules at the electrode-electrolyte region interface is very low. Hence, large systems sizes are needed to minimize the electrode-electrolyte region interfacial effects. To overcome these problems, a new technique based on the Gibbs Ensemble is proposed for simulation of an EDLC. In the proposed technique, each electrode is simulated in a separate simulation box. Application of periodic boundary conditions eliminates the interfacial effects. This in addition to the use of constant voltage ensemble allows for a more convenient comparison of simulation results with experimental measurements on typical EDLCs. PMID- 24811629 TI - Calculating vibrational spectra with sum of product basis functions without storing full-dimensional vectors or matrices. AB - We propose an iterative method for computing vibrational spectra that significantly reduces the memory cost of calculations. It uses a direct product primitive basis, but does not require storing vectors with as many components as there are product basis functions. Wavefunctions are represented in a basis each of whose functions is a sum of products (SOP) and the factorizable structure of the Hamiltonian is exploited. If the factors of the SOP basis functions are properly chosen, wavefunctions are linear combinations of a small number of SOP basis functions. The SOP basis functions are generated using a shifted block power method. The factors are refined with a rank reduction algorithm to cap the number of terms in a SOP basis function. The ideas are tested on a 20-D model Hamiltonian and a realistic CH3CN (12 dimensional) potential. For the 20-D problem, to use a standard direct product iterative approach one would need to store vectors with about 10(20) components and would hence require about 8 * 10(11) GB. With the approach of this paper only 1 GB of memory is necessary. Results for CH3CN agree well with those of a previous calculation on the same potential. PMID- 24811630 TI - An algorithm for nonrelativistic quantum-mechanical finite-nuclear-mass variational calculations of nitrogen atom in L = 0, M = 0 states using all electrons explicitly correlated Gaussian basis functions. AB - An algorithm for quantum-mechanical nonrelativistic variational calculations of L = 0 and M = 0 states of atoms with an arbitrary number of s electrons and with three p electrons have been implemented and tested in the calculations of the ground (4)S state of the nitrogen atom. The spatial part of the wave function is expanded in terms of all-electrons explicitly correlated Gaussian functions with the appropriate pre-exponential Cartesian angular factors for states with the L = 0 and M = 0 symmetry. The algorithm includes formulas for calculating the Hamiltonian and overlap matrix elements, as well as formulas for calculating the analytic energy gradient determined with respect to the Gaussian exponential parameters. The gradient is used in the variational optimization of these parameters. The Hamiltonian used in the approach is obtained by rigorously separating the center-of-mass motion from the laboratory-frame all-particle Hamiltonian, and thus it explicitly depends on the finite mass of the nucleus. With that, the mass effect on the total ground-state energy is determined. PMID- 24811631 TI - Strong field ionization rates simulated with time-dependent configuration interaction and an absorbing potential. AB - Ionization rates of molecules have been modeled with time-dependent configuration interaction simulations using atom centered basis sets and a complex absorbing potential. The simulations agree with accurate grid-based calculations for the ionization of hydrogen atom as a function of field strength and for charge resonance enhanced ionization of H2(+) as the bond is elongated. Unlike grid based methods, the present approach can be applied to simulate electron dynamics and ionization in multi-electron polyatomic molecules. Calculations on HCl(+) and HCO(+) demonstrate that these systems also show charge resonance enhanced ionization as the bonds are stretched. PMID- 24811632 TI - Equation-of-motion coupled cluster perturbation theory revisited. AB - The equation-of-motion coupled cluster (EOM-CC) framework has been used for deriving a novel series of perturbative corrections to the coupled cluster singles and doubles energy that formally converges towards the full configuration interaction energy limit. The series is based on a Moller-Plesset partitioning of the Hamiltonian and thus size extensive at any order in the perturbation, thereby remedying the major deficiency inherent to previous perturbation series based on the EOM-CC ansatz. PMID- 24811633 TI - Quantum mechanical/molecular mechanical/continuum style solvation model: second order Moller-Plesset perturbation theory. AB - A combined quantum mechanical/molecular mechanical/continuum (QM/MM/C) style second order Moller-Plesset perturbation theory (MP2) method that incorporates induced dipole polarizable force field and induced surface charge continuum solvation model is established. The Z-vector method is modified to include induced dipoles and induced surface charges to determine the MP2 response density matrix, which can be used to evaluate MP2 properties. In particular, analytic nuclear gradient is derived and implemented for this method. Using the Assisted Model Building with Energy Refinement induced dipole polarizable protein force field, the QM/MM/C style MP2 method is used to study the hydrogen bonding distances and strengths of the photoactive yellow protein chromopore in the wild type and the Glu46Gln mutant. PMID- 24811634 TI - Atomically precise (catalytic) particles synthesized by a novel cluster deposition instrument. AB - We report a new high vacuum instrument which is dedicated to the preparation of well-defined clusters supported on model and technologically relevant supports for catalytic and materials investigations. The instrument is based on deposition of size selected metallic cluster ions that are produced by a high flux magnetron cluster source. The throughput of the apparatus is maximized by collecting and focusing ions utilizing a conical octupole ion guide and a linear ion guide. The size selection is achieved by a quadrupole mass filter. The new design of the sample holder provides for the preparation of multiple samples on supports of various sizes and shapes in one session. After cluster deposition onto the support of interest, samples will be taken out of the chamber for a variety of testing and characterization. PMID- 24811635 TI - Homogenous nucleation rates of n-propanol measured in the Laminar Flow Diffusion Chamber at different total pressures. AB - Nucleation rates of n-propanol were investigated in the Laminar Flow Diffusion Chamber. Nucleation temperatures between 270 and 300 K and rates between 10(0) and 10(6) cm(-3) s(-1) were achieved. Since earlier measurements of n-butanol and n-pentanol suggest a dependence of nucleation rates on carrier gas pressure, similar conditions were adjusted for these measurements. The obtained data fit well to results available from literature. A small positive pressure effect was found which strengthen the assumption that this effect is attributed to the carbon chain length of the n-alcohol [D. Brus, A. P. Hyvarinen, J. Wedekind, Y. Viisanen, M. Kulmala, V. Zdimal, J. Smolik, and H. Lihavainen, J. Chem. Phys. 128, 134312 (2008)] and might be less intensive for substances in the homologous series with higher equilibrium vapor pressure. A comparison with the theoretical approach by Wedekind et al. [Phys. Rev. Lett. 101, 12 (2008)] shows that the effect goes in the same direction but that the intensity is much stronger in experiments than in theory. PMID- 24811636 TI - Pairing and unpairing electron densities in organic systems: two-electron three center through space and through bonds interactions. AB - Two-electron three-center bonding interactions in organic ions like methonium (CH5(+)), ethonium (C2H7(+)), and protonated alkanes n - C4H11(+) isomers (butonium cations) are described and characterized within the theoretical framework of the topological analysis of the electron density decomposition into its effectively paired and unpaired contributions. These interactions manifest in some of this type of systems as a concentration of unpaired electron cloud around the bond paths, in contrast to the well known paradigmatic boron hydrids in which it is not only concentrated close to the atomic nucleus and the bond paths but out of them and over the region defined by the involved atoms as a whole. This result permits to propose an attempt of classification for these interactions based in such manifestations. In the first type, it is called as interactions through bonds and in the second type as interactions through space type. PMID- 24811637 TI - Accounting for conformational flexibility and torsional anharmonicity in the H + CH3CH2OH hydrogen abstraction reactions: a multi-path variational transition state theory study. AB - This work reports a detailed theoretical study of the hydrogen abstraction reactions from ethanol by atomic hydrogen. The calculated thermal rate constants take into account torsional anharmonicity and conformational flexibility, in addition to the variational and tunneling effects. Specifically, the kinetics calculations were performed by using multi-path canonical variational transition state theory with least-action path tunneling corrections, to which we have added the two-dimensional non-separable method to take into account torsional anharmonicity. The multi-path thermal rate constant is expressed as a sum over conformational reaction channels. Each of these channels includes all the transition states that can be reached by internal rotations. The results show that, in the interval of temperatures between 250 and 2500 K, the account for multiple paths leads to higher thermal rate constants with respect to the single path approach, mainly at low and at high temperatures. In addition, torsional anharmonicity enhances the slope of the Arrhenius plot in this range of temperatures. Finally, we show that the incorporation of tunneling into the hydrogen abstraction reactions substantially changes the contribution of each of the transition states to the conformational reaction channel. PMID- 24811638 TI - Titanium embedded cage structure formation in Al(n)Ti+ clusters and their interaction with Ar. AB - Recently, Ar physisorption was used as a structural probe for the location of the Ti dopant atom in aluminium cluster cations, Al(n)Ti(+) [Lang et al., J. Am. Soc. Mass Spectrom. 22, 1508 (2011)]. As an experiment result, the lack of Ar complexes for n > nc determines the cluster size for which the Ti atom is located inside of an Al cage. To elucidate the decisive factors for the formation of endohedrally Al(n)Ti(+), experimentalists proposed detailed computational studies as indispensable. In this work, we investigated, using the density functional theory, the structural and electronic properties of singly titanium doped cationic clusters, Al(n)Ti(+) (n = 16-21) as well as the adsorption of an Ar atom on them. The first endohedral doped cluster, with Ti encapsulated in a fcc-like cage skeleton, appears at nc = 21, which is the critical number consistent with the exohedral-endohedral transition experimentally observed. At this critical size the non-crystalline icosahedral growth pattern, related to the pure aluminium clusters, with the Ti atom in the surface, changes into a endohedral fcc-like pattern. The map of structural isomers, relative energy differences, second energy differences, and structural parameters were determined and analyzed. Moreover, we show the critical size depends on the net charge of the cluster, being different for the cationic clusters (nc = 21) and their neutral counterparts (nc = 20). For the Al(n)Ti(+) . Ar complexes, and for n < 21, the preferred Ar adsorption site is on top of the exohedral Ti atom, with adsorption energy in very good agreement with the experimental value. Instead, for n = 21, the Ar adsorption occurs on the top an Al atom with very low absorption energy. For all sizes the geometry of the Al(n)Ti(+) clusters keeps unaltered in the Ar cluster complexes. This fact indicates that Ar adsorption does not influence the cluster structure, providing support to the experimental technique used. For nc = 21, the smallest size of endohedral Ti doped cationic clusters, the Ar binding energy decreases drastically, whereas the Ar-cluster distance increases substantially, point to Ar physisorption, as assumed by the experimentalists. Calculated Ar adsorption energies agree well with available experimental binding energies. PMID- 24811639 TI - Ionization photophysics and spectroscopy of cyanoacetylene. AB - Photoionization of cyanoacetylene was studied using synchrotron radiation over the non-dissociative ionization excitation range 11-15.6 eV, with photoelectron photoion coincidence techniques. The absolute ionization cross-section and spectroscopic aspects of the parent ion were recorded. The adiabatic ionization energy of cyanoacetylene was measured as 11.573 +/- 0.010 eV. A detailed analysis of photoelectron spectra of HC3N involves new aspects and new assignments of the vibrational components to excitation of the A(2)Sigma(+) and B(2)Pi states of the cation. Some of the structured autoionization features observed in the 11.94 to 15.5 eV region of the total ion yield (TIY) spectrum were assigned to two Rydberg series converging to the B(2)Pi state of HC3N(+). A number of the measured TIY features are suggested to be vibrational components of Rydberg series converging to the C(2)Sigma(+) state of HC3N(+) at ~17.6 eV and others to valence shell transitions of cyanoacetylene in the 11.6-15 eV region. The results of quantum chemical calculations of the cation electronic state geometries, vibrational frequencies and energies, as well as of the C-H dissociation potential energy profiles of the ground and electronic excited states of the ion, are compared with experimental observations. Ionization quantum yields are evaluated and discussed and the problem of adequate calibration of photoionization cross sections is raised. PMID- 24811640 TI - Structure and dynamics of TIP3P, TIP4P, and TIP5P water near smooth and atomistic walls of different hydroaffinity. AB - We perform molecular dynamics simulations to observe the structure and dynamics of water using different water models (TIP3P, TIP4P, TIP5P) at ambient conditions, constrained by planar walls, which are either modeled by smooth potentials or regular atomic lattices, imitating the honeycomb-structure of graphene. We implement walls of different hydroaffinity, different lattice constant, and different types of interaction with the water molecules. We find that in the hydrophobic regime the smooth wall generally represents a good abstraction of the atomically rough walls, while in the hydrophilic regime there are noticeable differences in structure and dynamics between all stages of wall roughness. For a small lattice constant however the smooth and the atomically rough wall still share a number of structural and dynamical similarities. Out of the three water models, TIP5P water shows the largest degree of tetrahedral ordering and is often the one that is least perturbed by the presence of the wall. PMID- 24811641 TI - Deducting the temperature dependence of the structural relaxation time in equilibrium far below the nominal Tg by aging the decoupled conductivity relaxation to equilibrium. AB - Using broadband dielectric spectroscopy we investigate the changes in the conductivity relaxation times tausigma observed during the physical aging of the protic ionic conductor carvedilol dihydrogen phosphate (CP). Due to the large decoupling of ion diffusion from host molecule reorientation, the ion conductivity relaxation time tausigma(Tage,tage) can be directly measured at temperatures Tage below Tg for exceedingly long aging times tage till tausigma(Tage,tage) has reached the equilibrium value tausigma(eq)(Tage). The dependence of tausigma(Tage,tage) on tage is well described by the stretched exponential function, tausigma(Tage, tage) = Aexp[-((tage)/(tauage(Tage)))(beta)] + tausigma(eq)(Tage), where beta is a constant and tauage(Tage) can be taken as the structural alpha-relaxation time of the equilibrium liquid at T = Tage. The value of tausigma(eq)(Tage) obtained after 63 days long annealing of CP, deviates from the Vogel-Fulcher-Tammann-Hesse (VFTHsigma) dependence of tausigma(T) determined from data taken above Tg and extrapolated down to Tage. Concurrently, tauage(Tage) also deviates from the Vogel-Fulcher-Tammann-Hesse (VFTHalpha) dependence. The results help to answer the longstanding question of whether the VFTH dependence of tausigma(T) as well as the structural alpha-relaxation time taualpha(T) holds or not in the equilibrium liquid state far below Tg. PMID- 24811642 TI - The inherent dynamics of a molecular liquid: geodesic pathways through the potential energy landscape of a liquid of linear molecules. AB - Because the geodesic pathways that a liquid follows through its potential energy landscape govern its slow, diffusive motion, we suggest that these pathways are logical candidates for the title of a liquid's "inherent dynamics." Like their namesake "inherent structures," these objects are simply features of the system's potential energy surface and thus provide views of the system's structural evolution unobstructed by thermal kinetic energy. This paper shows how these geodesic pathways can be computed for a liquid of linear molecules, allowing us to see precisely how such molecular liquids mix rotational and translational degrees of freedom into their dynamics. The ratio of translational to rotational components of the geodesic path lengths, for example, is significantly larger than would be expected on equipartition grounds, with a value that scales with the molecular aspect ratio. These and other features of the geodesics are consistent with a picture in which molecular reorientation adiabatically follows translation-molecules largely thread their way through narrow channels available in the potential energy landscape. PMID- 24811643 TI - 1H relaxation enhancement induced by nanoparticles in solutions: influence of magnetic properties and diffusion. AB - Magnetic nanoparticles that induce nuclear relaxation are the most promising materials to enhance the sensitivity in Magnetic Resonance Imaging. In order to provide a comprehensive understanding of the magnetic field dependence of the relaxation enhancement in solutions, Nuclear Magnetic Resonance (1)H spin-lattice relaxation for decalin and toluene solutions of various Fe2O3 nanoparticles was investigated. The relaxation experiments were performed in a frequency range of 10 kHz-20 MHz by applying Field Cycling method, and in the temperature range of 257-298 K, using nanoparticles differing in size and shape: spherical--5 nm diameter, cubic--6.5 nm diameter, and cubic--9 nm diameter. The relaxation dispersion data were interpreted in terms of a theory of nuclear relaxation induced by magnetic crystals in solution. The approach was tested with respect to its applicability depending on the magnetic characteristics of the nanocrystals and the time-scale of translational diffusion of the solvent. The role of Curie relaxation and the contributions to the overall (1)H spin-lattice relaxation associated with the electronic spin-lattice and spin-spin relaxation was thoroughly discussed. It was demonstrated that the approach leads to consistent results providing information on the magnetic (electronic) properties of the nanocrystals, i.e., effective electron spin and relaxation times. In addition, features of the (1)H spin-lattice relaxation resulting from the electronic properties of the crystals and the solvent diffusion were explained. PMID- 24811644 TI - Hardness of FeB4: density functional theory investigation. AB - A recent experimental study reported the successful synthesis of an orthorhombic FeB4 with a high hardness of 62(5) GPa [H. Gou et al., Phys. Rev. Lett. 111, 157002 (2013)], which has reignited extensive interests on whether transition metal borides compounds will become superhard materials. However, it is contradicted with some theoretical studies suggesting transition-metal boron compounds are unlikely to become superhard materials. Here, we examined structural and electronic properties of FeB4 using density functional theory. The electronic calculations show the good metallicity and covalent Fe-B bonding. Meanwhile, we extensively investigated stress-strain relations of FeB4 under various tensile and shear loading directions. The calculated weakest tensile and shear stresses are 40 GPa and 25 GPa, respectively. Further simulations (e.g., electron localization function and bond length along the weakest loading direction) on FeB4 show the weak Fe-B bonding is responsible for this low hardness. Moreover, these results are consistent with the value of Vickers hardness (11.7-32.3 GPa) by employing different empirical hardness models and below the superhardness threshold of 40 GPa. Our current results suggest FeB4 is a hard material and unlikely to become superhard (>40 GPa). PMID- 24811645 TI - Photoelectron spectroscopy of aqueous solutions: streaming potentials of NaX (X = Cl, Br, and I) solutions and electron binding energies of liquid water and X-. AB - The streaming potentials of liquid beams of aqueous NaCl, NaBr, and NaI solutions are measured using soft X-ray, He(I), and laser multiphoton ionization photoelectron spectroscopy. Gaseous molecules are ionized in the vicinity of liquid beams and the photoelectron energy shifts are measured as a function of the distance between the ionization point and the liquid beam. The streaming potentials change their polarity with concentration of electrolytes, from which the singular points of concentration eliminating the streaming potentials are determined. The streaming currents measured in air also vanish at these concentrations. The electron binding energies of liquid water and I(-), Br(-), and Cl(-) anions are revisited and determined more accurately than in previous studies. PMID- 24811646 TI - Second-order many-body perturbation and coupled-cluster singles and doubles study of ice VIII. AB - The structure, equation of state, IR, Raman, and inelastic neutron scattering (INS) spectra of high-pressure, proton-ordered phase VIII of ice are calculated by the second-order many-body perturbation and coupled-cluster singles and doubles methods. Nearly all the observed features of the pressure-dependence of the structures and spectra are reproduced computationally up to 60 GPa insofar as the anharmonic effects can be neglected. The calculations display no sign of the hypothetical isostructural transition in 2-3 GPa to phase VIII('), the existence of which has been a matter of controversy for over a decade, while they do not contradict the interpretation of the spectral anomaly at 10-14 GPa as a precursor of the VIII-X phase transition. The calculated INS spectra correct a systematic error in the peak positions of the observed spectra. PMID- 24811647 TI - Effect of quantum nuclear motion on hydrogen bonding. AB - This work considers how the properties of hydrogen bonded complexes, X-H?Y, are modified by the quantum motion of the shared proton. Using a simple two-diabatic state model Hamiltonian, the analysis of the symmetric case, where the donor (X) and acceptor (Y) have the same proton affinity, is carried out. For quantitative comparisons, a parametrization specific to the O-H?O complexes is used. The vibrational energy levels of the one-dimensional ground state adiabatic potential of the model are used to make quantitative comparisons with a vast body of condensed phase data, spanning a donor-acceptor separation (R) range of about 2.4 3.0 A, i.e., from strong to weak hydrogen bonds. The position of the proton (which determines the X-H bond length) and its longitudinal vibrational frequency, along with the isotope effects in both are described quantitatively. An analysis of the secondary geometric isotope effect, using a simple extension of the two-state model, yields an improved agreement of the predicted variation with R of frequency isotope effects. The role of bending modes is also considered: their quantum effects compete with those of the stretching mode for weak to moderate H-bond strengths. In spite of the economy in the parametrization of the model used, it offers key insights into the defining features of H-bonds, and semi-quantitatively captures several trends. PMID- 24811648 TI - Terahertz spectroscopy and solid-state density functional theory calculation of anthracene: effect of dispersion force on the vibrational modes. AB - The phonon modes of molecular crystals in the terahertz frequency region often feature delicately coupled inter- and intra-molecular vibrations. Recent advances in density functional theory such as DFT-D(*) have enabled accurate frequency calculation. However, the nature of normal modes has not been quantitatively discussed against experimental criteria such as isotope shift (IS) and correlation field splitting (CFS). Here, we report an analytical mode-decoupling method that allows for the decomposition of a normal mode of interest into intermolecular translation, libration, and intramolecular vibrational motions. We show an application of this method using the crystalline anthracene system as an example. The relationship between the experimentally obtained IS and the IS obtained by PBE-D(*) simulation indicates that two distinctive regions exist. Region I is associated with a pure intermolecular translation, whereas region II features coupled intramolecular vibrations that are further coupled by a weak intermolecular translation. We find that the PBE-D(*) data show excellent agreement with the experimental data in terms of IS and CFS in region II; however, PBE-D(*) produces significant deviations in IS in region I where strong coupling between inter- and intra-molecular vibrations contributes to normal modes. The result of this analysis is expected to facilitate future improvement of DFT-D(*). PMID- 24811649 TI - Polyelectrolyte adsorption onto like-charged surfaces mediated by trivalent counterions: a Monte Carlo simulation study. AB - Both experiments and theory have evidenced that multivalent cations can mediate the interaction between negatively charged polyelectrolytes and like-charged objects, such as anionic lipoplexes (DNA-cation-anionic liposome complexes). In this paper, we use Monte Carlo simulations to study the electrostatic interaction responsible for the trivalent-counterion-mediated adsorption of polyelectrolytes onto a like-charged planar surface. The evaluation of the Helmholtz free energy allows us to characterize both the magnitude and the range of the interaction as a function of the polyelectrolyte charge, surface charge density, [3:1] electrolyte concentration, and cation size. Both polyelectrolyte and surface charge favor the adsorption. It should be stressed, however, that the adsorption will be negligible if the surface charge density does not exceed a threshold value. The effect of the [3:1] electrolyte concentration has also been analyzed. In certain range of concentrations, the counterion-mediated attraction seems to be independent of this parameter, whereas very high concentrations of salt weaken the adsorption. If the trivalent cation diameter is doubled the adsorption moderates due to the excluded volume effects. The analysis of the integrated charge density and ionic distributions suggests that a delicate balance between charge inversion and screening effects governs the polyelectrolyte adsorption onto like-charged surfaces mediated by trivalent cations. PMID- 24811650 TI - Site-dependent charge transfer at the Pt(111)-ZnPc interface and the effect of iodine. AB - The electronic structure of ZnPc, from sub-monolayers to thick films, on bare and iodated Pt(111) is studied by means of X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and scanning tunneling microscopy. Our results suggest that at low coverage ZnPc lies almost parallel to the Pt(111) substrate, in a non planar configuration induced by Zn-Pt attraction, leading to an inhomogeneous charge distribution within the molecule and an inhomogeneous charge transfer to the molecule. ZnPc does not form a complete monolayer on the Pt surface, due to a surface-mediated intermolecular repulsion. At higher coverage ZnPc adopts a tilted geometry, due to a reduced molecule-substrate interaction. Our photoemission results illustrate that ZnPc is practically decoupled from Pt, already from the second layer. Pre-deposition of iodine on Pt hinders the Zn-Pt attraction, leading to a non-distorted first layer ZnPc in contact with Pt(111) I(?3*?3) or Pt(111)-I(?7*?7), and a more homogeneous charge distribution and charge transfer at the interface. On increased ZnPc thickness iodine is dissolved in the organic film where it acts as an electron acceptor dopant. PMID- 24811651 TI - Benchmarking the performance of density functional theory and point charge force fields in their description of sI methane hydrate against diffusion Monte Carlo. AB - High quality reference data from diffusion Monte Carlo calculations are presented for bulk sI methane hydrate, a complex crystal exhibiting both hydrogen-bond and dispersion dominated interactions. The performance of some commonly used exchange correlation functionals and all-atom point charge force fields is evaluated. Our results show that none of the exchange-correlation functionals tested are sufficient to describe both the energetics and the structure of methane hydrate accurately, while the point charge force fields perform badly in their description of the cohesive energy but fair well for the dissociation energetics. By comparing to ice Ih, we show that a good prediction of the volume and cohesive energies for the hydrate relies primarily on an accurate description of the hydrogen bonded water framework, but that to correctly predict stability of the hydrate with respect to dissociation to ice Ih and methane gas, accuracy in the water-methane interaction is also required. Our results highlight the difficulty that density functional theory faces in describing both the hydrogen bonded water framework and the dispersion bound methane. PMID- 24811652 TI - Water adsorption and dissociation on Ni(110): how is it different from its close packed counterparts? AB - Water adsorption and dissociation on Ni(110) surface is studied in detail and compared with its close packed counterparts using density functional theory calculations. Water adsorption occurs on the top site as found on Ni(100) and Ni(111) but the adsorption is stronger on Ni(110). H and OH preferably adsorb on the short bridge sites (brgshort) opposed to hollow sites on (100) and (111) surfaces. Energy barriers for water molecule dissociation on Ni(110) as obtained from the transition state (TS) calculations were low compared to other Ni low indexed surfaces. TS geometries at different positions of the lattice coordinate, Q, were obtained to study the effect of surface temperature on dissociation of H2O molecules. These calculations revealed that second layer atoms were also involved in the TS. Dissociation probabilities are obtained using a semi classical approximation by sampling Q for a Boltzmann distribution at different temperatures. Results showed that the increasing surface temperature significantly increases the dissociation probabilities at lower energies and saturates near the barrier for dissociation. Although the contribution from both top and second layers is similar at low surface temperatures, motion of top layer atoms contribute more towards dissociation probability at higher surface temperatures. Dissociation probabilities obtained are more than one order of magnitude higher than that on Ni(100) and Ni(111) surfaces suggesting Ni(110) to be more reactive among the low indexed Ni surfaces. PMID- 24811653 TI - Band structure engineering of anatase TiO2 by metal-assisted P-O coupling. AB - In this work, we demonstrate that the metal-assisted P-O coupling is an effective approach to improve the photoelectrochemical properties of TiO2. The (Sc + P) and (In + P) codoping effects on electronic structures and photocatalytic activities of anatase TiO2 are examined by performing hybrid density functional theory calculations. It is found that the coupling of P dopant with the second-nearest neighboring O atom assisted by acceptor metals (Sc/In) leads to the fully occupied and delocalized intermediate bands within the band gap of anatase TiO2, which is driven by the P-O antibonding states (pi*). This metal-assisted P-O coupling can prevent the recombination of photogenerated electron-hole pairs and effectively reduce the band gap of TiO2. Moreover, the band edge alignments in (Sc + P) and (In + P) codoped anatase TiO2 are desirable for water-splitting. The calculated optical absorption curves indicate that (Sc + P) and (In + P) codoping in anatase TiO2 can also effectively enhance the visible light absorption. PMID- 24811654 TI - The structure and properties of a simple model mixture of amphiphilic molecules and ions at a solid surface. AB - We investigate microscopic structure, adsorption, and electric properties of a mixture that consists of amphiphilic molecules and charged hard spheres in contact with uncharged or charged solid surfaces. The amphiphilic molecules are modeled as spheres composed of attractive and repulsive parts. The electrolyte component of the mixture is considered in the framework of the restricted primitive model (RPM). The system is studied using a density functional theory that combines fundamental measure theory for hard sphere mixtures, weighted density approach for inhomogeneous charged hard spheres, and a mean-field approximation to describe anisotropic interactions. Our principal focus is in exploring the effects brought by the presence of ions on the distribution of amphiphilic particles at the wall, as well as the effects of amphiphilic molecules on the electric double layer formed at solid surface. In particular, we have found that under certain thermodynamic conditions a long-range translational and orientational order can develop. The presence of amphiphiles produces changes of the shape of the differential capacitance from symmetric or non-symmetric bell like to camel-like. Moreover, for some systems the value of the potential of the zero charge is non-zero, in contrast to the RPM at a charged surface. PMID- 24811655 TI - Indirect-direct band gap transition through electric tuning in bilayer MoS2. AB - We investigate the electronic properties of bilayer MoS2 exposed to an external electric field by using first-principles calculations. It is found that a larger interlayer distance, referring to that by standard density functional theory (DFT) with respect to that by DFT with empirical dispersion corrections, makes indirect-direct band gap transition possible by electric control. We show that external electric field effectively manipulates the valence band contrast between the K- and Gamma-valleys by forming built-in electric dipole fields, which realizes an indirect-direct transition before a semiconductor-metal transition happens. Our results provide a novel efficient access to tune the electronic properties of two-dimensional layered materials. PMID- 24811656 TI - Physical origins of weak H2 binding on carbon nanostructures: insight from ab initio studies of chemically functionalized graphene nanoribbons. AB - We have performed ab initio density functional theory calculations, incorporating London dispersion corrections, to study the absorption of molecular hydrogen on zigzag graphene nanoribbons whose edges have been functionalized by OH, NH2, COOH, NO2, or H2PO3. We find that hydrogen molecules always preferentially bind at or near the functionalized edge, and display induced dipole moments. Binding is generally enhanced by the presence of polar functional groups. The largest gains are observed for groups with oxygen lone pairs that can facilitate local charge reorganization, with the biggest single enhancement in adsorption energy found for "strong functionalization" by H2PO3 (115 meV/H2 versus 52 meV/H2 on bare graphene). We show that for binding on the "outer edge" near the functional group, the presence of the group can introduce appreciable contributions from Debye interactions and higher-order multipole electrostatic terms, in addition to the dominant London dispersion interactions. For those functional groups that contain the OH moiety, the adsorption energy is linearly proportional to the number of lone pairs on oxygen atoms. Mixed functionalization with two different functional groups on a graphene edge can also have a synergistic effect, particularly when electron-donating and electron-withdrawing groups are combined. For binding on the "inner edge" somewhat farther from the functional group, most of the binding again arises from London interactions; however, there is also significant charge redistribution in the pi manifold, which directly reflects the electron donating or withdrawing capacity of the functional group. Our results offer insight into the specific origins of weak binding of gas molecules on graphene, and suggest that edge functionalization could perhaps be used in combination with other strategies to increase the uptake of hydrogen in graphene. They also have relevance for the storage of hydrogen in porous carbon materials, such as activated carbons. PMID- 24811657 TI - The DFT+Umol method and its application to the adsorption of CO on platinum model clusters. AB - Semi-local DFT approximations are well-known for their difficulty with describing the correct site preference for the adsorption of CO molecules on (111) surfaces of several late transition metals. To address this problem originating from a residual self-interaction in the CO LUMO, we present the DFT+Umol approach which generalizes the empirical DFT+U correction to fragment molecular orbitals. This correction is applied to examine CO adsorption energies at various sites on the (111) facets of cuboctahedral clusters Ptm(CO)8 (m = 79, 140, 225). The DFT+Umol correction leaves the electronic ground state of metal clusters, in particular their d-band structure, essentially unchanged, affecting almost exclusively the energy of the CO LUMO. As a result, that correction is significantly stronger for complexes at hollow sites, hence increases the propensity for adsorption at top sites. We also analyze competing edge effects on the (111) facets of the cluster models. PMID- 24811658 TI - Crystalline and quasicrystalline allotropes of Pb formed on the fivefold surface of icosahedral Ag-In-Yb. AB - Crystalline and quasicrystalline allotropes of Pb are formed by evaporation on the fivefold surface of the icosahedral (i) Ag-In-Yb quasicrystal under ultra high vacuum. Lead grows in three dimensional quasicrystalline order and subsequently forms fivefold-twinned islands with the fcc(111) surface orientation atop of the quasicrystalline Pb. The islands exhibit specific heights (magic heights), possibly due to the confinement of electrons in the islands. We also study the adsorption behavior of C60 on the two allotropes of Pb. Scanning tunneling microcopy reveals that a high corrugation of the quasicrystalline Pb limits the diffusion of the C60 molecules and thus produces a disordered film, similar to adsorption behavior of the same molecules on the clean substrate surface. However, the sticking coefficient of C60 molecules atop the Pb islands approaches zero, regardless of the overall C60 coverage. PMID- 24811659 TI - Thermoelectric performance of various benzo-difuran wires. AB - Using a first principles approach to electron transport, we calculate the electrical and thermoelectrical transport properties of a series of molecular wires containing benzo-difuran subunits. We demonstrate that the side groups introduce Fano resonances, the energy of which is changing with the electronegativity of selected atoms in it. We also study the relative effect of single, double, or triple bonds along the molecular backbone and find that single bonds yield the highest thermopower, approximately 22 MUV/K at room temperature, which is comparable with the highest measured values for single-molecule thermopower reported to date. PMID- 24811660 TI - The metallization and superconductivity of dense hydrogen sulfide. AB - Hydrogen sulfide (H2S) is a prototype molecular system and a sister molecule of water (H2O). The phase diagram of solid H2S at high pressures remains largely unexplored arising from the challenges in dealing with the pressure-induced weakening of S-H bond and larger atomic core difference between H and S. Metallization is yet achieved for H2O, but it was observed for H2S above 96 GPa. However, the metallic structure of H2S remains elusive, greatly impeding the understanding of its metallicity and the potential superconductivity. We have performed an extensive structural study on solid H2S at pressure ranges of 10-200 GPa through an unbiased structure prediction method based on particle swarm optimization algorithm. Besides the findings of candidate structures for nonmetallic phases IV and V, we are able to establish stable metallic structures violating an earlier proposal of elemental decomposition into sulfur and hydrogen [R. Rousseau, M. Boero, M. Bernasconi, M. Parrinello, and K. Terakura, Phys. Rev. Lett. 85, 1254 (2000)]. Our study unravels a superconductive potential of metallic H2S with an estimated maximal transition temperature of ~80 K at 160 GPa, higher than those predicted for most archetypal hydrogen-containing compounds (e.g., SiH4, GeH4, etc.). PMID- 24811661 TI - Order of wetting transitions in electrolyte solutions. AB - For wetting films in dilute electrolyte solutions close to charged walls we present analytic expressions for their effective interface potentials. The analysis of these expressions renders the conditions under which corresponding wetting transitions can be first- or second-order. Within mean field theory we consider two models, one with short- and one with long-ranged solvent-solvent and solvent-wall interactions. The analytic results reveal in a transparent way that wetting transitions in electrolyte solutions, which occur far away from their critical point (i.e., the bulk correlation length is less than half of the Debye length) are always first-order if the solvent-solvent and solvent-wall interactions are short-ranged. In contrast, wetting transitions close to the bulk critical point of the solvent (i.e., the bulk correlation length is larger than the Debye length) exhibit the same wetting behavior as the pure, i.e., salt-free, solvent. If the salt-free solvent is governed by long-ranged solvent-solvent as well as long-ranged solvent-wall interactions and exhibits critical wetting, adding salt can cause the occurrence of an ion-induced first-order thin-thick transition which precedes the subsequent continuous wetting as for the salt-free solvent. PMID- 24811662 TI - Multi-component modeling of quasielastic neutron scattering from phospholipid membranes. AB - We investigated molecular motions in the 0.3-350 ps time range of D2O-hydrated bilayers of 1-palmitoyl-oleoyl-sn-glycero-phosphocholine and 1,2-dimyristoyl-sn glycero-phosphocholine in the liquid phase by quasielastic neutron scattering. Model analysis of sets of spectra covering scale lengths from 4.8 to 30 A revealed the presence of three types of motion taking place on well-separated time scales: (i) slow diffusion of the whole phospholipid molecules in a confined cylindrical region; (ii) conformational motion of the phospholipid chains; and (iii) fast uniaxial rotation of the hydrogen atoms around their carbon atoms. Based on theoretical models for the hydrogen dynamics in phospholipids, the spatial extent of these motions was analysed in detail and the results were compared with existing literature data. The complex dynamics of protons was described in terms of elemental dynamical processes involving different parts of the phospholipid chain on whose motions the hydrogen atoms ride. PMID- 24811663 TI - Shear thinning behavior of linear polymer melts under shear flow via nonequilibrium molecular dynamics. AB - The properties of both untangled and entangled linear polymer melts under shear flow are studied by nonequilibrium molecular dynamics simulations. The results reveal that the dependence of shear viscosity eta on shear rate gamma, expressed by n ~ gamma(-n), exhibits three distinct regimes. The first is the well-known Newtonian regime, namely, eta independent of shear rate at small shear rates gamma < tau0(-1) (where tau0 is the longest polymer relaxation time at equilibrium). In the non-Newtonian regime (gamma > tau0(-1)) the shear dependence of viscosity exhibits a crossover at a critical shear rate gammac dividing this regime into two different regimes, shear thinning regime I (ST-I) and II (ST-II), respectively. In the ST-I regime (tau0(-1) < gamma < gammac), the exponent n increases with increasing chain length N, while in the ST-II regime (gamma > gammac) a universal power law n ~ gamma(-0.37) is found for considered chain lengths. Furthermore, the longer the polymer chain is, the smaller the shear viscosity for a given shear rate in the ST-II regime. The simulation also shows that a characteristic chain length, below which gammac will be equal to tau0(-1), lies in the interval 30 < N < 50. For all considered chain lengths in the ST-II regime, we also find that the first and second normal stress differences N1 and N2 follow power laws of N1 ~ gamma(2/3) and N2 ~ gamma(0.82), respectively; the orientation resistance parameter mG follows the relation mG ~ gamma(0.75) and the tumbling frequency ftb follows ftb ~ gamma(0.75). These results imply that the effects of entanglement on the shear dependences of these properties may be negligible in the ST-II regime. These findings may shed some light on the nature of shear thinning in flexible linear polymer melts. PMID- 24811664 TI - General model of phospholipid bilayers in fluid phase within the single chain mean field theory. AB - Coarse-grained model for saturated phospholipids: 1,2-didecanoyl-sn-glycero-3 phosphocholine (DCPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and unsaturated phospholipids: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC) is introduced within the single chain mean field theory. A single set of parameters adjusted for DMPC bilayers gives an adequate description of equilibrium and mechanical properties of a range of saturated lipid molecules that differ only in length of their hydrophobic tails and unsaturated (POPC, DOPC) phospholipids which have double bonds in the tails. A double bond is modeled with a fixed angle of 120 degrees , while the rest of the parameters are kept the same as saturated lipids. The thickness of the bilayer and its hydrophobic core, the compressibility, and the equilibrium area per lipid correspond to experimentally measured values for each lipid, changing linearly with the length of the tail. The model for unsaturated phospholipids also fetches main thermodynamical properties of the bilayers. This model is used for an accurate estimation of the free energies of the compressed or stretched bilayers in stacks or multilayers and gives reasonable estimates for free energies. The proposed model may further be used for studies of mixtures of lipids, small molecule inclusions, interactions of bilayers with embedded proteins. PMID- 24811665 TI - Fragmentation of the adenine and guanine molecules induced by electron collisions. AB - Secondary electron emission is the most important stage in the mechanism of radiation damage to DNA biopolymers induced by primary ionizing radiation. These secondary electrons ejected by the primary electron impacts can produce further ionizations, initiating an avalanche effect, leading to genome damage through the energy transfer from the primary objects to sensitive biomolecular targets, such as nitrogenous bases, saccharides, and other DNA and peptide components. In this work, the formation of positive and negative ions of purine bases of nucleic acids (adenine and guanine molecules) under the impact of slow electrons (from 0.1 till 200 eV) is studied by the crossed electron and molecular beams technique. The method used makes it possible to measure the molecular beam intensity and determine the total cross-sections for the formation of positive and negative ions of the studied molecules, their energy dependences, and absolute values. It is found that the maximum cross section for formation of the adenine and guanine positive ions is reached at about 90 eV energy of the electron beam and their absolute values are equal to 2.8 * 10(-15) and 3.2 * 10( 15) cm(2), respectively. The total cross section for formation of the negative ions is 6.1 * 10(-18) and 7.6 * 10(-18) cm(2) at the energy of 1.1 eV for adenine and guanine, respectively. The absolute cross-section values for the molecular ions are measured and the cross-sections of dissociative ionization are determined. Quantum chemical calculations are performed for the studied molecules, ions and fragments for interpretation of the crossed beams experiments. PMID- 24811666 TI - Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model. AB - Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an "induced fit" or "conformational selection" mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD. PMID- 24811668 TI - Sequence-dependent theory of oligonucleotide hybridization kinetics. AB - A theoretical approach to the prediction of the sequence and temperature dependent rate constants for oligonucleotide hybridization reactions has been developed based on the theory of relaxation kinetics. One-sided and two-sided melting reaction mechanisms for oligonucleotide hybridization reactions have been considered, analyzed, modified, and compared to select a physically consistent as well as robust model for prediction of the relaxation times of DNA hybridization reactions that agrees with the experimental evidence. The temperature- and sequence-dependent parameters of the proposed model have been estimated using available experimental data. The relaxation time model that we developed has been combined with the nearest neighbor model of hybridization thermodynamics to estimate the temperature- and sequence-dependent rate constants of an oligonucleotide hybridization reaction. The model-predicted rate constants are compared to experimentally determined rate constants for the same oligonucleotide hybridization reactions. Finally, we consider a few important applications of kinetically controlled DNA hybridization reactions. PMID- 24811669 TI - Comment on "Fermi resonance in solid CO2 under pressure" [J. Chem. Phys. 138, 074501 (2013)]. AB - The purpose of this comment is to point out that for a really rigorous treatment of the Fermi resonance in crystalline CO2 it is necessary to go beyond a single molecule approach and to fully consider solid state effects. PMID- 24811670 TI - Response to "Comment on 'Fermi resonance in solid CO2 under pressure'" [J. Chem. Phys. 140, 177101 (2014)]. PMID- 24811667 TI - Investigations of alpha-helix<->beta-sheet transition pathways in a miniprotein using the finite-temperature string method. AB - A parallel implementation of the finite-temperature string method is described, which takes into account the invariance of coordinates with respect to rigid-body motions. The method is applied to the complex alpha-helix<->beta-sheet transition in a beta-hairpin miniprotein in implicit solvent, which exhibits much of the complexity of conformational changes in proteins. Two transition paths are considered, one derived from a linear interpolant between the endpoint structures and the other derived from a targeted dynamics simulation. Two methods for computing the conformational free energy (FE) along the string are compared, a restrained method, and a tessellation method introduced by E. Vanden-Eijnden and M. Venturoli [J. Chem. Phys. 130, 194103 (2009)]. It is found that obtaining meaningful free energy profiles using the present atom-based coordinates requires restricting sampling to a vicinity of the converged path, where the hyperplanar approximation to the isocommittor surface is sufficiently accurate. This sampling restriction can be easily achieved using restraints or constraints. The endpoint FE differences computed from the FE profiles are validated by comparison with previous calculations using a path-independent confinement method. The FE profiles are decomposed into the enthalpic and entropic contributions, and it is shown that the entropy difference contribution can be as large as 10 kcal/mol for intermediate regions along the path, compared to 15-20 kcal/mol for the enthalpy contribution. This result demonstrates that enthalpic barriers for transitions are offset by entropic contributions arising from the existence of different paths across a barrier. The possibility of using systematically coarse-grained representations of amino acids, in the spirit of multiple interaction site residue models, is proposed as a means to avoid ad hoc sampling restrictions to narrow transition tubes. PMID- 24811671 TI - Comment on "Rethinking first-principles electron transport theories with projection operators: the problems caused by partitioning the basis set" [J. Chem. Phys. 139, 114104 (2013)]. AB - In a recent paper Reuter and Harrison [J. Chem. Phys. 139, 114104 (2013)] question the widely used mean-field electron transport theories, which employ nonorthogonal localized basis sets. They claim these can violate an "implicit decoupling assumption," leading to wrong results for the current, different from what would be obtained by using an orthogonal basis, and dividing surfaces defined in real-space. We argue that this assumption is not required to be fulfilled to get exact results. We show how the current/transmission calculated by the standard Greens function method is independent of whether or not the chosen basis set is nonorthogonal, and that the current for a given basis set is consistent with divisions in real space. The ambiguity known from charge population analysis for nonorthogonal bases does not carry over to calculations of charge flux. PMID- 24811672 TI - Response to "Comment on 'Rethinking first-principles electron transport theories with projection operators: the problems caused by partitioning the basis set'" [J. Chem. Phys. 140, 177103 (2014)]. AB - The thesis of Brandbyge's comment [J. Chem. Phys. 140, 177103 (2014)] is that our operator decoupling condition is immaterial to transport theories, and it appeals to discussions of nonorthogonal basis sets in transport calculations in its arguments. We maintain that the operator condition is to be preferred over the usual matrix conditions and subsequently detail problems in the existing approaches. From this operator perspective, we conclude that nonorthogonal projectors cannot be used and that the projectors must be selected to satisfy the operator decoupling condition. Because these conclusions pertain to operators, the choice of basis set is not germane. PMID- 24811674 TI - Quantum strain sensor with a topological insulator HgTe quantum dot. AB - We present a theory of electronic properties of HgTe quantum dot and propose a strain sensor based on a strain-driven transition from a HgTe quantum dot with inverted bandstructure and robust topologically protected quantum edge states to a normal state without edge states in the energy gap. The presence or absence of edge states leads to large on/off ratio of conductivity across the quantum dot, tunable by adjusting the number of conduction channels in the source-drain voltage window. The electronic properties of a HgTe quantum dot as a function of size and applied strain are described using eight-band k . p Luttinger and Bir Pikus Hamiltonians, with surface states identified with chirality of Luttinger spinors and obtained through extensive numerical diagonalization of the Hamiltonian. PMID- 24811675 TI - Arsenic stress in rice: redox consequences and regulation by iron. AB - Arsenic (As) contamination is a serious hazard to human health and agriculture. It has emerged as an important threat for rice cultivation mainly in South Asian countries. In this study, we investigated the effect of iron (Fe) supplementation on arsenic (As(V)) induced oxidative stress responses in rice (Oryza sativa L.). Rice seedlings treated with As(V) for 24 and 48 h in presence or absence of 2.5 mM Fe after which the root and shoot tissues were harvested for analysis. The results indicate significant (p <= 0.05) reduction in root and shoot length/dry biomass. Supplementation of Fe showed improved growth responses under stress as compared to As(V) alone. The scanning electron microscopy (SEM) analysis of roots under As(V) treatment for 48 h showed major alterations in root structure and integrity, although no noticeable changes were observed in Fe - supplemented seedlings. Significantly high (p <= 0.05) accumulation of As(V) was observed in root and shoot after 24 and 48 h of stress. However, under Fe - supplementation As accumulation in root and shoot were considerably low after 24 and 48 h of As(V) treatment. The hydrogen peroxide (H2O2) and malondialdehyde (MDA) content in both root and shoot increased significantly (p <= 0.05) after 24 and 48 h of As(V) treatment. In Fe - supplemented seedlings, the levels of H2O2 and MDA were considerably low as compared to As(V) alone. Ascorbate (AsA) and glutathione (GSH) levels also increased significantly (p <= 0.05) under As(V) stress as compared to control and Fe-supplemented seedlings. Activities of catalase (CAT) and superoxide dismutase (SOD) were significantly (p <= 0.05) high after 24 and 48 h of As(V) treatment as compared to Fe-supplemented seedlings. The gene expression analysis revealed up-regulation of metallothionein (MT1, MT2) and nodulin 26-like intrinsic protein (NIP2;1) genes after 5d of As treatment, while their expressions were repressed under Fe-supplementation. Our results indicate that Fe regulates oxidative stress and promotes growth under As stress. PMID- 24811676 TI - RING-type ubiquitin ligase McCPN1 catalyzes UBC8-dependent protein ubiquitination and interacts with Argonaute 4 in halophyte ice plant. AB - RING-type copines are a small family of plant-specific RING-type ubiquitin ligases. They contain an N-terminal myristoylation site for membrane anchoring, a central copine domain for substrate recognition, and a C-terminal RING domain for E2 docking. RING-type copine McCPN1 (copine1) from halophyte ice plant (Mesembryanthemum crystallinum L.) was previously identified from a salt-induced cDNA library. In this work, we characterize the activity, expression, and localization of McCPN1 in ice plant. An in vitro ubiquitination assay of McCPN1 was performed using two ice plant UBCs, McUBC1 and McUBC2, characterized from the same salt-induced cDNA library. The results showed that McUBC2, a member of the UBC8 family, stimulated the autoubiquitination activity of McCPN1, while McUBC1, a homolog of the UBC35 family, did not. The results indicate that McCPN1 has selective E2-dependent E3 ligase activity. We found that McCPN1 localizes primarily on the plasma membrane and in the nucleus of plant cells. Under salt stress, the accumulation of McCPN1 in the roots increases. A yeast two-hybrid screen was used to search for potential McCPN1-interacting partners using a library constructed from salt-stressed ice plants. Screening with full-length McCPN1 identified several independent clones containing partial Argonaute 4 (AGO4) sequence. Subsequent agro-infiltration, protoplast two-hybrid analysis, and bimolecular fluorescence complementation assay confirmed that McCPN1 and AGO4 interacted in vivo in the nucleus of plant cells. The possible involvement of a catalyzed degradation of AGO4 by McCPN1 in response to salt stress is discussed. PMID- 24811677 TI - Base substitution mutations in uridinediphosphate-dependent glycosyltransferase 76G1 gene of Stevia rebaudiana causes the low levels of rebaudioside A: mutations in UGT76G1, a key gene of steviol glycosides synthesis. AB - Steviol glycosides, extracted from the leaves of Stevia rebaudiana (Bert) Bertoni, are calorie-free sugar substitute of natural origin with intensely sweet (Boileau et al., 2012). Stevioside and rebaudioside A are the two main kinds of the diterpenic glycosides. We analyzed the concentration of stevioside and rebaudioside A in Stevia leaves of about 500 samples (hybrid progenies) and discovered a mutation plant "Z05" with very low levels of rebaudioside A. Because UGT76G1, a uridinediphosphate-dependent glycosyltransferases, is responsible for the conversion from stevioside to rebaudioside A (Richman et al., 2005), so mutation identification was done by sequencing the candidate gene, UGT76G1. In this study molecular analysis of two strains revealed a heterozygotic nonsense mutation of c.389T > G (p.L121X) in UGT76G1. Meanwhile, we found some amino acid substitutions significant change the protein structure. And the difference of enzyme activity between two strains proved the lack of functionality of UGT76G1 of the mutation "Z05". So the nonsense mutation and amino acid substitution mutation resulted in the low levels of rebaudioside A. PMID- 24811678 TI - Herbivory responsive C2H2 zinc finger transcription factor protein StZFP2 from potato. AB - While C2H2 zinc finger transcription factors (TF) are often regulated by abiotic stress, their role during insect infestation has been overlooked. This study demonstrates that the transcripts of the zinc finger transcription factors StZFP1 and StZFP2 are induced in potato (Solanum tuberosum L.) upon infestation by either the generalist tobacco hornworm (THW, Manduca sexta L.) or the specialist Colorado potato beetle (CPB, Leptinotarsa decemlineata Say). StZFP1 has been previously characterized as conferring salt tolerance to transgenic tobacco and its transcript is induced by Phytophthora infestans and several abiotic stresses. StZFP2 has not been characterized previously, but contains the hallmarks of a C2H2 zinc finger TF, with two conserved zinc finger domains and DLN motif, which encodes a transcriptional repressor domain. Expression studies demonstrate that StZFP2 transcript is also induced by tobacco hornworm and Colorado potato beetle. These observations expand the role of the C2H2 transcription factor in potato to include the response to chewing insect pests. PMID- 24811679 TI - Differential physiological and molecular response of barley genotypes to water deficit. AB - Changes in physiological parameters (relative water content (RWC), biomass, water use efficiency (WUE), net photosynthetic yield (PN) and quantum yield of PSII (Fv/Fm)), in proline and sugar content, and expression profile of genes reported to be associated with the barley response to water deficit, including LEA genes, NHX1, Hsdr4, BLT101 and genes encoding transcription factors (HvDREB1, HvABF1, HvABI5 and HvZIP1), were analyzed in seedlings of nine barley genotypes subjected to a progressive increase in water deficit. Seedlings of all genotypes wilted when the soil water content (SWC) declined from 65% (control conditions) to 10% (severe drought conditions), but recovered turgor within a few hours of re watering. However, when severe drought conditions were prolonged for a week, large differences in survival characteristics were observed between genotypes after re-watering. Multivariate analysis of the changes in physiological and molecular characteristics allowed several different homogenous groups within the genotypes to be distinguished, depending on stress intensity. Furthermore, integration between the stress-response traits was found and was shown to vary depending on the genotype and the stress level. Based on analysis of physiological traits and survival characteristics, two barley genotypes with high adaptability to the stress conditions (cv. Saida and breeding line Cam/B1), and two with low adaptability (cv. Express and breeding line Harmal), were identified. In addition, only changes in expression of the genes HvZIP1, encoding a b-ZIP-type transcription factor, and Hsdr4, encoding a protein of unknown function, were shown to be linked with adaptability of barley to water deficit. In summary, physiological and molecular data revealed large, stress-level dependent differences between the barley cultivars and breeding lines tested in their response to water deficit. PMID- 24811680 TI - Leaf micromorphology and sugar may contribute to differences in drought tolerance for two apple cultivars. AB - Apple trees (Malus domestica L.) are often exposed to severe water stress in the summertime. We determined how levels of nonstructural carbohydrates (NC) changed in the leaves of two cultivars - drought-tolerant 'QinGuan' and drought-sensitive 'NaganoFuji' - when plants were subjected for 10 d to a sudden water deficit. Photosynthetic performance was investigated in terms of gas exchange and antioxidant enzyme activity. Two separate irrigation scenarios were tested with one-year-old plants grafted onto Malus hupehensis (Pamp.) Rehd. rootstock: 1) water applied to 75% field capacity (FC) (Control, CK) and 2) irrigation withheld to achieve <75% FC ranging from 30 to 75% (Treatment, T). At Days 0, 1, 2, 4, 6, and 10 of the experiment, we recorded net CO2 assimilation, stomatal conductance, leaf transpiration rates, and intercellular CO2 concentrations. All of those parameters showed decreases in plants from both stress scenarios, although those declines were not as dramatic in 'QinGuan'. The photosynthetic rate reduced primarily because of stomatal closure. In both cultivars, water stress induced the accumulation of NC, especially sorbitol, suggesting that this polyol has a role in osmoregulation. The rise in sorbitol levels was much steeper in 'QinGuan'. Likewise, the interaction between superoxide dismutase and peroxidase activities varied between cultivars. In 'QinGuan', the malondialdehyde concentration was much lower and more closely correlated with a high Suc/NC ratio when compared with 'NaganoFuji'. Scanning electron microscopy revealed a drought resisting apparent structure in 'QinGuan'. Overall, our results from both external and internal examinations demonstrated that 'QinGuan' is more drought tolerant than 'NaganoFuji'. PMID- 24811681 TI - A comparative genomic analysis of the alkalitolerant soil bacterium Bacillus lehensis G1. AB - Bacillus lehensis G1 is a Gram-positive, moderately alkalitolerant bacterium isolated from soil samples. B. lehensis produces cyclodextrin glucanotransferase (CGTase), an enzyme that has enabled the extensive use of cyclodextrin in foodstuffs, chemicals, and pharmaceuticals. The genome sequence of B. lehensis G1 consists of a single circular 3.99 Mb chromosome containing 4017 protein-coding sequences (CDSs), of which 2818 (70.15%) have assigned biological roles, 936 (23.30%) have conserved domains with unknown functions, and 263 (6.55%) have no match with any protein database. Bacillus clausii KSM-K16 was established as the closest relative to B. lehensis G1 based on gene content similarity and 16S rRNA phylogenetic analysis. A total of 2820 proteins from B. lehensis G1 were found to have orthologues in B. clausii, including sodium-proton antiporters, transport proteins, and proteins involved in ATP synthesis. A comparative analysis of these proteins and those in B. clausii and other alkaliphilic Bacillus species was carried out to investigate their contributions towards the alkalitolerance of the microorganism. The similarities and differences in alkalitolerance-related genes among alkalitolerant/alkaliphilic Bacillus species highlight the complex mechanism of pH homeostasis. The B. lehensis G1 genome was also mined for proteins and enzymes with potential viability for industrial and commercial purposes. PMID- 24811682 TI - Characterization of the promoter and 5'-UTR intron of oleic acid desaturase (FAD2) gene in Brassica napus. AB - In the present study, we characterized the transcriptional regulatory region (KF038144) controlling the expression of a constitutive FAD2 in Brassica napus. There are multiple FAD2 gene copies in B. napus genome. The FAD2 gene characterized and analyzed in the study is located on chromosome A5 and was designated as BnFAD2A5-1. BnFAD2A5-1 harbors an intron (1,192 bp) within its 5' untranslated region (5'-UTR). This intron demonstrated promoter activity. Deletion analysis of the BnFAD2A5-1 promoter and intron through the beta glucuronidase (GUS) reporter system revealed that the -220 to -1 bp is the minimum promoter region, while -220 to -110 bp and +34 to +285 bp are two important regions conferring high-levels of transcription. BnFAD2 transcripts were induced by light, low temperature, and abscisic acid (ABA). These observations demonstrated that not only the promoter but also the intron are involved in controlling the expression of the BnFAD2A5-1 gene. The intron mediated regulation is an essential aspect of the gene expression regulation. PMID- 24811683 TI - Latino families with a child with Prader-Willi syndrome: exploring needs for support. AB - Prader-Willi syndrome (PWS) is a complex, genetically based disorder; caring for a family member with a disability such as PWS brings significant challenges to the whole family. However, no research has been conducted focusing on the impact of PWS in the dynamics of Latino families. This qualitative study explored the challenges and need for support services among Latino families of children with PWS. Findings of the study suggest the need for support services geared toward the whole family unit to help members cope with daily challenges at home. PMID- 24811684 TI - An 'Upp'-turn in bacteriocin receptor identification. AB - Bacteriocins are gene encoded, bacterially produced antimicrobial peptides that have been the focus of considerable scientific interest but which are relatively underutilized by the food, veterinary and medical industries. One means via which the latter issue can be overcome is through a better understanding of how these peptides work or, more specifically, the identification of bacteriocin receptors and the subsequent application of such information to enhance the potency, and commercial value, of bacteriocins. For a time since the identification of lipid II and subunits of the mannose phosphotransferase system as receptors for several class I (modified) and class II (unmodified) bacteriocins, respectively, there were relatively few developments in this area. However, a number of recent studies have addressed this issue, resulting in the identification of a maltose ABC transporter and metallopeptidase as the targets for the garvicin ML (class IIc) and LsbB (class IId) bacteriocins, respectively, and, most recently, the identification of UppP as the receptor for lactococcin G and enterocin 1071 (both class IIb). In addition to these exciting discoveries, the development, and further application, of new strategies to facilitate receptor identification has the potential to lead to even further breakthroughs in bacteriocin research. PMID- 24811685 TI - The importance of therapeutic drug monitoring (TDM) for parenteral busulfan dosing in conditioning regimen for hematopoietic stem cell transplantation (HSCT) in children. AB - BACKGROUND: Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM. MATERIAL AND METHODS: Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects. Busulfan concentrations were determined by high performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule. RESULTS: We observed trough levels of 25-1244 ug/L, peak levels of 849-4586 ug/L, and AUC of 2225-12818 ug/L.h following body weight-based high dose busulfan. The doses were changed in 54% of cases. AUC in 5 of 9 patients with VOD were within target, in 3 patients AUS was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC. Engraftment was 100%, but relapse occurred in 25% of cases. CONCLUSIONS: Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging. Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM. PMID- 24811686 TI - Cutaneous melanoma metastatic to the orbit: review of 15 cases. AB - PURPOSE: To describe the clinical features, management, and outcomes of 15 patients with cutaneous melanoma metastatic to the orbit. The authors review emerging treatments for metastatic melanoma and their ocular implications. METHODS: Retrospective chart review of 15 patients with orbital metastasis from cutaneous melanoma. RESULTS: At presentation of the orbital metastasis, systemic metastatic cutaneous melanoma was present in 13 (87%) patients. The mean interval from diagnosis of cutaneous melanoma to orbital metastasis was 40 months (median, 37 months; range, 0-117 months). The most common presenting signs were dysmotility (63%), proptosis (56%), and blepharoptosis (19%). Four patients (25%) presented with pain. Metastasis involved extraocular muscle in 6 orbits (35%), intraconal space in 4 (24%), extraconal space in 7 (41%), and lacrimal sac in 1 (6%). The tumor was unifocal in all cases, unilateral in 13 patients (87%), and bilateral in 2 (13%). The mean tumor basal dimension was 20 * 20 mm and mean thickness was 16 mm. Treatments included complete surgical excision in 1 patient (6%), external beam radiotherapy (EBRT) in 7 (47%), systemic chemotherapy in 8 (53%), and immunotherapy in 5 (33%). Orbital tumor control was achieved in 2 orbits (18%) following focal therapy alone (excision or EBRT), 4 (36%) following systemic therapy alone (chemotherapy or immunotherapy), and 3 (27%) following combination focal plus systemic therapy. Three patients required exenteration. Survival rates at 1 year/2 years were 100%/0% following focal therapy, 50%/25% following systemic therapy, and 100%/66% following combination therapy. CONCLUSIONS: Cutaneous melanoma metastatic to the orbit tends to involve muscle (35%) or intraconal soft tissue (24%) as a painless (75%), circumscribed (87%) mass. Treatment with systemic chemotherapy and/or immunotherapy resulted in orbital tumor control in 80% of cases. Overall survival was 25.1 months. PMID- 24811687 TI - Peptide receptor radionuclide therapy in patients with inoperable meningiomas: our experience and review of the literature. AB - OBJECTIVE: Few studies describe peptide receptor radionuclide therapy (PRRT) using (90)Y- or (177)Lu-labeled peptides in patients with recurrent meningiomas. No clinical data about (111)In-Pentetreotide in such patients are available. We report on (111)In-Pentetreotide therapy in patients with inoperable meningiomas and review the literature about PRRT of meningiomas. METHODS: We reviewed clinical records of 8 patients with meningioma/meningiomatosis showing high (111)In-Pentetreotide uptake on pretherapy scintigraphy who were treated with at least one cycle of (111)In-Pentetreotide. In 2 patients, a cocktail of (111)In Pentetreotide and beta-emitting radiolabeled peptides had been administered. RESULTS: No patient experienced acute toxicity, neurological or renal function impairment. Mild transient bone marrow toxicity was observed in 4 patients. Objective partial response was observed in 2 patients, stable disease in 5 and disease progression in one. There were no statistically significant correlations between objective response and patient age, tumor WHO grade, baseline Karnofsky performance score, (111)In-Pentetreotide tumoral uptake grade, tumor/nontumor ratio, disease state at baseline, and cumulative dose. CONCLUSIONS: In consideration of its efficacy and the lack of significant toxicity, PRRT of meningiomas using (111)In-Pentetreotide could be proposed even nowadays when the use of (177)Lu- or (90)Y-labeled peptides seems unsafe, namely in patients with renal impairment/toxicity. PMID- 24811688 TI - Use of EOS imaging for the assessment of scoliosis deformities: application to postoperative 3D quantitative analysis of the trunk. AB - PURPOSE: EOS imaging system is accessible to clinicians since 2007, allowing 3D spinal reconstructions in a functional standing position with reduced radiation. However, numerous ongoing research protocols continuously help implementing the dedicated software. The main principle and applications of the EOS device are discussed here, with an emphasis on future projects. In particular, the authors studied the postoperative modification of the rib cage and spinal morphology after posteromedial correction, in a consecutive series of adolescent idiopathic scoliosis (AIS) patients. METHODS: 49 thoracic AIS patients underwent low-dose stereoradiography preoperatively, postoperatively and at latest examination, with a minimum 2-year follow-up. Spinal and rib cages 3D reconstructions were obtained using dedicated software, and the postoperative modification of thoracic parameters was reported. RESULTS: All parameters were significantly improved after surgery. Mean thoracic volume increase was 8.4% (+/-8), influenced by the postoperative derotation of the apical vertebra. No difference was found in thoracic volume increase in patients who gained more than 10 degrees of thoracic kyphosis. A significant correlation was found between spinal penetration index at the apex and thoracic sagittal alignment (p = 0.02). CONCLUSIONS: EOS imaging device now reliably provides a global 3D quantitative analysis of scoliotic deformities in a context of routine clinical use. This innovative tool will help in the future to better understand scoliosis physiopathology and to evaluate treatment strategies. PMID- 24811689 TI - A novel technique for treatment of progressive scoliosis in young children using a 3-hook and 2-screw construct (H3S2) on a single sub-muscular growing rod: surgical technique. AB - INTRODUCTION: Several different growing rod techniques have been described in the literature to treat progressive scoliosis in young children. Nevertheless, none of these techniques has shown a real superiority, and the rate of complications remains high. The purpose of this report is to describe an original fusionless method of treatment for this problem. MATERIALS AND METHODS: The 3 hooks-2 screws (H3S2) construct consists of a single 5.5 mm titanium rod with three hooks proximally and two monoaxial pedicle screws distally, and some extra length of rod located distally and/or proximally that can be used for future lengthenings. To date, a total of 103 H3S2 constructs have been performed in our institution. This paper reports the preliminary results on 38 patients, with a minimum follow up of 2 years. RESULTS: This procedure was found to be effective in maintaining scoliosis correction while allowing continued spinal growth and was associated with a low rate of complications. CONCLUSIONS: The H3S2 construct was found to have several advantages over the growing rod techniques as previously described in the literature. These include no need for post-operative bracing, fewer lengthening procedures and a lower rate of complications. PMID- 24811690 TI - Surgical techniques in pediatric spine surgery. PMID- 24811692 TI - Function and evolution of vertebrate globins. AB - Globins are haem-proteins that bind O2 and thus play an important role in the animal's respiration and oxidative energy production. However, globins may also have other functions such as the decomposition or production of NO, the detoxification of reactive oxygen species or intracellular signalling. In addition to the well-investigated haemoglobins and myoglobins, genome sequence analyses have led to the identification of six further globin types in vertebrates: androglobin, cytoglobin, globin E, globin X, globin Y and neuroglobin. Here, we review the present state of knowledge on the functions, the taxonomic distribution and evolution of vertebrate globins, drawing conclusions about the functional changes underlying present-day globin diversity. PMID- 24811691 TI - Serum levels of B-cell activating factor in chronic hepatitis B virus infection: association with clinical diseases. AB - B-lymphocyte activation is a common characteristic of chronic hepatitis B virus (HBV) infection. B cell-activating factor (BAFF) plays a crucial role in the development and activation of B lymphocytes. This study investigated serum BAFF levels in 232 patients with different clinical diseases of chronic HBV infection [33 chronic asymptomatic HBV carrier (ASC), 53 chronic hepatitis (CH), 72 liver cirrhosis (LC), and 74 hepatocellular carcinoma (HCC)] and 61 gender- and age matched healthy controls. Serum BAFF levels in HBV patients were significantly elevated compared with healthy controls (P<0.001). HCC patients had significantly higher levels of serum BAFF than ASC, CH, and LC (all P<0.001). Serum levels of BAFF in LC were significantly higher than in ASC (P<0.001) and CH (P=0.002). Serum level of BAFF was an independent variable associated with the presence of HCC in comparison with other disease groups in multivariate analysis. The area under receiver-operating characteristic curve (AUC) value of BAFF levels was 0.914 for HCC versus ASC, 0.825 for HCC versus CH, and 0.607 for HCC versus LC, respectively. The AUC value of BAFF levels was 0.854 for LC versus ASC and 0.748 for LC versus CH, respectively. The AUC value of BAFF (0.888) for HCC was higher than that of alpha-fetoprotein (0.776). We first demonstrate that serum BAFF levels in chronic HBV infection are elevated, correlated with clinical diseases, and could be used as a biomarker for indicating disease mechanisms, activity, and diagnosis. PMID- 24811694 TI - Recognizing early dementia in the workplace: a case study. AB - A case study of diagnosis of early dementia is presented and recommendations for educating health care professionals to recognize and treat this condition among workers are offered. PMID- 24811693 TI - Respiratory exacerbations in indigenous children from two countries with non cystic fibrosis chronic suppurative lung disease/bronchiectasis. AB - BACKGROUND: Acute respiratory exacerbations (AREs) cause morbidity and lung function decline in children with chronic suppurative lung disease (CSLD) and bronchiectasis. In a prospective longitudinal cohort study, we determined the patterns of AREs and factors related to increased risks for AREs in children with CSLD/bronchiectasis. METHODS: Ninety-three indigenous children aged 0.5 to 8 years with CSLD/bronchiectasis in Australia (n = 57) and Alaska (n = 36) during 2004 to 2009 were followed for > 3 years. Standardized parent interviews, physical examinations, and medical record reviews were undertaken at enrollment and every 3 to 6 months thereafter. RESULTS: Ninety-three children experienced 280 AREs (median = 2, range = 0-11 per child) during the 3-year period; 91 (32%) were associated with pneumonia, and 43 (15%) resulted in hospitalization. Of the 93 children, 69 (74%) experienced more than two AREs over the 3-year period, and 28 (30%) had more than one ARE in each study year. The frequency of AREs declined significantly over each year of follow-up. Factors associated with recurrent (two or more) AREs included age < 3 years, ARE-related hospitalization in the first year of life, and pneumonia or hospitalization for ARE in the year preceding enrollment. Factors associated with hospitalizations for AREs in the first year of study included age < 3 years, female caregiver education, and regular use of bronchodilators. CONCLUSIONS: AREs are common in children with CSLD/bronchiectasis, but with clinical care and time AREs occur less frequently. All children with CSLD/bronchiectasis require comprehensive care; however, treatment strategies may differ for these patients based on their changing risks for AREs during each year of care. PMID- 24811695 TI - Respiratory protection competencies for the occupational health nurse. AB - Approximately 5 million workers employed at 1.3 million work settings are required to wear some form of respiratory protection as part of their jobs. Occupational health nurses can protect the respiratory health of America's workforce. In 2012, the American Association of Occupational Health Nurses Grants Committee Working Group conducted a nationwide survey of occupational health nurses to assess their knowledge, comfort, skills, and abilities relative to respiratory protection. The Working Group used the survey findings as a foundation for the development of respiratory protection competencies for occupational health nurses and a guide for the development of educational modules. PMID- 24811696 TI - Finnish occupational health nurses' view of work-related stress: a cross sectional study. AB - Occupational stress at work has been increasingly recognized as a major risk factor for chronic disease and poor quality of work life among employees. The purpose of this study was to examine how occupational health nurses in Finland manage work-related stress. A descriptive cross-sectional study design was used with a sample of 354 Finnish occupational nurses who responded to the survey. No specific standardized tools to assess or handle work-related stress in occupational health services or their client companies were identified. Open ended interviews together with burnout questionnaires were the most frequently used methods to assess the stress of employees. Interventions were directed at individual employees. A need for standardized stress assessment instruments and stress management by work organizations was found. Methods to cope with work related stress should be developed by the occupational health team and companies' health resources departments to ensure the adoption of common protocols. PMID- 24811697 TI - An integrative review of screening for obstructive sleep apnea in commercial vehicle drivers. AB - Obstructive sleep apnea has been a concern for commercial vehicle drivers for several decades. An increasing body of knowledge supports the idea that insufficient sleep can affect drivers' abilities to react efficiently and expediently, leading to motor vehicle accidents. Insufficient sleep can be described as short sleep periods, prolonged driving time, and dysfunctional sleep breathing. Commercial motor vehicle drivers are required to undergo physical examinations at least once every 2 years to maintain certification. Medical examiners are encouraged to screen for obstructive sleep apnea during these biannual examinations. Current literature identifies four frequently used screening tools for obstructive sleep apnea: STOP Questionnaire, STOP-Bang Questionnaire, Berlin Questionnaire, and Epworth Sleepiness Scale. Medical examiners must determine which screening method is valid, reliable, and has sufficient evidence to support its use. PMID- 24811698 TI - Review of worksite weight management programs. AB - This article explores worksite weight management programs by reviewing the literature and providing recommendations to address obesity, a major public health challenge. Ten full-text articles published between 2005 and 2013 were reviewed. The literature supports a combination of physical activity, education, and diet to either maintain weight or result in modest weight loss. PMID- 24811700 TI - Postsurgical hemodynamics of the aortic valve bypass operation evaluated with phase contrast magnetic resonance. AB - PURPOSE: To characterize the postsurgical hemodynamics in aortic valve bypass (AVB) patients, and to determine the relationship between presurgical native aortic valve pressure gradient and postsurgical hemodynamics. MATERIALS AND METHODS: Twenty patients scheduled for AVB surgery underwent presurgical transthoracic Doppler echocardiography to assess the degree of aortic stenosis and postsurgical cardiac magnetic resonance imaging (MRI) to acquire phase contrast magnetic resonance (PCMR) flow values along the ascending and descending aorta, and in the conduit. Net flow values were calculated from the PCMR images and compared to presurgical aortic valve pressure gradient measurements. RESULTS: PCMR showed that: 1) The blood flow split between the aorta and the conduit was 35%:65% of cardiac output and 2) 60% of patients had net retrograde blood flow in the superior thoracic aorta over the cardiac cycle. Patients with presurgical pressure gradient (DeltaP) > 45 mmHg had significantly less blood flow out of the native aorta than patients with DeltaP < 45 mmHg, and had significantly more retrograde flow in the superior thoracic aorta postsurgery. CONCLUSION: In patients undergoing AVB, presurgical aortic valve pressure gradient is associated with the volume of blood flow out the aorta and the direction of blood flow in the superior thoracic aorta after conduit addition as measured by PCMR. PMID- 24811699 TI - A potential role for immunotherapy in thyroid cancer by enhancing NY-ESO-1 cancer antigen expression. AB - BACKGROUND: NY-ESO-1 is one of the most immunogenic members of the cancer/testis antigen family and its levels can be increased after exposure to demethylating and deacetylating agents. This cytoplasmic antigen can serve as a potent target for cancer immunotherapy and yet has not been well studied in differentiated thyroid cancer cells. METHODS: We studied the baseline expression of NY-ESO-1 messenger RNA and protein before and after exposure to 5-aza-2'-deoxycytidine (DAC) (72 hours) in a panel of thyroid cancer cell lines using quantitative polymerase chain reaction and Western blot. HLA-A2+, NY-ESO-1+ thyroid cell lines were then co-cultured with peripheral blood lymphocytes transduced with NY-ESO-1 specific T-cell receptor (TCR) and assayed for interferon-gamma and Granzyme-B release in the medium. SCID mice injected orthotopically with BCPAP cells were treated with DAC to evaluate for NY-ESO-1 gene expression in vivo. RESULTS: None of the thyroid cancer cell lines showed baseline expression of NY-ESO-1. Three cell lines, BCPAP, TPC-1, and 8505c, showed an increase in NY-ESO-1 gene expression with DAC treatment and were found to be HLA-A2 positive. DAC-treated target BCPAP and TPC-1 tumor cells with up-regulated NY-ESO-1 levels were able to mount an appropriate interferon-gamma and Granzyme-B response upon co-culture with the NY-ESO-1-TCR-transduced peripheral blood lymphocytes. In vivo DAC treatment was able to increase NY-ESO-1 expression in an orthotopic mouse model with BCPAP cells. CONCLUSION: Our data suggest that many differentiated thyroid cancer cells can be pressed to express immune antigens, which can then be utilized in TCR-based immunotherapeutic interventions. PMID- 24811701 TI - Application of a real-time three-dimensional navigation system to various oral and maxillofacial surgical procedures. AB - The aim of this study was to confirm the effectiveness of a real-time three dimensional navigation system for use during various oral and maxillofacial surgeries. Five surgeries were performed with this real-time three-dimensional navigation system. For mandibular surgery, patients wore acrylic surgical splints when they underwent computed tomography examinations and the operation to maintain the mandibular position. The incidence of complications during and after surgery was assessed. No connection with the nasal cavity or maxillary sinus was observed at the maxilla during the operation. The inferior alveolar nerve was not injured directly, and any paresthesia around the lower lip and mental region had disappeared within several days after the surgery. In both maxillary and mandibular cases, there was no abnormal hemorrhage during or after the operation. Real-time three-dimensional computer-navigated surgery allows minimally invasive, safe procedures to be performed with precision. It results in minimal complications and early recovery. PMID- 24811703 TI - Children left behind. PMID- 24811704 TI - The epidemiology of childhood and adolescent traumatic spinal cord injury in the United States: 2007-2010. AB - The burden of acute traumatic spinal cord injury (TSCI) among U. S. children and adolescents was last described over a decade ago using inpatient data. We describe cumulative incidence, mortality, discharge disposition, and inflation adjusted charges of childhood and adolescent TSCI in the U.S. using emergency department (ED) data from the Nationwide Emergency Department Sample (2007-2010). Patients ages 17 years and younger with a diagnosis of acute TSCI were identified using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes 806.* and 952.* (N = 6132). The cumulative incidence of childhood and adolescent TSCI averaged 17.5 per million population per year. The median age at presentation was 15 years (interquartile range [IQR] = 12-16) and the majority of patients were male (72.5%). The overall median new injury severity score (NISS) was 16 (IQR = 9-27), remaining unchanged during the study duration (p=0.703). Children 5 years and younger were more likely to be injured from a road traffic accident (RTA; 50.9%), sustain C1-C4 injuries (47.4%), have more severe injury (median NISS = 22; IQR = 13-29), and concurrent brain injury (24%) compared to older children and adolescents, p<0.001. Firearms were implicated in 8.3% of injuries, of which 94.7% were among adolescents ages 13-17 years. Of the 35 TSCI-related ED deaths, 40% occurred among children ages 5 years and younger. 62.4% of patients required inpatient admission. Despite stable cumulative incidence and overall injury severity, ED treatment charge per visit increased on average $1394 from $3495 in 2007 to $4889 in 2010 (p=0.008). RTA-related TSCI disproportionately affects young children, while firearm-related TSCI is most common among adolescents. These findings inform TSCI prevention strategies. Prevention may be key in mitigating rising healthcare cost. PMID- 24811705 TI - Restoration of positive mood states in major depression as a potential drug development target. AB - Restoration of positive mood, in addition to reducing negative mood, is an important treatment goal in the management of depression. The need to restore positive mood states in depressed patients is not adequately addressed by available treatments for major depressive disorder (MDD), suggesting that this mood dimension could be a useful target for drug development. However, for positive mood restoration to become a valid target for antidepressant drug development certain questions should be answered: are symptoms of decreased positive mood phenomenologically distinct from other symptoms of MDD? Should they be considered a distinct aspect of MDD in the diagnostic nomenclature? Is there evidence for differential responsiveness to treatment? Is the underlying pathophysiology understood and different from that of other MDD symptoms? Is low positive mood specific to depression or does it contribute to psychopathology in other disorders? Beyond these basic questions, this review identifies a number of design issues that need to be considered when conducting studies that target improving positive mood. These design issues include (1) what population to study, (2) what line of treatment to target, (3) the appropriateness and validation of methods and measures to evaluate positive mood and its restoration, (4) the role of functional outcome measures in determining success of the treatment, and (5) optimal designs for add-on therapy versus monotherapy agents. PMID- 24811706 TI - Ten simple rules for internship in a pharmaceutical company. PMID- 24811708 TI - Three-year comparative study of polyphenol contents and antioxidant capacities in fruits of tomato (Lycopersicon esculentum Mill.) cultivars grown under organic and conventional conditions. AB - In the present study, four tomato cultivars were grown under organic and conventional conditions in separate unheated greenhouses in three consecutive years. The objective was to assess the influence of the cultivation system on the content of individual polyphenols, total phenolics, and antioxidant capacity of tomatoes. The fruits were analyzed for total phenolic content by the Folin Ciocalteau method and antioxidant capacity by the DPPH free radical scavenging assay. Individual phenolic compounds were analyzed using HPLC-DAD-MS/MS. Among 30 identified and quantified polyphenols, significantly higher contents of apigenin acetylhexoside, caffeic acid hexoside I, and phloretin dihexoside were found in all organic samples. The content of polyphenols was more dependent on year and cultivar than on cultivation conditions. Generally, the cultivation system had minor impact on polyphenols content, and only a few compounds were influenced by the mode of cultivation in all tested cultivars during all three years. PMID- 24811707 TI - A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation. AB - Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy. PMID- 24811710 TI - Genomic adaptations of the halophilic Dead Sea filamentous fungus Eurotium rubrum. AB - The Dead Sea is one of the most hypersaline habitats on Earth. The fungus Eurotium rubrum (Eurotiomycetes) is among the few species able to survive there. Here we highlight its adaptive strategies, based on genome analysis and transcriptome profiling. The 26.2 Mb genome of E. rubrum shows, for example, gains in gene families related to stress response and losses with regard to transport processes. Transcriptome analyses under different salt growth conditions revealed, among other things differentially expressed genes encoding ion and metabolite transporters. Our findings suggest that long-term adaptation to salinity requires cellular and metabolic responses that differ from short-term osmotic stress signalling. The transcriptional response indicates that halophilic E. rubrum actively counteracts the salinity stress. Many of its genes encode for proteins with a significantly higher proportion of acidic amino acid residues. This trait is characteristic of the halophilic prokaryotes as well, supporting the theory of convergent evolution under extreme hypersaline stress. PMID- 24811709 TI - Changes in HbA1c and frequency of measuring HbA1c and adjusting glucose-lowering medications in the 10 years following diagnosis of type 2 diabetes: a population based study in the UK. AB - AIMS/HYPOTHESIS: The aim of this work was to study levels of HbA1c and patterns of adjusting glucose-lowering drugs in patients with impaired glycaemic control over 10 years after diagnosis of type 2 diabetes. METHODS: We studied 4,529 individuals in The Health Improvement Network Database newly diagnosed with type 2 diabetes in the year 2000. RESULTS: From 6 months to 10 years after diagnosis, the HbA1c increased from 7.04% (53.4 mmol/mol) to 7.49% (58.3 mmol/mol) (average annual change: 0.047% [0.51 mmol/mol]). The greatest annual change occurred between 6 months and 2 years (0.21% [2.30 mmol/mol] increase per year, p < 0.001), followed by the 2-5 year time period (0.033% [0.36 mmol/mol] increase per year, p < 0.001). No significant increase in HbA1c occurred between 5 and 10 years (p = 0.20). In multivariable analyses, patients who were younger (p < 0.001), with higher BMI (p = 0.033) and who were current insulin users (p = 0.024) at diagnosis had greater increases in HbA1c between 6 months and 2 years. For individuals with HbA1c above 7.0% (53 mmol/mol) the mean time to next measurement of HbA1c was 0.53 years and increase in doses or changes to other glucose-lowering medications were performed in 26% of cases. CONCLUSIONS/INTERPRETATION: HbA1c increases by approximately 0.5% (5 mmol/mol) over 10 years after diagnosis of type 2 diabetes, with the main increase appearing in the first years after diagnosis. More frequent monitoring of HbA1c and adjustments of glucose-lowering drugs may be essential to prevent the decline. PMID- 24811712 TI - Photochemical redox reactions of copper(II)-alanine complexes in aqueous solutions. AB - The photochemical redox reactions of Cu(II)/alanine complexes have been studied in deaerated solutions over an extensive range of pH, Cu(II) concentration, and alanine concentration. Under irradiation, the ligand-to-metal charge transfer results in the reduction of Cu(II) to Cu(I) and the concomitant oxidation of alanine, which produces ammonia and acetaldehyde. Molar absorptivities and quantum yields of photoproducts for Cu(II)/alanine complexes at 313 nm are characterized mainly with the equilibrium Cu(II) speciation where the presence of simultaneously existing Cu(II) species is taken into account. By applying regression analysis, individual Cu(I) quantum yields are determined to be 0.094 +/- 0.014 for the 1:1 complex (CuL) and 0.064 +/- 0.012 for the 1:2 complex (CuL2). Individual quantum yields of ammonia are 0.055 +/- 0.007 for CuL and 0.036 +/- 0.005 for CuL2. Individual quantum yields of acetaldehyde are 0.030 +/- 0.007 for CuL and 0.024 +/- 0.007 for CuL2. CuL always has larger quantum yields than CuL2, which can be attributed to the Cu(II) stabilizing effect of the second ligand. For both CuL and CuL2, the individual quantum yields of Cu(I), ammonia, and acetaldehyde are in the ratio of 1.8:1:0.7. A reaction mechanism for the formation of the observed photoproducts is proposed. PMID- 24811714 TI - First episode psychosis in an adult area mental health service-a closer look at early and late-onset first episode psychosis. AB - OBJECTIVES: To review the characteristics of all patients presenting with a first episode of psychosis between the ages of 16 and 65 years to an adult area mental health service. METHODS: The early psychosis programme at St Vincent's Hospital Melbourne treats all patients presenting in the early stages of psychosis between the ages of 16 and 65 years. A database was developed to capture the demographic and diagnostic characteristics of the group. The characteristics of those with an onset under 26 years were compared with those with a later onset. RESULTS: A large proportion (55%) of those presenting with first episode psychosis presented after the age of 25 years. There were a higher number of cases of depression with psychotic features in the older onset patients (notably so for those over 40) and a trend towards greater metabolic morbidity. DISCUSSION: Older patients presenting with a first episode of psychosis are relatively understudied but appear to have certain distinguishing qualities. Understanding the needs of these patients is important in tailoring optimal treatment packages and service responses. PMID- 24811715 TI - A state-wide quality improvement system utilising nurse-led clinics for clozapine management. AB - OBJECTIVES: This paper describes the implementation of a state-wide clozapine management system to improve the quality of care for those with treatment resistant schizophrenia. This intervention includes standardised forms, computer based monitoring and alerting and nurse-led clinics for stable consumers. METHODS: Methods used during system development included medical record and clinical information system audit, consensus review of available evidence and qualitative review of existing forms, systems and stakeholder opinion. RESULTS: Nurse-led monitoring safely reduced medical outpatient appointments by 119 per week in metropolitan public clinics. In the 15 months following the implementation of all interventions, mortality associated with physical illness not related to malignancy was reduced from an average of 5 deaths per year to one. CONCLUSIONS: Differing interpretations of clozapine guidelines have contributed to confusion around monitoring. Standardised documentation has helped to increase understanding and improve protocol adherence. A regular training programme has increased basic knowledge of risks and protocols. Computer-based documentation and alerting systems have improved communication between hospital and community-based teams and prompted early intervention reducing the risk of adverse events. These factors have combined to help improve outcomes in clozapine management. Nurse-led clinics are a safe and efficient alternative for monitoring clozapine treatment. PMID- 24811713 TI - Insights into the architecture of the eIF2Balpha/beta/delta regulatory subcomplex. AB - Eukaryotic translation initiation factor 2B (eIF2B), the guanine nucleotide exchange factor for the G-protein eIF2, is one of the main targets for the regulation of protein synthesis. The eIF2B activity is inhibited in response to a wide range of stress factors and diseases, including viral infections, hypoxia, nutrient starvation, and heme deficiency, collectively known as the integrated stress response. eIF2B has five subunits (alpha-epsilon). The alpha, beta, and delta subunits are homologous to each other and form the eIF2B regulatory subcomplex, which is believed to be a trimer consisting of monomeric alpha, beta, and delta subunits. Here we use a combination of biophysical methods, site directed mutagenesis, and bioinformatics to show that the human eIF2Balpha subunit is in fact a homodimer, at odds with the current trimeric model for the eIF2Balpha/beta/delta regulatory complex. eIF2Balpha dimerizes using the same interface that is found in the homodimeric archaeal eIF2Balpha/beta/delta homolog aIF2B and related metabolic enzymes. We also present evidence that the eIF2Bbeta/delta binding interface is similar to that in the eIF2Balpha2 homodimer. Mutations at the predicted eIF2Bbeta/delta dimer interface cause genetic neurological disorders in humans. We propose that the eIF2B regulatory subcomplex is an alpha2beta2delta2 hexamer, composed of one alpha2 homodimer and two betadelta heterodimers. Our results offer novel insights into the architecture of eIF2B and its interactions with the G-protein eIF2. PMID- 24811716 TI - Psychiatry trainees confidence as teachers, perceptions of supervisor support and opportunities for further training. AB - OBJECTIVE: To investigate psychiatry trainees' confidence in their role as teachers, their perceptions of support and preferences for a program to support this role. METHODS: Psychiatry trainees in New South Wales (NSW) (Australia) in the first three years of psychiatry training (N = 118) were invited to complete a survey which included demographic data, self-assessment of teaching confidence and perceptions of support for teaching. RESULTS: A total of 63% (N = 74) agreed to participate. Overall, 62% percent of participants regarded teaching as an important part of their role, 46% felt supported in the role by their training supervisors, but only 18% regularly discussed their teaching role in routine supervision. CONCLUSIONS: Psychiatry trainees viewed teaching as part of their role. They reported a low level of formal training in teaching skills and perceived a low level of support from supervisors. Registrar training needs to address trainees' competencies in a range of teaching skills along with supervisor support. Further research is required to assess the impact of a teaching program on teaching performance and learner outcomes. PMID- 24811717 TI - A supported employment linkage intervention for people with schizophrenia who want a chance to work. AB - OBJECTIVE: Investigate feasibility and development of a linkage intervention to the evidence-based Individual Placement and Support (IPS) approach to supported employment (SE) for patients with schizophrenia on a mental health unit who want to work in competitive employment. METHOD: Literature review about the evidence based IPS approach to SE in schizophrenia and why it might not be implemented in mental health services. Analysis of 10 adult mental health unit multidisciplinary staff interviews for categories in the literature review of IPS implementation barriers and whether these barriers could be overcome. RESULTS: There was lack of full staff knowledge of the IPS approach to SE. However, all staff knew respect for patient choice was paramount, community employment programs existed for the disabled, an outreach linkage process to such a program and ongoing support for people with schizophrenia would be required. There was staff ambivalence about SE for patients with schizophrenia. CONCLUSION: Despite staff ambivalence about SE for people with schizophrenia there was still enough staff knowledge and openness to shape an IPS linkage intervention from a staff perspective. PMID- 24811718 TI - A letter from the new editor. PMID- 24811719 TI - Stripped of illusions? Exploring system justification processes in capitalist and post-Communist societies. AB - Sociologists and political scientists have often observed that citizens of Central and Eastern Europe express high levels of disillusionment with their social, economic and political systems, in comparison with citizens of Western capitalist societies. In this review, we analyze system legitimation and delegitimation in post-Communist societies from a social psychological perspective. We draw on system justification theory, which seeks to understand how, when and why people do (and do not) defend, bolster and justify existing social systems. We review some of the major tenets and findings of the theory and compare research on system-justifying beliefs and ideologies in traditionally Capitalist and post-Communist countries to determine: (1) whether there are robust differences in the degree of system justification in post-Communist and Capitalist societies, and (2) the extent to which hypotheses derived from system justification theory receive support in the post-Communist context. To this end, we summarize research findings from over 20 countries and cite previously unpublished data from a public opinion survey conducted in Poland. Our analysis confirms that there are lower levels of system justification in post-Communist countries. At the same time, we find that system justification possesses similar social and psychological antecedents, manifestations and consequences in the two types of societies. We offer potential explanations for these somewhat complicated patterns of results and conclude by addressing implications for theory and research on system justification and system change (or transition). PMID- 24811720 TI - Family income, parental education and internalizing and externalizing psychopathology among 2-3-year-old Chinese children: the mediator effect of parent-child conflict. AB - Using a sample of 156 Chinese children aged 2-3 years and their parents, this study examined the effects of socio-economic status, specifically family income and parental education, on the children's internalizing and externalizing psychopathology and whether these effects were mediated by mother-child and father-child conflict. Results indicated that family income, maternal education and paternal education all negatively predicted externalizing symptoms. Income also negatively predicted internalizing symptoms among boys but not girls. Maternal education negatively predicted internalizing symptoms among girls but not boys. The effects of income on psychopathology were fully mediated by mother child and father-child conflict. In contrast, the effects of education were not mediated or only partially mediated by conflict. Findings are discussed in the framework of the family stress model. PMID- 24811721 TI - Childhood experiences of parental rearing patterns reported by Chinese patients with borderline personality disorder. AB - The primary purposes of this study were to (1) compare the characteristics of childhood experiences of parental rearing patterns in China reported by patients with borderline personality disorder (BPD), patients with other personality disorders and patients without personality disorders; (2) identify the reported parental rearing patterns associated with BPD in China; and (3) determine whether these patterns differ for males and females. One hundred and fifty-two patients with BPD, 79 patients with other personality disorders and 55 patients without Axis II diagnoses were administered the Chinese version of the McLean Screening Instrument for BPD and completed the Egna Minnen av Barndoms Uppfostran (EMBU), a self-report measure of childhood parental rearing patterns. Parental rearing patterns reported by the BPD group were characterized by less emotional warmth, and greater punishment, rejection and control than patterns reported by the other two groups. Within the BPD group, males were more likely than females to report parental punishment, rejection and control. Paternal punishment, low maternal emotional warmth and female gender predicted BPD diagnosis. Negative parental rearing patterns appear to contribute to the development of BPD in China and vary with the gender of the child. Maternal emotional warmth may be a protective factor against BPD. PMID- 24811722 TI - Verbal irony processing: how do contrast and humour correlate? AB - Verbal irony relies on contrast, that is, incongruity between the situational context and the ironic assertion. But is the degree of contrast related to the perceived humorousness of ironic comments? We answered this question by conducting two experiments. In the first experiment, participants were asked to read a list of sentence pairs (ironic or control) and judge the extent to which the meaning of the first sentence contrasted with that of the second. In the second experiment, participants were invited to rate the humorousness of ironic comments compared with their literal counterparts. Results showed that ironic remarks were rated as more contrasting and more humorous than their literal counterparts, but that humour only emerged from a moderate contrast. PMID- 24811723 TI - Affective priming of perceived environmental restorativeness. AB - Research into the perceived restorativeness of environments tends to focus on the Kaplans' Attention Restoration Theory at the expense of the affective considerations of Ulrich's psychoevolutionary model. To better understand the role of emotion, this study used contextual text-based primers (newspaper articles) to manipulate participants' affective state (positive or negative) prior to them rating different environments using the Restorative Components Scale. Sixty-nine participants completed the web-based study, being pseudo randomly allocated to the positive- or negative-prime condition before rating three natural and three urban environments. Natural environments were rated as more restorative than urban, with negative-priming giving higher mean ratings for all environments. This effect was overall statistically significant for two components (Being Away and Fascination), but only Fascination showed a significant interaction of affective-prime and environment, a larger effect being seen for natural environments. Results are discussed in terms of current understanding of the interrelationship between attentional and affective processes. PMID- 24811724 TI - Twenty-two years of psychological science in Psychological Science. AB - The journal Psychological Science (PS) has undergone various changes over 22 years since its birth in 1990. Analysis of Web of Science's records shows that the publication has increased in volume and collaborations between authors, and has become more international. Keyword analysis suggests the new role of neuroscience in contemporary psychology and indicates that the PS of today is more oriented than in the 1990s towards psychosocial and emotional issues as well as natural situations in our daily lives (ecological validity). PMID- 24811725 TI - Viral and host factors determine innate immune responses in airway epithelial cells from children with wheeze and atopy. AB - BACKGROUND: Airway epithelial cells (AEC) from patients with asthma, appear to have an impaired interferon (IFN)-beta and -lambda response to infection with rhinovirus. OBJECTIVES: To determine if impaired IFN responses can be identified in young children at risk of developing asthma due to atopy and/or early life wheeze, and if the site of infection or the infecting virus influence the antiviral response. METHODS: Nasal (N) and tracheal (T) epithelial cells (EC) were collected from children categorised with atopy and/or wheeze based on specific IgE to locally common aeroallergens and a questionnaire concerning respiratory health. Submerged primary cultures were infected with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV), and IFN production, inflammatory cytokine expression and viral replication quantified. RESULTS: Nasal epithelial cells (NEC), but not tracheal epithelial cells (TEC), from children with wheeze and/or atopy produced less IFN-beta, but not IFN-lambda, in response to RSV infection; this was associated with higher viral shedding. However, IFN regulated factors IRF-7, Mx-1 and CXCL-10, and inflammatory cytokines were not differentially regulated. NECs and TECs from children with wheeze and/or atopy demonstrated no impairment of the IFN response (beta or lambda) to hMPV infection. Despite this, more hMPV was shed from these cells. CONCLUSIONS: AECs from children with wheeze and/or atopy do not have an intrinsic defect in the production of IFN-beta or -lambda, however, this response is influenced by the infecting virus. Higher viral load is associated with atopy and wheeze suggesting an impaired antiviral response to RSV and hMPV that is not influenced by production of IFNs. PMID- 24811727 TI - Household salt for retrospective dose assessments using OSL: signal integrity and its dependence on containment, sample collection, and signal readout. AB - The aim of this work was to determine how a latent optically stimulated luminescence (OSL) signal in irradiated household salt is preserved under various ambient conditions, from the time of exposure to the time of signal readout. The following parameters were examined: optical fading in fluorescent light and under darkroom conditions (red light), thermal stability of the OSL signal during storage in a light-tight container, optical fading in representative container types, and sensitization effects of the OSL signal in exposed household salt. Furthermore, the influence of grain mixing within the saltshaker or salt container was studied by determining the dose gradient within typical salt packages. Finally, the signal integrity of salt irradiated under field conditions in a village in Belarus contaminated by Chernobyl fallout was investigated. The results show that the OSL signal in household salt is preserved in large cardboard box containers, but not in white plastic salt containers or in small portion bags used in, e.g., fast food restaurants. Furthermore, the continuous wave blue OSL signal in household salt does not fade significantly during storage up to 140 days. On the contrary, the signal appears to slowly increase during storage ("inverse fading"). Field tests of two different salt containers (with and without black tape to block light) located in Belarussian households confirmed that the signal is preserved in white plastic salt containers when they are covered with extra light-shielding material. PMID- 24811726 TI - Protective effect of an antithyroid compound against gamma-radiation-induced damage in human colon cancer cells. AB - We have previously reported the radioprotective effect of propylthiouracil (PTU) on thyroid cells. The aim of the present study was to analyze whether tumor cells and normal cells demonstrate the same response to PTU. Human colon carcinoma cells were irradiated with gamma-irradiation with or without PTU. We evaluated the clonogenic survival, intracellular reactive oxygen species levels, catalase, superoxide dismutase and glutathione peroxidase activities, and apoptosis by nuclear cell morphology and caspase-3 activity assays. Cyclic AMP (cAMP) levels were measured by radioimmunoassay. PTU treatment increased surviving cell fraction at 2 Gy (SF2) from 56.9 +/- 3.6 in controls to 75.0 +/- 3.5 (p < 0.05) and diminished radiation-induced apoptosis. In addition, we observed that the level of antioxidant enzymes' activity was increased in cells treated with PTU. Moreover, pretreatment with PTU increased intracellular levels of cAMP. Forskolin (p < 0.01) and dibutyryl cAMP (p < 0.05) mimicked the effect of PTU on SF2. Co treatment with H89, an inhibitor of protein kinase A, abolished the radioprotective effect of PTU. PTU reduces the toxicity of ionizing radiation by increasing cAMP levels and also possibly through a reduction in apoptosis levels and in radiation-induced oxidative stress damage. We therefore conclude that PTU protects both normal and cancer cells during exposure to radiation in conditions mimicking the radiotherapy. PMID- 24811728 TI - Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident. AB - Sweden received about 5 % of the total release of (137)Cs from the Chernobyl nuclear power plant accident in 1986. The distribution of the fallout mainly affected northern Sweden, where some parts of the population could have received an estimated annual effective dose of 1-2 mSv per year. It is disputed whether an increased incidence of cancer can be detected in epidemiological studies after the Chernobyl nuclear power plant accident outside the former Union of Soviet Socialist Republics. In the present paper, a possible exposure-response pattern between deposition of (137)Cs and cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (2.2 million inhabitants in 1986). The activity of (137)Cs from the fallout maps at 1986 was used as a proxy for the received dose of ionizing radiation. Diagnoses of cancer (ICD-7 code 140-209) from 1980 to 2009 were received from the Swedish Cancer Registry (273,222 cases). Age-adjusted incidence rate ratios, stratified by gender, were calculated with Poisson regression in two closed cohorts of the population in the nine counties 1980 and 1986, respectively. The follow-up periods were 1980-1985 and 1986-2009, respectively. The average surface weighted deposition of (137)Cs at three geographical levels; county (n = 9), municipality (n = 95) and parish level (n = 612) was applied for the two cohorts to study the pre- and the post-Chernobyl periods separately. To analyze time trends, the age-standardized total cancer incidence was calculated for the general Swedish population and the population in the nine counties. Joinpoint regression was used to compare the average annual percent change in the general population and the study population within each gender. No obvious exposure response pattern was seen in the age-adjusted total cancer incidence rate ratios. A spurious association between fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of (137)Cs. Increasing the geographical resolution of exposure from nine county averages to 612 parish averages resulted in a two to three times higher value of variance in the regression model. There was a secular trend with an increase in age-standardized incidence of cancer in both genders from 1980 to 2009, but significant only in females. This trend was stronger and statistically significant for both genders in the general Swedish population compared to the nine counties. In conclusion, using both high quality cancer registry data and high resolution exposure maps of (137)Cs deposition, it was not possible to distinguish an effect of (137)Cs on cancer incidence after the Chernobyl nuclear power plant accident in Sweden. PMID- 24811729 TI - In vivo noninvasive measurement of skin autofluorescence biomarkers relate to cardiovascular disease in mice. AB - BACKGROUND AND OBJECTIVE: The formation of reactive oxygen species (ROS) is associated with cardiovascular disease (CVD). High dietary cholesterol can significantly alter the delicate balance between pro-oxidation and antioxidant defences leading to reactive oxygen species formation in the vasculature, without significant structural changes in tissue composition. We aimed to establish a methodology for the noninvasive assessment of skin fluorescent biomarkers in mice. MATERIALS AND METHODS: C57/black/6 wild-type (WT; n = 25) male mice were subdivided to receive normal rodent chow (n = 11) or a high cholesterol diet (2% cholesterol; n = 14) for 20 weeks. Skin autofluorescence measurements were made on the backs of anaesthetized (1.5-2% isoflurane in oxygen) mice. A laser probe was used to make simultaneous measurements of: collagen, elastin, nicotinamide pyridoxine, flavins, lipofuscin and beta-carotene. Results are expressed as group mean in arbitrary units (AU) +/- standard error (SE). Hearts were excised and weighed (mg); cardiac hypertrophy was measured by ratio [heart weight (mg)/bodyweight (g) +/- SE]. Student's t-test was used for statistical significance analysis (p <= 0.05). RESULTS: There were no significant differences between cholesterol- and chow-fed animals for collagen (34 +/- 5AU vs. chow 34 +/ 4 AU, p = 0.51) and elastin (66 +/- 6 AU vs. chow 82 +/- 7 AU, p = 0.11). Significant differences were evident for nicotinamide adenine dinucleotide (92 +/ 7 AU vs. chow 118 +/- 7 AU, p = 0.01), pyridoxine (56 +/- 4 AU vs. chow 73 +/- 4 AU, p = 0.01), flavins (44 +/- 3 AU vs. chow 57 +/- 4 AU, p = 0.01), lipofuscin (35 +/- 3 AU vs. chow 46 +/- 3 AU, p = 0.01) and beta-carotene (19 +/- 2 AU vs. chow 25 +/- 2 AU, p = 0.01). Cholesterol-fed animals had significantly heavier hearts (7 +/- 0.3 ratio vs. chow 5 +/- 0.1 ratio, p = 0.001). CONCLUSION: Cholesterol feeding induced cardiovascular disease as noted by cardiac hypertrophy in wild-type mice. A reduction was observed in pyridoxine, nicotinamide adenine dinucleotide, flavins, lipofuscin and beta-carotene, which are established risk factors for cardiovascular disease. We report no significant changes in structural proteins collagen and elastin, suggesting no generalized tissue restructuring, which might otherwise explain the observed pathological differences. PMID- 24811730 TI - Single-layered graphitic-C(3)N(4) quantum dots for two-photon fluorescence imaging of cellular nucleus. AB - A promising, safe, and economic fluorescent probe, g-C3 N4 single-layered QDs, is introduced for two-photon fluorescence imaging of the cellular nucleus for the first time. The large two-photon absorption cross section, the high photostability, good biocompatibility and non-toxicity, negligible photothermal effect, and specific interaction with DNA render the single-layered g-C3 N4 QDs as a promising candidate for in vivo and in vitro two-photon fluorescence imaging and further biomedical applications. PMID- 24811732 TI - Assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: systematic review and meta-regression. AB - OBJECTIVE: To assess the impact of inadequate water and sanitation on diarrhoeal disease in low- and middle-income settings. METHODS: The search strategy used Cochrane Library, MEDLINE & PubMed, Global Health, Embase and BIOSIS supplemented by screening of reference lists from previously published systematic reviews, to identify studies reporting on interventions examining the effect of drinking water and sanitation improvements in low- and middle-income settings published between 1970 and May 2013. Studies including randomised controlled trials, quasi randomised trials with control group, observational studies using matching techniques and observational studies with a control group where the intervention was well defined were eligible. Risk of bias was assessed using a modified Ottawa Newcastle scale. Study results were combined using meta-analysis and meta regression to derive overall and intervention-specific risk estimates. RESULTS: Of 6819 records identified for drinking water, 61 studies met the inclusion criteria, and of 12,515 records identified for sanitation, 11 studies were included. Overall, improvements in drinking water and sanitation were associated with decreased risks of diarrhoea. Specific improvements, such as the use of water filters, provision of high-quality piped water and sewer connections, were associated with greater reductions in diarrhoea compared with other interventions. CONCLUSIONS: The results show that inadequate water and sanitation are associated with considerable risks of diarrhoeal disease and that there are notable differences in illness reduction according to the type of improved water and sanitation implemented. PMID- 24811731 TI - Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice. AB - Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis. PMID- 24811733 TI - Cloning and characterization of Pangasianodon hypophthalmus growth hormone gene and its heterologous expression. AB - Pangasianodon hypophthalmus is one of the fast-growing catfish of freshwater origin, and its growth is attributed by the action of growth hormone (GH). In this study, the growth hormone gene (PhGH) of 3.0 kb was characterized, and it is composed of five exons and four introns and having characteristics of an upstream region that contains TATA, CAAT boxes, and binding sites of important transcription factors like Pit-1a, CRE, CREB, CREBP, Ap-1, SP1, and TBP. The full length cDNA sequence of 1,069 bp was isolated using RACE technique, and it is composed of untranslated regions of 60 and 403 bp at 5' and 3', respectively, with an open reading frame of 603 bp that encodes a putative polypeptide of 200 amino acids with an estimated molecular mass of 22.57 kDa. The precursor of PhGH is composed of 22 amino acid signal peptides and 178 amino acid mature peptides. Five conserved Cys residues (Cys(71), Cys(135), Cys(173), Cys(190), and Cys(198)) and two possible sites of N-glycosylation (145th and 197th) were detected on GH polypeptide. The PhGH gene showed more than 90 % sequence similarity with other catfishes, and the phylogeny constructed revealed the close proximity of Siluriformes fishes with Cypriniformes fishes. The PhGH gene was observed to be expressed predominantly in pituitary tissues while weekly expressed in extrapituitary tissues. Further, the recombinant PhGH was expressed in Escherichia coli using His-tag expression vector pET 32(a), and the recombinant protein of ~23 kDa was confirmed by western blotting. Our findings suggest that the identified functional GH gene would provide basic information in transgenic studies aiming for faster growth rate. This recombinant growth hormone (GH) may be produced in large scale to exploit its growth-promoting function in other cultured fishes. PMID- 24811734 TI - Evaluation of internal control for gene expression in Phalaenopsis by quantitative real-time PCR. AB - The selection of appropriate reference genes is one of the most important steps to obtain reliable results for normalizing quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) of MADS-box gene in Phalaenopsis. In this study, we cloned 12 candidate reference genes including 18S ribosomal RNA (18S), elongation factor 1 alpha (EF1alpha), cytoskeletal structural protein actin (ACT1, ACT2, ACT3, ACT4, ACT5), ubiquitin protein (UBQ1 and UBQ2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the cytoskeletal structural proteins alpha-tubulin (TUA) and beta-tubulin (TUB) in Phalaenopsis and evaluated their expression reliability. The expression of these candidate reference genes was analyzed using geNorm and normFinder software packages; the results showed that ACT2 and ACT4 were the highest stability reference genes for all experiment sets based on normFinder, followed by ACT1 or ACT3, while ACT3 and ACT4 were the highest stability reference genes for most experiment sets based on geNorm, then TUB or others. Taken together, Actin genes were the higher stability reference genes for all tissues at total developmental stages, and similar results came from analysis by normFinder. According to geNorm analysis, ACT3 and ACT4 were the most stable reference genes for all tissues tested and tissues at reproductive stages; TUB and ACT5 or ACT4 were the most stable reference genes for vegetative tissues or roots. The most stable reference genes for all vegetative tissues and only leaves were ACT4 and ACT5, ACT2 and ACT3, respectively; ACT1 and ACT3 were the most stable genes and sufficient for reliable normalization of flower tissues. While EF1alpha, UBQ1, UBQ2, and GAPDH were found to be unsuitable as a reference gene in our analysis for flower tissues, total tissues, and reproductive stages; UBQ2 and 18S were identified as the least stable reference genes for vegetative tissues at different stages, different tissues at vegetative stages; TUA and 18S were the least reliable reference genes for the samples from roots at all developmental stages. This is the first systematic report on the selection of reference genes in Phalaenopsis, and these data will facilitate future work on gene expression in orchid. PMID- 24811736 TI - Mendelian-mutationism: the forgotten evolutionary synthesis. AB - According to a classical narrative, early geneticists, failing to see how Mendelism provides the missing pieces of Darwin's theory, rejected gradual changes and advocated an implausible yet briefly popular view of evolution-by mutation; after decades of delay (in which synthesis was prevented by personal conflicts, disciplinary rivalries, and anti-Darwinian animus), Darwinism emerged on a new Mendelian basis. Based on the works of four influential early geneticists - Bateson, de Vries, Morgan and Punnett -, and drawing on recent scholarship, we offer an alternative that turns the classical view on its head. For early geneticists, embracing discrete inheritance and the mutation theory (for the origin of hereditary variation) did not entail rejection of selection, but rejection of Darwin's non-Mendelian views of heredity and variation, his doctrine of naturanon facitsaltum, and his conception of "natural selection" as a creative force that shapes features out of masses of infinitesimal differences. We find no evidence of a delay in synthesizing mutation, rules of discrete inheritance, and selection in a Mendelian-Mutationist Synthesis. Instead, before 1918, early geneticists had conceptualized allelic selection, the Hardy-Weinberg equilibrium, the evolution of a quantitative trait under selection, the probability of fixation of a new mutation, and other key innovations. Contemporary evolutionary thinking seems closer to their more ecumenical view than to the restrictive mid-twentieth-century consensus known as the Modern Synthesis. PMID- 24811735 TI - Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors. AB - Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as alpha-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile. PMID- 24811737 TI - Scribed transparency microplates mounted on a modified standard microplate. AB - The immense cost effectiveness of using transparencies as analyte handling implements in microplate instrumentation offers the possibility of application even in resource-limited laboratories. In this work, a standard microplate was adapted to serve as the permanent base for disposable scribed transparencies. The approach is shown to ameliorate evaporation, which can affect assay accuracy when analytes need to be incubated for some time. It also offers assurance against fluorescence measurement errors due to the cross-talk of samples from adjacent wells. PMID- 24811738 TI - A colorimetric aptasensor for the highly sensitive detection of 8-hydroxy-2' deoxyguanosine based on G-quadruplex-hemin DNAzyme. AB - A highly sensitive, low-cost colorimetric aptasensor was developed for the determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in human urine. The method is based on a conformational switching of the 8-OHdG aptamer to form a G quadruplex structure in the presence of 8-OHdG. The resulting G-quadruplex assembles into a peroxidase-like DNAzyme with hemin, which effectively catalyzes the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS(2-)) by H2O2 to ABTS(+), resulting in an increase in the absorption signal at 416nm along with a color change of the solution. The response signals linearly correlated with the concentration of 8-OHdG, ranging from 466pM to 247nM with a detection limit of 141pM. The relative standard deviation and the recovery were 1.97-3.47% (n=11) and 98.8-100.2%, respectively. The proposed method avoids the label and derivatization steps in common methods and allows direct analysis of the samples by the naked eye without costly instruments, which is reliable, inexpensive, and sensitive. PMID- 24811739 TI - Recovery of pituitary function following treatment of an unruptured giant cavernous carotid aneurysm using Surpass flow-diverting stents. AB - Giant aneurysms arising from the cavernous internal carotid artery (ICA) can mimic pituitary adenomas and may cause pituitary dysfunction due to their mass effect on the pituitary gland. We report a case of a 56-year-old man presenting with impotence, fatigue and panhypopituitarism who was found to have a giant unruptured aneurysm arising from the right cavernous ICA with severe mass effect on the pituitary gland. The patient underwent endovascular treatment of the giant aneurysm using two telescoping Surpass flow-diverting stents. At 6-month follow up, repeat cerebral angiography showed Raymond grade II occlusion of the aneurysm with a small neck remnant. At the 10-month follow-up the patient showed full recovery of his pituitary function and clinical resolution of impotence and fatigue. This is the first report of occlusion of a giant cavernous carotid aneurysm using next generation Surpass flow-diverting stents leading to complete recovery of pituitary function. PMID- 24811740 TI - Rupture Resemblance Score (RRS): toward risk stratification of unruptured intracranial aneurysms using hemodynamic-morphological discriminants. AB - OBJECTIVE: We have previously developed three logistic regression models for discriminating intracranial aneurysm rupture status from 119 aneurysms based on hemodynamic-morphological parameters. In this study we exploit their use as a tool for predicting the risk of rupture of aneurysms with a defined Rupture Resemblance Score (RRS). METHODS: We collected three-dimensional images of 85 consecutive aneurysms, applied the three regression models and compared model performance at predicting rupture status against anecdotal metrics (aneurysm size and aspect ratio). We then reinterpreted the model-predicted probability as RRS, where the higher the score the closer the resemblance to previously known rupture components, and applied the RRS prospectively to four unruptured aneurysms with borderline treatment decisions. RESULTS: All three models yielded excellent sensitivity (0.78-0.83) and specificity (0.78-0.84) at a cutoff score of 50%, whereas aneurysm size and aspect ratio showed poor sensitivities (0.28 and 0.33, respectively). Lowering the cutoff score to 30% improved sensitivity to 0.90. The RRS identified most of the ruptured aneurysms and also some unruptured ones that closely resembled ruptured aneurysms hemodynamically and/or morphologically. The prospective application of the RRS to unruptured aneurysms shows that it could provide additional insights for treatment decisions. CONCLUSIONS: Previous regression models based on hemodynamic-morphological parameters are able to discriminate rupture in a new cohort in the same population. A higher probability of rupture is associated with larger size ratio, lower normalized wall shear stress and higher oscillatory shear index. The RRS could potentially stratify rupture risk and assist in treatment decision-making for unruptured aneurysms. PMID- 24811741 TI - Outcomes of manual aspiration thrombectomy for acute ischemic stroke refractory to stent-based thrombectomy. AB - BACKGROUND AND PURPOSE: The optimal treatment for patients with acute stroke refractory to stent-based thrombectomy (SBT) is unclear. This study aimed to report clinical outcomes of manual aspiration thrombectomy (MAT) for the treatment of acute ischemic stroke refractory to SBT. METHODS: We retrospectively analyzed clinical and angiographic data of 30 patients who underwent MAT with a Penumbra reperfusion catheter because of refractory occlusion after SBT with a Solitaire stent as first-line endovascular therapy. Refractory occlusion was defined by a lack of successful revascularization (defined as Thrombolysis In Cerebral Infarction >=2b) after five retrieval attempts. A good outcome was defined as a modified Rankin scale score of <=2 at 3 months. RESULTS: Successful revascularization was achieved in 83.3% (25/30) of the patients who underwent MAT after failed SBT. There was no arterial rupture or dissection or symptomatic intracranial hemorrhage. Two embolic occlusions in a new arterial territory and five subarachnoid hemorrhages occurred, neither of which caused neurological worsening. At the 3-month follow-up, 36.7% (11/30) of patients exhibited a good outcome. The mortality rate was 6.7% (2/30) at 3 months. CONCLUSIONS: This study suggests that MAT with the Penumbra reperfusion catheter can further increase the revascularization rate without serious complications in patients with acute stroke with refractory occlusions after SBT with a Solitaire stent. PMID- 24811742 TI - Results of a national cerebrovascular neurosurgery survey on the management of cerebral vasospasm/delayed cerebral ischemia. AB - OBJECTIVE: Following aneurysmal subarachnoid hemorrhage, cerebral vasospasm/delayed cerebral ischemia accounts for significant morbidity and mortality. In this paper we provide the first glimpse of actual practice in the management of cerebral vasospasm in the USA. METHODS: All active members of the Joint American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Cerebrovascular Section were emailed the survey. The responses were collected anonymously. RESULTS: The response rate for this survey was 44% (177 responses/400 total members). Non-responders were characterized by the fact that multiple responders were not obtained from practices that had multiple providers with uniform practice. Both high-volume and low-volume centers were equally represented. Optimizing medical management is first-line treatment in practice. Although there is some variability regarding screening methods, the greatest variability occurs with regard to the choice of intra-arterial treatment drug and dose. There is also considerable variability in the perceived effectiveness of endovascular treatment for vasospasm. CONCLUSIONS: In this preliminary glimpse of actual cerebral vasospasm management practice in the USA, two salient points emerge: (1) there is considerable variability in intra arterial therapies for vasospasm; and (2) there are major differences in the perceived effectiveness of these therapies. Standardization of intra-arterial therapies may contribute to improved outcomes. A prospective randomized trial evaluating endovascular treatment for cerebral vasospasm is needed. PMID- 24811743 TI - Augmentation of N-butyl cyanoacrylate embolization of cranial, head, and neck tumors by simultaneous infusion of 5% dextrose solution. AB - BACKGROUND: N-Butyl cyanoacrylate (NBCA) is an adhesive liquid embolic agent widely used for embolization of cranial, head and neck tumors. Adequate distal penetration of NBCA into vessels with the smallest possible diameter, while preventing its reflux, is still a challenge, even in experienced hands. Simultaneous infusion of 5% dextrose in water solution (D5W) through the guiding catheter has been described before as a technique for improving embolization of dural arteriovenous malformations. OBJECTIVE: To describe our experience with a modified D5W guide catheter push technique during embolization of hemorrhagic cranial, head and neck tumors. The embolization technique and pitfalls which might lead to complications are discussed in detail. MATERIALS: A retrospective series of 20 patients treated with the D5W push technique during embolization of cranial, head and neck lesions between 2007 and 2013 is presented. The goal of embolization was preoperative or palliative embolization of hemorrhagic tumors. Localization and histopathologic diagnosis of lesions, concentration of NBCA used, subsequent surgical treatment, intraoperative blood loss, and complications were evaluated. RESULTS: A total of 44 arterial pedicles were embolized during 22 treatment sessions. Adequate embolization of the lesions was achieved in all cases. Transient ischemic attack due to atheroma embolization (from the aorta) was seen in one patient (4%). Persistent vascularity of tumor associated with minimal intraoperative bleeding was reported in one patient (4%). Recurrence of epistaxis was reported in two patients diagnosed with Osler-Weber-Rendu syndrome. CONCLUSIONS: The D5W push technique during NBCA embolization of cranial, head and neck tumors is a safe and effective method to enhance penetration of the embolizing agent. PMID- 24811744 TI - Differences in vitamin D concentration between metabolically healthy and unhealthy obese adults: associations with inflammatory and cardiometabolic markers in 4391 subjects. AB - AIM: This study aimed to compare concentrations of serum 25-hydroxy vitamin D and inflammatory markers in metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), and to determine whether the relationship between vitamin D levels and both cardiometabolic and inflammatory markers differs between MHO and MUO. METHODS: This cross-sectional study comprised 4391 obese subjects aged>18 years. A panel of cardiometabolic and inflammatory markers, including anthropometric variables, glycaemic indices, lipid profiles, liver enzymes, homocysteine, C-reactive protein (CRP), fibrinogen and serum 25-hydroxy vitamin D levels, was investigated. All cardiometabolic and inflammatory markers in MHO and MUO as well as in vitamin D deficiency were compared. RESULTS: Prevalence of MHO was 41.9% in our obese subjects using International Diabetes Federation criteria. Considering insulin resistance and inflammation, the prevalence of MHO was 38.4%. Individuals with MHO had significantly higher vitamin D concentrations compared with MUO, and this difference in vitamin D status persisted after accounting for BMI and waist circumference. Subjects with MHO had significantly better metabolic status, lower liver enzymes, lower inflammatory markers and higher serum 25-hydroxy vitamin D than those with MUO. Associations between vitamin D levels and inflammatory and cardiometabolic markers differed according to MHO/MUO status. Among MUO subjects, vitamin D deficiency was associated with higher liver marker and homocysteine levels. Serum vitamin D was negatively associated with fasting plasma glucose and HbA1c in MHO only. CONCLUSION: Serum 25-hydroxy vitamin D levels were lower in MUO vs MHO, and reduced vitamin D concentrations were more strongly associated with cardiometabolic and inflammatory markers in MUO than in MHO subjects. These findings suggest that a deficiency in vitamin D could be a key component of MUO. PMID- 24811745 TI - Plant volatiles and the environment. AB - Volatile organic compounds emitted by plants represent the largest part of biogenic volatile organic compounds (BVOCs) released into our atmosphere. Plant volatiles are formed through many biochemical pathways, constitutively and after stress induction. In recent years, our understanding of the functions of these molecules has made constant and rapid progress. From being considered in the past as a mere waste of carbon, BVOCs have now emerged as an essential element of an invisible language that is perceived and exploited by the plants' enemies, the enemies of plant enemies, and neighbouring plants. In addition, BVOCs have important functions in protecting plants from abiotic stresses. Recent advances in our understanding of the role of BVOC in direct and indirect defences are driving further attention to these emissions. This special issue gathers some of the latest and most original research that further expands our knowledge of BVOC. BVOC emissions and functions in (1) unexplored terrestrial (including the soil) and marine environments, (2) in changing climate conditions, and (3) under anthropic pressures, or (4) in complex trophic communities are comprehensively reviewed. Stepping up from scientific awareness, the presented information shows that the manipulation and exploitation of BVOC is a realistic and promising strategy for agricultural applications and biotechnological exploitations. PMID- 24811746 TI - Genetic characterization of a noncytopathic bovine viral diarrhea virus 2b isolated from cattle in China. AB - In January 2013, several clinical signs of cattle with diarrhea, cough, nasal discharge, and fever were reported in Jilin province, China. One virus named SD1301 was isolated and identified. Complete genome of the virus is 12258nt in length and contains a 5'UTR, one open reading frame encoding a polyprotein of 3,897 amino acids and a 3'UTR. Phylogenetic analysis of 5'UTR, N(pro), E1 and E2 gene demonstrated the virus belonged to BVDV 2b, and genetically related to the BVDV strain Hokudai-Lab/09 from Japan in 2010. This bovine viral diarrhea virus displays a unique genetic signature with 27-nucleotide deletion in the 5'UTR, which is similar to the bovine viral diarrhea virus C413 (AF002227). This was the first confirmed isolation of ncp BVDV2b circulating in bovine herd of China. PMID- 24811747 TI - Hydrogen bonding-assisted thermal conduction in beta-sheet crystals of spider silk protein. AB - Using atomistic simulations, we demonstrate that beta-sheet, an essential component of spider silk protein, has a thermal conductivity 1-2 orders of magnitude higher than that of some other protein structures reported in the literature. In contrast to several other nanostructured materials of similar bundled/layered structures (e.g. few-layer graphene and bundled carbon nanotubes), the beta-sheet is found to uniquely feature enhanced thermal conductivity with an increased number of constituting units, i.e. beta-strands. Phonon analysis identifies inter-beta-strand hydrogen bonding as the main contributor to the intriguing phenomenon, which prominently influences the state of phonons in both low- and high-frequency regimes. A thermal resistance model further verifies the critical role of hydrogen bonding in thermal conduction through beta-sheet structures. PMID- 24811748 TI - Recycling of polymers: a review. AB - Plastics are inexpensive, easy to mold, and lightweight. These and many other advantages make them very promising candidates for commercial applications. In many areas, they have substantially suppressed traditional materials. However, the problem of recycling still is a major challenge. There are both technological and economic issues that restrain the progress in this field. Herein, a state-of art overview of recycling is provided together with an outlook for the future by using popular polymers such as polyolefins, poly(vinyl chloride), polyurethane, and poly(ethylene terephthalate) as examples. Different types of recycling, primary, secondary, tertiary, quaternary, and biological recycling, are discussed together with related issues, such as compatibilization and cross-linking. There are various projects in the European Union on research and application of these recycling approaches; selected examples are provided in this article. Their progress is mirrored by granted patents, most of which have a very limited scope and narrowly cover certain technologies. Global introduction of waste utilization techniques to the polymer market is currently not fully developed, but has an enormous potential. PMID- 24811749 TI - Autoubiquitination of the 26S proteasome on Rpn13 regulates breakdown of ubiquitin conjugates. AB - Degradation rates of most proteins in eukaryotic cells are determined by their rates of ubiquitination. However, possible regulation of the proteasome's capacity to degrade ubiquitinated proteins has received little attention, although proteasome inhibitors are widely used in research and cancer treatment. We show here that mammalian 26S proteasomes have five associated ubiquitin ligases and that multiple proteasome subunits are ubiquitinated in cells, especially the ubiquitin receptor subunit, Rpn13. When proteolysis is even partially inhibited in cells or purified 26S proteasomes with various inhibitors, Rpn13 becomes extensively and selectively poly-ubiquitinated by the proteasome associated ubiquitin ligase, Ube3c/Hul5. This modification also occurs in cells during heat-shock or arsenite treatment, when poly-ubiquitinated proteins accumulate. Rpn13 ubiquitination strongly decreases the proteasome's ability to bind and degrade ubiquitin-conjugated proteins, but not its activity against peptide substrates. This autoinhibitory mechanism presumably evolved to prevent binding of ubiquitin conjugates to defective or stalled proteasomes, but this modification may also be useful as a biomarker indicating the presence of proteotoxic stress and reduced proteasomal capacity in cells or patients. PMID- 24811751 TI - Predictors of lapse and relapse to smoking in successful quitters in a varenicline post hoc analysis in Japanese smokers. AB - BACKGROUND: The efficacy of the smoking-cessation agent varenicline has been reported in Asian smokers; however, few studies have investigated factors that contribute to lapse and relapse. OBJECTIVE: This post hoc analysis aimed to identify predictors of smoking lapse and relapse. METHODS: This was a post-hoc analysis based on a double-blind, placebo-controlled, randomized, parallel-group study in which Japanese smokers (aged 20-75 years) who smoked >= 10 cigarettes/day and were motivated to quit were randomized to receive varenicline (0.25 mg twice daily [BID], 0.5 mg BID, 1 mg BID) or placebo for 12 weeks followed by a 40-week non-treatment follow-up. For inclusion in this analysis, participants must have been nicotine dependent (Tobacco Dependence Screener score >= 5) and must have successfully quit smoking continuously for 4 weeks (weeks 9 12). Lapse was defined by answering yes to >= 1 question in the Nicotine Use Inventory. Relapse was defined by participants having smoked for >= 7 days during follow-up measured by the Nicotine Use Inventory. RESULTS: Of the 619 randomized individuals, 515 had a Tobacco Dependence Screener score of >= 5, and 277 quit smoking continuously from weeks 9 to 12. Approximately 75% were male, with a mean (SD) BMI of 23.0 (3.0) kg/m(2). Maximum length of continuous abstinence (CA) during treatment and age (both P < 0.0001) were significant predictors of lapse. Maximum CA (P < 0.0001), age (P = 0.0002), Minnesota Nicotine Withdrawal Scale (MNWS) score for urge to smoke (P = 0.0019), and having made >= 1 serious quit attempt (P = 0.0063) were significant predictors of relapse. For participants with a maximum CA of 4 to 6 weeks versus those with a maximum CA of 10 to 11 weeks, the ORs for lapse and relapse were 4.649 (95% CI, 2.071-10.434) and 3.337 (95% CI, 1.538-7.239), respectively. In participants aged 21-34 years versus those aged 47-72 years, the ORs for lapse and relapse were 3.453 (95% CI 1.851, 6.441) and 3.442 (95% CI 1.795, 6.597), respectively. Participants with a MNWS urge to smoke score of 2 to 4 versus 0 had an OR for relapse of 3.175 (95% CI, 1.166-8.644). Participants having made >= 1 versus no serious quit attempts had an OR for relapse of 2.108 (95% CI, 1.168-3.805). CONCLUSION: Shorter maximum CA and younger age at quit attempt were associated with increased risk of lapse and relapse. Higher MNWS urge to smoke score and having made >= 1 serious quit attempt were associated with increased relapse risk. ClinicalTrials.gov identifier: NCT00139750. PMID- 24811750 TI - Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. AB - Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age. The molecular mechanisms responsible for these declines remain unclear. Here, we show that levels of NAD(+) and nicotinamide phosphoribosyltransferase (Nampt), the rate limiting enzyme in mammalian NAD(+) biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD(+) levels. Nampt is the main source of NSPC NAD(+) levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical in oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon insult. These phenotypes recapitulate defects in NSPCs during aging, giving rise to the possibility that Nampt-mediated NAD(+) biosynthesis is a mediator of age-associated functional declines in NSPCs. PMID- 24811752 TI - Evaluating the psychometric properties of the CAHPS Patient-centered Medical Home survey. AB - OBJECTIVE: The goal of this study was to evaluate the reliability and validity of the Consumer Assessment of Healthcare Providers and Systems (CAHPS) Patient Centered Medical Home (PCMH) survey. METHODS: We conducted a field test of the CAHPS PCMH survey with 2740 adults. We collected information by mail (n = 1746), telephone (n = 672), and from the Web (n = 322) from 6 sites of care affiliated with a West Coast staff model health maintenance organization. RESULTS: An overall response rate of 37% was obtained. Internal consistency reliability estimates for 7 multi-item scales were as follows: access to care, 5 items, alpha = 0.79; communication with providers, 6 items, alpha = 0.93; office staff courtesy and respect, 2 items, alpha = 0.80; shared decision making about medicines, 3 items, alpha = 0.67; self-management support, 2 items, alpha = 0.61; attention to mental health issues, 3 items, alpha = 0.80; and care coordination, 4 items, alpha = 0.58. The number of responses needed to get reliable information at the site of care level for the composites was generally acceptable (<300 for 0.70 reliability-level) except for self-management support and shared decision making about medicines. Item-scale correlations provided support for distinct composites except for access to care and shared decision making about medicines, which overlapped with the communication with providers scale. Shared decision making and self-management support were significantly, uniquely associated with the global rating of the provider (dependent variable), along with access and communication in a multiple regression model. CONCLUSIONS: This study provides further support for the reliability and validity of the CAHPS PCMH survey, but refinement of the self-management support and shared decision-making scales is needed. The survey can be used to provide information about the performance of different health plans on multiple domains of health care, but future efforts to improve some of the survey items is needed. PMID- 24811753 TI - Overview of classical test theory and item response theory for the quantitative assessment of items in developing patient-reported outcomes measures. AB - BACKGROUND: The US Food and Drug Administration's guidance for industry document on patient-reported outcomes (PRO) defines content validity as "the extent to which the instrument measures the concept of interest" (FDA, 2009, p. 12). According to Strauss and Smith (2009), construct validity "is now generally viewed as a unifying form of validity for psychological measurements, subsuming both content and criterion validity" (p. 7). Hence, both qualitative and quantitative information are essential in evaluating the validity of measures. METHODS: We review classical test theory and item response theory (IRT) approaches to evaluating PRO measures, including frequency of responses to each category of the items in a multi-item scale, the distribution of scale scores, floor and ceiling effects, the relationship between item response options and the total score, and the extent to which hypothesized "difficulty" (severity) order of items is represented by observed responses. RESULTS: If a researcher has few qualitative data and wants to get preliminary information about the content validity of the instrument, then descriptive assessments using classical test theory should be the first step. As the sample size grows during subsequent stages of instrument development, confidence in the numerical estimates from Rasch and other IRT models (as well as those of classical test theory) would also grow. CONCLUSION: Classical test theory and IRT can be useful in providing a quantitative assessment of items and scales during the content-validity phase of PRO-measure development. Depending on the particular type of measure and the specific circumstances, the classical test theory and/or the IRT should be considered to help maximize the content validity of PRO measures. PMID- 24811755 TI - Reversible posterior leukoencephalopathy syndrome in a child with hemolytic uremic syndrome. PMID- 24811754 TI - The STAR Study: a real-world, international, observational study of the safety and tolerability of, and adherence to, serum-free subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis. AB - BACKGROUND: Adverse reactions, particularly injection site reactions (ISRs), are common reasons for nonadherence to injectable multiple sclerosis (MS) treatments. Adherence to MS treatment is important to ensure good treatment outcomes. OBJECTIVE: The aim of this study was to assess the local tolerability of subcutaneous (SC) serum-free interferon (IFN) beta-1a in patients with relapsing MS over 1 year in a real-life, international setting. The study also assessed safety, disease activity, and adherence. METHODS: This was a prospective, international, multicenter, observational study of 251 patients with relapsing remitting MS treated with SC serum-free IFN beta-1a 44 MUg or 22 MUg 3 times weekly for 12 months or until early discontinuation. The primary end point was the proportion of patients with ISRs. Secondary end points included proportion of patients with adverse events (AEs); annualized relapse rate (ARR); proportion of patients remaining relapse-free; and adherence to treatment. RESULTS: During the observation period, 27.5% (69 of 251) of patients experienced nonserious ISRs, which was consistent with the incidence reported in clinical studies. Five patients discontinued treatment and 2 patients suspended treatment because of ISRs. Mean age was 35.8 years; patients were predominantly white (94.8%), and two thirds (66.1%) were female. The overall incidence of AEs was 63.7% (160 of 251), and overall safety and tolerability were assessed as excellent, very good, or good in >85% of patients. More than 70% of patients remained relapse-free, and the mean ARR was 0.4. More than 90% of patients had very good or good adherence to treatment; a significantly greater proportion of these were relapse-free at 12 months compared with those with fair or poor adherence (77.6% vs 50.0%; P = 0.0107), and their ARR was significantly lower (0.3 vs 0.9; P = 0.0055). Patients with fair or poor adherence had 4.6 times higher odds of experiencing a relapse than those with very good or good adherence. CONCLUSIONS: The incidence of ISRs and the overall safety profile in this observational study, in an international population in a real-life setting, confirm the good local tolerability of SC serum-free IFN beta-1a reported in clinical studies. The association between good adherence and a lower ARR underlines the importance of good adherence. The good local and general tolerability of SC IFN beta-1a may help ensure a high level of adherence, which is associated with better clinical outcomes. ClinicalTrials.gov identifier: NCT01080027. PMID- 24811756 TI - Green synthesis of reduced graphene oxide/polyaniline composite and its application for salt rejection by polysulfone-based composite membranes. AB - In this study, a novel, simple, and eco-friendly enzymatic-reaction-based approach to produce reduced graphene oxide/polyaniline (rGO/PANI) composite material was proposed. Glucose oxidase (GOx) was used as an effective catalyst producing hydrogen peroxide, in the presence of glucose, for the oxidative polymerization of aniline under ambient conditions. The prepared rGO/PANI composite was dispersed in polysulfone (PSf), and the mixed membranes were prepared by the phase inversion polymerization method. The morphology of membranes was investigated using scanning electron microscopy (SEM), atomic force microscopy (AFM), and contact angle (CA) techniques. The performance of membranes was studied in terms of salt rejection and pure water flux. The incorporation of rGO into the membrane matrix led to hydrophobic membrane surface with the enhanced macro-voids. On the contrary, the contact angle data revealed that the rGO/PANI-incorporated membrane surface is partly hydrophilic due to the PANI fibers in membrane, whereas SEM images showed the enhanced macro-voids. Membranes exhibited an improved salt rejection after rGO/PANI doping. The rGO/PANI-modified membrane loading exhibited a maximum of 82% NaCl rejection at an applied pressure of 10 bar. In addition, the results showed that the PSf-rGO/PANI composite membrane had the highest mean porosity and water flux. PMID- 24811757 TI - Prospective associations between sedentary behaviour and risk of depression in socio-economically disadvantaged women. AB - OBJECTIVE: Although recent cross-sectional research has suggested a positive association between sedentary behaviour and risk of depression, the direction of associations is unclear. This study aimed to investigate prospective associations between sedentary behaviour and risk of depression in both directions in socio economically disadvantaged women. METHODS: 1511 women, aged 18-45, completed self report validated measures of sedentary behaviour (TV viewing, computer use, overall sitting time and screen time) as well as depressive symptoms (CES-D-10) in 2007/08 (T1) and 2010/11 (T2). Linear regression analyses examined associations between sedentary behaviours at T1 and depressive symptoms at T2, and multinomial logistic regression analyses examined associations between depressive symptoms at T1 and sedentary behaviours at T2. RESULTS: Although prospective analyses indicated no association between T1 sedentary behaviours and depressive symptoms at T2, results showed that depressive symptoms at T1 were associated with higher levels of TV viewing (adjusted odds ratio: 1.032, 95% CI: 1.00, 1.07) at T2. CONCLUSIONS: Women's sedentary behaviour may not predict subsequent depressive symptoms; however, women's risk of depression may be predictive of engaging in greater amounts of TV viewing. Confirmation of these findings using further prospective and intervention study designs is required. PMID- 24811758 TI - Empowering adolescents to be physically active: three-year results of the Sigue la Huella intervention. AB - OBJECTIVE: To examine the effects of a school-based intervention called Sigue la Huella (Follow the Footstep) on adolescents' daily moderate-to-vigorous physical activity (MVPA). METHOD: This quasi-experimental, cohort study took place in four secondary schools in Huesca (Spain) during the 2009-2010, 2010-2011, and 2011 2012 academic years (students aged 12-15 years). Two schools were assigned to the experimental condition (n=368) and two schools to the control condition (n=314). Sigue la Huella was based on the social ecological model and self-determination theory. MVPA was measured for 7 days on 4 occasions using accelerometers. Data were analyzed with individual growth curve models. RESULTS: There was a significant difference in linear growth rate of daily MVPA between the experimental and the control group, independent of study wave, type of school (public vs. private), grade level and gender (p<0.001). Specifically, MVPA increased in the experimental group (beta=7.02, 95% confidence interval (CI)=1.27 to 12.78, p=0.017) and tended to decrease in the control group (beta=-5.26, 95% CI=-11.17 to 0.65, p<0.081). The observed increase was larger in boys than in girls (p=0.003). CONCLUSIONS: Sigue la Huella had a positive effect on adolescents' daily MVPA over three school years. Both genders benefited from the intervention, although boys to a greater extent. PMID- 24811760 TI - Community ecology theory predicts the effects of agrochemical mixtures on aquatic biodiversity and ecosystem properties. AB - Ecosystems are often exposed to mixtures of chemical contaminants, but the scientific community lacks a theoretical framework to predict the effects of mixtures on biodiversity and ecosystem properties. We conducted a freshwater mesocosm experiment to examine the effects of pairwise agrochemical mixtures [fertiliser, herbicide (atrazine), insecticide (malathion) and fungicide (chlorothalonil)] on 24 species- and seven ecosystem-level responses. As postulated, the responses of biodiversity and ecosystem properties to agrochemicals alone and in mixtures was predictable by integrating information on each functional group's (1) sensitivity to the chemicals (direct effects), (2) reproductive rates (recovery rates), (3) interaction strength with other functional groups (indirect effects) and (4) links to ecosystem properties. These results show that community ecology theory holds promise for predicting the effects of contaminant mixtures on biodiversity and ecosystem services and yields recommendations on which types of agrochemicals to apply together and separately to reduce their impacts on aquatic ecosystems. PMID- 24811759 TI - A comparison of different strategies used to invite subjects with a positive faecal occult blood test to a colonoscopy assessment. A randomised controlled trial in population-based screening programmes. AB - OBJECTIVE: The purpose of this parallel randomised controlled trial was to compare compliance with different modalities used to invite patients with a positive immunochemical faecal occult blood test (FIT+) for a total colonoscopy (TC). METHOD: FIT+ patients from nine Italian colorectal cancer screening programmes were randomised to be invited for a TC initially by mail or by phone and, for non-compliers, to be recalled by mail, for counselling with a general practitioner, or to meet with a specialist screening practitioner (nurse or healthcare assistant). RESULTS: In all, 3777 patients were randomised to different invitation strategies. Compliance with an initial invitation by mail and by phone was similar (86.0% vs. 84.0%, relative risk - RR: 1.02; 95%CI 0.97 1.08). Among non-responders to the initial invitation, compliance with a recall by appointment with a specialist practitioner was 50.4%, significantly higher than with a mail recall (38.1%; RR:1.33; 95%CI 1.01-1.76) or with a face-to-face counselling with the GP (30.8%; RR:1.45;95%CI 1.14-1.87). CONCLUSION: Compliance with an initial invitation for a TC by mail and by phone was similar. A personal meeting with a specialist screening practitioner was associated with the highest compliance among non-compliers with initial invitations, while the involvement of GPs in this particular activity seemed less effective. PMID- 24811761 TI - Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice. AB - The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations. PMID- 24811762 TI - A rare case of hemangiomatosis of the spleen and intrapancreatic accessory spleen. AB - We presented a very rare case of hemangiomatosis of the spleen and intrapancreatic accessory spleen in the tail of the pancreas. A previously healthy 45-year-old woman felt left back pain and received CT scan. Multiple splenic masses and a pancreatic mass in the tail were detected. Both the lesions presented gradual and weak enhancement and pooling of the contrast medium until very late phase on dynamic MRI. Since the lesions in the spleen and the pancreas presented the same characteristics on dynamic CT/MRI, ultrasonography, and positron emission tomography using fluorine-18-fluorodeoxyglucose, we suspected these lesions as hemangiomatosis of the spleen and intrapancreatic accessory spleen. We performed distal pancreatectomy with splenectomy, and pathological diagnosis was hemangiomatosis of the spleen and intrapancreatic accessory spleen. We should consider the possibility of splenic tumors arising from the spleen and intrapancreatic accessory spleen when we find similar lesions in the spleen and the tail of the pancreas. Gradual and weak enhancement and pooling of the contrast medium until very late phase may be important findings for diagnosing splenic hemangiomatosis. PMID- 24811764 TI - Preoperative diagnosis of gangrenous acute cholecystitis: usefulness of CEUS. AB - PURPOSE: To evaluate CEUS for the preoperative diagnosis of gangrenous acute cholecystitis. SUBJECTS AND METHODS: This prospective study was approved by our institution's ethical committee. Fifty-six patients who underwent both US and CEUS and were confirmed as presenting with acute cholecystitis at pathology were included. Clinical data, mean time until surgery, macroscopic appearance of the GB, and the presence of gangrene at pathology were noted. Baseline US images and CEUS cine clips were analyzed by two experienced radiologists. Statistical analyses were performed. RESULTS: Gangrenous acute cholecystitis was diagnosed in 23 (41%) patients and uncomplicated acute cholecystitis in 33 (59%). Patients with gangrenous acute cholecystitis were found to be older (p = 0.048). Mean time from CEUS to surgery was found to be shorter in patients presenting with gangrenous acute cholecystitis (p = 0.052). At US, GB short axis >=4 cm (p = 0.039) and GB wall interruption (p = 0.037) showed a statistically significant association with the diagnosis of gangrenous acute cholecystitis. On CEUS, discontinuous or irregular GB wall enhancement was reported in 19/23 (83%) patients with gangrenous acute cholecystitis and showed association with the presence of gangrene at pathology (p = 0.001). The interobserver agreement for the presence of discontinuous or irregular GB wall enhancement on CEUS images was good. CONCLUSION: Performing CEUS on patients presenting with US findings of acute cholecystitis is relevant, since the presence of a discontinuous or irregular enhancement of the GB wall appears to be correlated with the diagnosis of gangrenous acute cholecystitis. PMID- 24811763 TI - Accuracy of water-enema multidetector computed tomography (WE-MDCT) in colon cancer staging: a prospective study. AB - PURPOSE: To assess the accuracy of water-enema multidetector computed tomography (WE-MDCT) in extra-rectal colon cancer staging. MATERIALS AND METHODS: Fifty three patients (mean age 70 years) with extra-rectal colon cancer proven by colonoscopy and biopsy were prospectively evaluated by preoperative WE-MDCT. CT scans were both intraluminal (water enema or WE) and intravenous (iodinated) contrast enhanced (CE). All patients underwent surgery. Tumors were classified with the TNM staging system. Noted CT features were: tumor size and location; tumor form and edges; spread to the pericolic fat or neighboring organs; thickening of retroperitoneal fascia; number, size, and enhancement of the peritumoral lymph nodes. Tumors were classified on CT into 3 T-stage groups: T1/T2, T3, and T4. Lymph nodes were classified by their density after injection [positive over 100 Hounsfield units (HU)]. RESULTS: Tumor localization to the specific colon segment was correct in all the cases. The agreement between WE MDCT staging and histopathology staging was good (k = 0.64). An irregular and bowl-shaped aspect of the external edges of tumor provided excellent sensitivity for T3/T4 inclusion (Se 97.7%, NPV 85.7%). Thickening of a fascia or the abdominal wall provided good specificity for T4 stage (Sp 88.1%, NPV 94.9%). Enhancement over 100 HU of at least one peritumoral lymph node was the best criterion of N+ staging (Sp 67.7%, NPV 87.5%). CONCLUSION: WE-MDCT permits good staging of colon cancer based on objective features. PMID- 24811765 TI - Balanced steady state-free precession (b-SSFP) imaging for MRCP: techniques and applications. AB - Balanced steady state-free precession (b-SSFP) pulse sequences have a number of properties which can be useful in magnetic resonance cholangiopancreatography (MRCP), including short acquisition times, high signal-to-noise ratios, and T2/T1 contrast weighting. The utility and versatility of b-SSFP sequences for MRCP imaging are probably underappreciated, and this pictorial essay briefly discusses benefits and limitations of 2D and 3D b-SSFP techniques used in place of or in addition to conventional single-shot fast spin echo or 3D fast spin echo acquisitions and illustrates their appearance in several clinical cases. PMID- 24811766 TI - Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease using acoustic radiation force impulse elastography. AB - OBJECTIVES: To investigate the diagnostic performance of the acoustic radiation force impulse (ARFI) elastography for the assessment of the liver fibrosis in alcoholic liver disease (ALD). METHODS: We included 112 patients with ALD in whom liver biopsy, ARFI elastography, and aspartate-to-platelet ratio index (APRI) measurements were performed. RESULTS: ARFI elastography correlated significantly with histological fibrosis (r = 0.685, P < 0.001) in patients with ALD. The diagnostic accuracies expressed as areas under receiver operating characteristic (AUROC) curves for ARFI elastography and APRI were 0.846 and 0.763 for the diagnosis of significant fibrosis (S >= 2), 0.875 and 0.688 for the diagnosis of severe fibrosis (S >= 3), and 0.893 and 0.648 for the diagnosis of liver cirrhosis, respectively. The AUROC values of ARFI elastography were significantly better than those of APRI for predicting severe fibrosis (P = 0.02) and cirrhosis (P = 0.04). The optimum cutoff values for ARFI elastography were 1.33 m/s for S >= 2, 1.40 m/s for S >= 3, and 1.65 m/s for S = 4 in patients with elevated alanine aminotransferase (ALT) levels; these decreased to 1.24 m/s for S >= 2, 1.27 m/s for S >= 3, and 1.41 m/s for S = 4 in patients with normal ALT. CONCLUSION: ARFI elastography is an acceptable method for predicting the severity of fibrosis in patients with ALD. ARFI elastography is influenced by elevated aminotransferase levels in ALD. PMID- 24811767 TI - Multimodality imaging of diseases of the duodenum. AB - The duodenum is a unique segment of intestine, occupying both intra and extra peritoneal locations. There is a wide spectrum of abnormalities of the duodenum that range from congenital anomalies to traumatic, inflammatory, and neoplastic entities. The duodenum may be overlooked on cross-sectional imaging due to its location and small size. Duodenal pathologies may, therefore, be missed or wrongly diagnosed. Knowledge about duodenal pathologies and optimal imaging techniques can increase diagnostic yield and permit optimal patient management. Conventionally, the duodenum was evaluated with upper GI studies on fluoroscopy; however, endoluminal evaluation is better performed with endoscopy. Additionally, a broad array of cross-sectional imaging modalities permits comprehensive assessment of the duodenum and surrounding viscera. While endoscopic sonography is increasingly used to locally stage duodenal malignancies, MDCT remains the primary modality widely used in the detection and characterization of duodenal abnormalities. MRI is used as a "problem solving" modality in select conditions. We present a comprehensive review of duodenal abnormalities with an emphasis on accurate diagnosis and management. PMID- 24811768 TI - Testosterone and high-sensitive C-reactive protein in coronary artery disease patients awaiting coronary artery bypass graft. AB - Natural androgens inhibit atherosclerosis in men. This study aimed to examine whether testosterone and high-sensitive C-reactive protein differ between patients with coronary artery disease and those without coronary artery disease and to determine the association with the severity of coronary artery disease. Two hundred and six male subjects were recruited. Serum total testosterone and high-sensitive C-reactive protein were estimated. Severity of coronary artery disease was assessed by angiographic scores. Total testosterone level in patients was significantly different from controls (11.4 +/- 2.7 vs. 18.1 +/- 7.2 nmP = 0.001) and high-sensitive protein level in cases was significantly higher compared to controls (3.37 +/- 1.62 mg l(-1) vs. 1.71 +/- 0.60 mg l(-1) , P = 0.001). Testosterone levels were not significantly different with vessel (P = 0.592), Leaman (P = 0.694) and Gensini (P = 0.329) score groups, but high sensitive C-reactive protein showed significant positive correlation among the respective groups (P = 0.005, P = 0.028, P = 0.015). Testosterone was lower, while high-sensitive C-reactive protein was higher in patients compared to controls. Testosterone showed no correlation with the severity of atherosclerosis, but high-sensitive C-reactive protein showed significant positive correlation. PMID- 24811769 TI - Long-term outcome in patients with severe alcoholic hepatitis can be reliably determined using an in vitro measure of steroid sensitivity. PMID- 24811770 TI - A longitudinal study of language and speech in children who were internationally adopted at different ages. AB - PURPOSE: The author followed 56 internationally adopted children during the first 3 years after adoption to determine how and when they reached age-expected language proficiency in Standard American English. The influence of age of adoption was measured, along with the relationship between early and later language and speech outcomes. METHOD: Children adopted from Eastern Europe at ages 12 months to 4 years, 11 months, were assessed 5 times across 3 years. Norm referenced measures of receptive and expressive language and articulation were compared over time. In addition, mean length of utterance (MLU) was measured. RESULTS: Across all children, receptive language reached age-expected levels more quickly than expressive language. Children adopted at ages 1 and 2 "caught up" more quickly than children adopted at ages 3 and 4. Three years after adoption, there was no difference in test scores across age of adoption groups, and the percentage of children with language or speech delays matched population estimates. MLU was within the average range 3 years after adoption but significantly lower than other language test scores. CONCLUSIONS: Three years after adoption, age of adoption did not influence language or speech outcomes, and most children reached age-expected language levels. Expressive syntax as measured by MLU was an area of relative weakness. PMID- 24811771 TI - Janus nanoparticles: materials, preparation and recent advances in drug delivery. AB - INTRODUCTION: The term Janus particles was used to describe particles that are the combination of two distinct sides with differences in chemical nature and/or polarity on each face. Due to the exponential growth of interest on multifunctional nanotechnologies, such anisotropic nanoparticles are promising tools in the field of drug delivery. AREAS COVERED: The main preparation processes and the materials used have been described first. Then a specific focus has been done on therapeutic and/or diagnostic applications of Janus particles. EXPERT OPINION: Janus particles are demonstrated as interesting objects with advanced properties that combine features and functionalities of different materials in one single unit. Due to their dual structure, Janus particles are promising candidates for a variety of high-quality applications dealing with drug delivery purposes. Still, the main challenges for the future lie in the development of the preparation of shape-controlled and nano-sized particles with large-scale production processes and approved pharmaceutical excipients. PMID- 24811773 TI - Low temperature chemical reduction of fusional sodium metasilicate nonahydrate into a honeycomb porous silicon nanostructure. AB - Honeycomb porous silicon (hp-Si) has been synthesized by a low temperature (200 degrees C) magnesiothermic reduction of Na2SiO3.9H2O. This process can be regarded as a general synthesis method for other silicide materials. Significantly, hp-Si features excellent electrochemical properties after graphene coating. PMID- 24811774 TI - Maternal exposure to hurricane destruction and fetal mortality. AB - BACKGROUND: The majority of research documenting the public health impacts of natural disasters focuses on the well-being of adults and their living children. Negative effects may also occur in the unborn, exposed to disaster stressors when critical organ systems are developing and when the consequences of exposure are large. METHODS: We exploit spatial and temporal variation in hurricane behaviour as a quasi-experimental design to assess whether fetal death is dose-responsive in the extent of hurricane damage. Data on births and fetal deaths are merged with Parish-level housing wreckage data. Fetal outcomes are regressed on housing wreckage adjusting for the maternal, fetal, placental and other risk factors. The average causal effect of maternal exposure to hurricane destruction is captured by difference-in-differences analyses. RESULTS: The adjusted odds of fetal death are 1.40 (1.07-1.83) and 2.37 (1.684-3.327) times higher in parishes suffering 10 50% and >50% wreckage to housing stock, respectively. For every 1% increase in the destruction of housing stock, we observe a 1.7% (1.1-2.4%) increase in fetal death. Of the 410 officially recorded fetal deaths in these parishes, between 117 and 205 may be attributable to hurricane destruction and postdisaster disorder. The estimated fetal death toll is 17.4-30.6% of the human death toll. CONCLUSIONS: The destruction caused by Hurricanes Katrina and Rita imposed significant measurable losses in terms of fetal death. Postdisaster migratory dynamics suggest that the reported effects of maternal exposure to hurricane destruction on fetal death may be conservative. PMID- 24811775 TI - Stressful social relations and mortality: a prospective cohort study. AB - BACKGROUND: Few studies have examined the relationship between stressful social relations in private life and all-cause mortality. OBJECTIVE: To evaluate the association between stressful social relations (with partner, children, other family, friends and neighbours, respectively) and all-cause mortality in a large population-based study of middle-aged men and women. Further, to investigate the possible modification of this association by labour force participation and gender. METHODS: We used baseline data (2000) from The Danish Longitudinal Study on Work, Unemployment and Health, including 9875 men and women aged 36-52 years, linked to the Danish Cause of Death Registry for information on all-cause mortality until 31 December 2011. Associations between stressful social relations with partner, children, other family, friends and neighbours, respectively, and all-cause mortality were examined using Cox proportional hazards models adjusted for age, gender, cohabitation status, occupational social class, hospitalisation with chronic disorder 1980-baseline, depressive symptoms and perceived emotional support. Modification by gender and labour force participation was investigated by an additive hazards model. RESULTS: Frequent worries/demands from partner or children were associated with 50-100% increased mortality risk. Frequent conflicts with any type of social relation were associated with 2-3 times increased mortality risk. Interaction between labour force participation and worries/demands (462 additional cases per 100,000 person-years, p=0.05) and conflicts with partner (830 additional cases per 100,000 person-years, p<0.01) was suggested. Being male and experiencing frequent worries/demands from partner produced 135 extra cases per 100,000 person-years, p=0.05 due to interaction. CONCLUSIONS: Stressful social relations are associated with increased mortality risk among middle-aged men and women for a variety of different social roles. Those outside the labour force and men seem especially vulnerable to exposure. PMID- 24811776 TI - Mortality on match days of the German national soccer team: a time series analysis from 1995 to 2009. AB - BACKGROUND: There is inconsistent evidence on population mortality, especially cardiovascular disease mortality, on match days of national soccer teams during particular international tournaments. This study examines the number of deaths in Germany on match days of the national soccer team during a long-term period including several tournaments. METHODS: We analysed all registered daily deaths in Germany from 1995 to 2009 (11 225 966 cases) using time series analysis methods. Following the Box/Jenkins approach, we applied a seasonal autoregressive integrated moving average model. To assess the effect of match days, we performed an intervention analysis by including a transfer function model representing match days of the national team in the statistical analyses. We conducted separate analyses for all matches and for matches during international tournaments (European and World Championships) only. Time series and results were stratified in terms of sex, age (<50 years, 50-70 years, >70 years) and cause of death (cardiovascular deaths, injuries, others). We performed a further independent analysis focusing only on the effect of match results (victory, loss, draw) and kind of tournament (international championships, qualifications, friendly matches). RESULTS: Most of the results did not indicate a distinct effect of matches of the national team on general mortality. Moreover, all null value deviations were small when compared with the average number of daily deaths (n=2270). CONCLUSIONS: There is no relevant increase or decrease in mortality on match days of the German national soccer team. PMID- 24811778 TI - Supramolecular templating of hierarchically porous metal-organic frameworks. AB - This tutorial review summarises recent advances in the direct supramolecular templating of metal-organic frameworks (MOFs) with hierarchical porosity across the micro- and mesoporous regimes. These are set against the important synthetic considerations that need to be addressed to ensure that strong interactions between the MOF precursors and a stable template assembly allow the highest chance of success. The article is grouped by template type and each category is illustrated with key examples and, where reported, an evaluation of their enhanced properties arising from the hierarchical structuring of the porous networks. PMID- 24811777 TI - Deficits in metacognitive capacity distinguish patients with schizophrenia from those with prolonged medical adversity. AB - Research has suggested that many with schizophrenia experience decrements in synthetic metacognition, or the abilities to form integrated representations of oneself and others and then utilize that knowledge to respond to problems. Although such deficits have been linked with functional impairments even after controlling for symptoms and neurocognition, it is unclear to what extent these deficits can distinguish persons with schizophrenia from others experiencing significant life adversity but without psychosis. To explore this issue we conducted logistic regression analysis to determine whether assessment of metacognition could distinguish between 166 participants with schizophrenia and 51 adults with HIV after controlling for social cognition and education. Metacognition was assessed with the Metacognitive Assessment Scale Abbreviated (MAS-A), and social cognition with the Bell Lysaker Emotion Recognition Test. We observed that the MAS-A total score was able to correctly classify 93.4% of the schizophrenia group, with higher levels of metacognition resulting in increased likelihood of accurate categorization. Additional exploratory analyses showed specific domains of metacognition measured by the MAS-A were equally able to predict membership in the schizophrenia group. Results support the assertion that deficits in the abilities to synthesize thoughts about oneself and others into larger representations are a unique feature of schizophrenia. PMID- 24811779 TI - Maternal sympathetic stress impairs follicular development and puberty of the offspring. AB - Chronic cold stress applied to adult rats activates ovarian sympathetic innervation and develops polycystic ovary (PCO) phenotype. The PCO syndrome in humans originates during early development and is expressed before or during puberty, which suggests that the condition derived from in utero exposure to neural- or metabolic-derived insults. We studied the effects of maternal sympathetic stress on the ovarian follicular development and on the onset of puberty of female offspring. Timed pregnant rats were exposed to chronic cold stress (4 degrees C, 3 h/daily from 1000 to 1300 h) during the entire pregnancy. Neonatal rats exposed to sympathetic stress during gestation had a lower number of primary, primordial, and secondary follicles in the ovary and a lower recruitment of primary and secondary follicles derived from the primordial follicular pool. The expression of the FSH receptor and response of the neonatal ovary to FSH were reduced. A decrease in nerve growth factor (NGF) mRNA was found without change in the low-affinity NGF receptor. The FSH-induced development of secondary follicles was decreased. At puberty, estradiol plasma levels decreased without changes in LH plasma levels. Puberty onset (as shown by the vaginal opening) was delayed. Ovarian norepinephrine (NE) was reduced; there was no change in its metabolite, 3-methoxy-4-hydroxyphenylglycol, in stressed rats and no change in NE turnover. The changes in ovarian NE in prepubertal rats stressed during gestation could represent a lower development of sympathetic nerves as a compensatory response to the chronically increased NE levels during gestation and hence participate in delaying reproductive performance in the rat. PMID- 24811780 TI - Effect of single-chain ovine gonadotropins with dual activity on ovarian function in sheep. AB - We examined the half-life and biological activity of two single-chain proteins that combined portions of ovine FSH and LH. We proposed the hypothesis that these chimeric proteins would display LH and FSH activities and would promote follicle maturation in ewes. Estrus activity was synchronized using progestogen impregnated vaginal pessaries. To negate the impact of endogenous LH and FSH, animals received serum-containing antibodies against GNRH 1 day before pessary removal (PR). At PR sheep (five animals per group) received a single injection (10 IU/kg, i.v.) of either the ovine-based (oFcLcalpha) gonadotropin analog, an ovine-based analog containing oLHbeta truncated at the carboxyl terminus (oFcL(DeltaT)calpha), or a human-based gonadotropin analog (hFcLcalpha). Control animals received a comparable amount of gonadotropin-free protein. Ovulation was induced 3 days after PR using human chorionic gonadotropin (1000 IU, i.v.). Ovaries were collected 11 days after PR. Neither estradiol (E2) or progesterone (P4) production, development of preovulatory follicles or corpora lutea (CL) were noted in control animals receiving gonadotropin-free protein. Significant increase in the synthesis of E2 and P4 was noted in sheep receiving the dually active gonadotropin analogs. The number of CLs present 11 days after PR was significantly increased in sheep receiving the chimeric glycoproteins compared with control animals. The magnitude of the secretory and ovarian responses did not differ between hFcLcalpha and oFcLcalpha or between oFcLcalpha and oFcL(DeltaT)calpha. Immunoactivity of LH and FSH was low in control animals, but was significantly elevated in sheep receiving the gonadotropin analogs. In conclusion, ovine-based gonadotropin analogs are functionally active in sheep and a single injection is adequate to induce the development of multiple ovulatory follicles. PMID- 24811781 TI - Targeting the BET family for the treatment of leukemia. PMID- 24811782 TI - Epigenetics: a new frontier for post-traumatic stress disorder? PMID- 24811783 TI - Do epigenetic drug treatments hold the key to killing cancer progenitor cells? PMID- 24811785 TI - Highlights from the latest articles in epigenomics. PMID- 24811786 TI - Are epigenetic changes in the intrauterine environment related to newborn neurobehavior? PMID- 24811787 TI - DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes. AB - AIM: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway. MATERIAL & METHODS: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip. RESULTS: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes. CONCLUSION: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays. PMID- 24811788 TI - Epigenetic dysregulation of the IGF system in placenta of newborns exposed to maternal impaired glucose tolerance. AB - AIMS: To determine whether placental IGF1R, IGFBP3, INSR and IGF1 DNA methylation and mRNA levels were dysregulated when exposed to maternal impaired glucose tolerance (IGT) and investigate whether the epigenetic profile is associated with feto-placental developmental markers. PATIENTS & METHODS: The IGT diagnosis was made according to the WHO criteria (IGT: n = 34; normal glucose tolerance [NGT]: n = 106). DNA methylation and mRNA levels were quantified using bisulfite pyrosequencing and qRT-PCR, respectively. RESULTS: IGF1R and IGFBP3 DNA methylation levels were lower in placentas exposed to IGT compared with NGT ( 4.3%; p = 0.021 and -2.5%; p = 0.006 respectively) and correlated with 2-h post oral glucose tolerance test (OGTT) glycemia (r = -0.23; p = 0.010 and r = -0.20; p = 0.028, respectively). IGF1R mRNA levels were associated with newborns' growth markers (e.g., birth weight; r = 0.20; p = 0.032). CONCLUSION: These results support the growth-promoting role of the IGF system in placental/fetal development and suggest that the IGF1R and IGFBP3 DNA methylation profiles are dysregulated in IGT, potentially affecting the fetal metabolic programming. PMID- 24811789 TI - Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. AB - Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. Recent studies have put a greater spotlight on metabolic diseases, in particular Type 1 and Type 2 diabetes, as potential indications for which HDAC inhibition could be beneficial. Evidence suggests that inhibition of HDAC3 protects beta-cells from cytokine induced apoptosis, an important event in the development of Type 1 diabetes. On the other hand, the pathogenesis of Type 2 diabetes involves a combination of peripheral insulin resistance and pancreatic beta-cell failure. Again, data from the literature indicate that HDAC3 regulates genes involved in key metabolic events. Together, these results suggest that selective inhibition of HDAC3 may be an attractive strategy for targeting these diseases. PMID- 24811790 TI - Current and potential epigenetic targets in multiple myeloma. AB - Despite recent advances in therapy, subgroups of multiple myeloma continue to have a poor prognosis. Numerous epigenetic changes have been described and occur as both etiologic and secondary events, making myeloma a good disease in which to understand the role of epigenetic therapies. Here, we describe a number of current and potential epigenetic targets in myeloma. PMID- 24811791 TI - Personalized medicine and type 2 diabetes: lesson from epigenetics. AB - Similarly to genetic polymorphisms, epigenetic modifications may alter transcriptional activity and contribute to different traits of the Type 2 diabetes phenotype. The establishment of these epigenetic marks may precede diabetes onset and predict the disease. Current evidence now indicates that epigenetic differences represent markers of diabetes risk. Studies on epigenome plasticity revealed that cytokines and other metabolites, by affecting DNA methylation, may acutely reprogram gene expression and contribute to the Type 2 diabetes phenotype even in the adult life. The available evidence further indicates that epigenetic marks across the genome are subject to dynamic variations in response to environmental cues. Finally, different genes responsible for the interindividual variability in antidiabetic drug response are subjected to epigenetic regulation. Determining how specific epigenetic profiles determine diabetes is a challenging task. In the near future, the identification of epigenetic marks predictive of diabetes risk or response to treatment may offer unanticipated opportunities to personalize Type 2 diabetes management. PMID- 24811792 TI - The effect of diet on the intestinal epigenome. AB - The colorectal mucosal epithelium is composed of rapidly proliferating crypt cells derived by clonal expansion from stem cells. The aging human colorectal mucosa develops aberrant patterns of DNA methylation that may contribute to its increasing vulnerability to cancer. Various types of evidence suggest that age dependent loss of global methylation, together with hypermethylation of CpG islands associated with cancer-related genes, may be influenced by nutritional and metabolic factors. Folates are essential for the maintenance of normal DNA methylation, and folate metabolism is known to modify epigenetic mechanisms under experimental conditions. Human intervention trials and cross-sectional studies suggest a role for folates and other nutritional and metabolic factors as determinants of colorectal mucosal DNA methylation. Future studies should focus on the possibility that folic acid fortification may exert unforeseen effects on the human gastrointestinal epigenome. Naturally occurring DNA methyltransferase inhibitors in plant foods may be useful for the manipulation of epigenetic profiles in health and disease. PMID- 24811793 TI - Epigenetic-based immune intervention for rheumatic diseases. AB - Rheumatic disease is a large spectrum of heterogeneous conditions affecting the loco-motor system including joints, muscles, connective tissues, and soft tissues around the joints and bones. Many rheumatic diseases have an element of autoimmunity including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Aberrant epigenetic regulation of gene expression is emerging as a major factor within rheumatic disease, and indicates potential new therapeutic avenues of approach to these debilitating conditions. Understanding the precise role of epigenetics in the development and treatment of rheumatic diseases particularly those which have an associated autoimmune element may be important for the long-term management of such conditions. PMID- 24811795 TI - Facile fabrication of uniform hollow silica microspheres using a novel biological template. AB - Biological templates, due to their ease of preparation and surface modifications can be a promising approach to fabricate hollow structures. In this study, for the first time, a biological template was used for the production of hollow silica microspheres. Silica was successfully deposited on Staphylococcus aureus cells surface using the Stober method. The hollow silica spheres with a mesoporous shell of approximately 700nm in diameter were produced by applying this novel method. PMID- 24811796 TI - Genetic verification and chemical contents identification of Allamanda species (Apocynaceae). AB - Allamanda species (Apocynaceae) are popular ornamentals. Additionally, A. cathartica possesses medicinal properties whereas all other species have not been reported. This research aims to analyze genetics and chemical contents of Allamanda species existing in Thailand. The explored species are A. blanchetii, A. cathartica, A. neriifolia, A. schottii, and A. violacea. The dendrogram constructed from 16 inter-simple sequence repeat markers clearly distinguished species with genetic similarity values of 0.92-0.93 for species level and 0.50 0.76 for genus level. Diverse chemicals content in hexane extracts from A. blanchetii, A. neriifolia, A. schottii, and A. violacea were detected by gas chromatography-mass spectrometry. A high amount of squalene was found in A. blanchetii (55.81%) and A. violacea (51.09%). This content may function as a chemo preventative substance to protect people from cancer. alpha-Tocopherol, a form of vitamin E, was one of the predominant components found in A. violacea (26.325%), A. schottii (15.41%), and A. neriifolia (9.16%). One more substance, 9,12,15-octadecatrien-1-ol, was found to be relatively high in A. schottii (17.31%) and A. neriifolia (15.51%). Other minor and unknown compounds were also detected. The discovery of these chemicals provides an alternative and supplement for improving human well-being and pharmaceutical industries with natural resources, especially in light of the population increase. PMID- 24811797 TI - Development and evaluation of omeprazole pellets fabricated by sieving spheronization and extrusion - spheronization process. AB - Pelletized dosage forms can be prepared by different methods which, in general, are time consuming and labor intensive. The current study was carried out to investigate the feasibility of preparing the spherical pellets of omeprazole by sieving-spheronization. An optimized formulation was also prepared by extrusion spheronization process to compare the physical parameters between these two methods. The omeprazole pellets were consisted of microcrystalline cellulose, polyvinylpyrrolidone K 30, sodium lauryl sulphate and polyethylene glycol 6000. The omeprazole delay release system was developed by coating the prepared pellets with aqueous dispersion of Kollicoat 30 DP. The moisture content, spheronization speed and residence time found to influence the final properties of omeprazole pellets prepared by extrusion-spheronization and sieving-spheronization. The Mann Whitney test revealed that both methods produced closely similar characteristics of the pellets in terms of, friability (p=0.553), flowability (p=0.677), hardness (p=0.103) and density (bulk, p=0.514, tapped, p=0.149) except particle size distribution (p=0.004). The percent drug release from the coated formulation prepared by sieving-spheronization and extrusion spheronization was observed to be 84.12 +/- 1.10% and 82.67 +/- 0.96%, respectively. Dissolution profiles of both formulations were similar as indicated by values of f1 and f2, 1.52 and 89.38, respectively. The coated formulation prepared by sieving-spheronization and commercial reference product, Zimore (r) also showed similar dissolution profiles (f1=1.22, f2=91.52). The pellets could be prepared using sieving spheronization. The process is simple, easy, less time- and labor-consuming and economical as compared to extrusion-spheronization process. PMID- 24811798 TI - Therapeutical effect of Radix Aconiti and Astragalus extracts on models of experimental bradycardia animal. AB - The antibradycardia effect of extract of RAE (Radix Aconiti and Astragalus) on bradycardia animal models were evaluated. Bradycardia rat model was induced by amiodarone or propranolol, and sick sinus syndrome (SSS) rabbit model was induced by chemical stimulation on surface of sinus node. The heart rates of the animal models were calculated according to ECG recording. The value of sino-atrial conduction time (SACT) and correcting sinus node recovery time (CSNRT) of SSS rabbit model were measured by multi-channel physiological recorder. The blood flow of aorta and coronary the diabolic pressure of normal rat hearts in vitro were measured. Treatment with RAE could increase the heart rate of bradycardia animals induced by amiodarone, propranolol, or SSS rabbit model significantly. Treatment with RAE could decrease in the value of SACT and CSNRT of SSS rabbit model. Moreover, treatment with RAE could increase the blood flow of aorta and coronary and could decrease diabolic pressure of normal rat hearts in vitro. RAE has heart-rate-increasing effect, which might be related to its ameliorating the autorhythmicity of sinus node and improving the sino-atrial conductive function. Moreover, RAE could ameliorate cardiac blood supply and enhance cardiac function. PMID- 24811794 TI - Testing the efficiency of nested barriers to dispersal in the Mediterranean high mountain plant Edraianthus graminifolius (Campanulaceae). AB - Due to strong spatial heterogeneity and limited Pleistocene glaciation, the Balkan Peninsula is a major European biodiversity hot spot. Surprisingly little, however, is known about patterns and processes of intraspecific diversification of its biota in general and of high-altitude species in particular. A well-suited system to test hypotheses with respect to various isolating factors acting at different geographic scales and to explore full-range phylogeographic patterns on the Balkan Peninsula is Edraianthus graminifolius (Campanulaceae), distributed in the western Balkan mountain systems, the southwestern Carpathians and the Apennine Peninsula. To this end, we used a dense population sampling and employed amplified fragment length polymorphism (AFLP) markers and plastid DNA sequences supplemented by ecological niche modelling. The strongest splits were inferred to separate southern and northern Balkan populations from the central ones, from where range extension occurred to the Carpathians and, in more recent times, once or twice to the Apennine Peninsula. The three genetic groups in the western Balkan Peninsula were remarkably congruent among molecular markers, suggesting that the barriers to gene flow acted over long time periods facilitating allopatric differentiation. Each main group of Balkan populations contained genetically and geographically distinct subgroups, which likely are the result of local refugia during warmer periods. Evidently, the topographically highly complex and during the Last Glacial Maximum only locally glaciated Balkan Peninsula is a hot spot of species richness and endemism as well as a sanctuary of intraspecific genetic diversity, even if the underlying causes remain insufficiently understood. PMID- 24811799 TI - Analytical, nutritional and biological evaluation of various brands of fortified and non-fortified wheat flour. AB - In Pakistan, a funded flour fortification program was launched for malnourished population, residing mainly in rural low income areas, but the urban population having comparatively better nutritional as well as economic status was focused wherein excessive intake of fortificants might cause complications. Therefore, the present study describes the physicochemical properties, elemental composition, nutritional components and hemoglobin/ferritin increasing potential of fortified and non-fortified flour. Domesticated chicken (Gallus gallus domesticus), either sex, age one month, weight 380 +/- 18.28 g, were randomly segregated into 4 groups (n=6). The group I, II and III were fed on fortified flour, whereas group IV was fed on non-fortified flour for 30 days. The birds were weighed and blood samples of each of the birds were analyzed for determination of markers of iron status, hemoglobin (Hb) and serum ferritin (SF). Moisture, ash and iron contents were found to be lower in non-fortified flour than that of the fortified samples. Hb and SF levels in groups fed on fortified flour were significantly higher than the one received non-fortified flour (P < 0.05). The consumption of iron-fortified flour increases iron stores in the body without any further complication but long-term usage needs to be monitored. PMID- 24811800 TI - In vitro release of ketoprofen suppositories using the USP basket and the flow through cell dissolution methods. AB - In order to study the release characteristics of ketoprofen suppositories under the hydrodynamic environment generated by USP Apparatus 1 and 4, the dissolution profiles of the Mexican reference product (100 mg) were determined. Phosphate buffer pH 8 and 1% sodium lauryl sulfate (SLS) aqueous solutions were proved as dissolution mediums. Baskets were rotated at 100 rpm with USP Apparatus 1 and different flow rates from 16-32 mL/min with USP Apparatus 4 were used. Drug samples were taken and quantified during 60 min by UV analysis at 260 nm. Mean dissolution time (MDT) and dissolution efficiency (DE) were calculated by model independent methods. Data were also fitted to several kinetic models. Poor dissolution was found in both dissolution mediums when USP basket method was used (< 10% dissolved) while better results were obtained with USP Apparatus 4 when 1% SLS at 24 mL/min was used (43.6% dissolved, MDT of 25.5 min and DE of 25.0%). Kinetics showed a great variability when the USP Apparatus 1 was used, and Gompertz fitted well for data of 1% SLS at 24 mL/min (R(2)(adjusted) > 0.99). The results suggest the need to establish an adequate dissolution method to evaluate the release kinetics of ketoprofen from suppositories. PMID- 24811801 TI - Quality control of herbs: determination of amino acids in Althaea officinalis, Matricaria chamomilla and Taraxacum officinale. AB - Analysis of raw materials and final products need reliable methods for the standardization of natural product drugs. Legal guideline also emphasizes on the qualitative and quantitative analyses of the plant constituents in an herbal product. In this study, thin layer chromatography (TLC) and amino acid analyzer was used for the determination of amino acids in plant extracts. Samples for this study were standards and aqueous extracts from Althaea officinalis, Matricaria chamomilla and Taraxacum officinale. Different amino acids in the extracts were detected through TLC. An automatic amino acid analyzer was used for the quantification of amino acids in the plant extracts under study. PMID- 24811802 TI - A pharmacodynamic simulation to evaluate tigecycline in treatment of nosocomial pneumonia caused by multidrug-resistant Acinetobacter baumannii. AB - The shortage of effective antibiotics against multidrug-resistant Acinetobacter baumannii (MDR-Ab) has posed great threat to the public health. But the advent of tigecycline gives us new hope. The goal of our research was to assess the clinical efficacy of tigecycline at different doses by using a pharmacokinetic/pharmacodynamic (PK/PD) model which can incorporate pharmacokinetic data of tigecycline from patients with pneumonia and MICs of MDR Ab from a tertiary hospital. A 10000-patient Monte-Carlo Simulation based on the PK/PD model was conducted to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of tigecycline. 97% isolates displayed susceptibility and 3% were tigecycline-intermediate strains and the values of MIC ranged from 0.125 to 4 MU g/ml. A CFR of 61.62% was predicted for tigecycline at current dosage (50 mg q12h). When the dosage was increased, the predicted CFRs for 75 mg q12h, 100 mg q12h, 125 mg q12h, 150 mg q12h were 81.00%, 89.86%, and 94.57%, 96.77%, respectively. Despite presented higher susceptibility, the CFR obtained was not optimal at current dosage. A higher CFR indicating a better clinical efficacy can be gained by the increased dosage. PMID- 24811803 TI - Antioxidant and antibacterial activities of Hibiscus Rosa-sinensis Linn flower extracts. AB - Antioxidant and antibacterial potential of different solvent extracts of locally grown Hibiscus rosa-sinensis Linn was evaluated. The antioxidant activity was assessed by estimation of total flavonoids contents, total phenolic contents, DPPH free radical scavenging activity and percentage inhibition of linoleic acid oxidation capacity. Agar disc diffusion method was used to assess antibacterial potential of crude extract of H. rosa-sinensis. The yield of the crude extracts (23.21 +/- 3.67 and 18.36 +/- 2.98% in 80% methanol and ethanol solvents was calculated, respectively. Methanol and ethanol extract of H. rosa-sinensis showed total phenolics 61.45 +/- 3.23 and 59.31 +/- 4.31 mg/100g as gallic acid equivalent, total flavonoids 53.28 +/- 1.93 and 32.25+/-1.21 mg/100g as catechine equivalent, DPPH free radical scavenging activity 75.46+/-4.67 and 64.98 +/- 2.11% and inhibition of linoleic acid oxidation potential 75.8 +/-3.22 and 61.6 +/- 2.01% respectively, was measured. Antibacterial study against three human pathogens such as staphlococus sp. Bacillus sp. and Escherichia coli showed growth inhibitory effect in the range of 12.75 +/- 1.17 to 16.75 +/- 2.10 mm. These results showed H. rosa-sinensis indigenous to Kallar Kahar and its allied areas bear promising medicinal values and could be used for developing herbal medicines to target oxidative stress and infectious diseases. PMID- 24811804 TI - Phenolic contents and antimicrobial activity of squirting cucumber (Ecballium elaterium) extracts against food-borne pathogens. AB - Squirting cucumber (Ecballium elaterium), is an indigenous species of the south of Europe and the Mediterranean basin, sometimes cultivated for its use as a medicinal plant. This study compared phenolic contents in Ecballium elaterium organs and their antimicrobial activities against some foodborne pathogens. Our results indicated that the plant organs had different total polyphenol contents (ranging from 6.744 to 46.848 mg GAE g(-1) DW) the leaves and fruits contained about 6-fold higher phenol contents than the root. The same tendency was observed for flavonoid and tannin levels. An interesting antimicrobial activity was also observed against the food pathogens at concentrations ranging from 0.004 to 2.5 mg ml(-1). Ecballium elaterium extracts might therefore be a potential source of preservative candidates for use in food or pharmaceutical industries. PMID- 24811805 TI - Anti-dermatitis, anxiolytic and analgesic effects of Rhazya stricta from Balochistan. AB - Current study was carried out on Rhazya stricta. Plant material was collected from Jhalmagsi Dist. Balochistan, Pakistan. Methanolic extract of Rhazya stricta was tested for anti-dermatitis, analgesic, anxiolytic effects, insecticidal activity and Brine shrimp Bioassay. Crude extract showed significant anti dermatitis activity, as the results of intensity score showed mild Excoriation or erosion, moderate Edema or populations and absence of Erythema or hemorrhage, Scratching time was decreased to 1.45 and histological observations of mice treated with crude extract showed mild changes and few inflammatory cells in several microscopic fields. The results of analgesic activity were significant and the percentage inhibition of writhes were 73.54% and 69.38% at 300mg/kg and 500mg/kg respectively. The overall response of crude extract in anxiolytic activities were depressive and crude extract showed sedative effects. In Brine shrimp (Artemsia salina) lethality bioassay crude extract showed dose depended significant activity, and showed positive lethality with LD(50) 3.3004MUg/ml. Insecticidal activity was positive against Callosbruchus analis, the percent mortality was 40%. PMID- 24811806 TI - Determination of kaempferol and quercetin in Xindakang tablet by beta cyclodextrin modified micellar electrokinetic capillary chromatography. AB - A method was proposed to determine kaempferol and quercetin in Hippophae rhamnoides L medicinal preparation xindakang tablet by beta-cyclodextrin modified micellar electrokinetic capillary chromatography. Under the optimized conditions: buffer solution of 20 mmol/L Na(2)B(4)O(7)-KH(2)PO(4) (pH 9.0)-20mmol/L SDS 6mmol/L beta-CD-5%(v/v) MeCN, applied voltage of 16 kV and injection time of 8s, the two analytes were separated well within 10 minutes. The calibration was linear in the 0.02-0.80 and 0.02-0.70 mg/mL range for kaempferol and quercetin, respectively. The reproducibility based on migration time and peak height were 0.47% and1.87% for kaempferol, 0.55% and 2.02% for quercetin. The detection limits based on three times noise were 0.010 mg/mL and 0.008 mg/mL for kaempferol and quercetin, respectively. The developed method was utilized to analyze real samples and running recovery experiments with satisfactory results. PMID- 24811807 TI - Antihepatotoxic effect of golden berry (Physalis peruviana Linn.) in carbon tetrachloride (CCl4) intoxicated rats. AB - Liver is the main site in the body for intense metabolism and excretion. A number of chemicals and drugs which are used routinely cause liver damage. The present study investigates the antihepatotoxic effect of Physalis peruviana whole ripe fruit, water and ethanol extracts of fruit in normal as well as in carbon tetrachloride (CCl(4)) intoxicated rats. The CCl(4) treated rats showed marked elevation in liver enzymes: alanine transaminse, aspratate transaminase, alkaline phosphatase, lactate dehydrogenase and other biochemical parameters: bilirubin, creatinine and urea, thus indicating liver injury. Whereas animal treated/fed with various preparations of Physalis peruviana showed significant lowering effect (p<0.05) in the elevated levels of serum markers like ALAT, ASAT, ALP, LDH, creatinine, urea and bilirubin indicating the protection against hepatic cell damage. The water extract of Physalis peruviana showed highest activity in both rat models while ripe fruit and ethanol extract showed moderate activity compared to standard drug. PMID- 24811808 TI - An investigation into the drug release from ibuprofen matrix tablets with ethylcellulose and some poly-acrylate polymers. AB - This study was performed to achieve sustained-release Ibuprofen matrix tablets with a zero-order release kinetic while most of the previous formulations have shown Higuchi release kinetic. Considering the results from previous studies, ethyl cellulose, Carbopol 934P, Carbopol 974P, and Pemulen TR-1 were used at different amounts for preparation of the tablets by direct compression. The release profiles were studied in a two-stage release test using non-linear regression analysis. Carbopols 934P and 974P could not sustain the release adequately while Pemulen TR-1 had too strong sustaining effect. Therefore, combination formulations were considered and studied. The release profiles of ethyl cellulose formulation and the combination formulation consisting Carbopol 934P and Pemulen TR-1 best fitted in Higuchi model, although the zero-order model was not completely rejected. However, the kinetic model of release from the combination formulation consisting Carbopol 974P and Pemulen TR-1 changed to zero order indicating the most constant release rate among formulations. This was speculated to be due to some erosion of the gel, as well as some interaction of the hydrophobic chain of Pemulen TR-1 with Ibuprofen. Therefore, this formulation is suggested for directly compressed sustained-release matrix tablets of Ibuprofen with a more constant release rate. PMID- 24811809 TI - Nephroprotective potentials of Citrus aurantium: a prospective pharmacological study on experimental models. AB - Citrus aurantium is traditionally used in various kidney problems like burning of urine, urinary hesitancy and renal colic. The main objective of the present work was to evaluate the protective role of Citrus aurantium against gentamicin induced renal damage, due to its free radical scavenging properties to present experimental facts for their traditional use. 200 mg/kg/day of ethanolic extract of the plant employed in combination with the toxic doses of gentamicin for twenty-one days. The group GC-au (animals treated with co-administration of Citrus aurantium and gentamicin) protected renal damage expected with gentamicin, assessed by known functional and morphological parameters, significantly different from group G (animals treated with gentamicin). All the renal functioning parameters including; Blood urea nitrogen, Serum creatinine, Serum uric acid, Creatinine clearance, Serum electrolytes, Body weight, Urinary volume, Enzyme excretions, Urinary protein excretions and histological examination was performed for each and every group animals. The plant extract proved to have nephroprotective potentials may because of its known flavonoid contents and antioxidant properties. PMID- 24811810 TI - Quantitative determination of corosolic acid in rat plasma by LC-MS/MS-ESI: application to a pharmacokinetic study. AB - A sensitive and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of corosolic acid (CRA) in rat plasma. The plasma samples were prepared by a simple protein precipitation treatment. Chromatographic separation was performed on an Agela MG-C18 column (50 mm * 4.6 mm; i.d., 5 MUm) at 30 degrees C. The mobile phase consisting of methanol-10 mM ammonium acetate-formic acid (80:20:0.1, v/v/v; pH=3.8) was delivered with a flow rate of 0.6 ml/min and a running time of 2.5 min. Quantification was performed with positive electrospray ionization (ESI) in the multiple-reaction monitoring (MRM) mode at m/z 490 -> m/z 205 for CRA, and m/z 471 -> m/z 203 for TEOA (internal standard, IS), respectively. Linearity was evaluated over the concentration range of 1.00-1000 ng/ml with a lower limit of quantification (LLOQ) of 1.00 ng/ml. The validated method was successfully applied to the pharmacokinetic study of CRA after the drug was orally administered in Sprague-Dawley rats. PMID- 24811811 TI - Synthesis of some new biologically active N-substituted-2''- [(phenylsulfonyl)(piperidin-1-yl)amino]acetamide derivatives. AB - A new series of N-aryl/aralkyl substitued-2"-[(phenylsulfonyl)(piperidin-1 yl)amino]acetamide (7a-k) was synthesized. These derivatives were geared up by the pairing of benzenesulfonyl chloride (4) with 1-aminopiperidine (5) under dynamic pH control in aqueous media to afford parent compound N-(Piperidin-1-yl) benzenesulfonamide (6), followed by the substitution at nitrogen atom with different electrophiles N-aryl/aralkyl-substituted-2-bromoacetamides (3a-k) in the presence of sodium hydride (NaH) and N,N-Dimethylformamide (DMF) to give a new series of N-substituted derivatives of acetamide (7a-k) bearing piperidine moiety. All the synthesized compounds were confirmed on the basis of IR, EIMS and (1)H-NMR spectral data. The synthesized compounds were evaluated against acetylcholinesterase and butyrylcholinesterase (AChE and BChE) respectively and lipoxygenase (LOX) enzymes. Almost all the synthesized compounds displayed promising activity but few of them remained inactive against lipoxygenase enzymes. PMID- 24811812 TI - A validated RP-HPLC method to investigate finasteride in human skin after in vitro topically applying vesicular nanocarrier. AB - The pharmacotherapeutic efficiency of topical drug delivery systems is mainly dominated by the skin distribution of therapeutic agents. In this work, a sensitive, rapid and fully-validated reversed-phase high performance liquid chromatography (RP-HPLC) method was developed to determine finasteride in human cadaver skin after different vesicular formulations were applied. Drug in different depth of skin layers were measured with an EclipseXDB-C18 column. The mobile phase consisted of 75% (v/v) methanol containing 0.2% phosphoric acid buffered to pH 3.0 with triethylamine under isocratic conditions. The system was operated at 40 degrees C and the mobile phase flow rate was set at 1 mL/min. The standard-calibration curve was linear within range of 5 to 200 ng/ml with correlation coefficient 0.9996. The intra-assay precision was less than 3.9% while the inter-assay precision was less than 7.1% with the bias range of -8.6 to 4.1%. This method was found to be specific, accurate, and sensitive and was successfully used to determine the accumulation of finasteride after in-vitro percutaneous delivery by liposomal or ethosomal drug delivery nanocarriers. PMID- 24811813 TI - Incidence of medication error associated with the use of beta-blockers in Pakistan. AB - Medication errors (ME) are human errors, which are very frequent in cardiovascular patients and result in patient morbidity and mortality. This study was focused to evaluate the quality of prescriptions and to emphasize the placement of clinical pharmacist in health care team. This study was carried out in different outpatient settings of (in) Karachi, Pakistan. The study period was June 2011 till June 2012. Retrospective data was analyzed for the outpatients' prescription of beta blocker drugs. During the study, prescriptions (n=450) were collected from different outpatient settings of (in) Karachi, Pakistan. Prescription containing beta-blockers were analyzed for the essential elements to be mentioned in prescription. Drug-drug interactions were identified by the Micromedex.2.0 Drug-Reax database and severity of medication error was determined by NCCMERP Index. A total of 1627 medication errors were identified in 450 prescriptions. The most frequent error was not mentioning the patient's weight (95%), followed by missing diagnosis (79.4%) and drug-drug interactions (69.5%). Twenty-two prescriptions were placed in the most severe category I (4.88%). Average number of drugs per prescription was 4.76. Significant difference was observed (chi(2)=52.418, p<0.05) using SPSS 19 for those prescription orders having more than 5 drugs with Beta-blockers. This indicates that the errors in prescription such as drug-drug interactions, wrong dose etc. was significantly increased with the number of drugs per prescription. Results showed that medication errors are very frequent in prescription written in outpatient setting of various hospitals and clinics in Karachi. This shows that the irrational prescribing is a common practice in developing countries. Placement of skilled pharmacist in the health care system is the only solution for avoidance of these medication related problems. PMID- 24811814 TI - Effect of raw Radix Rehmanniae on the pharmacokinetics of pioglitazone in rats. AB - Raw Radix Rehmanniae (RRR) is a frequently used traditional Chinese medicine in the treatment of diabetes mellitus according to the statistics on all of the anti diabetic formulas recorded in New National Traditional Chinese Medicine. Pioglitazone and RRR may be co-administrated for presumably enhanced therapeutic effects because of the common indications. Therefore, the aim of the study was to evaluate the effect of RRR on the pharmacokinetics of pioglitazone in healthy rats and type 2 diabetic rats. The pharmacokinetic effect of RRR on pioglitazone was studied in healthy rats and type 2 diabetic rats. A validated UPLC-MS/MS method was used to analyze the concentration of pioglitazone in blood samples. The pharmacokinetic parameters were calculated using non-compartmental analyses by Winnonlin 5.0.1. In healthy group, the pre-treatment of RRR significantly (P<0.05) reduced the C(max) but enhanced the V/F of pioglitazone; whereas in T2DM group, significant increase of C(max) and decrease of V/F and T1/2 were found after the rats were pre-treated with RRR. However, AUC(0-t) and CL/F remained unchanged in both healthy group and T2DM group. In conclusion, co-administration with RRR could alter the pharmacokinetic profiles of pioglitazone to statistically significant levels. PMID- 24811815 TI - In vitro xanthine oxidase inhibitory and in vivo hypouricemic activity of herbal coded formulation (Gouticin). AB - Currently, natural products have been used in treating gouty arthritis and are recognized as xanthine oxidase inhibitors. Current study was designed to evaluate in vitro xanthine oxidase inhibitory potential of Gouticin and its ingredients extracts and in vivo hypouricemic activity of gouticin tablet 500 mg twice daily. Ethanol extracts of Gouticin and its ingredients were evaluated in vitro, at 200, 100, 50, 25 MU g/ml concentrations for xanthine oxidase inhibitory activity. IC(50) values of Gouticin and its ingredients were estimated. Further, in vivo therapeutic effect of Gouticin was investigated in comparison with allopathic medicine (Allopurinol) to treat gout. Total patients were 200 that were divided into test and control group. Herbal coded medicine (Gouticin) was given to test group and allopathic medicine allopurinol was administered to control group. In vitro, Gouticin has the highest percent inhibition at 96% followed by Allopurinol with 93% inhibition. In vivo study, mean serum uric acid level of patients was 4.62 mg/dl and 5.21mg/dl by use of Gouticin and Allopurinol at end of therapy. The study showed that herbal coded formulation gouticin and its ingredients are potential sources of natural xanthine oxidase inhibitors. Gouticin 500 mg twice daily is more effective than the allopurinol 300mg once daily in the management of gout. PMID- 24811816 TI - Formulation, standardization and pharmacological studies of Saraswataristam: a polyhedral preparation. AB - Ayurvedic preparations achieved paramount importance in contemporary life owing to the safety and efficacy when compared with those of synthetic drugs. But due to lack of proper standardization at each stage from starting to culmination results in inferior quality and less demand. Saraswataristam, a fermented ayurvedic preparation, has been employed for treating central nervous system disorders and dermatological problems. Saraswataristam, containing Centella asiatica (L) urban (Umbelliferae) as the major ingredient is prepared as per the Ayurvedic Pharmacopoeial specifications, characterized and standardized for determining the quality, safety and efficacy of herbs used in it. Saraswataristam was prepared and subjected to phytochemical screening by FTIR analysis and HPTLC fingerprinting, heavy metal determination by AAS, determination of alcohol content, test for E. coli, S. aureus, aerobic bacteria, yeasts and mould, oral toxicity studies and anti-epileptic activity by MES method. The physico-chemical studies showed total ash content as 1.1%, extractive values and some trace elements such as Lead, Mercury, Cadmium and Arsenic with 3.1, 0.047, 0.17 and 0.46 ppm respectively and all values are found within the acceptable limits specified by WHO. FTIR and HPTLC studies showed the presence of asiaticoside in Saraswataristam, resulting in its chemical standardization. The formulation showed signs of dose dependent significant (P<0.001) reduction in various episodes of epileptic seizures in comparison with standard phenytoin, thereby making it biologically standardized. The physico-chemical and pharmacological analysis to standardize Saraswataristam confirmed its use as a safe anti epileptic ayurvedic formulation. PMID- 24811817 TI - Neurochemical and behavioral effects of Cinnamomi cassiae (Lauraceae) bark aqueous extract in obese rats. AB - Obesity is a risk factor leading to a number of chronic and metabolic disorders. Obesity is the fifth leading cause of global deaths. At least 2.8 million adults are dying each year as being overweight or obese. Cinnamomi cassiae is widely used traditional medicinal plant, used indigenously, to decrease glucose and cholesterol. 5-Hydroxy tryptamine (5-HT; Serotonin) is an important neurotransmitter reported to be involved in the pathophysiology of anorexia. Present study was designed to investigate the neurochemical and behavioral effects of cinnamon bark aqueous extract (CBAE) in obese rats and to find the possible involvement of 5-HT in reducing the body weight in these experimental animals. CBAE was repeatedly administered orally in the test animals for 5 weeks. A decrease in the food intake along with a concomitant increase in brain 5-HT level was observed in rats administered with CBAE. Findings may help in extending therapeutics in the pathophysiology of obesity and related eating disorders. Decrease activities in behavioral models were also monitored in CBAE treated animals. PMID- 24811818 TI - Antitumor effects of a polypeptide isolated from Tegillarca granosa linnaeus and the related molecular mechanism. AB - This study is to investigate the anticancer effects and mechanisms of Tegillarca granosa Linnaeus-1 (TG-1) on renal carcinoma OS-RC-2 cells in vitro. The proliferation of OS-RC-2 cells was evaluated under various concentrations of TG-1 using MTT assay. The apoptosis of OS-RC-2 cells was analyzed using acridine orange/ethidium bromide staining. And the cell cycle distribution of OS-RC-2 cells was detected by flow cytometry. In addition, the expression level of Ki67 mRNA was examined by RT-PCR and level of casepase-3 was examined by Western blot analysis. TG-1 incubation significantly inhibited the proliferation of renal carcinoma OS-RC-2 cells and arrested cells at G0/G1 phase (P <0.05). And TG-1 also significantly inhibited the expression of Ki67 mRNA (P<0.05). Additionally, TG-1 significantly promoted apoptosis and the expression of caspase-3 in cells (P<0.05). Moreover, the optimal effects of TG-1 was achieved at the concentration of 100 mg/L The results indicate that TG-1 has antitumor effects on renal carcinoma OS-RC-2 cells and that the underlying mechanisms may be acted through inhibiting proliferation and Ki67 mRNA expression, and promoting apoptosis and caspase-3 expression. PMID- 24811819 TI - Weight loss in HCV patients can be used as a surrogate marker for evaluation of interferon (IFN-alpha) treatment efficacy - a prospective pilot study. AB - The aim of the study was to investigate whether weight loss followed the same pattern in HCV patients ('responders' and 'non-responders) after interferon (IFN alpha) treatment. A total of 20 male HCV positive patients (mean age 33.1+/-9.9) in Peshawar, Pakistan participated in this study. They were initially tested as HCV positive, and were given IFN/Ribavarin treatment for 6 months. Changes in body weight (BW), lean body mass (LBM) and body fat (BF) were monitored on monthly basis. End to treatment response (ETR) was established by a final undetectable HCV RNA in serum at the end of therapy and the patients were categorized as either 'responders' or 'non-responders'. The results show a total of 12 out of 20 patients as 'responders' (60%). All patients lost weight and the mean weight loss in 'responders' and 'non-responders' was 6.2 (+/-1.5) and 5.8 (+/-1.4) Kg, respectively. There was a significant difference in the mean change in BW, LBM, and BF between 'responders' and 'non-responders' during the last 3 month period only. This suggests that difference in drug response in HCV starts from month 4 and onwards (i.e. during the last 3 months). In conclusion, weight trends during treatment should be monitored as weight loss may be used as a surrogate marker for ERT to the current standard of care. PMID- 24811820 TI - Report: physicochemical and phytochemical analysis of Euphorbia helioscopia (L.). AB - The present study aimed to standardize the crude drug from "Euphorbia helioscopia" by doing qualitative and quantitative analysis of different pulverized plant parts and extracts. Physicochemical analysis (determination of moisture contents, total ash, water insoluble ash, sulphated ash, acid insoluble ash, and water and alcohol extractives) was done on powdered raw materials (stem and leaves). The moisture contents and the ash value were found within the normal recommended range (moisture contents 6% and ash value 20%). The value of water soluble extracts was higher as compared to alcohol soluble extractives. Percentage yield was highest in methanol solvent. The phytochemical analysis i.e. total lipids, total proteins and carbohydrates of crude powder showed that lipids and proteins contents were high (2.4% & 0.91% respectively) in pulverized stem while carbohydrate contents were high (78.27%) in pulverized leaves. Qualitative analysis by FTIR fingerprints and UV-scanning showed that stem and leaves of the plant contained the same constituents because their spectra are super-imposable. Aqueous-, ethanol-, petroleum ether-, chloroform- and methanol extracts were used in the study. Quantitative analysis was done by calculating the primary and secondary metabolites (total proteins, total glycosaponins, total alkaloids, total flavonoids, and total polyphenolics) in all the extracts using suitable markers. Chloroform gave very less percentage yield and nil primary metabolites so it was eliminated from secondary metabolites estimation. The maximum value of total proteins, total glycosaponins, total alkaloids, total flavonoids and total polyphenolics were found in the leaves methanol (36.56%), stem methanol (34%), stem ethanol (41.84%), leaves methanol (108.96%), and leaves petroleum ether (7.22%) respectively. Different pharmacological activities of the plants are due to their flavonoid contents. It is concluded that methanol is the best solvent for extraction. Any arial part of the plant can be used in pharmacological evaluations prior to pre-clinical and clinical studies because leaves and stem had superimposable spectra in FTIR and UV-scanning. PMID- 24811822 TI - Report: screening of selected medicinal plants for their enzyme inhibitory potential - a validation of their ethnopharmacological uses. AB - In present study four medicinal plants namely Valeriana wallichii, Xanthium strumarium, Achyranthes aspera and Duchesnea indica belonging to different families were collected in Khyber Pakhtunkhwa province and crude extract and subsequent fractions were analyzed for their inhibitory potential against acetylcholinesterase, butyrylcholinesterase and alpha-glucosidase enzymes. Valeriana wallichii, Xanthium strumarium and Achyranthes aspera were significantly active against cholinesterases. Chloroform and ethylacetate fractions of Valeriana wallichii exhibited significant activity against acetylcholinesterase (IC50: 61MUg/ml) and butyrylcholinesterase enzymes (IC50: 58MUg/ml), respectively. Similarly ethylacetate fraction of Achyranthes aspera showed significant activity against acetylcholinesterase (IC50: 61 MUg/ml) and butyrylcholinesterase enzymes (IC50: 61 MUg/ml), respectively. In case of alpha glucosidase enzyme, the chloroform fraction of Xanthium strumarium exhibited significant inhibitory activity (IC50: 72 MUg/ml) as compared to the standard compound acarbose (IC50: 483 MUg/ml). Duchesnea indica showed no such activities. PMID- 24811821 TI - Report: investigation of anti-cancer effects of cherry in vitro. AB - Cherry (Prunus Cerasus) is still one of the most popular preserve in Turkish cuisine. Cherry has been traditionally used for the treatment of inflammatory related symptoms. Recent researches have proved that cherry is a valuable natural source of some important bioactive compounds in human health preservation. Evidence suggests that, cherry consumption may decrease the risk of chronic diseases and cancer. The aim of the present study was to determine the effects of cherry on breast cancer cells lines, asymmetric dimethylarginine (ADMA) level and certain multidrug-resistant bacteria. The cancer cell proliferation activity and analysis of apoptotic-necrotic cells was evaluated by using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and scoring of apoptotic cell nuclei. Measurement of ADMA and the minimum inhibitory concentration was accomplished by HPLC and the micro dilution broth method. The results showed that, extracts of cherry exhibit anti-proliferative activity in mammary adenocarcinoma (MCF-7) & mouse mammary tumor cell (4T1) breast cancer cells lines as well as induction of apoptosis, lower ADMA concentrations in cell cultures treated with cherry extract and antibacterial effects against certain multidrug-resistant bacteria in vitro. These findings may open new horizons for traditional anti-inflammatory product as prophylactic-therapeutic agent from cancer, cardiovascular diseases and multidrug-resistant infections. PMID- 24811823 TI - Report: nutrient evaluation and elemental analysis of four selected medicinal plants of soon valley Khushab, Punjab, Pakistan. AB - To check the nutritional and mineral contents of four medicinal plants viz., Peganum hermla, Solanum nigrum, Mentha longifolia, Achryanthus aspera, which are used as medicine traditionally in Soon Valley Khushab, Pakistan. Proximate analysis of plant sample determined that protein (7.491%) and ash (22.79%) was highest in Mentha longifolia, carbohydrate (75.23%) in Peganum hermla, fats (12.595%) and moisture (6.82%) was highest in Achryanthus aspera. In comparative assessment of the various species, the results showed that Achryanthus aspera. is the most significant species having higher concentrations of fat, fibre values compared to the other species. Absorption Spectrometric method was used for the elemental analysis of essential elements such as Fe, Cd, Cu,Mn, Pb, Cr, Ni and Na in medicinal plants in different range. PMID- 24811824 TI - Report: structures and hepatocytotoxicity of co-occurring substances in oleanolic acid tablets. AB - Tablets of oleanolic acid (OA) have been approved by SFDA in China as an adjuvant therapy for acute and chronic hepatitis. Co-occurring substances present in the tablets of OA and their hepatocytotoxicity have not yet been reported. In the current investigation, the crude OA drug was separated by repeated column chromatography. The structures of the isolated compounds were characterized by spectral analysis and the cytotoxicity of each compound was evaluated in vitro against the human normal liver cell L02 at concentrations from 0.125 to 1000 MUmol/L using the MTT method. As a result, OA and its 11 co-occurring trace compounds including one new triterpenoid, 3-O- (4-oxo-pentanoyl)-olean-12- en-28 oic acid, were isolated and structurally characterized. Cytotoxicity tests indicated that these compounds were all non-toxic at concentrations up to 50MUmol/L. Clear structure-activity relationship (SAR) was also observed. The results suggested that OA tablets of similar origin might not cause obvious cytotoxicity to the normal liver cell. The work may facilitate further SAR studies of OA-type triterpenoids. PMID- 24811825 TI - Review: Ajwa date (Phoenix dactylifera)- an emerging plant in pharmacological research. AB - Date Fruits are consumed in Arab areas for a long time as a part of essential diet. Phoenix dactylifera belongs to family Arecaceae and its leaves, barks, pits, fruits and pollens have anticancer, antioxidant, hepatoprotective, antidiabetic, antihypertensive, antiulcertavie, anti-inflammatory, antiproliferative, antimutagenic, antidiarheal, antibacterial, antifungal and antiviral potential. Besides these, Dates also increase level of estrogen, testosterone, RBCs, Hb, PCV, reticulocytes and platelet counts. It can also cure lead induced heamotoxicity, side effects of methylprednisolon, male and female infertility. It has also cerebroprotective, neuroprotective and haemopoietic activity. Phoenix dactylifera can be used for number of complications if further evaluated and isolated. The present paper is an overview of pharmacological properties of Phoenix dactylifera reported in literature. PMID- 24811826 TI - Does mechanical disturbance affect the performance and species composition of submerged macrophyte communities? AB - Submerged macrophyte communities are frequently subjected to disturbance of various frequency and strength. However, there is still little experimental evidence on how mechanical disturbance affects the performance and species composition of such plant communities. In a greenhouse experiment, we constructed wetland communities consisting of five co-occurring clonal submerged macrophyte species (Hydrilla verticillata, Elodea canadensis, Ceratophyllum demersum, Chara fragilis, and Myriophyllum spicatum) and subjected these communities to three mechanical disturbance regimes (no, moderate and strong disturbance). Strong mechanical disturbance greatly decreased overall biomass, number of shoot nodes and total shoot length, and increased species diversity (evenness) of the total community. It also substantially decreased the growth of the most abundant species (H. verticillata), but did not affect growth of the other four species. Our data reveal that strong disturbance can have different effects on different submerged macrophyte species and thus alters the performance and species composition of submerged macrophyte communities. PMID- 24811827 TI - Self-crosslinked oxidized alginate/gelatin hydrogel as injectable, adhesive biomimetic scaffolds for cartilage regeneration. AB - Biopolymeric hydrogels that mimic the properties of extracellular matrix have great potential in promoting cellular migration and proliferation for tissue regeneration. The authors reported earlier that rapidly gelling, biodegradable, injectable hydrogels can be prepared by self-crosslinking of periodate oxidized alginate and gelatin in the presence of borax, without using any toxic crosslinking agents. The present paper investigates the suitability of this hydrogel as a minimally invasive injectable, cell-attractive and adhesive scaffold for cartilage tissue engineering for the treatment of osteoarthritis. Time and frequency sweep rheology analysis confirmed gel formation within 20s. The hydrogel integrated well with the cartilage tissue, with a burst pressure of 70+/-3mmHg, indicating its adhesive nature. Hydrogel induced negligible inflammatory and oxidative stress responses, a prerequisite for the management and treatment of osteoarthritis. Scanning electron microscopy images of primary murine chondrocytes encapsulated within the matrix revealed attachment of cells onto the hydrogel matrix. Chondrocytes demonstrated viability, proliferation and migration within the matrix, while maintaining their phenotype, as seen by expression of collagen type II and aggrecan, and functionality, as seen by enhanced glycosoaminoglycan (GAG) deposition with time. DNA content and GAG deposition of chondrocytes within the matrix can be tuned by incorporation of bioactive signaling molecules such as dexamethasone, chondroitin sulphate, platelet derived growth factor (PDGF-BB) and combination of these three agents. The results suggest that self-crosslinked oxidized alginate/gelatin hydrogel may be a promising injectable, cell-attracting adhesive matrix for neo-cartilage formation in the management and treatment of osteoarthritis. PMID- 24811828 TI - Phytofabrication of gold nanoparticles assisted by leaves of Suaeda monoica and its free radical scavenging property. AB - Development of biologically inspired experimental processes for the synthesis of nanoparticles is evolving into an important branch of nanotechnology. An eco friendly synthesis of inorganic nanoparticle is a fast growing research in the limb of nanotechnology. In the present study, it is reported that Suaeda monoica leaf mediated synthesis of gold nanoparticles by the reduction of gold ions. The formation of gold nanoparticle was confirmed by color changes from turbid brown to deep purple violet color and a characteristic peak at 535 nm. The morphology and structure of synthesized gold nanoparticles were characterized on Scanning Electron Microscopy (SEM) equipped with a Thermo EDAX attachment, Transmission Electron Microscopy (TEM), X-ray diffraction (XRD), (FT-IR), Dynamic Light Scattering (DLS) which reveals that the Au nanoparticles are spherical and the average particle size is 12.96 nm. Crystalline nature of the nanoparticles is confirmed from the XRD pattern. FTIR spectrum indicates that the biomolecules of carboxyl, amine and hydroxyl functional groups involved in the reduction of gold nanoparticles. The biosynthesized gold nanoparticles displayed considerable antioxidant capacity. PMID- 24811829 TI - Oral surgeon at centre of recent controversy had previously been reprimanded by GMC. PMID- 24811830 TI - Management of refractory hepatic hydrothorax. AB - PURPOSE OF REVIEW: Treatment of hepatic hydrothorax is challenging because of its rapid symptomatic recurrence. This review will focus on potential therapeutic approaches to hepatic hydrothorax. RECENT FINDINGS: Hepatic hydrothorax is refractory to salt restriction and diuretics in approximately 25% of cases. Primary management options for these patients include serial thoracenteses, transjugular intrahepatic portosystemic shunt (TIPS) placement, and insertion of an indwelling pleural catheter (IPC). Response rate to TIPS, being the first choice whenever possible, is about 80%. IPC is emerging as a feasible alternative in patients who require frequent therapeutic thoracenteses, particularly if TIPS is contraindicated. Pleurodesis is not advocated because of the low likelihood of a pleural symphysis owing to the rapid re-accumulation of pleural fluid. The only cure for hepatic hydrothorax, a defined complication of end-stage liver disease, is liver transplantation. SUMMARY: No single treatment option for refractory hepatic hydrothorax is ideal. However, in patients with contraindications to or who are awaiting liver transplantation, TIPS seems the most beneficial therapy, whereas IPC promises to be an alternative second-line consideration. PMID- 24811831 TI - Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. AB - PURPOSE OF REVIEW: This review gives a comprehensive overview on recent developments in the classification of neoplastic lung lesions with lepidic growth patterns, comprising the adenocarcinoma (ADC) precursor lesions atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA) as well as lepidic predominant adenocarcinoma (LPA). RECENT FINDINGS: The concept of a continuum between the precursor lesions AAH and AIS to MIA and frankly invasive ADC is backed by a wealth of recent data showing a gradual decrease in overall survival from 100% for AAH, AIS, and MIA to moderately lower rates for LPA. Further, it has been shown that the morphologic categorization of these tumors can be done with reasonable reliability and that nonmucinous lepidic tumors show distinct molecular alterations with high rates of epidermal growth factor receptor mutations. Importantly, lepidic tumor growth is also mirrored by specific characteristics in computed tomography images, arguing for a combined assessment of histomorphology and imaging data for an optimized classification of lepidic neoplasms. SUMMARY: The validity and clinical importance of the novel concept of ADC precursor lesions and LPA have been confirmed by clinical, radiological, morphological, and molecular data. Thereby, it has evolved into a valuable tool to aid in clinical decision-making. PMID- 24811832 TI - The health risk of chrysotile asbestos. AB - PURPOSE OF REVIEW: The word asbestos is a poorly attributed term, as it refers to two very different minerals with very different characteristics. One is the serpentine mineral of which the white asbestos, chrysotile, is the most common. The other is the amphibole asbestos, which includes the blue asbestos crocidolite and the brown asbestos amosite. Although today chrysotile is the only type used commercially, the legacy of past use of amphibole asbestos remains. This review clarifies the differences between the two mineral families referred to as asbestos and summarizes the scientific basis for understanding the important differences in the toxicology and epidemiology of these two minerals. RECENT FINDINGS: Biopersistence and sub-chronic inhalation toxicology studies have shown that exposure to chrysotile at up to 5000 times the current threshold limit value (0.1 fibers/cm) produces no pathological response. These studies demonstrate as well that following short-term exposure the longer chrysotile fibers rapidly clear from the lung and are not observed in the pleural cavity. In contrast, short-term exposure to amphibole asbestos results quickly in the initiation of a pathological response in the lung and the pleural cavity. SUMMARY: Significant progress has been made in understanding the factors that influence inhalation toxicology studies of fibers and epidemiological studies of workers. Evaluation of the toxicology and epidemiology studies of chrysotile indicates that it can be used safely under controlled use. In contrast, even short-term exposure to amphibole asbestos can result in disease. PMID- 24811833 TI - Endobronchial valve placement for the treatment of bronchopleural fistula: a review of the current literature. AB - PURPOSE OF REVIEW: Bronchopleural fistula is a cause of increased morbidity and mortality. Patients who develop bronchopleural fistula after lung resection or spontaneous pneumothorax often have multiple co-morbidities making them poor candidates for repeated surgical intervention. Previous nonsurgical treatments for bronchopleural fistula have had limited success. Endobronchial valves, originally designed for bronchoscopic lung volume reduction, have been used under a humanitarian use exception for the treatment of bronchopleural fistula. Numerous case series and reports have been published; however, guidelines for the use of endobronchial valves specifically for bronchopleural fistula have yet to be developed. RECENT FINDINGS: A number of case series and reports have described the use of one-way endobronchial valves for the treatment of bronchopleural fistula, after spontaneous pneumothorax, lung resection and complication of suppurative lung disease. In the largest series reported (40 patients), 93% of patients experienced improvement in air leak, with 48% having complete resolution. Other series have shown similar success. Complications are rare and include pneumonia, expectoration or migration of valves, and bacterial colonization. SUMMARY: The use of endobronchial valves for the treatment of bronchopleural fistula is well tolerated and effective. Controlled clinical trials are needed to further evaluate their efficacy and identify ideal patient populations for their use. PMID- 24811834 TI - High-grade neuroendocrine carcinoma. AB - PURPOSE OF REVIEW: This review presents an update on classification, diagnosis and potentially 'drugable' molecular alterations of small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC) of the lung. RECENT FINDINGS: The main controversies in the classification of lung neuroendocrine tumors are: whether SCC and LCNEC should remain separated or should be unified into a high grade category; and what the role is of Ki67 as an adjunct to the classical parameters (mitotic rate and necrosis). Regarding the diagnosis of SCC and LCNEC, in difficult cases it requires the combined evaluation of clinical-radiological data, histological and cytological material and selected immunostains. The prognosis of both tumors remains very poor. Despite the promising identification of potential molecular targets on preclinical studies, including antiangiogenetic drugs and tricyclic antidepressants, at the moment no specific molecular-driven therapy is available. SUMMARY: The field of high-grade neuroendocrine carcinomas remains complex in several respects, and studies on molecular targets are urgently needed. PMID- 24811835 TI - Pleural effusions in acute and chronic leukemia and myelodysplastic syndrome. AB - PURPOSE OF REVIEW: Pulmonary manifestations have been well described in leukemia, but pleural disease is less common. This review highlights pleural effusions in acute and chronic leukemia and myelodysplastic syndrome (MDS) based on the evidence to date. Diagnostic workup and recommendations for the management of these effusions are also outlined. RECENT FINDINGS: Pleural effusions in patients with leukemia are most often due to infection and to a lesser extent leukemic infiltration of the pleura. The prognostic implications of these effusions are unclear, but survival is most likely determined by the underlying malignancy and its response to treatment. New therapies have changed survival in these patients, and some of these treatments, such as tyrosine kinase inhibitors, have emerged as important causes for these effusions. Pleural interventions may be accomplished with few complications. SUMMARY: Pleural effusions may occur with acute and chronic leukemia and MDS. Infection remains the most common cause. Malignant pleural effusions tend to occur in advanced disease in chronic leukemia, but they can be seen at any time with acute leukemia and MDS. With standard precautions, pleural procedures may be performed safely in this population. In cases of unclear cause, pleural and bone marrow biopsy should be considered. PMID- 24811836 TI - Large-cell carcinoma of the lung: a diagnostic category redefined by immunohistochemistry and genomics. AB - PURPOSE OF REVIEW: The current classification system defines large-cell carcinoma (LCC) morphologically as an undifferentiated lung carcinoma lacking features of adenocarcinoma (ADC), squamous cell, or small-cell carcinoma. As a result, LCC has evolved into a clinicopathologically heterogeneous entity. In the current era of histology-driven predictive molecular testing and oncologic management, ambiguous diagnostic categories frustrate attempts to provide more personalized cancer care, thus the pathology community has engaged in a concerted effort to revise the criteria for LCC. RECENT FINDINGS: Most cases of LCC are immunophenotypically similar to ADC or squamous cell carcinoma. LCC lacking squamous and neuroendocrine features is clinically and genomically indistinguishable from solid ADC. Even cases of LCC lacking immunophenotypic differentiation may contain genomic alterations characteristic of other forms of lung carcinoma. SUMMARY: Applying ancillary techniques, most cases of LCC can be reclassified into more informative categories that may guide molecular testing for predictive biomarkers and enable selection of more appropriate therapies. PMID- 24811837 TI - The Lake Clinic - providing primary care to isolated floating villages on the Tonle Sap Lake, Cambodia. AB - CONTEXT: One of the most isolated areas in South-East Asia is the Tonle Sap Lake region in Cambodia. Scattered throughout the lake are remote fishing villages that are geographically isolated from the rest of the country. ISSUE: Receiving health care at a clinic or hospital often involves a full day of travel from the Tonle Sap Lake region, which is unaffordable for the vast majority of residents. INTERVENTION: The Lake Clinic (TLC) is a non-government organization established in 2007. In 2008, a ship was built that was designed for transport of a medical team and supplies to provide primary care to the fishing villages. Initially the project started with one team serving seven villages. TLC has since expanded to two full teams serving 19 villages. TLC provides adult and pediatric primary care, vaccinations, dental services, eyecare services, antenatal care and health education free of charge. From 2008 to 2012, there were a total of 13 160 pediatric visits and 17 722 adult visits. In addition to these services, 739 patients received dental care, 346 patients received eye care, there were 1239 antenatal visits, 116 family planning visits, and 1600 patients received health education. In total, 130 patients were referred to hospitals or health centers for a higher level of care. A total of 6627 immunizations were provided. The most common pediatric illness was upper respiratory infection (44.4%), and the most common adult illness observed was gastritis (20.6%). LESSONS LEARNED: Despite the challenges, TLC has been able to achieve a significant goal: to provide primary care medical services to a remote area of Cambodia where no medical services were previously available. TLC strives to strengthen healthcare delivery with the goal to provide the best possible care in the region. New partnerships have allowed laboratory capacity and a formalized hospital referral system for pediatric patients beginning in 2014. A new boat, which completed construction in December 2013 and is now fully operational, has allowed the TLC team to reach a greater number of patients more efficiently. PMID- 24811838 TI - Cumulative effects of variants identified by genome-wide association studies in IgA nephropathy. AB - The effect of genetic markers associated with IgA nephropathy on risk of disease in sub-phenotype and progression is uncertain. Data from 2096 Chinese patients were used to create both un-weighted (uw) and weighted (w) genetic risk score (GRS). The association between GRS with disease susceptibility and clinical parameters were assessed. All nine selected single nucleotide polymorphisms (SNPs) were associated with susceptibility to IgAN. uwGRS and wGRS showed a similar fit in disease associations. With every 1-unit increase in the uwGRS, the disease risk increased by approximately 20%; whereas every one standard deviation increase in the wGRS, disease risk increased by approximately 40% ~ 60%. Association between rs3803800 and serum IgA was replicated, and risk groups in GRSs were associated with increased IgA/IgA1 levels. uwGRS9 >= 16 was an independent predictor for end stage renal disease (ESRD) in IgAN, with a relative risk of 2.52 (p = 6.68 * 10(-3)). In conclusion, we observed that GRSs comprising nine SNPs identified in a GWAS of IgAN were strongly associated with susceptibility to IgAN. The high risk GRS9 group had a high risk of ESRD in follow-up. PMID- 24811839 TI - Glutamate supply positively affects serum cholesterol concentrations without increases in total protein and urea around the onset of puberty in goats. AB - Different neurotransmitter and neuromodulatory systems regulate synthesis and secretion of GnRH. Whereas the endocrine and neural systems are activated in response to the metabolic status and the circulating levels of specific blood metabolites, glutamate receptors have been reported at hepatic level. This study evaluated the possible effect of glutamate supplementation upon changes in serum concentrations across time for total protein (TP), urea (UR) and cholesterol (CL) around the onset of puberty in goats. Prepuberal female goats (n=18) were randomly assigned to: (1) excitatory amino acids group, GLUT, n=10; 16.52+/ 1.04kg live weight (LW), 3.4+/-0.12 body condition score (BCS) receiving an i.v. infusion of 7mgkg(-1) LW of l-glutamate, and (2) Control group, CONT, n=8; 16.1+/ 1.04kg LW, 3.1+/-0.12 BCS. General averages for LW (23.2+/-0.72kg), BCS (3.37+/ 0.10 units), serum TP (65.28+/-2.46mgdL(-1)), UR (23.42+/-0.95mgdL(-1)), CL (77.89+/-1.10mgdL(-1)) as well as the serum levels for TP and UR across time did not differ (P>0.05) between treatments. However, while GLUT positively affected (P<0.05) both the onset (207+/-9 vs. 225+/-12 d) and the percentage (70 vs. 25%) of females showing puberty, a treatment*time interaction effect (P<0.05) was observed in the GLUT group, with increases in serum cholesterol, coincident with the onset of puberty. Therefore, in peripuberal glutamate supplemented goats, serum cholesterol profile could act as a metabolic modulator for the establishment of puberty, denoting also a potential role of glutamate as modulator of lipid metabolism. PMID- 24811840 TI - Peroxisome proliferator-activated receptor alpha mediates di-(2-ethylhexyl) phthalate transgenerational repression of ovarian Esr1 expression in female mice. AB - Di-(2-ethylhexyl)-phthalate (DEHP) is a phthalate ester that binds peroxisome proliferator-activated receptor alpha (PPARalpha) to induce proliferation of peroxisomes and regulate the expression of specific target genes. The question of whether the effect of DEHP on female reproductive processes is mediated via PPARalpha-dependent signaling is controversial. In this study, we investigated the effect of exposure to DEHP on ovarian expression of estrogen receptor alpha (Esr1) and aromatase (Cyp19a1) in three generations of Sv/129 wild-type (WT, +/+) and PPARalpha (-/-) knockout mice. Compared with untreated controls, ovarian expression of Esr1 decreased in response to DEHP treatment in the F0 (0.56-fold, P=0.19), F1 (0.45-fold, P=0.023), and F2 (0.35-fold, P=0.014) generations of WT mice, but not PPARalpha-null mice. Our data indicate that transgenerational repression by DEHP of ovarian Esr1 gene expression is mediated by PPARalpha dependent pathways. Further studies are required to elucidate the mechanisms underlying crosstalk between PPARalpha and Esr1 signaling in reproductive processes. PMID- 24811841 TI - Parenting with a disability and child mental health: a propensity score analysis. AB - Little research has examined the impact of having a parent with a disability on child mental health. This study used data from 7,116 families of children who participated in the 2006 National Health Interview Survey and propensity score matching (PSM) to investigate this question. Prior to PSM, differences in Child Mental Health Brief scores were significant with a moderate effect size. After PSM, differences in Child Mental Health Brief scores were still significant, but the effect size was small. Results indicate that much of the mental health risk for children of parents with disabilities is connected to related issues. PMID- 24811842 TI - The effect of interventions to prevent and treat malnutrition in patients admitted for rehabilitation: a systematic review with meta-analysis. AB - BACKGROUND: Malnutrition occurs frequently among patients in rehabilitation, leading to poorer outcomes. Evidence of the effects of interventions to prevent or treat malnutrition is required to guide clinical practice in this setting. This systematic review aimed to determine the effect of oral nutrition interventions implemented in rehabilitation on nutritional and functional outcomes. METHODS: Five databases were searched to identify relevant publications; intervention trials of oral nutrition interventions (such as oral nutrition supplements, foodservice interventions, clinical care processes, enhanced eating environments) conducted with patients admitted for rehabilitation, reporting dietary intake, anthropometric, biochemical or functional outcomes. The reviewers determined study eligibility and assessed the included studies for risk of bias. Outcome data were combined narratively and by meta-analyses. RESULTS: From 1765 publications, 10 studies trialling oral nutrition supplements, foodservice interventions and clinical care processes (of neutral or positive quality) were identified. Compared to meals alone, oral nutritional supplements significantly improved energy and protein intake, with some evidence for improvements in anthropometry and length of stay. There was little evidence that speciality supplements were beneficial compared to standard versions. Meta-analyses demonstrated significantly greater energy [weighted mean difference (WMD) = 324 kcal, 212-436 kcal 95% confidence interval (CI)] and protein (WMD = 9.1 g, 0.2-17.9 g 95% CI) intake with energy dense meals. Opposing results were reported in studies investigating enhanced clinical care processes. CONCLUSIONS: The provision of oral nutrition supplements and energy dense meals improved energy and protein intake and therefore may comprise effective strategies for addressing malnutrition in rehabilitation. The effect of these strategies on other nutritional and functional outcomes should be explored further. PMID- 24811843 TI - Diurnal variation of retinal thickness in healthy subjects. AB - PURPOSE: To investigate diurnal fluctuations in retinal thickness using spectral domain optical coherence tomography (SD-OCT). METHODS: Spectralis SD-OCT was used to obtain data from the right eye of 21 healthy subjects (mean age, 31.3 years) at 7 AM, 1 PM, and 7 PM. For each eye, a full peripapillary retinal nerve fiber layer circular scan and a 19-line horizontal raster scan (6- by 6-mm area) centered on the fovea were performed. RESULTS: Retinal nerve fiber layer thickness was greater at 7 AM or 1 PM than at 7 PM for nasal (79.1 MUm [1 PM] vs. 77.6 [7 PM]; p = 0.024), inferior (134.1 [7 AM] vs. 131.9 [7 PM]; p = 0.009), and inferonasal (115.2 [7 AM] vs. 115.6 [1 PM] vs. 112.4 [7 PM]; p < 0.001) subfields. Macular thickness was greater at 7 AM than at 7 PM for inferior 6 mm (290.2 MUm [7 AM] vs. 287.8 [7 PM]; p < 0.001) ETDRS (Early Treatment Diabetic Retinopathy Study) subfield. Macular volume was greater at 7 AM than at 7 PM for nasal 3 mm (0.541 mm vs. 0.538; p = 0.028) and inferior 6 mm (1.538 vs. 1.525; p < 0.001) ETDRS subfields. The remaining studied areas did not show any significant change throughout the day. CONCLUSIONS: The Spectralis SD-OCT retinal thickness measurements showed a small but statistically significant diurnal variation in nasal and inferior subfields toward smaller values in the evening. However, the overall change is close to the instrument's resolution and repeatability. PMID- 24811844 TI - Rasch analysis of the Student Refractive Error and Eyeglass Questionnaire. AB - PURPOSE: To evaluate and refine a newly developed instrument, the Student Refractive Error and Eyeglasses Questionnaire (SREEQ), designed to measure the impact of uncorrected and corrected refractive error on vision-related quality of life (VRQoL) in school-aged children. METHODS: A 38-statement instrument consisting of two parts was developed: part A relates to perceptions regarding uncorrected vision and part B relates to perceptions regarding corrected vision and includes other statements regarding VRQoL with spectacle correction. The SREEQ was administered to 200 Native American 6th- through 12th-grade students known to have previously worn and who currently require eyeglasses. Rasch analysis was conducted to evaluate the functioning of the SREEQ. Statements on parts A and B were analyzed to examine the dimensionality and constructs of the questionnaire, how well the items functioned, and the appropriateness of the response scale used. RESULTS: Rasch analysis suggested two items be eliminated and the measurement scale for matching items be reduced from a four-point response scale to a three-point response scale. With these modifications, categorical data were converted to interval-level data to conduct an item and person analysis. A shortened version of the SREEQ was constructed with these modifications, the SREEQ-R, which included the statements that were able to capture changes in VRQoL associated with spectacle wear for those with significant refractive error in our study population. CONCLUSIONS: Although part B of the SREEQ appears to have a less-than-optimal reliability to assess the impact of spectacle correction on VRQoL in our student population, it is able to detect statistically significant differences from pretest to posttest on both the group and individual levels to show that the instrument can assess the impact that glasses have on VRQoL. Further modifications to the questionnaire, such as those included in the SREEQ-R, could enhance its functionality. PMID- 24811845 TI - Apparent inferior rectus palsy with gaze-dependent sensory adaptations. AB - PURPOSE: This report presents a case of apparent congenital inferior rectus palsy notable for sensory adaptations that appeared to vary with direction of gaze. It is shown that readily available clinical tests and an understanding of the physiology of ocular motility can be used to help distinguish from differential diagnoses such as contralateral inferior oblique palsy or the more commonly seen Brown syndrome. CASE REPORT: A 20-year-old male optometry student reported strabismus that had been noted at birth and was diagnosed as Brown syndrome in childhood. The Parks three-step test showed primary gaze hypertropia that increased in left gaze but the "third step" (Bielschowsky head tilt test) was not successful in establishing the apparently correct diagnosis, which was later confirmed by a Hess screen. A proposed "fourth" step by Bajandas proved to be more accurate in this case of inferior rectus palsy. Sensory tests revealed adaptation patterns that varied with gaze direction and showed a cyclotorsional element. The patient reported being relatively unconcerned about his condition as he seemed to be able to voluntarily use a form of shallow suppression to reduce awareness of diplopic images. CONCLUSIONS: Although it is common to consider suppression and retinal correspondence status as hardwired and relatively constant for an individual patient, this case demonstrates that these sensory adaptations are likely to be far more complex and transitory. An understanding of both motor and sensory repercussions of ocular motility dysfunction assists differentiation between benign and sinister causes of nonconcomitant strabismus. PMID- 24811846 TI - Test-retest reliability of retinal oxygen saturation measurement. AB - PURPOSE: To determine intrasession and intersession repeatability of retinal vessel oxygen saturation from the Oxymap Retinal Oximeter using a whole image based analysis technique and so determine optimal analysis parameters to reduce variability. METHODS: Ten fundus oximetry images were acquired through dilated pupils from 18 healthy participants (aged 22 to 38) using the Oxymap Retinal Oximeter T1. A further 10 images were obtained 1 to 2 weeks later from each individual. Analysis was undertaken for subsets of images to determine the number of images needed to return a stable coefficient of variation (CoV). Intrasession and intersession variability were quantified by evaluating the CoV and establishing the 95% limits of agreement using Bland and Altman analysis. Retinal oxygenation was derived from the distribution of oxygenation values from all vessels of a given width in an image or set of images, as described by Paul et al. in 2013. RESULTS: Grouped in 10-MUm-wide bins, oxygen saturation varied significantly for both arteries and veins (p < 0.01). Between 110 and 150 MUm, arteries had the least variability between individuals, with average CoVs less than 5% whose confidence intervals did not overlap with the greater than 10% average CoVs for veins across the same range. Bland and Altman analysis showed that there was no bias within or between recording sessions and that the 95% limits of agreement were generally lower in arteries. CONCLUSIONS: Retinal vessel oxygen saturation measurements show variability within and between clinical sessions when the whole image is used, which we believe more accurately reflects the true variability in Oxymap images than previous studies on select image segments. Averaging data from vessels 100 to 150 MUm in width may help to minimize such variability. PMID- 24811847 TI - Influence of contact lens power profile on peripheral refractive error. AB - PURPOSE: To measure the power profile across the optic zone (OZ) of four commercially available soft contact lenses and establish the impact on the peripheral refractive error of the eye. METHODS: The power profiles of a spherical conventional hydrogel contact lens (etafilcon A, J&J Vistakon, Jacksonville, FL USA) and three spherical silicone hydrogel contact lenses (lotrafilcon A and B, CIBA Vision, Duluth, GA USA; enfilcon A, CooperVision, Pleasanton, CA USA) with a labeled power of -3.00 and -6.00 diopters were measured using a Shack-Hartmann wavefront sensor power mapping device. Central and peripheral refraction across the horizontal meridian (nasal and temporal visual field at 20, 30, and 40 degrees) was measured with an open-field autorefractor (Shin Nippon NVision K5001, Osaka Japan) with and without contact lenses in 26 myopic subjects. The relative peripheral refractive error on the eye was estimated and compared with and without contact lenses and between contact lenses. RESULTS: Differences in the distribution of the power profile across the OZ were apparent between contact lens types and powers. No significant differences (p > 0.05) were found between contact lens types for their effect on on-axis refraction. Significant differences (p < 0.05) were found at all peripheral retinal eccentricities between contact lens types. CONCLUSIONS: For a given central power, the four contact lenses exhibited variations in optical power across the OZ of the lens. The distribution of optical power across the OZ has an influence on the peripheral refractive error of the eye. PMID- 24811848 TI - Parents' knowledge and perspective of optical methods for myopia control in children. AB - PURPOSE: To solicit parents' knowledge on myopia control strategies available; to investigate their attitudes toward the use of orthokeratology (ortho-k), daily wear soft lenses, and spectacles for myopia control, assuming all three optical strategies were equally effective for myopia control; and to collect their opinion on the age at which children can commence contact lens wear for vision correction. METHODS: Telephone interviews were conducted on parents who responded to the advertisement for two myopia control studies, one on ortho-k and one on soft lenses. RESULTS: Most of the 196 respondents (ortho-k group, 56%; soft lens group, 44%) were mothers, aged 36 to 45 years. Ortho-k was the most commonly known myopia control strategy (86%). Parents in the ortho-k group selected ortho k (49%) and spectacles (45%) (p < 0.001) as their preferred myopia control strategy, whereas parents in the soft lens group had no preference (p = 0.57). Decision was affected by prior knowledge of myopia control strategy. Major considerations were convenience and safety among parents selecting contact lenses and spectacles, respectively, as their preferred options. Overall, because of the lack of confidence in safety in contact lens wear, most parents (75%) were of the opinion that contact lenses for vision correction were only for children older than 14 years (53%) and not indicated for children younger than 8 years. CONCLUSIONS: Parents in Hong Kong were open to the use of contact lenses for myopia control in young children and they appeared to regard myopia control contact lenses as "treatment" and not as visual aids. They were more conservative in the use of contact lenses for vision correction in children. Parents' decision in selecting a myopia control strategy, assuming all three strategies to be equally effective, was affected by an individual's concerns of safety and additional benefits as well as influenced by positive evidence on myopia control effects. PMID- 24811849 TI - Restoring adult stereopsis: a vision researcher's personal experience. AB - In February 2012, the author acquired improved stereoscopic vision after viewing Martin Scorsese's film Hugo in 3D. The author had been deficient in stereo vision all of his life because in the first two decades, one eye deviated outward from the gaze position of the other. At that time, he was an alternator (alternating exotrope) showing strabismus (>20 prism diopters) without amblyopia. After viewing the 2-hour film, the Wirt stereo threshold decreased from 200 to 80 arcsec, and stereoscopic vision became a vivid experience. Exophoria decreased to 7 prism diopters. Numerous personal and research experiences throughout the author's career helped to interpret the phenomenon, which suggests a powerful new method for treating stereo-deficient patients. PMID- 24811850 TI - Proptosis from a Baerveldt tube shunt implant. AB - PURPOSE: The purpose of this case report is to describe a patient presenting with unilateral proptosis associated with a Baerveldt tube shunt implant that had been previously implanted for treatment of elevated intraocular pressure not sufficiently responsive to pressure-lowering medications. Because this particular device is impregnated with barium, it is radio-opaque and must be discriminated from ferromagnetic and other foreign bodies in the differential diagnosis of orbital space-occupying lesion. Although the incidence of proptosis resulting from glaucoma drainage devices is rare, radiologists and ophthalmic clinicians must be aware of this possibility as well as the appearance of these devices in orbital imaging. CASE REPORT: A patient with advanced glaucoma presented for an intraocular pressure check. Upon examination, proptosis was noted in the left eye. Exophthalmometry was performed and revealed asymmetry between the eyes. The patient was sent for a computed tomography scan of the orbits that revealed a foreign object in the left eye, which was identified as a Baerveldt tube shunt with surrounding fibrosis. The patient was sent to a glaucoma specialist for a consult regarding the efficacy of the implant. CONCLUSIONS: Late-onset proptosis is a rare complication of a glaucoma implant but can lead to concern for an orbital mass or other pathology, which should be ruled out. Also, because this particular device is impregnated with barium, it is radio-opaque and must be discriminated from other metallic foreign bodies. PMID- 24811851 TI - Late reactivation of herpes zoster keratitis results in band keratopathy. AB - PURPOSE: To report an unusual case of a late-stage reactivation of immune stromal keratitis associated with herpes zoster ophthalmicus (HZO), occurring without any apparent predisposing factors, more than 4 years after an acute zoster dermatomal rash. Significant corneal hypoesthesia and a central band keratopathy developed within 6 months of the late-stage reactivation. The clinical case management, issues associated with management, and management options are discussed, including the use of standardized, regulatory approved, antibacterial medical honey. CASE REPORT: An 83-year-old woman presented for routine review with a reactivation of right anterior stromal keratitis and mild anterior uveitis, occurring more than 4 years after an acute HZO dermatomal rash and an associated initial episode of anterior stromal keratitis. Corneal sensation became markedly impaired, and over the subsequent 6 months, a right central band keratopathy developed despite oral antiviral and topical steroid therapy. Visual acuity with pinhole was reduced to 20/100 in the affected eye and moderate irritation and epiphora were experienced. The patient declined the surgical intervention options of chelation, lamellar keratectomy, and phototherapeutic keratectomy to treat the band keratopathy. Longer-term management has involved preservative-free artificial tears, eyelid hygiene, standardized antibacterial medical honey, topical nonpreserved steroid, and UV-protective wraparound sunglasses. The clinical condition has improved over 14 months with this ocular surface management regimen, and visual acuity of 20/30 is currently achieved in a comfortable eye. CONCLUSIONS: The chronic and recurrent nature of HZO can be associated with significant corneal morbidity, even many years after the initial zoster episode. Long-term review and management of patients with a history of herpes zoster stromal keratitis are indicated following the initial corneal involvement. Standardized antibacterial medical honey can be considered in the management of the chronic ocular surface disease associated with HZO and warrants further evaluation in clinical trials. PMID- 24811852 TI - Gene expression profiles of similarly derived human embryonic stem cell lines correlate with their distinct propensity to exit stemness and their different differentiation behavior in culture. AB - Four normal-karyotype human embryonic stem cell (hESC) lines were generated using the same protocol and maintained under identical conditions. Despite these precautions, gene expression patterns were found to be dissimilar among the four lines. The observed differences were typical of each cell line, correlated with their distinct propensity to exit stemness, created heterogeneity among the cells during cell line maintenance, and correlated with their altered capacity as a source of differentiated cells. The capacity of some cell lines to give rise to more, and more mature, neurons within comparable time frames of directed differentiation reflected the distinct proportions of cells already predifferentiated at the onset. These findings demonstrate that the subsequent stages of neural differentiation were altered both in a quantitative and timely fashion. As a consequence, cell lines with apparent better and quicker ability to produce neurons were actually the less capable of reproducing proper differentiation. Previous data suggested that cell lines able to generate more neurons faster would be more suitable to clinical application. Our analysis of the differentiation process strongly suggests the opposite. The spontaneous tendency to predifferentiate of any particular hESC line should be known because it clearly impacts further experimental results. PMID- 24811853 TI - Chronic pain in multiple sclerosis: is there also fibromyalgia? An observational study. AB - BACKGROUND: Chronic pain is common in persons with multiple sclerosis (MS), but the co-morbidity of fibromyalgia (FM) has yet to be investigated in MS. Objectives of the study were to evaluate, among the various types of chronic pain, the frequency of FM in MS and its impact on MS patients' health-related quality of life (HRQoL). MATERIAL AND METHODS: 133 MS patients were investigated for the presence and characterization of chronic pain within 1 month of assessment. A rheumatologist assessed the presence FM according to the 1990 ACR diagnostic criteria. Depression, fatigue, and HRQoL were also assessed by means of specific scales. RESULTS: Chronic pain was present in 66.2% of patients (musculoskeletal in 86.3%; neuropathic in 13.7%; absent in 33.8% [called NoP]). Pain was diagnosed with FM (PFM+) in 17.3% of our MS patients, while 48.9% of them had chronic pain not FM type (PFM-); the prevalence of neuropathic pain in these 2 sub-groups was the same. PFM+ patients were prevalently females and had a higher EDSS than NoP. The PFM+ patients had a more pronounced depression than in the NoP group, and scored the worst in both physical and mental QoL. CONCLUSIONS: In our sample of MS patients we found a high prevalence of chronic pain, with those patients displaying a higher disability and a more severe depression. Moreover, FM frequency, significantly higher than that observed in the general population, was detected among the MS patients with chronic pain. FM occurrence was associated with a stronger impact on patients' QoL. PMID- 24811854 TI - Antibiotic prophylaxis during dental procedures in patients with in situ lower limb prosthetic joints. AB - The average age of patients presenting for total joint arthroplasty is decreasing. The number of primary and revision arthroplasty procedures performed in the UK, Europe and USA is increasing annually. As number of procedures performed increases, the life expectancy of our patients and therefore the in vivo duration of prosthetic joints increase, and the potential for complications such as infection increases. One potential source for this is bacterial dissemination during dental surgery. Many attempts have been made to address this issue in the form of national guidelines, but there is no clear consensus on antibiotic prophylaxis before these procedures in order to decrease the risk of prosthetic joint infection. This continues to be an area of indecision and uncertainty resulting in patients having delays in their treatment while decisions are made by oral and orthopaedic surgeons about prophylactic antibiotic use. This article reviews the existing national guidelines, highlighting the current views and issues surrounding this subject, and a critical appraisal of current evidence for the use of prophylactic antibiotics in this patient population is presented. We will also review the response in literature to the 2009 American Academy of Orthopaedic Surgeons information statement release on antibiotic prophylaxis in joint arthroplasty patients undergoing dental procedures. PMID- 24811855 TI - The economic burden of treatment failure amongst patients with irritable bowel syndrome with constipation or chronic constipation: a retrospective analysis of a Medicaid population. AB - OBJECTIVE: To compare healthcare resource utilization (HRU) and costs between patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC) with and without evidence of treatment failure. METHODS: Claims data from the Missouri Medicaid program were used to identify adults with IBS-C or CC treated for constipation. IBS-C patients were required to have >=2 constipation therapy claims, and the index date was defined as the date of the first constipation therapy claim within 12 months after an IBS diagnosis. For CC, the index date was defined as the date of the first constipation treatment claim followed by a second claim for constipation treatment or diagnosis between 60 days and 12 months later. Indicators of treatment failure were: switch/addition of constipation therapy, IBS- or constipation-related inpatient/emergency admission, megacolon/fecal impaction, constipation-related surgery/procedure, or aggressive prescription treatments. Annual incremental HRU and costs (public payer perspective) were compared between patients with and without treatment failure. Incidence rate ratios (IRRs) and cost differences are reported. RESULTS: In total, 2830 patients with IBS-C and 8745 with CC were selected. Approximately 50% of patients had >=1 indicator of treatment failure. After adjusting for confounding factors, patients with treatment failure experienced higher HRU, particularly in inpatient days (IRR = 1.75 for IBS-C; IRR = 1.54 for CC) and higher total healthcare costs of $4353 in IBS-C patients and $2978 in CC patients. Medical service costs were the primary driver of the incremental costs associated with treatment failure, making up 71.3% and 67.0% of the total incremental healthcare costs of the IBS-C and CC samples, respectively. LIMITATIONS: Sample was limited to Medicaid patients in Missouri. Claims data were used to infer treatment failure. CONCLUSION: Treatment failure is frequent among IBS-C and CC patients, and sub-optimal treatment response with available IBS-C and CC therapies may lead to substantial HRU and healthcare costs. PMID- 24811856 TI - On the antioxidant properties of erythropoietin and its association with the oxidative-nitrosative stress response to hypoxia in humans. AB - AIM: The aim of this study was to examine if erythropoietin (EPO) has the potential to act as a biological antioxidant and determine the underlying mechanisms. METHODS: The rate at which its recombinant form (rHuEPO) reacts with hydroxyl (HO), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and peroxyl (ROO) radicals was evaluated in-vitro. The relationship between the erythopoietic and oxidative nitrosative stress response to poikilocapneic hypoxia was determined separately in-vivo by sampling arterial blood from eleven males in normoxia and following 12 h exposure to 13% oxygen. Electron paramagnetic resonance spectroscopy, ELISA and ozone-based chemiluminescence were employed for direct detection of ascorbate (A( ) ) and N-tert-butyl-alpha-phenylnitrone spin-trapped alkoxyl (PBN-OR) radicals, 3-nitrotyrosine (3-NT) and nitrite (NO2-). RESULTS: We found rHuEPO to be a potent scavenger of HO (kr = 1.03-1.66 * 10(11) m(-1) s(-1) ) with the capacity to inhibit Fenton chemistry through catalytic iron chelation. Its ability to scavenge DPPH and ROO was also superior compared to other more conventional antioxidants. Hypoxia was associated with a rise in arterial EPO and free radical mediated reduction in nitric oxide, indicative of oxidative-nitrosative stress. The latter was confirmed by an increased systemic formation of A(-) , PBN-OR, 3 NT and corresponding loss of NO2- (P < 0.05 vs. normoxia). The erythropoietic and oxidative-nitrosative stress responses were consistently related (r = -0.52 to 0.68, P < 0.05). CONCLUSION: These findings demonstrate that EPO has the capacity to act as a biological antioxidant and provide a mechanistic basis for its reported cytoprotective benefits within the clinical setting. PMID- 24811857 TI - Prognostic impact of the current Japanese nodal classification on outcomes in resected non-small cell lung cancer. AB - BACKGROUND: The prognosis of N2 non-small cell lung cancer (NSCLC) has been reported to be heterogeneous. The recently revised Japanese nodal classification subcategorizes N2 disease according to the tumor-bearing lobe. We evaluated the prognostic impact of the Japanese nodal classification and its ability to define favorable N2 disease in resected NSCLC. METHODS: A total of 496 patients with NSCLC who underwent lobectomy with systematic lymph node dissection between 1998 and 2009 were analyzed retrospectively. N2 status was subdivided into N2a-1 and N2a-2, according to the Japanese nodal classification. Overall survival (OS), disease-free survival (DFS), and clinicopathologic features were compared between the two groups. RESULTS: There were 67 cases with N2 disease. The outcome of resected N2a-2 NSCLC was far poorer than that of the N2a-1 group (5-year OS, 28% vs 62%, P < .001; 5-year DFS, 5% vs 35%, P < .001). Multivariate analysis revealed that pathologic N2a-2 was an independent prognostic factor (hazard ratio, 2.86; P < .05). Patients in the N2a-2 group showed more involved nodes and stations, less skip metastasis, and more locoregional recurrence than did patients in the N2a-1 group. The outcome of the N2a-1 group was satisfactory, and there was no significant difference in OS and DFS between N1 and N2a-1. CONCLUSIONS: The Japanese nodal classification is able to identify a favorable N2 subgroup in resected NSCLC. Nodal staging by the Japanese system should be considered when a clinical trial of N2 disease is designed. PMID- 24811858 TI - Telemental health evaluations enhance access and efficiency in a critical access hospital emergency department. AB - INTRODUCTION: Mentally ill patients in crisis presenting to critical access hospital emergency rooms often face exorbitant wait times to be evaluated by a trained mental health provider. Patients may be discharged from the hospital before receiving an evaluation or boarded in a hospital bed for observation, reducing quality and increasing costs. This study examined the effectiveness of an emergency telemental health evaluation service implemented in a rural hospital emergency room. MATERIALS AND METHODS: Retrospective data collection was implemented to consider patients presenting to the emergency room for 212 days prior to telemedicine interventions and for 184 days after. The study compared measures of time to treatment, length of stay (regardless of inpatient or outpatient status), and door-to-consult time. RESULTS: There were 24 patients seen before telemedicine was implemented and 38 seen using telemedicine. All patients had a mental health evaluation ordered by a physician and completed by a mental health specialist. Significant reductions in all three time measures were observed. Mean and median times to consult were reduced from 16.2 h (standard deviation=13.2 h) and 14.2 h, respectively, to 5.4 h (standard deviation =6.4 h) and 2.6 h. Similar reductions in length of stay and door-to-consult times were observed. By t tests, use of telemedicine was associated with a statistically significant reduction in all three outcome measures. CONCLUSIONS: Telemedicine appears to be an effective intervention for mentally ill patients by providing more timely access to mental health evaluations in rural hospital emergency departments. PMID- 24811859 TI - Quantitative detection of cirrhosis: towards the development of computer-assisted detection method. AB - There are distinct morphologic features of cirrhosis on CT examinations; however, such impressions may be subtle or subjective. The purpose of this study is to build a computer-aided diagnosis (CAD) method to help radiologists with this diagnosis. One hundred sixty-seven abdominal CT examinations were randomly divided into training (n = 88) and validation (n = 79) sets. Livers were analyzed for morphological markers of cirrhosis and logistic regression models were created. Using the area under curve (AUC) for model performance, the best model had 0.89 for the training set and 0.85 for the validation set. For radiology reports, sensitivity of reporting cirrhosis was 0.45 and specificity 0.99. Using the predictive model adjunctively, radiologists' sensitivity increased to 0.63 and specificity slightly decreased to 0.97. This study demonstrates that quantifying morphological features in livers may be utilized for diagnosing cirrhosis and for developing a CAD method for it. PMID- 24811862 TI - Systematic temporal patterns in the relationship between housing development and forest bird biodiversity. AB - As people encroach increasingly on natural areas, one question is how this affects avian biodiversity. The answer to this is partly scale-dependent. At broad scales, human populations and biodiversity concentrate in the same areas and are positively associated, but at local scales people and biodiversity are negatively associated with biodiversity. We investigated whether there is also a systematic temporal trend in the relationship between bird biodiversity and housing development. We used linear regression to examine associations between forest bird species richness and housing growth in the conterminous United States over 30 years. Our data sources were the North American Breeding Bird Survey and the 2000 decennial U.S. Census. In the 9 largest forested ecoregions, housing density increased continually over time. Across the conterminous United States, the association between bird species richness and housing density was positive for virtually all guilds except ground nesting birds. We found a systematic trajectory of declining bird species richness as housing increased through time. In more recently developed ecoregions, where housing density was still low, the association with bird species richness was neutral or positive. In ecoregions that were developed earlier and where housing density was highest, the association of housing density with bird species richness for most guilds was negative and grew stronger with advancing decades. We propose that in general the relationship between human settlement and biodiversity over time unfolds as a 2 phase process. The first phase is apparently innocuous; associations are positive due to coincidence of low-density housing with high biodiversity. The second phase is highly detrimental to biodiversity, and increases in housing density are associated with biodiversity losses. The long-term effect on biodiversity depends on the final housing density. This general pattern can help unify our understanding of the relationship of human encroachment and biodiversity response. PMID- 24811860 TI - Risk of nephrogenic systemic fibrosis is low in patients with chronic liver disease exposed to gadolinium-based contrast agents. AB - PURPOSE: To determine the risk of nephrogenic systemic fibrosis (NSF) in a cohort of patients with chronic liver disease. MATERIALS AND METHODS: This retrospective, Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study was performed at a single tertiary liver center. The study cohort comprised 1167 patients with chronic liver disease followed in a liver clinic and exposed to gadolinium-based contrast agents (GBCAs) between February 2004 and October 2007. A retrospective review of medical records was performed. For each patient, data were collected on demographics, history of GBCA exposure, presence of purported risk factors for NSF, and histopathological evidence of NSF. RESULTS: Of the 1167 patients with chronic liver disease, 58% (n = 678) had cirrhosis. The patients had a total of 2421 separate GBCA exposures. Fifty-five percent (n = 646) had a single exposure, 19% (n = 218) had two exposures, and 26% (n = 303) had three or more exposures. Seventy-two percent (n = 843) of patients had renal insufficiency, 25 patients (2.1%) had hepatorenal syndrome, 80 patients (6.8%) were in the perioperative liver transplant period, and 49 patients (4.2%) had one or more additional risk factors for NSF. None of the 1167 patients developed NSF. CONCLUSION: Chronic liver disease does not appear to be a significant risk factor for NSF. PMID- 24811863 TI - FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non small cell lung cancer by downregulating the EGF/EGFR pathway. AB - The endocannabinoid anandamide (AEA), a neurotransmitter was shown to have anti cancer effects. Fatty acid amide hydrolase (FAAH) metabolizes AEA and decreases its anti-tumorigenic activity. In this study, we have analyzed the role of FAAH inhibition in non-small cell lung cancer (NSCLC). We have shown that FAAH and CB1 receptor which is activated by AEA are expressed in lung adenocarcinoma patient samples and NSCLC cell lines A549 and H460. Since the synthetic analogue of anandamide (Met-F-AEA) did not possess significant anti-tumorigenic effects, we used Met-F-AEA in combination with FAAH inhibitor URB597 which significantly reduced EGF (epidermal growth factor)-induced proliferative and chemotactic activities in vitro when compared to anti-tumorigenic activity of Met-F-AEA alone. Further analysis of signaling mechanisms revealed that Met-F-AEA in combination with URB597 inhibits activation of EGFR and its downstream signaling ERK, AKT and NF-kB. In addition, it inhibited MMP2 secretion and stress fiber formation. We have also shown that the Met-F-AEA in combination with URB597 induces G0/G1 cell cycle arrest by downregulating cyclin D1 and CDK4 expressions, ultimately leading to apoptosis via activation of caspase-9 and PARP. Furthermore, the combination treatment inhibited tumor growth in a xenograft nude mouse model system. Tumors derived from Met-F-AEA and URB597 combination treated mice showed reduced EGFR, AKT and ERK activation and MMP2/MMP9 expressions when compared to Met-F-AEA or URB597 alone. Taken together, these data suggest in EGFR overexpressing NSCLC that the combination of Met-F-AEA with FAAH inhibitor resulted in superior therapeutic response compared to individual compound activity alone. PMID- 24811864 TI - Subcutaneous wounding postirradiation reduces radiation lethality in mice. AB - The detonation of an improvised nuclear device during a radiological terrorist attack could result in the exposure of thousands of civilians and first responders to lethal or potentially lethal doses of ionizing radiation (IR). There is a major effort in the United States to develop phamacological mitigators of radiation lethality that would be effective particularly if administered after irradiation. We show here that giving female C57BL/6 mice a subcutaneous surgical incision after whole body exposure to an LD50/30 X-ray dose protects against radiation lethality and increases survival from 50% to over 90% (P = 0.0001). The increase in survival, at least in part, appears to be due to enhanced recovery of hematopoiesis, notably red blood cells, neutrophils and platelets. While a definitive mechanism has yet to be elucidated, we propose that this approach may be used to identify potentially novel mechanisms and pathways that could aid in the development of novel pharmacological radiation countermeasures. PMID- 24811866 TI - Biochemical characterization of the first fungal glycoside hydrolyase family 3 beta-N-acetylglucosaminidase from Rhizomucor miehei. AB - A novel beta-N-acetylglucosaminidase gene (RmNag) from Rhizomucor miehei was cloned and expressed in Escherichia coli. RmNag shares the highest identity of 37% with a putative beta-N-acetylglucosaminidase from Aspergillus clavatus. The recombinant enzyme was purified to homogeneity. The optimal pH and temperature of RmNag were pH 6.5 and 50 degrees C, respectively. It was stable in the pH range 6.0-8.0 and at temperatures below 45 degrees C. RmNag exhibited strict substrate specificity for p-nitrophenyl beta-N-acetylglucosaminide (pNP-GlcNAc) and N acetyl chitooligosaccharides. The apparent Km of RmNag toward pNP-GlcNAc was 0.13 mM. The purified enzyme displayed an exo-type manner as it released the only end product of GlcNAc from all the tested N-acetyl chitooligosaccharides. Besides, RmNag exhibited relatively high N-acetyl-beta-D-glucosaminide tolerance with an inhibition constant Ki value of 9.68 mM. The excellent properties may give the enzyme great potential in industries. This is the first report on a glycoside hydrolyase family 3 beta-N-acetylglucosaminidase from a fungus. PMID- 24811868 TI - The critical role of grain orientation and applied stress in nanoscale twinning. AB - Numerous recent studies have focused on the effects of grain size on deformation twinning in nanocrystalline fcc metals. However, grain size alone cannot explain many observed twinning characteristics. Here we show that the propensity for twinning is dependent on the applied stress, grain orientation and stacking fault energy. The lone factor for twinning dependent on grain size is the stress necessary to nucleate partial dislocations from a boundary. We use bulk processing of controlled nanostructures coupled with unique orientation mapping at the nanoscale to show the profound effect of crystal orientation on deformation twinning. Our theoretical model reveals an orientation-dependent critical threshold stress for twinning, which is presented in the form of a generalized twinnability map. Our findings provide a newfound orientation-based explanation for the grain size effect: as grain size decreases the applied stress needed for further deformation increases, thereby allowing more orientations to reach the threshold stress for twinning. PMID- 24811867 TI - Combined role of seizure-induced dendritic morphology alterations and spine loss in newborn granule cells with mossy fiber sprouting on the hyperexcitability of a computer model of the dentate gyrus. AB - Temporal lobe epilepsy strongly affects hippocampal dentate gyrus granule cells morphology. These cells exhibit seizure-induced anatomical alterations including mossy fiber sprouting, changes in the apical and basal dendritic tree and suffer substantial dendritic spine loss. The effect of some of these changes on the hyperexcitability of the dentate gyrus has been widely studied. For example, mossy fiber sprouting increases the excitability of the circuit while dendritic spine loss may have the opposite effect. However, the effect of the interplay of these different morphological alterations on the hyperexcitability of the dentate gyrus is still unknown. Here we adapted an existing computational model of the dentate gyrus by replacing the reduced granule cell models with morphologically detailed models coming from three-dimensional reconstructions of mature cells. The model simulates a network with 10% of the mossy fiber sprouting observed in the pilocarpine (PILO) model of epilepsy. Different fractions of the mature granule cell models were replaced by morphologically reconstructed models of newborn dentate granule cells from animals with PILO-induced Status Epilepticus, which have apical dendritic alterations and spine loss, and control animals, which do not have these alterations. This complex arrangement of cells and processes allowed us to study the combined effect of mossy fiber sprouting, altered apical dendritic tree and dendritic spine loss in newborn granule cells on the excitability of the dentate gyrus model. Our simulations suggest that alterations in the apical dendritic tree and dendritic spine loss in newborn granule cells have opposing effects on the excitability of the dentate gyrus after Status Epilepticus. Apical dendritic alterations potentiate the increase of excitability provoked by mossy fiber sprouting while spine loss curtails this increase. PMID- 24811865 TI - Linking the history of radiation biology to the hallmarks of cancer. AB - Hanahan and Weinberg recently updated their conceptual framework of the "Hallmarks of Cancer". The original article, published in 2000, is among the most highly cited reviews in the field of oncology. The goal of this review is to highlight important discoveries in radiation biology that pertain to the Hallmarks. We identified early studies that exemplified how ionizing radiation affects the hallmarks or how radiation was used experimentally to advance the understanding of key hallmarks. A literature search was performed to obtain relevant primary research, and topics were assigned to a particular hallmark to allow an organized, chronological account of the radiobiological advancements. The hallmarks are reviewed in an order that flows from cellular to microenvironmental effects. PMID- 24811869 TI - Contusio cordis, not an innocent diagnosis. AB - This report demonstrates two cases of traumatic valvular lesions of the heart. The first is a patient with severe mitral regurgitation after a blunt chest trauma and the second a severe aortic regurgitation due to rupture of a coronary cusp after a motor cycle accident. Both patients underwent successful surgery and recovered. Valvular lesions are a rare complication after blunt chest trauma. Physicians should always consider a traumatic valvular lesion as a possible cause of pulmonary oedema or haemodynamic instability after a blunt chest trauma. PMID- 24811870 TI - A giant 'sausage' thrombus in the left ventricle in a patient with preserved ventricular function. PMID- 24811871 TI - Isolated RV myocardial infarction presenting with systemic hypertension minimally responsive to nitroglycerin. PMID- 24811872 TI - An uncommon but important complication of renal biopsy. PMID- 24811873 TI - Nanocomposite YCrO3/Al2O3: characterization of the core-shell, magnetic properties, and enhancement of dielectric properties. AB - Multifuncionality in polycrystalline multiferroic ceramics can be improved using an advanced synthesis process. In this work, core-shell design is being proposed to enhance the transport properties of biferroic YCrO3. The atomic layer deposition (ALD) thin-film growth technique was used for the YCrO3/Al2O3 (Y@Al) nanocomposite fabrication. A continuous, amorphous, and uniform Al2O3 shell, a few nanometers thick, was obtained and characterized by X-ray photoelectron spectroscopy, X-ray diffraction, and high-resolution transmission electron microscopy. The transport properties of biferroic YCrO3 coated with 50, 500, and 1000 ALD cycles of insulating Al2O3 were investigated using magnetization and AC conductivity measurements. It is observed that the values of the magnetic coercive field and the magnetization are affected by the amorphous and partially crystallized Al2O3 shell. Additionally, the Y@Al nanocomposite experiments show a notorious decreasing in the loss tangent and the electrical conductivity. Accordingly, hysteresis loops in the polarization versus electric energy data confirm the decrease of the leakage current as a consequence of the Al2O3 shell acting as a barrier layer. The results shown here confirm that the core-shell architecture is a promising alternative for improvement of the magnetic and ferroelectric properties in bulk multiferroics. PMID- 24811875 TI - Introduction to the Special Section: The effectiveness of fear appeals in health promotion. PMID- 24811874 TI - Structural characterization of semen coagulum-derived SEM1(86-107) amyloid fibrils that enhance HIV-1 infection. AB - SEM1(86-107) is a 22-residue peptide corresponding to residues 86-107 in the semenogelin I protein. SEM1(86-107) is an abundant component of freshly liquefied semen and forms amyloid fibrils capable of enhancing HIV infection. To probe the factors affecting fibril formation and gain a better understanding of how differences in pH between semen and vaginal fluid affect fibril stability, this study determined the effect of pH on SEM1(86-107) fibril formation and dissociation. The SEM1(86-107) fibril structure (i.e., residues that comprise the fibrillar core) was also probed using hydrogen-deuterium exchange mass spectrometry (HDXMS) and hydroxyl radical-mediated protein modification. The average percent exposure to hydroxyl radical-mediated modification in the SEM1(86 107) fibrils was determined without requiring tandem mass spectrometry spectral acquisition or complete separation of modified peptides. It was found that the residue exposures calculated from HDXMS and hydroxyl radical-mediated modification were similar. These techniques demonstrated that three regions of SEM1(86-107) comprise the amyloid fibril core and that positively charged residues are exposed, suggesting that electrostatic interactions between SEM1(86 107) and HIV or the cell surface may be responsible for mediating HIV infection enhancement by the SEM1(86-107) fibrils. PMID- 24811876 TI - Sixty years of fear appeal research: current state of the evidence. AB - Fear arousal is widely used in persuasive campaigns and behavioral change interventions. Yet, experimental evidence argues against the use of threatening health information. The authors reviewed the current state of empirical evidence on the effectiveness of fear appeals. Following a brief overview of the use of fear arousal in health education practice and the structure of effective fear appeals according to two main theoretical frameworks-protection motivation theory and the extended parallel process model-the findings of six meta-analytic studies in the effectiveness of fear appeals are summarized. It is concluded that coping information aimed at increasing perceptions of response effectiveness and especially self-efficacy is more important in promoting protective action than presenting threatening health information aimed at increasing risk perceptions and fear arousal. Alternative behavior change methods than fear appeals should be considered. PMID- 24811877 TI - Threatening communication: a qualitative study of fear appeal effectiveness beliefs among intervention developers, policymakers, politicians, scientists, and advertising professionals. AB - Threatening communication is a widely applied method in behavior change interventions, which at the same time has been heavily criticized in the psychological literature. The current paper describes a study of the reasons for this persistent wide application of threatening communication. We conducted qualitative interviews with 33 key actors in behavior change intervention development in The Netherlands. Specifically, we interviewed intervention developers, policymakers, politicians, scientists, and advertising professionals. The interviews were transcribed and subsequently coded using NVivo. We found that participants most closely involved with the actual intervention development were generally convinced that threatening information was to be prevented, but often did not understand the exact processes involved. They were often under the impression that rather than a potent efficacy enhancing element, a behavioral suggestion would suffice to prevent threatening communication from backfiring. As participants were further removed from the actual intervention development, they generally tended to be more in favor of threatening communication. The main reasons for use of threatening information were to attract attention or prompt self-reflection through confrontation, because target population members were assumed to like threatening information and respond rationally to increased risk perceptions by changing their behavior, or simply because no alternatives were available. In addition, intervention developers frequently had to deal with supervisors or funders who preferred threatening communication. Thus, when communicating with practitioners, it seems fruitful to provide them with a toolbox of evidence-based behavior change methods that promote adaptive, rather than maladaptive, behavior; to promote basing interventions on the most relevant behavioral determinants as identified by determinant analyses; and to equip intervention developers with the tools to persuade other key stakeholders that fear is a bad counselor. PMID- 24811878 TI - Neuroscientific evidence for defensive avoidance of fear appeals. AB - Previous studies indicate that people respond defensively to threatening health information, especially when the information challenges self-relevant goals. The authors investigated whether reduced acceptance of self-relevant health risk information is already visible in early attention allocation processes. In two experimental studies, participants were watching high- and low-threat health commercials, and at the same time had to pay attention to specific odd auditory stimuli in a sequence of frequent auditory stimuli (odd ball paradigm). The amount of attention allocation was measured by recording event-related brain potentials (i.e., P300 ERPs) and reaction times. Smokers showed larger P300 amplitudes in response to the auditory targets while watching high-threat instead of low-threat anti-smoking commercials. In contrast, non-smokers showed smaller P300 amplitudes during watching high as opposed to low threat anti-smoking commercials. In conclusion, the findings provide further neuroscientific support for the hypothesis that threatening health information causes more avoidance responses among those for whom the health threat is self-relevant. PMID- 24811879 TI - The ethics of distress: toward a framework for determining the ethical acceptability of distressing health promotion advertising. AB - Distressing health promotion advertising involves the elicitation of negative emotion to increase the likelihood that health messages will stimulate audience members to adopt healthier behaviors. Irrespective of its effectiveness, distressing advertising risks harming audience members who do not consent to the intervention and are unable to withdraw from it. Further, the use of these approaches may increase the potential for unfairness or stigmatization toward those targeted, or be considered unacceptable by some sections of the public. We acknowledge and discuss these concerns, but, using the public health ethics literature as a guide, argue that distressing advertising can be ethically defensible if conditions of effectiveness, proportionality necessity, least infringement, and public accountability are satisfied. We do not take a broad view as to whether distressing advertising is ethical or unethical, because we see the evidence for both the effectiveness of distressing approaches and their potential to generate iatrogenic effects to be inconclusive. However, we believe it possible to use the current evidence base to make informed estimates of the likely consequences of specific message presentations. Messages can be pre-tested and monitored to identify and deal with potential problems. We discuss how advertisers can approach the problems of deciding on the appropriate intensity of ethical review, and evaluating prospective distressing advertising campaigns against the conditions outlined. PMID- 24811880 TI - Finding theory- and evidence-based alternatives to fear appeals: Intervention Mapping. AB - Fear arousal-vividly showing people the negative health consequences of life endangering behaviors-is popular as a method to raise awareness of risk behaviors and to change them into health-promoting behaviors. However, most data suggest that, under conditions of low efficacy, the resulting reaction will be defensive. Instead of applying fear appeals, health promoters should identify effective alternatives to fear arousal by carefully developing theory- and evidence-based programs. The Intervention Mapping (IM) protocol helps program planners to optimize chances for effectiveness. IM describes the intervention development process in six steps: (1) assessing the problem and community capacities, (2) specifying program objectives, (3) selecting theory-based intervention methods and practical applications, (4) designing and organizing the program, (5) planning, adoption, and implementation, and (6) developing an evaluation plan. Authors who used IM indicated that it helped in bringing the development of interventions to a higher level. PMID- 24811881 TI - Organizational justice and mental health: a multi-level test of justice interactions. AB - We examine main and interaction effects of organizational justice at the individual and the organizational levels on general health in a Kenyan sample. We theoretically differentiate between two different interaction patterns of justice effects: buffering mechanisms based on trust versus intensifying explanations of justice interactions that involve psychological contract violations. Using a two level hierarchical linear model with responses from 427 employees in 29 organizations, only interpersonal justice at level 1 demonstrated a significant main effect. Interactions between distributive and interpersonal justice at both the individual and the collective levels were found. The intensifying hypothesis was supported: the relationship between distributive justice and mental health problems was strongest when interpersonal justice was high. This contrasts with buffering patterns described in Western samples. We argue that justice interaction patterns shift depending on the economic conditions and sociocultural characteristics of employees studied. PMID- 24811882 TI - A multi-process model of self-regulation: influences of mindfulness, integrative self-knowledge and self-control in Iran. AB - Self-regulation presumably rests upon multiple processes that include an awareness of ongoing self-experience, enduring self-knowledge and self-control. The present investigation tested this multi-process model using the Five-Facet Mindfulness Questionnaire (FFMQ) and the Integrative Self-Knowledge and Brief Self-Control Scales. Using a sample of 1162 Iranian university students, we confirmed the five-factor structure of the FFMQ in Iran and documented its factorial invariance across males and females. Self-regulatory variables correlated negatively with Perceived Stress, Depression, and Anxiety and positively with Self-Esteem and Satisfaction with Life. Partial mediation effects confirmed that self-regulatory measures ameliorated the disturbing effects of Perceived Stress. Integrative Self-Knowledge and Self-Control interacted to partially mediate the association of Perceived Stress with lower levels of Satisfaction with Life. Integrative Self-Knowledge, alone or in interaction with Self-Control, was the only self-regulation variable to display the expected mediation of Perceived Stress associations with all other measures. Self-Control failed to be implicated in self-regulation only in the mediation of Anxiety. These data confirmed the need to further examine this multi-process model of self regulation. PMID- 24811883 TI - Motivational cues: the role of perceived senders' self-control ability in raters' deception judgements. AB - Previous studies have found that senders' personal traits may be used by others to make judgements about the senders' truthfulness. Two studies were conducted to examine whether perceived self-control ability has an effect on deception judgement. Perceived self-control was hypothesized to act as a motivational cue that participants would use to assess the sender's motivation to lie, which in turn would influence their deception judgement. Results revealed that when participants assessed the sender as having higher self-control ability, they would consider the sender to be less motivated to lie in daily life (Study 1), and judge the sender more truthful in a text-based deception judgement task (Study 2). However, the effect of perceived self-control ability disappeared in a video-based task (Study 2), likely due to the multitude of various cues available in audio-visual stimuli. The theoretical and applied implications of the results are discussed. PMID- 24811884 TI - The influence of item order on intentional response distortion in the assessment of high potentials: assessing pilot applicants. AB - An experiment was conducted to investigate the effects of item order and questionnaire content on faking good or intentional response distortion. It was hypothesized that intentional response distortion would either increase towards the end of a long questionnaire, as learning effects might make it easier to adjust responses to a faking good schema, or decrease because applicants' will to distort responses is reduced if the questionnaire lasts long enough. Furthermore, it was hypothesized that certain types of questionnaire content are especially vulnerable to response distortion. Eighty-four pre-selected pilot applicants filled out a questionnaire consisting of 516 items including items from the NEO five factor inventory (NEO FFI), NEO personality inventory revised (NEO PI-R) and business-focused inventory of personality (BIP). The positions of the items were varied within the applicant sample to test if responses are affected by item order, and applicants' response behaviour was additionally compared to that of volunteers. Applicants reported significantly higher mean scores than volunteers, and results provide some evidence of decreased faking tendencies towards the end of the questionnaire. Furthermore, it could be demonstrated that lower variances or standard deviations in combination with appropriate (often higher) mean scores can serve as an indicator for faking tendencies in group comparisons, even if effects are not significant. PMID- 24811885 TI - Developmental variation among Cochliomyia macellaria Fabricius (Diptera: Calliphoridae) populations from three ecoregions of Texas, USA. AB - Forensic entomologists rely on published developmental datasets to estimate the age of insects developing on human remains. Currently, these datasets only represent populations of targeted insects from specific locations. However, recent data indicate that populations can exhibit genetic variation in their development, including signatures of local adaptation demonstrated by regionally distinct plastic responses to their environments. In this study, three geographically distinct populations of the secondary screwworm, Cochliomyia macellaria Fabricius (Diptera: Calliphoridae; College Station, Longview, and San Marcos, TX, USA), a common blow fly collected from human remains in the southern USA, were reared in two distinct environments (cool 21 degrees C, 65 % relative humidity (RH); and warm 31 degrees C, 70 % RH) over 2 years (2011 and 2012) in order to determine differences in development time and mass. Significant differences in immature and pupal development time, as well as pupal mass, were shown to exist among strains derived from different populations and years. For immature development times, there was evidence of only an environmental effect on phenotype, while genotype by environment interactions was observed in pupal development times and pupal mass. College Station and San Marcos populations exhibited faster pupal development and smaller pupal sizes in the cooler environment relative to the Longview population, but showed an opposite trend in the warm environment. Rank order for College Station and Longview populations was reversed across years. Failure to take genetic variation into consideration when making such estimates can lead to unanticipated error and bias. These results indicate that genetics will have little impact on error when working with Texas genotypes of C. macellaria at ~30 degrees C and 70 % RH, but will have a more meaningful impact on error in postmortem interval estimates with this species in cooler, drier environments. PMID- 24811886 TI - Mutation rates of 15 X chromosomal short tandem repeat markers. AB - Though allele frequency data for a variety of X chromosomal short tandem repeat (STR) markers in a range of populations have been reported, fewer studies of mutation rates in these same markers or populations are available. In order to address possible mismatches during kinship analysis due to mutation, a robust estimate of the rate of mutation must be established. Here, mutation rates in three US populations have been determined for a total of 15 markers (DXS6789, DXS9902, DXS7132, DXS7130, DXS6795, DXS10147, DXS8378, DXS7423, HPRTB, DXS101, DXS7424, GATA31E08, GATA172D05, GATA165B12, and DXS6803). Eighteen mutations over 20,625 meioses were observed, and the overall X STR mutation rate in this study was found to be 8.73 * 10(-4) (95 % CI, 5.2-13.8 * 10(-4)). A review of published mutation rate studies revealed similar findings in other global populations, and allowed the compilation of a combined dataset of 81,310 meioses which can be employed by the forensic community. PMID- 24811887 TI - Estimates of radioxenon released from Southern Hemisphere medical isotope production facilities using measured air concentrations and atmospheric transport modeling. AB - The International Monitoring System (IMS) of the Comprehensive-Nuclear-Test-Ban Treaty monitors the atmosphere for radioactive xenon leaking from underground nuclear explosions. Emissions from medical isotope production represent a challenging background signal when determining whether measured radioxenon in the atmosphere is associated with a nuclear explosion prohibited by the treaty. The Australian Nuclear Science and Technology Organisation (ANSTO) operates a reactor and medical isotope production facility in Lucas Heights, Australia. This study uses two years of release data from the ANSTO medical isotope production facility and (133)Xe data from three IMS sampling locations to estimate the annual releases of (133)Xe from medical isotope production facilities in Argentina, South Africa, and Indonesia. Atmospheric dilution factors derived from a global atmospheric transport model were used in an optimization scheme to estimate annual release values by facility. The annual releases of about 6.8 * 10(14) Bq from the ANSTO medical isotope production facility are in good agreement with the sampled concentrations at these three IMS sampling locations. Annual release estimates for the facility in South Africa vary from 2.2 * 10(16) to 2.4 * 10(16) Bq, estimates for the facility in Indonesia vary from 9.2 * 10(13) to 3.7 * 10(14) Bq and estimates for the facility in Argentina range from 4.5 * 10(12) to 9.5 * 10(12) Bq. PMID- 24811888 TI - TLR2-ICAM1-Gadd45alpha axis mediates the epigenetic effect of selenium on DNA methylation and gene expression in Keshan disease. AB - Keshan disease (KD) is a fatal dilated cardiomyopathy with unknown etiology, and selenium deficiency is considered the main cause of KD. Several observations implicate a role for altered DNA methylation in selenium deficiency-related diseases. The aim of the present study was to investigate the epigenetic effects of selenium (Se) on DNA methylation and gene expression in Keshan disease. Using methylated DNA immunoprecipitation chip (MeDIP-Chip) and quantitative RT-PCR, we identified two inflammatory-related genes (TLR2 and ICAM1) that were differentially methylated and expressed between normal individuals and KD patients. Results from DNA methylation profile between KD patients and normal individuals showed that selenium deficiency decreased methylation of CpG islands in promoter regions of TLR2 and ICAM1 and upregulated messenger RNA (mRNA) and protein levels of TLR2 and ICAM1. In rat animal model of Keshan disease, selenite treatment could increase TLR2 and ICAM1 promoter methylation, suppress these genes expression, and reduce infiltration of myocardial inflammatory cells. In cell culture model of Keshan disease, we found 5-Aza-dC (DNMT1 inhibitor) treatment in the presence of selenium-reduced mRNA and protein levels of DNMT1 regardless of TLR2 and ICAM1 promoter methylation status and expression levels of these genes. Selenite treatment suppressed the expression of the Gadd45alpha, TLR2, and ICAM1 in a concentration-dependent manner, while selenium deficiency increased the expression of the Gadd45alpha, TLR2, and ICAM1 and decreased TLR2 and ICAM1 promoter methylation level in a time-dependent manner. Our results revealed that TLR2-ICAM1-Gadd45alpha axis might play an important role in gene specific active DNA demethylation during inflammatory response in myocardium. PMID- 24811889 TI - High-performance solution-processable N-shaped organic semiconducting materials with stabilized crystal phase. AB - N-shaped organic semiconductors are synthesized via four steps from a readily available starting material. Such semiconductors exhibit preferable ionization potential for p-type operation, thermally stable crystalline phase over 200 degrees C, and high carrier mobility up to 16 cm(2) V(-1) s(-1) (12.1 cm(2) V(-1) s(-1) on average) with small threshold voltages in solution-crystallized field effect transistors. PMID- 24811890 TI - Unique molecular signatures as a hallmark of patients with metastatic breast cancer: implications for current treatment paradigms. AB - Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors. PMID- 24811892 TI - NICE's cost-effectiveness range: should it be lowered? PMID- 24811891 TI - Polonium-210 and Caesium-137 in lynx (Lynx lynx), wolverine (Gulo gulo) and wolves (Canis lupus). AB - Wolves, lynx and wolverines are on the top of the food-chain in northern Scandinavia and Finland. (210)Po and (137)Cs have been analysed in samples of liver, kidney and muscle from 28 wolves from Sweden. In addition blood samples were taken from 27 wolves. In 9 of the wolves, samples of muscle, liver and blood were analysed for (210)Po. Samples of liver and muscle were collected from 16 lynx and 16 wolverines from Norway. The liver samples were analysed for (210)Po and (137)Cs. Only (137)Cs analyses were carried out for the muscle samples. The wolves were collected during the winter 2010 and 2011, while the samples for lynx and wolverines were all from 2011. The activity concentrations of (210)Po in wolves were higher for liver (range 20-523 Bq kg(-1) d.w.) and kidney (range 24 942 Bq kg(-1) d.w.) than muscle (range 1-43 Bq kg(-1) d.w.) and blood (range 2-54 Bq kg(-1) d.w.). Activity ratios, (210)Po/(210)Pb, in wolf samples of muscle, liver and blood were in the ranges 2-77, 9-56 and 2-54. Using a wet weight ratio of 3.8 the maximal absorbed dose from (210)Po to wolf liver was estimated to 3500 MUGy per year. Compared to wolf, the ranges of (210)Po in liver samples were lower in lynx (range 22-211 Bq kg(-1) d.w.) and wolverine (range16-160 Bq kg(-1) d.w.). Concentration of (137)Cs in wolf samples of muscle, liver, kidney and blood were in the ranges 70-8410 Bq kg(-1) d.w., 36-4050 Bq kg(-1) d.w., 31-3453 Bq kg(-1) d.w. and 4-959 Bq kg(-1) d.w., respectively. (137)Cs in lynx muscle and liver samples were in the ranges 44-13393 Bq kg(-1) d.w. and 125-10260 Bq kg(-1) d.w. The corresponding values for (137)Cs in wolverine were 22-3405 Bq kg(-1) d.w. for liver and 53-4780 Bq kg(-1) d.w. for muscle. The maximal absorbed dose from (137)Cs to lynx was estimated to 3000 MUGy per year. PMID- 24811893 TI - Global assessment of exposure to faecal contamination through drinking water based on a systematic review. AB - OBJECTIVES: To estimate exposure to faecal contamination through drinking water as indicated by levels of Escherichia coli (E. coli) or thermotolerant coliform (TTC) in water sources. METHODS: We estimated coverage of different types of drinking water source based on household surveys and censuses using multilevel modelling. Coverage data were combined with water quality studies that assessed E. coli or TTC including those identified by a systematic review (n = 345). Predictive models for the presence and level of contamination of drinking water sources were developed using random effects logistic regression and selected covariates. We assessed sensitivity of estimated exposure to study quality, indicator bacteria and separately considered nationally randomised surveys. RESULTS: We estimate that 1.8 billion people globally use a source of drinking water which suffers from faecal contamination, of these 1.1 billion drink water that is of at least 'moderate' risk (>10 E. coli or TTC per 100 ml). Data from nationally randomised studies suggest that 10% of improved sources may be 'high' risk, containing at least 100 E. coli or TTC per 100 ml. Drinking water is found to be more often contaminated in rural areas (41%, CI: 31%-51%) than in urban areas (12%, CI: 8-18%), and contamination is most prevalent in Africa (53%, CI: 42%-63%) and South-East Asia (35%, CI: 24%-45%). Estimates were not sensitive to the exclusion of low quality studies or restriction to studies reporting E. coli. CONCLUSIONS: Microbial contamination is widespread and affects all water source types, including piped supplies. Global burden of disease estimates may have substantially understated the disease burden associated with inadequate water services. PMID- 24811894 TI - Redox equilibration after one-electron reduction of cytochrome c oxidase: radical formation and a possible hydrogen relay mechanism. AB - Kinetic studies using UV/visible and EPR spectroscopy were carried out to follow the distribution of electrons within beef heart cytochrome c oxidase (CcO), both active and cyanide-inhibited, following addition of reduced cytochrome c as electron donor. In the initial one-electron reduced state the electron is shared between three redox centers, heme a, CuA and a third site, probably CuB. Using a rapid freeze system and the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) a protein radical was also detected. The EPR spectrum of the DMPO adduct of this radical was consistent with tyrosyl radical capture. This may be a feature of a charge relay mechanism involved in some part of the CcO electron transfer system from bound cytochrome c via CuA and heme a to the a3CuB binuclear center. PMID- 24811895 TI - Thiamin deficiency and heart failure: the current knowledge and gaps in literature. AB - The management of heart failure (HF) represents a significant challenge for both patients as well as the healthcare system in industrialized countries. Thiamin is a required coenzyme in the energy-producing reactions that fuel myocardial contraction. Therefore, thiamin deficiency (TD) may contribute to myocardial weakness by limiting the energy available for contraction. Previous studies have reported a wide range in the prevalence of TD in patients with HF (3-91 %). The impact of thiamin supplementation in patients with HF is inconclusive. Studies conducted to date are limited by their small sample size, indirect methods of assessing thiamin concentration, methodological inconsistencies, use of impractical means of thiamin supplementation, a focus on hospitalized patients, and lack a robust technique for the assessment of cardiac function. Future large prospective studies and randomized controlled trials are needed to improve our understanding of any change in nutritional requirements associated with chronic disease as well as the clinical benefit of supplementation. PMID- 24811896 TI - [Evaluation of the therapeutic response after stereotactic body radiation therapy for liver tumors]. AB - Stereotactic body radiation therapy takes more and more an important place in the therapeutic arsenal of primitive and secondary liver tumours. The administration of ablative radiation doses can result in specific changes to both the tumour and the healthy hepatic parenchyma, relative to conventional radiation therapy, making the assessment of local changes after stereotactic body radiation therapy, in terms of local control and reaction of healthy tissue, often difficult. It is mandatory to standardize and simplify our evaluation criteria to benefit from a better understanding of the effectiveness of this new treatment modality and allow better reproducibility of available imaging exams. This article presents a literature review of the various radiological changes observed after stereotactic body radiation therapy for liver tumours according to the multiple assessment methods used to determine local control. From the data available, we recommend using modified RECIST criteria proposed by the American Association for the Study of Liver Diseases (AASLD), as objective and relevant criteria of local control after stereotactic body radiation therapy for liver tumours. PMID- 24811898 TI - Reactive oxygen species, abscisic acid and ethylene interact to regulate sunflower seed germination. AB - Sunflower (Helianthus annuus L.) seed dormancy is regulated by reactive oxygen species (ROS) and can be alleviated by incubating dormant embryos in the presence of methylviologen (MV), a ROS-generating compound. Ethylene alleviates sunflower seed dormancy whereas abscisic acid (ABA) represses germination. The purposes of this study were to identify the molecular basis of ROS effect on seed germination and to investigate their possible relationship with hormone signalling pathways. Ethylene treatment provoked ROS generation in embryonic axis whereas ABA had no effect on their production. The beneficial effect of ethylene on germination was lowered in the presence of antioxidant compounds, and MV suppressed the inhibitory effect of ABA. MV treatment did not alter significantly ethylene nor ABA production during seed imbibition. Microarray analysis showed that MV treatment triggered differential expression of 120 probe sets (59 more abundant and 61 less abundant genes), and most of the identified transcripts were related to cell signalling components. Many transcripts less represented in MV-treated seeds were involved in ABA signalling, thus suggesting an interaction between ROS and ABA signalling pathways at the transcriptional level. Altogether, these results shed new light on the crosstalk between ROS and plant hormones in seed germination. PMID- 24811897 TI - Unique WSPA protein from terrestrial macroscopic cyanobacteria can confer resistance to osmotic stress in transgenic plants. AB - The terrestrial macroscopic cyanobacterium Nostoc commune exhibits remarkable resistance to desiccation stress. This species synthesizes abundant acidic water stress protein (WSPA) in cells upon desiccation and secretes it into the extracellular polysaccharide sheath upon rehydration. However, our knowledge about its cellular role in stress resistance is still rather limited. In this paper, we first revealed that WSPA also occurred in two other macroscopic cyanobacteria Nostoc flagelliforme and Nostoc sphaeroides, but it is more abundant in N. commune. The N. commune wspa1 gene was then heterologously expressed in Arabidopsis thaliana. Phenotypic observation found that WSPA1 conferred increased tolerance to osmotic stress in transgenic plants. The physiological indexes such as relative electrolyte leakage, malondialdehyde, proline accumulation and the maximal quantum efficiency of Photosystem II, were also improved in transgenic plants upon osmotic stress, compared to wild types. In addition, GFP fluorescence analysis of eGFP::wspa1 transgenic plant showed that WSPA1 was localized in the cytoplasm. Therefore, the role of WSPA revealed by this study mainly represented its intracellular function. In general, our research suggested that WSPA may act as a stress protein and involve cellular osmotic stress resistance. PMID- 24811899 TI - In vivo delivery of bovine viral diahorrea virus, E2 protein using hollow mesoporous silica nanoparticles. AB - Our work focuses on the application of mesoporous silica nanoparticles as a combined delivery vehicle and adjuvant for vaccine applications. Here we present results using the viral protein, E2, from bovine viral diarrhoea virus (BVDV). BVDV infection occurs in the target species of cattle and sheep herds worldwide and is therefore of economic importance. E2 is a major immunogenic determinant of BVDV and is an ideal candidate for the development of a subunit based nanovaccine using mesoporous silica nanoparticles. Hollow type mesoporous silica nanoparticles with surface amino functionalisation (termed HMSA) were characterised and assessed for adsorption and desorption of E2. A codon-optimised version of the E2 protein (termed Opti-E2) was produced in Escherichia coli. HMSA (120 nm) had an adsorption capacity of 80 MUg Opti-E2 per mg HMSA and once bound E2 did not dissociate from the HMSA. Immunisation studies in mice with a 20 MUg dose of E2 adsorbed to 250 MUg HMSA was compared to immunisation with Opti-E2 (50 MUg) together with the traditional adjuvant Quillaja saponaria Molina tree saponins (QuilA, 10 MUg). The humoral responses with the Opti-E2/HMSA nanovaccine although slightly lower than those obtained for the Opti-E2 + QuilA group demonstrated that HMSA particles are an effective adjuvant that stimulated E2 specific antibody responses. Importantly the cell-mediated immune responses were consistently high in all mice immunised with Opti-E2/HMSA nanovaccine formulation. Therefore we have shown the Opti-E2/HMSA nanoformulation acts as an excellent adjuvant that gives both T-helper 1 and T-helper 2 mediated responses in a small animal model. This study has provided proof-of-concept towards the development of an E2 subunit nanoparticle based vaccine. PMID- 24811900 TI - Ionic liquids and deep eutectic mixtures: sustainable solvents for extraction processes. AB - In recent years, ionic liquids and deep eutectic mixtures have demonstrated great potential in extraction processes relevant to several scientific and technological activities. This review focuses on the applicability of these sustainable solvents in a variety of extraction techniques, including but not limited to liquid- and solid-phase (micro) extraction, microwave-assisted extraction, ultrasound-assisted extraction and pressurized liquid extraction. Selected applications of ionic liquids and deep eutectic mixtures on analytical method development, removal of environmental pollutants, selective isolation, and recovery of target compounds, purification of fuels, and azeotrope breaking are described and discussed. PMID- 24811901 TI - Production of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) by Burkholderia sacchari using wheat straw hydrolysates and gamma-butyrolactone. AB - Burkholderia sacchari DSM 17165 is able to grow and produce poly(3 hydroxybutyrate) both on hexoses and pentoses. In a previous study, wheat straw lignocellulosic hydrolysates (WSH) containing high C6 and C5 sugar concentrations were shown to be excellent carbon sources for P(3HB) production. Using a similar feeding strategy developed for P(3HB) production based on WSH, fed-batch cultures were developed aiming at the production of the copolymer P(3HB-co-4HB) (poly(3 hydroxybutyrate-co-4-hydroxybutyrate)) by B. sacchari. The ability of this strain to synthesize P(3HB-co-4HB) was first shown in shake flasks using gamma butyrolactone (GBL) as precursor of the 4HB units. Fed-batch cultures using glucose as carbon source (control) and GBL were developed to achieve high copolymer productivities and 4HB incorporations. The attained P(3HB-co-4HB) productivity and 4HB molar% were 0.7g/(Lh) and 4.7molar%, respectively. The 4HB incorporation was improved to 6.3 and 11.8molar% by addition of 2g/L propionic and acetic acid, respectively. When WSH were used as carbon source under the same feeding conditions, the values achieved were 0.5g/(Lh) and 5.0molar%, respectively. Burkholderia sacchari, a strain able to produce biopolymers based on xylose-rich lignocellulosic hydrolysates, is for the first time reported to produce P(3HB-co-4HB) using gamma butyrolactone as precursor. PMID- 24811902 TI - Identification of important abiotic and biotic factors in the biodegradation of poly(l-lactic acid). AB - The biodegradation of four poly(l-lactic acid) (PLA) samples with molecular weights (MW) ranging from approximately 34 to 160kgmol(-1) was investigated under composting conditions. The biodegradation rate decreased, and initial retardation was discernible in parallel with the increasing MW of the polymer. Furthermore, the specific surface area of the polymer sample was identified as the important factor accelerating biodegradation. Microbial community compositions and dynamics during the biodegradation of different PLA were monitored by temperature gradient gel electrophoresis, and were found to be virtually identical for all PLA materials and independent of MW. A specific PLA degrading bacteria was isolated and tentatively designated Thermopolyspora flexuosa FTPLA. The addition of a limited amount of low MW PLA did not accelerate the biodegradation of high MW PLA, suggesting that the process is not limited to the number of specific degraders and/or the induction of specific enzymes. In parallel, abiotic hydrolysis was investigated for the same set of samples and their courses found to be quasi-identical with the biodegradation of all four PLA samples investigated. This suggests that the abiotic hydrolysis represented a rate limiting step in the biodegradation process and the organisms present were not able to accelerate depolymerization significantly by the action of their enzymes. PMID- 24811903 TI - Comparison of conventional in vitro fertilisation and intracytoplasmic sperm injection outcomes in patients with moderate oligoasthenozoospermia. AB - The method of choice for assisted reproductive technology treatment in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) is usually based on the evaluation of male infertility factors. Decisions for couples with moderate oligoasthenozoospermia (OA) are often empirical because uniform treatment criteria are lacking. This study aimed to evaluate the effect of patients with moderate OA treated with conventional IVF and ICSI. A total of 199 couples with moderate OA undergoing their first IVF/ICSI cycle were included in the study. The patients were divided into two groups according to the type of insemination: conventional IVF group (n = 97) and ICSI group (n = 102). All patients were randomised to be inseminated either by conventional IVF or ICSI. The fertilisation rate, embryo quality, implantation rate and clinical pregnancy rate were examined. No differences in the fertilisation, implantation and pregnancy rates were observed between conventional IVF and ICSI groups (P > 0.05). However, the number of good-quality embryos was significantly higher in the ICSI group than in the IVF group (P < 0.05). Couples with moderate OA did not influence on the overall clinical outcomes between IVF and ICSI treatments, and a negative influence by ICSI on blastocyst development was not confirmed. PMID- 24811904 TI - Culture, ethics, and humanitarian affairs: often relevant, sometimes compelling, always interesting. PMID- 24811906 TI - The journal of clinical hypertension has become the official journal of the world hypertension league. PMID- 24811905 TI - Occupational fatalities among driver/sales workers and truck drivers in the United States, 2003-2008. AB - BACKGROUND: This study provides a national profile of occupational fatalities among truck drivers and driver-sales workers. METHODS: Data from the 2003-2008 Census of Fatal Occupational Injuries were used. Cases were extracted specifically for occupational subcategories included in the Driver/Sales Workers and Truck Drivers occupational category: Driver/Sales Workers, Heavy and Tractor Trailer Truck Drivers, and Light Truck or Delivery Services Drivers. RESULTS: In 2003-2008, the group Driver/Sales Workers and Truck Drivers had 5,568 occupational fatalities, representing 17% of all occupational fatalities in the United States. The majority of these fatalities were in the subgroup Heavy and Tractor-Trailer Truck Drivers (85%) and due to transportation incidents (80%). Older and male drivers had higher fatality rates than their counterparts. CONCLUSIONS: Findings suggest a need for targeted interventions to reduce highway fatalities among heavy truck drivers. Better employment data are needed to separate the three occupational subcategories by worker characteristic and employment history for use in research and prevention efforts. PMID- 24811907 TI - New preclinical porcine model of femoral head osteonecrosis to test mesenchymal stromal cell efficiency in regenerative medicine. AB - PURPOSE: In order to evaluate new therapeutic approaches to human osteonecrosis of the femoral head (ONFH), this study proposed to improve the existing animal model by developing a new surgically induced pig model. METHODS: First, ONFH was induced with an easy and minimally invasive technique: cryogenic insult with repeated freeze-thaw cycle. Then, to compare and improve the efficacy of this first method, we combined the cryogenic insult to vascular coagulation of the posterior circumflex vessels. RESULTS: Cryoinjury with repeated freeze-thaw cycle alone is sufficient to induce, three weeks postsurgery, a subchondral necrosis as confirmed by magnetic resonance imaging (MRI) and histological analysis. However, a bone regeneration began at four weeks and was complete at eight weeks. To optimise this result, we combined cryoinjury with posterior circumflex vessel coagulation and observed the persistence of ONFH, with progression to collapse at 14 weeks postinduction. CONCLUSIONS: Cryoinjury associated with partial vascular coagulation is sufficient to obtain localised and sustainable necrosis in the subchondral area of the femoral head, reproducing all stages of the human disorder. The co-analysis by MRI and histology allowed us to confirm that the classic T1- and T2-weighted hyposignal regeneration front around a fatty high T1 weighted signal observed by MRI indicate signs of induced osteonecrosis. Our results indicate that our pig model induces all stages of human ONFH, which can be followed by MRI, making it relevant for clinical trials. PMID- 24811913 TI - Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. AB - Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma. PMID- 24811914 TI - Are people with chronic diseases interested in using telehealth? A cross sectional postal survey. AB - BACKGROUND: There is growing interest in telehealth-the use of technology to support the remote delivery of health care and promote self-management-as a potential alternative to face-to-face care for patients with chronic diseases. However, little is known about what precipitates interest in the use of telehealth among these patients. OBJECTIVE: This survey forms part of a research program to develop and evaluate a telehealth intervention for patients with two exemplar chronic diseases: depression and raised cardiovascular disease (CVD) risk. The survey was designed to explore the key factors that influence interest in using telehealth in these patient groups. METHODS: Thirty-four general practices were recruited from two different regions within England. Practice records were searched for patients with (1) depression (aged 18+ years) or (2) 10 year risk of CVD >=20% and at least one modifiable risk factor (aged 40-74 years). Within each general practice, 54 patients in each chronic disease group were randomly selected to receive a postal questionnaire. Questions assessed five key constructs: sociodemographics, health needs, difficulties accessing health care, technology-related factors (availability, confidence using technology, perceived benefits and drawbacks of telehealth), and satisfaction with prior use of telehealth. Respondents also rated their interest in using different technologies for telehealth (phone, email and Internet, or social media). Relationships between the key constructs and interest in using the three mediums of telehealth were examined using multivariable regression models. RESULTS: Of the 3329 patients who were sent a study questionnaire, 44.40% completed it (872/1740, 50.11% CVD risk; 606/1589, 38.14% depression). Overall, there was moderate interest in using phone-based (854/1423, 60.01%) and email/Internet based (816/1425, 57.26%) telehealth, but very little interest in social media (243/1430, 16.99%). After adjusting for health needs, access difficulties, technology-related factors, and prior use of telehealth, interest in telehealth had largely no association with sociodemographic variables. For both patient groups and for each of the three technology mediums, the most important constructs related to interest in telehealth were having the confidence to use the associated technology, as well as perceiving greater advantages and fewer disadvantages from using telehealth. To illustrate, greater confidence using phone technologies (b=.16, 95% CI 0.002-0.33), while also perceiving more benefits (b=.31, 95% CI 0.21-0.40) and fewer drawbacks (b=-.23, 95% CI -0.28 to 0.17) to using telehealth were associated with more interest in using phone-based telehealth technologies for patients with depression. CONCLUSIONS: There is widespread interest in using phone-based and email/Internet-based telehealth among patients with chronic diseases, regardless of their health status, access difficulties, age, or many other sociodemographic factors. This interest could be increased by helping patients gain confidence using technologies and through highlighting benefits and addressing concerns about telehealth. While the same pattern exists for social media telehealth, interest in using these technologies is minimal. PMID- 24811915 TI - Identifying and reducing early complications of surgical central lines in infants and toddlers. AB - BACKGROUND: Hospitalized infants>1 y old often require central venous catheters (CVC) for prolonged therapy. There are limited data describing the complication profile for this young population. The purpose of this study was to review outcomes associated with CVC insertion in this high-risk group and compare them to those in older children to develop directed quality improvement projects. MATERIALS AND METHODS: Patients receiving their first CVC, a tunneled central line or port-a-cath, from 2007-2010 were included. Femoral, non-tunneled, and hemodialysis catheters were excluded. Patients aged 0-12.0 mo (infants) were compared with those 12.1-36 mo (toddlers). Complications (<30 d) included infection, malposition, malfunction, intraoperative, and the need for operative exchange. Statistical analysis included Student t-test, chi-square, and a Kaplan Meier survival analysis. RESULTS: We identified 115 infants and 129 toddlers who underwent CVC insertion during the study period. Complication rates were higher in the infant group than in the toddler group, as was the operative exchange rate. Higher infection rates in the infant group appeared to contribute to the difference in early complications and exchange rates. A survival analysis indicated improved catheter duration in toddlers (P=0.001). CONCLUSIONS: In this cohort study, infants had a higher early complication rate, mostly attributable to infection, than their older counterparts. This difference could be explained by increased use of a tunneled central line for daily total parented nutrition in infants with gastrointestinal anomalies, as opposed to port-a-cath for chemotherapy infusion in older children. These data have prompted a number of targeted quality improvement initiatives to address relevant complications in this infant population. PMID- 24811916 TI - The effects of arterial pressure during normothermic kidney perfusion. AB - BACKGROUND: Ex vivo normothermic perfusion (EVNP) can reverse some of the detrimental effects of ischemic injury. However, in kidneys with warm and cold ischemic injury the optimal perfusion pressure remains undetermined. The aim of this study was to evaluate the effects of two different arterial pressures during EVNP. METHODS: Porcine kidneys underwent static cold storage for 23 h followed by 1 h of EVNP using leukocyte depleted blood at a mean arterial pressure of either 55 or 75 mm Hg. After this, kidneys were reperfused for 3 h to assess renal function and injury. This was compared with a control group that underwent 24 h cold storage. RESULTS: During EVNP, kidneys perfused at 75 mm Hg had a higher renal blood flow, increased oxygen consumption (median 59.9 mL/min/g (range 30.1 78.6] versus 31.8 [8.2-53.8] mL/min/g; P = 0.026), and produced more urine (P = 0.002) than kidneys perfused at 55 mm Hg. During ex vivo reperfusion, renal blood flow was significantly higher in the 75 mm Hg and 55 mm Hg groups compared with the control (area under the curve median 75 mm Hg 462 [228-745], 55 mm Hg 454 [254-923] versus control 262 [215-442] mL/min/100g.h; P = 0.040). There was a significant loss of renal function and increase in tubular injury in the 55 mm Hg group kidneys (P = 0.001, 0.007). Levels of endothelin 1 were significantly reduced in the 75 mm Hg group (P = 0.026). CONCLUSIONS: A mean arterial pressure of 75 mm Hg during EVNP resulted in less tubular damage and less endothelial injury during ex vivo reperfusion compared with kidneys perfused at 55 mm Hg. PMID- 24811918 TI - Psychological interventions for women with intellectual disabilities and forensic care needs: a systematic review of the literature. AB - OBJECTIVE: Research evidence to date concerning offending by people with intellectual disabilities (ID) has concentrated on male perpetrators and little is known about their female counterparts. This systematic literature review examines evidence on psycho-social therapies for the female intellectually disabled population within healthcare forensic facilities. METHODS: A search of health, psychology and social science databases was conducted, using a varying combination of search words to detect relevant literature for this review. Four studies published between 2001 and 2012 were identified for inclusion. Articles were organised and compared in relation to study characteristics, sample, kind of treatment, instruments used to measure treatment impact, and study findings. FINDINGS: In total, four studies were identified that met the inclusion criteria. A range of Cognitive Behaviour Therapy (CBT)-orientated group interventions for people with learning disabilities were evaluated and in most studies improvements were reported in relation to reducing problem behaviour. Evidence that has been generated by the studies is, however, limited in its explanatory value because of study design and related methodological issues. CONCLUSIONS: This review has identified a significant gap in relation to research-based therapies for women with ID and forensic care needs. In particular, more research is needed focusing on women with a dual diagnosis of ID and psychiatric disorder who present challenging or criminal behaviour. PMID- 24811917 TI - Copy number variation plays an important role in clinical epilepsy. AB - OBJECTIVE: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. METHODS: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy. PMID- 24811919 TI - Double-strand break repair and genetic recombination in topoisomerase and primase mutants of bacteriophage T4. AB - The effects of primase and topoisomerase II deficiency on the double-strand break (DSB) repair and genetic recombination in bacteriophage T4 were studied in vivo using focused recombination. Site-specific DSBs were induced by SegC endonuclease in the rIIB gene of one of the parents. The frequency/distance relationship was determined in crosses of the wild-type phage, topoisomerase II mutant amN116 (gene 39), and primase mutant E219 (gene 61). Ordinary two-factor (i*j) and three factor (i k*j) crosses between point rII mutations were also performed. These data provide information about the frequency and distance distribution of the single-exchange (splice) and double-exchange (patch) events. In two-factor crosses ets1*i, the topoisomerase and primase mutants had similar recombinant frequencies in crosses at ets1-i distances longer than 1000 bp, comprising about 80% of the corresponding wild-type values. They, however, differ remarkably in crosses at shorter distances. In the primase mutant, the recombinant frequencies are similar to those in the wild-type crosses at distances less than 100 bp, being a bit diminished at longer distances. In two-factor crosses ets1*i of the topoisomerase mutant, the recombinant frequencies were reduced ten-fold at the shortest distances. In three-factor crosses a6 ets1*i, where we measure patch related recombination, the primase mutant was quite proficient across the entire range of distances. The topoisomerase mutant crosses demonstrated virtually complete absence of rII(+) recombinants at distances up to 33 bp, with the frequencies increasing steadily at longer distances. The data were interpreted as follows. The primase mutant is fully recombination-proficient. An obvious difference from the wild-type state is some shortage of EndoVII function leading to prolonged existence of HJs and thus stretched out ds-branch migration. This is also true for the topoisomerase mutant. However, the latter is deficient in the ss-branch migration step of the DSB repair pathway and partially deficient in HJ initiation. In apparent contradiction to their effects on the DSB-induced site specific recombination, the topoisomerase and primase mutants demonstrated about 3-8-fold increase in the recombinant frequencies in the ordinary crosses, with the recombination running exclusively via patches. This implies that most of the spontaneous recombination events are not initiated by dsDNA ends in these mutants. PMID- 24811920 TI - Structural and functional studies of MutS2 from Deinococcus radiodurans. AB - The MutS2 homologues have been found widespread in most prokaryotes, which are involved in DNA repair and reactive oxygen species detoxification. The C-terminal small mutS-related (Smr) domain is critical for its endonucleolytic activity. However, the detailed catalytic mechanism is still unclear. In this study, we first investigated the in vivo role of drMutS2 in Deinococcus radiodurans, the most radiation-resistant organism exhibits the remarkable DNA repair capacity. mutS2 and recA mutS2 double knockout mutants were constructed because the phenotype was strongly masked by the predominant homologous recombination DNA repair pathway in this bacterium. Compared with the recA mutant, cells devoid of both genes showed increased sensitivity to ionizing radiation and oxidative agents, suggesting that drMutS2 is involved in RecA-independent mechanisms that enhance cellular resistance to oxidative stress-induced DNA damage. Moreover, the basal level of reductase activity and thiamine biosynthesis was induced in the absence of mutS2. To characterize its catalytic residues, the Smr domain was crystallized and soaked in buffer containing manganese ions. In contrast to native crystals, the space group of manganese-derivative crystals transformed from monoclinic to orthorhombic unexpectedly. This type of crystals showed improved diffraction resolution to 1.2 A, which has the highest resolution of currently known Smr structures. Structural comparison revealed that three acidic amino-acid residues, which are all located in the alpha1 helix, changed the rotamer states after metal soaking. Mutational analysis of conserved residue glutamic acid 710 to alanine yielded a drMutS2 variant with impaired nuclease activity, and could only partially rescue the radiosensitive phenotype of the mutS2 null strain, indicating that glutamic acid 710 is the catalytic residue. PMID- 24811922 TI - A single thiazole orange molecule forms an exciplex in a DNA i-motif. AB - A fluorescent exciplex of thiazole orange (TO) is formed in a single-dye conjugated DNA i-motif. The exciplex fluorescence exhibits a large Stokes shift, high quantum yield, robust response to pH oscillation and little structural disturbance to the DNA quadruplex, which can be used to monitor the folding of high-order DNA structures. PMID- 24811923 TI - Editorial comment. PMID- 24811921 TI - MicroRNAs in the control of metastatic bone disease. AB - Bone metastasis is a common and devastating complication of late-stage breast and prostate cancer. Complex interactions between tumor cells, bone cells, and a milieu of components in their microenvironment contribute to the osteolytic, osteoblastic, or mixed lesions present in patients with metastasis to bone. In the past decade microRNAs (miRNAs) have emerged as key players in cancer progression, but the importance of miRNAs in regulating cancer metastasis to bone is only now being appreciated. We emphasize here important concepts of bone biology and miRNAs in the context of breast and prostate cancer, and focus on recent advances that have improved our understanding of the role of specific miRNAs with direct involvement in metastatic bone disease. PMID- 24811924 TI - Editorial comment. PMID- 24811925 TI - Interfacial behavior of PEGylated lipids and their effect on the stability of squalenoyl-drug nanoassemblies. AB - Squalenoyl-gemcitabine (Sq-Gem) and squalenoyl-dideoxycytidine (Sq-ddC) are amphiphilic prodrugs that self-assemble in water to form nanoassemblies (NAs) with well-defined structures and size. However, like other drug nanocarriers, these nanoassemblies are rapidly cleared from the blood stream by the reticulo endothelial system. By adding squalenoyl-PEG (Sq-PEG) or cholesterol-PEG (Chol PEG) to the squalenoyl prodrugs, composite nanoassemblies (CNAs) were formed, with different sizes and structures. The effect of the PEG-lipids on the formation and stability of these nanoassemblies was assessed by transmission electron microscopy, quasi-elastic light scattering and surface tension measurements in various conditions. The results revealed different stabilities with time for Sq-ddC and Sq-Gem nanoassemblies in aqueous medium, the latter being much less stable than the former. They also demonstrated that the presence of Sq-PEG or Chol-PEG in composite Sq-ddC nanoassemblies contributed to their rapid destabilization. The analysis of the adsorption kinetics of Sq-PEG into a prodrug monolayer below and above its critical aggregation concentration allowed getting a better insight into prodrug-lipopolymer molecular interactions, and their consequences on the formation of composite prodrug nanoassemblies. PMID- 24811926 TI - Sulfur K-edge X-ray absorption spectroscopy and time-dependent density functional theory of arsenic dithiocarbamates. AB - S K-edge X-ray absorption spectroscopy (XAS) and time-dependent density functional theory (TDDFT) calculations were performed on a series of As[S2CNR2]3 complexes, where R2 = Et2, (CH2)5 and Ph2, to determine how dithiocarbamate substituents attached to N affect As[S2CNR2]3 electronic structure. Complimentary [PPh4][S2CNR2] salts were also studied to compare dithiocarbamate bonding in the absence of As. The XAS results indicate that changing the orientation of the alkyl substituents from trans to cis (R2 = Et2vs. (CH2)5) yields subtle variations whereas differences associated with a change from alkyl to aryl are much more pronounced. For example, despite the differences in As 4p mixing, the first features in the S K-edge XAS spectra of [PPh4][S2CNPh2] and As[S2CNPh2]3 were both shifted by 0.3 eV compared to their alkyl-substituted derivatives. DFT calculations revealed that the unique shift observed for [PPh4][S2CNPh2] is due to phenyl-induced splitting of the pi* orbitals delocalized over N, C and S. A similar phenomenon accounts for the shift observed for As[S2CNPh2]3, but the presence of two unique S environments (As-S and As...S) prevented reliable analysis of As-S covalency from the XAS data. In the absence of experimental values, DFT calculations revealed a decrease in As-S orbital mixing in As[S2CNPh2]3 that stems from a redistribution of electron density to S atoms participating in weaker As...S interactions. Simulated spectra obtained from TDDFT calculations reproduce the experimental differences in the S K-edge XAS data, which suggests that the theory is accurately modeling the experimental differences in As-S orbital mixing. The results highlight how S K-edge XAS and DFT can be used cooperatively to understand the electronic structure of low symmetry coordination complexes containing S atoms in different chemical environments. PMID- 24811927 TI - New regulations on medical devices in Europe: what to expect? AB - Medical devices (MDs) contribute to improve quality and effectiveness of healthcare. The MD industry is a heterogeneous, innovative, dynamic and growing sector. The existing regulatory framework for MDs has been in place for 20 years and needed a revision. In September 2012, the European Commission published a proposal for a new regulation on MDs which was amended by the Parliament in October 2013. This new regulation aims to harmonize practices, increase transparency and guarantee a high level of health protection. We conducted an analysis of the proposal to highlight the major upcoming changes. PMID- 24811928 TI - Routine versus selective histologic analysis of gallbladder specimens for the detection of incidental gallbladder cancers. A retrospective review over 9 years of activity with a special focus on patients' age. AB - BACKGROUND: Incidental gallbladder cancer (IGC) is an infrequent possibility in patients undergoing cholecystectomies. Routine histologic examination of all gallbladder specimens is the current approach to detect this disease. Our study presents the influence of age to perform a selective histologic analysis. METHODS: A retrospective review was conducted of all gallbladder specimens during the last 9 years in our hospital. The medical notes were retrieved for cases of IGC or dysplasia and perioperative data were collected. RESULTS: A total of 3,330 cholecystectomies were conducted over the study period, 3,041 for gallstone disease. Twelve patients were found with dysplasia and 13 patients with IGC, all of them occurred in gallbladders removed for gallstone diseases. There were 18 men with a median age of 65 years (range 18 to 85). Median age for cancer patients was 70 years (range 51 to 85) and 54 years for dysplasia (range 18 to 75). No patient below the age of 51 years (n = 1,464) experienced IGCs. CONCLUSION: Age should be considered as an additional factor for a selective approach to the histologic analysis of all gallbladder specimens following cholecystectomies. PMID- 24811929 TI - Arteriovenous grafts have higher secondary patency in the short term compared with autologous fistulae. AB - BACKGROUND: To estimate patency of arteriovenous fistulas (AVFs) and grafts (AVGs) for dialysis access. METHODS: Records of all adult patients who had a dialysis access placed from January 2008 to June 2011 were retrospectively reviewed. RESULTS: A total of 494 patients with 655 accesses (390 AVFs, 265 AVGs) were examined. We found that AVG fared worse in assisted primary patency. But AVG had superior secondary patency up to 1.2 years (hazard ratio [HR] .6, confidence interval [CI]: [.4 to .8]) and was no different than AVF after 1.2 years. (HR 1.6, CI: [.9 to 3.1]). On univariate analysis, dialysis catheters negatively impacted assisted primary patency (HR 1.4, CI: [1.09 to 1.77]). CONCLUSIONS: AVG can be maintained with higher rates of secondary patency in the short term and are no different in the long term. This result suggests that in patients with limited life expectancy an AVG may be an effective alternative to an AVF to reduce both catheter time and associated complications. PMID- 24811930 TI - William Hunter Harridge Lecture. Carotid endarterectomy versus stenting for stroke prevention: what we have and will learn from Carotid Revascularization Endarterectomy versus Stenting Trial. AB - The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) has major implications for the future of carotid revascularization and stroke prevention. The purpose of The William Hinter Harridge Lecture was to discuss the history of carotid revascularization before CREST, to delineate the emergence of carotid artery stenting as an alternative to carotid endarterectomy, analyze the key findings in CREST, and describe the next phase of investigation, CREST-2. PMID- 24811931 TI - Challenges in the treatment of angiosarcoma: a single institution experience. AB - BACKGROUND: Angiosarcomas are rare tumors that carry poor prognosis. Because of insidious growth rate, the diagnosis is often difficult and delayed. METHODS: Between 1990 and 2011, 72 (41 female, 31 male) patients were treated at our institution. Pathologic confirmation was obtained and multiple prognostic factors were evaluated for survival. RESULTS: Forty-four cases were sporadic and 28 cases were secondary. In the sporadic group, 16 (36%) patients had increased sun exposure, while in the secondary group, the majority (n = 23, 82%) of patients had prior exposure to radiation. The latent period between radiation exposure and diagnosis was predictive of survival (P = .037). Presentation was delayed by more than 3 months in 41% of patients. The majority of men developed head and neck angiosarcomas (n = 15, 48.5%), while women developed breast angiosarcomas (n = 21, 51%). Median survival was prolonged in patients treated initially with surgery. CONCLUSIONS: A delay in the diagnosis of angiosarcoma can affect survival. Clinical suspicion and prompt diagnosis are essential for successful multimodal therapy. Initial surgical resection with adjuvant chemotherapy provides survival advantage. PMID- 24811932 TI - Topical methotrexate pretreatment enhances the therapeutic effect of topical 5 aminolevulinic acid-mediated photodynamic therapy on hamster buccal pouch precancers. AB - BACKGROUND/PURPOSE: Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of human oral precancerous lesions. This animal study aimed to assess whether topical methotrexate (MTX) pretreatment could enhance the therapeutic effect of topical ALA-PDT on hamster buccal pouch precancerous lesions. METHODS: Twenty hamster buccal pouch precancerous lesions were treated with either topical ALA-PDT with topical MTX pretreatment (topical MTX-ALA-PDT group, n = 10) or topical ALA-PDT alone (topical ALA-PDT group, n = 10). The intracellular protoporphyrin IX (PpIX) level in another 12 precancerous lesions (n = 6 for either the topical MTX-ALA or topical ALA group) was monitored by fluorescence spectroscopy. RESULTS: The intracellular PpIX reached its peak level in precancerous lesions 6.5 hours and 2.5 hours after topical ALA application for the topical MTX-ALA group (5.63-fold higher in the lesion than in the normal mucosa) and topical ALA group (2.42-fold higher in the lesion than in the normal mucosa), respectively. The complete response rate of precancerous lesions was 80% for the topical MTX-ALA-PDT group and 70% for the topical ALA-PDT group. In addition, the topical MTX-ALA-PDT group required a significantly lower mean treatment number (2.1 +/- 0.6) to achieve complete response than the topical ALA-PDT group (4.4 +/- 1.3, p < 0.001)). Moreover, the topical MTX-ALA-PDT group had a lower recurrence rate (12.5%) than the topical ALA-PDT group (28.6%). CONCLUSION: We conclude that topical MTX-pretreatment can increase intracellular PpIX production in hamster buccal pouch precancerous lesions and significantly improves the outcomes of the precancerous lesions treated with topical ALA-PDT. PMID- 24811933 TI - Does Favorable Selection Among Medicare Advantage Enrollees Affect Measurement of Hospital Readmission Rates? AB - Literature indicates favorable selection among Medicare Advantage (MA) enrollees compared with fee-for-service (FFS) enrollees. This study examined whether favorable selection into MA affected readmission rates among Medicare-eligible veterans following hospitalization for congestive heart failure in the Veterans Affairs Health System (VA). We measured total (VA + Medicare FFS) 30-day all cause readmission rates across hospitals and all of VA. We used Heckman's correction to adjust readmission rates to be representative of all Medicare eligible veterans, not just FFS-enrolled veterans. The adjusted all-cause readmission rate among FFS veterans was 27.1% (95% confidence interval [CI] = 26.5% to 27.7%), while the adjusted readmission rate among Medicare-eligible veterans was 25.3% (95% CI = 23.6% to 27.1%) after correcting for favorable selection. Readmission rate estimates among FFS veterans generalize to all Medicare-eligible veterans only after accounting for favorable selection into MA. Estimation of quality metrics should carefully consider sample selection to produce valid policy inferences. PMID- 24811934 TI - Putting Health Back Into Health Insurance Choice. AB - What are the barriers to voluntary take-up of high-deductible plans? We address this question using a large-scale employer survey conducted after an open enrollment period in which a new high-deductible plan was first introduced. Only 3% of the employees chose this plan, despite the respondents' recognition of its financial advantages. Employees who believed that the high-deductible plan provided access to top physicians in the area were three times more likely to choose it than employees who did not share this belief. A framed field experiment using a similar choice menu showed that displaying additional financial information did not increase high-deductible plan take-up. However, when plans were presented as identical except for the deductible, respondents were highly likely to choose the high-deductible plan, especially in a two-way choice. These results suggest that informing plan choosers about high-deductible plans' health access provisions may affect choice more strongly than focusing on their financial advantages. PMID- 24811935 TI - A quality improvement assessment of multiple, concurrent flow cytometry analyses at a tertiary care center. AB - INTRODUCTION: The utility of flow cytometry (FC) in diagnosis and staging of hematologic malignancy is controversial. Often, multiple specimens from the same patient are processed concurrently for FC analyses, alongside tissue for histomorphologic diagnosis. METHODS: To assess the diagnostic utility of multiple, concurrent FC analyses, a 10-year retrospective review of cases with >=2 concurrent specimens (from the same patient) submitted for FC was conducted. Light microscopic (LM) diagnoses were compared to FC findings, and the contribution of FC results to final diagnoses was examined. RESULTS: Of 4058 specimens (predominantly lymph nodes, bone marrows, and oropharyngeal tissues) submitted for FC analyses, 129 (3.2%) represented cases with multiple (average: 2.19) concurrent FC analyses. All were accompanied by tissues and/or aspirates for LM examination. In 115 (89.1%) cases, multiple FC analyses were performed prior to morphologic examination. In 87.0% of those cases, >=1 FC result(s) aligned with LM findings. In 15 (13.0%) cases where FC results differed from morphologic diagnoses, 86.7% (13/15) failed to detect an abnormal cell population by FC in the presence of a hematologic malignancy by LM. In one case (0.9%), FC detected a lymphoma, without morphologic evidence by LM. CONCLUSIONS: Overall, multipart FC failed to demonstrate a significant contribution in initial diagnoses of hematologic malignancies compared with analysis of a single specimen. PMID- 24811936 TI - Revisiting the F-shaped molecule: is its identity solved? PMID- 24811937 TI - Distribution and conservation status of Rhinopithecus strykeri in China. AB - This paper summarizes the results of 358 interviews we conducted on Rhinopithecus strykeri in the Gaoligong Mountains, northwest Yunnan, China, between April 2011 and December 2012. Based on our interview records and selective field surveys (47 days of field survey for seven possible distribution areas), we suggest that there may be up to 10 groups of R. strykeri occurring in China between the Salween River and the border with Myanmar, and that the total population of R. strykeri in China should be between 490 and 620 animals. According to interviewees, Rhinopithecus strykeri tends to use conifer and mixed conifer-broad leaved forest, predominantly between 2,600 and 3,100 m above sea level. To better protect this globally threatened species, classified as critically endangered by the International Union for Conservation of Nature (IUCN), we suggest extensions to current nature reserve boundaries to better include the home ranges of China's remaining population. PMID- 24811938 TI - Selective expression and immunogenicity of the cancer/testis antigens SP17, AKAP4 and PTTG1 in non-small cell lung cancer: new candidates for active immunotherapy. AB - ABSTRACT BACKGROUND. Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the cancer/testis antigens (CTAs) Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. METHODS. We used RT-PCR, immunofluorescence, flow cytometry, ELISA and cytotoxicity assays to determine the expression levels and immunogenicity of SP17, AKAP4 and PTTG1 in human NSCLC cell lines and primary tumors. RESULTS. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in NSCLC cancer cell lines and primary tumor tissues from patients, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes (CTLs) from patients' peripheral blood mononuclear cells (PBMCs). CONCLUSIONS. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in NSCLC patients. Based on our findings, further studies are warranted to explore the feasibility of developing CTA-specific immunotherapeutic strategies for NSCLC patients. PMID- 24811939 TI - Transcriptionally regulated cell adhesion network dictates distal tip cell directionality. AB - BACKGROUND: The mechanisms that govern directional changes in cell migration are poorly understood. The migratory paths of two distal tip cells (DTC) determine the U-shape of the C. elegans hermaphroditic gonad. The morphogenesis of this organ provides a model system to identify genes necessary for the DTCs to execute two stereotyped turns. RESULTS: Using candidate genes for RNAi knockdown in a DTC specific strain, we identified two transcriptional regulators required for DTC turning: cbp-1, the CBP/p300 transcriptional coactivator homologue, and let-607, a CREBH transcription factor homologue. Further screening of potential target genes uncovered a network of integrin adhesion-related genes that have roles in turning and are dependent on cbp-1 and let-607 for expression. These genes include src-1/Src kinase, tln-1/talin, pat-2/alpha integrin and nmy-2, a nonmuscle myosin heavy chain. CONCLUSIONS: Transcriptional regulation by means of cbp-1 and let-607 is crucial for determining directional changes during DTC migration. These regulators coordinate a gene network that is necessary for integrin-mediated adhesion. Overall, these results suggest that directional changes in cell migration rely on the precise gene regulation of adhesion. PMID- 24811941 TI - Abdominal CT scan for recurrent seizures. PMID- 24811940 TI - Association between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis. AB - PURPOSE: Mechanical ventilation with lower tidal volumes (<=6 ml/kg of predicted body weight, PBW) could benefit patients without acute respiratory distress syndrome (ARDS). However, tidal volume reduction could be associated with increased patient discomfort and sedation needs, and consequent longer duration of ventilation. The aim of this individual patient data meta-analysis was to assess the associations between tidal volume size, duration of mechanical ventilation, and sedation needs in patients without ARDS. METHODS: Studies comparing ventilation with different tidal volume sizes in patients without ARDS were screened for inclusion. Corresponding authors were asked to provide individual participant data. Patients were assigned to three groups based on tidal volume size (<=6 ml/kg PBW, 6-10 ml/kg PBW, or >=10 ml/kg PBW). Ventilator free days, alive at day 28, and dose and duration of sedation (propofol and midazolam), analgesia (fentanyl and morphine), and neuromuscular blockade (NMB) were compared. RESULTS: Seven investigations (2,184 patients) were included in the analysis. The number of patients breathing without assistance by day 28 was higher in the group ventilated with tidal volume <=6 ml/kg PBW compared to those ventilated with tidal volume >=10 ml/kg PBW (93.1 vs. 88.6%; p = 0.027, respectively). Only two investigations (187 patients) could be included in the meta-analysis of sedation needs. There were neither differences in the percentage of study days that patients received sedatives, opioids, or NMBA nor in the total dose of benzodiazepines, propofol, opioids, and NMBA. CONCLUSIONS: This meta analysis suggests that use of lower tidal volumes in patients without ARDS at the onset of mechanical ventilation could be associated with shorter duration of ventilation. Use of lower tidal volumes seems not to affect sedation or analgesia needs, but this must be confirmed in a robust, well-powered randomized controlled trial. PMID- 24811942 TI - Capillary refill time exploration during septic shock. AB - BACKGROUND: During septic shock management, the evaluation of microvascular perfusion by skin analysis is of interest. We aimed to study the skin capillary refill time (CRT) in a selected septic shock population. METHODS: We conducted a prospective observational study in a tertiary teaching hospital. After a preliminary study to calculate CRT reproducibility, all consecutive patients with septic shock during a 10-month period were included. After initial resuscitation at 6 h (H6), we recorded hemodynamic parameters and analyzed their predictive value on 14-day mortality. CRT was measured on the index finger tip and on the knee area. RESULTS: CRT was highly reproducible with an excellent inter-rater concordance calculated at 80% [73-86] for index CRT and 95% [93-98] for knee CRT. A total of 59 patients were included, SOFA score was 10 [7-14], SAPS II was 61 [50-78] and 14-day mortality rate was 36%. CRT measured at both sites was significantly higher in non-survivors compared to survivors (respectively 5.6 +/- 3.5 vs 2.3 +/- 1.8 s, P < 0.0001 for index CRT and 7.6 +/- 4.6 vs 2.9 +/- 1.7 s, P < 0.0001 for knee CRT). The CRT at H6 was strongly predictive of 14-day mortality as the area under the curve was 84% [75-94] for the index measurement and was 90% [83-98] for the knee area. A threshold of index CRT at 2.4 s predicted 14-day outcome with a sensitivity of 82% (95% CI [60-95]) and a specificity of 73% (95% CI [56-86]). A threshold of knee CRT at 4.9 s predicted 14-day outcome with a sensitivity of 82% (95% CI [60-95]) and a specificity of 84% (95% CI [68-94]). CRT was significantly related to tissue perfusion parameters such as arterial lactate level and SOFA score. Finally, CRT changes during shock resuscitation were significantly associated with prognosis. CONCLUSION: CRT is a clinical reproducible parameter when measured on the index finger tip or the knee area. After initial resuscitation of septic shock, CRT is a strong predictive factor of 14-day mortality. PMID- 24811943 TI - Isomeric ionic lithium isonicotinate three-dimensional networks and single crystal-to-single-crystal rearrangements generating microporous materials. AB - Reaction between LiOH and isonicotinic acid (inicH) in the appropriate solvent or mixture of solvents affords a family of variously solvated forms of a simple ionic lithium salt, viz., Li(+)inic(-).S (where S = 0.5 morpholine, 0.5 dioxane, 0.25 n-hexanol, 0.5 N-methylpyrrolidinone, 0.5 N,N-dimethylformamide, 0.5 n propanol, 0.5 cyclohexanol, 0.5 pyridine, 0.5 t-butanol, 0.5 ethanol, and 0.5 methanol). Three-dimensional Li(+)inic(-) frameworks containing solvent-filled channels are present in all of these except for the MeOH and EtOH solvates. The nondirectional character of the electrostatic interactions between the Li(+) and inic(-) ions bestows an element of "plasticity" upon the framework, manifested in the observation of no less than five different framework structures within the family. Unusual single-crystal-to-single-crystal transformations accompany desolvation of Li(+)inic(-).S in which the Li(+)inic(-) framework undergoes a major rearrangement (from a structure containing "8484 chains" to one with "6666 chains"). The "before and after" structures are strongly suggestive of the mechanism and the driving force for these solid state framework rearrangements: processes which further demonstrate the "plasticity" of the ionic Li(inic) framework. A solid-state mechanism for these desolvation processes that accounts very satisfactorily for the formation of the channels and for the diverse geometrical/topological aspects of the transformation is proposed. The reverse process allows the regeneration of the solvated 8484 form. When the 6666 Li(+)inic(-) form is immersed in carbon disulfide, a single-crystal-to-single crystal transformation occurs to generate Li(+)inic(-).0.25CS2. The hydrate, Li(+)inic(-).2H2O which consists of discrete Li(inic).H2O chains obtained by recrystallizing the salt from water, can also be obtained by hydration of the 6666 form. A dense 3D network with the formula, Li(inic) can be obtained in a reversible process by the removal of the water from the hydrated form and also by crystallization from a t-amyl alcohol solution. PMID- 24811944 TI - Successful desensitization in patient with type 2 diabetes with an insulin allergy using insulin pump and glargine. PMID- 24811945 TI - Metal pollution in a contaminated bay: relationship between metal geochemical fractionation in sediments and accumulation in a polychaete. AB - Jinzhou Bay in Northern China has been seriously contaminated with metals due to the impacts of smelting activities. In this study, we investigated the relationship between metal accumulation in a deposit-feeding polychaete Neanthes japonica and metal concentration and geochemical fractionation (Cd, Cu, Pb, Zn and Ni) in sediments of Jinzhou Bay. Compared with the historical data, metals in the more mobile geochemical fraction (exchangeable and carbonate fractions) were gradually partitioned into the more stable fraction (Fe-Mn oxides) over time. Metal concentration and geochemical fractionation in sediment significantly affected metal bioavailability and accumulation in polychaetes, except for Ni. Metal accumulation in polychaetes was significantly influenced by Fe or Mn content, and to a lesser degree by organic matter. Prediction of metal bioaccumulation in polychaetes was greatly improved by normalizing metal concentrations to Mn content in sediment. The geochemical fractionation of metals in sediments including the exchangeable, organic matter and Fe-Mn oxides were important in controlling the sediment metal bioavailability to polychaetes. PMID- 24811946 TI - Evidence of altered fertility in female roach (Rutilus rutilus) from the River Seine (France). AB - A large variety of anthropogenic chemicals present in the aquatic environment have been shown to be able to alter the endocrine system of exposed organisms, potentially impacting their reproductive function. The aim of this study was to assess the effects of environmental pollution on the reproductive system of wild female roach (Rutilus rutilus) from the Seine River (Normandy, France). A suite of biomarkers of endocrine disruption including gonado-somatic index, plasmatic vitellogenin, gonadal aromatase activity and histological parameters (oocyte diameter and gonad maturation) were studied. Female fish from the polluted sites showed a number of reproductive alterations, including inhibited gonad maturation, reduced oocyte growth, reduced levels of plasmatic vitellogenin and 3 fold lower gonadal aromatase activity than females collected in the reference site. Overall, these results highlight the presence of endocrine disruption in female roach from the Seine River. PMID- 24811947 TI - Characteristics and cellular effects of ambient particulate matter from Beijing. AB - In vitro tests using human adenocarcinomic alveolar epithelial cell line A549 and small mouse monocyte-macrophage cell line J774A.1 were conducted to test toxicity of six PM (particulate matter) samples from Beijing. The properties of the samples differ significantly. The production of inflammatory cytokine (TNF-alpha for J774A.1) and chemokine (IL-8 for A549) and the level of intracellular reactive oxygen species (ROS) were used as endpoints. There was a positive correlation between water soluble organic carbon and DTT-based redox activity. Both cell types produced increased levels of inflammatory mediators and had higher level of intracelllar ROS, indicating the presence of PM-induced inflammatory response and oxidative stress, which were dose-dependent and significantly different among the samples. The releases of IL-8 from A549 and TNF alpha from J774A.1 were significantly correlated to PM size, Zeta potential, endotoxin, major metals, and polycyclic aromatic hydrocarbons. No correlation between ROS and these properties was identified. PMID- 24811948 TI - Pesticide transport simulation in a tropical catchment by SWAT. AB - The application of agrochemicals in Southeast Asia is increasing in rate, variety and toxicity with alarming speed. Understanding the behavior of these different contaminants within the environment require comprehensive monitoring programs as well as accurate simulations with hydrological models. We used the SWAT hydrological model to simulate the fate of three different pesticides, one of each usage type (herbicide, fungicide and insecticide) in a mountainous catchment in Northern Thailand. Three key parameters were identified: the sorption coefficient, the decay coefficient and the coefficient controlling pesticide percolation. We yielded satisfactory results simulating pesticide load dynamics during the calibration period (NSE: 0.92-0.67); the results during the validation period were also acceptable (NSE: 0.61-0.28). The results of this study are an important step in understanding the modeling behavior of these pesticides in SWAT and will help to identify thresholds of worst-case scenarios in order to assess the risk for the environment. PMID- 24811949 TI - Development of a ruthenium/phosphite catalyst system for domino hydroformylation reduction of olefins with carbon dioxide. AB - An efficient domino ruthenium-catalyzed reverse water-gas-shift (RWGS) hydroformylation-reduction reaction of olefins to alcohols is reported. Key to success is the use of specific bulky phosphite ligands and triruthenium dodecacarbonyl as the catalyst. Compared to the known ruthenium/chloride system, the new catalyst allows for a more efficient hydrohydroxymethylation of terminal and internal olefins with carbon dioxide at lower temperature. Unwanted hydrogenation of the substrate is prevented. Preliminary mechanism investigations uncovered the homogeneous nature of the active catalyst and the influence of the ligand and additive in individual steps of the reaction sequence. PMID- 24811951 TI - The correlation between prolonged corrected QT interval with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose. AB - Corrected QT interval (QTc) prolongation is long considered as a predisposing factor for the occurrence of torsade de pointes (TdP) and sudden cardiac arrest in methadone maintenance treatment. We aimed to elucidate the correlation between QTc prolongation and in-hospital death, respiratory arrest, and endotracheal intubation in acute methadone-intoxicated patients presenting to the emergency department and to assess the value of QTc in predicting these outcomes. A prospective cross-sectional study with a convenience sample of patients with acute methadone overdose was done. Participants were 152 patients aged 15-65 with negative urinary dipstick test for cyclic antidepressants, no history of other QTc-prolonging conditions and co-ingestions, no severe comorbidities affecting the outcomes, and positive urinary dipstick results for methadone. QTc intervals were measured and calculated in triage-time electrocardiogram (ECG). Death was correlated with QTc (P = 0.014) and length of ICU admission (P < 0.001). In multivariable analysis, death was independently associated only with length of ICU admission [odds ratio (OR) 95 % confidence intervals (95 % CI) 1.36 (1.14 1.61)]. Intubation and respiratory arrest were independently associated with QTc interval [OR (95 % CI) 1.03 (1.02-1.04) and 1.02 (1.01-1.03), respectively]. The receiver operating characteristics curves drawn to show the ability of QTc to predict death, intubation, and respiratory arrest showed thresholds of 470, 447.5, and 450 ms with sensitivity (95 % CI) and specificity (95 % CI) of 87.5 (47.3-99.7), 86.8 (74.7-94.5), and 77.3 (62.2-88.5), respectively. Our study showed that QTc is a potential predictor for adverse outcomes related to acute methadone intoxication. The correlations shown in this study between triage-time QTc and in-hospital respiratory arrest or intubation in methadone overdose may be of clinical value, whether these outcomes are hypothesized to be a reflection of background TdP or intoxication severity. PMID- 24811952 TI - Cardiogenic shock due to acute tramadol intoxication. AB - Tramadol is a common analgesic, widely prescribed because of its efficiency and safety. We report the case of a 7-year-old child admitted in cardiac intensive care unit for cardiogenic shock due to tramadol intoxication. Without any past history, the child was admitted at emergency room for generalised convulsion, followed by respiratory distress. Cardiogenic shock was suspected after clinical examination and chest X-ray and confirmed by transthoracic echocardiography showing low left ventricular ejection fraction (<30 %) with pulmonary hypertension. No evidence of cardiac infarction or myocarditis was found. Tramadol intoxication was suspected because of empty tramadol tablets found near the child and later confirmed by toxicologic analysis showing high blood concentration of tramadol (>1 mg/L) and O-desmethyltramadol (>1.5 mg/L). Hemodynamic support by inotropic drug infusion and diuretics was necessary. Left ventricular function normalised after 2 days of treatment allowing drug infusion weaning. Cardiac magnetic resonance imaging performed 3 days after admission confirmed normal left ventricular ejection fraction and volumes without evidence of late gadolinium enhancement. Cardiogenic shock due to tramadol intoxication is rare but exists. Negative inotropic effect of high doses of tramadol has been suspected. Quick recovery is possible. PMID- 24811953 TI - When do different C4 leaf anatomies indicate independent C4 origins? Parallel evolution of C4 leaf types in Camphorosmeae (Chenopodiaceae). AB - Broad-scale phylogenetic studies give first insights in numbers, relationships, and ages of C4 lineages. They are, however, generally limited to a model that treats the evolution of the complex C4 syndrome in different lineages as a directly comparable process. Here, we use a resolved and well-sampled phylogenetic tree of Camphorosmeae, based on three chloroplast and one nuclear marker and on leaf anatomical traits to infer a more detailed picture of C4 leaf type evolution in this lineage. Our ancestral character state reconstructions allowed two scenarios: (i) Sedobassia is a derived C3/C4 intermediate, implying two independent gains of C4 in Bassia and Camphorosma; or (ii) Sedobassia is a plesiomorphic C3/C4 intermediate, representing a syndrome ancestral to the Bassia/Camphorosma/Sedobassia lineage. In Bassia, a kochioid leaf type (Bassia muricata and/or Bassia prostrata type) is ancestral. At least three independent losses of water-storage tissue occurred, resulting in parallel shifts towards an atriplicoid leaf type. These changes in leaf anatomy are adaptations to different survival strategies in steppic or semi-desert habitats with seasonal rainfall. In contrast, Camphorosma shows a fixed C4 anatomy differing from Bassia types in its continuous Kranz layer, which indeed points to an independent origin of the full C4 syndrome in Camphorosma, either from an independent C3 or from a common C3/C4 intermediate ancestor, perhaps similar to its C3/C4 intermediate sister genus Sedobassia. The enlarged bundle sheath cells of Sedobassia might represent an important early step in C4 evolution in Camphorosmeae. PMID- 24811950 TI - The adverse cardiac effects of Di(2-ethylhexyl)phthalate and Bisphenol A. AB - The ubiquitous nature of plastics has raised concerns pertaining to continuous exposure to plastic polymers and human health risks. Of particular concern is the use of endocrine-disrupting chemicals in plastic production, including di(2 ethylhexyl)phthalate (DEHP) and bisphenol A (BPA). Widespread and continuous exposure to DEHP and BPA occurs through dietary intake, inhalation, dermal and intravenous exposure via consumer products and medical devices. This article reviews the literature examining the relationship between DEHP and BPA exposure and cardiac toxicity. In vitro and in vivo experimental reports are outlined, as well as epidemiological studies which examine the association between these chemicals and cardiovascular outcomes. Gaps in our current knowledge are also discussed, along with future investigative endeavors that may help resolve whether DEHP and/or BPA exposure has a negative impact on cardiovascular physiology. PMID- 24811954 TI - Chemical activation and changes in surface morphology of poly(epsilon caprolactone) modulate VEGF responsiveness of human endothelial cells. AB - The high degree of clinical routine in percutaneous transluminal coronary angioplasty (PTCA) with and without stenting has not changed the fact that a large number of coronary heart disease patients are still affected by post operative complications such as restenosis and thrombosis. Because re endothelialization is the crucial aspect of wound healing after cardiovascular implant surgery, there is a need for modern biomaterials to aid endothelial cells in their adhesion and functional recovery post-stenting. This study systematically examines the potential of numerous chemical polymer modifications with regard to endothelialization. Poly(epsilon-caprolactone) (PCL) and its chemically activated forms are investigated in detail, as well as the impact of polymer surface morphology and precoating with matrix protein. Human umbilical vein endothelial cells (HUVECs) are used to characterize endothelial cell responses in terms of in vitro viability and adhesion. As a potential component in drug eluting implants, VEGF is applied as stimulus to boost endothelial cell proliferation on the polymer. In conclusion, plasma chemical activation of PCL combined with VEGF stimulation best enhances in vitro endothelialization. Examining the impact of morphological, chemical and biological modifications of PCL, this study makes an important new contribution towards the existing body of work on polymer endothelialization. PMID- 24811955 TI - Nurses' evaluations of the CPOT use at 12-month post-implementation in the intensive care unit. AB - BACKGROUND: Performing routine pain assessments with all intensive care unit (ICU) patients is strongly recommended in clinical practice guidelines. As many ICU patients are unable to self-report, the Critical-Care Pain Observation Tool (CPOT) is one of the two behavioural pain scales suggested for clinical use. Still, no study has described the evaluations of its use in ICU daily practice. OBJECTIVE: To describe the nurses' evaluation of the feasibility, clinical relevance and satisfaction with the CPOT use 12 months after its implementation in the ICU. METHOD: A descriptive design was used. It was conducted in the medical-surgical ICU of a university affiliated setting at Greenfield Park (Quebec, Canada). A self-administered evaluation questionnaire including four sections (i.e. feasibility, clinical relevance, satisfaction and socio demographic information) was completed by ICU nurses who were all trained to use the CPOT. The questionnaires were completed anonymously. RESULTS: A total of 38 ICU nurses returned their completed questionnaire (63% participation rate). Regarding its feasibility, the majority rated the CPOT as quick to use, simple to understand and easy to complete (92-100%). According to clinical relevance, close to 70% of ICU nurses acknowledged that the CPOT had influenced their practice, but lower results (<50%) were found for effective communication of pain assessment findings with the physicians and other health professionals. More than 80% of ICU nurses were satisfied with its daily use. CONCLUSION: The CPOT use was deemed feasible and relevant in daily practice as per the nurses' evaluations but did not allow an effective communication with other ICU care team members. RELEVANCE TO CLINICAL PRACTICE: Training should be offered to all members of the ICU care team, and other implementation strategies should be explored as well to ensure optimal uptake of a pain assessment approach which impacts on their decision-making process for pain management. PMID- 24811956 TI - Harvesting, storing and utilising solar energy using MoO3 : modulating structural distortion through pH adjustment. AB - Nanostructured molybdenum oxide (alpha-MoO3 ) thin film photoelectrodes were synthesised by anodisation. Upon band gap-excitation by light illumination, alpha MoO3 is able to store a portion of the excited charges in its layered structure with the simultaneous intercalation of alkali cations. The stored electrons can be discharged from alpha-MoO3 for utilisation under dark conditions, and alpha MoO3 is able to recharge itself with successive illuminations to behave as a 'self-photo-rechargeable' alkali-ion battery. The alteration of the anodisation pH allowed the crystal structure and oxygen vacancy concentrations of alpha-MoO3 to be modulated to achieve (i) a distorted MoO6 octahedra for enhanced charge separation and storage, (ii) a layered structure with a greater exposed (010) crystal face for rich and reversible ion intercalation and (iii) a highly crystalline thin film that suppresses electron-hole pair recombination. Overall, the larger MoO6 octahedral distortion in alpha-MoO3 at a higher pH favours charge storage, whereas smaller octahedral distortion at a lower pH leads to anodic photocurrent enhancement. PMID- 24811958 TI - Climbazole increases expression of cornified envelope proteins in primary keratinocytes. AB - OBJECTIVE: Dandruff is a troubling consumer problem characterized by flaking and pruritus of the scalp and is considered a multifactorial condition with sebum, individual susceptibility and the fungus Malassezia all thought to play a part. The condition is commonly treated with shampoo products containing antifungal ingredients such as zinc pyrithione and climbazole. It is hypothesized that these ingredients may be delivering additional scalp skin benefits besides their antifungal activity helping to relieve dandruff effectively. The objective of this study was to evaluate the anti-dandruff ingredient climbazole for potential skin benefits using genomics and in vitro assays. METHODS: Microarray analysis was performed to profile gene expression changes in climbazole-treated primary human keratinocyte cells. Results were independently validated using qPCR and analysis of protein expression using ELISA and immunocytochemistry. RESULTS: Microarray analysis of climbazole-treated keratinocytes showed statistically significant expression changes in genes associated with the gene ontology groups encompassing epidermal differentiation, keratinization, cholesterol biosynthesis and immune response. Upregulated genes included a number encoding cornified envelope proteins such as group 3 late-cornified envelope proteins, LCE3 and group 2 small-proline-rich proteins, SPRR2. Protein analysis studies of climbazole-treated primary keratinocytes using ELISA and immunocytochemistry were able to demonstrate that the increase in gene transcripts translated into increased protein expression of these cornified envelope markers. CONCLUSION: Climbazole treatment of primary keratinocytes results in an upregulation in expression of a number of genes including those encoding proteins involved in cornified envelope formation with further studies demonstrating this did translate into increased protein expression. A climbazole-driven increase in cornified envelope proteins may improve the scalp skin barrier, which is known to be weaker in dandruff. These studies suggest climbazole, besides its antifungal activity, is delivering positive skin benefits helping to relive dandruff symptoms effectively. PMID- 24811957 TI - Breast cancer redox heterogeneity detectable with chemical exchange saturation transfer (CEST) MRI. AB - PURPOSE: Tissue redox state is an important mediator of various biological processes in health and diseases such as cancer. Previously, we discovered that the mitochondrial redox state of ex vivo tissues detected by redox scanning (an optical imaging method) revealed interesting tumor redox state heterogeneity that could differentiate tumor aggressiveness. Because the noninvasive chemical exchange saturation transfer (CEST) MRI can probe the proton transfer and generate contrasts from endogenous metabolites, we aim to investigate if the in vivo CEST contrast is sensitive to proton transfer of the redox reactions so as to reveal the tissue redox states in breast cancer animal models. PROCEDURES: CEST MRI has been employed to characterize tumor metabolic heterogeneity and correlated with the redox states measured by the redox scanning in two human breast cancer mouse xenograft models, MDA-MB-231 and MCF-7. The possible biological mechanism on the correlation between the two imaging modalities was further investigated by phantom studies where the reductants and the oxidants of the representative redox reactions were measured. RESULTS: The CEST contrast is found linearly correlated with NADH concentration and the NADH redox ratio with high statistical significance, where NADH is the reduced form of nicotinamide adenine dinucleotide. The phantom studies showed that the reductants of the redox reactions have more CEST contrast than the corresponding oxidants, indicating that higher CEST effect corresponds to the more reduced redox state. CONCLUSIONS: This preliminary study suggests that CEST MRI, once calibrated, might provide a novel noninvasive imaging surrogate for the tissue redox state and a possible diagnostic biomarker for breast cancer in the clinic. PMID- 24811959 TI - A randomized controlled trial comparing soft contact lens and rigid gas-permeable lens wearing in infantile nystagmus. AB - OBJECTIVE: To perform the first randomized controlled trial comparing soft contact lens (SCL) with rigid gas-permeable lens (RGPL) wearing in infantile nystagmus (IN), using spectacle wear as a baseline. DESIGN: Randomized, controlled cross-over trial with an intention-to-treat design. PARTICIPANTS AND CONTROLS: A total of 24 participants with IN (12 idiopathic, 12 with albinism). METHODS: Participants were randomized into 1 of 2 treatment arms receiving the following sequence of treatments (2-3 weeks for each treatment): (A) spectacles, SCL, RGPL, and spectacle wear; or (B) spectacles, RGPL, SCL, and spectacle wear. MAIN OUTCOME MEASURES: The main outcome measure was mean intensity of nystagmus at the null region viewing at 1.2 m. Secondary outcome measures included the same measure at 0.4 m viewing and across the horizontal meridian (measured over a +/ 30 degrees range at 3 degrees intervals) for distance and near. The nystagmus foveation characteristics were similarly assessed over +/-30 degrees and at the null region at 1.2 m and 0.4 m viewing. Visual outcome measures included best corrected visual acuity (BCVA) at 4 m and 0.4 m, gaze-dependent visual acuity (GDVA) (i.e., visual acuity when maintaining gaze angles over a +/-30 degrees range at 10 degrees intervals) at 4 m, and reading performance at 0.4 m derived from the Radner reading chart. RESULTS: There were no significant differences between SCL and RGPL wearing for any nystagmus characteristics or compared with spectacle wearing. The BCVA, reading acuity, and critical print size were significantly worse for SCL wearing compared with RGPL and baseline spectacle wear (P<0.05), although mean differences were less than 1 logarithm of the minimum angle of resolution (logMAR) line. CONCLUSIONS: Nystagmus was not significantly different during SCL and RGPL wearing in IN, and contact lens wearing does not significantly reduce nystagmus compared with baseline spectacle wearing. The wearing of SCL leads to a small but statistically significant deterioration in visual function compared with both RGPL and spectacle wearing at baseline, although mean effect sizes were not clinically relevant. PMID- 24811960 TI - Author reply: To PMID 23337555. PMID- 24811961 TI - Evaluation of optic nerve development in preterm and term infants using handheld spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate effects of prematurity on early optic nerve (ON) development and the usefulness of ON parameters as indicators of central nervous system (CNS) development and pathology. DESIGN: Prospective, cross-sectional, longitudinal study. PARTICIPANTS: Forty-four preterm infants undergoing retinopathy of prematurity (ROP) screening and 52 term infants. METHODS: We analyzed ON from portable handheld spectral-domain optical coherence tomography (SD-OCT) images (Bioptigen, Inc, Research Triangle Park, NC) of 44 preterm and 52 term infants. The highest-quality ON scan from either eye was selected for quantitative analysis. Longitudinal analysis was performed at 31-36 weeks and 37-42 weeks postmenstrual age (PMA). Preterm ON parameters also were assessed for correlation with indicators of cognitive, language, and motor development and CNS pathology. MAIN OUTCOME MEASURES: Vertical cup diameter (vCD), vertical disc diameter (vDD), vertical cup-to-disc ratio (vCDR), cup depth, and indicators of neurocognitive development and CNS pathology. RESULTS: At 37-42 weeks PMA, preterm infants had larger vCD and vCDR than term infants (908 vs. 700 MUm [P<0.001] and 0.68 vs. 0.53 MUm [P<0.001], respectively), whereas cup depth and vDD were not significantly different. Longitudinal changes (n = 26 preterm eyes; mean interval, 4.7 weeks) in vDD and in vCDR were an increase of 74 MUm (P = 0.008) and decrease of 0.05 (P = 0.015), respectively. In preterm infants (n = 44), periventricular leukomalacia was associated with larger vCD (1084 vs. 828 MUm; P = 0.005) and vCDR (0.85 vs. 0.63; P<0.001), posthemorrhagic hydrocephalus was associated with shallower cup (331 vs. 456 MUm; P = 0.030), and clinical magnetic resonance imaging was associated with larger vCDR (0.73 vs. 0.64; P = 0.023). In 23 preterm infants with Bayley Scales of Infant Development scores, larger vCDR was associated with lower cognitive scores (P = 0.049). CONCLUSIONS: This is the first analysis of ON parameters in premature infants using SD-OCT. It demonstrated that by age of term birth, vCD and vCDR are larger in preterm infants who were screened for ROP than in term infants. In this prospective pilot study, ON parameters in these preterm infants associate weakly with CNS pathology and future cognitive development. Future prospective studies with larger numbers are necessary before further conclusions can be made. PMID- 24811962 TI - Whole exome sequencing identifies CRB1 defect in an unusual maculopathy phenotype. AB - OBJECTIVE: To report a new phenotype caused by mutations in the CRB1 gene in a family with 2 affected siblings. DESIGN: Molecular genetics and observational case studies. PARTICIPANTS: Two affected siblings and 3 unaffected family members. METHODS: Each subject received a complete ophthalmic examination together with color fundus photography, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Microperimetry 1 (MP-1) mapping and electroretinogram (ERG) analysis were performed on the proband. Screening for disease-causing mutations was performed by whole exome sequencing in 3 family members followed by segregation analyses in the entire family. MAIN OUTCOME MEASURES: Appearance of the macula as examined by clinical examination, fundus photography, FAF imaging, SD-OCT, and visual function by MP-1 and ERG. RESULTS: The proband and her affected brother exhibited unusual, previously unreported, findings of a macular dystrophy with relative sparing of the retinal periphery beyond the vascular arcades. The FAF imaging showed severely affected areas of hypoautofluorescence that extended nasally beyond the optic disc in both eyes. A central macular patch of retinal pigment epithelium (RPE) sparing was evident in both eyes on FAF, whereas photoreceptor sparing was documented in the right eye only using SD-OCT. The affected brother presented with irregular patterns of autofluorescence in both eyes characterized by concentric rings of alternating hyper- and hypoautofluorescence, and foveal sparing of photoreceptors and RPE, as seen on SD-OCT, bilaterally. After negative results in screening for mutations in candidate genes including ABCA4 and PRPH2, DNA from 3 members of the family, including both affected siblings and their mother, was screened by whole exome sequencing resulting in identification of 2 CRB1 missense mutations, c.C3991T:p.R1331C and c.C4142T:p.P1381L, which segregated with the disease in the family. Of the 2, the p.R1331C CRB1 mutation has not been described before and the p.P1381L variant has been described in 1 patient with Leber congenital amaurosis. CONCLUSIONS: This report illustrates a novel presentation of a macular dystrophy caused by CRB1 mutations. Both affected siblings exhibited a relatively well-developed retinal structure and preservation of generalized retinal function. An unusual 5-year progression of macular atrophy alone was observed that has not been described in any other CRB1-associated phenotypes. PMID- 24811963 TI - Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study. AB - OBJECTIVE: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 MUg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. MAIN OUTCOME MEASURES: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. RESULTS: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment related. CONCLUSIONS: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated. PMID- 24811964 TI - Re: Hagstrom et al.: Pharmacogenetics for genes associated with age-related macular degeneration in the comparison of AMD treatments trials (CATT) (Ophthalmology 2013;120:593-9). PMID- 24811965 TI - Long-term outcomes of monocanalicular repair of canalicular lacerations. PMID- 24811966 TI - Adult orbital xanthogranuloma successfully treated with rituximab. PMID- 24811967 TI - Autism comes to the hospital: the experiences of patients with autism spectrum disorder, their parents and health-care providers at two Canadian paediatric hospitals. AB - Youth with autism spectrum disorder are a vulnerable, often poorly understood patient group, who may experience periodic and chronic health challenges, in addition to their primary developmental social and communication problems. Developmental and behavioural challenges can complicate management of acute health-care needs. To date, there is an absence of empirical research exploring the hospital experiences of children and youth with autism spectrum disorder, their families and their health-care providers. Therefore, the purpose of this study was to understand these experiences in order to inform hospital-based care. A total of 42 participants were interviewed (youth with autism spectrum disorder, their parents and health-care providers) at one of two Canadian paediatric hospitals, representing 20 distinct cases of patients with autism spectrum disorder. Results from the qualitative analyses indicated that patients with autism spectrum disorder faced several challenges in the context of health-care delivery in the hospital setting, as did their families and health-care provider team. Problems identified included communication and sensory challenges, and the degree of flexibility of health-care providers and the hospital organization. Supportive health-care providers were those who acknowledged parents as experts, inquired about the requirements of patients with autism spectrum disorder and implemented strategies that accommodated the unique clinical presentation of the individual patient. These recommendations have wide-reaching utility for hospital and health-care practices involving this patient group. PMID- 24811968 TI - Anxiety in Asperger's syndrome: Assessment in real time. AB - Anxiety is a major problem for many people with Asperger's syndrome who may have qualitatively different fears from a non-Asperger's syndrome population. Research has relied on measures developed for non-Asperger's syndrome populations that require reporting past experiences of anxiety, which may confound assessment in people with Asperger's syndrome due to problems with autobiographical memory as are often reported in this group.Experience sampling methodology was used to record real-time everyday experiences in 20 adults with Asperger's syndrome and 20 neurotypical adults. Within-subject analysis was used to explore the phenomenology of thoughts occurring in people with Asperger's syndrome when they were anxious. Comparisons were made with the group that did not have Asperger's syndrome. The Asperger's syndrome group were significantly more anxious than the comparison group. Factors associated with feelings of anxiety in the Asperger's syndrome group were high levels of self-focus, worries about everyday events and periods of rumination lasting over 10 min. People in the Asperger's syndrome group also had a tendency to think in the image form, but this was not associated with feelings of anxiety. The results are discussed with reference to psychological models of Asperger's syndrome, cognitive models of anxiety and implications for psychological therapy for this group. PMID- 24811969 TI - Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. AB - BACKGROUND: Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect. METHODS AND RESULTS: We performed an open-label, single center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6 1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC. CONCLUSIONS: This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each. PMID- 24811970 TI - Using injury severity to improve occupational injury trend estimates. AB - BACKGROUND: Hospitalization-based estimates of trends in injury incidence are also affected by trends in health care practices and payer coverage that may differentially impact minor injuries. This study assessed whether implementing a severity threshold would improve occupational injury surveillance. METHODS: Hospital discharge data from four states and a national survey were used to identify traumatic injuries (1998-2009). Negative binomial regression was used to model injury trends with/without severity restriction, and to test trend divergence by severity. RESULTS: Trend estimates were generally biased downward in the absence of severity restriction, more so for occupational than non occupational injuries. Restriction to severe injuries provided a markedly different overall picture of trends. CONCLUSIONS: Severity restriction may improve occupational injury trend estimates by reducing temporal biases such as increasingly restrictive hospital admission practices, constricting workers' compensation coverage, and decreasing identification/reporting of minor work related injuries. Injury severity measures should be developed for occupational injury surveillance systems. PMID- 24811971 TI - Mast cells in the periprosthetic breast capsule. AB - BACKGROUND: Symptomatic capsular contracture occurs in about 10 % of primary breast augmentations and in more than double that rate in reconstruction after mastectomy, especially in the setting of radiation. Mast cells, traditionally associated with immune response and inflammation, secrete profibrotic mediators and may play a role in capsule formation and contracture. We analyzed the mast cell and fibroblast populations in breast capsule tissue from patients who underwent capsular excision. METHODS: Capsule tissue was collected from patients who underwent exchange of tissue expanders for permanent implants, revision of reconstruction, or revision augmentation. Breast capsule tissues were prepared for histological analyses of mast cells, fibroblasts, and collagen. Mast cells and fibroblasts were isolated from capsule tissue and screened for mediators and receptor expression. RESULTS: In breast capsule tissue, the average numbers of mast cells and fibroblasts were 9 +/- 1/mm(2) and 33 +/- 10/mm(2), respectively. There were significantly more mast cells on the posterior side than on the anterior side of the capsule tissue (12 +/- 2 vs. 6 +/- 1/mm(2), p < 0.01). Baker grade IV capsules had an increased number of fibroblasts compared to Baker grade I capsules (93 +/- 9 vs. 40 +/- 19/mm(2), p < 0.001). In breast capsule tissue, mast cells contained renin, histamine, and TGF-beta, and their respective receptors, AT1R, H1R, and TGF-betaRI were expressed by fibroblasts. CONCLUSION: These data indicate that within breast capsule tissue mast cells contain mediators that may activate neighboring fibroblasts. Understanding the role of mast cells in pathologic periprosthetic breast capsule formation may lead to novel therapies to prevent and treat capsular contracture. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 24811972 TI - Critical care nurse work environments 2013: a status report. AB - BACKGROUND: The health of critical care nurse work environments has been shown to affect patient care outcomes as well as the job satisfaction and retention of registered nurses. The American Association of Critical-Care Nurses (AACN) Critical Care Nurse Work Environment Survey was first conducted in 2006 following the release of the AACN Standards for Establishing and Sustaining a Healthy Work Environment and was conducted again in 2008. This article reports the results of the third AACN Critical Care Nurse Work Environment Survey conducted in 2013. OBJECTIVE: To evaluate the current state of critical care nurse work environments. METHODS: A total of 8444 AACN members and constituents responded to an online survey. RESULTS: The overall health of critical care nurses' work environments has declined since 2008, as have nurses' perceptions of the quality of care. Respondents rated their overall work environment and factors associated with healthy work environments including quality of patient care, staffing, communication and collaboration, respect, physical and mental safety, moral distress, nursing leadership, support for certification and continuing education, meaningful recognition, job satisfaction, and career plans. Although some factors improved, declines in any factors are a concern. CONCLUSIONS: An increasing body of evidence has shown relationships between healthy nurse work environments and patient outcomes. The results of this 2013 survey identified areas in which the health of critical care nurse work environments needs attention and care, requiring the relentless true collaboration of everyone involved. PMID- 24811973 TI - Predictive value of ACR core set parameters for the development of rheumatoid arthritis in patients with positive anti-cyclic citrullinated peptide antibodies and undifferentiated arthritis. PMID- 24811974 TI - Hfq protein deficiency in Escherichia coli affects ColE1-like but not lambda plasmid DNA replication. AB - Hfq is a nucleic acid-binding protein involved in controlling several aspects of RNA metabolism. It achieves this regulatory function by modulating the translational activity and stability of different mRNAs, generally via interactions with stress-related small regulatory sRNAs. However, besides its role in the coordination of translation of bacterial mRNA, Hfq is also a nucleoid associated DNA-binding protein. Motivated by the above property of Hfq, we investigated if hfq gene mutation has implications for the regulation of DNA replication. Efficiency of ColE1-like (pMB1- and p15A replicons) and bacteriophage lambda-derived plasmids' replication has been investigated in wild type strain and otherwise isogenic hfq mutant of Escherichia coli. Significant differences in plasmid amount and kinetics of plasmid DNA synthesis were observed between the two tested bacterial hosts for ColE1-like replicons, but not for lambda plasmid. Furthermore, ColE1-like plasmids replicated more efficiently in wild-type cells than in the hfq mutant in the early exponential phase of growth, but less efficiently in late exponential and early stationary phases. Hfq levels in the wild-type host, estimated by Western-blotting, were increased at the latter phases relative to the former one. Moreover, effects of the hfq mutation on ColE1-like plasmid replication were impaired in the absence of the rom gene, coding for a protein enhancing RNA I-RNA II interactions during the control of the replication initiation. These results are discussed in the light of a potential mechanism by which Hfq protein may influence replication of some, but not all, replicons in E. coli. PMID- 24811975 TI - Biomarkers of vasospasm development and outcome in aneurysmal subarachnoid hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (SAH) is a neurologic emergency caused by a brain aneurysm burst, resulting in a bleeding into the subarachnoid space. Its incidence is estimated between 4 and 28/10,000 inhabitants and it is the main cause of sudden death from stroke. The prognosis of patients with SAH is directly related to neurological status on admission, to the magnitude of the initial bleeding, as well as to the development of cerebral vasospasm (CVS). Numerous researchers have studied the role of different biomarkers in CVS development. These biomarkers form part of the metabolic cascade that is triggered as a result of the SAH. Hence, among these metabolites we found biomarkers of oxidative stress, inflammation biomarkers, indicators of brain damage, and markers of vascular pathology. However, to the author knowledge, none of these biomarkers has been demonstrated as a useful tool for predicting neither CVS development nor outcome after SAH. In order to reach success on future researches, firstly it should be stated which pathophysiological process is mainly responsible for CVS development. Once this process has been determined, the temporal course of this pathophysiologic cascade should be characterized, and then, perform further studies on biomarkers already analyzed, as well as on new biomarkers not yet studied in the SAH pathology, focusing attention on the temporal course of the diverse metabolites and the sampling time for its quantification. PMID- 24811976 TI - Integrated enrichment analysis and pathway-centered visualization of metabolomics, proteomics, transcriptomics, and genomics data by using the InCroMAP software. AB - In systems biology, the combination of multiple types of omics data, such as metabolomics, proteomics, transcriptomics, and genomics, yields more information on a biological process than the analysis of a single type of data. Thus, data from different omics platforms is usually combined in one experimental setup to obtain insight into a biological process or a disease state. Particularly high accuracy metabolomics data from modern mass spectrometry instruments is currently more and more integrated into biological studies. Reflecting this trend, we extended InCroMAP, a data integration, analysis and visualization tool for genomics, transcriptomics, and proteomics data. Now, the tool is able to perform an integrated enrichment analysis and pathway-based visualization of multi-omics data and thus, it is suitable for the evaluation of comprehensive systems biology studies. PMID- 24811977 TI - Genome-enabled plant metabolomics. AB - The grand challenge currently facing metabolomics is that of comprehensitivity whilst next generation sequencing and advanced proteomics methods now allow almost complete and at least 50% coverage of their respective target molecules, metabolomics platforms at best offer coverage of just 10% of the small molecule complement of the cell. Here we discuss the use of genome sequence information as an enabling tool for peak identity and for translational metabolomics. Whilst we argue that genome information is not sufficient to compute the size of a species metabolome it is highly useful in predicting the occurrence of a wide range of common metabolites. Furthermore, we describe how via gene functional analysis in model species the identity of unknown metabolite peaks can be resolved. Taken together these examples suggest that genome sequence information is current (and likely will remain), a highly effective tool in peak elucidation in mass spectral metabolomics strategies. PMID- 24811978 TI - Recovery of oxygenated ignitable liquids by zeolites, Part II: Dual-mode heated passive headspace extraction. AB - Previous studies performed by our research group have suggested that zeolites are a suitable adsorbent for the recovery of oxygenates from fire debris through heated passive headspace extraction. Zeolite 13X, in particular, has been shown to be effective for recovering analytes with molecular diameters smaller than 10A. The primary aim of this study was to evaluate the addition of zeolite 13X to heated headspace extraction for the recovery of ignitable liquids. Comparative recoveries of petroleum and alcohol-based ignitable liquid mixtures were studied utilizing activated charcoal strips and zeolites, individually and in tandem. In the presence of both adsorption media within the same sample can, activated charcoal strips recovered the majority of gasoline components, while zeolites recovered the majority of oxygenated compounds. This phenomenon was attributed to the size exclusion properties, polarity, and available surface area of zeolites. This research supports the use of zeolites with activated charcoal strips in a "dual-mode" preparation for casework in which the presence of an ignitable liquid is suspected. The described method allows for the recovery and concentration of ignitable liquid residues in a single extraction procedure, whether the ignitable liquid is petroleum-based or oxygenated in nature. PMID- 24811979 TI - TACN-based oligomers with aromatic backbones for efficient nucleic acid delivery. AB - Cationic oligomers with a rigid aromatic backbone were first applied as non-viral gene delivery vectors. These materials showed better DNA condensation ability than their flexible analogues. In vitro transfection experiments revealed that the materials with more rigid backbone exhibited considerably higher TE and lower cytotoxicity than 25 kDa PEI. PMID- 24811980 TI - The connexin 30.3 of zebrafish homologue of human connexin 26 may play similar role in the inner ear. AB - The intercellular gap junction channels formed by connexins (CXs) are important for recycling potassium ions in the inner ear. CXs are encoded by a family of the CX gene, such as GJB2, and the mechanism leading to mutant connexin-associated diseases, including hearing loss, remains to be elucidated. In this study, using bioinformatics, we found that two zebrafish cx genes, cx27.5 and cx30.3, are likely homologous to human and mouse GJB2. During embryogenesis, zebrafish cx27.5 was rarely expressed at 1.5-3 h post-fertilization (hpf), but a relatively high level of cx27.5 expression was detected from 6 to 96 hpf. However, zebrafish cx30.3 transcripts were hardly detected until 9 hpf. The temporal experiment was conducted in whole larvae. Both cx27.5 and cx30.3 transcripts were revealed significantly in the inner ear by reverse transcription polymerase chain reaction (RT-PCR) and whole-mount in situ hybridization (WISH). In the HeLa cell model, we found that zebrafish Cx27.5 was distributed intracellularly in the cytoplasm, whereas Cx30.3 was localized in the plasma membrane of HeLa cells stably expressing Cx proteins. The expression pattern of zebrafish Cx30.3 in HeLa cells was more similar to that of cells expressing human CX26 than Cx27.5. In addition, we found that Cx30.3 was localized in the cell membrane of hair cells within the inner ear by immunohistochemistry (IHC), suggesting that zebrafish cx30.3 might play an essential role in the development of the inner ear, in the same manner as human GJB2. We then performed morpholino knockdown studies in zebrafish embryos to elucidate the physiological functions of Cx30.3. The zebrafish cx30.3 morphants exhibited wild-type-like and heart edema phenotypes with smaller inner ears at 72 hpf. Based on these results, we suggest that the zebrafish Cx30.3 and mammalian CX26 may play alike roles in the inner ear. Thus, zebrafish can potentially serve as a model for studying hearing loss disorders that result from human CX26 mutations. PMID- 24811981 TI - Behavioral responses of deafened guinea pigs to intracochlear electrical stimulation: a new rapid psychophysical procedure. AB - In auditory research the guinea pig is often preferred above rats and mice because of the easily accessible cochlea and because the frequency range of its hearing is more comparable to that of humans. Studies of the guinea-pig auditory system primarily apply histological and electrophysiological measures. Behavioral animal paradigms, in particular in combination with these histological and electrophysiological methods, are necessary in the development of new therapeutic interventions. However, the guinea pig is not considered an attractive animal for behavioral experiments. Therefore, the purpose of this study was to develop a behavioral task suitable for guinea pigs, that can be utilized in cochlear implant related research. Guinea pigs were trained in a modified shuttle-box in which a stream of air was used as unconditioned stimulus (UCS). A stream of air was preferred over conventionally used methods as electric foot-shocks since it produces less stress, which is a confounding factor in behavioral experiments. Hearing guinea pigs were trained to respond to acoustic stimuli. They responded correctly within only five sessions of ten minutes. The animals maintained their performance four weeks after the right cochlea was implanted with an electrode array. After systemic deafening, the animals responded in the first session immediately to intracochlear electrical stimulation. These responses were not affected by daily chronic electrical stimulation (CES). In conclusion, the present study demonstrates that guinea pigs can be trained relatively fast to respond to acoustic stimuli, and that the training has a lasting effect, which generalizes to intracochlear electrical stimulation after deafening. Furthermore, it demonstrates that bilaterally deafened guinea pigs with substantial (~50%) loss of spiral ganglion cells (SGCs), detect intracochlear electrical stimulation. PMID- 24811982 TI - The incidence and management of postoperative chylothorax after pulmonary resection and thoracic mediastinal lymph node dissection. AB - BACKGROUND: Our objective was to determine the incidence and optimal management of chylothorax after pulmonary resection with complete thoracic mediastinal lymph node dissection (MLND). METHODS: This is a retrospective review of patients who underwent pulmonary resection with MLND. RESULTS: Between January 2000 and December 2012, 2,838 patients underwent pulmonary resection with MLND by one surgeon (RJC). Forty-one (1.4%) of these patients experienced a chylothorax. Univariate analysis showed that lobectomy (p<0.001), a robotic approach (p=0.03), right-sided operations (p<0.001), and pathologic N2 disease (p=0.007) were significantly associated with the development of chylothorax. Multivariate analysis showed that lobectomy (p=0.011), a robotic approach (p=0.032), and pathologic N2 disease (p=0.027) remained predictors. All patients were initially treated with cessation of oral intake and 200 MUg subcutaneous somatostatin every 8 hours. If after 48 hours the chest tube output was less than 450 mL/day and the effluent was clear, patients was given a medium-chain triglyceride (MCT) diet and were observed for 48 hours in the hospital. If the chest tube output remained below 450 mL/day, the chest tube was removed, they were discharged home with directions to continue the MCT diet and to return in 2 weeks. Patients were instructed to consume a high-fat meal 24 hours before their clinic appointment. If the patient's chest roentgenogram was clear at that time, they were considered "treated." This approach was successful in 37 (90%) patients. The 4 patients in whom the initial treatment was unsuccessful underwent reoperation with pleurodesis and duct ligation. CONCLUSIONS: Chylothorax after pulmonary resection and MLND occurred in 1.4% of patients. Its incidence was higher in those with pathologic N2 disease and those who underwent robotic resection. Nonoperative therapy is almost always effective. PMID- 24811983 TI - Right ventricular unloading for heart failure related to Ebstein malformation. AB - BACKGROUND: Patients with Ebstein malformation (EM) and severe RV dilatation and dysfunction have increased operative risk. Early results with right ventricular unloading utilizing the bidirectional cavopulmonary shunt (BCPS) during repair of EM have been encouraging. We report our experience of the 1.5-ventricle repair strategy for this difficult group of patients. METHODS: Between July 1999 and January 2013, 62 patients with severe EM underwent BCPS at the time of tricuspid repair. Median age was 21.5 years (range, 9 months to 57 years), 51.6% were male, and 72.5% were children. Severe RV dilatation was present in all patients; severe RV dysfunction was present in 72.5% (n=45) and moderate to severe RV dysfunction in 22.5% (n=14). Mean RV systolic pressure was 32.7+/-0.7 mm Hg and mean PA pressure was 15.6+/-2.1 mm Hg. Mean preoperative left ventricular ejection fraction (LVEF) was 0.536+/-0.071; it was less than 40% in 10 patients (16.1%). New York Heart Association class III/IV heart failure was present in 43 patients (69.3%) preoperatively and 20 patients (32.2%) were initially referred for heart transplant evaluation. Prior EM surgery occurred in 35.4% (n=22; 8 prior valve repair, 8 prior valve replacement, Blalock-Taussig shunt in 4, atrial septal defect (ASD) closure in 2). RESULTS: Tricuspid repair was performed in 51.6% (n=32, 5 had re-repair). Bioprosthetic valve replacement was performed in 48.4% (n=30, 8 had rereplacement). The BCPS was a planned procedure in 53 patients (85.5%) because of RV dysfunction; BCPS was added after unsuccessful weaning from bypass in 7 (11.2%), and in the early postoperative period due to hemodynamic instability in 2. Concomitant procedures included ASD closure in 48.3%, maze in 38.7%, and mitral valve repair in 6.4%. Postoperative extracorporeal membrane oxygenation support was needed in 8 patients. Delayed chest closure was performed in 25.8%. Early mortality was 1.6% (n=1). Mean mechanical ventilation time was 69.7 hours. Mean intensive care unit and hospital stays were 5.4+/-3.5 and 10.7+/ 3.5 days, respectively. Mean follow-up was 3.6+/-2.6 years (maximum, 12.8 years). Patients (n=10) with low preoperative LVEF (0.362+/-0.035) improved to 0.517+/ 0.042 postoperatively (p=0.001). There was 1 late death in a patient with cystic fibrosis. Late reintervention was needed in 5 patients (8%). Late follow-up was available in 95% (n=59); all were acyanotic and 88% were in New York Heart Association functional class I/II. CONCLUSIONS: Concomitant BCPS is a useful adjunct in repair of advanced EM with severe RV dilatation and dysfunction. Operation can be performed with low early mortality. Intermediate-term survival and quality of life is good to excellent, and transplantation can be delayed or avoided in the majority. PMID- 24811984 TI - Patient genotypes impact survival after surgery for isolated congenital heart disease. AB - BACKGROUND: Survival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children. METHODS: This is an analysis of a cohort of nonsyndromic congenital heart disease patients who underwent cardiac surgery with cardiopulmonary bypass before 6 months of age (n=422). Six single nucleotide polymorphisms (SNPs) in six genes involved in oxidative stress and vascular response pathways, identified through a priori literature search, were tested for effects on transplant-free survival. Survival curves, adjusting for confounding covariates, were calculated using the Cox proportional hazard models. RESULTS: Long-term survival was strongly associated with vascular endothelial growth factor A gene SNP rs833069 (p=7.03*10(-4)) and superoxide dismutase 2 gene SNP rs2758331 (p=0.019). To test for joint effects of the two SNPs on transplant-free survival, the genotypes were grouped to form a risk score reflecting the cumulative number of risk alleles (0 to 4 alleles per patient). A higher risk score based on the VEGFA and SOD2 SNP genotypes was associated with worse transplant-free survival (p=3.02*10(-4)) after confounder adjustment. The total burden of risk alleles was additive; subjects with the highest risk score of 4 (n=59 subjects, 14.2% of the cohort) had a total covariate-adjusted hazard ratio of 15.64 for worse transplant-free survival. CONCLUSIONS: After cardiac surgery, infants who are homozygous for the high-risk alleles for both the VEGFA and SOD2 SNPs have an approximately 16-fold increased risk of death or heart transplant, suggesting that genetic variants are important modifiers of survival after surgery for congenital heart disease. PMID- 24811985 TI - Effects of aneurysm on the mechanical properties and histologic structure of aortic sinuses. AB - BACKGROUND: Aortic root aneurysms are relatively uncommon but their rupture is a detrimental event with acute hemodynamic compromise and high mortality, and there are few available data on their mechanical properties, although aneurysm rupture occurs when hemodynamic stresses exceed wall strength. This study aimed to fill this gap by examining the effect of aneurysm on the mechanical and structural properties of aortic sinuses. METHODS: Sinus tissue was procured from 16 aneurysmal patients during surgical repair and from 18 age-matched nonaneurysmal autopsy subjects, and grouped by age (young versus old), region (left versus right versus noncoronary), and direction (circumferential versus longitudinal). The tissue was submitted to histologic evaluation of elastin/collagen contents and to mechanical testing beyond rupture for the determination of failure properties and material characterization by the Fung-type model. RESULTS: Contrasting the direction-dependent (anisotropic) material constants and failure properties, and the primarily circumferential reinforcement of elastin/collagen fibers in healthy sinuses, near-similar (isotropic) properties and arbitrarily aligned fibers were found in the aneurysmal right and left coronary sinuses, together with less anisotropic properties in the aneurysmal noncoronary sinus. Variations between aneurysmal and healthy sinuses were comparable in young and old subjects. The former displayed significantly higher failure stress, failure stretch, and peak elastic modulus, justified by their increased elastin/collagen contents. CONCLUSIONS: We submit evidence of more isotropic histomechanical properties in the aneurysmal sinuses that seem consistent with the more axisymmetric stresses exerted on them owing to their more spherical shape, compared with the nondilated healthy sinuses that presented marked anisotropic properties. PMID- 24811986 TI - Ultrastructural features of spermatogenesis in Melanorivulus punctatus (Cyprinodontiformes: Rivulidae). AB - Fish belonging to the family Rivulidae possess one of the most complex reproductive systems. Rivulus, a genus of freshwater fish in the Rivulidae family, was recently reclassified into five genera, including Melanorivulus. Its type species, M. punctatus, is widely distributed and probably represents a species complex. The ultrastructure of sperm has been broadly used in systematics, and we hereby describe the ultrastructural features of spermatogenesis in M. punctatus. Ten M. punctatus males were collected from the reservoir of Parque Estadual da Quineira, municipality of Chapada dos Guimaraes, Mato Grosso, Brazil, and prepared for analysis by light microscopy and transmission electron microscopy. M. punctatus undergoes cystic spermatogenesis. Its cysts consist of groups of germ cells that are in synchronous development and are surrounded by cytoplasmic projections of Sertoli cells. With the breakdown of the cysts, the spermatozoa are released and their maturation is completed in the duct, where part of the cytoplasmic material is discarded through the vesicles. The mature spermatozoon is characterized by a spherical head with homogeneously condensed chromatin, a symmetric midpiece consisting of a pair of perpendicular centrioles, a ring of mitochondria, several vesicles, and one flagellum medial to the nucleus. Early stages of spermatogenesis show no peculiarities; however, in spermiogenesis, we observed that the spermatids remain interconnected by cytoplasmic bridges and have pockets of residual cytoplasm. The sperm is of the aquasperm type and is similar to that observed in the members of the family Rivulidae. The spermatozoa have a single flagellum that consists of a classic axoneme (9+2), as found in most groups of fish, despite the lateral extensions. PMID- 24811987 TI - Orientation relationship between alpha-Fe precipitate and alpha-Al2O3 matrix in iron-implanted sapphire. AB - Fe ions were implanted into alpha-Al2O3 single crystals (sapphire) at room temperature and annealed in a reducing atmosphere. The orientation relationships (ORs) between alpha-Fe particles and sapphire matrix were investigated using transmission electron microscopy (TEM). All the alpha-Fe particles have the orientation relationship (OR) of (111)alpha-Fe||(0001)sapphire and [11-0]alpha Fe||[112-0]sapphire with sapphire. This OR is predicted precisely by the coincidence of reciprocal lattice points (CRLP) method. The other OR of (110)alpha-Fe||(0001)sapphire and [111]alpha-Fe||[51-4-0]sapphire reported before is confirmed by the same method to be one of the secondary preferred orientation relationships in the alpha-Fe/sapphire system. PMID- 24811988 TI - Vacancy ordering and superstructure formation in dry and hydrated strontium tantalate perovskites: a TEM perspective. AB - Crystal structures of Sr4(Sr2Ta2)O11 and Sr4(Sr1.92Ta2.08)O11.12, synthesized by solid state reaction technique in dry and hydrated state have been studied mainly using Transmission Electron Microscopy. Due to the lesser ability of X-rays to probe details in oxygen sublattice, the change in crystal symmetry due to ordering of oxygen vacancies could be detected better using Transmission Electron Microscopy. After detailed analysis through TEM, it was observed that no major change occurs in the cation sublattice. The TEM observations are compared with XRD data and discussed. The crystal symmetries and corresponding unit cells of all the perovskites based on the ordering of oxygen vacancies is deduced. Crystal unit cells based on the observations are proposed with ideal atomic coordinates. Finally an attempt is made to explain the water uptake behaviour of these perovskites based on the proposed crystal structure. PMID- 24811989 TI - TEM preparation methods and influence of radiation damage on the beam sensitive CaCO3 shell of Emiliania huxleyi. AB - The ultrastructure of biologically formed calcium carbonate crystals like the shell of Emiliania huxleyi depends on the environmental conditions such as pH value, temperature and salinity. Therefore, they can be used as indicator for climate changes. However, for this a detailed understanding of their crystal structure and chemical composition is required. High resolution methods like transmission electron microscopy can provide those information on the nanoscale, given that sufficiently thin samples can be prepared. In our study, we developed sample preparation techniques for cross-section and plan-view investigations and studied the sample stability under electron bombardment. In addition to the biological material (Emiliania huxleyi) we also prepared mineralogical samples (Iceland spar) for comparison. High resolution transmission electron microscopy imaging, electron diffraction and electron energy-loss spectroscopy studies revealed that all prepared samples are relatively stable under electron bombardment at an acceleration voltage of 300 kV when using a parallel illumination. Above an accumulated dose of ~10(5) e/nm2 the material--independent whether its origin is biological or geological--transformed to poly-crystalline calcium oxide. PMID- 24811990 TI - Influence of TEM specimen preparation on chemical composition of Pb(Mg1/3Nb2/3)O3 PbTiO3 single crystals. AB - The influences of different transmission electron microscopy (TEM) specimen preparation techniques on the chemical composition of Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) single crystals was studied. Ion-milled samples where no cooling with liquid nitrogen (L-N2) was applied show permanently changed composition also deep inside the bulk material. When the PMN-PT samples were cooled to L-N2 temperature during the ion-milling process and in addition lower accelerating voltages were used, the chemical composition was altered only in the thinnest parts close to the specimen edge. Samples prepared using only tripod polishing technique show compositional irregularities close to the specimen edge. For the preparation of lead-containing samples, such as PMN-PT single crystals, a combination of tripod polishing and short Ar-ion-milling at low accelerating voltages while cooling the samples to liquid nitrogen temperature proved to be the most suitable to obtain artefact-free electron-transparent TEM lamellae. PMID- 24811991 TI - Are the evidences of forensic entomology preserved in ethanol suitable for SEM studies? AB - In forensic practice, the use of arthropod evidences to estimate the postmortem interval is a very good approach when the elapsed time from death is long, but it requires the correct identification of the specimens. This is a crucial step, not always easy to achieve, in particular when dealing with immature specimens. In this case, scanning electronic microscopy (SEM) can be useful, but the techniques used to preserve specimens in forensic practice are usually different from those used to prepare specimens for SEM studies. To determine whether forensic evidences preserving techniques are also compatible with SEM analysis, we have compared specimens of all the immature stages of Calliphora vicina Robineau Desvoidy, 1830 (Diptera, Calliphoridae) preserved in 70% ethanol, with others prepared with aldehydic fixative techniques that are more appropriate for SEM studies. At the same time, two drying techniques have also been compared with both fixative techniques, the critical point drying and air-drying following with hexamethyldisilizane treatment (HMDS). Our results indicate that there are not basis against recommending the use of ethanol to preserve forensic entomological evidences and that both drying methods appear to offer good results for second and third instar larvae, although HMDS behaves better with eggs and pupae. PMID- 24811992 TI - Practical aspects of strain measurement in thin SiGe layers by (004) dark-field electron holography in Lorentz mode. AB - Dark-field electron holography (DFEH) is a powerful transmission electron microscopy technique for mapping strain with nanometer resolution and high precision. However the technique can be difficult to set up if some practical steps are not respected. In this article, several measurements were performed on thin Si(1-x)Gex layers using (004) DFEH in Lorentz mode. Different practical aspects are discussed such as sample preparation, reconstruction of the holograms and interpretation of the strain maps in terms of sensitivity and accuracy. It was shown that the measurements are not significantly dependent on the preparation tool. Good results can be obtained using both FIB and mechanical polishing. Usually the most important aspect is a precise control of the thickness of the sample. A problem when reconstructing (004) dark-field holograms is the relatively high phase gradient that characterises the strained regions. It can be difficult to perform reconstructions with high sensitivity in both strained and unstrained regions. Here we introduce simple methods to minimise the noise in the different regions using a specific mask shape in Fourier space or by combining several reconstructions. As a test, DFEH was applied to the characterization of eight Si(1-x)Gex samples with different Ge concentrations. The sensitivity of the strain measured in the layers varies between 0.08% and 0.03% for spatial resolutions of 3.5-7 nm. The results were also compared to finite element mechanical simulations. A good accuracy of +/-0.1% between experiment and simulation was obtained for strains up to 1.5% and +/-0.25% for strains up to 2.5%. PMID- 24811993 TI - Serial sectioning methods for 3D investigations in materials science. AB - A variety of methods for the investigation and 3D representation of the inner structure of materials has been developed. In this paper, techniques based on slice and view using scanning microscopy for imaging are presented and compared. Three different methods of serial sectioning combined with either scanning electron or scanning ion microscopy or atomic force microscopy (AFM) were placed under scrutiny: serial block-face scanning electron microscopy, which facilitates an ultramicrotome built into the chamber of a variable pressure scanning electron microscope; three-dimensional (3D) AFM, which combines an (cryo-) ultramicrotome with an atomic force microscope, and 3D FIB, which delivers results by slicing with a focused ion beam. These three methods complement one another in many respects, e.g., in the type of materials that can be investigated, the resolution that can be obtained and the information that can be extracted from 3D reconstructions. A detailed review is given about preparation, the slice and view process itself, and the limitations of the methods and possible artifacts. Applications for each technique are also provided. PMID- 24811994 TI - A token centric part-of-speech tagger for biomedical text. AB - OBJECTIVE: Difficulties with part-of-speech (POS) tagging of biomedical text is accessing and annotating appropriate training corpora. These difficulties may result in POS taggers trained on corpora that differ from the tagger's target biomedical text (cross-domain tagging). In such cases where training and target corpora differ tagging accuracy decreases. This paper presents a POS tagger for cross-domain tagging called TcT. METHODS AND MATERIAL: TcT estimates a tag's likelihood for a given token by combining token collocation probabilities and the token's tag probabilities calculated using a Naive Bayes classifier. We compared TcT to three POS taggers used in the biomedical domain (mxpost, Brill and TnT). We trained each tagger on a non-biomedical corpus and evaluated it on biomedical corpora. RESULTS: TcT was more accurate in cross-domain tagging than mxpost, Brill and TnT (respective averages 83.9, 81.0, 79.5 and 78.8). CONCLUSION: Our analysis of tagger performance suggests that lexical differences between corpora have more effect on tagging accuracy than originally considered by previous research work. Biomedical POS tagging algorithms may be modified to improve their cross-domain tagging accuracy without requiring extra training or large training data sets. Future work should reexamine POS tagging methods for biomedical text. This differs from the work to date that has focused on retraining existing POS taggers. PMID- 24811995 TI - Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD. AB - BACKGROUND: Bacteria play a role in the onset and perpetuation of intestinal inflammation in IBD. Compositional alterations may also change the metabolic capacities of the gut bacteria. OBJECTIVE: To examine the metabolic activity of the microbiota of patients with Crohn's disease (CD), UC or pouchitis compared with healthy controls (HC) and determine whether eventual differences might be related to the pathogenesis of the disease. METHODS: Faecal samples were obtained from 40 HC, 83 patients with CD, 68 with UC and 13 with pouchitis. Disease activity was assessed in CD using the Harvey-Bradshaw Index, in UC using the UC Disease Activity Index and in pouchitis using the Pouchitis Disease Activity Index. Metabolite profiles were analysed using gas chromatography-mass spectrometry. RESULTS: The number of metabolites identified in HC (54) was significantly higher than in patients with CD (44, p<0.001), UC (47, p=0.042) and pouchitis (43, p=0.036). Multivariate discriminant analysis predicted HC, CD, UC and pouchitis group membership with high sensitivity and specificity. The levels of medium-chain fatty acids (MCFAs: pentanoate, hexanoate, heptanoate, octanoate and nonanoate), and of some protein fermentation metabolites, were significantly decreased in patients with CD, UC and pouchitis. Hexanoate levels were inversely correlated to disease activity in CD (correlation coefficient=-0.157, p=0.046), whereas a significant positive correlation was found between styrene levels and disease activity in UC (correlation coefficient=0.338, p=0.001). CONCLUSIONS: Faecal metabolic profiling in patients with IBD relative to healthy controls identified MCFAs as important metabolic biomarkers of disease-related changes. TRIAL REGISTRATION NO: NCT 01666717. PMID- 24811997 TI - A rare cause of dysphagia in a young Caucasian man. PMID- 24811996 TI - Therapeutic targeting of GSK3beta enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C. AB - OBJECTIVE: Impaired adaptive response to oxidative injuries is a fundamental mechanism central to the pathogenesis of chronic hepatitis C (CHC). Glycogen synthase kinase (GSK) 3beta is an indispensable regulator of the oxidative stress response. However, the exact role of GSK3beta in CHC is uncertain and was examined. DESIGN: GSK3beta and Nrf2 signalling pathways were examined in JFH1 HCV infected Huh7.5.1 hepatocytes, and also in liver biopsy specimens from CHC patients. RESULTS: HCV infection elicited prominent Nrf2 antioxidant response in hepatocytes, marked by elevated expression of the Nrf2-dependent molecule haem oxygenase-1 and subsequent protection from apoptotic cell death. Inhibitory phosphorylation of GSK3beta seems to be essential and sufficient for HCV-induced Nrf2 response. Mechanistically, GSK3beta associated and physically interacted with Nrf2 in hepatocytes. In silico analysis revealed that Nrf2 encompasses multiple GSK3beta phosphorylation consensus motifs, denoting Nrf2 as a cognate substrate of GSK3beta. In the presence of TGFbeta1, the HCV-induced GSK3beta phosphorylation was blunted via a protein phosphatase 1-dependent mechanism and the cytoprotective Nrf2 response drastically impaired. This effect was counteracted by lithium, a selective inhibitor of GSK3beta. In liver biopsy specimens from CHC patients, the expression of phosphorylated GSK3beta positively correlated with Nrf2 expression and was inversely associated with the degree of liver injury. Moreover, CHC patients who received long-term lithium carbonate therapy primarily for concomitant psychiatric disorders exhibited much less liver injury, associated with enhanced hepatic expression of Nrf2. CONCLUSIONS: Inhibition of GSK3beta exerts hepatoprotection in CHC possibly through its direct regulation of Nrf2 antioxidant response. PMID- 24811998 TI - Intestinal mucus affinity and biological activity of an orally administered antibacterial and anti-inflammatory peptide. AB - OBJECTIVE: Antimicrobial peptides (AMP) provide protection from infection by pathogenic microorganisms and restrict bacterial growth at epithelial surfaces to maintain mucosal homeostasis. In addition, they exert a significant anti inflammatory activity. Here we analysed the anatomical distribution and biological activity of an orally administered AMP in the context of bacterial infection and host-microbial homeostasis. DESIGN: The anatomical distribution as well as antibacterial and anti-inflammatory activity of the endogenous AMP cryptdin 2 and the synthetic peptide Pep19-2.5 at the enteric mucosal surface were analysed by immunostaining, functional viability and stimulation assays, an oral Salmonella enterica subsp. enterica sv. Typhimurium (S. Typhimurium) model and comparative microbiota analysis. RESULTS: Endogenous cryptdin 2 was found attached to bacteria of the enteric microbiota within the intestinal mucus layer. Similarly, the synthetic peptide Pep19-2.5 attached rapidly to bacterial cells, exhibited a marked affinity for the intestinal mucus layer in vivo, altered the structural organisation of endotoxin in a mucus matrix and demonstrated potent anti-inflammatory and antibacterial activity. Oral Pep19-2.5 administration induced significant changes in the composition of the enteric microbiota as determined by high-throughput 16S rDNA sequencing. This may have contributed to the only transient improvement of the clinical symptoms after oral infection with S. Typhimurium. CONCLUSIONS: Our findings demonstrate the anti-inflammatory activity and mucus affinity of the synthetic AMP Pep19-2.5 and characterise the influence on microbiota composition and enteropathogen infection after oral administration. PMID- 24811999 TI - Tracing PAKs from GI inflammation to cancer. AB - P-21 activated kinases (PAKs) are effectors of Rac1/Cdc42 which coordinate signals from the cell membrane to the nucleus. Activation of PAKs drive important signalling pathways including mitogen activated protein kinase, phospoinositide 3 kinase (PI3K/AKT), NF-kappaB and Wnt/beta-catenin. Intestinal PAK1 expression increases with inflammation and malignant transformation, although the biological relevance of PAKs in the development and progression of GI disease is only incompletely understood. This review highlights the importance of altered PAK activation within GI inflammation, emphasises its effect on oncogenic signalling and discusses PAKs as therapeutic targets of chemoprevention. PMID- 24812000 TI - Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease. AB - OBJECTIVE: Current diagnostic methods for gastro-oesophageal reflux disease (GORD) have moderate sensitivity/specificity and can be invasive and expensive. Pepsin detection in saliva has been proposed as an 'office-based' method for GORD diagnosis. The aims of this study were to establish normal values of salivary pepsin in healthy asymptomatic subjects and to determine its value to discriminate patients with reflux-related symptoms (GORD, hypersensitive oesophagus (HO)) from functional heartburn (FH). DESIGN: 100 asymptomatic controls and 111 patients with heartburn underwent MII-pH monitoring and simultaneous salivary pepsin determination on waking, after lunch and dinner. Cut off value for pepsin positivity was 16 ng/mL. Patients were divided into GORD (increased acid exposure time (AET), n=58); HO (normal AET and + Symptom Association Probability (SAP), n=26) and FH (normal AET and-SAP, n=27). RESULTS: 1/3 of asymptomatic subjects had pepsin in saliva at low concentration (0(0 59)ng/mL). Patients with GORD and HO had higher prevalence and pepsin concentration than controls (HO, 237(52-311)ng/mL and GORD, 121(29 252)ng/mL)(p<0.05). Patients with FH had low prevalence and concentration of pepsin in saliva (0(0-40) ng/mL). A positive test had 78.6% sensitivity and 64.9% specificity for diagnosis of GORD+HO (likelihood ratio: 2.23). However, one positive sample with >210 ng/mL pepsin suggested presence of GORD+HO with 98.2% specificity (likelihood ratio: 25.1). Only 18/84 (21.4%) of GORD+HO patients had 3 negative samples. CONCLUSION: In patients with symptoms suggestive of GORD, salivary pepsin testing may complement questionnaires to assist office-based diagnosis. This may lessen the use of unnecessary antireflux therapy and the need for further invasive and expensive diagnostic methods. PMID- 24812001 TI - Colorectal cancer screening uptake over three biennial invitation rounds in the English bowel cancer screening programme. AB - OBJECTIVE: To examine patterns of colorectal cancer (CRC) screening uptake over three biennial invitation rounds in the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) in England. METHODS: We analysed data from the BCSP's Southern Hub for individuals (n=62,099) aged 60-64 years at the time of first invitation to screening with a follow-up period that allowed for two further biennial invitations. Data on sex, age and a neighbourhood-level measure of socioeconomic deprivation were used in the analysis. Outcomes included uptake of guaiac-based faecal occult blood (gFOB) test screening, inadequate gFOB screening (>=1 test kit(s) returned but failed to complete further gFOB tests needed to reach a conclusive test result), test positivity, compliance with follow-up examinations (usually colonoscopy) and diagnostic outcomes. RESULTS: Overall gFOB uptake was 57.4% in the first, 60.9% in the second and 66.2% in third biennial invitation round. This resulted in 70.1% of the initial cohort having responded at least once, 60.7% at least twice and 44.4% three times. Participation in the first round was strongly predictive of participation in the second round ('Previous Responders': 86.6% vs. 'Previous Non-Responders': 23.1%). Participation in the third round was highest among 'Consistent Screeners' (94.5%), followed by 'Late Entrants' (78.0%), 'Dropouts' (59.8%) and 'Consistent Non-Responders' (14.6%). Socioeconomic inequalities in uptake were observed across the three rounds, but sex inequalities decreased over rounds. Inadequate gFOB screening was influenced by screening history and socioeconomic deprivation. Screening history was the only significant predictor of follow-up compliance. CONCLUSIONS: Screening history is associated with overall gFOB uptake, inadequate gFOB screening and follow-up compliance. Socioeconomic deprivation is also consistently associated with lower gFOB uptake and inadequate gFOB screening. Improving regular screening among identified 'at-risk' groups is important for the effectiveness of CRC screening programmes. PMID- 24812003 TI - Spontaneous pneumothorax. PMID- 24812002 TI - Endoderm-specific deletion of Tbx1 reveals an FGF-independent role for Tbx1 in pharyngeal apparatus morphogenesis. AB - BACKGROUND: The T-box transcription factor Tbx1, is essential for the normal development of multiple organ systems in the embryo. One of the most striking phenotypes in Tbx1-/- embryos is the failure of the caudal pharyngeal pouches to evaginate from the foregut endoderm. Despite considerable interest in the role of Tbx1 in development, the mechanisms whereby Tbx1 controls caudal pouch formation have remained elusive. In particular, the question as to how Tbx1 expression in the pharyngeal endoderm regulates pharyngeal pouch morphogenesis in the mouse embryo is not known. RESULTS: To address this question, we produced mouse embryos in which Tbx1 was specifically deleted from the pharyngeal endoderm and, as expected, embryos failed to form caudal pharyngeal pouches. To determine the molecular mechanism, we examined expression of Fgf3 and Fgf8 ligands and downstream effectors. Although Fgf8 expression is greatly reduced in Tbx1 deficient endoderm, FGF signaling levels are unaffected. Furthermore, pouch morphogenesis is only partially perturbed by the loss of both Fgf3 and Fgf8 from the endoderm, indicating that neither are required for pouch formation. CONCLUSIONS: Tbx1 deletion from the pharyngeal endoderm is sufficient to cause caudal pharyngeal arch segmentation defects by FGF-independent effectors that remain to be identified. PMID- 24812004 TI - Russia's ban on methadone for drug users in Crimea will worsen the HIV/AIDS epidemic and risk public health. PMID- 24812005 TI - NHS finances: the tanker en route for the iceberg. PMID- 24812006 TI - Parahydrogen-induced polarization of carboxylic acids: a pilot study of valproic acid and related structures. AB - Parahydrogen-induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non-Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. (13)C), thus improving the signal-to-noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the (1)H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized (13)C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP-based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. PMID- 24812007 TI - Bilateral pallidal stimulation for sargoglycan epsilon negative myoclonus. AB - We report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in two patients with myoclonus dystonia/essential myoclonus who lack mutations in the epsilon sarcoglycan gene. The primary outcome measures were the Burke-Fahn-Marsden Dystonia Scale motor severity and the Unified Myoclonus Rating Scale scores, and the secondary outcome measure was the 36-item Short Form Health Survey score at the last postoperative follow up. Neuronal firing rates were also calculated from microelectrode recordings. At the last postoperative follow-up (16 weeks for Patient 1 and 18 weeks for Patient 2), there was 57.1% (Patient 1) improvement in the Burke-Fahn-Marsden Dystonia Scale motor severity score and 31.3% (Patient 1) and 69% (Patient 2) in the Unified Myoclonus Rating Scale score while individual SF-36 scores showed improvement in most subdomains. Bilateral globus pallidus internus deep brain stimulation can be effective in ameliorating epsilon sarcoglycan negative myoclonus with or without concurrent dystonia. Whether an epsilon sarcoglycan negative status represents a less favorable prognostic factor for pallidal deep brain stimulation remains to be elucidated. PMID- 24812008 TI - Neurocognitive assessment in adult-onset primary cranial cervical dystonia - response to the letter. PMID- 24812009 TI - Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. AB - Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of U.S. adults and dose-dependently associated with obesity and non alcoholic fatty liver disease (NAFLD). PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator activated receptors (PPARs), liver-X-receptor (LXRalpha), and farnesoid-X receptor (FXR). This study evaluates Aroclor 1260, a PCB mixture with congener composition mimicking that of human adipose tissue, and selected congeners, as potential ligands for these receptors utilizing human hepatoma-derived (HepG2) and primate-derived (COS-1) cell lines, and primary human hepatocytes. Aroclor 1260 (20 MUg/ml) activated AhR, and PCB 126, a minor component, was a potent inducer. Aroclor 1260 activated PXR in a simple concentration-dependent manner at concentrations >=10 MUg/ml. Among the congeners tested, PCBs 138, 149, 151, 174, 183, 187, and 196 activated PXR. Aroclor 1260 activated CAR2 and CAR3 variants at lower concentrations and antagonize CAR2 activation by the CAR agonist, CITCO, at higher concentrations (>=20 MUg/ml). Additionally, Aroclor 1260 induced CYP2B6 in primary hepatocytes. At subtoxic doses, Aroclor 1260 did not activate LXR or FXR and had no effect on LXR- or FXR-dependent induction by the agonists T0901317 or GW4064, respectively. Aroclor 1260 (20 MUg/ml) suppressed PPARalpha activation by the agonist nafenopin, although none of the congeners tested demonstrated significant inhibition. The results suggest that Aroclor 1260 is a human AhR, PXR and CAR3 agonist, a mixed agonist/antagonist for CAR2, and an antagonist for human PPARalpha. PMID- 24812010 TI - Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. AB - Acrolein is a major reactive component of vehicle exhaust, and cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation, and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high-throughput technology, we found that treatment of cultured human umbilical vein endothelial cells with acrolein led to a significant (>1.5-fold) upregulation of 12, and downregulation of 15, miRNAs. Among the miRNAs upregulated were members of the let-7 family and this upregulation was associated with decreased expression of their protein targets, beta3 integrin, Cdc34, and K-Ras. Exposure to acrolein attenuated beta3 integrin-dependent migration and reduced Akt phosphorylation in response to insulin. These effects of acrolein on endothelial cell migration and insulin signaling were reversed by expression of a let-7a inhibitor. Also, inhalation exposure of mice to acrolein (1 ppm x 6 h/day x 4 days) upregulated let-7a and led to a decrease in insulin-stimulated Akt phosphorylation in the aorta. These results suggest that acrolein exposure has broad effects on endothelial miRNA repertoire and that attenuation of endothelial cell migration and insulin signaling by acrolein is mediated in part by the upregulation of let 7a. This mechanism may be a significant feature of vascular injury caused by inflammation, oxidized lipids, and exposure to environmental pollutants. PMID- 24812011 TI - High-throughput multi-parameter profiling of electrophysiological drug effects in human embryonic stem cell derived cardiomyocytes using multi-electrode arrays. AB - Human stem cell derived cardiomyocytes (hESC-CM) provide a potential model for development of improved assays for pre-clinical predictive drug safety screening. We have used multi-electrode array (MEA) analysis of hESC-CM to generate multi parameter data to profile drug impact on cardiomyocyte electrophysiology using a panel of 21 compounds active against key cardiac ion channels. Our study is the first to apply multi-parameter phenotypic profiling and clustering techniques commonly used for high-content imaging and microarray data to the analysis of electrophysiology data obtained by MEA analysis. Our data show good correlations with previous studies in stem cell derived cardiomyocytes and demonstrate improved specificity in compound risk assignment over convention single parametric approaches. These analyses indicate great potential for multi parameter MEA data acquired from hESC-CM to enable drug electrophysiological liabilities to be assessed in pre-clinical cardiotoxicity assays, facilitating informed decision making and liability management at the optimum point in drug development. PMID- 24812012 TI - Glutathione-mediated detoxification of halobenzoquinone drinking water disinfection byproducts in T24 cells. AB - Halobenzoquinones (HBQs) are a new class of drinking water disinfection byproducts (DBPs) and are capable of producing reactive oxygen species and causing oxidative damage to proteins and DNA in T24 human bladder carcinoma cells. However, the exact mechanism of the cytotoxicity of HBQs is unknown. Here, we investigated the role of glutathione (GSH) and GSH-related enzymes including glutathione S-transferase (GST) and glutathione peroxidase (GPx) in defense against HBQ-induced cytotoxicity in T24 cells. The HBQs are 2,6-dichloro-1,4 benzoquinone (DCBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ), 2,3,6 trichloro-1,4-benzoquinone (TriCBQ), and 2,6-dibromobenzoquinone (DBBQ). We found that depletion of cellular GSH could sensitize cells to HBQs and extracellular GSH supplementation could attenuate HBQ-induced cytotoxicity. HBQs caused significant cellular GSH depletion and increased cellular GST activities in a concentration-dependent manner. Our mass spectrometry study confirms that HBQs can conjugate with GSH, explaining in part the mechanism of GSH depletion by HBQs. The effects of HBQs on GPx activity are compound dependent; DCMBQ and DBBQ decrease cellular GPx activities, whereas DCBQ and TriCBQ have no significant effects. Pearson correlation analysis shows that the cellular GSH level is inversely correlated with ROS production and cellular GST activity in HBQ-treated cells. These results support a GSH and GSH-related enzyme-mediated detoxification mechanism of HBQs in T24 cells. PMID- 24812013 TI - Biotin-responsive basal ganglia disease: neuroimaging features before and after treatment. AB - BACKGROUND AND PURPOSE: Biotin-responsive basal ganglia disease is an autosomal recessive neurometabolic disorder presenting with subacute encephalopathy that can cause death if left untreated. The purpose of this study is to assess the neuroimaging and clinical features of the disease before and after treatment with biotin. MATERIALS AND METHODS: We retrospectively reviewed the clinical, laboratory, and neuroimaging features of 15 genetically-proved Middle Eastern cases of biotin-responsive basal ganglia disease. Brain MR imaging was done at the onset of symptoms in all cases and within 2-8 weeks after biotin and thiamine therapy in 14 patients. The MR imaging datasets were analyzed according to lesion location, extent, and distribution. RESULTS: Brain MR imaging showed bilateral lesions in the caudate nuclei with complete or partial involvement of the putamen and sparing of the globus pallidus in all cases. In 80%, discrete abnormal signals were observed in the mesencephalon, cerebral cortical-subcortical regions, and thalami. In 53%, when the disease was advanced, patchy deep white matter affection was found. The cerebellum was involved in 13.3%. The signal abnormality of the mesencephalon, cortex, and white matter disappeared after treatment whereas the caudate and putamen necrosis persisted in all patients, including those who became asymptomatic. CONCLUSIONS: Biotin-responsive basal ganglia disease is a treatable underdiagnosed disease. It should be suspected in pediatric patients with unexplained encephalopathy whose brain MR imaging shows bilateral and symmetric lesions in the caudate heads and putamen, with or without involvement of mesencephalon, thalami, and cortical-subcortical regions, as the therapeutic trial of biotin and thiamine can be lifesaving. PMID- 24812014 TI - Hyperintense basilar artery on FLAIR MR imaging: diagnostic accuracy and clinical impact in patients with acute brain stem stroke. AB - BACKGROUND AND PURPOSE: FLAIR-hyperintense vessels are known to be a sign of sluggish collateral blood flow in hemispheric vessel occlusion. Additionally, they seem to have a prognostic implication. The aim of the current study was to evaluate the hyperintense configuration of the basilar artery (FLAIR-hyperintense basilar artery) as a marker of basilar artery occlusion and as a predictor of patient outcome. MATERIALS AND METHODS: We retrospectively identified 20 patients with basilar artery occlusion who initially underwent MR imaging with subsequent DSA. The diagnostic accuracy of the FLAIR-hyperintense basilar artery sign was tested by 4 independent readers in a case-control design, and the relation among FLAIR-hyperintense basilar artery and DWI posterior circulation-ASPECTS, patient outcome, and patient survival was evaluated. To grade the extent of the FLAIR hyperintense basilar artery sign, we generated a score by counting the number of sections from the basilar tip to the foramen magnum in which a hyperintense signal in the vessel lumen was present multiplied by the section thickness. RESULTS: The FLAIR-hyperintense basilar artery sign showed moderate sensitivity (65%-95%) but very good specificity (95%-100%) and accuracy (85%-93%) for the detection of basilar artery occlusion. Substantial or excellent inter-reader agreement was observed (Cohen kappa, 0.64-0.85). The FLAIR-hyperintense basilar artery inversely correlated with the posterior circulation-ASPECTS (r = -0.67, P = .01). Higher FLAIR-hyperintense basilar artery scores were associated with patient death (28.3 +/- 13.7 versus 13.4 +/- 11.1, P < .05). CONCLUSIONS: The FLAIR-hyperintense basilar artery sign proved to be a valuable marker of vessel occlusion and may substantially support the diagnosis of basilar artery occlusion. The established FLAIR-hyperintense basilar artery score may be helpful for the prediction of individual patient survival. PMID- 24812015 TI - Cost-effectiveness of CT angiography and perfusion imaging for delayed cerebral ischemia and vasospasm in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Delayed cerebral ischemia and vasospasm are significant complications following SAH leading to cerebral infarction, functional disability, and death. In recent years, CTA and CTP have been used to increase the detection of delayed cerebral ischemia and vasospasm. Our aim was to perform comparative-effectiveness and cost-effectiveness analyses evaluating CTA and CTP for delayed cerebral ischemia and vasospasm in aneurysmal SAH from a health care payer perspective. MATERIALS AND METHODS: We developed a decision model comparing CTA and CTP with transcranial Doppler sonography for detection of vasospasm and delayed cerebral ischemia in SAH. The clinical pathways were based on the "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association" (2012). Outcome health states represented mortality and morbidity according to functional outcomes. Input probabilities of symptoms and serial test results from CTA and CTP, transcranial Doppler ultrasound, and digital subtraction angiography were directly derived from an SAH cohort by using a multinomial logistic regression model. Expected benefits, measured as quality adjusted life years, and costs, measured in 2012 US dollars, were calculated for each imaging strategy. Univariable, multivariable, and probabilistic sensitivity analyses were performed to determine the independent and combined effect of input parameter uncertainty. RESULTS: The transcranial Doppler ultrasound strategy yielded 13.62 quality-adjusted life years at a cost of $154,719. The CTA and CTP strategy generated 13.89 quality-adjusted life years at a cost of $147,097, resulting in a gain of 0.27 quality-adjusted life years and cost savings of $7622 over the transcranial Doppler ultrasound strategy. Univariable and multivariable sensitivity analyses indicated that results were robust to plausible input parameter uncertainty. Probabilistic sensitivity analysis results yielded 96.8% of iterations in the right lower quadrant, representing higher benefits and lower costs. CONCLUSIONS: Our model results suggest that CTA and CTP are the preferred imaging strategy in SAH, compared with transcranial Doppler ultrasound, leading to improved clinical outcomes and lower health care costs. PMID- 24812016 TI - Decreased infarct volume and intracranial hemorrhage associated with intra arterial nonionic iso-osmolar contrast material in an MCA occlusion/reperfusion model. AB - BACKGROUND AND PURPOSE: Infarct volume and intracranial hemorrhage after reperfusion with nonionic low-osmolar and iso-osmolar iodinated IRCM has not been previously compared. We postulated that iso-osmolar and low-osmolar iodinated contrast media exert varied effects on cerebral infarct after intra-arterial injection. We compared infarct volume and hemorrhagic changes following intra arterial infusion of iodixanol, iopamidol, or normal saline in a rat MCA occlusion/reperfusion model. MATERIALS AND METHODS: Infarct was induced in 30 rats by a previously validated method of MCA suture occlusion. Reperfusion was performed after 5 hours with either iodixanol (n = 9), iopamidol (n = 12), or saline (n = 9). MR images were obtained at both 6 and 24 hours after ischemia, followed by sacrifice. Infarct volume was measured with T2WI and DWI by semiautomatic segmentation. Incidence and area of hemorrhage were measured on brain sections postmortem. RESULTS: T2WI mean infarct volumes were 242 +/- 89, 324 +/- 70, and 345 +/- 92 mm(3) at 6 hours, and 341 +/- 147,470 +/- 91, and 462 +/- 71 mm(3) at 24 hours in the iodixanol, iopamidol, and saline groups, respectively. Differences in infarct volume among groups were significant at 6 hours (P < .03) and 24 hours (P < .05). In the iodixanol, iopamidol, and saline groups, mean areas for cortical intracranial hemorrhage were 0.8, 18.2, and 25.7 mm(2); and 28, 31, and 56.7 mm(2), respectively, for deep intracranial hemorrhage. The differences in intracranial hemorrhage area among groups were statistically significant for cortical intracranial hemorrhage (P < .01). CONCLUSIONS: Intra-arterial infusion of nonionic iso-osmolar iodixanol showed reduced infarct volume and reduced cortical intracranial hemorrhage areas in comparison with nonionic low-osmolar iopamidol and saline. Our results may be relevant in the setting of intra-arterial therapy for acute stroke in humans, warranting further investigation. PMID- 24812017 TI - Use of non-echo-planar diffusion-weighted MR imaging for the detection of cholesteatomas in high-risk tympanic retraction pockets. AB - BACKGROUND AND PURPOSE: Non-echo-planar DWI MR imaging (including the HASTE sequence) has been shown to be highly sensitive and specific for large cholesteatomas. The purpose of this study was to determine the diagnostic accuracy of HASTE DWI for the detection of incipient cholesteatoma in high-risk retraction pockets. MATERIALS AND METHODS: This was a prospective study of 16 patients who underwent MR imaging with HASTE DWI before surgery. Surgeons were not informed of the results, and intraoperative findings were compared against the radiologic diagnosis. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Among the 16 retraction pockets, 10 cholesteatomas were diagnosed intraoperatively (62.5%). HASTE showed 90% sensitivity, 100% specificity, 100% positive predictive value, and 85.7% negative predictive value in this group of patients. We found only 1 false-negative finding in an infected cholesteatoma. CONCLUSIONS: We demonstrate a high correlation between HASTE and surgical findings, suggesting that this technique could be useful for the early detection of primary acquired cholesteatomas arising from retraction pockets and could help to avoid unnecessary surgery. PMID- 24812018 TI - Establishing a rabbit spinal tumor model for nonvascular interventional therapy through CT-guided percutaneous puncture inoculation. AB - BACKGROUND AND PURPOSE: An animal spinal tumor model is needed to better simulate the clinical situation and to allow percutaneous puncture, which may provide an experimental platform for the new nonvascular interventional therapies. We established a rabbit spinal tumor model through a CT-guided percutaneous puncture inoculation technique for nonvascular interventional therapy. MATERIALS AND METHODS: VX2 tumor cells were inoculated into the lumbar vertebrae of 32 rabbits through a CT-guided percutaneous puncture technique; then, the development of hind limb paraparesis was observed in the rabbits twice a day. MR imaging and CT were performed on days 14, 21, and 28 postinoculation and at the development of hind limb paraparesis. On days 21 and 28 postinoculation, 2 rabbits, whose imaging suggested successful modeling without hind limb paraparesis, were chosen on each day. The lumbar vertebrae were sampled from 1 rabbit for histopathologic examination, and the other rabbit underwent PET-CT examination before percutaneous vertebroplasty. Finally the lesion vertebrae were sampled for histopathologic examination. RESULTS: The success rate of modeling was 90.6% (29/32) in our study. On day 21 postinoculation, successful modeling was achieved in 21 rabbits, with 19 having no hind limb paraparesis. On day 28 postinoculation, another 7 achieved successful modeling, and only 1 developed hind limb paraparesis. Percutaneous vertebroplasty treatment was successful for the 2 rabbit models. CONCLUSIONS: Establishment of a rabbit spinal tumor model through a CT-guided percutaneous puncture technique and inoculation of VX2 tumor is easy and has a high success rate. The established model can be used to study nonvascular interventional therapies for spinal tumor, including percutaneous vertebroplasty. PMID- 24812019 TI - Test development and use in five Iberian Latin American countries. AB - The abundance of scholarship on test development and use generally is higher in English-speaking than in Iberian Latin American countries. The purpose of this article is to help overcome this imbalance by describing and identifying similarities and differences in test development and use in two Iberian (Portugal and Spain) and three of the largest Latin American (Argentina, Brazil, and Venezuela) countries. The stages of test development in each country, roles of professional associations, presence of standards for test use, professionals' educational training, commonly used tests, together with prominent challenges to continued progress are discussed. Test development and use in these five countries are transitioning from a dependence on the use of translated tests to greater reliance on adapted and finally nationally constructed tests. Continued growth requires adherence to international standards guiding test development and use. Stronger alliance among professional associations in the Iberian Latin American countries could serve as a catalyst to promote test development in these regions. PMID- 24812020 TI - Role of drinking water copper in pathogenesis of oral submucous fibrosis: a prospective case control study. AB - Although oral submucous fibrosis (OSMF) is thought to be multifactorial in origin, the chewing of areca nut is thought to be the main cause. Alkaloids and tannins in areca nut are responsible for fibrosis, but recent evidence has suggested that copper ions are also an important mediator, and in a small pilot study we recently found that OSMF was significantly associated with a raised concentration of copper in drinking water. We have further investigated this association in a heterogeneous population in Hyderabad-Karnataka, India, a region with a high incidence of the condition. We evaluated 3 groups, each of 100 patients: those with OSMF who chewed gutkha, those who chewed gutkha but did not have OSMF, and healthy controls who did not chew gutkha. The difference between the groups in the mean concentration of copper in water measured by atomic absorption spectrometry was significant (p<0.001). There were also significant differences between the groups in mean concentrations of serum copper, salivary copper, and ceruloplasmin (p<0.001). Our results confirm that copper in drinking water contributes to the pathogenesis of OSMF, but ingestion of copper is unlikely to be the sole cause. PMID- 24812021 TI - Indications for the microvascular medial femoral condylar flap in craniomaxillofacial surgery. AB - The medial femoral condylar flap makes it possible to reconstruct bone, cartilage, and skin, but elongation of the pedicle is usually required to bridge the distances to the vascular connections in the neck. The indications in the maxillofacial area include reconstruction of the temporomandibular joint (TMJ), pseudarthrosis of the jaws, osteonecrosis of the jaws and skull, and augmentation of bone in irradiated or otherwise compromised tissue. If small bony defects require safe and reliable osseous, osteochondral, or osteocutaneous reconstruction, the medial femoral condylar flap can be used to fill the gap between small avascular, and larger microvascular, bone transplants. PMID- 24812022 TI - Use of non-assigned interventions in a randomized trial of internet and telephone treatment for smoking cessation. AB - INTRODUCTION: A recent meta-analysis of Internet interventions for smoking cessation found mixed evidence regarding effectiveness. One explanation may be differential use of non-assigned cessation treatments-including other Internet programs-that either amplify or mask study intervention effects. We examined the impact of non-assigned treatment use on cessation outcomes in The iQUITT Study, a randomized trial of Internet and telephone treatment for smoking cessation. METHODS: Participants were randomized to a basic Internet (BI) comparison condition (N = 675), enhanced Internet (EI: N = 651), or EI plus telephone counseling (EI+P: N = 679). The primary outcome was 30-day point prevalence abstinence (ppa) at 3 and 6 months. Assigned intervention use was assessed with automated tracking data. Assessment of non-assigned treatments included pharmacotherapy, behavioral, alternative, and non-study Internet treatments. Univariate and multivariate logistic regression models examined whether non assigned treatment use was associated with 30-day ppa. RESULTS: About 70% of participants used at least one non-assigned treatment. A higher rate of non-study Internet treatment among BI participants was the only treatment group difference at both 3 and 6 months. Multivariate models controlling for condition and baseline predictors of non-assigned treatment use showed that high-intensity non study Internet treatment was positively associated with 30-day ppa at 3 and 6 months, and pharmacotherapy and behavioral treatment use was negatively associated with 30-day ppa at 6 months. CONCLUSIONS: Non-assigned treatment use is an important factor to consider when evaluating Internet cessation interventions. Results highlight methodological issues in selecting a comparison condition. Researchers should report non-assigned treatment use alongside main trial outcomes. PMID- 24812023 TI - A preliminary randomized controlled trial of a behavioral exercise intervention for smoking cessation. AB - INTRODUCTION: Previous exercise intervention studies for smoking cessation have been challenged by a number of methodological limitations that confound the potential efficacy of aerobic exercise for smoking cessation. METHODS: The preliminary efficacy of a behavioral exercise intervention that incorporated features designed to address prior limitations was tested in a randomized controlled trial (RCT). Sixty-one smokers (65.6% female, mean age = 47.3 years, smoked a mean of 19.7 cigarettes/day) were randomized to receive either a 12-week exercise intervention or a 12-week health education contact control. Participants in both conditions received an 8-week telephone-delivered, standard smoking cessation protocol (with the transdermal nicotine patch). Follow-ups were conducted at the end of treatment (EOT), 6- and 12-month timepoints. RESULTS: There were no differences between conditions with respect to the number of weekly exercise or health education sessions attended (9.3+/-2.8 vs. 9.3+/-3.0, respectively). While not statistically significant, participants in the exercise condition demonstrated higher verified abstinence rates (EOT: 40% vs. 22.6%, odds ratio [OR] = 2.28; 6- and 12-month follow-ups: 26.7% vs. 12.9%, OR = 2.46). Irrespective of treatment condition, higher levels of moderate-to-vigorous exercise were associated with lower levels of depressive symptoms during the intervention. CONCLUSIONS: The results of this small RCT point toward the benefit of a behavioral exercise intervention designed to address previous methodological limitations for smoking cessation. Given the potential public health impact of the demonstrated efficacy of exercise for smoking cessation, the continued development and optimization of exercise interventions for smokers through larger RCTs merits pursuit. PMID- 24812024 TI - Smoking cessation is followed by increases in serum bilirubin, an endogenous antioxidant associated with lower risk of lung cancer and cardiovascular disease. AB - INTRODUCTION: Lower concentrations of serum bilirubin, an endogenous antioxidant, have been associated with risk of many smoking-related diseases, including lung cancer and cardiovascular disease, and current smokers are reported to have lower bilirubin levels than nonsmokers and past smokers. This study evaluates the effects of smoking cessation on bilirubin levels. METHODS: In a secondary analysis of a 6-week placebo-controlled trial of naltrexone for smoking cessation, indirect and total bilirubin concentrations were evaluated at baseline and following smoking cessation. Individuals who were continuously abstinent for 6 weeks (n = 155) were compared to those who were not (n = 193). Participants reported smoking >= 20 cigarettes daily at baseline and received smoking cessation counseling, 21 mg nicotine patch daily, and either placebo or 1 of 3 doses of naltrexone (25, 50, or 100mg) for 6 weeks. Change in indirect and total bilirubin following the quit date was measured at Weeks 1, 4, and 6 compared to baseline. RESULTS: Individuals who were continuously abstinent from smoking, independent of naltrexone condition, showed a significantly greater mean increase in indirect (~unconjugated) bilirubin (0.06 mg/dl, SD = 0.165) compared to those who did not (mean = 0.02, SD = 0.148, p = .015). Similar results were obtained for total bilirubin (p = .037). CONCLUSIONS: Smoking cessation is followed by increases in bilirubin concentration that have been associated with lower risk of lung cancer and cardiovascular disease. PMID- 24812026 TI - Occupational cadmium exposure-associated oxidative stress and erythrocyte fragility among jewelry workers in India. AB - BACKGROUND: Cadmium-induced pulmonary and renal target organ effects are well established although its association with oxidative stress and associated hematological effects for human toxicity remain understudied. METHODS: In a population of cadmium-exposed male jewelry manufacturing workers (n = 32) and referents without direct exposure (n = 21), all with urinary cadmium quantification, we measured plasma antioxidant enzymes (catalase, superoxide dismutase), lipid peroxidation (malondialdehyde), erythrocyte fragility, and surface irregularity of the erythrocyte membrane. RESULTS: Compared to referents, exposed workers manifested significantly lower plasma antioxidant enzymes, and increased malondialdehyde and erythrocyte fragility (for all, P < 0.01). Consistent with the exposure subcategories, activities of superoxide dismutase and catalase were reduced and lipid peroxidation and erythrocyte fragility were enhanced (P < 0.01 for all) in terms of Cd-effect indicating a strong impact on hematological system and oxidative stress. CONCLUSION: Cd exposure contributes to oxidative stress and related erythrocyte effects thus making the hematological system another end-organ target for chronic Cd toxicity. PMID- 24812025 TI - Exposure to secondhand smoke and attitudes toward smoke-free workplaces among employed U.S. adults: findings from the National Adult Tobacco Survey. AB - INTRODUCTION: This study assessed the prevalence and correlates of secondhand smoke (SHS) exposure and attitudes toward smoke-free workplaces among employed U.S. adults. METHODS: Data came from the 2009-2010 National Adult Tobacco Survey, a landline and cellular telephone survey of adults aged >=18 years in the United States and the District of Columbia. National and state estimates of past 7-day workplace SHS exposure and attitudes toward indoor and outdoor smoke-free workplaces were assessed among employed adults. National estimates were calculated by sex, age, race/ethnicity, education, annual household income, sexual orientation, U.S. region, and smoking status. RESULTS: Among employed adults who did not smoke cigarettes, 20.4% reported past 7-day SHS exposure at their workplace (state range: 12.4% [Maine] to 30.8% [Nevada]). Nationally, prevalence of exposure was higher among males, those aged 18-44 years, non Hispanic Blacks, Hispanics, and non-Hispanic American Indians/Alaska natives compared to non-Hispanic Whites, those with less education and income, those in the western United States, and those with no smoke-free workplace policy. Among all employed adults, 83.8% and 23.2% believed smoking should never be allowed in indoor and outdoor areas of workplaces, respectively. CONCLUSIONS: One-fifth of employed U.S. adult nonsmokers are exposed to SHS in the workplace, and disparities in exposure exist across states and subpopulations. Most employed adults believe indoor areas of workplaces should be smoke free, and nearly one quarter believe outdoor areas should be smoke free. Efforts to protect employees from SHS exposure and to educate the public about the dangers of SHS and benefits of smoke-free workplaces could be beneficial. PMID- 24812028 TI - REMOVED: Protective effect of Daucus carota against UV-DMBA induced skin cancer in mice. AB - This article has been removed: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been removed at the request of "Due to a processing error during the review process, this paper was erroneously published online prematurely. The Publisher apologizes to readers and the authors for any inconvenience caused." PMID- 24812027 TI - Prenatal and 5-year p,p'-DDE exposures are associated with altered sensory processing in school-aged children in Nunavik: a visual evoked potential study. AB - Due to their geographic location and traditional diet, rich in seafood and marine mammals, the Inuit living in Arctic Quebec are exposed to high amounts of pollutants, including organochlorine pesticides (OCPs). While the adverse developmental effects of these pesticides on child cognitive functions are well known, the effects of developmental exposure to OP on sensory processes have not been investigated. The aim of this longitudinal study was to assess the effects of prenatal and childhood exposure to 1,1,1-trichloro-2,2-bis(p chlorophenyl)ethane (p,p'-DDT) and its major metabolite 1,1,-dichloro-2,2-bis(p chlorophenyl)ethylene (p,p'-DDE), on visual processing in Inuit children in Nunavik (Arctic Quebec). p,p'-DDT and p,p'-DDE concentrations were determined from umbilical cord and 5- and 11-year plasma samples. Visual evoked potentials (VEPs) were successfully recorded in 150 children at 4 contrast levels (95%, 30%, 12%, and 4%). Hierarchical multiple regressions were conducted to determine the association between p,p'-DDT, or p,p'-DDE, exposure and VEPs while controlling for the effects of various confounders, including fish nutrients and other contaminants. p,p'-DDE measured in umbilical cord plasma was significantly related to the amplitude of the N150 response at the lowest contrast (4%). In addition, 5-year p,p'-DDE plasma concentration was significantly associated with decreased N75 amplitude. These findings indicate that p,p'-DDE exposure, both pre and postnatally, during early childhood is associated with visual processing impairment later in life. PMID- 24812029 TI - Induction of ROS-independent JNK-activation-mediated apoptosis by a novel coumarin-derivative, DMAC, in human colon cancer cells. AB - In this study, we investigated the antitumor activity of a novel coumarin derivative, 5,7-dihydroxy-4-methyl-6-(3-methylbutanoyl)-coumarin (DMAC), on colorectal carcinoma. DMAC treatment resulted in substantial proapoptotic activity against colon cancer HCT116 and LoVo cells. Induction of apoptotic characteristics, including cellular shrinkage, chromatin condensation, and Annexin V detection, was observed following DMAC treatment. Mechanistically, we observed that DMAC elicited induction of proteolytic cascade activation including cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) expression and loss of the antiapoptotic proteins, Mcl-1 and Bcl-XL, accompanied by an increase in expression of the proapoptotic protein, Bak. In addition, suppressing c-Jun N terminal protein kinase (JNK), but not extracellular-regulated protein kinase (ERK) or p38, substantially diminished DMAC-induced cell death and caspase-3 and PARP cleavage. However, pretreatment with antioxidants, including N-acetyl-l cysteine (NAC) and diphenylene iodonium (DPI), failed to protect against DMAC elicited apoptosis. Pretreatment with the JNK inhibitor, SP600125, suppressed DMAC-induced JNK phosphorylation, which was accompanied by a reversal of Bcl-XL expression. Moreover, combining DMAC treatment with the conventional anticancer drugs, 5-FU and CPT-11, considerably enhanced their therapeutic efficacies. Structural-activity relationship analyses further revealed that an alkylation substitution at position 6 of the coumarin ring was critical for inducing apoptosis, and the phenyl group at position 4 might have enhanced its bioactivity. Our data showed that DMAC can be used as part of a promising strategy to enhance therapeutic efficacies, and could be used to develop an approach for structure-based drug design for cancer treatment. PMID- 24812031 TI - Osteochondral articular defect repair using auricle-derived autologous chondrocytes in a rabbit model. AB - Hypothesizing that the implantation of non-articular (heterotopic) chondrocytes might be an alternative approach to support articular cartilage repair, we analyzed joint cartilage defect healing in the rabbit model after implantation of autologous auricle-derived (auricular) chondrocytes. Autologous lapine articular and auricular chondrocytes were cultured for 3 weeks in polyglycolic acid (PGA) scaffolds before being implanted into critical sized osteochondral defects of the rabbit knee femoropatellar groove. Cell-free PGA scaffolds and empty defects served as controls. Construct quality was determined before implantation and defect healing was monitored after 6 and 12 weeks using vitality assays, macroscopical and histological score systems. Neo-cartilage was formed in the PGA constructs seeded with both articular and auricular chondrocytes in vitro and in vivo. At the histological level, cartilage repair was slightly improved when using autologous articular chondrocyte seeded constructs compared to empty defects and was significantly superior compared to defects treated with auricular chondrocytes 6 weeks after implantation. Although only the immunohistological differences were significant, auricular chondrocyte implantation induced an inferior healing response compared with the empty defects. Elastic auricular chondrocytes might maintain some tissue-specific characteristics when implanted into joint cartilage defects which limit its repair capacity. PMID- 24812030 TI - Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts. AB - Bone morphogenetic proteins (BMPs) are a group of growth factors with dual functions in cancer development and progression. Recently, certain tumor promoting roles have been identified for selected antagonists/inhibitors (BMPIs) of this developmental pathway. A recent focus on the implication of BMP in colorectal cancer progression has emerged, mainly due to the presence of inactivating mutations in several members of the canonical signaling cascade. However, the detailed expression profiles of BMPIs remain largely unknown. Based on our previous work, whereby three specific BMPIs, gremlin-1 (GREM1), high temperature requirement A3 (HTRA3) and follistatin (FST) were collectively overexpressed in desmoplastic cocultures of colorectal cancer (CRC), here, we undertook an immunohistochemical approach to describe the patterns of their expression in CRC patients. Two major characteristics described the BMPI expression signature: First, the synchronous and coordinated stromal and epithelial overexpression of individual BMPIs in desmoplastic lesions, which demonstrated that all three of them contribute to increasing levels of BMP antagonism in such areas. Second, the presence of microenvironmental polarity in the BMPI pattern of expression, which was indicated through the preferential expression of HTRA3 in the stromal, and the parallel FST/GREM1 expression in the epithelial component of the investigated sections. In addition, expression of HTRA3 in the epithelial compartment of the tumors demonstrated a significant predictive power to discriminate between tumor-budding-bearing and tumor-budding free desmoplastic microenvironments. Together, these findings contribute to the understanding of signaling dynamics of BMP antagonism in the colorectal cancer desmoplastic invasion front. PMID- 24812033 TI - My life as Mae Tid Chua [mothers who contracted HIV disease]: motherhood and women living with HIV/AIDS in central Thailand. AB - BACKGROUND: literature suggests that many women living with HIV/AIDS have a desire to become mothers and indeed many of them have done so (Thiangtham and Bennett, 2009; Barnes, 2013; Cogna et al., 2013; Lazarus et al., 2013; Ross, 2013; Yeatman and Trinitapoli, 2013). However, there is still a lack of knowledge about the lived experiences of Thai women living with HIV/AIDS who have become mothers. In this paper, we explored the experiences of pregnancy and birth, motherhood, and infant feeding practices among women living with HIV/AIDS in Thailand. METHOD: in-depth interviews were conducted with 26 women living with HIV/AIDS in Thailand. FINDINGS: motherhood was considered desirable by women living with HIV/AIDS who participated in our study. Despite living with a serious illness, becoming a mother permitted them to have a meaningful life. Motherhood prompted the women to stay alive for their children. However, the women lived with constant anxiety about the condition of their infants. Reproductive needs of the women in our study were often questioned by their health care providers. Many were advised by their doctors and nurses not to breast feed their newborn babies as this could transmit HIV to the child. Most women took into account their ability to care for their children in the future and thus did not wish to have many children. CONCLUSION: this paper contributes to conceptual understanding about the lived experiences of motherhood among women living with HIV/AIDS in Thailand. The findings have implications for midwifery care. PMID- 24812032 TI - RUNX3 facilitates growth of Ewing sarcoma cells. AB - Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. PMID- 24812034 TI - Structural gray matter abnormalities in migraine relate to headache lateralization, but not aura. AB - BACKGROUND: The hallmark of migraine aura (MA) is transient cortical dysfunction but it is not known if MA is associated with structural cortical or subcortical changes. To determine the relation between MA and structural gray matter abnormalities, we studied a unique sample of 20 patients with frequent side locked MA, i.e. visual aura consistently occurring in the same hemifield. METHODS: We applied a highly sensitive within-patient design to assess anatomical differences with both voxel-based morphometry and surface-based morphometry on a whole-hemisphere level and for specific anatomical regions of interest. Within subject comparisons were made with regard to aura symptoms (N = 20 vs 20) and with regard to headache (N = 13 vs 13). RESULTS: We found no differences in gray matter structure with regard to aura symptoms in MA patients. Comparing the typical migraine headache side of the patients to the contralateral side revealed a difference in cortical thickness in the inferior frontal gyrus (mean difference 0.12 mm, p = 0.036). CONCLUSION: MA per se is associated with abnormal function but not with lateralized abnormalities of gray matter structure. Alteration of the inferior frontal cortex suggests structural reorganization of pain inhibitory circuits in response to the repeated intense nociceptive input due to the headache attacks. PMID- 24812035 TI - Occipital nerve stimulation for chronic migraine: a randomized trial on subthreshold stimulation. AB - INTRODUCTION: Occipital nerve stimulation (ONS) may provide pain relief in migraine patients. In this double-blinded trial we investigated the significance of paresthesia and possible placebo effects. METHODS: Patients already treated with ONS reporting stable treatment effect were included. "Effective stimulation," "subthreshold stimulation" and "no stimulation" were compared. Patients cycled through all three treatment groups. Outcome was measured using the visual analog scale (VAS) for pain, McGill Pain Questionnaire and SF-36. RESULTS: Eight patients were included, mean preoperative VAS was 8.20 +/- 1.22. A significant improvement in pain was observed in favor of suprathreshold stimulation compared to subthreshold stimulation (1.98 +/- 1.56 vs 5.65 +/- 2.11). Pain also significantly improved under subthreshold stimulation compared to no stimulation (5.65 +/- 2.11 vs 8.45 +/- 0.99). No changes in SF-36 were observed. CONCLUSIONS: Paresthesia is not required to achieve pain reduction but suprathreshold stimulation yields better results, underlining the significance of stimulation parameter customization. PMID- 24812036 TI - Fear of pain in pediatric headache. AB - OBJECTIVE: The current study provides the first measure of pain-related fear for pediatric headache patients. METHODS: From a large pediatric headache clinic, a cross-sectional cohort of 206 children and adolescents completed measures of pain related fear, anxiety sensitivity, catastrophizing, pain acceptance, functional disability, and school functioning. RESULTS: The two-factor solution of the Fear of Pain Questionnaire (FOPQ) was confirmed from the originally derived structure with pediatric headache patients. Simultaneously regressing FOPQ subscales fear of pain and activity avoidance on theorized construct validity measures demonstrated that fear of pain was more closely linked with anxiety sensitivity and pain catastrophizing while activity avoidance had a strong negative association with pain acceptance (activity engagement and pain willingness). Pain related fear was not significantly associated with pain level. After controlling for demographic factors and pain, fear of pain and activity avoidance accounted for an additional 26% of the variance in functional disability and school functioning outcomes, with activity avoidance accounting for much of this relationship. CONCLUSIONS: Although typically considered an influential construct among musculoskeletal patients, pain-related fear is also an important factor influencing functioning among pediatric headache patients, with the dimension of activity avoidance particularly salient. PMID- 24812037 TI - Prescription diuretic use and risk of basal cell carcinoma in the nationwide U.S. radiologic technologists cohort. AB - BACKGROUND: UV radiation (UVR) exposure is the primary risk factor for basal cell carcinoma (BCC). Although prescription diuretics have photosensitizing properties, the relationship between diuretic use and BCC remains unclear. METHODS: Using data from the United States Radiologic Technologists Study, a large, nationwide prospective cohort, we assessed the relationship between diuretic use and first primary BCC while accounting for sun exposure history, constitutional characteristics, lifestyle factors, and anthropometric measurements for geographically dispersed individuals exposed to a wide range of ambient UVR. RESULTS: After adjustment for potential confounders, we found a significantly increased risk of BCC associated with diuretic use [HR, 1.22; 95% confidence interval (CI), 1.07-1.38]. This relationship was modified by body mass index (P = 0.019), such that BCC risk was increased with diuretic use in overweight (HR, 1.43; 95% CI, 1.16-1.76) and obese individuals (HR, 1.43; 95% CI, 1.09-1.88), but not in normal weight individuals (HR, 0.99; 95% CI, 0.81-1.21). CONCLUSIONS: Increased risk of BCC associated with diuretic use in overweight and obese participants may be related to higher dosages, longer duration of medication use, reduced drug metabolism, or drug interactions. IMPACT: Future cohort studies should obtain more detailed information on medication use, consider factors that affect drug metabolism, and measure intermediate endpoints such as photosensitivity reactions. PMID- 24812038 TI - Circadian variation of melatonin, light exposure, and diurnal preference in day and night shift workers of both sexes. AB - BACKGROUND: Light-at-night has been shown in experimental studies to disrupt melatonin production but this has only partly been confirmed in studies of night shift workers. In this cross-sectional study, we examined the circadian variation of melatonin in relation to shift status, individual levels of light-at-night exposure, and diurnal preference, an attribute reflecting personal preference for activity in the morning or evening. METHODS: One hundred and seventeen workers (75 night and 42 day) of both sexes, ages 22 to 64 years, were recruited from four companies. Participants collected urine samples from all voids over 24 hours and wore a data logger continuously recording their light exposure. Sociodemographic, occupational, lifestyle, and diurnal preference information were collected by interview. Concentrations of urinary 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, were measured. RESULTS: Mean aMT6s levels were lower in night [10.9 ng/mg creatinine/hour; 95% confidence interval (CI), 9.5-12.6] compared with day workers (15.4; 95% CI, 12.3-19.3). The lowest aMT6s levels were observed in night workers with morning preference (6.4; 95% CI, 3.0 13.6). Peak time of aMT6s production occurred 3 hours later in night (08:42 hour, 95% CI, 07:48-09:42) compared with day workers (05:36 hour, 95% CI, 05:06-06:12). Phase delay was stronger among subjects with higher light-at-night exposure and number of nights worked. CONCLUSIONS: Night shift workers had lower levels and a delay in peak time of aMT6s production over a 24-hour period. Differences were modified by diurnal preference and intensity of light-at-night exposure. IMPACT: Night shift work affects levels and timing of melatonin production and both parameters may relate to future cancer risk. PMID- 24812040 TI - Endophytic bacteria in plant tissue culture: differences between easy- and difficult-to-propagate Prunus avium genotypes. AB - The endophytic bacterial communities of six Prunus avium L. genotypes differing in their growth patterns during in vitro propagation were identified by culture dependent and culture-independent methods. Five morphologically distinct isolates from tissue culture material were identified by 16S rDNA sequence analysis. To detect and analyze the uncultivable fraction of endophytic bacteria, a clone library was established from the amplified 16S rDNA of total plant extract. Bacterial diversity within the clone libraries was analyzed by amplified ribosomal rDNA restriction analysis and by sequencing a clone for each identified operational taxonomic unit. The most abundant bacterial group was Mycobacterium sp., which was identified in the clone libraries of all analyzed Prunus genotypes. Other dominant bacterial genera identified in the easy-to-propagate genotypes were Rhodopseudomonas sp. and Microbacterium sp. Thus, the community structures in the easy- and difficult-to-propagate cherry genotypes differed significantly. The bacterial genera, which were previously reported to have plant growth-promoting effects, were detected only in genotypes with high propagation success, indicating a possible positive impact of these bacteria on in vitro propagation of P. avium, which was proven in an inoculation experiment. PMID- 24812041 TI - Improving modeling of the 'dark part' of canopy carbon gain. PMID- 24812039 TI - The heritability of prostate cancer in the Nordic Twin Study of Cancer. AB - BACKGROUND: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age. METHODS: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability. RESULTS: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%-63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary. CONCLUSIONS: Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age. IMPACT: Findings affect the search for genetic and epigenetic markers and frame prevention efforts. PMID- 24812042 TI - Mean upper cervical cord area (MUCCA) measurement in long-standing multiple sclerosis: relation to brain findings and clinical disability. AB - BACKGROUND: The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown. OBJECTIVE: Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability. METHODS: MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability. RESULTS: MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56+/-9.82 and 82.24+/-7.80 mm2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT. CONCLUSION: MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures. PMID- 24812043 TI - The influence of patient demographics, disease characteristics and treatment on brain volume loss in Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), a phase 3 study of fingolimod in multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) lose brain volume (BV) faster than healthy individuals. OBJECTIVE: Our purpose, within the 12-month phase 3 TRANSFORMS study, was to examine the effect of treatment on BV loss in patient subgroups, establish correlations between baseline normalized BV (NBV) and baseline disease parameters, to identify variables predictive of baseline NBV and on-study percentage BV change (PBVC), and to establish correlations between on study PBVC and on-study efficacy outcomes. METHODS: Patients received fingolimod 0.5 mg or 1.25 mg, or intramuscular (IM) interferon beta-1a (IFNbeta-1a) for 12 months. The effect of treatment on PBVC was examined in patient demographic, disease and magnetic resonance imaging (MRI) characteristic subgroups. Pearson's correlation analyses and a stepwise linear regression model were used to identify variables predictive of NBV and PBVC. RESULTS: Fingolimod reduced BV loss over 12 months versus IFNbeta-1a IM in all patient subgroups assessed, including individuals with or without gadolinium (Gd)-enhancing lesions at baseline. Baseline T1 hypointense lesion volume had the strongest correlation with baseline NBV. Baseline Gd-enhancing T1 lesion count was most predictive of change in PBVC over 12 months. CONCLUSIONS: Our results improve understanding of the contributions of different baseline demographic, clinical and MRI characteristics to NBV, including factors that may be predictive of future BV loss. PMID- 24812044 TI - Disease modifying therapies in multiple sclerosis: could a baseline thyroid check up drive the therapeutic choice between interferon-beta and glatiramer acetate? PMID- 24812045 TI - Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence? AB - The use of natalizumab has likely been limited by its association with progressive multifocal leukoencephalopathy (PML), an infection caused by the human polyomavirus John Cunningham (JC). Three factors were recently identified that contribute to the overall risk of natalizumab-associated PML: (1) Positive serostatus for anti-JCV antibodies, (2) prior use of immunosuppressants, and (3) duration of natalizumab therapy. This risk stratification algorithm has not led to a reduction in the incidence of PML in natalizumab-treated patients with multiple sclerosis between April 2010 and February 2014. This observation may appear perplexing, as treatment duration and JCV serostatus are modifiable risk factors. Potential reasons for the lack of success of companion diagnostics that determine the overall risk of natalizumab-associated PML are discussed. PMID- 24812046 TI - The role of microglial activation in disease progression. AB - Microglia, a unique type of myeloid cell, play a key role in the inflammation mediated neurodegeneration occurring during both acute and chronic stages of multiple sclerosis (MS). These highly specialized cells trigger neurotoxic pathways, producing pro-inflammatory cytokines, reactive oxygen and nitrogen species and proteolytic enzymes, causing progressive neurodegeneration. Microglia have also been associated with development of cortical lesions in progressive MS, as well as with alterations of synaptic transmission in experimental autoimmune encephalomyelitis (EAE). However, they also play an important role in the promotion of neuroprotection, downregulation of inflammation, and stimulation of tissue repair. Notably, microglia undergo changes in morphology and function with normal aging, resulting in a decline of their ability to repair central nervous system damage, making axons and neurons more vulnerable with age. Modulation of microglial activation for therapeutic purposes must consider suppressing deleterious effects of these cells, while simultaneously preserving their protective functions. PMID- 24812047 TI - Human papillomavirus (HPV) and the usefulness of the HPV vaccine for men who have sex with men. PMID- 24812048 TI - Cytosolic double-stranded DNA induces nonnecroptotic programmed cell death in trophoblasts via IFI16. AB - The mechanisms underlying the immune defense by trophoblasts against pathogens remain ill defined. We demonstrated that placental cell death was increased upon in vivo exposure to Listeria monocytogenes. The death of infected cells is an important host innate defense mechanism. Meanwhile, double-stranded DNA (dsDNA) derived from intracellular bacteria or dsDNA viruses is emerging as a potent pathogen-associated molecular pattern recognized by host cells. We sought to characterize trophoblast death in response to cytosolic dsDNA challenge. Our results showed that dsDNA induced caspase-dependent and -independent cell death in human trophoblasts. However, necroptosis, a cell death pathway independent of caspase, could not be induced by dsDNA treatment, even in the presence of exogenously expressed RIPK3. L. monocytogenes-derived genomic DNA triggered a similar cell death pattern. Moreover, the cell death in response to dsDNA was IFI16 dependent. These data suggest that cytosolic dsDNA induces nonnecroptotic cell death in trophoblasts via IFI16, and this could contribute to placental barrier against infection. PMID- 24812049 TI - Reply to Sadlier et al. PMID- 24812050 TI - Testing the optimality properties of a dual antibiotic treatment in a two-locus, two-allele model. AB - Mathematically speaking, it is self-evident that the optimal control of complex, dynamical systems with many interacting components cannot be achieved with 'non responsive' control strategies that are constant through time. Although there are notable exceptions, this is usually how we design treatments with antimicrobial drugs when we give the same dose and the same antibiotic combination each day. Here, we use a frequency- and density-dependent pharmacogenetics mathematical model based on a standard, two-locus, two-allele representation of how bacteria resist antibiotics to probe the question of whether optimal antibiotic treatments might, in fact, be constant through time. The model describes the ecological and evolutionary dynamics of different sub-populations of the bacterium Escherichia coli that compete for a single limiting resource in a two-drug environment. We use in vitro evolutionary experiments to calibrate and test the model and show that antibiotic environments can support dynamically changing and heterogeneous population structures. We then demonstrate, theoretically and empirically, that the best treatment strategies should adapt through time and constant strategies are not optimal. PMID- 24812052 TI - Through the eyes of a bird: modelling visually guided obstacle flight. AB - Various flight navigation strategies for birds have been identified at the large spatial scales of migratory and homing behaviours. However, relatively little is known about close-range obstacle negotiation through cluttered environments. To examine obstacle flight guidance, we tracked pigeons (Columba livia) flying through an artificial forest of vertical poles. Interestingly, pigeons adjusted their flight path only approximately 1.5 m from the forest entry, suggesting a reactive mode of path planning. Combining flight trajectories with obstacle pole positions, we reconstructed the visual experience of the pigeons throughout obstacle flights. Assuming proportional-derivative control with a constant delay, we searched the relevant parameter space of steering gains and visuomotor delays that best explained the observed steering. We found that a pigeon's steering resembles proportional control driven by the error angle between the flight direction and the desired opening, or gap, between obstacles. Using this pigeon steering controller, we simulated obstacle flights and showed that pigeons do not simply steer to the nearest opening in the direction of flight or destination. Pigeons bias their flight direction towards larger visual gaps when making fast steering decisions. The proposed behavioural modelling method converts the obstacle avoidance behaviour into a (piecewise) target-aiming behaviour, which is better defined and understood. This study demonstrates how such an approach decomposes open-loop free-flight behaviours into components that can be independently evaluated. PMID- 24812053 TI - Hierarchical multiscale structure-property relationships of the red-bellied woodpecker (Melanerpes carolinus) beak. AB - We experimentally studied beaks of the red-bellied woodpecker to elucidate the hierarchical multiscale structure-property relationships. At the macroscale, the beak comprises three structural layers: an outer rhamphotheca layer (keratin sheath), a middle foam layer and an inner bony layer. The area fraction of each layer changes along the length of the beak giving rise to a varying constitutive behaviour similar to functionally graded materials. At the microscale, the rhamphotheca comprises keratin scales that are placed in an overlapping pattern; the middle foam layer has a porous structure; and the bony layer has a big centre cavity. At the nanoscale, a wavy gap between the keratin scales similar to a suture line was evidenced in the rhamphotheca; the middle foam layer joins two dissimilar materials; and mineralized collagen fibres were revealed in the inner bony layer. The nano- and micro-indentation tests revealed that the hardness (associated with the strength, modulus and stiffness) of the rhamphotheca layer (approx. 470 MPa for nano and approx. 320 MPa for micro) was two to three times less than that of the bony layer (approx. 1200 MPa for nano and approx. 630 MPa for micro). When compared to other birds (chicken, finch and toucan), the woodpecker's beak has more elongated keratin scales that can slide over each other thus admitting dissipation via shearing; has much less porosity in the bony layer thus strengthening the beak and focusing the stress wave; and has a wavy suture that admits local shearing at the nanoscale. The analysis of the woodpeckers' beaks provides some understanding of biological structural materials' mechanisms for energy absorption. PMID- 24812051 TI - Biomimetic interfaces based on S-layer proteins, lipid membranes and functional biomolecules. AB - Designing and utilization of biomimetic membrane systems generated by bottom-up processes is a rapidly growing scientific and engineering field. Elucidation of the supramolecular construction principle of archaeal cell envelopes composed of S-layer stabilized lipid membranes led to new strategies for generating highly stable functional lipid membranes at meso- and macroscopic scale. In this review, we provide a state-of-the-art survey of how S-layer proteins, lipids and polymers may be used as basic building blocks for the assembly of S-layer-supported lipid membranes. These biomimetic membrane systems are distinguished by a nanopatterned fluidity, enhanced stability and longevity and, thus, provide a dedicated reconstitution matrix for membrane-active peptides and transmembrane proteins. Exciting areas in the (lab-on-a-) biochip technology are combining composite S layer membrane systems involving specific membrane functions with the silicon world. Thus, it might become possible to create artificial noses or tongues, where many receptor proteins have to be exposed and read out simultaneously. Moreover, S-layer-coated liposomes and emulsomes copying virus envelopes constitute promising nanoformulations for the production of novel targeting, delivery, encapsulation and imaging systems. PMID- 24812054 TI - Epiregulin promotes the emergence and proliferation of adult liver progenitor cells. AB - We have previously reported that epiregulin is a growth factor that seems to act on liver progenitor cells (LPCs) during liver regeneration. However, the relationship between epiregulin and LPCs has remained unclear. The aim of the present study was to clarify the role of epiregulin during liver regeneration. The serum levels of epiregulin in patients with acute liver failure were examined. A liver injury model was developed using mice fed a diet containing 0.1% 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) to induce LPCs. We then evaluated the expression of epiregulin and LPCs in these mice. The proliferation of epithelial cell adhesion molecule + LPCs cultured with epiregulin was examined in vitro, and finally epiregulin was overexpressed in mouse liver. In patients with acute liver failure, serum epiregulin levels were elevated significantly. In DDC mice, LPCs emerged around the portal area. Epiregulin was also detected around the portal area during the course of DDC-induced liver injury and was partially coexpressed with Thy1. Serum epiregulin levels in DDC mice were also significantly elevated. Recombinant epiregulin augmented the proliferative capacity of the LPCs in a dose-dependent manner. In mice showing overexpression of epiregulin, the expression of PCNA on hepatocytes was increased significantly. Finally, LPCs emerged around the portal area after epiregulin gene delivery. We concluded that epiregulin promotes the proliferation of LPCs and DNA synthesis by hepatocytes and is upregulated in the serum of patients with liver injury. Furthermore, induction of epiregulin leads to the appearance of LPCs. Epiregulin would be a useful biomarker of liver regeneration. PMID- 24812056 TI - Activation of the gut calcium-sensing receptor by peptide agonists reduces rapid elevation of plasma glucose in response to oral glucose load in rats. AB - The calcium-sensing receptor (CaSR) is expressed in various tissues, including the gastrointestinal tract. To investigate the role of gut CaSR on glycemic control, we examined whether single oral administration of CaSR agonist peptides affected the glycemic response in rats. Glucose tolerance tests were performed under oral or duodenal administration of various CaSR agonist peptides (gammaGlu Cys, protamine, and poly-d-lysine hydrobromide) in conscious rats. Involvement of CaSR was determined by using a CaSR antagonist. Signaling pathways underlying CaSR agonist-modified glycemia were investigated using gut hormone receptor antagonists. The gastric emptying rate after the administration of CaSR agonist peptides was measured by the phenol red recovery method. Oral and duodenal administration of CaSR agonist peptides attenuated glycemic responses under the oral glucose tolerance test, but the administration of casein did not. The promotive effect on glucose tolerance was weakened by luminal pretreatment with a CaSR antagonist. Treatment with a 5-HT3 receptor antagonist partially diminished the glucose-lowering effect of peptides. Furthermore, the gastric emptying rate was decreased by duodenal administration of CaSR agonist peptides. These results demonstrate that activation of the gut CaSR by peptide agonists promotes glucose tolerance in conscious rats. 5-HT3 receptor and the delayed gastric emptying rate appear to be involved in the glucose-lowering effect of CaSR agonist peptides. Thus, activation of gut CaSR by dietary peptides reduces glycemic responses so that gut CaSR may be a potential target for the improvement of postprandial glycemia. PMID- 24812055 TI - Low pH enhances connexin32 degradation in the pancreatic acinar cell. AB - Decreased extracellular pH is observed in a number of clinical conditions and can sensitize to the development and worsen the severity of acute pancreatitis. Because intercellular communication through gap junctions is pH-sensitive and modulates pancreatitis responses, we evaluated the effects of low pH on gap junctions in the rat pancreatic acinar cell. Decreasing extracellular pH from 7.4 to 7.0 significantly inhibited gap junctional intracellular communication. Acidic pH also significantly reduced levels of connexin32, the predominant gap junction protein in acinar cells, and altered its localization. Increased degradation through the proteasomal, lysosomal, and autophagic pathways mediated the decrease in connexin32 under low-pH conditions. These findings provide the first evidence that low extracellular pH can regulate gap junctional intercellular communication by enhancing connexin degradation. PMID- 24812057 TI - Relaxin receptor antagonist AT-001 synergizes with docetaxel in androgen independent prostate xenografts. AB - Androgen hormones and the androgen receptor (AR) pathway are the main targets of anti-hormonal therapies for prostate cancer. However, resistance inevitably develops to treatments aimed at the AR pathway resulting in androgen-independent or hormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for the management of prostate cancer. We demonstrate that a relaxin hormone receptor antagonist, AT 001, an analog of human H2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgen independent human prostate tumor xenografts. Chemically synthesized AT-001, administered subcutaneously, suppressed PC3 xenograft growth by up to 60%. AT-001 also synergized with docetaxel, standard first-line chemotherapy for HRPC, to suppress tumor growth by more than 98% in PC3 xenografts via a mechanism involving the downregulation of hypoxia-inducible factor 1 alpha and the hypoxia induced response. Our data support developing AT-001 for clinical use as an anti relaxin hormonal therapy for advanced prostate cancer. PMID- 24812058 TI - Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer. AB - Zinc finger E-box-binding protein 2 (ZEB2) is known to help mediate the epithelial-to-mesenchymal transition, and thereby it facilitates cancer metastasis. This study was initiated to explore whether ZEB2 expression differs in prostate cancer (PCa, n=7) and benign prostatic hyperplasia (BPH, n=7) tissues. In PCa tissues, the levels of both immunoreactive ZEB2 and androgen receptor (AR) were found to be significantly higher (P<0.05) when compared with BPH tissues. Co-regulation of AR and ZEB2 prompted us to investigate the role of androgenic stimuli in ZEB2 expression. ZEB2 expression was found to be significantly (P<0.05) upregulated after androgen stimulation and downregulated following AR silencing in LNCaP cells, an androgen-dependent PCa cell line. This finding suggested AR as a positive regulator of ZEB2 expression in androgen dependent cells. Paradoxically, androgen-independent (AI) cell lines PC3 and DU145, known to possess low AR levels, showed significantly (P<0.05) higher expression of ZEB2 compared with LNCaP cells. Furthermore, forced expression of AR in PC3 (PC3-AR) and DU145 (DU-AR) cells led to reductions in ZEB2 expression, invasiveness, and migration. These cells also exhibited an increase in the levels of E-cadherin (a transcriptional target of ZEB2). Co-transfection of AR and ZEB2 cDNA constructs prevented the decline in invasiveness and migration to a significant extent. Additionally, ZEB2 downregulation was associated with an increase in miR200a/miR200b levels in PC3-AR cells and with a decrease in miR200a/miR200b levels in AR-silenced LNCaP cells. Thus, AR acts as a positive regulator of ZEB2 expression in androgen-dependent cells and as a negative regulator in AI PCa cells. PMID- 24812059 TI - Embracing change. PMID- 24812061 TI - Enzymatic maceration of bone: a gentler technique than boiling. AB - This proof of concept study investigates the removal of soft tissue from human ribs with the use of two common methods: boiling with a laundry detergent and using enzymes. Six individuals were autopsied, and one rib from each individual was removed for testing. Each rib was cut into pieces and afterwards macerated by one of the two methods. DNA extraction was performed to see the effect of the macerations on DNA preservation. Furthermore, the bone pieces were examined in a stereomicroscope to assess for any bone damage. The results demonstrated that both methods removed all flesh/soft tissue from the bones. The DNA analysis showed that DNA was preserved on all the pieces of bones which were examined. Finally, the investigation suggests that enzyme maceration could be gentler on the bones, as the edges appeared less frayed. The enzyme maceration was also a quicker method; it took three hours compared with the traditional method which took about 24 hours. However, a more standardised study should be performed to confirm this. PMID- 24812062 TI - Be my guest! Challenges and practical solutions of undertaking interviews with children in the home setting. AB - This article aims to share critical debate on undertaking interviews with children in the home setting and draws on the authors' extensive research fieldwork. The article focuses on three key processes: planning entry to the child's home, conducting the interviews and exiting the field. In planning entry, we include children's engagement and issues of researcher gender. In conducting the interviews, we consider issues such as the balance of power, the importance of building a rapport, the voluntary nature of consent and the need for a flexible interview structure. Finally, we address exiting from the child's home with sensitivity at the end of the interview and/or research study. Undertaking research in the child's home provides a known and familiar territory for the child, but it means that the researcher faces a number of challenges that require solutions whilst they are a guest in a child's home. PMID- 24812060 TI - The TLR signaling adaptor TRAM interacts with TRAF6 to mediate activation of the inflammatory response by TLR4. AB - TLRs act as sentinels in professional immune cells to detect and initiate the innate immune response to pathogen challenge. TLR4 is a widely expressed TLR, responsible for initiating potent immune responses to LPS. TRAM acts to bridge TLR4 with TRIF, orchestrating the inflammatory response to pathogen challenge. We have identified a putative TRAF6-binding motif in TRAM that could mediate a novel signaling function for TRAM in TLR4 signaling. TRAM and TRAF6 association was confirmed by immunoprecipitation of endogenous, ectopically expressed and recombinant proteins, which was ablated upon mutation of a key Glu residue in TRAM (TRAM E183A). TRAF6 and TRAM were observed colocalizing using confocal microscopy following ectopic expression in cells and the ability of TRAM and TRAM E183A to activate luciferase-linked reporter assays was determined in HEK293 and TRAF6-deficient cells. Importantly, TRAM-deficient macrophages reconstituted with TRAM E183A display significantly reduced inflammatory TNF-alpha, IL-6, and RANTES protein production compared with WT TRAM. These results demonstrate a novel role for TRAM in TLR4-mediated signaling in regulating inflammatory responses via its interaction with TRAF6, distinct from its role as a bridging adaptor between TLR4 and TRIF. PMID- 24812063 TI - Nursing culture: An enemy of evidence-based practice? A focus group exploration. AB - Evidence-based practice (EBP) is challenging for most nurses due to the time constraints of caring for patients and the emerging pressures of a changing health service. To explore these challenges, and thus to establish possible means of overcoming them, three focus groups (n = 17) with children's nurses were conducted. Participants were asked how they would define EBP, what the barriers to EBP were, what skills they needed to help access evidence and how they could integrate evidence into everyday practice. Data were analysed thematically and the anticipated themes of definitions of EBP, barriers, education and nursing culture were determined. Important subthemes were personal and employer disengagement, passivity and lack of resource utilisation. Passive use of evidence readily available in patient folders and on the wards was common. It seemed that little consideration was given to how often this evidence was updated. Nurses define their access to evidence as primarily passive in nature. This is reinforced by a lack of ready access to ongoing education and a perceived lack of investment at institutional level in their continued engagement with evidence. Promoting EBP needs to engage more with those ritual and traditional aspects of nursing culture to challenge these perceptions. PMID- 24812064 TI - Kinship analyses identify fish dispersal events on a temperate coastline. AB - Connectivity is crucial for the persistence and resilience of marine species, the establishment of networks of marine protected areas and the delineation of fishery management units. In the marine environment, understanding connectivity is still a major challenge, due to the technical difficulties of tracking larvae. Recently, parentage analysis has provided a means to address this question effectively. To be effective, this method requires limited adult movement and extensive sampling of parents, which is often not possible for marine species. An alternative approach that is less sensitive to constraints in parental movement and sampling could be the reconstruction of sibships. Here, we directly measure connectivity and larval dispersal in a temperate marine ecosystem through both analytical approaches. We use data from 178 single nucleotide polymorphism markers to perform parentage and sibship reconstruction of the black-faced blenny (Tripterygion delaisi) from an open coastline in the Mediterranean Sea. Parentage analysis revealed a decrease in dispersal success in the focal area over 1 km distance and approximately 6.5% of the juveniles were identified as self recruits. Sibship reconstruction analysis found that, in general, full siblings did not recruit together to the same location, and that the largest distance between recruitment locations was much higher (11.5 km) than found for parent offspring pairs (1.2 km). Direct measurements of dispersal are essential to understanding connectivity patterns in different marine habitats, and show the degree of self-replenishment and sustainability of populations of marine organisms. We demonstrate that sibship reconstruction allows direct measurements of dispersal and family structure in marine species while being more easily applied in those species for which the collection of the parental population is difficult or unfeasible. PMID- 24812066 TI - Determinants of epidemiologic transition in rural Africa: the role of socioeconomic status and drinking water source. AB - BACKGROUND: Many African countries experience a protracted epidemiologic transition, different from the classical transition in western societies. The factors driving this protracted transition are largely unknown. In northeast Ghana, we studied an ongoing epidemiologic transition and investigated the effects of socioeconomic status and drinking water source on the transition. METHODS: During a 9-year period, we followed a cohort of almost 30 000 individuals and collected information on mortality and fertility rates. In addition, using the standards set out by the WHO, we obtained the causes of death by verbal autopsy. Individuals were stratified according to their socioeconomic status and the households' use of an improved or unimproved drinking water source. RESULTS: Mortality rates decreased by -5.0% annually (p<0.001) and the main cause of death shifted from infectious to non-infectious diseases (p=0.014). General fertility rates and child-women ratios decreased annually by -12.7% (p<0.001) and -11.9% (p<0.001), respectively. There was no difference in the decline of mortality and fertility depending on socioeconomic status or drinking water source. CONCLUSIONS: Factors other than socioeconomic status and drinking water source are responsible for the observed declines in mortality and fertility observed during the protracted epidemiologic transition. Identifying the specific determinants of the ongoing transition is of importance, as they could be targeted in order to further improve public health in rural African countries. PMID- 24812065 TI - Human diarrhea infections associated with domestic animal husbandry: a systematic review and meta-analysis. AB - Domestic animal husbandry, a common practice globally, can lead to zoonotic transmission of enteric pathogens. However, this risk has received little attention to date. This systematic review and meta-analysis examines the evidence for an association between domestic exposure to food-producing animals and cases of human diarrhea and specific enteric infections. We performed a systematic review of available literature to examine domestic livestock and poultry as risk factors for diarrhea and applied pre-determined quality criteria. Where possible, we carried out meta-analysis of specific animal-pathogen pairs. We found consistent evidence of a positive association between exposure to domestic food producing animals and diarrheal illness across a range of animal exposures and enteric pathogens. Out of 29 studies included in the review, 20 (69.0%) reported a positive association between domestic animal exposure and diarrhea. Domestic exposure to poultry revealed a substantial association with human campylobacteriosis (OR 2.73, 95% CI 1.90-3.93). Our results suggest that domestic poultry and livestock exposures are associated with diarrheal illness in humans. Failure to ascertain the microbial cause of disease may mask this effect. Exposure to domestic animals should be considered a risk factor for human diarrheal illness and additional studies may identify potential mitigation strategies to address this risk. PMID- 24812067 TI - Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function. AB - INTRODUCTION: Kinesin superfamily (KIF) genes encode motor proteins that have fundamental roles in brain functioning, development, survival and plasticity by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Mouse knockout studies support these important functions in the nervous system. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes impinge on synaptic function. METHODS: By applying next-generation sequencing (NGS) in ID patients, we identified likely pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we performed functional studies at the level of synaptic function in primary rat hippocampal neurons. RESULTS AND CONCLUSIONS: Four males from a single family with a disruptive mutation in the X-linked KIF4A (c.1489-8_1490delins10; p.?- exon skipping) showed mild to moderate ID and epilepsy. A female patient with a de novo missense mutation in KIF5C (c.11465A>C; p.(Glu237Lys)) presented with severe ID, epilepsy, microcephaly and cortical malformation. Knock-down of Kif4a in rat primary hippocampal neurons altered the balance between excitatory and inhibitory synaptic transmission, whereas the mutation in Kif5c affected its protein function at excitatory synapses. Our results suggest that mutations in KIF4A and KIF5C cause ID by tipping the balance between excitatory and inhibitory synaptic excitability. PMID- 24812068 TI - The postprandial plasma rye fingerprint includes benzoxazinoid-derived phenylacetamide sulfates. AB - The bioavailability of whole-grain rye-derived phytochemicals has not yet been comprehensively characterized, and different baking and manufacturing processes can modulate the phytochemical composition of breads and other rye products. The aim of our study was to find key differences in the phytochemical profile of plasma after the consumption of 3 breads containing rye bran when compared with a plain white wheat bread control. Plasma metabolite profiles of 12 healthy middle aged men and women were analyzed using LC quadrupole time-of-flight mass spectrometry metabolomics analysis while fasting and at 60 min, 120 min, 240 min, and 24 h after consuming a meal that contained either 100% whole-grain sourdough rye bread or white wheat bread enriched with native unprocessed rye bran or bioprocessed rye bran. White wheat bread was used as the control. The meals were served in random order after a 12-h overnight fast, with at least 3 d between each occasion. Two sulfonated phenylacetamides, hydroxy-N-(2-hydroxyphenyl) acetamide and N-(2-hydroxyphenyl) acetamide, potentially derived from the benzoxazinoid metabolites, were among the most discriminant postprandial plasma biomarkers distinguishing intake of breads containing whole-meal rye or rye bran from the control white wheat bread. Furthermore, subsequent metabolite profiling analysis of the consumed breads indicated that different bioprocessing/baking techniques involving exposure to microbial metabolism (e.g., sourdough fermentation) have a central role in modulating the phytochemical content of the whole-grain and bran-rich breads. PMID- 24812069 TI - Urea recycling contributes to nitrogen retention in calves fed milk replacer and low-protein solid feed. AB - Urea recycling, with urea originating from catabolism of amino acids and hepatic detoxification of ammonia, is particularly relevant for ruminant animals, in which microbial protein contributes substantially to the metabolizable protein supply. However, the quantitative contribution of urea recycling to protein anabolism in calves during the transition from preruminants (milk-fed calves) to ruminants [solid feed (SF)-fed calves] is unknown. The aim of this study was to quantify urea recycling in milk-fed calves when provided with low-protein SF. Forty-eight calves [164 +/- 1.6 kg body weight (BW)] were assigned to 1 of 4 SF levels [0, 9, 18, and 27 g of dry matter (DM) SF . kg BW(-0.75) . d-1] provided in addition to an identical amount of milk replacer. Urea recycling was quantified after a 24-h intravenous infusion of [15N2]urea by analyzing urea isotopomers in 68-h fecal and urinary collections. Real-time qPCR was used to measure gene expression levels of bovine urea transporter B (bUTB) and aquaglyceroporin-3 and aquaglyceroporin-7 in rumen wall tissues. For every incremental gram of DM SF intake (g DM . kg(0.75)), nitrogen intake increased by 0.70 g, and nitrogen retention increased by 0.55 g (P < 0.01). Of this increase in nitrogen retention, 19% could be directly explained by urea recycling. Additionally, part of the observed increase in nitrogen retention could be explained by the extra protein provided by the SF and likely by a greater efficiency of postabsorptive use of nitrogen for gain. Ruminal bUTB abundance increased (P < 0.01) with SF provision. Aquaglyceroporin-3 expression increased (P < 0.01) with SF intake, but aquaglyceroporin-7 expression did not. We conclude that in addition to the increase in digested nitrogen, urea recycling contributes to the observed increase in nitrogen retention with increasing SF intake in milk fed calves. Furthermore, ruminal bUTB and aquaglyceroporin-3 expression are upregulated with SF intake, which might be associated with urea recycling. PMID- 24812070 TI - Mushrooms and Health Summit proceedings. AB - The Mushroom Council convened the Mushrooms and Health Summit in Washington, DC, on 9-10 September 2013. The proceedings are synthesized in this article. Although mushrooms have long been regarded as health-promoting foods, research specific to their role in a healthful diet and in health promotion has advanced in the past decade. The earliest mushroom cultivation was documented in China, which remains among the top global mushroom producers, along with the United States, Italy, The Netherlands, and Poland. Although considered a vegetable in dietary advice, mushrooms are fungi, set apart by vitamin B-12 in very low quantity but in the same form found in meat, ergosterol converted with UV light to vitamin D2, and conjugated linoleic acid. Mushrooms are a rare source of ergothioneine as well as selenium, fiber, and several other vitamins and minerals. Some preclinical and clinical studies suggest impacts of mushrooms on cognition, weight management, oral health, and cancer risk. Preliminary evidence suggests that mushrooms may support healthy immune and inflammatory responses through interaction with the gut microbiota, enhancing development of adaptive immunity, and improved immune cell functionality. In addition to imparting direct nutritional and health benefits, analysis of U.S. food intake survey data reveals that mushrooms are associated with higher dietary quality. Also, early sensory research suggests that mushrooms blended with meats and lower sodium dishes are well liked and may help to reduce intakes of red meat and salt without compromising taste. As research progresses on the specific health effects of mushrooms, there is a need for effective communication efforts to leverage mushrooms to improve overall dietary quality. PMID- 24812071 TI - Integrating group counseling, cell phone messaging, and participant-generated songs and dramas into a microcredit program increases Nigerian women's adherence to international breastfeeding recommendations. AB - In northern Nigeria, interventions are urgently needed to narrow the large gap between international breastfeeding recommendations and actual breastfeeding practices. Studies of integrated microcredit and community health interventions documented success in modifying health behaviors but typically had uncontrolled designs. We conducted a cluster-randomized controlled trial in Bauchi State, Nigeria, with the aim of increasing early breastfeeding initiation and exclusive breastfeeding among female microcredit clients. The intervention had 3 components. Trained credit officers led monthly breastfeeding learning sessions during regularly scheduled microcredit meetings for 10 mo. Text and voice messages were sent out weekly to a cell phone provided to small groups of microcredit clients (5-7 women). The small groups prepared songs or dramas about the messages and presented them at the monthly microcredit meetings. The control arm continued with the regular microcredit program. Randomization occurred at the level of the monthly meeting groups. Pregnant clients were recruited at baseline and interviewed again when their infants were aged >=6 mo. Logistic regression models accounting for clustering were used to estimate the odds of performing recommended behaviors. Among the clients who completed the final survey (n = 390), the odds of exclusive breastfeeding to 6 mo (OR: 2.4; 95% CI: 1.4, 4.0) and timely breastfeeding initiation (OR: 2.6; 95% CI: 1.6, 4.1) were increased in the intervention vs. control arm. Delayed introduction of water explained most of the increase in exclusive breastfeeding among clients receiving the intervention. In conclusion, a breastfeeding promotion intervention integrated into microcredit increased the likelihood that women adopted recommended breastfeeding practices. This intervention could be scaled up in Nigeria, where local organizations provide microcredit to >500,000 clients. Furthermore, the intervention could be adopted more widely given that >150 million women, many of childbearing age, are involved in microfinance globally. PMID- 24812073 TI - Continuous measurement of radiation from radionuclides deposited on the ground using in situ gamma-ray spectrometry. AB - Until recently, in situ measurements in a network of radiation-measuring sites at the Deutscher Wetterdienst could only be started if all components had been put up in an instrumentation shelter and the detector had been cooled for ~6 h. Within a project on partial automation of radioactivity monitoring, it has now become possible to permanently equip the measuring sites, i.e. the instrumentation shelter, with the components for in situ gamma-ray spectrometry. The cooling technology of the detectors changed from liquid nitrogen based to an electric system and the instrumentation shelters could be fixed with air conditioning to minimise the influence of changes in the outside temperature. PMID- 24812072 TI - A dose-response strategy reveals differences between normal-weight and obese men in their metabolic and inflammatory responses to a high-fat meal. AB - A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (iAUC) = 22.9 +/- 6.8 pg/mL * 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 +/- 0.5 mmol/L * 6 h vs. 6.0 +/- 0.5 mmol/L * 6 h; P = 0.015) but not in the normal-weight group (4.3 +/- 0.5 mmol/L * 6 h vs. 4.8 +/- 0.5 mmol/L * 6 h; P = 0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068. PMID- 24812074 TI - Characterizing switching and congruency effects in the Implicit Association Test as reactive and proactive cognitive control. AB - Recent research has identified an important role for task switching, a cognitive control process often associated with executive functioning, in the Implicit Association Test (IAT). However, switching does not fully account for IAT effects, particularly when performance is scored using more recent d-score formulations. The current study sought to characterize multiple control processes involved in IAT performance through the use of event-related brain potentials (ERPs). Participants performed a race-evaluative IAT while ERPs were recorded. Behaviorally, participants experienced superadditive reaction time costs of incongruency and task switching, consistent with previous studies. The ERP showed a marked medial frontal negativity (MFN) 250-450 ms post-stimulus at midline fronto-central locations that were more negative for incongruent than congruent trials but more positive for switch than for no-switch trials, suggesting separable control processes are engaged by these two factors. Greater behavioral IAT bias was associated with both greater switch-related and congruency-related ERP activity. Findings are discussed in terms of the Dual Mechanisms of Control model of reactive and proactive cognitive control. PMID- 24812075 TI - Mindfulness-based stress reduction for posttraumatic stress symptoms: building acceptance and decreasing shame. AB - Mindfulness-based psychotherapies are associated with reductions in depression and anxiety. However, few studies address whether mindfulness-based approaches may benefit individuals with posttraumatic stress symptoms. The current pilot study explored whether group mindfulness-based stress reduction therapy reduced posttraumatic stress symptoms, depression, and negative trauma-related appraisals in 9 adult participants who reported trauma exposure and posttraumatic stress or depression. Participants completed 8 sessions of mindfulness-based stress reduction treatment, as well as pretreatment, midtreatment, and posttreatment assessments of psychological symptoms, acceptance of emotional experiences, and trauma appraisals. Posttraumatic stress symptoms, depression, and shame-based trauma appraisals were reduced over the 8-week period, whereas acceptance of emotional experiences increased. Participants' self-reported amount of weekly mindfulness practice was related to increased acceptance of emotional experiences from pretreatment to posttreatment. Results support the utility of mindfulness based therapies for posttraumatic stress symptoms and reinforce studies that highlight reducing shame and increasing acceptance as important elements of recovery from trauma. PMID- 24812076 TI - The need for continued investigation of lung cancer risk in coal miners. PMID- 24812077 TI - Perplexing lesions of the sinonasal cavity and skull base: IgG4-related and similar inflammatory diseases. AB - OBJECTIVE: IgG4-related disease (IgG4RD) causing sinonasal and skull base pathology is uncommonly described. We present a series of suspected IgG4RD patients, with a pertinent review of the literature to highlight diagnostic challenges. STUDY DESIGN: Case series. SETTING: Academic tertiary care center. SUBJECTS AND METHODS: Case series of patients with IgG4RD or suspected IgG4RD involving the sinonasal cavity and skull base. RESULTS: We present 4 patients with atypical sinonasal and/or skull base disease who were noted to have IgG4 positive plasma cell infiltration on immunohistochemistry of biopsy specimens. IgG4RD, a recently described entity affecting multiple organs, is characterized by lymphoplasmacytic infiltration and often elevated serum IgG4. IgG4RD can masquerade as malignancy or infection but responds to glucocorticosteroid and immunosuppressant therapy. IgG4RD has been infrequently reported presenting as sinonasal or skull base lesions, and definitive diagnostic criteria for these regions are not established. In our series, IgG4RD was suspected in all 4 patients, but only 1 met all current criteria for definitive diagnosis. All 4 patients, however, responded to corticosteroid therapy, and 1 was placed on long term azathioprine. CONCLUSION: IgG4RD is rarely described in the sinonasal cavity and skull base, and specific diagnostic criteria for such disease have not been defined. We present a series of patients with IgG4-positive plasma cell inflammatory pathology who were suspected to have IgG4RD. Our series highlights diagnostic challenges associated with these patients. Tumefactive and destructive sinonasal-skull base lesions with a plasma cell-rich infiltrate should incite suspicion of IgG4RD, and immunohistochemistry for IgG4-positive plasma cells should be performed. PMID- 24812078 TI - Learning Progression in the Use of Sialendoscopy for Sialolithiasis: Effect on Gland Preservation. AB - OBJECTIVE: Evaluate how learning progression affects outcomes for the use of sialendoscopy for sialolithiasis. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care center. SUBJECTS AND METHODS: A retrospective chart review was conducted on 81 patients presenting with sialolithiasis between 2008 and 2012 who underwent surgical intervention on 85 salivary glands. Outcomes compared between the first 43 and subsequent 42 consecutive glands included successful removal, surgical method, and need for further intervention. RESULTS: For the first 43 patients (group A), mean age was 47.3 years (range, 15-77), and 44.2% were male. For the second 38 patients (group B), mean age was 49.9 (range, 23-76), and 50% were male. Mean stone size was similar in both groups; 8.3 versus 7.6 mm, respectively. In cases of stone visualization and removal, complete removal without gland excision was accomplished in 78.4% of cases in group A versus 94.3% in group B (P = .04). Endoscopic removal occurred in 24.3% of patients in group A, versus 45.8% in group B. A combined approach was used in 54.1% of patients in group A versus 48.6% in group B. In group A, 18.9% underwent gland removal as part of initial intervention versus 0% in group B (P = .007). Overall gland preservation was 81.4% in group A versus 97.6% in group B (P = .015). CONCLUSION: This study documents the effect of learning curve on sialendoscopy for the management of sialolithiasis. With experience, the success of sialendoscopy increases with a significant decrease in the number of gland excisions. PMID- 24812079 TI - Pathological review of turbinate tissue from functional nasal surgery: incurring costs without adding quality. AB - OBJECTIVE: Inferior turbinate surgery for nasal obstruction can be performed in a variety of ways. Only a few of these methods produce tissue that can be sent for pathologic analysis. According to the College of American Pathologists, turbinate tissues are not exempt from requisite pathologic evaluation. Our objectives were to evaluate the clinical value and cost implications of routine pathological examination of turbinate specimens. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: Charts of patients who underwent an inferior turbinate procedure for nasal obstruction between January 2008 and August 2011 were reviewed. RESULTS: Thirteen hundred consecutive cases from 17 surgeons were identified. Among these patients, 223 (17%) underwent an isolated turbinate reduction procedure and 779 (59%) underwent a reduction procedure in conjunction with a septoplasty. The remaining patients had a turbinate procedure in addition to another head and neck procedure. Only 591 (45%) turbinate reduction procedures were performed by methods that were tissue producing, and of these, 137 (23%) were sent for pathologic analysis. All submitted specimens received a gross examination and 123 (90%) also underwent histologic analysis. No abnormalities were reported. CONCLUSION: At our institution, most surgeons did not submit turbinate tissues for pathologic examination even when a specimen was produced. Of the specimens sent, no abnormal pathologic results were identified. Our results suggest that routine pathologic evaluation of inferior turbinate specimens may not contribute to patient care and perhaps represents an unnecessary cost. PMID- 24812080 TI - Vascular Anomalies in Otolaryngology-Head and Neck Surgery Resident Education. AB - The evaluation and treatment of vascular anomalies is rapidly evolving. In recent years, improved imaging, medical therapies, interventional radiology procedures, and technical advances have led to improved functional and aesthetic outcomes with reduced morbidity. With management of vascular anomalies becoming increasingly complex, we wanted to assess the opinions of otolaryngology-head and neck surgery resident trainees regarding education in this evolving subspecialty. The results of our survey show that a significant majority of trainees feel that vascular anomalies are best managed by a multidisciplinary team, consistent with practice in large vascular anomalies centers. While training in this area does not seem to be deficient, it may be helpful to identify those otolaryngology residents who are interested in gaining exposure to patients with vascular anomalies, so that they may seek additional subspecialty experiences to complement their otolaryngology training. PMID- 24812081 TI - Occult Primary Head and Neck Squamous Cell Carcinoma: Utility of Discovering Primary Lesions. AB - OBJECTIVE: Cancer of an unknown primary (CUP) squamous cell carcinoma metastatic to cervical lymph nodes is a challenging problem for the treating physician. Our aim is to determine if identification of the primary tumor is associated with improved oncologic outcomes and/or tumor characteristics including human papilloma virus (HPV) status. STUDY DESIGN: Retrospective, matched-pairs analysis contrasting 2 cohorts based upon discovery of primary lesion. SETTING: Tertiary teaching hospital. SUBJECTS AND METHODS: Records of 136 patients initially diagnosed as carcinoma of unknown primary were retrospectively reviewed (1980 2010) and divided into 2 cohorts based on discovery of the primary lesion. Primary outcome measures were overall survival and time to recurrence according to Kaplan-Meier analysis. A nested subset of 22 patients in which the primary was discovered were matched to 22 patients remaining undiscovered according to nodal stage and age. RESULTS: Discovered lesions were more likely to exhibit HPV positivity (P < .001). Matched-pairs analyses demonstrated that discovery of the primary was associated with better overall survival (HR = 0.125; 95% confidence interval [CI], 0.019-0.822; P = .030). Discovery of the primary was associated with improved cause-specific survival (HR = 0.142; 95% CI, 0.021-0.93; P = .0418) and disease-free survival (HR = 0.25; 95% CI, 0.069-0.91; P = .03). CONCLUSION: HPV positivity is associated with discovery of the primary tumor. Discovery of the primary lesion is associated with improved overall survival, cause-specific survival, and disease-free survival in patients initially presenting as CUP in matched-pair and cohort comparison analyses. PMID- 24812082 TI - Asymmetry of White Matter Pathways in Developing Human Brains. AB - Little is known about the emergence of structural asymmetry of white matter tracts during early brain development. We examined whether and when asymmetry in diffusion parameters of limbic and association white matter pathways emerged in humans in 23 brains ranging from 15 gestational weeks (GW) up to 3 years of age (11 ex vivo and 12 in vivo cases) using high-angular resolution diffusion imaging tractography. Age-related development of laterality was not observed in a limbic connectional pathway (cingulum bundle or fornix). Among the studied cortico cortical association pathways (inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus, and arcuate fasciculus), only the ILF showed development of age-related laterality emerging as early as the second trimester. Comparisons of ages older and younger than 40 GW revealed a leftward asymmetry in the cingulum bundle volume and a rightward asymmetry in apparent diffusion coefficient and leftward asymmetry in fractional anisotropy in the ILF in ages older than 40 GW. These results suggest that morphometric asymmetry in cortical areas precedes the emergence of white matter pathway asymmetry. Future correlative studies will investigate whether such asymmetry is anatomically/genetically driven or associated with functional stimulation. PMID- 24812083 TI - Robust Long-Range Coordination of Spontaneous Neural Activity in Waking, Sleep and Anesthesia. AB - Although the emerging field of functional connectomics relies increasingly on the analysis of spontaneous fMRI signal covariation to infer the spatial fingerprint of the brain's large-scale functional networks, the nature of the underlying neuro-electrical activity remains incompletely understood. In part, this lack in understanding owes to the invasiveness of electrophysiological acquisition, the difficulty in their simultaneous recording over large cortical areas, and the absence of fully established methods for unbiased extraction of network information from these data. Here, we demonstrate a novel, data-driven approach to analyze spontaneous signal variations in electrocorticographic (ECoG) recordings from nearly entire hemispheres of macaque monkeys. Based on both broadband analysis and analysis of specific frequency bands, the ECoG signals were found to co-vary in patterns that resembled the fMRI networks reported in previous studies. The extracted patterns were robust against changes in consciousness associated with sleep and anesthesia, despite profound changes in intrinsic characteristics of the raw signals, including their spectral signatures. These results suggest that the spatial organization of large-scale brain networks results from neural activity with a broadband spectral feature and is a core aspect of the brain's physiology that does not depend on the state of consciousness. PMID- 24812084 TI - Functional Network Development During the First Year: Relative Sequence and Socioeconomic Correlations. AB - The first postnatal year is characterized by the most dramatic functional network development of the human lifespan. Yet, the relative sequence of the maturation of different networks and the impact of socioeconomic status (SES) on their development during this critical period remains poorly characterized. Leveraging a large, normally developing infant sample with multiple longitudinal resting state functional magnetic resonance imaging scans during the first year (N = 65, scanned every 3 months), we aimed to delineate the relative maturation sequence of 9 key brain functional networks and examine their SES correlations. Our results revealed a maturation sequence from primary sensorimotor/auditory to visual to attention/default-mode, and finally to executive control networks. Network-specific critical growth periods were also identified. Finally, marginally significant positive SES-brain correlations were observed at 6 months of age for both the sensorimotor and default-mode networks, indicating interesting SES effects on functional brain maturation. To the best of our knowledge, this is the first study delineating detailed longitudinal growth trajectories of all major functional networks during the first year of life and their SES correlations. Insights from this study not only improve our understanding of early brain development, but may also inform the critical periods for SES expression during infancy. PMID- 24812085 TI - Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice. AB - Epilepsies are debilitating neurological disorders characterized by repeated episodes of pathological seizure activity. Absence epilepsy (AE) is a poorly understood type of seizure with an estimated 30% of affected patients failing to respond to antiepileptic drugs. Thus, novel therapies are needed for the treatment of AE. A promising cell-based therapeutic strategy is centered on transplantation of embryonic neural stem cells from the medial ganglionic eminence (MGE), which give rise to gamma-aminobutyric acidergic (GABAergic) interneurons during embyronic development. Here, we used the Stargazer (Stg) mouse model of AE to map affected loci using c-Fos immunohistochemistry, which revealed intense seizure-induce activity in visual and somatosensory cortices. We report that transplantation of MGE cells into the primary visual cortex (V1) of Stg mice significantly reduces AE episodes and lowers mortality. Electrophysiological analysis in acute cortical slices of visual cortex demonstrated that Stg V1 neurons exhibit more pronounced increases in activity in response to a potassium-mediated excitability challenge than wildtypes (WT). The defective network activity in V1 was significantly altered following WT MGE transplantation, associating it with behavioral rescue of seizures in Stgs. Taken together, these findings present MGE grafting in the V1 as a possible clinical approach in the treatment of AE. PMID- 24812086 TI - DICER1 is essential for survival of postmitotic rod photoreceptor cells in mice. AB - Photoreceptor cell death is the proximal cause of blindness in many retinal degenerative disorders; hence, understanding the gene regulatory networks that promote photoreceptor survival is at the forefront of efforts to combat blindness. Down-regulation of the microRNA (miRNA)-processing enzyme DICER1 in the retinal pigmented epithelium has been implicated in geographic atrophy, an advanced form of age-related macular degeneration (AMD). However, little is known about the function of DICER1 in mature rod photoreceptor cells, another retinal cell type that is severely affected in AMD. Using a conditional-knockout (cKO) mouse model, we report that loss of DICER1 in mature postmitotic rods leads to robust retinal degeneration accompanied by loss of visual function. At 14 wk of age, cKO mice exhibit a 90% reduction in photoreceptor nuclei and a 97% reduction in visual chromophore compared with those in control littermates. Before degeneration, cKO mice do not exhibit significant defects in either phototransduction or the visual cycle, suggesting that miRNAs play a primary role in rod photoreceptor survival. Using comparative small RNA sequencing analysis, we identified rod photoreceptor miRNAs of the miR-22, miR-26, miR-30, miR-92, miR 124, and let-7 families as potential factors involved in regulating the survival of rods. PMID- 24812087 TI - Polymerase I and transcript release factor (PTRF) regulates adipocyte differentiation and determines adipose tissue expandability. AB - Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet glucose-tolerant mice, and prediabetic mice with impaired glucose tolerance and reduced circulating insulin. Using proteomics, we compared subcutaneous adipose tissues from mice in these groups and found that the expression of PTRF (polymerase I and transcript release factor) associated selectively with their glucose tolerance status. Lentiviral and pharmacologically overexpressed PTRF, whose function is critical for caveola formation, compromised adipocyte differentiation of cultured 3T3-L1cells. In human adipose tissue, PTRF mRNA levels positively correlated with markers of lipolysis and cellular senescence. Furthermore, a negative relationship between telomere length and PTRF mRNA levels was observed in human subcutaneous fat. PTRF is associated with limited adipose tissue expansion underpinning the key role of caveolae in adipocyte regulation. Furthermore, PTRF may be a suitable adipocyte marker for predicting pathological obesity and inform clinical management. PMID- 24812088 TI - Syncytin proteins incorporated in placenta exosomes are important for cell uptake and show variation in abundance in serum exosomes from patients with preeclampsia. AB - Exosomes are extracellular vesicles that mediate intercellular communication and are involved in several biological processes. The objective of our study was to determine whether endogenous retrovirus group WE, member l (ERVWE1)/syncytin-1 and endogenous retrovirus group FRD, member 1 (ERVFRDE1)/syncytin-2, encoded by human endogenous retrovirus (HERV) envelope (env) genes, are present at the surface of exosomes produced by placenta-derived villous cytotrophoblasts and whether they play a role in cellular uptake of exosomes. In addition, we sought to determine whether these proteins are present in various abundances in serum derived exosomes from normal pregnant women vs. women with preeclampsia (PE). Isolated exosomes were analyzed for their content by Western blot, a bead associated flow cytometry approach, and a syncytin-2 ELISA. Binding and uptake were tested through confocal and electron microscopy using the BeWo choriocarcinoma cell line. Quality control of exosome preparations consisted of detection of exosomal and nonexosomal markers. Exosome-cell interactions were compared between cells incubated in the presence of control exosomes, syncytin-1 or syncytin-2-deprived exosomes, or exosomes solely bearing the uncleaved forms of these HERV env proteins. From our data, we conclude that villous cytotrophoblast exosomes are positive for both env proteins and are rapidly taken up by BeWo cells in a syncytin-1- and syncytin-2-dependent manner and that syncytin-2 is reduced in serum-derived exosomes from women with PE when compared to exosomes from normal pregnant women. PMID- 24812089 TI - No conspiracy regarding recommendation for a group B meningococcus vaccine. PMID- 24812091 TI - Glaucoma referral schemes could help save money in England. PMID- 24812090 TI - No evidence for political manipulation regarding the new group B meningococcus vaccine. PMID- 24812092 TI - Ophthalmologists should take an active role in community eye care. PMID- 24812093 TI - The need for more integration of primary and secondary eye care. PMID- 24812094 TI - Containing escalating referrals by bringing optometrists into the NHS. PMID- 24812095 TI - Current medical education is at odds with authenticity--a master stroke in comical understatement. PMID- 24812096 TI - Sabaratnam Arulkumaran: dreaming of entering politics. PMID- 24812097 TI - Council of Europe issues guide to end of life care. PMID- 24812098 TI - FDA questions use of aspirin for primary prevention of stroke and heart attack. PMID- 24812099 TI - Circumcision programme to prevent AIDS in Africa is starting to slow down. PMID- 24812100 TI - Stress distribution in the mini-screw and alveolar bone during orthodontic treatment: a finite element study analysis. AB - OBJECTIVE: This study aimed to investigate the reason for high failure rates of mini-screws during orthodontic treatment. We hypothesized that decreasing the length of the mini-screw outside the bone relative to the length inside the bone (outside/inside length ratio) and equalising it to the tooth crown/root ratio would lead to increased stability of the mini-screw against lateral loading when assessed using finite element analysis. METHODS: We analysed stress distribution of mini-screws in the cortical and trabecular bone and von Mises stress levels when a 2-N force was applied to the head of four mini-screws of 6, 8, 10 and 12 mm in length. The direction of the force was perpendicular to the major axis of the screws. RESULTS: Stress levels of screws in cortical bone increased in proportion to the length of mini-screws outside the bone. The length of mini screws inside the bone did not affect stress levels in the cortical bone. CONCLUSIONS: The results of this finite element analysis indicate that to stabilize the mini-screw, controlling the screw length outside the bone is more important than controlling the outside/inside length ratio. PMID- 24812101 TI - Empowerment in the field of health promotion: recognizing challenges in working toward equity. AB - Over the last 25 years, the language of empowerment has been woven into the guiding missions and descriptions of institutions, funding and projects globally. Although theoretical understandings of empowerment within the domain of health promotion remain contentious, we have little idea of how a shift toward an empowerment agenda has affected the daily work of those in the field of health promotion. A systematic examination of the implementation of the empowerment agenda is important as it can help us understand how redistributive agendas are received within the multiple institutional contexts in which health promotion work is carried out. The goal of this study, therefore, was to try to understand the empowerment agenda within the context of everyday health promotion. We conducted semi-structured interviews with health promoters from a variety of geographical regions, institutional backgrounds, and job capacities. Essentially we found that empowerment remains conceptually dear to health promoters' understanding of their work, yet at the same time, mainstreaming empowerment is at odds with central trends and initiatives that govern this work. We argue that many of the stumbling blocks that have hindered this specific agenda are actually central stumbling blocks for the wider field of health promotion. We examine some of the barriers to implementing transformational change. Overcoming the primary limitations uncovered in this exploration of empowerment is actually crucial to progressive work in health promotion in general, particularly work that would seek to lessen inequities. PMID- 24812102 TI - Stress generation and tailoring of electronic properties of expanded graphite by click chemistry. AB - The generation of stress in expanded graphite (E-GPT) due to covalent attachment of bulky side groups connected via a hetero atom is reported. Specifically, E-GPT is modified at different levels of grafting using "click" chemistry to graft 1 ethynyl-4-fluoro benzene onto graphene sheets via a triazole ring. In the range of grafting densitites examined, Raman spectroscopy indicates that the stress generated in graphene is linearly dependent on the extent of grafting. The functionalized graphene platelets with 6% functionalization transform from semi metal behavior of the pristine material to semi-conductor behavior and indicates the ability of functionalization to change optical and electronic properties of graphene platelets similar to the deposition of thin layers of top gate oxides onto graphene. PMID- 24812103 TI - Behavioural outcomes at 3 years of age among late preterm infants admitted to neonatal intensive care: a cohort study. AB - OBJECTIVE: Examine the behavioural outcomes at age 3 years of late preterm infants (LPIs) who were admitted to neonatal intensive care (NIC) in comparison with LPIs who were not admitted. METHOD: This cohort study prospectively recruited 225 children born late preterm (34-36(+6) weeks gestation) in 2006 in Northern Ireland, now aged 3 years. Two groups were compared: LPIs who received NIC (study; n=103) and LPIs who did not receive NIC (control; n=122). Parents/guardians completed the Child Behaviour Checklist/11/2-5. Descriptive maternal and infant data were also collected. RESULTS: As expected LPI children admitted to NIC had higher medical risk than the non-admitted comparison group (increased caesarean section, born at earlier gestation, lower birth weight and an episode of resuscitation at birth). LPIs admitted to NIC scored higher on the Child Behaviour Checklist/11/2-5 compared with those who were not admitted indicating more behavioural problems; this was statistically significant for the Aggressive Behaviour Subscale (z=-2.36) and the Externalising Problems Scale (z= 2.42). The group difference on the Externalising Problems Scale was no longer significant after controlling for gender, gestational age and deprivation score. CONCLUSIONS: This study provides valuable data on the behaviour at age 3 years of LPIs admitted to NIC compared with LPIs not admitted to NIC. Further research would be beneficial to explore medical and psychosocial explanations for observed differences between groups using large prospective cohort studies. PMID- 24812104 TI - CeasIng Cpap At standarD criteriA (CICADA): impact on weight gain, time to full feeds and caffeine use. AB - INTRODUCTION: In our previous randomised controlled trial (RCT), we have shown in preterm babies (PBs) <30 weeks gestation that CeasIng Cpap At standarD criteriA (CICADA (method 1)) compared with cycling off continuous positive airway pressure (CPAP) gradually (method 2) or cycling off CPAP gradually with low flow air/oxygen during periods off CPAP (method 3) reduces CPAP cessation time in PBs <30 weeks gestation. METHOD: This retrospective study reviewed weight gain, time to reach full feeds and time to cease caffeine in PBs previously enrolled in the RCT. RESULTS: Data were collected from 162 of the 177 PBs, and there was no significant difference in the projected weight gain between the three methods. Based on intention to treat, the time taken to reach full feeds for all three methods showed no significant difference. However, post hoc analysis showed the CICADA method compared with cycling off gradually just failed significance (30.3+/-1.6 vs 31.1+/-2.4 (weeks corrected gestational age (Wks CGA+/-SD)), p=0.077). Analysis of time to cease caffeine showed there was a significant difference between the methods with PBs randomised to the CICADA method compared with the cycling off method ceasing caffeine almost a week earlier (33.6+/-2.4 vs 34.5+/-2.8 (Wks CGA+/-SD), p=0.02). CONCLUSIONS: This retrospective study provides evidence to substantiate the optimum method of ceasing CPAP; the CICADA method, does not adversely affect weight gain, time to reach full feeds and may reduce time to cease caffeine in PBs <30 weeks gestation. PMID- 24812105 TI - The Putative E3 Ubiquitin Ligase ECERIFERUM9 Regulates Abscisic Acid Biosynthesis and Response during Seed Germination and Postgermination Growth in Arabidopsis. AB - The ECERIFERUM9 (CER9) gene encodes a putative E3 ubiquitin ligase that functions in cuticle biosynthesis and the maintenance of plant water status. Here, we found that CER9 is also involved in abscisic acid (ABA) signaling in seeds and young seedlings of Arabidopsis (Arabidopsis thaliana). The germinated embryos of the mutants exhibited enhanced sensitivity to ABA during the transition from reversible dormancy to determinate seedling growth. Expression of the CER9 gene is closely related to ABA levels and displays a similar pattern to that of ABSCISIC ACID-INSENSITIVE5 (ABI5), which encodes a positive regulator of ABA responses in seeds. cer9 mutant seeds exhibited delayed germination that is independent of seed coat permeability. Quantitative proteomic analyses showed that cer9 seeds had a protein profile similar to that of the wild type treated with ABA. Transcriptomics analyses revealed that genes involved in ABA biosynthesis or signaling pathways were differentially regulated in cer9 seeds. Consistent with this, high levels of ABA were detected in dry seeds of cer9. Blocking ABA biosynthesis by fluridone treatment or by combining an ABA-deficient mutation with cer9 attenuated the phenotypes of cer9. Whereas introduction of the abi1-1, abi3-1, or abi4-103 mutation could completely eliminate the ABA hypersensitivity of cer9, introduction of abi5 resulted only in partial suppression. These results indicate that CER9 is a novel negative regulator of ABA biosynthesis and the ABA signaling pathway during seed germination. PMID- 24812107 TI - The Arabidopsis NUCLEUS- AND PHRAGMOPLAST-LOCALIZED KINASE1-Related Protein Kinases Are Required for Elicitor-Induced Oxidative Burst and Immunity. AB - Plant immunity is activated through complex and cross-talking transduction pathways that include a mitogen-activated protein kinase phosphorylation cascade. Here, we have investigated the role in immunity of the Arabidopsis (Arabidopsis thaliana) gene subfamily that encodes the mitogen-activated protein triple kinases indicated as ARABIDOPSIS NUCLEUS- AND PHRAGMOPLAST-LOCALIZED KINASE1 RELATED PROTEIN KINASE1 (ANP1), ANP2, and ANP3. For this study, we used representative danger signals (elicitors) belonging to the classes of the damage- and pathogen-associated molecular patterns, i.e. oligogalacturonides, linear fragments derived from the plant cell wall homogalacturonan, and the peptide elf18 derived from the bacterial elongation factor thermo-unstable. Analyses of single and double as well as conditional triple mutants show that ANPs are required for elicitor-triggered defense responses and protection against the necrotrophic fungus Botrytis cinerea. Notably, ANPs are also required for both the elicitor-induced oxidative burst and the transduction of the hydrogen peroxide signal but not for the inhibition of auxin-induced gene expression, indicating that this response can be uncoupled from the activation of defense responses. Our findings point to ANPs as key transduction elements that coordinate damage- and pathogen-associated molecular pattern-triggered immunity and orchestrate reactive oxygen species accumulation and signaling. PMID- 24812106 TI - The Arabidopsis Endosomal Sorting Complex Required for Transport III Regulates Internal Vesicle Formation of the Prevacuolar Compartment and Is Required for Plant Development. AB - We have established an efficient transient expression system with several vacuolar reporters to study the roles of endosomal sorting complex required for transport (ESCRT)-III subunits in regulating the formation of intraluminal vesicles of prevacuolar compartments (PVCs)/multivesicular bodies (MVBs) in plant cells. By measuring the distributions of reporters on/within the membrane of PVC/MVB or tonoplast, we have identified dominant negative mutants of ESCRT-III subunits that affect membrane protein degradation from both secretory and endocytic pathways. In addition, induced expression of these mutants resulted in reduction in luminal vesicles of PVC/MVB, along with increased detection of membrane-attaching vesicles inside the PVC/MVB. Transgenic Arabidopsis (Arabidopsis thaliana) plants with induced expression of ESCRT-III dominant negative mutants also displayed severe cotyledon developmental defects with reduced cell size, loss of the central vacuole, and abnormal chloroplast development in mesophyll cells, pointing out an essential role of the ESCRT-III complex in postembryonic development in plants. Finally, membrane dissociation of ESCRT-III components is important for their biological functions and is regulated by direct interaction among Vacuolar Protein Sorting-Associated Protein20-1 (VPS20.1), Sucrose Nonfermenting7-1, VPS2.1, and the adenosine triphosphatase VPS4/SUPPRESSOR OF K+ TRANSPORT GROWTH DEFECT1. PMID- 24812108 TI - Flower morphology and floral sequence in Artemisia annua (Asteraceae)1. AB - * PREMISE OF THE STUDY: Artemisia annua produces phytochemicals possessing antimalarial, antitumor, anti-inflammatory, and anthelmintic activities. The main active ingredient, artemisinin, is extremely effective against malaria. Breeding to develop cultivars producing high levels of artemisinin can help meet worldwide demand for artemisinin and its derivatives. However, fundamental reproductive processes, such as the sequence of flowering and fertility, are not well understood and impair breeding and seed propagation programs.* METHODS: Capitulum structure and floral sequence were studied using light and scanning electron microscopy to describe inflorescence architecture, floret opening, and seed set.* KEY RESULTS: Florets are minute and born in capitula containing pistillate ray florets and hermaphroditic disk florets. Ray florets have elongated stigmatic arms that extend prior to disk floret opening. Disk florets exhibit protandry. During the staminate phase, pollen is released within a staminate tube and actively presented with projections at the tip of stigmas as the pistil elongates. During the pistillate phase, stigmatic arms bifurcate and reflex. Stigmas are of the dry type and stain positively for polysaccharides, lipids, and an intact cuticle. Floret numbers vary with genotype, and capitula are predominantly composed of disk florets. Both ray and disk florets produce filled seed.* CONCLUSIONS: Gynomonoecy, early opening of ray florets, and dichogamy of disk florets promote outcrossing in A. annua For breeding and seed development, flowering in genotypes can be synchronized under short days according to the floral developmental stages defined. Floret number and percentage seed fill vary with genotype and may be a beneficial selection criterion. PMID- 24812109 TI - Contrasts between whole-plant and local nutrient levels determine root growth and death in Ailanthus altissima (Simaroubaceae). AB - * PREMISE OF THE STUDY: There is an ongoing debate about the importance of whole plant control vs. local modular mechanisms for root growth. We conducted a split root experiment with different patch/background levels of nitrogen to examine whether local root growth and death are controlled by local resource levels or at the whole-plant level.* METHODS: Three microrhizotrons with 0, 10, and 100 ug N/g growth medium levels (74 g growth medium each) were attached to pots of high or low soil N in which one Ailanthus altissima individual was growing. One fine root was guided into each of the microrhizotrons and photographed every 4 d. Plants were harvested after 28 d; root growth and mortality in the microrhizotrons were recorded. Changes in root length, number of laterals, and interlateral length were determined from the photos and analyzed.* KEY RESULTS: While overall plant growth was influenced by background N level, both patch and background N levels influenced root growth and mortality in patches. Local roots proliferated most when the patch N level was high and background level low, and they proliferated least and showed highest mortality when patch N was low and the background level high.* CONCLUSIONS: The fate of roots growing in a patch is influenced by the resource environment of the plant's other roots as well as the resource levels in the patch itself. Thus, the growth and death of roots in patches is determined by both modular and whole-plant mechanisms. PMID- 24812110 TI - An experimental approach to explain the southern Andes elevational treeline. AB - * PREMISE OF THE STUDY: The growth limitation hypothesis (GLH) is the most accepted mechanistic explanation for treeline formation, although it is still uncertain whether it applies across taxa. The successful establishment of Pinus contorta--an exotic conifer species in the southern hemisphere--above the Nothofagus treeline in New Zealand may suggest a different mechanism. We tested the GLH in Nothofagus pumilio and Pinus contorta by comparing seedling performance and carbon (C) balance in response to low temperatures.* METHODS: At a southern Chilean treeline, we grew seedlings of both species 2 m above ground level, to simulate coupling between temperatures at the meristem and in the air (colder), and at ground level, i.e., decoupling air temperature (relatively milder). We recorded soil and air temperatures as well. After 3 yr, we measured seedling survival and biomass (as a surrogate of growth) and determined nonstructural carbohydrates (NSC).* KEY RESULTS: Nothofagus and Pinus did not differ in survival, which, as a whole, was higher at ground level than at the 2-m height. The root-zone temperature for the growing season was 6.6 degrees C. While biomass and NSC decreased significantly for Nothofagus at the 2-m height compared with ground level (C limitation), these trends were not significant for Pinus* CONCLUSIONS: The treeline for Nothofagus pumilio is located at an isotherm that fully matches global patterns; however, its physiological responses to low temperatures differed from those of other treeline species. Support for C limitation in N. pumilio but not in P. contorta indicates that the physiological mechanism explaining their survival and growth at treeline may be taxon dependent. PMID- 24812111 TI - The evolution of bark mechanics and storage across habitats in a clade of tropical trees. AB - * PREMISE OF THE STUDY: Bark functional strategies vary conspicuously within communities. As a result, predicting most community-level bark traits based on environment often reveals little association. To complement this community-based view, we took a clade-based approach to study potentially adaptive differences in bark water storage and biomechanics across habitats and examined ontogenetic mechanisms that lead to these differences.* METHODS: We studied the branches of nine species in the simaruba clade of Bursera in dry to wet, fire-free neotropical forests. We measured mechanical properties from branch tips to bases, as well as the relative area and water content of bark. Using raw data and phylogenetically independent contrasts, we then tested predictions regarding trait associations with environment and mapped branch tip-to-base ontogenetic changes.* KEY RESULTS: Across our wet-dry gradient, bark water storage was greater in drier habitats, whereas bark tissue mechanical rigidity was greater in the taller species of moister forests. Bark was the principal mechanical tissue in branch tips and an important contributor even in branches 3 m long. Within species, bark contributions to mechanical support and water storage came mostly through a tip-to-base increase in bark quantity rather than alterations in tissue properties. Quantitative developmental alterations in proportions of bark to wood led to habit differences.* CONCLUSIONS: Our clade-based approach shows that, in marked contrast to most community-based results, environment can strongly predict bark functional traits across species in ways that seem plausibly adaptive. PMID- 24812113 TI - Procedural sedation and analgesia for adults in the emergency department. PMID- 24812112 TI - Influence of healthy candidate bias in assessing clinical effectiveness for implantable cardioverter-defibrillators: cohort study of older patients with heart failure. AB - OBJECTIVE: To assess the potential contribution of unmeasured general health status to patient selection in assessments of the clinical effectiveness of implantable cardioverter-defibrillator (ICD) therapy. DESIGN: Retrospective cohort study. SETTING: Linked data from an ICD registry, heart failure registry, and Medicare claims data for ICDs implanted in 2005 through 2009. PARTICIPANTS: 29,426 patients admitted to hospital with heart failure aged 66 years or older and eligible for ICD therapy for primary prevention. MAIN OUTCOME MEASURES: Non traumatic hip fracture, admission to a skilled nursing facility, and 30 day mortality-outcomes unlikely to be improved by ICD therapy. RESULTS: Compared with 17,853 patients without ICD therapy, 11,573 patients with ICD therapy were younger and had lower ejection fraction and more cardiac admissions to hospital but fewer non-cardiac admissions to hospital and comorbid conditions. Patients with ICD therapy had greater freedom from unrelated events after adjusting for age and sex: hip fracture (hazard ratio 0.77, 95% confidence interval 0.64 to 0.92), skilled nursing facility admission (0.53, 0.50 to 0.55), and 30 day mortality (0.12, 0.10 to 0.15). CONCLUSIONS: Lower risks of measured outcomes likely reflect unmeasured differences in comorbidity and frailty. The findings highlight potential pitfalls of observational comparative effectiveness research and support physician consideration of general health status in selecting patients for ICD therapy. PMID- 24812114 TI - Worldwide maternal mortality rate falls by 45% in 13 years. PMID- 24812115 TI - Corruption ruins the doctor-patient relationship in India. PMID- 24812116 TI - Surgeon gives patient a vasectomy by mistake. PMID- 24812117 TI - Does routine pin re-torquing of patients wearing a halo-thoracic orthosis reduce the need for pin replacement? AB - BACKGROUND: The halo orthosis is a treatment option currently used in Australia for cervical spine immobilisation following trauma, fracture and post surgical stabilisation. In a previous study, the authors reported halo pin replacement to be a common complication. The aim of this study was to investigate the potential correlation between routine halo pin re-torquing and the incidence of pin replacement. CASE DESCRIPTION AND METHODS: A retrospective case series study was undertaken. A total of 258 charts were reviewed, with 170 patients included in the study. Patients were fitted with a Bremer HALO System with the initial application torque maintained by routine re-torquing throughout the duration of wear. FINDINGS AND OUTCOMES: A total of 680 pins (4 per patient) were inserted during the initial application of the halo orthoses, with only six pins replaced (0.88%) throughout the duration of the study. CONCLUSION: The findings from this study demonstrate a potential correlation between routinely re-torquing halo pins and decreasing the incidence of pin replacement. CLINICAL RELEVANCE: This case series study has identified a potential improvement in clinical management of patients wearing a halo-thoracic orthosis. PMID- 24812118 TI - Multidisciplinary team approach to residual limb lengthening using the Ilizarov technique: A case study. AB - BACKGROUND AND AIM: A 47-year-old male suffered a traumatic transtibial amputation; initial limb use was unsuccessful and the short tibial length was thought to be the cause of failure. CASE DESCRIPTION AND METHODS: The patient underwent gradual tibia lengthening using the Ilizarov technique and utilised a weight-bearing prosthesis to expedite bone growth and repair. FINDINGS AND OUTCOMES: The patient is now able to use his prosthesis successfully without aids. CONCLUSION: This case study demonstrates that combining a scientifically based surgical technique with a tailored rehabilitation approach had an improved outcome for the patient. CLINICAL RELEVANCE: This study reports one case where tibial lengthening using the Ilizarov technique combined with a collaborative team approach has enabled a patient to return to successful prosthetic limb use. PMID- 24812119 TI - The effects of custom-made foot orthosis using the Central Stabilizer Element on foot pain. AB - BACKGROUND: Foot orthoses have been applied for the management of lower limb disorders, mainly for those who develop foot pain. The Central Stabilizer Element (CSE) is a new element that contains the midfoot laterally when a plantar insole is manufactured. OBJECTIVES: To determine the effect on foot pain of adding the Central Stabilizer Element during the manufacturing process of foot orthosis, and to describe the proportions of Central Stabilizer Element in terms of width and length of this element. STUDY DESIGN: A clinical study. METHODS: A sample comprising 130 patients (57 males and 73 females) with foot pain was recruited for this study, with the patients having supinated, neutral, pronated and overpronated feet. All the patients received a custom-made foot orthosis with the Central Stabilizer Element. The Central Stabilizer Element was made of resins of polyvinyl chloride, and is a device insert in foot orthosis that contains the midfoot laterally to control pronation and supination movements. Perceived patient's foot pain was collected using a Visual Analog Scale at baseline, 15, 60 and 90 days after treatment. RESULTS: A statistically significant decrease was found after foot orthosis application at all times in all foot types. There was a statistically significant correlation between all the ratio proportions according to foot posture (Foot Posture Index scores), except for heel length proportion. CONCLUSIONS: The Central Stabilizer Element, applied at midfoot level of a custom made foot orthoses through a directly mould technique, can reduce foot pain, when a previous foot posture status is considered. CLINICAL RELEVANCE: The Central Stabilizer Element can be of interest for those professionals who are involved in the manufacturing process of foot orthosis, throughout the control of an excesive pronated or a supinated foot condition that is provoking foot pain. PMID- 24812121 TI - Interface strain-induced multiferroicity in a SmFeO3 film. AB - An epitaxial pseudocubic SmFeO3 thin film on (100) Nb-SrTiO3 was studied based on ferroelectric (FE) characterization and magnetic measurements. High-resolution transmission electron microscopy images clarify the nature of the epitaxial growth, the stress-induced structural distortion at the film/substrate interface, and the existence of two different orientation lattices. Clear grain boundaries can be seen, which could introduce an extra local distortion. Rectangular FE loops can be observed at room temperature, even by just applying a small voltage ranging from -1 to +1 V, indicative of the presence of FE polarization. Piezoelectric force microscopy images confirm the existence of FE domains and the switchable polarization. A strong ferromagnetic-like transition occurs around 185 K, which is much lower than the transition observed in the bulk sample. It is believed that the pseudocubic structure enhances FE polarization and decreases the magnetic ordering temperature, which is confirmed by the first-principles theoretical calculations. Meanwhile, the ferroelectricity in this thin film should originate from distortion and modification in the structural modules rather than from the exchange striction interaction that is found in the bulk SmFeO3. PMID- 24812122 TI - Hypoxia-regulated gene network in drug resistance and cancer progression. AB - Hypoxia is a common phenomenon of solid tumors and contributes to aggressive phenotype and treatment failure. Hypoxia-inducible factor (HIF), a versatile transcription factor that regulates more than 5% of total human genes, not only plays important roles in controlling physiological processes, but is also a crucial mediator in hypoxia-induced tumor progression and chemoresistance. Overexpression of HIF-1alpha is detected in a wide spectrum of cancers via different kinds of mechanisms, including reduced oxygen concentration, loss-of function of tumor suppressor gene, activating mutation of oncogenes, and hyperactivation of protein kinase signaling pathways. HIF-regulated genes involve in many pathological processes such as metabolic switch, drug efflux, angiogenesis, cell proliferation, and anti-apoptosis, which ultimately leads to increased tumor growth and drug resistance. Due to the common failure of classic chemotherapeutic agents in treating hypoxic cancers, novel strategies have been developed to target tumors under hypoxic conditions including inhibition of HIF activity and administration of bioreductive drugs. These new strategies may provide more effective and specific methods in targeting hypoxic tumors. PMID- 24812123 TI - MicroRNA-30a promotes invasiveness and metastasis in vitro and in vivo through epithelial-mesenchymal transition and results in poor survival of nasopharyngeal carcinoma patients. AB - Although microRNA-30a (miR-30a) has been shown to regulate cancer metastasis, the molecular mechanism has not yet been clearly elucidated in nasopharyngeal carcinoma (NPC). The present study was to investigate the miR-30a expression pattern and its potential functions and further to identify its target gene and corresponding clinical applications in NPC. MiR-30a was identified to be down regulated in NPC primary tumors compared with metastatic tumors using quantitative real-time PCR. Furthermore, over-expression of miR-30a transfected with precursor increased the ability of metastasis and invasion of NPC tumor cells in vivo and in vitro. E-cadherin was screened as a putative target gene of miR-30a by computational algorithms. Luciferase reporter assays showed that over expression of miR-30a directly reduced the activity of a luciferase transcript combined with the 3'-untranslated region (3'-UTR) of E-cadherin. Kaplan-Meier survival analysis and log-rank test were analyzed for 1077 NPC patients for overall survival, indicating that a high expression of E-cadherin was beneficial for NPC prognosis (P = 0.001). Importantly, NPC patients with high expression of E-cadherin had much lower risk of poor prognosis (hazard ratio = 0.757, P = 0.017) using multivariate analysis. In conclusion, miR-30a could play an important role in regulating NPC metastasis and potentially provide useful guidelines for individualized therapy. PMID- 24812124 TI - Author's reply to Elliott, Parkins, Shah and colleagues, and Dhua. PMID- 24812125 TI - Genetic variants of Adam17 differentially regulate TGFbeta signaling to modify vascular pathology in mice and humans. AB - Outcome of TGFbeta1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFbeta1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b(C57) haplotype suppresses prenatal lethality of Tgfb1(-/-) embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFbetaRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFbetaRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFbetaR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFbeta signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFbeta/bone morphogenetic protein receptor genes, ENG, encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFbeta-regulated vascular disease. PMID- 24812126 TI - Microbial diversity and the lability of dissolved organic carbon. PMID- 24812128 TI - Managing the fruits of our success. PMID- 24812127 TI - Performance-optimized hierarchical models predict neural responses in higher visual cortex. AB - The ventral visual stream underlies key human visual object recognition abilities. However, neural encoding in the higher areas of the ventral stream remains poorly understood. Here, we describe a modeling approach that yields a quantitatively accurate model of inferior temporal (IT) cortex, the highest ventral cortical area. Using high-throughput computational techniques, we discovered that, within a class of biologically plausible hierarchical neural network models, there is a strong correlation between a model's categorization performance and its ability to predict individual IT neural unit response data. To pursue this idea, we then identified a high-performing neural network that matches human performance on a range of recognition tasks. Critically, even though we did not constrain this model to match neural data, its top output layer turns out to be highly predictive of IT spiking responses to complex naturalistic images at both the single site and population levels. Moreover, the model's intermediate layers are highly predictive of neural responses in the V4 cortex, a midlevel visual area that provides the dominant cortical input to IT. These results show that performance optimization--applied in a biologically appropriate model class--can be used to build quantitative predictive models of neural processing. PMID- 24812130 TI - BRAFV600E-mutant melanoma presenting with cardiac involvement. AB - Melanoma is an aggressive skin cancer with historically limited treatment options. Approximately 50% of melanomas harbor BRAF(V600) mutations. This report describes a 32-year-old man with metastatic BRAF(V600)-mutant melanoma who presented with cardiac involvement. Recently developed treatment options for patients with BRAF-mutant melanoma include BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib), and immune-based therapeutics (interleukin-2 or ipilimumab), but the most effective strategy for first-line therapy is heavily debated. Opinions vary for treatment selection, but the general consensus recommends immune-based therapies initially for asymptomatic patients with low-volume disease, and BRAF inhibitors for those with highly symptomatic or rapidly progressing disease. In this case, melanoma with cardiac involvement, although clinically uncommon, presents challenging management decisions. PMID- 24812131 TI - Melanoma, version 4.2014. AB - The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease. PMID- 24812133 TI - International adaptations of NCCN Clinical Practice Guidelines in Oncology. AB - The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) are evidence- and consensus-based clinical practice guidelines addressing malignancies that affect more than 97% of all patients with cancer in the United States. The NCCN Guidelines are used extensively in the United States and globally. Use of the guidelines outside the United States has driven the need to adapt the guidelines based on local, regional, or national resources. The NCCN Guidelines Panels created, vetted, and continually update the NCCN Guidelines based on published scientific data on cancer detection, diagnosis, and treatment efficacy. The guidelines are developed within the context of commonly available resources, methods of payment, societal and cultural expectations, and governmental regulations as they exist in the United States. Although many of the cancer management recommendations contained in the NCCN Guidelines apply broadly from a global perspective, not all do. Disparities in availability and access to health care exist among countries, within countries, and among different social groups in the same country, especially regarding resources for cancer prevention, early detection, and treatment. In addition, different drug approval and payment processes result in regional variation in availability of and access to cancer treatment, especially highly expensive agents and radiation therapy. Differences in cancer risk, predictive biomarker expression, and pharmacogenetics exist across ethnic and racial groups, and therefore across geographic locations. Cultural and societal expectations and requirements may also require modification of NCCN Guidelines for use outside the United States. This article describes the adaptation process, using the recent Latin American adaptation of the 2013 NCCN Guidelines for Colorectal Cancer as an example. PMID- 24812134 TI - Should the ASCO/ASH Guidelines for the use of intravenous iron in cancer- and chemotherapy-induced anemia be updated? AB - Coadministration of intravenous (IV) iron improves responses to erythropoiesis stimulating agents (ESAs) in the treatment of cancer-associated (CAA) and chemotherapy-induced anemia (CIA). Twelve prospective studies have demonstrated synergy between parenteral iron and ESAs, with variable degrees of improved hemoglobin (Hgb) response rates, shorter times to target Hgb levels, and a lower ESA dose required for equivalent Hgb responses. Clinically significant adverse events (AEs) with currently available IV iron products are uncommon. Pretreatment serum hepcidin levels may predict response magnitude. Safety concerns among many oncologists are driven by reports of serious AEs from older IV iron formulations that are no longer available, and misinterpretation of the nature and frequency of minor infusion reactions. Premedication with antihistamines is of unproven benefit and can cause symptoms that mimic anaphylaxis, prompting intervention with vasopressors and converting self-limited reactions into hemodynamically significant AEs. Payer rules proscribing the administration of ESAs and IV iron on the same day also have limited the clinical adoption of IV iron and ESA coadministration. At a time when financial resources are scarce, the ability to reduce use of costly ESAs is beneficial. Despite a favorable risk/benefit ratio for IV iron in CAA and CIA, current IV iron recommendations in guidelines from ASCO/ASH, NCCN, and ESMO are inconsistent. The authors believe more routine use of IV iron for CAA and CIA is appropriate in view of existing evidence, and suggest reconsideration of the current ASCO/ASH guidelines, which state "there is insufficient evidence to consider the use of intravenous iron as a standard of care." PMID- 24812132 TI - Survivorship: sleep disorders, version 1.2014. AB - Sleep disorders, including insomnia and excessive sleepiness, affect a significant proportion of patients with cancer and survivors, often in combination with fatigue, anxiety, and depression. Improvements in sleep lead to improvements in fatigue, mood, and quality of life. This section of the NCCN Guidelines for Survivorship provides screening, diagnosis, and management recommendations for sleep disorders in survivors. Management includes combinations of sleep hygiene education, physical activity, psychosocial interventions, and pharmacologic treatments. PMID- 24812135 TI - Clinical discussion of the management of anaplastic oligodendroglioma/oligoastrocytoma (both codeleted and nondeleted). AB - Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are uncommon malignant tumors occurring in adults, but have garnered attention because of a high rate of response to chemotherapy in early studies. However, no clinical trial had demonstrated benefit with the addition of chemotherapy to radiotherapy alone until the long-term results of RTOG 9402 and EORTC 26951. These studies revealed prolonged survival in patients with anaplastic gliomas harboring the 1p/19q codeletion when treated with PCV (procarbazine, lomustine, and vincristine) and radiation therapy compared with radiation alone. These studies validated the use of 1p/19q codeletion status as a predictive biomarker in these tumors. Additional molecular characterization of these tumors may provide additional insight into treatment decisions, although these characterizations have yet to be fully elucidated. Even with the strength of the data advocating the use of combination therapy (PCV and radiotherapy), the incorporation of newer, less-toxic drugs such as temozolomide into many practices in the past decade raises important questions regarding the optimal chemotherapy regimen. Unfortunately, additional definitive phase III trials will take several years to answer remaining questions. Regardless, it is clear that patients with 1p/19q codeleted AO or AOA who can tolerate chemotherapy should not receive radiotherapy alone. PMID- 24812136 TI - Patient attitudes and issues in colon cancer screening. AB - Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, and is largely preventable by CRC screening (CRCS). Participation in CRCS, however, is much lower than participation in other forms of preventive care. Many reasons for low rates of participation have been identified, and can be generally divided into provider- and patient-specific issues. Lack of a provider recommendation is a well-established and widely reported patient barrier to CRCS. Numerous patient-specific issues have been identified, ranging from fear of CRCS test results to lack of knowledge about individual risk for CRC and inadequate resources to complete CRCS. This article discusses the impact of patient attitudes and issues toward CRCS, with particular attention to modifiable psychosocial factors, the importance of patient preferences for one CRCS test over another, knowledge of CRC risk, and the impact of educational tools on patient compliance with CRCS. PMID- 24812137 TI - Prostate cancer, version 2.2014. AB - Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website. PMID- 24812138 TI - Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes. AB - Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy. PMID- 24812139 TI - Intermittent versus continuous androgen deprivation therapy. AB - Androgen deprivation therapy (ADT) has been the standard of care for metastatic prostate cancer for decades; however, the choice of continuous or intermittent administration is a matter of debate. Two large phase III trials have reported results comparing these 2 forms of ADT administration. The National Cancer Institute of Canada (NCIC) PR-7 trial studied men with an increasing prostate specific antigen (PSA) level and no evidence of metastatic disease after definitive or salvage radiation therapy and radical prostatectomy. The Southwest Oncology Group 9346 trial studied men with newly diagnosed hormone-sensitive metastatic disease. The primary end point in both trials was overall survival with a noninferiority design. The NCIC trial showed that the overall survival in men treated with intermittent ADT was not inferior to that of men treated with continuous ADT, but the SWOG trial was inconclusive regarding noninferiority. Certain domains of quality of life were better in the intermittent arms of both trials. If using ADT in the setting of biochemical relapse, intermittent ADT should be strongly considered over continuous ADT, except perhaps in patients with Gleason score of 8 or higher. In men with metastatic disease, continuous ADT remains the standard of care, because the SWOG trial did not establish noninferiority of intermittent ADT with respect to survival. However, for those with significant side effects from ADT, establishing the risk group, as determined by PSA value after 7 months of ADT or the presence of pain at diagnosis, may help guide the choice of intermittent versus continuous ADT in men with metastatic disease. PMID- 24812140 TI - Underserved topics in oncology: the role of physical activity in improving quality of life and decreasing recurrence risk in patients with cancer. PMID- 24812142 TI - Intraclass Correlations and Covariate Outcome Correlations for Planning Two- and Three-Level Cluster-Randomized Experiments in Education. AB - BACKGROUND: Cluster-randomized experiments that assign intact groups such as schools or school districts to treatment conditions are increasingly common in educational research. Such experiments are inherently multilevel designs whose sensitivity (statistical power and precision of estimates) depends on the variance decomposition across levels. This variance decomposition is usually summarized by the intraclass correlation (ICC) structure and, if covariates are used, the effectiveness of the covariates in explaining variation at each level of the design. OBJECTIVES: This article provides a compilation of school- and district-level ICC values of academic achievement and related covariate effectiveness based on state longitudinal data systems. These values are designed to be used for planning group-randomized experiments in education. The use of these values to compute statistical power and plan two- and three-level group randomized experiments is illustrated. RESEARCH DESIGN: We fit several hierarchical linear models to state data by grade and subject to estimate ICCs and covariate effectiveness. The total sample size is over 4.8 million students. We then compare our average of state estimates with the national work by Hedges and Hedberg. PMID- 24812144 TI - Diagnosis of an abnormality of the left main coronary. PMID- 24812145 TI - Government denies that introduction of Better Care Fund will be delayed. PMID- 24812146 TI - Scottish emergency unit waiting times are lengthening. PMID- 24812147 TI - US hospitals have made "major strides" in quality improvement, says government report. PMID- 24812148 TI - Physical activity and social support in adolescents: a systematic review. AB - The objective of this review was to systematically synthesize the results of original studies on the association between physical activity and social support in adolescents, published until April 2011. Searches were carried out in Adolec, Eric, Lilacs, Medline, SciELO, Scopus, SportsDiscus and Web of Science electronic databases and the reference lists of selected articles. Searches for articles, data extraction and assessment of methodological quality were conducted independently by two reviewers. In total, 75 articles met inclusion criteria and were analyzed. Most studies were published over the past 6 years (2006-11), conducted in high-income countries, with a cross-sectional design, using subjective measures of physical activity (e.g. questionnaires and recall) and exhibited medium to high methodological quality level. Social support was positive and consistently associated with the physical activity level of adolescents in cross-sectional and longitudinal studies. Those who received more overall social support as well as support from both parents, friends and family showed higher levels of physical activity. It is concluded that social support is an important factor associated with physical activity level in adolescents and should be targeted in intervention programs that aim to increase physical activity levels in this population group. PMID- 24812149 TI - Excellence in healthcare is celebrated at The BMJ Awards 2014. PMID- 24812150 TI - Is one-time carbon monoxide intoxication harmless? Evaluation by argyrophilic nucleolar-organizing regions staining method. AB - In carbon monoxide (CO) poisoning, CO affects the oxygen-carrying capacity of the hemoglobin molecule. Nucleolar-organizing regions (NORs) are genetic loci on chromosomes that are composed of ribosomal DNA and proteins. NORs can be stained with silver. A total of 18 rats were exposed to CO in three different concentrations (1000, 3000, and 5000 ppm) with 6 rats as controls. The animals were euthanized 7 days after CO intoxication. Lung tissues were taken, embedded in paraffin blocks, and sectioned at 5 MUm thickness. Argyrophilic nucleolar organizing region (AgNOR) staining was carried out. One hundred nuclei per individual were evaluated, and total AgNOR number per total nuclear number and total AgNOR area per nuclear area (TAA/NA) for each nucleus were analyzed. The CO exposure groups had significantly higher TAA/NA values and AgNOR numbers than the control group (p < 0.05). Although the differences between 1000 ppm and the other two CO-exposed groups were meaningful (p < 0.05) in the TAA/NA values, there were no differences among the CO exposure groups for the AgNOR number (p > 0.05). The increase in TAA/NA value depends on the increase in the CO exposure. Significant correlations between both the AgNOR values and histopathological scoring methods were found. Therefore, AgNOR staining method may be used as an indirect indicator for evaluating the degree of cell damage rate. PMID- 24812151 TI - Valproate ameliorates thioacetamide-induced fibrosis by hepatic stellate cell inactivation. AB - Valproic acid (VPA) has been reported as inhibitor of histone deacetylases (HDACs). Several reports indicated that HDACs play a crucial role in the pathogenesis of fibrosis and hepatic stellate cell (HSC) activation. The present study was aimed to evaluate the anti-fibrotic effect of VPA against thioacetamide (TAA)-induced hepatic fibrosis and activation of the HSC in rat. VPA and TAA were administrated intraperitoneally at the dose of 400 and 200 mg/kg each at 2 days interval, respectively for a period of 6 weeks. Administration of TAA significantly increased the absolute and relative liver weight, aspartate aminotransferase and alanine aminotransferase levels, which were significantly decreased by VPA treatment as compared to TAA control. VPA treatment prevents the TAA-induced activation of HSC and decreases collagen deposition and infiltration of inflammatory cells as revealed by Sirius red and H&E staining. Interestingly, VPA co-treatment led to significantly increase the DNA damage and apoptosis in the activated HSC as compared to TAA control. Further, TAA decreased the expression of matrix metalloproteinase-2 (MMP-2), while VPA co-treatment significantly increased the expression of MMP-2 as compared to respective control. The present study clearly demonstrated that VPA treatment significantly alleviates TAA-induced activation of HSC and subsequent hepatic fibrosis. PMID- 24812152 TI - Identification of novel genes involved in gastric carcinogenesis by suppression subtractive hybridization. AB - Gastric cancer (GC) is one of the most common and life-threatening types of malignancies. Identification of the differentially expressed genes in GC is one of the best approaches for establishing new diagnostic and therapeutic targets. Furthermore, these investigations could advance our knowledge about molecular biology and the carcinogenesis of this cancer. To screen for the overexpressed genes in gastric adenocarcinoma, we performed suppression subtractive hybridization (SSH) on gastric adenocarcinoma tissue and the corresponding normal gastric tissue, and eight genes were found to be overexpressed in the tumor compared with those of the normal tissue. The genes were ribosomal protein L18A, RNase H2 subunit B, SEC13, eukaryotic translation initiation factor 4A1, tetraspanin 8, cytochrome c oxidase subunit 2, NADH dehydrogenase subunit 4, and mitochondrially encoded ATP synthase 6. The common functions among the identified genes include involvement in protein synthesis, involvement in genomic stability maintenance, metastasis, metabolic improvement, cell signaling pathways, and chemoresistance. Our results provide new insights into the molecular biology of GC and drug discovery: each of the identified genes could be further investigated as targets for prognosis evaluation, diagnosis, treatment, evaluation of the response to new anticancer drugs, and determination of the molecular pathogenesis of GC. PMID- 24812153 TI - A 12-week subchronic intramuscular toxicity study of risperidone-loaded microspheres in rats. AB - Long-acting injectable formulations of antipsychotics have been an important treatment option to increase the compliance of the patient with schizophrenia by monitoring drug administration and identifying medication noncompliance and to improve the long-term management of schizophrenia. Risperidone, a serotoninergic 5-HT2 and dopaminergic D2 receptor antagonist, was developed to be a long-acting sustained-release formulation for the treatment of schizophrenia. In this study, 12-week subchronic toxicity study of risperidone-loaded microspheres (RMs) in rats by intramuscular injection with an 8-week recovery phase was carried out to investigate the potential subchronic toxicity of a novel long-acting sustained release formulation. The results indicated that the dosage of 10-90 mg/kg of RM for 2 weeks did not cause treatment-related mortality. The main drug-related findings were contributed to the dopamine D2 receptor and alpha1-adrenoceptor antagonism of risperidone such as elevation of serum and pituitary prolactin levels and ptosis and changes in reproductive system (uterus, ovary, vagina, mammary gland, testis, seminal vesicle, epididymis, and prostate). In addition, foreign body granuloma in muscle at injection sites caused by poly-lactide-co glycolide was observed. At the end of the recovery phase, these changes mostly returned to normal. The results indicated that RM had a good safety profile in rats. PMID- 24812154 TI - Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats. AB - OBJECTIVE: To investigate the effects of overexpression of nuclear factor E2 related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning. METHODS: A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined. RESULTS: RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner (p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure (p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) (p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA (p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor kappaB (NF-kappaB) and decreased the levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ (p < 0.05). CONCLUSION: RU486-induced overexpression of NRF2 in lungs transfected with Ad RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2 antioxidant response element (ARE) pathway. PMID- 24812155 TI - Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. AB - The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histological procedures. Biochemical parameters and morphological changes were examined. In DM group, blood glucose levels were significantly increased, whereas body weights were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants (p < 0.05). STZ-induced histopathological alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Additionally, basement membrane thickening and sclerotic changes were observed in glomerulus. Transforming growth factor-beta1 positive cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathological changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage. PMID- 24812156 TI - Saha et al. respond to "Mortality displacement after heat waves". PMID- 24812157 TI - Estimating mortality displacement during and after heat waves. AB - The proportion of excess deaths occurring as a result of hot weather that are brought forward by only a short time ("displaced") is important but not easy to estimate. A recent proposal by Saha et al. (Am J Epidemiol. 2014;179(4):467-474) was to estimate this using a "displacement ratio" equal to the sum of deficits of daily deaths below an expected baseline divided by the sum of excesses over all days during and up to 15 days after a heat wave. Unfortunately, this method results in important artifacts due to natural Poisson variation in deaths by which deficits, and hence displacement ratios above zero, will occur even when there is no real short-term displacement. Simulations confirm this and further show spurious patterns, such as the displacement ratio diminishing with more severe waves. This displacement ratio cannot be relied upon for interpretation. Quantifying mortality displacement remains an incompletely resolved problem. PMID- 24812158 TI - African American race and HIV virological suppression: beyond disparities in clinic attendance. AB - Racial disparities in clinic attendance may contribute to racial disparities in plasma human immunodeficiency virus type 1 : HIV-1) RNA levels among HIV-positive patients in care. Data from 946 African American and 535 Caucasian patients receiving HIV care at the University of North Carolina Center for AIDS Research HIV clinic between January 1, 1999, and August 1, 2012, were used to estimate the association between African American race and HIV virological suppression (i.e., undetectable HIV-1 RNA) when racial disparities in clinic attendance were lessened. Clinic attendance was measured as the proportion of scheduled clinic appointments attended (i.e., visit adherence) or the proportion of six 4-month intervals with at least 1 attended scheduled clinic appointment (i.e., visit constancy). In analyses accounting for patient characteristics, the risk ratio for achieving suppression when comparing African Americans with Caucasians was 0.91 (95% confidence interval: 0.85, 0.98). Lessening disparities in adherence or constancy lowered disparities in virological suppression by up to 44.4% and 11.1%, respectively. Interventions that lessen disparities in adherence may be more effective in eliminating disparities in suppression than interventions that lessen disparities in constancy. Given that gaps in care were limited to be no more than 2 years for both attendance measures, the impact of lessening disparities in adherence may be overstated. PMID- 24812160 TI - Acute myocardial infarction in Scottish military veterans: a retrospective cohort study of 57,000 veterans and 173,000 matched nonveterans. AB - Few studies of veterans have examined cardiovascular disease as the primary outcome, other than in relation to specific conflicts or hazards. To assess the long-term risk and prognosis of acute myocardial infarction (AMI) in United Kingdom veterans from a broad range of military backgrounds and experience, we conducted a retrospective cohort study of 57,000 veterans resident in Scotland and 173,000 civilians matched on age, sex, and area of residence. Cox proportional hazards models were used to compare the risks of fatal/nonfatal AMI overall, by sex, and by year of birth, adjusting for the potentially confounding effect of socioeconomic status, and to compare rates of case-fatality following AMI at 30-day, 1-year, and 5-year follow-up. Over a mean follow-up period of 29 years between 1981 and 2012, a total of 2,106 (3.8%) veterans experienced an AMI as compared with 5,261 (3.1%) nonveterans (hazard ratio = 1.22, 95% confidence interval: 1.16, 1.29; P < 0.001). There was an increased risk of AMI among veterans born in 1945-1959 but not among those born from 1960 onward. Case fatality was lower among veterans at 30-day, 1-year, and 5-year follow-up. We conclude that health behaviors such as smoking may have increased the risk of AMI in older veterans but that younger veterans have benefited from in-service health promotion initiatives. PMID- 24812159 TI - Suicide mortality in relation to dietary intake of n-3 and n-6 polyunsaturated fatty acids and fish: equivocal findings from 3 large US cohort studies. AB - Intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs) has been implicated in the pathogenesis of depression. We sought to estimate the association between intake of fish and n-3 and n-6 PUFAs and suicide mortality over the course of long-term follow-up. In this prospective cohort study, biennial questionnaires were administered to 42,290 men enrolled in the Health Professionals Follow-up Study (1988-2008), 72,231 women enrolled in the Nurses' Health Study (1986-2008), and 90,836 women enrolled in Nurses' Health Study II (1993-2007). Dietary fish and n-3 and n-6 PUFA intakes were assessed every 4 years using a validated food frequency questionnaire. Suicide mortality was ascertained through blind physician review of death certificates and hospital or pathology reports. Adjusted relative risks of suicide mortality were estimated with multivariable Cox proportional hazards models and pooled across cohorts using random-effects meta-analysis. The pooled multivariable relative risks for suicide among persons in the highest quartile of intake of n-3 or n-6 PUFAs, relative to the lowest quartile, ranged from 1.08 to 1.46 for n-3 PUFAs (Ptrend = 0.11-0.52) and from 0.68 to 1.19 for n-6 PUFAs (Ptrend = 0.09-0.54). We did not find evidence that intake of n-3 PUFAs or fish lowered the risk of completed suicide. PMID- 24812161 TI - Hidradenitis suppurativa: number of diagnosed patients, demographic characteristics, and treatment patterns in the United States. AB - Recent regional and insurance database studies indicate that diagnoses of hidradenitis suppurativa (HS) are rare, with fewer than 200,000 affected patients in the United States. These findings are at odds with the generally accepted prevalence of approximately 1%. To estimate the number of patients diagnosed with HS, including patients enrolled in public health plans and the uninsured, we performed an investigation using National Center for Health Statistics databases of visits to health care providers. Survey data from physician offices and clinics, hospital outpatient departments, and emergency departments in the United States were analyzed. There were 254,000 (95% confidence interval: 180,000, 328,000) health care visits by patients with HS per year from 2002 to 2010. An annualized estimate of 118,000 (95% confidence interval: 83,000, 152,000) patients with HS diagnoses was determined. Excluding emergency department data, the annualized estimate was 100,000 (95% confidence interval: 67,000, 134,000) patients. Adults between 18 and 64 years of age comprised 92.8% (standard error, 2.6%) of HS patients. Of that working-age population, 31.5% (standard error, 5.6%) were enrolled in Medicare or Medicaid, which is a significantly higher proportion than for those in the same age group in the general population. A review of earlier surveys of HS prevalence was performed. HS is a rarely diagnosed disease, and epidemiologic data to support undiagnosed HS as a common disease are lacking. PMID- 24812162 TI - Reducing avoidable rehospitalization in ESRD: a shared accountability. PMID- 24812163 TI - Approaches to uremia. AB - The development of dialysis was a dramatic step forward in medicine, allowing people who would soon have died because of lack of kidney function to remain alive for years. We have since found, however, that the "artificial kidney" does not live up fully to its name. Dialysis keeps patients alive but not well. Part of the residual illness that dialysis patients experience is caused by retained waste solutes that dialysis does not remove as well as native kidney function does. New means are available to identify these toxic solutes, about which we currently know remarkably little, and knowledge of these solutes would help us to improve therapy. This review summarizes our current knowledge of toxic solutes and highlights methods being explored to identify additional toxic solutes and to enhance the clearance of these solutes to improve patient outcomes. PMID- 24812164 TI - Fetal and infant growth patterns and kidney function at school age. AB - Low birth weight is associated with ESRD. To identify specific growth patterns in early life that may be related to kidney function in later life, we examined the associations of longitudinally measured fetal and infant growth with kidney function in school-aged children. This study was embedded in a population-based prospective cohort study among 6482 children followed from fetal life onward. Fetal and childhood growth was measured during second and third trimesters of pregnancy, at birth, and at 6, 12, 24, 36, and 48 months postnatally. At the age of 6 years, we measured kidney volume by ultrasound. GFR was estimated using blood creatinine levels. Higher gestational age-adjusted birth weight was associated with higher combined kidney volume and higher eGFR (per 1 SD score increase in birth weight; 1.27 cm(3) [95% confidence interval, 0.61 to 1.93] and 0.78 ml/min per 1.73 m2 [95% CI, 0.16 to 1.39], respectively). Fetal weight, birth weight, and weight at 6 months were positively associated with childhood kidney volume, whereas higher second trimester fetal weight was positively associated with higher GFR (all P values<0.05). Fetal and childhood lengths were not consistently associated with kidney function. In this cohort, lower fetal and early infant weight growth is associated with smaller kidney volume in childhood, whereas only lower fetal weight growth is associated with lower kidney function in childhood, independent of childhood growth. Whether these associations lead to an increased risk of kidney disease needs to be studied further. PMID- 24812166 TI - The life cycle of the kidney: implications for CKD. PMID- 24812165 TI - The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. AB - A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p cresyl sulfate and support their roles in vascular and renal disease progression. PMID- 24812167 TI - Childhood kidney outcomes in relation to fetal blood flow and kidney size. AB - Impaired fetal abdominal blood flow may lead to smaller kidneys and subsequent impaired kidney function in later life. In a prospective cohort study among 923 pregnant women and their children, we measured fetal growth, kidney volumes, and umbilical and cerebral artery blood flow (median gestational age of 30.3 weeks; 95% range, 28.5-32.7 weeks). We used a higher umbilical/cerebral artery pulsatility index ratio as an indicator of preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs. At a median age of 5.9 years (95% range, 5.7-6.6 years), we measured childhood kidney volumes, creatinine and cystatin C blood levels, microalbuminuria, BP, and eGFR. A preferential fetal blood flow to the upper body parts at the expense of the intra abdominal organs associated only with a smaller combined kidney volume in childhood. Fetal combined kidney volume positively associated with childhood combined kidney volume and eGFR, and inversely associated with childhood creatinine and cystatin C levels (all P values <0.05), but did not associate with childhood microalbuminuria and BP. Children within the highest tertile of fetal umbilical/cerebral ratio and the lowest tertile of fetal combined kidney volume had the lowest eGFR (difference, -6.36 ml/min per 1.73 m(2); 95% confidence interval, -11.78 to -0.94 compared with children within the middle tertiles). These data suggest that impaired fetal blood to the abdominal organs and smaller fetal kidney size are associated with subclinical changes in kidney outcomes in school-aged children. PMID- 24812169 TI - WHO calls for better surveillance of AMR in animals. PMID- 24812170 TI - RCVS Council election results 2014. PMID- 24812168 TI - Physician visits and 30-day hospital readmissions in patients receiving hemodialysis. AB - A focus of health care reform has been on reducing 30-day hospital readmissions. Patients with ESRD are at high risk for hospital readmission. It is unknown whether more monitoring by outpatient providers can reduce hospital readmissions in patients receiving hemodialysis. In nationally representative cohorts of patients in the United States receiving in-center hemodialysis between 2004 and 2009, we used a quasi-experimental (instrumental variable) approach to assess the relationship between frequency of visits to patients receiving hemodialysis following hospital discharge and the probability of rehospitalization. We then used a multivariable regression model and published hospitalization data to estimate the cost savings and number of hospitalizations that could be prevented annually with additional provider visits to patients in the month following hospitalization. In the main cohort (n=26,613), one additional provider visit in the month following hospital discharge was estimated to reduce the absolute probability of 30-day hospital readmission by 3.5% (95% confidence interval, 1.6% to 5.3%). The reduction in 30-day hospital readmission ranged from 0.5% to 4.9% in an additional four cohorts tested, depending on population density around facilities, facility profit status, and patient Medicaid eligibility. At current Medicare reimbursement rates, the effort to visit patients one additional time in the month following hospital discharge could lead to 31,370 fewer hospitalizations per year, and $240 million per year saved. In conclusion, more frequent physician visits following hospital discharge are estimated to reduce rehospitalizations in patients undergoing hemodialysis. Incentives for closer outpatient monitoring following hospital discharge could lead to substantial cost savings. PMID- 24812171 TI - IEP will not be monitoring pilot badger culls in 2014, says Defra. PMID- 24812172 TI - Pirbright Institute fined for safety shortcomings during FMD experiments. PMID- 24812173 TI - RVC launches an exotics service for animals and their owners. PMID- 24812174 TI - PetSavers launches new fundraising initiative to mark its 40th anniversary. PMID- 24812175 TI - BVA launches e-petition calling for an end to non-stun slaughter. PMID- 24812178 TI - Hospital admissions for dog bites show a regional bias. PMID- 24812179 TI - WSAVA launches initiatives to improve companion animal care in Africa. PMID- 24812180 TI - Charity hospital opens its virtual doors. PMID- 24812181 TI - Trackside diagnostic imaging. PMID- 24812182 TI - Diagnoses of canine distemper virus in puppies. PMID- 24812183 TI - Restructuring the RCVS fellowship. PMID- 24812184 TI - Advanced practitioner status and old-style certificate holders. PMID- 24812185 TI - Cyanotoxins as a potential cause of dog poisonings in desert environments. PMID- 24812186 TI - BSE in buffaloes. PMID- 24812187 TI - RHDV variant 2 and Capillaria hepatica infection in rabbits. PMID- 24812188 TI - Sudden death of calves related to anticipation of feeding. PMID- 24812189 TI - A cross-sectional survey of essential surgical capacity in Somalia. AB - OBJECTIVE: To assess life-saving and disability-preventing surgical services (including emergency, trauma, obstetrics, anaesthesia) of health facilities in Somalia and to assist in the planning of strategies for strengthening surgical care systems. DESIGN: Cross-sectional survey. SETTING: Health facilities in all 3 administrative zones of Somalia; northwest Somalia (NWS), known as Somaliland; northeast Somalia (NES), known as Puntland; and south/central Somalia (SCS). PARTICIPANTS: 14 health facilities. MEASURES: The WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care was employed to capture a health facility's capacity to deliver surgical and anaesthesia services by investigating four categories of data: infrastructure, human resources, interventions available and equipment. RESULTS: The 14 facilities surveyed in Somalia represent 10 of the 18 districts throughout the country. The facilities serve an average patient population of 331 250 people, and 12 of the 14 identify as hospitals. While major surgical procedures were provided at many facilities (caesarean section, laparotomy, appendicectomy, etc), only 22% had fully available oxygen access, 50% fully available electricity and less than 30% had any management guidelines for emergency and surgical care. Furthermore, only 36% were able to provide general anaesthesia inhalation due to lack of skills, supplies and equipment. Basic supplies for airway management and the prevention of infection transmission were severely lacking in most facilities. CONCLUSIONS: According to the results of the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care survey, there exist significant gaps in the capacity of emergency and essential surgical services in Somalia including inadequacies in essential equipment, service provision and infrastructure. The information provided by the WHO tool can serve as a basis for evidence-based decisions on country-level policy regarding the allocation of resources and provision of emergency and essential surgical services. PMID- 24812190 TI - Associations between damage location and five main body region injuries of MAIS 3 6 injured occupants. AB - OBJECTIVES: To examine the damage location distribution of five main body region injuries of maximum abbreviated injury score (MAIS) 3-6 injured occupants for nearside struck vehicle in front-to-side impact crashes. DESIGN AND SETTING: MAIS 3-6 injured occupants information was extracted from the US-National Automotive Sampling System/Crashworthiness Data System in the year 2007; it included the head/face/neck, chest, pelvis, upper extremity and lower extremity. Struck vehicle collision damage was classified in a three-dimensional system according to the J224 Collision Deformation Classification of SAE Surface Vehicle Standard. PARTICIPANTS: Nearside occupants seated directly adjacent to the struck side of the vehicle with MAIS 3-6 injured, in light truck vehicles-passenger cars (LTV PC) side impact crashes. OUTCOME MEASURES: Distribution of MAIS 3-6 injured occupants by body regions and specific location of damage (lateral direction, horizontal direction and vertical direction) were examined. Injury risk ratio was also assessed. RESULTS: The lateral crush zone contributed to MAIS 3-6 injured occupants (n=705) and 50th centile injury risks when extended into zone 3. When the crush extended to zone 4, the injury risk ratio of MAIS 3-6 injured occupants approached 81%. The horizontal crush zones contributing to the highest injury risk ratio of MAIS 3-6 occupants were zones 'D' and 'Y', and the injury risk ratios were 25.4% and 36.9%, respectively. In contrast, the lowest injury risk ratio was 5.67% caused by zone 'B'. The vertical crush zone which contributed to the highest injury risk ratio of MAIS 3-6 occupants was zone 'E', whose injury risk ratio was 58%. In contrast, the lowest injury risk ratio was 0.14% caused by zone 'G+M'. CONCLUSIONS: The highest injury risk ratio of MAIS 3-6 injured occupants caused by crush intrusion between 40 and 60 cm in LTV-PC nearside impact collisions and the damage region of the struck vehicle was in the zones 'E' and 'Y'. PMID- 24812191 TI - The clinical relevance and newsworthiness of NIHR HTA-funded research: a cohort study. AB - OBJECTIVE: To assess the clinical relevance and newsworthiness of the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme funded reports. STUDY DESIGN: Retrospective cohort study. SETTING: The cohort included 311 NIHR HTA Programme funded reports publishing in HTA in the period 1 January 2007-31 December 2012. The McMaster Online Rating of Evidence (MORE) system independently identified the clinical relevance and newsworthiness of NIHR HTA publications and non-NIHR HTA publications. The MORE system involves over 4000 physicians rating publications on a scale of relevance (the extent to which articles are relevant to practice) and a scale of newsworthiness (the extent to which articles contain news or something clinicians are unlikely to know). MAIN OUTCOME MEASURES: The proportion of reports published in HTA meeting MORE inclusion criteria and mean average relevance and newsworthiness ratings were calculated and compared with publications from the same studies publishing outside HTA and non-NIHR HTA funded publications. RESULTS: 286/311 (92.0%) of NIHR HTA reports were assessed by MORE, of which 192 (67.1%) passed MORE criteria. The average clinical relevance rating for NIHR HTA reports was 5.48, statistically higher than the 5.32 rating for non-NIHR HTA publications (mean difference=0.16, 95% CI 0.04 to 0.29, p=0.01). Average newsworthiness ratings were similar between NIHR HTA reports and non-NIHR HTA publications (4.75 and 4.70, respectively; mean difference=0.05, 95% CI -0.18 to 0.07, p=0.402). NIHR HTA-funded original research reports were statistically higher for newsworthiness than reviews (5.05 compared with 4.64) (mean difference=0.41, 95% CI 0.18 to 0.64, p=0.001). CONCLUSIONS: Funding research of clinical relevance is important in maximising the value of research investment. The NIHR HTA Programme is successful in funding projects that generate outputs of clinical relevance. PMID- 24812192 TI - A comparative assessment of the price, brands and pack characteristics of illicitly traded cigarettes in five cities and towns in South Africa. AB - OBJECTIVE: The prevalence of illicitly traded cigarettes in South Africa has been reported to be 40-50%. However, these estimates do not account for the more nuanced characteristics of the illicit cigarette trade. With the goal of better understanding contraband cigarettes in South Africa, this study piloted three methods for assessing the price, brands, pack features and smoker's views about illicit cigarettes in five cities/towns. Data were collected in June and July 2012. SETTING: A convenience sample of three South African cities (Johannesburg, Durban and Nelspruit) and two smaller towns (Musina and Ficksburg) were chosen for this study. OUTCOME MEASURES: Three cross-sectional approaches were used to assess the characteristics of contraband cigarettes: (1) a dummy purchase of cigarettes from informal retailers, (2) the collection of discarded cigarette packs and (3) a survey of tobacco smokers. PARTICIPANTS: For the purposes of the survey, 40 self-reported smokers were recruited at taxi ranks in each downtown site. Adults who were over the age of 18 were asked to verbally consent to participate in the study and answer a questionnaire administered by a researcher. RESULTS: The leading reason for labelling a pack as illicit in each city/town was the absence of an excise stamp (28.6% overall), and the least common reason was an illegal tar or nicotine level (11.1% overall). The overall proportion of informal vendors who sold illicit cigarettes was 41%. Singles and packs of 20 were consistently cheaper at informal vendors. Survey participants' responses reflected varied perspectives on illicit cigarettes and purchasing preferences. CONCLUSIONS: Each approach generated an interesting insight into physical aspects of illicit cigarettes. While this pilot study cannot be used to generate generalisable statistics on illicit cigarettes, more systematic surveys of this nature could inform researchers' and practitioners' initiatives to combat illicit and legal cigarette sales and usage. PMID- 24812194 TI - A case study in creating oral health messages for rural low-income families: a comparison to the cultural appropriateness framework. AB - Culturally appropriate oral health messages are found to be an effective tool to improve oral health among rural, low-income families. Yet knowledge on how to best achieve such messages is lacking. Based on participatory, learner-based approach, this study examined various oral health messages (varied length, detail, and voice) among 75 rural, low-income mothers in nine states in the theoretical framework of cultural appropriateness model. Specifically, we compared the process of our message creation to the differential effects of linguistic, peripheral, evidential, and sociocultural approaches. Results of qualitative analysis showed that low-income mothers, who represent a "rural culture," prefer messages that (a) have a clear and concise connection between recommendations presented in the message and future economic consequences of inaction, with sufficient explanation; (b) mention problem-specific economic struggles and inaccessibility of resources; (c) include the sources of fluoride, community barriers, availability of professional resources, and the quality of local water; and (d) contain the voice of a dental authority over the voice of other mothers. The applicability of cultural appropriateness framework and policy implications are discussed. PMID- 24812193 TI - Testing the feasibility and acceptability of using the Nintendo Wii in the home to increase activity levels, vitality and well-being in people with multiple sclerosis (Mii-vitaliSe): protocol for a pilot randomised controlled study. AB - INTRODUCTION: The benefits of physical activity for people with multiple sclerosis (pwMS) have been recognised. However, exercise regimens can be difficult to maintain over the longer term and pwMS may face unique barriers to physical activity engagement. Pilot research suggests the Nintendo Wii can be used safely at home by pwMS with minimal mobility/balance issues and may confer benefits. We have developed a home-based physiotherapist supported Wii intervention ('Mii-vitaliSe') for pwMS that uses commercial software. This is a pilot study to explore the feasibility of conducting a full scale clinical and cost-effectiveness trial of Mii-vitaliSe. METHODS AND ANALYSIS: 30 ambulatory, relatively inactive pwMS will be randomised to receive Mii-vitaliSe immediately, or after 6 months. Outcomes, measured at baseline and 6 and 12 months later, will include balance, gait, mobility, hand dexterity and self-reported physical activity levels, fatigue, self-efficacy, mood and quality of life. Interviews conducted on a purposive sample of participants will explore experiences of participation in the study and barriers and facilitators to using the Wii. Mean recruitment, adherence rate and standard deviations (SDs) of potential primary outcomes for the full trial will be estimated and precision summarised using 95% confidence intervals (CIs). Interview transcripts will be thematically analysed using a generic qualitative approach. ETHICS AND DISSEMINATION: National Health Service (NHS; ref 12/SC/0420) and university ethical approvals have been obtained as has NHS Research and Development permission from the relevant trust. A home risk assessment will be undertaken for all potential participants. All adverse events will be closely monitored, documented and reported to the study Safety Monitoring Committee. At least one publication in a peer reviewed journal will be produced and research findings presented at a national and international conference. With service users, we will coproduce a summary of the findings for dissemination on our research unit's website and elsewhere. TRIAL REGISTRATION NUMBER: ISRCTN 49286846. PMID- 24812195 TI - Can health equity coexist with housing inequalities? A contemporary issue in historical context. AB - The housing policies established by the Federal Home Loan Bank Board, Federal Housing Administration, and the Veterans Administration transformed the American housing market. However, these policies intentionally excluded communities of color from the postwar American housing boom by defining them as contaminants eroding national property values. Hence, racially restrictive federal housing policies established an inequitable generational trajectory for residents in communities across the United States. Public health practitioners are faced with the monumental challenge of addressing health disparities that were in part created by non-public health policies. The purpose of this article is to examine how federal housing policies historically contributed to creating the built environment and therefore establishing a foundation for health disparities. These pervasive, exclusionary policies and the generational stigma associated with this issue raise serious questions about the ethics of contemporary policies, practices, and research aimed at achieving health equity. PMID- 24812197 TI - Effect of Postoperative Passive Motion on Rotator Cuff Reconstruction With Acellular Dermal Matrix Grafts in a Rat Model. AB - BACKGROUND: Although postoperative rehabilitation is critical for rotator cuff tendon-to-bone healing and shoulder function recovery, no standardized protocol has been established. HYPOTHESIS: Postoperative immediate passive motion is detrimental to tendon-to-bone remodeling and tendon maturation after rotator cuff acellular dermal matrix (ADM) grafting, although postoperative delayed passive motion does no harm. STUDY DESIGN: Controlled laboratory study. METHODS: Male Sprague-Dawley rats underwent rotator cuff reconstruction with ADM grafts. Their shoulders were immobilized for 2 weeks thereafter. The rats were assigned to 3 different rehabilitation protocols: (1) immobilization without passive motion (nonpassive motion [N-PM], controls), (2) immobilization with immediate passive motion (I-PM), and (3) immobilization with delayed passive motion (D-PM). Specimens obtained 2, 6, and 12 weeks postoperatively were analyzed histologically, and semiquantitative histomorphological measurements of collagen organization, vascularity, and cellularity were obtained; the area of interest was divided into 2 zones, the midsubstance of the graft and the graft-bone interface. Another set of samples taken at 12 weeks was subjected to biomechanical analysis. RESULTS: At 2 weeks, there was no significant difference among the groups in terms of semiquantitative histomorphological measurements of collagen organization, vascularity, and cellularity. At 6 weeks, collagen organization at the insertion site was significantly poorer in I-PM than in N-PM and D-PM rats (P = .0095). At 12 weeks, collagen organization at the insertion site and midsubstance of ADM grafts was also significantly poorer in I-PM rats (P = .0125 and P = .0018, respectively), and ultimate load-to-failure was lower in this group (P = .0043). CONCLUSION: While postoperative immediate passive motion was detrimental to remodeled tendon-to-bone healing and to the tendon maturation of ADM grafts placed in the rotator cuff tendon defects, delayed passive motion did no harm. CLINICAL RELEVANCE: For patients with 6-week immobilization after rotator cuff reconstruction, we recommend that early passive motion be started no sooner than 3 weeks after surgery. Immediate early passive motion should be avoided. PMID- 24812196 TI - Quantitative Magnetic Resonance Imaging UTE-T2* Mapping of Cartilage and Meniscus Healing After Anatomic Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: An anterior cruciate ligament (ACL) injury greatly increases the risk for premature knee osteoarthritis (OA). Improved diagnosis and staging of early disease are needed to develop strategies to delay or prevent disabling OA. PURPOSE: Novel magnetic resonance imaging (MRI) ultrashort echo time (UTE)-T2(*) mapping was evaluated against clinical metrics of cartilage health in cross sectional and longitudinal studies of human participants before and after ACL reconstruction (ACLR) to show reversible deep subsurface cartilage and meniscus matrix changes. STUDY DESIGN: Cohort study (diagnosis/prognosis); Level of evidence, 2. METHODS: Forty-two participants (31 undergoing anatomic ACLR; 11 uninjured) underwent 3-T MRI inclusive of a sequence capturing short and ultrashort T2 signals. An arthroscopic examination of the medial meniscus was performed, and modified Outerbridge grades were assigned to the central and posterior medial femoral condyle (cMFC and pMFC, respectively) of ACL reconstructed patients. Two years after ACLR, 16 patients underwent the same 3-T MRI. UTE-T2(*) maps were generated for the posterior medial meniscus (pMM), cMFC, pMFC, and medial tibial plateau (MTP). Cross-sectional evaluations of UTE-T2(*) and arthroscopic data along with longitudinal analyses of UTE-T2(*) changes were performed. RESULTS: Arthroscopic grades showed that 74% (23/31) of ACL reconstructed patients had intact cMFC cartilage (Outerbridge grade 0 and 1) and that 90% (28/31) were Outerbridge grade 0 to 2. UTE-T2(*) values in deep cMFC and pMFC cartilage varied significantly with injury status and arthroscopic grade (Outerbridge grade 0-2: n = 39; P = .03 and .04, respectively). Pairwise comparisons showed UTE-T2(*) differences between uninjured controls (n = 11) and patients with arthroscopic Outerbridge grade 0 for the cMFC (n = 12; P = .01) and arthroscopic Outerbridge grade 1 for the pMFC (n = 11; P = .01) only and not individually between arthroscopic Outerbridge grade 0, 1, and 2 of ACL reconstructed patients (P > .05). Before ACLR, UTE-T2(*) values of deep cMFC and pMFC cartilage of ACL-reconstructed patients were a respective 43% and 46% higher than those of uninjured controls (14.1 +/- 5.5 vs 9.9 +/- 2.3 milliseconds [cMFC] and 17.4 +/- 7.0 vs 11.9 +/- 2.4 milliseconds [pMFC], respectively; P = .02 for both). In longitudinal analyses, preoperative elevations in UTE-T2(*) values in deep pMFC cartilage and the pMM in those with clinically intact menisci decreased to levels similar to those in uninjured controls (P = .02 and .005, respectively), suggestive of healing. No decrease in UTE-T2(*) values for the MFC and new elevation in UTE-T2(*) values for the submeniscus MTP were observed in those with meniscus tears. CONCLUSION: This study shows that novel UTE-T2(*) mapping demonstrates changes in cartilage deep tissue health according to joint injury status as well as a potential for articular cartilage and menisci to heal deep tissue injuries. Further clinical studies of UTE-T2(*) mapping are needed to determine if it can be used to identify joints at risk for rapid degeneration and to monitor effects of new treatments to delay or prevent the development of OA. PMID- 24812198 TI - Characteristics and outcomes of patients with percutaneous coronary intervention for unprotected left main coronary artery disease: a Hong Kong experience. AB - OBJECTIVE: To evaluate the intermediate-term outcomes of patients with unprotected left main coronary artery stenosis who were treated with percutaneous coronary intervention in Hong Kong. DESIGN: Historical cohort. SETTING: A regional hospital in Hong Kong. PATIENTS: Patients with unprotected left main coronary artery disease undergoing stenting with bare-metal stents or drug eluting stents between January 2008 and September 2011. MAIN OUTCOME MEASURES: Incidence of restenosis and major adverse cardiac and cerebrovascular events including cardiac death, non-fatal myocardial infarction, stroke, and target lesion revascularisation. RESULTS: Of the 111 patients included in the study, 86 received drug-eluting stents and 25 received bare-metal stents. Procedural success was achieved in 98.2% of cases. Angiographic follow-up was available in 83.8% of cases and restenosis rate was significantly lower with drug-eluting stents than with bare-metal stents (14.0% vs 40.0%; P=0.004). After a mean clinical follow-up of 26.1 (standard deviation, 12.6) months, the incidences of cardiac death (5.8% vs 16.0%; P=0.191) and non-fatal myocardial infarction (3.5% vs 8.0%; P=0.262) were similar between drug-eluting stents and bare-metal stents. However, the risks of target lesion revascularisation (9.3% vs 32.0%; P=0.001) and major adverse cardiac and cerebrovascular events (19.8% vs 44.0%; P=0.004) were significantly lower with drug-eluting stents than with bare-metal stents. CONCLUSIONS: Performing percutaneous coronary intervention for unprotected left main coronary artery disease was safe and feasible in selected patients with high procedural success rate. The incidence of major adverse cardiac and cerebrovascular events in patients receiving drug-eluting stents remains low after intermediate-term follow-up. Compared with bare-metal stents, drug-eluting stents were associated with a lower need for repeating revascularisation without increasing the risk of death or myocardial infarction in patients with unprotected left main coronary artery disease. PMID- 24812199 TI - Social obstetrics: non-local expectant mothers admitted through accident and emergency department in a public hospital in Hong Kong. AB - OBJECTIVES: To review the pregnancy outcomes of non-booked, non-local pregnant women delivering in Kwong Wah Hospital via admission to the Accident and Emergency Department 1 year after the announcement by the Hospital Authority to stop antenatal booking for non-eligible persons; and to perform a literature review of local studies about non-eligible person deliveries over the last decade. DESIGN: Case series. SETTING: A public hospital in Hong Kong. PARTICIPANTS: All women who held the People's Republic of China passport or the two-way permit and those non-eligible persons whose spouses were Hong Kong Identity Card holders, who delivered in Kwong Wah Hospital from 1 April 2011 to 31 March 2012. RESULTS: Overall, 219 women who were non-eligible persons delivered 221 live births during the study period. Compared with the annual statistics of Kwong Wah Hospital in 2011, non-local mothers were of higher parity; more likely to have hypertensive disease (including pre-eclamptic toxaemia), preterm deliveries (ie at <37 weeks), babies needing admission to the special care baby unit, and macrosomic babies (ie weighing >4.0 kg). The rates of induction of labour and caesarean section were lower in this group. There was no significant difference in the maternal and neonatal outcomes between women who had no booking and those who had a booking in another Hospital Authority or private hospital. There were many incidents of near-miss obstetric complications or suboptimally managed obstetric conditions due to lack of well-structured and continuous antenatal care in this group of non-eligible persons. CONCLUSION: Non eligible person delivering babies in Hong Kong has become a social obstetrics phenomenon. Despite the introduction of policies, reduction in the number of deliveries (quantity) did not improve the obstetric outcomes (quality). Health care professionals should continue to be prepared for managing the potential near miss clinical complications in this group of 'travelling mothers'. PMID- 24812200 TI - Thoracoscopic operations in children. AB - Over the past two decades there has been an exponential growth in the use of thoracoscopy in children. Indeed, many advanced procedures-including lobectomy, repair of tracheoesophageal fistula, excision of mediastinal tumours, and diaphragmatic hernia repairs-can now be performed by this means in advanced paediatric surgical centres in the world. This review describes the historical perspectives and the current state of thoracoscopic surgery, including potential benefits and challenges, in children. PMID- 24812201 TI - Redefining racial residential segregation and its association with physical activity among African Americans 50 years and older: a mixed methods approach. AB - Physical inactivity is one of the factors contributing to disproportionate disease rates among older African Americans. Previous literature indicates that older African Americans are more likely to live in racially segregated neighborhoods and that racial residential segregation is associated with limited opportunities for physical activity. A cross-sectional mixed methods study was conducted guided by the concept of therapeutic landscapes. Multilevel regression analyses demonstrated that racial residential segregation was associated with more minutes of physical activity and greater odds of meeting physical activity recommendations. Qualitative interviews revealed the following physical activity related themes: aging of the neighborhood, knowing your neighbors, feeling of safety, and neighborhood racial identity. Perceptions of social cohesion enhanced participants' physical activity, offering a plausible explanation to the higher rates of physical activity found in this population. Understanding how social cohesion operates within racially segregated neighborhoods can help to inform the design of effective interventions for this population. PMID- 24812202 TI - What criteria guide national entrepreneurs' policy decisions on user fee removal for maternal health care services? Use of a best-worst scaling choice experiment in West Africa. AB - OBJECTIVE: Several countries in sub-Saharan Africa have implemented policies to remove or reduce user fees. Our aim was to identify criteria guiding such decisions among national policy entrepreneurs, those who link up problem definition, solution development and political processes. METHODS: We administered a best-worst scaling (BWS) experiment to 89 policy entrepreneurs, asking them to identify the most and the least important criteria on a series of predefined sets. Sets were compiled using a Balance Incomplete Block Design which generated random combinations of all 11 criteria included in the experiment. In turn, those had emerged from a prior set of focus group discussions organized among policy entrepreneurs. Ordered logit models were used to investigate the value of single criteria as well as heterogeneity of preferences. RESULTS: Political commitment was identified as the most important criterion guiding policy decisions on user fee abolition or reduction to the overall sample, but particularly so for more experienced respondents aged over 50 years. International pressure and donor money were identified as least important while equity and institutional capacity were deemed of relatively little importance. Respondents more involved in advising on policy than on formulating policy rated economic issues such as financial sustainability and cost-effectiveness as less important. CONCLUSIONS: It is feasible to apply BWS experiments in low-income countries, although whether the technique can be adjusted to elicit preferences among non-literate respondents in these settings is unclear. PMID- 24812203 TI - Predicting and correcting ataxia using a model of cerebellar function. AB - Cerebellar damage results in uncoordinated, variable and dysmetric movements known as ataxia. Here we show that we can reliably model single-joint reaching trajectories of patients (n = 10), reproduce patient-like deficits in the behaviour of controls (n = 11), and apply patient-specific compensations that improve reaching accuracy (P < 0.02). Our approach was motivated by the theory that the cerebellum is essential for updating and/or storing an internal dynamic model that relates motor commands to changes in body state (e.g. arm position and velocity). We hypothesized that cerebellar damage causes a mismatch between the brain's modelled dynamics and the actual body dynamics, resulting in ataxia. We used both behavioural and computational approaches to demonstrate that specific cerebellar patient deficits result from biased internal models. Our results strongly support the idea that an intact cerebellum is critical for maintaining accurate internal models of dynamics. Importantly, we demonstrate how subject specific compensation can improve movement in cerebellar patients, who are notoriously unresponsive to treatment. PMID- 24812205 TI - A phenomenological study of obesity and physical activity in southern African American older women. AB - African American women are more likely to be classified as overweight or obese than European American women and little is known about this phenomenon. The purpose of this qualitative study was to explore the lived experiences of overweight and obese African American older women living in the southern regions of the United States. Semistructured, audiotaped interviews were conducted to elicit narratives from nine participants. Interview data were transcribed verbatim and then coded and analyzed using Colaizzi's phenomenological analysis framework. Three major categories emerged: impact of health conditions, incongruent perceptions, and the desire for independence. The focus of culturally appropriate interventions aimed at increasing physical activity for this group should incorporate activities that will help them remain independent, because weight loss is not a primary motivator. PMID- 24812204 TI - PMP22 messenger RNA levels in skin biopsies: testing the effectiveness of a Charcot-Marie-Tooth 1A biomarker. AB - Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with increased gene dosage for PMP22. Therapeutic approaches are currently aiming at correcting PMP22 over-expression. It is unknown whether PMP22 can be used as a biological marker of disease progression and therapy efficacy. We performed quantitative real-time polymerase chain reaction on skin biopsies of 45 patients with CMT1A, obtained at study entry and after 24-months of treatment either with ascorbic acid or placebo. Data of a subgroup of patients were also compared with matched healthy subjects. Finally, we analysed PMP22 messenger RNA levels in sural nerve biopsies. We did not find significant differences in the levels of any known PMP22 transcripts in treated or untreated patients with CMT1A, thus confirming that ascorbic acid does not impact on the molecular features of CMT1A. Most importantly, we did not observe any correlation between PMP22 messenger RNA levels and the different clinical and electrophysiological outcome measures, underscoring the weakness of PMP22 to mirror the phenotypic variability of patients with CMT1A. We did not find increased PMP22 messenger RNA levels in skin and sural nerve biopsies of patients with CMT1A compared with relative controls. In conclusion, this study shows that ascorbic acid does not impact on PMP22 transcriptional regulation and PMP22 is not a suitable biomarker for CMT1A. PMID- 24812206 TI - Reaching the magnetic anisotropy limit of a 3d metal atom. AB - Designing systems with large magnetic anisotropy is critical to realize nanoscopic magnets. Thus far, the magnetic anisotropy energy per atom in single molecule magnets and ferromagnetic films remains typically one to two orders of magnitude below the theoretical limit imposed by the atomic spin-orbit interaction. We realized the maximum magnetic anisotropy for a 3d transition metal atom by coordinating a single Co atom to the O site of an MgO(100) surface. Scanning tunneling spectroscopy reveals a record-high zero-field splitting of 58 millielectron volts as well as slow relaxation of the Co atom's magnetization. This striking behavior originates from the dominating axial ligand field at the O adsorption site, which leads to out-of-plane uniaxial anisotropy while preserving the gas-phase orbital moment of Co, as observed with x-ray magnetic circular dichroism. PMID- 24812207 TI - Global rates of marine sulfate reduction and implications for sub-sea-floor metabolic activities. AB - Sulfate reduction is a globally important redox process in marine sediments, yet global rates are poorly quantified. We developed an artificial neural network trained with 199 sulfate profiles, constrained with geomorphological and geochemical maps to estimate global sulfate-reduction rate distributions. Globally, 11.3 teramoles of sulfate are reduced yearly (~15% of previous estimates), accounting for the oxidation of 12 to 29% of the organic carbon flux to the sea floor. Combined with global cell distributions in marine sediments, these results indicate a strong contrast in sub-sea-floor prokaryote habitats: In continental margins, global cell numbers in sulfate-depleted sediment exceed those in the overlying sulfate-bearing sediment by one order of magnitude, whereas in the abyss, most life occurs in oxic and/or sulfate-reducing sediments. PMID- 24812209 TI - Dose-response walking activity and physical function in older adults. AB - The aim of this study was to examine the dose-response relationship between walking activity and physical function (PF) in community-dwelling older adults. Physical activity (PA, pedometry) and PF (self-report [SF-36] and 6-minute walk test [6MWT]) were assessed in 836 individuals. Accumulated PA was categorized into four groups (1 = <= 2,500; 2 = 2,501-5,000; 3 = 5,001-7,500; and 4 = >= 7,501 steps/day). Across individual groups 1-4, SF-36 scores increased from 66.9 +/- 25.0% to 73.5 +/- 23.2% to 78.8 +/- 19.7% to 81.3 +/- 20.6%, and 6MWT increased from 941.7 +/- 265.4 ft to 1,154.1 +/- 248.2 ft to 1,260.1 +/- 226.3 ft to 1,294.0 +/- 257.9 ft. Both SF-36 and 6MWT scores were statistically different across all groups, apart from groups 3 and 4. PA and ranks of groups were highly significant predictors (p < .0001) for both SF-36 and 6MWT. There was a positive dose-response relationship evident for both SF-36 and 6MWT with increasing levels of PA. Low levels of PA appear to be an important indicator of poor functionality in older adults. PMID- 24812208 TI - The cellular and molecular origin of tumor-associated macrophages. AB - Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an "alternatively activated" phenotype. TAM terminal differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy. PMID- 24812210 TI - Nanotechnology in Dutch science cafes: Public risk perceptions contextualised. AB - Understanding public perceptions of and attitudes to nanotechnology is important in order to understand and facilitate processes of dialogue and public participation. This research quantitatively analysed risk perceptions and attitudes of Dutch science cafe participants (n = 233) and compared these with members of the Dutch public (n = 378) who had not attended a cafe but were interested in science and technology as well. A qualitative analysis of the meetings contextualised and enriched the quantitative findings. Both groups shared similar key attitudes and were positive about nanotechnology while the Dutch cafe participants were even more positive about nanotechnology than the group of non-participants. The perception that nanotechnology would lead to risk applications was only predictive of attitudes for the non-participants. The qualitative analysis showed that cafe participants and speakers considered discussion of the risks, benefits and related issues important. Further research could investigate how science cafes can play a role in the science-society debate. PMID- 24812211 TI - Draft Genome Sequence of the Novel Thermoacidophilic Archaeon Acidianus copahuensis Strain ALE1, Isolated from the Copahue Volcanic Area in Neuquen, Argentina. AB - Acidianus copahuensis is a recently characterized thermoacidophilic archaeon isolated from the Copahue volcanic area in Argentina. Here, we present its draft genome sequence, in which we found genes involved in key metabolic pathways for developing under Copahue's extreme environmental conditions, such as sulfur and iron oxidation, carbon fixation, and metal tolerance. PMID- 24812212 TI - Whole-genome sequences of 13 endophytic bacteria isolated from shrub willow (salix) grown in geneva, new york. AB - Shrub willow, Salix spp. and hybrids, is an important bioenergy crop. Here we report the whole-genome sequences and annotation of 13 endophytic bacteria from stem tissues of Salix purpurea grown in nature and from commercial cultivars and Salix viminalis * Salix miyabeana grown in bioenergy fields in Geneva, New York. PMID- 24812213 TI - Draft Genome Sequence of the First Isolate of Extensively Drug-Resistant Mycobacterium tuberculosis in New Zealand. AB - Extensively drug-resistant (XDR) tuberculosis has now been described in >90 countries worldwide. The first case of XDR tuberculosis (XDR-TB) in New Zealand was recorded in 2010. We report the draft whole-genome sequence of the New Zealand isolate, NZXDR1, and describe a number of single-nucleotide polymorphisms that relate to drug resistance. PMID- 24812214 TI - Draft Genome Sequence of Stenotrophomonas maltophilia SeITE02, a Gammaproteobacterium Isolated from Selenite-Contaminated Mining Soil. AB - Stenotrophomonas maltophilia strain SeITE02 was isolated from the rhizosphere of the selenium-hyperaccumulating legume Astragalus bisculcatus. In this report, we provide the 4.56-Mb draft genome sequence of S. maltophilia SeITE02, a gammaproteobacterium that can withstand high concentrations of selenite and reduce these to elemental selenium. PMID- 24812215 TI - Draft Genome Sequence of Geobacillus sp. Strain FW23, Isolated from a Formation Water Sample. AB - The thermophilic Geobacillus sp. strain FW23 was isolated from the Mehsana oil wells in Gujrat, India, during a screening for oil-degrading bacteria. Here, we report the draft genome sequence of Geobacillus sp. FW23, which may help reveal the genomic differences between this strain and the earlier reported species of the genus Geobacillus. PMID- 24812216 TI - Draft Genome Sequence of Elizabethkingia meningoseptica Isolated from a Traumatic Wound. AB - We report the draft genome assembly of Elizabethkingia meningoseptica strain 502. The sample was isolated from the wound of a repatriated military serviceperson who suffered major trauma from an improvised explosive device (IED), resulting in wounds with extensive environmental contamination. E. meningoseptica was isolated from wounds in both legs. The draft genome assembly has 21 contigs with a total size of 3,960,744 bases. The genome contains genes encoding 26 putative beta lactamases. PMID- 24812217 TI - Complete Genome Sequence of Neisseria meningitidis Serogroup A Strain NMA510612, Isolated from a Patient with Bacterial Meningitis in China. AB - Serogroup A meningococcal strains have been involved in several pandemics and a series of epidemics worldwide in the past. Determination of the genome sequence of the prevalent genotype strain will help us understand the genetic background of the evolutionary and epidemiological properties of these bacteria. We sequenced the complete genome of Neisseria meningitidis NMA510612, a clinical isolate from a patient with meningococcal meningitis. PMID- 24812218 TI - Draft Genome Sequence of Mycobacterium vulneris DSM 45247T. AB - We report the draft genome sequence of Mycobacterium vulneris DSM 45247(T) strain, an emerging, opportunistic pathogen of the Mycobacterium avium complex. The genome described here is composed of 6,981,439 bp (with a G+C content of 67.14%) and has 6,653 protein-coding genes and 84 predicted RNA genes. PMID- 24812219 TI - Whole-genome sequence of a classical Swine Fever virus isolated from the uttarakhand state of India. AB - We report the first complete genome sequence of a classical swine fever (CSF) virus of subgenotype 2.2. The virus (CSFV/IND/UK/LAL-290) was isolated from the Uttarakhand state of India from a backyard pig suspected of having CSF. This genome sequence will give useful insight for future molecular epidemiological studies and the development of an effective vaccine in India. PMID- 24812220 TI - Draft Genome Sequence of Erwinia mallotivora BT-MARDI, Causative Agent of Papaya Dieback Disease. AB - Erwinia mallotivora was isolated from papaya trees infected with dieback disease, which were planted at the Malaysian Agricultural Research and Development Institute (MARDI), Malaysia. Here, we report a draft genome sequence of E. mallotivora BT-MARDI, which offers an important source of information for understanding pathogen and host interaction during papaya dieback development. PMID- 24812221 TI - Draft Genome Sequence of Mycobacterium tuberculosis Clinical Strain G-12-005. AB - Infection caused by drug-resistant Mycobacterium tuberculosis is a growing concern, especially in eastern Europe. We report an annotated draft genome sequence of M. tuberculosis strain G-12-005 obtained from a patient in Georgia. PMID- 24812222 TI - Genome Sequence of Pseudomonas brassicacearum DF41. AB - Pseudomonas brassicacearum DF41, a Gram-negative soil bacterium, is able to suppress the fungal pathogen Sclerotinia sclerotiorum through a process known as biological control. Here, we present a 6.8-Mb assembly of its genome, which is the second fully assembled genome of a P. brassicacearum strain. PMID- 24812223 TI - Complete Genome Sequences of Lactobacillus johnsonii Strain N6.2 and Lactobacillus reuteri Strain TD1. AB - We report here the complete genome sequences of Lactobacillus johnsonii strain N6.2, a homofermentative lactic acid intestinal bacterium, and Lactobacillus reuteri strain TD1, a heterofermentative lactic acid intestinal bacterium, both isolated from a type 1 diabetes-resistant rat model. PMID- 24812224 TI - Genome Sequence of Salmonella enterica subsp. enterica Strain Durban. AB - We report the genome sequence of Salmonella enterica subsp. enterica strain Durban, isolated from a patient with salmonellosis and typhoid fever. The strain is closely related to S. enterica subsp. enterica strain P125109 but differs in loss of the SE20 prophage and acquisition of a prophage similar to ELPhiS. PMID- 24812225 TI - Draft Genome Sequence of Lactobacillus sucicola JCM 15457T, a Motile Lactic Acid Bacterium Isolated from Oak Sap. AB - Here, we report the draft genome sequence of a motile lactic acid bacterium, Lactobacillus sucicola JCM 15457(T), isolated from oak sap. Motility-related genes and their organization in the annotated genome were broadly similar to those in the sequenced genomes of related lactobacilli. PMID- 24812226 TI - Prevalence of unclassified bacteria in tropical coastal waters of malaysia revealed by metagenomic approach. AB - The metagenomes of marine prokaryotes from coastal seawaters in Malaysia are reported in this study. The investigation of the microbial communities using 16S rRNA gene amplicon metagenomic sequencing revealed that majority of the bacteria in the seawater samples remain unclassified. PMID- 24812227 TI - Genome Sequence of Chlamydia suis MD56, Isolated from the Conjunctiva of a Weaned Piglet. AB - Chlamydia suis is a natural pathogen of pigs (Sus scrofa) and causes conjunctivitis, pneumonia, enteritis, and various reproductive disorders that adversely impact this economically important animal. Here, we report the first C. suis genome, that of C. suis MD56, isolated from a conjunctival swab of a weaned piglet. PMID- 24812228 TI - Complete Genome Sequence of Pandoraea pnomenusa 3kgm, a Quorum-Sensing Strain Isolated from a Former Landfill Site. AB - Pandoraea pnomenusa strain 3kgm has been identified as a quorum-sensing strain isolated from soil. Here, we report the complete genome sequence of P. pnomenusa strain 3kgm by using the Pacific Biosciences single-molecule real-time (PacBio RS SMRT) sequencer high-resolution technology. PMID- 24812229 TI - Draft Genome Sequence of Escherichia coli E1728 Isolated from Marine Sediment in Hong Kong. AB - Recent findings of Escherichia coli persisting autochthonously in environmental matrices outside animal bodies have revealed largely unknown facets of the lifestyle and ecophysiology of the species that have yet to be explored. Here, we report the draft genome sequence of E. coli E1728 isolated from marine sediment. PMID- 24812230 TI - Changes in endogenous bioactive compounds of Korean native chicken meat at different ages and during cooking. AB - This study aimed to examine the effect of bird age on the contents of endogenous bioactive compounds, including carnosine, anserine, creatine, betaine, and carnitine, in meat from a certified meat-type commercial Korean native chicken strain (KNC; Woorimatdag). Additionally, the effects of the meat type (breast or leg meat) and the state of the meat (raw or cooked) were examined. Cocks of KNC were raised under similar standard commercial conditions at a commercial chicken farm. At various ages (10, 11, 12, 13, and 14 wk), breast and leg meats from a total of 10 birds from each age group were obtained. Raw and cooked meat samples were then prepared separately and analyzed for bioactive compounds. The age of the KNC had a significant effect only on the betaine content. The breast meat of KNC had higher amounts of carnosine and anserine but had lower amounts of betaine and carnitine than the leg meat (P < 0.05). The KNC meat lost significant amounts of all bioactive compounds during cooking (P < 0.05). Leg meat had high retention percentages of carnosine and anserine after cooking, whereas breast meat showed almost complete retention of betaine and carnitine. The results of this study provide useful and rare information regarding the presence, amounts, and determinants of endogenous bioactive compounds in KNC meat, which can be useful for selection and breeding programs, and also for popularizing indigenous chicken meat. PMID- 24812231 TI - Evaluation of free water and water activity measurements as functional alternatives to total moisture content in broiler excreta and litter samples. AB - Litter moisture contents vary greatly between and within practical poultry barns. The current experiment was designed to measure the effects of 8 different dietary characteristics on litter and excreta moisture content. Additionally, free water content and water activity of the excreta and litter were evaluated as additional quality measures. The dietary treatments consisted of nonstarch polysaccharide content (NSP; corn vs. wheat), particle size of insoluble fiber (coarse vs. finely ground oat hulls), viscosity of a nonfermentable fiber (low- and high viscosity carboxymethyl cellulose), inclusion of a clay mineral (sepiolite), and inclusion of a laxative electrolyte (MgSO4). The 8 treatments were randomly assigned to cages within blocks, resulting in 12 replicates per treatment with 6 birds per replicate. Limited effects of the dietary treatments were noted on excreta and litter water activity, and indications were observed that this measurement is limited in high-moisture samples. Increasing dietary NSP content by feeding a corn-based diet (low NSP) compared with a wheat-based diet (high NSP) increased water intake, excreta moisture and free water, and litter moisture content. Adding insoluble fibers to the wheat-based diet reduced excreta and litter moisture content, as well as litter water activity. Fine grinding of the oat hulls diminished the effect on litter moisture and water activity. However, excreta moisture and free water content were similar when fed finely or coarsely ground oat hulls. The effects of changing viscosity and adding a clay mineral or laxative deviated from results observed in previous studies. Findings of the current experiment indicate a potential for excreta free water measurement as an additional parameter to assess excreta quality besides total moisture. The exact implication of this parameter warrants further investigation. PMID- 24812232 TI - Developmental regulation of adipose tissue growth through hyperplasia and hypertrophy in the embryonic Leghorn and broiler. AB - The United States is a world leader in poultry production, which is the reason why achieving better performance and muscle growth each year is a necessity. Reducing accretion of adipose tissue is another important factor for poultry producers because this allows more nutrients to be directed toward muscle growth, but the effect of embryonic adipose growth on posthatch development has not been fully understood. The purpose of this study was to investigate the total DNA mass, morphological characteristics, differentiation markers, and triglyceride breakdown factors of embryonic adipose tissue, and their relation to hyperplastic and hypertrophic growth within layers (Leghorn) and meat-type chickens (broilers). After embryonic day (E) 12, broiler weight was significantly higher than Leghorn, and this trend continued throughout the rest of incubation and posthatch (P < 0.05). Neck and leg fat pad weights between the 2 breeds did not differ at most of the time points. A remarkable increase in total DNA mass was observed between E12 and E14 in both Leghorn and broilers (P < 0.05), indicating a high potential for hyperplastic growth during this time. Histological analysis revealed clusters of preadipocytes at E12; however, the majority of these cells differentiated by E14 and continued to grow until the time of hatch. The adipocyte sizes between both breeds did not generally differ, even though broilers are known to have larger adipocytes posthatch. Fatty acid-binding protein 4 expression levels in Leghorn and broilers continued to rise with each time point, which paralleled the expansion of mature adipocytes. Adipose triglyceride lipase was highly expressed at E20 and d 1 posthatch to mobilize triglyceride degradation for energy during hatching. Thus, embryonic chicken adipose tissue was found to develop by hyperplastic mechanisms followed by hypertrophy. At embryonic stages and early posthatch, layer- and meat-type chicken adipose growth does not differ, which suggests breed differences occur posthatch. PMID- 24812233 TI - Utilization of buffered vinegar to increase the shelf life of chicken retail cuts packaged in carbon dioxide. AB - Poultry processors commonly place whole parts of broilers in plastic packages and seal them in an atmosphere of 100% carbon dioxide before shipping them to food service and retail customers. This practice extends the shelf life of retail cuts to approximately 12 d under refrigerated conditions. The objective of this study was to determine the antimicrobial efficacy of vinegar for growth inhibition of mesophilic and lactic acid bacterial counts and enhancement of shelf life in CO2 packaged refrigerated chicken thigh samples. Meat quality, sensory differences, and microbial enumeration were evaluated for chicken thighs that were sprayed with 0, 0.5, or 1.0% vinegar. No differences were observed (P > 0.05) among treatments (control vs. 0.5 and 1.0% vinegar-treated chicken thighs) with respect to pH and Commission Internationale d'Eclairage L*a*b*for both chicken skin and the meat tissue. The difference from the control test indicated that trained panelists were not able to detect a difference (P > 0.05) in flavor between the chicken thigh treatments. The mesophilic and Lactobacillus bacterial counts were enumerated after 0, 4, 8, 12, 16, and 20 d of storage. The mesophilic bacterial load for the 1.0% vinegar treatment was less than all other treatments after 8, 12, 16, and 20 d of storage, whereas the 0.5% vinegar treatment had lower bacterial counts at d 12 than both controls and had an approximate shelf life of 16 d. For lactic acid bacteria, the vinegar 1.0% treatment had lower counts than the control treatments at d 12 and 16. The results from the study indicate that a combination of 1.0% vinegar with CO2 packaging can extend the shelf life from 12 to 20 d for chicken retail cuts without negatively affecting the quality and sensory properties of the broiler meat. PMID- 24812234 TI - Optimization of response surface and neural network models in conjugation with desirability function for estimation of nutritional needs of methionine, lysine, and threonine in broiler chickens. AB - The optimization algorithm of a model may have significant effects on the final optimal values of nutrient requirements in poultry enterprises. In poultry nutrition, the optimal values of dietary essential nutrients are very important for feed formulation to optimize profit through minimizing feed cost and maximizing bird performance. This study was conducted to introduce a novel multi objective algorithm, desirability function, for optimization the bird response models based on response surface methodology (RSM) and artificial neural network (ANN). The growth databases on the central composite design (CCD) were used to construct the RSM and ANN models and optimal values for 3 essential amino acids including lysine, methionine, and threonine in broiler chicks have been reevaluated using the desirable function in both analytical approaches from 3 to 16 d of age. Multi-objective optimization results showed that the most desirable function was obtained for ANN-based model (D = 0.99) where the optimal levels of digestible lysine (dLys), digestible methionine (dMet), and digestible threonine (dThr) for maximum desirability were 13.2, 5.0, and 8.3 g/kg of diet, respectively. However, the optimal levels of dLys, dMet, and dThr in the RSM based model were estimated at 11.2, 5.4, and 7.6 g/kg of diet, respectively. This research documented that the application of ANN in the broiler chicken model along with a multi-objective optimization algorithm such as desirability function could be a useful tool for optimization of dietary amino acids in fractional factorial experiments, in which the use of the global desirability function may be able to overcome the underestimations of dietary amino acids resulting from the RSM model. PMID- 24812235 TI - Comparison of broiler performance and carcass yields when fed diets containing genetically modified canola meal from event DP-O73496-4, near-isogenic canola meal, or commercial canola meals. AB - Genetically modified (GM) canola (Brassica napus L.) line containing event DP O73496-4 (hereafter referred to as 73496 canola) was produced by the insertion of the glyphosate acetyltransferase (gat4621) gene derived from Bacillus licheniformis. Expression of the GAT4621 protein present in 73496 canola plants confers in planta tolerance to the herbicidal active ingredient glyphosate. The objective of this study was to compare the nutritional performance of broiler chickens fed canola meal from 73496 canola seed with that of broiler chickens fed non-GM canola meal in a 42-d feeding trial. Diets were prepared using meal processed from seed from unsprayed 73496 plants or from plants sprayed with an in field application of glyphosate herbicide [73496(S)]. For comparison, additional diets were produced with canola meal obtained from the non-GM near-isogenic control or non-GM commercial reference DuPont Pioneer brand varieties 42H72, 42H73, 46A65, and 44A89. Diets were fed to Ross 708 broilers (n = 120/group, 50% male and 50% female) in 3 phases: starter and grower phases containing 10 or 20% canola meal, respectively, and a finisher phase with a common corn-soybean meal diet without any canola meal. No statistically significant differences were observed in growth performance measures or organ and carcass yields between broilers consuming diets produced with canola meal from unsprayed or sprayed 73496 seed and those consuming diets produced with canola meal from control seed. Additionally, all performance, organ, and carcass measures from control, 73496, and 73496(S) canola treatment groups were within tolerance intervals constructed using data from the reference canola groups. It was concluded from these results that meal processed from 73496 canola seed (unsprayed plants or plants sprayed with glyphosate) was nutritionally equivalent to meal processed from non-GM near isogenic control canola seed. PMID- 24812236 TI - Effect of perches on liver health of hens. AB - Fatty liver is a common energy metabolic disorder in caged laying hens. Considering that the egg industry is shifting from conventional cages to alternative housing systems such as enriched cages, the objective of this study was to determine the effects of perches on fat deposition and liver health in laying hens. Three hundred twenty-four 17-wk-old White Leghorn hens were housed in 1 of 4 treatments with 9 hens per cage. Treatment 1 hens never had access to perches during their life cycle. Treatment 2 hens had access to perches during the pullet phase only. Treatment 3 hens had access to perches during the laying phase only. Treatment 4 hens always had access to perches. Liver weight, abdominal fat pad weight, BW, liver fat, and circulating alanine transaminase, aspartate transaminase, and adiponectin were determined. Provision of perches during either the rearing or laying phase did not affect liver health in 71-wk old hens. However, perch access compared with no perch access during the egg laying phase reduced relative fat pad weight. These results suggest that providing perches as a means of stimulating activity reduced abdominal fat deposition in caged hens during the laying period. However, perch access in caged hens was ineffective in reducing fat deposition in the liver and altering enzyme activities related to improved liver function. PMID- 24812237 TI - Bacterial chondronecrosis with osteomyelitis in broilers: influence of sires and straight-run versus sex-separate rearing. AB - Two experiments (E1, E2) were conducted to compare the influence of sires (sire A on dam C vs. sire B on dam C) and straight-run versus sex-separate rearing on the incidence of bacterial chondronecrosis with osteomyelitis (BCO) in broilers. Fertile eggs from commercial breeder flocks were incubated and hatched at the University of Arkansas Poultry Research Hatchery. Male and female chicks were reared together (straight-run) or separately (sex-separate) in 3 * 3 m pens on litter or flat wire flooring with 65 (E1) or 60 (E2) birds per pen. Necropsies revealed lesions that are pathognomonic for BCO in >=98% of the birds that became lame. The SigmaStat Z-test was used to compare cumulative BCO incidences through 8 wk of age. For birds reared on litter, the incidences of BCO were low regardless of cross or sex (range: 1.7 to 5.1%; P >= 0.6). Within a cross and sex, rearing the broilers straight-run versus sex-separate on wire flooring did not significantly affect the incidence of BCO. Significant incidences of BCO did not develop until after d 40. Males from the sire A cross developed a higher incidence of BCO than males from the sire B cross in E1 (27 vs. 17%, respectively; P = 0.009) but not in E2 (28.5 vs. 22.6%, respectively; P = 0.141). In both experiments, males from the sire A cross developed higher incidences of BCO than females from the sire B cross (27 vs. 11.9%, in E1; 28.5 vs. 14.8%, in E2). With the sexes pooled, broilers from the sire A cross consistently developed higher incidences of BCO than broilers from the sire B cross (21.4 vs. 14.9%, P = 0.005 in E1; 26.5 vs. 18.7%, P = 0.003 in E2). High susceptibilities to both femoral head (all femoral head necrosis = 66 to 85% incidences) and tibial head (all tibial head necrosis = 81 to 96% incidences) BCO lesions were demonstrated in lame birds from both sexes and crosses. This study supports a sire influence on the susceptibility of broilers to BCO. Sire lines can be chosen to reduce BCO susceptibility when broilers are grown beyond 6 wk of age. PMID- 24812238 TI - The influence of dietary taurine and reduced housing density on hepatic functions in laying hens. AB - To investigate the influence of dietary taurine and reduced housing density on hepatic functions in laying hens, green-shell laying hens were randomly assigned to 3 groups: a free-range group, a caged group with low-density, and a caged group with high-density. Each group was further divided into the control (C) and taurine-treatment (T) groups. All the test birds were fed the same basic diet, except that the T groups were supplemented with 0.1% taurine. After 15 d, sera and liver were aseptically collected. The results show that dietary taurine supplementation and reduced housing density significantly attenuated physiopathological changes in the liver. When compared with the free-range group, serum alanine aminotransterase and aspartate aminotransterase in the caged hens were significantly higher and were deceased by taurine (P < 0.05). Serum inducible nitric oxide synthase activity in caged hens was higher than that in free-range hens, and taurine reduced serum inducible nitric oxide synthase activities in the low-density group (P < 0.05). Nuclear factor-kappaB DNA-binding activity increased significantly in the high-density housing group when compared with the other 2 housing patterns and was decreased by taurine (P < 0.05). Taurine reduced the expression of tumor necrosis factor-alpha mRNA in all 3 rearing patterns, IL-4 mRNA expression in the high-density group, and IL-10 in the low-density group (P < 0.05). Malondialdehyde levels decreased in serum and liver from T groups and serum total antioxidation capability levels increased significantly (P < 0.05) in the low-density group. Dietary taurine supplementation decreased acetyl-CoA and sterol regulatory element-binding protein-1c mRNA expression in the high-density groups (P < 0.05). Taurine significantly increased lipoprotein lipase mRNA expression in the high-density group and peroxisome proliferator receptor mRNA expression both in the low- and high-density groups (P < 0.05). Taurine supplementation reduced total cholesterol levels in the low- and high-density groups, decreased triglyceride and low density lipoprotein cholesterol levels in high-density groups, and increased high density lipoprotein cholesterol levels in all 3 rearing patterns (P < 0.05). Our data demonstrate that dietary taurine and reduced housing density offer significant protection from hepatic damage in laying hens. PMID- 24812239 TI - Effect of pH and postmortem aging on protein extraction from broiler breast muscle. AB - This study determined the effects of extraction buffer pH and postmortem aging on the extraction of salt-soluble and water-soluble proteins from broiler pectoralis muscle. Deboned broiler breast fillets were collected at 4 h postmortem, packaged, and then stored at 4 degrees C until 1, 5, or 8 d postmortem. After the designated aging period, salt-soluble and water-soluble protein extractions were performed using buffers at 7 different pH levels (pH 5.4, 6.4, 6.9, 7.2, 7.5, 8.0, 9.0). Protein concentrations of the extracts were measured and SDS-PAGE analysis was performed. Salt-soluble protein concentration increased (P < 0.0001) as buffer pH increased from pH 5.4 to 6.9 and then remained unchanged from pH 6.9 to 9.0. Water-soluble protein concentration increased (P < 0.0001) as buffer pH increased from pH 5.4 to 7.2 and then remained unchanged from pH 7.2 to 9.0. There was not a significant extraction buffer pH by aging treatment interaction for the total protein concentration of either the salt-soluble or water-soluble protein extracts. The protein concentrations of salt-soluble extracts were similar at both 1 and 8 d postmortem but lower (P < 0.0001) at 5 d postmortem. The protein concentrations of water-soluble extracts were similar at both 1 and 5 d postmortem, but higher (P < 0.0001) at 8 d. Both extraction buffer pH and postmortem aging influenced the SDS-PAGE protein profiles of salt-soluble and water-soluble protein extracts from breast muscles. Data demonstrate that postmortem aging and extraction buffer pH influence both the total amount and the composition of the myofibrillar and sarcoplasmic proteins that can be extracted from broiler breast fillets. PMID- 24812240 TI - The impact of phenotypic appearance on body weight and egg production in laying hens: a group-size- and experience-dependent phenomenon. AB - Alterations of birds' phenotypic appearance (PA) may lead to unwanted behaviors, potentially impairing poultry welfare, health, and productive performance. Likewise, group size may play an important role modulating the expression of adaptive behaviors. This study evaluates whether changes in the PA of Hy-line Brown laying hens may affect their BW and egg production, and if so, whether these effects depend on group size. A total of 1,050 one-day-old chicks were randomly assigned to 1 of 45 pens. Groups were of 10, 20, or 40 individuals (8 hens/m(2)). At arrival, the PA of 0, 30, 50, 70, or 100% of the birds within each group was artificially altered by marking the back of their heads black. The remaining birds within groups were unaltered. The 30% marked hens within groups of 10 individuals had a lower BW at 24 wk of age than their 70% unmarked counterparts, whereas the other groups showed similar BW. No differences were detected in egg laying performance during this phase. Next, within the initially homogeneous groups (0 and 100%), 30, 50, and 70% of the hens were either marked or unmarked (PA changed) sequentially at 34, 38, and 44 wk of age. Hens within the initially heterogeneous groups of 30, 50, and 70% marked birds remained unchanged and were used as controls. Groups of 40 individuals showed a reduction in BW gain and weekly hen-day-egg production after 30% PA changes, as compared with control counterparts. No differences were found in pens of 10 hens, and the groups of 20 showed intermediate results. A transient reduction in egg production was found after 50% PA changes. No further productive effects were observed after 70% changes. Our findings suggest that differences in hen appearance, which may occur due to variations in health status, injuries, and other natural causes, can be critical for production and welfare management practices depending both on the flock size and the birds' previous experience in exposure to group phenotypic heterogeneity. PMID- 24812241 TI - Use of organic acids and competitive exclusion product as an alternative to antibiotic as a growth promoter in the raising of commercial turkeys. AB - A study was conducted to investigate the effects of organic acids (OA) and competitive exclusion product (CE) on growth performance, intestinal morphology, and concentration of volatile fatty acids in the cecal content. The experiment lasted for 10 wk. Four hundred twenty 1-d-old female commercial cross turkey poults (British United Turkeys, BUT Big 9) were distributed into 4 treatments with 5 replicates/pen of 21 birds each. The birds were fed a basal diet without growth promoter (control), diet with lincomycin (44 mg/kg), diet with organic acids (2 g/kg), and diet with product of CE (10(9) cfu/kg). Dietary levels of other nutrients, housing, and general management practices were similar for all treatments. On the first week (d 0-7), the BW and BW gain of the birds that fed diets with OA were lower than in the control group. In the fattening phase (d 28 70), the feed intake of the OA-treated group was lower than compared with the control. The birds that received diet with OA and CE product presented higher concentrations of propionic acid, at 14 d, and butyric acid in cecal content at 28, 56, and 70 d, compared with the control. Dietary inclusion of additives had no significant effects on intestinal villus height, crypt depth, and villus:crypt ratio. Organic acids had negative effects either on early gain or feed intake throughout the study. Because the test was conducted under controlled experimental conditions, the additives that showed results similar to those found by using antibiotics should be studied further in commercial farms to obtain results that can be incorporated into practice. PMID- 24812242 TI - Evaluation of germination, distribution, and persistence of Bacillus subtilis spores through the gastrointestinal tract of chickens. AB - Spores are popular as direct-fed microbials, though little is known about their mode of action. Hence, the first objective of the present study was to evaluate the in vitro germination and growth rate of Bacillus subtilis spores. Approximately 90% of B. subtilis spores germinate within 60 min in the presence of feed in vitro. The second objective was to determine the distribution of these spores throughout different anatomical segments of the gastrointestinal tract (GIT) in a chicken model. For in vivo evaluation of persistence and dissemination, spores were administered to day-of-hatch broiler chicks either as a single gavage dose or constantly in the feed. During 2 independent experiments, chicks were housed in isolation chambers and fed sterile corn-soy-based diets. In these experiments one group of chickens was supplemented with 10(6) spores/g of feed, whereas a second group was gavaged with a single dose of 10(6) spores per chick on day of hatch. In both experiments, crop, ileum, and cecae were sampled from 5 chicks at 24, 48, 72, 96, and 120 h. Viable B. subtilis spores were determined by plate count method after heat treatment (75 degrees C for 10 min). The number of recovered spores was constant through 120 h in each of the enteric regions from chickens receiving spores supplemented in the feed. However, the number of recovered B. subtilis spores was consistently about 10(5) spores per gram of digesta, which is about a 1-log10 reduction of the feed inclusion rate, suggesting approximately a 90% germination rate in the GIT when fed. On the other hand, recovered B. subtilis spores from chicks that received a single gavage dose decreased with time, with only approximately 10(2) spores per gram of sample by 120 h. This confirms that B. subtilis spores are transiently present in the GIT of chickens, but the persistence of vegetative cells is presently unknown. For persistent benefit, continuous administration of effective B. subtilis direct-fed microbials as vegetative cells or spores is advisable. PMID- 24812243 TI - Effects of distance and barriers between resources on bone and tendon strength and productive performance of broiler chickens. AB - Lameness or leg weakness is becoming an important problem in broilers selected for rapid growth, and although the causes are not known, sedentary behavior could be a cause. Two experiments were conducted to study the effects of distance and the presence of ramps between resources (feed and water) on bone and tendon strength, ability to stand, and productive performance. In experiment 1, straight run Ross 708 chicks (n = 1,260) were randomly assigned to 1 of 3 treatments: 1.0, 3.3, or 6.6 m between resources (6 pen replicates/treatment). In experiment 2, Cobb 500 male chicks (n = 864) were randomly assigned to 1 of 4 treatments (2 * 2 factorial, 4 pen replications/treatment) consisting of 2 distances (3 or 8 m) with (WR) or without (NR) a ramp (a triangular prism 31 cm high and 132 cm wide at the base). At d 21, 45, and 56 (experiment 1), or at d 28, 35, 42, and 49 (experiment 2), birds were weighed, killed, and tibias collected to measure breaking strength (BBS), and abdominal fat (AbF) content. At d 49 (experiment 2), calcaneus tendons were also collected to measure breaking strength (TBS). Foot pad lesions and latency to lie (LTL) were determined before killing the birds. In experiment 1, distance did not affect BBS, LTL, foot pad lesions, or BW, but at d 49, birds in the 6.6 m treatment had lower AbF than birds in the other treatments. In experiment 2 at d 49, birds in the 8 m treatment tended to have a higher BBS than birds in the 3 m treatment (P = 0.09), whereas WR birds had lower tendon breaking strength than NR birds (P < 0.01); however, LTL was highest in 8 m NR birds. Final BW was not affected by distance, but birds in the NR group were heavier than birds in the WR group. Furthermore, AbF was lower in 8 m than in 3 m birds. Our results suggest that longer distances between resources have limited effects on bone strength, but increase the LTL, and may change feeding patterns and carcass characteristics, as evidenced by the lower AbF content. Ramps or inclination affected tendon breaking strength. PMID- 24812244 TI - Performance Evaluation of a New Dedicated Breast PET Scanner Using NEMA NU4-2008 Standards. AB - The aim of this work was to evaluate the performance characteristics of a newly developed dedicated breast PET scanner, according to National Electrical Manufacturers Association (NEMA) NU 4-2008 standards. METHODS: The dedicated breast PET scanner consists of 4 layers of a 32 * 32 lutetium oxyorthosilicate based crystal array, a light guide, and a 64-channel position-sensitive photomultiplier tube. The size of a crystal element is 1.44 * 1.44 * 4.5 mm. The detector ring has a large solid angle with a 185-mm aperture and an axial coverage of 155.5 mm. The energy windows at depth of interaction for the first and second layers are 400-800 keV, and those at the third and fourth layers are 100-800 keV. A fixed timing window of 4.5 ns was used for all acquisitions. Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated in accordance with NEMA NU 4-2008 standards. Human imaging was performed in addition to the evaluation. RESULTS: Radial, tangential, and axial spatial resolution measured as minimal full width at half maximum approached 1.6, 1.7, and 2.0 mm, respectively, for filtered backprojection reconstruction and 0.8, 0.8, and 0.8 mm, respectively, for dynamic row-action maximum-likelihood algorithm reconstruction. The peak absolute sensitivity of the system was 11.2%. Scatter fraction at the same acquisition settings was 30.1% for the rat-sized phantom. Peak noise-equivalent counting rate and peak true rate for the ratlike phantom was 374 kcps at 25 MBq and 603 kcps at 31 MBq, respectively. In the image quality phantom study, recovery coefficients and uniformity were 0.04-0.82 and 1.9%, respectively, for standard reconstruction mode and 0.09-0.97 and 4.5%, respectively, for enhanced-resolution mode. Human imaging provided high-contrast images with restricted background noise for standard reconstruction mode and high resolution images for enhanced-resolution mode. CONCLUSION: The dedicated breast PET scanner has excellent spatial resolution and high sensitivity. The performance of the dedicated breast PET scanner is considered to be reasonable enough to support its use in breast cancer imaging. PMID- 24812246 TI - Does PET/MR Imaging Improve Cancer Assessments? Literature Evidence from More Than 900 Patients. AB - Various integrated PET/MR imaging systems have recently been developed to provide improved clinical assessments of cancers in tissues that may be anatomically better characterized with MR imaging than with CT, to explore whether the combined anatomic and functional capabilities of MR imaging together with the molecular PET information provide new insights into disease phenotypes and biology, and to reduce radiation exposure to vulnerable populations such as children and women of child-bearing age. The following review summarizes the published studies and informs about the potential diagnostic advantages of this new technology. PMID- 24812245 TI - Timing of metabolic response monitoring during erlotinib treatment in non-small cell lung cancer. AB - The purpose of this study was to prospectively evaluate the timing of metabolic response monitoring with (18)F-FDG PET of (neoadjuvant) erlotinib treatment in patients with early-stage non-small cell lung cancer. METHODS: This study was designed as an open-label phase II trial performed in 4 hospitals in The Netherlands. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. Response evaluation was performed after 4-7 d and at 3 wk with (18)F-FDG PET/CT scans. Tumor (18)F-FDG uptake and changes were measured as standardized uptake values (SUVs). The metabolic response was classified on the basis of European Organization for Research and Treatment of Cancer criteria (>25% decrease in the maximum SUV) and was compared with histopathologic regression as observed in the resection specimen. RESULTS: From December 2006 to November 2010, 60 patients with non-small cell lung cancer eligible for surgical resection were enrolled in this study. For 43 patients (18 men and 25 women), baseline (18)F-FDG PET/CT scans as well as both monitoring scans and histopathologic response monitoring were available. A partial metabolic response on (18)F-FDG PET/CT scans was observed for 10 patients (23%) after 1 wk and for 14 patients (33%) after 3 wk. Histopathologic examination revealed regression (necrosis of >50%) in 11 patients (26%). In these patients, the maximum SUV decreased by a mean of 17% within 1 wk and a mean of 31% at 3 wk. Seven patients were identified as responders within 1 wk. CONCLUSION: Response monitoring with (18)F-FDG PET/CT within 1 wk after the start of erlotinib treatment identified approximately 64% of histopathologic responders on the basis of European Organization for Research and Treatment of Cancer criteria. PMID- 24812247 TI - 18F-FDG PET/CT for the Detection of Septic Embolisms in Patients with Infectious Endocarditis. PMID- 24812248 TI - Role of (18)F-FDG PET in Patients with Infectious Endocarditis. AB - It was our purpose to evaluate the clinical impact of systematic PET/CT for the diagnosis of infectious embolisms in patients with infectious endocarditis (IE) in comparison with a historic cohort of IE patients managed without this technique. Detection of extracardiac lesions is an essential component of the management and outcome of IE. Studies using PET/CT for the evaluation of patients with IE are scarce, lack a control group, evaluate a small number of patients, or consist of case reports. METHODS: We performed a prospective cohort study (47 patients with definite IE undergoing PET/CT) with matched controls (94 patients with definite IE not undergoing PET/CT) from January 2012 to July 2013 in a tertiary hospital. The results were compared with those of conventional diagnostic techniques and clinical follow-up. RESULTS: PET/CT revealed at least 1 lesion in 35 patients (74.5%): 18 showed an embolic complication, 8 showed pathologic uptake on the valves or cardiac devices, 1 showed both, 5 had incidental noninfectious findings, and the findings for 3 were considered false positive. The validity values for the efficacy of PET/CT in the diagnosis of septic lesions were as follows: sensitivity, 100%; specificity, 80%; positive predictive value, 90%; and negative predictive value, 100%. PET/CT was the only initially positive imaging technique in 15 true-positive cases (55.5%). The systematic use of PET/CT was associated with a 2-fold reduction in the number of relapses (9.6% vs. 4.2%, P = 0.25) and enabled significantly more infectious complications to be diagnosed (18% vs. 57.4%, P = 0.0001). CONCLUSION: PET/CT enables the extent of IE to be assessed using a single test. It is fast (<2 h) and comfortable for the patient, gathers whole-body data, and detects significantly more infectious complications. PMID- 24812250 TI - Against the odds: complete outcrossing in a monoecious clonal seagrass Posidonia australis (Posidoniaceae). AB - BACKGROUND AND AIMS: Seagrasses are marine, flowering plants with a hydrophilous pollination strategy. In these plants, successful mating requires dispersal of filamentous pollen grains through the water column to receptive stigmas. Approximately 40 % of seagrass species are monoecious, and therefore little pollen movement is required if inbreeding is tolerated. Outcrossing in these species is further impacted by clonality, which is variable, but can be extensive in large, dense meadows. Despite this, little is known about the interaction between clonal structure, genetic diversity and mating systems in hydrophilous taxa. METHODS: Polymorphic microsatellite DNA markers were used to characterize genetic diversity, clonal structure, mating system and realized pollen dispersal in two meadows of the temperate, monoecious seagrass, Posidonia australis, in Cockburn Sound, Western Australia. KEY RESULTS: Within the two sampled meadows, genetic diversity was moderate among the maternal shoots (R = 0.45 and 0.64) and extremely high in the embryos (R = 0.93-0.97). Both meadows exhibited a highly clumping (or phalanx) structure among clones, with spatial autocorrelation analysis showing significant genetic structure among shoots and embryos up to 10 15 m. Outcrossing rates were not significantly different from one. Pollen dispersal distances inferred from paternity assignment averaged 30.8 and 26.8 m, which was larger than the mean clone size (12.8 and 13.8 m). CONCLUSIONS: These results suggest highly effective movement of pollen in the water column. Despite strong clonal structure and moderate genetic diversity within meadows, hydrophilous pollination is an effective vector for completely outcrossed offspring. The different localized water conditions at each site (highly exposed conditions vs. weak directional flow) appear to have little influence on the success and pattern of successful pollination in the two meadows. PMID- 24812249 TI - Pectic-beta(1,4)-galactan, extensin and arabinogalactan-protein epitopes differentiate ripening stages in wine and table grape cell walls. AB - BACKGROUND AND AIMS: Cell wall changes in ripening grapes (Vitis vinifera) have been shown to involve re-modelling of pectin, xyloglucan and cellulose networks. Newer experimental techniques, such as molecular probes specific for cell wall epitopes, have yet to be extensively used in grape studies. Limited general information is available on the cell wall properties that contribute to texture differences between wine and table grapes. This study evaluates whether profiling tools can detect cell wall changes in ripening grapes from commercial vineyards. METHODS: Standard sugar analysis and infra-red spectroscopy were used to examine the ripening stages (green, veraison and ripe) in grapes collected from Cabernet Sauvignon and Crimson Seedless vineyards. Comprehensive microarray polymer profiling (CoMPP) analysis was performed on cyclohexanediaminetetraacetic acid (CDTA) and NaOH extracts of alcohol-insoluble residue sourced from each stage using sets of cell wall probes (mAbs and CBMs), and the datasets were analysed using multivariate software. KEY RESULTS: The datasets obtained confirmed previous studies on cell wall changes known to occur during grape ripening. Probes for homogalacturonan (e.g. LM19) were enriched in the CDTA fractions of Crimson Seedless relative to Cabernet Sauvignon grapes. Probes for pectic-beta (1,4)-galactan (mAb LM5), extensin (mAb LM1) and arabinogalactan proteins (AGPs, mAb LM2) were strongly correlated with ripening. From green stage to veraison, a progressive reduction in pectic-beta-(1,4)-galactan epitopes, present in both pectin-rich (CDTA) and hemicellulose-rich (NaOH) polymers, was observed. Ripening changes in AGP and extensin epitope abundance also were found during and after veraison. CONCLUSIONS: Combinations of cell wall probes are able to define distinct ripening phases in grapes. Pectic-beta-(1,4)-galactan epitopes decreased in abundance from green stage to veraison berries. From veraison there was an increase in abundance of significant extensin and AGP epitopes, which correlates with cell expansion events. This study provides new ripening biomarkers and changes that can be placed in the context of grape berry development. PMID- 24812251 TI - New insights into pioneer root xylem development: evidence obtained from Populus trichocarpa plants grown under field conditions. AB - BACKGROUND AND AIMS: Effective programmed xylogenesis is critical to the structural framework of the plant root system and its central role in the acquisition and long-distance transport of water and nutrients. The process of xylem differentiation in pioneer roots under field conditions is poorly understood. In this study it is hypothesized that xylogenesis, an example of developmental programmed cell death (PCD), in the roots of woody plants demonstrates a clearly defined sequence of events resulting in cell death. A comprehensive analysis was therefore undertaken to identify the stages of xylogenesis in pioneer roots from procambial cells to fully functional vessels with lignified cell walls and secondary cell wall thickenings. METHODS: Xylem differentiation was monitored in the pioneer roots of Populus trichocarpa at the cytological level using rhizotrons under field conditions. Detection and localization of the signalling molecule nitric oxide (NO) and hydrogen peroxide (H2O2) was undertaken and a detailed examination of nuclear changes during xylogenesis was conducted. In addition, analyses of the expression of genes involved in secondary cell wall synthesis were performed in situ. KEY RESULTS: The primary event in initially differentiating tracheary elements (TEs) was a burst of NO in thin-walled cells, followed by H2O2 synthesis and the appearance of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) positive nuclei. The first changes in nuclear structure were observed in the early stages of xylogenesis of pioneer roots, prior to lignification; however, the nucleus was detectable under transmission electron microscopy in differentiating cells until the stage at which vacuole integrity was maintained, indicating that their degradation was slow and prolonged. The subsequent sequence of events involved secondary cell wall formation and autophagy. Potential gene markers from the cinnamyl alcohol dehydrogenase (CAD) gene family that were related to secondary wall synthesis were associated with primary xylogenesis, showing clear expression in cells that undergo differentiation into TEs and in the thin-walled cells adjacent to the xylem pole. CONCLUSIONS: The early events of TE formation during pioneer root development are described, together with the timing of xylogenesis from signalling via NO, through secondary cell wall synthesis and autophagy events that are initiated long before lignification. This is the first work describing experiments conducted in planta on roots under field conditions demonstrating that the process of xylogenesis in vivo might be gradual and complex. PMID- 24812252 TI - Phylogenetic analyses provide the first insights into the evolution of OVATE family proteins in land plants. AB - BACKGROUND AND AIMS: The OVATE gene encodes a nuclear-localized regulatory protein belonging to a distinct family of plant-specific proteins known as the OVATE family proteins (OFPs). OVATE was first identified as a key regulator of fruit shape in tomato, with nonsense mutants displaying pear-shaped fruits. However, the role of OFPs in plant development has been poorly characterized. METHODS: Public databases were searched and a total of 265 putative OVATE protein sequences were identified from 13 sequenced plant genomes that represent the major evolutionary lineages of land plants. A phylogenetic analysis was conducted based on the alignment of the conserved OVATE domain from these 13 selected plant genomes. The expression patterns of tomato SlOFP genes were analysed via quantitative real-time PCR. The pattern of OVATE gene duplication resulting in the expansion of the gene family was determined in arabidopsis, rice and tomato. KEY RESULTS: Genes for OFPs were found to be present in all the sampled land plant genomes, including the early-diverged lineages, mosses and lycophytes. Phylogenetic analysis based on the amino acid sequences of the conserved OVATE domain defined 11 sub-groups of OFPs in angiosperms. Different evolutionary mechanisms are proposed for OVATE family evolution, namely conserved evolution and divergent expansion. Characterization of the AtOFP family in arabidopsis, the OsOFP family in rice and the SlOFP family in tomato provided further details regarding the evolutionary framework and revealed a major contribution of tandem and segmental duplications towards expansion of the OVATE gene family. CONCLUSIONS: This first genome-wide survey on OFPs provides new insights into the evolution of the OVATE protein family and establishes a solid base for future functional genomics studies on this important but poorly characterized regulatory protein family in plants. PMID- 24812255 TI - Building food safety into the company culture: a look at Maple Leaf Foods. AB - Maple Leaf Foods learned a hard lesson following its tragic 2008 Listeria outbreak that ended up taking the lives of 23 Canadians. The organization has since 2008 transformed its commitment to food safety with a strong drive and manifest in embedding sustainable food safety behaviours into the existing company culture. Its focus on combining technical risk analysis with behavioural sciences has led to the development and deployment of a food safety strategy deeply rooted in the company values and management commitment. Using five tactics described in this article the organization has been on a journey towards food safety transformation through adoption of best practices for people and systems. The approach to food safety has been one where food safety is treated as a non competitive issue and Maple Leaf Foods have been open to sharing learning about what happened and how the organization will continue to take a leadership position in food safety to continuously raise the bar for food safety across the industry. Maple Leaf Foods has benefited tremendously by learning about best practice from numerous companies in North America and around the world. The authors believe this brief story will bring value to others as we continue to learn and improve. PMID- 24812253 TI - RAV genes: regulation of floral induction and beyond. AB - BACKGROUND: Transcription factors of the RAV (RELATED TO ABI3 AND VP1) family are plant-specific and possess two DNA-binding domains. In Arabidopsis thaliana, the family comprises six members, including TEMPRANILLO 1 (TEM1) and TEM2. Arabidopsis RAV1 and TEM1 have been shown to bind bipartite DNA sequences, with the consensus motif C(A/C/G)ACA(N)2-8(C/A/T)ACCTG. Through direct binding to DNA, RAV proteins act as transcriptional repressors, probably in complexes with other co-repressors. SCOPE AND CONCLUSIONS: In this review, a summary is given of current knowledge of the regulation and function of RAV genes in diverse plant species, paying particular attention to their roles in the control of flowering in arabidopsis. TEM1 and TEM2 delay flowering by repressing the production of two florigenic molecules, FLOWERING LOCUS T (FT) and gibberellins. In this way, TEM1 and TEM2 prevent precocious flowering and postpone floral induction until the plant has accumulated enough reserves or has reached a growth stage that ensures survival of the progeny. Recent results indicate that TEM1 and TEM2 are regulated by genes acting in several flowering pathways, suggesting that TEMs may integrate information from diverse pathways. However, flowering is not the only process controlled by RAV proteins. Family members are involved in other aspects of plant development, such as bud outgrowth in trees and leaf senescence, and possibly in general growth regulation. In addition, they respond to pathogen infections and abiotic stresses, including cold, dehydration, high salinity and osmotic stress. PMID- 24812254 TI - Walking speed: the functional vital sign. AB - Walking speed (WS) is a valid, reliable, and sensitive measure appropriate for assessing and monitoring functional status and overall health in a wide range of populations. These capabilities have led to its designation as the "sixth vital sign". By synthesizing the available evidence on WS, this scholarly review article provides clinicians with a reference tool regarding this robust measure. Recommendations on testing procedures for assessing WS, including optimal distance, inclusion of acceleration and deceleration phases, instructions, and instrumentation are given. After assessing an individual's WS, clinicians need to know what this value represents. Therefore, WS cut-off values and the corresponding predicted outcomes, as well as minimal detectable change values for specific populations and settings are provided. PMID- 24812256 TI - Predicting child physical activity and screen time: parental support for physical activity and general parenting styles. AB - OBJECTIVE: To examine relationships between parenting styles and practices and child moderate-to-vigorous physical activity (MVPA) and screen time. METHODS: Participants were children (6.9 +/- 1.8 years) with a body mass index in the 70 95th percentile and their parents (421 dyads). Parent-completed questionnaires assessed parental support for child physical activity (PA), parenting styles and child screen time. Children wore accelerometers to assess MVPA. RESULTS: Parenting style did not predict MVPA, but support for PA did (positive association). The association between support and MVPA, moreover, varied as a function of permissive parenting. For parents high in permissiveness, the association was positive (greater support was related to greater MVPA and therefore protective). For parents low in permissiveness, the association was neutral; support did not matter. Authoritarian and permissive parenting styles were both associated with greater screen time. CONCLUSIONS: Parenting practices and styles should be considered jointly, offering implications for tailored interventions. PMID- 24812257 TI - Assessment of workers' exposure to bioaerosols in a French cheese factory. AB - Hundreds of different cheeses are produced in France, where 23.9kg of cheese were consumed per inhabitant in 2009, when it was ranked the second cheese-consuming nation. To meet this considerable demand, a large number of cheese factories exist where many workers, especially cheese washers, may be exposed to fungal bioaerosols that can lead to adverse toxinic and allergic effects. Airborne bacteria, fragments, or microbial by-products (endotoxins) are also found and contribute to total worker exposure. However, there is almost no published data concerning worker exposure or characteristics of bioaerosols emitted during these activities. Here, we measured the parameters (concentrations, species present, and size distribution) of the culturable fungal bioaerosol emitted in a French natural-rind cheese-maturing cellar. Concentrations of airborne bacteria and endotoxins were also measured. The main tasks were investigated using stationary or personal sampling over three consecutive days. Depending on the work area, high concentrations of culturable mesophilic microorganisms were measured (using closed-face cassettes): from 10(4) to 2*10(8) CFU m(-3) for fungi and from 10(3) to 10(6) CFU m(-3) for bacteria. These concentrations are 10- to 100000-fold higher than those measured at two reference points (indoor and outdoor) that are assumed not to be contaminated by the plant's activities. Endotoxin concentrations were between 10 and 300 EU m(-3) in the plant. Exposure was further assessed by identifying the predominant culturable fungi (allergenic Mucor fuscus and Penicillium sp.) and by measuring particle size distributions (cascade impactor). Airborne fungal entities (spores, mycelium strands and fragments, agglomerates, etc.) were found with aerodynamic diameters from 3 to over 20 um. A metrological approach was used to fully characterize the culturable fungal aerosols generated during cheese maturing in this plant. The results show that workers are exposed to concentrations of airborne culturable fungi, sometimes very high, throughout the manufacturing process. In addition to fungi, culturable bacteria and endotoxins are also present in the work atmosphere. All these microbial organisms thus contribute in a complex manner to total worker exposure. Despite the lack of both occupational exposure limit values and standardized measuring methods, our results suggest that an immunological risk may occur among workers, especially for cheese brushers, cheese washers, and packagers who are the most exposed workers in the factory. PMID- 24812258 TI - Assessment of health impacts of decreased smoking prevalence in Copenhagen: Application of the DYNAMO-HIA model. AB - AIMS: Tobacco smoking is among the leading risk factors for chronic disease and early death in developed countries, including Denmark, where smoking causes 14% of the disease burden. In Denmark, many public health interventions, including smoking prevention, are undertaken by the municipalities, but models to estimate potential health effects of local interventions are lacking. The aim of the current study was to model the effects of decreased smoking prevalence in Copenhagen, Denmark. METHODS: The DYNAMO-HIA model was applied to the population of Copenhagen, by using health survey data and data from Danish population registers. We modelled the effects of four intervention scenarios aimed at different target groups, compared to a reference scenario. The potential effects of each scenario were modelled until 2040. RESULTS: A combined scenario affecting both initiation rates among youth, and cessation and re-initiation rates among adults, which reduced the smoking prevalence to 4% by 2025, would have large beneficial effects on incidence and prevalence of smoking-related diseases and mortality. Health benefits could also be obtained through interventions targeting only cessation or re-initiation rates, whereas an intervention targeting only initiation among youth had marginal effects on morbidity and mortality within the modelled time frame. CONCLUSIONS: By modifying the DYNAMO-HIA model, we were able to estimate the potential health effects of four interventions to reduce smoking prevalence in the population of Copenhagen. The effect of the interventions on future public health depended on population subgroup(s) targeted, duration of implementation and intervention reach. PMID- 24812259 TI - Prevalence and determinants of hypertension in Estonian adults. AB - BACKGROUND: Although Eastern Europe, including Estonia, has one of the highest morbidity and mortality rates associated with hypertension, there is little information in the literature concerning the biochemical risk factor profile or its association with hypertension in Estonia. This study examined the cross sectional gender-stratified association between biochemical risk markers and hypertension in a population-based sample of adults in Estonia. METHODS: The study was carried out in Tallinn, Estonia and consisted of 511 men and 600 women with a mean age of 46 years. Physiological measurements were taken and blood samples drawn to measure the following markers: cholesterol, high- and low density lipoprotein cholesterol, apolipoproteins A-1 and B, lipoprotein(a), triglycerides, glucose, fibrinogen, high-sensitivity C-reactive protein and homocysteine. RESULTS: Overall, 36% of participants had hypertension, with approximately 80% being aware of their condition. A total of 40% of participants reported taking antihypertensive medication. Multivariate binary logistic regression analysis showed that a decrease in high-density lipoprotein cholesterol and increases in age, body mass index, apolipoprotein B, triglyceride and homocysteine levels were associated with an increased probability of hypertension. CONCLUSIONS: Elevations in biochemical markers and cardiovascular risk factors are associated with hypertension. Increasing body mass index, triglyceride, apolipoprotein B and homocysteine levels with decreasing high density lipoprotein cholesterol level should be investigated and monitored in Estonian adults. PMID- 24812264 TI - Prevalence of Social Isolation in Community-Dwelling Elderly by Differences in Household Composition and Related Factors: From a Social Network Perspective in Urban Japan. AB - OBJECTIVE: The aim of this study was to measure the prevalence of social isolation in community-dwelling elderly and related factors based on household composition differences. METHOD: We used the six-item Lubben Social Network Scale to measure social isolation in 2,000 individuals. Multiple logistic regression analysis was performed to examine factors related to social isolation with household composition after adjusting for gender and age. RESULTS: The prevalence of social isolation was 31.0% for elderly living alone and 24.1% for those living with family. For both, poor mental health and lack of social support from nonfamily members were associated with social isolation risk. For elderly living with family, low intellectual activities and poor health practice were associated with social isolation risk. DISCUSSION: This study showed high prevalence of social isolation. For prevention, promoting mental health and encouraging them to make friends may be important. For elderly living with family, promoting intellectual activities and good health practice is recommended. PMID- 24812265 TI - Culture-Sensitive Question Order Effects of Self-Rated Health Between Older Hispanic and Non-Hispanic Adults in the United States. AB - OBJECTIVE: The aim of this study is to examine context effects created by the question order for self-rated health (SRH) by race/ethnicity and language. METHOD: Differences in SRH estimates for non-Hispanic Whites and Hispanics were first examined with multiple observational data that asked SRH in different contexts. To examine context effects by socio-demographics and health-related characteristics, we conducted experiments on SRH question order. RESULTS: While Hispanics reported poorer health than non-Hispanic Whites, this difference, in part, depended on question contexts. With SRH asked after rather than before specific health questions, Hispanics, especially Spanish-speaking Hispanics, reported better health, while non-Hispanic Whites' reports remained consistent. Among Spanish-speaking Hispanics, the context effect was larger for unmarried and less educated persons and those with comorbidities. DISCUSSION: Question contexts influence SRH reports by Spanish-speaking older adults. Cross-cultural inquiries on the meaning of health and its dynamics with question contexts may explain what SRH measures for increasingly diverse populations. PMID- 24812268 TI - Say no to DMSO: dimethylsulfoxide inactivates cisplatin, carboplatin, and other platinum complexes. AB - The platinum drugs cisplatin, carboplatin, and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11%-34%) in prominent cancer journals utilizing cisplatin dissolved in DMSO. However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes to the structure of the complex. We examined the effect of DMSO on platinum complexes, including cisplatin, carboplatin, and oxaliplatin, finding that DMSO reacted with the complexes, inhibited their cytotoxicity and their ability to initiate cell death. These results render a substantial portion of the literature on cisplatin uninterpretable. Raising awareness of this significant issue in the cancer biology community is critical, and we make recommendations on appropriate solvation of platinum drugs for research. PMID- 24812269 TI - YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a Hippo-independent pathway. AB - Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients. PMID- 24812270 TI - Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. AB - Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment based therapeutic strategy. PMID- 24812271 TI - Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma. AB - Invasion and dissemination of medulloblastoma within the central nervous system is the principal factor predicting medulloblastoma treatment failure and death. Netrin-1 is an axon guidance factor implicated in tumor and vascular biology, including in invasive behaviors. We found that exogenous netrin-1 stimulated invasion of human medulloblastoma cells and endothelial cells in contrast to VEGF A, which promoted invasion of endothelial cells but not medulloblastoma cells. Furthermore, medulloblastoma cells expressed endogenous netrin-1 along with its receptors, neogenin and UNC5B. Blockades in endogenous netrin-1, neogenin, or UNC5B reduced medulloblastoma invasiveness. Neogenin blockade inhibited netrin-1 induced endothelial cells tube formation and recruitment of endothelial cells into Matrigel plugs, two hallmarks of angiogenesis. In patients with pediatric medulloblastoma, netrin-1 mRNA levels were increased 1.7-fold in medulloblastoma tumor specimens compared with control specimens from the same patient. Immunohistochemical analyses showed that netrin-1 was elevated in medulloblastoma tumors versus cerebellum controls. Notably, urinary levels of netrin-1 were 9 fold higher in patients with medulloblastoma compared with control individuals. Moreover, urinary netrin-1 levels were higher in patients with invasive medulloblastoma compared with patients with noninvasive medulloblastoma. Finally, we noted that urinary netrin-1 levels diminished after medulloblastoma resection in patients. Our results suggest netrin-1 is a candidate biomarker capable of detecting an invasive, disseminated phenotype in patients with medulloblastoma and predicting their disease status. PMID- 24812272 TI - Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization. AB - Metabolic targets offer attractive opportunities for cancer therapy. However, their targeting may activate alternative metabolic pathways that can still support tumor growth. A subset of human melanomas relies on PGC1alpha-dependent mitochondrial oxidative metabolism to maintain growth and survival. Herein, we show that loss of viability caused by suppression of PGC1alpha in these melanomas is rescued by induction of glycolysis. Suppression of PGC1alpha elevates reactive oxygen species levels decreasing hypoxia-inducible factor-1alpha (HIF1alpha) hydroxylation that, in turn, increases its protein stability. HIF1alpha reprograms melanomas to become highly glycolytic and dependent on this pathway for survival. Dual suppression of PGC1alpha and HIF1alpha causes energetic deficits and loss of viability that are partially compensated by glutamine utilization. Notably, triple suppression of PGC1alpha, HIF1alpha, and glutamine utilization results in complete blockage of tumor growth. These results show that due to high metabolic and bioenergetic flexibility, complete treatment of melanomas will require combinatorial therapy that targets multiple metabolic components. PMID- 24812273 TI - Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors. AB - Biomarker studies have shown that expression of the T-cell coregulatory ligand PDL1 on tumor cells correlates with clinical responsiveness to the PD1 antibody nivolumab. Here, we report the findings of a preclinical cancer vaccine study demonstrating vaccine-dependent PDL1 upregulation in the tumor microenvironment. We formulated an IFNgamma-inducing cancer vaccine called TEGVAX that combined GM CSF and multiple Toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic antitumor immunity. Unexpectedly, TEGVAX also upregulated PDL1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PDL1 upregulation in this setting relied upon IFNgamma-expressing tumor-infiltrating CD4(+) and CD8(+) T cells and administration of a PD1-blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNgamma-inducing cancer vaccines with immune checkpoint blockade. PMID- 24812274 TI - The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug tolerant tumor cell subpopulation. AB - Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced stage disease. However, their clinical benefit is typically short-lived because of the relatively rapid acquisition of drug resistance following treatment response. Accumulating preclinical and clinical data point to a role for a heterogeneous response to treatment within a subpopulation of tumor cells that are intrinsically drug-resistant, such as cancer stem cells. We have previously described an epigenetically determined reversibly drug-tolerant subpopulation of cancer cells that share some properties with cancer stem cells. Here, we define a requirement for the previously established cancer stem cell marker ALDH (aldehyde dehydrogenase) in the maintenance of this drug-tolerant subpopulation. We find that ALDH protects the drug-tolerant subpopulation from the potentially toxic effects of elevated levels of reactive oxygen species (ROS) in these cells, and pharmacologic disruption of ALDH activity leads to accumulation of ROS to toxic levels, consequent DNA damage, and apoptosis specifically within the drug tolerant subpopulation. Combining ALDH inhibition with other kinase-directed treatments delayed treatment relapse in vitro and in vivo, revealing a novel combination treatment strategy for cancers that might otherwise rapidly relapse following single-agent therapy. PMID- 24812275 TI - Re-engineering vesicular stomatitis virus to abrogate neurotoxicity, circumvent humoral immunity, and enhance oncolytic potency. AB - As cancer treatment tools, oncolytic viruses (OV) have yet to realize what some see as their ultimate clinical potential. In this study, we have engineered a chimeric vesicular stomatitis virus (VSV) that is devoid of its natural neurotoxicity while retaining potent oncolytic activity. The envelope glycoprotein (G) of VSV was replaced with a variant glycoprotein of the lymphocytic choriomeningitis virus (LCMV-GP), creating a replicating therapeutic, rVSV(GP), that is benign in normal brain but can effectively eliminate brain cancer in multiple preclinical tumor models in vivo. Furthermore, it can be safely administered systemically to mice and displays greater potency against a spectrum of human cancer cell lines than current OV candidates. Remarkably, rVSV(GP) escapes humoral immunity, thus, for the first time, allowing repeated systemic OV application without loss of therapeutic efficacy. Taken together, rVSV(GP) offers a considerably improved OV platform that lacks several of the major drawbacks that have limited the clinical potential of this technology to date. PMID- 24812276 TI - Synthesis of highly elastic biocompatible polyurethanes based on bio-based isosorbide and poly(tetramethylene glycol) and their properties. AB - Bio-based high elastic polyurethanes were prepared from hexamethylene diisocyanate and various ratios of isosorbide to poly(tetramethylene glycol) as a diol by a simple one-shot bulk polymerization without a catalyst. Successful synthesis of the polyurethanes was confirmed by Fourier transform-infrared spectroscopy and (1)H nuclear magnetic resonance. Thermal properties were determined by differential scanning calorimetry and thermogravimetric analysis. The glass transition temperature was -47.8C. The test results showed that the poly(tetramethylene glycol)/isosorbide-based elastomer exhibited not only excellent stress-strain properties but also superior resilience to the existing polyether-based polyurethane elastomers. The static and dynamic properties of the polyether/isosorbide-based thermoplastic elastomer were more suitable for dynamic applications. Moreover, such rigid diols impart biocompatible and bioactive properties to thermoplastic polyurethane elastomers. Degradation tests performed at 37C in phosphate buffer solution showed a mass loss of 4-9% after 8 weeks, except for the polyurethane with the lowest isosorbide content, which showed an initial rapid weight loss. These polyurethanes offer significant promise due to soft, flexible and biocompatible properties for soft tissue augmentation and regeneration. PMID- 24812277 TI - Chromatin modifications remodel cardiac gene expression. AB - Signalling and transcriptional control involve precise programmes of gene activation and suppression necessary for cardiovascular physiology. Deep sequencing of DNA-bound transcription factors reveals a remarkable complexity of co-activators or co-repressors that serve to alter chromatin modification and regulate gene expression. The regulated complexes characterized by genome-wide mapping implicate the recruitment and exchange of proteins with specific enzymatic activities that include roles for histone acetylation and methylation in key developmental programmes of the heart. As for transcriptional changes in response to pathological stress, co-regulatory complexes are also differentially utilized to regulate genes in cardiac disease. Members of the histone deacetylase (HDAC) family catalyse the removal of acetyl groups from proteins whose pharmacological inhibition has profound effects preventing heart failure. HDACs interact with a complex co-regulatory network of transcription factors, chromatin remodelling complexes, and specific histone modifiers to regulate gene expression in the heart. For example, the histone methyltransferase (HMT), enhancer of zeste homolog 2 (Ezh2), is regulated by HDAC inhibition and associated with pathological cardiac hypertrophy. The challenge now is to target the activity of enzymes involved in protein modification to prevent or reverse the expression of genes implicated with cardiac hypertrophy. In this review, we discuss the role of HDACs and HMTs with a focus on chromatin modification and gene function as well as the clinical treatment of heart failure. PMID- 24812278 TI - Tubulin polymerization disrupts cardiac beta-adrenergic regulation of late INa. AB - AIMS: The anticancer drug paclitaxel (TXL) that polymerizes microtubules is associated with arrhythmias and sinus node dysfunction. TXL can alter membrane expression of Na channels (NaV1.5) and Na current (INa), but the mechanisms are unknown. Calcium/calmodulin-dependent protein kinase II (CaMKII) can be activated by beta-adrenergic stimulation and regulates INa gating. We tested whether TXL interferes with isoproterenol (ISO)-induced activation of CaMKII and consequent INa regulation. METHODS AND RESULTS: In wild-type mouse myocytes, the addition of ISO (1 umol/L) resulted in increased CaMKII auto-phosphorylation (western blotting). This increase was completely abolished after pre-treatment with TXL (100 umol/L, 1.5 h). The mechanism was further investigated in human embryonic kidney cells. TXL inhibited the ISO-induced beta-arrestin translocation. Interestingly, both knockdown of beta-arrestin2 expression using small interfering RNA and inhibition of exchange protein directly activated by cAMP (Epac) blocked the ISO-induced CaMKII auto-phosphorylation similar to TXL. The generation of cAMP, however, was unaltered (Epac1-camps). CaMKII-dependent Na channel function was measured using patch-clamp technique in isolated cardiomyoctes. ISO stimulation failed to induce CaMKII-dependent enhancement of late INa and Na channel inactivation (negative voltage shift in steady-state activation and enhanced intermediate inactivation) after pre-incubation with TXL. Consistent with this, TXL also inhibited ISO-induced CaMKII-specific Na channel phosphorylation (at serine 571 of NaV1.5). CONCLUSION: Pre-incubation with TXL disrupts the ISO-dependent CaMKII activation and consequent Na channel regulation. This may be important for patients receiving TXL treatments, but also relevant for conditions of increased CaMKII expression and enhanced beta adrenergic stimulation like in heart failure. PMID- 24812279 TI - P53 inhibition exacerbates late-stage anthracycline cardiotoxicity. AB - AIMS: Doxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model. METHODS AND RESULTS: Two-week-old MHC-CB7 mice (which express dominant interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals. CONCLUSION: These data support a model wherein a p53 dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment. PMID- 24812282 TI - Modern management of anal incontinence. PMID- 24812280 TI - Impaired local regulation of ryanodine receptor type 2 by protein phosphatase 1 promotes atrial fibrillation. AB - AIMS: Altered Ca(2+) handling in atrial fibrillation (AF) has been associated with dysregulated protein phosphatase 1 (PP1) and subcellular heterogeneities in protein phosphorylation, but the underlying mechanisms remain unclear. This is due to a lack of investigation into the local, rather than global, regulation of PP1 on different subcellular targets such as ryanodine receptor type 2 (RyR2), especially in AF. METHODS AND RESULTS: We tested the hypothesis that impaired local regulation of PP1 causes RyR2 hyperphosphorylation thereby promoting AF susceptibility. To specifically disrupt PP1's local regulation of RyR2, we used the spinophilin knockout (Sp(-/-)) mice (Mus musculus) since PP1 is targeted to RyR2 via spinophilin. Without spinophilin, the interaction between PP1 and RyR2 was reduced by 64%, while RyR2 phosphorylation was increased by 43% at serine (S)2814 but unchanged at S2808. Lipid bilayer experiments revealed that single RyR2 channels isolated from Sp(-/-) hearts had an increased open probability. Likewise, Ca(2+) spark frequency normalized to sarcoplasmic reticulum Ca(2+) content was also enhanced in Sp(-/-) atrial myocytes, but normalized by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitors KN-93 and AIP and also by genetic inhibition of RyR2 S2814 phosphorylation. Finally, Sp(-/-) mice exhibited increased atrial ectopy and susceptibility to pacing-induced AF, both of which were also prevented by the RyR2 S2814A mutation. CONCLUSION: PP1 regulates RyR2 locally by counteracting CaMKII phosphorylation of RyR2. Decreased local PP1 regulation of RyR2 contributes to RyR2 hyperactivity and promotes AF susceptibility. This represents a novel mechanism for subcellular modulation of calcium channels and may represent a potential drug target of AF. PMID- 24812283 TI - Commentary on neoadjuvant therapy followed by local excision and two-stage total mesorectal excision: a new strategy for sphincter preservation in locally advanced ultra-low rectal cancer. PMID- 24812281 TI - Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy. AB - AIMS: To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy. METHODS AND RESULTS: Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at >=8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca(2+)]i, and sarcoplasmic reticulum (SR) Ca(2+) content} and ICa-L than age-matched control VMs and than myocytes isolated from 2 month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month old mdx mice to the same level as in age-matched control VMs. In the VMs of 12 month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2alpha1c, Cav1.2beta1, Cav1.2beta2, sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), and the Na(+)/Ca(2+) exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2alpha1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (beta1-AR) density and beta-adrenergic sensitivity. CONCLUSION: In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased beta1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response. PMID- 24812284 TI - Inflammation, new bone formation and treatment options in axial spondyloarthritis. PMID- 24812285 TI - JNK-dependent downregulation of FoxO1 is required to promote the survival of fibroblast-like synoviocytes in rheumatoid arthritis. AB - BACKGROUND: Forkhead box O (FoxO) transcription factors integrate environmental signals to modulate cell proliferation and survival, and alterations in FoxO function have been reported in rheumatoid arthritis (RA). OBJECTIVES: To examine the relationship between inflammation and FoxO expression in RA, and to analyse the mechanisms and biological consequences of FoxO regulation in RA fibroblast like synoviocytes (FLS). METHODS: RNA was isolated from RA patient and healthy donor (HD) peripheral blood and RA synovial tissue. Expression of FoxO1, FoxO3a and FoxO4 was measured by quantitative PCR. FoxO1 DNA binding, expression and mRNA stability in RA FLS were measured by ELISA-based assays, immunoblotting and quantitative PCR. FLS were transduced with adenovirus encoding constitutively active FoxO1 (FoxO1ADA) or transfected with small interfering RNA targeting FoxO1 to examine the effects on cell viability and gene expression. RESULTS: FoxO1 mRNA levels were reduced in RA patient peripheral blood compared with HD blood, and RA synovial tissue FoxO1 expression correlated negatively with disease activity. RA FLS stimulation with interleukin 1beta or tumour necrosis factor caused rapid downregulation of FoxO1. This effect was independent of protein kinase B (PKB), but dependent on c-Jun N-terminal kinase (JNK)-mediated acceleration of FoxO1 mRNA degradation. FoxO1ADA overexpression in RA FLS induced apoptosis associated with altered expression of genes regulating cell cycle and survival, including BIM, p27(Kip1) and Bcl-XL. CONCLUSIONS: Our findings identify JNK-dependent modulation of mRNA stability as an important PKB-independent mechanism underlying FoxO1 regulation by cytokines, and suggest that reduced FoxO1 expression is required to promote FLS survival in RA. PMID- 24812286 TI - Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. AB - INTRODUCTION: In rheumatoid arthritis (RA), several genetic risk factors and smoking are strongly associated with the presence of anticitrullinated protein antibodies (ACPA), while much less is known about risk factors for ACPA-negative RA. Antibodies against carbamylated proteins (anti-CarP) have been described in both ACPA-positive and ACPA-negative RA patients. In this study, we have analysed the relationships among anti-CarP antibodies, ACPA, genetic risk factors (HLA DRB1 alleles and PTPN22) and smoking in RA. METHODS: Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by inhouse ELISAs among RA cases in the Leiden Early Arthritis Clinic (n=846) and in the Swedish Epidemiological Investigation of Rheumatoid Arthritis (n=1985) cohorts. ORs for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in meta analysis in RA subsets defined by the presence/absence of anti-CarP and anticyclic citrullinated peptide (anti-CCP) antibodies. RESULTS: In both cohorts, anti-CarP antibody positivity was mainly detected in the anti-CCP-positive population (49%-73%), but also in the anti-CCP-negative population (8%-14%). No associations between anti-CarP antibodies and HLA-DRB1 shared epitope alleles could be identified, while there were data to support an association between anti CarP-FCS and HLA-DRB1*03. Further analyses did not reveal any specific associations of anti-CarP antibodies with other HLA-DRB1 alleles, PTPN22 genotypes or smoking. CONCLUSIONS: Anti-CarP antibodies were present in both ACPA positive and ACPA-negative RA. There were no significant associations among anti CarP antibodies and HLA-DRB1 alleles, PTPN22 or smoking. These data suggest that different biological mechanisms may underlie anti-CarP versus anti-CCP antibody formation. PMID- 24812287 TI - Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. AB - OBJECTIVES: Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. METHODS: Baseline disease activity score based on erythrocyte sedimentation rate (DAS28 ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1 year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. RESULTS: Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). CONCLUSIONS: In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. TRIAL REGISTRATION NUMBER: WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725. PMID- 24812288 TI - Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. AB - BACKGROUND: The aetiology of systemic sclerosis (SSc) is not clear, but there is an emerging evidence of gene-specific epigenetic dysregulation in the pathogenesis of SSc. METHODS: We performed a genome-wide DNA methylation study in dermal fibroblasts in six diffuse cutaneous SSc (dSSc) patients, six limited cutaneous SSc (lSSc) patients compared with 12 age-matched, sex-matched and ethnicity-matched healthy controls. Cytosine methylation was quantified in more than 485 000 methylation sites across the genome. Differentially methylated CpG sites between patients and controls with a fold difference >=1.2 were identified. Quantitative real-time RT-PCR was performed to assess correlation between DNA methylation changes and gene expression levels. RESULTS: We identified 2710 and 1021 differentially methylated CpG sites in dSSc and lSSc, respectively. Of the differentially methylated sites, 61% in dSSc and 90% in lSSc were hypomethylated. There were only 203 CpG sites differentially methylated in both dSSc and lSSc, representing 118 hypomethylated and 6 hypermethylated genes. Common hypomethylated genes include ITGA9, encoding an alpha integrin. Other relevant genes such as ADAM12, COL23A1, COL4A2 and MYO1E, and transcription factors genes RUNX1, RUNX2 and RUNX3 were also hypomethylated in both dSSc and lSSc. Pathway analysis of differentially methylated genes in both dSSc and lSSc revealed enrichment of genes involved in extracellular matrix-receptor interaction and focal adhesion. We demonstrate significant correlation between DNA methylation status and gene expression in the majority of genes evaluated. CONCLUSIONS: Our data highlight common and subset-specific aberrancies in dSSc and lSSc fibroblasts at the epigenomic levels and identify novel candidate genes in SSc. PMID- 24812289 TI - Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies. PMID- 24812290 TI - Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. AB - BACKGROUND: Previous data have shown that etanercept levels are associated with clinical response in rheumatoid arthritis. However, for ankylosing spondylitis (AS), data regarding this topic are inconclusive. OBJECTIVES: To investigate the relationship between etanercept levels and clinical response in patients with AS. METHODS: Observational prospective cohort study of 162 patients with AS =treated with etanercept, monitored during 24 weeks of treatment. Etanercept trough levels were determined, retrospectively, using an ELISA. Disease activity was measured using AS Disease Activity Score (ASDAS), including C-reactive protein (CRP) and Bath AS Disease Activity index (BASDAI). Active disease was defined as ASDAS>=2.1. Since etanercept is a drug administered at home there might have been some variation in trough level sampling. RESULTS: At 24 weeks etanercept levels were significantly higher in patients with ASDAS<2.1, (3.8 mg/L; IQR 2.5-5.2) compared with patients with ASDAS>=2.1 (2.3 mg/L; IQR 1.2-3.4; p<=0.001). Generalised estimating equation analysis demonstrated a statistically significant association between etanercept levels and ASDAS, BASDAI, CRP and erythrocyte sedimentation rate (all p<0.001). When patients were categorised into quartiles according to etanercept levels, the lowest quartile (etanercept<1.80 mg/L) comprised 35% of all patients with ASDAS>=2.1 while the highest quartile comprised only 14%. CONCLUSIONS: Disease activity and inflammation are associated with etanercept levels in patients with AS at 24 weeks of treatment. Measuring etanercept levels might help in identifying overtreatment and undertreatment and optimise etanercept therapy in AS. PMID- 24812291 TI - Inadequate corticosterone levels relative to arthritic inflammation are accompanied by altered mitochondria/cholesterol breakdown in adrenal cortex: a steroid-inhibiting role of IL-1beta in rats. AB - OBJECTIVES: In rheumatoid arthritis, inadequate cortisol secretion was observed relative to inflammation, but reasons are unknown. Human adrenal glands cannot be investigated due to ethical reasons. Thus, a model of arthritis was studied to test inadequate glucocorticoid secretion and adrenocortical alterations. METHODS: Arthritis in DA rats was induced by collagen type II. Plasma hormone (cytokine) levels were determined by ELISA or radioimmunoassay (Luminex). Adrenocortical cells were investigated making use of in vitro culture, immunohistochemistry and imaging techniques, cholesterol uptake studies and electron microscopical morphological analyses of adrenocortical lipid droplets and mitochondria. RESULTS: During the course of arthritis, corticosterone and adrenocorticotropic hormone (ACTH) levels were only elevated on day 1 after immunisation but were in the normal range from day 5 to 55. Serum levels of corticosterone relative to IL 1beta were markedly lower in arthritis than in controls. IL-1beta inhibited ACTH stimulated corticosterone secretion from adrenocortical cells in vitro. Cholesterol uptake receptor SR-BI protein was unchanged. Number of altered swollen and cavitated mitochondria increased during the course of arthritis (maximum on day 55), and this was correlated to reduced breakdown of lipid droplets and increased Sudan III-positive lipid accumulation from day 28 to 55. Reduced lipid breakdown measured as a high number of homogenous lipid droplets negatively correlated with plasma corticosterone (p=0.022). Adrenocortical tissue density of normal mitochondria positively correlated with serum corticosterone levels. CONCLUSIONS: This study on inadequate adrenal glucocorticoid secretion in arthritis demonstrated altered mitochondria and altered lipid breakdown paralleled by low corticosterone levels in relation to inflammation. IL-1beta is a key cytokine. PMID- 24812292 TI - Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort. AB - OBJECTIVES: To analyse the long-term relationship between disease activity and radiographic damage in the spine in patients with ankylosing spondylitis (AS). METHODS: Patients from the Outcome in AS International Study (OASIS) were followed up for 12 years, with 2-yearly clinical and radiographic assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity measures include the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient's global assessment and spinal pain. The relationship between disease activity measures and radiographic damage was investigated using longitudinal, autoregressive models with 2-year time lags. RESULTS: 184 patients were included (70% males, 83% HLA-B27 positive, mean (SD) age 43 (12) years, 20 (12) years symptom duration). Disease activity measures were significantly longitudinally associated with radiographic progression. Neither medication nor the presence of extra-articular manifestations confounded this relationship. The models with ASDAS as disease activity measure fitted the data better than models with BASDAI, CRP or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. A 'very high disease activity state' (ie, ASDAS >3.5) compared with 'inactive disease' (ie, ASDAS <1.3) resulted in an additional 2 year progression of 2.31 mSASSS units. The effect of ASDAS on mSASSS was higher in males versus females (0.98 vs -0.06 mSASSS units per ASDAS unit) and in patients with <18 years vs >=18 years symptom duration (0.84 vs 0.16 mSASSS units per ASDAS unit). CONCLUSIONS: This is the first study showing that disease activity contributes longitudinally to radiographic progression in the spine in AS. This effect is more pronounced in men and in the earlier phases of the disease. PMID- 24812293 TI - Universal pacemaker of genome evolution in animals and fungi and variation of evolutionary rates in diverse organisms. AB - Gene evolution is traditionally considered within the framework of the molecular clock (MC) model whereby each gene is characterized by an approximately constant rate of evolution. Recent comparative analysis of numerous phylogenies of prokaryotic genes has shown that a different model of evolution, denoted the Universal PaceMaker (UPM), which postulates conservation of relative, rather than absolute evolutionary rates, yields a better fit to the phylogenetic data. Here, we show that the UPM model is a better fit than the MC for genome wide sets of phylogenetic trees from six species of Drosophila and nine species of yeast, with extremely high statistical significance. Unlike the prokaryotic phylogenies that include distant organisms and multiple horizontal gene transfers, these are simple data sets that cover groups of closely related organisms and consist of gene trees with the same topology as the species tree. The results indicate that both lineage-specific and gene-specific rates are important in genome evolution but the lineage-specific contribution is greater. Similar to the MC, the gene evolution rates under the UPM are strongly overdispersed, approximately 2-fold compared with the expectation from sampling error alone. However, we show that neither Drosophila nor yeast genes form distinct clusters in the tree space. Thus, the gene-specific deviations from the UPM, although substantial, are uncorrelated and most likely depend on selective factors that are largely unique to individual genes. Thus, the UPM appears to be a key feature of genome evolution across the history of cellular life. PMID- 24812294 TI - First evidence of H10N8 Avian influenza virus infections among feral dogs in live poultry markets in Guangdong province, China. PMID- 24812295 TI - A major cause of pertussis resurgence: gaps in vaccination coverage. PMID- 24812296 TI - Reply to Livorsi and Eckerle. PMID- 24812297 TI - Reply to Seligman et Al. PMID- 24812298 TI - Pathogenesis of post-lyme disease symptoms. PMID- 24812299 TI - Developing local treatment guidelines for healthcare-associated pneumonia. PMID- 24812301 TI - Predictors of increasing BMI during the course of diabetes in children and adolescents with type 1 diabetes: data from the German/Austrian DPV multicentre survey. AB - OBJECTIVE: Increased weight gain has been reported prior to disease onset (accelerator hypothesis) and as a side effect of intensified insulin therapy in type 1 diabetes (T1D). Paediatric studies are complicated by the age-dependency and gender-dependency of BMI, and also by a trend towards obesity in the general population. The aim of this study was to evaluate factors related to the increase in BMI during the course of diabetes in children and adolescents with T1D in a large multicentre survey. DESIGN: Within the DPV database (Diabetespatienten Verlaufsdokumentation) a standardised, prospective, computer-based documentation programme, data of 53,108 patients with T1D, aged <20 years, were recorded in 248 centres. 12,774 patients (53% male, mean age 13.4+/-3.9, mean diabetes duration 4.7+/-3.0 years and mean age at diabetes onset 8.7+/-4.0 years) were included in this analysis. Population-based German reference data were used to calculate BMI SDS and define overweight and obesity. RESULTS: 12.5% of T1D patients were overweight and 2.8% were obese. Multiple longitudinal regression analysis revealed that female gender, low BMI at diabetes onset, intensified insulin therapy and higher insulin dose, as well as pubertal diabetes onset, long diabetes duration and onset in earlier calendar years among girls, were related to higher BMI-SDS increase during the course of diabetes (p<0.01; all). CONCLUSIONS: Intensified insulin regimen is associated with weight gain during T1D treatment, in addition to demographic variables. Optimisation of diabetes management, especially in females, might limit weight gain in order to reduce overweight and obesity together with comorbidities among paediatric T1D patients. PMID- 24812302 TI - Anxiety, depression and self-esteem in children with well-controlled asthma: case control study. AB - OBJECTIVE: Although asthma has been linked to psychological morbidity, this relationship may be confounded by poor asthma control. We aimed to compare the prevalence of anxiety, depression and low level of self-esteem in children with well-controlled asthma with that of healthy peers. SETTING: Dedicated asthma clinic in a general hospital. PATIENTS: 70 patients with mostly well-controlled asthma and 70 matched healthy controls. INTERVENTIONS: Comprehensive asthma education, management and follow-up for asthma patients. MAIN OUTCOME MEASURES: Validated Dutch versions of the Childhood Depression inventory (CDI), Revised Fear Survey for Children (RFSC), Self Perception Profile for Children (SPC-C) and Adolescents (SPC-A) and State-Trait Anxiety Inventory for Children (STAIC). Asthma control assessed by asthma control questionnaire. RESULTS: No significant differences were found in total scores between asthmatics and controls (95% CI for difference -0.2 to 2.9 for CDI, -5.9 to 11.2 for RFSC, -19.9 to 6.3 for SPC C, -24.1 to 5.0 for SPC-A and -2.7 to 0.01 for STAIC). There were also no significant differences between asthmatics and controls in the prevalence of scores exceeding cut-off levels for clinically relevant anxiety (13.3 vs 13.0%, p=0.605), depression (12.9 vs 5.7%, p=0.243) or low self-esteem (21.4 vs 12.9%, p=0.175). A significant correlation was found between poorer asthma control and CDI (p=0.012) and anxiety trait symptoms (p<0.001). CONCLUSIONS: Children with well-controlled asthma enrolled in a comprehensive asthma management programme do not have an increased risk of anxiety, depression and poor self-esteem. Earlier reports of psychological comorbidity in asthma may have been related to inadequately controlled asthma. PMID- 24812303 TI - Management of chronic hepatitis B infection. AB - The spectrum of chronic hepatitis B infection in children ranges from asymptomatic carriage with minimal disease, to progression to cirrhosis and risk of hepatocellular carcinoma in adulthood. Identifying those who will benefit from treatment is a challenge. Interferon-based therapies have limited efficacy, while prolonged use of nucleos(t)ide analogues may promote resistance. New antiviral agents have improved barriers to resistance, but long-term outcome is not yet known. Untreated infection, however, may in some, lead to natural seroconversion and reduce risk of further disease. Hepatitis B e antigen-positive infection is the most common scenario in chronically infected children, with e antigen negative hepatitis rarely encountered. This paper reviews the clinical guidelines published in 2013 by the National Institute for Health and Care Excellence (NICE) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and focuses on the guidance for treatment in e antigen-positive children. The most significant difference is the lower threshold for starting treatment recommended by NICE guidelines. The need for regular evaluation of each child, in the light of new evidence and new drugs as they emerge, must remain the focus of each clinician involved in the care of children with hepatitis B virus infection. PMID- 24812304 TI - Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. AB - BACKGROUND: Mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with heart failure but can cause hyperkalemia, which contributes to reduced use of these drugs. Hypokalemia also leads to worse outcomes in patients with heart failure and may be attenuated by mineralocorticoid receptor antagonists. METHODS AND RESULTS: We assessed incidence and predictors of hyperkalemia (potassium >=5.5 mmol/L) and hypokalemia (potassium <3.5 mmol/L) and the relationship to outcomes in 1663 patients with class III or IV heart failure and left ventricular ejection fraction <35% randomized to treatment with spironolactone 25 mg or placebo in the Randomized Aldactone Evaluation Study (RALES) trial. All-cause mortality rates and the influence of potassium levels on the effectiveness of spironolactone were assessed in a landmark analysis and in relation to time-varying potassium levels. After 1 month, mean potassium levels increased in the spironolactone group but not in the placebo group (4.54+/-0.49 versus 4.28+/-0.50 mmol/L; P<0.001) and remained elevated during the trial. Although the extremes of hypokalemia and hyperkalemia at 4 weeks were associated with increased risk of mortality in both treatment arms, participants in the spironolactone arm had lower mortality rates at all potassium levels throughout the duration of the trial. The treatment benefit of spironolactone was maintained at least until potassium exceeded 5.5 mmol/L. CONCLUSIONS: With appropriate surveillance of potassium and creatinine, the use of spironolactone was associated with less hypokalemia and improved survival in patients with severe heart failure even in the setting of moderate hyperkalemia. PMID- 24812305 TI - The scaffold protein muscle A-kinase anchoring protein beta orchestrates cardiac myocyte hypertrophic signaling required for the development of heart failure. AB - BACKGROUND: Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein beta (mAKAPbeta) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPbeta signalosomes to pathological remodeling and heart failure in vivo remains unknown. METHODS AND RESULTS: Using conditional, cardiac myocyte-specific gene deletion, we now demonstrate that mAKAPbeta expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPbeta targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPbeta knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPbeta knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPbeta scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPbeta knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold. CONCLUSIONS: mAKAPbeta orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPbeta signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure. PMID- 24812306 TI - Balancing selection in species with separate sexes: insights from Fisher's geometric model. AB - How common is balancing selection, and what fraction of phenotypic variance is attributable to balanced polymorphisms? Despite decades of research, answers to these questions remain elusive. Moreover, there is no clear theoretical prediction about the frequency with which balancing selection is expected to arise within a population. Here, we use an extension of Fisher's geometric model of adaptation to predict the probability of balancing selection in a population with separate sexes, wherein polymorphism is potentially maintained by two forms of balancing selection: (1) heterozygote advantage, where heterozygous individuals at a locus have higher fitness than homozygous individuals, and (2) sexually antagonistic selection (a.k.a. intralocus sexual conflict), where the fitness of each sex is maximized by different genotypes at a locus. We show that balancing selection is common under biologically plausible conditions and that sex differences in selection or sex-by-genotype effects of mutations can each increase opportunities for balancing selection. Although heterozygote advantage and sexual antagonism represent alternative mechanisms for maintaining polymorphism, they mutually exist along a balancing selection continuum that depends on population and sex-specific parameters of selection and mutation. Sexual antagonism is the dominant mode of balancing selection across most of this continuum. PMID- 24812307 TI - Effect of domestication on the spread of the [PIN+] prion in Saccharomyces cerevisiae. AB - Prions (infectious proteins) cause fatal neurodegenerative diseases in mammals. In the yeast Saccharomyces cerevisiae, many toxic and lethal variants of the [PSI+] and [URE3] prions have been identified in laboratory strains, although some commonly studied variants do not seem to impair cell growth. Phylogenetic analysis has revealed four major clades of S. cerevisiae that share histories of two prion proteins and largely correspond to different ecological niches of yeast. The [PIN+] prion was most prevalent in commercialized niches, infrequent among wine/vineyard strains, and not observed in ancestral isolates. As previously reported, the [PSI+] and [URE3] prions are not found in any of these strains. Patterns of heterozygosity revealed genetic mosaicism and indicated extensive outcrossing among divergent strains in commercialized environments. In contrast, ancestral isolates were all homozygous and wine/vineyard strains were closely related to each other and largely homozygous. Cellular growth patterns were highly variable within and among clades, although ancestral isolates were the most efficient sporulators and domesticated strains showed greater tendencies for flocculation. [PIN+]-infected strains had a significantly higher likelihood of polyploidy, showed a higher propensity for flocculation compared to uninfected strains, and had higher sporulation efficiencies compared to domesticated, uninfected strains. Extensive phenotypic variability among strains from different environments suggests that S. cerevisiae is a niche generalist and that most wild strains are able to switch from asexual to sexual and from unicellular to multicellular growth in response to environmental conditions. Our data suggest that outbreeding and multicellular growth patterns adapted for domesticated environments are ecological risk factors for the [PIN+] prion in wild yeast. PMID- 24812308 TI - Detecting local haplotype sharing and haplotype association. AB - A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org. PMID- 24812309 TI - A randomized clinical trial of the effect of intensive versus non-intensive counselling on discontinuation rates due to bleeding disturbances of three long acting reversible contraceptives. AB - STUDY QUESTION: Does intensive counselling before insertion and throughout the first year of use have any influence on discontinuation rates due to unpredictable menstrual bleeding in users of three long-acting reversible contraceptives (LARCs)? SUMMARY ANSWER: Intensive counselling had a similar effect to routine counselling in terms of discontinuation rates due to unpredictable menstrual bleeding in new users of the contraceptives. WHAT IS KNOWN ALREADY: Contraceptive efficacy and satisfaction rates are very high with LARCs, including the etonogestrel (ENG)-releasing implant, the levonorgestrel releasing intrauterine system (LNG-IUS) and the TCu380A intrauterine device (IUD). However, unpredictable menstrual bleeding constitutes the principal reason for premature discontinuation, particularly in the cases of the ENG-implant and the LNG-IUS. STUDY DESIGN, SIZE, DURATION: A randomized clinical trial was conducted between 2011 and 2013, and involved 297 women: 98 ENG-implant users, 99 LNG-IUS users and 100 TCu380A IUD users. PARTICIPANTS, SETTING, METHODS: Women accepting each contraceptive method were randomized into two groups after the women chose their contraceptive method. Group I received routine counselling at the clinic, including information on safety, efficacy and side effects, as well as what to expect regarding bleeding disturbances. Group II received 'intensive counselling'. In addition to the information provided to those in Group I, these women also received leaflets on their chosen method and were seen by the same three professionals, the most experienced at the clinic, throughout the year of follow-up. These three professionals went over all the information provided at each consultation. Women in both groups were instructed to return to the clinic after 45 (+/-7) days and at 6 and 12 (+/-1) months after insertion. They were instructed to record all bleeding episodes on a menstrual calendar specifically provided for this purpose. Additionally, satisfaction with the method was evaluated by a questionnaire completed by the women after 12 months of use of the contraceptive method. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences between the intensive and routine counselling groups on the discontinuation rates due to unpredictable menstrual bleeding of the three contraceptives under evaluation. The 1-year cumulative discontinuation rates due to menstrual bleeding irregularities were 2.1, 2.7 and 4.0% and the continuation rates were 82.6, 81.0 and 73.2%, for the ENG-implant, the LNG-IUS or the TCu380A IUD users, respectively. The main reasons for discontinuation of the methods were weight gain in users of the ENG-implant and expulsion of the TCu380A. LIMITATIONS, REASONS FOR CAUTION: The main limitations are that we cannot assure generalization of the results to another settings and that the routine counselling provided by our counsellors may already be appropriate for the women attending the clinic and so consequently intensive counselling including written leaflets was unable to influence the premature discontinuation rate due to unpredictable menstrual bleeding. Additionally, counselling could discourage some women from using the LARC methods offered in the study and consequently those women may have decided on other contraceptives. WIDER IMPLICATIONS OF THE FINDINGS: Routine counselling may be sufficient for many women to help reduce premature discontinuation rates and improve continuation rates and user satisfaction among new users of LARC methods. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (NCT01392157). STUDY FUNDING/COMPETING INTEREST(S): The study was partially funded by the Fundacao de Apoio a Pesquisa do Estado de Sao Paulo (FAPESP) grant # 2012/01379-0, the Brazilian National Research Council (CNPq) grant #573747/2008-3 and by Merck (MSD), Brazil under an unrestricted grant. The LNG-IUS were donated by the International Contraceptive Access Foundation (ICA) and the copper IUD by Injeflex, Sao Paulo, Brazil. L.B. has occasionally served on the Board of MSD, Bayer and Vifor. PMID- 24812310 TI - Epigenetic status in the offspring of spontaneous and assisted conception. AB - STUDY QUESTION: Is DNA methylation in buccal cell DNA from children born following IVF (in vitro fertilization) and ICSI (intra-cytoplasmic sperm injection) different from that of spontaneously conceived children? SUMMARY ANSWER: DNA methylation in the imprinted gene, small nuclear ribonucleoprotein polypeptide N (SNRPN), was higher in children conceived by ICSI and in those born to women with the longest duration of infertility regardless of the method of conception. WHAT IS KNOWN ALREADY: Fertility treatment is associated with a small but significant increase in the risk of a range of adverse obstetric outcomes, birth defects and longer term sequelae, but the biological basis for this is unknown. A growing evidence base suggests that epigenetics may play a role in subfertility and the link between fertility and health. STUDY DESIGN, SIZE, DURATION: In this retrospective cohort study of children born between 2002 and 2008, we measured DNA methylation in paternally expressed gene 3 (PEG3), insulin like growth factor II (IGF2), SNRPN, long interspersed nuclear element 1 (LINE1) and the insulin gene (INS) in buccal cell DNA from children born following IVF (n = 49) and ICSI (n = 20) and compared them with a matched spontaneous conception group (n = 86). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were identified from the Aberdeen Maternity and Neonatal Databank and IVF and ICSI pregnancies were matched to spontaneous conception pregnancies on year of birth and maternal age at delivery. Only singleton pregnancies following fresh embryo transfer were included. DNA methylation was determined by pyrosequencing. Regression with adjustment for covariates was used to determine the effect of infertility on offspring DNA methylation. MAIN RESULTS AND THE ROLE OF CHANCE: SNRPN methylation in the offspring was linked to fertility treatment in the parents. This effect was specific to children conceived using ICSI and was apparent in the comparison of ICSI versus spontaneous conception (1.03%; 95% CI 0.10, 1.97; P = 0.031), ICSI versus standard IVF (1.13%; 95% CI 0.04, 2.23; P = 0.043) and ICSI versus standard IVF and spontaneous conception (1.05; 95% CI 0.15, 1.94; P = 0.023). In all comparisons, the use of ICSI was associated with a higher level of SNRPN methylation in the offspring. A higher level of SNRPN methylation in the offspring was also associated with a longer duration of infertility in the parents. This was observed in all cases of infertility (0.18% per year of infertility; 95% CI 0.02, 0.33; P = 0.026) and after excluding ICSI cases (0.21% per year of infertility; 95% CI 0.04, 0.37; P = 0.017). There was a significant increase in the level of LINE1 methylation with age between birth and 7 years (0.77% per year; 95% CI 0.49, 1.05; P < 0.001). Methylation in the INS gene decreased significantly over the same period (-0.46% per year; 95% CI -0.89, -0.03; P = 0.035). There was no evidence from this cross-sectional data that methylation within the imprinted genes changed over the first 7 years of life. LIMITATIONS, REASONS FOR CAUTION: The ICSI sample size was limited but the groups were carefully selected and well matched and the SNRPN findings were consistent across different outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide support for a role for epigenetics, and imprinting in particular, in fertility. The specific changes point to possible long-term consequences of fertility treatment for the health and fertility of future generations. STUDY FUNDING/COMPETING INTEREST(S): The authors report no conflict of interest in relation to this work. Funding was provided by the University of Aberdeen and the Scottish Government. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 24812311 TI - Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men. AB - STUDY QUESTION: Is consumption of sugar-sweetened beverages (SSB) associated with semen quality? SUMMARY ANSWER: Higher consumption of SSB was associated with lower sperm motility among healthy, young men. WHAT IS KNOWN ALREADY: The existing literature on the potential role of SSBs on male reproductive function is scarce and primarily focused on the relation between caffeinated beverages and semen quality. However, a rodent model suggests that SSBs may hamper male fertility. STUDY DESIGN, SIZE, DURATION: The Rochester Young Men's Study; a cross sectional study of 189 healthy young men carried out at the University of Rochester during 2009-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 18 22 years provided semen and blood samples, underwent a physical examination and completed a previously validated food frequency questionnaire (FFQ). Linear regression was used to analyze the association of SSBs with sperm parameters and reproductive hormone levels while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: SSB intake was inversely related to progressive sperm motility. Men in the highest quartile of SSB intake (>=1.3 serving/day) had 9.8 (95% CI: 1.9,17.8) percentage units lower progressive sperm motility than men in the lowest quartile of intake (<0.2 serving/day) (P, trend = 0.03). This association was stronger among lean men (P, trend = 0.005) but absent among overweight or obese men (P, trend = 0.98). SSB intake was unrelated to other semen quality parameters or reproductive hormones levels. LIMITATIONS, REASONS FOR CAUTION: As in all cross-sectional studies, causal inference is limited. An additional problem is that only single semen sample was obtained from each subject. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the relation between SSB intake and low semen quality beyond the contribution of caffeinated beverages. While our findings are in agreement with recent experimental data in rodents, more studies are required to draw conclusions on the relation of SSB with semen quality or male infertility. STUDY FUNDING/COMPETING INTEREST(S): Supported by the European Union Seventh Framework Program (Environment), 'Developmental Effects of Environment on Reproductive Health' (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 and T32HD060454 from the National Institutes of Health. None of the authors has any conflicts of interest to declare. PMID- 24812313 TI - The association between embryo quality and perinatal outcome of singletons born after single embryo transfers: a pilot study. AB - STUDY QUESTION: Does the quality of a single transferred embryo have an effect on the pregnancy outcome? SUMMARY ANSWER: After adjusting for confounding maternal variables, poor embryo quality was not associated with adverse obstetric or perinatal outcome in this small pilot study. WHAT IS ALREADY KNOWN: Embryo quality is a major predictor of the success of in vitro fertilization treatment and studies have demonstrated a strong association between embryo morphology, implantation and clinical pregnancy rates. However, the association with obstetric and perinatal outcomes has not been evaluated. STUDY DESIGN, SIZE AND DURATION: This single center, retrospective cohort study included 1541 fresh single embryo transfers (SETs) using non-donor oocytes in women <=40 years between December 2008 and 2012. We compared the cycle outcome and singleton live births resulting from the transfer of a single fresh good quality (Grade 2) embryo with those resulting from the transfer of a single poor quality (fair, Grade 3 or poor, Grade 4) embryo in the cleavage or blastocyst stages. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cycle outcome parameters were biochemical pregnancy and clinical intrauterine pregnancy. The pregnancy outcomes were live birth, miscarriages and stillbirths after 20 weeks of gestation. Among the live births, perinatal outcome parameters included birthweight, small for gestational age, preterm delivery, pre-eclampsia, placental abruption and neonatal complications. Covariates were maternal age, body mass index, smoking status, parity and gender of the baby. MAIN RESULTS AND ROLE OF CHANCE: There were 1193 good quality SETs and 348 poor quality embryo transfers. SETs performed during the study period resulted in 563 pregnancies and 440 singleton births. There was a higher clinical pregnancy rate (41.5%) and live birth rate (32.3%) in the good quality embryo transfer group compared with that in the poor quality transfer group (19.2 and 15.5%, respectively; P < 0.0001). There was no significant difference in the miscarriage rate between the transfers of a single good or poor quality embryo. Multivariable logistic regression analyses for pregnancy complications revealed no increased risk of maternal or neonatal complications with the transfer of a poor quality embryo. There was no difference in the obstetric or perinatal outcome of the live births resulting from a good or poor quality embryo after stratification by day of transfer. LIMITATIONS, REASONS FOR CAUTION: The main limitations of this study are the retrospective nature of the study, the relative subjectivity of embryo scoring and the small number of live births after transfer of poor quality embryos. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may be used to reassure women that transfer of a single poor quality embryo, whether a cleavage or a blastocyst, does not appear to be associated with increased risks of adverse obstetric and perinatal outcomes. STUDY FUNDING/COMPETING INTEREST (S): Only internal funding was used. There is no conflict of interest in relation to the study. PMID- 24812314 TI - The protein source in embryo culture media influences birthweight: a comparative study between G1 v5 and G1-PLUS v5. AB - STUDY QUESTION: Does protein source or human serum albumin (HSA) in embryo culture media influence the subsequent birthweight? SUMMARY ANSWER: A significant difference was observed in gestational age- and gender-adjusted birthweight (Z scores) and the proportion of large-for-gestational age (LGA) babies between embryos cultured in G1 v5 and those cultured in G1-PLUS v5 media. WHAT IS KNOWN ALREADY: It has been reported that the birthweights of singletons born from embryos cultured in Vitrolife are significantly higher than those cultured in the Cook group of media, and that G1-PLUS (Vitrolife, Gothenburg, Sweden) is associated with increased birth and placenta weights compared with Medicult ISMI. STUDY DESIGN, SIZE, AND DURATION: This study was a retrospective analysis of neonatal birthweights, and included 1097 singletons born from fresh embryo transfer cycles at the Center for Reproductive Medicine of Peking University Third Hospital between January 2011 and August 2012. The number of singletons born from G1 v5 culture media was 489, and the number of singletons born from G1 PLUS v5 media was 608. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Patients <40 years of age with a BMI <30 kg/m2 were analysed. Only data from newborns from singleton pregnancies and born alive after the 28th week of gestation were included. Patients with a vanishing twin or with pregnancy-related complications, such as diabetes and hypertension, were excluded, as were patients who received preimplantation genetic diagnosis or used donor oocytes. Multiple linear regression analysis was performed to determine the influence of individual factors on birthweights of singleton newborns. The birthweights and Z scores of singletons and LGA babies were compared between the G1 v5 and G1-PLUS v5 media groups. MAIN RESULTS AND THE ROLE OF CHANCE: The absolute birthweights for singletons resulting from G1-PLUS v5 were not different from singletons resulting from G1 v5 (3375.9 +/- 479.6 g versus 3333.2 +/- 491.6 g, respectively; P = 0.14). However the Z scores for singletons from embryos cultured in G1-PLUS v5 were significantly higher than for singletons cultured in G1 v5 (0.28 +/- 1.12 versus 0.09 +/- 1.15, respectively; P = 0.04), and more LGA babies were born from G1-PLUS v5 culture compared with G1 v5 (16.8 versus 12.1%, respectively; P = 0.03) culture. Finally, multiple linear regression analysis suggested that female weight (P = 0.00), male height (P = 0.04), gestational age at birth (P = 0.00), infant gender (P = 0.00) and culture media (P = 0.04) all had significant effects on the birthweights of singleton newborns. LIMITATIONS AND REASONS FOR CAUTION: This study was limited by its retrospective design. WIDER IMPLICATIONS OF THESE FINDINGS: Our study suggests that protein source/HSA has a significant effect on birthweights of singleton newborns. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Natural Science Foundation of China for Young Scholars (81300483). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 24812315 TI - Can healthy babies originate from oocytes with smooth endoplasmic reticulum aggregates? A systematic mini-review. AB - STUDY QUESTION: Is it time to reconsider whether oocytes affected by smooth endoplasmic reticulum aggregates (SERa) should still be destroyed? SUMMARY ANSWER: At the time of writing, the literature shows that 171 apparently healthy babies have been born from SERa+ cycles amongst which 22 were from SERa+ oocytes. WHAT IS KNOWN ALREADY: The SER dysmorphism has been associated with negative embryological, clinical and neonatal outcomes, which led to a recommendation in 2011 to avoid inseminating affected oocytes. The data in the literature are nevertheless conflicting and some centres have continued using SERa+ oocytes. STUDY DESIGN, SIZE, DURATION: A systematic mini-review of the literature to 7 November 2013 was performed with the keywords 'Smooth Endoplasmic Reticulum' and 'oocyte', limited to humans and written in English. PARTICIPANTS/MATERIALS, SETTING, METHODS: Articles (Pubmed) and major abstracts where the effect of the SER dysmorphism was studied as an individual feature on embryological, clinical or neonatal outcomes were included in this review. MAIN RESULTS AND THE ROLE OF CHANCE: From a total of 297 publications identified, 13 were selected as being relevant to this review. One hundred eighty-three babies have been reported to be born from SERa+ cycles, 171 were healthy, 8 live births presented malformations, 3 were neonatal deaths, 1 was a stillborn and additionally 4 terminations of pregnancy occurred. LIMITATIONS, REASONS FOR CAUTION: Data concerning SERa+ oocytes in the literature are scarce, the studies are small, heterogeneous and results are conflicting. The malformations observed could be due to over reporting of scattered alarming results. Alternatively, an under-reporting of complications cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Centres that have or that are including transfers of SERa+ embryos in their IVF procedures should publish their clinical and neonatal outcomes as well as the follow-up of children. The birth of healthy babies from SERa+ embryos is encouraging and might lead in the future to a revision of the current consensus on the SER dysmorphism. Further research is needed to understand the origin of this dysmorphism and help avoid its occurrence. Therefore, until we have a better understanding of the situation, transfers of affected embryos should be carried out with caution. STUDY FUNDING/COMPETING INTEREST(S): We have no conflicts of interest to declare and no funding was received. PMID- 24812316 TI - Ultrasonographic caput epididymis diameter is reduced in non-obstructive azoospermia compared with normozoospermia but is not predictive for successful sperm retrieval after TESE. AB - STUDY QUESTION: Is the ultrasonographic determination of the caput epididymis diameter predictive for sperm retrieval after testicular sperm extraction (TESE) in non-obstructive azoospermia (NOA)? SUMMARY ANSWER: Ultrasonographic determination of the caput epididymis diameter did not give any relevant clinical information in NOA and was not predictive for positive sperm retrieval after TESE. WHAT IS KNOWN ALREADY: The diameter of the caput epididymis in ultrasonography (US) has a diagnostic relevance in azoospermic men to correctly identify obstructive azoospermia; however, its clinical value in NOA is not yet determined. STUDY DESIGN, SIZE, DURATION: We performed a retrospective study of 100 azoospermic and 160 normozoospermic men attending a university infertility clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were submitted to scrotal US to determine the mean value of bilateral testicular volumes (ml), the bilateral longitudinal caput diameter (mm) and the antero-posterior diameter of the corpus (mm) epididymis. The number of spermatozoa retrieved after TESE and the testicular histology of azoospermic men was obtained and the percentage of seminiferous tubules with elongated spermatids (%T) was used to classify cases with normal spermatogenesis (obstructive azoospermia) (OA) (n = 20; %T >= 80) or with NOA (n = 80; %T < 70). MAIN RESULTS AND THE ROLE OF CHANCE: The US testes volumes and caput diameters were reduced (P < 0.05) in NOA compared with OA and with normozoospermia, but the corpus values were not different. The caput diameter in the side submitted to biopsy was significantly reduced when germinal epithelium was absent (Sertoli cell only) (P < 0.05) and the lowest value of caput diameter was observed when the seminiferous epithelium and tubule lumen were absent (testicular hyalinosis). On the contrary, a total arrest of spermatogenesis at the first meiosis level, or a defect of spermiogenesis resulting in scattered elongated spermatids in each tubule, did not show a reduced diameter of caput epididymis compared with normozoospermia. The caput diameter did not show any difference between NOA patients with or without successful sperm retrieval at TESE. On the contrary testicular volume was significantly reduced in NOA patients with no sperm retrieval (P = 0.0037). The caput diameter was not correlated with the number of retrieved sperm, the serum level of follicle stimulating hormone, or with the percentage of tubules with elongated spermatids at histological analysis. LIMITATIONS, REASONS FOR CAUTION: The aetiology of NOA was not included in the statistical analysis due to the low rate of cases with a specific aetiology for a testicular failure. Larger studies should exclude the possibility that besides testicular histology, aetiology of NOA might influence the diameter of caput epididymis. Moreover, whether a reduced diameter of caput epididymis is only a result of a testicular pathologic phenotype or whether it may underscore a primitive dysfunction influencing the number of ejaculated spermatozoa is not yet determined. WIDER IMPLICATIONS OF THE FINDINGS: We reported that US diameter of the caput epididymis is reduced in cases of NOA but, in contrast with the testicular volume, it is independent of the completion of spermatogenesis and subsequent presence of spermatozoa in the epididymis. Therefore ultrasonographic determination of caput epididymis diameter is not predictive for positive sperm retrieval after TESE in cases of a primitive testicular failure. Our novel findings may help to define which reproducible parameters of scrotal US should be assessed in the work-up of male infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Ministero dell'Universita e Ricerca (I) PRIN 2009. The authors declare no competing interest. PMID- 24812317 TI - The impact of a self-administered coping intervention on emotional well-being in women awaiting the outcome of IVF treatment: a randomized controlled trial. AB - STUDY QUESTION: What is the effect of the positive reappraisal coping intervention (PRCI) on anxiety in women awaiting the outcome of an IVF/ICSI cycle? SUMMARY ANSWER: Women reported significantly more anxiety during the waiting period than before treatment, but the use of the PRCI did not significantly reduce anxiety during the waiting period. WHAT IS KNOWN ALREADY: Waiting for the outcome of IVF/ICSI treatment after embryo transfer is one of the most stressful periods of fertility treatments. At present, no evidence-based coping interventions are available to assist women though this waiting period. The PRCI has been designed to address this unmet need by promoting positive reappraisal coping. STUDY DESIGN, SIZE, DURATION: A three-armed randomized controlled trail (RCT) was designed to evaluate the PRCI in women undergoing IVF/ICSI. Data were collected between October 2010 and June 2012. A total of 377 participants were randomized to receive either the PRCI and emotional monitoring, emotional monitoring only, or routine care. Only the PRCI-monitoring group received the coping intervention, comprising an explanatory leaflet and ten statements to be read at least once in the morning and once in the evening. PARTICIPANT, MATERIALS, SETTING, METHODS: To capture the general impact of the PRCI, all three groups completed questionnaires at three time points: just before the waiting period (time 1: stimulation phase), on Day 10 of the 14-day waiting period (time 2: waiting period) and 6 weeks after the start of the waiting period (time 3: 6-week follow-up). In addition, to capture the specific impacts of the PRCI on the days of the waiting period, the PRCI-monitoring group and the monitoring-control group also rated their emotions and reactions daily, for the 14-day waiting period. MAIN RESULTS AND THE ROLE OF CHANCE: Of the women who agreed to participate and who met eligibility criteria, 377 were randomized. All study participants reported significantly more anxiety and depression during the waiting period than before treatment (P < 0.001). The mean difference in anxiety between time 1 versus time 2 was 1.465 (95% CI 1.098-1.832). The mean difference in depression between time 1 versus time 2 was 0.514 (95% CI 0.215-0.813). Use of the PRCI did not significantly reduce anxiety or depression, or daily negative emotions during the waiting period. However, patients randomized to the PRCI reported significantly more positive emotions during the waiting period (P < 0.001) than the monitoring-control group, and reported the intervention to be easy to use, and as having a positive psychological effect. No significant differences were found between the groups in treatment outcome. LIMITATIONS, REASONS FOR CAUTION: The lack of difference observed in the present study for anxiety levels between the PRCI and the monitoring-control group could have been due to the effects of monitoring itself or its ability to attenuate or obscure the effects of the PRCI intervention in unknown ways. A randomized group of women who used only the PRCI without daily monitoring would provide more insight. WIDER IMPLICATIONS OF THE FINDINGS: The PRCI was shown to help women reinterpret the demands of the waiting period in a more positive way. These results are consistent with previous studies showing that positive reappraisal coping is a useful strategy for unpredictable and uncontrollable situations represented by a medical waiting period. This simple low cost self-help coping intervention increases positive affect during the waiting period in an IVF/ICSI treatment. STUDY FUNDING/COMPETENT INTEREST(S): The Women and Baby Division of the University Medical Centre Utrecht funded the study. The authors have no conflicting interest(s). TRIAL REGISTRATION NUMBER: The study is registered at the Clinical Tials.gov (NCT01701011). PMID- 24812318 TI - Major congenital anomalies in children born after frozen embryo transfer: a cohort study 1995-2006. AB - STUDY QUESTION: Is there a different risk for major congenital anomalies (CAs) in children born after frozen-thawed embryo transfer (FET) compared with children born after fresh embryo transfer (ET)? SUMMARY ANSWER: Children born after FET have a similar risk of developing major CAs as children born after fresh ET. WHAT IS KNOWN ALREADY: The perinatal outcome in children born after FET is as good as that after fresh ET. Children born as a result of assisted reproductive technology (ART) have an increased risk for CAs when compared with spontaneously conceived children, but the knowledge on the risk for CAs in specific organ systems of children born after FET is limited. STUDY DESIGN, SIZE, DURATION: This register-based cohort study includes women who have undergone ART treatments with ET leading to singleton births (n = 4772) between the years 1995 and 2006. The women were identified from the registers of the infertility clinics, and the corresponding births were matched with data from the Finnish Medical Birth Register (FMBR). The 10% random sample of women with spontaneous pregnancies from the FMBR served as the reference group (n = 31,243). The study data were linked with the Register of Congenital Malformations using the mothers' and children's personal identification numbers to get information on CAs. Furthermore, the personal identification numbers of the ART women were linked with the Register of Induced Abortions to find their selective terminations of pregnancy for severe foetal anomalies. PARTICIPANTS, SETTING, METHODS: The study was focused on singleton births and included 1830 children born after FET, 2942 children born after fresh ET and 31 243 children born after spontaneous pregnancies. Only major CAs were analysed in keeping with European Concerted Action on Congenital Anomalies and Twins. The risk estimates for CAs were adjusted for the children's year of birth and maternal age, parity and socioeconomic status. The total prevalence of major CAs was counted, including both births and selective terminations of pregnancy for major fetal anomalies (n = 33). MAIN RESULTS AND THE ROLE OF CHANCE: Among singletons at least one major CA was reported in 77 cases (4.2%) in the FET group, 132 cases (4.5%) in the fresh ET group and 994 cases (3.2%) in the reference group. The risk for at least one major CA of the children born after FET was not increased compared with the children born after fresh ET [adjusted odd ratio (aOR) 0.95; 0.71-1.27]. Furthermore, no increased risks according to the organ system affected were found between these two ART groups. When comparing the children born after ART (FET and fresh ET) with the reference group children, the risk of having at least one major CA was moderately increased in the ART group (aOR 1.24; 1.05-1.47). LIMITATIONS, REASONS FOR CAUTION: Because of the study design we were neither able to examine the aetiology of infertility nor could we compare the data with a group of subfertile women to account for the effect of infertility per se on CAs. WIDER IMPLICATIONS OF THE FINDINGS: Perinatal outcomes of FET children, including the risks for CAs, are good and comparable with outcomes of other ART children indicating that slow freezing is a safe method to use during ART treatments. STUDY FUNDING/COMPETING INTEREST(S): University Hospital of Oulu and Helsinki, Finland. THL covered the data linkages and the work of Annukka Ritvanen and Mika Gissler. There are no competing interests to be reported. PMID- 24812319 TI - The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency. AB - STUDY QUESTION: Are fragile X mental retardation gene 1 (FMR1) CGG repeats in the normal and intermediate range (up to 55 repeats) associated with primary ovarian insufficiency (POI) in a large case-control study? SUMMARY ANSWER: No association was found between CGG repeats of intermediate size and POI compared with controls. WHAT IS KNOWN ALREADY: CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have consistenly associated with POI. Intermediate range CGG repeats have been considered for a potential association with POI. STUDY DESIGN, SIZE: A case-control study in 375 well-phenotyped Dutch women diagnosed with POI and 3368 controls with natural menopause >=40 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in women diagnosed with POI and women with a known age at natural menopause >=40 years. The prevalence of intermediate sized CGG repeats (45-54 repeats) was compared between POI cases and controls using Fisher's exact test. Differences in mean CGG repeat lengths on allele 1 and allele 2 between POI cases and controls were tested using analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of intermediate sized CGG repeats on the allele with the longest triple repeat number was not statistically significantly different between POI cases and controls (2.7 and 3.8%, respectively, odds ratio 0.72, 95% confidence interval: 0.38-1.39, P = 0.38). In women with POI, linear regression analysis for age at POI diagnosis and CGG repeat size also failed to show any association (beta = -0.018, P = 0.74). LIMITATIONS, REASONS FOR CAUTION: FMR1 CGG repeat lengths in POI cases and controls were genotyped in two different laboratories. The distributions of CGG repeats may vary among the different ethnic populations in our study. Also, in our study women with primary amenorrhea (N = 17) were included in the POI group. WIDER IMPLICATIONS OF THE FINDINGS: We found no association between intermediate sized CGG repeats and POI compared with controls. Therefore, a role for FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process may be questioned. Moreover, there seems limited value in the evaluation of normal- and intermediate FMR1 repeat size in the diagnostic work-up of women affected by POI, or for prognostic purposes in women at risk of developing POI. STUDY FUNDING/COMPETING INTERESTS: The Prospect-EPIC study was funded by 'Europe Against Cancer' Program of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development; World Cancer Research Fund (WCRF) and the Dutch Heart Association. PMID- 24812320 TI - Combination gefitinib and methotrexate treatment for non-tubal ectopic pregnancies: a case series. AB - Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1-2 doses of i.m. methotrexate (50 mg/m2 on Day 1, +/- Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies. PMID- 24812321 TI - Redox regulation of 14-3-3zeta controls monocyte migration. AB - OBJECTIVE: Metabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration, and recruitment into vascular lesions by increasing actin remodeling. The mechanism linking metabolic stress to accelerated actin turnover and enhanced monocyte migration was not known. We tested the hypothesis that in metabolically primed monocytes, the acceleration of monocyte chemoattractant protein-1-induced chemotaxis is mediated by the hyperactivation of cofilin. APPROACH AND RESULTS: Metabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, that is, human native low-density lipoprotein plus high glucose concentrations. In healthy monocytes, monocyte chemoattractant protein-1 induced the phosphorylation and inactivation of cofilin. This response was completely blocked in metabolically primed monocytes but restored by overexpression of the thiol transferase, glutaredoxin 1. Cofilin kinase, LIM kinase 1, and cofilin phosphatase, Slingshot-1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the Slingshot-1L-binding protein 14-3-3zeta (zeta), resulting in its caspase dependent degradation. Glutaredoxin 1 overexpression inhibited low-density lipoprotein plus high glucose-induced S-glutathionylation and degradation of 14-3 3zeta. The C25S mutant of 14-3-3zeta was resistant to both S-glutathionylation and degradation induced by low-density lipoprotein plus high glucose. Overexpression of the C25S mutant restored monocyte chemoattractant protein-1 induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3zeta increases the pool of free Slingshot-1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation. CONCLUSIONS: By preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3zeta promotes the conversion of blood monocytes into a hypermigratory, proatherogenic phenotype. PMID- 24812322 TI - Aortic reservoir pressure corresponds to cyclic changes in aortic volume: physiological validation in humans. AB - OBJECTIVE: Aortic reservoir pressure indices independently predict cardiovascular events and mortality. Despite this, there has never been a study in humans to determine whether the theoretical principles of the mathematically derived aortic reservoir pressure (RP(derived)) and excess pressure (XP(derived)) model have a real physiological basis. This study aimed to directly measure the aortic reservoir (AR(direct); by cyclic change in aortic volume) and determine its relationship with RP(derived), XP(derived), and aortic blood pressure (BP). APPROACH AND RESULTS: Ascending aortic BP and Doppler flow velocity were recorded via intra-arterial wire in 10 men (aged 62 +/- 12 years) during coronary artery bypass surgery. Simultaneous ascending aortic transesophageal echocardiography was used to measure AR(direct). Published mathematical formulae were used to determine RP(derived) and XP(derived). AR(direct) was strongly and linearly related to RP(derived) during systole (r=0.988; P<0.001) and diastole (r=0.985; P<0.001). Peak cross-correlation (r=0.98) occurred at a phase lag of 0.004 s into the cardiac cycle, suggesting close temporal agreement between waveforms. The relationship between aortic BP and AR(direct) was qualitatively similar to the cyclic relationship between aortic BP and RP(derived), with peak cross correlations occurring at identical phase lags (AR(direct) versus aortic BP, r=0.96 at 0.06 s; RP(derived) versus aortic BP, r=0.98 at 0.06 s). CONCLUSIONS: RP(derived) is highly correlated with changes in proximal aortic volume, consistent with its physiological interpretation as corresponding to the instantaneous volume of blood stored in the aorta. Thus, aortic reservoir pressure should be considered in the interpretation of the central BP waveform. PMID- 24812323 TI - Abdominal aortic calcium, coronary artery calcium, and cardiovascular morbidity and mortality in the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC). APPROACH AND RESULTS: We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the <= 50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 (P=0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 (P=0.001), and for CAC, it was 1.9, P=0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results. CONCLUSIONS: AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality. PMID- 24812324 TI - Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterized as a progressive dilation and degradation of the aortic wall, associated with activation of matrix metalloproteinases (MMPs) and inflammation. Emerging evidence indicates a role for microRNAs (miRNAs) in AAA pathogenesis, but it is unclear whether abdominal aortic endothelial miRNAs play a role in the disease process. We aimed to identify miRNAs in the abdominal aortic endothelium that play a critical role in AAA development. APPROACH AND RESULTS: The mouse model of AAA induced by angiotensin II infusion was used in this study. Through a miRNA array and validation study, we initially identified the murine-specific miR-712 and subsequently its human/murine homolog miR-205 as angiotensin II-induced miRNAs in the abdominal aortic endothelium in vivo and in vitro. Mechanistically, miR-712 stimulated MMP activity in the aortic wall by directly targeting 2 MMP inhibitors: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion inducing cysteine-rich protein with kazal motifs (RECK). Silencing of miR-712 and miR-205 by using anti-miR-712 and anti-miR-205, respectively, significantly decreased the aortic MMP activity and inflammation, preventing AAA development in angiotensin II-infused ApoE(-/-) mice. Further, upregulation of 4 angiotensin II sensitive miRNAs, miR-205, -21, -133b, and -378, identified in this murine study were confirmed in human AAA samples compared with nondiseased control. CONCLUSIONS: Our results demonstrate that angiotensin II-sensitive miR-712 and its human homolog miR-205 downregulate TIMP3 and RECK, which in turn stimulate aortic MMP activity and inflammation, leading to AAA development. Targeting these miRNAs may be a novel therapeutic strategy to prevent AAA. PMID- 24812325 TI - CXCR3 controls T-cell accumulation in fat inflammation. AB - OBJECTIVE: Obesity associates with increased numbers of inflammatory cells in adipose tissue (AT), including T cells, but the mechanism of T-cell recruitment remains unknown. This study tested the hypothesis that the chemokine (C-X-C motif) receptor 3 (CXCR3) participates in T-cell accumulation in AT of obese mice and thus in the regulation of local inflammation and systemic metabolism. APPROACH AND RESULTS: Obese wild-type mice exhibited higher mRNA expression of CXCR3 in periepididymal AT-derived stromal vascular cells compared with lean mice. We evaluated the function of CXCR3 in AT inflammation in vivo using CXCR3 deficient and wild-type control mice that consumed a high-fat diet. Periepididymal AT from obese CXCR3-deficient mice contained fewer T cells than obese controls after 8 and 16 weeks on high-fat diet, as assessed by flow cytometry. Obese CXCR3-deficient mice had greater glucose tolerance than obese controls after 8 weeks, but not after 16 weeks. CXCR3-deficient mice fed high-fat diet had reduced mRNA expression of proinflammatory mediators, such as monocyte chemoattractant protein-1 and regulated on activation, normal T cell expressed and secreted, and anti-inflammatory genes, such as Foxp3, IL-10, and arginase-1 in periepididymal AT, compared with obese controls. CONCLUSIONS: These results demonstrate that CXCR3 contributes to T-cell accumulation in periepididymal AT of obese mice. Our results also suggest that CXCR3 regulates the accumulation of distinct subsets of T cells and that the ratio between these functional subsets across time likely modulates local inflammation and systemic metabolism. PMID- 24812326 TI - Single-cell genomics for dissection of complex malaria infections. AB - Most malaria infections contain complex mixtures of distinct parasite lineages. These multiple-genotype infections (MGIs) impact virulence evolution, drug resistance, intra-host dynamics, and recombination, but are poorly understood. To address this we have developed a single-cell genomics approach to dissect MGIs. By combining cell sorting and whole-genome amplification (WGA), we are able to generate high-quality material from parasite-infected red blood cells (RBCs) for genotyping and next-generation sequencing. We optimized our approach through analysis of >260 single-cell assays. To quantify accuracy, we decomposed mixtures of known parasite genotypes and obtained highly accurate (>99%) single-cell genotypes. We applied this validated approach directly to infections of two major malaria species, Plasmodium falciparum, for which long term culture is possible, and Plasmodium vivax, for which no long-term culture is feasible. We demonstrate that our single-cell genomics approach can be used to generate parasite genome sequences directly from patient blood in order to unravel the complexity of P. vivax and P. falciparum infections. These methods open the door for large-scale analysis of within-host variation of malaria infections, and reveal information on relatedness and drug resistance haplotypes that is inaccessible through conventional sequencing of infections. PMID- 24812327 TI - Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development. AB - During differentiation of embryonic stem cells, chromatin reorganizes to establish cell type-specific expression programs. Here, we have dissected the linkages between DNA methylation (5mC), hydroxymethylation (5hmC), nucleosome repositioning, and binding of the transcription factor CTCF during this process. By integrating MNase-seq and ChIP-seq experiments in mouse embryonic stem cells (ESC) and their differentiated counterparts with biophysical modeling, we found that the interplay between these factors depends on their genomic context. The mostly unmethylated CpG islands have reduced nucleosome occupancy and are enriched in cell type-independent binding sites for CTCF. The few remaining methylated CpG dinucleotides are preferentially associated with nucleosomes. In contrast, outside of CpG islands most CpGs are methylated, and the average methylation density oscillates so that it is highest in the linker region between nucleosomes. Outside CpG islands, binding of TET1, an enzyme that converts 5mC to 5hmC, is associated with labile, MNase-sensitive nucleosomes. Such nucleosomes are poised for eviction in ESCs and become stably bound in differentiated cells where the TET1 and 5hmC levels go down. This process regulates a class of CTCF binding sites outside CpG islands that are occupied by CTCF in ESCs but lose the protein during differentiation. We rationalize this cell type-dependent targeting of CTCF with a quantitative biophysical model of competitive binding with the histone octamer, depending on the TET1, 5hmC, and 5mC state. PMID- 24812328 TI - Methods for quantifying gene expression in ecoimmunology: from qPCR to RNA-Seq. AB - Historically, the use of cutting-edge molecular techniques to study immunological gene expression and related cellular pathways has been largely limited to model organisms. Few studies have been performed that quantify the molecular immunological responses of non-model species, especially in response to environmental factors, life-history events, or exposure to parasites. This dearth of information has largely occurred due to the lack of available non-model species-specific gene sequences and immunological reagents and also due to prohibitively expensive technology. However, with the rapid development of various sequencing and transcriptomic technologies, profiling the gene expression of non-model organisms has become possible. Technologies and concepts explored here include an overview of current technologies for quantifying gene expression, including: qPCR, multiplex branched DNA assays, microarrays, and profiling gene expression (RNA sequencing [RNA-Seq]) based on next-generation sequencing. Examples of the advancement of these technologies in non-model systems are discussed. Additionally, applications, limitations, and feasibility of the use of these methodologies in non-model systems to address questions in ecological immunology and disease-ecology are specifically addressed. PMID- 24812329 TI - Predicting performance and plasticity in the development of respiratory structures and metabolic systems. AB - The scaling laws governing metabolism suggest that we can predict metabolic rates across taxonomic scales that span large differences in mass. Yet, scaling relationships can vary with development, body region, and environment. Within species, there is variation in metabolic rate that is independent of mass and which may be explained by genetic variation, the environment or their interaction (i.e., metabolic plasticity). Additionally, some structures, such as the insect tracheal respiratory system, change throughout development and in response to the environment to match the changing functional requirements of the organism. We discuss how study of the development of respiratory function meets multiple challenges set forth by the NSF Grand Challenges Workshop. Development of the structure and function of respiratory and metabolic systems (1) is inherently stable and yet can respond dynamically to change, (2) is plastic and exhibits sensitivity to environments, and (3) can be examined across multiple scales in time and space. Predicting respiratory performance and plasticity requires quantitative models that integrate information across scales of function from the expression of metabolic genes and mitochondrial biogenesis to the building of respiratory structures. We present insect models where data are available on the development of the tracheal respiratory system and of metabolic physiology and suggest what is needed to develop predictive models. Incorporating quantitative genetic data will enable mapping of genetic and genetic-by-environment variation onto phenotypes, which is necessary to understand the evolution of respiratory and metabolic systems and their ability to enable respiratory homeostasis as organisms walk the tightrope between stability and change. PMID- 24812330 TI - Physiological correlates of urbanization in a desert songbird. AB - Rapid worldwide urbanization is creating novel environments to which animals must adapt, a topic of growing interest for biologists. Studies of how organisms are affected by cities historically centered on large-scale censusing of populations, but recent investigations have considered finer-scaled, urban-rural differences among individuals and species in their behavior, morphology, and physiology, specifically as they relate to urban stress. A number of factors (e.g., corticosterone (CORT)-related stress response) may contribute to the degree of stress experienced by animals living under urban versus natural conditions, but several physiological variables have yet to be considered together in a large scale assessment. Here, in a widespread species of desert passerine (the house finch, Haemorhous mexicanus), we quantified variation in plasma oxidative stress, plasma concentrations of vitamins and carotenoids, and body-mass of males in three successive seasons (winter, spring, and late summer/early fall) along an urban-rural gradient in Phoenix, Arizona, USA. We found that degree of urbanization was: (1) negatively related to circulating vitamin A concentrations in winter, (2) positively correlated with body-mass during spring, and (3) negatively associated with plasma concentrations of two carotenoids: zeaxanthin (during breeding) and 3-hydroxy-echinenone (3HE) (during molting). The striking link between 3HE levels and urbanization is consistent with previous research showing that urban songbirds have lower carotenoid levels and faded plumage; our finding is the first to implicate specific effects on a metabolically derived carotenoid for coloration. The fact that we observed only season-specific links between urbanization and indicators of quality in finches suggests that (at least for these metrics) there are no strong, lasting urban pressures imposed on finch physiology over the year. Interestingly, we found that a metric of plasma oxidative stress (lipid peroxidation) was positively correlated with levels of two carotenoids (lutein during breeding and 3HE during molting), which is consistent with a prior study of ours showing that finches with redder plumage deposit higher levels of CORT in their feathers; taken together, our studies suggest complex associations between carotenoids and stress. PMID- 24812331 TI - Prognosis of patients with carcinoid heart disease after valvular surgery. AB - A best evidence topic in cardiac surgery was written according to a structured protocol. We addressed the following question: in patients who are diagnosed with carcinoid heart disease (CHD), do valvular surgeries improve their prognosis? Fifty percent of the patients with clinically diagnosed carcinoid syndrome had cardiac involvement which was present either as valvular dysfunction or as cardiac metastases. These patients often require surgery due to their heightened risk of cardiac disease. Altogether 217 relevant papers were identified as a result of the below-mentioned search, of which 10 papers represented the best evidence to answer the question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. Of the patients who were identified to have carcinoid heart disease in different studies, 193 patients had valve procedure, mainly replacements at tricuspid, mitral and aortic valve positions and either valvuloplasty or replacement at pulmonary valve. Tricuspid and pulmonary valves represented the majority of the excised valves among patients undergoing valvular surgery for CHD. The pathology of carcinoid valve was attributed to the presence of plaque, causing thickening and retraction. Pure regurgitation was the most common finding in all the valves except pulmonary valve which had both stenosis and insufficiency. Thirty-day mortality was 17% (range 1-63%) and long-term survivors were reported to be alive at an average of 58 months (28-80 months) after the valve surgery. The evidence demonstrates that surgical intervention can lead to improved prognosis and reduce the symptoms of heart failure. Postoperative mortality was mainly due to the carcinoid disease itself and not as a complication of the surgery. Therefore, surgery could be considered for symptomatic palliation in carefully selected individuals. PMID- 24812332 TI - High levels of free haemoglobin in neonates and infants undergoing surgery on cardiopulmonary bypass. AB - OBJECTIVES: Haemolysis is known to occur during surgery on cardiopulmonary bypass (CPB) and to be responsible for kidney injury. The aim of this study was to assess, in a cohort of infants, the reference levels of free haemoglobin (fHb) and their change over time postoperatively; the predicting variables of haemolysis in the intraoperative phase; and the association between fHb and renal function. METHODS: A retrospective analysis in infants undergoing surgery on CPB was conducted. Children with preoperative renal dysfunction and need for extracorporeal membrane oxygenation support were excluded. fHb was sampled before and after CPB and on the first 2 postoperative days (POD). RESULTS: Twenty-two patients with a median (interquartile) age of 111 (63-184) days and Aristotle score of 8 (6.4-9) were enrolled. fHb had a baseline value of 29 (24-41) mg/dl, peaked to 75 (65-109) mg/dl at CPB weaning and returned to 35 (30-55) mg/dl on POD 2 (P <0.0001). The median normalized index of haemolysis was 0.15 (0.09-0.19) g of fHb per 100 l of pumped blood. A multivariable regression model showed that, at CPB weaning, fHb levels were independently associated with left atrial venting flow (P = 0.02), and that CPB time remained the only independent variable (P = 0.034), when left atrial venting was excluded from the analysis. Acute kidney injury (AKI) occurred in 10 patients (45%). fHb levels in the 48 post-CPB hours were not significantly different between AKI and non-AKI patients: However, a significant correlation was present between creatinine on POD1 and CPBw-fHb (r = 0.48; P = 0.045); and between cystatin C on POD1 and CPBw-fHb (r = 0.58; P = 0.02). CONCLUSIONS: A high rate of fHb is released during paediatric surgery with CPB in infants. fHb mainly depends on the left atrial venting flow rate and CPB duration. However, such peaks of fHb levels were not associated with renal dysfunction. PMID- 24812333 TI - Response to 'Position statement on ethics, equipoise and research on charged particle therapy'. AB - In August 2011, a group of medical doctors, ethicists, academic and medical physicists were asked to debate and reach consensus on the potential need for randomised control trials to test charged particle radiation therapy (CPRT) for treating tumours. The outcome of the meeting was a paper recently published in the Journal of Medical Ethics entitled "Position statement on ethics, equipoise and research on charged particle therapy" by Sheehan et al. However 6 of the 30 meeting participants withdrew from authorship of the 'position statement' because their views were not adequately represented. The 'position statement' did not state our reasons for withdrawing from the statement, which is a considerable omission. We had two principal objections: (1) the case for the benefits to patients and society of randomized trials to test CPRT was not adequately represented, and (2) the complexities and potential harms of CPRT were not clearly stated. In this response we explain and justify our objections. Patients, doctors and policymakers seeking to make independent judgments about whether equipoise exists for the relative benefits of CPRT should therefore read this document alongside the 'position' statement. PMID- 24812334 TI - Making sense of assessment in medical ethics and law. AB - Are curricula in medical ethics and law effective in producing ethical doctors? Assessment is central to this question, both in setting the standards that students are expected to meet and in establishing the extent to which learning correlates with these. Medical ethics and law: a practical guide to the assessment of the core content of learning from the Education Steering Group of the Institute of Medical Ethics is an excellent guide for educators in approaching this curriculum task. If the teaching moment is temporally antecedent to assessment, it is not logically prior to assessment decisions as if these were simply retrospective, and we cannot speak meaningfully of assessment without also speaking of intended learning. The IME assessment guide places emphasis on the alignment of learning, teaching and assessment in curriculum design; on specifying in advance the learning opportunities available to students; on delivering these via appropriate forms of learning; and on matching suitable methods for testing this learning in both summative and formative modes. Variety in assessment is essential across the cognitive, the affective and the psychomotor domains of learning, and the IME assessment guide provides illustrative examples of, and templates for, types of assessment that are relevant to these. The practical advice offered is as applicable in schools of nursing and in dental schools as it is in medical education. PMID- 24812335 TI - Narrating the self-injured body. AB - Illness narratives have traditionally been used as a conceptual tool for exploring experiences of chronic illness or disease. In this paper, I suggest that Frank's typology of illness narratives (chaos, restitution and quest) also offers an illuminating approach to analysing accounts of self-injury, demonstrating the diverse ways in which self-injury is practiced, experienced and narrated. Drawing on 24 narrative interviews with 12 people who had self-injured, I focus on participants' accounts of their self-injured bodies. The approach is phenomenological, and concerned with talk about the experience of living with and in a body that has been marked by self-injury. Thus, the act of self-injury is not the sole focus, and particular attention is paid to accounts of the bodily aftermath: scars, marks and wounds. Scars left by self-injury can be seen as communicative, and the analysis developed here demonstrates some of the various ways that these marks may be read. Attending to these diverse narratives can contribute to the provision of compassionate, non-judgemental care for patients who have self-injured. Further, highlighting the existence of different ways of narrating the self-injured body may offer an optimistic resource for people who have self-injured. PMID- 24812336 TI - fastGapFill: efficient gap filling in metabolic networks. AB - MOTIVATION: Genome-scale metabolic reconstructions summarize current knowledge about a target organism in a structured manner and as such highlight missing information. Such gaps can be filled algorithmically. Scalability limitations of available algorithms for gap filling hinder their application to compartmentalized reconstructions. RESULTS: We present fastGapFill, a computationally efficient tractable extension to the COBRA toolbox that permits the identification of candidate missing knowledge from a universal biochemical reaction database (e.g. Kyoto Encyclopedia of Genes and Genomes) for a given (compartmentalized) metabolic reconstruction. The stoichiometric consistency of the universal reaction database and of the metabolic reconstruction can be tested for permitting the computation of biologically more relevant solutions. We demonstrate the efficiency and scalability of fastGapFill on a range of metabolic reconstructions. AVAILABILITY AND IMPLEMENTATION: fastGapFill is freely available from http://thielelab.eu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24812337 TI - SEK: sparsity exploiting k-mer-based estimation of bacterial community composition. AB - MOTIVATION: Estimation of bacterial community composition from a high-throughput sequenced sample is an important task in metagenomics applications. As the sample sequence data typically harbors reads of variable lengths and different levels of biological and technical noise, accurate statistical analysis of such data is challenging. Currently popular estimation methods are typically time-consuming in a desktop computing environment. RESULTS: Using sparsity enforcing methods from the general sparse signal processing field (such as compressed sensing), we derive a solution to the community composition estimation problem by a simultaneous assignment of all sample reads to a pre-processed reference database. A general statistical model based on kernel density estimation techniques is introduced for the assignment task, and the model solution is obtained using convex optimization tools. Further, we design a greedy algorithm solution for a fast solution. Our approach offers a reasonably fast community composition estimation method, which is shown to be more robust to input data variation than a recently introduced related method. AVAILABILITY AND IMPLEMENTATION: A platform-independent Matlab implementation of the method is freely available at http://www.ee.kth.se/ctsoftware; source code that does not require access to Matlab is currently being tested and will be made available later through the above Web site. PMID- 24812338 TI - RNASeqGUI: a GUI for analysing RNA-Seq data. AB - We present RNASeqGUI R package, a graphical user interface (GUI) for the identification of differentially expressed genes across multiple biological conditions. This R package includes some well-known RNA-Seq tools, available at www.bioconductor.org. RNASeqGUI package is not just a collection of some known methods and functions, but it is designed to guide the user during the entire analysis process. RNASeqGUI package is mainly addressed to those users who have little experience with command-line software. Therefore, thanks to RNASeqGUI, they can conduct analogous analyses using this simple graphical interface. Moreover, RNASeqGUI is also helpful for those who are expert R-users because it speeds up the usage of the included RNASeq methods drastically. AVAILABILITY AND IMPLEMENTATION: RNASeqGUI package needs the RGTK2 graphical library to run. This package is open source and is freely available under General Public License at http://bioinfo.na.iac.cnr.it/RNASeqGUI/Download. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24812340 TI - Inferring the paths of somatic evolution in cancer. AB - MOTIVATION: Cancer cell genomes acquire several genetic alterations during somatic evolution from a normal cell type. The relative order in which these mutations accumulate and contribute to cell fitness is affected by epistatic interactions. Inferring their evolutionary history is challenging because of the large number of mutations acquired by cancer cells as well as the presence of unknown epistatic interactions. RESULTS: We developed Bayesian Mutation Landscape (BML), a probabilistic approach for reconstructing ancestral genotypes from tumor samples for much larger sets of genes than previously feasible. BML infers the likely sequence of mutation accumulation for any set of genes that is recurrently mutated in tumor samples. When applied to tumor samples from colorectal, glioblastoma, lung and ovarian cancer patients, BML identifies the diverse evolutionary scenarios involved in tumor initiation and progression in greater detail, but broadly in agreement with prior results. AVAILABILITY AND IMPLEMENTATION: Source code and all datasets are freely available at bml.molgen.mpg.de. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24812339 TI - Bioinformatics-driven discovery of rational combination for overcoming EGFR mutant lung cancer resistance to EGFR therapy. AB - MOTIVATION: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in the United States. Targeted tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) have been widely and successfully used in treating NSCLC patients with activating EGFR mutations. Unfortunately, the duration of response is short-lived, and all patients eventually relapse by acquiring resistance mechanisms. RESULT: We performed an integrative systems biology approach to determine essential kinases that drive EGFR-TKI resistance in cancer cell lines. We used a series of bioinformatics methods to analyze and integrate the functional genetics screen and RNA-seq data to identify a set of kinases that are critical in survival and proliferation in these TKI-resistant lines. By connecting the essential kinases to compounds using a novel kinase connectivity map (K-Map), we identified and validated bosutinib as an effective compound that could inhibit proliferation and induce apoptosis in TKI-resistant lines. A rational combination of bosutinib and gefitinib showed additive and synergistic effects in cancer cell lines resistant to EGFR TKI alone. CONCLUSIONS: We have demonstrated a bioinformatics-driven discovery roadmap for drug repurposing and development in overcoming resistance in EGFR mutant NSCLC, which could be generalized to other cancer types in the era of personalized medicine. AVAILABILITY AND IMPLEMENTATION: K-Map can be accessible at: http://tanlab.ucdenver.edu/kMap. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24812342 TI - PhenoNet: identification of key networks associated with disease phenotype. AB - MOTIVATION: At the core of transcriptome analyses of cancer is a challenge to detect molecular differences affiliated with disease phenotypes. This approach has led to remarkable progress in identifying molecular signatures and in stratifying patients into clinical groups. Yet, despite this progress, many of the identified signatures are not robust enough to be clinically used and not consistent enough to provide a follow-up on molecular mechanisms. RESULTS: To address these issues, we introduce PhenoNet, a novel algorithm for the identification of pathways and networks associated with different phenotypes. PhenoNet uses two types of input data: gene expression data (RMA, RPKM, FPKM, etc.) and phenotypic information, and integrates these data with curated pathways and protein-protein interaction information. Comprehensive iterations across all possible pathways and subnetworks result in the identification of key pathways or subnetworks that distinguish between the two phenotypes. AVAILABILITY AND IMPLEMENTATION: Matlab code is available upon request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24812341 TI - Probabilistic partitioning methods to find significant patterns in ChIP-Seq data. AB - MOTIVATION: We have witnessed an enormous increase in ChIP-Seq data for histone modifications in the past few years. Discovering significant patterns in these data is an important problem for understanding biological mechanisms. RESULTS: We propose probabilistic partitioning methods to discover significant patterns in ChIP-Seq data. Our methods take into account signal magnitude, shape, strand orientation and shifts. We compare our methods with some current methods and demonstrate significant improvements, especially with sparse data. Besides pattern discovery and classification, probabilistic partitioning can serve other purposes in ChIP-Seq data analysis. Specifically, we exemplify its merits in the context of peak finding and partitioning of nucleosome positioning patterns in human promoters. AVAILABILITY AND IMPLEMENTATION: The software and code are available in the supplementary material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24812343 TI - GEPdb: a database for investigating the ternary association of genotype, gene expression and phenotype. AB - GEPdb integrates both genome-wide association studies and expression quantitative trait loci information, the two primary sources of genome-wide mapping for genotype-phenotype and genotype-expression associations together with phenotype associated gene lists. The GEPdb provides simultaneous interpretation of both genetic risks and potential gene regulatory pathways toward phenotypic outcome by establishing the ternary relationship of genotype-expression-phenotype (GEP). The analytic scope is further extended by linkage disequilibrium from five different populations of the international HapMap Project. AVAILABILITY AND IMPLEMENTATION: http://ercsbweb.ewha.ac.kr/gepdb. PMID- 24812344 TI - SAMBLASTER: fast duplicate marking and structural variant read extraction. AB - MOTIVATION: Illumina DNA sequencing is now the predominant source of raw genomic data, and data volumes are growing rapidly. Bioinformatic analysis pipelines are having trouble keeping pace. A common bottleneck in such pipelines is the requirement to read, write, sort and compress large BAM files multiple times. RESULTS: We present SAMBLASTER, a tool that reduces the number of times such costly operations are performed. SAMBLASTER is designed to mark duplicates in read-sorted SAM files as a piped post-pass on DNA aligner output before it is compressed to BAM. In addition, it can simultaneously output into separate files the discordant read-pairs and/or split-read mappings used for structural variant calling. As an alignment post-pass, its own runtime overhead is negligible, while dramatically reducing overall pipeline complexity and runtime. As a stand-alone duplicate marking tool, it performs significantly better than PICARD or SAMBAMBA in terms of both speed and memory usage, while achieving nearly identical results. AVAILABILITY AND IMPLEMENTATION: SAMBLASTER is open-source C+ + code and freely available for download from https://github.com/GregoryFaust/samblaster. PMID- 24812345 TI - LIPCAR: a mitochondrial lnc in the noncoding RNA chain? PMID- 24812346 TI - Platelet TLR4: a critical link in pulmonary arterial hypertension. PMID- 24812347 TI - Is nitrite the circulating endocrine effector of remote ischemic preconditioning? PMID- 24812348 TI - It takes two to tango: monocyte and macrophage duality in the infarcted heart. PMID- 24812349 TI - Wrestling with heart failure: SUMO-1 to the rescue. PMID- 24812350 TI - Bone marrow mononuclear cell therapy for acute myocardial infarction: a perspective from the cardiovascular cell therapy research network. AB - To understand the role of bone marrow mononuclear cells in the treatment of acute myocardial infarction, this overview offers a retrospective examination of strengths and limitations of 3 contemporaneous trials with attention to critical design features and provides an analysis of the combined data set and implications for future directions in cell therapy for acute myocardial infarction. PMID- 24812351 TI - Genetically encoded Ca2+ indicators in cardiac myocytes. AB - Genetically encoded Ca(2+) indicators constitute a powerful set of tools to investigate functional aspects of Ca(2+) signaling in isolated cardiomyocytes, cardiac tissue, and whole hearts. Here, we provide an overview of the concepts, experiences, state of the art, and ongoing developments in the use of genetically encoded Ca(2+) indicators for cardiac cells and heart tissue. This review is supplemented with in vivo viral gene transfer experiments and comparisons of available genetically encoded Ca(2+) indicators with each other and with the small molecule dye Fura-2. In the context of cardiac myocytes, we provide guidelines for selecting a genetically encoded Ca(2+) indicator. For future developments, we discuss improvements of a broad range of properties, including photophysical properties such as spectral spread and biocompatibility, as well as cellular and in vivo applications. PMID- 24812352 TI - Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. AB - Chronic inflammation in response to lipoprotein accumulation in the arterial wall is central in the development of atherosclerosis. Both innate and adaptive immunity are involved in this process. Adaptive immune responses develop against an array of potential antigens presented to effector T lymphocytes by antigen presenting cells, especially dendritic cells. Functional analysis of the role of different T-cell subsets identified the Th1 responses as proatherogenic, whereas regulatory T-cell responses exert antiatherogenic activities. The effect of Th2 and Th17 responses is still debated. Atherosclerosis is also associated with B cell activation. Recent evidence established that conventional B-2 cells promote atherosclerosis. In contrast, innate B-1 B cells offer protection through secretion of natural IgM antibodies. This review discusses the recent development in our understanding of the role of T- and B-cell subsets in atherosclerosis and addresses the role of dendritic cell subpopulations in the control of adaptive immunity. PMID- 24812353 TI - G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism. AB - Heart failure (HF) causes a tremendous burden on the worldwide healthcare system, affecting >23 million people. There are many cardiovascular disorders that contribute to the development of HF and multiple risk factors that accelerate its occurrence, but regardless of its underlying cause, HF is characterized by a marked decrease in myocardial contractility and loss of pump function. One biomarker molecule consistently shown to be upregulated in human HF and several animal models is G protein-coupled receptor kinase-2 (GRK2), a kinase originally discovered to be involved in G protein-coupled receptor desensitization, especially beta-adrenergic receptors. Higher levels of GRK2 can impair beta adrenergic receptor-mediated inotropic reserve and its inhibition, or molecular reduction has shown to improve pump function in several animal models including a preclinical pig model of HF. Recently, nonclassical roles for GRK2 in cardiovascular disease have been described, including negative regulation of insulin signaling, a role in myocyte cell survival and apoptotic signaling, and it has been shown to be localized in/on mitochondria. These new roles of GRK2 suggest that GRK2 may be a nodal link in the myocyte, influencing both cardiac contractile function and cell metabolism and survival and contributing to HF independent of its canonical role in G protein-coupled receptor desensitization. In this review, classical and nonclassical roles for GRK2 will be discussed, focusing on recently discovered roles for GRK2 in cardiomyocyte metabolism and the effects that these roles may have on myocardial contractile function and HF development. PMID- 24812354 TI - Phospholipase C-related catalytically inactive protein (PRIP) controls KIF5B mediated insulin secretion. AB - We previously reported that phospholipase C-related catalytically inactive protein (PRIP)-knockout mice exhibited hyperinsulinemia. Here, we investigated the role of PRIP in insulin granule exocytosis using Prip-knockdown mouse insulinoma (MIN6) cells. Insulin release from Prip-knockdown MIN6 cells was higher than that from control cells, and Prip knockdown facilitated movement of GFP-phogrin-labeled insulin secretory vesicles. Double-immunofluorescent staining and density step-gradient analyses showed that the KIF5B motor protein co localized with insulin vesicles in Prip-knockdown MIN6 cells. Knockdown of GABAA receptor-associated protein (GABARAP), a microtubule-associated PRIP-binding partner, by Gabarap silencing in MIN6 cells reduced the co-localization of insulin vesicles with KIF5B and the movement of vesicles, resulting in decreased insulin secretion. However, the co-localization of KIF5B with microtubules was not altered in Prip- and Gabarap-knockdown cells. The presence of unbound GABARAP, freed either by an interference peptide or by Prip silencing, in MIN6 cells enhanced the co-localization of insulin vesicles with microtubules and promoted vesicle mobility. Taken together, these data demonstrate that PRIP and GABARAP function in a complex to regulate KIF5B-mediated insulin secretion, providing new insights into insulin exocytic mechanisms. PMID- 24812356 TI - Estimating the surface area of birds: using the homing pigeon (Columba livia) as a model. AB - Estimation of the surface area of the avian body is valuable for thermoregulation and metabolism studies as well as for assessing exposure to oil and other surface active organic pollutants from a spill. The use of frozen carcasses for surface area estimations prevents the ability to modify the posture of the bird. The surface area of six live homing pigeons in the fully extended flight position was estimated using a noninvasive method. An equation was derived to estimate the total surface area of a pigeon based on its body weight. A pigeon's surface area in the fully extended flight position is approximately 4 times larger than the surface area of a pigeon in the perching position. The surface area of a bird is dependent on its physical position, and, therefore, the fully extended flight position exhibits the maximum area of a bird and should be considered the true surface area of a bird. PMID- 24812355 TI - p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex. AB - Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1 binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis. PMID- 24812357 TI - Overdrive pacing from downstream sites on multielectrode catheters to rapidly detect fusion and to diagnose macroreentrant atrial arrhythmias. AB - BACKGROUND: Entrainment criteria for macroreentrant arrhythmias are based on detecting fusion between tachycardia and paced wavefronts, but this is often difficult for atrial tachycardias (AT) after ablation of atrial fibrillation. METHODS AND RESULTS: With the use of a multipolar catheter, pacing was performed from electrodes within the coronary sinus showing activation later than adjacent electrodes (downstream overdrive pacing) during 66 ATs in 62 patients: 20 cavotricuspid isthmus-dependent ATs, 20 perimitral ATs, 13 focal ATs with sequential coronary sinus activation, and 13 other macroreentrant left atrial ATs. The paced cycle length was 10 to 30 milliseconds below the tachycardia cycle length (TCL), and activation at the neighboring upstream electrodes was assessed. Downstream overdrive pacing at 48 sites close to a macroreentrant circuit (PPI TCL <40 milliseconds, where PPI is postpacing interval) produced constant fusion demonstrated by a long stimulus to upstream atrial electrogram interval (S-Au) >75% TCL and was consistent with orthodromic activation of the upstream site despite its close proximity to the pacing site. In contrast, downstream overdrive pacing at 18 sites during focal AT or remote from the macroreentrant AT circuit (PPI-TCL >40 milliseconds) always demonstrated a comparatively short S-Au <25% of TCL (12+/-4% versus 89+/-4% of TCL; P<0.001), consistent with direct activation. CONCLUSIONS: Selection of a downstream activation site for overdrive pacing can facilitate rapid recognition of macroreentry and proximity to the reentry circuit using a single multielectrode catheter by recognizing a PPI-TCL <40 milliseconds and S-Au >75% of TCL. Recognition of intracardiac constant fusion with this method is a novel criterion for transient entrainment. PMID- 24812358 TI - Roseivivax marinus sp. nov., isolated from deep water. AB - A Gram-stain-negative, strictly aerobic, non-motile, cream, long rod-shaped bacterium, designated strain ZL136(T), was isolated from deep water of the South China Sea. Phylogenetic analysis based on 16S rRNA gene sequences indicated that this strain belonged to the genus Roseivivax with highest sequence similarity to Roseivivax halodurans OCh 239(T) (97.0%), followed by Roseivivax isoporae sw-2(T) (96.9%). Growth occurred at 4-37 degrees C (optimum 32 degrees C), pH 6.0-10.0 (optimum 8.0) and in the presence of 0-12% (w/v) NaCl (optimum 3-4%) in marine broth 2216. Strain ZL136(T) did not produce bacteriochlorophyll a. The predominant fatty acids were C(18 : 1)omega7c and/or C(18 : 1)omega6c, C(18 : 0), C(16 : 0) and 11-methyl C(18 : 1)omega7c. The major polar lipids of ZL136(T) were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and an unidentified lipid. The major respiratory quinone was ubiquinone Q-10. The genomic DNA G+C content of strain ZL136(T) was 67.0 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic analysis, strain ZL136(T) was classified as a representative of a novel species in the genus of Roseivivax, for which the name Roseivivax marinus sp. nov. is proposed. The type strain is ZL136(T) ( = JCM 19386(T) = KCTC 32470(T)). PMID- 24812360 TI - Streptomyces graminifolii sp. nov., isolated from bamboo (Sasa borealis) litter. AB - The taxonomic position of strain JL-22(T), isolated from litter of a bamboo (Sasa borealis) forest, was determined using a polyphasic approach. The organism had phenotypic and morphological properties consistent with it being a member of the genus Streptomyces. Phylogenetic analysis of the 16S rRNA gene sequence showed that strain JL-22(T) was closely related to Streptomyces prunicolor NRRL B 12281(T) (99.2%), Streptomyces galilaeus JCM 4757(T) (99.0%) and Streptomyces chartreusis NBRC 12753(T) (99.0%). However, the results of DNA-DNA hybridization and physiological and biochemical tests showed that strain JL-22(T) could be differentiated from its closest phylogenetic relatives both genotypically and phenotypically. Based on phenotypic and genotypic data, strain JL-22(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces graminifolii sp. nov. is proposed. The type strain is JL-22(T) ( = KACC 17180(T) = NBRC 109806(T)). PMID- 24812359 TI - Thiophaeococcus fuscus sp. nov., isolated from a lagoon. AB - A brown-coloured bacterium, designated strain JA633(T), was purified from a photoheterotrophic enrichment culture obtained from black sand of a lagoon. Cells of strain JA633(T) were coccoid-spherical, Gram-stain-negative and motile by means of polar flagella. Strain JA633(T) had an obligate requirement for NaCl and could tolerate up to 4% (w/v) NaCl. Internal photosynthetic membranes were present as vesicles. Photo-organoheterotrophy was the only growth mode observed. Strain JA633(T) contained bacteriochlorophyll a and a major (>85%) unidentified carotenoid of the spirilloxanthin series. Thiamine and p-aminobenzoic acid were required for growth. Major fatty acids were C(18 : 1)omega7c/C(18 : 1)omega6c, C(16 : 0) and C(16 : 1)omega7c/C(16 : 1)omega6c. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphotidylcholine and an unknown aminophospholipid were the major polar lipids in strain JA633(T). The DNA G+C content of strain JA633(T) was 64.5 mol%. Strain JA633(T) shared highest 16S rRNA gene sequence similarity with the type strains of Thiorhodococcus kakinadensis (96.9%), Thiophaeococcus mangrovi (96.3%) and Thiorhodococcus bheemlicus (96.2%), which belonged to the class Gammaproteobacteria. However, phylogenetic analysis based on 16S rRNA gene sequences showed that strain JA633(T) formed a separate clade along with Thiophaeococcus mangrovi JA304(T) whereas the members of the genus Thiorhodococcus remained as two distinct phylogenetic lineages. Based on morphological, physiological, chemotaxonomic and molecular evidence, strain JA633(T) was significantly different from the type strain of Thiophaeococcus mangrovi of the family Chromatiaceae. It is thus proposed that the strain be classified as a representative of a novel species, for which the name Thiophaeococcus fuscus sp. nov. is proposed. The type strain is JA633(T) ( = KCTC 15337(T) = NBRC 109958(T)). PMID- 24812361 TI - Luteococcus sediminum sp. nov., isolated from deep subseafloor sediment of the South Pacific Gyre. AB - A Gram-stain-positive, strictly aerobic, coccus-shaped, non-motile, yellow pigmented bacterium, designated strain XH208(T), was isolated from a deep subseafloor sediment sample collected from the South Pacific Gyre (41 degrees 58' S 163 degrees 11' W) during the Integrated Ocean Drilling Program (IODP) Expedition 329. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain XH208(T) belonged to the genus Luteococcus and showed the highest 16S rRNA gene sequence similarities with Luteococcus peritonei CCUG 38120(T) (96.9%), Luteococcus japonicus DSM 10546(T) (95.4%) and Luteococcus sanguinis CCUG 33897(T) (95.2%). The DNA G+C content of strain XH208(T) was 66.9 mol%. The cell wall of strain XH208(T) possessed a type A3gamma peptidoglycan (ll-diaminopimelic acid-glycine), and ribose, glucose and galactose as the major whole-cell sugars. The major fatty acids were C(17 : 1)omega8c, C(17 : 1)omega6c, and C(16 : 1)omega6c and/or C(16 : 1)omega7c (summed feature 3). The major respiratory quinone was menaquinone MK-9(H4). The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol and phosphatidylinositol. On the basis of data from the polyphasic analysis, strain XH208(T) is considered to represent a novel species in the genus Luteococcus, for which the name Luteococcus sediminum sp. nov. is proposed. The type strain is XH208(T) ( = DSM 27277(T) = JCM 19259(T)). PMID- 24812362 TI - Litoreibacter ascidiaceicola sp. nov., isolated from the golden sea squirt Halocynthia aurantium. AB - A Gram-stain-negative, aerobic, non-motile and coccoid, ovoid or rod-shaped bacterial strain, designated RSS4-C1(T), was isolated from a golden sea squirt (Halocynthia aurantium) collected from the East Sea, South Korea. The novel strain grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 1.0 3.0% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain RSS4-C1(T) fell within the clade comprising the type strains of species of the genus Litoreibacter . Strain RSS4-C1(T) exhibited the highest 16S rRNA gene sequence similarity (99.6%) to the type strain of Litoreibacter albidus and sequence similarities of 96.5-98.5% to type strains of other recognized species of the genus Litoreibacter. Strain RSS4-C1(T) contained Q-10 as the predominant ubiquinone and C(18 : 1)omega7c and 11-methyl-C(18 : 1)omega7c as the major fatty acids. The major polar lipids of strain RSS4-C1(T) were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, one unidentified lipid and one unidentified aminolipid. The DNA G+C content of strain RSS4-C1(T) was 58.0 mol% and its DNA-DNA relatedness values with type strains of four species of the genus Litoreibacter were 21-34%. The differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain RSS4-C1(T) is distinct from other species of the genus Litoreibacter. On the basis of the data presented, strain RSS4-C1(T) is considered to represent a novel species of the genus Litoreibacter, for which the name Litoreibacter ascidiaceicola sp. nov. is proposed. The type strain is RSS4-C1(T) ( = KCTC 42050(T) = CECT 8539(T)). PMID- 24812363 TI - Sphingorhabdus arenilitoris sp. nov., isolated from a coastal sand, and reclassification of Sphingopyxis rigui as Sphingorhabdus rigui comb. nov. and Sphingopyxis wooponensis as Sphingorhabdus wooponensis comb. nov. AB - A Gram-stain-negative, strictly aerobic, non-flagellated and rod-shaped bacterial strain, designated GJR-7(T), was isolated from coastal sand of the South Sea of South Korea. Strain GJR-7(T) grew optimally at 30 degrees C, at pH 7.0-7.5 and without NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain GJR-7(T) clustered with the type strains of Sphingopyxis wooponensis, Sphingopyxis rigui and Sphingorhabdus planktonica, with which it exhibited 16S rRNA gene sequence similarity values of 96.0-96.3%. Sequence similarities to the type strains of other recognized species were less than 95.5%. Strain GJR-7(T) contained Q-10 as the predominant ubiquinone and C(18 : 1)omega7c, 11-methyl C(18 : 1)omega7c and summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c) or C(14 : 0) 2-OH. The major polar lipids were sphingoglycolipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and one unidentified glycolipid. The DNA G+C content of strain GJR-7(T) was 55.5 mol%. Differential phenotypic properties, together with phylogenetic distinctiveness, revealed that strain GJR-7(T) is separated from the type strains of Sphingopyxis wooponensis, Sphingopyxis rigui and Sphingorhabdus planktonica. On the basis of the data presented, strain GJR-7(T) is considered to represent a novel species of the genus Sphingorhabdus, for which the name Sphingorhabdus arenilitoris sp. nov. is proposed. The type strain is GJR-7(T) ( = KCTC 42051(T) = CECT 8531(T)). It is also proposed that Sphingopyxis wooponensis and Sphingopyxis rigui should be reclassified as members of the genus Sphingorhabdus. PMID- 24812364 TI - Descriptions of Roseiarcus fermentans gen. nov., sp. nov., a bacteriochlorophyll a-containing fermentative bacterium related phylogenetically to alphaproteobacterial methanotrophs, and of the family Roseiarcaceae fam. nov. AB - A light-pink-pigmented, microaerophilic bacterium was obtained from a methanotrophic consortium enriched from acidic Sphagnum peat and designated strain Pf56(T). Cells of this bacterium were Gram-negative, non-motile, thick curved rods that contained a vesicular intracytoplasmic membrane system characteristic of some purple non-sulfur alphaproteobacteria. The absorption spectrum of acetone/methanol extracts of cells grown in the light showed maxima at 363, 475, 505, 601 and 770 nm; the peaks at 363 and 770 nm are characteristic of bacteriochlorophyll a. However, in contrast to purple non-sulfur bacteria, strain Pf56(T) was unable to grow phototrophically under anoxic conditions in the light. Best growth occurred on some sugars and organic acids under micro-oxic conditions by means of fermentation. The fermentation products were propionate, acetate and hydrogen. Slow chemo-organotrophic growth was also observed under fully oxic conditions. Light stimulated growth. C1 substrates were not utilized. Strain Pf56(T) grew at pH 4.0-7.0 (optimum pH 5.5-6.5) and at 15-30 degrees C (optimum 22-28 degrees C). The major cellular fatty acids were 19 : 0 cyclo omega8c and 18 : 1omega7c; quinones were represented by ubiquinone Q-10. The G+C content of the DNA was 70.0 mol%. Strain Pf56 displays 93.6-94.7 and 92.7-93.7% 16S rRNA gene sequence similarity to members of the families Methylocystaceae and Beijerinckiaceae, respectively, and belongs to a large cluster of environmental sequences retrieved from various wetlands and forest soils in cultivation independent studies. Phenotypic, genotypic and chemotaxonomic characteristics of strain Pf56(T) suggest that it represents a novel genus and species of bacteriochlorophyll a-containing fermentative bacteria, for which the name Roseiarcus fermentans gen. nov., sp. nov. is proposed. Strain Pf56(T) ( = DSM 24875(T) = VKM B-2876(T)) is the type strain of Roseiarcus fermentans, and is also the first characterized member of a novel family within the class Alphaproteobacteria, Roseiarcaceae fam. nov. PMID- 24812365 TI - Paracoccus sediminis sp. nov., isolated from Pacific Ocean marine sediment. AB - Strain CMB17(T) was a short rod-shaped bacterium isolated from marine sediment of the Pacific Ocean. Cells were Gram-stain-negative and non-motile. Optimal growth occurred at 25-30 degrees C, pH 6.5-7 and 0.5-1% (w/v) NaCl. The major fatty acid was C(18 : 1)omega7c (87.59%), and ubiquinone-10 was detected as the only isoprenoid quinone. The DNA G+C content of the genomic DNA was 62.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CMB17(T) is most closely related to Paracoccus stylophorae KTW-16(T) (96.7%), P. solventivorans DSM 6637(T) (96.4%) and P. saliphilus YIM 90738(T) (96.4%). Based on phenotypic, genotypic and phylogenetic characteristics, strain CMB17(T) is proposed to represent a novel species, denominated Paracoccus sediminis sp. nov. (type strain CMB17(T) = JCM 18467(T) = DSM 26170(T) = CGMCC 1.12681(T)). PMID- 24812367 TI - Lipomyces chichibuensis sp. nov., isolated in Japan, and reidentification of the type strains of Lipomyces kononenkoae and Lipomyces spencermartinsiae. AB - We isolated two strains of a novel Lipomyces species from soil collected in Chichibu forest, Saitama prefecture, Japan. Based on their morphological and biochemical characteristics, along with multilocus sequence typing using the D1/D2 domain of the large-subunit (LSU) rRNA gene, the internal transcribed spacer (ITS) region and the translation elongation factor 1 alpha gene (EF 1alpha), the two strains were shown to represent a novel species of the genus Lipomyces, described as Lipomyces chichibuensis sp. nov. (type strain CB08-2(T) = NBRC 109582(T) = CBS 12929(T); Mycobank no. MB808164). In addition, we reidentified the type strains of Lipomyces kononenkoae and Lipomyces spencermartinsiae maintained in culture collections based on phenotypic characters and/or DNA-DNA hybridization to ensure correct future identification of species of the genus Lipomyces. The correct type strains of L. kononenkoae and L. spencermartinsiae are NBRC 107661(T) ( = CBS 2514(T)) and NBRC 10376(T) ( = CBS 5608(T)), respectively. PMID- 24812366 TI - Enterococcus olivae sp. nov., isolated from Spanish-style green-olive fermentations. AB - Six strains of a hitherto unknown, Gram-stain-positive coccus were recovered from samples of Spanish-style green-olive fermentations. The 16S rRNA gene sequences from these isolates shared 98.7% and 98.5% of their nucleotide positions with those from Enterococcus saccharolyticus subsp. taiwanensis 812(T) and from E. saccharolyticus subsp. saccharolyticus ATCC 43076(T), respectively. The sequence of the rpoA gene in the isolates was 95% similar to that of E. saccharolyticus CECT 4309(T) ( = ATCC 43076(T)). The 16S rRNA and rpoA gene phylogenies revealed that the isolates grouped in a statistically well-supported cluster separate from E. saccharolyticus. Enzyme activity profiles as well as fermentation patterns differentiated the novel bacteria from other members of the Enterococcus genus. Finally, phenotypic, genotypic and phylogenetic data supported the identification of a novel species of the genus Enterococcus, for which the name Enterococcus olivae sp. nov. is proposed. The type strain is IGG16.11(T) ( = CECT 8063(T) = DSM 25431(T)). PMID- 24812368 TI - Young brains on drugs. PMID- 24812373 TI - Scientific integrity. Fresh misconduct charges hit Dutch social psychology. PMID- 24812374 TI - Archaeology. New sites bring the earliest Americans out of the shadows. PMID- 24812375 TI - Global change. 'Sea butterflies' are a canary for ocean acidification. PMID- 24812376 TI - Aging. 'Rejuvenation factor' in blood turns back the clock in old mice. PMID- 24812377 TI - Synthetic biology. Designer microbes expand life's genetic alphabet. PMID- 24812378 TI - Maritime ambitions. PMID- 24812379 TI - Breast cancer and environmental research. PMID- 24812380 TI - Copper limits: opportunity costs. PMID- 24812381 TI - Comment on "Revealing nature's cellulase diversity: the digestion mechanism of Caldicellulosiruptor bescii CelA". AB - Brunecky et al. (Reports, 20 December 2013, p. 1513) compared the cellulolytic activity of bacterial multimodular cellulase CelA with fungal Cel7A (cellobiohydrolase I from Trichoderma reesei). If more active Cel7A from another fungus were used as a reference enzyme under optimal conditions with beta glucosidase added, the reported difference between bacterial and fungal enzymes would be less dramatic. PMID- 24812382 TI - Response to Comment on "Revealing nature's cellulase diversity: the digestion mechanism of Caldicellulosiruptor bescii CelA". AB - Gusakov critiques our methodology for comparing the cellulolytic activity of the bacterial cellulase CelA with the fungal cellulase Cel7A. We address his concerns by clarifying some misconceptions, carefully referencing the literature, and justifying our approach to point out that the results from our study still stand. PMID- 24812383 TI - Copper limits: recycling potential. PMID- 24812384 TI - Copper limits: human agency. PMID- 24812386 TI - Science education. Convergence between science and environmental education. PMID- 24812388 TI - Astronomy. Next steps for cosmology. PMID- 24812387 TI - Cell biology. A SWELL channel indeed. PMID- 24812389 TI - AIDS/HIV. Host controls of HIV neutralizing antibodies. PMID- 24812390 TI - Biochemistry. Trigger factor flexibility. PMID- 24812391 TI - Materials science. An internal cure for damaged polymers. PMID- 24812392 TI - Psychology. Rice, psychology, and innovation. PMID- 24812393 TI - Neuroscience. A price to pay for adult neurogenesis. PMID- 24812394 TI - Hippocampal neurogenesis regulates forgetting during adulthood and infancy. AB - Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species. PMID- 24812395 TI - Large-scale psychological differences within China explained by rice versus wheat agriculture. AB - Cross-cultural psychologists have mostly contrasted East Asia with the West. However, this study shows that there are major psychological differences within China. We propose that a history of farming rice makes cultures more interdependent, whereas farming wheat makes cultures more independent, and these agricultural legacies continue to affect people in the modern world. We tested 1162 Han Chinese participants in six sites and found that rice-growing southern China is more interdependent and holistic-thinking than the wheat-growing north. To control for confounds like climate, we tested people from neighboring counties along the rice-wheat border and found differences that were just as large. We also find that modernization and pathogen prevalence theories do not fit the data. PMID- 24812396 TI - Fermi surface and pseudogap evolution in a cuprate superconductor. AB - The unclear relationship between cuprate superconductivity and the pseudogap state remains an impediment to understanding the high transition temperature (T(c)) superconducting mechanism. Here, we used magnetic field-dependent scanning tunneling microscopy to provide phase-sensitive proof that d-wave superconductivity coexists with the pseudogap on the antinodal Fermi surface of an overdoped cuprate. Furthermore, by tracking the hole-doping (p) dependence of the quasi-particle interference pattern within a single bismuth-based cuprate family, we observed a Fermi surface reconstruction slightly below optimal doping, indicating a zero-field quantum phase transition in notable proximity to the maximum superconducting T(c). Surprisingly, this major reorganization of the system's underlying electronic structure has no effect on the smoothly evolving pseudogap. PMID- 24812397 TI - Simultaneous transitions in cuprate momentum-space topology and electronic symmetry breaking. AB - The existence of electronic symmetry breaking in the underdoped cuprates and its disappearance with increased hole density p are now widely reported. However, the relation between this transition and the momentum-space (k-space) electronic structure underpinning the superconductivity has not yet been established. Here, we visualize the Q = 0 (intra-unit-cell) and Q ? 0 (density-wave) broken-symmetry states, simultaneously with the coherent k-space topology, for Bi2Sr2CaCu2O(8+delta) samples spanning the phase diagram 0.06 <= p <= 0.23. We show that the electronic symmetry-breaking tendencies weaken with increasing p and disappear close to a critical doping p(c) = 0.19. Concomitantly, the coherent k-space topology undergoes an abrupt transition, from arcs to closed contours, at the same p(c). These data reveal that the k-space topology transformation in cuprates is linked intimately with the disappearance of the electronic symmetry breaking at a concealed critical point. PMID- 24812398 TI - Direct, nonoxidative conversion of methane to ethylene, aromatics, and hydrogen. AB - The efficient use of natural gas will require catalysts that can activate the first C-H bond of methane while suppressing complete dehydrogenation and avoiding overoxidation. We report that single iron sites embedded in a silica matrix enable direct, nonoxidative conversion of methane, exclusively to ethylene and aromatics. The reaction is initiated by catalytic generation of methyl radicals, followed by a series of gas-phase reactions. The absence of adjacent iron sites prevents catalytic C-C coupling, further oligomerization, and hence, coke deposition. At 1363 kelvin, methane conversion reached a maximum at 48.1% and ethylene selectivity peaked at 48.4%, whereas the total hydrocarbon selectivity exceeded 99%, representing an atom-economical transformation process of methane. The lattice-confined single iron sites delivered stable performance, with no deactivation observed during a 60-hour test. PMID- 24812399 TI - Restoration of large damage volumes in polymers. AB - The regenerative power of tissues and organs in biology has no analog in synthetic materials. Although self-healing of microscopic defects has been demonstrated, the regrowth of material lost through catastrophic damage requires a regenerative-like approach. We demonstrate a vascular synthetic system that restores mechanical performance in response to large-scale damage. Gap-filling scaffolds are created through a two-stage polymer chemistry that initially forms a shape-conforming dynamic gel but later polymerizes to a solid structural polymer with robust mechanical properties. Through the control of reaction kinetics and vascular delivery rate, we filled impacted regions that exceed 35 mm in diameter within 20 min and restored mechanical function within 3 hours. After restoration of impact damage, 62% of the total absorbed energy was recovered in comparison with that in initial impact tests. PMID- 24812400 TI - In situ TEM observation of a microcrucible mechanism of nanowire growth. AB - The growth of metal oxide nanowires can proceed via a number of mechanisms such as screw dislocation, vapor-liquid-solid process, or seeded growth. Transmission electron microscopy (TEM) can resolve nanowires but invariably lacks the facility for direct observation of how nanowires form. We used a transmission electron microscope equipped with an in situ heating stage to follow the growth of quaternary metal oxide nanowires. Video-rate imaging revealed barium carbonate nanoparticles diffusing through a porous matrix containing copper and yttrium oxides to subsequently act as catalytic sites for the outgrowth of Y2BaCuO5 nanowires on reaching the surface. The results suggest that sites on the rough surface of the porous matrix act as microcrucibles and thus provide insights into the mechanisms that drive metal oxide nanowire growth at high temperatures. PMID- 24812401 TI - Spatially distributed local fields in the hippocampus encode rat position. AB - Although neuronal spikes can be readily detected from extracellular recordings, synaptic and subthreshold activity remains undifferentiated within the local field potential (LFP). In the hippocampus, neurons discharge selectively when the rat is at certain locations, while LFPs at single anatomical sites exhibit no such place-tuning. Nonetheless, because the representation of position is sparse and distributed, we hypothesized that spatial information can be recovered from multiple-site LFP recordings. Using high-density sampling of LFP and computational methods, we show that the spatiotemporal structure of the theta rhythm can encode position as robustly as neuronal spiking populations. Because our approach exploits the rhythmicity and sparse structure of neural activity, features found in many brain regions, it is useful as a general tool for discovering distributed LFP codes. PMID- 24812402 TI - Gibberellin acts positively then negatively to control onset of flower formation in Arabidopsis. AB - The switch to reproductive development is biphasic in many plants, a feature important for optimal pollination and yield. We show that dual opposite roles of the phytohormone gibberellin underpin this phenomenon in Arabidopsis. Although gibberellin promotes termination of vegetative development, it inhibits flower formation. To overcome this effect, the transcription factor LEAFY induces expression of a gibberellin catabolism gene; consequently, increased LEAFY activity causes reduced gibberellin levels. This allows accumulation of gibberellin-sensitive DELLA proteins. The DELLA proteins are recruited by SQUAMOSA PROMOTER BINDING PROTEIN-LIKE transcription factors to regulatory regions of the floral commitment gene APETALA1 and promote APETALA1 up-regulation and floral fate synergistically with LEAFY. The two opposing functions of gibberellin may facilitate evolutionary and environmental modulation of plant inflorescence architecture. PMID- 24812403 TI - Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. AB - Limited evidence exists that humans mount a mutation-specific T cell response to epithelial cancers. We used a whole-exomic-sequencing-based approach to demonstrate that tumor-infiltrating lymphocytes (TIL) from a patient with metastatic cholangiocarcinoma contained CD4+ T helper 1 (T(H)1) cells recognizing a mutation in erbb2 interacting protein (ERBB2IP) expressed by the cancer. After adoptive transfer of TIL containing about 25% mutation-specific polyfunctional T(H)1 cells, the patient achieved a decrease in target lesions with prolonged stabilization of disease. Upon disease progression, the patient was retreated with a >95% pure population of mutation-reactive T(H)1 cells and again experienced tumor regression. These results provide evidence that a CD4+ T cell response against a mutated antigen can be harnessed to mediate regression of a metastatic epithelial cancer. PMID- 24812404 TI - Sound strategies for hearing restoration. AB - Hearing loss is the most common sensory deficit in humans, with some estimates suggesting up to 300 million affected individuals worldwide. Both environmental and genetic factors contribute to hearing loss and can cause death of sensory cells and neurons. Because these cells do not regenerate, the damage tends to accumulate, leading to profound deafness. Several biological strategies to restore auditory function are currently under investigation. Owing to the success of cochlear implants, which offer partial recovery of auditory function for some profoundly deaf patients, potential biological therapies must extend hearing restoration to include greater auditory acuity and larger patient populations. Here, we review the latest gene, stem-cell, and molecular strategies for restoring auditory function in animal models and the prospects for translating these approaches into viable clinical therapies. PMID- 24812405 TI - Structural basis for protein antiaggregation activity of the trigger factor chaperone. AB - Molecular chaperones prevent aggregation and misfolding of proteins, but scarcity of structural data has impeded an understanding of the recognition and antiaggregation mechanisms. We report the solution structure, dynamics, and energetics of three trigger factor (TF) chaperone molecules in complex with alkaline phosphatase (PhoA) captured in the unfolded state. Our data show that TF uses multiple sites to bind to several regions of the PhoA substrate protein primarily through hydrophobic contacts. Nuclear magnetic resonance (NMR) relaxation experiments show that TF interacts with PhoA in a highly dynamic fashion, but as the number and length of the PhoA regions engaged by TF increase, a more stable complex gradually emerges. Multivalent binding keeps the substrate protein in an extended, unfolded conformation. The results show how molecular chaperones recognize unfolded polypeptides and, by acting as unfoldases and holdases, prevent the aggregation and premature (mis)folding of unfolded proteins. PMID- 24812406 TI - Two cross-sectional studies in south India assessing the effect of an HIV prevention programme for female sex workers on reducing syphilis among their clients. AB - OBJECTIVE: To assess the impact of the Avahan HIV prevention programme for female sex workers (FSWs) in south India on reducing syphilis prevalence among their clients, by comparing rates of syphilis over time as reported in two large-scale surveys of FSWs' clients. METHODS: A random-effect multilevel logistic regression analysis was performed using syphilis as the dependent variable, with individual independent variables (from the two survey rounds) at level 1 and the district level programme (from the Avahan computerised monitoring and information system) and contextual variables (from Indian government datasets) at level 2. Programme variables included their 2006 value and their difference in value between 2008 and 2006, as well as the interaction between the latter and the study round. The analysis also controlled for baseline syphilis prevalence and its interaction with the study round. RESULTS: Syphilis decreased significantly among FSWs' clients, from 4.8% (round 1) to 2.6% (round 2), p<0.001. The OR of the interaction term between the difference in programme coverage of FSWs and the round was 0.98 (p=0.023), suggesting that increased coverage was associated with a reduced incidence of syphilis. CONCLUSIONS: This study suggests that the Avahan intervention programme among FSWs reduced syphilis rates among their clients. PMID- 24812407 TI - Human papillomavirus prevalence among men in sub-Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: We performed a systematic review and meta-analysis to summarise the available data on the prevalence of human papillomavirus (HPV) among men in sub Saharan Africa. METHODS: PubMed and Embase were searched up to 10 March 2014. Random effects meta-analyses were used to calculate a pooled prevalence of any HPV and high-risk (HR) HPV. RESULTS: A total of 11 studies comprising 9342 men were identified. We found that HPV is very common among men in sub-Saharan Africa, the prevalence of any HPV ranging between 19.1% and 100%. Using random effects meta-analysis, the pooled prevalence of any HPV was 78.2% (95% CI 54.2 to 91.6) among HIV-positive and 49.4% (95% CI 30.4 to 68.6) among HIV-negative men (p=0.0632). When restricting the analyses to PCR-based studies, the pooled prevalence of any HPV was 84.5% (95% CI 74.2 to 91.2) among HIV-positive and 56.4% (95% CI 49.7 to 62.9) among HIV-negative men (p<0.0001). Of the HPV types included in the nine-valent HPV vaccine, the most common HR HPV types were HPV16 and HPV52, and HPV6 was the most common low-risk HPV type. When examining the prevalence of HPV in relation to age no clear trend was observed. CONCLUSIONS: The prevalence of HPV is high among men in sub-Saharan Africa, which could contribute to the high rates of penile and cervical cancer in this part of the world. Implementation of the prophylactic HPV vaccines could potentially help prevent this large burden of HPV and HPV-associated disease in sub-Saharan Africa. CLINICALTRIALS.GOV IDENTIFIER: NCT00932009. PMID- 24812408 TI - Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. AB - PURPOSE: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. EXPERIMENTAL DESIGN: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. RESULTS: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFgamma. In PD-L1-exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. CONCLUSIONS: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1-exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. PMID- 24812409 TI - Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach. AB - PURPOSE: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens. EXPERIMENTAL DESIGN: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system. RESULTS: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options. CONCLUSION: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing. PMID- 24812410 TI - Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition. AB - PURPOSE: The EGFR-independent activation of the RAS/RAF/MEK/MAPK pathway is one of the resistance mechanisms to cetuximab. EXPERIMENTAL DESIGN: We have evaluated, in vitro and in vivo, the effects of BAY 86-9766, a selective MEK1/2 inhibitor, in a panel of human colorectal cancer cell lines with primary or acquired resistance to cetuximab. RESULTS: Among the colorectal cancer cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, and SW480) and one with a BRAF mutation (HT29) were resistant to the antiproliferative effects of cetuximab, whereas two cells (GEO and SW48) were highly sensitive. Treatment with BAY 86-9766 determined dose-dependent growth inhibition in all cancer cells, including two human colorectal cancer cells with acquired resistance to cetuximab (GEO-CR and SW48-CR), with the exception of HCT15 cells. Combined treatment with cetuximab and BAY 86-9766 induced a synergistic antiproliferative and apoptotic effects with blockade in the MAPK and AKT pathway in cells with either primary or acquired resistance to cetuximab. The synergistic antiproliferative effects were confirmed using other two selective MEK1/2 inhibitors, selumetinib and pimasertib, in combination with cetuximab. Moreover, inhibition of MEK expression by siRNA restored cetuximab sensitivity in resistant cells. In nude mice bearing established human HCT15, HCT116, SW48-CR, and GEO-CR xenografts, the combined treatment with cetuximab and BAY 86-9766 caused significant tumor growth inhibition and increased mice survival. CONCLUSION: These results suggest that activation of MEK is involved in both primary and acquired resistance to cetuximab and the inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance in patients with colorectal cancer. PMID- 24812411 TI - Presence of somatic mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in cisplatin-resistant germ cell tumors. AB - PURPOSE: A previous study noted frequent B-RAF mutations among European patients with cisplatin-resistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center. EXPERIMENTAL DESIGN: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom. RESULTS: Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS). CONCLUSIONS: BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors. PMID- 24812412 TI - Testis cancer: the forgotten poster child. AB - In germ cell cancers, the unique reversibility of malignancy and the balance between somatic differentiation and dedifferentiation may be critical to late relapse that is dominated by non-germ cell elements. Targeting regulators of differentiation may provide a solution, and this may be elucidated via serial liquid biopsies (via circulating tumor cells). PMID- 24812413 TI - MET as a target in papillary renal cell carcinoma. AB - The biology underlying papillary renal cell carcinoma (pRCC) is largely unknown, and no specific therapies have been developed for advanced disease. The elucidation of the MET pathway status in types I and II pRCC may help to select patients who are more likely to benefit from MET inhibitors. PMID- 24812414 TI - Pleural fluid biochemistry - old controversies, new directions. PMID- 24812415 TI - Usefulness of a thyroglobulin liquid chromatography-tandem mass spectrometry assay for evaluation of suspected heterophile interference. PMID- 24812416 TI - From lost in translation to paradise found: enabling protein biomarker method transfer by mass spectrometry. PMID- 24812418 TI - A Monte Carlo method for variance estimation for estimators based on induced smoothing. AB - An important issue in statistical inference for semiparametric models is how to provide reliable and consistent variance estimation. Brown and Wang (2005. Standard errors and covariance matrices for smoothed rank estimators. Biometrika 92: , 732-746) proposed a variance estimation procedure based on an induced smoothing for non-smooth estimating functions. Herein a Monte Carlo version is developed that does not require any explicit form for the estimating function itself, as long as numerical evaluation can be carried out. A general convergence theory is established, showing that any one-step iteration leads to a consistent variance estimator and continuation of the iterations converges at an exponential rate. The method is demonstrated through the Buckley-James estimator and the weighted log-rank estimators for censored linear regression, and rank estimation for multiple event times data. PMID- 24812417 TI - Factors related to thrombosis of gastric varix during balloon-occluded retrograde transvenous obliteration. AB - BACKGROUND: Balloon-occluded retrograde transvenous obliteration (B-RTO) has become known as an effective treatment for gastric varices with a gastrorenal shunt. However, the appropriate duration to maintain inflation of the catheter balloon for sufficient thrombosis has been unknown. PURPOSE: To evaluate retrospectively the factors related to the development of thrombus in gastric varices by evaluating the necessity of the addition of a sclerosing agent on the second day in overnight B-RTO. MATERIAL AND METHODS: Sixty-five patients who underwent B-RTO for gastric varices with a gastrorenal shunt were studied. The B RTO catheter was retained overnight in all patients. Incidence of and factors influencing the necessity of additional injections of a sclerosing agent on the second day were investigated. RESULTS: In all 65 patients (100%), B-RTO was technically successful and in 61 patients (93.8%) complete thrombosis of the gastric varices was achieved. In 46 of the 65 patients (70.8%), the sclerosing agent was added on the second day. Higher Child-Pugh score, in particular, lower serum albumin level, and higher prothrombin time-international normalized ratio (PT-INR) were significantly associated with the need for the addition of the sclerosing agent on the second day. Optimal cut-off values for the serum albumin level and PT-INR were 3.6 g/dL and 1.13, respectively. CONCLUSION: Liver function might influence the development of thrombosis of gastric varices in B-RTO. Serum albumin and PT-INR levels would provide information for deciding on the duration of retention of the B-RTO catheter to obtain sufficient therapeutic effectiveness. PMID- 24812419 TI - Estimating effect of environmental contaminants on women's subfecundity for the MoBa study data with an outcome-dependent sampling scheme. AB - Motivated by the need from our on-going environmental study in the Norwegian Mother and Child Cohort (MoBa) study, we consider an outcome-dependent sampling (ODS) scheme for failure-time data with censoring. Like the case-cohort design, the ODS design enriches the observed sample by selectively including certain failure subjects. We present an estimated maximum semiparametric empirical likelihood estimation (EMSELE) under the proportional hazards model framework. The asymptotic properties of the proposed estimator were derived. Simulation studies were conducted to evaluate the small-sample performance of our proposed method. Our analyses show that the proposed estimator and design is more efficient than the current default approach and other competing approaches. Applying the proposed approach with the data set from the MoBa study, we found a significant effect of an environmental contaminant on fecundability. PMID- 24812420 TI - On shrinkage and model extrapolation in the evaluation of clinical center performance. AB - We consider statistical methods for benchmarking clinical centers based on a dichotomous outcome indicator. Borrowing ideas from the causal inference literature, we aim to reveal how the entire study population would have fared under the current care level of each center. To this end, we evaluate direct standardization based on fixed versus random center effects outcome models that incorporate patient-specific baseline covariates to adjust for differential case mix. We explore fixed effects (FE) regression with Firth correction and normal mixed effects (ME) regression to maintain convergence in the presence of very small centers. Moreover, we study doubly robust FE regression to avoid outcome model extrapolation. Simulation studies show that shrinkage following standard ME modeling can result in substantial power loss relative to the considered alternatives, especially for small centers. Results are consistent with findings in the analysis of 30-day mortality risk following acute stroke across 90 centers in the Swedish Stroke Register. PMID- 24812421 TI - Weighted pairwise likelihood estimation for a general class of random effects models. AB - Models with random effects/latent variables are widely used for capturing unobserved heterogeneity in multilevel/hierarchical data and account for associations in multivariate data. The estimation of those models becomes cumbersome as the number of latent variables increases due to high-dimensional integrations involved. Composite likelihood is a pseudo-likelihood that combines lower-order marginal or conditional densities such as univariate and/or bivariate; it has been proposed in the literature as an alternative to full maximum likelihood estimation. We propose a weighted pairwise likelihood estimator based on estimates obtained from separate maximizations of marginal pairwise likelihoods. The derived weights minimize the total variance of the estimated parameters. The proposed weighted estimator is found to be more efficient than the one that assumes all weights to be equal. The methodology is applied to a multivariate growth model for binary outcomes in the analysis of four indicators of schistosomiasis before and after drug administration. PMID- 24812422 TI - The ethics of offering dialysis for AKI to the older patient: time to re evaluate? AB - Older patients are more susceptible to AKI. In the elderly, AKI has been associated with increased morbidity and mortality, and it is a significant risk factor for CKD and dialysis-dependent ESRD. There are now accumulating data that the start of dialysis for some older patients is associated with poor outcomes, such as high treatment intensity, suffering, and limited life prolongation, which occur at the expense of dignity and quality of life. The biomedicalization of aging is a relatively recent field of ethical inquiry with two directly relevant features to decisions about starting dialysis for older patients with AKI: (1) the routinization of geriatric clinical interventions, such as dialysis, which results in the overshadowing of patient choice, and (2) the transformation of the technological imperative into the moral imperative. A major consequence of the biomedicalization of aging is that societal expectations about standard medical care have resulted in the relatively unquestioned provision of dialysis for AKI to older patients. This paper calls for nephrologists to re-examine the data and their attitudes to offering dialysis to older patients with AKI, especially those patients with underlying CKD and significant comorbidities. Shared decision making and the reinforcement of the right of the patient to make a choice need to slow down the otherwise ineluctable routinization of starting old and very sick patients on dialysis. In the process of shared decision-making, nephrologists should not automatically recommend dialysis for older patients; in those patients who can be predicted to do poorly, recommending against dialysis upholds the Hippocratic maxim to be of benefit and do no harm. This paper challenges the automatic transformation of the technological imperative into the moral imperative for older patients with AKI and points to the need for a re-evaluation of dialysis ethics in this population. PMID- 24812423 TI - Retinopathy and progression of CKD: The CRIC study. AB - BACKGROUND AND OBJECTIVES: Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed. RESULTS: Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P<0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P<0.001). CONCLUSIONS: The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors. PMID- 24812424 TI - Sleep fragmentation during late gestation induces metabolic perturbations and epigenetic changes in adiponectin gene expression in male adult offspring mice. AB - Sleep fragmentation (SF) is a common condition among pregnant women, particularly during late gestation. Gestational perturbations promote the emergence of adiposity and metabolic disease risk in offspring, most likely through epigenetic modifications. Adiponectin (AdipoQ) expression inversely correlates with obesity and insulin resistance. The effects of SF during late gestation on metabolic function and AdipoQ expression in visceral white adipose tissue (VWAT) of offspring mice are unknown. Male offspring mice were assessed at 24 weeks after dams were exposed to SF or control sleep during late gestation. Increased food intake, body weight, VWAT mass, and insulin resistance, with reductions in AdipoQ expression in VWAT, emerged in SF offspring. Increased DNMT3a and -b and global DNA methylation and reduced histone acetyltransferase activity and TET1, -2, and 3 expression were detected in VWAT of SF offspring. Reductions in 5 hydroxymethylcytosine and H3K4m3 and an increase in DNA 5-methylcytosine and H3K9m2 in the promoter and enhancer regions of AdipoQ emerged in adipocytes from VWAT and correlated with AdipoQ expression. SF during late gestation induces epigenetic modifications in AdipoQ in male offspring mouse VWAT adipocytes along with a metabolic syndrome-like phenotype. Thus, altered gestational environments elicited by SF impose the emergence of adverse, long-lasting metabolic consequences in the next generation. PMID- 24812426 TI - Glycoprotein 130 receptor signaling mediates alpha-cell dysfunction in a rodent model of type 2 diabetes. AB - Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of alpha-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary alpha-cells and stimulated glucagon secretion. Pancreatic alpha-cell gp130 knockout (alphagp130KO) mice showed no differences in glycemic control, alpha cell function, or alpha-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, alphagp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved alpha-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of alpha-cell gp130 receptor signaling has deleterious effects on alpha-cell function, promoting hyperglycemia. Antagonism of alpha-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes. PMID- 24812425 TI - Catalase overexpression prevents nuclear factor erythroid 2-related factor 2 stimulation of renal angiotensinogen gene expression, hypertension, and kidney injury in diabetic mice. AB - This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-kappaB and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice. PMID- 24812427 TI - Dicarbonyl stress in the absence of hyperglycemia increases endothelial inflammation and atherogenesis similar to that observed in diabetes. AB - The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications. PMID- 24812428 TI - Blockade of Na+ channels in pancreatic alpha-cells has antidiabetic effects. AB - Pancreatic alpha-cells express voltage-gated Na(+) channels (NaChs), which support the generation of electrical activity leading to an increase in intracellular calcium, and cause exocytosis of glucagon. Ranolazine, a NaCh blocker, is approved for treatment of angina. In addition to its antianginal effects, ranolazine has been shown to reduce HbA1c levels in patients with type 2 diabetes mellitus and coronary artery disease; however, the mechanism behind its antidiabetic effect has been unclear. We tested the hypothesis that ranolazine exerts its antidiabetic effects by inhibiting glucagon release via blockade of NaChs in the pancreatic alpha-cells. Our data show that ranolazine, via blockade of NaChs in pancreatic alpha-cells, inhibits their electrical activity and reduces glucagon release. We found that glucagon release in human pancreatic islets is mediated by the Nav1.3 isoform. In animal models of diabetes, ranolazine and a more selective NaCh blocker (GS-458967) lowered postprandial and basal glucagon levels, which were associated with a reduction in hyperglycemia, confirming that glucose-lowering effects of ranolazine are due to the blockade of NaChs. This mechanism of action is unique in that no other approved antidiabetic drugs act via this mechanism, and raises the prospect that selective Nav1.3 blockers may constitute a novel approach for the treatment of diabetes. PMID- 24812430 TI - Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. AB - Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease. PMID- 24812429 TI - ZnT8-reactive T cells are weakly pathogenic in NOD mice but can participate in diabetes under inflammatory conditions. AB - Autoantibodies to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identified in patients with type 1 diabetes. Here we examined for CD4 T-cell reactivity to ZnT8 epitopes in the NOD mouse. Immunization with a cytoplasmic domain of the protein or with peptides predicted to bind to I-A(g7) resulted in a CD4 T-cell response, indicating a lack of deletional tolerance. However, presentation by intraislet antigen-presenting cells (APC) to the T cells was not detectable in prediabetic mice. Presentation by islet APC was found only in islets of mice with active diabetes. In accordance, a culture assay indicated the weak transfer of ZnT8 reactivity from insulinomas or primary beta-cells to APC for presentation to T cells. A T cell directed to one peptide (345-359) resulted in the transfer of diabetes, but only in conditions in which the recipient NOD mice or NOD.Rag1(-/-) mice were subjected to light irradiation. In late diabetic NOD mice, CD4 T cells were found as well as a weak antibody response. We conclude that in NOD mice, ZnT8 is a minor diabetogenic antigen that can participate in diabetes in conditions in which the islet is first made receptive to immunological insults. PMID- 24812431 TI - IKKepsilon is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity. AB - IKK epsilon (IKKepsilon) is induced by the activation of nuclear factor-kappaB (NF-kappaB). Whole-body IKKepsilon knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKepsilon is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKepsilon in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-kappaB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKepsilon activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKepsilon may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism. PMID- 24812432 TI - Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to target trial. AB - OBJECTIVE: Insulin degludec/insulin aspart (IDegAsp) is the first combination of a basal insulin with an ultralong duration of action, and a rapid-acting insulin in a single injection. This trial compared IDegAsp with biphasic insulin aspart 30 (BIAsp 30) in adults with type 2 diabetes inadequately controlled with once- or twice-daily (OD or BID) pre- or self-mixed insulin with or without oral antidiabetic drugs. RESEARCH DESIGN AND METHODS: In this 26-week, randomized, open-label, multinational, treat-to-target trial, participants (mean age 58.7 years, duration of diabetes 13 years, BMI 29.3 kg/m(2), and HbA1c 8.4% [68 mmol/mol]) were exposed (1:1) to BID injections of IDegAsp (n = 224) or BIAsp 30 (n = 222), administered with breakfast and the main evening meal and dose titrated to a self-measured premeal plasma glucose (PG) target of 4.0-5.0 mmol/L. RESULTS: After 26 weeks, mean HbA1c was 7.1% (54 mmol/mol) for both groups, with IDegAsp achieving the prespecified noninferiority margin for mean change in HbA1c (estimated treatment difference [ETD] -0.03% points [95% CI -0.18 to 0.13]). Treatment with IDegAsp was superior in lowering fasting PG (ETD -1.14 mmol/L [95% CI -1.53 to -0.76], P < 0.001) and had a significantly lower final mean daily insulin dose (estimated rate ratio 0.89 [95% CI 0.83-0.96], P = 0.002). Fewer confirmed, nocturnal confirmed, and severe hypoglycemia episodes were reported for IDegAsp compared with BIAsp 30. CONCLUSIONS: IDegAsp BID effectively improves HbA1c and fasting PG levels with fewer hypoglycemia episodes versus BIAsp 30 in patients with uncontrolled type 2 diabetes previously treated with once- or twice daily pre- or self-mixed insulin. PMID- 24812433 TI - beta-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. AB - OBJECTIVE: This article examines the foundation of beta-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS: A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS: The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of beta-cell failure, natural history of beta-cell failure, and impact of therapeutic interventions. CONCLUSIONS: beta-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased beta-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to (1) impact the natural history of beta-cell failure; (2) identify and characterize genetic loci for T2D; (3) target beta-cell signaling, metabolic, and genetic pathways to improve function/mass; (4) develop alternative sources of beta-cells for cell-based therapy; (5) focus on metabolic environment to provide indirect benefit to beta-cells; (6) improve understanding of the physiology of responses to bypass surgery; and (7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and beta-cells. PMID- 24812434 TI - Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. AB - OBJECTIVE: There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS: ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3 24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS: Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05-2.55) and 3.31 (1.57-6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65 4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS: Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes. PMID- 24812435 TI - The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia. AB - Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis - a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA. PMID- 24812436 TI - Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease. AB - A point mutation in the Drosophila gene that codes for the major adult isoform of adenine nuclear translocase (ANT) represents a model for human diseases that are associated with ANT insufficiency [stress-sensitive B(1) (sesB(1))]. We characterized the organismal, bioenergetic and molecular phenotype of sesB(1) flies then tested strategies to compensate the mutant phenotype. In addition to developmental delay and mechanical-stress-induced seizures, sesB(1) flies have an impaired response to sound, defective male courtship, female sterility and curtailed lifespan. These phenotypes, excluding the latter two, are shared with the mitoribosomal protein S12 mutant, tko(25t). Mitochondria from sesB(1) adults showed a decreased respiratory control ratio and downregulation of cytochrome oxidase. sesB(1) adults exhibited ATP depletion, lactate accumulation and changes in gene expression that were consistent with a metabolic shift towards glycolysis, characterized by activation of lactate dehydrogenase and anaplerotic pathways. Females also showed downregulation of many genes that are required for oogenesis, and their eggs, although fertilized, failed to develop to the larval stages. The sesB(1) phenotypes of developmental delay and mechanical-stress induced seizures were alleviated by an altered mitochondrial DNA background. Female sterility was substantially rescued by somatic expression of alternative oxidase (AOX) from the sea squirt Ciona intestinalis, whereas AOX did not alleviate developmental delay. Our findings illustrate the potential of different therapeutic strategies for ANT-linked diseases, based on alleviating metabolic stress. PMID- 24812438 TI - Friends as a Bridge to Parental Influence: Implications for Adolescent Alcohol Use. AB - The current study investigates the possibility that friendship networks connect adolescents to influence from a broader group of adults beyond their own families. In doing so, we combine two rich traditions of research on adult influence on children and adolescents. Family research has suggested a number of ways in which effective parenting can reduce deviant behavior among adolescents. In addition, research on neighborhoods has advanced the idea that adults outside of the immediate family can exert social control that may reduce deviance. We employ longitudinal social network analysis to examine data drawn from the PROSPER Peers Project, a longitudinal study of adolescents following over 12,000 students in 27 non-metropolitan communities as they moved from 6th through 9th grade. We find evidence that the behavior of friends' parents is linked, both directly and indirectly, to adolescent alcohol use. Findings suggest that much of the influence from friends' parents is mediated through peer behavior, but that parental knowledge reported by friends continues to be associated with alcohol use even when controlling for competing mechanisms. Furthermore, adolescents tend to choose friends who report similar levels of parenting as themselves. Our results provide support for the position that friendships in adolescence connect youth to a broader network of adults and illustrate how adults outside of the family contribute to the social control of adolescents. PMID- 24812437 TI - Zebrafish yolk lipid processing: a tractable tool for the study of vertebrate lipid transport and metabolism. AB - Dyslipidemias are a major cause of morbidity and mortality in the world, particularly in developed nations. Investigating lipid and lipoprotein metabolism in experimentally tractable animal models is a crucial step towards understanding and treating human dyslipidemias. The zebrafish, a well-established embryological model, is emerging as a notable system for studies of lipid metabolism. Here, we describe the value of the lecithotrophic, or yolk-metabolizing, stages of the zebrafish as a model for studying lipid metabolism and lipoprotein transport. We demonstrate methods to assay yolk lipid metabolism in embryonic and larval zebrafish. Injection of labeled fatty acids into the zebrafish yolk promotes efficient uptake into the circulation and rapid metabolism. Using a genetic model for abetalipoproteinemia, we show that the uptake of labeled fatty acids into the circulation is dependent on lipoprotein production. Furthermore, we examine the metabolic fate of exogenously delivered fatty acids by assaying their incorporation into complex lipids. Moreover, we demonstrate that this technique is amenable to genetic and pharmacologic studies. PMID- 24812439 TI - Fertility Transition: Is sub-Saharan Africa Different? PMID- 24812440 TI - Identification and quantification of flavonoids of Mexican oregano (Lippia graveolens) by LC-DAD-ESI/MS analysis. AB - LC-DAD-ESI/MS was used to identify 23 flavonoids in the extract of Mexican oregano (Lippia graveolens H.B.K.), a spice and herb, used in the USA and Mexico. The identification of luteolin-7-O-glucoside, apigenin 7-O-glucoside, phloridzin, taxifolin, eriodictyol, scutellarein, luteolin, quercetin, naringenin, pinocembrin and galangin was confirmed by direct comparison with standards. Identification of 6-hydroxyluteolin, two 6-hydroxyluteolin 7-O-glycosides, three pentahydroxyflavanone hexosides, scutellarein 7-O-hexoside, 3-hydroxyphloretin hexoside, and three other flavones, was made by detailed analysis of their UV and mass spectral data. The identification of the flavonoid glycosides was further confirmed through detection of their aglycones following hydrolysis of the samples. The concentration of the identified flavonoids in three samples was also estimated. This is the first report of detection of over 20 flavonoids, including chalcones, in this plant material. PMID- 24812441 TI - Psychopaths and blame: The argument from content. AB - The recent debate over the moral responsibility of psychopaths has centered on whether, or in what sense, they understand moral requirements. In this paper, I argue that even if they do understand what morality requires, the content of their actions is not of the right kind to justify full-blown blame. I advance two independent justifications of this claim. First, I argue that if the psychopath comes to know what morality requires via a route that does not involve a proper appreciation of what it means to cause another harm or distress, the content of violations of rules against harm will be of a lower grade than the content of similar actions by normal individuals. Second, I argue that in order to intend a harm to a person-that is, to intend the distinctive kind of harm that can only befall a person-it is necessary to understand what personhood is and what makes it valuable. The psychopath's deficits with regard to mental time travel ensure that s/he cannot intend this kind of harm. PMID- 24812442 TI - Major histocompatibility complex I mediates immunological tolerance of the trophoblast during pregnancy and may mediate rejection during parturition. AB - During pregnancy in larger mammals, the maternal immune system must tolerate the fetus for months while resisting external infection. This tolerance is facilitated by immunological communication between the fetus and the mother, which is mediated by Major Histocompatibility Complex I (MHC I) proteins, by leukocytes, and by the cytokines secreted by the leukocytes. Fetal-maternal immunological communication also supports pregnancy by inducing physiological changes in the mother. If the mother "misunderstands" the signal sent by the fetus during pregnancy, the fetus will be miscarried or delivered preterm. Unlike any other maternal organ, the placenta can express paternal antigens. At parturition, paternal antigens are known to be expressed in cows and may be expressed in horses, possibly so that the maternal immune system will reject the placenta and help to expel it. This review compares fetal-maternal crosstalk that is mediated by the immune system in three species with pregnancies that last for nine months or longer: humans, cattle, and horses. It raises the possibility that immunological communication early in pregnancy may prepare the mother for successful expulsion of fetal membranes at parturition. PMID- 24812444 TI - Estimating Gompertz Growth Curves from Marine Mammal Strandings in the Presence of Missing Data. AB - Stranded bottlenose dolphins (Tursiops truncatus) off the coast of South Carolina (SC) provide data essential for population health assessment. Of the 598 bottlenose dolphin strandings in SC from 1993 to 2007, 91 were of sufficient body condition to obtain organ weights. Of these 91 animals, only 52 were brought back to the laboratory for total body weight measurements. Because it is more feasible to transport smaller animals to the laboratory setting for necropsy procedures, a selection bias is present in that data for larger animals are often missing. Regression and propensity score multiple imputation methods are utilized to account for missing data needed to compute growth. Fitted Gompertz growth curves for SC animals with and without adjustment for missing data are compared to those found from the northwestern Gulf of Mexico. South Carolina animals display a trend in lower asymptotic mean total body weights and faster growth rates compared to the Gulf of Mexico population. The differences generally increased in magnitude after imputation methods. South Carolina females were originally estimated to reach larger maximum sizes than Gulf of Mexico females, but after imputation this relationship reversed. The findings suggest selection bias should be accounted for in sampling stranded dolphins. PMID- 24812443 TI - Metabolic and genetic screening of electromagnetic hypersensitive subjects as a feasible tool for diagnostics and intervention. AB - Growing numbers of "electromagnetic hypersensitive" (EHS) people worldwide self report severely disabling, multiorgan, non-specific symptoms when exposed to low dose electromagnetic radiations, often associated with symptoms of multiple chemical sensitivity (MCS) and/or other environmental "sensitivity-related illnesses" (SRI). This cluster of chronic inflammatory disorders still lacks validated pathogenetic mechanism, diagnostic biomarkers, and management guidelines. We hypothesized that SRI, not being merely psychogenic, may share organic determinants of impaired detoxification of common physic-chemical stressors. Based on our previous MCS studies, we tested a panel of 12 metabolic blood redox-related parameters and of selected drug-metabolizing-enzyme gene polymorphisms, on 153 EHS, 147 MCS, and 132 control Italians, confirming MCS altered (P < 0.05-0.0001) glutathione-(GSH), GSH-peroxidase/S-transferase, and catalase erythrocyte activities. We first described comparable-though milder metabolic pro-oxidant/proinflammatory alterations in EHS with distinctively increased plasma coenzyme-Q10 oxidation ratio. Severe depletion of erythrocyte membrane polyunsaturated fatty acids with increased omega 6/ omega 3 ratio was confirmed in MCS, but not in EHS. We also identified significantly (P = 0.003) altered distribution-versus-control of the CYP2C19*1/*2 SNP variants in EHS, and a 9.7-fold increased risk (OR: 95% C.I. = 1.3-74.5) of developing EHS for the haplotype (null)GSTT1 + (null)GSTM1 variants. Altogether, results on MCS and EHS strengthen our proposal to adopt this blood metabolic/genetic biomarkers' panel as suitable diagnostic tool for SRI. PMID- 24812448 TI - What's new in emergencies, trauma and shock? studying traffic related injuries in India. PMID- 24812449 TI - What's new in emergencies, trauma and shock? Studying the injury patterns in Nigeria. PMID- 24812450 TI - Injuries associated with cycle rickshaws accidents. AB - CONTEXT: Cycle rickshaw is an important means of transportation in Urban India. Pedestrians, rickshaw users, rickshaw pullers, two wheeled vehicle users and cyclists are among the most vulnerable road user groups in terms of injuries and fatalities resulting from road traffic accidents in India. Our objectives were to study characteristics of crashes and nature of injuries associated with cycle rickshaw. PATIENTS AND METHODS: Between August 2008 to July 2009, a hospital based observational study was done of patients who presented to King George medical college trauma center with injury sustained due to cycle rickshaw in emergency department. Age, time of trauma, mode of trauma, contributing factors and type of injury were recorded. RESULTS: The mean age of the patient was 32.1. Seventeen patients were rickshaw pullers and the rest were occupants of the rickshaw. Overloading with more than two passengers was found in 24 cases (28.5%). Most common cause of injury was collision with a moving vehicle (56 patients, %) followed by fall from rickshaw. The most common contributing factor was the overloading of rickshaw. On arrival to the hospital, the mean Injury severity score (ISS) was 3.5 +/- 2.2 and the mean Glasgow coma scale (GCS) was 13.4 +/- 4.3. Nine patients were admitted to ICU (Intensive care unit). The median ICU stay was 4 (1-24 days). Six of the ICU admitted patients had head injury. CONCLUSION: Rickshaw pullers and occupants are vulnerable to road traffic accidents. Urgent preventive measures targeted towards this group are needed to reduce the morbidity and mortality resulting from injuries involving rickshaws. The need for improved understanding of the risk characteristics of cycle rickshaw is emphasized. PMID- 24812451 TI - The epidemiology and type of injuries seen at the accident and emergency unit of a Nigerian referral center. AB - BACKGROUND: A plethora of injuries present at any accident and emergency unit, but the pattern of the injuries varies from region to region especially in ours with the increased ethno-religious clashes and terrorist attacks. This study aims to determine the epidemiology and type of injuries presenting to our center with the possibility of developing injury surveillance initiatives in our center and Nigeria as a whole. MATERIALS AND METHODS: Injured patients consecutively presenting to the accident and emergency department of the Jos University Teaching Hospital within the period February 2011 to January 2012 were prospectively recorded. RESULTS: A total of 720 injured patients admitted with an age range of 8 months to 75 years (mean = 37.9; SD = +/-52.4), which consists of 544 males and 176 females giving a male to female ratio of 3.1:1. Patients aged 20-29 years were in the majority (n = 220, 30.6%) with peak incidences in the period of communal clashes. Injuries sustained from motorcycles were the highest (n = 248, 34.4%). Others were 160 (22.2%) in other vehicular and pedestrian injuries, machete (n = 128), gunshots (n = 92), burns (n = 36), bomb blast injuries (n = 16), fall from heights (n = 32) and miscellaneous (n = 8). Injuries sustained in communal clashes and terrorist attacks accounted for 236 (32.8%) presentations. The most common site of injury was the head (n = 30 4, 42.2%). Relatives, passersby and law enforcement agencies brought patients to the hospital with times between injury and presentation ranging from 1 h to 3 weeks. 40 (5.6%) patients were brought in dead. CONCLUSION: A collective effort - on the part of the government and the citizenry is required to ensure better outcomes and a safer society for all. PMID- 24812452 TI - The use of furosemide in critically ill trauma patients: A retrospective review. AB - INTRODUCTION: Excessive fluid administration in critically ill post-traumatic patients is common and is associated with poorer outcomes. Once resuscitation is complete; however, assisted diuresis with furosemide is not an option commonly exercised. We hypothesize that diuresis with furosemide in hemodynamically stable, critically ill trauma patients is safe and effective in promoting diuresis. MATERIALS AND METHODS: In this retrospective chart review, all injured patients admitted to the trauma ICU between March 2007 and June 2009 were identified. Data collection included demographic data, traumatic mechanism, physiologic data, laboratory data, medications, complications, ventilator days, ICU and hospital length of stay. Statistical analyses using two-sample t tests, Wilcoxon rank sum tests, chi-square tests, paired t-tests, and one-sample signed rank tests were performed. RESULTS: Of 162 screened patients, 85 were identified as eligible. Twenty-seven patients (31.8%) received furosemide within the first 14 ICU days, and there were no significant differences in age, ISS, gender, blunt mechanism, co-morbid conditions, overall complications, or mortality when compared to patients who did not receive diuresis. Furosemide administration resulted in a median of 45% increased 24 h urine output and a median of 82% less 24 h net fluid gain without any significant change in HR, MAP, CVP, Hct, creatinine, or potassium. CONCLUSIONS: Administration of furosemide in stable, significantly fluid positive critically ill trauma patients results in significantly increased urine output and significantly less net fluid gain with no detrimental effect on hemodynamic parameters or laboratory values. PMID- 24812453 TI - Blunt traumatic injury in the Arab Middle Eastern populations. AB - BACKGROUND: Trauma represents a global public health concern with an estimated 5 million deaths annually. Moreover, the incidence of blunt traumatic injuries (BTI) particularly road traffic accidents (RTAs) and workplace-related injuries are rising throughout the world-wide. OBJECTIVES: We aimed to review the epidemiology and prevention of BTI, in the Arab Middle East. MATERIALS AND METHODS: A traditional narrative literature review was carried out using PubMed, MEDLINE and EMBASE search engines. We used the keywords "traumatic injuries", "blunt" "epidemiology", "Arab Middle East" between December 1972 and March 2013. RESULTS: The most common mechanisms of BTI in our region are RTAs, falls from height, struck by heavy objects and pedestrian motor vehicle trauma crashes. The rate of RTA and occupational injuries are markedly increased in the region due to rapid industrial development, extreme climatic conditions and unfamiliar working environment. However, lack of reliable information on these unintentional injuries is mainly responsible for the underestimation of this trauma burden. This knowledge deficit shields the extent of the problem from policy makers, leading to continued fatalities. These preventable injuries in turn add to the overall financial burden on the society through loss of productivity and greater need of medical and welfare services. CONCLUSION: In the Arab Middle East, population-based studies on the incidence, mechanism of injury, prevention and outcome of BTI are not well-documented. Therefore, region-specific BTI studies would strengthen surveillance to better understand the burden of these injuries in the region. PMID- 24812454 TI - A systematic examination of the bone destruction pattern of the two-shot technique. AB - INTRODUCTION: The two-shot technique is an effective stopping power method. The precise mechanisms of action on the bone and soft-tissue structures of the skull; however, remain largely unclear. The aim of this study is to compare the terminal ballistics of the two-shot and single-shot techniques. MATERIALS AND METHODS: 40 fresh pigs' heads were randomly divided into 4 groups (n = 10). Either a single shot or two shots were fired at each head with a full metal jacket or a semi jacketed bullet. Using thin-layer computed tomography and photography, the diameter of the destruction pattern and the fractures along the bullet path were then imaged and assessed. RESULTS: A single shot fired with a full metal jacket bullet causes minor lateral destruction along the bullet path. With two shots fired with a full metal jacket bullet, however, the maximum diameter of the bullet path is significantly greater (P < 0.05) than it is with a single shot fired with a full metal jacket bullet. In contrast, the maximum diameter with a semi-jacketed bullet is similar with the single-shot and two-shot techniques. CONCLUSION: With the two-shot technique, a full metal jacket bullet causes a destruction pattern that is comparable to that of a single shot fired with a semi jacketed bullet. PMID- 24812456 TI - Is there a correlation of sonographic measurements of true vocal cords with gender or body mass indices in normal healthy volunteers? AB - BACKGROUND: Ultrasound is a readily available, non-invasive technique to visualize airway dimensions at the patient's bedside and possibly predict difficult airways before invasively looking; however, it has rarely been used for emergency investigation of the larynx. There is limited literature on the sonographic measurements of true vocal cords in adults and normal parameters must be established before abnormal parameters can be accurately identified. OBJECTIVES: The primary objective of the following study is to identify the normal sonographic values of human true vocal cords in an adult population. A secondary objective is to determine if there is a difference in true vocal cord measurements in people with different body mass indices (BMIs). The third objective was to determine if there was a statistical difference in the measurements for both genders. MATERIALS AND METHODS: True vocal cord measurements were obtained in healthy volunteers by ultrasound fellowship trained emergency medicine physicians using a high frequency linear transducer orientated transversely across the anterior surface of the neck at the level of the thyroid cartilage. The width of the true vocal cord was measured perpendicularly to the length of the cord at its mid-portion. This method was duplicated from a previous study to create a standard of measurement acquisition. RESULTS: A total of 38 subjects were enrolled. The study demonstrated no correlation between vocal cord measurements and patient's characteristics of height, weight, or BMI's. When accounting for vocal cord measurements by gender, males had larger BMI's and larger vocal cord measurements compared with females subjects with a statistically significant different in right vocal cord measurements for females compared with male subjects. CONCLUSION: No correlation was seen between vocal cord measurements and person's BMIs. In the study group of normal volunteers, there was a difference in size between the male and female vocal cord size. PMID- 24812457 TI - An epidemiological study on pattern of thoraco-abdominal injuries sustained in fatal road traffic accidents of Bangalore: Autopsy-based study. AB - BACKGROUND: The statistical profile reflects a global estimate of 5.1 million deaths in 2000, which was due to injuries that accounted for 10% of deaths due to all causes. Out of this, a quarter of injury-related deaths occurred in the South East Asian region. Road Traffic Accident (RTA) is one among the top 5 causes of morbidity and mortality in South-East Asian countries. Most common cause of blunt abdominal trauma in India is road traffic accident followed by pedestrian accidents, abdominal blows, and fall from heights. AIMS: To analyze the epidemiology and pattern of fatal thoraco-abdominal injuries in road traffic accidents. MATERIALS AND METHODS: An autopsy-based cross-sectional study conducted. A purposive sampling technique was applied to select the study sample of 100 post-mortems of road traffic accident between November 2008 and May 2010 subjected to medico-legal autopsy at the department of Forensic Medicine, KIMS Hospital Bangalore. RESULTS: The majority of the victims were aged 21 to 40 years, 50 (50.0%), most of the victims were male 92 (92.0%); and male/female ratio was 11.5:1. Commonest offending agents in heavy motor vehicles were 54 (54.0%). Bony cage sustained injuries were observed in 71; out of this, fractures of ribs were observed in 45 (63.3%) victims, clavicle in 14 (19.7%), sternum was 6 (8.4%), and vertebrae 6 (8.4%) of fatal road traffic accidents. Internal thoracic injuries were observed in 26 cases. Among internal thoracic injuries, lungs were the most commonly involved organ 24 (92.3%) followed by the heart 2 (7.6%). Lung sustained more lacerations 19 (79.1%) than contusions 5 (20.8%). Internal abdominal injuries were observed in 49 cases. In road traffic accidents, the most commonly injured abdominal organs were solid organs such as liver 16 (32.6%) followed by spleen 9 (18.3%). CONCLUSIONS: Majority of the times in road traffic accidents, young and productive males were injured or lost their life. This study may help the planners to take safety measures, to implement strict traffic rules, to risk stratification in the susceptible population to educate the people, and the study of nature of offending agent in RTA can help the authorities to plan better availability of health care on roads. PMID- 24812455 TI - Use of recombinant factor VIIa (rFVIIa) as pre-hospital treatment in a swine model of fluid percussion traumatic brain injury. AB - CONTEXT: Recombinant factor VIIa (rFVIIa) has been used as an adjunctive therapy for acute post-traumatic hemorrhage and reversal of iatrogenic coagulopathy in trauma patients in the hospital setting. However, investigations regarding its potential use in pre-hospital management of traumatic brain injury (TBI) have not been conducted extensively. AIMS: In the present study, we investigated the physiology, hematology and histology effects of a single pre-hospital bolus injection of rFVIIa compared to current clinical practice of no pre-hospital intervention in a swine model of moderate fluid percussion TBI. MATERIALS AND METHODS: Animals were randomized to receive either a bolus of rFVIIa (90 MUg/kg) or nothing 15 minutes (T15) post-injury. Hospital arrival was simulated at T60, and animals were euthanized at experimental endpoint (T360). RESULTS: Survival was 100% in both groups; baseline physiology parameters were similar, vital signs were comparable. Animals that received rFVIIa demonstrated less hemorrhage in subarachnoid space (P = 0.0037) and less neuronal degeneration in left hippocampus, pons, and cerebellum (P = 0.00009, P = 0.00008, and P = 0.251, respectively). Immunohistochemical staining of brain sections showed less overall loss of microtubule-associated protein 2 (MAP2) and less Flouro-Jade B positive cells in rFVIIa-treated animals. CONCLUSIONS: Early pre-hospital administration of rFVIIa in this swine TBI model reduced neuronal necrosis and intracranial hemorrhage (ICH). These results merit further investigation of this approach in pre-hospital trauma care. PMID- 24812458 TI - An introduction of Tertiary Peritonitis. AB - Intraperitoneal infection known as peritonitis is a major killer in the practice of clinical surgery. Tertiary peritonitis (TP) may be defined as intra-abdominal infection that persists or recurs 348 h following successful and adequate surgical source control. A planned or on-demand relaparotomy after an initial operation is probably most frequent way to diagnose TP, but is a late event to occur. Hence it is desirable to have timely and nonoperative diagnosis of TP after the initial operation and subsequent initiation of an appropriate therapy to reduce the complications and to improve the outcome. PMID- 24812459 TI - Parkinsonism as late sequela of organophosphate intoxication. AB - Delayed morphologic and metabolic change of organophosphate intoxication is rarely reported than those of acute episode. The patient was a 52-year-old woman who had a history of acute organophosphate intoxication, which paralyzed her for one week when she was 25 years old. She recovered slowly to near normal after one year. After 22 years of the acute episode, tremor developed in 2007 followed by bradykinesia, rigidity, and postural instabilities. Brain MRI showed linear atrophy in bilateral striatal area and multiple cysts in anterior caudate nucleus. F-18 fluorodeoxyglucose positron emission tomography revealed multiple hypometabolic areas in bilateral striatum, cerebellar hemisphere, and occipital area. PMID- 24812460 TI - Indian common krait envenomation presenting as coma and hypertension: A case report and literature review. AB - Neuroparalytic snake bite is a common emergency situation encountered in India. Common krait (Bungarus caeruleus) and cobra (Naja naja) are important snakes causing neuroparalysis in North India. Despite severe neuroparalysis, patients who receive antivenin and ventilator support in time recover completely. Autonomic disturbances resulting in resting tachycardia, labile hypertension and sweating have been described in common krait envenomation. We present a case of common krait (B. caeruleus) envenomation presenting in the locked-in state and severe hypertension that remained in such a state for over 96 h before a gradual and sustained recovery. PMID- 24812461 TI - Images in medicine: Spontaneous aortocaval fistula complicating abdominal aortic aneurysm. AB - Aortocaval fistula represents a rare, life-threatening complication of abdominal aortic aneurysm that needs emergency surgical treatment. The presentation couples that of a rupturing aneurysm with other more characteristic features resulting from the massive arteriovenous shunt. Early recognition and emergency surgical treatment are essential in reducing mortality and morbidity. Prompt investigation with multidetector computed tomography (CT) angiography quickly and accurately establishes a precise preoperative diagnosis, thereby enabling proper planning of operative treatment. PMID- 24812462 TI - Myocardial infarction in organophosphorus poisoning: Association or just chance? PMID- 24812463 TI - Cervical spinal cord injury without bone injuries in an alcohol-intoxicated patient with atlantoaxial osteoarthritis. PMID- 24812464 TI - Frequent emergency department visits and parents/guardians' level of awareness of asthma in the pediatric population. PMID- 24812465 TI - Fishing with Magill forceps. PMID- 24812466 TI - Other than a few cracked ribs: An interesting case of post-cardio pulmonary resuscitation complication. PMID- 24812467 TI - Fibrotic stenosis of the third duodenum complicating a post-traumatic pancreatitis, about a rare case. PMID- 24812468 TI - Salutary path for progress. PMID- 24812470 TI - Anticandidal efficacy of denture cleansing tablet, Triphala, Aloe vera, and Cashew leaf on complete dentures of institutionalized elderly. AB - With an increase in the number of dependent elderly, there is a need to introduce few natural products for denture cleansing, which are easily and economically available. Hence the aim of this study was to compare the anticandidal efficacy of denture cleansing tablet (sodium bicarbonate and sodium perborate monohydrate), Triphala (Phyllanthus emblica, Terminalia chebula and Terminalia belerica fruits powders in equal proportion), cashew leaf, Aloe vera and water (control) on complete dentures of institutionalized elderly. Study population consisted of 50 institutionalized elderly of Mangalore, Karnataka, with 10 in each group. Swabs were collected from the dentures before and after the use of denture cleansing tablet, Triphala, cashew leaf, Aloe vera, and water (control). Thereafter, the swabs were cultured on Sabouraud dextrose agar and the total candida counts were determined. Denture cleansing tablet and Triphala Churna showed a statistically significant reduction in Candida counts (P < 0.05). Denture cleansing tablet and Triphala Churna were found to be more effective. PMID- 24812469 TI - Insights from Ayurveda for translational stem cell research. AB - Ayurveda, the traditional Indian system of medicine has given great emphasis to the promotion of health. Ayurveda therapies are based on restoration of body balance and nourishment of dhatus or tissues. Rasayana concept of Ayurveda explains tissue regeneration and cell renewal. The drugs and therapies explained as rasayana provide research opportunities for biology of regeneration. Specific rasayana stimulate and nourish respective dhatus. Interpretation of this description offers clues for specific differentiation of stem cells with appropriate extract. The preliminary experiments on Medhya drugs suggest neuronal stem cells differentiation. Authors highlight the potential of Ayurveda and its possible contributions in regenerative medicine. Authors propose a protocol based on integrative approach derived from Ayurveda concepts and current understanding of regenerative medicine. The advanced understanding about adult and embryonic stem cells along with concepts of regeneration in Ayurveda has immense potential in the development of regenerative medicine. PMID- 24812471 TI - Prakriti and its associations with metabolism, chronic diseases, and genotypes: Possibilities of new born screening and a lifetime of personalized prevention. AB - Ayurveda is one of the oldest health sciences of the world with concepts of tridosha and prakriti being core philosophies. These core concepts allow implementation of ways for not only personalized medicine and treatment but also personalized prevention. In the light of modern or current science, evidence has surfaced connecting the concepts of tridosha and prakriti with metabolic pathways, chronic diseases, and various genotypes. Such evidence has thrown up insights about the universality of Ayurvedic concepts as well as their apparent association with concepts in current science. This review was undertaken to consolidate the evidence of such associations which exist between prakriti and metabolic systems, chronic diseases, and genotypes with the objective that a case can be made for drawing out the clear linkages that might exist for prakritis being distinct phenotypes representing certain genotypes. A corollary to such discoveries can be the possibility of newborns being screened for their prakriti by genetic testing, which will enable the prevention of various chronic diseases for such children via the implementation of various dietary, lifestyle, and habitual changes, as required, from an early age. This implementation of preventive practices from an early age may result in such children leading healthy, disease-free, more productive lives. Thus, eventually, this can be an opportunity to practice personalized preventive health, which is not a possibility in other systems of medicine especially western systems of medicine. Personalized preventive health is one step further than personalized medicine and is a very novel idea with far-reaching implications. PMID- 24812472 TI - Protective effect of Cissus quadrangularis Linn. on diabetes induced delayed fetal skeletal ossification. AB - BACKGROUND: Delayed fetal skeletal ossification is one of the known complications of maternal diabetes. OBJECTIVE: The present study was designed to evaluate the protective role of petroleum ether extract of Cissus quadrangularis (PECQ) on diabetes-induced delayed fetal skeletal ossification. MATERIALS AND METHODS: Female Wistar rats were rendered diabetic with streptozotocin (STZ, 40 mg/kg, intraperitonial) before mating. After confirmation of pregnancy, the pregnant rats were divided into three groups: normal control group, diabetic control group, and diabetic + CQ group. The diabetic + CQ group pregnant rats were treated with PECQ (500 mg/kg body weight) throughout their gestation period. Immediately after delivery, pups were collected from all three groups and processed for alizarin red S-alcian blue staining in order to examine the pattern of skeletal ossification. RESULTS: Fewer ossification centers and decreased extent of ossification of forelimb and hindlimb bones were observed in the neonatal pups of diabetic control group as compared to those in the normal control group. PECQ pretreatment significantly restored the ossification centers and improved the extent of ossification of forelimb and hindlimb bones in the neonatal pups of diabetic + CQ group as compared to those in the diabetic control group. CONCLUSIONS: The results suggested that PECQ treatment is effective against diabetes-induced delayed fetal skeletal ossification. However, further studies on the isolation and characterization of active constituents of PECQ, which can cross the placental barrier and are responsible for the bone anabolic activity are warranted. PMID- 24812473 TI - Activity of Plumbago zeylanica Linn. root and Holoptelea integrifolia Roxb. bark pastes in acute and chronic paw inflammation in Wistar rat. AB - BACKGROUND: The pastes prepared from roots of Plumbago zeylanica Linn. and barks of Holoptelea integrifolia Roxb. are widely used by traditional healers for the treatment of arthritis in rural northern Karnataka. OBJECTIVE: The present study was undertaken to scientifically evaluate the safety and efficacy of traditionally used formulations in experimental animals. MATERIALS AND METHODS: The study, approved by IAEC was carried out in male Wistar rats and dermal toxicity in rabbits. Carrageenan model was used to assess effect on acute inflammation. Paw volume were measured at 1, 2, 4, and 6(th) hour postchallenge. Chronic inflammation was developed by using Complete Freund's Adjuvant (CFA). Paw volume, ankle joint circumference, and body weight were assessed on 1(st), 4(th), 8(th), 14(th), 17(th), and 21(st) day. Paste was applied once every day to the inflamed area of the paw of respective groups of animals, continuously for 14 days. STATISTICS: The data were analyzed by one way analysis of variance followed by Dunnett's post hoc test. P <= 0.05 was considered as significant. RESULTS: The formulations did not show any dermal toxicity and found to be safe. Both the pastes significantly (P < 0.05) suppressed, carrageenan-induced paw edema at 6(th) hour and Holoptelea integrifolia appears to be more effective than Plumbago zeylanica. Significant reduction was observed in paw volume, ankle joint circumference and animal body weight gained. CONCLUSIONS: The tested formulations (P. zeylanica root and H. integrifolia bark pastes) showed significant antiinflammatory activity. The present findings therefore support its utility in arthritic pain, inflammation and the claim of traditional practitioners. PMID- 24812474 TI - Gastroprotective effect of Piper betle Linn. leaves grown in Sri Lanka. AB - BACKGROUND: Piper betle Linn. (Piperaceae) is used as a remedy for gastric ulcers in traditional medicinal systems in Sri Lanka. However, the gastroprotective activity has never been proven scientifically using betel leaves grown in Sri Lanka. OBJECTIVE: To evaluate the gastroprotective activity of hot aqueous extract (HAE) and cold ethanolic extract (CEE) of P. betle in rats as the experimental model. MATERIALS AND METHODS: Three doses (200, 300, and 500 mg/kg/bw) of both extracts were evaluated for the gastroprotective activity against ethanol induced gastric ulcers in rats. The parameters evaluated were (a) effects of HAE on mucus content adhering to the wall of the gastric mucosa, (b) acidity (total and free), (c) volume and (d) pH of the gastric juice. RESULTS: ORAL ADMINISTRATION OF HAE AND CEE PROVIDED MARKED DOSE DEPENDENT (HAE: r (2) = 0.97; CEE: r (2) = 0.96) and significant (P <= 0.05) protection against gastric damage caused by absolute ethanol. The gastroprotective effect of CEE was comparable with that of HAE. Further, gastroprotective activity of the highest dose of both extracts were significantly greater (P <= 0.05) than that of misoprostol, the reference drug. The HAE significantly (P <= 0.05) increased the mucus content adhering to the wall of the gastric mucosa and inhibited the volume of gastric acid. However, acidity (total and free) and pH of the gastric juice remained unaltered. CONCLUSION: It is concluded that both HAE and CEE of P. betle leaves have a strong gastroprotective activity. PMID- 24812475 TI - Immunophenotyping of normal individuals classified on the basis of human dosha prakriti. AB - BACKGROUND: Human variations related to immune response and disease susceptibility is well-documented in Ayurveda. Prakriti (body constitution) is the basic constitution of an individual established at the time of birth and distinguishes variations, into three broad phenotype categories such as vata, pitta and kapha. Variation in immune response is often attributed to and measured from the difference in cluster differentiation (CD) markers expressed in lymphocytes. Currently, there are no reports available on the expression of CD markers related to prakriti. OBJECTIVE: This is a pilot study performed to evaluate a panel of lymphocyte subset CD markers in dominant prakriti individuals. MATERIALS AND METHODS: Immunophenotyping was carried out using whole blood from a total of healthy 222 subjects, who are grouped into kapha (n = 95), pitta (n = 57) and vata (n = 70) prakritis. CD markers such as CD3, CD4, CD8, CD14, CD25, CD56, CD69, CD71 and HLA-DR were analyzed using flow cytometry method. Differences between groups were analyzed using one-way ANOVA or Kruskal Wallis analysis of variance (ANOVA) and multiple comparisons between groups were performed by Bonferroni or Mann-Whitney U test with corrections for type I error respectively. Significance was evaluated by ANOVA and Pearson's correlation. RESULTS: We observed a significant difference (P < 0.05) in the expression of CD markers such as CD14 (monocytes), CD25 (activated B cells) and CD56 (Natural killer cells) between different prakriti groups. CD25 and CD56 expression was significantly higher in kapha prakriti samples than other prakriti groups. Similarly, slightly higher levels of CD14 were observed in pitta prakriti samples. CONCLUSION: Significant difference in the expression of CD14, CD25 and CD56 markers between three different prakriti is demonstrated. The increased level of CD25 and CD56 in kapha prakriti may indicate ability to elicit better immune response, which is in conformity with textual references in Ayurveda. PMID- 24812476 TI - The short-term effect of gloving in combination with Traditional Thai Massage, heat, and stretching exercise to improve hand mobility in scleroderma patients. AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disorder characterized by autoimmune activation, microvascular endothelium damage, and excessive collagen proliferation. The most affected hand presents claw hand deformity and microvascular disease. Deformed hands can cause functional disability and decrease the quality of life. A daily home program can improve mobility of scleroderma patients. OBJECTIVE: We sought to determine the effect of a daily home exercise program on hand mobility among scleroderma patients. MATERIALS AND METHODS: This was a randomized control trial. Twenty eight participants were divided into two groups, both of which received the same daily home treatment: Group 1 with gloves (n = 14) and Group 2 without gloves (n = 14). The 2-week daily home program combined traditional Thai massage (TTM) with stretching exercises and heat. Hand mobility was assessed using hand mobility in scleroderma (HAMIS). The study was conducted in patients who were already on vasodilator drugs. RESULTS: Both groups showed a significant improvement in hand mobility after 2 weeks of daily home exercise program (P < 0.05). Wearing the glove, however, resulted in better thumb mobility. CONCLUSIONS: A daily home exercise program improved hand mobility among patients with scleroderma and wearing gloves may improve thumb mobility. PMID- 24812477 TI - Rehabilitative potential of Ayurveda for neurological deficits caused by traumatic spinal cord injury. AB - Spinal cord injury (SCI) is associated with worst outcomes and requires a prolonged rehabilitation. Ayurvedic indigenous methods of rehabilitation are often utilized to treat such conditions. A case of SCI was followed up for 3 months upon an Ayurvedic composite intervention and subsequently reported. The composite treatment plan involved Ayurvedic oral medications as well as a few selected external and internal pancha karma procedures. A substantial clinical and patient centered outcome improvement in existing neurological deficits and quality of life was observed after 3 months of the Ayurvedic treatment given to this case. PMID- 24812478 TI - Katupila (Securinega leucopyrus) as a potential option for diabetic wound management. AB - In acute and chronic wounds, Katupila (Securinega leucopyrus) (Willd.) Muell is a commonly used folklore remedy in Sri Lanka and Saurashtra region of India. We report a case of Madhumehajanya Dushta Vrana (chronic diabetic wound) that was treated with local application of S. leucopyrus in paste form once daily. Wound healed within a month with normal pigmentation and minimal scar. This case also demonstrated possible antimicrobial potential in the treatment of Dushta Vrana. PMID- 24812479 TI - Determinants of symptomatic vulvovaginal candidiasis among human immunodeficiency virus type 1 infected women in rural KwaZulu-Natal, South Africa. AB - INTRODUCTION: We sought to determine the association between HIV-induced immunosuppression, virologic correlates, and vulvovaginal candidiasis (VVC). METHODS: This is a retrospective cohort study, where HIV infected and uninfected women were studied with VVC being the primary outcome. Ninety-seven HIV-infected and 101 HIV-uninfected women were enrolled between June and December 2011. Cases of VVC were confirmed. HIV RNA load was determined by RT-PCR and CD4 counts were obtained from medical records. RESULTS: Fifty-two of 97 (53.6%) HIV-infected and 38/101 (37.6%) HIV-uninfected women were diagnosed with VVC (P = 0.032). The relative risk for VVC amongst HIV-infected patients was 1.53 (95% CI: 1.04-2 P = 0.024). Cases of VVC increased at CD4+ T cell count below 200 cells/mm(3) (P < 0.0001) and plasma HIV RNA load above 10 000 copies/mL (P < 0.0001). VVC was associated with increased genital shedding of HIV (P = 0.002), and there was a linear correlation between plasma HIV load and genital HIV shedding (r = 0.540; R (2) = 0.292; P < 0.0001). Women on HAART were 4-fold less likely (P = 0.029) to develop VVC. CONCLUSION: CD4 counts below 200 cells/mm(3) and plasma HIV loads >=10 000 copies/mL were significantly associated with VVC. PMID- 24812480 TI - A multistep screening method to identify genes using evolutionary transcriptome of plants. AB - We introduced a multistep screening method to identify the genes in plants using microarrays and ribonucleic acid (RNA)-seq transcriptome data. Our method describes the process for identifying genes using the salt-tolerance response pathways of the potato (Solanum tuberosum) plant. Gene expression was analyzed using microarrays and RNA-seq experiments that examined three potato lines (high, intermediate, and low salt tolerance) under conditions of salt stress. We screened the orthologous genes and pathway genes involved in salinity-related biosynthetic pathways, and identified nine potato genes that were candidates for salinity-tolerance pathways. The nine genes were selected to characterize their phylogenetic reconstruction with homologous genes of Arabidopsis thaliana, and a Circos diagram was generated to understand the relationships among the selected genes. The involvement of the selected genes in salt-tolerance pathways was verified by reverse transcription polymerase chain reaction analysis. One candidate potato gene was selected for physiological validation by generating dehydration-responsive element-binding 1 (DREB1)-overexpressing transgenic potato plants. The DREB1 overexpression lines exhibited increased salt tolerance and plant growth when compared to that of the control. Although the nine genes identified by our multistep screening method require further characterization and validation, this study demonstrates the power of our screening strategy after the initial identification of genes using microarrays and RNA-seq experiments. PMID- 24812481 TI - The Range of Uncertainty: a Tool for Efficiently Addressing Result Variability Around Clinical Decision Points for Hepatitis C Response-guided Therapy. AB - Despite efforts to standardize molecular diagnostic tests, performance differences are not rare. Laboratories are challenged in situations where treatment rules have been established using a reference assay that is different from the assays being used in daily practice. Assessing the viral load status of patients with chronic hepatitis C under modern triple therapy is a recognized example. We demonstrate the use of the range of uncertainty as an easy and efficient tool that can provide information on the certainty of a test result's interpretation in the context of making hepatitis C virus treatment decisions. PMID- 24812482 TI - Prognostic value of DNA and mRNA e6/e7 of human papillomavirus in the evolution of cervical intraepithelial neoplasia grade 2. AB - OBJECTIVE: This study aimed at evaluating whether human papillomavirus (HPV) groups and E6/E7 mRNA of HPV 16, 18, 31, 33, and 45 are prognostic of cervical intraepithelial neoplasia (CIN) 2 outcome in women with a cervical smear showing a low-grade squamous intraepithelial lesion (LSIL). METHODS: This cohort study included women with biopsy-confirmed CIN 2 who were followed up for 12 months, with cervical smear and colposcopy performed every three months. RESULTS: Women with a negative or low-risk HPV status showed 100% CIN 2 regression. The CIN 2 regression rates at the 12-month follow-up were 69.4% for women with alpha-9 HPV versus 91.7% for other HPV species or HPV-negative status (P < 0.05). For women with HPV 16, the CIN 2 regression rate at the 12-month follow-up was 61.4% versus 89.5% for other HPV types or HPV-negative status (P < 0.05). The CIN 2 regression rate was 68.3% for women who tested positive for HPV E6/E7 mRNA versus 82.0% for the negative results, but this difference was not statistically significant. CONCLUSIONS: The expectant management for women with biopsy-confirmed CIN 2 and previous cytological tests showing LSIL exhibited a very high rate of spontaneous regression. HPV 16 is associated with a higher CIN 2 progression rate than other HPV infections. HPV E6/E7 mRNA is not a prognostic marker of the CIN 2 clinical outcome, although this analysis cannot be considered conclusive. Given the small sample size, this study could be considered a pilot for future larger studies on the role of predictive markers of CIN 2 evolution. PMID- 24812483 TI - Application of Nanofiber-packed SPE for Determination of Urinary 1-Hydroxypyrene Level Using HPLC. AB - It is always desirable to achieve maximum sample clean-up, extraction, and pre concentration with the minimum possible organic solvent. The miniaturization of sample preparation devices was successfully demonstrated by packing 10 mg of 11 electrospun polymer nanofibers into pipette tip micro column and mini disc cartridges for efficient pre-concentration of 1-hydroxypyrene in urine samples. 1 hydroxypyrene is an extensively studied biomarker of the largest class of chemical carcinogens. Excretory 1-hydroxypyrene was monitored with HPLC/fluorescence detector. Important parameters influencing the percentage recovery such as fiber diameter, fiber packing amount, eluent, fiber packing format, eluent volume, surface area, porosity, and breakthrough parameters were thoroughly studied and optimized. Under optimized condition, there was a near perfect linearity of response in the range of 1-1000 MUg/L with a coefficient of determination (r (2)) between 0.9992 and 0.9999 and precision (% RSD) <=7.64% (n = 6) for all the analysis (10, 25, and 50 MUg/L). The Limit of detection (LOD) was between 0.022 and 0.15 MUg/L. When compared to the batch studies, both disc packed nanofiber sorbents and pipette tip packed sorbents exhibited evident dominance based on their efficiencies. The experimental results showed comparable absolute recoveries for the mini disc packed fibers (84% for Nylon 6) and micro columns (80% for Nylon 6), although the disc displayed slightly higher recoveries possibly due to the exposure of the analyte to a larger reacting surface. The results also showed highly comparative extraction efficiencies between the nanofibers and conventional C-18 SPE sorbent. Nevertheless, miniaturized SPE devices simplified sample preparation, reducing back pressure, time of the analysis with acceptable reliability, selectivity, detection levels, and environmental friendliness, hence promoting green chemistry. PMID- 24812484 TI - Comparing responsible and non-responsible drivers to assess determinants of road traffic collisions: time to standardise and revisit. AB - OBJECTIVES: In 1994, Robertson and Drummer formalised the responsibility analysis as an alternative to case-control studies in the study of road traffic crashes. Our objective was to assess whether published responsibility studies respected standards defining adequate case-control studies. SETTING: Using Web of Science, Scopus and Google Scholar, we identified responsibility studies indexed until October 2013, which cited Robertson and Drummer's paper. After reviewing titles, abstracts and reference lists, we selected original studies comparing responsible and non-responsible drivers, published in peer-reviewed journals or proceedings. DATA AND ANALYSIS: We applied a grid to judge the conformity of the responsibility assessment to the original definition, and whether methods addressing representativeness of selection, accuracy of measures of exposures, confounding variables, and power met standards defining adequate case-control studies. RESULTS: Of 205 titles, we identified 20 papers. Methods of responsibility assessment were the original in three papers. Variations across studies concerned the number of mitigating factors included, or the use of questionnaires rather than police data (n=3). The ratio responsible/non responsible drivers varied from 0.90 to 5.31, due to major variations in sampling methods, threshold selection, and data completeness. Selection or measurement issues were discussed in 13 papers, but seldom addressed in the design. A comparison of confounding factors in responsible and non-responsible drivers was presented in five papers. CONCLUSIONS: Basic requirements of case-control studies are often not or not clearly met in responsibility studies. There is a need to revisit the method and to adapt existing publication standards to the way responsibility studies are reported. PMID- 24812485 TI - Outpatient- and inpatient-based buckling surgery: a comparative study. AB - PURPOSE: To evaluate the clinical outcomes of ambulatory buckling surgery, comparing outpatient- with inpatient-based surgery. METHODS: The authors performed a retrospective study of 80 consecutive cases of rhegmato genous retinal detachment from January 2009 to December 2011 treated by scleral buckling surgery. Two groups of patients were defined according to inpatient (group 1) or outpatient (group 2) surgery, and a comparison of several parameters between these two groups was performed. RESULTS: Of the 80 subjects in this study, the average age of group 1 (50 patients) was 49.7 years, and that of group 2 (30 patients) was 47.5 years. There were no statistically significant differences in the average logarithm of the minimum angle of resolution-visual acuity, the condition of the lens, or the presence of retinal lattice degeneration prior to the surgery between the groups. There were no statistically significant differences in the patterns of tear or retinal detachment or in surgical procedure between the groups. Comparing the best-corrected visual acuity after 6 months with that prior to the surgery, the changes in group 1 and group 2 were 0.26 and 0.31, respectively. The functional success rates of group 1 and group 2 after 6 months were 90% and 93%, respectively, and the anatomical success rates of group 1 and group 2 after 6 months were 94% and 96%, respectively, but these were also statistically insignificant. CONCLUSION: Hospitalization is not essential for buckling surgery in uncomplicated rhegmatogenous retinal detachment surgery. PMID- 24812486 TI - Effect of initial retinal thickness on outcome of intravitreal bevacizumab therapy for diabetic macular edema. AB - PURPOSE: To investigate whether eyes with diabetic macular edema (DME) and central retinal thickness (CRT) >400 MUm had better visual and anatomical outcomes compared to eyes with a CRT <400 MUm when treated with intravitreal bevacizumab in a real-world setting. PATIENTS AND METHODS: Patients undergoing intravitreal bevacizumab therapy for DME were identified from the departmental database of a tertiary referral unit. Following the initial injection, a retreatment was performed for any persistent macular edema, unless there had been no previous response to repeated doses. Recorded parameters included visual acuity, CRT on optical coherence tomography (spectral domain optical coherence tomography [SD-OCT]), and SD-OCT characteristics. Comparisons were made between data at baseline and 12 months after the first injection, and differences were tested for statistical significance using the Student's t-test. RESULTS: In all, 175 eyes of 142 patients were analyzed. Patients in group 2 (CRT >400 MUm) had significantly more injections than group 1 (CRT <400 MUm) (4.0 versus 3.3; P=0.003). Both groups had similar numbers of eyes with preexisting epiretinal membrane and/or vitreomacular traction at baseline. The reduction in CRT was significantly greater in group 2 when compared to group 1 (P<0.0001). In terms of visual gain between baseline and month 12, each gained significantly by a mean of 0.12 logarithm of the minimum angle of resolution units (P=0.0001), but there was no difference between groups 1 and 2 (P=0.99). CONCLUSION: These results do not support a 400 MUm baseline CRT cut-off for treating DME with bevacizumab, in contrast to published data on ranibizumab. Our results also indicate that patients with a thicker CRT require more bevacizumab injections, making treatment less cost-effective for these patients. Our results could be used by practitioners to support the use of bevacizumab in DME without applying a CRT cut off. PMID- 24812487 TI - Cloudy corneas as an initial presentation of multiple myeloma. AB - SUMMARY: We report a case of previously unsuspected myeloma, presenting with cornea verticillata due to intracorneal paraprotein deposition. HISTORY: An 85 year-old female presented via her optician with a 4-month history of cloudy vision. She had undergone an uneventful bilateral phacoemulsification surgery 7 years earlier. Extensive spiraling corneal epithelial opacification was noted on slit-lamp examination. On further investigation, she was found to have a previously unsuspected low-grade multiple myeloma. We established the nature of the corneal deposits with corneal epithelial biopsy histopathology and electron microscopy. It is very rare for multiple myeloma to present in this fashion. Ophthalmologists should be aware that such a presentation may rarely be due to systemic multiple myeloma. PMID- 24812488 TI - Epithelium-on corneal cross-linking treatment of progressive keratoconus: a prospective, consecutive study. AB - PURPOSE: To evaluate the outcome of collagen cross-linking (CXL) without corneal epithelial debridement in patients treated for progressive keratoconus for whom the standard epithelium-off treatment cannot be applied, as their central corneal thickness (CCT) is less than 400 MUm. PATIENTS AND METHODS: This was a prospective, uncontrolled, interventional study involving 32 eyes of 30 patients with progressive keratoconus and CCT of less than 400 MUm. All patients received CXL treatment with application of riboflavin and exposure to ultraviolet light A for 30 minutes without corneal epithelial debridement. Patients were followed up to 12 months postoperatively. The main outcomes were changes in maximum-K reading, manifest refractive spherical equivalent, CCT, and best-corrected visual acuity (logarithm of minimum angle of resolution). Patients were also asked to report any pain or discomfort during the procedure. RESULTS: At the end of the 12 month follow-up, CCT showed no significant change: from 392+/-5.17 MUm preoperatively to 390+/-4.45 MUm (P=0.102). Maximum-K reading decreased significantly, from 49.19+/-2.30 D preoperatively to 46.96+/-6.03 D postoperatively (P<0.05). The mean manifest spherical equivalent showed no significant change: from 4.04+/-1.51 D preoperatively to 4.17+/-1.63 D postoperatively (P=0.110). Mean best-corrected visual acuity showed no significant change: from 0.29+/-0.12 preoperatively to 0.31+/-0.11 postoperatively (P=0.110). CONCLUSION: Epithelium-on CXL exhibits potential as a method for treating patients with progressive keratoconus and CCT of less than 400 MUm, in which the standard epithelium-off CXL cannot be applied. Over 12 months of follow-up, the epithelium-on CXL was safe and effective, with results comparable to that achieved with the epithelium-off technique in thicker corneas, and reduced rates of operative and postoperative discomfort. PMID- 24812489 TI - The effect of posterior sub-Tenon's capsule triamcinolone acetonide injection to that of pars plana vitrectomy for diabetic macular edema. AB - PURPOSE: To compare the effect of posterior sub-Tenon's capsule triamcinolone acetonide (STTA) injection to that of pars plana vitrectomy (PPV) for diabetic macular edema (DME). PATIENTS AND METHODS: The medical records of 50 patients (52 eyes) with DME were reviewed. Twenty-six eyes underwent STTA (20 mg) and the other 26 eyes underwent vitrectomy combined with cataract surgery. The central macular thickness (CMT), measured by optical coherence tomography, and best corrected visual acuity (BCVA) were determined before and 1, 3, and 6 months after treatment. RESULTS: The differences in the BCVA and the CMT between the STTA group and the PPV group were not significant before or at any time after the treatment. In both the STTA and PPV groups, there were significant differences between the pre-treatment CMT and BCVA at any time after treatment. CONCLUSION: We recommend STTA injection for the treatment of DME. PMID- 24812490 TI - Benefits of omega-3 fatty acid dietary supplementation on health-related quality of life in patients with meibomian gland dysfunction. AB - BACKGROUND: We assessed the impact of a dietary supplement based on the combination of omega-3 essential fatty acids and antioxidants on health-related quality of life in patients with meibomian gland dysfunction (MGD). METHODS: Patients of either sex (aged 18-85 years) diagnosed with MGD according to criteria identified at a 2011 International Workshop on Meibomian Gland Dysfunction participated in this randomized, double-masked, placebo-controlled study. Group A patients (controls) received an oral placebo supplement and group B patients received the oral study supplement (Brudysec((r)) 1.5 g; Brudy Laboratories, Barcelona, Spain). At baseline and at 3-month follow-up, the patients completed the 36-Item Short Form Health Survey questionnaire using a Spanish validated version. The Physical (PCS) and Mental (MCS) Component Summary scores were the main outcome variables. RESULTS: A total of 61 patients completed the study (group A, n=31; group B, n=30). There were no significant differences in PCS and MCS scores at baseline between the two study groups, but after 3 months of treatment, significantly higher mean PCS and MSC scores were observed in patients treated with the active omega-3 dietary supplement as compared with controls (mean [standard deviation] PCS score 53.33+/-5.57 versus 47.46+/-7.31, P=0.008; mean MCS score 54.60+/-5.64 versus 47.80+/-8.45, P=0.0005). Moreover, mean differences between values at 3 months as compared with baseline were statistically significant for patients in group B (PCS score 7.14+/-5.81, 95% confidence interval 4.97-9.31, P=0.000; MCS score 5.96+/-7.64, 95% confidence interval 3.10-8.81, P=0.0002), whereas mean differences in patients assigned to group A were not statistically significant. CONCLUSION: Dietary supplementation with a combination of omega-3 essential fatty acids and antioxidants had a significant beneficial effect on HRQoL (health-related quality of life) in patients with MGD. PMID- 24812491 TI - Periocular and anterior orbital necrosis after upper eyelid gold weight loading: operation-related or self-inflicted? AB - A 44-year-old woman, who had undergone gold-weight implantation due to facial palsy and lagophthalmos, arrived at the ophthalmology ward with eyelid swelling and erythema, which rapidly deteriorated under intravenous antibiotics to a necrotic process involving the periocular tissues, the eye, and the anterior orbit. Despite prompt removal of the gold weight, the patient's ocular and systemic condition continued to deteriorate, necessitating evisceration and debridement of necrotic tissue. Cultures showed growth of Staphylococcus epidermidis, Staphylococcus capitis, Candida glabrata, and Candida albicans, and histopathology demonstrated an acute nonspecific necrotizing panophthalmitis. Later on, the patient was admitted to a plastic surgery ward with recurrent severe burns of her thigh, which were highly suggestive of being self-induced, raising the possibility of self-induced damage. PMID- 24812492 TI - Formulation development for the orexin receptor antagonist almorexant: assessment in two clinical studies. AB - Almorexant, a dual orexin receptor antagonist, was investigated for the treatment of insomnia. The following observations initiated further formulation development: the active pharmaceutical ingredient (API) was sticking to the apparatus used during tablet compression; almorexant has an absolute bioavailability of 11.2%; and almorexant modestly decreased the latency to persistent sleep by 10.4 minutes in patients. Two randomized crossover studies were performed to investigate the pharmacokinetics of several new formulations in healthy subjects. In study I, the old "sticky" tablet was compared to two new formulations developed to prevent sticking: a qualitatively similar tablet but with a larger API crystal size and a tablet with 30% more excipients as well as a larger API crystal size. This latter formulation was available in two strengths. The geometric mean ratios and 90% confidence interval of the area under the curve (AUC) were within the bioequivalence range of 0.80-1.25 for the different comparisons between formulations. In study II, 100 mg of the reference tablet was compared to 25 and 50 mg of a liquid-filled hard gelatin capsule developed to increase the bioavailability of almorexant. The geometric mean ratios of the maximum concentration and AUC comparing the new 25 and 50 mg capsule formulations to the reference tablet did not exceed 0.25 and 0.50, respectively, indicating that the new capsule formulation did not increase the maximum concentration of or the total exposure to almorexant. In conclusion, a new tablet was developed but formulation development aimed at increasing the bioavailability of almorexant failed. PMID- 24812493 TI - Patient education preferences in ophthalmic care. AB - BACKGROUND: The learning preferences of ophthalmology patients were examined. METHODS: Results from a voluntary survey of ophthalmology patients were analyzed for education preferences and for correlation with race, age, and ophthalmic topic. RESULTS: To learn about eye disease, patients preferred one-on-one sessions with providers as well as printed materials and websites recommended by providers. Patients currently learning from the provider were older (average age 59 years), and patients learning from the Internet (average age 49 years) and family and friends (average age 51 years) were younger. Patients interested in cataracts, glaucoma, macular degeneration, and dry eye were older; patients interested in double vision and glasses were younger. There were racial differences regarding topic preferences, with Black patients most interested in glaucoma (46%), diabetic retinopathy (31%), and cataracts (28%) and White patients most interested in cataracts (22%), glaucoma (22%), and macular degeneration (19%). CONCLUSION: MOST OPHTHALMOLOGY PATIENTS PREFERRED PERSONALIZED EDUCATION: one-on-one with their provider or a health educator and materials (printed and electronic) recommended by their provider. Age-related topics were more popular with older patients, and diseases with racial risk factors were more popular with high risk racial groups. PMID- 24812494 TI - Satisfaction of hospitalized psychiatry patients: why should clinicians care? AB - BACKGROUND: The aim of this study was to determine the relationship between inpatient satisfaction and health outcomes, quality of life, and adherence to treatment in a sample of patients with schizophrenia, while considering key sociodemographic and clinical confounding factors. METHODS: This cross-sectional study was conducted in the psychiatric departments of two public university hospitals in France. The data collected included sociodemographic information, clinical characteristics, quality of life (using the 36-Item Short Form Health Survey), nonadherence to treatment (Medication Adherence Report Scale), and satisfaction (a specific self-administered questionnaire based exclusively on patient point of view [Satispsy-22] and a generic questionnaire for hospitalized patients [QSH]). Multiple linear regressions were performed to assess the associations between satisfaction and quality of life and between satisfaction and nonadherence. Two sets of models were performed, ie, scores on the Satispsy 22 and scores on the QSH. RESULTS: Ninety-one patients with schizophrenia were enrolled. After adjustment for confounding factors, patients with better personal experience during hospitalization (Satispsy-22) had a better psychological quality of life (SF36-mental composite score, beta=0.37; P=0.004), and patients with higher levels of satisfaction with quality of care (Satispsy-22) showed better adherence to treatment (Medication Adherence Report Scale total score, beta=-0.32; P=0.021). Higher QSH scores for staff and structure index were linked to better adherence with treatment (respectively, beta=-0.33; P=0.019 and beta= 0.30; P=0.032), but not with quality of life. CONCLUSION: Satisfaction was the only factor associated with quality of life and was one of the most important features associated with nonadherence. These findings confirm that satisfaction with hospitalization should not be neglected in clinical practice and that it may improve the management of patients with schizophrenia. PMID- 24812495 TI - Impact of symptomatic hypoglycemia on medication adherence, patient satisfaction with treatment, and glycemic control in patients with type 2 diabetes. AB - BACKGROUND: The purpose of this study was to evaluate the impact of symptomatic hypoglycemia on medication adherence, satisfaction with treatment, and glycemic control in patients with type 2 diabetes based on the treatment goals stated in the Swedish national guidelines. METHODS: This cross-sectional, multicenter study was carried out between January and August 2009 in 430 consecutive primary health care patients on stable doses of metformin and sulfonylureas for at least 6 months. The patients completed questionnaires covering their experiences of low blood glucose and adherence, as well as barriers to and satisfaction with drug treatment (using the Treatment Satisfaction Questionnaire for Medication). Physicians collected the data from medical records. RESULTS: Patients who experienced moderate or worse symptoms of hypoglycemia reported poorer adherence to medication (46% versus 67%; P<0.01) and were more likely to perceive barriers such as "bothered by medication side effects" (36% versus 14%; P<0.001) compared with patients with no or mild symptoms. Patients with moderate or worse symptoms of hypoglycemia were less satisfied with their treatment than those with no or mild symptoms as determined by the Treatment Satisfaction Questionnaire for Medication-Global satisfaction (67.0 versus 71.2; P<0.05). Overall, achievement of target glycated hemoglobin (HbA1c) based on the treatment goals stated in the Swedish national guidelines was 40%. Despite poorer adherence, patients who experienced moderate or worse symptoms of hypoglycemia had lower mean HbA1c values than patients with no or mild symptoms (7.0% versus 7.3% [Diabetes Control and Complications Trial standard]; P<0.05). CONCLUSION: Symptomatic hypoglycemia in patients with type 2 diabetes on metformin and sulfonylureas was associated with nonadherence and decreased treatment satisfaction despite lower mean HbA1c values. A broader understanding of patient preferences and self-reported outcomes could improve the management of patients with type 2 diabetes. PMID- 24812496 TI - Computational Insights of the Interaction among Sea Anemones Neurotoxins and Kv1.3 Channel. AB - Sea anemone neurotoxins are peptides that interact with Na(+) and K(+) channels, resulting in specific alterations on their functions. Some of these neurotoxins (1ROO, 1BGK, 2K9E, 1BEI) are important for the treatment of about 80 autoimmune disorders because of their specificity for Kv1.3 channel. The aim of this study was to identify the common residues among these neurotoxins by computational methods, and establish whether there is a pattern useful for the future generation of a treatment for autoimmune diseases. Our results showed eight new key common residues between the studied neurotoxins interacting with a histidine ring and the selectivity filter of the receptor, thus showing a possible pattern of interaction. This knowledge may serve as an input for the design of more promising drugs for autoimmune treatments. PMID- 24812497 TI - Promise and reality in the expanding field of network interaction analysis: metabolic networks. AB - In the last few decades, metabolic networks revealed their capabilities as powerful tools to analyze the cellular metabolism. Many research fields (eg, metabolic engineering, diagnostic medicine, pharmacology, biochemistry, biology and physiology) improved the understanding of the cell combining experimental assays and metabolic network-based computations. This process led to the rise of the "systems biology" approach, where the theory meets experiments and where two complementary perspectives cooperate in the study of biological phenomena. Here, the reconstruction of metabolic networks is presented, along with established and new algorithms to improve the description of cellular metabolism. Then, advantages and limitations of modeling algorithms and network reconstruction are discussed. PMID- 24812498 TI - Impact of type 2 diabetes mellitus on hospitalization costs in older patients with acute myocardial infarction. AB - BACKGROUND: The purpose of this study was to evaluate the impact of type 2 diabetes mellitus on hospitalization costs in older patients with acute myocardial infarction (MI). METHODS: Retrospective analysis of data from the case retrieval system of Qilu Hospital of Shandong University located in Jinan city of Shandong Province was done for patients with acute MI from January 1, 2011 to December 31, 2012. RESULTS: Stenting was an important factor affecting older patients' total hospitalization costs (beta=0.685, P=0.000) and treatment costs during the follow-up period (duration of hospital stay only, beta=0.508, P=0.000). Stenting was also a protective factor in the prevention of acute heart failure (HF) in older patients with acute MI during the follow-up period (odds ratio 0.189, 95% confidence interval 0.059-0.602, P=0.005). Implementation of percutaneous coronary intervention reduced the incidence of acute HF in older inpatients with acute MI (27.8% versus 4.3%, P=0.001) and without diabetes (18.2% versus 3.8%, P=0.001). Moreover, among the elderly, the incremental cost effectiveness ratio estimate for implementing percutaneous coronary intervention in diabetic patients was higher than in nondiabetic patients. CONCLUSION: Stenting was a protective factor for preventing acute HF in the elderly during the follow-up period. From the perspective of reducing the incidence of acute HF in inpatients, implementation of percutaneous coronary intervention after an acute MI is more cost-effective in older patients with diabetes mellitus than in those without it. PMID- 24812499 TI - Ulceration of the oral mucosa following direct contact with ferrous sulfate in elderly patients: a case report and a review of the French National Pharmacovigilance Database. AB - OBJECTIVE: To report a series of cases of ulceration of the oral mucosa linked to direct contact with ferrous sulfate in elderly patients. CASE SUMMARY: The first case report concerns the occurrence of widespread oral ulceration in an 87-year old woman with Alzheimer's disease. The ulceration extended from the side of the tongue to the floor of the mouth. No clear explanation was found and various local treatments were ineffective. Once it was realized that the ferrous sulfate tablets (given as an iron supplement) were crushed prior to administration (due to the patient's deglutition disorder), withdrawal of this treatment led to rapid resolution of the ulceration. Nine other cases of oral ulcerations associated with ferrous sulfate were identified in the French National Pharmacovigilance Database. All but one of the patients were over 80 years of age and the youngest patient (a 54-year-old) had dysphagia associated with facial paralysis. DISCUSSION: Only two other reports of oral ulceration due to ferrous sulfate have been published to date. Mucosal toxicity of ferrous sulfate (which is probably related to oxidative stress) has previously been reported for the hypopharynx, the esophageal lumen, and (after inhalation of a tablet) the tracheobronchial tree. CONCLUSION: The mucosal toxicity of ferrous sulfate must be taken into account when deglutition disorders are present (as in elderly patients) and appropriate pharmaceutical formulations (such as syrups) should be administered to at-risk patients. The use of iron salts other than ferrous sulfate could be considered. PMID- 24812500 TI - 24 weeks of Pilates-aerobic and educative training to improve body fat mass in elderly Serbian women. PMID- 24812501 TI - A longitudinal cohort study of the impact of first- and both-eye cataract surgery on falls and other injuries in Vietnam. AB - AIM: Little information exists on the impact of cataract surgery on falls and other injuries in Vietnam. The aim of this study was to determine the impact of first and both eye cataract surgery on the number of falls and other injuries among bilateral cataract patients in Ho Chi Minh City, Vietnam. MATERIALS AND METHODS: A longitudinal cohort study was conducted involving 413 bilateral cataract patients aged 50+ years. Participants were assessed at three time points: 1 week before, 1-3 months after, and 1 year after first-eye cataract surgery. Visual measures (visual acuity, contrast sensitivity and stereopsis) were taken, and self-reported falls and injury data were collected. A multilevel longitudinal Poisson regression model was used to investigate change in the number of falls after surgery. RESULTS: The risk of falls decreased by 78% (incidence-rate ratio [IRR] 0.22, 95% confidence interval [CI] 0.06-0.77; P=0.018) in the year after cataract surgery for participants who had first-eye surgery only and 83% (IRR 0.17, 95% CI 0.04-0.69; P=0.012) for participants who had the second eye operated on compared to before surgery. The risk of falls was three times higher for females than males (IRR 3.13, 95% CI 1.53-6.40; P=0.002). Improved binocular contrast sensitivity was also associated with a decrease in falls (IRR 0.40, 95% CI 0.17-0.97; P=0.042). The prevalence of other injuries also decreased after cataract surgery. CONCLUSION: Cataract surgery reduced the number of falls and other injuries in Vietnam. Contrast sensitivity may be important for ophthalmologists to consider when prioritizing patients for surgery and assessing their fall risk. PMID- 24812502 TI - Clinical use of aclidinium in patients with COPD. AB - Chronic obstructive pulmonary disease (COPD) is the sixth-leading cause of death in the US. The Global initiative for Chronic Obstructive Lung Disease (GOLD) guidelines provide evidence-based recommendations for the clinical management of chronic COPD. Long-acting inhaled bronchodilators continue to be the mainstay of current management. Aclidinium bromide (TudorzaTM PressairTM) joins tiotropium as a long-acting inhaled antimuscarinic bronchodilator approved by the US Food and Drug Administration for the maintenance treatment of COPD. Early studies demonstrated aclidinium's significant bronchodilatory effects supporting once daily dosing; however, two Phase III studies, Aclidinium Clinical Trial Assessing Efficacy and Safety in Moderate to Severe COPD Patients (ACCLAIM/COPD) I and ACCLAIM/COPD II, in which patients were randomized to receive aclidinium 200 MUg daily, failed to achieve the minimal clinically important difference in improvement of trough forced expiratory volume in 1 second (FEV1), suggesting the need for higher doses or more frequent dosing. Additional studies - Aclidinium to Treat Airway Obstruction in COPD Patients (ATTAIN) and Aclidinium in Chronic Obstructive Respiratory Disease (ACCORD) I - were undertaken to compare 200 and 400 MUg twice-daily dosing. The mean improvements from baseline in trough FEV1 in the 400 MUg groups were +129 mL over 24 weeks and +124 mL over 12 weeks in ATTAIN and ACCORD I, respectively. Aclidinium also had beneficial effects on health related quality of life and other endpoints, such as rescue medication use and rates of exacerbations. Aclidinium bromide inhalation powder is generally well tolerated in patients with COPD, with headache, cough, diarrhea, and rhinosinusitis among the most commonly reported adverse events. Cardiovascular side effects were rarely reported. Patient satisfaction studies found that patients using the aclidinium delivery device had fewer errors affecting drug delivery than those using the tiotropium device and, overall, the aclidinium device was preferred to the tiotropium device. In conclusion, aclidinium bromide is approved for use in the US at a dose of 400 MUg twice daily and is a promising alternative to tiotropium. PMID- 24812503 TI - Expert consensus on acute exacerbation of chronic obstructive pulmonary disease in the People's Republic of China. AB - Chronic obstructive pulmonary disease (COPD) is a common disease that severely threatens human health. Acute exacerbation of COPD (AECOPD) is a major cause of disease progression and death, and causes huge medical expenditures. This consensus statement represents a description of clinical features of AECOPD in the People's Republic of China and a set of recommendations. It is intended to provide clinical guidelines for community physicians, pulmonologists and other health care providers for the prevention, diagnosis, and treatment of AECOPD. PMID- 24812504 TI - Cytokine inhibition in the treatment of COPD. AB - Cytokines play an important part in many pathobiological processes of chronic obstructive pulmonary disease (COPD), including the chronic inflammatory process, emphysema, and altered innate immune response. Proinflammatory cytokines of potential importance include tumor necrosis factor (TNF)-alpha, interferon-gamma, interleukin (IL)-1beta, IL-6, IL-17, IL-18, IL-32, and thymic stromal lymphopoietin (TSLP), and growth factors such as transforming growth factor-beta. The current objectives of COPD treatment are to reduce symptoms, and to prevent and reduce the number of exacerbations. While current treatments achieve these goals to a certain extent, preventing the decline in lung function is not currently achievable. In addition, reversal of corticosteroid insensitivity and control of the fibrotic process while reducing the emphysematous process could also be controlled by specific cytokines. The abnormal pathobiological process of COPD may contribute to these fundamental characteristics of COPD, and therefore targeting cytokines involved may be a fruitful endeavor. Although there has been much work that has implicated various cytokines as potentially playing an important role in COPD, there have been very few studies that have examined the effect of specific cytokine blockade in COPD. The two largest studies that have been reported in the literature involve the use of blocking antibody to TNFalpha and CXCL8 (IL-8), and neither has provided benefit. Blocking the actions of CXCL8 through its CXCR2 receptor blockade was not successful either. Studies of antibodies against IL-17, IL-18, IL-1beta, and TSLP are currently either being undertaken or planned. There is a need to carefully phenotype COPD and discover good biomarkers of drug efficacy for each specific target. Specific groups of COPD patients should be targeted with specific anticytokine therapy if there is evidence of high expression of that cytokine and there are features of the clinical expression of COPD that will respond. PMID- 24812505 TI - The successful treatment of hypercapnic respiratory failure with oral modafinil. AB - Hypercapnic respiratory failure is common in advanced chronic obstructive pulmonary disease and is usually treated by nasal ventilation. Not all patients requiring such ventilation can tolerate it, with anxiety and phobia influencing their reaction, along with treatment failure. We report the case histories of six patients with hypercapnic respiratory failure who were at risk of death due to refusal of nasal ventilation or its failure despite ongoing treatment. We report their improvement with oral modafinil 200 mg tablets used as a respiratory stimulant, which led to discharge, improved arterial blood gases, and offset further admissions with hypercapnic respiratory failure. This drug is licensed for narcolepsy and is said to stimulate the respiratory system via the central nervous system. Its use in respiratory failure is an unlicensed indication, and there are no case reports or studies of such use in the literature. Its respiratory stimulant effects appear better than those with protriptyline, which was a drug previously used until its production was discontinued. Our findings suggest that a study of modafinil in hypercapnic respiratory failure would be warranted, especially for patients with treatment failure or intolerance to nasal ventilation. This may offer a way of shortening hospital stay, improving outcome and quality of life, and reducing death and readmissions. PMID- 24812507 TI - Passing through the renal clearance barrier: toward ultrasmall sizes with stable ligands for potential clinical applications. AB - The use of nanoparticles holds promise for medical applications, such as X-ray imaging, photothermal therapy and radiotherapy. However, the in vivo toxicity of inorganic nanoparticles raises some concern regarding undesirable side effects which prevent their further medical application. Ultrasmall sub-5.5 nm particles can pass through the barrier for renal clearance, minimizing their toxicity. In this letter we address some recent interesting work regarding in vivo toxicity and renal clearance, and discuss the possible strategy of utilizing ultrasmall nanomaterials. We propose that small hydrodynamic sized nanoclusters can achieve both nontoxic and therapeutic clinical features. PMID- 24812506 TI - Nanomedicines in the treatment of hepatitis C virus infection in Asian patients: optimizing use of peginterferon alfa. AB - Asia is endemic for hepatitis C virus (HCV) infection, which is the leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplantation worldwide. HCV has six major genotypes and each HCV genotype has its specific geographic distribution. HCV genotypes 1, 2, 3, and 6 are common in Asia. The aim of HCV treatment is to eradicate the virus by effective therapeutic agents; viral clearance is durable after long-term post-treatment follow-up. In most Asian countries, peginterferon alfa (PEG-IFN alpha) in combination with ribavirin remains the standard of care, and the overall sustained viral response (SVR) rate in Asian HCV patients is higher than that in Western patients. The differences are most significant in patients with HCV genotype 1 (HCV-1) infection, which is attributed to the higher frequency of IFN-responsive or favorable interleukin-28B (IL-28B) genotype in Asian populations than in other ethnic populations. In addition, the introduction of response-guided therapy, where the optimized treatment duration is based on the early viral kinetics during the first 12 weeks of treatment, increases the SVR rate. Recently, telaprevir or boceprevir-based triple therapy was found to further improve the SVR rate in treated and untreated HCV-1 patients and has become the new standard of care in Western and some Asian countries. Many novel direct-acting antiviral agents, either in combination with PEG-IFN alpha plus ribavirin or used as IFN free regimens are under active investigation. At the time of this writing, simeprevir and sofosbuvir have been approved in the US. Because the SVR rates in Asian HCV patients receiving PEG-IFN alpha plus ribavirin therapy are high, health care providers should judiciously determine the clinical usefulness of these novel agents on the basis of treatment duration, anticipated viral responses, patient tolerance, financial burdens, and drug accessibility. PMID- 24812508 TI - Polyhydroxylated fullerene attenuates oxidative stress-induced apoptosis via a fortifying Nrf2-regulated cellular antioxidant defence system. AB - Polyhydroxylated derivatives of fullerene C60, named fullerenols (C60[OH]n), have stimulated great interest because of their potent antioxidant properties in various chemical and biological systems, which enable them to be used as a new promising pharmaceutical for the future treatment of oxidative stress-related diseases, but the details remain unknown. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a principal transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element and plays a crucial role in cellular defence against oxidative stress. In this study we investigated whether activation of the Nrf2/antioxidant response element pathway contributes to the cytoprotective effects of C60(OH)24. Our results showed that C60(OH)24 enhanced nuclear translocation of Nrf2 and upregulated expression of phase II antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1, and gamma-glutamate cysteine ligase in A549 cells. Treatment with C60(OH)24 resulted in phosphorylation of p38 mitogen activated protein kinases (p38 MAPK), extracellular signal-regulated kinases, and c-Jun-N-terminal kinases. By using inhibitors of cellular kinases, we showed that pretreatment of A549 cells with SB203580, a specific inhibitor of p38 MAPK, abolished nuclear translocation of Nrf2 and induction of HO-1 protein induced by C60(OH)24, indicating an involvement of p38 MAPK in Nrf2/HO-1 activation by C 60(OH)24. Furthermore, pretreatment with C60(OH)24 attenuated hydrogen peroxide induced apoptotic cell death in A549 cells, and knockdown of Nrf2 by small interfering ribonucleic acid diminished C60(OH)24-mediated cytoprotection. Taken together, these findings demonstrate that C60(OH)24 may attenuate oxidative stress-induced apoptosis via augmentation of Nrf2-regulated cellular antioxidant capacity, thus providing insights into the mechanisms of the antioxidant properties of C60(OH)24. PMID- 24812509 TI - Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery. AB - In order to limit the adverse reactions caused by polysorbate 80 in Taxotere((r)), a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO) with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis. PMID- 24812510 TI - Evaluation of renal quantitative T2* changes on MRI following administration of ferumoxytol as a T2* contrast agent. AB - PURPOSE: To evaluate the time-dependent changes in regional quantitative T2* maps of the kidney following intravenous administration of ferumoxytol. MATERIALS AND METHODS: Twenty-four individuals with normal kidney function underwent T2* weighted MRI of the kidney before, immediately after, and 48 hours after intravenous administration of ferumoxytol at a dose of 4 mg/kg (group A, n=12) or 6 mg/kg (group B, n=12). T2* values were statistically analyzed using two-tailed paired t-tests. RESULTS: In group A, the percentage changes from baseline to immediate post and baseline to 48 hours were 85.3% and 64.2% for the cortex and 90.8% and 64.6% for the medulla, respectively. In group B, the percentage changes from baseline to immediate post and baseline to 48 hours were 85.2% and 73.4% for the cortex and 94.5% and 74% for the medulla, respectively. This difference was significant for both groups (P<0.0001). CONCLUSION: There is significant and differential uptake of ferumoxytol in the cortex and medulla of physiologically normal kidneys. This differential uptake may offer the ability to interrogate renal cortex and medulla with possible clinical applications in medical renal disease and transplant organ assessment. We propose an organ of interest based dose titration of ferumoxytol to better differentiate circulating from intracellular ferumoxytol particles. PMID- 24812511 TI - Low-temperature growth of well-aligned zinc oxide nanorod arrays on silicon substrate and their photocatalytic application. AB - Well-aligned and single-crystalline zinc oxide (ZnO) nanorod arrays were grown on silicon (Si) substrate using a wet chemical route for the photodegradation of organic dyes. Structural analysis using X-ray diffraction, high-resolution transmission electron microscopy, and selected area electron diffraction confirmed the formation of ZnO nanorods grown preferentially oriented in the (001) direction and with a single phase nature with a wurtzite structure. Field emission scanning electron microscopy and transmission electron microscopy micrographs showed that the length and diameter of the well-aligned rods were about ~350-400 nm and ~80-90 nm, respectively. Raman scattering spectra of ZnO nanorod arrays revealed the characteristic E2 (high) mode that is related to the vibration of oxygen atoms in the wurtzite ZnO. The photodegradation of methylene blue (MB) using ZnO nanorod arrays was performed under ultraviolet light irradiation. The results of photodegradation showed that ZnO nanorod arrays were capable of degrading ~80% of MB within 60 minutes of irradiation, whereas ~92% of degradation was achieved in 120 minutes. Complete degradation of MB was observed after 270 minutes of irradiation time. Owing to enhanced photocatalytic degradation efficiency and low-temperature growth method, prepared ZnO nanorod arrays may open up the possibility for the successful utilization of ZnO nanorod arrays as a future photocatalyst for environmental remediation. PMID- 24812512 TI - Solitary skull metastasis as the first symptom of hepatocellular carcinoma: case report and literature review. AB - Skull metastasis from hepatocellular carcinoma (HCC) is reported rarely. In addition, solitary skull metastasis as the first symptom of HCC is reported even less. Here, we reported a case of solitary skull metastasis as the first symptom of HCC and reviewed the literature on skull metastasis. A 49-year-old male patient was admitted to Jinjiang Hospital of Quanzhou Medical College with a painless parietal-occipital scalp mass, and he denied any history of hepatic disease. A cranial computed tomography demonstrated a hypervascular enhancement with osteolytic change in the right parietal-occipital region, cranial magnetic resonance imaging indicated a highly enhanced and osteolytic skull tumor, and abdominal computed tomography showed a huge tumor in the liver. The other examinations showed no other metastases. Laboratory data showed no liver dysfunction while hepatitis B surface antigen was positive, and alpha fetal protein level was high. A craniectomy was performed and the mass was totally removed. The histological diagnosis was skull metastasis from HCC. The patient was subsequently treated by transcatheter arterial chemoembolization. In a review of published literature, the incidence of skull metastasis from HCC in the period between 1990 and 2011 has significantly increased. The misdiagnosis rate of skull metastases as the first symptom from HCC was high. Therefore, it is necessary to give each patient with a scalp mass that has invaded the skull a liver ultrasound or computed tomography scan. On the other hand, we found that metastases that occurred in the calvaria site were more frequent than those that occurred in the skull base and facial skeleton. This may be worthy of further investigation in the future. PMID- 24812513 TI - Increased serum dehydroepiandrosterone sulfate in the first episode but not in subsequent episodes in male patients with schizophrenia. AB - BACKGROUND: Many studies have investigated the relationship between blood levels of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S), cortisol, progesterone, and testosterone and the onset, prognosis, symptom severity, and treatment response of schizophrenia. In the present study, we assessed potential differences in blood levels of neurosteroids between drug-naive first-episode patients with schizophrenia (FES), and drug-free patients with schizophrenia who were not in the first episode but were in a phase of acute exacerbation (DFP). MATERIALS AND METHODS: The present study included 32 male FES, 28 male DFP, and 24 male healthy controls (HC). Groups were compared in terms of blood levels of adrenocorticotropic hormone (ACTH), cortisol, testosterone, progesterone, and DHEA-S. RESULTS: Blood levels of ACTH, cortisol, testosterone, and progesterone were similar among the groups. The mean value of serum DHEA-S was significantly different among the groups (P<0.001). The value of serum DHEA-S was higher in the FES group than in the DFP and HC groups (both P<0.001). The mean values of serum DHEA-S in the HC and DFP groups were found to be similar (P=0.33). CONCLUSION: We suggest that higher values of DHEA-S in the FES group compared with both the DFP and HC groups indicate that this neurosteroid response is unique to first-episode schizophrenia patients. Further studies are needed to investigate the difference in blood levels of neurosteroids in different groups in terms of age of diagnosis. PMID- 24812514 TI - Comparative clinical utility of once-weekly subcutaneous abatacept in the management of rheumatoid arthritis. AB - Biologic therapies in rheumatoid arthritis are now part of standard practice for disease that proves difficult to control with conventional disease-modifying anti rheumatic drugs. While anti-tumor necrosis factor therapies have been commonly used, other targeted biologic therapies with different mechanisms of action are becoming increasingly available. Abatacept is a recombinant fusion protein that inhibits the T-cell costimulatory molecules required for T-cell activation. Intravenous abatacept has good clinical efficacy with an acceptably low toxicity profile in rheumatoid arthritis, but the subcutaneous mode of delivery has only recently become available. In this article, we examine key efficacy and safety data for subcutaneous abatacept in rheumatoid arthritis, incorporating evidence from five large Phase III studies that included people with an inadequate response to methotrexate and an inadequate response to biologic disease-modifying anti-rheumatic drugs. The results demonstrate that subcutaneous abatacept has efficacy and safety comparable with that of intravenous abatacept and adalimumab. In addition, inhibition of radiographic progression at year 1 in relatively early rheumatoid arthritis is consistent with that of adalimumab. Subcutaneous abatacept is well tolerated, with very low rates of discontinuation in both short term and long-term follow-up. PMID- 24812515 TI - The 24-hour pulse wave velocity, aortic augmentation index, and central blood pressure in normotensive volunteers. AB - The purpose of this study was to examine the pulse wave velocity, aortic augmentation index corrected for heart rate 75 (AIx@75), and central systolic and diastolic blood pressure during 24-hour monitoring in normotensive volunteers. Overall, 467 subjects (206 men and 261 women) were recruited in this study. Participants were excluded from the study if they were less than 19 years of age, had blood test abnormalities, had a body mass index greater than 2 7.5 kg/m(2), had impaired glucose tolerance, or had hypotension or hypertension. Ambulatory blood pressure monitoring (ABPM) with the BPLab((r)) device was performed in each subject. ABPM waveforms were analyzed using the special automatic Vasotens((r)) algorithm, which allows the calculation of pulse wave velocity, AIx@75, central systolic and diastolic blood pressure for "24-hour", "awake", and "asleep" periods. Circadian rhythms and sex differences in these indexes were identified. Pending further validation in prospective outcome-based studies, our data may be used as preliminary diagnostic values for the BPLab ABPM additional index in adult subjects. PMID- 24812516 TI - Mental health-promoting dialogues from the perspective of community-dwelling seniors with multimorbidity. AB - Mental health promotion needs to be studied more deeply within the context of primary care, because persons with multiple chronic conditions are at risk of developing poor mental health. In order to make progress in the understanding of mental health promotion, the aim of this study was to describe the experiences of health-promoting dialogues from the perspective of community-dwelling seniors with multimorbidity - what these seniors believe is important for achieving a dialogue that may promote their mental health. Seven interviews with six women and one man, aged 83-96 years, were analyzed using qualitative content analysis. The results were summarized into nine subcategories and three categories. The underlying meaning of the text was formulated into an overarching theme that embraced every category, "perceived and well-managed as a unique individual". These seniors with multimorbidity missed someone to talk to about their mental health, and needed partners that were accessible for health dialogues that could promote mental health. The participants missed friends and relatives to talk to and they (crucially) lacked health care or social service providers for health promoting dialogues that may promote mental health. An optimal level of care can be achieved through involvement, continuity, and by providing a health-promoting dialogue based on seniors' needs and wishes, with the remembrance that general health promotion also may promote mental health. Implications for clinical practice and further research are discussed. PMID- 24812517 TI - Intake and urinary amounts of biotin in Japanese elementary school children, college students, and elderly persons. AB - Biotin enzymes such as pyruvate carboxylase and acetyl-CoA carboxylase are involved with the most basic metabolism. Thus, it is very important to monitor the biotin nutritional status for maintaining good health. We examined urinary excretion and the intake of biotin in a Japanese sample population of 60 boys and 36 girls (10-12 y), 37 male and 135 female college students (18-27 y), and 35 female elderly persons (70-84 y) living freely. All food consumed, and the corresponding weighing, for 4 consecutive days were recorded. A 24-hour urine sample was collected on the fourth day, and the urine biotin was measured. The urine biotin at the fourth day was 57.8, 50.9, 81.0, 66.2, and 82.3 nmol/day in boys, girls, male students, female students, and elderly persons, respectively. The average intake of biotin for 4 consecutive days was 35, 31, 28, 26, and 32 MUg/day in boys, girls, male students, female students, and elderly persons, respectively. PMID- 24812518 TI - Nutritional Status of Water-soluble Vitamins Did not Differ According to Intake Levels of Wheat and Wheat Alternatives and Rice and Rice Alternatives as a Staple Food in Pregnant Japanese Women. AB - The objective of this study was to investigate whether the intake level of a staple food influences the nutritional status of water-soluble vitamins in pregnant Japanese women. Urinary excretion of water-soluble vitamins was used as a biomarker for nutritional assessment. Twenty-four-hour urine samples were collected and vitamin intake was surveyed using a validated self-administered comprehensive diet history questionnaire. Subjects were categorized into bottom, middle, and upper tertiles according to the percentage of total energy intake from wheat and wheat alternatives or rice and rice alternatives. The present study showed that the nutritional status of water-soluble vitamins did not differ with intake level of wheat and wheat alternatives or rice and rice alternatives as a staple food in pregnant Japanese women. PMID- 24812519 TI - Intense exercise increases protein oxidation in spleen and liver of mice. AB - Studies have indicated that sports anemia is mainly associated with intravascular hemolysis induced by exercise. We hypothesized that such exercise-induced hemolysis leads to oxidative damage due to an increase in free iron caused by hematocyte destruction. Thirty-one male ICR mice were randomly divided into 3 groups: a rested control group, an intense-exercise group, and a group rested for 24 hours after intense exercise. The serum haptoglobin level of the intense exercise group decreased compared with that of the rested control group, suggesting hemolysis. Tissue iron and protein carbonyl levels in the liver were increased after exercise, and the protein carbonyl level in the spleen on the day after exercise was significantly increased compared with that of the resting state. These results suggest that the spleen and liver, where extravascular hemolysis occurs, were subjected to oxidative modification by the free iron, which was released from large numbers of hemocytes that were destroyed due to the intense exercise. PMID- 24812520 TI - A Randomized Double Blind Controlled Safety Trial Evaluating d-Lactic Acid Production in Healthy Infants Fed a Lactobacillus reuteri-containing Formula. AB - BACKGROUND: d-Lactic acidosis in infants fed lactic acid bacteria-containing products is a concern. METHODS: The primary objective of this non-inferiority trial was to compare urinary d-lactic acid concentrations during the first 28 days of life in infants fed formula containing Lactobacillus reuteri (1.2 * 10(6) colony forming units (CFU)/ml) with those fed a control formula. The non inferiority margin was set at a two-fold increase in d-lactic acid (0.7 mmol/mol creatinine, log-transformed). Healthy term infants in Greece were enrolled between birth and 72 hours of age, and block randomized to a probiotic (N = 44) or control (N = 44) group. They were exclusively fed their formulae until 28 days of age and followed up at 7, 14, 28, 112, and 168 +/- 3 days. Anthropometric measurements were taken at each visit and tolerance recorded until 112 days. Urine was collected before study formula intake and at all visits up to 112 days and blood at 14 days. RESULTS: d-Lactic acid concentration in the probiotic group was below the non-inferiority margin at 28 days: treatment effect -0.03 (95% confidence interval [CI]: [-0.48 to 0.41]) mmol/mol creatinine but was above the non-inferiority margin at 7 and 14 days-treatment effect 0.50 (95% CI: [0.05 0.96]) mmol/mol creatinine and 0.45 (95% CI: [0.00-0.90]) mmol/mol creatinine, respectively. Blood acid excess and pH, anthropometry, tolerance, and adverse events (AEs) were not significantly different between groups. CONCLUSION: Intake of L. reuteri-containing formula was safe and did not cause an increase in d lactic acid beyond two weeks. PMID- 24812521 TI - Raxibacumab: potential role in the treatment of inhalational anthrax. AB - Anthrax is a highly contagious and potentially fatal human disease caused by Bacillus anthracis, an aerobic, Gram-positive, spore-forming rod-shaped bacterium with worldwide distribution as a zoonotic infection in herbivore animals. Bioterrorist attacks with inhalational anthrax have prompted the development of more effective treatments. Antibodies against anthrax toxin have been shown to decrease mortality in animal studies. Raxibacumab is a recombinant human monoclonal antibody developed against inhalational anthrax. The drug received approval after human studies showed its safety and animal studies demonstrated its efficacy for treatment as well as prophylaxis against inhalational anthrax. It works by preventing binding of the protective antigen component of the anthrax toxin to its receptors in host cells, thereby blocking the toxin's deleterious effects. Recently updated therapy guidelines for Bacillus anthracis recommend the use of antitoxin treatment. Raxibacumab is the first monoclonal antitoxin antibody made available that can be used with the antibiotics recommended for treatment of the disease. When exposure is suspected, raxibacumab should be given with anthrax vaccination to augment immunity. Raxibacumab provides additional protection against inhalational anthrax via a mechanism different from that of either antibiotics or active immunization. In combination with currently available and recommended therapies, raxibacumab should reduce the morbidity and mortality of inhalational anthrax. PMID- 24812522 TI - Economic evaluation of SQ-standardized grass allergy immunotherapy tablet (Grazax((r))) in children. AB - BACKGROUND: Grass pollen-induced rhinoconjunctivitis is a common allergic respiratory disorder affecting over 20% of the UK population in terms of quality of life and sleep, work, and school patterns. The SQ-standardized grass allergy immunotherapy tablet (AIT) has been demonstrated as a disease-modifying treatment which gives a sustained effect even after completion of a treatment course. The objective of this study was to provide an economic assessment of whether treatment with the SQ-standardized grass AIT, Grazax((r)) (Phleum pratense) in combination with symptomatic medications is preferable to the standard of care using symptomatic medications only. The analysis was performed for children with grass pollen-induced rhinoconjunctivitis, with or without concomitant asthma, in the UK. METHODS: The model evaluated the two treatment regimens in a cohort of 1,000 children from a payer's perspective. Treatment was modeled in terms of management of symptoms, impact on resource use, and development of allergic asthma. The analysis modeled the use of SQ-standardized grass AIT and the sustained effects of treatment over a 9-year time horizon (ie, 3 years of treatment, with modeled long-term benefits). Data inputs were drawn from a recent clinical trial, published studies, and databases. RESULTS: SQ-standardized grass AIT improves patient outcomes, generating an incremental cost per quality adjusted life year gained of L12,168. This is below commonly accepted thresholds in the UK. CONCLUSION: The resulting incremental cost per QALY falls below commonly accepted willingness to pay thresholds. Therefore, the SQ-standardized grass AIT is a cost-effective option for the treatment of grass pollen-induced rhinoconjunctivitis in the UK pediatric population. PMID- 24812523 TI - Respiratory syncytial virus: current and emerging treatment options. AB - Respiratory syncytial virus (RSV) is an important respiratory pathogen in infants and children worldwide. Although RSV typically causes mild upper respiratory infections, it frequently causes severe morbidity and mortality, especially in premature infants and children with other chronic diseases. Treatment of RSV is limited by a lack of effective antiviral treatments; however, ribavirin has been used in complicated cases, along with the addition of intravenous immune globulin in specific patients. Vaccination strategies for RSV prevention are heavily studied, but only palivizumab (Synagis((r))) has been approved for use in the United States in very select patient populations. Research is ongoing in developing additional vaccines, along with alternative therapies that may help prevent or decrease the severity of RSV infections in infants and children. To date, we have not seen a decrement in RSV morbidity and mortality with our current options; therefore, there is a clear need for novel RSV preventative and therapeutic strategies. In this review, we discuss the current and evolving trends in RSV treatment for infants and children. PMID- 24812524 TI - Embolic renal infarction mimicking renal colic. AB - Atrial fibrillation is a major health problem with risk of systemic arterial embolism. Acute embolic renal infarction is a rare condition with symptoms that are often nonspecific. We present a 36-year-old previously healthy man with acute embolic renal infarction secondary to new onset atrial fibrillation, who presented with flank pain mimicking renal colic. The patient was treated successfully with anticoagulation therapy, beta-blockers, broad-spectrum antibiotics, and supportive treatment. PMID- 24812526 TI - Patient safety and minimizing risk with insulin administration - role of insulin degludec. AB - Diabetes is a lifelong condition requiring ongoing medical care and patient self management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long-term hypoglycemia or reduce diabetes-related complications. PMID- 24812525 TI - Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. AB - The microRNAs (miRNAs) are a class of small, 20-22 nucleotides in length, endogenously expressed noncoding RNAs that regulate multiple targets posttranscriptionally. Interestingly, miRNAs have emerged as regulators of most physiological and pathological processes, including metastatic tumor progression, in part by controlling a reversible process called epithelial-to-mesenchymal transition (EMT). The activation of EMT increases the migratory and invasive properties fundamental for tumor cell spread while activation of the reverse mesenchymal-to-epithelial transition is required for metastasis outgrowth. The EMT triggering leads to the activation of a core of transcription factors (EMT TFs) - SNAIL1/SNAIL2, bHLH (E47, E2-2, and TWIST1/TWIST2), and ZEB1/ZEB2 - that act as E-cadherin repressors and, ultimately, coordinate EMT. Recent evidence indicates that several miRNAs regulate the expression of EMT-TFs or EMT activating signaling pathways. Interestingly, some miRNAs and EMT-TFs form tightly interconnected negative feedback loops that control epithelial cell plasticity, providing self-reinforcing signals and robustness to maintain the epithelial or mesenchymal cell status. Among the most significant feedback loops, we focus on the ZEB/miR-200 and the SNAIL1/miR-34 networks that hold a clear impact in the regulation of the epithelial-mesenchymal state. Recent insights into the p53 modulation of the EMT-TF/miRNA loops and epigenetic regulatory mechanisms in the context of metastasis dissemination will also be discussed. Understanding the regulation of EMT by miRNAs opens new avenues for the diagnosis and prognosis of tumors and identifies potential therapeutic targets that might help to negatively impact on metastasis dissemination and increasing patient survival. PMID- 24812527 TI - Discharged from a mental health admission ward: is it safe to go home? A review on the negative outcomes of psychiatric hospitalization. AB - Before psychiatry emerged as a medical discipline, hospitalizing individuals with mental disorders was more of a social stigmatizing act than a therapeutic act. After the birth of the mental health disciplines, psychiatric hospitalization was legitimized and has proven to be indispensable, preventing suicides and helping individuals in need. However, despite more than a century passing since this legitimization occurred, psychiatric hospitalization remains a controversial issue. There is the question of possible negative outcomes after a psychiatric admission ceases to take its protective effect, and even of whether the psychiatric admission itself is related to a negative setback after discharge. This review aims to summarize some of the most important negative outcomes after discharge from a psychiatric institution. These experiences were organized into two groups: those after a brief psychiatric hospitalization, and those after a long-stay admission. The author further suggests possible ways to minimize these adversities, emphasizing the need of awareness related to this important issue. PMID- 24812528 TI - Evaluating the potentiating effect of amethocaine on tropicamide-induced mydriasis in darkly pigmented irides, using infrared pupillometry. AB - PURPOSE: To determine whether prior instillation of amethocaine would increase the rate and magnitude of tropicamide-induced pupillary dilatation in darkly pigmented irides. METHOD: A total of 50 healthy Africans aged 18-40 years, with darkly pigmented irides, received a drop of amethocaine in one eye and a drop of placebo in the contralateral eye, followed by two drops of tropicamide in both eyes. Serial pupil diameters were measured using a monocular infrared video pupillometer. Rate of pupillary dilatation was compared in both eyes. Survival statistics were calculated for the time taken to reach a clinically effective dilatation, clinically effective diameter (CED) of 6.0 mm. RESULTS: Mean difference in pupil diameters between amethocaine- and placebo-treated eyes was 0.30 +/- 0.09 mm (P < 0.002). In all, 62% of amethocaine-treated eyes and only 46% of placebo-treated eyes reached the CED. CONCLUSION: We observed a small but statistically significant potentiating effect of a drop of amethocaine on tropicamide-induced dilatation within 20 minutes. PMID- 24812529 TI - Antiphospholipid Antibody Syndrome Associated with Graves' Disease Presenting As Inferior Vena Cava Thrombosis with Bilateral Lower Limb DVT. AB - We report a case of a 60-year-old lady who presented with bilateral lower limb swelling and a thyroid swelling with clinical features consistent with thyrotoxicosis. Investigations revealed the presence of a thrombus in bilateral external, internal iliac veins, and inferior vena cava extending up to its infrahepatic part. Hormone profile and radioiodine uptake scan confirmed the diagnosis of Graves' disease. Further workup revealed the presence of antiphospholipid antibodies (confirmed after a repeat test at 12 weeks). The patient was treated with antithyroid drugs and anticoagulants. The patient improved with normalization of thyroid function and partial recanalization of the infrahepatic part of inferior vena cava. Hyperthyroidism has been implicated as a potential hypercoagulable state; however, the association of Graves' disease with antiphospholipid antibody syndrome is limited to isolated case reports. This case highlights a new mechanism underlying hypercoagulability associated with Graves' disease. PMID- 24812530 TI - A rare case of chronic ectopic pregnancy presenting as large hematosalpinx. AB - Ectopic pregnancy is defined as implantation and subsequent development of an embryo outside the uterine lining. It has wide range of presentation from acute hemoperitoneum to chronic ectopic pregnancy. This is an unusual case of chronic ectopic pregnancy with large hematosalpinx without classical symptoms. A 22-year old South Indian woman reported to the outpatient clinic with irregular spotting for a duration of 2 months which was not associated with pain. There was no preceding amenorrhea and previous menstrual cycles were regular. Clinically, the patient was hemodynamically stable but severely anemic. The abdomen was soft on palpation, cervical movements were not tender, and human chorionic gonadotropin was absent in the urine. Ultrasound revealed a complex adnexal mass. Magnetic resonance imaging (MRI) revealed a large hematosalpinx. Laparoscopic left salpingectomy was conducted and histopathology confirmed ectopic pregnancy. Ectopic pregnancy presents diagnostic dilemmas in the absence of classical symptoms. MRI and laparoscopy are important tools in such a diagnostic dilemma. PMID- 24812531 TI - Educational effects of a tailored leaflet addressing drinking during pregnancy. AB - OBJECTIVE: To examine the educational effects of a tailored leaflet on current drinking behavior, thoughts about drinking alcohol during pregnancy, and knowledge of fetal alcohol syndrome (FAS) among pregnant women. DESIGN: Intervention. PARTICIPANTS: We recruited pregnant women who were participating in maternity classes held at five municipal health centers in Saitama Prefecture and Tokyo in Japan. METHODS: Questionnaires were administered before and after distribution of either a tailored or a non-tailored leaflet and again after the women delivered their babies. RESULTS: More women read the non-tailored leaflet than the tailored one; this was because they felt they could read the non tailored leaflet immediately. As for educational effects, the tailored leaflet was not superior to the non-tailored one in changing the women's behavior, thoughts, or knowledge. CONCLUSION: It is more important for health education leaflets to seem easy to read in terms of volume than to be tailored. PMID- 24812532 TI - Selective inhibition of steroidogenic enzymes by ketoconazole in rat ovary cells. AB - OBJECTIVE: Ketoconazole (KCZ) is an anti-fungal agent extensively used for clinical applications related to its inhibitory effects on adrenal and testicular steroidogenesis. Much less information is available on the effects of KCZ on synthesis of steroid hormones in the ovary. The present study aimed to characterize the in situ effects of KCZ on steroidogenic enzymes in primary rat ovary cells. METHODS: Following the induction of folliculogenesis in gonadotropin treated rats, freshly prepared ovarian cells were incubated in suspension for up to four hours while radiolabeled steroid substrates were added and time dependent generation of their metabolic products was analyzed by thin layer chromatography (TLC). RESULTS: KCZ inhibits the P450 steroidogenic enzymes in a selective and dose dependent manner, including cholesterol side-chain cleavage cytochrome P450 (CYP11A1/P450scc), the 17alpha-hydroxylase activity of CYP17A1/P450c17, and CYP19A1/P450arom, with IC50 values of 0.3, 1.8, and 0.3 MUg/mL (0.56, 3.36, and 0.56 MUM), respectively. Unaffected by KCZ, at 10 MUg/mL, were the 17,20 lyase activity of CYP17A1, as well as five non-cytochrome steroidogenic enzymes including 3beta-hydroxysteroid dehydrogenase-Delta(5-4) isomerase type 1 (3betaHSD1), 5alpha-reductase, 20alpha-hydroxysteroid dehydrogenase (20alpha HSD), 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), and 17beta-hydroxysteroid dehydrogenase type 1 (17HSD1). CONCLUSION: These findings map the effects of KCZ on the ovarian pathways of progestin, androgen, and estrogen synthesis. Hence, the drug may have a potential use as an acute and reversible modulator of ovarian steroidogenesis in pathological circumstances. PMID- 24812533 TI - Medical treatment of essential tremor. AB - Essential tremor (ET) is the most common pathological tremor characterized by upper limb action-postural tremor (PT)/kinetic tremor (KT). There are no specific neuropathological or biochemical abnormalities in ET. The disability is consequent to amplitude of KT, which may remain mild without handicap or may become disabling. The most effective drugs for sustained tremor control are propranolol and primidone. Symptomatic drug treatment must be individualized depending on the circumstances that provoke the tremor-related disability. Broad guidelines for treatment are discussed in this review. Patients may be treated intermittently only on stressful occasions with propranolol, clonazepam, or primidone monotherapy, or an alcoholic drink. Those with persistently disabling tremor need continued treatment. PMID- 24812534 TI - Association between lung function and metabolic syndrome independent of insulin in Japanese men and women. AB - PURPOSE: We examined the cross-sectional association between lung function and metabolic syndrome (MetS), independent of fasting immunoreactive insulin (F-IRI). METHODS: A total of 3,072 middle-aged, apparently healthy subjects who participated in a general health check-up were included. Lung function, which was expressed as forced vital capacity (%FVC predicted) or forced expiratory volume in 1 second (FEV1% predicted) was examined. Multivariable logistic regression analysis was performed to assess the association between lung function and MetS. RESULTS: Men with the lowest quartile of FVC% predicted, or those with the lowest quartile of FEV1% predicted, had a 3.5-fold or 2.6-fold increased risk of MetS, respectively, compared with those with the highest quartile of FVC% predicted or FEV1% predicted. F-IRI had a positive, significant, and independent association with MetS in both sexes. CONCLUSION: Impaired lung function increased the risk of MetS, independent of F-IRI and smoking in men, but not in women. PMID- 24812535 TI - Extracurricular research activities among senior medical students in Kuwait: experiences, attitudes, and barriers. AB - BACKGROUND: Research is the foundation of scientific advancement and improvement in quality of health care, which ensures the good health of the community. The aim of this study is to explore experiences, attitudes, and barriers of medical students in Kuwait University (KU) in regards to extracurricular research. METHODS: A questionnaire about extracurricular research activities (ie, any research activity that is not part of the required undergraduate curriculum, such as publishing a paper, research elective, etc) was distributed to 175 senior medical students (years 6 and 7). Descriptive and chi-square analyses were used to analyze the responses, considering a P-value of <0.05 as the cut-off level for significance. The main outcome was defined as taking part in any of the extracurricular research activities. RESULTS: Of the 150 participants (response rate = 85.7%), 26 (17.3%), 68 (45.3%), 52 (34.7%), and 17 (11.3%) had published their required medical school research, presented abstracts in conferences, conducted extracurricular research, and completed a research elective/course, respectively; 99 (66.0%) took part in any of these activities. Participants who read medical journals regularly (81; 54%) reported higher participation in extracurricular research activities than those who did not read journals (P=0.003). Improving the availability of mentors for students' extracurricular research was ranked by the participants as the most important factor to improve their participation in extracurricular research (4.05/5.00). CONCLUSION: Despite the lack of adequate support, extracurricular research activities among medical students of KU were comparable to students from other countries. Barriers for these activities should be addressed by KU medical educators in order to enhance research activities among the students. PMID- 24812536 TI - FRACTIONAL INTEGRATION TOOLBOX. AB - The problems formulated in the fractional calculus framework often require numerical fractional integration/differentiation of large data sets. Several existing fractional control toolboxes are capable of performing fractional calculus operations, however, none of them can efficiently perform numerical integration on multiple large data sequences. We developed a Fractional Integration Toolbox (FIT), which efficiently performs fractional numerical integration/differentiation of the Riemann-Liouville type on large data sequences. The toolbox allows parallelization and is designed to be deployed on both CPU and GPU platforms. PMID- 24812537 TI - Theory of the Self-learning Q-Matrix. AB - Cognitive assessment is a growing area in psychological and educational measurement, where tests are given to assess mastery/deficiency of attributes or skills. A key issue is the correct identification of attributes associated with items in a test. In this paper, we set up a mathematical framework under which theoretical properties may be discussed. We establish sufficient conditions to ensure that the attributes required by each item are learnable from the data. PMID- 24812538 TI - Pre-pregnancy restless legs syndrome (Willis-Ekbom Disease) is associated with perinatal depression. AB - OBJECTIVES: Both restless legs syndrome ([RLS], also known as Willis-Ekbom Disease [WED]) and depression are common during pregnancy. However, no prior studies have assessed if pregnant women with RLS have an elevated risk of depression during and/or after pregnancy. METHODS: 1,428 women who were pregnant in gestational week 16-17 were asked to participate in a longitudinal survey. They were followed by web-based questionnaires in gestational week 17 and 32, and 6 weeks after delivery. Data were also retrieved from prenatal and birth records. Two different sets of criteria were used to examine the prevalence of RLS in the cohort (International Restless Legs Syndrome Society Group standard criteria and the later developed CH-RLSQ11 questionnaire). The latter questionnaire attempts to exclude those with common "mimics" of RLS. RESULTS: Adjusted odds ratio for depression in gestational week 17, 32, and postpartum week 6 in relation to pre pregnancy RLS onset and moderate to severe symptom severity were 4.74 (2.30 - 9.76), 3.67 (1.85 - 7.28), and 2.58 (1.28 - 5.21), respectively. No significant associations were seen in pregnant women with de novo RLS during pregnancy. When using the standard diagnostic RLS criteria and frequency of symptoms more than 2 3 days per week, the prevalence of RLS was 12.3%. With the CH-RLSQ11 questionnaire and the same threshold for frequency of symptoms the prevalence was 6.5%. CONCLUSION: Women with RLS onset before pregnancy with moderate or severe symptoms had an increased risk of both antenatal and postnatal depression. The self-reported prevalence of RLS during pregnancy is lower when a questionnaire dealing with "mimics" is used. PMID- 24812539 TI - The effects of sleep dysfunction on cognition, affect, and quality of life in individuals with cerebellar ataxia. AB - STUDY OBJECTIVE: Cerebellar ataxia comprises a group of debilitating diseases that are the result of progressive cerebellar degeneration. Recent studies suggest that, like other neurodegenerative diseases, sleep impairments are common in cerebellar ataxia. In light of the role of sleep in mood regulation and cognition, we sought to assess interactions between sleep, cognition, and affect in individuals with cerebellar ataxia. METHODS: A survey of 176 individuals with cerebellar ataxia was conducted. The battery of instruments included a modified International Cooperative Ataxia Rating Scale, Pittsburgh Sleep Quality Index, Restless Leg Syndrome Questionnaire, REM Behavior Disorder Questionnaire, Beck Depression Inventory, Epworth Sleepiness Scale, and a Composite Cognitive Questionnaire. RESULTS: Fifty-one percent of individuals indicated significant sleep disturbances on the Pittsburgh Sleep Quality Index, 73% of participants had two or more symptoms of restless leg syndrome, and 88% had two or more symptoms of REM behavior disorder. Ataxia severity, based on the modified International Cooperative Ataxia Rating Scale, predicted scores on the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale and REM Behavior Disorder Questionnaire. Median split analyses revealed that cognitive function appeared to be reduced and depressive symptoms were greater for those individuals with poor subjective sleep quality and severe RLS. Importantly, sleep appears to play a mediatory role between disease severity and depressive symptoms. CONCLUSIONS: These results suggest that disturbed sleep may have detrimental effects on cognition and affect in individuals with cerebellar ataxia. While objective measures are needed, such results suggest that treating sleep deficits in these individuals may improve cognitive and mental health as well as overall quality of life. PMID- 24812540 TI - Effects of pregabalin in patients with hypnotic-dependent insomnia. AB - STUDY OBJECTIVES: Long-term use of hypnotics runs the risk of dependency, and subjects usually experience difficulties in withdrawal. The objective of this study was to investigate the success of withdrawal using pregabalin and its efficacy on sleep in patients with hypnotic-dependent insomnia. METHODS: We enrolled patients with hypnotic-dependent insomnia who were 18 years or older. The starting dosage of pregabalin was 75 mg/day and was increased up to as much as 300 mg/day, depending on the individual patient's condition, while tapering off hypnotics. After 4 weeks of titration, the final dosage amount was maintained for at least another 4 weeks. Sleep and clinical variables were evaluated at baseline and after treatment, using the Korean versions of various sleep questionnaires as well as polysomnography. RESULTS: Forty subjects were enrolled, with a mean age of 52.0 +/- 8.5 years, of whom 28 (70.0%) were women. Twenty-one (52.5%) subjects successfully withdrew from hypnotics. The duration of withdrawal was 42.1 +/- 16.0 days (range: 27.0~84.0). The mean pregabalin dose was 121.4 +/- 69.0 mg/day (range: 75.0~300.0). After pregabalin treatment, there was a significant improvement in the total score of the Pittsburgh Sleep Quality Index (15.0 +/- 2.1, 8.9 +/- 3.0, p < 0.001), and insomnia severity index (20.9 +/- 4.3, 9.6 +/- 4.4, p < 0.001); however, most of the sleep variables of the PSG showed no differences. The main adverse effects of pregabalin were nausea and dizziness. CONCLUSIONS: Our results showed pregabalin may be a promising candidate for withdrawal from hypnotics and improved sleep in patients with hypnotic-dependent insomnia. PMID- 24812541 TI - A psychometric study of the Fear of Sleep Inventory-Short Form (FoSI-SF). AB - STUDY OBJECTIVES: Fear of sleep may play a significant role in sleep disturbances in individuals with posttraumatic stress disorder (PTSD). This report describes a psychometric study of the Fear of Sleep Inventory (FoSI), which was developed to measure this construct. METHODS: The psychometric properties of the FoSI were examined in a non-clinical sample of 292 college students (Study I) and in a clinical sample of 67 trauma-exposed adults experiencing chronic nightmares (Study II). Data on the 23 items of the FoSI were subjected to exploratory factor analyses (EFA) to identify items uniquely assessing fear of sleep. Next, reliability and validity of a 13-item version of the FoSI was examined in both samples. RESULTS: A 13-item Short-Form version (FoSI-SF) was identified as having a clear 2-factor structure with high internal consistency in both the non clinical (alpha = 0.76-0.94) and clinical (alpha = 0.88-0.91) samples. Both studies demonstrated good convergent validity with measures of PTSD (0.48-0.61) and insomnia (0.39-0.48) and discriminant validity with a measure of sleep hygiene (0.19-0.27). The total score on the FoSI-SF was significantly higher in the clinical sample (mean = 17.90, SD = 12.56) than in the non-clinical sample (mean = 4.80, SD = 7.72); t(357) = 8.85 p < 0.001. CONCLUSIONS: Although all items are recommended for clinical purposes, the data support the use of the 13 item FoSI-SF for research purposes. Replication of the factor structure in clinical samples is needed. Results are discussed in terms of limitations of this study and directions for further research. PMID- 24812542 TI - Correlation of salivary alpha amylase level and adenotonsillar hypertrophy with sleep disordered breathing in pediatric subjects. AB - STUDY OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) and sleep disordered breathing (SDB) can affect the sympathetic adrenomedullary system (SAM). As a biomarker of SAM activity, salivary alpha-amylase (sAA) in pediatric subjects was evaluated whether it has any correlation with polysomnographic (PSG) parameters related to SDB. METHODS: Sixty-seven children who attended our clinic during 1 year were enrolled prospectively and underwent clinical examinations and in-lab polysomnography. The sAA was measured at 2 points--at night before PSG and in the early morning after PSG. RESULTS: Subjects were divided into control (n = 26, apneahypopnea index [AHI] < 1) and OSAS (n = 41, AHI >= 1) groups. The OSAS group was subdivided according to AHI (mild-moderate, 1 <= AHI < 10; severe, AHI >= 10). The sAA subtraction and ratio (p = 0.014 and p < 0.001, respectively) were significantly higher in severe OSAS than in the mild-moderate and control groups. Although oxygen desaturation index (ODI) and AHI were significantly associated with sAA, sAA in the OSAS group was not related to lowest oxygen saturation or adenotonsillar hypertrophy. CONCLUSION: sAA was well related to polysomnographic (PSG) parameters related to SDB, such as AHI and ODI. Therefore, screening test for sAA in children suspected to have SBD may help to identify OSAS patients from control. PMID- 24812544 TI - Complex sleep apnea associated with use of nasal expiratory positive airway (nEPAP) device. AB - Complex sleep apnea syndrome (CompSAS) is characterized by predominant obstructive sleep disordered breathing with evolution of central disordered breathing following exposure to nasal continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea (OSA) patients. We report a case of CompSAS associated with use of a nasal expiratory positive airway (nEPAP, Provent) device. We therefore recommend obtaining objective sleep data to confirm treatment effectiveness of the nEPAP device for OSA prior to long-term prescription. Further research is warranted to understand the underlying pathophysiological mechanisms and risk factors associated with CompSAS. PMID- 24812543 TI - Fish consumption, sleep, daily functioning, and heart rate variability. AB - STUDY OBJECTIVES: This study investigated the effects of fatty fish on sleep, daily functioning and biomarkers such as heart rate variability (HRV), vitamin D status (serum 25-hydroxyvitamin D (25OHD), and eicosapentaenoic acid (EPA, 20:5n 3) + docosahexaenoic acid (DHA, 22:6n-3) in red blood cells. Moreover the relationship among sleep, daily functioning, HRV, vitamin D status, and levels of EPA+DHA was investigated. METHODS: Ninety-five male forensic patients from a secure forensic inpatient facility in the USA were randomly assigned into a Fish or a Control group. The Fish group received Atlantic salmon three times per week from September to February, and the Control group was provided an alternative meal (e.g., chicken, pork, beef), but with the same nutritional value as their habitual diet, three times per week during the same period. Sleep (sleep latency, sleep efficiency, actual sleep time, and actual wake time), self-perceived sleep quality and daily functioning, as well as vitamin D status, EPA+DHA, and HRV, were assessed pre- and post-intervention period. RESULTS: There was a significant increase in sleep latency from pre- to post-test in the Control group. The Fish group reported better daily functioning than the Control group during post-test. Fish consumption throughout the wintertime had also an effect on resting HRV and EPA+DHA, but not on vitamin D status. However, at post-test, the vitamin D status in the Fish group was still closer to the level regarded as optimal compared to the Control group. Vitamin D status correlated negatively with actual wake time and positively with sleep efficiency during pre-test, as well as positively with daily functioning and sleep quality during post-test. Finally, HRV correlated negatively with sleep latency and positively with daily functioning. CONCLUSIONS: Fish consumption seemed to have a positive impact on sleep in general and also on daily functioning, which may be related to vitamin D status and HRV. PMID- 24812545 TI - Advanced practice registered nurses and physician assistants in sleep centers and clinics: a survey of current roles and educational background. AB - STUDY OBJECTIVES: To survey Advanced Practice Registered Nurse (APRN) and Physician Assistant (PA) utilization, roles and educational background within the field of sleep medicine. METHODS: Electronic surveys distributed to American Academy of Sleep Medicine (AASM) member centers and APRNs and PAs working within sleep centers and clinics. RESULTS: Approximately 40% of responding AASM sleep centers reported utilizing APRNs or PAs in predominantly clinical roles. Of the APRNs and PAs surveyed, 95% reported responsibilities in sleep disordered breathing and more than 50% in insomnia and movement disorders. Most APRNs and PAs were prepared at the graduate level (89%), with sleep-specific education primarily through "on the job" training (86%). All APRNs surveyed were Nurse Practitioners (NPs), with approximately double the number of NPs compared to PAs. CONCLUSIONS: APRNs and PAs were reported in sleep centers at proportions similar to national estimates of NPs and PAs in physicians' offices. They report predominantly clinical roles, involving common sleep disorders. Given current predictions that the outpatient healthcare structure will change and the number of APRNs and PAs will increase, understanding the role and utilization of these professionals is necessary to plan for the future care of patients with sleep disorders. Surveyed APRNs and PAs reported a significant deficiency in formal and standardized sleep-specific education. Efforts to provide formal and standardized educational opportunities for APRNs and PAs that focus on their clinical roles within sleep centers could help fill a current educational gap. PMID- 24812546 TI - The future of sleep technology: report from an American Association of Sleep Technologists summit meeting. AB - The American Association of Sleep Technologists (AAST) Board of Directors hosted a Sleep Technology Summit on September 21, 2013 with the goals of identifying changes in the delivery of diagnostic and treatment services to sleep disorders patients, predicting the impact on sleep technologists, identifying new roles for sleep technologists, and determining appropriate education to prepare technologists for the future. A carefully chosen panel of speakers focused on the business skills necessary to provide care cost effectively and the clinical skills that will be essential for the technologist of the future to help care for patients with sleep disorders. A group of selected leaders, educators, and industry professionals reviewed the current state of affairs and examined opportunities to sustain the profession and define the role of the sleep technologist of the future. Facilitated group discussions of these critical topics followed each session. There was a clear consensus that regulatory and economic pressures are changing the way sleep disorders patients are diagnosed and treated. Private insurers are requiring pre-authorization for laboratory sleep studies and are incentivizing home sleep testing for most patients suspected of obstructive sleep apnea. Reimbursement for home testing will be lower than for laboratory testing, and further reductions in overall reimbursement are anticipated. These factors will almost certainly reduce the need for technologists to perform laboratory diagnostic studies and pressure sleep centers to reduce payrolls. Remaining laboratory patients will have more complicated sleep disorders, have more comorbidity, and require a higher level of care than most of the patients currently tested in sleep centers. Testing these patients will require technologists with a higher level of training, experience, and sophistication. A second area of consensus was that the focus in medicine is changing from diagnosis to outcomes. New models of integrated care will include an increased focus on patient education, monitoring, and follow-up. The most effective treatments will require an individualized, patient-centered approach. A workforce analysis shows that the number of trained physician specialists will be inadequate to provide this care. Well-trained sleep medicine practitioners at many levels will be needed to meet treatment goals, including some roles appropriate for sleep technologists. These factors provide challenges and opportunities for sleep technologists. In order to maintain viability as an allied health profession, the majority of sleep technologists will need to be better educated and demonstrate competency in more roles than overnight monitoring and record scoring. Models for this transition already exist, with several programs moving technologists from night work to days and from diagnosis to patient education, provision of treatment, and monitoring of adherence. The challenge for the professional association is to define new roles for sleep technologists and provide the education that the membership will require to flourish in those new roles. PMID- 24812547 TI - A 54-year-old man with acute onset orthopnea and sleep-related hypoxia. PMID- 24812548 TI - Expectancy and the Treatment of Depression: A Review of Experimental Methodology and Effects on Patient Outcome. AB - Expectancies are a class of psychological and neurobiological processes that may be responsible for part of the improvement observed with psychiatric treatments. Patients' expectations can substantially affect the results of clinical trials, and managing them is an important part of clinical care. This review describes the history of research on expectancy effects in Major Depressive Disorder (MDD), the relationship between expectancies and placebo effects, and what is currently known about the mechanisms of action of expectancy. Meta-analyses of antidepressant trials show that placebo response rates are high (typically ~30%) and often larger than the difference in response rates between drug and placebo (typically ~10%). Some of the response to placebo is due to natural history, but a growing literature suggests that much of the improvement on placebo treatment is due to active neurobiological processes related to expectancy. Several studies have shown that higher expectation of therapeutic improvement leads to greater improvement in psychiatric symptoms, particularly in MDD. New research on the mechanisms of action of expectancy is therefore a priority that could lead to improved interventions. This review discusses the evidence to date and methodological considerations in the design of new studies. PMID- 24812549 TI - Effects of the loss of conjunctival Muc16 on corneal epithelium and stroma in mice. AB - PURPOSE: To examine the role of conjunctival Muc16 in the homeostasis of the ocular surface epithelium and stroma using Muc16-null knockout (KO) mice. METHODS: We used KO mice (n = 58) and C57/BL6 (WT) mice (n = 58). Histology and immunohistochemistry were employed to analyze the phenotypes in the ocular surface epithelium. The expression of phospho-Stat3, AP-1 components, interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) in the cornea and conjunctiva was examined. The shape of the nuclei of corneal epithelial cells was examined to evaluate intraepithelial cell differentiation. Epithelial cell proliferation was studied using bromo-deoxyuridine labeling. Finally, the wound healing of a round defect (2-mm diameter) in the corneal epithelium was measured. The keratocyte phenotype and macrophage invasion in the stroma were evaluated after epithelial repair. RESULTS: The loss of Muc16 activated Stat3 signal, affected JunB signal, and upregulated the expression of IL-6 in the conjunctiva. Basal-like cells were observed in the suprabasal layer of the corneal epithelium with an increase in proliferation. The loss of Muc16 accelerated the wound healing of the corneal epithelium. The incidence of myofibroblast appearance and macrophage invasion were more marked in KO stroma than in WT stroma after epithelial repair. CONCLUSIONS: The loss of Muc16 in the conjunctiva affected the homeostasis of the corneal epithelium and stroma. The mechanism might include the upregulation of the inflammatory signaling cascade (i.e., Stat3 signal, and IL-6 expression in the KO conjunctiva). Current data provides insight into the research of the pathophysiology of dry eye syndrome. PMID- 24812551 TI - Longitudinal alterations in the dynamic autoregulation of optic nerve head blood flow revealed in experimental glaucoma. AB - PURPOSE: To use a novel dynamic autoregulation analysis (dAR) to test the hypothesis that the optic nerve head (ONH) blood flow (BF) autoregulation is disrupted during early stages of experimental glaucoma (EG) in nonhuman primates. METHODS: Retinal nerve fiber layer thickness (RNFLT, assessed by optical coherence tomography) and ONH BF (assessed by laser speckle imaging technique) were measured biweekly before and after unilateral laser treatment to the trabecular meshwork. Each nonhuman primate was followed until reaching either an early stage of damage (RNFLT loss < 20%, n = 6) or moderate to advanced stages of damage (RNFLT loss > 20%, n = 9). At each test, dAR was assessed by characterizing ONH BF changes during the first minute of rapid manometrical intraocular pressure (IOP) elevation from 10 to 40 mm Hg. The dAR analysis extracted the following parameters: baseline BF, average BF 10 seconds before IOP elevation; BFDeltamax, maximum BF change from baseline BF; Tr, time from baseline BF to the BFDeltamax; Kr, average descending BF rate. RESULTS: Mean postlaser IOP was 20.2 +/- 5.9 and 12.3 +/- 2.6 mm Hg in EG and control eyes, respectively (P < 0.0001). Compared with prelaser values, baseline BF was higher in early EG, but lower in moderate to advanced EG (P = 0.01). Tr was increased and Kr was reduced in both stages (P < 0.01). BFDeltamax was smaller in the early EG (P = 0.05) and remained low in the moderate to advanced EG (P = 0.15). No changes in the parameters were observed in control eyes. CONCLUSIONS: Chronic IOP elevation causes ONH autoregulation dysfunction in the early stage of EG, characterized by a disrupted BF response and delayed Tr, revealed by dAR analysis. PMID- 24812550 TI - FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression. AB - PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy. PMID- 24812552 TI - Sigma receptor ligand, (+)-pentazocine, suppresses inflammatory responses of retinal microglia. AB - PURPOSE: To evaluate the effects of the sigma 1 receptor (sigmaR1) agonist, (+) pentazocine, on lipopolysaccharide (LPS)-induced inflammatory changes in retinal microglia cells. METHODS: Retinal microglia cells were isolated from Sprague Dawley rat pups. Cells were treated with LPS with or without (+)-pentazocine and with or without the sigmaR1 antagonist BD1063. Morphologic changes were assayed. Cell viability was assessed by using MTT assay. Supernatant levels of tumor necrosis factor alpha (TNF-alpha), interleukin 10, (IL-10), monocyte chemoattractant protein-1 (MCP-1), and nitric oxide (NO) were determined. Reactive oxygen species (ROS) formation was assayed, and levels of mitogen activated protein kinases (MAPKs) were analyzed by using Western blot. RESULTS: The sigmaR1 protein was expressed in retinal microglia. Incubation with LPS and/or (+)-pentazocine did not alter cell viability or sigmaR1 protein levels. Incubation with LPS for 24 hours induced a marked change in microglial morphology and a significant increase in secreted levels of TNF-alpha, IL-10, MCP-1, and NO. Pretreatment with (+)-pentazocine inhibited the LPS-induced morphologic changes. Release of TNF-alpha, IL-10, MCP-1, and NO was reduced with (+)-pentazocine. Intracellular ROS formation was suppressed with (+)-pentazocine. Phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was reduced in the presence of (+)-pentazocine. The sigmaR1 antagonist BD1063 blocked the (+)-pentazocine-mediated inhibition of LPS-induced morphologic changes. In addition, BD1063 treatment blocked (+)-pentazocine-mediated suppression of LPS-induced TNF-alpha, IL-10, MCP-1, NO, and intracellular ROS release. CONCLUSIONS: Treatment with (+)-pentazocine suppressed inflammatory responses of retinal microglia and inhibited LPS-induced activation of ERK/JNK MAPK. In neurodegenerative disease, (+)-pentazocine may exert neuroprotective effects through manipulation of microglia. PMID- 24812554 TI - Parallelism for quantitative image analysis of photoreceptor-retinal pigment epithelium complex alterations in diabetic macular edema. AB - PURPOSE: To propose a new method to quantitatively and comprehensively evaluate photoreceptor-RPE complex alterations on spectral-domain optical coherence tomography (SD-OCT) imaging in eyes with diabetic macular edema (DME). METHODS: Spectral-domain OCT images from a consecutive series of 90 eyes in 79 patients with DME and 30 healthy eyes in 30 volunteers were analyzed retrospectively. The subfoveal area covering the photoreceptor layers was skeletonized and the orientation of the segmented lines was termed "parallelism," which reflects image complexity. Photoreceptor layer status at the fovea was categorized by graders, including continuity of the external limiting membrane (ELM) line, inner segment ellipsoid line, and the presence of hyperreflective foci in the outer retinal layers. The relationships among parallelism, visual acuity, and photoreceptor layer status were evaluated. RESULTS: Parallelism was significantly lower in eyes with DME than in normal eyes (P < 0.0001), and correlated strongly with visual acuity in eyes with DME (R = -0.592; P < 0.0001). Eyes with an intact inner segment ellipsoid line or ELM line had significantly better visual acuity (VA) and higher parallelism than eyes with a discontinuous or absent inner segment ellipsoid line or ELM line. Parallelism was significantly higher (P < 0.0001) and logMAR VA significantly better (P < 0.0001) in the group without hyperreflective foci in the outer retinal layers than in the group with hyperreflective foci in the outer retinal layers. CONCLUSIONS: Parallelism has the potential to reflect structural changes of the photoreceptor layers in DME. PMID- 24812555 TI - Dysregulation of CXCR3 expression on peripheral blood leukocytes in patients with neovascular age-related macular degeneration. AB - PURPOSE: The chemokine receptor CXCR3 has been strongly related to inhibition of angiogenesis. The purpose of this study was to investigate the association between expression of CXCR3 on peripheral blood leukocytes and age-related wet macular degeneration. Furthermore, we measured the plasma concentration of chemokines CXCL9 to -11. METHODS: The study group consisted of patients with age related macular degeneration (AMD) attending our department. Patients referred for reasons other than AMD were enrolled as control subjects. The expression of CXCR3 on T cells and the plasma concentration of CXCL9 to -11 were measured using flow cytometry. RESULTS: We looked at all CD8(+) T cells expressing CXCR3 and found a significantly lower percentage of these cells in the neovascular AMD group compared to the age-matched control group (P = 0.05). When dividing the CD8(+) cells into functional groups according to their expression of CXCR3, we found a significantly lower percentage of CD8(+) CXCR3(high) cells in the group with neovascular AMD compared to the control group (P = 0.038). We found a lower percentage of CD4(+)CD69(+)CXCR3(+) T cells in the group of patients with neovascular AMD when compared to the age-matched control group (P = 0.052). CONCLUSIONS: Our results point toward a systemic dysregulation of CXCR3 in patients with neovascular AMD. Since there is evidence to suggest that CXCR3 is able to alter the response of VEGF, the primary driver of choroidal neovascularization (CNV) formation, low levels of CXCR3 could potentially drive some patients toward a more angiogenic profile leading to CNV formation and growth. CXCR3-enhancing molecules could therefore be a possible target for treatment of AMD. PMID- 24812556 TI - Object detection based on template matching through use of best-so-far ABC. AB - Best-so-far ABC is a modified version of the artificial bee colony (ABC) algorithm used for optimization tasks. This algorithm is one of the swarm intelligence (SI) algorithms proposed in recent literature, in which the results demonstrated that the best-so-far ABC can produce higher quality solutions with faster convergence than either the ordinary ABC or the current state-of-the-art ABC-based algorithm. In this work, we aim to apply the best-so-far ABC-based approach for object detection based on template matching by using the difference between the RGB level histograms corresponding to the target object and the template object as the objective function. Results confirm that the proposed method was successful in both detecting objects and optimizing the time used to reach the solution. PMID- 24812553 TI - Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis. AB - PURPOSE: Loss-of-function mutations in hemojuvelin (HJV) cause juvenile hemochromatosis, an iron-overload disease. Deletion of Hjv in mice results in excessive iron accumulation and morphologic changes in the retina. Here, we studied the retinal vasculature in Hjv(-/-) mice. METHODS: Age-matched wild-type and Hjv(-/-) mice were used for fluorescein angiography and preparation of retinal cryosections, flat-mounts, and trypsin-digested blood vessels. Retinal angiogenesis was monitored by immunofluorescent detection of isolectin-B4, endoglin, and VEGF. Retinal vasculogenesis was monitored by immunofluorescent detection of collagen IV. Reactive gliosis was assessed based on the expression of glial fibrillary acidic protein and vimentin and CD11b/c as markers for Muller cells and microglia. RESULTS: Between 18 and 24 months of age, retinas of Hjv(-/ ) mice displayed marked disruptions in angiogenesis and vasculogenesis. Blood vessels in Hjv(-/-) mice were tortuous and dilated, with a decrease in the tight junction protein occludin. There was also evidence of neovascularization in Hjv( /-) mice with blood vessels appearing in the vitreous, which were leaky. There was reactive gliosis in these mice involving both Muller cells and microglia. Such changes were not detected at 2 weeks of age. Even at the age of 4 months, retinas of Hjv(-/-) mice were almost normal with changes just beginning to appear. Thus, the vascular changes in Hjv(-/-) mouse retinas represent an age dependent phenomenon. CONCLUSIONS: Deletion of Hjv in mice leads to abnormal retinal angiogenesis/vasculogenesis, with proliferation of new, leaky blood vessels in the vitreous. These changes are accompanied with reactive gliosis involving Muller cells and microglia. PMID- 24812557 TI - The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort. AB - Colorectal cancers arising via the serrated pathway are often associated with BRAF V600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association between BRAF V600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such as MLH1, p16, and IGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated with BRAF mutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%). MLH1 methylation was mainly observed in the proximal colon and was significantly associated with BRAF mutation and CIMP-high. The number of samples methylated for p16 and IGFBP7 was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes. PMID- 24812558 TI - Testosterone deficiency, cardiac health, and older men. AB - Low levels of testosterone are manifested by erectile dysfunction, reduced sexual desire, and loss of morning erections with increasing numbers of men are being diagnosed and require treatment. The prevalence rates of testosterone deficiency vary according to different studies but may be as high as 40% in populations of patients with type 2 diabetes. There is increasing evidence that testosterone deficiency is associated with increased cardiovascular and all-cause mortality. Screening for low testosterone is recommended in a number of high risk groups including those with type 2 diabetes and metabolic syndrome. There are recent data to suggest that testosterone replacement therapy may reduce cardiovascular mortality as well as improving multiple surrogate markers for cardiovascular events. Specific clinical trials of testosterone replacement therapy are needed in selected populations but in the meantime we must treat patients based on the best current evidence. PMID- 24812559 TI - Repeat FNA Significantly Lowers Number of False Negative Results in Patients with Benign Nodular Thyroid Disease and Features of Chronic Thyroiditis. AB - Purpose. The aim of the study was to compare the risk of thyroid malignancy and efficacy of repeat FNA in patients with thyroid nodules diagnosed cytologically as benign lesion (BL) with features of chronic thyroiditis (BL-CT) and BL without CT features (BL-nCT). Methods. The analysis included 917 patients with BL-CT and 7046 with BL-nCT in the first FNA. Repeat biopsy was carried out in 787 patients of BL-CT and 5147 of BL-nCT; 218 patients of BL-CT and 2462 of BL-nCT were operated; in 88 cases of BL-CT and 563 of BL-nCT both ways of follow-up were available. Results. Outcome of repeat cytology implied surgery more frequently in patients with BL-CT than with BL-nCT-3.2% versus 1.9%, P < 0.05. Incidence of cancer (including incidentalomas) was higher in patients with BL-CT operated after one benign cytology than in patients with two benign FNA outcomes: 10.8% versus 1.6%, P < 0.05. In patients with BL-nCT that difference was not significant: 3.2% versus 2.6%. Conclusions. Patients with thyroid nodules diagnosed as BL with CT features have higher risk of malignancy than patients with BL without CT features. Repeat biopsy significantly lowers percentage of FN results in patients with BL-CT in the first FNA. PMID- 24812560 TI - Removal of total coliforms, thermotolerant coliforms, and helminth eggs in Swine production wastewater treated in anaerobic and aerobic reactors. AB - The present work evaluated the performance of two treatment systems in reducing indicators of biological contamination in swine production wastewater. System I consisted of two upflow anaerobic sludge blanket (UASB) reactors, with 510 and 209 L in volume, being serially arranged. System II consisted of a UASB reactor, anaerobic filter, trickling filter, and decanter, being also organized in series, with volumes of 300, 190, 250, and 150 L, respectively. Hydraulic retention times (HRT) applied in the first UASB reactors were 40, 30, 20, and 11 h in systems I and II. The average removal efficiencies of total and thermotolerant coliforms in system I were 92.92% to 99.50% and 94.29% to 99.56%, respectively, and increased in system II to 99.45% to 99.91% and 99.52% to 99.93%, respectively. Average removal rates of helminth eggs in system I were 96.44% to 99.11%, reaching 100% as in system II. In reactor sludge, the counts of total and thermotolerant coliforms ranged between 10(5) and 10(9) MPN (100 mL)(-1), while helminth eggs ranged from 0.86 to 9.27 eggs g(-1) TS. PMID- 24812561 TI - A case series of emphysematous pyelonephritis. AB - Introduction. Emphysematous pyelonephritis (EPN) is an uncommon infection characterized by gas in the renal parenchyma and surrounding tissues. It is rapidly progressive, requiring appropriate therapy to salvage the infected kidney. Case Description. The case series presents 5 patients with a clinical and radiologic diagnosis of EPN. Each patient had a unique predisposing factor for developing EPN. Early goal directed therapy with intravenous fluids and antibiotics was given. This was followed by less invasive urologic interventions in an attempt to avoid nephrectomy and thereby salvage the infected kidney. All five patients were discharged in clinically stable conditions. Discussion and Conclusion. This case series provides added practice based support to available literature for managing EPN. Early goal directed medical therapy for sepsis coupled with interventional urologic procedures is a valuable alternative to circumvent an upfront emergent nephrectomy, except in cases where a fulminant infection may be present at the time of admission or develop later on in the course of the patients illness despite conservative line of therapy. It also highlights the importance of considering a diagnosis of EPN in patients with urinary infections, who have certain common predisposing factors listed in our case series. PMID- 24812562 TI - Plasmodium falciparum Malaria Complicated by Symmetrical Peripheral Gangrene, Bowel Ischemia, Repeated Candidemia, and Bacteraemia. AB - A 63-year-old Caucasian woman developed severe Plasmodium falciparum malaria when travelling back from Cameroun. No antimalarial chemoprophylaxis had been observed. The patient was immediately admitted to the intensive care unit after evidence of multiple organ failure (coma, shock, acute respiratory distress syndrome, acute renal failure, etc.). However, initial parasitemia was less than 1%. The patient was managed by intravenous quinine and norepinephrine infusion due to refractory shock. The patient developed as an early complication ischemic lesions of both arms and feet. In addition to laboratory changes consistent with disseminated intravascular coagulation, there was also evidence for a low activity of the von Willebrand factor (VWF) cleaving protease ADAMTS13. Later complications included repeated candidemia and bacteraemia despite appropriate therapy; the origin appeared to be diffuse ischemic injury of the gastrointestinal tract. The patient ultimately recovered, but quadriamputation was necessary to treat symmetrical peripheral gangrene (SPG). In severe Plasmodium falciparum malaria, ischemic changes may be due to microvascular obstruction, but, in patients with low parasitemia, other endothelial factors may also be involved as observed in other groups of thrombotic microangiopathies. PMID- 24812563 TI - The effect of probiotics on childhood constipation: a randomized controlled double blind clinical trial. AB - Background. Inconsistent data exist about the role of probiotics in the treatment of constipated children. The aim of this study was to investigate the effectiveness of probiotics in childhood constipation. Materials and Methods. In this placebo controlled trial, fifty-six children aged 4-12 years with constipation received randomly lactulose plus Protexin or lactulose plus placebo daily for four weeks. Stool frequency and consistency, abdominal pain, fecal incontinence, and weight gain were studied at the beginning, after the first week, and at the end of the 4th week in both groups. Results. Forty-eight patients completed the study. At the end of the fourth week, the frequency and consistency of defecation improved significantly (P = 0.042 and P = 0.049, resp.). At the end of the first week, fecal incontinence and abdominal pain improved significantly in intervention group (P = 0.030 and P = 0.017, resp.) but, at the end of the fourth week, this difference was not significant (P = 0.125 and P = 0.161, resp.). A significant weight gain was observed at the end of the 1st week in the treatment group. Conclusion. This study showed that probiotics had a positive role in increasing the frequency and improving the consistency at the end of 4th week. PMID- 24812564 TI - Long-term effects of goshajinkigan in prevention of diabetic complications: a randomized open-labeled clinical trial. AB - Objective. This clinical trial was designed to investigate whether goshajinkigan reduces the onset of diabetic complications or not. Materials and Methods. A total of 332 type 2 diabetic mellitus patients were registered from 9 clinical centers from March 2000 to August 2007. Patients were randomly assigned to take goshajinkigan extract powder, 2.5 grams for 3 times a day or no kampo therapy, additionally to the regular treatment. The primary endpoints were the onset of macrovascular diseases or progression of nephropathy or retinopathy. Statistical analysis was performed by the intention-to-treat method. Results. After 5 years of observation, 116 patients were submitted to analysis. Among them, no macrovascular events were observed in both groups. Although 43 participants had upstaging of retinopathy or nephropathy in total, there was no significant difference between goshajinkigan group and control group. Deterioration of ankle reflex was suppressed in goshajinkigan group. Also glycated hemoglobin, and fasting plasma glucose were decreased in the goshajinkigan group. Conclusion. Although the power of analysis was too low to demonstrate any effects of goshajinkigan on the progression of macrovascular diseases, retinopathy or nephropathy, goshajinkigan may be beneficial for diabetic neuropathy and glycemic control. PMID- 24812565 TI - Protection Effect of Zhen-Wu-Tang on Adriamycin-Induced Nephrotic Syndrome via Inhibiting Oxidative Lesions and Inflammation Damage. AB - Zhen-wu-tang (ZWT), a well-known formula in China, is widely used to treat chronic kidney diseases. However, very little information on ZWT's mechanism of action is currently available. In this study, we investigated the possible protective role and underlying mechanism of ZWT on nephrotic syndrome (NS) induced by Adriamycin (intravenous injection, 6.0 mg/kg) in rats using biochemical and histopathological approaches. ZWT decreased urine protein excretion and the serum levels of total cholesterol, triglycerides, blood urea nitrogen, and creatinine significantly in diseased rats. A decrease in plasma levels of total protein and albumin was also recorded in nephropathic rats. Pathological results show an improved pathological state and recovering glomerular structure in ZWT treatment groups. ZWT decreased renal IL-8 level but increased renal IL-4 level. In addition, rats subjected to ZWT exhibited less IgG deposition in glomerulus compared with model group. RT-PCR results showed that ZWT decreased the mRNA expression of NF- kappa B p65 and increased the mRNA expression of I kappa B. Furthermore, ZWT reduced the level of MDA and increased SOD activity. These results demonstrated that ZWT ameliorated Adriamycin-induced NS in rats possibly by inhibiting Adriamycin-induced inflammation damage, enhancing body's antioxidant capacity, thereby protecting glomerulus from injury. PMID- 24812566 TI - Effects of acupuncture applied to sanyinjiao with different stimuli on uterine contraction and microcirculation in rats with dysmenorrhea of cold coagulation syndrome. AB - In this study, we try to evaluate the effects of acupuncture stimulation with different amounts at Sanyinjiao (SP6) on uterine contraction and uterus microcirculation in rats with dysmenorrhea of cold coagulation syndrome and to explore whether there is direct relativity between "De qi" and needle stimulus intensity. Diestrus female rats were randomly divided into 4 groups, including saline control group, model control group, "A" stimulus group (with strong stimulus), and "B" stimulus group (with weak stimulus). We found that dysmenorrhea rats of the cold coagulation syndrome present a high intensity in uterine tension and high contraction of microvascular diameter. Acupuncture applied with two different stimuli could relieve the symptoms, but, compared with "B" stimulus, "A" stimulus leads to better outcomes on reducing uterine contraction and increasing diameter of uterine microvascular; moreover, hand manipulation during needling mediates the curative effect on the microvascular diameter. Our finding indicates that using thick needles and deep insertion with hand manipulation are more effective and achieve desired level of "De qi" in dysmenorrhea rats. PMID- 24812567 TI - Effect of "jian-pi-zhi-dong decoction" on gamma-aminobutyric Acid in a mouse model of tourette syndrome. AB - The purpose of this study was to explore the positive effects of Jian-Pi-Zhi-Dong Decoction (JPZDD) on Tourette syndrome (TS) by investigating the expression of gamma-aminobutyric acid (GABA) and its type A receptor (GABAAR) in the striatum of a TS mice model. The model was induced by 3,3'-iminodipropionitrile (IDPN) treatment; then mice were divided into 4 groups (n=22, each); control and IDPN groups were gavaged with saline and the remaining 2 groups were gavaged with tiapride and JPZDD. We recorded the stereotypic behaviors of TS mice and measured the content of GABA in striatum by HPLC and GABAAR expression by immunohistochemistry and real-time PCR. Our results showed that JPZDD inhibited the abnormal behaviors of TS model mice and decreased GABA levels and GABAAR protein and mRNA expression in the striatum of TS model mice. In brief, the mechanism by which JPZDD alleviates TS symptoms may be associated with GABAAR expression downregulation in striatum which may regulate GABA metabolism. PMID- 24812568 TI - Extracts and Fractions from Edible Roots of Sechium edule (Jacq.) Sw. with Antihypertensive Activity. AB - Sechium edule is traditionally used in Mexico as a therapeutic resource against renal diseases and to control high blood pressure. The purpose of this work is to evaluate the antihypertensive effect of the hydroalcoholic extract obtained from the roots of this plant, including its fractions and subfractions, on different hypertension models induced with angiotensin II (AG II). The hydroalcoholic extract was tested on an in vitro study of isolated aorta rings denuded of endothelial cells, using AG II as the agonist; this assay proved the vasorelaxant effect of this extract. Vagotomized rats were administered different doses of AG II as well as the Hydroalcoholic extract, which reduced blood pressure in 30 mmHg approximately; subsequently this extract was separated into two fractions (acetone and methanol) which were evaluated in the acute hypertension mouse model induced with AG II, where the acetone fraction was identified as the most effective one and was subsequently subfractioned using an open chromatographic column packed with silica gel. The subfractions were also evaluated in the acute hypertension model. Finally, the extract, fraction, and active subfraction were analyzed by MS-PDA-HPLC, identifying cinnamic derivative compounds like cinnamic acid methyl ester. PMID- 24812569 TI - Proapoptotic and Antiproliferative Effects of Thymus caramanicus on Human Breast Cancer Cell Line (MCF-7) and Its Interaction with Anticancer Drug Vincristine. AB - Thymus caramanicus Jalas is one of the species of thymus that grows in the wild in different regions of Iran. Traditionally, leaves of this plant are used in the treatment of diabetes, arthritis, and cancerous situation. Therefore, the present study was designed to investigate the selective cytotoxic and antiproliferative properties of Thymus caramanicus extract (TCE). MCF-7 human breast cancer cells were used in this study. Cytotoxicity of the extract was determined using MTT and neutral red assays. Biochemical markers of apoptosis (caspase 3, Bax, and Bcl-2) and cell proliferation (cyclin D1) were evaluated by immunoblotting. Vincristine was used as anticancer control drug in extract combination therapy. The data showed that incubation of cells with TCE (200 and 250 MU g/mL) significantly increased cell damage, activated caspase 3 and Bax/Bcl2 ratio. In addition, cyclin D1 was significantly decreased in TCE-treated cells. Furthermore, concomitant treatment of cells with extract and anticancer drug produced a significant cytotoxic effect as compared to extract or drugs alone. In conclusion, thymus extract has a potential proapoptotic/antiproliferative property against human breast cancer cells and its combination with chemotherapeutic agent vincristine may induce cell death effectively and be a potent modality to treat this type of cancer. PMID- 24812570 TI - A wonderful network unraveled - Detailed description of capillaries in the prosomal ganglion of scorpions. AB - INTRODUCTION: Though it has long been known that the prosomal ganglion of scorpions is supplied by a dense system of arteries, the pattern of this network has never been described and analyzed in detail. Using MicroCT in combination with computer aided 3D-reconstruction we provide the first detailed description of the pattern of arteries in the prosomal ganglion of Brotheas granulatus (Scorpiones, Chactidae) and other scorpion species. RESULTS: The entire prosomal ganglion in scorpions is supplied by a network of arteries that branch off the major arteries of the anterior aorta system. The most prominent of these are the nine transganglionic arteries which run through the nerve mass along the midline of the body and branch terminally, i.e. below the neuropils, into smaller arteries. These arteries reticulate into a dense network between the surrounding somata and the centrally located neuropil structures of the ganglion. CONCLUSIONS: We demonstrate the presence in the prosomal ganglion of scorpions of a capillary system made up of afferent arteries which deliver hemolymph into the ganglion and efferent arteries which transport the hemolymph out of the ganglion. Adopting the structural definition used for vertebrate circulatory systems, this capillary network can also be termed a bipolar rete mirabile (located as it is between afferent and efferent arteries) analogous to those found in vertebrates and some echinoderms. Within the rete mirabile of the scorpion prosomal ganglion, some regions (i.e. neuropils) are better supplied than others. The structural information provided here can now be used in functional neuronal studies to determine the physiological and computational significance of the various neuropils in the complex scorpion nervous system. PMID- 24812571 TI - Integrating gene expression and protein interaction data for signaling pathway prediction of Alzheimer's disease. AB - Discovering the signaling pathway and regulatory network would provide significant advance in genome-wide understanding of pathogenesis of human diseases. Despite the rich transcriptome data, the limitation for microarray data is unable to detect changes beyond transcriptional level and insufficient in reconstructing pathways and regulatory networks. In our study, protein-protein interaction (PPI) data is introduced to add molecular biological information for predicting signaling pathway of Alzheimer's disease (AD). Combining PPI with gene expression data, significant genes are selected by modified linear regression model firstly. Then, according to the biological researches that inflammation reaction plays an important role in the generation and deterioration of AD, NF- kappa B (nuclear factor-kappa B), as a significant inflammatory factor, has been selected as the beginning gene of the predicting signaling pathway. Based on that, integer linear programming (ILP) model is proposed to reconstruct the signaling pathway between NF- kappa B and AD virulence gene APP (amyloid precursor protein). The results identify 6 AD virulence genes included in the predicted inflammatory signaling pathway, and a large amount of molecular biological analysis shows the great understanding of the underlying biological process of AD. PMID- 24812572 TI - Mathematical modeling of transmission dynamics and optimal control of vaccination and treatment for hepatitis B virus. AB - Hepatitis B virus (HBV) infection is a worldwide public health problem. In this paper, we study the dynamics of hepatitis B virus (HBV) infection which can be controlled by vaccination as well as treatment. Initially we consider constant controls for both vaccination and treatment. In the constant controls case, by determining the basic reproduction number, we study the existence and stability of the disease-free and endemic steady-state solutions of the model. Next, we take the controls as time and formulate the appropriate optimal control problem and obtain the optimal control strategy to minimize both the number of infectious humans and the associated costs. Finally at the end numerical simulation results show that optimal combination of vaccination and treatment is the most effective way to control hepatitis B virus infection. PMID- 24812573 TI - Propolis volatile compounds: chemical diversity and biological activity: a review. AB - Propolis is a sticky material collected by bees from plants, and used in the hive as building material and defensive substance. It has been popular as a remedy in Europe since ancient times. Nowadays, propolis use in over-the-counter preparations, "bio"-cosmetics and functional foods, etc., increases. Volatile compounds are found in low concentrations in propolis, but their aroma and significant biological activity make them important for propolis characterisation. Propolis is a plant-derived product: its chemical composition depends on the local flora at the site of collection, thus it offers a significant chemical diversity. The role of propolis volatiles in identification of its plant origin is discussed. The available data about chemical composition of propolis volatiles from different geographic regions are reviewed, demonstrating significant chemical variability. The contribution of volatiles and their constituents to the biological activities of propolis is considered. Future perspectives in research on propolis volatiles are outlined, especially in studying activities other than antimicrobial. PMID- 24812574 TI - Heterogeneous base catalysts for edible palm and non-edible Jatropha-based biodiesel production. AB - BACKGROUND: Transesterification catalyzed by solid base catalyst is a brilliant technology for the noble process featuring the fast reaction under mild reacting condition in biodiesel production. Heterogeneous base catalysts are generally more reactive than solid acid catalysts which require extreme operating condition for high conversion and biodiesel yield. In the present study, synthesis of biodiesel was studied by using edible (palm) or non-edible (Jatropha) feedstock catalyzed by heterogeneous base catalysts such as supported alkali metal (NaOH/Al2O3), alkaline-earth metal oxide (MgO, CaO and SrO) and mixed metal oxides catalysts (CaMgO and CaZnO). RESULTS: The chemical characteristic, textural properties, basicity profile and leaching test of synthesized catalysts were studied by using X-ray diffraction, BET measurement, TPD-CO2 and ICP-AES analysis, respectively. Transesterification activity of solid base catalysts showed that > 90% of palm biodiesel and > 80% of Jatropha biodiesel yield under 3 wt.% of catalyst, 3 h reaction time, methanol to oil ratio of 15:1 under 65 degrees C. This indicated that other than physicochemical characteristic of catalysts; different types of natural oil greatly influence the catalytic reaction due to the presence of free fatty acids (FFAs). CONCLUSIONS: Among the solid base catalysts, calcium based mixed metal oxides catalysts with binary metal system (CaMgO and CaZnO) showed capability to maintain the transesterification activity for 3 continuous runs at ~ 80% yield. These catalysts render high durability characteristic in transesterification with low active metal leaching for several cycles. PMID- 24812575 TI - The Bangla clubfoot tool: a repeatability study. AB - BACKGROUND: 'Walk for Life' (WFL) is the sustainable clubfoot program in Bangladesh, where there are many challenges in implementing the Ponseti technique in a poor and highly populated country. The relapsing tendency of congenital clubfoot deformity means that initial results may well differ from those of the medium and longer term. Over 10000 children with16668 clubfeet have been treated by WFL since its inception in 2009. Such a large project provides both the need to evaluate each individual child's case, and also the opportunity to evaluate the wider WFL program results. Such systematic review requires a measure that is sufficiently robust, yet contextually practical, hence the aim of this work was to develop a tool for this purpose, and to report the examiner reliability. METHODS: The Bangla clubfoot tool was largely developed from components of existing validated clubfoot assessment measures, and adapted for local use. Three areas of examination are included: parent satisfaction, gait, clinical examination of the clubfoot. A same-subject repeated measures study design was used to assess the intra-rater reliability of a local WFL physiotherapist, and a visiting WFL volunteer. The inter-rater reliability was also assessed, which is relevant for other examiners and other clubfoot projects undertaking evaluation of medium and longer term results. RESULTS: The reliability study was conducted in 37 children who had commenced treatment for congenital clubfoot deformity using Ponseti method within the previous two years. The mean age of the children was 2.6 years, with gender 28 male: 9 female. The intra-rater reliability results [ICCs (95% CI)] were: 0.87 (0.76 - 0.93) for the local WFL examiner, and 0.82 (0.64 - 0.91) for the visiting examiner. Inter-rater reliability results [ICCs (95% CI)] were: 0.92 (0.88 - 0.96). Hence the tool showed very good intra-rater and inter-rater reliability, rendering it suitable for use. CONCLUSIONS: The Bangla clubfoot tool has been developed to suit the context of the large WFL clubfoot program in Bangladesh, and shown to be a very reliable evaluation instrument. PMID- 24812576 TI - Muscle weakness and myalgia as the initial presentation of serous ovarian carcinoma: a case report. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) has one of the worst prognoses among gynecologic cancers. An appropriate screening method is not available for EOC, and the initial symptoms such as abdominal pain or bloating, anorexia, and urinary urgency are vague. As a result, most cases of EOC are diagnosed at an advanced stage. CASE PRESENTATION: We report novel insights gained from the case of a 45-year-old, gravida 0, para 0 woman who presented to the emergency department with complaints of general weakness, fatigue, and myalgia over the previous two months. She reported progressive muscle weakness of the upper and lower extremities leading to difficulty walking. Serum muscle enzymes, such as creatine phosphokinase, were markedly elevated. No evidence of malignancy was detected upon imaging. A biopsy of the left vastus medialis muscle was performed, and the results were consistent with primary myopathy with myofibrillar disarray, suggesting paraneoplastic necrotizing myopathy. Explorative laparotomy was performed to evaluate these results, and histopathological analysis of the full specimen revealed a grade 3 ovarian serous adenocarcinoma with direct invasion to the rectum. CONCLUSIONS: Because of the lack of screening tools for EOC, any clinical findings suggesting its presence are valuable, and the possibility of EOC should be considered in unknown primary malignancies with initial complaints of muscle weakness or myalgia. PMID- 24812577 TI - MIER1 (mesoderm induction early response 1 homolog (Xenopus laevis)). PMID- 24812580 TI - Uniaxial cyclic strain of human adipose-derived mesenchymal stem cells and C2C12 myoblasts in coculture. AB - Tissue engineering skeletal muscle in vitro is of great importance for the production of tissue-like constructs for treating tissue loss due to traumatic injury or surgery. However, it is essential to find new sources of cells for muscle engineering as efficient in vitro expansion and culture of primary myoblasts are problematic. Mesenchymal stem cells may be a promising source of myogenic progenitor cells and may be harvested in large numbers from adipose tissue. As skeletal muscle is a mechanically dynamic tissue, we have investigated the effect of cyclic mechanical strain on the myogenic differentiation of a coculture system of murine C2C12 myoblasts and human adipose-derived mesenchymal stem cells. Fusion of mesenchymal stem cells with nascent myotubes and expression of human sarcomeric proteins was observed, indicating the potential for myogenic differentiation of human mesenchymal stem cells. Cyclic mechanical strain did not affect the fusion of mesenchymal stem cells, but maturation of myotubes was perturbed. PMID- 24812578 TI - Intimate Partner Violence among California Couples: Multilevel Analysis of Environmental and Partner Risk Factors. AB - This study assessed the extent to which environmental (Census block-group alcohol outlet density, neighborhood demographic characteristics) and partner risk factors (e.g., hazardous drinking, psychosocial characteristics) contribute to the likelihood of intimate partner violence among 1,753 couples residing in 50 medium-to-large California cities. Multilevel logistic regression models were used to analyze the role of alcohol outlets (off-premise outlets, bars/pubs and restaurants), neighborhood demographic characteristics, and partner risk factors in relation to male-to-female partner violence (MFPV) and female-to-male partner violence (FMPV) risk. Approximately 12% of couples reported past-year partner violence. Results showed that none of the environmental measures were related to MFPV or FMPV. Male partner's impulsivity and each partner's adverse childhood experiences were associated with MFPV risk. Risk factors for FMPV were male partner's impulsivity and frequency of intoxication and female partner's adverse childhood experiences. Individual/couple characteristics appear to be the most salient IPV risk factors. The male partner's heavy drinking may lead to negative partner/spousal interactions that result in FMPV. The male partner's impulsivity, and each partner's adverse childhood experiences, may potentiate couple conflict and result in aggression. Interventions that target prevention of family dysfunction during childhood may help reduce interpersonal violence in adulthood. PMID- 24812579 TI - Freeze-dried allograft-mediated gene or protein delivery of growth and differentiation factor 5 reduces reconstructed murine flexor tendon adhesions. AB - Advances in allograft processing have opened new horizons for clinical adaptation of flexor tendon allografts as delivery scaffolds for antifibrotic therapeutics. Recombinant adeno-associated-virus (rAAV) gene delivery of the growth and differentiation factor 5 (GDF-5) has been previously associated with antifibrotic effects in a mouse model of flexor tendoplasty. In this study, we compared the effects of loading freeze-dried allografts with different doses of GDF-5 protein or rAAV-Gdf5 on flexor tendon healing and adhesions. We first optimized the protein and viral loading parameters using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and in vivo bioluminescent imaging. We then reconstructed flexor digitorum longus (FDL) tendons of the mouse hindlimb with allografts loaded with low and high doses of recombinant GDF-5 protein and rAAV-Gdf5 and evaluated joint flexion and biomechanical properties of the reconstructed tendon. In vitro optimization studies determined that both the loading time and concentration of the growth factor and viral vector had dose-dependent effects on their retention on the freeze-dried allograft. In vivo data suggest that protein and gene delivery of GDF-5 had equivalent effects on improving joint flexion function, in the range of doses used. Within the doses tested, the lower doses of GDF-5 had more potent effects on suppressing adhesions without adversely affecting the strength of the repair. These findings indicate equivalent antifibrotic effects of Gdf5 gene and protein delivery, but suggest that localized delivery of this potent factor should also carefully consider the dosage used to eliminate untoward effects, regardless of the delivery mode. PMID- 24812581 TI - Extracellular matrix formation in self-assembled minimalistic bioactive hydrogels based on aromatic peptide amphiphiles. AB - The hitherto inconsistency in clinical performance for engineered skin drives the current development of novel cell-scaffolding materials; one challenge is to only extract essential characteristics from the complex native ECM (extracellular matrix) and incorporate them into a scaffold with minimal complexity to support normal cell functions. This study involved small-molecule-based bioactive hydrogels produced by the co-assembly of two aromatic peptide amphiphiles: Fmoc FF (Fluorenylmethoxycarbonyl-diphenylalanine) and Fmoc-RGD (arginine-glycine aspartic acid). Three-dimensionally cultured human dermal fibroblasts deposited dense ECM networks including fibronectin and collagen I within the hydrogels in a 14-day culture. The fibroblasts organized the fibrous ECM and contracted the gel without differentiating into myofibroblasts. The stiffness of the cell-gel constructs increased dramatically due to ECM formation and gel contraction. This created an economical biomimetic model-scaffold to further understand skin reconstruction in vitro and supplied a design pathway to create versatile cell scaffolds with varied bioactivities and simplicity. PMID- 24812582 TI - Immunogenicity of undifferentiated and differentiated allogeneic mouse mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) are multipotential cells with utility in tissue engineering and regenerative medicine. However, the immunological properties and immunogenicity of allogeneic MSC remain poorly defined. Recent studies investigating their immunogenicity remain inconclusive and this has hampered their clinical application. This study investigated the (1) immunogenicity and (2) immunomodulatory properties of bone marrow-derived MSC using an allogeneic mouse model involving Balb/c (responder) and C3H (stimulator) mice. Dermal fibroblasts (DF) were used as controls for cells of mesenchymal origin. Adaptations of the lymphocyte transformation assay (LTA) and mixed lymphocyte reaction (MLR) were used to investigate the immunogenicity and immunomodulatory properties of allogeneic undifferentiated and chondrogenic-differentiated MSC and DF. Both MSC and DF displayed a similar phenotypic profile with the exception of lower expression of CD44 and CD105 in DF. Tri-lineage differentiation of MSC and DF into adipocytes, chondrocytes and osteocytes confirmed their multipotency. In LTA, both undifferentiated and chondrogenic-differentiated allogeneic MSC stimulated lymphocyte proliferation. Allogeneic DF were non-stimulatory but chondrogenic-differentiated DF triggered responder lymphocyte proliferation. In one-way MLR, both allogeneic MSC and DF significantly suppressed Balb/c lymphocyte proliferation. The current challenges in distinguishing between MSC and fibroblasts were apparent throughout the work. These findings support the notion that although MSC possess immunosuppressive properties, they may not be immunoprivileged. Thus, clinical application of allogeneic MSC should be taken with due consideration of their potential immunogenicity. PMID- 24812584 TI - Variation in alpha radioactivity of plants with the use of different fertilizers and radon measurement in fertilized soil samples. AB - BACKGROUND: People are exposed to ionizing radin from the radionuclides that are present in different types of natural sources, of which phosphate fertilizer is one of the most important sources. Fertilizers are commonly used in agricultural field worldwide to enhance the crop yield. MATERIALS AND METHODS: In the present investigation, a control study was carried out on the lady's finger plants grown in earthen pots. To observe the effect of fertilizers their equal amounts were added to the soil just before the plantation. The alpha track densities were measured using solid state nuclear track detectors (SSNTDs), a sensitive detector for alpha particles. RESULTS: The measured alpha track densities (T cm(-2)d(-1)) in lady's finger plants on top and bottom face of leaves after 30, 50 and 70 days of plantation varied from 49 +/- 11 to 206 +/- 2.6, 49 +/- 16 to 248 +/- 16 and 57 +/- 8.5 to 265 +/- 32 respectively in various leaf samples. CONCLUSIONS: The alpha track densities were found to vary with nature of fertilizers added to the soil and an increase was also observed with time. The alpha track densities were also measured in soil samples mixed with different fertilizers. The radon exhalation rates in various soil samples and soil to plant transfer factor (TF) of alpha tracks were also calculated. PMID- 24812583 TI - Positive Emotion Regulation and Psychopathology: A Transdiagnostic Cultural Neuroscience Approach. AB - There is burgeoning interest in the study of positive emotion regulation and psychopathology. Given the significant public health costs and the tremendous variance in national prevalence rates associated with many disorders of positive emotion, it is critical to reach an understanding of how cultural factors, along with biological factors, mutually influence positive emotion regulation. Progress in this domain has been relatively unexplored, however, underscoring the need for an integrative review and empirical roadmap for investigating the cultural neuroscientific contributions to positive emotion disturbance for both affective and clinical science domains. The present paper thus provides a multidisciplinary, cultural neuroscience approach to better understand positive emotion regulation and psychopathology. We conclude with a future roadmap for researchers aimed at harnessing positive emotion and alleviating the burden of mental illness cross-culturally. PMID- 24812585 TI - Manual removal of the placenta after vaginal delivery: an unsolved problem in obstetrics. AB - The third stage of labor is associated with considerable maternal morbidity and mortality. The major complication is postpartum hemorrhage (PPH), which is the leading cause of maternal morbidity and mortality worldwide. Whereas in the event of PPH due to atony of the uterus there exist numerous treatment guidelines; for the management of retained placenta the general consensus is more difficult to establish. Active management of the third stage of labour is generally accepted as standard of care as already its duration is contributing to the risk of PPH. Despite scant evidence it is commonly advised that if the placenta has not been expelled 30 minutes after delivery, manual removal of the placenta should be carried out under anaesthesia. Pathologic adhesion of the placenta in the low risk situation usually is diagnosed at the time of delivery; therefore a pre- or intrapartum screening opportunity for placenta accreta would be desirable. But diagnosis of abnormalities of placentation other than placenta previa remains a challenge. Nevertheless the use of ultrasound and doppler sonography might be helpful in the third stage of labor. An improvement might be the implementation of standardized operating procedures for retained placenta which could contribute to a reduction of maternal morbidity. PMID- 24812587 TI - Graft-versus-Host Disease after Living-Unrelated Kidney Transplantation. AB - Graft-versus-host disease (GVHD) is a rare complication after solid organ transplantation and consists of a reaction of donor derived immune cells directed against host tissues. The vast majority of cases reported in the literature involve liver, small intestine and pancreas transplantation. We report a case of GVHD in a 48-year-old man after living-unrelated kidney transplantation at another center. Six months postoperatively he developed a skin rash, anorexia, and diarrhea that resulted in malnutrition and a 90 pound weight loss. At this point he was transferred to our center with a BMI of 16 and severe cachexia. Intravenous hyperalimentation was initiated and an extensive work-up for an infectious etiology was performed and was negative. An esophagogastroduodenoscopy was performed and revealed nodularity of the gastric mucosa, atrophy, and edema in the first and second portion of his duodenum. Biopsy findings were consistent with GVHD. Aggressive immunosuppressive therapy was instituted with a good response. The anorexia and diarrhea resolved, and he was discharged on hospital day 20. Three months later, there had been no recurrence of the diarrhea, the patient had gained an additional 40 pounds, BMI of 25, and a repeat upper endoscopy revealed complete resolution of the initial endoscopic abnormalities. PMID- 24812586 TI - Polarity specific suppression effects of transcranial direct current stimulation for tinnitus. AB - Tinnitus is the perception of a sound in the absence of an external auditory stimulus and affects 10-15% of the Western population. Previous studies have demonstrated the therapeutic effect of anodal transcranial direct current stimulation (tDCS) over the left auditory cortex on tinnitus loudness, but the effect of this presumed excitatory stimulation contradicts with the underlying pathophysiological model of tinnitus. Therefore, we included 175 patients with chronic tinnitus to study polarity specific effects of a single tDCS session over the auditory cortex (39 anodal, 136 cathodal). To assess the effect of treatment, we used the numeric rating scale for tinnitus loudness and annoyance. Statistical analysis demonstrated a significant main effect for tinnitus loudness and annoyance, but for tinnitus annoyance anodal stimulation has a significantly more pronounced effect than cathodal stimulation. We hypothesize that the suppressive effect of tDCS on tinnitus loudness may be attributed to a disrupting effect of ongoing neural hyperactivity, independent of the inhibitory or excitatory effects and that the reduction of annoyance may be induced by influencing adjacent or functionally connected brain areas involved in the tinnitus related distress network. Further research is required to explain why only anodal stimulation has a suppressive effect on tinnitus annoyance. PMID- 24812589 TI - Studies on the anti-inflammatory effect and its mechanisms of sophoridine. AB - This work is to study the anti-inflammatory effect and its mechanisms of sophoridine in vitro and in vivo. For this aim, the influences of sophoridine on several inflammatory mediators were investigated. Excessive inflammatory response in vitro model was developed by using lipopolysaccharide (LPS) to stimulate the mouse peritoneal macrophages and HL-60 cells to produce IL-6 and IL-8. Carrageenin-induced mouse paw edema model was used as inflammatory response in vivo model. MTT method, ultraviolet spectrophotometric method, and radioimmunoassay were used to measure the changes of TNF alpha , IL-6, PGE2, and IL-8 in in vitro cell culture supernatant or in the local inflammatory exudates. The results showed that sophoridine inhibited the production of IL-8 in in vitro cell culture supernatant and inhibited the production of TNF alpha , PGE2, and IL 8 in the local inflammatory exudates but had no significant effects on the production of IL-6 in vitro and in vivo. It is demonstrated that sophoridine's anti-inflammatory effect was due to its ability to inhibit the production of cytokine and inflammatory mediators. PMID- 24812588 TI - Comparison of Clinical Profile between P. vivax and P. falciparum Malaria in Children: A Tertiary Care Centre Perspective from India. AB - Background. Malaria is a one of the leading causes of morbidity and mortality in tropical countries. Plasmodium vivax (P. vivax) is usually thought to be causing benign malaria with low incidence of complications as compared to Plasmodium falciparum (P. falciparum). Methods. This retrospective observational study included malaria patients who were admitted to K.T. Children Hospital and P.D.U. Government Medical College, Rajkot, a tertiary care teaching hospital, Gujarat, western India, during the period January 2012 to December 2012. Inclusion criteria were patients in whom either P. falciparum or P. vivax was positive on rapid malaria antigen test and peripheral blood smear. Patients showing mixed infections were excluded from study. Results. A total of 79 subjects (mean age 5.4 +/- 3.6 years) were included in the study. It consisted of 47 P. vivax and 32 P. falciparum cases. The P. vivax cases consisted of 33 (70.2%) males and 11 (19.8%) females while P. falciparum cases consisted of 14 (43.8%) males and 18 (56.2%) females. One patient of each P. vivax and P. falciparum expired. There was no statistical significant difference found between complications such as anemia, thrombocytopenia, liver and renal dysfunction, ARDS, and cerebral malaria between P. vivax and P. falciparum. Conclusion. We conclude that P. vivax monoinfection tends to have as similar course and complications as compared to malaria due to P. falciparum monoinfection. PMID- 24812590 TI - One to rule them all: A highly conserved motif in mariner transposase controls multiple steps of transposition. AB - The development of transposon-based genome manipulation tools can benefit greatly from understanding transposons' inherent regulatory mechanisms. The Tc1-mariner transposons, which are being widely used in biotechnological applications, are subject to a self-inhibitory mechanism whereby increasing transposase expression beyond a certain point decreases the rate of transposition. In a recent paper, Liu and Chalmers performed saturating mutagenesis on the highly conserved WVPHEL motif in the mariner-family transposase from the Hsmar1 element. Curiously, they found that the majority of all possible single mutations were hyperactive. Biochemical characterizations of the mutants revealed that the hyperactivity is due to a defect in communication between transposase subunits, which normally regulates transposition by reducing the rate of synapsis. This provides important clues for improving transposon-based tools. However, some WVPHEL mutants also showed features that would be undesirable for most biotechnological applications: they showed uncontrolled DNA cleavage activities and defects in the coordination of cleavage between the two transposon ends. The study illustrates how the knowledge of inhibitory mechanisms can help improve transposon tools but also highlights an important challenge, which is to specifically target a regulatory mechanism without affecting other important functions of the transposase. PMID- 24812591 TI - A case of horizontal gene transfer from Wolbachia to Aedes albopictus C6/36 cell line. AB - Horizontal gene transfer plays an essential role in evolution and ecological adaptation, yet this phenomenon has remained controversial, particularly where it occurs between prokaryotes and eukaryotes. There are a handful of reported examples of horizontal gene transfer occurring between prokaryotes and eukaryotes in the literature, with most of these documented cases pertaining to invertebrates and endosymbionts. However, the vast majority of these horizontally transferred genes were either eventually excluded or rapidly became nonfunctional in the recipient genome. In this study, we report the discovery of a horizontal gene transfer from the endosymbiont Wolbachia in the C6/36 cell line derived from the mosquito Aedes albopictus. Moreover, we report that this horizontally transferred gene displayed high transcription level. This finding and the results of further experimentation strongly suggest this gene is functional and has been expressed and translated into a protein in the mosquito host cells. PMID- 24812592 TI - Unique and conserved features of the plant ER-shaping GTPase RHD3. AB - The architectural integrity of the endoplasmic reticulum (ER) network depends on the function of membrane-associated dynamin-like GTPases that include metazoan atlastins, plant RHD3 and yeast Sey1p. The evidence that these proteins are sufficient to drive membrane fusion of reconstituted proteoliposomes, and that loss-of-function mutations lead to conspicuous ER shape defects indicates that atlastins, RHD3 and Sey1p promote ER membrane fusion. However, complementation experiments in reciprocal loss-of-function backgrounds have also suggested that RHD3 and Sey1p may be not functionally equivalent, supporting that ER fusion mechanisms may be not entirely conserved in eukaryotes. In this Letter, we provide a brief overview of the field as well as evidence that may explain the functional differences of the plant and yeast ER-shaping dynamin-like GTPases. PMID- 24812593 TI - Seminal pharmacokinetics and antiviral efficacy of once-daily maraviroc plus lopinavir/ritonavir in HIV-infected patients. PMID- 24812594 TI - The Effect of Incarceration on Adult Male BMI Trajectories, United States, 1981 2006. AB - The prevalence of obesity and overweight is socially patterned, with higher prevalence among women, racial/ethnic minorities, and those with lower socio economic status. Contextual factors also affect obesity risk. However, an omitted factor has been incarceration, particularly since it disproportionately affects minorities. This study examines the effects of incarceration on adult male body mass index (BMI) in the United States over the life course, and whether effects vary by race/ethnicity and education. BMI trajectories were analyzed over age using growth curve models of men ages 18-49 from the National Longitudinal Survey of Youth panel study. BMI was based on self-reported height/weight (kg/m2). Being currently incarcerated increased BMI, but the effect varied by race/ethnicity and education: blacks experienced the largest increases, while effects were lowered for men with more education than a high school diploma. Cumulative exposure to prison increased BMI for all groups. These results suggest a differential effect of incarceration on adult male BMI among some racial/ethnic-education minority groups. Particularly given that these groups are most commonly imprisoned, incarceration may help structure obesity disparities and disadvantage across the life course. PMID- 24812595 TI - LFER Studies Evaluating Solvent Effects on an alpha-Chloro-and two beta,beta,beta Trichloro-Ethyl Chloroformate Esters. AB - To provide insight and to identify the occurrence of mechanistic changes in relation to variance in solvent-type, the solvent effects on the rates of solvolysis of three substrates, 2,2,2-trichloro-1,1-dimethylethyl chloroformate, 2,2,2-trichloroethyl chloroformate, and 1-chloroethyl chloroformate, are analyzed using linear free energy relationships (LFERs) such as the extended Grunwald Winstein equation, and a similarity-based LFER model approach that is based on the solvolysis of phenyl chloroformate. At 25.0 degrees C, in four common solvents, the alpha-chloroethyl chloroformate was found to react considerably faster than the two beta,beta,beta-trichloro-substituted analogs. This immense rate enhancement can be directly related to the proximity of the electron withdrawing alpha-chlorine atom to the carbonyl carbon reaction center. In the thirteen solvents studied, 1-chloroethyl chloroformate was found to strictly follow a carbonyl addition process, with the addition-step being rate determining. For the two beta,beta,beta-trichloro-substrates, in aqueous mixtures that are very rich in a fluoroalcohol component, there is compelling evidence for the occurrence of side-by-side addition-elimination and ionization mechanisms, with the ionization pathway being predominant. The presence of the two methyl groups on the alpha-carbon of 2,2,2-trichloro-1,1-dimethylethyl chloroformate has additive steric and stereoelectronic implications, causing its rate of reaction to be significantly slower than that of 2,2,2-trichloroethyl chloroformate. PMID- 24812596 TI - Can combination of osteopontin and peritumor-infiltrating macrophages be a prognostic marker of early-stage hepatocellular carcinoma? AB - Hepatocellular carcinoma (HCC) is one of the most frequent malignancy worldwide. The increasing incidence of HCC in the worldwide has sparked an emerging interest in prognostic markers of HCC. Osteopontin (OPN) is a secreted phosphoprotein which has been associated with progression and metastasis of HCC. Also, peritumoral macrophage (PTM) have been reported to facilitate tumor progression and metastasis. Recently, one study reported that combination of OPN with PTM may predict the prognosis of HCC after curative resection. The authors successfully identified that combination of these two markers is an independent predictor of tumor recurrence and survival in patients with HCC, especially for those with early-stage disease. These findings might support the possibility that combination of OPN and PTM levels can be a prognostic tool. However, further investigations should be conducted before tumor OPN combined with PTMs can be accepted as a valid prognostic marker in clinical practice. PMID- 24812597 TI - Laparoscopic resection for hepatocellular carcinoma: comparison between Middle Eastern and Western experience. AB - BACKGROUND: Laparoscopic liver resection (LLR) is growing in popularity, but the short- and long-term outcome of patients undergoing LLR for hepatocellular carcinoma (HCC) has not yet been established. METHODS: A literature search was performed using PubMed, Scopus, and Web of Science (WoS) from cited English and Chinese publications. Clinical and survival parameters were extracted. The search was last conducted in October 2013. After application of selective criteria, 24 remaining original studies with more than 15 patients were analyzed. RESULTS: In the Western experience, mean operative time was between 150 to 300 minutes, and mean blood loss ranged from 55 to 452 mL. Transfusion was required in all series, ranging from 2.8% to 50%. The conversion rate ranged from 5% to 19.4%. Three cases of death were reported. General morbidity rate ranged from 1.5% to 25%. Specific complications were divided into hemorrhage (2.4% to 25%), ascites (3.7% to 15.3%), and biliary collection (0.6% to 5%). Liver insufficiency was reported in two cases. Mean hospital stay ranged from 5.4 to 15 days. In all case-matched studies, LLR was statistically associated with a shorter hospital stay. The 5 year overall survival rate ranged from 55% to 70%. No trocar-site recurrence was observed. The recurrence rate ranged from 21.4% to 50%. Comparative studies did not demonstrate any significant difference in terms of recurrence between LLR and open liver resection (OLR). In the Middle Eastern experience, mean operative time ranged from 147 to 325 minutes, and mean blood loss ranged from 88 to 808 mL. Transfusion was required, ranging from 1.8% to 19.2%. The conversion rate ranged from 1.8% to 18.6%, and four series reported no conversion. There was no mortality. The main specific complication was ascites (1.7% to 26.6%). A biliary collection was reported in only two series (10.7% and 13.3%), and only one case of postoperative liver insufficiency was reported. Mean hospital stay ranged from 4 to 11.5 days. Statistically, three comparative studies reported a shorter postoperative hospital stay following LLR versus OLR. The 5-year overall survival rate ranged from 50% to 76.6%. Comparative studies did not demonstrate any significant difference in terms of overall survival and recurrence rate between LLR and OLR. No trocar-site recurrence was reported. The recurrence rate ranged from 26.9% to 45.5%, and two series reported no recurrence. CONCLUSIONS: Laparoscopic surgery should be considered an acceptable alternative for the treatment of HCC. PMID- 24812598 TI - Real-time 3D image reconstruction guidance in liver resection surgery. AB - BACKGROUND: Minimally invasive surgery represents one of the main evolutions of surgical techniques. However, minimally invasive surgery adds difficulty that can be reduced through computer technology. METHODS: From a patient's medical image [US, computed tomography (CT) or MRI], we have developed an Augmented Reality (AR) system that increases the surgeon's intraoperative vision by providing a virtual transparency of the patient. AR is based on two major processes: 3D modeling and visualization of anatomical or pathological structures appearing in the medical image, and the registration of this visualization onto the real patient. We have thus developed a new online service, named Visible Patient, providing efficient 3D modeling of patients. We have then developed several 3D visualization and surgical planning software tools to combine direct volume rendering and surface rendering. Finally, we have developed two registration techniques, one interactive and one automatic providing intraoperative augmented reality view. RESULTS: From January 2009 to June 2013, 769 clinical cases have been modeled by the Visible Patient service. Moreover, three clinical validations have been realized demonstrating the accuracy of 3D models and their great benefit, potentially increasing surgical eligibility in liver surgery (20% of cases). From these 3D models, more than 50 interactive AR-assisted surgical procedures have been realized illustrating the potential clinical benefit of such assistance to gain safety, but also current limits that automatic augmented reality will overcome. CONCLUSIONS: Virtual patient modeling should be mandatory for certain interventions that have now to be defined, such as liver surgery. Augmented reality is clearly the next step of the new surgical instrumentation but remains currently limited due to the complexity of organ deformations during surgery. Intraoperative medical imaging used in new generation of automated augmented reality should solve this issue thanks to the development of Hybrid OR. PMID- 24812599 TI - Management of hepatocellular carcinoma should consider both tumor factors and background liver factors. AB - As progression and outcome of relapsed hepatocellular carcinoma (HCC) are distinct from those of a second primary tumor, clonal analyses of initial and recurrent HCCs are thus clinically useful. Although several studies in Japan and Taiwan had shown that the multicentric origin (MO) recurrences were more common than intrahepatic metastases (IM), a recent report from China indicated that IM cases outnumber MO recurrences. In managing HCC cases, both tumor malignancy and background liver function are important considerations (and which we characterize as tumor factors and background liver factors, respectively); they indicate both appropriate treatment, and likely post-surgical outcome. In this editorial, we explain why the report had shown such a different conclusion. We also discuss current management of HCC. PMID- 24812600 TI - Amplification of MPZL1/PZR gene in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality worldwide. It is noted that metastasis is a fundamental biological behavior of HCC and the main cause of treatment failure. The identification of somatic alterations and their specific inhibitors may contribute to reduce side effects and prolong patient survival in HCC. Chromosomal copy number alterations (CNAs) are important subclasses of somatic mutations and can be used as an effective method of identifying driver genes with causal roles in carcinogenesis. Jia et al. identified a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. They also found that MPZL1 may recruit the SHP-2 and subsequently activate/phosphorylate Src kinase at Tyr426, promoting phosphorylation of cortactin and migration of HCC cells. It is noted that phosphorylation of Tyr416 in the activation loop of the kinase domain up-regulates enzyme activity of Src. In addition, the active state of c-Src, p-Tyr416-c-Src, is an independent prognostic marker of poor patient survival in HCC. Therefore, c-Src signaling may be a druggable target and c-Src targeted therapy may improve patient outcome in this specific subtype of HCC patient with a gain of the recurrent focal amplicon, 1q24.1-24.2. PMID- 24812601 TI - Glucose intolerance and hepatocellular carcinoma: recent findings for old diseases. AB - In the last years, an increasing number of evidences on the influence of metabolic syndrome on the occurrence of hepatocellular carcinoma (HCC) have been developed. Type 2 mellitus diabetes (T2MD) has been found to increase the occurrence of primary liver tumors and to define a more aggressive carcinogenetic process. Furthermore, several preclinical and observational studies and a recent meta-analysis have shown that anti-diabetic drugs can modify the risk of HCC development in patients with T2DM. However, despite these evidences, underlying molecular mechanisms linking both pathological conditions have to be completely cleared yet. The study published by Gao et al. has found a possible molecular link between the two conditions, describing the predisposition to T2DM and HCC given by the haploinsufficiency of nuclear receptor coactivator 5 (NCOA5) in murine models. The authors have generated Ncoa5+/- (haploinsufficient) male mice and shown that 94% of male mutant mice developed HCC within 18 months of age, this in contrast with Ncoa5+/+ and Ncoa5+/- female mice. These results suggest that NCOA5 haploinsufficiency is linked to HCC development in male mice. Moreover, mutant male mice showed significantly elevated levels of fasting blood glucose and markedly decreased glucose tolerance and insulin sensitivity compared to Ncoa5+/+ littermates. This well-constructed work sheds light on the molecular link between T2DM and HCC and opens the way to further biological and clinical studies in the field of liver tumor prevention and treatment. PMID- 24812602 TI - Decoding hepatocellular carcinoma: the promise of microRNAs. AB - MicroRNAs (miRNAs) may play an important role in the development and progression of hepatocellular carcinoma (HCC). Understanding the mechanism of specific miRNAs may provide opportunity for development of biomarkers and novel therapeutics in hepatocellular carcinoma which are desperately needed. PMID- 24812603 TI - Dissecting the pleiotropic actions of HBx mutants against hypoxia in hepatocellular carcinoma. AB - Error-prone integration of the hepatitis B virus X protein (HBx) into the hepatocellular genome generates a multitude of mutants exerting diverse effects on the development and progression of hepatocellular carcinoma (HCC). A recent study by Lai and colleagues revealed the disparate regulatory activity of clinically-predominant HBx mutants towards hypoxia-inducible factor-1alpha (HIF 1alpha), a central regulator of tumor angiogenesis, proliferation, metastasis and differentiation. These findings have shed insight into specific viral contribution of hypoxic response during hepatocarcinogenesis. PMID- 24812604 TI - Importance of tumor/stroma interactions in prognosis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third largest cause of cancer deaths worldwide. It seems to be needed to find new ways to address the mechanisms involved in the progression of HCC, which can provide a prognostic evaluation and new therapeutic targets. Several studies have established that crosstalk between tumor cells and the microenvironment plays a key role in tumor progression and metastasis. In this context, the work of Zhu et al. contributes to assess interactions between tumor and microenvironment associated-macrophages promoting tumor progression and metastasis. Indeed, they concluded that the interplay of osteopontin (OPN) and peritumoral macrophages (PTMs) represents a new insight into tumor progression and therapeutic targets for HCC. Historically, tumor infiltrating leukocytes have been considered to be manifestations of an intrinsic defensive mechanism against developing tumors, however, now, it is know that that leukocytes infiltration can promote tumor phenotypes, such as angiogenesis, growth, and invasion. Characterization of functional heterogeneity of stromal cell components, and specifically the analysis of stromal fibroblasts can provide a new focus on mechanisms involved in the progression of HCC. All of this opens the possibility to provide prognostic information for HCC based on biological parameters derived from peritumoral status from tumors. PMID- 24812606 TI - Professor Real Lapointe: the impact of portal embolization on postoperative morbidity and mortality after liver resection. PMID- 24812605 TI - Obstructive jaundice suspected hilar cholangiocarcinoma. PMID- 24812607 TI - Estimating rate of insulin resistance in patients with preeclampsia using HOMA-IR index and comparison with nonpreeclampsia pregnant women. AB - Women with preeclampsia, independent of obesity and glucose intolerance, exhibit insulin resistance during pregnancy. The purpose of the present study is to determine whether early diagnosis of insulin resistance during pregnancy can predict preeclampsia. Through a case-control study, 675 pregnant women were selected and their first trimester blood was taken. Their fasting blood glucose and insulin were also measured after diagnosis of preeclampsia by 20 weeks of pregnancy. Based on the experiments conducted on 675 women who were 20 weeks past their pregnancy, 375 cases with preeclampsia were selected and assigned to the case group. 35 other pregnant women were put in the control group. Diagnosis criteria for the participants included blood pressure above 140/90 and proteinuria above 300 mg or above +1. Both groups were matched according to age, parity, gestational age, and BMI. Homa-Irand rate of insulin resistance was calculated by HOMA-IR and patients were followed up. Homeostatic model assessments (HOMA-IR) revealed that the average insulin resistance increased during pregnancy among both the case and control groups. There was a significant difference between insulin resistance of these two groups in both first trimester and third trimester and after developing preeclampsia (P < 0.001, P = 0.021). Insulin-resistance of the group with preeclampsia was higher in first trimester prior to diagnosis as well as the third trimester after diagnosis compared to natural pregnancy under similar conditions. Measurement of insulin resistance in first trimester may be useful in predicting the risk of preeclampsia. PMID- 24812608 TI - Enhanced osteogenicity of bioactive composites with biomimetic treatment. AB - PURPOSE: This study aimed to explore if initiation of biomimetic apatite nucleation can be used to enhance osteoblast response to biodegradable tissue regeneration composite membranes. MATERIALS AND METHODS: Bioactive thermoplastic composites consisting of poly(epsilon-caprolactone/DL-lactide) and bioactive glass (BAG) were prepared at different stages of biomimetic calcium phosphate deposition by immersion in simulated body fluid (SBF). The modulation of the BAG dissolution and the osteogenic response of rat mesenchymal stem cells (MSCs) were analyzed. RESULTS: SBF treatment resulted in a gradual calcium phosphate deposition on the composites and decreased BAG reactivity in the subsequent cell cultures. Untreated composites and composites covered by thick calcium phosphate layer (14 days in SBF) expedited MSC mineralization in comparison to neat polymers without BAG, whereas other osteogenic markers--alkaline phosphatase activity, bone sialoprotein, and osteocalcin expression--were initially decreased. In contrast, surfaces with only small calcium phosphate aggregates (five days in SBF) had similar early response than neat polymers but still demonstrated enhanced mineralization. CONCLUSION: A short biomimetic treatment enhances osteoblast response to bioactive composite membranes. PMID- 24812609 TI - The role of imaging in radiation therapy planning: past, present, and future. AB - The use of ionizing radiation for cancer treatment has undergone extraordinary development during the past hundred years. The advancement of medical imaging has been critical in helping to achieve this change. The invention of computed tomography (CT) was pivotal in the development of treatment planning. Despite some disadvantages, CT remains the only three-dimensional imaging modality used for dose calculation. Newer image modalities, such as magnetic resonance (MR) imaging and positron emission tomography (PET), are also used secondarily in the treatment-planning process. MR, with its better tissue contrast and resolution than those of CT, improves tumor definition compared with CT planning alone. PET also provides metabolic information to supplement the CT and MR anatomical information. With emerging molecular imaging techniques, the ability to visualize and characterize tumors with regard to their metabolic profile, active pathways, and genetic markers, both across different tumors and within individual, heterogeneous tumors, will inform clinicians regarding the treatment options most likely to benefit a patient and to detect at the earliest time possible if and where a chosen therapy is working. In the post-human-genome era, multimodality scanners such as PET/CT and PET/MR will provide optimal tumor targeting information. PMID- 24812610 TI - Nutritional biomarkers in children and adolescents with Beta-thalassemia-major: An Egyptian center experience. AB - BACKGROUND AND AIM: Trace elements and vitamins play a vital role in human body to perform its function properly. Thalassemic patients are at risk of micronutrient deficiency. This study estimated levels of vitamins A, C, E, B12, folic acid, total homocysteine (tHcy), and methylmalonic acid (MMA) along with trace elements, zinc, copper, and selenium in Beta-thalassemia-major patients. METHODS: This study included 108 patients with Beta-thalassemia-major and 60 age and sex matched healthy children. Serum levels of vitamin A, E, C, tHcy, and MMA were estimated by high pressure liquid chromatography while serum levels of folic acid and B12 were estimated by thin layer chromatography. Serum zinc, copper, and selenium were determined by atomic absorption spectrometry. RESULTS: There was a significant decrease of vitamins A, C, E, and B12 and trace elements zinc, copper, and selenium in thalassemic patients as compared to controls. tHcy and MMA were significantly elevated in patients. No significant correlations were found between the serum levels of the studied vitamins and trace elements as regards age, frequency of transfusion, duration of transfusion, and serum ferritin. CONCLUSION: The level of various nutritional biomarkers (vitamins A, C, E, and B12 and trace elements zinc, copper, selenium) was reduced in chronically transfused Egyptian thalassemic patient. These patients should have periodic nutritional evaluation and supplementation. Multicenter studies are highly recommended. PMID- 24812611 TI - Gene expression changes induced by Trypanosoma cruzi shed microvesicles in mammalian host cells: relevance of tRNA-derived halves. AB - At present, noncoding small RNAs are recognized as key players in novel forms of posttranscriptional gene regulation in most eukaryotes. However, canonical small RNA pathways seem to be lost or excessively simplified in some unicellular organisms including Trypanosoma cruzi which lack functional RNAi pathways. Recently, we reported the presence of alternate small RNA pathways in T. cruzi mainly represented by homogeneous populations of tRNA- and rRNA-derived small RNAs, which are secreted to the extracellular medium included in extracellular vesicles. Extracellular vesicle cargo could be delivered to other parasites and to mammalian susceptible cells promoting metacyclogenesis and conferring susceptibility to infection, respectively. Here we analyzed the changes in gene expression of host HeLa cells induced by extracellular vesicles from T. cruzi. As assessed by microarray assays a large set of genes in HeLa cells were differentially expressed upon incorporation of T. cruzi-derived extracellular vesicles. The elicited response modified mainly host cell cytoskeleton, extracellular matrix, and immune responses pathways. Some genes were also modified by the most abundant tRNA-derived small RNAs included in extracellular vesicles. These data suggest that microvesicles secreted by T. cruzi could be relevant players in early events of the T. cruzi host cell interplay. PMID- 24812612 TI - Prophylaxis of contrast-induced nephrotoxicity. AB - Contrast-induced nephrotoxicity (CIN) is a form of acute kidney injury that follows intravascular contrast media exposure. CIN may be preventable because its risk factors are well established and the timing of renal insult is commonly known in advance. However, contrast-induced nephrotoxicity is still the third leading cause of iatrogenic renal failure. This important complication accounts up to 10% of acute renal failure cases in hospitalized patients and it is associated with increased short- and long-term morbidity and mortality. Prolonged hospitalization follows and overall increases healthcare resource utilization. This paper will discuss the various prophylactic procedures tested in clinical trials. PMID- 24812613 TI - An infrastructure to mine molecular descriptors for ligand selection on virtual screening. AB - The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data warehouse-based infrastructure to mine molecular descriptors for virtual screening (VS). We performed experiments that consider as target the receptor HIV-1 protease and different compounds for this protein. A set of 9 molecular descriptors are taken as the predictive attributes and the free energy of binding is taken as a target attribute. By applying the J48 algorithm over the data we obtain decision tree models that achieved up to 84% of accuracy. The models indicate which molecular descriptors and their respective values are relevant to influence good FEB results. Using their rules we performed ligand selection on ZINC database. Our results show important reduction in ligands selection to be applied in VS experiments; for instance, the best selection model picked only 0.21% of the total amount of drug-like ligands. PMID- 24812615 TI - Regenerative medicine. PMID- 24812614 TI - An intelligent clinical decision support system for patient-specific predictions to improve cervical intraepithelial neoplasia detection. AB - Nowadays, there are molecular biology techniques providing information related to cervical cancer and its cause: the human Papillomavirus (HPV), including DNA microarrays identifying HPV subtypes, mRNA techniques such as nucleic acid based amplification or flow cytometry identifying E6/E7 oncogenes, and immunocytochemistry techniques such as overexpression of p16. Each one of these techniques has its own performance, limitations and advantages, thus a combinatorial approach via computational intelligence methods could exploit the benefits of each method and produce more accurate results. In this article we propose a clinical decision support system (CDSS), composed by artificial neural networks, intelligently combining the results of classic and ancillary techniques for diagnostic accuracy improvement. We evaluated this method on 740 cases with complete series of cytological assessment, molecular tests, and colposcopy examination. The CDSS demonstrated high sensitivity (89.4%), high specificity (97.1%), high positive predictive value (89.4%), and high negative predictive value (97.1%), for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In comparison to the tests involved in this study and their combinations, the CDSS produced the most balanced results in terms of sensitivity, specificity, PPV, and NPV. The proposed system may reduce the referral rate for colposcopy and guide personalised management and therapeutic interventions. PMID- 24812616 TI - Evaluation of the usefulness of the MRI jelly method for diagnosing complete cul de-sac obliteration. AB - OBJECTIVE: We conducted a single-center study to evaluate the usefulness of the magnetic resonance (MR) imaging jelly method for diagnosing endometriosis associated adhesions in the Pouch of Douglas. METHODS: Thirty women with menstrual pain, dyspareunia, and chronic pelvic pain were enrolled in the study. All had been scheduled for laparoscopic surgery on the basis of pelvic and/or ultrasonographic (US) evaluation. All underwent MR imaging both with and without application of US jelly to the vagina and rectum. The images were compared and analyzed postsurgically in a random and blinded fashion by a radiology specialist and a radiology fellow. The radiologists' interpretations of the images were compared to the surgical findings recorded on DVDs. RESULTS: Adhesions in the Pouch of Douglas were found in 21 patients. The sensitivity and specificity of MR imaging without jelly administration were 85.7% and 55.6%, respectively, for the specialist and 81.0% and 55.6%, respectively, for the fellow; with jelly administration, values were 95.2% and 88.9% for the specialist and 90.5% and 66.7% for the fellow. Opacity produced by the jelly increased the sensitivity and specificity for both radiologists. CONCLUSION: The MRI jelly method is a potentially useful, beneficial, and simple approach for diagnosing Pouch of Douglas adhesions. PMID- 24812617 TI - Early Trypanosoma cruzi infection reprograms human epithelial cells. AB - Trypanosoma cruzi, the causative agent of Chagas disease, has the peculiarity, when compared with other intracellular parasites, that it is able to invade almost any type of cell. This property makes Chagas a complex parasitic disease in terms of prophylaxis and therapeutics. The identification of key host cellular factors that play a role in the T. cruzi invasion is important for the understanding of disease pathogenesis. In Chagas disease, most of the focus is on the response of macrophages and cardiomyocytes, since they are responsible for host defenses and cardiac lesions, respectively. In the present work, we studied the early response to infection of T. cruzi in human epithelial cells, which constitute the first barrier for establishment of infection. These studies identified up to 1700 significantly altered genes regulated by the immediate infection. The global analysis indicates that cells are literally reprogrammed by T. cruzi, which affects cellular stress responses (neutrophil chemotaxis, DNA damage response), a great number of transcription factors (including the majority of NF kappa B family members), and host metabolism (cholesterol, fatty acids, and phospholipids). These results raise the possibility that early host cell reprogramming is exploited by the parasite to establish the initial infection and posterior systemic dissemination. PMID- 24812618 TI - Dried fruit of the Luffa sponge as a source of chitin for applications as skin substitutes. AB - LUFFACHITIN obtained from the residue of the sponge-like dried fruit of Luffa aegyptiaca was developed as a weavable skin substitute in this study. A chemical analysis revealed that LUFFACHITIN was composed of a copolymer containing N acetyl-glucosamine (~40%) as a major monomer with a filamentary structure as demonstrated by both optical and scanning electron microscopy. The pulp-like white residue of the sponge-like dried fruit of Luffa aegyptiaca after treatment was then woven into a thin, porous membrane by filtration and lyophilization as a skin substitute for conducting wound-healing study on rats. The results indicated that the LUFFACHITIN membrane showed significant wound-healing enhancement (25 days to complete healing) compared to cotton gauze (>30 days), but not inferior to that of SACCHACHITIN. Furthermore, the LUFFACHITIN membrane had advantages of having a high yield, better physical properties for fabrication, and a more attractive appearance. PMID- 24812619 TI - Chitinase from a novel strain of Serratia marcescens JPP1 for biocontrol of aflatoxin: molecular characterization and production optimization using response surface methodology. AB - Chitinase is one of the most important mycolytic enzymes with industrial significance, and produced by a number of organisms. A chitinase producing isolate Serratia marcescens JPP1 was obtained from peanut hulls in Jiangsu Province, China, and exhibited antagonistic activity against aflatoxins. In this study, we describe the optimization of medium composition with increased production of chitinase for the selected bacteria using statistical methods: Plackett-Burman design was applied to find the key ingredients, and central composite design of response surface methodology was used to optimize the levels of key ingredients for the best yield of chitinase. Maximum chitinase production was predicted to be 23.09 U/mL for a 2.1-fold increase in medium containing 12.70 g/L colloidal chitin, 7.34 g/L glucose, 5.00 g/L peptone, 1.32 g/L (NH4)2SO4, 0.7 g/L K2HPO4, and 0.5 g/L MgSO4 . 7H2O. Polymerase chain reaction (PCR) amplification of the JPP1 chitinase gene was performed and obtained a 1,789 bp nucleotide sequence; its open reading frame encoded a protein of 499 amino acids named as ChiBjp. PMID- 24812620 TI - Technical development of a new semispherical radiofrequency bipolar device (RONJA): ex vivo and in vivo studies. AB - The aim of this study is to inform about the development of a new semispherical surgical instrument for the bipolar multielectrode radiofrequency liver ablation. Present tools are universal; however they have several disadvantages such as ablation of healthy tissue, numerous needle punctures, and, therefore, longer operating procedure. Our newly designed and tested semispherical surgical tool can solve some of these disadvantages. By conducting an in vivo study on a set of 12 pigs, randomly divided into two groups, we have compared efficiency of the newly developed instrument with the commonly used device. Statistical analysis showed that there were no significant differences between the groups. On average, the tested instrument RONJA had shorter ablation time in both liver lobes and reduced the total operating time. The depth of the thermal alteration was on average 4 mm larger using the newly tested instrument. The new radiofrequency method described in this study could be used in open liver surgery for the treatment of small liver malignancies (up to 2 cm) in a single application with the aim of saving healthy liver parenchyma. Further experimental studies are needed to confirm these results before clinical application of the method in the treatment of human liver malignancies. PMID- 24812621 TI - alpha-Mangostin suppresses the viability and epithelial-mesenchymal transition of pancreatic cancer cells by downregulating the PI3K/Akt pathway. AB - alpha -Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report that alpha -mangostin suppressed the viability and epithelial mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells with alpha -mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed that alpha -mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results, alpha -mangostin decreased the expression of MMP-2, MMP-9, N cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found that alpha -mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation by alpha -mangostin. Finally, alpha -mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest that alpha -mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers. PMID- 24812622 TI - Evaluation of insulin medium or chondrogenic medium on proliferation and chondrogenesis of ATDC5 cells. AB - BACKGROUND: The ATDC5 cell line is regarded as an excellent cell model for chondrogenesis. In most studies with ATDC5 cells, insulin medium (IM) was used to induce chondrogenesis while chondrogenic medium (CM), which was usually applied in chondrogenesis of mesenchymal stem cells (MSCs), was rarely used for ATDC5 cells. This study was mainly designed to investigate the effect of IM, CM, and growth medium (GM) on chondrogenesis of ATDC5 cells. METHODS: ATDC5 cells were, respectively, cultured in IM, CM, and GM for a certain time. Then the proliferation and the chondrogenesis progress of cells in these groups were analyzed. RESULTS: Compared with CM and GM, IM promoted the proliferation of cells significantly. CM was effective for enhancement of cartilage specific markers, while IM induced the cells to express endochondral ossification related genes. Although GAG deposition per cell in CM group was significantly higher than that in IM and GM groups, the total GAG contents in IM group were the most. CONCLUSION: This study demonstrated that CM focused on induction of chondrogenic differentiation while IM was in favor of promoting proliferation and expression of endochondral ossification related genes. Combinational use of these two media would be more beneficial to bone/cartilage repair. PMID- 24812623 TI - Knowledge of signs and symptoms of heart attack and stroke among Singapore residents. AB - AIM: To determine the level of knowledge of signs and symptoms of heart attack and stroke in Singapore resident population, in comparison to the global community. METHODS: A population based, random sample of 7,840 household addresses was selected from a validated national sampling frame. Each participant was asked eight questions on signs and symptoms of heart attack and 10 questions on stroke. RESULTS: The response rate was 65.2% with 4,192 respondents. The level of knowledge for preselected, common signs and symptoms of heart attack and stroke was 57.8% and 57.1%, respectively. The respondents scored a mean of 5.0 (SD 2.4) out of 8 for heart attack, while they scored a mean of 6.8 (SD 2.9) out of 10 for stroke. Respondents who were >= 50 years, with lower educational level, and unemployed/retired had the least knowledge about both conditions. The level of knowledge of signs and symptoms of heart attack and stroke in Singapore is comparable to USA and Canada. CONCLUSION: We found a comparable knowledge of stroke and heart attack signs and symptoms in the community to countries within the same economic, educational, and healthcare strata. However older persons, those with lower educational level and those who are unemployed/retired, require more public health education efforts. PMID- 24812624 TI - PTEN mediates the antioxidant effect of resveratrol at nutritionally relevant concentrations. AB - INTRODUCTION: Antioxidant properties of resveratrol have been intensively studied for the last years, both in vivo and in vitro. Its bioavailability after an oral dose is very low and therefore it is very important to make sure that plasma concentrations of free resveratrol are sufficient enough to be active as antioxidant. AIMS: In the present study, using nutritionally relevant concentrations of resveratrol, we aim to confirm its antioxidant capacity on reducing peroxide levels and look for the molecular pathway involved in this antioxidant effect. METHODS: We used mammary gland tumor cells (MCF-7), which were pretreated with different concentrations of resveratrol for 48 h, and/or a PTEN inhibitor (bpV: bipy). Hydrogen peroxide levels were determined by fluorimetry, PTEN levels and Akt phosphorylation by Western Blotting, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Resveratrol treatment for 48 h lowered peroxide levels in MCF-7, even at low nutritional concentrations (1 nM). This effect was mediated by the activation of PTEN/Akt pathway, which resulted in an upregulation of catalase and MnSOD mRNA levels. CONCLUSION: Resveratrol acts as an antioxidant at nutritionally relevant concentrations by inducing the expression of antioxidant enzymes, through a mechanism involving PTEN/Akt signaling pathway. PMID- 24812626 TI - The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience. AB - BACKGROUND: To date, there is no standard treatment for recurrent glioblastoma. We analyzed the feasibility of second surgery plus carmustine wafers followed by intravenous fotemustine. METHODS: Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy. RESULTS: Twenty four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia. CONCLUSION: This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions. PMID- 24812625 TI - Detection of Newcastle disease virus minor genetic variants by modified single stranded conformational polymorphism analysis. AB - Newcastle disease and Avian Influenza are considered to be the most dangerous fowl diseases which may cause huge economic losses. Newcastle disease is caused by the enveloped, and single-stranded RNA virus (NDV, APMV-1; belonging to Paramyxoviridae family), which can be further divided into sixteen different genotypes grouped into five pathotypes according to their pathogenicity. It has been reported that low pathogenic virus can greatly increase its pathogenicity even during a single passage. Additionally, due to the widespread use of live vaccines, a mixture of two or more different viruses in one sample can be detected. Hence, there is a great need for establishment of fast, inexpensive, sensitive, and relatively simple diagnostic method for multistrain and quasispecies detection of NDV infection. In this paper we describe a diagnostic method based on RT-PCR followed by a modified version of single-stranded conformational polymorphism analysis using short DNA fragments of gene encoding viral F protein. The method allows for rapid diagnosis of genetic variant emerging from previously stable population which may prevent the spread of the pathogenic viral variant. PMID- 24812627 TI - Biologic propensities and phytochemical profile of Vangueria madagascariensis J. F. Gmelin (Rubiaceae): an underutilized native medicinal food plant from Africa. AB - Vangueria madagascariensis (VM), consumed for its sweet-sour fruits, is used as a biomedicine for the management of diabetes and bacterial infections in Africa. The study aims to assess the potential of VM on alpha -amylase, alpha glucosidase, glucose movement, and antimicrobial activity. The antioxidant properties were determined by measuring the FRAP, iron chelating activity, and abilities to scavenge DPPH, HOCl, (?) OH, and NO radicals. Leaf decoction, leaf methanol, and unripe fruit methanol extracts were observed to significantly inhibit alpha -amylase. Active extracts against alpha -glucosidase were unripe fruit methanol, unripe fruit decoction, leaf decoction, and ripe fruit methanol, which were significantly lower than acarbose. Kinetic studies revealed a mixed noncompetitive type of inhibition. Leaf methanolic extract was active against S. aureus and E. coli. Total phenolic content showed a strong significant positive correlation (r = 0.88) with FRAP. Methanolic leaf extract showed a more efficient NO scavenging potential and was significantly lower than ascorbic acid. Concerning (?) OH-mediated DNA degradation, only the methanol extracts of leaf, unripe fruit, and ripe fruit had IC50 values which were significantly lower than alpha -tocopherol. Given the dearth of information on the biologic propensities of VM, this study has established valuable primary information which has opened new perspectives for further pharmacological research. PMID- 24812628 TI - High-intensity intermittent swimming improves cardiovascular health status for women with mild hypertension. AB - To test the hypothesis that high-intensity swim training improves cardiovascular health status in sedentary premenopausal women with mild hypertension, sixty-two women were randomized into high-intensity (n = 21; HIT), moderate-intensity (n = 21; MOD), and control groups (n = 20; CON). HIT performed 6-10 * 30 s all-out swimming interspersed by 2 min recovery and MOD swam continuously for 1 h at moderate intensity for a 15-week period completing in total 44 +/- 1 and 43 +/- 1 sessions, respectively. In CON, all measured variables were similar before and after the intervention period. Systolic BP decreased (P < 0.05) by 6 +/- 1 and 4 +/- 1 mmHg in HIT and MOD; respectively. Resting heart rate declined (P < 0.05) by 5 +/- 1 bpm both in HIT and MOD, fat mass decreased (P < 0.05) by 1.1 +/- 0.2 and 2.2 +/- 0.3 kg, respectively, while the blood lipid profile was unaltered. In HIT and MOD, performance improved (P < 0.05) for a maximal 10 min swim (13 +/- 3% and 22 +/- 3%), interval swimming (23 +/- 3% and 8 +/- 3%), and Yo-Yo IE1 running performance (58 +/- 5% and 45 +/- 4%). In conclusion, high-intensity intermittent swimming is an effective training strategy to improve cardiovascular health and physical performance in sedentary women with mild hypertension. Adaptations are similar with high- and moderate-intensity training, despite markedly less total time spent and distance covered in the high-intensity group. PMID- 24812630 TI - Computational systems biology methods in molecular biology, chemistry biology, molecular biomedicine, and biopharmacy. PMID- 24812629 TI - The evolution of cardiovascular surgery in elderly patient: a review of current options and outcomes. AB - Due to the increase in average life expectancy and the higher incidence of cardiovascular disease with advancing age, more elderly patients present for cardiac surgery nowadays. Advances in pre- and postoperative care have led to the possibility that an increasing number of elderly patients can be operated on safely and with a satisfactory outcome. Currently, coronary artery bypass surgery, aortic and mitral valve surgery, and major surgery of the aorta are performed in elderly patients. The data available show that most cardiac surgical procedures can be performed in elderly patients with a satisfactory outcome. Nevertheless, the risk for these patients is only acceptable in the absence of comorbidities. In particular, renal dysfunction, cerebrovascular disease, and poor clinical state are associated with a worse outcome in elderly patients. Careful patient selection, flawless surgery, meticulous hemostasis, perfect anesthesia, and adequate myocardial protection are basic requirements for the success of cardiac surgery in elderly patients. The care of elderly cardiac surgical patients can be improved only through the strict collaboration of geriatricians, anesthesiologists, cardiologists, and cardiac surgeons, in order to obtain a tailored treatment for each individual patient. PMID- 24812631 TI - The female pattern hair loss: review of etiopathogenesis and diagnosis. AB - Female pattern hair loss (FPHL) is the most common hair loss disorder in women. Initial signs may develop during teenage years leading to a progressive hair loss with a characteristic pattern distribution. The condition is characterized by progressive replacement of terminal hair follicles over the frontal and vertex regions by miniaturized follicles, that leads progressively to a visible reduction in hair density. Women diagnosed with FPHL may undergo significant impairment of quality of life. FPHL diagnosis is mostly clinical. Depending on patient history and clinical evaluation, further diagnostic testing may be useful. The purpose of the paper is to review the current knowledge about epidemiology, pathogenesis, clinical manifestations, and diagnosis of FPHL. PMID- 24812632 TI - Therapeutic potential of microRNA: a new target to treat intrahepatic portal hypertension? AB - Intrahepatic portal hypertension accounts for most of the morbidity and mortality encountered in patients with liver cirrhosis, due to increased portal inflow and intrahepatic vascular resistance. Most treatments have focused only on portal inflow or vascular resistance. However, miRNA multitarget regulation therapy may potentially intervene in these two processes for therapeutic benefit in cirrhosis and portal hypertension. This review presents an overview of the most recent knowledge of and future possibilities for the use of miRNA therapy. The benefits of this therapeutic modality--which is poorly applied in the clinical setting- are still uncertain. Increasing the knowledge and current understanding of the roles of miRNAs in the development of intrahepatic portal hypertension and hepatic stellate cells (HSCs) functions, as well as their potential as novel drug targets, is critical. PMID- 24812633 TI - Metformin rescues the MG63 osteoblasts against the effect of high glucose on proliferation. AB - AIMS. To study the proliferation of osteoblasts and genes expression under normal glucose, high glucose, and metformin (Met). METHODS. MG63 osteoblast-like cells were cultured in osteogenic medium supplemented with normal glucose (glucose 5.5 mmol/L) or high glucose (glucose 16.7 mmol/L) and metformin + high glucose (Met 300 MUmol/L + glucose 16.7 mmol/L). Proliferation was detected with CCK-8 assay at days 1, 3, and 7. Real-time PCR and Western blot were performed to compare the expression of collagen I (Col I), osteocalcin (OCN), osteoprotegerin (OPG), receptor activator for NF- kappaB ligand (RANKL), and metal matrix proteinases 1 and 2 (MMP1, MMP2). Alkaline phosphatase (ALP) activity was also detected at days 6, 12, and 18. RESULTS. Exposure to high glucose inhibited the proliferation of osteoblasts (P < 0.05), with suppressed OCN and OPG. Meanwhile, Col I, RANKL, MMP1, and MMP2 were unaffected. Metformin attenuated the suppression on proliferation with increased expression of Col I, OCN, and OPG, meanwhile suppressing MMP1 and MMP2. High glucose lowered the intracellular ALP, while metformin raised it. Metformin attenuated the downregulation of ALP completely at day 6, partly at day 12, but not at day 18. CONCLUSIONS. Metformin attenuated the suppression effect of high glucose to the osteoblast proliferation and gene expression, more prominently in earlier stage. PMID- 24812635 TI - miR-375 and miR-30d in the effect of chromium-containing Chinese medicine moderating glucose metabolism. AB - In China, TianMai Xiaoke tablet (TM) is used to treat type 2 diabetes. However, the exact mechanism of TM is not clear. This study is to investigate the effect of TM on glucose metabolism in diabetic rats and to identify whether TM takes a direct action through microRNAs on islet. Rats were divided into control group, diabetic group, low dose of TM group (TML), and high dose of TM group (TMH). Pancreas samples were analyzed using microRNA array and Q-PCR. Eight-week treatment with TM significantly decreased fasting blood glucose. The blood glucose was significantly reduced in TM-treated groups before and after oral glucose administration. Fasting insulin and HOMA-IR were suppressed in TM-treated groups. miR-448, let-7b, miR-540, miR-296, miR-880, miR-200a, miR-500, miR-10b, miR-336, miR-30d, miR-208, let-7e, miR-142-5p, miR-874, miR-375, miR-879, miR 501, and miR-188 were upregulated, while miR-301b, miR-134, and miR-652 were downregulated in TMH group. Through target gene analysis and real-time PCR verification, we found that these miRNAs, especially miR-375 and miR-30d, can stimulate insulin secretion in islet. Our data suggest that TM can improve blood glucose in diabetic rats which involved increasing the expression of miR-375 and miR-30d to activate insulin synthesis in islet. PMID- 24812634 TI - Role of the unfolded protein response in beta cell compensation and failure during diabetes. AB - Pancreatic beta cell failure leads to diabetes development. During disease progression, beta cells adapt their secretory capacity to compensate the elevated glycaemia and the peripheral insulin resistance. This compensatory mechanism involves a fine-tuned regulation to modulate the endoplasmic reticulum (ER) capacity and quality control to prevent unfolded proinsulin accumulation, a major protein synthetized within the beta cell. These signalling pathways are collectively termed unfolded protein response (UPR). The UPR machinery is required to preserve ER homeostasis and beta cell integrity. Moreover, UPR actors play a key role by regulating ER folding capacity, increasing the degradation of misfolded proteins, and limiting the mRNA translation rate. Recent genetic and biochemical studies on mouse models and human UPR sensor mutations demonstrate a clear requirement of the UPR machinery to prevent beta cell failure and increase beta cell mass and adaptation throughout the progression of diabetes. In this review we will highlight the specific role of UPR actors in beta cell compensation and failure during diabetes. PMID- 24812636 TI - Injury to the endothelial surface layer induces glomerular hyperfiltration rats with early-stage diabetes. AB - Glomerular endothelial surface layer (ESL) may play a role in the mechanisms of albuminuria in diabetic nephropathy, which lack evidence in vivo. The effects of high glucose on the passage of albumin across the glomerular ESL were analysed in streptozotocin-induced diabetic Sprague-Dawley rats for 4 weeks. Albuminuria and glomerular mesangial matrix were significantly increased in diabetic rats. The passage of albumin across the ESL, as measured by albumin-colloid gold particle density in the glomerular basement membrane (GBM), was increased significantly in diabetic rats. The thickness of the glomerular ESL, examined indirectly by infusing Intralipid into vessels using an electron microscope, was significantly decreased and the GBM exhibited little change in diabetic rats. In summary, the glomerular ESL may play a role in the pathogenesis of albuminuria in rats with early-stage diabetes. PMID- 24812637 TI - Antiphospholipase A2 receptor autoantibodies: a comparison of three different immunoassays for the diagnosis of idiopathic membranous nephropathy. AB - BACKGROUND: The recent identification of circulating autoantibodies directed towards the M-type phospholipase A2 receptor (PLA2R) has been a major advancement in the serological diagnosis of idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults. The goal of this study was to compare the performance characteristics of two commercial assays as well as the first addressable laser bead immunoassay (ALBIA) developed for the detection of anti PLA2R antibodies. METHODS: Serum samples of 157 IMN patients and 142 controls were studied. Samples were tested by a cell based immunofluorescence assay (CBA IFA, Euroimmun, Germany), by ELISA (Euroimmun), and by a novel ALBIA employing an in vivo expressed recombinant human PLA2R. RESULTS: Overall, the three assays showed significant qualitative and quantitative correlation. As revealed by receiver operating characteristic analysis, the ALBIA correlated better with the CBA-IFA than the ELISA (P = 0.0003). The clinical sensitivities/specificities for IMN were 60.0% (51.0-68.5%)/98.6% (95.0-99.8%) and 56.2% (47.2-64.8%)/100.0% (97.4-100.0%) for ALBIA and CBA-IFA, respectively. CONCLUSION: The ALBIA represents a promising assay for the detection of anti-PLA2R antibodies showing similar performance to the CBA-IFA and the advantage of ease of use and suitability for high throughput, rapid turnaround times, and multiplexing. PMID- 24812638 TI - Current Understanding and Future Directions for Vocal Fold Mechanobiology. AB - The vocal folds, which are located in the larynx, are the main organ of voice production for human communication. The vocal folds are under continuous biomechanical stress similar to other mechanically active organs, such as the heart, lungs, tendons and muscles. During speech and singing, the vocal folds oscillate at frequencies ranging from 20 Hz to 3 kHz with amplitudes of a few millimeters. The biomechanical stress associated with accumulated phonation is believed to alter vocal fold cell activity and tissue structure in many ways. Excessive phonatory stress can damage tissue structure and induce a cell-mediated inflammatory response, resulting in a pathological vocal fold lesion. On the other hand, phonatory stress is one major factor in the maturation of the vocal folds into a specialized tri-layer structure. One specific form of vocal fold oscillation, which involves low impact and large amplitude excursion, is prescribed therapeutically for patients with mild vocal fold injuries. Although biomechanical forces affect vocal fold physiology and pathology, there is little understanding of how mechanical forces regulate these processes at the cellular and molecular level. Research into vocal fold mechanobiology has burgeoned over the past several years. Vocal fold bioreactors are being developed in several laboratories to provide a biomimic environment that allows the systematic manipulation of physical and biological factors on the cells of interest in vitro. Computer models have been used to simulate the integrated response of cells and proteins as a function of phonation stress. The purpose of this paper is to review current research on the mechanobiology of the vocal folds as it relates to growth, pathogenesis and treatment as well as to propose specific research directions that will advance our understanding of this subject. PMID- 24812639 TI - Pushed aside: Parentheticals, Memory and Processing. AB - In the current work, we test the hypothesis that 'at-issue' and 'not-at-issue' content (Potts, 2005) are processed semi-independently. In a written rating study comparing restrictive relative clauses and parentheticals in interrogatives and declaratives, we observe a significantly larger length penalty for restrictive relative clauses than for parentheticals. This difference cannot be attributed to differences in how listeners allocate attention across a sentence: a second study confirms that readers are equally sensitive to agreement violations in at-issue and not-at-issue content. A third rating experiment showed that the results do not depend on the restrictive relative clause intervening on the subject-verb dependency. A final experiment showed that the observed effects obtain with definite determiners and demonstratives alike. Taken jointly the results suggest that the parenthetical structures are processed independently of their embedding utterance, which in turn suggests that syntactic memory may be more differentiated than is typically assumed. PMID- 24812640 TI - Biophysical Stimulation for Bone Regeneration. PMID- 24812641 TI - Effects of ballistic stretching training on the properties of human muscle and tendon structures. AB - The purpose of this study was to investigate the influence of a 6-wk ballistic stretching training program on various parameters of the human gastrocnemius medialis muscle and the Achilles tendon. It is known that ballistic stretching is an appropriate means of increasing the range of motion (RoM), but information in the literature about the mechanical adaptation of the muscle-tendon unit (MTU) is scarce. Therefore, in this study, a total of 48 volunteers were randomly assigned into ballistic stretching and control groups. Before and following the stretching intervention, we determined the maximum dorsiflexion RoM with the corresponding fascicle length and pennation angle. Passive resistive torque (PRT) and maximum voluntary contraction (MVC) were measured with a dynamometer. Muscle-tendon junction (MTJ) displacement allowed us to determine the length changes in tendon and muscle, and hence to calculate stiffness. Mean RoM increased significantly from 33.8 +/- 6.3 degrees to 37.8 +/- 7.2 degrees only in the intervention group, but other functional (PRT, MVC) and structural (fascicle length, pennation angle, muscle stiffness, tendon stiffness) parameters were unaltered. Thus the increased RoM could not be explained by structural changes in the MTU and was likely due to increased stretch tolerance. PMID- 24812642 TI - Bone loss patterns in cortical, subcortical, and trabecular compartments during simulated microgravity. AB - Disuse studies provide a useful model for bone adaptation. A direct comparison of these studies is, however, complicated by the different settings used for bone analysis. Through pooling and reanalysis of bone data from previous disuse studies, we determined bone loss and recovery in cortical, subcortical, and trabecular compartments and evaluated whether the study design modulated skeletal adaptation. Peripheral quantitative tomographic (pQCT) images from control groups of four disuse studies with a duration of 24, 35, 56, and 90 days were reanalyzed using a robust threshold-free segmentation algorithm. The pQCT data were available from 27 young healthy men at baseline, and at specified intervals over disuse and reambulation phases. The mean maximum absolute bone loss (mean +/- 95% CI) was 6.1 +/- 4.5 mg/mm in cortical, 2.4 +/- 1.6 mg/mm in subcortical, and 9.8 +/- 9.1 mg/mm in trabecular compartments, after 90 days of bed rest. The percentage changes in all bone compartments were, however, similar. During the first few weeks after onset of reambulation, the bone loss rate was systematically greater in the cortical than in the trabecular compartment (P < 0.002), and this was observed in all studies except for the longest study. We conclude that disuse-induced bone losses follow similar patterns irrespective of study design, and the largest mean absolute bone loss occurs in the cortical compartment, but apparently only during the first 60 days. With longer study duration, trabecular loss may become more prominent. PMID- 24812643 TI - Age-related differences in heat loss capacity occur under both dry and humid heat stress conditions. AB - This study examined the progression of impairments in heat dissipation as a function of age and environmental conditions. Sixty men (n = 12 per group; 20-30, 40-44, 45-49, 50-54, and 55-70 yr) performed four intermittent exercise/recovery cycles for a duration of 2 h in dry (35 degrees C, 20% relative humidity) and humid (35 degrees C, 60% relative humidity) conditions. Evaporative heat loss and metabolic heat production were measured by direct and indirect calorimetry, respectively. Body heat storage was measured as the temporal summation of heat production and heat loss during the sessions. Evaporative heat loss was reduced during exercise in the humid vs. dry condition in age groups 20-30 (-17%), 40-44 (-18%), 45-49 (-21%), 50-54 (-25%), and 55-70 yr (-20%). HE fell short of being significantly different between groups in the dry condition, but was greater in age group 20-30 yr (279 +/- 10 W) compared with age groups 45-49 (248 +/- 8 W), 50-54 (242 +/- 6 W), and 55-70 yr (240 +/- 7 W) in the humid condition. As a result of a reduced rate of heat dissipation predominantly during exercise, age groups 40-70 yr stored between 60-85 and 13-38% more heat than age group 20-30 yr in the dry and humid conditions, respectively. These age-related differences in heat dissipation and heat storage were not paralleled by significant differences in local sweating and skin blood flow, or by differences in core temperature between groups. From a whole body perspective, combined heat and humidity impeded heat dissipation to a similar extent across age groups, but, more importantly, intermittent exercise in dry and humid heat stress conditions created a greater thermoregulatory challenge for middle-aged and older adults. PMID- 24812644 TI - Plasma K+ dynamics and implications during and following intense rowing exercise. AB - We investigated whether potassium (K(+)) disturbances during and following intense exercise may be pronounced when utilizing a large contracting muscle mass, examining maximal 2,000-m rowing exercise effects on radial arterial plasma K(+) concentration ([K(+)]a) in 11 healthy adults. Blood was sampled at baseline, preexercise, each 30 s during rowing, and for 30 min postexercise. Time to complete 2,000 m was 7.26 +/- 0.59 min; power output at 30 s was 326 +/- 81 W (mean +/- SD). With exercise time expressed in deciles, power output fell 16.5% from the first to fourth decile (P < 0.05) and 19.9% at the ninth decile (P < 0.05); EMG median frequency declined 4.6% by the third decile and 5.5% by the eighth decile (P < 0.05). Plasma [K(+)]a increased from 3.89 +/- 0.13 mM at rest to 6.13 +/- 0.46 mM by 90 s rowing (P < 0.001) and was then sustained until end exercise (P < 0.001). In recovery, [K(+)]a decreased abruptly, reaching 3.33 +/- 0.22 mM at 5 min postexercise (P < 0.001) and remaining below preexercise after 30 min (P < 0.005). At end exercise, blood [lactate]a (preexercise 0.64 +/- 0.18 mM) reached 10.87 +/- 1.33 mM, plasma volume decreased 9.7 +/- 2.3% from preexercise, and pHa decreased to 7.10 +/- 0.07 units (P < 0.001). In conclusion, arterial hyperkalemia was sustained during exhaustive rowing reflecting a balance between K(+) release and reuptake in contracting muscles and K(+) uptake by inactive muscles. While high, the [K(+)]a was lower than anticipated compared with maximal cycling or sprinting, possibly reflecting greater adrenergic response and Na(+),K(+)-ATPase activity in contracting muscles; fatigue was evidenced by reduced power output and EMG median frequency. A prolonged hypokalemia after rowing likely reflected continuing muscular Na(+),K(+)-ATPase activity. PMID- 24812646 TI - Ten years and counting. PMID- 24812645 TI - Quantitative measurement of XLR11 and UR-144 in oral fluid by LC-MS-MS. AB - Availability and consumption of synthetic cannabinoids have risen recently in the USA and Europe. These drugs have adverse effects, including acute psychosis and bizarre behavior. In 2012, the United States Drug Enforcement Agency permanently banned five of the synthetic cannabinoids and in 2013, temporarily added XLR11, UR-144 and AKB48 to Schedule I of the Controlled Substances Act. As synthetic cannabinoid strains are added to the Schedule I list, new strains are being introduced into the market. XLR11 and UR-144 are two of the most recent additions to the synthetic cannabinoid drug class. To test collected oral fluid samples for XLR11 and UR-144, we developed a bioanalytical method that initially purifies the sample with solid-phase extraction and then quantitatively identifies the drugs with ultra-high-performance liquid chromatography-tandem mass spectrometry. The method was validated according to United States Food and Drug Administration guidelines and Scientific Working Group for Forensic Toxicology guidelines and the validation data showed that the method is an accurate, precise, robust and efficient method suited for high-throughput toxicological screening applications. We tested human subject samples with the developed method and found the presence of parent drugs (XLR11 and UR-144), their metabolites and their pyrolysis products in oral fluid. PMID- 24812647 TI - Preadmission Screening and Resident Review (PASRR) regulation and its implications for patients, hospitals, nursing homes, and the taxpayers. AB - BACKGROUND: This study assessed the impact of the revision of the Preadmission Screening and Resident Review (PASRR) regulation changes in September 2011, which increased the turnaround time for PASRR evaluations from 3 to 5 days to 2 to 3 weeks. METHODS: From January 2013 to March 2013, we tracked all patients' charts in a 25-bed inpatient geriatric psychiatric unit in New York where PASRR evaluations were requested. The turnaround time and related issues were analyzed. RESULTS: There were 27 patients who had PASRR requests during the study period; 9 patients were not included in the study because of incomplete data. The average turnaround time for the 18 patients was 14.89 days and the additional hospital bed cost per patient was $11,911.11. CONCLUSIONS: Although PASRR has played a positive role in identifying persons with serious mental illness and the need to provide the services they need, the recent revision of the PASRR regulation in 2011 has significantly increased the hospital bed costs. PMID- 24812648 TI - An empirical data comparison of regulatory agency and malpractice legal problems for psychiatrists. AB - BACKGROUND: Our objective is to compare legal difficulties that psychiatrists encounter in regulatory agency and malpractice (insurance) settings. METHODS: Data sources included a literature search of malpractice and medical board discipline from 1990 to 2009 (rates and types of discipline); publicly available insurance data (malpractice frequency and type); and data from the National Practitioner Data Bank (NPDB) (required reports of malpractice settlements and hospital discipline). RESULTS: Medical board discipline findings indicate that psychiatrists are at increased risk of disciplinary action compared with other specialties. NPDB data indicated relatively infrequent problems for psychiatrists. In malpractice, psychiatry accounted for a small percentage of overall claims and settlements. Overall, more years in practice and a lack of board certification increased the risk of legal difficulties. CONCLUSIONS: There are shared and separate risk factors in the malpractice and regulatory agency areas, but there is evidence that these 2 legal areas are distinct from each other. PMID- 24812649 TI - Empathy and childhood maltreatment: a mixed-methods investigation. AB - BACKGROUND: Impaired empathy is regarded as a psychological consequence of childhood maltreatment, yet few studies have explored this relationship empirically. We investigated whether empathy differed in healthy and maltreated individuals by examining their emotional responses to people in distress. METHODS: Forty-nine individuals (age 20 to 60) viewed short film clips from the South African Truth and Reconciliation Commission testimonies depicting dialogues between victims and perpetrators of gross human rights violations. Participants were divided into 3 groups based on their scores on the Childhood Trauma Questionnaire: control (n = 18), moderate maltreatment (n = 21), and severe maltreatment (n = 10). We employed a mixed-methods design to explore empathic responses to film clips both quantitatively and qualitatively. RESULTS: Quantitative results indicated that self-reported empathy was lower in the moderate maltreatment group compared to the control group, but of similar strengths in the severe maltreatment and control groups. However, qualitative thematic analysis indicated that both maltreatment groups displayed themes of impaired empathy. CONCLUSIONS: Our results support the notion that childhood maltreatment is associated with impaired empathy, and suggest that such impairment may differ depending on the level of maltreatment: moderate maltreatment was associated with emotional blunting and impaired cognitive empathy, whereas severe maltreatment was associated with emotional over-arousal and diminished cognitive insight. PMID- 24812650 TI - A current review of cytochrome P450 interactions of psychotropic drugs. AB - BACKGROUND: The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drug-drug interactions. The majority of psychotropic agents are biotransformed by hepatic enzymes, which can lead to significant drug-drug interactions. Most drug-drug interactions of psychotropics occur at metabolic level involving the hepatic cytochrome P450 enzyme system. METHODS: We searched the National Library of Medicine, PsycINFO, and Cochrane reviews from 1981 to 2012 for original studies including clinical trials, double-blind, placebo-controlled studies, and randomized controlled trials. In addition, case reports, books, review articles, and hand-selected journals were utilized to supplement this review. RESULTS: Based on the clinical intensity of outcome, cytochrome interactions can be classified as severe, moderate, and mild. Severe interactions include effects that might be acutely life threatening. They are mainly inhibitory interactions with cardiovascular drugs. Moderate interactions include efficacy issues. Mild interactions include nonserious side effects, such as somnolence. CONCLUSIONS: Psychotropic drugs may interact with other prescribed medications used to treat concomitant medical illnesses. A thorough understanding of the most prescribed medications and patient education will help reduce the likelihood of potentially fatal drug-drug interactions. PMID- 24812651 TI - Clozapine in borderline personality disorder: a review of the evidence. AB - BACKGROUND: Borderline personality disorder (BPD) is a serious mental disorder that is difficult to treat. Possible targets for pharmacotherapy include affective symptoms, cognitive disturbances, and impulsive, self-injurious behaviors. Although many of the medications tested for treatment of BPD have been demonstrated to be useful, no clear pharmacologic treatment has emerged. Clozapine is one of the medications that has been evaluated for the treatment of severe BPD. The aim of this review is to summarize the evidence examining the effectiveness of clozapine in the treatment of BPD. METHODS: A comprehensive search of the health science databases PubMed, EMBASE, CINAHL, PsycINFO, Web of Science, Cochrane Library, and Google Scholar was performed for studies describing the use of clozapine in the treatment of BPD. RESULTS: After the initial search, no randomized controlled trials evaluating the effectiveness of clozapine in BPD were identified. Therefore, case reports and case series were reviewed, with 12 articles selected for final review. CONCLUSIONS: This review suggests that clozapine may be a beneficial treatment option for BPD especially in controlling symptom severity, psychotic symptoms, impulsivity, self mutilation, number of days on enhanced observation, use of restraint, and overall functioning. PMID- 24812652 TI - Levonorgestrel intrauterine device (IUD) exacerbation of PMS symptoms. PMID- 24812653 TI - Does change in ECT electrode placement help temporomandibular joint pain? PMID- 24812654 TI - Obstructive sleep apnea and risk for late-life depression. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by repetitive pharyngeal collapse. Because of the association between OSA, ischemia, and late-life depression, we hypothesized that older patients with OSA would have a higher prevalence of depression relative to their younger counterparts. METHODS: We retrospectively reviewed charts of patients evaluated at the Sleep Disorders Center (SDC) at University of Iowa Hospitals and Clinics. A total of 617 patients age>=18 seen at SDC for diagnostic and therapeutic sleep studies were identified. Patients with a chart diagnosis of depressive disorder or treatment with antidepressants were identified as having a depressive disorder. Patients with an Apnea/Hypopnea Index>=5 were identified as having OSA. RESULTS: No evidence of an escalating prevalence of depression with age was found in patients with OSA relative to those without the disorder. Prevalence of depression was similar in the OSA and the nonapnea groups (40.9% vs 40.3%, respectively; chi2=0.02; df=1; P=.89). Individuals with OSA had a significantly higher body mass index and greater number of chart diagnoses of hypertension, diabetes mellitus, and coronary artery disease compared with the nonapnea group. CONCLUSIONS: The prevalence of depression among individuals with OSA does not appear to be moderated by age. Similarly high rates of depression were observed across the population of individuals referred for sleep studies, whether or not they were diagnosed with OSA. PMID- 24812655 TI - Capgras delusion with violent behavior in Alzheimer dementia: case analysis with literature review. AB - BACKGROUND: Capgras delusion (CD) has multiple etiologies including neurodegenerative disorders and can be associated with violent behavior. CD is a common complication of Alzheimer dementia (AD); however, CD with violent behavior is uncommon in AD. We report escalating violent behavior by a patient with advanced AD and CD who presented to the emergency department (ED) and required admission to an academic medical center. METHODS: Case analysis with PubMed literature review. RESULTS: A 75-year-old male with a 13-year history of progressive AD, asymptomatic bipolar disorder, chronic kidney disease, hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with recurrent/escalating violence toward his wife, whom he considered an impostor. His psychotropic regimen included potentially inappropriate medications (PIMs) for geriatric/AD patients topiramate/amitriptyline/chlordiazepoxide/olanzapine-that are associated with delirium, cognitive decline, dementia, and mortality. Renal dosing for topiramate, reduction in PIMs/anticholinergic burden, and substituting haloperidol for olanzapine resolved his violent behavior and CD. CONCLUSIONS: CD in AD is a risk factor for violent behavior. As the geriatric population in the United States grows, CD in patients with AD may present more frequently in the ED, requiring proper treatment. Pharmacovigilance is necessary to minimize PIMs in geriatric/AD patients. Clinicians and other caregivers require further education to appropriately address CD in AD. PMID- 24812656 TI - Base-catalyzed bicyclization of dialkyl glutaconates with cinnamoylacetamides: a synthetic strategy for isoquinolinedione derivatives. AB - We report here that polysubstituted dihydroisoquinolones and isoquinolones can be constructed by the one-pot reaction of the readily available acyclic alpha,beta unsaturated carbonyl precursors and dialkyl glutaconates under mild basic conditions (1-45 min for the former vs. 1-6 h for the latter) via the domino process involving [3+3] annulation/intramolecular aza-cyclization. PMID- 24812657 TI - Boronic acid ester with dopamine as a tool for bioconjugation and for visualization of cell apoptosis. AB - Boronic esters are investigated as a pathway to conjugate biological molecules to polymers. Although the stability of the boronic ester was slightly dependent on the molecular weight of the polymer and the pH value, the conjugates were stable when micelles were endocytosed by cells. Only the onset of apoptosis led to cleavage of the boronic ester. PMID- 24812658 TI - A new cosensitization method using the Lewis acid sites of a TiO2 photoelectrode for dye-sensitized solar cells. AB - Co-sensitized dye-sensitized solar cells using black dye and a pyridine-anchor dye (NI5 or YNI-2) showing site-selective adsorption behaviour at the TiO2 surface have been prepared for the first time to reduce the competitive adsorption between the two dyes. PMID- 24812659 TI - ortho-Hydroxylation of aromatic acids by a non-heme Fe(V)=O species: how important is the ligand design? AB - There is a growing interest in probing the mechanism of catalytic transformations effected by non-heme iron-oxo complexes as these reactions set a platform for understanding the relevant enzymatic reactions. The ortho-hydroxylation of aromatic compounds is one such reaction catalysed by iron-oxo complexes. Experimentally [Fe(II)(BPMEN)(CH3CN)2](2+) (1) and [Fe(II)(TPA)(CH3CN)2](2+) (2) (where TPA = tris(2-pyridylmethyl)amine and BPMEN = N,N'-dimethyl-N,N'-bis(2 pyridylmethyl)ethane-1,2-diamine) complexes containing amino pyridine ligands along with H2O2 are employed to carry out these transformations where complex 1 is found to be more reactive than complex 2. Herein, using density functional methods employing B3LYP and dispersion corrected B3LYP (B3LYP-D) functionals, we have explored the mechanism of this reaction to reason out the importance of ligand design in fine-tuning the reactivity of such catalytic transformations. Dispersion corrected B3LYP is found to be superior to B3LYP in predicting the correct ground state of these species and also yields lower barrier heights than the B3LYP functional. Starting the reaction from the Fe(III)-OOH species, both homolytic and heterolytic cleavage of the O...O bond is explored leading to the formation of the transient Fe(IV)=O and Fe(V)=O species. For both the ligand systems, heterolytic cleavage was energetically preferable and our calculations suggest that both the reactions are catalyzed by an elusive high-valent Fe(V)=O species. The Fe(V)=O species undergoes the reaction via an electrophilic attack of the benzene ring to effect the ortho-hydroxylation reaction. The reactivity pattern observed for 1 and 2 are reflected in the computed barrier heights for the ortho-hydroxylation reaction. Electronic structure analysis reveals that the difference in reactivity between the ligand architectures described in complex 1 and 2 arise due to orientation of the pyridine ring(s) parallel or perpendicular to the Fe(V)=O bond. The parallel orientation of the pyridine ring is found to mix with the (piFe(dyz)-O(py))* orbital of the Fe-oxo bond leading to a reduction in the electrophilicity of the ferryl oxygen atom. Our calculations highlight the importance of ligand design in this chemistry and suggest that this concept can be used to (i) stabilize high-valent intermediates which can be trapped and thoroughly characterized (ii) enhance the reactivity and efficiency of the oxidants by increasing the electrophilicity of the ferryl oxygen containing FeVO species. Our computed results are in general agreement with the experimental results. PMID- 24812660 TI - Regulatory effects of resveratrol on glucose metabolism and T-lymphocyte subsets in the development of high-fat diet-induced obesity in C57BL/6 mice. AB - High-fat diet (HFD)-induced obesity is often associated with immune dysfunction. Resveratrol (trans-3,5,4'-trihydroxystilbene), which has well-founded immunity related beneficial properties, was used to elucidate the regulatory effect on glucose metabolism and T-lymphocyte subsets in the development of HFD-induced obesity. Resveratrol, being associated with decreases of plasma leptin and plasma lipids and the release of oxidative stress, significantly decreased the body weight and fat masses in HF mice after 26 weeks of feeding. Furthermore, resveratrol decreased the fasting blood glucose and fasting plasma insulin and increased the CD3(+)CD4(+)/CD3(+)CD8(+) subsets percentages and the regulatory T cells (Tregs) production after 13 and 26 weeks of feeding. The results indicate that resveratrol, as an effective supplement for HFD, maintained glucose homeostasis by activating the PI3K and SIRT1 signaling pathways. Moreover, resveratrol activated the Nrf2 signaling pathway-mediated antioxidant enzyme expression to alleviate inflammation by protecting against oxidative damage and T lymphocyte subset-related chronic inflammatory response in the development of HFD induced obesity. PMID- 24812661 TI - Caterpillar locomotion-inspired valveless pneumatic micropump using a single teardrop-shaped elastomeric membrane. AB - This paper presents a microfluidic pump operated by an asymmetrically deformed membrane, which was inspired by caterpillar locomotion. Almost all mechanical micropumps consist of two major components of fluid halting and fluid pushing parts, whereas the proposed caterpillar locomotion-inspired micropump has only a single, bilaterally symmetric membrane-like teardrop shape. A teardrop-shaped elastomeric membrane was asymmetrically deformed and then consecutively touched down to the bottom of the chamber in response to pneumatic pressure, thus achieving fluid pushing. Consecutive touchdown motions of the teardrop-shaped membrane mimicked the propagation of a caterpillar's hump during its locomotory gait. The initial touchdown motion of the teardrop-shaped membrane at the centroid worked as a valve that blocked the inlet channel, and then, the consecutive touchdown motions pushed fluid in the chamber toward the tail of the chamber connected to the outlet channel. The propagation of the touchdown motion of the teardrop-shaped membrane was investigated using computational analysis as well as experimental studies. This caterpillar locomotion-inspired micropump composed of only a single membrane can provide new opportunities for simple integration of microfluidic systems. PMID- 24812662 TI - Air, aqueous and thermal stabilities of Ce3+ ions in cerium oxide nanoparticle layers with substrates. AB - Abundant oxygen vacancies coexisting with Ce(3+) ions in fluorite cerium oxide nanoparticles (CNPs) have the potential to enhance catalytic ability, but the ratio of unstable Ce(3+) ions in CNPs is typically low. Our recent work, however, demonstrated that the abundant Ce(3+) ions created in cerium oxide nanoparticle layers (CNPLs) by Ar ion irradiation were stable in air at room temperature. Ce valence states in CNPs correlate with the catalytic ability that involves redox reactions between Ce(3+) and Ce(4+) ions in given application environments (e.g. high temperature in carbon monoxide gas conversion and immersion conditions in biomedical applications). To better understand the mechanism by which Ce(3+) ions achieve stability in CNPLs, we examined (i) extra-long air-stability, (ii) thermal stability up to 500 degrees C, and (iii) aqueous stability of Ce(3+) ions in water, buffer solution and cell culture medium. It is noteworthy that air stability of Ce(3+) ions in CNPLs persisted for more than 1 year. Thermal stability results showed that oxidation of Ce(3+) to Ce(4+) occurred at 350 degrees C in air. Highly concentrated Ce(3+) ions in ultra-thin CNPLs slowly oxidized in water within 1 day, but stability was improved in the cell culture medium. Ce(3+) stability of CNPLs immersed in the medium was associated with phosphorus adsorption on the Ce(3+) sites. This study also illuminates the potential interaction mechanisms of stable Ce(3+) ions in CNPLs. These findings could be utilized to understand catalytic mechanisms of CNPs with abundant oxygen vacancies in their application environments. PMID- 24812663 TI - Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction. AB - The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region. PMID- 24812664 TI - Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. AB - Tregs control various functions of effector T cells; however, where and how Tregs exert their immunomodulatory effects remain poorly understood. Here we developed a murine model of adoptive T cell therapy and found that Tregs induce a dysfunctional state in tumor-infiltrating CTLs that resembles T cell exhaustion and is characterized by low expression of effector cytokines, inefficient cytotoxic granule release, and coexpression of coinhibitory receptors PD-1 and TIM-3. Induction of CTL dysfunction was an active process, requiring local TCR signals in tumor tissue. Tregs infiltrated tumors only subsequent to Ag-dependent activation and expansion in tumor-draining LNs; however, Tregs also required local Ag reencounter within tumor tissue to induce CTL dysfunction and prevent tumor rejection. Multiphoton intravital microscopy revealed that in contrast to CTLs, Tregs only rarely and briefly interrupted their migration in tumor tissue in an Ag-dependent manner and formed unstable tethering-interactions with CD11c+ APCs, coinciding with a marked reduction of CD80 and CD86 on APCs. Activation of CTLs by Treg-conditioned CD80/86lo DCs promoted enhanced expression of both TIM-3 and PD-1. Based on these data, we propose that Tregs locally change the costimulatory landscape in tumor tissue through transient, Ag-dependent interactions with APCs, thus inducing CTL dysfunction by altering the balance of costimulatory and coinhibitory signals these cells receive. PMID- 24812665 TI - Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. AB - In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1 containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1 induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE 1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans. PMID- 24812666 TI - KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. AB - The transcription factor Kruppel-like factor 4 (KLF4) has the ability, along with other factors, to reprogram somatic cells into induced pluripotent stem (iPS) cells. Here, we determined that KLF4 is expressed in kidney glomerular podocytes and is decreased in both animal models and humans exhibiting a proteinuric. Transient restoration of KLF4 expression in podocytes of diseased glomeruli in vivo, either by gene transfer or transgenic expression, resulted in a sustained increase in nephrin expression and a decrease in albuminuria. In mice harboring podocyte-specific deletion of Klf4, adriamycin-induced proteinuria was substantially exacerbated, although these animals displayed minimal phenotypical changes prior to adriamycin administration. KLF4 overexpression in cultured human podocytes increased expression of nephrin and other epithelial markers and reduced mesenchymal gene expression. DNA methylation profiling and bisulfite genomic sequencing revealed that KLF4 expression reduced methylation at the nephrin promoter and the promoters of other epithelial markers; however, methylation was increased at the promoters of genes encoding mesenchymal markers, suggesting selective epigenetic regulation of podocyte gene expression. Together, these results suggest that KLF4 epigenetically modulates podocyte phenotype and function and that the podocyte epigenome can be targeted for direct intervention and reduction of proteinuria. PMID- 24812667 TI - Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. AB - Prostaglandin E2 (PGE2) promotes Th17 expansion while otherwise inhibiting other CD4+ T cell subsets. Here, we identified a PGE2-dependent pathway that induces pathogenic Th17 cells in autoimmune disease and is regulated by the transcription factor RORC. Compared with other CD4+ cell types from healthy subjects, there is a surprising lack of the prostaglandin receptor EP2 on Th17 cells; therefore, we examined the hypothesis that RORgammat, which is highly expressed in Th17 cells, mediates EP2 downregulation. Chromatin immunoprecipitation followed by DNA sequencing revealed that RORgammat binds directly to Ptger2 (the gene encoding EP2 receptor) in Th17 cells isolated from WT mice. In Th17 cells isolated from humans, RORC repressed EP2 by directly silencing PTGER2 transcription, and knock down of RORC restored EP2 expression in Th17 cells. Compared with Th17 cells from healthy individuals, Th17 cells from patients with MS exhibited reduced RORC binding to the PTGER2 promoter region, resulting in higher EP2 levels and increased expression of IFN-gamma and GM-CSF. Finally, overexpression of EP2 in Th17 cells from healthy individuals induced a specific program of inflammatory gene transcription that produced a pathogenic Th17 cell phenotype. These findings reveal that RORC directly regulates the effects of PGE2 on Th17 cells, and dysfunction of this pathway induces a pathogenic Th17 cell phenotype. PMID- 24812668 TI - Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. AB - Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity. PMID- 24812671 TI - Expression of concern. Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. PMID- 24812669 TI - Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. AB - Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress-associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor-bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-approved BTK inhibitor, synergized to induce apoptosis in B cell leukemia, lymphoma, and multiple myeloma. These data indicate that targeting XBP-1 has potential as a treatment strategy, not only for multiple myeloma, but also for mature B cell leukemia and lymphoma. PMID- 24812672 TI - "All-on-four": where are we now? PMID- 24812670 TI - Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm. AB - Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D expressing HSCs, which serve as JMML/MP-CMML-initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML-like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP CMML. PMID- 24812673 TI - Increased survival among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals. AB - OBJECTIVE: To compare survival times of HIV-1 single and HIV-1 and HIV-2 dual infected individuals. DESIGN: Prospective open cohort study. METHODS: We analysed data from 259 HIV-1-seroincident cases (either HIV-1 single or HIV-1 and HIV-2 dual-infected) from a cohort with long follow-up (~20 years) in order to study the influence of type of infection and infection order on mortality. Sex and age at HIV-1 infection date was controlled for in a Cox proportional-hazards model. RESULTS: Dual-infected individuals had a 42% longer time from HIV-1 infection to death compared with single-infected individuals, adjusting for age asymmetries between groups. Dual-infected individuals with an HIV-2 infection preceding the HIV-1 infection had a more than two-fold lower mortality risk during follow-up than HIV-1 single-infected individuals. CONCLUSION: Survival time is longer and the risk of progression to death is lower among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals. This natural inhibition could have implications for the development of future HIV-1 vaccines and therapeutics. PMID- 24812674 TI - Author Response. PMID- 24812676 TI - Continuing education: Study broad and deep. PMID- 24812675 TI - Occurrence and dissipation of benzotriazoles and benzotriazole ultraviolet stabilizers in biosolid-amended soils. AB - Benzotriazoles (BTs) and benzotriazole ultraviolet (UV) stabilizers (BUVSs) are commonly used industrial and household chemicals, but little is known about their dissipation behavior in the soil environment associated with biosolid application. The authors investigated the occurrence and dissipation of 4 BTs (BT, 5-methyl-1H-benzotriazole [5-TT], 5-chloro-1H-benzotriazole [CBT], and 5,6 dimethyl-1H-benzotriazole [XT]) and 5 BUVSs (UV-326, UV-327, UV-328, UV-329, and UV-P) in biosolid-amended soil of 3 trial sites (Zhejiang, Hunan, and Shandong) in China following 2 treatments (treatment 1: a single application of biosolid; treatment 2: repeated application of biosolid). The results showed that except for CBT and XT, the other 7 compounds could be detected in most of the biosolid and biosolid-amended soils at levels of a few to tens of nanograms per gram and that the concentrations of the 7 compounds for treatment 2 were obviously higher than those for treatment 1. In the 1-yr monitoring of the Shandong site, 2 BTs (BT and 5-TT) and 5 BUVSs (UV-326, UV-327, UV-328, UV-329, and UV-P) were significantly dissipated in the biosolid-amended soils. The field half-lives of BT and 5-TT ranged from 217 d to 345 d, while those for the BUVSs ranged between 75 d and 218 d. The field half-lives of target compounds in soil were found to be comparable to the modeling results. The results suggest the persistence of BTs and BUVSs in soil environments with quite slow dissipation rates. PMID- 24812677 TI - Embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs prey capture by zebrafish larvae. AB - As a ubiquitous, persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) has the potential to cause lethal deformities in larval fishes. Few studies have examined its impacts on larval growth and craniofacial development in conjunction with feeding capability. The authors used morphological and behavioral assessments to demonstrate that feeding capability of larvae is impaired even when craniofacial structures are not grossly malformed. Zebrafish embryos were exposed to 25 pg TCDD/mL, 50 pg TCDD/mL, or 100 pg TCDD/mL or <0.1% dimethyl sulfoxide for 1 h at 4 h postfertilization and then raised in clean water for 21 d or 90 d to assess craniofacial morphology, feeding capability, and long-term survival. The lower jaw was 5% smaller in 21-d larvae exposed to >= 50 pg TCDD/mL, and those larvae caught 10% fewer prey items; survival was reduced by 13% to 23%. The direct cause of TCDD's impacts on feeding capability is not known, but feeding success was correlated with growth, length of lower jaw, and survival. Since low larval mortality rates are key for recruitment, this suggests that exposure to concentrations of TCDD during embryonic development that do not initially cause mortality still has the potential to impact the recruitment success of feral fish. Furthermore, the present work provides additional evidence that behavioral end points are often more sensitive than morphological ones and should be included when assessing the sublethal toxicity of environmental contaminants. PMID- 24812678 TI - Oxidative potential of ultraviolet-A irradiated or nonirradiated suspensions of titanium dioxide or silicon dioxide nanoparticles on Allium cepa roots. AB - The effect of ultraviolet-A irradiated or nonirradiated suspensions of agglomerates of titanium dioxide (TiO(2)) or silicon dioxide (SiO(2)) nanoparticles on roots of the onion (Allium cepa) has been studied. The reactive potential of TiO(2) nanoparticles, which have photocatalytic potential, and the nonphotocatalytic SiO(2) nanoparticles with the same size of agglomerates was compared. The authors measured the activity of antioxidant enzymes glutathione reductase, ascorbate peroxidase, guaiacol peroxidase, and catalase as well as lipid peroxidation to assess the oxidative stress in exposed A. cepa roots. A wide range of concentrations of nanoparticles was tested (0.1-1000 ug/mL). The sizes of agglomerates ranged in both cases from 300 nm to 600 nm, and the exposure time was 24 h. Adsorption of SiO(2) nanoparticles on the root surface was minimal but became significant when roots were exposed to TiO(2) agglomerates. No significant biological effects were observed even at high exposure concentrations of SiO(2) and TiO(2) nanoparticles individually. Plants appear to be protected against nanoparticles by the cell wall, which shields the cell membrane from direct contact with the nanoparticles. The authors discuss the need to supplement conventional phytotoxicity and stress end points with measures of plant physiological state when evaluating the safety of nanoparticles. PMID- 24812680 TI - A cosmic history. PMID- 24812679 TI - Tribal gathering. PMID- 24812681 TI - The game is on. PMID- 24812682 TI - Synthetic biology: How best to build a cell. PMID- 24812683 TI - Society: Realizing China's urban dream. PMID- 24812684 TI - A highly sensitive CE-chemiluminescence method for the determination of sympathomimetic drugs in urine samples by a facile precolumn derivatization using acridinium ester. AB - As one of the most sensitive detection mode for CE, chemiluminescence (CL) detection is less developed compared to some other detection modes such as MS and LIF, despite its low equipment cost and simple design. The fact is partly due to the limitation of CL systems suitable for CE. In this paper, a highly sensitive CE-CL strategy was established for the determination of dopamine (DA) and cimbuterol (CM) using acridinium ester as derivatization reagent. Catalyst was not required in this CL detection system. Also, a good sensitivity was obtained due to its quite low background and strong signal. Under the optimal conditions, the presented method has been successfully applied to analyze DA and CM with LODs (S/N = 3) of 2.0 and 0.50 ng/mL, respectively. The linear ranges were 5.0-1500 ng/mL and 2.0-1000 ng/mL for DA and CM, respectively. To validate our method, the levels of DA in human urine samples were detected by this method, and the results showed acceptable accordance with those of ELISA. All the analysis procedure could be completed in 400 s, and the results showed satisfactory sensitivity and selectivity.The approach could also be further extended to rapid analysis of many other compounds including primary and second amines in clinical medicine and biopharmaceutical analysis using acridinium ester as CL derivatization reagent. PMID- 24812686 TI - Development of imaged capillary isoelectric focusing method and use of capillary zone electrophoresis in hepatitis B vaccine RECOMBIVAX HB(r). AB - The hepatitis B virus vaccine consists of a major surface antigen called HBsAg, which is a lipid-bound protein that self-assembles into 22 nm spherical noninfectious virus-like particles (VLPs). The HBsAg VLP particles are expressed in yeast and have been well-characterized biochemically and biophysically employing various analytical techniques. In fact, a CZE method has been developed for monitoring process purification of the hepatitis B vaccine. Another CE-based method, imaged capillary IEF (icIEF) has been used extensively in the field of protein-based drug development as a tool for product identification,stability monitoring, and characterization. Here we describe the development of the icIEF method using the iCE280 instrument from ProteinSimple for measuring the pI and monitoring the profiles of HBsAg VLP particles. This method was applied to characterize the stability of the HBsAg VLP particles in three different formulation buffers. The results show that HBsAg VLP particles have a pI of 2.7 and it is one of most acidic particles that we have measured by icIEF. In addition to icIEF, we have also employed a CZE method to measure the electrophoretic mobility of HBsAg VLP particles and compared the results with icIEF and dynamic light scattering methods, showing consistent correlation among the three methods in terms of HBsAg VLP particles aggregation. PMID- 24812685 TI - Sialic acid methylation refines capillary electrophoresis laser-induced fluorescence analyses of immunoglobulin G N-glycans of ovarian cancer patients. AB - Alterations in IgG N-glycosylation coincide with the development of a number of diseases including cancer and could potentially be used as diagnostic markers. CE LIF of 8-aminopyrene-1,3,6-trisulfonic acid labeled N-glycans is a well established rapid method to characterize IgG N-glycans that needs only low amounts of starting material. However,sialylated N-glycans have short migration times due to their negative charge. As a result,some of them are not well resolved and co-migrate with neutral glycans. In this work, we neutralized the negative charge of sialic acids by methylation and optimized the protocol using the commercially available disialylated biantennary oligosaccharide (A2G2S2). IgGN-glycans isolated from healthy human serum were then analyzed using this method. We could demonstrate that co-migration of A2, FA2G2S1, and FA2B[3]G1S1 was prevented,which allowed an accurate quantification of these N-glycans. Finally, we investigated the IgG N-glycan profiles of patients suffering from ovarian cancer using the conventional and methylation methods.With both methods, we observed an increase of agalactosylated structures that was accompanied by a decrease in digalactosylated structures. Finally, using the methylation protocol, we could further demonstrate an increase of A2, which was technically impossible with the conventional method. PMID- 24812687 TI - Coexistence of cardiomyopathy and pericardial effusion: A challenging diagnosis. Reply. PMID- 24812688 TI - Editorial Comment to Sacral neuromodulation is an effective option for non obstructive urinary retention in men with cerebral palsy. PMID- 24812689 TI - Commitment to health theory: a graphic model. AB - Graphic models can improve understanding of theoretical concepts and the relationship between concepts. This article introduces a model of Commitment to Health Theory, which describes the process of behavior change from action to the maintenance stage of change. Commitment to health means that a new or modified health behavior will be used regardless of socioeconomic factors, race, gender, employment category, and age. Findings were based on three cross-sectional survey studies of approximately 1,085 predominantly manufacturing workers sampled from across the United States. Commitment to Health Theory was used to identify those in the action stage of change with mid-level commitment and predict the likelihood of successfully changing health behavior. Monitoring levels of commitment to health can determine appropriate intervention strategies to assist clients who currently exhibit unhealthy diet and exercise behaviors. PMID- 24812690 TI - Occupational health nurses' achievement of competence and comfort in respiratory protection and preferred learning methods results of a nationwide survey. AB - Additional findings are presented from a 2012 nationwide survey of 2,072 occupational health nurses regarding how they achieved competence in respiratory protection, their preferred methods of learning, and how they motivated employees to use respiratory protection. On-the-job training, taking a National Institute for Occupational Safety and Health spirometry course, or attending professional conferences were the primary ways occupational health nurses gained respiratory protection knowledge. Attending professional conferences was the preferred method of learning, varying by type of industry and years of occupational health nurse experience. Employee motivational strategies were not widely used; the most common strategy was to tailor respiratory protection training to workplace culture. Designing training methods that match learning preferences, within the context of the organization's safety and quality improvement culture, is a key recommendation supported by the literature and these findings. Including respiratory protection content and competencies in all levels of academic nursing education is an additional recommendation. Additional research is needed to link training strategies with consistent and correct use of respiratory protection by employees. PMID- 24812691 TI - The impact of Sun Solutions educational interventions on select health belief model constructs. AB - The purpose of this study was to offer the Sun Solutions intervention to operating engineers (N = 232) to decrease sun exposure and skin cancer. The majority (82%) of the engineers worked outside between 10 a.m. and 3 p.m., 4 to 5 hours a day; 81.4% reported more than one sunburn during the past year and 70% sometimes or never used sunscreen compared to 30% who wore sunscreen approximately 50% or more of the time. Most reported that the intervention was helpful (97%), most were satisfied (96%) with the intervention, and 84% expressed a future intention to use sunscreen. Regarding sun protective behaviors, the intervention significantly improved perceived self-efficacy (p < .05) and increased perceived barriers (p < .05). Regarding sunburn and skin cancer, the intervention increased perceived benefits (p < .05), susceptibility (p < .05), and severity (p < .05) for sunburning, but not skin cancer (p > .10). The Sun Solutions intervention showed the potential to increase sunscreen use and decrease the risk of sunburn and skin cancer among operating engineers. PMID- 24812692 TI - Insulin therapy improves islet functions by restoring pancreatic vasculature in high-fat diet-fed streptozotocin-diabetic rats. AB - BACKGROUND: In a previous study, we showed early insulin therapy could improve beta-cell function in type 2 diabetic patients. However, the molecular mechanism was not clear. In the present study, we addressed this question by analyzing the pancreatic microvasculature in diabetic rats after insulin treatment. METHODS: Diabetes was induced in rats by a combination of low dose streptozotocin (STZ; 40 mg/kg) and feeding of a high-fat diet. After the induction of diabetes, rats were treated with neutral protamine Hagedorn insulin (NPH; 6-8 U/day, s.c.) for 3 weeks. Three days after the end of treatment, rats were subjected to an intraperitoneal glucose tolerance test (IPGTT). The pancreatic microvasculature and the amount and size of the islets were evaluated by immunohistochemistry. Western blot analysis was used to determine levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGF-R2) protein. RESULTS: Treatment with NPH improved insulin secretion from beta-cells during the IPGTT and increased pancreatic islet size. The density of the microvasculature in the pancreas was determined by quantification of CD31, a marker of endothelial cells. Insulin treatment increased CD31 protein levels, as well as the expression of VEGF and VEGFR2. CONCLUSIONS: The results suggest that insulin treatment improves islet recovery by increasing angiogenesis in the pancreas. The mechanism is related to the induction of VEGF and VEGFR2 expression in diabetic rats. PMID- 24812693 TI - Rapid separation and identification of Strychnos alkaloids metabolites in rats by ultra high performance liquid chromatography with linear ion trap Orbitrap mass spectrometry. AB - An in vivo study of Strychnos alkaloids metabolites in rats by ultra high performance liquid chromatography with linear ion trap Orbitrap MS is reported for the first time. Two major Strychnos alkaloids compounds including strychnine and brucine were investigated. To obtain optimal extraction efficiency, samples were pretreated by using an SPE plate. The structures of metabolites and their fragment ions were characterized based on the accurate mass and MSn data. Forty seven metabolites were identified in rat urine, of which 25 were reported for the first time. Four new metabolism pathways were proposed on the basis of the identified metabolites. This study provides a practical approach for rapidly identifying complicated metabolites, a methodology that could be widely applied not only in forensic and clinically toxicological relevant cases, but also for the structural characterization of metabolites of other compounds. PMID- 24812694 TI - Rapid determination of natural and synthetic hormones in biosolids and poultry manure by isotope dilution GC-MS/MS. AB - The release of hormones into the environment due to land application of biosolids and manure is a cause of concern for their potential impacts. This paper presents the development of a rapid and sensitive method, based on extraction, for the analysis of 13 hormones in biosolids and poultry manure. A simultaneous derivatization of hydroxyl and ketone groups was carried out for the determination of hormones by GC-MS/MS. The method was validated in three matrices (sewage sludge, manure, and broiler litter). Recoveries from spiked samples at three concentration levels (50, 25, and 10 ng/g) ranged from 76 to 124% with relative SDs <= 16%. Method detection limits for the three matrices were in the range of 0.5-3.0 ng/g dry weight. The optimized method was applied to biosolid and poultry manure samples collected in Spain. Only seven of the 13 studied hormones were detected in the different samples. trans-Androsterone was detected at high levels (up to 3.1 MUg/g in biosolid samples). Estrone and estradiol were the two hormones detected at higher levels in layer manure, whereas estrone and 4 androstene-3,17-dione presented the highest levels in broiler litter. PMID- 24812695 TI - Cell therapy in amyotrophic lateral sclerosis: a significant step forward. PMID- 24812696 TI - Leadership in neurology: a social network analysis. AB - OBJECTIVE: Two important leadership posts in American neurology are the presidents of the American Academy of Neurology (AAN) and the American Neurological Association (ANA). In this article, we use social network analysis, based on graph theory, to map the professional ties of presidents of the AAN and ANA since 1948. We examined whether institution ranking was related to being president of either organization, and whether there were core groups of presidents, institutions of employment during presidency, or training programs (residency and fellowship) in the combined and separate AAN and ANA networks. METHODS: Using archival data, we constructed a series of relational tables of the presidents and their affiliations. We used a chi-square analysis to test the relation between institution ranking and organization affiliation. For network data, we used a 2-mode analysis with measures of node, dyad, and network characteristics. RESULTS: ANA presidents were more likely to be employed at ranked institutions compared to AAN presidents. Ten presidents bridged both organizations, and therefore had the highest centrality in the combined network. Presidents trained in a core group of similar residency and fellowship programs that included Harvard, Columbia, Cornell, and Mayo Clinic for AAN presidents, and Harvard, Columbia, Yale, and University College London for ANA presidents. In contrast, during their presidency, AAN and ANA presidents worked at a diffuse set of institutions without a core group. INTERPRETATION: Training programs are leadership hubs, and should be targeted to develop future presidents and influence trends in the neurology leadership network. PMID- 24812697 TI - Traumatic brain injury and young onset dementia: a nationwide cohort study. AB - OBJECTIVE: To investigate the association between traumatic brain injuries (TBIs) and the risk of young onset dementia (YOD), that is, dementia before 65 years of age. METHODS: The study cohort comprised 811,622 Swedish men (mean age 5 18 years) conscripted for military service between 1969 and 1986. TBIs, dementia, and covariates were extracted from national registers. Time-dependent exposures using Cox proportional hazard regression models were evaluated. RESULTS: During a median follow-up period of 33 years, there were 45,249 men with at least 1 TBI in the cohort. After adjustment for covariates, 1 mild TBI (hazard ratio [HR] 5 1.0, 95% confidence interval [CI] 5 0.5-2.0), at least 2 mild TBIs (HR 5 2.5, 95% CI 5 0.8-8.1), or 1 severe TBI (HR 5 0.7, 95% CI 5 0.1-5.2) were not associated with Alzheimer dementia (AD). Other types of dementia were strongly associated with the risk of 1 mild TBI (HR 5 3.8, 95% CI 5 2.8-5.2), at least 2 mild TBIs (HR 5 10.4, 95% CI 5 6.3-17.2), and 1 severe TBI (HR 5 11.4, 95% CI 5 7.4-17.5) in age adjusted analysis. However, these associations were largely attenuated after adjustment for covariates (1 mild TBI: HR 5 1.7; at least 2 mild TBIs: HR 5 1.7; 1 severe TBI: HR 5 2.6; p < 0.05 for all). INTERPRETATION: In the present study, we found strong associations between YOD of non-AD forms and TBIs of different severity. These associations were, however, markedly attenuated after multivariate adjustment. PMID- 24812698 TI - Isolated unilateral infarction of the cerebellar tonsil: ocular motor findings. AB - The oculomotor abnormalities with isolated infarction of the cerebellar tonsil are unknown. In a patient with acute infarction of the right tonsil, we found (1) nearly completely abolished ipsilateral smooth pursuit and impaired contralateral pursuit, (2) a low-amplitude ipsilesional right-beating nystagmus without fixation, (3) gaze-holding deficits, and (4) normal vestibulo-ocular reflex. These findings contrast with striking vestibular abnormalities reported with unilateral flocculus and anterior tonsil infarction. Taken together, these findings allow more diagnostic certainty in cerebellar patients, help resolve controversies about interpretation of experimental findings in monkeys, and clarify homologies between the monkey and human cerebellum. PMID- 24812699 TI - Frederick Sanger (1918-2013). PMID- 24812700 TI - Ubiquitin-negative, eosinophilic neuronal cytoplasmic inclusions associated with stress granules and autophagy: an immunohistochemical investigation of two cases. AB - Identification of the proteinaceous components of the pathological inclusions is an important step in understanding the associated disease mechanisms. We immunohistochemically examined two previously reported cases with eosinophilic neuronal cytoplasmic inclusions (NCIs)(case 1, Mori et al. Neuropathology 2010; 30: 648-53; case 2, Kojima et al. Acta Pathol Jpn 1990; 40: 785-91) using 67 antibodies against proteins related to cytoskeletal constituents, ubiquitin proteasome system, autophagy-lysosome pathway and stress granule formation. Regional distribution pattern of eosinophilic NCIs in case 1 was substantially different from that in case 2. However, NCIs in both cases were immunonegative for ubiquitin and p62 and were immunopositive for stress granule markers as well as autophagy-related proteins, including valosin-containing protein. Considering that eukaryotic stress granules are cleared by autophagy and valosin-containing protein function, our findings suggest that eosinophilic NCIs in the present two cases may represent the process of autophagic clearance of stress granules. PMID- 24812701 TI - Globoid cell leukodystrophy (Krabbe's disease) in a Japanese domestic cat. AB - A male Japanese domestic cat developed progressive limb paralysis from 4 months of age. The cat showed visual disorder, trismus and cognitive impairment and died at 9 months of age. At necropsy, significant discoloration of the white matter was observed throughout the brain and spinal cord. Histologically, severe myelin loss and gliosis were observed, especially in the internal capsule and cerebellum.In the lesions, severe infiltration of macrophages with broad cytoplasm filled with PAS-positive and nonmetachromatic granules (globoid cells) was evident. On the basis of these findings, the case was diagnosed as feline globoid cell leukodystrophy (Krabbe's disease). Immunohistochemical observation indicated the involvement of oxidative stress and small HSP in the disease. PMID- 24812702 TI - Intracranial teratoma in children: the role of chromosome 21 trisomy. AB - Teratomas are very rare intracranial tumors and cytogenetic information on this group remains rare. We report a case of a mature teratoma with abnormal +21 trisomy in tumor karyotype ocurring in a non-Down syndrome(DS) infant. Additionally, the evidence for the contribution of chromosome 21 trisomy in this neoplasia are briefly reviewed. The 6-month-old male baby presented with a posterior fossa tumor. Histological evaluation of tumor specimen showed a mature teratoma composed of fully differentiated ectodermal, mesodermal and endodermal components. Although somatic karyotyping of the index case was normal, composite tumor karyotype depicted 47,XY,+21[6]/46,XY[6]. Besides previous reports of children with DS and intracranial teratomas, this is the first report to describe the occurrence of an isolated chromosome 21 trisomy within the tumor of a non-DS child. The participation of chromosome 21 in this rare pediatric tumor, either somatic or restricted to tumor specimen,may deserve special interest and further investigation. PMID- 24812703 TI - Ependymosarcoma with eosinophilic granular cells. AB - Ependymosarcoma is a new entity of malignant gliomas composed of ependymal and sarcomatous components. Were port a rare case of ependymosarcoma with eosinophlic cells which occurred to the right trigon of the lateral ventricle.A 62-year-old man complained of headaches over a 2-month period. A hard, gray mass was found in the right trigon of the lateral ventricle during the operation.Although he received radiation and chemotherapy, the patient died due to tumor disseminating through the whole brain within 7 months after the operation. The histological examination revealed that the anaplastic glial components intermingled with the sarcomatous components. Immunohistochemically, sarcomatous cells were positive for alpha smooth muscle actin and desmin. However, anaplasticglial cells were not positive for these markers. In addition, Masson trichrome stain showed a plethora of collagen fibers between sarcomatous cells, but no collagen fibers were produced by the glial tumor cells. Solid focal papillary lesions of the glial tumor showed dot-like epithelial membrane antigen and diffuse cytoplasmic D2-40 immunoreactivity. Based on the above findings, these anaplastic glial tumor cells should show focal ependymal differentiation, and sarcomatous cells show myofibroblastic differentiation. In addition, almost 10%of the tumor cells in the neoplasm showed bright eosinophilic granules in the cytoplasm. These cytoplasmic eosinophilic granules and bundles were negative on PAS staining. Intracytoplasmic eosinophilic granules of tumor cells were strongly positive for alphaB crystallin, HSP 27 and GFAP, respectively. These findings suggest that the clinicopathological characteristics of the present case should be consistent with the criterion of ependymosarcoma by Rodriguez et al. PMID- 24812704 TI - Is perioperative care still an issue now that we have the robot? PMID- 24812705 TI - Packed red blood cell transfusions in the intensive care unit: treating the patient or the doctor? PMID- 24812706 TI - Medicine in small doses. PMID- 24812707 TI - Patients' recollection and understanding of informed consent: a literature review. AB - OBJECTIVE: To explore patients' recollection and understanding of the proposed medical procedures for which they have consented. METHODS: Six databases were searched from January 1995 to March 2013 for articles using the MeSH terms 'informed consent', 'patients' and 'comprehension', and the free text search term 'patient understanding'. This search identified 354 articles. Once duplicates (n = 213) were removed, the remaining 141 articles were screened, resulting in 13 high-quality studies that met the inclusion criteria. RESULTS: When asked to reflect on the consenting process, between 21% and 86% of patients were able to recall the potential risks and complications of their medical procedure. The degree of understanding of the consenting process decreased with age. Some patients were of the opinion that the primary purpose of the consent procedure was to protect hospitals and doctors. PATIENTS: Level of education, literacy and language competency, combined with physicians' ability to effectively explain the medical procedure and the inherent risks and complications, were important determinants of patients' capacity to provide fully informed consent. The use of education materials delivered in written form or embedded in an interactive multimedia process led to improvements in patients' understanding of the implications of surgery. CONCLUSIONS: This review found that patients' recollection and understanding of the medical procedure, risks and complications is often low, particularly among older individuals. The use of interactive multimedia and written material that are easy-to-read and comprehend, and prepared for individual patients has been shown to increase patient awareness, recollection and understanding of the consenting procedure. PMID- 24812708 TI - Is distal screw entry point associated with subtrochanteric fracture after intracapsular hip fracture fixation? AB - BACKGROUND: Subtrochanteric fracture is a recognized complication following cannulated screw fixation of intracapsular hip fracture. We investigated the incidence of subtrochanteric fracture in a consecutive series of 304 patients and its association with screw entry point in the lateral femoral cortex. METHODS: A retrospective consecutive case series of patients treated with internal fixation for intracapsular hip fracture by our unit between January 2003 and January 2010 were included. Two authors reviewed radiographs independently to determine distal screw entry point in the lateral femoral cortex. Hickey zone 1 was an entry point above the level of the upper border of the lesser trochanter. Hickey zone 2 was defined as an entry point between the upper and lower borders of the lesser trochanter. Hickey zone 3 was an entry point below the lower border of the lesser trochanter. Clinical notes were reviewed for subsequent subtrochanteric fracture. Association between subtrochanteric fracture and distal screw entry point in the lateral femoral cortex in relation to the upper border of the lesser trochanter was determined. RESULTS: Two hundred and fifty-six post-operative radiographs were available for analysis. Mean patient age was 73 years (30-98), 75% were women. There were 24 patients with screw entry point in Hickey zone 1, 225 in Hickey zone 2, and 7 in Hickey zone 3. Two patients sustained subtrochanteric fracture. No subtrochanteric fractures occurred in patients with Hickey zone two screw entry. CONCLUSION: Subtrochanteric fracture is rare following cannulated screw fixation of intracapsular neck of femur fracture (0.78%). In this retrospective consecutive case series, no subtrochanteric fractures occurred when the entry point of the lowest screw in the lateral femoral cortex is between the levels of the upper and lower borders of the lesser trochanter. PMID- 24812709 TI - Using multimedia to enhance the consent process for bunion correction surgery. AB - BACKGROUND: Obtaining informed consent from patients considering bunion surgery can be challenging. This study assessed the efficacy of a multimedia technology as an adjunct to the informed consent process. METHODS: A prospective, cohort study was conducted involving 55 patients (7 males, 48 females) who underwent a standardized verbal discussion regarding bunion correction surgery followed by completion of a knowledge questionnaire. A multimedia educational program was then administered and the knowledge questionnaire repeated. Additional supplementary questions were then given regarding satisfaction with the multimedia program. RESULTS: Patients answered 74% questions correctly before the multimedia module compared with 94% after it (P < 0.0001). Patients rated the ease of understanding and the amount of information provided by the module highly. Eighty-four percent of patients considered that the multimedia tool performed as well as the treating surgeon. CONCLUSION: Multimedia technology is useful in enhancing patient knowledge regarding bunion surgery for the purposes of obtaining informed consent. PMID- 24812710 TI - The role of single-patient neonatal intensive care unit rooms for preterm infants. PMID- 24812711 TI - Are the new Danish 2014 growth references really more appropriate than the World Health Organization standards? PMID- 24812712 TI - How mothers perceive infants with unspecific gastrointestinal symptoms suggestive of cow's milk allergy? AB - AIM: To determine whether specific infant behavioural characteristics are present in children suspected of cow's milk allergy because of gastrointestinal symptoms. METHODS: We prospectively recruited 57 children (median age 8.7 months) with a suspicion of gastrointestinally manifested cow's milk protein allergy (GI-CMPA). None had detectable cow's milk-specific IgE. Mothers were asked to complete the Parenting Stress Index (PSI) Child Domain, and those with children below 18 months of age (n = 49) also the Infant Temperament Questionnaire (ITQ). GI-CMPA was diagnosed with the double-blind, placebo-controlled food challenge. Control group (n = 22) consisted of patients (age range 4-26 months), attending the Pediatric Allergy Unit, who did not have diagnosed or suspected food allergies. RESULTS: The scores were significantly higher for the PSI (n = 48) Child Domain (p < 0.0001) and for the ITQ (n = 44) subscale Difficultness (p = 0.0045) compared with the control patients without suspected/diagnosed food allergy. The difference between the challenge positive (n = 18) and negative (n = 39) patients remained statistically insignificant. After 6 months, in both groups, the scores (PSI Child Domain p = 0.0004, ITQ Difficultness p = 0.0393) were lower, but the ITQ Difficultness score still remained higher than in the controls (p = 0.0453). CONCLUSION: The mothers often perceive infants with unspecific symptoms suggestive of GI-CMPA as demanding and temperamentally difficult. PMID- 24812713 TI - Children under the age of two are more likely to watch inappropriate background media than older children. AB - AIM: To establish whether young children watched foreground electronic media or background media that was not aimed at them or was inappropriate for their age. METHODS: We performed a longitudinal analysis of mother-infant dyads participating in a larger parenting study. The primary dependent variable was maternal reports of watching habits from media diaries at 6, 14, 24 and 36 months. Independent variables were child age, programme content and whether the programme was turned on specifically for the child. RESULTS: We analysed 3570 programme exposures in 527 children, mostly from television. Children were significantly more likely to actually watch programmes if they were older, if the content was coded as 'educational young child' or if the parent tuned on the programme specifically so the child could watch it. Children under the age of two were more likely than older children to watch background media that featured age inappropriate content or had not been turned on for them to watch [30% versus 16% of programmes; AOR = 2.19 (95%CI 1.82-2.65)]. CONCLUSION: Young children under the age of two frequently watch background media that has age-inappropriate content or has not been turned on for them to watch. PMID- 24812714 TI - High-flow nasal cannula on transport: moving with the times. PMID- 24812715 TI - Does relative remoteness affect chronic disease outcomes? Geographic variation in chronic disease mortality in Australia, 2002-2006. AB - OBJECTIVE: To examine the variation of chronic disease mortality by remoteness areas of Australia, including states and territories. METHODS: Australian Bureau of Statistics (ABS) death registration data, by Statistical Local Area (SLA), were used to identify chronic disease mortality by remoteness category for states and territories and Australia. The analysis used multiple cause of death for six common chronic diseases: diabetes, ischaemic heart disease, stroke, hypertension, chronic obstructive pulmonary disease and renal disease. ABS correspondence files were used to adjust the SLA level death records and population. RESULTS: The chronic disease mortality rate for Australian residents living in a very remote area (512 per 100,000 persons) was respectively 1.3, 1.4, 1.5, and 1.6 times higher than Remote, Outer Regional, Inner Regional and Major Cities categories. This pattern was consistent for the two age groups of 35-64 years and 65 years and over, all six chronic diseases and all states and territories except Victoria. CONCLUSION AND IMPLICATIONS: This study shows that chronic disease mortality increases with increasing relative remoteness. The results highlight the importance and opportunity to redress poorer health outcomes for rural and remote area populations. The study is limited by absence of reliable Indigenous identification in national death data. PMID- 24812716 TI - Mortality due to rheumatic heart disease in the Kimberley 2001-2010. AB - OBJECTIVE: To determine the mortality burden of rheumatic heart disease (RHD) in the Kimberley. METHODS: A retrospective medical record audit was conducted for patients identified by the Western Australian (WA) RHD Program as deceased between 2001 and 2010. Patients with documented evidence strongly suggesting or confirming RHD were included in the study. Crude and age-standardised death rates were calculated. RESULTS: A total of 34 patients were identified as having RHD, 15 of whom died of RHD-attributable causes and 93% of whom were Aboriginal. The most common causes of death were arrhythmias and heart failure. The mean age at death of Aboriginal people was 41 years. The age-standardised death rate in Aboriginal people attributable to RHD in the Kimberley was 12.5 per 100,000 people per year, which is 1.6 times the rate of Indigenous Australians nationally. RHD contributed to 342 potential life years lost over the 10-year period. CONCLUSION: RHD contributes to significant premature mortality and higher rates of death in Aboriginal people in the Kimberley, which is consistent with other areas of northern Australia. While the recent establishment of the WA RHD Program will endeavour to improve mortality and morbidity due to RHD in the Kimberley, further research and investment is needed to address this disease of socioeconomic disadvantage. PMID- 24812717 TI - Separating burst from background spikes in multichannel neuronal recordings using return map analysis. AB - We propose a preprocessing method to separate coherent neuronal network activity, referred to as "bursts", from background spikes. High background activity in neuronal recordings reduces the effectiveness of currently available burst detection methods. For long-term, stationary recordings, burst and background spikes have a bimodal ISI distribution which makes it easy to select the threshold to separate burst and background spikes. Finite, nonstationary recordings lead to noisy ISIs for which the bimodality is not that clear. We introduce a preprocessing method to separate burst from background spikes to improve burst detection reliability because it efficiently uses both single and multichannel activity. The method is tested using a stochastic model constrained by data available in the literature and recordings from primary cortical neurons cultured on multielectrode arrays. The separation between burst and background spikes is obtained using the interspike interval return map. The cutoff threshold is the key parameter to separate the burst and background spikes. We compare two methods for selecting the threshold. The 2-step method, in which threshold selection is based on fixed heuristics. The iterative method, in which the optimal cutoff threshold is directly estimated from the data. The proposed preprocessing method significantly increases the reliability of several established burst detection algorithms, both for simulated and real recordings. The preprocessing method makes it possible to study the effects of diseases or pharmacological manipulations, because it can deal efficiently with nonstationarity in the data. PMID- 24812718 TI - [Frontline drug therapy for pulmonary hypertension]. PMID- 24812719 TI - The Cancer Genome Atlas expression profiles of low-grade gliomas. AB - Differentiating between low-grade gliomas (LGGs) of astrocytic and oligodendroglial origin remains a major challenge in neurooncology. Here the authors analyzed The Cancer Genome Atlas (TCGA) profiles of LGGs with the goal of identifying distinct molecular characteristics that would afford accurate and reliable discrimination of astrocytic and oligodendroglial tumors. They found that 1) oligodendrogliomas are more likely to exhibit the glioma-CpG island methylator phenotype (G-CIMP), relative to low-grade astrocytomas; 2) relative to oligodendrogliomas, low-grade astrocytomas exhibit a higher expression of genes related to mitosis, replication, and inflammation; and 3) low-grade astrocytic tumors harbor microRNA profiles similar to those previously described for glioblastoma tumors. Orthogonal intersection of these molecular characteristics with existing molecular markers, such as IDH1 mutation, TP53 mutation, and 1p19q status, should facilitate accurate and reliable pathological diagnosis of LGGs. PMID- 24812720 TI - The art of general practice. PMID- 24812721 TI - Balancing the professional equation. PMID- 24812722 TI - Altruism: selfless or selfish? PMID- 24812723 TI - The challenge of communicating effectively in a volunteer membership organization. PMID- 24812724 TI - Why is dental treatment of the gravid patient regarded with caution? When is the appropriate time for care--be it emergent or routine--in the gravid patient? AB - There are myths surrounding pregnancy and the oral cavity, such as, "having a baby causes your gums to swell and your teeth to weaken," or "I don't need to see a dentist, there's nothing wrong with my teeth" or "with each child say bye to a tooth or two." All these myths are just that, myths. During pregnancy, women may experience pregnancy gingivitis or may suffer from pre-existing periodontal disease. The myth of tooth loss during pregnancy, according to the ADA (American Dental Association), has "no histological, chemical or radiographic evidence to support [it]". The biggest myth or misconception is that dental care is unnecessary during pregnancy, and until problems arise, some gravid women draw back from seeking dental treatment. Also, professionals sometimes shy away from care of the gravid patient for reasons associated with teratogenicity and fetotoxicity. Teratogenic effects take place from three to eight weeks after conception, and fetotoxicity can occur at the latter end of the initial trimester on to delivery, according to Donaldson and Goodchild, authors of Pregnancy, breast-feeding and drugs used in dentistry in JADA's (The Journal of the American Dental Association) August, 2012 issue. This article includes reasons dental treatment is regarded with caution; therefore, appropriate timing of dental care and suggested clinical recommendations as they relate to the pregnant patient are reviewed. PMID- 24812725 TI - Oral pathology quiz #82. Case number 1. Regional odontodysplasia. PMID- 24812726 TI - Oral pathology quiz #82. Case number 2. Frictional hyperkeratosis. PMID- 24812727 TI - Oral pathology quiz #82. Case Number 3. Odontogenic keratocyst. PMID- 24812728 TI - Oral Pathology Quiz #82. Case number 4. Florid cemento-osseous dysplasia. PMID- 24812729 TI - Opinion piece oral surgery in Plainfield, 1958. PMID- 24812730 TI - Angina bullosa hemorrhagica--case report. PMID- 24812731 TI - Five things to know about teeth in a day with dental implants. AB - This is a brief educational evidence-based article intended to be useful to practicing clinicians. Five key statements focused on the most significant information on immediate implants are reviewed. PMID- 24812732 TI - The top 10 tips to successful practice acquisitions. PMID- 24812733 TI - Avoiding extraction of bicuspid's, is it at all possible? PMID- 24812734 TI - Passing the gavel. PMID- 24812735 TI - Early treatment with the ALF functional appliance. AB - The aim of this study is to report five cases of children treated with an interceptive technique utilizing ALF (Advanced Light Force) functional orthodontic appliances in anterior and/or posterior cross bites in primary and early mixed dentition. PMID- 24812736 TI - Effectiveness of a fixed anterior bite plane in Class II deep-bite patients. AB - Orthodontic treatment of patients with distoclusion combined with dental deep bite and linguo version of the front upper teeth is one of the most difficult forms of malocclusion to treat to a functional and morphological optimum. Our objective was to analyze the efficacy of a fixed anterior bite plane appliance to disclude the teeth and correct this type of malocclusion. At the Department of Orthodontics MSUMD (Moscow State University of Medicine and Dentistry), we proposed the use of a fixed anterior bite plane for the effective treatment of patients with distoclusion combined to a dental deep bite. This appliance was used in 35 patients aged 11 to 15 years (13.2 +/- 1.2) with distoclusion combined with deep bite in a therapeutical approach that also involved an osteopathic correction. The appliance permitted the correction of the distoclusion by discluding the posterior teeth, allowing eruption of the molars and premolars which improved the occlusal plane line (Curve of Spee) and changed the inclination of the upper incisors which liberated the mandible from its retruded position. We also noted an effect on the postural status of the patient. PMID- 24812737 TI - Craniofacial imaging in orthodontics--past present and future. AB - Images of the craniofacial region are an important component of the orthodontic patient record. The gold standard that orthodontic records attempt to achieve is the accurate replication or portrayal of the "anatomic truth". The anatomic truth is the accurate three-dimensional anatomy, static and in function, as it exists in vivo. Despite the diverse image acquisition technologies currently available, the types and standards for imaging presently used in practice have been adopted in an effort to balance the anticipated benefits with associated costs and risks to the patient. Because of these considerations, orthodontists routinely use an array of two-dimensional static imaging techniques to record the three dimensional anatomy of the craniofacial region. The development of an interactive 3D digital model of a patient's anatomy would greatly improve our ability to determine different treatment options, to monitor changes over time (the fourth dimension), to predict and display final treatment results, and to measure treatment outcomes more accurately. This review explores the different techniques of 3D imaging of the teeth, as well as the recent efforts to create the 'virtual orthodontic patient' by using 3D soft and hard tissue data. A brief overview of some of the commercially available 3D-based technologies, such as OrthoCAD and Invisalign is given at the end. The objective of this review is to provide the clinician with an overview of the currently used imaging methods along with those of the past and also a look at the innovations in craniofacial imaging that are likely to greatly enhance the depiction of craniofacial structures. PMID- 24812738 TI - NTRDC retainer: a novel approach for both retention and habit control--a follow up of 2 years. AB - Many methods have been used to correct abnormal tongue habits. A mechanical device such as tongue spurs or cribs offers help till they are in the mouth, but the habit often returns when the device is removed. Patients with tongue thrusting habits complain to their clinician, of reopening of spaces, proclination of anteriors and contraction of arch, though the clinician successfully treated the case. PMID- 24812739 TI - Simple "TRS" Auxiliary tube for retraction of anterior segment using segmental T loop mechanics. AB - Segmental T loop is the most popular frictionless mechanics so far. This biomechanically sound system was designed for the Burstone's canine bracket, which can be extra inventory for the clinicians who want to practice the segmental T loop routinely. The present manuscript provides the alternate to Burstones canine bracket for the retraction of the anterior segment. PMID- 24812741 TI - Prestrecher. AB - Elastomeric ligatures are routinely used in any Orthodontic setup. The biggest challenge at the onset lies in ligating rotated teeth. If conventional elastomeric ligatures are used on such teeth there are two associated problems: First due to tautness of the ligature tie the bracket may debond and second the patient may feel discomfort due to excessive pressure (Figures 1 - 4). A simple and a versatile instrument is described which helps in circumventing these problems associated with elastomeric ligatures and elastics. PMID- 24812740 TI - Tooth separation potential problems. AB - A displaced orthodontic elastic separator was proposed as being the source of a gingival abscess that progresses to severe bone loss and exfoliation in a healthy adolescent patient with sound periodontal status prior to commencement of orthodontic treatment. After one year of undergoing orthodontic treatment, the patient presented with dull pain and mobility in the left upper permanent molar for which there was no apparent etiology. On clinical examination the patient had gingival inflammation, associated with a deep pocket and severe mobility (Grade III) in relation to the same teeth. Radiographic examination ofan Orthopantomogram (OPG) and IntraOral Periapical Radiograph (IOPAR) revealed a chronic periodontal abscess with severe necrosis of the periodontal ligament and severe alveolar bone loss. On curettage it was found that there was orthodontic elastic separator which was displaced sub gingivally. Active orthodontic forces were temporarily removed and splinting was done. 6 month follow up showed no mobility and significant improvement of alveolar bone height. PMID- 24812742 TI - Upper incisors' positions after extraction. AB - The aim of this research was to verify the amount of horizontal and vertical movement and incisor inclination of upper incisors and correlate these with Edgewise and Alexander brackets use and the presence of overbite during anterior retraction in sliding mechanics. The sample was composed of 40 adult patients divided into 2 groups, treated with Edgewise and Alexander brackets (20 each) subdivided in 2 groups (10 each), according to the presence or absence of deep bite. Treatment consisted of 4 extraction cases with sliding mechanics with the 2 different brackets. Pre- and post-treatment cephalograms were measured and the values of interest submitted to descriptive statistical analysis, ANOVA at 5%, the Tukey test and Pearson's correlation. Upper incisor retraction was not related to the brackets used nor to the presence of deep bite, though lingual tipping was greater when Edgewise brackets were used and deep bite was absent. No statistically significant differences in upper incisor vertical movements were observed and no correlation was determined between upper incisor intrusion and lower incisor labial tipping in overbite correction or in upper incisor retraction and lower incisor labial tipping for overjet correction. Bracket prescription and its interaction with deep bite were significant and Edgewise brackets without deep bite showed the worst inclination control. It was concluded that bracket prescriptions are important to increase control of sliding mechanics. PMID- 24812743 TI - A review of laser applications in orthodontics. AB - Laser technique now is widely applied in orthodontic treatment and proved to have many benefits. Soft tissue lasers can be used to perform gingivectomy, frenectomy and surgical exposure of tooth with less bleeding and swelling, improved precision, reduced pain and less wound contraction. Other laser applications include enamel etching and bonding and bracket debonding. Lower level lasers have the potential effects of pain control and accelerating tooth movement. Clinicians must be aware of the safety issues and risks associated with laser and receive proper training before the laser treatment is started. PMID- 24812744 TI - The use of Twin Force functional fixed orthopedic appliance in the treatment of Class II division 1 malocclusion. AB - Fixed protruding appliances are interesting tools for correction of Class II dental malocclusion in adult and growing patients. The appliances most commonly used for this purpose are: Herbst, Forsus and Jasper Jumper. The present clinical case report shows an alternative called Twin Force Bite Corrector which was used for 3 months by a patient aged 10 years and 6 months associated with the Andrews prescription fixed appliance (Abzil 3M). After treatment, malocclusion was found to be adjusted to Class I dental occlusion in a single stage. PMID- 24812745 TI - From concept to reality ... practically. PMID- 24812746 TI - [Comparative study of polymerization shrinkage and related properties of flowable composites and an unfilled resin]. AB - OBJECTIVES: The polymerization shrinkage and shrinkage stress of dental composites are in the center of the interest of researchers and manufacturers. It is a great challenge to minimize this important property as low as possible. Many factors are related and are in complicated correlation with each other affecting the polymerization shrinkage. Polymerization shrinkage stress degree of conversion and elasticity has high importance from this aspect. Our aim was to study the polymerization shrinkage and related properties (modulus of elasticity, degree of conversion, shrinkage stress) of three flowable composite (Charisma Opal Flow, SDR, Filtek Ultimate) and an unfilled composite resin. MATERIALS AND METHODS: Modulus of elasticity was measured using three point flexure tests on universal testing machine. The polymerization shrinkage stress was determined using bonded-disc technique. The degree of conversion measurements were performed by FT-IR spectroscopy. And the volumetric shrinkage was investigated using Archimedes principle and was measured on analytical balance with special additional equipment. RESULTS: The unfilled resin generally showed higher shrinkage (8,26%), shrinkage stress (0,8 MPa) and degree of conversion (38%), and presented the lowest modulus of elasticity (3047,02MPa). CONCLUSIONS: Highest values of unfilled resin correspond to the literature. The lack of fillers enlarges the shrinkage, and the shrinkage stress, but gives the higher flexibility and higher degree of conversion. Further investigations needs to be done to understand and reveal the differences between the composites. PMID- 24812747 TI - [Advantages and disadvantages of applying yttrium stabilized zirconium-dioxide post and core restorations]. AB - Full ceramic restorations are associated with metal free post and core prosthodontics for teeth with seriously destroyed clinical crowns. Using custom made zirconium-dioxide post and cores can be flattering not only to give a good aesthetic result, but also to provide excellent retention. As none of the post systems stands all demands, prudent planning is mandatory. Our paper deals with favourable and unfavourable conditions as well as common causes of failures of post and core restorations. We took morphological, esthetical and functional considerations that can help to achieve the best results. Amongst them individual anatomic constitution, shape, width and length of the root and root canal, shape of the clinical crown, direction and magnitude of chewing forces are the most important factors. To give examples we present two cases of zirconium-dioxide post and core restorations. In our first case the missing clinical crown and a too wide root canal entrance created a questionable prognosis. To minimize adverse effect of the missing ferrule effect we applied custom-made zirconium dioxide post and core and an additional abutment. After 7 years the restoration is still functioning. The second case represented a much favourable situation with 1,5 mm clinical crown height. The restoration was a custom-made zirconia post and core and a full-ceramic crown as a single tooth restoration. Although in this case we expected a better prognosis, 15 months later the patient showed up with a post fracture for applying extreme forces on the crown. PMID- 24812748 TI - [Dr. Katalin Kalocsai, 1968-2013]. PMID- 24812749 TI - [Treatment of localized intrabony periodontal defects with enamel matrix derivative (Emdogain). Case series]. AB - The solitary vertical or horisonto-vertical bone lesions are mainly characteristic of aggressive periodontitis. Only a combined conservative-surgical approach can result in predictable healing. From the early 50's basically two surgical techniques were used for correcting vertical bony defects. The so called bone resective techniques combined with apically positioned flap resulted in the flattening of the bone contour by removing substantial amount of alveolar bone but compromising the periodontal support of the neighboring teeth. The other surgical approach was the facilitation of the reformation of new periodontal attachment and bone with or without bone grafting. Since the mid 80's the gold standard in the therapy of deep vertical bony defects is the guided tissue regeneration (GTR), although an alternative approach has also been developed using different growth and differentiation factors promoting periodontal wound healing. Today in the clinical practices both in periodontal osseous and mucogingival surgeries the most widely used biological factor is the amelogenin and its commercially available product the Enamel Matrix Derivative (Emdogain). With the presented five solitary horisonto-vertical bony defects of three patients the possibilities and the late results are presented that could have been achieved with the application of EMD and thorough postoperative follow-up. The clinical results were comparable to the current data presented by articles in peer reviewed periodontal journals. PMID- 24812750 TI - [Complex treatment of a large radicular cyst due to traumatic dental injury--a case report]. AB - A 28-year-old male came to the clinic for control visit and scaling. Panoramic radiograph was taken before any treatment. The radiograph revealed a large size periapical lesion extending from the lower right first premolar to the lower left canine. History of dental trauma in childhood was recorded. The asymptomatic, injured teeth were not treated by dentist. Upon clinical examination a discolored lower right central incisor and more teeth with pulpal necrosis were found. After the endodontic treatments a cystostomy was performed. Obturator was used by the patient in the healing period. The success of complex treatment is proven by the highly recovered bone forming shown during the regular recalls. For the correct diagnosis and planning of the complete treatment dentist should be careful on general- and dental anamnesis and complete clinical and radiographic examination. Small clinical signs and pathoses should alert the dentist. This case is a reminder that the careful anamnesis, clinical examination and early diagnosis of any pathosis are very important. PMID- 24812751 TI - Policy and practice. PMID- 24812752 TI - The year that was. PMID- 24812753 TI - Overhaul of dental legislation sought. PMID- 24812754 TI - Cancer in Ireland. PMID- 24812755 TI - Quiz. Impacted canines. PMID- 24812756 TI - Futurabond U--dual-curing universal adhesive. PMID- 24812757 TI - Restoring class II cavities with composite resin, utilising the bulk filling technique. PMID- 24812758 TI - Policy planner. Interview by Paul O'Grady. PMID- 24812759 TI - An evaluation of washer-disinfectors (WD) and dishwashers (DW) effectiveness in terms of processing dental instruments. AB - PURPOSE: The aim of this study is to consider the effectiveness of a small sample of dishwashers (DW) compared to washer-disinfectors (WD) for cleaning dental instruments prior to sterilisation. Processing instruments in the context of this article means cleaning and disinfecting the instruments. MATERIALS AND METHODS: A number of tests were carried out on three domestic dishwashers and two instrument washer-disinfectors. These tests included: visual test; soil test; residual protein test; and, the TVC of the final rinse water. RESULTS: The washer disinfectors (one bench-top and one under-bench) passed all the tests. The results indicate that the instruments cleaned in the dishwashers were visibly clean and dishwashers passed the TOSI soil test. There was residual protein on some of the instruments cleaned in the all of the dishwashers and the final rinse water did not comply with standard ISO 15883. CONCLUSION: Dishwashers are not effective for cleaning instruments and they do not disinfect the instruments either. They cannot be validated and there is no record available outlining the parameters of the process. Dishwashers are not designed by manufactures for processing dental instruments prior to sterilisation. The authors do not recommend the use of dishwashers in dental clinical practice. PMID- 24812760 TI - Case report: sublingual epidermoid cyst in an elderly patient. AB - The occurrence of epidermoid cysts in the floor of the mouth is uncommon, particularly in elderly patients. We present the case of a 77-year-old female, who presented with minimal symptoms, despite a large floor-of-mouth swelling, which obscured her tongue from vision. The mass was removed via an intraoral approach under local anaesthesia (LA) and intravenous (IV) sedation, keeping complications and recovery time to a minimum. The mass was revealed to be an epidermoid cyst and the patient made a swift recovery. The features and classification of these cysts are discussed. PMID- 24812761 TI - Members save a fortune. PMID- 24812762 TI - [A clinical investigation of new patients who had already received treatment with dental implants at other clinics in seventeen years]. AB - The purpose of this study was to investigate new patients who had already received treatment with dental implants. The subjects were patients who visited the clinic for oral implants at Tokyo Medical and Dental University Hospital from April 1995 to March 2012. The results were as follows: 1) Of the total number of patients, there were 2,419 patients (14.0%) with dental implants. 2) Of the 2,419 patients, 252 patients (10.4%) had been referred from operating doctors or operating clinics. 3) There were 1,516 (62.7%) patients with complaints related to the implant therapy. 4) There were 1,367 (56.5%) patients who had ill feelings toward their attending doctors. 5) There were 1,112 (46.0%) patients with biological complications. 6) Regarding patients with or without a referral from the doctor who had performed their dental implant, those patients who had been referred showed significantly higher occurrence of loss of implants, neurological symptoms, doctor's recommendation, prosthetic problems, and surgical problems. Almost implant therapies were treated with other treatments for natural teeth, including surgical treatment, prosthetic treatment, periodontal treatment and maintenance. These were too complex to enable the results to be forecast before treatment, therefore unpredictable symptoms often occur in patients with implant therapy. Informed consent including patient education is important, but the results of this study suggest that it is insufficient at present. PMID- 24812763 TI - [Comparison of fibroblastic cell compatibility of type I collagen-immobilized titanium between electrodeposition and immersion]. AB - Titanium is widely used for medical implants. While many techniques for surface modification have been studied for optimizing its biocompatibility with hard tissues, little work has been undertaken to explore ways of maximizing its biocompatibility with soft tissues. We investigated cell attachment to titanium surfaces modified with bovine Type I collagen immobilized by either electrodeposition or a conventional immersion technique. The apparent thickness and durability of the immobilized collagen layer were evaluated prior to incubation of the collagen-immobilized titanium surfaces with NIH/3T3 mouse embryonic fibroblasts. The initial cell attachment and expression of actin and vinculin were evaluated. We determined that the immobilized collagen layer was much thicker and more durable when placed using the electrodeposition technique than the immersion technique. Both protocols produced materials that promoted better cell attachment, growth and structural protein expression than titanium alone. However, electrodeposition was ultimately superior to immersion because it is quicker to perform and produces a more durable collagen coating. We conclude that electrodeposition is an effective technique for immobilizing type I collagen on titanium surfaces, thus improving their cytocompatibility with fibroblasts. PMID- 24812764 TI - [The time-course change of brain activity during learning new movement patterns of pronunciation with orthodontic appliances and its correlation with self evaluation of pronunciation difficulty: an fMRI study]. AB - Pronunciation requires speed and accuracy, like many other fundamental activities such as breathing, eating, and walking. People can pronounce almost automatically without paying much attention to correctness, also like other activities. However, people may have to focus carefully on pronunciation when learning a foreign language, wearing dental appliances or rehabilitating after an injury or disease that affects speech. In the present study, we investigated neural changes underlying the process of learning new movement patterns of pronunciation in such cases. Nine healthy adults participated in the study. Difficulty of pronunciation was evaluated and cortical activity was measured under three conditions (overt and covert speaking, and silent reading) by fMRI three times after they wore orthodontic appliances. We found that the right superior temporal gyrus (STG) was involved in the auditory feedback control of pronunciation with the appliances, and the activity of the right STG was well correlated with the subjective difficulty of pronunciation and its time-dependent reduction. On the other hand, neural changes related to somatosensory feedback control and motor control of pronunciation did not show any time-dependent change. Our findings indicate that auditory feedback control of pronunciation is more important than motor control and somatosensory feedback control for learning new movements related to pronunciation. PMID- 24812765 TI - [An investigation of oral colonization by Candida albicans in immunodeficient animal with decreasing saliva volume]. AB - Candida albicans is a commensal fungus that commonly colonizes human mucosal surfaces. When the host immune defenses are impaired, C. albicans triggers recurrent infections of the oral mucosa and tongue. We previously reported that the characteristics in NOD/SCID. e2f1(-/-) mice that have naturally decreased saliva and T and B cells that do not develop increase the susceptibility of oral bacterial infection in the oral cavity. Next, we sought to establish a C. albicans infection model in NOD/SCID. e2f1(-/-) mice. C. albicans yeast forms were introduced by wiping a cotton swab moistened with C. albicans solution on the tongue after disinfection by 0.2 Chlorhexidine for the first time. After an interval of 60 min, the inoculation was performed by pipette 2 or 4 times at an interval of 60 min. The number of C. albicans colonized on the tongue significantly increased but there were no significant difference between NOD/SCID. e2f1(+/+) mice and NOD/SCID. e2f1(-/-) mice at 120-240 minutes. However, a significant difference between these mice was observed at 24 hours after the last inoculation. Moreover, 5 inoculations/day were also performed for 2-4 days and significant differences between mice arose, and the maximum level of infection was found at 24 hours after consecutive inoculation for 3, 4 and 5 days, but the levels were reduced after 48 h. It is suggested that the saliva volume and flow are important for preventing 24-hour colonization of C. albicans. NOD/SCID. e2f1(-/-) mice are a relevant mouse model for 24-hour colonization on the tongue. PMID- 24812766 TI - [Effects of shortened mandibular dental arch on human brain activity during chewing: an fMRI study]. AB - According to the shortened dental arch concept, missing molars should not always be restored with prosthetic treatment. A shortened dental arch with missing molars is associated with a decrease in masticatory function. However, it is not known whether a shortened dental arch influences brain activity during chewing. This study aimed to clarify the effect of posterior arch length of mandibular bilateral distal extension removable partial dentures (RPDs) on brain activity during chewing. Eleven subjects with bilaterally missing mandibular molars (mean age, 66.1 years) participated in the study. RPDs with full dental arch and shortened dental arch were fabricated and brain activity during gum chewing under each dental condition was measured using functional magnetic resonance imaging. Brain activation during gum chewing with the full dental arch was observed in the middle frontal gyrus, primary sensorimotor cortex extending to the premotor cortex, supplementary motor area, putamen, insula and cerebellum. However, activation of the middle frontal gyrus was not observed during gum chewing with the shortened dental arch. The results of this study suggest that human brain activity during chewing in the middle frontal gyrus may be associated with chewing in the presence of the molar region. PMID- 24812767 TI - [Nuclear translocation of epidermal growth factor receptor and its relation to clinicopathological factors in oral squamous cell carcinomas]. AB - The epidermal growth factor receptor (EGFR) is one of the receptor tyrosine kinases. Some EGFRs are transferred from membrane to nucleus upon ligand binding and an increase of this translocation causes high-level expression of nuclear EGFR. The high-level expression of nuclear EGFR was reported to be a poor prognostic factor in various cancers such as breast cancer, ovarian cancer, gallbladder cancer, prostate cancer and oropharyngeal cancer. Regarding oral cancers, one report indicated that nuclear EGFR is detected in oral squamous cell carcinoma (OSCC) on immunohistochemical staining, but did not mention the clinicopathological prognostic value in detail. Therefore, we investigated the expression of nuclear EGFR in OSCC cell lines and primary tumor specimens of tongue SCCs to see whether nuclear EGFR could be a useful prognostic value. We verified the expression level of nuclear EGFR in OSCC cell lines and observed an increase in the amount of nuclear EGFR upon EGF stimulation with the expression level reaching its peak after 15 minutes. Nuclear EGFR positive tumors were found in 23 patients (28.0%) with tongue SCCs. However, we could not find any correlation between clinicopathological factors and the expression of nuclear EGFR in patients with tongue SCCs. PMID- 24812768 TI - Lies, damn lies and the federal government's industrial relations agenda. PMID- 24812769 TI - 4am reflection. PMID- 24812770 TI - Caring about the unbefriended elderly. PMID- 24812771 TI - Flying under the radar: the health of refugees and asylum seekers in Australia. PMID- 24812772 TI - Otitis media in remote communities. PMID- 24812773 TI - Mentoring in nursing: an invaluable exchange. PMID- 24812774 TI - Four steps to beating overwhelm. PMID- 24812775 TI - Asylum seekers and mental illness in Australia: a nursing response. PMID- 24812776 TI - Two hats, one aim: nurses in partnership for better indigenous health. PMID- 24812777 TI - The PCEHR's role in primary and community care. PMID- 24812778 TI - Better mental health care hope for older rural people. PMID- 24812779 TI - Supporting Aboriginal women's health needs. PMID- 24812780 TI - Home-based palliative care and interdisciplinary teamwork. PMID- 24812781 TI - Do residential parenting education programs work? PMID- 24812782 TI - Pap smear preceptor program. PMID- 24812783 TI - Nursing in general practice program. PMID- 24812784 TI - Keeping Australia's nurses safe: the importance of choosing and using gloves correctly. PMID- 24812785 TI - Walking a tightrope: women's experiences of having an eating disorder while pregnant. PMID- 24812786 TI - Supporting primary health care nurses to provide health care to men. PMID- 24812787 TI - Health literacy and nursing. PMID- 24812788 TI - Breast cancer during pregnancy. PMID- 24812789 TI - Informing and educating undergraduates on HIV. PMID- 24812790 TI - Reflecting on past achievements. PMID- 24812791 TI - Thank you from Tanzania. PMID- 24812792 TI - Mandatory assessments? PMID- 24812793 TI - Tackling bullies. PMID- 24812794 TI - Complexity compression impacts us all. PMID- 24812795 TI - Sexual predators as patients. PMID- 24812796 TI - Board of Dentistry Feb. 21. 2014. PMID- 24812797 TI - Re: The restorative cycle in dentistry. PMID- 24812798 TI - Accelerating the complete denture rehabilitation process. PMID- 24812799 TI - A powerful experiential lesson. PMID- 24812800 TI - Application approved! PMID- 24812801 TI - Diagnostic discussion. Zygomycosis (mucormycosis). PMID- 24812802 TI - The community dental health coordinator. A valued new member of the dental team. PMID- 24812803 TI - Creating the ultimate doctor-patient hygiene exam. PMID- 24812804 TI - Health care reform: a moving target. PMID- 24812805 TI - [Case of AIDS complicated with pneumocystis pneumonia]. PMID- 24812806 TI - [Effect of paeoniflorin on secretion of TGF-beta1 from macrophages in mice]. AB - OBJECTIVE: To explore the effect of paeoniflorin (PAE) on the production of transforming growth factor beta1 (TGF-beta1) from peritoneal macrophages(PMs) stimulated by soluble egg antigen (SEA) of Schistosoma japonicum. METHODS: SEA was prepared by trituration and added into culture plank, flask and dish containing PMs which were cultured for 24 h. TGF-beta1 secreted from PMs was measured by ELISA. TGF-beta1 mRNA and protein produced from PMs were evaluated by RT-PCR and Western blotting, respectively. SEA (10 mg/L) 5 ml was added into culture flask and dish containing PMs. PMs were cultured for 12 h, and PAE at different concentrations (0, 7.5, 15, 30, 60, 120 mg/L) was added into the culture flask and dish, and PMs were cultured consecutively for another 12 h and 24 h, respectively. TGF-beta1 mRNA and protein from PMs stimulated by SEA were evaluated by RT-PCR and Western blotting, respectively. RESULTS: TGF-beta1 (235.86 +/- 3.43 ng/L) was produced from PMs under stimulation of SEA at 10 mg/L, and the expression of TGF-beta1 mRNA and protein in PMs were depressed significantly by PAE in a concentration-dependent manner (r = -0.827, P < 0.01; r = -0.952, P < 0.01, respectively). CONCLUSION: PAE inhibits the production of TGF beta1 from PMs stimulated by SEA. PMID- 24812807 TI - [Identification of six Trichinella isolates from China by multiplex PCR]. AB - OBJECTIVE: To identify and classify six isolates of swine-originated Trichinella from China. METHODS: Five specific pairs of primers were synthesized based on DNA sequence of expansion segment V region and internal transcribed spacers (ITS1 and ITS2) of ribosomal DNA repeat from Trichinella. International reference strains of five Trichinella species [Trichinella spiralis (T1), T. nativa (T2), T. britovi (T3), T. pseudospiralis (T4) and T. nelsoni (T7)] were used as control. Six swine Trichinella isolates from Henan, Yunnan, Harbin, Tongjiang of Heilongjiang, Hubei and Tianjin were identified by multiplex PCR and its effecting factors of PCR amplification were observed. RESULTS: Electrophoresis results of multiplex PCR products of Trichinella larvae showed that the band (173 bp) of the six isolates was the same as T. spiralis (T1). The specific band (173 bp) was detected by multiplex PCR through amplification from issues of single T. spiralis larva, the larvae conserved in 80% ethanol for 6 months, the larvae stored in 10% formaldehyde, in 0.05% formaldehyde, 0.2% sodium azide or 0.05% merthiotate for 2 weeks, or fresh mouse muscle with larvae. CONCLUSION: All the six swine Trichinella isolates are identified as T. spiralis (T1) by multiplex PCR. PMID- 24812808 TI - [A case-control study on the risk factors of cerebral schistosomiasis japonica]. AB - OBJECTIVE: To explore the risk factors of cerebral schistosomiasis japonica. METHODS: A total of 37 confirmed cases, diagnosed during 1999-2004 in Anhui Province, were involved in the study as case group. Three controls for each case were selected from the general population either without schistosomiasis, with chronic schistosomiasis or with acute schistosomiasis. The relevant risk factors on the disease were analyzed. RESULTS: Four factors with labour intensity, physical, economical and nutritional conditions before illness between case group and normal control group, 7 factors including epilepsy history, hypersensitivity, intensity and times of infection between case group and acute schistosomiasis control group, 10 factors including intensity of infection, times of infection and treatment between case group and chronic schistosomiasis control group, all showed statistical significance (p < 0.05) . Five factors showed statistical significance (p < 0.05) between case group and the 3 control groups. CONCLUSION: The intensity of schistosome infection and treatment history are the main risk factors for cerebral schistosomiasis, and the physical and psychosocial conditions of the patients show some effect on the disease. PMID- 24812809 TI - [Genotyping and polymorphism analysis of Plasmodium falciparum isolates by nest PCR and PCR-RFLP]. AB - OBJECTIVE: To analyze the efficiency and specificity of MSP2 alleles genotyping for Plasmodium falciparum isolates by Nest-PCR and PCR-RFLP. METHODS: MSP2 alleles from Plasmodium falciparum isolates of Yunnan and Hainan were genotyped by Nest-PCR and PCR-RFLP, respectively, and the efficiency and specificity of the two methods were analyzed. RESULTS: The conventional Nest-PCR method could detect 79.8% (166/208) alleles of MSP2, and 65.7% (65/99) for 3D7 family, but could not identify the type of any allele. While PCR-RFLP showed 25.3% higher genotyping efficiency than Nest-PCR. Moreover, this method could identify the allele types. CONCLUSION: PCR-RFLP genotyping technique is more efficient and specific than conventional Nest-PCR, and it is a convenient tool in the study on molecular epidemiology of malaria. PMID- 24812810 TI - [Current prevalence of Clonorchis sinensis infection in endemic areas of China]. AB - OBJECTIVE: To investigate the current prevalence of Clonorchis sinensis infection in the known endemic areas of China. METHODS: According to different endemic level and river system, the lamination stochastic group sampling was carried out in 27 Provinces/Municipalities/Autonomous Regions (P/M/A) from 2002 to 2004. Eggs in stool were examined by modified Kato-Katz thick smears method. RESULT: A total of 5,230 cases of Clonorchis infection was found from 217,829 sampled population of 27 P/M/A, and the mean prevalence was 2.40% by which the number of infected people was estimated to be 12.49 millions. The geometry mean worm egg density was 2,208 EPG (stool). Light, moderate and heavy infection occupied 78.93%, 17.40%, and 3.67% respectively. Infection was found in 19 out of 27 P/M/A investigated, with the highest prevalence in the provinces of Guangdong (16.42%, 2,278/13,876), Guangxi (9.75%, 1,365/13,990) and Heilongjiang (4.72%, 636/13,458). Males showed higher prevalence (2.94%, 3,267/111,262) than females (1.84%, 1,963/106,567). There was infection in all age groups,with the highest prevalence in the group of 50 to 59 years (9.16%). By occupations, more infections were found in businessmen (13.42%, 124/924), followed by factory workers ((7.9%, 298/3,773), and retirees and veterans (5.28%, 70/1,327). Adults showed heavier infection in some provinces where the main infection way was raw fish-eating, but in children in other provinces. For geographical distribution, the terrain in network of rivers and lakes showed higher prevalence (5.23%, 687/13,125) than the hilly terrain (2.34%, 1,111/47,552). Prevalence showed family-aggregation feature. CONCLUSION: Clonorchiasis is widely endemic in China with a high prevalence in some provinces. Male adults have been more involved with a family aggregation. PMID- 24812811 TI - [New polymorphic microsatellite loci identified using genomic resource for Schistosoma japonicum]. AB - OBJECTIVE: To identify new microsatellite loci from genome sequence database for the study of polymorphism of Schistosoma japonicum. METHODS: Schistosoma japonicum isolates were obtained from seven endemic sites in China: Tongling and Guichi counties of Anhui Province, Duchang county of Jiangxi Province, Changde and Yueyang Cities of Hunan Province, Shashi City of Hubei Province, Xichang City of Sichuan Province. In order to study the genetic variance, genomic DNAs of 96 individual adult worms were screened against 17 new Schistosoma japonicum microsatellites and the raw data were analyzed by GenMapper 4.0. Furthermore, the varieties of alleles were inverstigated using GenA1Ex 6 and genetic distances within a subpopulation (GenClone) and among populations(UPGMA, MEGA 3.1) were analyzed. RESULTS: High levels of polymorphism were found between and within population samples, and significant genetic diversity was observed among the seven subpopulations. Within Jiangxi population, most genetic distances (17 loci) among samples range from 25 to 32, indicating a significant genetic diversity. There are three clusters among the seven populations: Jiangxi, Tonglin, Shashi and Changde population, with the genetics distances ranging from 0.0178 to 0.0363; Guichi and Yueyang population belong to another cluster, with the genetic distance of 0.0247; However, Xichang population is an unique group. Its genetic distances to other populations are notable with a range from 0.019 2 to 0.069 3. CONCLUSION: The 17 new polymorphic microsatellites identified may be used as suitable markers for the study on population genetics of Schistosoma japonicum and the genetic variance of the worms seems to be complicated. PMID- 24812812 TI - [Cloning and expression of PbTIP analogous gene from Plasmodium berghei ANKA and preparation of its polyclonal antibody]. AB - OBJECTIVE: To clone and express a novel protein analogous to TIP (T cell immunomodulatory protein) of Plasmodium berghei ANKA and prepare its polyclonal antibody. METHODS: The PbTIP encoding nucleotide sequence was searched from the Plasmodium berghei genomic database and amplified by PCR. The gene was sub-cloned into prokaryotic expression vector pGEX4T-1 and expressed in E.coli BL21 (DE3). After induction by IPTG, the expression of PbTIP-GST fusion protein was characterized by SDS-PAGE and Western blotting. The inclusion bodies of GST-PbTIP fusion protein were injected into BALB/c mouse. Anti-sera were identified by indirect fluorescent antibody test and western blotting. RESULTS: The PbTIP-GST fusion protein was successfully expressed in the form of inclusion bodies, by controlling the temperature and concentration of IPTG. Anti-PbTIP-GST sera were acquired with high titer. The sera specifically recognized the PbTIP with a band of 60 000 in P.berghei infected erythrocyte protein. CONCLUSION: PbTIP/GST fusion protein and polyclonal antibody have been obtained. PMID- 24812813 TI - [Studies on immunomodulation effect of recombinant Sj16 from Schistosoma japonicum on inflammation response of host]. AB - OBJECTIVE: To study the immunomodulation effect of the recombination Sj16 from Schistosoma japonicum (reSj16) on inflammation response of host. METHODS: reSj16 expressed in pGEX-4T-1 was purified by GST purification kit and detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectra (MS). The immunomodulation effect of reSj16 was observed by means of dimethylbenzene inducing mouse ear edema model, carrageenan inducing rat voix pedis swell model and acetic acid inducing mouse experiment peritonitis model. RESULTS: The soluble protein of reSjl6 was obtained and identified by SDS-PAGE and MS. reSjl6 1.0, 5.0, 10.0 microg/kg evidently suppressed the mouse ear edema induced by dimethyl-benzene, significantly mitigated the rat voix pedis swelling induced by carrageenan, and remarkably suppressed the increase of the capillary permeability of abdominal cavity in experiment peritonitis mouse model. CONCLUSION: The results further prove that Sj16 may be a potential immunosuppressive molecule and may have a notable effect on immunomodulation. PMID- 24812814 TI - Protective immunity and antibody response of rats infected with Trichinella spiralis. AB - OBJECTIVE: To study the protective immunity and antibody (IgG, IgG1 and IgG2a) response against adult and larva infection of T. spiralis Korean isolate in rats. METHODS: Forty-six rats were randomly divided into 7 groups. Group A (A1, A2, 10 rats) was used for the determination of protective efficacy from adult stage infection, group B (B1, B2, 14 rats) was for the protective efficacy from muscle larva stage infection, group C (C1, C2, 17 rats) was for challenge control, and group D (5 rats) served as normal control. Rats in groups A, B and C were infected with 1,000 T.spiralis muscle larvae, and the infected rats were treated with flubendazole (20 mg/kg, 10 d) at day 7 (A1, A2) and at day 30 (B1, B2). Rats in groups A and B were re-infected with 500 T. spiralis muscle larvae at day 10 after treatment. Rats in groups A1 and B1 were killed at day 7 and day 30 to inspect the reduction of adult worms in the intestines. Rats in groups A2 and B2 were killed at day 30 to detect the reduction of muscle larvae in diaphragms. Rats in groups C and D were killed at the same time, and all rats were bled at the same time. Specific anti-Trichinella IgG, IgG1 and IgG2a were detected by ELISA. RESULTS: Adult stage infection induced protective efficacy by 100% against adult stage and by 99.96% against larva stage. Larval stage infection induced protective efficacy by 99.92% against adult stage and 99.89% against muscle larvae. Anti-muscle stage larval ES Ag (IgG 3.0, IgG1 2.2, IgG2a 0.8) and anti adult crude Ag antibodies (IgG 1.9, IgG1 0.8, IgG2a 0.3) significantly increased in the muscle larval stage infection compared to normal control (IgG 0.5, IgG1 0.1, IgG2a 0.1) and adult stage infection (IgG 0.5, IgG1 0.09, IgG2a 0.09) (P < 0.01). Higher specific IgG1 antibody (IgG1 2.2) in larva stage infection was shown than specific IgG2a antibody response (IgG2a 0.8)(P < 0.01). CONCLUSION: Protective immunity against both adult and larva worms has been induced from adult and muscle larva stage infections of T. spiralis. PMID- 24812815 TI - [Construction and expression of recombinant baculovirus with Schistosoma japonicum SjPP gene]. AB - OBJECTIVE: To express the soluble recombinant Schistosoma japonicum SjPP proteins in TN5B1-4 cells. METHODS: The total RNA was extracted from adult worms of Schistosoma japonicum. The whole coding sequence of SjPP gene was synthesized by RT-PCR and cloned into donor plasmid. The recombinant donor pFastBac-SjPP was transformed into E.coli DH10Bac forming Bacmid-SjPP which was transfected into insect cell with cational lipofectin. The fusion protein SjPP was analyzed with SDS-PAGE and Western blotting. RESULTS: The infective recombinant baculovirus Bacmid-SjPP was obtained and SjPP protein was expressed in insect cells. CONCLUSION: The recombinant protein SjPP has been expressed in insect TN5B1-4 cells with proper antigenicity. PMID- 24812816 TI - [A newly identified endemic area of visceral leishmaniasis in Minfeng county of South Xinjiang I. epidemiological survey]. AB - OBJECTIVE: To investigate the epidemiological status of visceral leishmaniasis in Minfeng county, a newly identified endemic area in south Xinjiang, China. METHODS: Based on a hint of possible existence of patients, a retrospective survey was carried out house by house in Andier Township of the county to find cases with suspected signs/symptoms of the disease in the past 20 years including those died. Meanwhile, a survey on current status was conducted, including physical examination(liver and spleen palpation) to those under 15 years-old, leishmanin skin test and rk39 immunochromatographic strip test for part of the residents. RESULTS: The investigation covered 313 local residents and revealed no case with present illness but 60 cases with a history of suspected signs/symptoms including 13 deaths, traced back as visceral leishmaniasis. Leishmanin skin test was performed in 171 people with a positive rate of 99.4% and 28 out of 29 suspected cases showed positive (96.6%). rk39 immunochromatographic strip test was conducted in 197 people with a positive rate of 10.2% (20/197) and 19.4% (6/31) in those with a history of suspected signs/symptoms. CONCLUSION: The epidemiological investigation indicates that the Andier Township of Minfeng County is an endemic area of visceral leishmaniasis. PMID- 24812817 TI - [A newly identified endemic area of visceral leishmaniasis in Minfeng county of south Xinjiang II. Investigation on phlebotomine vectors]. AB - OBJECTIVE: To investigate the transmitting phlebotomine sandfly in Minfeng County, a newly-identified endemic area of visceral leishmaniasis in the south of Talim Pendi of Xinjiang. METHODS: Sandflies were collected using routine methods in and around the Yatonggusi village of Andier Township. The sandflies were identified to get their composition. Sandfly density was calculated following an observation at a given spot and time-period, and their appearance was recorded at night-time and day-time. Sandflies were dissected to analyze the gonotrophic cycle and to find infection of promastigotes. RESULTS: Phlebotomus wui was identified as the transmitting vector of visceral leishmaniasis in Andier Township, which occupied 99.2% of the sandflies collected. The first and second ten-day period of June was the first peak of its seasonal distribution. Analysis of the gonotrophic cycle revealed that Ph. wui was an exophilic species and appeared nocturnally for feeding with preference to human blood. Natural infection with promastigotes was found in 2 sandflies. CONCLUSION: Phlebotomus wui is the transmitting vector for visceral leishmaniasis in the newly found endemic area of south Xinjiang. PMID- 24812818 TI - [Human serum trypanosome lytic factor and serum resistance-associated protein of trypanosome]. AB - Human African trypanosomiasis is caused by the infection of Trypanosoma brucei gambiense or T.b. rhodesiense, while another morphologically identical subspecies, T.b. brucei, and other closely related species, T. equiperdum and T. evansi, are considered not infectious to human. This is highly related to the trypanosome lytic factor (TLF) found in normal human serum (NHS) and the serum resistance-associated (SRA) protein of trypanosomes infectious to human. We reviewed the research progress in TLF and its role in trypanosome lysis as well as the mechanism of SRA against the TLF. PMID- 24812819 TI - [Research progress on chloroquine resistance in Plasmodium falciparum and resistance reversal agent]. AB - Emergence and broad spread of chloroquine resistance urge human beings to change drug policy in malaria control and to find more effective new drugs. Nevertheless, chloroquine is still used in the treatment of falciparum malaria in some poor endemic regions due to economic and development reasons. It should be of great significance to understand the mechanism of chloroquine resistance and find the way to reverse it in order to bring chloroquine with high efficacy and low cost back to the first line of the combat to malaria. Advent and development of resistance reversal agents provide a new clue for this purpose. When used together with chloroquine, it can partly restore the efficacy of chloroquine in resistant Plasmodium falciparum. The article summarizes the research progress on chloroquine resistance in P. falciparum and resistance reverses. PMID- 24812820 TI - [Diagnosis and treatment of major protozoal infections among acquired immune deficiency syndrome patients]. AB - Protozoal infection is one of the most important opportunistic infections among patients with acquired immune deficiency syndrome (AIDS). In order to enhance the knowledge of protozoal infections in AIDS, the current status of diagnosis and treatment of toxoplasmic encephalitis, cryptosporidiosis, microsporidiosis and isosporiasis was reviewed in this paper. PMID- 24812821 TI - [Analysis of karyotype and preparation of C-band and G-band in Schistosoma japonicum]. AB - Chromosomes of Schistosoma japonicum were prepared by usual air drying method, C band and G-band were made by modified BSG method and enzyme digestion method respectively. Results showed that the karyotype of S. japonicum was 4m + 6Sm + 4St + 2sex chromosome and the C-band formula was 2n = 5CIt + 4CI(+) + 3CI + 2CT +2CT. PMID- 24812822 TI - [Polymorphism in the partial mitochondrial nad4 gene of Schistosoma japonicum]. AB - The partial NADH dehydrogenase subunit 4 (pnad4) fragment was amplified by polymerase chain reaction (PCR) from Schistosoma japonicum collected from 4 areas in Hunan province, and the amplicons were cloned and sequenced. A 480 bp sequence was obtained and the nucleotide difference between samples from the four locations were 0.4%-1.3%. Low level of sequence variability between and within different populations of S. japonicum was detected. The results are worthwhile for further study on the population genetic structures of S. japonicum. PMID- 24812823 TI - [Surgical treatment of patients with cerebral schistosomiasis]. AB - Clinical data from 48 cases with cerebral schistosomiasis, who received surgery, were analyzed retrospectively. Surgical treatment was performed when the patient had the following conditions: mass focus confirmed by CT scanning, cranial hypertension, or ineffective drug therapy, or indistinguishable from glioma by iconographic diagnosis. Treatment of praziquantel was given when the patients got improved. Among the 48 patients with surgical treatment, 35 cases recovered, 8 showed an exacerbation of hemiparalysis, 5 had hemianesthesia, and epilepsy occurred in 2 cases, no cases died during or after the operation. Surgery combined with praziquantel therapy has been an effective way for the treatment of cerebral schistosomiasis. PMID- 24812824 TI - [In vitro effect of allitridium on the ultrastructure of Acanthamoeba castellanii]. AB - Acanthamoeba castellanii (T4) was cultured with different concentrations of allitridium for 24 hours, and examined by transmission electron microscope. The results showed that the ultrastructure of Acanthamoeba trophozoites was destroyed gently at concentration of 50 microg/ml allitridium and seriously destroyed under the concentration of 500 microg/ml, indicating that allitridium is effective in destroying Acanthamoeba. PMID- 24812825 TI - [FTA/PCR detection for Cryptosporidium added in beverage]. AB - An established FVA/PCR protocol was applied to detect Cryptosporidium oocysts which were added in beverage, and proved to be as sensitive as 1.0 oocyst/ml detected within 6 hours. The study indicates that this technique is sensitive, time-saving and easy to perform. PMID- 24812826 TI - [Improved preparation of pure alive eggs of Schistosoma japonicum]. AB - To prepare a large amount of pure alive Schistosoma japonicum eggs, rabbit was infected with 2000 cercariae and its liver was taken aseptically 38-45 days after infection and homogenized. The homogenate was screened through different sieves(60, 120, 200, 300, 360 meshes per inch respectively), and washed with 1.2% NaCl. The eggs and leftover were then digested with 0.25% trypsin for 2 hours, sieved over 360 meshes per inch and washed with RPMI 1640 medium. The collected eggs reached to (95.1 +/- 6.4)% of live eggs, with a high efficiency. PMID- 24812827 TI - [Immune response in mice induced by complex gene vaccine pcSAG1-ROP5 of Toxoplasma gondii]. AB - OBJECTIVE: To observe the immune response induced by complex gene vaccine pcSAG1 ROP5 of Toxoplasma gondii in mice. METHODS: The recombinant eukaryotic expression plasmids pcSAG1, pcROP5 and pcSAG1-ROP5 were constructed and identified by PCR, restriction enzyme digestion, and sequencing. The three recombinant plasmids were transfected into HeLa cells to express in vitro and identified by Western blotting analysis. Seventy Kunming mice were randomly divided into 5 groups with 14 each, i.e. pcSAG1 group, pcROP5 group, pcSAG1-ROP5 group, blank plasmid group and PBS control group. The mice were immunized intramuscularly with pcSAG1, pcROP5, pcSAG1-ROP5, pcDNA3.1, and PBS, respectively, every two weeks for three times. Sera were collected before each injection and 2 weeks after the last immunization. The titer of mice serum in pcSAG1-ROP5 group combined with recombinant protein SAG1, ROP5 and SAG1-ROP5 and the level of IgG against T. gondii in 5 groups were determined by ELISA. Three weeks after the last immunization, ten mice of each group were challenged with 10(3) tachyzoites of the virulent T. gondii RH strain to observe the survival time. One week later, the rest four mice in each group were sacrificed and the supernatant of cultured splenocytes was collected for the detection of IFN-gamma and IL-4. RESULTS: Western blotting showed that the recombinant plasmids pcSAG1, pcROP5 and pcSAG1 ROP5 were expressed in HeLa cells with M(r) 31 000, 57 000, and 88 000, respectively. The serum titer in pcSAG1-ROP5 group combined with SAG1, ROP5 and SAG1-ROP5 was 1:320, 1:160, and 1:2560, respectively. The IgG level kept rising in pcSAG1, pcROP5 and pcSAG1-ROP5 groups. Two weeks after the last immunization, the IgG level in pcSAG1-ROP5 group was higher than those in other groups (P<0.05). After a lethal challenge of T. gondii RH strain, the survival time of the mice in pcSAG1-ROP5 group was (288 +/- 7) h, which was 48 h and 96h longer than the groups of pcSAG1 and pcROP5, respectively (P< 0.05). Four weeks after the last immunization, IFN-gamma in splenocyte culture of pcSAG1-ROP5 group [(908.52 +/- 6.31) pg/ml] was higher than other groups (P<0.05), with no significant difference in IL-4 (P>0.05). CONCLUSION: Compared with the single gene vaccines pcSAG1 and pcROP5, higher levels of IgG and IFN-gamma and longer survival time are observed in mice immunized with pcSAG1-ROP5. PMID- 24812828 TI - [Separation and identification of the surface and secreted proteins in Toxoplasma gondii by biotin labeling and proteomics methods]. AB - OBJECTIVE: To separate and identify the surface proteins and secreted proteins of Toxoplasma gondii tachyzoites of RH strain. METHODS: T. gondii tachyzoites were cultured in Vero cells, and purified by filtration and Percoll cell separation solution. The biotin-labeled tachyzoites were lysed, and the surface and secreted proteins were separated by NeutrAvidin agarose beads. After condensation and SDS PAGE, the protein were collected, digested and identified by LC/MS-MS. RESULTS: A total of 785 T. gondii proteins were identified, 81 (10.3%) of which were originally annotated as the surface or secreted proteins. Among the highly expressed (PSM>10) 65 proteins, 43 (66%) were originally annotated as surface or secreted proteins, while the others were predicted unknown proteins. CONCLUSION: The surface and secreted proteins of T. gondii are separated by biotin labeling and avidin chromatography, among which some potential new surface or secreted proteins of T. gondii are identified. PMID- 24812829 TI - [Cloning, expression and immunogenicity analysis of malate dehydrogenase gene of Toxoplasma gondii]. AB - OBJECTIVE: To clone and express the malate dehydrogenase (MDH) gene of Toxoplasma gondii, and analyze the immunogenicity. METHODS: Total RNA was extracted from tachyzoites of RH strain of T. gondii (GenBank accession No. AY650028). The coding region of TgMDH was amplified with a pair of specific primers. The product of RT-PCR was digested with double restriction enzyme and ligated into pET30a (+) vector. The recombinant pET30a (+)-TgMDH plasmid was transformed into E. coli DH5alpha. The positive clones were confirmed by the double restriction enzyme digestion, PCR and sequencing. The correct plasmid was transformed into E. coli BL21 and induced by IPTG. The expressed proteins were analyzed by SDS-PAGE. Conditions for expression were optimized. Abundant soluble rTgMDH protein was purified with Ni-NTA affinity chromatography. Mice was intranasally immunized with purified rTgMDH and murine anti-rTgMDH serum was prepared. Western blotting with murine anti-rTgMDH serum and rabbit anti-T. gondii serum was used to analyze its immunogenicity. RESULTS: The product of RT-PCR was with 951 bp. The recombinant plasmid pET30a(+)-TgMDH was confirmed by the double restriction enzyme digestion, PCR and sequencing. A soluble recombinant protein with relative molecular weight of 36 000 was analyzed by SDS-PAGE, followed by coomassie blue staining. Western blotting revealed that rTgMDH can be recognized by murine anti rTgMDH serum and rabbit anti-T. gondii serum. CONCLUSION: TgMDH gene has been expressed in prokaryotic expression system and shows immunogenicity. PMID- 24812830 TI - [Preparation of paraffin section of Oncomelania hupensis cerebral ganglions]. AB - Following the method used in other mollusks, the specimen of the Oncomelania hupensis cerebral ganglions was fixed, dehydrated, transparentized, embedded in paraffin, sectioned, and stained with haematoxylin-eosin. The histological structure of the snail cerebral ganglions was clear in the permanent specimen under the microscope. PMID- 24812831 TI - [Screening of host cell proteins that interact with Toxoplasma gondii ROP18 via yeast two-hybrid system]. AB - OBJECTIVE: To screen the host cell proteins that can interact with Toxoplasma gondii ROP18 by using yeast two-hybrid system. METHODS: The ROP18 gene fragments were amplified by RT-PCR from mRNA of T. gondii RH strain. The product of RT-PCR was digested with double restriction enzyme and was subcloned into the bait vector pGBKT7. The recombinant plasmid was transferred into yeast AH109 strain. Its toxicity and the autonomous activating activity were tested. The human fetal brain cDNA library was screened with pGBKT7-ROP18(25-251aa) as the bait plasmid by yeast two-hybrid system. RESULTS: The bait was constructed and AH109/PGBKT7 ROP18 showed an autonomous activity. The yeast strain AH109/pGBKT7-ROP18(25 251aa) line was then mated with the Mate & PlateTM Human Fetal Brain cDNA library. Using the selection procedures, eight novel host cell proteins were obtained: damage-specific DNA binding protein 1 (DDB1), torsin A interacting protein 1 (TOR1AIP1), integrin beta 1, solute carrier family 3 (SLC3A2), tyrosyl protein sulfotransferase (TPST2), OCIA domain containing 1 (OCIAD1), Derl-like domain family member 2 (DERL2), in addition to Homo sapiens activating transcription factor 6 beta(ATF6). CONCLUSION: Eight novel host cell proteins have been obtained via yeast two-hybrid system, which can interact with TgROP18. PMID- 24812832 TI - [Prokaryotic expression and histological localization of the Taenia solium CDC37 gene]. AB - OBJECTIVE: To express Taenia solium gene encoding cell division cycle 37 protein (TsCDC37) and investigate its antigenicity and localization in adults of Taenia solium. METHODS: The complete coding sequence of TsCDC37 was amplified by PCR based on the recombinant plasmid clone from the cDNA library of adult Taenia solium. The PCR product was cloned into a prokaryotic expression vector pET-28a (+). The recombinant expression plasmid was identified by PCR, double endonuclease digestion and sequencing. The recombinant plasmid was transformed into E. coli BL21/DE3 and followed by expression of the protein induced by IPTG. The mice were immunized subcutaneously with purified recombinant TsCDC37 formulated in Freund's adjuvant. The antigenicity of the recombinant protein was examined by Western blotting. The localization of TsCDC37 in adult worms was demonstrated by immunofluorescent technique. RESULTS: The recombinant expression vector was constructed successfully. The recombinant protein was about M(r) 52 000, it was then purified and specifically recognized by immuno sera of SD rats and sera from patients infected with Taenia solium, Taenia saginata or Taenia asiatica. The immunofluorescence assay revealed that TsCDC37 located at the tegument of T. solium adult and the eggs. CONCLUSION: TsCDC37 gene has been expressed with immunoreactivity. The recombinant protein is mainly expressed in tegument and egg, and is a common antigen of the three human taenia cestodes. PMID- 24812833 TI - [Screening and analysis of peptides specifically binding to the schistosomulum tegument of Schistosoma japonicum]. AB - OBJECTIVE: To screen and analyze the peptides in 12 phage-display peptide library specifically binding to the schistosomulum, not cercaria, tegument of Schistosoma japonicum. METHODS: A 12 phage-display peptide library was screened with the S. japonicum schistosomula and cercariae as the target cells for biopanning by degrees, 15 positive clones were picked randomly and deduced by DNA sequencing. According the sequencing result, ELISA test, elution recovery test and immunohistochemical staining were performed to determine the specificity of the phages to the tegument. To further examine its binding properties, the positive peptide conjugated to RhB and recombinant pEGFP-C2 plasmid were similarly synthesized. RESULTS: After 3 rounds of biopanning, the phage recovery rate increased from 3.50 x 10(-5)% to 3.20 x 10(-2)%, indicating that the phage library was successfully enriched in the tegument of schistosomula. The analyzed sequences were identical with 3 peptide sequence of ZL6, ZL4 and ZL1. ELISA showed that the P/N value of MppZL4, MppZL6 and MppZL binding the schistosomulum membrane protein was 6.72, 3.65 and 2.22, while 1.58, 5.15 and 1.20 of binding the membrane protein of cercariae, respectively. Elution recovery test showed that the elution recovery rate of MppZL4 [(4.60 +/- 0.27) x 10(-2)%] was much higher than that of MppZL6 [(2.10 +/- 0.23) x 10(-3)%], MppZL1 [(1.20 +/- 0.28) x 10(-3)%] and M13KE [(1.30 +/- 0.60) x 10(-7)%] (P<0.01). Immunohistochemical staining showed that MppZL4 specifically bound to the tegument of schistosomula with a positive rate of 83.0% (83/100). Fluorescent microscopy revealed that the synthesized RhB-ZL4 bound to the tegument of schistosomula. The ZL4/pEGFP-C2 plasmid was introduced into juvenile S. japonicum and expressed in the parasite. CONCLUSION: The peptide of ZL4 specifically binds to the schistosomulum tegument but not to that of cercaria. PMID- 24812834 TI - [The binding property of different regions in Duffy-binding-like domain alpha of Plasmodium falciparum erythrocyte membrane protein 1 to heparin]. AB - OBJECTIVE: To clone and express Plasmodium falciparum erythrocyte membrane protein 1 DBLalpha (PfEMP1-DBLalpha) and three fragments genes, and screen the strongest affinity sequence with the red blood cell surface receptors-heparin or heparin sulfate in the structure of PfEMP1-DBLalpha. METHODS: The sequence of PfEMP1-DBLalpha1245 was optimized according to the characteristics of E. coli codon, synthesized, and divided into three fragments (DBLaA, DBLalphaB, and DBLalphaC) by PCR. Full-length gene and three gene fragments were subcloned into PGEX-4T-1 vector, and transformed into E. coli BL21 and then induced with IPTG for expression. The recombinant protein was purified from bacterial lysates using glutathione-Sepharose 4B. Heparin affinity test and glycosaminoglycan (GAG) inhibition test were used to analyze the affinity between recombinant protein and heparin. RESULTS: Four recombinant proteins(DBLalpha1245, DBLalphaA, DBLalphaB, and DBLalphaC) were expressed as solubility and the relative molecular weight (M(r) 73 600, M(r) 41 600, M(r) 42 500, and M(r) 41 500) were conformed to the prediction size. Heparin affinity test and GAG inhibition test showed that the four recombinant proteins were binded to the heparin-Sepharose, but not for the GST control. DBLalphaC (Q285-Y415) had the strongest affinity to heparin. CONCLUSION: The strongest affinity sequence with heparin or heparin sulfate in the structure of PfEMP1-DBLalpha is Q285-Y415, which plays a role in binding of Plasmodium falciparum infected red blood cells to the peripheral red blood cells. PMID- 24812835 TI - [A new species of the genus Nanhaipotamon (Decapoda:Potamidae) serving as intermediate host of Paragonimus skrjabini]. AB - OBJECTIVE: To describe a new species of the genus Nanhaipotamon. METHODS: Freshwater crabs were collected in the counties of Yongtai, Minqing, Youxi, Songxi, Zhenghe and Shouning, Fujian Province. The morphological characteristics of the crabs were described. The habitats were observed and crabs examined for the presence of Paragonimus metacerariae. RESULTS: A new species of freshwater crabs named as Nanhaipotamon fujianense sp. nov. was described: holotype (FJ6132 1): male, carapace length 18.44 mm, breadth 23.64 mm, thickness 12.61 mm; allotype (FJ6132-2): female, length 18.76 mm, breadth 25.25 mm, thicknes 14.31 mm, collected from Yongtai County in the middle of Fujian (N 25 degrees 44,778'; E118 degrees 32,278', and 232 m above sea lever). Distal segment of the first male pleopod with triangle convex inner-distal angle, and the axe-like expanded out-distal angle. The out-lateral border slightly sloped downwards. The segment length is 2.1 times as long as the subdistal segment. The crabs usually lived in the crevice of small stream. Paragonimus metacerariae were found in the crabs collected from Yongtai, Minqing, Youxi, Songxi and Zhenghe Counties. CONCLUSION: A new species of freshwater crab (Nanhaipotamon fujianense sp. nov.) has been recorded which serves as the intermediate hosts of Paragonimus skrjabini. PMID- 24812836 TI - [Analysis of Pfcrt gene polymorphism in Plasmodium falciparum from imported cases]. AB - OBJECTIVE: To identify the incidence of the K76T mutation in Pfcrt gene of imported Plasmodium falciparum and study the Pfcrt gene polymorphism in Plasmodium falciparum. METHODS: Seventy-two blood samples were collected from patients infected with P. falciparum returning from Africa (Nigeria, Equatorial Guinea, Congo, Liberia, Angora and Mali) and Southeast Asia (Myanmar and Indonesia) from 2008 to 2012. According to Pfcrt gene sequence of P. falciparum, nested PCR primers were designed, and the reaction was applied with P. falciparum DNA in the blood samples as templates. PCR products were identified by Apo I digestion. RESULTS: Among 72 blood samples of P. falciparum, mutant Pfcrt alleles were found in 41 samples (57.7%, 41/71) and wild type Pfcrt alleles were found in 30 samples (42.3%, 30/71). There were 25 samples (50%, 25/50) each with mutant Pfcrt alleles or wild type that were from Africa, while 16 samples (76.2%, 16/21) with mutant Pfcrt alleles and 5 samples (23.8%, 5/21) with wild type that were from Southeast Asia, respectively. CONCLUSION: The incidence of Pfcrt gene mutation is different in P. falciparum isolates from different regions. PMID- 24812838 TI - [Relationship between snails and recent water level in different marshlands in Xingzi County, Jiangxi Province]. AB - OBJECTIVE: To study the longitudinal change of data on Oncomelania hupensis surveillance in different marshlands and the impact of recent water level in Xingzi County, Jiangxi Province. METHODS: All information including water level of hydrometric station and the data of snails at the marshlands of Xiguanhu, Majiawan and Ximiaoqian was collected to explore the longitudinal change of snails and analyze the relationship between snail distribution and recent water level with Spearman rank correlation analysis. RESULTS: The highest proportion of frames with living snails and living snail densities at Majiawan and Ximiaoqian was 89.66% (442/493) in 2002 and 66.72% (872/1 307) in 2007, 8.33 in 2001 and 7.39 snails per frame in 2006, respectively, and the lowest was 13.26% (126/950) in 2010 and 4.60% (55/1 195) in 2005, 0.42 in 2010 and 0.22 snails per frame in 2002, respectively, and tended to decrease gradually after 2007. At Majiawan, infected snails were found in 2005 and 2009, the density and proportion of infected snails were 0.0033 and 0.0025 snails per frame, 0.09% (3/3 306) and 0.22% (3/1 389). Infected snails were found in Ximiaoqian in 2001, 2003, 2005 and 2009, the highest density and proportion of infected snails were 0.005 0 snails per frame and 0.88% (6/684) in 2005. Infected snails were found in Xiguanhu in 2002 and 2003 with a density and proportion of 0.0029 and 0.0027 snails per frame, 0.10% (1/974) and 0.32% (1/312), respectively. The correlation analysis between proportion of frames with living snails and density at Xiguanhu with the average water level of the first and second month before snail survey showed statistical significance, the correlation coefficient was 0.76, 0.71, 0.82 and 0.78 (P<0.05), respectively. The correlation between proportion of frames with living snails and density at Majiawan showed no statistical significance with the average water level of recent three months before snail survey. The proportion of frames with living snails and density at Xiguanhu were negatively correlated with the average water level of the first and second month before snail survey, the correlation coefficient was -0.67, -0.75, -0.79 and -0.72 (P<0.05), respectively. CONCLUSION: The change trend of snail indicators in different marshlands in the County and impact of water level in recent three months on snail population are both different, and the snail control strategy in marshlands should therefore be adjusted. PMID- 24812837 TI - [Immunogenicity analysis of recombinant GST protein of Fasciola hepatica in SD rats]. AB - OBJECTIVE: To analyze the immunogenicity of recombinant glutathione S-transferase protein of Fasciola hepatica (FhGST) in SD rats. METHODS: The recombinant expression plasmid pET30a-FhGST was transformed into E. coli BL21 (DE3) cells and induced with IPTG for protein expression. The recombinant protein FhGST was analyzed by SDS-PAGE and identified by Western blotting. Twenty SD rats were randomly divided into two groups: immunized group and adjuvant control group. SD rats in immunized group were injected subcutaneously with 200 microg of purified FhGST protein. The adjuvant control group with 10 SD rats received only adjuvants emulsified with PBS. All the rats received three immunizations at 3-week intervals. Serum samples were collected at pre-immunization, the day after each immunization, 3 weeks and 6 weeks after the final immunization. The IgG antibody of rats' sera was examined by indirect ELISA and spleen lymphocyte proliferation (SLP) was tested by MTT. RESULTS: The molecular weight of purified FhGST was about M(r) 31 300. The recombinant FhGST was recognized by pool sera of goats naturally infected with F. hepatica. The recombinant protein induced specific antibody IgG against GST protein in SD rats significantly higher than that of the control, and the antibody titer reached the peak at 9 weeks after the first immunization (GMT 1:89 144). FhGST protein significantly enhanced the growth and proliferation of rat splenocytes. CONCLUSION: The recombinant FhGST protein induces specific immune response in SD rats. PMID- 24812839 TI - [Analysis of larval echinococcosis cases from the National Web-based Infectious Diseases Report System in China in 2011]. AB - OBJECTIVE: To analyze the relevant information of echinococcosis cases from the National Web-based Infectious Diseases Report System in China in 2011. METHODS: Data of echinococcosis in 2011 were collected from the Report System of the Chinese Center for Disease Control and Prevention. SPSS 16.0 software was used to analyze the data. RESULTS: A total of 3 225 cases were reported in 2011, including 1 death and 3 013 effective cases. The three provinces (autonomous region) with high incidence were Xinjiang (occupying 41.5%, 1251/3013), Gansu (16.9%, 509/3 013) and Qinghai (12.0%, 363/3 013). Cases distributed in all age groups, with the highest incidence in the group of 31-40-year-old. Male to female ratio was 1:1.01. The incidence of farmers and herdsmen was highest. CONCLUSION: In 2011, the reported cases are mainly distributed in Xinjiang, Qinghai, Inner Mongolia, Gansu, Ningxia, Sichuan and Tibet. Echinococcosis is mainly prevalent in western China. PMID- 24812840 TI - [Rapid risk assessment on the import of American trypanosomiasis to China]. AB - American trypanosomiasis, as one of the "neglected tropical diseases", is a zoonosis induced by Trypanosoma cruzi. It is endemic in 18 countries in the Central and South America, especially in rural areas. A rapid risk assessment was carried out to analyze the potential threat of imported cases to China, which would provide information to policy makers in health authorities. PMID- 24812841 TI - [Advances in research on the MAPK signal transduction pathway of Echinococcus]. AB - Mitogen-activated protein kinase (MAPK) is an important signaling transduction molecules, which can enter the nucleus and activate target gene when it was stimulated and become phosphorylation. MAPK signaling pathway is closely associated with various diseases. Recent studies have indicated that MAPK signaling transduction pathway is also involved in the growth and development of Echinococcus. This review summarizes the progress on the relationship between MAPK signal pathway and Echinococcus. PMID- 24812842 TI - [Advance of proteomic research on schistosome]. AB - Schistosome proteome research may greatly enhance the understanding of immune mechanism, exploration of new diagnostic and vaccine candidates, and the development of new drugs. This article reviews the progress of proteomic research on schistosome from different life-cycle stages. PMID- 24812843 TI - [In vitro metabolism of fenbendazole prodrug]. AB - Synthesized fenbendazole prodrug N-methoxycarbonyl-N'-(2-nitro-4 phenylthiophenyl) thiourea (MPT) was analyzed in vitro in artificial gastric juice, intestinal juice and mouse liver homogenate model by using HPLC method, and metabolic curve was then generated. MPT was tested against Echinococcus granulosus protoscolices in vitro. The result showed that MPT could be metabolized in the three biological media, and to the active compound fenbendazole in liver homogenate, with a metabolic rate of 7.92%. Besides, the prodrug showed a weak activity against E. granulosus protoscolices with a mortality of 45.9%. PMID- 24812844 TI - [Survey on human soil-borne nematode infection in Xining City]. AB - Five fields were selected from Xining City by stratified cluster sampling method for the survey. 4589 people above 3 years old were examined for nematode infections using Kato-Katz method and children under 12 years old were detected for pinworm infection using transparent tape method from June to August in 2011. The results showed that the total nematode infection rate was 3.0% (136/4 589) with the highest of 3.8% (123/3284) in rural area. The major species was Ascaris lumbricoides, and the infection rate in 15-20 age group was 1.5% (4/264), which was significantly lower than that of the age groups of 60-70 (6.9%, 23/335), above 70 (5.3%, 6/114) and of 10-15 (5.1%, 19/372)(P<0.05). The prevalence of A. lumbricoides among the preschool children (9.5%, 12/127) was statistically higher than those in other occupation groups (P<0.05), and the infection rate showed no statistical significance by gender, ethnic and degree of education (P>0.05). Pinworm infection in children under 12 years old was only 0.5% (2/437). PMID- 24812845 TI - [Secretory expression of salivary ATP diphosphohydrolase (apyrase) from Aedes albopictus in Pichia pastoris]. AB - The gene-coding mature apyrase protein from Aedes albopictus was amplified by RT PCR and cloned in frame with the a-factor secretion signal peptide into Pichia pastoris secreting expression vector pGAPZalpha-A resulting in the pGAPZa-A apyrase. After being linearized by Bln I restriction enzyme, the recombinant pGAPZalpha-A-apyrase was trans-formed into Pichia pastoris GS115 by electroporation. Recombinant strains pGAPZalpha-A-apyrase/GS115 were screened on YPDS plates containing Zeocin and identified by PCR. The recombinant protein of apyrase (M(r) 60000) has been expressed in the supernatant of Pichia pastoris. PMID- 24812846 TI - [Investigation on the infection of Blastocystis hominis in populations in Bama Yao Autonomous County of Guangxi]. AB - 497 fecal specimens were collected from 5 randomly selected villages of Bama County in December 2011, and tested for Blastocystis hominis infection using improved centrifugal sedimentation with hydrochloric acid-ether. Data were analyzed by villages, gender, occupation, age groups and ethnic populations. The results showed that 215 people of 497 were positive, with a prevalence of 43.3% (215/497). Pandang village had the highest infection rate of 55.7% (68/122), significantly higher than the other villages (P<0.05). There was no significant difference in genders, occupations, age groups and ethnic populations (P>0.05). PMID- 24812847 TI - [Laboratory testing for a case of imported Plasmodium ovale infection in Zhejiang Province]. AB - Blood sample obtained from a patient, which returned from Equatorial Guinea, with clinical diagnosis of Plasmodium infection was confirmed as imported P. ovale infection by etiology and molecular biological methods. 50 microl blood was obtained before taking anti-malarial drugs to make thin and thick blood smears, Giemsa stained, and observed by microscopy. Genomic DNA was extracted from the blood sample, and detected for DNA fragment of P. ovale, P. vivax, P. falciparum or P. malariae by real-time fluorescent quantitative PCR. P. ovale parasites were found in both thin and thick blood smears, and confirmed by quantitative PCR. With the results of laboratory testing, epidemiological history and clinical manifestations, the patient was diagnosed as imported P. ovale infection. PMID- 24812848 TI - [Two cases of Strongyloides stercoralis infection]. PMID- 24812849 TI - [One case of Thelazia callipaeda infection in eye conjunctival sac]. PMID- 24812850 TI - [Comparative observation on inhibition of hemozoin formation and their in vitro and in vivo anti-schistosome activity displayed by 7 antimalarial drugs]. AB - OBJECTIVE: To observe and compare the inhibition of hemozoin formation and the in vitro as well as in vivo antischistosomal activity induced by seven antimalarial drugs. METHODS: Inhibition of hemozoin formation displayed by chloroquine phosphate, quinine hydrochloride, quinidine, mefloquine hydrochloride, pyronaridine phosphate and lumefantrine at 25 micromol/L, and artemether at 100 micromol/L was performed by assay of inhibition of beta-hematin formation in 1 mol/L sodium acetate buffers containing hematin with various pH of 4.0, 4.2, 4.4, 4.6, 4.8, and 5.0. In in vitro antischistosomal study, the medium of RPMI 1640 supplemented by 10% calf serum was used to maintain the adult Schistosoma japonicum, and the 50% and 95% lethal concentrations (LC50 and LC95) to kill the adult worms of each drug were then determined. Meanwhile, the interaction of quinine, pyronaridine and chloroquine combined with hemin against adult schistosomes was also undertaken. As to in vivo test, the efficacy of seven antimalarial drugs administered orally or intraperitoneally to mice infected with adult schistosomes was observed. RESULTS: In the acidic acetate-hematin solution, 25 micromol/L pyronaridine showed significant inhibition of beta-hematin formation at pH 4.4-5.0 with inhibition rates of 81.3%-97.0%. At pH 4.6, the inhibition rates of beta-hematin formation in acetate-hematin solution induced by mefloquine, chloroquine or quinine at concentration of 25 beta mol/L were 79.7%, 72.8% or 65.8%, respectively, and the beta-hematin formation was continually inhibited by these 3 antimalarial drugs at pH 4.8 and 5.0 with inhibition rates of 83.1%-90.6%, 41.9%-49.0% or 53.2-62.0%. The inhibition rates of beta-hematin formation at pH 4.6 and 4.8-5.0 induced by lumefantrine 25 micromol/L were 74.3% and 40.4%-40.5%, respectively. While under the same concentration of quinidine, 53.4% and 50.9% inhibition rates of beta-hematin formation were observed at pH 4.8 and 5.0. As to artemether, higher concentration of 100 micromol/L only showed light inhibition of beta-hematin formation at pH 4.4-4.8 with inhibition rates of 16.6%-25.0%. As regard to in vitro test, the LC50 and LC95 of mefloquine, pyronaridine, quinine and quinidine were 4.93 and 6.123 microg/ml, 37.278 and 75.703 microg/ml, 93.688 and 134.578 microg/ml, as well as 101.534 and 129.957 microg/ml, respectively. When adult schistosomes were exposed to the medium containing chloroquine, lumefantrine or artemether at higher concentrations of 100 or 120 microg/ml for 72 h, no or only individual worms died. Hence the LC50 and LC95 of these 3 drugs could not be determined. In other in vitro test, adult schistosomes exposed to quinine 50 micromol/L (20 microg/ml) in combination with 153.4 micromol/L (100 microg/ml) hemin, all worms died within 72 h post incubation. While the worms exposed to 50 micromol/L (26 microg/ml) chloroquine combined with the same concentration of hemin, only 18.8%(3/16) of worm died at 72 h post exposure. Unexpectedly, in schistosomes exposed to pyronaridine at a toxic concentrations of 50 micromol/L (46 microg/ml) in combination with 153.4 mol/L (100 microg/ml) hemin for 72 h, all of the worms were protected from the toxic action induced by pyronaridine, which revealed in normal motor activity and appearance of morphology in majority of the worms. In in vivo test, mice infected with adult schistosomes were treated orally with chloroquine, pyronaridine or lumefantrine at a daily dose of 400 mg/kg for 3 days, or intraperitoneally with chloroquine or pyronaridine at a daily dose of 100 mg/kg for 2 or 3 days, no apparent efficacy was seen. When mefloquine, quinine, quinidine or artemether were administered orally to infected mice at a single dose of 400 mg/kg or 200 mg/kg (mefloquine), all groups of mice treated showed moderate or higher efficacy with worm burden reductions of 61.1%-98.1%. CONCLUSION: Among the seven antimalarial drugs tested, their inhibitions of hemozoin (beta-hematin) exhibit no definite correlation to their in vitro and in vivo antischistosomal activity. Quinine in combination with hemin shows synergistic effect against schistosomes in vitro. While antagonist effect is observed in pyronaridine combined with hemin. PMID- 24812851 TI - [Eukaryotic expression of SjE16, SjPPIase and SjRobl genes from Schistosoma japonicum egg and evaluation of their role in immunodiagnosis]. AB - OBJECTIVE: To express Schistosoma japonicum egg proteins by eukaryotic system and evaluate their role in schistosomiasis immunodiagnosis. METHODS: S. japonicum egg RNA was extracted and reversed to cDNA. Egg specific or highly expressed genes: SJCHGC01695 (SjE16), SJCHGC00856 (SjlMA8), SJCHGC06249 (SjTOR), SJCHGC06324 (SjP40), SJEFTD02 (SjSLP), SJCHGC06679 (SjPPIase) and SJCHGC06529 (SjRobl), were amplified and sub-cloned to eukaryotic expression vector pPIC9K. Recombinant vectors were transformed to yeast GS115 and the recombinant yeast was induced by methanol. Proteins were purified with Ni-NTA affinity chromatography and analyzed by SDS-PAGE and Western blotting. For the detection of specific antibodies, the wells of microtiter plate were coated with soluble egg antigen (SEA), SjE16, SjPPIase and SjRobl, respectively, or combination of recombinant proteins. The specific antibody reactivity in sera from schistosome-infected mice and patients were examined by ELISA. RESULTS: The highly expressed genes from S. japonicum eggs were cloned by PCR. The recombinant proteins of SjE16, SjPPIase and SjRobl were expressed and identified by SDS-PAGE and Western blotting. Those recombinant SjE16, SjPPIase and SjRobl were recognized by IgM and IgG in schistosome-infected mouse and patient sera. The sensitivity of the three antigens in detecting IgM and IgG in acute patients were 80%, 60%, 80% and 40%, 80%, 70%, respectively, while that of the combination of SjE16 and SjRobl in detecting IgM was 100%. CONCLUSION: The above three S. japonicum egg enriched proteins were expressed using eukaryotic expression system and can be used in acute schistosomiasis diagnosis. PMID- 24812852 TI - [Microglial activation and inflammatory cytokine expression in the brain of chronic Toxoplasma gondii-infected mice]. AB - OBJECTIVE: To investigate microglial activation and inflammatory cytokine expression in chronic Toxoplasma gondii infection. METHODS: Thirty mice were randomly divided into chronic T. gondii infection group and normal control group. Each mouse in infection group was infected orally with 30 cysts of the TgCtwh6 strain. Normal group received 0.3 ml normal saline. On the 60th day after infection, immunohistochemical staining was performed to assess the number of microglia and morphological change. The expression of inflammatory cytokines (IL 1beta, IL-6, and TNF-alpha) was measured by RT-PCR. The expression of iNOS was determined by Western blotting and immunofluorescence. RESULTS: Immunohistochemistry analysis showed that the number of Iba-1 positive cells in the cortex and hippocampus of infection group (16.5 +/- 0.8 and 17.9 +/- 1.1) was higher than that of the control (8.4 +/- 0.2 and 10.3 +/- 0.8)(P < 0.05). Iba-1 positive cells (i.e. microglia) had larger cell bodies and ramified morphology. RT-PCR result indicated that mRNA level of IL-1beta, IL-6, and TNF-alpha in infection group (0.862 +/- 0.169, 0.407 +/- 0.158, and 0.305 +/- 0.073) was significantly higher than that of the control (0.149 +/- 0.030, 0.037 +/- 0.008, and 0.001 +/- 0.001) (P < 0.05). The iNOS protein expression in infection group (0.252 +/- 0.164) was higher than that of the control (0.0433 +/- 0.004) (P < 0.05). Immunofluorescence demonstrated that iNOS protein released by activated microglia. CONCLUSION: Chronic T. gondii infection caused microglial activation, which up-regulate the level of IL-1beta, IL-6, TNF-alpha, and iNOS. PMID- 24812853 TI - [Development of an IMS-qPCR method for detection of Cryptosporidium parvum in water]. AB - OBJECTIVE: To develop a detection method for Cryptosporidium parvum oocysts from water samples, which combined immunomagnetic separation (IMS) with Taqman real time PCR (qPCR). METHODS: Conditions of separation and enrichment of IMS method by using specific streptavidin magnetic beads coated with monoclonal antibodies Cp23 directed against C. parvum oocysts were optimized. Special primers of PCR and Taqman probes were designed referring to the 18S rDNA gene of C. parvum (GenBank Accession No. AB513881.1). The conserved genes were amplified from genomic DNA of C.parvum, and then cloned into Peasy-T1 vector. Tenfold dilutions of positive plasmids (10(4)-10(8) copy/microl) were used to construct a standard curves by Taqman qPCR. The specificity of the assay was determined using genomic DNA of C. baileyi, Toxoplasma gondii, C. canis and Escherichia coli. The sensitivity of this assay was evaluated by analyzing 10-fold serially dilutions of plasmids ranging from 10(0) to 10(8) copy/microl. Both IMS-qPCR assay and indirect immunofluorescent-antibody assay (IFA) were applied to detect 50 water samples collected from the dairy cattle farms in Hebei. RESULTS: The optimal incubation concentration and time of antibody Cp23 were 20 ng/ml and 30 min, respectively, and the catching time was 30 min, the recovery rate was more than 95%. PCR product was 272 bp, and identified by restriction enzyme digestion and nucleotide sequencing. There was a good linear relationship between the standard plasmids and Ct value (correlation r2 = 0.996 1) of the Taqman qPCR. No cross reactivity was observed with C. baileyi, T. gondii, C. canis and E. coli. The sensitivity of C. parvum-specific assay was 10 copy/microl. Compared with IFA as golden standard method, the specificity and sensitivity of IMS-qPCR for 50 water samples was 100%(18/18) and 93.8% (30/32), respectively. CONCLUSION: The IMS-qPCR assay can be used to specifically detect C. parvum oocysts in water samples. PMID- 24812854 TI - [Species identification of Echinococcus isolates collected from canines and Tibetan foxes in Chengduo County, Qinghai Province]. AB - OBJECTIVE: To identify Echinococcus isolates collected from Tibetan foxes(Vulpes ferrilata) and dogs in Chengduo county, Yushu Prefecture, Qinghai Province. METHODS: Six Tibetan foxes and 6 Tibetan dogs died accidently. Small intestines were dissected from the animals. The adult tap-worms were collected by sedimentation technique. The worms were stained with borax carmine and observed under microscope. The isolates were identified initially by morphology and the infection intensity for each animal was calculated. Eight isolates of E. multilocularis and 2 isolates of E. shiquicus were selected for the extraction of total DNA. The mitochondrion DNA CO I gene was amplified with specific primers by PCR, then sequenced and analyzed. RESULTS: E. multilocularis and E. shiquicus were found. Two out of 6 Tibetan foxes were infected with E. multilocularis, the infection intensity was 1,640 and 839. One Tibetan fox was infected by E. shiquicus with an infection intensity of 833. Two Tibetan dogs were infected with E. multilocularis, and the infection intensity was 10,195 and 78, respectively. The obtained partial sequences of CO I gene were 450 bp. The CO I gene from 8 isolates of E. multilocularis shared 100% homology with the isolates collected from Tibetan dogs in Sichuan Province (Accession No. AB461417). The CO I gene from 2 isolates of E. shiquicus showed high sequence homology (99.2%) with the isolates collected from Ochotona curzoniae in Shiqu County, Sichuan Province(Accession No. AB159136). CONCLUSION: E. multilocularis and E. shiquicus have been identified in the small intestines of wild foxes, and E. multilocularis in Tibetan dogs. PMID- 24812855 TI - [Different Echinococcus granulosus antigens induced indoleamine 2,3-dioxygenase expression in dendritic cells]. AB - OBJECTIVE: To observe the expression of indoleamine 2, 3-dioxygenase (IDO) in dendritic cells (DCs) via different Echinococcus granulosus antigens in vitro. METHODS: Bone Marrow DCs generated from bone marrow precursor cells of C57BL/6 mice and cultured in the presence of recombinant mouse GM-CSF (rmGM-CSF). Then, DCs were induced with 15 microg/ml recombinant antigen B (rAgB), 5 mg/ml mouse hydatid fluid (MHF), 1,000 U/ml IFN-gamma (as positive control), and RPMI 1640 complete medium (as negative control), respectively. Meanwhile, the treated DCs and cell supernatants were collected at 18, 24 and 48 h after induction. The positive expressions of D40, CD80, CD86 and I- A/I-E on DCs were determined by flow cytometry. By real-time fluorescent quantitative reverse-transcription polymerase chain reaction (FQ-RT-PCR), the expression level of IDO mRNA in DCs was measured. Concentrations of tryptophan (Try) were tested by high-performance liquid chromatography (HPLC) assay in cell supernatant. RESULTS: The data from flow cytometry showed that the positive expressions of CD40, CD80, CD86, I-A/I-E were decreased after stimulated by rAgB and MHF. At 24 h after induction, there was significant difference in the level of CD40, CD86 and I-A/I-E among rAgB treated group [(22.60 +/- 2.69)%, (35.50 +/- 4.38)%, (57.30 +/- 4.38)%], MHF treated group [(38.00 +/- 3.54)%, (53.00 +/- 3.39)%, (77.10 +/- 1.70)%] and negative control [(37.95 +/- 3.61)%, (19.55 +/- 1.06)% and (85.45 +/-1.63)%] (P < 0.05). At 18, 24 and 48 h after induction, the levels of IDO mRNA in rAgB-treated group [(9.20 +/- 0.01), (29.44 +/- 0.02), (16.48 +/- 0.04)] and MHF-treated group [(9.67 +/- 0.02), (17.52 +/- 0.01), (16.81 +/- 0.01)] was higher than that of negative control group [(2.46 +/- 0.01), (7.77 +/- 0.01), and (10.56 +/- 0.01)] (P < 0.01). And significant difference was found between rAgB-treated group and MHF-treated group (P < 0.05). At 18, 24 and 48 h after induction, the concentrations of Try were lowest in rAgB-treated group [(23.65 +/- 0.64), (13.95 +/- +1.06), (19.0 +/- 00.64) micro.mol/L]. At 24h after induction, Try concentration in negative control group (22.9 +/- 0.14) was higher than that of MHF-treated group (20.65 +/- 0.34) ( P < 0.05). CONCLUSION: Under in vitro condition, rAgB and MHF can up-regulate IDO expression. The ability of rAgB to up regulate IDO activity was stronger than that of MHF at 24 h after induction. PMID- 24812856 TI - [Effect of long-term use of albendazole on mice liver]. AB - OBJECTIVE: To observe the change in serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), direct bilirubin (DBL), indirect bilirubin (IBIL), albumin (ALB) and globulin (GLB), and mouse liver ultrastructure during 1-16 weeks of albendazole treatment. METHODS: 180 female Kunming mice were divided randomly into albendazole treatment group and negative control group. Each mouse of albendazole treatment group was treated with 136.3 mg/(kg x d) albendazole. The mice in control group were given same amount of physiological saline. After 1, 2, 4, 6, 8, 10, 12, 14 and 16 weeks of treatment, 10 mice from each group were randomly selected, serum samples were collected and analyzed for the above seven liver function indices. Pathological changes of liver were observed by transmission electron microscopy. Linear regression analysis was conducted for the relationship between liver function indices(dependent variable) and pathological scores (independent variable). RESULTS: During 1-16 weeks of albendazole treatment, there was no significant difference in serum levels of DBL, IBIL, ALB and GLB between albendazole treatment group and control group. Compared with other treatment period, after 12 weeks of treatment the serum levels of ALT (55.2 +/- 23.7), AST(176.4 +/- 49.2) and ALP(141.1 +/- 19.4) in albendazole treatment group were higher than that of the control (35.5 +/- 8.6, 108.2 +/- 21.9, 84.0 +/- 24.8) (P < 0.05). After 2, 8, 10, 12 and 14 weeks of treatment, the pathological score of albendazole treatment group was 11.8 +/- 4.8, 10.6 +/- 4.8, 13.6 +/- 3.5, 29.8 +/- 10.7, and 5.6 +/- 2.5, respectively, which was higher than that of the control (0.8 +/- 0.4, 1.2 +/ 0.8, 2.4 +/- 2.0, 1.2 +/- 0.4, 1.4 +/- 1.1) (P < 0.05). Among the three liver function indices AST, ALT and ALP, AST was the best fit index for linear regression. The regression formula was Y = -17.616 + 0.188X. CONCLUSION: Long term treatment with albendazole at a dosage of 136.3 mg/(kg x d) for mice can cause significant elevation of serum levels of ALT, AST and ALP, and result in mild pathological changes in the liver. PMID- 24812857 TI - [Position analysis of three recombinant proteins of Echinococcus granulosus protoscolex with two-dimensional electrophoresis]. AB - OBJECTIVE: To obtain specific antibodies of the three recombinant antigens obtained previously, rEgZW-5, rEg14-3-3 and rEgP-29, for identifying the corresponding proteins in two-dimensional electrophoretogram of Echinococcus granulosus protoscolex. METHODS: The distribution of proteins from E. granulosus protoscoleces was judged by SDS-PAGE previously. Two-dimensional electrophoresis was used to separate proteins from E. granulosus protoscoleces, and the result was scanned and analyzed by the PDquest software to get the information about the quantity of proteins as well as their isoelectric point (IP) and relative molecular mass (MA,). Rabbits were immunized with the 3 recombinant antigens and antibodies were purified from antisera. Western blotting was used to identify the protein as marker in two-dimensional electrophoretogram of protoscolex. RESULTS: SDS-PAGE displayed that the proteins separated from Echinococcus granulosus protoscoleces mainly distributed in the M, region of 18,000-90,000. 240 proteins were obtained by two-dimensional electrophoresis with M, 15,790-117,050 and IP 4.0-9.5, and 85.8% (206/241) of the proteins showed the IP ranged from 5 to 9. Western blotting showed that the specific antibody of rEg14-3-3 identified the 14 3-3 protein in two-dimensional electrophoretogram of protoscolex with Mr 33 000 and IP 4.86, the specific antibody of rEgZW-5 identified the ZW-5 protein with Mr 23,000 and IP 4.98, and the specific antibody of rEg P-29 identified the P-29 protein with Mr 29,000 and IP 5.65. CONCLUSION: The antibodies against the three recombinant proteins from Echinococcus granulosus protoscoleces can identify corresponding proteins in the two-dimensional electrophoregrams. PMID- 24812858 TI - [The species and ecological distribution of medical mollusca in Weifang, Shandong Province]. AB - OBJECTIVE: To investigate the species and distribution of mollusca with medical importance in Weifang, Shandong Province. METHODS: Species identification and quantitative statistics analysis was studied based on field-collected snails from the districts of Weifang, Shouguang, Anqiu and Changyi, Shandong Province. RESULTS: A total of 1,791 medical mollusca specimens were collected, belonging to two Classes, 9 families and 14 species. Some important species were discovered including Parafossarulus striatulus (383), Alocinma longicornis (34), Galba pervia (63), Radix swinhoei (137), R. auricularia (95), Physa acuta (677) and Hippeutis cantori (22). The dominant species were P. acuta and P. striatulus. CONCLUSION: There remains a higher diversity of medical mollusca in Weifang, Shandong Province. PMID- 24812859 TI - [Evaluation of the comprehensive schistosomiasis control measures with emphasis on infection source of replacing cattle with machine]. AB - OBJECTIVE: To evaluate the effect of comprehensive measures with an emphasis on schistosomiasis infection source control by replacing cattle with machine. METHODS: In 2011, 2 villages from each of Jingzhou District, Jianli County and Jiangling County, Hubei Province, were selected as intervention group where the comprehensive measures were implemented, while 2 villages from Shishou City served as control with routine control activities. A cluster random sampling was carried out in the 8 villages with more than 300 people in each village were sampled. Stool examination using modified Kato-Katz was applied for identification of the infected persons and hatching test for cattle survey. The systemic sampling was applied for snail survey, fecal specimens from the field were examined by hatching test. Each sample was examined three times. Data were collected for the analysis of control effect between intervention and control groups in 2007 (baseline), 2009 (before implementation of comprehensive measures) and 2011 (post-intervention). RESULTS: In intervention villages, the overall prevalence in human reduced significantly from 3.6% (135/3 772) in 2007 and 2.0% (63/3 116) in 2009 to 0.9% (21/2 396) in 2011 (chi2 = 43.411, chi2 = 11.840, P < 0.05). Until 2011, there were no cattle in intervention group; the prevalence decreased by 52.6% in human and about 100% in cattle from 2010 to 2011. In control group, the infection rate in residents in 2007, 2009 and 2011 was 4.5% (64/1 410), 2.6% (34/1 294) and 1.8% (24/1,320), respectively (chi2 = 16.178, P < 0.05), and 5.1% (8/158) in 2007, 1.6% (3/187) in 2009 and 1.6% (3/189) in 2011 in cattle, respectively (chi2 = 3.387, P > 0.05). The infection rate in human and cattle fell by 25.0% and 5.9% from 2010 to 2011, respectively. There was a significant difference in human infection rate between the intervention and control groups after intervention (chi2 = 6.309, P < 0.05). No infected snails were detected in intervention and control groups. No positive feces from the field was found in the intervention group, 7.5% positive rate was recorded in the control. CONCLUSION: The comprehensive measures focused on infection source control by replacing cattle with machine can effectively control Schistosoma japonicum transmission, with a significant decrease of the prevalence in human and cattle. PMID- 24812860 TI - [Extraction and morphological observation of Oncomelania hupensis haemocytes]. AB - Haemocytes were collected from Oncomelania hupensis snails by using tissue disruption and filtration method, stained by Giemsa and methylene blue, respectively, and observed under microscope. Number of haemocytes from one snail was counted. Out of 54 haemocytes, 3 types of cells were found: big round cells with particles, small round cells with oval nuclei and spindle cells with oblong nuclei. The diameter of big round cells with particles and small round cells with oval nuclei was (21.59-31.97) and (13.24-20.77) microm, respectively. Spindle cells with oblong nuclei was about (17.60-25.47) microm x (27.19-30.25) microm. The nucleocytoplasmic ratio of the above three type cells was 0.38, 0.44 and 0.38, and occupied 35.95% (19/54), 12.42% (28/54) and 51.63% (7/54), respectively. About 194 600 haemocytes were filtered from one single snail. It means that this filtration method is an effective one to extract haemocytes from O. hupensis. PMID- 24812861 TI - [Preliminary application of moving percentile method on surveillance and early warning on visceral leishmaniasis in endemic areas]. AB - OBJECTIVE: To apply moving percentile method on surveillance and early-warning on visceral leishmaniasis in Kashgar Region and evaluate its effect. METHODS: Incidence data of visceral leishmaniasis in Kashgar Region were collected from the National Web-based Infectious Diseases Report System. Monthly detection was carried out by using moving percentile method. The 50th percentile (P50), 70th percentile (P70) and 90th percentile (P90) of historical baseline data were calculated for drawing a control chart, and P70 was adopted as the warning threshold to determine whether an epidemic would appear. If the number of cases in one month is higher than the corresponding P70 of historical baseline data, the warning signal will be generated. The sensitivity, specificity and positive predictive value were calculated for the evaluation of early-warning effect. RESULTS: During the study period, 61.0% cases were reported in the year of 2008 and 2009, the incidence peak was from September to December, accounting for 51.9%, and infants under 3 years old were the population most threatened by visceral leishmaniasis, accounting for 62.7%. A total of 58 detections were performed, and 17 warning signals were generated by the threshold on P70. Among them, the numbers of cases in 9 detections were higher than the corresponding P90 of historical-baseline data. Based on the actually epidemic status of visceral leishmaniasis in study period, according to the threshold on P70, a total of 10 warning signals of 11 epidemics were detected, and the sensitivity of the warning model was 90.9% (10/11). 7 wrongly signals of 47 non-epidemics were detected, and the specificity was 85.1% (40/47). 10 of 17 signals were proved to be correct, and the positive predictive value was 58.8% (10/17). CONCLUSION: The moving percentile method can effectively perform surveillance and early-warning on visceral leishmaniasis in Kashgar Region. PMID- 24812862 TI - [Clinical analysis of 25 sparganosis cases]. AB - OBJECTIVE: To analyse the clinical features of sparganosis patients and improve cognition in the disease. METHODS: The epidemic data, clinical manifestations, auxiliary examinations, diagnosis and treatments of 25 sparganosis patients in the hospital were retrospectively analyzed. RESULTS: Among the 23 patients with definite epidemiological data , 22 cases were food-borne, one case of contact infection. According to the clinical manifestation, there were 14 cases of central nervous system (CNS) sparganosis, 7 cases of cutaneous sparganosis, 3 cases of visceral sparganosis and 1 case of ocular sparganosis. Eosinophilia in peripheral blood was found in 4 cases including the 3 cases of visceral sparganosis. 22 patients were diagnosed by serologic IgG antibody test. MRI showed positive finding in all CNS sparganosis patients. 11 cases received surgical excision or biopsy, worms were found in 8 cases. 80% of the cases were once misdiagnosed by other disorders. 18 patients were cured and 7 alleviated after treatment. CONCLUSION: Sparganosis is mostly a food-borne infection, more involving central nervous system. Serologic test is important for diagnosis, and eosinophilia is uncommon. PMID- 24812863 TI - [Species identification in 5 imported cases previously diagnosed as Vivax malaria by parasitological and nested PCR techniques]. AB - OBJECTIVE: To identify the species of malaria parasites in 5 imported cases previously diagnosed as vivax malaria. METHODS: Epidemiological information and blood samples were collected from five patients who returned from Africa and were diagnosed as vivax malaria. The detection was conducted by microscopy, right VIEW rapid malaria test (RDTs) and nested PCR with Plasmodium genus-specific and species-specific primers. The amplified products were sequenced and Blast analysis was performed. RESULTS: Three of the 5 cases had a history of malaria attack. Microscopically, 4 cases were confirmed as Plasmodium ovale infection, 1 (case 1) was co-infected with P. vivax and P. ovale. All 5 cases showed negative RDT results. Nested PCR detection revealed that the 5 cases had a P. ovale specific fragment (800 bp), while case 1 had a P. vivax-specific fragment (120 bp) concurrently. Blast analysis showed that the amplified sequence of the 5 cases had a high sequence homology (99%) with P. ovale gene for small subunit ribosomal RNA from GenBank, and that of case 1 also shared 99% homology with P. vivax isolate SV5 18S ribosomal RNA gene (GenBank accession number: JQ627157.1). CONCLUSION: Among the five cases, four were infected by Plasmodium ovale, and one was co-infected with both P. vivax and P. ovale. PMID- 24812864 TI - [Epidemic analysis of echinococcosis in Ganzi Tibetan Autonomous Prefecture of Sichuan Province from 2006 to 2011]. AB - OBJECTIVE: To provide scientific evidence for further improving of the prevention and control strategies for echinococcosis in Ganzi Tibetan Autonomous Prefecture, Sichuan Province, according to the epidemiological characteristics of echinococcosis surveyed in this prefecture. METHODS: Data of echinococcosis cases and surveillance information of Ganzi Tibetan Autonomous Prefecture from 2006 to 2011 were downloaded from the National Infectious Diseases Reporting System, and statistically analyzed by using SPSS 19.0 and Epi info3.5 software. RESULTS: A total of 8939 echinococcosis cases was reported during the observed period, the prevalence rate was 818.7/100000, and 88.9% of the patients were herdsmen. Cases distributed in all the 18 counties and counted for 66.8% (217/325) of the townships in Ganzi Prefecture, pasturing and farming-pastoral areas were the highly risk areas. 84.3% cases were reported from Shiqu and Seda Counties, where were the most heavy epidemic regions for echinococcosis prevalence in Sichuan Province. The minimum, maximum and mean age of these cases was 1, 99 and 41 years old. Among them 84.3% were aged from 20 to 60 years old, and the prevalence rate of females was significantly higher than that of males (P<0.01). The serological positive rate of children (P<0.01) and the prevalence rate of livestock in 2011 (P<0.01) was significantly decreased, comparing with that of in 2007, respectively. There was no statistical difference between the positive rates of dog coproantigen in 2011 and 2007 (P > 0.05). CONCLUSION: The prevalence of echinococcosis in Ganzi Tibetan Autonomous Prefecture, Sichuan, was still high, comprehensive prevention and control strategies needed to adopt in the control program in order to reduce the infection of echinococcosis. PMID- 24812865 TI - [Research progress on fascioliasis]. AB - Fascioliasis is an important zoonosis caused by Fasciola spp. It can cause pathological damages to human liver and gallbladder, as well as economic loss in animal husbandry. Fascioliasis can be easily misdiagnosed with other hepatobiliary diseases. The appearance of resistance to triclabendazole is an issue problem for fascioliasis control. Therefore, research for better diagnostic methods, effective drugs and vaccines become to the focus of fascioliasis control. This article summarizes the progress on epidemiological status, diagnostic method, therapy, drug resistance, vaccine and omics of fascioliasis. PMID- 24812866 TI - [Research progress on diagnostic methods for Babesia microti infection]. AB - Human babesiosis, a malaria-like zoonosis transmitted by the tick, is mainly distributed in Europe, USA and some Asian countries. There are various kinds of diagnostic methods for babesiosis caused by Babesia microti, but many of them are still in the preliminary stage. This article reviews the main diagnostic techniques and the existing problems. PMID- 24812867 TI - [Pathogen associated molecular patterns of parasite]. AB - With the research progress of classical pathogen associated molecular patterns (PAMPs) from pathogenic microbes, the presence of the parasite PAMPs has been confirmed. The parasite PAMPs show some differences from classical PAMPs in molecular structures, receptor binding ways, intracellular signal transduction pathways, and induced effects. This review focuses on the issues of parasite PAMPs. PMID- 24812868 TI - [Report on 16 cases of small intestine ascariasis diagnosed by capsule endoscopy]. AB - The clinical data and capsule endoscopy image of 16 adult patients with small intestine ascariasis were reviewed and analyzed retrospectively from June 2006 to June 2012 in West China Hospital. Among the 16 patients, 15 cases manifested as gastrointestinal bleeding, 15 cases showed anemia (3 severe, 10 moderate, and 2 mild), 2 had hypoalbuminemia, 1 had peripheral blood eosinophilia. All the cases were found to be fecal occult blood positive, but no Ascaris eggs found in the feces. Capsule endoscopy showed they were infected with Ascaris worms. The worms were found in the proximal small intestine in 14 patients and 2 in the distal intestine. Mucosal erythema and erosions around the worm were observed in 3 cases, and 7 cases were found with active bleeding or old haemorrhage in small intestine. PMID- 24812869 TI - [Effect of transposase on the transposition activity of piggyBac transposon transfected into Toxoplasma gondii]. AB - To determine the transfection efficiency about PBase to piggyBac transposon in transfecting to Toxoplasma gondii, T. gondii RH strain tachyzoites were transfected with plasmid PB-Toxo-RFP which was expressed piggyBac transposon with a red fluorescent protein and Toxo-PBase plasmid which is a transposable enzyme. T. gondii tachyzoites were transfected with PB-Toxo-RFP plasmid alone as control group. The expression of red fluorescent protein was detected by flow cytometry at 24 h after transfection. The transposition efficiency in PB-Toxo-RFP+Toxo PBase group and PB-Toxo-RFP group was 73% and 43%, respectively (P < 0.01). It suggests that the PBase transposase can improve the transfection efficiency of piggyBac transposon in T. gondii tachyzoites. PMID- 24812870 TI - [One case of scrub typhus patient with clinical manifestation of acute pyelonephritis]. PMID- 24812871 TI - [Molecular cloning and characterization of a novel Clonorchis sinensis antigenic protein containing tandem repeat sequences]. AB - OBJECTIVE: To find and clone new antigen genes from the lambda-ZAP cDNA expression library of adult Clonorchis sinensis, and determine the immunological characteristics of the recombinant proteins. METHODS: The cDNA expression library of adult C. sinensis was screened by pooled sera of clonorchiasis patients. The sequences of the positive phage clones were compared with the sequences in EST database, and the full-length sequence of the gene (Cs22 gene) was obtained by RT PCR. cDNA fragments containing 2 and 3 times tandem repeat sequences were generated by jumping PCR. The sequence encoding the mature peptide or the tandem repeat sequence was respectively cloned into the prokaryotic expression vector pET28a (+), and then transformed into E. coli Rosetta DE3 cells for expression. The recombinant proteins (rCs22-2r, rCs22-3r, rCs22M-2r, and rCs22M-3r) were purified by His-bind-resin (Ni-NTA) affinity chromatography. The immunogenicity of rCs22-2r and rCs22-3r was identified by ELISA. To evaluate the immunological diagnostic value of rCs22-2r and rCs22-3r, serum samples from 35 clonorchiasis patients, 31 healthy individuals, 15 schistosomiasis patients, 15 paragonimiasis westermani patients and 13 cysticercosis patients were examined by ELISA. To locate antigenic determinants, the pooled sera of clonorchiasis patients and healthy persons were analyzed for specific antibodies by ELISA with recombinant protein rCs22M-2r and rCs22M-3r containing the tandem repeat sequences. RESULTS: The full-length sequence of Cs22 antigen gene of C. sinensis was obtained. It contained 13 times tandem repeat sequences of EQQDGDEEGMGGDGGRGKEKGKVEGEDGAGEQKEQA. Bioinformatics analysis indicated that the protein (Cs22) belonged to GPI-anchored proteins family. The recombinant proteins rCs22-2r and rCs22-3r showed a certain level of immunogenicity. The positive rate by ELISA coated with the purified PrCs22-2r and PrCs22-3r for sera of clonorchiasis patients both were 45.7% (16/35), and 3.2% (1/31) for those of healthy persons. There was no cross reaction with sera of schistosomiasis and cysticercosis patients. The cross reaction with sera of paragonimiasis westermani patients was 1/15. The recombinant proteins rCs22M-2r and rCs22M-3r which only contained tandem repeats were specifically recognized by pooled sera of clonorchiasis patients. CONCLUSION: The Cs22 antigen gene of Clonorchis sinensis is obtained, and the recombinant proteins have certain diagnostic value. The antigenic determinant is located in tandem repeat sequences. PMID- 24812872 TI - [Enterobius vermicularis infection status among children in 9 provinces/autonomous regions/municipalities of China]. AB - OBJECTIVE: To investigate the infection status of Enterobius vermicularis among children in 9 Provinces/Autonomous regions/Municipalities (P/A/M) of China, and analyze its risk factors. METHOD: From April to December 2011, one provincial capital (prefecture-level city) and one county (city, district) were chosen as investigation spots from Guangdong, Guangxi, Hainan, Chongqing, Sichuan, Zhejiang, Fujian, Anhui and Guizhou, respectively. Children aged 2 to 12 were examined by using adhesive cellophane anal swab with round-bottom tube. Information of children's family condition, health behavior and school environment were collected by questionnairing. RESULTS: 14 964 children were examined, and 14 582 qualified questionnaires were collected. The total prevalence was 17.8% (2 659/14 964). Of the 9 P/A/M, the prevalence was highest in Hainan Province (51.1%, 869/1 701) and lowest in Anhui Province (0.8%, 13/1 589). The prevalence in urban areas (7.3%, 552/7 581) was lower than that of rural areas (28.5%, 2 107/7 383) (chi2 = 1156.73, P < 0.01). The highest prevalence in urban and rural areas was found in Haikou City(38.0%, 322/847) and Wanning City (64.1%, 547/854) of Hainan Province. The prevalence rate in males and females was 17.4% (1 410/8 128) and 18.3% (1249/6 834), respectively (chi2 = 2.192, P > 0.05). The highest prevalence in males (61.2%, 300/490) and females (67.9%, 247/364) was found in children of Wanning City. Multivariate logistic regression analysis showed that residence, education level of parents, occupation of parents, nail biting, types of classroom ground and type of boarding were the risk factors on E. vermicularis infection. CONCLUSION: The prevalence of enterobiasis in children is still high in many areas of China, and the prevention and control measures should be taken according to the risk factors. PMID- 24812873 TI - [Tissue localization and expression difference of endogenous beta-glucosidase in digestive system of Musca domestica third instar larvae]. AB - OBJECTIVE: To study the tissue localization and expression difference of endogenous beta-glucosidase in digestive system of Musca domestica third instar larvae. METHODS: The digestive system of the 3rd instar larvae of Musca domestic was taken for the below tests. Tissue localization of endogenous beta-glucosidase mRNA was identified by in situ hybridization. Cellulase was localized by immunohistochemistry. The enzymatic activity of beta-glucosidase was measured by 3, 5-dinitrosalicylic acid(DNS) assay. The relative mRNA expression levels of M. domestica beta-glucosidase gene in these organs were determined by RT-PCR. RESULTS: Beta-glucosidase mRNA, with in situ hybridization, was shown in the epithelial cells of midgut, salivary glands and foregut of the larvae. The immunohistochemical analysis on larvae tissues revealed that cellulase was produced and secreted by the epithelial cells of the midgut, salivary glands and foregut. beta-glucosidase activity in salivary glands, foregut, midgut, and hindgut was (0.80 +/- 0.06), (0.38 +/- 0.02), (1.20 +/- 0.05) and (0.26 +/- 0.02) IU/mg, respectively. There was significant difference in beta-glucosidase activity among these digestive organs (P < 0.05). The activity level of beta glucosidase was highest in midgut [(45.45 +/- 1.27)%], and lowest in hindgut [(9.85 +/- 0.88)%]. However, beta-glucosidase gene were only expressed in the salivary gland, foregut and midgut. Significant differences in gene expression level of beta-glucosidase was found among these organs (P < 0.05). The relative expression quantity of beta-glucosidase gene in midgut and salivary glands were 5 and 3 times higher than that in foregut. CONCLUSION: The endogenous beta glucosidase gene is expressed in the foregut, midgut and salivary glands. The midgut and salivary glands of Musca domestica 3rd instar larvae are the primary organs of this enzyme secretion. PMID- 24812874 TI - [Investigation on pinworm infection and relative factors on prevalence among urban and rural preschool children in Xianyang City]. AB - A total of Eight hundred eighty-six children from 3 to 7 years old in 8 kindergartens were sampled in urban and rural area in Xianyang City from March to May 2012. The cellophane tape swab technique was used to examine pinworm eggs. Children's hygiene habits, clinical symptoms and hygienic condition were surveyed by questionnairing. The total infection rate of pinworm was 11.2% (99/886). The rate in males and females was 10.4% (52/500) and 12.2% (47/386), respectively. The infection rate in rural kindergartens (19.1%, 70/367) was higher than that of urban kindergartens (5.6%, 29/519) (chi2 = 39.39, P < 0.01). Among the investigated children aged 3-7 years, the infection rate in 4-5 years group (12.7%) was the highest, but no statistical difference was found among age groups (P> 0.05). Multivariate logistic regression analysis showed that the hygiene habits such as washing hands before eating (OR = 0.180), drinking unboiled water and eating non-cooked food (OR = 2.473), cleaning perianal region frequently (OR = 0.836), cutting nails frequently (OR = 0.450), drying the quilt regularly (OR = 0.224) and health education (OR = 0.639) were the influence factors on pinworm infection. The main symptoms of pinworm infection include pruritus and bruxism. PMID- 24812875 TI - [Genetic variations of the elastase gene among eight populations of Schistosoma japonicum]. AB - OBJECTIVE: To investigate genetic diversity in the elastase gene among eight Schistosoma japonicum populations, and whether natural selection occur. METHODS: S. japonicum populations were collected from the provinces of Anhui (Tongling and Guichi), Hunan (Yueyang), Hubei (Shashi), Sichuan (Xichang), Yunnan (Eryuan), Taiwan (Puye) in China, and the Philippines. The elastase gene from different populations was amplified by PCR and then sequenced. Watterson's theta, Tajima's pi, dN/dS ratio, Tajima's D and fixation index (F(st)) of each population were calculated. The phylogenetic networks based on the elastase gene were constructed by median-joining algorithm. RESULTS: A total of 73 elestase gene sequences (GenBank No. KF297654-KF297681) were obtained from 8 populations. The sequence analysis indicated that higher genetic diversity was found in the populations from the middle and lower reaches of the Yangtze River (i.e. Tongling City of Anhui, Yueyang City of Hunan), while there was no genetic variations in Hubei or Philippines populations. The value of Tajima's D was positive in Hunan population, while negative in the other populations. The dN/dS ratio was higher than 1 in Tongling population, whereas lower than 1 in Taiwan population. Significant genetic differentiations were observed between Taiwan population and other populations. CONCLUSION: The genetic diversity of the elastase gene among S. japonicum populations is very high, and a high level of gene flow has been detected among the populations from the middle and lower reaches of the Yangtze River. The S.japonicum elastase gene might have been under a positive selection. The level of genetic divergence is the highest between Taiwan population and others. PMID- 24812876 TI - [Screening and evaluation of Schistosoma japonicum SjRibosomal_L18a protein and its B cell epitopes]. AB - OBJECTIVE: To screen a ribosomal protein (SjRibosomal_L18a) of Schistosoma japonicum and predict its B cell epitopes, and evaluate the potential diagnostic value of the recombinant protein and the synthetic B cell epitopes. METHOD: S. japonicum protein sequences were screened and analyzed by using B-cell epitope prediction softwares. The immunogenic protein was selected based on the predicted score and the quantity of epitopes. The epitopes with higher score (P1 and P2) were synthesized. The relative molecular mass (M(r)), isoelectric point, grand average of hydropathicity, signal peptide, and transmembrane domain were predicted by bioinformatics tools. RT-PCR was used to analyze the transcription level of the different development stages. The encoding sequence was amplified by PCR, and cloned into pET28a vector. The recombinant plasmid was transformed into in E. coli BL21 (DE3) cells and induced with IPTG. The recombinant SjRibosomal_L18a protein was purified with Ni-NTA resin. ELISA was used to evaluate the potential diagnostic value of the recombined protein and the synthetic B cell epitopes. RESULTS: SjRibosomal_L18a protein was obtained, its B cell epitopes and physicochemical properties were predicted. The open reading frame of SjRibosomal_L18a was composed of 531 bp, and encoded a 176-amino-acid protein with M(r) 20 741, pI 11.12. RT-PCR result showed that this gene was transcribed at high level in each developmental stage. The recombinant plasmid SjRibosomal_L18a/pET-28a was constructed and the protein was expressed as inclusion bodies (M(r) 26069). The sensitivity and specificity of recombined protein, P1 and P2 were 53.3% (8/15) and 100% (15/15), 60% (9/15) and 100% (15/15), 73.3% (11/15) and 100% (15/15), respectively. CONCLUSION: The recombinant protein (SjRibosomal_L18a) and its epitopes with higher immunogenicity are obtained. The sensitivity of the two epitopes (P1 and P2) was higher than that of SjRibosomal_L18a protein. PMID- 24812877 TI - [Protective effect of radix sophorae flavescentis mixture on intestinal mucosa in mice infected with Cryptosporidium parvum]. AB - OBJECTIVE: To investigate the protective effect of radix sophorae flavescentis (RSF) mixture on intestinal mucosa in mice infected with Cryptosporidium parvum. METHODS: Thirty BALB/c male mice were randomly divided into control group, infection group and RSF mixture treatment group. Mice of the posterior two groups were inoculated intragastrically with 1 x 10(5) C. parvum oocysts, immunosuppressed with dexamethasone (5 microg/ml) and gentamycin sulfate (40 microg/ml) in drinking water. At the 8th day post-infection, mice in RSF mixture treatment group were treated with 0.2 ml dose of RSF mixture twice a week (three day intervals) for three weeks. The mice in infection group and RSF mixture treatment group were monitored for oocyst shedding in fecal pellets every two days after treatment. At 28 days after infection, experimental mice were sacrificed, jejunal tissue was removed for preparation of paraffin-embedded sections. The changes of CD3+, CD4+, CD8+ T lymphocytes and IgA plasmocytes in intestinal mucosa were determined by immunohistochemistry. In addition, jejunum of infected mice and treated mice were collected, and ultrastructural changes were observed under electron microscopy. RESULTS: Compared with infection group, the level of oocyst shedding was obviously lower and the time of the oocyst discharging was significantly shorter in RSF mixture treatment group. The proportion of CD3+, CD4+ T lymphocyte and CD4+/CD8+ T cell ratio in infection group (49.7% +/- 2.4%, 25.7% +/- 2.2%, 1.1 +/- 0.3) were significantly lower than that of treatment group (62.4% +/- 1.4%, 37.5% +/- 3.1%, 1.5 +/- 0.3) and control group (66.5% +/- 1.9%, 40.1% +/- 1.8%, 1.5 +/- 0.2) (P < 0.01). CD8+ T lymphocytes showed no significant difference in each group (P > 0.05). The number of IgA plasmocytes in treatment group (52.7 +/- 3.5) was significantly higher than that of control group (8.3 +/- 2.3) and infection group (33.7 +/- 2.6) (P < 0.01). After administration for three weeks, the damaged C. parvum parasites were seldom seen in mouse jejunum, and lysosomes appeared in large number, RSF mixture treatment improved mitochondrial structure and repaired microvilli. In infection group, mitochondria ridges were significantly broken and microvilli surrounding C. parvum oocysts were shed, resulting in the appearance of crater-like lesions on the surface, the oocyst wall and host cell membrane fused together. CONCLUSION: RSF mixture is effective against Cryptosporidium parvum. The damage of intestinal mucosa in infected mice can be repaired after treatment. PMID- 24812879 TI - Evaluation on the immune response induced by DNA vaccine encoding MIC8 co immunized with IL-12 genetic adjuvant against Toxoplasma gondii infection. AB - OBJECTIVE: To examine the immunoprotection effect induced by MIC8 DNA vaccine co immunized with a plasmid encoding murine IL-12 (pcIL-12) as an adjuvant in mice against the challenge of Toxoplasma gondii. METHODS: The gene sequence encoding MIC8 of T. gondii RH strain was inserted into eukaryotic expression vector pcDNA3.1 to construct the pcMIC8 expression plasmid. The recombinant plasmid was transfected into HeLa cells to test its expression and the recombinant protein was then characterized by Western blotting. Eighty Kunming mice were randomly divided into 5 groups (16 per group): 3 control groups (PBS, pcDNA3.1, and pcIL 12), pcMIC8 group, and pcMIC8 plus pcIL-12 group. Mice in the pcMIC8 plus pcIL-12 group were co-injected intramuscularly at a dosage of 100 microl each of pcMIC8 and pcIL-12 suspended in 100 microg sterile PBS. Mice in other groups were inoculated with PBS, pcDNA3.1, pcIL-12, and pcMIC8 respectively following the same protocol. All the mice received three immunizations at 2-week intervals. Serum samples were collected on day 0, 13, 27, 41, and 55 before each inoculation for determining antibody IgG, IgG subclass IgG2a. Four weeks after the final immunization, IFN-gamma and IL-4 levels in splenocytes cultures from immunized mice were detected by ELISA. The mice were challenged with 10(3) tachyzoites of the virulent T. gondii RH strain three weeks after the last immunization to observe the survival time. RESULTS: Western blotting showed that the protein extracts in HeLa cells upon transfection with pcMIC8 were effectively expressed in cells. The levels of IgG (0.51 +/- 0.028) and IgG2a (0.261 +/- 0.04)(on day 55) in mice immunized with pcMIC8 plus pcIL-12 were higher than pcMIC8 group (497.65 +/- 98.15) and control groups (PBS 47.18 +/- 2.73, pcDNA3.1 50.08 +/- 4.62, pcIL-12 118.15 +/- 12.73) (P < 0.05). There was no significant difference in the level of IgG 1 and IL-4 among the five groups (P > 0.05). After a lethal challenge of T. gondii RH strain, the survival time in mice immunized with pcMIC8 plus pcIL-12 (15d) was prolonged in comparison to that of pcMIC8 (10d) and control groups (PBS 5 d, pcDNA3.1 6d, pcIL-12 8 d) (P < 0.05). CONCLUSION: The immune responses induced by the combined use of the recombinant plasmid encoding MIC8 of T. gondii with murine IL-2 gene adjuvant can be enhanced. PMID- 24812878 TI - [Effect of Toxoplasma gondii infection on thymus cells in rats]. AB - OBJECTIVE: To study the pathological damage of thymus and thymus cell apoptosis of male rats infected with Toxoplasma gondii. METHODS: Fifty Wistar male rats (7 8-week-old) were randomly divided into infection group (40) and control group (10). Rats in infection group were infected with 5 x 10(4) tachyzoites by intraperitoneal injection, while those in control group received same volume of PBS. On the 3rd, 6th, 9th and 12th day post infection, ten rats from infection group and two from control group were sacrificed, the thymus glands were removed. The thymus tissue sections were stained with hematoxylin and eosin (HE) for observation on histopathological changes. Single thymus cell suspensions were prepared. Cell cycle analysis was performed by flow cytometry, and proliferation index was calculated. Thymus frozen sections were stained with Hoechst 33258, and morphologic changes in apoptotic nuclei were observed under fluorescence microscope. Expression of Bcl-2 and Bax proteins were determined by using immunohistochemistry. RESULTS: Microscopic examination showed that pathological changes occurred in thymus grand on the 3rd day after infection. The space between connective tissue capsules was widened, cells in cortex and medulla cells were sparse, and more phagocytes and extravasated blood were found in thymus. On the 6th day post infection the thymus damage was aggravated, and no significant improvement was seen on day 12. On the 3rd, 6th, 9th and 12th day after infection, thymocyte proliferation index was (11.15 +/- 0.99)%, (6.17 +/- 1.02)%, (5.45 +/- 0.96)% and (6.63 +/- 1.52)%, respectively, and each of them was significantly lower than that of the control [(13.81 +/- 1.18)%] (P < 0.01). On the 3rd day after infection, the number of apoptotic cells increased, significantly increased on day 6, and there was no much difference in the number of apoptotic cells between day 6 and day 12. The immunohistochemistry results showed that on the 3rd, 6th, 9th and 12th day post-infection, the gray scale value of Bax positive cells was 88.21 +/- 4.74, 64.69 +/- 6.82, 83.62 +/- 5.79, and 101.09 +/- 6.72, respectively, and each of them was significantly lower than that of the control (128.69 +/- 8.95) (P < 0.01), while there was no significant change in the Bcl-2 protein level (P > 0.05). CONCLUSION: T. gondii causes severe pathological damage in host thymus tissue with a decrease in the proliferation index, an increase in the number of apoptotic cells, and high expression of Bax protein. PMID- 24812880 TI - [Cloning and prokaryotic expression of casein kinase II subunit beta gene fragment of Dirofilaria immitis]. AB - OBJECTIVE: To clone and express the partial fragment of Csnk2b gene of Dirofilaria immitis in prokaryotic cells, and analyze the immunoreactivity. METHODS: The partial fragment of Csnk2b gene was amplified by PCR with a pair of specific primers. The PCR product was cloned into pMD18-T, and then sub-cloned to pGEX-4T-1 expression vector. The constructed plasmid pGEX-4T-1-Csnk2b was transformed into E. coli Rosetta (DE3) and followed by expression of the protein induced by IPTG. The recombinant protein was analyzed by SDS-PAGE and identified by Western blotting. RESULTS: The PCR product was about 700 bp. Enzyme digestion and DNA sequencing confirmed that the recombinant plasmid pGEX-4T-1-Csnk2b was constructed. SDS-PAGE results showed that the relative molecular weight (M(r)) of the fusion protein (GST-Csnk2b) was about 45 000. GST-Csnk2b reacted positively with mouse anti-D. immitis serum. CONCLUSION: The partial Csnk2b gene has been expressed in prokaryotic expression system and shows immunoreactivity. PMID- 24812881 TI - [Biological safety of Aspergillus fumigatus SL-30 to non-target organisms]. AB - OBJECTIVE: To evaluate biological safety of Aspergillus fumigatus SL-30, a potential molluscicide, to non-target organisms. METHODS: A. fumigatus SL-30 spores were scattered in the water (200 ml) from Yangtze River, lake, rain and tap water to forming 6 x 10(6) cfu/ml, the number of spores were then determined and recorded every 2 days. Effect of A. fumigatus SL-30 spores with concentration ranging from 10(4) cfu/ml to 10(6) cfu/ml on Brachydanio rerio, Macrobrachium nippoensis and tadpoles of Rana limnochris was tested by standard laboratory procedure, and survival rate of the above animals in 30 days was recorded. The tests included acute oral toxicity in mice, acute dermal toxicity and acute inhalation toxicity in rats. RESULTS: Spores of A. fumigatus SL-30 can survive for about 12 days in each water samples. Under the spore concentration of 10(4) cfu/ml, 10(5) cfu/ml and 10(6) cfu/ml, there was no significant dose-dependent relationship between spore concentration and survival rate of experiment animals. No significant difference in survival rate was found between the three kinds of aquatic organisms treated with A. fumigatus SL-30 and de-chlorinous water (P > 0.05). According to the experiment results of acute oral toxicity, acute dermal toxicity and acute inhalation toxicity, the acute toxicity of A. fumigatus SL-30 on animal was low. And the animals in experiment group did not show any obvious poisoning symptoms, anatomical abnormalities and pathologic change of the tissues. CONCLUSION: Aspergillus fumigatus SL-30 is comparatively safe to environment and tested non-target organisms. PMID- 24812882 TI - [Dynamic changes in professional and non-professional antigen presenting cells in the spleen from mice infected with Schistosoma japonicum]. AB - OBJECTIVE; To observe the changes in various dendritic cell (DC) subsets, macrophages, basophils, eosinophils and mast cells in mouse spleen before and after Schistosoma japonicum infection induced Th2 response. METHODS: C57BL6 mice were infected with 20 S. japonicum cercariae via abdominal skin. Before infection and at 2, 4, and 6 weeks post-infection, the mice were sacrificed and spleen was removed. The frequencies of non-T, non-B basophils (NTNB), eosinophils, mast cells, subsets of DC and macrophages in the spleen were measured by flow cytometry. RESULTS: At 4 weeks after infection, when Th2 cells started to occur, the proportion of CD11c+CD8+DC and CD11c+CD4+DC in B220CD11c+DC increased from 7.4% and 7.9% before infection to 17.1% and 12.0%, respectively. During the infection, CD11c+CD4-CD8-DC, the majority of B220CD11c+DC, remained on a nearly constant level (70%); the percentage of B220+ CD11c+ DC in NTNB decreased. The macrophages were subdivided into two subsets: F4/80+CD11b(int) and F4/80+CD11b(high). The percentage of F4/80+CD11b(int) and F4/80+CD11b(high) in NTNB dropped from 15.4% and 13.7% before infection to 2.7% and 8.6% at 4 weeks post-infection. The proportion of CD11b high macrophages in F4/80+ cells significantly increased from 47.1% before infection to 75.5% at 4 weeks after infection. During S. japonicum infection, eosinophil percentage in the spleen gradually increased, while the frequency of basophils and mast cells in NTNB greatly decreased. CONCLUSION: At the time when Th2 response starts to occur, the frequency of CD11c+CD8+DC and CD11c+CD4+DC in CD11c+ dendritic cells increases. Once Th2 immune response established, the eosinophil frequency increases. PMID- 24812883 TI - [Investigation of chigger mites on small mammals in a flatland area of Menghan, Xishuangbanna, Yunnan Province]. AB - OBJECTIVE: To investigate the species composition and distribution of chigger mites on small mammals in flatland area in Menghan, Xishuangbanna of Yunnan Province. METHODS: The field investigation was made in a flatland area near Lancangjiang River in Menghan, Xishuangbanna of Yunnan Province. Small mammals were captured with mouse cages and traps. All mites on the hosts were collected and preserved in 70% ethanol. Hoyer's solution was used to mount the chiggers on glass slides. The specimens of the chigger mites on the slides were finally identified into species under microscope. The constituent ratio, infestation rate, mean abundance and mean intensity of chigger mites in different habitats or on different hosts were used to measure the community structure. The species richness and community diversity were analyzed. RESULTS: A total of 233 small mammal hosts were captured (belonging to 2 families, 3 genera and 5 species). 5 763 individuals of chigger mites were identified as 2 subfamilies, 7 genera, and 45 species. Rattus tanezumi (R. flavipectus) was the dominant species among the captured hosts, accounting for 97.4% (227/233). The mite infestation rate, average ectoparasite abundance, and mean mite intensity on R. tanezumi was 56.4% (128/227), 24.7 (5 600/227) and 43.8 (5 600/128), respectively. Leptotrombidium deliense was dominant chigger mite species and account for 57.9% (3 337/5 763), mainly infested R. tanezumi. Compared with indoor and cultivated field habitats, the species richness and community diversity of chigger mites in shrub habitat were higher, and 41 species of chigger mites were collected. CONCLUSION: The species composition and community structure is relatively simple in the flatland area in Xishuangbanna. L. deliense is the most dominant species of chigger mites and its main host is R. tanezumi. PMID- 24812884 TI - [Influence factors of Schistosoma japonicum infection among fishermen in eastern Dongting Lake Region]. AB - OBJECTIVE: To investigate schistosome infection among the professional fishermen in Yueyang County, East Dongting Lake Region and its influence factors. METHODS: A total of 275 fishermen from two fisherman villages in Yueyang County were selected in 2009. They were investigated by fecal examination and questionnairing. The stool-egg positive individuals were detected by B ultrasound. The multivariate unconditional Logistic regression analysis was used to explore the related factors of schistosome infection and liver in fishermen. RESULTS: The total infection rate in fishermen was 40.4% (111/275), and the geometric mean of EPG was 17.4 +/- 4.4. B ultrasound data showed among 111 egg positive individuals, 39 (35.1%) cases manifested as hepatomegaly, 22 (19.8%) had splenomegaly, 11 (9.9%) had portal vein expansion and 65 (58.6%) had hepatic fibrosis. Multivariate unconditional Logistic regression analysis showed that age groups (OR = 0.630), fishing working years (OR = 2.470), chemotherapy frequency (OR = 0.425) and chemotherapy in 2008 (OR = 0.290) were the influence factors on schistosome infection (P < 0.01). CONCLUSION: Schistosome infection rate is high, Schistosoma japonicum-induced liver and spleen injuries are still severe in fisherman of Eastern Dongting Lake Region. PMID- 24812885 TI - [Prospect on the investigation of sandflies (Diptera: Psychodidae) in China]. AB - Through literature review of the investigations on relevant sandflies (Dipter: Psychodidae) and his personal practical experience over the years, the author raises 5 issues referring to the taxonomy and biology of sandflies, density surveillance, transmission of Leishmania parasites, and their distribution status which need to be further studied, and the author looks forward to an attention from medical entomologists in China. PMID- 24812886 TI - [Research advances in s48/45 protein family of Plasmodium falciparum]. AB - The s48/45 domain is a beta-sandwich fold domain, and usually includes 6 cysteines. Proteins containing s48/45 domain exist in each developmental stages of Plasmodium parasite, and play an important role in the invasion into host cells. According to the features and functions of the protein molecule, members of the s48/45 protein family could be used as the vaccine candidates against Plasmodium falciparum in different stages. This article focuses on the research progress of P. falciparum protein family containing s48/45 domain. PMID- 24812887 TI - [Research progress on genotype and genotype-associated pathogenesis of Toxoplasma gondii]. AB - Toxoplasmosis is a disease caused by the protozoan Toxoplasma gondii, which is widely prevalent in animals and human throughout the world. It causes serious harm to human health and the development of animal husbandry. T. gondii isolates were considered a single species without geographical boundaries. However, high diversity has been revealed within and between T. gondii populations collected from around the world defined by the multi-locus enzyme electrophoresis (MLEE), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or microsatellite analysis. Different strains of T. gondii may exhibit differences in virulence to mice. This paper summarizes the research progress on the genotypes from T. gondii isolates in different geographic regions around the world, and the relationship between genotype and virulence of T. gondii. PMID- 24812888 TI - [Enhancement of in vitro protoscolicidal effects of high-intensity focused ultrasound by a superabsorbent polymer and ultrasound contrast agent]. AB - This study evaluated whether or not a superabsorbent polymer (SAP) combined with ultrasound contrast agent (UCA) could enhance damage efficacy of high intensity focused ultrasound (HIFU) on Echinococcus granulosus protoscoleces in vitro. Thirty test tubes each with 6 000-7 500 protoscolices were divided into 5 groups: group A (blank control) without HIFU treatment, group B treated with HIFU (50 W) only, group C treated with 10 microl UCA and HIFU, group D treated with 0.01 g SAP and HIFU, group E treated with 10 microl UCA, 0.01 g SAP, and HIFU. In group B, echo enhancement of ultrasound image, suspension temperature (26.0 degrees C +/- 0.2 degrees C) and protoscoleces mortality (30.4%) were higher than that of group A (18.0 degrees C +/- 0.1 degrees C, 1.9%) (P < 0.01). Compared with group B, the echo enhancement of ultrasound image, suspension temperature (27.0 degrees C +/- 0.2 degrees C, 28.2 degrees C +/- 0.2 degrees C) and protoscoleces mortality (50.0%, 53.7%) of groups C and D increased significantly (P < 0.01). In group E, more protoscoleces were stained in red and their internal structures were indistinct. By chi-square test, the protoscoleces mortality of group E (69.7%) was higher than that of groups C and D (P < 0.01). There was no significant difference in suspension temperature among the 3 groups. PMID- 24812889 TI - [Allergen detection among 2 769 children with allergic symptoms in Ningbo area]. AB - A total of 2 769 children with allergic disease were admitted from October 2010 to December in Ningbo Women & Children's Hospital. Fourteen kinds of serum specific-IgE were detected by immunoblotting method. Among the 2 769 children, the total positive rate of sIgE was 76.0% (2 105/2 769). The sIgE positive rate in males (80.0%, 1 344/1 679) was significantly higher than that of females (69.8%, 761/1 090)(P < 0.05). The top three allergens were dust mites (33.2%), milk (12.6%) and fungi (12.6%). There were statistical differences of positive reaction to dust mites among 4 seasons (19.4%, 33.9%, 39.3%, 36.0%) (P < 0.05). Significant differences were found in the positive rates of dust mites, milk, fungi, and egg among the age groups (P < 0.05). The level of dust mite specific IgE were mainly in grade 3-6 (613/918, 66.8%). PMID- 24812890 TI - [Consensus of diagnosing and treating acute myocardial infarction by integrative medicine (draft)]. PMID- 24812891 TI - [Effect of Kuanxiong aerosol on coronary heart disease angina patients: a multicenter randomized controlled clinical study]. AB - OBJECTIVE: To evaluate the anginal attack-relieving efficacy and safety of Kuanxiong Aerosol (KA) in patients with coronary heart disease (CHD). METHODS: A total of 780 patients confirmatively diagnosed as CHD angina from November 2011 to December 2012 in 13 medical centers in the mainland area were assigned to 2 groups by blocked randomization, the treatment group (376 cases) and the control group (374 cases). When the angina attacked, patients in the treatment group received sublingual spray three times, 0.6 mL each time, while those in the control group sublingually dissolved Nitroglycerin Tablet (NT), 0.5 mg each tablet. The effective rate of angina relief, efficacy of electrocardiogram (ECG), and the incidence of adverse reactions were observed. RESULTS: The 3 min and 5 min remission rates of angina attack were 53.72% (202/376) and 94.41% (355/376) in the treatment group, and 47.86% (179/374) and 90.64% (339/374) in the control group. The 95% confidence interval (CI) of the difference between the 2 groups of 3 min and 5 min remission rates of angina attacks were [(-1.84%, 12.32%) and ( 1.33%, 6.85%) respectively, P > 0.05]. The total improvement rates of ST-T changes in the treatment group and the control group after treatment were 74.07% and 73.13% respectively (P > 0.05). The adverse reaction rate was 9.31 (35/376 cases) in the treatment group and 22.46% (84/374 cases) in the control group (P < 0.01). CONCLUSION: KA was not inferior to NT in relieving anginal attacks and improving ischemic ECG changes, and had obviously less adverse reaction. PMID- 24812892 TI - [Changes of left ventricular remodeling in hypertension patients with carotid atherosclerosis of phlegm-dampness syndrome]. AB - OBJECTIVE: To study changes of left ventricular remodeling (LVR) in hypertension patients with carotid atherosclerosis (CAS) of phlegm-dampness syndrome (PDS). METHODS: Doppler ultrasonography data of CAS were observed in 223 hypertension patients with CAS (as the hypertension group, including 119 patients of the PDS group and 104 of the non-PDS group), 81 CAS patients with non-hypertension, and 19 non-hypertension non-CAS patients (as the control group). The difference in the degree of LVR was compared among the above groups. RESULTS: The left ventricular posterior wall thickness (LVPWT), inter ventricular septum thickness (IVS), E/A were higher in the hypertension group than in the non-hypertension group (P < 0.05). The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic diameter (LVESD), stroke volume (SV) were higher in the soft plaque hypertension group and the soft plaque non-hypertension group than in the hard plaque group, the thickening intimal group, and the normal intimal group (P < 0.01 , P < 0.05). The LVEDD, LVESD, and SV were higher, and the ejection fraction (EF) was lower in the PDS hypertension group than in the non-PDS hypertension group (all P < 0.05). Of them, LVEDD, LVESD, and SV were higher in the soft plaque group than in the hard plaque group (P < 0.01), the thickening intimal group (P < 0.01) and the normal intimal group (P < 0.05). There was no statistical difference in PDS hypertension between the soft plaque group and the hard plaque group (P > 0.05). CONCLUSION: The hypertension patients with CAS of PDS might be correlated to LVR, and LVR was more obviously in the soft plaque patients. PMID- 24812893 TI - [Assessing Chinese herbal medicines for benefiting qi and activating blood circulation in treating unstable angina based on Markov model: a long-term clinical effectiveness exploration]. AB - OBJECTIVE: To assess the long-term clinical effectiveness of Chinese herbal medicines for benefiting qi and activating blood circulation (CHMBQABC) plus routine Western medical intervention in treating unstable angina (UA) patients of qi deficiency blood stasis syndrome (QDBSS) after percutaneous coronary intervention (PCI) based on Markov model. METHODS: A Markov model was established based on prognosis and sequelae of UA patients after PCI treated by CHMBQABC plus routine Western medical intervention or by routine Western medical intervention. According to the transition probabilities of 40 Markov cycles and quality adjusted life years (QALYs) averagely gained, we assessed the therapeutic advantage of CHMBQABC plus routine Western medical intervention. RESULTS: By the prediction of Markov model for 20 years, the transition probabilities of revascularization, non-fatal myocardial infarction, non-fatal stroke, and all cause death in the CHMBQABC plus routine Western medical intervention group was 56.65%, 6.53%, 5.16%, and 31.66%, respectively, and the QALYs averagely gained was 12.95; while the transition probabilities of revascularization, non-fatal myocardial infarction, non-fatal stroke, and all-cause death in the Western medical intervention group was 55.31%, 6.87%, 5.25%, and 32.57%, respectively, and the QALYs averagely gained was 12.84. Compared with the Western medical intervention group, the QALYs averagely gained was 0.11 in the CHMBQABC plus routine Western medical intervention group. CONCLUSION: Based on predicted results of the Markov model, CHMBQABC plus routine Western medical intervention got better efficacy in treating UA patients after PCI, indicating CHMBQABC plus routine Western medical intervention could improve the long-term clinical effectiveness for UA patients of QDBSS after PCI. PMID- 24812894 TI - [Efficacy and safety of integrative medical program based on blood cooling and detoxification recipe in treating patients with hepatitis B virus related acute on-chronic liver failure: a randomized controlled clinical study]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of integrative medical program based on blood cooling and detoxification recipe (BCDR) in treating patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) of heat-toxicity accumulation syndrome (HTAS). METHODS: Adopting randomized controlled clinical design, a total of 105 HBV-ACLF patients of HTAS were randomly assigned to the trial group (64 cases) and the control group (41 cases). Patients in the control group were treated with comprehensive Western therapy, while those in the trial group were treated with comprehensive Western therapy plus BCDR. All were treated for 8 weeks and followed up for 40 weeks. Effect and safety of the treatment were assessed, including fatality, liver functions [total bilirubin (TBIL), albumin (ALB), alanine aminotransferase (ALT), and aspartate transaminase (AST)], and prothrombin activity (PTA) after treatment and at week 48 of follow-ups. RESULTS: After 8-week treatment, there was statistical difference in the overall fatality rate (15.63% vs 34.15%), the fatality rate in the mid-term (25.0% vs 64.7%), TBIL at week 8 (64.54 +/- 79.75), AST [at week 2: (178.97 +/- 44.24) U/L vs (288.48 +/- 58.49) U/L; at week 4: (61.65 +/- 27.36) U/L vs (171.12 +/- 89.11) U/L] and PTA [at week 4: (58.30 +/- 15.29) vs (42.56 +/ 15.27); at week 6: (60.77 +/- 20.40) vs (43.08 +/- 12.79)] (all P < 0.05). At week 48 of the followup, the fatality rate of the trial group (21.88%) decreased by 17. 14% when compared with that of the control group (39.02%; P < 0.05). No obvious adverse event occurred in the two groups during the 8-week treatment period. CONCLUSION: BCDR could significantly reduce the mortality of HBV-ACLF patients. PMID- 24812895 TI - [Functions of T lymphocytes mediated by in vitro dendritic cells of chronic HBV infection patients in different immune states: a clinical research]. AB - OBJECTIVE: To explore the improvement of dendritic cells' (DCs) functions in chronic hepatitis B (CHB) patients by two different drugs plasma, i.e., Shen supplementing and detoxification (SSD) and Pi invigorating and detoxification (PID), thus comparing which method was more effective to activate DCs to improve T lymphocyte functions. METHODS: Totally 30 CHB outpatients were recruited. They were assigned to the immune tolerant group and the immune clearance group, 15 in each group. Totally 60 mL peripheral blood was extracted to isolate and develop mature DCs. Chinese compound containing (Liuwei Ganlu Syrup for SSD) and (Sijun Ganlu Syrup for PID) plasma were added to promote the maturation of DCs on the 7th day. Besides, non-drug plasma was taken as the control. On the ninth day, HBV core 18-27 loaded core peptide and its own T lymphocyte were co-cultivated for 72 h. Then T lymphocytes were collected. The expression levels of CD3, CD28, CD4, and CD8, programmed death-1 (PD-1) were detected using flow cytometry. RESULTS: Compared with non-drug plasma, the expression levels of CD3, CD4, and CD28 could be improved, and the expression levels of CD8 and PD-1 could be reduced by the two methods, showing statistical difference (P < 0.05). Besides, SSD containing plasma showed better effect in improving the molecular CD28 expression rate, and reducing the molecular PD-1 expression rate on the T cell surface, showing statistical difference when compared with that of PID containing plasma (P < 0.05). CONCLUSIONS: In vitro intervention of DCs by SSD and PID containing plasmas combined co-cultivation of its own T lymphocytes could promote the activation of DCs to improve the function of T cells and the expression of T cell surface molecules. Besides, SSD showed more significant effect on infection immune of HBV patients in the tolerance stage. PMID- 24812896 TI - [Efficacy of tongfu mixture for treating post-ERCP pancreatitis: a clinical study]. AB - OBJECTIVE: To observe the clinical efficacy of Tongfu Mixture (TM) for post-ERCP pancreatitis (PEP). METHODS: Totally 54 PEP patients were randomly assigned to the control group (treated by routine therapy, 26 cases) and the TM treatment group (treated by TM, 28 cases). Clinical indices including the alleviation time of abdominal pain/distention, gastrointestinal function recovery time, and the post-surgical length of stay were observed. Blood amylase (AMY), C-reactive protein (CRP), plasma endotoxin (PLS), TNF-alpha, and IL-6 were detected before surgery, 12 h, 48 h, and 96 h after surgery. RESULTS: The alleviation time of abdominal pain/distention, the gastrointestinal function recovery time, and the post-surgical length of stay were obviously shorter in the TM treatment group than those in the control group (P < 0.05). The recovery of AMY and CRP were better in the TM treatment group than in the control group at post-operative 48 h and 96 h (P < 0.05). The levels of LPS, TNF-alpha, and IL-6 were lower in the TM group than in the control group at post-operative 96 h (P < 0.05). CONCLUSION: TM showed better clinical efficacy and could significantly decrease the post surgical length of stay. post-ERCP pancreatitis; integrative medicine; Tongfu Mixture PMID- 24812897 TI - [Xifeng zhidong tablet and the placebo control treatment of tic disorder children patients of internal disturbance of Gan-wind with phlegm syndrome: a clinical study]. AB - OBJECTIVE: To assess the efficacy and safety of Xifeng Zhidong Tablet (XZT) in treating tic disorder children patients of internal disturbance of Gan-wind with phlegm syndrome (IDGWPS). METHODS: A stratified randomized, double-blinded, parallel control of placebo, multi-center trial was conducted in 160 subjects from 5 hospitals in China. They were randomly assigned to 2 groups, the test group and the control group, 80 in each group. Those in the test group were treated with XZT, while those in the control group were treated with placebos. The therapeutic course was 4 weeks for all. The effectiveness indicators covered main indicators and secondary indicators. Yale global tic severity scale (YGTSS) was taken as the main indicators. The amelioration of social function impairment, efficacy, single index of Chinese medical syndromes, Chinese medical syndrome efficacy as well as disappearance rate of single Chinese medical symptoms were evaluated as secondary indicators. The safety indicators included clinical adverse events, vital signs, blood/urine/stool routines, renal and liver functions, and electrocardiogram (ECG). RESULTS: As for main indicators, the score of YGTSS decreased from 22.10 +/- 6.38 to 11.34 +/- 6.58 in the test group, while it decreased from 22.65 +/- 6.70 to 16.82 +/- 6.53 in the control group, showing statistical difference when compared with the same group before treatment (P < 0.01). Besides, the decrement was more significant in the test group after treatment (P < 0.05). As for secondary indicators, the total effective rate was 83.54% in the test group and 34.18% in the controlled group, showing statistical difference between the two groups (P < 0.05). As for social function impairment, 20,38, 16, 3, 1 case(s) in the test group were ranked as normal, minimal, mild, moderate, obvious degree, while 1, 24, 45, 7, and 0 case(s) in the control group were ranked as normal, minimal, mild, moderate, obvious degree. Better effect was obtained in the test group (P < 0.05).As for Chinese medical syndrome efficacy, it was 87.34% in the test group and 64.56% in the control group (P < 0.05). As for single index of Chinese medical syndromes, the disappearance rate of motor tics, irritability, dreaminess, abnormal tongue proper,abnormal tongue fur, and abnormal tongue pulse condition was 78.67%, 34.72%, 62.26%, 34.62%, 58.97%, and 39.74%, respectively in the test group, while they were 34.67%, 13.11%, 21.82%, 15.58%, 25.97%, and 19.48%, respectively in the control group. Better results were shown in the test group (P < 0.05). Totally 5 adverse events occurred. The incidence of adverse events was 3.75% in the test group and 2.53% in the control group. CONCLUSIONS: After 4 weeks of XZT treatment, the integral of YGTSS could be obviously reduced, the degree of social function impairment ameliorated, and Chinese medical syndromes improved. In addition, no adverse reaction occurred in this study. PMID- 24812898 TI - [Treatment of cerebral palsy children by integrative medical sequential method: a clinical efficacy observation]. AB - OBJECTIVE: To observe the efficacy of integrative medical sequential method in treating cerebral palsy (CP) children's intelligence development, muscular tension, serum interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). METHODS: Totally 111 CP children were randomly assigned to the control group (50 cases) and the treatment group (61 cases). All patients received comprehensive rehabilitation training and intravenous dripping of Monosialotetrahexosylganglioside Sodium Injection for 10 days. But those in the treatment group additionally received Chinese medical enema for brain resuscitation, relieving rigidity of muscles and activating collaterals for 14 days. Then they started another medication cycle and lasted for a total of 6 cycles. Serum IL-6 levels and TNF-alpha contents were determined before treatment. Scoring for muscular tension, Gesell score for intelligence development, contents of serum IL-6 and TNF-alpha were assessed before and after treatment in the two groups. RESULTS: Compared with before treatment in this group, muscular tension, Gesell scores for intelligence development all decreased in the two groups (P < 0.05). As for inter-group comparison, the decrement was more obvious in the treatment group than in the control group (P < 0.05). The total effective rate was 86.9% in the treatment group and 76.0% in the control group (P < 0.05). The contents of IL-6 and TNF-alpha were obviously reduced in the treatment group and the control group after treatment (P < 0.01). The decrement was more obvious in the treatment group (P < 0.05). CONCLUSION: The two treatment methods were effective for CP children, but the efficacy was superior in the treatment group than in the control group, indicating integrative medical methods could play a synergistic effect and optimize the treatment program for CP. PMID- 24812899 TI - [Effect of Ningdong Granule on the levels of IL-12 and TNF-alpha in children patients with Tourette's syndrome]. AB - OBJECTIVE: To observe the effect of Ningdong Granule (NG) on serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) of children patients with Tourette's syndrome (TS). METHODS: Totally 90 TS children patients were randomly assigned to the NG group, the NG + Tiapride group (abbreviated as the combined treatment group), and the Tiapride group, 30 in each group. Besides,another 30 healthy children were recruited as the healthy control group. Patients in the NG group were treated with NG (consisting of all gastrodia rhizome, Codonopsis pilosula, Ophiopogon japonicus, white peony root, Rhinocerotidae, oyster, earthworm, licorice root, etc.), one dose daily, administered by dissolving it in boiled water, taken in two portions in the morning and in the evening respectively. Patients in the Tiapride group took Tiapride Tablet, 50 -100 mg each time, twice daily. The dosage was adjusted according to individual difference and changes of pathogenic conditions. The maximal dosage was 300 mg per day. Those in the combined treatment group were treated with equal dose of NG and Tiapride Tablet in combination. The treatment course was 3 months for all. Changes of pathogenic condition before and after treatment were assessed by Yale global tic severity scale (YGTSS). Serum levels of IL-12 and TNF-alpha were detected by enzyme-labeled immunosorbent assay (ELISA) before and after treatment. RESULTS: (1) The total effective rate of the NG group, the combined treatment group, and the Tiapride group was 79.3%, 83.3%, and 67.9%, respectively. It was the lowest in the Tiapride group (P < 0.05). It was significantly higher in the combined treatment group than in the NG group (P < 0.05). (2) The post-treatment YGTSS score was obviously lower in each group after treatment than before treatment (P < 0.05). The posttreatment YGTSS score was obviously lower in the NG group and the combined treatment group than in the Tiapride group (P < 0.05), but with no statistical difference between the fromer two groups (P > 0.05).(3) Compared with the healthy control group before treatment, serum levels of IL-12 and TNF-alpha (pg/mL) were 124.95 +/- 22.78 and 209.52 +/- 21.69 in the NG group, 126.14 +/- 25.65 and 208.97 +/- 22.46 in the combined treatment group, 123.00 +/- 24.26 and 205.10 +/- 26.16 in the Tiapride group, being higher than those in the healthy control group (64.56 +/- 27.59 and 78.13 +/- 33.42; P < 0.05). After treatment, serum levels of of IL-12 and TNF alpha were 104.67 +/- 16.84 and 183.01 +/- 24.95 in the NG group, 109.04 +/- 16.81 and 179.87 +/- 23.45 in the combined treatment group, significantly lower than before treatment (P < 0.05). But there was no statistical difference in serum levels of IL-12 or TNF-alpha in the Tiapride group between before treatment (123.00 +/- 24.26 and 205.10 +/- 26.16) and after treatment (117.75 +/- 16.79 and 199.76 +/- 33.21; P > 0.05). CONCLUSION: NG could modulate abnormal serum levels of IL-12 and TNF-alpha in TS children patients, which might be one of its pharmacodynamic mechanisms for treating TS. PMID- 24812900 TI - [Treating primary dysmenorrhea by lingtong capsule: a randomized double-blind clinical observation]. AB - OBJECTIVE: To observe the clinical effect of Lingtong Capsule (LC) in treating primary dysmenorrhea (PD). METHODS: Totally 59 PD patients took LC, while 59 patients in the placebo group took placebo capsule, two pills immediately when they felt dysmenorrhea. Their pain levels were quantitatively classified. The pain score was assessed at an interval of 30 min using visual analogue scale/score (VAS) while taking medicine and within two h after taking medicine. It was assessed as effective when the pain level was reduced by more than or equal to 50% within 2 h. RESULTS: The total effective rate was 69.49% (41/ 59) in the LC group and 20.34% (12/59) in the placebo group (P < 0.01). The analgesia effect was obviously superior in the LC group 60 min after taking medicine (P < 0.01). LC showed better effect in treating mild, moderate, and severe PD (P < 0.05). CONCLUSION: LC showed obvious analgesia effect on PD. PMID- 24812901 TI - [Effect of Qiju Dihuang Pill on serum levels of IFN-gamma and IL-4 in pregnant women of Gan-Shen yin deficiency syndrome]. AB - OBJECTIVE: To observe the effect of Qiju Dihuang Pill (QDP) on changes of Chinese medical syndrome types in pregnant women of Gan-Shen yin deficiency syndrome (GSYDS), and to explore the correlation between imbalanced cytokine levels and GSYDS. METHODS: This was a random controlled trail. A total of 163 pregnant women of GSYDS at 12 -16 gestational weeks were randomly allocated into the experimental group (86 cases) and the control group (77 cases). Patients in the experimental group took QDP for 2 -4 weeks. Changes of Chinese medical syndrome types and serum interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels were observed and compared between the two groups before and after treatment. RESULTS: (1) Totally 41 patients (47.7%) in the experimental group were transformed to normal Chinese medical syndrome type. In the same period of the follow-ups, 9 patients (11.7%) in the control group were transformed to normal Chinese medical syndrome type, showing statistical difference (P < 0.05). (2) In the experimental group, the serum level of IFN-gamma and the ratio of IFN-gamma/IL-4 in the peripheral blood were obviously lower after treatment than before treatment (P < 0.01), and obviously lower than those in the control group (P < 0.01). The level of IL-4 after treatment in the experimental group was higher than that before treatment, and also higher than that in the control group, but with no statistical difference. CONCLUSIONS: These results indicated that there was imbalanced IFN-gamma/IL-4 ratio in the peripheral blood of pregnant women of GSYDS. QDP might play a role in immunoregulation by affecting the IFN-gamma level. PMID- 24812902 TI - [Assessing drug targeting of Yougui Pill, Zuogui Pill, and their disassembled prescriptions using infrared thermography]. AB - OBJECTIVE: To dynamically assess drug targeting of Yougui Pill (YP) and Zuogui Pill (ZP) using infrared thermography. METHODS: In this self-control experiment, five healthy volunteers were recruited. By using infrared thermography 10 to 11 thermal images of different body locations were taken from each participant after they took warm water, YP, ZP, and their dissembled prescriptions at 30, 70, 100, 130, and 160 min, respectively. The heat values in the lower quadrant abdomen, uterus, Du channel, and Shenque (CV8) were statistically analyzed after scanning for 125 times. RESULTS: Administration of YP and its disassembled prescriptions enhanced the heat value of the locations of the Du channel and Shenque (CV8), but did no enhance the heat value of the lower quadrant abdomen at 30 min. Administration of ZP and its disassembled prescriptions reduced the heat value in the locations of the lower quadrant abdomen, uterus, Du channel, and Shenque (CV8) at each time point. CONCLUSION: The drug targeting of ZP and YP focused on the locations of the Du channel and Shenque (CV8), not on the locations of the lower quadrant abdomen or uterus. PMID- 24812903 TI - [Effect of Weifuchun on inhibiting inflammation of Helicobacter pylori-infected GES-1 cells and NF-kappaB signaling pathway]. AB - OBJECTIVE: To study the effect of Weifuchun on inflammation of Helicobacter pylori (Hp)-infected gastric epithelial cells (GES-1) and its correlation with NF kappaB signaling pathway. METHODS: Hp standard home-made strain (CagA +, VacA +) NCTCI 1637 infected GES-1 cells were used. Weifuchun was used as intervention. Weifuchun of different concentrations (5,10, and 20 microg/mL) were screened by MTT assay. A blank group and the model group were set up. Then the growth inhibition rate of drugs on gastric epithelial GES-1 cells was detected with MTT assay. Cell cycle was detected using flow cytometry. The supernatant liquid was separated to detect the contents of IL-8 and IL-4 by ELISA.The protein expression level of NF-kappaB was detected by Western blot analysis. RESULTS: MTT assay indicated significantly inhibitory effect of Weifuchun on GES-1 cells [5% inhibiting concentration (IC5)] was 10 microg/ml in the Weifuchun group. After GES-1 and Hp were cultured together,the contents of IL-8 in the supernatant were more obviously higher in the model group than in the blank group (P < 0.05), and then gradually decreased. After treatment with different concentrations of Weifuchun, the levels of IL-8 in the supernatant were less when compared with the model group at 12, 24, 48, and 72 h (P < 0.05). The decrement was the most significant in the high dose Weifuchun group. The IL-4 level in the supernatant was obviously lower in the model group than in the blank group. It obviously increased in the high concentration Weifuchun group (P < 0.05). There was no statistical difference in the IL-4 level between middle, low concentration Weifuchun group and the blank group (P > 0.05). The protein expression of intranuclear P65 increased and that of IkBalpha decreased 60 min after Hp infection. But the protein expression of intranuclear P65 decreased and the protein expression of IkBalpha increased after intervention of Weifuchun. CONCLUSIONS: Weifuchun adjusted H. pylori induced IL-8 and IL-4 production by gastric epithelial cells through blocking NF-kappaB pathways. Its mechanisms might possibly lie in inhibiting p65 from entry into nucleus and the degradation of IkBalpha. Weifuchun was an effective drug for treatment of Hp correlated chronic gastritis. PMID- 24812904 TI - [Exploration of the theory of "Fei and Dachang being interior-exteriorly related" from observing changes of inflammatory cytokines and oxygen free radicals in the lung tissue of ulcerative colitis rats]. AB - OBJECTIVE: To explore the theory of "Fei and Dachang being interior-exteriorly related" and the pathogenesis of lung injury by observing changes of inflammatory cytokines and oxygen free radicals in ulcerative colitis (UC) rats. METHODS: Totally 50 healthy male Wistar rats were randomly divided into two groups, the normal control group and the model group, 25 rats in each group. The UC model was established by allergizing colon mucosa combined with TNBS-alcohol (50%) enema. Another 25 rats were recruited as the normal control group. At week 2 and 4 after modeling, the pathomorphological changes of the lung were observed. Furthermore, the contents of tumor necrosis factor alpha (TNF-alpha) and IL-1beta were determined by ELISA. The activities of superoxide dismutase (SOD) and malondialdehyde (MDA) were evaluated with colorimetry. RESULTS: Compared with the normal control group, the pathomorphology of the lung tissue in the model group appeared abnormal at week 2 and 4. Compared with the normal control group, levels of TNF-alpha, IL-1beta, and MDA in the lung tissue significantly increased in the model group (P < 0. 01) and the activities of SOD significantly decreased (P < 0.05, P < 0.01). CONCLUSION: TNF-alpha, IL-1beta, SOD, and MDA might be common material bases for the large intestine involved in lung disease of UC patients, thus providing a modern scientific basis for the theory of Fei and Dachang being interior-exteriorly related. PMID- 24812905 TI - [Effect of Ginkgo biloba extract on the function of alveolar polymorphonuclear neutrophils in severe acute pancreatitis rats complicated with lung injury]. AB - OBJECTIVE: To explore the effect of Ginkgo biloba extract (GBE) on the function of alveolar polymorphonuclear neutrophils (PMN) in severe acute pancreatitis (SAP) rats complicated with lung injury (LI). METHODS: Forty-eight adult SD rats were randomly divided into three groups, i.e., the sham-operation group, the SAP group, and the GBE treatment group, 16 in each group. The SAP model was successfully induced by retrograde injection of 5% sodium taurocholate solution into the biliopancreatic duct. Rats in the sham-operation group only received flipping of the duodenum. Those in the GBE treatment group received GBE intervention based on SAP model. Equal volume of normal saline was given to rats in the sham-operation group and the SAP group. Rats were sacrificed at 6 and 12 h after operation respectively. The lung tissue was sampled to evaluate the LI score. The wet/dry ratio (W/D) of lung tissues was detected. The activity of myeloperoxidase (MPO) was measured. Alveolar PMN was harvested by bronchoalveolar lavage. The content of neutrophil elastase (NE) in bronchoalveolar lavage fluid (BALF) was measured by enzyme-linked immunoabsorbent assay (ELISA). The percentage of CD11b/CD18 double positive PMN was detected using flow cytometry. The expression of intercellular adhesion molecule-1 (ICAM-1) and NE protein in the lung tissue was detected by Western blot. RESULTS: Compared with the sham operation group, significant pathologic lesion occurred in the lung tissue of rats in the SAP group; the pathologic LI score, lung tissue W/D ratio, MPO, and NE content in BALF significantly increased, the expression of ICAM-1 and NE in the lung tissue was obviously up-regulated, and the percentage of CD11b/CD18 double positive PMN significantly increased (P < 0.01). Compared with the SAP group, pathological lesion of the lung tissue was obviously attenuated, and the above indices were all significantly declined in the GBE treatment group (P < 0.01). CONCLUSIONS: Expression of ICAM-1 in the lung tissue and the percentage of D11b/ CD18 double positive PMN were up-regulated in SAP rats complicated with LI, resulting in the adherence of PMN to pulmonary vascular endothelial cells, and then activating PMN to release NE and aggravate LI. GBE could alleviate LI through down-regulating the expression ICAM-1 and CD11b/CD18, and hindering the adherence and activation of PMN to pulmonary vascular endothelial cells. PMID- 24812906 TI - [Effect of jujube on the expression of CYP2E1 and TNF-alpha in the hepatic tissue of mice with alcoholic liver disease]. AB - OBJECTIVE: To observe the effect of jujube pretreatment on serum levels of AST and ALT, liver pathology, and the expression of cytochrome P4502e1 (CYP2E1) and tumor necrosis factor-alpha (TNF-alpha) in the liver tissue of alcoholic liver disease (ALD) mice. METHODS: Totally 88 Kunming mice were randomly divided into the control group (n = 28), the model group (n = 32), and the jujube treatment group (n = 28). The animal model was prepared using intragastric alcoholism for mice in the model group and the jujube treatment group, while distilled water was intragastrically given to those in the control group. Extraction of jujube was intragastrically given to mice in the jujube treatment group at week 4, while equal volume of distilled water was intragastrically given to mice in the rest two groups. The therapeutic course lasted for 12 weeks. Serum levels of AST and ALT, liver pathology, and the expression of CYP2E1 and TNF-alpha in the liver tissue of ALD mice were observed after administration of jujube. RESULTS: Compared with the model group, serum levels of AST and ALT decreased, the liver pathology was improved, and the expression of CYP2E1 and TNF-alpha in the liver tissue decreased, showing statistical difference (P < 0.05). CONCLUSION: Jujube had certain effect in treating ALD. PMID- 24812907 TI - [Effect of Xiaoyao Powder on the ethology, morphology, and activities of neurotransmitters of Alzheimer's disease model mice]. AB - OBJECTIVE: To investigate the effect of Xiaoyao Powder (XP) and its compatible prescriptions on the ethology, morphology, and activities of neurotransmitters, thus exploring their effects and mechanism in preventing and treating D-galactose induced Alzheimer's disease (AD) model mice, and clarifying the compatibility mechanism for soothing Gan, nourishing blood, and invigorating Pi. METHODS: Sixty SPF mice were randomly divided into the blank control group, the model group, and the XP group, Shugan Jianpi group (SJ), Shugan Yangxue group (SY), and Jianpi Yangxue group (JY), 10 in each group.The AD mouse model was prepared by peritoneal injecting D-galactose. Meanwhile, mice in the blank control group and the model group were administered with physiological saline (at the daily dose of 24 mL/kg) by gastrogavage. Mice in the XP group (2.485 g/kg), the SY group (1.136 g/kg), the SJ group (1.775 g/kg), and the JY group (2.059 g/kg) were administered with corresponding medicated decoction by gastrogavage, with the gastric volume of 24 mL/kg. On the 41st day the training of capability for learning and memory was started. On the 42nd day capability for learning and memory was tested. The brain tissue was cut. One half was used to determine the contents of homogenate acetyl cholinesterase (AchE), choline acetyltransferase (ChAT), and monoamine oxidase (MAO).Another half was used to carry out morphological observations. RESULTS: The capability for learning and memory could be improved and the latency time could be lowered in all the treatment groups. Besides, the homogenate AchE and MAO could also be elevated, ChAT could be lowered; the morphology, number, and distribution of neurons could be improved. But the improvement of ethology, morphology, and activities of neurotransmitters were most obviously seen in the XP group. CONCLUSIONS: XP could improve the ethology, morphology, and activities of neurotransmitters, and showed better effects on prevention and treatment of AD. The rationality of compatibility methods and combination thinking ways of soothing Gan, nourishing blood, and invigorating Pi were clarified. PMID- 24812908 TI - [Effect of Guilingji Capsule on the fertility, liver functions, and serum LDH of male SD rats exposed by 900 mhz cell phone]. AB - OBJECTIVE: To observe the effect of Guilingji Capsule (GC) on the fertility, liver functions, and serum lactate dehydrogenase (LDH) of adult male SD rats exposed by 900 MHz cell phone. METHODS: Totally 18 adult male SD rats and 36 adult female rats in child-bearing period were selected and randomly divided into three groups according to weight equilibrium principle, i.e., the normal group, the radiated group, and the GC group, 6 males and 12 females in each group. Male rats in the normal group and all female rats were not radiated. Male rats in the radiated group and the GC group received radiation for 4 h per day, lasting for 18 successive days. Rats in the GC group received GC suspension at the daily dose of 0. 15 g/kg by gastrogavage at the same time. Equal volume of normal saline was administrated to other male rats. Then male rats were mated with corresponding female rats from the 14th radiation night to the 18th radiation night in the ratio of 1:2. Male rats were killed following on the next morning of ending the radiation. Female rats were normally fed and then killed before delivery. The pregnant outcomes of female rats in responding groups (the rates of pregnancy and the number of death fetus, birth weight, body length, and tail length) were observed and compared. Serum alanine aminotransferase (ALT), aspartate transferase (AST), AST/ALT, and LDH levels of the male rats were detected by colorimetry. Histological and morphological changes of liver were observed by HE staining. RESULTS: Compared with the normal group, the pregnancy rates of female rats decreased and the number of death fetus increased, the serum LDH level obviously increased in the radiated group (P < 0.05). Serum levels of ALT, AST, and AST/ALT were no significantly changed in the radiated group. The hepatocyte nuclear atrophy and cytoplasm vacuolar degeneration appeared. Compared with the radiated group, the pregnancy rates increased, the number of death fetus dropped, and the serum level of LDH decreased in the GC group (P < 0.05). There was no obvious change in serum levels of ALT, AST, or AST/ALT. The hepatocyte nuclear atrophy and cytoplasm vacuolar degeneration were significantly attenuated. The histomorphological structures recovered to normal basically in the GC group. CONCLUSIONS: The pregnancy rates could be decreased, the number of death fetus increased, histomorphological structures abnormal, and serum LDH level increased by exposure toy GSM 900 MHz cell phone. GC could prevent and treat the aforesaid lesion. But there was no statistical difference in serum ALT or AST levels. PMID- 24812909 TI - [Comparative research on computer simulation of two different therapeutic principles and formulae for osteoarthritis]. AB - OBJECTIVE: To compare the effect of reinforcing Shen method (RSM) and activating blood method (ABM) in treating osteoarthritis (OA) at the molecular level. METHODS: The physical and chemical characteristics of components from respective recipes of RSM and ABM, and network features of component-target interaction network were analyzed by computer simulation methods including chemical space, molecular docking, and biological network, etc. RESULTS: The chemical components of RSM and ABM were scarcely scattered with larger overlapping. Among established networks, the distribution of network features was partially similar in RSM and ABM. The average target number correlated with each component was 1.86 in RSM and 2.11 in ABM respectively. Each average target number was respectively correlated with 4.46 compounds and 3.93 compounds, reflecting multi-component and multi target actions. CONCLUSION: Computer simulation could intuitively trace out similarities and differences of two different methods and their interaction with targets, which revealed that the compatibility of RSM and ABM could have broader protein targets and potential synergism at the molecular level. PMID- 24812910 TI - [Effect of genistein combined with anastrozole on mammary tumors in ovariectomized rats]. AB - OBJECTIVE: To evaluate the inhibitory effect of genistin combined with anastrozole on the growth and apoptosis of breast tumor tissue, and to study their anti-cancer mechanism by using the model of 7,12-dimethylbenz [alpha] anthracene (DMBA)-induced mammary tumors following ovariectomy in Sprague-Dawley (SD) rats. METHODS: The DMBA induced postmenopausal SD rats were randomly divided into the control group, the genistein group, the anastrozole group, and the genistein combined with anastrozole group. The growth of tumors was observed in each group. The proliferation index and apoptosis index of tumor cells were determined. Moreover, estradiol (E2) and 17beta-HSD1 mRNA levels were determined by ELISA and RT-PCR respectively. RESULTS: The tumor growth was inhibited in the genistein group and the anastrozole group. The inhibitory ratio was significantly higher in the genistein combined with anastrozole group (P < 0.05). Compared with the control group, levels of E2 and 17beta-HSD1 mRNA decreased more significantly in the genistein combined with anastrozole group (P < 0.05). CONCLUSIONS: Genistein could suppress the growth of mammary tumors in postmenopausal rats. It showed synergistic effect when combined with anastrozole, which resulted in reduced levels of E2 and 17beta-HSD1 mRNA. It had inhibitory effect on the growth of breast tumors. PMID- 24812911 TI - [Treatment of senile diseases should prescribe Chinese patent medicine scientifically]. AB - Treatment of senile diseases by Chinese patent medicine should prescribe according to physiological and pathological specialty of the aged. It's necessary for treatment according to syndrome differentiation associating with the disease,reasonable combination of drugs avoiding adverse reactions,gentle medicine character but not fierce,small medicine quantity but not great, the use of Chinese patent medicine mild and tonic used properly but not excessively. PMID- 24812912 TI - [Hyphenation in English translation of Chinese Medical Terminology]. PMID- 24812913 TI - [An overview of apoptosis passageway after cerebral ischemia and its regulation of acupuncture]. PMID- 24812914 TI - [Basic research progress of treating osteoporosis by effective components of Chinese drugs]. PMID- 24812915 TI - [Basic research progress of natural anticancer target drugs of elemene liposomes series]. PMID- 24812916 TI - Dermatoglyphics--a possible biomarker in the neurodevelopmental model for the origin of mental disorders. AB - INTRODUCTION: Dermatoglyphic pattern formation and differentiation are complex processes which have been in the focus of research interest ever since dermatoglyphics became a science. The patterns' early differentiation and genetic uniqueness as well as the relatively simple methods used to obtain and store fingerprints make it possible to study the relationship between certain dermatoglyphic characteristics and the underlying pathological processes in a number of diseases, including mental disorders. AIM: The present review reports published data from fundamental and clinical studies on dermatoglyphics primarily in schizophrenia and bipolar disorder to lend additional support for the neurodevelopmental hypothesis in the etiology of these disorders. Following an analysis of the theories of dermatoglyphics formation and the complex association between ridge patterns and central nervous system in early embryogenesis, an attempt is made to present dermatoglyphics as possible biological markers of impaired neurodevelopment. CONCLUSIONS: The contradictory data in the literature on dermatoglyphics in mental disorders suggest the need for further studies on these biological markers in order to identify their place in the neurodevelopmental etiological model of these diseases. PMID- 24812917 TI - Comparative analysis of the results obtained after unicondylar knee arthroplasty and high tibial osteotomy in isolated gonarthrosis. AB - The AIM of this study was to analyse the results of the surgery and compare the outcomes of unicondylar knee arthroplasty and high tibial osteotomy performed in isolated gonarthrosis. PATIENTS AND METHODS: Between 2007 and 2011, 65 patients were implanted a partial knee endo-prosthesis in the Clinic of Orthopedics and Traumatology. Men were 23 (35.4%) and women were 42 (64.6%). High tibial osteotomy was performed to manage the unicompartmental gonarthrosis in 92 patients (47 men and 45 women) for 13 years between 1975 and 1987. These two modalities were used only in cases in which one of the knee joint compartments was affected. Clinical, para-clinical, functional tests and radiographic examination were conducted of the affected knee joint. RESULTS: The results of the study were assessed by the rating system proposed by the Knee Society and modified by John Insall. At four-year follow-up study the outcomes of the partial prosthesis were assessed as excellent in 85.13%, good--in 13.11% and satisfactory in 1.77% of patients. After high tibial osteotomy the results were considered very good in 54.18% of patients, good--in 32.29%, satisfactory--in 6.25%, and poor--in 7.8%. CONCLUSIONS: Partial knee arthroplasty is a resurfacing procedure, while high tibial osteotomy is used only to slow the overall degenerative process with gradual progressive exacerbation of osteoarthritis with age. The results after prosthetic treatment had a better dynamics than that in high tibial osteotomy. PMID- 24812918 TI - Brain-derived neurotrophic factor and its serum levels in schizophrenic patients. AB - INTRODUCTION: Neurotrophins have an important role in regulating the development and maintenance of the peripheral and central nervous systems' function. Thus, the neurotrophin hypothesis of schizophrenia has postulated that the changes in the brain of schizophrenic patients are the result of disturbances of developing processes involving these molecules. AIM: We analyse in the present study the changes in the serum levels of brain-derived neurotrophic factor (BDNF) in schizophrenic patients as possible epiphenomena of underlying alterations of the neurotrophic factor in central nervous system, reflecting its role in the pathophysiology of schizophrenia. PATIENTS AND METHODS: Twenty-one schizophrenic patients satisfying the DSM-IV criteria for diagnosis of schizophrenia were enrolled in the study. The control group consisted of 28 age-matched mentally healthy subjects. Serum BDNF levels were determined in patients and normal controls using ELISA (Chemicon International, USA & Canada). The data were analyzed statistically with Student's t- test in SPSS 9.0. RESULTS: The serum BDNF levels were lower in the schizophrenic patients than in the control subjects, reaching statistically significant difference (t = 2.72, p = 0.009). Female patients had lower serum BDNF levels than the male patients but the difference fell short of statistical significance (t = 0.1, p = 0.9). CONCLUSIONS: The BDNF reduction in serum indicates a potential deficit in neurotrophic factor release in patients with schizophrenia and support the concept that BDNF might be associated with schizophrenia. PMID- 24812920 TI - Snake venom poisoning in the Plovdiv region from 2004 to 2012. AB - INTRODUCTION: Envenomation by poisons of biological origin is very common globally in the tropical and subtropical areas mainly, where the biological diversity of the species clearly leads to evolution of highly toxic species. The weather warming trend in Bulgaria, whether cyclic or permanent, allows for a change in the biological response of reptiles and insects inhabiting the temperate zone by a possible migration of biological species from the subtropical zone towards the temperate zone because of the new environmental conditions. There are very few studies on snake bite envenoming in Bulgaria. The AIM of the study was to find the incidence of the acute accidental intoxication (AAI) caused by snake venom in adult individuals in a large region of Bulgaria between 2004 and 2012 and characterises it by number, type, main clinical features, course and socio-demographic parameters of the victims so that preventive measures can be taken, wherever necessary. MATERIALS AND METHODS: We studied retrospectively all 68 cases of AAI caused by snake venom in adult individuals (> 18 years old) hospitalized in the Clinic of Toxicology in St. George University Hospital, Plovdiv over the period from 2004 to 2012 by 23 quantitative and qualitative parameters. RESULTS: We found that the average annual incidence of snake venom AAI in adult population in the region of Plovdiv was relatively low for the specified period (9.5 per 100000 residents); the snake venom AAI increases or decreases every other year, with no clearly delineated trend for now. The prevalence of envenomation by poisons of biological origin increased from 2.3% in 1990-1998 to 9.5-10.33% between 2007 and 2012. The main sociodemographic characteristics of snake bite victims are similar to those in other Balkan and Central European countries. The clinical response to poisons of biological origin is generally identical with the response to the viper (Vipera ammodytes)--mild to medium intensity with predominantly local toxic syndrome. CONCLUSIONS: The algorithm of Clinical Pathway 293 (CP) is effective and conducive to the reduction of duration of the morbid condition. There are, however, still aspects of it that can be optimised. PMID- 24812919 TI - Influence of serum levels of thyroid-stimulating hormone and anti-thyroid peroxidase antibodies, age and gender on depression as measured by the Zung Self Rating Depression Scale. AB - The AIM of the present study was to explore the level of depression in the respondents using the Zung self-rating depression scale (SDS) and find a correlation with the levels of the thyroid-stimulating hormone (TSH) and the anti thyroid peroxidase antibodies (anti-TPO), the age and gender of the participants. PATIENTS AND METHODS: 2401 subjects aged 20-84 yrs were included, 1344 of them female aged 48.7 +/- 14.4 yrs and 1057 male, aged 46.5 +/- 14.5 yrs (p < 0.001). All participants completed the Zung SDS questionnaire and a depressive score was calculated and interpreted as follows: less than 49 points--no depression, between 50 and 59 points--mild depression, between 60 and 69 points--moderate depression and more than 69 points-- severe depression. Body height and weight were measured and serum TSH and Anti-TPO were determined. RESULTS: SDS was higher in the females (47.6 +/- 9.7 vs. 41.7 +/- 8.6, p < 0.001) and correlated with the subjects' age (Spearman's rho(female) = 0.447, p < 0.001, P(male) = 0.402, p < 0.001). Depression was more prevalent in the females (all p < 0.001) with hypothyroidism than in the euthyroid subjects (odds ratio 1.8, 95% CI 1.15-2.80, p < 0.011). The odds ratio for depression was 3.47 (2.64-4.57) for the female gender and the risk of depression increased by 6% (5 - 7) with each added year of age. The anti-TPO, BMI and waist circumference did not influence the regression models. CONCLUSION: The depressive score was higher in the females and increased with age. Hypothyroidism determined a higher risk of depression in the females. PMID- 24812921 TI - The retroaortic left renal vein abnormalities in cross-sectional imaging. AB - OBJECTIVE: The normal anatomic course of the left renal vein (LRV) from the kidney to inferior vena cava (IVC) is usually preaortic. It is called retroaortic left renal vein (RLRV) when located between the aorta and vertebra; the circumaortic left renal vein (CLRV) has both a preaortic and retroaortic course. In this study, we aimed to find the incidence and characteristics of LRV abnormalities in routine abdominal CT and MR examinations conducted in our clinic. MATERIALS AND METHODS: A total of 2189 abdominal CT and MR examinations, performed between April 2007 and June 2009, were reviewed retrospectively for retroaortic and circumaortic LRV abnormalities. RESULTS: LRV abnormalities were detected in 50 (2.3%) examinations. Forty-four of these (2%) were RLRV and 6 (0.3%) were circumaortic LRV abnormalities. CONCLUSIONS: Preoperative knowledge of LRV abnormalities facilitates the safe performance of surgery and reveals the clinical symptoms. It is easy to see LRV and its drainage way on routine CT and MR imagings. PMID- 24812922 TI - Experimental study on the role of 5-HT2 serotonin receptors in the mechanism of anti-inflammatory and antihyperalgesic action of antidepressant fluoxetine. AB - INTRODUCTION: Fluoxetine is an antidepressant that has anti-inflammatory and antihyperalgesic effects in experimental models of pain and inflammation. The AIM of the present study was to determine the role of 5-HT2 receptors in the mechanism of anti-inflammatory and antihyperalgesic action of fluoxetine after single and repeated administration of the drug. MATERIALS AND METHODS: 40 male Wistar rats were randomly divided in five groups (n = 8) treated for 14 days with saline (control), diclofenac (positive control), fluoxetine, cyproheptadine (5 HT2 antagonist), and fluoxetine + cyproheptadine, respectively. We used the experimental model of inflammation induced by intraplantar injection of carrageenan and nociceptive test with mechanical pressure on the inflamed hind paw. RESULTS: Single and repeated administration of fluoxetine showed that it had significant anti-inflammatory and antihyperalgesic effects when compared with the control (p < 0.05). Cyproheptadine did not change significantly the anti inflammatory effect of fluoxetine in the first 4 hours, after a single administration. At 24 hours the combination did not differ statistically when compared with the control. Cyproheptadin did not change significantly the anti inflammatory effect of fluoxetine after repeated administration. After prolonged treatment the group that received fluoxetine + cyproheptadine showed a statistically significant increase in paw pressure to withdraw the hind paw compared with that treated with fluoxetine alone (p < 0.05). CONCLUSIONS: Fluoxetine has anti-inflammatory and antihyperalgesic effects in the carrageenan model of inflammation. 5-HT2 receptor mediated its anti-inflammatory effect in single dose treated animals. Spinal 5-HT2 receptors are involved in the antihyperalgesic effect of fluoxetine after repeated administration. PMID- 24812923 TI - The structure of trauma patients, its management and health care in the University Hospital of Alexandroupolis. AB - OBJECTIVE: The present study was designed to describe the patterns of trauma patients using a newly-introduced trauma registry, as well as retrospectively assess the management and outcome facts of these patients. MATERIALS AND METHODS: The study included 2346 patients (62.15% male) with a mean age of 34.06 +/- 23.77 years. Of these patients, 355 were multiple trauma patients. Privately owned vehicles were used as a mode of transportation for most of the trauma patients (96.65%). Data regarding patient demographics, arrival at the Emergency Department, mechanism of injury, injury severity, anatomical location and type of injury were collected and analyzed. RESULTS: Falls were the most prevalent mechanism of injury, accounting for 62.19% of the total admitted cases, with other causes (that also included occupational accidents and machinery trauma) being the second most prevalent, and MVAs--the third with a rate of 11.46%. The most commonly injured body regions were the extremities (50.26%), the head (42.50%), and the torso (19.39%). Fractures represented 11.46% of the injuries, while open wounds were much more frequent (29.41%). The mean abbreviated injury severity (AIS) score was 1.78 +/- 1.48 for all admitted patients and 3.56 +/- 1.02 for multiple trauma patients. A multi-disciplinary approach was required for 23% of the multiple trauma patients. The clinic admission rate for the whole patient sample was 13.55% and 48.96% for multiple trauma patients. The mean duration of stay for all clinic admissions was 2.7 days and 2.9 days for multiple trauma patients. CONCLUSIONS: With the epidemiology of trauma in Greece being rather poorly investigated, the present study manages to identify the major epidemiological patterns of trauma cases presenting to a tertiary regional hospital and addresses the need for development and implementation of injury prevention activities and policies. PMID- 24812924 TI - Laparoscopic resection of the pancreatic tail with preservation of the spleen in a patient with a large pseudopapillary tumor of the pancreas. AB - Laparoscopic resections of the pancreas have gained in popularity in the last few years. Those preserving the integrity of the spleen are performed very rarely and are a challenge for every surgeon. We hereby report a case of laparoscopic resection of the pancreatic tail with preservation of the spleen and the integrity and the blood supply to the spleen in a 26 year-old patient with a large pseudopapillary tumor of the pancreas. Postoperative recovery was quick and without complications. The functional and aesthetic result was satisfactory. Laparoscopic resection of the pancreas is a safe and effective therapeutic procedure in selected patients. PMID- 24812925 TI - Long-term follow up of complete bladder exstrophy repair. A case report. AB - OBJECTIVE: Bladder exstrophy is a congenital anomaly which is not always successfully managed by surgery. Major goals of surgical intervention in such cases are preservation of normal renal function, development of adequate bladder function and urinary continence and avoidance of future urinary tract infections. We present 5-year data on a patient who underwent complete repair of the bladder exstrophy. CASE REPORT: We describe a full term female infant who presented at birth with complete bladder exstrophy. Complete repair of the condition was performed 3 days after birth (Ransley technique). During hospitalization the patient had a positive urinary culture with Candida lusitaniae, enterococcus and septicemia with Klebsiella pneumoniae ESBL. The patient had no complications until the age of 20 months when she developed an episode of pyelonephritis and five further episodes of cystitis with E. coli. Radiographic testing showed small bladder capacity (23 ml at the age of 3 years), bilateral vesicoureteral reflux, a long stenotic urethra and no loss of renal function. Because of the recurrent urinary tract infections, dilatations of the stenotic urethra (Scheldinger technique) were successfully performed at the age of 3. Twenty-two months later the child had negative urinary cultures, a normal renal function and had also gained partial control of the bladder sphincters. CONCLUSIONS: Surgical repair of bladder exstrophy remains a challenging surgery for the pediatric urologist. Following surgical correction both early and long-term post-operative complications may be present. Longitudinal follow up is required by an experienced team of health care professionals. PMID- 24812926 TI - [Form of the particulate matter ambient air standards in China]. AB - Based on the principles from the World Health Organization (WHO) and the United States, an analysis was conducted to study the form of 24-hour standard of particulate matter in China by methods of statistical regression, proportional rollback and controlling contrast maps, using the monitoring data of inhalable particulate matter (PM10) from 120 cities in China during year 2005 to 2012. It was found that for cities in China, when the annual arithmetic mean of PM10 was equal to the national standard, the non-exceedance rates of daily average PM10 in most cities were higher than 95.0% , and the average rate for all cities was 97.1%. The average non-exceedance rate was 96.3% for cities in North China and Northwest China, 96.6% for Northeast China, 97.2% for East China and Central South China, and 98.1% for Southwest China. When the 97th percentile was chosen as the form of 24-hour standard of particulate matter for China, the 24-hour standard had an equal controlling strength with the annual standard. The 24-hour standard will become the controlling standard when larger percentiles were chosen, otherwise the contrary. By considering together the statistical characteristics of PM10 level in China, the robustness of the percentiles and protection of human health, the 95th percentile was suitable as the preferred form of the 24-hour standard of PM10 and PM2.5 in China. PMID- 24812927 TI - [Seasonal variation of carcinogenic heavy metals in PM2.5 and source analysis in Beijing]. AB - During April, July, October 2009 and January 2010, daily (24-h average) PM2.5 samples were collected at urban sites in Beijing and 29 metal elements were analyzed by the ICP-MS. The characteristics of 7 carcinogenic heavy metal mass concentrations, enrichment, and possible sources were discussed. The annual average concentrations of As, Cd, Co, Cr, Ni, Pb and Se were (11.6 +/- 14.0), (2.6 +/- 2.4), (1.0 +/- 0.7), (11.3 +/- 9.4), (4.0 +/- 2.4), (142.5 +/- 98.9) and (3.3 +/- 2.2) ng m(-3), respectively. Only annual average concentration of As exceeded WHO standard by a factor of 0.8. Higher enrichment factors of As, Cd, Pb and Se were found and their enrichment factors exceeded 500. Their enrichment factors in summer were much higher than those in other seasons. The local coal combustion and vehicle exhaust should be the dominant sources for the above four carcinogenic heavy metals in spring, autumn and winter, while regional transportation contributed more in summer. PMID- 24812928 TI - [Temporal and spatial distribution of PM2.5 and PM10 pollution status and the correlation of particulate matters and meteorological factors during winter and spring in Beijing]. AB - Fogs and hazes broke out many times in winter and spring of 2012-2013 in Beijing, inducing severe pollution of respirable particulate matters (PM10). As a fine particle component in PM10, PM2.5 would cause more severe air pollution if the proportion of PM2.5 to PM10 is high. Based on this, 30 monitoring stations recording the concentration of PM2.5 and PM1.0 all over Beijing were selected, and the contamination characteristics of particulate matters were analyzed, which further served to determine the characteristics of temporal and spatial pollution variations of PM2.5 and PM10. The distribution of PM2.5 and PM10 mass concentration in winter and spring in Beijing were derived by the Original Kriging interpolation method, and it was depicted from the figure that the concentration of particulate matters gradually increased from the northern mountain area to the southern part of Beijing; in the central urban area, the particulate concentration of the western region was generally higher than that of the eastern region, with certain differences between urban and rural area within some local areas. Monthly variation curve of PM2.5 and PM10 mass concentration showed single peak-valley pattern: the maximum was in January and the minimum was in April; daily variation indicated a good correlation between PM2.5 and PM10, both of which were significantly influenced by meteorological conditions; diurnal variation curve showed a double peak-valley type. Meteorological factors such as daily average temperature (degrees C), relative humidity (%), wind speed (wind scale), precipitation (mm) were chosen and their individual relationships with concentrations of PM10 and PM2.5 were investigated using Spearman rank correlation analyses. It was demonstrated that the concentrations of PM10 and PM2.5 were positively correlated with temperature and relative humidity, respectively, and strongly negatively correlated with wind speed; wind speed and relative humidity were two key factors affecting the distributions of PM2.5 and PM10 concentration. PMID- 24812929 TI - [Inversion and spatial-temporal distribution analysis on PM5.0 inhalable particulate in Beijing]. AB - Study on urban spatial characteristics of inhalable particulate and its influencing factors has an important practical significance for the development of more effective inhalable particulate pollution control policy. On the basis of the actual sampling and remote sensing data processing, a correlation model was established between the difference vegetation index (DVI) values of TM images and the measured values of the corresponding PM5.0 particulate matter, and PM5.0 distributions from 2008 to 2010 in Beijing were acquired by the use of inversion experiments and their accuracies were tested. Furthermore, the impact of NDBI and NDMI on PM5.0 was explored, as well as the spatial and temporal characteristics of inhalable particulate within the five rings of Beijing. The results showed that: (1) the PM5.0 inversion method using DVI was feasible, and the inversion accuracy was acceptable; (2) Overall, in 2008, PM5.0 particulate matter pollution was the lightest in the study area. The higher values of particle pollution were distributed between the southwest third ring road and southwest fourth ring road, as well as between the southeast third ring road and southeast fourth ring road, and the lower values of particle pollution were distributed around the northwest fifth ring road; (3) NDBI and NDMI had equal significant impact on inhalable particulate, which respectively showed significant negative correlation and positive correlation. PMID- 24812930 TI - [Characterization of ultrafine particle size distribution in the urban atmosphere of Hangzhou in spring]. AB - Continuous measurement and analysis of the atmospheric ultrafine particle number concentration were performed in Hangzhou from March to May, 2012 by using the fast mobility particle sizer (FMPS). The result showed that daily number concentration of nucleation mode (5.6-20 nm), Aitken mode (20-100 nm), and accumulation mode (100-560 nm) particles, and total particles were 0.84 x 10(4), 1.08 x 10(4), 0.47 x 10(4) and 2.38 x 10(4) cm(-3) respectively. The concentration of Aitken mode particles was higher than that of other mode particles in sunny day. The nucleation mode and Aitken mode particles usually started to increase around 10:00-11:00 and ended up after 3-4 h. This indicated the solar radiation promoted the formation of new particles. Human activities caused the concentration distribution of each mode particles having an obvious difference between workdays and weekends. Combined with the meteorological factors, analysis showed that the wind speed and wind direction also directly influenced particulate concentration. The analysis of particulate concentration and visibility showed that the concentration of accumulation mode particles had a negative relationship with the atmospheric visibility, while those of nucleation mode and Aitken mode particles had a slight influence on it. PMID- 24812931 TI - [Size distributions of aerosol during the Spring Festival in Nanjing]. AB - In order to investigate the firework burning impacts on spectrum distribution of atmospheric aerosol during the Spring Festival in Nanjing, number concentration and mass concentration of aerosol as well as mass concentration of gas pollutants were measured during January 19-31, 2012. The results indicated that the concentration of aerosol between 10-20 nm decreased, aerosol concentration in the range of 50-100 nm, 100-200 nm and 200-500 nm increased during the firework burning period comparing to those during the non-burning period. However, there was no obvious variation for aerosol between 20-50 nm and 0.5-10 microm. The spectrum distribution of number concentration was bimodal during the non-burning period and unimodal during the burning period, with the peak value shifting to large diameter section. The mass concentration presented a bimodal distribution, the value of PM2.5/PM10 and PM10/PM10 increased by 10% during the burning period. The firework burning events had big influence on the density of aerosol between 1.0-2.1 microm. PMID- 24812932 TI - [Size distributions of organic carbon and elemental carbon in Nanjing aerosol particles]. AB - The concentrations and size distributions of organic carbon (OC) and elemental carbon (EC) in particles collected in Nanjing Normal University representing urban area and in Nanjing College of Chemical Technology standing for industrial area were analyzed using Model 2001A Thermal Optical Carbon Analyzer. The mass concentrations were the highest with the size below 0.43 microm in urban and industrial area. OC accounted for 20.9%, 21.9%, 29.6%, 27.9% respectively and those were 24.0%, 23.5%, 31.4%, 22.6% respectively for EC in the four seasons in urban area. In the industrial area, OC accounted for 18.6%, 45.8%, 26.6%, 25.9% respectively and the proportions of EC were 16.7%, 60.9%, 26.3%, 24.3% respectively. Overall, OC and EC were enriched in fine particles below 2.1 microm and they accounted for the highest proportion in summer in urban area while it did not show significant seasonal variation for industrial area. SOC in fine particles achieved high values in summer while the unobvious seasonal variation in coarse particles might be attributed to the contribution of different pollution sources and meteorological factors. Correlations and OC/EC ratio method implied that OC and EC mainly came from vehicles exhaust and coal combustion in fine particles while they were also related to biomass combustion and cooking in coarse particles. PMID- 24812933 TI - [Characterization of organic and elemental carbon in PM10 in Xinzhou City]. AB - PM10 samples were collected at four sampling sites to study pollution characteristics of carbonaceous aerosols in Xinzhou during heating period (March) and non-heating period (July), 2011. Organic carbon (OC) and elemental carbon (EC) in PM10 were analyzed by Elementar Analysensysteme GmbH vario EL cube, and the characteristics including pollution levels, temporal and spatial distributions of OC and EC as well as OC/EC ratios were investigated in detail. The results were as following: OC and EC mass concentrations of PM10 in Xinzhou were (18.5 +/- 4.5) microg x m(-3) and (16.1 +/- 4.3) microg x m(-3), respectively. The concentrations of total carbon aerosol (TCA) accounted for 70.7% of PM10 during the heating period, and 43.8% during the non-heating period. The concentrations of OC at four sites during the heating period were higher than those during the non-heating period, and this trend was consistent with that of EC concentrations except for SQ site, which indicated coal combustion was a dominant source of OC and EC during the heating period. OC concentration at XT site and EC concentration at DC site were the highest, which were 24.1 microg x m(-3) and 22.0 microg x m(-3) respectively, while the concentrations of OC and EC at SQ site were both the lowest, which were 17.2 microg x m(-3) and 14.5 microg x m(-3), respectively, which indicated that the spatial distributions of OC and EC were obviously different. The average values of OC/EC ratios were all below 2, which indicated that the primary pollution was predominant. The correlation between OC and EC during the non-heating period was good with R2 of 0.55, indicating the emission sources were consistent and the vehicle exhaust played an important role, while the correlation was weak during the heating period (R2 = 0.13), which revealed that the emission sources of OC and EC were complicated. Carbonaceous aerosol pollution should be reduced by controlling the primary emissions such as coal combustion, vehicle exhaust, biomass burning and other industrial sources to improve the air quality in Xinzhou City. PMID- 24812934 TI - [Seasonal variation of concentrations and distribution characteristics of PCDD/Fs in atmosphere of an industrial area, Guangzhou]. AB - Atmospheric concentrations of 2,3,7,8-substituted polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) were measured seasonally in an industrial area of Guangzhou City. And seasonal variation of concentrations and distribution characteristics of 2,3,7,8- PCDD/Fs was investigated. The PCDD/Fs concentrations and corresponding I-TEQ (toxic equivalent quantity) values were in the range of 2.33-75.4 pg x m(-3) (mean = 23.2 pg x m(-3)) and 0.229-10.7 pg x m(-3) (mean = 2.00 pg x m(-3)), respectively. The seasonal variation of PCDD/Fs concentrations was obvious, with the highest concentration was found in spring (37.8 pg x m(-3)) and the lowest in summer (13.5 pg x m(-3)). However, no obvious difference of concentrations was observed for autumn (22.3 pg x m(-3)) and winter (19.1 pg x m( 3)). The seasonal variation of I-TEQ values is as follows: spring (5.58 pg x m( 3)) > summer (1.06 pg x m(-3)) > autumn (0.839 pg x m(-3)) > winter (0.525 pg x m(-3)). The influences of monsoon and rainfall on the concentration of PCDD/Fs in atmosphere are discussed. PMID- 24812935 TI - [Hazard evaluation modeling of particulate matters emitted by coal-fired boilers and case analysis]. AB - In order to evaluate the hazard of PM2.5 emitted by various boilers, in this paper, segmentation of particulate matters with sizes of below 2. 5 microm was performed based on their formation mechanisms and hazard level to human beings and environment. Meanwhile, taking into account the mass concentration, number concentration, enrichment factor of Hg, and content of Hg element in different coal ashes, a comprehensive model aimed at evaluating hazard of PM2.5 emitted by coal-fired boilers was established in this paper. Finally, through utilizing filed experimental data of previous literatures, a case analysis of the evaluation model was conducted, and the concept of hazard reduction coefficient was proposed, which can be used to evaluate the performance of dust removers. PMID- 24812936 TI - [Chemical characteristics of precipitation in South China Sea]. AB - Rainwater samples were collected in the summer on "Shiyan 3" during the 2012 South China Sea Sectional Scientific Survey. The concentrations of anion and cation, and pH in precipitation were determined and backward trajectories of air mass were simulated to analyze the chemical characteristics of ions and examine the source of ions. The results indicated that the mean pH value of precipitation was 6.3, with 5.6 of minimal value in summer in South China Sea. The order of anion and cation abundance was Cl(-) > S04(2-) > NO3(-) and Na(+) > Mg(2+) > Ca(2+) > K(+). Cl(-) was the major anion and Na(+) was the major cation, with concentrations of 2 637.5 microeq x L(-1) and 2095.5 microeq x L(-1), respectively, showing that they were the characteristics of marine atmospheric precipitation. There was a good linear relationship between each pair of 7 ions, with correlation coefficient above 0.9, suggesting that they may have a common source. However, the correlation coefficients were lower between NO3(-) and other ions than the others, suggesting that NO3(-) had more complex sources. The concentrations of Ca(2+) and K(+) in precipitation may be related to coral environment in South China Sea. The backward trajectories in 6 stations showed that the air mass was from south and southwest of South China Sea, without passing through above the continent. These results suggested that precipitation affected by human ion source can be ignored in summer in South China Sea. PMID- 24812937 TI - [Analysis of acid rain characteristics of Lin'an Regional Background Station using long-term observation data]. AB - Using long-term observation data of acid rain at Lin'an Regional Background Station (Lin'an RBS), this paper studied the interannual and monthly variations of acid rain, the reasons for the variations, and the relationships between acid rain and meteorological factors. The results showed that interannual variation of acid rain at Lin'an RBS had a general increasing trend in which there were two obvious intensifying processes and two distinct weakening processes, during the period ranging from 1985 to 2012. In last two decades, the monthly variation of acid rain at Lin'an RBS indicated that rain acidity and frequency of severe acid rain were increasing but the frequency of weak acid rain was decreasing when moving towards bilateral side months of July. Acid rain occurrence was affected by rainfall intensity, wind speed and wind direction. High frequency of severe acid rain and low frequency of weak acid rain were on days with drizzle, but high frequency of weak acid rain and low frequency of severe acid rain occurred on rainstorm days. With wind speed upgrading, the frequency of acid rain and the proportion of severe acid rain were declining, the pH value of precipitation was reducing too. Another character is that daily dominant wind direction of weak acid rain majorly converged in S-W section ,however that of severe acid rain was more likely distributed in N-E section. The monthly variation of acid rain at Lin'an RBS was mainly attributed to precipitation variation, the increasing and decreasing of monthly incoming wind from SSE-WSW and NWN-ENE sections of wind direction. The interannual variation of acid rain could be due to the effects of energy consumption raising and significant green policies conducted in Zhejiang, Jiangsu and Shanghai. PMID- 24812938 TI - [Characteristics of atmospheric nitrogen wet deposition in Beijing urban area]. AB - With the ion-exchange resin method, the atmospheric nitrogen wet deposition in Beijing urban area within the Fifth Ring Road was investigated from June to October, 2012. The relationship between atmospheric nitrogen wet deposition and rainfall precipitation was investigated, the differences of nitrogen wet deposition in different months, different ring roads (the Fifth Ring Road, the Fourth Ring Road, the Third Ring Road and the Second Ring Road) and different functional areas (institutes and colleges district, ring-road, residential areas, railway station and public garden) were also investigated. The results showed that the average value and standard deviation of ammonia-nitrogen, nitrate nitrogen and nitrite-nitrogen were significantly different during different months in 2012. The atmospheric nitrite nitrogen deposition first decreased and then increased, the maximum value appeared in September. The positive relationships between ammonia nitrogen (nitrate nitrogen) and mean monthly precipitation and negative relationships between nitrite nitrogen and mean monthly precipitation were both significant (P < 0.05). The three nitrogen depositions of ring-road and railway station were higher than other functional areas, but only the nitrite nitrogen deposition had obvious regional difference. The differences of the three nitrogen depositions among different ring roads were all not significant and it meant that the nitrogen wet deposition was equally distributed in Beijing urban area. PMID- 24812939 TI - [Studies of ozone formation potentials for benzene and ethylbenzene using a smog chamber and model simulation]. AB - Ozone formation potentials from irradiations of benzene-NO(x) and ethylbenzene NO(x) systems under the conditions of different VOC/NO(x) ratios and RH were investigated using a characterized chamber and model simulation. The repeatability of the smog chamber experiment shows that for two sets of ethylbenzene-NO(x) irradiations with similar initial concentrations and reaction conditions, such as temperature, relative humidity and relative light intensity, the largest difference in O3 between two experiments is only 4% during the whole experimental run. On the basis of smog chamber experiments, ozone formation of photo-oxidation of benzene and ethylbenzene was simulated in terms of the master chemical mechanism (MCM). The peak ozone values for benzene and ethylbenzene simulated by MCM are higher than the chamber data, and the difference between the MCM-simulated results and chamber data increases with increasing RH. Under the conditions of sunlight irradiations, with benzene and ethylbenzene concentrations being in the range of (10-50) x 10(-9) and NO(x) concentrations in the range of (10-100) x 10(-9), the 6 h ozone contributions of benzene and ethylbenzene were obtained to be (3.1-33) x 10(-9) and (2.6-122) x 10(-9), whereas the peak O3 contributions of benzene and ethylbenzene were (3.5-54) x 10(-9) and (3.8-164) x 10(-9), respectively. The MCM-simulated maximum incremental reactivity (MIR) values for benzene and ethylbenzene were 0.25/C and 0.97/C (per carbon), respectively. The maximum ozone reactivity (MOR) values for these two species were obtained to be 0.73/C and 1.03/C, respectively. The MOR value of benzene from MCM is much higher than that obtained by carter from SAPRC, indicating that SAPRC may underestimate the ozone formation potential of benzene. PMID- 24812940 TI - [Characteristics of fly ash particles deposition in the snowpack of Laohugou Glacier no. 12 in western Qilian Mountains, China]. AB - This research aimed to identify and characterize individual spherical fly ash particles extracted from surface snow at Laohugou Glacier No. 12, western Qilian Mountains, China. Characterization of the spherical particles (i. e. morphology, chemical composition and genesis) was obtained by scanning electron microscopy coupled with energy dispersive X-ray spectrometer (SEM-EDX). Spherical particles and agglomerates were identified according to their morphology in nine snow samples. Prevalent particle types in all samples were granular spherical particles, hollow spherical particles, and agglomerates. The vast majority of spherical particles in our samples had mostly smooth and glossy surfaces. Individual particle analyses of elemental composition showed that particles formed in combustion were mainly composed of silicon, aluminum and trace elements. On the basis of chemical information obtained from EDX, the fly ash particles deposited in the snow could be classified into three types, which were Si-dominant particles, Fe-dominant particles, and Ti-dominant spherical particles. Backward air mass trajectory and dispersion analysis suggested that the developed urban regions of central Asia and surrounding Yumen city contributed the primary fly ash particles from industrial combustion to the study site through the high-level atmospheric circulation. PMID- 24812941 TI - [Odor emission rate of municipal solid waste from landfill working area]. AB - Emission rates of volatile organic compounds (VOCs), H2S and odor unit from the surface of a municipal solid waste (MSW) landfill working area were measured with a wind tunnel sampler. The results show that the emission rate of odor from the non-point source of landfill is the function of environmental temperature and surface sweeping velocity. The emission rate measured in the high temperature season can be 6 times higher of that in the low temperature season. Within the experimental range of 0.6-4 m x s(-1) wind sweeping velocity, the emission rate shows a linear relationship with wind sweeping velocity. In summer, the emission rates of VOCs (measured by PID as isobutylene), H2S and odor unit are 385-680 microg x (m(2) x s)(-1), 4-7 microg x (m(2) x s)(-1), and 46.5-136 OU x (m(2) x s)(-1) respectively. The continuous sweeping experiment shows that the emission rate measured with clean air sweeping is the maximum possible emission rate, which needs to be adjusted when it is used to estimate the odor concentration of more than 10 min sample time or an area emission load. PMID- 24812942 TI - [Gaseous phenol removal in a bio-trickling filter]. AB - The performance of a bio-trickling filter (BTF) for treatment of phenol, a model pollutant, was presented. Influences of factors on phenol removal efficiency were studied. The BTF exhibited a high removal efficiency for phenol. The experimental results showed that the phenol efficiency reached 99.5% and kept 98% in the long term run. The optimal residence time, pH value and spray density were 20.6 s, 7.0 and 1.67 m(3) x (m(2) x h)(-1), respectively. The microbial community structures in the bio-trickling filter for phenol removal were assessed by PCR-DGGE. Based on the 16S rDNA sequence data,results showed that the predominant bacteria for degradation of phenol were Polaromonas sp., Acinetobacter sp., Acidovorax sp., Veillonella parvula and Corynebacterium sp., GC-MS was used to detect component of BTF's outlet gases and pyruvic acid (CH3COCOOH) was found as one kind of intermediates of phenol degradation. Then one possible biodegradation pathway of phenol was inferred. PMID- 24812943 TI - [Particulate distribution characteristics of Chinese phrase V diesel engine based on butanol-diesel blends]. AB - With a common rail diesel engine without any modification and the engine exhaust particle number and particle size analyzer EEPS, this study used the air-fuel ratio to investigate the particulate number concentration, mass concentration and number distribution characteristics of a diesel engine fueled with butanol-diesel blends (Bu10, Bu15, Bu20, Bu30 and Bu40) and petroleum diesel. The results show: for all test fuels, the particle number distributions turn to be unimodal. With the increasing of butanol, numbers of nucleation mode particles and small accumulation mode particle decrease. At low speed and low load conditions, the number of large accumulation mode particle increases slightly, but under higher speed and load conditions, the number does not increase. When the fuels contain butanol, the total particle number concentration and mass concentration in all conditions decrease and that is more obvious at high speed load. PMID- 24812944 TI - [Effects of turning frequency on emission of greenhouse gas and ammonia during swine manure windrow composting]. AB - It is of great concern for greenhouse gas (GHG) reduction of animal manure management in China due to the extreme lack of GHG emission data during animal manure composting. Therefore, the purpose of this study was to investigate the effects of turning frequency on the emission of GHG (CH4, N2O) and NH3 during swine manure windrow composting through on-site observation of a full scale test in Beijing. Results showed that the turning frequency had significant impacts on the emission of both GHG and ammonia, which did not only increase the emission of GHG and ammonia, but also increased the percentage of total nitrogen loss due to NH3 emission (42.2% at turning once a week and 70.05% at turning twice a week, respectively). Compared with N2O emission, CH4 emission was the main contributor to Global Warming Potentials (GWPs). PMID- 24812945 TI - [Oxidation of mercury by CuBr2 decomposition under controlled-release membrane catalysis condition]. AB - CuBr2 in the multi-porous ceramic membrane can release Br2 at high temperature, which was employed as the oxidant for Hg0 oxidation. Hg0 oxidation efficiency was studied by a membrane catalysis device. Meanwhile, a reaction and in situ monitoring device was designed to avoid the impact of Br2 on the downstream pipe. The result showed that the MnO(x)/alpha-Al2O3 catalysis membrane had a considerable "controlled-release" effect on Br2 produced by CuBr2 decomposition. The adsorption and reaction of Hg0 and Br2 on the surface of catalysis membrane obeyed the Langmuir-Hinshelwood mechanism. The removal efficiency of Hg0 increased with the rising of Br2 concentration. However, when Br2 reached a certain concentration, the removal efficiency was limited by adsorption rate and reaction rate of Hg0 and Br2 on the catalysis membrane. From 473 K to 573 K, the variation of Hg0 oxidation efficiency was relatively stable. SO2 in flue gas inhibited the oxidation of Hg0 while NO displayed no obvious effect. PMID- 24812946 TI - [Distributions and influencing factors of total dissolved inorganic antimony in the coastal area of Zhejiang and Fujian]. AB - Antimony has been ubiquitously present in the aquatic environment as a toxic and rare metalloid element. The contamination of antimony and its compounds in the environment is increasingly severe, so it has been received extensive attention by the international scientific community. The cruise was carried out in the coastal area of Zhejiang and Fujian provinces in the East China Sea (ECS) in May 2008. The concentrations of total dissolved inorganic antimony (TDISb) were measured by Hydride Generation-Atomic Fluorescence (HG-AFS). The concentration ranges of TDISb in the surface and bottom layer were 0.68-5.64 nmol x L(-1) and 0.71-5.25 nmol x L(-1) with averages of 2.25 and 1.79 nmol x L(-1), respectively. The concentration of TDISb in the study area was lower than the environmental quality standards for surface water of China and drinking water standards of World Health Organization (about 41.08 nmol x L(-1)), indicating that it remained at the pristine level. The concentration of TDISb decreased gradually from the coastal area to the central ECS shelf with higher concentration in the surface layer than the bottom. Water mass mixing, adsorption/desorption behavior on the surface of the suspended particulate matters (SPM) and biological activities were the main influence factors of TDISb biogeochemistry in the study area. PMID- 24812947 TI - [Calculation of allowable pollution loads for lake and reservoir based on bi direction algorithm and its case study]. AB - Based on the reviews and summaries of water environment carrying capacity researches and practices, the main problems of allowable pollutants load estimation and its allocation in China were analyzed. Then a bi-direction algorithm for allowable pollutants loads calculation was proposed to support the pollutants loads management in the lake and reservoir control units. It was the combination of forward algorithm and backward algorithm. The two major steps were modeling and scenario analysis. Firstly, the basic scenario was proposed using the estimation model. Then the basic scenario was analyzed using the water quality simulation model to assess the compliance of water quality objectives. The allowable pollutant loads were calculated after several loops of scenario simulation, result analysis and scenario optimization. Finally, the Chaihe Reservoir in Liaoning Province, China was used as a case study using Environmental Fluid Dynamic Code (EFDC) model as the kernel model. The results demonstrated that the algorithm proposed provided an efficient and appropriate methodology for allowable pollutant load calculation. PMID- 24812948 TI - [Risk assessment of quaternary groundwater contamination in Beijing Plain]. AB - Firstly, advances in investigation and evaluation of groundwater pollution in China in the last decade were presented, and several issues in the field which hinder the development of groundwater environment were pointed out. Then, four key concepts in risk assessment of groundwater pollution were briefly described with more emphasis on the difference between groundwater pollution assessment and groundwater quality assessment in this paper. After that, a method on risk assessment of groundwater pollution which included four indicators, the pollution assessment, the quality assessment, the vulnerability and the pollution load of groundwater, was presented based on the regional characteristics of Beijing Plain. Also, AHP and expert scoring method were applied to determine the weight of the four evaluation factors. Finally, the application of this method in Beijing Plain showed the area with high, relative high, medium, relative low and low risk of groundwater contamination was 1 232.1 km2, 699.3 km2, 1 951.4 km, 2 644 km2, and 133.2 km2, respectively. The study results showed that the higher risk in the western region was likely caused by the higher pollution load and its higher vulnerability, while the relatively high risk in the southeast of Beijing plain area, the Tongzhou District, is mainly caused by historical pollution sources. PMID- 24812949 TI - [Mixing behavior of nutrients in different seasons at Liaohe Estuary]. AB - The distribution and species of nutrients in the Daliaohe Estuary were studied in April, July and November, 2010. Concentrations of nutrients displayed obviously seasonal variability in the Daliaohe Estuary. Highest concentrations of PO4(3-) P, DOP, DTP and TP were in April, and the lowest were in July. While the highest PP was in November, the lowest was in July. The contents of NO3(-) -N and NO2(-) N reached the highest point in July, and the lowest was in April; however, the highest NH4(+) -N, DON and PN were in April and the lowest were in November. The main existing form of TN was NH4(+) -N in April, while in July and November NO3( ) -N was the dominant. The behavior of NO3(-) -N,DIN and TN was conservative in various seasons; the behavior of NO2(-) -N, NH4(+) -N and DON was conservative in April and November, while nonconservative in July, which indicated the exist of the extra source in the interior of the estuary. The SiO3(2-) of the Daliaohe Estuary was conservative, with the highest average concentration in November and the lowest in April. PMID- 24812950 TI - [Distribution of nitrogen in the sediment of Taige south river estuary]. AB - To characterize the distribution of nitrogen in the sediment of Taige south river estuary, column samples of sediments were collected and analyzed in April, 2012. Our results revealed that a synchronized trend existed among the levels of ammonium nitrogen (NH4(+) -N), organic nitrogen (Org-N) and total nitrogen (TN) in the surface layer of sediment. The NH4(+) -N positively correlated with TN and Org-N significantly (P < 0.05) while TN highly significantly correlated with Org N (P < 0.01). Org-N was the major form of nitrogen, comprising 93.38% of total nitrogen (TN) averagely. Both horizontal and vertical distribution of nitrogen in sediments apparently changed along the distance to stream outlet. In the horizontal dimension in sediments, Org-N and TN decreased progressively as forwarding into the lake in the extending direction of the main stream, while showed a "W"-type fluctuation in the diverged direction away from the main stream. The level of NH4(+) -N decreased rapidly within 100 m to the stream outlet and remained constantly at a lower level beyond 100 m. However, the level of nitrate nitrogen (NO3(-) -N) stabilized within 0-800 m and increased greatly beyond 800 m. In the vertical dimension in sediments, the level of NH4(+) -N increased with increasing depth. As the distance to the stream outlet increasing, the enrichment of NO3(-) -N was enhanced in surface layers rather than in lower subsurface layers. Alternatively, the enrichment of Org-N and TN were reduced in surface layers but enhanced in subsurface layers. PMID- 24812951 TI - [Selection and purification potential evaluation of woody plant in vertical flow constructed wetlands in the subtropical area]. AB - In order to solve the problem that wetland herbaceous plants tend to die during winter in subtropics areas, selection and purification potential evaluation experiments were carried out by introducing into the constructed wetlands 16 species of woody wetland plants. Cluster analysis was performed by including the morphological characteristics, physiological characteristics, as well as nitrogen and phosphorus accumulation of the woody wetland plants. The results indicated that there were significant differences among the tested woody plants in their survival rate, height increase, root length increase and vigor, Chlorophyll content, Superoxide dismutase, Malonaldehyde, Proline, Peroxidase, biomass, average concentration and accumulation of nitrogen and phosphorus. Based on the established evaluation system, the tested plants were clustered into 3 groups. The plants in the 1st group possessing high purification potentials are Nerium oleander and Hibiscus syriacus. Those in the 2nd group possessing moderate purification potentials are Trachycarpus fortune, Llex latifolia Thunb., Gardenia jasminoides, Serissa foetida and Ilex crenatacv Convexa. And those in the 3rd group with low purification potentials are Jasminum udiflorum, Hedera helix, Ligustrum vicaryi, Ligustrum lucidum, Buxus sempervives, Murraya paniculata, Osmanthus fragrans, Mahoniafortune and Photinia serrulata. PMID- 24812952 TI - [Correlation of substrate structure and hydraulic characteristics in subsurface flow constructed wetlands]. AB - The correlation of substrate structure and hydraulic characteristics was studied by numerical simulation combined with experimental method. The numerical simulation results showed that the permeability coefficient of matrix had a great influence on hydraulic efficiency in subsurface flow constructed wetlands. The filler with a high permeability coefficient had a worse flow field distribution in the constructed wetland with single layer structure. The layered substrate structure with the filler permeability coefficient increased from surface to bottom could avoid the short-circuited flow and dead-zones, and thus, increased the hydraulic efficiency. Two parallel pilot-scale constructed wetlands were built according to the numerical simulation results, and tracer experiments were conducted to validate the simulation results. The tracer experiment result showed that hydraulic characteristics in the layered constructed wetland were obviously better than that in the single layer system, and the substrate effective utilization rates were 0.87 and 0.49, respectively. It was appeared that numerical simulation would be favorable for substrate structure optimization in subsurface flow constructed wetlands. PMID- 24812953 TI - [Impacts of Eichhornia crassipes (Mart.) Solms stress on the growth characteristics, microcystins and nutrients release of Microcystis aeruginosa]. AB - Due to the large-scale application of Eichhornia crassipes (Mart.) Solms on the bioremediation of eutrophic lake in China, the influence of growth, physiological characteristics, microcystins production and release of M. aeruginosa by E. crassipes was investigated. Meanwhile, the release risk of nutrients from M. aeruginosa and the accumulation risk of microcystins in E. crassipe were explored through semi-continuous co-existence experiments. Our results indicated that M. aeruginosa was promoted by E. crassipes to undergo the cell death. Under the stress of E. crassipes, direct damage of phycocyanin and phycocyanin/allophycocyanin ratio in M. aeruginosa occurred, while the photosystem II-Hill reaction in M. aeruginosa was not interrupted. The PC/APC levels in the treatment of 10% and 20% water exchange rate were respectively decreased to 54.93% +/- 7.07% and 55.81% +/- 1.97% of the level in their relative controls after 8 days. Then, the final significant decrease of specific superoxide dismutase activity and the striking elevation of malondialdehyde content in M. aeruginosa could be the results of oxidative damage by E. crassipes. Algal malondialdehyde content in the treatment of 10% and 20% water exchange rate were respectively 2.95 +/- 0.074 and 2.22 +/- 0.086 times of the level in their relative controls on day 8. The release of nutrients from M. aeruginosa was accelerated because the decay and lysis of algal cells were promoted by E. crassipes. After 12-day co-existence experiments, the concentration of total dissolved nitrogen in water was brought back to the initial level and the release of total dissolved phosphorus was faster than nitrogen nutrients under the stress of E. crassipes. In addition, the microcystins production in M. aeruginosa was not stimulated and the extracellular microcystins were significantly eliminated by the influence of E. crassipes. The extracellular microcystins contents in the treatment of 10% and 20% water exchange rate were respectively decreased to 12.07 microg x L(-1) +/- 0.63 microg x L(-1) and 11.36 microg x L(-1) +/- 0.04 microg x L(-1) after 12 days. But the microcystins level in the whole plants of E. crassipes co-cultured with M. aeruginosa for 12 days was only about 5.95 ng x g(-1) +/- 0.76 ng x g(-1) FW. The increase of water exchange rate could reduce the damage of M. aeruginosa by E. crassipes, but had no significant effect on the microcystins elimination. PMID- 24812954 TI - [Effects of different pre-oxidants on DBPs formation potential by chlorination and chloramination of Yangtze River raw water]. AB - Yangtze River raw water from Yangshupu Water Plant, Shanghai was studied in this paper for reduced formation potential of chlorination and chloramination disinfection by-products (DBPs) after pre-oxidation by three kinds of common pre oxidants, whiich were potassium permanganate, chlorine and chlorine dioxide. Results of chlorination showed that removal effectiveness of all the selected oxidants on total chlorination DBPs was not significant, and the reduction percentages by ClO2, Cl2 and KMnO4 were 8.4%, 5.7% and 3.9%, respectively. The order of DBPs control effect was ClO2, > Cl2 > KMnO4. As to Yangtze River raw water in case of chlorine disinfection, using ClO2 as pre-oxidation agent showed relatively better effect on removal of DBPs. However, chloramination results demonstrated that impacts of the three preoxidants on DBPs formation potential were quite different, and the reduction percentages by ClO2 and KMnO4 were 18.1% and 4.1%, respectively, while pre-chlorination increased the potential by 12.3%. These results revealed that ClO2 had the highest removal effectiveness, meanwhile pre-chlorination should be avoided due to its notable increase in DBPs formation. PMID- 24812955 TI - [Adsorption of phenanthrene from aqueous solution on cetylpyridinium bromide (CPB) -modified zeolite]. AB - Surfactant-modified zeolites (SMZs) with different coverage types were prepared by loading of different amounts of cetylpyridinium bromide (CPB) onto natural zeolites and were used as adsorbents to remove phenanthrene from aqueous solution. The adsorption of phenanthrene from aqueous solution on monolayer and bilayer SMZs as a function of adsorbent dosage, initial phenanthrene concentration, contact time, and temperature was investigated using batch experiments. Results showed monolayer and bilayer SMZs were effective for the removal of phenanthrene from aqueous solution. The phenanthrene removal efficiency of SMZs increased with increasing adsorbent dosage, but the amount of phenanthrene adsorbed on SMZs decreased with increasing adsorbent dosage. The adsorption kinetics of phenanthrene on SMZs well followed a pseudo-second-order kinetic model. The equilibrium adsorption data of phenanthrene on SMZs at a low concentration of phenanthrene in solution could be described by the Linear equation and Freundlich equation. The main mechanism for phenanthrene adsorption onto monolayer SMZ is hydrophobic interaction, and the main mechanism for phenanthrene adsorption onto bilayer SMZ is organic partitioning. The calculated thermodynamic parameters such as Gibbs free energy change (deltaG(theta)), enthalpy changes (deltaH(theta)), and entropy change (deltaS(theta)) showed that the adsorption process of phenanthrene on SMZs is spontaneous and exothermic in nature. When the CPB loading amount of bilayer SMZ was twice as much as that of monolayer SMZ, the phenanthrene adsorption capacity for bilayer SMZ was slightly higher than that for monolayer SMZ. In a conclusion, both monolayer and bilayer SMZs are promising adsorbents for the removal of phenanthrene from water and wastewater, and monolayer SMZ is a more cost-effective adsorbent for phenanthrene removal than bilayer SMZ. PMID- 24812956 TI - [Characteristics and selectivity of photocatalytic-degradation of tetracycline hydrochloride]. AB - The photocatalytic-degradation behavior of tetracycline hydrochloride (TTC) was studied. The catalyst used was photosensitive semiconductor titanium dioxide (TiO2). The results showed that the photocatalytic degradation of TTC was well fitted to first order reaction kinetics model, and the adsorption was the control step of the whole photocatalytic-degradation process, indicating that the main degradation path was the photocatalytic reaction of TTC adsorbed on the surface of TiO2. Besides, through photocatalytic-degradation of the mixed solution of TTC and sulfamethoxazole or amoxicillin, the degradation of the two antibiotics showed obvious selectivity when the pH, TiO2 dosage and other conditions were changed. PMID- 24812957 TI - [Characterization of biocatalysed sulfate reduction in a cathode of microbial electrolysis system]. AB - In order to improve H2 utilization efficiency and to reduce energy consumption during the hydrogenotrophic sulfate reduction process, a two-chambered microbial electrolysis system (MES) with a biocathode was constructed. The performance of MES in terms of sulfate removal and the electron utilization was studied. With an applied voltage of 0.8 V, biocathode removed about 109.8 mg x L(-1) of SO4(2-) from the wastewater within 36 h of operation, and average reductive rate reached 73.2 mg x (L x d)(-1). The highest current density obtained from the MES was 50 60 A x m(-3). The total coulomb efficiency achieved in a cycle was (43.3 +/- 10.7)%, and around 90% of the effective electrons were used by the cathode bacteria for SO4(2-) reduction. During the operation of MES, the major products of SO4(2-) bio-reduction are sulfide and hydrogen sulfide. With an applied voltage of 0.4 V, both the SO4(2-) removal rate and electron output decreased compared with that of 0.8 V; however, the electric charge efficiency obtained by the MES increased and reached 70% when 0.4 V was applied. Meanwhile, ignorable H2 gas was detected at the end of the cycle, indicating bacteria might directly use cathode as the electron donor thus enhanced energy efficiency. The bacteria could use cathode of the MES as electron donor to reduce SO4(2-) effectively, which may provide a new method to lower energy consumption of the hydrogenotrophic sulfate reduction process, making advanced treatment for sulfate containing wastewater more affordable for practical applications. PMID- 24812958 TI - [Characteristics of dissolved organic matter in A/DAT-IAT system for municipal wastewater treatment based on ecological safety]. AB - To ensure the water-quality safety and harmlessness of effluent from municipal wastewater, based on the lab-scale improved SBR-A/DAT-IAT process, dissolved organic matter (DOM) in municipal wastewater, demand aeration tank (DAT) supernatant and final effluent were classified and separated by applying the ultrafiltration membranes, and indexes such as TOC, UV254, 3D-EEM and toxicity were measured, to find out the sources of the toxic substances. The results showed that the lab-scale A/DAT-IAT process performed well on each molecular weight fraction of DOM. The main composition in the effluent was humic-like substance. Along the process, The DOM distribution presented a trend of shifting to high molecular weight. Meanwhile, the aromaticity of DOM in the fraction with relative molecular weight below 1 x 10(3) increased significantly, leading to the increase in the reactivity of effluent with chlorine, which then increased the risk of disinfection by-products. In the raw wastewater, the toxic effects were originated from the fraction with relative molecular weight below 1 x 10(3), although the toxic effects were still originated from the same fraction in the effluent, they came from the biological treatment itself instead of the raw wastewater. Based on the analysis of TOC, UV254, 3D-EEM and toxicity, the removal of low molecular-weight humic-like substance should be emphasized to achieve the effluent organic emissions standards and to control the risk of chlorination by products and toxicity. Therefore, future studies should focus on the removal of this fraction of DOM by adjusting technological parameters or adding a targeted processing unit. PMID- 24812959 TI - [Membrane surface fouling properties in MBRs for high-salinity wastewater treatment]. AB - The properties of membrane foulants in MBR treating high-salinity wastewater were studied. Results showed that the removal efficiency of organics and NH4(+) -N was stable and high-quality effluent was obtained after the operation time of 121 d; the ratio of VSS/ SS decreased and SVI declined at the same time, indicating that the inorganic content of sludge increased which might lead to more compact flocs and higher settling ability; SMP and EPS of the sludge were largely changed with a lower proportion of protein and a higher proportion of humic acid. Scanning electron microscope-energy diffusive X-ray analyzer (SEM-EDX) demonstrated that Na, Al, Mg, Ca, K, Fe, Ti, Cr, W, Si and Cl were the major inorganic elements in membrane foulants; Gel filtration chromatography (GFC) illustrated that there were organic matters with high molecular weight trapped by membrane and formed the membrane foulants; Fourier transform infrared (FTIR) spectroscopy and Excitation emission matrix (EEM) fluoresce spectroscopy discovered that carbohydrates, protein and humic acid were the main content of organics in membrane foulants.; quantitative analysis of membrane foulants showed that the amount of inorganic membrane foulants were significant when treating high salinity wastewater. PMID- 24812960 TI - [Treatment of petrochemical secondary effluent by ozone-biological aerated filter]. AB - The advanced treatment of petrochemical secondary wastewater by ozone- aerated biological filter was carried out in this study. The effect of pH on ozonation and the removal of COD and UV254 by the ozone-aerated biological filter combined process were investigated. In addition, the variation of relative molecular mass distribution of organics and the characteristics of three-dimensional fluorescence spectra of the wastewater were also investigated. The results showed that the suitable operating conditions of the ozonation unit were: ozone dosage 10 mg x L(-1), contact time 4 min and slightly alkaline pH. Ozonation can transfer macromolecular organics into small molecular organics, resulting in a 15% increase in the percentage of the organics with small relative molecular mass (less than 1 000). The biodegradability of the petrochemical secondary effluent was significantly improved by ozonation, making it more suitable for the treatment by aerated biological filter. The removal efficiency of COD and UV254 were 40.8% and 45.8% when the hydraulic retention time was 3 hours and the gas to water ratio was 3:1 for BAF. The average COD of the petrochemical wastewater was 86.5 mg x L(-1) while the average COD of the effluent of the combined process was 49.4 mg x L(-1) when it was operated under optimal conditions. PMID- 24812961 TI - [Treatment of pectin wastewater by anaerobic biological process]. AB - Anaerobic biological process was used to treat pectin wastewater with acclimated sludge. The effects of the influent pectin concentration and the degradation temperature were investigated, and the intermediate products in pectin degradation were measured. Compared with the unacclimated sludge, the results showed that using acclimated sludge, the pectin removal efficiency was increased by 59.2%. The degradation rate of pectin at influent concentrations of 100, 2500 and 4500 mg x L(-1) were 4.5, 49.8 and 74.0 mg x (L x h)(-1), respectively, indicating that the degradation rate increased with the increase of the influent pectin concentration. The COD removal efficiency was relatively low (41.6% 82.0%) when the influent pectin concentration was lower than 500 mg x L(-1), but it could maintain above 91% when the influent pectin concentration was beyond 1000 mg x L(-1). The higher the temperature was, the shorter the time was needed for pectin degradation. The COD removal efficiency of anaerobic sludge for pectin wastewater was increased from 38.6% to 91.5% when the temperature ranged from 5 degrees C to 35 degrees C, but it was gradually weakened when the temperature exceeded 35 degrees C. The main intermediate products in pectin degradation were supposed to be acetic acid, propionic acid, lower ester, and alkyl alcohols (C12 C40). PMID- 24812962 TI - [Sorption mechanism of ofloxacin by carbon nanotubes]. AB - Sorption of ofloxacin (OFL) by carbon nanotubes is an effective method to control its fate in aquatic environment. The sorption process of OFL by mixed acid treated and non-treated multi-walled carbon nanotubes was discussed. Sorption kinetics, sorption isotherm, desorption, sorption thermodynamics and effect of pH were investigated. The results indicated that the sorption kinetics followed the pseudo-second order kinetics model. The equilibrium sorption capacity of OFL on MWCNTs-O was higher. The sorption isotherm could be fitted by both the Langmuir and Freundlich models. The equilibrium sorption capacity dropped when the pH of aqueous solution was in the range of 6.0 to 10.0. Obvious desorption hysteresis was observed during the desorption experiments, especially on MWCNTs-O. Sorption thermodynamics analysis showed that the interactions between the OFL and sorbents were mainly between molecules. More oxygen-containing functional groups introduced on MWCNTs provided OFL molecules with more sorptive sites, which facilitated the generation of hydrogen bonds, a relatively strong interaction. The hydrogen bonds dominated the sorption process of OFL by MWCNTs/MWCNTs-O, explaining the experimental phenomena. PMID- 24812963 TI - [Biosorption characteristics of Cu2+ by spent substrate of pleurotus oyster]. AB - To solve the problems of heavy metal pollution and agricultural wastes reclamation, spent substrate of pleurotus oyster was used as adsorbents to remove Cu2+ from aqueous solution. The effects of pH value, adsorption time, temperature and initial Cu2+ concentration on the adsorption behavior were determined by single factor experiments. The mechanisms were preliminarily investigated by SEM EDX, FTIR and XRD analysis. The results of single factor experiments showed that the adsorption rate and capacity reached 74.46% and 0.7446 mg x g(-1) respectively at an adsorbent concentration of 10 g x L(-1), a pH of 6, an adsorption time of 120 min, an adsorption temperature of 30 degrees C and an initial Cu2+ concentration of 8 mg x L(-1). The experimental data fitted well with Langmuir isotherm models and R2 reached 0.994 9, indicating the adsorption was a monolayer chemisorption. SEM-EDX, FTIR and XRD analysis indicated that the adsorption process mainly depended on the physical and chemical adsorption onto the substrate surface through electrostatic attraction, complexation and coordination reaction. The -OH, -COOH and -NH were the functioning groups for Cu2+ adsorption. PMID- 24812964 TI - [Adsorption dynamics and breakthrough characteristics based on the fluidization condition]. AB - Few studies on the adsorption dynamics and breakthrough characteristics based on the fluidization condition have been reported. In a fluidized bed adsorption reactor with phenol as the adsorbate and granular activated carbon as the adsorbent, the adsorption efficiency, adsorption dynamic characteristics, adsorption breakthrough curves and adsorption capacities were studied and compared with those of a fixed bed operated under the same conditions. The results showed that the adsorption efficiencies exceeded 93% in 5 min in both the fluidized conditions and fixed conditions at the superficial velocities of 8 mm x s(-1) and 13 mm x s(-1). Meanwhile, the above adsorption reactions fitted to Pseudo-second-order with linear correlation coefficients greater than 0.999. The adsorption capacity of fluidized conditions was 8.77 mg x g(-1) and 24.70 mg x g( 1) at the superficial velocities of 6 mm x s(-1) and 8 mm x s(-1). Generally, the fluidized bed reactor showed a higher adsorption efficiency and greater adsorption capacity than the fixed bed reactor. PMID- 24812965 TI - [Characteristics of speciation and evaluation of ecological risk of heavy metals in sewage sludge of Guangzhou]. AB - Contents of heavy metals in different sewage sludges were analyzed and the speciation distribution and bioavailability of heavy metals were investigated, and the risk assessment code (RAC) and toxicity characteristic leaching procedure for solid waste were used to evaluate the potential ecological risk and leaching toxicity risk of heavy metals in sludge samples, respectively. The results showed that contents of Cu, Cr, Pb and Zn were high and presented a great difference by different sources in sewage sludges. Most of heavy metals existed in non-residual fractions and percentages of the mobile fraction (acid soluble fraction) of heavy metals in acidic sludge were higher. According to the results of single extraction, 1 mol x L(-1) NaOAc solution (pH 5.0) and 0.02 mol x L(-1) EDTA + 0.5 mol x L(-1) NH4OAc solution (pH 4.6) were suitable for evaluating bioavailable heavy metals in acidic and alkaline sludge, respectively. Percentages of bioavailable heavy metals were higher with the stronger of sludge acidity. The mobile ability of heavy metals resulted in the high ecological risk of sludge samples, and the bioavailability of heavy metals caused acidic sludges with a very high ecological risk but alkaline sludges with the middle ecological risk. Leaching toxicity risk was very high in sludge samples except domestic sewage sludge. After the removal of bioavailable heavy metals, leaching toxicity risk of sludge samples was still high in spite of its decrease; however, part type of sludges could be implemented landfill disposal. PMID- 24812966 TI - [Spatial distribution and accumulation of heavy metal in arable land soil of China]. AB - Based on the domestic and foreign published papers about soil heavy metal contents, the present study explored the spatial variations of heavy metal contents in agricultural soil in China. Totally, 173 studies on soil Pb, 138 on Cd, 156 on Cu, 139 on Zn and 140 on Cr were collected. Firstly, the abnormal values were selected and removed, then the spatial distributions were obtained through Kriging method and the average values in the provinces were calculated. Results show that the spatial distributions of heavy metals have obvious regional characteristics and the southwest part of China has relatively high heavy metal concentrations in soils. Compared with the background value of soil heavy metal concentrations, nearly all of the provinces have higher Pb, Cd, Cu and Zn concentrations. Pb and Cd have the most obviously higher values than the background values. The highest difference of Pb concentration is in Yunnan Province with 1.91 times of the background, and the highest Cd difference is in Liaoning Province with 23.04 times of the background; The highest Zn enrichment is in Yunnan, with 1.55 times of the background; and the highest Cu difference with 2.92 times of the background value. PMID- 24812967 TI - [Pollution patterns and health risk assessment for polychlorinated biphenyls in soils from a capacitor storage site]. AB - Concentration profiles of polychlorinated biphenyls (PCBs) and toxicity risks of dioxin-like PCBs were investigated in soils collected from a capacitor-burial site. Based on the USEPA model of human health risk assessment, cancer and non cancer risks for these soils were also estimated when used for residential and industrial purposes. It was observed that the average concentrations of total PCBs (sigma PCBs, 22 congeners) in the soils were 6.23, 19.3, and 1 540 mg x kg( 1) at different depths of 0-30 cm, 30-100 cm, and 200-250 cm, respectively. Tri CBs and Tetra-CBs were the largest contributors to the total concentrations in the soils, making up 75.7%-94.0%. The toxic equivalent concentration (TEQs) of total PCBs was up to 457 microg x kg(-1), and PCB 126 had the highest contribution. Health risk assessment showed that under residential land uses, children was the most sensitive receptor although cumulative non-carcinogenic risks for both children and adults (0.927-1 760) nearly exceeded the acceptable level, while under industrial land uses except for the topsoil, the total non carcinogenic risks for workers exceeded the acceptable level. Under residential and industrial land uses, PCBs in the soils had high carcinogenic risks that were more than the acceptable level of carcinogenic risks (10(-6)-10(-5)). Inhalation exposure was the major way subjected to the carcinogenic risk as well as to the non-carcinogenic risk, regardless of children, adults, and workers involved. PMID- 24812968 TI - [Occurrence and spatial differentiation of polycyclic aromatic hydrocarbons in surface soils from Shenzhen, China]. AB - 188 surface soil samples were collected in Shenzhen of China to determine the occurrence and spatial differentiation of polycyclic aromatic hydrocarbons (PAHs), based on which we studied the correlation between PAHs concentrations and urbanization levels, as well as the PAHs ecological risk. The total concentrations of 28 PAHs (sigma28 PAHs), 16 EPA PAHs (sigma 16 PAHs) and 7 carcinogenic PAHs (sigma7 CarPAHs) ranged from 5 to 7939 ng x g(-1), 2 to 6745 ng x g(-1) and not detected to 3786 ng x g(-1), respectively. 8 kinds of land use types according to sigma16 PAHs average levels in descending order were: transportation lands, commercial lands, industrial lands, agricultural lands, residential lands, urban green space, orchards and woodland. And sigma16 PAHs of construction and non-construction lands samples were mainly derived from combustion of various fossil fuels with contribution of 75.1% and 68.2%, respectively. Significant positive correlation was also found between PAHs concentrations of high molecular weight and urbanization levels. And PAHs pollution in the top soils of Shenzhen was at a low-end level of the world. PMID- 24812969 TI - [Risk assessment and countermeasures of heavy metals pollution in Wanquan segment of Yanghe River]. AB - In order to investigate heavy metals contamination status in Wanquan segment of Yanghe River, Zhangjiakou, 9 water and sediments samples were collected respectively for analyzing Cu, Ni, Cd, Zn, Cr, Pb, Hg and As, with water quality indicators determined at the same time. The potential ecological risk index (PERI) was then employed to evaluate potential ecological risk of heavy metals in sediments. Results indicated that the concentrations of Cu, Ni, Cd, Zn, Cr, Pb, Hg and As in water samples ranged from 1.28-24.13, 1.13-16.84, 0.08-0.11, 1.80 10.65, 1.40-19.12, 0.13-2.05, 0.06-0.99, 0.46-4.22 microg x L(-1), respectively, which are all below the national water quality standard for the demands of industrial use and agricultural irrigation. Principal component analysis (PCA) was conducted to reveal the relationship between water quality indicators and heavy metals pollution in water samples. Concentrations of Cu, Ni, Cd, Zn, Cr, Pb, Hg and As in sediments ranged from 5.90-110.11, 17.34-56.04, 0.07-0.31, 38.71 116.74, 40.39-85.77, 18.65-22.74, nd-0.047, 0.85-9.98 mg x kg(-1), respectively. The descending order of potential ecological risk intensity caused by different heavy metals was: Cd > Cu > Hg > Ni > As > Pb > Cr > Zn, and the average value of each heavy metal was low, while middle-grade risk level of Cd and Hg were also found in several sites. Among all monitoring sites, the descending order of PERI of all target heavy metals was: YH-07 > YH-03 > YH-09 > YH-02 > YH-06 > YH-04 > YH-05 > YH-01, and the average value reached slight grade, while middle-grade risk level was detected in YH-07. Sampling locations in YH-02-YH-03 and YH-07-YH 09 were found with relatively high ecological risk level because of agricultural and anthropogenic activities, respectively. Finally, three risk management regions were figured out and corresponding countermeasures for improving the environmental quality of the watershed were proposed based on the research results. PMID- 24812970 TI - [Effects of group matching curing agent on exchangeable Pb, Cd, Zn contents in the potted soils and their accumulation in rice plants]. AB - A pot experiment was conducted to study the effects of a group matching curing agent (limestone plus sepiolite) with different concentrations (0, 1.0, 2.0, 4.0, 8.0, 16.0 g x kg(-1)) on the exchangeable Pb, Cd, and Zn contents in the potted soil collected from a mining area in southern China and their cumulative distribution in rice plants. The results showed that: (1) Exchangeable Pb, Cd, and Zn contents in the potted soils decreased obviously with the increase in the amounts of group matching curing agent by 15.3%-99.9%, 9.2%-99.9%, and 7.0% 99.9%, respectively, compared with the CK, indicating that the addition of limestone plus sepiolite effectively inhibited the uptake of Pb, Cd, Zn from soils into rice plants. (2) Growth conditions of rice plants were improved, and the heights of rice plants increased with the increase in the amounts of group matching curing agent. The rice yield reached the optimal level and was increased by 60.4% compared with the CK, when the amount of limestone plus sepiolite was 1.0 g x kg(-1). The uptake of heavy metals in different organs of rice plants decreased obviously with the increasing amounts of the group matching curing agent, and the Pb, Cd, and Zn contents of rice grains decreased by 2.2%-13.1%, 29.3%-79.3%, 19.5%-43.3% with different concentrations (1.0-16.0 g x kg(-1)) of the group matching curing agent, respectively, compared with the CK. PMID- 24812971 TI - [Impact of compounded chelants on removal of heavy metals and characteristics of morphologic change in soil from heavy metals contaminated sites]. AB - Na2 EDTA (EDTA) has been extensively applied in remediation of soil contaminated by heavy metals (HMs). However, it poses a threat to the environment due to its difficulty of degradation. In addition, it is of great importance to clarify the morphological distribution of these metals in soil, as it is related to the environmental risk of contaminated sites. Thus, in order to cut back the use of EDTA, a series of batch washing experiments were conducted to evaluate the removal of arsenic, cadmium, copper, and lead from the contaminated soil collected in a chemical plant. Furthermore, adopting the optimal ratio of EDTA/EDDS, the change of morphological distribution of HMs before and after washing was studied. The results indicated that the removal of arsenic, cadmium and lead reached the maximum when the ratio of EDTA/EDDS was 7:3 and the optimal value was 12.67%, 38.71% and 31.09%, respectively. The removal of copper reached 16.91% at an EDTA/EDDS ratio of 9:1. After washing, the absolute Fe-Mn oxide fraction concentration of arsenic was higher, which would increase the environmental risk; the morphological fraction distribution of cadmium was similar to the original soil; the removal of copper and lead was mainly derived from the Fe-Mn oxide fraction; as to lead, the absolute concentration of Fe-Mn oxide fraction decreased dramatically, was and the same was observed for the percentage in the organic fraction. Employing the compounded system, the removal of HMs could be improved, and meanwhile the amounts of bioavailable HMs declined. Hence, it is beneficial for providing theoretical support for HMs remediation. PMID- 24812972 TI - [Characterization of manganese oxidation by Pseudomonas sp. QJX-1]. AB - A manganese-oxidizing bacteria (QJX-1) was isolated from the soil of a manganese mine. It was identified as Pseudomonas sp. QJX-1 by 16S rDNA sequencing. Experimental results showed that the Pseudomonas sp. QJX-1 has a multi-copper oxidase gene CumA, which is an essential component for manganese oxidation by Pseudomonas sp. Under the condition of low initial inoculum level (D600, 0.020), 5.05 mg x L(-1 Mn2+ could be oxidized by QJX-1 within 48 h with a conversion rate of as high as 99.4%. In comparison with the eutrophic conditions, the oligotrophic condition dramatically increased the biological manganese oxidation rate. Biofilm formation by employing the quartz sand could further improve the oxidation rate of Mn2+. Based on these results, it is speculated that biological manganese oxidation in underground water treatment is comparatively high. PMID- 24812973 TI - [Effects of the ratio of NO3(-) -N to NO2(-) -N on the removal of sulfide and nitrogen by mixed culture and pure culture]. AB - Effects of the ratio of NO3(-) -N to NO2(-) -N on removal of sulfide and nitrogen by Pseudomonas fluorescens, Pseudomonas aeruginosa and mixed culture were investigated at the pH value of 7.0, temperature of 30 degrees C, ratio of sulfide to nitrate of 5/3 and anaerobic condition. Along with the decrease of ratio of NO3(-) -N to NO2(-) -N, NO(x)(-) -N, the removal rate by Pseudomonas fluorescens and Pseudomonas aeruginosa increased gradually, while S(2-) removal rate reduced. The NO(x)(-) -N removal rate by mixed culture increased first and became steady along with the decrease of ratio of NO3(-) -N to NO2(-) -N. The ratio of NO3(-) -N to NO2(-) -N had hardly influence on S(2-) removal by mixed culture. Accumulation of NO2(-) -N occurred due to a faster rate of NO3(-) -N reduction over NO2(-) -N reduction in the liquid culture of Pseudomonas fluorescens. Accumulation of NO2(-) -N did not occur in the liquid culture of Pseudomonas aeruginosa because it has a stronger ability to convent NO2(-) -N than Pseudomonas fluorescens. The behavior of NO(x)(-) -N by mixed culture in located between Pseudomonas fluorescens and Pseudomonas aeruginosa. The optimum ratio of NO3(-) -N to NO2(-) -N to achieve high removals of sulfide and nitrogen for Pseudomonas fluorescens and mixed culture were 5/5, 10/0 for Pseudomonas aeruginosa. The performance of sulfide and nitrogen removal by the mixed culture was higher than that by Pseudomonas fluorescens and Pseudomonas aeruginosa. PMID- 24812974 TI - [Carbon metabolic characteristics of airborne microbes in Hangzhou]. AB - Carbon metabolic characteristics in four sampling sites including Yan'an Road Business Street (YRBS), Tianmushan Jiaogong Cross Road (TJCR), Zhejiang Gongshang University Jiaogong Campus (ZJGSUJC) and Breeze-ruffled Lotus at Quyuan Garden (BLQG) in Hangzhou were analyzed using Biolog technology in this study. Results showed that average well color development (AWCD) values were at stationary phase after 240 h cultivation in all four selected sampling sites. Significant differences in sole carbon utilization characterized as AWCD value were found among the four sampling sites, and the highest carbon utilization capacity was observed at YRBS, followed by TJCR and ZJGSUJC, and the lowest at BLQG. The species abundance and diversity of airborne microbes deceased in the order of YRBS, TJCR, ZJGSUJC, and BLQG. In addition, sugar and amino acid utilization capacity of airborne microbes was significantly higher that other carbons sources in all four sampling sites. Significant differences in different sole carbon utilization of airborne microbes in the same sampling site were found. The sugar utilization capacity was the highest, and polymer utilization capacity was the lowest at YRBS. At BLQG, highest sugar and lowest amine utilization capacity was detected. Principal component analysis showed that the contribution of PC1 and PC2 was 43.8% and 23.4%, respectively, in different sampling sites. Significant differences in carbon metabolic characteristics of microbial community in the air were found among YRBS, BLQG and TJCR, and no differences were observed between TJCR and ZJGSUJC. PMID- 24812975 TI - [Study on the backward extraction of cellulase in rhamnolipid reverse micelles]. AB - This paper studied the backward extraction of cellulase in RL/isooctane/n-hexanol reverse micelles system. Several key parameters influencing the backward extraction efficiency and activity recovery of cellulase were investigated, including stripping aqueous pH, stripping time, salt type and ionic strength, and addition of alcohols. The experiment results indicated that the optimal parameter values as follows: stripping aqueous pH 7.0, stripping time 30 min, 0.15 mol x L( 1) of KCl, dosage of n-butanol 2%. Under above optimum conditions, the backward extraction efficiency and activity recovery were up to 76.22% and 93.39%, respectively. The backward extraction of cellulase using reverse micelles based on biosurfactant RL performs well. Furthermore, RL has many advantages such as high biodegradability, low critical micelle concentration, etc. The application prospects of RL reverse micelles are extensive. PMID- 24812976 TI - [Inner- and inter-species differences of mercury concentration in common fishes from the Yellow Sea]. AB - Mercury concentration in marine fishes and its influencing factors are the key problems in the study of mercury biomagnification in marine ecosystems. In order to understand the inner- and inter-species differences of mercury concentration in fishes from the Yellow Sea, a total of 164 marine wild fishes covering nine different species were collected from the area from August to October, 2012. Mercury (total mercury) concentration in fish muscle tissue was measured by a direct mercury analyzer. Body length and wet weight of each sample were also determined. Moreover, feeding habit and trophic level of different species were examined. Hg concentrations (dry weight) in the muscle tissues of the 164 individuals ranged from 0.025 micro x g(-1) to 0.526 microg x g(-1), with an average of (0.124 +/- 0.096) microg x g(-1). By an inner-species analysis, log10 Hg concentration was significantly correlated to their body length and wet weight. Predator fishes with trophic level > 2.8 were more readily to be contaminated by Hg than the filter feeder with trophic level < 2.8. Furthermore, species with higher increasing rate of weight had lower Hg concentration in the muscle due to growth dilution. The results suggest that length and weight are the main factors affecting the inner- species difference of mercury concentration in common fishes from the Yellow Sea, while dietary preference, trophic level and increasing rate of weight are the main factors affecting the inter-species difference from the Yellow Sea. PMID- 24812977 TI - [Study on the effect of enzymatic activity and acute toxicity of three PAEs on Eisenia foetida]. AB - The acute toxic effects of DMP, DEP and DBP to earthworms (Eisenia foetida) were examined in this study. The two pollutants are tested by filter paper contact method and natural soil method, results indicated that they were both poisonous to earthworms. Earthworms were exposed to DMP and DEP for 48 h by filter paper contact method, LC50 (DMP) is 129.603 microg x cm(-2) and LC50 (DEP) is 145.336 microg x cm(-2). Earthworms were exposed to DMP and DEP for 14 d by natural soil method, LC50 (DMP) is 1 560. 120 mg x kg(-1) and LC50 (DEP) is 1516. 186 mg x kg( 1). While non-calculatable for the LC50 of DBP due to its low water solubility, penetrating into the skin and cells of earthworm is not easy. The natural soil test method was used to study the effects of DMP, DEP and DBP on enzyme activities of earthworms, activities of superoxide dismutase (SOD), catalase (CAT) and acetylcholinesterase (AChE) were measured. SOD activity was induced by DMP and DEP, CAT is the most sensitive and the activity was induced by DEP and DBP at the low concentration and inhibited at the high concentration. AChE activity was inhibited by DEP and DBP at the low concentration and induced at the high concentration, finally exhibited a tendency to recover to the control level at 28 d. PMID- 24812978 TI - [Environmental safety assessment on the new super absorbent polymers applied into a soil-Chinese cabbage system]. AB - Super absorbent polymers (SAPs), a new water retention material, have a potential for application in water-saving agricultural production. In this study, we investigated the effects of SAPs, synthesized from natural plant extracts, on Chinese cabbage fresh weight, soil water content, soil water stable aggregates, soil microbial biomass (carbon) and soil microbial respiration under three water conditions (excessive, normal and deficient) and two SAPs application strategies (bulk treatment and spraying treatment). The results showed that the SAPs significantly promoted the soil water content, water-stable aggregates (> 0.25 mm) and the soil microbial activities, especially under the water deficient conditions. Meanwhile, SAP application strategy was of great significance to the effects on Chinese cabbage and soil properties. Compared with the control treatment under normal water condition, spraying treatment of Jaguar C (S-JC) could reduce irrigation water amount by about 25% without reducing the crop production. Furthermore, compared with the control treatment under the same water condition with S-JC (deficient), it could increase Chinese cabbage production by 287%. Thus, SAPs is an environmental friendly water-saving technique in agricultural production. PMID- 24812979 TI - [Study on dynamics of hydrogen sulfide and carbonyl sulfide emission fluxes from Suaeda salsa marsh in the Yellow River estuary]. AB - The H2S and COS emission fluxes from Suaeda salsa marsh in the Yellow River estuary were measured using the static chamber and Chromatogram method during the growth season (May to October), the results showed that the seasonal and diurnal variations of H2S and COS emission fluxes were obvious, and Suaeda salsa marsh in the Yellow River estuary was the sources for both H2S and COS during the growth time, and the mean H2S and COS emission fluxes from Suaeda salsa marsh were 4.97 microg x (m2 x h)(-1) and 0.92 microg x (m2 x h)(-1), respectively. Different environmental factors had different effects on the emission fluxes of H2S and COS from Suaeda salsa marsh, in which the SO4(2-) content and water content in the soil were the main factors that affected the H2S and COS emission fluxes, respectively. Sulfur gases emissions from Suaeda salsa marsh may be affected by many factors, such as plant, tide status and so on, so that should be further studied. PMID- 24812981 TI - HCI's Top Ten Tech Trends 2014: getting the big picture. PMID- 24812980 TI - [Key microbial processes in nitrous oxide emissions of agricultural soil and mitigation strategies]. AB - Nitrous oxide (N2O) is a powerful atmospheric greenhouse gas, which does not only have a strong influence on the global climate change but also depletes the ozone layer and induces the enhancement of ultraviolet radiation to ground surface, so numerous researches have been focused on global climate change and ecological environmental change. Soil is the foremost source of N2O emissions to the atmosphere, and approximately two-thirds of these emissions are generally attributed to microbiological processes including bacterial and fungal denitrification and nitrification processes, largely as a result of the application of nitrogenous fertilizers. Here the available knowledge concerning the research progress in N2O production in agricultural soils was reviewed, including denitrification, nitrification, nitrifier denitrification and dissimilatory nitrate reduction to ammonium, and the abiotic (including soil pH, organic and inorganic nitrogen, organic matter, soil humidity and temperature) and biotic factors that have direct and indirect effects on N2O fluxes from agricultural soils were also summarized. In addition, the strategies for mitigating N2O emissions and the future research direction were proposed. Therefore, these studies are expected to provide valuable and scientific evidence for the study on mitigation strategies for the emission of greenhouse gases, adjustment of nitrogen transformation processes and enhancement of nitrogen use efficiency. PMID- 24812982 TI - Trend: personalized medicine. Putting genetic data in clinicians' hands. Researchers make progress on decision support, but gaps remain in standards, integration, workflow. PMID- 24812983 TI - Trend: standards development. Catching FHIR. A new HL7 draft standard may boost web services development in healthcare. PMID- 24812984 TI - Trend: imaging and HIE. Picture show. In the new, connected healthcare, where will the image live? PMID- 24812985 TI - Trend: readmissions reduction. Harnessing analytics. A long, complex journey ahead, but there is reason for optimism. PMID- 24812986 TI - Trend: social media. The surface is being scratched. Providers are using social media to engage patients, collaborate with each other. PMID- 24812987 TI - Trend: patient-generated health data. Transforming data into decision support. The advance of patient-facing connected technologies will allow providers to track patients on a daily basis. PMID- 24812988 TI - Trend: mobile and messaging. Green light on clinician-to-clinician texting. Healthcare organizations are giving their providers the ability to text each other, but security remains a challenge. PMID- 24812989 TI - Trend: EHR optimization. Post-implementation advancements. Leaders from various healthcare organizations explain how they have been moving forward with their EHRs following implementation. PMID- 24812990 TI - Trend: smart devices. Paving the way to the future. Technology advancements are promising better patient care, but is the industry moving too fast? PMID- 24812991 TI - Trend: security and privacy. Perfect storm. Rapidly evolving technology, policy developments and consolidation are putting new security demands on provider organizations. PMID- 24812992 TI - Keeping data safe. The threat of security breaches can fuel preventive strategies. PMID- 24812993 TI - Edward Marx, CIO of the year, 'bullish' on HIT. Award honoree discusses opportunities, challenges for the industry. PMID- 24812994 TI - Beyond interpretation. How radiologists can survive in a value-based care model. PMID- 24812995 TI - Flourishing as a collaborative payer model in Missouri. Essence healthcare is accomplishing healthcare's triple aim 'plus one'. PMID- 24812996 TI - Integration comes to life in Michigan. How one hospital brought together many disparate players to launch a highly integrated 'intelligent' care delivery system. PMID- 24812997 TI - New hiring rules. Can a personal habit be a dealbreaker for highly qualified candidates? If you are a smoker in Florida, maybe so. PMID- 24812998 TI - Co-metabolic degradation of benzo(e)pyrene by halophilic bacterial consortium at different saline conditions. AB - Polyaromatic hydrocarbons (PAHs) with high molecular weight (more than three benzene rings) were difficult to degrade in saline environment. The present study details about the bacterial consortium enriched from industrial sludge from salt manufacturing company, Tuticorin, Tamilnadu (India), which was capable of degrading 1, 4 dioxane (Emerging micropollutant) and also phenanthrene as sole carbon source under saline condition. The halophilic bacterial consortium was able to degrade low molecular weight (LMW) phenanthrene, but unable to degrade high molecular weight (HMW) benzo(e)pyrene. To overcome this problem, phenanthrene was added as co-substrate along with benzo(e)pyrene which enhanced the biodegradation process by co-metabolism under saline conditions. The consortium potentially degraded 80% and 99% of benzo(e)pyrene in 7 days and phenanthrene in 5 days at 30 g l-1 of NaCl concentration. When the saline concentration increased to 60 g l-1, degradation of phenanthrene (97% in 8 days) and benzo(e)pyrene (65% in 10 days) was observed. Further increase in saline concentration to 90 g I-1 of NaCI showed reduction in the percent degradation of phenanthrene and benzo(e)pyrene leads to 30.3% and 9% respectively in 6 days. Potential bacterial strains, present in PAHs degrading bacterial consortium were identified as Achromobacter sp. AYS3 (JQ419751), Marinobacter sp. AYS4 (JQ419752) and Rhodanobacter sp. AYS5 (JQ419753). The present study details about the effect of salinity on PAHs degradation and vital role of co-metabolism on biodegradation of benzo(e)pyrene with phenanthrene under saline conditions. PMID- 24812999 TI - The influence of different types of grassland on soil quality in upland areas of Czech Republic. AB - The diversity of grassland in upland areas of Czech Republic was studied on selected soil characteristics of these biotopes. In the first phase, 44 soil characteristics were studied and mutual correlations were found between many of them. In the following phase characteristics were chosen which correlated most with other soil characteristics and, at the same time, were easy to evaluate in practise. A great number of correlations were also evidenced between many soil characteristics and the content of humus and nitrogen, which are closely linked to organic matter in soil. In studying these characteristics on selected areas with different types of grassland and consequential cluster analysis and further evaluation, the grassland plots were divided into three groups, from newly established vegetation to species-rich communities. Non-parametric analysis was carried out on the results and a statistically significant difference was proved between the species rich and poorvegetation and carbon and nitrogen content of the soil. Slightly different humus quality (higher amount of HA) was also found under richer vegetation. These results show that at 0-20 cm layer, 58.9 tonnes of carbon ha-1 was measured under species-poor pastureland and 106.1 tonnes of carbon ha under species-rich vegetation. The results showed that besides supporting species diversity, the described quality change can also be important for carbon sequestration. The difference of about 40-50 tonnes of carbon ha and converting 10% of grassland in the Czech Republic to species-rich vegetation would mean sequestration of about 3.9 Mt carbon. If only agroenvironmentally subsidized areas are converted, carbon sequestration in such vegetation could amountto 1.7 Mt. PMID- 24813000 TI - Effect of straw enriched environment on behaviors of nursery piglets reared in the farrowing pens. AB - The aim of the present study was to study the effects of straw enriched environment on behaviors of nursery piglets reared in the farrowing pens. Fourteen litters (Large White x Landrace) weaned at 35 days of age were reared in the modified farrowing pens, flatdecks (F) or straw enriched pens (P), until 70 days of age. The behavior was observed from 7 to 10 weeks of age. Results showed that straw enriched pens significantly increased walking, total exploring and active behavior, reduced lying and exploring behavior direct to pen, but not that direct to penmates. Meanwhile, in wk8-wk10, the number of fighting piglets in P was significantly more than that in F. With increasing age, piglets exploring in total or direct to pen, and active piglets decreased gradually in F. In P, piglets exploring in total or that direct to straw decreased, and reached a trough in wk9, then rose up. Lying piglets in F increased with age while that in P increased only at 9 or 10 weeks of age. Walking piglets decreased significantly with age in both environments. The number of fighting piglets in F was a maximum in wk7 while it in P was fewer in wk7 or wk8. Furthermore, the activity of piglets in F was at peak during 08:00-10:00 hr and reached a trough during 11:00 13:00 hr. In P, refreshed straw kept piglets at a more active state during morning, shortened the activities trough at noon, and showed high activity in the afternoon. In conclusion, present straw enriched pen can prevent fighting, increase total exploring, reduce exploring direct to pen, and even affect the rhythm of behavior. It is applicable for improving welfare of nursery piglets. PMID- 24813001 TI - Changes in nutrients ratio along the central Bay of Bengal coast and its influence on chlorophyll distribution. AB - Elemental ratio of nutrients and its influence on chlorophyll a distribution was studied along the central coast of Bay of Bengal using multivariate statistical methods. High chlorophyll concentration was observed during summer (1.81 MUg l-1) and premonsoon (1.95 MUgl-1), however, it was high in top 20 m during premonsoon season in tandem with high nitrate (N) and silicate (Si) concentration. N:P (phosphate) ratio was less than Redfield ratio (16:1) during all seasons, indicating the Bay of Bengal as nitrate limited and confirmed the results of Principal ComponentAnalysis (PCA) with positive loading and multiple regression analysis showing negative correlation between this ratio and chlorophyll concentration during all seasons. Whereas, N:Si ratio was < 1 and Si:P ratio > 7 in top 20 m during all seasons explained the deficiency of phosphorus and enrichment of silicate in the central Bay of Bengal. Regression analysis between Si:P and N:Si ratios with chlorophyll showed negative correlation during premonsoon and summer respectively. Thus, the present results confirmed that nutrient molar ratios such as N:P<16; Si:P>7 and N:Si<1 was indicative of a potential N and Si limitation and are the primary limiting nutrients in the central Bay of Bengal in determining chlorophyll concentration. PMID- 24813002 TI - Efficacy of aggregation pheromone in trapping red palm weevil (Rhynchophorus ferrugineus Olivier) and rhinoceros beetle (Oryctes rhinoceros Linn.) from infested coconut palms. AB - Red palm weevil and Rhinoceros beetle are the major pests inflicting severe damage to coconut palms. Due to ineffectiveness of the current management practices to control the two important pests on coconut, a study was conducted to know the attractiveness of red palm weevil and rhinoceros beetle to aggregation pheromone. Olfactometer studies indicated that the aggregation pheromone of red palm weevil and rhinoceros beetle attracted significantly more number of weevils (13.4 females and 7.6 male weevils) and beetles (6.5 male and 12.3 female beetles), respectively than control. Similarly, field studies found that both 750 and 1000 mg pheromone dosage lures of red palm weevil and rhinoceros beetle trapped significantly higher numbers of weevils (695.80 and 789 weevils, respectively) and beetles (98 and 108 beetles, respectively) in traps (P < 0.05), respectively. On an average (n = 6 field trials) 80-85% red palm weevil and 72 78% rhinoceros beetle population got trapped. Observations indicated activity of red palm weevil throughout the year and of rhinoceros beetle from September to March around Bangalore, South India. Pheromone traps for red palm weevil can be placed in fields from June to August and October to December and September to February for rhinoceros beetle. Population reductions of the two coleopteran pests by pheromone traps are compatible with mechanical and cultural management tools with cumulative effects. PMID- 24813003 TI - Evaluation of morphological variation and biomass growth of Nostoc commune under laboratory conditions. AB - Nostoc commune is a blue green alga used for health food and herbal medicine due to its nutritional values and antioxidant properties. However, wild type N. commune has been decreasing in quantity as a result of ever-growing market demand and environmental pollution. Therefore, artificial culture of N. commune is important as it can bring great social and economic benefits. In this article, N. commune was cultured in BG11 medium, under which condition morphological variation and biomass growth of N. commune were investigated. Results indicated that concentration, fresh weight and dry weight of the colony increased fastest at 40 rpm from the 1st day to 14th day and the fresh and dry weight increased as the culturing time was prolonged, and reached 27.22 g l-1 and 0.88 g l-1 respectively on 56th day. Aggregated cell mass formed on 4th day and it expanded to asteriated colonies on 10th day. Single microcolonies formed on the 21st day had diameters 200-250 MUm. Macrocolonies obtained after 28 days had diameters of 5 mm on 42nd day. Discoid colonies were formed as macrocolonies ruptured on 49th day and the diameter reached 15 mm on 56th day. Results of the present study can promote large-scale industrial production of N. commune. PMID- 24813004 TI - Anti-oxidative enzyme changes associated with chickpea calli tolerant to Ascochyta rabiei culture filtrate. AB - Ascochyta blight caused by Ascochyta rabiei (Pass.) Labrousse is a major biotic constraint in production of chickpea. In the present investigation, all chickpea genotypes [E100Y (m), Gaurav, Pb-7 and L550] induced 100% callus on standard medium with greenish colour and fragile structure. These calli were used for in vitro screening against pathogen, A. rabiei culture filtrate at 0, 5, 10, 15 and 20% concentrations. Survival rate of calli in all chickpea's genotypes were reduced significantly at higher concentration (15%) of culture filtrate. The culture filtrate concentration of 20 % was lethal for calli of all chickpea's genotypes. Hence, biochemical changes viz. total soluble proteins and activities of anti-oxidative enzymes (polyphenol oxidase, peroxidase and catalase) were estimated at 15% and below concentration of culture filtrate. Tolerant calli of resistant genotype, E100 Y (m) revealed significantly higher total soluble proteins (10.04 mg g-1 f.wt. of callus) and activity of anti-oxidative enzymes, polyphenol oxidase (9.0 unit absorbance change min-1 mg-1 protein) and peroxidase (19.09 unit absorbance change min-1 mg-1 protein) and lower catalase (18.65 MU moles of H2O2 utilized min-1 mg-1 protein) at higher (15%) concentration of culture filtrate followed by moderately resistant (Gaurav), and susceptible genotypes (Pb-7 and L550). Thus, higher polyphenol oxidase and peroxidase and lower catalase activity in chickpea's genotypes against culture filtrate of A. rabiei could be used as parameters for screening resistant genotypes to pathogen, A. rabiei. PMID- 24813005 TI - Concordance between macrophytes and macroinvertebrates in a Mediterranean river of central Apennine region. AB - The main aim of this study was to improve the knowledge about the concordance among macrophytes and macroinvertebrates to provide complementary information and facilitate the procedures for quality assessment of river ecosystems. Macrophytes and macroinvertebrates were collected in 11 sampling sites along a central Apennine calcareous river in October 2008 and June 2009. The concordance between the two biomonitoring groups was tested according to several environmental parameters. The comparison of data matrix similarities by Mantel test showed differences in the assemblage of macrophytes and macroinvertebrates along the river since correlation values were 0.04, p > 0.05 in October 2008 and 0.39, p > 0.05 in June 2009. The study revealed lack of concordance between the two groups, emphasizing that the information provided by macrophytes and macroinvertebrates does not overlap in terms of response to environmental parameters. Indeed, the two different biological groups resulted useful descriptors of different parameters. Together, they could represent a complementary tool to reflect the river environmental quality. PMID- 24813006 TI - Interactive effect of ultraviolet-B and mineral nutrients on accumulation and translocation of trace elements in wheat crop. AB - Field study was conducted in two wheat cultivars (Triticum aestivum L. cv. HD 2329 and HUW 234) by supplimenting UV-B irradiation with different levels of mineral nutrients in order to evaluate the accumulation and translocation of trace elements. sUV-B significantly affected accumulation and translocation of most of the metals studied. Application of nutrients at higher doses enhanced the accumulation of trace elements in plants and grains of both cultivars. A higher dose of nutrient along with sUV-B resulted in increased accumulation of lead both in plants and grains, cadmium and chromium in grains, and copper in plants and decreased accumulation of cadmium in plants, copper in grains, chromium in plants and iron in plants and grains of both the tested cultivars. Nickel concentration increased in plants of HUW 234 due to simultaneous stress. Trace element concentration did not differ noticeably in the tested cultivars but the stress response differed perceptibly. Cultivar HD 2329 showed more significant interaction than HUW 234. PMID- 24813008 TI - Enzymatic bioremediation of polyaromatic hydrocarbons by fungal consortia enriched from petroleum contaminated soil and oil seeds. AB - The present study focuses on fungal strains capable of secreting extracellular enzymes by utilizing hydrocarbons present in the contaminated soil. Fungal strains were enriched from petroleum hydrocarbons contaminated soil samples collected from Chennai city, India. The potential fungi were isolated and screened for their enzyme secretion such as lipase, laccase, peroxidase and protease and also evaluated fungal enzyme mediated PAHs degradation. Total, 21 potential PAHs degrading fungi were isolated from PAHs contaminated soil, which belongs to 9 genera such as Aspergillus, Curvularia, Drechslera, Fusarium, Lasiodiplodia, Mucor Penicillium, Rhizopus, Trichoderma, and two oilseed associated fungal genera such as Colletotrichum and Lasiodiplodia were used to test their efficacy in degradation of PAHs in polluted soil. Maximum lipase production was obtained with P. chrysogenum, M. racemosus and L. theobromae VBE1 under optimized cultural condition, which utilized PAHs in contaminated soil as sole carbon source. Fungal strains, P. chrysogenum, M. racemosus and L. theobromae VBE1, as consortia, used in the present study were capable of degrading branched alkane isoprenoids such as pristine (C17) and pyrene (C18) present in PAHs contaminated soil with high lipase production. The fungal consortia acts as potential candidate for bioremediation of PAHs contaminated environments. PMID- 24813007 TI - Studies on kinetics of water quality factors to establish water transparency model in Neijiang River, China. AB - The basis for submerged plant restoration in surface water is to research the complicated dynamic mechanism of water transparency. In this paper, through the impact factor analysis of water transparency, the suspended sediment, dissolved organic matter, algae were determined as three main impactfactors for water transparency of Neijiang River in Eastern China. And the multiple regression equation of water transparency and sediment concentration, permanganate index, chlorophyll-a concentration was developed. Considering the complicated transport and transformation of suspended sediment, dissolved organic matter and algae, numerical model of them were developed respectively for simulating the dynamic process. Water transparency numerical model was finally developed by coupling the sediment, water quality, and algae model. These results showed that suspended sediment was a key factor influencing water transparency of Neijiang River, the influence of water quality indicated by chemical oxygen demand and algal concentration indicated by chlorophyll a were indeterminate when their concentrations were lower, the influence was more obvious when high concentrations are available, such three factors showed direct influence on water transparency. PMID- 24813009 TI - Optimization of parameters for phenol degradation using immobilized Candida tropicalis SSK01 in batch reactor. AB - Bioremediation of phenol was done using Candida tropicalis SSK01 immobilized cells isolated from petroleum contaminated soil. Optimization of phenol degradation studies was carried at 30 degrees C to 40 degrees C, pH 6 to 8 and initial concentration of 300 mgl-1 to 900 mgl-1. Candida tropicalis SSK01 cells immobilized using sodium alginate were used in phenol degradation studies. Optimization of phenol degradation was performed by Central Composite Design (CCD). A total of 20 experiments were carried out and the optimal degradation of 95.2% was observed at 34.20 degrees C at pH 6.86 with initial concentration of 610 mgl-1 The R2, adjusted R2 and Predicted R2 values were 0.9976, 0.9955 and 0.9919 respectively which indicates that experimental values are in good agreement with the predicted values. PMID- 24813010 TI - Inhibitory effects of seaweed extracts on the growth of the vaginal bacterium Gardnerella vaginalis. AB - Of 44 species of seaweed screened for potential anti-Gardnerella vaginalis activity, 27 (61.4%) showed antimicrobial activity by the agar disk-diffusion method. Among them, the strongest activities against the pathogen were exhibited by Chlorophyta, with Ulva pertusa producing an 11.3-mm zone of inhibition at 5 mg disk-1. The MIC values of U. pertusa extracts against both G. vaginalis KCTC 5096 and KCTC 5097, the main cause of vaginosis, were 312 MUg ml-1, while the MIC values against both Candida albicans KCTC 7270 and KCTC 7965, the main cause of candidiasis, were 2.5 mg ml-1. Against Lactobacillus gasseri KCTC 3173 and Lactobacillus jensenii KCTC 5194, members of the normal vaginal microflora, no inhibitory effect was seen even at 10 mg ml-1. To identify the primary active compounds, a U. pertusa powder was successively fractionated according to polarity, and the main active agents against G. vaginalis KCTC 5096 were determined to be nitrogenous compounds (156 MUg ml-1 of the MIC value). According to these results, it was suggested that extracts of the seaweed U. pertusa are valuable for the development of natural therapeutic agents for treating women with bacterial vaginosis. PMID- 24813011 TI - Drying, burning and emission characteristics of beehive charcoal briquettes: an alternative household fuel of Eastern Himalayan Region. AB - Beehive charcoal briquettes were produced from powdered charcoal in which soil was added as binder. It was found to be an eco-friendly, clean and economic alternative source of household fuel for the people of Eastern Himalayan Region. Experiments were conducted to determine natural drying behaviour, normalised burn rate, temperature profile and emission of CO, CO2, UBHC (unburnt hydrocarbons) and NO(x) of beehive briquettes prepared from 60:40; 50:50 and 40:60 ratios of charcoal and soil. It was observed that under natural drying conditions (temperature, humidity) briquettes took 433 hr to reach equilibrium moisture content of 5.56-10.29%. Page's model was found suitable to describe the drying characteristics of all three combinations. Normalised burn rate varied between 0.377-0.706% of initial mass min-1. Total burning time of briquette ranged between 133-143 min. The peak temperature attained by briquettes ranged from 437 degrees C to 572 degrees C. All the briquette combinations were found suitable for cooking and space heating. Emission of CO, CO2, UBHC, NO and NO2 ranged between 68.4-107.2, 922-1359, 20.9-50.8, 0.19-0.29 and 0.34-0.64 g kg-1, respectively which were less than firewood. PMID- 24813012 TI - Aerobic biodegradation of azo dye Acid Black-24 by Bacillus halodurans. AB - Bacillus halodurans MTCC 865 was employed for decolorization of textile azo dye, Acid Black-24 (AB-24). Thousand mgl-1 of AB-24 was decolorized with 90% efficiency by the strain within 6 hrs at pH 9 and 37 degrees C with 5% NaCl under static conditions in screening medium. Decolorization was evaluated by measuring the periodic decrease in absorbance at 557 nm (lambda(max)). Biodegradation of Acid Black-24 was determined by FTIR and HPLC. The FTIR spectrum of the AB-24 dye suggests the presence of azo bond (-N = N-) peak at 1618.28 cm-1. Absence of the azo bond in the degraded sample spectrum indicates biodegradation of the dye. Formation of metabolites with different retention times in HPLC analysis further confirmed degradation of the azo dye, Acid Black 24 by Bacillus halodurans. PMID- 24813013 TI - Molecular characterization of cellulose-degrading Bacillus pumilus from the soil of tea garden, Darjeeling hills, India. AB - Bio-fuel produced from ethanol is economically and environmentally advantageous in context of changing global climate. A large number of microorganisms are capable of cellulase production but most of them cannot be utilized commercially due to their low activity. In the present study, an effiecient cellulose degrading strain of Bacillus pumilus was obtained after thorough screening for the production of extracellular cellulases. Out of a total of 144 microbes isolated from soils of Darjeeling hills of India, nineteen were found to be cellulose degrader under in vitro conditions as observed by clearing zone on CMC agar plates. Isolate #35 had high cellulolytic activity as observed by a clearing zone of 26.83 mm diameter formed on CMC - agar plate. The isolate was characterized and identified as Bacillus pumilus. The isolate was submitted to National Agriculturally Important Microbial Culture Collection (NAIMCC), NBAIM, Mau with Accession number NAIMCC-B-01415. Transposon (Tn5) mutants of wild type isolate Bacillus pumilus NAIMCC-B-01415 were generated and screened for the absence of cellulose degradation. Of 365 B. pumilus NAIMCC-B-01415 mutants obtained, only two were unable to degrade cellulose under in vitro conditions. Inverse PCR studies with B. pumilus NAIMCC-B-01415 :: TL5, a cellulose degradation mutant of B. pumilus NAIMCC -B-01415 revealed presence of Cys B (Cystein protein regulatory) gene involved in cellulose degradation. The participation of Cys B gene in cellulase degradation is reported here. PMID- 24813014 TI - Real time detecting of harmful dinoflagellate Cochlodinium polykrikoides using unmanned surface vehicle in dynamic environments. AB - Since the first occurrence in 1982, red tides have been observed annually in Korean coastal waters in the form of harmful dinoflagellate Cochlodinium polykrikoides blooms. The distinction in the proposed method for red tide monitoring is the focus on the narrow stripe red tide at an early stage to allow for advanced actions. The distance graph between Head of Narrow Red tide (HNR) and location of the robot have suggested in reference to unknown searching area. With mapping and path planning, then, it can quickly keep tracking out even if the magnitude and direction of current flow was changed. The one-hundred times simulations of different situations were attempted to comparison by box plot both algorithms of speed by reaching the right side of simulation window. Consequently, the red tide tracking algorithm is based on the red tide probability map and the tracking & recovering path planner. Inputs to the algorithm include the measured flow velocities and the detection or non-detection state at each robot location. Furthermore, a USV (Unmanned Surface Vehicle) model is added to evaluate the effectiveness of the algorithm. This approach for red tide monitoring may lead to a breakthrough in the field of environmental surveillance. PMID- 24813015 TI - Analysis of oil content of Jatropha curcas seeds under storage condition. AB - Jatropha curcas has been recognized as an ideal plant for biodiesel. There are unlimited reasons to consider Jatropha curcas a better tree borne oilseed plants than any other as it grows well on arid soils and entail minimal investment. The present study evaluates the effect of seed storage on quality and quantity of oil content such that it can be used for oil extraction and ensures availability of biodiesel throughout the year. The seeds were collected and stored at four temperatures viz. -5 degrees C, 0 degrees C, 5 degrees C and room temperature (open air condition) for 15 months of storage durations and evaluated at every three months interval. There was a significant decrease in oil content and oil quality with increase in storage duration. Although, the seed stored at temperature 5 degrees C gave the highest quality and quantity attributes at all durations. The first 3 months of storage account for the least decline as in the initial oil content in Kernel weight basis (54.61%) and seed weight basis (36.12%), there was a only decrease of 4.67% and 4.97% respectively at 5 degrees C whereas in other temperatures viz. -5 degrees C, 0 degrees C and room temperature (open air condition), there was a decline of 18.11, 14.48 and 9.06% in kernel weight basis and 18.36, 15.14 and 9.30% in seed weight basis respectively which accelerated with duration. Similarly, quality parameters viz. moisture content, acid value, iodine value, saponification value, refractive index (30 degrees C), relative viscosity and specific gravity were initially as 7.59%, 1.42 mg KOH g-1 oil, 108.61 g l2 100 g-1 oil, 189.37 mg KOH g-1 oil, 1.466, 21.30 and 0.911 respectively which change to 13.71%, 1.74 mg KOH g-1 oil, 107.95 g l2 100 g-1 oil, 191.48 mg KOH g-1 oil, 1.470, 23.45 and 0.918, respectively after 3 months of storage. Hence, change in quality and quantity parameters indicated the importance of proper seed storage on availability of bio diesel throughout the year and economics in its processing i e., transesterification. PMID- 24813016 TI - Modelling system dynamics and phytoplankton diversity at Ranchi lake using the carbon and nutrient mass balance equations. AB - Modelling system dynamics in a hyper-eutrophic lake is quite complex especially with a constant influx of detergents and sewage material which continually changes the state variables and interferes with the assessment of the chemical rhythm occurring in polluted conditions as compared to unpolluted systems. In this paper, a carbon and nutrient mass balance model for predicting system dynamics in a complex environment was studied. Studies were conducted at Ranchi lake to understand the altered environmental dynamics in hyper-eutrophic conditions, and its impact on the plankton community. The lake was monitored regularly for five years (2007 - 2011) and the data collected on the carbon flux, nitrates, phosphates and silicates was used to design a mass balance model for evaluating and predicting the system. The model was then used to correlate the chemical rhythm with that of the phytoplankton dynamics and diversity. Nitrates and phosphates were not limiting (mean nitrate and phosphate concentrations were 1.74 and 0.83 mgl-1 respectively). Free carbon dioxide was found to control the system and, interacting with other parameters determined the diversity and dynamics of the plankton community. N/P ratio determined which group of phytoplankton dominated the community, above 5 it favoured the growth of chlorophyceae while below 5 cyanobacteria dominates. TOC/TIC ratio determined the abundance. The overall system was controlled by the availability of free carbon dioxide which served as a limiting factor. PMID- 24813017 TI - Prevalence of arsenic exposure in population of Ballia district from drinking water and its correlation with blood arsenic level. AB - An investigation was carried out to ascertain the effect of arsenic in the blocks of Ballia district in Uttar Pradesh in the upper and middle Ganga plain, India. Analysis of 100 drinking water samples revealed that arsenic concentration was below 10 MUg l-1 in 60% samples, 10-50 MUg l-1 in 6%, 100 MUg l-1 in 24% and 200 MUg l-1 in 10% samples, respectively. The arsenic concentration in drinking water ranged from 12.8 to 132.2 MUg l-1. The depth of source of drinking water (10-60 m) was also found with a mean of 36.12 +/- 13.61 MUg l-1 arsenic concentration. Observations revealed that at depth ranging from 10 to 20 m, the mean level of arsenic concentration was 17.398 +/- 21.796 MUg l-1, while at 21 to 40 m depth As level was 39.685 +/- 40.832 MUg l-1 and at 41 to 60 m As level was 46.89 +/- 52.80 MUg l-1, respectively. These observations revealed a significant positive correlation (r = 0.716, t = 4.215, P < 0.05) between depth and arsenic concentration in drinking water. The age of water sources were ranged from zero to 30 years. The study indicates that the older sources of drinking water showed higher chance of contamination. Results showed that group 21-30 years having maximum arsenic concentration with mean value of 52.57 +/- 53.79 MUg l-1. Correlation analysis also showed a significant positive correlation (r = 0.801, t = 5.66, P < 0.05) between age of drinking water sources and their respective arsenic concentration (MUg l-1). Arsenic concentration in blood with mean value 0.226 +/- 0.177 MUg dl-1 significantly increased as compared to control. The blood arsenic content correlated significantly (r = 0.6823, t = 3.93, P < 0.05) with drinking water arsenic level and exposure time (r = 0.545, t = 3.101 & *P < 0.05) for populations residing in Ballia districts. Observations and correlation analysis revealed that individuals having depth of drinking water sources 20-30 m were less affected with arsenic exposure. PMID- 24813018 TI - Physiological studies of native cyanobacterial species Lyngbya contorta and Phormidium foveolarum in sewage waste water. AB - A variety of Cyanobacterial species predominantly ensheathed forms occurs in sewage water receiving areas. A study was conducted to analyse the potential of using native Lyngbya contorta and Phormidium foveolarum isolated from sewage water irrigated soils, for biomass production under sewage waste water. The native Cyanobacterial strains were characterised and changes in their biochemical composition in response to different concentrations of sewage waste water were investigated. Results showed that biomass(3.5-6.6 mg 10 ml-1, 2.6-5.6 mg 10 ml-1) and photosynthetic pigment contents increased with incubation time (chlorophyll 1.21-3.09 ug ml-1, 1.92-9.51 ug ml-1; carotenoid 20.8-34.8 ug ml-1, 16.4-32.8 ug ml-1) and decreased thereafter as nutrients became limiting. On the other hand, soluble proteins, after showing a decline, recovered faster with maximum concentration (42.6-63.3 ug ml-1 and 59-79.8 ug ml-1) recorded on day 8. Total carbohydrate content also increased (19.27-31.45 ug ml-1, 14.1-28.21 ug ml-1) in response to various concentrations of sewage waste water. The overall response was better for 50% sewage waste water concentration which showed that these native strains were suitable candidates for cultivation after proper dilution. PMID- 24813019 TI - Molecular detection and partial characterization of a begomovirus causing leaf curl disease of potato in sub-Himalayan West Bengal, India. AB - The characteristic disease symptoms of apical leaf curl, crinkled leaves and conspicuous mosaic were observed in potato plants grown in areas of Coochbehar, one of the distinct agroclimatic zones of sub-Himalayan West Bengal. Whitefly (Bemisia tabaci) population was also observed in and around the infected plants. The characteristic disease symptoms and presence of whitefly (Bemisia tabaci) population indicated the possibility of begomovirus infection. Total DNA was extracted from infected samples and PCR was carried out using begomovirus specific primers. PCR product of 1539 nucleotide long containing pre-coat protein, coat protein, AC5, AC3, AC2 and partial AC1 gene of DNA-Asegment and 1001 nucleotide long DNA-B containing BV1 and BC1 genes were submitted to the GenBank (accession numbers HQ597033 for DNA-A and JN390432 for DNA-B). The amplified DNA-A and DNA-B segment showed highest 98% and 99% nucleotide sequence similarity respectively with Tomato leaf curl New Delhi virus (ToLCNDV). In phylogenetic analysis also the virus sequence clustered with ToLCNDV isolates. The disease was successfully transmitted to healthy tomato plants using both whitefly vector, B. tabaci and mechanical sap inoculation using sap of infected potato leaves. It is the first record of begomovirus infection of cultivated potato in sub-Himalayan West Bengal of Eastern India. PMID- 24813020 TI - NbHSWP11, a microsporidia Nosema bombycis protein, localizing in the spore wall and membranes, reduces spore adherence to host cell BME. AB - Microsporidia are obligate intracellular parasites, and a derivative of fungi, which harbor a rigid spore wall to resist adverse environmental pressures. The spore wall protein, which is thought to be the first and direct protein interacting with the host cell, may play a key role in the process of microsporidia infection. In this study, we report a protein, NbHSWP11, with a dnaJ domain. The protein also has 6 heparin-binding motifs which are known to interact with extracellular glycosaminoglycans. Syntenic analysis indicated that gene loci of Nbhswp11 are conserved and syntenic between Nosema bombycis and Nosema ceranae. Phylogenetic tree analysis showed that Nbhswp11 clusters with fungal dnaJ proteins and has 98% identity with an N. bombycis dnaJ protein. Nbhswp11 was transcribed throughout the entire life stages, and gradually increased during 1-7 days, in a silkworm that was infected by N. bombycis, as determined by reverse-transcription PCR (RT-PCR). The recombinant protein NbHSWP11 (rSWP11-HIS) was obtained and purified using gene cloning and prokaryotic expression. Western blotting analysis displayed NbHSWP11 expressed in the total mature spore proteins and spore coat proteins. Indirect immunofluorescence assay revealed NbHSWP11 located at the spore wall of mature spores and the spore coats. Furthermore, immune electron microscopy showed that NbHSWP11 localized in the cytoplasm of the sporont. Within the developmental process of N. bombycis, a portion of NbHSWP11 is targeted to the spore wall of sporoblasts and mature spores. However, most of NbHSWP11 distributes on the membraneous structures of the sporoblast and mature spore. In addition, using a host cell binding assay, native protein NbHSWP11 in the supernatant of total soluble mature spore proteins is shown to bind to the host cell BmE surface. Finally, an antibody blocking assay showed that purified rabbit antibody of NbHSWP11 inhibits spore adherence and decreases the adherence rate of spores by 20% compared to untreated spores. Collectively, the present results suggest that NbHSWP11 is involved in host cell adherence in vitro. Therefore NbHSWP11, which has a dnaJ domain, may modulate protein assembly, disassembly, and translocation in N. bombycis. PMID- 24813021 TI - The expression of epidermal growth factor receptors and their ligands (epidermal growth factor, neuregulin, amphiregulin) in the bitch uterus during the estrus cycle. AB - In order to study the possible role of EGFR receptors in the bitch reproductive process, we have analyzed the expression pattern and localization of EGFR receptors and some of their ligands epidermal growth factor (EGF), neuregulin (NRG), amphiregulin (AREG), in the uterus during the estrus cycle using immunohistochemistry. The immunostaining for receptors and ligands of EGFR/ligand system was confined to membrane and cytoplasm of the target cells. Variations were observed, not only at the different stages of the estrous cycle, but also in the different tissue compartments of the uterus. However, it was detected that the immunostainings for NRG and AREG in the different cells do not show important differences at stages of the estrus cycle. In the luminal epithelium, strong immunostaining for ErbB1/HER1, ErbB2/HER2, ErbB4/HER4 and EGF was found at estrus. In the glandular epithelium, strong immunostaining for ErbB4/HER4 was observed at diestrus, while strong immunostaining for EGF was detected in both of estrus and diestrus. ErbB3/HER3 immunoreactivity in the stromal cells was higher at diestrus and anestrus, while ErbB4/HER4 immunoreactivity was lower at anestrus. In the myometrium, the highest levels of immunoreactivity of ErbB2/HER2 were found at estrus, while ErbB3/HER3 immunoreactivity was higher at anestrus. EGF immunoreactivity was lower at anestrus compared to other stage of cycle. Altered EGFR/ligand system expression during the estrus cycle suggests this growth factor system is a potent regulator of proliferation and differentiation events during preparation for implantation of bitch uterus. PMID- 24813022 TI - Faradaurate-940: synthesis, mass spectrometry, electron microscopy, high-energy X ray diffraction, and X-ray scattering study of Au~940+/-20(SR)~160+/-4 nanocrystals. AB - Obtaining monodisperse nanocrystals and determining their composition to the atomic level and their atomic structure is highly desirable but is generally lacking. Here, we report the discovery and comprehensive characterization of a 2.9 nm plasmonic nanocrystal with a composition of Au940+/-20(SCH2CH2Ph)160+/-4, which is the largest mass spectrometrically characterized gold thiolate nanoparticle produced to date. The compositional assignment has been made using electrospray ionization and matrix-assisted laser desorption ionization mass spectrometry (MS). The MS results show an unprecedented size monodispersity, where the number of Au atoms varies by only 40 atoms (940 +/- 20). The mass spectrometrically determined composition and size are supported by aberration corrected scanning transmission electron microscopy (STEM) and synchrotron-based methods such as atomic pair distribution function (PDF) and small-angle X-ray scattering (SAXS). Lower-resolution STEM images show an ensemble of particles 1000s per frame-visually demonstrating monodispersity. Modeling of SAXS data on statistically significant nanoparticle population-approximately 10(12) individual nanoparticles-shows that the diameter is 3.0 +/- 0.2 nm, supporting mass spectrometry and electron microscopy results on monodispersity. Atomic PDF based on high-energy X-ray diffraction experiments shows decent match with either a Marks decahedral or truncated octahedral structure. Atomic resolution STEM images of single particles and their fast Fourier transform suggest face-centered cubic arrangement. UV-visible spectroscopy data show that Faradaurate-940 supports a surface plasmon resonance peak at 505 nm. These monodisperse plasmonic nanoparticles minimize averaging effects and have potential application in solar cells, nano-optical devices, catalysis, and drug delivery. PMID- 24813023 TI - Transdermal clonidine in patients with swallowing dysfunction. AB - Patients with swallowing dysfunction are usually very ill and have a constellation of challenging issues requiring palliation. Accumulation of oropharyngeal secretions leads to a substantial effort of medical teams including doctors, nurses, respiratory therapists, and ancillary staff. We present 10 patients successfully treated with application of transdermal clonidine film. It was well tolerated, provided quick control of secretions, and reduced staff labor. We suggest that transdermal clonidine can be used as antisialogogue in patients with swallowing dysfunction. Clonidine pharmacology is physiologic grounds for this clinical application. PMID- 24813024 TI - Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials. AB - BACKGROUND: Motility-related gastrointestinal (GI) adverse drug reactions (GADRs) such as diarrhea and constipation are a common and deleterious feature associated with drug development. Novel biomarkers of GI function are therefore required to aid decision making on the GI liability of compounds in development. METHODS: Fifteen compounds associated with or without clinical GADRs were used to assess the ability of an in vitro colonic motility bioassay to predict motility-related GADRs. Compounds were examined in a blinded fashion for their effects on mouse colonic peristaltic motor complexes in vitro. For each compound concentration response relationships were determined and the results compared to clinical data. Compounds were also assessed using GI transit measurements obtained using an in vivo rat charcoal meal model. KEY RESULTS: Within a clinically relevant dosing range, the in vitro assay identified five true and three false positives, four true and three false negatives, which gave a predictive capacity of 60%. The in vivo assay detected four true and four false positives, four false and three true negatives, giving rise to a predictive capacity for this model of 47%. CONCLUSIONS & INFERENCES: Overall these results imply that both assays are poor predictors of GADRs. Further analysis would benefit from a larger compound set, but the data show a clear need for improved models for use in safety pharmacology assessment of GI motility. PMID- 24813026 TI - A double-blind efficacy and safety study of duloxetine flexible dosing in children and adolescents with major depressive disorder. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of duloxetine flexible dose in children (7-11 years) and adolescents (12-17 years) with major depressive disorder (MDD). METHODS: Patients (n=337) in this 36 week study (10 week acute and 26 week extension treatment) received duloxetine (60-120 mg once daily [QD], n=117), fluoxetine (20-40 mg QD, n=117), or placebo (n=103). Measures included: Children's Depression Rating Scale-Revised (CDRS-R), treatment emergent adverse events (TEAEs), and Columbia-Suicide Severity Rating Scale (C SSRS). RESULTS: Neither active drug (duloxetine or fluoxetine) separated significantly (p<0.05) from placebo on mean change from baseline to end-point (10 weeks) on the CDRS-R total score. There were no significant differences between the duloxetine or fluoxetine groups compared with placebo on serious AEs (SAEs), total TEAEs, or discontinuation for AE during acute treatment. There were no completed suicides or deaths, and no clinically significant electrocardiogram (ECG) abnormalities observed during the study. One fluoxetine and one duloxetine patient experienced alanine aminotransferase (ALT) three or more times the upper limit of normal, which resolved during the study. A total of 8 (7.1%) duloxetine patients, 7 (6.8%) placebo patients, and 9 (8.0%) fluoxetine patients had worsening of suicidal ideation from baseline during acute treatment. Of the patients with suicidal ideation at baseline, 15/19 (79%) duloxetine, 19/19 (100%) placebo, and 16/19 (84%) fluoxetine had improvement in suicidal ideation at end point during acute treatment. One duloxetine and two fluoxetine patients had treatment-emergent suicidal behavior during the 36 week study. CONCLUSION: Trial results were inconclusive, as neither the investigational drug (duloxetine) nor the active control (fluoxetine) separated from placebo on the CDRS-R at 10 weeks. No new duloxetine safety signals were identified relative to those seen in adults. Clinical Trial Registry Number: NCT00849901. PMID- 24813027 TI - Stigma and mental illness. PMID- 24813025 TI - PEG-polypeptide block copolymers as pH-responsive endosome-solubilizing drug nanocarriers. AB - Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG-polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide-alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH responsive manner under a range of biologically relevant conditions. The self assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model. PMID- 24813028 TI - Adapted cognitive-behavioral therapy for religious individuals with mental disorder: a systematic review. AB - Cognitive-behavioral therapy (CBT) is considered an evidence-based psychological intervention for various mental disorders. However, mental health clinicians should be cognizant of the population that was used to validate the intervention and assess its acceptability to a target group that is culturally different. We systematically reviewed published empirical studies of CBT adapted for religious individuals with mental disorder to determine the extent to which religiously modified CBT can be considered an empirically supported treatment following the criteria delineated by the American Psychological Association Task Force on Promotion and Dissemination of Psychological Procedures. Overall, nine randomized controlled trials and one quasi-experimental study were included that compared the effectiveness of religiously modified CBT to standard CBT or other treatment modalities for the treatment of depressive disorders, generalized anxiety disorder, and schizophrenia. The majority of these studies either found no difference in effectiveness between religiously modified CBT compared to standard CBT or other treatment modalities, or early effects that were not sustained. Considering the methodological limitations of the reviewed studies, religiously modified CBT cannot be considered a well-established psychological intervention for the treatment of the foregoing mental disorders following the a priori set criteria at this juncture. Nevertheless, melding religious content with CBT may be an acceptable treatment modality for individuals with strong religious convictions. PMID- 24813029 TI - Impulsivity in remitted depression: a meta-analytical review. AB - AIM: Depressive disorder and suicide have been associated with impulsivity in several studies. This paper aimed to review measures of trait impulsivity in remitted depressive disorder. METHODS: We used keywords "impulsivity and depression"; "impulsivity and depressive disorder" to narrow down our search on Medline, EMBASE and Psychinfo to include those studies that had reported impulsivity scores using validated and reliable assessment measures in remitted depressive disorder. We searched all English language studies from 1990 to December 2012 with 9 reports meeting the inclusion criteria for depression, which were then reviewed by the two reviewers independently. We generated weighted mean differences (WMDs) for depression from the pooled data using RevManager 5.1 from Cochrane analysis. RESULTS: The Barratt Impulsivity Scale (BIS) 11 was the instrument commonly used in depression. 9 studies met inclusion criteria in depression, which yielded a WMD of 10.12 on BIS 11 total scores. CONCLUSION: There is a strong association of impulsivity and depression, which persists even in remission. PMID- 24813030 TI - Gender differences in obsessive-compulsive disorder: findings from a large Indian sample. AB - AIM: Gender has been considered as one of the possible factors mediating phenotypic expression of obsessive-compulsive disorder (OCD). We examined gender differences in a large sample of subjects with OCD from India with respect to socio-demographic parameters, symptom characteristics, and comorbidity patterns. METHODS: Consecutive patients (n=545) who consulted a specialty OCD clinic over 5 years at a large psychiatric hospital in India were evaluated. RESULTS: Men (n=332) compared to women (n=213) with OCD had an earlier onset (p<0.001), higher frequency of sexual (p<0.001) and religious obsessions (p=0.001) pathological doubts (p<0.001) and checking (p<0.001) and repeating compulsions (p<0.001), and a greater tendency to have comorbid social phobia (p=0.006). Women compared to men were more likely to be married, had a higher frequency of fear of contamination (p=0.017), comorbid depression (p=0.014) and greater suicidal risk (p=0.003). CONCLUSIONS: Our study provides further evidence for gender related differences in clinical features of obsessive-compulsive disorder. Our findings are only partly comparable with results from studies across the world possibly due to various biological and cultural factors mediating the phenotypic expression of OCD across the genders. There is a need to examine the biological basis for these gender differences. PMID- 24813031 TI - Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: a clinical masquerader. AB - Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature. PMID- 24813032 TI - The relationship of the Korean version of the WHO Five Well-Being Index with depressive symptoms and quality of life in the community-dwelling elderly. AB - BACKGROUND: Depression in the geriatric population is becoming markedly more prevalent. Quality of life has been linked with the development of depression. A screening tool for assessing both geriatric depression and quality of life is needed. OBJECTIVE: The purpose of this study was to assess the utility of the Korean version of the World Health Organization Five Well-Being Index (WHO-5) in evaluating geriatric depression and quality of life as compared to the widely used Short Geriatric Depression Scale of Korean version (SGDS-K). METHODS: Two hundred and forty four elderly people (>60-years-of-age) living in the Yanggu and Inje areas of Gangwon Province, Korea, were interviewed and responded to scales including WHO-5, SGDS-K, Mini Mental Status Examination in the Korean version of the CERAD assessment packet (MMSE-KC), and Geriatric Quality of Life-Dementia (GQOL-D). A total WHO-5 score<13 indicated low well-being. RESULTS: The SGDS-K score showed a reverse correlation with the WHO-5, MMSE-KC, and GQOL-D scores. The WHO-5 score reversely correlated with the SGDS-K score and positively correlated with GQOL-D, but showed no significant correlation with MMSE-KC score. Subjects ranked as having poor well-being (WHO-5 score<13) had a significantly lower GQOL-D score and a significantly higher SGDS-K score. In multiple regression analysis, WHO-5 was significantly associated with GQOL-D and SGDS-K. CONCLUSION: The Korean version of WHO-5 is useful in evaluating both depressive symptoms and quality of life of community-dwelling elderly. PMID- 24813033 TI - Prevalence and risk factors associated with tardive dyskinesia among Indian patients with schizophrenia. AB - BACKGROUND: Tardive dyskinesia (TD) is one of the most distressing side effects of antipsychotic treatment. As prevalence studies of TD in Asian population are scarce, a cross-sectional study was performed to assess the frequency of TD in Indian patients with schizophrenia and risk factors of TD. METHOD: Cross sectional study of 160 Indian patients fulfilling the DSM-IV TR criteria for schizophrenia and who received antipsychotics for at least one year, were examined with two validated scales for TD. Logistic regression analyses were used to examine the relationship between TD and clinical risk factors. RESULTS: The frequency of probable TD in the total sample was 26.4%. The logistic regression yielded significant odds ratios between TD and age, intermittent treatment, and total cumulative antipsychotic dose. The difference of TD between SGA and FGA disappeared after adjusting for important co-variables in regression analysis. CONCLUSION: Indian patients with schizophrenia and long-term antipsychotic treatment have a high risk of TD, and TD is associated with older age, intermittent antipsychotic treatment, and a high total cumulative antipsychotic dose. Our study findings suggest that there is no significant difference between SGAs with regards to the risk of causing TD as compared to FGAs. PMID- 24813034 TI - Paraoxonase 1 activity and lipid profile in schizophrenic patients. AB - OBJECTIVE: This study aimed to investigate the variations of paraoxonase 1 (PON1) activity and lipid profile in patients with schizophrenia and the association of this activity with the sociodemographic, clinical and therapeutical characteristics of this population. PATIENTS AND METHODS: Our cross-sectional study included 140 schizophrenic patients and 119 control subjects aged respectively 37.3+/-10.4 and 41.4+/-10 years. PON1 activity was determined using Konelab 30TM equipment (Thermo Electron Corporation). Plasma total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (c-HDL) and low density lipoprotein cholesterol (c-LDL) concentrations were determined using Cobas 6000TM (Roche Diagnostics), apolipoproteins (ApoA1, ApoB) and lipoprotein (a) (Lp(a)) were determined using Integra 400 plus (Roche Diagnostics). RESULTS: Compared to controls, patients had no significant decrease of PON1 activity and significantly lower ApoA1, c-HDL levels, and significantly higher levels of TG, ApoB, Lp(a) and TC/c-HDL and ApoB/ApoA1 ratios. Furthermore, PON1 activity was correlated with TG/c-HDL ratio. The lowest PON1 activity was noted in obese patients, in paranoid sub-type and in patients treated with combination of typical and atypical antipsychotics without significant difference. Moreover, it was associated with gender and cigarette smoking but not with alcohol consumption status. CONCLUSION: Schizophrenic patients had a decrease in PON1 activity and perturbations in their lipid profiles that contribute to increase the risk of cardiovascular diseases. In addition, our results revealed that there was no association between the decrease of PON1 activity and any demographic or clinical characteristics. Therefore, such patients require specific care, particularly with regard to their lipid profile. PMID- 24813035 TI - Substance abuse in relation to religiosity and familial support in Iranian college students. AB - BACKGROUND AND OBJECTIVES: Drug abuse and alcohol use in young adults are a major public health problem. The aims of present study were to determine the prevalence of alcohol use and substance abuse and related factors in a sample of Iranian college students. METHODS: The study took place in Tabriz (northwest of Iran) in April and May, 2011. The randomly selected sample consisted of 1837 college students. Data were collected in a survey. A self-administered questionnaire was used to measure smoking, sexual behavior, alcohol and drug use, religious belief, and parental support. RESULTS: The prevalence of alcohol use in the past 30 days and ever drug abuse were 7.7% and 8.0%, respectively. After adjusting for other factors, living in dormitory in comparison to parental home (OR=0.61) and having higher score of religious beliefs (OR=0.98) were protective factors for ever use of illicit drugs. Being male (OR=1.89), living in the single house in comparison to parental home (OR=2.64), smoking (OR=2.0), alcohol use (OR=4.71), hookah smoking (OR=2.89), and having unsafe sex (OR=2.40) were risk factors ever use of illicit drugs. CONCLUSION: Our results show low prevalence of alcohol use and drug abuse in Iranian college students and determined some of its associated factors. The findings of this research can be used for planning and evaluating interventions by considering risk and protective factors. PMID- 24813036 TI - Predictors of disability: a 5-year cohort study of first-episode schizophrenia. AB - BACKGROUND: There is a dearth of information about the predictors of disability in schizophrenia from low and middle-income countries. This study attempted to investigate the impact of socio-demographic and clinical variables on disability in a cohort of first episode schizophrenia. METHOD: Patients diagnosed to have DSM IV schizophrenia (n=131) were assessed prospectively for psychopathology, functioning, insight and explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Disability was assessed at 5 years. Multiple linear regression was employed to adjust for common confounders. RESULTS: We could follow-up 95 (72.5%) patients. Sixty-five of these patients (68.4%) achieved remission. Disability scores at 5 years were associated negatively with episodic nature of illness at baseline, functional assessments at 6 and 12 months and return to pre-morbid level function. Disability correlated positively with psychopathology at 6 and 12 months and time spent in psychotic episodes. It was also associated with psychopathology, remission, insight and patient perspectives at the 5th year cross-sectional evaluation. While employment status at recruitment was not associated with disability, it was associated with unemployment at follow-up. CONCLUSIONS: Disability at 5 years was associated with illness variables - episodic nature of illness at baseline, psychopathology and functioning, duration in psychotic episode and return to pre-morbid function. Patient perspectives about their illness (insight and patient explanatory models) were only associated cross-sectionally at 60 months but not earlier and are more suggestive of a coping response rather than being predictive of outcome. The relationship between unemployment and disability suggests that they are products of the same disease process. PMID- 24813037 TI - Clinical and socio-demographic determinants of psychological health and burden in family caregivers of patients with unipolar depression. AB - INTRODUCTION: Depression affects nearly 350 million people worldwide and is currently among the most disabling diagnosis in the world. Caregiver burden can be immense in unipolar depression. The present study seeks to fill the knowledge gap by evaluating sociodemographic factors affecting psychological health and burden in caregivers of patients with unipolar depression. METHOD: Eighty outpatients with unipolar depression and their primary caregivers were included in the study. The patients were evaluated using clinical interview, DSM-IV TR criteria for Major Depressive Episode, Hamilton Depression Rating Scale (HDRS), Global Assessment of Functioning Scale (GAF) and Multidimensional Scale for Perceived Social Support (MSPSS). The caregivers were evaluated using HDRS and Zarit Burden Interview (ZBI). RESULTS: Caregiver burden was significantly higher in female spouse, employed caregivers and spouse caregivers married within the last one year as compared to caregivers other than wife, those unemployed and those married for more than one year. Caregiver burden in moderate as well as severe depressive episode did not show significant difference, although the more prolonged and non-responsive episodes placed a higher degree of burden on the caregivers. CONCLUSION: Early psychosocial intervention especially in the vulnerable family caregivers of depressed patients is an unmet need of mental health services which should be addressed by the clinician early to improve outcome and reduce caregiver burden in unipolar depression. PMID- 24813038 TI - Dhat syndrome: evidence for a depressive spectrum subtype. AB - INTRODUCTION: Dhat syndrome is a condition described in the Indian subcontinent, in which patients present with concerns about loss of semen. Though this condition has been conceptualized as a culture-bound syndrome, some authors have also considered it a manifestation of depression. This calls for a closer examination of the possible genetic link between Dhat syndrome and depression. METHOD: We examined the relationship between Dhat syndrome and the depressive spectrum, as conceptualized by Winokur, using a retrospective design. The case records of 46 patients with Dhat syndrome were reviewed, and patients were divided into two groups - family history positive (FH+) and family history negative (FH-) - based on the presence of depressive spectrum conditions in first degree relatives. These two groups were compared in terms of demographic variables, symptom profile and comorbidity. RESULTS: The FH+ group had significantly higher rates of depressive disorders and substance use disorders (alcohol and nicotine dependence). They were also more likely to report concerns about penile size. DISCUSSION: These results suggest that a subgroup of patients with the Dhat syndrome can be viewed as suffering from a depressive spectrum disorder. Dhat syndrome may be better understood as a heterogeneous group than as a single diagnostic entity. Identifying such sub-groups can help in choosing optimal treatments for patients with Dhat syndrome, such as selecting antidepressants for the group described in this study. PMID- 24813039 TI - Sleep duration and its association with sleepiness and depression in "ronin-sei" preparatory school students. AB - PURPOSES: The Japanese word "ronin-sei" refers to a student who has failed their university entrance examination and is preparing to re-take the examination in the following year. We aimed to determine how sleep duration is associated with daytime sleepiness or depression in ronin-sei because impaired daytime performance is known to result from sleep deprivation. METHODS: The participants in this cross-sectional study were 1075 ronin-sei and 285 university students. Sleepiness and depressive symptoms were assessed using the Epworth Sleepiness Scale (ESS) and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. RESULTS: Ronin-sei had significantly shorter sleep duration and earlier bed- and rise-times than university students. There was no significant difference in CES-D between the groups; however, the ESS score of university students was significantly higher than that of ronin-sei. Ronin-sei who slept for 5 to <6h had higher ESS scores than those who slept for 6 to <7h. The mean CES-D score in ronin-sei who slept <5h was significantly higher than in those who slept for 5 to <6h, from 6 to <7h, and from 7 to <8h. Ronin-sei who slept for more than 8h also had higher depression scores. CONCLUSIONS: Sleep deprivation appears to be common among ronin-sei. Furthermore, a U-shaped relationship was found between sleep duration and depressive symptoms, revealing that ronin-sei who had too little or too much sleep were more likely to exhibit an increase in depressive symptoms. PMID- 24813040 TI - The 2D:4D ratio of the hand and schizotypal personality traits in schizophrenia patients and healthy control persons. AB - Prenatal estrogen/testosterone exposure is known to be involved in early brain development. In this context, the ratio of the index finger to ring finger length (2D:4D) has been put forward as an indicator of the intrauterine sex hormonal level. A previous study by Collinson et al. (2010) examined 2D:4D ratios in Asian patients with schizophrenia and found an increased 2D:4D pattern in male patients compared to male healthy controls. In the current study, we tried to replicate the result of this study on the 2D:4D ratio in schizophrenia patients and controls in a Chinese sample. Moreover, we investigated the link between 2D:4D ratios and schizotypal personality traits in the participants of the study. No significant difference between cases and controls in 2D:4D ratios for both hands could be observed. However, a positive association between right 2D:4D ratio and schizotypal personality traits was found in healthy controls (both in the male and female subsamples) suggesting that a high 2D:4D ratio could represent a vulnerability factor for schizophrenia in healthy males and females. Same results were observed for the digit ratio of the left hand and the SPQ in the healthy total and healthy female subsample. Therefore, the inclusion of personality measures to study the link between the digit ratio and schizophrenia might help to provide insights in a potential continuum from healthy to schizophrenic behavior. PMID- 24813041 TI - Perceived mental health related stigma, gender, and depressive symptom severity in a psychiatric facility in South India. AB - BACKGROUND: Few studies exist on the topic of gender associated with depression and mental health-related stigma coming out of non-Western countries such as India. We aimed to add to the literature by assessing these relationships among adults seeking psychiatric services in India. METHODS: Participants were 60 individuals seeking care at a psychiatric clinic in Bangalore, India. The majority of participants were female with a mean age of 36 years (SD=9.75). RESULTS: Contrary to our prediction, there were no significant differences between men (M=28.96; SD=9.85) and women (M=33.03; SD=12.08) on depression severity, t(58)=1.42, p=.16. Yet, women (M=10.09, SD=8.23) reported significantly more perceived stigma than men (M=5.79, SD=5.86), t(58)=2.30, p=.02. CONCLUSION: While men and women seeking psychiatric services at the psychiatric clinic in India report similar levels of depression severity, women reported more perceived mental illness stigma. Having experienced regular forms of discrimination associated with female status in India, it may be the case that women are more attuned to other forms of stigma, such as mental health stigma investigated in the present study. Given the detrimental impact of stigma on treatment adherence and engagement in care, additional research is needed support this work, including research on interventions to reduce stigma and improve engagement in care. PMID- 24813042 TI - Outcome of a school-based intervention to promote life-skills among young people in Cambodia. AB - BACKGROUND: Most of the school-based interventions to prevent suicide are from high income countries and there is a need for evidence based interventions in resource-poor settings. The aim of this study is to evaluate the outcome of a school based intervention to reduce risk factors for suicide among young people in Cambodia by promoting life skills. METHOD: Six classes were randomly selected from two schools each, one designated as experimental and the other as control school, respectively. In experimental school 168 young people (M=92, F=76) received 6 sessions of life skills education and in the control school 131 students (M=53, F=78) received three general sessions on health. We looked at the pre-post differences on Life-Skills Development Scale Adolescent Form (LSDS-AF)- and Youth Self-Report (YSR) questionnaire to measure the effect size (ES) from the intervention after 6 months. We analyzed the data by stratifying for gender and for those who reported more severe suicidal expressions at baseline (high risk group). RESULTS: The girls showed improvement in Human Relationship (ES=0.57), Health Maintenance (ES=0.20) and the Total Life Skills Dimensions (ES=0.24), whereas boys with high-risk behavior improved on Human Relationship (ES=0.48), Purpose in Life (ES=0.26) and Total Life Skills Dimensions (ES=0.22). Effect size for YSR-syndrome scores among all individuals showed no improvement for either gender. Among high-risk individuals boys had a small to moderate effect size from intervention on Withdrawn/Depressed (ES=0.40), Attention problems (ES=0.46), Rule breaking behavior (ES=0.36), Aggressive behavior (ES=0.48) and Externalizing syndrome (ES=0.64). CONCLUSION: Promoting life skills in schools may enhance the overall mental health of young people, indirectly influencing suicide, particularly among boys with high-risk behavior in Cambodia. PMID- 24813043 TI - Difficulties in diagnosing delirium in elderly patients in a general hospital. PMID- 24813044 TI - Duration of untreated illness and early treatment response in children with attention deficit/hyperactivity disorder - a preliminary study. PMID- 24813045 TI - Successful treatment of antipsychotic-induced restless legs syndrome with gabapentin. PMID- 24813046 TI - Supported employment initiative for persons with mental illness in Indian setting: an expanded case report. PMID- 24813047 TI - Unusual substance use: using lizards for addiction. PMID- 24813048 TI - Prevalence of bipolar disorders among a sample of medical students of Tehran University of Medical Sciences. PMID- 24813049 TI - How to teach a psychiatry trainee: individual and team supervision. AB - Individual and group supervision of psychiatry residents are a critical vehicle to develop core competences of medical knowledge, clinical care, interpersonal communication, professionalism, practice-based learning and improvement, and systems-based practice. Effective trainee supervision involves setting clear goals, timely, specific and constructive feedback with follow-up, and a graduated approach to move the trainee from direct supervision toward autonomy. PMID- 24813050 TI - Blood feuds trap young girls in 'compensation marriages': a psychiatric torture. PMID- 24813051 TI - Interleukin (IL)-17A, F and AF in inflammation: a study in collagen-induced arthritis and rheumatoid arthritis. AB - Interleukin (IL)-17 plays a critical role in inflammation. Most studies to date have elucidated the inflammatory role of IL-17A, often referred to as IL-17. IL 17F is a member of the IL-17 family bearing 50% homology to IL-17A and can also be present as heterodimer IL-17AF. This study elucidates the distribution and contribution of IL-17A, F and AF in inflammatory arthritis. Neutralizing antibody to IL-17A alone or IL-17F alone or in combination was utilized in the mouse collagen-induced arthritis (CIA) model to elucidate the contribution of each subtype in mediating inflammation. IL-17A, F and AF were all increased during inflammatory arthritis. Neutralization of IL-17A reduced the severity of arthritis, neutralization of IL-17A+IL-17F had the same effect as neutralizing IL 17A, while neutralization of IL-17F had no effect. Moreover, significantly higher levels of IL-17A and IL-17F were detected in peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) in comparison to patients with osteoarthritis (OA). IL-17A and AF were detected in synovial fluid mononuclear cells (SFMC) in RA and OA, with IL-17A being significantly higher in RA patients. Enriched CD3(+) T cells from RA PBMCs produced singnificantly high levels of IL-17A and IL-17AF in comparison to OA peripheral blood CD3(+) T cells. IL-17A, F and AF were undetectable in T cells from SFMCs from RA and OA. While IL 17A, F, and AF were all induced during CIA, IL-17A played a dominant role. Furthermore, production of IL-17A, and not IL-17F or IL-17AF, was elevated in PBMCs, SFMCs and enriched peripheral blood CD3(+) T in RA. PMID- 24813053 TI - Comparison of outcomes after autologous stem cell transplantation between myeloma patients with skeletal and soft tissue plasmacytoma. AB - We aimed to compare the characteristics of skeletal and soft tissue plasmacytomas and to analyze clinical outcomes and prognostic factors of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients with plasmacytoma. We retrospectively reviewed data from 93 myeloma patients with detectable extramedullary (EM) plasmacytoma at diagnosis or during the course of the disease, who underwent ASCT. Soft tissue plasmacytoma occurred more frequently in male patients and had higher levels of serum beta2-microglobulin and lactate dehydrogenase and high frequency of advanced disease according to International Staging System compared to the skeletal plasmacytoma group. Both soft tissue and skeletal plasmacytoma groups showed similar plasmacytoma relapse patterns after ASCT and relapsed with EM plasmacytoma slightly more frequently in the bone compared to soft tissue sites. Compared to patients with skeletal plasmacytoma, patients with soft tissue plasmacytoma had worse median progression-free survival (PFS) (12 vs. 28 months) (P = 0.001) and overall survival (OS) (37 vs. 67 months) (P = 0.037) after ASCT. In a multivariate analysis, soft tissue plasmacytoma was an only independent poor prognostic factor for both PFS (HR, 2.398; 95% CI, 1.304 4.410) and OS (HR, 2.811; 95% CI, 1.107-7.135) after ASCT. These results demonstrate that, even though ASCT achieved a strong response in myeloma patients with soft tissue plasmacytoma, the presence of EM disease still contributed to a poor prognosis after ASCT compared to skeletal plasmacytoma, and these poor outcomes were not overcome by ASCT. PMID- 24813052 TI - Genome-wide gene expression profiling reveals unsuspected molecular alterations in pemphigus foliaceus. AB - Pemphigus foliaceus (PF) is a complex autoimmune disease characterized by bullous skin lesions and the presence of antibodies against desmoglein 1. In this study we sought to contribute to a better understanding of the molecular processes in endemic PF, as the identification of factors that participate in the pathogenesis is a prerequisite for understanding its biological basis and may lead to novel therapeutic interventions. CD4+ T lymphocytes are central to the development of the disease. Therefore, we compared genome-wide gene expression profiles of peripheral CD4+ T cells of various PF patient subgroups with each other and with that of healthy individuals. The patient sample was subdivided into three groups: untreated patients with the generalized form of the disease, patients submitted to immunosuppressive treatment, and patients with the localized form of the disease. Comparisons between different subgroups resulted in 135, 54 and 64 genes differentially expressed. These genes are mainly related to lymphocyte adhesion and migration, apoptosis, cellular proliferation, cytotoxicity and antigen presentation. Several of these genes were differentially expressed when comparing lesional and uninvolved skin from the same patient. The chromosomal regions 19q13 and 12p13 concentrate differentially expressed genes and are candidate regions for PF susceptibility genes and disease markers. Our results reveal genes involved in disease severity, potential therapeutic targets and previously unsuspected processes involved in the pathogenesis. Besides, this study adds original information that will contribute to the understanding of PF's pathogenesis and of the still poorly defined in vivo functions of most of these genes. PMID- 24813054 TI - Successful treatment of palmoplantar nail lichen planus with cyclosporine. PMID- 24813056 TI - Development of genomic resources for Nothofagus species using next-generation sequencing data. AB - Using next-generation sequencing, we developed the first whole-genome resources for two hybridizing Nothofagus species of the Patagonian forests that crucially lack genomic data, despite their ecological and industrial value. A de novo assembly strategy combining base quality control and optimization of the putative chloroplast gene map yielded ~32,000 contigs from 43% of the reads produced. With 12.5% of assembled reads, we covered ~96% of the chloroplast genome and ~70% of the mitochondrial gene content, providing functional and structural annotations for 112 and 52 genes, respectively. Functional annotation was possible on 15% of the contigs, with ~1750 potentially novel nuclear genes identified for Nothofagus species. We estimated that the new resources (13.41 Mb in total) included ~4000 gene regions representing ~6.5% of the expected genic partition of the genome, the remaining contigs potentially being nongenic DNA. A high-quality single nucleotide polymorphisms resource was developed by comparing various filtering methods, and preliminary results indicate a strong conservation of cpDNA genomes in contrast to numerous exclusive nuclear polymorphisms in both species. Finally, we characterized 2274 potential simple sequence repeat (SSR) loci, designed primers for 769 of them and validated nine of 29 loci in 42 individuals per species. Nothofagus obliqua had more alleles (4.89) on average than N. nervosa (2.89), 8 SSRs were efficient to discriminate species, and three were successfully transferred in three other Nothofagus species. These resources will greatly help for future inferences of demographic, adaptive and hybridizing events in Nothofagus species, and for conserving and managing natural populations. PMID- 24813055 TI - ATP-binding cassette transporter 1 attenuates ovalbumin-induced neutrophilic airway inflammation. AB - Apolipoprotein A-I (apoA-I) is an important component of high-density lipoprotein particles that mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette transporter 1 (ABCA1). apoA-I has also been shown to attenuate neutrophilic airway inflammation in experimental ovalbumin (OVA) induced asthma by reducing the expression of granulocyte colony-stimulating factor (G-CSF). Here, we hypothesized that overexpression of the ABCA1 transporter might similarly attenuate OVA-induced neutrophilic airway inflammation. Tie2-human ABCA1 (hABCA1) mice expressing human ABCA1 under the control of the Tie2 promoter, which is primarily expressed by vascular endothelial cells, but can also be expressed by macrophages, received daily intranasal OVA challenges, 5 d/wk for 5 weeks. OVA-challenged Tie2-hABCA1 mice had significant reductions in total bronchoalveolar lavage fluid (BALF) cells that reflected a decrease in neutrophils, as well as reductions in peribronchial inflammation, OVA-specific IgE levels, and airway epithelial thickness. The reduced airway neutrophilia in OVA-challenged Tie2-hABCA1 mice was associated with significant decreases in G-CSF protein levels in pulmonary vascular endothelial cells, alveolar macrophages, and BALF. Intranasal administration of recombinant murine G-CSF to OVA-challenged Tie2-hABCA1 mice for 5 days increased BALF neutrophils to a level comparable to that of OVA-challenged wild-type mice. We conclude that ABCA1 suppresses OVA-induced airway neutrophilia by reducing G CSF production by vascular endothelial cells and alveolar macrophages. These findings suggest that ABCA1 expressed by vascular endothelial cells and alveolar macrophages may play important roles in attenuating the severity of neutrophilic airway inflammation in asthma. PMID- 24813057 TI - Photoswitchable ratchet surface topographies based on self-protonating spiropyran NIPAAM hydrogels. AB - In this work, self-protonating spiropyran-based poly(N-isopropylacrylamide) polymer networks are prepared. These photoresponsive hydrogel coatings can change their surface topography upon exposure with visible light in a neutral environment. Photoresponsive surface-constrained films have been fabricated for which the swelling behavior can be controlled in a reversible manner. In a first step, symmetrical switchable surface topologies with varying cross-link density are obtained by polymerization-induced diffusion. Under light exposure, the areas with low cross-link density swell more than the areas with high cross-link density, thus forming a corrugated surface. Asymmetric ratchet-like photoresponsive surfaces have been prepared on prestructured asymmetric substrates. As a result of thickness variation of the surface-confined hydrogel layer, an asymmetric swelling behavior is obtained. Depending on the cross-link density of the hydrogel, it is possible to switch between a ratchet and flat surface topography or even an inverse ratchet surface by light. PMID- 24813059 TI - Identifying frequent users of emergency department resources. AB - BACKGROUND: There is growing focus on frequent users of acute care resources. If these patients can be identified, interventions can be established to offer more consistent management plans to decrease inappropriate utilization. OBJECTIVE: To compare a hospital-specific approach with a region-wide approach to identify frequent Emergency Department (ED) users. METHODS: A retrospective multi-center cohort study of hospital ED visits from all 18 nonmilitary, acute care hospitals serving the San Diego region (population 3.2 million) between 2008 and 2010 using data submitted to the California Office of Statewide Health Planning and Development. Frequent users and super users were defined as having 6 to 20 and 21 or more visits, respectively, during any consecutive 12 months in the study period. Comparisons between community-wide and hospital-specific methods were made. RESULTS: There were 925,719 individual patients seen in an ED, resulting in 2,016,537 total visits. There were 28,569 patients identified as frequent users and 1661 identified as super users, using a community-wide approach. Individual hospitals could identify 15.6% to 62.4% of all frequent users, and from 0.3% to 15.2% of all the super users who visited their facility. Overall, the hospital specific approach identified 20,314 frequent users and 571 super users, failing to identify 28.9% of frequent users and 65.6% of super users visiting San Diego County EDs that would otherwise have been identified using a community-wide approach. CONCLUSIONS: A community-wide identification method resulted in greater numbers of individuals being identified as frequent and super ED users than when utilizing individual hospital data. PMID- 24813058 TI - Values and preferences for oral antithrombotic therapy in patients with atrial fibrillation: physician and patient perspectives. AB - BACKGROUND: Exploration of values and preferences in the context of anticoagulation therapy for atrial fibrillation (AF) remains limited. To better characterize the distribution of patient and physician values and preferences relevant to decisions regarding anticoagulation in patients with AF, we conducted interviews with patients at risk of developing AF and physicians who manage patients with AF. METHODS: We interviewed 96 outpatients and 96 physicians in a multicenter study and elicited the maximal increased risk of bleeding (threshold risk) that respondents would tolerate with warfarin vs. aspirin to achieve a reduction in three strokes in 100 patients over a 2-year period. We used the probabilistic version of the threshold technique. RESULTS: The median threshold risk for both patients and physicians was 10 additional bleeds (10 P = 0.7). In both groups, we observed large variability in the threshold number of bleeds, with wider variability in patients than clinicians [patient range: 0-100, physician range: 0-50]. We observed one cluster of patients and physicians who would tolerate <10 bleeds and another cluster of patients, but not physicians, who would accept more than 35. CONCLUSIONS: Our findings suggest wide variability in patient and physician values and preferences regarding the trade-off between strokes and bleeds. Results suggest that in individual decision making, physician and patient values and preferences will often be discordant; this mandates tailoring treatment to the individual patient's preferences. PMID- 24813060 TI - Whole-genome profiling and shotgun sequencing delivers an anchored, gene decorated, physical map assembly of bread wheat chromosome 6A. AB - Bread wheat (Triticum aestivum L.) is the most important staple food crop for 35% of the world's population. International efforts are underway to facilitate an increase in wheat production, of which the International Wheat Genome Sequencing Consortium (IWGSC) plays an important role. As part of this effort, we have developed a sequence-based physical map of wheat chromosome 6A using whole-genome profiling (WGPTM). The bacterial artificial chromosome (BAC) contig assembly tools fingerprinted contig (fpc) and linear topological contig (ltc) were used and their contig assemblies were compared. A detailed investigation of the contigs structure revealed that ltc created a highly robust assembly compared with those formed by fpc. The ltc assemblies contained 1217 contigs for the short arm and 1113 contigs for the long arm, with an L50 of 1 Mb. To facilitate in silico anchoring, WGPTM tags underlying BAC contigs were extended by wheat and wheat progenitor genome sequence information. Sequence data were used for in silico anchoring against genetic markers with known sequences, of which almost 79% of the physical map could be anchored. Moreover, the assigned sequence information led to the 'decoration' of the respective physical map with 3359 anchored genes. Thus, this robust and genetically anchored physical map will serve as a framework for the sequencing of wheat chromosome 6A, and is of immediate use for map-based isolation of agronomically important genes/quantitative trait loci located on this chromosome. PMID- 24813061 TI - Pain after hernia repair with simultaneous extraperitoneal laparoscopic radical prostatectomy. AB - PURPOSE: To compare postoperative pain levels and postoperative morbidity between patients who underwent extraperitoneal laparoscopic radical prostatectomy (EPLRP) concomitant hernia repair and patients who underwent only EPLRP, by matched-pair analyses. METHODS: From December 2003 to December 2012, 54 patients who underwent EPLRP with simultaneous hernia repair were categorized as group 1. Their postoperative pain levels were quantitatively compared with those of 54 patients who underwent only EPLRP (group 2), in matched-pair analyses, including age, body mass index, and American Society of Anesthesiologists scoring. Preoperative tumor characteristics, operative and postoperative data were recorded. Pain levels were evaluated by using the visual analog scale (VAS) scoring, every day, during the first postoperative week. Statistical analyses were performed. RESULTS: Mean follow-up was 21 months. Mean age was 65+/-0.5 years. Preoperative, perioperative, and postoperative data were similar in the two groups. Group 1 needed a mean of 9.17 mg and group 2 needed a mean of 8.06 mg morphine derivative analgesic (piritramide) postoperatively. Total mean VAS scores were 5.65 and 4.98, in group 1 and group 2, respectively (P=0.06). Moreover, there was no significant difference between groups for complications. CONCLUSION: Simultaneous hernia repair does not affect pain levels after EPLRP. The procedure also does not result in prolongation of operative time and does not increase complication rates. PMID- 24813062 TI - Enhancement of the nonamyloidogenic pathway by exogenous NGF in an Alzheimer transgenic mouse model. AB - Nerve growth factor (NGF) is an important nerve cell growth regulatory factor and has an indispensable role in the development, survival and regeneration of the cholinergic basal forebrain (CBF) neurons, and it has multiple targets when used for Alzheimer's Disease (AD) therapy. In this study, we observed whether NGF can affect cholinergic neurons to change amyloid-beta precursor protein (APP) metabolism process and reduce amyloidosis in AD brains. NGF was administered intranasally to APP/PS1 double-transgenic mice for 14weeks. We observed an increase in APP695 and ADAM10 and a decrease in BACE1 and PS1 protein levels and, subsequently, a reduction in Abeta1-40 and Abeta1-42 levels and Abeta burden were present in NGF-treated mice brains, suggesting that NGF enhanced the APP nonamyloidogenic cleavage pathway and reduced the Abeta generation in the APP/PS1 transgenic mice brains. PMID- 24813063 TI - Reliability of contrast echocardiography to rule out pulmonary arteriovenous malformations and avoid CT irradiation in pediatric patients with hereditary hemorrhagic telangiectasia. AB - BACKGROUND: The overall risk of cancer is higher in people exposed to computed tomography (CT) scans in childhood or adolescence compared to adults. Transthoracic contrast echocardiography (TTCE) has recently been used to screen for pulmonary arteriovenous malformations (PAVMs) in children with hereditary hemorrhagic telangiectasia (HHT), but the value of TTCE to rule out PAVMs and avoid chest CT radiation has yet to be discussed. METHODS: Between 2003 and 2013, 92 pediatric patients with >=3 Curacao criteria and/or genetic mutation underwent TTCE and chest CT on the same day. We used the classification proposed by Barzilai for TTCE quantification of shunting. We considered CT findings as negative when no PAVMs or only one microscopic PAVM was detected. RESULTS: Mean age was 11.2 +/- 4.1 years. The shunt was grade 0 on TTCE in 27.3%, grade 1 in 17%, grade 2 in 29.6%, grade 3 in 23.9%, and grade 4 in 2.2%. We found PAVMs on chest CT in 52.2%. All the patients with a grade 0 or 1 had a negative CT. The sensitivity and specificity of TTCE for the detection of PAVMs were 100% and 95.1%, respectively. The negative predictive value (NPV) was 100% and the positive predictive value (PPV) was 96%. CONCLUSIONS: A low-grade classification (Barzilai 0 or 1) could presumably exclude the presence of PAVMs and allow CT irradiation to be avoided in children and adolescents. The screening algorithm using TTCE first would allow more than 40% of the pediatric patients screened for PAVMs to be spared the radiation dose of CT. PMID- 24813064 TI - Thermal structural transitions and carbon dioxide adsorption properties of zeolitic imidazolate framework-7 (ZIF-7). AB - As a subset of the metal-organic frameworks, zeolitic imidazolate frameworks (ZIFs) have potential use in practical separations as a result of flexible yet reliable control over their pore sizes along with their chemical and thermal stabilities. Among many ZIF materials, we explored the effect of thermal treatments on the ZIF-7 structure, known for its promising characteristics toward H2 separations; the pore sizes of ZIF-7 (0.29 nm) are desirable for molecular sieving, favoring H2 (0.289 nm) over CO2 (0.33 nm). Although thermogravimetric analysis indicated that ZIF-7 is thermally stabile up to ~400 degrees C, the structural transition of ZIF-7 to an intermediate phase (as indicated by X-ray analysis) was observed under air as guest molecules were removed. The transition was further continued at higher temperatures, eventually leading toward the zinc oxide phase. Three types of ZIF-7 with differing shapes and sizes (~100 nm spherical, ~400 nm rhombic-dodecahedral, and ~1300 nm rod-shaped) were employed to elucidate (1) thermal structural transitions while considering kinetically relevant processes and (2) discrepancies in the N2 physisorption and CO2 adsorption isotherms. The largest rod-shaped ZIF-7 particles showed a delayed thermal structural transition toward the stable zinc oxide phase. The CO2 adsorption behaviors of the three ZIF-7s, despite their identical crystal structures, suggested minute differences in the pore structures; in particular, the smaller spherical ZIF-7 particles provided reversible CO2 adsorption isotherms at ~30-75 degrees C, a typical temperature range of flue gases from coal-fired power plants, in contrast to the larger rhombic-dodecahedral and rod shaped ZIF-7 particles, which exhibited hysteretic CO2 adsorption/desorption behavior. PMID- 24813065 TI - Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. AB - OBJECTIVE: Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs). METHOD: The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI resistant MDD (DSM-IV criteria) received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011. RESULTS: Seventy-five patients were enrolled. Patients with specific biological (body mass index >= 30 kg/m2, elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2 nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P <= .05) greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with L-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P <= .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo. CONCLUSIONS: Biomarkers associated with inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with L methylfolate 15 mg. Confirmatory studies are needed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00955955. PMID- 24813066 TI - The right to health and medicines: the case of recent multilateral negotiations on public health, innovation and intellectual property. AB - The negotiations of the intergovernmental group known as the 'IGWG', undertaken by the Member States of the WHO, were the result of a deadlock in the World Health Assembly held in 2006 where the Member States of the WHO were unable to reach an agreement on what to do with the 60 recommendations in the report on 'Public Health, Innovation and Intellectual Property Rights submitted to the Assembly in the same year by a group of experts designated by the Director General of the WHO. The result of these negotiations was the 'Global strategy and plan of action on public health, innovation and intellectual property' which was approved by the World Health Assembly in 2008. The intention of the Global Strategy and Plan of Action (GSPOA) which was produced by the IGWG was to substantially reform the pharmaceuticals' research and development system in view of the findings that this system, whose purpose is to produce medicines for diseases which affect the greater part of the world population which lives in developing countries, had failed. The intellectual property rights imposed by the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) and the recent trade agreements could become one of the main obstacles to access to medicines. The GSPOA makes a critical analysis of this reality, and opens the door to searching for new solutions to this problem. PMID- 24813067 TI - Reply: To PMID 24813069. PMID- 24813068 TI - Phenotype-directed management of interstitial cystitis/bladder pain syndrome. AB - OBJECTIVE: To assess a flexible therapeutic strategy for patients referred to a specialized interstitial cystitis/bladder pain syndrome (IC/BPS) clinic using an individualized phenotype-directed treatment plan based on clinically based urinary, psychosocial, organ-specific, infection, neurologic or nonbladder, and tenderness of pelvic floor (UPOINT) categorization, instead of the traditional algorithmic stepwise approach. METHODS: Consecutive patients referred to a specialized tertiary IC/BPS clinic with at least 1 follow-up posttreatment visit were categorized according to their UPOINT status and treated according to previously published individualized phenotype-based treatment plan. Patients were assessed at baseline and up to 2 years with validated symptom scores (interstitial cystitis symptom score [ICSI]; and pain urgency frequency questionnaire) as well as pain and voiding assessments. RESULTS: Follow-up visit data were available for 93 patients (mean age, 45.2 years; median age, 44 years; mean ICSI, 13.2+/-3.6). Patients reported a median of 4 UPOINT domains (mean, 3.7+/-0.94) with the following distribution: U=100%; P=31.2%; O=97.8%; I=45.2%; N=39.8%; and T=55.9%. The mean decrease in ICSI was 3.4 points. Significant clinical improvement (>30% decrease in ICSI) was observed in 46.2% compared with initial baseline visit. Pain urgency frequency, and pain and urgency scoring changes were comparable. No correlation between severity of symptoms and number of domains and ICSI decrease was observed. CONCLUSION: Almost 50% of patients referred to a tertiary IC/BPS clinic, regardless of the complexity or severity of condition, experienced clinically significant improvement using an individualized phenotype-directed therapeutic approach. PMID- 24813069 TI - Editorial comment. PMID- 24813070 TI - Hybrid transvaginal nephrectomy: development of our technique. AB - OBJECTIVE: To evaluate the development of natural orifice transluminal endoscopic surgery (NOTES) transvaginal nephrectomy and present the initial experience. METHODS: Thirty-eight female patients were submitted to hybrid NOTES transvaginal nephrectomy for tumor (n=23) and nonfunctioning renal unit (n=15) in 2 academic medical centers. Patients underwent surgery from July 2010 to June 2012 and none of them were candidates for partial nephrectomy (clinical stage T1b or higher). The procedure was performed by the use of multi-instrument ports or flexible cannulas inserted through umbilical and vaginal incisions. A 30 degrees lens extra-long camera and combinations of conventional laparoscopic and prebent instruments were used. Specially designed extra-long, prebent straight instruments were found to be particularly useful for transvaginal manipulations. Prospective data regarding patient demographics, intraoperative and postoperative course of the patients, and pathology results were collected. RESULTS: Average tumor diameter was 6 cm (range, 4.9-7.5 cm). Average operative time was 114.1 minutes (range, 90-190 minutes). Estimated blood loss ranged between 50 and 150 mL (average, 80 mL). Intraoperatively, 2 bladder perforations occurred and were treated by suturing. Postoperatively, 2 patients suffered from fever of unknown origin and 2 patients required transfusions due to bleeding. Average hospital stay was 3.3 days (range, 3-5 days). Positive surgical margins were not detected. CONCLUSION: Hybrid NOTES transvaginal nephrectomy is a feasible and safe alternative to standard laparoscopic nephrectomy in selected patients. Difficulties arising from limitations in current instrumentation have been addressed by the use of specially designed instruments. Further clinical studies are required to ascertain this approaches' place among nephrectomy techniques. PMID- 24813071 TI - Investigating the role of smooth muscle cells in large elastic arteries: a finite element analysis. AB - Physiological loading in large elastic arteries is considered to be mainly carried by the passive components of the media but it is not known how much the contraction of the smooth muscle cells is actually involved in the load carrying. Smooth muscle contraction is considered to occur in a relatively slow time domain but the contraction is able to produce significant tension. In the present work the role of smooth muscle contraction in large elastic arteries is investigated by analyzing how changes in the intracellular calcium, and thereby the active tone of smooth muscle cells, influence the deformation and stress behavior; different intracellular calcium functions and medial wall thicknesses with cycling internal pressure are studied. In particular, a recently proposed mechanochemical model (Murtada et al., 2012. J. Theor. Biol. 297, 176-186), which links intracellular calcium with mechanical contraction and an anisotropic model representing the elastin/collagen composite, was implemented into a 3D finite element framework. Details of the implementation procedure are described and a verification of the model implementation is provided by means of the isometric contraction/relaxation analysis of a medial strip at optimal muscle length. In addition, numerically obtained pressure-radius relationships of arterial rings modeled with one and two layers are analyzed with different geometries and at different calcium levels; a comparison with the Laplace equation is provided. Finally, a two-layer arterial ring is loaded with a realistic pressure wave and with various intracellular calcium functions (different amplitudes and mean values) and medial wall thicknesses; residual stresses are considered. The finite element results show that changes in the calcium amplitudes hardly have an influence on the current inner ring radius and the circumferential stress. However, an increase in the mean intracellular calcium value and the medial wall thickness leads to a clear influence on the deformation and the stress behavior. PMID- 24813072 TI - Modeling the functional network of primary intercellular Ca2+ wave propagation in astrocytes and its application to study drug effects. AB - We introduce a simple procedure of multivariate signal analysis to uncover the functional connectivity among cells composing a living tissue and describe how to apply it for extracting insight on the effect of drugs in the tissue. The procedure is based on the covariance matrix of time resolved activity signals. By determining the time-lag that maximizes covariance, one derives the weight of the corresponding connection between cells. Introducing simple constraints, it is possible to conclude whether pairs of cells are functionally connected and in which direction. After testing the method against synthetic data we apply it to study intercellular propagation of Ca(2+) waves in astrocytes following an external stimulus, with the aim of uncovering the functional cellular connectivity network. Our method proves to be particularly suited for this type of networking signal propagation where signals are pulse-like and have short time delays, and is shown to be superior to standard methods, namely a multivariate Granger algorithm. Finally, based on the statistical analysis of the connection weight distribution, we propose simple measures for assessing the impact of drugs on the functional connectivity between cells. PMID- 24813074 TI - HIV vaccines: a brief overview. AB - The scope of the article is to review the different approaches that have been used for HIV vaccines. The review is based on articles retrieved by PubMed and clinical trials from 1990 up to date. The article discusses virus complexity, protective and non-protective immune responses against the virus, and the most important approaches for HIV vaccine development. PMID- 24813073 TI - Infection control for norovirus. AB - Norovirus infections are notoriously difficult to prevent and control, owing to their low infectious dose, high shedding titre, and environmental stability. The virus can spread through multiple transmission routes, of which person-to-person and foodborne are the most important. Recent advances in molecular diagnostics have helped to establish norovirus as the most common cause of sporadic gastroenteritis and the most common cause of outbreaks of acute gastroenteritis across all ages. In this article, we review the epidemiology and virology of noroviruses, and prevention and control guidelines, with a focus on the principles of disinfection and decontamination. Outbreak management relies on sound infection control principles, including hand hygiene, limiting exposure to infectious individuals, and thorough environmental decontamination. Ideally, all infection control recommendations would rely on empirical evidence, but a number of challenges, including the inability to culture noroviruses in the laboratory and the challenges of outbreak management in complex environments, has made it difficult to garner clear evidence of efficacy in certain areas of infection control. New experimental data on cultivable surrogates for human norovirus and on environmental survivability and relative resistance to commonly used disinfectants are providing new insights for further refinining disinfection practices. Finally, clinical trials are underway to evaluate the efficacy of vaccines, which may shift the current infection control principles to more targeted interventions. PMID- 24813075 TI - Effect of high-fructose corn syrup on Streptococcus mutans virulence gene expression and on tooth demineralization. AB - High-fructose corn syrup-55 (HFCS-55) has been widely welcomed in recent years as a substitute for sucrose on the basis of its favourable properties and price. The objective of this study was to determine the influence of HFCS-55 on the expression of Streptococcus mutans UA159 virulence genes and on tooth demineralization. Real-time reverse-transcription PCR (real-time RT-PCR) and microhardness evaluations were performed to examine gene expression and enamel demineralization, respectively, after treatment with HFCS-55 and/or sucrose. Significant up-regulation of glucosyltransferase B (gtfB) by HFCS-55 was found. A mixture of HFCS-55 and sucrose could positively enhance expression of glucan binding protein (gbp) genes. Regarding acidogenicity, expression of the lactate dehydrogenase (ldh) gene was unaffected by HFCS-55. A notable finding in this study was that 5% HFCS-55 significantly enhanced expression of the intracellular response gene of the two-component VicRK signal transduction system (vicR). Demineralization testing showed that the microhardness of teeth decreased by a greater extent in response to HFCS-55 than in response to sucrose. The results indicate that HFCS-55 can enhance S. mutans biofilm formation indirectly in the presence of sucrose and that HFCS-55 has a more acidogenic potential than does sucrose. Summing up the real-time PCR and demineralization results, HFCS-55 appears to be no less cariogenic than sucrose in vitro - at least, not under the conditions of our experiments. PMID- 24813076 TI - State variability in supply of office-based primary care providers: United States, 2012. AB - KEY FINDINGS: Data from the National Ambulatory Medical Care Survey (NAMCS) and the NAMCS Electronic Health Records Survey In 2012, 46.1 primary care physicians and 65.5 specialists were available per 100,000 population. From 2002 through 2012, the supply of specialists consistently exceeded the supply of primary care physicians. Compared with the national average, the supply of primary care physicians was higher in Massachusetts, Rhode Island, Vermont, and Washington; it was lower in Arkansas, Georgia, Mississippi, Nevada, New Mexico, and Texas. In 2012, 53.0% of office-based primary care physicians worked with physician assistants or nurse practitioners. Compared with the national average, the percentage of physicians working with physician assistants or nurse practitioners was higher in 19 states and lower in Georgia. Primary care providers include primary care physicians, physician assistants, and nurse practitioners. Primary care physicians are those in family and general practice, internal medicine, geriatrics, and pediatrics (1). Physician assistants are state-licensed health professionals practicing medicine under a physician's supervision. Nurse practitioners are registered nurses (RNs) with advanced clinical training (2-6). The ability to obtain primary care depends on the availability of primary care providers (3). This report presents state estimates of the supply of primary care physicians per capita, as well as the availability of physician assistants or nurse practitioners in primary care physicians' practices. Estimates are based on data from the National Ambulatory Medical Care Survey (NAMCS), Electronic Health Records (EHR) Survey, a nationally representative survey of office-based physicians. PMID- 24813077 TI - Posttraumatic stress disorder in close Relatives of Intensive Care unit patients' Evaluation (PRICE) study. AB - BACKGROUND: There is a high risk of post-traumatic stress disorder (PTSD) in relatives of intensive care unit (ICU) patients. AIMS: To determine the prevalence and predictors of symptoms of PTSD in relatives of an Australian critically ill population. METHODS: 108 consecutive patients staying >48 h in a mixed, level three ICU were identified. On day three of admission, their next-of kin were contacted and consent obtained for a telephonic questionnaire to be done at 90 days after ICU discharge. This consisted of the Hospital Anxiety and Depression Scale and the Impact of Event Scale-Revised (IES-R) questionnaires administered to relatives at 90 days post-discharge from the ICU. An IES-R score of >26 was used to define PTSD symptoms. RESULTS: Eight subjects were excluded because the next-of-kin details were unavailable. 37 other subjects refused to participate. Out of a total of 108, 63 family members were included, including 49 next-of-kin of patients who survived. The prevalence of PTSD symptoms was 41.2% (26/63, 95% CI 29.0-54.4%). The anxiety score was found to be a predictor of PTSD symptoms (relative risk=1.07; 95% CI 1.00-1.14, p=0.05). CONCLUSION: There is a high prevalence of PTSD symptoms in next-of-kin of Australian patients admitted to the ICU. High anxiety scores were a predictor for developing PTSD symptoms. PMID- 24813078 TI - TALEN-mediated genetic tailoring as a tool to analyze the function of acquired mutations in multiple myeloma cells. AB - Multiple myeloma (MM) is a clonal plasma cell malignancy that is initiated by a number of mutations and the process of disease progression is characterized by further acquisition of mutations. The identification and functional characterization of these myelomagenic mutations is necessary to better understand the underlying pathogenic mechanisms in this disease. Recent advancements in next-generation sequencing have made the identification of most of these mutations a reality. However, the functional characterization of these mutations has been hampered by the lack of proper and efficient tools to dissect these mutations. Here we explored the possible utility of transcription activator like effector nuclease (TALEN) genome engineering technology to tailoring the genome of MM cells. To test this possibility, we targeted the HPRT1 gene and found that TALENs are a very robust and efficient genome-editing tool in MM cells. Using cotransfected green fluorescent protein as an enrichment marker, single-cell subclones with desirable TALEN modifications in the HPRT1 gene were obtained in as little as 3-4 weeks of time. We believe that TALENs will greatly facilitate the functional study of somatic mutations in MM as well as other cancers. PMID- 24813080 TI - Cancer-testis antigen MAGE-C2/CT10 induces spontaneous CD4+ and CD8+ T-cell responses in multiple myeloma patients. PMID- 24813079 TI - Induced pluripotent stem cells in hematology: current and future applications. AB - Reprogramming somatic cells into induced pluripotent stem (iPS) cells is nowadays approaching effectiveness and clinical grade. Potential uses of this technology include predictive toxicology, drug screening, pathogenetic studies and transplantation. Here, we review the basis of current iPS cell technology and potential applications in hematology, ranging from disease modeling of congenital and acquired hemopathies to hematopoietic stem and other blood cell transplantation. PMID- 24813081 TI - Safe and effective use of outpatient non-myeloablative allogeneic stem cell transplantation for myeloma. PMID- 24813082 TI - How to manage peroperative haemorrhage when vaginally treating genital prolapse. AB - Surgery of genital prolapse causes haemorrhagic complications in about 1% of cases. The pelvis is highly vascular and accessing the usual landmarks of vaginal surgery, in particular the sciatic spine, is delicate work. Meticulous dissection of closed spaces is often difficult, and exposure and haemostatic procedures will be challenging in the event of any bleeding complication. When fixing prosthesis to the sacrospinous ligament, the inferior gluteal artery and its coccygeal branch are at risk. Fixation to the sacrospinous ligament must be performed more than 25mm away from the sciatic spine and, if possible, must not transfixiate it. Safe insertion of prosthesis requires sufficient experience, and an adequate learning curve. Being aware of vascular anatomy allows one to understand and treat haemorrhagic incidents. Packing or selective embolization seem to be the two methods to adopt, depending on the severity of bleeding and the conditions of exposure on the one hand, and on the technical resources available for embolization, on the other. Hypogastric ligature appears to be ineffective in this context. PMID- 24813083 TI - Investigation of diagnostic potentials of nine different biomarkers in endometriosis. AB - OBJECTIVE: To investigate the diagnostic potentials of the serum levels of nine different biomarkers in endometriosis. STUDY DESIGN: In this case-controlled, prospective clinical study, 80 women underwent laparoscopy or laparotomy with a preliminary diagnosis of chronic pelvic pain, severe secondary dysmenorrhea, infertility, pelvic endometriosis or pelvic mass. The 60 women with confirmed pelvic endometriosis constituted the endometriosis group, and the other 20 women without endometriosis constituted the control group. Preoperative blood samples were obtained for serum biomarker measurements. Serum levels of nine different serum biomarkers including alpha-enolase, macrophage migration inhibitory factor, leptin, interleukin-8, anti-endometrial antibody, phosphoinositide dependent protein kinase 1, CA125, syntaxin-5, and laminin-1 were measured concurrently and compared between the control and endometriosis groups, and among control group and endometriosis subgroups including stage I, stage II, stage III and stage IV endometriosis. RESULTS: The serum levels of alpha-enolase, macrophage migration inhibitory factor, leptin, interleukin-8 and antiendometrial antibodies showed a statistically significant difference neither between control and endometriosis groups nor among control group and endometriosis subgroups. The serum levels of CA125, syntaxin-5 and laminin-1 showed a statistically significant difference both between the control and endometriosis groups (p<0.01) and among control group and endometriosis subgroups (p<0.01). Serum levels of laminin-1 in stage II and IV endometriosis; syntaxin-5 in stage I and II endometriosis; and CA125 in stage III and IV endometriosis were found to have the different levels compared to control group. CONCLUSIONS: These findings show that the concurrent measurement of CA125, syntaxin-5 and laminin-1 might be a useful non-invasive test in strengthening the diagnosis of endometriosis and in predicting its severity. PMID- 24813084 TI - Severe postpartum haemorrhage after vaginal delivery: a statistical process control chart to report seven years of continuous quality improvement. AB - Severe postpartum haemorrhage after vaginal delivery: a statistical process control chart to report seven years of continuous quality improvement OBJECTIVE: To use statistical process control charts to describe trends in the prevalence of severe postpartum haemorrhage after vaginal delivery. This assessment was performed 7 years after we initiated a continuous quality improvement programme that began with regular criteria-based audits STUDY DESIGN: Observational descriptive study, in a French maternity unit in the Rhone-Alpes region. INTERVENTION: Quarterly clinical audit meetings to analyse all cases of severe postpartum haemorrhage after vaginal delivery and provide feedback on quality of care with statistical process control tools. MAIN OUTCOME MEASURES: The primary outcomes were the prevalence of severe PPH after vaginal delivery and its quarterly monitoring with a control chart. The secondary outcomes included the global quality of care for women with severe postpartum haemorrhage, including the performance rate of each recommended procedure. Differences in these variables between 2005 and 2012 were tested. RESULTS: From 2005 to 2012, the prevalence of severe postpartum haemorrhage declined significantly, from 1.2% to 0.6% of vaginal deliveries (p<0.001). Since 2010, the quarterly rate of severe PPH has not exceeded the upper control limits, that is, been out of statistical control. The proportion of cases that were managed consistently with the guidelines increased for all of their main components. CONCLUSION: Implementation of continuous quality improvement efforts began seven years ago and used, among other tools, statistical process control charts. During this period, the prevalence of severe postpartum haemorrhage after vaginal delivery has been reduced by 50%. PMID- 24813085 TI - Re-intervention after uterine leiomyoma embolisation is related to incomplete infarction and presence of submucous leiomyomas. AB - OBJECTIVE: To evaluate outcome of invasive gynecological re-interventions after uterine artery embolisation (UAE) in relation to leiomyoma characteristics. DESIGN: A cohort of 114 women with symptomatic myomas underwent UAE. Myoma characteristics were determined by contrast-enhanced magnetic resonance imaging (MRI) before and 6 months after treatment. The median follow-up time after UAE was 55.9 months; (range 20-116). Data on gynecological re-interventions were obtained for all patients and were analysed using the Kaplan-Meier method. Data were obtained on frequency of invasive re-interventions: major myoma procedures (hysterectomy, re-embolisation, laparoscopic or abdominal myomectomy) and outpatient hysteroscopic myoma procedures. Myoma characteristics with impact on outcome of re-interventions were determined by statistical analysis. RESULTS: Total re-intervention rate was 35.1%. Hysterectomy was performed due to myoma related symptoms in 6.1% of patients, but 23.7% of patients underwent additional uterine procedures, mainly outpatient hysteroscopy (15%). Major myoma re intervention correlated with the extent of the infarct at follow-up MRI (n=107). Patients had undergone major re-intervention (3 years) as follows: infarct group C (<80%, n=16) 44%, infarct group B (80-99%, n=16) 19%, and infarct group A (100%, n=75) 10.1% ((p<0.01) for both A vs B+C and A+B vs C). Major re interventions were not associated with the presence of submucous myomas; but the hazard ratio (CI 95%) for undergoing hysteroscopic re-intervention was 8.4 (2-29) (p=0.001) in patients with submucous myomas, but 12.7 (5-35) (p<0.0001) in patients with more than one submucous myomas. CONCLUSIONS: Complete infarction after UAE reduces the need for major re-interventions. Assessment of complete infarction may be considered to improve quality in UAE procedures. Patients with more than one submucous myoma at UAE may often have hysteroscopic removal of residual myomas. PMID- 24813086 TI - Early plasmapheresis as a successful treatment in hypertriglyceridemia-induced acute pancreatitis in first trimester pregnancy following in vitro fertilization. PMID- 24813087 TI - Molecular and morphological variability within the Aphidius colemani group with redescription of Aphidius platensis Brethes (Hymenoptera: Braconidae: Aphidiinae). AB - We have identified the following three taxa related to the Aphidius colemani species group, which are important biological control agents: Aphidius colemani, Aphidius transcaspicus and Aphidius platensis. Using partial sequences of the mitochondrial cytochrome oxidase subunit I (mtCOI) gene and geometric morphometric analysis of the forewing shape, we have explored the genetic structure and morphological variability of the A. colemani group from different aphid host/plant associations covering a wide distribution area. The topology of the maximum parsimony and maximum likelihood trees were identical with 98-100% bootstrap support, clustering A. colemani, A. platensis and A. transcaspicus into separate species. The distances among the taxa ranged from 2.2 to 4.7%, which is a common rate for the between-species divergence within the subfamily Aphidiinae. Differences in the shape of the forewing investigated within the biotypes of A. colemani group are congruent with their genetic diversification. Both A. platensis and A. colemani share a common host range pattern, and it would be interesting to estimate and compare the role of these two species in future biological control strategies against aphids of economic importance. Our results indicate that 'genetic screening' is a reliable approach for identification within the A. colemani group. The high variation in the wing shape among species, including a significant divergence in the wing shape among specimens that emerged from different hosts, makes the forewing shape and wing venation less reliable for species determination. Aphidius platensis is diagnostified and redescribed, and the key for the A. colemani group is presented. PMID- 24813088 TI - The effects of orchidectomy on toxicological responses to dietary ochratoxin A in Wistar rats. AB - Ochratoxin A (OTA) causes pathological lesions in the organs of animals. Males are more sensitive to OTA exposure than females but the reasons for this are unknown. The objective of this study was to explore the role of testosterone in male rats with OTA-related pathogenesis. To test the effect of testosterone on OTA toxicity, the testes of a group of rats were surgically removed. Male and female rats (approximately 300 and 200 g) were fed with OTA-contaminated feed (initially approximately 300 MUg kg(-1) b.w. per day) for 24 weeks. The organs of all the animals were collected and their organ lesion pathology, caspase-3 expression, OTA plasma and organ concentrations and total plasma testosterone concentrations were evaluated. OTA treatment created serious lesions in the kidney, liver and testes of rats. The major histopathological changes in the kidney and liver were karyomegaly, hemorrhages and vacuolization. In the testes, there was a marked decrease in the amount of spermatozoon. The degrees of organ lesion were evaluated and the castrated males had the lowest kidney and liver lesion scores, indicating that testosterone reduction in males dramatically reduces OTA-related organ damage. The plasma OTA levels for the intact males, the castrated and the females were 6.34, 8.42 and 12.5 MUg ml(-1), respectively. In conclusion, despite the similar plasma OTA levels of the intact and castrated males, OTA is less toxic in the castrated males. Therefore, the well-known gender specific toxicity of OTA seems to be related to the testosterone levels of rats. PMID- 24813089 TI - Proposal for a new MEG-MRI co-registration: a 3D laser scanner system. AB - OBJECTIVE: Co-registration between the head shape extracted from anatomical images that are obtained using a 3D digitizer is a non-negligible factor for magnetoencephalographic (MEG) utilization. The study aimed to propose a novel quick system based on a laser scanning technique involving a 3D laser scanner system that allows instant measurement while maintaining high accuracy and reproducibility. METHODS: The measurement duration, accuracy, and reproducibility of the finger representations in response to tactile stimulation between the 3D laser scanner-based method and the conventional magnetic field digitizer-based method were compared in 11 healthy subjects. Day-to-day variance in target registration error (TRE), day-to-day and session-to-session variability in head position indicator error (HRE) and source localization accuracy were evaluated with visualization of the source estimation and analysis of variance (ANOVA). RESULTS: Our proposed one-snapshot approach enabled 3D digitization measurements in <5s, and significantly reduced TRE, while mean HREs were a comparable level. Although there was less dramatic improvement of source localization, we found a significant reduction in session-to-session variability and day-to-day variance using our proposed method. CONCLUSIONS: Our results clearly demonstrated improvements in speed, comfort, accuracy, and reproducibility when using our new MEG co-registration method. SIGNIFICANCE: A systematic improvement in MEG measurement will be beneficial for routine clinical use. PMID- 24813090 TI - Estimating functional liver reserve following hepatic irradiation: adaptive normal tissue response models. AB - PURPOSE: To estimate the limit of functional liver reserve for safe application of hepatic irradiation using changes in indocyanine green, an established assay of liver function. MATERIALS AND METHODS: From 2005 to 2011, 60 patients undergoing hepatic irradiation were enrolled in a prospective study assessing the plasma retention fraction of indocyanine green at 15-min (ICG-R15) prior to, during (at 60% of planned dose), and after radiotherapy (RT). The limit of functional liver reserve was estimated from the damage fraction of functional liver (DFL) post-RT [1-(ICG-R15pre-RT/ICG-R15post-RT)] where no toxicity was observed using a beta distribution function. RESULTS: Of 48 evaluable patients, 3 (6%) developed RILD, all within 2.5 months of completing RT. The mean ICG-R15 for non-RILD patients pre-RT, during-RT and 1-month post-RT was 20.3%(SE 2.6), 22.0%(3.0), and 27.5%(2.8), and for RILD patients was 6.3%(4.3), 10.8%(2.7), and 47.6%(8.8). RILD was observed at post-RT damage fractions of >=78%. Both DFL assessed by during-RT ICG and MLD predicted for DFL post-RT (p<0.0001). Limiting the post-RT DFL to 50%, predicted a 99% probability of a true complication rate <15%. CONCLUSION: The DFL as assessed by changes in ICG during treatment serves as an early indicator of a patient's tolerance to hepatic irradiation. PMID- 24813091 TI - Histopathologic validation of 3'-deoxy-3'-18F-fluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude mice. AB - BACKGROUND AND PURPOSE: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrates accelerated tumor repopulation during fractionated irradiation with pathological validation (Ki-67 and BrdUrd makers) in a xenograft model system. However, these and other functional assays must be performed ex vivo and post hoc. We propose a novel, in vivo, real-time assay utilizing (18)F-FLT PET. MATERIAL AND METHODS: Nude mice with FaDu-hSCC were irradiated with 12 or 18 fractions of 1.8 Gy ([Dm]=3.0 Gy), either daily or every second day. (18)F-FLT micro-PET scans were performed at different time points, FLT parameters (SUVmax, SUVmean, and T/NT) were measured. Tumor sections were stained for Ki-67 and BrdUrd, a labeling index (LI) was calculated. Imaging-pathology correlation was determined by comparing FLT parameters and immunohistochemical results. RESULTS: Measured SUVmax, SUVmean and T/NT decreased significantly after daily irradiation with 12 fractions in 12 days (P<0.05) and 18 fractions in 18 days (P<0.05). In contrast, these parameters increased in mice treated with 12 fractions in 24 days (P>0.05) and 18 fractions in 36 days (P>0.05), suggesting accelerated repopulation. Similarly, Ki-67 and BrdUrd LIs demonstrated significant decreases with daily irradiation (P<0.05), and increases with every-second-day irradiation (P>0.05). (18)F-FLT parameters correlated strongly with proliferation markers (r(2): 0.679-0.879, P<0.001). CONCLUSIONS: (18)F-FLT parameters were in good agreement with Ki-67 and BrdUrd Li. These results may support a potential role for (18)F-FLT PET in real-time detection of tumor repopulation during fractionated radiotherapy. PMID- 24813093 TI - The future has begun in radiogenomics! PMID- 24813092 TI - Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines. AB - BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines"). MATERIALS AND METHODS: Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation(r)12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. RESULTS: Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. CONCLUSION: GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance. PMID- 24813094 TI - Radiation therapy quality assurance in clinical trials--Global Harmonisation Group. PMID- 24813095 TI - Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. AB - Breast cancer radiotherapy represents an essential component in the overall management of both early stage and locally advanced breast cancer. As the number of breast cancer survivors has increased, chronic sequelae of breast cancer radiotherapy become more important. While recently published data suggest a potential for an increase in cardiac events with radiotherapy, these studies do not consider the impact of newer radiotherapy techniques commonly utilized. Therefore, the purpose of this review is to evaluate cardiac dose sparing techniques in breast cancer radiotherapy. Current options for cardiac protection/avoidance include (1) maneuvers that displace the heart from the field such as coordinating the breathing cycle or through prone patient positioning, (2) technological advances such as intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT), and (3) techniques that treat a smaller volume around the lumpectomy cavity such as accelerated partial breast irradiation (APBI), or intraoperative radiotherapy (IORT). While these techniques have shown promise dosimetrically, limited data on late cardiac events exist due to the difficulties of long-term follow up. Future studies are required to validate the efficacy of cardiac dose sparing techniques and may use surrogates for cardiac events such as biomarkers or perfusion imaging. PMID- 24813096 TI - Stereotactic radiotherapy of benign meningioma in the elderly: clinical outcome and toxicity in 121 patients. AB - BACKGROUND AND PURPOSE: To investigate the outcome of definitive stereotactic based radiotherapy in elderly patients (>=70 years of age) with benign intracranial meningiomas. MATERIALS AND METHODS: 121 patients were treated with either fractionated stereotactic radiotherapy (FRTS; n=74), hypofractionated FSRT (hFSRT; n=35) or stereotactic radiosurgery (SRS; n=12), depending on tumor size and location. Local control (LC), overall survival (OS), cause-specific survival (CSS), symptomatology and acute and late toxicity were assessed. The prognostic value of factors such as age, sex, tumor location, Karnofsky performance scale, target volume and radiotherapy schedule was examined. RESULTS: The median follow up was 40 months (range, 12-124 months). LC, OS and CSS at 3 years were 98.3%, 92% and 99% and at 5 years they accounted 94.7%, 79% and 94.3%, respectively. We failed to identify any significant prognostic factor for outcome. Only Grade I-II toxicity was observed, whereas no new neurologic deficits or treatment-related mortality were encountered. CONCLUSION: This is the first study to assess the outcome following radiotherapy in elderly patients with intracranial meningiomas. The high local control, the low toxicity and the lack of treatment-associated mortality make stereotactic radiotherapy an attractive option in an age population where neurosurgery is often correlated with some mortality. PMID- 24813097 TI - Technical tips: dualplate fixation technique for comminuted proximal humerus fractures. AB - The authors report dualplate fixation technique for providing stable fixation in comminuted proximal humerus fractures. This technique has been used for proximal humerus fractures with metaphyseal comminution and provides excellent anatomical reduction and neck shaft angle (NSA). The recently locking plate is clinically more widely used due to its small size, low rigidity, high elasticity, and biomechanical properties such as fixed initial angle and rotational stability. However, in severely comminuted complex type proximal metaphyseal humerus fractures, the use of locking plate alone does not provide stable fixation, leading to complications such as varus collapse, anterior-posterior angulation, screw cutout, nonunion, malunion, and metal failure. Therefore, a more robust and enhanced fixation method, the dual plating technique using the locking compression plate (Proximal Humeral Internal Locking System and Variable Angle Locking Compression Plate) was developed. PMID- 24813098 TI - Delayed bone healing following high tibial osteotomy related to increased implant stiffness in locked plating. AB - INTRODUCTION: Asymmetrical callus formation and incomplete bone formation underneath stiff locking plates have been reported recently in clinical and experimental fracture healing studies. After similar effects were observed in the outcome of high tibial osteotomy (HTO) patients, a retrospective study was performed to quantify the frequency and level of such incomplete healing cases. MATERIAL AND METHODS: Twenty-three patients treated with medial open wedge HTO and locking plate (TomofixTM) for posttraumatic or congenital genu varum were investigated. No bone grafts were applied to fill the osteotomy gap. The median correction angle was 8 degrees (5-18 degrees ). Elective hardware removal was performed after a median of 19.5 months (12-58 months) following an uneventful clinical course. The most recent postoperative X-ray available (median 21 months; 13-56 months) was evaluated for consolidation of the osteotomy. We performed an in vitro biomechanical experiment using the same HTO on a loaded cadaver knee joint to compare interfragmentary movements (IFMs) when using regular locking screws with the TomofixTM plate and screws that enabled dynamic stabilisation of this plate. RESULTS: Fifteen patients (65%) displayed incomplete consolidation of the osteotomy underneath the locking plate (10.9% of the osteotomy length) and cortical deficiency. The time to implant removal for these patients of 27 months was longer than the 21 months for the patients with a complete osteotomy gap healing. The biomechanical experiment demonstrated that very low IFMs and corresponding interfragmentary strain occur underneath the plate when using regular locking screws. Replacement with dynamic screws resulted in an increased IFM. DISCUSSION AND CONCLUSIONS: These results support the hypothesis that low bone formation underneath locking plates is induced by increased stiffness. This high stiffness situation could be altered by replacing the standard screws with dynamic screws which allow for a movement of 0.35mm perpendicular to the screw axis. This resulted in an approximately threefold increase in the IFM and may be a potential concept to avoid incomplete bone healing under stiff plate fixations. PMID- 24813099 TI - A randomised controlled trial of expectant management versus surgical evacuation of early pregnancy loss. AB - OBJECTIVE: To show whether a clinically significant difference in success rates exists between expectant and surgical management of early pregnancy loss. STUDY DESIGN: Randomised controlled trial comparing expectant versus surgical management of early pregnancy loss over a 1-year period from 1st January to 31st December 2009 at Sultanah Aminah Hospital, Johor Bahru. Pregnant women with missed or incomplete miscarriages at gestations up to 14 weeks were recruited in this study. The success rate in the surgical group was measured as curettage performed without any complications during or after the procedure, while the success rate in the expectant group was defined as complete spontaneous expulsion of products of conception within 6 weeks without any complication. RESULTS: A total of 360 women were recruited and randomised to expectant or surgical management, with 180 women in each group. There was no statistically significant difference in the success rate between the groups and between the different types of miscarriage. With expectant management, 131 (74%) patients had a complete spontaneous expulsion of products of conception, of whom 106 (83%) women miscarried within 7 days. However, the rates of unplanned admissions (18.1%) and unplanned surgical evacuations (17.5%) in the expectant group were significantly higher than the rates (7.4% and 8% respectively) in the surgical group. The complications in both groups were similar. PMID- 24813100 TI - Concomitant hysteroscopic endometrial ablation and Essure procedure: feasibility, efficacy and satisfaction. AB - OBJECTIVE: Hysteroscopic endometrial destruction procedures for abnormal uterine bleeding are an alternative to hysterectomy. Such procedures are not contraceptive and are performed on fertile patients, requiring long-term contraception. This is the first study evaluating long-term results of a combined procedure associating endometrial destruction and concomitant hysteroscopic tubal sterilization by Essure((r)) micro-inserts. Our goal is to evaluate efficacy of endometrial destruction as well as hysteroscopic sterilization and satisfaction after a combined procedure in the case of abnormal uterine bleeding in non menopausal patients. STUDY DESIGN: This is a retrospective study (Canadian task force II-2) that includes 131 patients operated with combined endometrial destruction and hysteroscopic tubal sterilization between 2002 and 2011 at our university hospital. The patients were contacted to answer a questionnaire. Statistical analysis was performed with SAS(c) version 9.2. (SAS Institute Inc., Cary, NC). RESULTS: Ninety-three patients out of 131 could be reached. The mean follow-up was of 37.8 months (min=8, max=87, SD=6.2). Thirty-eight patients (29%) were lost to follow-up. Essure((r)) micro-inserts introduction success rate (evaluated on 131 patients) was 95.8%, and their position was appropriate in 81.1% of the 106 patients with position control. Efficacy of the procedure on the haemorrhagic symptoms (evaluated on 93 patients) was 80.6%. Twelve patients (12.9%) underwent a hysterectomy, 7 of which (58.3%) were a direct consequence of treatment failure. No pregnancies were reported. Satisfaction rate was of 90.3%. CONCLUSION: Inadequate position rates of the micro-inserts after 3 months seem somewhat above literature findings, though no pregnancy has been reported. However, recurrent bleeding symptoms and hysterectomy rates are consistent with those observed after an endometrial destruction procedure alone. Limitations are the limited number of patients, the bias inherent to retrospective studies (lost of follow-up, selection bias). The concomitant endometrial destruction and tubal sterilization by micro-inserts is a safe and efficient procedure. PMID- 24813102 TI - The role of alveolar corticotomies in orthodontic anchorage management. AB - The aim of this article is to describe our therapeutic approach in the management of Class III malocclusions requiring repositioning of the anterior-inferior segment. This approach is based on the reasoned use of selective alveolar corticotomies in anchorage management. The patient was a 17-year-old young woman presenting severe antero-inferior crowding, a Class III malocclusion and residual spaces in the upper arch. Orthodontic treatment consisted of extraction of the mandibular 1st premolars and maximum anchorage. A local mandibular corticotomy was performed prior to orthodontic treatment from the distal aspect of the right canine to the distal surface of the left canine, sparing the premolar segments. The maxillary arch received no corticotomy and was treated by conventional orthodontic techniques. En masse retraction of the 6 antero-inferior teeth was done using sliding mechanics. Active treatment was completed in 8 months. The corrections are still stable 2 years post-retention. PMID- 24813103 TI - Bi-maxillary advancement surgery: Technique, indications and results. AB - Esthetic analysis of the face in some patients presenting a dental Class II can reveal the need for maxillo-mandibular advancement surgery. In these cases, mandibular advancement alone would provide a result which was satisfactory from the occlusal viewpoint but esthetically displeasing. Using bi-maxillary advancement, the impact of nasal volume is reduced and the nasolabial relationship is corrected. The sub-mandibular length is increased, thus creating a better-defined cervico-mental angle. This treatment technique involving a prior mandibular procedure has the advantage of restoring patients' dental occlusion while optimizing their facial esthetics. PMID- 24813105 TI - Cationic copper(II)-containing surfactants: molecular structures, film morphology, and influence on the alignment of nematic mesogens. AB - We discuss the synthesis and amphiphilic behavior of the cationic metallosurfactants [(L(Py14))2Cu(II)ClO4]ClO4 (1), [(L(Py16))2Cu(II)ClO4]ClO4 (2), [(L(Py18))2Cu(II)ClO4]ClO4 (3), [(L(Py18))2Cu(II)NO3]NO3 (4), [(L(Py18))2Cu(II)Cl]Cl (5), and [(L(Py18))2Cu(II)Br]Br (6) obtained by treatment of the appropriate alkylaminemethyl-2-pyridine ligand containing tetra-, hexa-, or octadecyl chains with copper salts. These metallosurfactants show excellent agreement between infrared spectroscopic bands, spectrometric masses with isotopic patterns, and elemental composition. Single-crystal X-ray data available for 1, 2, 5 and the previously published 3 reveal a trigonal bipyramidal copper(II) ion bound at the basal plane to the amine and pyridine of each alkylaminemethylpyridine ligand and an anionic coligand to the apical position. Except for the surfactant with the shortest tetradecyl (C14) chain, these species yield Langmuir films with collapse pressures of 45-55 mN.m(-1) and average areas of ca. 50 A(2). A plateau around 15 mN.m(-1) is observed for 3, 4, and 5 and associated with the formation of dendritic domains about 50 MUm in size. Species 2 and 6 lack this plateau and show domains of ca. 5 MUm. Once transferred onto solid substrates, the resulting Langmuir-Blodgett film of 3 at 18 mN.m(-1) influences the alignment of the nematic liquid crystal N-(4-methoxybenzylidene)-4 butylaniline. PMID- 24813106 TI - Neuroprotective effects of therapeutic hypercapnia on spatial memory and sensorimotor impairment via anti-apoptotic mechanisms after focal cerebral ischemia/reperfusion. AB - A number of studies have demonstrated that therapeutic hypercapnia ameliorates neurological deficits and attenuates the histological damage of cerebral ischemia reperfusion injury. However, the effects of therapeutic hypercapnia on impaired spatial memory have not been reported. Here we aimed to investigate the effects and mechanisms of therapeutic hypercapnia on spatial memory in a rat model of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Adult male rats were randomly assigned into three experimental groups: sham (sham operation), IR (MCAO/R), and hypercapnia [arterial blood CO2 tension (PaCO2) 80-100 mmHg+IR] groups. Sensorimotor deficits and spatial memory testing were evaluated by an 18-point scoring system and an 8-arm radial maze task, respectively. The hippocampal histological damage and the percentage of apoptotic neurons were evaluated by hematoxylin and eosin (HE) staining as well as flow cytometry. Western blotting was used to investigate the changes of the apoptosis related Bcl-2 and Bax proteins. The results indicated that hypercapnia treatment significantly improved the abilities of impaired sensorimotor and spatial memory after MCAO/R. Moreover, hypercapnia treatment significantly increased the percentage of surviving neurons and decreased the percentage of apoptotic neurons in the hippocampus after MCAO/R damage. The expressions of anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax were significantly increased and decreased in the hypercapnia treated rats, respectively. These findings suggest that therapeutic hypercapnia can attenuate neuronal apoptosis and improve impaired spatial memory and sensorimotor after MCAO/R, which may be attributable to its anti-apoptotic effects through modulation of apoptosis-related protein. PMID- 24813107 TI - Impaired brain development and reduced cognitive function in phospholipase D deficient mice. AB - The phospholipases D (PLD1 and 2) are signaling enzymes that catalyze the hydrolysis of phosphatidylcholine to phosphatidic acid, a lipid second messenger involved in cell proliferation, and choline, a precursor of acetylcholine (ACh). In the present study, we investigated development and cognitive function in mice that were deficient for PLD1, or PLD2, or both. We found that PLD-deficient mice had reduced brain growth at 14-27 days post partum when compared to wild-type mice. In adult PLD-deficient mice, cognitive function was impaired in social and object recognition tasks. Using brain microdialysis, we found that wild-type mice responded with a 4-fold increase of hippocampal ACh release upon behavioral stimulation in the open field, while PLD-deficient mice released significantly less ACh. These results may be relevant for cognitive dysfunctions observed in fetal alcohol syndrome and in Alzheimer' disease. PMID- 24813108 TI - Effect of microinjecting of 5-aza-2-deoxycytidine into ventrolateral orbital cortex on depressive-like behavior in rats. AB - DNA methylation and histone modification are two major epigenetic mechanisms involved in the pathophysiology of major depressive disorder (MDD) and the action of antidepressants. We and others have recently shown that epigenetic regulation through histone acetylation within ventrolateral orbital cortex (VLO) contributes to the antidepressant-like effects of histone deacetylase inhibitors [HDACi, such as valproic acid (VPA) and MS-275] observed in rats. However, there is so far no investigation focused on the effect of DNA methylation in VLO on depressive-like behaviors. Here, we examined the effects of the DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-aza) on rat forced swimming test (FST) and locomotor activity when microinjected into VLO. We found that bilateral intra-VLO injections of 5-aza increased the duration of immobility in FST in a dose dependent manner compared to vehicle-treated controls. The effects of 5-aza observed in the FST paradigms could not be attributed to non-specific decreases in activity since the inhibition of DNA methylation in VLO did not cause general impairment in locomotor activity. These results add to the evidence that DNA hypomethylation in VLO is involved in regulating depressive-like behaviors, and suggest that the effect of DNA methylation on depressive-like behaviors appear to be brain region-dependent. PMID- 24813109 TI - Exercise ameliorates depression-like behavior and increases hippocampal BDNF level in ovariectomized rats. AB - The aims of the present study were to investigate whether exercise can improve the depression-like behavior caused by estrogen deficiency. Given that decreased level of brain-derived neurotrophic factor (BDNF) in many brain areas including hippocampus and prefrontal cortex is associated with estrogen deficiency-induced depression-like behavior, we also determined whether exercise affects the levels of BDNF and its receptor in hippocampus and prefrontal cortex (PFC). It was found that ovariectomy (OVX) caused an increase in depression-like behavior in rats and a decrease in BDNF level in hippocampus but not in PFC. The expression of TrkB, a high affinity BDNF receptor in hippocampus and PFC was not affected by OVX. 17beta-estradiol (E2) treatment ameliorated depression-like behavior and increased BDNF level in hippocampus in OVX rats. Serum E2 level inversely correlated to depression-like behavior and positively correlated to BDNF level in hippocampus. Exercise ameliorated depression-like behavior, increased serum E2 level and BDNF level in hippocampus in OVX rats. The increased E2 level did not correlate to BDNF level but correlated with some of the behaviors in the rats subjected to exercise. Our results suggested that E2 maintains BDNF in hippocampus, thereby ameliorating depression-like behavior. Exercise amelioration of depression-like behavior in OVX rats is partly due to increased serum E2 level. PMID- 24813110 TI - Nonadiabatic tapered optical fiber sensor for measurement of antimicrobial activity of silver nanoparticles against Escherichia coli. AB - Silver nanoparticles (SNPs) exhibit antibacterial properties via bacterial inactivation and growth inhibition but the mechanism is not yet completely understood. In this study a label free and rapid detection method for study of antimicrobial activity of the SNP against Escherichia coli (E. coli K-12) is investigated using a nonadiabtic tapered fiber optic (NATOF) biosensor. The results show that SNPs interact with bacteria either by anchoring to or penetrating into the bacterial cell layer. These mechanism changes the refractive index (RI) of the tapered region, which in turn lead to the changes in the optical characteristics of the tapered fiber and output signals. With similar conditions for bacteria, the inhibition rate of the E. coli growth was measured by colony counting method as an experimental control and the results were compared with those obtained from the fiber sensor measurements. For SNP concentrations ranging from 0 to 50 MUg ml(-1) the inhibition rates of the E. coli growth were measured to be from 1.27 h(-1) to -0.69 h(-1) and from -3.00*10( 3) h(-1) to -1.98*10(-2) h(-1) for colony counting and optical fiber biosensor, respectively. The results demonstrate the potential of the proposed NATOF biosensor as a label free and rapid sensing platform for understanding the mechanism of antibacterial effects of SNPs. PMID- 24813111 TI - An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franz diffusion cells. AB - The use of isolated animal models to assess percutaneous absorption of molecules is frequently reported. The porcine buccal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies avoiding unnecessary sacrifice of animals. But it is not always easy to obtain fresh buccal mucosa. Consequently, human and porcine buccal mucosa is sometimes frozen and stored in liquid nitrogen, but this procedure is not always feasible. One cheaper and simpler alternative is to freeze the buccal mucosa of freshly slaughtered pigs in a mechanical freezer, using DMSO and albumin as cryoprotective agents. This study compared the ex vivo permeability parameters of propranolol hydrochloride through porcine buccal mucosa using a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were evaluated. Equally histological studies were performed. Furthermore, the use of the parameter transmucosal water loss (TMWL) as an indicator of the buccal mucosa integrity was evaluated just as transepidermal water loss (TEWL) is utilized for skin integrity. The results showed no difference between fresh and frozen mucosal flux, permeability coefficient or lag time of propranolol. However, statistical significant difference in TMWL between fresh and frozen mucosa was observed. PMID- 24813112 TI - Intranasal administration of carbamazepine to mice: a direct delivery pathway for brain targeting. AB - The currently available antiepileptic drugs are typically administered via oral or intravenous (IV) routes which commonly exhibit high systemic distribution into non-targeted tissues, leading to peripheral adverse effects and limited brain uptake. In order to improve the efficacy and tolerability of the antiepileptic drug therapy, alternative administration strategies have been investigated. The purpose of the present study was to assess the pharmacokinetics of carbamazepine administered via intranasal (IN) and IV routes to mice, and to investigate whether a direct transport of the drug from nose to brain could be involved. The similar pharmacokinetic profiles obtained in all matrices following both administration routes indicate that, after IN delivery, carbamazepine reaches quickly and extensively the bloodstream, achieving the brain predominantly via systemic circulation. However, the uneven biodistribution of carbamazepine through the brain regions with higher concentrations in the olfactory bulb and frontal cortex following IN instillation, in comparison with the homogenous brain distribution pattern after IV injection, strongly suggests the involvement of a direct transport of carbamazepine from nose to brain. Therefore, it seems that IN delivery represents a suitable and promising alternative route to administer carbamazepine not only for the chronically use of the drug but also in emergency conditions. PMID- 24813113 TI - The diagnostic accuracy of specific IgE to Ara h 6 in adults is as good as Ara h 2. AB - Specific IgE (sIgE) to Ara h 2 is useful in diagnosing peanut allergy. Our aim was to assess the diagnostic value of sIgE to Ara h 6, another 2S albumin, in an adult population suspected of peanut allergy. Subjects with suspected peanut allergy between 2002 and 2013 were included if a diagnostic double-blind, placebo controlled food challenge with peanut was performed. sIgE to Ara h 2 and Ara h 6 was measured by ImmunoCAP ISAC 112. Of 107 challenged subjects, 65 had a positive challenge (61%). The discriminative ability of sIgE to Ara h 2 and Ara h 6 was comparable: AUC 0.81 vs. 0.82. Positive predictive value for both tests was 95% using a cutoff value >=1 ISU/l with poor corresponding sensitivity values (58% for Ara h 2, 62% for Ara h 6), but good specificity values (95% for both tests). In conclusion, the diagnostic value of sIgE to Ara h 6 on population level was as good as sIgE to Ara h 2. On individual level, however, 5% of the subjects showed contradicting results between both tests using a cutoff of 0.3 ISU/l, leading to a risk of misdiagnosis if only one of both tests is used. PMID- 24813114 TI - The potassium channel opener NS1619 modulates calcium homeostasis in muscle cells by inhibiting SERCA. AB - NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl) 2H-benzimidazole-2-one) is widely used as a large-conductance Ca(2+)-activated K(+) (BKCa) channel opener. It was previously reported that activation of BKCa channels by NS1619 could protect the cardiac muscle against ischaemia and reperfusion injury. This study reports the effects of NS1619 on intracellular Ca(2+) homeostasis in H9C2 and C2C12 cells as well as its molecular mechanism of action. The effects of NS1619 on Ca(2+) homeostasis in C2C12 and H9C2 cells were assessed using the Fura-2 fluorescence method. Ca(2+) uptake by sarcoplasmic reticulum (SR) vesicles isolated from rat skeletal muscles and sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity were measured. The effect of NS1619 on the isometric force of papillary muscle contraction in the guinea pig heart was also examined. H9C2 and C2C12 cells treated with NS1619 released Ca(2+) from internal stores in a concentration-dependent manner. Ca(2+) accumulation by the SR vesicles was inhibited by NS1619 treatment. NS1619 also decreased the activity of SERCA derived from rat skeletal muscle. The calcium release from cell internal stores and inhibition of SERCA by NS1619 are pH dependent. Finally, NS1619 had a profound effect on the isometric force of papillary muscle contraction in the guinea pig heart. These results indicate that NS1619 is a potent modulator of the intracellular Ca(2+) concentration in H9C2 and C1C12 cells due to its interaction with SRs. The primary target of NS1619 is SERCA, which is located in SR vesicles. The effect of NS1619-mediated SERCA inhibition on cytoprotective processes should be considered. PMID- 24813115 TI - Cell Calcium. Special issue: Ca2+ signaling and secretory function. Preface. PMID- 24813116 TI - A methodology for the characterization and diagnosis of cognitive impairments Application to specific language impairment. AB - OBJECTIVES: The diagnosis of mental disorders is in most cases very difficult because of the high heterogeneity and overlap between associated cognitive impairments. Furthermore, early and individualized diagnosis is crucial. In this paper, we propose a methodology to support the individualized characterization and diagnosis of cognitive impairments. The methodology can also be used as a test platform for existing theories on the causes of the impairments. We use computational cognitive modeling to gather information on the cognitive mechanisms underlying normal and impaired behavior. We then use this information to feed machine-learning algorithms to individually characterize the impairment and to differentiate between normal and impaired behavior. We apply the methodology to the particular case of specific language impairment (SLI) in Spanish-speaking children. METHODS AND MATERIALS: The proposed methodology begins by defining a task in which normal and individuals with impairment present behavioral differences. Next we build a computational cognitive model of that task and individualize it: we build a cognitive model for each participant and optimize its parameter values to fit the behavior of each participant. Finally, we use the optimized parameter values to feed different machine learning algorithms. The methodology was applied to an existing database of 48 Spanish speaking children (24 normal and 24 SLI children) using clustering techniques for the characterization, and different classifier techniques for the diagnosis. RESULTS: The characterization results show three well-differentiated groups that can be associated with the three main theories on SLI. Using a leave-one-subject out testing methodology, all the classifiers except the DT produced sensitivity, specificity and area under curve values above 90%, reaching 100% in some cases. CONCLUSIONS: The results show that our methodology is able to find relevant information on the underlying cognitive mechanisms and to use it appropriately to provide better diagnosis than existing techniques. It is also worth noting that the individualized characterization obtained using our methodology could be extremely helpful in designing individualized therapies. Moreover, the proposed methodology could be easily extended to other languages and even to other cognitive impairments not necessarily related to language. PMID- 24813117 TI - Distal metatarsal synostosis: a case report. AB - We report a rare case of distal metatarsal synostosis of the 4th and 5th metatarsals in an 11 year old male. He was referred with forefoot pain. Clinical examination and radiographs have confirmed an osseous connection of the distal 4th and 5th metatarsal. This was treated surgically with bony bridge excision and the patient is now asymptomatic. PMID- 24813118 TI - [Ocular toxocariasis: a case report]. PMID- 24813119 TI - [Multicenter Ozurdex(r) assessment for diabetic macular edema: MOZART study]. AB - PURPOSE: To evaluate the efficiency and safety of intravitreal implant of 0.7mg dexamathasone in visual impairment due to diabetic macular edema (DME). MATERIALS AND METHODS: This was a retrospective, multicenter, study. Seventy-four patients, with a mean age of 65 years, followed for at least 6 months (mean follow-up: 9.8 months) were included in 5 French eye clinics (P 1.5 collective). The mean systolic blood pressure was 138mmHg and the mean HbA1c was 7.2%. We monitored 2 systemic parameters: blood pressure and glycemic balance. Best-corrected visual acuity (BCVA), central retinal thickness (CRT, Spectralis OCT), intraocular pressure (IOP) and cataract progression are studied at baseline and then at 1, 2, 4 and 6 months. RESULTS: The average CRT decrease was: 239MUm at month 2 (M2) and 135MUm at month 6 (M6). The mean improvement from baseline of BCVA is 8.5 letters at M2 and 7.6 letters at M6. A gain greater than 15 letters is found in 27% of patients at M6. For naive patients the BCVA is 71 letters versus 60 letters (P<0.05). Patients with a baseline CRT <500mmHg have a BCVA of 66 letters versus 57 letters (P<0.05). The mean rate injections was 1.2 at 6 months with an average of 5.4 months for reinjection. Ocular hypertension greater than 25mmHg, managed by topical treatment, is observed in 13.4% of patients. No glaucoma surgery was necessary. CONCLUSION: Dexamethasone has an anatomical and functional effectiveness in the treatment of DME. Outcomes for naive patients and lower CRT suggest that the duration of diabetes mellitus and previous treatments are negative factors of recovery. Side effects are rare and manageable. Ozurdex((r)) seems to be a treatment for visual impairment due to DME with a favorable safety profile. Patient follow-up must be adapted to half-life of the product with a control before M1 (intraocular pressure) and before M5 (DME recurrence, BCVA). PMID- 24813120 TI - Cystoviral polymerase complex protein P7 uses its acidic C-terminal tail to regulate the RNA-directed RNA polymerase P2. AB - In bacteriophages of the cystovirus family, the polymerase complex (PX) encodes a 75-kDa RNA-directed RNA polymerase (P2) that transcribes the double-stranded RNA genome. Also a constituent of the PX is the essential protein P7 that, in addition to accelerating PX assembly and facilitating genome packaging, plays a regulatory role in transcription. Deletion of P7 from the PX leads to aberrant plus-strand synthesis suggesting its influence on the transcriptase activity of P2. Here, using solution NMR techniques and the P2 and P7 proteins from cystovirus phi12, we demonstrate their largely electrostatic interaction in vitro. Chemical shift perturbations on P7 in the presence of P2 suggest that this interaction involves the dynamic C-terminal tail of P7, more specifically an acidic cluster therein. Patterns of chemical shift changes induced on P2 by the P7 C-terminus resemble those seen in the presence of single-stranded RNA suggesting similarities in binding. This association between P2 and P7 reduces the affinity of the former toward template RNA and results in its decreased activity both in de novo RNA synthesis and in extending a short primer. Given the presence of C-terminal acidic tracts on all cystoviral P7 proteins, the electrostatic nature of the P2/P7 interaction is likely conserved within the family and could constitute a mechanism through which P7 regulates transcription in cystoviruses. PMID- 24813121 TI - Novel interaction of the Z-DNA binding domain of human ADAR1 with the oncogenic c Myc promoter G-quadruplex. AB - Both G-quadruplex and Z-DNA can be formed in G-rich and repetitive sequences on genome, and their formation and biological functions are controlled by specific proteins. Z-DNA binding proteins, such as human ADAR1, have a highly conserved Z DNA binding domain having selective affinity to Z-DNA. Here, our study identifies the Z-DNA binding domain of human ADAR1 (hZalphaADAR1) as a novel G-quadruplex binding protein that recognizes c-myc promoter G-quadruplex formed in NHEIII1 region and represses the gene expression. An electrophoretic migration shift assay shows the binding of hZalphaADAR1 to the intramolecular c-myc promoter G quadruplex-forming DNA oligomer. To corroborate the binding of hZalphaADAR1 to the G-quadruplex, we conducted CD and NMR chemical shift perturbation analyses. CD results indicate that hZalphaADAR1 stabilizes the parallel-stranded conformation of the c-myc G-quadruplex. The NMR chemical shift perturbation data reveal that the G-quadruplex binding region in hZalphaADAR1 was almost identical with the Z-DNA binding region. Finally, promoter assay and Western blot analysis show that hZalphaADAR1 suppresses the c-myc expression promoted by NHEIII1 region containing the G-quadruplex-forming sequence. This finding suggests a novel function of Z-DNA binding protein as a regulator of G-quadruplex-mediated gene expression. PMID- 24813123 TI - Alteration of the C-terminal ligand specificity of the erbin PDZ domain by allosteric mutational effects. AB - Modulation of protein binding specificity is important for basic biology and for applied science. Here we explore how binding specificity is conveyed in PDZ (postsynaptic density protein-95/discs large/zonula occludens-1) domains, small interaction modules that recognize various proteins by binding to an extended C terminus. Our goal was to engineer variants of the Erbin PDZ domain with altered specificity for the most C-terminal position (position 0) where a Val is strongly preferred by the wild-type domain. We constructed a library of PDZ domains by randomizing residues in direct contact with position 0 and in a loop that is close to but does not contact position 0. We used phage display to select for PDZ variants that bind to 19 peptide ligands differing only at position 0. To verify that each obtained PDZ domain exhibited the correct binding specificity, we selected peptide ligands for each domain. Despite intensive efforts, we were only able to evolve Erbin PDZ domain variants with selectivity for the aliphatic C terminal side chains Val, Ile and Leu. Interestingly, many PDZ domains with these three distinct specificities contained identical amino acids at positions that directly contact position 0 but differed in the loop that does not contact position 0. Computational modeling of the selected PDZ domains shows how slight conformational changes in the loop region propagate to the binding site and result in different binding specificities. Our results demonstrate that second sphere residues could be crucial in determining protein binding specificity. PMID- 24813122 TI - Flipping of the ribosomal A-site adenines provides a basis for tRNA selection. AB - Ribosomes control the missense error rate of ~10(-4) during translation though quantitative contributions of individual mechanistic steps of the conformational changes yet to be fully determined. Biochemical and biophysical studies led to a qualitative tRNA selection model in which ribosomal A-site residues A1492 and A1493 (A1492/3) flip out in response to cognate tRNA binding, promoting the subsequent reactions, but not in the case of near-cognate or non-cognate tRNA. However, this model was recently questioned by X-ray structures revealing conformations of extrahelical A1492/3 and domain closure of the decoding center in both cognate and near-cognate tRNA bound ribosome complexes, suggesting that the non-specific flipping of A1492/3 has no active role in tRNA selection. We explore this question by carrying out molecular dynamics simulations, aided with fluorescence and NMR experiments, to probe the free energy cost of extrahelical flipping of 1492/3 and the strain energy associated with domain conformational change. Our rigorous calculations demonstrate that the A1492/3 flipping is indeed a specific response to the binding of cognate tRNA, contributing 3kcal/mol to the specificity of tRNA selection. Furthermore, the different A-minor interactions in cognate and near-cognate complexes propagate into the conformational strain and contribute another 4kcal/mol in domain closure. The recent structure of ribosome with features of extrahelical A1492/3 and closed domain in near-cognate complex is reconciled by possible tautomerization of the wobble base pair in mRNA-tRNA. These results quantitatively rationalize other independent experimental observations and explain the ribosomal discrimination mechanism of selecting cognate versus near-cognate tRNA. PMID- 24813124 TI - A medieval approach to head injuries from the golden era of Islamic medicine from the writings of Abn Bakr Muhammad Ibn Zakariya al-Razi-Rhazes (865-925). PMID- 24813125 TI - Partial anterior petrosectomy: old wine, new bottle. PMID- 24813126 TI - Screening for unruptured intracranial aneurysms: who and when? PMID- 24813127 TI - How much is enough? The question of extent of resection in glioblastoma multiforme. PMID- 24813128 TI - Unilateral basal interhemispheric approach through the sphenoid sinus. PMID- 24813129 TI - Low-grade gliomas and quality of life. PMID- 24813130 TI - The alchemy of brain arteriovenous malformation management. PMID- 24813131 TI - Bundling sleep promotion with delirium prevention: ready for prime time? PMID- 24813132 TI - The effect of a multicomponent multidisciplinary bundle of interventions on sleep and delirium in medical and surgical intensive care patients. AB - Sleep deprivation is common among intensive care patients and may be associated with delirium. We investigated whether the implementation of a bundle of non pharmacological interventions, consisting of environmental noise and light reduction designed to reduce disturbing patients during the night, was associated with improved sleep and a reduced incidence of delirium. The study was divided into two parts, before and after changing our practice. One hundred and sixty seven and 171 patients were screened for delirium pre- and post-intervention, respectively. Compliance with the interventions was > 90%. The bundle of interventions led to an increased mean (SD) sleep efficiency index (60.8 (3.5) before vs 75.9 (2.2) after, p = 0.031); reduced mean sound (68.8 (4.2) dB before vs 61.8 (9.1) dB after, p = 0.002) and light levels (594 (88.2) lux before vs 301 (53.5) lux after, p = 0.003); and reduced number of awakenings caused by care activities overnight (11.0 (1.1) before vs 9.0 (1.2) after, p = 0.003). In addition, the introduction of the care bundle led to a reduced incidence of delirium (55/167 (33%) before vs 24/171 (14%) after, p < 0.001), and less time spent in delirium (3.4 (1.4) days before vs 1.2 (0.9) days after, p = 0.021). Increases in sleep efficiency index were associated with a lower odds ratio of developing delirium (OR 0.90, 95% CI 0.84-0.97). The introduction of an environmental noise and light reduction programme as a bundle of non pharmacological interventions in the intensive care unit was effective in reducing sleep deprivation and delirium, and we propose a similar programme should be implemented more widely. PMID- 24813134 TI - Outcome by mode of anaesthesia for hip fracture surgery. PMID- 24813135 TI - Confounding factors in observational hip fracture studies. PMID- 24813136 TI - Outcome differences after elective or emergency hip operations. PMID- 24813137 TI - Spinal, or spinal and sedation, for patients with hip fracture? PMID- 24813138 TI - A reply. PMID- 24813139 TI - Interpreting national hip fracture data. PMID- 24813140 TI - McGrath((r)) series 5 videolaryngoscope evaluation for double-lumen tube intubation. PMID- 24813141 TI - The effects of general anaesthesia on memory in children. PMID- 24813142 TI - Portex EpifuseTM blockage remains a problem. PMID- 24813143 TI - Ultrasonographic identification of the cricothyroid membrane. PMID- 24813144 TI - Lung ultrasound artefacts due to oesophageal Doppler monitoring. PMID- 24813145 TI - Unexpected spike in inspired oxygen and anaesthetic agent values. PMID- 24813146 TI - The ageing intensivist. PMID- 24813147 TI - Syringe labelling - bridging the gap. PMID- 24813148 TI - Enrichment and particle size dependence of polonium and other naturally occurring radionuclides in coal ash. AB - Coal fired thermal power contributes 70% of power in India. Coal fired power generation results in huge amounts of fly ash and bottom ash of varying properties. Coal, which contains the naturally occurring radionuclides, on burning results in enrichment of these radionuclides in the ashes. In the present study, coal, bottom ash and fly ash samples collected from six coal-fired power plants in India were measured for (210)Po using alpha spectrometry and for natural U, (226)Ra, (232)Th and (40)K by an HPGe gamma-ray spectrometer. (210)Po in fly ash ranged from 25.7 to 70 Bq/kg with a mean value of 40.5 Bq/kg. The range and mean activities of (238)U, (226)Ra, (232)Th, (40)K in fly ash were 38.5 101 (78.1), 60-105.7 (79), 20-125 (61.7) and 43.6-200 (100) Bq/kg respectively. Fly ash and bottom ash contains two to five times more natural radionuclides than feed coal. The results were compared with the available data from earlier studies in other countries. The effect of particle size on enrichment factor of the nuclides in fly ash was studied. (210)Po showed the largest size dependence with its concentration favoring the smaller particle size while (232)Th showed least size dependence. (238)U and (226)Ra showed behavior intermediate to that of (210)Po and (232)Th. Also the correlation between sulfur content of the feed coal and activity of (210)Po was investigated. Increased sulfur content in feed coal enhanced enrichment of (210)Po in ash. PMID- 24813149 TI - Dissociating contributions of ACC and vmPFC in reward prediction, outcome, and choice. AB - Acting in an uncertain environment requires estimating the probability and the value of potential outcomes. These computations are typically ascribed to various parts of the medial prefrontal cortex (mPFC), but the functional architecture of this region remains debated. The anterior cingulate cortex (ACC) encodes reward prediction and outcome (i.e. win vs lose, Silvetti, Seurinck, & Verguts, 2013. Cortex, 49(6), 1627-35. doi:10.1016/j.cortex.2012.05.008). An outcome-related value signal has also been reported in the ventromedial Prefrontal Cortex (vmPFC, Rangel & Hare, 2010. Current Opinion in Neurobiology, 20(2), 262-70. doi:10.1016/j.conb.2010.03.001). Whether a functional dissociation can be traced in these regions with respect to reward prediction and outcome has been suggested but not rigorously tested. Hence an fMRI study was designed to systematically examine the contribution of ACC and vmPFC to reward prediction and outcome. A striking dissociation was identified, with ACC coding for positive prediction errors and vmPFC responding to outcome, irrespective of probability. Moreover, ACC has been assigned a crucial role in the selection of intentional actions (decision-making) and computing the value associated to these actions (action based value). Conversely, vmPFC seems to implement stimulus-based value processing (Rudebeck et al., 2008. Journal of Neuroscience, 28(51), 13775-85. doi:10.1523/JNEUROSCI.3541-08.2008; Rushworth, Behrens, Rudebeck, & Walton, 2007. Trends in Cognitive Sciences, 11(4), 168-76. doi:10.1016/j.tics.2007.01.004). Therefore, a decision-making factor (choice vs. no choice condition) was also implemented in the present paradigm to distinguish stimulus-based versus action based value coding in the mPFC during both decision and outcome phase. We found that vmPFC was more activated during the outcome phase in the no-choice than in the choice condition, potentially confirming the role of this area in stimulus based (more than action-based) value processing. PMID- 24813151 TI - rTMS-induced virtual lesion of the posterior parietal cortex (PPC) alters the control of reflexive shifts of social attention triggered by pointing hands. AB - In highly social groups like human and non-human primates, gaze and pointing cues are fundamentally important for directing the attention of conspecifics. Although neuroimaging studies indicate that shifts of attention triggered by observation of social cues activate the onlookers' fronto-parietal cortices, information on whether these regions play a causative role in orienting and re-orienting of social attention is lacking. To advance our understanding of this, we used event related repetitive dual pulse transcranial magnetic stimulation to interfere with neural activity in the right frontal eye field (rFEF) and posterior parietal cortex (rPPC). This procedure allowed us to explore how inhibiting rFEF and rPPC influences shifts of attention triggered by the observation of body-related (gaze and hand) and non body-related (arrow) directional distractors. Participants were asked to perform a leftward or rightward pointing movement according to the color change of a central imperative signal while ignoring a distractor, which was either a gaze, a pointing hand or an arrow. Stimulation of rPPC in a region supposedly linked to attentional re-orienting and to planning and execution of upper limb movements increased the reflexive tendency to follow distracting pointing hands but not oriented gaze or arrows. These findings suggest that inhibition of cortical structures that control attentional shifts triggered by social stimuli brings forth an increase of the cost of attentional re-orienting. Moreover, our results provide the first causative evidence that reflexive social attention in humans may be coded according to body-part-centered frames of reference. PMID- 24813150 TI - Omega-3 fatty acids moderate effects of physical activity on cognitive function. AB - Greater amounts of physical activity (PA) and omega-3 fatty acids have both been independently associated with better cognitive performance. Because of the overlapping biological effects of omega-3 fatty acids and PA, fatty acid intake may modify the effects of PA on neurocognitive function. The present study tested this hypothesis by examining whether the ratio of serum omega-6 to omega-3 fatty acid levels would moderate the association between PA and executive and memory functions in 344 participants (Mean age=44.42 years, SD=6.72). The Paffenbarger Physical Activity Questionnaire (PPAQ), serum fatty acid levels, and performance on a standard neuropsychological battery were acquired on all subjects. A principal component analysis reduced the number of cognitive outcomes to three factors: n-back working memory, Trail Making test, and Logical Memory. We found a significant interaction between PA and the ratio of omega-6 to omega-3 fatty acid serum levels on Trail Making performance and n-back performance, such that higher amounts of omega-3 levels offset the deleterious effects of lower amounts of PA. These effects remained significant in a subsample (n=299) controlling for overall dietary fat consumption. There were no significant additive or multiplicative benefits of higher amounts of both omega-3 and PA on cognitive performance. Our results demonstrate that a diet high in omega-3 fatty acids might mitigate the effect of lower levels of PA on cognitive performance. This study illuminates the importance of understanding dietary and PA factors in tandem when exploring their effects on neurocognitive health. PMID- 24813152 TI - Thyroid transcription factor-1 is a specific marker of benign but not malignant feline lung tumours. AB - Feline lung tumours are currently subclassified according to the criteria of the World Health Organisation, but this scheme contains overlap in the tumour phenotype. The aims of the present study were to re-evaluate the histological features of feline lung tumours and to correlate these with expression of the markers thyroid transcription factor (TTF)-1 and Ki67. TTF-1 was found to be a highly specific marker for neoplastic and non-neoplastic lung tissue and thyroid tissue, but was expressed only weakly in invasive lung tumours. A combined semiquantitative score for Ki67 and TTF-1 expression correlated well with differentiation and invasive behaviour of the tumours and may thus be of potential value for evaluation of feline lung tumours. PMID- 24813153 TI - Disseminated Mycobacterium genavense infection in a chinchilla (Chinchilla lanigera). AB - A 1-year-old neutered male chinchilla (Chinchilla lanigera) was presented with emaciation and a 1-month history of progressive weight loss. The animal was bright and responsive on clinical examination, but had poor body condition. Serum biochemical analysis revealed elevated alanine amino transferase and alkaline phosphatase. Ultrasound examination was unremarkable. Thoracic radiography showed changes consistent with bullous emphysema and severe pneumonia. Antibiotic therapy was initiated, but the chinchilla died 6 weeks later. Necropsy examination revealed granulomatous lesions in the lungs and liver. Numerous acid fast bacilli were present in the cytoplasm of macrophages. Sequencing of genetic material isolated from fixed tissue classified the pathogen as Mycobacterium genavense. PMID- 24813154 TI - Immunohistochemical investigation of extracellular matrix components in the lymphoid organs of healthy pigs and pigs with systemic disease caused by circovirus type 2. AB - The extracellular matrix (ECM) provides a scaffold for cell growth, impacts on cellular behaviour and plays an important role in pathological conditions. Several components of the ECM of lymphoid tissues have been shown to be crucial in the maturation, differentiation and migration of lymphocytes and other immune cells and, therefore, in the development of immune responses. Little is known of the composition and function of the ECM in porcine lymphoid tissues. The present study characterizes immunohistochemically the expression of several ECM-related molecules (i.e. hyaluronan [HA] and its receptor CD44, tenascin-C [TN-C] and versican) in primary and secondary lymphoid organs of healthy pigs and animals affected by porcine circovirus type 2-systemic disease (PCV2-SD). These ECM molecules displayed a highly defined expression pattern in healthy animals, suggesting that they may have a role in the compartmentalization of immune cells within lymphoid tissues. HA was abundant in the medulla of the thymus and follicles of secondary organs; CD44 and TN-C were present in the thymic medulla and parafollicular areas of secondary lymphoid organs; however, there was minimal expression of versican in healthy tissues. In PCV2-SD-affected animals, HA and CD44 showed a similar but more diffuse distribution. TN-C was increased in the T cell-dependent areas and in tonsillar crypts, and versican was more abundantly expressed, with expression restricted to vascular structures and trabeculae and also surrounding tonsillar crypts. The altered expression in PCV2-SD-affected pigs was most probably related to a higher content of connective tissue secondary to tissue destruction and remodelling attempts as part of the disease process. PMID- 24813155 TI - Immunohistochemical expression of cyclooxygenase-2 in normal, hyperplastic and neoplastic canine lymphoid tissues. AB - There is much interest in the potential use of selective inhibitors of cyclooxygenase (COX)-2 in combination with other cancer therapeutics. COX-2 is a key enzyme in prostaglandin synthesis and has been implicated in the pathogenesis of numerous canine and feline malignancies. There are few data on the potential role of COX-2 in the pathogenesis of canine lymphoma. The present study examined COX-2 expression in normal, hyperplastic and neoplastic canine lymphoid tissues. Immunohistochemical expression was evaluated in 12 samples of non-pathologically enlarged normal lymph nodes, 24 samples of hyperplastic lymph node and 44 samples of lymphoma (22 B-cell and 22 T-cell lymphomas). The labelling was scored semiquantitatively and a score of +2 or +3 was interpreted as overexpression. In hyperplastic lymph nodes only a few macrophages were COX-2-positive while six of the 44 lymphomas (13.6%; three B- and three T-cell lymphomas) overexpressed COX 2. These data provide a rationale for further investigation of COX-2 expression in canine lymphoma for prognostic, chemopreventive and chemotherapeutic purposes. PMID- 24813156 TI - Systemic mastocytosis in an African fat-tail gecko (Hemitheconyx caudicinctus). AB - A 3-year-old African fat-tail gecko (Hemitheconyx caudicinctus) suddenly became lethargic and died 2 days later. Necropsy examination revealed a submandibular mass and discolouration of the liver, kidneys and skeletal muscles of the tail. Microscopical evaluation revealed neoplastic mast cells in the skin, liver, kidneys, skeletal muscles, bones, spleen, uterus, ovaries and lungs. Exfoliative cytological, histopathological and ultrastructural features were consistent with systemic mastocytosis. Neoplastic proliferative disorders of mast cells are rare in reptiles and this is the first report of mast cell neoplasia in geckos. PMID- 24813157 TI - Succinate dehydrogenase subunit D and succinate dehydrogenase subunit B mutation analysis in canine phaeochromocytoma and paraganglioma. AB - Phaeochromocytomas (PCs) are tumours of the adrenal medulla chromaffin cells. Paragangliomas (PGLs) arise in sympathetic ganglia (previously called extra adrenal PCs) or in non-chromaffin parasympathetic ganglia cells that are usually non-secretory. Parenchymal cells from these tumours have a common embryological origin from neural crest ectoderm. Several case series of canine PCs and PGLs have been published and a link between the increased incidence of chemoreceptor neoplasia in brachycephalic dog breeds and chronic hypoxia has been postulated. A similar link to hypoxia in man led to the identification of germline heterozygous mutations in the gene encoding succinate dehydrogenase subunit D (SDHD) and subsequently SDHA, SDHB and SDHC in similar tumours. We investigated canine PCs (n = 6) and PGLs (n = 2) for SDHD and SDHB mutations and in one PGL found a somatic SDHD mutation c.365A>G (p.Lys122Arg) in exon 4, which was not present in normal tissue from this brachycephalic dog. Two PCs were heterozygous for both c.365A>G (p.Lys122Arg) mutation and an exon 3 silent variant c.291G>A. We also identified the heterozygous SDHB exon 2 mutation c.113G>A (p.Arg38Gln) in a PC. These results illustrate that genetic mutations may underlie tumourigenesis in canine PCs and PGLs. The spontaneous nature of these canine diseases and possible association of PGLs with hypoxia in brachycephalic breeds may make them an attractive model for studying the corresponding human tumours. PMID- 24813158 TI - Cutaneous angioleiomyoma in a black-tailed prairie dog (Cynomys iudovicianus). AB - A 3-year-old male black-tailed prairie dog (Cynomys iudovicianus) was presented with a dome-shaped cutaneous mass over the left femur. Microscopically, the mass was encapsulated and composed of proliferating spindle cells arranged in haphazard, interlacing bundles. There were vascular structures within the mass and some spindle cells had transitioned from the peripheral regions of the vascular wall. Immunohistochemically, the cells expressed vimentin, alpha-smooth muscle actin, desmin and heavy caldesmon. Based on these findings, the mass was diagnosed as a cutaneous angioleiomyoma. To the best of our knowledge, this is the first case of cutaneous angioleiomyoma in a black-tailed prairie dog. PMID- 24813160 TI - In for the long haul: 20 years of malaria surveillance. PMID- 24813159 TI - The rise and fall of malaria in a West African rural community, Dielmo, Senegal, from 1990 to 2012: a 22 year longitudinal study. AB - BACKGROUND: A better understanding of the effect of malaria control interventions on vector and parasite populations, acquired immunity, and burden of the disease is needed to guide strategies to eliminate malaria from highly endemic areas. We monitored and analysed the changes in malaria epidemiology in a village community in Senegal, west Africa, over 22 years. METHODS: Between 1990 and 2012, we did a prospective longitudinal study of the inhabitants of Dielmo, Senegal, to identify all episodes of fever and investigate the relation between malaria host, vector, and parasite. Our study included daily medical surveillance with systematic parasite detection in individuals with fever. We measured parasite prevalence four times a year with cross-sectional surveys. We monitored malaria transmission monthly with night collection of mosquitoes. Malaria treatment changed over the years, from quinine (1990-94), to chloroquine (1995-2003), amodiaquine plus sulfadoxine-pyrimethamine (2003-06), and finally artesunate plus amodiaquine (2006-12). Insecticide-treated nets (ITNs) were introduced in 2008. FINDINGS: We monitored 776 villagers aged 0-101 years for 2 378 150 person-days of follow-up. Entomological inoculation rate ranged from 142.5 infected bites per person per year in 1990 to 482.6 in 2000, and 7.6 in 2012. Parasite prevalence in children declined from 87% in 1990 to 0.3 % in 2012. In adults, it declined from 58% to 0.3%. We recorded 23 546 fever episodes during the study, including 8243 clinical attacks caused by Plasmodium falciparum, 290 by Plasmodium malariae, and 219 by Plasmodium ovale. Three deaths were directly attributable to malaria, and two to severe adverse events of antimalarial drugs. The incidence of malaria attacks ranged from 1.50 attacks per person-year in 1990 to 2.63 in 2000, and to only 0.046 in 2012. The greatest changes were associated with the replacement of chloroquine and the introduction of ITNs. INTERPRETATION: Malaria control policies combining prompt treatment of clinical attacks and deployment of ITNs can nearly eliminate parasite carriage and greatly reduce the burden of malaria in populations exposed to intense perennial malaria transmission. The choice of drugs seems crucial. Rapid decline of clinical immunity allows rapid detection and treatment of novel infections and thus has a key role in sustaining effectiveness of combining artemisinin-based combination therapy and ITNs despite increasing pyrethroid resistance. FUNDING: Pasteur Institutes of Dakar and Paris, Institut de Recherche pour le Developpement, and French Ministry of Cooperation. PMID- 24813161 TI - Ovarian reserve and PGD treatment outcome in women with myotonic dystrophy. AB - Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults. There are conflicting reports about its effect on female fertility. This study investigated ovarian reserve and IVF-preimplantation genetic diagnosis (PGD) outcome in women with DM1. A total of 21 women undergoing PGD for DM1 were compared with 21 age- and body mass index-matched women undergoing PGD for other diseases. Ovarian reserve markers, response to stimulation, embryo quality and clinical pregnancy and live birth rates were compared. Day-3 FSH concentration was higher, while anti-Mullerian hormone concentration and antral follicle count were lower in the DM1 group (median, range: 6.9 (1.8-11.3) versus 5.7 (1.5 10.7)IU/l; 0.9 (0.17-5.96) versus 2.68 (0.5-9.1)ng/ml; and 13 (0-63) versus 23 (8 40) follicles, respectively, all P < 0.05). Total FSH dose was higher (5200 versus 2250 IU, P = 0.004), while the numbers of oocytes retrieved (10 versus 16, P < 0.04) and metaphase-II oocytes (9 versus 12, P < 0.03) were lower in the DM1 group. The number of cycles with top-quality embryos and the clinical pregnancy rate were lower in the DM1 group. In conclusion, there is evidence of diminished ovarian reserve and less favourable IVF-PGD outcome in women with DM1. Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults. There is evidence of subfertility in males affected with the disease but conflicting reports about the effect of the disease on female fertility. The aim of our study was to investigate ovarian reserve and IVF-PGD results in women with DM. Twenty one women undergoing preimplantation genetic diagnosis (PGD) treatment for DM were compared to 21 age- and BMI matched women undergoing PGD treatment for other diseases. The two groups were compared for antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) levels (the best known markers of ovarian reserve and fertility potential), ovarian response, embryo quality and pregnancy and live birth rates. AFC and the AMH levels were statistically significant lower in the DM group. Total medication dose needed for ovarian stimulation was higher, the number of oocytes and mature oocytes retrieved, and the number of cycles with top quality embryos were lower in the DM group compared to the controls. In conclusion, there is evidence of diminished ovarian reserve, and less favorable IVF-PGD outcome in women with DM. Therefore, we recommend advising these women about the possibility of early decreasing ovarian function in order to prevent any delay in reproductive planning. PMID- 24813162 TI - Development and psychometric testing of a chinese version of the caregiver burden index for parents of children with allergies. AB - BACKGROUNG: No specific instrument has thus far been developed for measuring the caregiver burden perceived by parents of children with allergies (CWA). OBJECTIVES: To determine the psychometric properties of the Caregiver Burden Index (CBI). METHODS: A mixed-methods design was adopted to evaluate the psychometric properties of the scale. RESULTS: The content validity index was 0.89, and the internal consistency was high with a coefficient alpha of 0.98. Three factors were extracted after exploratory factor analysis. CONCLUSION: The study findings suggest that the CBI has sufficient reliability and validity to evaluate the caregiver burden of parents of CWA. PMID- 24813164 TI - Inclusion complexes of beta-cyclodextrin-dinitrocompounds as UV absorber for ballpoint pen ink. AB - 2,4-Dinitrophenol (2,4-DNP), 2,4-dinitroaniline (2,4-DNA), 2,6-dinitroaniline (2,6-DNA) and 2,6-dinitrobenzoic acid (2,6-DNB) has appeared for the UV absorption bands in different wavelength region below 400 nm, a combination of these dinitro aromatic compounds gave the broad absorption spectra within the UV region. The absorption intensities have been increased by preparation of the inclusion complex of dinitro compounds with beta-cyclodextrin (beta-CD). Prepared inclusion complexes are used to improve the UV protection properties of the ball point pen ink against photo degradation. The formation of solid inclusion complexes was characterized by FT-IR, and (1)H NMR spectroscopy. The UV protecting properties of these inclusion complexes were calculated their sun protection factor (SPF) is also discussed. The stability of the ballpoint pen ink has been confirmed by UV-Visible spectroscopic method. PMID- 24813163 TI - The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. AB - Afferent lymph-borne dendritic cells essentially rely on the chemokine receptor CCR7 for their transition from the subcapsular lymph node sinus into the parenchyma, a migratory step driven by putative gradients of CCR7 ligands. We found that lymph node fringes indeed contained physiological gradients of the chemokine CCL21, which depended on the expression of CCRL1, the atypical receptor for the CCR7 ligands CCL19 and CCL21. Lymphatic endothelial cells lining the ceiling of the subcapsular sinus, but not those lining the floor, expressed CCRL1, which scavenged chemokines from the sinus lumen. This created chemokine gradients across the sinus floor and enabled the emigration of dendritic cells. In vitro live imaging revealed that spatially confined expression of CCRL1 was necessary and sufficient for the creation of functional chemokine gradients. PMID- 24813165 TI - Characterization of protein and carbohydrate mid-IR spectral features in crop residues. AB - To the best of our knowledge, a few studies have been conducted on inherent structure spectral traits related to biopolymers of crop residues. The objective of this study was to characterize protein and carbohydrate structure spectral features of three field crop residues (rice straw, wheat straw and millet straw) in comparison with two crop vines (peanut vine and pea vine) by using Fourier transform infrared spectroscopy (FTIR) technique with attenuated total reflectance (ATR). Also, multivariate analyses were performed on spectral data sets within the regions mainly related to protein and carbohydrate in this study. The results showed that spectral differences existed in mid-IR peak intensities that are mainly related to protein and carbohydrate among these crop residue samples. With regard to protein spectral profile, peanut vine showed the greatest mid-IR band intensities that are related to protein amide and protein secondary structures, followed by pea vine and the rest three field crop straws. The crop vines had 48-134% higher spectral band intensity than the grain straws in spectral features associated with protein. Similar trends were also found in the bands that are mainly related to structural carbohydrates (such as cellulosic compounds). However, the field crop residues had higher peak intensity in total carbohydrates region than the crop vines. Furthermore, spectral ratios varied among the residue samples, indicating that these five crop residues had different internal structural conformation. However, multivariate spectral analyses showed that structural similarities still exhibited among crop residues in the regions associated with protein biopolymers and carbohydrate. Further study is needed to find out whether there is any relationship between spectroscopic information and nutrition supply in various kinds of crop residue when fed to animals. PMID- 24813166 TI - The effect of sugar removal on the structure of the Fc region of an IgG antibody as observed with single molecule Forster Resonance Energy Transfer. AB - The deglycosylation of immunoglobulin G (IgG) antibodies leads to a diminished immune response. This reduction in immune response is thought to arise from weakened binding of IgG antibodies to effector molecules as a result of a conformational change in the antibody. The nature of this structural alteration is uncertain due to the conflicting results obtained from different experimental methods. We have examined the impact of deglycosylation by the endoglycosidase PNGase F on the structure of the Fc region of a human IgG antibody using single molecule Forster Resonance Energy Transfer (FRET). The FRET efficiency histograms obtained indicate that the structure of the Fc region becomes more flexible upon deglycosylation. This is demonstrated by a change in the width of the energy transfer efficiency peak, which increases from 0.19 +/- 0.02 to 0.6 +/- 0.1 upon deglycosylation. PMID- 24813167 TI - Radiation dose of nurses during IR procedures: a controlled trial evaluating operator alerts before nursing tasks. AB - PURPOSE: To compare radiation exposure of nurses when performing nursing tasks associated with interventional procedures depending on whether or not the nurses called out to the operator before approaching the patient. MATERIALS AND METHODS: In a prospective study, 93 interventional radiology procedures were randomly divided into a call group and a no-call group; there were 50 procedures in the call group and 43 procedures in the no-call group. Two monitoring badges were used to calculate effective dose of nurses. In the call group, the nurse first told the operator she was going to approach the patient each time she was about to do so. In the no-call group, the nurse did not say anything to the operator when she was about to approach the patient. RESULTS: In all the nursing tasks, the equivalent dose at the umbilical level inside the lead apron was below the detectable limit. The equivalent dose at the sternal level outside the lead apron was 0.16 MUSv +/- 0.41 per procedure in the call group and 0.51 MUSv +/- 1.17 per procedure in the no-call group. The effective dose was 0.018 MUSv +/- 0.04 per procedure in the call group and 0.056 MUSv +/- 0.129 per procedure in the no-call group. The call group had a significantly lower radiation dose (P = .034). CONCLUSIONS: Radiation doses of nurses were lower in the group in which the nurse called to the operator before she approached the patient. PMID- 24813168 TI - Endothelial dysfunction and altered mechanical and structural properties of resistance arteries in a murine model of graft-versus-host disease. AB - A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph. The expression of endothelial (eNOS) and inducible nitric oxide (NO)-synthase (iNOS) was quantified and vessel wall ultrastructure was investigated with electron microscopy. The myograph study revealed an endothelial dysfunction in allogeneic transplant recipients, whereas endothelium-independent vasodilation was similar to syngeneic-transplant recipients or untreated controls. The expression of eNOS was decreased and iNOS increased, possibly contributing to endothelial dysfunction. Additionally, arteries of allogeneic transplant recipients exhibited a geometry-independent increase in vessels strain. For both findings, electron microscopy provided a structural correlate by showing severe damage of the whole vessel wall in allogeneic-transplant recipient animals. Our study provides further data to prove, and is the first to characterize, functional and structural vascular alterations in the early course after allogeneic transplantation directly in an ex vivo setting and, therefore, strongly supports the hypothesis of a vascular form of GVHD. PMID- 24813169 TI - "To combine or not to combine": optimizing risk assessment before allogeneic hematopoietic cell transplantation. PMID- 24813170 TI - Blocking activator protein 1 activity in donor cells reduces severity of acute graft-versus-host disease through reciprocal regulation of IL-17-producing T cells/regulatory T cells. AB - Acute graft-versus-host disease (aGVHD) is a major cause of mortality in allogeneic bone marrow transplantation. Here, the diminishing effect of activator protein 1 (AP-1) blocking with a synthetic retinoid (SR11302) on the severity of aGVHD in a murine model was investigated. MHC-mismatched strain combinations were used in vivo: C57BL/6 (H-2k(b)) donors into lethally irradiated BALB/c (H-2k(d)) recipients. SR11302 inhibited alloreactive T cell response in a dose-dependent manner and negatively regulated signal transducer and activator of transcription 3 (STAT3) activation. AP-1 blocking in T cells inhibited the differentiation of Th1 and Th17. Conversely, Foxp3(+) regulatory T cells (Treg) population dramatically expanded. Transfer of SR11302-treated donor splenocytes into lethally irradiated recipients diminished the lethality and clinical severity of aGVHD. In line with these results, AP-1 blocking in donor splenocytes exhibited reduced Th17/Th1 population and enhanced in vivo Treg population. Beneficial Treg expanding property of SR11302 was associated with the induction of Foxp3 and STAT5 transcription factor, where the inhibiting property of Th17 was achieved by suppressing the phosphorylated form of STAT3 and enhancing SOCS3. In conclusion, the preventive potential of AP-1 inhibitor in aGVHD may be accomplished by altering CD4(+) T cell differentiation through modulating transcription factors. PMID- 24813171 TI - Impact of age on quality of life, functional status, and survival in patients with chronic graft-versus-host disease. AB - Although older patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) may experience higher morbidity, the impact of chronic graft-versus-host disease (GVHD) on quality of life (QOL) and survival outcomes for older compared with younger patients is currently unknown. We utilized data of patients with moderate or severe chronic GVHD (N = 522, 1661 follow-up visits, a total of 2183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between age group (adolescent and young adult, "AYA," 18 to 40 years; "middle-aged," 41 to 59 years; and "older," >= 60 years) and QOL (Functional Assessment of Cancer Therapy Bone Marrow Transplantation [FACT-BMT]), physical functioning (Human Activity Profile [HAP]), functional status (2-minute walk test [2MWT]), nonrelapse mortality, and overall survival. Because of multiple testing, P values < .01 were considered significant. This study included 115 (22%) AYA, 279 (53%) middle-aged, and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD. Despite more physical limitations in older patients as measured by worse functional status (shorter 2MWT [P < .001] and lower HAP scores [P < .001]) relative to AYA and middle-aged patients, older patients reported better QOL (FACT-BMT, P = .004) compared with middle-aged patients and similar to AYA patients (P = .99). Nonrelapse mortality and overall survival were similar between the age groups. Therefore, despite higher physical and functional limitations, older patients who are selected to undergo HSCT and survive long enough to develop moderate or severe chronic GVHD have preserved QOL and similar overall survival and nonrelapse mortality when compared with younger patients. Therefore, we did not find evidence that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD. PMID- 24813172 TI - Detection of gene rearrangements in targeted clinical next-generation sequencing. AB - The identification of recurrent gene rearrangements in the clinical laboratory is the cornerstone for risk stratification and treatment decisions in many malignant tumors. Studies have reported that targeted next-generation sequencing assays have the potential to identify such rearrangements; however, their utility in the clinical laboratory is unknown. We examine the sensitivity and specificity of ALK and KMT2A (MLL) rearrangement detection by next-generation sequencing in the clinical laboratory. We analyzed a series of seven ALK rearranged cancers, six KMT2A rearranged leukemias, and 77 ALK/KMT2A rearrangement-negative cancers, previously tested by fluorescence in situ hybridization (FISH). Rearrangement detection was tested using publicly available software tools, including Breakdancer, ClusterFAST, CREST, and Hydra. Using Breakdancer and ClusterFAST, we detected ALK rearrangements in seven of seven FISH-positive cases and KMT2A rearrangements in six of six FISH-positive cases. Among the 77 ALK/KMT2A FISH negative cases, no false-positive identifications were made by Breakdancer or ClusterFAST. Further, we identified one ALK rearranged case with a noncanonical intron 16 breakpoint, which is likely to affect its response to targeted inhibitors. We report that clinically relevant chromosomal rearrangements can be detected from targeted gene panel-based next-generation sequencing with sensitivity and specificity equivalent to that of FISH while providing finer scale information and increased efficiency for molecular oncology testing. PMID- 24813173 TI - Dpp/BMP signaling in flies: from molecules to biology. AB - Decapentaplegic (Dpp), the fly homolog of the secreted mammalian BMP2/4 signaling molecules, is involved in almost all aspects of fly development. Dpp has critical functions at all developmental stages, from patterning of the eggshell to the determination of adult intestinal stem cell identity. Here, we focus on recent findings regarding the transcriptional regulatory logic of the pathway, on a new feedback regulator, Pentagone, and on Dpp's roles in scaling and growth of the Drosophila wing. PMID- 24813174 TI - A sonographic lesion index for Crohn's disease helps monitor changes in transmural bowel damage during therapy. AB - BACKGROUND & AIMS: Therapeutic antibodies against tumor necrosis factor alpha (anti-TNF) are effective in patients with Crohn's disease (CD). Mucosal healing is a surrogate marker of efficacy, but little is known about the effects of anti TNF agents on structural damage in the intestine. Small-intestine contrast ultrasonography (SICUS) is a valuable tool for assessing CD lesions. A new sonographic quantitative index (the sonographic lesion index for CD [SLIC]) was developed to quantify changes in CD lesions detected by SICUS. We explored whether the SLIC can be used to monitor transmural bowel damage in CD patients during anti-TNF therapy. METHODS: We performed a prospective study of 29 patients with ileal or ileocolonic CD treated with anti-TNF agents; patients underwent SICUS before and after scheduled induction and maintenance therapy. To determine whether changes that can be detected by SICUS occur independently of anti-TNF therapy, 7 patients with ileal CD treated with mesalamine were enrolled as controls. A clinical response was defined as steroid-free remission, with CD activity index scores less than 150. RESULTS: We observed significant improvements in SLIC scores and subscores after induction and maintenance therapy with anti-TNFs, compared with before therapy. SLIC scores and subscores and index classes were improved significantly in patients with vs without clinical responses. Controls had no improvements in terms of CD activity index or SLIC scores, or index classes. CONCLUSIONS: Sonographic assessment using the quantitative index SLIC can be used to monitor changes in transmural bowel damage during anti-TNF therapy for CD. PMID- 24813175 TI - Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder. AB - BACKGROUND & AIMS: Surveillance of patients with cirrhosis for hepatocellular carcinoma (HCC) with liver ultrasound every 6 months has been linked to longer survival and greater use of definitive treatment. However, less than 20% of patients typically undergo routine surveillance. METHODS: We conducted a quasi experimental study to assess whether a primary care-oriented, point-of-care clinical reminder improves HCC surveillance. Our study included patients with cirrhosis who made 1 or more primary care visits to 8 Veterans Affairs (VA) facilities over 18 months. Clinicians at 1 facility were sent a reminder to perform liver ultrasound assessments for patients with cirrhosis who had not received surveillance in the preceding 6 months. Outcomes included the proportion of patients receiving adequate HCC surveillance (defined as >2 instances of liver imaging >6 months apart) and HCC diagnosis and stage. Because it was a quality improvement project, this study did not require approval by an institutional review board under Federal law and VA policy. RESULTS: Baseline rates of adequate HCC surveillance were similar at all facilities (18.2% at the intervention site vs 16.1% elsewhere; P = .23). After the reminder was implemented, adequate surveillance at the intervention site (for 790 patients) increased by 51%, but was unchanged at the other facilities (for 2094 patients) (27.6% vs 17.5%; P < .001). Adequate surveillance occurred more often at the intervention site (adjusted odds ratio, 1.29; 95% confidence interval, 1.03-1.61; P = .02). A higher crude percentage of patients was diagnosed with HCC at the intervention site than elsewhere (3.2% vs 1.9%; P = .03). We detected no difference in tumor stage at diagnosis. CONCLUSIONS: In a VA population, a clinical reminder system increased HCC surveillance in patients with cirrhosis. PMID- 24813176 TI - Association between reduced plasma 25-hydroxyvitamin D and increased risk of cancer in patients with inflammatory bowel disease. PMID- 24813177 TI - Job integration factors as predictors of travel nurse job performance: a mixed methods study. AB - Concerns about insufficient work setting familiarity and orientation of temporary nurses affecting job performance are documented in the literature. This mixed methods study identified unique needs and characteristics of travel nurses, using Web conference focus groups and an Internet survey to reach this geographically dispersed workforce. New knowledge emerged to facilitate more effective travel nurse orientation strategies. PMID- 24813178 TI - Respiratory resynchronization. PMID- 24813179 TI - Borderline ankle-brachial index value of 0.91-0.99 is associated with endothelial dysfunction. AB - BACKGROUND: An ankle-brachial index (ABI) value of 0.91-0.99 is considered borderline and associated with an increased risk of cardiovascular events. However, there is no information on the relationship between borderline ABI and endothelial function. METHODS AND RESULTS: We measured ABI and assessed vascular function by flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation in 389 subjects who underwent health examinations. Subjects were divided into 3 groups according to ABI (normal group: 1.00-1.40, borderline group: 0.91-0.99, abnormal group: <=0.90 or >1.40). FMD was significantly smaller in both the borderline and the abnormal group than in the normal group. There was no significant difference in the vascular responses to nitroglycerin between the normal and borderline groups. Vascular response to nitroglycerin was significantly higher in the normal group than in the abnormal group. Borderline and abnormal ABI values were significantly associated with an increased odds ratio of low tertile of FMD levels, using the normal ABI group as the reference. Multiple logistic regression analysis for FMD revealed that age, sex, hypertension, diabetes mellitus, and borderline ABI independently remained associated with FMD. CONCLUSIONS: ABI of 0.91-0.99 is associated with endothelial dysfunction. ABI examination is a simple and cost-effective method for obtaining the additional information on the initial step of atherosclerosis beyond the assessment of peripheral artery disease. PMID- 24813180 TI - The evolution of language from social cognition. AB - Despite their differences, human language and the vocal communication of nonhuman primates share many features. Both constitute a form of joint action, rely on similar neural mechanisms, and involve discrete, combinatorial cognition. These shared features suggest that during evolution the ancestors of modern primates faced similar social problems and responded by evolving similar systems of perception, communication and cognition. When language later evolved from this common foundation, many of its distinctive features were already in place. PMID- 24813181 TI - Health assessment of gasoline and fuel oxygenate vapors: reproductive toxicity assessment. AB - Vapor condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000mg/m(3), 6h/day, 7days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study. Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME offspring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000mg/m(3) for all vapor condensates except for lower offspring NOAELs of 10,000mg/m(3) for G/TBA and 2000mg/m(3) for G/TAME. PMID- 24813182 TI - A newly discovered role of evolution in previously published consumer-resource dynamics. AB - Consumer-resource interactions are fundamental components of ecological communities. Classic features of consumer-resource models are that temporal dynamics are often cyclic, with a 1/4-period lag between resource and consumer population peaks. However, there are few published empirical examples of this pattern. Here, we show that many published examples of consumer-resource cycling show instead patterns indicating eco-evolutionary dynamics. When prey evolve along a trade-off between defence and competitive ability, two-species consumer resource cycles become longer and antiphase (half-period lag, so consumer maxima coincide with minima of the resource species). Using stringent criteria, we identified 21 two-species consumer-resource time series, published between 1934 and 1997, suitable to investigate for eco-evolutionary dynamics. We developed a statistical method to probe for a transition from classic to eco-evolutionary cycles, and find evidence for eco-evolutionary type cycles in about half of the studies. We show that rapid prey evolution is the most likely explanation for the observed patterns. PMID- 24813183 TI - Pyrilamine inhibits nicotine-induced catecholamine secretion. AB - Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation. PMID- 24813184 TI - Detecting cognitive impairment after concussion: sensitivity of change from baseline and normative data methods using the CogSport/Axon cognitive test battery. AB - Concussion-related cognitive impairments are typically evaluated with repeated neuropsychological assessments where post-injury performances are compared with pre-injury baseline data (baseline method). Many cases of concussions, however, are evaluated in the absence of baseline data by comparing post-injury performances with normative data (normative method). This study aimed to compare the sensitivity and specificity of these two methods using the CogSport/Axon test battery. Normative data and reliable change indices were computed from a non injured athlete sample (n = 235). Test-retest data from non-injured (n = 260) and recently concussed (n = 29) athlete samples were then used to compare the two methods. The baseline method was found to be more sensitive than the normative method, and both methods had high specificity and overall correct classification rates. This suggests that while the normative method identifies most cases of recent concussions, the baseline method remains a more precise approach to assessing concussion-related cognitive impairments. PMID- 24813185 TI - Monitoring radionuclides in the atmosphere over the Czech Republic after the Fukushima Nuclear Power Plant accident. AB - This paper presents the results of atmospheric radioactivity monitoring over the Czech Republic, as obtained by the Radiation Monitoring Network, following the Fukushima Dai-Ichi Nuclear Power Plant accident. Maximum values for (131)I were 5.6 mBq m(-3) in aerosol form and 13 mBq m(-3) in gaseous form. The maximum values for (134)Cs and (137)Cs were 0.64 and 0.72 mBq m(-3), respectively. The estimated effective half-time for removing the activity from the atmosphere was 6 7 d and 3.5 d for caesium and iodine, respectively. The gaseous-to-total activity ratios of (131)I ranged between 0.3 and 0.9, with an arithmetic mean value of 0.77. The mean value for the (134)Cs/(137)Cs ratios was close to 1.0. The effective inhalation dose due to the accident for an adult living in the Czech Republic was estimated at <4 * 10(-5) mSv, out of which the proportion of (131)I was 88%. PMID- 24813186 TI - Environmental sustainability in hospitals - a systematic review and research agenda. AB - OBJECTIVES: Hospitals are significant contributors to natural resource depletion and environmental change. Our objective was to establish the extent to which hospital environmental sustainability has been studied and the key issues that emerge for policy, practice and research. METHODS: The PubMed, Engineering Village, Cochrane and King's Fund databases were searched for articles relating to hospital environmental sustainability published in English between 1 January 1990 and 1 October 2013. Further studies were found by review of reference lists. One hundred ninety-three relevant articles were found and 76 were selected for inclusion in the review. RESULTS: Common research themes were identified: hospital design, direct energy consumption, water, procurement, waste, travel and psychology and behaviour. Some countries (particularly the United Kingdom) have begun to invest systematically in understanding the environmental effects of hospitals. We found large variability in the extent of the evidence base according to topic. Research regarding the architectural fabric of hospital buildings is at a relatively mature stage. Similarly, there is a developed research base regarding devices and technologies used within hospitals to reduce the environmental effects of direct hospital energy and water use. Less is known about the clinical, psychological and social factors that influence how health care professionals use resources, travel to/from hospital, and interact with the buildings and technologies available. A significant part of the environmental footprint of hospitals relates to clinical practice, e.g. decisions regarding the use of pharmaceuticals and medical devices. Medical 'cradle to grave' life cycle assessment studies have been published to understand the full financial and environmental costs of hospital activities. The effects of preventive or demand management measures which avoid unnecessary hospital procedures are likely to be much greater than incremental changes to how hospital procedures are performed. CONCLUSIONS: There remain significant gaps in the evidence base on hospital sustainability. Assessments of environmental impacts and natural resource use are beginning to be produced, both at the level of individual hospitals and at the health system level. These are an important start, but in many areas do not yet provide sufficiently detailed information to guide decision-making. There are many areas where the interests of patients and the environment coincide, but others where tensions exist. Rising resource costs and climate change mitigation measures are likely to create an increasing stimulus for research on hospital sustainability. Such research will benefit from inter-disciplinary coordination across research funders and countries. PMID- 24813188 TI - A large nonconserved region of the tethering protein Leashin is involved in regulating the position, movement, and function of Woronin bodies in Aspergillus oryzae. AB - The Woronin body is a Pezizomycotina-specific organelle that is typically tethered to the septum, but upon hyphal wounding, it plugs the septal pore to prevent excessive cytoplasmic loss. Leashin (LAH) is a large Woronin body tethering protein that contains highly conserved N- and C-terminal regions and a long (~2,500-amino-acid) nonconserved middle region. As the involvement of the nonconserved region in Woronin body function has not been investigated, here, we functionally characterized individual regions of the LAH protein of Aspergillus oryzae (AoLAH). In an Aolah disruptant, no Woronin bodies were tethered to the septum, and hyphae had a reduced ability to prevent excessive cytoplasmic loss upon hyphal wounding. Localization analysis revealed that the N-terminal region of AoLAH associated with Woronin bodies dependently on AoWSC, which is homologous to Neurospora crassa WSC (Woronin body sorting complex), and that the C-terminal region was localized to the septum. Elastic movement of Woronin bodies was observed when visualized with an AoLAH N-terminal-region-enhanced green fluorescent protein (EGFP) fusion protein. An N- and C-terminal fusion construct lacking the nonconserved middle region of AoLAH was sufficient for the tethering of Woronin bodies to the septum. However, Woronin bodies were located closer to the septum and exhibited impaired elastic movement. Moreover, expression of middle-region-deleted AoLAH in the Aolah disruptant did not restore the ability to prevent excessive cytoplasmic loss. These findings indicate that the nonconserved middle region of AoLAH has functional importance for regulating the position, movement, and function of Woronin bodies. PMID- 24813189 TI - Stress induces changes in the phosphorylation of Trypanosoma cruzi RNA polymerase II, affecting its association with chromatin and RNA processing. AB - The phosphorylation of the carboxy-terminal heptapeptide repeats of the largest subunit of RNA polymerase II (Pol II) controls several transcription-related events in eukaryotes. Trypanosomatids lack these typical repeats and display an unusual transcription control. RNA Pol II associates with the transcription site of the spliced leader (SL) RNA, which is used in the trans-splicing of all mRNAs transcribed on long polycistronic units. We found that Trypanosoma cruzi RNA Pol II associated with chromatin is highly phosphorylated. When transcription is inhibited by actinomycin D, the enzyme runs off from SL genes, remaining hyperphosphorylated and associated with polycistronic transcription units. Upon heat shock, the enzyme is dephosphorylated and remains associated with the chromatin. Transcription is partially inhibited with the accumulation of housekeeping precursor mRNAs, except for heat shock genes. DNA damage caused dephosphorylation and transcription arrest, with RNA Pol II dissociating from chromatin although staying at the SL. In the presence of calyculin A, the hyperphosphorylated form detached from chromatin, including the SL loci. These results indicate that in trypanosomes, the unusual RNA Pol II is phosphorylated during the transcription of SL and polycistronic operons. Different types of stresses modify its phosphorylation state, affecting pre-RNA processing. PMID- 24813190 TI - Literature-based gene curation and proposed genetic nomenclature for cryptococcus. AB - Cryptococcus, a major cause of disseminated infections in immunocompromised patients, kills over 600,000 people per year worldwide. Genes involved in the virulence of the meningitis-causing fungus are being characterized at an increasing rate, and to date, at least 648 Cryptococcus gene names have been published. However, these data are scattered throughout the literature and are challenging to find. Furthermore, conflicts in locus identification exist, so that named genes have been subsequently published under new names or names associated with one locus have been used for another locus. To avoid these conflicts and to provide a central source of Cryptococcus gene information, we have collected all published Cryptococcus gene names from the scientific literature and associated them with standard Cryptococcus locus identifiers and have incorporated them into FungiDB (www.fungidb.org). FungiDB is a panfungal genome database that collects gene information and functional data and provides search tools for 61 species of fungi and oomycetes. We applied these published names to a manually curated ortholog set of all Cryptococcus species currently in FungiDB, including Cryptococcus neoformans var. neoformans strains JEC21 and B 3501A, C. neoformans var. grubii strain H99, and Cryptococcus gattii strains R265 and WM276, and have written brief descriptions of their functions. We also compiled a protocol for gene naming that summarizes guidelines proposed by members of the Cryptococcus research community. The centralization of genomic and literature-based information for Cryptococcus at FungiDB will help researchers communicate about genes of interest, such as those related to virulence, and will further facilitate research on the pathogen. PMID- 24813191 TI - The early origins of COPD in severe asthma: the one thing that leads to another or the two things that come together? PMID- 24813192 TI - Stomach versus lungs: the case of a giant hiatal hernia. PMID- 24813193 TI - Efficacy of lower-limb muscle training modalities in severely dyspnoeic individuals with COPD and quadriceps muscle weakness: results from the DICES trial. PMID- 24813194 TI - Reply: Criticizing the effect of ovarian suspension on adhesions in laparoscopic surgery for endometriosis. PMID- 24813195 TI - Criticizing the effect of ovarian suspension on adhesions in laparoscopic surgery for endometriosis. PMID- 24813196 TI - Administration of corifollitropin alfa on Day 2 versus Day 4 of the cycle in a GnRH antagonist protocol: a randomized controlled pilot study. AB - STUDY QUESTION: Does the initiation of corifollitropin alfa administration on cycle day 4 instead of cycle day 2 result in a reduced total rFSH consumption in a GnRH antagonist protocol? SUMMARY ANSWER: Initiation of corifollitropin alfa on cycle day 4 compared with day 2 results in significantly reduced total rFSH consumption at the end of the follicular phase. WHAT IS KNOWN ALREADY: In vitro fertilization treatment is associated with significant physical, psychological and emotional stress in infertile patients. This notion has fuelled the search for simplified treatment approaches that may reduce the treatment burden. The introduction of corifollitropin alfa has provided a more patient-friendly treatment protocol because it obviates the need for daily hormonal injections. In addition, postponing the initiation of hormonal stimulation should also reduce the total gonadotrophin consumption and the number of injections needed. STUDY DESIGN, SIZE, DURATION: A prospective randomized controlled pilot study was conducted in a university centre in Belgium. Between December 2011 and March 2013, 59 patients were randomized in the study and 52 of these patients received the allocated intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients were randomly assigned to the control group (CD2), with initiation of corifollitropin alfa on cycle day 2, or to the study group (CD4) with initiation of stimulation on day 4. The GnRH antagonist was administered from cycle day 7 onwards in both treatment arms. The main outcome measure was the total rFSH consumption at the end of the follicular phase after corifollitropin alfa treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The total dose of rFSH at the end of the follicular phase was significantly reduced in the CD4 group compared with the CD2 group (324 (276) IU in the CD2 group versus 173 (255) IU in the CD4 group, P = 0.015, mean difference -151, 95% confidence interval (CI) -301 to -1). A significant reduction of total duration of rFSH stimulation in the CD4 group was also observed (8.6 (1.4) days in CD2 group versus 7.8 (1.2) days in the CD4 group, P = 0.008, mean difference -0.8, 95% CI -1.6 to -0.1). The number of cumulus-oocyte-complexes was comparable in both treatment groups (12.8 (7.3) in CD2 group versus 14.7 (8.8) in the CD4 group, P = 0.461, mean difference 1.8, 95% CI -2.7 to 6.4). Ongoing pregnancy rates of 48% in the CD2 group and 41% in the CD4 group were achieved (P = 0.60, relative risk (RR) 0.85, 95% CI 0.46-1.56). Final oocyte maturation was triggered with GnRH agonist instead of hCG in two patients in the CD2 group and in eight patients in the CD4 group, because of an increased risk of ovarian hyperstimulation syndrome (P = 0.078, RR 3.7 (95% CI 0.88-15.8). LIMITATIONS, REASONS FOR CAUTION: Before general implementation can be advised, this trial should be validated in a much larger randomized trial. WIDER IMPLICATIONS OF THE FINDINGS If the approach of starting ovarian stimulation on Day 4 of the cycle could be implemented in a large population of infertile patients, it would result in a significant reduction of gonadotrophin consumption. STUDY FUNDING/COMPETING INTEREST(S): No external finance was involved in this study. C.B and N.P.P. have received fees from MSD. Otherwise the authors declare no conflict of interest regarding this study. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (NCT01633580). PMID- 24813197 TI - Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome. AB - STUDY QUESTION: Are differences in metabolic dysfunction between polycystic ovary syndrome (PCOS) and control women related to differences in their fat to lean mass (F/L) ratio? SUMMARY ANSWER: Compared with controls of similar body mass index (BMI), women with PCOS demonstrate adverse body composition characterized by increased whole body fat relative to lean mass (i.e. a higher F/L ratio), which is associated with differences in metabolic dysfunction between the two groups. WHAT IS KNOWN ALREADY: Previous studies examining body composition and insulin resistance (IR) in PCOS have yielded conflicting results. Excess total fat mass (i.e. fat mass index [fat BMI]) correlates with IR, whereas increased total lean mass (i.e. lean BMI) has been associated with higher insulin sensitivity. However, the role of the F/L ratio, which integrates the antagonistic effects of both fat and lean mass depots, on IR in PCOS, has not been investigated. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cross sectional study of 120 women between the ages of 22-44 years to study the relation of the F/L ratio with measures of insulin action and secretion in both steady and dynamic states. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixty PCOS (by NIH, 1990 criteria) and 60 control (age, race and BMI-matched) women were prospectively studied for body composition (by bioelectrical impedance analysis [BIA]) and basal IR and insulin secretion by the homeostasis model assessment (HOMA-IR and HOMA-%beta-cell function, respectively) in a tertiary care academic referral center. A subset of 12 PCOS and 12 matched control women also underwent a modified frequently sampled intravenous glucose tolerance test (FSIVGTT) to determine glucose uptake and insulin secretion in dynamic state. MAIN RESULTS AND THE ROLE OF CHANCE: Our results indicate that women with PCOS demonstrated greater degrees of hyperandrogenism, and higher waist-to-hip ratio (WHR), %body fat, fat BMI, F/L, fasting insulin levels, and HOMA-IR and HOMA-%beta-cell values, than controls. In models adjusted for WHR and free testosterone and diagnostic groups, fasting insulin levels, HOMA-IR, and HOMA-%beta cell function were positively related to the F/L ratio. A positive relationship was also found in both study groups between F/L and the FSIVGTT measures insulin sensitivity (Si) and acute insulin response to glucose (AIRg). The F/L tended to negatively correlate with glucose effectiveness or non-insulin-mediated glucose transport (Sg) only in PCOS women. LIMITATIONS, REASONS FOR CAUTION: Regional tissue sub compartments, which have been shown to have potential independent associations with metabolic variables, cannot be determined by bioelectrical impedance analysis (BIA). WIDER IMPLICATIONS OF THE FINDINGS: The current results suggest that BIA could be used to assess F/L in place of dual energy X-ray absorptiometry (DXA) in research protocols, and that F/L could possibly be used as an alternative to WHR as a surrogate marker of metabolic dysfunction in clinical practice. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants R01-DK073632 and R01-HD29364 from the NIH and an endowment of the Helping Hand of Los Angeles, Inc. (to R.A.). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 24813198 TI - A retroperitoneal enteric duplication cyst communicating with the right upper ureter in an infant. AB - We report an extremely rare case of isolated retroperitoneal enteric duplication cyst with gastric mucosa causing haematuria and dysuria by communicating with the urinary system. A 9-month-old male child was admitted to our hospital with persistent haematuria, dysuria and anaemia. Investigations revealed a retroperitoneal cyst abutting the hydronephrotic non-functioning right kidney. At surgery an isolated retroperitoneal cyst communicating with the right pelviureteric junction was found. The kidney and associated cyst were excised. Histology of the cystic lesion revealed an enteric duplication cyst lined by ectopic gastric mucosa. Isolated retroperitoneal enteric duplication cyst communicating with the urinary tract has not been previously reported in the English literature. We propose that acid secretion into the right renal system was the cause of the haematuria-dysuria syndrome which promptly resolved postoperatively. PMID- 24813199 TI - Development of VVF following double J stent placement. AB - Double J stent (DJ stent) is commonly used in various urological conditions. Theoretically stent-induced tissue erosion can be a possibility, but fistula formation is rarely reported. The present case was a case of genitourinary tuberculosis diagnosed 4 years ago and had received complete treatment. Two months ago she presented with recurrent urinary tract infection and diagnosed to have vesicoureteric reflux with secondary obstruction for which DJ stent was placed, after 15 days of which the patient reported leakage of urine per vagina. She was diagnosed to have vesicovaginal fistula (VVF) with in situ stent eroding through the bladder wall. Stent was removed and fistula was corrected surgically. This is the first reported case of stent-induced VVF, a rare complication of ureteral stent placement. PMID- 24813200 TI - Rare cause of hip pain in a young girl. AB - Synovial chondromatosis (SC) is a rare benign disorder of unknown aetiology resulting in multiple cartilaginous loose bodies that form within a synovial joint. It is predominantly seen in men (2:1) in the third and fifth decade of life and is extremely rare in children. Hip joint is an extremely rare and unusual site of presentation thus leading to delay in diagnosis and associated morbidity. We report a successfully treated case of SC in a 12-year-old girl complaining of hip pain over a year. In addition, this is also the first case of a child with SC of the hip being treated arthroscopically. PMID- 24813201 TI - Brodie's abscess of the posterior ilium: a rare cause for low back pain in children. AB - Brodie's abscess of the pelvis is very rare in healthy children. It can be missed because of its varied presentation. We present an 11-year-old boy who presented with low back pain. Investigations revealed a well-defined lesion in the posterior ilium. He underwent open biopsy and debridement. At the end of the final follow-up, he was asymptomatic and there was no recurrence. We present this case for the rare site of Brodie's abscess and for its unusual presentation as low back pain. PMID- 24813202 TI - Bilateral ureteric obstruction: an unusual complication of male-to-female gender reassignment surgery. AB - Gender reassignment surgery is a form of treatment for gender dysphoria. It can be male-to-female or female-to-male. We present a patient who underwent male to female reassignment and had a vaginal reconstruction. She presented almost a year later with acute kidney injury and bilateral ureteric obstruction, subsequently ending up with nephrectomy for a non-functioning kidney. PMID- 24813203 TI - Effect of CDR3 sequences and distal V gene residues in regulating TCR-MHC contacts and ligand specificity. AB - The mature T cell repertoire has the ability to orchestrate immunity to a wide range of potential pathogen challenges. This ability stems from thymic development producing individual T cell clonotypes that express TCRs with unique patterns of Ag reactivity. The Ag specificity of TCRs is created from the combinatorial pairing of one of a set of germline encoded TCR Valpha and Vbeta gene segments with randomly created CDR3 sequences. How the amalgamation of germline encoded and randomly created TCR sequences results in Ag receptors with unique patterns of ligand specificity is not fully understood. Using cellular, biophysical, and structural analyses, we show that CDR3alpha residues can modulate the geometry in which TCRs bind peptide-MHC (pMHC), governing whether and how germline encoded TCR Valpha and Vbeta residues interact with MHC. In addition, a CDR1alpha residue that is positioned distal to the TCR-pMHC binding interface is shown to contribute to the peptide specificity of T cells. These findings demonstrate that the specificity of individual T cell clonotypes arises not only from TCR residues that create direct contacts with the pMHC, but also from a collection of indirect effects that modulate how TCR residues are used to bind pMHC. PMID- 24813204 TI - IFN-alpha suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells. AB - CD4(+) Th2 development is regulated by the zinc finger transcription factor GATA3. Once induced by acute priming signals, such as IL-4, GATA3 poises the Th2 cytokine locus for rapid activation and establishes a positive-feedback loop that maintains elevated GATA3 expression. Type I IFN (IFN-alpha/beta) inhibits Th2 cells by blocking the expression of GATA3 during Th2 development and in fully committed Th2 cells. In this study, we uncovered a unique mechanism by which IFN alpha/beta signaling represses the GATA3 gene in human Th2 cells. IFN-alpha/beta suppressed expression of GATA3 mRNA that was transcribed from an alternative distal upstream exon (1A). This suppression was not mediated through DNA methylation, but rather by histone modifications localized to a conserved noncoding sequence (CNS-1) upstream of exon 1A. IFN-alpha/beta treatment led to a closed conformation of CNS-1, as assessed by DNase I hypersensitivity, along with enhanced accumulation of H3K27me3 mark at this CNS region, which correlated with increased density of total nucleosomes at this putative enhancer. Consequently, accessibility of CNS-1 to GATA3 DNA binding activity was reduced in response to IFN-alpha/beta signaling, even in the presence of IL-4. Thus, IFN-alpha/beta disrupts the GATA3-autoactivation loop and promotes epigenetic silencing of a Th2 specific regulatory region within the GATA3 gene. PMID- 24813205 TI - Antigen-dependent versus -independent activation of invariant NKT cells during infection. AB - CD1d-reactive invariant NKT cells (iNKT) play a vital role in determining the characteristics of immune responses to infectious agents. Previous reports suggest that iNKT cell activation during infection can be: 1) solely driven by cytokines from innate immune cells, 2) require microbial Ag, or 3) require self Ag. In this study, we examined the role of Ag receptor stimulation in iNKT cells during several bacterial and viral infections. To test for Ag receptor signaling, Nur77(gfp) BAC transgenic mice, which upregulate GFP in response to Ag receptor but not inflammatory signals, were analyzed. iNKT cells in the reporter mice infected with mouse CMV produced IFN-gamma but did not upregulate GFP, consistent with their reported CD1d-independent activation. However, two bacteria known to produce lipid Ags for iNKT cells induced GFP expression and cytokine production. In contrast, although Salmonella typhimurium was proposed to induce the presentation of a self-lipid, iNKT cells produced IFN-gamma but did not upregulate GFP postinfection in vivo. Even in CD1d-deficient hosts, iNKT cells were still able to produce IFN-gamma after S. typhimurium infection. Furthermore, although it has been proposed that endogenous lipid presentation is a result of TLR stimulation of APCs, injection of different TLR agonists led to iNKT cell IFN gamma but not increased GFP expression. These data indicate that robust iNKT cell responses to bacteria, as well as viruses, can be obtained in the absence of antigenic stimulation. PMID- 24813207 TI - IgG-mediated anaphylaxis to a synthetic long peptide vaccine containing a B cell epitope can be avoided by slow-release formulation. AB - Synthetic long peptides (SLP) are a promising vaccine modality to induce therapeutic T cell responses in patients with chronic infections and tumors. We studied different vaccine formulations in mice using SLP derived from carcinoembryonic Ag. We discovered that one of the SLP contains a linear Ab epitope in combination with a CD4 epitope. Repeated vaccination with this carcinoembryonic Ag SLP in mice shows improved T cell responses and simultaneously induced high titers of peptide-specific Abs. These Abs resulted in unexpected anaphylaxis after a third or subsequent vaccinations with the SLP when formulated in saline. Administration of low SLP doses in the slow-release vehicle IFA prevented the anaphylaxis after repeated vaccination. This study underscores both the immunogenicity of SLP vaccination, for inducing T cell as well as B cell responses, and the necessity of safe administration routes. PMID- 24813206 TI - RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events. AB - TLRs 7 and 8 are pattern recognition receptors controlling antiviral host defense or autoimmune diseases. Apart from foreign and host RNA, synthetic RNA oligoribonucleotides (ORN) or small molecules of the imidazoquinoline family activate TLR7 and 8 and are being developed as therapeutic agonists. The structure-function relationships for RNA ORN and imidazoquinoline sensing and consequent downstream signaling by human TLR7 and TLR8 are unknown. Proteome- and genome-wide analyses in primary human monocyte-derived dendritic cells here showed that TLR8 sensing of RNA ORN versus imidazoquinoline translates to ligand specific differential phosphorylation and transcriptional events. In addition, TLR7 and 8 ectodomains were found to discriminate between RNA ORN and imidazoquinolines by overlapping and nonoverlapping recognition sites to which murine loss-of-function mutations and human naturally occurring hyporesponsive polymorphisms map. Our data suggest TLR7 and TLR8 can signal in two different "modes" depending on the class of ligand. Considering RNA ORN and imidazoquinolines have been regarded as functionally interchangeable, our study highlights important functional incongruities whose understanding will be important for developing TLR7 or 8 therapeutics with desirable effector and safety profiles for in vivo application. PMID- 24813208 TI - TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. AB - Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3' repair exonuclease 1 (TREX1) have been linked to the type I IFN-associated autoimmune disease Aicardi-Goutieres syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP-AMP synthase completely abrogates spontaneous induction of IFN stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP-AMP synthase for the initiation of self-DNA-induced autoimmune disorders, thus providing important implications for novel therapeutic approaches. PMID- 24813209 TI - A clinically useful self-report measure of the DSM-5 anxious distress specifier for major depressive disorder. AB - OBJECTIVE: To acknowledge the clinical significance of anxiety in depressed patients, DSM-5 included criteria for an anxious distress specifier for major depressive disorder. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we modified our previously published depression scale to include a subscale assessing the DSM-5 anxious distress specifier. METHOD: From December 1995 to August 2013, 773 psychiatric outpatients with major depressive disorder completed the Clinically Useful Depression Outcome Scale (CUDOS) supplemented with questions for the DSM-5 anxious distress specifier (CUDOS-A). To examine discriminant and convergent validity, the patients were rated on clinician severity indices of depression, anxiety, and irritability. Discriminant and convergent validity was further examined in a subset of patients who completed other self-report symptom severity scales. Test-retest reliability was examined in a subset who completed the CUDOS A twice. We compared patients who did and did not meet the DSM-5 anxious distress specifier on indices of psychosocial functioning and quality of life. RESULTS: The CUDOS-A subscale had high internal consistency and test-retest reliability; was more highly correlated with other self-report measures of anxiety than with measures of depression, substance use problems, eating disorders, and anger; and was more highly correlated with clinician severity ratings of anxiety than depression and irritability. CUDOS-A scores were significantly higher in depressed outpatients with a current anxiety disorder than in depressed patients without a comorbid anxiety disorder (P < .001). Finally, patients who met the DSM 5 anxious distress specifier reported poorer psychosocial functioning and quality of life than patients who did not meet the anxious distress specifier. CONCLUSIONS: In the present study of a large sample of psychiatric outpatients, the CUDOS-A was a reliable and valid measure of the DSM-5 anxious distress specifier for major depressive disorder. PMID- 24813210 TI - Lamotrigine treatment of adolescents with unipolar and bipolar depression: a retrospective chart review. AB - OBJECTIVE: The purpose of this study was to investigate the preliminary effectiveness and safety of lamotrigine for the treatment of depressive episodes in adolescents. METHODS: This was a 12 week retrospective chart review of lamotrigine treatment among 37 adolescents (mean age 16.3+/-1.3 years) with depressive episodes (15 with bipolar disorder and 22 with major depressive disorder). Illness severity at the 4th, 8th, and 12th weeks were retrospectively scored using Clinical Global Impressions - Severity (CGI-S) and Clinical Global Impressions - Improvement (CGI-I). RESULTS: The mean dose of lamotrigine was 65.4+/-37.5 mg/day (range 12.5-181.7 mg/day) for a mean duration of 199.9+/-217.4 days (range 14-879 days). The CGI-S scores were significantly decreased over 12 weeks (F=39.611, p<0.001, partial eta2=0.531). Seventeen subjects (45.9%) showed a treatment response at 12 week follow up (defined by a CGI-I score <=2). There were no differences in treatment effectiveness between the bipolar and unipolar groups. Overall, lamotrigine was well tolerated. The most common adverse event was skin rash (n=5, 13.5%), which resolved spontaneously after drug discontinuation. CONCLUSION: Our results provide preliminary evidence of the effectiveness and safety of lamotrigine in adolescents with bipolar and depressive disorders. Large, prospective, placebo-controlled studies are needed to confirm these findings. PMID- 24813211 TI - A framework for installable external tools in Skyline. AB - Skyline is a Windows client application for targeted proteomics method creation and quantitative data analysis. The Skyline document model contains extensive mass spectrometry data from targeted proteomics experiments performed using selected reaction monitoring, parallel reaction monitoring and data-independent and data-dependent acquisition methods. Researchers have developed software tools that perform statistical analysis of the experimental data contained within Skyline documents. The new external tools framework allows researchers to integrate their tools into Skyline without modifying the Skyline codebase. Installed tools provide point-and-click access to downstream statistical analysis of data processed in Skyline. The framework also specifies a uniform interface to format tools for installation into Skyline. Tool developers can now easily share their tools with proteomics researchers using Skyline. AVAILABILITY AND IMPLEMENTATION: Skyline is available as a single-click self-updating web installation at http://skyline.maccosslab.org. This Web site also provides access to installable external tools and documentation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813212 TI - lncRNAtor: a comprehensive resource for functional investigation of long non coding RNAs. AB - MOTIVATION: A number of long non-coding RNAs (lncRNAs) have been identified by deep sequencing methods, but their molecular and cellular functions are known only for a limited number of lncRNAs. Current databases on lncRNAs are mostly for cataloging purpose without providing in-depth information required to infer functions. A comprehensive resource on lncRNA function is an immediate need. RESULTS: We present a database for functional investigation of lncRNAs that encompasses annotation, sequence analysis, gene expression, protein binding and phylogenetic conservation. We have compiled lncRNAs for six species (human, mouse, zebrafish, fruit fly, worm and yeast) from ENSEMBL, HGNC, MGI and lncRNAdb. Each lncRNA was analyzed for coding potential and phylogenetic conservation in different lineages. Gene expression data of 208 RNA-Seq studies (4995 samples), collected from GEO, ENCODE, modENCODE and TCGA databases, were used to provide expression profiles in various tissues, diseases and developmental stages. Importantly, we analyzed RNA-Seq data to identify coexpressed mRNAs that would provide ample insights on lncRNA functions. The resulting gene list can be subject to enrichment analysis such as Gene Ontology or KEGG pathways. Furthermore, we compiled protein-lncRNA interactions by collecting and analyzing publicly available CLIP-seq or PAR-CLIP sequencing data. Finally, we explored evolutionarily conserved lncRNAs with correlated expression between human and six other organisms to identify functional lncRNAs. The whole contents are provided in a user-friendly web interface. AVAILABILITY AND IMPLEMENTATION: lncRNAtor is available at http://lncrnator.ewha.ac.kr/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813213 TI - PeakLink: a new peptide peak linking method in LC-MS/MS using wavelet and SVM. AB - MOTIVATION: In liquid chromatography-mass spectrometry/tandem mass spectrometry (LC-MS/MS), it is necessary to link tandem MS-identified peptide peaks so that protein expression changes between the two runs can be tracked. However, only a small number of peptides can be identified and linked by tandem MS in two runs, and it becomes necessary to link peptide peaks with tandem identification in one run to their corresponding ones in another run without identification. In the past, peptide peaks are linked based on similarities in retention time (rt), mass or peak shape after rt alignment, which corrects mean rt shifts between runs. However, the accuracy in linking is still limited especially for complex samples collected from different conditions. Consequently, large-scale proteomics studies that require comparison of protein expression profiles of hundreds of patients can not be carried out effectively. METHOD: In this article, we consider the problem of linking peptides from a pair of LC-MS/MS runs and propose a new method, PeakLink (PL), which uses information in both the time and frequency domain as inputs to a non-linear support vector machine (SVM) classifier. The PL algorithm first uses a threshold on an rt likelihood ratio score to remove candidate corresponding peaks with excessively large elution time shifts, then PL calculates the correlation between a pair of candidate peaks after reducing noise through wavelet transformation. After converting rt and peak shape correlation to statistical scores, an SVM classifier is trained and applied for differentiating corresponding and non-corresponding peptide peaks. RESULTS: PL is tested in multiple challenging cases, in which LC-MS/MS samples are collected from different disease states, different instruments and different laboratories. Testing results show significant improvement in linking accuracy compared with other algorithms. AVAILABILITY AND IMPLEMENTATION: M files for the PL alignment method are available at http://compgenomics.utsa.edu/zgroup/PeakLink. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813214 TI - Efficient RNA isoform identification and quantification from RNA-Seq data with network flows. AB - MOTIVATION: Several state-of-the-art methods for isoform identification and quantification are based on [Formula: see text]-regularized regression, such as the Lasso. However, explicitly listing the-possibly exponentially-large set of candidate transcripts is intractable for genes with many exons. For this reason, existing approaches using the [Formula: see text]-penalty are either restricted to genes with few exons or only run the regression algorithm on a small set of preselected isoforms. RESULTS: We introduce a new technique called FlipFlop, which can efficiently tackle the sparse estimation problem on the full set of candidate isoforms by using network flow optimization. Our technique removes the need of a preselection step, leading to better isoform identification while keeping a low computational cost. Experiments with synthetic and real RNA-Seq data confirm that our approach is more accurate than alternative methods and one of the fastest available. AVAILABILITY AND IMPLEMENTATION: Source code is freely available as an R package from the Bioconductor Web site (http://www.bioconductor.org/), and more information is available at http://cbio.ensmp.fr/flipflop. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813215 TI - compcodeR--an R package for benchmarking differential expression methods for RNA seq data. AB - compcodeR is an R package for benchmarking of differential expression analysis methods, in particular, methods developed for analyzing RNA-seq data. The package provides functionality for simulating realistic RNA-seq count datasets, an interface to several of the most commonly used differential expression analysis methods and extensive functionality for evaluating and comparing different approaches on real and simulated data. AVAILABILITY AND IMPLEMENTATION: compcodeR is available from http://www.bioconductor.org/packages/release/bioc/html/compcodeR.html. PMID- 24813216 TI - Ceiba: scalable visualization of phylogenies and 2D/3D image collections. AB - Phylogenetic trees with hundreds of thousands of leaves are now being inferred from sequence data, posing significant challenges for visualization and exploratory analysis. Image data supplying valuable context for species in trees (and cues for exploring them) are becoming increasingly available in biodiversity databases and elsewhere but have rarely been built into tree visualization software in a scalable way. Ceiba lets the user explore large trees and inspect image collection arrays (sets of 'homologous' images) comprising mixtures of 2D and 3D image objects. Ceiba exploits recent improvements in graphics hardware, OpenGL toolkits and many standard high-performance computer graphics strategies, such as texture compression, level of detail control, culling, animations and image caching. Its tree layouts can be tuned by user-provided phylogenetic definitions of subtrees. The code has been extensively tested on phylogenies of up to 55,000 leaves and images. AVAILABILITY AND IMPLEMENTATION: A manual, datasets, source code (distributed under GPL) and binaries for OS X are available at http://sourceforge.net/projects/ceiba. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813217 TI - Expression profiles of myostatin, myogenin, and Myosin heavy chain in skeletal muscles of two rabbit breeds differing in growth rate. AB - The purpose of the present study was to compare mRNA levels of myostatin (MSTN), myogenin (MyoG), and fiber type compositions in terms of myosin heavy chain (MyHC) in skeletal muscles of two rabbit breeds with different body sizes and growth rates. Longissimus dorsi and biceps femoris muscles of 16 Californian rabbits (CW) and 16 Germany great line of ZIKA rabbits (GZ) were collected at the ages of 35d and 84d (slaughter age). The results showed that the live weights of GZ rabbits of 35d and 84d old were approximately 36% and 26% greater than those of CW rabbits, respectively. Quantitative real-time PCR analysis revealed that at the age of 84d GZ rabbits contained significantly lower MSTN mRNA level and higher MyoG mRNA level in both longissimus dorsi and biceps femoris muscles than CW rabbits, and mRNA levels of MSTN and MyoG exhibited opposite changes from the age of 35d to 84d, suggesting that GZ rabbits were subjected to less growth inhibition from MSTN at slaughter age, which occurred most possibly in skeletal muscles. Four types of fiber were identified by real-time PCR in rabbit muscles, with MyHC-1 and MyHC-2D, MyHC-2B were the major types in biceps femoris and longissimus dorsi muscles, respectively. At the age of 84d, GZ rabbits contained greater proportion of MyHC-1 and decreased proportion of MyHC-2D and decreased lactate dehydrogenase activity in biceps femoris than CW rabbits, and the results were exactly opposite in longissimus dorsi, suggesting that GZ rabbits show higher oxidative capacity in biceps femoris muscle than CW rabbits. In conclusion, the trends of mRNA levels of MSTN and fiber types in GZ rabbits' skeletal muscles might be consistent with the putative fast growth characteristic of GZ rabbits compared to CW rabbits. PMID- 24813218 TI - Characterization of the genetic diversity and population structure for the yellow cattle in Taiwan based on microsatellite markers. AB - In recent years, the population size of Taiwan yellow cattle has drastically declined, even become endangered. A preservation project, Taiwan Yellow Cattle Genetic Preservation Project (TYCGPP), was carried out at the Livestock Research Institute (LRI) Hengchun branch (1988-present). An analysis of intra- and inter- population variability was performed to be the first step to preserve this precious genetic resource. In this work, a total number of 140 individuals selected from the five Taiwan yellow cattle populations were analyzed using 12 microsatellite markers (loci). These markers determined the level of genetic variation within and among populations as well as the phylogenetic structure. The total number of alleles detected (122, 10.28 per locus) and the expected heterozygosity (0.712) indicated that these five populations had a high level of genetic variability. Bayesian cluster analysis showed that the most likely number of groups was 2 (K = 2). Genetic differentiation among clusters was moderate (F ST = 0.095). The result of AMOVA showed that yellow cattle in Taiwan had maintained a high level of within-population genetic differentiation (91%), the remainder being accounted for by differentiation among subpopulations (4%), and by differentiation among regions (5%). The results of STRUCTURE and principal component analysis (PCA) revealed two divergent clusters. The individual unrooted phylogenetic tree showed that some Kinmen yellow cattle in the Hengchun facility (KMHC individuals) were overlapped with Taiwan yellow cattle (TW) and Taiwan yellow cattle Hengchun (HC) populations. Also, they were overlapped with Kinmen * Taiwan (KT) and Kinmen yellow cattle (KM) populations. It is possible that KMHC kept similar phenotypic characteristics and analogous genotypes between TW and KM. A significant inbreeding coefficient (F IS = 0.185; P < 0.01) was detected, suggesting a medium level of inbreeding for yellow cattle in Taiwan. The hypothesis that yellow cattle in Taiwan were derived from two different clusters was also supported by the phylogenetic tree constructed by the UPGMA, indicating that the yellow cattle in Taiwan and in Kinmen should be treated as two different management units. This result will be applied to maintain a good level of genetic variability and rusticity (stress-resistance) and to avoid further inbreeding for yellow cattle population in Taiwan. PMID- 24813219 TI - Genetic polymorphisms in the bovine toll-like receptor 4 (TLR4) and monocyte chemo attractant protein-1(CCL2) genes: SNPs distribution analysis in Bos indicus Sahiwal cattle breed. AB - Toll-like receptor 4 gene (TLR4) that recognizes the Gram negative bacterial ligand LPS was sequenced in the Bos indicus Sahiwal cattle breed. Ninety four single nucleotide polymorphisms (SNPs) were detected within 10.8 kb gene region. Seventeen of the SNPs were in the coding regions and the one at position 9589(A > G) in exon3 resulted in an amino acid change from Valine to Isoleucine. These SNPs led to generation of 27 TLR4 gene haplotypes. All the Sahiwal animals studied presently showed the occurrence of the genotype CC at gene position 9662, which codes for the amino acid threonine at position 674 of the TLR4 protein, and which had been reported to be associated with lower somatic cell score and, therefore, a lower susceptibility to mastitis, in Taurus cattle. This nucleotide configuration of the Toll-like receptor 4 gene of the Bos indicus Sahiwal cattle breed could possibly indicate toward a lower susceptibility to mastitis in the Sahiwal animals. Monocyte chemo-attractant protein-1 (CCL2) gene encoding for small inducible cytokine A2 that belongs to the CC chemokine family was also sequence characterized in these Sahiwal animals. The CCL2 gene was observed to have 12 polymorphic sites in 3.3 kb region of which one SNP at position 2500 (A > G) in exon 3 resulted in amino acid change from Valine to Isoleucine at position 46 of the mature CCL2 peptide. Seventeen haplotypes of the CCL2 gene were predicted corresponding to 12 genotypes detected. PMID- 24813220 TI - Biomedical applications of ovarian transvaginal ultrasonography in cattle. AB - Ovarian transvaginal ultrasonography (OTU) has been used world-wide for commercial ovum pick-up programs for in vitro embryo production in elite herds, providing an excellent model for the elucidation of factors controlling bovine oocyte developmental competence. Noninvasive sampling and treatment of ovarian structures is easily accomplished with bovine OTU techniques providing a promising system for in vivo delivery of transgenes directly into the ovary. The current review summarizes existing bovine OTU models and provides prospective applications of bovine OTU to undertake research in reproductive topics of biomedical relevance, with special emphasis on the development of in vivo gene transfer strategies. PMID- 24813221 TI - Production of healthy cloned pigs with neural stem cells as nuclear donors. AB - The objectives of the present study were to establish a porcine neural stem cell (NSC) line and to determine if these NSCs could be used to produce cloned pigs. NSCs were isolated from the brains of three embryonic day 30 fetal pigs and were induced to differentiate in vitro . NSCs and the differentiated cells were harvested for analysis of markers by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). The NSCs at passage 10 were used for nuclear transfer, and the cloned embryos at the two-cell stage were transferred into the oviducts of surrogate mothers. The results showed that three NSC lines (2 male and 1 female) were successfully established. All NSCs at passage 17 continued to express nestin and Sox2. NSCs could differentiate into neurons (TUBB3+), astrocytes (GFAP+), and oligodendrocytes (O4+). After NSC nuclear transfer, 2020 two-cell stage embryos formed. After embryo transfer, 6 of 10 surrogates were pregnant, and 40 piglets (18 males and 22 females) were born. Twenty-two of these piglets reached sexual maturity and were found to be fertile. The other piglets died within 45 days post-partum. In conclusion, 3 porcine NSC lines capable of self-renewal and differentiation were established, and the cloned embryos derived from these cells could develop to term. Thus, NSCs could be efficient alternative nuclear donors for pig cloning. PMID- 24813223 TI - Nanostructured lipid carriers and their current application in targeted drug delivery. AB - In the last few decades, various drug-delivery technologies have emerged and a fascinating part of this has been the development of nanoscale drug delivery devices. Nanoparticles (NPs) and other colloidal drug-delivery systems modify the kinetics, drug distribution in the body and release profile of an associated drug. Nanostructured lipid carriers (NLCs) have been reported to be an alternative system to emulsions, liposomes, microparticles, solid lipid nanoparticles (SLNs) and their polymeric counterparts due to their numerous advantages. This paper basically reviews the types of NLCs, mechanism of skin penetration, stability related issues along with their production techniques, characterisation and applications towards targeted drug delivery. PMID- 24813224 TI - Amphiphilic polyvinyl alcohol adsorbent for the removal of low-density lipoprotein. AB - Spacer can effectively reduce the steric hindrance and synergistic effect of the hydrophilic and hydrophobic ligands immobilized in adsorbents can improve the specific adsorption for low-density lipoprotein (LDL). In this paper, in order to improve the adsorption capacity for the Low-density lipoprotein-cholesterol (LDL C), specifically, amphiphilic adsorbent based on polyvinyl alcohol (PVA) containing cholesterol ligand and sulfonic dextran ligands was synthesized. All kinds of factors affecting the synthesis yield and adsorption properties were studied in detail. Results showed that the amphiphilic PVA adsorbent has higher adsorption capacity for total cholesterol (TC), (LDL-C), triglyceride (TG), and lower adsorption capacity, and percentage for high-density lipoprotein cholesterol (HDL-C), while the ligand ratio of cholesterol to sulfonic ligands is 1.57:1, the adsorption percentage and adsorption capacity for TC, LDL-C, TG, and HDL-C were 54.4%, 67.6%, 42.5%, 10.4% and 4.02, 3.612, 2.154, 0.168 mg/g, respectively. PMID- 24813225 TI - Necrotic regions are absent in fiber-shaped cell aggregates, approximately 100 MUm in diameter. AB - Microscopic, fiber-shaped cell aggregates, have been used as building blocks for fabricating macroscopic three-dimensional tissue architectures, in the field of tissue engineering. In this study, we examined the occurrence of necrotic regions in the most widely used, fiber-shaped cell aggregates, approximately 100 MUm in diameter. Alginate hydrogel hollow microfibers were used as templates for the cell aggregates. We demonstrated negligible necrotic region formation occurred in the cell aggregates formed in the hollow microfibers. Furthermore, we improved on previously-reported methods for preparing the hollow microfibers to avoid common microfiber tangling during the fiber preparation process. PMID- 24813226 TI - Complementary and alternative medicine in inflammatory bowel diseases: what is the future in the field of herbal medicine? AB - The use of complementary and alternative medicine is wide-spread not only in Eastern countries, but also in the Western world. Despite the increasing evidence on the harmful effects induced by several naturopathic/homeopathic products, patients seem to appreciate these remedies, in particular because they consider them to be absolutely safe. This same phenomenon is common among inflammatory bowel disease (IBD) patients. As a result there is a significant request for scientific data to evaluate both the efficacy and safety of these remedies, and to support the use of such medications as adjuvant treatments to biological and synthetic drugs. We aimed to review the current evidence on efficacy and safety of some natural products that are believed to be effective in inflammatory bowel disease. Further perspectives for the clinical use of herbal products and strategies for improving knowledge about herbal products in IBD are also discussed. PMID- 24813227 TI - Generation of myostatin B knockout yellow catfish (Tachysurus fulvidraco) using transcription activator-like effector nucleases. AB - Myostatin (Mstn), a member of the transforming growth factor beta superfamily, plays an inhibiting role in mammalian muscle growth. Mammals like human, cattle, mouse, sheep, and dog carrying null alleles of Mstn display a double-muscle phenotype. Mstn is conserved in fish; however, little is known whether the fish with mutated mstn display a similar phenotype to mammals because of the lack of mutant fish with mstn null alleles. Previously, we knocked out one of the duplicated copies of myostatin gene (mstna) in yellow catfish using zinc-finger nucleases. In this study, we report the identification of the second myostatin gene (mstnb) and knockout of mstnb in yellow catfish. The gene comprises three exons. It is predicted to encode 373 amino acid residues. The predicted protein exhibits 59.3% identity with yellow catfish Mstna and 57.3% identity with human MSTN. Employing TALEN (transcription activator-like effector nucleases) technology, we obtained two founders (from four randomly selected founders) of yellow catfish carrying the mutated mstnb gene in their germ cells. Totally, six mutated alleles of mstnb were obtained from the founders. Among the six alleles, four are nonframeshift and two are frameshift mutation. The frameshift mutated alleles include mstnb(nju22), an 8 bp deletion, and mstnb(nju24), a complex type of mutation comprising a 7 bp deletion and a 12 bp insertion. They are predicted to encode function null Mstnb. Our results will help to understand the roles of mstn genes in fish growth. PMID- 24813228 TI - First births to older women continue to rise. AB - KEY FINDINGS: Data from the National Vital Statistics System The first birth rate for women aged 35-39 increased from 1970 to 2006, decreased from 2006 to 2010, and increased again in both 2011 and 2012. The first birth rate for women aged 40 44 was steady in the 1970s and started increasing in the 1980s. The rate more than doubled from 1990 to 2012. For women aged 35-39 and 40-44 all race and Hispanic origin groups had increasing first birth rates from 1990 to 2012. Since 2000, 46 states and DC had an increase in the first birth rate for women aged 35 39. For women aged 40-44, rates increased in 31 states and DC. The average age of women at first birth has risen over the past 4 decades (1-3). This increase is in part a reflection of the shift in first births to women 35 years and older. Delayed childbearing affects the size, composition, and future growth of the population in the United States (2). Increased health risks to older mothers, especially those 40 years and older, and their infants are well documented (4-7), first time older mothers are generally better educated and more likely to have more resources including higher incomes than those at the youngest reproductive ages (8). This report explores trends in first births to women aged 35-39 and 40 44 years from 1970 to 2012, and by race and Hispanic origin from 1990 to 2012 (the most recent year for which comparable data are available). Trends in first births for older women by state are examined for the recent period, 2000 to 2012. PMID- 24813229 TI - The plant hormone zeatin riboside inhibits T lymphocyte activity via adenosine A2A receptor activation. AB - Cytokinins are plant hormones that play an integral role in multiple aspects of plant growth and development. The biological functions of cytokinins in mammalian systems are, however, largely uncharacterized. The naturally occurring cytokinin zeatin riboside has recently been demonstrated to activate the mammalian adenosine A(2A) receptor, which is broadly expressed by various cell types including immune system cells, with the activation of the A(2A)R playing a role in the regulation of cells involved in both innate and adaptive immunity. We show for the first time that zeatin riboside modulates mammalian immune system activity via an A(2A)R-dependent mechanism. Specifically, zeatin riboside treatment induces the production of cyclic adenosine monophosphate (cAMP) by T lymphocytes and inhibits the production by CD3(+)CD4(+) T cells of interferon (IFN)-gamma, IL-2, tumor-necrosis factor (TNF)-alpha, IL-4 and IL-13, and the production by CD3(+)CD8(+) T cells of IFN-gamma, IL-2 and TNF-alpha. Additionally, the upregulation of CD25, CD69 and CD40L by activated T lymphocytes is modulated by zeatin riboside. Zeatin riboside treatment also potently inhibits thioglycollate-induced peritoneal leukocytosis. The immunomodulatory activities of zeatin riboside are blocked by co-treatment with the selective A(2A)R antagonist ZM241385. These data suggest that zeatin riboside possesses therapeutic potential as a mammalian immunomodulatory agent. PMID- 24813231 TI - Description of Metchnikovella spiralis sp. n. (Microsporidia: Metchnikovellidae), with notes on the ultrastructure of metchnikovellids. AB - The present paper reports results of a transmission electron microscopy study of a new metchikovellid microsporidium. It was isolated from gregarines Polyrhabdina sp. inhabiting guts of polychaetes Pygospio elegans sampled at the White Sea silt littoral zone. Free sporogony (FS) occurred in the life cycle of the microsporidium alongside sac-bound sporogony (BS). Free spores resided in a parasitophorous vacuole and were of typical metchnikovellidean structure, uninucleate and oblong. They measured on sections 2.0-3.2*1.3-1.9 MUm. The life cycle included pre-sporogonial stages represented by dikaryotic cells and 4 nucleate cells with coupled nuclei. A multinucleate sporogonial plasmodium of FS split in numerous (>10) sporoblasts. In BS segregation of sporoblasts occurred within thick-walled cysts by internal budding. Spore sacs of this microsporidium, measuring on average 11.6*4.7 MUm, were limited by a thick electron-dense wall, externally ornamented with spirally wound cords of dense material. These oval spore sacs contained eight barrel-shaped spores, comparable in size and ultrastructure to FS spores. Ultrastructure of both types of spores and intracellular development of the new microsporidium and Metchnikovella spp. were similar, suggesting they belong to the same genus. In this paper we describe a new species Metchnikovella spiralis and discuss morphology of metchnikovellids in the context of putative evolutionary history of Microsporidia. PMID- 24813230 TI - Ovarian tumor-associated microRNA-20a decreases natural killer cell cytotoxicity by downregulating MICA/B expression. AB - MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs, and changes in miRNAs are involved in tumor origin and progression. Studies have shown that miR-20a is overexpressed in human ovarian cancer tissues and that this miRNA enhances long-term cellular proliferation and invasion capabilities. In this study, a positive correlation between serum miR-20a expression and ovarian cancer stage was observed. We found that miR-20a binds directly to the 3'-untranslated region of MICA/B mRNA, resulting in its degradation and reducing its protein levels on the plasma membrane. Reduction of membrane-bound MICA/B proteins, which are ligands of the natural killer group 2 member D (NKG2D) receptor found on natural killer (NK) cells, gammadelta(+) T cells and CD8(+) T cells, allows tumor cells to evade immune-mediated killing. Notably, antagonizing miR-20a action enhanced the NKG2D-mediated killing of tumor cells in both in vitro and in vivo models of tumors. Taken together, our data indicate that increased levels of miR 20a in tumor cells may indirectly suppress NK cell cytotoxicity by downregulating MICA/B expression. These data provide a potential link between metastasis capability and immune escape of tumor cells from NK cells. PMID- 24813232 TI - A case-control study of childhood trauma in the development of irritable bowel syndrome. AB - BACKGROUND: The etiology of irritable bowel syndrome (IBS) is not been fully elucidated, but childhood trauma may disturb the brain-gut axis and therefore be important. Thus, we conducted a family based case-control study of IBS cases and their relatives with the aims to (i) determine the frequency of childhood trauma among IBS cases and controls as well as their relatives, and (ii) assess childhood trauma among IBS cases with affected relatives (familial IBS). METHODS: Outpatients with IBS, matched controls, and their first-degree relatives completed a self-report version of Bremner' Early Trauma Inventory. Percent of cases and controls with a family history were compared and odds ratios were computed using chi-squared test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations. KEY RESULTS: Data were collected from 409 cases, 415 controls, 825 case relatives, and 921 control relatives. IBS cases had a median age of 50 and 83% were women. Of IBS cases, 74% had experienced any general trauma compared to 59% among controls, yielding an odds ratio of 1.56 (95% CI: 1.13-2.15, p < 0.008). There were no statistical differences between IBS relatives and control relatives with regards to lifetime trauma. CONCLUSIONS & INFERENCES: IBS is associated with childhood trauma, and these traumas often occur prior to onset of IBS symptoms. This provides further insight into how traumatic childhood events are associated with development of adult IBS. PMID- 24813234 TI - Zeolitic imidazolate framework as formaldehyde gas sensor. AB - Traditional semiconducting metal oxide-based gas sensors are always limited on low surface areas and high operating temperatures. Considering the high surface area and high stability of zeolitic imidazolate framework (ZIF), ZIF-67 (surface area of 1832.2 m(2) g(-1)) was first employed as a promising formaldehyde gas sensor at a low operating temperature (150 degrees C), and the gas sensor could detect formaldehyde as low as 5 ppm. This work develops a new promising application approach for porous metal-organic frameworks. PMID- 24813235 TI - Effect of therapeutic plasma exchange on plasma levels of oxidative biomarkers in a patient with thrombotic thrombocytopenic purpura. AB - BACKGROUND: The role of oxidative stress in the initiation and progression of endothelial damage in thrombotic thrombocytopenic purpura (TTP) syndrome has been the subject of much speculation in the recent past. OBJECTIVES: The aim of this study was to measure the concentration of plasma advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and carbonyl groups (CG) as markers of oxidative stress in plasma of a patient with TTP during the course of the disease until recovery and to evaluate the effect of plasmapheresis (PE) on these biomarkers. MATERIALS AND METHODS: The study consisted of plasma analysis of the patient, and 23 healthy subjects served as controls. In the patient with TTP, AOPP, AGE, and CG analysis was performed before and after each PE at the days +1 (Talpha), +2, +4, +6, +10, +9, and +17 after the last plasmapheresis (Tomega). RESULTS: Plasma concentrations of AOPPs were increased in the acute phase of TTP, and at Talpha, the patient had AOPPs levels higher than 99 degrees 0/00 of controls. AOPPs decreased in the recovery phase, and at Tomega, their values were between 84 degrees and 85 degrees 0/00 of controls. No significant difference was found in AOPP levels before and after each PE. No significant differences for AGEs or CG concentrations were found at Talpha with respect to the control group, while only a trend was observed for reduction of plasma AGEs after each plasmapheresis. CONCLUSION: Our data seem to confirm the hypothesis that oxidative stress is a critical component of the pathogenesis of TTP. PMID- 24813236 TI - Insights into the binding of pyridines to the iron-sulfur enzyme IspH. AB - (E)-1-Hydroxy-2-methylbut-2-enyl 4-diphosphate reductase (IspH) is a [Fe4S4] cluster-containing enzyme involved in isoprenoid biosynthesis in many bacteria as well as in malaria parasites and is an important drug target. Several inhibitors including amino and thiol substrate analogues, as well as acetylene and pyridine diphosphates, have been reported. Here, we investigate the mode of binding of four pyridine diphosphates to Escherichia coli IspH by using X-ray crystallography. In three cases, one of the iron atoms in the cluster is absent, but in the structure with (pyridin-3-yl)methyl diphosphate, the most potent pyridine-analogue inhibitor reported previously, the fourth iron of the [Fe4S4] cluster is present and interacts with the pyridine ring of the ligand. Based on the results of quantum chemical calculations together with the crystallographic results we propose a side-on eta(2) coordination of the nitrogen and the carbon in the 2-position of the pyridine ring to the unique fourth iron in the cluster, which is in the reduced state. The X-ray structure enables excellent predictions using density functional theory of the (14)N hyperfine coupling and quadrupole coupling constants reported previously using HYSCORE spectroscopy, as well as providing a further example of the ability of such [Fe4S4]-containing proteins to form organometallic complexes. PMID- 24813238 TI - Development and psychometric properties of the Swedish ALPS-Neo pain and stress assessment scale for newborn infants. AB - AIM: To validate and evaluate the psychometric properties of the ALPS-Neo, a new pain assessment scale created for the continuous evaluation of pain and stress in preterm and sick term infants. METHODS: A unidimensional scale for continuous pain, Astrid Lindgren Children's Hospital Pain Scale (ALPS 1), was developed further to assess continuous pain and stress in infants treated in the neonatal intensive care unit (NICU). The pain scale includes observations of five behaviours. A manual was created, clarifying the scoring criteria. An internal and an external panel assessed face validity. Psychometric properties were evaluated in three different steps. Inter-rater reliability was estimated from video-based assessments (n = 625) using weighted kappa statistics (test I). Inter rater reliability was further evaluated in test II (n = 125) and test III (n = 96) by real-time assessments using the intraclass correlation coefficient (ICC) and Cronbach's alpha. RESULTS: The final inter-rater reliability (test III) was assessed as good with ICC 0.91 for the total score and 0.62-0.81 for the five items. Cronbach's alpha showed 0.95 for the total score. CONCLUSION: ALPS-Neo is a new assessment tool for optimising the management of pain and stress in newborn infants in the NICU. It has proved easy to implement and user-friendly, permitting fast, reliable observations with high inter-rater reliability. PMID- 24813237 TI - Sequence effects of self-assembling multidomain peptide hydrogels on encapsulated SHED cells. AB - Here we report three new nanofibrous, self-assembling multidomain peptide (MDP) sequences and examine the effect of sequence on the morphology and expansion of encapsulated Stem cells from Human Exfoliated Deciduous teeth (SHED). We modified our previously reported set of serine-based MDPs, changing the serine residues in the amphiphilic region to threonine. The three new threonine-based sequences self assemble into antiparallel beta-sheet nanofibers, confirmed by CD and IR. AFM and negative-stained TEM show that the nanofibers formed by the new sequences are more curved than their serine-containing predecessors. Despite this change in nanofiber morphology, SEM illustrates that all three new sequences still form porous hydrogels. K(TL)2SLRG(TL)3KGRGDS, with a designed cleavage site, is able to be degraded by Matrix Metalloprotease 2. We then examine SHED cell response to these new sequences as well as their serine-based predecessors. We observe faster cell attachment and spreading in hydrogels formed by K2(SL)6K2GRGDS and K(SL)3RG(SL)3KGRGDS. By day 3, the SHEDs in all of the serine-based sequences exhibit a fibroblast-like morphology. Additionally, the SHED cells expand more rapidly in the serine-based gels while the cell number remains relatively constant in the threonine-based peptides. In hydrogels formed by K2(TL)6K2GRGDS and K(TL)2SLRG(TL)3KGRGDS, this low expansion rate is accompanied by changes in morphology where SHEDs exhibit a stellate morphology after 3 days in culture; however, by day 7 they appear more fibroblast-shaped. Throughout the duration of the experiment, the SHED cells encapsulated in the K2(TL)6K2 hydrogels remain rounded. These results suggest that the basic MDP structure easily accommodates modifications in sequence and, for SHED cells, the threonine-containing gels require the integrin-binding RGDS sequence for cell attachment to occur, while the serine-based gels are less selective and support an increase in cell number, regardless of the presence or absence of RGDS. PMID- 24813239 TI - Poly(methyl methacrylate)-supported polydiacetylene films: unique chromatic transitions and molecular sensing. AB - Polydiacetylenes (PDAs) constitute a family of conjugated polymers exhibiting unique colorimetric and fluorescence transitions, and have attracted significant interest as chemo- and biosensing materials. We spin-coated PDA films upon poly(methyl methacrylate) (PMMA), and investigated the photophysical properties and sensing applications of the new PDA configuration. Specifically, the as polymerized blue PDA layer underwent distinct transformations to purple, red, and yellow phases, which could be quantified through conventional color scanning combined with application of image analysis algorithms. Furthermore, we recorded a reversible red-purple PDA transition that was induced by ultraviolet irradiation, a phenomenon that had not been reported previously in PDA film systems. We show that distinct color and fluorescence transitions were induced in the PMMA-supported PDA films by amphiphilic substances-surfactants and ionic liquids-and that the chromatic transformations were correlated to the analyte structures and properties. Overall, this study presents a new chromatic PDA film system in which noncovalent interactions between the PMMA substrate and spin coated PDA give rise to distinct chromatic properties and molecular sensing capabilities. PMID- 24813240 TI - Interleukin-17 facilitates the immune suppressor capacity of high-grade glioma derived CD4 (+) CD25 (+) Foxp3 (+) T cells via releasing transforming growth factor beta. AB - High-grade glioma is a malignant tumour; the pathogenesis is to be further investigated. Interleukin (IL)-17 is an inflammatory cytokine. Chronic inflammation is a pathological feature of cancer. This study aimed to characterize the glioma-derived IL-17(+) regulatory T cells (Treg). In this study, single cells were isolated from surgically removed high-grade glioma tissue and examined by flow cytometry. The immune suppressor effect of IL-17(+) Tregs on CD8(+) T cells was assessed in vitro. The results showed that abundant IL-17(+) Tregs were found in high-grade glioma tissue. The immune suppressor molecule, transforming growth factor (TGF)-beta, was detected in the IL-17(+) Tregs. The proliferation of CD8(+) T cells was suppressed by culturing with the IL-17(+) Tregs, which was partially abrogated by neutralizing antibodies of either TGF-beta or IL-17 and completely abrogated by neutralizing antibodies against both TGF-beta and IL-17. In conclusion, IL-17(+) Tregs exist in the high grade glioma tissue; this subset of T cells can suppress CD8(+) T cell activities via releasing TGF-beta and IL-17. PMID- 24813241 TI - Atypical aneurysm of the great saphenous vein clinically presenting as a subcutaneous tumor of the thigh. PMID- 24813243 TI - Patient and public involvement: how much do we spend and what are the benefits? AB - BACKGROUND AND OBJECTIVES: Patient and public involvement (PPI) is seen as a way of helping to shape health policy and ensure a patient-focused health-care system. While evidence indicates that PPI can improve health-care decision making, it also consumes monetary and non-monetary resources. Given the financial climate, it is important to start thinking about the costs and benefits of PPI and how to evaluate it in economic terms. DESIGN: We conducted a literature review to assess the potential benefits and costs of involvement and the challenges in carrying out an economic evaluation of PPI. RESULTS: The benefits of PPI include effects on the design of new projects or services, on NHS governance, on research design and implementation and on citizenship and equity. Economic evaluation of PPI activities is limited. The lack of an appropriate analytical framework, data recording and understanding of the potential costs and benefits of PPI, especially from participants' perspectives, represent serious constraints on the full evaluation of PPI. CONCLUSIONS: By recognizing the value of PPI, health-care providers and commissioners can embed it more effectively within their organizations. Better knowledge of costs may prompt organizations to effectively plan, execute, evaluate and target resources. This should increase the likelihood of more meaningful activity, avoid tokenism and enhance organizational efficiency and reputation. PMID- 24813244 TI - Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. AB - Aging results in deterioration of the immune system, which is associated with increased susceptibility to infection and impaired wound healing in the elderly. Phagocytosis is an essential process in both wound healing and immune defence. As such, age-related impairments in phagocytosis impact on the health of the elderly population. Phagocytic efficiency in peritoneal macrophages, bone marrow-derived macrophages and bone marrow monocytes from young and old mice was investigated. Aging significantly impaired phagocytosis by peritoneal macrophages, both in vitro and in vivo. However, bone marrow-derived macrophages and bone marrow monocytes did not exhibit age-related impairments in phagocytosis, suggesting no intrinsic defect in these cells. We sought to investigate underlying mechanisms in age-related impairments in phagocytosis by peritoneal macrophages. We hypothesized that microenvironmental factors in the peritoneum of old mice impaired macrophage phagocytosis. Indeed, macrophages from young mice injected into the peritoneum of old mice exhibited impaired phagocytosis. Proportions of peritoneal immune cells were characterized, and striking increases in numbers of T cells, B1 and B2 cells were observed in the peritoneum of old mice compared with young mice. In addition, B cell-derived IL-10 was increased in resting and LPS-activated peritoneal cell cultures from old mice. These data demonstrate that aging impairs phagocytosis by tissue-resident peritoneal macrophages, but not by bone marrow-derived macrophages/monocytes, and suggest that age-related defects in macrophage phagocytosis may be due to extrinsic factors in the tissue microenvironment. As such, defects may be reversible and macrophages could be targeted therapeutically in order to boost immune function in the elderly. PMID- 24813245 TI - Diagnosis of small-fibre neuropathies: comparison between quantitative sensory testing and the measurement of intraepidermal nerve fibre density. PMID- 24813246 TI - Identification of a recently active Prunus-specific non-autonomous Mutator element with considerable genome shaping force. AB - Miniature inverted-repeat transposable elements (MITEs) are known to contribute to the evolution of plants, but only limited information is available for MITEs in the Prunus genome. We identified a MITE that has been named Falling Stones, FaSt. All structural features (349-bp size, 82-bp terminal inverted repeats and 9 bp target site duplications) are consistent with this MITE being a putative member of the Mutator transposase superfamily. FaSt showed a preferential accumulation in the short AT-rich segments of the euchromatin region of the peach genome. DNA sequencing and pollination experiments have been performed to confirm that the nested insertion of FaSt into the S-haplotype-specific F-box gene of apricot resulted in the breakdown of self-incompatibility (SI). A bioinformatics based survey of the known Rosaceae and other genomes and a newly designed polymerase chain reaction (PCR) assay verified the Prunoideae-specific occurrence of FaSt elements. Phylogenetic analysis suggested a recent activity of FaSt in the Prunus genome. The occurrence of a nested insertion in the apricot genome further supports the recent activity of FaSt in response to abiotic stress conditions. This study reports on a presumably active non-autonomous Mutator element in Prunus that exhibits a major indirect genome shaping force through inducing loss-of-function mutation in the SI locus. PMID- 24813242 TI - Challenges to barcoding an entire flora. AB - DNA barcodes are species-specific genetic markers that allow taxonomic identification of biological samples. The promise of DNA barcoding as a rapid molecular tool for conducting biodiversity inventories has catalysed renewed efforts to document and catalogue the diversity of life, parallel to the large scale sampling conducted by Victorian naturalists. The unique contribution of DNA barcode data is in its ability to identify biotic material that would be impossible to classify using traditional taxonomic keys. However, the utility of DNA barcoding relies upon the construction of accurate barcode libraries that provide a reference database to match to unidentified samples. Whilst there has been much debate in the literature over the choice and efficacy of barcode markers, there has been little consideration of the practicalities of generating comprehensive barcode reference libraries for species-rich floras. Here, we discuss several challenges to the generation of such libraries and present a case study from a regional biodiversity hotspot in southern Quebec. We suggest that the key challenges include (i) collection of specimens for rare or ephemeral species, (ii) limited access to taxonomic expertise necessary for reliable identification of reference specimens and (iii) molecular challenges in amplifying and matching barcode data. To be most effective, we recommend that sampling must be both flexible and opportunistic and conducted across the entire growing season by expert taxonomists. We emphasize that the success of the global barcoding initiative will depend upon the close collaboration of taxonomists, plant collectors, and molecular biologists. PMID- 24813247 TI - Chemometric study of retention indices of some thiazolidinediones derivatives in two low polarity stationary phases. AB - Application of chemometric methods in the study of the retention indices of thirteen 5-arylidene-2,4- thiazolidinediones in two low polarity high-performance thin-layer chromatographic (HPTLC) stationary phases (RP-18 and RP-CN) and six aqueous mobile phases. Principal component analysis classified chromatographic systems into four specific groups while one system remained non-classified. Hierarchical clustering analysis enabled grouping of the chromatographic systems into three clusters, and the studied compounds into three main classes. The color map enabled more in-depth interpretation of the relationships between the studied compounds and HPTLC systems applied. PMID- 24813248 TI - Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis. AB - BACKGROUND: Anaphylactic reactions to neuromuscular blocking agents (NMBAs) can be severe and even fatal. Our aim was to evaluate mortality rate in France from anaphylactic reactions to NMBAs, to identify risk factors for a fatal outcome, and to describe management of the cases that proved fatal. METHODS: The French National Pharmacovigilance Database was queried for reports of NMBA anaphylaxis that occurred between January 2000 and December 2011. A questionnaire was sent to regional pharmacovigilance centers to obtain further information on the management of cases with a fatal outcome. RESULTS: Two thousand and twenty-two cases of NMBA hypersensitivity were retrieved, of which 84 were fatal (4.1%). Among the 1247 cases of severe NMBA anaphylaxis (grades 3 and 4), independent risk factors associated with a fatal outcome in a multivariate analysis were male gender (female gender: OR = 0.4; 95% CI 0.2-0.7; P = 0.0004), an emergency setting (OR = 2.6; 95% CI 1.5-4.6; P = 0.0007), a history of hypertension (OR = 2.5; 95% CI 1.5-4.4; P = 0.0010) or of other cardiovascular disease (OR = 4.4; 95% CI 2.4-8.1; P < 0.0001), obesity (OR = 2.4; 95% CI 1.1-5.3; P = 0.0376), and ongoing beta-blocker treatment (OR = 4.2; 95% CI 1.8-9.8; P = 0.0011). All 31 patients with a fatal outcome received epinephrine in a titrated manner according to international guidelines. CONCLUSION: Obese males with a history of cardiovascular disease receiving ongoing beta-blocker treatment and undergoing surgery in an emergency setting were at high risk of a fatal outcome after NMBA induced anaphylaxis. Some epinephrine-resistant cases may play a role in our high mortality rate. New therapeutic approaches need to be developed to treat these cases. PMID- 24813249 TI - Lung microbiota promotes tolerance to allergens in neonates via PD-L1. AB - Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood. PMID- 24813250 TI - Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis. AB - We previously demonstrated that low biosynthesis of omega-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet fed mice. These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in Il6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes. PMID- 24813251 TI - Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. AB - Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. PMID- 24813253 TI - Strain, depressed mood and suicidal thoughts among maltreated adolescents in the United States. AB - Almost one-fourth of maltreated adolescents report they have thought about killing themselves in the last two weeks. We draw on Agnew's strain theory to develop a model to account for variability in suicidal thoughts among this high risk group. We used data from a nationally representative sample of 572 maltreated adolescents, aged 11-15. One dimension of relational strain (poorer relationship with peers) and greater depressed mood were directly related to whether adolescents did or did not think about suicide. Depressed mood mediated the relationship between two strain variables (relationship with caregiver and with school) and suicidal thoughts. Child maltreatment strain (being severely harmed) and substance use were not directly related to suicidal thoughts; however, depressed mood appeared to mediate the relationship between drug use and suicidal thoughts. Adolescents who experience child maltreatment and who appear to be disconnected from caregivers, friends and school should be screened for depression and suicidal thoughts. PMID- 24813252 TI - Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. AB - Study of monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combined patient derived and genetically engineered induced pluripotent stem cells (iPSCs) with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene encoding tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS 'heart-on-chip' tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole-cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies and advances iPSC-based in vitro modeling of cardiomyopathy. PMID- 24813254 TI - Association of maternal developmental disorder traits with child mistreatment: a prospective study in Japan. AB - Maternal mental disorders are known risk factors for child mistreatment. However, little is known about the involvement of maternal developmental disorder traits. The aim of this study was to examine maternal traits related to Pervasive Developmental Disorder (PDD) and Attention Deficit Hyperactivity Disorder (ADHD), and their possible association with child mistreatment. Maternal PDD and ADHD were assessed through a self-administered questionnaire (N=846) during mid pregnancy using the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) and Adult ADHD Self-Report Scale (ASRS). The mothers completed another questionnaire on child mistreatment when the offspring was approximately 18 months of age. The associations between maternal PDD and ADHD traits and child mistreatment score were analyzed using linear regression models adjusted for covariates. Mothers who exhibited stronger PDD traits showed significantly higher child mistreatment score, even after adjustment for maternal characteristics at baseline and ADHD traits. At the same time, ADHD traits were significantly associated with child mistreatment after adjustment of covariates, although the association became non-significant after adjustment of PDD traits. Mothers who showed PDD and ADHD traits during pregnancy were more likely to mistreat their children. It is essential to educate mothers with such traits with appropriate, easy-to-follow childcare instructions, preferably in simple language combined with pictorial aids. PMID- 24813255 TI - The Church and child protection: the safe families story: volunteers offer hospitality to families in need. PMID- 24813256 TI - Characterization of the first report of Mycobacterium timonense infecting an HIV patient in an Ecuadorian hospital. AB - Mycobacterium timonense is a non-tuberculous mycobacteria (NTM) described in southern France in 2009, and to our knowledge, not reported again as a human pathogen in indexed literature. The aim of this work was to characterize the first clinical isolate of M. timonense in Ecuador. Time of growth, biochemical tests, thin layer growth test, PCR-RFLP analysis of the hsp65 gene and MALDI-TOF spectra analysis were not able to identify the species. The species identification was achieved through sequencing of rrs, hsp65 and rpoB genes. The results highlight the necessity to set up a sequencing method to identify emerging NTM in Ecuadorian clinical facilities. PMID- 24813258 TI - Quality of life after intra-arterial therapy for acute ischemic stroke. AB - Few data exist about health-related quality of life outcomes after intra-arterial therapy (IAT) for acute ischemic stroke (AIS). We assessed stroke-specific quality of life (SS-QOL) in survivors of stroke after IAT. Consecutive patients undergoing IAT for AIS from 2005 to 2010 were retrospectively identified via an institutional database. SS-QOL (using the SS-QOL score) and disability status (modified Rankin Scale [mRS]) were prospectively assessed via mailed questionnaire. We analyzed quality of life (QOL) scores by domain and summary score, with a summary score of 4 or more defined as a good outcome. Analysis of variance (ANOVA) was used to model the effect of final recanalization status, stroke severity, and mRS on total QOL score. ANOVA and Pearson correlations were used to test the association between stroke severity/mRS and QOL/time since stroke, respectively. Of 99 patients with AIS, 61 responded, yielding 11 interim deaths, 7 incomplete surveys, and 43 complete surveys for analysis. Among responding survivors, overall QOL score was 3.9 (standard deviation 0.7); 77% of these reported good QOL. Scores were higher in recanalized patients in 11 of 12 domains but was significant only for mood. Although mRS was associated with stroke severity, QOL was independent of both. Seventy-seven percent of survivors of AIS who received IAT reported good QOL. Furthermore, these data suggest that SS-QOL is an independent outcome from stroke severity and disability status. PMID- 24813259 TI - Triple balloon protection technique using the mo.ma ultra with the carotid GuardWire for carotid stenting: technical note. AB - BACKGROUND: We describe the "triple balloon protection technique" (TBPT) using the Mo.Ma Ultra in combination with the Carotid GuardWire during carotid artery stenting (CAS). This technique is expected to prevent distal embolism to the internal and external carotid arteries, and is suitable for East Asians in whom the origin of the superior thyroid artery is lower than that in Caucasians. METHODS: From December 2012 to May 2013, 11 patients underwent CAS using TBPT in our center. RESULTS: Procedural success was achieved in all patients. Complete flow blockade by angiography could not be obtained in 8 patients (72.7%) by proximal occlusion using the Mo.Ma Ultra only. Complete angiographic flow blockade was obtained in all patients by TBPT. No major adverse cardiovascular events, including stroke, myocardial infarction, or death because of any cause, occurred within 30 days. CONCLUSIONS: The use of TBPT for CAS may be effective for preventing distal embolisms, especially for East Asians. PMID- 24813260 TI - Nanometer-scale features on micrometer-scale surface texturing: a bone histological, gene expression, and nanomechanical study. AB - Micro- and nanoscale surface modifications have been the focus of multiple studies in the pursuit of accelerating bone apposition or osseointegration at the implant surface. Here, we evaluated histological and nanomechanical properties, and gene expression, for a microblasted surface presenting nanometer-scale texture within a micrometer-scale texture (MB) (Ossean Surface, Intra-Lock International, Boca Raton, FL) versus a dual-acid etched surface presenting texture at the micrometer-scale only (AA), in a rodent femur model for 1, 2, 4, and 8weeks in vivo. Following animal sacrifice, samples were evaluated in terms of histomorphometry, biomechanical properties through nanoindentation, and gene expression by real-time quantitative reverse transcription polymerase chain reaction analysis. Although the histomorphometric, and gene expression analysis results were not significantly different between MB and AA at 4 and 8 weeks, significant differences were seen at 1 and 2 weeks. The expression of the genes encoding collagen type I (COL-1), and osteopontin (OPN) was significantly higher for MB than for AA at 1 week, indicating up-regulated osteoprogenitor and osteoblast differentiation. At 2 weeks, significantly up-regulated expression of the genes for COL-1, runt-related transcription factor 2 (RUNX-2), osterix, and osteocalcin (OCN) indicated progressive mineralization in newly formed bone. The nanomechanical properties tested by the nanoindentation presented significantly higher-rank hardness and elastic modulus for the MB compared to AA at all time points tested. In conclusion, the nanotopographical featured surfaces presented an overall higher host-to-implant response compared to the microtextured only surfaces. The statistical differences observed in some of the osteogenic gene expression between the two groups may shed some insight into the role of surface texture and its extent in the observed bone healing mechanisms. PMID- 24813261 TI - Physical activity interventions for people with mental illness: a systematic review and meta-analysis. AB - OBJECTIVE: To determine effects of physical activity on depressive symptoms (primary objective), symptoms of schizophrenia, anthropometric measures, aerobic capacity, and quality of life (secondary objectives) in people with mental illness and explore between-study heterogeneity. DATA SOURCES: MEDLINE, Cochrane Controlled Trials Register, PsycINFO, CINAHL, Embase, and the Physiotherapy Evidence Database (PEDro) were searched from earliest record to 2013. STUDY SELECTION: Randomized controlled trials of adults with a DSM-IV-TR, ICD-10, or clinician-confirmed diagnosis of a mental illness other than dysthymia or eating disorders were selected. Interventions included exercise programs, exercise counseling, lifestyle interventions, tai chi, or physical yoga. Study methodological quality and intervention compliance with American College of Sports Medicine (ACSM) guidelines were also assessed. DATA EXTRACTION AND ANALYSIS: Two investigators extracted data. Data were pooled using random-effects meta-analysis. Meta-regression was used to examine sources of between-study heterogeneity. RESULTS: Thirty-nine eligible trials were identified. The primary meta-analysis found a large effect of physical activity on depressive symptoms (n = 20; standardized mean difference (SMD) = 0.80). The effect size in trial interventions that met ACSM guidelines for aerobic exercise did not differ significantly from those that did not meet these guidelines. The effect for trials with higher methodological quality was smaller than that observed for trials with lower methodological quality (SMD = 0.39 vs 1.35); however, the difference was not statistically significant. A large effect was found for schizophrenia symptoms (SMD = 1.0), a small effect was found for anthropometry (SMD = 0.24), and moderate effects were found for aerobic capacity (SMD = 0.63) and quality of life (SMD = 0.64). CONCLUSIONS: Physical activity reduced depressive symptoms in people with mental illness. Larger effects were seen in studies of poorer methodological quality. Physical activity reduced symptoms of schizophrenia and improved anthropometric measures, aerobic capacity, and quality of life among people with mental illness. TRIAL REGISTRATION: PROSPERO registration #CRD42012002012. PMID- 24813262 TI - Salinity-dependent copper accumulation in the guppy Poecilia vivipara is associated with CTR1 and ATP7B transcriptional regulation. AB - Copper (Cu) accumulation and regulation of key-genes involved in Cu homeostasis were evaluated in freshwater- and saltwater-acclimated guppies Poecilia vivipara. Fish were exposed (96h) to environmentally relevant concentrations of dissolved Cu (0, 5.0, 9.0 and 20.0MUg/L). In freshwater guppies, gill and liver Cu accumulation was dependent on Cu concentration in the exposure medium. In saltwater guppies, this dependence was observed only in the gut. These findings indicate that Cu accumulation was salinity- and tissue-dependent. Key genes involved in Cu metabolism were sequenced for the first time in P. vivipara. Transcripts coding for the high-affinity copper transporter (CTR1) and copper transporting ATPase (ATP7B) were identified using polymerase chain reaction (PCR) and gene sequencing. The full-length CTR1 open reading frame (1560bp) and a partial ATP7B (690bp) were discovered. Predicted amino acid sequences shared high identities with the CTR1 of Fundulus heteroclitus (81%) and the ATP7B of Sparus aurata (87%). Basal transcriptional levels addressed by RT-qPCR in control fish indicate that CTR1 and ATP7B was highly transcribed in liver of freshwater guppies while CTR1 was highly transcribed in gut of saltwater guppies. This could explain the higher Cu accumulation observed in liver of freshwater guppies and in gut of saltwater guppies, because CTR1 is involved in Cu uptake. Reduced gill mRNA expression of CTR1 was observed in freshwater guppies exposed to 20.0MUg/L Cu and in saltwater guppies exposed to 5.0MUg/L Cu. In turn, reduced mRNA expression of gut ATP7B was observed in freshwater and salt water guppies exposed to 9.0 and 20.0MUg/L Cu. Liver CTR1 and ATP7B transcription were not affected by Cu exposure. These findings suggest that gill CTR1 and gut ATP7B are down regulated to limit Cu absorption after exposure to dissolved Cu, while liver CTR1 and ATP7B levels are maintained to allow Cu storage and detoxification. In conclusion, findings reported here indicate that Cu accumulation in the euryhaline guppy P. vivipara is tissue specific and dependent on water salinity. They also suggest that Cu homeostasis involves a differential transcriptional regulation of the newly identified Cu transporters, CTR1 and ATP7B. PMID- 24813263 TI - Crude oil exposure results in oxidative stress-mediated dysfunctional development and reproduction in the copepod Tigriopus japonicus and modulates expression of cytochrome P450 (CYP) genes. AB - In this study, we investigated the effects of the water-accommodated fraction (WAF) of crude oil on the development and reproduction of the intertidal copepod Tigriopus japonicus through life-cycle experiments. Furthermore, we investigated the mechanisms underlying the toxic effects of WAF on this benthic organism by studying expression patterns of cytochrome P450 (CYP) genes. Development of T. japonicus was delayed and molting was interrupted in response to WAF exposure. Hatching rate was also significantly reduced in response to WAF exposure. Activities of antioxidant enzymes such as glutathione S-transferase (GST), glutathione reductase (GR), and catalase (CAT) were increased by WAF exposure in a concentration-dependent manner. These results indicated that WAF exposure resulted in oxidative stress, which in turn was associated with dysfunctional development and reproduction. To evaluate the involvement of cytochrome P450 (CYP) genes, we cloned the entire repertoire of CYP genes in T. japonicus (n=52) and found that the CYP genes belonged to five different clans (i.e., Clans 2, 3, 4, mitochondrial, and 20). We then examined expression patterns of these 52 CYP genes in response to WAF exposure. Three TJ-CYP genes (CYP3024A2, CYP3024A3, and CYP3027C2) belonging to CYP clan 3 were significantly induced by WAF exposure in a time- and concentration-dependent manner. We identified aryl hydrocarbon responsive elements (AhRE), xenobiotic responsive elements (XREs), and metal response elements (MRE) in the promoter regions of these three CYP genes, suggesting that these genes are involved in detoxification of toxicants. Overall, our results indicate that WAF can trigger oxidative stress and thus induce dysfunctional development and reproduction in the copepod T. japonicus. Furthermore, we identified three TJ-CYP genes that represent potential biomarkers of oil pollution. PMID- 24813264 TI - Effects of metal nanoparticles on the lateral line system and behaviour in early life stages of zebrafish (Danio rerio). AB - The unique physicochemistry and potential toxicity of manufactured nanoparticles (NPs) requires innovative approaches for the assessment of toxicity to aquatic organisms. Here, the toxicity of Cu-NPs, Ag-NPs and TiO2-NPs on the lateral line system of free-swimming zebrafish embryos was investigated and compared to appropriate metal salts or bulk material controls. Fish were exposed for 4h at 96 h post-fertilization. Metal salt (CuSO4 and AgNO3) controls reduced the number of functional lateral line neuromasts (LLN) to <5% of unexposed controls, but no effect on LLN was observed for TiO2-NPs or Ag-NPs. Exposure to Cu-NPs caused only a 15% reduction in LLN. Performance of positive rheotaxis was reduced by Cu-NPs, Ag-NPs, and the metal salt controls. The data show that some metal NPs can affect LLN and fish behaviour (rheotaxis) important for survival, and that effects were different from those of comparable metal ion controls. Capsule: We demonstrate that behaviour is a particularly sensitive indicator of metal NP exposure in fish and highlight the interaction between behaviour and external tissue surfaces. PMID- 24813265 TI - A light in the darkness: new biotransformation genes, antioxidant parameters and tissue-specific responses in oysters exposed to phenanthrene. AB - Phenanthrene (PHE), a major component of crude oil, is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in aquatic ecosystems, and is readily bioavailable to marine organisms. Understanding the toxicity of PAHs in animals requires knowledge of the systems for xenobiotic biotransformation and antioxidant defence and these are poorly understood in bivalves. We report, for the first time, new transcripts and tissue-specific transcription in gill and digestive gland from the oyster Crassostrea brasiliana following 24h exposure to 100 and 1000MUgL(-1) PHE, a model PAH. Six new cytochrome P450 (CYP) and four new glutathione S-transferase (GST) genes were analysed by means of quantitative reverse transcription PCR (qRT-PCR). Different antioxidant endpoints, including both enzymatic and non-enzymatic parameters, were assessed as potential biomarkers of oxidative stress. GST activity was measured as an indicator of phase II biotransformation. Rapid clearance of PHE was associated with upregulation of both phase I and II genes, with more pronounced effects in the gill at 1000MUgL(-1) PHE. After 24h of exposure, PHE also caused impairment of the antioxidant system, decreasing non-protein thiols and glutathione levels. On the other hand, no change in antioxidant enzymes was observed. PHE treatment (100MUgL(-1)) significantly decreased GST activity in the gill of exposed oysters. Both CYP and GST were transcribed in a tissue-specific manner, reflecting the importance of the gill in the detoxification of PAHs. Likewise, the antioxidant parameters followed a similar pattern. The data provide strong evidence that these genes play key roles in C. brasiliana biotransformation of PHE and highlight the importance of gill in xenobiotic metabolism. PMID- 24813266 TI - Chemical dispersants used in the Gulf of Mexico oil crisis are cytotoxic and genotoxic to sperm whale skin cells. AB - The 2010 Deepwater Horizon oil rig explosion in the Gulf of Mexico drew attention to the need for toxicological studies of chemical dispersants. We are still learning the effects these spills had on wildlife. Little is known about the toxicity of these substances in marine mammals. The objective of this study was to determine the toxicity of the two dispersants (Corexit 9500 and 9527). Corexit 9500 and 9527 were both cytotoxic to sperm whale skin fibroblasts. Corexit 9527 was less cytotoxic than 9500. S9 mediated metabolism did not alter cytotoxicity of either dispersant. Both dispersants were genotoxic to sperm whale skin fibroblasts; S9 mediated metabolism increased Corexit 9527 genotoxicity. PMID- 24813267 TI - The effects of ammonia and water hardness on the hormonal, osmoregulatory and metabolic responses of the freshwater silver catfish Rhamdia quelen. AB - The aim of the present study was to assess the effects of ammonia and water hardness on endocrine, osmoregulatory and metabolic parameters in silver catfish (Rhamdia quelen). The specimens (60-120g) were subjected to six treatments in triplicate, combining three levels of un-ionized ammonia (NH3) (0.020+/-0.008mg/L [1.17+/-0.47MUM], 0.180+/-0.020mg/L [10.57+/-1.17MUM] and 0.500+/-0.007mg/L [29.36+/-0.41MUM]) and two levels of water hardness (normal: 25mgCaCO3/L and high: 120mgCaCO3/L), and sampled after two exposure times (1 and 5 days post transfer). Plasma cortisol, metabolites, osmolality and ionic values were determined concomitantly with the mRNA expression levels of different adenohypophyseal hormones (growth hormone, GH; prolactin, PRL; and somatolactin, SL). Previously, full-length PRL and SL as well as beta-actin cDNAs from R. quelen were cloned. Exposure to high NH3 levels enhanced plasma cortisol levels in fish held under normal water hardness conditions but not in those kept at the high hardness value. The increase in water hardness did not alter plasma metabolites, whereas it modulated the osmolality and ion changes induced by high NH3 levels. However, this hardness increase did not lead to the decreased GH expression that was observed 5 days after exposure to 0.18mg/L NH3 in fish held at the normal water hardness level, whereas PRL expression was enhanced after one day of exposure under the increased hardness conditions. Additionally, SL expression decreased in specimens exposed for 5 days to 0.18mg/L NH3 and maintained at the high water hardness level. The results showed that increasing water hardness attenuated the hormonal parameters evaluated in R. quelen specimens exposed to high NH3 levels, although plasma metabolism do not appear to suffer major changes. PMID- 24813268 TI - Sensitivity of the vitellogenin assay to diagnose exposure of fathead minnows to 17alpha-ethynylestradiol. AB - Vitellogenin is frequently used as a biomarker of exposure to environmental estrogens due to its specificity and sensitivity. Appropriate incorporation of this biomarker into environmental monitoring and assessment necessitates evaluation of its critical performance parameters. In this study, we characterize the sensitivity of both vitellogenin gene (vtg) mRNA transcripts in liver and protein (VTG) in plasma over a range of concentrations and exposure durations. Male fathead minnows were exposed to 17alpha-ethynylestradiol (EE2) in a flow through system for 2, 4 and 7 days at multiple EE2 concentrations in order to provide information regarding the sensitivity of each of these biomarkers to diagnose exposure to this representative estrogen. Measurements of the expression of the vitellogenin gene and protein both reliably detected exposures to EE2 at concentrations of 5ng/l and higher at all time points. Vtg mRNA and plasma VTG appear to have similar sensitivities, though the lower variability in VTG in control fish may make it more sensitive to small changes in expression compared to vtg. For lower concentrations, sensitivity may be improved by increasing exposure duration. A sample size of ~12 fish was sufficient in many cases to produce a statistically significant increase in vitellogenin. Larger sample sizes may provide more sensitivity at low concentrations, but detecting exposure to estrogens in the lower range of environmentally relevant concentrations may need larger sample sizes. These data will assist in designing experiments that have sufficient statistical power necessary to determine if fish have been exposed to estrogens. PMID- 24813269 TI - Re: Liam Bourke, Stephen Gilbert, Richard Hooper, et al. Lifestyle changes for improving disease-specific quality of life in sedentary men on long-term androgen deprivation therapy for advanced prostate cancer: a randomised controlled trial. Eur Urol 2014;65:865-72; Re: Daniel A. Galvao, Nigel Spry, James Denham, et al. A multicentre year-long randomised controlled trial of exercise training targeting physical functioning in men with prostate cancer previously treated with androgen suppression and radiation from TROG 03.04 RADAR. Eur Urol 2014;65:856-64; Re: Nancy L. Keating, Pang-Hsiang Liu, A. James O'Malley, Stephen J. Freedland, Matthew R. Smith. Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur Urol 2014;65:816-24; Re: Christina G. Jespersen, Mette Norgaard, Michael Borre. Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol 2014;65:704-9. PMID- 24813270 TI - Salvage lymph node dissection for biochemical recurrence following radical prostatectomy: is the evidence there? PMID- 24813271 TI - Synthesis, an experimental and quantum chemical computational study of a new nonlinear optical material: 2-picolinium hydrogensquarate. AB - The experimental and theoretical investigation results of a novel organic non linear optical (NLO) organic squarate salt of 2-Picolinium hydrogensquarate (1), C6H8N+.C4HO4-, were reported in this study. The space group of the title compound was found in the monoclinic C2/c space group. It was found that the asymmetric unit consists of one monohydrogen squarate anion together with mono protonated 2 Picolinium, forming the (1) salt. The X-ray analysis clearly indicated that the crystal packing has shown the hydrogen bonding ring pattern of D2(2)(10) (alpha dimer) through NH?O interactions. The hydrogensquarate anions form alpha-dimer, while 2-Picolinium molecule interacts through NH?O and CH?O with the hydrogensquarate anion. The structural and vibrational properties of the compound were also studied by computational methods of ab initio performed on the compound at DFT/B3LYP/6-31++G(d,p) (2) and HF/6-31++G(d,p) (3) level of theory. The calculation results on the basis of two models for both the optimized molecular structure and vibrational properties for the 1 obtained are presented and compared with the X-ray analysis result. On the other the molecular electrostatic potential (MEP), electronic absorption spectra, frontier molecular orbitals (FMOs), conformational flexibility and non-linear optical properties (NLO) of the title compound were also studied at the 2 level and the results are reported. In order to evaluate the suitability for NLO applications thermal analysis (TG, DTA and DTG) data of 1 were also obtained. PMID- 24813272 TI - Influences of pH, urea and metal ions on the interaction of sinomenine with Lysozyme by steady state fluorescence spectroscopy. AB - The interaction between sinomenine and Lysozyme (Lys) in aqueous solution has been systemically investigated by fluorescence spectroscopic techniques at pH 7.4. The quenching rate constants and binding constants calculated indicated the static quenching mechanism and medium binding force. The effect of sinomenine on the conformation of Lys was analyzed using synchronous fluorescence and three dimensional (3D) fluorescence. In addition, influence of pH on the binding of sinomenine to Lys was investigated and the binding ability of the drug to Lys deceased under other pH conditions (pH 9.0, 3.5, and 1.9) as compared with that at pH 7.4. As compared with the binding ability of sinomenine to native Lys, that of sinomenine to denatured Lys deceases dramatically. Furthermore, the effect of many metal ions on the binding constant of sinomenine with Lys was investigated. PMID- 24813273 TI - Spectroscopic studies on the antioxidant activity of ellagic acid. AB - Ellagic acid (EA, C14H6O8) is a natural dietary polyphenol whose benefits in a variety of diseases shown in epidemiological and experimental studies involve anti-inflammation, anti-proliferation, anti-angiogenesis, anticarcinogenesis and anti-oxidation properties. In vitro radical scavenging and antioxidant capacity of EA were clarified using different analytical methodologies such as total antioxidant activity determination by ferric thiocyanate, hydrogen peroxide scavenging, 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) scavenging, 2,2' azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging activity and superoxide anion radical scavenging, ferrous ions (Fe2+) chelating activity and ferric ions (Fe3+) reducing ability. EA inhibited 71.2% lipid peroxidation of a linoleic acid emulsion at 45 MUg/mL concentration. On the other hand, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), alpha tocopherol and ascorbic acid displayed 69.8%, 66.8%, 64.5% and 59.7% inhibition on the peroxidation of linoleic acid emulsion at the same concentration, respectively. In addition, EA had an effective DPPH* scavenging, ABTS+ scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe3+) reducing power and ferrous ions (Fe2+) chelating activities. Also, those various antioxidant activities were compared to BHA, BHT, alpha tocopherol and ascorbic acid as references antioxidant compounds. These results suggested that EA can be used in the pharmacological, food industry and medicine because of these properties. PMID- 24813274 TI - Molecular structure and spectral properties of ethyl 3-quinolinecarboxylate (E3Q) and [Ag(E3Q)2(TCA)] complex (TCA=Trichloroacetate). AB - A new [Ag(E3Q)2(TCA)] complex; (E3Q=Ethyl 3-quinolinecarboxylate and TCA=Trichloroacetate) has been synthesized and characterized using elemental analysis, FTIR, NMR and mass spectroscopy. The molecular geometry and spectroscopic properties of the complex as well as the free ligand have been calculated using the hybrid B3LYP method. The calculations predicted a distorted tetrahedral arrangement around Ag(I) ion. The vibrational spectra of the studied compounds have been assigned using potential energy distribution (PED). TD-DFT method was used to predict the electronic absorption spectra. The most intense absorption band showed a bathochromic shift and lowering of intensity in case of the complex (233.7 nm, f=0.5604) compared to E3Q (lambdamax=228.0 nm, f=0.9072). The calculated (1)H NMR chemical shifts using GIAO method showed good correlations with the experimental data. The computed dipole moment, polarizability and HOMO-LUMO energy gap were used to predict the nonlinear optical (NLO) properties. It is found that Ag(I) enhances the NLO activity. The natural bond orbital (NBO) analyses were used to elucidate the intramolecular charge transfer interactions causing stabilization for the investigated systems. PMID- 24813275 TI - Vibrational assignment, HOMO-LUMO and NBO analysis of (2S)-2-[(2-{[(2S)-1 hydroxybutan-2-yl]amino}ethyl)amino]butan-1-ol by density functional theory. AB - The FTIR and FT-Raman spectra of (2S)-2-[(2-{[(2S)-1-hydroxybutan-2 yl]amino}ethyl)amino]butan-1-ol have been recorded in the region 4000-400 cm( 1)and 4000-100 cm(-1) respectively. Utilizing the observed FTIR and FT-Raman data, a complete vibrational assignment and analysis of the fundamental vibrational modes of the compound were carried out. The optimized molecular geometry, harmonic vibrational frequencies, infrared intensities and Raman scattering were calculated by HF and density functional theory (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr) quantum chemical method with 6-31G(d,p), 6-31+G(d,p), 6-31++G(d,p) basis sets. The theoretical and optimized geometric parameters and vibrational frequencies have been found in good agreement with the corresponding experimental data and results in the literature. Ultraviolet-visible spectrum of the title molecule was recorded and has been calculated using TD-DFT method. The first-order hyperpolarizability (betao) and other related properties (MU, alphao) of the compound are calculated using DFT method on a finite field approach. The most stable geometry of the compound under investigation has been determined from the potential energy scan. Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital analysis (NBO). Besides, molecular electrostatic potential (MESP), HOMO and LUMO analysis, Mulliken population analysis and several other thermodynamic properties were performed by HF and DFT method. PMID- 24813276 TI - Development and validation of a rapid stability indicating HPLC-method using monolithic stationary phase and two spectrophotometric methods for determination of antihistaminic acrivastine in capsules. AB - Simple, rapid and accurate high performance liquid chromatographic (HPLC) and spectrophotometric methods are described for determination of antihistaminic acrivastine in capsules. The first method (method A) is based on accurate, sensitive and stability indicating chromatographic separation method. Chromolith(r) Performance RP-18e column, a relatively new packing material consisting of monolithic rods of highly porous silica, was used as stationary phase applying isocratic binary mobile phase of ACN and 25 mM NaH2PO4 pH 4.0 in the ratio of 22.5:77.5 at flow rate of 5.0 mL/min and 40 degrees C. A diode array detector was used at 254 nm for detection. The elution time of acrivastine was found to be 2.080+/-0.032. The second and third methods (methods B and C) are based on the oxidation of acrivastine with excess N-bromosuccinimide (NBS) and determination of the unconsumed NBS with, metol-sulphanilic acid (lambdamax: 520 nm) or amaranth dye (lambdamax: 530 nm). The reacted oxidant corresponds to the drug content. Beer's law is obeyed over the concentration range 1.563-50, 2.0-20 and 1.0-10 MUg mL(-1) for methods A, B and C, respectively. The limits of detection and quantitation were 0.40, 0.292 and 0.113 MUg mL(-1) and 0.782, 0.973 and 0.376 MUg mL(-1) for methods A, B and C, respectively. The HPLC method was validated for system suitability, linearity, precision, limits of detection and quantitation, specificity, stability and robustness. Stability tests were done through exposure of the analyte solution for four different stress conditions and the results indicate no interference of degradants with HPLC-method. The proposed methods was favorably applied for determination of acrivastine in capsules formulation. Statistical comparison of the obtained results from the analysis of the studied drug to those of the reported method using t- and F-tests showed no significant difference between them. PMID- 24813277 TI - Investigation of hydrogen bonds properties in the terephthalic acid crystal, using molecular dynamics method. AB - The aim of this study was to perform calculations using the method of Car Parrinello molecular dynamics, leading to the optimized geometry of the molecules of 1,4-benzenedicarboxylic acid (terephthalic acid) in crystals, for the hydrogen form and three variants of substitution of deuterium atoms inside a carboxyl group. Based on the results, trajectories and dipole moments were calculated, what makes possible to simulate vibrations in different systems, and to make calculation of theoretical infrared spectra and atomic power spectra. Theoretical results were compared with the experimental spectra, which verifies the correctness of the method and also was compared with the results obtained by quantum-mechanical calculations using DFT for the isolated dimer. Comparison of the spectra of different forms, allowed for in-depth analysis of the effect of isotopic substitution on the frequency of vibrations and shapes of bands, and confirm the presence of possible coupling effects and intra- and intermolecular interactions. Comparison with the DFT results for the dimer show influence of the crystal structure on the spectra. PMID- 24813278 TI - Structural, molecular orbital and optical characterizations of binuclear mixed ligand copper (II) complex of phthalate with N,N,N',N'-tetramethylethylenediamine and its applications. AB - A new binuclear mixed ligand complex, [Cu2(Phth)(Me4en)2(H2O)2(NO3)2].H2O (where, Phth=phthalate, and (Me4en)=N,N,N',N'tetramethylethylenediamine) was synthesized and characterized using analytical, spectral, magnetic, molar conductance, thermal gravimetric analysis (TGA), X-ray diffraction (XRD) and transmission electron microscope (TEM) measurements. The XRD data of Cu(II)-complex was analyzed on the basis of Williamson-Hall (W-H) and compared with TEM results. The results indicate that the complex is well crystalline and correspond to hexagonal crystal structure. Analysis of the absorption coefficient near the absorption edge reveals that the optical band gaps are indirect allowed transition with values of 1.17 and 1.78 eV. The d-d absorption bands of the complex (dissolved in various solvents) exhibit a color changes (solvatochromic). Specific and non specific interactions of solvent molecules with the complex were investigated using Multiple Linear Regression Analysis (MLRA). Transient photocurrent characteristics of Cu(II)-complex/n-Si heterojunctions indicate that photocurrent under illumination increase with increasing of light intensity and explained by continuous distribution of traps. Structural parameters of the free ligands and their Cu(II)-complex were calculated on the basis of semi-empirical PM3 level and compared with the experimental data. The present copper (II) complex was screened for its antimicrobial activity against some Gram-positive and Gram-negative bacteria and fungus strain. PMID- 24813279 TI - Spectroscopic and quantum chemical electronic structure investigations of 3,4 dihydrocoumarin and 3-methylcoumarin. AB - A complete vibrational analysis of 3,4-dihydrocoumarin and 3-methylcoumarin have been performed according to SQM force field method based on ab initio and DFT calculation 6-311++G(d,p) basis set and their frequencies are compared. The influences of carbon-oxygen bond and methyl group to the vibrational frequencies of the title compounds have been discussed. The pronounced decrease of the lone pair orbital occupancy and the molecular stabilization energy show the hyperconjugation interaction from the NBO analysis. Calculations of molecular orbital geometry show that the visible absorption maxima of DHC and 3MC correspond to the electron transition between frontier orbitals such as translation from HOMO to LUMO. Gauge-including atomic orbital (GIAO) 1H and 13C chemical shift calculations have been calculated. Area of high, neutral and low electrostatic potential is determined for DHC and 3MC. PMID- 24813280 TI - Vibrational (FT-IR and FT-Raman), electronic (UV-Vis), NMR (1H and 13C) spectra and reactivity analyses of 4,5-dimethyl-o-phenylenediamine. AB - The structure of 4,5-dimethyl-o-phenylenediamine (C8H12N2, DMPDA) was investigated on the basis of spectroscopic data and theoretical calculations. The sterochemical structure was determined by FT-IR, FT-Raman, UV, 1H and 13C NMR spectra. An experimental study and a theoretical analysis were associated by using the B3LYP method with Gaussian09 package program. FT-IR and FT-Raman spectra were recorded in the region of 4000-400 cm(-1) and 4000-10 cm(-1), respectively. The vibrational spectra were calculated by DFT method and the fundamental vibrations were assigned on the basis of the total energy distribution (TED), calculated with scaled quantum mechanics (SQM) method with Parallel Quantum Solutions (PQS) program. The UV absorption spectrum of the compound that dissolved in ethanol solution were recorded in the range of 190-400 nm. Total density of state (TDOS) and partial density of state (PDOS) of the DMPDA in terms of HOMOs and LUMOs were calculated and analyzed. Chemical shifts were reported in ppm relative to tetramethylsilane (TMS) for 1H and 13C NMR spectra. The compound was dissolved in dimethyl sulfoxide (DMSO). Also, 1H and 13C chemical shifts calculated using the gauge independent atomic orbital (GIAO) method. Mullikan atomic charges and other thermo-dynamical parameters were investigated with the help of B3LYP (DFT) method using 6-311++G** basis set. On the basis of the thermodynamic properties of the title compound at different temperatures have been carried out, revealing the correlations between heat capacity (C), entropy (S), enthalpy changes (H) and temperatures. The optimized bond lengths, bond angles, chemical shifts and vibrational wavenumbers showed the best agreement with the experimental results. PMID- 24813281 TI - Thermally induced single crystal to single crystal transformation leading to polymorphism. AB - The robust complex [La(1,10-phen)2(NO3)3] (1,10-phen=1,10-phenanthroline) exhibits thermally induced single crystal to single crystal transformation from one polymorphic phase to another. The complex crystallizes in monoclinic C2/c space group with C2 molecular symmetry at 293K while at 100K it shows P21/c space group with C1 molecular symmetry. Supramolecular investigation shows that at 100K the complex forms 2D achiral sheets whereas at 293K forms two different homochiral 2D sheets. Low temperature DSC analysis indicates that this structural transformation occurs at 246K and also this transformation is reversible in nature. We have shown that thermally induced coherent movement of ligands changes the molecular symmetry of the complex and leads to polymorphism. Photoluminescence property of complex has been studied in both solid state and in methanolic solution at room temperature. The effect of the presence low-lying LUMO orbital of pi-character in the complex is elucidated by theoretical calculation using DFT method. PMID- 24813282 TI - Comparison of pigment content of paint samples using spectrometric methods. AB - The aim of the paper was to evaluate the influence of pigment concentration and its distribution in polymer binder on the possibility of colour identification and paint sample comparison. Two sets of paint samples: one containing red and another one green pigment were prepared. Each set consisted of 13 samples differing gradually in the concentration of pigment. To obtain the sets of various colour shades white paint was mixed with the appropriate pigment in the form of a concentrated suspension. After solvents evaporation the samples were examined using spectrometric methods. The resin and main filler were identified by IR method. Colour and white pigments were identified on the base of Raman spectra. Colour of samples were compared based on Vis spectrometry according to colour theory. It was found that samples are homogenous (parameter measuring colour similarity DeltaE<3). The values of DeltaE between the neighbouring samples in the set revealed decreasing linear function and between the first and following one--a logarithmic function. PMID- 24813283 TI - Combined NIR/MIR analysis: a novel method for the classification of complex substances such as Illicium verum Hook. F. and its adulterants. AB - A novel combined near- and mid-infrared (NIR and MIR) spectroscopic method has been researched and developed for the analysis of complex substances such as the Traditional Chinese Medicine (TCM), Illicium verum Hook. F. (IVHF), and its noxious adulterant, Iuicium lanceolatum A.C. Smith (ILACS). Three types of spectral matrix were submitted for classification with the use of the linear discriminant analysis (LDA) method. The data were pretreated with either the successive projections algorithm (SPA) or the discrete wavelet transform (DWT) method. The SPA method performed somewhat better, principally because it required less spectral features for its pretreatment model. Thus, NIR or MIR matrix as well as the combined NIR/MIR one, were pretreated by the SPA method, and then analysed by LDA. This approach enabled the prediction and classification of the IVHF, ILACS and mixed samples. The MIR spectral data produced somewhat better classification rates than the NIR data. However, the best results were obtained from the combined NIR/MIR data matrix with 95-100% correct classifications for calibration, validation and prediction. Principal component analysis (PCA) of the three types of spectral data supported the results obtained with the LDA classification method. PMID- 24813284 TI - Coordination of Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Pd(II) and Pt(II) with 2,5-hexanedione bis(thiosemicarbazone), HBTS: crystal structure of cis-[Pd(HBTS)]Cl2 and 1-(2,5-dimethyl-1H-pyrrol-yl)-thiourea. AB - Metal complexes of Fe3+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+, Pd2+ or Pt2+ with 2,5-hexanedione bis(thiosemicarbazone), HBTS; have been prepared and spectroscopically investigated. The empirical formulae of the complexes were suggested based on the elemental analysis. Single crystal of Pd(II) has been solved to be cis-form of square-planar geometry by the X-ray crystallography. 1H and 13C NMR spectra have been recorded for HBTS, Zn(II), Cd(II), Hg(II), Pd(II) and Pt(II) complexes, in DMSO-d6, showing the mode of chelation. The ligand acts as a neutral or a binegative tetradentate (N2S2) or neutral bidentate on the basis of FT-IR. The magnetic moments and electronic spectra provide information about the geometry of the complexes which supported by calculating the ligand field parameters for the Co(II) and Fe(III) complexes. The Ni(II) complex has subnormal magnetic moment (0.71 BM) indicative of a mixed stereochemistry of square-planar and tetrahedral structure. [Cu(HBTS-2H)] measured 0.93 BM indicating high interaction between the copper centers. The ligand may be ordered at the top of the spectrochemical series which giving high ligand field splitting energy (10 Dq=17,900 cm(-1) for Co2+ complex). The mass spectra of some complexes proved their stable chemical formulae while the TGA depicts the degradation steps and the final residue. In evaporating the mother liquor during the preparation of HBTS, new compound is obtained naming 1-(2,5-dimethyl-1H-pyrrol-yl)thiourea and its crystal was solved. PMID- 24813285 TI - A selective, long-lived deep-red emissive ruthenium(II) polypyridine complexes for the detection of BSA. AB - A selective, label free luminescence sensor for bovine serum albumin (BSA) is investigated using ruthenium(II) complexes over the other proteins. Interaction between BSA and ruthenium(II) complexes has been studied using absorption, emission, excited state lifetime and circular dichroism (CD) spectral techniques. The luminescence intensity of ruthenium(II) complexes (I and II), has enhanced at 602 and 613 nm with a large hypsochromic shift of 18 and 5 nm respectively upon addition of BSA. The mode of binding of ruthenium(II) complexes with BSA has analyzed using computational docking studies. PMID- 24813286 TI - Hemoglobin fructation promotes heme degradation through the generation of endogenous reactive oxygen species. AB - Protein glycation is a cascade of nonenzymatic reactions between reducing sugars and amino groups of proteins. It is referred to as fructation when the reducing monosaccharide is fructose. Some potential mechanisms have been suggested for the generation of reactive oxygen species (ROS) by protein glycation reactions in the presence of glucose. In this state, glucose autoxidation, ketoamine, and oxidative advance glycation end products (AGEs) formation are considered as major sources of ROS and perhaps heme degradation during hemoglobin glycation. However, whether fructose mediated glycation produces ROS and heme degradation is unknown. Here we report that ROS (H2O2) production occurred during hemoglobin fructation in vitro using chemiluminescence methods. The enhanced heme exposure and degradation were determined using UV-Vis and fluorescence spectrophotometry. Following accumulation of ROS, heme degradation products were accumulated reaching a plateau along with the detected ROS. Thus, fructose may make a significant contribution to the production of ROS, glycation of proteins, and heme degradation during diabetes. PMID- 24813287 TI - On the spectroscopic analyses of Perylene-66. AB - In the present work, a combined experimental and theoretical study on molecular structure and vibrational frequencies of Perylene-66 were reported. The FT-IR spectrum of Perylene-66 is recorded in the solid phase. The equilibrium geometries, harmonic vibrational frequencies, thermo-chemical parameters, total dipole moment and HOMO-LUMO energies are calculated by DFT/B3LYP utilizing 6 311G(d,p) basis set. Results showed that Perylene-66 is highly recommended to be a promising structure for many applications in optoelectronic devices due to its high calculated dipole moment value (3.6 Debye) and lower HOMO-LUMO energy gap of 3.2 eV. PMID- 24813288 TI - Structure evolution characterization of Anyang anthracites via H2O2 oxidization and HF acidification. AB - The structural characteristics of the raw coal (AY), the H2O2 oxidized coals (AY H2O2) and the HF acidized AY-H2O2 (AY-H2O2-HF) were investigated by SEM, X-ray diffraction, Raman and FTIR spectroscopy. The results indicate that the derivative coals show an obvious increase in the aromaticity, crystalline carbon content and hydroxyl content, especially the AY-H2O2-HF. The stacking layer number of crystalline carbon decreases and the aspect ratio (La/Lc) remarkably increases for AY-H2O2 and AY-H2O2-HF. The crystalline layers become much thinner. The particle size of AY-H2O2-HF in width significantly decreases from 1 MUm to less than 100 nm. The combination of H2O2 oxidization and HF acidification is effective to reduce the size of the aromatic layers and to increase the reactivity of derivative coals. The process can help us obtain the superfine crystalline carbon materials like graphite structure. PMID- 24813289 TI - Transition-metal-doped ZnO nanoparticles: synthesis, characterization and photocatalytic activity under UV light. AB - ZnO nanoparticles doped with transition metals (Mn and Co) were prepared by a co precipitation method. The synthesized nanoparticles were characterized using X ray diffraction, scanning electron microscopy, energy dispersive X-rays, Fourier transform infrared spectroscopy, electron spin resonance spectroscopy and diffuse reflectance spectroscopy. The photocatalytic activities of the transition-metal doped ZnO nanoparticles were evaluated in the degradation of methyl orange under UV irradiation. ZnO nanoparticles doped with 12 at.% of Mn and Co ions exhibited the maximum photodegradation efficiency. The experiment also demonstrated that the photodegradation efficiency of Mn-doped ZnO nanoparticles was higher than that of Co-doped ZnO nanoparticles. These results indicate that charge trapping states due to the doping were the decisive factor rather than the average particle size and energy gap. Moreover the effect of pH values on the degradation efficiency was discussed in the photocatalytic experiments using 12 at.% Mn- and Co-doped ZnO nanoparticles. PMID- 24813290 TI - Studies on molecular structure, vibrational spectra and molecular docking analysis of 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate. AB - The molecular structure, vibrational analysis and molecular docking analysis of the 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate (MDDNAB) molecule have been carried out using FT-IR and FT-Raman spectroscopic techniques and DFT method. The equilibrium geometry, harmonic vibrational wave numbers, various bonding features have been computed using density functional method. The calculated molecular geometry has been compared with experimental data. The detailed interpretation of the vibrational spectra has been carried out by using VEDA program. The hyper-conjugative interactions and charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The simulated FT-IR and FT-Raman spectra satisfactorily coincide with the experimental spectra. The PES and charge analysis have been made. The molecular docking was done to identify the binding energy and the Hydrogen bonding with the cancer protein molecule. PMID- 24813291 TI - Quantum mechanical study and spectroscopic (FT-IR, FT-Raman, UV-Visible) study, potential energy surface scan, Fukui function analysis and HOMO-LUMO analysis of 3-tert-butyl-4-methoxyphenol by DFT methods. AB - This study represents an integral approach towards understanding the electronic and structural aspects of 3-tert-butyl-4-methoxyphenol (TBMP). Fourier-transform Infrared (FT-IR) and Fourier-transform Raman (FT-Raman) spectra of TBMP was recorded in the region 4000-400 cm(-1) and 3500-100 cm(-1), respectively. The molecular structures, vibrational wavenumbers, infrared intensities and Raman activities were calculated using DFT (B3LYP and LSDA) methods using 6-311++G (d,p) basis set. The most stable conformer of TBMP was identified from the computational results. The assignments of vibrational spectra have been carried out with the help of normal co-ordinate analysis (NCA) following the scaled quantum mechanical force field (SQMFF) methodology. The first order hyperpolarizability (beta0) and related properties (beta, alpha0 and Deltaalpha) of TBMP have been discussed. The stability and charge delocalization of the molecule was studied by Natural Bond Orbital (NBO) analysis. UV-Visible spectrum and effects of solvents have been discussed and the electronic properties such as HOMO and LUMO energies were determined by time-dependent TD-DFT approach with B3LYP/6-311++G (d,p) level of theory. The molecule orbital contributions are studied by density of energy states (DOSs). The reactivity sites are identified by mapping the electron density into electrostatic potential surface (MEP). Mulliken analysis of atomic charges is also calculated. The thermodynamic properties at different temperatures were calculated, revealing the correlations between standard heat capacities, standard entropy and standard enthalpy changes with temperatures. Global hardness, global softness, global electrophilicity and ionization potential of the title compound are determined. PMID- 24813292 TI - Natural bond orbital analysis, electronic structure and vibrational spectral analysis of N-(4-hydroxyl phenyl) acetamide: a density functional theory. AB - The Fourier transform infrared (FT-IR) and FT-Raman spectra of N-(4-hydroxy phenyl) acetamide (N4HPA) of painkiller agent were recorded in the region 4000 450 cm(-1) and 4000-50 cm(-1) respectively. Density functional theory (DFT) has been used to calculate the optimized geometrical parameter, atomic charges, and vibrational wavenumbers and intensity of the vibrational bands. The computed vibrational wave numbers were compared with the FT-IR and FT-Raman experimental data. The computational calculations at DFT/B3LYP level with 6-31G(d,p), 6 31++G(d,p), 6-311G(d,p) and 6-311++G(d,p) basis sets. The complete vibrational assignments were performed on the basis of the potential energy distribution (PED) of the vibrational modes calculated using Vibrational energy distribution analysis (VEDA 4) program. The oscillator's strength calculated by TD-DFT and N4HPA is approach complement with the experimental findings. The NMR chemical shifts 13C and 1H were recorded and calculated using the gauge independent atomic orbital (GIAO) method. The molecular electrostatic potential (MESP) and electron density surfaces of the molecule were constructed. The Natural charges and intermolecular contacts have been interpreted using Natural Bond orbital (NBO) analysis the HOMO-LUMO energy gap has been calculated. The thermodynamic properties like entropy, heat capacity and zero vibrational energy have been calculated. PMID- 24813293 TI - La(III) complex involving the O,N-donor environment of quinazoline-4(3H)-one Schiff's base and their antimicrobial attributes against methicillin-resistant Staphylococcus aureus (MRSA). AB - The incidence of methicillin-resistant Staphylococcus aureus increased during the past few decades, so there is an urgent need of new antimicrobial agents if public health is concerned. Though the Schiff's bases and La(III) complex have enormous biological activity, but less attention was given in their synthesis. In the present investigation, we synthesized a new (E)-3-((2-hydroxynaphthalen-1-yl) methyleneamino)-2-methylquinazoline-4(3H)-one HNMAMQ Schiff's base by the condensation of 3-(2-aminophenyl) quinazolin-2-methyl-4(3H)-one and 2-hydroxy-1 naphthaldehyde. The Schiff's base HNMAMQ and its La(III) complex were characterized by elemental analyses, IR, NMR, mass spectra, and thermal studies. The newly synthesized Schiff's base HNMAMQ and its La(III) complex were evaluated for their antimicrobial activity against methicillin-resistant Staphylococcus aureus isolated from the Gulbarga region in India. The Schiff's base HNMAMQ and its La(III) complex showed good antimicrobial activity and thus represents a potential new drug of choice. PMID- 24813294 TI - Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice. AB - Mas-related G-protein-coupled receptor subtype C (mouse MrgC11 and rat rMrgC), expressed specifically in small-diameter primary sensory neurons, may constitute a novel pain inhibitory mechanism. We have shown previously that intrathecal administration of MrgC-selective agonists can strongly attenuate persistent pain in various animal models. However, the underlying mechanisms for MrgC agonist induced analgesia remain elusive. Here, we conducted patch-clamp recordings to test the effect of MrgC agonists on high-voltage-activated (HVA) calcium current in small-diameter dorsal root ganglion (DRG) neurons. Using pharmacological approaches, we show for the first time that an MrgC agonist (JHU58) selectively and dose-dependently inhibits N-type, but not L- or P/Q-type, HVA calcium channels in mouse DRG neurons. Activation of HVA calcium channels is important to neurotransmitter release and synaptic transmission. Patch-clamp recordings in spinal cord slices showed that JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury. These findings indicate that activation of endogenously expressed MrgC receptors at central terminals of primary sensory fibers may decrease peripheral excitatory inputs onto SG neurons. Together, these results suggest potential cellular and molecular mechanisms that may contribute to intrathecal MrgC agonist-induced analgesia. Because MrgC shares substantial genetic homogeneity with human MrgX1, our findings may suggest a rationale for developing intrathecally delivered MrgX1 receptor agonists to treat pathological pain in humans and provide critical insight regarding potential mechanisms that may underlie its analgesic effects. PMID- 24813295 TI - Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury. AB - Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na(+)-K(+)-2Cl(-) (NKCC1) and neuron-specific K(+)-Cl(-) (KCC2) cotransporters are involved in setting the strength and polarity of GABAergic/glycinergic transmission. After nerve injury, the balance between these cotransporters changes, leading to a decrease in the inhibitory tone. However, the role that NKCC1 and KCC2 play in pain-processing brain areas is unknown. Our goal was to study the effects of peripheral nerve injury on NKCC1 and KCC2 expression in dorsal root ganglia (DRG), spinal cord, ventral posterolateral (VPL) nucleus of the thalamus, and primary somatosensory (S1) cortex. After sciatic nerve section and suture in adult rats, assessment of mechanical and thermal pain thresholds showed evidence of hyperalgesia during the following 2 months. We also found an increase in NKCC1 expression in the DRG and a downregulation of KCC2 in spinal cord after injury, accompanied by later decrease of KCC2 levels in higher projection areas (VPL and S1) from 2 weeks postinjury, correlating with neuropathic pain signs. Administration of bumetanide (30 mg/kg) during 2 weeks following sciatic nerve lesion prevented the previously observed changes in the spinothalamic tract projecting areas and the appearance of hyperalgesia. In conclusion, the present results indicate that changes in NKCC1 and KCC2 in DRG, spinal cord, and central pain areas may contribute to development of neuropathic pain. PMID- 24813296 TI - Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats. AB - Serotonin (5-HT) plays pivotal roles in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5-HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2 arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT 3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD, the anandamide synthesizing enzyme) protein gradually declined from day 1 to 5. The time dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS. PMID- 24813297 TI - Basal inflammation and innate immune response in chronic multisite musculoskeletal pain. AB - Dysregulation of the immune system may play a role in chronic pain, although study findings are inconsistent. This cross-sectional study examined whether basal inflammatory markers and the innate immune response are associated with the presence and severity of chronic multisite musculoskeletal pain. Data were used on 1632 subjects of the Netherlands Study of Depression and Anxiety. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multisite musculoskeletal pain. Subjects were categorized in a chronic multisite musculoskeletal pain group (n=754) and a control group (n=878). Blood levels of the basal inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were determined. To obtain a measure of the innate immune response, 13 inflammatory markers were assessed after lipopolysaccharide (LPS) stimulation in a subsample (n=707). Subjects with chronic multisite musculoskeletal pain showed elevated levels of basal inflammatory markers compared with controls, but statistical significance was lost after adjustment for lifestyle and disease variables. For some LPS-stimulated inflammatory markers, we did find elevated levels in subjects with chronic multisite musculoskeletal pain both before and after adjustment for covariates. Pain severity was not associated with inflammation within chronic pain subjects. An enhanced innate immune response in chronic multisite musculoskeletal pain may be examined as a potential biomarker for the onset or perpetuation of chronic pain. PMID- 24813299 TI - CD8(+) granulomatous cutaneous T-cell lymphoma: a potential association with immunodeficiency. AB - BACKGROUND: Granulomatous cutaneous T-cell lymphoma (G-CTCL) is a rarely encountered entity. Most G-CTCL is CD4(+), with granulomatous mycosis fungoides representing the vast majority of cases. Because of the rarity of CD8(+) G-CTCL, there is a paucity of data regarding the clinicopathologic features and expected course. OBJECTIVE: To describe the clinical and histopathologic features of G CTCL. METHODS: This is a retrospective review of collected cases. RESULTS: We present 4 cases of CD8(+) G-CTCL. Patients presented with papules and nodules on the trunk and extremities without antecedent patch or plaque disease. In all cases, biopsy specimens were obtained, and these revealed a dense granulomatous infiltrate accompanied by an atypical lymphoid infiltrate of CD8(+) T cells. T cell clonality studies were positive in 3 of 4 cases. Staging was negative for nodal involvement, but lung granulomas were seen in all cases. In all 4 cases, the patient's medical history was significant for immunodeficiency, either primary or iatrogenic. All 4 patients had slowly progressive disease. LIMITATIONS: This is a small retrospective case series. CONCLUSIONS: CD8(+) G CTCL appears to be associated with immunodeficiency. The finding of a CD8(+) G CTCL should prompt an evaluation for underlying immunodeficiency. Additional studies are required to validate these conclusions. PMID- 24813298 TI - Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. AB - Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option. PMID- 24813300 TI - Application of Mohs micrographic surgery appropriate-use criteria to skin cancers at a university health system. AB - BACKGROUND: Mohs micrographic surgery (MMS) is an effective treatment for skin cancer. Until recently, it has been difficult to determine the percentage of skin cancers best treated with MMS. The appropriate-use criteria represents an opportunity to more accurately estimate this number. OBJECTIVE: We sought to apply the appropriate-use criteria retrospectively to University of Virginia Health System skin cancers so as to determine the proportion that met appropriate use within 8 months. METHODS: A list of all biopsy-proven skin cancers, excluding invasive melanoma, at the University of Virginia Health System during an 8-month period was generated. Patient and tumor data were collected retrospectively from hospital records and each skin cancer was classified as appropriate, inappropriate, or uncertain based on the appropriate-use criteria. RESULTS: Among 1059 skin cancers, MMS was appropriate in 72.0% of cases, inappropriate in 20.4%, and uncertain in 7.6%. Altogether, 59.3% of skin cancers occurred in H and M areas, which include the head, neck, hands, feet, ankles, genitalia, nipples/areola, and pretibial surface. LIMITATIONS: Patient and tumor information was collected retrospectively at 1 institution. CONCLUSIONS: Using recently published appropriate-use criteria, 72.0% of skin cancers at this institution were appropriate for MMS. Tumor location was the most important factor in determining appropriate use. PMID- 24813301 TI - Commentary: Implementation of the appropriate-use criteria will not increase Mohs micrographic surgery utilization. PMID- 24813303 TI - Effect of Tran on virulence through regulating metabolism and stress tolerance of Streptococcus suis serotype 2. AB - Streptococcus suis (SS) is an important zoonotic pathogen causing a variety of life-threatening infections in pigs and humans. Tran, a novel transcriptional regulator which was identified to be an infection-related factor in S. suis serotype 2 using suppression subtractive hybridization (SSH), has been reported by our group. In this study, a tran deletion mutant was constructed to compare with the wild-type ZY05719 in some biological characteristics. It is suggested that longer chains and relatively slower growth could be observed in tran deletion mutants. In order to identify gene transcription profiles, microarray analysis was performed. It indicated that the inactivation of Tran led to 130 differentially expressed genes spread throughout the genome. Among these, 21 genes were upregulated, and 109 genes were downregulated. Most of the differentially expressed genes were involved in bacterial metabolism, such as the phosphotransferase system (PTS), and heat shock proteins. In the case of glucose scarcity, the growth characteristics of tran deletion mutants were impacted significantly, meanwhile Deltatran mutant was highly sensitive to environmental stresses. Moreover, cell adherence decreased by 22.2%, and virulence in zebrafish declined to more than five times in Deltatran mutants. These data demonstrate the role of Tran in regulation in S. suis serotype 2, that is affect bacterial virulence by influencing bacterial metabolism and stress tolerance of external environment. PMID- 24813304 TI - StSTE12 is required for the pathogenicity of Setosphaeria turcica by regulating appressorium development and penetration. AB - In filamentous fungi, the pathogenic mitogen-activated protein kinase (PMK) pathway performs an important function in plant infection. STE12-like genes found in higher eukaryotes encode transcription factors and are regulated by the PMK pathway. However, the functions of STE12-like genes in foliar pathogens remain poorly understood. In this study, we cloned StSTE12 from Setosphaeria turcica and investigated its functions by RNA interference. Transformants ste12-3, ste12-2 and, ste12-1, in which the StSTE12 silencing efficiency increased in order, were confirmed by real time PCR. Compared with the wild-type (WT) strain, the transformants showed reduced growth rate, lighter colony color, and obviously decreased conidium production. More importantly, different to WT strain and ste12 3 with lower StSTE12silencing efficiency, ste12-1 and ste12-2 with higher StSTE12 silencing efficiency were nonpathogenic on intact leaves, but pathogenic on wounded leaves. However, the biological activity of HT-toxin from all transformants showed no difference on corn leaves. Furthermore, ste12-1 and ste12 2 did not penetrate artificial cellophane membrane and showed abnormal and delayed development appressoria. Although it could penetrate the cellophane membranes, ste12-3 formed appressoria after 48 h of inoculation more than WT. Therefore, StSTE12 was involved in vegetative growth, conidiation, appressorial development, penetration as well as the pathogenicity, but it was not related to HT-toxin biosynthesis. More interestingly, all the results suggested that StSTE12 was crucial for pathogenicity due to involvement in regulating appressoria development and penetration. PMID- 24813302 TI - Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. AB - Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence. PMID- 24813305 TI - Large unruptured sinus of valsalva aneurysm dissecting into interventricular septum and presenting as a complex myocardial cystic mass. AB - Unruptured aneurysm of sinus of Valsalva (SOV) is extremely rare. They may be asymptomatic and diagnosed incidentally or can present with either fatal outcome following rupture or manifest acutely with compression of surrounding structures. Dissection of unruptured aneurysm of left SOV into interventricular septum (IVS) and presenting as intramyocardial mass is not reported in the literature. We are reporting a case of 21-year-old man who was referred to us following a seizure episode and was incidentally diagnosed with aneurysm of left SOV dissecting into IVS. Multimodality imaging confirmed the diagnosis. He successfully underwent surgical repair and was asymptomatic during follow-up. PMID- 24813306 TI - Circulating adipocyte fatty acid binding protein is increased in chronic and acute renal dysfunction. AB - BACKGROUND AND AIMS: The adipokine adipocyte fatty acid binding protein (AFABP) is positively associated with the development of the metabolic syndrome, diabetes mellitus, and cardiovascular disease. We hypothesized that AFABP also increases with deteriorating renal function. METHODS AND RESULTS: Serum AFABP levels were quantified by enzyme linked immunosorbent assay in 532 patients with chronic kidney disease (CKD) covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5 (study population 1). Furthermore, AFABP was measured in 32 patients before and within 30 h after elective unilateral nephrectomy, a model of acute kidney dysfunction (AKD) (study population 2). Moreover, circulating AFABP was investigated in rats undergoing bilateral nephrectomy (BNE) as compared to sham-operated animals. Median serum AFABP levels adjusted for age, gender, and body mass index significantly increased with increasing eGFR category (G1: 22.0 MUg/l; G2: 34.6 MUg/l; G3: 56.7 MUg/l; G4: 95.2 MUg/l; and G5: 173.9 MUg/l). Furthermore, renal dysfunction remained positively associated with AFABP in multivariate analysis in this cohort. In patients undergoing unilateral nephrectomy, AFABP increased significantly after surgery (42.1 MUg/l) as compared to pre-surgical values (29.3 MUg/l). Furthermore, relative changes of post-to-pre-surgical AFABP levels were independently associated with relative changes of post-to-pre-surgical creatinine concentrations. After BNE in rats, AFABP increased significantly as compared to sham-operated animals. CONCLUSIONS: We show that AFABP is significantly elevated in CKD and AKD patients. Furthermore, measures of renal function are associated with circulating AFABP. Moreover, animal experiments indicate that AFABP levels strongly depend on renal function. PMID- 24813307 TI - Painful and painless channelopathies. AB - The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Nav1.8 (SCN10A) and Nav1.9 (SCN11A) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively. Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development-eg, using human sensory neurons differentiated from human induced pluripotent stem cells. Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development. PMID- 24813308 TI - Combined effect of serum gamma-glutamyltransferase and uric acid on Framingham risk score. AB - BACKGROUND AND AIMS: Gamma-glutamyltransferase (GGT) and uric acid (UA) are novel coronary heart disease (CHD) risk factors. In the present study we investigated the combined effects of GGT and UA on Framingham risk score (FRS) in a Korean population. METHODS: A total of 10,096 subjects (5,124 females and 4,972 males) were enrolled in this study. A 10-year coronary heart disease (CHD) risk was calculated using the FRS modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). Levels of circulating GGT and UA were measured using validated assays. RESULTS: The 10-year CHD risk gradually augmented with increase in the circulating levels of GGT and UA. For the highest quartile of GGT and UA, odds ratio (OR) of intermediate-risk and beyond for CHD (10-year risk >=10%) compared with the lowest quartile was 3.44 (95% CI: 2.60 4.55, p <0.001) and 1.97 (95% CI: 1.56-4.55, p <0.001) after adjusting for confounders, respectively. OR of intermediate-risk and beyond for CHD in both 3(rd) and 4(th) quartile of GGT and UA was 9.9 (95% CI: 5.2-18.6) compared with the first quartile of those. CONCLUSIONS: GGT and UA levels are well associated with the 10-year CHD risk estimated using NCEP ATP III in Koreans after adjusting for confounders and combination of GGT and UA levels can have a strong synergy in predicting the development of CHD. PMID- 24813309 TI - Survival analysis of pure seminoma at post-chemotherapy retroperitoneal lymph node dissection. AB - PURPOSE: Viable seminoma encountered at post-chemotherapy retroperitoneal lymph node dissection for pure testicular seminoma is rare due to the chemosensitivity of this germ cell tumor. In this study we define the natural history of viable seminoma at post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: The Indiana University testis cancer database was queried from 1988 to 2011 to identify all patients with primary testicular or retroperitoneal pure seminoma and who were found to have pure seminoma at post-chemotherapy retroperitoneal lymph node dissection. Clinical characteristics were reviewed and survival analysis was performed. RESULTS: A total of 36 patients met the study inclusion criteria. All patients received standard first line cisplatin based chemotherapy and 17 received salvage chemotherapy. The decision to proceed to retroperitoneal lymph node dissection was based on enlarging retroperitoneal mass and/or positron emission positivity in the majority of cases. Seven patients had undergone previous retroperitoneal lymph node dissection. Additional surgical procedures were required in 19 patients to achieve a complete resection. The 5 year cancer specific survival rate was 54%. However, only 9 of 36 patients remained continuously free of disease and of these patients 4 received adjuvant chemotherapy. Mean time from post-chemotherapy retroperitoneal lymph node dissection to death was 6.9 months. Second line chemotherapy, reoperative retroperitoneal lymph node dissection and earlier era of treatment were associated with poorer cancer specific survival. CONCLUSIONS: A total of 36 patients with pure seminoma were found to have viable pure seminoma at post chemotherapy retroperitoneal lymph node dissection. While 5-year cancer specific survival was 54%, these surgeries are technically demanding and only a minority of patients achieves a durable cure from surgery alone. PMID- 24813310 TI - Efficacy and safety of sirolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: a systematic review. AB - PURPOSE: We evaluate the efficacy and safety of sirolimus in the treatment of renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. MATERIALS AND METHODS: A systematic search of MEDLINE(r), Embase(r), ACP (American College of Physicians) Journal Club, Cochrane CENTRAL (Central Register of Controlled Trials) and Cochrane Database of Systematic Reviews was performed. A secondary hand search was performed in relevant journals, references and the grey literature. The screening, quality assessment and data extraction of the retrieved articles were independently performed by 2 reviewers in duplicate. Studies that reported an angiomyolipoma response or adverse events after the treatment of sirolimus were included in the analysis. RESULTS: Four prospective nonrandomized studies involving 94 patients were included in the study. The overall response rate of angiomyolipoma was 46.8% (44 of 94) in the first year. In the second year the angiomyolipoma response rate for those patients still being treated with sirolimus was 43.5% (20 of 46) and the response rate of the patients whose sirolimus treatment was discontinued was 5% (2 of 40). The most common sirolimus related adverse reactions were stomatitis, respiratory infection, skin lesions and hyperlipidemia, while serious adverse reactions were rarely observed. CONCLUSIONS: This study shows that renal angiomyolipoma shrank during sirolimus therapy but tended to regrow after the therapy was stopped. In general, sirolimus is an effective and safe therapy for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. PMID- 24813311 TI - Emerging role of mitochondria dysfunction in the onset of neurodegenerative diseases. AB - Mitochondria play a pivotal role in a number of biochemical processes in the neuron including energy metabolism and ATP production, intracellular Ca2+ homeostasis and cell signalling which are all implicated in the regulation of neuronal excitability. For this reason, it is not surprising that alterations in mitochondrial function have emerged as a hallmark of aging and various age related neurodegenerative diseases in which a progressive functional decline of mitochondria has been described. The evidence that mitochondria are concentrated in synapses, together with the observation that synaptic dysfunction identifies an early forerunner of a later neurodegeneration, strongly suggests that significant alterations to synaptic mitochondrial localization, number, morphology, or function can be detrimental to synaptic transmission and might characterize the early stages of many neurological diseases. Thus, the characterization of both molecular players and pathway involved in mitochondria dysfunction will provide new chances to identify pharmacological target for new mitochondria-based drugs aimed at interrupting or slowing down pathological processes and/or ameliorating symptoms of neurological disorders. In this review we provide a current view on the role of mitochondria for neuronal function and how mitochondrial functions impinge on neurological diseases. PMID- 24813312 TI - Nitric oxide and sphingolipids control apoptosis and autophagy with a significant impact on Alzheimer's disease. AB - Aberrant regulation of signalling pathways promoting and regulating apoptosis and autophagy contributes to the development of most human neurodegenerative diseases characterised by progressive dysfunction and death of neuronal and glial cells. Both in central and peripheral nervous systems cell death is either apoptotic or autophagic, depending on the cellular setting and the initial pathogenic cue. While some mixed phenotypes have been reported, apoptosis and autophagy tend to develop into mutually exclusive ways to such an extent that they inhibit each other. The sphingolipid ceramide is a key intracellular signalling molecule involved in many cellular processes leading to either survival or death; in most of these processes also the short-lived gaseous messenger nitric oxide (NO) plays a crucial role. The crosstalk between these two messengers and their downstream mediators has been thus extensively investigated and we now have a deep understanding of it and of its multiple feedback controls. What we provide here are details on how NO- and sphingolipid-dependent signalling and their crosstalk impact on degenerative brain diseases, in particular Alzheimer?s disease; we also describe how the ability of these molecules to regulate autophagy and apoptosis plays a significant role in determining the pathogenic evolution of these diseases. The evidence reported in this review suggests that targeting the NO and sphingolipid-dependent signalling pathways is worth exploiting in therapeutic perspective. In order to pursue these strategies, however, we still need to understand conclusively how the crosstalk between the NO and ceramide/sphingolipid pathways balances towards beneficial vs. toxic effects. In view of the nature of the signalling pathways involved and their multiple roles, the type of crosstalk involved is complex and intermingled with other signalling pathways. PMID- 24813313 TI - Cholesterol metabolism-associated molecules in late onset Alzheimer's disease. AB - Alzheimer?s disease (AD) is the most common cause of dementia and, with an aging population, poses a huge public health problem. Although a small per cent is caused by single gene changes, most AD is sporadic and unexplained. Of many modifying factors, changes in brain cholesterol homeostasis are the best studied. We present a review of the role of altered cholesterol metabolism and hypercholesterolemia in APP processing and Abeta generation. We also provide an overview of the potential pharmacological modulation of cholesterol homeostasis in the brain by cholesterol-lowering agents and beta-cyclodextrins. PMID- 24813314 TI - Pharmacological modulation of long-term potentiation in animal models of Alzheimer'?s disease. AB - The discovery of long-term potentiation (LTP) of hippocampal synaptic transmission, which represents a classical model for learning and memory at the cellular level, has stimulated over the past years substantial progress in the understanding of pathogenic mechanisms underlying cognitive disorders, such as Alzheimer?s disease (AD). Multiple lines of evidence indicate synaptic dysfunction not only as a core feature but also a leading cause of AD. Multiple pathways may play a significant role in the execution of synaptic dysfunction and neuronal death triggered by beta-amyloid (Abeta) in AD. Following intensive investigations into LTP in AD models, a variety of compounds have been found to rescue LTP impairment via numerous molecular mechanisms. Yet very few of these findings have been successfully translated into disease-modifying compounds in humans. This review recapitulates the emerging disease-modifying strategies utilized to modulate hippocampal synaptic plasticity with particular attention to approaches targeting ligand-gated ion channels, G-protein-coupled receptors (GPCRs), Receptor Tyrosine Kinases (RTKs) and epigenetic mechanisms. It is hoped that novel multi-targeted drugs capable of regulating spine plasticity might be effective to counteract the progression of AD and related cognitive syndromes. PMID- 24813315 TI - Bimodal effect of D-aspartate on brain aging processes: insights from animal models. AB - Nowadays it is widely recognized that D-amino acids are present in bacteria as well as in eukaryotes, including mammals. In particular, free D-serine and D aspartate are found in the brain of mammals. Notably, D-aspartate occurs at substantial levels in the embryo brain to then consistently decrease at post natal phases. Temporal regulation of D-aspartate content depends on the post natal onset of D-aspartate oxidase expression, the only known enzyme able to catabolize this D-amino acid. Pharmacological evidence indicates that D-aspartate binds and activates NMDA receptors (NMDARs). To decipher the physiological function of D-aspartate in mammals, in the last years, genetic and pharmacological mouse models with abnormally higher levels of this D-amino acid have been generated. Overall, these animal models have pointed out a significant neuromodulatory role for D-aspartate in the regulation of NMDAR-dependent functions. Indeed, increased content of D-aspartate are able to increase hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory of adult mice. However, if exposure to elevated levels of D-Asp lasts for the entire lifetime of mice, enhancement of synaptic plasticity turns into a dramatic worsening, thus triggering an acceleration of the NMDAR-dependent aging processes in the hippocampus. Nonetheless, administration of D-Asp to old mice can restore the physiological age-related decay of hippocampal NMDA-related LTP. Besides its effect on hippocampus-dependent processes in mouse models, different points of evidence are indicating, today, a potential role for D-Asp in neurologic and psychiatric disorders associated with aberrant signalling of NMDARs. PMID- 24813316 TI - Endocannabinoid signaling in Alzheimer?s disease: current knowledge and future directions. AB - The importance of the endocannabinoid system (ECS) in the modulation functions of the central nervous system has been extensively investigated during the last few years. In particular, accumulated evidence has implicated ECS in the pathophysiology of Alzheimer?s disease (AD), that is a progressive, degenerative, and irreversible disorder characterized by the accumulation in the brain of beta amyloid fragments forming insoluble plaques, and of intracellular neurofibrillary tangles (NTFs) associated with synaptic and neuronal loss. In all the processes involved in the formation of both plaques and NFTs, the key-role played by the ECS has been documented. Here, we review current knowledge and future directions of ECS modulation both in animal models of AD and in human tissues, underlying the role of endocannabinoid signaling in the development of AD hallmarks. Overall, the available data suggest that next generation therapeutics might target distinct ECS elements, for instance CB2 receptor or fatty acid amide hydrolase, as a promising approach to halt or at least to slow down disease progression. PMID- 24813317 TI - The heme oxygenase/biliverdin reductase system: a potential drug target in Alzheimer?s disease. AB - Alzheimer?s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of cognitive function, the inability to perform the activities of daily living and psychiatric symptoms. The formation of toxic aggregates of amyloid-beta-peptide (Abeta), through the activities of beta - and gamma- secretases, is considered as the earlier event in the pathogenesis of the disease. The deposition of both Abeta and the following hyperphosphorylation of tau protein, trigger an exaggerate immune-inflammatory response culminating with the production of excess reactive oxygen and nitrogen species responsible for damage on cellular nucleic acids, proteins and lipids. One of the mechanisms used by neural cells to counteract oxidative/nitrosative damage in AD is the enhancement of the cell stress response. Among the main components of the cell stress response is the heme oxygenase/biliverdin reductase (HO/BVR) axis, which catalyzes the degradation of heme which is toxic if produced in excess or under redox unbalanced conditions. However, the HO/BVR system and its by-products, carbon monoxide and bilirubin, have also been shown to be neuroprotective by activating pro-survival pathways and scavenging free radicals. Nevertheless, recent research demonstrated as both the inducible isoform of HO, known as HO-1, and BVR undergo oxidative/nitrosative/phosphorylative post-translational modifications in AD brain which alter the ability of HO-1 and BVR to activate the cell stress response. In this light, naturally occurring substances or drugs (e.g. statins) that prevent the post-translational modifications leading to a controlled up-regulation of the HO/BVR system have been proposed as potential new tools for the treatment of AD. PMID- 24813318 TI - Intrabodies for protein interference in Alzheimer?s disease. AB - Several open questions call for new studies on pathogenic mechanisms leading to Alzheimer?s Disease (AD), with the search for upstream drivers of the neurodegeneration cascade, such as neurotrophic deficits, early misfolding events of AD-related proteins (Abeta and tau) and understanding the multifactorial basis of AD pathogenesis. Since seminal immunosympathectomy experiment which represents the first example of a knock out experiment (albeit a protein knock-out), antibodies have had a long and successful history as a tool to selectively interfere with the function of proteins in cells and in organisms and antibody technologies represent a major weapon in the set of target validation techniques. Here, we describe a technology, pioneered by our group, based on recombinant antibody domains exploited as intracellular antibodies (intrabodies) whereby antibodies are used as genes, rather than as proteins. We discuss several applications and new promising developments of the intrabody approach for protein interference, especially in the field of AD research. PMID- 24813319 TI - Potential neurodegenerative effect of anabolic androgenic steroid abuse. AB - Anabolic androgenic steroids (AASs) are synthetic androgen-like compounds which are abused in sport communities despite their side effects. AAS abuse has been coupled with several medical complications, such as sterility, gynecomastia, and increased risk of cardiovascular and hepatic diseases. More recently, it has been observed that non-medical use of these steroids is frequently associated with changes in mood as well as cognitive deficits. Although the nature of this association is still largely unexplored, recent animal studies have shown the neurodegenerative potential of these compounds ranging from neurotrophin unbalance to increased neuronal susceptibility to apoptotic stimuli. Hence, exposure to AASs may result in a compromised brain, more susceptible, later in life, to the onset or progression of diseases not usually linked to drug abuse, especially neurodegenerative diseases. PMID- 24813320 TI - NeuroAIDS: virological aspects of HIV infection. AB - NeuroAIDS is one of the main complications of chronic HIV-infection. The Central Nervous System is an immunologic sanctuary for HIV and allows the persistence of the virus despite an efficient antiretroviral therapy. HIV-1 could promote the neurodegeneration through the induction of inflammation by the release of neurotoxins from infected cells. In addition, several viral proteins can directly contribute to the neuronal damages, activate cell-signaling involved in the control of cellular survival and apoptosis, favoring functional alterations in the target cells. Macrophages play a key role in the pathogenesis of NeuroAIDS, they are the main reservoirs of the infection in brain, promoting the inflammatory escalation, astrogliosis and degeneration process. This review aims to highlight the virological aspects associated with NeuroAIDS including pathogenesis, and treatment of HIV-1 in the CNS sanctuaries. PMID- 24813321 TI - Magnetic resonance imaging evaluation of normal glenoid length and width: an anatomic study. AB - PURPOSE: The purpose of this study was to evaluate the measured dimensions of the normal glenoid on sagittal magnetic resonance (MR) imaging to determine whether a fixed ratio of glenoid length and width can be determined. METHODS: MR images of 90 glenoids in 84 patients were analyzed. The mean age was 54.8 years, with 44 male and 40 female patients. Glenoid length and width at the widest dimension were measured and recorded by 3 independent examiners. The ratio of length to width and the ratio of the length of the superior pole at the widest point to the total length were calculated. Intraclass correlation coefficients, Spearman and Pearson correlations, regression analysis with cross validation, and coefficients of variation were calculated. RESULTS: The mean glenoid length was 37.5 +/- 3.8 mm, whereas the mean width was 24.4 +/- 2.9 mm. The mean ratio of length to width was 1.55 +/- 0.1, whereas the mean ratio of the distance from the superior pole to the widest point to the total glenoid length was 0.64 +/- 0.03. The calculated ratios were less variable than the absolute length and width. Cross validation of length for width showed a 95% prediction band width of 4.48 mm, with an average absolute error of prediction of 1.46 mm, and was equally specific when separated by gender. The width was equal to 0.65 times the length. CONCLUSIONS: Measurement of glenoid length and width using MR imaging results in a consistent ratio of length to width independent of patient age and gender, where the width was equal to 0.65 times the length at a point two-thirds along the inferosuperior axis. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24813322 TI - Ultrasound-guided barbotage for calcific tendonitis of the shoulder: a systematic review including 908 patients. AB - PURPOSE: A systematic review was performed to assess the outcomes and complications of ultrasound-guided barbotage (repeated injection and aspiration) for calcific tendonitis of the shoulder. METHODS: A literature search of the Medline, Embase, and Cochrane databases using all relevant keywords found 1,454 original articles. After removal of duplicates and application of inclusion criteria, 13 original articles were selected for review. Articles that used fluoroscopic guidance rather than ultrasound guidance were excluded from the review. All studies analyzed except 1 were case series, with no comparative studies being available. RESULTS: Thirteen articles with a total of 908 patients were analyzed. In all articles reviewed, the authors reported a good clinical outcome, with many achieving marked improvement in clinical scores or overall satisfaction with the treatment. CONCLUSIONS: Ultrasound-guided barbotage is a safe technique, with a high success rate and low complication rate. There is no evidence assessing its effectiveness compared with other major treatment modalities; a randomized trial comparing ultrasound-guided barbotage, extracorporeal shock wave therapy, and arthroscopic calcific deposit excision would be of great value. However, while awaiting such a trial, on the basis of the results of this systematic review, we can recommend ultrasound-guided barbotage. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 24813323 TI - Prevention of venous thromboembolic events with low-molecular-weight heparin in the non-major orthopaedic setting: meta-analysis of randomized controlled trials. AB - PURPOSE: To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. METHODS: A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. RESULTS: Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). CONCLUSIONS: This meta analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. LEVEL OF EVIDENCE: Level II, meta-analysis of Level II studies or Level I studies with inconsistent results. PMID- 24813324 TI - Early passive motion versus immobilization after arthroscopic rotator cuff repair. AB - PURPOSE: To provide a synthesis of the highest-quality literature available comparing early passive motion (EPM) with strict sling immobilization during the first 4 to 6 weeks after surgery. METHODS: The Medline, Cochrane, and Embase databases were searched for eligible studies. We reviewed 886 citations, and 5 randomized clinical trials (RCTs) (Level II) met the inclusion criteria for meta analysis. Four RCTs contributed to the analysis of range of motion, and 5 contributed to the analysis of retear rates. A single Level IV study was available for qualitative review. Random-effects models were used for meta analysis, computing mean differences for continuous variables and risk ratios for dichotomous variables. RESULTS: EPM resulted in improved shoulder forward flexion at 3 months (mean difference, 14.70 degrees ; 95% confidence interval [CI], 5.52 degrees to 23.87 degrees ; P = .002), 6 months (mean difference, 4.31 degrees ; 95% CI, 0.17 degrees to 8.45 degrees ; P = .04), and 12 months (mean difference, 4.18 degrees ; 95% CI, 0.36 degrees to 8.00 degrees ; P = .03). External rotation at the side was only superior with EPM at 3 months (mean difference, 10.43 degrees ; 95% CI, 4.51 degrees to 16.34 degrees ; P = .0006). Rotator cuff retear rates (16.3% for immobilization v 21.1% for EPM; risk ratio, 0.82; 95% CI, 0.57 to 1.20; P = .31) were not significantly different between EPM and immobilization at a minimum of 1 year of follow-up. CONCLUSIONS: A small number of RCTs with low to moderate risks of bias are currently available. Meta-analysis suggests that after primary arthroscopic rotator cuff repair of small to medium tears, EPM results in 15 degrees of improved forward flexion at 3 months and approximately 5 degrees at 6 and 12 months. External rotation is improved by 10 degrees with EPM at 3 months only. The clinical importance of these differences has yet to be determined. Retear rates at a minimum of 1 year of follow-up are not clearly affected by type of rehabilitation. LEVEL OF EVIDENCE: Level II, meta analysis of Level II studies and qualitative review of Level IV study. PMID- 24813325 TI - Effect of lingual enamel sandblasting with aluminum oxide of different particle sizes in combination with phosphoric acid etching on indirect bonding of lingual brackets. AB - OBJECTIVE: To compare bond strength and bond failure location of lingual brackets indirectly bonded after lingual enamel sandblasting with 27-, 50-, and 90-um aluminum oxide particles followed by 37% phosphoric acid etching. MATERIAL AND METHODS: Eighty maxillary premolars were randomly divided into four equal groups according to the method of lingual enamel surface conditioning: Group 1 (control) was etched with 37% phosphoric acid, and group 2, group 3, and group 4 were sandblasted with 27-, 50-, and 90-um aluminum oxide particles, respectively, prior to acid etching. Lingual brackets were indirectly bonded using the same protocol and adhesive (Sondhi) in all groups. The maximum shear bond strength required to debond the brackets was measured using a testing machine, and the bond failure location was classified according to the adhesive remnant index (ARI). Analysis of variance was used to compare the mean bond strength between groups. The differences between ARI scores were evaluated using the Kruskal Wallis test. RESULTS: There were no statistically significant differences in mean shear bond strength or ARI scores between the four enamel-conditioning procedures. CONCLUSION: Lingual enamel sandblasting using different particle sizes of aluminum oxide prior to phosphoric acid etching did not increase the shear bond strength of indirectly bonded brackets and did not affect the amount of adhesive remnant on the enamel. PMID- 24813326 TI - Intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke in a patient treated with rivaroxaban. PMID- 24813327 TI - Anti-GM2, -GD1a and -GD1b positive purely isolated facial diplegia. PMID- 24813328 TI - Insights into the activation and inhibition of angiotensin II type 1 receptor in the mechanically loaded heart. AB - In the heart, mechanical load is a crucial regulator of myocardial structure and function; however, mechanical overload is a pathogenesis or comorbidity existing in a variety of heart diseases, such as hypertension, aortic regurgitation and myocardial infarction. Mechanical overload can be generally differentiated into 2 types, pressure overload (PO) and volume overload (VO), causing concentric and eccentric cardiac hypertrophy, respectively. The angiotensin II (AngII) type 1 receptor (AT1-R) is a 7 transmembrane G protein-coupled receptor that plays a critical role in load-induced cardiac hypertrophy. Early studies revealed the involvement of autocrine/paracrine mechanisms through stretch-induced release of AngII. Recent conceptually inspiring studies unraveled that the AT1-R could be also directly activated by mechanical stress. The activated AT1-R initiates intricate intracellular signaling pathways through G protein-dependent and G protein-independent mechanisms. AT1-R blocker (ARB) antagonizes the activation of AT1-R to regress cardiac remodeling. Some ARBs show properties of inverse agonism and arrestin-biased agonism at the AT1-R, which are potential therapeutic targets for the treatment of load-induced cardiac hypertrophy. This review summarizes the progress in the understanding of ligand- and mechanical stress-dependent activation of AT1-R, highlights recent data that investigate the role of AT1-R in the differentiation of PO- and VO-induced cardiac hypertrophy, and discusses the clinical relevance of inverse agonism and biased agonism of AT1-R ligands. PMID- 24813329 TI - Behavior of encapsulated MG-63 cells in RGD and gelatine-modified alginate hydrogels. AB - Achieving cell spreading and proliferation inside hydrogels that are compatible with microencapsulation technology represents a major challenge for tissue engineering scaffolding and for the development of three-dimensional cell culture models. In this study, microcapsules of 650-900 MUm in diameter were fabricated from oxidized alginate covalently cross-linked with gelatine (AlGel). Schiff's base bond formed in AlGel, detected by Fourier transform infrared spectroscopy, which confirmed the cross-linking of oxidized alginate with gelatine. Biological properties of alginate based hydrogels were studied by comparing the viability and morphology of MG-63 osteosarcoma cells encapsulated in gelatine and RGD modified alginate. We hypothesized that the presence of gelatine and RGD will support cell adhesion and spreading inside the microcapsules and finally, also vascular endothelial growth factor (VEGF) secretion. After 4 days of incubation, cells formed extensive cortical protrusions and after 2 weeks they proliferated, migrated, and formed cellular networks through the AlGel material. In contrast, cells encapsulated in pure alginate and in RGD-modified alginate formed spherical aggregates with limited cell mobility and VEGF secretion. Metabolic activity was doubled after 5 days of incubation, making AlGel a promising material for cell encapsulation. PMID- 24813330 TI - Role of vitamin D in acquired immune and autoimmune diseases. AB - Vitamin D has been attributed roles in the pathogenesis and prevention of several diseases such as cancer, cardiovascular disease, multiple sclerosis, diabetes, autism and autoimmune diseases. The concomitant expression of the 25 hydroxyvitamin D3-1alpha-hydroxylase and of the vitamin D3 receptor in animal and human tissues and organs other than bone supports this paradigm. Translated into the clinical field, meta-analyses and systematic reviews have also revealed an association between vitamin D insufficiency or deficiency and non-osseous diseases. Although relying on the large databases, they are diverse in nature and involve participants of varying age and evolving in different environments. Furthermore, they do not allow any analysis of a possible causal relationship between vitamin D supplementation and clinical outcomes. Following a brief historical account, this review addresses these caveats, and gives examples of randomized controlled trials conducted in the fields of acquired immune and autoimmune diseases. PMID- 24813331 TI - Saxitoxins induce cytotoxicity, genotoxicity and oxidative stress in teleost neurons in vitro. AB - The aim of this study was establish a protocol for isolation and primary culture of neurons from tropical freshwater fish species Hoplias malabaricus for assessment of the effects of neurotoxic substances as saxitoxins (STXs). Cells from brain of H. malabaricus were treated with different concentrations of trypsin, dispase and papain for tissue dissociation. Cells type was separated by cellular gradient and basic fibroblast growth factor (bFGF) supplement nutrition media were added. The dissociated cells were plated with medium and different STXs concentrations and the toxic cellular effects such as oxidative stress, neurotoxicity, and genotoxicity and apoptosis process were evaluated. Cultures treated with bFGF showed the greatest adherence, survival and cellular development. STXs increased specific activity of glutathione peroxidase and lipoperoxidation levels, were cytotoxic and genotoxic indicated by the comet assay. Although the STXs effects due the blockage of sodium channels is reported to be reversible, the time exposure and concentration of STXs suggested cellular injuries which can lead to neuropathology. The establishment of primary neuronal culture protocol enables new applications for neurotoxicological assessments. PMID- 24813332 TI - Tetrodotoxin-producing Bacillus sp. from the ribbon worm (Nemertea) Cephalothrix simula (Iwata, 1952). AB - Specimens of the toxic ribbon worm Cephalothrix simula from the Sea of Japan were screened for tetrodotoxin-producing bacteria. A single TTX-producing bacterial strain (No 1839) was isolated from tissues of C. simula and studied by immunohistochemical methods (including immunoelectron and immunofluorescent microscopies) with anti-TTX antibodies. Sequencing of 16S rRNA gene of the strain 1839 showed that it is most likely Bacillus sp. CU040510-015 and Bacillus asahii. Based on its morphological and biochemical properties, however we suppose that the isolated Bacillus sp. 1839 should be classified as representing a new species. Microdistribution of TTX in bacterial cell was investigated under electron microscope by immunoenzymatic methods. TTX was concentrated in the forespore and free spores, but it was not detected in the vegetative cells of Bacillus sp. 1839. We suggest that release of free mature spores from sporangium of Bacillus sp. 1839 leads to appearance of toxin in tissues of C. simula. Confocal laser-scanning microscopy (CLSM) method with anti-TTX antibodies can be recommended for preliminary detection of apparent TTX accumulation. PMID- 24813333 TI - The intrahippocampal infusion of crotamine from Crotalus durissus terrificus venom enhances memory persistence in rats. AB - Previous research has shown that crotamine, a toxin isolated from the venom of Crotalus durissus terrificus, induces the release of acetylcholine and dopamine in the central nervous system of rats. Particularly, these neurotransmitters are important modulators of memory processes. Therefore, in this study we investigated the effects of crotamine infusion on persistence of memory in rats. We verified that the intrahippocampal infusion of crotamine (1 MUg/MUl; 1 MUl/side) improved the persistence of object recognition and aversive memory. By other side, the intrahippocampal infusion of the toxin did not alter locomotor and exploratory activities, anxiety or pain threshold. These results demonstrate a future prospect of using crotamine as potential pharmacological tool to treat diseases involving memory impairment, although it is still necessary more researches to better elucidate the crotamine effects on hippocampus and memory. PMID- 24813334 TI - An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory. AB - BACKGROUND: Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. METHODS: In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. RESULTS: Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. CONCLUSIONS: These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. PMID- 24813336 TI - The number of competitor species is unlinked to sexual dimorphism. AB - Sexual size dimorphism (SSD) can allow males and females of the same species to specialize on different sized food items and therefore minimize intraspecific competition. Interspecific competition, however, is thought to limit sexual dimorphism, as larger competitors in the community will prevent the larger sex from evolving larger size, and smaller species may prevent the smaller sex from becoming even smaller. We tested this prediction using data on the sexual size dimorphism of lizards, and mammalian carnivores, on islands world-wide. Because insular communities are depauperate, and guilds are species-poor, it is often assumed that enhanced sexual size dimorphism is common on islands. The intensity of interspecific competition, hindering enhanced dimorphism, is thought to increase with competitor richness. We tested whether intraspecific sexual size dimorphism of mammalian carnivores and lizards decreases with increasing island species richness. We further computed the average sexual dimorphism of species on islands and tested whether species-rich islands are inhabited by relatively monomorphic species. Within families and guilds across carnivores and lizards, and with both intraspecific and interspecific approaches, we consistently failed to find support for the notion that species-poor islands harbour more sexually dimorphic individuals or species. We conclude that either interspecific competition does not affect the sexual size dimorphism of insular lizards and carnivores (i.e. character displacement and species sorting are rare in these taxa), or that the number of species in an assemblage or guild is a poor proxy for the intensity of interspecific competition in insular assemblages. PMID- 24813335 TI - Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior. AB - BACKGROUND: Cognitive inflexibility is a core symptom of several mental disorders including schizophrenia. Brain imaging studies in schizophrenia patients performing cognitive tasks have reported decreased activation of the mediodorsal thalamus (MD). Using a pharmacogenetic approach to model MD hypofunction, we recently showed that decreasing MD activity impairs reversal learning in mice. While this demonstrates causality between MD hypofunction and cognitive inflexibility, questions remain about the elementary cognitive processes that account for the deficit. METHODS: Using the Designer Receptors Exclusively Activated by Designer Drugs system, we reversibly decreased MD activity during behavioral tasks assessing elementary cognitive processes inherent to flexible goal-directed behaviors, including extinction, contingency degradation, outcome devaluation, and Pavlovian-to-instrumental transfer (n = 134 mice). RESULTS: While MD hypofunction impaired reversal learning, it did not affect the ability to learn about nonrewarded cues or the ability to modulate action selection based on the outcome value. In contrast, decreasing MD activity delayed the ability to adapt to changes in the contingency between actions and their outcomes. In addition, while Pavlovian learning was not affected by MD hypofunction, decreasing MD activity during Pavlovian learning impaired the ability of conditioned stimuli to modulate instrumental behavior. CONCLUSIONS: Mediodorsal thalamus hypofunction causes cognitive inflexibility reflected by an impaired ability to adapt actions when their consequences change. Furthermore, it alters the encoding of environmental stimuli so that they cannot be properly utilized to guide behavior. Modulating MD activity could be a potential therapeutic strategy for promoting adaptive behavior in human subjects with cognitive inflexibility. PMID- 24813337 TI - Prediction of sorption of aromatic and aliphatic organic compounds by carbon nanotubes using poly-parameter linear free-energy relationships. AB - The accurate prediction of distribution coefficients of organic compounds from water to carbon-based nanomaterials (CNM) is of major importance for the understanding of environmental processes and a risk assessment of released CNM. Poly-parameter linear free-energy relationships (ppLFER) have previously been shown to offer such an accurate prediction of sorption processes. The aim of this study was to identify and quantify the contribution of individual molecular interactions to overall sorption by multi-walled carbon nanotubes (MWCNTs). To this end, a large data set of experimental sorption isotherms by MWCNTs of 20 aliphatic and 14 aromatic compounds covering various relevant molecular interactions was produced. A thermodynamic cycle was used to obtain MWCNT-air distribution coefficients (KMWCNT/a) for the interpretation of direct sorbate MWCNTs interactions. The thereby derived ppLFER log KMWCNT/a = (0.59 +/- 0.59)E + (2.23 +/- 0.59)S + (3.90 +/- 0.67)A + (3.23 +/- 0.71)B + (0.98 +/- 0.17)L - (0.05 +/- 0.50) shows the contribution of non-specific interactions, represented by the hexadecane-air partitioning constant (L), and specific interactions related to the solute polarity (S) as well as the H-bond interactions (A, B). Measured MWCNT water distribution coefficients were clearly more accurately calculated by the ppLFER equations (R(2) 0.85-0.86) compared to the classical prediction by single parameter model based on the octanol-water partitioning constant (R(2) 0.64 0.78). In addition, the ppLFER presented here allow a more accurately prediction of sorption by MWCNTs compared to literature ppLFER, especially for aliphatic compounds and at environmentally relevant concentrations. PMID- 24813338 TI - Evaluation of three activated carbons for combined adsorption and biodegradation of PCBs in aquatic sediment. AB - Three commercial granular activated carbons (GACs) were studied at laboratory scale with a view to the combined adsorption and biodegradation of PCBs in aquatic sediment. The three GACs, with contrasting physico-chemical characteristics, all show a high adsorption of PCBs and are thus capable of reducing aqueous pollutant concentrations. After a one-month incubation with 'Aroclor 1242'-spiked sediment, the three GACs were each colonized by a multispecies biofilm, although with different amounts of attached bacterial biomass and significantly distinct genetic bacterial communities; interestingly, the highest bacterial biomass was attached to the microporous vegetable GAC. The multispecies biofilms developed on the three GACs were all predominantly composed of Proteobacteria, especially the beta-, gamma- and delta- subclasses, Chloroflexi and Acidobacteria, with genera previously found in environments containing PCBs or biphenyls, or able to perform cometabolic and direct PCB degradation. After an eight-month incubation under aerobic conditions, it was only the vegetable Picabiol GAC, with its low microporous volume, high total surface area and acidic property, that showed a significant (21%) reduction of tri- through penta-CB. Our results suggest that PCB bio-transformation by the bacterial community attached to the GAC is influenced by GAC's physico-chemical characteristics. Thus, a properly selected GAC could effectively be used to a) sequestrate and concentrate PCB from contaminated aquatic sediment and b) act as a support for efficient PCB degradation by an autochthonous bacterial biofilm. PMID- 24813339 TI - Contrasting effects of rising CO2 on primary production and ecological stoichiometry at different nutrient levels. AB - Although rising CO2 concentrations are thought to promote the growth and alter the carbon : nutrient stoichiometry of primary producers, several studies have reported conflicting results. To reconcile these contrasting results, we tested the following hypotheses: rising CO2 levels (1) will increase phytoplankton biomass more at high nutrient loads than at low nutrient loads, but (2) will increase their carbon : nutrient stoichiometry more at low than at high nutrient loads. We formulated a mathematical model to predict dynamic changes in phytoplankton population density, elemental stoichiometry and inorganic carbon chemistry in response to rising CO2 . The model was tested in chemostat experiments with the freshwater cyanobacterium Microcystis aeruginosa. The model predictions and experimental results confirmed the hypotheses. Our findings provide a novel theoretical framework to understand and predict effects of rising CO2 concentrations on primary producers and their nutritional quality as food for herbivores under different nutrient conditions. PMID- 24813340 TI - Fate of abstracts presented at the 2009 American Transplant Congress. AB - INTRODUCTION: Oral and poster presentations at major meetings serve to rapidly present and share study results with the scientific community. On the other hand, full-text publication of abstracts in peer-reviewed journals provides dissemination of knowledge. The purpose of this study was to evaluate the publication rate of abstracts presented at the 2009 American Transplant Congress (ATC), to assess the factors influencing publication and determine the impact factor of these journals. METHODS: All abstracts presented at the 2009 ATC were included in the study. A Pubmed-Medline search was performed to identify a matching journal article. Topics, country of origin, study type, study center and publication year were tabulated. Journals and impact factors of publication were noted. RESULTS: Out of 1938 oral and posters abstracts presented, 103 (16.6%) of oral abstracts and 141 poster abstracts (10.9%) were published as full-text articles. Publication rates according to topics of the meeting and country of origin did demonstrate statistical significant differences (p < 0.05). Single centered studies had higher publication rates 70.87% (73/103) than multi-centered studies among oral abstracts. Abstracts from multi-centered studies had higher publication rates among poster abstracts (68.09% vs. 31.91%), and the journals they were published in had higher impact factors than single center studies (4.578 vs. 3.897). The median impact factor of the journals was 4.2 (4.8 for oral presentations and 3.627 for poster presentations) that went on to be published as full text manuscripts. When comparing multi-center and single institutions, the difference between 12 month and 24 month publication rates was not statistically significant (p = 0.5443 and 0.1134). However, oral and poster abstracts published by study center (multi/single) did demonstrate a statistically significant difference (p < 0.0001); comparing the type of study, there was also a statistically significant difference between the oral and poster abstract (p < 0.0001). CONCLUSION: The publication rate for abstracts of this 2009 ATC was lower than rates from other fields of medicine. Factors leading to failure require elucidation. Encouraging authors to submit their presentations for full text publication might improve the rate of publication. Authors should be wary of accepting oral and poster abstracts as dogma; authors should refrain from citing them in publications especially if they are from outside United States and are about liver and kidney transplantation. PMID- 24813341 TI - The unmet need for a national surgical quality improvement curriculum: a systematic review. AB - INTRODUCTION: The Accreditation Council for Graduate Medical Education Next Accreditation System will require general surgery training programs to demonstrate outstanding clinical outcomes and education in quality improvement (QI). The American College of Surgeons-National Surgical Quality Improvement Project Quality In-Training Initiative reports the results of a systematic review of the literature investigating the availability of a QI curriculum. METHODS: Using defined search terms, a systematic review was conducted in Embase, PubMed, and Google Scholar (January 2000-March 2013) to identify a surgical QI curriculum. Bibliographies from selected articles and other relevant materials were also hand searched. Curriculum was defined as an organized program of learning complete with content, instruction, and assessment for use in general surgical residency programs. Two independent observers graded surgical articles on quality of curriculum presented. RESULTS: Overall, 50 of 1155 references had information regarding QI in graduate medical education. Most (n = 24, 48%) described QI education efforts in nonsurgical fields. A total of 31 curricular blueprints were identified; 6 (19.4%) were specific to surgery. Targeted learners were most often post graduate year-2 residents (29.0%); only 6 curricula (19.4%) outlined a course for all residents within their respective programs. Plan, Do, Study, Act (n = 10, 32.3%), and Root Cause Analysis (n = 5, 16.1%) were the most common QI content presented, the majority of instruction was via lecture/didactics (n = 26, 83.9%), and only 7 (22.6%) curricula used validated tool kits for assessment. CONCLUSION: Elements of QI curriculum for surgical education exist; however, comprehensive content is lacking. The American College of Surgeons-National Surgical Quality Improvement Project Quality In-Training Initiative will build on the high-quality components identified in our review and develop data-centered QI content to generate a comprehensive national QI curriculum for use in graduate surgical education. PMID- 24813342 TI - Cytokine expression in patients with bladder pain syndrome/interstitial cystitis ESSIC type 3C. AB - PURPOSE: Bladder wall nitric oxide production in patients with bladder pain syndrome type 3C is increased compared to undetectable nitric oxide in patients with nonHunner bladder pain syndrome and healthy controls. However, the underlying mechanism/s of the increased nitric oxide production is largely unknown. We compared mRNA expression of a select group of cytokines in patients with bladder pain syndrome/interstitial cystitis type 3C and in pain-free controls. MATERIALS AND METHODS: Cold cup biopsies from 7 patients with bladder pain syndrome type 3C and 6 healthy subjects were analyzed. mRNA expression of IL 4, 6, 10 and 17A, iNOS, TNF-alpha, TGF-beta and IFN-gamma was estimated by real time polymerase chain reaction. IL-17 protein expression was determined by immunohistochemistry. Mast cells were labeled with tryptase to evaluate cell appearance and count. RESULTS: IL-6, 10 and 17A, and iNOS mRNA levels as well as the number of mast cells infiltrating the bladder mucosa were significantly increased in patients with bladder pain syndrome type 3C compared to healthy controls. TNF-alpha, TGF-beta and IFN-gamma mRNA levels were similar in patients and controls. IL-17A expression at the protein level was up-regulated and localized to inflammatory cells and urothelium in patients with bladder pain syndrome type 3C. CONCLUSIONS: Patients with bladder pain syndrome/interstitial cystitis had increased mRNA levels of IL-17A, 10 and 6, and iNOS. IL-17A might be important in the inflammatory process. To our knowledge the increase in IL-17A is a novel finding that may have new treatment implications. PMID- 24813343 TI - Nationwide population based study of infections after transrectal ultrasound guided prostate biopsy. AB - PURPOSE: Transrectal ultrasound guided biopsy is the gold standard for detecting prostate cancer but international reports suggest that increasing risks are associated with the procedure. We estimated incidence and risk factors for infection after prostate biopsy as well as 90-day mortality using a nationwide Swedish sample. MATERIAL AND METHODS: We performed a population based study of 51,321 men from PCBaSe between 2006 and 2011. Primary outcome measures were dispensed prescriptions of antibiotics for urinary tract infection and hospitalization with a discharge diagnosis of urinary tract infection. Multivariable logistic regression was used to examine risk factors for infection in men who underwent prostate biopsy. RESULTS: During the 6 months before biopsy the background incidence of urinary tract infection was approximately 2%. Within 30 days after biopsy 6% of the men had a dispensed prescription for urinary tract antibiotics and 1% were hospitalized with infection. The strongest risk factors for an antibiotic prescription were prior infection (OR 1.59, 95% CI 1.45-1.73), high Charlson comorbidity index (OR 1.25, 95% CI 1.11-1.41) and diabetes (OR 1.32, 95% CI 1.17-1.49). Risk of an antibiotic prescription after biopsy decreased from 2006 to 2011 (OR 0.79, 95% CI 0.70-0.90) but the risk of hospital admission increased (OR 2.14, 95% CI 1.58-2.94). No significant increase was observed in 90-day mortality. CONCLUSIONS: Severe infections with hospitalization after prostate biopsy are increasing in Sweden. The risk of post-biopsy infection is highest in men with a history of urinary tract infection and those with significant comorbidities. PMID- 24813344 TI - Definition of biochemical success following primary whole gland prostate cryoablation. AB - PURPOSE: We identified an evidence-based definition of biochemical success following primary whole gland prostate cryoablation. MATERIALS AND METHODS: The COLD Registry was queried for a risk stratified cohort of otherwise treatment naive patients who underwent primary whole gland prostate cryoablation, of whom none had received any type of adjuvant therapy. Minimum followup in all study patients was 5 years. Variables included patient age, prostate specific antigen at diagnosis, Gleason score, D'Amico risk category and followup prostate specific antigen. Biochemical progression-free survival was studied based on Kaplan-Meier results using the Phoenix definition. HRs were calculated using proc PHReg. RESULTS: Of 1,111 patients 891 achieved nadir prostate specific antigen less than 0.4 ng/ml, which correlated with a 5-year biochemical progression-free survival rate of 90.4% in those at low risk, 81.1% in those at intermediate risk and 73.6% in those at high risk. Nadir prostate specific antigen 0.4 ng/ml or greater was associated with 24-month biochemical failure of 29.2% in those at low risk, 46.4% in those at intermediate risk and 48.9% in those at high risk. Statistical analysis failed to reveal a superior prostate specific antigen end point compared to 0.4 ng/ml. HR findings supported the relevance of the end point of less than 0.4 ng/ml (p <0.0001). CONCLUSIONS: To our knowledge this study represents the first evidence-based definition of biochemical success after primary whole gland prostate cryoablation. Nadir prostate specific antigen less than 0.4 ng/ml was the best objective indicator of biochemical success. Nadir prostate specific antigen 0.4 ng/ml or greater was associated with less favorable biochemical progression, precluding the use of a higher nadir prostate specific antigen end point (HR 5.649, 95% CI 4.33-7.38, p <0.0001). PMID- 24813345 TI - Reperfusion therapy for ST-segment elevation myocardial infarction: has ECG information been underutilized? AB - This perspective makes a contentious viewpoint that ECG information is underutilized in ST-segment elevation myocardial infarction (STEMI) and the next breakthrough rests on its full utilization. This is to better diagnose difficult cases such as ST changes during bundle branch block, posterior ST elevation and right-sided ST elevation during normal conduction, and aVR ST elevation. More importantly, this is to better characterize the STEMI for tailored reperfusion. The proposal is to develop a system capable of recording from multiple electrodes that one can apply onto oneself, and having analysis coordinated centrally via phone-internet transmission. This provides 'longitudinal' in addition to 'cross sectional' ECG information. STEMI will be classified on a gray-scale according to its potential size and speed of Q wave evolution. The hypothesis is that large rapidly progressive STEMI is best treated by on-site fibrinolysis with prompt transferral to a percutaneous coronary intervention center; while small stuttering STEMI is best treated by primary percutaneous coronary intervention despite a long delay. PMID- 24813346 TI - Safety climate in dialysis centers in Saudi Arabia: a multicenter study. AB - OBJECTIVE: The aim of this study was to assess the safety climate as perceived by nurses and physicians in the dialysis units in Saudi Arabia. METHODS: This is a cross-sectional survey-based multicenter study using the Safety Climate Scale, which assesses the perception by staff of the prevailing climate of safety. We used 17 items in this survey. These could be further divided into 3 summative categories: (a) handling of errors and safety concerns (9 items), (b) leadership emphasis of safety (7 items), and (c) overall safety recommendation (1 item). The survey uses 5 Likert scale options (1, disagree strongly; 2, disagree slightly; 3, neutral; 4, agree slightly; and 5, agree strongly). RESULTS: There were 509 respondents--a response rate of 76.6% and 53.3% among nurses and physicians, respectively. The internal consistency using Cronbach alpha was 0.899. The overall mean (SD) of satisfaction with safety climate was higher among the nurses than the physicians (4.13 [1.1] and 4.05 [1.7], respectively; P = 0.029). The overall agreement rate was 73.8%, with more nurses than physicians agreeing that safety climate prevails the dialysis center (75.4% versus 72.1%, respectively; P = 0.047).The respondents perceived a stronger commitment to safety from their clinical area leaders than from senior leaders in the organization (76.2% and 72.4%, respectively). In addition, the physicians gave lower scores to more questions than the nurses particularly in 3 areas, namely, "leadership is driving us to be a safety-centered institution" (71.5% versus 76.5%; P = 0.037), "I am encouraged by my colleagues to report any patient safety concerns I may have" (67.4% versus 84.7%; P = 0.03), and "I know proper channels to ask questions about safety" (69.6% versus 87.2%; P = 0.002).The scores by the physicians in all the 3 summative categories were again less than the scores by the nurses, but this did not reach a statistical significance. CONCLUSIONS: The nurses had higher perceptions of a prevailing safety climate than the physicians. There was a perception of a stronger commitment to safety from their clinical area leaders than from senior leaders in the organization. Senior management needs to relay their commitments to safety more effectively especially to physicians and to open clear and easily accessible channels for communication for safety issues. PMID- 24813347 TI - Vascular extravasation of contrast medium in radiological examinations: University of California San Diego Health System Experience. AB - INTRODUCTION: Extravasation is a well-recognized complication estimated to be between 0.1% and 0.9% of contrast medium administrations. According to the UC San Diego (UCSD) health system policy, all contrast medium extravasation (CME) reports are reviewed by the department of Risk Management, and the appropriate action is taken. Despite this strategy, a decrease in the incidence of CME could not be demonstrated. AIM: The aims of this study were to determine the frequency, management, and outcome of CME in UC San Diego patients and to assess the knowledge regarding CME among radiology technologists based on policy and guidelines. The secondary aim was to assess the manual ability of the radiology technologists in the performance of the procedure. METHODS: The study has 2 parts; the first was retrospective, including data collection and interpretation of all radiology procedures using intravenous contrast medium injection between January 1, 2010, and September 30, 2011, and the second was prospective, including proactive observations and knowledge questionnaire. RESULTS: There were 83 (0.48%) cases of CME of 17,200 patients, 54 women (0.64%) and 29 men (0.33%), P = 0.005. The patients with CME were older, and their cannula was inserted in other departments than Radiology Department, P < 0.000. There was a gap between the high theoretical knowledge that was found in the knowledge questionnaire and its implementation that was demonstrated in the proactive observation. CONCLUSIONS: Our data demonstrate that sex, age, and where the cannula was inserted are predictive factors for CME. We believe that CME could be prevented by proper educational program and establishment of efficient strategy. PMID- 24813348 TI - Channelopathy: a novel mutation in the SCN9A gene causes insensitivity to pain and autonomic dysregulation. PMID- 24813349 TI - Antimicrobial peptides and proteins in mycobacterial therapy: current status and future prospects. AB - Tuberculosis (TB), an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb), kills about 1.5 million people every year worldwide. An increase in the prevalence of drug-resistant strains of Mtb in the last few decades now necessitates the development of novel drugs that combat infections by both drug-sensitive and resistant Mtb. Moreover, as Mtb can persist in host cells by modulating their immune responses, it is essential that anti-TB agents be able to penetrate macrophages and kill the pathogen intracellularly without harming the host cells. In this context, antimicrobial peptides (AMPs) and proteins are being harnessed as anti-infective agents for the treatment of various diseases. Due to their direct and rapid bactericidal activity it is unlikely that pathogens acquire resistance against AMPs. Several short and potent AMP derivatives have been prepared by peptide engineering, and several of them are currently evaluated in clinical trials. The present review summarizes the role of endogenously expressed AMPs and proteins in the treatment of tuberculosis infections. In addition, mechanisms of direct anti-mycobacterial activity, manipulation of host immune responses, and future prospects of AMPs as therapeutic agents are discussed. PMID- 24813350 TI - Inpatient resource utilization, disease severity, mortality and insurance coverage for patients hospitalized for hepatitis C virus in the United States. AB - Although the incidence of new hepatitis C virus (HCV) infection has fallen, HCV related complications are on the rise. Our aim was to assess and describe the 2005-2009 national inpatient mortality and resource utilization trends for patients with HCV. Data from the National Inpatient Sample (NIS) and the National Hospital Discharge Survey (NHDS) between 2005 and 2009 were analyzed. Included were all adult hospital discharges with HCV-related ICD-9 codes. Incremental hospital charge, in-hospital mortality and length of stay (LOS) were estimated using n = 1000 bootstrap replicates clustered by unique hospital identifier. A total of 123 939 (0.38%) discharges were related to HCV (primary or secondary diagnosis). In-hospital mortality increased from 1.7% (2005) to 2.6% (2009) (P < 0.001). Inflation-adjusted charges increased 2% annually from 2005 ($16 455 +/- $570) to 2009 ($17 532 +/- $1007, P = 0.029). This increase occurred despite the average LOS (5 days) and hospital costs ($6500) remaining stable while at the same time, hospital-to-hospital transfer admissions and disposition to home health care increased. HCV-related hepatocellular carcinoma predicted longer hospital stay and death; older age predicted death; and receiving more procedures predicted higher hospital costs. The percentage of patients with private insurance significantly decreased (4.7%), while government-sponsored insurance and uninsured increased by 2.5% and 2.1%, respectively (P < 0.05). Uninsured patients had a 49%-72% greater chance of dying during hospitalization than those with government-sponsored insurance. HCV-related inpatient mortality and resource utilization have increased. HCC was the largest predictor for mortality and resource utilization. These data are consistent with the rising clinical and societal burden of chronic hepatitis C in the United States. PMID- 24813351 TI - Effect of interlayer cations of montmorillonite on the biodegradation and adsorption of crude oil polycyclic aromatic compounds. AB - Cation exchange capacity, surface acidity and specific surface area are surface properties of clay minerals that make them act as catalysts or supports in most biogeochemical processes hence making them play important roles in environmental control. However, the role of homoionic clay minerals during the biodegradation of polycyclic aromatic compounds is not well reported. In this study, the effect of interlayer cations of montmorillonites in the removal of some crude oil polycyclic aromatic compounds during biodegradation was investigated in aqueous clay/oil microcosm experiments with a hydrocarbon degrading microorganism community. The homoionic montmorillonites were prepared via cation exchange reactions by treating the unmodified montmorillonite with the relevant metallic chloride. The study indicated that potassium-montmorillonite and zinc montmorillonite did not enhance the biodegradation of the polycyclic aromatic hydrocarbons whereas calcium-montmorillonite, and ferric-montmorillonite enhanced their biodegradation significantly. Adsorption of polycyclic aromatic hydrocarbons was significant during biodegradation with potassium- and zinc montmorillonite where there was about 45% removal of the polycyclic aromatic compounds by adsorption in the experimental microcosm containing 5:1 ratio (w/w) of clay to oil. PMID- 24813352 TI - Multifunctional organic phototransistor-based nonvolatile memory achieved by UV/ozone treatment of the Ta2O5 gate dielectric. AB - An organic phototransistor (OPT) shows nonvolatile memory effect due to its novel optical writing and electrical erasing processes. In this work, we utilize an organic light-emitting diode (OLED) as the light source to investigate OPT-based memory (OPTM) performance. It is found that the OPTM can be used as either flash memory or write-once read-many-times memory by adjusting the properties of the Ta2O5 gate dielectric layer. UV/ozone treatment is applied to effectively change dielectric properties of the Ta2O5 film. The mechanisms for this are examined by X-ray photoelectron spectroscopy and capacitance-voltage measurement. It turns out that the densities of oxygen vacancies and defects in the first 1.8 nm Ta2O5 films near the Ta2O5/semiconductor interface are reduced. Furthermore, for the first time, we use this multifunctional OPTM, which unites the photosensitive and memory properties in one single device, as an optical feedback system to tune the brightness of the OLED. Our study suggests that these OPTMs have potential applications in tuning the brightness uniformity, improving the display quality and prolonging the lifetime of flat panel displays. PMID- 24813353 TI - Ventricular hypertrophy amplifies transmural dispersion of repolarization by preferentially increasing the late sodium current in endocardium. AB - BACKGROUND: The late sodium current (INa-L) contributes importantly to rate dependent change in action potential duration (APD) and transmural dispersion of repolarization (TDR). However, little is known about the mechanisms of increased APD rate-dependence and amplified TDR in left ventricular hypertrophy (LVH) and failure. The purpose of this study was to investigate the role of INa-L in rate adaptation of transmural APD heterogeneity. METHODS: APD, its rate-dependence and INa-L current were examined in myocytes isolated from the endocardium and epicardium of the control and LVH rabbits. AP was recorded using the standard microelectrode technique, and INa-L was recorded using the whole-cell patch clamp technique. RESULTS: Early afterdepolarizations (EADs) were frequently recorded in the isolated myocytes of the LVH rabbits but not in those of controls. LVH prolonged APD more significantly in the endocardial myocytes than in the epicardium (31.7+/-3.4 vs. 21.6+/-1.5% n=6, p<0.05), leading to a marked increase in TDR. LVH endocardial myocytes exhibited a greater rate-dependent change in APD compared to the epicardial myocytes. INa-L densities were significantly increased in both LVH endocardium and epicardium. However, LVH increased the INa-L density preferentially in the endocardial myocytes compared to the epicardial myocytes (54.5+/-4.8% vs. 39.2+/-3.3%, n=6, p<0.05). CONCLUSIONS: Our results demonstrate that LVH increased the INa-L preferentially in the endocardium over the epicardium, which contributes importantly to the stronger rate-dependent change in repolarization and longer APD in the endocardium. This results in an amplified TDR capable of initiating EAD and ventricular arrhythmias. PMID- 24813354 TI - Consideration of QRS complex in addition to ST-segment abnormalities in the estimation of the "risk region" during acute anterior or inferior myocardial infarction. AB - The myocardial area at risk (MaR) is an important aspect in acute ST-elevation myocardial infarction (STEMI). It represents the myocardium at the onset of the STEMI that is ischemic and could become infarcted if no reperfusion occurs. The MaR, therefore, has clinical value because it gives an indication of the amount of myocardium that could potentially be salvaged by rapid reperfusion therapy. The most validated method for measuring the MaR is (99m)Tc-sestamibi SPECT, but this technique is not easily applied in the clinical setting. Another method that can be used for measuring the MaR is the standard ECG-based scoring system, Aldrich ST score, which is more easily applied. This ECG-based scoring system can be used to estimate the extent of acute ischemia for anterior or inferior left ventricular locations, by considering quantitative changes in the ST-segment. Deviations in the ST-segment baseline that occur following an acute coronary occlusion represent the ischemic changes in the transmurally ischemic myocardium. In most instances however, the ECG is not available at the very first moments of STEMI and as times passes the ischemic myocardium becomes necrotic with regression of the ST-segment deviation along with progressive changes of the QRS complex. Thus over the time course of the acute event, the Aldrich ST score would be expected to progressively underestimate the MaR, as was seen in studies with SPECT as gold standard; anterior STEMI (r=0.21, p=0.32) and inferior STEMI (r=0.17, p=0.36). Another standard ECG-based scoring system is the Selvester QRS score, which can be used to estimate the final infarct size by considering the quantitative changes in the QRS complex. Therefore, additional consideration of the Selvester QRS score in the acute phase could potentially provide the "component" of infarcted myocardium that is missing when the Aldrich ST score alone is used to determine the MaR in the acute phase, as was seen in studies with SPECT as gold standard: anterior STEMI (r=0.47, p=0.02) and inferior STEMI (r=0.58, p<0.001). The aim of this review will be to discuss the findings regarding the combining of the Aldrich ST score and initial Selvester QRS score in determining the MaR at the onset of the event in acute anterior or inferior ST elevation myocardial infarction. PMID- 24813355 TI - Increased circulating inflammatory markers may indicate that formula-fed children are at risk of atherosclerosis. AB - AIM: The aim of this study was to determine whether formula-fed children have higher serum monocyte chemoattractant protein-1 (MCP-1) and uric acid levels than breast-fed children and to evaluate the association between these inflammatory markers and breastfeeding duration. METHODS: The study group consisted of 87 patients aged between five and 32 months. Participants were divided into breast fed and formula-fed groups and into age groups of <=12 months and >12 months. MCP 1 was measured by the commercial immunoenzymatic ELISA kit, and uric acid was assessed using the colorimetric method. RESULTS: Children in the formula-fed group had statistically significant higher serum MCP-1 and uric acid levels than breast-fed children (p < 0.01 and p < 0.05, respectively). Anthropometric parameters were comparable in both groups. Serum MCP-1 and uric acid levels were negatively correlated with duration of breastfeeding (p < 0.01 and p < 0.05). There was a positive relationship between serum MCP-1 and uric acid concentrations (r = 0.27, p < 0.05). CONCLUSION: Increased circulating inflammatory markers may indicate that formula-fed children are at risk of atherosclerosis. However, further studies are needed. PMID- 24813356 TI - The quality of healing. PMID- 24813357 TI - Assessing quality of healing in skin: review of available methods and devices. AB - The process of wound healing is dynamic and takes place over months to years, during which there is a resolution of angiogenesis, continued wound contraction, and connective tissue remodeling. The outcome of this process is most commonly the formation of a scar, defined as a fibrous tissue replacing normal tissues destroyed by injury or disease. Scars often have a lowered or total loss of vital skin functions and imbue a large burden on both the patient and the health care system as a whole. Scar treatments are plentiful but are often unsatisfactory or inconsistent. No single treatment method has been universally adopted. To evaluate the clinical treatment as well as research focused on developing novel methods for scar management, objective studies of the progression of scar formation and the properties of mature scars are needed. Several parameters, including barrier function as well as mechanical and physiological properties, need to be taken into account when both categorizing and treating healing wounds and scars. To date, there is no available methodology that provides a comprehensive evaluation of a scar's properties. This review aims at presenting an overview of available scar assessment methods and devices, ranging from analysis of collagen properties in tissue biopsies to noninvasive methods for studies of mechanical parameters such as breaking strength and skin elasticity. In the cases where conclusive studies have been performed, the differences between normal skin and scar with respect to the above parameters are presented. Furthermore, this review highlights areas where the development of additional modalities are needed. PMID- 24813358 TI - Healing of grafted adipose tissue: current clinical applications of adipose derived stem cells for breast and face reconstruction. AB - Since their isolation and characterization nearly a decade ago, adipose-derived stem cells (ASCs) have become one of the most popular adult stem cell populations for soft tissue engineering and regenerative medicine applications. Compared with other stem cell sources, ASCs offer several advantages including abundant autologous source, minor invasive harvesting (liposuction), significant proliferative capacity in culture, and multilineage potential. In this mini review, we focus on some of the more salient published clinical and preclinical data to date regarding ASC treatment for breast and facial soft tissue reconstruction. PMID- 24813359 TI - Wound healing in acutely injured fascia. AB - Fascial healing following acute injury, such as that occurring during surgical procedures, is defined functionally. For example, failure of fascial healing following celiotomy is only identified when incisional hernias are diagnosed. Such hernias incur billions of dollars per year in medical costs. Despite the importance of fascial healing, there is a paucity of data regarding the quality such healing. In clinical settings, the quantification of fascial wound healing is limited to a binary state: either there is no clinically apparent functional deficit and full fascia healing is assumed, or an incisional hernia or other functional failure is visible and the fascia did not heal. There are no clinical methods to isolate and functionally test fascia in patients. Recent studies have revealed unexpected findings regarding the recovery of tensile strength, specific surgical methods that optimize fascial healing, and the potential impact of biological pharmaceuticals in eliminating fascial healing failure. However, much remains unknown about the biology of fascial healing. PMID- 24813360 TI - Quality of healing: defining, quantifying, and enhancing skeletal muscle healing. AB - Skeletal muscle injury is common in everyday physical activity and athletics, as well as in orthopedic trauma and disease. The overall functional disability resulting from muscle injury is directly related to the intrinsic healing properties of muscle and extrinsic treatment options designed to maximize repair and/or regeneration of muscle tissue all while minimizing pathologic healing pathways. It is important to understand the injury and repair pathways in order to improve the speed and quality of recovery. Recent military conflicts in Iraq and Afghanistan have highlighted the importance of successfully addressing muscular injury and showed the need for novel treatment options that will maximize functional regeneration of the damaged tissue. These severe, wartime injuries, when juxtaposed to peacetime, sports-related injuries, provide us with interesting case examples of the two extreme forms of muscular damage. Comparing and contrasting the differences in these healing pathways will likely provide helpful cues that will help physicians recapitulate the near complete repair and regeneration in less traumatic injuries in addition to more severe cases. PMID- 24813361 TI - Advances in the healing of flexor tendon injuries. AB - The intrasynovial flexor tendons of the hand are critical for normal hand function. Injury to these tendons can result in absent finger flexion, and a subsequent loss of overall hand function. The surgical techniques used to repair these tendons have improved in the past few decades, as have the postoperative rehabilitation protocols. In spite of these advances, intrasynovial flexor tendon repairs continue to be plagued by postoperative scar formation, which limits tendon gliding and prevents a full functional recovery. This paper describes the current challenges of flexor tendon repair, and evaluates the most recent advances and strategies for achieving an excellent functional outcome. PMID- 24813362 TI - The quality of healing: articular cartilage. AB - Articular cartilage lacks an intrinsic capacity for self-repair, and once damaged, it never heals. This creates an opportunity for surgical intervention, whether to stimulate a healing response that results in the formation of a lower quality fibrocartilaginous scar or formal cartilage repair in the form of cartilage transplants. This article will review the nature of cartilage injury and discuss indications and techniques for repair. PMID- 24813363 TI - Quality of bone healing: perspectives and assessment techniques. AB - Bone regeneration and healing is an area of extensive research providing an ever expanding set of not only therapeutic solutions for surgeons but also diagnostic tools. Multiple factors such as an ideal graft, the appropriate biochemical and mechanical wound environment, and viable cell populations are essential components in promoting healing. While bony tissue performs many functions, critical is mechanical strength, followed closely by structure. Many tools are available to evaluate bone quality in terms of quantity, structure, and strength; the purpose of this article is to identify the factors that can be evaluated and the advantages and disadvantages of each in assessing the quality of bone healing in both preclinical research and clinical settings. PMID- 24813364 TI - Mechanisms of mRNA export. AB - Release of properly processed and assembled mRNPs from the actively transcribing genes, movement of the mRNPs through the interchromatin and interaction with the Nuclear Pore Complexes, leading to cytoplasmic export, are essential steps of eukaryotic gene expression. Here, we review these intranuclear gene expression steps. PMID- 24813365 TI - Angiogenesis in zebrafish. AB - The vasculature consists of an extensively branched network of blood and lymphatic vessels that ensures the efficient circulation and thereby the supply of all tissues with oxygen and nutrients. Research within the last decade has tremendously advanced our understanding of how this complex network is formed, how angiogenic growth is controlled and how differences between individual endothelial cells contribute to achieving this complex pattern. The small size and the optical clarity of the zebrafish embryo in combination with the advancements in imaging technologies cleared the way for the zebrafish as an important in vivo model for elucidating the mechanisms of angiogenesis. In this review we discuss the recent contributions of the analysis of zebrafish vascular development on how vessels establish their characteristic morphology and become patent. We focus on the morphogenetic cellular behaviors as well as the molecular mechanisms that drive these processes in the developing zebrafish embryo. PMID- 24813366 TI - Adaptive memory: animacy effects persist in paired-associate learning. AB - Recent evidence suggests that animate stimuli are remembered better than matched inanimate stimuli. Two experiments tested whether this animacy effect persists in paired-associate learning of foreign words. Experiment 1 randomly paired Swahili words with matched animate and inanimate English words. Participants were told simply to learn the English "translations" for a later test. Replicating earlier findings using free recall, a strong animacy advantage was found in this cued recall task. Concerned that the effect might be due to enhanced accessibility of the individual responses (e.g., animates represent a more accessible category), Experiment 2 selected animate and inanimate English words from two more constrained categories (four-legged animals and furniture). Once again, an advantage was found for pairs using animate targets. These results argue against organisational accounts of the animacy effect and potentially have implications for foreign language vocabulary learning. PMID- 24813367 TI - Changes in waist circumference relative to body mass index in Chinese adults, 1993-2009. AB - BACKGROUND: Although body mass index (BMI) and waist circumference (WC) are correlated, the relationship between WC and BMI may have changed over time. OBJECTIVES: To describe temporal trends in BMI and WC distributions and quantify the increase in WC at a given BMI over time. SUBJECTS/METHODS: Data on adults aged 20-59 years from two waves (1993 and 2009) of the China Health and Nutrition Survey were used in a pooled cross-sectional analysis. Quantile regression examined age-adjusted temporal trends in the distributions of BMI and WC. Linear regression examined changes in mean WC over time, adjusting for BMI, age at survey and survey year. All models were stratified by gender. RESULTS: There was a significant increase in BMI and WC over time, particularly at the 95th quantile: on average, men had 2.8 kg m(-2) (95% confidence interval (CI): 2.4, 3.3) and women 1.5 kg m(-)(2) (95% CI: 1.1, 2.0) higher BMI in 2009 compared with their counterparts in 1993. WC increased by 9.0 cm (95% CI: 7.5, 10.1) and 5.0 cm (95% CI: 3.4, 6.6) for men and women, respectively. On average, men and women had a 3.2 cm (95% CI: 2.8, 3.7) and 2.1 cm (95% CI: 1.7, 2.5) higher WC in 2009 compared with their counterparts in 1993, holding BMI and age constant. WC adjusted for BMI increased to a larger extent among obese versus lean individuals and among younger versus older women. CONCLUSIONS: For both genders, BMI and WC increased significantly over time, with particularly greatest increase in magnitude in the upper tail of the BMI and WC distributions. Furthermore, WC at equivalent BMIs was higher in 2009, compared with their counterparts in 1993. Our findings suggest that even if BMI remained constant from 1993 to 2009, adults in 2009 might be at increased cardiometabolic risk as a result of their higher WC. PMID- 24813368 TI - Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. AB - OBJECTIVE: Fibroblast growth factor (FGF)-21, and possibly FGF19, protect against type 2 diabetes mellitus (T2DM) and obesity in rodents. We investigated the circulating levels of FGF21 and FGF19 in obese patients with varying degrees of abnormal glucose homeostasis, and we determined gene expression for FGF receptors (FGFR1-4) and the co-receptor beta-Klotho, in liver and adipose tissues. SUBJECTS AND METHODS: We analyzed 35 lean healthy (71% men) and 61 obese patients (49% men, median body mass index (BMI): 40.5 kg m(-2), interquartile range: 34.7 46.2). Among obese patients, 36 were normoglycemic, 15 showed impaired glucose tolerance and 10 had T2DM. Biopsies from liver and visceral and subcutaneous fat from a subset of obese patients and controls were analyzed. FGF19 and FGF21 levels were measured using enzyme-linked immunosorbent assay, and tissue mRNA and protein levels by reverse transcription-polymerase chain reaction and immunoblotting. RESULTS: FGF21 serum levels were significantly increased in obese patients compared with controls (P<0.001), whereas FGF19 levels were decreased (P < 0.001). FGF21 levels were positively correlated with homeostasis model assessment of insulin resistance (P = 0.0002, r = 0.37) and insulin (P = 0.001, r = 0.32), whereas FGF19 levels were negatively correlated (P = 0.007, r = -0.27; P=0.003, r = -0.28; respectively). After adjusting for BMI, the correlations of FGF21 and FGF19 levels with indicators of abnormal glucose homeostasis were not significant. In obese patients, the hepatic expression of FGF21 was increased. (P = 0.04). beta-Klotho transcript levels in visceral fat (P = 0.002) and beta Klotho protein levels in subcutaneous (P = 0.03) and visceral fat (P = 0.04) were significantly reduced in obese patients, whereas hepatic levels for beta-Klotho (P = 0.03), FGFR1 (P = 0.04) and FGFR3 (P = 0.001) transcripts were significantly increased. CONCLUSIONS: Obesity is characterized by reciprocal alterations in FGF19 (decrease) and FGF21 (increase) levels. Although worsened in diabetic obese patients, obesity itself appears as the predominant determinant of the abnormalities in FGF21 and FGF19 levels. Opposite changes in beta-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity. PMID- 24813369 TI - A systematic review of the effectiveness of individual, community and societal level interventions at reducing socio-economic inequalities in obesity among adults. AB - BACKGROUND: Socioeconomic inequalities in obesity are well established in high income countries. There is a lack of evidence of the types of intervention that are effective in reducing these inequalities among adults. OBJECTIVES: To systematically review studies of the effectiveness of individual, community and societal interventions in reducing socio-economic inequalities in obesity among adults. METHODS: Nine electronic databases were searched from start date to October 2012 along with website and grey literature searches. The review examined the best available international evidence (both experimental and observational) of interventions at an individual, community and societal level that might reduce inequalities in obesity among adults (aged 18 years or over) in any setting and country. Studies were included if they reported a body fatness-related outcome and if they included a measure of socio-economic status. Data extraction and quality appraisal were conducted using established mechanisms and narrative synthesis was conducted. RESULTS: The 'best available' international evidence was provided by 20 studies. At the individual level, there was evidence of the effectiveness of primary care delivered tailored weight loss programmes among deprived groups. Community based behavioural weight loss interventions and community diet clubs (including workplace ones) also had some evidence of effectiveness-at least in the short term. Societal level evaluations were few, low quality and inconclusive. Further, there was little evidence of long term effectiveness, and few studies of men or outside the USA. However, there was no evidence to suggest that interventions increase inequalities. CONCLUSIONS: The best available international evidence suggests that some individual and community based interventions may be effective in reducing socio-economic inequalities in obesity among adults in the short term. Further research is required particularly of more complex, multi-faceted and societal-level interventions. PMID- 24813370 TI - Sugar-sweetened beverages and dental caries in adults: a 4-year prospective study. AB - OBJECTIVES: To explore the association between frequency of consumption of sugar sweetened beverages (SSB) and caries increment over 4 years in adults. A second objective was to explore whether the association between frequency of SSB consumption and caries increment varied by socio-demographic characteristics and use of fluoride toothpaste. METHODS: Data from 939 dentate adults who participated in both the Health 2000 Survey and the Follow-Up Study of Finnish Adults' Oral Health were analysed. At baseline, participants provided information on demographic characteristics, education and dental behaviours, including two questions on frequency of SSB consumption. The 4-year net DMFT increment was calculated using data from baseline and follow-up clinical oral examinations. The association was tested in negative binomial regression models and the moderating role of sex, age, education and use of fluoride toothpaste was examined by adding their two-way interaction with SSB consumption to the main effects model. RESULTS: A positive association was found between frequency of SBS consumption and 4-year net DMFT increment, regardless of participants' socio-demographic and behavioural characteristics. Adults drinking 1-2 and 3+ SSB daily had, respectively, 31% (Incidence Rate Ratio: 1.31; 95%CI: 1.02-1.67) and 33% (IRR: 1.33; 95%CI; 1.03-1.72) greater net DMFT increments than those not drinking any SSB. None of the four two-way interaction terms was significant (all p>0.05). CONCLUSION: There seems to be a dose-response relationship between frequency of SSB consumption and caries increment in adults. That association was consistent across socio-demographic characteristics, and more importantly, use of fluoride toothpaste. CLINICAL SIGNIFICANCE: Drinking sugar-sweetened beverages on a daily basis is related to greater caries risk in adults. PMID- 24813371 TI - Blossoming of nanosheet structures via a disturbed self-assembly. AB - Nanofabrication has been critical in all kinds of nanotechnology, not only for achieving various nanostructures or nanosystems but also for the application of the nanotechnology. To achieve controllable but simple nanofabrication is one of the central aspirations for many research communities; here, for the first time, we report the growth of nanosheet structures simply by introducing internal disturbances (adding nanoparticles and surface tension) or external disturbances (deformations) to the self-assembly of copolymers induced by evaporation. Nanoparticles, curved surface, and deformations by such as writing or extension have been employed to demonstrate the sensitivity of the nanosheet structures to various disturbances. Finally, a physical model has been proposed to explain how the disturbances contribute to the formation of the nanosheet structures. These significant results indicate a scalable, writable, cost-effective and environmentally friendly nanotechnology that will stimulate new nanofabrication research. PMID- 24813372 TI - Evaluating the performance of integrated approaches for hazard identification of skin sensitizing chemicals. AB - The currently available animal-free methods for the detection of skin sensitizing potential of chemicals seem promising. However, no single method is able to comprehensively represent the complexity of the processes involved in skin sensitization. To ensure a mechanistic basis and cover the complexity, multiple methods should be integrated into a testing strategy, in accordance with the adverse outcome pathway that describes all key events in skin sensitization. Although current majority voting testing strategies have proven effective, the performance of individual methods is not taken into account. To that end, we designed a tiered strategy based on complementary characteristics of the included methods, and compared it to a majority voting approach. This tiered testing strategy was able to correctly identify all 41 chemicals tested. In terms of total number of experiments required, the tiered testing strategy requires less experiments compared to the majority voting approach. On the other hand, this tiered strategy is more complex due the number of different alternative methods required, and predicted costs are similar for both strategies. Both the tiered and majority voting strategies provide a mechanistic basis for skin sensitization testing, but the strategy most suitable for regulatory decision-making remains to be determined. PMID- 24813373 TI - Hypothesis-driven weight of evidence analysis to determine potential endocrine activity of MTBE. AB - Endocrine-related endpoints in animals have been reported to respond to high doses of methyl tertiary-butyl ether (MTBE), however, a systematic and transparent evaluation of endocrine potential has not been published. Resolving whether MTBE exhibits endocrine activity is important given regulatory and public interest in endocrine disrupting substances and their potential for causing adverse effects in humans or wildlife. A weight-of-evidence (WoE) analysis was conducted, focusing on hypotheses related to the potential for MTBE to interact with estrogen, androgen, and thyroid pathways, and steroidogenesis. To reach scientifically justified conclusions based on the totality of evidence, this WoE procedure involved a semi-quantitative relevance weighting of each endpoint for each hypothesis and systematic consideration of each endpoint in various study designs. This procedure maximized use of an extensive body of relevant and reliable literature on MTBE with evidence supporting or opposing a given mode of action hypothesis. Evaluating the strength and consistency of observations from many MTBE studies also provided a way to assess whether high doses used in experiments with MTBE confound identification of direct endocrine system responses. Based on results of studies using mammalian and fish models and in vitro screening assays, this WoE assessment reveals that MTBE lacks direct endocrine activity. PMID- 24813375 TI - Axle length does not affect switching dynamics in degenerate molecular shuttles with rigid spacers. AB - For a series of [2]rotaxane molecular shuttles possessing linear rigid rod-like axles of varying lengths between degenerate recognition sites, the activation barrier for shuttling motion was clearly shown to be constant. Moreover, dynamic NMR studies have revealed that both the entropic and enthalpic contributions to the shuttling motion remain constant regardless of the actual length of the rigid rod-like axles employed herein. PMID- 24813374 TI - Dopamine transporter genotype and stimulant dose-response in youth with attention deficit/hyperactivity disorder. AB - OBJECTIVES: This study seeks to determine if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (D-MPH) and mixed amphetamine salts (MAS) in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Fifty-six children and adolescents (mean age=11.7+/-2.2) participated in a double-blind, two period crossover, dose-response study with a randomized placebo week in each 4 week drug period. Each period consisted of sequential week-long exposures to three dose levels (10, 20, 25-30 mg, depending upon weight) of D-MPH or MAS. RESULTS: Doses of 10-20 mg of either D-MPH or MAS had little to no effect on hyperactivity impulsivity and total ADHD symptom scores in subjects with the 9/9 genotype; this was in contrast to the dose-response curves of subjects with either the 10/10 or 10/9 genotype. CONCLUSIONS: ADHD youth with the 9/9 genotype may require higher stimulant doses to achieve adequate symptom control. PMID- 24813376 TI - Stimulation of duodenal biopsies and whole blood from dogs with food-responsive chronic enteropathy and healthy dogs with Toll-like receptor ligands and probiotic Enterococcus faecium. AB - The composition of the microbiome plays a significant role in the pathogenesis of inflammatory bowel disease (IBD) in humans and chronic enteropathies (CE) in dogs. The administration of probiotic micro-organisms is one way of modulating the microbiome, but experiments elucidating mechanisms of action of probiotics in the intestine of healthy and CE dogs are lacking. The aim of our study was to investigate the effects of different Toll-like receptor (TLR) ligands and Enterococcus faecium (EF) on ex vivo cultured duodenal samples and whole blood (WB) from dogs with food-responsive chronic enteropathy (FRE) when compared to healthy dogs. Biopsy stimulation was performed in 17 FRE and 11 healthy dogs; WB stimulation was performed in 16 FRE and 16 healthy dogs. Expression of TLR2, 4, 5 and 9, IL-17A, IL-22, IFNy, TNFalpha, IL-4, IL-10, TGFbeta and PPARy was determined in biopsies by quantitative polymerase chain reaction (PCR). In addition, production of TNFalpha, IL-10, IFNy and IL-17A protein in WB and biopsy supernatants was assessed by ELISA. Treatment with individual TLR ligands or EF induced a variety of changes in the expression of different TLRs and cytokines, but not necessarily a consistent change with a single stimulating agent. Even though cytokine protein could not be detected in supernatants from ex vivo stimulated biopsies, we found TNFalpha protein responses in blood to be opposite of the transcriptional responses seen in the biopsies. Stimulation of canine duodenal biopsies with TLR ligands can potentially induce anti-inflammatory gene expression, especially in healthy tissue, whereas the effects of EF were limited. PMID- 24813377 TI - Fragmented QRS as a candidate marker for high-risk assessment in hypertrophic cardiomyopathy. AB - BACKGROUND: The relationship between a fragmented QRS complex (fQRS) on 12-lead ECG and fatal arrhythmic events in hypertrophic cardiomyopathy (HCM) remains unclear. OBJECTIVE: The purpose of this study was to investigate whether fQRS is associated with ventricular arrhythmic events (VAEs) in HCM patients. METHODS: Of an initial cohort of 273 patients (57% male, mean age 55 years) diagnosed with HCM, 167 patients were included and divided into 2 groups: those with fQRS (n = 67) and those without fQRS (n = 100). fQRS was defined as notching of the R or S wave in 2 contiguous leads. VAEs were defined as nonsustained or sustained ventricular tachycardia (VT) or sudden cardiac death (SCD). Major arrhythmic events (MAEs) were sustained VT or SCD. RESULTS: During mean follow-up of 6.3 years, univariate analysis showed that fQRS was significantly associated with increased VAEs (unadjusted hazard ratio [HR] 6.17, 95% confidence interval [CI] 2.46-15.49, P < .001) and MAEs (unadjusted HR 5.12, 95% CI 1.38-19.01, P = .014). Multivariate analysis revealed that fQRS was a strong independent predictor of VAEs (adjusted HR 6.28, 95% CI 2.49-15.84, P < .001) and MAEs (adjusted HR 6.04, 95% CI 1.49-24.39, P = .011). fQRS in the inferior leads was most closely related to MAEs compared to fQRS in other myocardial territories, and its inclusion in a risk calculator for mortality in HCM patients increased the positive predictive value from 8% to 25% in low-risk patients. CONCLUSION: Presence of an fQRS may be a good candidate marker for prediction of VAE in patients with HCM. PMID- 24813378 TI - Combination therapy of cilostazol and bepridil suppresses recurrent ventricular fibrillation related to J-wave syndromes. AB - BACKGROUND: Brugada syndrome and idiopathic ventricular fibrillation (VF) associated with inferolateral early repolarization patterns are termed "J-wave syndromes." In such patients, an implantable cardioverter-defibrillator (ICD) is first-line therapy for prevention of sudden cardiac death. However, frequent ICD shocks due to recurrent VF remain serious problems. OBJECTIVE: The purpose of this study was to ascertain if combination therapy of cilostazol and bepridil could suppress recurrent VF. METHODS: We enrolled 7 patients with J-wave syndromes who experienced ICD shocks due to recurrent VF after ICD implantation. At first, cilostazol was instituted. In all subjects, palpitations due to sinus tachycardia caused by cilostazol were symptomatic. Addition of bepridil attenuated cilostazol-induced palpitations and maintained the suppressive effect of cilostazol against VF (87 +/- 12 bpm to 66 +/- 7 bpm, P < .01). RESULTS: Six patients remained free of VF. Three patients underwent replacement of the ICD generator 4-5 years after ICD placement. Cilostazol was discontinued 2 days before replacement because of its antiplatelet effects. In all 3 patients, temporary discontinuation of cilostazol led to the reappearance of J waves, culminating in VF and an appropriate ICD shock in 1 patient. J waves disappeared with reinstitution of cilostazol. CONCLUSION: These data suggest that combination therapy of cilostazol and bepridil may be effective and safe in suppressing VF recurrence in some cases of J-wave syndromes. PMID- 24813379 TI - Mortality and cerebrovascular events after radiofrequency catheter ablation of atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is associated with a significant increase in the risk of stroke and mortality. It is unclear whether maintaining sinus rhythm (SR) after radiofrequency ablation (RFA) is associated with an improvement in stroke risk and survival. OBJECTIVE: The purpose of this study was to determine whether SR after RFA of AF is associated with an improvement in the risk of cerebrovascular events (CVEs) and mortality during an extended 10-year follow-up. METHODS: RFA was performed in 3058 patients (age 58 +/- 10 years) with paroxysmal (n = 1888) or persistent AF (n = 1170). The effects of time-dependent rhythm status on CVEs and cardiac and all-cause mortality were assessed using multivariable Cox models adjusted for baseline and time-dependent variables during 11,347 patient-years of follow-up. RESULTS: Independent predictors of a higher arrhythmia burden after RFA were age (estimated beta coefficient [beta] = 0.017 per 10 years, 95% confidence interval [CI] 0.006-0.029, P = .003), left atrial (LA) diameter (beta = 0.044 per 5-mm increase in LA diameter, 95% CI 0.034 0.055, P <.0001), and persistent AF (beta = 0.174, 95% CI 0.147-0.201, P <.0001). CVEs and cardiac and all-cause mortality occurred in 71 (2.3%), 33 (1.1%), and 111 (3.6%), respectively. SR after RFA was associated with a significantly lower risk of cardiac mortality (hazard ratio [HR] 0.41, 95% CI 0.20-0.84, P = .015). There was not a significant reduction in all-cause mortality (HR 0.86, 95% CI 0.58-1.29, P = .48) or CVEs (HR 0.79, 95% CI 0.48-1.29, P = .34) in patients who remained in SR after RFA. CONCLUSION: Maintenance of SR after RFA is associated with a reduction in cardiovascular mortality in patients with AF. PMID- 24813380 TI - Modern wound care - practical aspects of non-interventional topical treatment of patients with chronic wounds. AB - The treatment of patients with chronic wounds is becoming increasingly complex. It was therefore the aim of the members of the working group for wound healing (AGW) of the German Society of Dermatology (DDG) to report on the currently relevant aspects of non-interventional, topical wound treatment for daily practice. -Beside necessary procedures, such as wound cleansing and debridement, we describe commonly used wound dressings, their indications and practical use. Modern antiseptics, which are currently used in wound therapy, usually contain polyhexanide or octenidine. Physical methods, such as negative-pressure treatment, are also interesting options. It is always important to objectify and adequately treat pain symptoms which often affect these patients. Modern moist wound therapy may promote healing, reduce complications, and improve the quality of life in patients with chronic wounds. Together with the improvement of the underlying causes, modern wound therapy is an important aspect in the overall treatment regime for patients with chronic wounds. PMID- 24813381 TI - Novel de novo mutations of the interleukin-10 receptor gene lead to infantile onset inflammatory bowel disease. AB - BACKGROUND AND AIMS: Defects in the interleukin 10 (IL-10) signalling pathway have been shown to cause very early onset inflammatory bowel disease (IBD). We report a patient with severe infantile-onset IBD with a compound heterozygous IL 10 receptor alpha subunit (IL-10RA) mutation, one of which was paternally inherited and the other occurring de novo. METHODS: Deep sequencing of IL-10, IL 10RA and IL-10 receptor beta subunit (IL-10RB) were performed. Peripheral blood mononuclear cell (PBMC) surface expression of IL-10RA was analysed by flow cytometry. IL-10 signalling pathway was examined by measuring phosphorylated STAT3 in PBMC cultured in the presence of IL-6 or IL-10. RESULT: We identified a missense mutation in exon 4 of IL-10RA (c.583T>C) in one allele and a nonsense mutation in exon 7 of IL-10RA (c.1368G>T) in the other allele. Neither mutation has been reported previously. The patient has functional IL-10RA deficiency despite normal IL-10RA expression. CONCLUSION: This represents the first case report of a de novo mutation of IL-10RA that is associated with very early onset severe IBD. Therefore, IL-10 pathway defect should be considered in patients with infantile-onset IBD even if the parents are non-consanguineous. PMID- 24813382 TI - Long term results of acute Achilles repair with triple-bundle technique and early rehabilitation protocol. AB - BACKGROUND: The best treatment for acute rupture of the Achilles tendon is still under debate. Our purpose was to evaluate surgical triple-bundle technique in selected patients with full subcutaneous rupture of Achilles tendon. METHODS: Sixty-six consecutive patients (56 men, 10 women; age range 20-61 years) with full unilateral rupture of the Achilles tendon were surgically treated by the triple-bundle technique. Seventy-four percent of the lesions occurred during sport activity. Each patient was assessed by: (1) The American Orthopaedic Foot and Ankle Society (AOFAS) score; (2) the Leppilahti score; (3) the range of movement measurement of ankle joint; (4) ipsilateral thigh, calf, and ankle circumferences compared to the contralateral limb; (5) functional evaluation with isokinetic dynamometry of both limbs. RESULTS: 80.3% of the patients were fully satisfied (AOFAS >=90) with treatment and resumed their previous level of sport. Concerning the outcomes, (1) the mean AOFAS score at 36 months was 93.9; (2) the mean Leppilahti score at 36 months was 91.8; (3) the mean difference in dorsiflexion and plantarflexion between the healthy side and the operated side was 4.3 degrees and 6.9 degrees , respectively. We observed calf muscle hypotrophy in two cases and scar complication in one. No re-ruptures occurred. Isokinetic tests performed 36 months after surgery showed a good restoration of plantarflexion. At univariate analysis AOFAS was influenced by age and difference between the healthy side and the operated side in dorsiflexion, plantarflexion, and circumference at all three levels and strenght at 60 degrees /s. At univariate analysis, Leppilahti score confirmed the significant parameters of the AOFAS with the exception of age and difference of thigh circumference. The only predictive parameters in multivariate analysis were dorsiflexion difference (O.R. = 0.831; 95% C.I. 0.694-0.995; p = 0.044) and plantarflexion difference (O.R. = 0.777; 95% C.I. 0.631-0.958; p = 0.018). CONCLUSION: In this case series the triple-bundle technique showed a low rate of complications and good functional restore tested with isokinetic tests. For these reasons afforded by biomechanical strength test reported in literature, this technique has to be considered a valid choice for the treatment of Achilles tendon rupture in young patients with a high level of sport activity. PMID- 24813383 TI - Comparison of outcomes after triceps split versus sparing surgery for extra articular distal humerus fractures. AB - OBJECTIVES: To compare elbow range of motion (ROM), triceps extension strength, and functional outcome of AO/OTA type A distal humerus fractures treated with a triceps-split or -sparing approach. DESIGN: Retrospective review. SETTING: Two level one trauma centres. PATIENTS: Sixty adult distal humerus fractures (AO/OTA 13A2, 13A3) presenting between 2008 and 2012 were reviewed. Exclusion criteria removed 18 total patients from analysis and three patients died before final follow-up. INTERVENTION: Patients were divided into two surgical approach groups chosen by the treating surgeon: triceps split (16 patients) or triceps sparing (23 patients). MAIN OUTCOME MEASUREMENTS: Elbow ROM and triceps extension strength testing were completed in patients after fractures had healed. All patients were also given the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. RESULTS: Compared to the triceps-split cohort, the triceps-sparing cohort had greater elbow flexion (sparing 143 +/- 7 degrees compared to split 130 +/- 12 degrees , p=0.03) and less extension contracture (sparing 6 +/- 8 degrees compared to split 23 +/- 4 degrees , p<0.0001). Triceps strength compared to the uninjured arm also favoured the triceps-sparing cohort (sparing 88.9 +/- 28.3% compared to split 49.4 +/- 17.0%, p=0.007). DASH scores were not statistically significant between the two cohorts (sparing 14.5 +/- 12.2 compared to split 23.6 +/- 22.3, p=0.333). CONCLUSIONS: A triceps-sparing approach for surgical treatment of extra-articular distal humerus fractures can result in better elbow ROM and triceps strength than a triceps-splitting approach. Both approaches, however, result in reliable union and similar functional outcome. LEVEL OF EVIDENCE: Level III. PMID- 24813385 TI - Species limits in avian malaria parasites (Haemosporida): how to move forward in the molecular era. AB - Delimiting species of malaria parasites (Haemosporida) has become increasingly problematic as new lineages of parasites are identified solely by molecular information, particularly mitochondrial cytochrome b sequence data. In this review, we highlight some of the issues, both historical and contemporary, that have hindered the development of objective criteria to diagnose, delimit and define species of haemosporidians. Defining species is not the focal interest of most researchers, most of whom merely wish to determine whether lineages identified in their samples match those of other researchers, and if so, where and in which host species. Rather than revisiting all the issues with respect to delimiting and naming species, we instead focus on finding a practical near-term resolution to the 'species problem' that utilizes the community's largest resource: mitochondrial cytochrome b DNA sequences. We recommend a standardized procedure to 'tag' these sequences, based on per cent sequence similarity, that will allow researchers to directly assess the novelty, known hosts and geographic distribution of avian malaria parasite lineages. PMID- 24813384 TI - Participation of chronic patients in medical consultations: patients' perceived efficacy, barriers and interest in support. AB - AIMS: Chronic patients are increasingly expected to participate actively in medical consultations. This study examined (i) patients' perceived efficacy and barriers to participation in consultations, (ii) patients' interest in communication support and (iii) correlates of perceived efficacy and barriers, with an emphasis on differences across providers' disciplines. METHODS: A representative panel of chronic patients (n = 1314) filled out the short Perceived Efficacy in Patient-Provider Interaction scale and were questioned about barriers to participation and interest in communication support. Potential correlates included socio-demographic (age, sex, education, living situation), clinical (discipline care provider, type of illness, comorbidity, illness duration, functional disabilities, health consultations in last year) and personal characteristics (information preference, health literacy, level of general patient activation). RESULTS: Most patients felt efficacious in consultations, although 46% reported barriers to participation and 39% had an interest in support. Barriers most frequently recognized were 'not wanting to be bothersome', 'perception there is too little time' and 'remembering subjects only afterwards'. Patients most frequently endorsed relatively simple support. Patients perceived the least barriers and were least likely to endorse support when seeing a nurse. In multivariate models, consistent risk factors for low efficacy and perceived barriers were low health literacy and a low general patient activation. CONCLUSIONS: Many chronically ill patients feel confident in medical interactions. Still, a significant number might benefit from support. Often this concerned more generally vulnerable patients, that is, the low literate and generally less activated. Relatively simple supportive interventions are likely to be endorsed and might overcome frequent barriers. PMID- 24813386 TI - Insight into the effect of hydrogenation on efficiency of hydrothermal liquefaction and physico-chemical properties of biocrude oil. AB - Hydrothermal liquefaction of Nannochloropsis salina (N. salina) and larvae vermicompost were conducted under both non-hydrogenating and hydrogenating subcritical conditions using H2 and Ni-Mo/Al2O3. Hydrogenation raised biocrude yields from 33.2% to 43.5% (vermicompost) and 55.6% to 78.5% (N. salina), whereas high heat values increased from 32.89 to 34.24 MJ/kg (vermicompost) and 36.30 to 37.53 MJ/kg (N. salina). Compared with the non-hydrogenated HTL process, the contents of acids, amides, phenols, and alcohols decreased, whereas hydrocarbons content increased. More branched cyclic nitrogenous compounds were detected in the hydrogenated biocrudes, whereas the aromatic/hetero-aromatic functionality was somewhat decreased. Smaller molecular weights and polydispersity index of the hydrogenated biocrudes were also detected. Results show that hydrogenation enhanced the removal of hydrophilic functional groups and the stabilization of radicals, thereby leading to the inhibition of loss of mass toward liquid and gaseous products and the upgrading of oil quality. PMID- 24813387 TI - Selective removal of polycyclic aromatic hydrocarbons (PAHs) from soil washing effluents using biochars produced at different pyrolytic temperatures. AB - Wheat straw biochars produced at 400, 600 and 800 degrees C (BC400, BC600 and BC800) were used to selectively adsorb PAHs from soil washing effluents. For soil washing effluents contained Phenanthrene (PHE), Fluoranthene (FLU), Pyrene (PYR) and Triton X-100 (TX100), biochars at 2 (for BC800) or 6 g L(-1) (for BC400 and BC600) can remove 71.8-98.6% of PAHs while recover more than 87% of TX100. PAH removals increase with increasing biochar dose. However, excess biochar is detrimental to the recovery of surfactant. For a specific biochar dose, PAH removal and TX100 loss increase with increasing pyrolytic temperature. For BC400 and BC600, PAH removal follows the order of PHE>FLU>PYR, while the order is reversed with PYR>FLU>PHE for BC800. Biochars have much higher sorption affinity for PAHs than for TX100. It is therefore suggested that biochar is a good alternative for selective adsorption of PAHs and recovery of TX100 in soil washing process. PMID- 24813388 TI - A new absorbent by modifying walnut shell for the removal of anionic dye: kinetic and thermodynamic studies. AB - A novel, low cost and easy regeneration biosorbent, chem-modified walnut shell (MWNS), was studied to investigate its potential for removal of an anionic dye, reactive brilliant red K-2BP. The MWNS was synthesized with epichlorohydrin and diethylenetriamine as etherifying agent and crosslinking agent, respectively, and its characteristics were performed with Fourier transform infrared spectroscopy, scanning electron microscope, electron dispersive spectroscopy and thermogravimetric analysis. The influences of pH (0.5-11) and adsorbent dosage (0.1-6g/L) on adsorption capacity of MWNS were evaluated. The maximum K-2BP adsorption capacities (Qm) calculated by best fitting model (Langmuir) were 568.18 mg/g at 313 K, which was almost 10 times than that of raw material. The adsorption kinetic was well confirmed with pseudo-second-order equation. Thermodynamic studies demonstrated adsorption process by MWNS was spontaneous and endothermic. Furthermore, the regeneration capability of MWNS implied MWNS was a cheap, excellent and promising biosorbent for K-2BP removal in azo dye wastewater treatment. PMID- 24813389 TI - Evaluating the effects of scaling up on the performance of bioelectrochemical systems using a technical scale microbial electrolysis cell. AB - This study focuses on the challenges of the scaling up process of bioelectrochemical systems on the example of a technical scale microbial electrolysis cell referred to as the "prototype". Anodically treating real wastewater and operated in continuous mode at a hydraulic retention time of 1.23 d with an average chemical oxygen demand (COD)-loading rate of 0.5 g O2 d(-1) L Reactor(-1) the prototype on average showed COD removal efficiency of 67% with effluent concentrations of 210 mg O2 L(-1) and an ammonium elimination rate of 17.8 +/- 3.9 mg Nd(-1) L Reactor(-1) resulting in effluent concentrations of 30.7 +/- 3.7 mg NL(-1) with a removal efficiency of 40% at a current generation of 72 MUA cm(-2) and Coulomb efficiency of 11%. A model is described as a method for comparing conventional and BES based technology using the above mentioned criteria and balancing them against the respective loading rates. PMID- 24813390 TI - Improved antitumor activity and reduced cardiotoxicity of epirubicin using hepatocyte-targeted nanoparticles combined with tocotrienols against hepatocellular carcinoma in mice. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Epirubicin (EPI), an anthracycline derivative, is one of the main line treatments for HCC. However, serious side effects including cardiomyopathy and congestive heart failure limit its long term administration. Our main goal is to develop a delivery strategy that ensures improved efficacy of the chemotherapeutic agent together with reduced cardiotoxicity. In this context, EPI was loaded in chitosan-PLGA nanoparticles linked with asialofetuin (EPI-NPs) selectively targeting hepatocytes. In an attempt to reduce cardiotoxicity, targeted EPI-NPs were coadministered with tocotrienols. EPI-NPs significantly enhanced the antiproliferative effect compared to free EPI as studied on Hep G2 cell line. Nanoencapsulated EPI injected in HCC mouse model revealed higher p53 mediated apoptosis and reduced angiogenesis in the tumor. Combined therapy of EPI NPs with tocotrienols further enhanced apoptosis and reduced VEGF level in a dose dependent manner. Assessment of cardiotoxicity indicated that EPI-NPs diminished the high level of proinflammatory cytokine tumor necrosis factor-alpha (TNF alpha) as well as oxidative stress-induced cardiotoxicity as manifested by reduced level of lipid peroxidation products (TBARS) and nitric oxide (NO). EPI NPs additionally restored the diminished level of superoxide dismutase (SOD) and reduced glutathione (GSH) in the heart. Interestingly, tocotrienols provided both antitumor activity and higher protection against oxidative stress and inflammation induced by EPI in the heart. This hepatocyte-targeted biodegradable nanoparticle/tocotrienol combined therapy represents intriguing therapeutic strategy for EPI providing not only superior efficacy but also higher safety levels. PMID- 24813391 TI - Biodegradable nanoparticles composed of dendrigraft poly-L-lysine for gene delivery. AB - We developed novel gene vectors composed of dendrigraft poly-L-lysine (DGL). The transgene expression efficiency of the pDNA/DGL complexes (DGL complexes) was markedly higher than that of the control pDNA/poly-L-lysine complex. However, the DGL complexes caused cytotoxicity and erythrocyte agglutination at high doses. Therefore, gamma-polyglutamic acid (gamma-PGA), which is a biodegradable anionic polymer, was added to the DGL complexes to decrease their toxicity. The resultant ternary complexes (DGL/gamma-PGA complexes) were shown to be stable nanoparticles, and those with gamma-PGA to pDNA charge ratios of >8 had anionic surface charges. The transgene expression efficiency of the DGL/gamma-PGA complexes was similar to that of the DGL complexes; however, they exhibited lower cytotoxicity and did not induce erythrocyte agglutination at high doses. After being intravenously administered to mice, the DGL6 complex demonstrated high transfection efficiency in the liver, lungs, and spleen, whereas the DGL6/gamma PGA8 complex only displayed high transfection efficiency in the spleen. Future studies should examine the utility of DGL and DGL/gamma-PGA complexes for clinical gene therapy. PMID- 24813392 TI - What features differentiate unilateral from bilateral restless legs syndrome? A comparative observational study of 195 patients. AB - OBJECTIVE: Restless legs syndrome (RLS) is frequently misdiagnosed, mainly due to variability in the description of symptoms by patients. We observed some patients with classical RLS manifesting symptoms involving limbs on one side. This study was planned to evaluate various clinical and investigational parameters which might differentiate the profile of patients with unilateral versus bilateral RLS. METHODS: All patients diagnosed with RLS during an eight-year period, attending the Sleep Disorders Clinic, All India Institute of Medical Sciences, were studied. Clinical assessment was carried out from a pre-structured proforma, including details of the diagnostic criteria proposed by the International Restless Legs Syndrome Study Group of the National Institutes of Health. A detailed hemogram, serum ferritin, liver and kidney function tests, and nerve conduction studies with sympathetic skin response recording were obtained for all patients. To identify features, which differentiated patients with unilateral RLS versus those with bilateral RLS, various statistical tests of significance were used, as applicable. RESULTS: Among 195 patients, 161 (69 male, 92 female) with bilateral and 34 (12 male, 22 female) with unilateral RLS (mean age of 42 years +/-10-14), both with similar age and gender distribution, were enrolled. These could be further subdivided into those with strictly unilateral RLS and those with strictly unilateral onset (n=23), with later involvement of the opposite side, but with persistent asymmetry (n=11). Variables significantly differentiating unilateral from bilateral RLS group were: RLS being secondary versus primary (44% versus 55% in unilateral; 76% versus 23% in bilateral; OR, 4.2; CI, 2-9) and positive family history (36% in bilateral, 11% in unilateral; OR, 2.6; CI, 1.1-8). All other features were similar in both groups. CONCLUSIONS: Unilateral RLS is not rare (17%) and although similar to bilateral RLS in clinical features, this entity may more often be secondary and less often associated with a positive family history. These differences emerge from exploratory evaluations, however, and would need further confirmation through future studies. PMID- 24813393 TI - Narcolepsy in China: when the east meets the west. PMID- 24813394 TI - Excessive daytime sleepiness and nocturia in women. AB - OBJECTIVE: To investigate associations between excessive daytime sleepiness and nocturia in women. METHOD: A total of 488 women aged 18-89 years who underwent screening for cervical cancer at one institution in Florianopolis, Brazil, took part in this investigation. Sleep issues and daytime sleepiness, urinary frequency, and nutritional status were investigated. RESULTS: The prevalence of excessive daytime sleepiness was 31.3%. Most of the women reported having nocturia, since 32.4% reported one nocturnal voiding, and 24.3% two or more nocturnal voidings. Higher nocturnal voiding frequency was identified in women who spent longer in bed (P=0.028) and had worse quality of sleep (P<0.001), higher daytime sleepiness (P=0.016) and excess body weight (P<0.001). A higher prevalence of daytime sleepiness was also observed in those women assumed to have urine leakage (P=0.006). Women with two or more nocturnal voidings presented 1.58 (CI: 1.06-2.37) higher prevalence of daytime sleepiness independent of time in bed (P=0.030). CONCLUSION: Women with at least two nocturnal voidings presented higher prevalence of daytime sleepiness, worse sleep quality, and longer time in bed. Moreover, women with daytime sleepiness presented higher frequency of urine leakage. PMID- 24813395 TI - Changes in salivary cortisol levels in pediatric patients with obstructive sleep apnea syndrome after adenotonsillectomy. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) activates the stress response system, including the hypothalamic-pituitary-adrenocortical (HPA) axis. The salivary cortisol, as an index of free circulating cortisol levels, may be used as a measure of HPA axis activity. We examined the change in the salivary cortisol level in pediatric OSAS patients before and after adenotonsillectomy (AT). METHODS: Forty-eight subjects from 80 subjects suspicious of having OSAS were diagnosed with OSAS by overnight PSG, 34 of 48 OSAS patients undergoing AT, and 13 of 34 OSAS patients were finally enrolled prospectively for this study. Before and three months after the AT, the saliva was collected at night before PSG (n-sCor) and in the early morning after PSG (m-sCor) for the measurements of the salivary cortisol level. RESULTS: Children in the study population (n=13) were divided into mild (1< or = AHI <5, n=5), moderate (5 < or = AHI <10, n=3), and severe (AHI > or =10, n=5) OSAS groups. The mean preoperative AHI in the children was 14.7, and the mean postoperative AHI was 0.33. The percentage of children with AHI <1 after AT was 92.3%. Postoperative m-sCor, the difference of cortisol level (sub-sCor: m-sCor minus n-sCor), and the ratio of cortisol level (r-sCor: m-sCor/n-sCor) showed significant difference postoperatively. CONCLUSIONS: AT was associated with improvements in PSG and subjective symptoms in pediatric OSAS patients. In addition, these improvements were significantly related to normalization of salivary cortisol level after AT. Although further study on salivary cortisol levels needs to be done, the measurement of salivary cortisol level before and after AT may predict the outcome of AT as a treatment of OSAS. PMID- 24813397 TI - The type 1 copper site of pseudoazurin: axial and rhombic. AB - We report on a high-frequency electron-paramagnetic-resonance study of the type 1 copper site of pseudoazurin. The spectra fully resolve the contribution of a nearly axial spectrum besides the rhombic spectrum, which unequivocally proves the existence of two conformations of the copper site. Pseudoazurins have been considered from Achromobacter cycloclastes including eight mutants and from Alcaligenes faecalis. The two conformations are virtually the same for all pseudoazurins, but the rhombic/axial population varies largely, between 91/9 and 33/67. These observations are discussed in relation to optical absorption spectra and X-ray diffraction structures. A similar observation for fern plastocyanin from Dryopteris crassirhizoma suggests that dual conformations of type 1 copper sites are more common. PMID- 24813398 TI - Metal ions modulate thermal aggregation of beta-lactoglobulin: a joint chemical and physical characterization. AB - Molecular basis of the role played by Cu(2+) and Zn(2+) ions during the thermal aggregation processes of beta-lactoglobulin (BLG) was studied by using a joint application of different techniques. In particular, Raman spectroscopy was very useful in identifying the different effects caused by the two metals at molecular level (i.e. changes in His protonation state, disulfides bridge conformation, and micro-environment of aromatic residues), evidencing the primary importance of the protein charge distribution during the aggregation process. Both metal ions are able to act on this factor and favor the protein aggregation, but Zn(2+) is able to alter the natural conformational state of BLG, causing a slight unfolding, whereas Cu(2+) ions play a role only during the thermal treatment. Thus, Zn(2+) ions favor the formation of bigger aggregates and branched fibril-like structures, whereas for Cu(2+) ions a greater number of cross-beta structures during thermal incubation and finally, fibrillar structures. The aggregation process occurs in two phases, as suggested by the measurements on the time evolution of the BLG aggregates: the first one is characterized by a partial unfolding of the protein and aggregate growth, forming oligomers and protofibrils, whereas the second one is characterized by further supramolecular assembly, leading to the formation of fibrils. PMID- 24813396 TI - Suppression of MAPK/JNK-MTORC1 signaling leads to premature loss of organelles and nuclei by autophagy during terminal differentiation of lens fiber cells. AB - Although autophagic pathways are essential to developmental processes, many questions still remain regarding the initiation signals that regulate autophagy in the context of differentiation. To address these questions we studied the ocular lens, as the programmed elimination of nuclei and organelles occurs in a precisely regulated spatiotemporal manner to form the organelle-free zone (OFZ), a characteristic essential for vision acuity. Here, we report our discovery that inactivation of MAPK/JNK induces autophagy for formation of the OFZ through its regulation of MTORC1, where MAPK/JNK signaling is required for both MTOR activation and RPTOR/RAPTOR phosphorylation. Autophagy pathway proteins including ULK1, BECN1/Beclin 1, and MAP1LC3B2/LC3B-II were upregulated in the presence of inhibitors to either MAPK/JNK or MTOR, inducing autophagic loss of organelles to form the OFZ. These results reveal that MAPK/JNK is a positive regulator of MTORC1 signaling and its developmentally regulated inactivation provides an inducing signal for the coordinated autophagic removal of nuclei and organelles required for lens function. PMID- 24813399 TI - PERK pathway are involved in NO-induced apoptosis in endothelial cells cocultured with RPE under high glucose conditions. AB - Although excessive nitric oxide (NO) induced from iNOS is critical for dysfunction of vascular endothelial cells (ECs) in the diabetic retina, its role on ECs injury remains unknown. RPE (retinal pigment epithelium) is the pigmented cell layer just outside the neurosensory retina that constitutes the blood retinal-barrier (BRB) with ECs, and also serves as the limiting transport factor that maintains the retinal environment. Dysfunction of the RPE is related to oxidative stress that contributes to the progression of diabetic retina. Using a co-cultural biosystem, we demonstrate that NO generation and iNOS expression was increased in both ECs and RPE cells after high glucose treatment. Increased NO in ECs cocultured with RPE activate the endoplasmic reticulum (ER) and protein kinase RNA (PKR)-like ER kinase (PERK) pathway and involved in ECs apoptosis. Blockade of the iNOS pathway, or depletion of PERK effectively, reverses NO mediated apoptosis. Our study demonstrates that iNOS and subsequently excessive NO generation in RPE cells can have an unanticipated effect by activating PERK pathways in ECs, resulting in a novel mechanism for vascular endothelium to avoid injury from prolonged hyperglycemia. PMID- 24813400 TI - The role of poverty status and obesity on school attendance in the United States. AB - PURPOSE: Several studies have shown that obesity influences school performance. Little is known about the joint effect of poverty and obesity associated with school attendance. METHODS: Data are from the National Survey of Children's Health (N = 93,151), a nationally representative sample of U.S. youth aged 10-17 years. Our dependent variable was >=11 days of school days missed per year. Body mass index was classified as normal, overweight, and obese using age- and sex specific criteria. Federal poverty level (FPL) was classified as <200%, 200% 399%, and >=400% (high income). Covariates included gender, age, child's race or ethnicity, maternal physical and mental health, child's health, family composition, and household tobacco use. Logistic regression models and prevalence ratios were estimated, accounting for the complex survey design. RESULTS: The odds of missing >=11 days of school among overweight youth was 1.5 times that of normal-weight youth (95% confidence interval (CI) = 1.22-1.85) and 1.7 (95% CI = 1.35-2.13) times among obese youth in fully adjusted models. In joint effects models, the probability of missing school was significantly greater for obese youth in both the <200% FPL group (prevalence ratio = 1.78, CI = 1.36-2.34) and the >=400% FPL group (prevalence ratio = 2.88, CI = 1.91-4.35), when compared with their normal-weight, higher income peers. Predicted probabilities revealed sharper gradients for higher income youth. CONCLUSIONS: Obesity influences school absenteeism across all income categories. Nonetheless, there may be distinct reasons for missing school for lower and higher income youth, and the long-term consequences of school absences may also differ for these populations. PMID- 24813401 TI - PCR based differentiation between Streptococcus dysgalactiae subsp. equisimilis strains isolated from humans and horses. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE) can be severely pathogenic in humans and is increasingly isolated from horses with respiratory, reproductive or other diseases, although it is often considered a commensal bacterium. Here a PCR protocol is described for identifying SDSE recovered from humans. A multiplex PCR targeting the 16S rRNA and the streptokinase precursor gene has been optimized for differentiating between SDSE strains isolated from humans and those isolated from horses. Previously, the sequence of the streptokinase precursor gene of SDSE recovered from horses has been found in two human cases of pneumonia in Japan. Although further evaluation is required, the findings of this study suggest that SDSE strains are host-specific and this multiplex PCR protocol can be useful in further epidemiological studies and for investigating the zoonotic potential of SDSE. PMID- 24813402 TI - Clinical characteristics and outcome of patients with Clostridium difficile infection diagnosed by PCR versus a three-step algorithm. AB - Clinical features of Clostridium difficile infections (CDI) detected by PCR, but not by conventional methods, are poorly understood. We compared the clinical features of CDI cases detected by PCR only and cases detected by both PCR and a three-step algorithm. We performed a retrospective cohort study of patients fulfilling a standardized definition over a 13-month period. Stool specimens were tested in parallel by PCR and an algorithm based on enzyme immunoassay and cytotoxicity assay (EIA/CCA). Clinical features of CDI cases detected by PCR only and cases detected by PCR and EIA/CCA were compared by univariate logistic regression. In all, 97 patients (31 PCR+ and 66 PCR+EIA/CCA+) met the inclusion criteria. Compared with cases detected by both PCR and EIA/CCA, CDI cases detected by PCR only were younger (65.4 versus 76.3 years; p 0.001), had a lower absolute neutrophil count (mean, 9.4 * 10(9) /L versus 12.5 * 10(9) /L; p 0.04), were less likely to receive oral vancomycin (2/31 versus 25/66; p 0.005) or combination therapy (0/31 versus 16/66; p 0.04), and had fewer complications (6/31 versus 29/66; p 0.02), despite presenting a higher number of bowel movements on the day of diagnosis (median, 6.0 versus 3.0; p 0.02). They had also a lower C. difficile faecal bacterial load (mean, 5.04 versus 6.89 log10 CFU/g; p <0.001). The CDI cases detected by PCR only and cases detected by both PCR and EIA/CCA have different clinical features, but whether these two populations can be managed differently remains to be determined. PMID- 24813403 TI - Schizophrenia: mechanism of action of current and novel treatments. PMID- 24813404 TI - The impact of cannabis and stimulant disorders on diagnostic stability in psychosis. AB - BACKGROUND: Substance abuse adds to diagnostic uncertainty in psychosis and may increase the risk of transition from brief and affective psychoses to schizophrenia. This study examined whether comorbid substance disorder was associated with diagnostic instability and progression from other psychosis diagnoses to schizophrenia and whether effects differed for cannabis and stimulant-related disorders. METHOD: We identified 24,306 individuals admitted to hospital with an ICD-10 psychosis diagnosis between 2000 and 2011. We examined agreement between initial diagnosis and final diagnosis over 2-5 years and predictors of diagnostic change toward and away from a final diagnosis of schizophrenia. RESULTS: Nearly half (46%) of participants with initial brief, atypical, or drug-induced psychoses were later diagnosed with schizophrenia. Persisting illicit drug disorders did not increase the likelihood of progression to schizophrenia (OR = 0.97; 95% CI, 0.89-1.04) but increased the likelihood of revision of index psychosis diagnosis away from schizophrenia (OR = 1.55; 95% CI, 1.40-1.71). Cannabis disorders predicted an increased likelihood of progression to schizophrenia (OR =1.12; 95% CI, 1.01-1.24), while stimulant disorders predicted a reduced likelihood (OR = 0.81; 95% CI, 0.67-0.97). Stimulant disorders were associated with greater overall diagnostic instability. CONCLUSIONS: Many people with initial diagnoses of brief and affective psychoses are later diagnosed with schizophrenia. Cannabis disorders are associated with diagnostic instability and greater likelihood of progression to schizophrenia. By contrast, comorbid stimulant disorders may be associated with better prognosis in psychosis, and it may be important to avoid premature closure on a diagnosis of schizophrenia when stimulant disorders are present. PMID- 24813405 TI - The changing landscape of psychiatry. PMID- 24813406 TI - Attention-deficit/hyperactivity disorder symptom expression: a comparison of individual age at onset using item response theory. AB - BACKGROUND: The DSM-IV age at onset criterion for attention-deficit/hyperactivity disorder (ADHD) has been a subject of debate. In DSM-5, the required age at onset (ie, the age by which impairing symptoms must have been present) has increased from 7 years to 12 years. The present study examined measurement properties of ADHD symptoms according to age at onset. METHOD: Data were derived from the 2004 2005 National Epidemiologic Survey on Alcohol and Related Conditions, which included 34,653 US participants. Among participants with a lifetime DSM-IV diagnosis of ADHD (assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV), we compared the psychometric properties of the 18 ADHD symptoms according to 3 categories of age at onset (<= 7 years, > 7 and <= 12 years, and > 12 and <= 18 years). A 2-parameter item response model was used to estimate differential item functioning (DIF) between these groups. RESULTS: 364 participants with a lifetime DSM-IV diagnosis of ADHD had an age at onset <= 7 years, 252 had an age at onset > 7 and <= 12 years, and 148 had an age at onset > 12 and <= 18 years. In both dimensions of ADHD (ie, inattention and hyperactivity-impulsivity), there was no significant DIF between age at onset groups. CONCLUSIONS: Expression of DSM-IVADHD symptoms was not affected by age at onset in the 3 groups considered. This study provides psychometric support to the change in the age criterion introduced by DSM-5 and further suggests that the age at onset criterion could be extended to 18 years without changing the psychometric properties of the ADHD symptoms. PMID- 24813407 TI - Relationship between acculturation, discrimination, and suicidal ideation and attempts among US Hispanics in the National Epidemiologic Survey of Alcohol and Related Conditions. AB - OBJECTIVE: Acculturation is the process by which immigrants acquire the culture of the dominant society. Little is known about the relationship between acculturation and suicidal ideation and attempts among US Hispanics. Our aim was to examine the impact of 5 acculturation measures (age at migration, time in the United States, social network composition, language, race/ethnic orientation) on suicidal ideation and attempts in the largest available nationally representative sample of US Hispanics. METHOD: Study participants were US Hispanics (N = 6,359) from Wave 2 of the 2004-2005 National Epidemiologic Survey of Alcohol and Related Conditions (N = 34,653). We used linear chi(2) tests and logistic regression models to analyze the association between acculturation and risk of suicidal ideation and attempts. RESULTS: Factors associated with a linear increase in lifetime risk for suicidal ideation and attempts were (1) younger age at migration (linear chi(2)(1) = 57.15; P < .0001), (2) longer time in the United States (linear chi(2)(1)= 36.09; P < .0001), (3) higher degree of English language orientation (linear chi(2)(1) = 74.08; P <.0001), (4) lower Hispanic composition of social network (linear chi(2)(1) = 36.34; P < .0001), and (5) lower Hispanic racial/ethnic identification (linear chi(2)(1) = 47.77; P <.0001). Higher levels of perceived discrimination were associated with higher lifetime risk for suicidal ideation (beta = 0.051; P < .001) and attempts (beta = 0.020; P = .003). CONCLUSIONS: There was a linear association between multiple dimensions of acculturation and lifetime suicidal ideation and attempts. Discrimination was also associated with lifetime risk for suicidal ideation and attempts. Our results highlight protective aspects of the traditional Hispanic culture, such as high social support, coping strategies, and moral objections to suicide, which are modifiable factors and potential targets for public health interventions aimed at decreasing suicide risk. Culturally sensitive mental health resources need to be made more available to decrease discrimination and stigma. PMID- 24813408 TI - Climate and prevalence of mood disorders: a cross-national correlation study. PMID- 24813409 TI - Latest guidelines and advances for treatment of restless legs syndrome. AB - Restless legs syndrome (RLS) is a common disorder that can have a considerable impact on a patient's functioning and quality of life. The pharmacologic armamentarium for RLS contains dopamine agonists, a-2d ligands, and opioids, among other agents. Each of these types of drugs has strengths and limitations, and treatment selection should be based on the frequency of RLS symptoms and any accompanying pain. Dopaminergic augmentation, which exacerbates RLS symptoms, is the most common and challenging side effect of long-term RLS treatment with dopamine agonists and requires special clinical consideration. Iron status is also important to the effective management of RLS. PMID- 24813410 TI - Recognizing primary vs secondary negative symptoms and apathy vs expression domains. AB - Negative symptoms of schizophrenia include blunted affect, alogia, asociality, anhedonia, and avolition. Rating scales are helpful for recognizing and monitoring these symptoms, but clinicians must determine whether the symptoms are primary or secondary. Secondary negative symptoms can be caused by depression, psychotic symptoms, medication side effects, and substance abuse, and they usually improve with treatment of the underlying cause. On most rating scales, negative symptoms have been found to load onto 1 of 2 domains-apathy or diminished expression. This distinction may facilitate the development of new treatments. PMID- 24813411 TI - Acute and maintenance treatments for bipolar depression. AB - Patients with bipolar disorder are symptomatic about half of the time, experiencing depression more often than mania/hypomania. Because patients usually seek treatment during a depressive episode (rather than a manic episode), bipolar depression is commonly misdiagnosed as unipolar depression. Providing an accurate and timely bipolar depression diagnosis is critical for the proper treatment of the patient. Some FDA-approved treatments are helpful during acute and maintenance phases of therapy, but there is a significant unmet need for effective bipolar depression treatments with favorable side-effect profiles. Newer agents offer the promise of improvements in tolerability, but additional research is needed to actualize this promise into better treatments for patients struggling with bipolar depression. PMID- 24813412 TI - Potentially significant versus clinically significant drug interactions: pomegranate juice as a case in point. AB - In vitro and in vivo laboratory data show that pomegranate juice consistently inhibits intestinal CYP2C9 and CYP3A4 enzymes. Pomegranate juice may therefore increase the bioavailability of drugs that are metabolized by these enzymes. However, studies in humans find that pomegranate juice does not increase exposure to either CYP2C9 or CYP3A4 substrates. These contradictory findings suggest that potential drug interactions identified in the laboratory may not necessarily translate into clinically significant drug interactions in humans, and hence that laboratory data are insufficient grounds upon which clinical decisions may be based. PMID- 24813413 TI - Translating molecular advances in fragile X syndrome into therapy: a review. AB - Fragile X syndrome is an inherited disease with cognitive, behavioral, and neurologic manifestations, resulting from a single genetic mutation. A variety of treatments that target individual symptoms of fragile X syndrome are currently utilized with limited efficacy. Research in animal models has resulted in the development of potential novel pharmacologic treatments that target the underlying molecular defect in fragile X syndrome, rather than the resultant symptoms. This review describes recent advances in our understanding of the molecular basis of fragile X syndrome and summarizes the ongoing clinical research programs. PMID- 24813414 TI - Determinants of antipsychotic response in schizophrenia: implications for practice and future clinical trials. AB - BACKGROUND: Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials. OBJECTIVE: We aimed to understand determinants of response to antipsychotic treatment. METHOD: Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580). RESULTS: While it is conventional for trials to be 6 weeks long, drug placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P <= .04), being a young adult patient who is a few years beyond the first episode (P <= .03), having prominent positive and negative symptoms (P <= .03), and living in Eastern Europe versus North America (P <= .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented. CONCLUSIONS: Proof of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments. PMID- 24813416 TI - Monodispersed Ag nanoparticles as catalyst: preparation based on crystalline supramolecular hybrid of decamethylcucurbit[5]uril and silver ions. AB - Monodispersed silver nanoparticles (Ag(0) NPs) have been first prepared on the basis of a postsynthesis via mild reduction from a new crystalline supramolecular hybrid solid assembled from Ag(+) ions and decamethylcucurbit[5]uril (Me10CB[5]). Uniform growth of nearly spherical Ag(0) NPs with an average size of ca. 4.4 nm was observed on the organic Me10CB[5] support to form Ag@Me10CB[5] composite material. The as-synthesized composite material was characterized by a range of physical measurements (PXRD, TGA, XPS, ICP, TEM, etc.) and was further exploited as a heterogeneous catalyst for the reduction of various nitrophenols in the presence of NaBH4. The kinetics of the reduction process was monitored under various experimental conditions. The Ag@Me10CB[5] composite material showed excellent catalytic performance over the reduction reactions and remained active after several consecutive cycles. PMID- 24813415 TI - Intranasal immunisation of the recombinant Toxoplasma gondii receptor for activated C kinase 1 partly protects mice against T. gondii infection. AB - Nasal vaccination is an effective therapeutic regimen for preventing certain infectious diseases. The mucosal immune response is important for resistance to Toxoplasma gondii infection. In this study, we evaluated the immune responses elicited in BALB/c mice by nasal immunisation with recombinant T. gondii receptor for activated C kinase 1 (rTgRACK1) and their protective efficacy against T. gondii RH strain during both chronic and lethal infections. Nasal vaccination with rTgRACK1 increased the level of secretory IgA in nasal, intestinal and vesical washes, and the level of IFN-gamma and IL-2 in intestinal washes, indicating that rTgRACK1 vaccination promotes mucosal immune responses. The mice immunised with rTgRACK1 also displayed increased levels of rTgRACK1-specific IgA, total IgG, IgG1 and in particular IgG2a in their blood sera, increased production of IFN-gamma, IL-2 and IL-4 but not IL-10 from their isolated spleen cells, and enhanced splenocyte proliferation in vitro. rTgRACK1-vaccinated mice were effectively protected against infection with T. gondii RH strain, showing over 50% reduction of tachyzoite burdens in their liver and brain tissues during a chronic infection, and also a 45% increase in their survivals during a lethal challenge. These results indicate that rTgRACK1 might represent an intriguing immunogen for developing a mucosal vaccine against toxoplasmosis. PMID- 24813417 TI - Genomic analysis of clonal eosinophils by CGH arrays reveals new genetic regions involved in chronic eosinophilia. AB - To assess the presence of genetic imbalances in patients with myeloproliferative neoplasms (MPNs), 38 patients with chronic eosinophilia were studied by array comparative genomic hybridization (aCGH): seven had chronic myelogenous leukaemia (CML), BCR-ABL1 positive, nine patients had myeloproliferative neoplasia Ph- (MPN Ph-), three had a myeloid neoplasm associated with a PDGFRA rearrangement, and the remaining two cases were Lymphoproliferative T neoplasms associated with eosinophilia. In addition, 17 patients had a secondary eosinophilia and were used as controls. Eosinophilic enrichment was carried out in all cases. Genomic imbalances were found in 76% of all MPN patients. Losses on 20q were the most frequent genetic abnormality in MPNs (32%), affected the three types of MPN studied. This study also found losses at 11q13.3 in 26% of patients with MPN-Ph- and in 19p13.11 in two of the three patients with an MPN associated with a PDGFRA rearrangement. In addition, 29% of patients with CML had losses on 8q24. In summary, aCGH revealed clonality in eosinophils in most MPNs, suggesting that it could be a useful technique for defining clonality in these diseases. The presence of genetic losses in new regions could provide new insights into the knowledge of these MPN associated with eosinophilia. PMID- 24813419 TI - Cuprate superconductors: Dynamic stabilization? PMID- 24813418 TI - Proton switch for modulating oxygen reduction by a copper electrocatalyst embedded in a hybrid bilayer membrane. AB - Molecular switches gate many fundamental processes in natural and artificial systems. Here, we report the development of an electrochemical platform in which a proton carrier switches the activity of a catalyst. By incorporating an alkyl phosphate in the lipid layer of a hybrid bilayer membrane, we regulate proton transport to a Cu-based molecular oxygen reduction reaction catalyst. To construct this hybrid bilayer membrane system, we prepare an example of a synthetic Cu oxygen reduction reaction catalyst that forms a self-assembled monolayer on Au surfaces. We then embed this Cu catalyst inside a hybrid bilayer membrane by depositing a monolayer of lipid on the self-assembled monolayer. We envisage that this electrochemical system can give a unique mechanistic insight not only into the oxygen reduction reaction, but into proton-coupled electron transfer in general. PMID- 24813420 TI - Intense low-energy ferromagnetic fluctuations in the antiferromagnetic heavy fermion metal CeB6. AB - Heavy-fermion metals exhibit a plethora of low-temperature ordering phenomena . Among these are the so-called hidden-order phases that, in contrast to conventional magnetic order, are invisible to standard neutron diffraction experiments. One of the structurally most simple hidden-order compounds, CeB6, has been intensively studied for an elusive phase that was attributed to the antiferroquadrupolar ordering of cerium-4f moments . As the ground state of CeB6 is characterized by a more conventional antiferromagnetic (AFM) order , the low temperature physics of this system has generally been assumed to be governed solely by AFM interactions between the dipolar and multipolar Ce moments . Here we overturn this established picture by observing an intense ferromagnetic (FM) low-energy collective mode that dominates the magnetic excitation spectrum of CeB6. Inelastic neutron-scattering data reveal that the intensity of this FM excitation significantly exceeds that of conventional spin-wave magnons emanating from the AFM wavevectors, thus placing CeB6 much closer to a FM instability than previously anticipated. This propensity for ferromagnetism may account for much of the unexplained behaviour of CeB6, and should lead to a re-examination of existing theories that have so far largely neglected the role of FM interactions. PMID- 24813421 TI - Bacteria-instructed synthesis of polymers for self-selective microbial binding and labelling. AB - The detection and inactivation of pathogenic strains of bacteria continues to be an important therapeutic goal. Hence, there is a need for materials that can bind selectively to specific microorganisms for diagnostic or anti-infective applications, but that can be formed from simple and inexpensive building blocks. Here, we exploit bacterial redox systems to induce a copper-mediated radical polymerization of synthetic monomers at cell surfaces, generating polymers in situ that bind strongly to the microorganisms that produced them. This 'bacteria instructed synthesis' can be carried out with a variety of microbial strains, and we show that the polymers produced are self-selective binding agents for the 'instructing' cell types. We further expand on the bacterial redox chemistries to 'click' fluorescent reporters onto polymers directly at the surfaces of a range of clinical isolate strains, allowing rapid, facile and simultaneous binding and visualization of pathogens. PMID- 24813422 TI - Optically enhanced coherent transport in YBa2Cu3O6.5 by ultrafast redistribution of interlayer coupling. AB - Nonlinear optical excitation of infrared active lattice vibrations has been shown to melt magnetic or orbital orders and to transform insulators into metals. In cuprates, this technique has been used to remove charge stripes and promote superconductivity, acting in a way opposite to static magnetic fields. Here, we show that excitation of large-amplitude apical oxygen distortions in the cuprate superconductor YBa2Cu3O6.5 promotes highly unconventional electronic properties. Below the superconducting transition temperature (Tc = 50 K) inter-bilayer coherence is transiently enhanced at the expense of intra-bilayer coupling. Strikingly, even above Tc a qualitatively similar effect is observed up to room temperature, with transient inter-bilayer coherence emerging from the incoherent ground state and similar transfer of spectral weight from high to low frequency. These observations are compatible with previous reports of an inhomogeneous normal state that retains important properties of a superconductor, in which light may be melting competing orders or dynamically synchronizing the interlayer phase. The transient redistribution of coherence discussed here could lead to new strategies to enhance superconductivity in steady state. PMID- 24813423 TI - Munchausen syndrome: another point of view. PMID- 24813424 TI - Reply: pulmonary hemorrhage in very-low-birth-weight Infants. PMID- 24813425 TI - Review of novel aspects of the regulation of ghrelin secretion. AB - The role of ghrelin in regulating metabolism and energy balance has been a subject of intense focus ever since its discovery. Ghrelin regulates energy balance in the short term by induction of appetite and in the longer term by increasing body weight and adiposity. It is the only known peripheral orexigenic hormone and one of the most potent endogenous orexigenic factors discovered to date. However, whilst extensively studied, the mechanism of ghrelin secretion is not well understood. A better understanding of the pathways controlling ghrelin secretion could be useful in the development of new therapeutic approaches to appetite-related disorders. Here, we discuss current knowledge of the processes that control ghrelin secretion, focusing on neural, chemical and hormonal stimuli. In addition, we share our view on the potential of targeting ghrelin for the treatment of eating disorders such as obesity, anorexia nervosa and cachexia. PMID- 24813426 TI - Review and research on feature selection methods from NMR data in biological fluids. Presentation of an original ensemble method applied to atherosclerosis field. AB - Metabolic pools of biological matrices can be extensively analyzed by NMR. Measured data consist of hundreds of NMR signals with different chemical shifts and intensities representing different metabolites' types and levels, respectively. Relevant predictive NMR signals need to be extracted from the pool using variable selection methods. This paper presents both a review and research on this metabolomics field. After reviews on discriminant potentials and statistical analyses of NMR data in biological fields, the paper presents an original approach to extract a small number of NMR signals in a biological matrix A (BM-A) in order to predict metabolic levels in another biological matrix B (BM B). Initially, NMR dataset of BM-A was decomposed into several row-column homogeneous blocks using hierarchical cluster analysis (HCA). Then, each block was subjected to a complete set of Jackknifed correspondence analysis (CA) by removing separately each individual (row). Each CA condensed the numerous NMR signals into some principal components (PCs). The different PCs representing the (n - 1) active individuals were used as latent variables in a stepwise multi linear regression to predict metabolic levels in BM-B. From the built regression model, metabolite level in the outside individual was predicted (for next model validation). >From all the PCs-based regression models resulting from all the jackknifed CA applied on all the individuals, the most contributive NMR signals were identified by their highest absolute contributions to PCs. Finally, these selected NMR signals (measured in BMA) were used to build final population and sub-population regression models predicting metabolite levels in BM-B. PMID- 24813427 TI - Impact of the 'Giving Cigarettes is Giving Harm' campaign on knowledge and attitudes of Chinese smokers. AB - OBJECTIVE: To date there is limited published evidence on the efficacy of tobacco control mass media campaigns in China. This study aimed to evaluate the impact of a mass media campaign 'Giving Cigarettes is Giving Harm' (GCGH) on Chinese smokers' knowledge of smoking-related harms and attitudes towards cigarette gifts. METHODS: Population-based, representative data were analysed from a longitudinal cohort of 3709 adult smokers who participated in the International Tobacco Control (ITC) China Survey conducted in six Chinese cities before and after the campaign. Logistic regression models were estimated to examine associations between campaign exposure and attitudes towards cigarette gifts measured post-campaign. Poisson regression models were estimated to assess the effects of campaign exposure on post-campaign knowledge, adjusting for pre campaign knowledge. FINDINGS: Fourteen percent (n=335) of participants recalled the campaign within the cities where the GCGH campaign was implemented. Participants in the intervention cities who recalled the campaign were more likely to disagree that cigarettes are good gifts (71% vs 58%, p<0.01) and had greater levels of campaign-targeted knowledge than those who did not recall the campaign (mean=1.97 vs 1.62, p<0.01). Disagreeing that cigarettes are good gifts was higher in intervention cities than in control cities. Changes in campaign targeted knowledge were similar in both cities, perhaps due to a secular trend, low campaign recall or contamination issues. CONCLUSIONS: These findings suggest that the GCGH campaign increased knowledge of smoking harms, which could promote downstream cessation. This study provides evidence to support future campaign development to effectively fight the tobacco epidemic in China. PMID- 24813428 TI - Effect of shoot removal on remobilization of carbon and nitrogen during regrowth of nitrogen-fixing alfalfa. AB - The contribution of carbon and nitrogen reserves to regrowth following shoot removal has been studied in the past. However, important gaps remain in understanding the effect of shoot cutting on nodule performance and its relevance during regrowth. In this study, isotopic labelling was conducted at root and canopy levels with both (15) N2 and (13) C-depleted CO2 on exclusively nitrogen fixing alfalfa plants. As expected, our results indicate that the roots were the main sink organs before shoots were removed. Seven days after regrowth the carbon and nitrogen stored in the roots was invested in shoot biomass formation and partitioned to the nodules. The large depletion in nodule carbohydrate availability suggests that root-derived carbon compounds were delivered towards nodules in order to sustain respiratory activity. In addition to the limited carbohydrate availability, the upregulation of nodule peroxidases showed that oxidative stress was also involved during poor nodule performance. Fourteen days after cutting, and as a consequence of the stimulated photosynthetic and N2 fixing machinery, availability of Cnew and Nnew strongly diminished in the plants due to their replacement by C and N assimilated during the post-labelling period. In summary, our study indicated that during the first week of regrowth, root derived C and N remobilization did not overcome C- and N-limitation in nodules and leaves. However, 14 days after cutting, leaf and nodule performance were re established. PMID- 24813429 TI - Item-level assessment of the irritable bowel syndrome quality of life questionnaire in patients with diarrheal irritable bowel syndrome. AB - BACKGROUND: In previous studies, the Irritable Bowel Syndrome Quality of Life (IBS-QOL) instrument has been determined to have good measurement properties for general irritable bowel syndrome (IBS) and the diarrheal IBS (IBS-d) subtype in clinical trials. OBJECTIVE: This article aims to extend the true-score analyses that have been previously conducted to evaluate the IBS-QOL in IBS-d patients. METHODS: Item response theory analysis was conducted by fitting models to responses from 753 patients with severe IBS-d from a recent clinical trial. Three item response theory models, the constrained graded response model (CGRM), the unconstrained GRM (UGRM), and the testlet response model (TRM), were fit to the 34 items of the IBS-QOL questionnaire. Subsequently, differential item functioning (DIF) for patient sex was assessed by fitting nested models by applying likelihood ratio tests. Model latent trait estimates were then compared with the IBS-QOL score and the IBS Symptom Severity Score. RESULTS: Model fits improved with complexity, with the TRM model fitting best compared with the CGRM and UGRM. The DIF evaluation for patient sex flagged 17 items for the CGRM and 9 items for the UGRM; however, these items were not found to have much effect on the overall estimation of the latent trait. Differential testlet functioning was not indicated, and no items exhibited potential DIF under the TRM because likelihood ratio tests were not statistically significant. Comparison of latent trait estimates to the IBS Symptom Severity Score and IBS-QOL questionnaire revealed high Spearman correlations (0.47 and >=0.99, respectively). CONCLUSION: Previous true-score approach results were supported by the IBS-QOL item-level analysis. Further, the IBS-QOL total score was found to be a valid measure of perceived quality of life for IBS-d patients when compared with more sophisticated model-based estimates of perceived quality of life. ClinicalTrials.gov identifier: NCT01130272. PMID- 24813430 TI - Correspondence between the RAND-Negative Impact of Asthma on Quality of Life item bank and the Marks Asthma Quality of Life Questionnaire. AB - BACKGROUND: In many research and clinical settings in which patient-reported outcome (PRO) measures are used, it is often desirable to link scores across disparate measures or to use scores from 1 measure to describe scores on a separate measure. However, PRO measures are scored by using a variety of metrics, making such comparisons difficult. OBJECTIVE: The objective of this article was to provide an example of how to transform scores across disparate measures (the Marks Asthma Quality of Life Questionnaire [AQLQ-Marks] and the newly developed RAND-Negative Impact of Asthma on Quality of Life item bank [RAND-IAQL-Bank]) by using an item response theory (IRT)-based linking method. METHODS: Our sample of adults with asthma (N = 2032) completed 2 measures of asthma-specific quality of life: the AQLQ-Marks and the RAND-IAQL-Bank. We use IRT-based co-calibration of the 2 measures to provide a linkage, or a common metric, between the 2 measures. Co-calibration refers to the process of using IRT to estimate item parameters that describe the responses to the scales' items according to a common metric; in this case, a normal distribution transformed to a T scale with a mean of 50 and an SD of 10. RESULTS: Respondents had an average age of 43 (15), were 60% female, and predominantly non-Hispanic White (56%), with 19% African American, 14% Hispanic, and 11% Asian. Most had at least some college education (83%), and 90% had experienced an asthma attack during the last 12 months. Our results indicate that the AQLQ-Marks and RAND-IAQL-Bank scales measured highly similar constructs and were sufficiently unidimensional for IRT co-calibration. Once linked, scores from the 2 measures were invariant across subgroups. A crosswalk is provided that allows researchers and clinicians using AQLQ-Marks to crosswalk to the RAND-IAQL toolkit. CONCLUSIONS: The ability to translate scores from the RAND-IAQL toolkit to other "legacy" (ie, commonly used) measures increases the value of the new toolkit, aids in interpretation, and will hopefully facilitate adoption by asthma researchers and clinicians. More generally, the techniques we illustrate can be applied to other newly developed or existing measures in the PRO research field to obtain crosswalks with widely used traditional legacy instruments. PMID- 24813432 TI - The effects of season and sex on dentate gyrus size and neurogenesis in a wild rodent, Richardson's ground squirrel (Urocitellus richardsonii). AB - Sex and reproductive status affect hippocampal neurogenesis and dentate gyrus (DG) size in rodents. Relatively few studies, however, address these two effects simultaneously and even fewer studies address this issue in wild populations. Here, we examined seasonal and sex differences in neurogenesis and DG size in a wild, polygynous and social rodent, Richardson's ground squirrel (Uriocitellus richardsonii). Based on the behavioral ecology of this species, we predicted that both neurogenesis and DG size would be sexually dimorphic and the degree of dimorphism would be greatest in the breeding season. Using unbiased stereology and doublecortin (DCX) immunohistochemistry, we found that brain volume, DG size and number of DCX cells varied significantly between breeding and non-breeding seasons, but only brain volume and the number of DCX labeled cells differed between the sexes. Both sex and seasonal differences likely reflect circulating hormone levels, but the extent to which these differences relate to space use in this species is unclear. Based on the degree of seasonal differences in neurogenesis and the DG, we suggest that ground squirrels could be considered model species in which to examine hippocampal plasticity in an ecologically valid context. PMID- 24813433 TI - A novel combined model of intracerebral and intraventricular hemorrhage using autologous blood-injection in rats. AB - Intracerebral hemorrhage (ICH) is the least treatable form of stroke and is associated with the worst prognosis. In up to 40% of cases, ICH is further complicated by intraventricular hemorrhage (IVH), which predisposes to hydrocephalus, and increases case-mortality to 80%. However, IVH is not present in widely used preclinical models of ICH. Here, we characterize a novel rat model of combined ICH and IVH. Rats were injected with different volumes of autologous whole blood into the right deep basal ganglia region (100MUL, 150MUL, 200MUL, and 250MUL, n=10 per group). MRI was performed immediately, and at 24, 48, 72h, and 1week after blood injection, along with neurological evaluations. Injected blood volume reliably correlated with blood volumes measured from MRI obtained after blood injection. Brain edema was most prominent in the ?200MUL groups, peaking at 48h in all groups, being statistically different between the ?200MUL and <200MUL groups at all-time points. Presence of hydrocephalus was detected in most of the animals, most clearly in the 200MUL and 250MUL groups, both being statistically different from the 100MUL group at all-time points, with tendency to worsen during the whole follow-up period. Most deteriorating neurological and behavioral outcomes as well as the highest mortality rates were detected in groups injected with 200MUL and 250MUL of autologous blood, 40% and 70%, respectively. These volumes were most similar to the clinical scenario of combined ICH and IVH, demonstrating that this novel rat model is a promising starting point for future ICH+IVH research. PMID- 24813431 TI - Attenuated orexinergic signaling underlies depression-like responses induced by daytime light deficiency. AB - Light has profound effects on mood, as exemplified by seasonal affective disorder (SAD) and the beneficial effects of bright light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD (Leach et al., 2013a,b). By utilizing a 12:12-h dim light:dark (DLD) paradigm that simulates the lower light intensity of winter, we showed that the animals housed in DLD exhibited increased depression-like behaviors in the forced swim test (FST) and sweet solution preference (SSP) compared to animals housed in bright light during the day (BLD). The objective of the present study was to test the hypothesis that light affects mood by acting on the brain orexinergic system in the diurnal grass rat model of SAD. First, orexin A immunoreactivity (OXA-ir) was examined in DLD and BLD grass rats. Results revealed a reduction in the number of OXA-ir neurons in the hypothalamus and attenuated OXA-ir fiber density in the dorsal raphe nucleus of animals in the DLD compared to those in the BLD group. Then, the animals in BLD were treated systemically with SB-334867, a selective orexin 1 receptor (OX1R) antagonist, which led to a depressive phenotype characterized by increased immobility in the FST and a decrease in SSP compared to vehicle-treated controls. Results suggest that attenuated orexinergic signaling is associated with increased depression like behaviors in grass rats, and support the hypothesis that the orexinergic system mediates the effects of light on mood. PMID- 24813434 TI - Preventive effect of alpha-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia. AB - Some pathophysiological models of schizophrenia posit that prenatal inflammation sensitizes the developing brain to second insults in early life and enhances brain vulnerability, thereby increasing the risk of developing the disorder during adulthood. We previously developed a two-hit animal model, based on the well-established prenatal immune challenge with poly-inosinic/cytidylic acid (polyI:C), followed by juvenile restraint stress (RS). We observed an additive disruption of prepulse inhibition (PPI) of acoustic startle in juvenile mice submitted to both insults. Previous studies have also reported that oxidative stress is associated with pathophysiological mechanisms of psychiatric disorders, including schizophrenia. We report here that PPI disruption in our two-hit animal model of schizophrenia is associated with an increase in oxidative stress. These findings led us to assess whether alpha-lipoic acid, an antioxidant, can prevent both increase in oxidative status and PPI deficits in our juvenile in vivo model of schizophrenia. In the offspring submitted to prenatal injection of polyI:C and to RS, treatment with alpha-lipoic acid prevented the development of PPI deficits 24h after the last period of RS. alpha-Lipoic acid also improved PPI performance in control mice. The reversal effect of alpha-lipoic acid pretreatment on these behavioral alterations was further accompanied by a normalization of the associated oxidative status and dopaminergic and GABAergic abnormalities in the prefrontal cortex. Based on our double insult paradigm, these results support the hypothesis that oxidative stress plays an important role in the development of PPI deficits, a well-known behavior associated with schizophrenia. These findings form the basis of future studies aiming to unravel mechanistic insights of the putative role of antioxidants in the treatment of schizophrenia, especially during the prodromal stage. PMID- 24813435 TI - The cortical distribution of multisensory neurons was modulated by multisensory experience. AB - Previous studies have indicated a sparse distribution of multisensory neurons in the transition zones between cortical areas associated with specific sensory modalities. However, little is known about the distribution and functional properties of such neurons. The bimodal visual-auditory neurons in the transition area between visual and auditory cortices in rats were examined to determine whether these neurons are modulated by simultaneous input from visual and auditory modalities. Visual-auditory neurons were found to have a non-uniform distribution within this region, instead gathering together and forming a small zone. Electrophysiological recordings revealed that visual-auditory neurons possess integrative characteristics similar to neurons of the superior colliculus, a midbrain structure in the visual pathway. Exposing adult animals to combined visual and auditory stimuli resulted in an expansion of bimodal neuron distribution in the visual-auditory transition area. These effects were more pronounced in young animals; in this case, the distribution of visual-auditory neurons extended past the limits of the transition area and invaded the flanking modality-specific cortical areas. These results provide a direct demonstration of the role of sensory experience in shaping cortical structure, which can have implications for neuronal integration and cognitive function. PMID- 24813436 TI - Dirt and disgust as key drivers in nurses' infection control behaviours: an interpretative, qualitative study. AB - BACKGROUND: Infection prevention remains a significant challenge for healthcare systems. Yet despite considerable work to provide clear policies and scientifically proven techniques to reduce infection transmission, beliefs and practices of healthcare workers do not always concur with scientific rationale. AIM: To provide explanations for nurses' infection prevention behaviours. METHODS: An interpretative, qualitative approach was taken using semi-structured interviews. Twenty interviews with registered nurses working in an acute hospital setting were conducted. Analysis was conducted using the Framework method. FINDINGS: This paper focuses on the theme 'protection from dirt'. Within the findings clear distinction was made between infection and dirt. Fear of contact with dirt, particularly dirt belonging to those who were unknown, was a key driver in behaviour carried out to reduce threat. Familiarity with the patient resulted in a reduction of the protective behaviours required. These behaviours, which initially appeared as part of an infection prevention strategy, were primarily a form of self-protection from patients, who at first encounter were considered as dirty. CONCLUSION: Behaviours do not always fit with a rational response to infection, but instead may be responses to dirt. Any programme that simply attempts to address scientific knowledge and behaviour deficits is unlikely to have the desired goals if it does not take into account existing social constructions of dirt and the response it evokes. PMID- 24813437 TI - Altered emotion regulation capacity in social phobia as a function of comorbidity. AB - Social phobia (SP) has been associated with amygdala hyperreactivity to fear relevant stimuli. However, little is known about the neural basis of SP individuals' capacity to downregulate their responses to such stimuli and how such regulation varies as a function of comorbid depression and anxiety. We completed an functional magnetic resonance imaging (fMRI) study wherein SP participants without comorbidity (n = 30), with comorbid depression (n = 18) and with comorbid anxiety (n = 19) and healthy controls (n = 15) were scanned while completing an affect labeling emotion regulation task. Individuals with SP as a whole exhibited a reversal of the pattern observed in healthy controls in that they showed upregulation of amygdala activity during affect labeling. However, subsequent analyses revealed a more complex picture based on comorbidity type. Although none of the SP subgroups showed the normative pattern of amygdala downregulation, it was those with comorbid depression specifically who showed significant upregulation. Effects could not be attributed to differences in task performance, amygdala reactivity or right ventral lateral prefrontal cortex (RVLPFC) engagement, but may stem from dysfunctional communication between amygdala and RVLPFC. Furthermore, the particularly altered emotion regulation seen in those with comorbid depression could not be fully explained by symptom severity or state anxiety. Results reveal altered emotion regulation in SP, especially when comorbid with depression. PMID- 24813438 TI - Prognostic implications of tissue Doppler imaging-derived e/ea ratio in acute heart failure patients. AB - BACKGROUND: Tissue Doppler-derived transmitral to mitral annular early diastolic velocity ratio (E/Ea), as a noninvasive estimation of left ventricular (LV) filling pressures, is a strong prognosticator in various cardiac scenarios including chronic heart failure; nevertheless, its utility for risk stratification in the whole spectrum of acute heart failure (AHF) patients remains elusive. Thus, the aim of this study was to determine the association between E/Ea ratio and 1-year mortality in nonselected patients with AHF. METHODS: The study included 417 consecutive patients admitted for AHF. Twenty-two patients were excluded due to nonaccurate Ea measurements, leaving the final sample to be 395 patients. E-wave, septal, and lateral Ea velocities were measured following initial stabilization and according to current recommendations. The association of mean E/Ea ratio with all-cause mortality was assessed using Cox regression analysis. RESULTS: At a median follow-up of 306 days (interquartile range, 118-564), 89 deaths (22.5%) were registered. Mean age and E/Ea ratio were 72 +/- 11.5 and 20 +/- 3. Proportion of LV ejection fraction >=50% was 47%. In multivariate analysis, after adjusting for well-known prognostic factors, including natriuretic peptides, E/Ea ratio was linearly associated with an increase risk of all-cause mortality (HR 1.04, 95% CI 1.03 1.05; P < 0.001, per increase in one unit of E/Ea). The threshold of risk was identified above 20. No significant interactions among the most important subgroups were found. CONCLUSION: In AHF patients, tissue Doppler imaging derived E/Ea ratio is independently associated with an increased risk of all-cause mortality. PMID- 24813439 TI - E.T. phone home! PMID- 24813440 TI - Rectal site and suboptimal nodal yield predict systemic recurrence in resected colorectal carcinoma: a case-control study. AB - We assessed the contribution of histopathological features to systemic recurrence (SR) in patients with colorectal cancer, using a case-control design: 71 cases and 184 controls were included, with a mean time until SR of 1.4 +/- 0.1 years and a mean follow-up of controls of 1.6 +/- 0.06 years. Cases had significantly greater odds of rectal site (odds ratio [OR] = 1.82), stage >= pT3 (OR = 2.11), suboptimal (<12) lymph node yield (OR = 4.6), stage >= pN1 (OR = 2.46), KRAS mutation (OR = 2.76), and extramural venous invasion (OR = 1.97). By multiple regression analysis, rectal site, stage >= pT3, suboptimal lymph node yield, and lymph node positivity independently predicted SR. Rectal cancers were more likely to have a suboptimal node yield than nonrectal cancers (relative risk = 1.6) among the entire cohort. We conclude that rectal cancers have greater risk of SR than colon cancers. A lower yield of lymph nodes in rectal cancer specimens may contribute to this. PMID- 24813441 TI - Insulin-like growth factor-1 prevents miR-122 production in neighbouring cells to curtail its intercellular transfer to ensure proliferation of human hepatoma cells. AB - miRNAs are 20-22 nt long post-transcriptional regulators in metazoan cells that repress protein expression from their target mRNAs. These tiny regulatory RNAs follow tissue and cell-type specific expression pattern, aberrations of which are associated with various diseases. miR-122 is a liver-specific anti-proliferative miRNA that, we found, can be transferred via exosomes between human hepatoma cells, Huh7 and HepG2, grown in co-culture. Exosomal miR-122, expressed and released by Huh7 cells and taken by miR-122 deficient HepG2 cells, was found to be effective in repression of target mRNAs and to reduce growth and proliferation of recipient HepG2 cells. Interestingly, in a reciprocal process, HepG2 secretes Insulin-like Growth Factor 1 (IGF1) that decreases miR-122 expression in Huh7 cells. Our observations suggest existence of a reciprocal interaction between two different hepatic cells with distinct miR-122 expression profiles. This interaction is mediated via intercellular exosome-mediated miR-122 transfer and countered by a reciprocal IGF1-dependent anti-miR-122 signal. According to our data, human hepatoma cells use IGF1 to prevent intercellular exosomal transfer of miR-122 to ensure its own proliferation by preventing expression of growth retarding miR-122 in neighbouring cells. PMID- 24813442 TI - In vivo imaging of protein-protein and RNA-protein interactions using novel far red fluorescence complementation systems. AB - Imaging of protein-protein and RNA-protein interactions in vivo, especially in live animals, is still challenging. Here we developed far-red mNeptune-based bimolecular fluorescence complementation (BiFC) and trimolecular fluorescence complementation (TriFC) systems with excitation and emission above 600 nm in the 'tissue optical window' for imaging of protein-protein and RNA-protein interactions in live cells and mice. The far-red mNeptune BiFC was first built by selecting appropriate split mNeptune fragments, and then the mNeptune-TriFC system was built based on the mNeptune-BiFC system. The newly constructed mNeptune BiFC and TriFC systems were verified as useful tools for imaging protein protein and mRNA-protein interactions, respectively, in live cells and mice. We then used the new mNeptune-TriFC system to investigate the interactions between human polypyrimidine-tract-binding protein (PTB) and HIV-1 mRNA elements as PTB may participate in HIV mRNA processing in HIV activation from latency. An interaction between PTB and the 3'long terminal repeat region of HIV-1 mRNAs was found and imaged in live cells and mice, implying a role for PTB in regulating HIV-1 mRNA processing. The study provides new tools for in vivo imaging of RNA protein and protein-protein interactions, and adds new insight into the mechanism of HIV-1 mRNA processing. PMID- 24813444 TI - Insights into how Spt5 functions in transcription elongation and repressing transcription coupled DNA repair. AB - Spt5, a transcription elongation factor, and Rpb4, a subunit of RNA polymerase II (RNAP II) that forms a subcomplex with Rpb7, play important roles in transcription elongation and repression of transcription coupled DNA repair (TCR) in eukaryotic cells. How Spt5 physically interacts with RNAP II, and if and/or how Spt5 and Rpb4/7 coordinate to achieve the distinctive functions have been enigmatic. By site-specific incorporation of the unnatural amino acid p-benzoyl-L phenylalanine, a photoreactive cross-linker, we mapped interactions between Spt5 and RNAP II in Saccharomyces cerevisiae. Through its KOW4-5 domains, Spt5 extensively interacts with Rpb4/7. Spt5 also interacts with Rpb1 and Rpb2, two largest subunits of RNAP II, at the clamp, protrusion and wall domains. These interactions may lock the clamp to the closed conformation and enclose the DNA being transcribed in the central cleft of RNAP II. Deletion of Spt5 KOW4-5 domains decreases transcription elongation and derepresses TCR. Our findings suggest that Spt5 is a key coordinator for holding the RNAP II complex in a closed conformation that is highly competent for transcription elongation but repressive to TCR. PMID- 24813443 TI - Distinct nucleic acid interaction properties of HIV-1 nucleocapsid protein precursor NCp15 explain reduced viral infectivity. AB - During human immunodeficiency virus type 1 (HIV-1) maturation, three different forms of nucleocapsid (NC) protein-NCp15 (p9 + p6), NCp9 (p7 + SP2) and NCp7 appear successively. A mutant virus expressing NCp15 shows greatly reduced infectivity. Mature NCp7 is a chaperone protein that facilitates remodeling of nucleic acids (NAs) during reverse transcription. To understand the strict requirement for NCp15 processing, we compared the chaperone function of the three forms of NC. NCp15 anneals tRNA to the primer-binding site at a similar rate as NCp7, whereas NCp9 is the most efficient annealing protein. Assays to measure NA destabilization show a similar trend. Dynamic light scattering studies reveal that NCp15 forms much smaller aggregates relative to those formed by NCp7 and NCp9. Nuclear magnetic resonance studies suggest that the acidic p6 domain of HIV 1 NCp15 folds back and interacts with the basic zinc fingers. Neutralizing the acidic residues in p6 improves the annealing and aggregation activity of NCp15 to the level of NCp9 and increases the protein-NA aggregate size. Slower NCp15 dissociation kinetics is observed by single-molecule DNA stretching, consistent with the formation of electrostatic inter-protein contacts, which likely contribute to the distinct aggregate morphology, irregular HIV-1 core formation and non-infectious virus. PMID- 24813445 TI - Alignment-Annotator web server: rendering and annotating sequence alignments. AB - Alignment-Annotator is a novel web service designed to generate interactive views of annotated nucleotide and amino acid sequence alignments (i) de novo and (ii) embedded in other software. All computations are performed at server side. Interactivity is implemented in HTML5, a language native to web browsers. The alignment is initially displayed using default settings and can be modified with the graphical user interfaces. For example, individual sequences can be reordered or deleted using drag and drop, amino acid color code schemes can be applied and annotations can be added. Annotations can be made manually or imported (BioDAS servers, the UniProt, the Catalytic Site Atlas and the PDB). Some edits take immediate effect while others require server interaction and may take a few seconds to execute. The final alignment document can be downloaded as a zip archive containing the HTML files. Because of the use of HTML the resulting interactive alignment can be viewed on any platform including Windows, Mac OS X, Linux, Android and iOS in any standard web browser. Importantly, no plugins nor Java are required and therefore Alignment-Anotator represents the first interactive browser-based alignment visualization. AVAILABILITY: http://www.bioinformatics.org/strap/aa/ and http://strap.charite.de/aa/. PMID- 24813446 TI - Amides are excellent mimics of phosphate internucleoside linkages and are well tolerated in short interfering RNAs. AB - RNA interference (RNAi) has become an important tool in functional genomics and has an intriguing therapeutic potential. However, the current design of short interfering RNAs (siRNAs) is not optimal for in vivo applications. Non-ionic phosphate backbone modifications may have the potential to improve the properties of siRNAs, but are little explored in RNAi technologies. Using X-ray crystallography and RNAi activity assays, the present study demonstrates that 3' CH2-CO-NH-5' amides are excellent replacements for phosphodiester internucleoside linkages in RNA. The crystal structure shows that amide-modified RNA forms a typical A-form duplex. The amide carbonyl group points into the major groove and assumes an orientation that is similar to the P-OP2 bond in the phosphate linkage. Amide linkages are well hydrated by tandem waters linking the carbonyl group and adjacent phosphate oxygens. Amides are tolerated at internal positions of both the guide and passenger strand of siRNAs and may increase the silencing activity when placed near the 5'-end of the passenger strand. As a result, an siRNA containing eight amide linkages is more active than the unmodified control. The results suggest that RNAi may tolerate even more extensive amide modification, which may be useful for optimization of siRNAs for in vivo applications. PMID- 24813447 TI - OncoSearch: cancer gene search engine with literature evidence. AB - In order to identify genes that are involved in oncogenesis and to understand how such genes affect cancers, abnormal gene expressions in cancers are actively studied. For an efficient access to the results of such studies that are reported in biomedical literature, the relevant information is accumulated via text-mining tools and made available through the Web. However, current Web tools are not yet tailored enough to allow queries that specify how a cancer changes along with the change in gene expression level, which is an important piece of information to understand an involved gene's role in cancer progression or regression. OncoSearch is a Web-based engine that searches Medline abstracts for sentences that mention gene expression changes in cancers, with queries that specify (i) whether a gene expression level is up-regulated or down-regulated, (ii) whether a certain type of cancer progresses or regresses along with such gene expression change and (iii) the expected role of the gene in the cancer. OncoSearch is available through http://oncosearch.biopathway.org. PMID- 24813448 TI - A short RNA stem-loop is necessary and sufficient for repression of gene expression during early logarithmic phase in trypanosomes. AB - We have compared the transcriptomes of cultured procyclic Trypanosoma brucei cells in early and late logarithmic phases and found that ~200 mRNAs were differentially regulated. In late log phase cells, the most upregulated mRNA encoded the nucleobase transporter NT8. The 3' untranslated region (UTR) of NT8 contains a short stem-loop cis-element that is necessary for the regulation of NT8 expression in response to external purine levels. When placed in the 3'-UTR of an unregulated transcript, the cis-element is sufficient to confer regulation in response to purines. To our knowledge, this is the first example of a discrete RNA element that can autonomously regulate gene expression in trypanosomes in response to an external factor and reveals an unprecedented purine-dependent signaling pathway that controls gene expression in eukaryotes. PMID- 24813449 TI - HIV-1 DIS stem loop forms an obligatory bent kissing intermediate in the dimerization pathway. AB - The HIV-1 dimerization initiation sequence (DIS) is a conserved palindrome in the apical loop of a conserved hairpin motif in the 5'-untranslated region of its RNA genome. DIS hairpin plays an important role in genome dimerization by forming a 'kissing complex' between two complementary hairpins. Understanding the kinetics of this interaction is key to exploiting DIS as a possible human immunodeficiency virus (HIV) drug target. Here, we present a single-molecule Forster resonance energy transfer (smFRET) study of the dimerization reaction kinetics. Our data show the real-time formation and dissociation dynamics of individual kissing complexes, as well as the formation of the mature extended duplex complex that is ultimately required for virion packaging. Interestingly, the single-molecule trajectories reveal the presence of a previously unobserved bent intermediate required for extended duplex formation. The universally conserved A272 is essential for the formation of this intermediate, which is stabilized by Mg(2+), but not by K(+) cations. We propose a 3D model of a possible bent intermediate and a minimal dimerization pathway consisting of three steps with two obligatory intermediates (kissing complex and bent intermediate) and driven by Mg(2+) ions. PMID- 24813450 TI - WormNet v3: a network-assisted hypothesis-generating server for Caenorhabditis elegans. AB - High-throughput experimental technologies gradually shift the paradigm of biological research from hypothesis-validation toward hypothesis-generation science. Translating diverse types of large-scale experimental data into testable hypotheses, however, remains a daunting task. We previously demonstrated that heterogeneous genomics data can be integrated into a single genome-scale gene network with high prediction power for ribonucleic acid interference (RNAi) phenotypes in Caenorhabditis elegans, a popular metazoan model in the study of developmental biology, neurobiology and genetics. Here, we present WormNet version 3 (v3), which is a new network-assisted hypothesis-generating server for C. elegans. WormNet v3 includes major updates to the base gene network, which substantially improved predictions of RNAi phenotypes. The server generates various gene network-based hypotheses using three complementary network methods: (i) a phenotype-centric approach to 'find new members for a pathway'; (ii) a gene centric approach to 'infer functions from network neighbors' and (iii) a context centric approach to 'find context-associated hub genes', which is a new method to identify key genes that mediate physiology within a specific context. For example, we demonstrated that the context-centric approach can be used to identify potential molecular targets of toxic chemicals. WormNet v3 is freely accessible at http://www.inetbio.org/wormnet. PMID- 24813451 TI - Elements of margin of safety, toxicity and action of sodium selenite in a lipopolysaccharide rat model. AB - PROJECT: Both septic shock and sodium selenite (Na2SeO3) lead to multiple organ failure through oxidation. Na2SeO3 has direct oxidant effects above the nutritional level and indirect anti-oxidant properties. In a lipopolysaccharide (LPS) rat model we assessed margin of safety, toxicity and beneficial effect of pentahydrate Na2SeO3 (5H2O.Na2SeO3) at oxidant doses. PROCEDURE: In a three-step study on 204 rats we: (i) observed toxic effects of Na2SeO3 injected intraperitoneously (IP) and determined its Minimum Dose Without Toxic effect (MDWT) 0.25-0.35 mg/kg selenium (Se) content; (ii) injected IP LPS at 70% lethal dose (LD) followed, or not, one hour later by IP Na2SeO3 at MDWT and (iii) by doses>MDWT. At 48 h, in survivors, we measured plasma creatinine, lactate, aspartate and alanine aminotransferase (AST, ALT), nitric oxide (NO) and Se concentrations. RESULTS: (i) Na2SeO3 alone did not increase NO and lactate. Encephalopathy appeared at 1mg Se/kg. Creatinine increased at 1-1.75 mg Se/kg, AST, ALT at 3-4.5 mg Se/kg, and the minimum LD was 3 mg Se/kg. (ii) Mortality after LPS was 37/50 (74%, [62-86%]) vs. 20/30 (67%, [50-84%]) when followed by Na2SeO3 at MDWT (p=0.483) with a decreased in NO (-31%, p=0.038) a trend for lactate decrease (-19%, p=0.068) and an increased Se in plasma of survivals. (iii) All rats died at doses >=0.6 mg/kg (p<0.001). CONCLUSION: Mechanisms of LPS and Na2SeO3 toxicity differ (i.e. NO, lactate). In septic shock 5H2O.Na2SeO3 toxicity increased, margin of safety decrease, but IP administration of dose considered as oxidant of 5H2O.Na2SeO3 showed beneficial effects. PMID- 24813452 TI - Body mass index, iron absorption and iron status in childbearing age women. AB - BACKGROUND: The prevalence of obesity has increased at an alarming rate worldwide. Some studies have observed an association between iron (Fe) deficiency (ID) and obesity, however more research is needed. OBJECTIVE: To assess whether body mass index (BMI) is associated with both Fe absorption and Fe status. METHODS: A cross sectional sample of 318 Chilean childbearing age women was studied. The women received either a single dose of 0.5mg of Fe (n=137, group 1) or 3mg of Fe plus ascorbic acid (1:2 molar ratio) (n=181, group 2), both as FeSO4 with labeled radioisotopes. Fe absorption was assessed through radio Fe erythrocyte incorporation. Fe status was determined by hemoglobin (Hb), mean corpuscular volume, serum Fe, total iron binding capacity, transferrin saturation, erythrocyte Zn protoporphyrin and serum ferritin (SF). RESULTS: 29%, 47% and 24% of the women were classified as normal, overweight or obese, respectively. Fe absorption was significantly lower in obese women (p<0.05). In group 1, the geometric mean and range +/-1 SD of the percentage of Fe absorption for normal-weight women was 32.9% vs. 19.7% in obese. For group 2, this percentage was 36% vs. 30%, respectively (2-way ANOVA: BMI classification and Fe dose p<0.05; interaction p=0.34). Although Fe absorption was lower in obese women, they had higher SF (p<0.01) and Hb (p<0.05) concentrations. CONCLUSION: Although we did not observe a relationship between BMI and Fe status, obese women displayed lower Fe absorption compared with overweight and normal weight women, possibly due to subclinical inflammation associated with obesity. PMID- 24813453 TI - Valvular heart disease in pregnancy. AB - In women with valvular heart disease, pregnancy-associated cardiovascular changes can contribute to maternal, foetal and neonatal complications. Ideally, a woman with valvular heart disease should receive preconception assessment and counselling from a cardiologist with expertise in pregnancy. For women with moderate- and high-risk valve lesions, appropriate risk stratification and management during pregnancy will optimise outcomes. Pregnancy in women with high risk lesions, such as severe aortic stenosis, severe mitral stenosis and those with mechanical valves, requires careful planning and coordination of antenatal care by a multidisciplinary team. The purpose of this overview is to describe the expected haemodynamic changes in pregnancy, review pregnancy risks for women with valvular heart disease and discuss strategies for management. PMID- 24813454 TI - The concentration distribution around a growing gas bubble in a bio tissue under the effect of suction process. AB - The concentration distribution around a growing nitrogen gas bubble in the blood and other bio tissues of divers who ascend to surface too quickly is obtained by Mohammadein and Mohamed model (2010) for variant and constant ambient pressure through the decompression process. In this paper, the growing of gas bubbles and concentration distribution under the effect of suction process are studied as a modification of Mohammadein and Mohamed model (zero suction). The growth of gas bubble is affected by ascent rate, tissue diffusivity, initial concentration difference, surface tension and void fraction. Mohammadein and Mohamed model (2010) is obtained as a special case from the present model. Results showed that, the suction process activates the systemic blood circulation and delay the growth of gas bubbles in the bio tissues to avoid the incidence of decompression sickness (DCS). PMID- 24813455 TI - Multiple potential roles for B cells in atherosclerosis. AB - The development of atherosclerosis is the major etiological factor causing cardiovascular disease and constitutes a lipid-induced, chronic inflammatory and autoimmune disease of the large arteries. A long-standing view of the protective role of B cells in atherosclerosis has been challenged by recent studies using B cell depletion in animal models. Whereas complete B cell deficiency increases atherosclerosis, depletion of B2 but not B1 cells reduces atherosclerosis. This has led to a re-evaluation of the multiple potential pathways by which B cells can regulate atherosclerosis, and the apparent opposing roles of B1 and B2 cells. B cells, in addition to having the unique ability to produce antibodies, are now recognized to play a number of important roles in the immune system, including cytokine production and direct regulation of T cell responses. This review summarizes current knowledge on B cell subsets and functions, and how these could distinctly influence atherosclerosis development. PMID- 24813456 TI - Sleep duration and insulin resistance in individuals without type 2 diabetes: the PPP-Botnia study. AB - INTRODUCTION: Both short and long sleep duration may increase risk of type 2 diabetes (diabetes). We studied if short and long sleep durations were associated with insulin resistance (IR) and insulin secretion in individuals without diabetes, and if the associations remained after we excluded individuals who reported more frequent and severe complaints of sleep apnea and insomnia. PARTICIPANTS AND METHODS: An oral glucose tolerance test (OGTT) was performed for 722 adults without diabetes. Indices of IR and insulin secretion were calculated. Sleep duration and complaints of sleep apnea and insomnia were self-reported. RESULTS: In comparison to average sleepers (6-9 h/night), short sleepers (< 6 h/night) had higher 120-min insulin and AUC glucose, and long sleepers (>= 9 h/night) had higher fasting and 120-min insulin, 120-min glucose, and HOMAIR and lower Insulin Sensitivity Index. After adjusting for confounders and after excluding individuals who reported more frequent and severe complaints of sleep apnea and insomnia, long sleep duration remained significantly associated with IR and insulin secretion. DISCUSSION: Long but not short sleep duration is associated with IR and insulin secretion in individuals without diabetes whether or not accompanied by sleep complaints. Long sleepers may benefit from targeted preventions and interventions that aim at reducing risk of future diabetes. PMID- 24813457 TI - Outcome after coronary artery bypass surgery and percutaneous coronary intervention in patients with atrial fibrillation and oral anticoagulation. AB - AIM: This study was planned to compare the clinical characteristics and outcome of patients on warfarin treatment for atrial fibrillation (AF) undergoing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). METHODS: This is a retrospective analysis of 121 patients who underwent isolated CABG and 301 patients who underwent PCI. RESULTS: PCI patients were older (mean age, 72.9 versus 69.8 years) and more often had prior cardiac surgery (15.9% versus 1.7%) and acute coronary syndrome (53.8% versus 21.5%). CABG patients more often had two- and three-vessel disease (95.0% versus 60.2%) and left main stenosis (32.2% versus 7.0%). The 30-day outcome was similar after PCI and CABG. At 3 years, PCI was associated with lower overall survival (72.0% versus 86.4%, P = 0.006), freedom from repeat revascularization (85.3% versus 98.2%, P < 0.001), freedom from myocardial infarction (83.4% versus 93.8%, P = 0.008), and freedom from major cardiovascular events (57.4% versus 78.9%, P < 0.001). Propensity score adjusted analysis showed that PCI was associated with increased risk of all-cause mortality (P = 0.016, RR 2.166, CI 1.155-4.060), myocardial infarction (P = 0.017, RR 3.161, 95% CI 1.227-8.144), repeat revascularization (P = 0.001, RR 13.152, 95% CI 2.799-61.793), and major cardiac and cerebrovascular complications (P = 0.001, RR 2.347, 95% CI 1.408-3.914). There was no difference in terms of stroke and bleeding episodes at any time point. CONCLUSION: In clinical practice, PCI is the preferred revascularization strategy in these frail patients. Patients selected for CABG have a relatively low operative risk and better mid-term outcome in spite of warfarin treatment. The poor prognosis after PCI may mainly reflect frequent co-morbidities in this patient group. PMID- 24813458 TI - Increased type I collagen synthesis in victims of sudden cardiac death due to idiopathic myocardial fibrosis. AB - AIMS: Idiopathic myocardial fibrosis (IMF) was observed to be the most prevalent autopsy finding in the victims of sudden cardiac death (SCD) under the age of 40 years in the FinGesture cohort. To elucidate further the mechanisms of IMF, we examined the collagen composition from the myocardial samples taken from the victims of IMF-associated SCD. METHODS: Eighteen cases with IMF as a cause of death, confirmed by autopsy, were selected for the analysis. Controls (n = 27) included were cases in whom no cardiac or non-cardiac disease could be found as a cause of unexpected death at autopsy. In addition to conventional histological examination, immunohistochemical staining of procollagens I and III (PINP and PIINP), mature collagen III (IIINTP), and the cross-linked collagen I degradation product (ICTP) were performed. RESULTS: Increased accumulation of PINP was observed in the fibrotic tissue of the IMF cases in comparison with control samples. In contrast, type III collagen was not as frequently expressed in the fibrotic areas. CONCLUSION: Myocardial accumulation of PINP in the victims of IMF associated SCD indicates increased type I collagen synthesis. Future studies on the role of circulating type I collagen biomarkers are needed to study further the implications of the described association. PMID- 24813459 TI - HLA and rheumatoid arthritis: how do they connect? AB - Rheumatoid arthritis (RA) is a destructive autoimmune disease that mainly affects synovial joints. RA patients can be subdivided in two distinct disease subsets based on the presence of anti-citrullinated protein antibodies (ACPA). These two disease phenotypes are associated with different environmental and genetic risk factors and clinical parameters. The HLA class II locus is the most important risk factor for ACPA-positive RA (ACPA+ RA). ACPA can be found up to 10 years before diagnosis and can be used as a predictive biomarker. During progression from breaking tolerance to a citrullinated protein to ACPA+ RA, the ACPA response matures. Recent work implicates the HLA class II locus as a risk factor in the progression from ACPA positivity to ACPA+ RA. We now propose that this locus directly influences the maturation of the ACPA response, most likely via antigen specific T-cells providing help to ACPA-producing B-cells allowing for maturation of the citrullinated protein-specific autoantibody response. We present and discuss several models and underlying data, including antibody cross-reactivity, molecular mimicry, and neo-antigen formation, that could explain the HLA-RA connection. PMID- 24813460 TI - Pulmonary embolism complicated by air embolism. PMID- 24813461 TI - Parasitic aphrodisiacs: manipulation of the hosts' behavioral defenses by sexually transmitted parasites. AB - Animals have a number of behavioral defenses against infection. For example, they typically avoid sick conspecifics, especially during mating. Most animals also alter their behavior after infection and thereby promote recovery (i.e., sickness behavior). For example, sick animals typically reduce the performance of energetically demanding behaviors, such as sexual behavior. Finally, some animals can increase their reproductive output when they face a life-threatening immune challenge (i.e., terminal reproductive investment). All of these behavioral responses probably rely on immune/neural communication signals for their initiation. Unfortunately, this communication channel is prone to manipulation by parasites. In the case of sexually transmitted infections (STIs), these parasites/pathogens must subvert some of these behavioral defenses for successful transmission. There is evidence that STIs suppress systemic signals of immune activation (e.g., pro-inflammatory cytokines). This manipulation is probably important for the suppression of sickness behavior and other behavioral defenses, as well as for the prevention of attack by the host's immune system. For example, the cricket, Gryllus texensis, is infected with an STI, the iridovirus IIV 6/CrIV. The virus attacks the immune system, which suffers a dramatic decline in its ability to make proteins important for immune function. This attack also hampers the ability of the immune system to activate sickness behavior. Infected crickets cannot express sickness behavior, even when challenged with heat-killed bacteria. Understanding how STIs suppress sickness behavior in humans and other animals will significantly advance the field of psychoneuroimmunology and could also provide practical benefits. PMID- 24813462 TI - A systems approach to integrative biology: an overview of statistical methods to elucidate association and architecture. AB - An organism's ability to maintain a desired physiological response relies extensively on how cellular and molecular signaling networks interpret and react to environmental cues. The capacity to quantitatively predict how networks respond to a changing environment by modifying signaling regulation and phenotypic responses will help inform and predict the impact of a changing global enivronment on organisms and ecosystems. Many computational strategies have been developed to resolve cue-signal-response networks. However, selecting a strategy that answers a specific biological question requires knowledge both of the type of data being collected, and of the strengths and weaknesses of different computational regimes. We broadly explore several computational approaches, and we evaluate their accuracy in predicting a given response. Specifically, we describe how statistical algorithms can be used in the context of integrative and comparative biology to elucidate the genomic, proteomic, and/or cellular networks responsible for robust physiological response. As a case study, we apply this strategy to a dataset of quantitative levels of protein abundance from the mussel, Mytilus galloprovincialis, to uncover the temperature-dependent signaling network. PMID- 24813464 TI - Characteristics of fluid composition of left displaced abomasum in beef cattle fed high-starch diets. AB - To clarify the pathophysiology of left displaced abomasum (LDA), beef cattle fed high-starch diets were examined. The abomasal pH in beef cattle with LDA was lower than that in non-LDA reference animals (data from beef cattle at an abattoir), suggesting that it facilitated acidity. Bacteriological examinations of the abomasal fluid in cattle with LDA revealed the presence of Pseudomonas spp., Clostridium spp. and Candida spp., presumably reflecting the accelerated influx of ruminal fluid into the abomasum. Biochemical analyses of serum revealed that LDA cattle had higher lactic acid and lower vitamin A and E levels than non LDA reference animals. These results indicate that beef cattle with LDA may suffer from vitamin A and E deficiencies due to maldigestion of starch and the high acidity of abomasal fluid. PMID- 24813463 TI - Transgenerational epigenetics: the role of maternal effects in cardiovascular development. AB - Transgenerational epigenetics, the study of non-genetic transfer of information from one generation to the next, has gained much attention in the past few decades due to the fact that, in many instances, epigenetic processes outweigh direct genetic processes in the manifestation of aberrant phenotypes across several generations. Maternal effects, or the influences of maternal environment, phenotype, and/or genotype on offsprings' phenotypes, independently of the offsprings' genotypes, are a subcategory of transgenerational epigenetics. Due to the intimate role of the mother during early development in animals, there is much interest in investigating the means by which maternal effects can shape the individual. Maternal effects are responsible for cellular organization, determination of the body axis, initiation and maturation of organ systems, and physiological performance of a wide variety of species and biological systems. The cardiovascular system is the first to become functional and can significantly influence the development of other organ systems. Thus, it is important to elucidate the role of maternal effects in cardiovascular development, and to understand its impact on adult cardiovascular health. Topics to be addressed include: (1) how and when do maternal effects change the developmental trajectory of the cardiovascular system to permanently alter the adult's cardiovascular phenotype, (2) what molecular mechanisms have been associated with maternally induced cardiovascular phenotypes, and (3) what are the evolutionary implications of maternally mediated changes in cardiovascular phenotype? PMID- 24813465 TI - Effective treatment for improving the survival rate of raccoon dogs infected with Sarcoptes scabiei. AB - Sarcoptes scabiei is one of the important external parasites. Although ivermectin is the recommended treatment, many raccoon dogs (Nyctereutes procyonoides) that were rescued and brought to the Kanazawa Zoological Gardens (Yokohama, Japan) have died because of S. scabiei, even after receiving single ivermectin treatment. Therefore, supportive treatment should be required. The present study revealed the number of animals that survived was greater after the administration of ivermectin along with an antibiotic for all raccoon dogs, as well as following the administration of fluid therapy to the debilitated raccoon dogs infected with S. scabiei, immediately after the rescue. During the initial period, treatment to improve the general clinical condition was required prior to deworming treatment for S. scabiei. PMID- 24813466 TI - Choline-PET in prostate cancer management: the point of view of the radiation oncologist. AB - Among PET radiotracers, FDG seems to be quite accepted as an accurate oncology diagnostic tool, frequently helpful also in the evaluation of treatment response and in radiation therapy treatment planning for several cancer sites. To the contrary, the reliability of Choline as a tracer for prostate cancer (PC) still remains an object of debate for clinicians, including radiation oncologists. This review focuses on the available data about the potential impact of Choline-PET in the daily clinical practice of radiation oncologists managing PC patients. In summary, routine Choline-PET is not indicated for initial local T staging, but it seems better than conventional imaging for nodal staging and for all patients with suspected metastases. In these settings, Choline-PET showed the potential to change patient management. A critical limit remains spatial resolution, limiting the accuracy and reliability for small lesions. After a PSA rise, the problem of the trigger PSA value remains crucial. Indeed, the overall detection rate of Choline-PET is significantly increased when the trigger PSA, or the doubling time, increases, but higher PSA levels are often a sign of metastatic spread, a contraindication for potentially curable local treatments such as radiation therapy. Even if several published data seem to be promising, the current role of PET in treatment planning in PC patients to be irradiated still remains under investigation. Based on available literature data, all these issues are addressed and discussed in this review. PMID- 24813467 TI - To ED or not to ED--is erectile dysfunction in obstructive sleep apnea related to endothelial dysfunction? AB - Both obstructive sleep apnea (OSA) and erectile dysfunction (ErectD) are highly prevalent and largely under diagnosed medical conditions. These disorders often co-exist, with about half of the male OSA population having ErectD and vice versa. OSA is strongly associated with an increased risk of cardiovascular mortality while ErectD has been proposed as a phenotypic marker of cardiovascular disease. This implies that the two conditions may be linked by a common pathophysiological mechanism. In this review we provide evidence supporting the hypothesis that endothelial dysfunction (EndoD) may be the common pathophysiological mechanism linking OSA with both ErectD and cardiovascular complications. EndoD is one of the earliest markers of cardiovascular disease and substantial evidence suggests that OSA independently causes EndoD. There is also strong evidence that causally links EndoD with organic ErectD. Further research should be directed at determining the value of simultaneously assessing both ErectD and OSA in patients presenting with symptoms of either condition. In both ErectD and OSA clinics, identifying both conditions could improve overall cardiovascular risk stratification whilst treatment of OSA could reduce both ErectD and cardiovascular risk. PMID- 24813468 TI - The reorganisation of memory during sleep. AB - Sleep after learning promotes the quantitative strengthening of new memories. Less is known about the impact of sleep on the qualitative reorganisation of memory, which is the focus of this review. Studies have shown that, in the declarative system, sleep facilitates the abstraction of rules (schema formation), the integration of knowledge into existing schemas (schema integration) and creativity that requires the disbandment of existing patterns (schema disintegration). Schema formation and integration might primarily benefit from slow wave sleep, whereas the disintegration of a schema might be facilitated by rapid eye movement sleep. In the procedural system, sleep fosters the reorganisation of motor memory. The neural mechanisms of these processes remain to be determined. Notably, emotions have been shown to modulate the sleep-related reorganisation of memories. In the final section of this review, we propose that the sleep-related reorganisation of memories might be particularly relevant for mental disorders. Thus, sleep disruptions might contribute to disturbed memory reorganisation and to the development of mental disorders. Therefore, sleep related interventions might modulate the reorganisation of memories and provide new inroads into treatment. PMID- 24813469 TI - New way to achieve frontal facial photographs of the head in its natural position. AB - Frontal photographs of the head in its natural position are not as easy to achieve as lateral ones. We describe a new way to obtain standard 2-dimensional images of its natural position in full-face frontal view using a customised photographic system, which may provide supplementary information for traditional lateral facial imaging, and be helpful for standard assessment of 3-dimensional facial images. PMID- 24813470 TI - Impact of template choice on homology model efficiency in virtual screening. AB - Homology modeling is a reliable method of predicting the three-dimensional structures of proteins that lack NMR or X-ray crystallographic data. It employs the assumption that a structural resemblance exists between closely related proteins. Despite the availability of many crystal structures of possible templates, only the closest ones are chosen for homology modeling purposes. To validate the aforementioned approach, we performed homology modeling of four serotonin receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R) for virtual screening purposes, using 10 available G-Protein Coupled Receptors (GPCR) templates with diverse evolutionary distances to the targets, with various approaches to alignment construction and model building. The resulting models were further validated in two steps by means of ligand docking and enrichment calculation, using Glide software. The final quality of the models was determined in virtual screening-like experiments by the AUROC score of the resulting ROC curves. The outcome of this research showed that no correlation between sequence identity and model quality was found, leading to the conclusion that the closest phylogenetic relative is not always the best template for homology modeling. PMID- 24813471 TI - Yersinia pestis requires the 2-component regulatory system OmpR-EnvZ to resist innate immunity during the early and late stages of plague. AB - Plague is transmitted by fleas or contaminated aerosols. To successfully produce disease, the causal agent (Yersinia pestis) must rapidly sense and respond to rapid variations in its environment. Here, we investigated the role of 2 component regulatory systems (2CSs) in plague because the latter are known to be key players in bacterial adaptation to environmental change. Along with the previously studied PhoP-PhoQ system, OmpR-EnvZ was the only one of Y. pestis' 23 other 2CSs required for production of bubonic, septicemic, and pneumonic plague. In vitro, OmpR-EnvZ was needed to counter serum complement and leukocytes but was not required for the secretion of antiphagocyte exotoxins. In vivo, Y. pestis lacking OmpR-EnvZ did not induce an early immune response in the skin and was fully virulent in neutropenic mice. We conclude that, throughout the course of Y. pestis infection, OmpR-EnvZ is required to counter toxic effectors secreted by polymorphonuclear leukocytes in the tissues. PMID- 24813473 TI - Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side effects of efavirenz. AB - BACKGROUND: Neurological pathogenesis is associated with mitochondrial dysfunction and differences in neuronal/glial handling of oxygen and glucose. The main side effects attributed to efavirenz involve the CNS, but the underlying mechanisms are unclear. METHODS: Human cell lines and rat primary cultures of neurons and astrocytes were treated with clinically relevant efavirenz concentration. RESULTS: Efavirenz alters mitochondrial respiration, enhances reactive oxygen species generation, undermines mitochondrial membrane potential, and reduces adenosine triphosphate (ATP) levels in a concentration-dependent fashion in both neurons and glial cells. However, it activates adenosine monophosphate-activated protein kinase only in glial cells, upregulating glycolysis and increasing intracellular ATP levels, which do not occur in neurons. To reproduce the conditions that often exist in human immunodeficiency virus-related neuroinflammatory disorders, the effects of efavirenz were evaluated in the presence of exogenous nitric oxide, an inflammatory mediator and mitochondrial inhibitor. The combination potentiated the effects on mitochondrial parameters in both neurons and glial cells, but ATP generation and lactate production were enhanced only in glial cells. CONCLUSIONS: Efavirenz affects the bioenergetics of neurons through a mechanism involving acute mitochondrial inhibition, an action exacerbated in neuroinflammatory conditions. A similar scenario of glial cells survival and degeneration of neurons with signs of mitochondrial dysfunction and oxidative stress has been associated with neurocognitive disorders. PMID- 24813475 TI - Dietary modulators of statin efficacy in cardiovascular disease and cognition. AB - Cardiovascular disease remains the leading cause of morbidity and mortality in the United States and other developed countries, and is fast growing in developing countries, particularly as life expectancy in all parts of the world increases. Current recommendations for the prevention of cardiovascular disease issued jointly from the American Academy of Cardiology and American Heart Association emphasize that lifestyle modification should be incorporated into any treatment plan, including those on statin drugs. However, there is a dearth of data on the interaction between diet and statins with respect to additive, complementary or antagonistic effects. This review collates the available data on the interaction of statins and dietary patterns, cognition, genetics and individual nutrients, including vitamin D, niacin, omega-3 fatty acids, fiber, phytochemicals (polyphenols and stanols) and alcohol. Of note, although the available data is summarized, the scope is limited, conflicting and disparate. In some cases it is likely there is unrecognized synergism. Virtually no data are available describing the interactions of statins with dietary components or dietary pattern in subgroups of the population, particularly those who may benefit most were positive effects identified. Hence, it is virtually impossible to draw any firm conclusions at this time. Nevertheless, this area is important because were the effects of statins and diet additive or synergistic harnessing the effect could potentially lead to the use of a lower intensity statin or dose. PMID- 24813476 TI - Treatment patterns with topicals, traditional systemics and biologics in psoriasis - a Swedish database analysis. AB - BACKGROUND: Little data exist on real-world treatment patterns in psoriasis, especially from European settings. OBJECTIVE: To estimate, for topicals, systemics and biologics, the time to non-persistency, switching, augmentation and insufficient treatment result (only for biologics), as well as to estimate the time to restart, in patients treated with each treatment class in Sweden based on registry data. METHODS: This database analysis utilized data from patients with psoriasis from several Swedish administrative registers. Patients were identified through combinations of diagnoses from two regional registers and filled prescriptions for relevant treatments from the Swedish Prescribed Drug Register. Kaplan-Meier time-to-event ('survival') functions were estimated with relevant treatment events as failure and the proportions of patients having experienced an event at specific time-points were derived from the failure rates. RESULTS: For topicals, systemics and biologics the number of indexed treatment episodes were 25,396, 2963, and 628 respectively. One year after treatment initiation, the proportion of patients who were classed as non-persistent with topicals, systemics and biologics were estimated at 88.3%, 47.9% and 43.2% respectively. Among patients who remained persistent, within 1 year of treatment start the proportions of treatment episodes in which patients were augmented were estimated at 56.0% for topicals, 45.3% for systemics and 58.9% for biologics. In addition, within 1 year of non-persistence, 49.0% of topicals, 60.8% of systemics and 80.2% of biologics treatment episodes were re-initiated, with 35.4-52.5% re-initiated on the non-persistent treatment depending on treatment class. In addition, among patients on biologics, 29.2% of treatment episodes had an insufficient treatment result within 1 year of treatment start. CONCLUSION: Persistency to psoriasis treatments may be sub-optimal and patients who remain persistent relatively frequently receive augmentation therapy or switch to another therapy. Therefore, current treatment options in psoriasis may be insufficient. PMID- 24813472 TI - Monocyte-activation phenotypes are associated with biomarkers of inflammation and coagulation in chronic HIV infection. AB - BACKGROUND: Soluble biomarkers of inflammation predict non-AIDS related morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. Exploring associations between plasma biomarkers and cellular phenotypes may identify sources of excess inflammation. METHODS: Plasma biomarkers (interleukin 6 [IL-6] level, D-dimer level, high-sensitivity C-reactive protein [hsCRP] level, soluble CD14 [sCD14] level, and soluble CD163 [sCD163] level) were measured from cryopreserved samples from the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). We performed immunophenotyping of peripheral blood mononuclear cells for markers of T-cell and monocyte activation, maturation, and migration. We evaluated associations between cellular phenotypes and soluble biomarkers by Spearman rank correlation and multivariate linear regression. RESULTS: Participants' (n = 670) median age was 41 years, 88% were prescribed antiretroviral therapy, 72% had a plasma HIV RNA load of <400 copies/mL, and the median CD4(+) T-lymphocyte count was 471 cells/uL. After adjustment, CD14(++)CD16(+) monocytes were associated with higher levels of IL-6, hsCRP, and sCD163; associations with IL-6 and hsCRP persisted in persons with suppressed HIV replication. While CCR5(+) monocytes positively associated with D-dimer levels, CCR2(+) monocytes were inversely associated with hsCRP levels. CONCLUSIONS: Plasma inflammatory biomarkers that predict morbidity and mortality were strongly associated with monocyte activation and migration, modestly associated with T-cell maturation, and not associated with CD8(+) T-cell activation phenotypes. These findings suggest that strategies to control monocyte activation warrant further investigation. PMID- 24813474 TI - Application of best practice approaches for designing decision support tools: the preparatory education about clinical trials (PRE-ACT) study. AB - OBJECTIVE: This article describes the rigorous development process and initial feedback of the PRE-ACT (Preparatory Education About Clinical Trials) web-based- intervention designed to improve preparation for decision making in cancer clinical trials. METHODS: The multi-step process included stakeholder input, formative research, user testing and feedback. Diverse teams (researchers, advocates and developers) participated including content refinement, identification of actors, and development of video scripts. Patient feedback was provided in the final production period and through a vanguard group (N=100) from the randomized trial. RESULTS: Patients/advocates confirmed barriers to cancer clinical trial participation, including lack of awareness and knowledge, fear of side effects, logistical concerns, and mistrust. Patients indicated they liked the tool's user-friendly nature, the organized and comprehensive presentation of the subject matter, and the clarity of the videos. CONCLUSION: The development process serves as an example of operationalizing best practice approaches and highlights the value of a multi-disciplinary team to develop a theory-based, sophisticated tool that patients found useful in their decision making process. Practice implications Best practice approaches can be addressed and are important to ensure evidence-based tools that are of value to patients and supports the usefulness of a process map in the development of e-health tools. PMID- 24813477 TI - The 5-lipoxygenase inhibitor tepoxalin induces oxidative damage and altered PTEN status prior to apoptosis in canine osteosarcoma cell lines. AB - The 5-lipoxygenase (5-LOX) inhibitor tepoxalin has been shown to slow canine osteosarcoma (OSA) tumour xenografts growth, yet the mechanisms are poorly elucidated. Further examination of tepoxalin in canine OSA cell lines shows that tepoxalin treated cells undergo apoptosis through caspase-3 activation and annexin staining. Interestingly, apoptosis is superseded by an increase in reactive oxygen species (ROS), as measured by activation of dihydrorhodamine 123 and mitosox. This increase in ROS appears to be related to the 5-LOX inhibitor regardless of cellular 5-LOX status, and was not observed after treatment with the tepoxalin metabolite RWJ20142. Additionally, 5-LOX inhibition by tepoxalin appears to increase phosphatase and tensin (PTEN) homolog activity by preventing its alkylation or oxidation. PTEN modification or inhibition allows phosphoinositide-3 (PI3) kinase activity thereby heightening activation of protein kinase B (AKT) phosphorylation. Our data suggest that off target oxidation and LOX inhibition play roles in the apoptotic response. PMID- 24813478 TI - Children's relative age in class and use of medication for ADHD: a Danish Nationwide Study. AB - BACKGROUND: Previous studies from North America and Iceland have shown that the youngest children within a grade are up to twice as likely to be diagnosed and treated for attention-deficit/hyperactivity disorder (ADHD) compared with their older classmates. We aimed to investigate whether younger age in class is associated with an increased probability of being prescribed medication for ADHD among school-aged children in Denmark. METHODS: We followed all Danish children between 2000 and 2012 from 1st through 6th grade (7-12 years). Among children who started school on their age-assigned grade level, we estimated the prevalence proportion ratio (PPR) of receiving ADHD medication between the youngest children in class (born in October-December) and the oldest in class (born in January March), specified by grade level, calendar year and gender. As a sensitivity analysis, we added children not on their age-assigned grade level to the main calculations. RESULTS: We identified 932,032 eligible children for the main analysis, of whom 17.3% were among the youngest and 26.5% among the oldest in class. In total, 1.2% eligible children filled at least one prescription for ADHD medication in 2000-2012. The average PPR over the study period was 1.08 (95% CI, 1.04-1.12) and remained stable across subgroups and sensitivity analyses. Overall, 40% of children born October-December had entered school a year after their age-assigned grade level. CONCLUSIONS: Contrary to previous study results, we observed almost no relative age effect on medication use for ADHD among children in Denmark. We postulate that this may be due to the high proportion of relatively young children held back by 1 year in the Danish school system and/or a generally low prevalence of ADHD medication use in the country. PMID- 24813479 TI - 19F NMR as a probe of ligand interactions with the iNOS binding site of SPRY domain-containing SOCS box protein 2. AB - SPRY domain-containing SOCS box protein 2 (SPSB2) regulates inducible nitric oxide synthase (iNOS) by targeting it for proteasomal degradation. Inhibiting this interaction prolongs the intracellular lifetime of iNOS, leading in turn to enhanced killing of infectious pathogens such as bacteria and parasites. SPSB2 recognizes a linear motif (DINNN) in the disordered N-terminus of iNOS, and ligands that target the DINNN binding site on SPSB2 are potentially novel anti infective agents. We have explored (19)F NMR as a means of probing ligand binding to SPSB2. All six Trp residues in SPSB2 were replaced with 5-fluorotryptophan (5 F-Trp) by utilizing a Trp auxotroph strain of Escherichia coli. The labeled protein was well folded and bound a DINNN-containing peptide with similar affinity to native SPSB2. Six well-resolved 5-F-Trp resonances were observed in the (19)F NMR spectrum and were assigned using site-directed mutagenesis. The (19)F resonance of W207 was significantly perturbed upon binding to DINNN containing peptides. Other resonances were perturbed to a lesser extent although in a way that was sensitive to the composition of the peptide. Analogues of compounds identified in a fragment screen also perturbed the W207 resonance, confirming their binding to the iNOS peptide-binding site on SPSB2. (19)F NMR promises to be a valuable approach in developing inhibitors that bind to the DINNN binding site. PMID- 24813480 TI - [Doctors and management]. PMID- 24813481 TI - [Analysis of the Cochrane Review: Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non valvular atrial fibrillation. Cochrane Database Syst Rev. 2014,3:CD009893]. AB - Ischemic stroke is one of the most important complications of lone (non-valvular) atrial fibrillation. Its prevention is usually accomplished through oral anticoagulation. Until a few years ago warfarin was the most used agent, but recently two new pharmacologic classes have been introduced for stroke prevention in these patients: oral direct thrombin inhibitors (dabigatran and ximelagatran) and oral factor Xa inhibitors (rivaroxaban, apixaban and edoxaban). In this systematic review, oral direct thrombin inhibitors were compared with warfarin for efficacy and safety. The results indicate that there is no difference in terms of efficacy (except dabigatran 150 mg BID). Oral direct thrombin inhibitors presented less hemorrhages but increased treatment withdrawal due to adverse side effects (the authors performed post-hoc analyses excluding ximelagatran because this drug was withdrawn from the market owing to safety concerns). There was no difference in terms of mortality between the agents. PMID- 24813482 TI - Do vaccines save lives? Yes they do! AB - Since their introduction and widespread use, vaccines have been very successful in reducing morbidity and mortality of the diseases they target, at an individual level and through herd immunity. The impact on the mortality has been rapid and easy to measure for some diseases, such as diphtheria, pertussis and measles. For other diseases, including hepatitis B and human papillomavirus infections, deaths averted occur many years after vaccination, and it takes years until the full potential of the vaccine can be established. Finally, in middle and high income countries, the impact of vaccination against some diseases, like invasive pneumococcal disease and rotavirus gastro-enteritis, is measured by decrease in incidence of the disease and reduction in hospitalization rather than impact on mortality. But in the countries with the highest incidence of these diseases, mortality remains high due to low availability of these vaccines, and millions of deaths could be averted by optimal use of vaccines in these regions. Major challenges for vaccination programmes are to maintain and strengthen trust in the benefits of vaccination and adapt immunization schedules according to the changing epidemiological landscape. PMID- 24813483 TI - The Zarit Burden Interview in Portugal: Validity and recommendations in dementia and palliative care. AB - The impact of dementia on informal or family caregivers became a public health issue. One well-established tool for the assessment of emotional, physical and social impact on caregivers is the Zarit Burden Interview. Worldwide, it is widely used in epidemiological studies, drug or psychosocial clinical trials, and health services research. The original focus on burden among dementia caregivers has spread to other clinical contexts, mostly in old age and palliative care. Given these diverse applications, issues around the validity and reliability of national translations are crucial to assure that all evidence gathered is indeed of high quality. Moreover, caution is needed on the use of cut-offs for categorizing levels of caregiver strain or of subscales derived from recurrent exploratory factor analyses in small-scale local studies. As with other translations of measures in the health field, researchers and clinicians in Portugal must be aware of how to address bias in using the Zarit Burden Interview and interpreting findings. PMID- 24813484 TI - [Adaptation and psychometric proprieties study for the Portuguese version of the Adolescent Coping Scale - Escala de Coping para Adolescentes]. AB - INTRODUCTION: Coping is a psychological process that prompts the individual to adapt to stressful situations. The Adolescent Coping Scale is a widely used research and clinical tool. This study aimed to develop a Portuguese version of the Adolescent Coping Scale and to analyze the strategies and coping styles of young people in our sample. MATERIAL AND METHODS: An anonymous questionnaire comprising the Adolescent Coping Scale was submitted and replied by 1 713 students (56% female, from 12 to 20 years, average age 16) The validity study of the scale included: principal component and reliability analysis; confirmatory analysis using structural equation modelling Subsequently, a gender comparison of both the strategies and the coping styles was conducted through independent samples t tests. RESULTS: The final structure of the Adolescent Coping Scale adaptation retained 70 items assessing 16 coping strategies grouped into three major styles. The scales showed good internal consistency (Cronbach alpha values between 0.63. and 0.86, with the exception of one dimension that as shown a value of 0.55) and the confirmatory model showed a good fit (goodness of fit index values between 0.94 e 0.96). Two coping strategies were eliminated on statistical grounds (insufficient saturations of items in the corresponding dimensions). We found that the style of coping focused on problem solving is the most used by youths from our sample, in both sexes. Females had higher mean values in non productive coping style and reference to others. DISCUSSION: This adapted version has high similarity with the original scale, with expectable minor changes, given that coping is influenced by cultural, geographical and socio-economic variables. CONCLUSION: The present study represents an important part of the validation protocol Portuguese Adolescent Coping Scale, including its linguistic adaptation and its internal consistency and factor structure studies. PMID- 24813485 TI - [HIV infection and non-AIDS-defining malignancies: an outpatient clinic experience]. AB - INTRODUCTION: Human Immunodeficiency Virus infected patients have an increased risk for developing different types of cancer. After the introduction of highly active antiretroviral therapy (HAART), and consequent increased survival, a shift has been seen in the spectrum and evolution of HIV infection related diseases, particularly oncological ones, with a tendency to increase non-AIDS-defining malignancies (NADM) as opposed to AIDS defining malignancies. MATERIAL AND METHODS: Characterization of the Human Immunodeficiency Virus infected patients with a non-AIDS defining malignancy diagnosis, followed over 16 years at an outpatient clinic in Lisbon through the review of medical records and retrospective evaluation of demographic, epidemiological, clinical and laboratorial parameters, treatment and mortality. RESULTS: Of the 1042 patients evaluated, there were 34 Non-AIDS defining malignancy cases identified, mostly in men (78%), with a median age of 55 years. The most common cancers were: lung (20.6%), bladder (17.6%), prostate (8.8%), and anal carcinoma (5.9%). The mean time between Human Immunodeficiency Virus infection and non-AIDS-defining malignancy diagnosis was 6.8 +/- 4 years. At the time of non-AIDS- defining malignancy diagnosis the majority of patients (78.8%) was receiving HAART for a mean period of 5.7 +/- 3 years, most of whom were immune and virologically controlled (64%). There were 45.5% deaths, mainly in patients with lung cancer (20%). CONCLUSION: Given the risk of developing a non-AIDS-defining malignancy in Human Immunodeficiency Virus-infected patients, it is essential to continue to invest in prevention strategies, promote smoking cessation as well as vaccination programs, as well as applying screening protocols adjusted to this population. PMID- 24813486 TI - [First-trimester biochemical markers and small-for-gestational-age infants]. AB - INTRODUCTION: Several studies suggested an association between first trimester biochemical markers (PAPP-A and beta-HCG) and infants below 10th percentile. Our goal was to describe this relationship of biochemical markers with small-for gestational-age fetuses in our population. MATERIAL AND METHODS: Retrospective analytic study of 2 035 pregnant women that underwent first-trimester screening in the period between March 2009 and September 2011. Small-for-gestational-age infants below 10th percentile were compared with control group (term newborn with birth weight above 10th percentile). Infants below 3rd percentile and control group were also compared. Multiple and logistic regression analysis were done with PAPP-A, beta-HCG (multiples of the expected normal median) and demographic maternal characteristics (ethnicity, weight and smoker status). RESULTS: This study demonstrated an independent contribution of PAPP-A, maternal weight and smoker status in predicting small-for-gestational-age infants. For PAPP-A, the odds ratio for small-for-gestational age below 10th and 3rd percentile was 2.41 and 3.41, respectively (p < 0.01). For beta-HCG, odds ratio below 10th percentile was 1.70 (p = 0.03) and for birth weight below the 3rd percentile, the odds ratio was 3.22 (p < 0.01). CONCLUSIONS: Low levels of PAPP-A and beta-HCG (values below 5th percentile of the study population) were associated with an increased risk of small-for-gestational-age infants in the pregnant population included in this study. PMID- 24813487 TI - [Relation between metformin treatment and the development of hyperlactacidemia at the emergency room]. AB - INTRODUCTION: In type 2 diabetic patients treated with metformin the development of hyperlactacidemia or even lactic acidosis seems to result from an acute precipitating event. This study aims to assess the prevalence and relative risk of hyperlactacidemia in diabetic patients admitted in the Emergency Room, the predictive factors for high lactate concentration and the influence of hyperlactacidemia in patients' prognosis. MATERIAL AND METHODS: Transversal observational study including patients observed between June and October 2012: 138 type 2 diabetics, 66 treated with metformin, and 83 non-diabetic patients. Studies' variables: age, sex, cause of admition, blood pressure, drugs, personal history, analytical study (biochemistry and arterial blood gas analyses with lactate) and destination. Statistical analysis was performed using SPSS 21.0((r)). RESULTS: Mean lactate concentration and hyperlactacidemia prevalence were significantly higher in diabetic patients (2.1 +/- 0.1 mmol/L vs 1.1 +/- 0.1 mmol/L, p < 0.001 and 39.1% vs 3.6%, p < 0.001, respectively) and in those under metformin compared to other diabetics (2.7 +/- 0.2 mmol/L vs 1.6 +/- 0.1 mmol/L, p < 0.001 and 56.9% vs 23.3%, p < 0.001, respectively). Diabetics on metformin presented a 25-fold increased risk of hyperlactacidemia (OR = 25.10, p < 0.05). Creatinine was the only independent predictive factor for lactate concentrations (B = 1.33, p < 0.05). Patients with hyperlactacidemia had 4.4 times higher odds of being hospitalized or dying (OR = 4.37, p < 0.05). When hospitalized, they had longer hospitalization periods (21.66 +/- 5.86 days vs 13.68 +/- 5.33 days, p < 0.001) and higher rate of deaths (12.5% (n = 4) vs 4.3% (n = 2), p < 0.05). CONCLUSION: There was an increased risk of hyperlactacidemia in patients with type 2 diabetes, particularly for those under metformin. Serum creatinine represented the only independent associated factor of lactate concentration. The presence of hyperlactacidemia was associated with worse prognosis. PMID- 24813488 TI - [Brucellar spondylodiscitis: case series of the last 25 years]. AB - INTRODUCTION: Brucellosis is an endemic zoonosis in Portugal. Brucellar spondylodiscitis is one of the most frequent focal manifestations which may cause severe sequelae despite appropriate therapy. MATERIAL AND METHODS: Retrospective study of patients with diagnosis of brucellar spondylodiscitis admitted to the Infectious Diseases Department of Centro Hospitalar e Universitario de Coimbra, over a 25-year period (1988-2012). RESULTS: We identified 54 patients, 55.6% male, mean age of 54.8 years. In 81.5% an epidemiological context was identified, mostly contact with sheep and goats. The duration of symptoms prior to diagnosis was 5.5 months. The most common signs and symptoms were pain (98.1%), fever (46.3%) and neurological deficits (25.9%). Spinal magnetic resonance imaging was the most used imaging method (77.8%) showing abscesses in 29.6% of patients. Lumbar location predominated (77.7%). Diagnosis was attained in 47 patients (87.0%): positive blood cultures (3 patients), positive serology (32 patients) or by both methods (12 patients). Combined regimens of doxycycline and rifampicin (64.8%), or streptomycin (24.1%) were most used, for an average duration of 4.4 months. A patient was referred for surgery for abscess drainage. Evolution was mostly favorable (92.6%), no deaths occurring. DISCUSSION: Research of the epidemiologic context turned out to be a major key leading to the diagnosis. Treatment of osteoarticular brucellosis is still controversial. CONCLUSIONS: Brucellar spondylodiscitis should be considered in the differential diagnosis of patients with low back pain, even in the absence of fever, particularly in regions where the disease is endemic. Antibiotic regimen, its' duration and the need for surgery should be individualized to achieve a better prognosis. Cases have declined over the years, a fact related to better control of animal endemic. PMID- 24813489 TI - [Acute respiratory distress syndrome: case series, two years at an intensive care unit]. AB - INTRODUCTION: Acute Respiratory Distress Syndrome has a significant incidence and mortality at Intensive Care Units. Therefore, more studies are necessary in order to develop new effective therapeutic strategies. The authors have proposed themselves to characterize Acute Respiratory Distress Syndrome patients admitted to an Intensive Care Unit for 2 years. MATERIAL AND METHODS: This was an observational retrospective study of the patients filling the Acute Respiratory Distress Syndrome criteria from the American-European Consensus Conference on ARDS, being excluded those non invasively ventilated. Demographic data, Acute Respiratory Distress Syndrome etiology, comorbidities, Gravity Indices, PaO2/FiO2, ventilator modalities and programmation, pulmonary compliance, days of invasive mechanical ventilation, corticosteroids use, rescue therapies, complications, days at Intensive Care Unit and obits were searched for and were submitted to statistic description and analysis. RESULTS: A 40 patients sample was obtained, with a median age of 72.5 years (interquartile range = 22) and a female:male ratio of ~1:1.86. Fifty five percent of the Acute Respiratory Distress Syndrome cases had pulmonary etiology. The mean minimal PaO2/FiO2 was 88 mmHg (CI 95%: 78.5-97.6). The mean maximal applied PEEP was 12.4 cmH2O (Standard Deviation 4.12) and the mean maximal used tidal volume was 8.2 mL/ Kg ideal body weight (CI 95%: 7.7-8.6). The median invasive mechanical ventilation days was 10. Forty seven and one half percent of the patients had been administered corticosteroids and 52.5% had been submitted to recruitment maneuvers. The most frequent complication was Ventilator Associated Pneumonia (20%). The median Intensive Care Unit stay was 10.7 days (interquartile range 10.85). The fatality rate was 60%. The probability of the favorable outcome 'non-death in Intensive Care Unit' was 4.4x superior for patients who were administered corticosteroids and 11x superior for patients < 65 years old. DISCUSSION AND CONCLUSIONS: Acute Respiratory Distress Syndrome is associated with long hospitalization and significant mortality. New prospective studies will be necessary to endorse the potential benefit of steroid therapy and to identify the subgroups of patients that warrant its use. PMID- 24813490 TI - Impact of preoperative analytical values on post-operative mortality rate of intertrochanteric fractures. AB - INTRODUCTION: Intertrochanteric fractures incidence has been increasing over the past few years and therefore so have all the problems associated with it. It is important to search for possible ways to reduce comorbidities as well as postoperative mortality. We decided to assess the impact of some routine pre operative analytical values on post-operative mortality of patients with inter trochanteric fractures 65 years or older. MATERIAL AND METHODS: From all intertrochanteric fracture admissions between January 2007 and May 2012, 160 patients were included in this study. The variables studied were age, gender, length of hospital stay, and analytical data such as hemoglobin, total leucocyte count, platelets, urea, creatinin and plasma sodium. Follow-up data on mortality were obtained from the civil registry and, considering 6 months as the cut-off point, patients were divided into 2 groups based on their survival. Mann-Whitney and Chi square statistics were used to study the association between our variables and patients survival. RESULTS: Our population showed a median age of 82 years old and a majority of women (79.4%). Within the first 6 months after surgery, 27 patients of the initial 160 (16.1%) died. Mortality was associated with low hemoglobin, high platelets, high creatinin and low plasma sodium. CONCLUSIONS: Postoperative mortality of hip surgery is high. Our findings could be used to reduce this rate by correcting some analytical values preoperatively. PMID- 24813491 TI - Quality of health information on acute myocardial infarction and stroke in the world wide web. AB - INTRODUCTION: The quality of health information in the Internet may be low. This is a concerning issue in cardiovascular diseases which warrant patient self management. We aimed to assess the quality of Portuguese websites as a source of health information on acute myocardial infarction and stroke. MATERIAL AND METHODS: We used the search terms 'enfarte miocardio' and 'acidente vascular cerebral' (Portuguese terms for myocardial infarction and stroke) on Google((r)), on April 5th and 7th 2011, respectively, using Internet Explorer((r)). The first 200 URL retrieved in each search were independently visited and Portuguese websites in Portuguese language were selected. We analysed and classified 121 websites for structural characteristics, information coverage and accuracy of the web pages with items defined a priori, trustworthiness in general according to the Health on the Net Foundation and regarding treatments using the DISCERN instrument (48 websites). RESULTS: Websites were most frequently commercial (49.5%), not exclusively dedicated to acute myocardial infarction/ stroke (94.2%), and with information on medical facts (59.5%), using images, video or animation (60.3%). Websites' trustworthiness was low. None of the websites displayed the Health on the Net Foundation seal. Acute myocardial infarction/ stroke websites differed in information coverage but the accuracy of the information was acceptable, although often incomplete. CONCLUSION: The quality of information on acute myocardial infarction/ stroke in Portuguese websites was acceptable. Trustworthiness was low, impairing users' capability of identifying potentially more reliable content. PMID- 24813492 TI - [Neurological diseases in the Dalton Trevisan's short stories]. AB - INTRODUCTION: The relationship between fictional literature and Medicine, particularly Neurology, is very wide. The aim of this review is to analyze the Dalton Trevisan's work, considered the most important Brazilian short stories writer, focusing in the description of neurological diseases. MATERIAL AND METHODS: A comprehensive evaluation of Dalton Trevisan's texts in books published between 1959 and 2012. RESULTS: Descriptions of the common neurological diseases embedded in Trevisan's work, such as, epilepsy and stroke, are presented. DISCUSSION: This review disclosed neurological conditions highly prevalent in the general population, namely epilepsy and stroke, which have deserved a practical and objective approach by the Brazilian master of the short stories. CONCLUSION: The fictional World of the famous Brazilian writer Dalton Trevisan is punctuated by everyday routine facts, which are however flavored with the tragic-grotesque touch so peculiar to the author. Neurological diseases, particularly epilepsy and stroke, are no exception to this universe and are exquisitely described by the writer. PMID- 24813493 TI - Comparing the performance of the SF-6D and the EQ-5D in different patient groups. AB - INTRODUCTION: This research aims to explore the performance of the SF-6D and the EQ-5D in patients suffering from asthma, chronic obstructive pulmonary disease, cataracts, and rheumatoid arthritis. In particular, the aim of this research is twofold: 1) to study the level of agreement between the indexes and the descriptive systems of the dimensions of the SF-6D and the EQ-5D, and 2) to analyze the discriminative ability of the instruments. MATERIAL AND METHODS: A sample of 643 patients completed both the SF-36v2 and the EQ-5D. The discriminative ability of the instruments was analyzed. Furthermore, the level of agreement between the indexes and the descriptive systems of the dimensions of the SF-6D and the EQ-5D were studied. The level of agreement between instruments was investigated using correlation coefficients and the Bland-Altman plots, while the influence of medical condition and other socio-demographic variables was analyzed using nonparametric tests. Paired-samples tests were used to identify differences between the scores. RESULTS AND DISCUSSION: The results show a strong correlation and agreement between both indexes. Overall, questionnaire indexes differ by medical condition and socio-demographic groups and both instruments are able to discriminate between socio-demographic groups. CONCLUSION: This study confirmed the hypothesis that the SF-6D generates higher utility values in less healthy individuals. The SF-6D and the EQ-5D seem to perform differently in each of the diseases studied since the descriptive statistics differ between instruments and the level of correlation is not uniform. Results show that the instruments generate different utility values, but there is a strong agreement between both indexes. Thus, the two instruments are not interchangeable and their results cannot be directly comparable. PMID- 24813494 TI - [Demography of physicians in Portugal: prospective analysis]. AB - INTRODUCTION: The study modelled the physicians predictable allocation by medical specialty, in the horizon of 2025. It was based on the physicians demographics in Portugal and through the development of different future scenarios. MATERIAL AND METHODS: In the study was developed a Supply Model, which represents the capacity of medical training installed in Portugal, and a Necessity Model that perspective possible futures for the provision of medical professionals. RESULTS: Each model comprehends several scenarios, according to different context variables (introduction or not of limits to postgraduate training capacity, demographic trends, ratios recommended by Colleges Specialty ...). DISCUSSION/CONCLUSION: The models comparison lead to the conclusion that the training system has the capacity to meet the needs of physicians in all scenarios developed, and it even generates a surplus of medical professionals that may not be absorbed by the healthcare system, in the horizon of 2025. PMID- 24813495 TI - [Interleukin-17 as a therapeutic target in psoriasis]. AB - Psoriasis is a chronic, immune-mediated inflammatory disease that affects up to 1 3% of the general population. An advanced understanding of the immune pathogenesis of psoriasis has led to the development of new drugs that refine existing treatments or target novel molecular and immunologic pathways. IL-17 and Th17 cells play an important role in the pathogenesis of several autoimmune and immune-mediated disorders, including psoriasis. IL-17A, a pro-inflammatory cytokine, is produced by Th17 cells along with other effector cytokines, such as IL-17F an IL-22, but it is also expressed by other cells of the innate immune system, including mast cells, neutrophils or dendritic cells, that are found in psoriatic lesions. For this reason IL-17 has emerged as an attractive therapeutic target. Agents that inhibit IL-17 are in development and preliminary clinical results are promising, confirming the importance of IL-17 in psoriasis pathophysiology. Their selective intervention in the immune system makes them an attractive therapeutic approach to autoimmune diseases, particularly psoriasis, being possible that in the near future these novel therapies could be a valid alternative for currently available biologic agents. PMID- 24813496 TI - [How xenon works: neuro and cardioprotection mechanisms]. AB - INTRODUCTION: The Xenon, a noble gas, has anesthetics properties, associated with remarkable hemodynamic stability as well as cardioprotective, neuroprotective proprieties. Its physicochemical characteristics give him a quick induction and emergence of anesthesia, being free of deleterious effects in all organs and showing no teratogenicity. Such properties have led to a growing interest in improving the knowledge about this noble gas, in order to assess the mechanisms of neuro and cardioprotection induced and to assess the clinical indications for its use. MATERIAL AND METHODS: Qualitative review of clinical trials on anesthesia with xenon. Studies were identified from MEDLINE and by hand searching, using the following keywords: xenon, xenon anestesia, xenon neuroprotection, xenon cradioprotection. RESULTS: After several studies, including two randomized multicenter controlled trials, the use of xenon as an anesthetic in patients ASA I-II was approved in March 2007. However his use in clinical practice has been strongly limited by it's high price. It seems unlikely that the advantages it offers in relation to other anesthetics justify it's use in patients ASA I-II. Although, xenon may be a valuable asset in the reduction of co-morbilities and mortality in anesthesia of patients ASA III-IV, unfortunately, there are no large randomized control studies to prove it. DISCUSSION: Unfortunately, there are still no randomized or multicentric studies showing a favourable cost-benefit profile of xenon in ASA III-IV patients vs. other anaesthetics. CONCLUSION: The usefulness of xenon in Anesthesiology requires more studies to be defined. PMID- 24813497 TI - [Cognitive decline of medicamentous etiology]. AB - In the elderly there is a high risk of inappropriate medication and adverse effects of polypharmacy. A 68 year-old female patient resorted to the Emergency Room for suspected stroke. According to the husband, in the six months prior to admission, she became progressively disorientated and dependent. She had resorted to various appointments from different specialties and was polymedicated. It was impossible to clarify the exact dosage. On neurological examination she presented disturbance in attention and memory, disorientation, constructional apraxia, myoclonus and gait imbalance. After the suspension of all chronic medication, she showed gradual improvement. By the time of discharge, her neurological examination was completely normal. Iatrogenic effect of drugs as a cause of reversible dementia should be considered. All patients, particularly the elderly and their caregivers, should be suitably informed about the drugs that are prescribed and the dosages used. Using the biopsychosocial model could prevent inappropriate polypharmacy and iatrogeny. PMID- 24813498 TI - Tubulointerstitial Nephritis and Uveitis Syndrome with non caseating granuloma in bone marrow biopsy. AB - The Tubulointerstitial Nephritis and Uveitis syndrome is a very rare condition, probably under-diagnosed in clinical practice. It is characterized by the combination of an interstitial nephritis and uveitis, and is an exclusion diagnosis. Tissue non caseating granuloma can be rarely present, with only 6 cases reported on bone marrow. We present a case of a 55 year old female with a 3 month history of asthenia and weight loss. Blood tests showed anemia and renal insufficiency. Renal biopsy revealed interstitial nephritis and the bone marrow biopsy showed caseating granuloma. One month later anterior uveitis of the left eye appeared. An extensive exclusion of all possible causes allowed a diagnosis of Tubulointerstitial Nephritis and Uveitis syndrome with caseating granuloma in bone marrow. As ocular and renal manifestations may not occur simultaneously, Tubulointerstitial Nephritis and Uveitis Syndrome should be systematically considered in cases of interstitial nephritis and/or uveitis, and tissue granulomas can be part of this rare syndrome. PMID- 24813499 TI - [Von Meyenburg complex or liver metastasis? Case report and literature review]. AB - Hepatic lesions represent a common finding in clinical practice. Bile ducts hamartomas, also known as Von Meyenburg complex, are benign hepatic malformations composed of small dilated cystic bile ducts lined by fibrous stroma. They represent a rare and asymptomatic clinic-pathological entity. Imagiological findings are variable, and may present as multiple small scattered lesions, or rarely as a single nodule. These findings may resemble secondary lesions and, although benign, there are cases of progression to colangiocarcinoma. Thus it is important to include this complex in the differential diagnoses of focal hepatic lesions, being necessary a detailed investigation for their differentiation. This case represents an atypical presentation of a rare and not frequently considered entity in clinical practice. PMID- 24813500 TI - [Axillary polymastia: a postpartum diagnosis]. PMID- 24813501 TI - [Supernumerary teeth: a radiographic finding]. PMID- 24813502 TI - [Regarding: S Fernandes, E Leite, F Vieira, J Costa Santos. The disclosed DSM-5: what impact will it have on forensic psychiatry? Acta Med Port 2014;27:126-34]. PMID- 24813503 TI - [Medicine on the work of Amadeo de Souza-Cardoso]. AB - Amadeo de Souza-Cardoso, one of the pivotal figures of the Portuguese Modernist movement, studied painting and began his work in Paris where he arrived at the age of 19. Interestingly, Amadeo cemented strong friendships with some physicians from his time. The first was Manuel Laranjeiro, physician, poet and essayist, who has been a major influence on his choice of studying visual arts. In 1909, the painter met the dermatologist Paul Alexander and later Dr. Martins, who diagnosed him with a dermatosis, which led the painter to have to interrupt his work. Described as an eczema, which affected his face and hands, probably an allergic contact dermatitis to paints or other products that did not become clarified, with the artist's early death at age of 30 by pneumonic fever. Occupational diseases affect the practice of many professions and artists, including painters, who constitute an important risk group. Contact with several components of paints and solvents are associated with the contact sensitization. However, allergens responsible for allergic contact dermatitis change over the time according to the usage trends and products' composition. PMID- 24813504 TI - Clinical Q & A: translating therapeutic temperature management from theory to practice. PMID- 24813505 TI - Physiological and kinetic characterization of a suspended cell anammox culture. AB - Anammox related technologies are currently widely applied for nitrogen removal from sewage sludge digester rejection water. Nevertheless, many aspects of the anammox process like the kinetic characteristics and the reaction stoichiometry are still subject of debate. Parameter values reported in literature are often hampered by mass transfer limitation or by the presence of a significant side population. In this study a membrane bioreactor (MBR) based method for growing a highly enriched anammox microbial community is described. The almost pure free cells suspension of highly active anammox bacteria was used for detailed kinetic and stoichiometric analysis of the anammox process. The anammox culture enriched during this study had a biomass specific maximum growth rate of 0.21 d(-)(1) which is higher than ever reported before in literature. Using an experimental methodology based on imposing dynamic process conditions combined with process modeling and parameter estimation, the intrinsic nitrite half saturation constant was identified to be as low as 35 MUg-N L(-)(1). This was confirmed to be an accurate estimation in the pH range of 6.8-7.5. PMID- 24813506 TI - Distribution of dissolved and particulate radiocesium concentrations along rivers and the relations between radiocesium concentration and deposition after the nuclear power plant accident in Fukushima. AB - This study involved measurement of concentrations of dissolved and particulate radiocesium ((134)Cs and (137)Cs) in river water, and determination of the quantitative relations between the amount of deposited (137)Cs and (137)Cs concentrations in river waters after the Fukushima Daiichi nuclear power plant accident. First, the current concentrations of dissolved and particulate (134)Cs.(137)Cs were determined in a river watershed from 20 sampling locations in four contaminated rivers (Abukuma, Kuchibuto, Shakado, and Ota). Distribution characteristics of different (137)Cs forms varied with rivers. Moreover, a higher dissolved (137)Cs concentration was observed at the sampling location where the (137)Cs deposition occurred much more heavily. In contrast, particulate (137)Cs concentration along the river was quite irregular, because fluctuations in suspended solids concentrations occur easily from disturbance and heavy precipitation. A similar tendency with dissolved (137)Cs distribution was observed for the (137)Cs concentration per unit weight of suspended solids. Regression analysis between deposited (137)Cs and dissolved/particulate (137)Cs concentrations was performed for the four rivers. The results showed a strong correlation between deposited (137)Cs and dissolved (137)Cs, and a relatively weak correlation between deposited (137)Cs and particulate (137)Cs concentration for each river. However, if the particulate (137)Cs concentration was converted to (137)Cs concentration per unit weight of suspended solid, the values showed a strong correlation with deposited (137)Cs. PMID- 24813507 TI - Regulated fracture in tooth enamel: a nanotechnological strategy from nature. AB - Tooth enamel is a very brittle material; however it has the ability to sustain cracks without suffering catastrophic failure throughout the lifetime of mechanical function. We propose that the nanostructure of enamel can play a significant role in defining its unique mechanical properties. Accordingly we analyzed the nanostructure and chemical composition of a group of teeth, and correlated it with the crack resistance of the same teeth. Here we show how the dimensions of apatite nanocrystals in enamel can affect its resistance to crack propagation. We conclude that the aspect ratio of apatite nanocrystals in enamel determines its resistance to crack propagation. According to this finding, we proposed a new model based on the Hall-Petch theory that accurately predicts crack propagation in enamel. Our new biomechanical model of enamel is the first model that can successfully explain the observed variations in the behavior of crack propagation of tooth enamel among different humans. PMID- 24813508 TI - Production of trichodiene by Trichoderma harzianum alters the perception of this biocontrol strain by plants and antagonized fungi. AB - Trichothecenes are phytotoxic sesquiterpenic mycotoxins that can act as virulence factors in plant diseases. Harzianum A (HA) is a non-phytotoxic trichothecene produced by Trichoderma arundinaceum. The first step in HA biosynthesis is the conversion of farnesyl diphosphate to trichodiene (TD), a volatile organic compound (VOC), catalysed by a sesquiterpene synthase encoded by the tri5 gene. Expression of tri5 in the biocontrol strain Trichoderma harzianum CECT 2413 resulted in production of TD in parallel with a reduction of ergosterol biosynthesis and an unexpected increase in the level of squalene. Transformants expressing tri5 displayed low chitinase activity and induced expression of Botrytis cinerea BOT genes, although their total antagonistic potential against phytopathogenic fungi was not reduced. VOCs released by the tri5-transformant induced expression of tomato defence genes related to salicylic acid (SA), and TD itself strongly induced the expression of SA-responsive genes and reduced the development of lateral roots. Together, these results suggest that TD acts as a signalling VOC in the interactions of Trichoderma with plants and other microorganisms by modulating the perception of this fungus to a given environment. Moreover, the TD ability to induce systemic defences indicates that complex trichothecene structures may not be necessary for inducing such responses. PMID- 24813511 TI - Eosinophilic esophagitis: clinical presentation in children. AB - Eosinophilic esophagitis (EoE) is increasing in western nations. Symptoms in infants and young children include feeding difficulties, failure to thrive, and gastroesophageal reflux. School-aged children may present with vomiting, abdominal pain, and regurgitation; adolescents and adults with dysphagia and food impaction. Delayed diagnosis increases risk of stricture formation. Children with untreated EoE have tissue changes resembling airway remodeling. Endoscopy does not always correlate. Management centers on food elimination. Approaches include skin prick and patch testing, removal of foods, or an amino acid formula diet. Long-term elimination diets can produce nutritional deficiencies and have poor adherence. PMID- 24813509 TI - Eosinophilic esophagitis: historical perspective on an evolving disease. AB - Initial case series describing children and adults with symptoms related to esophageal dysfunction and dense esophageal eosinophilia lead to recognition of a "new" disease, eosinophilic esophagitis (EoE). Clinical, basic, and translational studies have provided a deeper understanding of this somewhat enigmatic disease that mechanistically is defined as an antigen-driven condition limited to the esophagus. This article summarizes many of the key historical features of EoE and provides a glimpse of potential future developments. PMID- 24813510 TI - Epidemiology of eosinophilic esophagitis. AB - In this article, the epidemiology of eosinophilic esophagitis (EoE) is reviewed. Demographic features and natural history are described, the prevalence and incidence of EoE are highlighted, and risk factors for EoE are discussed. EoE can occur at any age, there is a male predominance, it is more common in whites, and there is a strong association with atopic diseases. EoE is chronic, relapses are frequent, and persistent inflammation increases the risk of fibrostenotic complications. The prevalence is currently estimated at 0.5-1 in 1000, and EoE is now the most common cause of food impaction. The incidence of EoE is approximately 1/10,000 new cases per year, and the increase in incidence is outpacing increases in recognition and endoscopy volume, but the reasons for this evolving epidemiology are not yet fully delineated. PMID- 24813512 TI - Clinical presentation of eosinophilic esophagitis in adults. AB - Eosinophilic esophagitis (EoE) is an increasingly recognized immune antigen mediated esophageal disease found in both children and adults. It is defined as a clinicopathologic disease characterized by symptoms of esophageal dysfunction accompanied by an eosinophil-predominant esophageal inflammation that occurs in the absence of other causes of esophageal eosinophilia. Classic symptoms in adults include dysphagia to solids and food bolus impaction but a variety of other symptoms are also encountered. Despite the increasing awareness of EoE among practicing physicians, a long delay from onset of symptoms to diagnosis remains a problem in this disease. PMID- 24813514 TI - Histopathologic features of eosinophilic esophagitis and eosinophilic gastrointestinal diseases. AB - Eosinophilic esophagitis (EoE) shows characteristic microscopic pathologic features in endoscopically obtained esophageal biopsies, including an eosinophil rich inflammatory infiltrate in esophageal epithelium, but other inflammatory cells are also increased. Additional alterations are found in epithelium and lamina propria. Esophageal biopsy pathology is a sensitive but not specific marker for EoE related to antigen exposure. Several of the pathologic features of EoE correlate with dysregulated genes in the EoE transcriptome. Eosinophilic gastrointestinal diseases affecting the remainder of the gastrointestinal tract are less well characterized; this article discusses pathologic features in mucosal biopsies that could form the basis for diagnosis and future study. PMID- 24813513 TI - Eosinophilic esophagitis: interactions with gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) are not mutually exclusive. The notion that GERD and EoE can be distinguished by the response to proton pump inhibitor (PPI) treatment is based on the mistaken assumption that gastric acid suppression is the only important therapeutic effect of PPIs, and therefore only GERD can respond to PPIs. We believe that a clinical or histologic response to PPIs does not rule in GERD or rule out EoE. We recommend a trial of PPI therapy for patients with symptomatic esophageal eosinophilia, even if the diagnosis of EoE seems clear-cut. PMID- 24813515 TI - Genetic and epigenetic underpinnings of eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a complex, polygenic disorder caused by genetic predisposition and environmental exposures. Because of the recent emergence of EoE as a bona fide global health concern, a paucity of available therapeutic and diagnostic options exists. However, rapid progress has been made in an effort to rectify this lack and to improve understanding of the factors that cause EoE. This article highlights key advances in elucidating the genetic (and epigenetic) components involved in EoE. PMID- 24813516 TI - Allergic mechanisms in eosinophilic esophagitis. AB - Eosinophilic esophagitis is rapidly increasing in incidence. It is associated with food antigen-triggered, eosinophil-predominant inflammation, and the pathogenic mechanisms have many similarities to other chronic atopic diseases. Studies in animal models and from patients have suggested that allergic sensitization leads to food-specific IgE and T-helper lymphocyte type 2 cells, both of which seem to contribute to the pathogenesis along with basophils, mast cells, and antigen-presenting cells. In this review our current understandings of the allergic mechanisms that drive eosinophilic esophagitis are outlined, drawing from clinical and translational studies in humans as well as experimental animal models. PMID- 24813517 TI - Clinical implications and pathogenesis of esophageal remodeling in eosinophilic esophagitis. AB - In eosinophilic esophagitis (EoE), remodeling changes are manifest histologically in the epithelium and subepithelium where lamina propria fibrosis, expansion of the muscularis propria, and increased vascularity occur. The clinical symptoms and complications of EoE are largely consequences of esophageal remodeling. Available therapies have demonstrated variable ability to reverse existing remodeling changes of the esophagus. Systemic therapies have the potential of addressing subepithelial remodeling. Esophageal dilation remains a useful, adjunctive therapeutic maneuver in symptomatic adults with esophageal stricture. As novel treatments emerge, it is essential that therapeutic end points account for the fundamental contributions of esophageal remodeling to overall disease activity. PMID- 24813519 TI - Eosinophilic esophagitis: overview of clinical management. AB - A validated disease-specific symptom-assessment tool for eosinophilic esophagitis (EoE) has yet to be approved by regulatory authorities for use in clinical trials. Relevant end points for daily practice include EoE-related symptoms and esophageal eosinophilic inflammation. Endoscopic features should also be taken into account when establishing a therapy plan. A reasonable clinical goal is to achieve a reduction in EoE-related symptoms and esophageal eosinophilic inflammation. Evidence is increasing to support an anti-inflammatory maintenance therapy, as this can reduce esophageal remodeling. In EoE patients in clinical remission, annual disease monitoring with symptom, endoscopic, and histologic assessments of sustained treatment response is recommended. PMID- 24813518 TI - Eosinophilic gastroenteritis and related eosinophilic disorders. AB - Eosinophilic gastroenteritis (EGE) represents one member within the spectrum of diseases collectively referred to as eosinophilic gastrointestinal disorders, which includes eosinophilic esophagitis (EoE), gastritis, enteritis, and colitis. EGE is less common than EoE and involves a different site of disease but otherwise shares many common features with EoE. The clinical manifestations of EGE are protean and can vary from nausea and vomiting to protein-losing enteropathy or even bowel obstruction requiring surgery. Although systemic corticosteroids are an effective treatment for EGE, their use results in substantial corticosteroid toxicity. Accordingly, there is a great need for improved therapies for these patients. PMID- 24813520 TI - Steroids in pediatric eosinophilic esophagitis. AB - Swallowed fluticasone and oral viscous budesonide are effective first-line therapies for eosinophilic esophagitis in children. Side effects are minimal without evidence of Cushing syndrome, as seen in treatment with systemic corticosteroids. New studies on alternative delivery systems and different corticosteroids (eg, ciclesonide) are encouraging. As knowledge of corticosteroids in eosinophilic esophagitis expands, newer questions continue to arise concerning dose, delivery, and choice of corticosteroids; long-term adverse effects; and maintenance therapies. PMID- 24813521 TI - Steroid treatment of eosinophilic esophagitis in adults. AB - Topical steroid therapy has been used to treat eosinophilic esophagitis (EoE) for more than 15 years. We review the treatment trials of topical steroid therapy in adult patients with EoE. Currently, there is no commercially available preparation designed to deliver the steroid to the esophagus. Current regimens consist of swallowing steroid preparations designed for inhalation treatment for asthma. In the short term, steroids are associated with an approximately 15% to 25% incidence of asymptomatic esophageal candidiasis, but otherwise appear to be well tolerated. PMID- 24813522 TI - Dietary treatment of eosinophilic esophagitis. AB - Emerging evidence supports impaired epithelial barrier function as the key initial event in the development of eosinophilic esophagitis (EoE) and other allergic diseases. Symptom resolution, histologic remission, and prevention of both disease and treatment-related complications are the goals of treatment. Successful dietary treatments include elemental, empirical elimination and allergy test directed diets. Dietary therapy with exclusive elemental diet offers the best response. Cow's milk, wheat, egg, soy, peanut/tree nut, and fish/shellfish are the 6 food antigens most likely to induce esophageal inflammation. PMID- 24813523 TI - Eosinophilic esophagitis: emerging therapies and future perspectives. AB - Twenty years have passed since eosinophilic esophagitis was first recognized as a new and distinct entity. Current treatment modalities for eosinophilic esophagitis include the "3 Ds": drugs, allergen avoidance with diet, and esophageal dilation. Drugs entail the limitation that only corticosteroids have a proven efficacy; most other compounds evoke only a minimal effect. Diets must be maintained continuously and they interfere markedly with the quality of life, possibly even involving some risk of malnutrition. A greater understanding of the immunopathogenesis, natural history, and disease spectrum will inevitably lead to improved therapeutic outcomes for this emerging entity. PMID- 24813524 TI - Eosinophilic esophagitis. PMID- 24813525 TI - Eosinophilic esophagitis. PMID- 24813526 TI - On taeniasis, hydatidosis and 'figatellu'. PMID- 24813527 TI - Opioid receptors in the prelimbic cortex modulate restraint stress-induced cardiovascular responses in the rat. AB - The prelimbic cortex (PL) is involved in the control of behavioral and autonomic responses to stress. The present study aimed to investigate whether opioid neurotransmission in the PL modulates autonomic responses evoked by restraint stress (RS). Bilateral microinjection of 0.03, 0.3 and 3 nmol/100 nL of the nonselective opioid antagonist naloxone into the PL reduced pressure and tachycardiac responses evoked by RS. However, no effects were observed after its injection at doses of 0.003 and 30 nmol/100 nL, thus resulting in an inverted U shaped dose-inhibition curve. Similar to naloxone, the selective MU-opioid antagonist CTAP, and the selective kappa-opioid antagonist nor-BNI, also reduced MAP and HR increases induced by RS when injected into the PL, whereas treatment with the selective delta-opioid antagonist naltrindole did not affect the pressor and tachycardiac response caused by RS. Blockade of opioid neurotransmission in the PL did not affect the fall in tail temperature and increase in body temperature induced by RS. The present results confirm the involvement of PL opioid neurotransmission in the modulation of cardiovascular responses evoked during the exposure to an aversive situation, and suggest that responses observed after the blockade of local opioid receptors is due to alterations in PL neuronal activity. Furthermore, these results suggest that a distinct circuitry is involved in modulation of the sympathetic output to different vascular territories. PMID- 24813528 TI - Epigenetic deregulation in myeloid malignancies. AB - Abnormal epigenetic patterning commonly is observed in cancer, including the myeloid malignancies acute myeloid leukemia and myelodysplastic syndromes. However, despite the universal nature of epigenetic deregulation, specific subtypes of myeloid disorders are associated with distinct epigenetic profiles, which accurately reflect the biologic heterogeneity of these disorders. In addition, mutations and genetic alterations of epigenetic-modifying enzymes frequently have been reported in these myeloid malignancies, emphasizing the importance of epigenetic deregulation in the initiation, progression, and outcome of these disorders. These aberrant epigenetic modifiers have become new targets for drug design, because their inhibition can potentially reverse the altered epigenetic landscapes that contribute to the development of the leukemia. In this review, we provide an overview of the role of epigenetic deregulation in leukemic transformation and their potential for therapeutic targeting. PMID- 24813529 TI - Reliability of semiquantitative 18F-FDG PET parameters derived from simultaneous brain PET/MRI: a feasibility study. AB - PURPOSE: Simultaneous brain PET/MRI faces an important issue of validation of accurate MRI based attenuation correction (AC) method for precise quantitation of brain PET data unlike in PET/CT systems where the use of standard, validated CT based AC is routinely available. The aim of this study was to investigate the feasibility of evaluation of semiquantitative (18)F-FDG PET parameters derived from simultaneous brain PET/MRI using ultrashort echo time (UTE) sequences for AC and to assess their agreement with those obtained from PET/CT examination. METHODS: Sixteen patients (age range 18-73 years; mean age 49.43 (19.3) years; 13 men 3 women) underwent simultaneous brain PET/MRI followed immediately by PET/CT. Quantitative analysis of brain PET images obtained from both studies was undertaken using Scenium v.1 brain analysis software package. Twenty ROIs for various brain regions were system generated and 6 semiquantitative parameters including maximum standardized uptake value (SUV max), SUV mean, minimum SUV (SUV min), minimum standard deviation (SD min), maximum SD (SD max) and SD from mean were calculated for both sets of PET data for each patient. Intra-class correlation coefficients (ICCs) were determined to assess agreement between the various semiquantitative parameters for the two PET data sets. RESULTS: Intra class co-relation between the two PET data sets for SUV max, SUV mean and SD max was highly significant (p<0.00) for all the 20 predefined brain regions with ICC>0.9. SD from mean was also found to be statistically significant for all the predefined brain regions with ICC>0.8. However, SUV max and SUV mean values obtained from PET/MRI were significantly lower compared to those of PET/CT for all the predefined brain regions. CONCLUSION: PET quantitation accuracy using the MRI based UTE sequences for AC in simultaneous brain PET/MRI is reliable in a clinical setting, being similar to that obtained using PET/CT. PMID- 24813530 TI - Shear wave elastography versus real-time elastography on evaluation thyroid nodules: a preliminary study. AB - OBJECTIVE: To comparatively evaluate shear wave elastography (SWE) and real-time elastography (RTE) in distinguishing malignant from benign thyroid nodules. METHODS: 49 patients with 64 focal thyroid nodules were enrolled and underwent SWE and RTE before surgery. SWE elasticity indices (mean, minimum and maximum value of 2-mm region of interest) of nodules were measured. For RTE, elastograms were assessed by Rago criteria and nodules with scores of 4 or 5 were classified as suspicious for malignancy. Surgery histopathologic results were adopted as diagnostic standard. RESULTS: Of the 64 nodules, 19 were papillary thyroid carcinomas and 45 were benign. SWE indices were significantly higher in malignant than benign nodules (P<0.05). Areas under the ROC curves (AUC) of SWE parameters were 0.840, 0.831 and 0.788, which were not significantly different from that of RTE showed as 0.880 (P=0.148-0.482). When the most accurate cut-off, 38.3kPa for mean value was applied to predict malignancy, the diagnostic specificity, sensitivity, accuracy, positive predictive value and negative predictive value of SWE and RTE were 68.4% versus 79.0%, 86.7% versus 84.4%, 81.3% versus 78.1%, 68.4% versus 64.7% and 86.7% versus 83.3%, respectively (P=0.683-1.000). CONCLUSION: SWE as a promising tool can be performed in differentiating thyroid nodules with comparable results to RTE. PMID- 24813531 TI - Ultrasound-guided procedures around the wrist and hand: how to do. AB - Ultrasound has emerged as a low-cost, radiation-free and effective imaging technique to detect joint abnormalities and to guide percutaneous procedures. Being superficial, wrist and hand tendons and joints represent a good target to perform such procedures using ultrasound guidance. This kind of approach allows for a clear and real-time visualization of the needles during their whole path. In this setting, the knowledge of technical aspects and tips is essential to act in the most accurate way on target tissues that can be as small as a few millimetres. The aim of this review is to summarize the local treatments of inflammatory and degenerative disease described in literature (such as treatment of De Quervain's tenosynovitis, trigger finger, trapezio-metacarpal joint osteoarthritis, etc.), emphasizing precautions and tricks based on day-by-day experience that may help to improve the outcome of percutaneous ultrasound-guided procedures around the wrist and hand. PMID- 24813532 TI - Prelacteal feeding of newborns in postconflict Timor-Leste. AB - OBJECTIVES: The aim of the present study was to investigate the prevalence of prelacteal feeding and its associated factors in Timor-Leste using updated data from the national survey. METHODS: Complex sample analysis was undertaken to account for the 2-stage cluster design of the Demographic and Health Survey 2009 2010. Backward stepwise logistic regression was conducted to ascertain factors associated with the prevalence of prelacteal feeding. RESULTS: A total of 4821 mother-infant pairs were included in the analysis. The prevalence of prelacteal feeding was 12.3% (95% confidence interval [CI] 11.1-13.5). The most popular prelacteal food was plain water (50.7%), followed by glucose/sugar water (32.5%) and milk other than breast milk (22.7%). Older mothers (35-49 years), mothers with upper socioeconomic status, those who perceived their newborns as small size, and those residing in urban areas were approximately 1.5 times more likely to give prelacteal feeds, whereas women who followed religions other than Roman Catholic had twice the risk (adjusted odds ratio 1.98; 95% CI 1.16-3.41). CONCLUSIONS: Antenatal and postnatal counselling sessions that promote exclusive breast-feeding and discourage prelacteal feeding are needed that specifically target these vulnerable subgroups of Timorese mothers. PMID- 24813533 TI - Intraepithelial lymphocyte eotaxin-2 expression and perineural mast cell degranulation differentiate allergic/eosinophilic colitis from classic IBD. AB - OBJECTIVES: Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. METHODS: A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor. RESULTS: Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin 1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD. CONCLUSIONS: Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation. PMID- 24813534 TI - Withdrawal of immunosuppression following pediatric liver transplantation: a Markov analysis. AB - OBJECTIVES: Survivors of pediatric liver transplantation are at risk for developing complications related to posttransplant immunosuppressive medications. Withdrawal is possible in selected patients but carries the risk of graft rejection and loss. We modeled the effect of withdrawing immunosuppressive medications on survival, cost, and quality-adjusted life-years (QALYs) in a hypothetical cohort of pediatric patients who received transplantation for biliary atresia with stable liver enzymes and no recent episodes of rejection, and who were free from immunosuppression-related adverse effects. METHODS: A decision analysis tree was developed, and Monte Carlo simulations were used to track patients through the model during a 10-year time course with 1-year cycles. Data from the literature were used to assign probabilities to major clinical events and preference-based utility scores to the values of health outcomes. One way and probabilistic sensitivity analyses were used to evaluate the impact of uncertainty. RESULTS: Patients following the withdrawal strategy had a 10-year survival rate of 95.8% and experienced 8.61 QALYs versus 88.6% survival and 8.01 QALYs for those taking immunosuppressive medications. Each additional QALY is attained at a cost of -$18,992.41 and was therefore cost saving. CONCLUSIONS: Patients in our model who had their immunosuppression withdrawn had improved survival and QALYs with lower costs. Although every effort was made to validate the model, it is limited by the accuracy of the underlying assumptions. Therefore, clinical trials are needed to determine predictors of successful immunosuppression withdrawal to allow for personalization of medication regimens. PMID- 24813535 TI - A Multiseptated Gallbladder in a 16-Year-Old Boy With Abdominal Pain. PMID- 24813536 TI - A case of lichen planus pemphigoides with autoantibodies to the NC16a and C terminal domains of BP180 and to desmoglein-1. AB - Lichen planus pemphigoides (LPP) is a rare autoimmune blistering disease that occurs in association with lichen planus (LP). This report describes a 59-year old Japanese female patient with LPP. The patient first showed LP lesions on her hands, and subsequently developed bullae on her extremities and erosions of the oral mucosa. The patient's serum was positive for IgG autoantibodies against the BP180 NC16a domain, the BP180 C-terminal domain and desmoglein-1. However, a serum sampled one and a half years before the diagnosis of LPP was negative for autoantibodies against BP180 NC16a and BP180 C-terminal domains. These findings strongly suggest that the damage to the basal cells in the LP lesions exposed a sequestered antigen or formed neoantigens, leading to the production of pathogenic autoantibodies for LPP. Most of the previous cases of LPP have produced autoantibodies to the NC16a domain of BP180. This is the first case in which autoantibodies to the C-terminal domain of BP180 were detected. The oral mucosal symptoms in this case may have been caused by autoantibodies to the BP180 C-terminal domain. PMID- 24813537 TI - Paralysis lost: a new cause for a common parasomnia? PMID- 24813538 TI - Translation and validation of a Chinese version of the 8-item Morisky medication adherence scale in myocardial infarction patients. AB - RATIONALE, AIMS AND OBJECTIVES: Poor medication adherence is a major global public health challenge. A valid, reliable, cost-effective tool for measuring medication adherence would lead to a better understanding of non-adherence and lay the groundwork for interventions aimed at facilitating adherence to therapies. The aim of this study was to translate and evaluate the psychometric properties of the Chinese version of the 8-item Morisky medication adherence scale (C-MMAS-8) in Chinese myocardial infarction (MI) patients. METHODS: Psychometric testing of the C-MMAS-8 was conducted using a convenience sample of 176 MI patients recruited from four major hospitals in Guangzhou in southern China. Socio-demographic data, C-MMAS-8 and three subscales of the revised illness perception questionnaire (treatment control, personal control and illness coherence subscales) were administered to the MI patients. Thirty MI patients participated in a 4-week retest. RESULTS: The C-MMAS-8 demonstrated good internal consistency (Cronbach's alpha = 0.77) and test-retest reliability (r = 0.88, P < 0.001). Significant correlations with treatment control subscale (r = 0.32, P < 0.01), personal control subscale (r = 0.47, P < 0.01), and illness coherence subscale (r = 0.44, P < 0.01) of the revised illness perception questionnaire demonstrated good construct validity. CONCLUSIONS: The psychometric properties of the C-MMAS-8 are satisfactory. PMID- 24813539 TI - Controllable fabrication of zinc borate hierarchical nanostructure on brucite surface for enhanced mechanical properties and flame retardant behaviors. AB - A novel and efficient halogen-free composite flame retardant (CFR) consisting of a brucite core and a fine zinc borate [Zn6O(OH)(BO3)3] hierarchical nanostructure shell was designed and synthesized via a facile nanoengineering route. It had been demonstrated that this unique hybrid structure possessed a high BET specific surface area (65 m(2)/g) and could significantly enhance the interfacial interaction when mixing with ethylene-vinyl acetate (EVA). This improved the transfer of stress between CFR particles and EVA matrix and increased the viscosity of EVA/EVA blends, which was beneficial for droplet inhibition and char forming. The mechanical properties and flammability behaviors of the EVA/CFR blends had been compared with the EVA/physical mixture (PM, with the given proportion of brucite and Zn6O(OH)(BO3)3). The mechanical properties of EVA/CFR blends, especially the tensile strength (TS), presented a remarkable increase reaching at least a 20% increment. Meanwhile, with the same 45 wt % of fillers, the EVA/CFR formulation could achieve a limiting oxygen index (LOI) value of 33 (37.5 % higher than that of EVA/PM blends) and UL-94 V-0 rating. Moreover, the heat release rate (HRR), peak heat release rate (PHRR), total heat released (THR), smoke production rate (SPR) and mass loss rate (MLR) were considerably reduced, especially PHRR and SPR for EVA/CFR blends were reduced to 32%. According to this study, the design of fine structure might pave the way for the future development of halogen-free flame retardants combining both enhanced mechanical properties and excellent flame retardant behaviors. PMID- 24813540 TI - Prospective memory in preschool children: influences of agency, incentive, and underlying cognitive mechanisms. AB - Prospective memory (PM) is remembering to perform an action in the future and is crucial to achieving goal-directed activities in everyday life. Doing so requires that an intention is encoded, retained during a delay interval, and retrieved at the appropriate time of execution. We examined PM ability in preschool children by manipulating factors related to agency and incentive. We further explored how metacognition, executive functioning, and theory of mind-factors known to account for individual differences in PM-influenced performance on these PM tasks. A sample of 31 preschool children were asked to carry out a delayed intention or to remind an adult to carry out an intention that was of high or low incentive to the children. Findings indicated that individual differences in theory of mind were related to individual differences in preschoolers' performance on low incentive PM tasks, independent of executive functioning contributions, whereas individual differences in executive functioning were related to performance on the high-incentive tasks. These findings suggest that changes in theory of mind and executive functioning are important to consider in models of PM and that different PM tasks (e.g., high vs. low incentive) may involve different cognitive requirements for young children. PMID- 24813541 TI - Exploring protein domain organization by recognition of secondary structure packing interfaces. AB - MOTIVATION: Protein domains are fundamental units of protein structure, function and evolution; thus, it is critical to gain a deep understanding of protein domain organization. Previous works have attempted to identify key residues involved in organization of domain architecture. Because one of the most important characteristics of domain architecture is the arrangement of secondary structure elements (SSEs), here we present a picture of domain organization through an integrated consideration of SSE arrangements and residue contact networks. RESULTS: In this work, by representing SSEs as main-chain scaffolds and side-chain interfaces and through construction of residue contact networks, we have identified the SSE interfaces well packed within protein domains as SSE packing clusters. In total, 17 334 SSE packing clusters were recognized from 9015 Structural Classification of Proteins domains of <40% sequence identity. The similar SSE packing clusters were observed not only among domains of the same folds, but also among domains of different folds, indicating their roles as common scaffolds for organization of protein domains. Further analysis of 14 small single-domain proteins reveals a high correlation between the SSE packing clusters and the folding nuclei. Consistent with their important roles in domain organization, SSE packing clusters were found to be more conserved than other regions within the same proteins. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813542 TI - SNPsea: an algorithm to identify cell types, tissues and pathways affected by risk loci. AB - We created a fast, robust and general C+ + implementation of a single-nucleotide polymorphism (SNP) set enrichment algorithm to identify cell types, tissues and pathways affected by risk loci. It tests trait-associated genomic loci for enrichment of specificity to conditions (cell types, tissues and pathways). We use a non-parametric statistical approach to compute empirical P-values by comparison with null SNP sets. As a proof of concept, we present novel applications of our method to four sets of genome-wide significant SNPs associated with red blood cell count, multiple sclerosis, celiac disease and HDL cholesterol. AVAILABILITY AND IMPLEMENTATION: http://broadinstitute.org/mpg/snpsea. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813543 TI - Universal dynamical properties preclude standard clustering in a large class of biochemical data. AB - MOTIVATION: Clustering of chemical and biochemical data based on observed features is a central cognitive step in the analysis of chemical substances, in particular in combinatorial chemistry, or of complex biochemical reaction networks. Often, for reasons unknown to the researcher, this step produces disappointing results. Once the sources of the problem are known, improved clustering methods might revitalize the statistical approach of compound and reaction search and analysis. Here, we present a generic mechanism that may be at the origin of many clustering difficulties. RESULTS: The variety of dynamical behaviors that can be exhibited by complex biochemical reactions on variation of the system parameters are fundamental system fingerprints. In parameter space, shrimp-like or swallow-tail structures separate parameter sets that lead to stable periodic dynamical behavior from those leading to irregular behavior. We work out the genericity of this phenomenon and demonstrate novel examples for their occurrence in realistic models of biophysics. Although we elucidate the phenomenon by considering the emergence of periodicity in dependence on system parameters in a low-dimensional parameter space, the conclusions from our simple setting are shown to continue to be valid for features in a higher-dimensional feature space, as long as the feature-generating mechanism is not too extreme and the dimension of this space is not too high compared with the amount of available data. AVAILABILITY AND IMPLEMENTATION: For online versions of super-paramagnetic clustering see http://stoop.ini.uzh.ch/research/clustering. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24813544 TI - Synthesis and biological evaluation of fucoidan-mimetic glycopolymers through cyanoxyl-mediated free-radical polymerization. AB - The sulfated marine polysaccharide fucoidan has been reported to have health benefits ranging from antivirus and anticancer properties to modulation of high blood pressure. Hence, they could enhance the biological function of materials for biomedical applications. However, the incorporation of fucoidan into biomaterials has been difficult, possibly due to its complex structure and lack of suitable functional groups for covalent anchoring to biomaterials. We have developed an approach for a rapid synthesis of fucoidan-mimetic glycopolymer chains through cyanoxyl-mediated free-radical polymerization, a method suitable for chain-end functionalizing and subsequent linkage to biomaterials. The resulting sulfated and nonsulfated methacrylamido alpha-L-fucoside glycopolymers' fucoidan-mimetic properties were studied in HSV-1 infection and platelet activation assays. The sulfated glycopolymer showed similar properties to natural fucoidan in inducing platelet activation and inhibiting HSV-1 binding and entry to cells, thus indicating successful syntheses of fucoidan-mimetic glycopolymers. PMID- 24813545 TI - Use of naltrexone in ketamine dependence. AB - Ketamine is used as a cheap alternative to anaesthetic agents in developing countries. It is also misused as a rave drug because of its psychedelic effect. There are no guidelines for effective management of ketamine withdrawal effects or dependence. Herein we report a case of ketamine dependence and its successful treatment with opioid receptor antagonist naltrexone. PMID- 24813546 TI - Laboratory-induced cue reactivity among individuals with prescription opioid dependence. AB - Prescription opioid (PO) dependence is a critical health problem. Although examination of drug cue reactivity paradigms has advanced the understanding of risk factors for relapse for a variety of substances (e.g., cocaine, alcohol, nicotine), no PO specific drug cue paradigm has been developed. The current study addressed this gap in the literature and evaluated the ability of a newly developed PO drug cue paradigm to elicit subjective, physiological, and neuroendocrine changes among PO-dependent participants (n = 20) as compared to controls (n = 17). The drug cue paradigm included an induction script, viewing and handling paraphernalia (e.g., bottle of oxycontin pills, pill crusher) and watching a video depicting people using POs as well as places related to POs (e.g., pharmacies). Consistent with hypotheses, the PO group demonstrated significant pre- to post-cue increases on subjective ratings of craving, difficulty resisting POs, stress, and anger. The control group did not demonstrate significant changes on any of the subjective measures. Both the PO group and the control group evidenced significant pre- to post-cue increases in physiological responses (e.g., blood pressure, skin conductance), as expected given the arousing nature of the drug cue stimuli. The PO group, but not the control group, evidenced a significant pre- to post-cue increase in heart rate and salivary cortisol levels. The development and validation of a drug cue paradigm for POs may help inform future research and treatment development efforts for patients with PO dependence. PMID- 24813547 TI - Treatment models for targeting tobacco use during treatment for cannabis use disorder: case series. AB - Approximately 50% of individuals seeking treatment for cannabis use disorders (CUD) also smoke tobacco, and tobacco smoking is a predictor of poor outcomes for those in treatment for CUD. Quitting tobacco is associated with long-term abstinence from alcohol and illicit drugs, yet there are no established treatments for CUD that also target tobacco smoking. This report highlights issues related to cannabis and tobacco co-use and discusses potential treatment approaches targeting both substances. Data is shared from the first six participants enrolled in an intervention designed to simultaneously target tobacco use in individuals seeking treatment for CUD. The twelve-week program comprised computer-assisted delivery of Motivational Enhancement Therapy, Cognitive Behavioral Therapy, and Contingency Management, i.e., abstinence-based incentives for CUD. In addition, participants were encouraged to complete an optional tobacco intervention consisting of nicotine-replacement therapy and computer-assisted delivery of a behavioral treatment tailored for tobacco and cannabis users. All participants completed the cannabis intervention and at least a portion of the tobacco intervention: all completed at least one tobacco computer module (mean=2.5 modules) and 50% initiated nicotine replacement therapy. Five of six participants achieved abstinence from cannabis. The number of tobacco quit attempts was lower than expected, however all participants attempted to reduce tobacco use during treatment. Simultaneously targeting tobacco during treatment for CUD did not negatively impact cannabis outcomes. Participation in the tobacco intervention was high, but cessation outcomes were poor suggesting that alternative strategies might be needed to more effectively prompt quit attempts and enhance quit rates. PMID- 24813548 TI - PTSD symptomatology and readiness to quit smoking among women with serious mental illness. AB - INTRODUCTION: Posttraumatic stress disorder (PTSD) is a risk factor for tobacco addiction. The majority of research on PTSD and smoking has been conducted with men, particularly combat veterans, and little is known about the association among women. In a clinical sample of women civilian smokers with serious mental illness (SMI), we examined the prevalence of PTSD symptomatology and associations with physical and mental health functioning, co-occurring substance use, nicotine dependence, and readiness to quit smoking. METHODS: 376 adult women smokers aged 18-73 were recruited from 7 acute inpatient psychiatry units and screened by diagnostic interview for current PTSD symptomatology (PTSD(+)). In multiple regressions, we examined the associations of screening PTSD(+) with physical and mental health functioning; past-month drug use; past-year substance use disorders; nicotine dependence and readiness to quit smoking. RESULTS: Nearly half the sample (43%) screened PTSD(+), which was significantly associated with the use of stimulants (OR=1.26) and opiates (OR=1.98), drug use disorders (OR=2.01), and poorer mental health (B=-2.78) but not physical health functioning. PTSD(+) status was unrelated to nicotine dependence, but predicted greater desire to quit smoking (B=2.13) and intention to stop smoking in the next month (OR=2.21). In multivariate models that adjusted for substance use disorders, physical and mental health functioning, and nicotine dependence, screening PTSD(+) remained predictive of greater desire and intention to quit smoking. CONCLUSION: PTSD symptomatology was common in our sample of women smokers with SMI and associated with not only worse substance use and mental health, but also greater readiness to quit smoking, suggesting the need for and potential interest in integrative PTSD-addiction treatment among women. PMID- 24813549 TI - The predictive utility of micro indicators of concern about smoking: findings from the International Tobacco Control Four Country study. AB - This study explored the association between six "micro indicators" of concern about smoking (1. stubbing out cigarettes before finishing; 2. forgoing cigarettes due to packet warning labels; thinking about... 3. the harms to oneself of smoking; 4. the harms to others of one's smoking; 5. the bad conduct of tobacco companies; and 6. money spent on cigarettes) and cessation outcomes (making quit attempts, and achieving at least six months of sustained abstinence) among adult smokers from Australia, Canada, the United Kingdom, and the United States of America. Participants were 12,049 individuals from five survey waves of the International Tobacco Control Four Country Survey (interviewed between 2002 and 2006, and followed-up approximately one year later). Generalized estimating equation logistic regression analysis was used, enabling us to control for within participant correlations due to possible multiple responses by the same individual over different survey waves. The frequency of micro indicators predicted making quit attempts, with premature stubbing out, forgoing, and thinking about the harms to oneself of smoking being particularly strong predictors. An interaction effect with expressed intention to quit was observed, such that stubbing out and thinking about the harms on oneself predicted quit attempts more strongly among smokers with no expressed plans to quit. In contrast, there was a negative association between some micro indicators and sustained abstinence, with more frequent stubbing out, forgoing, and thinking about money spent on cigarettes associated with a reduced likelihood of subsequently achieving sustained abstinence. In countries with long-established tobacco control programs, micro indicators index both high motivation by smokers to do something about their smoking at least partly independent of espoused intention and, especially those indicators not part of a direct pathway to quitting, reduced capacity to quit successfully. PMID- 24813550 TI - The mediating role of depression in the relationship between anxiety sensitivity and alcohol dependence. AB - BACKGROUND: Many studies have reported that Anxiety Sensitivity (AS) is positively associated with alcohol use or other alcohol-related variables. More recent mediator and moderator models have shown promise in elucidating mechanisms within this relationship; the literature to date suggests that the relationship between AS and alcohol is likely mediated by problematic coping motives. However, few studies have considered the effects of depression within the AS-alcohol use relationship, despite a strong body of evidence linking AS to subsequent depression and depression to subsequent alcohol use problems, independently. Therefore, the current study assessed depression as a potential mediator of this relationship. METHOD: Participants were 418 sequential admissions to a substance abuse treatment facility. A mediation analysis using bootstrapping was utilized in order to estimate indirect effects of AS on alcohol dependence through depression. RESULTS: Results reveal an indirect effect suggesting that the effects of anxiety sensitivity on alcohol dependence are mediated by symptoms of depression. More specifically, the effects of AS total score and AS somatic sensations on alcohol dependence were mediated by symptoms of depression. Lastly, a dual mediator model demonstrated that both depression and problematic coping uniquely mediate the relationship between AS and alcohol dependence. CONCLUSIONS: While preliminary in nature, the current study provides evidence supporting the hypothesis that depression is an important factor to consider when examining the relationship between AS and alcohol dependence. PMID- 24813551 TI - Is there any evidence of changes in patterns of concurrent drug use among young Australians 18-29 years between 2007 and 2010? AB - BACKGROUND: A significant minority of Australians engage in concurrent drug use (using more than one drug in a given period). We examined clusters and correlates of concurrent drug use using the latest available nationally representative survey data on Australian young adults. SAMPLE: 3836 participants aged 18-29 years (mean age 24 years) from the 2010 National Drug Strategy Household Survey (NDSHS). METHOD: Clusters were distilled using latent class analysis of past year use of alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, ketamine, GHB, inhalants, steroids, barbiturates, meth/amphetamines, heroin, methadone/buprenorphine, other opiates, painkillers and tranquillisers/sleeping pills. RESULTS: Concurrent drug use in this sample was best described using a 4 class solution. The majority (87.5%) of young adults predominantly used alcohol only (50.9%) or alcohol and tobacco (36.6%). 10.2% reported using alcohol, tobacco, marijuana, and ecstasy, and 2.3% reported using an extensive range of drugs. CONCLUSION: Most drug use clusters were robust in their profile and stable in their prevalence, indicating little meaningful change at the population level from 2007. The targeting of alcohol and tobacco use remains a priority, but openness to experiencing diverse drug-related effects remains a significant concern for 12.5% of young people in this age group. PMID- 24813552 TI - The impacts of problem gambling on concerned significant others accessing web based counselling. AB - The 'concerned significant others' (CSOs) of people with problem gambling frequently seek professional support. However, there is surprisingly little research investigating the characteristics or help-seeking behaviour of these CSOs, particularly for web-based counselling. The aims of this study were to describe the characteristics of CSOs accessing the web-based counselling service (real time chat) offered by the Australian national gambling web-based counselling site, explore the most commonly reported CSO impacts using a new brief scale (the Problem Gambling Significant Other Impact Scale: PG-SOIS), and identify the factors associated with different types of CSO impact. The sample comprised all 366 CSOs accessing the service over a 21 month period. The findings revealed that the CSOs were most often the intimate partners of problem gamblers and that they were most often females aged under 30 years. All CSOs displayed a similar profile of impact, with emotional distress (97.5%) and impacts on the relationship (95.9%) reported to be the most commonly endorsed impacts, followed by impacts on social life (92.1%) and finances (91.3%). Impacts on employment (83.6%) and physical health (77.3%) were the least commonly endorsed. There were few significant differences in impacts between family members (children, partners, parents, and siblings), but friends consistently reported the lowest impact scores. Only prior counselling experience and Asian cultural background were consistently associated with higher CSO impacts. The findings can serve to inform the development of web-based interventions specifically designed for the CSOs of problem gamblers. PMID- 24813553 TI - How alike are young non-drinkers, former-drinkers, low-risk drinkers, and hazardous drinkers? AB - The aim of this study was to examine whether - in terms of personality characteristics and beliefs--former-drinkers and people who have never consumed alcohol exist on a continuum that includes low-risk drinkers and hazardous drinkers, or are distinct groups. An online questionnaire hosted on a secure server was completed by 1418 young people (642 men and 776 women) aged 16-21 living in South-East England. Participants' scores on the Alcohol Use Disorders Identification Test (AUDIT) were used to classify them as non-drinkers, former drinkers, low-risk drinkers or hazardous drinkers. Multinomial logistic regression identified eight significant multivariate correlates that explained 39% of the variance in men's AUDIT category membership (chi(2)(24) = 263.32, p < .01), and seven significant multivariate correlates that explained 41% of the variance in women's AUDIT category membership (chi(2)(21) = 332.91, p < .01). The results suggest that non-drinkers and former-drinkers are more similar to each other than they are to both low risk and hazardous drinkers. We should not, therefore, treat these groups of young people as representing a drinking continuum. In particular, interventions for high risk young drinkers may be more effective if distinguished from general campaigns intended for all young people. PMID- 24813554 TI - Factors related to psychosocial barriers to drug treatment among Chinese drug users. AB - Although substance abuse treatment has been considerably scaled up in China, impediments to accessing these services remain among drug users. The authors examine the primary psychosocial barriers to drug treatment in this population and evaluate factors associated with these barriers. Barriers to accessing drug treatment were measured using the Barriers to Treatment Inventory (BTI). A Structural Equation Model was used to examine whether the internal barriers were associated with treatment history and frequent methamphetamine use as well as how demographic characteristics influence such barriers. We found four primary factors of internal barriers to drug treatment--absence of problem, negative social support, fear of treatment, and privacy concerns--to fit well. Demographic factors, notably age and employment status, indirectly influence barriers to treatment via other factors. Frequency of methamphetamine use and drug treatment history are directly associated with the absence of problem and negative social support dimensions of the BTI, and it is through these pathways that demographic factors such as age and employment status shape barriers to treatment. The findings indicate that perceived absence of a problem and negative social support are the barriers most influenced by the personal domains of Chinese drug users' lives. Efforts to engage drug users in China about drug treatment options may consider how these barriers are differentially perceived in order to effectively reach this population. PMID- 24813556 TI - Amplitude-integrated electroencephalography shows that doxapram influences the brain activity of preterm infants. AB - AIM: The aim of this study was to measure the brain activity of preterm infants treated with caffeine citrate and doxapram for preterm apnoea, using amplitude integrated electroencephalography (aEEG), to identify any adverse effects on cerebral function. METHODS: We analysed the aEEG tracings of 13 preterm infants <30 weeks of gestation before, during and after doxapram treatment, with regard to background activity (percentages of continuous and discontinuous patterns), occurrence of sleep-wake cycling and appearance of electrographic seizure activity. They were also compared with 61 controls without doxapram treatment. RESULTS: During doxapram treatment, aEEG tracings showed an increase in continuous background activity (19 +/- 30% before treatment, 38 +/- 35% during treatment) and a decrease in discontinuous patterns. In addition, they showed more frequent electrographic seizure activity (0% before treatment, 15 +/- 37% during treatment) and less frequent sleep-wake cycling (92 +/- 27% before treatment, 85 +/- 37% during treatment) could be observed. These results were confirmed when compared to the control group. CONCLUSION: Doxapram treatment influences aEEG in preterm infants, showing higher percentages of continuous activity as well as more electrographic seizure activity and less sleep-wake cycling. It should, therefore, be used with caution in very preterm infants. PMID- 24813555 TI - Identifying the facets of impulsivity that explain the relation between ADHD symptoms and substance use in a nonclinical sample. AB - Adults with attention-deficit/hyperactivity disorder (ADHD) are at higher risk to use substances than their nonclinical peers. Increased levels of impulsivity are generally thought to contribute to their increased levels of risk. Impulsivity is a multifaceted construct, however, and little research to date has attempted to identify which facets of impulsivity contribute to the increased rates of substance abuse among individuals with ADHD. The current study examined the relation among ADHD symptom clusters (i.e., hyperactivity/impulsivity and inattention), substance use rates (i.e., alcohol use, nicotine use, and marijuana use), and personality processes associated with impulsive behavior in a group of young adults. Participants were 361 undergraduate students. Both symptom clusters were positively associated with rates of substance use. Specifically, hyperactive/impulsive symptoms were associated with alcohol and nicotine use, and inattentive symptoms were associated with alcohol use. Several pathways from hyperactive/impulsive symptoms to alcohol, nicotine, and marijuana use via specific facets of impulsivity were identified. These findings have implications for understanding the relation between ADHD symptoms and substance use, as well as clinical implications for preventing and treating substance use problems in individuals with symptoms of ADHD. PMID- 24813558 TI - Plasma nesfatin-1 level in obese patients after acupuncture: a randomised controlled trial. AB - BACKGROUND: Nesfatin-1 is an anorexigenic hormone suggested to regulate obesity. OBJECTIVE: To investigate the relationship between nesfatin-1 level and anthropometric and metabolic parameters in obese patients, and examine the change in plasma nesfatin-1 level after acupuncture treatment. METHODS: 64 obese adult patients without diabetes and 58 normal weight control subjects were enrolled in this study. The obese patients were randomly divided into an acupuncture plus diet group (n=32) and a diet only group (n=32). Measurements were repeated after 45 days. RESULTS: Body mass index (BMI), waist and hip circumferences, serum insulin, lipoprotein and insulin resistance measures were significantly higher, and plasma nesfatin-1 level was significantly lower, in obese patients than in normal weight controls. In addition, negative correlations were found between plasma nesfatin-1 level and BMI, waist and hip circumferences. Weight reduction in participants after acupuncture and diet restriction was 7.0% and 4.3%, respectively. Plasma nesfatin-1 level increased from 2.75+/-1.16 to 3.44+/-1.28 ng/mL and from 2.86+/-1.07 to 3.23+/-1.06 ng/mL in acupuncture and diet groups, respectively; the difference was significant, p<0.05. CONCLUSIONS: Plasma nesfatin-1 level is reduced in obese adults, and is increased after acupuncture. The beneficial effect of acupuncture on obesity is associated with increased plasma nesfatin-1 level. PMID- 24813559 TI - Positioning the work of child and adolescent psychiatric nurses. PMID- 24813560 TI - ACAPN division news: division dialog from the 2014 conference. PMID- 24813561 TI - Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects. AB - Macitentan is an orally active dual endothelin receptor antagonist, which demonstrated a reduction of the risk of morbidity/mortality events in pulmonary arterial hypertension patients. This double-blind, randomized, placebo- and positive-controlled, four-way crossover thorough QTc study was designed to investigate the effects of therapeutic and supratherapeutic doses of macitentan on cardiac repolarization in healthy male and female subjects. Each subject received the following treatments: moxifloxacin 400 mg, macitentan 10 mg, macitentan 30 mg, and placebo. Each treatment period lasted 9 days and was followed by at least 10 days of washout. The primary endpoint of this study was the baseline-adjusted, placebo-corrected QT interval corrected using the Fridericia method (DeltaDeltaQTcF). Pharmacokinetic (PK), safety, and tolerability assessments were performed during each treatment. A total of 64 subjects were randomized. The upper bound of the 2-sided 90% confidence interval for DeltaDeltaQTcF following macitentan was <10 ms at all time points and no correlation was observed between DeltaDeltaQTcF and PK parameters. Findings in the analysis of the morphological patterns of the ECGs were randomly distributed across all treatments and did not indicate an association with macitentan. Macitentan was well tolerated in this study. Headache and nasopharyngitis were the most frequently reported adverse events. No effects on clinical laboratory and vital signs parameters were observed. In summary, repeated doses of macitentan 10 mg and 30 mg did not indicate any pro-arrhythmic potential. PMID- 24813562 TI - Coupling between hydrogen atoms transfer and stacking interaction in adenine thymine/guanine-cytosine complexes: a theoretical study. AB - Four different complexes of two base pairs, an adenine-thymine and a guanine cytosine one, have been studied in order to understand the modifications induced by the staking interaction between the two base pairs on the hydrogen atoms transfers between the bases in either base pair. The inclusion of these two kinds of interactions allows us to clarify if some properties, as the mechanism of hydrogen transfer, is exclusively a local effect of a base pair or can be modified by a more long-range interaction between the base pairs. The results on these four complexes are compared with those of the monomeric systems, the A-T and G-C base pair, and with those of the A-T and G-C dimers. The specificity of each complex and of each hydrogen bond has been analyzed. PMID- 24813563 TI - An eye movement based reading intervention in lexical and segmental readers with acquired dyslexia. AB - Due to their brain damage, aphasic patients with acquired dyslexia often rely to a greater extent on lexical or segmental reading procedures. Thus, therapy intervention is mostly targeted on the more impaired reading strategy. In the present work we introduce a novel therapy approach based on real-time measurement of patients' eye movements as they attempt to read words. More specifically, an eye movement contingent technique of stepwise letter de-masking was used to support sequential reading, whereas fixation-dependent initial masking of non central letters stimulated a lexical (parallel) reading strategy. Four lexical and four segmental readers with acquired central dyslexia received our intensive reading intervention. All participants showed remarkable improvements as evident in reduced total reading time, a reduced number of fixations per word and improved reading accuracy. Both types of intervention led to item-specific training effects in all subjects. A generalisation to untrained items was only found in segmental readers after the lexical training. Eye movement analyses were also used to compare word processing before and after therapy, indicating that all patients, with one exclusion, maintained their preferred reading strategy. However, in several cases the balance between sequential and lexical processing became less extreme, indicating a more effective individual interplay of both word processing routes. PMID- 24813565 TI - Color, organic matter and sulfate removal from textile effluents by anaerobic and aerobic processes. AB - An upflow anaerobic sludge blanket (UASB)-submerged aerated biofilter (SAB) system was evaluated to remove color and chemical oxygen demand (COD) from real textile effluent. The system was operated for 335 days in three phases (P-1, P-2, P-3) with total hydraulic retention time varying from 21 h to 14 h. The results showed that high sulfate levels (>300 mg SO4(2-)/L) impaired the dye reduction. The best color removal efficiencies of 30% and 96% for the UASB and the reactor system, respectively, were obtained in P-1; the SAB higher efficiency was associated with adsorption. The best COD removal efficiency of 71% for the reactor system was obtained in P-2. Precipitation of some material composed mostly of sulfur (98%) and some metals occurred in the UASB. However, the precipitated sulfur was again oxidized in the SAB. The system also showed an effective toxicity reduction in tests (Daphnia magna) with the treated effluent. PMID- 24813564 TI - Facets of diazotrophy in the oxygen minimum zone waters off Peru. AB - Nitrogen fixation, the biological reduction of dinitrogen gas (N2) to ammonium (NH4(+)), is quantitatively the most important external source of new nitrogen (N) to the open ocean. Classically, the ecological niche of oceanic N2 fixers (diazotrophs) is ascribed to tropical oligotrophic surface waters, often depleted in fixed N, with a diazotrophic community dominated by cyanobacteria. Although this applies for large areas of the ocean, biogeochemical models and phylogenetic studies suggest that the oceanic diazotrophic niche may be much broader than previously considered, resulting in major implications for the global N-budget. Here, we report on the composition, distribution and abundance of nifH, the functional gene marker for N2 fixation. Our results show the presence of eight clades of diazotrophs in the oxygen minimum zone (OMZ) off Peru. Although proteobacterial clades dominated overall, two clusters affiliated to spirochaeta and archaea were identified. N2 fixation was detected within OMZ waters and was stimulated by the addition of organic carbon sources supporting the view that non phototrophic diazotrophs were actively fixing dinitrogen. The observed co occurrence of key functional genes for N2 fixation, nitrification, anammox and denitrification suggests that a close spatial coupling of N-input and N-loss processes exists in the OMZ off Peru. The wide distribution of diazotrophs throughout the water column adds to the emerging view that the habitat of marine diazotrophs can be extended to low oxygen/high nitrate areas. Furthermore, our statistical analysis suggests that NO2(-) and PO4(3-) are the major factors affecting diazotrophic distribution throughout the OMZ. In view of the predicted increase in ocean deoxygenation resulting from global warming, our findings indicate that the importance of OMZs as niches for N2 fixation may increase in the future. PMID- 24813566 TI - Transformation of dissolved organic matters in swine, cow and chicken manures during composting. AB - The changes of dissolved organic matters (DOMs) extracted from swine, cow and chicken manures were assessed by Fourier transform infrared, ultraviolet, gel permeation chromatography (GPC), excitation-emission-matrix fluorescence (EEM FL), Biolog Eco and (1)H NMR during 60-day composting. Pumice was adopted to eliminate the disturbing of common organic bulking agents. The results showed chicken manure had the highest DOC, DTN (dissolved total nitrogen) and lowest DOC/DTN among the three manures; cow manure had the highest volatile solids, lowest DTN, slowest DOMs hydrolysis rate and the fastest bio-stabilization rate. (1)H NMR showed the decrease rates of OC band and saturated carbon chain were distinctly faster than that of olefinic and aromatic structures. The molecular size distribution of DOMs in the three manures was in the range of 1-10 kDa detected by GPC. Microbial carbon utilization capacity decreased in cow manure with composting time, but the contrast was observed in the chicken and swine manures. PMID- 24813567 TI - Production of biodiesel fuel from canola oil with dimethyl carbonate using an active sodium methoxide catalyst prepared by crystallization. AB - In this study, a novel method for the production of biodiesel under mild conditions using fine particles of sodium methoxide formed in dimethyl carbonate (DMC) is proposed. Biodiesel is generally produced from vegetable oils by the transesterification of triglycerides with methanol. However, this reaction produces glycerol as a byproduct, and raw materials are not effectively utilized. Transesterification with DMC has recently been studied because glycerol is not formed in the process. Although solid-state sodium methoxide has been reported to be inactive for this reaction, the catalytic activity dramatically increased with the preparation of fine catalyst powders by crystallization. The transesterification of canola oil with DMC was studied using this catalyst for the preparation of biodiesel. A conversion greater than 96% was obtained at 65 degrees C for 2h with a 3:1M ratio of DMC and oil and 2.0 wt% catalyst. PMID- 24813568 TI - Developing and evaluating a machine learning based algorithm to predict the need of pediatric intensive care unit transfer for newly hospitalized children. AB - BACKGROUND: Early warning scores (EWS) are designed to identify early clinical deterioration by combining physiologic and/or laboratory measures to generate a quantified score. Current EWS leverage only a small fraction of Electronic Health Record (EHR) content. The planned widespread implementation of EHRs brings the promise of abundant data resources for prediction purposes. The three specific aims of our research are: (1) to develop an EHR-based automated algorithm to predict the need for Pediatric Intensive Care Unit (PICU) transfer in the first 24h of admission; (2) to evaluate the performance of the new algorithm on a held out test data set; and (3) to compare the effectiveness of the new algorithm's with those of two published Pediatric Early Warning Scores (PEWS). METHODS: The cases were comprised of 526 encounters with 24-h Pediatric Intensive Care Unit (PICU) transfer. In addition to the cases, we randomly selected 6772 control encounters from 62516 inpatient admissions that were never transferred to the PICU. We used 29 variables in a logistic regression and compared our algorithm against two published PEWS on a held-out test data set. RESULTS: The logistic regression algorithm achieved 0.849 (95% CI 0.753-0.945) sensitivity, 0.859 (95% CI 0.850-0.868) specificity and 0.912 (95% CI 0.905-0.919) area under the curve (AUC) in the test set. Our algorithm's AUC was significantly higher, by 11.8 and 22.6% in the test set, than two published PEWS. CONCLUSION: The novel algorithm achieved higher sensitivity, specificity, and AUC than the two PEWS reported in the literature. PMID- 24813569 TI - Sustained behavioral effects of lithium exposure during early development in zebrafish: involvement of the Wnt-beta-catenin signaling pathway. AB - Lithium has been the paradigmatic treatment for bipolar disorder since 1950s, offering prophylactic and acute efficacy against maniac and depressive episodes. Its use during early pregnancy and the perinatal period remains controversial due to reports of negative consequences on the newborn including teratogenic and neurobehavioral effects generally referred as Floppy baby syndrome. The mechanisms underlying lithium therapeutic action are still elusive but exacerbation of Wnt signaling pathway due to GSK-3 inhibition is believed to represent its main effect. In this study we evaluated the impact of lithium exposure during zebrafish embryonic and early development including behavioral and molecular characterization of Wnt-beta-catenin pathway components. Wild-type zebrafish embryos were individually treated for 72 hpf with LiCl at 0.05, 0.5 and 5mM. No significant teratogenic and embryotoxic effects were observed. At the end of treatment period western blot analysis of selected Wnt-beta-catenin system components showed increased beta-catenin and decreased N-cadherin protein levels, without significant changes in Wnt3a, supporting GSK-3 inhibition as lithium's main target. At 10 dpf 0.5 and 5mM lithium-treated larvae showed a dose-dependent decrease in locomotion among other exploratory parameters, resembling lithium induced Floppy baby syndrome neurobehavioral symptoms in humans. At this later period previously altered proteins returned to control levels in treated groups, suggesting that the neurobehavioral effects are a lasting consequence of lithium exposure during early development. RT-qPCR analysis of beta-catenin and N cadherin gene expression showed no effects of lithium at 3 or 10 dpf, suggesting that protein fluctuations were likely due to post-transcriptional events. Other Wnt target genes were evaluated and only discrete alterations were observed. These results suggest that zebrafish may be a valuable model for investigation of early effects of lithium that may be mediated by effects on the Wnt signaling pathway. PMID- 24813570 TI - Gender and injuries predict stimulant medication use. AB - OBJECTIVE: The purpose of this article was to examine whether injuries in early childhood and gender predict prescriptions of stimulant medication in three groups of children: With attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other psychiatric disorders (OPD). METHODS: This was a population-based study with prospective and complete follow-up of children with ADHD (n=11,553), ASD (n=9698), and OPD (n=48,468), of whom 61%, 16%, and 3%, respectively, were treated with stimulants. For all 69,719 individual children data on psychiatric diagnoses, injuries, and drug prescriptions were obtained from national registers and merged. RESULTS: Having sustained an injury before 5 years of age increased the likelihood of later stimulant treatment, in children with ADHD (odds ratio [OR]=1.09; 95% confidence interval [CI]=1.01-1.21), ASD (OR=1.19; 95% CI=1.02-1.40), and OPD (OR=1.24; 95% CI=1.08-1.42), with each injury increasing the likelihood by 3%, 10%, and 7%, respectively. Head injury did not increase the likelihood of later stimulant treatment. Within each of the three groups, ADHD, ASD, and OPD boys were more likely than girls to receive stimulant medication, OR=1.17 (95% CI=1.07-1.28); OR=1.71 (95% CI=1.47-2.01), and OR=2.41 (95% CI=2.16-2.71), respectively. CONCLUSIONS: To our knowledge, this is the first prospective study assessing early life predictors of later ADHD medication in children with a psychiatric disorder, taken from a national cohort with complete follow-up of all cases. We found that the number of injuries prior to diagnosis was associated with initiation of stimulant treatment in all three groups of patients. In addition, male gender predicted treatment with ADHD medications. Our results suggest that the number of injuries early in life prior to diagnosis is associated with stimulant treatment, and may serve as a proxy for the level of later severity of ADHD symptoms, as it is universally associated with pharmacological treatment for ADHD. PMID- 24813571 TI - Verbal working memory predicts co-speech gesture: evidence from individual differences. AB - Gesture facilitates language production, but there is debate surrounding its exact role. It has been argued that gestures lighten the load on verbal working memory (VWM; Goldin-Meadow, Nusbaum, Kelly, & Wagner, 2001), but gestures have also been argued to aid in lexical retrieval (Krauss, 1998). In the current study, 50 speakers completed an individual differences battery that included measures of VWM and lexical retrieval. To elicit gesture, each speaker described short cartoon clips immediately after viewing. Measures of lexical retrieval did not predict spontaneous gesture rates, but lower VWM was associated with higher gesture rates, suggesting that gestures can facilitate language production by supporting VWM when resources are taxed. These data also suggest that individual variability in the propensity to gesture is partly linked to cognitive capacities. PMID- 24813572 TI - Eye movements guided by morphological structure: evidence from the Uighur language. AB - It is generally accepted that low-level features (e.g., inter-word spaces) are responsible for saccade-target selection in eye-movement control during reading. In two experiments using Uighur script known for its rich suffixes, we demonstrate that, in addition to word length and launch site, the number of suffixes influences initial landing positions. We also demonstrate an influence of word frequency. These results are difficult to explain purely by low-level guidance of eye movements and indicate that due to properties specific to Uighur script low-level visual information and high-level information such as morphological structure of parafoveal words jointly influence saccade programming. PMID- 24813573 TI - The multidimensional nature of hyperspeech: evidence from Japanese vowel devoicing. AB - We investigate the hypothesis that infant-directed speech is a form of hyperspeech, optimized for intelligibility, by focusing on vowel devoicing in Japanese. Using a corpus of infant-directed and adult-directed Japanese, we show that speakers implement high vowel devoicing less often when speaking to infants than when speaking to adults, consistent with the hyperspeech hypothesis. The same speakers, however, increase vowel devoicing in careful, read speech, a speech style which might be expected to pattern similarly to infant-directed speech. We argue that both infant-directed and read speech can be considered listener-oriented speech styles-each is optimized for the specific needs of its intended listener. We further show that in non-high vowels, this trend is reversed: speakers devoice more often in infant-directed speech and less often in read speech, suggesting that devoicing in the two types of vowels is driven by separate mechanisms in Japanese. PMID- 24813574 TI - Acquiring English as a second language via print: the task for deaf children. AB - Only a minority of profoundly deaf children read at age-level. We contend this reflects cognitive and linguistic impediments from lack of exposure to a natural language in early childhood, as well as the inherent difficulty of learning English only through the written modality. Yet some deaf children do acquire English via print. The current paper describes a theoretical model of how children could, in principle, acquire a language via reading and writing. The model describes stages of learning which represent successive, conceptual insights necessary for second/foreign language learning via print. Our model highlights the logical difficulties present when one cannot practice a language outside of reading/writing, such as the necessity of translating to a first language, the need for explicit instruction, and difficulty that many deaf children experience in understanding figurative language. Our model explains why learning to read is often a protracted process for deaf children and why many fail to make progress after some initial success. Because language acquisition is thought to require social interaction, with meaning cued by extralinguistic context, the ability of some deaf individuals to acquire language through print represents an overlooked human achievement worthy of greater attention by cognitive scientists. PMID- 24813575 TI - Detection and cellular imaging of human cancer enzyme using a turn-on, wavelength shiftable, self-immolative profluorophore. AB - A frontier area in the development of activatable (turn-on) fluorescence-based probes is that concerned with rapid and selective stimulus triggering of probe activation so as to allow for biomarker identification and cellular imaging. The work here is concerned with a cloaked fluorophore composed of a reporter whose fluorescence is efficiently quenched by it being bound to an activatable trigger group through a novel self-immolative linker. Highly selective and rapid activation of the trigger group is achieved by chemical and enzymatic means that result in activated trigger group detachment from the self-immolative linker, with the latter subsequently cleaved from the reporter autonomously, thereby unmasking intense, red-shifted fluorescence emission. To achieve this success, we used a trimethyl-locked quinone propionic acid trigger group and an N-methyl-p aminobenzyl alcohol self-immolative linker attached to the reporter. Delineated here are the synthesis and characterization of this cloaked fluorophore and the evaluation of its triggered turning on in the presence of an up-regulated enzyme in human cancer cells, NAD(P)H: quinone oxidoreductase-1 (NQO1, DT-diaphorase, EC 1.6.99.2). PMID- 24813576 TI - Phylogeny of a relapsing fever Borrelia species transmitted by the hard tick Ixodes scapularis. AB - The discovery of Borrelia species that were related to the agents of relapsing fever but were transmitted by hard ticks rather than soft ticks challenged previous taxonomies based largely on microbe-host specificities and geographic considerations. One of these newly-identified organisms is the Borrelia miyamotoi sensu lato strain LB-2001 from North America and transmitted by Ixodes scapularis. This or related strains have been identified as the cause of human disease, but comparatively little is known about their biology or genetics. Using recently acquired chromosome sequence of LB-2001 together with database sequences and additional sequences determined here, I carried out comparisons of the several species of Borrelia, including those in the two major clades: the relapsing fever group of species and the Lyme disease group of species. Phylogenetic inference at the species level was based on four data sets: whole chromosomes of ~1Mb each, and concatenated sequences of 19 ribosomal protein genes, 3 conserved nucleic acid enzymes (rpoC, recC, and dnaE), and 4 contiguous genes for nucleotide salvage on a large plasmid. Analyses using neighbor-joining, maximum likelihood, and Bayesian methods were largely concordant for each of the trees. They showed that LB-2001 and related hard tick-associated organisms, like Borrelia lonestari, are deeply positioned within the RF group of species and that these organisms did not, as some earlier estimations had suggested, constitute a paraphyletic group. The analyses also provided further evidence that major changes in host ranges and life cycles, such as hard to soft ticks or vice versa, may not correlate well with overall sequence differences. The genetic differences between LB-2001 and B. miyamotoi sensu stricto justify provisional use of the "sensu lato" designation for LB-2001. PMID- 24813577 TI - Modulation of metallothionein and metal partitioning in liver and kidney of Solea senegalensis after long-term acclimation to two environmental temperatures. AB - Juveniles of Solea senegalensis were fed with commercial pellets under controlled conditions at two environmental Mediterranean temperatures (15 and 20 degrees C) for two months. After this period, the accumulation of essential and non essential metals and metallothionein (MT) levels was measured in liver and kidney by inductively coupled plasma mass spectrometry (ICP-MS) and pulse polarography, respectively. The bioaccumulation factor (BAF) for selected metals in both tissues was calculated in relation to levels present in the feed. Tissue partitioning (liver/kidney) and molar ratios, considering the metal protective mechanisms: MT and Selenium (Se), were included for evaluating the detoxification capacity of each tissue. Ag, Cd, Cu and Mn were preferentially accumulated in the liver whereas Co, Fe, Hg, Se and Zn were found in larger concentrations in the kidney, and higher temperature enhanced the accumulation of some of them, but not all. MT content in liver, but not in kidney, was also influenced by temperature changes and by length of exposure. The BAF revealed that Cu was taken up mainly by the liver whereas Se was efficiently taken up by both tissues. The high molar ratios of MT and most metals denoted the kidney's remarkable spare capacity for metal detoxification through MT binding. Moreover, the potential protective role of Se was also more evident in kidney as a higher Se:Cd and Se:Ag molar ratios were reached in this organ. In contrast to other fish, the storage of Cd in kidney was particularly low. PMID- 24813578 TI - Occupational secondhand smoke is the main determinant of hair nicotine concentrations in bar and restaurant workers. AB - OBJECTIVE: To evaluate the relative contribution of occupational vs. non occupational secondhand tobacco smoke exposure to overall hair nicotine concentrations in non-smoking bar and restaurant employees. METHOD: We recruited 76 non-smoking employees from venues that allowed smoking (n=9), had mixed policies (smoking and non-smoking areas, n=13) or were smoke-free (n=2) between April and August 2008 in Santiago, Chile. Employees used personal air nicotine samplers during working and non-working hours for a 24-h period to assess occupational vs. non-occupational secondhand tobacco smoke exposure and hair nicotine concentrations to assess overall secondhand tobacco smoke exposure. RESULTS: Median hair nicotine concentrations were 1.5 ng/mg, interquartile range (IQR) 0.7 to 5.2 ng/mg. Time weighted average personal air nicotine concentrations were higher during working hours (median 9.7, IQR 3.3-25.4 ug/m(3)) compared to non-working hours (1.7, 1.0-3.1 ug/m(3)). Hair nicotine concentration was best predicted by personal air nicotine concentration at working hours. After adjustment, a 2-fold increase in personal air nicotine concentration in working hours was associated with a 42% increase in hair nicotine concentration (95% confidence interval 14-70%). Hair nicotine concentration was not associated with personal air nicotine concentration during non-working hours (non-occupational exposure). CONCLUSIONS: Personal air nicotine concentration at working hours was the major determinant of hair nicotine concentrations in non-smoking employees from Santiago, Chile. Secondhand tobacco smoke exposure during working hours is a health hazard for hospitality employees working in venues where smoking is allowed. PMID- 24813579 TI - Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR inhibitors in organ transplant recipients. AB - BACKGROUND: Organ transplant recipients are prone to the development of non melanoma skin cancer. Organ transplant recipients often develop multiple non melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR-inhibitors such as everolimus or sirolimus can have an antitumor effect. PATIENTS AND METHODS: In a monocentric retrospective study we evaluated organ transplant recipients who presented with non-melanoma skin cancer in the years 2008-2010. Experience with patients who were switched to an mTOR-inhibitor due to non-melanoma skin cancer are reported in detail, and recent clinical studies are reviewed. RESULTS: 60 organ transplant recipients with non-melanoma skin cancer were evaluated. Due to the development of multiple non-melanoma skin cancer within a few years, the immunosuppressive regimen was switched to everolimus in 7 patients and to sirolimus in 5 patients. Eight patients were evaluable for the effect of mTOR-inhibitors on the development of non-melanoma skin cancer; 4 patients had to discontinue the medication with mTOR-inhibitors early due to various side effects. In the year before the switch to mTOR-inhibitors, 8 patients developed 16 squamous cell carcinomas, 3 Basal cell carcinomas and 22 cases of Bowen's disease. All tumors were histologically confirmed. In the year after switch of immunosuppression, the rate of squamous cell carcinomas (n = 2) and Bowen's disease (n = 3), but not of basal cell carcinomas (n = 2) was significantly reduced. Moreover, 5 prospective randomized trials recently have demonstrated a reduced number of non-melanoma skin cancers in organ transplant recipients after switch of the immunosuppressive regimen to mTOR-inhibitors. CONCLUSION: Switch of the immunosuppressive regimen to mTOR-inhibitors should be considered for organ transplant recipients suffering from multiple non-melanoma skin cancers. PMID- 24813580 TI - Choose your tool wisely: u charts are more informative than run charts with or without tests of significance. A comment on Unbeck et al. (2014), Unbeck et al. (2013) and Kottner (2014). PMID- 24813581 TI - Comparison study of upper arm and forearm non-invasive blood pressures in adult Emergency Department patients. AB - BACKGROUND: Forearm blood pressures have been suggested as an alternative site to measure blood pressures when the upper arm is unavailable. However there is little evidence utilising clinical populations to support this substitution. OBJECTIVES: To determine agreement between blood pressures measured in the left upper arm and forearm using a singular oscillometric non-invasive device in adult Emergency Department patients. The secondary objective was to explore the relationship of blood pressure differences with age, sex, ethnicity, smoking history and obesity. DESIGN: Single centre comparison study. SETTING: Adult Emergency Department, Tertiary Trauma Centre. PARTICIPANTS: Forty-four participants who met inclusion/exclusion criteria selected sequentially from the Emergency Department arrival board. METHODS: A random assignment of order of measurement for left upper arm and forearm blood pressures was utilised. Participants were eligible if they were aged 18 years or older, had been assigned an Australasian Triage Scale code of 2, 3, 4, or 5, were able to consent, and able to have blood pressures measured on their left arm whilst lying at a 45 degrees angle. The Bland-Altman method of statistical analysis was used, with the level of agreement for clinical acceptability for the systolic, diastolic and mean arterial pressure defined as +/-10 mmHg. RESULTS: The forearm measure overestimated systolic (mean difference 2.2 mmHg, 95% limits of agreement +/-19 mmHg), diastolic (mean difference 3.4 mmHg, 95% limits of agreement +/-14.4 mmHg), and mean arterial pressures (mean difference 4.1 mmHg, 95% limits of agreement +/-13.7 mmHg). The systolic measure was not significantly different from zero. Evidence of better agreement was found with upper arm/forearm systolic measures below 140 mmHg compared to systolic measures above 140 mmHg using the Levene's test (p=0.002, F-statistic=11.09). Blood pressure disparity was not associated with participant characteristics. CONCLUSIONS: Forearm measures cannot routinely replace upper arm measures for blood pressure measurement. If the clinical picture requires use of forearm blood pressure, the potential variance from an upper arm measure is +/-19 mmHg for systolic pressure, although the variability may be close to +/-10 mmHg if the systolic blood pressure is below 140 mmHg. PMID- 24813582 TI - Factors that impact residents' transition and psychological adjustment to long term aged care: a systematic literature review. AB - AIM: To identify the factors that impact residents' transition and adjustment to long-term aged care and influence their relocation experience. BACKGROUND: The transition to long-term aged care can be an emotional and stressful event for older people as well as their families and carers. The challenges triggered by relocation derive from home being on the move. The concept of home and Bridges' three stages of transition framework provide conceptual models for better understanding the needs and aspiration of older people who are in the process of this late life transition. METHOD: We searched Academic Search Premier, Cinahl, Medline, PyscINFO, Psychology and Behavioral Sciences Collection and Scopus databases for observational, descriptive studies published between January 1995 and July 2013 using subject headings and free-text search terms including adjustment, nursing homes, relocation and transition. RESULTS AND DISCUSSION: The search identified 348 potentially relevant articles. Once duplicates were removed, 214 articles were screened for inclusion in this review; 42 articles were assessed for eligibility, resulting in 19 high-quality observational, descriptive studies that met the inclusion criteria. Key determinants of residents' relocation experience include the extent to which they were able to exert control over the decision to move to an aged care facility, preserve their autonomy, and retain meaningful social relationships. Encouraging the development of new relationships with other residents and staff is an important role for staff to play. Providing residents with opportunities to talk about their feelings, their life experience, and their involvement in the decision to relocate to an aged care facility can help them in their transition to an aged care facility. Preadmission screening that provides staff with an understanding of personal, lifestyle and cultural needs that might facilitate improved transition may also be beneficial in care planning. CONCLUSION AND IMPLICATIONS: An understanding of the factors that impact residents' transition to long-term aged care, and their experience of relocation will assist aged care providers to create the conditions to ease adjustment anxiety and to facilitate a person's transition into his/her 'last home'. PMID- 24813583 TI - Outcome detection using hospital activity data: implications for development of nursing-sensitive quality monitoring and reporting in Australia (commentary on Schreuders et al., Int. J. Nurs. Stud. 51 (3) (2014) 470-478). PMID- 24813584 TI - Measuring the quality of surgical decisions for Latina breast cancer patients. AB - BACKGROUND: A high-quality decision for breast cancer surgery requires that patients are well informed, meaningfully involved in decision making, and receive treatments that match their goals. There is little in the existing literature that examines a comprehensive measure of decision quality for Latina breast cancer patients. OBJECTIVE: To examine the quality of surgical decisions among Latina breast cancer survivors and explore factors associated with decision quality and decision regret. DESIGN: Cross-sectional mailed survey. MAIN OUTCOME MEASURES: English and certified Spanish translations of Breast Cancer Surgery Decision Quality Instrument (BCS-DQI), Short Acculturation Scale for Hispanics (SASH) and decision regret. PARTICIPANTS AND SETTING: Ninety-seven breast cancer survivors of Hispanic or Spanish descent identified through the cancer registry from Orange or San Diego Counties in California. RESULTS: The 97 respondents were on average 55.7 years old, 39.1% had high school diploma or more education, and 62.9% had low acculturation (SASH scores < 2.99). The average knowledge score was 48.2%, the average decision process score was 67.5%, and many (77.3%) received treatments that matched their goals. In multivariable models, there were no significant associations with education, age, acculturation and any aspect of decision quality or decision regret in this sample. Respondents who had higher decision process scores, indicating more involvement in decision making, had significantly lower decision regret. CONCLUSIONS: The BCS-DQI may require some adaptation for Latina populations to improve acceptability. The different aspects of decision quality, including knowledge, decision process and concordance, did not vary by level of acculturation. PMID- 24813585 TI - [Factorial structure of the French version of the Nursing Home Behavior Problem Scale]. AB - Several measuring devices are available to assess specific behavioural problems of dementia patients residing in nursing homes but only a few have been translated and validated in French. This study's main objective was to determine the factorial structure of the French version of the Nursing Home Behavior Problem Scale (NHBPS) with people suffering from dementia. A secondary objective was to document the variables associated with the global score of the NHBPS and the underlying dimensions of the instrument. Participants (n = 155) were diagnosed with dementia and resided in three nursing homes and a hospital's long term care unit. The presence of behavioural problems and other characteristics were assessed by two nurses. A factor analysis revealed five key dimensions in the francophone version of the questionnaire. Several variables were associated with the total score of the NHBPS and its five underlying dimensions. Although the factorial solution of the French version of the NHBPS is similar to the English versions, our results also show differences that may depend on methodological characteristics. PMID- 24813586 TI - Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments. AB - The behavior and fate of cells in tissues largely rely upon their cross-talk with the tissue microenvironment including neighboring cells, the extracellular matrix (ECM), and soluble cues from the local and systemic environments. Dysregulation of tissue microenvironment can drive various inflammatory diseases and tumors. The ECM is a crucial component of tissue microenvironment. ECM proteins can not only modulate tissue microenvironment but also regulate the behavior of surrounding cells and the homeostasis of tissues. As a nonstructural ECM protein, periostin is generally present at low levels in most adult tissues; however, periostin is often highly expressed at sites of injury or inflammation and in tumors within adult organisms. Current evidence demonstrates that periostin actively contributes to tissue injury, inflammation, fibrosis and tumor progression. Here, we summarize the roles of periostin in inflammatory and tumor microenvironments. PMID- 24813587 TI - Infant behaviors influence mothers' provision of responsive and directive behaviors. AB - Mother-infant interactions are important to infant development because they are predictive of infants' social, cognitive, and language development (Lamb, Bornstein, & Teti, 2002; Tamis-LeMonda, Bornstein, & Baumwell, 2001). Because maternal responsive and directive behaviors are associated with differential infant outcomes, it is important to investigate influences on mothers' provision of responsive and directive behaviors. Yet, the dyadic interaction literature is predominantly unidirectional from maternal behavior to infant outcomes. Therefore, the current study examined infant initiating behaviors and consequent maternal responses in a sample of 26 13-month-old infants and their mothers, videotaped during 5 min of free-play. Findings revealed that infants produced a variety of initiatives, and that these different infant initiatives prompted differential patterns of maternal responsive versus directive behaviors. Further, results of analyses of divergent types of maternal directive behaviors - Responsive Directives, ReDirectives, and Intrusive Directives - also may help clarify major discrepancies in the current literature regarding the positive and negative effects of maternal directiveness. PMID- 24813588 TI - An examination of referential and affect specificity with five emotions in infancy. AB - Referential specificity and affect specificity were examined in 12- to 14-month olds (n=20), and 16- to 18-month-olds (n=20). Infants were presented with a televised social referencing paradigm involving an actress who emoted a simple descriptive message to one of two objects appearing on the video. The actress altered her affective message using a neutral baseline first, followed by 5 discrete emotions (anger, fear, sadness, happiness, surprise). Infants were given 30s to interact with the objects after watching the affective episode. Older infants demonstrated referential and affect specificity, as evidenced by their differential treatment of the target and distracter toy in response to messages of anger, fear, surprise, and happiness. In contrast, the younger infants did not show evidence of either referential or affect specificity, as evidenced by the lack of differentiation in their treatment of the target and distracter toy in response to positive and negative emotional messages across all emotional episodes. PMID- 24813589 TI - The effects of SES on infant and maternal diurnal salivary cortisol output. AB - The present study directly compared diurnal salivary cortisol output and maternal infant synchrony in low and high socio-economic status (SES) mother-infant dyads. Saliva cortisol samples were collected from 32 6-12-month-old infants and their mothers on the same day in the morning, afternoon and evening, and assayed for free cortisol concentration. Low-SES infants and mothers exhibited higher average salivary cortisol output, without dysregulation, compared to high-SES infants. Low-SES infants and mothers also showed reduced synchrony in cortisol output compared to high-SES infants and mothers. Results are discussed with respect to maternal sensitivity and early stress reduction interventions. PMID- 24813590 TI - Antimicrobial susceptibility pattern of nasal Staphylococcus aureus among Dessie Referral Hospital health care workers, Dessie, Northeast Ethiopia. AB - BACKGROUND: Staphylococcus aureus is a major pathogen in skin and soft tissue infections. Methicillin-resistant S. aureus (MRSA) is prevalent in most of the countries in which it is sought. MRSA is one of the important pathogens implicated in hospital-acquired infections. The main objectives of this study were to determine the antimicrobial susceptibility pattern of S. aureus isolates, the prevalence of MRSA, and the nasal carriage rate in healthy hospital staff members. METHODS: A total of 118 health care workers (HCWs) were enrolled using a cross-sectional study design. Nasal swabs were collected and cultured on mannitol salt agar (MSA). The slide coagulase test was performed. Susceptibility testing was carried out on Mueller-Hinton agar using the modified Kirby-Bauer disk diffusion method with 10 antibiotics. RESULTS: Of the 118 HCWs, 34 had S. aureus and 15 had MRSA, with overall positivity rates of 28.8% and 12.7%, respectively. None of the S. aureus isolates were sensitive to penicillin. MRSA isolates were resistant to commonly available antibiotics. Only two (13.3%) of the nasal isolates were vancomycin-resistant. CONCLUSIONS: A high rate of nasal carriage and multidrug-resistant S. aureus was found in this study, indicating the need for standard infection control to prevent transmission in our health care setting. PMID- 24813591 TI - Relationship between toll-like receptor 2 Arg677Trp and Arg753Gln and toll-like receptor 4 Asp299Gly polymorphisms and cytomegalovirus infection. AB - OBJECTIVES: The association among specific single-nucleotide polymorphisms (SNPs) in TLR2 (Arg677Trp, Arg753Gln) and TLR4 (Asp299Gln) and human cytomegalovirus (CMV) infection was studied in infants and adults. METHODS: The TLR2 and TLR4 polymorphisms were genotyped in 151 patients with CMV infections and in 78 unrelated healthy individuals. Genotyping was performed by restriction fragment length polymorphism (RFLP) analysis of PCR-amplified fragments. The viral load was measured by quantitative real-time PCR. RESULTS: Almost all of the patients with CMV infections were wild-type homozygotes without TLR2 and TLR4 polymorphisms. No significant differences in TLR2 and TLR4 polymorphisms were observed between infants with or without CMV infection. Compared with adults with CMV infections, heterozygosity for the TLR2 Arg677Trp and TLR4 Asp299Gly SNPs was detected more frequently in healthy individuals (p<0.05). Logistic regression analysis showed that the wild-type TLR2 genotype was associated with an increased risk of CMV infection and that heterozygosity for TLR2 and TLR4 SNPs diminished the risk of CMV infection in adult patients. An association between CMV load and the TLR4 SNP was found. CONCLUSION: Our results suggest that the wild-type TLR2 genotype may be a risk factor for CMV replication in adult patients. PMID- 24813592 TI - Predicting help-seeking intention of women with urinary incontinence in Jinan, China: a theory of planned behaviour model. AB - AIMS AND OBJECTIVES: To develop and test a predictive model of women's help seeking intention for urinary incontinence that was developed using the theory of planned behaviour and to identify factors that influenced women's help-seeking intention. BACKGROUND: Urinary incontinence is a chronic progressive condition if left untreated, but few women seek help from healthcare providers. Reasons for not seeking help have been studied in Western countries while relatively little information is available from mainland China. DESIGN: Questionnaire-based cross sectional survey was performed in this study. METHODS: From May-October 2011, a cross-sectional survey was conducted with a representative sample of 346 incontinent women from three communities in Jinan using strict inclusion and exclusion criteria. Data were collected via a self-administered pencil-and-paper survey that consisted of a multi-item questionnaire. Predictive model estimation was performed using structural equation model. RESULTS: The resultant model demonstrated that incontinent women's help-seeking intention could be predicted by their perceived self-efficacy and perceived social impact from urine loss. Perceived self-efficacy was the negative predictor, while the perceived social impact was the positive one. Overall, the predictive model explained 36% of the variance for incontinent women's help-seeking intention. CONCLUSION: The theory of planned behaviour can be used to predict help-seeking intention in women who have urinary incontinence. Community nurses should increase patients' help seeking intention by addressing perceived social impact and perceived self efficacy in managing incontinent symptoms. RELEVANCE TO CLINICAL PRACTICE: Our findings suggest that high perceived self-efficacy in dealing with incontinent symptoms could hinder incontinent women from seeking help from healthcare providers. The strong social impact women perceived, however, facilitates intention to seek help. Nurses should understand and address these factors through education and evidence-based practices to increase help-seeking in incontinent women. PMID- 24813593 TI - Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice. AB - INTRODUCTION: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme induced by stress. Heart failure is a condition of chronic stress-induced remodeling and is often accompanied by comorbidities such as age and hypertension. HO-1 is known to be protective in the setting of acute myocardial infarction. The role of HO-1 in heart failure is not known, particularly in the setting of pressure overload. METHODS: Mice with alpha-myosin heavy chain restricted expression of HO-1 were aged for 1 year. In addition, mice underwent transverse aortic constriction (TAC) or were infused with isoproterenol (ISO) to induce heart failure. RESULTS: HO-1 transgenic mice developed spontaneous heart failure after 1 year compared to their wild-type littermates and showed accelerated cardiac dysfunction 2 weeks following TAC. Wild-type mice undergoing pressure overload demonstrated extensive interstitial fibrosis that was prevented by HO-1 overexpression, yet HO-1 transgenic mice had reduced capillary density, contractile reserve, and elevated end-diastolic pressure. However, HO-1 transgenic mice had significantly attenuated ISO-induced cardiac dysfunction, interstitial fibrosis, and hypertrophy compared to control. Isolated cardiomyocytes from HO-1 transgenic mice treated with ISO did not show evidence of hypercontracture/necrosis and had reduced NADH oxidase activity. CONCLUSIONS: HO-1 is an effective mechanism for reducing acute myocardial stress such as excess beta-adrenergic activity. However, in our age and pressure overload models, HO-1 showed detrimental rather than therapeutic effects in the development of heart failure. PMID- 24813594 TI - In vitro and in vivo activities of piperacillin-tazobactam and meropenem at different inoculum sizes of ESBL-producing Klebsiella pneumoniae. AB - The inoculum effect is a laboratory phenomenon in which the minimal inhibitory concentration (MIC) of an antibiotic is increased when a large number of organisms are exposed. Due to the emergence of extended-spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-Kpn) infections, the inoculum effect of ESBL-Kpn on beta-lactams was studied in vitro and in vivo using an experimental model of pneumonia. The in vitro inoculum effect of 45 clinical ESBL-Kpn isolates on beta-lactams was evaluated at standard (10(5) CFU/mL) and high (10(7) CFU/mL) organism concentrations. The MIC50 of piperacillin-tazobactam, cefotaxime and cefepime was increased eight-fold or more and that of meropenem was increased two fold. The in vivo inoculum effect was evaluated in an ESBL-Kpn pneumonia mouse model treated with bacteriostatic effect-adjusted doses of piperacillin tazobactam (1000 mg/kg four times daily, %T>MIC; 32.60%) or meropenem (100 mg/kg twice daily, %T>MIC; 28.65%) at low/standard (10(4) CFU/mouse) and high (10(6) CFU/mouse) inocula. In mice administered a low inoculum, no mice died after treatment with piperacillin-tazobactam or meropenem, whereas all the control mice died. In contrast, in the high inoculum model, all mice in the piperacillin tazobactam-treated group died, whereas all meropenem-treated mice survived and had a decreased bacterial load in the lungs and no invasion into the blood. In conclusion, meropenem was more resistant to the inoculum effect of ESBL-Kpn than piperacillin-tazobactam both in vitro and in vivo. In the management of severe pneumonia caused by ESBL-Kpn, carbapenems may be the drugs of choice to achieve a successful outcome. PMID- 24813595 TI - Preliminary evidence that cinnamon improves menstrual cyclicity in women with polycystic ovary syndrome: a randomized controlled trial. AB - OBJECTIVE: To determine the effect of cinnamon on menstrual cyclicity and metabolic dysfunction in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: In a prospective, placebo controlled, double-blinded randomized trial, 45 women with PCOS were randomized (1:1) to receive cinnamon supplements (1.5 g/d) or placebo for 6 months. Menstrual cyclicity (average cycles/month) during the 6 months study period was compared between the 2 groups using the Mann-Whitney U test. Changes in menstrual cyclicity and insulin resistance between baseline and the 6 month study period were compared between the 2 groups using Wilcoxon signed rank tests. RESULTS: The 45 women were randomized, 26 women completed 3 months of the study, and 17 women completed the entire 6 months of the study. During the 6 month intervention, menstrual cycles were more frequent in patients taking cinnamon compared with patients taking placebo (median, 0.75; interquartile range, 0.5-0.83 vs median, 0.25; interquartile range, 0-0.54; P = .0085; Mann Whitney U). In patients taking cinnamon, menstrual cyclicity improved from baseline (+ 0.23 cycles/month 95% confidence interval, 0.099-0.36), yet did not improve for women taking placebo. (P = .0076, Wilcoxon signed rank). Samples (n = 5) of serum from the luteal phase in different patients within the cinnamon group were thawed and ovulatory progesterone levels (>3 ng/mL) confirmed. Luteal phase progesterone levels (>3 ng/mL, n = 5) confirmed ovulatory menses. Measures of insulin resistance or serum androgen levels did not change for either group. CONCLUSION: These preliminary data suggest that cinnamon supplementation improves menstrual cyclicity and may be an effective treatment option for some women with PCOS. PMID- 24813596 TI - Elevated neonatal insulin-like growth factor I is associated with fetal hypertrophic cardiomyopathy in diabetic women. AB - OBJECTIVE: We sought to determine if fetal hypertrophic cardiomyopathy (HCM) or cardiac dysfunction is associated with elevated maternal or neonatal insulin-like growth factor (IGF)-I levels in women with diabetes. STUDY DESIGN: In a prospective cohort study, fetal echocardiogram findings at 36 weeks' gestation in women with pregestational diabetes mellitus were compared to those in women without diabetes mellitus. HCM was defined as septal or free wall thickness >=5 mm and cardiac dysfunction as a modified myocardial performance index >=0.43. Cord serum IGF-I levels at delivery were measured with enzyme-linked immunosorbent assay. Neonates with abnormal fetal echocardiogram were followed up until resolution or 6 months of life. RESULTS: In all, 75 participants completed fetal echocardiography (55 diabetics and 20 controls). In the diabetic group, 33 of 55 (60%) had abnormal fetal echocardiograms with cardiac dysfunction in 21 of 55 (38.2%) and HCM in 8 of 55 (14.5%) and both in 4 of 55 (7.3%). At 6 months of age, 1 of 12 (8%) had persistent HCM. None in the comparison group had abnormal findings. There were no significant clinical differences in those diabetic women with normal vs abnormal fetal echocardiograms. However, among diabetic women, mean neonatal IGF-I was significantly higher in fetuses with HCM (80 +/- 16 ng/mL) as compared to those without HCM (61 +/- 18 ng/mL), (P < .001). CONCLUSION: Elevated neonatal IGF-I appears to be associated with fetal HCM in fetuses of diabetic women. PMID- 24813597 TI - Genetic variations in the GLUT3 gene associated with myelomeningocele. AB - OBJECTIVE: Our objectives were to examine the extent of described sequence variation in the glucose transporter 3 (GLUT3) gene in children with myelomeningocele (MM), identify novel variations in the GLUT3 gene in these children, and determine whether these variations may confer a risk of MM. STUDY DESIGN: We sequenced the 10 exons of GLUT3, including exon-intron boundaries, on 96 children with MM. Sequencing was performed with Sanger methods and results analyzed with deoxyribonucleic acid analysis software. Frequencies of known single-nucleotide polymorphisms were identified, and those differing from the reference sequence (GRCh37/hg19 assembly) were considered variations. RESULTS: Six novel and 9 previously described, genetic variations were identified in our population. The novel variations included a large, 83 base pair deletion involving the core promoter region and part of exon 1 (1 of 96 children), and a 2 base pair deletion in the coding sequence of exon 4 (1 of 96 children). The remaining novel variations were located in the introns in the proximity of the splice sites. Novel mutations in GLUT3 were observed among 6.25% of our population. Additionally, the frequency of the rare allele for rs17847972 located in a splice donor site is higher (P < .001) in MM in our population than expected. CONCLUSION: We identified previously undescribed deletions and single nucleotide variations involving the GLUT3 gene that may be associated with increased susceptibility to MM. Of particular interest, the 2 deletions involve both an important core promoter site and a coding region predicted to have a deleterious effect. The functional significance of these findings is under investigation. PMID- 24813598 TI - Residual anastomoses in twin-twin transfusion syndrome after laser: the Solomon randomized trial. AB - OBJECTIVE: Residual anastomoses after fetoscopic laser surgery for twin-to-twin transfusion syndrome (TTTS) may lead to severe postoperative complications, including recurrent TTTS and twin anemia-polycythemia sequence (TAPS). A novel technique (Solomon technique) using laser coagulation of the entire vascular equator was recently investigated in a randomized controlled trial (Solomon trial) and compared with the Standard selective laser technique. The aim of this secondary analysis was to evaluate the occurrence and characteristics of residual anastomoses in placentas included in the Solomon trial. STUDY DESIGN: International multicenter randomized controlled trial in TTTS, randomized 1:1 ratio to either the Solomon laser technique or Standard laser technique. At time of laser, surgeons recorded whether they considered the procedure to be complete. Placental dye injection was performed after birth in the participating centers to evaluate the presence of residual anastomoses. RESULTS: A total of 151 placentas were included in the study. The percentage of placentas with residual anastomoses in the Solomon group and Standard group was 19% (14/74) and 34% (26/77), respectively (P = .04). The percentage of placentas with residual anastomoses in the subgroup of cases where the procedure was recorded as complete was 8/65 (12%) and 22/69 (32%) in the Solomon group and Standard group, respectively (P < .01). CONCLUSION: The Solomon laser technique reduces the risk of residual anastomoses. However, careful follow-up remains essential also after the Solomon technique, as complete dichorionization is not always achieved. PMID- 24813599 TI - Public reporting of assisted reproductive technology outcomes: past, present, and future. AB - The clinic-specific public reporting of assisted reproductive technology (ART) outcomes has been mandated by Federal law since 1992. As of late, a series of scientific and medical advances have all but deconstructed ART practice patterns thereby demanding that current reporting platforms be reevaluated for their continued ability to afford the public with credible and understandable estimates of conception per initiated cycle. In this Clinical Opinion, we trace the history of the public reporting of ART, describe the recently modified (present day) reporting platform, and explore potential future improvements thereof. PMID- 24813600 TI - Proliferation at the heart of preadolescence. AB - Cardiomyocytes, the cells of the heart muscle, lose nearly all of their proliferative capacity after birth, limiting the heart's ability to regenerate. Naqvi et al. now identify a transient burst of cardiomyocyte proliferation during preadolescence, driven by a thyroid hormone surge, with therapeutic implications for congenital and acquired heart diseases. PMID- 24813601 TI - Deciphering functions of branched ubiquitin chains. AB - The anaphase-promoting complex/cyclosome targets proteins for degradation by catalyzing homotypic ubiquitin chains of different linkage types. In this issue of Cell, Meyer and Rape diversify the degradation signals by demonstrating that the APC/C and its cognate E2 conjugating enzymes enhance the rate of substrate degradation by decorating them with branched Lys11 and Lys48 ubiquitin chains. PMID- 24813602 TI - Tic-TACs: refreshing hair growth. AB - Although stem cells are subject to niche control, evidence is emerging that they also contribute to generating the niche through their offspring. Using the hair follicle as a model, Hsu at al. demonstrate that the transient-amplifying cells, downstream of stem cells and well-known cell producers, signal back to stem cells to maintain long-term regenerative capacity. PMID- 24813603 TI - Reconstructing complex tissues from single-cell analyses. AB - Techniques for profiling individual cells are rapidly advancing and are providing an unprecedented opportunity for studying the genetic regulation of development and disease. In this issue, Durruthy-Durruthy et al. analyze gene expression at the single-cell level for a simple but highly organized three-dimensional structure, the mouse otocyst. PMID- 24813604 TI - From connections to function: the mouse brain connectome atlas. AB - Mapping synaptic connections and projections is crucial for understanding brain dynamics and function. In a recent issue of Nature, Oh et al. present a wiring diagram of the whole mouse brain, where standardized labeling, tracing, and imaging of axonal connections reveal new details in the network organization of neuronal connectivity. PMID- 24813605 TI - The fire within: microbes inflame tumors. AB - The immune system and the microbiota mutually interact to maintain homeostasis in the intestine. However, components of the microbiota can alter this balance and promote chronic inflammation, promoting intestinal tumor development. We review recent advances in understanding the complex interactions between the microbiota and the innate and adaptive immune systems and discuss their potential to lead us in new directions for understanding cancer biology and treatment. PMID- 24813606 TI - Population genomics reveal recent speciation and rapid evolutionary adaptation in polar bears. AB - Polar bears are uniquely adapted to life in the High Arctic and have undergone drastic physiological changes in response to Arctic climates and a hyper-lipid diet of primarily marine mammal prey. We analyzed 89 complete genomes of polar bear and brown bear using population genomic modeling and show that the species diverged only 479-343 thousand years BP. We find that genes on the polar bear lineage have been under stronger positive selection than in brown bears; nine of the top 16 genes under strong positive selection are associated with cardiomyopathy and vascular disease, implying important reorganization of the cardiovascular system. One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans. PMID- 24813607 TI - A proliferative burst during preadolescence establishes the final cardiomyocyte number. AB - It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ~40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases. PMID- 24813608 TI - Structurally distinct Ca(2+) signaling domains of sperm flagella orchestrate tyrosine phosphorylation and motility. AB - Spermatozoa must leave one organism, navigate long distances, and deliver their paternal DNA into a mature egg. For successful navigation and delivery, a sperm specific calcium channel is activated in the mammalian flagellum. The genes encoding this channel (CatSpers) appear first in ancient uniflagellates, suggesting that sperm use adaptive strategies developed long ago for single-cell navigation. Here, using genetics, super-resolution fluorescence microscopy, and phosphoproteomics, we investigate the CatSper-dependent mechanisms underlying this flagellar switch. We find that the CatSper channel is required for four linear calcium domains that organize signaling proteins along the flagella. This unique structure focuses tyrosine phosphorylation in time and space as sperm acquire the capacity to fertilize. In heterogeneous sperm populations, we find unique molecular phenotypes, but only sperm with intact CatSper domains that organize time-dependent and spatially specific protein tyrosine phosphorylation successfully migrate. These findings illuminate flagellar adaptation, signal transduction cascade organization, and fertility. PMID- 24813609 TI - Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. AB - The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBalpha, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbalpha gene or pharmacological inhibition of REV-ERBalpha activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBalpha repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBalpha could be targeting in the treatment of circadian rhythm-related affective disorders. PMID- 24813610 TI - A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. AB - Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome. PMID- 24813611 TI - Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. AB - Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA-deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD(+)-SIRT1-PGC 1alpha axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition or by supplementation with NAD(+) precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a nuclear mitochondrial crosstalk that is critical for the maintenance of mitochondrial health. PMID- 24813612 TI - The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. AB - The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells. Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging. PMID- 24813613 TI - Enhanced protein degradation by branched ubiquitin chains. AB - Posttranslational modification of cell-cycle regulators with ubiquitin chains is essential for eukaryotic cell division. Such chains can be connected through seven lysine residues or the amino terminus of ubiquitin, thereby allowing the assembly of eight homogenous and multiple mixed or branched conjugates. Although functions of homogenous chain types have been described, physiological roles of branched structures are unknown. Here, we report that the anaphase-promoting complex (APC/C) efficiently synthesizes branched conjugates that contain multiple blocks of K11-linked chains. Compared to homogenous chains, the branched conjugates assembled by the APC/C strongly enhance substrate recognition by the proteasome, thereby driving degradation of cell-cycle regulators during early mitosis. Our work, therefore, identifies an enzyme and substrates for modification with branched ubiquitin chains and points to an important role of these conjugates in providing an improved signal for proteasomal degradation. PMID- 24813614 TI - GroEL/ES chaperonin modulates the mechanism and accelerates the rate of TIM barrel domain folding. AB - The GroEL/ES chaperonin system functions as a protein folding cage. Many obligate substrates of GroEL share the (betaalpha)8 TIM-barrel fold, but how the chaperonin promotes folding of these proteins is not known. Here, we analyzed the folding of DapA at peptide resolution using hydrogen/deuterium exchange and mass spectrometry. During spontaneous folding, all elements of the DapA TIM barrel acquire structure simultaneously in a process associated with a long search time. In contrast, GroEL/ES accelerates folding more than 30-fold by catalyzing segmental structure formation in the TIM barrel. Segmental structure formation is also observed during the fast spontaneous folding of a structural homolog of DapA from a bacterium that lacks GroEL/ES. Thus, chaperonin independence correlates with folding properties otherwise enforced by protein confinement in the GroEL/ES cage. We suggest that folding catalysis by GroEL/ES is required by a set of proteins to reach native state at a biologically relevant timescale, avoiding aggregation or degradation. PMID- 24813615 TI - Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. AB - Transit-amplifying cells (TACs) are an early intermediate in tissue regeneration. Here, using hair follicles (HFs) as a paradigm, we show that emerging TACs constitute a signaling center that orchestrates tissue growth. Whereas primed stem cells (SCs) generate TACs, quiescent SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). TAC generation is independent of autocrine SHH, but the TAC pool wanes if they can't produce SHH. We trace this paradox to two direct actions of SHH: promoting quiescent-SC proliferation and regulating dermal factors that stoke TAC expansion. Ingrained within quiescent SCs' special sensitivity to SHH signaling is their high expression of GAS1. Without sufficient input from quiescent SCs, replenishment of primed SCs for the next hair cycle is compromised, delaying regeneration and eventually leading to regeneration failure. Our findings unveil TACs as transient but indispensable integrators of SC niche components and reveal an intriguing interdependency of primed and quiescent SC populations on tissue regeneration. PMID- 24813616 TI - Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription. AB - A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation. PMID- 24813618 TI - SnapShot: Epithelial tight junctions. AB - Tight junctions form a morphological and functional border between the apical and basolateral cell surface domains that serves as a paracellular diffusion barrier, enabling epithelial cells to separate compartments of different composition. Tight junctions also contribute to the generation and maintenance of cell polarity and regulate signaling mechanisms that guide cell behavior, shape, and gene expression. This SnapShot illustrates their components, organization, and functions. PMID- 24813617 TI - Programming and inheritance of parental DNA methylomes in mammals. AB - The reprogramming of parental methylomes is essential for embryonic development. In mammals, paternal 5-methylcytosines (5mCs) have been proposed to be actively converted to oxidized bases. These paternal oxidized bases and maternal 5mCs are believed to be passively diluted by cell divisions. By generating single-base resolution, allele-specific DNA methylomes from mouse gametes, early embryos, and primordial germ cell (PGC), as well as single-base-resolution maps of oxidized cytosine bases for early embryos, we report the existence of 5hmC and 5fC in both maternal and paternal genomes and find that 5mC or its oxidized derivatives, at the majority of demethylated CpGs, are converted to unmodified cytosines independent of passive dilution from gametes to four-cell embryos. Therefore, we conclude that paternal methylome and at least a significant proportion of maternal methylome go through active demethylation during embryonic development. Additionally, all the known imprinting control regions (ICRs) were classified into germ-line or somatic ICRs. PMID- 24813619 TI - Reversible switching of the coordination modes of a pyridine-functionalized quinonoid zwitterion; its di- and tetranuclear palladium complexes. AB - The coordination chemistry of a new functional quinonoid zwitterion (E)-3-oxo-4 ((2-(pyridin-2-yl)ethyl)amino)-6-((2-(pyridin-2-yl)ethyl)iminio)cyclohexa-1,4 dienolate (2, H2L), in which a CH2CH2 spacer connects the N substituents of the quinonoid core with a pyridine group, was explored in Pd(II) chemistry. Different coordination modes have been observed, depending on the experimental conditions and the reagents. The reaction of H2L with [Pd(MU-Cl)(dmba)]2 (dmba = o C6H4CH2NMe2-C,N) afforded the dinuclear complex [{PdCl(dmba)}2(H2L)] (3) in which H2L acts as a NPy,NPy bidentate ligand. Deprotonation of this complex with NaH resulted in the formation of the dinuclear complex [{Pd(dmba)}2(MU-L)] (4) in which a shift of the Pd(II) centers from the NPy sites to the N,O donor sites of the zwitterion core has occurred, resulting in a N2O2 tetradentate behavior of ligand L. Reaction of 4 with HCl regenerates 3 quantitatively. Chloride abstraction from 3 with AgOTf (OTf = trifluoromethanesulfonate) resulted in loss of one of the two dmba ligands and formation of an unusual tetranuclear Pd(II) complex, [{Pd(dmba)}(MU-L)Pd]2(OTf)2 (5), in which two dinuclear entities have dimerized, one pyridine donor group from each dimer forming a bridge with the other dinuclear entity. This results in a N2, O2, NPy, NPy hexadentate behavior for the ligand L. Complexes 3 and 4 constitute an unprecedented reversible, switchable system where deprotonation or protonation promotes the reversible migration of the [Pd(dmba)](+) moieties, from the NPy sites in 3, to the N,O donor sites of the quinonoid core in 4, respectively. This switch modifies the extent of pi-delocalization involving the potentially antiaromatic quinonoid moiety and is accompanied by a significant color change, from red in 3 to green in 4. The presence of uncoordinated pyridine donor groups in 4 allowed the use of this complex for the preparation of the neutral tetranuclear complex [{Pd(dmba)}2(MU-L){PdCl(dmba)}2] (6) in which 4 acts as a NPy,NPy-bidentate metalloligand toward two PdCl(dmba) moieties. Halide abstraction from 6 afforded the monocationic, tetranuclear complex [{Pd(dmba)}2(MU-L){Pd(dmba)}2(MU-Cl)]PF6 (7) in which the two Pd(dmba) moieties are connected by ligand L and a bridging chloride. By Cl/PF6 anion metathesis, it was possible to switch quantitatively from complex 6 to 7 and vice versa. All new compounds were unambiguously characterized by IR, NMR, and mass spectroscopy. Single-crystal X-ray diffraction is also available for molecules 2-5 and 7. PMID- 24813620 TI - Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study. AB - OBJECTIVE: A subset analysis of the randomised, phase 3, MDS-004 study to evaluate outcomes in patients with International Prognostic Scoring System (IPSS) defined Low-/Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) with isolated del(5q). METHODS: Patients received lenalidomide 10 mg/d (days 1-21; n = 47) or 5 mg/d (days 1-28; n = 43) on 28-d cycles or placebo (n = 45). From the placebo and lenalidomide 5 mg groups, 84% and 58% of patients, respectively, crossed over to lenalidomide 5 or 10 mg at 16 wk, respectively. RESULTS: Rates of red blood cell-transfusion independence (RBC-TI) >=182 d were higher in the lenalidomide 10 mg (57.4%; P < 0.0001) and 5 mg (37.2%; P = 0.0001) groups vs. placebo (2.2%). Cytogenetic response rates (major + minor responses) were 56.8% (P < 0.0001), 23.1% (P = 0.0299) and 0%, respectively. Two-year cumulative risk of acute myeloid leukaemia progression was 12.6%, 17.4% and 16.7% in the lenalidomide 10 mg, 5 mg, and placebo groups, respectively. In a 6-month landmark analysis, overall survival was longer in lenalidomide-treated patients with RBC TI >=182 d vs. non-responders (P = 0.0072). The most common grade 3-4 adverse event was myelosuppression. CONCLUSIONS: These data support the clinical benefits and acceptable safety profile of lenalidomide in transfusion-dependent patients with IPSS-defined Low-/Int-1-risk MDS with isolated del(5q). PMID- 24813621 TI - Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells. AB - Ionizing radiation induces cellular senescence to suppress cancer cell proliferation. However, it also induces deleterious bystander effects in the unirradiated neighboring cells through the release of senescence-associated secretory phenotypes (SASPs) that promote tumor progression. Although autophagy has been reported to promote senescence, its role is still unclear. We previously showed that radiation induces senescence in PTTG1-depleted cancer cells. In this study, we found that autophagy was required for the radiation-induced senescence in PTTG1-depleted breast cancer cells. Inhibition of autophagy caused the cells to switch from radiation-induced senescence to apoptosis. Senescent cancer cells exerted bystander effects by promoting the invasion and migration of unirradiated cells through the release of CSF2 and the subsequently activation of the JAK2 STAT3 and AKT pathways. However, the radiation-induced bystander effects were correlated with the inhibition of endogenous autophagy in bystander cells, which also resulted from the activation of the CSF2-JAK2 pathway. The induction of autophagy by rapamycin reduced the radiation-induced bystander effects. This study reveals, for the first time, the dual role of autophagy in radiation induced senescence and bystander effects. PMID- 24813622 TI - Autophagy plays an important role in the containment of HIV-1 in nonprogressor infected patients. AB - Recent in vitro studies have suggested that autophagy may play a role in both HIV 1 replication and disease progression. In this study we investigated whether autophagy protects the small proportion of HIV-1 infected individuals who remain clinically stable for years in the absence of antiretroviral therapy, these named long-term nonprogressors (LTNP) and elite controllers (EC). We found that peripheral blood mononuclear cells (PBMC) of the HIV-1 controllers present a significantly higher amount of autophagic vesicles associated with an increased expression of autophagic markers with respect to normal progressors. Of note, ex vivo treatment of PBMC from the HIV-1 controllers with the MTOR inhibitor rapamycin results in a more efficient autophagic response, leading to a reduced viral production. These data lead us to propose that autophagy contributes to limiting viral pathogenesis in HIV-1 controllers by targeting viral components for degradation. PMID- 24813623 TI - [Radiocarpal dislocation after a trivial injury]. AB - Radiocarpal dislocation is an extremely uncommon injury in Traumatology, and is usually produced by high energy trauma. There are two types of dislocation, type I: pure radiocarpal dislocation and type II: fracture-dislocation. The gold standard treatment according to the literature is surgical treatment fixing the fractures and repairing the injured ligaments. We report a clinical case of radiocarpal dislocation type I in a healthy 19 year-old male after a minor trauma. The dislocation was reduced by traction, and the wrist immobilized in a plaster cast. The functional outcome 12 months after the injury was excellent. PMID- 24813624 TI - Determination of damage-free crystal structure of an X-ray-sensitive protein using an XFEL. AB - We report a method of femtosecond crystallography for solving radiation damage free crystal structures of large proteins at sub-angstrom spatial resolution, using a large single crystal and the femtosecond pulses of an X-ray free-electron laser (XFEL). We demonstrated the performance of the method by determining a 1.9 A radiation damage-free structure of bovine cytochrome c oxidase, a large (420 kDa), highly radiation-sensitive membrane protein. PMID- 24813625 TI - Correlated cryogenic photoactivated localization microscopy and cryo-electron tomography. AB - Cryo-electron tomography (CET) produces three-dimensional images of cells in a near-native state at macromolecular resolution, but identifying structures of interest can be challenging. Here we describe a correlated cryo-PALM (photoactivated localization microscopy)-CET method for localizing objects within cryo-tomograms to beyond the diffraction limit of the light microscope. Using cryo-PALM-CET, we identified multiple and new conformations of the dynamic type VI secretion system in the crowded interior of Myxococcus xanthus. PMID- 24813626 TI - Supplementation of Bolton broth with triclosan improves detection of Campylobacter jejuni and Campylobacter coli in chicken carcass rinse. AB - We compared Bolton enrichment broth supplemented with antimicrobial triclosan (T Bolton broth) and normal Bolton broth for the isolation of Campylobacter jejuni (C. jejuni) and Campylobacter coli (C. coli) from chicken carcass rinse. Whole chickens were rinsed with buffered peptone water prior to enrichment in normal Bolton broth or T-Bolton broth, followed by inoculation onto modified charcoal cefoperazone-deoxycholate agar (mCCDA). Suspect colonies were confirmed by PCR. We observed a significantly higher number of C. jejuni or C. coli-positive samples in the T-Bolton broth (71.3%) than in the normal Bolton broth (27.5%) (p<0.05). Furthermore, the number of contaminated mCCDA plates was lower after enrichment in T-Bolton broth (3.8%) than in the normal Bolton broth (75%) (p<0.05), indicating that T-Bolton broth has higher selectivity. Finally, we identified extended-spectrum beta-lactamase-producing Escherichia coli as the predominant competing flora in normal Bolton broth. In conclusion, the use of T Bolton broth results in significant elimination of competing bacteria. PMID- 24813627 TI - Population heterogeneity and dynamics in starter culture and lag phase adaptation of the spoilage yeast Zygosaccharomyces bailii to weak acid preservatives. AB - The food spoilage yeast Zygosaccharomyces bailii shows great resistance to weak acid preservatives, including sorbic acid (2, 4-hexadienoic acid). That extreme resistance was shown to be due to population heterogeneity, with a small sub population of cells resistant to a variety of weak acids, probably caused by a lower internal pH reducing the uptake of all weak acids. In the present paper, it was found that resistant cells were extremely rare in exponential cultures, but increased by up to 8000-fold in stationary phase. Inoculation of media containing sorbic acid with a population of Z. bailii cells gave rise to what appeared to be a prolonged lag phase, suggesting adaptation to the conditions before the cells entered the period of exponential growth. However, the apparent lag phase caused by sorbic acid was largely due to the time required for the resistant sub population to grow to detectable levels. The slow growth rate of the sub population was identical to that of the final total population. The non-resistant bulk population remained viable for 3 days but had lost viability by 6 days and, during that time, there was no indication of any development of resistance in the bulk population. The sub-population growing in sorbic acid showed very high population diversity in colony size and internal pH. After removal of sorbic acid, the population rapidly reverted back to the normal, largely non-resistant, population distribution. The data presented suggest that a reevaluation of the lag phase in microbial batch culture is required, at least for the resistance of Z. bailii to sorbic acid. Furthermore, the significance of phenotypic diversity and heterogeneity in microbial populations is discussed more broadly with potential relevance to bacterial "persisters", natural selection and evolution. PMID- 24813628 TI - Peptide substrates for G protein-coupled receptor kinase 2. AB - G protein-coupled receptor kinases (GRKs) control the signaling and activation of G protein-coupled receptors through phosphorylation. In this study, consensus substrate motifs for GRK2 were identified from the sequences of GRK2 protein substrates, and 17 candidate peptides were synthesized to identify peptide substrates with high affinity for GRK2. GRK2 appears to require an acidic amino acid at the -2, -3, or -4 positions and its consensus phosphorylation site motifs were identified as (D/E)X1-3(S/T), (D/E)X1-3(S/T)(D/E), or (D/E)X0-2(D/E)(S/T). Among the 17 peptide substrates examined, a 13-amino-acid peptide fragment of beta-tubulin (DEMEFTEAESNMN) showed the highest affinity for GRK2 (Km, 33.9 MUM; Vmax, 0.35 pmol min(-1) mg(-1)), but very low affinity for GRK5. This peptide may be a useful tool for investigating cellular signaling pathways regulated by GRK2. PMID- 24813629 TI - MiR-152 reduces human umbilical vein endothelial cell proliferation and migration by targeting ADAM17. AB - As a cleavage enzyme of precursor TNF-alpha, the high expression level of ADAM17 in endothelial cells is an important factor in atherosclerosis. In this study, we demonstrate that ADAM17 is the target of miR-152. We found that miR-152 could reduce TNF precursor cleavage and inhibit cell proliferation and migration by targeting ADAM17 in human umbilical vein endothelial cells (HUVECs). Furthermore, the expression pattern of miR-152 and corresponding target ADAM17 was opposite in HUVECs under hypoxic conditions. The levels of circulating miR-152 in AS patient sera were lower than those detected in the sera of normal individuals. Our results indicate that miR-152 may be involved in the development of human atherosclerosis and could be used as diagnostic biomarker or therapeutic target in atherosclerosis. PMID- 24813630 TI - Proposed classification of posterior staphylomas based on analyses of eye shape by three-dimensional magnetic resonance imaging and wide-field fundus imaging. AB - PURPOSE: To determine the incidence and types of posterior staphylomas in eyes with pathologic myopia by analyzing the entire eye shape by 3-dimensional (3D) magnetic resonance imaging (MRI). DESIGN: Observational, case series. PARTICIPANTS: A total of 105 patients with pathologic myopia (spherical equivalent <-8.0 diopters or axial length >=26.5 mm) were examined by 3D MRI and Optos (Optos, PLC, Dunfermline, Scotland). METHODS: Staphyloma was defined as an outpouching of the wall of the eye that had a radius of curvature less than the surrounding curvature of the wall of the eye. The presence and types of staphylomas were determined by the entire eye shape in 3D MRI scans. Fundus abnormalities suggesting the staphyloma border were analyzed in the fundus images, fundus autofluorescence images, and infrared images by Optos. MAIN OUTCOME MEASURES: Incidence and types of posterior staphylomas, and the correlation between the type of staphyloma by MRI and the Optos images. RESULTS: A total of 198 eyes (105 patients) met the inclusion criteria of pathologic myopia (mean age, 64.3+/-11.5 years; mean axial length, 30.0+/-2.3 mm). Among 198 eyes, 98 (49.5%) had no staphylomas in 3D MRI scans and showed a barrel-shaped globe. The other 100 eyes (50.5%) had posterior staphyloma by 3D MRI. The most predominant type was wide, macular staphyloma (74% of eyes with staphyloma), followed by narrow, macular staphyloma (14% of eyes with staphyloma). In eyes with peripapillary and nasal staphylomas, the change of the curvature was slight and the eye had a nasally distorted shape. Optos images showed pigmentary abnormalities or abnormal reflectance along the staphyloma border. The patients with staphylomas were significantly older and had significantly worse visual function and more frequent chorioretinal changes than patients without staphyloma. CONCLUSIONS: Three-dimensional MRI was useful in analyzing the shape of eyes with and without staphyloma. Even in elderly individuals with severe myopia, approximately one half of the patients did not show clear outpouching suggesting staphyloma. Correlating the MRI data to Optos images provided useful information on the relationship between the eye shape and the fundus appearances in the Optos images. PMID- 24813631 TI - Endothelial PAS domain-containing protein 1 (EPAS1) gene polymorphisms and response to anti-VEGF therapy in the comparison of AMD treatments trials (CATT). PMID- 24813632 TI - Age-related macular degeneration: prevalence and risk factors from Korean National Health and Nutrition Examination Survey, 2008 through 2011. AB - OBJECTIVE: To investigate the prevalence and risk factors of age-related macular degeneration (AMD) in the Korean population. DESIGN: A cross-sectional study using a complex, stratified, multistage, probability-cluster survey, which can produce nationally representative estimates. PARTICIPANTS: Using the database of Korean National Health and Nutrition Examination Survey from 2008 through 2011, 14 352 participants 40 years of age or older with gradable fundus photographs were included. METHODS: Age-related macular degeneration was determined by fundus photograph. Prevalences of AMDs were estimated. Risk factor analyses were conducted using logistic regression analyses (LRAs). MAIN OUTCOME MEASURES: Prevalence and risk factors of AMD. RESULTS: The prevalence of AMD was 6.62% (95% confidence interval [CI], 6.15%-7.09%) in the Korean population: 6.02% (95% CI, 5.56%-6.48%) were early AMD and 0.60% (95% CI, 0.45%-0.75%) were late AMD. The prevalence of early AMD in women (6.73%; 95% CI, 6.11%-7.35%) was higher than that in men (5.25%; 95% CI, 4.61%-5.89%; P<0.001), and the prevalence of late AMD in women (0.37%; 95% CI, 0.22%-0.52%) was lower than that in men (0.85%; 95% CI, 0.59%-1.12%; P<0.001). However, in multiple LRAs both early and late AMD had no association with gender, house income, residence, sun exposure, or systemic comorbidities, including hypertension, diabetes mellitus, and cardiovascular diseases. Early AMD had positive associations with older age groups (P<0.001), lower education (P = 0.027), occupation (P<0.001), anemia (P = 0.027), hepatitis B surface antigen carrier status (P<0.001), not being overweight (body mass index [BMI], P = 0.032; waist circumference, P = 0.041, in separate analyses), and higher serum high-density lipoprotein (HDL) level (P = 0.046), but not with smoking status. Late AMD had positive associations with age groups (P<0.001), current smokers (P = 0.022), and lower BMI (P = 0.037). CONCLUSIONS: The results suggest that there are 1.21 million individuals with early AMD and 121 000 individuals with late AMD in Korea. Nonoverweight status and higher HDL levels, generally assumed as positive health indicators, as well as anemia and hepatitis B infection had harmful associations with AMD in our study, implying a possible different pathophysiologic process of AMD in Asians compared with that of white persons. PMID- 24813633 TI - Scanning ion-selective electrode technique and X-ray microanalysis provide direct evidence of contrasting Na+ transport ability from root to shoot in salt sensitive cucumber and salt-tolerant pumpkin under NaCl stress. AB - Grafting onto salt-tolerant pumpkin rootstock can increase cucumber salt tolerance. Previous studies have suggested that this can be attributed to pumpkin roots with higher capacity to limit the transport of Na(+) to the shoot than cucumber roots. However, the mechanism remains unclear. This study investigated the transport of Na(+) in salt-tolerant pumpkin and salt-sensitive cucumber plants under high (200 mM) or moderate (90 mM) NaCl stress. Scanning ion selective electrode technique showed that pumpkin roots exhibited a higher capacity to extrude Na(+), and a correspondingly increased H(+) influx under 200 or 90 mM NaCl stress. The 200 mM NaCl induced Na(+)/H(+) exchange in the root was inhibited by amiloride (a Na(+)/H(+) antiporter inhibitor) or vanadate [a plasma membrane (PM) H(+) -ATPase inhibitor], indicating that Na(+) exclusion in salt stressed pumpkin and cucumber roots was the result of an active Na(+)/H(+) antiporter across the PM, and the Na(+)/H(+) antiporter system in salt stressed pumpkin roots was sufficient to exclude Na(+) X-ray microanalysis showed higher Na(+) in the cortex, but lower Na(+) in the stele of pumpkin roots than that in cucumber roots under 90 mM NaCl stress, suggesting that the highly vacuolated root cortical cells of pumpkin roots could sequester more Na(+), limit the radial transport of Na(+) to the stele and thus restrict the transport of Na(+) to the shoot. These results provide direct evidence for pumpkin roots with higher capacity to limit the transport of Na(+) to the shoot than cucumber roots. PMID- 24813634 TI - The protective effect of autophagy on mouse spermatocyte derived cells exposure to 1800MHz radiofrequency electromagnetic radiation. AB - The increasing exposure to radiofrequency (RF) radiation emitted from mobile phone use has raised public concern regarding the biological effects of RF exposure on the male reproductive system. Autophagy contributes to maintaining intracellular homeostasis under environmental stress. To clarify whether RF exposure could induce autophagy in the spermatocyte, mouse spermatocyte-derived cells (GC-2) were exposed to 1800MHz Global System for Mobile Communication (GSM) signals in GSM-Talk mode at specific absorption rate (SAR) values of 1w/kg, 2w/kg or 4w/kg for 24h, respectively. The results indicated that the expression of LC3 II increased in a dose- and time-dependent manner with RF exposure, and showed a significant change at the SAR value of 4w/kg. The autophagosome formation and the occurrence of autophagy were further confirmed by GFP-LC3 transient transfection assay and transmission electron microscopy (TEM) analysis. Furthermore, the conversion of LC3-I to LC3-II was enhanced by co-treatment with Chloroquine (CQ), indicating autophagic flux could be enhanced by RF exposure. Intracellular ROS levels significantly increased in a dose- and time-dependent manner after cells were exposed to RF. Pretreatment with anti-oxidative NAC obviously decreased the conversion of LC3-I to LC3-II and attenuated the degradation of p62 induced by RF exposure. Meanwhile, phosphorylated extracellular-signal-regulated kinase (ERK) significantly increased after RF exposure at the SAR value of 2w/kg and 4w/kg. Moreover, we observed that RF exposure did not increase the percentage of apoptotic cells, but inhibition of autophagy could increase the percentage of apoptotic cells. These findings suggested that autophagy flux could be enhanced by 1800MHz GSM exposure (4w/kg), which is mediated by ROS generation. Autophagy may play an important role in preventing cells from apoptotic cell death under RF exposure stress. PMID- 24813635 TI - Effects of PAMAM dendrimers in the mouse brain after a single intranasal instillation. AB - Dendrimers are highly branched spherical nanomaterials produced for use in diagnostic and therapeutic applications such as a drug delivery system. The toxicological profiles of dendrimers are largely unknown. We investigated the in vivo effects of nasal exposure to polyamidoamine (PAMAM) dendrimers on their effects on neurological biomarkers in the mouse brain. A single dose of PAMAM dendrimers (3 or 15MUg/mouse) was intranasally administered to 8-week old male BALB/c mice. Twenty-four hours after administration, the olfactory bulb, hippocampus, and cerebral cortex were collected and potential biomarkers in the blood and brain were examined using blood marker, microarray and real-time RT-PCR analyses. No remarkable changes in standard serum biochemical markers were observed in the blood. A microarray analysis showed the alterations of the genes expression level related to pluripotent network, serotonin-anxiety pathway, TGF beta receptor signaling, prostaglandin synthesis-regulation, complement coagulation cascades, and chemokine-signaling pathway and non-odorant GPCR signaling pathways in brain tissues. Brain derived-neurotrophic factor mRNA was up-regulated in the hippocampus and cerebral cortex in mice treated with a high dose of dendrimers. These findings suggest that PAMAM dendrimers may reach the brain via the systemic circulation or an olfactory nerve route after intranasal instillation, and indicate that a single intranasal administration of PAMAM dendrimers may potentially lead to neuronal effects by modulating the gene expression of brain-derived neurotrophic factor signaling pathway. PMID- 24813636 TI - Estradiol replacement extends the window of opportunity for hippocampal function. AB - We previously reported that treating aged female rats, ovariectomized (OVX) as young adults, with acute proestrous levels of 17beta estradiol (E2) increases CA1 spine density, NMDAR to AMPAR ratio, GluN2B-mediated NMDAR current, and long-term potentiation at CA3-CA1 synapses if administered by 15, but not at 19-month post OVX, defining the critical window of opportunity. Importantly, when rats are aged with ovaries intact until OVX at 20 months, hippocampal E2 responsiveness is maintained, indicating the deficit at 19-month post-OVX is a consequence of the duration of hormone deprivation and not chronological age. Here, we find the beneficial effect of E2 on novel object recognition in OVX rats was constrained by the same critical window. Furthermore, chronic low-level E2 replacement, commenced by 11-month post-OVX using subcutaneous capsules removed 2 weeks before acute proestrous E2 treatment, prevents the loss of hippocampal responsiveness at 19-month post-OVX. These data define the dynamic nature of the critical window showing that chronic replacement with physiological E2 levels within a certain period post-OVX can lengthen the window. PMID- 24813637 TI - HIV genomic mutations causing resistance to antiretroviral drugs in seropositive Sicilians. AB - Through the use of highly active antiretroviral therapy a significant reduction occurred in mortality and morbidity caused by Human Immunodeficiency Virus. The use of antiretroviral drugs resulted in the emergence of resistant viral strains due to mutations that cause a selective advantage to the virus. The aim of our study is to monitor the HIV-1 infection in Sicilians patients evaluating the presence of mutations that make the virus resistant to the therapy. The QIAGEN QIAamp Viral RNA Mini Kit was used to extract HIV-1 viral RNA from 300 patients while the TRUGENE HIV-1 Genotyping Kit and the OpenGene DNA Sequencing System determined viral mutations in the RNA samples. The analysis showed that from 300 subjects, 116 developed Antiretroviral Drug Resistance. The percentage of patients with resistance to nucleoside reverse transcriptase inhibitor (NRTI), non nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor was 26%, 23% and 20%, respectively. Comparison between drug resistances and mutations showed that 134 individuals had mutations in genes codifying for reverse transcriptase but a little more than 50% were associated with resistance to reverse transcriptase inhibitors, in particular 78 and 68 subjects developed drug resistances to NRTI and NNRTI classes respectively. Subjects that showed mutations in genes codifying for protease were 216 but only 59 of these were associated with resistance to protease inhibitors. Our findings emphasize the importance of continued resistance surveillance. Monitoring of transmitted resistance continues to be needed among treatment-exposed patients because of the benefit it provides for the development of drugs effective against the most frequently found drug-resistant viruses. PMID- 24813638 TI - Anatomic versus effective orifice area in a bicuspid aortic valve. PMID- 24813639 TI - Enterohemorrhagic Escherichia coli OmpT regulates outer membrane vesicle biogenesis. AB - Enterohemorrhagic Escherichia coli (EHEC) infection from food or water often results in severe diarrheal disease and is a leading cause of death globally. Outer membrane vesicles (OMVs) secreted from E. coli induce lethality in mice. The omptin outer membrane protease OmpT from E. coli inactivates antimicrobial peptides and may enhance colonization of the uroepithelium, but its precise function remains unclear. Given OmpT is an outer membrane protease, we hypothesized it may have a role in OMV biogenesis. To further characterize the effect of OmpT on OMV production, a genetic approach using wild type, an ompT deletion mutant and an ompT overexpressing construct in EHEC were employed. ompT gene deletion markedly decreased OMV production and stainable lipid but increased vesicle diameter. Conversely, ompT overexpression profoundly increased OMV biogenesis but decreased stainable lipid, protein content, and vesicle diameter. Alterations in EHEC ompT gene expression have an impact on the biogenesis, composition, and size of OMVs. Changes in ompT gene expression may dynamically alter OMV formation, composition, and diameter in response to different host environments and contribute to cell-free intercellular communication to enhance bacterial growth and survival. PMID- 24813640 TI - Immunogenicity and escape mechanisms of allogeneic tendon-derived stem cells. AB - The immunogenicity of tendon-derived stem cells (TDSCs) has implications for their clinical use for the promotion of tendon repair. The immunogenicity and escape mechanisms of rat patellar TDSCs were examined after allogeneic transplantation. Our results showed that TDSCs exhibited low immunogenicity as evidenced by the following: (i) the incubation of target TDSCs with immunized serum did not show antibody recognition and did not induce the complement dependent cytotoxicity; (ii) target TDSCs elicited a very low level of lymphocyte proliferation and did not exhibit host lymphocyte-mediated cytotoxicity; and (iii) target TDSCs dose dependently suppressed the phorbol 12-myristate 13 acetate (PMA)- and ionomycin-induced host lymphocyte proliferation. For the mechanistic studies, TDSCs expressed major histocompatibility complex (MHC)-I but a very low level of MHC-II, CD86 and CD80 for the induction of T-cell response. Also, TDSCs were found to express intracellular Fas and FasL. gamma-IFN pretreatment did not increase the level of MHC-II and CD86 for the upregulation of immune response. Moreover, the immunosuppressive mediators indoleamine 2,3 dioxygenase (IDO) and transforming growth factor-beta 1 (TGF-beta1) were found not to be involved in the escape mechanism of target TDSCs from host lymphocyte attack. In conclusion, allogeneic TDSCs exhibited low immunogenicity. Allogeneic TDSCs might be used for transplantation. PMID- 24813641 TI - Epidemiology of stimulant misuse and abuse: implications for future epidemiologic and neuropharmacologic research. AB - Stimulants are a diverse array of drugs that range from everyday caffeine to prescription medications and illicitly manufactured street drugs. The surveillance of misuse and abuse of stimulants many times confounds prescription and illicit street drugs such that the data are not specific enough to guide mitigation efforts or assess their impact. This review highlights the surveillance efforts that are conducted in the United States (US) for stimulant misuse and abuse. These surveillance efforts include national level surveys as well as reporting systems such as Poison Centers and emergency departments. This epidemiologic analysis has implications for interpreting the current known neuropharmacology of stimulants and possibly informing future neuropharmacology research that may contribute to a better understanding of potential neuropharmacologic factors influencing differing patterns of use, abuse, and adverse consequences associated with various stimulants. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID- 24813642 TI - Suppression by resveratrol of prostaglandin D2-stimulated osteoprotegerin synthesis in osteoblasts. AB - Resveratrol, a natural polyphenol with health-related properties mainly existing in grape skins and red wine, possesses beneficial effects on human being. We have previously reported that prostaglandin D2 (PGD2) stimulates heat shock protein 27 (HSP27) induction via activation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the mechanism behind the effect of PGD2 on osteoprotegerin (OPG) synthesis and the effect of resveratrol on the OPG synthesis in MC3T3-E1 cells. PGD2 significantly stimulated both the OPG release and the expression levels of OPG mRNA. Resveratrol and SRT1720, an activator of SIRT1, markedly suppressed the PGD2-induced OPG release and the mRNA levels of OPG. PD98059, a specific MEK inhibitor, SB203580, a specific p38 MAP kinase inhibitor, and SP600125, a specific SAPK/JNK inhibitor suppressed the PGD2-stimulated OPG release. PGD2 induced phosphorylation of p38 MAP kinase and SAPK/JNK was attenuated by resveratrol or SRT1720. However, resveratrol or SRT1720 failed to affect the phosphorylation of myosin phosphatase-targeting subunit-1 (MYPT-1), a downstream substrate of Rho-kinase and p44/p42 MAP kinase. These results strongly suggest that resveratrol suppresses PGD2-stimulated OPG synthesis through inhibiting p38 MAP kinase and SAPK/JNK in osteoblasts, and that the suppressive effect is exerted at the point downstream of Rho-kinase but upstream of p38 MAP kinase or SAPK/JNK. PMID- 24813643 TI - Association between polyunsaturated fatty acid concentrations in maternal plasma phospholipids during pregnancy and offspring adiposity at age 7: the MEFAB cohort. AB - Prenatal polyunsaturated fatty acid (PUFA) concentrations may be involved in the prenatal programming of adiposity. In this study we therefore explored the association between maternal PUFA concentrations, measured up to four times during pregnancy, and offspring adiposity at age 7 in 234 mother-child pairs of the Maastricht Essential Fatty Acid Birth cohort. Only dihomo-gamma-linolenic acid (DGLA, an n-6 fatty acid) concentration was associated with adiposity: per standard deviation increase in relative DGLA concentration, BMI increased by 0.44kg/m(2) (CI95: 0.16, 0.72), sum of skinfolds increased by 3.41mm (CI95: 1.88, 4.95), waist circumference increased by 1.09cm (CI95: 0.40, 1.78), and plasma leptin concentration increased by 0.66ug/l (CI95: 0.20, 1.11). In conclusion, maternal DGLA throughout gestation was associated with increased BMI and some additional measures of adiposity at age 7. This suggests that maternal DGLA might play a role in or reflect the prenatal programming of adiposity. PMID- 24813644 TI - Sensitivity enhancement of Si nanowire field effect transistor biosensors using single trap phenomena. AB - Trapping-detrapping processes in nanostructures are generally considered to be destabilizing factors. However, we discovered a positive role for a single trap in the registration and transformation of useful signal. We use switching kinetics of current fluctuations generated by a single trap in the dielectric of liquid-gated nanowire field effect transistors (FETs) as a basic principle for a novel highly sensitive approach to monitor the gate surface potential. An increase in Si nanowire FET sensitivity of 400% was demonstrated. PMID- 24813645 TI - Fenugreek seed powder mitigates cadmium-induced testicular damage and hepatotoxicity in male rats. AB - Cadmium is a potential environmental and industrial pollutant affecting human tissues and organs including liver and testes. The protective role of fenugreek seed powder (FSP) was investigated in male rats subjected to cadmium-induced testicular injury and hepatic dysfunction. Testicular damage and hepatotoxicity were induced by oral administration of cadmium chloride (5 mg/kg body weight, once a day) for 7 weeks. FSP was given at 5% w/w in chow diet for 8 weeks, starting 1 week before cadmium administration. FSP intake significantly increased serum testosterone level and testis weight that were reduced by cadmium. FSP also compensated deficits in hepatic and testicular antioxidant defense system, interleukin-4 and nitric oxide levels, reduced serum liver function enzyme activities and suppressed lipid peroxidation in hepatic and testicular tissues resulted from cadmium administration. Additionally, FSP attenuated the cadmium induced elevations in hepatic and testicular tumor necrosis factor-alpha and transforming growth factor-beta1 levels as well as cadmium deposition and hydroxyproline content. The protective effect afforded by FSP was mainly due its antioxidant, antifibrotic and anti-inflammatory effects. In conclusion, the results of the present work indicated that FSP may represent a promising medicinal herb to protect hepatic and testicular tissues from the detrimental effects of cadmium. PMID- 24813646 TI - Effects of adenosine triphosphate (ATP) on early recovery after total knee arthroplasty (TKA): a randomized, double-blind, controlled study. AB - Functional exercise after total knee arthroplasty (TKA) is necessary. However, it may be a difficult and painful process for the patient. Desirable methods of relieving the patient's pain are worth exploring. Oral supplement of adenosine triphosphate (ATP) is a potential option. In the present study, we decide to investigate whether short-term administration of ATP benefits patients undergoing TKA. A total of 244 subjects were randomized to receive 120mg ATP or placebo each day for 4weeks. Significant differences in quadriceps strength, pain scores at postoperative days 7, 14, 21, and 28 and total opioid consumption were detected. It follows that oral supplement of ATP could benefit patients recovering from TKA. PMID- 24813647 TI - No additional benefit with use of a fibrin sealant to decrease peri-operative blood loss during primary total knee arthroplasty. AB - Blood loss remains a substantial problem associated TKA. This study evaluated the efficacy of a fibrin sealant on: (1) blood loss; (2) blood transfusions; and (3) length of stay. We evaluated the records of 113 consecutive patients with sealant and 70 without sealant. There was no significant difference in the hemoglobin levels (all 9.5-10 g/dL) on each of three postoperative days. There was also no significant difference in the intraoperative blood loss, postoperative blood loss or the total perioperative blood loss in both groups. The mean requirement in each patient was 2.5 +/- 2.4 units in the fibrin sealant group compared to 2.0 +/ 0.8 units in the non-fibrin sealant group. We have stopped using fibrin sealant based on this study. PMID- 24813648 TI - Predominantly Inattentive Type of ADHD is Associated With Social Anxiety Disorder. AB - OBJECTIVE: The aim of this study was to determine the frequency of childhood ADHD comorbidity in patients with social anxiety disorder (SAD), and the influence of this comorbidity on various demographic and clinical variables in SAD. METHOD: A total of 130 patients with SAD were assessed with K-SADS-PL's (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) behavioral disorders module to determine the childhood diagnosis of ADHD. Patients with or without a comorbid childhood ADHD were compared in terms of clinical characteristics and rating scores. RESULTS: The mean age at onset of SAD was lower, and lifetime major depressive disorder and bipolar disorder (BD) comorbidity were higher in the SAD-ADHD group than in the SAD-without ADHD group. CONCLUSION: We have found high ADHD comorbidity in patients with SAD. Presence of comorbid ADHD was associated with increased severity, functional impairment, and BD comorbidity. PMID- 24813649 TI - Do BK channels mediate glioma hypoxia-tolerance? PMID- 24813650 TI - Low concentrations of recombinant granulocyte macrophage-colony stimulating factor derived from Chinese hamster ovary cells augments long-term bioactivity with delayed clearance in vitro. AB - To date, the biological activity of granulocyte macrophage-colony stimulating factor (GM-CSF) has been investigated by using mostly Escherichia coli- or yeast cell-derived recombinant human GM-CSF (erhGM-CSF and yrhGM-CSF, respectively). However, Chinese hamster ovary cell-derived recombinant human GM-CSF (crhGM-CSF), as well as natural human GM-CSF, is a distinct molecule that includes modifications by complicated oligosaccharide moieties. In the present study, we reevaluated the bioactivity of crhGM-CSF by comparing it with those of erhGM-CSF and yrhGM-CSF. The effect of short-term stimulation (0.5h) on the activation of neutrophils/monocytes or peripheral blood mononuclear cells (PBMCs) by crhGM-CSF was lower than those with erhGM-CSF or yrhGM-CSF at low concentrations (under 60pM). Intermediate-term stimulation (24h) among the different rhGM-CSFs with respect to its effect on the activation of TF-1 cells, a GM-CSF-dependent cell line, or PBMCs was not significantly different. In contrast, the proliferation/survival of TF-1 cells or PBMCs after long-term stimulation (72 168h) was higher at low concentrations of crhGM-CSF (15-30pM) than that of cells treated with other GM-CSFs. The proportion of apoptotic TF-1 cells after incubation with crhGM-CSF for 72h was lower than that of cells incubated with other rhGM-CSFs. These effects were attenuated by desialylation of crhGM-CSF. Clearance of crhGM-CSF but not desialylated-crhGM-CSF by both TF-1 cells and PBMCs was delayed compared with that of erhGM-CSF or yrhGM-CSF. These results suggest that sialylation of oligosaccharide moieties delayed the clearance of GM CSF, thus eliciting increased long-term bioactivity in vitro. PMID- 24813651 TI - Sunitinib-induced pseudoporphyria. PMID- 24813652 TI - The clinical effectiveness and cost-effectiveness of brief intervention for excessive alcohol consumption among people attending sexual health clinics: a randomised controlled trial (SHEAR). AB - BACKGROUND: Excessive use of alcohol is associated with poor sexual health, but the clinical effectiveness and cost-effectiveness of brief alcohol intervention in this setting has not been investigated. OBJECTIVE: To examine the effects and cost-effectiveness of brief intervention for excessive alcohol consumption among people who attend sexual health clinics. DESIGN: A two-arm, parallel-group, single-blind, pragmatic, randomised controlled trial. Participants were randomised via an independent and remote telephone randomisation service using permuted blocks, stratified by clinic. SETTING: Study participants were recruited from three sexual health clinics in central and west London. PARTICIPANTS: For inclusion, potential participants had to be aged >= 19 years, drink excessive alcohol according to the Modified-Single Alcohol Screening Question, and be willing to provide written informed consent. We excluded those who were unable to communicate in English sufficiently well to complete the baseline assessment and those who could not provide contact details for the follow-up assessment. INTERVENTIONS: Brief advice was delivered by the treating clinician and comprised feedback on the possible health consequences of excessive drinking, a discussion of whether the participant's clinic attendance was linked to current alcohol use, written information on alcohol and health and an offer of an appointment with an alcohol health worker (AHW). Appointments with AHWs took place either in person or by telephone, lasted up to 30 minutes, and used the 'FRAMES' (Feedback about the adverse effects of alcohol, an emphasis on personal Responsibility for changing drinking behaviour, Advice about alcohol consumption, a Menu of options for further help and advice, an Empathic stance towards the patient and an emphasis on Self-efficacy) approach. Those in the control arm of the trial were offered a copy of a leaflet providing general information on health and lifestyle. MAIN OUTCOME MEASURES: Outcomes were assessed 6 months after randomisation. The primary outcome was mean weekly alcohol consumption during the previous 90 days. The main secondary outcome was unprotected sex during this period. RESULTS: Eight hundred and two people were recruited to the study of whom 592 (74%) were followed up 6 months later. Among 402 participants who were randomised to brief intervention, 397 (99%) received brief advice from the treating clinician and 81 (20%) also received input from an AHW. The adjusted mean difference in alcohol consumption after 6 months was -2.33 units per week [95% confidence interval (CI) -4.69 to 0.03 units per week, p = 0.053] for those in the active arm compared with the control arm. Unprotected sex was reported by 154 (53%) of those who received brief intervention and by 178 (59%) of controls (adjusted odds ratio 0.89, 95% CI 0.63 to 1.25, p = 0.496). Participants randomised to brief intervention reported drinking a mean of 10.4 units of alcohol per drinking day compared with 9.3 units among control participants (difference 1.10, 95% CI 0.29 to 1.96, p = 0.009). We found no statistically significant differences in other outcomes. Brief intervention (brief advice and input from an AHW) cost on average L12.60 per person to deliver and did not appear to provide a cost-effective use of resources. CONCLUSIONS: Introduction of universal screening and brief intervention for excessive alcohol use among people who attend sexual health clinics does not result in clinically important reductions in alcohol consumption or provide a cost-effective use of resources. While people attending sexual health clinics may want to achieve better sexual health, attempts to reduce alcohol consumption may not be seen by them as a necessary means of trying to achieve this aim. TRIAL REGISTRATION: This trial is registered as ISRCTN 99963322. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 30. See the NIHR Journals Library website for further project information. PMID- 24813653 TI - Patient perception and knowledge of acetaminophen in a large family medicine service. AB - The use of acetaminophen is currently under increased scrutiny by the US Food and Drug Administration (FDA) due to the risk of intentional and more concerning, unintentional overdose-related hepatotoxicity. Acetaminophen is responsible for an estimated 48% of all acute liver failure diagnoses. The purpose of this study is to evaluate patient perception and knowledge of the safe use and potential toxicity of acetaminophen-containing products. The authors conducted a descriptive, 2-week study using a convenience sample from a large family medicine clinic waiting room. Survey questions assessed ability to identify acetaminophen, knowledge of the current recommended maximum daily dose, respondent acetaminophen use patterns, common adverse effects associated with acetaminophen, and respondent self-reported alcohol consumption. Acetaminophen safety information was provided to all persons regardless of participation in the study. Of the 102 patients who chose to participate, 79% recognized acetaminophen as a synonym of Tylenol, whereas only 9% identified APAP as a frequently used abbreviation. One third of respondents thought acetaminophen was synonymous with ibuprofen and naproxen. Approximately one fourth of patients correctly identified the then maximum recommended daily acetaminophen dose of 4 g. Seventy-eight percent of patients correctly identified hepatotoxicity as the most common serious adverse effect. We conclude that patient deficiencies in knowledge of acetaminophen recognition, dosing, and toxicity warrant public education by health professionals at all levels of interaction. Current initiatives are promising; however, further efforts are required. PMID- 24813654 TI - A transit compartment model unmasks OxyContin's reflective pharmacokinetics from urine measurements in humans. AB - The absorption pattern of orally administered OxyContin (OXC) reflected in urine indicates that its appearance into systemic circulation undergoes transit absorption delays. The authors developed an OXC transit-delay compartment model that identified a new source of oxycodone hydrochloride (OC): the rate of appearance of OC due to OXC tablet dissolution in transit through the gastrointestinal (GI) tract (R(a)(GI)), which is due to disintegration of OXC's AcroContin delivery system. R(a)(GI) is independent of the biphasic dissolution and release of OC from the delivery system. The authors conclude that an OXC transit-delay compartment model can be of value in the interpretation of OXC pharmacokinetics. PMID- 24813655 TI - Moral justification of Phase 1 oncology trials. AB - This article attempts to answer the following normative questions: Can one consider the design of Phase 1 trials ethically appropriate due to the unfavorable ratio of risks and benefits? What are some ethical safeguards for Phase 1 oncology research? A comparative review of literature contributed to the consolidation of the proposed ethical framework for Phase 1 oncology trials. This framework gives a special attention to issues of therapeutic misconception and vulnerability. The benefits and dangers associated with the enrollment in trials are described as well as the absence of alternatives, treatment-specific optimism, and vagueness in factual presentation during the informed consent process. The notion of therapeutic misconception is contrasted with optimism despite realism that stems from psychological, cultural, and religious factors and not necessarily from the lack of information. Close attention is given to the possible ways in which the inherent uncertainty and resulting cognitive biases may affect the informed consent process and the definition of therapeutic misconception. The article ends with recommendations for an ethical way of enrolling palliative patients in early stages of oncology research, giving special attention to provision of adequate consent, protection of vulnerability, and avoidance of therapeutic misconception. PMID- 24813656 TI - Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection. AB - BACKGROUND AND AIMS: Some full-term neonates presenting seizures show diffusion restricted lesions in the cerebral white matter on brain diffusion-weighted imaging (DWI). The purpose of this study was to describe the clinical characteristics and DWI findings in a group of neonates with seizures, white matter lesions on DWI, and a high incidence of rotavirus infection. METHODS: Total 30 full-term neonates with seizures were admitted between 2008 and 2010. Of these, 13 (group A) had the following characteristics on brain DWI: (1) diffusion restricted lesions in the diffuse symmetric cerebral white matter, including the corpus callosum, and (2) no cerebral cortical lesions. The remaining 17 patients (group B) did not exhibit the DWI findings. The clinical characteristics were compared between the 2 groups. RESULTS: The 1-min and 5-min Apgar scores ranged between 7 and 10 in all group A patients, whereas the scores were more diverse in the group B patients. Patients' age at seizure onset was 4.6 +/- 0.6 days (range, 4-6 days) in group A and 8.3 +/- 7.4 days (range, 1-27 days) in group B. Twelve of 13 patients (92.3%) in group A tested positive for stool rotavirus antigen, while only 2 of 12 (16.7%) in group B tested positive (p < 0.001). Six of 10 group A patients showed normal neurodevelopment, but 4 had delayed development between 6 and 30 months. CONCLUSIONS: Rotavirus infection should be considered in neonates with seizures accompanied by diffuse cerebral white matter lesions on DWI, particularly around 5 days of life. PMID- 24813657 TI - Identifying relevant areas of functioning in children and youth with Cerebral Palsy using the ICF-CY coding system: from whose perspective? AB - AIMS: A standardized methodology endorsed by the World Health Organization was used to select the most relevant International Classification of Functioning, Disability and Health for children and youth (ICF-CY) categories to inform the development of the ICF Core Sets for CY with Cerebral Palsy (CP). The aim of this study was to appraise comparatively the results of the four studies included in the preparatory phase of the project exploring relevant areas of functioning in CY with CP. METHODS: ICF-CY categories identified in the preparatory studies - systematic review, global expert survey, qualitative study, and clinical study - were ranked. We compared the ranking percentile scores of the categories across studies. RESULTS: Each study emphasized different ICF-CY components and provided unique categories. Professionals from the health, education and social sectors described areas of functioning that were well distributed across the ICF-CY components (global expert survey), CY with CP and caregivers highlighted areas within the components activity and participation (a & p) and environmental factors (qualitative study), while the research community and clinical encounters mainly focused on body functions and a & p (systematic review and clinical study). INTERPRETATION: This study highlights the need to consider all relevant perspectives when describing the functional profile of CY with CP. PMID- 24813659 TI - Dipeptidyl petidase-IV inhibitor (gemigliptin) inhibits tunicamycin-induced endoplasmic reticulum stress, apoptosis and inflammation in H9c2 cardiomyocytes. AB - The direct effects of dipeptidyl peptidase-IV (DPP-IV) inhibitors on endoplasmic reticulum (ER) stress-induced apoptosis and inflammation in cardiomyocytes have not been elucidated. H9c2 cell viability, which was reduced by tunicamycin, was increased after DPP-IV inhibitor gemigliptin treatment. Gemigliptin significantly decreased the tunicamycin-mediated increase in glucose regulated protein 78 (GRP78) expression and ER stress-mediated signaling molecules such as protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C-EBP homologous protein (CHOP) and inositol-requiring enzyme 1alpha (IRE1alpha)/c-Jun N-terminal kinase (JNK)-p38. Furthermore, gemigliptin effectively induced Akt phosphorylation in a dose-dependent manner. Using flow cytometry and Hoechst staining, we showed that treatment with Akt inhibitor significantly blocked the anti-apoptotic effects mediated by gemigliptin. The reduction in tunicamycin-induced GRP78 level and PERK/CHOP pathway activity by gemigliptin was reversed after treatment with Akt inhibitor. In conclusion, gemigliptin effectively inhibited ER stress-induced apoptosis and inflammation in cardiomyocytes via Akt/PERK/CHOP and IRE1alpha/JNK p38 pathways, suggesting its direct protective role in cardiovascular diseases. PMID- 24813660 TI - Inhibition and structural changes of liver alkaline phosphatase by tramadol. AB - Tramadol is a potent analgesic drug which interacts with mu-opioid and has low effect on other opioid receptors. Unlike other opioids, it has no clinically significant effect on respiratory or cardiovascular parameters. Alakaline phosphatase is a hydrolase enzyme that prefers alkaline condition and removes phosphate group from different substrates. In this study, the interaction between tramadol and calf liver alkaline phosphatase was investigated. The results showed that tramadol can bind to alakaline phosphatase and inhibit the enzyme in an un competitive manner. Ki and IC50 values of tramadol were determined as about 91 and 92 MUM, respectively. After enzyme purification, structural changes on alakaline phosphatase-drug interaction were studied by circular dichroism and fluorescence measurement. These data revealed the alteration in the content of secondary structures and also conformational changes in enzyme occurred when the drug bound to enzyme-substrate complex. PMID- 24813658 TI - Epigenetic-related gene expression profile in medullary thyroid cancer revealed the overexpression of the histone methyltransferases EZH2 and SMYD3 in aggressive tumours. AB - Epigenetic control of gene expression plays a major influence in the development and progression of many cancer types. Aim of the present study was to investigate the expression of epigenetic regulators in a large cohort of medullary thyroid carcinomas (MTC), correlating the data with the clinical outcome and mutational status of the patients. Taqman Low Density Arrays (TLDAs) were used to analyze expression levels of several genes involved in the epigenetic control of transcription in a series of 54 MTCs. The patients cohort included 13 familial MTCs and 41 sporadic forms; 33 hosted a RET mutation and 13 a RAS somatic mutation. The expression profiling revealed in the more aggressive diseases (i.e. occurrence of metastases; persistent disease; disease-related death) a significant increase of EZH2 and SMYD3 gene expression. The increased levels of EZH2 and SMYD3 did not correlate significantly with mutational status of RET or RAS genes. Thus, the histone methyltransferases EZH2 and SMYD3 mRNA expression may represent useful prognostic biomarkers tailoring the most appropriate follow up and timing of therapeutic approaches. PMID- 24813661 TI - Non-surgical and supportive periodontal therapy: predictors of compliance. AB - AIM: To identify predictors of compliance during non-surgical and supportive periodontal therapy (SPT). MATERIALS AND METHODS: In this retrospective study, demographic, dental, medical data of 427 new patients in a private practice were collected. Data were analysed in statistical models with non-surgical therapy and SPT compliance used as dependent variables. RESULTS: Of the 427 patients, 17.3% never agreed to initial therapy, 10.7% never completed therapy and 20.8% completed treatment, but never entered SPT. Of the 218 SPT patients, 56% became non-attenders after a period of 20 months, 33% were erratic attenders and 10.5% were regular attenders until the end of the observation period (5.5-6.5 years). Patients became erratic attenders after a mean period of regular attendance of 18.1 +/- 16.2 months, whereas 49.6% of the patients, who abandoned SPT, were regular attenders until the time they stopped. In a univariate correlation model, periodontal disease severity emerged as a significant predictor of the completion of non-surgical periodontal therapy (p = 0.01). In a multivariate linear regression model, smoking was negatively associated with SPT compliance (p = 0.047). CONCLUSIONS: A low compliance of the population was observed. Smoking and periodontal disease severity represented significant, but modest modifiers of a patient compliance with SPT and initial therapy respectively. PMID- 24813662 TI - An anaerobic incubation study of metal lability in drinking water treatment residue with implications for practical reuse. AB - Drinking water treatment residue (WTR) is an inevitable by-product generated during the treatment of drinking water with coagulating agents. The beneficial reuse of WTR as an amendment for environmental remediation has attracted growing interest. In this work, we investigated the lability of Al, As, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Pb, Sr, V and Zn in Fe/Al hydroxide-comprised WTR based on a 180-day anaerobic incubation test using fractionation, in vitro digestion and a toxicity characteristic leaching procedure. The results indicated that most metals in the WTR were stable during anaerobic incubation and that the WTR before and after incubation could be considered non-hazardous in terms of leachable metal contents according to US EPA Method 1311. However, the lability of certain metals in the WTR after incubation increased substantially, especially Mn, which may be due to the reduction effect. Therefore, although there is no evidence presented to restrict the use of WTR in the field, the lability of metals (especially Mn) in WTR requires further assessment prior to field application. In addition, fractionation (e.g., BCR) is recommended for use to determine the potential lability of metals under various conditions. PMID- 24813663 TI - An intelligent displacement pumping film system: a new concept for enhancing heavy metal ion removal efficiency from liquid waste. AB - A concept of electrochemically switched ion exchange (ESIX) hybrid film system with piston-like proton pumping effect for the removal of heavy metal ions was proposed. Based on this concept, a novel ESIX hybrid film composed of layered alpha zirconium phosphate (alpha-Zr(HPO4)2; alpha-ZrP) nanosheets intercalated with a potential-responsive conducting polyaniline (PANI) was developed for the removal of Ni(2+) ions from wastewater. It is expected that the space between alpha-ZrP nanosheets acts as the reservoir for the functional ions while the intercalated PANI works as the potential-sensitive function element for piston like proton pumping in such ESIX hybrid films. The prepared ESIX hybrid film showed an excellent property of rapid removal of Ni(2+) ions from wastewater with a high selectivity. The used film was simply regenerated by only altering the applied potential. The ion pumping effect for the ESIX of Ni(2+) ions using this kind of film was proved via XPS analysis. The proposed ESIX hybrid film should have high potential for the removal of Ni(2+) ions and/or other heavy metal ions from wastewater in various industrial processes. PMID- 24813664 TI - Adsorption behavior and mechanism of perfluorinated compounds on various adsorbents--a review. AB - Perfluorinated compounds (PFCs) have drawn great attention recently due to their wide distribution in aquatic environments and potential toxic to animals and human beings. Adsorption not only is an effective technology to remove PFCs from water or wastewater, but also affects PFC distribution at solid-liquid interfaces and their fate in aquatic environments. This article reviews the adsorption behavior of different PFCs (mainly perfluorooctane sulfonate and perfluorooctanoate) on various adsorptive materials. Some effective adsorbents are introduced in detail in terms of their preparation, characteristics, effects of solution chemistry and PFC properties on adsorption. Adsorption mechanisms of PFCs on different adsorbents are summarized, and various interactions including electrostatic interaction, hydrophobic interaction, ligand exchange, and hydrogen bond are fully reviewed. The adsorbents with amine groups generally have high adsorption capacity for PFCs, and formation of micelles/hemi-micelles plays an important role in achieving high adsorption capacity of perfluorinated surfactants on some porous adsorbents. Hydrophobic interaction is mainly responsible for PFC adsorption, but the difference between PFCs and traditional hydrocarbons has not clearly clarified. This review paper would be helpful for the preparation of effective adsorbents for PFC removal and understanding interfacial process of PFCs during their transport and fate in aquatic environments. PMID- 24813665 TI - Chemometric approach to visualize and easily interpret data from sequential extraction procedures applied to sediment samples. AB - The aim of this study was to assess metal mobility/availability in coastal surface (oxic) sediment samples from the Bahia Blanca estuary. Particularly, two sequential extraction procedures able to discriminate metals associated to amorphous Fe and Mn oxides and those associated with crystalline oxides of Fe were applied. Sequential procedures differ in the number of steps, type of reagents used, and in the order in which metals associated to organic matter are extracted. The studied metals were Cd, Cr, Cu, Pb, Ni and Zn because of their hazardous potential and relative abundance in the estuary. Tucker4 model with three factors describes appropriately the data sets (explained variance of 64.05%). This model made it possible to visualize and explain the information underlying in the data set. From the multivariate analysis, it was possible to evaluate the metal behaviour and their availability. In this way, Cd and Zn are associated to the more available fractions whereas Ni, Cr, Cu and Pb are mainly associated to the unavailable fractions. On the other hand, Zn and Cu are associated to organic matter fraction. Despite the fact that the two fractionation schemes are quite different, the results obtained with both schemes are comparable. PMID- 24813666 TI - Electrocoagulation pretreatment of wet-spun acrylic fibers manufacturing wastewater to improve its biodegradability. AB - The electrocoagulation (EC) process was used to pretreat wastewater from the manufacture of wet-spun acrylic fibers, and the effects of varying the operating parameters, including the electrode area/wastewater volume (A/V) ratio, current density, interelectrode distance and pH, on the EC treatment process were investigated. About 44% of the total organic carbon was removed using the optimal conditions in a 100 min procedure. The optimal conditions were a current density of 35.7 mA cm(-2), an A/V ratio of 0.28 cm(-1), a pH of 5, and an interelectrode distance of 0.8 cm. The biodegradability of the contaminants in the treated water was improved by the EC treatment (using the optimal conditions), increasing the five-day biological oxygen demand/chemical oxygen demand ratio to 0.35, which could improve the effectiveness of subsequent biological treatments. The improvement in the biodegradability of the contaminants in the wastewater was attributed to the removal and degradation of aromatic organic compounds, straight chain paraffins, and other organic compounds, which we identified using gas chromatography-mass spectrometry and Fourier transform infrared spectroscopy. The EC process was proven to be an effective alternative pretreatment for wastewater from the manufacture of wet-spun acrylic fibers, prior to biological treatments. PMID- 24813667 TI - Superdiffusive cusp-like waves in the mercuric iodide precipitate system and their transition to regular reaction bands. AB - We report a two-dimensional (2D) reaction-diffusion system that exhibits a superdiffusive propagating wave with anomalous cusp-like contours. This wave results from a leading precipitation reaction (wavefront) and a trailing redissolution (waveback) between initially separated mercuric chloride and potassium iodide to produce mercuric iodide precipitate (HgI2) in a thin sheet of a solid hydrogel (agar) medium. The propagation dynamics is accompanied by continuous polymorphic transformations between the metastable yellow crystals and the stable red crystals of HgI2. We study the dynamics of wavefront and waveback propagation that reveals interesting anomalous superdiffusive behavior without the influence of external enhancement. We find that a transition from superdiffusive to subdiffusive dynamics occurs as a function of outer iodide concentration. Inner mercuric concentrations lead to the transition from the anomalous cusp-like to cusp-free regular bands. While gel concentration affects the speed of propagation of the wave, it has no effect on its shape or on its superdiffusive dynamics. Microscopically, we show that the macroscopic wave propagation and polymorphic transformations are accompanied by an Ostwald ripening mechanism in which larger red HgI2 crystals are formed at the expense of smaller yellow HgI2 crystals. PMID- 24813668 TI - Efficient polymer solar cells based on poly(3-hexylthiophene) and indene-C60 bisadduct fabricated with non-halogenated solvents. AB - The photovoltaic performance of poly(3-hexylthiophene) (P3HT) has been improved greatly by using indene-C60 bisadduct (ICBA) as acceptor instead of phenyl-C61 butyric acid methyl ester (PCBM). However, the solvent of dichlorobenzene (DCB) used in fabricating polymer solar cells (PSCs) limited the application of the PSCs, because of the environmental problem caused by the harmful halogenated solvent. In this work, we fabricated the PSCs based on P3HT/ICBA processed with four low-harmful non-halogenated solvents of toluene, o-xylene, m-xylene, and p xylene. The PSCs based on P3HT/ICBA (1:1, w/w) with toluene as the solvent exhibit the optimized power conversion efficiency (PCE) of 4.5% with open-circuit voltage (Voc) of 0.84 V, short circuit current density (Jsc) of 7.2 mA/cm(2), and fill factor (FF) of 71%, under the illumination of AM 1.5G at 100 mW/cm(2). Upon using 1% N-methyl pyrrolidone (NMP) as a solvent additive in the toluene solvent, the PCE of the PSCs was greatly improved to 6.6% with a higher Jsc of 10.3 mA/cm(2) and a high FF of 75%, which is even higher than that of the devices fabricated with halogenated DCB solvent. The X-ray diffraction (XRD) measurement shows that the crystallinity of P3HT increased with the NMP additive. The investigations on morphology of the active layers by atomic force microscopy (AFM) and transmission electron microscopy (TEM) indicate that the NMP additive promotes effective phase separation and formation of nanoscaled interpenetrating network structure of the active layer, which is beneficial to the improvement of Jsc and PCE for the PSCs fabricated with toluene as the solvent. PMID- 24813669 TI - The influence of feeding pattern on changes in plasma ghrelin in the Holstein cow. AB - We measured the plasma ghrelin and cortisol concentrations in non-lactating cows under fixed-time feeding conditions followed by an acute or gradual fasting treatment. During the 4 days before fasting, animals in Group 1 were fed a fixed amount of rations at 0800 and 1600 hr, and those in Group 2 were fed a gradually reduced amount. Thereafter, the plasma ghrelin concentrations of each animal were measured for 40 hr. The plasma ghrelin concentrations, which were low at the onset of fasting, increased before and after 0800 during fasting in Group 1, but not in Group 2. There were no significant differences in the plasma cortisol concentration within or between the groups. It was demonstrated that acute fasting induces elevation of the plasma ghrelin concentration, but that gradual fasting does not. This result suggests that fixed-time and fixed-quantity feeding caused a daily ghrelin rhythm in the cow and that this rhythm influenced changes in plasma ghrelin. PMID- 24813670 TI - Cost-effectiveness of classroom-based cognitive behaviour therapy in reducing symptoms of depression in adolescents: a trial-based analysis. AB - BACKGROUND: A substantial minority of adolescents suffer from depression and it is associated with increased risk of suicide, social and educational impairment, and mental health problems in adulthood. A recently conducted randomized controlled trial in England evaluated the effectiveness of a manualized universally delivered age-appropriate CBT programme in school classrooms. The cost-effectiveness of the programme for preventing low mood and depression for all participants from a health and social care sector perspective needs to be determined. METHODS: A trial-based cost-effectiveness analysis based on a cluster randomized controlled trial (trial registration--ISRCTN 19083628) comparing classroom-based CBT with usual school provision of Personal Social and Health Education. Per-student cost of intervention was estimated from programme records. The study was undertaken in eight mixed-sex U.K. secondary schools, and included 3,357 school children aged 12 to 16 years (in the two trial arms evaluated in the cost-effectiveness analysis). The main outcome measures were individual self reported data on care costs, Quality-Adjusted Life-Years (QALYs, based on the EQ 5D health-related quality-of-life instrument) and symptoms of depression (Short Mood and Feelings Questionnaire) at baseline, 6 and 12 months. RESULTS: Although there was lower quality-adjusted life-years over 12 months (-.05 QALYs per person, 95% confidence interval -.09 to -.005, p = .03) with CBT, this is a 'clinically' negligible difference, which was not found in the complete case analyses. There was little evidence of any between-arm differences in SMFQ scores (0.19, 95% CI -0.57 to 0.95, p = .62), or costs (L142, 95% CI -L132 to L415, p = .31) per person for CBT versus usual school provision. CONCLUSIONS: Our analysis suggests that the universal provision of classroom-based CBT is unlikely to be either more effective or less costly than usual school provision. PMID- 24813671 TI - Limited professional guidance and literature are available to guide the safe use of neuromuscular block in infants. AB - AIM: Neuromuscular blocking agents (NMBAs) are used in a range of critical illnesses in neonates and infants, despite a lack of guidelines and professional standards. This study reviewed the current evidence base and ascertained UK practice regarding the continuous use of these agents in this age range. METHODS: We reviewed the literature and carried out a telephone questionnaire of all tertiary units in England and specialist children's hospital neonatal units in the UK. RESULTS: No best practice guidelines or general consensus statements were found, and the only randomised trial to feature an NMBA protocol expressed concerns about its use in such young babies. Of the 56 units contacted, 54 (96.4%) shared information. Only three of the 56 (5.4%) used intermittent boluses of NMBAs, 91.1% used NMBA infusions, 11 (19.6%) routinely used regular neuromuscular blocker pause to assess depth, and only one (1.8%) used peripheral nerve stimulation monitoring. All the units carried out clinical assessments, but only one (1.8%) had a written protocol. CONCLUSION: There is a paucity of literature and professional standards to guide the safe use of NMBAs in infants. Of the 54 units who participated in the survey, only one had a protocol for using NMBAs in babies. PMID- 24813672 TI - H2S exposure elicits differential expression of candidate genes in fish adapted to sulfidic and non-sulfidic environments. AB - Disentangling the effects of plasticity, genetic variation, and their interactions on organismal responses to environmental stressors is a key objective in ecological physiology. We quantified the expression of five candidate genes in response to hydrogen sulfide (H2S) exposure in fish (Poecilia mexicana, Poeciliidae) from a naturally sulfide-rich environment as well as an ancestral, non-sulfidic population to test for constitutive and environmentally dependent population differences in gene expression patterns. Common garden raised individuals that had never encountered environmental H2S during their lifetime were subjected to short or long term H2S exposure treatments or respective non-sulfidic controls. The expression of genes involved in responses to H2S toxicity (cytochrome c oxidase, vascular endothelial growth factor, and cytochrome P450-2J6), H2S detoxification (sulfide:quinone oxidoreductase), and endogenous H2S production (cystathionine gamma lyase) was determined in both gill and liver tissues by real time PCR. The results indicated complex changes in expression patterns that--depending on the gene--not only differed between organs and populations, but also on the type of H2S exposure. Populations differences, both constitutive and H2S exposure dependent (i.e., plastic), in gene expression were particularly evident for sulfide:quinone oxidoreductase, vascular endothelial growth factor, and to a lesser degree for cytochrome P450-2J6. Our study uncovered putatively adaptive modifications in gene regulation that parallel previously documented adaptive changes in phenotypic traits. PMID- 24813673 TI - Evidence for intraspecific endocrine disruption of Geukensia demissa (Atlantic ribbed mussel) in an urban watershed. AB - Populations undergo physiological adaptations in response to environmental stressors. Our 5-year bio-monitoring study of the Bronx River Estuary demonstrates comparatively low dissolved oxygen concentrations in this urbanized watershed. Additionally, our current results establish altered hormonal levels, resulting from endocrine disruption, in Geukensia demissa (Atlantic ribbed mussel) from the Bronx River Estuary. No studies have yet investigated a correlation between low dissolved oxygen and endocrine disruption in field collected bivalves. Testosterone, estradiol, and progesterone levels were collected from male and female mussels in the oxygen depleted Bronx River and well-oxygenated Greenwich Cove. Bronx River mussels exhibited higher testosterone levels and lower estradiol levels than Greenwich Cove mussels. The resulting abnormal hormonal ratio seems to indicate that environmental conditions in the Bronx River facilitate an allosteric inhibition of the cytochrome P450 aromatase enzyme, which aids conversion of testosterone to estradiol. Low progesterone levels suggest that Bronx River mussels are experiencing a delay in sexual maturation, and morphometric data show a stalling of shell and tissue growth. To confirm that the mussels collected from both sites are the same species, the universal mitochondrial cytochrome c oxidase subunit I gene was analyzed, through DNA barcoding. Minimal sequential heterogeneity confirmed the mussels are the same species. Such findings suggest intraspecific divergence in various endocrine processes, resulting from environmentally induced stress. PMID- 24813674 TI - Framing the future by mastering the new public health. PMID- 24813675 TI - Blockade of lymphocyte trafficking in inflammatory bowel diseases therapy: importance of specificity of endothelial target. AB - Inflammatory bowel diseases (IBD) are chronic, relapsing to continuously active inflammatory disorders of the gastrointestinal tract, of potentially destructive nature. So far, the excessive and/or unbalanced immune response has been the target of the majority of the IBD treatments. Despite the increasing use of immunosuppressants and anti-TNF-alpha inhibitors, about 30% of patients with Crohn's disease and about one-tenth of patients with ulcerative colitis still require major abdominal surgery at 5-10 years. As a result, new therapeutic approaches are urgently needed. The endothelium has a key role in the development of the inflammation, as it selectively governs the leukocyte trafficking and the influx of leukocytes into the intestinal mucosa. Drugs blocking such crossing, specifically at intestinal level, are going to be a new therapeutic option in IBD. PMID- 24813676 TI - Fumaderm(r) in daily practice for psoriasis: dosing, efficacy and quality of life. AB - BACKGROUND: Patients with psoriasis suffer from chronic skin disease and impaired quality of life. With a prevalence of 1-3% of the population, psoriasis is one of the most common chronic inflammatory autoimmune diseases. Fumaric acid esters (Fumaderm((r))) are approved for the treatment of psoriasis in Germany, but regular Fumaderm therapy with six tablets per day is often limited due to adverse events. OBJECTIVES: This observational study recorded data on quality of life, treatment efficacy and drug dosing in patients suffering from psoriasis treated with Fumaderm under conditions of daily practice in 78 dermatological centres. PATIENTS AND METHODS: In this prospective, multicentre, noninterventional trial we included adult patients with severe plaque psoriasis under outpatient conditions receiving Fumaderm according to the current summary of product characteristics for systemic treatment of psoriasis. At baseline and after 3, 6 and 12 months the dosing regimen under daily conditions, Dermatology Life Quality Index (DLQI) and clinical efficacy with the Psoriasis Area and Severity Index (PASI) were documented. RESULTS: A total of 249 patients were included. The mean DLQI score at study entry was 9.95; the mean PASI was 16.8. The average treatment dose of Fumaderm was 2.8 tablets daily. More than 70% of patients were treated with one to three tablets daily and < 30% were treated with a dose ranging from four to six tablets daily. DLQI and PASI improved in the entire study population by 67.2% and 66.6%, respectively. Specifically, when analysing patients who started Fumaderm within 4 weeks before baseline the mean DLQI score decreased from 11.8 to 2.9 (75% reduction) and the mean PASI score from 19.84 to 7.35 after 12 months (63% improvement). CONCLUSIONS: This is the first field study analysing the use of Fumaderm and the improvement of quality of life in patients with psoriasis under daily outpatient conditions. The improvement of DLQI obtained with Fumaderm was comparable with the improvement observed in patients with psoriasis treated with modern biologics. Importantly, in most patients with good clinical response, the treatment dose was one to three tablets daily. PMID- 24813677 TI - Discussion. PMID- 24813679 TI - Removal of Acid Orange 7 from aqueous solution using magnetic graphene/chitosan: a promising nano-adsorbent. AB - Magnetic graphene/chitosan (MGCh) nanocomposite was fabricated through a facile chemical route and its application as a new adsorbent for Acid Orange 7 (AO7) removal was also investigated. After synthesis, the full characterization with various techniques (FTIR, XRD, VSM, and SEM) was achieved revealing many possible interactions/forces of dye-composite system. The results showed that, benefiting from the surface property of graphene oxide, the abundant amino and hydroxyl functional groups of chitosan, and from the magnetic property of Fe3O4, the adsorbent possesses quite a good and versatile adsorption capacity to the dye under investigation, and can be easily and rapidly extracted from water by magnetic attraction. The maximum absorption capacity was reached at initial pH 3 and 120min contact time. The batch adsorption experiments showed that the adsorption of the AO7 is considerably dependent on pH of milieu, amount of adsorbent, and contact time. The adsorption kinetics and isotherms were investigated to indicate that the kinetic and equilibrium adsorption were well described by pseudo-first order kinetic and Langmuir isotherm model, respectively. The adsorption behavior suggested that the adsorbent surface was homogeneous in nature. The study suggests that the MGCh is a promising nano adsorbent for removal of anionic azo dyes from aqueous solution. PMID- 24813680 TI - Cutaneous amyloidoses: a minimum common denominator in their amino acid sequence. AB - BACKGROUND: Peptides forming amyloid fibrils in cutaneous amyloidoses are derived from various precursors, often unrelated to each other. We aimed to identify an amino acid pattern shared by disease-relevant peptides associated with newly reported and already known cutaneous amyloidoses. METHOD: We probed proteins of cutaneous and non-cutaneous amyloidoses for the amyloid motif identified previously ("D/E/N/Q, A/G, D/E/N/Q, 4-20X, V/I/L/M, D/E/N/Q, R/K/H, 0-6X, V/I/L/M, 0-5X, F/Y/W, 4-5X, D/E/N/Q, 0-2X, R/K/H, 0-12X, A/G, V/I/L/M, 0-3X, V/I/L/M, 0-2X, A/G"). Once segments containing the motif were found, these were subject to multiple alignment to detect similarities and dissimilarities between them. RESULTS: The amyloid motif was present, totally or partially, in all proteins; in turn, it was contained, completely or incompletely, in segments of such proteins known to be deposited in the corresponding amyloidoses. The aligned segments of the cutaneous amiloidoses were more similar to each other than to those of the noncutaneous amyloidoses. CONCLUSIONS: The motif-based approach can contribute to the multidisciplinary solution of the complex problem of the pathogenesis of amyloidosis, and could help to identify possible new amyloid forming proteins. PMID- 24813681 TI - Time-series analysis in the medical domain: a study of Tacrolimus administration and influence on kidney graft function. AB - There exists a major concern regarding toxic effects of immunosuppressive medication on the kidney graft during post-transplant care, with observed variation in individual susceptibility to adverse drug effects amongst patients. To date, there has been no possibility to identify susceptible patients prospectively. This study analyzes medical data which includes time series of measures of renal function and trough levels of immunosuppressive drug Tacrolimus, with the main aim of identifying patients susceptible to drug toxicity. We evaluate a plethora of time-series distance measures, determining their appropriateness to the domain based on two criteria: (1) preserving the expected correlations between distances, and (2) ability to detect the expected patterns of interaction between immunosuppressive drug levels and renal function. Besides identifying the most suitable time-series distance measures, we observed that the majority of patients do not exhibit an association between impaired graft function and higher Tacrolimus dosing. On the other hand, the minority of patients determined most sensitive to varying Tacrolimus levels showed a strong tendency to prefer low Tacrolimus dosing. PMID- 24813682 TI - Temperature impacts differentially on the methanogenic food web of cellulose supplemented peatland soil. AB - The impact of temperature on the largely unresolved intermediary ecosystem metabolism and associated unknown microbiota that link cellulose degradation and methane production in soils of a moderately acidic (pH 4.5) fen was investigated. Supplemental [(13) C]cellulose stimulated the accumulation of propionate, acetate and carbon dioxide as well as initial methane production in anoxic peat soil slurries at 15 degrees C and 5 degrees C. Accumulation of organic acids at 15 degrees C was twice as fast as that at 5 degrees C. 16S rRNA [(13) C]cellulose stable isotope probing identified novel unclassified Bacteria (79% identity to the next cultured relative Fibrobacter succinogenes), unclassified Bacteroidetes (89% identity to Prolixibacter bellariivorans), Porphyromonadaceae, Acidobacteriaceae and Ruminococcaceae as main anaerobic degraders of cellulose derived carbon at both 15 degrees C and 5 degrees C. Holophagaceae and Spirochaetaceae were more abundant at 15 degrees C. Clostridiaceae dominated the degradation of cellulose-derived carbon only at 5 degrees C. Methanosarcina was the dominant methanogenic taxa at both 15 degrees C and 5 degrees C. Relative abundance of Methanocella increased at 15 degrees C whereas that of Methanoregula and Methanosaeta increased at 5 degrees C. Thaumarchaeota closely related to Nitrosotalea (presently not known to grow anaerobically) were abundant at 5 degrees C but absent at 15 degrees C indicating that Nitrosotalea sp. might be capable of anaerobic growth at low temperatures in peat. PMID- 24813683 TI - Cytotoxic benzophenone and triterpene from Garcinia hombroniana. AB - Garcinia hombroniana (seashore mangosteen) in Malaysia is used to treat itching and as a protective medicine after child birth. This study was aimed to investigate the bioactive chemical constituents of the bark of G. hombroniana. Ethyl acetate and dichloromethane extracts of G. hombroniana yielded two new (1, 9) and thirteen known compounds which were characterized by the spectral techniques of NMR, UV, IR and EI/ESI-MS, and identified as; 2,3',4,5' tetrahydroxy-6-methoxybenzophenone(1), 2,3',4,4'-tetrahydroxy-6 methoxybenzophenone (2), 2,3',4,6-tetrahydroxybenzophenone (3), 1,3,6,7 tetrahydroxyxanthone (4), 3,3',4',5,7-pentahydroxyflavone (5),3,3',5,5',7 pentahydroxyflavanone (6), 3,3',4',5,5',7-hexahydroxyflavone (7), 4',5,7 trihydroxyflavanone-7-rutinoside (8), 18(13->17)-abeo-3beta-acetoxy-9alpha,13beta lanost-24E-en-26-oic acid (9), garcihombronane B (10), garcihombronane D (11), friedelan-3-one (12), lupeol (13), stigmasterol (14) and stigmasterol glucoside (15). In the in vitro cytotoxicity against MCF-7, DBTRG, U2OS and PC-3 cell lines, compounds 1 and 9 displayed good cytotoxic effects against DBTRG cancer cell lines. Compounds 1-8 were also found to possess significant antioxidant activities. Owing to these properties, this study can be further extended to explore more significant bioactive components of this plant. PMID- 24813685 TI - N-valproyl-L-phenylalanine as new potential antiepileptic drug: synthesis, characterization and in vitro studies on stability, toxicity and anticonvulsant efficacy. AB - Valproic acid (VPA) is considered first-line drug in treatment of generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, (13)C and (1)H- NMR analyses. The Log D(pH7.4) value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h. The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated. These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations. PMID- 24813684 TI - Synthesis and in vitro evaluation of tropane halogenated-derivatives against malaria, sleeping sickness, Chagas disease and leishmaniasis. AB - A series of twelve analogs carrying fluoro, chloro, bromo and iodo halogens on the ortho, meta and para positions of a benzoyloxytropane skeleton were synthesized by a simple acylation of 8-methyl-8-aza-bicyclo[3.2.1]octan- 3alpha ol by halogenobenzoyl chlorides. The compounds were evaluated in vitro against Plasmodium falciparum (P. f.), Trypanosoma brucei brucei (T. b. b.), Trypanosoma cruzi (T. c.) and Leishmania infantum (L. i.). This study shows that the presence of a halogenated atom and its position on the aromatic ring are important for in vitro activity. Compounds 4 (IC50 = 3.6 uM), 8 (IC50 = 6.7 uM), 5 (IC50 = 8.1 uM) and 7 (IC50 = 9.5 uM) were found the most active against P. f., whereas compounds 12 (IC50 = 5.1 uM), 11 (IC50 = 5.6 uM) and 9 (IC50 = 5.8 uM) exhibited the most pronounced activity against T. b. b. This series of compounds can be considered as non-toxic to the human cell line MRC-5. PMID- 24813686 TI - Functionalization of tetracycline and evaluation of its antibacterial activity including against resistant bacteria. AB - Ever growing resistance of pathogenic bacteria against the existing antibiotics has forced researchers to look for new methods and techniques to design effective antimicrobial agents. In the present study a new tetracycline-based antimicrobial polymer (AMP) was synthesized from tetracycline and methacrylic acid (MAAc) using lipase as catalyst. The AMP, thus obtained, was transformed into nanoparticles via an emulsion method. The AMP and its nano-form were characterized by FTIR, NMR, XRD, SEM and EDAX. The antibacterial activity of the AMP was studied against both resistant (-) [P. aeruginosa] and susceptible (+) [S. aureus] bacteria. The synthesized AMP, including its nanoform, was observed to be more potent and efficient antimicrobial agent than the precursor tetracycline. PMID- 24813687 TI - Whole genome mapping of the first reported case of KPC-2-positive Klebsiella pneumoniae ST258 in Nebraska. AB - Three ertapenem-resistant Klebsiella pneumoniae carrying bla(KPC-2) were isolated from a single patient in Nebraska over a span of 5 months. A comparative analysis of the genetic relatedness of these isolates was investigated using pulsed-field gel electrophoresis, multilocus sequence typing, and whole genome mapping. PMID- 24813688 TI - In vitro susceptibility and distribution of beta-lactamases in Enterobacteriaceae causing intra-abdominal infections in North America 2010-2011. AB - The Study for Monitoring Antimicrobial Resistance Trends has been monitoring the activity of antimicrobials indicated for the treatment of intra-abdominal infections since 2004. This report documents the in vitro activity of several recommended antimicrobials against 3449 gram-negative bacilli isolated from the 30 and 25 participating sites in North America in 2010-2011, respectively, and characterizes the extended-spectrum beta-lactamases (ESBL) identified in ESBL positive and ertapenem-non-susceptible isolates of Enterobacteriaceae. Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Klebsiella oxytoca, Citrobacter freundii, Enterobacter aerogenes, Serratia marcescens, and Morganella morgannii were the most common species isolated. The incidence of beta-lactamase production was 8.8% and 8.9% for E. coli and K. pneumoniae, respectively. Overall the most active antimicrobials were amikacin, piperacillin-tazobactam, imipenem, and ertapenem, although beta-lactamase production reduced the activity of most agents. Characterization of beta lactamase genes determined that bla(SHV), bla(CTX-M), bla(AmpC), and bla(KPC) were commonly found in most beta-lactamase-positive isolates. PMID- 24813689 TI - Unraveling architecture of the pluripotent genome. AB - Genomes are folded into sophisticated configurations that both shape, and are shaped by, a diverse range of nuclear functions. High-throughput variations of Chromosome-Conformation-Capture-based technologies now enable analysis of architecture at unprecedented resolution and scale. Here I discuss the complex structure-function relationship of the mammalian genome using the model system of embryonic stem cells, and the progression from pluripotency to terminal differentiation and back again. PMID- 24813690 TI - Economic impact of 13-valent pneumococcal conjugate vaccine in Finnish adults >=50 years with underlying chronic medical conditions. AB - RATIONALE, AIMS AND OBJECTIVES: Invasive pneumococcal diseases (IPD) are associated with substantial burden in adults (>=50 years). Moreover, adults with vascular, metabolic or respiratory diseases have been shown to have a 3-6 times higher risk of IPD when compared with their healthy controls. These persons at higher risk are likely to benefit most from pneumococcal vaccinations. The 13 valent pneumococcal conjugate vaccine (PCV13) was recently introduced to prevent the 13 most prevalent serotypes causing invasive pneumococcal disease in adults. The objective of this study was to estimate the expected 5-year economic impact of targeted PCV13 vaccination compared with no vaccination in Finnish adults (>=50 years) at moderate or high risk for IPD. METHODS: A budget impact model was developed to predict the impact of PCV13 vaccination in terms of the costs and IPD events avoided for years 2012-2016. RESULTS: Approximately 35% of the 2.2 million Finns over 50 years of age can be considered to be at moderate or high risk for IPD because of underlying chronic medical conditions. Vaccination of these people with PCV13 could provide an estimated net budget savings of about ?218 million compared with the current no-vaccination situation over the next 5 years. Among the risk groups considered, the largest absolute net savings (?66.2 million) could be expected to be obtained by vaccinating people with heart disease, due to its high prevalence in the target population. CONCLUSION: In Finland, the immunization with PCV13 vaccine, of adults (>=50 years) at moderate and high risk of IPD, is estimated to lead to substantial cost savings in the 5 years after vaccination. PMID- 24813691 TI - 20S proteasome activity is modified via S-glutathionylation based on intracellular redox status of the yeast Saccharomyces cerevisiae: implications for the degradation of oxidized proteins. AB - Protein S-glutathionylation is a post-translational modification that controls many cellular pathways. Recently, we demonstrated that the alpha5-subunit of the 20S proteasome is S-glutathionylated in yeast cells grown to the stationary phase in rich medium containing glucose, stimulating 20S core gate opening and increasing the degradation of oxidized proteins. In the present study, we evaluated the correlation between proteasomal S-glutathionylation and the intracellular redox status. The redox status was controlled by growing yeast cells in distinct carbon sources which induced respiratory (glycerol/ethanol) or fermentative (glucose) metabolism. Cells grown under glycerol/ethanol displayed higher reductive power when compared to cells grown under glucose. When purified from cells grown in glucose, 20S proteasome alpha5-subunit exhibited an intense anti-glutathione labeling. A higher frequency of the open catalytic chamber gate was observed in the S-glutathionylated preparations as demonstrated by transmission electron microscopy. Therefore, cells that had been grown in glucose displayed an increased ability to degrade oxidized proteins. The results of the present study suggest that 20S proteasomal S-glutathionylation is a relevant adaptive response to oxidative stress that is capable to sense the intracellular redox environment, leading to the removal of oxidized proteins via a process that is not dependent upon ubiquitylation and ATP consumption. PMID- 24813692 TI - Lorazepam in the treatment of posttraumatic feeding disorder. PMID- 24813693 TI - Cyclo[6]pyridine[6]pyrrole: a dynamic, twisted macrocycle with no meso bridges. AB - A large porphyrin analogue, cyclo[6]pyridine[6]pyrrole, containing no meso bridging atoms, has been synthesized through Suzuki coupling. In its neutral form, this macrocycle exists as a mixture of two figure-eight conformers that undergo fast exchange in less polar solvents. Upon protonation, the dynamic twist can be transformed into species that adopt a ruffled planar structure or a figure eight shape depending on the extent of protonation and counteranions. Conversion to a bisboron difluoride complex via deprotonation with NaH and treatment with BF3 acts to lock the macrocycle into a figure-eight conformation. The various forms of cyclo[6]pyridine[6]pyrrole are characterized by distinct NMR, X-ray crystallographic, and spectroscopic features. PMID- 24813694 TI - Switching of perpendicular magnetization by spin-orbit torques in the absence of external magnetic fields. AB - Magnetization switching by current-induced spin-orbit torques is of great interest due to its potential applications in ultralow-power memory and logic devices. The switching of ferromagnets with perpendicular magnetization is of particular technological relevance. However, in such materials, the presence of an in-plane external magnetic field is typically required to assist spin-orbit torque-driven switching and this is an obstacle for practical applications. Here, we report the switching of out-of-plane magnetized Ta/Co(20)Fe(60)B(20)/TaO(x) structures by spin-orbit torques driven by in-plane currents, without the need for any external magnetic fields. This is achieved by introducing a lateral structural asymmetry into our devices, which gives rise to a new field-like spin orbit torque when in-plane current flows in these structures. The direction of the current-induced effective field corresponding to this field-like spin-orbit torque is out-of-plane, facilitating the switching of perpendicular magnets. PMID- 24813695 TI - Scalable synthesis of hierarchically structured carbon nanotube-graphene fibres for capacitive energy storage. AB - Micro-supercapacitors are promising energy storage devices that can complement or even replace batteries in miniaturized portable electronics and microelectromechanical systems. Their main limitation, however, is the low volumetric energy density when compared with batteries. Here, we describe a hierarchically structured carbon microfibre made of an interconnected network of aligned single-walled carbon nanotubes with interposed nitrogen-doped reduced graphene oxide sheets. The nanomaterials form mesoporous structures of large specific surface area (396 m(2) g(-1)) and high electrical conductivity (102 S cm(-1)). We develop a scalable method to continuously produce the fibres using a silica capillary column functioning as a hydrothermal microreactor. The resultant fibres show a specific volumetric capacity as high as 305 F cm(-3) in sulphuric acid (measured at 73.5 mA cm(-3) in a three-electrode cell) or 300 F cm(-3) in polyvinyl alcohol (PVA)/H(3)PO(4) electrolyte (measured at 26.7 mA cm(-3) in a two-electrode cell). A full micro-supercapacitor with PVA/H(3)PO(4) gel electrolyte, free from binder, current collector and separator, has a volumetric energy density of ~6.3 mWh cm(-3) (a value comparable to that of 4 V-500 uAh thin film lithium batteries) while maintaining a power density more than two orders of magnitude higher than that of batteries, as well as a long cycle life. To demonstrate that our fibre-based, all-solid-state micro-supercapacitors can be easily integrated into miniaturized flexible devices, we use them to power an ultraviolet photodetector and a light-emitting diode. PMID- 24813697 TI - Nanomagnonic devices based on the spin-transfer torque. AB - Magnonics is based on signal transmission and processing by spin waves (or their quanta, called magnons) propagating in a magnetic medium. In the same way as nanoplasmonics makes use of metallic nanostructures to confine and guide optical frequency plasmon-polaritons, nanomagnonics uses nanoscale magnetic waveguides to control the propagation of spin waves. Recent advances in the physics of nanomagnetism, such as the discovery of spin-transfer torque, have created possibilities for nanomagnonics. In particular, it was recently demonstrated that nanocontact spin-torque devices can radiate spin waves, serving as local nanoscale sources of signals for magnonic applications. However, the integration of spin-torque sources with nanoscale magnetic waveguides, which is necessary for the implementation of integrated spin-torque magnonic circuits, has not been achieved to date. Here, we suggest and experimentally demonstrate a new approach to this integration, utilizing dipolar field-induced magnonic nanowaveguides. The waveguides exhibit good spectral matching with spin-torque nano-oscillators and enable efficient directional transmission of spin waves. Our results provide a practical route for the implementation of integrated magnonic circuits utilizing spin transfer. PMID- 24813698 TI - Systematic review of the psychosocial aspects of living with Marfan syndrome. AB - The purpose of this study was to explore the literature on the psychosocial aspects of Marfan syndrome (MFS), to critically appraise and to synthesize relevant literature. A mixed-method systematic review was performed by searching the published literature databases using available medical, psychological, pedagogical and social databases and other sources. All studies that addressed psychosocial aspects of MFS, published in peer-reviewed journals were assessed. Of 81 search results, 15 articles (four articles based on same study population) satisfied the eligibility criteria. All studies were cross-sectional; no intervention or randomized controlled trial (RCT) studies were found. Most studies were of small sample sizes, had low response rate or participants without a verified diagnosis. Despite these limitations, all studies described, that MFS has a significant impact on the psychosocial aspects of people's lives: Decreased quality of life; challenges in education, work and family life, depression and anxiety. Some studies indicated that the subjective perception of discomfort did not necessarily match the medical severity of a disease. The research of the psychosocial aspects of MFS is limited in size and quality. More research is needed on the psychosocial aspects of MFS in samples with a verified diagnosis to develop evidence-based knowledge and appropriate guidelines. PMID- 24813696 TI - In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. AB - Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis. PMID- 24813699 TI - Cerebellar hallmarks of conditioned preference for cocaine. AB - Pavlovian conditioning tunes the motivational drive of drug-associated stimuli, fostering the probability of those environmental stimuli to promote and trigger drug seeking and taking. Interestingly, different areas in the cerebellum are involved in the formation and long-lasting storage of Pavlovian emotional memory. Very recently, we have shown that conditioned preference for an odour associated with cocaine was directly correlated with cFOS expression in cells at the dorsal region of the granule cell layer of the cerebellar vermis. The main goal of the current investigation was to further extend the description of cFOS-IR patterns in cerebellar circuitry after training mice in a cocaine-odour Pavlovian conditioning procedure, including now the major inputs (the inferior olive and pontine nuclei) and one of the output nuclei (the medial deep nucleus) of the cerebellum. The results showed that the cerebellar hallmark of preference towards an odour cue associated to cocaine is an increase in cFOS expression in the dorsal part of the granule cell layer. cFOS-IR levels expressed in the granule cell layer of mice that did not show cocaine conditioned preference did not differ from the basal levels. Remarkably, mice subjected to a random cocaine odour pairing procedure (the unpaired group) exhibited higher cFOS-IR in the inferior olive, the pontine nuclei and in the deep medial nucleus. Therefore, our findings suggest that inputs and the output of cerebellar circuitry are enhanced when contingency between the CS+ and cocaine is lacking. PMID- 24813700 TI - Changes in the sexual behavior and testosterone levels of male rats in response to daily interactions with estrus females. AB - Male rat sexual behavior has been intensively studied over the past 100 years, but few studies have examined how sexual behavior changes over the course of several days of interactions. In this experiment, adult male rats in the experimental group (n=12) were given daily access to estrus females for 30 min per day for 15 consecutive days while control males (n=11) did not interact with females. Ovariectomized females were induced into estrus with hormonal injections, and males interacted with a different female each day. The amount of sexual activity (mounts, intromissions, and ejaculations) was found to cycle with a period of approximately 4 days in most male rats. Additionally, blood was collected every other day following sexual interactions to assess serum testosterone levels. Testosterone was found to peak on the first day of interaction and then fell back to near the level of control rats that did not interact with females. Following the initial peak, testosterone concentrations fluctuated less in males exposed to females than in controls. Sexual activity was not found to predict testosterone concentration. We conclude that when male rats have daily sexual interactions, sexual behavior tends to show cyclic changes and testosterone is significantly elevated only on the first day of interactions. PMID- 24813701 TI - The anorectic effects of alpha-lipoicacid are mediated by central AMPK and are not due to taste aversion in chicken (Gallus gallus). AB - AMP-activated protein kinase (AMPK) is an evolutionary conserved cellular energy sensor, which plays a pivotal role in mammalian energy homeostasis. The present study was aimed to explore the possible involvement of hypothalamic AMPK in feed intake regulation of broiler chickens. Hence, diets with 0, 0.05% or 0.1% alpha lipoicacid (alpha-LA), a known AMPK inhibitor in mammals, were provided to broiler chicks for 7days. Alpha-LA exerted an anorectic effect, and the conditioned taste aversion test demonstrated that the effect was due to the alteration in satiety and not taste effects. However, the curtailed feed intake induced by alpha-LA disappeared on day 7. Hypothalamic AMPKalpha1 mRNA levels were significantly decreased by the dietary alpha-LA in concert with the reduced abundance in total AMPKalpha protein. The phosphorylated AMPKalpha was also decreased to a similar extend, resulting in an unaltered phosphorylated AMPKalpha/total AMPKalpha ratio. In addition, hypothalamic corticotropin releasing hormone mRNA levels were enhanced by alpha-LA. Interestingly, the mRNA expressions of hypothalamic orexigenic agouti-related peptide and neuropeptide Y were up-regulated, while the anorexigenic proopiomelanocortin and its transcription regulator hypoxia-inducible factor-1alpha were down-regulated, probably as a physiological reaction in order to counteract the altered energy balance. In conclusion, dietary alpha-LA decreased feed intake of broiler chicks. The anorectic effect was due to the reduced hypothalamic phosphorylated AMPKalpha as reflected in its decreased mRNA and protein levels. However, the anorectic effect of alpha-LA was progressively diminished after 7days of treatment, likely by a physiological counteractive feedback via changing neuropeptides involved in energy balance regulation. PMID- 24813702 TI - On the role of individual differences in female odor and ultrasonic vocalizations for male's choice of partner. AB - Intrasexual competition for access to a female mate is believed to be unusual in wild male rats, which suggests that female choosiness could be important. Even if competition is unusual, males still have to inevitably approach one partner first for copulation. In females, it has been shown that females spend longer time with one male compared to the others when tested in a multiple partner paradigm. The male mate preference was investigated in this study. In addition, the role of ultrasonic vocalizations (USVs) and female odors in the male's initial choice to approach one female instead of another was studied in this experiment. Male rats could choose between three different sexually receptive females. The experiment started with a 15-minute period with inaccessible females followed by a 15-minute period with accessible females in which the males could copulate with the females of his choice. The results showed that male rats spent more time with the female of 1st entry over the second or third females visited. No differences were found in USV subtype patterns emitted by the different females or the number of sniff episodes towards the different female chambers. Thus, the present experiments did not offer any evidence suggesting that USVs or individual differences in female odors play any role in male mate choice. Other factors that were not investigated in this study might be involved in male mate selection, but it should also be considered that mate selection could be random. PMID- 24813703 TI - Short term consequences of preventing visitor access to kennels on noise and the behaviour and physiology of dogs housed in a rescue shelter. AB - Re-homing centres present a range of potential stressors to kennelled dogs which are likely to impact negatively on their welfare. Despite the presence of visitors to the kennel often being considered a potential stressor, empirical investigation into their impact on the behaviour and welfare of kennelled dogs in re-homing centres is lacking. This study investigated the influence of changing visitor access policy from open access to prohibited viewing at kennels (with organised single meetings for viewing dogs outside of the kennel environment) on the welfare of 15 dogs housed in a dog-only re-homing facility. Data were collected across a number of domains comprising kennel noise levels, behavioural measures (activity, repetitive behaviour, response to human approach); physiological measures (urinary cortisol:creatinine ratios); sickness events and faecal scoring. The general kennel noise levels were significantly lower when visitor access to the kennel area was restricted. Furthermore, dogs were found to display behaviour indicative of improved welfare during this time period; dogs spent significantly more time sedentary, less time moving and exhibited significantly fewer episodes of repetitive behaviours. No significant change was seen in the urinary cortisol:creatinine ratio, nor in sickness behaviour, faecal scoring or response to a human approach test. Overall, the results from this study suggest that restricting visitors from viewing the dogs while in their kennels may be better for the dogs' short term welfare. PMID- 24813704 TI - Genetic deletion of the MT1 or MT2 melatonin receptors abrogates methamphetamine induced reward in C3H/HeN mice. AB - The drug of abuse methamphetamine (METH) is known for its ability to enhance reward responses. The rewarding properties of psychostimulants have been shown to vary across time of day in mice. The goal of this study was to determine the role of the MT1 and MT2 melatonin receptors in METH-induced reward, as measured by the conditioned place preference (CPP) paradigm during the light and dark phases. C3H/HeN wild-type mice were trained for METH-induced CPP at either ZT 6-8 (ZT: Zeitgeber time; ZT 0=lights on), when endogenous melatonin levels are low, or ZT 19-21, when melatonin levels are high. These time points also correspond to the high and low points for expression of the circadian gene Period1, respectively. The locomotor response to METH (1.2mg/kg, ip) treatment was of similar magnitude at both times; however only C3H/HeN mice conditioned to METH at ZT 6-8 developed a place preference. C3H/HeN mice with a genetic deletion of either the MT1 (MT1KO) or MT2 (MT2KO) receptor tested at ZT 6-8 or ZT 19-21 did not develop a place preference for METH, though both showed a similar increase in locomotor activity following METH treatment when compared to wild-type mice. We conclude that in our mouse model METH-induced CPP is dependent on time of day and the presence of the MT1 or MT2 receptors, suggesting a role for melatonin in METH induced reward. PMID- 24813705 TI - Minimizing aggression during mixing of gestating sows with supplementation of a tryptophan-enriched diet. AB - Gestation stalls are criticized for its negative physical and psycho physiological effects on sow welfare. Group housing benefits sow well-being and when planned properly can minimize aggression during mixing. This study aimed to evaluate the effect of short-term feeding of a TRP-enriched diet at a concentration of 220% the control (CTL) diet, on aggressiveness at mixing of sows at 4weeks of gestation. Treatment diets were fed for 7 consecutive days; from days 1 to 5 sows were housed in stalls, early in the morning on day 6 sows were grouped by parity and assessed until day 7. Eighteen pens with 4 sows each (n=72) of similar parity were assigned to CTL and TRP treatments. Sows' behaviors were recorded daily for 12h, from days 1 to 7. Inactive and active behaviors (alert, walking (pen), rooting, feeding, drinking, eliminating), stereotypic behaviors (bar biting and sham-chewing), and postures (standing, sitting, lying) were assessed by 10-minute scan sampling. Occurrence of agonistic interactions, number of actions such as bites, head knocks and pursuits and their sum per interaction were recorded for each pen using 2-h continuous behavioral observation, at days 6 and 7. Skin lesion scores were assessed from each sow at day 5 and at 48h post mixing, using a sow body map subdivided into anterior, central and posterior body regions. A linear mixed model with day as repeated measure, stall or pen as experimental unit, tested the fixed effects of treatment, day, period within day, their interactions, and block by treatment interaction; stall (trt) or pen (trt) as appropriate was used as random effect. Blood concentration of TRP was higher on the mixing day in TRP-fed sows compared to baseline (76%) and CLT-fed sows at mixing (79%; P<0.05), while serotonin concentration did not differ between treatments (P>0.05). The TRP-enriched diet was effective in reducing sham-chewing in stall housed sows of parity 5-9 (P<0.05). In pens, TRP-fed sows spent more time rooting (TRP=28.0 vs. CTL=20.7+/-1.0%; P<0.05) and consequently less time lying down than CTL-fed sows (TRP=56.1 vs. CTL=65.1+/-2.0%; P<0.05). The total number of offensive actions per interaction was greater in the morning than afternoon for both days (P<0.05), but this was less evident in TRP-fed compared to CTL sows mainly on the morning following mixing (3.4 vs. 7.2+/-1.0, respectively; Trt*period (day)=P<0.05). The average lesion score was lower in the anterior body region of TRP-fed compared to CTL sows (2.1 vs. 2.5+/-0.2; P<0.05), the most affected area during fights. The TRP-enriched diet reduced sow aggression while increasing behavioral activity, as evidenced by more time rooting and standing while sows had fewer offensive actions per agonistic interaction and lower skin lesion score 48h post-mixing. A TRP enriched diet provided to gestating sows for a short period prior to social mixing and continued for a short time after is an effective means of reducing aggression and improving the welfare of sows during group formation. PMID- 24813706 TI - A new silylating reagent - dimethyl(3,3,3-trifluoropropyl)silyldiethylamine - for the derivatisation of non-steroidal anti-inflammatory drugs prior to gas chromatography-mass spectrometry analysis. AB - This paper discusses a new silylating reagent - dimethyl(3,3,3 trifluoropropyl)silyldiethylamine (DIMETRIS) - for the derivatisation of non steroidal anti-inflammatory drugs (NSAIDs) prior to GC-MS analysis. DIMETRIS reacts with seven target compounds (diclofenac, ibuprofen, ketoprofen, naproxen, flurbiprofen and paracetamol, as well as salicylic acid, a degradation product of acetylsalicylic acid) at 30 degrees C for 30min, producing mono-O dimethyltrifluoropropylsilyl (mono-O-DMTFPS) derivatives. The mass spectra of these new derivatives are given and fully interpreted. The usefulness of mono-O DMTFPS derivatives for the qualitative and quantitative analysis of NSAIDs using GC-MS is compared with that of trimethylsilyl and methyl analogues. Methyl derivatives are found to be less appropriate for this purpose because they yield the lowest detector responses during GC-MS measurements. Both silyl derivatives are more suitable for determining such NSAIDs, although the matrix effect with mono-O-DMTFPS derivatives is smaller. Finally, SPE-GC-MS(SIM) based on the derivatisation of NSAIDs by DIMETRIS is evaluated, validated and applied to the determination of these drugs in sea water (Baltic Sea) and wastewater samples collected in Poland. This work confirms that DIMETRIS is suitable for the trace analysis of NSAIDs in real samples and provides an interesting alternative to silylating and methylating reagents. PMID- 24813707 TI - Multivariate data analysis to characterize gas chromatography columns for dioxin analysis. AB - Principal component analysis (PCA) was applied for evaluating the selectivity of 22 GC columns for which complete retention data were available for the 136 tetra- to octa-chlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). Because the hepta- and octa-homologues are easy to separate the PCA was focused on the 128 tetra- to hexa-CDD/Fs. The analysis showed that 21 of the 22 GC columns could be subdivided into four groups with different selectivity. Group I consists of columns with non-polar thermally stable phases (Restek 5Sil MS and Dioxin 2, SGE BPX-DXN, Supelco Equity-5, and Agilent DB-1, DB-5, DB-5ms, VF-5ms, VF-Xms and DB XLB). Group II includes ionic liquid columns (Supelco SLB-IL61, SLB-IL111 and SLB IL76) with very high polarity. Group III includes columns with high-percentage phenyl and cyanopropyl phases (Agilent DB-17 and DB-225, Quadrex CPS-1, Supelco SP-2331, and Agilent CP-Sil 88), and Group IV columns with shape selectivity (Dionex SB-Smectic and Restek LC-50, Supelco betaDEXcst, Agilent VF-Xms and DB XLB). Thus, two columns appeared in both Group I and IV (Agilent VF-Xms and DB XLB). The selectivity of the other column, Agilent DB-210, differs from those of these four groups. Partial least squares (PLS) regression was used to correlate the retention times of the tetra- to hexa-CDD/Fs on the 22 stationary phases with a set of physicochemical and structural descriptors to identify parameters that significantly influence the solute-stationary phase interactions. The most influential physicochemical parameters for the interaction were associated with molecular size (as reflects in the total energy, electron energy, core-core repulsion and standard entropy), solubility (aqueous solubility and n octanol/water partition coefficient), charge distribution (molecular polarizability and dipolar moment), and reactivity (relative Gibbs free energy); and the most influential structural descriptors were related to these parameters, in particular, size and dipolar moment. Finally, the PCA and PLS analyses were complemented with linear regression analysis to identify the most orthogonal column combinations, which could be used in comprehensive two-dimensional gas chromatography (GC*GC) to enhance PCDD/F separation and congener profiling. PMID- 24813709 TI - Akt-ing up on SRPK1: oncogene or tumor suppressor? AB - In this issue of Molecular Cell, Wang et al. (2014) report that the splicing kinase SRPK1 can function as both an oncogene and a tumor suppressor by modulating the activation state of the protein kinase Akt. This is shown to be mediated by the ability of SRPK1 to bind to the Akt phosphatase PHLPP1. PMID- 24813710 TI - Fragile X mental retardation protein and the ribosome. AB - In this issue of Molecular Cell, Chen et al. (2014) provide evidence that FMRP represses translation by binding the ribosome, suggesting a novel form of translational control. PMID- 24813708 TI - The dynamic nature of DNA methylation: a role in response to social and seasonal variation. AB - An organism's ability to adapt to its environment depends on its ability to regulate and maintain tissue specific, temporal patterns of gene transcription in response to specific environmental cues. Epigenetic mechanisms are responsible for many of the intricacies of a gene's regulation that alter expression patterns without affecting the genetic sequence. In particular, DNA methylation has been shown to have an important role in regulating early development and in some human diseases. Within these domains, DNA methylation has been extensively characterized over the past 60 years, but the discovery of its role in regulating behavioral outcomes has led to renewed interest in its potential roles in animal behavior and phenotypic plasticity. The conservation of DNA methylation across the animal kingdom suggests a possible role in the plasticity of genomic responses to environmental cues in natural environments. Here, we review the historical context for the study of DNA methylation, its function and mechanisms, and provide examples of gene/environment interactions in response to social and seasonal cues. Finally, we discuss useful tools to interrogate and dissect the function of DNA methylation in non-model organisms. PMID- 24813711 TI - When breaking is bad but repair is worse. AB - DNA double-strand breaks (DSBs) are a major source of genome instability; however, recent studies from Lee et al. (2014) and Orthwein et al. (2014) show why, at least during mitosis, suppression of DSB repair is important. PMID- 24813712 TI - HDMX folds the nascent p53 mRNA following activation by the ATM kinase. AB - Regulated protein synthesis via changes in mRNA structures forms an important part of how prokaryotic cells adapt protein expression in response to changes in the environment. Little is known regarding how this concept has adapted to regulate mRNA translation via signaling pathways in mammalian cells. Here, we show that following phosphorylation by the ataxia telangiectasia mutated (ATM) kinase at serine 403, the C-terminal RING domain of HDMX binds the nascent p53 mRNA to promote a conformation that supports the p53 mRNA-HDM2 interaction and the induction of p53 synthesis. HDMX and its homolog HDM2 bind the same p53 internal ribosome entry sequences (IRES) structure but with different specificity and function. The results show how HDMX and HDM2 act as nonredundant IRES trans acting factors (ITAFs) to bring a positive synergistic effect on p53 expression during genotoxic stress by first altering the structure of the newly synthesized p53 mRNA followed by stimulation of translation. PMID- 24813713 TI - Transcriptional profiling in dioecious plant Populus cathayana reveals potential and sex-related molecular adaptations to solar UV-B radiation. AB - There is increasing evidence confirming that dioecious plants have evolved a series of sex-related physiological mechanisms allowing acclimation to environmental stresses, but few studies have attempted to thoroughly uncover the potential molecular regulation underlying these responses. Recently, we found in the dioecious plant, Populus cathayana, that males possess a greater tolerance to enhanced UV-B radiation than do females. To continue this work further, comparative transcriptome analyses were carried out. A total of 362 and 296 differentially expressed genes (DEGs) were detected in males and females, respectively. Similarly, as shown in previous studies, these DEGs were involved in a set of conserved functions and pathways related to UV-B stress, regardless of the sex. On the other hand, sex-related responses via transcriptome remodeling were detected, as changes in sex-related gene expression occurred in some pathways. For example, many DEGs involved in amino acid metabolism were mainly upregulated in males but downregulated in females. In some pathways, DEGs were expressed predominantly or exclusively in one sex. This may directly contribute to sex-related physiological responses. Taken together, our results not only provide strong evidence that males and females have adopted sex-related molecular strategies in response to solar UV-B radiation but also suggest many new insights, in particular into molecular regulation, via sex-biased gene expression. We conclude that these results can further enhance the sustainable exploitation and management of P. cathayana plants. PMID- 24813714 TI - Malaria prevention in the pregnant traveller: a review. AB - Malaria is still a major threat to health in tropical regions. Particular attention should be directed to malaria prevention in infants and pregnant women as they are at high risk for plasmodial infection and complicated malaria. In this review, we summarize and discuss current evidence on malaria prevention in pregnant travellers. As neither anti-mosquito measures nor anti-malarial drugs have been proven to be unequivocally safe or toxic in pregnant women, the individual risk assessment should take into account the risk of transmission at the destination, the benefit of travelling despite being pregnant as well as the individual risk perception. All three factors may differ in various groups of travellers like tourist travellers, expatriate travellers as well as those visiting friends and relatives. For pregnant women, mefloquine appears to be the drug of choice for prophylaxis and stand by-therapy if no contraindications exist - despite recent renewed warnings related to prolonged side effects. In areas with high resistance against mefloquine or in women with contraindications to mefloquine, atovaquone-proguanil or artemether-lumefantrine should be considered as an option for stand-by emergency therapy. Nevertheless, evidence on the safety of anti-malarials especially during the first trimester is still insufficient. PMID- 24813715 TI - Imported malaria at Buraidah Central Hospital, Qassim, Saudi Arabia: a retrospective analysis. AB - BACKGROUND: Malaria is a major threat to global health and it is a widespread throughout tropical and subtropical countries with an increasing risk to travellers. METHODS: A retrospective analysis was conducted to investigate the epidemiology of imported malaria at Buraidah in Qassim region, Saudi Arabia during the period of January 2010 through April 2013. RESULTS: There were 46 imported malaria cases. These cases were Plasmodium vivax (89.1%), Plasmodium falciparum (0.02%) and were mixed in 4 cases. Their age range between 14 and 54 and the mean was 29.7 years. Around three quarter (71.2%) of the patients were males. Most of the patients were Indian (54.3%) and Pakistani (23.9%). Over half (54.3%) of the patients had severe malaria, mainly severe anaemia, jaundice and hypotension. There was no mortality among the patients. CONCLUSIONS: Most of the detected malaria cases in this setting were among expatriates, particularly from the Indian subcontinent, while the predominant species was P. vivax. More than 50% of the cases presented with severe malaria. PMID- 24813716 TI - delta-Amyrone, a specific inhibitor of cyclooxygenase-2, exhibits anti inflammatory effects in vitro and in vivo of mice. AB - The whole plant of Sedum lineare Thunb has been used as traditional folk medicines for the treatment of sore throat, persistent hepatitis, jaundice and dysentery. delta-Amyrone (13(18)-Oleanen-3-one), a pentacyclic triterpene compound from S. lineare Thunb, was found to possess a potent anti-inflammatory effect in different inflammation model animals. Pretreatment with delta-Amyrone (i.p.) inhibited the ear edema in xylene-induced mouse ear edema. delta-Amyrone also decreased the level of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6) and leukocyte numbers in acetic acid-induced peritonitis in vivo. To clarify the possible mechanism of delta-Amyrone, we investigated the effect of delta-Amyrone in lipopolysaccharide (LPS) induced peritoneal macrophages. The data indicated that delta-Amyrone notably inhibited IL-6, TNF alpha and NO production. In addition, the result showed that delta-Amyrone may control the cyclooxygenase-2 (COX-2) regulation and not the cyclooxygenase-1 (COX 1) at protein levels. These results suggest that delta-Amyrone is a bioactive agent which possesses anti-inflammatory effects, which may be relevant to the regulation of COX-2. PMID- 24813718 TI - Automatic multiple sclerosis lesion detection in brain MRI by FLAIR thresholding. AB - Magnetic resonance imaging (MRI) is frequently used to detect and segment multiple sclerosis lesions due to the detailed and rich information provided. We present a modified expectation-maximisation algorithm to segment brain tissues (white matter, grey matter, and cerebro-spinal fluid) as well as a partial volume class containing fluid and grey matter. This algorithm provides an initial segmentation in which lesions are not separated from tissue, thus a second step is needed to find them. This second step involves the thresholding of the FLAIR image, followed by a regionwise refinement to discard false detections. To evaluate the proposal, we used a database with 45 cases comprising 1.5T imaging data from three different hospitals with different scanner machines and with a variable lesion load per case. The results for our database point out to a higher accuracy when compared to two of the best state-of-the-art approaches. PMID- 24813717 TI - Laparoscopic skills and cognitive function are not affected in surgeons during a night shift. AB - OBJECTIVE: To monitor surgeons' performance and cognition during night shifts. DESIGN: Surgeons were monitored before call and on call (17-hour shift). Psychomotor performance was assessed by laparoscopic simulation and cognition by the d2 test of attention. The surgeons performed the laparoscopic simulation and the d2 test of attention at 8 a.m. before call and at 4 a.m. on call. Sleep was measured by wrist actigraphy and sleepiness by the Karolinska sleepiness scale. SETTING: Department of Surgery at Herlev Hospital, Denmark. PARTICIPANTS: Overall, 30 interns, residents, and attending surgeons were included and completed the study. One participant was subsequently excluded owing to myxedema. RESULTS: The surgeons slept significantly less on call than before call. There was increasing sleepiness on call; however, no significant differences were found in the precall laparoscopic simulation values compared with on-call values. The d2 test of attention showed significantly improved values on call compared with before call. CONCLUSION: Sleep deprivation during a 17-hour night shift did not impair surgeons' psychomotor or cognitive performance. PMID- 24813719 TI - Cancer risk and all-cause mortality among Norwegian military United Nations peacekeepers deployed to Kosovo between 1999 and 2011. AB - OBJECTIVE: Media reports of leukaemia and other cancers among European United Nations (UN) peacekeepers who served in the Balkans, and a scientific finding of excess Hodgkin lymphoma among Italian UN peacekeepers who served in Bosnia, suggested a link between cancer incidence and depleted uranium (DU) exposure. This spurred several studies on cancer risk among UN peacekeepers who served in the Balkans. Although these studies turned out to be negative, the debate about possible cancers and other health risks caused by DU exposure continues. The aim of the present study was to investigate cancer incidence and all-cause mortality in a cohort of 6076 (4.4% women) Norwegian military UN peacekeepers deployed to Kosovo between 1999 and 2011. METHODS: The cohort was followed for cancer incidence and mortality from 1999 to 2011. Standardised incidence ratios for cancer (SIR) and mortality ratios (SMR) were calculated from national rates. RESULTS: Sixty-nine cancer cases and 38 deaths were observed during follow-up. Cancer incidence in the cohort was similar to that in the general Norwegian population. No cancers in the overall cohort significantly exceeded incidence rates in the general Norwegian population, but there was an elevated SIR for melanoma of skin in men of 1.90 (95% confidence interval [CI] 0.95-3.40). A fivefold increased incidence of bladder cancer was observed among men who served in Kosovo for >= 1 year, based on 2 excess cases (SIR=5.27; 95% CI 1.09-15.4). All-cause mortality was half the expected rate (SMR=0.49; 95% CI 0.35-0.67). CONCLUSION: Our study did not support the suggestion that UN peacekeeping service in Kosovo is associated with increased cancer risk. PMID- 24813720 TI - Peer reviewing: the benefits and value. PMID- 24813721 TI - Bone marrow stromal cell paracrine factors direct osteo/odontogenic differentiation of dental pulp cells. AB - Growth factors play an important role in osteo/odontogenic differentiation of human dental pulp cells (hDPCs). The aim of this in vitro study was to compare the biological effects of recombinant human growth differentiation factor 5 (rhGDF-5) alone and a cocktail of soluble growth factors (conditioned medium) released from human bone marrow mesenchymal stem cells (hBMMSCs) on the morphology, proliferation and osteo/odontogenic differentiation potential of hDPCs. Passage 4 hDPCs were harvested for culture in four different media: (a) DMEM with 10% FBS, (b) odontogenic induction medium (OM), (c) OM plus 500 ng/mL rhGDF-5, and (d) OM plus conditioned medium (CM). Morphological changes at 48 and 120 h were determined by crystal violet staining. The proliferation rates at 3, 24, 48, and 120 h were assayed by MTT. Using real-time reverse transcription polymerase chain reaction (RT-PCR), the mRNA levels of dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1), collagen type I (Col 1), Runt-related transcription factor 2 (Cbfa1/Runx2), alkaline phosphatase (ALP), osteocalcin (OC), beta3 tubulin (TUBB3), glial cell-derived neurotrophic factor (GDNF), angiopoietin-1 (Ang1), and vascular endothelial growth factor A (VEGFA), were determined at 2, 5, and 9 days. Protein expression of dental sialoprotein (DSP), DMP1, OC, and TUBB3 was recorded at 5 days, using western blot and immunocytochemistry. The effect of the different culture media on mineralization was determined by ALP staining at day 5 and Alizarin red S staining at days 7 and 14. In response to the different culture media, the shape of the hDPCs varied from spindled to polygonal and cuboidal. CM inhibited the cellular proliferation rate, while rhGDF-5 had no effect at early time points, but promoted cellular proliferation at 120 h of culture. In the CM group, the mRNA levels of Cbfa1/Runx2, Col 1, ALP, VEGFA, Ang1, and TUBB3 decreased and the levels of GDNF and OC increased. The mRNA levels of DSPP and DMP1 were inconsistent at the time points evaluated. The staining assays also demonstrated that compared with the other groups, the CM group exhibited lower expression of ALP and higher mineralization levels. Protein expression of DSP, DMP1, OC, and TUBB3 was pronounced by the CM-treated cells. It is concluded that under these in vitro conditions, CM released from hBMMSCs have a greater osteo/odontogenic inductive effect on hDPCs than rhGDF-5. PMID- 24813722 TI - Using microsimulation to reassess aging trends in Canada. AB - Population aging is the population issue of the XXI century and many indices are used to measure its level and pace. In Science (2010), Sanderson and Scherbov suggested improvements to the measure of elderly dependency ratio. They identified several limitations to the use of chronological age as the main variable and proposed a new index, the Adult Disability Dependency Ratio, defined as the number of adults at least 20 years old with disabilities divided by the number of similarly aged adults without disabilities. They used the Sullivan prevalence-based method by multiplying derived disability rates to macro population projections. They showed results for several ECE and OECD countries; results for Canada (see online annex, available at https://www.sciencemag.org/content/329/5997/1287/suppl/DC1) were derived using coefficients of Italy. However, disability is a complex multidimensional process (see Carriere, Keefe, Legare, Lin, & Rowe, 2007; Legare and Decarie, 2011), and microsimulation can take into account its implied complexity. Our results for Canada, presented here, exceed those in Science to show how more-sophisticated projections of disabled older adults can improve the analysis. We used LifePaths, a Statistics Canada's microsimulation model, to provide a perspective of the phenomena unobtainable with prevalence-based methods. PMID- 24813723 TI - Exoskeleton formation in Apis mellifera: cuticular hydrocarbons profiles and expression of desaturase and elongase genes during pupal and adult development. AB - Cuticular hydrocarbons (CHCs) are abundant in the superficial cuticular layer (envelope) of insects where they play roles as structural, anti-desiccation and semiochemical compounds. Many studies have investigated the CHC composition in the adult insects. However, studies on the profiles of these compounds during cuticle formation and differentiation are scarce and restrict to specific stages of a few insect species. We characterized the CHCs developmental profiles in the honeybee workers during an entire molting cycle (from pupal-to-adult ecdyses) and in mature adults (forager bees). Gas chromatography/mass spectrometry (GC/MS) analysis revealed remarkable differences in the relative quantities of CHCs, thus discriminating pupae, developing and newly-ecdysed adults, and foragers from each other. In parallel, the honeybee genome database was searched for predicted gene models using known amino acid sequences of insect enzymes catalyzing lipid desaturation (desaturases) or elongation (elongases) as queries in BLASTP analysis. The expression levels of six desaturase genes and ten elongase genes potentially involved in CHC biosynthesis were determined by reverse transcription and real time polymerase chain reaction (RT-qPCR) in the developing integument (cuticle and subjacent epidermis). Aiming to predict roles for these genes in CHC biosynthesis, the developmental profiles of CHCs and desaturase/elongase transcript levels were evaluated using Spearman correlation coefficient. This analysis pointed to differential roles for these gene products in the biosynthesis of certain CHC classes. Based on the assumption that homologous proteins may share a similar function, phylogenetic trees were reconstructed as an additional strategy to predict functions and evolutionary relationships of the honeybee desaturases and elongases. Together, these approaches highlighted the molecular complexity underlying the formation of the lesser known layer of the cuticular exoskeleton, the envelope. PMID- 24813725 TI - Overexpression of OsMYB4P, an R2R3-type MYB transcriptional activator, increases phosphate acquisition in rice. AB - R2R3 MYB transcription factors play regulatory roles in plant responses to various environmental stresses and nutrient deficiency. In this study, we isolated and designated OsMYB4P, an R2R3 MYB transcription factor, from rice (Oryza sativa L. 'Dongjin') under phosphate-deficient conditions. OsMYB4P was localized in the nucleus and acted as a transcriptional activator. Transcriptional levels of OsMYB4P in cell suspension, shoots, and roots of rice increased under phosphate-deficient conditions. Shoots and roots of OsMYB4P overexpressing plants grew well in high- and phosphate-deficient conditions. In addition, root system architecture was altered considerably as a result of OsMYB4P overexpression. Under both phosphate-sufficient and -deficient conditions, more Pi accumulated in shoots and roots of OsMYB4P-overexpressing plants than in the wild type. Overexpression of OsMYB4P led to greater expression of Pi transporter-family proteins OsPT1, OsPT2, OsPT4, OsPT7, and OsPT8 in shoots, and to decreased or unchanged expression of these proteins in roots, with the exception of OsPT8. These results demonstrate that OsMYB4P may be associated with efficient utilization of Pi in rice through transcriptional activation of Pi homeostasis-related genes. PMID- 24813724 TI - Chronic central nervous system expression of HIV-1 Tat leads to accelerated rarefaction of neocortical capillaries and loss of red blood cell velocity heterogeneity. AB - OBJECTIVES: HIV-1 infection of the CNS is associated with impairment of CBF and neurocognitive function, and accelerated signs of aging. As normal aging is associated with rarefaction of the cerebral vasculature, we set out to examine chronic viral effects on the cerebral vasculature. METHODS: DOX-inducible HIV-1 Tat-tg and WT control mice were used. Animals were treated with DOX for three weeks or five to seven months. Cerebral vessel density and capillary segment length were determined from quantitative image analyses of sectioned cortical tissue. In addition, movement of red blood cells in individual capillaries was imaged in vivo using multiphoton microscopy, to determine RBCV and flux. RESULTS: Mean RBCV was not different between Tat-tg mice and age-matched WT controls. However, cortical capillaries from Tat-tg mice showed a significant loss of RBCV heterogeneity and increased RBCF that was attributed to a marked decrease in total cortical capillary length (35-40%) compared to WT mice. CONCLUSIONS: Cerebrovascular rarefaction is accelerated in HIV-1 Tat-transgenic mice, and this is associated with alterations in red cell blood velocity. These changes may have relevance to the pathogenesis of HIV-associated neurocognitive disorders in an aging HIV-positive population. PMID- 24813726 TI - Silicon-mediated changes in polyamine and 1-aminocyclopropane-1-carboxylic acid are involved in silicon-induced drought resistance in Sorghum bicolor L. AB - The fact that silicon application alleviates drought stress has been widely reported, but the mechanism it underlying remains unclear. Here, morphologic and physiological changes were investigated in sorghum (Sorghum bicolor L.) seedlings treated with silicon and exposed to PEG-simulated drought stress for seven days. Drought stress dramatically decreased growth parameters (biomass, root/shoot ratio, leaf area, chlorophyll concentration and photosynthetic rate), while silicon application reduced the drought-induced decreases in those parameters. Leaf relative water content and transpiration rate were maintained at high levels compared to those in seedlings without silicon. The soluble sugar contents were increased, but the proline contents and the osmotic potential were decreased, showing that osmotic adjustment did not contribute to the silicon induced-drought resistance. Furthermore, levels of both free and conjugated polyamines (PAs) levels, including putrescine, spermidine and spermine, were all found to be increased by silicon under drought stress both in leaf and root. Meanwhile, 1 aminocyclopropane-1-carboxylic acid (ACC), the precursor of ethylene, was markedly decreased by supplemental silicon. Several key PA synthesis genes were upregulated by silicon under drought stress. These results suggest that silicon improves sorghum drought resistance by mediating the balance of PAs and ethylene levels. In leaf, the increased PAs and decreased ACC help to retard leaf senescence. In root, the balance between PAs and ACC participates in the modulation of root plasticity, increases the root/shoot ratio, and contributes to an increase in water uptake. These results suggest that silicon increases drought resistance through regulating several important physiological processes in plants. PMID- 24813727 TI - How reactive oxygen species and proline face stress together. AB - Reactive oxygen species (ROS) are continuously generated as a consequence of plant metabolic processes due to incomplete reduction of O2. Previously considered to be only toxic by-products of metabolism, ROS are now known to act as second messengers in intracellular signalling cascades to trigger tolerance of various abiotic and biotic stresses. The accumulation of proline is frequently observed during the exposure of plants to adverse environmental conditions. Interestingly proline metabolism may also contribute to ROS formation in mitochondria, which play notably a role in hypersensitive response in plants, life-span extension in worms and tumor suppression in animals. Here we review current knowledge about the regulation of proline metabolism in response to environmental constraints and highlight the key role of ROS in the regulation of this metabolism. The impact of proline on ROS generation is also investigated. Deciphering and integrating these relationships at the whole plant level will bring new perspectives on how plants adapt to environmental stresses. PMID- 24813728 TI - The desiccation tolerant secrets of Selaginella lepidophylla: what we have learned so far? AB - Selaginella lepidophylla is a desiccation tolerant plant able to survive complete vegetative tissue dehydration and revive ('resurrect') in water conditions. Vegetative desiccation tolerance is an adaptive feature acquired by S. lepidophylla to withstand the long dry periods in its natural habitat, the Chihuahuan desert. Understanding the molecular basis of its drought stress tolerance may be of great benefit to help in developing novel strategies for improvement of drought stress tolerance in crops. Cell biological (e.g. gene discovery, comparative EST analysis, proteomics, metabolite profiling), ultrastructural and physiological studies have brought modest but already important insights in the desiccation tolerance mechanisms adapted by S. lepidophylla. Until recently, the desiccation tolerant mechanism of S. lepidophylla was related to its high trehalose levels. However, large-scale comparative metabolic analysis between S. lepidophylla and its desiccation susceptible relative Selaginella moellendorffii, unexpectedly revealed that S. moellendorffii contains higher trehalose levels than S. lepidophylla. Interestingly, polyols, such as sorbitol and xylitol are 100* more abundant in S. lepidophylla compared to S. moellendorffii. Whether this is linked to the higher stress tolerance remains to be established. Apart from these metabolites, we will also discuss the ultrastructural features that seem to play an important role in the desiccation tolerance of S. lepidophylla. Finally we discuss desiccation tolerance mechanism in other plant species. PMID- 24813729 TI - Antiplasmodial activity of synthetic ellipticine derivatives and an isolated analog. AB - Ellipticine has been shown previously to exhibit excellent in vitro antiplasmodial activity and in vivo antimalarial properties that are comparable to those of the control drug chloroquine in a mouse malaria model. Ellipticine derivatives and analogs exhibit antimalarial potential however only a few have been studied to date. Herein, ellipticine and a structural analog were isolated from Aspidosperma vargasii bark. A-ring brominated and nitrated ellipticine derivatives exhibit good in vitro inhibition of Plasmodium falciparum K1 and 3D7 strains. Several of the compounds were found not to be toxic to human fetal lung fibroblasts. 9-Nitroellipticine (IC50=0.55MUM) exhibits greater antiplasmodial activity than ellipticine. These results are further evidence of the antimalarial potential of ellipticine derivatives. PMID- 24813730 TI - Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKbeta inhibitors. AB - Inactivation of the NF-kappaB signaling pathway by inhibition of IKKbeta is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKbeta inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-alpha, which are well-known inflammatory responses generated by activated NF kappaB. However, no inhibitory activity against IKKbeta was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1MUM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML. PMID- 24813731 TI - Total synthesis and antiplasmodial activity of pohlianin C and analogues. AB - The first synthesis of the glycine-rich cyclic octapeptide pohlianin C is reported, confirming the structure of this natural product. Screening against Plasmodium falciparum reveals moderate antiplasmodial activity, consistent with data obtained from the natural sample. In addition, the synthesis of three analogues reveals that the antiplasmodial activity of pohlianin C can be preserved or increased with simplified structures. PMID- 24813732 TI - Evaluation of the antiviral efficacy of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives against the nucelocapsid protein of the Feline Immunodeficiency Virus (FIV) as a model for HIV infection. AB - A diverse library of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives were prepared for evaluation of activity against the nucleocapsid protein of the Feline Immunodeficiency Virus (FIV) as a model for HIV, using an in vitro cell culture approach, yielding nanomolar active compounds with low toxicity. PMID- 24813733 TI - Phospho-carboxylic anhydride of a homologated nucleoside leads to primer degradation in the presence of a polymerase. AB - Starting from thymidine, through a series of key synthetic transformations (e.g., Wittig reaction, hydroboration, Mitsunobu reaction and TEMPO oxidation) a nucleoside homologue bearing a phospho-carboxylic anhydride group at 6' position was synthesized. The potential of polymerases to catalyze amide bond formation was investigated by using a modified primer with an amino group at 3' position and the synthesized phosphoanhydro compound as substrate. Unfortunately, we did not observe the desired product either by gel electrophoresis or mass spectrometry. In contrast, the instability of the phosphoanhydro compound could lead to pyrophosphate formation and thus, to pyrophosphorolysis of the primer rather than to primer extension. PMID- 24813734 TI - Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase. AB - Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo. PMID- 24813735 TI - Discovery of 1-arylpyrrolidone derivatives as potent p53-MDM2 inhibitors based on molecule fusing strategy. AB - Introducing an aryl moiety to our previous pyrrolidone scaffold by molecule fusing strategy afforded two sets of isopropylether-pyrrolidone and alpha phenylethylamine-pyrrolidone derivatives. Two novel compounds 8b and 8g of the latter serial showed potent p53-MDM2 inhibitory activities with Ki values of 90nM which were three-time higher than that of the parent compound. We also confirmed compound 8b can activate p53 proteins in lung cancer A549 cells. The results offered us valuable information for further lead optimization. PMID- 24813736 TI - Narrow SAR in odorant sensing Orco receptor agonists. AB - The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification. PMID- 24813738 TI - Design and synthesis of lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells. AB - Structure modifications of lupeol at the isopropylene moiety have been described via allylic oxidation using selenium dioxide. The antidiabetic efficacy of lupeol analogues were evaluated in vitro as glucose uptake stimulatory effect in L6 skeletal muscle cells. From all tested compounds, 2, 3, 4b and 6b showed significant stimulation of glucose uptake with respective percent stimulation of 173.1 (p <0.001), 114.1 (p <0.001), 98.3 (p <0.001) and 107.3 (p <0.001) at 10MUM concentration. Stimulation of glucose uptake by these compounds is associated with enhanced translocation of glucose transporter 4 (GLUT4) and activation of IRS-1/PI3-K/AKT-dependent signaling pathway in L6 cells. Structure-activity relationship analysis of these analogues demonstrated that the integrity of alpha,beta-unsaturated carbonyl and acetyl moieties were important in the retention of glucose uptake stimulatory effect. It is therefore proposed that naturally occurring lupeol and their analogues might reduce blood glucose, at least in part, through stimulating glucose utilization by skeletal muscles. PMID- 24813737 TI - Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2. AB - The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts. PMID- 24813739 TI - Pyranocoumarins from Glehnia littoralis inhibit the LPS-induced NO production in macrophage RAW 264.7 cells. AB - A new dihydropyranocoumarin, (+)-cis-(3'S,4'S)-diisobutyrylkhellactone (1), together with five known compounds, 3'-senecioyl-4'-acetylkhellactone (2), 3' isovaleryl-4'-acetylkhellactone (3), 3',4'-disenecioylkhellactone (4), 3' isovaleryl-4'-senecioylkhellactone (5), and 3',4'-diisovalerylkhellactone (6), was isolated from Glehnia littoralis. Their chemical structures were elucidated based on the spectroscopic data interpretation, particularly 1D and 2D NMR data including HMQC and HMBC. All the isolated compounds showed the potential to inhibit LPS-induced nitric oxide production in RAW 264.7 cells with IC50 values ranging from 7.4 to 44.3MUM. PMID- 24813740 TI - Synthesis and antihyperglycemic evaluation of new 2-hydrazolyl-4-thiazolidinone-5 carboxylic acids having pyrazolyl pharmacophores. AB - In the search of new antihyperglycemic agents and following rational approach of drug designing here new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids (4a-g) with pyrazolyl pharmacophore have been synthesized via thia Michael addition reaction of 1-((3-(4-substituted phenyl)-1-phenyl-1H-pyrazol-4 yl)methylene)thiosemicarbazides (3a-g) with maleic anhydride. The required precursors, (3a-g) were obtained by condensing known 3-(4-substituted phenyl)-1 phenyl-1H-pyrazole-4-carbaldehydes (1a-g) with thiosemicarbazide in ethanol. The newly synthesized compounds (4a-g) have been evaluated for the antihyperglycemic activity in sucrose loaded rat model and among these compounds 4d, 4f and 4g have displayed significant antihyperglycemic activity. PMID- 24813741 TI - Multivalent design of long-acting beta(2)-adrenoceptor agonists incorporating biarylamines. AB - A series of potent beta2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical beta2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human beta2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting beta2-agonist discovery programs. PMID- 24813742 TI - Dual carbonic anhydrase/matrix metalloproteinase inhibitors incorporating bisphosphonic acid moieties targeting bone tumors. AB - A set of bisphosphonate matrix metalloproteinase (MMP) inhibitors was investigated for inhibitory activity against several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, some of which are overexpressed in hypoxic tumors. Some of the bisphosphonate revealed to be very potent inhibitors (in the low nanomolar range) of the cytosolic isoform CA II and the membrane-bound CA IX, XII and XIV isozymes, a feature useful for considering them as interesting compounds for bone resorption inhibition applications. We suggest here that it is possible to develop dual enzyme inhibitors bearing bisphosphonate moieties that may target both MMPs and CAs, two families of enzymes involved in tumor formation, growth, and metastasis. PMID- 24813743 TI - Progress in developing a living human tissue-engineered tri-leaflet heart valve assembled from tissue produced by the self-assembly approach. AB - The aortic heart valve is constantly subjected to pulsatile flow and pressure gradients which, associated with cardiovascular risk factors and abnormal hemodynamics (i.e. altered wall shear stress), can cause stenosis and calcification of the leaflets and result in valve malfunction and impaired circulation. Available options for valve replacement include homograft, allogenic or xenogenic graft as well as the implantation of a mechanical valve. A tissue engineered heart valve containing living autologous cells would represent an alternative option, particularly for pediatric patients, but still needs to be developed. The present study was designed to demonstrate the feasibility of using a living tissue sheet produced by the self-assembly method, to replace the bovine pericardium currently used for the reconstruction of a stented human heart valve. In this study, human fibroblasts were cultured in the presence of sodium ascorbate to produce tissue sheets. These sheets were superimposed to create a thick construct. Tissue pieces were cut from these constructs and assembled together on a stent, based on techniques used for commercially available replacement valves. Histology and transmission electron microscopy analysis showed that the fibroblasts were embedded in a dense extracellular matrix produced in vitro. The mechanical properties measured were consistent with the fact that the engineered tissue was resistant and could be cut, sutured and assembled on a wire frame typically used in bioprosthetic valve assembly. After a culture period in vitro, the construct was cohesive and did not disrupt or disassemble. The tissue engineered heart valve was stimulated in a pulsatile flow bioreactor and was able to sustain multiple duty cycles. This prototype of a tissue-engineered heart valve containing cells embedded in their own extracellular matrix and sewn on a wire frame has the potential to be strong enough to support physiological stress. The next step will be to test this valve extensively in a bioreactor and at a later date, in a large animal model in order to assess in vivo patency of the graft. PMID- 24813744 TI - Prevalence and genetic characterization of Toxoplasma gondii infection in bats in southern China. AB - Toxoplasma gondii can infect a wide variety of warm-blooded animals, including bats. Limited information on T. gondii infection in bats is available in China. The objective of the present study was to determine prevalence and genetic diversity of T. gondii infection in bats in southern China. A total of 608 bats representing 12 species, including 120 Aselliscus stoliczkanus, 59 Myotis chinensis, 11 Miniopterus schreibersii, 53 Rhinolophus affinis, 32 Rhinolophus pusillus, 81 Hipposideros armiger, 28 Hipposideros fulvus, 32 Cynopterus brachyotis, 14 Cynopterus sphinx, 45 Eonycteris spelaea, 109 Hipposideros larvatus, and 24 Taphozous melanopogon, were collected from Yunnan and Guangxi provinces, southern China. They were examined for the presence of T. gondii DNA by amplification of the B1 gene using a nested PCR, and the positive samples were genotyped at 11 genetic loci (SAG1, 5'- and 3'-SAG2, alternative SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico) using multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Fifty nine (9.7%) of these bats were detected positive by PCR but only five of these positive DNA samples were completely typed at all loci; of which 4 samples, 2 from A. stoliczkanus, and 2 from H. larvatus, belonged to ToxoDB Genotype #10, and the other one from H. larvatus was identified as ToxoDB Genotype #9 (http://toxodb.org/toxo/). To our knowledge, this is the first report of molecular detection and genetic characterization of T. gondii infection in bats in China. The results show that these bats are potential reservoirs for T. gondii transmission, which may pose a threat to human health. PMID- 24813745 TI - Vertical transmission of Theileria lestoquardi in sheep. AB - This is the first report of an outbreak of Theileria lestoquardi abortion and stillbirth in a mob of 450 ewes in July 2012, during which, approximately 35 late term ewes lost their fetuses over a 5-day period. A dead ewe and her aborted fetus were transported to the Ahvaz Veterinary Hospital for the diagnostic evaluation. The microbial cultures from the ewe vaginal discharges and fetal abomasal contents and the liver were negative. The blood films of the ewe and her fetus contained Theileria piroplasms and the impression smears from ewe liver and fetal spleen were positive for Theileria Koch blue bodies. The DNA was extracted from the liver and spleen of ewe and her fetus, respectively, and analyzed by polymerase chain reaction (PCR) using specific primers derived from the nucleotide sequences of 18S ribosomal DNA (rDNA) gene of T. lestoquardi. A single fragment of 428-bp fragment was amplified. The PCR product was directly sequenced and the alignment of the sequence with similar sequences in GenBank((r)) showed 100% identities with 18S rDNA gene of T. lestoquardi. The present study is the first report of the T. lestoquardi vertical transmission that could be related to the abortion. PMID- 24813746 TI - Relative potency of macrocyclic lactones in in vitro assays with larvae of susceptible and drug-resistant Australian isolates of Haemonchus contortus and H. placei. AB - The present study used in vitro assays to determine the relative potency of commercial macrocyclic lactone (ML) anthelmintics against larvae of drug susceptible and drug-resistant Australian isolates of important parasites of sheep and cattle, Haemonchus contortus and Haemonchus placei, respectively. Cattle pour-on products containing abamectin, ivermectin, eprinomectin, doramectin or moxidectin were diluted in DMSO and used in larval development assays. Abamectin was the most potent chemical (lowest IC50 value) towards the drug-susceptible H. contortus Kirby isolate. The abamectin IC50 was approximately 2-fold lower than those for ivermectin, moxidectin, eprinomectin and doramectin. Moxidectin and abamectin were the most potent chemicals towards the resistant H. contortus Wallangra isolate. This isolate showed resistance ratios up to 70-fold towards eprinomectin. The resistance ratio for this species was lowest with moxidectin (ratio of 4.0-fold). Abamectin was also the most potent chemical towards both drug-susceptible (Bremner) and drug-resistant (Dayboro) H. placei isolates. The larval development assay only showed low levels of resistance for the drug-resistant H. placei, with resistance ratios ranging from 1.7 to 2.0 fold for moxidectin and abamectin, up to 3.3-fold for eprinomectin. This study examined the readily-accessible larval life stages of these parasites in in vitro assays, and, hence, the relationship between our findings and relative drug efficacies in vivo remains to be determined. Despite this, the study accords with some evidence from the use of these anthelmintics in the field in demonstrating the potency of moxidectin and abamectin against ML-resistant H. contortus. The study also highlights the usefulness of eprinomectin as a readily-available compound which is a more sensitive marker for ML resistance in in vitro larval development assays than the other commercial ML compounds examined. PMID- 24813747 TI - Beyond poly(ethylene glycol): linear polyglycerol as a multifunctional polyether for biomedical and pharmaceutical applications. AB - Polyglycerols (sometimes also called "polyglycidols") represent a class of highly biocompatible and multihydroxy-functional polymers that may be considered as a multifunctional analogue of poly(ethylene glycol) (PEG). Various architectures based on a polyglycerol scaffold are feasible depending on the monomer employed. While polymerization of glycidol leads to hyperbranched polyglycerols, the precisely defined linear analogue is obtained by using suitably protected glycidol as a monomer, followed by removal of the protective group in a postpolymerization step. This review summarizes the properties and synthetic approaches toward linear polyglycerols (linPG), which are at present mainly based on the application of ethoxyethyl glycidyl ether (EEGE) as an acetal-protected glycidol derivative. Particular emphasis is placed on the manifold functionalization strategies including, e.g., the synthesis of end-functional linPGs or multiheterofunctional modifications at the polyether backbone. Potential applications like bioconjugation and utilization as a component in degradable biomaterials or for diagnostics, in which polyglycerol acts as a promising PEG substitute are discussed. In the last section, the important role of linear polyglycerol as a macroinitiator or as a highly hydrophilic segment in block co- or terpolymers is highlighted. PMID- 24813748 TI - Advanced diagnostic imaging in privately insured patients: recent trends in utilization and payments. AB - Recent studies have reported that the rate of growth in utilization of noninvasive diagnostic imaging has slowed, with a concomitant reduction in total payments to providers in the Medicare Part B fee-for-service population. Utilization and payment growth trends in commercially insured populations, however, are not as well understood. We used the Truven Health Analytics MarketScan(r) Commercial Claims and Encounters database containing more than 29 million individuals to investigate commercially insured population trends in utilization of and payments for CT, MRI, PET, and ultrasound procedures in the years 2007-2011. We found that imaging use--after a brief downturn in 2010--rose again in 2011, coupled with substantial increases in adjusted payments for all four imaging modalities, raising concerns about future efforts to stem growth in imaging use and associated spending. PMID- 24813749 TI - ICSI pregnancy outcomes following hysteroscopic placement of Essure devices for hydrosalpinx in laparoscopic contraindicated patients. AB - This study investigated the use of hysteroscopic Essure device placement for the treatment of hydrosalpinx-related infertility in patients with laparoscopic contraindications and compared their pregnancy outcomes following assisted conception treatment with those of patients having had laparoscopic tubal ligation. A total of 102 infertile patients were diagnosed with unilateral or bilateral hydrosalpinges: 26 patients had laparoscopic contraindications and were treated hysterscopically and 76 patients were treated laparoscopically. In total, 66 intracytoplasmic sperm injection (ICSI) and 39 frozen embryo transfer (FET) procedures were performed. In the hysteroscopy group, 13 ICSI and eight FET in 16 patients resulted in 10 pregnancies (pregnancy rates 47.6% per transfer and 62.5% per patient), and in the laparoscopy group, 53 ICSI and 31 FET embryo transfers in 54 patients resulted in 36 pregnancies (pregnancy rates 42.9% per transfer and 66.7% per patient). Live birth rates per assisted reproduction procedure were 23.8% (5/21) in the hysteroscopy group and 32.1% (27/84) for the laparoscopy group. The hysteroscopic placement of Essure devices to isolate hydrosalpinx prior to assisted conception treatment produced pregnancy outcomes comparable to those produced following laparoscopic tubal ligation. The live birth rates indicate that a larger, more comparative, prospectively randomized study is required. Infertile patients with tubal disease require surgical treatment before they can continue with fertility treatment. There are two main surgical methods that can be used, hysteroscopic and laparoscopic, the latter being the standard surgical method. However, some patients have disease that makes the use of laparoscopy inappropriate. For these patients the placement of Essure(r) devices by hysteroscopic surgery maybe the most suitable treatment method. One hundred and two patients were diagnosed with unilateral or bilateral hydrosalpinges - tubal disease. Twenty six patients had to have hysterscopic surgery and 76 patients had laparoscopic surgery. After their tubal surgery some patients continued to have fertility treatment, 66 ICSI and 39 frozen embryo transfers (FET) were performed. Thirteen ICSI and 8 FET embryo transfers in 16 patients from the hysteroscopy group resulted in 10 pregnancies, a 47.6% per transfer and 62.5% per patient pregnancy rate. Fifty three ICSI and 31 FET embryo transfers in 54 patients from the laparoscopic group resulted in 36 pregnancies, a 42.9% per transfer and 66.7% per patient rate. Live birth rates per ART procedure were 23.8% (5/21) in the hysteroscopic group compared with 32.1% (27/84) for the laparoscopic group. The hysteroscopic placement of Essure(r) devices for tubal disease prior to fertility treatments resulted in pregnancy outcomes that were comparable to the outcomes obtained following laparoscopic surgery. PMID- 24813750 TI - Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development. AB - Developmental toxicity caused by exposure to a mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviours, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase susceptibility of offspring to diseases. There is evidence to suggest that the developmental toxicological mechanisms of chemicals and lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased ROS generation overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Data on the involvement of oxidative stress in the mechanism of developmental toxicity following exposure to environmental pollutants are reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on post-natal development and health outcomes. Developmental toxicity caused by exposure to mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides and heavy metals, as well as unhealthy lifestyle behaviors, mainly tobacco smoking, alcohol consumption and medical drug abuse, are major factors that adversely influence prenatal development and increase the susceptibility of offspring to development complications and diseases. There is evidence to suggest that the developmental toxicological mechanisms of human-made chemicals and unhealthy lifestyle factors involve the generation of reactive oxygen species (ROS) and cellular oxidative damage. Overproduction of ROS induces oxidative stress, a state where increased generation of ROS overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules. Exposure to various environmental pollutants induces synergic and cumulative dose additive adverse effects on prenatal development, pregnancy outcomes and neonate health. Data from the literature on the involvement of oxidative stress in the mechanism of developmental toxicity following in vivo exposure to environmental pollutants will be reviewed in an attempt to provide an updated basis for future studies on the toxic effect of such pollutants, particularly the notion of increased risk for developmental toxicity due to combined and cumulative exposure to various environmental pollutants. The aims of such studies are to better understand the mechanisms by which environmental pollutants adversely affect conceptus development and to elucidate the impact of cumulative exposures to multiple pollutants on postnatal development and health outcomes. PMID- 24813751 TI - State-mandated insurance coverage is associated with the approach to hydrosalpinges before IVF. AB - The aim of this study was to determine whether practice in states with infertility insurance mandates is associated with physician-reported practice patterns regarding hydrosalpinx management in assisted reproduction clinics. A cross-sectional, internet-based survey of 442 members of Society for Reproductive Endocrinology and Infertility or Society of Reproductive Surgeons was performed. Physicians practising in states without infertility insurance mandates were more likely to report performing diagnostic surgery after an inconclusive hysterosalpingogram than physicians practising in states with mandates (RR 1.2, 95% CI 1.1-1.3, P < 0.01). Additionally, respondents in states without mandates were more likely to report that, due to lack of infertility insurance coverage, they did not perform salpingectomy (SPX) or proximal tubal occlusion (PTO) before assisted reproduction treatment (RR 1.4, 95% CI 1.1-1.8, P = 0.01). Finally, respondents in states without mandates were less likely to report that the presence of assisted reproduction treatment coverage determined the urgency with which they pursued SPX or PTO before treatment (RR 0.7, 95% CI 0.5-1.0, NS). These results persisted after controlling for physician years in practice, age and clinic volume. In conclusion, self-reported physician practice interventions for hydrosalpinges before assisted reproduction treatment may be associated with state-mandated infertility insurance. Fallopian tube dysfunction is a known cause of infertility and severe dysfunction is manifested by dilation and occlusion, known as hydrosalpinx. Outcomes with assisted reproductive techniques (ART) are lower when hydrosalpinges are present and while there are several theories for this, reproductive specialist recommend "neutralizing" the tube either by occlusion or removal in order to enhance pregnancy rates. In the United States, coverage for infertility services is not uniform with only 15 states having some legislation requiring infertility benefits. Some states where ART is covered liberally, physicians might have different practice patterns related to the neutralization of hydrosalpinges compared to those who are in non -mandated states. We utilized a survey of over 400 providers in the United States to examine their practice patterns as it relates to hydrosalpinges based on which state they practice in and whether or not that state has mandated coverage of not. PMID- 24813752 TI - Combined coenzyme Q10 and clomiphene citrate for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome. AB - This prospective randomized controlled trial evaluated the effect of combined oral coenzyme Q10 (CoQ10) and clomiphene citrate for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome (PCOS). A total of 101 infertile women with PCOS resistant to clomiphene citrate were randomized either to combined CoQ10 and clomiphene citrate (51 patients, 82 cycles) or to clomiphene citrate alone (50 patients, 71 cycles). The outcome measures were number of follicles, serum oestradiol, serum progesterone, endometrial thickness and ovulation, clinical pregnancy and miscarriage rates. Numbers of follicles >14 mm and >=18 mm were significantly higher in the CoQ10 group. Endometrial thickness on the day of human chorionic gonadotrophin was significantly greater in the CoQ10 group (8.82 +/- 0.27 mm versus 7.03 +/- 0.74 mm). Ovulation occurred in 54/82 cycles (65.9%) in the CoQ10 group and 11/71 cycles (15.5%) in the control group. Clinical pregnancy rate was significantly higher in the CoQ10 group (19/51, 37.3%) versus the control group (3/50, 6.0%). Combination of CoQ10 and clomiphene citrate in the treatment of clomiphene-citrate-resistant PCOS patients improves ovulation and clinical pregnancy rates. It is an effective and safe option and can be considered before gonadotrophin therapy or laparoscopic ovarian drilling. PMID- 24813753 TI - Long-term follow up of couples initially randomized between immobilization and immediate mobilization subsequent to IUI. AB - A previous randomized clinical trial compared immobilization for 15 min with immediate mobilization subsequent to intrauterine insemination (IUI) and showed higher ongoing pregnancy rates in couples immobilizing subsequent to IUI. The current study compared the long-term effectiveness of immobilization subsequent to IUI. All couples (n = 391) included in the trial were followed for 3 years after randomization and pregnancies and treatments were recorded. After the initial trial period, couples in both groups were offered treatment according to local protocol. The primary outcome was an ongoing pregnancy during the 3 years after the initial trial. In this time period, there were 143 ongoing pregnancies in the immobilization group (n = 199 couples) and 112 ongoing pregnancies in the immediate mobilization group (n = 192). The ongoing pregnancy rates were 72% and 58%, respectively (relative risk 1.2, 95% CI 1.1-1.4). The persistent significant difference in ongoing pregnancy rates underpins the importance of immobilization after IUI. There is no valid reason to withhold women from immobilizing for 15 min after IUI. PMID- 24813754 TI - Proteomics, oxidative stress and male infertility. AB - Oxidative stress has been established as one of the main causes of male infertility and has been implicated in many diseases associated with infertile men. It results from high concentrations of free radicals and suppressed antioxidant potential, which may alter protein expression in seminal plasma and/or spermatozoa. In recent years, proteomic analyses have been performed to characterize the protein profiles of seminal ejaculate from men with different clinical conditions, such as high oxidative stress. The aim of the present review is to summarize current findings on proteomic studies performed in men with high oxidative stress compared with those with physiological concentrations of free radicals, to better understand the aetiology of oxidative stress-induced male infertility. Each of these studies has suggested candidate biomarkers of oxidative stress, among them are DJ-1, PIP, lactotransferrin and peroxiredoxin. Changes in protein concentrations in seminal plasma samples with oxidative stress conditions were related to stress responses and to regulatory pathways, while alterations in sperm proteins were mostly associated to metabolic responses (carbohydrate metabolism) and stress responses. Future studies should include assessment of post-translational modifications in the spermatozoa as well as in seminal plasma proteomes of men diagnosed with idiopathic infertility. Oxidative stress, which occurs due to a state of imbalance between free radicals and antioxidants, has been implicated in most cases of male infertility. Cells that are in a state of oxidative stress are more likely to have altered protein expression. The aim of this review is to better understand the causes of oxidative stress-induced male infertility. To achieve this, we assessed proteomic studies performed on the seminal plasma and spermatozoa of men with high levels of oxidative stress due to various clinical conditions and compared them with men who had physiological concentrations of free radicals. A variety of sperm and seminal plasma proteins were found to be expressed either in abundance (over expressed) or in a lesser amount (underexpressed), while other proteins were found to be unique either to men with oxidative stress or to men with a balanced ratio of antioxidants/free radicals. Each study included in this review suggested several proteins that could possibly act as biomarkers of oxidative stress induced male infertility, such as protein DJ-1, PIP, lactotransferrin and peroxiredoxin. Pathway analysis performed in these studies revealed that the changes in seminal plasma proteins in men with oxidative stress could be attributed to stress responses and regulatory pathways, while changes in sperm proteins were linked to stress responses and metabolic responses. Subsequent studies could look into post-translational modifications in the protein profile of men with idiopathic infertility. We hope that the information in this review will contribute to a better understanding of the main causes of idiopathic male infertility. PMID- 24813755 TI - Multicentre study of the clinical relevance of screening IVF patients for carrier status of the annexin A5 M2 haplotype. AB - Thrombophilia and impaired placental vasculature are a major cause of adverse pregnancy outcome. In 2007, a new hereditary factor for obstetric complications and recurrent pregnancy loss (RPL) was identified as a sequence variation in the core promoter of the annexin A5 gene, ANXA5, called the M2 haplotype. M2 carriership has been demonstrated in couples with recurrent miscarriage and its origin is embryonic rather than specifically maternal, confirmed by subsequent papers. The M2 haplotype is the first report of a hereditary factor related to pregnancy pathology caused by embryonic-induced anticoagulation. It has been demonstrated that couples with RPL had equal and significantly increased M2 carriership and that maternal and paternal carriership confers equal risk. Given its importance for patients with RPL, and potentially implantation failure, this study assessed the incidence of carrier status for the M2 ANXA5 haplotype in both the male and female of couples attending five CARE IVF centres. In 314 patients (157 couples), 44% of couples (one or both partners), 24% of females, 26% of males and 37% of couples with unexplained infertility were M2 carriers. This high incidence has provoked further urgent studies on specific patient populations and on the value of post embryo-transfer therapy. PMID- 24813756 TI - Progesterone elevation on the day of HCG administration may affect rescue ICSI. AB - To investigate the relationship between serum progesterone concentration on the day of human chorionic gonadotrophin (HCG) administration and rescue intracytoplasmic sperm injection (ICSI), a total of 9858 patients who underwent IVF or rescue ICSI were retrospectively analysed. The results showed a significant difference in serum progesterone concentration on the day of HCG administration between the IVF group and rescue ICSI group (P < 0.01). Multivariate logistic regression showed that progesterone concentration was positively and significantly associated with rescue ICSI (OR 1.297, 95% CI 1.153 1.460, P < 0.001). Moreover, an increased rescue ICSI rate was associated with progressively higher progesterone concentrations in all cycles. In addition, patients with progesterone >1.5 ng/ml demonstrated a significantly higher rescue ICSI rate compared with patients with progesterone concentration <=1.5 ng/ml (P < 0.05). In conclusion, elevated progesterone on the day of HCG administration had an adverse effect on oocyte fertilization; thus, greater attention should be paid to these patients in an attempt to avoid fertilization failure, especially when progesterone is >1.50 ng/ml. For the issue of oocytes fertilization, most literatures have found the presence of a negative association between P elevation and fertilization. They suggested that P elevation may only influence the endometrium, leading to impaired endometrial receptivity and had no adverse effect on the fertilization of oocytes. On the contrary, we enrolled 9,858 fresh cycles and found elevated P had an adverse effect on the oocytes fertilization, especially if the P concentration >1.50 ng/mL. It is the first report about the relationship between the rescue ICSI and serum P levels. PMID- 24813757 TI - Influence of ovarian stimulation for IVF/ICSI on the antioxidant defence system and relationship to outcome. AB - Ovarian stimulation is used with IVF/intracytoplasmic sperm injection (ICSI) cycles to obtain multiple oocytes and improve pregnancy rates; however, it also induces perturbation in the oxidant-antioxidant balance leading to oxidation stress. The present study monitored the plasma antioxidant status in women undergoing a long agonist protocol of ovarian stimulation at three different time points: at baseline (T0), after pituitary suppression (T1) and on the day of oocyte retrieval (T2). The antioxidant composition of follicular fluid samples collected on T2 was also evaluated. Significant decreases (P < 0.05) of plasma vitamin C, vitamin E and carotenoids were found between T1 and T2 but not between T0 and T1. At T2, high plasma vitamin E was associated with high numbers of total and mature oocytes retrieved per patient, which, in turn, were favourable for achieving pregnancy. Accordingly, women who became pregnant presented higher vitamin E concentrations both in plasma and FF than those who did not. In conclusion, this study confirmed the occurrence of significant modifications of the plasma antioxidant profile during ovarian stimulation with gonadotrophins; at the same time, it was found that both systemic and follicular antioxidant status may be related to IVF/ICSI outcome. PMID- 24813758 TI - Evidence-based research and practice: attitudes of reproduction nurses, counsellors and doctors. AB - The importance of providing evidence-based health care in reproduction medicine has resulted in a wealth of research which has largely focused on patient outcomes. Comparatively little is known about the knowledge and attitudes of health professionals who are often required to contribute to research. This study sought to examine the knowledge and attitudes to research of reproductive medicine health professionals and to explore the motivators and barriers to participating in research. A cross-sectional online survey was developed from previous research. The survey was distributed to members of the Fertility Society of Australia between November 2012 and February 2013. Ninety-six health professionals consented to participate and completed the questionnaire. The majority acknowledged the importance of research in informing practice and improving patient outcomes. While many clinicians expressed an interest in participating in research, time and resources were acknowledged as barriers that hindered their involvement. Collaborations with academics may offer a pathway to building the evidence to improve patient care. There is increasing focus on improving patient outcomes from reproductive treatment by using research to inform clinical practice. However little is known about the views of reproductive nurses, counsellors and doctors about the role of research in their day to day clinical work. This study examined the knowledge and attitudes to research of reproductive medicine health professionals, and explored factors that may motivate or create barriers to their involvement in research. We conducted a survey in Australia between November 2012 and February 2013. Ninety-six health professionals consented to participate and completed the questionnaire. The majority indicated the importance of research influencing their clinical practice, and the role research has with improving patient outcomes. Many clinicians indicated they would like to participate in research, however time and resources were acknowledged as barriers which stopped their involvement. PMID- 24813759 TI - Physical activity before IVF and ICSI cycles in infertile obese women: an observational cohort study. AB - This study assessed the relationship between regular physical activity and reproductive performance in obese infertile patients who receive assisted reproduction cycles with stable bodyweight. A total of 216 obese infertile women at their first fresh assisted reproduction attempt with stable body mass index (BMI) and available data on their physical activity carried out up to the beginning of the treatment cycle were enrolled in this observational cohort study. Clinical and biological data were recorded and analysed. There were 41 obese patients who did regular physical activity and 175 obese controls who did not. Total pregnancies (16/41, 39.0% versus 28/175, 16.0%, respectively; P = 0.002) and live births (10/41, 24.4% versus 13/175, 7.4%, respectively; P = 0.004) were significantly higher in patients who did physical activity regularly compared with those who did not. After adjusting for confounders, in obese infertile patients who did physical activity regularly, the relative risks for a clinical pregnancy and live birth were 3.22 (95% CI 1.53-6.78; P = 0.002) and 3.71 (95% CI 1.51-9.11; P = 0.004), respectively. In conclusion, regular physical activity carried out before a assisted reproduction cycle is significantly related with improved reproductive performance in obese infertile patients, irrespective of bodyweight loss. Body weight loss improves not only spontaneous pregnancy rates but also those of assisted reproductive techniques (ARTs). Moreover, almost all studies refer to body weight loss due to lifestyle intervention programs consisting in hypocaloric diet and increased physical activity. Instead, very little is known about the specific effects of physical activity alone on human reproduction. Based on these considerations, we designed the present study to assess the relationship between regular physical activity and reproductive outcome in infertile obese patients who receive ARTs. Two hundred-sixteen obese infertile women with stable body mass index (BMI) and at their first fresh ART attempt were enrolled, and clinical and biological data were recorded and analyzed. Our results demonstrate that the chances to obtain a pregnancy and a baby are 3-fold higher in obese infertile patients who does physical activity regularly in comparison with those who does not, suggesting that regular physical activity before ART cycles improves the reproductive performance in obese women irrespective to body weight loss. PMID- 24813760 TI - Safety of PVAP and PVAP-T including a 90-day dietary toxicity study in rats and genotoxicity tests with polyvinyl acetate phthalate (PVAP). AB - The safety of PVAP was evaluated in a 90-day subchronic toxicity study in rats. Sprague Dawley Crl:CD(SD) rats were administered a dietary concentration of 0.75%, 1.5% and 5.0% PVAP for a minimum of 90days. There were no adverse effects reported. The no-observed-adverse-effect level (NOAEL) in the 90-day sub chronic study was the 5% dietary concentration, which corresponds to a dose of 3120mg/kg/day for males and 3640mg/kg/day for females, the highest level tested. PVAP is co-processed with titanium dioxide to produce polyvinyl acetate phthalate and titanium dioxide (PVAP-T). The chemical composition, physiochemical properties and specifications of PVAP-T are unchanged during manufacturing process based on various analytical studies. Therefore, the toxicological data that support the safety of PVAP can be used to support the use of PVAP-T as a pharmaceutical excipient. An independent expert panel evaluated the safety of PVAP and PVAP-T. Based on the toxicology study results, safety assessment and the estimated exposure assessment for PVAP and PVAP-T, the expert panel concluded that PVAP and PVAP-T could safely be used in drug products up to 829mg per day which was the estimated exposure provided to the expert panel for current applications of PVAP and PVAP-T. PMID- 24813761 TI - A market basket survey of As, Zn and Se in rice imports in Qatar: health implications. AB - Qatar is dependent on importation of rice, its staple dish, and is therefore susceptible to compromises of food quality in the global market. This market basket study assesses potential health risks of As exposure from rice consumption in Qatar and examines its contribution to the recommended nutritional intakes (RNI) for Zn and Se. Fifty-six rice types and 12 products sold in Qatar were analyzed by ICP/MS. Mean concentrations and ranges were 96.2+/-54.1MUg/kg (9.76 258MUg/kg) for As; 12.5+/-5.35mg/kg (2.79-29.9mg/kg) for Zn and 103+/-113MUg/kg (<5.94-422MUg/kg) for Se. Calculated risk quotient shows rice consumption in Qatar is not a significant route of As exposure but can contribute up to 100% and 50% of the RNI for Se and Zn, respectively. Results indicate that children in Qatar may be at elevated risk of arsenic exposure from rice-based infant cereals but more data is needed to obtain a definitive assessment. PMID- 24813762 TI - Evidence for horizontal gene transfer, gene duplication and genetic variation as driving forces of the diversity of haemolytic phenotypes in Photobacterium damselae subsp. damselae. AB - Photobacterium damselae subsp. damselae, a marine bacterium that causes infections in marine animals and in humans, produces up to three different haemolysins involved in virulence, which include the pPHDD1 plasmid-encoded damselysin (Dly) and HlyApl , and the chromosome-encoded HlyAch . We screened 45 isolates from different origins, and found a correlation between their haemolytic phenotypes and the differential haemolysin gene content. All highly and medium haemolytic strains harboured pPHDD1, with amino acid substitutions in HlyApl and HlyAch being the cause of the medium haemolytic phenotypes in some pPHDD1 harbouring strains. Weakly haemolytic strains contained only hlyAch , whereas nonhaemolytic isolates, in addition to lacking pPHDD1, either lacked hlyAch or contained a hlyAch pseudogene. Sequence analysis of the genomic context of hlyAch uncovered an unexpected genetic diversity, suggesting that hlyAch is located in an unstable chromosomal region. Phylogenetic analysis suggested that hlyApl and hlyAch originated by gene duplication within P. damselae subsp. damselae following acquisition by horizontal transfer. These observations together with the differential distribution of pPHDD1 plasmid among strains suggest that horizontal gene transfer has played a main role in shaping the haemolysin gene baggage in this pathogen. PMID- 24813764 TI - Relapsed/refractory diffuse large B-cell lymphoma: review of the management of transplant-eligible patients. AB - Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is difficult to treat, with limited therapeutic options. Review of prognostic indices, DLBCL genetic classification, previous rituximab exposure, interval from previous therapy, chemosensitivity to salvage therapy and response on imaging is helpful when deciding upon appropriate candidates for further therapy. For appropriately selected patients, the primary strategy is to obtain remission with salvage therapy and proceed to autologous stem cell transplant (ASCT). However, salvage therapy and transplant conditioning regimens are suboptimal, as are therapeutic options for patients who relapse following ASCT. Recent research highlights the ongoing difficulty in the treatment of relapsed/refractory DLBCL, and novel treatments are needed. PMID- 24813765 TI - Young adult females' views regarding online privacy protection at two time points. AB - PURPOSE: Risks associated with adolescent Internet use include exposure to inappropriate information and privacy violations. Privacy expectations and policies have changed over time. Recent Facebook security setting changes heighten these risks. The purpose of this study was to investigate views and experiences with Internet safety and privacy protection among older adolescent females at two time points, in 2009 and 2012. METHODS: Two waves of focus groups were conducted, one in 2009 and the other in 2012. During these focus groups, female university students discussed Internet safety risks and strategies and privacy protection. All focus groups were audio recorded and manually transcribed. Qualitative analysis was conducted at the end of each wave and then reviewed and combined in a separate analysis using the constant comparative method. RESULTS: A total of 48 females participated across the two waves. The themes included (1) abundant urban myths, such as the ability for companies to access private information; (2) the importance of filtering one's displayed information; and (3) maintaining age limits on social media access to avoid younger teens' presence on Facebook. CONCLUSIONS: The findings present a complex picture of how adolescents view privacy protection and online safety. Older adolescents may be valuable partners in promoting safe and age-appropriate Internet use for younger teens in the changing landscape of privacy. PMID- 24813766 TI - Palmoplantar pustulosis--a retrospective review of comorbid conditions. PMID- 24813767 TI - Cofilin/actin rod formation by dysregulation of cofilin-1 activity as a central initial step in neurodegeneration. AB - Cofilin-1 protein, which main function is to regulate actin cytoskeleton dynamics, appears to be involved with many steps in the neurotoxicity processes found in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the dynamics of actin filaments play a major role in several cellular processes, the primary involvement of cofilin-1 dysfunctions in the pathophysiology of these disorders may be related to a cytoskeleton stress. However, recently cofilin-1 has also been related to other biological processes such as cell death by apoptosis. In both cases, ATP depletion associated with the presence of reactive species and other stressors regulate cofilin-1 by inducing the formation of aggregates composed primarily by actin and cofilin-1, known as cofilin/actin rods. These structures seem to be formed initially as a neuroprotective response to mitochondrial damage; but once the stressor persists they are thought to act as inducers of further impairments and loss of neuronal functions. Therefore, here we provide a brief overview of the current knowledge about the central role of cofilin/actin rods formation, where its dysregulation and malfunction might be the trigger to neurodegeneration. PMID- 24813768 TI - Utility of soil linear alkylbenzenes to assess regional anthropogenic influences with special reference to atmospheric transport. AB - Tracing regional anthropogenic influences is important for assessing the magnitude of human interferences with the environment. In the present study, the utility of soil linear alkylbenzenes (LABs) as indicators of anthropogenic influences was examined, with the emphasis on the role of atmospheric transport in dissipating LABs from input sources to remote areas. The Pearl River Delta, South China, which has experienced rapid economic growth and urbanization, was selected as the study region. The concentrations of LABs (mean: 8.6 ng/g and median: 5.7 ng/g, with an outlier of 2,020 ng/g excluded) suggested that sewage contamination throughout the entire study region was generally light. The spatial variation of sewage pollution was significantly positively correlated with population density and per capita gross domestic product, with hot spots concentrated in the central PRD. Atmospheric deposition was hypothesized as an important input route for soil LABs in forestry and drinking water source areas with little impact of irrigation or direct wastewater discharge. This proposition could explain the opposite spatial patterns of LAB concentrations and values of a biodegradation index (5-C12+5-C13)/(5-C11+5-C10), where i-Cn defines a specific LAB congener with i and n indicating the position of the phenyl group and the number of carbon atoms on the alkyl chain, respectively. These findings somewhat validated LABs as tracers of regional anthropogenically derived contamination, with atmospheric transport of LABs as a viable dissipating mechanism. PMID- 24813769 TI - Toxicity and bioconcentration of the pharmaceuticals moxifloxacin, rosuvastatin, and drospirenone to the unionid mussel Lampsilis siliquoidea. AB - Pharmaceuticals and personal care products (PPCPs) and their metabolites are continually released from wastewater treatment plants into the aquatic environment; however, their impact on aquatic biota is poorly understood. This study examined the toxicity and bioconcentration of three pharmaceuticals: moxifloxacin, rosuvastatin, and drospirenone to the unionid mussel Lampsilis siliquoidea. Effects of moxifloxacin and rosuvastatin were assessed through aqueous 21-d static-renewal tests using 2-year-old mussels, at 0.01, 0.1, 1, 10 and 100mg/L (nominal concentrations). Following exposure, survival, behavior, algal clearance rate, hemocyte viability and density, and glutathione S transferase (GST) activity were assessed. In addition, the acute (48 h) toxicity of moxifloxacin (0-100mg/L) and drospirenone (0-3mg/L) to glochidia (larval mussels) were examined. In 21 day exposures (2-yr old mussels), there were no differences in survival, oxygen consumption, hemocyte density, or GST activity over the range of concentrations examined; however, the proportion of time mussels spent filtering, and consequently the algal clearance rate, decreased at the higher moxifloxacin and rosuvastatin concentrations. Bioconcentration factors (BCFs) ranged between 0.03 and 70 for moxifloxacin, and between 0 and 0.05 for rosuvastatin for exposures up to 100mg/L. The BCF for moxifloxacin at the highest exposure concentration was lower than that at the mid-level concentrations, likely due to decreased filtering activity at the higher exposure levels. The feeding rates declined and the amount of time the subadult mussels spent with their valves closed increased at the higher moxifloxacin and rosuvastatin exposures. Glochidia viability did not vary with exposure to drospirenone, but declined at the highest moxifloxacin concentration, resulting in an EC50 of 120 mg/L. Overall, observed sublethal and lethal effects occurred at concentrations which exceed expected environmental concentrations through aqueous exposure, suggesting a low risk to freshwater mussels from these particular PPCPs. PMID- 24813770 TI - Aging effect on Zn retention on a calcareous soil: column experiments and synchrotron X-ray micro-spectroscopic investigation. AB - In this study, a combination of column experiments and micro-analytical techniques exploiting synchrotron generated X-rays was used to assess the effect of aging time on Zn retention and mobility in the specific case of calcareous soils (high pH value, ~ 8). The samples were subjected to aging for 2, 6, 17, and 63 days. Freshly added Zn mainly existed as an exchangeable form, and this metal fraction decreased over time due to Zn redistribution to stronger binding sites. Thus, after aging for 63 days, 45% of Zn is remobilized from exchangeable sites to stronger binding sites. MU-XRF maps were used to find correlations among elements in the sample, and MU-XANES spectra were recorded to precise Zn speciation. These analyses evidenced an increasing partitioning of Zn from organic matter to iron oxy(hydr)oxides over time. The occurrence of hydrozincite is evidenced in all samples. PMID- 24813771 TI - Isotopic evidence for anthropogenic impacts on aquatic food web dynamics and mercury cycling in a subtropical wetland ecosystem in the US. AB - Quantifying and predicting the food web consequences of anthropogenic changes is difficult using traditional methods (based on gut content analysis) because natural food webs are variable and complex. Here, stable and radioactive carbon isotopes are used, in conjunction with nitrogen isotopes and mercury (Hg) concentration data, to document the effects of land-use change on food webs and Hg bioaccumulation in the Everglades - a subtropical wetland ecosystem in the US. Isotopic signatures of largemouth bass and sunfish in reference (relatively pristine) wetlands indicate reliance on the food supply of modern primary production within the wetland. In contrast, both fish in areas impacted by agricultural runoff had radiocarbon ages as old as 540 years B.P., and larger isotopic variability than counterparts in reference wetlands, reflecting differences in the food web between impacted and reference wetlands. Consistent with this difference, particulate and dissolved organic matter in impacted areas had old radiocarbon ages (>600 years B.P.), indicating that old carbon derived from historic peat deposits in the Everglades Agricultural Area was passed along the food chain to consumers. Significant radiocarbon deficiencies in largemouth bass and sunfish, relative to mosquitofish, in impacted areas most likely indicate a reduced dependence on small fish. Furthermore, largemouth bass and sunfish from impacted areas had much lower Hg contents than those from reference wetlands. Taken together, these data suggest a shift toward lower trophic levels and a possible reduction in mercury methylation in impacted wetlands. Our study provides clear evidence that hydrological modification and land-use change in the Everglades have changed the system from one driven primarily by in-situ productivity to one that is partially dependent on allochthonous carbon input from peat soils in the agricultural area and altered the Hg biogeochemical cycle in the wetlands. The results have implications for the restoration and management of wetland ecosystems. PMID- 24813772 TI - OBIA based hierarchical image classification for industrial lake water. AB - Water management is very important in water mining regions for the sustainability of the natural environment and for industrial activities. This study focused on Acigol Lake, which is an important wetland for sodium sulphate (Na2SO4) production, a significant natural protection area and habitat for local bird species and endemic species of this saline environment, and a stopover for migrating flamingos. By a hierarchical classification method, ponds representing the industrial part were classified according to in-situ measured Baume values, and lake water representing the natural part was classified according to in-situ measurements of water depth. The latter is directly related to the water level, which should not exceed a critical level determined by the regulatory authorities. The resulting data, produced at an accuracy of around 80%, illustrates the status in two main regions for a single date. The output of the analysis may be meaningful for firms and environmental researchers, and authorizations can provide a good perspective for decision making for sustainable resource management in the region which has uncommon and specific ecological characteristics. PMID- 24813773 TI - Novel retromandibular subparotideomasseteric fascial approach for placement of a temporomandibular joint prosthesis. AB - For placement of a temporomandibular joint prosthesis, preauricular and retromandibular approaches are used. The main complication of the retromandibular approach is marginal mandibular nerve damage. In this technical study, the retromandibular subparotideomasseteric fascial approach is introduced as an alternative to avoid the complications of the conventional retromandibular approach. PMID- 24813774 TI - Cardiac metastases from head and neck cancer mimicking a myocardial infarction. AB - Cardiac metastases from head and neck cancer are rare. We present 2 patients with primary head and neck cancer found to have cardiac metastases. Electrocardiograms showed a persistent acute infarction pattern due to myocardial tumor infiltration. No cardiac symptoms were present. Both patients died of metastatic disease. PMID- 24813775 TI - Clinicopathologic features of oral squamous cell carcinoma: do they vary in different age groups? AB - PURPOSE: To analyze clinicopathologic parameters of oral squamous cell carcinoma (OSCC) in different age groups. We hypothesized that clinical and pathologic parameters of OSCCs will vary in different age groups. MATERIALS AND METHODS: A retrospective cohort study was performed. All patients who were treated for a primary manifestation of OSCC at a single institution from 2001 to 2012 were reviewed and allocated to predefined age groups (predictor variable) as follows: young (<=40 years), middle-aged (40-80 years), and very elderly (>=80 years). The following outcome variables were recorded: demographic parameters, classic risk factors, tumor location and size, neck node involvement, histopathologic and therapeutic details, and association with human papillomavirus (HPV). The descriptive statistics were computed. Parametric and nonparametric tests were used for additional analysis. The significance level was set at P < .05. RESULTS: We reviewed 739 patients and identified 11 (1.4%) young (mean age 34.2 +/- 2.8 years) and 17 (2.3%) very elderly patients (mean age 83.1 +/- 1.2 years). The predilection site for OSCC was the oral tongue (63%) in young patients, the floor of the mouth (52%) in middle-aged patients, and the alveolar process (60%) in very elderly patients. One patient in the young group (9%) and 8 patients in the very elderly group (47%) had been exposed to risk factors; however, all of the examined middle-aged patients had had such exposure. The association of OSCC with HPV was distributed equally among the age groups. No age-related differences in the histopathologic parameters of OSCC were found. CONCLUSIONS: The features of OSCC that vary at different ages are the anatomic predilection site and the association with classic risk factors. HPV was not an age-related independent risk factor for OSCC development in the present study. PMID- 24813776 TI - Outcome following lingual nerve repair with vein graft cuff: a preliminary report. AB - PURPOSE: The object of this study was to assess the effects of an inside-out vein graft as a cuff after direct suture on human lingual nerve regeneration and recovery after iatrogenic lingual nerve injury. PATIENTS AND METHODS: Ten patients with unilateral lingual nerve anesthesia as a complication of iatrogenic injury after third molar extraction underwent microneurosurgical procedures for the injured lingual nerve under general anesthesia. The patients were randomized into 2 groups. In group A, after removing the neuromas and peripheral scars surrounding the torn nerves, the 2 nerve ends were sutured without tension. In group B, after the same procedure, including the same suturing procedure, an inside-out vein graft was placed as a cuff after the direct suture. Each group was followed at least once every 6 months for 1 year after the procedure. Postoperative outcomes were evaluated using the Pogrel criteria, the Sunderland grade, and the British Medical Research Council Scale (MRCS). RESULTS: There were no particular differences between groups A and B at 6 and 12 months after the operation. However, based on the MRCS criteria, there was a clearly better result in group B than in group A at 6 and 12 months after the operation, and the recovery of gustatory sensation tended to be better in group B than in group A 1 year after the operation. CONCLUSION: This inside-out vein graft as a cuff after direct suturing may facilitate faster lingual nerve regeneration than the traditional direct suture approach. The inside-out vein graft as a cuff may provide the advantages of preventing axonal escape at the suture lines, minimizing nerve entrapment, and preventing neuroma formation in the space between the sutured nerves. PMID- 24813777 TI - Continuous noninvasive hemoglobin measurement is useful in patients undergoing double-jaw surgery. AB - PURPOSE: Continuous measurement of hemoglobin by pulse CO-oximetry (SpHb; Masimo Radical 7 device, Masimo Corp, Irvine, CA) may be helpful during double-jaw surgery when massive hemorrhage is anticipated. Given the possible influence of low blood pressure on the detection of hemoglobin levels, the agreement of the SpHb was evaluated in patients undergoing orthognathic surgery when using hypotensive anesthesia. MATERIALS AND METHODS: Patients who underwent elective Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSO) were enrolled in this observational prospective cohort study. SpHb was compared with time-matched arterial total hemoglobin (tHb) before incision, at Le Fort I osteotomy, at BSSO, and at skin closure. The correlation between simultaneous SpHb and tHb measurement pairs was evaluated. Agreement was assessed by a comparison of SpHb with tHb using the intraclass correlation coefficient (ICC) and the Bland-Altman plot. RESULTS: The average age of 51 patients was 23 +/- 5 years and 32 patients were male. The correlations of SpHb and tHb measurements were 0.72, 0.85, 0.89, and 0.78 before incision, at Le Fort I osteotomy, at BSSO, and at closure, respectively. Bland-Altman analysis for SpHb and tHb showed respective bias values of 0.12, 0.07, -0.09, and -0.90 g/dL. ICC values between SpHb and tHb were 0.82, 0.90, 0.91, and 0.87, respectively. CONCLUSIONS: Continuous monitoring of hemoglobin may help to determine the appropriate time to perform an invasive measurement of hemoglobin in patients who undergo double-jaw surgery. PMID- 24813778 TI - Emergency department visits with facial fractures among children and adolescents: an analysis of profile and predictors of causes of injuries. AB - PURPOSE: The objectives of this study were to provide nationally representative estimates of hospital-based emergency department (ED) visits for facial fractures in children and adolescents, examine the burden associated with such visits, identify common types of facial fracture, and examine the role of patient-related demographic factors on the causes of facial fractures. MATERIALS AND METHODS: The Nationwide Emergency Department Sample for 2008 to 2010 was used. All ED visits with a diagnosis of facial fractures in those no older than 21 years were selected. Demographic characteristics, types of facial fracture, causes of injuries, and hospital charges were examined. RESULTS: During the study period, 336,124 ED visits were for facial fractures in those no older than 21 years. Late adolescents (18 to 21 yr old) and middle adolescents (15 to 17 yr old) comprised 45.6% and 26.6% of all ED visits, respectively. Male patients comprised 74.7% of ED visits. The most common facial fractures were those of the nasal bones and mandible. Younger children were more likely to have falls, pedal cycle accidents, pedestrian accidents, and transport accidents, whereas older groups were more likely to have firearm injuries, motor vehicle traffic accidents, and assaults (P < .05). Female patients were more likely to have falls, motor vehicle traffic accidents, and transport accidents, whereas male patients were more likely to have firearm injuries, pedal cycle accidents, and assaults (P < .05). Those residing at low annual income household levels were at a high risk for having firearm injuries, motor vehicle traffic accidents, and transport accidents (P < .05). CONCLUSIONS: Late adolescents, middle adolescents, and male patients comprise a significant proportion of these ED visits. Age, gender, and household income levels are significantly associated with the causes of facial fracture injuries. PMID- 24813779 TI - Multiple primary squamous cell carcinomas of the oral cavity. AB - PURPOSE: There is a subset of patients who develop multiple primary squamous cell carcinomas (SCCs) of the oral cavity. The aim of this study was to better characterize this group of patients and determine whether there are any associated risk factors. MATERIALS AND METHODS: This is a retrospective review of all patients treated for oral SCCs at the University of Maryland Department of Oral and Maxillofacial Surgery from November 1989 to February 2013. The inclusion criteria were patients who developed at least 3 primary oral cancers. Lesions were considered separate primaries if they involved different anatomic regions within the oral cavity and were more than 2 cm apart or if they occurred more than 5 years apart. RESULTS: Of 1,478 patients treated during this time frame, 20 met the inclusion criteria. There were 14 women and 6 men (female-to-male ratio, 2.3:1). Nineteen were Caucasian and 1 was of Indian ethnicity. The average number of primaries per patient was 3.9 (range, 3 to 6 primaries). The mean age at first diagnosis was 63.3 years (44 to 86 yr). The mean interval between the different primaries was 32 months (0 to 228 months). The most common site involved was the gingiva (45% of cases), followed by the tongue, buccal mucosa, retromolar fossa, and soft or hard palate. The mean follow-up was 118 months (22 to 342 months). Eleven patients developed nodal disease. Of those 11 patients, 9 died of the disease (<20% survival). The average time to neck involvement was 66.4 months. The average time from last neck involvement to death was 11.5 months. More than half the patients were nonsmokers or had quit more than 10 years before the first diagnosis. All patients quit smoking during the course of their treatment yet continued to develop multiple primaries. Three patients had proliferative verrucous leukoplakia (PVL), and 4 patients had biopsy-proved lichen planus. CONCLUSION: The incidence of multiple primary SCCs within the oral cavity appears to more commonly involve Caucasian women without risk factors, although lichen planus and PVL might play a role. The gingiva appears to be the most commonly involved primary site, and subsequent primaries tend to be restricted to the oral cavity. Close observation and early expectant treatment appear to improve prognosis and survival in these patients. Cervical nodal metastases adversely affected survival (P = .02) as did the development of more than 4 primary carcinomas (P = .04). PMID- 24813780 TI - The benefits of electronic diaries in understanding the experience of health. PMID- 24813781 TI - Detection of carbapenemases in Enterobacteriaceae: a challenge for diagnostic microbiological laboratories. AB - Carbapenemase-producing bacteria have now spread all over the world. Infections caused by those bacteria are difficult to treat. Therefore, there is an urgent need for accurate and fast detection of carbapenemases in diagnostic laboratories. In this review, we summarize screening methods for suspected isolates, direct assays for confirmation of carbapenemase activity (e.g. the Carba NP test and matrix-assisted laser desorption ionization time-of-flight mass spectrometry carbapenem hydrolysis assay), inhibitor-based methods for carbapenemase classification, and molecular-genetic techniques for precise identification of carbapenemase genes. We also propose a workflow for carbapenemase identification in diagnostic laboratories. PMID- 24813782 TI - Nanocrystals of medium soluble actives--novel concept for improved dermal delivery and production strategy. AB - After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g. rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol((r)) 981 (e.g. 20% caffeine in ethanol propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process e.g. 660 nm (optimal for hair follicle accumulation) to 250 nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept. PMID- 24813783 TI - Preclinical evaluation of a ricinoleic acid poloxamer gel system for transdermal eyelid delivery. AB - Our previous study has shown that pluronic lecithin organogel (PLO gel) made of ricinoleic acid has the potential for use as a transdermal eyelid delivery system. The present study deals with the evaluation of ocular tissue concentrations of dexamethasone in a rabbit model following topical application of the gel formulation onto the eyelids. The PLO gel formulation containing dexamethasone was applied to the outside of the eyelid skin. Rabbits were sacrificed at regular time intervals of 2, 4, 8, 12, 20 and 24h. Maxidex((r)) eye drops were used as a control. Rabbits were sacrificed and dexamethasone concentrations were analyzed in anterior segment tissues such as the cornea, conjunctiva, aqueous humor, lens, and iris-ciliary body by liquid chromatography tandem mass spectrometry (LC-MS/MS). Rabbit eyes were also examined for ocular irritation and scored using the modified Draize scoring system. No significant irritation or redness was observed in the eyes as compared to the control rabbit eyes. PLO gel formulation resulted in constant dexamethasone concentrations in the anterior segment tissues for up to 24h, which was equivalent or higher than Maxidex((r)) eye drops. The findings of this investigation indicate that the ricinoleic acid PLO gel formulation may be clinically effective as a new treatment modality for anterior segment diseases. PMID- 24813784 TI - Bioresponsive nanohydrogels based on HEAA and NIPA for poorly soluble drugs delivery. AB - Environmentally sensitive hydrogels have gained considerable attention in recent years as one of the most promising drug delivery systems. In the present study, two new formulations of pH and temperature stimuli-responsive nanogels (NGs) based on poly-N-isopropylacrylamide (NIPA), N-hydroxyethyl acrylamide (HEAA) and tert-butyl 2-acrylamidoethyl carbamate (2AAECM) were synthesized and evaluated for passive targeting of paclitaxel (PTX). Nanogels were prepared by microemulsion polymerization method using N-methylenebis(acrylamide) (NMBA) as crosslinking agent. TEM images and DLS results showed nanosized spherical hydrogels. FTIR spectra confirmed the synthesis of nanogels by radical polymerization among vinyl groups of monomers. The PTX loading capacity, encapsulation efficiency and in vitro release were analyzed by HPLC. The cumulative release profile of the PTX-loaded nanohydrogels within 144h showed a faster drug release at acid pH (pH 5), similar to those observed at lysosome compartment, whereas a fewer PTX amount was released from NGs at pH similar to plasma levels. Cellular uptake assays revealed rapid penetration and intracellular accumulation of those nanogels in MCF7, HeLa and T47D cells after 48h incubation. MTT assays showed cell viability dependence on concentration and time incubation. Finally, the PTX effect on cell viability showed a G2/M cell arrest after using PTX-loaded NGs and pure PTX. PMID- 24813785 TI - Role of AKAP 149-PKA-PDE4A complex in cell survival and cell differentiation processes. AB - The cellular localization of A-kinase anchoring proteins (AKAPs), protein kinase A (PKAs) and phosphodiesterases (PDEs) is a key step to the spatiotemporal regulation of the second messenger adenosine 3',5'-cyclic monophosphate (cAMP). In this paper the cellular distribution of the mitochondrial AKAP 149-PKA-PDE4A complex and its implications in the cell death induced by YTX treatment, a known PDE modulator, was studied. K-562 cell line was incubated with YTX for 24 or 48 h. Under these conditions AKAP 149, PKA and type-4A PDE (PDE4A) levels were measured in the cytosol, in the plasma membrane and in the nucleus. Apoptotic hallmarks were also measured after the same conditions. In addition, YTX effect on cell viability was checked after AKAP 149 and PDE4A silencing. The results obtained show a decrease in AKAP 149-PKA-PDE4A levels in cytosol after YTX exposure. 24h after the toxin addition, the complex expression increased in the plasma membrane and after 48 h in the nucleus domain. Furthermore Bcl-2 levels were decreased and the expression of caspase 3 together with caspase 8 activity were increased after 24h of toxin incubation but not after 48 h. These results suggest apoptotic cell death at 24h and a non-apoptotic cell death after 48 h. When AKAP 149 and PDE4A were silenced YTX did not induce cellular death. In summary, AKAP 149-PKA-PDE4A complex localization is related with YTX effect in K 562 cell line. When this complex is mainly located in the plasma membrane apoptosis is activated while when the complex is in the nuclear domain non apoptotic cellular death or cellular differentiation is activated. Therefore AKAP 149-PKA-PDE4A distribution and integrity have a key role in cellular survival. PMID- 24813786 TI - Where are we with Wolbachia and doxycycline: an in-depth review of the current state of our knowledge. AB - Dirofilaria immitis, the cause of canine and feline heartworm disease, was the first filarial nematode described to harbour the bacterial endosymbiont Wolbachia. This ground-breaking discovery has led to intense research aimed at unravelling the nature of the endosymbiotic relationship; genomic studies have revealed how the bacteria may interact with the parasite and help explain why each is so dependent on the other. Analysis of the immune response to these bacteria may elucidate the mechanisms through which filarial parasites are able to survive for long periods of time in otherwise immune-competent hosts. Finally, studies aimed at the removal of the bacteria using specific antibiotic treatment in infected hosts is leading to the development of novel approaches for interrupting the transmission cycle and for the treatment and control of heartworm disease. PMID- 24813787 TI - Prospective evaluation of serum pancreatic lipase immunoreactivity and troponin I concentrations in Leishmania infantum-infected dogs treated with meglumine antimonate. AB - Canine leishmaniosis (CanL) caused by Leishmania infantum is an important zoonotic disease. One of the most commonly used drugs for the treatment of CanL is meglumine antimonate. Drugs of this class have been associated with pancreatitis and cardiotoxicity in humans infected with Leishmania spp. The aim of this study was to measure serum canine pancreatic lipase immunoreactivity (Spec cPL) and cardiac troponin I (cTnI) concentrations in dogs with leishmaniosis during treatment with meglumine antimonate, and to compare them with those of dogs with leishmaniosis not treated with this drug. A total of 30 non-uremic dogs with leishmaniosis, living in Greece, were prospectively enrolled into the study. Of the 30 dogs, 20 (Group A) were treated with a combination of meglumine antimonate (100mg/kg, SC, q24 h) and allopurinol (10mg/kg, PO, q12h) for 28 days, while 10 dogs (Group B) were treated with allopurinol alone (10mg/kg, PO, q12h) for 28 days. Blood samples were collected at timepoint 0 (before treatment) and at 14 and 28 days after the initiation of treatment. None of the dogs treated with meglumine antiomonate had a Spec cPL concentration suggestive of pancreatitis (>= 400 MUg/L) or clinical signs suggestive of pancreatitis at any of the timepoints. Similarly, none of the dogs treated with meglumine antiomonate had a serum cTnI concentration above the upper limit of the reference range (>0.5 ng/mL) or clinical evidence of cardiotoxicity at any of the 3 timepoints. In the present study, meglumine antimonate treatment in dogs with leishmaniosis did not result in clinical or laboratory evidence of either pancreatitis or cardiotoxicity. PMID- 24813788 TI - Immunoproteomic approach for identification of Ascaris suum proteins recognized by pigs with porcine ascariasis. AB - Ascaris suum, the causative agent of porcine ascariasis, is responsible for marked economic losses in pig farms worldwide. Despite recent advances in research, including the characterization of the genome of A. suum, knowledge about the parasite/host relationship in porcine ascariasis at the molecular level is scarce and chemotherapy is the only effective option for parasite control. The aim of this study was to identify immunogenic proteins of A. suum somatic antigens associated with the pathogenicity/survival mechanisms of the parasite, by using two-dimensional (2-D) electrophoresis, 2-D Western blot and mass spectrometry (MS). A total of 24 parasite proteins recognized by serum samples from pigs naturally infected with A. suum were identified. Most of them (23/24) were identified as being involved in parasite survival mechanisms, including functions related to energy generation (12 proteins) and redox processes (5 proteins). These results may aid the search for effective chemo-therapeutic targets in porcine ascariasis. Further studies are needed, however, to illustrate the effect of the host immune response on the survival mechanisms of A. suum. PMID- 24813789 TI - Daily activity patterns in remitted first-episode schizophrenia. AB - BACKGROUND: Impairment in community functioning is characteristic of many individuals with schizophrenia. Despite a wealth of literature documenting such functional impairments, how patients spend their time on a daily basis and the types of activities they engage in remains less clear. The present investigation set out to examine the daily activity patterns of remitted first-episode patients with schizophrenia. METHODS: Twenty-eight first-episode schizophrenia patients in symptomatic remission and twenty-eight age-, gender-, and education-matched healthy comparison subjects participated in the present study. The Day Reconstruction Method (DRM) was employed to evaluate daily life activities, while the Social and Occupational Functional Assessment Scale was used to for assessment of community functioning. Psychopathology was assessed using the Positive and Negative Syndrome Scale, depressed mood using the Calgary Depression Scale for Schizophrenia, and clinical insight using the Schedule for the Assessment of Insight. Neurocognition was also evaluated with the Brief Assessment of Cognition in Schizophrenia. RESULTS: First-episode schizophrenia patients experienced marked impairment in functioning, despite being in symptomatic remission. Patients and controls did not differ in the number of activities reported throughout their day. However, first-episode schizophrenia patients had significantly shorter days than comparison subjects and spent significantly less time engaged in non-passive (i.e., effortful) activities, which was related to poorer functional status. CONCLUSIONS: Individuals with first-episode schizophrenia and in symptomatic remission demonstrate decreased levels of non-passive activities and poorer functional outcomes. A better understanding of the underlying factors is very likely critical to the development of strategies aimed at enhancing functional recovery in schizophrenia. PMID- 24813790 TI - Is alexithymia linked with marital satisfaction or attachment to the partner? A study in a pregnancy cohort of parents-to-be. AB - OBJECTIVE: To investigate possible associations of alexithymia with marital satisfaction and mutual attachment between the partners in a group of parents-to be during pregnancy. METHODS: The present study was conducted in a pregnancy cohort. Cross-sectional data were available for 151 mothers and 106 fathers, and altogether 102 couples. The 20-item Toronto Alexithymia Scale (TAS-20) was used to assess alexithymia, the Index of Marital Satisfaction (IMS) to assess romantic relationship satisfaction and the Experiences in Close Relationships Scale (ECR) to evaluate attachment-related anxiety and avoidance. Kruskal-Wallis test was used for categorized variable comparisons. For continuous variables, Spearman correlation analyses and linear regression analyses were conducted. RESULTS: The TAS-20 total score, as well as, two of its dimensions, difficulties in identifying and describing feelings, were significantly correlated (p<0.01) with both the IMS scores and the ECR anxiety and avoidance scores. In the regression analyses, the most significant predictive factor for the subjects' IMS scores was their partners' corresponding scores, although among fathers the IMS scores were partly explained by their own TAS-20 factor 1 scores (p=0.004). The subjects' own TAS-20 scores explained the ECR anxiety and avoidance scores to a significant extent, but the fathers' TAS-20 factor 3 scores were also associated with the mothers' avoidance scores (p=0.037). CONCLUSION: Alexithymia was not directly related to marital satisfaction. However, alexithymia appears to have a significant effect on relationship-related anxiety and avoidance. This association should be further studied in parents and their offspring in a longitudinal setting. PMID- 24813791 TI - [Coronary microcirculation and hydrogen peroxide as an endothelium-derived hyperpolarizing factor]. PMID- 24813792 TI - [Role of nitric oxide synthases in the pathogenesis of cardiovascular disease]. PMID- 24813793 TI - [Pathophysiological roles of adrenomedullin and its receptor activity modifying system]. PMID- 24813794 TI - [Recent developments in targeted therapy for cancers and drug discovery]. PMID- 24813795 TI - [Transporter-mediated drug interaction]. PMID- 24813796 TI - [FRET analysis of the activation of GPCR]. PMID- 24813797 TI - [Strategic construction of an innovative drug development pipeline by industry academia cooperation - consortium for drug innovation in the Tokai region of Japan]. PMID- 24813798 TI - [Memory-enhancing drugs]. PMID- 24813799 TI - [New drug development competition for LDL receptor]. PMID- 24813800 TI - [Orphan receptor and chaperon functions of sigma-1 receptor]. PMID- 24813801 TI - Principles of membrane tethering and fusion in endosome and lysosome biogenesis. AB - Endosomes and lysosomes receive cargo via vesicular carriers that arrive along multiple trafficking routes. On both organelles, tethering proteins have been identified that interact specifically with Rab5 on endosomes and Rab7 on late endosomes/lysosomes and that facilitate the SNARE-driven membrane fusion. Even though the structure and stoichiometry of the involved proteins and protein complexes differ strongly, they may operate by similar principles. Within this review, we will provide insights into their common functions and discuss the open questions in the field. PMID- 24813802 TI - Transesophageal echocardiography during pulmonary vein cryoballoon ablation for atrial fibrillation. AB - We describe our first 20 cases of cryoablation of atrial fibrillation (AF) using transesophageal echocardiography (TEE). Continuous procedural monitoring with TEE by a cardiologist and senior sonographer assists the electrophysiologist in performance of the cryoballoon procedure of AF. Previously using intracardiac echocardiography (ICE) we have found TEE to have better overall procedural imaging, and monitoring for pericardial effusion or thrombus formation. We have found TEE monitoring to be helpful with positioning for interatrial septal (IAS) puncture, catheter tip avoidance of the left atrial appendage (LAA), and guidance of the balloon catheter into each pulmonary vein (PV), with proper positioning within each PV orifice, and documentation of PV occlusion for the cryoballoon procedure. Procedural equipment and the cryoballoon protocol used are presented in detail. The role of TEE imaging during the procedure and in preventing potential dangers is illustrated. It is the goal of this study to demonstrate how the electrophysiology and echocardiography laboratories work together in this cryoablation procedure. PMID- 24813803 TI - ADHD and risky sexual behavior in adolescents: conduct problems and substance use as mediators of risk. AB - BACKGROUND: Recent studies have linked attention-deficit/hyperactivity disorder (ADHD) to elevated rates of risky sexual behavior (RSB) in adult samples. The current study tested whether ADHD symptoms were associated with RSB among adolescents, and examined comorbid conduct problems and problematic substance use as joint mediators of this association. METHODS: ADHD symptoms, conduct problems (oppositional defiant disorder/conduct disorder symptoms), problematic alcohol use (alcohol use disorder symptoms, alcohol use frequency), problematic marijuana use (marijuana use disorder symptoms, marijuana use frequency), and RSB were assessed among an ethnically diverse cross-sectional sample of adolescents (N = 115; mean age = 14.9 years) involved in the juvenile justice system. RESULTS: Bootstrapped mediation models revealed an initial association between ADHD symptoms and RSB that was accounted for fully by the influence of problematic alcohol and marijuana use, but not conduct problems. A follow-up multiple groups mediation analysis demonstrated that the relationship between ADHD symptoms and RSB emerged only among youth with clinically elevated conduct problems, and that problematic marijuana use fully accounted for this relationship. Hyperactive/impulsive, but not inattentive, symptoms were related to RSB, although the pattern of indirect effects was consistent with the multiple groups analysis. CONCLUSIONS: The association between ADHD and adolescent RSB is restricted to youth with elevated comorbid conduct problems and reflects the contributions of comorbid marijuana use problems, and to a lesser extent alcohol use problems. Early identification and treatment of these comorbid conditions may be important for the prevention of negative sexual health outcomes among youth with ADHD. PMID- 24813804 TI - Electron propagator calculations on the ground and excited states of C60(-). AB - Electron propagator calculations in two approximations-the third-order algebraic, diagrammatic construction and the outer valence Green's function (OVGF)-have been performed on the vertical electron affinities of C60 and the vertical electron detachment energies of several states of C60(-) with a variety of basis sets. These calculations predict bound (2)T1u and (2)T1g anions, but fail to produce (2)T2u or (2)Hg anionic states that are more stable than ground-state C60. The electron affinity for the (2)Ag state is close to zero, but no definitive result on its sign has been obtained. This state may be a resonance or marginally bound anion. The OVGF prediction for the vertical electron detachment energy of (2)T1u C60(-), 2.63 eV, is in excellent agreement with recent anion photoelectron spectra. PMID- 24813805 TI - Adolescent alcohol exposure and persistence of adolescent-typical phenotypes into adulthood: a mini-review. AB - Alcohol use is typically initiated during adolescence, which, along with young adulthood, is a vulnerable period for the onset of high-risk drinking and alcohol abuse. Given across-species commonalities in certain fundamental neurobehavioral characteristics of adolescence, studies in laboratory animals such as the rat have proved useful to assess persisting consequences of repeated alcohol exposure. Despite limited research to date, reports of long-lasting effects of adolescent ethanol exposure are emerging, along with certain common themes. One repeated finding is that adolescent exposure to ethanol sometimes results in the persistence of adolescent-typical phenotypes into adulthood. Instances of adolescent-like persistence have been seen in terms of baseline behavioral, cognitive, electrophysiological and neuroanatomical characteristics, along with the retention of adolescent-typical sensitivities to acute ethanol challenge. These effects are generally not observed after comparable ethanol exposure in adulthood. Persistence of adolescent-typical phenotypes is not always evident, and may be related to regionally specific ethanol influences on the interplay between CNS excitation and inhibition critical for the timing of neuroplasticity. PMID- 24813806 TI - Conditioned taste aversion, drugs of abuse and palatability. AB - We consider conditioned taste aversion to involve a learned reduction in the palatability of a taste (and hence in amount consumed) based on the association that develops when a taste experience is followed by gastrointestinal malaise. The present article evaluates the well-established finding that drugs of abuse, at doses that are otherwise considered rewarding and self-administered, cause intake suppression. Our recent work using lick pattern analysis shows that drugs of abuse also cause a palatability downshift and, therefore, support conditioned taste aversion learning. PMID- 24813808 TI - A randomised controlled trial of an automated oxygen delivery algorithm for preterm neonates receiving supplemental oxygen without mechanical ventilation. AB - AIM: Providing consistent levels of oxygen saturation (SpO2 ) for infants in neonatal intensive care units is not easy. This study explored how effectively the Auto-Mixer((r)) algorithm automatically adjusted fraction of inspired oxygen (FiO2 ) levels to maintain SpO2 within an intended range in extremely low birth weight infants receiving supplemental oxygen without mechanical ventilation. METHODS: Twenty extremely low birth weight infants were randomly assigned to the Auto-Mixer((r)) group or the manual intervention group and studied for 12 h. The SpO2 target was 85-93%, and the outcomes were the percentage of time SpO2 was within target, SpO2 variability, SpO2 >95%, oxygen received and manual interventions. RESULTS: The percentage of time within intended SpO2 was 58 +/- 4% in the Auto-Mixer((r)) group and 33.7 +/- 4.7% in the manual group, SpO2 >95% was 26.5% vs 54.8%, average SpO2 and FiO2 were 89.8% vs 92.2% and 37% vs 44.1%, and manual interventions were 0 vs 80 (p < 0.05). Brief periods of SpO2 < 85% occurred more frequently in the Auto-Mixer((r)) group. CONCLUSION: The Auto Mixer((r)) effectively increased the percentage of time that SpO2 was within the intended target range and decreased the time with high SpO2 in spontaneously breathing extremely low birth weight infants receiving supplemental oxygen. PMID- 24813807 TI - Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation. AB - It has emerged that palindrome-mediated genomic instability generates DNA-based rearrangements. The presence of palindromic AT-rich repeats (PATRRs) at the translocation breakpoints suggested a palindrome-mediated mechanism in the generation of several recurrent constitutional rearrangements: the t(11;22), t(17;22), and t(8;22). To date, all reported PATRR-mediated translocations include the PATRR on chromosome 22 (PATRR22) as a translocation partner. Here, the constitutional rearrangement, t(3;8)(p14.2;q24.1), segregating with renal cell carcinoma in two families, is examined. The chromosome 8 breakpoint lies in PATRR8 in the first intron of the RNF139 (TRC8) gene, whereas the chromosome 3 breakpoint is located in an AT-rich palindromic sequence in intron 3 of the FHIT gene (PATRR3). Thus, the t(3;8) is the first PATRR-mediated, recurrent, constitutional translocation that does not involve PATRR22. Furthermore, we detect de novo translocations similar to the t(11;22) and t(8;22), involving PATRR3 in normal sperm. The breakpoint on chromosome 3 is in proximity to FRA3B, the most common fragile site in the human genome and a site of frequent deletions in tumor cells. However, the lack of involvement of PATRR3 sequence in numerous FRA3B-related deletions suggests that there are several different DNA sequence based etiologies responsible for chromosome 3p14.2 genomic rearrangements. PMID- 24813809 TI - Is postoperative adjuvant chemoradiotherapy efficacious and safe for gastric cancer patients with D2 lymphadenectomy? A meta-analysis of the literature. AB - BACKGROUND: Adjuvant chemoradiotherapy (CRT) for patients with gastric cancer after D2 lymphadenectomy remains controversial. The objective of the present meta analysis was to analyze efficacy and safety of postoperative CRT and establish a consensus on whether it is suitable for the patients. METHODS: We searched PubMed, Ovid, Cochrane, and Web of Science. Statistical analysis was carried out by STATA version 12.0 software. The quality of evidence was assessed by Jadad and the Newcastle-Ottawa quality assessment scale. RESULTS: Six studies involving 2135 patients were included for the meta-analysis. The results showed that, compared with non-CRT, postoperative adjuvant CRT was associated with a significant improvement in 5-year overall survival (OS) (HR = 0.79, 95% CI 0.68 0.92, P = 0.002) and 5-year relapse-free survival (RFS) (HR = 0.81, 95% CI 0.70 0.93, P = 0.004). However, there were no differences in distant metastasis (RR = 0.93, 95% CI 0.82-1.06, P = 0.304) and treatment-related toxicity between the two groups. CONCLUSIONS: From the results of our study, postoperative adjuvant CRT may be associated with longer 5-year OS and 5-year RFS in patients with D2 lymphadenectomy, but might not improve 5-year disease-free survival compared to non-CRT. Methodologically high-quality comparative studies are needed for further evaluation. PMID- 24813810 TI - Outcomes in patients undergoing nephrectomy for renal cancer on chronic anticoagulation therapy. AB - AIMS: To report our experience on surgical resection of renal tumors for patients with a history of chronic anticoagulation (ACT) or aspirin use. METHODS: We performed a retrospective analysis of 2473 patients who underwent surgery for renal tumors between 2005 and 2012. Prior to surgery, 172 were on chronic ACT and 695 on aspirin. Multivariable linear and logistic regression models were used to compare transfusion and overall complication rates between patients undergoing renal surgery who were on therapy to patients who were on aspirin and to patients with no therapy. RESULTS: Compared to no therapy and aspirin patients those on ACT were older (57.3 (IQR 48.4-66.10) vs 63.9, (IQR 57.3-71.5) vs 68.4, (IQR 60.4 73.5); p < 0.001), with a higher percentage having an ASA score of 3 or 4 (42.4 vs 57.9 vs 82.6%; p < 0.001), respectively. ACT patients had a higher 30-day transfusion rate, 22.7% vs 7.6% vs 6.9%, and 90-day complication rate, 17.4% vs 7.2% vs 7.3%, both p < 0.001. The median length of stay differed statistically between groups (p < 0.001), with a modest longer stay in the anticoagulation group (OR 1.11 SE 0.26; p < 0.001). Transfusion and complication rates for patients on therapy undergoing minimally invasive surgery vs open surgery were not statistically different. CONCLUSIONS: Patients on chronic ACT had higher transfusion and overall complication rates compared to patients on no treatment or on chronic aspirin. These findings did not correlate to clinical differences in length of stay or grade 3-5 complications. PMID- 24813811 TI - Defining the role for submental intubation. AB - Submental intubation, a less invasive alternative to tracheostomy, was first described for acute airway management of maxillofacial trauma patients, where nasoendotracheal intubation was contraindicated and oral intubation was not possible due to the desire to establish dental relationships perioperatively. While submental intubation is used most commonly in trauma patients, the range of indications for its use has broadened to include many orthognathic and skull base surgical procedures. Submental intubation is a safe, effective technique for many maxillofacial procedures, requiring the cooperation of both anesthesiologists and maxillofacial surgeons. PMID- 24813812 TI - Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets. AB - Data from massively parallel sequencing or 'Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7 dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening. PMID- 24813813 TI - Pulsed-dye laser treatment for recalcitrant viral warts: a retrospective case series of 227 patients. PMID- 24813814 TI - Redox and label-free array detection of protein markers in human serum. AB - A substantial outstanding challenge in diagnostics and disease monitoring is an ability to rapidly and conveniently assay for protein biomarkers within complex biological media. Label-free electroanalytical methods present, arguably, the most promising and scalable means of achieving this but, as with all label-free assays, can struggle with response selectivity issues that arise from nonspecific surface interactions. Impedimetric methods are ultrasensitive and have been applied to the quantification of a wide range of proteins but have not previously been utilized in a multiplexed format capable of operation in complex analytical fluid. Herein, we present the use of thermally cross-linked poly(ethylene glycol) (PEG) polymer sensory array interfaces in the ultrasensitive quantification of two protein markers, insulin and C-reactive protein (CRP). This was achieved with detection limits of 171 +/- 19 fM and 150 +/- 10 pM, respectively. Significantly, the arrays not only enable the simultaneous, fast, nonamplified, and label-free detection of both markers without reagent addition but do so with little cross talk, even in human serum. A blind analysis of 17 real patient samples generated results in excellent agreement with those obtained through a clinically approved chemiluminescence assay. PMID- 24813815 TI - Sense of coherence and incidence of periodontal disease in adults. AB - AIM: To assess whether sense of coherence (SOC) predicts the 4-year incidence of periodontal disease in adults. METHODS: Data from 848 adults who participated in both the Health 2000 Survey and the Follow-Up Study of Finnish Adults' Oral Health were analysed. At baseline, participants provided information on demographic characteristics, education level, the SOC scale, pre-existing diabetes and dental behaviours. The outcome measure was the change in number of teeth with pocketing >= 4 mm over 4 years over 4 years. Two separate sets of longitudinal analyses were conducted. The first set was conducted with all the 848 subjects who participated in both surveys and the second set was conducted with the 305 subjects who had no pocketing >= 4 mm at baseline. RESULTS: In the full sample, baseline SOC was not associated with change in number of teeth with pocketing over 4 years (coefficient from linear regression: -0.28; 95% CI: -0.74 to 0.18). Similarly, baseline SOC was not associated with number of teeth with pocketing after 4 years (Rate Ratio: 0.94; 95%CI: 0.80 to 1.11) among those with no pocketing at baseline. CONCLUSION: This 4-year prospective study suggests that SOC measured in adulthood does not explain change in the number of teeth with periodontal pocketing >= 4 mm. PMID- 24813816 TI - Ustekinumab in severe complicated erythrodermic psoriasis: rapid clearing, safety, and sustained remission. AB - Erythrodermic psoriasis is a severe type of psoriasis associated with comorbidities and high mortality. Patients with erythrodermic psoriasis need hospitalization and systemic treatment. Conventional drugs and biologic agents may not manage to control refractory and complicated erythrodermic psoriasis resulting from treatment failure. Ustekinumab, a human monoclonal antibody against interleukin-12 and 23, seems to be an effective therapeutic option in erythrodermic psoriasis whenever other therapies have failed. PMID- 24813817 TI - Academic bigotry. PMID- 24813818 TI - Risk factors associated with rectal neuroendocrine tumors: a cross-sectional study. AB - BACKGROUND: The incidence of rectal neuroendocrine tumors (NET) has been increasing since the implementation of the screening colonoscopy. However, very little is known about risk factors associated with rectal NETs. We examined the prevalence of and the risk factors for rectal NETs in a Korean population. METHODS: A cross-sectional study was performed on 62,171 Koreans who underwent screening colonoscopy. The clinical characteristics and serum biochemical parameters of subjects with rectal NET were compared with those of subjects without rectal NET using multivariate logistic regression. RESULTS: Of a total of 57,819 participants, 101 [OR, 0.17%; 95% confidence interval (CI), 0.14-0.20] had a rectal NET. Young age (<50 years; OR, 2.09; 95% CI, 1.06-4.15), male gender (OR, 1.92; 95% CI, 1.15-3.20), alcohol drinking [adjusted OR (AOR), 1.56; 95% CI, 1.01-2.42], and a low high-density lipoprotein-cholesterol (HDL-C) level (AOR, 1.85; 95% CI, 1.10-3.11) were independent risk factors for rectal NETs. Cigarette smoking, fatty liver, metabolic syndrome, higher triglyceride level (>=150 mg/dL), and higher homeostasis model assessment of insulin resistance (>=2.5) were not independently associated with rectal NETs, although these factors were more common in individuals with rectal NETs in the univariate analysis. CONCLUSIONS: Young age (<50 years), male gender, alcohol drinking, and a low HDL C level were risk factors for rectal NETs. Our results suggest that gender, behavioral factors, and dyslipidemia may affect the risk for developing rectal NETs. IMPACT: The findings of this study contribute to a better understanding of the influence of gender, behavioral factors, and dyslipidemia in developing rectal NETs. PMID- 24813819 TI - The effects of test preference, test access, and navigation on colorectal cancer screening. AB - BACKGROUND: Little is known about how colorectal cancer screening test preferences operate together with test access and navigation to influence screening adherence in primary care. METHODS: We analyzed data from a randomized trial of 945 primary care patients to assess the independent effects of screening test preference for fecal immunochemical test (FIT) or colonoscopy, mailed access to FIT and colonoscopy, and telephone navigation for FIT and colonoscopy, on screening. RESULTS: Preference was not associated with overall screening, but individuals who preferred FIT were more likely to complete FIT screening (P = 0.005), whereas those who preferred colonoscopy were more likely to perform colonoscopy screening (P = 0.032). Mailed access to FIT and colonoscopy was associated with increased overall screening (OR = 2.6, P = 0.001), due to a 29 fold increase in FIT use. Telephone navigation was also associated with increased overall screening (OR = 2.1, P = 0.005), mainly due to a 3-fold increase in colonoscopy performance. We estimated that providing access and navigation for both screening tests may substantially increase screening compared with a preference-tailored approach, mainly due to increased performance of nonpreferred tests. CONCLUSIONS: Preference influences the type of screening tests completed. Test access increases FIT and navigation mainly increases colonoscopy. Screening strategies providing access and navigation to both tests may be more effective than preference-tailored approaches. IMPACT: Preference tailoring in colorectal cancer screening strategies should be avoided if the objective is to maximize screening rates, although other factors (e.g., costs, necessary follow-up) should also be considered. PMID- 24813820 TI - Expert panel evaluation of health information technology effects on adverse events. AB - RATIONALE, AIMS AND OBJECTIVES: Adverse events (AEs) among hospitalized patients occur frequently and result in significant sequelae. Federal policy is incentivizing health information technology (HIT) use, although research demonstrating safety benefits from HIT is mixed. Our objective was to evaluate the potential effects of HIT on reducing 21 different inpatient AEs. Identifying AEs most likely to be reduced by HIT can inform the design of future studies evaluating its effectiveness. METHODS: We conducted a modified Delphi panel of national experts in HIT and safety. We conducted a focused literature review to inform the experts. Using a novel framework, experts rated each AE as 'definitely reduced by health IT,' 'possibly reduced by health IT' and 'not likely to be reduced by health IT'. RESULTS: From our panel discussion, experts identified six AEs as 'definitely reduced by health IT': (1) adverse drug events (ADEs) associated with digoxin; (2) ADE associated with IV heparin; (3) ADE associated with hypoglycaemic agents; (4) ADE associated with low molecular weight heparin and factor Xa inhibitor; (5) contrast nephropathy associated with catheter angiography; and (6) ADE hospital-acquired antibiotic-associated Clostridium difficile. CONCLUSIONS: Understanding the effects of HIT on patient outcomes will be essential to ensuring that the significant federal investment results in anticipated improvements. This study serves as an important early step in helping with the design of future work evaluating level of HIT infrastructure and rates of inpatient AEs. PMID- 24813821 TI - Synthesis of carbazoles by copper-catalyzed intramolecular C-H/N-H coupling. AB - A Cu-catalyzed intramolecular C-H amination for the synthesis of carbazoles has been developed. The key to success is the installation of the picolinamide-based directing group, which is spontaneously removed after the coupling event. The Cu catalysis proceeded smoothly under Pd- and I(III)-free conditions, and its mild oxidation aptitude enables the rapid and concise construction of heteroatom incorporated carbazole core pi-systems. PMID- 24813822 TI - Prophenoloxidase system, lysozyme and protease inhibitor distribution in the common cuttlefish Sepia officinalis. AB - The immune system of cephalopods remains poorly understood. The aim of this study was to determine the specific activity of immune enzymes in epithelial barriers, circulatory and digestive systems of the common cuttlefish Sepia officinalis. Three enzyme groups with putative functions in immunity were investigated: phenoloxidases (POs), lysozymes and protease inhibitors (PIs). Consistent with a role in immunity, highest PO activities were found in the integument as well as the respiratory and circulatory organs under zymogenic (proPO) and active form. Surprisingly, high PO activities were also found in the digestive gland and its appendages. Similarly, high lysozyme activities were detected in the integument and circulatory organs, but also in the posterior salivary glands, highlighting the implication of this antibacterial enzyme group in most tissues exposed to the environment but also within the circulatory system. Albeit highest in digestive organs, the ubiquitous detection of PI activity in assayed compartments suggests immune function(s) in a wide range of tissues. Our study reports proPO/PO, lysozyme and PI distributions in S. officinalis body compartments for the first time, and thus provides the fundamental basis for a better understanding of the humoral immune system in cephalopods as well as invertebrates. PMID- 24813823 TI - Spatial distribution of digestive proteinases in the midgut of the Pacific white shrimp (Litopenaeus vannamei) indicates the existence of endo-ectoperitrophic circulation in Crustacea. AB - The effect of dietary protein concentration on the spatial distribution of digestive proteinases in the shrimp Litopenaeus vannamei indicates the existence of endo-ectoperitrophic enzyme circulation in this species. Samples recovered from the midgut gland tissues, stomach contents, three different portions of the midgut and feces were used for quantitative and qualitative analyses of the composition and distribution of the digestive proteinases. Animals were divided into three different groups: (1) animals (controls) fed with a commercial 35% protein diet, (2) animals fed with a commercial diet supplemented with ovalbumin to a final protein concentration of 60%; (3) animals fed with an 80% protein diet. Quantitative determinations using different substrates and zymograms showed that increasing protein concentration in the diet alters the distribution of proteinases along the digestive tract. Composition of proteinases in the midgut gland, stomach contents, midgut sections and feces were similar, but not identical. Chymotrypsin and trypsin paralogues were identified in all enzyme sources in a concentration gradient along the midgut in the control shrimp, the expected distribution supporting the existence of a recycling mechanism. The occurrence of a peritrophic membrane in other Decapoda suggests that endo ectoperitrophic circulation of digestive enzymes and nutrients may also occur in other crustaceans and also extends beyond the Insecta. PMID- 24813824 TI - Deformation of articular cartilage during static loading of a knee joint- experimental and finite element analysis. AB - Novel conical beam CT-scanners offer high resolution imaging of knee structures with i.a. contrast media, even under weight bearing. With this new technology, we aimed to determine cartilage strains and meniscal movement in a human knee at 0, 1, 5, and 30 min of standing and compare them to the subject-specific 3D finite element (FE) model. The FE model of the volunteer's knee, based on the geometry obtained from magnetic resonance images, was created to simulate the creep. The effects of collagen fibril network stiffness, nonfibrillar matrix modulus, permeability and fluid flow boundary conditions on the creep response in cartilage were investigated. In the experiment, 80% of the maximum strain in cartilage developed immediately, after which the cartilage continued to deform slowly until the 30 min time point. Cartilage strains and meniscus movement obtained from the FE model matched adequately with the experimentally measured values. Reducing the fibril network stiffness increased the mean strains substantially, while the creep rate was primarily influenced by an increase in the nonfibrillar matrix modulus. Changing the initial permeability and preventing fluid flow through noncontacting surfaces had a negligible effect on cartilage strains. The present results improve understanding of the mechanisms controlling articular cartilage strains and meniscal movements in a knee joint under physiological static loading. Ultimately a validated model could be used as a noninvasive diagnostic tool to locate cartilage areas at risk for degeneration. PMID- 24813826 TI - Sc2@C66 revisited: an endohedral fullerene with scandium ions nestled within two unsaturated linear triquinanes. AB - The geometries of fullerenes are governed by the isolated pentagon rule (IPR), which states that stable fullerenes have each of their 12 pentagons surrounded by five hexagons. At the dawn of fullerene science, it was widely believed that the IPR would also be applicable for endohedral fullerenes. In 2000, that idea was altered by the discovery of the first non-IPR fullerenes, Sc2@C66 and Sc3N@C68. The structural data for Sc2@C66 were interpreted to indicate the presence of a pair of doubly fused pentagons. However, that structure has remained a long standing mystery, since it is thermodynamically unfavorable. Here, we demonstrate definitively that Sc2@C66 does not have the structure that was long believed to be but a brand new type. 2D NMR spectroscopic and single-crystal X-ray analyses disclose that Sc2@C66 has a C2v(4059)-C66 cage containing two sets of unsaturated linear triquinanes (ULTs), in which three pentagons abut one another and two scandium ions are located within the folds of each of the ULT units. PMID- 24813825 TI - Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling. AB - Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation. PMID- 24813827 TI - Huddling facilitates expression of daily torpor in the large Japanese field mouse Apodemus speciosus. AB - Small endotherms employ multiple adaptations to maintain energy balance in winter, including spontaneous daily torpor and simultaneous huddling. The relationships between these adaptations have been discussed in several previous studies, but it has not been well-established if huddling actually affects the expression of torpor in small endotherms. We examine whether and how huddling affects the expression of torpor in the large Japanese field mouse Apodemus speciosus, which is known to become torpid under artificial winter conditions. The mice were found to adjust expression of torpor in response to the number of cage mates. Torpor frequency and minimum torpid body temperature were both significantly elevated when the number of cage mates was increased, but there was no significant change in torpor bout length. Rewarming rate on arousal was lower when the number of cage mates was increased, suggesting reduction in endogenous rewarming due to exogenous passive rewarming. Food consumption per mouse decreased significantly with increasing number of cage mates. Thus, our study demonstrates that social thermoregulatory behaviors such as huddling can facilitate expression of spontaneous daily torpor in small rodents. These findings suggest that energy constraints, such as ambient temperature and food availability may not be the only modulating factors on the expression of daily torpor. PMID- 24813828 TI - Assessment of SOMNOwatch plus EEG for sleep monitoring in healthy individuals. AB - Polysomnography (PSG) is still the standard in sleep monitoring, with several alternative solutions developed, including simplified electroencephalographic recorders such as SOMNOwatch plus EEG. In this study, we aimed to evaluate the validity of the recordings and of the analysis of the proprietary software of this solution, compared to PSG and semiautomatic scoring, respectively. From thirteen healthy adults, we recorded 27 nights simultaneously with a classical EEG amplifier (NeuroScan system) and the ambulatory SOMNOwatch plus EEG. Thereafter, we performed (semi-) automatic sleep analysis in Somnolyzer 24x7 and DOMINO Light (SOMNOwatch software). AASM scoring sensitivity of SOMNOwatch plus EEG, as revealed by Somnolyzer 24x7, was 97.79%, and specificity 87.19%. Paired T tests revealed no significant differences between the recordings of the two EEG systems, with intraclass correlation coefficients ranging from moderate to very good. When data were analyzed in DOMINO Light, sensitivity was 92.99% and specificity was 80.90%. Our data suggest that SOMNOwatch plus EEG might serve as a reliable instrument for recording sleep in healthy individuals, but its proprietary software, DOMINO Light, still seems to have weaknesses in terms of automatic sleep staging. PMID- 24813829 TI - Exercise prevents raphe nucleus mitochondrial overactivity in a rat depression model. AB - Monoamine deficit and mitochondrial dysfunction may underlie depression. Serotoninergic neurons from raphe nuclei project widely and may be involved in depression. This study used chronic unpredictable stress (CUS) in rats as a model of depression to assess the effects of CUS, exercise and fluoxetine on mitochondrial function and serotonin levels in the raphe nuclei. Rats were divided into 4 groups (6 per group): control (C); depression (D), CUS for 28days; depression+exercise (DE), treadmill exercises from days 11-28 of CUS; depression+fluoxetine (DF), fluoxetine (5mg/kg/d i.g.) from days 11 to 28 of CUS. Behavioral changes were assessed using body weight, sucrose consumption tests (anhedonia) and open field tests (locomotor/exploratory behavior). Raphe nucleus mitochondrial function was determined using the respiratory control ratio, ATP synthesis rate, and activities of superoxide dismutase and glutathione peroxidase. Serotonin levels were measured in the raphe nuclei and hippocampus. On day 28 of CUS, body weight was higher in group C than in groups D, DE and DF (P<0.001), and higher in group DE than in group D or DF (P<0.05). Sucrose consumption was higher in group C than in groups D, DE and DF (P<0.001), higher in group DE than in groups D (P<0.001) or DF (P<0.05), and higher in group DF than in group D (P<0.05). All measures of mitochondrial function were increased in group D compared with the other groups (P<0.01). Hippocampal serotonin was lower in group D than in the other groups (P<0.01); levels in the raphe nuclei were elevated in group DE compared with the remaining groups (P<0.001). CUS in rats may cause overactivation of the mitochondria in the raphe nuclei, and exercise training may suppress these changes. PMID- 24813830 TI - Schisantherin A recovers Abeta-induced neurodegeneration with cognitive decline in mice. AB - Schisantherin A (STA) is a main bioactive lignan isolated from Schisandra chinensis (Turcz.) Baill., which has been widely used as a tonic in traditional Chinese medicine for many years. Lots of studies have reported that STA exhibited anti-inflammatory and antioxidant effects. This paper was designed to investigate the effects of STA on cognitive function and neurodegeneration in the mouse control of Alzheimer's disease (AD) induced by Abeta1-42. It was found that successive intracerebroventricular (ICV) administration of STA (0.01 and 0.1mg/kg) for 5days significantly attenuated Abeta1-42-induced learning and memory impairment as measured by the Y-maze test, shuttle-box test and Morris water maze test. Furthermore, STA at a dose of 0.1mg/kg restored the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as the levels of Abeta1-42, malondialdehyde (MDA) and glutathione (GSH) to some extent in the hippocampus and cerebral cortex. It also noticeably improved the histopathological changes in the hippocampus. The results suggested that STA might protect against cognitive deficits, oxidative stress and neurodegeneration induced by Abeta1-42, and serve as a potential agent in treatment of AD. PMID- 24813831 TI - Psychosocial factors and risk of chronic widespread pain: an 11-year follow-up study--the HUNT study. AB - Few studies have used prospective designs in large population surveys to assess the risk of developing chronic widespread pain (CWP). We wanted to examine 1) how many people without CWP developed it after 11years, and 2) how anxiety, depression, alcohol use, smoking, sleeping problems, and body mass index (BMI) were associated with this development. This study was based on a representative population-based Norwegian cohort attending both the second (1995 to 1997) and the third (2006 to 2008) wave of the Nord-Trondelag Health Study (HUNT2 and HUNT3, respectively). Only those adults attending both surveys (N=28,367) were included. Approximately 19,000 individuals without CWP in HUNT2 were assessed for later CWP development in HUNT3, where we looked for symptoms of anxiety, depression, monthly frequency of alcohol use, smoking, sleeping problems, and BMI. Data were analyzed with logistic regression adjusted for age, sex, education, marital status, physical exercise, and pain symptoms not meeting the CWP criteria at baseline. After 11 years, 12% of those without CWP developed CWP. Anxiety and depression, former and current smoking status, BMI<18.5 kg/m(2), BMI?25 kg/m(2), and sleeping problems were all associated with an increased risk of CWP. High and moderate levels of alcohol use were associated with a reduced risk of CWP. In summary, this study indicates that CWP develops over a long-term period for a substantial group of healthy people, and that both psychosocial and lifestyle factors influence the risk of CWP onset. PMID- 24813832 TI - Pain assessment in special patient groups such as those with dementia: at the finishing line or just starting from scratch? PMID- 24813833 TI - The effect of cognitive bias modification for interpretation on avoidance of pain during an acute experimental pain task. AB - Research confirms that patients with chronic pain show a tendency to interpret ambiguous stimuli as pain related. However, whether modifying these interpretive pain biases impacts pain outcomes is unknown. This study aimed to demonstrate that interpretation biases towards pain can be modified, and that changing these biases influences pain outcomes in the cold pressor task. One hundred and six undergraduate students were randomly allocated to receive either threatening or reassuring information regarding the cold pressor. They also were randomly allocated to 1 of 2 conditions in the Ambiguous Scenarios Task, in which they were trained to have either a threatening interpretation of pain (pain bias condition) or a nonthreatening interpretation of pain (no pain bias condition). Therefore, the study had a 2 (threat/reassuring)*2 (pain bias/no pain bias) design. Analyses showed that a bias was induced contingent on condition, and that the threat manipulation was effective. Participants in the pain bias condition hesitated more before doing the cold pressor task than those in the no pain bias condition, as did those in the threat compared with the reassurance condition. The major finding was that interpretive bias mediated the relationship between bias condition and hesitance time, supporting the causal role of interpretive biases for avoidance behaviors in current chronic pain models. No differences were found on other pain outcomes regarding bias or threat, and the efficacy of the bias modification was not impacted by different levels of threat. These results suggest that cognitive bias modification should be further explored as a potential intervention in pain. PMID- 24813834 TI - Biophysical characterization of genistein-membrane interaction and its correlation with biological effect on cells - The case of EYPC liposomes and human erythrocyte membranes. AB - With application of EPR and (1)H NMR techniques genistein interaction with liposomes formed with egg yolk lecithin and with erythrocyte membranes was assessed. The present study addressed the problem of genistein localization and its effects on lipid membrane fluidity and protein conformation. The range of microscopic techniques was employed to study genistein effects on HeLa cells and human erythrocytes. Moreover, DPPH bioassay, superoxide anion radical test and enzymatic measurements were performed in HeLa cells subjected to genistein. The gathered results from both EPR and NMR techniques indicated strong ordering effect of genistein on the motional freedom of lipids in the head group region and the adjacent hydrophobic zone in liposomal as well as in red blood cell membranes. EPR study of human ghost showed also the changes in the erythrocyte membrane protein conformation. The membrane effects of genistein were correlated with the changes in internal membranes arrangement of HeLa cells as it was noticed using transmission electron microscopic and fluorescent techniques. Scanning electron and light microscopy methods showed that one of the aftermaths of genistein incorporation into membranes was creation of echinocytic form of the red blood cells with reduced diameter. Genistein improved redox status of HeLa cells treated with H2O2 by lowering radicals' level. In conclusion, the capacity of genistein to incorporate, to affect membrane organization and to change its biophysical properties is correlated with the changes inside the cells. PMID- 24813835 TI - Melanoma--clinical, dermatoscopical, and histopathological morphological characteristics. AB - Melanoma is one of the most malignant skin tumors with constantly rising incidence worldwide, especially in fair-skinned populations. Melanoma is usually diagnosed at the average age 50, but, nowadays is also diagnosed more frequently in younger adults, and very rarely in childhood. There is no unique or specific clinical presentation of a melanoma. The clinical presentation of melanomas varies depending on the anatomic localization and the type of growth, i.e., the histopathological type of the cancer. There are four major histopathological types of melanoma--superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Although dermatoscopy is a very useful tool in early melanoma detection, dermatoscopical features of melanomas are also variable. Therefore, experience and education in dermatoscopy is crucial in the evaluation of skin tumors. Differential diagnosis of melanomas includes a wide range of benign and malignant skin lesions, due to their clinical presentation and resemblance to various dermatological entities. In this review we present the most important aspects of clinical, dermatoscopical, and histopathological features of melanomas. PMID- 24813836 TI - A retrospective study of 231 Japanese vitiligo patients with special reference to phototherapy. AB - Although the outcomes of various treatment modalities for vitiligo have been studied extensively, the influence of the participant's characteristics on treatment response has not been thoroughly investigated. Therefore, we retrospectively investigated treatment effects and their association with clinical characteristics in Japanese patients with vitiligo. The charts of patients with vitiligo treated in our institution were reviewed. Clinical response was evaluated as a marked response rate, defined as repigmentation in >75% of the initial lesional area. 162 patients were treated with phototherapy, while 69 were treated with topical mono-therapy. The patients treated with phototherapy and those treated with both phototherapy and topical treatment demonstrated significantly higher clinical response rates compared to patients treated solely with topical mono-therapy (marked response rate: 19.1% vs. 5.8%, P<0.05; and 23.5% vs. 5.8%, P<0.01, respectively). Among the phototherapy-treated patients, younger subjects (<=15 years old) were more responsive to phototherapy compared to older patients (37.0% vs. 15.6%; P=0.015). The disease subtypes did not affect treatment response. In conclusion, phototherapy appears to have a therapeutic effect superior to topical mono-therapy on both focal and generalized vitiligo, especially in younger patients. Thus, any type of psychosocially devastating lesions in a pediatric patient may be a good target for phototherapy. PMID- 24813837 TI - Hepato-splenic and lipid profile abnormalities--do they exist in children affected with vitiligo? AB - Autoimmune disturbances and metabolic abnormalities observed in vitiligo, a disease of still unclear etiology, may provide evidence on the systemic nature of the disease. The aim of the study was to assess functional and morphological parameters of the liver and spleen, as well as the lipid profile in vitiligo affected children, in order to ascertain whether any metabolic abnormalities or structural changes in these organs accompanied the course of vitiligo. The study included 34 patients with vitiligo hospitalized at the Department of Dermatology at the Medical University of Lublin and a control group of 35 healthy individuals, aged 7-15 years. Children with the active phase of vitiligo and at least 6 month history of vitiligo lesions were studied. Ultrasound examination of the liver and spleen enabled assessment of the size and parenchyma of the organs. Liver and spleen functions were assessed by means of the following additional examinations: blood test, transaminases, protein electrophoresis, lipid profile, autoantibodies, and HCV antibodies. The size of the liver was not significantly different in the vitiligo and control groups. The ultrasonographic pictures of the spleen revealed no abnormalities in organ size and structure. The concentration of HDL-cholesterol was significantly lower, whereas the concentration of LDL-cholesterol was significantly higher in patients with vitiligo than in healthy controls. The value of the LDL/HDL ratio was significantly higher in vitiligo patients. The results of our study indicate lipid disturbances in vitiligo-affected children. Since no structural and functional abnormalities in the liver and spleen were found, it seems likely that lipid disturbances in vitiligo may result from disturbed metabolic processes in the adipose tissue as well as from oxidative stress. PMID- 24813838 TI - Prevalence of skin diseases in female prisoners in Turkey: analysis of impact of prison conditions and psychological stress. AB - Prisons have been studied as communal places where risk of contagious diseases and dermatological diseases associated with stress are more frequent. We aimed to investigate the prevalence of skin diseases in female prisoners with special focus on psychological stress. We held a day-time dermatology polyclinic for 6 weeks. The patients were given Beck Depression Inventory (BDI) and a questionnaire on the psychological impact of skin disease. A total of 383 female prisoners were examined; 41 dermatological diseases were diagnosed. Acne was the most prevalent condition (34%), followed by hair loss (19%), dry skin (16%), and eczema (12%). Thirty-six percent of the prisoners felt embarrassed, 34% felt anxious, and 45% felt sad about their skin disease. Fourty seven of the responders were found to be in severe depression according to BDI responses. We could not find any association between BDI results and any kind of skin disease diagnosed in inmates. Our study demonstrates that prisoners have benign and common skin conditions similar to those in the general population. PMID- 24813839 TI - Quality of life in patients with hand eczema as health promotion: a case control study. AB - Health promotion has been defined by the World Health Organization's (WHO) 2005 Bangkok Charter for Health Promotion as "the process of enabling people to increase control over their health and its determinants, and thereby improve their health". One of the most important determinants of health is quality of life. Hand eczema is a common skin disease that can adversely affect the quality of life of patients. The aim of this study was to determine the quality of life in patients with hand eczema. This case-control study was performed on 70 patients with hand eczema and 70 healthy controls. All the patients filled out two questionnaires: Short Form 36 (SF-36) and Dermatology Life Quality index (DLQI). The data were analyzed using the statistical software package for social sciences (SPSS). The mean score score of quality of life in dimensions of physical functioning, vitality, and general health in the SF-36 was lower compared to the control group. The mean score in DLQI in patients with hand eczema was 8.68. There was a significant negative correlation between the scores of different dimensions of QOL obtained in the two questionnaires (SF36 and DLQI). The study demonstrated that the quality of life in patients with hand eczema was lower than that of controls. It seems advisable that psychiatric consultations or psychotherapy be included in the treatment of chronic hand eczema. PMID- 24813840 TI - Treatment of anogenital warts in an 18-month-old girl with 5% imiquimod cream. AB - Possible modes of transmission of the human papilloma virus (HPV) in children include perinatal transmission, sexual transmission, or extragenital contact. Conventional treatment options with chemical and physical destruction methods can be difficult and painful and often require general anesthesia. Imiquimod is a topically active immunomodulatory agent that has been shown to successfully treat pediatric anogenital warts. We report on a case of extensive anogenital warts in a 18-month-old girl who was successfully treated with topical 5% imiquimod cream. PMID- 24813841 TI - Extreme dermatology--the intensive care skills of dermatologists in three case presentations of acute skin failure. AB - Dermatological emergencies include a number of clinical conditions usually accompanied by systemic symptoms that can lead to life-threatening complications. From the broad spectrum of life-threatening dermatoses, three cases are presented: a case of febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a case of pemphigus vulgaris mimicking Stevens-Johnson syndrome (SJS), and a case of toxic epidermal necrolysis (TEN). Those cases were considered extreme, and presented to illustrate the positive outcome of timely intensive dermatological care. An interdisciplinary approach is essential in the diagnosis, treatment, management, and follow up of patients with life-threatening dermatoses. PMID- 24813842 TI - A case of superficial granulomatous pyoderma mimicking a basal cell carcinoma. AB - Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis of unknown etiology with distinct clinical manifestations, frequently associated with systemic diseases. Four clinical and histological variants have been described: ulcerative, pustular, bullous, and vegetative. We report on a case of superficial granulomatous pyoderma (SGP), a vegetative form of PG, in a 40-year-old woman. Physical examination revealed an erythematous crusted plaque, measuring 2 cm in diameter, located on her left hip, which had appeared 18 months ago. Dermoscopy showed lack of pigment network, large gray-blue ovoid nests, irregular peripheral vessels, and ulceration. Laboratory examinations were normal; smears and cultures for bacteria and fungi were negative. Clinical and dermatoscopical presentation suggested basal cell carcinoma. The lesion was completely removed: histological examination showed pseudoepitheliomatous hyperplasia with intraepidermal micro abscesses and prominent dermal inflammatory infiltrate with typical three-layered granulomas consisting of palisading suppurative granulomas surrounded by plasma cells and eosinophils (diffuse neutrophilic infiltration with dermal inflammatory infiltrates consisting of epithelioid histiocytes, lymphocytes, and multinucleated giant cells). Based on clinical and histological correlation, the diagnosis of SPG was definitively established. PMID- 24813843 TI - Nerve sheath myxoma of the tongue. AB - Nerve sheath myxoma (NSM) of the oral mucosa is a slow-growing, benign, often asymptomatic submucosal mass. We report on a case of classical NSM of the tongue, with diagnostic and therapeutic approach to the case. Many NSM arise within the endoneurium of a peripheral nerve. It is a rare condition with no apparent differences between sexes in its prevalence. It can occur at any age. PMID- 24813844 TI - Confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome) in two brothers. PMID- 24813845 TI - Vanishing seborrhoeic keratosis. PMID- 24813846 TI - Generalized pyoderma gangrenosum associated with unrecognized ulcerative colitis. PMID- 24813847 TI - A case of nail psoriasis-associated psoriatic arthritis successfully treated with adalimumab. PMID- 24813848 TI - Erosive pustular dermatosis of the scalp treated with 0.1% mometasone furoate cream. PMID- 24813849 TI - RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. AB - Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1(-/-) mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1(-/-) progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1(-/-) neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1(-/-)Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal lethality, but only Ripk1(-/-)Ripk3(-/-)Casp8(-/-) mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation. PMID- 24813851 TI - Does language ambiguity in clinical practice justify the introduction of standard terminology? An integrative review. AB - AIMS AND OBJECTIVES: To research the use of ambiguous language in written information concerning patients' functioning and to identify problems resulting from the use of ambiguous language in clinical practice. BACKGROUND: Many projects that aimed to introduce standard terminology concerning patients' functioning in clinical practice are unsuccessful because standard terminology is rarely used in clinical practice. These projects mainly aim to improve communication by reducing ambiguous language. Considering their lack of success, the validity of the argument that language ambiguity is used in clinical practice is questioned. DESIGN: An integrative literature review. METHODS: A systematic search of the MEDLINE (1950-2012) and CINAHL (1982-2012) databases was undertaken, including empirical and theoretical literature. The selected studies were critically appraised using a data assessment and extraction form. RESULTS: Seventeen of 767 papers were included in the review and synthesis. The use of ambiguous language in written information concerning patients' functioning was demonstrated. Problems resulting from the use of ambiguous language in clinical practice were not identified. However, several potential problems were suggested, including hindered clinical decision-making and limited research opportunities. CONCLUSION: The results of this review demonstrated the use of ambiguous language concerning patients' functioning, but health professionals in clinical practice did not experience this issue as a problem. This finding might explain why many projects aimed at introducing standard terminology concerning functioning in clinical practice to solve problems caused by ambiguous language are often unsuccessful. Language ambiguity alone is not a valid argument to justify the introduction of standard terminology. RELEVANCE TO CLINICAL PRACTICE: The introduction of standard terminology concerning patients' functioning will only be successful when clinical practice requires the aggregation and reuse of data from electronic patient records for different purposes, including multidisciplinary decision-making and research. PMID- 24813850 TI - RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. AB - Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1(-/-) mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1(-/-)tnfr1(-/-) mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1. PMID- 24813852 TI - Spermatangium formation and sperm discharge in the Japanese pygmy squid Idiosepius paradoxus. AB - In cephalopods, sperm discharge is an important event not only for sperm transfer but also influencing sperm storage capacity of attached spermatangia (everted spermatophores). To investigate sperm discharge from spermatangia and the condition of naturally attached spermatangia in Japanese pygmy squid (Idiosepius paradoxus) we (i) investigated the morphology of spermatophores and spermatangia, and the process of spermatophore evagination and sperm discharge from spermatangia obtained in vitro; (ii) observed spermatangia that were naturally attached to female squids at 6, 12, 18, 24 and 48 h after copulation to investigate alterations in naturally attached spermatangia with time. The spermatophore of I. paradoxus is slender and cylindrical and consists of a sperm mass, a cement body and an ejaculatory apparatus, which is similar to those of loliginid squids. The spermatangium is fishhook-shaped, its distal end being open and narrow. After the spermatangium is formed, the sperm mass gradually moves to the open end of the spermatangium, from where sperm are released. Sperm discharge is a rapid process immediately after the beginning of sperm release, but within 5 min changes to an intermittent release of sperm. Although the volume of residual spermatozoa differed among spermatangia that were naturally attached to a single individual, the probability that spermatangia would be empty increased with time. Most naturally attached spermatangia discharged almost all of their spermatozoa within 24h after copulation, and no spermatangia were attached to females 48 h after copulation. These results suggest that sperm transfer from the spermatangium to the seminal receptacle must occur within 24h, and that the spermatangium functions as a transient sperm storage organ in pygmy squids. PMID- 24813853 TI - Understanding carbamoyl phosphate synthetase (CPS1) deficiency by using the recombinantly purified human enzyme: effects of CPS1 mutations that concentrate in a central domain of unknown function. AB - Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an inborn error of the urea cycle that is due to mutations in the CPS1 gene. In the first large repertory of mutations found in CPS1D, a small CPS1 domain of unknown function (called the UFSD) was found to host missense changes with high frequency, despite the fact that this domain does not host substrate-binding or catalytic machinery. We investigate here by in vitro expression studies using baculovirus/insect cells the reasons for the prominence of the UFSD in CPS1D, as well as the disease causing roles and pathogenic mechanisms of the mutations affecting this domain. All but three of the 18 missense changes found thus far mapping in this domain in CPS1D patients drastically decreased the yield of pure CPS1, mainly because of decreased enzyme solubility, strongly suggesting misfolding as a major determinant of the mutations negative effects. In addition, the majority of the mutations also decreased from modestly to very drastically the specific activity of the fraction of the enzyme that remained soluble and that could be purified, apparently because they decreased V(max). Substantial although not dramatic increases in K(m) values for the substrates or for N-acetyl-L-glutamate were observed for only five mutations. Similarly, important thermal stability decreases were observed for three mutations. The results indicate a disease causing role for all the mutations, due in most cases to the combined effects of the low enzyme level and the decreased activity. Our data strongly support the value of the present expression system for ascertaining the disease-causing potential of CPS1 mutations, provided that the CPS1 yield is monitored. The observed effects of the mutations have been rationalized on the basis of an existing structural model of CPS1. This model shows that the UFSD, which is in the middle of the 1462-residue multidomain CPS1 protein, plays a key integrating role for creating the CPS1 multidomain architecture leading us to propose here a denomination of "Integrating Domain" for this CPS1 region. The majority of these 18 mutations distort the interaction of this domain with other CPS1 domains, in many cases by causing improper folding of structural elements of the Integrating Domain that play key roles in these interactions. PMID- 24813854 TI - Utility of the diagnostic interview schedule for children for assessing Tourette syndrome in children. AB - OBJECTIVE: The Diagnostic Interview Schedule for Children IV (DISC) has been used extensively in research and screening. Despite wide use, little information exists on the validity of the DISC for diagnosing tic disorders. METHODS: Participants were 181 youth with expert clinician-diagnosed Tourette syndrome (TS). RESULTS: Using expert clinician-diagnosed TS as the gold standard, the sensitivity of the DISC-Y (youth, 0.27) and DISC-P (parent, 0.44) was poor. The DISC-Y identified 29.7% of youth with diagnosed TS whereas the DISC-P identified 47.4% of cases. Only 54% of cases of TS were detected by either the DISC-Y or -P. Diagnostic agreement between the DISC and expert clinician diagnosis was poor. The DISC-Y/P results did not differ as a function of tic severity. CONCLUSIONS: Despite utility for assessing child psychiatric disorders, the sensitivity of the DISC for detecting TS appears poor. This study suggests that DISC has low agreement with expert clinician diagnosis of TS. Findings highlight the need for modification of the DISC and/or the identification and development of more sensitive measures for TS screening. PMID- 24813856 TI - Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells. AB - Alternative RNA splicing (AS) regulates proteome diversity, including isoform specific expression of several pluripotency genes. Here, we integrated global gene expression and proteomic analyses and identified a molecular signature suggesting a central role for AS in maintaining human pluripotent stem cell (hPSC) self-renewal. We demonstrate that the splicing factor SFRS2 is an OCT4 target gene required for pluripotency. SFRS2 regulates AS of the methyl-CpG binding protein MBD2, whose isoforms play opposing roles in maintenance of and reprogramming to pluripotency. Although both MDB2a and MBD2c are enriched at the OCT4 and NANOG promoters, MBD2a preferentially interacts with repressive NuRD chromatin remodeling factors and promotes hPSC differentiation, whereas overexpression of MBD2c enhances reprogramming of fibroblasts to pluripotency. The miR-301 and miR-302 families provide additional regulation by targeting SFRS2 and MDB2a. These data suggest that OCT4, SFRS2, and MBD2 participate in a positive feedback loop, regulating proteome diversity in support of hPSC self renewal and reprogramming. PMID- 24813858 TI - Inhibition of vascular calcification by block of intermediate conductance calcium activated potassium channels with TRAM-34. AB - Vascular calcifications are a hallmark of advanced cardiovascular disease in patients with chronic kidney disease. A key event is the transition of contractile vascular smooth muscle cells (VSMC) into an osteoblast-like phenotype, promoting a coordinated process of vascular remodeling resembling bone mineralization. Intermediate-conductance calcium-activated potassium channels (KCa3.1) are expressed in various tissues including VSMC. Aiming for novel therapeutic targets in vascular calcification, we here studied effects of KCa3.1 inhibition on VSMC calcification by the specific KCa3.1 inhibitor TRAM-34. Calcification in the murine VSMC cell line MOVAS-1 and primary rat VSMC was induced by calcification medium (CM) containing elevated levels of PO4(3-) and Ca(2+). Cell signaling, calcification markers, and release of nitric oxide and alkaline phosphatase were assessed by luciferase reporter plasmids, RT-PCR and specific enzymatic assays, respectively. KCa3.1 gene silencing was achieved by siRNA experiments. TRAM-34 at 10nmol/l, decreased CM-induced calcification and induced NO release of VSMC accompanied by decreased TGF-beta signaling. The CM induced mRNA expressions of osterix, osteocalcin, matrix-metalloproteinases (MMP) 2/-9 were reduced by TRAM-34 while osteopontin expression was increased. Further, TRAM-34 attenuated the CM- and TNF-alpha-induced activation of NF-kappaB and reduced the release of MMP-2/-9 by VSMC. Finally, TRAM-34 abrogated CM-induced apoptosis and KCa3.1 gene silencing protected VSMC from CM-induced onset of calcification. In summary, TRAM-34 interferes with calcification relevant signaling of NF-kappaB and TGF-beta thereby blocking the phenotypic transition/calcification of VSMC. We conclude that the results provide a rationale for further studies regarding a possible therapeutic role of KCa3.1 inhibition by TRAM-34 or other inhibitors in vascular calcification. PMID- 24813859 TI - The burden of caring for people with dementia at the end of life in nursing homes: a postdeath study among nursing staff. AB - AIMS: To investigate how often nursing staff perceive caring for nursing home residents with dementia at the end of life as an emotional and/or physical burden, and to identify associated factors. DESIGN: Postdeath study conducted in 2010 in Flanders, Belgium. Nursing homes were selected through random clustersampling. METHODS: All residents who died with dementia in a three-month period were identified, and a structured questionnaire was completed by the nurse mostly involved. Nursing staff were asked to indicate how they perceived burden of caregiving for this resident on 10-point scale. RESULTS: Sixty-nine out of 120 nursing homes (response rate 58%) participated in the study. In 37% and 32% of cases, respectively, the nursing staff reported that they perceived themselves as experiencing a high emotional and physical burden. In cases where the resident had capacity for medical decision making during the last week of life and where the nurse had spoken with a relative about wishes for medical end-of-life treatments, they were more likely to report an emotional burden. A physical burden was more likely to be reported where the resident had decubitus ulcers or had developed pneumonia. CONCLUSION: In one-third of cases, nursing staff experienced a high emotional and/or physical burden. While experiencing a physical burden seems to be related to the poorer clinical status of the resident, an emotional burden was more likely to be related to greater and closer contact with the resident or a relative and to the nurse being involved in the process of care and decision making in the last phase of life. IMPLICATIONS FOR PRACTICE: This study highlights the need to support nursing home staff in providing compassionate end-of-life care for people with dementia and suggests that both the physical and emotional burdens in staff should be monitored regularly to achieve optimal working. PMID- 24813857 TI - Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. AB - Hematopoietic stem cells (HSCs) maintain homeostasis and regenerate the blood system throughout life. It has been postulated that HSCs may be uniquely capable of preserving their genomic integrity in order to ensure lifelong function. To directly test this, we quantified DNA damage in HSCs and downstream progenitors from young and old mice, revealing that strand breaks significantly accrue in HSCs during aging. DNA damage accumulation in HSCs was associated with broad attenuation of DNA repair and response pathways that was dependent upon HSC quiescence. Accordingly, cycling fetal HSCs and adult HSCs driven into cycle upregulated these pathways leading to repair of strand breaks. Our results demonstrate that HSCs are not comprehensively geno-protected during aging. Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. These results provide a potential mechanism through which premalignant mutations accrue in HSCs. PMID- 24813860 TI - Inpatient dysglycemia and clinical outcomes: association or causation? PMID- 24813861 TI - An unusual case of drug-resistant epilepsy in a child with non-celiac gluten sensitivity. PMID- 24813862 TI - Ruling out Legionella in community-acquired pneumonia. AB - BACKGROUND: Assessing the likelihood for Legionella sp. in community-acquired pneumonia is important because of differences in treatment regimens. Currently used antigen tests and culture have limited sensitivity with important time delays, making empirical broad-spectrum coverage necessary. Therefore, a score with 6 variables recently has been proposed. We sought to validate these parameters in an independent cohort. METHODS: We analyzed adult patients with community-acquired pneumonia from a large multinational database (Community Acquired Pneumonia Organization) who were treated between 2001 and 2012 with more than 4 of the 6 prespecified clinical variables available. Association and discrimination were assessed using logistic regression analysis and area under the curve (AUC). RESULTS: Of 1939 included patients, the infectious cause was known in 594 (28.9%), including Streptococcus pneumoniae in 264 (13.6%) and Legionella sp. in 37 (1.9%). The proposed clinical predictors fever, cough, hyponatremia, lactate dehydrogenase, C-reactive protein, and platelet count were all associated or tended to be associated with Legionella cause. A logistic regression analysis including all these predictors showed excellent discrimination with an AUC of 0.91 (95% confidence interval, 0.87-0.94). The original dichotomized score showed good discrimination (AUC, 0.73; 95% confidence interval, 0.65-0.81) and a high negative predictive value of 99% for patients with less than 2 parameters present. CONCLUSIONS: With the use of a large independent patient sample from an international database, this analysis validates previously proposed clinical variables to accurately rule out Legionella sp., which may help to optimize initial empiric therapy. PMID- 24813863 TI - Massive: hemorrhagic adrenal pseudocyst. PMID- 24813865 TI - Serum irisin levels, precocious myocardial infarction, and healthy exceptional longevity. AB - BACKGROUND: Skeletal muscles produce irisin. Growing controversy exists on the association between this myokine and chronic disease risk. On the basis of the potential protective effects that irisin could exert on both vascular function and skeletal muscle mass, we hypothesized that an elevated level of this molecule may contribute to successful aging. METHODS: Serum irisin levels were measured using enzyme-linked immunosorbent assay in disease-free centenarians, young healthy controls, and patients with precocious acute myocardial infarction. RESULTS: We found the highest levels of serum irisin in disease-free centenarians (35.3 +/- 5.5 ng/mL) compared with young healthy controls (20.7 +/- 6.3 ng/mL) and especially with young patients with acute myocardial infarction (15.1 +/- 5.4 ng/mL). CONCLUSIONS: Our study demonstrates that healthy centenarians are characterized by increased serum irisin levels, whereas levels of this molecule were found to be significantly lower in young patients with myocardial infarction. Our findings may prompt further research into the role played by irisin not only in vascular disorders but also in life span modulation. PMID- 24813864 TI - Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985-2009). AB - BACKGROUND: The clinical epidemiology of venous thromboembolism has changed recently because of advances in identification, prophylaxis, and treatment. We sought to describe secular trends in the occurrence of venous thromboembolism among residents of the Worcester, Massachusetts, metropolitan statistical area. METHODS: Population-based methods were used to monitor trends in event rates of first-time or recurrent venous thromboembolism in 5025 Worcester, Massachusetts, metropolitan statistical area residents who were diagnosed with acute pulmonary embolism or lower-extremity deep vein thrombosis during 9 annual periods between 1985 and 2009. Medical records were reviewed by abstractors and validated by clinicians. RESULTS: Age- and sex-adjusted annual event rates for first-time venous thromboembolism increased from 73 (95% confidence interval [CI], 64-82) per 100,000 in 1985/1986 to 133 (CI, 122-143) in 2009, primarily because of an increase in pulmonary embolism. The rate of recurrent venous thromboembolism decreased from 39 (CI, 32-45) in 1985/1986 to 19 (CI, 15-23) in 2003, and then increased to 35 (CI, 29-40) in 2009. There was an increasing trend in using noninvasive diagnostic testing, with approximately half of tests being invasive in 1985/1986 and almost all noninvasive by 2009. CONCLUSIONS: Despite advances in identification, prophylaxis, and treatment between 1985 and 2009, the annual event rate of venous thromboembolism has increased and remains high. Although these increases partially may be due to increased sensitivity of diagnostic methods, especially for pulmonary embolism, they also may imply that current prevention and treatment strategies are less than optimal. PMID- 24813866 TI - Exposure to 9,10-phenanthrenequinone accelerates malignant progression of lung cancer cells through up-regulation of aldo-keto reductase 1B10. AB - Inhalation of 9,10-phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust, exerts fatal damage against a variety of cells involved in respiratory function. Here, we show that treatment with high concentrations of 9,10-PQ evokes apoptosis of lung cancer A549 cells through production of reactive oxygen species (ROS). In contrast, 9,10-PQ at its concentrations of 2 and 5 MUM elevated the potentials for proliferation, invasion, metastasis and tumorigenesis, all of which were almost completely inhibited by addition of an antioxidant N-acetyl-l cysteine, inferring a crucial role of ROS in the overgrowth and malignant progression of lung cancer cells. Comparison of mRNA expression levels of six aldo-keto reductases (AKRs) in the 9,10-PQ-treated cells advocated up-regulation of AKR1B10 as a major cause contributing to the lung cancer malignancy. In support of this, the elevation of invasive, metastatic and tumorigenic activities in the 9,10-PQ-treated cells was significantly abolished by the addition of a selective AKR1B10 inhibitor oleanolic acid. Intriguingly, zymographic and real time PCR analyses revealed remarkable increases in secretion and expression, respectively, of matrix metalloproteinase 2 during the 9,10-PQ treatment, and suggested that the AKR1B10 up-regulation and resultant activation of mitogen activated protein kinase cascade are predominant mechanisms underlying the metalloproteinase induction. In addition, HPLC analysis and cytochrome c reduction assay in in vitro 9,10-PQ reduction by AKR1B10 demonstrated that the enzyme catalyzes redox-cycling of this quinone, by which ROS are produced. Collectively, these results suggest that AKR1B10 is a key regulator involved in overgrowth and malignant progression of the lung cancer cells through ROS production due to 9,10-PQ redox-cycling. PMID- 24813868 TI - Pressing mitochondrial genetics forward. AB - Mitochondria are crucial for many cellular functions. In this issue of Cell Reports, studies from Lanning et al. and Wolf and Mootha describe RNAi approaches to screening the mitochondrial proteome. Unexpectedly, they uncover key roles for two poorly characterized mitochondrial proteins: AK4 and FASTKD4. These studies provide examples of the power of forward genetic screens, even when screening a subset of genes, in deciphering functions of previously mysterious mitochondrial proteins. PMID- 24813867 TI - Depth-related distribution of a key gene of the tetraether lipid biosynthetic pathway in marine Thaumarchaeota. AB - The distribution of isoprenoid glycerol dialkyl glycerol tetraethers (GDGT) lipids synthesized by Thaumarchaeota has been shown to be temperature-dependent in world oceans. Depth-related differences in the ammonia monooxygenase (amoA) of Thaumarchaeota have led to the classification of 'shallow' and 'deep water' clusters, potentially affecting GDGT distributions. Here, we investigate if this classification is also reflected in a key gene of the thaumarchaeotal lipid biosynthetic pathway coding for geranylgeranylglyceryl phosphate (GGGP) synthase. We investigated metagenomic databases, suspended particulate matter and surface sediment of the Arabian Sea oxygen minimum zone. These revealed significant differences in amoA and GGGP synthase between 'shallow' and 'deep water' Thaumarchaeota. Intriguingly, amoA and GGGP synthase sequences of benthic Thaumarchaeota clustered with the 'shallow water' rather than with 'deep water' Thaumarchaeota. This suggests that pressure and temperature are unlikely factors that drive the differentiation, and suggests an important role of ammonia concentration that is higher in benthic and 'shallow water' niches. Analysis of the relative abundance of GDGTs in the Arabian Sea and in globally distributed surface sediments showed differences in GDGT distributions from subsurface to deep waters that may be explained by differences in the GGGP synthase, suggesting a genetic control on GDGT distributions. PMID- 24813869 TI - Relationship between increases in BMI and changes in periodontal status: a prospective cohort study. AB - AIM: The purpose of this prospective cohort study was to investigate whether body mass index (BMI) and oral health behaviour are related to changes in periodontal status in Japanese university students. MATERIALS AND METHODS: Students (n = 224) who were interested in receiving oral health examinations before entering university and before graduation were included in the analysis. Subjects were investigated regarding the correlations of oral health behaviours and increases in BMI with the percentage of bleeding on probing (%BOP) and Community Periodontal Index (CPI) scores as indicators of changes in periodontal status. RESULTS: The risk of increased %BOP was associated with the non-use of dental floss (adjusted odds ratio [OR]: 3.11; 95% confidence interval [CI]: 1.31-7.37; p < 0.05), whereas the risk of increased CPI score was associated with increases in BMI (OR: 1.95; 95% CI: 1.05-3.65; p < 0.05) and simplified oral hygiene index score (OR: 2.28; 95% CI: 1.23-4.22; p < 0.01). CONCLUSION: Increases in BMI were associated with worsening of periodontal status, defined as increased CPI score in Japanese university students, whereas lack of inter-dental cleaning was associated with exacerbated gingival bleeding. PMID- 24813870 TI - Cervicomedullary spinal stenosis and ventriculomegaly in a child with developmental delay due to chromosome 16p12.1 microdeletion syndrome. AB - We present a case of a 1-year-old female child who was referred to the Early Intervention Clinic for evaluation of developmental delay and progressively enlarging head size. Developmental assessment revealed significant motor delay with borderline cognitive impairment. MRI of the brain revealed generalized ventriculomegaly secondary to narrowing of the spinal canal at the cervicomedullary junction. Targeted array-based comparative genomic hybridization showed deletion of approximately 602 kbp from band p12.2 region of the short arm of chromosome 16, which encompasses 16p12.1 microdeletion syndrome. The 16p12.1 microdeletion syndrome has been recently recognized as an important contributor of developmental delay and other neuropsychiatric phenotypes in the child. To date, no case of cervicomedullary spinal canal stenosis with hydrocephalus has been reported with 16p12.1 microdeletion syndrome. PMID- 24813871 TI - Ecology of phlebotomine sand flies and Leishmania infantum infection in a rural area of southern Italy. AB - Phlebotomine sand flies are insects of major medico-veterinary significance in the Mediterranean region, as they may transmit pathogens to animals and humans, including viruses and protozoa. The present study was conducted in southern Italy, in an area where visceral leishmaniasis caused by Leishmania infantum is endemic. Insects were collected monthly during two consecutive years using light traps set in five different ecologic contexts (i.e., a stonewall near a woodhouse, a tree near volcanic rocks in a high-altitude area, a tree trunk in a meadow habitat, a sheep stable, and a chicken coop) and weekly in one site (the garage of a private house). A total of 13,087 specimens were collected and six species identified (i.e., Phlebotomus perfiliewi, Phlebotomus perniciosus, Phlebotomus neglectus, Phlebotomus papatasi, Phlebotomus mascittii, and Sergentomyia minuta), representing 75% of the total number of phlebotomine species found in Italy. P. perfiliewi was the most abundant species, comprising 88.14% of the specimens identified. The greatest species diversity and abundance was recorded in human dwellings and in animal sheds. Sand flies were active from June to October, peaking in July-August in 2010 and July-September in 2011. Part of the females (n=8865) was grouped into 617 pools (range, 1-10 insects each) according to species, feeding status, day and site of collection. A total of four pools (10 non-engorged specimens each) and one engorged female of P. perfiliewi were positive for L. infantum. This study confirms that phlebotomine vectors in southern Italy are highly adapted to human-modified environments (e.g., animal sheds) and that P. perfiliewi is a major vector of L. infantum in some regions of southern Italy. PMID- 24813872 TI - Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. AB - Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p.His183Leu/p.Arg190dup (P1 and P2) and the previously described mutations p.Ile96Thr/p.Ser174fs (P3 and P4). Expression analysis showed p.His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species (ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type. PMID- 24813873 TI - Incidence, risk factors, and outcomes for Enterococcus spp. blood stream infections: a population-based study. AB - BACKGROUND: Enterococci are a clinically significant cause of bloodstream infections (BSI), particularly in the nosocomial setting. The purpose of this study was to characterize the incidence, risk factors for acquisition, microbiological characteristics and mortality of enterococcal BSI within the well defined population of a large Canadian health region. METHODS: Surveillance for all episodes of enterococcal BSI occurring among residents of the Calgary Health Zone (population 1.2 million) between 2000 and 2008 was conducted using an electronic surveillance system. Clinical features, microbiology, and outcomes were obtained. RESULTS: A total of 710 incident episodes of enterococcal BSI were identified for an annual incidence of 6.9 episodes per 100,000; the incidences of E. faecalis and E. faecium BSI were 4.5, and 1.6 per 100,000, respectively. Enterococcus faecalis infections were associated with a urinary focus, genitourinary malignancy, and abnormal genitourinary anatomy. E. faecium infections were associated with a gastrointestinal focus. Resistance to ampicillin, vancomycin and ciprofloxacin was higher in E. faecium infection. The overall case fatality rate was 22.8%, and was higher for E. faecium infection. CONCLUSIONS: This is the second population-based study to assess the risk factors for enterococcal BSI and compare the characteristics of infection with E. faecalis and E. faecium. Results suggest that BSI with E. faecalis and E. faecium should be regarded as two clinically different entities with unique sets of risk factors and microbiologic characteristics. PMID- 24813875 TI - Serial home-based self-collection of anterior nasal swabs to detect Staphylococcus aureus carriage in a randomized population-based study in Germany. AB - OBJECTIVES: Participant-collected serial nasal swabs would be a cost-efficient feature of prospective population-based microbiological studies. We examined the feasibility of serial anterior nasal self-swabbing for Staphylococcus aureus detection in a prospective population-based study in Braunschweig, Germany, and assessed the impact of three interventions on participation and compliance. METHODS: Two thousand twenty-six inhabitants were selected randomly from the resident registries and asked to self-collect a nasal swab monthly from July 2012 to January 2013 and return it by mail. The swabs were tested for the presence of S. aureus. Participation and compliance were assessed in four study groups (incremental cash incentive, participation in a lottery, reminder by mail, and control group without incentive or reminder). RESULTS: Baseline participation was highest in the cash incentive group (24%; 123/504) and lowest in the reminder group (16%; 83/509). Approximately 90% of the participants in all groups returned the swabs each month, demonstrating high compliance irrespective of the intervention. Laboratory analyses showed that most swabs were usable for bacteriological studies. S. aureus was detected at the expected frequency of 20 27%. CONCLUSIONS: Home-based serial nasal self-swabbing proved to be feasible and highly acceptable and promises to be a cost-efficient tool for large-scale prospective population-based studies on bacterial infection or colonization. PMID- 24813874 TI - Complex prosthetic joint infections due to carbapenemase-producing Klebsiella pneumoniae: a unique challenge in the era of untreatable infections. AB - OBJECTIVES: Limited clinical experience exists regarding the management of prosthetic joint infection (PJI) due to multidrug-resistant (MDR) Gram-negative organisms. We review three cases of carbapenem-resistant Klebsiella pneumoniae (CRKP) complicating PJI. METHODS: This was a retrospective study of all patients at a tertiary care institution with CRKP complicating PJI between January 2007 and December 2010. Demographic data, procedures, organisms involved, length of stay, antibiotic treatments, and outcomes were collected. Antimicrobial susceptibility testing was performed on CRKP isolates, and the mechanism of resistance was ascertained by PCR. RESULTS: This analysis demonstrated that: (1) the CRKP possessed blaKPC and were difficult to eradicate (persistent) in PJI; (2) multiple surgeries and antibiotic courses were undertaken and patients required a prolonged length of stay; (3) resistance to colistin and amikacin emerged on therapy; (4) the same strain of CRKP may be responsible for relapse of infection; (5) significant morbidity and mortality resulted. CONCLUSIONS: These cases highlight the opportunistic and chronic nature of CRKP in PJIs and the need for aggressive medical and surgical treatment. Further investigations of the management of CRKP PJI and new drug therapies for infections due to MDR Gram negative organisms are urgently needed. PMID- 24813876 TI - [A strategic plan for the Spanish Academy of Dermatology and Venereology]. PMID- 24813877 TI - Quinazolines: new horizons in anticonvulsant therapy. AB - The search for novel anticonvulsants with more selectivity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. The potency and selectivity in the pharmacological response of quinazolines as anticonvulsant have attracted the attention of many researchers to explore this framework for its potential. It is, therefore, topic of interest to study development of new synthetic strategies and their anticonvulsant potential based on the most recent knowledge emerging from the latest research. This review reports current progress in the area of new biologically active quinazoline scaffold as potent anticonvulsant. It is a sincere attempt to compile the synthetic and design aspects of quinazoline derivatives with significant anticonvulsant action. This structural class of compound can prove to be useful for the design and development of potent anticonvulsant agents. PMID- 24813878 TI - In vitro and in vivo evaluation of the antidiabetic activity of ursolic acid derivatives. AB - In this study, a series of ursolic acid derivatives were synthesized, and their structures were confirmed. The activity of the synthesized compounds against alpha-glucosidase was determined in vitro. The results suggested that all compounds have significant inhibitory activity, especially compounds 3-5 and 8, the IC50 values of which were 2.66 +/- 0.84, 1.01 +/- 0.44, 3.26 +/- 0.22, and 3.24 +/- 0.21 MUM. These compounds were more potent than acarbose (positive control) against alpha-glucosidase. Kinetic studies were performed to determine the mechanism of inhibition by compounds 3-5 and 8. The kinetic inhibition studies indicated that compound 3 was a non-competitive inhibitor, and the inhibition constant Ki was calculated to be 2.67 +/- 0.19 MUM. Moreover, the kinetic inhibition studies of compounds 4, 5 and 8 demonstrated that they were mixed-type inhibitors. Furthermore, the actual pharmacological potentials of synthesized compounds 3 and 4 were demonstrated by the reduction of postprandial blood glucose levels in normal Kunming mice. The hypoglycemic effects of these compounds were more evident 30 and 60 min after maltose ingestion (P < 0.05), which was similar to the effect displayed by the positive control, acarbose. PMID- 24813879 TI - Anticonvulsant evaluation of clubbed indole-1,2,4-triazine derivatives: a synthetic approach. AB - A series of thirty indole C-3 substituted 5-amino-6-(5-substituted-2-phenyl-1H indol-1-yl)-4,5-dihydro-1,2,4-triazine-3(2H)-thione 5a-f, 6a-f, 7a-f, 8a-f and 9a f were synthesized to explore prospective anticonvulsant agents. The derivative 1 (1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H indol-3-yl)ethanone (6b) had significant activity in maximal electroshock test with minimal duration of limb extension (5.40 +/- 0.61 s) and quantitative median dose of 7 mg/kg. In subcutaneous pentylenetetrazole screen 1-(5-amino-3-thioxo 2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indole-3-sulfonamide (7b) increased the seizure latency to onset of clonus and was effective at a median dose of 35 mg/kg. An in vitro radioligand binding assay on sodium channel and gamma-amino butyric acid estimation was also performed on active compounds to perceive the mechanistic procedure responsible for it action. PMID- 24813881 TI - Benzofurazan derivatives as antifungal agents against phytopathogenic fungi. AB - A series of benzofurazan derivatives were prepared and evaluated for their biological activities against four important phytopathogenic fungi, namely, Rhizoctonia solani, Sclerotinia sclerotiorum, Fusarium graminearum and Phytophthora capsici, using the mycelium growth inhibition method. The structures of these compounds were characterized by (1)H NMR, (13)C NMR, and HRMS. N-(3 chloro-4-fluorophenyl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (A3) displayed the maximum antifungal activity against R. solani (IC50 = 1.91 MUg/mL), which is close to that of the positive control Carbendazim (IC50 = 1.42 MUg/mL). For other benzofurazan derivatives with nitro group at R(4) position (A series), 9 out of 30 compounds exhibited high antifungal effect against strain R. solani, with IC50 values less than 5 MUg/mL. Most of the derivatives with substituents at R(2) and R(3) positions (B series) displayed moderate growth inhibition against S. sclerotiorum (IC50 < 25 MUg/mL). Also, several benzofuran derivatives with nitro group at R(4) position and another conjugated aromatic ring at the R(1) position of the phenyl ring displayed high antifungal capability against strain R. solani. Compounds with substituents at R(2) and R(3) position had moderate efficacy against strain S. sclerotiorum. PMID- 24813880 TI - Probing the aurone scaffold against Plasmodium falciparum: design, synthesis and antimalarial activity. AB - A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds. PMID- 24813882 TI - Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease. AB - The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic alpha-aminotrile4-(1 benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 +/- 0.7 MUM; MAO B (IC50 = 10.2 +/- 0.9 MUM); AChE (IC50 = 1.8 +/- 0.1 MUM); BuChE (IC50 = 1.6 +/- 0.25 MUM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice. PMID- 24813884 TI - Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. AB - Previous work has shown that some cancer cells are highly dependent on serine/glycine uptake for proliferation. Although serine and glycine can be interconverted and either might be used for nucleotide synthesis and one-carbon metabolism, we show that exogenous glycine cannot replace serine to support cancer cell proliferation. Cancer cells selectively consumed exogenous serine, which was converted to intracellular glycine and one-carbon units for building nucleotides. Restriction of exogenous glycine or depletion of the glycine cleavage system did not impede proliferation. In the absence of serine, uptake of exogenous glycine was unable to support nucleotide synthesis. Indeed, higher concentrations of glycine inhibited proliferation. Under these conditions, glycine was converted to serine, a reaction that would deplete the one-carbon pool. Providing one-carbon units by adding formate rescued nucleotide synthesis and growth of glycine-fed cells. We conclude that nucleotide synthesis and cancer cell proliferation are supported by serine--rather than glycine--consumption. PMID- 24813883 TI - Isolation of chromatin from dysfunctional telomeres reveals an important role for Ring1b in NHEJ-mediated chromosome fusions. AB - When telomeres become critically short, DNA damage response factors are recruited at chromosome ends, initiating a cellular response to DNA damage. We performed proteomic isolation of chromatin fragments (PICh) in order to define changes in chromatin composition that occur upon onset of acute telomere dysfunction triggered by depletion of the telomere-associated factor TRF2. This unbiased purification of telomere-associated proteins in functional or dysfunctional conditions revealed the dynamic changes in chromatin composition that take place at telomeres upon DNA damage induction. On the basis of our results, we describe a critical role for the polycomb group protein Ring1b in nonhomologous end joining (NHEJ)-mediated end-to-end chromosome fusions. We show that cells with reduced levels of Ring1b have a reduced ability to repair uncapped telomeric chromatin. Our data represent an unbiased isolation of chromatin undergoing DNA damage and are a valuable resource to map the changes in chromatin composition in response to DNA damage activation. PMID- 24813885 TI - MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. AB - Although mixed lineage kinase domain-like (MLKL) protein has emerged as a specific and crucial protein for necroptosis induction, how MLKL transduces the death signal remains poorly understood. Here, we demonstrate that the full four helical bundle domain (4HBD) in the N-terminal region of MLKL is required and sufficient to induce its oligomerization and trigger cell death. Moreover, we found that a patch of positively charged amino acids on the surface of the 4HBD binds to phosphatidylinositol phosphates (PIPs) and allows recruitment of MLKL to the plasma membrane. Importantly, we found that recombinant MLKL, but not a mutant lacking these positive charges, induces leakage of PIP-containing liposomes as potently as BAX, supporting a model in which MLKL induces necroptosis by directly permeabilizing the plasma membrane. Accordingly, we found that inhibiting the formation of PI(5)P and PI(4,5)P2 specifically inhibits tumor necrosis factor (TNF)-mediated necroptosis but not apoptosis. PMID- 24813886 TI - MUS81-EME2 promotes replication fork restart. AB - Replication forks frequently stall at regions of the genome that are difficult to replicate or contain lesions that cause replication blockage. An important mechanism for the restart of a stalled fork involves endonucleolytic cleavage that can lead to fork restoration and replication progression. Here, we show that the structure-selective endonuclease MUS81-EME2 is responsible for fork cleavage and restart in human cells. The MUS81-EME2 protein, whose actions are restricted to S phase, is also responsible for telomere maintenance in telomerase-negative ALT (Alternative Lengthening of Telomeres) cells. In contrast, the G2/M functions of MUS81, such as the cleavage of recombination intermediates and fragile site expression, are promoted by MUS81-EME1. These results define distinct and temporal roles for MUS81-EME1 and MUS81-EME2 in the maintenance of genome stability. PMID- 24813887 TI - The drug vehicle and solvent N-methylpyrrolidone is an immunomodulator and antimyeloma compound. AB - N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP was identified as an acetyllysine mimetic and candidate bromodomain ligand. Accordingly, NMP-treated cells demonstrated transcriptional overlap with BET-bromodomain inhibition, including downregulation of cMYC and IRF4. NMP's immunomodulatory activity occurred at sub-BET inhibitory concentrations, and, despite phenotypic similarities to lenalidomide, its antimyeloma activity was independent of the IMiD targets cereblon and Ikaros-1/3. Thus, low-affinity yet broad-spectrum bromodomain inhibition by NMP mediates biologically potent, cereblon-independent immunomodulation and at higher doses targets malignant cells directly via BET antagonism. These data reveal that NMP is a functional acetyllysine mimetic with pleotropic antimyeloma and immunomodulatory activities. Our studies highlight the potential therapeutic benefits of NMP, the consequences of current human NMP exposures, and the need for reassessment of scientific literature where NMP was used as an "inert" drug delivery vehicle. PMID- 24813888 TI - Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. AB - Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs. PMID- 24813889 TI - Growth of the developing cerebral cortex is controlled by microRNA-7 through the p53 pathway. AB - Proper growth of the mammalian cerebral cortex is crucial for normal brain functions and is controlled by precise gene-expression regulation. Here, we show that microRNA-7 (miR-7) is highly expressed in cortical neural progenitors and describe miR-7 sponge transgenic mice in which miR-7-silencing activity is specifically knocked down in the embryonic cortex. Blocking miR-7 function causes microcephaly-like brain defects due to reduced intermediate progenitor (IP) production and apoptosis. Upregulation of miR-7 target genes, including those implicated in the p53 pathway, such as Ak1 and Cdkn1a (p21), is responsible for abnormalities in neural progenitors. Furthermore, ectopic expression of Ak1 or p21 and specific blockade of miR-7 binding sites in target genes using protectors in vivo induce similarly reduced IP production. Using conditional miRNA sponge transgenic approaches, we uncovered an unexpected role for miR-7 in cortical growth through its interactions with genes in the p53 pathway. PMID- 24813890 TI - Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions. AB - Leptin has beneficial effects on glucose metabolism via actions in the hypothalamus, but the roles of specific subgroups of neurons responsible for these antidiabetic effects remain unresolved. We generated diabetic Lep(ob/ob) or Lepr(db/db) mice lacking or re-expressing leptin receptors (LepRb) in subgroups of neurons to explore their contributions to leptin's glucose-lowering actions. We show that agouti-related peptide (AgRP)-expressing neurons are both required and sufficient to correct hyperglycemia by leptin. LepRb in pro-opiomelanocortin (POMC) neurons or steroidogenic factor-1 (SF1) neurons are not required. Furthermore, normalization of blood glucose by leptin is blunted in Lep(ob/ob)/MC4R-null mice, but not in Lep(ob/ob) mice lacking neuropeptide Y (NPY) or gamma-aminobutyric acid (GABA) in AgRP neurons. Leptin's ability to improve glucose balance is accompanied by a reduction in circulating glucagon. We conclude that AgRP neurons play a crucial role in glucose-lowering actions by leptin and that this requires the melanocortin system, but not NPY and GABA. PMID- 24813891 TI - The histone methyltransferase activity of MLL1 is dispensable for hematopoiesis and leukemogenesis. AB - Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here, we show that the SET domain, and thus HMT activity of MLL1, is dispensable for maintaining HSCs and supporting leukemogenesis driven by the MLL AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation is selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 is sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function. PMID- 24813894 TI - High-resolution mapping of protein concentration reveals principles of proteome architecture and adaptation. AB - A single yeast cell contains a hundred million protein molecules. How these proteins are organized to orchestrate living processes is a central question in biology. To probe this organization in vivo, we measured the local concentration of proteins based on the strength of their nonspecific interactions with a neutral reporter protein. We first used a cytosolic reporter and measured local concentrations for ~2,000 proteins in S. cerevisiae, with accuracy comparable to that of mass spectrometry. Localizing the reporter to membranes specifically increased the local concentration measured for membrane proteins. Comparing the concentrations measured by both reporters revealed that encounter frequencies between proteins are primarily dictated by their abundances. However, to change these encounter frequencies and restructure the proteome, as in adaptation, we find that changes in localization have more impact than changes in abundance. These results highlight how protein abundance and localization contribute to proteome organization and reorganization. PMID- 24813893 TI - Single-cell RNA sequencing reveals T helper cells synthesizing steroids de novo to contribute to immune homeostasis. AB - T helper 2 (Th2) cells regulate helminth infections, allergic disorders, tumor immunity, and pregnancy by secreting various cytokines. It is likely that there are undiscovered Th2 signaling molecules. Although steroids are known to be immunoregulators, de novo steroid production from immune cells has not been previously characterized. Here, we demonstrate production of the steroid pregnenolone by Th2 cells in vitro and in vivo in a helminth infection model. Single-cell RNA sequencing and quantitative PCR analysis suggest that pregnenolone synthesis in Th2 cells is related to immunosuppression. In support of this, we show that pregnenolone inhibits Th cell proliferation and B cell immunoglobulin class switching. We also show that steroidogenic Th2 cells inhibit Th cell proliferation in a Cyp11a1 enzyme-dependent manner. We propose pregnenolone as a "lymphosteroid," a steroid produced by lymphocytes. We speculate that this de novo steroid production may be an intrinsic phenomenon of Th2-mediated immune responses to actively restore immune homeostasis. PMID- 24813892 TI - Life extension factor klotho enhances cognition. AB - Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages. PMID- 24813895 TI - Regulation of FAS exon definition and apoptosis by the Ewing sarcoma protein. AB - The Ewing sarcoma protein EWS is an RNA and DNA binding protein implicated in transcription, pre-mRNA splicing, and DNA damage response. Using CLIP-seq, we identified EWS RNA binding sites in exonic regions near 5' splice sites. A prominent target was exon 6 of the FAS/CD95 receptor, which is alternatively spliced to generate isoforms with opposing activities in programmed cell death. Depletion and overexpression experiments showed that EWS promotes exon 6 inclusion and consequently the synthesis of the proapoptotic FAS/CD95 isoform, whereas an EWS-FLI1 fusion protein characteristic of Ewing sarcomas shows decreased activity. Biochemical analyses revealed that EWS binding promotes the recruitment of U1snRNP and U2AF65 to the splice sites flanking exon 6 and therefore exon definition. Consistent with a role for EWS in the regulation of programmed cell death, cells depleted of EWS show decreased sensitivity to FAS induced apoptosis, and elevated EWS expression enhances apoptosis in EWS haploinsufficient Ewing sarcoma cells. PMID- 24813897 TI - Cadm4 restricts the production of cardiac outflow tract progenitor cells. AB - Heart assembly requires input from two populations of progenitor cells, the first and second heart fields (FHF and SHF), that differentiate at distinct times and create different cardiac components. The cardiac outflow tract (OFT) is built through recruitment of late-differentiating, SHF-derived cardiomyocytes to the arterial pole of the heart. The mechanisms responsible for selection of an appropriate number of OFT cells from the SHF remain unclear. Here, we find that cell adhesion molecule 4 (cadm4) is essential for restricting the size of the zebrafish OFT. Knockdown of cadm4 causes dramatic OFT expansion, and overexpression of cadm4 results in a greatly diminished OFT. Moreover, cadm4 activity limits the production of OFT progenitor cells and the duration of their accumulation at the arterial pole. Together, our data suggest a role for cell adhesion in restraining SHF deployment to the OFT, perturbation of which could cause congenital OFT defects. PMID- 24813898 TI - In vitro antimicrobial activity of hydroxypyridinone hexadentate-based dendrimeric chelators alone and in combination with norfloxacin. AB - The antimicrobial activity of one 3-hydroxypyridin-4-one (HPO) hexadentate (1) and three HPO hexadentate-based dendrimeric chelators (2-4) was evaluated. They were found to exhibit marked inhibitory effect on the growth of two Gram-positive bacteria and two Gram-negative bacteria. The combination treatment of dendrimeric chelator 2 with norfloxacin against Staphyloccocus aureus and Escherichia coli showed a dramatic synergistic bactericidal effect. As the dendrimeric chelator has a large molecular weight, its combination with norfloxacin may find application in the treatment of external infections. PMID- 24813896 TI - APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. AB - Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways. PMID- 24813899 TI - Early detection and diagnosis of vascular calcification in patients with chronic kidney disease. PMID- 24813900 TI - OPRM1 polymorphism and lifetime suicide attempts among stabilized, methadone maintained outpatients. PMID- 24813901 TI - Extra-aortic commissuroplasty concomitant with fenestrated Fontan operation for neoaortic valve regurgitation after Norwood reconstruction. AB - We introduce a simple, less invasive surgical technique for treating neoaortic valve regurgitation (neoAR) after the Norwood procedure, with the aim of delaying reoperation for neoAR. A 31-month-old girl, with hypoplastic left heart syndrome, previously underwent 4 median sternotomies and was admitted to our hospital for a fenestrated Fontan operation. She presented with moderate neoAR, originating from a tricuspid neoaortic valve (neoAV), with the regurgitation oriented from the centre. Her neoAV annulus was dilated to twice its normal size. With the aim of delaying future neoAV intervention and minimizing the surgical invasiveness, we performed extra-aortic commissuroplasties on the 2 commissures that could be approached from the front during the Fontan operation, without inducing cardiac arrest. We used direct echocardiography and transoesophageal echocardiography to confirm the feasibility before applying this procedure. Her postoperative course was uneventful, and the postoperative echocardiography did not reveal any residual neoAR 5 months postoperatively. We believe that this technique is a useful surgical option for patients with moderate neoAR oriented from its centre and well-balanced tricuspid native pulmonary valves, and it might help to delay future neoAV interventions, with minimal surgical risk. PMID- 24813902 TI - Prognostic use of lactate to predict inpatient mortality in acute gastrointestinal hemorrhage. AB - BACKGROUND: Gastrointestinal hemorrhage (GIH) is a common complaint seen in the emergency department (ED) and carries a small but significant mortality rate. The principal purpose of this investigation was to determine whether an ED venous lactate as part of initial laboratory studies is predictive of mortality in patients admitted to the hospital for GIH. METHODS: Retrospective cohort study for 6 years at an urban tertiary referral hospital included all ED patients with the charted diagnosis of acute GIH. Serum lactate was drawn at the bedside as part of patient care after arrival to the ED at the discretion of the clinical team. Clinical parameters and inpatient mortality were collected from the medical record. Optimal cut points for lactate were derived using receiver operating characteristics curves and imputed into a multivariable logistic regression model. RESULTS: Of the 2834 medical records that had GIH diagnoses, 1644 had an ED lactate recorded. A lactate greater than 4 mmol/L conferred a 6.4-fold increased odds of in-hospital mortality (94% specificity, P < .001). Controlling for age, initial hematocrit, and heart rate, every 1-point increase in lactate conferred a 1.4-fold increase in the odds of mortality. CONCLUSIONS: Elevated initial lactate drawn in the ED can be associated with in-hospital mortality for ED patients with acute GIH. Prospective validation studies are warranted. PMID- 24813903 TI - The author responds. PMID- 24813904 TI - Injury and illness sustained by human competitors in the 2010 iditarod sled dog race. AB - OBJECTIVE: Alaska's 1049-mile Iditarod Trail Sled Dog Race is the world's longest sled dog race and the flagship event in the sport of sled dog racing. Race conditions are typically harsh. Physicians are not officially enlisted to care for human competitors. Instead, medical needs are met through an informal system of volunteers, local health care providers, and a fleet of bush planes. The goals of this study were to identify the types of human injury and illness experienced and the methods by which these conditions are treated. METHODS: Competitors in the 2010 Iditarod were surveyed at the halfway point and at the finish of the race. Survey elements included specific types and frequencies of injuries and illnesses, and the sources and types of treatments. RESULTS: Seventy-one teams entered the race, 62 participated in the halfway point survey, and 55 completed the finish line survey. Ninety-nine injuries were reported by 42 (68%) of the survey respondents. Frostbite was the most common injury, occurring in 20 (31%) of the respondents. Musculoskeletal pain was also commonly reported. Two mushers sustained closed head injuries, with 1 requiring evacuation. Twenty-three mushers (37%) reported an acute nontraumatic condition, most frequently an upper respiratory infection (9 respondents). In most instances, medical conditions were self-managed. Race veterinarians and support staff, as well as local village clinicians, administered the majority of care, typically wound care or oral antibiotic administration. CONCLUSIONS: Most injuries and illnesses sustained by mushers in the Iditarod are minor and self-treatable. Life-threatening conditions are rare, and the need for an organized medical care system seems low. PMID- 24813905 TI - A three-step kinetic model for electrochemical charge transfer in the hopping regime. AB - Single-step nonadiabatic electron tunneling models are widely used to analyze electrochemical rates through self-assembled monolayer films (SAMs). For some systems, such as nucleic acids, long-range charge transfer can occur in a "hopping" regime that involves multiple charge transfer events and intermediate states. This report describes a three-step kinetic scheme to model charge transfer in this regime. Some of the features of the three-step model are probed experimentally by changing the chemical composition of the SAM. This work uses the three-step model and a temperature dependence of the charge transfer rate to extract the charge injection barrier for a SAM composed of a 10-mer peptide nucleic acid that operates in the hopping regime. PMID- 24813906 TI - An outbreak of enterotoxigenic Escherichia coli (ETEC) infection in Norway, 2012: a reminder to consider uncommon pathogens in outbreaks involving imported products. AB - We investigated an outbreak of gastroenteritis following a Christmas buffet served on 4-9 December 2012 to ~1300 hotel guests. More than 300 people were reported ill in initial interviews with hotel guests. To identify possible sources of infection we conducted a cohort investigation through which we identified 214 probable cases. Illness was associated with consumption of scrambled eggs (odds ratio 9.07, 95% confidence interval 5.20-15.84). Imported chives added fresh to the scrambled eggs were the suspected source of the outbreak but were unavailable for testing. Enterotoxigenic Escherichia coli (ETEC) infection was eventually confirmed in 40 hotel guests. This outbreak reinforces that ETEC should be considered in non-endemic countries when the clinical picture is consistent and common gastrointestinal pathogens are not found. Following this outbreak, the Norwegian Food Safety Authority recommended that imported fresh herbs should be heat-treated before use in commercial kitchens. PMID- 24813907 TI - Chronic idiopathic axonal polyneuropathy and vitamin B6: a controlled population based study. AB - Vitamin B6 intoxication can result in a sensory ataxic neuropathy, but the association with a milder predominantly sensory or sensorimotor phenotype in chronic idiopathic axonal polyneuropathy (CIAP) remains unclear. A total of 381 patients with CIAP and 140 healthy controls were prospectively included. In a standardized fashion the use of vitamin B6 containing supplements and vitamin B6 levels were compared between patients and controls. On follow-up, patients were questioned about cessation of supplement use and the impact on the symptoms of polyneuropathy. Vitamin B6 levels in patients (median: 99 nmol/l, range: 38-2,967 nmol) were not significantly higher than in controls (median: 109 nmol/l, range: 41-2,373 nmol/l, p = 0.58), nor were daily dose, cumulative dose or duration of supplement use. However, more patients (31%) than controls (22%) used vitamin B6 containing supplements (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.0 2.7, p = 0.032). Follow-up of patients confirming the cessation of supplements showed slow progression of symptoms in 64%, stabilization in 26%, and regression in 10%. On the basis of our prospective case-control study and review of the literature, an association between CIAP and vitamin B6 exposure or elevated vitamin B6 levels appears unlikely. PMID- 24813908 TI - Surface plasmon resonance characterization of monoclonal and polyclonal antibodies of malaria for biosensor applications. AB - Surface plasmon resonance (SPR) screening of monoclonal and polyclonal antibodies of Plasmodium falciparum (MoabPf and PoabPf) for recombinant Histidine rich protein-II antigen (Ag) of Pf (rHRP-II Ag) was conducted in a real-time and label free manner to select an appropriate antibody (Ab) for biosensor applications. In this study 4-mercaptobenzoic acid (4-MBA) modified gold SPR chip was used for immobilizing the Ag and then Ab was interacted. SEM image showed modification of SPR chip with 4-MBA and EDAX confirmed the presence of 4-MBA on the SPR chip. Equilibrium constant (KD) and maximum binding capacity of analyte (Bmax) values for the interaction of MoabPf or PoabPf with the immobilized rHRP-II Ag were calculated and found to be 0.517 nM and 48.61 m degrees for MoabPf and 2.288 nM and 46.80 m degrees for PoabPf, respectively. In addition, thermodynamic parameters such as DeltaG, DeltaH and DeltaS were determined for the interaction between rHRP-II Ag and MoabPf or PoabPf and the values revealed that the interaction is spontaneous, exothermic and driven by entropy. The kinetics and thermodymanic results of this study revealed that the interaction between MoabPf and rHRP-II Ag is more effective than that of PoabPf due to the fact that MoabPf was derived from a single epitope (single clone) whereas the PoabPf was from the mixture of a number of epitopes (polyclones). Finally, SPR methodology was developed for the sensing of malarial antibodies. The limit of detection was found to be 5.6 pg with MoabPf which was found to be the best in our study. PMID- 24813909 TI - Procalcitonin sensitive detection based on graphene-gold nanocomposite film sensor platform and single-walled carbon nanohorns/hollow Pt chains complex as signal tags. AB - Septicemia is a serious disease that requires early diagnosis, and procalcitonin (PCT) serves as a diagnostic biomarker for this disease. Traditional clinical detection (via immune-gold chips) remains difficult and expensive. An electrochemical immunosensor based on new nanomaterials may provide a solving approach. Herein, an ultrasensitive sandwich electrochemical strategy for PCT detection was developed. Firstly, reduced graphene oxide (rGO)-gold (Au) nano composite film was used as the immunosensor platform to increase the amount of PCT antibody 1(Ab1) immobilized. Next, single-walled carbon nanohorns (SWCNHs)/hollow Pt chains (HPtCs) complex was firstly utilized to label PCT Ab2 as signal tags. For SWCNHs with few side effects, high surface area and HPtCs with higher specific surface, better catalytic activity, complex synthesized from both may provide more advantages. Moreover, to amplify signal, HPtC catalytic activity with H2O2 was enhanced by horseradish peroxidase (HRP) for dual synergy amplification. The whole results demonstrated that the proposed immunosensor exhibited fast operation, high sensitivity, good reproducibility, acceptable stability and ideal selectivity compared with traditional method. The linear calibration of the immunosensor ranged from 1.00 pg/mL to 2.00 * 10(1)ng/mL with a detection limit of 0.43 pg/mL. Analytical application results revealed that the immunosensor matched with the real concentrations of serum samples. Overall this immunosensor may provide a new alternative strategy for PCT detection. PMID- 24813910 TI - Electrochemical impedance spectroscopy aptasensor for ultrasensitive detection of adenosine with dual backfillers. AB - A highly sensitive and label-free electrochemical impedance spectroscopy (EIS) aptasensor for the detection of adenosine was fabricated by co-assembling thiolated aptamer, dithiothreitol (DTT) and 6-mercaptohexanol (MCH) on gold electrode surface, forming Au/aptamer-DTT/MCH. The interfacial electron transfer resistance (Ret) of the aptasensor using [Fe(CN)6](3-/4-) as the probe increased with adenosine concentration, and the change in Ret (?Ret) against the logarithm of adenosine concentration was linear over the range from 0.05 pM to 17 pM with a detection limit of 0.02 pM. Compared to that of aptasensors fabricated with MCH or DTT alone as the backfiller, the detection limit was improved dramatically (LOD was 0.03 nM and 0.2 pM for Au/aptamer/MCH and Au/aptamer-DTT, respectively), which was attributed primarily to the coupling of the cyclic- and linear configuration backfillers. The coupling showed remarkably higher resistance to nonspecific adsorption, leading to low background noise and high response signal. The aptasensor reported herein is applicable for the detection of other kinds of aptamer-binding chemicals and biomolecules. PMID- 24813911 TI - Amplified amperometric aptasensor for selective detection of protein using catalase-functional DNA-PtNPs dendrimer as a synergetic signal amplification label. AB - In this work, we present a new strategy to construct an electrochemical aptasensor for sensitive detection of platelet-derived growth factor BB (PDGF-BB) based on the synergetic amplification of a three-dimensional (3D) nanoscale catalase (CAT) enzyme-functional DNA-platinum nanoparticles (PtNPs) dendrimer through autonomous layer-by-layer assembly. Firstly, polyamidoaminedendrimer (PAMAM) with a hyper-branched and three-dimensional structure was served as nanocarriers to coimmobilize a large number of PDGF-BB binding aptamer (PBA II) and ssDNA 1 (S1) to form PBA II-PAMAM-S1 bioconjugate. In the presence of PDGF BB, the bioconjugate was self-assembled on the electrode by sandwich assay. Following that, the carried S1 propagated a chain reaction of hybridization events between CAT-PtNPs-S1 and CAT-PtNPs-ssDNA 2 (S2) to form a 3D nanoscale CAT functional PtNPs-DNA dendrimer, which successfully immobilized substantial CAT enzyme and PtNPs with superior catalysis activity. In this process, the formed negatively charged double-helix DNA could cause the intercalation of hexaammineruthenium(III) chloride (RuHex) into the groove via electrostatic interactions. Thus, numerous RuHex redox probes and CAT were decorated inside/outside of the dendrimer. In the presence of H2O2 in electrolytic cell, the synergistic reaction of CAT and PtNPs towards electrocatalysis could further amplify electrochemical signal. Under optimal condition, the CAT-PtNPs-DNA dendrimer-based sensing system presented a linear dependence between the reduction peak currents and logarithm of PDGF-BB concentrations in the range of 0.00005-35 nM with a relatively low detection limit of 0.02 pM. PMID- 24813912 TI - A novel potentiometric sensor based on a poly(anilineboronic acid)/graphene modified electrode for probing sialic acid through boronic acid-diol recognition. AB - A novel potentiometric approach was described for probing sialic acid (SA) using a poly(anilineboronic acid)/graphene modified glassy carbon (GC) electrode. The proposed electrode was prepared by electrodeposition of reduced graphene oxide (ERGO) at a GC electrode and then coated with a poly(anilineboronic acid) (PABA) film by electropolymerization of its monomer. Principle of SA detection at the PABA/ERGO/GC electrode was ascribed to a reversible and covalent boronic acid diol binding which was sensitive to the electrochemical potential of the prepared sensor. The graphene layer introduced on the electrode surface was shown to dramatically improve the sensitivity of the sensor response. Under optimum conditions, the proposed sensor exhibited low detection limit of 0.8 MUM with a wide linear range of 2 MUM-1.38 mM, high stability, good regeneration, and remarkable selectivity. For the analysis of SA in human blood serum, the high accuracy and good recoveries revealed the great potential in the practical applications. PMID- 24813913 TI - Evolution of biogenic amine concentrations in foods through their induced chemiluminescence inactivation of layered double hydroxide nanosheet colloids. AB - Turn-on/off fluorescence and visual sensors through hydrogen bonding recognition have been clearly established in the literature. There is apparently no good reason to disregard hydrogen bonding-induced inactivation of chemiluminescence (CL). In this work, serving as novel CL catalyst and CL resonance energy transfer acceptor (CRET), layered double hydroxide (LDH) nanosheet colloids can induce a significant increase in the CL intensity of bis(2,4,6-trichlorophenyl) oxalate (TCPO)-H2O2 system. On the other hand, biogenic amines can selectively inhibit the CL intensity of the LDH nanosheet-TCPO-H2O2 system as a result of inactivation of photoluminescence LDH nanosheets through the displacement of O-H ? O bonding by O-H ? N bonding. In addition, histamine is used as a common indicator of food spoilage, and it is found that the CL intensity is linear with histamine concentration in the range of 0.1-100 uM, and the detection limit for histamine (S/N=3) is 3.2 nM. The proposed method has been successfully applied to trace histamine evolution of spoiled fish and pork meat samples, displaying a time-dependent increase in the biogenic amines levels in such samples. PMID- 24813914 TI - Strongly structured DNA sequences as targets for genosensing: sensing phase design and coupling to PCR amplification for a highly specific 33-mer gliadin DNA fragment. AB - Electrochemical genosensors are becoming cost-effective miniaturizable alternatives to real-time PCR (RT-PCR) methods for the detection of sequence specific DNA fragments. We report on the rapid detection of PCR amplicons without the need of purification or strand separation. A challenging target sequence for both PCR amplification and electrochemical detection allowed us to address some difficulties associated to hybridization on electrode surfaces. The target was a highly specific oligonucleotide sequence of wheat encoding the most immunogenic peptide of gliadin that triggers the immune response of celiac disease (CD), the 33-mer. With a sandwich assay format and a rational design of the capture and tagged-signaling probes the problems posed by the strong secondary structure of the target and complementary probes were alleviated. Using a binary self assembled monolayer and enzymatic amplification, a limit of detection of 0.3 nM was obtained. The genosensor did not respond to other gluten-containing cereals such as rye and barley. Coupling to PCR to analyze wheat flour samples required tailoring both the capture and signaling probes. This is the first time that deleterious steric hindrance from long single-stranded regions adjacent to the electrode surface is reported for relatively short amplicons (less than 200 bp). The importance of the location of the recognition site within the DNA sequence is discussed. Since the selected gene fragment contains several repetitions of short sequences, a careful optimization of the PCR conditions had to be performed to circumvent the amplification of non-specific fragments from wheat flour. PMID- 24813915 TI - Cu(II)-coordinated GpG-duplex DNA as peroxidase mimetics and its application for label-free detection of Cu2+ ions. AB - Herein a facile method is proposed to construct DNA-based peroxidase mimetics simply assembled by polymorphic DNA and Cu(2+) ions. The Cu(II)-catalyzed oxidation of TMB in the presence of H2O2 can be significantly accelerated through Cu(II)-coordination with DNA scaffolds, of which a colorimetric change can be discerned by naked-eye. The reaction rates of DNA-Cu(II) complexes are directly associated with sequence composition as well as the secondary structure of DNA scaffold, e.g., the reaction rate decreases in the following order: GpG-duplex ~ G-rich coil > G-quadruplex > C-rich coil > i-motif. It is the first report to explore a colorimetric Cu(2+) sensing system on the basis of peroxidase mimicking activities of polymorphic DNA-Cu(II) complexes. One of our most intriguing results is that the GpG-duplex DNA demonstrates the ability to sense Cu(2+) ions in aqueous solution without significant interference from other metal ions. The Cu(2+) detection limit of 1.2 nM is achieved with a linear response range of 1.2 100 nM, and the developed sensing system is potentially applicable for quantitative determination of Cu(2+) in drinking water samples. PMID- 24813916 TI - A new system for the amplification of biological signals: RecA and complimentary single strand DNA probes on a leaky surface acoustic wave biosensor. AB - This research describes a new amplification signals system of the leaky surface acoustic wave (LSAW) bis-peptide nucleic acid (bis-PNA) biosensor for the simple, sensitive and rapid detection of the target double-stranded DNA (dsDNA). The system consists of a RecA protein-coated complementary single-stranded DNA (cssDNA) probe complex that amplifies the biological signal to improve the sensitivity of the biosensor. The bis-PNA probe for detecting HPV was first immobilized on a gold surface membrane of the detection channel. After the probe was completely hybridized with the corresponding target DNA, different concentrations of the "RecA protein-complementary single strand DNA probe" were added to react with the bis-PNA/dsDNA complex. The phase shift of the LSAW biosensors, which was measured and found to be most significant when the RecA protein was 45 MUg/mL and the ATPgammaS was 2.5 mmol/L. Compared with other concentrations (P<0.01) of RecA and ATPgammaS, the value of the phase shift was (11.74 +/- 1.03) degrees and the ratio of the phase shift and hybridization time clearly outperformed that of the other concentrations. Compared to the direct hybridization of the bis-PNA probe and the target DNA sequence, the sensitivity was effectively improved and the detection time was significantly shortened. PNA binding adjacent to the area of the target sequence homologous to the probe significantly increased the yield of the hybridization reaction between the PNA/dsDNA complex and the RecA protein-coated cssDNA probe. In this condition, the phase shift was significantly obvious and the detection time was significantly shortened. In conclusion, the combination of the RecA protein coated cssDNA probe and the LSAW bis-PNA biosensor provides sensitivity and simple and rapid detection of clinical trace pathogenic microorganisms. PMID- 24813917 TI - Electrochemical detection of Pseudomonas aeruginosa in human fluid samples via pyocyanin. AB - The ability to quickly detect the presence of pathogenic bacteria in patient samples is of the outmost importance to expedient patient care. Here we report the direct, selective, and sensitive detection of the opportunistic pathogen Pseudomonas aeruginosa, spiked in human whole blood with sodium heparin, urine, sputum, and bronchial lavage samples using unmodified, disposable carbon electrode sensors that detect the presence of pyocyanin, a virulence factor that is unique to this species. Square wave voltammetry scans of biological fluids from healthy individuals spiked with P. aeruginosa showed a clear pyocyanin response within one day of culturing at 37 degrees C. Scans of supernatants taken from cultures of P. aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermis, and Bacillus cereus taken over a span of three days in the potential range from -0.5 to 0 V vs. an Ag/AgCl reference showed no electrochemically detectable molecules with the exception of P. aeruginosa. The results indicate the potential to sensitively and selectively determine the presence of P. aeruginosa in human samples via the electrochemical detection of pyocyanin in less than 5 min, without any sample preparation or separation steps. PMID- 24813918 TI - Circulating miRNA markers show promise as new prognosticators for multiple myeloma. PMID- 24813919 TI - Impact of chemotherapy delay on short- and long-term survival in younger and older AML patients: a Danish population-based cohort study. PMID- 24813920 TI - Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia. AB - Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias. PMID- 24813921 TI - Structure of the Neisserial outer membrane protein Opa60: loop flexibility essential to receptor recognition and bacterial engulfment. AB - The structure and dynamics of Opa proteins, which we report herein, are responsible for the receptor-mediated engulfment of Neisseria gonorrheae or Neisseria meningitidis by human cells and can offer deep understanding into the molecular recognition of pathogen-host receptor interactions. Such interactions are vital to understanding bacterial pathogenesis as well as the mechanism of foreign body entry to a human cell, which may provide insights for the development of targeted pharmaceutical delivery systems. The size and dynamics of the extracellular loops of Opa60 required a hybrid refinement approach wherein membrane and distance restraints were used to generate an initial NMR structural ensemble, which was then further refined using molecular dynamics in a DMPC bilayer. The resulting ensemble revealed that the extracellular loops, which bind host receptors, occupy compact conformations, interact with each other weakly, and are dynamic on the nanosecond time scale. We predict that this conformational sampling is critical for enabling diverse Opa loop sequences to engage a common set of receptors. PMID- 24813922 TI - Engineered skeletal muscle units for repair of volumetric muscle loss in the tibialis anterior muscle of a rat. AB - Volumetric muscle loss (VML) is the traumatic, degenerative, or surgical loss of muscle tissue, which may result in function loss and physical deformity. To date, clinical treatments for VML--the reflected muscle flap or transferred muscle graft--are limited by tissue availability and donor site morbidity. To address the need for more innovative skeletal muscle repair options, our laboratory has developed scaffoldless tissue-engineered skeletal muscle units (SMUs), multiphasic tissue constructs composed of engineered skeletal muscle with engineered bone-tendon ends, myotendinous junctions, and entheses, which in vitro can produce force both spontaneously and in response to electrical stimulation. Though phenotypically immature in vitro, we have shown that following 1 week of implantation in an ectopic site, our muscle constructs develop vascularization and innervation, an epimysium-like outer layer of connective tissue, an increase in myosin protein content, formation of myofibers, and increased force production. These findings suggest that our engineered muscle tissue survives implantation and develops the interfaces necessary to advance the phenotype toward adult muscle. The purpose of this study was to evaluate the potential of our SMUs to restore muscle tissue to sites of acute VML. Our results indicate that our SMUs continue to mature in vivo with longer recovery times and have the potential to repair VML sites by providing additional muscle fibers to damaged muscles. We conclude from this study that our SMUs have the potential to restore lost tissue volume in cases of acute VML. PMID- 24813923 TI - Social functions of individual vasopressin-oxytocin cell groups in vertebrates: what do we really know? AB - Vasopressin-oxytocin (VP-OT) nonapeptides modulate numerous social and stress related behaviors, yet these peptides are made in multiple nuclei and brain regions (e.g., >20 in some mammals), and VP-OT cells in these areas often exhibit overlapping axonal projections. Furthermore, the magnocellular cell groups release peptide volumetrically from dendrites and soma, which gives rise to paracrine modulation in distal brain areas. Nonapeptide receptors also tend to be promiscuous. Hence, behavioral effects that are mediated by any given receptor type (e.g., the OT receptor) in a target brain region cannot be conclusively attributed to either VP or OT, nor to a specific cell group. We here review what is actually known about the social behavior functions of nonapeptide cell groups, with a focus on aggression, affiliation, bonding, social stress, and parental behavior, and discuss recent studies that demonstrate a diversity of sex-specific contributions of VP-OT cell groups to gregariousness and pair bonding. PMID- 24813924 TI - Home-based administration of Sayana(r) Press: review and assessment of needs in low-resource settings. AB - A new presentation of the subcutaneous (SC) injectable contraceptive depot medroxyprogesterone acetate (DMPA) increases the possibilities for home and self administration of this popular contraceptive method. Sayana(r) Press is DMPA-SC in the prefilled UnijectTM injection system and consists of one dose that provides 3 months of contraceptive protection. Studies indicate that lay caregiver and self-injection of various medications, including other injectable presentations of DMPA-SC, are acceptable and effective. Introduction of Sayana(r) Press in developing countries could extend injectable contraceptive delivery safely and effectively beyond the clinic and, eventually, into the home, allowing lay caregiver or self-administration. Research needs for low-resource settings include assessing the acceptability and feasibility of self-injection with Sayana(r) Press. Feasibility studies necessary for implementing a sustainable home-based delivery program include assessment of training, health systems, policies, infrastructure needs and programmatic considerations to optimize women's ability to manage their self-injection schedule. PMID- 24813925 TI - Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy. AB - Diagnosis of muscular dystrophies is currently based on invasive methods requiring muscle biopsies or blood tests. The aim of the present study was to identify urinary biomarkers as a diagnostic tool for muscular dystrophies. Here, the urinary proteomes of Duchenne muscular dystrophy (DMD) patients and healthy donors were compared with a bottom-up proteomic approach. Label-free analysis of more than 1100 identified proteins revealed that 32 of them were differentially expressed between healthy controls and DMD patients. Among these 32 proteins, titin showed the highest fold change between healthy subjects and DMD patients. Interestingly, most of the sequenced peptides belong to the N-terminal and C terminal parts of titin, and the presence of the corresponding fragments in the urine of DMD patients was confirmed by Western blot analysis. Analysis of a large cohort of DMD patients and age-matched controls (a total of 104 individuals aged from 3 to 20 years) confirmed presence of the N-ter fragment in all but two patients. In two DMD patients aged 16 and 20 years this fragment was undetectable and two healthy controls of 16 and 19 years with serum CK >800 IU/L demonstrated a low level of the fragment. N- and C-terminal titin fragments were also detected in urine from patients with other muscular dystrophies such as Becker muscular dystrophy and Limb-girdle muscular dystrophy (type 1D, 2D and 2J) but not in neurogenic spinal muscular atrophy. They were also present in urine of dystrophin deficient animal models (GRMD dogs and mdx mice). Titin is the first urinary biomarker that offers the possibility to develop a simple, non-invasive and easy to-use test for pre-screening of muscular dystrophies, and may also prove to be useful for the non-invasive follow up of DMD patients under treatment. PMID- 24813926 TI - [Travel-acquired dengue in Aragon (Spain)]. PMID- 24813927 TI - [Young male with fever and muscle pain after a visit to the dentist]. PMID- 24813928 TI - ['Third day intervention': an analysis of the factors associated with following the recommendations on the prescribing of antibiotics]. AB - INTRODUCTION: Stewardship programs on the use of antibiotics usually include interventions based on non-compulsory recommendations for the prescribers. Factors related to the adherence to expert recommendations, and the implementation of these programmes in daily practice, are of interest. METHODS: A randomized, controlled, multicentre intervention study was performed in 32 hospitalization units. Antibiotic prescriptions were evaluated by an infectious disease specialist on the third day. We describe the implementation of the intervention, the factors associated with adherence to recommendations, and the impact of the intervention. RESULTS: A total of 3,192 interventions were carried out. Information sources used to prepare the recommendations varied significantly between centres. A modification was recommended in 65% of cases: withdrawal (47%), change in administration route (26%), change of drugs or number of antibiotics (27%), and change in dose (5%). Simplification of treatment accounted for 75% of all recommendations. Adherence was 68%, with significant differences between hospitals, and higher when the recommendations consisted of a dose adjustment or change of route, during the first intervention period, and also when recommendations were personally commented on, in addition to writing a note in the clinical chart. We did not find any reduction in antibiotic consumption or variation in the incidence of resistant pathogens. CONCLUSIONS: An important proportion of antibiotic prescriptions may be susceptible to improvement, most of them towards simplification. The adherence to the intervention was high, but significant variations at different centres were observed, depending on the type of recommendation, and the study period. Those recommendations that were personally commented on were more followed more than those only written. PMID- 24813929 TI - Nrf2 protects against furosemide-induced hepatotoxicity. AB - Furosemide is a diuretic drug, but its reactive intermediates lead to acute liver injury in mice. Given the essential role of Nrf2 as a cellular defense regulator, we investigated whether Nrf2 would protect against furosemide-induced liver injury using the Nrf2 "gene-dose response" mouse model (Nrf2-null with Nrf2 knock out, wild-type with normal expression of Nrf2, Keap1-KD with enhanced Nrf2 activation and Keap1-HKO mice with maximum Nrf2 activation). Twenty-four hours after furosemide administration (250mg/kg, i.p.), serum ALT activities and histopathological analysis indicated severe hepatotoxicity in Nrf2-null and WT mice, but significantly less in the Nrf2-overexpressing Keap1-KD and Keap1-HKO mice. Furosemide increased the mRNA of genes involved in the acute phase response (hemeoxygenase-1 and metallothionein-1), ER stress (C/Ebp-homologous protein and Growth arrest and DNA-damage-inducible protein), inflammatory cytokine (interleukin 1 beta), chemokines (macrophage inflammatory protein 2 and mouse keratinocyte-derived chemokine), as well as apoptosis (early growth response factor and BCL2-associated X protein) in livers of Nrf2-null and wild-type mice, but these genes increased less in mice with more Nrf2. The two genotypes of over expressed Nrf2 mice had increased expression of the Nrf2 target genes Gclm, Gclc and Nqo1 prior to furosemide administration, and the expressions of these genes were increased further after furosemide administration. Thus, our findings provide strong evidence that over-expression of Nrf2 in Keap1-KD and Keap1-HKO mice and the increases in mRNA of a number of genes involved in anti-oxidative stress, anti-inflammation, anti-ER stress and anti-apoptosis protect against furosemide-induced hepatotoxicity. PMID- 24813930 TI - Effect of boat noise and angling on lake fish behaviour. AB - The effects of disturbances from recreational activities on the swimming speed and habitat use of roach Rutilus rutilus, perch Perca fluviatilis and pike Esox lucius were explored. Disturbances were applied for 4 h as (1) boating in short intervals with a small outboard internal combustion engine or (2) boating in short intervals combined with angling with artificial lures between engine runs. The response of the fish species was evaluated by high-resolution tracking using an automatic acoustic telemetry system and transmitters with sub-minute burst rates. Rutilus rutilus swimming speed was significantly higher during disturbances [both (1) and (2)] with an immediate reaction shortly after the engine started. Perca fluviatilis displayed increased swimming activity during the first hour of disturbance but not during the following hours. Swimming activity of E. lucius was not significantly different between disturbance periods and the same periods on days without disturbance (control). Rutilus rutilus increased their use of the central part of the lake during disturbances, whereas no habitat change was observed in P. fluviatilis and E. lucius. No difference in fish response was detected between the two types of disturbances (boating with and without angling), indicating that boating was the primary source of disturbance. This study highlights species-specific responses to recreational boating and may have implications for management of human recreational activities in lakes. PMID- 24813931 TI - Strategies to improve quality of life in bladder cancer patients. AB - Bladder cancer is a heterogeneous disease that includes both tumors with low risk of dissemination as well as highly malignant tumors with a considerable potential to metastasize. The patient's quality of life is closely related to the management of the disease. The challenge for the urologist is to acknowledge the malignant potential of the cancer and to adjust the approach to the patient accordingly. Patients with low-risk bladder cancer should avoid an exaggerated follow-up, but on the other hand high-risk patients must be sufficiently surveyed to secure that definitive surgical treatment is performed before it's too late. When the decision to perform a cystectomy has been made, it is crucial that the patient understands the consequences of the surgery as well as the possible options for urinary reconstruction. This review focuses on aspects of bladder cancer management that we believe are vital for the quality of life of these patients. PMID- 24813932 TI - Quantitation of phosphatidic acid and lysophosphatidic acid molecular species using hydrophilic interaction liquid chromatography coupled to electrospray ionization high resolution mass spectrometry. AB - A method for a highly selective and sensitive identification and quantitation of lysophosphatidic acid (LPA) and phosphatidic acid (PA) molecular species was developed using hydrophilic interaction liquid chromatography (HILIC) followed by negative-ion electrospray ionization high resolution mass spectrometry. Different extraction methods for the polar LPA and PA species were compared and a modified Bligh & Dyer extraction by addition of 0.1M hydrochloric acid resulted in a ~1.2 fold increase of recovery for the 7 PA and a more than 15-fold increase for the 6 LPA molecular species of a commercially available natural mix compared to conventional Bligh & Dyer extraction. This modified Bligh & Dyer extraction did not show any artifacts resulting from hydrolysis of natural abundant phospholipids. The developed HILIC method is able to separate all PA and LPA species from major polar membrane lipid classes which might have suppressive effects on the minor abundant lipid classes of interest. The elemental compositions of intact lipid species are provided by the high mass resolution of 100,000 and high mass accuracy below 3ppm of the Orbitrap instrument. Additionally, tandem mass spectra were generated in a parallel data dependent acquisition mode in the linear ion trap to provide structural information at molecular level. Limits of quantitation were identified at 45fmol on column and the dynamic range reaches 20pmol on column, covering the range of natural abundance well. By applying the developed method to mouse brain it can be shown that phosphatidic acid contains less unsaturated fatty acids with PA 34:1 and PA 36:1 as the major species. In contrast, for LPA species a high content of polyunsaturated fatty acids (LPA 20:4 and LPA 22:6) was quantified. PMID- 24813933 TI - Adenovirus purification by two-column, size-exclusion, simulated countercurrent chromatography. AB - Adenovirus serotype 5 (Ad5) was successfully separated by size-exclusion chromatography (SEC) using a simple, yet efficient, two-column, quasi-continuous, simulated moving-bed process operated in an open-loop configuration. The operating cycle is divided into two identical half-cycles, each of them consisting of the following sequence of sub-steps: (i) elution of the upstream column and direction of the effluent of the downstream column to waste; (ii) elution of the upstream column and redirection of its effluent to waste while the downstream column is fed with the clarified bioreaction bulk and its effluent collected as purified product; (iii) operation of the system as in step (i) but collecting the effluent of the downstream column as product; (iv) elution of the upstream column and direction of its effluent to waste while the flow through the downstream column is temporarily halted. Clearance of impurities, namely DNA and host cell protein (HCP), were experimentally assessed. The pilot-scale run yielded a virus recovery of 86%, and a clearance of 90% and 89% for DNA and HCP, respectively, without any fine tunning of the predetermined operating parameters. These figures compare very favorably against single-column batch chromatography for the same volume of size-exclusion resin. However, and most importantly, the virus yield was increased from 57% for the batch system to 86% for the two-column SEC process because of internal recycling of the mixed fractions of contaminated Ad5, even though the two-column process was operated strictly in an open-loop configuration. And last, but not least, the productivity was increased by 6-fold with the two-column process. In conclusion, the main drawbacks of size-exclusion chromatography, namely low productivity and low product titer, were overcome to a considerable extent by an innovative two-column configuration that keeps the mixed fractions inside the system at all times. PMID- 24813934 TI - Comparison of peak shape in hydrophilic interaction chromatography using acidic salt buffers and simple acid solutions. AB - The retention and peak shape of neutral, basic and acidic solutes was studied on hydrophilic interaction chromatography (HILIC) stationary phases that showed both strong and weak ionic retention characteristics, using aqueous-acetonitrile mobile phases containing either formic acid (FA), ammonium formate (AF) or phosphoric acid (PA). The effect of organic solvent concentration on the results was also studied. Peak shape was good for neutrals under most mobile phase conditions. However, peak shapes for ionised solutes, particularly for basic compounds, were considerably worse in FA than AF. Even neutral compounds showed deterioration in performance with FA when the mobile phase water concentration was reduced. The poor performance in FA cannot be entirely attributed to the negative impact of ionic retention on ionised silanols on the underlying silica base materials, as results using PA at lower pH (where their ionisation is suppressed) were inferior to those in AF. Besides the moderating influence of the salt cation on ionic retention, it is likely that salt buffers improve peak shape due to the increased ionic strength of the mobile phase and its impact on the formation of the water layer on the column surface. PMID- 24813935 TI - Identification of the effective constituents for anti-inflammatory activity of Ju Zhi-Jiang-Tang, an ancient traditional Chinese medicine formula. AB - The anti-inflammatory constituents of Ju-Zhi-Jiang-Tang (JZJT), a formula used for thousands of years in China, were identified by LC-MS and pharmacological activity evaluation. In this study, the whole extract of formula was separated into multiple components to facilitate the analytical process. To characterize their contributions to pharmacological activity of formula, activity indexes of constituents were proposed and calculated for the first time, which integrated the chemical and pharmacological information of multiple components. Among the 151 constituents detected in JZJT by LC-Q-TOF-MS and LC-IT-MS, a total number of 108 constituents were identified unambiguously or tentatively, including eighteen potential novel compounds. And, the structures of some constituents were confirmed by NMR. According to their activity indexes, polymethoxy flavones were indicated as the major active constituents responsible for the anti-inflammatory activity of JZJT. To verify the feasibility of activity indexes in predicting the active constituents, nine compounds with positive and negative index values were selected to validate their anti-inflammatory activity in vitro. The results showed that two polymethoxy flavones with higher positive index values, i.e., nobiletin and tangeretin can significantly exert anti-inflammatory effects, while other compounds with negative values did not show any activity. In conclusion, our results indicated the proposed approach might be an efficient and rapid way to identify active constituents of TCM formulae. PMID- 24813936 TI - Comparison of accelerated hypofractionation and stereotactic body radiotherapy for Stage 1 and node negative Stage 2 non-small cell lung cancer (NSCLC). AB - PURPOSE: Stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) have favorable local control (LC) relative to conventional fractionation in the treatment of stage I non-small cell lung cancer (NSCLC). We report the results of our single institution experience with the treatment of early stage NSCLC with SBRT or AHRT in cases where SBRT was felt to be suboptimal. METHODS: One hundred and sixty patients with Stage 1 and node negative Stage 2 NSCLC were treated with SBRT or AHRT from 2003 to 2011. Median follow-up was 29.4 and 19 months (mo), respectively. The median dose was 54Gy in 3 fractions (fx) (SBRT) and 70.2Gy in 26 fx (AHRT). Acute and late toxicities (tox) were graded (G) per CTCAE v4. Time to local (LF), regional (RF) and distant (DF) failure were estimated using the Kaplan-Meier method. The impact of patient and tumor related factors on LF were estimated by multivariate Cox proportional hazard model. RESULTS: Three-year LC rates were 87.7% (SBRT) and 71.7% (AHRT). The 3-year freedom from DF was 73.3% and 68.1%. Median OS was 38.4 (95% CI 29.7-51.6) and 35 (95% CI 22-48.3) mo. No G3 or 4 tox were observed. At 1 year, 30% and 50% of complications resolved, while (5-6%) had persistent chest wall pain. Multivariate analysis demonstrated that increasing dose per fraction and tumor size (>5.5 vs. 4cm) in the AHRT and SBRT group were found to be associated with a reduced (HR 0.33 95% CI 0.13-0.84, p=0.021) and increased (HR: 6.372 95% CI 1.23-32.92, p=0.027) hazard for local failure respectively. CONCLUSIONS: Our results compare favorably with other reports of treatment for early stage NSCLC. AHRT patients had comparable LC despite increased size and central disease. Toxicity was limited and overall survival, regional and distant recurrences were similar between groups. PMID- 24813937 TI - Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-kappaB) prior to seizure in transgenic NF-kappaB/EGFP reporter mice. AB - Predicting seizurogenic properties of pharmacologically active compounds is difficult due to the complex nature of the mechanisms involved and because of the low sensitivity and high variability associated with current behavioral-based methods. To identify early neuronal signaling events predictive of seizure, we exposed transgenic NF-kappaB/EGFP reporter mice to multiple low doses of kainic acid (KA), postulating that activation of the stress-responsive NF-kappaB pathway could be a sensitive indicator of seizurogenic potential. The sub-threshold dose level proximal to the induction of seizure was determined as 2.5mg/kg KA, using video EEG monitoring. Subsequent analysis of reporter expression demonstrated significant increases in NF-kappaB activation in the CA3 and CA1 regions of the hippocampus 24h after a single dose of 2.5mg/kg KA. This response was primarily observed in pyramidal neurons with little non-neuronal expression. Neuronal NF kappaB/EGFP expression was observed in the absence of glial activation, indicating a lack of neurodegeneration-induced neuroinflammation. Protein expression of the immediate-early gene, Nurr1, increased in neurons in parallel to NF-kappaB activation, supporting that the sub-threshold doses of KA employed directly caused neuronal stress. Lastly, KA also stimulated NF-kappaB activation in organotypic hippocampal slice cultures established from NF-kappaB/EGFP reporter mice. Collectively, these data demonstrate the potential advantages of using genetically encoded stress pathway reporter models in the screening of seizurogenic properties of new pharamacologically active compounds. PMID- 24813938 TI - MRD detection of leukemia relapse using HLA typing by FACS in combination with FISH after mismatched allogeneic stem cell transplantation. AB - Loss of mismatched HLA is a cause of relapse following HLA-mismatched allo-SCT. We directly detected the loss of mismatched HLA alleles in relapsed leukemic cells at a MRD level using HLA typing by multicolor FACS (HLA-Flow) in combination with FISH in the BM of two patients with MLL-AF9-positive AML, at 6 and 10 months after mismatched allo-SCT. HLA-Flow with FISH analysis detected relapsed leukemic cells not expressing a mismatched HLA allele and harboring the MLL rearrangement. Simultaneously, real-time quantitative RT-PCR detected a low copy number of MLL-AF9 transcripts, consistent with MRD detection. HLA-Flow with FISH is a powerful method for detecting molecular relapse after mismatched allo SCT and provides important information on the HLA expression status of the relapsed leukemic cells to help determine the next intervention. PMID- 24813939 TI - Student perceptions of stress, coping, relationships, and academic civility: a longitudinal study. AB - Academic incivility can increase student stress, jeopardize learning, damage relationships, and negatively impact the academic environment. This 3-year longitudinal study measured a cohort of prelicensure nursing students' progressive perceptions of stress, coping, student-student and faculty-student relationships, and levels of academic civility. While civility scores remained mild to moderately high overall, there was a slightly declining trend over the 3 year period. Perceived stressors and coping strategies and ways to improve academic civility are identified and discussed. PMID- 24813940 TI - A description of nurses' decision-making in managing electrocardiographic monitor alarms. AB - AIMS AND OBJECTIVES: To describe the cues and factors that nurses use in their decision-making when responding to clinical alarms. BACKGROUND: Alarms are designed to be very sensitive, and as a result, they are not very specific. Lack of adherence to the practice standards for electrocardiographic monitoring in hospital settings has been observed, resulting in overuse of the electrocardiographic monitoring. Monitoring without consideration of clinical indicators uses scarce healthcare resources and may even produce untoward circumstances because of alarm fatigue. With so many false alarms, alarm fatigue represents a symptom of a larger problem. It cannot be fixed until all of the factors that contribute to its existence have been examined. DESIGN: This was a qualitative descriptive study. METHOD: This study was conducted at an academic medical centre located in the Northeast United States. Eight participants were enrolled using purposive sampling. Nurses were observed for two three-hour periods. Following each observation, the nurse was interviewed using the critical decision method to describe the cognitive processes related to the alarm activities. Qualitative data from the conducted interviews were analysed via an a priori framework founded in the critical decision method. RESULTS: This study reveals information, experience, guidance and decision-making as the four prominent categories contributing to nurses' decision-making in relation to alarm management. Managing technology was a category not identified a priori that emerged in the data analysis. CONCLUSION: Nurses revealed a breadth of information needed to adequately identify and interpret monitor alarms, and how they used that information to put the alarms into the particular context of an individual patient's situations. RELEVANCE TO CLINICAL PRACTICE: Understanding the cues and factors nurses use when responding to cardiac alarms will guide the development of learning experiences and inform policies to guide practice. PMID- 24813941 TI - Different Pearl Indices in studies of hormonal contraceptives in the United States: impact of study population. AB - OBJECTIVE: To examine the impact of subject characteristics on efficacy as measured by the Pearl Index (PI) in clinical trials and to make study populations similar by matching. METHODS: Our analysis used US data from four large Phase III studies. We compared results from one fertility control patch study with pooled data from three studies with virtually identical design on oral hormonal contraceptives. First, we identified three characteristics that had the most impact on the PI. Second, we used these three variables and matched subjects from the patch study with those from the oral contraceptive (OC) studies. Finally, we calculated the PIs for matched and unmatched subjects from both the patch study and the OC studies. RESULTS: A total of 3706 subjects were included in our analysis. The variables 'Hispanic ethnicity', 'previous pregnancy' and 'previous use of hormonal contraceptives' had the most impact on the PI. The PIs for the matched patch cohort and the matched OC cohort were 2.97 and 2.48, respectively. Those for the unmatched patch cohort and the unmatched OC cohort were 10.17 and 0.90, respectively. CONCLUSION: Subject characteristics strongly influence the PI in clinical studies of hormonal contraceptives. In particular, Hispanic ethnicity, previous pregnancies and no previous use of hormonal contraceptives result in a higher PI. IMPLICATIONS: PIs from different clinical trials cannot be meaningfully compared unless subject characteristics that have most impact on the PI are similar or are made to be similar statistically as we did here by matching. PMID- 24813942 TI - Histopathological progression of a mycosis fungoides mimic to classic vitiligo. PMID- 24813944 TI - Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2. AB - Methylated cytosine of CpG dinucleotides in vertebrates may be oxidized by Tet proteins, a process that can lead to DNA demethylation. The predominant oxidation product, 5-hydroxymethylcytosine (5hmC), has been implicated in embryogenesis, cell differentiation, and human diseases. Recently, the SRA domain of UHRF2 (UHRF2-SRA) has been reported to specifically recognize 5hmC, but how UHRF2 recognizes this modification is unclear. Here we report the structure of UHRF2 SRA in complex with a 5hmC-containing DNA. The structure reveals that the conformation of a phenylalanine allows the formation of an optimal 5hmC binding pocket, and a hydrogen bond between the hydroxyl group of 5hmC and UHRF2-SRA is critical for their preferential binding. Further structural and biochemical analyses unveiled the role of SRA domains as a versatile reader of modified DNA, and the knowledge should facilitate further understanding of the biological function of UHRF2 and the comprehension of DNA hydroxymethylation in general. PMID- 24813943 TI - Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. AB - The Hippo pathway, evolutionarily conserved from flies to mammals, promotes cell death and inhibits cell proliferation to regulate organ size. The core component of this cascade, Mst1 in mammalian cells, is sufficient to promote apoptosis. However, the mechanisms underlying both its activation and its ability to elicit cell death remain largely undefined. We here identify a signaling cassette in cardiac myocytes consisting of K-Ras, the scaffold RASSF1A, and Mst1 that is localized to mitochondria and promotes Mst1 activation in response to oxidative stress. Activated Mst1 phosphorylates Bcl-xL at Ser14, which resides in the BH4 domain, thereby antagonizing Bcl-xL-Bax binding. This, in turn, causes activation of Bax and subsequent mitochondria-mediated apoptotic death. Our findings demonstrate mitochondrial localization of Hippo signaling and identify Bcl-xL as a target that is directly modified to promote apoptosis. PMID- 24813945 TI - Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. AB - UHRF1 is a multidomain protein crucially linking histone H3 modification states and DNA methylation. While the interaction properties of its specific domains are well characterized, little is known about the regulation of these functionalities. We show that UHRF1 exists in distinct active states, binding either unmodified H3 or the H3 lysine 9 trimethylation (H3K9me3) modification. A polybasic region (PBR) in the C terminus blocks interaction of a tandem tudor domain (TTD) with H3K9me3 by occupying an essential peptide-binding groove. In this state the plant homeodomain (PHD) mediates interaction with the extreme N terminus of the unmodified H3 tail. Binding of the phosphatidylinositol phosphate PI5P to the PBR of UHRF1 results in a conformational rearrangement of the domains, allowing the TTD to bind H3K9me3. Our results define an allosteric mechanism controlling heterochromatin association of an essential regulatory protein of epigenetic states and identify a functional role for enigmatic nuclear phosphatidylinositol phosphates. PMID- 24813946 TI - RNA specificity and regulation of catalysis in the eukaryotic polynucleotide kinase Clp1. AB - RNA-specific polynucleotide kinases of the Clp1 subfamily are key components of various RNA maturation pathways. However, the structural basis explaining their substrate specificity and the enzymatic mechanism is elusive. Here, we report crystal structures of Clp1 from Caenorhabditis elegans (ceClp1) in a number of nucleotide- and RNA-bound states along the reaction pathway. The combined structural and biochemical analysis of ceClp1 elucidates the RNA specificity and lets us derive a general model for enzyme catalysis of RNA-specific polynucleotide kinases. We identified an RNA binding motif referred to as "clasp" as well as a conformational switch that involves the essential Walker A lysine (Lys127) and regulates the enzymatic activity of ceClp1. Structural comparison with other P loop proteins, such as kinases, adenosine triphosphatases (ATPases), and guanosine triphosphatases (GTPases), suggests that the observed conformational switch of the Walker A lysine is a broadly relevant mechanistic feature. PMID- 24813947 TI - Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. AB - Transcription factors (TFs) preferentially bind sites contained in regions of computationally predicted high nucleosomal occupancy, suggesting that nucleosomes are gatekeepers of TF binding sites. However, because of their complexity mammalian genomes contain millions of randomly occurring, unbound TF consensus binding sites. We hypothesized that the information controlling nucleosome assembly may coincide with the information that enables TFs to bind cis regulatory elements while ignoring randomly occurring sites. Hence, nucleosomes would selectively mask genomic sites that can be contacted by TFs and thus be potentially functional. The hematopoietic pioneer TF Pu.1 maintained nucleosome depletion at macrophage-specific enhancers that displayed a broad range of nucleosome occupancy in other cell types and in reconstituted chromatin. We identified a minimal set of DNA sequence and shape features that accurately predicted both Pu.1 binding and nucleosome occupancy genome-wide. These data reveal a basic organizational principle of mammalian cis-regulatory elements whereby TF recruitment and nucleosome deposition are controlled by overlapping DNA sequence features. PMID- 24813948 TI - Distribution and apoptotic function of outer membrane proteins depend on mitochondrial fusion. AB - Cells deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane and matrix components. Because outer-mitochondrial membrane (OMM) constituents insert directly from the cytoplasm, a role for fusion in their intermitochondrial transfer was unanticipated. Here, we show that fibroblasts lacking the GTPases responsible for OMM fusion, mitofusins 1 and 2 (MFN1 and MFN2), display more heterogeneous distribution of OMM proteins. Proteins with different modes of OMM association display varying degrees of heterogeneity in Mfn1/2(-/-) cells and different kinetics of transfer during fusion in fusion-competent cells. Proapoptotic Bak exhibits marked heterogeneity, which is normalized upon expression of MFN2. Bak is critical for Bid-induced OMM permeabilization and cytochrome c release, and Mfn1/2(-/-) cells show dysregulation of Bid-dependent apoptotic signaling. Bid sensitivity of Bak deficient mitochondria is regained upon fusion with Bak-containing mitochondria. Thus, OMM protein distribution depends on mitochondrial fusion and is a locus of apoptotic dysfunction in conditions of fusion deficiency. PMID- 24813949 TI - Disruption and molecular characterization of calpains-related (MoCAPN1, MoCAPN3 and MoCAPN4) genes in Magnaporthe oryzae. AB - Calpains are intracellular, cysteine proteases found in plants, animals and fungi functioning as signal transduction components in different cellular pathways including sporulation and alkaline adaptation in fungi. Calpains-related MoCAPN1 (MGG_14872), MoCAPN3 (MGG_15810) and MoCAPN4 (MGG_04818) genes from Magnaporthe oryzae genome which are 2604, 3513 and 771-bp in length and encoding identical proteins of 867, 1170 and 256 amino acids were functionally characterized for different phenotypes through gene disruption method. All the mutants except those for MoCAPN1 showed normal phenotypes. In pathogenicity test, the mutants did not lead to any visible changes in phenotypes causing similar blast lesions on blast susceptible rice and barley leaves as those of the Guy-11 strain suggesting no major role in pathogenicity. Germ tubes formation, appressorium formation, mycelium radial growth and mating with 2539 strain were indistinguishable among the mutants and Guy-11 strains. Cell wall integrity (congo red) test, stress response under chemical pressure (ZnSO4, CuSO4 and CdCl2), osmotic and oxidative (NaCl and H2O2) stress response, growth response on glucose and nitrogen deficient media resulted in similar results in the mutants and Guy-11 strains. However, mutants for DeltaMoCAPN1 gene produced reduced (0.57+/-0.15B and 0.54+/ 0.05B) conidia compared to that (1.69+/-0.13A) of the Guy-11 strain showing its involvement in conidiation. PMID- 24813950 TI - Recent nanoarchitectures in metal nanoparticle-graphene nanocomposite modified electrodes for electroanalysis. AB - While increasing attention has been devoted to the use of carbon-based nanomaterials or metal nanoparticles (MNPs) as electrode modifiers for electroanalysis, there is a noticeable development in studies using MNP-graphene nanocomposites or nanohybrids in very recent years. In this review, first, very recent nanoarchitectures in MNP-graphene nanocomposites for modifying electrodes (mainly in 2013) are summarized together with the targets and achievements of electroanalysis. The variety of nanoarchitectures comes from the fact that graphene oxide and metal precursor ions can be reduced chemically or electrochemically, and concurrently or stepwisely. By browsing various preparation methods of the modified electrodes, some characteristic and interesting features of the preparations of MNP-graphene nanocomposites are described together with the possibilities and prospects as electrode modifiers for electroanalysis. PMID- 24813951 TI - Split luciferase complementation for analysis of intracellular signaling. AB - Bioluminescent proteins such as luciferases are unique analytical tools with high sensitivity and wide dynamic ranges. However, applicability of the proteins has remained limited to reporter gene analysis. Split luciferase complementation technique is a new powerful strategy to detect protein-protein interactions and their related intracellular signaling in living cells. This review presents a summary of recent topics for the analysis of biological events using split luciferase complementation techniques. Different applications such as G-protein coupled receptor (GPCR) screening, monitoring phosphorylations, protein-protein interactions, and pH differences in living tissues are described. PMID- 24813952 TI - CdSe/ZnS quantum dots conjugated with a fluorescein derivative: a FRET-based pH sensor for physiological alkaline conditions. AB - Dual pH-dependent fluorescence peaks from a semiconductor quantum dot (QD) and a pH-dependent fluorescent dye can be measured by irradiating with a single wavelength light, and the pH can be estimated from the ratio of the fluorescent intensity of the two peaks. In this work, ratiometric pH sensing was achieved in an aqueous environment by a fluorescent CdSe/ZnS QD appended with a pH-sensitive organic dye, based on fluorescence resonance energy transfer (FRET). By functionalizing the CdSe/ZnS QD with 5-(and 6)-carboxynaphthofluorescein succinimidyl ester as a pH-dependent fluorescent dye, we succeeded in fabricating sensitive nanocomplexes with a linear response to a broad range of physiological pH levels (7.5-9.5) when excited at 450 nm. We found that a purification process is important for increasing the high-fluorescence intensity ratio of a ratiometric fluorescence pH-sensor, and the fluorescence intensity ratio was improved up to 1.0 at pH 8.0 after the purification process to remove unreacted CdSe/ZnS QDs even though the fluorescence of the dye could not be observed without the purification process. The fluorescence intensity ratio corresponds to the fluorescence intensity of the dye, and this fluorescent dye exhibited pH dependent fluorescence intensity changes. These facts indicate that the fluorescence intensity ratio linearly increased with increasing pH value of the buffer solution containing the QD and the dye. The FRET efficiencies changed from 0.3 (pH 7.5) to 6.2 (pH 9.5). PMID- 24813953 TI - Quantification of proteins by measuring the sulfur content of their constituent peptides by means of nano HPLC-ICPMS. AB - The sulfur (S) concentrations of three peptides were determined by using nano HPLC-ICPMS under a flow of O2 in an octapole reaction cell, and the determined values showed a good agreement with theoretical values. This method was then applied to trypsin-digested peptides from human albumin for protein quantification. Assigning of the number of S atoms in each peptide/peak and the tryptic digestion efficiency were important for protein quantification. The number of S atoms in each peptide/peak was assigned by using verification scores that gave the lowest standard deviation of the peptide S concentration and the highest S recovery. The peptide concentrations were calculated as the ratio of the S concentration/the number of S atoms in the peptide/peak. The tryptic digestion efficiency was calculated as the sum of the S concentration in the mono peptides divided by the total S concentration in a native polyacrylamide gel electrophoresis (PAGE) band before tryptic digestion. Our result indicates that a protein can be quantified through peptide quantification, after taking into account the tryptic digestion efficiency, via S quantification using ICPMS. PMID- 24813954 TI - A simple, sensitive colorimetric assay for coralyne based on target induced split G-quadruplex formation. AB - The screening of potential drugs specifically binding to polydeoxyadenosine (poly(dA)) has been of great interest in recent studies. We have developed a simple colorimetric strategy through the mechanism of target induced split G quadruplex formation for detecting coralyne, a poly(dA)-binding drug with noticeable antitumor activity. Two DNA oligonucleotides containing a split G quadruplex sequence and an adenine-rich sequence are used in our strategy. In the presence of coralyne, the adenine-rich sequences of two oligonucleotides are drawn into close proximity, resulting in the formation of a split G-quadruplex DNAzyme that catalyzes the generation of a colored product. The DNAzyme-based colorimetric assay for coralyne has a linear range of from 0.033 to 1.667 MUM with a low detection limit of 16 nM. The developed method is simple, cost effective and visible; it holds great potential for applications in drug screening. PMID- 24813955 TI - Rapid and highly sensitive detection by a real-time polymerase chain reaction using a chip coated with its reagents. AB - On-site detection by flow-through polymerase chain reaction (PCR) microfluidic systems for rapid and highly sensitive analysis, are significantly desired for bioanalytical and medical research. The conventional continuous-flow PCR chips realized rapid detection, but their sensitivity was very low (10(6) to 10(8) copies MUL(-1)). We improved this drawback by coating the chip with a PCR reagents mixture, and succeed to obtain a rapid and highly sensitive detection by using a segment-flow PCR system. In the present work, we developed a portable segment-flow PCR system for practical use. PCR was performed for the uid A gene in E. coli. By real-time segment-flow PCR using coated chips, we realized rapid detection in 8 min and a high sensitivity of 4 cells MUL(-1). The sensitivity by the segment-flow PCR chip was the same as that of a conventional thermal cycler. Moreover, the detection speed of our segment-flow PCR chip was 15-times as rapid as that of the conventional thermal cycler. PMID- 24813956 TI - In situ measurements of the desorption of water from a TiO2 surface under dry air by collecting the photoemission yield with an open counter. AB - We investigated the desorption of water from a TiO2 surface under a dry atmosphere by collecting the photoemission yield spectra with an open counter. For this purpose, a new attachment for the photoemission yield measurement was prepared. This apparatus is capable of detecting, in the open air, low-energy electrons excited by photons under dried atmospheres; the dew point is below -35 degrees C. A significant change in the photoemission yield spectra due to exposure to a dry atmosphere was observed. To gain a better understanding of these results, observations of the change in the photoemission yield spectra caused by the thermal desorption of adsorbed water were also carried out. The results are consistent with those obtained by exposure to a dry atmosphere. Based on the relationship between the photoemission yield and the thickness of the water layer, the time dependence of the change in the thickness was explained by the second-order reaction rate equation. PMID- 24813957 TI - Fabrication of polymerized crystalline colloidal array thin film modified beta cyclodextrin polymer for paraoxon-ethyl and parathion-ethyl detection. AB - We have developed an optical chemical sensor for the detection of organophosphate (OP) compounds using a polymerized crystalline colloidal array (PCCA) thin film composed of a close-packed colloidal array of polystyrene particles. The PCCA thin film was modified with beta-cyclodextrin (beta-CD) polymer as a capping cavity for the selective detection of paraoxon-ethyl and parathion-ethyl chemical agents. The fabrication of the modified PCCA thin film was optimized and the structure was characterized using scanning electron microscopy (SEM). The arrangement of polystyrene particles in the PCCA follows a pattern of the fcc (111) planes with strong diffraction peak in the visible spectral region and pH dependence. The diffraction peak of the beta-CD modified PCCA thin film showed a red shift according to the change of paraoxon-ethyl and parathion-ethyl concentrations at a fast response time (10 s) and high sensitivity with detection limits of 2.0 and 3.4 ppb, respectively. Furthermore, the proposed interaction mechanism of beta-CD with paraoxon-ethyl and parathion-ethyl in the beta-CD modified PCCA thin film were discussed. PMID- 24813958 TI - A simple levulinate-based ratiometric fluorescent probe for sulfite with a large emission shift. AB - A simple 4-hydroxynaphthalimide-derived colorimetric and ratiometric fluorescent probe (1) containing a receptor of levulinate moiety was designed and synthesized to monitor sulfite. Probe 1 could quantificationally detect sulfite by a ratiometric fluorescence spectroscopy method with high selectivity and sensitivity. Specially, probe 1 exhibited a 100 nm red-shifted absorption spectrum along with the color changes from colorless to yellow, and 103 nm red shifted emission spectra upon the addition of sulfite. Thus, 1 can serve as a "naked-eye" probe for sulfite. Further, the recognition mechanism of probe 1 for sulfite was confirmed using nuclear magnetic resonance and electrospray ionization mass spectrometry. Also, the preliminary practical application demonstrated that our proposed probe provided a promising method for the determination of sulfite. PMID- 24813959 TI - Determination of the standard entropy changes of ion transfer for 1 alkylpyridinium ions by thermal modulation voltammetry with laser heating at a water/1,2-dichloroethane interface. AB - When laser light impinges upon a liquid-liquid interface between an optically transparent aqueous and opaque organic phase from the aqueous to organic phase, the temperature at the interface and the interfacial region rises. Using this rise in temperature, we have proposed and developed thermal modulation voltammetry at an interface between two immiscible electrolyte solutions (TMV ITIES) and have determined the standard entropy changes of ion transfer, DeltaS(tr)( degrees ,O->W). In this work, we have determined DeltaS(tr)( degrees ,O->W) for four 1-alkylpridinium ions, namely 1-methylpyridinium ion (MePy(+)), 1 ethylpyridinium ion (EtPy(+)), 1-propylpyridinium ion (PrPy(+)), and 1 buthylpyridinium ion (BuPy(+)) by TMV-ITIES. As a result, we obtained the DeltaS(tr)( degrees ,O->W) values of 108.0 +/- 0.5 (n = 3), 75.8 +/- 4.4, 55.6 +/ 1.2, and 42.7 +/- 0.9 J K(-1) mol(-1) for MePy(+), EtPy(+), PrPy(+), and BuPy(+), respectively. From these values of DeltaS(tr)( degrees ,O->W), we have suggested that MePy(+), EtPy(+), and PrPy(+) are classified as water structure breaking ions and BuPy(+) as a weak water structure-making ion. Further, we discuss the relationship between the standard free energy change, DeltaG(tr)( degrees ,O->W), and DeltaS(tr)( degrees ,O->W) of ion transfer for 1 alkylpridinium ions and tetraalkylammonium ions. PMID- 24813960 TI - Metal assisted approach to develop molecularly imprinted mesoporous material exhibiting pockets for the fast uptake of diethyl phthalate as copper complex. AB - A new molecularly imprinted mesoporous material (MIM) containing specific pockets for the extraction of diethyl phthalate (DEP) as copper complex has been prepared for the first time. The mesoporous material was developed by utilizing copper phthalate complex (Cu-DEP) as the template molecule, 3-aminopropyltriethoxysilane (APS) as a functional monomer and tetraethoxyorthosilicate (TEOS) as the silica source for polymer network formation. The mesoporous material showed fast uptake kinetics, and equilibrium was obtained within 30 min due to the introduction of copper, which provides an additional site for interaction with the functional monomer. Synthesized polymer was well characterized using UV-Vis spectrophotometry, IR spectroscopy, TGA studies, and TEM. To achieve efficient extraction of the template molecule, various factors including sorption kinetics, quantity of MIM, time required for equilibrium set-up, sorption isotherm and reuse of MIM were optimized. The extracted DEP samples were analyzed quantitatively at 310 nm using an HPLC-DA system. The prepared material is robust and can be reused. In addition, it was found to be selective for DEP as compared to other phthalates. PMID- 24813961 TI - Suppression of the incoherent molecular formation effect by oxygen gas in arsenic analysis by ICP-MS. AB - The Incoherent Molecular Formation (IMF) effect, which involves the molecular formation of arsenic (As) atoms depends, on its oxidation state in the inductively coupled plasma. This leads to determination errors, when As is measured by inductively coupled plasma mass spectrometry (ICP-MS). The sensitivity of As(V) is 4-7% higher than that of As(III) at m/z 75, since the final ionization rates of As(V) and As(III) are different from each other due to the IMF effect. A precise measurement of As by ICP-MS is generally very difficult. Recently, the collision/reaction cell is widely used for ICP-MS to eliminate spectral interferences caused by polyatomic molecules. Especially, oxygen gas (O2) is one of the most useful reaction cell gases for As analysis, because As(+) is oxygenated into AsO(+), which is free from the such interferences as ArCl(+). In addition, the use of O2 as a reaction gas is extremely effective for reducing the IMF effect and eliminating the sensitivity difference between As(III) and As(V). PMID- 24813962 TI - Rotating disk sorptive extraction of Cu-bisdiethyldithiocarbamate complex from water and its application to solid phase spectrophotometric quantification. AB - This study demonstrates the first use of polydimethylsiloxane (PDMS) immobilized on a rotating disk for the extraction of copper from aqueous matrices and its subsequent direct determination by solid phase UV-Visible spectrophotometry. To accomplish the solid-phase extraction and the direct solvent-free spectrophotometric measurement, sodium diethyldithiocarbamate (NaDDTC) was used as an analytical reagent to form the uncharged chromophore complex Cu(DDTC)2, which absorbs at 432 nm. Different physicochemical conditions (pH, temperature, reagent concentration, chemical modifiers) and hydrodynamic factors (rotation velocity, extraction time, sample volume) were optimized. Under the optimized conditions, extraction equilibrium times of 30, 53 and 90 min were obtained for 100, 500 and 1000 mL of sample, respectively, with preconcentration factors of 286, 712 and 1284, respectively. The methodology was precise (repeatability and reproducibility of 7.2 and 8.4%, respectively, as relative standard deviation) and accurate (recovery of 96.7%) when analyzing a multielement certified reference standard. The latter study also confirmed the high selectivity of the extraction and determination of the copper chromophore over other metal ions. The obtained limits of detection and quantification reached values lower than 12 MUg L(-1), which can be reduced further by increasing the sample volume. Accuracy was also assessed using both recovery tests on drinking water matrices (95.5% recovery) and comparison with results obtained by an independent method using inductively coupled plasma-optical emission spectroscopy (ICP-OES); no significant differences were observed. PMID- 24813963 TI - Study on photocatalytic organic reactions using photocatalytic microreactors. AB - Photocatalytic organic reactions were performed using automatic photocatalytic microreactor, where several open-end capillaries with photocatalytic materials coated inside were just soaked in a test tube including a reactant solution. Organic reactions of the alkyl radicals generated from carboxylic acids due to the photo-Kolbe reaction was studied, in analogy with the reactions using a photosensitizer. This methodology features the reusability of the reactor and an easy process for analysis due to easy separation of the reactant solution. PMID- 24813965 TI - Influence of vegetation size on the clinical presentation and outcome of lead associated endocarditis: results from the MEDIC registry. AB - OBJECTIVES: The purpose of this study was to determine whether the clinical presentation of lead-associated endocarditis (LAE) is related to the size of lead vegetations and how size is related to bacteriology and clinical outcomes. BACKGROUND: Cardiac implantable electronic device (CIED) infection may present as either local pocket infection or bloodstream infection with or without LAE. LAE is associated with significant morbidity and mortality. METHODS: The clinical presentation and course of LAE were evaluated by the MEDIC (Multicenter Electrophysiologic Device Cohort) registry, an international registry enrolling patients with CIED infection. Consecutive LAE patients enrolled in the MEDIC registry between January 1, 2009 and December 31, 2012 were analyzed. The clinical features and outcomes of 2 groups of patients were compared based on the size of the lead vegetation detected by echocardiography (> or <1 cm in diameter). RESULTS: There were 129 patients with LAE enrolled into the MEDIC registry. Of these, 61 patients had a vegetation <1 cm in diameter (Group I) whereas 68 patients had a vegetation >=1 cm in diameter (Group II). Patients in Group I more often presented with signs of local pocket infection, whereas Group II patients presented with clinical evidence of systemic infection. Staphylococcus aureus was the organism most often responsible for LAE, whereas infection with coagulase-negative staphylococci was associated with larger vegetations. Outcomes were improved among those who underwent complete device removal. However, major complications were associated with an open surgical approach for device removal. CONCLUSIONS: The clinical presentation of LAE is influenced by the size of the lead vegetation. Prompt recognition and management of LAE depends on obtaining blood cultures and echocardiography, including transesophageal echocardiography, in CIED patients who present with either signs of local pocket or systemic infection. PMID- 24813966 TI - CMR-guided approach to localize and ablate gaps in repeat AF ablation procedure. AB - OBJECTIVES: The aim of this study was to test the feasibility and usefulness of a new delayed-enhancement cardiac magnetic resonance (DE-CMR)-guided approach to ablate gaps in redo procedures. BACKGROUND: Recurrences of atrial fibrillation (AF) after pulmonary vein isolation (PVI) may be related to gaps at the ablation lines. DE-CMR allows identification of radiofrequency lesions and gaps (CMR gaps). METHODS: Fifteen patients undergoing repeated AF ablations were included (prior procedure was PVI in all patients and roof-line ablation in 8 patients). Pre-procedure 3-dimensional (3D) DE-CMR was performed with a respiratory navigated (free-breathing) and electrocardiographically gated inversion-recovery gradient-echo sequence (voxel size 1.25 * 1.25 * 2.5 mm). Endocardium and epicardium were manually segmented to create a 3D reconstruction (DE-CMR model). A pixel signal intensity map was projected on the DE-CMR model and color-coded (thresholds 40 +/- 5% and 60 +/- 5% of maximum intensity). The DE-CMR model was imported into the navigation system to guide the ablation of CMR gaps, with the operator blinded to electrical data. Fifteen conventional procedures were used as controls to compare procedural duration, radiofrequency, and fluoroscopy times. RESULTS: Fifteen patients (56 pulmonary veins [PVs]; 57 +/- 8 years of age; 9 with paroxysmal AF) were analyzed. In total, 67 CMR gaps were identified around PVs (mean 4.47 gaps/patient; median length 13.33 mm/gap) and 9 at roof line. All of the electrically reconnected PVs (87.5%) had CMR gaps. The site of electrical PV reconnection (assessed by circular mapping catheter) matched with a CMR gap in 79% of PVs. CMR-guided ablation led to reisolation of 95.6% of reconnected PVs (median radiofrequency time of 13.3 [interquartile range: 7.5 to 21.7] min/patient) and conduction block through the roof line in all patients (1.4 [interquartile range: 0.7 to 3.1] min/patient). Compared with controls, the CMR guided approach shortened radiofrequency time (1,441 +/- 915 s vs. 930 +/- 662 s; p = 0.026) but not the procedural duration or fluoroscopy time. CONCLUSIONS: DE CMR can successfully guide repeated PVI procedures by accurately identifying and localizing gaps and may reduce procedural duration and radiofrequency application time. PMID- 24813967 TI - Association of CMR-measured LA function with heart failure development: results from the MESA study. AB - OBJECTIVES: The goal of this study was to assess the association between left atrial (LA) volume and function measured with feature-tracking cardiac magnetic resonance (CMR) and development of heart failure (HF) in asymptomatic individuals. BACKGROUND: Whether alterations of LA structure and function precede or follow HF development remains incompletely understood. We hypothesized that significant alterations of LA deformation and architecture precede the development of HF in the general population. METHODS: In a case-control study nested in MESA (Multi-Ethnic Study of Atherosclerosis), baseline LA volume and function assessed using CMR feature-tracking were compared between 112 participants with incident HF (mean age 68.4 +/- 8.2 years; 66% men) and 224 age- and sex-matched controls (mean age 67.7 +/- 8.9 years; 66% men). Participants were followed up for 8 years. All individuals were in normal sinus rhythm at the time of imaging, without any significant valvular abnormalities and free of clinical cardiovascular diseases. RESULTS: Individuals with incident HF had greater maximal and minimal LA volume indexes (LAVImin) than control subjects (40 +/- 13 mm(3)/m(2) vs. 33 +/- 10 mm(3)/m(2) [p <0.001] for maximal LA index and 25 +/- 11 mm(3)/m(2) vs. 17 +/- 7 mm(3)/m(2) [p <0.001] for LAVImin). The HF case subjects also had smaller global peak longitudinal atrial strain (PLAS) (25 +/- 11% vs. 38 +/- 16%; p <0.001) and lower LA emptying fraction (40 +/- 11% vs. 48 +/- 9%; p <0.001) at baseline. After adjustment for traditional cardiovascular risk factors, left ventricular mass, and N-terminal pro-B-type natriuretic peptide, global PLAS (odds ratio: 0.36 per SD [95% confidence interval: 0.22 to 0.60]) and LAVImin (odds ratio: 1.65 per SD [95% confidence interval: 1.04 to 2.63]) were independently associated with incident HF. CONCLUSIONS: Deteriorations in LA structure and function preceded development of HF. Lower global PLAS and higher LAVImin, measured using CMR feature-tracking, were independent markers of incident HF in a multiethnic population of asymptomatic individuals. PMID- 24813968 TI - LGE and NT-proBNP identify low risk of death or arrhythmic events in patients with primary prevention ICDs. AB - OBJECTIVES: The aim of this study was to investigate whether late gadolinium enhancement (LGE) magnetic resonance imaging or N-terminal pro-B-type natriuretic peptide (NT-proBNP) could identify patients with a low risk of death or use of implantable cardioverter-defibrillator (ICD) in patients receiving a primary prevention ICD. BACKGROUND: ICDs reduce mortality in patients with heart failure (HF), although two-thirds may never use their device. Current risk stratification, based on New York Heart Association functional class and left ventricular ejection fraction, still leads to implantation of ICDs in patients who may never need their device. METHODS: We examined 157 patients with HF (61 with ischemic cardiomyopathy and 96 with dilated cardiomyopathy; mean age 50.5 years; 78% male) who underwent primary prevention defibrillator implantation. Presence and volume of LGE was measured before device implantation, and serum NT proBNP level was measured before ICD implantation. The combined primary endpoint was cardiovascular death or appropriate ICD therapy (either appropriate shock or antitachycardia pacing). RESULTS: The primary outcome occurred in 32 patients (20.4%) over a median follow-up period of 915 days. Percentage of LGE (hazard ratio [HR]: per 1% increase: 1.06; 95% confidence interval [CI]: 1.04 to 1.09; p < 0.001) and (ln) NT-proBNP (HR: 1.44; 95% CI: 1.04 to 1.98; p = 0.027) were predictors of death or appropriate ICD activation and remained significant when entered into multivariable analysis. When the cohort was stratified into tertiles based on LGE percentage and NT-proBNP, we were able to identify a low-risk group (event rate 3% per year, compared with the intermediate- and high-risk groups [6% and 10% per year, respectively]). CONCLUSIONS: Both percentage of LGE and NT proBNP were associated with higher risk of death or appropriate ICD activation. The use of these markers in combination may be useful in identifying individuals most likely to benefit from this costly intervention, and more specifically, in the identification of a group at lower risk in whom ICD implantation may be deferred. PMID- 24813969 TI - The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study. AB - OBJECTIVE: The aim of the Prospective Observational Trial to Optimize Pediatric Health in IUGR Study was to evaluate the optimal management of fetuses with an estimated fetal weight less than the 10th centile. The objective of this secondary analysis was to describe the role of the cerebroplacental ratio (CPR) in the prediction of adverse perinatal outcome. STUDY DESIGN: More than 1100 consecutive singleton pregnancies with intrauterine growth restriction (IUGR) were recruited over 2 years at 7 centers, undergoing serial sonographic evaluation including multivessel Doppler measurement. CPR was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. RESULTS: Data for CPR calculation was available in 881 cases, which was performed at a mean gestational age of 33 weeks (interquarile range, 28.7-35.9). Of the 146 cases with CPR less than 1, 18% (n = 27) had an adverse perinatal outcome. This conferred an 11-fold increased risk (odds ratio, 11.7; P < .0001) when compared with cases with normal CPR (2%; 14 of 735). An abnormal CPR was present in all 3 cases of mortality. Prediction of adverse outcomes was comparable when using all definitions of abnormal CPR. CONCLUSION: Irrespective of the CPR calculation used, brain sparing is significantly associated with an adverse perinatal outcome in IUGR. This adds further weight to integrating CPR evaluation into the clinical assessment of IUGR pregnancies. The impact of this finding on long-term neurodevelopmental outcomes in this patient cohort is underway. PMID- 24813970 TI - Timing of delivery in placenta accreta. PMID- 24813971 TI - Type-specific HPV and Pap test results among low-income, underserved women: providing insights into management strategies. AB - OBJECTIVE: The primary cervical cancer screening strategy for women over age 30 is high-risk human papillomavirus (HPV) testing combined with Papanicolaou (Pap) testing (cotesting) every 5 years. This combination strategy is a preventive service that is required by the Affordable Care Act to be covered with no cost sharing by most health insurance plans. The cotesting recommendation was made based entirely on prospective data from an insured population that may have a lower proportion of women with HPV positive and Pap negative results (ie, discordant results). The discordant group represents a very difficult group to manage. If the frequency of discordant results among underserved women is higher, health care providers may perceive the cotesting strategy to be a less favorable screening strategy than traditional Pap testing every 3 years. STUDY DESIGN: The Centers for Disease Control and Prevention's Cervical Cancer Study was conducted at 15 clinics in 6 federally qualified health centers across Illinois. Providers at these clinics were given the option of cotesting for routine cervical cancer screening. Type-specific HPV detection was performed on residual extracts using linear array. RESULTS: Pap test results were abnormal in 6.0% and HPV was positive in 7.2% of the underserved women screened in this study (mean age, 45.1 years). HPV prevalence decreased with age, from 10.3% among 30- to 39-year-olds to 4.5% among 50- to 60-year-olds. About 5% of the women had a combination of a positive HPV test and normal Pap test results; HPV 16/18 was identified in 14% of discordant women. CONCLUSION: The rate of discordant results among underserved women was similar to those reported throughout the US in a variety of populations. Typing for HPV 16/18 appears to assist in the management in a small proportion of women with discordant results. PMID- 24813972 TI - Evaluation of outcomes after implementation of an induction-of-labor protocol. AB - OBJECTIVE: The purpose of this study was to determine whether adherence to an induction of labor (IOL) protocol decreases the rate of failed IOL (FIOL). STUDY DESIGN: We performed a 1-year retrospective chart review around the implementation of a hospital IOL protocol and compared maternal and neonatal outcomes from deliveries managed per protocol (n = 369) with those deliveries that were not (n = 230). Women at least 24 weeks' gestation with cervical dilation up to 2 cm who underwent an indicated IOL were included. Protocol adherent (PA) inductions had amniotomy within 24 hours of starting oxytocin, intrauterine pressure catheter placement in latent labor, Montevideo units titrated to 200-300 or to adequate cervical change, and oxytocin administered for at least 12 hours after amniotomy before FIOL was diagnosed (defined as delivery by cesarean during latent labor as a result of failure to enter active labor). The primary outcome was the rate of FIOL. Control for possible confounders was made by stratification and multivariate modeling. RESULTS: FIOL rates were lowest in the PA group, which remained significant after stratification on parity and multivariate analysis (nulliparous women, 3.8% vs 9.8%; P = .043; multiparous women, 0% vs 6%; P < .0004). Median time to delivery was shortest in the PA group by 3.5 hours in nulliparous women (16.0 vs 19.5 hours, respectively; P = .0002) and 1.5 hours in multiparous women (10.75 vs 12.25 hours, respectively; P < .0001). There were no differences in infectious morbidity or neonatal outcomes between the groups. CONCLUSION: Adherence to a standardized IOL protocol is associated with a decreased rate of FIOL and length of labor. PMID- 24813973 TI - Appearances can be deceiving: ovarian mass presents as vaginal prolapse. PMID- 24813974 TI - Reply: To PMID 24055579. PMID- 24813975 TI - Alternative way of removing pessaries that cause genital incarceration. PMID- 24813976 TI - Reply: To PMID 24096181. PMID- 24813977 TI - International vs. hospital acquired infection. PMID- 24813978 TI - Courts, patents, litigation & patient care. PMID- 24813979 TI - Rasch analysis of the illness management and recovery scale-clinician version. AB - RATIONALE, AIMS AND OBJECTIVES: The illness management and recovery scale clinician version (IMRS-C) is a measure of outcomes thought to be important indicators of progress for consumers participating in illness management and recovery (IMR). Prior research has examined the psychometric properties of the IMRS-C; extant research supports certain aspects of the scale's reliability (test retest) and validity (sensitivity to interventions). Analyses based on Rasch provide certain advantages and have not been applied to the IMRS-C. METHOD: This study used an archival IMRS database including responses regarding 697 participants with severe mental illness from a variety of community-based settings. Rasch analyses were utilized to determine item functioning and utility of the IMRS-C. RESULTS: Results of Rasch analyses using the IMRS-C as one unidimensional scale were problematic. Analyses grouping items into three separate scales measuring recovery, management and biological vulnerability were more promising, but the third scale had other limitations. CONCLUSIONS: Results suggest that the items included in the IMRS-C can form two screeners, one for recovery and one for management; items regarding biological vulnerability were inadequate. The assessment could be supplemented by more refined measures of coping/self-management and recovery constructs. PMID- 24813980 TI - Quantitative modelling to estimate the transfer of pharmaceuticals through the food production system. AB - Use of pharmaceuticals in animal production may cause an indirect route of contamination of food products of animal origin. This study aimed to assess, through mathematical modelling, the transfer of pharmaceuticals from contaminated soil, through plant uptake, into the dairy food production chain. The scenarios, model parameters, and values refer to contaminants in emission slurry production, storage time, immission into soil, plant uptake, bioaccumulation in the animal's body, and transfer to meat and milk. Modelling results confirm the possibility of contamination of dairy cow's meat and milk due the ingestion of contaminated feed by the cattle. The estimated concentration of pharmaceutical residues obtained for meat ranged from 0 to 6 ng kg(-1) for oxytetracycline, from 0.011 to 0.181 MUg kg(-1) for sulfamethoxazole, and from 4.70 to 11.86 MUg kg(-1) for ketoconazole. The estimated concentrations for milk were: zero for oxytetracycline, lower than 40 ng L(-1) for sulfamethoxazole, and from 0.98 to 2.48 MUg L(-1) for ketoconazole. Results obtained for the three selected pharmaceuticals indicate a minor risk for human health. This study showed that supply chain modelling could be an effective tool in assessing the indirect contamination of feedstuff and animal products by residues of pharmaceuticals. The model can easily be adjusted to other contaminants and supply chain and, in this way, present a valuable tool to underpin decision making. PMID- 24813981 TI - Pollution characteristics and environmental risk assessment of typical veterinary antibiotics in livestock farms in Southeastern China. AB - Scientific interest in pollution from antibiotics in animal husbandry has increased during recent years. However, there have been few studies on the vertical exposure characteristics of typical veterinary antibiotics in different exposure matrices from different livestock farms. This study explores the distribution and migration of antibiotics from feed to manure, from manure to soil, and from soil to vegetables, by investigating the exposure level of typical antibiotics in feed, manure, soil, vegetables, water, fish, and pork in livestock farms. A screening environmental risk assessment was conducted to identify the hazardous potential of veterinary antibiotics from livestock farms in southeast China. The results show that adding antibiotics to drinking water as well as the excessive use of antibiotic feed additives may become the major source of antibiotics pollution in livestock farms. Physical and chemical properties significantly affect the distribution and migration of various antibiotics from manure to soil and from soil to plant. Simple migration models can predict the accumulation of antibiotics in soil and plants. The environmental risk assessment results show that more attention should be paid to the terrestrial eco-risk of sulfadiazine, sulfamethazine, sulfamethoxazole, tetracycline, oxytetracycline, chlorotetracycline, ciprofloxacin, and enrofloxacin, and to the aquatic eco-risk of chlorotetracycline, ciprofloxacin, and enrofloxacin. This is the first systematic analysis of the vertical pollution characteristics of typical veterinary antibiotics in livestock farms in southeast China. It also identifies the ecological and human health risk of veterinary antibiotics. PMID- 24813982 TI - Tea bag filter paper as a novel protective membrane for micro-solid phase extraction of butachlor in aqueous samples. AB - An innovative, cost-effective, simple, and environmental friendly tea bag filter paper protected micro-solid phase extraction (MU-SPE) technique was developed for the first time with the aim to miniaturize and minimize the use of organic solvents for the extraction and determination of butachlor in aqueous samples. The MU-SPE device was produced by packing 3.0 mg of an easily synthesized new sorbent, hydroxyl-functionalized polypyrrole (OH-PPY), inside a small tea bag filter paper sachet (1.0 cm * 0.5 cm) that served as a protective envelope. Both the extraction and desorption procedures were facilitated by sonication. Due to the high porosity and the fast water absorption of the tea bag filter paper, the analyte could easily diffuse through and enhance the interaction with the sorbent. Under the optimized conditions for the GC-ECD and the MU-SPE, the limit of detection (S/N >= 3) was 2.0 MUg L(-1) while the limit of quantitation (S/N >= 10) was 10.0 MUg L(-1). The recoveries of the butachlor spiked at 0.050, 0.10, and 0.50 MUg mL(-1) ranged from 77.9 +/- 3.0 to 112.5 +/- 2.9%. The proposed method was successfully applied for the determination of butachlor in water samples from paddy cultivation sites. The levels found were from non-detectable to 24.71 +/- 0.37 MUg L(-1). PMID- 24813983 TI - High-performance liquid chromatography (HPLC) as a tool for monitoring the fate of fluazinam in soil. AB - Fluazinam is a widely used pesticide employed against the fungal disease late blight in potato cultivation. A specific, repeatable, and rapid high-performance liquid chromatography (HPLC) method utilizing a diode array detector (DAD) was developed to determine the presence of fluazinam in soil. The method consists of acetonitrile (ACN) extraction, clean-up with solid-phase extraction (SPE), and separation using a mobile phase consisting of 70% ACN and 30% water (v/v), including 0.02% acetic acid. HPLC was performed with a C18 column and the detection wavelength was 240 nm. The method was successfully applied to an incubation experiment and to soil samples taken from potato fields where fluazinam had been applied two to three times during the on-going growing season. In the 90-day incubation experiment, analytical standard fluazinam and the commercial fungicide Shirlan((r)) were added to soil samples that had never been treated with fluazinam, and were then extracted with ACN and 0.01 M calcium chloride (CaCl2). Fluazinam was not extractable with CaCl2, indicating that it does not leach to watercourses in the dissolved form. Recovery with ACN extraction for sandy soils was 72-95% immediately after application and 53-73% after 90 days of incubation. Out of the eight potato field soil samples, fluazinam was found in two samples at concentrations of 2.1 mg kg(-1) and 1.9 mg kg(-1), well above the limit of quantification (0.1 mg kg(-1)). PMID- 24813984 TI - Detection of residual organochlorine and organophosphorus pesticides in agricultural soil in Rio Verde region of San Luis Potosi, Mexico. AB - Organochlorine pesticides were intensively used in Mexico from 1950 until their ban and restriction in 1991. However, the presence of these compounds is commonly reported in many regions of the country. The aim of the present study was to identify and quantify residual organochlorine and organophosphorus pesticides in agricultural soil in Rio Verde region, San Luis Potosi state, which has been identified as possibly polluted by pesticides. Composed samples from 24 zones covering an area of approximately 5,440 ha were analyzed. The most frequently found pesticides were p,p'-DDT followed by ,p,p'-DDE, heptachlor, endosulfan and gamma-HCH whose frequency rates were 100, 91, 83 and 54%, respectively. The concentration of p,p'-DDT in the crops grown in these soils was in the following order: chili > maize > tomato > alfalfa. The results obtained in this study show that p,p'-DDT values are lower or similar to those found in other agricultural regions of Mexico. Methyl and ethyl parathion were the most frequent organophosphate pesticide detected in 100% and 62.5% of the samples with average concentrations of 25.20 and 47.48 MUg kg(-1), respectively. More research is needed to establish the background levels of pesticides in agricultural soils and their potential ecological and human health effects in this region. PMID- 24813985 TI - Antibacterial activity against Clostridium genus and antiradical activity of the essential oils from different origin. AB - In the present study, the antimicrobial and antiradical activities of 15 essential oils were investigated. The antimicrobial activities were determined by using agar disc diffusion and broth microdilution methods against Clostridium genus and antioxidant properties of essential oils by testing their scavenging effect on DPPH radicals activities. We determined the antibacterial activity of Clostridium butyricum, Clostridium hystoliticum, Clostridium intestinale, Clostridium perfringens and Clostridium ramosum. We obtained the original commercial essential oils samples of Lavandula angustifolia, Carum carvi, Pinus montana, Mentha piperita, Foeniculum vulgare Mill., Pinus sylvestris, Satureia montana, Origanum vulgare L. (2 samples), Pimpinella anisum, Rosmarinus officinalis L., Salvia officinalis L., Abies alba Mill., Chamomilla recutita L. Rausch and Thymus vulgaris L. produced in Slovakia (Calendula a.s., Nova Lubovna, Slovakia). The results of the disk diffusion method showed very high essential oils activity against all tested strains of microorganisms. The best antimicrobial activity against C. butyricum was found at Pimpinella anisum, against C. hystoliticum was found at Pinus sylvestris, against C. intestinale was found at Satureia hortensis L., against C. perfringens was found at Origanum vulgare L. and against C. ramosum was found at Pinus sylvestris. The results of broth microdilution assay showed that none of the essential oils was active against C. hystoliticum. The best antimicrobial activity against C. butyricum was found at Abies alba Mill., against C. intestinale was found at Abies alba Mill., against C. perfringens was found at Satureia montana and against C. ramosum was found at Abius alba and Carum carvi. Antioxidant DPPH radical scavenging activity was determined at several solutions of oil samples (50 MUL.mL(-1)-0.39 MUL.mL( 1)) and the best scavenging effect for the highest concentration (50 MUL.mL(-1)) was observed. The antioxidant properties were different in particular plant species. The highest% of inhibition after 30 min. of reaction was observed at Origanum vulgare (93%), Satureia montana (90.66%) and Lavandula augustifolia (90.22%). PMID- 24813986 TI - Persistence and dissipation kinetics of trifloxystrobin and tebuconazole in onion and soil. AB - The persistence and dissipation kinetics of trifloxystrobin and tebuconazole on onion were studied after application of their combination formulation at a standard and double dose of 75 + 150 and 150 + 300 g a.i. ha(-1). The fungicides were extracted with acetone, cleaned-up using activated charcoal (trifloxystrobin) and neutral alumina (tebuconazole). Analysis was carried out by gas chromatograph (GC) and confirmed by gas chromatograph mass spectrometry (GC MS). The recovery was above 80% and limit of quantification (LOQ) 0.05 mg kg(-1) for both fungicides. Initial residue deposits of trifloxystrobin were 0.68 and 1.01 mg kg(-1) and tebuconazole 0.673 and 1.95 mg kg(-1) from standard and double dose treatments, respectively. Dissipation of the fungicides followed first-order kinetics and the half life of degradation was 6-6.6 days. Matured onion bulb (and field soil) harvested after 30 days was free from fungicide residues. These findings suggest recommended safe pre-harvest interval (PHI) of 14 and 25 days for spring onion consumption after treatment of Nativo 75 WG at the standard and double doses, respectively. Matured onion bulbs at harvest were free from fungicide residues. PMID- 24813987 TI - Mercury in the Grisette, Amanita vaginata Fr. and soil below the fruiting bodies. AB - This study examined the mercury concentration in the Grisette Amanita vaginata Fr. and soil below the fruiting bodies collected between 2000 and 2008 from the wild at seven distant sites across Poland. The Hg content in samples was determined by cold atomic absorption method (CV-AAS) at a wavelength of 253.7 nm. Mean Hg contents varied from 0.096 +/- 0.052 to 0.48 +/- 0.13 mg kg(-1) dry matter (dm) in caps (range, 0.043-0.73 mg kg(-1)), from 0.047 +/- 0.02 to 0.23 +/ 0.07 mg kg(-1) dm (range, 0.028-0.47 mg kg(-1)) in stipes, and in underlying soil were from 0.035 +/- 0.018 to 0.096 +/- 0.036 mg kg(-1) dm (range, 0.017 to 0.16 mg kg(-1)). The median Qc/s values ranged from 1.2 to 2.2 (mean 1.2 +/- 0.4 to 2.1 +/- 0.5) indicating that Hg content in stipes was generally lower than in caps. This mushroom species has some potential to bioconcentrate Hg in the fruiting bodies, as the values of the bioconcentration factor (BCF) varied for the sites between 1.2 +/- 0.6 to 11 +/- 5 for caps and 0.61 +/- 0.26 to 7.4 +/- 3.9 for stipes. Also available literature data on Hg in A. vaginata are reviewed and discussed. PMID- 24813988 TI - Wild tomato leaf extracts for spider mite and cowpea aphid control. AB - Glandular trichomes on the leaves of wild tomato, L. hirsutum f. hirsutum Mull, also known as Solanum habrochaites (Solanaceae), synthesize and accumulate high levels of methyl ketones (MKs). L. hirsutum accession LA 407, having high concentration of MKs, was grown from seeds under greenhouse conditions. Four MKs (2-undecanone, 2-dodecanone, 2-tridecanone, and 2-pentadecanone) were screened for their toxicity to spider mites, Tetranychus urticae Koch and cowpea aphids, Aphis craccivora Koch. The objectives of this investigation were to: (1) develop a bioassay for testing MKs on spider mite and cowpea aphid mortality and (2) compare the efficacies of wild tomato leaf crude extracts and pure standard materials of MKs against spider mite and cowpea aphid mortality. Our results revealed that spider mites are most sensitive to 2-tridecanone (LC50 = 0.08 MUmole cm(-2) of treated leaf surface) and least sensitive to 2-undecanone (LC50 = 1.5 MUmole cm(-2) of treated leaf surface) 4 h after treatment. Similarly, 2 tridecanone caused greatest mortality (LC50 = 0.2 MUmole cm(-2) of treated leaf surface), whereas 2-undecanone caused the lowest morality (LC50 = 0.48 MUmole cm( 2) of treated surface) of cowpea aphid. We concluded that all MKs tested in this investigation are toxic to spider mites and aphids. 2-Tridecanone is more effective in killing mites and aphids compared to other MKs. Toxicity of crude extracts, prepared from the leaves of L. hirsutum accession LA 407, to spider mites and cowpea aphids revealed greater mortality compared to a combined mixture of MKs standard material (used at the same concentration as found on LA 407 leaves). This indicates that in addition to MKs, other unidentified compounds in LA 407 leaf extract also have pesticidal properties. Accordingly, leaf extracts of LA 407 could be explored in crop protection, and they might open a new area of MK formulations and discovery of biorational alternatives for pest control in agricultural fields. PMID- 24813989 TI - Effects of acidifying reagents on microwave treatment of dairy manure. AB - Dairy manure, acidified using organic acids (acetic, oxalic, and citric acid) were treated with microwave enhanced advanced oxidation process (MW/H2O2-AOP). The effect of a mixture of oxalic acid and commonly used mineral acids (sulfuric and hydrochloric acid) on MW/H2O2-AOP was also examined. Substantial amounts of phosphorus were released under MW/H2O2-AOP, regardless of organic acid or mineral acid used. All three organic acids were good acidifying reagents; however, only oxalic acid could remove free calcium ion in the solution, and improve settleability of dairy manure. The MW/H2O2-AOP and calcium removal process could be combined into a single-stage process, which could release phosphate, solubilize solids and remove calcium from dairy manure at the same time. A mixture of oxalic acid and mineral acid produced the maximum volume of clear supernatant and had an ideal molar ratio of calcium to magnesium for effective struvite (magnesium ammonium phosphate) crystallization process. A single-stage MW/H2O2-AOP would simplify the process and reduce mineral acid consumption compared to a two-stage operation. The results of a pilot scale study demonstrate that MW/H2O2-AOP is effective in treating manure and recovering resource from dairy farms. PMID- 24813990 TI - Two distinct domains of Flo8 activator mediates its role in transcriptional activation and the physical interaction with Mss11. AB - Flo8 is a transcriptional activator essential for the inducible expression of a set of target genes such as STA1, FLO11, and FLO1 encoding an extracellular glucoamylase and two cell surface proteins, respectively. However, the molecular mechanism of Flo8-mediated transcriptional activation remains largely elusive. By generating serial deletion constructs, we revealed here that a novel transcriptional activation domain on its extreme C-terminal region plays a crucial role in activating transcription. On the other hand, the N-terminal LisH motif of Flo8 appears to be required for its physical interaction with another transcriptional activator, Mss11, for their cooperative transcriptional regulation of the shared targets. Additionally, GST pull-down experiments uncovered that Flo8 and Mss11 can directly form either a heterodimer or a homodimer capable of binding to DNA, and we also showed that this formed complex of two activators interacts functionally and physically with the Swi/Snf complex. Collectively, our findings provide valuable clues for understanding the molecular mechanism of Flo8-mediated transcriptional control of multiple targets. PMID- 24813991 TI - Time-resolved FRET reveals the structural mechanism of SERCA-PLB regulation. AB - We have used time-resolved fluorescence resonance energy transfer (TR-FRET) to characterize the interaction between phospholamban (PLB) and the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA) under conditions that relieve SERCA inhibition. Unphosphorylated PLB inhibits SERCA in cardiac SR, but inhibition is relieved by either micromolar Ca(2+) or PLB phosphorylation. In both cases, it has been proposed that inhibition is relieved by dissociation of the complex. To test this hypothesis, we attached fluorophores to the cytoplasmic domains of SERCA and PLB, and reconstituted them functionally in lipid bilayers. TR-FRET, which permitted simultaneous measurement of SERCA-PLB binding and structure, was measured as a function of PLB phosphorylation and [Ca(2+)]. In all cases, two structural states of the SERCA-PLB complex were resolved, probably corresponding to the previously described T and R structural states of the PLB cytoplasmic domain. Phosphorylation of PLB at S16 completely relieved inhibition, partially dissociated the SERCA-PLB complex, and shifted the T/R equilibrium within the bound complex toward the R state. Since the PLB concentration in cardiac SR is at least 10 times that in our FRET measurements, we calculate that most of SERCA contains bound phosphorylated PLB in cardiac SR, even after complete phosphorylation. 4 MUM Ca(2+) completely relieved inhibition but did not induce a detectable change in SERCA-PLB binding or cytoplasmic domain structure, suggesting a mechanism involving structural changes in SERCA's transmembrane domain. We conclude that Ca(2+) and PLB phosphorylation relieve SERCA-PLB inhibition by distinct mechanisms, but both are achieved primarily by structural changes within the SERCA-PLB complex, not by dissociation of that complex. PMID- 24813992 TI - Therapeutic potential of flurbiprofen against obesity in mice. AB - Obesity is associated with several diseases including diabetes, nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease, and cancer. Therefore, anti-obesity drugs have the potential to prevent these diseases. In the present study, we demonstrated that flurbiprofen, a nonsteroidal anti inflammatory drug (NSAID), exhibited therapeutic potency against obesity. Mice were fed a high-fat diet (HFD) for 6 months, followed by a normal-chow diet (NCD). The flurbiprofen treatment simultaneously administered. Although body weight was significantly decreased in flurbiprofen-treated mice, growth was not affected. Flurbiprofen also reduced the HFD-induced accumulation of visceral fat. Leptin resistance, which is characterized by insensitivity to the anti-obesity hormone leptin, is known to be involved in the development of obesity. We found that one of the possible mechanisms underlying the anti-obesity effects of flurbiprofen may have been mediated through the attenuation of leptin resistance, because the high circulating levels of leptin in HFD-fed mice were decreased in flurbiprofen-treated mice. Therefore, flurbiprofen may exhibit therapeutic potential against obesity by reducing leptin resistance. PMID- 24813993 TI - Intermediate conformation between native beta-sheet and non-native alpha-helix is a precursor of trifluoroethanol-induced aggregation of human carbonic anhydrase II. AB - In the present work, we examined the correlation between 2,2,2-trifluoroethanol (TFE)-induced conformational transitions of human carbonic anhydrase II (HCAII) and its aggregation propensity. Circular dichroism data indicates that protein undergoes a transition from beta-sheet to alpha-helix on addition of TFE. The protein was found to aggregate maximally at moderate concentration of TFE at which it exists somewhere between beta-sheet and alpha-helix, probably in extended non-native beta-sheet conformation. Thioflavin-T (ThT) and Congo-Red (CR) assays along with fluorescence microscopy and transmission electron microscopy (TEM) data suggest that the protein aggregates induced by TFE possess amyloid-like features. Anilino-8-naphthalene sulfonate (ANS) binding studies reveal that the exposure of hydrophobic surface(s) was maximum in intermediate conformation. Our study suggests that the exposed hydrophobic surface and/or the disruption of the structural features protecting a beta-sheet protein might be the major reason(s) for the high aggregation propensity of non-native intermediate conformation of HCAII. PMID- 24813994 TI - Expression of filaggrin-2 protein in the epidermis of human skin diseases: a comparative analysis with filaggrin. AB - Filaggrin-2 is a member of the S100 fused-type protein family, and the structural features and expression of filaggrin-2 are similar to those of profilaggrin, a protein essential for keratinization. In the present study, we investigated the expression profile of filaggrin-2 in patients with skin diseases using antibodies against the repetitive region of filaggrin-2. In tissue samples from patients with skin diseases which are associated with a decrease in filaggrin, including ichthyosis vulgaris, atopic dermatitis and psoriasis vulgaris, the expression level of filaggrin-2 was markedly decreased compared to that in normal skin samples. In contrast, the expression of filaggrin-2 increased in parallel with that of filaggrin in samples of tissue from patients with skin diseases associated with hyperkeratosis, such as lichen planus and epidermolytic ichthyosis. Interestingly, filaggrin-2 signals were observed in slightly higher layers of the epidermis in comparison to those of filaggrin. Similarly, the expression of filaggrin-2 proteins was induced slightly later than filaggrin in the cultured keratinocytes. These findings suggest that filaggrin-2 may play an overlapping role with filaggrin in epithelial cornification; however, it may also have a partially distinct role in the molecular processes of cornification. PMID- 24813995 TI - Time-resolved fluorescence of 2-aminopurine in DNA duplexes in the presence of the EcoP15I Type III restriction-modification enzyme. AB - EcoP15I is a Type III DNA restriction and modification enzyme of Escherichia coli. We show that it contains two modification (Mod) subunits for sequence specific methylation of DNA and one copy of a restriction endonuclease (Res) subunit for cleavage of DNA containing unmethylated target sequences. Previously the Mod2 dimer in the presence of cofactors was shown to use nucleotide flipping to gain access to the adenine base targeted for methylation (Reddy and Rao, J. Mol. Biol. 298 (2000) 597-610.). Surprisingly the Mod2 enzyme also appeared to flip a second adenine in the target sequence, one which was not subject to methylation. We show using fluorescence lifetime measurements of the adenine analogue, 2-aminopurine, that only the methylatable adenine undergoes flipping by the complete Res1Mod2 enzyme and that this occurs even in the absence of cofactors. We suggest that this is due to activation of the Mod2 core by the Res subunit. PMID- 24813996 TI - Novel distribution of calreticulin to cardiomyocyte mitochondria and its increase in a rat model of dilated cardiomyopathy. AB - BACKGROUND: Calreticulin (CRT), a Ca(2+)-binding chaperone of the endoplasmic reticulum, can also be found in several other locations including the cytosol, nucleus, secretory granules, the outer side of the plasma membrane, and the extracellular matrix. Whether CRT is localized at mitochondria of cardiomyocytes and whether such localization is affected under DCM are still unclear. METHODS AND RESULTS: The DCM model was generated in rats by the daily oral administration of furazolidone for thirty weeks. Echocardiographic and hemodynamic studies demonstrated enlarged left ventricular dimensions and reduced systolic and diastolic function in DCM rats. Immuno-electron microscopy and Western blot showed that CRT was present in cardiomyocyte mitochondria and the mitochondrial content of CRT was increased in DCM hearts (P<0.05). Morphometric analysis showed notable myocardial apoptosis and mitochondrial swelling with fractured or dissolved cristae in the DCM hearts. Compared with the control group, the mitochondrial membrane potential level of the freshly isolated cardiac mitochondria and the enzyme activities of cytochrome c oxidase and succinate dehydrogenase in the model group were significantly decreased (P<0.05), and the myocardial apoptosis index and the caspase activities of caspase-9 and caspase-3 were significantly increased (P<0.05). Pearson linear correlation analysis showed that the mitochondrial content of CRT had negative correlations with the mitochondrial function, and a positive correlation with myocardial apoptosis index (P<0.001). The protein expression level of cytochrome c and the phosphorylation activity of STAT3 in the mitochondrial fraction were significantly decreased in the model group compared with the control group (P<0.05). CONCLUSIONS: These data demonstrate that CRT is localized at cardiomyocyte mitochondria and its mitochondrial content is increased in DCM hearts. PMID- 24813997 TI - Selection of RNA aptamers against the M. tuberculosis EsxG protein using surface plasmon resonance-based SELEX. AB - Tuberculosis (TB), which is caused by Mycobacterium tuberculosis, remains one of the most prevalent infectious diseases worldwide which causes high morbidity and mortality. However, there is still limited understanding of the physiological processes that allow M. tuberculosis to survive in its host environment. One of the challenges is the limited availability of molecular probes that can be used to study some of the complex systems in mycobacteria. One such system is the ESX 3 secretion system, a specialized type VII secretion (T7S) system. This system is essential for optimal growth of pathogenic mycobacteria in low iron environments similar to that encountered by mycobacteria in macrophages during infection. EsxG, a protein of unknown function, is both encoded within the ESX-3 locus and secreted by the ESX-3 system. There are currently no molecular probes with high affinity and specificity to the EsxG protein that can be used to study it. Here we demonstrate the use of surface plasmon resonance-based systematic evolution of ligands by exponential enrichment (SELEX) to identify two aptamers, G43 and G78 that bind EsxG with high affinities, KD of 8.04+/-1.90 nM and 78.85+/-9.40 nM, respectively. Moreover, these aptamers preferentially bind EsxG over its homologue EsxA. Availability of such probes enables biological investigation of the role of this protein in mycobacteria and its potential as a biomarker for TB diagnosis. PMID- 24813998 TI - Sensitization of cancer cells to radiation by selenadiazole derivatives by regulation of ROS-mediated DNA damage and ERK and AKT pathways. AB - X-ray-based radiotherapy represents one of the most effective ways in treating human cancers. However, radioresistance and side effect remain as the most challenging issue. This study describes the design and application of novel selenadiazole derivatives as radiotherapy sensitizers to enhance X-ray-induced inhibitory effects on A375 human melanoma and Hela human cervical carcinoma cells. The results showed that, pretreatment of the cells with selenadiazole derivatives dramatically enhance X-ray-induced growth inhibition and colony formation. Flow cytometry analysis indicates that the sensitization by selenadiazole derivatives was mainly caused by induction of G2/M cell cycle arrest. Results of Western blotting demonstrated that the combined treatment induced A375 cells growth inhibition was achieved by triggering reactive oxygen species-mediated DNA damage involving inactivation of AKT and MAPKs. Further investigation revealed that selenadiazole derivative in combination with X-ray could synergistically inhibit the activity of thioredoxin reductase-1 in A375 cells. Taken together, these results suggest that selenadiazole derivatives can act as novel radiosensitizer with potential application in combating human cancers. PMID- 24813999 TI - Identification of hepatitis B virus-specific CTL epitopes presented by HLA A*33:03 in peripheral blood mononuclear cells from patients and transgenic mice. AB - Cytotoxic T lymphocyte (CTL) epitopes in the HBV protein of hepatitis B virus (HBV) may play a key role in viral control and liver damage. The aim of this study was to identify and study the function of HLA-A(*)33:03-restricted CTL epitopes in HBV protein of the HBV genotypes B and C, which are epidemic in China. Sixteen HBV peptides were predicated by computational analysis, and synthesized peptides were examined for their affinity to HLA-A(*)33:03 using a stable cell line. After being analyzed by enzyme-linked immunospot and cytolytic activity assays, as well as the tetramers staining method using peripheral blood mononuclear cells isolated from HBV-infected patients, five peptides (Hbs245-253, HBs335-343, HBc119-127, HBc104-112, and HBp391-399) were chosen to further confirm their HLA_A(*)33:03 restriction in transgenic mice. PMID- 24814000 TI - Simultaneous determination of seven beta-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies. AB - There is strong evidence in literature supporting the benefit of monitoring plasma concentrations of beta-lactam antibiotics in the critically ill to ensure appropriateness of dosing. The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6 MUm, 2.1 * 50 mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control samples (QCs) ranging from 95 to 107% and 95 to 108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12% and 5 to 14%, respectively. The lower limit of quantification was 0.1 MUg/mL for each antibiotic except flucloxacillin (0.25 MUg/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected beta-lactam antibiotics. PMID- 24814001 TI - Determination of deltamethrin in rat plasma and brain using gas chromatography negative chemical ionization mass spectrometry. AB - Quantification of the pyrethroid deltamethrin (DLM) in small (100 MUL) biological samples from rodents is essential for toxicokinetic studies of trace levels of the insecticide in foods. Such empirical kinetic data are necessary for construction of valid physiologically-based toxicokinetic models. There are no validated methods in the literature for determining deltamethrin in 100 MUL plasma and brain samples. Plasma and brain samples were stabilized using sodium fluoride as an esterase inhibitor, and the DLM was extracted by protein precipitation using acetonitrile and phosphoric acid. The samples were vortexed, centrifuged, evaporated to dryness, and reconstituted in toluene prior to injection into a gas chromatograph equipped with a quadrupole mass analyzer. Samples were ionized via electron capture in the negative ion mode using methane, and the molecular ion and fragment ions of DLM were monitored using Selected-Ion Monitoring (SIM) for quantitation and verification of the analyte. Cis-permethrin was used as the internal standard for the method, which was validated according to current US FDA guidelines. Linearity was determined between 0.3 and 1,000 ng/mL, with a limit of detection of 150 pg/mL. The intra- and inter-batch variation for precision (as % relative standard deviation, RSD) and accuracy (as % bias) of the method were better than 20% at the limit of quantitation and better than 15% across the remaining linear range (n=18), with recoveries of 113% and 68% for plasma and brain respectively. Benchtop stability, autosampler stability, and freeze/thaw stability studies of the method (over a 3-day freeze/thaw cycle) were found to be within the acceptance criteria of 20% RSD and bias. This optimized method was applied to the quantitation of DLM in plasma and brain homogenate samples obtained up to 12h after oral dosing of Sprague-Dawley rats with 1mg DLM/kg body weight. PMID- 24814002 TI - Rapid screening and identification of alpha-amylase inhibitors from Garcinia xanthochymus using enzyme-immobilized magnetic nanoparticles coupled with HPLC and MS. AB - alpha-Amylase inhibitors play an important role in management of diabetes and obesity. In order to rapidly discover potent alpha-amylase inhibitors from medicinal plants, a ligands-screening method based on enzyme-immobilized magnetic nanoparticles integrated with HPLC was developed. Amine-terminated magnetic nanoparticles were prepared for the immobilization of alpha-amylase. Based on the affinity theory, the alpha-amylase-coated magnetic nanoparticles were employed to fish out the ligands from the extracts of Garcinia xanthochymus, and the elutes were examined by HPLC. As a result, three ligands were screened out. Isolation and identification were carried out subsequently. By analyzing the UV, MS and NMR spectra, they were identified as three biflavonoids including GB2a glucoside (2), GB2a (3) and fukugetin (4). The IC50 values of the three compounds were also determined. The results suggest the proposed approach is efficient and accurate, and has great potential in rapid discovery of drug candidates from medical plants. PMID- 24814003 TI - Enrichment and purification of six Aconitum alkaloids from Aconiti kusnezoffii radix by macroporous resins and quantification by HPLC-MS. AB - Aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine and benzoylhypaconine are six main Aconitum alkaloids from traditional Chinese medicine, Aconiti kusnezoffii radix, which possess highly bioactive as well as highly toxic character for medicinal use. In the present study, for the purpose of better utilizing the toxic herbal material, the performance characteristics of NKA-II, D101, X-5, AB-8, S-8, HPD722 and HPD750 macroporous resins for the enrichment and purification of these six Aconitum alkaloids were critically evaluated. Results showed that NKA-II offered the best adsorption and desorption capacities for six Aconitum alkaloids among the seven macroporous resins tested, which were affected significantly by the pH value. Subsequently, dynamic adsorption and desorption experiments had been carried out with the column packed by NKA-II resin to optimize the separation process of six Aconitum alkaloids. After one run treatment with NKA-II resin, the content of total six Aconitum alkaloids were increased from 5.87% to 60.3%, the recovery was 75.8%. Meanwhile, a validated HPLC-MS method had been developed to qualitative and quantitative these six Aconitum alkaloids. This method would provide scientific references to the large-scale production of six Aconitum alkaloids from Aconiti kusnezoffii radix or other plants and might also expand the secure application of these highly toxic components for pharmacy. PMID- 24814004 TI - A semi-automated LC-MS/MS method for the determination of LCI699, a steroid 11beta-hydroxylase inhibitor, in human plasma. AB - A novel liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the determination of LCI699 was developed and validated with dynamic ranges of 0.0500-50.0 ng/mL and 1.00-1,000 ng/mL using 0.0500 mL and 0.100mL, respectively, of human plasma. LCI699 and the internal standard, [M+6]LCI699, were extracted from fortified human plasma via protein precipitation. After transfer or dilution of the supernatant followed by solvent evaporation and/or reconstitution, the extract was injected onto the LC-MS/MS system. Optimal chromatographic separation was achieved on an ACE C18 (50 mm * 4.6mm, 3 MUm) column with 30% aqueous methanol (containing 0.5% acetic acid and 0.05% TFA) as the mobile phase run in isocratic at a flow rate of 1.0 mL/min. The total analysis cycle time is approximately 3.5 min per injection. The addition of an ion-pair reagent, TFA (0.05%, v/v), to the mobile phases significantly improved the chromatographic retention and resolution of the analyte on silica based reversed-phase column. Although addition of TFA to the mobile phase suppresses the ESI signals of the analyte due to its ion-pairing characteristics in the gas phase of MS source, this negative impact was effectively alleviated by adding 0.5% acetic acid to the mobile phase. The current method was validated for sensitivity, selectivity, linearity, reproducibility, stability and recovery. For the low curve range (0.0500-50.0 ng/mL), the accuracy and precision for the LLOQs (0.0500 ng/mL) were -13.0 to 2.0% bias and 3.4-19.2% CV, respectively. For other QC samples (0.100, 6.00, 20.0 and 40.0 ng/mL), the precision ranged from 1.2 to 9.0% and from 3.8 to 8.8% CV, respectively, in the intra-day and inter-day evaluations. The accuracy ranged from -11.3 to 8.0% and -7.2 to 1.6% bias, respectively, in the intra-day and inter-day batches. For the high curve range (1.00-1,000 ng/mL), the accuracy and precision for the LLOQs (1.00 ng/mL) were 1.0-15.0% bias and 7.4-9.2% CV, respectively. For the other QC samples (3.00, 20.0, 200 and 750 ng/mL), the precision ranged from 0.8 to 7.0% and from 1.9 to 5.2% CV, respectively, in the intra-day and inter-day evaluations. The accuracy ranged from -2.5 to 4.0% and 0.7-1.0% bias, respectively, in the intra-day and inter-day batches. Additional assessments of incurred sample stability (ISS) and incurred sample reanalysis (ISR) were conducted to demonstrate the ruggedness and robustness of the assay method. The absence of adverse matrix effect and carryover was also demonstrated. The validated method was successfully used to support rapid turnaround human pharmacokinetic studies. PMID- 24814005 TI - Application of magnetic solid phase extraction for separation and determination of aflatoxins B 1 and B2 in cereal products by high performance liquid chromatography-fluorescence detection. AB - A simple and sensitive method based on the magnetic solid phase extraction with modified magnetic nanoparticles followed by high performance liquid chromatography with fluorescence detection has been developed for extraction and determination of aflatoxins B1 (AFB1) and B2 (AFB2) in cereal products. Magnetic nanoparticle coated with 3-(trimethoxysilyl)-1-propanthiol (TMSPT) and modified with 2-amino-5-mercapto-1,3,4-thiadiazole (AMT) was used as an antibody-free adsorbent. Under the optimal conditions, the calibration curves for AFB1 and AFB2 were linear in the ranges of 0.2-15 MUg L(-1) and 0.04-3 MUg L(-1), respectively. Detection limit was 0.041 MUg L(-1) for AFB1 and 0.013 MUg L(-1) for AFB2. The proposed method was successfully applied to the determination of AFB1 and AFB2 in spiked corn and rice samples with an average recovery of 93.5%. The results demonstrated that the developed method is simple, rapid, inexpensive, accurate and remarkably free from interference effects. PMID- 24814006 TI - A study on the nature of interactions of mixed-mode ligands HEA and PPA HyperCel using phenylglyoxal modified lysozyme. AB - Mixed mode chromatography, or multimodal chromatography, involves the exploitation of combinations of several interactions in a controlled manner, to facilitate the rapid capture of proteins. Mixed-mode ligands like HEA and PPA HyperCelTM facilitate different kinds of interactions (hydrophobic, ionic, etc.) under different conditions. In order to better characterize the nature of this multi-modal interaction, we sought to study a protein, lysozyme, which is normally not retained by these mixed mode resins under normal binding conditions. Lysozyme was modified specifically at Arginine residues by the action of phenylglyoxal, and was extensively studied in this work to better characterize the mixed-mode interactions of HEA HyperCelTM and PPA HyperCelTM chromatographic supports. We show here that the adsorption behaviour of lysozyme on HEA and PPA HyperCelTM mixed mode sorbents varies depending on the degree of charge modification at the surface of the protein. Experiments using conventional cation exchange and hydrophobic interaction chromatography confirm that both charge and hydrophobicity modification occurs at the surface of the protein after lysozyme reaction with phenylglyoxal. The results emanating from this work using HEA and PPA HyperCel sorbents strongly suggest that mixed mode chromatography can efficiently separate closely related proteins of only minor surface charge and/or hydrophobicity differences. PMID- 24814007 TI - Effects of Paclitaxel and Carboplatin combination on mechanical myocardial and microvascular functions: a transthoracic Doppler echocardiography and two dimensional strain imaging study. AB - AIM: Paclitaxel and carboplatin are frequently used chemotherapy drugs in the treatment of gynecologic malignancies. Little is known about their effects on left ventricular mechanical and coronary microvascular functions. METHODS: Thirty consecutive patients were prospectively enrolled. Patients underwent transthoracic echocardiography (TTE) before and after chemotherapy, to evaluate left ventricular mechanical functions and coronary flow reserve (CFR). A comprehensive TTE, tissue Doppler and two-dimensional (2D) strain imaging were performed and coronary flow velocity was measured at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic peak flow velocities. Mitral annular velocities by tissue Doppler, peak strain, and systolic strain rate by velocity vector imaging (VVI) were measured. Baseline measurements were compared with healthy controls (n = 26). RESULTS: No patient developed heart failure (HF) symptoms, no significant change occurred in left ventricular ejection fraction or cardiac output and no significant difference was observed in CFR after chemotherapy. Baseline mean longitudinal peak strain and systolic stain rate were similar between patients and controls: 17.5 +/- 2.6% versus -17.6 +/- 2.2% (P = NS) and -1.04 +/- 0.14/sec versus -1.05 +/- 0.12/sec (P = NS). Peak strain and systolic strain rate decreased significantly after chemotherapy (from -17.5 +/- 2.6% to -16.2 +/- 2.5%, P < 0.02; and from -1.05 +/- 0.12/sec to -0.96 +/- 0.11/sec, P = 0.01, respectively). However, mean longitudinal velocity did not change significantly. CONCLUSION: Paclitaxel and carboplatin combination did not impair CFR; however, this chemotherapy combination could induce subtle impairment in myocardial mechanical function which can be detected by advanced deformation imaging techniques rather than by tissue Doppler imaging or conventional 2D and Doppler echocardiography. PMID- 24814008 TI - Measurement of size-dependent composition variations for gamma prime (gamma') precipitates in an advanced nickel-based superalloy. AB - Energy-dispersive X-ray (EDX) spectroscopy in the scanning transmission electron microscope (STEM) has been used to demonstrate the presence of size-dependent compositional variation for L12-structured Ni3Al-type gamma-prime (gamma') precipitates within a commercial RR1000 Ni-based superalloy. This semi quantitative elemental analysis has been achieved using electrochemical extraction of the gamma' precipitates from the gamma matrix. The applicability of this approach to size-dependent compositional analysis of precipitates was confirmed by a comparison of the size distribution for the extracted precipitates with those present in traditional electropolished foil specimens in the size range 20-250nm. By applying suitable thickness-dependent absorption-corrections we have demonstrated that the composition of gamma' precipitates in our material depends on the size of the precipitate in the range of 5nm to 3MUm. In particular, the Al content was observed to increase in smaller gamma' precipitates while Ti and Ta contents are constant for all sizes of precipitate. Hf was observed to be present only in the largest precipitates. This type of local compositional information provides invaluable input to assess the accuracy of microstructural modelling for these complex alloys and provides new evidence supporting the importance of anti-site diffusion. PMID- 24814009 TI - Total synthesis of (-)-lepistine. AB - The first total synthesis of (-)-lepistine has been accomplished in 11 steps from (S)-glycidol. The synthesis features construction of the 10-membered ring via an intramolecular epoxide opening by nosylamide, regioselective dehydration to form an enol ether, and construction of the aminal moiety induced by cleavage of the nosyl groups. PMID- 24814010 TI - Clinical manifestations and experimental studies on the spine extract of the toadfish Porichthys porosissimus. AB - Toadfish are fish from the family Batrachoididae that are found in marine and brackish environment around the world. Among the toadfish, Porichthys genus is very common, where Porichthys porosissimus, also called Atlantic Midshipman is found in Southwest Atlantic, from Rio de Janeiro, Brazil to eastern Argentina. There was no consensus about the classification of the genus Porichthys as venomous fish because so far there are no published studies regarding human envenomations and/or toxic activities induced in animal models. Herein, we report two conclusive envenoming in human beings caused by P porosissimus spines, with clear signs and symptoms that were very important for the development of our experimental studies. We demonstrated that the P. porosissimus spine extract, now venom, can induce nociceptive and edematogenic responses in mice as well an induction of an inflammatory response elicited by intravital microscopy and leukocyte migration. Finally, we identified in the P. porosissimus spine extract, through analysis by mass spectrometry, the presence of proteins previously detected in the venoms of other fish species and other venomous animals. We believe that based on our studies we will dismiss the non-venomous nature of this fish and clarify this issue. PMID- 24814011 TI - Metabolic cost of venom replenishment by Prairie Rattlesnakes (Crotalus viridis viridis). AB - Snakes demonstrate a great deal of variation in the amount of venom injected in both predatory and defensive strikes. There is some evidence that snakes can adaptively meter venom dosage. An underlying assumption in the evolution of venom metering is that the production of venom is energetically costly. To date there has been very little research that has quantified the metabolic costs associated with venom production. We used open-flow respirometry to test for significant differences between Prairie Rattlesnakes (Crotalus v. viridis) that had venom extracted and control snakes that did not. Although previous studies demonstrated high metabolic costs for venom production, we found that snakes that had venom extracted did not have significantly higher metabolic rates than control snakes. The pattern of metabolic deviation from baseline measurements was similar for both treatments, and on average snakes that had venom extracted only exhibited a 1.1% increase over baseline compared to a 2.5% increase in control snakes. Our data suggest that venom is not energetically costly to produce and that perhaps other costs associated with venom can better explain the variability in venom expenditure. PMID- 24814012 TI - Snake venom glutaminyl cyclases: purification, cloning, kinetic study, recombinant expression, and comparison with the human enzyme. AB - Among various snake venom components, glutaminyl cyclase (vQC) is one of the least understood protein family and none of its members has been purified or characterized. Here we confirmed the presence of vQC activity in a wide spectrum of venom species via enzymatic assay using a synthetic fluorogenic substrate. We have also cloned novel vQC cDNAs from seven species including Crotalus atrox. The results revealed more than 96% sequence similarities among vQCs and ~75% sequence identities between vQCs and human secretory QC (hQC). The vQC glycoprotein of 43 kDa was isolated from C. atrox venom, and its N-terminal sequence was determined. The optimal pH range for vQC reaction was 7.5-8.0, and the enzymes were stable up to 50 degrees C. Similar to hQC, vQCs were substantially inactivated by 1 mM 1,10-phenanthroline but slightly affected by 20 mM EDTA, suggestive of a similar zinc-catalytic environment for these enzymes. Although their catalytic residues were highly conserved, vQCs were less susceptible to inhibition by synthetic imidazole derivatives which potently inhibited hQC. The 3D-models revealed that vQC and hQC structures display different surface charge distributions around the active sites, which might affect substrate and inhibitor binding affinities. The recombinant vQCs prepared from Escherichia coli displayed weaker substrate binding affinities relative to the native vQCs, possibly due to the lack of glycosylation. The present report offers new structural and functional insights into vQCs and sheds light on the specificity differences between vQCs and hQC. PMID- 24814013 TI - Lebecin, a new C-type lectin like protein from Macrovipera lebetina venom with anti-tumor activity against the breast cancer cell line MDA-MB231. AB - C-type lectins like proteins display various biological activities and are known to affect especially platelet aggregation. Few of them have been reported to have anti-tumor effects. In this study, we have identified and characterized a new C type lectin like protein, named lebecin. Lebecin is a heterodimeric protein of 30 kDa. The N-terminal amino acid sequences of both subunits were determined by Edman degradation and the entire amino acid sequences were deduced from cDNAs. The precursors of both lebecin subunits contain a 23-amino acid residue signal peptide and the mature alpha and beta subunits are composed of 129 and 131 amino acids, respectively. Lebecin is shown to be a potent inhibitor of MDA-MB231 human breast cancer cells proliferation. Furthermore, lebecin dose-dependently inhibited the integrin-mediated attachment of these cells to different adhesion substrata. This novel C-type lectin also completely blocked MDA-MB231 cells migration towards fibronectin and fibrinogen in haptotaxis assays. PMID- 24814014 TI - A comparison of the ability of Bellucia dichotoma Cogn. (Melastomataceae) extract to inhibit the local effects of Bothrops atrox venom when pre-incubated and when used according to traditional methods. AB - Bellucia dichotoma Cogn. (Melastomataceae) is one of various plant species used in folk medicine in the west of the state of Para, Brazil, to treat snake bites. Many studies have been carried out to evaluate the effectiveness of anti-snake bite plants, but few of these use the same preparation methods and doses as those traditionally used by the local populations. This study therefore compared inhibition of the main local effects of B. atrox venom (BaV) by aqueous extract of B. dichotoma (AEBd) administered according to traditional methods and pre incubated with BaV). The concentrations of phenolic compounds (tannins and flavonoids) in AEBd were determined by colorimetric assays. The effectiveness of AEBd in inhibiting the hemorrhagic and edematogenic activities of BaV was evaluated in mice in four different experimental in vivo protocols: (1) pre incubation (venom:extract, w/w); (2) pre-treatment (p.o.); (3) post-treatment (p.o.); and (4) AEBd (p.o.) in combination with Bothrops antivenom (BA) (i.v.). To assess in vitro inhibition of BaV phospholipase A2 activity, the pre incubation method or incorporation of AEBd or BA in agarose gels were used. The effect of AEBd on BaV was determined by SDS-PAGE, zymography and Western blot. Colorimetric assays revealed higher concentrations of (condensed and hydrolyzable) tannins than flavonoids in AEBd. Hemorrhagic activity was completely inhibited using the pre-incubation protocol. However, with pre treatment there was no significant inhibition for the concentrations tested, and with the post-treatment only the 725 mg/kg dose of AEBd was able to inhibit 40.5% (p = 0.001) of the hemorrhagic activity of BaV. Phospholipase A2 activity was only inhibited when AEBd was pre-incubated with BaV. BaV-induced edema was completely inhibited with pre-incubation (p < 0.05) and significantly reduced (p < 0.05) with pre- and post-treatment (p.o.) for the concentrations tested. The reduction in local edema was even greater when AEBd was administered in combination with BA. The SDS-PAGE profiles showed that several of the BaV protein (SDS-PAGE) and enzyme (zymography) bands were not detected when the venom was pre incubated, and Western blot revealed that this was not caused by the AEBd enzymes observed in the zymogram. The "pseudo inhibition" observed after pre-incubation in this study may be due to the presence of tannins in the extract, which could act as chelating agents, removing metalloproteins and Ca2+ ions and thus inhibiting hemorrhagin and PLA2 activity. However, when administered according to traditional methods, B. dichotoma extract was effective in blocking BaV-induced edematogenic activity and had an additional effect on inhibition of this activity by BA. PMID- 24814015 TI - Melanotic and non-melanotic malignancies of the face and external ear - A review of current treatment concepts and future options. AB - Skin has the highest incidence and variety of tumors of all organs. Its structure is of great complexity, and every component has the potential to originate a skin neoplasm (SN). Because of its exposed nature, skin is vulnerable to carcinogenic stimuli such as UV radiation. Various entities can cause SN. Nonmelanotic skin cancers (NMSC) are the most common of all cancers, with over one million cases diagnosed annually in the US. Basal cell carcinoma (BCC) accounts for approximately 80% of all NMSC, most of the remaining 20% being squamous cell carcinoma (SCC). The skin of the head and neck is the most common site for tumors, accounting for more than 80% of all NMSC. BCC, SCC, and malignant melanomas (MM) represent 85-90% of all SN. Merkel cell tumors (MCC), lymphoepithelioma-like carcinomas of the skin (LELCS), dermato-fibro-sarcomas, leiomyosarkomas, and Kaposi-sarcomas are less frequent in the facial skin region and the external ear. Based on data from the German Federal Cancer Registry (2003/2004), 140,000 people in Germany were affected by SN (100,000 BCC, 22,000 SCC, 22,000 MM). This number increases considerably if malignant precursors, such as actinic keratosis, are included. Each year, the frequency of SN diagnosis rises by 3-7%. Among all known malignant tumors, MM exhibits the highest rate of increase in incidence. In the past, SN was primarily diagnosed in people aged 50 years or older. However, recently, the risk for developing SN has shifted, and younger people are also affected. Early diagnosis is significantly correlated with prognosis. Resection of SN creates defects that must be closed with local or microvascular flaps to avoid functional disturbing scar formation and deflection of the nose, eyelids, or lips. All therapeutic strategies for SN, the current standard for adjuvant and systemic treatment, and the management of the increasing number of patients under permanent blood thinner medication are described with regard to the treatment of SN. PMID- 24814016 TI - How the win-lose balance situation affects subsequent decision-making: functional magnetic resonance imaging evidence from a gambling task. AB - Humans have been consistently shown to be bad at making decisions, especially in disadvantageous situations. In this study, we designed a task that simulates real life non-strategic gambling to examine the effect of win-lose balance situations (WIN, LOSS, TIE) on decision-making. In behavioral performances, participants showed shorter response time (RT) in LOSS than in WIN and TIE conditions. Imaging results revealed that decisions in WIN are associated with increased brain activations in the posterior cingulate cortex; decisions in LOSS are associated with increased brain activations in the insula and decreased activations in the inferior frontal gyrus (IFG). Positive correlation was found between brain activation in IFG and RT in LOSS. Overall, we concluded that, in disadvantageous conditions, participants are frustrated by their negative results and tend to make a random selection without full consideration. In advantageous conditions, participants' motivations to gamble are elicited and they tend to engage in more endeavors in making decisions. PMID- 24814017 TI - Coculture with embryonic stem cells improves neural differentiation of adipose tissue-derived stem cells. AB - Embryonic stem (ES) cells secrete some soluble factors which may affect the differentiation potential of adult stem cells toward different lineages. In the present study, we evaluated neural differentiation of mouse adipose tissue derived stem cells (ADSCs) following coculture with ES cells. For this purpose, ADSCs were induced in a medium supplemented with a synthetic serum replacement and various concentrations of retinoic acid (RA). Then, third-passaged ADSCs were indirectly cocultured with ES cells, and the expression levels of pluripotency markers, OCT4 and Sox2, mesenchymal stem cell markers, CD73 and CD105, and proliferating cell nuclear antigen (PCNA), were assessed in the cocultured ADSCs. Moreover, the control and cocultured ADSCs were differentiated with or without RA treatment. We showed here that 2-week differentiated ADSCs expressed several neuron-specific genes, and RA treatment improved neural differentiation of the ADSCs. The expression levels of OCT4, Sox2 and PCNA were upregulated in the cocultured ADSCs. Moreover, coculture with the ES cells significantly improved neural differentiation of the ADSCs. Treatment of the cocultured ADSCs with RA diminished the expression of neural maturation markers. Coculture with the ES cells efficiently improves neural differentiation of the ADSCs. Non-contact coculture with the ES cells may be used as an efficient strategy to improve differentiation potential of adult stem cells for developmental studies and regenerative medicine. PMID- 24814018 TI - Direct brain projections onto the spinal generator of ejaculation in the rat. AB - A spinal generator for ejaculation (SGE) has been identified in the rat that orchestrates peripheral events leading to ejaculation. Despite physiological evidence of cerebral influences exerted on the SGE, brain-descending pathways to the SGE have not been fully delineated. A tracing study combining retrograde and anterograde approaches was undertaken in adult male rats in order to identify brain sites containing neurons that directly project onto SGE neurons. Fluorogold (FG) was microinjected as a retrograde tracer into the SGE area in the central medial gray of the third lumbar (L3) spinal segment. FG-positive neurons were found in various structures in medulla oblongata, pons, and forebrain. Among the brain structures already known as participating in the brain control of ejaculation and harboring retrogradelly-labeled neurons, the ventrolateral part of the gigantocellular nucleus and the raphe pallidus/magnus in medulla oblongata as well as the lateral hypothalamus were targeted with the anterograde tracer dextran amine (DA). Galanin and substance P receptor (NK1) were used as markers of SGE neurons. DA-positive fibers and varicosities originating in the targeted brain sites were found to make close appositions with neurons expressing galanin or NK1 receptors in central medial gray of L3-L4 spinal segments. This study provides new insights regarding the anatomical support for the brain control of ejaculation via direct influences onto the SGE. PMID- 24814019 TI - Potentiation of convergent synaptic inputs onto pyramidal neurons in somatosensory cortex: dependence on brain wave frequencies and NMDA receptor subunit composition. AB - N-methyl-d-aspartate receptors (NMDARs) at layer (L)1/primary whisker motor cortex synaptic inputs are distinct from thalamic/striatal (Str) synaptic inputs onto L5 pyramidal neurons in the rat somatosensory cortex. However, the consequences of differential expression of putative GluN3A-containing triheteromeric NMDARs at L1 inputs and GluN2A-containing diheteromeric NMDARs at Str inputs on plasticity of the underlying synapses at the respective inputs remain unknown. Here we demonstrate that L1, but not Str, synapses are potentiated following delta burst stimulation (dBS). This potentiation is blocked by d-serine and/or intracellular 1,2-bis(o-aminophenoxy)ethane-N,N,N',N' tetraacetic acid (BAPTA) suggesting that it is subunit-specific and dependent on elevations in intracellular Ca(2+). Interestingly, ifenprodil, the GluN2B preferring antagonist, suppresses baseline L1 responses but does not prevent induction of dBS-evoked potentiation. Unlike L1, Str synapses are maximally potentiated following theta burst stimulation (tBS) and this potentiation is blocked with BAPTA and/or the GluN2A-preferring antagonist NVP-AAM077. We show further that while dBS is both necessary and sufficient to potentiate L1 synapses, tBS is most effective in potentiating Str synapses. Our data suggest distinct potentiating paradigms for the two convergent inputs onto pyramidal neurons in the somatosensory cortex and co-dependence of synaptic potentiation on brain wave-tuned frequencies of burst stimulation and subunit composition of underlying NMDARs. A model for predicting the likelihood of enhancing synaptic efficacy is proposed based on Ca(2+) influx through these receptors and integration of EPSPs at these inputs. Together, these findings raise the possibility of input-specific enhancements of synaptic efficacy in neurons as a function of the animal's behavioral state and/or arousal in vivo. PMID- 24814020 TI - Targeted electrophysiological analysis of viscerofugal neurons in the myenteric plexus of guinea-pig colon. AB - Enteric viscerofugal neurons are mechanosensory interneurons that form the afferent limb of intestino-intestinal reflexes involving prevertebral sympathetic neurons. Fast synaptic inputs to viscerofugal neurons arise from other enteric neurons, but their sources are unknown. We aimed to describe the origins of synaptic inputs to viscerofugal neurons by mapping the locations of their cell bodies within the myenteric plexus. Viscerofugal neuron somata were retrogradely traced with 1,1'-didodecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) from colonic nerve trunks and impaled with microelectrodes, in longitudinal muscle/myenteric plexus preparations of the guinea-pig distal colon (39 impalements, n=14). Thirty-eight viscerofugal neurons were uni-axonal and had the electrophysiological characteristics of myenteric S-neurons; one neuron was multipolar with AH-neuron electrophysiological characteristics. Depolarizing current pulses evoked either single- or multiple action potentials in viscerofugal neurons (range 1-25 spikes, 500 ms, 100-900 pA, 21 cells). Electrical stimulation of internodal strands circumferential to viscerofugal neurons evoked fast excitatory postsynaptic potentials (EPSPs) in 19/24 cells. Focal pressure-ejection of the nicotinic agonist 1,1-dimethyl-4 phenylpiperazinium iodide (DMPP, 10 MUm) directly onto viscerofugal nerve cell bodies evoked large depolarizations and action potentials (23 +/- 10 mV, latency 350 +/- 230 ms, 21/22 cells). DMPP was then focally applied to multiple sites, up to 3mm from the recorded viscerofugal neuron, to activate other myenteric S neurons. In a few sites in myenteric ganglia, DMPP evoked repeatable fast EPSPs in viscerofugal neurons (latency 300 +/- 316 ms, 38/394 sites, 10 cells). The cellular sources of synaptic inputs to viscerofugal neurons were located both orally and aborally (19 oral, 19 aboral), but the amplitude of oral inputs was consistently greater than aboral inputs (13.1 +/- 4.3 mV vs. 10.1 +/- 4.8 mV, respectively, p<0.05, paired t-test, n=6). Most impaled viscerofugal neurons were nitric oxide synthase (NOS) immunoreactive (20/27 cells tested). Thus, the synaptic connections onto viscerofugal neurons within the myenteric plexus suggest that multiple enteric neural pathways feed into intestino-intestinal reflexes, involving sympathetic prevertebral ganglia. PMID- 24814021 TI - Differences in the reinstatement of ethanol seeking with ganaxolone and gaboxadol. AB - The endogenous neuroactive steroid allopregnanolone (ALLO) has previously been shown to induce reinstatement of ethanol seeking in rodents. ALLO is a positive allosteric modulator at both synaptic and extrasynaptic GABAA receptors. The contribution of each class of GABAA receptors in mediating reinstatement of ethanol seeking is unknown. The first aim of the present study was to determine whether ganaxolone (GAN), a longer-acting synthetic analog of ALLO, also promotes reinstatement of ethanol seeking. The second aim was to examine whether preferentially activating extrasynaptic GABAA receptors with the selective agonist gaboxadol (THIP) was sufficient to reinstate responding for ethanol in mice. Male C57BL/6J mice were trained to lever press for access to a 10% ethanol (v/v) solution (10E), using a sucrose-fading procedure. Following extinction of the lever-pressing behavior, systemic THIP (0, 4 and 6mg/kg) and GAN (0, 10, and 15mg/kg) were tested for their ability to reinstate ethanol-appropriate responding in the absence of 10E access. GAN significantly increased lever pressing on the previously active lever, while THIP did not alter lever-pressing behavior. The results of this study suggest that direct activation of extrasynaptic GABAA receptors at the GABA site is not sufficient to induce ethanol seeking in the reinstatement procedure. Future studies are necessary to elucidate the mechanisms and brain areas by which differences in the pharmacological activity of GAN and THIP at the GABAA receptor contribute to the dissimilarity in their effect on the reinstatement of ethanol seeking. Nonetheless, based on the increased use of these drugs in clinical trials across multiple disease states, the effects of GAN or THIP on alcohol seeking may be an important consideration if these drugs are to be used clinically in a population with a co-occurring alcohol use disorder. PMID- 24814022 TI - Glycemic control after brain injury: boon and bane for the brain. AB - Hyperglycemia is a common phenomenon in the early phase of brain injury (BI). The management of blood glucose levels after BI, however, is subject of a growing debate. The occurrence of elevated blood glucose concentrations is linked to increased mortality and worse neurologic outcomes indicating the necessity for therapeutic glucose-lowering. Intensive glucose-lowering therapy, on the other hand, inevitably results in an increased rate of hypoglycemic episodes with detrimental effects on the injured brain. In this review, we give an overview on the current knowledge about causes and pathophysiological consequences of dysglycemia in patients with BI and offer some suggestions for clinical glucose management. PMID- 24814024 TI - Cryogelation of chitosan using noble-metal ions: in situ formation of nanoparticles. AB - One of the purposes of the project was to develop the method of preparation of 3D macroporous hydrogel with a structure of interconnected pores by the use of noncovalent interactions. The combination of chitosan and noble-metal complexes was investigated as cross-linking agents for the preparation of ionic cryogels (ICs). Furthermore, the treatment of the ICs containing gold complex by glutaraldehyde results in spontaneous formation of gold nanoparticles (AuNPs) and chemical cross-linking of the cryogel. The characterization of prepared macroporous materials was carried out by the use of FTIR, SEM, TEM techniques, and texture analyzer. A new strategy for control of size distribution of AuNPs was suggested. The size distribution of obtained AuNPs and their population inside of walls of cryogels was estimated. A method for quantifying unreacted chloroauric acid in the presence of acetic acid was proposed. The possibility of use of prepared cryogels with immobilized AuNPs as a catalytic flow through reactor is shown. PMID- 24814025 TI - Involvement of cAMP-CRP in transcription activation and repression of the pck gene encoding PEP carboxykinase, the key enzyme of gluconeogenesis. AB - cAMP receptor protein (CRP) is the best characterized global regulator of Escherichia coli. After genomic SELEX screening, a total of minimum 378 promoters have been identified as its regulation targets on the E. coli genome. Among a number of promoters carrying two CRP-binding sites, several promoters carry two CRP-binding sites, one upstream but another downstream of transcription initiation sites. The regulatory role of downstream CRP site remains unsolved. Using the pck gene encoding phosphoenolpyruvate carboxykinase as a model promoter, we analyzed the role of CRP-associated downstream of the transcription initiation site. Gel shift assay and AFM observation indicate that CRP binds to both the promoter-distal site (CRP box-1) at -90.5 and the site (CRP box-2) at +13.5 downstream of transcription initiation site. The binding affinity is higher for CRP box-1. Roles of two CRP sites were examined using in vitro transcription assay and in vivo reporter assay. In both cases, transcription repression was observed in the presence of high concentrations of CRP. Taken together, we propose that cAMP-CRP associated at downstream CRP box-2 plays as a repressor for pck transcription only in the presence of high levels of cAMP-CRP. PMID- 24814026 TI - [Intubation in intensive care medicine: we could improve our practices!]. PMID- 24814023 TI - Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction. AB - We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin-converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. We examined tissue swelling, the production of reactive oxygen species (ROS), and cell death in the cerebral cortex (CX) and the hippocampal CA1 region during OGD. Expression levels of NADPH oxidase (Nox) isoforms, Nox2 and Nox4 were measured using western blots. Results show that SARA mice and R+A+ mice treated with the Mas receptor agonist Ang-(1-7) had less swelling, cell death, and ROS production in CX and CA1 areas compared to those in R+A+ animals. Treatment of slices from SARA mice with the Mas antagonist A779 eliminated this protection. Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD result from diminished ROS production coupled with lower expression of Nox isoforms. Thus, the ACE2/Ang-(1 7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production. PMID- 24814027 TI - Pulmonary mummification in a Coptic mummy from ancient Egypt. PMID- 24814028 TI - Changes in clinical presentation and staging of lung cancer over two decades. AB - INTRODUCTION: Important clinical and epidemiological changes have been observed in lung cancer (LC) in our healthcare area compared to the previous decade. In the last 10 years, specific LC care circuits have been implemented and the active search for cases has been stepped up. The aim of this study was to analyze the progress of these changes over the last 20 years. METHODS: This is a retrospective study comparing clinical and epidemiological changes between 2 historical cohorts of LC patients (1992-1994 [group 1, 164 patients] and 2004 2006 [group 2, 250 patients]) and a current group from the period 2011-2012 (group 3, 209 patients) RESULTS: Two hundred and nine (209) LC patients were included in group 3 (2011-2012 period). After comparing groups 3 and 2, a non significant rise in smoking was observed in women (59% vs 41%, p=.25), while the prevalence of adenocarcinoma was unchanged (45% vs 44%, p=.9). The main changes observed were the increase in cases with previous malignancies (23% vs 16%, p=.04), the rise in patients with no associated LC symptoms (33% vs 16%, p<.001), and an increased number of localized NSCLC (non-small cell LC) diagnoses (42% vs 24% in series 2, p<.001 and 14.2% in series 1, p<.001). CONCLUSIONS: The number of LC patients diagnosed in localized stages has increased significantly. Furthermore, the number of patients with no symptoms associated with LC and with a history of previous malignancy were significantly increased. PMID- 24814029 TI - Partial anomalous pulmonary venous connection with pulmonary hypertension. PMID- 24814030 TI - Rasmussen's pseudoaneurysm in a patient with a history of pulmonary tuberculosis. PMID- 24814031 TI - Live imaging in Drosophila: The optical and genetic toolkits. AB - Biological imaging based on light microscopy comes at the core of the methods that let us understanding morphology and its dynamics in synergy to the spatiotemporal distribution of cellular and molecular activities as the organism develops and becomes functional. Non-linear optical tools and superesolution methodologies are under constant development and their applications to live imaging of whole organisms keep improving as we speak. Genetically coded biosensors, multicolor clonal methods and optogenetics in different organisms and, in particular, in Drosophila follow equivalent paths. We anticipate a brilliant future for live imaging providing the roots for the holistic understanding, rather than for individual parts, of development and function at the whole-organism level. PMID- 24814032 TI - Chemical inputs from a karstic submarine groundwater discharge (SGD) into an oligotrophic Mediterranean coastal area. AB - The impacts of nutrient and other chemical inputs released by a submarine groundwater discharge (SGD) on the marine environment of an oligotrophic Mediterranean coastal area (Messiniakos Gulf, SE Ionian Sea) are investigated through a multidisciplinary approach. Nutrients and organic pollutants associated with the SGD are presented to study the chemical characteristics of the SGD and to investigate its effect on the marine ecosystem in comparison to freshwater discharges of the water bodies of Messinia Prefecture. Nutrient and organic pollutant fluxes were calculated from (214)Bi-based SGD estimates. An average of 22*10(3) mol of silicate per month and 8*10(3) mol of nitrate per month were released via the SGD. Nutrient concentrations at the mouth of the SGD were three times higher than in Messiniakos Gulf, and NO3(-) was the primary Dissolved Inorganic Nitrogen form discharged by SGD. Organic pollutant concentrations associated with agricultural activities were low at the SGD. The implementation of a Eutrophication Index (E.I.) showed that the water column at the SGD site corresponds to Moderate/Bad ecological quality, whereas the status switches rapidly to Good at a small distance from the SGD. Coastal areas influenced by river or sewage discharge correspond to a Moderate/Good ecological status. The BENTIX index used for the classification of the ecological quality status of the benthic macroinvertebrate communities showed that the SGD has a minor influence compared to the other freshwater discharges in Messiniakos Gulf. Though the SGD has a considerable outflow, morphology and hydrodynamics of the area favor the rapid dispersion of the upwelling water and degrades the SGD's effect even on a regional scale. PMID- 24814033 TI - Diagnosis of abnormal patterns in multivariate microclimate monitoring: a case study of an open-air archaeological site in Pompeii (Italy). AB - Chemometrics has been applied successfully since the 1990s for the multivariate statistical control of industrial processes. A new area of interest for these tools is the microclimatic monitoring of cultural heritage. Sensors record climatic parameters over time and statistical data analysis is performed to obtain valuable information for preventive conservation. A case study of an open air archaeological site is presented here. A set of 26 temperature and relative humidity data-loggers was installed in four rooms of Ariadne's house (Pompeii). If climatic values are recorded versus time at different positions, the resulting data structure is equivalent to records of physical parameters registered at several points of a continuous chemical process. However, there is an important difference in this case: continuous processes are controlled to reach a steady state, whilst open-air sites undergo tremendous fluctuations. Although data from continuous processes are usually column-centred prior to applying principal components analysis, it turned out that another pre-treatment (row-centred data) was more convenient for the interpretation of components and to identify abnormal patterns. The detection of typical trajectories was more straightforward by dividing the whole monitored period into several sub-periods, because the marked climatic fluctuations throughout the year affect the correlation structures. The proposed statistical methodology is of interest for the microclimatic monitoring of cultural heritage, particularly in the case of open-air or semi-confined archaeological sites. PMID- 24814034 TI - Drought to flood: a comparative assessment of four parallel surface water treatments during the 2010-2012 inflows to the Murray-Darling Basin, South Australia. AB - Four treatment processes; conventional coagulation, magnetic ion exchange (MIEX)/coagulation, with and without granular activated carbon (GAC), and membrane treatment combining microfiltration (MF) and nanofiltration (NF), were operated in parallel using the same source water from the Murray-Darling basin in South Australia. During the two year study, high levels of natural organic matter and turbidity arising from floods affecting the Murray-Darling basin in 2010-2012 challenged the four processes. The comparative study indicated that all four processes could effectively meet basic water quality guidelines of turbidity and colour despite challenging source water quality but that the more advanced treatments improved overall organic and bacterial removal. Interestingly, the high organics and turbidity arising from the floods resulted in improved treatment efficiency for all treatments incorporating coagulation to the extent that, despite flood conditions, treated water quality could remain comparatively constant provided that the process was operated and optimised effectively. PMID- 24814035 TI - Tissue-specific bioconcentration of antidepressants in fish exposed to effluent from a municipal sewage treatment plant. AB - Tissue-specific bioconcentration of selected antidepressants was studied in rainbow trout (Oncorhynchus mykiss) exposed to undiluted effluent from a Swedish municipal sewage treatment plant for 13 days. Citalopram, sertraline and venlafaxine were found in the brains and livers of most fish, but not in blood plasma or muscle. Venlafaxine was the only drug found in plasma (3/20 fish). Fluoxetine was not detected in any fish tissue, in accordance with a low concentration in the effluent and a comparably high limit of quantification in tissues. Concentrations of citalopram, sertraline and venlafaxine in fish brain were up to 1/12, 1/8 and 1/26, respectively, of the lowest concentrations found in the brains of mammals treated with therapeutic doses. Thus, given co-exposure to several antidepressants and an assumed similar potency in fish, the margin of safety for target-related effects in fish residing in effluent-dominated streams is relatively low. Furthermore, the non-detectable levels of these drugs in blood plasma suggest that analyses of concentrations in target tissues (brain) would be more informative in field studies and other studies with environmentally realistic exposure concentrations. PMID- 24814036 TI - Investigating sources and pathways of perfluoroalkyl acids (PFAAs) in aquifers in Tokyo using multiple tracers. AB - We employed a multi-tracer approach to investigate sources and pathways of perfluoroalkyl acids (PFAAs) in urban groundwater, based on 53 groundwater samples taken from confined aquifers and unconfined aquifers in Tokyo. While the median concentrations of groundwater PFAAs were several ng/L, the maximum concentrations of perfluorooctane sulfonate (PFOS, 990 ng/L), perfluorooctanoate (PFOA, 1800 ng/L) and perfluorononanoate (PFNA, 620 ng/L) in groundwater were several times higher than those of wastewater and street runoff reported in the literature. PFAAs were more frequently detected than sewage tracers (carbamazepine and crotamiton), presumably owing to the higher persistence of PFAAs, the multiple sources of PFAAs beyond sewage (e.g., surface runoff, point sources) and the formation of PFAAs from their precursors. Use of multiple methods of source apportionment including principal component analysis-multiple linear regression (PCA-MLR) and perfluoroalkyl carboxylic acid ratio analysis highlighted sewage and point sources as the primary sources of PFAAs in the most severely polluted groundwater samples, with street runoff being a minor source (44.6% sewage, 45.7% point sources and 9.7% street runoff, by PCA-MLR). Tritium analysis indicated that, while young groundwater (recharged during or after the 1970s, when PFAAs were already in commercial use) in shallow aquifers (<50 m depth) was naturally highly vulnerable to PFAA pollution, PFAAs were also found in old groundwater (recharged before the 1950s, when PFAAs were not in use) in deep aquifers (50-500 m depth). This study demonstrated the utility of multiple uses of tracers (pharmaceuticals and personal care products; PPCPs, tritium) and source apportionment methods in investigating sources and pathways of PFAAs in multiple aquifer systems. PMID- 24814037 TI - Antioxidative effects of Korean red ginseng in postmenopausal women: a double blind randomized controlled trial. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Red ginseng (RG) has been widely used to treat various diseases in East Asian countries. Previous studies have shown the anti oxidative and anti-diabetic effects of RG. This study aimed to investigate the effects of RG on oxidative stress and insulin resistance in postmenopausal women. MATERIALS AND METHODS: We performed a randomized, double-blind, placebo controlled trial in 82 postmenopausal women aged 45-60 years. Participants were randomized to receive 3g red ginseng daily or placebo for 12 weeks. Antioxidant enzymes activity (superoxide dismutase, glutathione peroxidase) and oxidative stress markers (malondialdehyde, 8-hydroxydeoxyguanosine) were assessed, and the homeostatic model assessment of insulin resistance index was calculated at the baseline and at the end of the trial. RESULTS: A total of 71 postmenopausal women completed the study. Serum superoxide dismutase activity was significantly increased after the 12-week RG supplementation (P<0.001), and these changes were statistically significant compared with the placebo group (P=0.004). Serum malondialdehyde levels showed a tendency to decrease after the 12-week RG supplementation (P=0.001), but these changes were not statistically significant compared with the placebo group (P=0.064). No statistically significant changes in serum glutathione peroxidase and 8-hydroxydeoxyguanosine were noted. Further, RG supplementation showed no effects on fasting glucose, fasting insulin, and insulin resistance. CONCLUSIONS: The results suggest that RG may reduce oxidative stress by increasing antioxidant enzyme activity in postmenopausal women. PMID- 24814038 TI - Hempseed oil induces reactive oxygen species- and C/EBP homologous protein mediated apoptosis in MH7A human rheumatoid arthritis fibroblast-like synovial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal efficacy of hempseed (Cannabis sativa L.), which is rich in polyunsaturated fatty acids, in atopic dermatitis, inflammation, and rheumatoid arthritis (RA) has been suggested for centuries. Hempseed has been used as a treatment for these diseases in Korean and Chinese folk medicine. The aim of the study is to investigate the effects of hempseed oil (HO) on MH7A human RA fibroblast-like synovial cells. MATERIALS AND METHODS: MH7A cells were used to study the anti-rheumatoid effects of hempseed (Cannabis sativa L., cv. Cheungsam/Cannabaceae) oil by investigating cell viability, apoptosis, lipid accumulation, oxidative stress, and endoplasmic reticulum (ER) stress induced apoptosis. RESULTS: HO treatment reduced the survival rate of MH7A cells and promoted apoptotic cell death in a time- and dose-dependent manner. Both lipid accumulation and the level of intracellular reactive oxygen species (ROS) increased in HO-treated MH7A cells. Co-treatment with the antioxidant Tiron effectively abrogated the cytotoxic effects of HO; the ROS level was reduced, cell viability was recovered, and apoptotic cell death was significantly diminished. Moreover, HO-treated cells exhibited increased expression of the major ER stress markers, glucose-regulated protein 78 and C/EBP homologous protein (CHOP). The siRNA-mediated knockdown of CHOP prevented HO-induced apoptosis. CONCLUSIONS: Our results suggest that HO treatment induced lipid accumulation, ROS production, CHOP expression, and apoptosis in MH7A cells, and that CHOP functions as an anti-rheumatoid factor downstream of HO in MH7A cells. PMID- 24814040 TI - Using capacity alert calls to reduce overcrowding in a major public hospital. AB - OBJECTIVE: To investigate the efficacy of capacity alert calls in reducing acute hospital overcrowding through addressing rising occupancy, high patient throughput and increased access block. METHODS: Retrospective analysis of 24 months of in-patient, emergency department, and capacity alert call log data from a large metropolitan public hospital in Australia. The analysis explored statistical differences in patient flow parameters between capacity alert call days and other days including a control case set of days with statistically similar levels of occupancy. RESULTS: The study identified a significant (P<0.05) reduction in occupancy, patient throughput and access block on capacity alert call days. Capacity alert call days reversed rising occupancy trends, with 6 out of 7 flow parameters reporting significant improvement (P<0.05) over the 48 h following the call. Only 3 of these 7 flow parameters were significantly improved 48 h after control case days, confirming value in the alert mechanism and that the results are not a regression toward the mean phenomenon. CONCLUSIONS Escalation processes that alert and engage the whole hospital in tackling overcrowding can successfully deliver sustained improvements in occupancy, patient throughput and access block. The findings support and validate the use of capacity alert escalation calls to manage overcrowding, but suggest the need to improve the consistency of trigger mechanisms and the efficiency of the processes initiated by the capacity alert call. PMID- 24814039 TI - Oral magnesium supplementation decreases C-reactive protein levels in subjects with prediabetes and hypomagnesemia: a clinical randomized double-blind placebo controlled trial. AB - BACKGROUND AND AIMS: It has been suggested that magnesium deficiency is associated with the triggering of acute phase response, which may contribute to type 2 diabetes and cardiovascular disease risk. We undertook this study to determine whether oral magnesium supplementation modifies serum levels of high sensitivity C-reactive protein (hsCRP) in apparently healthy subjects with prediabetes and hypomagnesemia. METHODS: A total of 62 men and non-pregnant women aged 18-65 year, with new diagnosis of prediabetes (glucose 5.6 <7.0 mmol/L and/or post-load glucose >=7.7 <11.1 mmol/L) and hypomagnesemia (serum magnesium levels <0.74 mmol/L) were enrolled in a clinical double-blind placebo-controlled trial and randomly allocated to receive either magnesium chloride (30 mL of MgCl2 5% solution) or NaHCO3 0.1% solution, once daily for 3 months. RESULTS: At basal conditions, anthropometric and biochemical variables were similarly distributed in both groups. At the end of follow-up, participants who received magnesium chloride showed higher serum magnesium levels (0.86 +/- 0.08 vs. 0.69 +/- 0.16 mmol/L, p = 0.002) and lower hsCRP levels (4.8 +/- 15.2 vs. 17.1 +/- 21.0 nmol/L, p = 0.01) compared with participants in the control group. CONCLUSIONS: Oral magnesium supplementation decreases hsCRP levels in apparently healthy subjects with prediabetes and hypomagnesemia. PMID- 24814041 TI - Peritumoral indoleamine 2,3-dioxygenase expression in melanoma: an early marker of resistance to immune control? AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an emerging immunomodulating factor in cancer. IDO expression in tumour-negative sentinel lymph nodes (SLNs) of patients with melanoma has a negative prognostic value. OBJECTIVES: To analyse the expression pattern of IDO and associated immunological changes in corresponding primary melanomas (PMs), SLNs and metastases. METHODS: In 120 patients with melanoma, PMs with corresponding SLNs (n = 85) and metastases (n = 18) were analysed by immunohistochemical staining for IDO and FoxP3. Tumour infiltrating lymphocytes (TILs) were scored. IDO expression in stimulated peripheral blood mononuclear cells (PBMCs) was analysed in 27 patients. RESULTS: IDO expression in the sentinel node strongly correlated with endothelial IDO expression in the peritumoral stroma of the corresponding primary (P < 0.001) and metastatic melanoma (P < 0.05). Sentinel IDO positivity was inversely correlated with CD8+ lymphocytes (P = 0.01) and TILs (P = 0.05) in PM. Both IDO expression in the sentinel (P < 0.01) and the PM (P = 0.04) had a negative prognostic effect on overall survival, independent of Breslow thickness, sex, age, ulceration and sentinel invasion. IDO expression by PBMCs after stimulation with cytotoxic T lymphocyte antigen 4 was not correlated with sentinel IDO expression but tended to correlate with disease stage (P = 0.04). CONCLUSIONS: Endothelial IDO expression is highly consistent in primary, sentinel and metastatic tissues of patients with melanoma, indicating that immune suppression in melanoma is determined very early in the disease course. This supports that IDO expression in melanoma is a marker of antitumour immune response with an independent prognostic value. PMID- 24814043 TI - Education to reduce potentially harmful medication use among residents of assisted living facilities: a randomized controlled trial. AB - OBJECTIVES: The objectives of this study were (1) to investigate the effect of nurse training on the use of potentially harmful medications; and (2) to explore the effect of nurse training on residents' health-related quality of life (HRQoL), health service utilization, and mortality. DESIGN: A randomized controlled trial. SETTING AND PARTICIPANTS: In total, 227 residents in 20 wards of assisted living facilities in Helsinki were recruited. The 20 wards were randomized into those in which (1) staff received two 4-hour training sessions on appropriate medication treatment (intervention group), and (2) staff received no additional training and continued to provide routine care (control group). INTERVENTION: Two 4-hour interactive training sessions for nursing staff based on constructive learning theory to recognize potentially harmful medications and corresponding adverse drug events. MEASUREMENTS: Use of potentially harmful medications, HRQoL assessed using the 15 dimensional instrument of health-related quality of life, health service utilization, and mortality assessed at baseline, and 6 and 12 months. RESULTS: During the 12-month follow-up, the mean number of potentially harmful medications decreased in the intervention wards [-0.43, 95% confidence interval (CI) -0.71 to -0.15] but remained constant in the control wards (+0.11, 95% CI -0.09 to +0.31) (P = .004, adjusted for age, sex, and comorbidities). HRQoL declined more slowly in the intervention wards (-0.038 (95% CI -0.054 to -0.022) than in the control wards (-0.072 (95% CI -0.089 to -0.055) (P = .005, adjusted for age, sex, and comorbidities). Residents of the intervention wards had significantly less hospital days (1.4 days/person/year, 95% CI 1.2-1.6) than in the control wards (2.3 days/person/year; 95% CI 2.1-2.7) (relative risk 0.60, 95% CI 0.49-0.75, P < .001, adjusted for age, sex, and comorbidities). CONCLUSIONS: Activating learning methods directed at nurses in charge of comprehensive care can reduce the use of harmful medications, maintain HRQoL, and reduce hospitalization in residents of assisted living facilities. PMID- 24814044 TI - Super-stable, highly monodisperse plasmonic Faradaurate-500 nanocrystals with 500 gold atoms: Au(~500)(SR)(~120). AB - Determining the composition of plasmonic nanoparticles is challenging due to a lack of tools to accurately quantify the number of atoms within the particle. Mass spectrometry plays a significant role in determining the nanoparticle composition at the atomic level. Significant progress has been made in understanding ultrasmall gold nanoparticles such as Au25(SR)18 and Au38(SR)24, which have Au core diameters of 0.97 and 1.3 nm, respectively. However, progress in 2-5 nm-diameter small plasmonic nanoparticles is currently impeded, partially because of the challenges in synthesizing monodisperse nanoparticles. Here, we report a plasmonic nanocrystal that is highly monodisperse, with unprecedentedly small size variability. The composition of the superstable plasmonic nanocrystals at 115 kDa was determined as Au(500+/-10)SR(120+/-3). The Au(~500) system, named Faradaurate-500, is the largest system to be characterized using high resolution electrospray (ESI) mass spectrometry. Atomic pair distribution function (PDF) data indicate that the local atomic structure is consistent with a face-centered cubic (fcc) or Marks decahedral arrangement. High resolution scanning transmission electron microscopy (STEM) images show that the diameter is 2.4 +/- 0.1 nm. The size and the shape of the molecular envelope measured by small-angle X-ray scattering (SAXS) confirms the STEM and PDF analysis. PMID- 24814042 TI - Determining the incidence of drug-associated acute kidney injury in nursing home residents. AB - OBJECTIVE: Although acute kidney injury (AKI) is well studied in the acute care setting, investigation of AKI in the nursing home (NH) setting is virtually nonexistent. The goal of this study was to determine the incidence of drug associated AKI using the RIFLE (Risk, Injury, Failure, Loss of kidney function, or End-Stage kidney disease) criteria in NH residents. DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: We conducted a retrospective study between February 9, 2012, and February 8, 2013, for all residents at 4 UPMC NHs located in southwest Pennsylvania. The TheraDocTM Clinical Surveillance Software System, which monitors laboratory and medication data and fires alerts when patients have a sufficient increase in serum creatinine, was used for automated case detection. An increase in serum creatinine in the presence of an active medication order identified to potentially cause AKI triggered an alert, and drug associated AKI was staged according to the RIFLE criteria. Data were analyzed by frequency and distribution of alert type by risk, injury, and failure. RESULTS: Of the 249 residents who had a drug-associated AKI alert fire, 170 (68.3%) were women, and the mean age was 74.2 years. Using the total number of alerts (n = 668), the rate of drug-associated AKI was 0.41 events per 100 resident-days. Based on the RIFLE criteria, there were 191, 70, and 44 residents who were classified as AKI risk, injury, and failure, respectively. The most common medication classes included in the AKI alerts were diuretics, angiotensin converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs), and antibiotics. CONCLUSION: Drug-associated AKI was a common cause of potential adverse drug events. The vast majority of cases were related to the use of diuretics, ACEIs/ARBs, and antibiotics. Future studies are needed to better understand patient, provider, and facility risk factors, as well as strategies to enhance the detection and management of drug-associated AKI in the NH. PMID- 24814045 TI - BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. AB - Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon-intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing. PMID- 24814046 TI - Methylation of TNFRSF13B and TNFRSF13C in duodenal mucosa in canine inflammatory bowel disease and its association with decreased mucosal IgA expression. AB - Although decreased intestinal IgA expression has been reported in dogs with inflammatory bowel disease (IBD), the mechanism underlying this decrease is unknown. Transmembrane activator and calcium-modulating cyclophilin-ligand interactor (TACI) and B cell-activating factor of the TNF family (BAFF) receptor (BAFF-R) are key receptors for T cell-independent IgA class switching by the binding of IgA-inducing cytokine a proliferation-inducing ligand (APRIL) and BAFF. Here we show decreased TACI and BAFF-R mRNA expression and hypermethylation of their corresponding genes TNFRSF13B and TNFRSF13C, respectively in the duodenal mucosa of dogs with IBD. To examine whether DNA methylation of the TNFRSF13B and TNFRSF13C influences the mRNA expression of TACI and BAFF-R, respectively, we first analyzed methylation and mRNA expression levels in vitro using 2 canine B lymphoid cell lines, GL-1 and CLBL-1. Methylation profiles in the cells were examined by bisulfite sequencing and methylation-specific PCR (MSP) with primer pairs specific to methylated or unmethylated sequences. These methylation analyses revealed hypermethylation of the CpG islands of both TNFRSF13B and TNFRSF13C in GL-1, but not in CLBL-1 cells. The mRNA expression levels of TACI and BAFF-R were significantly lower in GL-1 than in CLBL-1 cells. Treatment with 5-aza-2'-deoxycytidine significantly increased TACI and BAFF-R mRNA expression in GL-1 cells through demethylation of TNFRSF13B and TNFRSF13C, respectively. These results suggest that the mRNA expression of TACI and BAFF-R is regulated through methylation of their genes in canine B cells. Quantitative real-time MSP showed significant hypermethylation of the CpG islands of TNFRSF13B and TNFRSF13C in the duodenal mucosa of dogs with IBD. Furthermore, duodenal mRNA expression levels of TACI and BAFF-R were significantly lower in dogs with IBD than in healthy controls. The mRNA expression levels of TACI positively correlated with intestinal IgA expression, whereas the methylation level of its gene (TNFRSF13B) negatively correlated with IgA expression. The present results suggest the role of TACI in the regulation of mucosal IgA expression through epigenetic modifications. PMID- 24814047 TI - Tumor suppressor p53 induces miR-1915 processing to inhibit Bcl-2 in the apoptotic response to DNA damage. AB - The antiapoptotic protein Bcl-2 is overexpressed in human cancers, and confers resistance to antitumor agents in cancer cells. Bcl-2 is negatively regulated by the tumor suppressor p53 in response to DNA damage during apoptotic cell death. However, this molecular mechanism remains unclear. The available evidence indicates that miR-1915 represses Bcl-2 expression at the post-transcriptional level in human colorectal carcinoma cells, which is correlated with drug resistance. Here, we show that p53 controls miR-1915 expression in response to DNA damage. Induction of p53 affects the expression of precursor and mature, but not primary, miR-1915. Inhibition of miR-1915 abrogates downregulation of Bcl-2 expression following treatment with genotoxin. These findings demonstrate that p53 negatively regulates Bcl-2 expression by targeting miR-1915 processing from primary into precursor miRNA. Taken together, the findings of the current study reveal a novel mechanism whereby p53 negatively modulates Bcl-2 by controlling miR-1915. PMID- 24814048 TI - Transcription factor networks regulating hepatic fatty acid metabolism. AB - Tight regulation of lipid levels is critical for cellular and organismal homeostasis, not only in terms of energy utilization and storage, but also to prevent potential toxicity. The liver utilizes a set of hepatic transcription factors to regulate the expression of genes implicated in all aspects of lipid metabolism including catabolism, transport, and synthesis. In this article, we will review the main transcriptional mechanisms regulating the expression of genes involved in hepatic lipid metabolism. The principal regulatory pathways are composed of simple modules of transcription factor crosstalks, which correspond to building blocks of more complex regulatory networks. These transcriptional networks contribute to the regulation of proper lipid homeostasis in parallel to posttranslational mechanisms and end product-mediated modulation of lipid metabolizing enzymes. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. PMID- 24814049 TI - Induction of insulin secretion by apolipoprotein M, a carrier for sphingosine 1 phosphate. AB - BACKGROUNDS: High-density lipoprotein (HDL) has been proposed to enhance beta cell functions. Clinical studies have suggested that apolipoprotein M (apoM), which rides mainly on HDL, is involved in diabetes; however, the underlying mechanism has not yet been elucidated. Recently, apoM was shown to be a carrier for sphingosine 1-phosphate (S1P), a bioactive lipid mediator. In the present study, we investigated the modulation of insulin secretion by apoM through the action of S1P. METHODS AND RESULTS: We overexpressed apoM in the livers of C57BL6 mice using adenovirus gene transfer and found that the blood glucose levels under ad libitum feeding conditions were lower in the apoM-overexpressing mice. While an insulin tolerance test revealed that insulin sensitivity was not significantly affected, a glucose tolerance test revealed that apoM-overexpressing mice had a better glucose tolerance because of enhanced insulin secretion, a phenomenon that was reversed by treatment with VPC 23019, an antagonist against S1P1 and S1P3 receptor. In vitro experiments with MIN6 cells also revealed that apoM-containing lipoproteins enhanced insulin secretion, which was again inhibited by VPC 23019. ApoM retarded the degradation of S1P, and an increase in Pdx1 expression, the attenuation of endoreticulum stress, and the phosphorylation of Akt, AmpK, and Erk were observed as possible underlying mechanisms for the effect of S1P, maintained at a high concentration by apoM, on the increase in insulin secretion. CONCLUSIONS: ApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions. PMID- 24814050 TI - ATP-mediated kinome selectivity: the missing link in understanding the contribution of individual JAK Kinase isoforms to cellular signaling. AB - Kinases constitute an important class of therapeutic targets being explored both by academia and the pharmaceutical industry. The major focus of this effort was directed toward the identification of ATP competitive inhibitors. Although it has long been recognized that the intracellular concentration of ATP is very different from the concentrations utilized in biochemical enzyme assays, little thought has been devoted to incorporating this discrepancy into our understanding of translation from enzyme inhibition to cellular function. Significant work has been dedicated to the discovery of JAK kinase inhibitors; however, a disconnect between enzyme and cellular function is prominently displayed in the literature for this class of inhibitors. Herein, we demonstrate utilizing the four JAK family members that the difference in the ATP Km of each individual kinase has a significant impact on the enzyme to cell inhibition translation. We evaluated a large number of JAK inhibitors in enzymatic assays utilizing either 1 mM ATP or Km ATP for the four isoforms as well as in primary cell assays. This data set provided the opportunity to examine individual kinase contributions to the heterodimeric kinase complexes mediating cellular signaling. In contrast to a recent study, we demonstrate that for IL-15 cytokine signaling it is sufficient to inhibit either JAK1 or JAK3 to fully inhibit downstream STAT5 phosphorylation. This additional data thus provides a critical piece of information explaining why JAK1 has incorrectly been thought to have a dominant role over JAK3. Beyond enabling a deeper understanding of JAK signaling, conducting similar analyses for other kinases by taking into account potency at high ATP rather than Km ATP may provide crucial insights into a compound's activity and selectivity in cellular contexts. PMID- 24814051 TI - Reasons for opioid use among patients with dependence on prescription opioids: the role of chronic pain. AB - The number of individuals seeking treatment for prescription opioid dependence has increased dramatically, fostering a need for research on this population. The aim of this study was to examine reasons for prescription opioid use among 653 participants with and without chronic pain, enrolled in the Prescription Opioid Addiction Treatment Study, a randomized controlled trial of treatment for prescription opioid dependence. Participants identified initial and current reasons for opioid use. Participants with chronic pain were more likely to report pain as their primary initial reason for use; avoiding withdrawal was rated as the most important reason for current use in both groups. Participants with chronic pain rated using opioids to cope with physical pain as more important, and using opioids in response to social interactions and craving as less important, than those without chronic pain. Results highlight the importance of physical pain as a reason for opioid use among patients with chronic pain. PMID- 24814052 TI - 'It's the little things that count'. Families' experience of roles, relationships and quality of care in rural nursing homes. AB - BACKGROUND: Entry to long-term care is an emotional time for older people and their families. Poor communication and uncertainty about roles and responsibilities in the post-placement period can cause distress for families and staff, further exacerbating an already difficult situation. However, there are limited studies that specifically address roles and relationships between families and care home staff in the post-placement period. AIM: The aim of this study was to explore the experiences of families following the nursing home placement of an older relative. DESIGN: A qualitative approach using grounded theory methodology was used to conduct the study. METHOD: Semi structured interviews were conducted with 29 relatives of nursing home residents in a region of the UK. Consistent with grounded theory methodology, data collection and analysis occurred simultaneously. FINDINGS: Data analysis revealed five distinct categories that captured the experience of families in the post-placement period. These were: communication with staff, involvement in relative's care, the importance of 'the little things', quality of care and areas for improvement. CONCLUSIONS: Developing caring partnership is crucial if the resources of care home staff and families are to be maximised for the benefit of all concerned. IMPLICATIONS FOR PRACTICE: A number of programmes and initiatives already exist to enhance the quality of life of older people in care homes and their families. Serious consideration should be given to more widespread uptake of these initiatives. PMID- 24814053 TI - Comparative study of the effects of organic selenium on hen performance and productivity of broiler breeders. AB - 1. A 10-week experiment was conducted with Ross 308 broiler breeder chickens in cages to evaluate the influence of organic and inorganic sources of selenium (Se) supplementation. A total of 600 birds at 29 weeks of age were divided at random into 4 groups and fed on a maize-soya basal diet supplemented with different forms of Se. 2. The first (control) group was given the basal diet without Se supplementation, whereas the second, third and fourth groups were given, respectively, the basal diet with 0.3 mg/kg of inorganic Se in the form of sodium selenite or 0.3 and 0.5 mg/kg of organic Se in the form of Se enriched yeast (Se yeast). 3. The experiment was carried out for 10 weeks to compare and evaluate the influence of Se supplementation on breeder performance, egg production, hatchability and the quality of eggs. Samples were collected for analysis at weeks 0, 5 and 10 of the experimental period. 4. At the end of the experiment (39 weeks), there was a reduction in mortality in breeders given diets supplemented with 0.5 mg/kg of Se-yeast. Supplementation of feed with 0.5 mg/kg organic Se increased egg production, percentage of settable eggs and hatchability. 5. Selenium supplementation increased egg weight and specific gravity compared to the control diet. However, no significant variation was found in albumen or yolk protein content at the end of week 10. 6. Selenium accumulation and glutathione peroxidase (GSHPx) activity were lower in the egg albumen and yolk of control compared with Se-supplemented treatments. Se accumulation and GSHPx activity were higher in the group given 0.3 mg/kg organic compared to 0.3 mg/kg of inorganic Se. 7. The results favour the use of Se-yeast at the dose of 0.5 mg/kg in broiler breeder diets for better productivity of eggs, settable eggs, hatchability and higher Se accumulation and antioxidant status in eggs. PMID- 24814054 TI - Long-term changes in straylight induced by corneal refractive therapy: a pilot study. AB - PURPOSE: To assess long-term intraocular straylight changes induced by corneal refractive therapy (CRT) and to determine whether these changes persist after cessation of CRT lens wear. METHODS: A single-center, prospective, longitudinal study was performed in 22 subjects (group 1) undergoing overnight corneal refractive therapy for 1 year. Ten right eyes of 10 subjects (group 2) with emmetropia served as controls. In each subject, high contrast visual acuity (HCVA), manifest refraction and intraocular straylight were determined at several time points during treatment and 1 month after discontinuing treatment. Straylight was measured using the van den Berg straylight meter (third generation). EDTRS charts (logMAR units) were used to assess HCVA. For both groups, only data for the right eyes were analyzed. RESULTS: Straylight (mean +/- standard deviation) significantly fell from baseline (0.98 +/- 0.13) to values recorded after 1 month (0.88 +/- 0.13, p=0.011), 3 months (0.88 +/- 0.13, p=0.004), 6 months (0.88 +/- 0.13, p=0.000) and 12 months (0.76 +/- 0.12, p=0.003) of treatment. One month after discontinuing CRT lens wear, straylight was still significantly lower than baseline (0.89 +/- 0.13, p=0.003). No correlations were observed between intraocular straylight and HCVA. CONCLUSIONS: Good refractive outcomes and reductions in straylight were observed in response to corneal refractive therapy for myopia. The reduction in straylight observed after discontinuing CRT warrents further investigation. PMID- 24814055 TI - Development of a new grading scale for tear ferning. AB - PURPOSE: This paper reports on the development of a new tear ferning (TF) subjective grading scale, and compares it with the Rolando scale. METHOD: TF patterns obtained from tear film samples collected from normal and dry eye subjects in previous studies were collated into a large image library. From this library, 60 images were selected to represent the full range of possible TF patterns, and a further sub-set of 15 images was chosen for analysis. Twenty-five optometrists were asked to rank the images in increasing order between extreme anchors on a scale of TF patterns. Interim statistical analysis of this ranking found 7 homogeneous sub-sets, where the image rankings overlapped for a group of images. A representative image (typically the mean) from each group was then adopted as the grade standard. Using this new 7-point grading scale, 25 optometrists were asked to grade the entire 60 image library at two sessions: once using the 4-point Rolando scale and once using the new 7-point scale, applying 0.25 grade unit interpolation. RESULTS: Statistical analysis found that for the larger image set, the Rolando scale produced 3 homogeneous sub-sets, and the 7-point scale produced 5 homogeneous sub-sets. With this refinement, a new 5 point TF scale (Grades 0-4) was obtained. CONCLUSIONS: The Rolando grading scale lacks discrimination between its Type I and II grades, reducing its reliability. The new 5-point grading scale is able to differentiate between TF patterns, and may provide additional support for the use of TF for both researcher and clinician. PMID- 24814056 TI - Seizures associated with synthetic cathinone exposures in the pediatric population. AB - BACKGROUND: Synthetic cathinones or "bath salts" are an increasing problem in the United States. Their adverse effects are related to sympathomimetic toxicity and seizures have been listed among the side effects. This study details the seizures that occur after synthetic cathinone exposure in the pediatric population. METHODS: We used the American Association of Poison Control Centers database to capture all known synthetic cathinone exposures in children <20 years of age from January 1, 2010 through January 31, 2013. Demographic data along with signs of fever, acidosis, hallucinations and/or delusions, hypertension, tachycardia, electrolyte abnormalities, and coingested substances were collected for all synthetic cathinone users and compared with those users who experienced seizure activity. RESULTS: Over the specified time period, there were 1328 pediatric synthetic cathinone exposures. Seizures complicated 73 (5.5%) of the cases, with 37 (50.7%) of those cases experiencing a single seizure, 29 (39.7%) multiple seizures, and seven (9.6%) status epilepticus. Fever and acidosis were associated with single seizures, multiple seizures, and status epilepticus. There was no correlation found between any seizure activity and electrolyte abnormalities, hallucinations and/or delusions, tachycardia, or hypertension. Coingestants were present in 33 (45%) of the seizure cases. The most commonly coingested substances were tetrahydrocannabinol, alcohol, and opioids. CONCLUSIONS: Seizures complicated 5.5% of synthetic cathinone exposures in the pediatric population. Fever and acidosis were associated with seizure activity. The presence of fever after a synthetic cathinone exposure may warrant more aggressive monitoring and treatment. PMID- 24814057 TI - The prognosis of pediatric headaches--a 30-year follow-up study. AB - BACKGROUND: Although headaches in childhood are common, there are few data available on their long-term prognosis. We have monitored a group of patients since diagnosis in 1983. METHODS: Patients who were part of the 20-year follow-up study in 2003 were contacted, and data were collected using a standardized telephone interview. Details of headache characteristics and identified precipitants and alleviating factors were gathered. The most effective means of controlling the headaches were also recorded. RESULTS: Follow-up was achieved for 28 of 60 patients (47%). Over the 30 years since diagnosis, eight patients (29%) reported a complete resolution of headaches, including three whose headaches resolved between the 20- and 30-year follow-up studies. The type of headache varied over the 30-year time interval with only three patients maintaining the same headache type at all four time periods of 1983, 1993, 2003, and 2013. Only one patient used prescription medication as the primary method for controlling headaches. The most commonly used intervention was nonprescription analgesia, self-relaxation and/or hypnosis, and precipitant avoidance. CONCLUSIONS: Headaches persist in approximately 70% of children 30 years after diagnosis. Encouraging children to manage their headaches with simple analgesia and precipitant avoidance appears to have long-term benefits. PMID- 24814058 TI - Unusual late neurological complication in a child after an Indian krait bite. AB - BACKGROUND: Neurological manifestations of elapid snakebites include neuromuscular paralysis and cerebrovascular complications. Autonomic manifestations are observed in almost two third of patients following moderate to severe envenomation. PATIENT SUMMARY: A 10-year-old boy presented with acute onset flaccid quadriparesis with encephalopathy, cranial neuropathy, and respiratory failure after bite of a common Indian krait. He also had features of autonomic instability in the form of hypertension and variable heart rate. Within 10 days, he was weaned from the ventilator and discharged on multiple oral antihypertensives. Within a week, he returned with focal status epilepticus. MRI of the brain suggested posterior reversible leukoencephalopathy. He recovered completely within 2 days with visual impairments while recovering. Within next 1 month, his antihypertensives were tapered completely. MRI of the brain, repeated after 3 months, confirmed complete resolution. CONCLUSIONS: This patient highlights the fact that posterior reversible leukoencephalopathy can be a late complication of Indian krait bite secondary to autonomic instability with systemic hypertension. PMID- 24814060 TI - Rachischisis totalis without acrania in a newborn male. AB - BACKGROUND: Rachischisis totalis is a rare open neural tube defect often associated with lethal acrania. When acrania is not present, mortality remains high and morbidity for survivors is extreme. PATIENT: We describe is a term newborn with in-utero diagnosed rachischisis totalis without acrania and Chiari II malformation with subsequent hydrocephalus. RESULTS: At birth, clinical examination revealed rachischisis totalis without acrania. The spinal defect extended from the mid-cervical to the lower sacral vertebrae. Serial cranial ultrasonography and brain MRI revealed Chiari II malformation with severe hydrocephalus. The spinal defect was closed and a ventriculoperitoneal shunt placed to relieve the hydrocephalus. The clinical course was complicated by significant central apnea, often necessitating aggressive resuscitation and chest compressions. The infant has survived with expected severe developmental delay but has graduated from hospice care. CONCLUSION: This report demonstrates that survival with variable function and quality of life is possible with severe open neural tube defects. A multidisciplinary team approach including family-centered care must be used early to overcome the many ethical challenges that such patients present. PMID- 24814059 TI - Cross-sectional evaluation of electrical impedance myography and quantitative ultrasound for the assessment of Duchenne muscular dystrophy in a clinical trial setting. AB - BACKGROUND: Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown. METHODS: We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2 to 14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual. RESULTS: Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P < 0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = -0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = -0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = -0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = -0.40; P = 0.054 and rho = -0.32; P = 0.13, respectively). CONCLUSIONS: Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted. PMID- 24814061 TI - Noncompaction cardiomyopathy: manifestation as a surgical pitfall - rare but real. AB - OBJECTIVES: Noncompaction cardiomyopathy is characterized by hyper-trabeculation of the myocardium. The patients present with heart failure and variable combination of arrhythmias and thromboembolism. Although several articles have shed light on the medical aspect of this disease, none have highlighted its surgical relevance. A death following ligation of a patent ductus arteriosus prompted us to evaluate the surgical aspects of this disease. METHODS: Autopsy records from 2003 to 2012 were reviewed, and cases identified as noncompaction cardiomyopathy were retrieved and analyzed. Cases with obligatory hyper trabeculation were excluded. RESULTS: Thirteen patients were found to have noncompaction cardiomyopathy in 9427 autopsies performed. Their ages ranged from 4 months to 55 years; 10 were children, and all 3 adults were over 45 years of age. Only one patient had an antemortem diagnosis of noncompaction cardiomyopathy on echocardiography. There were 7 postoperative deaths. CONCLUSIONS: Although noncompaction cardiomyopathy is rare, missing its diagnosis in a patient operated on for another indication can spell disaster postoperatively. As the clinical picture is nonspecific and the disease is not very well known, it needs vigilance on the part of the echocardiographer and surgeon. PMID- 24814063 TI - Fungal physiology: Reaching the right location. PMID- 24814062 TI - An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer. AB - The RAS pathway is one of the most commonly deregulated pathways in human cancer. Mutations in RAS genes occur in nearly 30% of all human tumors. However in some tumor types RAS mutations are conspicuously absent or rare, despite the fact that RAS and downstream effector pathways are hyperactivated. Recently, RAS GTPase Activating Proteins (RAS GAPs) have emerged as an expanding class of tumor suppressors that, when inactivated, provide an alternative mechanism of activating RAS. RAS GAPs normally turn off RAS by catalyzing the hydrolysis of RAS-GTP. As such, the loss of a RAS GAP would be expected to promote excessive RAS activation. Indeed, this is the case for the NF1 gene, which plays an established role in a familial tumor predisposition syndrome and a variety of sporadic cancers. However, there are 13 additional RAS GAP family members in the human genome. We are only now beginning to understand why there are so many RAS GAPs, how they differentially function, and what their potential role(s) in human cancer are. This review will focus on our current understanding of RAS GAPs in human disease and will highlight important outstanding questions. PMID- 24814064 TI - Viral pathogenesis: Vpu puts the brakes on ADCC. PMID- 24814065 TI - The microbial ecology of permafrost. AB - Permafrost constitutes a major portion of the terrestrial cryosphere of the Earth and is a unique ecological niche for cold-adapted microorganisms. There is a relatively high microbial diversity in permafrost, although there is some variation in community composition across different permafrost features and between sites. Some microorganisms are even active at subzero temperatures in permafrost. An emerging concern is the impact of climate change and the possibility of subsequent permafrost thaw promoting microbial activity in permafrost, resulting in increased potential for greenhouse-gas emissions. This Review describes new data on the microbial ecology of permafrost and provides a platform for understanding microbial life strategies in frozen soil as well as the impact of climate change on permafrost microorganisms and their functional roles. PMID- 24814067 TI - Guglielmi detachable coils. PMID- 24814066 TI - The hybrid nature of the Eukaryota and a consilient view of life on Earth. AB - The origin of the eukaryotic cell, which is known as eukaryogenesis, has puzzled scientists for more than 100 years, and many hypotheses have been proposed. Recent analyses of new data enable the safe elimination of some of these hypotheses, whereas support for other hypotheses has increased. In this Opinion article, we evaluate the available theories for their compatibility with empirical observations and conclude that cellular life consists of two primary, paraphyletic prokaryotic groups and one secondary, monophyletic group that has symbiogenic origins - the eukaryotes. PMID- 24814068 TI - Low neurologic intensive care unit hemoglobin as a predictor for intra-arterial vasospasm therapy and poor discharge modified Rankin Scale in aneurysmal subarachnoid haemorrhage-induced cerebral vasospasm. AB - BACKGROUND: Intra-arterial vasospasm therapy (IAVT) with vasodilators, balloon angioplasty, and cerebral blood flow augmentation devices are therapies for aneurysmal subarachnoid hemorrhage-induced symptomatic cerebral vasospasm refractory to maximal medical management. Our aim was to identify clinical factors predictive of IAVT and/or poor outcome. METHODS: A cross-sectional retrospective analysis was performed of 130 patients with aneurysmal subarachnoid hemorrhage including patients without and with symptomatic cerebral vasospasm requiring IAVT. The data were analysed by Student t test, univariate analysis and binary logistic regression. RESULTS: The mean+/-SD patient age was 54+/-12.2 years, admission hemoglobin was 13.6+/-1.5 g/dL, and neurologic intensive care unit (NICU) hemoglobin 11+/-1.4 g/dL. The median Hunt and Hess grade was 2 (range 1,4), Fisher grade 3 (range 3,3), and discharge modified Rankin Scale (mRS) 0.5 (range 0,2). Lower mean NICU hemoglobin was found in patients receiving IAVT than in those not receiving IAVT (M=10.4+/-0.9 g/dL vs M=11.2+/-1.4 g/dL, t(115)= 2.52, p=0.01). Further, lower mean NICU hemoglobin was associated with increased IAVT (rho=-0.3, p<0.01) and higher discharge mRS (rho=-0.5, p<0.01). In binary logistic regression, lower mean NICU hemoglobin was an independent predictor of IAVT (OR 0.6, 95% CI 0.4 to 0.9, p<0.05) as well as poor discharge mRS (OR 0.6, 95% CI 0.4 to 0.9, p<0.05). Hunt and Hess grade was also an independent predictor of these outcomes. CONCLUSIONS: Lower mean hemoglobin during the acute phase of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm is an independent predictor of IAVT and poor discharge mRS. This relationship warrants further evaluation. PMID- 24814069 TI - Children with asthma have significantly lower long-term cortisol levels in their scalp hair than healthy children. AB - AIM: Noninvasive measurement of long-term cortisol levels is a useful way of evaluating the effect of chronic disease on the hypothalamic-pituitary-adrenal axis in children. The aim of this pilot study was to compare hair cortisol levels in children using inhaled corticosteroids for asthma and healthy children and to determine the association with short-term salivary cortisol levels. METHODS: Cortisol levels were measured in the scalp hair and saliva of prepubertal children with asthma (n = 10) and without asthma (n = 10). Asthma control was assessed using an asthma questionnaire and pulmonary function tests. RESULTS: The median (95% CI) cortisol level in the scalp hair of the children with asthma (2.0 pg/mg; 1.4-4.1) was significantly lower than the healthy children (4.3 pg/mg; 1.8 5.9). Morning salivary cortisol levels were significantly lower for the children with asthma (5.9 nmol/L; 3.2-11.1) than the healthy children (9.0 nmol/L; 4.4 31.6). There was no significant association between cortisol levels in hair and saliva. CONCLUSION: Long-term cortisol levels were significantly lower in children with asthma than healthy children. Measuring long-term cortisol levels in scalp hair is an attractive, noninvasive tool that can evaluate the effect of asthma and its treatment on the hypothalamic-pituitary-adrenal axis. PMID- 24814070 TI - ABM Board of Directors--have you ever thought about it? PMID- 24814071 TI - Effect of smoking and indoor air pollution on the risk of tuberculosis: smoking, indoor air pollution and tuberculosis. AB - INTRODUCTION: Although epidemiological studies have reported an association between smoking and increases in tuberculosis, the relationship between indoor air pollution and risk of tuberculosis is not fully understood. A limited number of studies have suggested that smoking and indoor air pollution may play a role in the pathogenesis of tuberculosis. In this study, we investigated the effect of smoking and indoor air pollution on the risk of active tuberculosis. MATERIALS AND METHODS: It is prospectively recorded age matched case-control study. Three hundred sixty two active tuberculosis cases and 409 healthy controls were included to the study. All participants were interviewed face to face by using a questionnaire including smoking habit, quantity and duration of smoking, number of room/person in the house, monthly income of the family, indoor heating system, and environmental tobacco smoke. RESULTS: Patients who smoke had a five fold (95% CI: 3.2-7.5, p< 0.0001) higher odds of having active tuberculosis compared with patients who do not smoke. Similarly, patients using coal or wood for indoor heating had a 1.6 fold (95% CI: 1.179-2.305, p< 0.003) higher odds having tuberculosis. People who have less income (< 200 Euro/month) had 3.2 fold (95% CI: 2.113-5.106, p< 0.0001) higher odds of having tuberculosis compared with people having high income. There was a significant correlation between heavy smoking (>= 20 packet/year, p< 0.0001) and age onset of smoking (< 16 years of age, p< 0.041). There was no significant association between environmental tobacco smoke and tuberculosis. CONCLUSION: Smoking and indoor air pollution may increase the risk of tuberculosis. There is a complex interaction between smoking, socioeconomic conditions, indoor air quality and tuberculosis. Our results suggest that effective indoor air quality control could help to prevent tuberculosis risk. PMID- 24814072 TI - Lack of association of 1513 A/C polymorphism in P2X7 gene with susceptibility to pulmonary and extrapulmonary tuberculosis. AB - INTRODUCTION: Tuberculosis, is one of the a leading causes of death worldwide, is characterized by different clinical forms including: latent, localized pulmonary infection and extrapulmonary tuberculosis. Candidate gene association studies have implicated common polymophisms in genes that may influence the development of tuberculosis. This study, aimed to elucidate the role of P2X7 gene in 1513A/C polymorphism the etiopathogenesis of tuberculosis. MATERIALS AND METHODS: The study included 160 patients with tuberculosis (71 pulmonary and 89 extrapulmonary tuberculosis) and 160 healthy controls. Genomic DNA was isolated and 1513A/C polymorphism in P2X(7) gene was genotyped by PCR-RFLP method. RESULTS: Frequency of P2X7 AA genotype was 47.5% in controls and 56.87% in patients, AC frequency was 39.37% controls and 32.5% in patients, CC genotype was 13.12% in controls and 10.62% in patients. No significant difference in allele and genotype frequencies (1513A/C polymorphism) between tuberculosis patients and controls was found. CONCLUSION: The results suggest that 1513A/C polymorphism of P2X7 gene is not associated with pulmonary and extrapulmonary tuberculosis in the Eastern Turkey. PMID- 24814073 TI - Wells score and Pulmonary Embolism Rule Out Criteria in preventing over investigation of pulmonary embolism in emergency departments. AB - INTRODUCTION: Unnecessary diagnostic tests are usually ordered to most of the patients with dyspnea or pleuritic chest pain, because of the worse outcomes of missed diagnosis of pulmonary embolism (PE). To identify rates and causes of over investigation for PE and to search whether it was possible to reduce this over investigation by using Wells score and Pulmonary Embolism Rule Out Criteria (PERC). MATERIALS AND METHODS: A retrospective observational cohort study performed in an emergency department of a tertiary care university hospital. All patients who were ordered diagnostic with the suspicion of PE were included in the study. They were grouped into two as PE (+) and PE (-) and compared. RESULTS: Among 108 patients, 53 (49%) were diagnosed as PE (+) and overdiagnosis was present in 55 (51%) patients i.e., PE (-). The sensitivity of high Wells score was 43%, specificity 78%, positive predictive value 66% and negative predictive value 59%. PERC criteria found to be negative (when all of the eight criteria were fulfilled) in only five patients. The sensitivity of the test was 98%, specificity 7%, positive predictive value 50%, negative predictive value 80%. When individual parameters of PERC were evaluated solely for the exclusion of PE; "no leg swelling" and "no previous deep venous thrombosis or PE history" were found significantly negatively correlated with PE diagnosis (p= 0.001, r= -0.325 and p= 0.013, r= -0.214 respectively). CONCLUSION: Over investigation of PE in emergency departments still remains as an important problem. In order to prevent this, the clinical prediction rules must be developed further and their use in combination should be searched in future studies. PMID- 24814074 TI - [The evaluation of geriatric patients aged 90 and over in the pulmonary department]. AB - INTRODUCTION: Since the number of geriatric clinics in our country is inadequate, Chest physicians play a very important role in diagnosis, follow-up and treatment of that group of patients in many centers. In this study, 90 years and older geriatric patients hospitalized in pulmonology services was investigated regarding course of disease. MATERIALS AND METHODS: Ninety years and older geriatric patients hospitalized in Pulmonology Department of Duzce University and Duzce Ataturk State Hospital was retrospectively analyzed during three-year period between January 2010 and December 2012. RESULTS: Thirty (57.7%) out of 52 patients was women. The mean age was 93.3 +/- 3.9. The most common cause of admission was pneumonia (65.4%). Hypertension was the most common concomitant disease (51.6%). Diabetes mellitus, congestive heart failure was other most common concomitant disease, respectively. 80.8% of all patients was accompanied by at least one concomitant disease. All patients had a mortality rate of 17.3%. CONCLUSION: The most common cause of admission and concomitant disease in 90 years and older geriatric patients was pneumonia and hypertension respectively. Most of the patients discharged from hospital. Further examination and treatment in patients over the age of 90 should be implemented. PMID- 24814075 TI - [The changes in smoking related behaviours and second hand smoke after the smoking ban in Izmir]. AB - INTRODUCTION: The aim of the study is to determine the views about law, change of second hand smoke (SHS) quantity, people's smoking related behaviours after the publishment of law which prohibits use of tobacco products in closed public areas. MATERIALS AND METHODS: Questionnaire including 47 questions was performed to 600 people, who were selected by Turkey Statistics Instutition to present population of Izmir. RESULTS: 53.7% of participants were female and 46.3% was male; the mean age was 41.5 +/- 15.6. 98% of all participants were aware of the law and 91.5% of them were supporting it. 42% of participants who succeeded in quitting had managed it after the ban. Restriction of areas, rise of prices and effects of SHS were the most popular reasons of reducing/quitting smoking after the law. Non-smokers were exposed to SHS at homes; 35.1%, at vehicles: 14.9%, at work places: 14.4%. The number of smoking cigarettes was reduced by 3.19 cigarettes/day. The rate of violation of the ban was 32.3%; only 21.3% of violators were warned. 96.4% of law supporters found law successful and sufficient. CONCLUSION: A big amount of participants thinks about quitting in Izmir; law is thought to have important effect on this decision. SHS has reduced mostly in public areas with ban, but law must be enlarged to prevent SHS at private areas such as houses, vehicles and workplaces. As a result; the ban encouraged smokers to quit and reduced SHS at public areas. We believe that paying more attention for law sanction and extending the borders of law and reviewing the ban, will make our country more smoke free from now. PMID- 24814076 TI - Is obesity related to worse control in children with asthma? AB - INTRODUCTION: Asthma and obesity are related diseases however the influence of obesity on asthma severity is not clear yet. Therefore, the aim of our study was to evaluate the association between obesity and asthma control evaluated on the basis of symptoms and asthma control questionnaire (ACQ). MATERIALS AND METHODS: We enrolled 98 children with asthma aged 4 to 14 years consecutively and recorded their disease characteristics and severity parameters as well as the symptom scores. All children filled in the ACQ. Children were classified as obese and non obese according to body mass index. Obesity was defined as body mass index over 90th percentile. RESULTS: Mean age of the children in the obese group (n= 27) was 8.1 +/- 2.6 while that in the non-obese group (n= 71) was 8.6 +/- 2.9 (p= 0.41). Asthma symptom score in obese and non-obese groups were not significantly different (p= 0.73). Children in the obese group had lower ACQ scores when compared to the non-obese group (1.2 +/- 0.9 vs 1.7 +/- 1.0, p= 0.04) however this significance was lost when controlled for age and gender in the regression model. CONCLUSION: The results of this study suggest that obesity is not significantly associated with worse asthma control when adjusted for age and gender. PMID- 24814077 TI - [Determination of sentinel lymph node by Tc(99m) in small-cell lung cancer]. AB - INTRODUCTION: In the prospective study was aimed to be the actual node staging identified sentinel and mediastinel lymph nodes and mapping in patient with operable non-small cell lung carcinomas. MATERIALS AND METHODS: Twelve patients underwent pulmonary resections due to non-small cell bronchial carcinoma in the study were included . Intraoperatively, by injecting Tc99m to peritumoral tissues, average 96 minutes later, radioactivity levels of the tumoral tissue and lymph nodes were measured. All patients were evaluated by bronchoscopy for endobronchial lesions. The patients were scanned for the metastasis of solid organs in order to pre-operative staging. RESULTS: The interlobar lymph node stations as a sentinel lymph nodes were detected in 45% of the patient. Lobes of specific, lymph node stations and skip metastasis detected lymph nodes were identified. Sentinel lymph node was in 77% of patients at the level N1 and in 66%of patients at the level N2. It were at two different stations in 66% of patients and at single-station in 33% of patient . In 1 (11%) of 9 patients identified sentinel lymph node, the metastasis has been reported by the routine histopathological examination. CONCLUSION: To detection sentinel lymph node, micrometastasis also allows for a more detailed pathological examination. It provides making true node staging in patients and postoperative therapy helps to organize appropriate support with non-small cell lung cancer. PMID- 24814078 TI - [Treatment of severe asthma: expert opinion]. AB - Severe asthmatics account 10% of the all asthmatic population. Those asthmatics whose disease is inadequately controlled account for up to half of the cost for asthma, because they have more emergency room visits, more hospital admission and greater absenteeism from work. New therapeutic options were tried in those patients whose asthma was uncontrolled with standart high dose inhaled corticosteroid and long acting beta-2 agonsit combination therapy. In this paper taking into account the conditions of our country, current literature was reviewed and treatment options was discussed and graded recommendations are made for daily clinical practice in patients with severe treatment-refractory asthma. PMID- 24814079 TI - [The treatment of central sleep-apnea syndrome, updated information, and review of the literature]. AB - Central sleep-apnea syndrome (CSAS) is a disease state characterized by respiratory arrest as a result of decrease or lack of respiratory drive originating from respiratory center. Although it is seen in less than 5% of the casses who consult to the sleep disorders center, incidence of CSAS increases in the presence of congestive heart and/or renal failure, and central nervous system abnormalities. Treatment of CSAS which has been analyzed under six headings in the last version of International Classification of Sleep Disorders (ICSD-2), differs among each type of CSAS. In this review, our aim is to analyze treatment alternatives for CSAS in the light of currently updated information. PMID- 24814080 TI - [From the 7th TNM staging to the 8th in lung cancer]. AB - The anatomic extent of disease, that is described by the TNM-classification remains the most important prognostic factor for lung cancer. Based on the changes in tumor characteristics, advances in diagnostic methods and treatment strategies, TNM-classifications are updated from time to time. The 7th TNM classification was created on the basis of an international, large, and retrospective database. However due to retrospective data, there are still unanswered questions. Therefore "Prospective Lung Cancer Staging Project" is designed. In this project, in addition to the detailed evaluation of T, N, M descriptors; other factors, which were not considered to be relevant to lung cancer staging before, were also analyzed such as demographic data, histologic characteristics, certain biochemical and molecular prognostic and predictive factors. This project will be the basis of 8th TNM-classification for lung cancer. In this manuscript, we discuss the probable changes from the 7th TNM classification to the 8th. PMID- 24814081 TI - [Elastofibroma dorsi: report of 11 cases analysis and review of the literature]. PMID- 24814082 TI - Tibia metastasis from small cell lung cancer. PMID- 24814083 TI - Giant intrapulmonary malignant localized fibrous tumor: a case presentation. PMID- 24814084 TI - [A case of endobronchial metastases of renal cell carcinoma treated with interventional bronchoscopy]. PMID- 24814085 TI - Osteoporosis: can it be related to silicosis? PMID- 24814086 TI - Vitamin B2 in nanoscopic environments under visible light: photosensitized antioxidant or phototoxic drug? AB - Vitamin B2 has been studied as a conventional antioxidant (in the dark) since its discovery in 1926. The effect of visible light on vitamin B2-containing food has a long history of scientific investigation. Although photodegradation of the vitamin producing several photoproducts is evident in certain experimental conditions, phototoxicity revealing an additional oxidative stress in the medium is also clear from some reports. Here we report the photosensitized antioxidant effect of the vitamin, which is found to be greater than 2 orders of magnitude more efficient than that in the dark condition. The photoinduced antioxidant property is apparently paradoxical compared to the reported phototoxic effect of the vitamin. Our present study unravels a unified picture underlying the difference in character of vitamin B2 under visible light irradiation. UV-vis absorption and fluorescence studies in a number of physiologically relevant nanoscopic environments (micelles and reverse micelles) reveal the antioxidant activity to a well-known oxidative stress marker 2,2-diphenyl-1-picrylhydrazyl (DPPH) as well as a phototoxicity effect resulting in self-degradation of the vitamin. Picosecond-resolved Forster resonance energy transfer (FRET) from the vitamin to the marker DPPH in the biomimetic environments clearly reveals the role of proximity of an oxidizing agent in the photoinduced effect of the vitamin. Our systematic and detailed studies unravel a simple picture of the mechanistic pathway of the photosensitized vitamin in the physiologically important environments leading to the antioxidant/phototoxicity effect of the vitamin. The excited vitamin transfers its electron to the oxidizing agent in proximity for the antioxidant effect, but otherwise it employs oxygen to generate reactive oxygen species (ROS), resulting in phototoxicity/self-degradation. PMID- 24814087 TI - Leaving no one behind: an agenda for equity. PMID- 24814088 TI - Etrolizumab in moderate-to-severe ulcerative colitis. PMID- 24814089 TI - Mandatory polio vaccination for travellers: protecting global public health. PMID- 24814090 TI - Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. AB - BACKGROUND: Etrolizumab is a humanised monoclonal antibody that selectively binds the beta7 subunit of the heterodimeric integrins alpha4beta7 and alphaEbeta7. We aimed to assess etrolizumab in patients with moderately-to-severely active ulcerative colitis. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 study, patients with moderately-to-severely active ulcerative colitis who had not responded to conventional therapy were recruited from 40 referral centres in 11 countries. Eligible patients (aged 18-75 years; Mayo Clinic Score [MCS] of 5 of higher [or >=6 in USA]; and disease extending 25 cm or more from anal verge) were randomised (1:1:1) to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2; or 420 mg loading dose [LD] at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo. The primary endpoint was clinical remission at week 10, defined as MCS of 2 or less (with no individual subscore of >1), analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who had received at least one dose of study drug, had at least one post-baseline disease activity assessment, and had a centrally read screening endoscopic subscore of >=2). This study is registered with ClinicalTrials.gov, number NCT01336465. FINDINGS: Between Sept 2, 2011, and July 11, 2012, 124 patients were randomly assigned, of whom five had a endoscopic subscore of 0 or 1 and were excluded from the mITT population, leaving 39 patients in the etrolizumab 100 mg group, 39 in the etrolizumab 300 mg plus LD group, and 41 in the placebo group for the primary analyses. No patients in the placebo group had clinical remission at week 10, compared with eight (21% [95% CI 7-36]) patients in the etrolizumab 100 mg group (p=0.0040) and four (10% [0.2-24]) patients in the 300 mg plus LD group (p=0.048). Adverse events occurred in 25 (61%) of 41 patients in the etrolizumab 100 mg group (five [12%] of which were regarded as serious), 19 (48%) of 40 patients in the etrolizumab 300 mg plus LD group (two [5%] serious), and 31 (72%) of 43 patients in the placebo group (five [12%] serious). INTERPRETATION: Etrolizumab was more likely to lead to clinical remission at week 10 than was placebo. Therefore, blockade of both alpha4beta7 and alphaEbeta7 might provide a unique therapeutic approach for the treatment of ulcerative colitis, and phase 3 studies have been planned. FUNDING: Genentech. PMID- 24814091 TI - Colonic marbling in Clostridium difficile pancolitis. PMID- 24814092 TI - Cultural commentary or gender scholarship? PMID- 24814094 TI - Finding the right fit: chiseling structures out of cryo-electron microscopy maps. AB - Cryo-electron microscopy is a central tool for studying the architecture of macromolecular complexes at subnanometer resolution. Interpretation of an electron microscopy map requires its computational integration with data about the structure's components from all available sources, notably atomic models. Selecting a protocol for EM density-guided integrative structural modeling depends on the resolution and quality of the EM map as well as the available complimentary datasets. Here, we review rigid, flexible, and de novo integrative fitting into EM maps and provide guidelines and considerations for the design of modeling experiments. Finally, we discuss efforts towards establishing unified criteria for map and model assessment and validation. PMID- 24814093 TI - Neural Substrates of Dopamine D2 Receptor Modulated Executive Functions in the Monkey Prefrontal Cortex. AB - Dopamine D2 receptors (D2R) play a major role in cognition, mood and motor movements. Their blockade by antipsychotic drugs reduces hallucinatory and delusional behaviors in schizophrenia, but often fails to alleviate affective and cognitive dysfunctions. The prefrontal cortex (PFC) expresses D2R and is altered in schizophrenia. We investigated how D2R modulate behavior and PFC function in monkeys. Two monkeys learned new and performed highly familiar visuomotor associations, where each cue was associated with a saccade to a right or left target. We recorded neural spikes and local field potentials from multiple electrodes while injecting the D2R antagonist eticlopride in the lateral PFC. Blocking prefrontal D2R impaired associative learning and cognitive flexibility, reduced motivation, but left the performance of familiar associations intact. Eticlopride reduced saccade-direction selectivity of prefrontal neurons, leading to a decrease in neural information about the associations, and an increase in alpha oscillations. These results, together with our recent study using a D1R antagonist, suggest that D1R and D2R in the primate lateral PFC cooperate to modulate several executive functions. Our findings help to gain insight into why antipsychotic drugs, with strong antagonistic actions on D2R, fail to ameliorate cognitive and emotional deficits in schizophrenia. PMID- 24814095 TI - Tissue inhibitor of metalloproteinase-1 and -3 improves cardiac function in an ischemic cardiomyopathy model rat. AB - Matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs) may contribute to myocardial remodeling in heart failure. TIMPs are the main inhibitors of MMPs and have other MMP-independent functions. Because little is known of the role of TIMPs in the heart, we examined the effects of TIMPs on cardiac fibroblasts (CFs) and cardiomyocytes. In vitro, TIMP-1-4 enhanced smooth muscle actin (SMA) expression in CFs, and TIMP-1 and TIMP-3 enhanced the expression of phosphorylated Smad-3 and phosphorylated transforming growth factor (TGF)-beta type 1 receptor in CFs; this effect was inhibited by TGF-beta receptor blocker SB-505124. TIMPs-1, -3, and -4 also inhibited the FAK, AKT, and ERK pathways that induce cardiac hypertrophy. TIMP-1 and TIMP-2 suppressed apoptosis in cardiomyocytes; in contrast, TIMP-4 induced apoptosis in CFs. TIMP-2 stimulated collagen synthesis. Collagen gels containing TIMP-1 or TIMP-3, which exhibit cardioprotective effects in vitro, were transplanted to the left ventricular anterior wall of a rat heart model of myocardial infarction. Gel-released TIMP-1 and TIMP-3 significantly improved cardiac function and myocardial remodeling and enhanced SMA expression in the infarcted area in ischemic cardiomyopathy model rats. Further, the transplantation of TIMP-1 or TIMP-3 gels inhibited apoptosis in the ischemic myocardium and reduced MMP-2 activity. TIMPs may be an ideal target of cardiac regeneration therapy. PMID- 24814096 TI - In vein: blinding bilateral ophthalmic thrombosis. PMID- 24814097 TI - A savage sequence: ST-segment elevations with pulmonary embolism. PMID- 24814098 TI - Lyme borreliosis in southern United Kingdom and a case for a new syndrome, chronic arthropod-borne neuropathy. AB - This series of serologically confirmed Lyme disease is the largest reported in the UK and represents 508 patients who presented to one hospital in the South of England between 1992 and 2012. The mean rate of borreliosis throughout this period was 9.8/100,000 population, much higher than the reported national rate of 1.7/100,000. The actual rate increased each year until 2009 when it levelled off. Patients clinically presented with rash (71%), neurological symptoms (16%, of whom half had VII cranial nerve palsies), arthropathy (8%), pyrexia (5%), cardiac abnormalities (1%) or other manifestations (<1%). Twenty percent of patients had additional non-specific symptoms of fatigue, myalgia, and cognitive changes. Serological diagnosis was with a two-tiered system of ELISA and immunoblot. There was a marked seasonal presentation in the summer months and in the first and sixth decades of life. A third of patients gave a clear history of a tick bite. The median interval between tick bite and clinical symptoms was 15 days [interquartile range (IQR) 9-28 days], with a further interval of 14 days to clinical diagnosis/treatment (IQR 2-31 days). Most cases were acquired locally and only 5% abroad. Patients responded to standard antibiotic therapy and recurrence or persistence was extremely rare. A second group of patients, not included in the clinical case series, were those who believed they had Lyme disease based on a probable tick bite but were seronegative by currently available validated tests and presented with subjective symptoms. This condition is often labelled chronic Lyme disease. These patients have a different disease from Lyme disease and therefore an alternative name, chronic arthropod-borne neuropathy (CAN), and case definition for this condition is proposed. We suggest that this chronic condition needs to be distinguished from Lyme disease, as calling the chronic illness 'Lyme disease' causes confusion to patients and physicians. We recommend research initiatives to investigate the aetiology, diagnosis and therapy of CAN. PMID- 24814099 TI - Upper thermal limits of cardiac function for Arctic cod Boreogadus saida, a key food web fish species in the Arctic Ocean. AB - The objective of this study was to determine the upper thermal limits of Arctic cod Boreogadus saida by measuring the response of maximum heart rate (f(Hmax)) to acute warming. One set of fish were tested in a field laboratory in Cambridge Bay (CB), Nunavut (north of the Arctic Circle), and a second set were tested after air transport to and 6 month temperature acclimation at the Vancouver Aquarium (VA) laboratory. In both sets of tests, with B. saida acclimated to 0 degrees C, f(Hmax) increased during acute warming up to temperatures considerably higher than the acclimation temperature and the near-freezing Arctic temperatures in which they are routinely found. Indeed, f(Hmax) increased steadily between 0.5 and 5.5 degrees C, with no significant difference between the CB and VA tests (P > 0.05) and with an overall mean +/- s.e. Q10 of 2.4 +/- 0.5. The first Arrhenius breakpoint temperature (T(AB)) for f(Hmax) was also statistically indistinguishable for the two sets of tests (mean +/- s.e. 3.2 +/- 0.3 and 3.6 +/ 0.3 degrees C), suggesting that the temperature optimum for B. saida could be reliably measured after live transport to a more southerly laboratory location. Continued warming above 5.5 degrees C revealed a large variability among individuals in the upper thermal limits that triggered cardiac arrhythmia (T(arr)), ranging from 10.2 to 15.2 degrees C with mean +/- s.e. 12.4 +/- 0.4 degrees C (n = 11) for the field study. A difference did exist between the CB and VA breakpoint temperatures when the Q10 value decreased below 2 (the Q10 breakpoint temperature; T(QB)) at 8.0 and 5.5 degrees C, respectively. These results suggest that factors, other than thermal tolerance and associated cardiac performance, may influence the realized distribution of B. saida within the Arctic Circle. PMID- 24814102 TI - Pulp fibroblasts synthesize functional complement proteins involved in initiating dentin-pulp regeneration. AB - The complement system is an efficient plasma immune surveillance system that controls tissue injury and infection. Although the liver constitutes the primary circulating complement protein synthesis site, extrahepatic synthesis is known to optimize local tissue inflammatory reaction. Because dentin-pulp regeneration is known to be regulated locally, we investigated activation of the local complement system within the dental pulp and its role in initiating the regeneration process. Membrane attack complex (C5b-9) formation and Gram's staining revealed that complement activation is correlated with the presence of Gram-positive bacteria in carious human teeth. RT-PCR analysis demonstrated that cultured human pulp fibroblasts stimulated with lipoteichoic acid produce all the proteins required for efficient complement activation. This was demonstrated in vitro by C5b-9 formation and C5a active fragment production in the absence of plasma proteins. Finally, the dynamic migration assays performed in MU-Slide chemotaxis chambers and use of a C5aR-specific antagonist (W54011) demonstrated that the activation of complement proteins synthesized by pulp fibroblasts and the subsequent release of C5a specifically induced pulp progenitor cell recruitment. Our study reveals human pulp fibroblasts as the first nonimmune cell type capable of synthesizing all complement proteins. These fibroblasts cells contribute significantly to tissue regeneration by recruiting pulp progenitors via complement activation, which suggests to a potential therapeutic strategy of targeting pulp fibroblasts in dentin-pulp regeneration. PMID- 24814100 TI - Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study. AB - Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN. PMID- 24814101 TI - IL-19 reduces ligation-mediated neointimal hyperplasia by reducing vascular smooth muscle cell activation. AB - We tested the hypothesis that IL-19, a putative member of the type 2 helper T cell family of anti-inflammatory interleukins, can attenuate intimal hyperplasia and modulate the vascular smooth muscle cell (VSMC) response to injury. Ligated carotid artery of IL-19 knockout (KO) mice demonstrated a significantly higher neointima/intima ratio compared with wild-type (WT) mice (P = 0.04). More important, the increased neointima/intima ratio in the KO could be reversed by injection of 10 ng/g per day recombinant IL-19 into the KO mouse (P = 0.04). VSMCs explanted from IL-19 KO mice proliferated significantly more rapidly than WT. This could be inhibited by addition of IL-19 to KO VSMCs (P = 0.04 and P < 0.01). IL-19 KO VSMCs migrated more rapidly compared with WT (P < 0.01). Interestingly, there was no type 1 helper T-cell polarization in the KO mouse, but there was significantly greater leukocyte infiltrate in the ligated artery in these mice compared with WT. IL-19 KO VSMCs expressed significantly greater levels of inflammatory mRNA, including IL-1beta, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 in response to tumor necrosis factor alpha stimulation (P < 0.01 for all). KO VSMCs expressed greater adhesion molecule expression and adherence to monocytes. Together, these data indicate that IL-19 is a previously unrecognized counterregulatory factor for VSMCs, and its expression is an important protective mechanism in regulation of vascular restenosis. PMID- 24814103 TI - Nurses' and midwives' acquisition of competency in spiritual care: a focus on education. AB - BACKGROUND: The debate that spirituality is 'caught' in practice rather than 'taught' implies that spiritual awareness comes about through clinical experience and exposure, requiring no formal education and integration within the curricula. This is challenged as it seems that providing students with a 'taught' component equips students with tools to identify and strengthen resources in 'catching' the concept. AIM: This study forms part of a modified Delphi study, which aims to identify the predictive effect of pre- and post-registration 'taught' study units in spiritual care competency of qualified nurses/midwives. METHODS: A purposive sample of 111 nurses and 101 midwives were eligible to participate in the study. Quantitative data were collected by the Spiritual Care Competency Scale (SCCS) (Van Leeuwen et al., 2008) [response rate: nurses (89%; n=99) and midwives (74%; n=75)]. RESULTS: Overall nurses/midwives who had undertaken the study units on spiritual care scored higher in the competency of spiritual care. Although insignificant, nurses scored higher in the overall competency in spiritual care than the midwives. CONCLUSION: 'Taught' study units on spiritual care at pre- or post-registration nursing/midwifery education may contribute towards the acquisition of competency in spiritual care. PMID- 24814104 TI - Paulo Friere and the Pedogogy of the Oppressed. PMID- 24814105 TI - An exploration of a restorative space: a creative approach to reflection for nurse lecturer's focused on experiences of compassion in the workplace. AB - This study was undertaken as part of a larger programme of research; the Leadership in Compassionate Care Programme. The aim of this study was to explore and respond to the perceptions of nurse lecturers in regard to experiences of compassion in the workplace. A participatory action research approach was adopted. The study took place in a large school of nursing and midwifery in the United Kingdom, eight lecturers participated in this study. A series of four facilitated reflective workshops titled a restorative space were provided and participants used the medium of collage as a process for reflection. Data was gathered in the form of collages, field and reflective notes. Data analysis involved an iterative process between facilitators and participants during the workshops and resulting actions were implemented. Findings from this study identified three key themes related to compassion in the workplace; leadership, culture, professional and personal development. Actions identified and implemented as a consequence of these findings included opportunities for lecturers to participate in a leadership development programme and implementing rapid feedback processes between lecturers and the senior management team. The restorative space workshops and utilisation of the creative medium of collage provided a valuable process for practitioners to collaboratively reflect on their workplace experiences. PMID- 24814106 TI - Quo vadis cardiology? PMID- 24814107 TI - Coronary stent thrombosis: beware of an allergic reaction and of Kounis syndrome. PMID- 24814108 TI - Characteristics, treatment and one-year outcomes of patients with acute coronary syndrome in a tertiary hospital in India. AB - BACKGROUND: Coronary artery disease (CAD) is a major cause of death in India. Data on outcome of CAD is scarce in the Indian population. This study determined the characteristics, treatment and one-year outcomes of acute coronary syndrome (ACS) in an Indian Cardiac Centre. METHODS: We carried out a cross sectional retrospective analysis of 1468 ACS patients hospitalized between January 2008 and December 2010 and followed up for 1 year in the Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai. Mortality at 1 year, its determinants and 1 year major adverse cardiac events (MACE) were determined. RESULTS: The patients were aged 62.2 +/- 11.2 years; males (75.2%) and had ST segment elevation myocardial infarction (STEMI) (33.9%), non ST segment elevation myocardial infarction (44.2%) and unstable angina (21.9%). Key pharmacotherapy included aspirin (98.2%), clopidogrel (95.1%), statins (95.6%), angiotensin converting enzyme inhibitor/angiotensin receptor blocker (50.6%) and beta blocker (83.1%). Angiography rate was 80.6%. In the STEMI group, 53.3% had primary angioplasty, 20.3% were thrombolysed and 16.1% received sole medical therapy. Overall coronary artery bypass graft rate was 12.4%. At one year, all-cause mortality and composite MACE were 2.5% and 9.7%, respectively. MACE included death (2.5%), reinfarction (4.0%), resuscitated cardiac arrest (1.8%), stroke (1.1%) and bleeding (0.4%). Main factors associated with mortality were combined left ventricular systolic and diastolic dysfunction (OR = 20.0, 95% CI = 6.63 69.4) and positive troponin I (OR = 12.56, 95% CI = 1.78-25.23). Troponin I independently predicted mortality. CONCLUSIONS: ACS population was older than previously described in India. Evidence-based pharmacotherapy and interventions, and outcomes were comparable to the developed nations. PMID- 24814109 TI - Patient profile and results of percutaneous transvenous mitral commissurotomy in mitral restenosis following prior percutaneous transvenous mitral commissurotomy vs surgical commissurotomy. AB - BACKGROUND: Patients with mitral restenosis who have undergone prior PTMC or surgical commissurotomy have increased. Predictors of outcome of repeat PTMC in either subgroup of patients may be different. AIMS AND OBJECTIVES: Aim was to assess and compare the immediate results of PTMC in patients who had undergone a prior PTMC or surgical commissurotomy. METHODS AND RESULTS: This is a single center, prospective, open label study. Of 70 patients in study, 44 (62.85%) patients had prior history of PTMC and 26 (37.15%) had prior surgical commissurotomy (closed/open). Average time from the initial procedure was 8.88 +/ 5.36 years overall, 6.75 +/- 3.38 for patients with prior PTMC and 16.73 +/- 3.67 for patients with prior surgical commissurotomy. Prior PTMC group had 75% female, patients with prior surgical commissurotomy were older (44 +/- 7 vs 33.57 +/- 9.1 years, p = 0.001), had higher NYHA class (III/IV in100% vs 86.36%, p = 0.006.), higher atrial fibrillation (73.1% vs 25% p < 0.0001) and higher Wilkins' score (>8 in 88.46% vs 68.18%, p = 0.05). Successful PTMC was lower (65.4% vs 84.1%) in patients with prior surgical commissurotomy, though statistically not significant (p = 0.07). After PTMC, mitral valve area, PA systolic pressure, LA mean pressure and trans-mitral gradient were similar. Post procedure complications were not different in both the groups. CONCLUSION: PTMC for mitral restenosis in patients with prior surgical valvotomy is as effective as in patients with prior PTMC despite older age, higher NYHA class, higher Wilkins score and atrial fibrillation and can be considered in all patients with restenosis irrespective of the type of past procedures done. PMID- 24814110 TI - A single center multioperator initial experience of 4,195 patients at a primary radial intervention program in a tertiary level center. AB - BACKGROUND: There has been an increase the acceptability and the number of the procedures via the radial approach. We present our experience pertaining to the clinical characteristics, procedural details and post procedural outcome of patients undergoing radial artery access, coronary angiographies over a period of 4 years at a primary care tertiary level center. MATERIALS AND METHODS: A retrospective analysis of all the coronary artery procedures during the last 4 years was done and the various parameters related to these procedures noted. RESULTS: In 4195 procedures performed, success in radial artery procedures was achieved in 3975 (94.8%) procedures. The average puncture time and total procedure time was 9.5 + 3 min (min) and 15 + 2.5 min in the initial 500 patients, whereas the times taken in the final 695 patients were just 1.5 + 0.5 min and 3.0 + 1.5 min respectively. The total fluoroscopy time was not significantly different among the groups, when performed by an operator with training in the femoral route for angiography. Cardiology fellows needed more fluoroscopy time when mastering the radial route. Crossover of access sites was seen in 220 patients (5.2%). CONCLUSIONS: After 100 procedures, radial access coronary angiographies take less than 4.5 min, with first attempt radial artery access and negligible complication rates. Prior experience of coronary angiography helps in the reduction of fluoroscopy time during the learning curve. PMID- 24814111 TI - Assessment of right ventricular strain and strain rate in patients with severe mitral stenosis before and after balloon mitral valvuloplasty. AB - OBJECTIVE: Right ventricular (RV) dysfunction in isolated severe mitral stenosis (MS) patients have prognostic significance. Study aim was to assess RV function in these subjects by strain and strain rate analysis, pre and post-balloon mitral valvuloplasty (BMV). METHODS: Twenty five patients with isolated severe MS in sinus rhythm were assessed for RV function by two dimensional (2D) longitudinal strain & strain rate imaging before and after BMV and compared with that from twelve healthy age matched controls. RESULTS: Patients with severe MS had significantly lower global RV systolic strain; segmental strain at basal, mid, apical septum and basal RV free wall; but similar strain at mid and apical RV free wall as compared to controls. The systolic strain rate was significantly lower only at mid septum. In addition, they had higher estimated pulmonary artery systolic pressure and RV myocardial performance index; lower tricuspid annular plane systolic excursion (TAPSE), peak systolic velocity at lateral tricuspid annulus, isovolumic acceleration and fractional area change (FAC). Global RV systolic strain as well as, segmental strain at basal, mid and apical septum showed a statistically significant rise after BMV. TAPSE and FAC also increased significantly post BMV. CONCLUSIONS: RV systolic function is impaired in patients with severe MS and can be assessed by global and segmental RV strain before the appearance of clinical signs of systemic venous congestion. Impaired global and segmental RV strain values in these patients are primarily due to increased after load and improve after BMV with reduction in RV afterload. PMID- 24814112 TI - B-type natriuretic peptide levels predict extent and severity of coronary artery disease in non-ST elevation acute coronary syndrome and normal left ventricular function. AB - BACKGROUND: B-type natriuretic peptide has been used as a biological marker for prognosis in patients with acute coronary syndrome (ACS). However, a relation between the quantity of BNP levels and the severity of coronary artery disease has not been systematically evaluated. METHODS: 197 patients with ACS without ST elevation with normal LV systolic function were enrolled. BNP was measured in all recruited patients within 12 h of hospitalization. All patients underwent coronary angiography. We correlated BNP levels in patients with unstable angina (USAP) and non ST-elevation myocardial infarction (NSTEMI) with angiographic disease severity including Gensini Score. RESULTS: BNP levels were significantly higher in the NSTEMI group in comparison to the USAP Group (161 +/- 149.3 vs 79.6 +/- 94.2 pg/mL; p < 0.001). BNP levels rose significantly with increasing number of vessels involved (1-vessel = 51.4 +/- 31.6; 2-vessels = 114.0 +/- 67.8; 3 vessels = 265.4 +/- 188.8 pg/mL, p < 0.001). Most importantly, BNP> 80 pg/ml was found to strongly predict the presence of Triple vessel disease (odds ratio 18.87; 95% confidence intervals 5.36-66.36), and Double vessel disease (odds ratio 3.62; 95% confidence intervals 1.75-7.47). In single vessel group, BNP was significantly higher when LAD was involved vessel (64.78 vs 49.76 pg/mL, p < 0.05). Gensini Score showed a strong correlation with BNP levels (r = 0.675, p < 0.01), and Gensini Score was significantly higher in those with BNP> 80 pg/ml (40.9 +/- 29.7 vs 13.4 +/- 16.5 p < 0.001). CONCLUSION: Circulating BNP levels appear elevated in Non ST Elevation ACS, even in the absence of LV systolic dysfunction. High BNP levels are associated with multi-vessel disease and diffuse coronary atherosclerosis. PMID- 24814113 TI - Detection of paroxysmal atrial fibrillation or flutter in patients with acute ischemic stroke or transient ischemic attack by Holter monitoring. AB - BACKGROUND AND PURPOSE: Paroxysmal atrial fibrillation and flutter are strong risk factors for stroke. Due to high recurrence rate of ischemic events and given the benefit of oral anticoagulation over antiplatelet drugs, it is important to identify this arrhythmia. Unfortunately, paroxysmal AF or flutter is asymptomatic in majority and therefore, difficult to detect. METHODS: Consecutive patients presenting with symptoms of acute ischemic stroke or transient ischemic attack were included. All patients free of AF or flutter on presentation underwent 24 h Holter monitoring within 7 days of admission. RESULTS: Overall, fifty two (52) patients (mean age 59.51 +/- 13.45 years) with acute stroke (80.8%) and TIA (19.8%) underwent 24 h Holter monitoring. Paroxysmal AF was detected in 3 cases (5.8%), all 3 patients had acute stroke and were older than age 60 years. Type of stroke was the only factor which was associated with greater risk of having paroxysmal AF or flutter, AF accounted for 50% cases (2 out of 4) of clinically suspected cardio embolic stroke. CONCLUSION: Screening consecutive patients with ischemic stroke with routine Holter monitoring will identify new atrial fibrillation/flutter in approximately one in 17 patients. Older age and type of stroke are strongly associated with increased risk. By carefully selecting the patients, the detection rates could be further increased. PMID- 24814114 TI - Early and mid-term results of minimally invasive coronary artery bypass grafting. AB - INTRODUCTION: Minimally invasive coronary artery bypass grafting (MICABG) is a less invasive method of performing surgical revascularization. This technique coupled with use of off pump technique of surgical revascularization makes it truly less invasive. This method is highly effective even in high-risk patients. Results of this procedure are comparable to standard off pump technique and are better than percutaneous coronary intervention utilizing drug-eluting stent. We present an early and mid-term result of the use of this technique. METHOD: We enrolled 33 patients for analysis operated between 2008 and 2012. Operation was performed utilizing off-pump technique of coronary artery bypass grafting through a minimal invasive incision. Left internal mammary artery graft was done for single vessel disease and radial artery was utilized for other grafts if required. Median follow up of 2.5 years (6 months-4 years) is available. RESULTS: Median age was 58.5 years (41-77) and all were male. Single vessel disease was present in 7, double vessel in 14 and triple vessel disease in 12 patients. All the patients had normal left ventricular size and function. There was no operative and 30-day mortality. Conversion to median sternotomy to complete the operation was done in 6.6% (2 out of 33 patients). One patient had acute myocardial infarction and there were no deaths during follow up. CONCLUSION: MICABG is a safe and effective method of revascularization in low risk candidates for coronary artery bypass grafting. PMID- 24814115 TI - Study of clinical profile and management of patients with pulmonary embolism - single center study. AB - OBJECTIVE: To study the clinical profile, diagnostic methods and management in patients with symptomatic pulmonary embolism (PE). METHODS: Retrospective assessment of clinical features and management of patients presenting with symptomatic pulmonary embolism from January 2005 to March 2012. RESULTS: 35 patients who were newly diagnosed to have pulmonary embolism with a mean age of 52.1 years were included in the study. Dyspnea (91.4%) and syncope (22.8%) were the predominant symptoms. Echocardiography was done in all patients. 30 patients (85.7%) had pulmonary arterial hypertension, 31 patients (88.5%) had evidence of RV dysfunction and 4 patients (16.7%) had evidence of thrombus in PA, RV. Out of 35 patients, 34 patients (97.14%) showed positive d-dimer reports. Among 35 patients, 24 (68.5%) had positive troponin values. V/Q scan was done in 14 patients (40%) and CT pulmonary angiogram (CTPA) was done in 24 patients (68.5%.). Thrombolysis was done is 24 patients (68.5%). All patients received low molecular weight heparin followed by warfarin. Of the 35 patients, 34 (97.1%) were discharged and were under regular follow up for 6 months and one patient died during the hospital stay. CONCLUSION: Pulmonary embolism is a common problem and can be easily diagnosed provided it is clinically suspected. Early diagnosis and aggressive management is the key to successful outcome. PMID- 24814116 TI - Off-pump coronary artery bypass grafting in India. AB - Off-pump Coronary Artery Bypass Grafting (OPCAB) is the latest innovation in cardiac surgery. However OPCAB is not adopted universally. Even there have been suggestions of abandoning OPCAB in a special report. In India, OPCAB has been successfully adopted across the board. There are various evidences which favor OPCAB and are discussed in this review. The purpose of this review is to put forward the perspective of the OPCAB surgeons of our country and critically look at the suggestion of abandoning OPCAB. PMID- 24814117 TI - Transcatheter aortic valve implantation under conscious sedation - the first Indian experience. AB - Transcatheter aortic valve implantation (TAVI) is maturing strongly as an alternative to surgical aortic valve replacement (SAVR) in patients who are inoperable/high risk for open heart surgery. General anesthesia (GA) is the usual mode of anesthesia in these patients, but local anesthesia with conscious sedation (LACS) has recently been described as a safe alternative with some added advantages. We report 2 cases who were unfit for GA and were done successfully under LACS. PMID- 24814118 TI - Percutaneous balloon pulmonary valvuloplasty: a modified over-the-wire Inoue balloon technique for difficult right ventricular anatomy. AB - Percutaneous balloon pulmonary valvuloplasty (BPV) is the mainstay of treatment for significant pulmonary stenosis with doming leaflets. Various techniques have been described in the literature including the use of Inoue Percutaneous Transseptal Mitral Commissurotomy (PTMC) catheter with standard 0.025" guidewire. But if right ventricular anatomy is not suitable, 0.025" guidewire doesn't provide enough support to track the Inoue PTMC catheter. Here, we report a case of successful BPV using a novel technique of slenderizing the Inoue Percutaneous Transseptal Mitral Commissurotomy (PTMC) catheter over an Amplatz superstiff 0.035" guidewire. This technique may be useful during BPV in difficult right ventricular inflow and outflow tract anatomy in patients with congenital pulmonary valve stenosis. PMID- 24814119 TI - Anomalous origin of left circumflex artery from pulmonary artery. PMID- 24814120 TI - Stent thrombosis with an aneurysm 7 years after a drug eluting stent implantation. AB - We report a case of very late stent thrombosis 7 years post sirolimus eluting stent implantation presenting as ST elevation MI while on dual antiplatelet therapy. Angiography revealed an aneurysm at the proximal end of the stent. The patient was managed successfully by primary percutaneous coronary intervention (PCI) with adjunct thrombus aspiration and intracoronary abciximab administration followed by deploying a mesh-covered stent MGuard. This very late complication is a rare presentation after a drug illuting stent (DES). PMID- 24814121 TI - Case report of isolated congenital absence of right pulmonary artery with collaterals from coronary circulation. AB - Isolated unilateral absence of a proximal pulmonary main artery is a rare congenital lesion which is often associated with other cardiovascular abnormalities and a diverse clinical presentation. It is usually diagnosed in childhood. Patients who survive into adulthood is uncommon. We report a case of 46 year old hypertensive and obese female who presented with progressive dyspnea. She had features of pulmonary hypertension. The diagnosis was confirmed by CT pulmonary angiography which showed absence of right pulmonary artery and conventional pulmonary angiography which showed ipsilateral lung receiving collaterals from Right coronary artery and its branches. The purpose of this report is to highlight the fact that UAPA, although a rare entity, should be kept in mind in patients with unexplained PAH and prolonged respiratory symptoms unresponsive to routine treatment modalities. PMID- 24814122 TI - Peripartum cardiomyopathy - case series. AB - OBJECTIVES: To study the pattern of presentation, course of disease and outcome of pregnancy in Peripartum Cardiomyopathy. METHODS: A prospective study of sixteen cases of PPCM was conducted at Apple Saraswati Multispecialty Hospital and Dr. D.Y. Patil Medical College and Hospital, Kolhapur, Maharashtra, India from January 2006 to December 2012. Data included age distribution, parity, gestational age, symptoms and risk factors. Medical management and pregnancy outcome were documented. Serial echocardiography data was compiled for a period of one year. RESULTS: In our study 9/16 (56%) were primigravidae, 4/16 (25%) had pre-eclamsia and 6/16 (35%) had co-existing hypertension. The difference in Echocardiography parameters observed between recovered and non-recovered patients was significant: Left Ventricular End diastolic dimension (5.6 cm vs 6.06 cm), Left Ventricular Ejection Fraction (28.7% vs 22.4%) and Left Ventricular fractional shortening (17.5% vs 13.4%). Thirteen out of sixteen patients were followed up for a period of one year out of which 61% (8/13) patients recovered completely. There was one mortality. CONCLUSION: PPCM is a diagnosis of exclusion. Majority were young primigravidae presenting postnatally. Pre eclampsia and hypertension were risk factors. ECHO parameters were reliable predictors of recovery. Future pregnancies are better avoided. PMID- 24814123 TI - Post Blalock-Taussig shunt mediastinal mass - a single shadow with two different destinies. AB - The modified Blalock-Taussig shunt is a synthetic shunt between the subclavian and pulmonary artery, used in the treatment of congenital cyanotic heart diseases with pulmonary hypoperfusion. Delayed complications include progressive failure of the shunt, serous fluid leak, and pseudoaneurysm formation. We report two different and rare mediastinal vascular complications following modified BT shunt surgery in this case report. The first one is a seroma, due to serous fluid leakage through the shunt graft, which is a relatively benign complication. The second one is a pseudoaneurysm, arising from the shunt, a frequently fatal complication. Generally, X-ray chest is used for screening in these patients. CT angiography plays a vital role in the diagnosis of both these conditions. Management in pseudoaneurysm should be aggressive, as timely intervention may be life saving, while in seroma the management is most often conservative occasionally requiring surgical intervention. PMID- 24814124 TI - Left circumflex to right atrial coronary arterio-venous fistula - role of multimodality imaging for diagnosis. AB - We report an interesting case presenting with progressive dyspnea and palpitations. The patient underwent multimodal imaging procedures consisting of two dimensional echocardiography, MRI, cardiac catheterization and also a three dimensional transesophageal echocardiographic reconstruction. All the investigations taken together helped us in finally arriving at accurate anatomical diagnosis of a coronary AV fistula from the left circumflex artery to the right atrium. The patient finally underwent a successful non-surgical closure using an Amplatzer device. The role of three-dimensional echocardiographic evaluation in defining the anatomy for planning the treatment is emphasized. PMID- 24814125 TI - Esophageal-left atrial fistula: an unsual cause. AB - A 55-year-old male presented with progressive dyspnea, swelling of legs and abdominal distension for past one week. Routine investigation showed presence of large pericardial effusion. Pericardiocentesis tapped a yellow colored sterile fluid with predominant polymorphs. However sequence of events following pericardiocentesis were unusual as patient developed stroke. MRI brain and CECT thorax were done. MRI brain showed small infarct and CECT showed presence of open safety pin eroding through esophagus and communicating with left atrium with thrombus and an air pocket within. Patient developed progressive encephalopathy and CT brain revealed multiple infarcts with pneumocephalus. PMID- 24814126 TI - Aspergilloma of the heart. PMID- 24814127 TI - Malignant phyllodes tumor of the left atrium. AB - Metastatic tumors to the heart usually involve right sided chambers. We report a rare case of malignant phyllodes tumor of breast with metastatic involvement of left atrium occurring through direct invasion from mediastinal micro-metastasis and presenting as a left atrial mass causing arrhythmia. PMID- 24814128 TI - Cardiac magnetic resonance imaging for non-invasive diagnosis of lipomatous hypertrophy of inter-atrial septum. AB - A 71-year-old asymptomatic woman is found to have an incidental cardiac mass on transthoracic echocardiography. Cardiac magnetic resonance (CMR) findings are consistent with lipotamous hypertrophy of the inter-atrial septum. Given the characteristic appearances on CMR, biopsy or surgery was not indicated and the patient was managed conservatively. PMID- 24814129 TI - Optical coherence tomogram of spontaneous coronary artery dissection managed with drug eluting stent. PMID- 24814130 TI - Letter to the editor for sponsored article "pharmacologic reperfusion therapy with indigenous tenecteplase in 15,222 patients with ST elevation myocardial infarction - the Indian registry" by Iyengar et al. PMID- 24814131 TI - Rejoinder. PMID- 24814132 TI - Successful treatment of aortic prosthetic valve thrombosis with bolus dose Tenecteplase. PMID- 24814133 TI - Cardiology blooms at ACC 2014 at Washington DC but no cherry blossoms. PMID- 24814134 TI - Target hematologic values in the management of essential thrombocythemia and polycythemia vera. AB - Treatment of essential thrombocythemia (ET) and polycythemia vera (PV) is aimed at preventing vascular complications, which are the main cause of morbidity and mortality in these diseases. Over the years, clinical trials have demonstrated that the incidence of thrombosis and bleeding can be reduced by controlling the blood cell counts, but the target hematological levels have varied across the studies. In this article, we review the evidence supporting the use of predefined target hematologic values for the management of ET and PV in routine clinical practice. At present, the recommended target hematocrit in PV is below 45%, regardless of the patients' risk profile. Concerning platelet counts, no direct correlation has been demonstrated with thrombotic risk in either ET or PV. Thus, although cytoreductive treatment reduces the rate of vascular complications in high-risk patients, no particular threshold of the platelet counts has been shown to be more protective against thrombosis. Extreme thrombocytosis is a risk factor for bleeding, particularly when aspirin or anagrelide are given. Leukocytosis at baseline or during follow-up appears to be a risk factor for thrombosis, mostly in high-risk patients. However, the clinical benefit of strictly controlling this parameter is not yet established. Finally, standardized definitions of response to cytoreductive treatment in ET and PV have recently been published. Nevertheless, they have been produced to compare the efficacy of new therapies in clinical trials, whereas its relevance in clinical practice has been questioned in retrospective studies showing that such response definitions do not correlate with the patients' clinical outcome. PMID- 24814135 TI - Blunting of the HPA-axis underlies the lack of preventive efficacy of early post stressor single-dose Delta-9-tetrahydrocannabinol (THC). AB - The therapeutic value of Delta-9-tetrahydrocannabinol (Delta9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Delta9-THC administered intraperitoneally following exposure to psychogenic stress. Animals were exposed to predator scent stress and treated 1h later with Delta9-THC (1, 5 and 10mg/kg) or vehicle. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 1, 6 and 24 h or 7 days after exposure and freezing behavior upon exposure to a trauma cue on day 8. Pre-set cut-off behavioral criteria classified exposed animals as those with "extreme," "minimal" or "intermediate" (partial) response. Circulating corticosterone levels were assessed over 2h after exposure with and without Delta9-THC. The behavioral effects of a CB1 antagonist (AM251) administered systemically 1h post exposure were evaluated. In the short term (1-6 h), 5 mg/kg of Delta9-THC effectively attenuated anxiety-like behaviors. In the longer-term (7 days), it showed no effect in attenuating PTSD-like behavioral stress responses, or freezing response to trauma cue. Delta9-THC significantly decreased corticosterone levels. In contrast, administration of AM251 (a CB1 antagonist/inverse agonist) 1 h post exposure attenuated long-term behavioral stress responses through activation of the HPA-axis. The demonstrated lack of preventive efficacy of early Delta9-THC treatment and reports of its anxiogenic effects in many individuals raises doubts not only regarding its potential clinical value, but also the advisability of clinical trials. The endocannabinoids exert complex effects on behavioral responses mediating glucocorticoid effects on memory of traumatic experiences. PMID- 24814136 TI - Longitudinal micromorphological 15-year results of posterior composite restorations using three-dimensional scanning electron microscopy. AB - OBJECTIVES: Hybrid composite restorations in posterior teeth were evaluated over 15 years using the semiquantitative Clinical, Photographic and Micromorphologic (CPM) index. It was a further aim to quantitate the surface morphology by three dimensional scanning electron microscopy (3D-SEM). METHODS: Thirty seven hybrid composite restorations (Ketac-Bond/Visio-Molar X, ESPE, Seefeld/Germany) were longitudinally followed up. Parallel to clinical assessment replicas were taken at baseline, after 1, 5, 10 and 15 years and evaluated by SEM, and profilometrical analyses of 3D-SEM data were computed. The profilometrical results were statistically analysed by ANOVA. The level of significance was set to p<0.05. RESULTS: The semiquantitative micromorphological evaluation exhibited the most considerable deterioration within the first year and up to 5 years of function. Less change was detected during the next 10 years. The profilometrical quantification showed raising depth of the negative marginal ledges with a mean of 27.2MUm (range 0.6-94.5MUm) after 10 years, with no statistically significant changes from 5 to 10 and 10 to 15 years. The 3D-SEM revealed marginal grooves beneath the level of the ledges (mean 34.5MUm after 5 years) within the bonding zone, exposing enamel margins. Leakages, marginal fractures and surface roughness did not seriously deteriorate the quality of restorations. CONCLUSIONS: Hybrid composite restorations of Class I and II cavities surviving the first five years performed well over 15 years of function. Quantitative 3D-SEM profilometrical measurements revealed the dynamics of marginal behaviour over time. CLINICAL SIGNIFICANCE: Long-term parallel clinical and micromorphological evaluation of posterior composite restorations of Class I and Class II cavities documented the clinical safety and acceptable longevity. The longitudinal 3D micromorphologic assessment of the surface changes and of the marginal behaviour revealed deteriorating as well as improving factors hidden in clinical performance. PMID- 24814137 TI - In vivo comparative model of oxygen plasma and nanocomposite particles on PLGA membranes for guided bone regeneration processes to be applied in pre-prosthetic surgery: a pilot study. AB - OBJECTIVES: To evaluate the bone regeneration potential of a new membrane fabricated with polyglycolide acid (PLGA) after being treated with oxygen plasma (PO2), and/or being functionalized with silicon dioxide (SiO2) or titanium dioxide (TiO2) nanoparticles. METHODS: Bone defects (5 mm 3 mm) were produced on the top of 3 experimentation rabbits' skulls and were covered with variously modified PLGA scaffolds. After the animals were sacrificed, neoformed bone (%), mineralized bone (mm), bone resorption (%), osteoclasts/mm2, and intensity of osteosynthetic activity, were assessed under microscope. RESULTS: The following groups were formed depending on the type of membrane: PLGA (control); PLGA/PO2; PLGA/SiO2; PLGA/TiO2; PLGA/PO2/SiO2; and PLGA/PO2/TiO2. The histological sections showed bone layers in advanced stages of formation. The highest percentages of neoformed bone corresponded to PLGA/PO2/SiO2 membranes (59.07%; p = 0.31) followed by PLGA/PO2 barriers (50.27%). The controls showed the lowest mineralization (13.89 mm; p = 0.24). PLGA/TiO2 scaffolds exhibited the least bone resorption (4.45%; p = 0.77) and osteoclasts/ mm2 (1.58; p = 0.86). PLGA/SiO2 and PLGA/TiO2 membranes stimulated the maximum osteosynthetic activity. CONCLUSIONS: The treatment of PLGA barriers with PO2 increased bone regeneration in rabbits. When comparing the effect of PO2/SiO2 and PO2/TiO2, higher percentages of neoformed bone were encountered after silicon-dioxide coating. CLINICAL SIGNIFICANCE: The incorporation of SiO2 nanoparticles onto PO2-treated PLGA membranes was the most promising technique out of those investigated to promote bone formation in rabbits. The addition of SiO2 or TiO2 layers to PLGA substrates may stimulate the osteosynthetic activity, which might be useful to restore bone dimensions in preparation for naturally appearing dental prostheses. PMID- 24814138 TI - Bonding performance of universal adhesives in different etching modes. AB - OBJECTIVES: The aim of this study was to compare the microtensile bond strength (MUTBS) and resin penetration into dentine of three universal adhesives (UAs) applied in two different etching modes (i.e. self-etch or etch-and-rinse). The effect of thermocycling on the MUTBS was also evaluated. METHODS: The occlusal third of sound human molars was removed and the exposed surfaces were treated with three UAs (Futurabond Universal, Scotchbond Universal Adhesive and All-Bond Universal) in self-etch or etch-and-rinse mode. Two one-step self-etch adhesives (Futurabond DC and Futurabond M) were applied on additional teeth as reference. After composite build up, the specimens were stored for 24 h in distilled water at 37 degrees C or thermocycled for 5000 cycles. Composite/dentine beams were prepared (1 mm(2)) and MUTBS test was performed. Data was analyzed using three way ANOVA and Tukey's test (alpha=0.05). One additional tooth was prepared for each group for evaluation of infiltration ability into dentine by dyeing the adhesives with a fluorochrome (Rhodamine B). After longitudinal sectioning, the generated interfaces were examined under confocal laser scanning microscopy. RESULTS: The addition of an etching step did not significantly affect the MUTBS of none of the UAs, when compared to their self-etch application mode. All pre etched specimens showed considerably longer resin tags and thicker hybrid layers. Thermocycling had no significant effect on the MUTBS of the UAs. CONCLUSIONS: Application of an etching step prior to UAs improves their dentine penetration, but does not affect their bond strength to dentine after 24h or after thermocycling for 5000 cycles. CLINICAL SIGNIFICANCE: Similar bond strength values were observed for the UAs regardless of application mode, which makes them reliable for working under different clinical conditions. PMID- 24814139 TI - A recently-discovered NMDA receptor gene, GRIN3B, is associated with duration mismatch negativity. AB - The study explored associations between mismatch negativity and N-methyl-d aspartic acid receptor subunit genes, GRIN1, GRIN2B and GRIN3B in healthy subjects and schizophrenia. Nineteen single-nucleotide polymorphisms were genotyped in 138 schizophrenia patients and 103 healthy subjects. Rs2240158 of GRIN3B was significantly associated with mismatch negativity in healthy subjects. PMID- 24814140 TI - Negative symptoms and everyday functioning in schizophrenia: a cross-sectional study in a real world-setting. AB - Negative symptoms have been suggested to have a greater impact on real-world functioning in schizophrenia than other symptoms. We aimed to examine the relationship of specific negative symptoms components ("expressive deficits" - DE - which include alogia and blunted affect, and "avolition" - AA - which includes amotivation, anhedonia, and asociality), with separate domains of real-world outcomes (the Personal and Social Performance Scale - PSP - and selected items of the Heinrichs Quality of Life Scale - QLS - that did not overlap with negative symptoms) and two functional milestones (recent employment and marriage). Regression analyses were performed to identify the determinants of QLS and PSP scores and of the two milestones, in 92 consecutive outpatients with stable schizophrenia. AA was the strongest predictor of QLS interpersonal relations and social network (IRSN), PSP total score and the first three PSP domains. The variance explained ranged from 36% for PSP self care to 54% for the PSP personal and social relationships. Moreover, higher scores in AA were significant predictors of the single status. DE does not appear to have an impact at real world functional performance. Taken together, our analysis indicates a relatively specific set of relationships between the AA subdomain and aspects of real-world functioning in schizophrenia. These findings, if confirmed, could have important implications for research, diagnostics and treatment: in fact our results would suggest that AA and DE should be analyzed as separate and distinct domains to be rated and treated individually. PMID- 24814141 TI - Promoter variation in the catechol-O-methyltransferase gene is associated with remission of symptoms during fluvoxamine treatment for major depression. AB - We investigated the association between remission of depressive symptoms in fluvoxamine treatment and catechol-O-methyltransferase (COMT) gene. Sixteen SNPs in the COMT gene were investigated in 123 outpatients with major depression. Three single nucleotide polymorphisms located in the 5' region were associated with remission in fluvoxamine-treated outpatients with moderate to severe depression. PMID- 24814142 TI - Gender differences in oxytocin-associated disruption of decision bias during emotion perception. AB - Oxytocin is associated with differences in the perception of and response to socially mediated information, such as facial expressions. Across studies, however, oxytocin's effect on emotion perception has been inconsistent. Outside the laboratory, emotion perception involves interpretation of perceptual uncertainty and assessment of behavioral risk. An account of these factors is largely missing from studies of oxytocin's effect on emotion perception and might explain inconsistent results across studies. Of relevance, studies of oxytocin's effect on learning and decision-making indicate that oxytocin attenuates risk aversion. We used the probability of encountering angry faces and the cost of misidentifying them as not angry to create a risky environment wherein bias to categorize faces as angry would maximize point earnings. Consistent with an underestimation of the factors creating risk (i.e., encounter rate and cost), men given oxytocin exhibited a worse (i.e., less liberal) response bias than men given placebo. Oxytocin did not influence women's performance. These results suggest that oxytocin may impair men's ability to adapt to changes in risk and uncertainty when introduced to novel or changing social environments. Because oxytocin also influences behavior in non-social realms, oxytocin pharmacotherapy could have unintended consequences (i.e., risk-prone decision-making) while nonetheless normalizing pathological social interaction. PMID- 24814143 TI - The search for novel therapeutic strategies in the treatment of recurrent glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with <=10% patients surviving 5 years from the time of diagnosis. After tumor progression on frontline therapy with concomitant chemoradiotherapy followed by consolidation temozolomide there are few effective treatment options. Bevacizumab and nitrosureas are the most commonly used systemic options in this instance but no overall survival benefit has been demonstrated. In this review we outline the major avenues of research for treatment of recurrent GBM including anti-angiogenic, signaling pathway blockade and immunotherapy approaches. Results of recent trials as well as pertinent ongoing studies are discussed. Enrollment of patients to clinical trials as well as incorporation of correlative translational science studies to identify predictive biomarkers of treatment response will be key to improving outcomes in this devastating disease. PMID- 24814144 TI - Nonmuscle myosin II isoforms coassemble in living cells. AB - Nonmuscle myosin II (NM II) powers myriad developmental and cellular processes, including embryogenesis, cell migration, and cytokinesis [1]. To exert its functions, monomers of NM II assemble into bipolar filaments that produce a contractile force on the actin cytoskeleton. Mammalian cells express up to three isoforms of NM II (NM IIA, IIB, and IIC), each of which possesses distinct biophysical properties and supports unique as well as redundant cellular functions [2-8]. Despite previous efforts [9-13], it remains unclear whether NM II isoforms assemble in living cells to produce mixed (heterotypic) bipolar filaments or whether filaments consist entirely of a single isoform (homotypic). We addressed this question using fluorescently tagged versions of NM IIA, IIB, and IIC, isoform-specific immunostaining of the endogenous proteins, and two color total internal reflection fluorescence structured-illumination microscopy, or TIRF-SIM, to visualize individual myosin II bipolar filaments inside cells. We show that NM II isoforms coassemble into heterotypic filaments in a variety of settings, including various types of stress fibers, individual filaments throughout the cell, and the contractile ring. We also show that the differential distribution of NM IIA and NM IIB typically seen in confocal micrographs of well polarized cells is reflected in the composition of individual bipolar filaments. Interestingly, this differential distribution is less pronounced in freshly spread cells, arguing for the existence of a sorting mechanism acting over time. Together, our work argues that individual NM II isoforms are potentially performing both isoform-specific and isoform-redundant functions while coassembled with other NM II isoforms. PMID- 24814145 TI - Large-scale metagenomic-based study of antibiotic resistance in the environment. AB - Antibiotic resistance, including multiresistance acquisition and dissemination by pathogens, is a critical healthcare issue threatening our management of infectious diseases [1-3]. Rapid accumulation of resistance phenotypes implies a reservoir of transferable antibiotic resistance gene determinants (ARGDs) selected in response to inhibition of antibiotic concentrations, as found in hospitals [1, 3-5]. Antibiotic resistance genes were found in environmental isolates, soil DNA [4-6], secluded caves [6, 7], and permafrost DNA [7, 8]. Antibiotics target essential and ubiquitous cell functions, and resistance is a common characteristic of environmental bacteria [8-11]. Environmental ARGDs are an abundant reservoir of potentially transferable resistance for pathogens [9 12]. Using metagenomic sequences, we show that ARGDs can be detected in all (n=71) environments analyzed. Soil metagenomes had the most diverse pool of ARGDs. The most common types of resistances found in environmental metagenomes were efflux pumps and genes conferring resistance to vancomycin, tetracycline, or beta-lactam antibiotics used in veterinary and human healthcare. Our study describes the diverse and abundant antibiotic resistance genes in nonclinical environments and shows that these genes are not randomly distributed among different environments (e.g., soil, oceans or human feces). PMID- 24814146 TI - Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut. AB - BACKGROUND: Enteroendocrine cells populate gastrointestinal tissues and are known to translate local cues into systemic responses through the release of hormones into the bloodstream. RESULTS: Here we report a novel function of enteroendocrine cells acting as local regulators of intestinal stem cell (ISC) proliferation through modulation of the mesenchymal stem cell niche in the Drosophila midgut. This paracrine signaling acts to constrain ISC proliferation within the epithelial compartment. Mechanistically, midgut enteroendocrine cells secrete the neuroendocrine hormone Bursicon, which acts-beyond its known roles in development as a paracrine factor on the visceral muscle (VM). Bursicon binding to its receptor, DLGR2, the ortholog of mammalian leucine-rich repeat-containing G protein-coupled receptors (LGR4-6), represses the production of the VM-derived EGF-like growth factor Vein through activation of cAMP. CONCLUSIONS: We therefore identify a novel paradigm in the regulation of ISC quiescence involving the conserved ligand/receptor Bursicon/DLGR2 and a previously unrecognized tissue intrinsic role of enteroendocrine cells. PMID- 24814147 TI - Chromosomal rearrangements as a major mechanism in the onset of reproductive isolation in Saccharomyces cerevisiae. AB - Understanding the molecular basis of how reproductive isolation evolves between individuals from the same species offers valuable insight into patterns of genetic differentiation as well as the onset of speciation [1, 2]. The yeast Saccharomyces cerevisiae constitutes an ideal model partly due to its vast ecological range, high level of genetic diversity [3-6], and laboratory-amendable sexual reproduction. Between S. cerevisiae and its sibling species in the Saccharomyces sensu stricto complex, reproductive isolation acts postzygotically and could be attributed to chromosomal rearrangements [7], cytonuclear incompatibility [8, 9], and antirecombination [10, 11], although the implication of these mechanisms at the incipient stage of speciation remains unclear due to further divergence in the nascent species. Recently, several studies assessed the onset of intraspecific reproductive isolation in S. cerevisiae by evaluating the effect of the mismatch repair system [12-14] or by fostering incipient speciation using the same initial genetic background [15-18]. Nevertheless, the overall genetic diversity within this species was largely overlooked, and no systematic evaluation has been performed. Here, we carried out the first species-wide survey for postzygotic reproductive isolation in S. cerevisiae. We crossed 60 natural isolates sampled from diverse niches with the reference strain S288c and identified 16 cases of reproductive isolation with reduced offspring viabilities ranging from 44% to 86%. Using different mapping strategies, we identified reciprocal translocations in a large fraction of all isolates surveyed, indicating that large-scale chromosomal rearrangements might play a major role in the onset of reproductive isolation in this species. PMID- 24814148 TI - Proteins of the ciliary axoneme are found on cytoplasmic membrane vesicles during growth of cilia. AB - The cilium is a specialized extension of the cell in which many specific proteins are admitted and retained, while many others are excluded or expelled. In order to maintain the organelle, the cell must possess mechanisms for the selective gating of protein entry, as well as for the targeted transport of proteins to the cilium from their sites of synthesis within the cell [1-4]. We hypothesized that the cell employs cytoplasmic vesicles as vehicles not only for the transport of proteins destined for the ciliary membrane but also for the transport of axonemal proteins to the cilium by means of peripheral association with vesicles. To test this hypothesis, we employed two different experimental strategies: (1) isolation and biochemical characterization of cytoplasmic vesicles that carry ciliary proteins, and (2) in situ localization of ciliary proteins on cytoplasmic vesicle surfaces using gold labeling and electron microscopy. Our findings indicate that structural proteins destined for the ciliary axoneme are attached to the outer surfaces of cytoplasmic vesicles that carry integral ciliary membrane proteins during the process of ciliary growth. PMID- 24814149 TI - Nociceptive sensitization reduces predation risk. AB - Sublethal injury triggers long-lasting sensitization of defensive responses in most species examined, suggesting the involvement of powerful evolutionary selection pressures [1]. In humans, this persistent nociceptive sensitization is often accompanied by heightened sensations of pain and anxiety [2]. While experimental [3] and clinical [4] evidence support the adaptive value of immediate nociception during injury, no direct evidence exists for adaptive benefits of long-lasting sensitization after injury. Recently, we showed that minor injury produces long-term sensitization of behavioral and neuronal responses in squid, Doryteuthis pealei [5, 6]. Here we tested the adaptive value of this sensitization during encounters between squid and a natural fish predator. Locomotion and other spontaneous behaviors of squid that received distal injury to a single arm (with or without transient anesthesia) showed no measurable impairment 6 hr after the injury. However, black sea bass given access to freely swimming squid oriented toward and pursued injured squid at greater distances than uninjured squid, regardless of previous anesthetic treatment. Once targeted, injured squid began defensive behavioral sequences [7, 8] earlier than uninjured squid. This effect was blocked by brief anesthetic treatment that prevented development of nociceptive sensitization [6, 9]. Importantly, the early anesthetic treatment also reduced the subsequent escape and survival of injured, but not uninjured, squid. Thus, while minor injury increases the risk of predatory attack, it also triggers a sensitized state that promotes enhanced responsiveness to threats, increasing the survival (Darwinian fitness) of injured animals during subsequent predatory encounters. PMID- 24814150 TI - Impact of care pathway-based approach on outcomes in a specialist intellectual disability inpatient unit. AB - Specialist intellectual disability inpatient units have come under increased scrutiny, leading to questions about the quality of service provision in this sector. A care pathway-based approach was implemented in such a unit and its impact on outcome variables was measured. The care pathway-based approach resulted in the turnover of more patients, increased capacity for admissions to the unit, reduced lengths of stay in hospital, timely assessments and treatments, which resulted in better outcomes in patients. Care pathway-based approach to service provision provides not only better outcomes in patients but also a reliable way of ensuring true multi-agency working and accountability. If used widely, it can reduce the variability in the quality of current service provision. PMID- 24814151 TI - Systemic administration of a recombinant AAV1 vector encoding IGF-1 improves disease manifestations in SMA mice. AB - Spinal muscular atrophy is a progressive motor neuron disease caused by a deficiency of survival motor neuron. In this study, we evaluated the efficacy of intravenous administration of a recombinant adeno-associated virus (AAV1) vector encoding human insulin-like growth factor-1 (IGF-1) in a severe mouse model of spinal muscular atrophy. Measurable quantities of human IGF-1 transcripts and protein were detected in the liver (up to 3 months postinjection) and in the serum indicating that IGF-1 was secreted from the liver into systemic circulation. Spinal muscular atrophy mice administered AAV1-IGF-1 on postnatal day 1 exhibited a lower extent of motor neuron degeneration, cardiac and muscle atrophy as well as a greater extent of innervation at the neuromuscular junctions compared to untreated controls at day 8 posttreatment. Importantly, treatment with AAV1-IGF-1 prolonged the animals' lifespan, increased their body weights and improved their motor coordination. Quantitative polymerase chain reaction and western blot analyses showed that AAV1-mediated expression of IGF-1 led to an increase in survival motor neuron transcript and protein levels in the spinal cord, brain, muscles, and heart. These data indicate that systemically delivered AAV1-IGF-1 can correct several of the biochemical and behavioral deficits in spinal muscular atrophy mice through increasing tissue levels of survival motor neuron. PMID- 24814153 TI - Applications of imaging fluorescence correlation spectroscopy. AB - Imaging fluorescence correlation spectroscopy (imaging FCS), or the acquisition of fluorescence correlation functions at contiguous points in an imaging format, is a recent addition to quantitative bioimaging. Imaging FCS has been implemented in various modalities. These techniques provide excellent time resolution, have single molecules sensitivity and can be combined with super-resolution techniques, thus combining high spatial and temporal resolution. Although still at its beginning it has been applied in different forms to biological problems. This review looks at applications of imaging FCS in the last two years with the aim to give the reader an overview of the capabilities of these new techniques. PMID- 24814152 TI - Efficient transient genetic manipulation in vitro and in vivo by prototype foamy virus-mediated nonviral RNA transfer. AB - Vector systems based on different retroviruses are widely used to achieve stable integration and expression of transgenes. More recently, transient genetic manipulation systems were developed that are based on integration- or reverse transcription-deficient retroviruses. Lack of viral genome integration is desirable not only for reducing tumorigenic potential but also for applications requiring transient transgene expression such as reprogramming or genome editing. However, all existing transient retroviral vector systems rely on virus-encoded encapsidation sequences for the transfer of heterologous genetic material. We discovered that the transient transgene expression observed in target cells transduced by reverse transcriptase-deficient foamy virus (FV) vectors is the consequence of subgenomic RNA encapsidation into FV particles. Based on this initial observation, we describe here the establishment of FV vectors that enable the efficient transient expression of various transgenes by packaging, transfer, and de novo translation of nonviral RNAs both in vitro and in vivo. Transient transgene expression levels were comparable to integrase-deficient vectors but, unlike the latter, declined to background levels within a few days. Our results show that this new FV vector system provides a useful, novel tool for efficient transient genetic manipulation of target tissues by transfer of nonviral RNAs. PMID- 24814154 TI - Transition from hospital to home following pediatric solid organ transplant: qualitative findings of parent experience. AB - Transplant providers are challenged to determine appropriate interventions for patients and families due to limited published research regarding the context of the post-discharge experience from the perspective of parents of transplanted children. The purpose of this study is to describe the parent perspective of the transition from hospital to home following their child's solid organ transplant. Within a mixed-methods design, 37 parents of pediatric heart, kidney, and liver transplant recipients from three pediatric hospitals responded to qualitative interview questions on the day of hospital discharge and three wk following hospital discharge. Insight to the discharge preparation process revealed necessary education components. Post-discharge themes were identified for coping, knowledge, and adherence. The parents' responses provide awareness as to specific stressors and concerns parents are faced with when their child is discharged from the hospital after solid organ transplant and opportunities for ways the transplant team can provide support. PMID- 24814155 TI - Arabidopsis AtSUC2 and AtSUC4, encoding sucrose transporters, are required for abiotic stress tolerance in an ABA-dependent pathway. AB - Sucrose transporters (SUCs or SUTs) play a central role, as they orchestrate sucrose allocation both intracellularly and at the whole plant level. Previously, we found AtSUC4 mutants changing sucrose distribution under drought and salt stresses. Here, we systematically examined the role of Arabidopsis AtSUC2 and AtSUC4 in response to abiotic stress. The results showed significant induction of AtSUC2 and AtSUC4 in salt, osmotic, low temperature and exogenous abscisic acid (ABA) treatments by public microarray data and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses. The loss-of-function mutation of AtSUC2 and AtSUC4 led to hypersensitive responses to abiotic stress and ABA treatment in seed germination and seedling growth. These mutants also showed higher sucrose content in shoots and lower sucrose content in roots, as compared with that in wild-type plants, and inhibited the ABA-induced expression of many stress- and ABA-responsive genes, especially ABFs and ABF-downstream and upstream genes. The loss-of-function mutant of AtSUC3, a unique putative sucrose sensor, reduced the expression of AtSUC2 and AtSUC4 in response to abiotic stresses and ABA. These findings confirmed that AtSUC2 and AtSUC4 are important regulators in plant abiotic stress tolerance that use an ABA signaling pathway, which may be crossed with sucrose signaling. PMID- 24814156 TI - Comparing mortality outcomes of major burns and toxic epidermal necrolysis in a tertiary burns centre. AB - INTRODUCTION: Our aim was to provide descriptive information to burn clinicians, who have extensive experience treating major burns and determining prognosis, as to whether significant differences in mortality exist between major burns injuries and the comparatively less common toxic epidermal necrolysis for a given age and total body surface area percentage. METHODS: Retrospective data was analyzed of all deceased patients admitted to the Victorian Adult Burns Service in Melbourne, Australia over a period of 10 years with greater than 30% total body surface area burned or greater than 30% total body surface area epidermal detachment in the case of toxic epidermal necrolysis. Retrospective data was also collected on all patients, survivors and deceased, with toxic epidermal necrolysis and these patients were matched with burns patients by age and % total body surface area burned. Comparisons in outcomes were performed with mortality being the primary variable of interest. RESULTS: Toxic epidermal necrolysis patients that died were older (median: 68.5 vs 57 yrs; P=0.04), had a longer length of hospital stay (36.5 vs 0.8 days; P=0.001) and significantly longer periods of mechanical ventilation (1404 vs 14.5h; P=0.011) than major burns patients that died. When toxic epidermal necrolysis patients were matched to major burns patients by age and total body surface area burned, there were no significant differences between the two groups with respect to mortality. CONCLUSION: Palliative care approaches are more frequently administered at the time of presentation for major burns patients in comparison to toxic epidermal necrolysis patients. This may be due to a perception that if toxic epidermal necrolysis patients can survive their initial systemic injury, they are likely to survive, as opposed to major burns patients who often undergo extensive surgery and for whom other factors should be taken into account in the context of end-of life decision making. PMID- 24814157 TI - Bead-based multiplex sexually transmitted infection profiling. AB - OBJECTIVES: Sexually transmitted infections are a significant cause of genital disease, infertility and hospital admissions. The economic impact is high. An accurate diagnosis is often difficult and time consuming. We report the development and validation of a novel bead-based multiplex sexually transmitted infection profiling (STIP) assay that detects 18 sexually transmitted infections using a multiplex PCR followed by Luminex bead-based hybridisation. METHODS: STIP was validated using urogenital samples pretested by commercially available quantitative PCR, microscopy or by culturing methods. RESULTS: STIP specifically detects Chlamydia trachomatis, Herpes simplex virus 1 and 2, Treponema pallidum, Trichomonas vaginalis, Neisseria gonorrhoeae, Mycoplasma (M.) genitalium, M. hominis, M. pneumonia, M. spermatophilum, Ureaplasma urealyticum and U. parvum, and quantifies bacterial vaginosis-associated Atopobium vaginae and Gardnerella vaginalis as well as three Candida species and normal genital flora-associated Lactobacillus species. STIP reached an overall concordance of 95-100% with commercially available quantitative PCR tests. Compared to Nugent score, STIP reached a sensitivity of 95% and a specificity of 86% for bacterial vaginosis detection. Candida specimens, pretested by direct culturing, were identified with a sensitivity of 97% and a specificity of 99%. CONCLUSIONS: STIP is a powerful high-throughput tool in assessing a broad spectrum of urogenital infections. PMID- 24814158 TI - Is gingival bleeding a symptom of patients with type 1 von Willebrand disease? A case-control study. AB - BACKGROUND: Von Willebrand disease (VWD) is the most common inherent bleeding disorder resulting in prolonged bleeding time. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also known as a leading symptom of plaque-induced gingivitis and untreated periodontal disease. Gingival bleeding in VWD patients (VWD) may be triggered by gingival inflammation and not a genuine symptom. Thus, this study evaluated whether type 1 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm. METHODS: Fifty cases and 40 controls were examined haematologically (VWF antigen, VWF Ristocetin cofactor, factor VIII activity) and periodontally [Gingival Bleeding Index (GBI), bleeding on probing (BOP), Plaque Control Record (PCR), periodontal inflamed surface area (PISA), vertical probing attachment level]. RESULTS: GBI was significantly higher in controls (12.2%) than in VWD (10%). The study failed to find a significant difference regarding BOP between VWD (17%) and controls (17.2%). Multiple regressions identified PCR and PISA to be associated with GBI and BOP. VWD was negatively associated with GBI. Smoking and number of remaining teeth was negatively associated with BOP. CONCLUSION: VWD is not associated with a more pronounced inflammatory response to the oral biofilm in terms of GBI and BOP. PMID- 24814159 TI - Outbreak of meningitis due to Serratia marcescens after spinal anaesthesia. AB - This article describes an outbreak of meningitis caused by Serratia marcescens in patients who had undergone spinal anaesthesia for caesarean section. Bacterial meningitis was diagnosed in 12 of the 46 patients who underwent a caesarean section under spinal anaesthesia in a 75-bed private hospital between 6(th) and 14(th) March 2011. S. marcescens was isolated from samples taken from four prefilled syringes and one bag containing 5% dextrose with norepinephrine, suggesting that medications used in spinal anaesthesia were contaminated extrinsically. Strategies for prevention of anaesthesia-associated infections in operating theatres are discussed. PMID- 24814160 TI - Rituals in nursing: intramuscular injections. AB - AIMS AND OBJECTIVES: To consider to what extent intramuscular injection technique can be described to remain entrenched in ritualistic practice and how evidence based practice should be considered and applied to the nursing practice of this essential skill. BACKGROUND: The notion of rituals within nursing and the value or futile impact they afford to this essential nursing skill will be critically reviewed. DESIGN: Discursive paper. METHOD: Literature review from 2002-2013 to review the current position of intramuscular injection injections. RESULTS: Within the literature review, it became clear that there are several actions within the administration of an intramuscular injection that could be perceived as ritualistic and require consideration for contemporary nursing practice. CONCLUSIONS: The essential nursing skill of intramuscular injection often appears to fit into the description of a ritualised practice. By providing evidence-based care, nurses will find themselves empowered to make informed decisions based on clinical need and using their clinical judgement. RELEVANCE TO CLINICAL PRACTICE: For key learning, it will outline with rationale how site selection, needle selection, insertion technique and aspiration can be cited as examples of routinised or ritualistic practice and why these should be rejected in favour of an evidence-based approach. The effect on some student nurses of experiencing differing practices between what is taught at university and what is often seen in clinical practice will also be discussed. PMID- 24814161 TI - Fabrication route for the production of coplanar, diamond insulated, boron doped diamond macro- and microelectrodes of any geometry. AB - Highly doped, boron doped diamond (BDD) is an electrode material with great potential, but the fabrication of suitable electrodes in a variety of different geometries both at the macro- and microscale, with an insulating material that does not compromise the material properties of the BDD, presents technical challenges. In this Technical Note, a novel solution to this problem is presented, resulting in the fabrication of coplanar macro- and microscale BDD electrodes, insulated by insulating diamond, at the single and multiple, individually addressable level. Using a laser micromachining approach, the required electrode(s) geometry is machined into an insulating diamond substrate, followed by overgrowth of high quality polycrystalline BDD (pBDD) and polishing to reveal approximately nanometer roughness, coplanar all-diamond structures. Electrical contacting is possible using both top and bottom contacts, where the latter are defined using the laser to produce non-diamond-carbon (NDC) in the vicinity of the back side of the BDD. We present the fabrication of individually addressable ring, band, and disk electrodes with minimum, reproducible controlled dimensions of 50 MUm (limited only by the laser system employed). The pBDD grown into the insulating diamond recesses is shown to be free from NDC and possesses excellent electrochemical properties, in terms of extended solvent windows, electrochemical reversibility, and capacitance. PMID- 24814162 TI - Undetectable specific striatal [123I]-ioflupane binding in patients with parkinsonism. AB - [(123)I]-Ioflupane single photon emission computed tomography (SPECT) is widely used to evaluate the impairment of the nigrostriatal pathway in patients with parkinsonism. We describe a patient with visually undetectable specific striatal [123I]-ioflupane binding in the striatum. Of the 950 [123I]-ioflupane SPECT scans of patients acquired in our department, only one did not show any visually detectable striatal binding. To investigate this issue, we described multimodality imaging in this patient, including a second [123I]-ioflupane SPECT with a higher dose of [123I]-ioflupane, a [18F]-fluoro-l-dopa positron emission tomography (PET), a new MRI and an FDG-PET. Clinical and imaging data (FDG-PET and MRI) led to a diagnosis of progressive supranuclear palsy (PSP). Visual analysis of the second [(123)I]-ioflupane SPECT performed with a higher dose of [(123)I]-ioflupane confirmed nearly undetectable specific striatal binding of the tracer. The [(18)F]-fluoro-l-dopa-PET striatal binding was decreased. After ruling out all technical issues, an undetectable specific [(123)I]-ioflupane striatal binding in a patient with parkinsonism can be a sign of severe DaT loss as we have observed in a case of probable PSP even with moderate motor signs. PMID- 24814163 TI - Effect of iron and zinc supplementation and its discontinuation on lipid profile in rats. AB - The aim of this research was to investigate whether combined iron/zinc supplementation is more beneficial than iron supplementation alone from the perspective of the lipid profile in rats. The study was conducted on 6-week male Wistar rats in 3 stages: (1) 4-week adaptation to the diets: C (AIN-93M) and D (mineral mix without iron); (2) 4-week supplementation: 10-times more iron or iron and zinc compared to C; (3) 2-week post-supplementation period (the same diets as in the first stage). The iron and zinc content in serum was measured using ASA. Total cholesterol (TC), HDL cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C) and triglycerides (TG) were determined. After 4-week supplementation (stage II) and post-supplementation (stage III) periods combined iron/zinc supplementation decreased HDL-C and increased non-HDL-C concentrations in control rats, and in contrast to iron supplementation alone TG concentration decreased. After stage II combined iron/zinc supplementation did not result in increased non HDL-C and TG concentrations in iron deficient rats in contrast to iron supplementation alone. After stage III both iron and simultaneous iron/zinc supplementation were the cause of TC increase which was the result of the increase of non-HDL-C but not HDL-C concentration in iron deficient rats. In conclusion, there were no beneficial effects of simultaneous iron and zinc supplementation on the lipid profile of rats fed control and iron deficient diets. Combined iron and zinc supplementation may contribute to lower HDL-C and higher non-HDL-C concentrations. PMID- 24814164 TI - To the letter: early readers trust print-based over oral instructions to guide their actions. AB - Children have many opportunities to learn from others through oral and written sources. Recent evidence suggests that early readers place more trust in written over oral testimony when learning names for unfamiliar objects. Across three studies, we examined whether the authority of print extends beyond mere naming to guide children's actions in the physical world. In Study 1, 3- to 6-year-olds received conflicting oral and print-based advice from two puppets about how to operate a novel apparatus. Whereas pre-readers were indiscriminate in their trust, early readers preferred to follow the print-based advice. In Study 2, we replicated this finding, controlling for the amount of corroborating evidence presented by both sources, and the location of the print. In Study 3, we explored whether readers' preference for print-based information was due to a global preference for external representations, or a more specific preference for text. Children were presented with conflicting instructions based on text versus a coloured circle. Whereas pre-readers preferred to follow the colour circle, readers preferred to follow the text. Together, the results suggest that when children learn to read, they rapidly come to regard the written word as a particularly authoritative source of information about how to act in the world. PMID- 24814165 TI - Perineal and genital pityriasis versicolor due to Malassezia globosa. PMID- 24814166 TI - Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells. AB - We report a case of an 88-year-old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium-to-large-sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death-1 (PD 1), Bcl-6 and CXCL13. Flow cytometry analysis showed that CD4(+) PD-1(hi) T cells also expressed CD10, inducible T-cell co-stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T-cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH) cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept. PMID- 24814167 TI - Predictors of sustained intraocular pressure elevation in eyes receiving intravitreal anti-vascular endothelial growth factor therapy. AB - PURPOSE: To determine the intravitreal anti-vascular endothelial growth factor (VEGF) injection techniques and preferences within the retinal community and to identify potential factors associated with the development of sustained intraocular pressure (IOP) elevation in patients treated with intravitreal anti VEGF therapy for neovascular age-related macular degeneration (AMD). DESIGN: Cross-sectional physician survey. METHODS: Five hundred and thirty retina specialists spanning both private and academic practices were surveyed regarding current anti-VEGF intravitreal injection protocols, including the anti-VEGF drug of choice, needle gauge, injection volume, injection technique, and self-reported prevalence of sustained IOP elevation. Multivariate logistic regressions were performed to assess the potential influence of these factors on long-term IOP. RESULTS: Two hundred ninety-two specialists (55%) reported believing that intravitreal anti-VEGF therapy may cause sustained IOP elevation. Of these responses, the most common reported prevalence was 1%-2% (48%), followed by 3%-5% (34%). There was no relationship between the frequency of sustained IOP elevation and anti-VEGF drug of choice. Physicians who injected greater than 0.05 cc in less than 1 second were 5.56 times more likely to observe a high frequency of sustained IOP elevation (P=.006, 95% CI 1.64-18.89). CONCLUSIONS: Based on physician survey data, serial anti-VEGF injections using higher injection volumes with a rapid injection technique may potentially lead to sustained IOP elevation. The underlying mechanism for this complication may be injury to the trabecular meshwork resulting from rapid elevations in IOP. Further investigation of the relationship between injection techniques and sustained IOP elevation in the form of retrospective or prospective clinical studies is warranted. PMID- 24814169 TI - Fluoro- vs hydrocarbon surfactants: why do they differ in wetting performance? AB - Fluorosurfactants are the most effective compounds to lower the surface tension of aqueous solutions, but their wetting properties as related to low energy hydrocarbon solids are inferior to hydrocarbon trisiloxane surfactants, although the latter demonstrate higher surface tension in aqueous solutions. To explain this inconsistency available data on the adsorption of fluorosurfactants on liquid/vapour, solid/liquid and solid/vapour interfaces are discussed in comparison to those of hydrocarbon surfactants. The low free energy of adsorption of fluorosurfactants on hydrocarbon solid/water interface should be of a substantial importance for their wetting properties. PMID- 24814168 TI - Worse cardiometabolic health in African immigrant men than African American men: reconsideration of the healthy immigrant effect. AB - BACKGROUND: The healthy immigrant effect is a phrase that has been used for decades to describe better cardiometabolic health in African immigrants than African Americans. The recent global increase in cardiometabolic diseases raises the possibility that immigrant health may be changing. Therefore, a new assessment of cardiometabolic health in African immigrants is warranted. METHODS: Glucose tolerance status, blood pressure, and visceral adipose tissue (VAT) volume were compared in 214 self-identified healthy men comprised of 138 African immigrants, 76 African Americans, mean age 36+/-9 years [mean+/-standard deviation (SD); range 20-64 years]. Insulin resistance was defined by the lowest quartile of the insulin sensitivity index (SI<=2.28 mU/L(-1).min(-1)). The waist circumference (WC) which predicts insulin resistance was determined using receiver operating characteristic curves and the Youden index. RESULTS: Body mass index (BMI) and WC were lower in African immigrants than African Americans (BMI, 27.4+/-3.8 vs. 29.3+/-5.5 kg/m(2), P<0.01; WC, 91+/-11 vs. 97+/-16 cm, P<0.01). However, blood pressure, fasting glucose, and 2-hr glucose were higher in the African immigrants (all P<0.01). In addition, African immigrants had a higher prevalence of previously undiagnosed diabetes (8% vs. 0%, P<0.01) and prediabetes (35% vs. 22%, P<0.01). After adjusting for WC, African immigrants had more visceral adipose tissue (VAT) than African Americans (P<0.01). Consequently, the WC that predicted insulin resistance was 92 cm in African immigrants but 102 cm in African Americans. CONCLUSION: African immigrants were less obese than African Americans but had worse cardiometabolic health, specifically higher glucose levels, more hypertension, and greater visceral adiposity. Overall, the healthy immigrant effect may no longer be valid. PMID- 24814170 TI - Roles of notch signalling in mandibular condylar cartilage. AB - IMPORTANCE: Notch proteins are cell surface transmembrane spanning receptors which mediate critically important cellular functions through direct cell-cell contact. Interactions between Notch receptors and their ligands regulate cell fate decisions such differentiation, proliferation and apoptosis in numerous tissues. We have previously shown using immunohistochemistry that Notch1 is localized primarily to the prechondroblastic (chondroprogenitor) layer of the mandibular condylar cartilage (MCC). OBJECTIVE: To test if Notch signalling changes patterns of proliferation and differentiation in the MCC and to investigate if Notch signalling acts downstream of Fibroblast Growth Factor 2 (FGF-2). METHODS: Condylar cartilage explants were cultured over serum-free DMEM containing either 0 or 50nM DAPT, a Notch signal inhibitor. Explants were used for RNA extraction and immunohistochemistry. RESULTS: Analysis of gene array data demonstrated that the perichondrial layer of the MCC is rich in Notch receptors (Notch 3 and 4) and Notch ligands (Jagged and Delta) as well as various downstream facilitators of Notch signalling. Disruption of Notch signalling in MCC explants decreased proliferation (Cyclin B1 expression) and increased chondrocyte differentiation (Sox9 expression). Moreover, we found that the actions of FGF-2 in MCC are mediated in part by Notch signalling. CONCLUSION: These data suggest that Notch signalling contributes to the regulation of proliferation and differentiation in the MCC. PMID- 24814171 TI - Continuous fever-range heat stress induces thermotolerance in odontoblast-lineage cells. AB - OBJECTIVE: Heat shock during restorative procedures can trigger damage to the pulpodentin complex. While severe heat shock has toxic effects, fever-range heat stress exerts beneficial effects on several cells and tissues. In this study, we examined whether continuous fever-range heat stress (CFHS) has beneficial effects on thermotolerance in the rat clonal dental pulp cell line with odontoblastic properties, KN-3. METHODS: KN-3 cells were cultured at 41 degrees C for various periods, and the expression level of several proteins was assessed by Western blot analysis. After pre-heat-treatment at 41 degrees C for various periods, KN-3 cells were exposed to lethal severe heat shock (LSHS) at 49 degrees C for 10min, and cell viability was examined using the MTS assay. Additionally, the expression level of odontoblast differentiation makers in surviving cells was examined by Western blot analysis. RESULTS: CFHS increased the expression levels of several heat shock proteins (HSPs) in KN-3 cells, and induced transient cell cycle arrest. KN-3 cells, not pre-heated or exposed to CFHS for 1 or 3h, died after exposure to LSHS. In contrast, KN-3 cells exposed to CFHS for 12h were transiently lower on day 1, but increased on day 3 after LSHS. The surviving cells expressed odontoblast differentiation markers, dentine sialoprotein and dentine matrix protein-1. These results suggest that CFHS for 12h improves tolerance to LSHS by inducing HSPs expression and cell cycle arrest in KN-3 cells. CONCLUSIONS: The appropriate pretreatment with continuous fever-range heat stress can provide protection against lethal heat shock in KN-3 cells. PMID- 24814172 TI - Up-regulation of PKMzeta expression in the anterior cingulate cortex following experimental tooth movement in rats. AB - OBJECTIVE: To explore the involvement of synaptic plasticity in pain induced by experimental tooth movement, we evaluated the expression of protein kinase M zeta (PKMzeta), an enzyme necessary for maintaining long-term potentiation (LTP) in the anterior cingulate cortex (ACC). METHODS: Male Sprague-Dawley rats weighing 250-300g were used. The change of the expression of PKMzeta in the ACC was measured by western blot, and the mRNA of PKMzeta was detected by quantitative real-time PCR 1, 3, 7 days after experimental tooth movement. The average time spent on mouth-wiping behaviour of rats involved in pain perception was detected. After that a selective PKMzeta inhibitor, called myristoylated zeta pseudosubstrate inhibitory peptide (ZIP) was injected into ACC, and the effects of ZIP were evaluated. RESULTS: The mouth-wiping behaviour of rats was significantly increased 1, 3, and 7 days after experimental tooth movement. Changes in PKMzeta levels were not detected on day 1 but were found to be increased 3 days following the tooth movement, and then declined to the baseline 7 days after tooth movement in the ACC. PKMzeta mRNA levels were not significantly different between the experimental and sham-treated groups at the three time points. Time spent on mouth-wiping behaviour was reduced after ZIP was injected into ACC 3 days after tooth movement, and the analgesic effect last for at least 24h. CONCLUSION: PKMzeta in the ACC acts to maintain the pain induced by experimental tooth movement. Increased expression of PKMzeta protein is attributed to persistent translation of PKMzeta mRNA. Synaptic plasticity may be involved in the development of tooth movement pain. PMID- 24814173 TI - Managing coeliac disease in patients with diabetes. AB - The association between coeliac disease and type 1 diabetes has long been established. The combination of genetic susceptibility along with a potential role for gluten in the pathogenesis of autoimmunity makes defining gluten's role in type 1 diabetes extremely important. Evidence supporting the role of a gluten free diet to improve complications associated with type 1 diabetes is not robust. However there is evidence to support improved growth, bone density and potentially the prevention of additional autoimmune diseases in patients with coeliac disease and type 1 diabetes. The gluten free diet is expensive and challenging to adhere to in people already on a modified diet. Early identification of those who have coeliac disease and would benefit from a gluten free diet is of utmost importance to prevent complications associated with type 1 diabetes and coeliac disease. PMID- 24814174 TI - Neural population models for perception of motion in depth. AB - Changing disparity (CD) and interocular velocity difference (IOVD) are two possible mechanisms for stereomotion perception. We propose two neurally plausible models for the representation of motion-in-depth (MID) via the CD and IOVD mechanisms. These models create distributed representations of MID velocity as the responses from a population of neurons selective to different MID velocity. Estimates of perceived MID velocity can be computed from the population response. They can be applied directly to binocular image sequences commonly used to characterize MID perception in psychophysical experiments. Contrary to common assumptions, we find that the CD and IOVD mechanisms cannot be distinguished easily by random dot stereograms that disrupt correlations between the two eyes or through time. We also demonstrate that the assumed spatial connectivity between the units in these models can be learned through exposure to natural binocular stimuli. Our experiments with these developmental models of MID selectivity suggest that neurons selective to MID are more likely to develop via the CD mechanism than the IOVD mechanism. PMID- 24814175 TI - Simulated cystic renal lesions: quantitative X-ray phase-contrast CT--an in vitro phantom study. AB - PURPOSE: To determine if grating-based x-ray phase-contrast computed tomography (CT) can allow differentiation of simulated simple, protein-rich, hemorrhagic, and enhancing cystic renal lesions in an in vitro phantom. MATERIALS AND METHODS: An in vitro phantom specifically designed to simulate simple, protein-rich, hemorrhagic, and enhancing renal cysts was scanned with an experimental grating based phase-contrast CT setup consisting of a Talbot-Lau interferometer with a rotating anode x-ray tube and a single photon counting detector. Various combinations of serum and saline (100% and 0% to 0% and 100%), blood and saline, blood and serum (100% and 0% to 6.25% and 93.75% for both), and an iodinated contrast agent and saline (7.6-1.6 mg per milliliter of saline) were used to reproduce the chemical composition of the different types of cysts. A thickened solution of an iodinated contrast agent calibrated with a clinical multidetector CT scanner served as contrast agent-enhanced renal parenchyma (195 HU at 80 kVp, 400 mAs and 98 HU at 140 kVp, 200 mAs). Standard attenuation- and phase-contrast images were reconstructed from the raw projection data. Quantitative values for attenuation and phase contrast and image noise were determined. Contrast-to-noise ratios were calculated. Simulated lesions were assessed for visual differentiability by means of pairwise comparison of the attenuation- and phase contrast images and both images simultaneously. RESULTS: Attenuation-contrast imaging showed large differences in Hounsfield units with increasing concentrations of iodine (118.9 HU for 1.6 mg/mL vs 331.4 HU for 7.6 mg/mL). Values for phase-contrast imaging were substantially distinguishable for saline, serum, and blood (7.9, 23.7, and 52.8 HU, respectively). Both imaging modalities combined allowed differentiation of all four types of simulated cysts (100% saline, 100% serum, 100% blood, and 1.6-7.6 mg of iodine per milliliter of saline) with one imaging acquisition. CONCLUSION: Grating-based phase-contrast CT allows differentiation of simulated simple, protein-rich, hemorrhagic, and enhancing renal cysts in an in vitro phantom through simultaneous assessment of their distinct attenuation- and phase-contrast signal. PMID- 24814176 TI - Calcaneal attachment of the plantar fascia: MR findings in asymptomatic volunteers. AB - PURPOSE: To determine the spectrum of magnetic resonance (MR) imaging findings at the calcaneal attachment of the plantar fascia in asymptomatic volunteers. MATERIALS AND METHODS: The study was approved by the institutional review board, and informed consent was obtained from all subjects. MR imaging was performed in 77 asymptomatic volunteers (mean age, 48.0 years; age range, 23-83 years) with use of a 1.5-T system. There were 40 women (mean age, 49.0 years; age range, 24 83 years) and 37 men (mean age, 48.0 years; age range, 23-83 years). Signal intensity characteristics and thickness of the medial, central, and lateral fascicles of the plantar fascia were assessed independently by two radiologists. The presence of soft-tissue edema, bone marrow edema, and bone spur formation at the attachment of the plantar fascia was noted. Datasets were analyzed with inferential statistic procedures. RESULTS: The mean thickness of the plantar fascia was 0.6 mm (medial fascicle), 4.0 mm (central fascicle), and 2.3 mm (lateral fascicle). Increased signal intensity in the plantar fascia was seen with the T1-weighted sequence in 16 of the 77 volunteers (21%), the T2-weighted sequence in six (7.8%), and the short inversion time inversion-recovery sequence in six (7.8%). Soft-tissue edema was seen deep to the plantar fascia in five of the 77 volunteers (6.5%) and superficial to the plantar fascia in 16 (21%). A calcaneal spur was detected in 15 of the 77 volunteers (19%). Calcaneal bone marrow edema was present in four volunteers (5.2%). CONCLUSION: T1-weighted signal intensity changes in the plantar fascia, soft-tissue edema superficial to the plantar fascia, and calcaneal spurs are common findings in asymptomatic volunteers and should be used with caution in the diagnosis of plantar fasciitis. Increased signal intensity within the plantar fascia with fluid-sensitive sequences is uncommon in asymptomatic volunteers. PMID- 24814177 TI - Detection of urolithiasis: comparison of 100% tube exposure images reconstructed with filtered back projection and 50% tube exposure images reconstructed with sinogram-affirmed iterative reconstruction. AB - PURPOSE: To compare images acquired with 50% tube exposure with a dual-source computed tomographic (CT) scanner and reconstructed with sinogram-affirmed iterative reconstruction (SAFIRE) with 100% exposure images reconstructed with filtered back projection (FBP) for reader ability to detect stones, reader confidence, and findings outside the urinary tract. MATERIALS AND METHODS: In this HIPAA-compliant, institutional review board-approved study, imaging examinations in 99 patients with urolithiasis were assessed. Data from both tubes were reconstructed with FBP; data from the primary tube only were reconstructed with SAFIRE. Seven readers evaluated randomized studies for calculi in nine regions. Reader confidence was scored by using a five-point scale. Ancillary findings were noted. Nonparametric methods for clustered data were used to estimate the area under the receiver operating characteristic curves with 95% confidence intervals to test for noninferiority of 50% exposure with SAFIRE. RESULTS: Calculi were found in 113 locations (pyelocalyceal ureter, 86; proximal ureter, seven; midureter, four; distal ureter, 15; bladder, one) and not found in 752 locations. Mean area under the receiver operating characteristic curve for FBP was 0.879 (range, 0.607-0.967) and for SAFIRE, 0.883 (range, 0.646-0.971; 95% confidence interval: -0.025, 0.031). The SAFIRE images were not significantly inferior to FBP images (P = .001). Reader confidence levels for images with stones were similar with FBP and SAFIRE (P = .963). For the 52 patients who had extraurinary findings, readers reported them correctly in 74.4% (271 of 364) and 72.0% (262 of 364) of cases (P = .215) for FBP and SAFIRE, respectively. For the nine patients with potentially important findings per the reference standard, the detection rates were 44% (28 of 63) and 33% (21 of 63, P = .024), respectively. For the 43 patients with unimportant or likely unimportant findings, the false detection rates were 15% (44 of 301) and 14% (43 of 301, P = .756), respectively. CONCLUSION: The 50% tube exposure CT images reconstructed with SAFIRE were not inferior to 100% exposure images reconstructed with FBP for diagnosis of urolithiasis, without decreases in reader confidence. PMID- 24814178 TI - Predicting renal cryoablation complications: new risk score based on tumor size and location and patient history. AB - PURPOSE: To identify tumor and patient-related risk factors for major complications following renal cryoablation and to develop a model for predicting these adverse events. MATERIALS AND METHODS: Institutional review board approval and informed patient consent were obtained for this HIPAA-compliant retrospective study. All 398 renal cryoablation procedures performed from 2003 through 2011 were reviewed to identify tumor and patient-related risk factors associated with major complications (Clavien-Dindo classification, >= grade III). A scoring system for predicting these adverse events was then developed using risk factor weighting obtained from a multivariate logistic regression model. To internally validate this model, the scoring system was then applied to all 73 renal cryoablation procedures performed during 2012. RESULTS: Among tumor-related factors evaluated, Maximal tumor diameter (P = .0006) and Central tumor location (P = .02) were significantly associated with major complications. Among patient related factors evaluated, prior Myocardial infarction (MI) (P = .002) and Complicated diabetes mellitus (P = .01) were significantly associated with major complications. This resulted in the (MC)2 risk scoring system, with (MC)2 risk score = 2.5 points (for tumors <= 2.5 cm in maximal diameter) or 0.1 points for each millimeter of maximal tumor diameter (for tumors > 2.5 cm) + 1.5 points (if central tumor location) + 2.5 points (if patient history of prior MI) + 3.0 points (if patient history of complicated diabetes). Mean (MC)2 risk score for all renal cryoablations was 4.7 (standard deviation, 1.9; range, 2.5-15.3). The observed major complication rates were 2.0% (95% confidence interval [CI]: 0.6%, 4.6%) in the low-risk group (score < 5.0), 12.8% (95% CI: 7.5%, 19.9%) in the moderate-risk group (score of 5.0-8.0), and 39.1% (95% CI: 19.7%, 61.5%) in the high-risk group (score > 8.0). Application of the (MC)2 scoring system to the validation group yielded a concordance index of 0.82 (95% CI: 0.62, 1.00). CONCLUSION: The results of this study suggest that the (MC)2 risk score is a valuable tool for predicting major complications in patients undergoing renal cryoablation. However, external validation is warranted. PMID- 24814179 TI - Cortical bone water concentration: dependence of MR imaging measures on age and pore volume fraction. AB - PURPOSE: To quantify bulk bone water to test the hypothesis that bone water concentration (BWC) is negatively correlated with bone mineral density (BMD) and is positively correlated with age, and to propose the suppression ratio (SR) (the ratio of signal amplitude without to that with long-T2 suppression) as a potentially stronger surrogate measure of porosity, which is evaluated ex vivo and in vivo. MATERIALS AND METHODS: Human subject studies were conducted in compliance with institutional review board and HIPAA regulations. Healthy men and women (n = 72; age range, 20-80 years) were examined with a hybrid radial ultrashort echo time magnetic resonance (MR) imaging sequence at 3.0 T, and BWC was determined in the tibial midshaft. In a subset of 40 female subjects, the SR was measured with a similar sequence. Cortical volumetric BMD (vBMD) was measured by means of peripheral quantitative computed tomography (CT). The method was validated against micro-CT-derived porosity in 13 donor human cortical bone specimens. Associations among parameters were evaluated by using standard statistical tools. RESULTS: BWC was positively correlated with age (r = 0.52; 95% confidence interval [CI]: 0.22, 0.73; P = .002) and negatively correlated with vBMD at the same location (r = -0.57; 95% CI: -0.76, -0.29; P < .001). Data were suggestive of stronger associations with SR (r = 0.64, 95% CI: 0.39, 0.81, P < .001 for age; r = -0.67, 95% CI: -0.82, -0.43, P < .001 for vBMD; P < .001 for both), indicating that SR may be a more direct measure of porosity. This interpretation was supported by ex vivo measurements showing SR to be strongly positively correlated with micro-CT porosity (r = 0.88; 95% CI: 0.64, 0.96; P < .001) and with age (r = 0.87; 95% CI: 0.62, 0.96; P < .001). CONCLUSION: The MR imaging-derived SR may serve as a biomarker for cortical bone porosity that is potentially superior to BWC, but corroboration in larger cohorts is indicated. PMID- 24814180 TI - Breast tissue characterization with photon-counting spectral CT imaging: a postmortem breast study. AB - PURPOSE: To investigate the feasibility of breast tissue characterization in terms of water, lipid, and protein contents with a spectral computed tomographic (CT) system based on a cadmium zinc telluride (CZT) photon-counting detector by using postmortem breasts. MATERIALS AND METHODS: Nineteen pairs of postmortem breasts were imaged with a CZT-based photon-counting spectral CT system with beam energy of 100 kVp. The mean glandular dose was estimated to be in the range of 1.8-2.2 mGy. The images were corrected for pulse pile-up and other artifacts by using spectral distortion corrections. Dual-energy decomposition was then applied to characterize each breast into water, lipid, and protein contents. The precision of the three-compartment characterization was evaluated by comparing the composition of right and left breasts, where the standard error of the estimations was determined. The results of dual-energy decomposition were compared by using averaged root mean square to chemical analysis, which was used as the reference standard. RESULTS: The standard errors of the estimations of the right-left correlations obtained from spectral CT were 7.4%, 6.7%, and 3.2% for water, lipid, and protein contents, respectively. Compared with the reference standard, the average root mean square error in breast tissue composition was 2.8%. CONCLUSION: Spectral CT can be used to accurately quantify the water, lipid, and protein contents in breast tissue in a laboratory study by using postmortem specimens. PMID- 24814181 TI - Primary central nervous system lymphoma and atypical glioblastoma: multiparametric differentiation by using diffusion-, perfusion-, and susceptibility-weighted MR imaging. AB - PURPOSE: To compare multiparametric diagnostic performance with diffusion weighted, dynamic susceptibility-weighted contrast material-enhanced perfusion weighted, and susceptibility-weighted magnetic resonance (MR) imaging for differentiating primary central nervous system lymphoma (PCNSL) and atypical glioblastoma. MATERIALS AND METHODS: This retrospective study was institutional review board-approved and informed consent was waived. Pretreatment MR imaging was performed in 314 patients with glioblastoma, and a subset of 28 patients with glioblastoma of atypical appearance (solid enhancement with no visible necrosis) was selected. Parameters of diffusion-weighted (apparent diffusion coefficient [ADC]), susceptibility-weighted (intratumoral susceptibility signals [ITSS]), and dynamic susceptibility-weighted contrast-enhanced perfusion-weighted (relative cerebral blood volume [rCBV]) imaging were evaluated in these 28 patients with glioblastoma and 19 immunocompetent patients with PCNSL. A two-sample t test and chi(2) test were used to compare parameters.The diagnostic performance for differentiating PCNSL from glioblastoma was evaluated by using logistic regression analyses with leave-one-out cross validation. RESULTS: Minimum, maximum, and mean ADCs and maximum and mean rCBVs were significantly lower in patients with PCNSL than in those with glioblastoma (P < .01, respectively), whereas mean ADCs and mean rCBVs allowed the best diagnostic performance. Presence of ITSS was significantly lower in patients with PCNSL (32% [six of 19]) than in those with glioblastoma (82% [23 of 28]) (P < .01). Multiparametric assessment of mean ADC, mean rCBV, and presence of ITSS significantly increased the probability for differentiating PCNSL and atypical glioblastoma compared with the evaluation of one or two imaging parameters (P < .01), thereby correctly predicting histologic results in 95% (18 of 19) of patients with PCNSL and 96% (27 of 28) of patients with atypical glioblastoma. CONCLUSION: Combined evaluation of mean ADC, mean rCBV, and presence of ITSS allowed reliable differentiation of PCNSL and atypical glioblastoma in most patients, and these results support an integration of advanced MR imaging techniques for the routine diagnostic workup of patients with these tumors. PMID- 24814182 TI - Dual-energy multi-detector row CT with virtual monochromatic imaging for improving patient-to-patient uniformity of aortic enhancement during CT angiography: an in vitro and in vivo study. AB - PURPOSE: To determine whether virtual monochromatic imaging from a dual-energy acquisition can improve patient-to-patient uniformity of aortic enhancement during multi-detector row computed tomographic (CT) angiography. MATERIALS AND METHODS: This retrospective single-center HIPAA-compliant study was approved by the institutional review board, with a waiver of informed consent. A proprietary tapered hollow phantom that contained a bone-mimicking insert and a hollow tube insert that mimicked the aorta was used. The aortic insert was filled with different iodine dilutions to mimic various degrees of enhancement. The phantom was imaged with both dual-energy and single-energy multi-detector row CT at four energy levels (80, 100, 120, and 140 kVp). Dual-energy multi-detector row CT was also performed in 62 patients (38 men; mean age, 60 years +/- 12.7 [standard deviation]). For both the phantom and the patients, virtual monochromatic images were reconstructed from 40 to 140 keV, at 20-keV increments. The relationship between aortic attenuation and effective diameter was assessed by using a statistical model. RESULTS: For all polychromatic data sets, the mean aortic attenuation decreased proportionally to the effective diameter of the phantom (slope, >=3.0 HU/cm). For virtual monochromatic data sets ranging from 80 to 140 keV, the regression slopes of aortic attenuation as a function of the phantom's effective diameter were negligible (slope, <1.0 HU/cm) for all iodine-to-water dilutions. In patients, the slope of the regression lines was also negligible ( 0.69 < slope < 0.16) for virtual monochromatic data sets ranging from 100 to 140 keV. CONCLUSION: Within an energy range of 100-140 keV, virtual monochromatic images improve patient-to-patient uniformity of aortic enhancement compared with conventional polychromatic acquisitions. PMID- 24814184 TI - Free radical entrapment and crystallinity of resin composites after accelerated aging as a function of the expiration date. AB - This study evaluated the spin concentration and the crystallinity in different classifications of dental composites as a function of the material condition (new, aged and expired). Specimens were obtained according to the factors: composites: Filtek P60, Filtek Z250, Filtek Z350XT, and Filtek Silorane; and material conditions: new, aged, and expired. The syringe composites underwent an accelerated aging protocol (Arrhenius model). The magnetic properties of the composites were characterized using Electron Paramagnetic Resonance (EPR) and the concentration of spins (number of spins/mass) was calculated. The crystallinity of the composites tested was characterized with X-ray diffraction (XRD). Filtek P60 and Filtek Z250 presented similarities in terms of spin concentration and crystallinity, irrespective of the material condition. The aging protocol influenced the composite Filtek Z350XT that exhibited a significant increase in the spin concentration. Besides, lower intensity peaks of the organic matrix and amorphous silica were also observed for both aged and expired Filtek Z350XT. Although a significant lower spin concentration was observed for the silorane composite in comparison to that of the methacrylates, a decrease in the relative intensity of peaks of the amorphous region related to the organic components in the diffractograms was observed. The material conditions tested influence the crystallinity and the magnetic properties of the composites evaluated. PMID- 24814185 TI - The relation between hydration and mechanical behavior of bovine cornea in tension. AB - The cornea is a transparent soft tissue covering the front of the eye. The biomechanical properties of the cornea have been commonly investigated by uniaxial tensile and inflation testing methods. The cornea like many other hydrated tissue swells when immersed in an ionic solution. Previous studies on hydrated tissues have shown that mechanical properties and hydration are closely related. The present study was designed to investigate the effects of thickness (hydration) variation due to swelling/dehydration on non-linear stress-strain response of the bovine cornea. Corneal strips were first air-dried and then soaked in a bathing solution until they reached an average thickness ranging from 0.3mm to 1.1mm. Based on their thickness, the samples were divided into different groups and uniaxial tests were performed to measure tensile properties. All experiments were done in mineral oil to prevent any hydration gain or loss during the tests. It was observed that swollen corneas had softer tensile properties in comparison with dehydrated ones. In particular, there was a significant difference between elastic tangent modulus of different groups (P<0.05). It was also shown that tensile behavior of bovine strips at any thickness within the range of 0.4-1.1mm can be obtained from a single experiment conducted on samples with known thickness (hydration). The findings of the present study confirm that mechanical properties obtained from uniaxial tensile experiments are strongly dependent on thickness (water amount) of samples; therefore, careful attention must be taken in interpreting previous studies which did not fully control the thickness of specimens. PMID- 24814183 TI - Identification of a gene set to evaluate the potential effects of loud sounds from seismic surveys on the ears of fishes: a study with Salmo salar. AB - Functional genomic studies were carried out on the inner ear of Atlantic salmon Salmo salar following exposure to a seismic airgun. Microarray analyses revealed 79 unique transcripts (passing background threshold), with 42 reproducibly up regulated and 37 reproducibly down-regulated in exposed v. control fish. Regarding the potential effects on cellular energetics and cellular respiration, altered transcripts included those with roles in oxygen transport, the glycolytic pathway, the Krebs cycle and the electron transport chain. Of these, a number of transcripts encoding haemoglobins that are important in oxygen transport were up regulated and among the most highly expressed. Up-regulation of transcripts encoding nicotinamide riboside kinase 2, which is also important in energy production and linked to nerve cell damage, points to evidence of neuronal damage in the ear following noise exposure. Transcripts related to protein modification or degradation also indicated potential damaging effects of sound on ear tissues. Notable in this regard were transcripts associated with the proteasome-ubiquitin pathway, which is involved in protein degradation, with the transcript encoding ubiquitin family domain-containing protein 1 displaying the highest response to exposure. The differential expression of transcripts observed for some immune responses could potentially be linked to the rupture of cell membranes. Meanwhile, the altered expression of transcripts for cytoskeletal proteins that contribute to the structural integrity of the inner ear could point to repair or regeneration of ear tissues including auditory hair cells. Regarding potential effects on hormones and vitamins, the protein carrier for thyroxine and retinol (vitamin A), namely transthyretin, was altered at the transcript expression level and it has been suggested from studies in mammalian systems that retinoic acid may play a role in the regeneration of damaged hair cells. The microarray experiment identified the transcript encoding growth hormone I as up-regulated by loud sound, supporting previous evidence linking growth hormone to hair cell regeneration in fishes. Quantitative (q) reverse transcription (RT) polymerase chain reaction (qRT-PCR) analyses confirmed dysregulation of some microarray identified transcripts and in some cases revealed a high level of biological variability in the exposed group. These results support the potential utility of molecular biomarkers to evaluate the effect of seismic surveys on fishes with studies on the ears being placed in a priority category for development of exposure-response relationships. Knowledge of such relationships is necessary for addressing the question of potential size of injury zones. PMID- 24814186 TI - [Application of the Pediatric Index of Mortality 2 in pediatric patients with complex chronic conditions]. AB - OBJECTIVE: To evaluate the performance of the Pediatric Index of Mortality 2 (PIM2) in a pediatric intensive care unit (PICU) with a high prevalence of patients with complex chronic conditions (CCCs), and compare the performance between patients with and without CCCs. METHODS: A prospective cohort study was conducted in a PICU in Brazil, with patients admitted between 2009 and 2011. The performance was evaluated through discrimination and calibration. Discrimination was assessed by calculating the area under the ROC curve, and calibration was determined using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: A total of 677 patients were included in the study, of which 83.9% had a CCC. Overall mortality was 9.7%, with a trend of higher mortality among patients with CCCs when compared to patients without CCCs (10.3% vs. 6.4%, p = 0.27), but with no difference in the mean probability of death estimated by PIM2 (5.9% vs. 5.6%, p = 0.5). Discrimination was considered adequate in the general population (0.840) and in patients with and without CCCs (0.826 and 0.944). Calibration was considered inadequate in the general population and in patients with CCCs (p < 0.0001 and p < 0.0001), but it was considered adequate in patients without CCCs (p = 0.527). CONCLUSIONS: PIM2 showed poor performance in patients with CCCs and in the general population. This result may be secondary to differences in the characteristics between the study samples (high prevalence of patients with CCCs); the performance of the PIM2 should not be ruled out. PMID- 24814187 TI - The HORMA domain: an evolutionarily conserved domain discovered in chromatin associated proteins, has unanticipated diverse functions. AB - The HORMA domain (for Hop1p, Rev7p and MAD2) was discovered in three chromatin associated proteins in the budding yeast Saccharomyces cerevisiae. This domain has also been found in proteins with similar functions in organisms including plants, animals and nematodes. The HORMA domain containing proteins are thought to function as adaptors for meiotic checkpoint protein signaling and in the regulation of meiotic recombination. Surprisingly, new work has disclosed completely unanticipated and diverse functions for the HORMA domain containing proteins. A. M. Villeneuve and colleagues (Schvarzstein et al., 2013) show that meiosis-specific HORMA domain containing proteins plays a vital role in preventing centriole disengagement during Caenorhabditis elegans spermatocyte meiosis. Another recent study reveals that S. cerevisiae Atg13 HORMA domain acts as a phosphorylation-dependent conformational switch in the cellular autophagic process. PMID- 24814188 TI - Codon usage bias in human cytomegalovirus and its biological implication. AB - Human cytomegalovirus (HCMV) infection, a worldwide contagion, causes a serious disorder in infected individuals. Analysis of codon usage can reveal much molecular information about this virus. The effective number of codon (ENC) values, relative synonymous codon usage (RSCU) values, codon adaptation index (CAI), and nucleotide contents was investigated in approximately 160 coding sequences (CDS) among 17 human cytomegalovirus genomes using the software CodonW. Linear regression analysis and logistic regression were performed to explore the preliminary data. The results showed that, overall, HCMV genomes had low codon usage bias (mean ENC=47.619). However, the ENC of individual CDS varied widely and was distributed unevenly between host-related genes and viral-self-function genes (P=0.002, odds ratio (OR)=3.194), as did the GC content (P=0.016, OR=2.178). The ENC values correlated with CAI, GC content, and the nucleotide composing at the 3rd codon position (GC3s) (P<0.001). There was a significant variation in the codon preference that depended on the RSCU data. The predicted ENC curve suggested that mutational pressure, rather than natural selection, was one of the main factors that determined the codon usage bias in HCMV. Among 123 genes with known function, the genes related to viral self-replication and viral host interaction showed different ENC and CAI values, and GC and GC3s contents. In conclusion, the detailed codon usage bias theoretically revealed information concerning HCMV evolution and could be a valuable additional parameter for HCMV gene function research. PMID- 24814189 TI - Signatures of natural selection in the mitochondrial genomes of Tachycineta swallows and their implications for latitudinal patterns of the 'pace of life'. AB - Latitudinal variation in avian life histories can be summarized as a slow-fast continuum, termed the 'pace of life', that encompasses patterns in life span, reproduction, and rates of development among tropical and temperate species. Much of the variation in avian pace of life is tied to differences in rates of long term metabolic energy expenditure. Given the vital role of the mitochondrion in metabolic processes, studies of variation in the mitochondrial genome may offer opportunities to establish mechanistic links between genetic variation and latitudinal 'pace of life' patterns. Using comparative genomic analyses, we examined complete mitochondrial genome sequences obtained from nine, broadly distributed Tachycineta swallow species to test for signatures of natural selection across the mitogenome within a phylogenetic framework. Our results show that although purifying selection is the dominant selective force acting on the mitochondrial genome in Tachycineta, three mitochondrial genes (ND2, ND5, and CYTB) contain regions that exhibit signatures of diversifying selection. Two of these genes (ND2 and ND5) encode interacting subunits of NADH dehydrogenase, and amino residues that were inferred to be targets of positive selection were disproportionately concentrated in these genes. Moreover, the positively selected sites exhibited a phylogenetic pattern that could be indicative of adaptive divergence between "fast" and "slow" lineages. These results suggest that functional variation in cytochrome b and NADH dehydrogenase could mechanistically contribute to latitudinal 'pace of life' patterns in Tachycineta. PMID- 24814190 TI - Light and electron microscopic analyses of Vasa expression in adult germ cells of the fish medaka. AB - Germ cells of diverse animal species have a unique membrane-less organelle called germ plasm (GP). GP is usually associated with mitochondria and contains RNA binding proteins and mRNAs of germ genes such as vasa. GP has been described as the mitochondrial cloud (MC), intermitochondrial cement (IC) and chromatoid body (CB). The mechanism underlying varying GP structures has remained incompletely understood. Here we report the analysis of GP through light and electron microscopy by using Vasa as a marker in adult male germ cells of the fish medaka (Oryzias latipes). Immunofluorescence light microscopy revealed germ cell specific Vasa expression. Vasa is the most abundant in mitotic germ cells (oogonia and spermatogonia) and reduced in meiotic germ cells. Vasa in round spermatids exist as a spherical structure reminiscent of CB. Nanogold immunoelectron microscopy revealed subcellular Vasa redistribution in male germ cells. Vasa in spermatogonia concentrates in small areas of the cytoplasm and is surrounded by mitochondria, which is reminiscent of MC. Vasa is intermixed with mitochondria to form IC in primary spermatocytes, appears as the free cement (FC) via separation from mitochondria in secondary spermatocyte and becomes condensed in CB at the caudal pole of round spermatids. During spermatid morphogenesis, Vasa redistributes and forms a second CB that is a ring-like structure surrounding the dense fiber of the flagellum in the midpiece. These structures resemble those described for GP in various species. Thus, Vasa identifies GP and adopts varying structures via dynamic reorganization at different stages of germ cell development. PMID- 24814191 TI - Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness. AB - Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(*)48] and c.3709C>T [p.Arg1237(*)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(*)] and c.6232G>T [p.Glu2078(*)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes. PMID- 24814194 TI - Thromboembolism in pregnancy: challenges and controversies in the prevention of pregnancy-associated venous thromboembolism and management of anticoagulation in women with mechanical prosthetic heart valves. AB - Thromboembolism in pregnancy is an important clinical issue. Despite identification of maternal and pregnancy-specific risk factors for development of pregnancy-associated venous thromboembolism, limited data are available to inform on optimal approaches for prevention. The relatively low overall prevalence of pregnancy-associated venous thromboembolism has prompted debate about the validity of recommendations, which are mainly based on expert opinion, and have resulted in an increased use of pharmacological thromboprophylaxis in pregnancy and postpartum. A pragmatic approach is required in the absence of more robust data. Anticoagulation management of pregnant women with mechanical prosthetic heart valves is particularly challenging. Continuation of therapeutic anticoagulation during pregnancy is essential to prevent valve thrombosis. Warfarin, the most effective anticoagulant, is associated with adverse fetal outcomes, including embryopathy and stillbirth. Fetal outcome is improved with therapeutic-dose low-molecular-weight heparin, but there may be more thromboembolic complications. More intensive anticoagulation, targeting higher trough anti-Xa levels, may reduce the risk of valve thrombosis. PMID- 24814193 TI - Mutations in EMP2 cause childhood-onset nephrotic syndrome. AB - Nephrotic syndrome (NS) is a genetically heterogeneous group of diseases that are divided into steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). SRNS inevitably leads to end-stage kidney disease, and no curative treatment is available. To date, mutations in more than 24 genes have been described in Mendelian forms of SRNS; however, no Mendelian form of SSNS has been described. To identify a genetic form of SSNS, we performed homozygosity mapping, whole exome sequencing, and multiplex PCR followed by next-generation sequencing. We thereby detected biallelic mutations in EMP2 (epithelial membrane protein 2) in four individuals from three unrelated families affected by SRNS or SSNS. We showed that EMP2 exclusively localized to glomeruli in the kidney. Knockdown of emp2 in zebrafish resulted in pericardial effusion, supporting the pathogenic role of mutated EMP2 in human NS. At the cellular level, we showed that knockdown of EMP2 in podocytes and endothelial cells resulted in an increased amount of CAVEOLIN-1 and decreased cell proliferation. Our data therefore identify EMP2 mutations as causing a recessive Mendelian form of SSNS. PMID- 24814195 TI - FOXO3a mediates the cytotoxic effects of cisplatin in lung cancer cells. AB - Cisplatin is one of the major chemotherapeutic agents used against different human cancers. A better understanding of the downstream cellular targets of cisplatin will provide information on its mechanism of action. FOXO3a is a member of the FOXO transcription factor family, which modulates the expression of genes involved in cell cycle arrest, apoptosis, and other cellular processes. In this study, we have investigated the effects of cisplatin in a panel of lung cancer cell lines. The results showed that cisplatin inhibited the proliferation of these lung cancer cell lines by inhibiting the PI3K/AKT pathway, with evidence of decreasing phosphorylation of PI3K and AKT under cisplatin treatment, and constitutively activating AKT1 could reduce cisplatin-induced cell apoptosis. More importantly, cisplatin significantly inhibited FOXO3a phosphorylation (at Thr32, AKT phosphorylation site) and induced FOXO3a nuclear accumulation, which in turn increased the expression of FOXO3a-dependent apoptotic protein Bim. Knockdown of FOXO3a expression using small interfering RNA attenuated cisplatin induced apoptosis. Furthermore, activation of FOXO3a induced cell apoptosis irrespective of p53 status, whereas p53 may act as FOXO3a downstream molecules involved in cisplatin-induced cell apoptosis. Together, our findings suggested that FOXO3a is a relevant mediator of the cytotoxic effects of cisplatin in lung cancer cells. PMID- 24814192 TI - Return of genomic results to research participants: the floor, the ceiling, and the choices in between. AB - As more research studies incorporate next-generation sequencing (including whole genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles. PMID- 24814196 TI - Impaired digital reactive hyperemia and the risk of restenosis after primary coronary intervention in patients with acute coronary syndrome. AB - AIM: Reactive hyperemia peripheral arterial tonometry (RH-PAT) can be used to noninvasively assess the vascular function with respect to the digital microcirculation. Abnormalities are associated with coronary endothelial dysfunction. We therefore investigated whether impaired digital reactive hyperemia is associated with restenosis after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). METHODS: This study included 86 patients with ACS who underwent successful primary PCI of native vessels for de novo lesions. The reactive hyperemia index (RHI) was calculated using RH-PAT at three weeks and eight months after ACS. The RHI was defined as the ratio of the digital pulse volume during reactive hyperemia to that observed at baseline. Restenosis was defined as diameter stenosis of >= 50% in the in segment area based on the findings of quantitative coronary angiography performed at eight months. RESULTS: Restenosis was detected in 17 patients (20%). There were no differences in the RHI at three weeks between the patients with and without restenosis (1.70 vs. 1.87; p=0.13); however, the RHI values at eight months were significantly attenuated in the patients with restenosis versus those without (1.75 vs. 2.12; p=0.03). A univariate logistic regression analysis showed that the eight-month RHI (<2, obtained from a receiver operating characteristic analysis) was a significant risk factor for restenosis (odds ratio: 4.23, 95% confidence interval: 1.25 to 14.28, p=0.02). CONCLUSIONS: Impairment of the digital hyperemic response at eight months is associated with restenosis after primary intervention in patients with ACS, suggesting the potential of RH-PAT as a noninvasive test for identifying patients with a high risk of restenosis. PMID- 24814197 TI - Discovery of novel 2-((pyridin-3-yloxy)methyl)piperazines as alpha7 nicotinic acetylcholine receptor modulators for the treatment of inflammatory disorders. AB - Herein we report the design, synthesis, and structure-activity relationships for a new class of alpha7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5 b]pyridine, (R)-18, and 4-methoxyphenylurea, (R)-47, were identified as potent and selective modulators of the alpha7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (R)-18 was shown to be an agonist. Compound (R)-47 demonstrated silent agonist activity. These data support the hypothesis that the anti inflammatory activity of the alpha7 nAChR is mediated by a signal transduction pathway that is independent of ion current. PMID- 24814198 TI - Epilepsy-burning questions and emerging therapies. PMID- 24814199 TI - Dietary advanced glycation end-products, its pulmonary receptor, and high mobility group box 1 in aspiration lung injury. AB - BACKGROUND: Gastric aspiration is a significant cause of acute lung injury and acute respiratory distress syndrome. Environmental risk factors, such as a diet high in proinflammatory advanced glycation end-products (AGEs), may render some patients more susceptible to lung injury after aspiration. We hypothesized that high dietary AGEs increase its pulmonary receptor, RAGE, producing an amplified pulmonary inflammatory response in the presence of high mobility group box 1 (HMGB1), a RAGE ligand and an endogenous signal of epithelial cell injury after aspiration. MATERIALS AND METHODS: CD-1 mice were fed either a low AGE or high AGE diet for 4 wk. After aspiration injury with acidified small gastric particles, bronchoalveolar lavage and whole-lung tissue samples were collected at 5 min, 1 h, 5 h, and 24 h after injury. RAGE, soluble RAGE (sRAGE), HMGB1, cytokine and chemokine concentrations, albumin levels, neutrophil influx, and lung myeloperoxidase activity were measured. RESULTS: We observed that high AGE fed mice exhibited greater pulmonary RAGE levels before aspiration and increased bronchoalveolar lavage sRAGE levels after aspiration compared with low AGE-fed mice. Lavage HMGB1 levels rose immediately after aspiration, peaking at 1 h, and strongly correlated with sRAGE levels in both dietary groups. High AGE-fed mice demonstrated higher cytokine and chemokine levels with increased pulmonary myeloperoxidase activity over 24 h versus low AGE-fed mice. CONCLUSIONS: This study indicates that high dietary AGEs can increase pulmonary RAGE, augmenting the inflammatory response to aspiration in the presence of endogenous damage signals such as HMGB1. PMID- 24814200 TI - Short-term effect of ascorbate on bacterial content, plasminogen activator inhibitor-1, and myeloperoxidase in septic mice. AB - BACKGROUND: Sepsis, a potential risk associated with surgery, leads to a systemic inflammatory response including the plugging of capillary beds. This plugging may precipitate organ failure and subsequent death. We have shown that capillary plugging can be reversed rapidly within 1 h by intravenous injection of ascorbate in mouse skeletal muscle. It is unknown whether, in parallel with this effect, ascorbate negatively affects the protective responses to sepsis involving the fibrinolytic and immune systems. We hypothesized that treatment with ascorbate for 1 h does not alter bacterial content, plasminogen activator inhibitor 1 (PAI 1), and neutrophil infiltration in lung, kidney, spleen, and liver (organs with high immune response) of septic mice. MATERIALS AND METHODS: Sepsis was induced by feces injection into the peritoneum. Mice were injected intravenously with ascorbate at 6 h (10 mg/kg), and samples of peritoneal fluid, arterial blood, and organs collected at 7 h were subjected to analyses of bacterial content, PAI-1 messenger RNA and enzymatic activity, and myeloperoxidase (MPO) (a measure of neutrophil infiltration). RESULTS: Sepsis increased bacterial content in all fluids and organs and increased PAI-1 messenger RNA and enzymatic activity in the lung and liver. Sepsis increased the myeloperoxidase level in the lung and liver, and lowered it in the spleen. Except for decreasing the bacterial content in blood, these responses to sepsis were not altered by ascorbate. CONCLUSIONS: The rapid effect of ascorbate against capillary plugging in the septic mouse skeletal muscle is not accompanied by alterations in PAI-1 or myeloperoxidase responses in the organs with high immune response. PMID- 24814202 TI - Comparison of propofol and dexmedetomedine techniques in children undergoing magnetic resonance imaging. AB - BACKGROUND: Propofol (PRO) and dexmedetomidine (DEX) are commonly used to produce anesthesia and sedation for routine MRI procedures. Children with complex conditions often require much lengthy MRI for multi-body-part scans with frequent scanner coil changes and patient body reposition. This study compared PRO and DEX techniques on outcomes for the particular MRI setting with longer than 1 h duration. METHODS: 95 children, aged from 1 to 7 years, scheduled for MRI >75 min were randomly assigned to PRO or DEX group. After induced with sevoflurane, a loading dose of PRO (2 mg.kg(-1)) was administrated and followed by continuous infusion (200 MUg.kg(-1) .min(-1)); a loading dose of DEX (2 MUg.kg(-1)) was administrated and followed by continuous infusion (2 MUg.kg(-1) .h(-1)). Patients received O(2) by nasal cannula. The observed outcomes were times for induction, MRI, emergence, and recovery, and total time (induction to discharge); MRI pauses from patient movement; incidence of technique failure and critical events; emergence and behavior in postanesthesia care unit (PACU); parental satisfaction; and arterial pressure (BP) and heart rate (HR) during anesthesia. RESULTS: PRO compared with DEX showed significantly less time for anesthesia induction (16.3 versus 24.2 min), emergence (21.2 versus 39.9 min), PACU (35.7 versus 62.5 min), and total time (135 versus 173 min) (all P < 0.001). There were significantly fewer pauses during MRI and lower failure rate to complete MRI in PRO versus DEX (0.22 versus 0.81, P = 0.01 and 1 versus 15, P < 0.001), less behavioral disturbances in PACU, and higher parental satisfaction in PRO versus DEX (P < 0.01). There were no critical events in either group: In PRO, mean BP during MRI (from 52 +/- 8 to 58 +/- mmHg) was significantly less than before anesthesia (80 +/- 12 mmHg), while HR remained relatively constant (range of 97-103) at its baseline of 108 +/- 21, but in DEX, mean BP remained unchanged (from 76 +/- 12 to 78 +/- 15) during anesthesia compared with before anesthesia (79 +/- 14 mmHg), while HR decreased (74 +/- 16 to 78 +/- 15) during anesthesia from its baseline (102 +/- 17). CONCLUSION: For children undergoing lengthy multicomponent MRI, the propofol technique yielded overall better outcomes than the dexmedetomedine technique in terms of timeliness, PACU emergence characteristics, and parental satisfaction. PMID- 24814201 TI - The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma. AB - BACKGROUND: Although papillary thyroid carcinoma (PTC) has favorable prognosis, it is prone to cervical lymph node metastasis. Chemokine receptors play a role in metastasis of tumor cells, and accumulating evidence suggests an important role for the chemokine receptor CXCR7 in cancer development. We previously demonstrated high expression of CXCR7 protein in PTC tissue. In this study, we further evaluated the role of CXCR7 in PTC. METHODS: The expression of CXCR7 messenger RNA and protein in 79 cases of PTC and peritumoral tissues was detected by real-time quantitative polymerase chain reaction and Western blot. The association between CXCR7 expression and clinicopathologic characteristics in PTC was analyzed. Stable CXCR7 overexpression and knockdown PTC cells were constructed and used to examine proliferation, cell cycle, apoptosis and invasion of PTC cells by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, propidium iodide staining, 7-amino-actinomycin D staining, and invasion assay. We examined cell cycle regulatory protein levels by Western blot. RESULTS: CXCR7 messenger RNA and protein levels were markedly increased in PTC and correlated with tumor progression. CXCR7 could regulate proliferation, cell cycle, apoptosis, invasion, and the expression of cell cycle regulatory proteins involved in the S-G2 phase transition. Knockdown of CXCR7 in PTC cells suppressed cell proliferation and invasion, decreased expression of cyclin A, CDK2 and PCNA, increased expression of p21 and p57, induced S phase arrest, and promoted apoptosis. CONCLUSIONS: CXCR7 plays an important role in regulating growth and metastasis ability of PTC cell and provides a potential target for therapeutic interventions in PTC. PMID- 24814203 TI - Developmental changes in the visual-proprioceptive integration threshold of children. AB - The ability to detect artificially induced visual-proprioceptive asynchrony reflects an awareness of the first-person experience of self-generated movement. The current study assessed children's (5- to 8-year-olds) and adults' ability to integrate asynchronous visual and proprioceptive stimulation by delaying the visual feedback of self-generated action in videos. Children and adults observed a monitor showing their movements of a joystick at varying delay durations and were then asked to make judgments on whether their movements appeared to be delayed or live. Children demonstrated age-related differences in their reporting of delay judgments across all delay conditions. Adults' performances on the same task exceeded those of children. The results of this study provide a mapping of visual-proprioceptive integration abilities in 5 to 8 year old children. The age related increase in sensitivity to visual-proprioceptive asynchrony is suggestive of increasing sensitivity to the temporal properties of multisensory feedback of self-generated movement with development. PMID- 24814204 TI - The development of cognitive flexibility beyond the preschool period: an investigation using a modified Flexible Item Selection Task. AB - We explored the development of cognitive flexibility in typically developing 6-, 8-, and 10-year-olds and adults by modifying a common cognitive flexibility task, the Flexible Item Selection Task (FIST). Although performance on the standard FIST reached ceiling by 8 years, FIST performance on other variations continued to improve until 10 years of age. Within a detailed task analysis, we also explored working memory storage and processing components of executive function and how these contribute to the development of cognitive flexibility. The findings reinforce the notion that cognitive flexibility is a multifaceted construct but that the development of working memory contributes in part to age related change in this ability. PMID- 24814205 TI - Infants transfer nonobvious properties from pictures to real-world objects. AB - The current research examined infants' ability to generalize information about the nonobvious properties of objects depicted in picture books to their real world referents. Infants aged 13, 15, and 18 months (N=135) were shown a series of pictures depicting an adult acting on a novel object to elicit a nonobvious property of that object. Infants were subsequently tested on their extension of the nonobvious property to the real-world object depicted in the book and their generalization of this property to a different color exemplar of the depicted object. Results indicated that, regardless of age, infants expected the real world objects to have the nonobvious property, as indicated by their attempts to elicit this property with these objects. These findings indicate that early in their second year of life, infants are beginning to make inductive inferences about nonobvious object properties based on information provided in pictures. PMID- 24814206 TI - The roles of maternal mind-mindedness and infant security of attachment in predicting preschoolers' understanding of visual perspective taking and false belief. AB - This study is a follow-up to a previous study that examined two aspects of mother child relationships-mothers' mind-mindedness and infant attachment security-in relation to toddlers' early manifestations of theory of mind understanding at 2 years of age. The current study aimed to assess the same two aspects of mother child relationships in relation to children's (N=59) theory of mind performance at 4 years of age. Results of the current study confirmed and expanded on relations observed at 2 years. Mothers' use of appropriate mind-related comments specifically during toy-based free play at 12 months of age predicted preschoolers' understanding of false belief and Level 2 visual perspective taking over and above earlier perspective-taking abilities. Furthermore, more securely attached boys, but not girls, performed better on a task requiring Level 2 visual perspective taking. The similarity of results across the two time points suggests the reliability of associations among mothers' use of mind-related comments during toy-based play, boys' attachment security, and children's subsequent social understanding. The current results also suggest that maternal mind mindedness may be most relevant to children's social cognition when assessed in toy-based play contexts. PMID- 24814207 TI - Evaluating the effect of vehicle impoundment policy on illegal construction and demolition waste dumping: Israel as a case study. AB - Construction and demolition (C&D) waste dumped alongside roads and in open areas is a major source of soil and underground water pollution. Since 2006, Israeli ministry for environmental protection enacted a policy of vehicle impoundment (VI) according to which track drivers caught while dumping C&D waste illegally have their vehicles impounded. The present study attempted to determine whether the VI policy was effective in increasing the waste hauling to authorized landfill sites, thus limiting the number of illegal unloads of C&D waste at unauthorized landfill sites and in open areas. During the study, changes in the ratio between the monthly amount of C&D waste brought to authorized landfills sites and the estimated total amount of C&D waste generated in different administrative districts of Israel were examined, before and after the enactment of the 2006 VI policy. Short questionnaires were also distributed among local track drivers in order to determine the degree of awareness about the policy in question and estimate its deterrence effects. According to the study's results, in the district of Haifa, in which the VI policy was stringently enacted, the ratio between C&D waste, dumped in authorized landfill sites, and the total amount of generated C&D waste, increased, on the average, from 20% in January 2004 to 35% in October 2009, with the effect attributed to the number of vehicle impoundments being highly statistically significant (t=2.324; p<0.05). By contrast, in the Jerusalem and Southern districts, in which the VI policy was less stringently enforced, the effect of VI on the above ratio was found to be insignificant (p>0.1). The analysis of the questionnaires, distributed among the local truck drivers further indicated that the changes observed in the district of Haifa are not coincident and appeared to be linked to the VI policy's enactment. In particular, 62% of the truck drivers, participated in the survey, were aware of the policy and 47% of them personally knew a driver whose vehicle was impounded. Furthermore, the drivers estimated the relative risk of being caught for unloading C&D waste in unauthorized sites, on the average, as high as 67%, which is likely to become a deterrent on its own. Our conclusion is that the VI policy appears to have a deterring effect on truck drivers, by encouraging them to haul C&D waste to authorized landfill sites. As we suggest, the research methodology implemented in the study and its results may help policy makers in other regions and countries, which experience similar environment enforcement problem, to analyze policy responses. PMID- 24814208 TI - Network-dependent modulation of brain activity during sleep. AB - Brain activity dynamically changes even during sleep. A line of neuroimaging studies has reported changes in functional connectivity and regional activity across different sleep stages such as slow-wave sleep (SWS) and rapid-eye movement (REM) sleep. However, it remains unclear whether and how the large-scale network activity of human brains changes within a given sleep stage. Here, we investigated modulation of network activity within sleep stages by applying the pairwise maximum entropy model to brain activity obtained by functional magnetic resonance imaging from sleeping healthy subjects. We found that the brain activity of individual brain regions and functional interactions between pairs of regions significantly increased in the default-mode network during SWS and decreased during REM sleep. In contrast, the network activity of the fronto parietal and sensory-motor networks showed the opposite pattern. Furthermore, in the three networks, the amount of the activity changes throughout REM sleep was negatively correlated with that throughout SWS. The present findings suggest that the brain activity is dynamically modulated even in a sleep stage and that the pattern of modulation depends on the type of the large-scale brain networks. PMID- 24814210 TI - Audio-visual synchrony modulates the ventriloquist illusion and its neural/spatial representation in the auditory cortex. AB - An essential task of our perceptual systems is to bind together the distinctive features of single objects and events into unitary percepts, even when those features are registered in different sensory modalities. In cases where auditory and visual inputs are spatially incongruent, they may still be perceived as belonging to a single event at the location of the visual stimulus - a phenomenon known as the 'ventriloquist illusion'. The present study examined how audio visual temporal congruence influences the ventriloquist illusion and characterized its neural underpinnings with functional magnetic resonance imaging (fMRI). Behaviorally, the ventriloquist illusion was reduced for asynchronous versus synchronous audio-visual stimuli, in accordance with previous reports. Neural activity patterns associated with the ventriloquist effect were consistently observed in the planum temporale (PT), with a reduction in illusion related fMRI-signals ipsilateral to visual stimulation for central sounds perceived peripherally and a contralateral increase in illusion-related fMRI signals for peripheral sounds perceived centrally. Moreover, it was found that separate but adjacent regions within the PT were preferentially activated for ventriloquist illusions produced by synchronous and asynchronous audio-visual stimulation. We conclude that the left-right balance of neural activity in the PT represents the neural code that underlies the ventriloquist illusion, with greater activity in the cerebral hemisphere contralateral to the direction of the perceived shift of sound location. PMID- 24814209 TI - Age-related increase of resting metabolic rate in the human brain. AB - With age, many aspects of the brain structure undergo a pronounced decline, yet individuals generally function well until advanced old age. There appear to be several compensatory mechanisms in brain aging, but their precise nature is not well characterized. Here we provide evidence that the brain of older adults expends more energy when compared to younger adults, as manifested by an age related increase (P=0.03) in cerebral metabolic rate of oxygen (CMRO2) (N=118, men=56, ages 18 to 74). We further showed that, before the mean menopausal age of 51years old, female and male groups have similar rates of CMRO2 increase (P=0.015) and there was no interaction between age and sex effects (P=0.85). However, when using data from the entire age range, women have a slower rate of CMRO2 change when compared to men (P<0.001 for age*sex interaction term). Thus, menopause and estrogen level may have played a role in this sex difference. Our data also revealed a possible circadian rhythm of CMRO2 in that brain metabolic rate is greater at noon than in the morning (P=0.02). This study reveals a potential neurobiological mechanism for age-related compensation in brain function and also suggests a sex-difference in its temporal pattern. PMID- 24814211 TI - The preBotzinger complex as a hub for network activity along the ventral respiratory column in the neonate rat. AB - In vertebrates, respiratory control is ascribed to heterogeneous respiration modulated neurons along the Ventral Respiratory Column (VRC) in medulla, which includes the preBotzinger Complex (preBotC), the putative respiratory rhythm generator. Here, the functional anatomy of the VRC was characterized via optical recordings in the sagittaly sectioned neonate rat hindbrain, at sampling rates permitting coupling estimation between neuron pairs, so that each neuron was described using unitary, neuron-system, and coupling attributes. Structured coupling relations in local networks, significantly oriented coupling in the peri inspiratory interval detected in pooled data, and significant correlations between firing rate and expiratory duration in subsets of neurons revealed network regulation at multiple timescales. Spatially averaged neuronal attributes, including coupling vectors, revealed a sharp boundary at the rostral margin of the preBotC, as well as other functional anatomical features congruent with identified structures, including the parafacial respiratory group and the nucleus ambiguus. Cluster analysis of attributes identified two spatially compact, homogenous groups: the first overlapped with the preBotC, and was characterized by strong respiratory modulation and dense bidirectional coupling with itself and other groups, consistent with a central role for the preBotC in respiratory control; the second lay between preBotC and the facial nucleus, and was characterized by weak respiratory modulation and weak coupling with other respiratory neurons, which is congruent with cardiovascular regulatory networks that are found in this region. Other groups identified using cluster analysis suggested that networks along VRC regulated expiratory duration, and the transition to and from inspiration, but these groups were heterogeneous and anatomically dispersed. Thus, by recording local networks in parallel, this study found evidence for respiratory regulation at multiple timescales along the VRC, as well as a role for the preBotC in the integration of functionally disparate respiratory neurons. PMID- 24814212 TI - Structural connectivity differences in left and right temporal lobe epilepsy. AB - Our knowledge on temporal lobe epilepsy (TLE) with hippocampal sclerosis has evolved towards the view that this syndrome affects widespread brain networks. Diffusion weighted imaging studies have shown alterations of large white matter tracts, most notably in left temporal lobe epilepsy, but the degree of altered connections between cortical and subcortical structures remains to be clarified. We performed a whole brain connectome analysis in 39 patients with refractory temporal lobe epilepsy and unilateral hippocampal sclerosis (20 right and 19 left) and 28 healthy subjects. We performed whole-brain probabilistic fiber tracking using MRtrix and segmented 164 cortical and subcortical structures with Freesurfer. Individual structural connectivity graphs based on these 164 nodes were computed by mapping the mean fractional anisotropy (FA) onto each tract. Connectomes were then compared using two complementary methods: permutation tests for pair-wise connections and Network Based Statistics to probe for differences in large network components. Comparison of pair-wise connections revealed a marked reduction of connectivity between left TLE patients and controls, which was strongly lateralized to the ipsilateral temporal lobe. Specifically, infero lateral cortex and temporal pole were strongly affected, and so was the perisylvian cortex. In contrast, for right TLE, focal connectivity loss was much less pronounced and restricted to bilateral limbic structures and right temporal cortex. Analysis of large network components revealed furthermore that both left and right hippocampal sclerosis affected diffuse global and interhemispheric connectivity. Thus, left temporal lobe epilepsy was associated with a much more pronounced pattern of reduced FA, that included major landmarks of perisylvian language circuitry. These distinct patterns of connectivity associated with unilateral hippocampal sclerosis show how a focal pathology influences global network architecture, and how left or right-sided lesions may have differential and specific impacts on cerebral connectivity. PMID- 24814213 TI - Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults. AB - Important risk factors for Alzheimer's disease (AD) are ageing and the Apolipoprotein E (APOE) epsilon4 allele, with female APOE epsilon4 carriers having the greatest risk. In this study we investigated effects of AD risk factors on connectivity of the hippocampus, a structure that shows early AD related pathology. Resting-state functional magnetic resonance imaging and diffusion tensor imaging data from 86 cognitively healthy subjects aged 30 to 78years were analysed. Female APOE epsilon4 carriers showed overall significantly reduced functional connectivity between the hippocampus and precuneus/posterior cingulate cortex (PCC) and a significant age-related decrease in connectivity of these regions. In females and APOE epsilon4 carriers we found significantly reduced white matter integrity of the tract connecting the hippocampus and PCC with a significant positive correlation of white matter integrity and resting state connectivity. Increased vulnerability of the connection between the hippocampus and PCC might be one reason for increased AD risk in female APOE epsilon4 carriers. Interventions targeting hippocampal connectivity might be especially effective in this at risk population. PMID- 24814215 TI - Noninvasive evaluation of swallowing sound is an effective way of diagnosing feeding maturation in newborn infants. AB - AIM: Despite extensive research, there is still controversy regarding the time at which sucking and swallowing functions mature in preterm infants. This study aimed to evaluate maturation using the noninvasive method of swallowing sound. METHODS: We compared 52 preterm infants of between 27 and 36 weeks' gestational age with a control group of 42 healthy full-term infants. Feeding performance was based on swallowing data collected during two-minute audio recordings. The following variables were generated for each evaluation: total number of swallows, total number of rhythmic swallows, total number of resting intervals, average time between resting intervals, average time between swallows, average time between rhythmic swallows, maximum number of rhythmic swallows and volume of milk ingested. The dependency of the variables on postmenstrual age was also investigated. RESULTS: The volume of milk ingested by the preterm infants and the maximum number of rhythmic swallows were positively correlated with postmenstrual age (PMA). The preterm infants reached the 10th percentile of the control infants at 34-35 weeks' PMA and were not significantly different from the control infants at 38-40 weeks' PMA. CONCLUSION: Swallowing sound can be used to assess feeding maturation in preterm infants during neonatal intensive care unit follow-up. PMID- 24814214 TI - Language-general and -specific white matter microstructural bases for reading. AB - In the past decade, several studies have investigated language-general and specific brain regions for reading. However, very limited research has examined the white matter that connects these cortical regions. By using diffusion tensor imaging (DTI), the current study investigated the common and divergent relationship between white matter integrity indexed by fractional anisotropy (FA) and native language reading abilities in 89 Chinese and 93 English speakers. Conjunction analysis revealed that for both groups, reading ability was associated with the FA of seven white matter fiber bundles in two main anatomical locations in the left hemisphere: the dorsal corona radiate/corpus callosum/superior longitudinal fasciculus which might be for phonological access, and the ventral uncinate fasciculus/external capsule/inferior fronto-occipital fasciculus which might be for semantic processing. Contrast analysis showed that the FA of the left temporal part of superior longitudinal fasciculus contributed more to reading in English than in Chinese, which is consistent with the notion that this tract is involved in grapheme-to-phoneme conversion for alphabetic language reading. These results are the first evidence of language-general and specific white matter microstructural bases for reading. PMID- 24814216 TI - Gender differences in the clustering patterns of risk behaviours associated with non-communicable diseases in Brazilian adolescents. AB - OBJECTIVE: The aim of this study is to investigate gender differences in the clustering of risk behaviours associated with chronic non-communicable diseases in Brazilian adolescents. METHODS: A cross-sectional survey was conducted in 2011 comprising 6529 adolescents aged 15-19years from Santa Catarina State, Brazil. Excessive screen-time, insufficient moderate to vigorous physical activity (MVPA), low fruit/vegetable intake and consumption of alcohol were investigated. Poisson regression was performed in the analysis of sociodemographic factors associated with the clustering of three or more risk behaviours. RESULTS: Girls presented with higher insufficient MVPA (76.3%), while boys presented with lower fruit or vegetable intake (53.0%) and greater consumption of alcohol (40.8%). A total of 21.2% of the teenagers had one risk behaviour, 37.3% had two, 28.5% had three, and 8.0% had all of the measured risk behaviours. Adolescents who did not work and boys who lived in urban areas exhibited more risk behaviours, whereas girls aged 17-19years old and boys who had mothers with >=12years of study exhibited fewer risk behaviours. CONCLUSION: There was a difference between genders for individual risk behaviours, and a high degree of clustering in both genders. Prevention programs could focus on these behaviours in order to reduce negative health outcomes in adolescents. PMID- 24814217 TI - Pheomelanin-induced oxidative stress: bright and dark chemistry bridging red hair phenotype and melanoma. AB - The complex interplay of genetic and epigenetic factors linking sun exposure to melanoma in the red hair phenotype hinges on the peculiar physical and chemical properties of pheomelanins and the underlying biosynthetic pathway, which is switched on by the effects of inactivating polymorphisms in the melanocortin 1 receptor gene. In addition to the long recognized UV-dependent pathways of toxicity and cell damage, a UV-independent pro-oxidant state induced by pheomelanin within the genetically determined background of the red hair phenotype has recently been disclosed. This review provides a detailed discussion of the possible UV-dependent and UV-independent chemical mechanisms underlying pheomelanin-mediated oxidative stress, with special reference to the oxygen dependent depletion of glutathione and other cell antioxidants. The new concept of pheomelanin as a 'living' polymer and biocatalyst that may grow by exposure to monomer building blocks and may trigger autooxidative processes is also discussed. As a corollary, treatment of inflammatory skin diseases in RHP patients is briefly commented. Finally, possible concerted strategies for melanoma prevention in the red hair phenotype are proposed. PMID- 24814219 TI - Development of redox-switchable resorcin[4]arene cavitands. AB - CONSPECTUS: Within the framework of miniaturization of electromechanical devices, the development of a redox-switchable molecular gripper as a tool for nanorobotics is appealing both from an academic and from a practical perspective. Such a tool should be able to controllably grab a molecular cargo, translocate it over considerable distances and time scales, and release it. Resorcin[4]arene cavitands seem to be an ideal platform for the development of molecular grippers due to their ability to adopt two spatially well-defined conformations: an expanded kite and a contracted vase. Furthermore, they possess "legs" for functionalization and attachment to metal surfaces. While changes in temperature, pH, and metal-ion concentration were known to induce conformational switching, redox-switchable cavitands remained a challenge. In this Account, we describe our efforts toward the development of a new class of resorcin[4]arene cavitands that are redox-switchable. First, we introduced the naphthoquinone moiety as a redox active wall component and showed that cavitands containing four quinone walls strongly prefer the open kite conformation in both the quinone and hydroquinone redox states, while cavitands that contain two quinone and two quinoxaline walls can adopt both the vase and the kite conformations depending on solvent but not on redox state. Next, in order to introduce a driving force for the conformational switching process in diquinone cavitands, we designed cavitands with hydrogen bond acceptor groups on the quinoxaline walls. These acceptors were sought to establish hydrogen bonds with the hydroquinone groups in the reduced redox state, thereby stabilizing the vase form. Oxidation to the quinone state would remove these interactions, switching the cavitand back to the kite form. Cavitands equipped with different hydrogen bond acceptor groups were synthesized and evaluated. We found that carboxamide moieties are best suited to assist redox induced switching of conformational and binding properties. With the goal of further increasing association constants and reducing guest-exchange rates via steric congestion, we exchanged the naphthoquinone with the triptycene-quinone moiety. The congesting influence of the triptycene-quinone moiety on the binding properties was quantified both in the presence and in the absence of additional hydrogen bond interactions that stabilize the vase form. X-ray crystallographic studies provided insights into the solid-state structures of the cavitands in different solvents and redox states. A significant enhancement of association constants and reduction in guest release rates was observed in the reduced redox state compared with the top-open system, yielding redox-switchable cavitand baskets. These studies represent a step towards the development of redox switchable molecular grippers on metal surfaces. Future challenges will consist in the development of cavitands that will no longer rely on an external proton source for the switching process, allowing redox-switching to be performed in purely aprotic media. Finally, suitable leg functionalization would enable the grippers to be interfaced with metal surfaces. PMID- 24814218 TI - Type AII lantibiotic bovicin HJ50 with a rare disulfide bond: structure, structure-activity relationships and mode of action. AB - Lantibiotics are ribosomally synthesized antimicrobial peptides containing unusual amino acids. As promising alternatives to conventional antibiotics, they have a high potential for alleviating the problem of emergent antibiotic resistance, with possible applications in many industries that have antibacterial demand. Bovicin HJ50 is a type AII lantibiotic, the largest group of lantibiotics, comprising a linear N-terminal region and a globular C-terminal region. Interestingly, bovicin H50 has a disulfide bond that is rare in this group. Owing to limited information about the spatial structures of type AII lantibiotics, the functional regions of this type and the role of the disulfide bond are still unknown. In the present study, we resolved the solution structure of bovicin HJ50 using NMR spectroscopy. This is the first spatial structure of a type AII lantibiotic. Bovicin HJ50 exhibited high flexibility in aqueous solution, whereas varied rigidities were observed in the different rings with the conserved ring A being the most rigid. The charged residues Lys11, Asp12 and Lys30, as well as the essential disulfide bond were critical for antimicrobial activity. Importantly, bovicin HJ50 showed not only peptidoglycan precursor lipid II-binding ability, but also pore-forming activity, which is significantly different from other bacteriostatic type AII lantibiotics, suggesting a novel antimicrobial mechanism. PMID- 24814220 TI - Drug transporter expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line. AB - Ovarian cancer is characterized by the higher mortality among gynecological cancers. In results of MDR development during chemotherapy cancer cells become resistant to further treatment. Microarray techniques can provide information about MDR development at gene expression level. ABC and SLC transporters are most important proteins responsible for this phenomenon. In this study changes of ABC and SLC genes expression pattern in drugs resistant sublines of the A2780 ovarian cancer cell line were demonstrated. The cytostatic resistant sublines were generated by culture of A2780 cell line with an increasing concentration of the indicated drugs. As screening methods, we used Affymetrix U219 Human Genome microarrays. Independent t-tests were used to determinate statistical significances of results. Genes that expression levels were higher than assumed threshold (upregulated above threefold and downregulated under -3 fold) were visualized using scatter plot method, selected and listed in table. Between the ABC genes increased expression of seven genes and decreased expression of three genes were observed. Expression of two genes was increased or decreased depending on the cell line. We observed significant (more than tenfold) increase in expression of four ABC genes: ABCA8, ABCB1, ABCB4 and ABCG2 and decreased expression of ABCA3 gene. We also observed changes in expression of 32 SLC genes. Between them we observe increased expression of 17 genes and decreased expression of 15 genes. Expression of four genes was increased or decreased dependent on cell line. The expression of nine SLC genes increased or decreased very significantly (more than tenfold). Five genes were significantly upregulated: SLC2A9, SLC16A3, SLC16A14, SLC38A4 and SLC39A8. Four additional genes were significantly downregulated: SLC2A14, SLC6A15, SLC8A1 and SLC27A2. Expression profiles of these genes give strong arguments for assumption of correlation between expression of ABC and SLC genes and drug resistance phenomenon. Identifying correlations between specific drug transporters and cytostatic drug resistance will require further investigation. PMID- 24814221 TI - The root of the problem: increasing root vegetable intake in preschool children by repeated exposure and flavour flavour learning. AB - Children's vegetable consumption falls below current recommendations, highlighting the need to identify strategies that can successfully promote intake. The current study aimed to investigate the effectiveness of flavour flavour learning as one such strategy for increasing vegetable intake in preschool children. Children (N = 29) aged 15 to 56 months were recruited through participating nurseries. Each received a minimum of six and maximium eight exposures to a root vegetable puree with added apple puree (flavour-flavour learning) alternating with six to eight exposures to another with nothing added (repeated exposure). A third puree acted as a control. Pre- and post-intervention intake measures of the three purees with nothing added were taken to assess change in intake. Follow-up measures took place 1 month (n = 28) and 6 months (n = 10) post-intervention. Intake increased significantly from pre- to post intervention for all purees (~36 g), with no effect of condition. Magnitude of change was smaller in the control condition. Analysis of follow-up data showed that intake remained significantly higher than baseline 1 month (p < 0.001) and 6 months (p < 0.001) post-intervention for all conditions. Children under 24 months ate consistently more across the intervention than the older children (>=24 m) with no differences found in response to condition. This study confirms previous observations that repeated exposure increases intake of a novel vegetable in young children. Results also suggest that mere exposure (to the food, the experimenters, the procedure) can generalise to other, similar vegetables but the addition of a familiar flavour confers no added advantage above mere exposure. PMID- 24814222 TI - Fetal echocardiographic characteristics of fused heart in thoracopagus conjoined twins. AB - Conjoined twins (CT) are rare with possible serious malformations in which soft tissue, bone, or some organs are joined in utero. The extent of cardiac fusion and intracardiac anatomy of CT determine the viability, natural history, and outcome of potential surgical intervention. Early prenatal diagnosis and assessment may provide a window of opportunity to counsel the family for their informed decision on the pregnancy and to plan for prenatal and perinatal care. In this report, we describe a case of thoracopagus twins diagnosed by fetal echocardiography at 23-week gestation. The 2 hearts fused at the atrial and ventricular levels. The outcome and review of literature on fetal echocardiographic characteristics of this malformation are discussed. PMID- 24814223 TI - Missed opportunities in crystallography. AB - Scrutinized from the perspective of time, the giants in the history of crystallography more than once missed a nearly obvious chance to make another great discovery, or went in the wrong direction. This review analyzes such missed opportunities focusing on macromolecular crystallographers (using Perutz, Pauling, Franklin as examples), although cases of particular historical (Kepler), methodological (Laue, Patterson) or structural (Pauling, Ramachandran) relevance are also described. Linus Pauling, in particular, is presented several times in different circumstances, as a man of vision, oversight, or even blindness. His example underscores the simple truth that also in science incessant creativity is inevitably connected with some probability of fault. PMID- 24814224 TI - Excited state electronic structures of 5,10-methenyltetrahydrofolate and 5,10 methylenetetrahydrofolate determined by Stark spectroscopy. AB - Folates are ubiquitous cofactors that participate in a wide variety of critical biological processes. 5,10-Methenyltetrahydrofolate and its photodegradation product 5,10-methylenetetrahydrofolate are both associated with the light-driven DNA repair protein DNA photolyase and its homologues (e.g., cryptochromes). The excited state electronic properties of these folate molecules have been studied here using Stark spectroscopy and complementary quantum calculations. The tetrahydrofolates have relatively large difference dipole moments (ca. 6-8 Debye) and difference polarizabilities (ca. 100 A(3)). This extensive excited state charge redistribution appears to be due largely to the pendant p-aminobenzoic acid group, which helps shuttle charge over the entirety of the molecule. Simple calculations based on the experimental difference dipole moments suggest that tetrahydrofolates should have large two photon cross sections sufficient to enable two photon microscopy to selectively detect and follow folate-containing proteins both in vitro and in vivo. PMID- 24814225 TI - Metabolomics analysis of collagen-induced arthritis in rats and interventional effects of oral tolerance. AB - A serum metabolomics method based on rapid resolution liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (RRLC-Q-TOF-MS) was performed for a holistic evaluation of the metabolic changes of collagen-induced arthritis (CIA) in rats and to assess the interventional effects of type II collagen (CII) in this model. Partial least-squares-discriminant analysis (PLS DA) was employed to study the metabolic profiling of CIA rats and control rats. Ten metabolites, namely, 12(S)-HHTrE, 12(S)-HEPE, PGE2, TXB2, 12(S)-HETE, LysoPE(16:0), PE(O-18:0/0:0), Lyso-PE(18:2), Lyso-PE(20:4), and Lyso-PC(22:5) were identified as differential metabolites associated with the pathogenesis of CIA. These results suggested that dysregulation of the arachidonic acid (AA) and phospholipid metabolic networks is involved in the pathomechanism of CIA. Differential metabolomics and histopathological analyses demonstrated that CII inhibits the progress of arthritis. Furthermore, the therapeutic effects of CII on CIA may involve regulation of the disordered AA and phospholipid metabolic networks. This metabolomics study provides new insights into the pathogenesis of arthritis and, furthermore, indicates the potential mechanism underlying the significantly increased prevalence of metabolic syndrome, defined as a clustering of cardiovascular disease (CVD) risk factors, in arthritis patients. PMID- 24814227 TI - Welfare states and population health: the role of minimum income benefits for mortality. AB - The causes of cross-national differences in population health are subject for intense discussion, often focusing on the role of structural economic factors. Although population health is widely believed to reflect the living conditions in society, surprisingly few comparative studies systematically assess policy impacts of anti-poverty programs. In this paper we estimate the influence of minimum income benefits on mortality using international data on benefit levels in 18 countries 1990-2009. Included are all major non-contributory benefits that low-income households may receive. Our analyses, based on fixed effects pooled time-series regression, show that minimum income benefits improve mortality, measured in terms of age-standardized death rates and life expectancy. The results on country-level links between minimum income benefits and mortality are remarkably robust in terms of measured confounding effects. PMID- 24814226 TI - Equilibrium and dynamic design principles for binding molecules engineered for reagentless biosensors. AB - Reagentless biosensors rely on the interaction of a binding partner and its target to generate a change in fluorescent signal using an environment-sensitive fluorophore or Forster resonance energy transfer. Binding affinity can exert a significant influence on both the equilibrium and the dynamic response characteristics of such a biosensor. We here develop a kinetic model for the dynamic performance of a reagentless biosensor. Using a sinusoidal signal for ligand concentration, our findings suggest that it is optimal to use a binding moiety whose equilibrium dissociation constant matches that of the average predicted input signal, while maximizing both the association rate constant and the dissociation rate constant at the necessary ratio to create the desired equilibrium constant. Although practical limitations constrain the attainment of these objectives, the derivation of these design principles provides guidance for improved reagentless biosensor performance and metrics for quality standards in the development of biosensors. These concepts are broadly relevant to reagentless biosensor modalities. PMID- 24814228 TI - Working time and cigarette smoking: evidence from Australia and the United Kingdom. AB - Cigarette smoking is a risk factor in a range of serious diseases, including cardiovascular disease, cancer, stroke and type II diabetes. Theory suggests that working long hours will increase smoking propensities among workers. Consequently there is a significant body of evidence on the relationship between working time and smoking. Results, however, are inconsistent and therefore inconclusive. This paper provides new evidence on how working time affects smoking behaviour using nationally representative panel data from Australia (from 2002 to 2011) and the United Kingdom (from 1992 to 2011). We exploit the panel design of the surveys to look at within-person changes in smoking behaviour over time as working time changes. In contrast to most previous studies, this means we control for time invariant aspects of personality and genetic inheritance that may affect both smoking propensities and choice of working hours. We find that working long hours tends to increase the chances that former smokers will relapse, reduce the chances that smokers will quit and increase cigarette consumption among regular smokers, and that these effects tend to become more pronounced for workers who usually work very long hours (50 or more hours a week) compared to those who work moderately long hours (40-49 h a week). PMID- 24814229 TI - Electronic patient journey boards a vital piece of the puzzle in patient flow. AB - OBJECTIVE: Internationally, there is growing interest in the applicability of visual management in healthcare, although little is known about the extent of its effectiveness. In the past 5 years technical advances have permitted the integration of all relevant data into a singular display that can improve staff efficiency, accelerate decisions, streamline workflow processes and reduce oversights and errors in clinical practice. The aim of the case study is to describe the features and application of electronic patient journey boards (EPJBs) as an enabler to accelerate patient flow that has been demonstrated and evaluated in Queensland Health hospitals. METHODS: In 2012 and 2013 we collected ward-specific data that was sourced from the Queensland Hospital Admitted Patient Data Collection, determining the top 10 overnight diagnostic-related groups (DRGs) for each ward participating in the pilots. The Statistical Output Unit within Queensland Health then provided data and analysis on the ALOS for each of these DRGs for the period following an EPJB installation, along with the ALOS for the same DRGs for the corresponding period in the previous year. RESULTS: Patient length of stay reduced and display of estimated discharge dates improved with the introduction of EPJBs along with improved communication and information management resulting in time savings from 20 min per staff member per shift to 2.5h per ward a day. CONCLUSION: Queensland and South Australian Health systems have succeeded in 'making the hospital patient journey visible' through an innovative combination of information management and prominent display of key information related to patient care portrayed on large liquid crystal display (LCD) screens in hospital wards. PMID- 24814230 TI - Characteristics of patients undergoing supraglottoplasty for laryngomalacia. AB - OBJECTIVE: To examine the characteristics of patients undergoing supraglottoplasty for the treatment of laryngomalacia and to better understand the features of laryngomalacia that may predispose patients to the need for supraglottoplasty. METHODS: Review of patients who underwent supraglottoplasty for laryngomalacia at our academic tertiary care children's hospital between 2005 and 2012 examining demographic information, medical comorbidities, symptoms, indications for surgery, operative findings and procedure, site of laryngeal obstruction, operative techniques, and surgical success rates. RESULTS: Seventeen patients with laryngomalacia underwent nineteen procedures. The most common indications for supraglottoplasty were persistent stridor beyond 18 months of age (64.7%), difficulty feeding (47%), and failure to thrive (29.4%). The most common comorbidities were gastroesophageal reflux (88.2%) and cardiopulmonary disease (35.3%). Operative findings included shortened aryepiglottic folds in sixteen patients (94.1%), retropositioned epiglottis in sixteen (94.1%), and prolapsed arytenoid mucosa in five (29.4%). Fifteen patients (88.2%) underwent division of the aryepiglottic folds and four underwent ablation of arytenoid mucosa (23.5%). Of the seventeen patients who had followed up at the time of study conclusion, sixteen (94.1%) had symptom improvement and twelve (70.6%) had complete resolution of their symptoms. CONCLUSIONS: Supraglottoplasty is an effective treatment for laryngomalacia. Outcomes in our patients are similar to those reported in prior literature. The findings of shortened aryepiglottic folds and a retropositioned epiglottis appear to be disproportionately represented in our cohort of patients undergoing supraglottoplasty. PMID- 24814232 TI - Identification of a novel splice site variant of OTOF in the Korean nonsyndromic hearing loss population with low prevalence of the OTOF mutations. AB - PURPOSE: (1) To describe the frequency of the OTOF mutations among Korean ARNSHL (autosomal recessive nonsyndromic hearing loss) populations; (2) to report the vertical transmission of DFNB9 in a family, where two related DFNB9 patients in the family manifested a different audiological phenotype. METHOD: We analyzed the prevalence of OTOF mutations among 71 Korean sporadic or possible ARNSHL pediatric patients, as well as among AN/AD (auditory neuropathy/auditory dys synchrony) patients by direct PCR (polymerase chain reaction) sequencing or targeted resequencing of known deafness genes. RESULTS: The AN/AD phenotype which was characterized by preservation of OAE (otoacoustic emission) was present in 5 (7%) of 71 probands, and the prevalence of OTOF mutations was calculated to be 20% (1/5) and 1.4% (1/71) among AN/AD patients and total sporadic/ARNSHL patients, respectively. PJVK mutations did not account for Non-DFNB9 AN/AD patients. To our interest, the only proband (SB4-11) with two OTOF mutant alleles in our cohort had deaf parents, who also turned out to be DFNB9. We identified a novel splice site variant of OTOF from the mother (SB4-13) of SB4-11. This was the first observation of vertical transmission of DFNB9 phenotype from parents to son in this population where the prevalence of OTOF is very low and consanguineous marriage is not allowed. Another DFNB9 patient (SB4-12), the father of SB4-11, carried a homozygous p.Y374X mutation that affected only the long isoform of OTOF and did not manifest AN/AD. CONCLUSION: The OTOF mutations do not contribute significantly to Korean ARNSHL and AN/AD unlike in Japan and Taiwan. This low prevalence mandates a search for other etiologies. Our observation of the discordant audiologic phenotype within the same DFNB9 family is more likely due to the loss of OAE over time rather than a genotype-phenotype correlation. PMID- 24814231 TI - Pain management following myringotomy and tube placement: intranasal dexmedetomidine versus intranasal fentanyl. AB - PURPOSE: Despite the brevity of the procedure, bilateral myringotomy and tympanostomy tube placement (BMT) can result in significant postoperative pain and discomfort. As the procedure is frequently performed without intravenous access, non-parenteral routes of administration are frequently used for analgesia. The current study prospectively compares the efficacy of intranasal (IN) dexmedetomidine with IN fentanyl for children undergoing BMT. METHODS: This prospective, double-blinded, randomized clinical trial included pediatric patients undergoing BMT. The patients were randomized to receive either IN dexmedetomidine (1 MUg/kg) or fentanyl (2 MUg/kg) after the induction of general anesthesia with sevoflurane. All patients received rectal acetaminophen (40 mg/kg) and the first 50 patients also received premedication with oral midazolam. Postoperative pain and recovery were assessed using pediatric pain and recovery scales, and any adverse effects were monitored for. RESULTS: The study cohort included 100 patients who ranged in age from 1 to 7.7 years and in weight from 8.6 to 37.4 kg. They were divided into 4 groups with 25 patients in each group: (1) midazolam premedication+IN dexmedetomidine; (2) midazolam premedication+IN fentanyl; (3) no premedication+IN dexmedetomidine; and (4) no premedication+IN fentanyl. Pain scores were comparable when comparing groups 2, 3 and 4, but were higher in group 1 (midazolam premedication with IN dexmedetomidine). There was no difference in total time in the post-anesthesia care unit (PACU) or time from arrival in the PACU until hospital discharge between the 4 groups. The heart rate (HR) was significantly lower in group 3 when compared to the other groups at several different times after arrival to the PACU. No clinically significant difference was noted in blood pressure. CONCLUSION: Following BMT, when no premedication is administered, there was no clinical advantage when comparing IN dexmedetomidine (1 MUg/kg) to IN fentanyl (2 MUg/kg). The addition of oral midazolam as a premedication worsened the outcome measures particularly for children receiving IN dexmedetomidine. PMID- 24814233 TI - Comparative analysis of fracture characteristics of the developing mandible: the Mayo Clinic experience. AB - OBJECTIVE: To review and compare the epidemiology and treatment of mandibular fractures in subgroups of a pediatric population. METHODS: We conducted a retrospective review of pediatric patients (age, <=18 years) with mandibular fractures treated at our institution from January 1996 through November 2011. RESULTS: We identified 122 patients (93 [76%] male) with 216 mandibular fractures. The prevalent mechanisms of injury were motor vehicle accidents (n=52 [43%]), sports injuries (n=24 [20%]), and assault (n=13 [11%]). The most common fracture sites were subcondylar, parasymphyseal, angle, and body. Two patients (2%) were treated conservatively by observation only, 67 (55%) underwent maxillomandibular fixation alone, 41 (34%) underwent maxillomandibular fixation with plate fixation, and 7 (5.7%) underwent plate fixation only. The average duration of maxillomandibular fixation was 26 days (range, 7-49 days). Complications occurred in 11 patients (9.0%) over a mean follow-up of 92 days (range, 21-702 days). Fifty patients (41.0%) had comorbid conditions or a history of mental illness at the time of injury, including attention deficit hyperactivity disorder (n=11 [9%]), mental disorders other than attention deficit hyperactivity disorder (n=23 [19%]), and asthma (n=17 [14%]). Twenty-six patients (21%) had a history of substance use, the most common being tobacco (n=18 [15%]), alcohol (n=13 [11%]), and marijuana (n=11 [9%]). CONCLUSIONS: Treatment approach and outcomes were affected by age and fracture characteristics. In addition, a marked proportion of this cohort had preexisting mental disorders and history of substance use, which may have implications on treatment approach. PMID- 24814234 TI - A congenital mucocele of the anterior dorsal tongue. AB - We report on a new-born with a congenital mucocele on the anterior dorsal side of the tongue. The presentation as well as the differential diagnosis of congenital oral swellings is discussed. Because of breastfeeding problems the mucinous swelling was incised and drained two days after birth. Immediately after drainage the swelling disappeared. Congenital oral swellings are rare. Most of them are mucoceles. Post-partum treatment is surgically, but spontaneous remission has been described. High incidence of recurrence should be taken into account when (micro-)marsupialization or incision as sole treatment is performed. PMID- 24814235 TI - Facial soft tissues of mouth-breathing children: do expectations meet reality? AB - OBJECTIVE: To quantify the differences between the facial soft tissue morphology of severely obstructed mouth breathing (MB) and that of predominantly nasal breathing (NB) children. METHODS: Soft tissue measurements were performed in the lateral cephalograms of 64 severely obstructed MB children (mean age 6.7 +/- 1.6) compared with 64 NB children (mean age 6.5 +/- 1.3). Groups were paired by age, gender, skeletal maturation status and sagittal skeletal pattern. Based on the assumption of normality and homoscedasticity, comparison of the means and medians of soft tissue measurements between the two groups was performed. RESULTS: The facial convexity and anterior facial height ratio of MB were similar to NB children. The upper lip of MB children was protruded, and its base was thinner compared with NB; however, the length was not affected. The lower lip was shorter and more protruded in MB children. The nasolabial angle, nasal prominence, and chin thickness were smaller in MB children. CONCLUSIONS: The facial soft tissue of severely obstructed MB children is different than in NB children. Changes in lips, nasolabial angle, nasal prominence, and chin thickness are associated with severe airway obstruction in children. PMID- 24814236 TI - Observation of permeability of blood-labyrinth barrier during cytomegalovirus induced hearing loss. AB - OBJECTIVE: Congenital cytomegalovirus (CMV) infection is the most common infectious cause of sensorineural hearing loss in children. This study aims to investigate the pathogenesis CMV-induced hearing loss from the view of integrity of blood-labyrinth-barrier (BLB). METHODS: Newborn BALB/c mice were randomly divided into three groups (n=22, respectively): CMV group, control group and normal group. The CMV group and control group were intracerebrally injected with equal volume (15 MUl) of murine CMV (MCMV; 10(4)IU/0.1 ml) and PBS, respectively, and normal group did not receive any treatment. After three weeks, auditory evoked brainstem response was assessed, and permeability of BLB was evaluated by Evans blue method. Means between groups were compared using t-test. RESULTS: We observed that mice injected with MCMV had a hearing loss and it was connected with the permeability changes of BLB. Besides, using hematoxylin-eosin staining, we noticed hyperaemia in stria vascularis and spiral ligament and bleeding in scala vestibule and scala tympani in CMV group. CONCLUSION: All these data indicated the possible association between CMV-induced hearing loss and BLB dysfunction with the characteristics of inflammation. Our data provide a possible path to investigate the mechanism of CMV-induced hearing damage. PMID- 24814237 TI - Knowledge, experience and practice of SLTs regarding (re)habilitation in deaf children with cochlear implants. AB - OBJECTIVES: To assess the knowledge, experience and practices of speech and language therapists (SLTs) in Greece regarding children with cochlear implants. METHODS: A special designed questionnaire was originally completed electronically by 313 SLTs via surveymonkey platform. RESULTS: From the 313 respondents 35% had worked with implanted children, 37% received course training and 44% had participated in post-graduate seminars. Although 96% believe that there are differences in the management of these children, almost 47% of the participants did not have adequate knowledge on the candidacy criteria for implantation and 70% regarding the available technology for implanted children. Knowledge and skills on CI were better for those SLTs who worked with hearing-impairment. Diverse practice models were noted. Interestingly, more than 87% of the participants advocated toward further training and supervision in the field, even the ones who had less than extensive knowledge in working with CI. As for practice, a lack of organizational interdisciplinary structure became evident. CONCLUSIONS: There is a growing need for well organized professional training and team networks for SLTs in order for them to further improve their knowledge and service delivery to implanted children. PMID- 24814238 TI - Plasmocytoid dendritic cell deficit of early response to toll-like receptor 7 agonist stimulation in multiple sclerosis patients. AB - Plasmacytoid dendritic cells (pDCs), an important immunoregulatory population, are characterized by vigorous secretion of type I interferons (IFNs) in response to toll-like receptor (TLR) 7 and 9 stimulation. We studied the function of pDCs in multiple sclerosis (MS) patients by analysis of TLR7 responses. We assessed a pDC secretion pattern of cytokines in the short term PBMC cultures stimulated with TLR7 agonist. pDCs sorted from PBMCs of both MS patients and controls were used to assess TLR7 expression profile. TLR7 induced signaling in pDCs has been analyzed with intracellular flow cytometry. We have identified a clinically correlated significant decrease of the TLR7-induced IFN-alfa (IFNa) secretion by pDCs from MS patients. This deficit has been accompanied by insufficient intracellular phosphorylation of protein kinase Akt and a decrease of the TLR7 gene expression in MS pDCs. Our results demonstrated a selective pDC deficit in MS supporting a relationship between pDCs and mechanisms of MS. PMID- 24814241 TI - Physiological responses of spring rapeseed (Brassica napus) to red/far-red ratios and irradiance during pre- and post-flowering stages. AB - Early shade signals promote the shade avoidance syndrome (SAS) which causes, among others, petiole and shoot elongation and upward leaf position. In spite of its relevance, these photomorphogenic responses have not been deeply studied in rapeseed (Brassica napus). In contrast to other crops like maize and wheat, rapeseed has a complex developmental phenotypic pattern as it evolves from an initial rosette to the main stem elongation and an indeterminate growth of floral raceme. In this work, we analyzed (1) morphological and physiological responses at individual level due to low red/far-red (R/FR) ratio during plant development, and (2) changes in biomass allocation, grain yield and composition at crop level in response to high R/FR ratio and low irradiance in two modern spring rapeseed genotypes. We carried out pot and field experiments modifying R/FR ratios and irradiance at vegetative or reproductive stages. In pot experiments, low R/FR ratio increased the petiole and lamina length, upward leaf position and also accelerated leaf senescence. Furthermore, low R/FR ratio reduced main floral raceme and increased floral branching with higher remobilization of soluble carbohydrates from the stems. In field experiments, low irradiance during post flowering reduced grain yield, harvest index and grain oil content, and high R/FR ratio reaching the crop partially alleviated such effects. We conclude that photomorphogenic signals are integrated early during the vegetative growth, and irradiance has stronger effects than R/FR signals at rapeseed crop level. PMID- 24814239 TI - Phenotypes and distribution of mucosal memory B-cell populations in the SIV/SHIV rhesus macaque model. AB - As vaccine-elicited antibodies have now been associated with HIV protective efficacy, a thorough understanding of mucosal and systemic B-cell development and maturation is needed. We phenotyped mucosal memory B-cells, investigated isotype expression and homing patterns, and defined plasmablasts and plasma cells at three mucosal sites (duodenum, jejunum and rectum) in rhesus macaques, the commonly used animal model for pre-clinical vaccine studies. Unlike humans, macaque mucosal memory B-cells lacked CD27 expression; only two sub-populations were present: naive (CD21(+)CD27(-)) and tissue-like (CD21(-)CD27(-)) memory. Similar to humans, IgA was the dominant isotype expressed. The homing markers CXCR4, CCR6, CCR9 and alpha4beta7 were differentially expressed between naive and tissue-like memory B-cells. Mucosal plasmablasts were identified as CD19(+)CD20(+/-)HLA-DR(+)Ki-67(+)IRF4(+)CD138(+/-) and mucosal plasma cells as CD19(+)CD20(-)HLA-DR(-)Ki-67(-)IRF4(+)CD138(+). Both populations were CD39(+/ )CD27(-). Plasma cell phenotype was confirmed by spontaneous IgA secretion by ELISpot of positively-selected cells and J-chain expression by real-time PCR. Duodenal, jejunal and rectal samples were similar in B-cell memory phenotype, isotype expression, homing receptors and plasmablast/plasma cell distribution among the three tissues. Thus rectal biopsies adequately monitor B-cell dynamics in the gut mucosa, and provide a critical view of mucosal B-cell events associated with development of vaccine-elicited protective immune responses and SIV/SHIV pathogenesis and disease control. PMID- 24814242 TI - Headless bone screw fixation for combined volar lunate facet distal radius fracture and capitate fracture: case report. AB - We report a case of concomitant fractures of the volar lunate facet of the distal radius and capitate body. Surgical fixation was achieved with open reduction internal fixation using headless compression screws for both fractures. Because of the nature of complications seen after both operative and nonsurgical management, these fractures warrant particular attention. PMID- 24814243 TI - Calcium signalling from the type I inositol 1,4,5-trisphosphate receptor is required at early phase of liver regeneration. AB - BACKGROUND & AIMS: Liver regeneration is a multistage process that unfolds gradually, with different mediators acting at different stages of regeneration. Calcium (Ca(2+) ) signalling is essential for liver regeneration. In hepatocytes, Ca(2+) signalling results from the activation of inositol 1,4,5-trisphosphate receptors (InsP3 R) of which two of the three known isoforms are expressed (InsP3 R-I and InsP3 R-II). Here, we investigated the role of the InsP3 R-I-dependent Ca(2+) signals in hepatic proliferation during liver regeneration. METHODS: Partial hepatectomy (HX) in combination with knockdown of InsP3 R-I (AdsiRNA-I) was used to evaluate the role of InsP3 R-I on liver regeneration and hepatocyte proliferation, as assessed by liver to body mass ratio, PCNA expression, immunoblots and measurements of intracellular Ca(2+) signalling. RESULTS: AdsiRNA I efficiently infected the liver as demonstrated by the expression of beta galactosidase throughout the liver lobules. Moreover, this construct selectively and efficiently reduced the expression of InsP3 R-I, as evaluated by immunoblots. Expression of AdsiRNA-I in liver decreased peak Ca(2+) amplitude induced by vasopressin in isolated hepatocytes 2 days after HX. Reduced InsP3 R-I expression prior to HX also delayed liver regeneration, as measured by liver to body weight ratio, and reduced hepatocyte proliferation, as evaluated by PCNA staining, at the same time point. At later stages of regeneration, control hepatocytes showed a decreased expression of InsP3 R, as well as reduced InsP3 R-mediated Ca(2+) signalling, events that did not affect liver growth. CONCLUSION: Together, these results show that InsP3 R-I-dependent Ca(2+) signalling is an early triggering pathway required for liver regeneration. PMID- 24814240 TI - Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury. AB - Ischemia, lack of blood flow, and reperfusion, return of blood flow, are a common phenomenon affecting millions of Americans each year. Roughly 30,000 Americans per year experience intestinal ischemia-reperfusion (IR), which is associated with a high mortality rate. Previous studies of the intestine established a role for neutrophils, eicosanoids, the complement system and naturally occurring antibodies in IR-induced pathology. Furthermore, data indicate involvement of a lipid or lipid-like moiety in mediating IR-induced damage. It has been proposed that antibodies recognize exposure of neo-antigens, triggering action of the complement cascade. While it is evident that the pathophysiology of IR-induced injury is complex and multi-factorial, we focus this review on the involvement of eicosanoids, phospholipids and neo-antigens in the early pathogenesis. Lipid changes occurring in response to IR, neo-antigens exposed and the role of a phospholipid transporter, phospholipid scramblase 1 will be discussed. PMID- 24814245 TI - Effects of broiler breeder-feeding programme and feeder space change at photostimulation using maize- or wheat-based diets on eggshell properties and progeny bone development. AB - 1. The effects of diet type, feeding programme and fast- or slow-feed allocation in fast-feathering Cobb 500 broiler breeder hens on eggshell properties and broiler progeny bone development were investigated in a 2 * 2 * 2 factorial experiment. 2. The birds were fed on either maize- or wheat-based diets during rearing and production and on a fast- or slow-feed allocation programme from 14 to 29 weeks of age. At 22 weeks, 69 females from each pen were placed in a layer house where feeder space (FS) either remained similar or was increased. 3. Eggs produced at 33 weeks were incubated, eggshell conductance (G) was determined and a sample of 14 chicks from each treatment combination was taken to obtain bone traits at hatching. 4. Diet type did not influence G, yolk-free body weight (BW), residual yolk weight or relative asymmetry (RA) of any bilateral traits of leg bones of hatchlings. However, breeder diet type was involved on two-way and three way interaction effects on progeny leg bone traits. 5. Breeders feed restricted according to the slow-feeding programme laid eggs with greater G compared to those managed with the fast-feeding programme, but there was no effect of feeding programme on progeny bone traits at hatching. 6. Eggs from breeders given more FS at photostimulation had greater G than those from breeders provided with similar FS. Maternal FS change did not influence hatchling yolk-free BW; however, breeders given more FS produced progeny with heavier tibias and shanks and longer femurs compared with those provided with similar FS, but only when breeders were fed on maize. Moreover, increased maternal FS at photostimulation was associated with an increased RA of femur length in the progeny. 7. It was concluded that breeder FS change at photostimulation influenced eggshell conductance and consistently affected bone development of the broiler progeny. PMID- 24814244 TI - Interferon-gamma responses in sheep exposed to virulent and attenuated Brucella melitensis strains. AB - Antibody detection is the basis of large-scale sheep brucellosis diagnosis because of its sensitivity and specificity. In contrast, information on the cellular mediated immune (CMI) response triggered after Brucella melitensis infection, a cornerstone in the protection against this pathogen, is more limited, particularly regarding the effect of the virulence of the infecting strain in the induced CMI reaction. Here, the interferon-gamma (IFN-gamma) profiles evoked after exposure by different routes to virulent (H38) and attenuated (Rev.1) B. melitensis strains in 14 pregnant sheep and 87 ewe lambs, respectively, were characterized accounting for different host-related factors, and compared with their serological response and with the basal IFN-gamma responses observed in 155 animals non exposed to Brucella. No significant differences in the IFN-gamma response of Rev.1 vaccinated animals depending on the inoculation route was observed, in contrast with their serological results. Response in H38-challenged followed a similar trend although peaked later, and an effect of the abortion on the IFN-gamma response was detected. This information could help to understand the interaction bacteria-host that leads to its intracellular survival and could be useful for the design of new diagnostic approaches. PMID- 24814246 TI - The genome-wide molecular signature of transcription factors in leukemia. AB - Transcription factors control expression of genes essential for the normal functioning of the hematopoietic system and regulate development of distinct blood cell types. During leukemogenesis, aberrant regulation of transcription factors such as RUNX1, CBFbeta, MLL, C/EBPalpha, SPI1, GATA, and TAL1 is central to the disease. Here, we will discuss the mechanisms of transcription factor deregulation in leukemia and how in recent years next-generation sequencing approaches have helped to elucidate the molecular role of many of these aberrantly expressed transcription factors. We will focus on the complexes in which these factors reside, the role of posttranslational modification of these factors, their involvement in setting up higher order chromatin structures, and their influence on the local epigenetic environment. We suggest that only comprehensive knowledge on all these aspects will increase our understanding of aberrant gene expression in leukemia as well as open new entry points for therapeutic intervention. PMID- 24814247 TI - High specific activity for anammox bacteria enriched from activated sludge at 10 degrees C. AB - Anammox in the water line of a waste water treatment plant (WWTP) saves energy for aeration and allows for recovering biogas from organic material. Main challenges for applying the anammox process in the water line are related to the low temperature of <20 degrees C, causing a significant drop in the specific anammox activity. The aim of this research was to enrich a cold-adapted anammox species, with a high specific activity. This was achieved in a 4.2L reactor operated at 10 degrees C, fed with 61 mg (NH4+NO2)-N/L and inoculated with activated sludge from two selected municipal WWTPs. Candidatus Brocadia fulgida was the dominant species in the enriched biomass, with a specific activity was 30 44 mg N/(g VS d). This is two times higher than previously reported at 10 degrees C, which is beneficial for full scale application. Biomass yield was 0.046 g biomass/g N converted, similar to that at higher temperatures. PMID- 24814248 TI - Ratio of intracellular precursors concentration and their flux influences hyaluronic acid molecular weight in Streptococcus zooepidemicus and recombinant Lactococcus lactis. AB - HA molecular weight variation in Streptococcus zooepidemicus and two recombinant Lactococcus lactis strains were investigated by chemostat experiments and metabolic flux analysis (MFA). The study showed that intracellular flux ratio of UDP-GlcUA to UDP-GlcNAc correlated directly with HA molecular weight, for all the three strains. The ratio of intracellular concentration of these HA precursors also exhibited a similar trend. Phosphoglucoisomerase activity and glucose flux towards lactic acid formation were found to be the major bottlenecks for HA production in all the three strains. The study suggests that environmental conditions and genetic manipulations that balance the intracellular flux and HA precursors concentrations will result in increased molecular weight. PMID- 24814249 TI - Membrane photobioreactors for integrated microalgae cultivation and nutrient remediation of membrane bioreactors effluent. AB - The feasibility of a new concept of wastewater treatment by combining a membrane bioreactor (MBR) and a microalgae membrane photobioreactor (MPBR) is assessed in this study. In this system, the organic carbon present in wastewater is expected to be fully oxidized in the MBR, while the nutrients are removed via the subsequent MPBR treatment. The effluent of a lab-scale MBR was fed into a PBR and a MPBR which served as growing medium for Chlorella vulgaris. The MPBRs demonstrated their superiority by limiting the algae wash-out, thus increasing the allowable optimum dilution rate (Dopt). At these corresponding Dopt values, 3.5 and 2 times higher biomass concentrations and volumetric productivities respectively were achieved by the MPBR. It is also possible to run the MPBR at still higher biomass concentration, thus enabling a smaller footprint and higher nutrient removal efficiency. However, reduced nutrient removal efficiencies were found to be one possible drawback. PMID- 24814250 TI - From a diagnostic and particular approach to a person-centred approach: a development project. AB - AIMS AND OBJECTIVES: To investigate changes over time in an interdisciplinary group that was engaged in development work regarding pain and pain assessment. BACKGROUND: The outcomes of nursing research do not always find their way to the daily care of patients. This is evident within, for instance, physical rehabilitation, where relieving patients' pain is a major challenge. To gain new understanding, develop and change, registered nurses have a great part in engaging their staff. DESIGN: A qualitative study using a participatory action research approach was used, and a hermeneutic analysis was conducted. METHODS: A group of three registered nurses, two assistant nurses and a physiotherapist took part in focus group sessions. This group was followed with seven repeated sessions during a period of five months from January 2010 until June 2010. A hermeneutic analysis was used. RESULTS: The participants changed their attitudes towards the patient in pain, their own caring role and the team's role towards a more person-centred care. CONCLUSIONS: Participation and reflection were key aspects as means to transfer knowledge into action and establish change. The participants came to the sessions, shared actively their experiences and expressed pride in the work they accomplished. This can be seen as an expression of a need to share and a joy to be working together in a person-oriented development area. In addition, the approach seemed to contribute to increased job satisfaction. RELEVANCE TO CLINICAL PRACTICE: The participants expressed that their work resulted in a changed approach to pain and pain assessment in their daily practice at the ward. The participants were actively engaged in enhancing their work with pain and pain assessment in their own daily practice and in implementing research-based knowledge. PMID- 24814251 TI - Underwater noise pollution in a coastal tropical environment. AB - Underwater noise pollution has become a major concern in marine habitats. Guanabara Bay, southeastern Brazil, is an impacted area of economic importance with constant vessel traffic. One hundred acoustic recording sessions took place over ten locations. Sound sources operating within 1 km radius of each location were quantified during recordings. The highest mean sound pressure level near the surface was 111.56+/-9.0 dB re 1 MUPa at the frequency band of 187 Hz. Above 15 kHz, the highest mean sound pressure level was 76.21+/-8.3 dB re 1 MUPa at the frequency 15.89 kHz. Noise levels correlated with number of operating vessels and vessel traffic composition influenced noise profiles. Shipping locations had the highest noise levels, while small vessels locations had the lowest noise levels. Guanabara Bay showed noise pollution similar to that of other impacted coastal regions, which is related to shipping and vessel traffic. PMID- 24814252 TI - A study of anthropogenic and climatic disturbance of the New River Estuary using a Bayesian belief network. AB - The present paper utilizes a Bayesian Belief Network (BBN) approach to intuitively present and quantify our current understanding of the complex physical, chemical, and biological processes that lead to eutrophication in an estuarine ecosystem (New River Estuary, North Carolina, USA). The model is further used to explore the effects of plausible future climatic and nutrient pollution management scenarios on water quality indicators. The BBN, through visualizing the structure of the network, facilitates knowledge communication with managers/stakeholders who might not be experts in the underlying scientific disciplines. Moreover, the developed structure of the BBN is transferable to other comparable estuaries. The BBN nodes are discretized exploring a new approach called moment matching method. The conditional probability tables of the variables are driven by a large dataset (four years). Our results show interaction among various predictors and their impact on water quality indicators. The synergistic effects caution future management actions. PMID- 24814253 TI - Sensory and cognitive neurophysiology in rats. Part 2: Validation and demonstration. AB - BACKGROUND: We have developed a novel setup for rats that allows for controlled sensory input to an animal engaged in a task while recording both electrophysiological signals and behavioral output. NEW METHOD: Our setup is described in a companion paper. RESULTS: We validate our setup by replicating (1) the functionally nonspecific spread of neural activity following tactile stimulation, and (2) the effects of anesthesia on the tactile evoked responses. We also demonstrate for the first time that the ECoG can be used to record evoked responses in a signal that reflects neural output (spiking activity), and illustrate the usefulness of our setup by demonstrating that these evoked responses are modulated by both the phase of pre-stimulus oscillations and by expectation. COMPARISON WITH EXISTING METHODS: Compared with high-density wire recordings, micro-ECoG offers a much more stable signal without readjustments, and a much better scalability. Compared with extracranial and regular ECoG recordings, micro-ECoG allows us to measure signals that reflect both neural input and neural output. CONCLUSIONS: For sensory and cognitive research, our setup provides a unique combination of possibilities that cannot be achieved in other setups for rodents. PMID- 24814254 TI - Can therapy dogs evoke awareness of one's past and present life in persons with Alzheimer's disease? AB - BACKGROUND: Persons with Alzheimer's disease (AD) sometimes express themselves through behaviours that are difficult to manage for themselves and their caregivers, and to minimise these symptoms alternative methods are recommended. For some time now, animals have been introduced in different ways into the environment of persons with dementia. Animal-Assisted Therapy (AAT) includes prescribed therapy dogs visiting the person with dementia for a specific purpose. AIM: This study aims to illuminate the meaning of the lived experience of encounters with a therapy dog for persons with Alzheimer's disease. METHOD: Video recorded sessions were conducted for each visit of the dog and its handler to a person with AD (10 times/person). The observations have a life-world approach and were transcribed and analysed using a phenomenological hermeneutical approach. RESULTS: The result shows a main theme 'Being aware of one's past and present existence', meaning to connect with one's senses and memories and to reflect upon these with the dog. The time spent with the dog shows the person recounting memories and feelings, and enables an opportunity to reach the person on a cognitive level. CONCLUSIONS: The present study may contribute to health care research and provide knowledge about the use of trained therapy dogs in the care of older persons with AD in a way that might increase quality of life and well being in persons with dementia. IMPLICATIONS FOR PRACTICE: The study might be useful for caregivers and dog handlers in the care of older persons with dementia. PMID- 24814255 TI - MET expression is associated with disease-specific survival in breast cancer patients in the neoadjuvant setting. AB - MET and RON receptor tyrosine kinases play an important role in tumor progression. The aim of this study was to determine the predictive or prognostic impact of MET and RON in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Immunohistochemical analyses were performed to retrospectively examine the predictive or prognostic impact of MET and RON expression in 129 breast cancer patients treated with NAC followed by definitive surgical resection. MET-positive tumors were detected in 89 patients (68.9%) and RON-positive tumors in 94 patients (72.9%). Survival analysis showed that MET expression was correlated with longer disease-specific survival (DSS; P=0.016), whereas RON expression was not associated with survival rates. MET expression was a significant factor for DSS in the non-pCR group in subgroup analysis (P=0.024) and a marginal significant independent prognostic factor for DSS in multivariate analysis. The MET-positive group had higher pCR than the MET-negative group but the difference was not statistically significant (P=0.266). MET expression is a prognostic factor for DSS in breast cancer patients receiving NAC and may provide additional prognostic information in patients not achieving a pCR. PMID- 24814256 TI - Incorporating a hybrid urease-carbon nanotubes sensitive nanofilm on capacitive field-effect sensors for urea detection. AB - The ideal combination among biomolecules and nanomaterials is the key for reaching biosensing units with high sensitivity. The challenge, however, is to find out a stable and sensitive film architecture that can be incorporated on the sensor's surface. In this paper, we report on the benefits of incorporating a layer-by-layer (LbL) nanofilm of polyamidoamine (PAMAM) dendrimer and carbon nanotubes (CNTs) on capacitive electrolyte-insulator-semiconductor (EIS) field effect sensors for detecting urea. Three sensor arrangements were studied in order to investigate the adequate film architecture, involving the LbL film with the enzyme urease: (i) urease immobilized directly onto a bare EIS [EIS-urease] sensor; (ii) urease atop the LbL film over the EIS [EIS-(PAMAM/CNT)-urease] sensor; and (iii) urease sandwiched between the LbL film and another CNT layer [EIS-(PAMAM/CNT)-urease-CNT]. The surface morphology of all three urea-based EIS biosensors was investigated by atomic force microscopy (AFM), while the biosensing abilities were studied by means of capacitance-voltage (C/V) and dynamic constant-capacitance (ConCap) measureaments at urea concentrations ranging from 0.1 mM to 100 mM. The EIS-urease and EIS-(PAMAM/CNT)-urease sensors showed similar sensitivity (~18 mV/decade) and a nonregular signal behavior as the urea concentration increased. On the other hand, the EIS-(PAMAM/CNT)-urease CNT sensor exhibited a superior output signal performance and higher sensitivity of about 33 mV/decade. The presence of the additional CNT layer was decisive to achieve a urea based EIS sensor with enhanced properties. Such sensitive architecture demonstrates that the incorporation of an adequate hybrid enzyme nanofilm as sensing unit opens new prospects for biosensing applications using the field-effect sensor platform. PMID- 24814257 TI - Reliability of pain tolerance threshold testing by applying an electrical current stimulus to the alveolar ridge. AB - The purpose of this study was to assess the reliability of testing pain tolerance threshold (PTT) by applying an electrical current stimulus to the alveolar ridge. Twenty volunteers studying or working at the Nihon University School of Dentistry at Matsudo participated in this study. Participants were seated comfortably on a dental chair in a quiet room during testing. A single operator obtained mucosal PTT measurements around the right greater palatine foramen using a Neurometer CPT/C((r)) device (Neurotron Inc., Baltimore, MD, USA) to deliver electrical stimulation at frequencies of 5, 250 and 2000 Hz. The participant released a button to automatically discontinue the stimulus when it could no longer be tolerated. Two types of factors were confirmed: the consistency of repeated measurements and a potential carry-over effect on PTTs. The consistency and carry over effects of pain with regard to PTT measurements were analysed via Cronbach's coefficient alpha. The Cronbach's coefficient alpha of PTTs calculated more than 6 days of PTT testing at 5, 250 and 2000 Hz was 0.97, 0.95 and 0.97, respectively, suggesting that the consistency of the measurements was excellent. The Cronbach's coefficient alpha calculated when the three frequencies of 5, 250 and 2000 Hz were applied in different orders was 0.91, 0.87 and 0.90, respectively, suggesting no carry-over effect. In conclusion, the measurement of PTTs at the alveolar ridge as assessed by applying an electrical current stimulus with an electro-diagnostic device exhibited excellent reliability, and thus, it constitutes a widely available option for PTT measurement in the clinical setting. PMID- 24814258 TI - Manganese accumulation in membrane fractions of primary astrocytes is associated with decreased gamma-aminobutyric acid (GABA) uptake, and is exacerbated by oleic acid and palmitate. AB - Manganese (Mn) exposure interferes with GABA uptake; however, the effects of Mn on GABA transport proteins (GATs) have not been identified. We sought to characterize how Mn impairs GAT function in primary rat astrocytes. Astrocytes exposed to Mn (500 MUM) had significantly reduced (3)H-GABA uptake despite no change in membrane or cytosolic GAT3 protein levels. Co-treatment with 100 MUM oleic or palmitic acids (both known to be elevated in Mn neurotoxicity), exacerbated the Mn-induced decline in (3)H-GABA uptake. Mn accumulation in the membrane fraction of astrocytes was enhanced with fatty acid administration, and was negatively correlated with (3)H-GABA uptake. Furthermore, control cells exposed to Mn only during the experimental uptake had significantly reduced (3)H GABA uptake, and the addition of GABA (50 MUM) blunted cytosolic Mn accumulation. These data indicate that reduced GAT function in astrocytes is influenced by Mn and fatty acids accumulating at or interacting with the plasma membrane. PMID- 24814259 TI - Hepatic expression patterns of aryl hydrocarbon receptor, pregnane X receptor, two cytochrome P450s and five phase II metabolism genes responsive to 17alpha methyltestosterone in rare minnow Gobiocypris rarus. AB - 17Alpha-methyltestosterone (MT), a synthetic androgen, is widely used in aquaculture. Aquatic organisms can receive continuous exposure to residual MT throughout their lives. Aiming to evaluate the effects of MT on genes involved in biotransformation pathway, meanwhile attempting to unravel the MT metabolic pathway at the transcriptional level in fish, here we isolated the cDNAs of previously unreported AHR2, Sult1 st1, Ugt2a1 and Ugt2b6 in rare minnow, and predominantly investigated the hepatic transcriptional patterns of AHR2, PXR and five biotransformation genes after MT exposure in both genders adult rare minnow Gobiocypris rarus. The present findings suggest that AHR2 and PXR should play important roles in regulating biotransformation enzymes related to MT catabolism, moreover, CYP1A, CYP3A, SULT1 ST4, SULT1 ST6 and UGT2A1 may play certain roles in catabolism of MT in adult G. rarus. Additionally, UGT2A1 may make greater contribution than SULT1 ST4 and SULT1 ST6 in MT catabolism in males. PMID- 24814260 TI - Use of acetylcholinesterase, glutathione S-transferase and cytochrome P450 1A1 in Capoeta umbla as biomarkers for monitoring of pollution in Uzuncayir Dam Lake (Tunceli, Turkey). AB - Uzuncayir Dam Lake is one of the most important water bodies in Tunceli. It is polluted by domestic wastewaters together with natural contamination and pesticides, which have had cumulatively negative effects. This study analyzes the effects of pollution by using the fish species, Capoeta umbla as a sentinel species, with a biomarker approach. The approach comprehends a general biomarker of individual fish health, the condition factor and specific biomarkers of contaminant exposure such as glutathione S-transferase (GST) and cytochrome P450 1A1 (CYP1A1) and acetylcholinesterase (AChE) activity. The general water physico chemical parameters were measured at each sampling sites during each fish sampling period. Strong seasonal and locational variations were observed among selected markers. In conclusion, the multibiomarker approach used in the present study clearly revealed differences in the fish health among reference and potentially contaminated sites. The study shows that changes of biomarkers such as acetylcholinesterase, glutathione S-transferase and cytochrome P450 1A1 might be useful for the assessment of environmental contamination in the Uzuncayir Dam Lake (Tunceli, Turkey). PMID- 24814261 TI - Eupolyphaga sinensis Walker inhibits human chronic myeloid leukemia cell K562 growth by inducing G2-M phase cell cycle arrest and targeting EGFR signaling pathway and in S180 tumor-bearing mice. AB - Eupolyphaga sinensis Walker is not only used as a food to enhance immunity, but is used as a traditional Chinese medicine and is known as the "preferred drug to regulate blood flow". Previous studies have reported its potential biological activities including anticoagulation, antithrombotic, liver protective effect and antitumor effects. Our results indicated that E. sinensis Walker 70% ethanol extract exhibited anti-tumor effects on S180 (murine sarcoma cell line) cells implanted mice. It effectively inhibited K562 (human chronic myeloid leukemia cell line) cells proliferation and induced G(2)-M phase arrest accompanying through up-regulation of cyclin B1, cdc2 and down-regulation of cyclin D1, cyclin E1, cdc25c and p53. In addition, it inhibited EGF secretion and EGFR kinase activity. Western blotting analysis indicated that it also inhibited the phosphorylation EGFR and activation of its downstream signaling molecules AKT and ERK. These results suggested that the antitumor mechanism of E. sinensis Walker involved altering the cell cycle and inhibiting EGFR phosphorylation in the EGFR signaling pathway. PMID- 24814262 TI - Frequency distribution of high risk alleles of CYP2C19, CYP2E1, CYP3A4 genes in Haryana population. AB - The genotype of an individual can significantly influence the disposition of a chemical, and determine their susceptibility to its toxicity. Many enzymes involved in either activation or detoxification of chemical carcinogen metabolism are polymorphically expressed, with the alleles presenting different enzymatic activities and some of them having been associated with susceptibility to cancer. Cytochrome P450 (P450 or CYP) constitutes the most important phase I enzyme group responsible for the metabolism of endogenous and exogenous (xenobiotics) substances. The present study was aimed to analyze the frequencies of commonly known polymorphisms of human xenobiotic metabolizing genes (XMG) in the Haryana State population of North India. The study was conducted in 308 healthy Haryana volunteers. DNA was extracted from leucocytes and the genetic polymorphisms in CYP2C19*2, CYP2C19*3, CYP2E1*5B and CYP3A4*1B were determined by digesting the PCR Product with restriction enzymes BamHI, SmaI, PstI and PstI respectively. The genotype frequencies of CYP2C19*2, CYP2C19*3, CYP2E1*5B, and CYP3A4*1B were found to be 22.0%, 0.0%, 2.11% and 2.0% respectively. The North Indian population which is known to be Caucasoid Aryans is ethnically different from South Indians known as Caucasoid Dravidians but no significant difference in genetic polymorphism was found. PMID- 24814263 TI - Endocrine disrupting effects of dichlorodiphenyltrichloroethane analogues on gonadotropin hormones in pituitary gonadotrope cells. AB - It has been shown that exposure to dichlorodiphenyltrichloroethane (DDT) analogues leads to disharmony of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, the effects and mechanisms of DDT analogues on the expression of gonadotropin genes (FSHbeta, LHbeta and Cgalpha), which is the rate-limiting step of FSH and LH biosynthesis, remain unknown. In this study, we assessed the effects of p,p'-DDT, o,p'-DDT, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and methoxychlor (MXC) on gonadotropin genes expression and hormones synthesis in gonadotrope cells. p,p'-DDT and MXC at test concentrations ranging from 10(-9) to 10(-7)mol/L, stimulated gonadotropin genes expression and hormones synthesis in a dose-dependent manner. The activation of extracellular signal regulated kinase (ERK) was required for the induction of gonadotropin genes expression and hormones synthesis by p,p'-DDT or MXC exposure. This study showed for the first time that p,p'-DDT and MXC regulated gonadotropin genes expression and hormones synthesis through ERK pathway in gonadotrope cells. PMID- 24814264 TI - Failure of recovery from lead induced hepatoxicity and disruption of erythrocyte antioxidant defence system in Wistar rats. AB - Lead acetate (PbA) is one of the major environmental contaminants with grave toxicological consequences both in the developing and developed countries. The liver and erythrocyte antioxidant status and markers of oxidative were assessed. Exposure of rats to PbA led to significant decline (p < 0.05) in hepatic and erythrocyte glutathione peroxidase (GPx), glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) content. Similarly, malondialdehyde (MDA) and H(2)O(2) concentrations were significantly (p < 0.05) elevated. Histopathology and immunohistology of liver of rats exposed to PbA showed focal areas of necrosis and COX-2 expression after 6 weeks of PbA withdrawal. Taken together, hepatic and erythrocytes antioxidant defence system failed to recover after withdrawal of the exposed PbA for the period of the study. In conclusion, experimental animals exposed to PbA did not recover from hepatotoxicity and disruption of erythrocyte antioxidant defence system via free radical generation and oxidative stress. PMID- 24814265 TI - Comparison of U.S. Environmental Protection Agency and U.S. Composting Council microbial detection methods in finished compost and regrowth potential of Salmonella spp. and Escherichia coli O157:H7 in finished compost. AB - Bacterial pathogens may survive and regrow in finished compost due to incomplete thermal inactivation during or recontamination after composting. Twenty-nine finished composts were obtained from 19 U.S. states and were separated into three broad feedstock categories: biosolids (n=10), manure (n=4), and yard waste (n=15). Three replicates of each compost were inoculated with ~ 1-2 log CFU/g of nonpathogenic Escherichia coli, Salmonella spp., and E. coli O157:H7. The U.S. Environmental Protection Agency's (EPA) protocols and U.S. Composting Council's (USCC) Test Methods for the Examination of Composting and Compost (TMECC) were compared to determine which method recovered higher percentages of inoculated E. coli (representing fecal coliforms) and Salmonella spp. from 400-g samples of finished composts. Populations of Salmonella spp. and E. coli O157:H7 were determined over 3 days while stored at 25 degrees C and compared to physicochemical parameters to predict their respective regrowth potentials. EPA Method 1680 recovered significantly (p=0.0003) more inoculated E. coli (68.7%) than TMECC 07.01 (48.1%) due to the EPA method using more compost in the initial homogenate, larger transfer dilutions, and a larger most probable number scheme compared to TMECC 07.01. The recoveries of inoculated Salmonella spp. by Environmental Protection Agency Method 1682 (89.1%) and TMECC 07.02 (72.4%) were not statistically significant (p=0.44). The statistically similar recovery percentages may be explained by the use of a nonselective pre-enrichment step used in both methods. No physicochemical parameter (C:N, moisture content, total organic carbon) was able to serve as a sole predictor of regrowth of Salmonella spp. or E. coli O157:H7 in finished compost. However, statistical analysis revealed that the C:N ratio, total organic carbon, and moisture content all contributed to pathogen regrowth potential in finished composts. It is recommended that the USCC modify TMECC protocols to test larger amounts of compost in the initial homogenate to facilitate greater recovery of target organisms. PMID- 24814266 TI - A windy day in a sheep saleyard: an outbreak of Q fever in rural South Australia. AB - In December 2004, the Department of Human Services investigated an outbreak of Q fever in South Australia. A case-control study tested an association between attending a local saleyard and human illness. A case was defined as a person with clinical illness and evidence of seroconversion or high phase II IgM. Controls were selected from a database of community controls matched on sex, age group and postcode. Matched analysis of the first 15 cases with 45 controls indicated that contracting Q fever was associated with attending the saleyard on one particular day (adjusted odds ratio 15.3, 95% confidence interval 1.7-undefined, P = 0.014). Saleyard conditions were windy and conducive for airborne dispersal of contaminated particles. In total, 25 cases were detected. Of these, 22 cases had attended a local saleyard on the same day. This outbreak suggests cases were probably infected by a single exposure at a saleyard from infected sheep and dust. The investigation resulted in an increase in the local uptake of Q fever vaccination and extension of the Australian national vaccination programme. PMID- 24814267 TI - Thermoswitching microgel carriers improve neuronal cell growth and cell release for cell transplantation. AB - Successful cell replacement therapy in the central nervous system (CNS) depends on both the transplanted cell type and the cell delivery method. It was established that differentiated neurons are the most desirable cell source; however, they are highly sensitive to dissociation shear; removing them from the growth surface inflicts serious damage, rendering them less viable for transplantation. Pilot experiments using glass colloids as injectable cell carriers for cell transplantation in the adult rat hippocampus have greatly improved neuron survival and long-term neuron integration. However, these early studies have highlighted glass particle shortcomings. They are uncompressible, and, thus, only a small number of beads can be injected, limiting the transplanted cell number. Moreover, they remain permanently in the brain. To improve colloidal carriers properties for cell transplantation and establish a basis for the next generation of cell delivery supports, we have designed a broadly applicable engineering strategy to enable neuronal cell growth on and release from hydrogel particles before transplantation. Here, we describe poly(N isopropylacrylamide) (pNIPAM) particle preparation, and we demonstrate that these hydrogel particles both facilitate manipulation of neurons and enable the increase in the number of viable transplanted cells in the young adult rat hippocampus. The absence of long-term cell association to beads suggested that pNIPAM thermoswitching properties enable the separation of cells from the beads during injection, which minimizes the number of injected carriers. Contrary to observations with glass carriers, no particle clumping was observed at the injection site, which indicates minimal risk of long-term inflammatory responses. Taken together, the properties of hydrogel particles make them a promising micro carrier to improve neuronal cell transplantation. PMID- 24814268 TI - The use of social media in pharmacy practice and education. AB - BACKGROUND: Social media is becoming increasingly ubiquitous. It has significant potential as a health communication and educational tool, and may provide a medium for the delivery of health-related services. OBJECTIVES: This systematic review aimed to investigate the use of social media in professional pharmacy practice and pharmacy education, and includes an evaluation of the research designs utilized. METHODS: Medline, Embase, PubMed, IPA, and CINAHL databases were broadly searched for peer-reviewed research studies about pharmacy and social media (SM). The search was restricted to years 2000 to June 2013, with no other restrictions applied. Key words used were within three concept areas: "social media" and "pharmacist or student" and "pharmacy." RESULTS: Twenty-four studies met the inclusion criteria. SM was broadly addressed as a general concept in 3 of the 24 studies. The other 21 studies investigated/used specific SM tools. Fourteen of those addressed social networking sites (SNS), four wikis, two blogs, and one Twitter. The studies' foci were to describe SM use (n = 17 studies) by pharmacist, pharmacy educators, and pharmacy students and investigate usage related topics (such as e-professionalism and student-educator boundary issues); or the use of SM as an educational tool in pharmacy education (n = 7). Pharmacy students were the subject of 12 studies, pharmacists of six, and faculty members and administrators of four. Survey methods were used in 17 studies, alone or with an additional method; focus groups were used in two; interviews in one; and direct observation of social media activity in seven. Results showed that SM in general and SNS in particular were used mainly for personal reasons. Wikis, Facebook, and Twitter were used as educational tools in pharmacy education with positive feedback from students. CONCLUSION: Research investigating the use of SM in the practice of pharmacy is growing; however, it is predominantly descriptive in nature with no controlled studies identified. Although some studies have used SM to deliver and enhance pharmaceutical education, none have focused on the delivery of pharmacy services through SM. PMID- 24814270 TI - IgG4-related dacryoadenitis in a 13-year-old girl. AB - IgG4-related disease is a recently described fibroinflammatory condition, often with systemic involvement. Several authors have reported IgG4-related orbital inflammation in adults. Pediatric cases of IgG4-related disease have been reported in the literature involving other areas of the body, with only 1 recent report of probable orbital involvement. The first case of probable IgG4-related dacryoadenitis is reported in a child. PMID- 24814269 TI - Nitrogen bisphosphonate-induced orbital inflammatory disease: gamma delta T cells -a report and review of 2 cases. AB - With the increased use of nitrogen bisphosphonate therapy for osteoporosis, multiple myeloma, metastatic prostate carcinoma, and Paget disease, it is now recognized that orbital inflammation is a potential sequelae of treatment. To date, 15 isolated cases of orbital inflammation exist in the literature with additional 2 cases reported herein. While the precise triggering mechanism for orbital inflammation is not definitively understood, it appears that a regulatory response from gamma delta T cells is the most likely causative factor. Nitrogen bisphosphonates are a causative agent of orbital inflammatory disease. These case reports adhered to the principles of Helsinki and the Health Insurance Portability and Accountability Act. PMID- 24814271 TI - Squamous Cell Carcinoma of the Caruncle. AB - Squamous cell carcinoma (SCC) of the lacrimal caruncle is a rare entity. The authors report the management and outcomes of 3 cases of caruncle SCC. Case 1 underwent wide margin surgical excision with adjuvant topical chemotherapy for a poorly differentiated SCC. He later developed regional lymph node metastasis and required modified radical neck dissection. Case 2 underwent wide margin surgical excision with cryotherapy and adjuvant topical chemotherapy for an invasive moderately differentiated SCC. She later developed a recurrence and underwent orbital exenteration. Case 3 was a moderately differentiated SCC treated with wide margin excision alone and had no recurrence during 5-year follow up. Careful surveillance of caruncle SCC is required, given the observed propensity for local recurrence and/or regional metastasis. PMID- 24814272 TI - Effect of autologous fat injection on lower eyelid position. AB - PURPOSE: To evaluate the effect of autologous periorbital fat injections on lower eyelid position. METHODS: Retrospective review of patients treated with autologous periorbital (malar/eyelid tear trough) fat injections for aesthetic purposes by a single surgeon (S.N.) between March 2007 and June 2011. The primary outcome, lower eyelid position as defined by marginal reflex distance 2 and inferior scleral show, was measured by standardizing and comparing pretreatment and posttreatment follow-up digital photos. Photographs were randomized and measured by 2 masked investigators. RESULTS: Seventy patients (5 male; mean age, 53; range, 33 to 77 years) were treated with autologous fat injections to the malar and lower eyelid tear trough for aesthetic purposes. A mean decrease in marginal reflex distance 2 of 0.5 mm in both OS and OD was found when pre- and posttreatment measurements were compared. Primary and secondary mean follow-up period was at 117 and 316 days, respectively. The effect of the autologous periorbital fat injection was not diminished (n=21) between follow-up periods. A mean change in scleral show of 0.5 mm was found when pre- and posttreatment measurements were compared. The overall mean follow-up period for scleral show was 125 days. Minor complications occurred in 7% (n=5) of patients who had postinjection subcutaneous induration. CONCLUSION: Autologous fat injections are well tolerated and have potential to be an effective adjuvant or primary treatment for mild lower eyelid retraction. PMID- 24814273 TI - Patient-reported outcomes: comprehensive analysis for the oculofacial clinician. PMID- 24814274 TI - A case report of orbital inflammatory syndrome secondary to ipilimumab. AB - Ipilimumab is a monoclonal antibody to cytotoxic T-lymphocyte antigen-4, a negative regulator of T-cell-mediated immune response. Ipilimumab is approved by the US Food and Drug Administration for the treatment of advanced melanoma. However, its use frequently has been associated with immune-related side effects, which can be explained by its mechanism of action. More common adverse effects include dermatitis, colitis, hepatitis, and endocrinopathies, but many less common immune-related adverse effects that involve various tissues and organ systems have been reported with more widespread use of ipilimumab since its approval in 2011. A case of bilateral orbital inflammatory syndrome secondary to ipilimumab, in a patient undergoing adjuvant treatment for metastatic melanoma, is reported. PMID- 24814275 TI - Microscopic and ultrastructural changes of Muller's muscle in patients with simple congenital ptosis. AB - PURPOSE: To study microscopic and ultrastructural changes of Muller's muscle in patients with isolated congenital ptosis. METHODS: In this prospective, observational case-control study, Muller's muscle specimens were collected during ptosis surgical correction for 18 consecutive patients. Each specimen was divided into 2 parts. One part was embedded in formalin for light microscopy, and the other one was fixed in 3% glutaraldehyde for electron microscopy. A neuropathologist, serving as a masked evaluator, blindly reviewed all the different features for every case and counted the number of myocytes showing distinct myofilaments in the whole grid for every case. Statistical analysis using compare means and correlation tests was conducted to investigate potential associations and/or differences within and across groups. RESULTS: Twelve Muller's muscle specimens from patients with simple congenital ptosis of various severities and 6 specimens from patients with aponeurotic ptosis (controls) were collected and studied. Under light microscopy, congenital ptosis slides showed a small number of dispersed myocytes in a fibrotic background, whereas acquired ptosis slides showed a greater number of well-defined myocytes. Under electron microscopy, all congenital ptosis specimens had only a very small number of myocytes with clear, distinct myofilaments. Most myocytes in the aponeurotic ptosis group showed clear, distinct myofilaments, indicating a well-preserved muscle. No relationship existed between the number of clear, distinct myofilaments observed in the congenital ptosis group by transmission electron microscopy and patient age or ptosis severity. CONCLUSION: Substantial Muller's muscle atrophy was observed in patients with different severities of isolated congenital ptosis. PMID- 24814276 TI - Indocyanine green-guided sentinel lymph node biopsy for periocular tumors. AB - PURPOSE: To compare the accuracy of indocyanine green (ICG)-guided sentinel lymph node biopsy to sentinel lymph node biopsy performed with technetium-99m in eyelid and in conjunctival malignancies. METHODS: Review of a consecutive series of adult patients undergoing sentinel lymph node biopsy for eyelid and conjunctival malignancies between 2009 and 2013. Only patients undergoing both ICG-guided and technetium-99m-guided sentinel lymph node biopsies were included. RESULTS: Five patients were identified: 3 women and 2 men. Four had conjunctival melanoma and 1 had eyelid melanoma. ICG aided in localization and confirmation of the sentinel nodes identified by technetium-99m, and all sentinel lymph nodes identified by technetium-99m were identified by ICG. All patients who underwent both sentinel lymph node modalities had negative lymph node biopsies for micrometastasis, but metastatic disease eventually developed in 1 patient. No safety concerns were identified with the use of ICG in the ocular adnexal region. CONCLUSIONS: For certain periocular malignancies, ICG-guided sentinel lymph node biopsy safely identifies sentinel lymph nodes intraoperatively possibly to a similar extent compared with technetium-99m-guided methods. PMID- 24814277 TI - En bloc resection of lacrimal sac tumors and simultaneous orbital reconstruction: surgical and functional outcomes. AB - PURPOSE: To describe a surgical technique of en bloc resection of lacrimal sac tumors by the shared expertise of 2 specialists to achieve optimal tumor margin clearance and the simultaneous reconstruction of the bony defect to preserve ocular functions and cosmesis. METHODS: All patients who had resection of malignant nasolacrimal drainage system tumors using the combined technique and posttreatment protocol between 1997 and 2011 were studied in this retrospective, noncomparative, interventional case series. A combined medial maxillectomy and medial orbitotomy for en bloc resection of the lacrimal sac tumor was followed by reconstruction with a tailored contoured titanium mesh to support the globe and eyelid. Disease relapse, disease survival, ocular functions (vision loss, motility, globe dystopia, and diplopia), and cosmesis (medial canthal tendon dystopia and eyelid retraction) were documented. RESULTS: Fourteen patients with malignant lacrimal sac tumors underwent en bloc resection. Postoperative radiation was ultimately administered to 9 patients. All patients but one were alive at last follow up. Tumor recurred locally in 2 patients with a regional recurrence in a third patient. Complications from radiation therapy included skin breakdown over the mesh (9/14 patients) with nasocutaneous fistula, medial canthal tendon dystopia (2/14 patients), and corneal perforation in a patient with recurrent disease. Despite removal of the tear drainage system, only 7 of 14 patients reported epiphora. None of the patients developed diplopia after resection and radiation therapy. CONCLUSIONS: The combined sinus-orbit approach is an effective method of managing lacrimal sac tumors to achieve optimal tumor clearance from the orbit and nasal cavity. Simultaneous reconstruction of the bony defect with a contoured titanium mesh provides a fixation anchor for the medial canthal tendon and globe support and serves as a supporting platform for the lower eyelid and cheek to minimize midface collapse. Postoperative radiation is associated with skin flap breakdown and nasocutaneous fistula formation. PMID- 24814278 TI - Exenteration and Custom Implant Brachytherapy as a Treatment for Recurrent Primary Extraskeletal Orbital Ewing Sarcoma. AB - A 6-year-old boy initially presented to an outside hospital with a right orbital mass with biopsy positive for translocation involving EWS RNA-binding protein 1 gene and imaging consistent with primary extraskeletal Ewing sarcoma (ES). There was no evidence of metastatic disease. Patient underwent gross tumor resection and adjuvant chemotherapy (VAdriaC/IE) followed by postoperative 45-Gy proton beam radiation. After 19 months, a solitary in-field local recurrence occurred, which was unsuccessfully surgically resected. Thereafter, treatment commenced with irinotecan and temozolomide, and the patient presented to the center of the authors. MRI showed locally recurrent disease without evidence of metastatic disease. Right orbital exenteration was performed, and an orbital mold was fashioned to deliver brachytherapy. There were no complications. The patient had no evidence of recurrent disease at 37-month follow up. This is the first report of orbital implant brachytherapy for recurrent primary ES of the orbit, and an additional report of primary extraskeletal ES of the orbit, which is a rare primary orbital tumor. PMID- 24814279 TI - [Analysis of adverse events associated with interhospital transfer of critically ill patients. Safety checklist]. AB - INTRODUCTION: Mobilization entails a risk for critically ill patients. It is therefore important to design and apply the tools to detect any safety lapses and to improve the quality of patient healthcare. OBJECTIVES: To identify which adverse events (AE) are related to interhospital transfer of assisted patients and how enabling a protocol may prevent potential risks. MATERIAL AND METHOD: Descriptive, observational study. We analyzed 110 transfers during morning shift in an Intensive Care Unit at a reference hospital between January and March 2011. Variables related to underlying security factors were collected. RESULTS: The average transfer time was 37.16 minutes. 61.82% of the transfers were carried out on a scheduled basis. An 18.18% of AE were detected. In both cases, desaturation and hemodynamic instability made up to 2.7% of the cases. 5.5% of the cases were underlying factors related to monitoring during transfer, and those related to ventilation during transfer accounted for 2.7%. Not having all materials by the stretcher constituted 1.8%. We detected 31 AE for non-compliance with the protocol, that being a 27.15% of all transfers. CONCLUSIONS: Before each hospital transfer, a risk-benefit assessment is recommended in order to avoid potential alterations in the patient's pathophysiologic condition. Both the protocol and the safety checklist are key to detect underlying factors and improve security during interhospital transfers. PMID- 24814280 TI - [Correlation between body mass index and development of pressure ulcers in intensive care medicine]. AB - OBJECTIVES: This study aims to evaluate the association between body mass index (BMI), incidence and severity of pressure ulcers (PU) in patients admitted to the Intensive Care Unit (ICU), and describe the differential prognosis of patients with PU and factors that modify it. MATERIAL AND METHODS: Case-control study with observation period of 15 months. We collected baseline variables, prognostic scales, therapies and clinical outcome. Univariate analysis was performed for each outcome variable between cases and controls using the appropriate hypothesis test depending on the nature of the variables. ROC curve for BMI and PU. Logistic regression with PU as dependent variable and the covariates that reached p<0.05 in the bivariate analysis. Correlation using Pearson or Spearman was made between BMI, albumin, days to diagnosis of UPP, immobilization, and PU degree. Significance level at p <0.05. RESULTS: 77 patients developed PU and 231 controls were chosen. The cases had higher APACHE II (p=0.043) and SAPS 3 (p=0.023), length of stay in ICU and mechanical ventilation (p<0.001). BMI>=40 was associated with UPP (p=0.024 OR=3.23 CI95% 1.17-8.93). There was a significant association between PU degree, length of stay and MV (p<0,001), but not with immobilization, dynamic support surface and death rate. Multivariate analysis found association between PU, length of MV (p=0.013, OR 1.08, CI95% 1.01-1.16) and kidney replacement therapy (p=0.013, OR 3.55 CI95% 1.31-9.64), with BMI>=40 as a confounding factor. CONCLUSIONS: Length of mechanical ventilation and renal replacement therapy are risk factors for pressure ulcer development, and BMI>=40 acts as a confounding factor. PU development and its maximum degree are not associated with a worse prognosis. PMID- 24814281 TI - [Pain assessment of tracheal suctioning on brain injury patients by pain behavioral indicator scale (ESCID)]. AB - OBJECTIVE: To assess pain response on patients with moderate to severe head injury before a common nursing procedure: tracheal suctioning. MATERIAL AND METHOD: An observational longitudinal pilot study with consecutive sampling performed from September to December of 2012. Pain was assessed by a pain behavioral indicator scale 5 minutes before, meanwhile and 15 minutes after tracheal suctioning the days 1, 3 and 6 of their intensive care unit (ICU) stay, as well as a non-painful procedure: rubbing with gauze the forearm of the patient. Pseudo-analgesia and hemodynamic variables were also recorded. Descriptive analysis of the variables, inferential statistics with t-student and Anova with SPSS 17.0; statistical tests were considered significant if the critical level observed was less than 5% (P<.05). RESULTS: Pain was assessed on 27 patients. 82% suffered from severe head trauma and 18% moderate. The average pain value during nursing procedure day 1 was 3, 18+/-2.6, day 3: 2, 59+/-2 and day 6: 3, 94+/-2.3. There was a significant increase in mean pain while performing suctioning during the three days of assessment (P<.05); however no significant differences between the average pain value on the three days of the assessment (P>.05) were shown. Data for the painless procedure were significantly different on day 6 (P<.05) CONCLUSION: During tracheal suctioning in patients with head injury in the first 6 days in the ICU, objective mild-moderate pain according to ESCID scale has been detected. PMID- 24814282 TI - Acquired discrete subaortic stenosis in solid organ transplant recipients. AB - DSS is a rare acquired abnormality of the LV outflow tract in children and adults. DSS can be seen with or without associated congenital heart disease, but the mechanism of its emergence has been poorly understood. Here, we report two cases of DSS that developed after solid organ transplant in childhood. One patient underwent liver and kidney transplant at three yr of age for hereditary polycystic disease, and the other had liver transplant at three months of age due to uncontrollable high-output failure secondary to a large hepatic hemangioma. Both patients developed mild dynamic LV outflow tract obstruction and systemic hypertension soon after transplant, both of which resolved by the time of discharge. Transient LV hypertrophy was observed in both cases. Corticosteroids, cyclosporine A, and tacrolimus were used as initial immunosuppressants. Both patients developed DSS long after the regression of the initial dynamic LV outflow tract obstruction. Herein, we report DSS as an atypical late cardiovascular complication after solid organ transplant and postulate that transient post-transplant hyperdynamic LV outflow tract obstruction and chronic immunosuppressive treatment may lead to subendocardial remodeling resulting in a fibromuscular membranous ridge in susceptible subjects. PMID- 24814283 TI - Anesthetic considerations for Cesarean section in a parturient with Charcot-Marie Tooth disease and HELLP syndrome. PMID- 24814284 TI - 16S rRNA-targeted oligonucleotide probes for direct detection of Propionibacterium freudenreichii in presence of Lactococcus lactis with multicolour fluorescence in situ hybridization. AB - Multicolour fluorescence in situ hybridization (FISH) has been applied to detect Lactococcus lactis and Propionibacterium freudenreichii cells in mixed populations in medium and skimmed milk, using epifluorescent microscopy. The 16S rRNA-targeted 18-mer oligonucleotide probes, specific for P. freudenreichii were designed and evaluated. Based on multiple alignments of designed sequences, eight 16S rRNA probes were selected for in vitro studies. The permeabilization protocol was optimized for simultaneous hybridization of propionibacteria and lactococci cells. The probes GLO62 (62-80), PEU64 (64-82) and PFX311 (311-329) were found specific for P. freudenreichii in analysis in vitro. Lactococcus lactis cells were labelled with LactV5 (822-840), (S-S-L.lact-0821-a-A-18) probe. The following combinations of oligonucleotide probes: LactV5/GLO62 , LactV5/PEU64 and LactV5/PFX311 , enabled differentiation of Lc. lactis and P. freudenreichii cells in culture media and in skimmed milk. SIGNIFICANCE AND IMPACT OF THE STUDY: Results showed that three newly designed 16S rRNA-targeted oligonucleotide probes specific for Propionibacterium freudenreichii in combination with a probe specific for Lactococcus lactis can be used to differentiate lactic and propionic acid bacteria in mixed communities using multicolour fluorescence in situ hybridization (FISH), without applying permeabilization step. This is a first study on simultaneous detection of both bacterial species with FISH, which was found as rapid, useful and culture-independent tool for direct visualization of bacteria on single cell level. It might be applied in monitoring of mixed starter cultures in dairy industry. PMID- 24814286 TI - Evolution of centromeric retrotransposons in grasses. AB - Centromeric retrotransposons (CRs) constitute a family of plant retroelements, some of which have the ability to target their insertion almost exclusively to the functional centromeres. Our exhaustive analysis of CR family members in four grass genomes revealed not only horizontal transfer (HT) of CR elements between the oryzoid and panicoid grass lineages but also their subsequent recombination with endogenous elements that in some cases created prolific recombinants in foxtail millet and sorghum. HT events are easily identifiable only in cases where host genome divergence significantly predates HT, thus documented HT events likely represent only a fraction of the total. If the more difficult to detect ancient HT events occurred at frequencies similar to those observable in present day grasses, the extant long terminal repeat retrotransposons represent the mosaic products of HT and recombination that are optimized for retrotransposition in their host genomes. This complicates not only phylogenetic analysis but also the establishment of a meaningful retrotransposon nomenclature, which we have nevertheless attempted to implement here. In contrast to the plant-centric naming convention used currently for CR elements, we classify elements primarily based on their phylogenetic relationships regardless of host plant, using the exhaustively studied maize elements assigned to six different subfamilies as a standard. The CR2 subfamily is the most widely distributed of the six CR subfamilies discovered in grass genomes to date and thus the most likely to play a functional role at grass centromeres. PMID- 24814285 TI - Repeated evolution of chimeric fusion genes in the beta-globin gene family of laurasiatherian mammals. AB - The evolutionary fate of chimeric fusion genes may be strongly influenced by their recombinational mode of origin and the nature of functional divergence between the parental genes. In the beta-globin gene family of placental mammals, the two postnatally expressed delta- and beta-globin genes (HBD and HBB, respectively) have a propensity for recombinational exchange via gene conversion and unequal crossing-over. In the latter case, there are good reasons to expect differences in retention rates for the reciprocal HBB/HBD and HBD/HBB fusion genes due to thalassemia pathologies associated with the HBD/HBB "Lepore" deletion mutant in humans. Here, we report a comparative genomic analysis of the mammalian beta-globin gene cluster, which revealed that chimeric HBB/HBD fusion genes originated independently in four separate lineages of laurasiatherian mammals: Eulipotyphlans (shrews, moles, and hedgehogs), carnivores, microchiropteran bats, and cetaceans. In cases where an independently derived "anti-Lepore" duplication mutant has become fixed, the parental HBD and/or HBB genes have typically been inactivated or deleted, so that the newly created HBB/HBD fusion gene is primarily responsible for synthesizing the beta-type subunits of adult and fetal hemoglobin (Hb). Contrary to conventional wisdom that the HBD gene is a vestigial relict that is typically inactivated or expressed at negligible levels, we show that HBD-like genes often encode a substantial fraction (20-100%) of beta-chain Hbs in laurasiatherian taxa. Our results indicate that the ascendancy or resuscitation of genes with HBD-like coding sequence requires the secondary acquisition of HBB-like promoter sequence via unequal crossing-over or interparalog gene conversion. PMID- 24814287 TI - Distinguishing between "function" and "effect" in genome biology. AB - Much confusion in genome biology results from conflation of possible meanings of the word "function." We suggest that, in this connection, attention should be paid to evolutionary biologists and philosophers who have previously dealt with this problem. We need only decide that although all genomic structures have effects, only some of them should be said to have functions. Although it will very often be difficult or impossible to establish function (strictly defined), it should not automatically be assumed. We enjoin genomicists in particular to pay greater attention to parsing biological effects. PMID- 24814288 TI - FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug resistant MES-SA/Dx5 cancer cells. AB - Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCdelta hypomethylation and overexpression of genes in the PKCdelta/AP-1 pathway in the human uterus sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCdelta signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCdelta inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCdelta was up regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCdelta shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCdelta shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA knockdown MES-SA/Dx5 cells, indicating involvement of PKCdelta in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCdelta, and the PKCdelta/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells. PMID- 24814289 TI - Peroxiredoxin 2 nuclear levels are regulated by circadian clock synchronization in human keratinocytes. AB - Circadian rhythms are highly conserved time tracking systems regulating important biological processes at both systemic and cellular levels. The present study was aimed to identify proteins and biological functions circadian regulated in human keratinocytes. HaCaT keratinocytes were entrained by temperature cycles, and a proteomic study was performed on cell fractions isolated under free running conditions at constant temperature. Bioinformatics analysis revealed that molecular clock entrainment was associated with changes in molecular components regulating cell proliferation, energy metabolism, transcription, translation and redox balance. Nuclear levels of the antioxidant enzyme Peroxiredoxin 2 (PRDX2) were found to oscillate rhythmically over two entire 24h long cycles. Donwregulation of PRDX2 resulted in upregulation of the mitochondrion-specific Peroxiredoxin 3 (PRDX3), all other members of the Peroxiredoxin family remained unaltered. Furthermore, PRDX2 knockdown increased intracellular levels of reactive oxygen species (ROS) and impaired cell cycle progression and proliferation. HaCaT cells transduced with a scramble shRNA were used as control. Our work is the first to show that nuclear levels of PRDX2 display circadian oscillation participating in the regulation of human keratinocytes redox balance. PMID- 24814291 TI - Effect of tannins and saponins in Samanea saman on rumen environment, milk yield and milk composition in lactating dairy cows. AB - The objective of this study was to investigate the effects of tannins and saponins in Samanea saman on rumen fermentation, milk yield and milk composition in lactating dairy cows. Four multiparous early-lactating dairy cows (Holstein Friesian cross-bred, 75%) with an initial body weight (BW) of 405 +/- 40 kg and 36 +/- 8 day in milk were randomly assigned to receive dietary treatments according to a 4 * 4 Latin square design. The four dietary treatments were unsupplemented (control), supplemented with rain tree pod (S. saman) meal (RPM) at 60 g/kg, supplemented with palm oil (PO) at 20 g/kg, and supplemented with RPM at 60 g/kg and PO at 20 g/kg (RPO), of total dry matter (DM) intake. Cows were fed with concentrate diets at a ratio of concentrate to milk yield of 1:2, and chopped 30 g/kg of urea-treated rice straw was fed ad libitum. The RPM contained condensed tannins and crude saponins at 88 and 141 g/kg of DM respectively. It was found that supplementation with RPM and/or PO to dairy cows diets did not show negative effect on ruminal pH, blood urea nitrogen and milk urea nitrogen concentration (p > 0.05). However, supplementation with RPM resulted in lower ammonia nitrogen (NH3 -N) concentration (p < 0.05). In addition, propionic acid and milk production increased while acetic acid, acetic to propionic ratio, methane production, methanogens and protozoal population decreased with RPM and/or PO supplementation. Furthermore, addition of PO and RPO in the diets increased milk fat while supplementation of RPM resulted in greater milk protein and Fibrobacter succinogenes numbers (p < 0.05). The population of Ruminococcus flavefaciens and Ruminococcus albus were not affected by any treatments. The findings on the present study showed that supplementation with RPM and RPO to diets of cows improved the rumen environment and increased milk yield, content of milk protein and milk fat. PMID- 24814290 TI - Short and prolonged exposure to hyperglycaemia in human fibroblasts and endothelial cells: metabolic and osmotic effects. AB - High blood glucose levels are the main feature of diabetes. However, the underlying mechanism linking high glucose concentration to diabetic complications is still not fully elucidated, particularly with regard to human physiology. Excess of glucose is likely to trigger a metabolic response depending on the cell features, activating deleterious pathways involved in the complications of diabetes. In this study, we aim to elucidate how acute and prolonged hyperglycaemia alters the biology and metabolism in human fibroblasts and endothelial cells. We found that hyperglycaemia triggers a metabolic switch from oxidative phosphorylation to glycolysis that is maintained over prolonged time. Moreover, osmotic pressure is a major factor in the early metabolic response, decreasing both mitochondrial transmembrane potential and cellular proliferation. After prolonged exposure to hyperglycaemia we observed decreased mitochondrial steady-state and uncoupled respiration, together with a reduced ATP/ADP ratio. At the same time, we could not detect major changes in mitochondrial transmembrane potential and reactive oxygen species. We suggest that the physiological and metabolic alterations observed in healthy human primary fibroblasts and endothelial cells are an adaptive response to hyperglycaemia. The severity of metabolic and bioenergetics impairment associated with diabetic complications may occur after longer glucose exposure or due to interactions with cell types more sensitive to hyperglycaemia. PMID- 24814292 TI - Clinical results of combined meniscus and femoral osteochondral allograft transplantation: minimum 2-year follow-up. AB - PURPOSE: To determine clinical results after combined femoral osteochondral allograft and meniscus transplantation. METHODS: Thirty-two patients with a minimum 2-year follow-up were identified who had previously undergone combined meniscus allograft transplantation and fresh osteochondral allograft transplantation. Demographic and intraoperative data, including condylar defect size, as well as the preoperative and postoperative International Knee Documentation Committee (IKDC) score, Short Form 12 score, Knee Injury and Osteoarthritis Outcome Score (KOOS), and Lysholm score, were recorded. Paired tests and regression analysis were used, and an alpha value of .05 was set as significant with Bonferroni correction used in the case of multiple comparisons. RESULTS: The mean follow-up period was 4.2 years (range, 2 to 11 years). The mean condylar defect size was 4.7 +/- 2.0 cm2 at the time of the index procedure. Lysholm scores, IKDC scores, and all KOOS subdomains showed significant improvement from preoperatively to postoperatively (P < .001). Patients with condylar defects of less than 4 cm2 had a significantly greater increase in the preoperative versus postoperative IKDC score (P = .010), Lysholm score (P = .018), and KOOS (P = .016) than those with condylar defects greater than 4 cm2. Femoral condyle defect size was also significantly inversely correlated with the postoperative IKDC score (P = .015), KOOS (P = .003), and Lysholm score (P = .010). The rate of patient satisfaction with the procedure was 82%. CONCLUSIONS: Patients undergoing combined meniscus allograft and femoral osteochondral allograft transplantation showed improved functional scores after surgery. The postoperative scores, however, indicated residual knee dysfunction, and the reoperation rate was high. There was an inverse association between postoperative functional scores and the size of the condylar defect. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24814293 TI - Accuracy analysis of a novel electromagnetic navigation procedure versus a standard minimally invasive method for arthroscopically assisted acromioclavicular joint reconstructions. AB - PURPOSE: The aim of this cadaveric study was to evaluate the accuracy, feasibility, and operation time of a novel electromagnetic navigation system (ENS) and procedure for transclavicular-transcoracoid tunnel placement compared with a standard minimally invasive (SMI) reconstruction method for minimally invasive arthroscopically assisted anatomic acromioclavicular joint reconstruction. METHODS: Ten arthroscopically assisted electromagnetic-navigated transclavicular-transcoracoid drilling procedures and 10 SMI procedures were performed on 10 human cadavers using 2 TightRope reconstructions (Arthrex, Naples, FL) for each site. Postoperative computed tomography scans were acquired to determine tunnel placement accuracy. Optimal coracoid tunnel placement was defined according to the anatomic insertions of the trapezoid and conoid ligaments with the oblong button placed in a center-base position at the coracoid undersurface without cortical breach or fracture. Both reconstruction procedures were performed without fluoroscopy. RESULTS: Successful tunnel placement was accomplished in 98.8% using the ENS method and in 83.8% using the SMI procedure (P = .087). The mean overall operation time was 28.5 +/- 6.6 minutes for the ENS method and 35.2 +/- 3.9 minutes for the SMI method (P = .012). The ENS procedure required no directional readjustments or restarts. Drill misguidance with subsequent cortical breach occurred twice in the SMI group. In both groups no fractures were documented. CONCLUSIONS: In this descriptive laboratory study, both the ENS and the SMI techniques achieved the desired anatomic reconstruction. Compared with the SMI method, the ENS procedure showed higher accuracy, required a shorter operation time, and was associated with no complications. CLINICAL RELEVANCE: Length of surgery, drilling accuracy, and reduction of radiation exposure in acromioclavicular joint reconstruction procedures affect the safety of both patients and surgeons. PMID- 24814294 TI - Simplified 2,4-dinitrophenylhydrazine spectrophotometric assay for quantification of carbonyls in oxidized proteins. AB - This work proposes a modification of the 2,4-dinitrophenylhydrazine (DNPH) spectrophotometric assay commonly used to evaluate the concentration of carbonyl groups in oxidized proteins. In this approach NaOH is added to the protein solution after the addition of DNPH, shifting the maximum absorbance wavelength of the derivatized protein from 370 to 450nm. This reduces the interference of DNPH and allows the direct quantification in the sample solution without the need for the precipitation, washing, and resuspension steps that are carried out in the traditional DNPH method. The two methods were compared under various conditions and are statistically equivalent. PMID- 24814295 TI - Evaluation of synthase and hemisynthase activities of glucosamine-6-phosphate synthase by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Glucosamine-6-phosphate synthase (GlmS, EC 2.6.1.16) catalyzes the first and rate limiting step in the hexosamine biosynthetic pathway, leading to the synthesis of uridine-5'-diphospho-N-acetyl-D-glucosamine, the major building block for the edification of peptidoglycan in bacteria, chitin in fungi, and glycoproteins in mammals. This bisubstrate enzyme converts D-fructose-6-phosphate (Fru-6P) and L glutamine (Gln) into D-glucosamine-6-phosphate (GlcN-6P) and L-glutamate (Glu), respectively. We previously demonstrated that matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) allows determination of the kinetic parameters of the synthase activity. We propose here to refine the experimental protocol to quantify Glu and GlcN-6P, allowing determination of both hemisynthase and synthase parameters from a single assay kinetic experiment, while avoiding interferences encountered in other assays. It is the first time that MALDI-MS is used to survey the activity of a bisubstrate enzyme. PMID- 24814296 TI - Transient prominent elevation of circulating thymus and activation-regulated chemokine/CCL17 after food-induced anaphylaxis. PMID- 24814297 TI - Inhaled silica-coated TiO2 nanoparticles induced airway irritation, airflow limitation and inflammation in mice. AB - The wide use of nanotechnology is here to stay. However, the knowledge on the health effects of different engineered nanomaterials (ENMs) is lacking. In this study, irritation and inflammation potential of commercially available silica coated TiO2 ENMs (10 * 40 nm, rutile) were studied. Single exposure (30 min) at mass concentrations 5, 10, 20 and 30 mg/m(3), and repeated exposure (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) at mass concentration of 30 mg/m(3) to silica-coated TiO2 induced first phase of pulmonary irritation (P1), which was seen as rapid, shallow breathing. During repeated exposures, P1 effect was partly evolved into more intense pulmonary irritation. Also sensory irritation was observed at the beginning of both single and repeated exposure periods, and the effect intensified during repeated exposures. Airflow limitation started to develop during repeated exposures. Repeated exposure to silica-coated TiO2 ENMs induced also pulmonary inflammation: inflammatory cells infiltrated in peribronchial and perivascular areas of the lungs, neutrophils were found in BAL fluids, and the number of CD3 and CD4 positive T cells increased significantly. In line with these results, pulmonary mRNA expression of chemokines CXCL1, CXCL5 and CXCL9 was enhanced. Also expression of mRNA levels of proinflammatory cytokines TNF-alpha and IL-6 was elevated after repeated exposures. Taken together, these results indicated that silica-coated TiO2 ENMs induce pulmonary and sensory irritation after single and repeated exposure, and airflow limitation and pulmonary inflammation after repeated exposure. PMID- 24814298 TI - Psoriasis: snapshots of the unspoken: using novel methods to explore patients' personal models of psoriasis and the impact on well-being. AB - BACKGROUND: People with psoriasis report high levels of undermanaged distress. This is compounded by the problem that some patients find it difficult to discuss their emotions. Distress prevents optimal self-management, which may exacerbate psoriasis flares, thereby creating a vicious cycle. OBJECTIVES: To offer people with psoriasis a novel way of expressing their personal models of psoriasis in order to gain a better understanding of their experiences of living with the condition. METHODS: We used a qualitative technique - asking people with psoriasis to complete a postcard entitled 'Dear Psoriasis...' - to collect survey data on their personal models of psoriasis. RESULTS: One hundred and four returned postcards provided new insights into the extent of and reasons for distress in psoriasis. Seven dominant themes emerged: identity and relationships; battleground; control; emotional consequences; hypervigilance; coping; treatment burden. CONCLUSIONS: Reports of distress were common, and for many it was long standing. Some reported low self-esteem and self-denigration bordering on self loathing, and described being hypervigilant and in a constant battle with their skin. Many people did not expect to have intimate relationships, resulting in reduced social support for patients in the future. This research underscores the need for patient support and psychological treatment to be made available as part of routine care. PMID- 24814302 TI - Relationship between heat shock protein 70 expression and life span in Daphnia. AB - The longevity of an organism is directly related to its ability to effectively cope with cellular stress. Heat shock response (HSR) protects the cells against accumulation of damaged proteins after exposure to elevated temperatures and also in aging cells. To understand the role of Hsp70 in regulating life span of Daphnia, we examined the expression of Hsp70 in two ecotypes that exhibit strikingly different life spans. Daphnia pulicaria, the long lived ecotype, showed a robust Hsp70 induction as compared to the shorter lived Daphnia pulex. Interestingly, the short-lived D. pulex isolates showed no induction of Hsp70 at the mid point in their life span. In contrast to this, the long-lived D. pulicaria continued to induce Hsp70 expression at an equivalent age. We further show that the Hsp70 expression was induced at transcriptional level in response to heat shock. The transcription factor responsible for Hsp70 induction, heat shock factor-1 (HSF-1), although present in aged organisms did not exhibit DNA binding capability. Thus, the decline of Hsp70 induction in old organisms could be attributed to a decline in HSF-1's DNA-binding activity. These results for the first time, present a molecular analysis of the relationship between HSR and life span in Daphnia. PMID- 24814303 TI - Oxidative stress increases in retinas of dogs in acute glaucoma but not in chronic glaucoma. AB - OBJECTIVE: To test the hypothesis that oxidative stress occurs early in the pathogenesis of glaucoma in dogs. ANIMALS: Sections from eight control retinas and 25 retinas from dogs with primary glaucoma. METHODS: For retinas embedded in paraffin, sections were immunohistochemically stained for malondialdehyde (MDA) and 3-nitrotyrosine (NT). For retinas embedded in plastic, serial 0.5-MUm sections were immunogold-stained for total glutathione, taurine, and glutamate. RESULTS: Increased immunostaining for MDA and NT, markers of oxidative stress, occurred in retinal ganglion cells (RGCs) and other neurons in acute glaucoma, but not in chronic glaucoma. In minimally damaged regions, immunostaining for the antioxidant glutathione was decreased in RGCs, neurons of the inner nuclear layer (INL), and Muller cell processes. The loss of glutathione immunostaining in RGCs occurred without a decrease in glutamate immunostaining. Neurons with nuclear damage in the INL had low levels of glutathione, taurine, and glutamate. In severely damaged regions, immunostaining for glutathione was increased in the remaining retinal tissue. CONCLUSIONS: Immunohistochemical staining revealed an increase in markers of oxidative stress and loss of glutathione in neurons with minimal damage during acute glaucoma. Oxidative changes were no longer present in chronic glaucomatous retinas, suggesting transient oxidative stress occurs early in glaucoma. The loss of glutathione in minimally damaged regions occurred without a significant redistribution of glutamate, suggesting oxidative stress may occur before glutamate redistribution. Alteration in markers of oxidative stress occurs early in canine glaucoma, suggesting oxidative stress may contribute to subsequent glutamate redistribution and other damaging processes. PMID- 24814304 TI - How eye movements in EMDR work: changes in memory vividness and emotionality. AB - BACKGROUND AND OBJECTIVES: Eye movements (EM) during recall of an aversive memory is a treatment element unique to Eye Movement Desensitization and Reprocessing (EMDR). Experimental studies have shown that EM reduce memory vividness and/or emotionality shortly after the intervention. However, it is unclear whether the immediate effects of the intervention reflect actual changes in memory. The aim of this study was to test whether immediate reductions in memory vividness and emotionality persist at a 24 h follow up and whether the magnitude of these effects is related to the duration of the intervention. METHODS: Seventy-three undergraduates recalled two negative autobiographical memories, one with EM ("recall with EM") and one without ("recall only"). Half of participants recalled each memory for four periods of 24 s, the other half for eight periods of 24 s. Memory vividness/emotionality were self-rated at a pre-test, an immediate post test, and a 24 h follow-up test. RESULTS: In both duration groups, recall with EM, but not recall only, caused an immediate decrease in memory vividness. There were no immediate reductions in memory emotionality. Furthermore, only the 'eight periods' group showed that recall with EM, but not recall only, caused a decrease in both memory emotionality and memory vividness from the pre-test to the follow up. LIMITATIONS: Only self-report measures were used. CONCLUSIONS: The findings suggest that recall with EM causes 24-h changes in memory vividness/emotionality, which may explain part of the EMDR treatment effect, and these effects are related to intervention duration. PMID- 24814305 TI - Secondary modification into aortouniiliac configuration to salvage failed endovascular aneurysm repair is safe and effective but not associated with higher intervention rates during long-term follow-up. AB - BACKGROUND: Reports of secondary modifications into aortouniiliac configuration to salvage-failed endovascular aneurysm repair (EVAR) are limited. We evaluated long-term results after these procedures and compared them with those after primary aortouniiliac endografting (AUE). METHODS: A retrospective review of all EVAR performed from March 1995 until July 2011 was conducted. Patients were included when primary AUE (group I) or modification into aortouniiliac configuration (group II) was done. RESULTS: Data analysis obtained 27 group I and 23 group II patients. Salvage of failed EVAR could be achieved in 96% of group II patients, and mortality was zero. Frequency of adverse events and amount of interventions to maintain aneurysm exclusion were not increased after secondary AUE. Kaplan-Meier estimates for long-term survival between groups were comparable (P = .36). CONCLUSIONS: Secondary AUE allows correction of graft-related endoleaks potentially leading to late aneurysm rupture. Complications and adverse events throughout long-term follow-up were not necessarily increased when compared with primary AUE. PMID- 24814306 TI - Classifying errors in preventable and potentially preventable trauma deaths: a 9 year review using the Joint Commission's standardized methodology. AB - BACKGROUND: Benchmarking and classification of avoidable errors in trauma care are difficult as most reports classify errors using variable locally derived schemes. We sought to classify errors in a large trauma population using standardized Joint Commission taxonomy. METHODS: All preventable/potentially preventable deaths identified at an urban, level-1 trauma center (January 2002 to December 2010) were abstracted from the trauma registry. Errors deemed avoidable were classified within the 5-node (impact, type, domain, cause, and prevention) Joint Commission taxonomy. RESULTS: Of the 377 deaths in 11,100 trauma contacts, 106 (7.7%) were preventable/potentially preventable deaths related to 142 avoidable errors. Most common error types were in clinical performance (inaccurate diagnosis). Error domain involved primarily the emergency department (therapeutic interventions), caused mostly by knowledge deficits. Communication improvement was the most common mitigation strategy. CONCLUSION: Standardized classification of errors in preventable trauma deaths most often involve clinical performance in the early phases of care and can be mitigated with universal strategies. PMID- 24814307 TI - Falls in the elderly: a modern look at an old problem. AB - BACKGROUND: Falls are a leading cause of unintentional injury among adults, especially those over 65 years of age. With increasing longevity and improving access to health care, falls are affecting a more mobile senior citizen population that does not fit the typical profile. We set out to evaluate the current nature of these falls in the elderly. METHODS: This is a 2-year retrospective chart review of all falls in patients 65 years or older at an urban Level I trauma center. Demographics, location and height of fall, associated injuries, and outcomes were obtained from chart review. RESULTS: There were 400 patients meeting inclusion criteria. The cohort had a mean age of 78.3 +/- 8.8 years, 50% were male, and 72.5% had at least 1 comorbidity. Non-ground level falls (Non-GLF) were recorded in 56 patients (14%). These patients suffered a significantly higher injury burden. Non-GLF were associated with significantly higher intensive care unit length of stay (2.6 +/- 5.6 vs 4.6 +/- 6.7 days, P = .016) and a trend toward higher mortality than GLF. CONCLUSIONS: Falls remain a source of considerable healthcare expenditure, especially among the elderly. Non GLF account for 14% of cases and are associated with a significantly higher burden of injury and morbidity. Fall prevention strategies should include these active older individuals at risk of high-level falls. PMID- 24814308 TI - Preventing intraperitoneal adhesions with linezolid and hyaluronic acid/carboxymethylcellulose: a comparative study in cecal abrasion model. AB - BACKGROUND: We aimed to compare the effectiveness of linezolid in preventing intraperitoneal adhesions with hyaluronic acid + carboxymethylcellulose (Seprafilm). METHODS: Thirty rats were divided randomly into 3 groups: Group I (control), untreated; Group II (Seprafilm); and Group III (linezolid). All rats were sacrificed on the 14th day after surgery. Macroscopic adhesion, inflammation, and fibrosis were evaluated. RESULTS: The multiple comparisons between groups showed a statistically significant difference for adhesion. There were statistically significant differences between Group I and II and I and III, but no statistically significant difference between Group II and III. The multiple comparisons between the groups showed a statistically significant difference for inflammation and fibrosis. For inflammation and fibrosis, there was a statistically significant difference between Group I and II and I and III, but no statistically significant difference between Group II and III. CONCLUSION: The efficiency of linezolid in reducing the formation of intraperitoneal adhesions was statistically significant compared with the control group. PMID- 24814309 TI - The effects of video games on laparoscopic simulator skills. AB - BACKGROUND: Recently, there has been a growth in studies supporting the hypothesis that video games have positive effects on basic laparoscopic skills. This review discusses all studies directly related to these effects. DATA SOURCES: A search in the PubMed and EMBASE databases was performed using synonymous terms for video games and laparoscopy. All available articles concerning video games and their effects on skills on any laparoscopic simulator (box trainer, virtual reality, and animal models) were selected. CONCLUSIONS: Video game experience has been related to higher baseline laparoscopic skills in different studies. There is currently, however, no standardized method to assess video game experience, making it difficult to compare these studies. Several controlled experiments have, nevertheless, shown that video games cannot only be used to improve laparoscopic basic skills in surgical novices, but are also used as a temporary warming-up before laparoscopic surgery. PMID- 24814310 TI - p27 expression in post-treatment rectal cancer: a potential novel approach for predicting residual nodal disease. AB - BACKGROUND: Expression profiles of p21, p27, p53, Ki-67, and thymidylate synthase may be associated with response to neoadjuvant chemoradiation. The relationship between post-treatment protein expression and regional lymph node involvement has not been fully explored. METHODS: Tumor cores from 126 rectal cancer patients underwent immunohistochemical analysis for the aforementioned proteins. Staining indices (SIs) using percentage of stained cells and staining intensity were calculated for 10 tumor cores per patient. SI for each marker was compared between node negative and node positive patients. RESULTS: Twenty-six (20.6%) cancer patients had a pathologic complete response and 37 had inadequate tissue or cancer cells, leaving 63 for analysis. Thirty-seven (58.7%) cancer patients were node negative and 26 (41.3%) were node positive. There was an association between increased p27 SI and nodal positivity (P = .04). CONCLUSION: Increased p27 expression in post-treatment rectal cancer is associated with nodal positivity and may determine which patients are suitable for local excision. PMID- 24814311 TI - Neoadjuvant endocrine treatment in breast cancer: analysis of daily practice in large cancer center to facilitate decision making. AB - BACKGROUND: To examine outcomes of neoadjuvant endocrine therapy in daily practice to inform decision making. METHODS: We retrospectively selected 204 patients who received neoadjuvant endocrine therapy with T2 (>=30 mm) or T3 tumors, examining subsequent breast-sparing surgery and long-term outcomes. RESULTS: Neoadjuvant endocrine therapy was administered for 7.3 months (median) and breast-sparing surgery was achievable in 53% of patients. Smaller initial tumor size and modified version of the Scarff-Bloom and Richardson grades 1 to 2 were associated with breast-sparing surgery. Disease progression during treatment was 6.9%; actuarial risk of local relapse was 3% at 5 years and 15% at 10 years. Five- and 10-year metastasis relapse-free survival was 78% and 63%, respectively. Grade 3, negative progesterone receptors, and absence or slow response to neoadjuvant therapy were associated prognostic factors. CONCLUSION: These daily practice data provide important information about feasibility, efficacy, and long term results of neoadjuvant endocrine therapy and can be used to inform patients for decision making between mastectomy and endocrine induction therapy. PMID- 24814312 TI - Mental health indicators and quality of life among individuals with musculoskeletal chronic pain: a nationwide study in Iceland. AB - OBJECTIVES: Musculoskeletal chronic pain is a costly public health threat. The aim of our study was to investigate mental health indicators, including self reported symptoms of depression, sleep disruption, stress, well-being, and quality of life (QoL), among men and women with musculoskeletal chronic pain in a general population. METHOD: This was a cross-sectional study; a postal questionnaire was mailed to a stratified random sample of 9807 eligible Icelanders retrieved from a national registry, of whom 5906 responded (response rate = 60.2%). Chronic pain conditions included reports of current chronic back pain, chronic neck symptoms, and/or fibromyalgia. Gender-stratified associations of chronic pain conditions with mental health indicators were estimated with logistic regression analyses adjusting for age, income, body mass index (BMI), smoking, education, and residence. RESULTS: We observed higher odds of low satisfaction with life [adjusted odds ratio (OR(adj)) women 2.0, 95% confidence interval (CI) 1.5-2.6; OR(adj) men 2.3, 95% CI 1.7-3.1], higher levels of perceived stress (OR(adj) women 1.7, 95% CI 1.3-2.2; OR(adj) men = 1.5, 95% CI 1.1-2.1), depressive symptoms (OR(adj) women 2.4, 95% CI 1.9-3.0; OR(adj) men 2.8, 95% CI 2.1-3.7), and sleep disruption (OR(adj) women 2.8, 95% CI 2.2-3.5; OR(adj) men 2.2, 95% CI 1.5-3.1), and diminished QoL (OR(adj) women 1.6, 95% CI 1.2-2.1; OR(adj) men 1.5, 95% CI 1.0-2.1) among individuals with chronic pain compared with those without the condition. CONCLUSIONS: Our data indicate that individuals with musculoskeletal chronic pain have increased risk of poor mental health and diminished QoL. Further studies are needed on treatment and preventative measures of a decline in mental health among individuals with chronic pain. PMID- 24814313 TI - Effect of repeated administration of lipopolysaccharide on inflammatory and stress markers in saliva of growing pigs. AB - Although saliva could be considered to be an ideal biological sample for evaluation of biomarkers relating to stress and inflammatory responses in pigs, little is known about how these might be influenced by the presence of endotoxaemia. In the present study, the response to repeated administrations of lipopolysaccharide (LPS) was investigated, using a panel of salivary stress markers such as chromogranin A (CgA) and cortisol, as well as inflammatory/immune markers such as haptoglobin (Hp), C-reactive protein (CRP) and immunoglobulin A (IgA). Sixteen growing pigs were adapted to experimental conditions for 3 weeks, after which, 10 of the pigs were selected to receive three doses of LPS at 48 h intervals. Saliva samples were taken from all pigs prior to any LPS administration (baseline) and at time points corresponding to 3 h after each injection of LPS (T1, T2 and T3). Results showed that repeated administration of LPS induced significant elevation of salivary markers of hypothalamic-pituitary adrenal (cortisol) and immune (Hp, CRP and IgA) activity compared to baseline levels (P < 0.05). However, rectal temperature, CRP and cortisol data suggested that the amplitude of the inflammatory response decreased with successive LPS administrations. Thus, measurement of salivary biomarkers could be a practical tool for evaluating the inflammatory response to endotoxaemia in pigs. In the case of chronic inflammatory states, salivary Hp and IgA might be more sensitive markers than CRP or cortisol. PMID- 24814314 TI - Ontogeny of critical and prolonged swimming performance for the larvae of six Australian freshwater fish species. AB - Critical (<30 min) and prolonged (>60 min) swimming speeds in laboratory chambers were determined for larvae of six species of Australian freshwater fishes: trout cod Maccullochella macquariensis, Murray cod Maccullochella peelii, golden perch Macquaria ambigua, silver perch Bidyanus bidyanus, carp gudgeon Hypseleotris spp. and Murray River rainbowfish Melanotaenia fluviatilis. Developmental stage (preflexion, flexion, postflexion and metalarva) better explained swimming ability than did length, size or age (days after hatch). Critical speed increased with larval development, and metalarvae were the fastest swimmers for all species. Maccullochella macquariensis larvae had the highest critical [maximum absolute 46.4 cm s(-1) and 44.6 relative body lengths (L(B)) s(-1)] and prolonged (maximum 15.4 cm s(-1), 15.6 L(B) s(-1)) swimming speeds and B. bidyanus larvae the lowest critical (minimum 0.1 cm s(-1), 0.3 L(B) s(-1)) and prolonged swimming speeds (minimum 1.1 cm s(-1), 1.0 L(B) s(-1)). Prolonged swimming trials determined that the larvae of some species could not swim for 60 min at any speed, whereas the larvae of the best swimming species, M. macquariensis, could swim for 60 min at 44% of the critical speed. The swimming performance of species with precocial life-history strategies, with well-developed larvae at hatch, was comparatively better and potentially had greater ability to influence their dispersal by actively swimming than species with altricial life-history strategies, with poorly developed larvae at hatch. PMID- 24814315 TI - Cultural adaptation in measuring common client characteristics with an urban Mainland Chinese sample. AB - OBJECTIVES: This study aimed to develop a culturally adapted version of the Systematic Treatment Selection-Innerlife (STS) in China. METHODS: A total of 300 nonclinical participants collected from Mainland China and 240 nonclinical US participants were drawn from archival data. A Chinese version of the STS was developed, using translation and back-translation procedures. After confirmatory factor analysis (CFA) of the original STS sub scales failed on both samples, exploratory factor analysis (EFA) was then used to access whether a simple structure would emerge on these STS treatment items. Parallel analysis and minimum average partial were used to determine the number of factor to retain. RESULTS: Three cross-cultural factors were found in this study, Internalized Distress, Externalized Distress and interpersonal relations. CONCLUSIONS: This supported that regardless of whether one is in presumably different cultural contexts of the USA or China, psychological distress is expressed in a few basic channels of internalized distress, externalized distress, and interpersonal relations, from which different manifestations in different culture were also discussed. PMID- 24814317 TI - A calcium dialog mediated by the FERONIA signal transduction pathway controls plant sperm delivery. AB - Sperm delivery for double fertilization of flowering plants relies on interactions between the pollen tube (PT) and two synergids, leading to programmed cell death (PCD) of the PT and one synergid. The mechanisms underlying the communication among these cells during PT reception is unknown. We discovered that the synergids control this process by coordinating their distinct calcium signatures in response to the calcium dynamics and growth behavior of the PT. Induced and spontaneous aberrant calcium responses in the synergids abolish the two coordinated PCD events. Components of the FERONIA (FER) signaling pathway are required for initiating and modulating these calcium responses and for coupling the PCD events. Intriguingly, the calcium signatures are interchangeable between the two synergids, implying that their fates of death and survival are determined by reversible interactions with the PT. Thus, complex intercellular interactions involving a receptor kinase pathway and calcium-mediated signaling control sperm delivery in plants. PMID- 24814316 TI - Tensin-4-dependent MET stabilization is essential for survival and proliferation in carcinoma cells. AB - Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with beta1-integrin cytoplasmic tail positively regulates beta1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer. PMID- 24814318 TI - Inhibitory effect of rhynchophylline on contraction of cerebral arterioles to endothelin 1: role of rho kinase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhynchophylline (Rhy) is a major ingredient of Uncaria rhynchophylla (UR) used to reduce blood pressure and ameliorate brain ailments. This study was to examine the role of Rho kinase (ROCK) in the inhibition of Rhy on contraction of cerebral arterioles caused by endothelin 1 (ET-1). MATERIALS AND METHODS: Cerebral arterioles of male Wistar rats were constricted with ET-1 for 10 min followed by perfusion of Rhy for 20 min. Changes in the diameters of the arterioles were recorded. The effects of Rhy on contraction of middle cerebral arteries (MCAs) were determined by a Multi Myograph. Western blotting and immunofluorescent staining were used to examine the effects of Rhy on RhoA translocation and myosin phosphatase target subunit 1 (MYPT1) phosphorylation. RESULTS: In vivo, Rhy (30-300 uM) relaxed cerebral arterioles constricted with ET-1 dose-dependently. In vitro, Rhy at lower concentrations (1-100 uM) caused relaxation of rat MCAs constricted with KCl and Bay-K8644 (an agonist of L-type voltage-dependent calcium channels (L-VDCCs)). Rhy at higher concentrations (>100 uM) caused relaxation of rat MCAs constricted with ET-1, which was inhibited by Y27632, a ROCK's inhibitor. Western blotting of rat aortas showed that Rhy inhibited RhoA translocation and MYPT1 phosphorylation. Immunofluorescent staining of MCAs confirmed that phosphorylation of MYPT1 caused by ET-1 was inhibited by Rhy. CONCLUSIONS: These results demonstrate that Rhy is a potent inhibitor of contraction of cerebral arteries caused by ET-1 in vivo and in vitro. The effect of Rhy was in part mediated by inhibiting RhoA-ROCK signaling. PMID- 24814319 TI - Radioprotective effects of dragon's blood and its extracts on radiation-induced myelosuppressive mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dragon's blood, a traditional Chinese herb, has been used to "panacea of blood activating" and its major biological activity appears to be from phenolic compounds. In this study, our research aims to examine the effects of Dragon's blood (DB) and its extracts (DBE) on radiation induced myelosuppressive mice. MATERIALS AND METHODS: Adult BALB/C mice were exposed to the whole body irradiation with 4 Gy (60)Co gamma-rays. DB and DBE were respectively administered orally for 5 constitutive days prior to irradiation treatment. The radioprotective effects and relevant mechanisms of DB and DBE in radiation-induced bone marrow injury were investigated by ex vivo examination. RESULTS: We found that the administration of DB and DBE significantly increased the numbers of peripheral blood cells and colony forming unit of bone marrow-derived stem/progenitor cells. Interestingly, compared with the irradiation group, the administration of DB and DBE significantly decreased the levels of the inflammatory cytokines such as IL-6, TNF-alpha and IFN-gamma and oxidative stress injury such as SOD, CAT, GSH, MDA in serum of mice. Furthermore, DBE markedly improved the morphology of bone marrow histopathology. CONCLUSIONS: Our data suggest that DB and DBE effectively attenuate radiation induced damage in bone marrow, which is likely associated with the anti-oxidative and anti-inflammatory properties of DB and DBE. PMID- 24814320 TI - The effects of humor therapy on nursing home residents measured using observational methods: the SMILE cluster randomized trial. AB - OBJECTIVES: To evaluate the effects of humor therapy assessed using observational methods on agitation, engagement, positive behaviors, affect, and contentment. DESIGN: Single-blind cluster randomized controlled trial. SETTING: A total of 35 Sydney nursing homes. PARTICIPANTS: All eligible residents within geographically defined areas within each nursing home were invited to participate. INTERVENTION: Professional "ElderClowns" provided 9 to 12 weekly humor therapy sessions, augmented by resident engagement by trained staff "LaughterBosses." Controls received usual care. MEASUREMENTS: The Behavior Engagement Affect Measure (BEAM) touchpad observational tool was used to capture real-time behavioral data. The tool assesses the duration in seconds of agitation, positive behavior toward others, engagement, and affect (angry, anxious, happy, neutral, sad). RESULTS: Seventeen nursing homes (189 residents) received the intervention and 18 homes (209 residents) received usual care. Over 26 weeks, in comparison with controls, the humor therapy group decreased in duration of high agitation (effect size = 0.168 and 0.129 at 13 and 26 weeks, respectively) and increased in duration of happiness (effect size = 0.4 and 0.236 at 13 and 26 weeks, respectively). CONCLUSION: We confirmed that humor therapy decreases agitation and also showed that it increases happiness. Researchers may consider evaluating impacts of nonpharmaceutical interventions on positive outcomes. Computer-assisted observational measures should be considered, particularly for residents with dementia and when the reliability of staff is uncertain. PMID- 24814321 TI - Are the new guidelines for cholesterol and hypertension age friendly? PMID- 24814324 TI - Aortic arch rerouting and OPCAB in a patient with situs inversus totalis. AB - Endovascular therapy approaches for aortic aneurysm have lowered the mortality and morbidity rates even in high-risk patients; moreover, these approaches are applied in the management of aortic arch pathologies by transposition of the supra-aortic branches. We present the case of a 75-year-old female patient with situs inversus totalis on hemodialysis. The patient underwent off-pump aortic arch rerouting and thoracic endovascular aortic repair concomitant with coronary artery bypass grafting for distal aortic arch aneurysm and ischemic heart disease. PMID- 24814322 TI - Are investments in disease prevention complements? The case of statins and health behaviors. AB - We obtain estimates of associations between statin use and health behaviors. Statin use is associated with a small increase in BMI and moderate (20-33%) increases in the probability of being obese. Statin use was also associated with a significant (e.g., 15% of mean) increase in moderate alcohol use among men. There was no consistent evidence of a decrease in smoking associated with statin use, and exercise worsened somewhat for females. Statin use was associated with increased physical activity among males. Finally, there was evidence that statin use increased the use of blood pressure medication and aspirin for both males and females, although estimates varied considerably in magnitude. These results are consistent with the hypothesis that healthy diet is a strong substitute for statins, but there is only uneven evidence for the hypothesis that investments in disease prevention are complementary. PMID- 24814323 TI - Maximizing MR signal for 2D UTE slice selection in the presence of rapid transverse relaxation. AB - Ultrashort TE (UTE) sequences allow direct visualization of tissues with very short T2 relaxation times, such as tendons, ligaments, menisci, and cortical bone. In this work, theoretical calculations, simulations, and phantom studies, as well as in vivo imaging were performed to maximize signal-to-noise ratio (SNR) for slice selective RF excitation for 2D UTE sequences. The theoretical calculations and simulations were based on the Bloch equations, which lead to analytic expressions for the optimal RF pulse duration and amplitude to maximize magnetic resonance signal in the presence of rapid transverse relaxation. In steady state, it was found that the maximum signal amplitude was not obtained at the classical Ernst angle, but at an either lower or higher flip angle, depending on whether the RF pulse duration or amplitude was varied, respectively. PMID- 24814325 TI - Assessment of circumferential endocardial extent of myocardial edema and infarction in patients with reperfused acute myocardial infarction: a cardiovascular magnetic resonance study. AB - T2 weighted (T2W) images on cardiovascular magnetic resonance (CMR) visualizes myocardial edema, which reflects the myocardial area at risk (AAR) in reperfused acute myocardial infarction (AMI). Late gadolinium enhancement (LGE) demonstrates myocardial infarction. LGE images cover the whole left ventricle, but T2W images are obtained from a few slices of the left ventricle due to the long sequence time, so the quantification of AAR of the entire left ventricle is difficult. We hypothesize that we can quantify AAR with only LGE images if there is a strong correlation between the circumferential endocardial extent of myocardial edema and infarction. Thirty patients with first AMI were enrolled. All patients underwent successfully reperfusion therapy and CMR was performed within the first week after the event. We measured the circumferential extent of edema and infarction on short-axis views (T2 angle and LGE angle), respectively. A total of 82 short-axis slices showed transmural edema on T2W images. Corresponding LGE images were analyzed for the circumferential extent of infarction. The median [interquartile range] of T2 angle and DE angle were 147 degrees [116 degrees 219 degrees ] and 134 degrees [104 degrees -200 degrees ] in patients with LAD culprit lesion, 91 degrees [87 degrees -101 degrees ] and 85 degrees [80 degrees -90 degrees ] in LCX, and 110 degrees [94 degrees -123 degrees ] and 104 degrees [89 degrees -118 degrees ] in RCA, respectively. T2 angle was well correlated with LGE angle (r = 0.99, P < 0.01). There is a strong correlation between the circumferential extent of edema and infarction in reperfused AMI. Thus, T2 weighted imaging can be skipped to quantify the amount of AAR. PMID- 24814326 TI - Incidence and anatomical locations of catheter instability during circumferential pulmonary vein isolation using contact force. AB - In addition to contact force (CF), catheter stability is considered to be an important factor in creating radiofrequency lesions.To evaluate the catheter stability during pulmonary vein isolation (PVI) using CF-sensing catheter.PVI was performed in 32 patients using a CF-sensing catheter. Operators were blinded to CF. The application was arbitrarily defined as a "visually unstable" point if the catheter moved >= 4 mm. Data were analyzed according to 6 predefined segments for the ipsilateral PVs. As a parameter of catheter stability, the standard deviation (SD) of CF and relative standard deviation (RSD = 100 * SD of CF /average CF) were introduced.A total of 932 RF applications with 426 visually unstable points (UP; 45.7%) and 506 stable points (SP; 54.3%) were analyzed. SD was significantly higher at UP (8.0 g versus 5.7 g, P < 0.001), and RSD was significantly higher at UP (43.7% versus 26.5%, P < 0.001). Higher RSD was associated with visual instability in all the segments of both PVs, however, higher SD of CF was not in all segments. At the antero-superior segment of the LPV, and the roof and posteroinferior segments of the RPV, the RSD values were over 50%, suggesting catheter instability.Catheter instability occurred in 45% of ablations during PVI and was predominantly located in the antero-superior segment of the LPV and postero-inferior segment of the RPV, which may result in incomplete lesion formation. RSD had significant correlation with visual catheter stability. PMID- 24814327 TI - Prognostic value of circulating regulatory T cells for worsening heart failure in heart failure patients with reduced ejection fraction. AB - Regulatory T cells (Tregs) play a crucial role in the negative regulation of immune responses. Recent studies suggest that Tregs are involved in the pathogenesis of atherosclerosis and myocarditis. Here, we investigated the involvement of Tregs on worsening heart failure (HF) in patients with reduced ejection fraction (HF-REF). The study population consisted of 32 HF-REF patients who were hospitalized for worsening HF, and 18 control subjects. Cardiac function was evaluated by echocardiography. A single venous blood sample was collected before discharge. Circulating T cells were evaluated by flow cytometry. Tregs were defined as CD4(+)CD25(+)Foxp3(+)T cells, and the correlations between the frequency of Tregs and CRP, IL-6 and several echoparameters were analysed. Furthermore, all HF-REF patients were followed up to 12 months from discharge to examine the predictors of recurrent hospitalization.In HF-REF patients, Tregs were significantly decreased (5.9 +/- 1.4 versus 8.0 +/- 2.2%, P < 0.01), while CD4(+)HLADR(+)T cells were increased (10.1 +/- 5.4 versus 7.3 +/- 3.1%, P < 0.05), compared with controls. Tregs were negatively correlated with left ventricular end-diastolic dimension, and levels of CRP and IL-6. Eleven of 32 HF REF patients were rehospitalized for worsening HF within 12 months. Multivariate Cox regression analysis showed that CD4/CD8 and frequency of Tregs were independent predictors for recurrent hospitalization. Furthermore, HF-REF patients expressing under 6% Treg/CD4(+)T cells showed a significantly higher incidence of recurrent hospitalization for worsening HF within 12 months.Our data suggest that Tregs might be involved in the pathogenesis of decompensated HF, and may be a novel predictor of poor prognosis in HF-REF patients. PMID- 24814328 TI - Which drugs are associated with highest risk for being arrested for driving under the influence? A case-control study. AB - The aim of this study was to determine the association between drug type and arrest for driving under the influence of drugs (DUID) by calculating odds ratios (ORs) using a case-control design. A DUID arrest is in most cases related to aberrant or risky driving and might therefore be regarded as a proxy for a drug related traffic crash. The 'cases' were 2738 drivers arrested on suspicion of drugged driving from April 2008 to March 2009 with blood alcohol concentrations below the legal limit of 0.2g/L; 794 were arrested due to involvement in road traffic crashes, whereas 1944 were arrested for other reasons, mainly dangerous driving, suspected impairment when stopped in traffic controls, or because of phone calls to the police from other road users or observers. The 'controls' were 9375 random drivers in normal traffic, also with alcohol concentrations below this limit. Blood samples from 'cases' and oral fluid samples from 'controls' were analyzed for 15 drugs that have legislative concentration limits in Norway, in addition to two other commonly detected psychoactive drugs. The most prevalent illicit drug in the control group was tetrahydrocannabinol (THC; 0.58%), which was also commonly found in samples from drivers arrested due to road crash (15.6%) or arrested for other reasons (21.8%). Amphetamine/methamphetamine was most prevalent among arrested drivers involved in crashes (30.6%) and drivers arrested for other reasons (56.9%), whereas only 0.18% of the control group was positive for amphetamine/methamphetamine. The single-use substances which gave highest OR for police arrest were amphetamine/methamphetamine, alprazolam, clonazepam and oxazepam. The majority of the alprazolam and clonazepam findings were probably due to non-therapeutic use of medicinal drugs purchased on the illegal market. Combinations of two or more drugs yielded higher ORs than the use of single substances; combinations of amphetamine/methamphetamine and benzodiazepines gave the highest risk. PMID- 24814329 TI - 14C Analysis of protein extracts from Bacillus spores. AB - Investigators of bioagent incidents or interdicted materials need validated, independent analytical methods that will allow them to distinguish between recently made bioagent samples versus material drawn from the archives of a historical program. Heterotrophic bacteria convert the carbon in their food sources, growth substrate or culture media, into the biomolecules they need. The F(14)C (fraction modern radiocarbon) of a variety of media, Bacillus spores, and separated proteins from Bacillus spores was measured by accelerator mass spectrometry (AMS). AMS precisely measures F(14)C values of biological materials and has been used to date the synthesis of biomaterials over the bomb pulse era (1955 to present). The F(14)C of Bacillus spores reflects the radiocarbon content of the media in which they were grown. In a survey of commercial media we found that the F(14)C value indicated that carbon sources for the media were alive within about a year of the date of manufacture and generally of terrestrial origin. Hence, bacteria and their products can be dated using their (14)C signature. Bacillus spore samples were generated onsite with defined media and carbon free purification and also obtained from archived material. Using mechanical lysis and a variety of washes with carbon free acids and bases, contaminant carbon was removed from soluble proteins to enable accurate (14)C bomb-pulse dating. Since media is contemporary, (14)C bomb-pulse dating of isolated soluble proteins can be used to distinguish between historical archives of bioagents and those produced from recent media. PMID- 24814330 TI - On the interpretation of likelihood ratios in forensic science evidence: Presentation formats and the weak evidence effect. AB - Likelihood ratios are increasingly being adopted to convey expert evaluative opinions to courts. In the absence of appropriate databases, many of these likelihood ratios will include verbal rather than numerical estimates of the support offered by the analysis. However evidence suggests that verbal formulations of uncertainty are a less effective form of communication than equivalent numerical formulations. Moreover, when evidence strength is low a misinterpretation of the valence of the evidence - a "weak evidence effect" - has been found. We report the results of an experiment involving N=404 (student and online) participants who read a brief summary of a burglary trial containing expert testimony. The expert evidence was varied across conditions in terms of evidence strength (low or high) and presentation method (numerical, verbal, table or visual scale). Results suggest that of these presentation methods, numerical expressions produce belief-change and implicit likelihood ratios which were most commensurate with those intended by the expert and most resistant to the weak evidence effect. These findings raise questions about the extent to which low strength verbal evaluative opinions can be effectively communicated to decision makers at trial. PMID- 24814331 TI - Nano characterization of gunshot residues from Brazilian ammunition. AB - Gunshot residues (GSR) from a total of nine different caliber ammunitions produced in Brazil were analyzed and characterized by transmission (TEM) and scanning electron microscopy (SEM). GSR particles are composed of spherical particles of several micrometers of diameter containing distinct amounts of lead, barium and antimony, along with other organic and inorganic elements arising from the primer, gunpowder, the gun and the bullet itself. This study was carried out to obtain additional information on the properties of GSR nanoparticles originated from different types of regular ammunition produced in Brazil by CBC. Besides the SEM, we have used a TEM, exploring its high magnification capability and ability to explore internal structure and chemical composition of submicron particles. We observed that CBC ammunition generated smaller particles than usually reported for other ammunitions and that the three component particles are not a majority. TEM analysis revealed that GSR are partially composed of sub micron particles as well. The electron diffraction pattern from these particles confirmed them to be mainly composed of lead oxides crystalline nanoparticles that may be agglomerated into larger particles. Energy dispersive X-ray spectroscopy revealed that most of them were composed of two elements, especially PbSb. Ba was not a common element found in the nanoparticles. PMID- 24814332 TI - Carbon and nitrogen isotope ratios of factory-produced RDX and HMX. AB - RDX and HMX are explosive compounds commonly used by the military and also occasionally associated with acts of terrorism. The isotopic characterization of an explosive can be a powerful approach to link evidence to an event or an explosives cache. We sampled explosive products and their reactants from commercial RDX manufacturers that used the direct nitration and/or the Bachmann synthesis process, and then analyzed these materials for carbon and nitrogen isotope ratios. For manufacturers using the Bachmann process, RDX (13)C enrichment relative to the hexamine substrate was small (+0.90/00) compared to RDX produced using the direct nitration process (+8.20/00 to +12.00/00). RDX (15)N depletion relative to the nitrogen-containing substrates (-3.60/00) was smaller in the Bachmann process than in the direct nitration process (-12.60/00 to -10.60/00). The sign and scale of these differences agree with theorized mechanisms of mass-dependent fractionation. We also examined the isotopic relationship between RDX and HMX isolated from explosive samples. The delta(13)C and delta(15)N values of RDX generally matched those of the HMX with few exceptions, most notably from a manufacturer known to make RDX using two different synthesis processes. The range in delta(13)C values of RDX in a survey of 100 samples from 12 manufacturers spanned 330/00 while the range spanned by delta(15)N values was 260/00; these ranges were much greater than any previously published observations. Understanding the relationship between products and reactants further explains the observed variation in industrially manufactured RDX and can be used as a diagnostic tool to analyze explosives found at a crime scene. PMID- 24814333 TI - Novosphingobium chloroacetimidivorans sp. nov., a chloroacetamide herbicide degrading bacterium isolated from activated sludge. AB - Strain BUT-14(T), a Gram-reaction-negative, non-spore-forming, ellipse-shaped bacterium, was isolated from activated sludge of a chloroacetamide-herbicides manufacturing wastewater treatment facility. The strain was able to degrade more than 90% of butachlor, acetochlor and alachlor (100 mg l(-1)) within 5 days of incubation. The taxonomic position was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain BUT 14(T) was a member of the genus Novosphingobium and showed the highest sequence similarities to Novosphingobium soli DSM 22821(T) (97.9%), N. naphthalenivorans KACC 15258(T) (97.4%), N. pentaromativorans JCM 12182(T) (97.4%) and N. barchaimii DSM 25411(T) (97.1%) and lower (<97%) sequence similarities to all other species of the genus Novosphingobium. Chemotaxonomic analysis revealed that strain BUT-14(T) possessed Q-10 as the predominant ubiquinone, spermidine as the major polyamine and C(18 : 1)omega7c (46.9%), C(17 : 1)omega6c (17.9%), summed feature 3, C(14 : 0) 2-OH (4.4%), C(15 : 0) 2-OH (3.1%) and C(16 : 0) (5.51%) as the major fatty acids. The polar lipids included lipid, glycolipid, phosphatidylglycerol, phospholipid, phosphatidylethanolamine, phosphatidylcholine, sphingoglycolipid and phospatidyldimethylethanolamine. Strain BUT-14(T) showed low DNA-DNA relatedness with N. soli DSM 22821(T) (41.5+/ 2.9%), N. naphthalenivorans JCM 12182(T) (49.2+/-4.2%), N. pentaromativorans KACC 12295(T) (53.2+/-1.9%) and N. barchaimii DSM 25411 (51.2+/-4.5%). The DNA G+C content was 66+/-0.3 mol%. The combination of phylogenetic analysis, phenotypic characteristics, chemotaxonomic data and DNA-DNA hybridization supports the suggestion that strain BUT-14(T) represents a novel species of the genus Novosphingobium, for which the name Novosphingobium chloroacetimidivorans sp. nov. is proposed. The type strain is BUT-14(T) ( = CCTCC AB 2013086(T) = KACC 17147(T) = JCM 19923(T)). PMID- 24814334 TI - Thermomicrobium carboxidum sp. nov., and Thermorudis peleae gen. nov., sp. nov., carbon monoxide-oxidizing bacteria isolated from geothermally heated biofilms. AB - Two thermophilic, Gram-stain-positive, rod-shaped, non-spore-forming bacteria (strains KI3(T) and KI4(T)) were isolated from geothermally heated biofilms growing on a tumulus in the Kilauea Iki pit crater on the flank of Kilauea Volcano (Hawai'i, USA). Strain KI3(T) grew over an examined temperature range of 50-70 degrees C (no growth at 80 degrees C) and a pH range of 6.0-9.0, with optimum growth at 70 degrees C and pH 7.0. Strain KI4(T) grew at temperatures of 55-70 degrees C and a pH range of 5.8-8.0, with optimum growth at 65 degrees C and pH 6.7-7.1. The DNA G+C contents of strains KI3(T) and KI4(T) were 66.0 and 60.7 mol%, respectively. The major fatty acid for both strains was 12-methyl C(18 : 0). Polar lipids in strain KI3(T) were dominated by glycolipids and phosphatidylinositol, while phosphatidylinositol and phosphoglycolipids dominated in strain KI4(T). Strain KI3(T) oxidized carbon monoxide [6.7+/-0.8 nmol CO h(-1) (mg protein)(-1)], but strain KI4(T) did not. 16S rRNA gene sequence analyses determined that the strains belong to the class Thermomicrobia, and that strains KI3(T) and KI4(T) are related most closely to Thermomicrobium roseum DSM 5159(T) (96.5 and 91.1% similarity, respectively). 16S rRNA gene sequence similarity between strain KI3(T) and strain KI4(T) was 91.4%. Phenotypic features and phylogenetic analyses supported the affiliation of strain KI3(T) to the genus Thermomicrobium, while results of chemotaxonomic, physiological and biochemical assays differentiated strains KI3(T) and KI4(T) from Thermomicrobium roseum. Strain KI3(T) ( = DSM 27067(T) = ATCC BAA-2535(T)) is thus considered to be the type strain of a novel species, for which the name Thermomicrobium carboxidum sp. nov. is proposed. Additionally, the characterization and phylogenetic position of strain KI4(T) showed that it represents a novel species of a new genus, for which the name Thermorudis peleae gen. nov., sp. nov. is proposed. The type strain of Thermorudis peleae is KI4(T) ( = DSM 27169(T) = ATCC BAA-2536(T)). PMID- 24814335 TI - Lysinibacillus halotolerans sp. nov., isolated from saline-alkaline soil. AB - A novel aerobic, halotolerant bacterium, designated strain LAM612(T), was isolated from saline-alkaline soil samples from Lingxian County, Shandong Province, China. Cells of strain LAM612(T) were Gram-reaction-positive, endospore forming, motile and rod-shaped. The optimal temperature and pH for growth were 35 degrees C and pH 6.0, respectively. Strain LAM612(T) could grow in the presence of up to 10% (w/v) NaCl. The genomic DNA G+C conten was 36.4 mol% as detected by the T(m) method. Comparative analysis of 16S rRNA gene sequences revealed that LAM612(T) was closely related to Lysinibacillus sinduriensis KACC 16611(T) (98.0%), L. chungkukjangi KACC 16626(T) (97.5%), L. massiliensis KCTC 13178(T) (97.4%), L. xylanilyticus KACC 15113(T) (97.2%), L. macroides DSM 54(T) (97.0%) and L. manganicus DSM 26584(T) (96.5%). The DNA-DNA hybridization values between strain LAM612(T) and its closest relatives ranged from 20.6% to 41.9%. The major fatty acids of strain LAM612(T) were iso-C(15 : 0) (40.8%), iso-C(16 : 0) (15.2%) and anteiso-C(15 : 0) (10.8%). The cell-wall peptidoglycan content was A4alpha (L Lys-D-Asp). The predominant menaquinone was MK-7 and the main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unknown phospholipids, five unknown glycolipids and an unknown lipid. Based on the DNA-DNA hybridization results and phenotypic, phylogenetic and chemotaxonomic properties, strain LAM612(T) could be distinguished from the recognized species of the genus Lysinibacillus, and was suggested to represent a novel species of this genus, for which the name Lysinibacillus halotolerans sp. nov. is proposed. The type strain is LAM612(T) ( = ACCC 00718(T) = JCM 19611(T)). PMID- 24814336 TI - Chitinophaga ginsengihumi sp. nov., isolated from soil of ginseng rhizosphere. AB - A novel strain designated SR18(T) was isolated from the rhizosphere soil of a ginseng in Korea. Cells were Gram-staining-negative, motile by gliding, catalase positive and oxidase-negative, non-spore-forming rods. The isolate grew aerobically at 15-45 degrees C (optimum 28 degrees C), pH 5.5-7.5 (optimum pH 7.0) and with 0-3.0% (w/v) NaCl (optimum 1.5% NaCl). Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain SR18(T) belongs to the genus Chitinophaga with sequence similarity of 97.2% and 97.0% to Chitinophaga japonensis 758(T) and Chitinophaga rupis CS5-B1(T), respectively. Similarity to other species of the genus Chitinophaga was 92.8-95.5%. The predominant menaquinone was MK-7. Major fatty acids were iso-C(15 : 0) and C(16 : 1)omega5c. The polar lipids included phosphatidylethanolamine, unidentified phospholipids, unknown aminolipids and unknown lipids. The genomic DNA G+C content was 45.3 mol%. DNA-DNA relatedness between strain SR18(T) and C. japonensis NBRC 16041(T) was 29-32%. On the basis of polyphasic analysis from this study, strain SR18(T) represents a novel species of the genus Chitinophaga, for which the name Chitinophaga ginsengihumi sp. nov. is proposed. The type strain is SR18(T) ( = KACC 17604(T) = NBRC 109832(T)). PMID- 24814337 TI - Streptomyces chumphonensis sp. nov., isolated from marine sediments. AB - Two actinomycete strains, KK1-2(T) and CPB4-7, were isolated from marine sediments collected in Chumphon province, Thailand. Chumphon province, Thailand. Their taxonomic positions were determined using a polyphasic approach. The morphological, cultural and chemotaxonomic characteristics of these isolates were consistent with the classification of the strains as representing a member of the genus Streptomyces. They contained LL-diaminopimelic acid in their cell wall peptidoglycan; the whole-cell sugars were ribose and glucose. The predominant menaquinones were MK9-(H6) and MK9-(H8). The major polar lipids were phosphatidylethanolamine, phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol mannosides. The predominant cellular fatty acids were anteiso-C(15 : 0), iso-C(16 : 0) and iso-C(15 : 0). On the basis of 16S rRNA gene sequence similarity studies, these isolates were determined to be closely related to Streptomyces xinghaiensis JCM 16958(T) (98.2%), Streptomyces rimosus subsp. paromomycinus JCM 4541(T) (98.1%), Streptomyces sclerotialus JCM 4828(T) (98.1%) and Streptomyces flocculus JCM 4476(T) (98.0%). The G+C contents of the genomic DNA of strains KK1-2(T) and CPB4 7 were 73.3 and 74.2 mol%, respectively. They could be clearly distinguished from the related type strains by a low DNA-DNA relatedness and phenotypic differences. On the basis of these results, these strains represent a novel species of the genus Streptomyces, for which the name Streptomyces chumphonensis sp. nov. (type strain KK1-2(T) = JCM 18522(T) = TISTR 2106(T) = PCU 330(T)) is proposed. PMID- 24814338 TI - Falls in hospital increase length of stay regardless of degree of harm. AB - RATIONALE, AIMS AND OBJECTIVES: Acute inpatient falls are common and serious adverse events that lead to injury, prolonged hospitalization and increased cost of care. To determine the difference in total acute hospital care length of stay (LOS) for patients with and without an in-hospital fall (IHF), regardless of degree of harm. METHODS: This was a retrospective observational study at a 728 bed acute care teaching hospital. We used propensity scores to match 292 patients with 330 controls by case mix group, sex, Resource Intensity Weights and week of admission. We used two administrative databases: hospital fall incident reporting system and Discharge Abstract Database. We reviewed all IHF incidents for patients 18 years and older, admitted to inpatient acute care hospital units/programs between 1 November 2009 and 31 August 2011. RESULTS: The average LOS for IHF cases was 37.2 days [median 26.5 days; interquartile range (IQR) 14, 54] and 25.7 days (median 13 days; IQR 5, 33) for matched control patients. Survival analysis results indicated that patients who did not have an IHF were 2.4 times (95% CI 2.1, 2.7; P < 0.001) more likely to be discharged earlier from acute care than patients who had an IHF. CONCLUSIONS: Experiencing either an injurious or a non-injurious fall during an acute care hospitalization was associated with prolonged LOS. PMID- 24814339 TI - Squamous cell carcinoma of the parotid gland: a population-based analysis of 2545 cases. AB - PURPOSE: Squamous cell carcinoma (SCC) of the parotid gland is an uncommon tumor, which generally affects older patients. In this study, we explore various aspects of this entity using a national population-based database. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was used to extract data on frequency, incidence, and disease-specific survival (DSS) from 1973 to 2009. Variables analyzed included age, gender, race, histologic grade, stage and treatment. Cox proportional hazards analysis was conducted. RESULTS: A total of 2545 cases were identified. Parotid SCC was most common in males (79.8%), whites (92.9%), and patients aged >=75 years (51.4%). Incidence increased slightly over the past three decades (annual percent change 1.90%, p<0.05). Overall 5-year DSS was 54.4%. Statistically significant poor prognostic factors included black race, age >=75 years, tumor T3 or greater, and higher clinical stage at diagnosis. Elective neck dissection (END) in patients staged N0 was associated with higher DSS (78.3% versus 51.1%, p<0.0001). The omission of END was associated with a three-fold greater hazard of death (hazard ratio 3.19, 95% confidence interval 1.53-7.26, p=0.0016), regardless of whether or not radiotherapy was given. CONCLUSION: Parotid SCC is uncommon, and data on treatment decisions are limited. Our study profiles the demographic, clinicopathologic, incidence, and survival features of this entity. Perhaps most notably, our results support the practice of END of the N0 neck. PMID- 24814340 TI - Castleman disease of the parotid in childhood: a case report. PMID- 24814341 TI - Amygdala interneuron subtypes control fear learning through disinhibition. AB - Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning--a simple form of associative learning--through two distinct disinhibitory mechanisms. During an auditory cue, PV(+) interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM(+) interneurons, thereby enhancing auditory responses and promoting cue shock associations. During an aversive footshock, however, both PV(+) and SOM(+) interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons. PMID- 24814342 TI - Co-opting sulphur-carrier proteins from primary metabolic pathways for 2 thiosugar biosynthesis. AB - Sulphur is an essential element for life and is ubiquitous in living systems. Yet how the sulphur atom is incorporated into many sulphur-containing secondary metabolites is poorly understood. For bond formation between carbon and sulphur in primary metabolites, the major ionic sulphur sources are the persulphide and thiocarboxylate groups on sulphur-carrier (donor) proteins. Each group is post translationally generated through the action of a specific activating enzyme. In all reported bacterial cases, the gene encoding the enzyme that catalyses the carbon-sulphur bond formation reaction and that encoding the cognate sulphur carrier protein exist in the same gene cluster. To study the production of the 2 thiosugar moiety in BE-7585A, an antibiotic from Amycolatopsis orientalis, we identified a putative 2-thioglucose synthase, BexX, whose protein sequence and mode of action seem similar to those of ThiG, the enzyme that catalyses thiazole formation in thiamine biosynthesis. However, no gene encoding a sulphur-carrier protein could be located in the BE-7585A cluster. Subsequent genome sequencing uncovered a few genes encoding sulphur-carrier proteins that are probably involved in the biosynthesis of primary metabolites but only one activating enzyme gene in the A. orientalis genome. Further experiments showed that this activating enzyme can adenylate each of these sulphur-carrier proteins and probably also catalyses the subsequent thiolation, through its rhodanese domain. A proper combination of these sulphur-delivery systems is effective for BexX catalysed 2-thioglucose production. The ability of BexX to selectively distinguish sulphur-carrier proteins is given a structural basis using X-ray crystallography. This study is, to our knowledge, the first complete characterization of thiosugar formation in nature and also demonstrates the receptor promiscuity of the A. orientalis sulphur-delivery system. Our results also show that co-opting the sulphur-delivery machinery of primary metabolism for the biosynthesis of sulphur-containing natural products is probably a general strategy found in nature. PMID- 24814343 TI - CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. AB - The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3' untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA 3'-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-sequencing data for novel APA events, we identified at least 1,450 genes with shortened 3' UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNAs in human cells. Marked increases in the expression of several known oncogenes, including cyclin D1, are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3' UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, whereas CFIm25 overexpression reduces these properties and inhibits tumour growth. These findings identify a pivotal role of CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity. PMID- 24814344 TI - Purkinje-cell plasticity and cerebellar motor learning are graded by complex spike duration. AB - Behavioural learning is mediated by cellular plasticity, such as changes in the strength of synapses at specific sites in neural circuits. The theory of cerebellar motor learning relies on movement errors signalled by climbing-fibre inputs to cause long-term depression of synapses from parallel fibres to Purkinje cells. However, a recent review has called into question the widely held view that the climbing-fibre input is an 'all-or-none' event. In anaesthetized animals, there is wide variation in the duration of the complex spike (CS) caused in Purkinje cells by a climbing-fibre input. Furthermore, the amount of plasticity in Purkinje cells is graded according to the duration of electrically controlled bursts in climbing fibres. The duration of bursts depends on the 'state' of the inferior olive and therefore may be correlated across climbing fibres. Here we provide a potential functional context for these mechanisms during motor learning in behaving monkeys. The magnitudes of both plasticity and motor learning depend on the duration of the CS responses. Furthermore, the duration of CS responses seems to be a meaningful signal that is correlated across the Purkinje-cell population during motor learning. We suggest that during learning, longer bursts in climbing fibres lead to longer-duration CS responses in Purkinje cells, more calcium entry into Purkinje cells, larger synaptic depression, and stronger learning. The same graded impact of instructive signals for plasticity and learning might occur throughout the nervous system. PMID- 24814345 TI - Ribosomal oxygenases are structurally conserved from prokaryotes to humans. AB - 2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components and in the hydroxylation of transcription factors and splicing factor proteins. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA and ribosomal proteins have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone N(epsilon)-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases. PMID- 24814346 TI - PTEN is a protein tyrosine phosphatase for IRS1. AB - The biological function of the PTEN tumor suppressor is mainly attributed to its lipid phosphatase activity. This study demonstrates that mammalian PTEN is a protein tyrosine phosphatase that selectively dephosphorylates insulin receptor substrate-1 (IRS1), a mediator of insulin and IGF signals. IGF signaling was defective in cells lacking NEDD4, a PTEN ubiquitin ligase, whereas AKT activation triggered by EGF or serum was unimpaired. Defective IGF signaling caused by NEDD4 deletion, including phosphorylation of IRS1 and AKT, was rescued by PTEN ablation. We demonstrate the nature of PTEN as an IRS1 phosphatase by direct biochemical analysis and cellular reconstitution, showing that NEDD4 supports insulin-mediated glucose metabolism and is required for the proliferation of IGF1 receptor-dependent but not EGF receptor-dependent tumor cells. Thus, PTEN is a protein phosphatase for IRS1, and its antagonism by NEDD4 promotes signaling by IGF and insulin. PMID- 24814347 TI - The DNA-binding domain mediates both nuclear and cytosolic functions of p53. AB - Under conditions of genotoxic stress, human p53 activates the apoptotic effectors BAX or BAK to result in mitochondrial outer-membrane permeabilization and apoptosis. Antiapoptotic BCL-2 family member BCL-xL opposes this activity by sequestering cytosolic p53 via association with its DNA-binding domain, an interaction enhanced by p53 tetramerization. Here we characterized the BCL-xL-p53 complex by NMR spectroscopy and modulated it through mutagenesis to determine the relative contributions of BCL-xL's interactions with p53 or other BCL-2 family proteins to the BCL-xL-dependent inhibition of UV irradiation-induced apoptosis. Under our experimental conditions, one-third of the antiapoptotic activity of BCL xL was mediated by p53 sequestration and the remaining two-thirds through sequestration of proapoptotic BCL-2 family members. Our studies define the contributions of cytosolic p53 to UV irradiation-induced apoptosis and provide opportunities to explore its contributions to other p53-dependent apoptotic signaling pathways. PMID- 24814348 TI - Human nuclear Dicer restricts the deleterious accumulation of endogenous double stranded RNA. AB - Dicer is a central enzymatic player in RNA-interference pathways that acts to regulate gene expression in nearly all eukaryotes. Although the cytoplasmic function of Dicer is well documented in mammals, its nuclear function remains obscure. Here we show that Dicer is present in both the nucleus and cytoplasm, and its nuclear levels are tightly regulated. Dicer interacts with RNA polymerase II (Pol II) at actively transcribed gene loci. Loss of Dicer causes the appearance of endogenous double-stranded RNA (dsRNA), which in turn leads to induction of the interferon-response pathway and consequent cell death. Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping noncoding-RNA transcription units. Failure to do so has catastrophic effects on cell function. PMID- 24814349 TI - Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism. AB - ABCC8 encodes a subunit of the beta-cell potassium channel (KATP ) whose loss of function is responsible for congenital hyperinsulinism (CHI). Patients with two recessive mutations of ABCC8 typically have severe diffuse forms of CHI unresponsive to diazoxide. Some dominant ABCC8 mutations are responsible for a subset of diffuse diazoxide-unresponsive forms of CHI. We report the analysis of 21 different ABCC8 mutations identified in 25 probands with diazoxide unresponsive diffuse CHI and carrying a single mutation in ABCC8. Nine missense ABCC8 mutations were subjected to in vitro expression studies testing traffic efficiency and responses of mutant channels to activation by MgADP and diazoxide. Eight of the 9 missense mutations exhibited normal trafficking. Seven of the 8 mutants reaching the plasma membrane had dramatically reduced response to MgADP or to diazoxide (<10% of wild-type response). In our cohort, dominant KATP mutations account for 22% of the children with diffuse unresponsive-diazoxide CHI. Their clinical phenotype being indistinguishable from that of children with focal CHI and diffuse CHI forms due to two recessive KATP mutations, we show that functional testing is essential to make the most reliable diagnosis and offer appropriate genetic counseling. PMID- 24814350 TI - Risk factors for mental disorders in patients with hypertensive intracerebral hemorrhage following neurosurgical treatment. AB - BACKGROUND: Mental disorders are commonly observed among surgically treated patients with hypertensive intracerebral hemorrhage (HICH), leading to serious negative impacts on the patient's treatment, rehabilitation, and prognosis. The study aimed to establish the prevalence rates and risk factors for mental disorders following the surgical treatment of HICH. METHODS: This was a prospective study. Surgically treated patients with HICH were assessed 6 months following surgical treatment. The sociodemographic data were obtained from each subject, and clinical characteristics were collected for each patient from his or her hospital records. Mental disorder-related risk factors were examined using unpaired t-tests for continuous variables and chi(2) for categorical data, respectively, followed by multiple logistic regression analysis. RESULTS: A total of 96 patients were recruited for this study. The incidence of mental disorders following surgical treatment of HICH was 32.3%. Univariate analysis revealed that the occurrence of postoperative mental disorders was correlated with gender, income, social interaction, relationship between family members, hematoma localization, hematoma volume, preoperative Glasgow Coma Scale (GCS) score, surgical approach, Barthel Index, hospitalization time, and discharged patients' caregivers. Multivariate logistic regression analysis indicated that female patients, social barriers, surgical treatment with a craniotomy, and bad relationship between family members were the independent risk factors for mental disorders following surgical treatment of HICH. CONCLUSIONS: Postoperative mental disorders in patients with HICH were more likely to occur in female patients and patients who faced social barriers, those who were treated with a craniotomy, and those who experienced bad relationships between their family members. More attention and supports should be provided to this group of patients. PMID- 24814351 TI - Thrombotic complications in children from short-term percutaneous central venous catheters: what can we do? AB - The reported incidence of venous thromboembolism (VTE) in children has increased dramatically over the past decade, and the primary risk factor for VTE in neonates and infants is the presence of a central venous catheter (CVC). Although the associated morbidity and mortality are significant, very few trials have been conducted in children to guide clinicians in the prophylaxis, diagnosis, and treatment of CVC-related VTE. Furthermore, pediatric guidelines for prophylaxis and management of VTE are largely extrapolated from adult data. How then should the anesthesiologist approach central access in children of different ages to lessen the risk of CVC-related VTE or in children with prior thrombosis and vessel occlusion? A comprehensive review of the pediatric and adult literature is presented with the goal of assisting anesthesiologists with point-of-care decision-making regarding the risk factors, diagnosis, and treatment of CVC related VTE. Illustrative cases are also provided to highlight decision-making in varying situations. The only risk factor strongly associated with CVC-related VTE formation in children is the duration of the indwelling CVC. Several other factors show a trend toward altering the incidence of CVC-related VTE formation and may be under the control of the anesthesiologist placing and managing the catheter. In particular, because children with VTE may live decades with its sequelae and chronic vein thrombosis, careful consideration of lessening the risk of VTE is warranted in every child. Further studies are needed to form a clearer understanding of the risk factors, prophylaxis, and management of CVC-related VTE in children and to guide the anesthesiologist in lessening the risk of VTE. PMID- 24814352 TI - Quality and safety education for nurses: a nursing leadership skills exercise. AB - The Quality and Safety Education for Nurses (QSEN) initiative was established to answer the Institute of Medicine's trio of reports that stress the need to enhance the quality and safety of health care in the United States. The initiative has resulted in six competencies, along with innovative curricular guides to better prepare nurses to improve the health care systems within which they work. Participating in a root cause analysis (RCA) is one of several teaching strategies common to the development of QSEN competencies. This article describes the development, evaluation, and revision of a nursing leadership skills exercise that enabled students to participate in an RCA. In addition to making learning relevant, this exercise focused student attention on the nation's concern about the quality and safety of health care in the United States. PMID- 24814353 TI - Using a kinesthetic learning strategy to engage nursing student thinking, enhance retention, and improve critical thinking. AB - This article reports the outcomes of a kinesthetic learning strategy used during a cardiac lecture to engage students and to improve the use of classroom-acquired knowledge in today's challenging clinical settings. Nurse educators are constantly faced with finding new ways to engage students, stimulate critical thinking, and improve clinical application in a rapidly changing and complex health care system. Educators who deviate from the traditional pedagogy of didactic, content-driven teaching to a concept-based, student-centered approach using active and kinesthetic learning activities can enhance engagement and improve clinical problem solving, communication skills, and critical thinking to provide graduates with the tools necessary to be successful. The goals of this learning activity were to decrease the well-known classroom-clinical gap by enhancing engagement, providing deeper understanding of cardiac function and disorders, enhancing critical thinking, and improving clinical application. PMID- 24814354 TI - Teaching civility to undergraduate nursing students using a virtue ethics-based curriculum. AB - As professionals, nurses are expected to engage in respectful relationships with clients, other health care professionals, and each other. Regulatory bodies set standards and codes of ethics for professional behavior in nursing that clearly communicate expectations for civility. However, the wealth of literature on incivility in the profession indicates that nurses often fall short of meeting these standards in their interactions with other nurses. Currently, few effective strategies exist for nurse educators to teach civility to nursing students and prepare them to engage in healthy relationships with their colleagues. This article argues for the use of virtue ethics as a philosophical framework for teaching civility to undergraduate nursing students. The pedagogical strategies proposed may help students contribute to the development of healthy workplaces. PMID- 24814355 TI - Using guided debates to teach current issues. AB - A guided-debate strategy was developed for a graduate-level core course in current issues based on the Jesuit method of discernment (group decision making). The strategy encourages students to use up-to-date Internet sources to determine the range of opinions on current controversies in the discipline. In addition to providing a structured process to engage in persuasive discussion of difficult issues, the strategy facilitates critical thinking about the quality of the debate itself. Thus, students learn to avoid the pitfalls associated with consensus, such as failing to express reservations or negative opinions that might be important, while learning how to express concerns that might not be easily received by others in a group. PMID- 24814356 TI - Large-scale phylogenomic analysis reveals the phylogenetic position of the problematic taxon Protocruzia and unravels the deep phylogenetic affinities of the ciliate lineages. AB - The Ciliophora is one of the most studied protist lineages because of its important ecological role in the microbial loop. While there is an abundance of molecular data for many ciliate groups, it is commonly limited to the 18S ribosomal RNA locus. There is a paucity of data when it comes to availability of protein-coding genes especially for taxa that do not belong to the class Oligohymenophorea. To address this gap, we have sequenced EST libraries for 11 ciliate species. A supermatrix was constructed for phylogenomic analysis based on 158 genes and 42,158 characters and included 16 ciliates, four dinoflagellates and nine apicomplexans. This is the first multigene-based analysis focusing on the phylum Ciliophora. Our analyses reveal two robust superclades within the Intramacronucleata; one composed of the classes Spirotrichea, Armophorea and Litostomatea (SAL) and another with Colpodea and Oligohymenophorea. Furthermore, we provide corroborative evidence for removing the ambiguous taxon Protocruzia from the class Spirotrichea and placing it as incertae sedis in the phylum Ciliophora. PMID- 24814358 TI - Conditional survival for long-term colorectal cancer survivors in the Netherlands: who do best? AB - AIM: With the increase in the number of long-term colorectal cancer (CRC) survivors, there is a growing need for subgroup-specific analysis of conditional survival. METHODS: All 137,030 stage I-III CRC patients diagnosed in the Netherlands between 1989 and 2008 aged 15-89 years were selected from the Netherlands Cancer Registry. We determined conditional 5-year relative survival rates, according to age, subsite and tumour stage for each additional year survived up to 15 years after diagnosis as well as trends in absolute risks for and distribution of causes of death during follow-up. RESULTS: Minimal excess mortality (conditional 5-year relative survival >95%) was observed 1 year after diagnosis for stage I colon cancer patients, while for rectal cancer patients this was seen after 6 years. For stage II and III CRC, minimal excess mortality was seen 7 years after diagnosis for colon cancer, while for rectal cancer this was 12years. The differences in conditional 5-year relative survival between colon and rectal cancer diminished over time for all patients, except for stage III patients aged 60-89 years. The absolute risk to die from CRC diminished sharply over time and was below 5% after 5 years. The proportion of patients dying from CRC decreased over time after diagnosis while the proportions of patients dying from other cancers, cardiovascular disease and other causes increased. CONCLUSION: Prognosis for CRC survivors improved with each additional year survived, with the largest improvements in the first years after diagnosis. Quantitative insight into conditional relative survival estimates is useful for caregivers to inform and counsel patients with stage I-III colon and rectal cancer during follow-up. PMID- 24814359 TI - Fractionation of microbial populations in a PHA accumulating mixed culture and associated PHA content and composition. AB - The uniformity of PHA composition and content across groups of organisms in mixed cultures was considered. An activated sludge microbial community, with an average PHA content of 20wt%, was fractioned by Percoll assisted buoyant density separation. The microbial community in the two principal fractions was characterised using amplicon pyrosequencing. While organisms were common to both fractions, the relative abundances of species were found to be different between the two fractions. The average PHA content in one of the fractions was found to be higher (24wt%) than the other (16wt%); separation was considered to be in part driven by the density difference associated with PHA content, but also by other factors such as cell dimension and cellular morphology. But while differences in PHA content were observed, the PHA composition in both fractions was found to be approximately the same (43-44mol% HV), which shows that distinct groups of microbial populations within mixed cultures may generate PHA with similar average copolymer composition. PMID- 24814360 TI - Do mammographic tumor features in breast cancer relate to breast density and invasiveness, tumor size, and axillary lymph node involvement? AB - BACKGROUND: Breast density and mammographic tumor features of breast cancer may carry prognostic information. The potential benefit of using the combined information obtained from breast density, mammographic tumor features, and pathological tumor characteristics has not been extensively studied. PURPOSE: To investigate how mammographic tumor features relate to breast density and pathological tumor characteristics. MATERIAL AND METHODS: This retrospective study was carried out within the Malmo Diet and Cancer Study: a population-based cohort study recruiting 17,035 women during 1991-1996. A total of 826 incident breast cancers were identified during follow-up. Mammography images were collected and analyzed according to breast density and tumor features at diagnosis. Pathological data were retrieved from medical reports. Mammographic tumor features in relation to invasiveness, tumor size, and axillary lymph node involvement were analyzed using logistic regression yielding odds ratios (OR) with 95% confidence intervals (CI) and adjusted for age at diagnosis, mode of detection, and breast density. RESULTS: Tumors presenting as an ill-defined mass or calcifications were more common in dense breasts than tumors presenting as a distinct mass or with spiculated appearance. Invasive cancer was more common in tumors with spiculated appearance than tumors presenting as a distinct mass (adjusted OR, 5.68 [1.81-17.84]). Among invasive tumors, an ill-defined mass was more often large (>20 mm) compared with a distinct mass, (adjusted OR, 3.16 [1.80 5.55]). CONCLUSION: Tumors presenting as an ill-defined mass or calcifications were more common in dense breasts. Spiculated appearance was related to invasiveness, and ill-defined mass to larger tumor size, regardless of mode of detection and breast density. The potential role of mammographic tumor features in clinical decision-making warrants further investigation. PMID- 24814361 TI - Rosiglitazone attenuates atrial structural remodeling and atrial fibrillation promotion in alloxan-induced diabetic rabbits. AB - INTRODUCTION: The pleiotropic effects of glitazones may favorably affect atrial remodeling. We sought to investigate the effects of peroxisome proliferator activated receptor-gamma (PPAR-gamma) activator rosiglitazone on atrial structural remodeling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits. METHODS: Twenty alloxan-induced diabetic rabbits were randomly divided into two groups (10 animals in each group), namely the diabetic rosiglitazone group (treated with rosiglitazone 2 mg/day/kg for 4 weeks) and the nontreated diabetic group, while 10 additional healthy rabbits served as controls. Moreover, isolated Langendorff-perfused rabbit hearts were used to evaluate atrial electrophysiological parameters and vulnerability to AF, examined by burst pacing. Histological examination was also performed, whereas plasma oxidative stress and inflammatory biomarkers were measured. RESULTS: The duration of induced AF was significantly prolonged in the alloxan-induced diabetic rabbits compared with controls (1.6 +/- 0.4 s vs. 0 s; P < 0.05). Rosiglitazone treatment significantly reduced the duration of induced AF in the treated rabbits (1.6 +/- 0.4 s vs. 1.2 +/- 0.05 s; P < 0.05). Moreover, rosiglitazone attenuated atrial structural remodeling reducing the interatrial activation time (35.4 +/- 12.1 ms vs. 24.2 +/- 10.8 ms, P < 0.05; control 23.3 +/- 10.4 ms) and the atrial interstitial fibrosis as well (collagen volume fraction: 5.6 +/- 3.9% vs. 2.4 +/- 2.1%, P < 0.05; control 1.6 +/- 0.8%). Rosiglitazone increased plasma superoxide dismutase (SOD) activity and, on the other hand, decreased malondialdehyde (MDA), hs-C-reactive protein, and tumor necrosis factor-alpha levels. CONCLUSION: Rosiglitazone attenuates arrhythmogenic atrial structural remodeling and AF promotion in alloxan-induced diabetic rabbits. Also, it seems to modulate oxidative stress and inflammation in this experimental model. PMID- 24814357 TI - Cystatin C: a new renal marker and its potential use in small animal medicine. AB - The occurrence of chronic kidney disease is underestimated in both human and veterinary medicine. Glomerular filtration rate (GFR) is considered the gold standard for evaluating kidney function. However, GFR assessment is time consuming and labor-intensive and therefore not routinely used in practice. The commonly used indirect GFR markers, serum creatinine (sCr) and urea, are not sufficiently sensitive or specific to detect early renal dysfunction. Serum cystatin C (sCysC), a proteinase inhibitor, has most of the properties required for an endogenous GFR marker. In human medicine, numerous studies have evaluated its potential use as a GFR marker in several populations. In veterinary medicine, this marker is gaining interest. The measurement is easy, which makes it an interesting parameter for clinical use. This review summarizes current knowledge about cystatin C (CysC) in humans, dogs, and cats, including its history, assays, relationship with GFR, and biological and clinical variations in both human and veterinary medicine. PMID- 24814362 TI - Flaminal enzyme alginogel: a novel approach to the control of wound exudate, bioburden and debridement. AB - A multidisciplinary panel of Woundcare experts of international repute was assembled to review the clinical evidence and advise on the classification of the Flaminal products. This is based on their exact role in wound management and is to be defined on the basis of clinical efficacy, evidence and utility. Experts of international repute from Australia, Belgium, Czech Republic, France, Germany, Italy, Netherlands, and UK participated in this exercise. PMID- 24814363 TI - Chasing the dreams of early connectionists. AB - Mapping and examining the wiring pattern of neural systems is a fundamental pillar of neuroscience. In this Viewpoint, we review a recently described mesoscale connectome map of the mouse brain. We underscore the map's high spatial resolution and discuss key organizational network attributes of the presented connectome, its potential impact on neuroscience, and the general importance of connectome maps to obtain insight in the workings of the brain at a system's level. PMID- 24814364 TI - [Ehlers-Danlos and dystonia. Positive effects of amantadine]. PMID- 24814365 TI - Unhealed tooth extraction wound in a breast cancer patient. PMID- 24814366 TI - Impact of asymptomatic acute cellular rejection on left ventricle myocardial function evaluated by means of two-dimensional speckle tracking echocardiography in heart transplant recipients. AB - BACKGROUND: Our objective was to evaluate the impact of asymptomatic acute cellular rejection (ACR) in left ventricular myocardial strain in heart transplant (HT) recipients by means of two-dimensional speckle tracking echocardiography (2DSTE). METHODS: From September 1, 2009 to December 15, 2010 a conventional echocardiography and 2DSTE exam was performed on all consecutive HT recipients in their first year posttransplantation within 3 hours of the surveillance endomyocardial biopsies, as well as on 14 healthy controls. The association of strain echocardiographic variables with different grades of ACR was investigated. RESULTS: Of the 78 studies performed 4 +/- 3 months after HT in 20 patients, 32 studies were coincident with grade 0R rejection, 41 with grade 1R, and 5 with grade 2R. Significantly lower values of average radial strain were found with higher grades of ACR (29.1 +/- 7.7%, 23.2 +/- 8.5%, and 14.3 +/- 8.8% for grades 0R, 1R, and 2R of ACR, P = 0.001). Average deformation was similar for controls versus transplanted patients, in the absence of acute rejection: radial 29.1 +/- 10.0% versus 29.1 +/- 7.7%, P = 0.98; circumferential -19.3 +/- 3.2% versus -20.2 +/- 5.9%, P = 0.62; and longitudinal -20.7 +/- 4.1% versus -18.5 +/- 5.4%, P = 0.19. An average radial strain <25% presented 100% sensitivity, 48% specificity, 6% positive predictive value, and 100% negative predictive value for the presence of 2R rejection (area under the curve 0.80, IC 95% 0.60-0.99, P = 0.048). CONCLUSION: In this study, HT recipients showed significantly lower values of average radial left ventricle strain, evaluated by means of 2DSTE, with the presence of ACR. PMID- 24814367 TI - A morphometric study of the larynx. AB - OBJECTIVE: Describe anatomical measurements of a selection of laryngeal structures, performing a comparison of such measurements between men and women and between different age groups. STUDY DESIGN: Populational morphometric study. PARTICIPANTS: Larynges from 50 male and 50 female fresh cadavers of older than 40 years were removed during autopsy. METHODS: The following measurements were made on the external angle laryngeal framework between the blades of the thyroid cartilage: width of the thyroid cartilage, distance from the thyroid notch to the anterior commissure (AC), distance from the AC to the inferior thyroid border, distance from the AC to the larynx proeminence, length of membranacea part of vocal fold (VF), length of cartilaginea part of VF, width and thickness of true VF. RESULTS: The differences between men and women were highly significant. All measured values of larynx obtained in the study were greater in men than in women, except for the thyroid angle, which was higher in women (P < 0.05). A significant difference in the comparison between the morphological measurements in the age groups for both men and women was not observed (P > 0.05). CONCLUSION: The comparison of larynx dimensions showed the presence of sexual dimorphism in the group of South Brazilian people studied. There was no morphometric difference between the larynx samples of the individuals of the same sex after 40 years of age. PMID- 24814368 TI - Characterization of human variants in obesity-related SIM1 protein identifies a hot-spot for dimerization with the partner protein ARNT2. AB - The bHLH (basic helix-loop-helix) PAS (Per/Arnt/Sim) transcription factor SIM1 (single-minded 1) is important for development and function of regions of the hypothalamus that regulate energy homoeostasis and the feeding response. Low activity SIM1 variants have been identified in individuals with severe early onset obesity, but the underlying molecular causes of impaired function are unknown. In the present study we assess a number of human SIM1 variants with reduced activity and determine that impaired function is frequently due to defects in dimerization with the essential partner protein ARNT2 (aryl hydrocarbon nuclear translocator 2). Equivalent variants generated in the highly related protein SIM2 (single-minded 2) produce near-identical impaired function and dimerization defects, indicating that these effects are not unique to the structure of SIM1. On the basis of these data, we predict that other select SIM1 and SIM2 variants reported in human genomic databases will also be deficient in activity, and identify two new low-activity SIM1 variants (V290E and V326F) present in the population. The cumulative data is used in homology modelling to make novel observations about the dimerization interface between the PAS domains of SIM1 and ARNT2, and to define a mutational 'hot-spot' in SIM1 that is critical for protein function. PMID- 24814370 TI - Aerobic oxidative C-H olefination of cyclic N-sulfonyl ketimines catalyzed by a rhodium catalyst. AB - A useful method for the synthesis of ortho-olefinated ketimines from readily accessible cyclic N-sulfonyl ketimines and various olefins has been achieved. The reactions proceeded by Rh(III)-catalyzed, N-sulfonyl ketimine-directed C-H cleavage under aerobic conditions. Further synthetic transformations of the olefinic products led to interesting heterocyclic molecules. PMID- 24814369 TI - Interactions of disulfide-deficient selenocysteine analogs of MU-conotoxin BuIIIB with the alpha-subunit of the voltage-gated sodium channel subtype 1.3. AB - Inhibitors of the alpha-subunit of the voltage-gated sodium channel subtype 1.3 (NaV 1.3) are of interest as pharmacological tools for the study of neuropathic pain associated with spinal cord injury and have potential therapeutic applications. The recently described MU-conotoxin BuIIIB (MU-BuIIIB) from Conus bullatus was shown to block NaV 1.3 with submicromolar potency (Kd = 0.2 MUm), making it one of the most potent peptidic inhibitors of this subtype described to date. However, oxidative folding of MU-BuIIIB results in numerous folding isoforms, making it difficult to obtain sufficient quantities of the active form of the peptide for detailed structure-activity studies. In the present study, we report the synthesis and characterization of MU-BuIIIB analogs incorporating a disulfide-deficient, diselenide-containing scaffold designed to simplify synthesis and facilitate structure-activity studies directed at identifying amino acid residues involved in NaV 1.3 blockade. Our results indicate that, similar to other MU-conotoxins, the C-terminal residues (Trp16, Arg18 and His20) are most crucial for NaV 1 blockade. At the N-terminus, replacement of Glu3 by Ala resulted in an analog with an increased potency for NaV 1.3 (Kd = 0.07 MUm), implicating this position as a potential site for modification for increased potency and/or selectivity. Further examination of this position showed that increased negative charge, through gamma-carboxyglutamate replacement, decreased potency (Kd = 0.33 MUm), whereas replacement with positively-charged 2,4 diamonobutyric acid increased potency (Kd = 0.036 MUm). These results provide a foundation for the design and synthesis of MU-BuIIIB-based analogs with increased potency against NaV 1.3. PMID- 24814371 TI - Secondary organic aerosol composition from C12 alkanes. AB - The effects of structure, NOx conditions, relative humidity, and aerosol acidity on the chemical composition of secondary organic aerosol (SOA) are reported for the photooxidation of three C12 alkanes: n-dodecane, cyclododecane, and hexylcyclohexane. Acidity was modified through seed particle composition: NaCl, (NH4)2SO4, and (NH4)2SO4 + H2SO4. Off-line analysis of SOA was carried out by solvent extraction and gas chromatography-mass spectrometry (GC/MS) and direct analysis in real-time mass spectrometry. We report here 750 individual masses of SOA products identified from these three alkane systems and 324 isomers resolved by GC/MS analysis. The chemical compositions for each alkane system provide compelling evidence of particle-phase chemistry, including reactions leading to oligomer formation. Major oligomeric species for alkane SOA are peroxyhemiacetals, hemiacetals, esters, and aldol condensation products. Furans, dihydrofurans, hydroxycarbonyls, and their corresponding imine analogues are important participants in these oligomer-producing reactions. Imines are formed in the particle phase from the reaction of the ammonium sulfate seed aerosol with carbonyl-bearing compounds present in all the SOA systems. Under high-NO conditions, organonitrate products can lead to an increase of aerosol volume concentration by up to a factor of 5 over that in low-NO conditions. Structure was found to play a key role in determining the degree of functionalization and fragmentation of the parent alkane, influencing the mean molecular weight of the SOA produced and the mean atomic O:C ratio. PMID- 24814372 TI - Phosphorylation of protein kinase C sites Ser42/44 decreases Ca(2+)-sensitivity and blunts enhanced length-dependent activation in response to protein kinase A in human cardiomyocytes. AB - Protein kinase C (PKC)-mediated phosphorylation of troponin I (cTnI) at Ser42/44 is increased in heart failure. While studies in rodents demonstrated that PKC mediated Ser42/44 phosphorylation decreases maximal force and ATPase activity, PKC incubation of human cardiomyocytes did not affect maximal force. We investigated whether Ser42/44 pseudo-phosphorylation affects force development and ATPase activity using troponin exchange in human myocardium. Additionally, we studied if pseudo-phosphorylated Ser42/44 modulates length-dependent activation of force, which is regulated by protein kinase A (PKA)-mediated cTnI-Ser23/24 phosphorylation. Isometric force was measured in membrane-permeabilized cardiomyocytes exchanged with human recombinant wild-type troponin or troponin mutated at Ser42/44 or Ser23/24 into aspartic acid (D) or alanine (A) to mimic phosphorylation and dephosphorylation, respectively. In troponin-exchanged donor cardiomyocytes experiments were repeated after PKA incubation. ATPase activity was measured in troponin-exchanged cardiac muscle strips. Compared to wild-type, 42D/44D decreased Ca(2+)-sensitivity without affecting maximal force in failing and donor cardiomyocytes. In donor myocardium, 42D/44D did not affect maximal ATPase activity or tension cost. Interestingly, 42D/44D blunted the length dependent increase in Ca(2+)-sensitivity induced upon PKA-mediated phosphorylation. Since the drop in Ca(2+)-sensitivity at physiological Ca(2+) concentrations is relatively large phosphorylation of Ser42/44 may result in a decrease of force and associated ATP utilization in the human heart. PMID- 24814373 TI - Dose-dependent functionality and toxicity of green tea polyphenols in experimental rodents. AB - A large number of physiologically functional foods are comprised of plant polyphenols. Their antioxidative activities have been intensively studied for a long period and proposed to be one of the major mechanisms of action accounting for their health promotional and disease preventive effects. Green tea polyphenols (GTPs) are considered to possess marked anti-oxidative properties and versatile beneficial functions, including anti-inflammation and cancer prevention. On the other hand, some investigators, including us, have uncovered their toxicity at high doses presumably due to pro-oxidative properties. For instance, both experimental animal studies and epidemiological surveys have demonstrated that GTPs may cause hepatotoxicity. We also recently showed that diets containing high doses (0.5-1%) of a GTP deteriorated dextran sodium sulfate (DSS)-induced intestinal inflammation and carcinogenesis. In addition, colitis mode mice fed a 1% GTP exhibited symptoms of nephrotoxicity, as indicated by marked elevation of serum creatinine level. This diet also increased thiobarbituric acid-reactive substances, a reliable marker of oxidative damage, in both kidneys and livers even in normal mice, while the expression levels of antioxidant enzymes and heat shock proteins (HSPs) were diminished in colitis and normal mice. Intriguingly, GTPs at 0.01% and 0.1% showed hepato-protective activities, i.e., they significantly suppressed DSS-increased serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, those diets remarkably restored DSS-down-regulated expressions of heme oxygenase-1 and HSP70 in livers and kidneys. Taken together, while low and medium doses of GTPs are beneficial in colitis model mice, unwanted side-effects occasionally emerge with high doses. This dose-dependent functionality and toxicity of GTPs are in accordance with the concept of hormesis, in which mild, but not severe, stress activates defense systems for adaptation and survival. PMID- 24814375 TI - PACES/HRS expert consensus statement on the evaluation and management of ventricular arrhythmias in the child with a structurally normal heart. PMID- 24814378 TI - Attachment-related expectations and mother-referent memory bias in middle childhood. AB - Understanding the cognitive processing of attachment-relevant information has become a major focus of attachment research. Previous research demonstrated links between attachment and memory for attachment-related information, but results were contradictory and did not control for mood-effects. The current study aimed to provide a conceptual framework to capture inconsistencies. A straightforward memory bias hypothesis was derived and tested. Fifty children (aged 10-12) completed questionnaires assessing confidence in maternal support and depressive symptoms, and a memory task in which they recalled positive and negative words that referred to previous interactions with mother. Less confidence in maternal support and more depressive symptoms were linked to a more negative mother related memory bias. The effect of confidence in maternal support remained marginally significant when controlling for depressive symptoms, explaining the initial effect of depressive symptoms. These findings support attachment theory's hypothesis that attachment-relevant information is processed in an attachment expectation-congruent way. PMID- 24814377 TI - PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD). PMID- 24814379 TI - [Evaluation of conjunctival epithelium of filtering blebs by impression cytology]. AB - PURPOSE: To study the ocular surface in filtering blebs using impression cytology, comparing the bleb side and areas outside the bleb edges. METHODS: Twelve filtering blebs of 8 patients were included: 4 cases of trabeculectomy without mitomycin C (MMC), 6 cases of trabeculectomy with MMC, and 2 cases of non penetrating glaucoma surgery. Impression cytology specimens were taken from filtering blebs as well as outside the bleb area. A classification scale from 0 to 3 was used to describe the distribution of epithelial cells and the density of goblet cells. Grade 0 indicated cohesive epithelial cells and abundant goblet cells; and the grade 3 indicated loss of epithelial cohesion and absence of goblet cells. RESULTS: The mean grade of cytology in filtering blebs was 2.4 +/- 0.9, and in the outside bleb area of 0.8 +/- 0.3 (P<.001). These differences were independent of the use of MMC (P=.48). The large majority (83%) of filtering blebs showed a decrease in epithelial cohesion and absence of goblet cells. Outside the bleb area, 100% of the cases had cohesive epithelial cells with different grades of goblet cells. CONCLUSION: The conjunctival epithelium overlying the filtering blebs showed significant changes that consisted of increased intercellular spaces and loss of goblet cells. These increased intercellular spaces could explain the trans-epithelial pathway of aqueous humor. The least amount of mucin due to loss of goblet cells could contribute to increase the risk of infection in filtering blebs. PMID- 24814380 TI - Reply to "letter to the editor: issues to consider in children's dietary assessment" by T. Burrows and Erratum. PMID- 24814381 TI - Issues to consider in children's dietary assessment. PMID- 24814382 TI - Role of a prudent breakfast in improving cardiometabolic risk factors in subjects with hypercholesterolemia: a randomized controlled trial. AB - BACKGROUND & AIMS: It is unclear whether advising a prudent breakfast alone is sufficient to improve blood lipids and cardiometabolic risk factors in overweight hypercholesterolemic subjects. The aim of this study was to investigate whether a prudent low-fat breakfast (PB) rich in dietary fiber lowers low-density lipoprotein cholesterol (LDL-C) and other cardiometabolic risk factors in subjects with elevated LDL-cholesterol levels. METHODS: In a parallel, controlled, 12-week study, 79 healthy overweight subjects (all regular breakfast eaters) were randomly allocated to a group that received a PB based on Nordic foods provided ad libitum or a control group that consumed their usual breakfast. The primary outcome was plasma LDL-C. Secondary outcomes were other blood lipids, body weight, sagittal abdominal diameter (SAD), glucose tolerance, insulin sensitivity and inflammation markers (C-reactive protein [CRP] and tumor necrosis factor receptor-2 [TNF-R2]), and blood pressure. The PB was in accordance with national and Nordic nutrition recommendations and included oat bran porridge with low-fat milk or yogurt, bilberry or lingonberry jam, whole grain bread, low-fat spread, poultry or fatty fish, and fruit. RESULTS: No differences were found in LDL-C, other blood lipids, body weight, or glucose metabolism, but SAD, plasma CRP, and TNF-R2 decreased more during PB compared with controls (p < 0.05). In the overall diet, PB increased dietary fiber and beta-glucan compared with controls (p < 0.05). CONCLUSIONS: Advising a prudent breakfast for 3 months did not influence blood lipids, body weight, or glucose metabolism but reduced markers of visceral fat and inflammation. The trial was registered in the Current Controlled Trials database (http://www.controlled-trials.com); International Standard Randomized Controlled Trial Number (ISRCTN): 84550872. PMID- 24814384 TI - Inverse relationship between "a body shape index" (ABSI) and fat-free mass in women and men: Insights into mechanisms of sarcopenic obesity. AB - BACKGROUND & AIMS: Sarcopenic obesity may be defined by a high fat to fat-free mass (FM/FFM) ratio. Skeletal muscle may be negatively influenced by the pro inflammatory milieu associated with visceral fat, while the loading effect induced by a heavier body mass index (BMI) may enhance muscle anabolism. Recently, a new anthropometric measure based on waist circumference (A Body Shape Index, ABSI) was developed. In this study we have assessed the predictive power of ABSI on the FFM index (FFMI), a surrogate marker of lean mass. METHODS: Standard anthropometric parameters and ABSI as well as body composition data (fat and fat-free mass determined by bioelectrical impedance analysis) were assessed in 111 female and 89 male overweight/obese subjects, with no clinically significant co-morbidities. Groups with higher- or lower-ABSI were identified according to median values of this index. RESULTS: In women and men, ABSI did not correlate with BMI, while multiple linear regression indicated that BMI (beta coefficients: 0.62 and 0.77, respectively) and ABSI (beta-coefficients: -0.26 and -0.22, respectively) independently predicted FFMI (multiple R: 0.72 and 0.83, respectively, P < 0.001). Men and women with lower-ABSI exhibited significantly greater FFMI than the higher-ABSI groups for comparable values of BMI. In men, ABSI was correlated positively with C-reactive protein (CRP) (R = 0.30; P < 0.05) and negatively with the reciprocal of insulin (R = 0.28; P < 0.05), an index of insulin sensitivity. FM/FFM ratio significantly (P < 0.01) correlated with CRP (R = 0.31) in women only. CONCLUSIONS: ABSI, a recently introduced marker of abdominal adiposity, may contribute to define the risk of sarcopenia in overweight/obese individuals. PMID- 24814383 TI - Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group. AB - The aging process is associated with gradual and progressive loss of muscle mass along with lowered strength and physical endurance. This condition, sarcopenia, has been widely observed with aging in sedentary adults. Regular aerobic and resistance exercise programs have been shown to counteract most aspects of sarcopenia. In addition, good nutrition, especially adequate protein and energy intake, can help limit and treat age-related declines in muscle mass, strength, and functional abilities. Protein nutrition in combination with exercise is considered optimal for maintaining muscle function. With the goal of providing recommendations for health care professionals to help older adults sustain muscle strength and function into older age, the European Society for Clinical Nutrition and Metabolism (ESPEN) hosted a Workshop on Protein Requirements in the Elderly, held in Dubrovnik on November 24 and 25, 2013. Based on the evidence presented and discussed, the following recommendations are made (a) for healthy older people, the diet should provide at least 1.0-1.2 g protein/kg body weight/day, (b) for older people who are malnourished or at risk of malnutrition because they have acute or chronic illness, the diet should provide 1.2-1.5 g protein/kg body weight/day, with even higher intake for individuals with severe illness or injury, and (c) daily physical activity or exercise (resistance training, aerobic exercise) should be undertaken by all older people, for as long as possible. PMID- 24814385 TI - A pre-injury high ethanol intake in rats promotes brain edema following traumatic brain injury. AB - Drinking is a risk factor for traumatic brain injury (TBI), and ethanol can aggravate the outcome by promoting brain edema. The mechanism involved is not fully understood. It has been confirmed that aquaporin-4 (AQP4) and vascular endothelial growth factor (VEGF) play pivotal roles in cytotoxic/vasogenic brain edema individually, and both of these proteins are downstream regulatory factors of hypoxia-inducible factor-1alpha (HIF-1alpha). In this study, we used a fluid percussion injury (FPI) model in rats to determine the effects of acute ethanol intake on the expression levels of HIF-1alpha, AQP4, and VEGF prior to FPI. The animals were sacrificed 1, 2, 3, and 4 days post-injury. We found that the expression levels of HIF-1alpha and AQP4 were significantly upregulated in the ethanol-pretreated groups, whereas the VEGF expression level was not. In addition, there was a positive correlation between HIF-1alpha and AQP4. The results of this study indicate that cytotoxic brain edema may play an important role in the early stage of FPI in ethanol-pre-treated animals and that HIF-1alpha and AQP4 might be involved. PMID- 24814386 TI - Astrocyte's endogenous apoE generates HDL-like lipoproteins using previously synthesized cholesterol through interaction with ABCA1. AB - Apolipoprotein E (apoE) in the brain is predominantly synthesized in and secreted from astrocytes to generate apoE-containing high-density lipoprotein-like particles (apoE/HDL). However, the mechanism underlying generation of apoE/HDL has not been completely understood. The newly synthesized cholesterol, which is synthesized in rat astrocytes within 24 h using [(3)H]-acetate as a cholesterol precursor, was assembled as lipoproteins with densities of 1.12-1.17 g/mL (higher density HDL), although apoE was secreted as lipoproteins with lower densities of 1.08-1.12 g/mL from the cells. This finding suggests that the newly synthesized cholesterol is released without the association with apoE, which is like that from apoE-deficient mouse (apoE-KO) astrocytes. The cholesterol released from rat astrocytes at 3 days after the onset of its synthesis (previously synthesized cholesterol) was assembled as apoE/HDL with the densities of 1.08-1.12 g/mL (lower density HDL). These findings indicate that the endogenous apoE participates in the release of previously synthesized cholesterol but not newly synthesized one. Whereas, exogenously added human apoE induced release of both newly synthesized and previously synthesized cholesterols to generate apoE/HDL with lower density, suggesting that the cellular pool of cholesterol released by endogenous and exogenous apoE is different. The endogenous apoE was distributed in the caveolin-1-rich domain along with ATP-binding cassette transporter A1 (ABCA1) in the membrane fraction and immuno-precipitated using an anti-ABCA1 antibody. However, this is not the case for ABCA1-KO astrocytes. These findings suggest that endogenous apoE generates lower density HDL to produce more lipidated HDL using previously synthesized cholesterol through the interaction with ABCA1 in caveolin-1-rich domain of astrocytes. PMID- 24814387 TI - Blood-brain barrier disruption induced by hemoglobin in vivo: Involvement of up regulation of nitric oxide synthase and peroxynitrite formation. AB - Accumulating evidence has demonstrated that up-regulation of nitric oxide synthase (NOS) and subsequent peroxynitrite (ONOO(-)) formation exert a devastating effect on the damage of BBB in multiple diseases. However, considerably less attention has been focused on the role of NOS/ONOO(-) in BBB disruption after intracerebral hemorrhage (ICH). Using an experimental stroke model by injecting hemoglobin (Hb) into the caudate nucleus of male Sprague Dawley rats, we explored the role of NOS/ONOO(-) in BBB disruption after ICH. Brain edema content, behavioral changes, alterations of TJ proteins (claudin-5 and ZO-1), expression of neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS), formation of 3-nitrotyrosine (3-NT), as well as NO production were investigated. Hb in the rat brain led to a significant brain edema production and neurological deficits. Overexpressed NOS was concomitant with large quantities of 3-NT formation. Moreover, sites of enhanced nNOS, iNOS, eNOS and 3-NT immunoreactivity were colocalized with diminished or discontinuous ZO-1 and/or claudin-5 staining as evidenced by Western blot and immunofluorescence, indicating the involvement of NOS and ONOO(-) in the BBB disruption. Meaningfully, levels of 3-NT in serum, which had a similar tendency with that of in brain tissues (r=0.934, P<0.001), had a marked correlation with brain edema content (r=0.782, P<0.001) and neurological deficits (r=0.851, P<0.001). We concluded that ONOO(-) formation by the upregulation of NOS may play a central role in promoting the BBB damage following ICH. Moreover, ONOO(-) may be a promising biomarker for the judgment or prediction of brain injury and clinical prognosis after ICH. PMID- 24814388 TI - Mericitabine and ritonavir-boosted danoprevir with or without ribavirin in treatment-naive HCV genotype 1 patients: INFORM-SVR study. AB - BACKGROUND & AIMS: Safety and tolerability of peginterferon-based hepatitis C virus (HCV) infection therapy remains suboptimal, even when direct-acting antiviral agents are added. This study assessed the efficacy, safety and tolerability of mericitabine combined with ritonavir-boosted danoprevir (danoprevir/r) +/- ribavirin for up to 24 weeks in treatment-naive HCV genotype (G)1 infected patients. METHODS: Patients received twice daily mericitabine (1000 mg) and danoprevir/r (100 mg/100 mg) plus either ribavirin (1000/1200 mg/day; Arm A) or placebo (Arm B) for 12 or 24 weeks. Patients with HCV RNA <43 IU/ml between Weeks 2 and 8 and HCV RNA <15 IU/ml at Week 10 were rerandomized (1:1) at Week 12 to discontinue/continue assigned regimens until Week 24. Because of unacceptable relapse rates in both 12-week arms and in ribavirin-free Arm B, treatment was extended to 24 weeks and patients in Arm B received peginterferon alfa 2a/ribavirin. The primary outcome was sustained virological response 24 weeks after end of treatment (SVR24). RESULTS: In Arm A, the SVR24 rate in patients receiving 24 weeks of therapy was 37.9% (25/66); 63.6% (14/22) in G1b and 25.0% (11/44) in G1a patients. Virologic breakthrough and relapse were associated with danoprevir-resistant virus in most cases. The mericitabine-resistance mutation (NS5BS282T) was detected in two patients bearing dual resistant virus NS3 R155K/NS5B S282T and dual resistance mutation L159F/L320F in one patient. Treatment was safe and well tolerated. CONCLUSIONS: Mericitabine, danoprevir/r plus ribavirin for 24 weeks were safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients. PMID- 24814391 TI - Opsoclonus-myoclonus syndrome and limbic encephalitis associated with GABAB receptor antibodies in CSF. AB - We report a case of a woman who had two consecutive autoimmune neurological disorders, including an opsoclonus-myoclonus syndrome (OMS) and limbic encephalitis (LE), with positive titers of GABAB receptor antibodies. The patient never developed seizures or had an underlying tumor after 4 years of follow-up. PMID- 24814390 TI - B1 cells are unaffected by immune modulatory treatment in remitting-relapsing multiple sclerosis patients. AB - In this study we aimed to investigate whether treatment with an immune modulatory drug had an effect on the distribution of B cell subpopulations in patients with remitting-relapsing multiple sclerosis (RRMS). We investigated the first-line drugs glatiramer acetate, interferon-beta and natalizumab. Our data show that the frequency of the CD27(+)CD43(+) B1 cell subset was significantly diminished in RRMS patients compared to healthy subjects and that this subset was unaffected by treatment. Regardless of their true nature, we believe that these cells are part of the autoimmune disease pattern. PMID- 24814392 TI - Postcardioplegia ventricular fibrillation: no impact on subsequent survival. AB - OBJECTIVES: At aortic declamping after cardioplegic cardiac arrest, the initial rhythm can be broadly classified as ventricular fibrillation (VF) or non-VF. VF can be treated with potassium-induced conversion and direct-current countershock is only applied if potassium treatment fails. We aimed to investigate whether there are any differences between these groups of patients in regard to outcomes. DESIGN: From January 1999 through December 2010, 12,113 patients underwent various types of cardiac surgery. Data from every patient were consecutively registered. Survival was established through the Norwegian National Registry. Cox multivariable modeling with adjustment for clinical, biochemical, and medication baseline data was used for survival analysis. RESULTS: The mean follow-up time was 7.4 years and total patient-years were 89,268. The percentage of all-cause deaths was 24.9. Adjusted survival for patients with no postcardioplegia VF (n = 9723) and patients with successful potassium-induced conversion (n = 1877) was completely identical. Four hundred patients with electrical conversion after failed potassium treatment had a nonsignificant trend toward an increased mortality (hazard ratio, 95% confidence interval: 1.19 (0.99-1.4); p = 0.07). CONCLUSIONS: This is the first study reporting the association between postcardioplegia VF, its treatment with potassium and outcome. No impact was found on outcome as judged by all-cause mortality. PMID- 24814389 TI - Computer aided enzyme design and catalytic concepts. AB - Gaining a deeper understanding of enzyme catalysis is of great practical and fundamental importance. Over the years it has become clear that despite advances made in experimental mutational studies, a quantitative understanding of enzyme catalysis will not be possible without the use of computer modeling approaches. While we believe that electrostatic preorganization is by far the most important catalytic factor, convincing the wider scientific community of this may require the demonstration of effective rational enzyme design. Here we make the point that the main current advances in enzyme design are basically advances in directed evolution and that computer aided enzyme design must involve approaches that can reproduce catalysis in well-defined test cases. Such an approach is provided by the empirical valence bond method. PMID- 24814393 TI - Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala. AB - Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population. PMID- 24814394 TI - Potential role of tubulin tyrosine ligase-like enzymes in tumorigenesis and cancer cell resistance. AB - Polyglutamylation of tubulin and other non-tubulin substrates is a reversible posttranslational modification brought about by tubulin tyrosine-like ligases. Altered polyglutamylation is linked to tumorigenesis and resistance to chemotherapeutic drugs that target the microtubule, and therefore is a potential pharmacological target in cancer therapy. Despite the large amount of research focused on the development of anticancer agents, only a small number of well characterized inhibitors of polyglutamylases have been identified, including the phosphinic acid-based inhibitors of Ttll7. In this minireview, we summarize the role of polyglutamylation in cancer, and draw attention to the largely unexplored area of polyglutamylase inhibition in the treatment of cancer. PMID- 24814395 TI - Chemosensitization of rhabdomyosarcoma cells by the histone deacetylase inhibitor SAHA. AB - Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with a dismal prognosis, highlighting the need for novel treatment strategies. Here, we identify a novel synthetic lethal interaction between the histone deacetylase inhibitor (HDACI) SAHA and anticancer drugs in RMS cells. Importantly, SAHA significantly increases chemotherapeutic drug-induced apoptosis in both embryonal and alveolar RMS cell lines, including several anticancer agents that are used in the clinic for the treatment of RMS such as Doxorubicin, Etoposide, Vincristine and Cyclophosphamide. Calculation of combination index (CI) reveals that the interaction of SAHA and Doxorubicin or Etoposide is synergistic. Mechanistically, SAHA causes acetylation of histone H3 protein in RMS cells, indicating that SAHA alters the chromatin context. Also, cotreatment with SAHA and Doxorubicin changes the ratio of pro- and antiapoptotic Bcl-2 proteins with downregulation of Mcl-1 and Bcl-xL, dephosphorylation of Bcl-2 and upregulation of BimEL, thus shifting the balance towards apoptosis. Consistently, SAHA and Doxorubicin cooperate to stimulate activation of Bax and Bak, caspase activation and caspase-dependent apoptosis. Overexpression of Bcl-2 significantly rescues SAHA/Doxorubicin mediated apoptosis, underscoring the requirement of the mitochondrial apoptotic pathway for the synergistic induction of apoptosis by SAHA and Doxorubicin. Caspase-dependent apoptotic cell death is confirmed by the use of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk), which significantly decreases SAHA/Doxorubicin-triggered apoptosis. In conclusion, these findings demonstrate that the HDACI SAHA represents a promising strategy to prime RMS cells for chemotherapy-induced apoptosis and warrants further investigation in combination regimens. PMID- 24814396 TI - Preparation of highly developed mesoporous activated carbon fiber from liquefied wood using wood charcoal as additive and its adsorption of methylene blue from solution. AB - Activated carbon fiber (C-WACF) with super high surface area and well-developed small mesopores were prepared by liquefied wood and uses wood charcoal (WC) as additive. The characterization and properties of C-WACF were investigated by XRD, XPS and N2 adsorption. Results showed the pore development was significant at temperatures >750 degrees C, and reached a maximum BET surface area (2604.7 m(2)/g) and total pore volume (1.433 cm(3)/g) at 850 degrees C, of which 86.8% was from the contribution of the small mesopores of 2-4 nm. It was also found that the mesopore volume and methylene blue adsorption of C-WACF were highly increased as the temperature increases from 750 to 850 degrees C. Additionally, the reduction of graphitic layers, the obvious changes of functional groups and the more unstable carbons on the surface of C-WACF, which played important roles in the formation of mesopores, were also observed. PMID- 24814397 TI - Formate production through carbon dioxide hydrogenation with recombinant whole cell biocatalysts. AB - The biological conversion of CO2 and H2 into formate offers a sustainable route to a valuable commodity chemical through CO2 fixation, and a chemical form of hydrogen fuel storage. Here we report the first example of CO2 hydrogenation utilising engineered whole-cell biocatalysts. Escherichia coli JM109(DE3) cells transformed for overexpression of either native formate dehydrogenase (FDH), the FDH from Clostridium carboxidivorans, or genes from Pyrococcus furiosus and Methanobacterium thermoformicicum predicted to express FDH based on their similarity to known FDH genes were all able to produce levels of formate well above the background, when presented with H2 and CO2, the latter in the form of bicarbonate. In the case of the FDH from P. furiosus the yield was highest, reaching more than 1 g L(-1)h(-1) when a hydrogen-sparging reactor design was used. PMID- 24814398 TI - Patient involvement climate: views and behaviours among registered nurses in myocardial infarction care. AB - AIMS AND OBJECTIVES: To introduce and define the patient involvement climate and measure its quality and strength via views and behaviours among nurses in coronary care units. BACKGROUND: Patient involvement is receiving increased attention among healthcare providers. To better understand and optimise the interpersonal dynamics of patient involvement, it is important to study the organisational context in which the patient-provider interaction occurs. DESIGN: Cross-sectional, self-report questionnaire study. METHODS: Registered nurses across 12 coronary care units (n = 303) completed a questionnaire reporting their views and behaviours regarding patient involvement. Analyses assessed climate quality (the positive or negative nature of nurses' perceptions) and climate strength (the degree of consensus within coronary care units). RESULTS: Climate quality and strength were greatest for the dimensions measuring nurses' views of patient involvement, the nurse-patient information exchange process and nurses' responsiveness to patient needs. Climate quality and strength were weaker for the dimensions measuring nurses' views of the hindrances associated with patient involvement, discussion of daily activities and efforts to motivate patients to take responsibility for their health. In units with consensus that patient involvement poses hindrances, nurses were less likely to address patient needs. CONCLUSIONS: When nurses perceived patient involvement as less of a hindrance in their work, they were more responsive to patient needs. A patient involvement climate characterised by motivational behaviour among nurses was marked by better information exchange and discussion of suitable activities postdischarge. RELEVANCE TO CLINICAL PRACTICE: Managers can capitalise on positive climate aspects by encouraging ward activities that facilitate active patient involvement among nurses. One suggestion is educational interventions at the workplace focused on reducing perceptions of patient involvement as a hindrance and encouraging the attitudes that it can enrich nursing work and patient outcomes. PMID- 24814399 TI - The floral scents of Nymphaea subg. Hydrocallis (Nymphaeaceae), the New World night-blooming water lilies, and their relation with putative pollinators. AB - Night-blooming water lilies are characterized by intense emission of floral VOCs. Their unique scent-oriented pollinators, cyclocephaline scarabs (Scarabaeidae, Cyclocephalini), are attracted to flowers that they use as reliable sources of food and as mating aggregation sites. Chemical analysis of floral scent samples of seven species of Nymphaea subg. Hydrocallis established remarkably simple fragrant blends, each of which was dominated by one or two prominent compounds that alone accounted for over 95% of total scent emission. A total of 22 VOCs were identified: aliphatics (9), C5-branched chain compounds (5) and aromatics (8). Anisole was the dominant constituent in the floral scents of Nymphaea amazonum subsp. amazonum, N. amazonum subsp. pedersenii and N. tenerinervia, whereas (methoxymethyl)benzene was the most abundant VOC in samples of N. lasiophylla and N. lingulata. Flowers of N. rudgeana and N. gardneriana emitted high amounts of methyl hexanoate and methyl 2-methylbutanoate. Comparisons of floral VOC composition including other day- and night-blooming species of Nymphaea and Victoria obtained from the literature evidenced disparities related to habitus. While flowers of day-blooming species mostly emit aromatic alcohols and ethers, nocturnal species are particularly rich in aromatic ethers, aliphatic esters and C5-branched chain esters. These findings strongly suggest that the floral scent composition within closely related Nymphaea and Victoria is linked to pollinator selection, and the putative role of floral VOCs in pollinator attractiveness is discussed. PMID- 24814400 TI - Development and application of a monoclonal antibody against grouper iridovirus (GIV) major capsid protein. AB - The major capsid protein (MCP) is a main structural protein of iridoviruses, and is used as a marker for the identification, differentiation and classification of ranaviruses. In the present study, six monoclonal antibodies (mAbs) against recombinant MCP of grouper iridovirus (GIV) were produced and characterized. All of the six mAbs were of IgG1 isotype. Among the mAbs, GIV-MCP-mAb-21 showed the highest reactivity in ELISA and was used to further characterize the expression of GIV-MCP during viral replication. RT-PCR and Western blot analyses revealed that GIV-MCP is a late gene during GIV infection. By immunofluorescence assay, the presence of GIV-MCP was observed in not only the cytoplasm but also the nucleus of GIV-infected cells, a surprising finding that might indicate additional role of GIV-MCP. In conclusion, the newly established GIV-MCP-mAbs are a valuable tool for GIV diagnostic and future studies on GIV pathogenesis. PMID- 24814401 TI - [Comparison between Goldmann, Icare Pro and Corvis ST tonometry]. AB - PURPOSE: To compare intraocular pressure (IOP) between the new non-contact tonometer Corvis ST (CST), the Goldmann applanation tonometry (GAT) and Icare Pro rebound tonometer (PRO). METHODS: A total of 178 eyes of 178 healthy subjects were selected for the study. Measurements of IOP were made in a random order with GAT, PRO and CST. Central corneal thickness (CCT) was determined by ultrasound pachymetry. The mean of three valid measurements of each variable was used in the statistical analysis. The relationship between the tonometers was established using Bland-Altman plots. RESULTS: Mean IOP was 15.5 +/- 2.8 mmHg for GAT, 15.4 +/- 2.8 mmHg for CST, and 14.6 +/- 2.3 mmHg for PRO. The mean differences between pairs of tonometers were: GAT-PRO=0.9 +/- 1.7 mmHg (P<.001), GAT-CST: 0.1 +/- 2.2 (P=.398), and PRO-CST: -0.8 +/--0.7 mmHg, p<0.001. A positive relationship was detected between CCT and the three tonometers: GAT: r=0.325, P<.001; PRO: r = 0.385, P<.001, and CST: r = 0.428; P<.001. CONCLUSIONS: The differences found between PRO and GAT were significantly higher than those found between CST and GAT, which showed non-significant differences. The measurements of the three tonometers were affected by the CCT. PMID- 24814402 TI - Histopathologic examination of routine tonsillectomies in times of Greek austerity. Necessity or luxury? A retrospective study of 823 patients. PMID- 24814403 TI - DNA assembled gold nanoparticles polymeric network blocks modular highly sensitive electrochemical biosensors for protein kinase activity analysis and inhibition. AB - A highly sensitive electrochemical biosensor was built for the detection of kinase activity based on the DNA induced gold nanoparticles (AuNPs) polymeric network block signal amplification. In this strategy, the DNA1 conjugated AuNPs were integrated with the phosphorylated peptide by Zr(4+) and assembled into DNA AuNPs polymeric network block by the hybridization of cDNA with each side sequences of DNA1 and joint DNA2. The kinase activity was determined by the amperometric responses of [Ru(NH3)6](3+) absorbed on the network block by electrostatic interaction. Due to its excellent electroactivity and high accommodation of the DNA-AuNPs polymeric network block for [Ru(NH3)6](3+), the current signal was significantly amplified, affording a highly sensitive electrochemical analysis of kinase activity. The as-proposed biosensor presents a low detection limit of 0.03 U mL(-1) for protein kinase A (PKA) activity, wide linear range (from 0.03 to 40 U mL(-1)), and excellent stability even in cell lysates and serum samples. This biosensor can also be applied for quantitative kinase inhibitor screening. Finally, the PKA activities from BE4S-2B, A549, and MCF-7 cell lysates were further analyzed, which provided a valuable strategy in developing a high-throughput assay of in vitro kinase activity and inhibitor screening for clinic diagnostics and therapeutics. PMID- 24814404 TI - Prognostic effect of serum and tissue YKL-40 levels in bladder cancer. AB - OBJECTIVES: YKL-40 is a novel inflammatory serum protein shown to be associated with the presence and prognosis of several malignancies. However, its prognostic relevance has not yet been analyzed in bladder cancer (BC). Therefore, the aim of this study was to assess the tissue, serum, and urinary levels of YKL-40 and their prognostic value in BC. METHODS AND MATERIALS: YKL-40 gene expression levels were analyzed in frozen tissue samples of 91 patients with BC; YKL-40 concentrations were measured in 120 serum (101 patients with BC and 19 controls) and 154 urine samples (125 patients with BC and 29 controls). In 16 cases, corresponding serum samples collected before and after radical cystectomy were analyzed for YKL-40. Results were correlated with clinicopathological parameters and follow-up data. RESULTS: YKL-40 gene expressions and serum concentrations were higher in patients with BC compared with controls; however, urinary YKL-40 levels remained under the detection limit in both patients and controls. Higher tissue gene expressions and serum concentrations were associated with poor patients' survival in the univariable analysis (P = 0.037 and 0.022, respectively), but only high YKL-40 serum levels proved to be independent prognostic factors in BC (hazard ratio = 1.755, 95% CI: 1.014-3.039, P = 0.045). We found no significant difference between preoperative and postoperative serum concentrations of YKL-40. CONCLUSIONS: YKL-40 serum levels are associated with the presence of BC and poor patients' survival. The independent prognostic relevance of YKL-40 is of particular interest in patients with muscle-invasive BC treated with radical surgery. Our data suggest that BC tissue is not the main source of serum YKL-40 levels. PMID- 24814405 TI - The Hedgehog pathway: potential biomarker and therapeutic applications in urologic malignancies. AB - The Hedgehog pathway has been implicated in the development of several non urologic malignancies. Recent work suggests that the activation of the glioma associated GLi family of zinc finger transcription factors may play a role in some urologic malignancies. This review surveys the potential role of the Hedgehog pathway as a new class of biomarker in some urologic cancers. PMID- 24814406 TI - Calcium channel blockers and prostate cancer. AB - The relationship between calcium channel blockers and prostate cancer has been an area of increased interest to investigators. Calcium channel blockers have been shown to influence cell proliferation, differentiation, and apoptosis. Clinically, the association between calcium channel blockers and the development of prostate cancer has been controversial. However, on a basic science level, there is evidence that calcium channel blockers induce cytotoxicity in androgen receptor positive cell lines and may offer an innovative strategy for the treatment of castration-resistant prostate cancer. PMID- 24814407 TI - The clinical presentation and outcome of urothelial atypia on biopsy of the bladder. AB - OBJECTIVES: To examine the presentation and clinical outcome of patients diagnosed with reactive urothelial atypia (RUA) or urothelial atypia of unknown significance (AUS) on tissue biopsy of the bladder. METHODS AND MATERIALS: We performed a retrospective cohort study of all patients who were diagnosed with either RUA or AUS on biopsy of the bladder at our institution from November 2000 to May 2008. Excluded from the analysis were patients with a history of or a concurrent diagnosis of urothelial carcinoma. A total of 66 patients were available for final analysis. RESULTS: The mean patient age at diagnosis was 63 years (range: 18-89 years). There were 46 men (70%) and 20 women (30%). The indication for cystoscopic examination included lower urinary tract symptoms in 29 (44%), gross hematuria in 17 (26%), microscopic hematuria in 12 (18%), urolithiasis in 2 (3%), and hydronephrosis in 6 (9%) patients. On biopsy, 54 (82%) had RUA and 12 (18%) had AUS. The mean follow-up was 36 months (range: 0 271 months). During this period, 37 (56%) patients underwent at least 1 additional cystoscopy with negative result. None of the 66 (0%) patients developed biopsy-proven urothelial carcinoma. CONCLUSION: Urothelial atypia is common in men older than 60 years and often presents with either hematuria or lower urinary tract symptoms. Both RUA and AUS have a similar benign clinical course. Therefore, after diagnosis, further intervention or surveillance is unnecessary. PMID- 24814408 TI - Marginal bone resorption around immediate and delayed loaded implants supporting a locator-retained mandibular overdenture. A 1-year randomised controlled trial. AB - The aim of this 1-year study was to evaluate and compare crestal bone loss and clinical outcomes of immediate and delayed loaded implants supporting mandibular overdentures with Locator attachments. In a randomised controlled clinical trial, 36 completely edentulous patients (mean age 59.6 years) who desired to improve the stability of their mandibular dentures were randomly assigned into two groups. Each patient received two implants in the canine area of the mandible after a minimal flap reflection. Implants were loaded by mandibular overdentures either 3 months (delayed loading group, G1) or the same day (immediate loading group, G2) after implant placement. Locator attachments were used to retain all overdentures to the implants. Peri-implant vertical (VBL) and horizontal (HBLO) bone losses and clinical parameters [plaque scores (PI), gingival scores (GI), probing depths (PD) and implant stability (ISQ)] were assessed at time of overdenture insertion (T0), 6 months (T6) and 12 months (T12) after overdenture insertion. After 12 months of overdenture insertion, two implants (5.5%) failed in G2. Vertical bone loss was significantly higher in G2 compared with G1, while HBLO demonstrated insignificant differences between groups. All clinical parameters (PI, GI, PD and ISQ) did not differ significantly between groups. Vertical bone loss was significantly correlated with PD and HBLO. Immediately loaded two implants supporting a Locator-retained mandibular overdenture are associated with more vertical bone resorption when compared to delayed loaded implants after 1 year. Clinical outcomes do not differ significantly between loading protocols. PMID- 24814409 TI - Lifetime cumulative exposure to waterpipe smoking is associated with coronary artery disease. AB - OBJECTIVE: Globally, waterpipe (WP) smoking is becoming a more prevalent form of tobacco consumption. Whilst research so far has demonstrated a significant link between WP use and a number of health outcomes, little is known of its association with heart disease. We examine in this study the association of WP smoking with angiographically confirmed coronary artery disease (CAD). METHODS: A total of 1210 patients, aged 40 years and over and free from smoking-associated illnesses or history of cardiovascular procedures, admitted for coronary angiography at four major hospitals in Lebanon, were included. The extent of CAD was summarized in two ways, firstly as diseased (>= 50% and >= 70% occlusion in at least one main coronary artery) versus non-diseased (entirely normal coronaries), and secondly, as CAD cumulative score based on Duke CAD Prognostic Index. A score of WP-years, capturing intensity and lifetime duration of exposure, was estimated for each individual. RESULTS: Lifetime exposure exceeding 40 WP-years was associated with a threefold significant increase in the odds of having severe stenosis (>= 70%) compared to non-smokers (OR = 2.94, 95% CI 1.04 8.33) as well as with the CAD Index (beta = 7.835, p-value = 0.027), net of the effect of socio-demographic characteristics, health behaviors and co-morbidity. A dose-response relationship between WP-years and percent stenosis was also established. WP smoking status (never, past and current) did not associate with CAD. CONCLUSIONS: Cumulative exposure to WP smoking is significantly associated with severe CAD. There is a need to monitor WP use among cardiac patients and include this information in their medical charts in the same manner cigarettes smoking is documented. This is likely to increase awareness of the hazards of WP smoking and prompt physicians to target WP tobacco control by providing advice to their patients on WP smoking cessation. PMID- 24814410 TI - 7-ketocholesteryl-9-carboxynonanoate enhances ATP binding cassette transporter A1 expression mediated by PPARgamma in THP-1 macrophages. AB - BACKGROUND: ATP binding cassette transporter A1 (ABCA1) is a member of the ATP binding cassette transporter family. It plays an essential role in mediating the efflux of excess cholesterol. It is known that peroxisome proliferator-activated receptor gamma (PPARgamma) promoted ABCA1 expression. We previously found 7 ketocholesteryl-9-carboxynonanoate (oxLig-1) upregulated ABCA1 partially through CD36 mediated signals. In the present study, we intended to test if PPARgamma signally is involved in the upregulation mediated by oxLig-1. METHODS AND RESULTS: First, we docked oxLig-1 and the ligand-binding domain (LBD) of PPARgamma by using AutoDock 3.05 and subsequently confirmed the binding by ELISA assay. Western blotting analyses showed that oxLig-1 induces liver X receptor alpha (LXRalpha), PPARgamma and consequently ABCA1 expression. Furthermore, oxLig 1 significantly enhanced ApoA-I-mediated cholesterol efflux. Pretreatment with an inhibitor for PPARgamma (GW9662) or/and LXRalpha (GGPP) attenuated oxLig-1 induced ABCA1 expression. Under PPARgamma knockdown by using PPARgamma-shRNA, oxLig-1-induced ABCA1 expression and cholesterol efflux in THP-1 macrophages was blocked by 62% and 25% respectively. CONCLUSIONS: These observations suggest that oxLig-1 is a novel PPARgamma agonist, promoting ApoA-I-mediated cholesterol efflux from THP-1 macrophages by increasing ABCA1 expression via induction of PPARgamma. PMID- 24814411 TI - Detecting familial hypercholesterolaemia in the community: impact of a telephone call from a chemical pathologist to the requesting general practitioner. AB - OBJECTIVE: To determine whether a telephone call from a chemical pathologist to the requesting general practitioner (GP) of individuals at high risk of familial hypercholesterolaemia (FH) increases specialist referral and detection of FH. METHOD: Individuals with an LDL-cholesterol >= 6.5 mmol/L without secondary causes were identified from a community laboratory; 100 cases and 96 historical controls. All laboratory reports (cases and controls) received interpretative comments highlighting FH. In addition, the cases' GPs received a telephone call from the chemical pathologist to highlight their patient's risk of FH and suggest specialist referral, whereas with the controls' GPs were not telephoned. RESULTS: After 12 months follow-up, 27 (27%) cases were referred to clinic compared with 4 (4%) controls (p < 0.0001). 25 cases were reviewed at clinic, 12 (48%) had definite FH and 18 (72%) had probable or definite FH according to the Dutch Lipid Clinic Network Criteria, 2 cases did not attend their clinic appointments. Genetic testing was performed in 23 individuals: 7 (30%) had pathogenic FH mutations. Genotypic cascade screening of 4 kindreds from the intervention group detected an additional 7 individuals with FH and excluded 5 mutation-negative family members. CONCLUSIONS: A telephone call from a chemical pathologist to the requesting GP of patients at high risk of FH was associated with significantly higher rates of FH detection and specialist referral. Over 70% of individuals with an LDL-cholesterol >= 6.5 mmol/L were diagnosed with FH. However, further investigation is required to improve the relatively low referral rate. PMID- 24814412 TI - The use of the non-fasting lipid profile for lipid-lowering therapy in clinical practice - point of view. AB - Current guidelines for the management of dyslipidaemias recommend measuring lipid profiles in the fasting state. The primary lipid targets are traditionally plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. However, triglycerides, apolipoprotein (apo) B and non-high-density lipoprotein cholesterol (non-HDL-C) are also suitable parameters to assess cardiovascular risk and to guide lipid-lowering therapy. The advantage of the use of these variables is that they can be used in both the fasting and non-fasting state. In most cases, postprandial lipid profiles in combination with apo B are as useful as fasting lipid profiles for the differentiation between familial lipid disorders, such as heterozygous familial hypercholesterolemia, familial combined hyperlipidemia and familial hypertriglyceridemia. This article will address the interpretation, applications and limitations of a non-fasting lipid profile for daily clinical practice. PMID- 24814413 TI - Secondary traumatization among former prisoners of wars' adult children: the mediating role of parental bonding. AB - BACKGROUND AND OBJECTIVES: The aversive impact of combat and parents' combat induced posttraumatic stress disorder (PTSD) on young children has been examined in a few studies. However, the long-term toll of war captivity on secondary traumatization (ST) and the parental bonding of adult children remain unknown. This study examined ST symptoms and parental bonding among adult children of former prisoners of war (ex-POWs' children) that were compared to adult children of comparable veterans (controls' children). Furthermore, we examined the mediating role of parental bonding and exposure to stress in the association between group and ST symptoms. DESIGN: A correlative, cross-sectional study. METHODS: Participants were Israeli ex-POWs' children (N = 98) and controls' children (N = 90), whose fathers fought in the 1973 Yom Kippur War. All participants completed a battery of self-reported questionnaires. RESULTS: Ex POWs' children reported a higher number of ST symptoms and lower levels of fathers' care, as compared to controls' children. Importantly, exposure to stress stemming from fathers' behaviors and fathers' care was found to mediate the association between research group and ST. CONCLUSIONS: Forty years after the war ended, the experience of living with ex-POWs is associated with ex-POWs' children psychological outcome. PMID- 24814414 TI - Assessment and treatment of post patent ductus arteriosus ligation syndrome. AB - OBJECTIVE: To compare differences in tissue Doppler imaging, global longitudinal strain (GLS), and cardiac troponin T (cTnT) between infants with low (<200 mL/kg/min) and high (>200 mL/kg/min) left ventricular (LV) output 1 hour after duct ligation and assess the impact of milrinone treatment on cardiac output and myocardial performance. STUDY DESIGN: LV function was assessed preoperatively and 1 and 18 hours postoperatively. Infants were categorized into a low-output or a normal-output group based on the echocardiographic assessment of LV output at 1 hour. RESULTS: Thirty infants with a mean gestation of 25.3 weeks were enrolled. LV basal lateral S', basal septal S', and basal right ventricular S' were lower in the low-output group (n = 19) at 1 hour postoperatively, with no significant difference in GLS (low-output -10.3% vs high-output -14.4%, P >.05) or cTnT between the groups. Patients in the low-output group were treated with milrinone, and by 18 hours LV performance recovered to levels comparable with the high output group. cTnT values increased at 18 hours in the whole cohort with no significant difference between the groups. CONCLUSION: Tissue Doppler imaging and GLS provide novel insights and further characterization of myocardial performance immediately after patent ductus arteriosus ligation. A reduction in tissue Doppler-derived LV systolic velocity may further help in monitoring cardiac performance after patent ductus arteriosus ligation and for monitoring the effects of treatment. PMID- 24814415 TI - Risk of bias in randomized trials of pharmacological interventions in children and adults. AB - OBJECTIVE: To determine whether randomized controlled trials of pharmacologic interventions in children are more likely to be biased than similar trials in adults. STUDY DESIGN: Trials involving only children and published in MEDLINE between January 2008 and October 2009 (n=100) were randomly selected and matched, by drug class and therapeutic area, with a similar trial completed in adults. The Cochrane risk of bias tool was used to compare the pediatric and adult trials. RESULTS: The characteristics of adult and pediatric trials included were similar, except that adult studies were more likely to be conducted in Europe and published in specialty journals. Two-thirds of all trials were single center, and 62% had 100 or fewer participants. Many trials had an unclear risk of bias for allocation concealment (65% adult, 52% pediatric). More pediatric trials had a low risk of bias for random sequence generation (59% pediatric, 41% adult, P=.002) and blinding of outcome assessment (63% pediatric, 48% adult, P=.04) than adult trials; however, a sensitivity analysis of trials published since 2008 (and so matched by year of publication) did not confirm this finding, suggesting year of publication was an important confounder. CONCLUSIONS: When randomized controlled trials are matched for drug class and therapeutic area, trials involving children display a similar risk of bias. Differences in the risk of bias between pediatric and adult trials are not caused by differences in the capacity of researchers to conduct and report trials of high quality. PMID- 24814416 TI - Pyriform sinus perforation in nonaccidental trauma. PMID- 24814417 TI - Coupling tendencies during exploratory behaviours of competing players in rugby union dyads. AB - This study investigated interpersonal coordination tendencies in 1vs.1 dyads in rugby union, here expressed by participants' movement velocity towards or away from the sideline as they competed to score or prevent a try. We examined whether coupling tendencies of members of each dyad shaped key performance outcomes (try or successful tackle). Data on movement displacement trajectories of eight male rugby union players (aged 11-12 years) were analysed during performance in 47 trials. To assess coordination tendencies during exploratory behaviours in the dyads, analyses of performance time series data were undertaken using variable time graphs, running correlations and cross-correlations. Results revealed distinct coupling patterns characterised by shifts between synchronous coordination and asynchronous coordination tendencies and uncoordinated actions. Observed behaviours were interpreted as attempts of competing participants to create and perceive possibilities for action while seeking to achieve specific performance goals. Findings also revealed that a variety of patterned relations between participants resulted in different performance outcomes. PMID- 24814418 TI - Trends in macrolide resistance of respiratory tract pathogens in the paediatric population in Serbia from 2004 to 2009. AB - We report the first study of macrolide resistance in respiratory tract pathogens in a Serbian paediatric population. It included 5293 Streptococcus pneumoniae, 4297 Streptococcus pyogenes, 2568 Moraxella catarrhalis and 1998 Haemophilus influenzae isolates derived from the respiratory tract and 110 invasive isolates from children aged up to 18 years during 2004-2009. Over the 6-year period, a significant increase (P < 0.01) in macrolide resistance was found in both S. pneumoniae and S. pyogenes that reached 45% and 19%, respectively, in 2009. In the same period, consumption of macrolides increased continually from 2.46 to 5.8 defined daily dose/1000 inhabitants per day. The increase in macrolide resistance in S. pyogenes correlated with consumption of total macrolide and long-acting macrolides (r = 0.879, P = 0.05 and r = 0.922, P = 0.026, respectively). A similar trend was observed in pneumoccoci, although it did not reach statistical significance. The growing problem of macrolide resistance in pneumococci and S. pyogenes in Serbia requires further vigilant surveillance. PMID- 24814419 TI - Guide wire thrombus formation during trans-femoral TAVI. PMID- 24814420 TI - African-American patients are less likely to receive drug-eluting stents during percutaneous coronary intervention. AB - BACKGROUND: Previous research has shown that African-Americans, patients without insurance, and those with government-sponsored insurance are less likely to be referred for invasive cardiovascular procedures. We therefore sought to compare the impact of race and insurance type upon the use of drug-eluting stents (DES). METHODS: Patients undergoing percutaneous coronary intervention (PCI) with stenting from January 2008 to December 2012 at Los Angeles County Hospital and Keck Hospital of USC were retrospectively analyzed. Race was categorized as African-American, Hispanic, or non-African-American/non-Hispanic. Insurance was categorized as private, Medicare, Medicaid, incarcerated, or uninsured. Multivariable logistic regression was performed, with receipt of >=1 DES the outcome variable of interest. RESULTS: Among 2763 patients undergoing PCI, 62.8% received >=1 DES, 45.4% were Hispanic, 6.7% were African-American, 33.2% were uninsured, 28.5% had Medicaid, 22.5% had Medicare, 14.1% had private insurance, and 1.7% were incarcerated. Following multivariable adjustment, African Americans, in comparison to non-African-American/non-Hispanic patients, were less likely to receive >=1 DES (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.40-0.82, p=0.002). Hispanic patients, however, were not less likely to receive DES. Uninsured patients (OR 1.51, 95% CI 1.13-2.03, p=0.006) and those with Medicaid (OR 1.49, 95% CI 1.11-2.00, p=0.008) were more likely to receive DES than patients with private insurance, whereas those with Medicare were less likely to receive DES (OR 0.71, 95% CI 0.52-0.95, p=0.02). CONCLUSIONS: African American race continues to have a significant impact upon the decision to use DES. Future research should focus upon patient and provider perceptions at the time of PCI. SUMMARY: This study is a retrospective analysis of the impact of race and insurance status upon the utilization of drug-eluting stents. Multivariable logistic regression showed that African-American race was associated with less utilization of drug-eluting stents. PMID- 24814421 TI - The role of mouse mast cell proteases in the proliferative phase of wound healing in microdeformational wound therapy. AB - BACKGROUND: Stored in the secretory granules of cutaneous mouse mast cells are mouse mast cell proteases (mMCP-4, -5, and -6). Using transgenic mouse lines that lacked these enzymes, it was shown that mMCP-4 and mMCP-5 modulate the outcome of burn-induced skin injury. Whether or not these proteases also play a role in the repair of surgically damaged skin, with or without microdeformational wound therapy, remains to be determined. METHODS: Wild-type C57BL/6 mice and transgenic C57BL/6 mouse lines lacking mMCP-4, -5, or -6 were subjected to surgical wounding of their skin. Wounds were splinted with a stabilizing patch, and the mice received either microdeformational wound therapy (n = 5) or occlusive dressing (n = 5) for 7 days. Wound healing parameters were assessed in the proliferative phase. RESULTS: Cell proliferation in the wounded wild-type mice receiving microdeformational wound therapy was 60 +/- 3 percent. Cell proliferation was only 35 +/- 5 percent, 25 +/- 5 percent, and 45 +/- 4 percent for the treated mMCP-4-, mMCP-5-, and mMCP-6-null mice, respectively (p = 0.005). Blood vessel sprouting was higher in the control mice with microdeformational wound therapy (170 +/- 40 vessels/high-power field) compared with mouse mast cell protease 6 null mice with microdeformational wound therapy (70 +/- 20 vessels/high-power field; p = 0.005), and higher in the control mice with occlusive dressing (110 +/ 30 vessels/high-power field) compared with mMCP-4-null mice with occlusive dressing (50 +/- 20 vessels/high-power field; p = 0.01). Qualitatively, the granulation tissue of all the protease-deficient groups receiving microdeformational wound therapy was disrupted. CONCLUSION: Results suggest that mouse mast cell proteases 4, 5, and 6 are mediators of the critical role mast cells play in microdeformational wound therapy in the proliferative phase of healing. PMID- 24814422 TI - Individualized risk of surgical-site infection: an application of the breast reconstruction risk assessment score. AB - BACKGROUND: Risk factors for surgical-site infection following beast reconstruction have been thoroughly investigated at a population level. However, traditional population-based measures may not always capture the nuances of individual patients. The authors aimed to develop a validated breast reconstruction risk assessment calculator for surgical-site infection that informs risk at an individual level. METHODS: Mastectomies with immediate reconstruction (n = 16,069) from 2005 to 2011 were identified from the National Surgical Quality Improvement Program database. A multiple logistic regression model was created for postoperative surgical-site infection. Hosmer-Lemeshow, C statistic, and Brier score were computed to assess model performance. Bootstrap analysis validated the model. RESULTS: A robust, validated risk model for surgical-site infection was developed using 11 covariates. The model Hosmer Lemeshow p value was 0.371, the Brier score was 0.0357, and the C statistic was 0.682 (optimism-corrected C statistic, 0.678). The distribution of individual risks demonstrated a positive skew. Population-derived risk underestimated or overestimated individual risk by at least 1.5-fold in nearly one-fifth of all patients. CONCLUSIONS: The breast reconstruction risk assessment score risk calculator for surgical-site infection mitigates the potentially inaccurate interpolation of population-based risk to individual patients. The authors concomitantly developed an online interface-accessible by patients and surgeons alike-to quantify a patient's risk for surgical-site infection, better informing evidence-based decisions and managing patient expectations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 24814423 TI - Variation in hospital-based acute care within 30 days of outpatient plastic surgery. AB - BACKGROUND: When complications arise following outpatient plastic surgery, patients may require hospital-based acute care after discharge. The extent to which these events vary across centers may reflect the quality of care provided. The authors conducted this study to describe the frequency and variation of hospital-based acute care rates across ambulatory surgery centers. METHODS: From the 2009 to 2010 California, Florida, Nebraska, and New York ambulatory surgery databases, the authors identified adult patients who underwent common outpatient plastic surgery procedures between July of 2009 and September of 2010. Hospital based acute care was defined as any emergency department visit or hospital admission within 30 days of discharge. Performance across centers was assessed by calculating observed-to-expected ratios derived from multivariable logistic regression models. RESULTS: The authors identified 72,308 discharges from 519 centers. Most were female patients (80.9 percent); self-pay patients (41.5 percent); and underwent blepharoplasty (36.9 percent), breast augmentation (14.2 percent), or multiple procedures (12.2 percent). The observed hospital-based, acute care rate was 42.8 encounters per 1000 discharges, with most managed in the emergency department for symptoms or complications of care. The median charges associated with these encounters were $2183 and $26,299 for emergency department visits and hospital admissions, respectively. Wide variation was noted in hospital-based acute care rates, with 15 centers (2.9 percent) performing significantly better and 27 (5.2 percent) performing significantly worse than expected after adjusting for case mix. CONCLUSIONS: The overall rate of hospital based acute care after common outpatient plastic surgery procedures is low but measurable. However, the frequency of these events varies across centers and may reflect the quality of care provided. PMID- 24814424 TI - Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model. AB - Nanocarriers and nanoparticles remain an intense pharmaceutical and medical imaging technology interest. Their entry into clinical use is hampered by the lack of reliable in vitro models that accurately predict in vivo toxicity. This study evaluates a 3-D kidney organoid proximal tubule culture to assess in vitro toxicity of the hydroxylated generation-5 PAMAM dendrimer (G5-OH) compared to previously published preclinical in vivo rodent nephrotoxicity data. 3-D kidney proximal tubule cultures were created using isolated murine proximal tubule fractions suspended in a biomedical grade hyaluronic acid-based hydrogel. Toxicity in these cultures to neutral G5-OH dendrimer nanoparticles and gold nanoparticles in vitro was assessed using clinical biomarker generation. Neutral PAMAM nanoparticle dendrimers elicit in vivo-relevant kidney biomarkers and cell viability in a 3-D kidney organoid culture that closely reflect toxicity markers reported in vivo in rodent nephrotoxicity models exposed to this same nanoparticle. PMID- 24814425 TI - Repair of the injured spinal cord by implantation of a synthetic degradable block copolymer in rat. AB - The present study is designed to assess the properties of a new degradable PLA-b PHEMA block copolymer hydrogel and its therapeutic effectiveness after implantation following a thoracic spinal cord hemisection on rats. Degradable characteristics and porous aspect of the scaffold are respectively analyzed by the evaluation of its mass loss and by electron microscopy. The biomaterial toxicity is measured through in vitro tests based on motoneuron survival and neurite growth on copolymer substrate. Functional measurements are assessed by the Basso, Beattie and Bresnahan (BBB) and the Dynamic Weight Bearing (DWB) tests during 8 weeks post-surgery. Histological analyses are achieved to evaluate the presence of blood vessels and axons, the density of the glial scar, the inflammatory reaction and the myelination at the lesion site and around it. The results indicate that the synthetic PLA-b-PHEMA block copolymer is a non-toxic and degradable biomaterial that provides support for regenerating axons and seems to limit scar tissue formation. Additionally, the implantation of the porous PLA b-PHEMA scaffold enhances locomotor improvement. The observed functional recovery highlights the potential benefits of plain tissue engineering material, which can further be optimized by bioactive molecule functionalization or transplanted cell encapsulation. PMID- 24814426 TI - Protein cytoplasmic delivery using polyampholyte nanoparticles and freeze concentration. AB - A protein delivery method using freeze concentration was presented with a variety of polyampholyte nanocarriers. In order to develop protein nanocarriers, hydrophobically modified polyampholytes were synthesized by the succinylation of epsilon-poly-l-lysine with dodecyl succinic anhydride and succinic anhydride. The self-assembled polyampholyte aggregated form nanoparticles through intermolecular hydrophobic and electrostatic interactions when dissolved in aqueous media. The cationic and anionic nanoparticles were easily prepared by changing the succinylation ratio. Anionic or cationic proteins were adsorbed on/into the nanoparticles depending on their surface charges. The protein-loaded nanoparticles were stable for at least 7 d. When L929 cells were frozen with the protein-loaded nanoparticles in the presence of a cryoprotectant, the adsorption of the protein-loaded nanoparticles was enhanced and can be explained by the freeze concentration mechanism. After thawing, proteins were internalized into cells via endocytosis. This was the first report that showed that the efficacy of protein delivery was successfully enhanced by the freeze concentration method. This method could be useful for in vitro cytoplasmic protein or peptide delivery to various cells for immunotherapy or phenotype transformations. PMID- 24814427 TI - Tumor targeting by pH-sensitive, biodegradable, cross-linked N-(2-hydroxypropyl) methacrylamide copolymer micelles. AB - Increasing the molecular weight of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers by using micellar structures could result in more pronounced enhanced permeability and retention effect, thus increase the tumor accumulation of drug. However, most micellar formulations are relatively unstable and release their drug non-specifically. To improve on these disadvantages, we developed a micellar drug delivery system based on self-assembly of HPMA copolymers. Amphiphilic conjugates were synthesized by conjugating the hydrophobic drug doxorubicin and hydrophobic beta-sitosterol to the hydrophilic HPMA polymer backbone via pH sensitive hydrazone linkages. This linkage is quite stable at physiological pH but hydrolyzes easily at acidic pH. After conjugates self-assembly into micelles, HPMA copolymer side chains were cross-linked through the hydrazone linkages to ensure micelle stability in the blood. Using this approach, cross-linked micelles were obtained with molecular weight of 1030 KD and diameter of 10-20 nm. These micelles remained stable with undetectable doxorubicin release at pH 7.4 or mouse plasma, whereas collapsed quickly with 80% of the drug released at pH 5 which corresponds to the pH of lyso/endosome compartments of tumor cells. Both cross linked and non-cross-linked micelles displayed similar in vitro anti-tumor activity as linear copolymer conjugates in Hep G2 and A549 cancer cell lines with internalization mechanism by caveolin, clathrin, and giant macropinocytosis. In vivo studies in an H22 mouse xenograft model of hepatocarcinoma showed the tumor accumulation (1633 MUCi/L*h) and anti-tumor rate (71.8%) of cross-linked micelles were significantly higher than non-cross-linked ones (698 MUCi/L*h, 64.3%). Neither type of micelle showed significant toxicity in heart, lung, liver, spleen or kidney. These results suggest that cross-linked HPMA copolymer micelles with pH-sensitivity and biodegradability show excellent potential as carriers of anti cancer drugs. PMID- 24814428 TI - Fates of Fe3O4 and Fe3O4@SiO2 nanoparticles in human mesenchymal stem cells assessed by synchrotron radiation-based techniques. AB - Superparamagnetic iron oxide nanoparticles (SPIOs) have been widely used as the magnetic resonance imaging (MRI) contrast agent in biomedical studies and clinical applications, with special interest recently in in vivo stem cell tracking. However, a full understanding of the fate of SPIOs in cells has not been achieved yet, which is particularly important for stem cells since any change of the microenvironment may disturb their propagation and differentiation behaviors. Herein, synchrotron radiation-based X-ray fluorescence (XRF) in combination with X-ray absorption spectroscopy (XAS) were used to in situ reveal the fate of Fe3O4 and Fe3O4@SiO2 NPs in human mesenchymal stem cells (hMSCs), in which the dynamic changes of their distribution and chemical speciation were precisely determined. The XAS analysis evidences that Fe3O4 NPs cultured with hMSCs are quite stable and almost keep their initial chemical form up to 14 days, which is contradictory to the previous report that Fe3O4 NPs were unstable in cell labeling assessed by using a simplified lysosomal model system. Coating with a SiO2 shell, Fe3O4@SiO2 NPs present higher stability in hMSCs without detectable changes of their chemical form. In addition, XRF analysis demonstrates that Fe3O4@SiO2 NPs can label hMSCs in a high efficiency manner and are solely distributed in cytoplasm during cell proliferation, making it an ideal probe for in vivo stem cell tracking. These findings with the help of synchrotron radiation based XAS and XRF improve our understanding of the fate of SPIOs administered to hMSCs and will help the future design of SPIOs for safe and efficient stem cells tracking. PMID- 24814429 TI - The potential role of pretransplant MIBG diagnostic scintigraphy in targeted administration of 131I-MIBG accompanied by ASCT for high-risk and relapsed neuroblastoma: a pilot study. AB - MIBG is an effective component in treatment of neuroblastoma. Furthermore, MIBG scintigraphy is an imaging modality in primary assessments. None of the previous studies have evaluated the role of pretransplant MIBG scintigraphy in decision making for neuroblastoma treatment. We selected therapeutic regimen based on pretransplant (131) I-MIBG scintigraphy. Twenty high-risk patients were enrolled. On day -30, patients underwent diagnostic MIBG scintigraphy. Patients were then subdivided into two groups (10 cases in each arm). MIBG-avid subgroup received MIBG (12 mCi/kg), etoposide (1200 mg/m2), carboplatin (1500 mg/m2), and melphalan (210 mg/m2). Non-MIBG-avid subgroup received etoposide (600 mg/m2), carboplatin (1200 mg/m2), and melphalan (150 mg/m2). Patients received CRA after ASCT. Mean age at diagnosis was 42.5 months (range, 17-65) in MIBG-avid and 38.9 months (range, 18-65) in non-MIBG-avid patients. Mean age at diagnosis and transplantation did not reveal significant difference between two subgroups. In MIBG-avid patients, the three-yr OS was 66 +/- 21%. In MIBG-non-avid subgroup, the three-yr OS was 53 +/- 20%. In MIBG-avid and non-MIBG-avid subgroups, the three-yr EFS were 66 +/- 21% and 47 +/- 19%, respectively. These findings may suggest an effective role in selecting the therapeutic strategy for pre-ASCT MIBG scintigraphy in high-risk neuroblastoma. MIBG-avid subset may benefit from the combination of therapeutic MIBG and high dose of chemotherapy. PMID- 24814430 TI - [Pelvic fracture, outpatient care]. PMID- 24814431 TI - Mortality risk score for Klebsiella pneumoniae bacteraemia. AB - BACKGROUND: Klebsiella pneumoniae bacteraemia (KPB) has been associated with multiple risk factors. However association of these risk factors with mortality secondary to KPB has been poorly documented. OBJECTIVES: To assess underlying co morbidities in patients with KPB and any associated presentations. These findings were then used to devise a score to estimate the risk of in-hospital mortality in patients with underlying KPB. METHODS: A retrospective analysis of all patients diagnosed with KPB between November 2007 and March 2012 at Mater Dei hospital in Malta was carried out. Using the odds ratios of risk factors for mortality associated with KPB, a mortality risk score was then prepared. RESULTS: 186 patients (mean age 62 years; mean hospital stay 22.6 days) were included. 51 patients died as inpatients. Being admitted to intensive care (Overall risk (OR): 9, p<0.0001), having a solid organ tumour (OR 3, p<0.005), and having an underlying pneumonia (OR 3, p<0.021) were statistically significant risk factors associated with mortality. There were 0% mortality in patients with a score of 0, and progressively increasing mortalities with increasing scores up to a 100% mortality in patients with scores of >15. This translated into a validated risk score where an increasing score reflected an increasing mortality. CONCLUSIONS: Klebsiella pneumoniae bacteraemia is associated with high in-patient mortality. ICU admission, underlying solid tumours, and co-existent pneumonias are among the factors used in our mortality risk score. This needs to be further validated in larger populations. PMID- 24814432 TI - Low seroprevalence of diphtheria, tetanus and pertussis in ambulatory adult patients: the need for lifelong vaccination. AB - BACKGROUND: Tetanus, diphtheria, pertussis and measles are vaccine preventable diseases that have been reported to cause morbidity and mortality in adult population in the recent years. We aimed to document the seropositivity rates and vaccination indication for these four vaccine preventable diseases among adult and elderly patients who were seen as outpatients in a university hospital. METHODS: Blood samples for tetanus, diphtheria, pertussis and measles antibodies were obtained. Results were evaluated with regards to protection levels and booster vaccine indications according to the cut-off values. RESULTS: A total of 1367 patients consented for the study and 1303 blood samples were available for analysis at the end of the study. The antibody levels against measles conferred protection in 98% of patients. However, 65% of the patients had no protection for diphtheria, 69% had no protection for tetanus and 90% of the patients had no protection for pertussis. Only 1.3% of the study population had seropositivity against three of the diseases-Tdap booster was indicated in 98.7%. Multivariable logistic regression showed that tetanus protection decreased with increasing age. Having a chronic disease was associated with a lower rate of protective antibodies for pertussis. CONCLUSIONS: We demonstrated very low rates of protection against three of the vaccine preventable diseases of childhood diphtheria, pertussis and tetanus. Booster vaccinations are required in adult life in accordance with national and international adult vaccination guidelines. The concept of "lifelong vaccination" should be implemented and every encounter with the patient should be regarded as a chance for catch-up. PMID- 24814434 TI - Endpoints in PAH clinical trials in the era of combination therapy: how do we decide whether something is working without going bankrupt? AB - There has been substantial progress in the treatment of pulmonary arterial hypertension using specific disease-targeted therapies. As the number of agents available grows, and as new treatment strategies emerge, it is essential that the endpoints we use to assess efficacy are sufficiently meaningful and sensitive enough to detect changes that are often subtle. Although the six-minute walk has been the traditional primary endpoint in clinical trials, there is now a move towards more patient-centred composite endpoints such as time to clinical worsening. These endpoints need to be more clearly defined and universally applied so as to make direct comparison between new drugs and new combinations possible. PMID- 24814433 TI - Use of Bacillus subtilis isolates from Tua-nao towards nutritional improvement of soya bean hull for monogastric feed application. AB - Soya bean hull (SBH) is a cheap and high-fibre content feed ingredient that obtained after soya bean oil extraction. Microbial fermentation was expected to improve SBH qualities before applying to animals, especially monogastric animals. Two bacterial strains, Bacillus subtilis MR10 and TK8 that were isolated from Tua nao, a traditional fermented soya bean in northern Thailand, were used for fermented soya bean hull (FSBH) production. Both could easily grow at 37 degrees C in SBH as the sole substrate. MR10 produced the highest beta-mannanase activity (400 U g(-1) SBH) on day 2, while TK8 produced the highest cellulase activity (14.5 U g(-1) SBH) on day 3. After fermentation, the nutritional quality of SBH was obviously improved by an increase in soluble sugars, soluble proteins, crude protein and crude lipid, and a decrease in the content of raffinose family oligosaccharides. Scavenging activity (%) of SBH against ABTS radical cation was also increased from 14 to 27 and 20% by MR10 and TK8 fermentation, respectively. According to the GRAS property of these both strains and various improvements of nutritional values, the fermented SBH proved to be a potential feed ingredient, especially for the monogastric animals. SIGNIFICANCE AND IMPACT OF THE STUDY: Normally, soya bean hull has been recognized as only a worthless by-product from soya bean oil production process because of its low utilizable nutrients. Our study introduced an alternative way to utilize this worthless residue using biotechnological knowledge. The nutritional quality of soya bean hull was improved by microbial fermentation. Fermented soya bean hull can be used as a cheap, safe and high-nutrient feed ingredient for livestock production, especially monogastric animals, to promote their growth performances, instead of using antibiotics in some regions of the world. PMID- 24814435 TI - mitoNEET as a novel drug target for mitochondrial dysfunction. AB - Mitochondrial dysfunction plays an important part in the pathology of several diseases, including Alzheimer's disease and Parkinson's disease. Targeting mitochondrial proteins shows promise in treating and attenuating the neurodegeneration seen in these diseases, especially considering their complex and pleiotropic origins. Recently, the mitochondrial protein mitoNEET [also referred to as CDGSH iron sulfur domain 1 (CISD1)] has emerged as the mitochondrial target of thiazolidinedione drugs such as the antidiabetic pioglitazone. In this review, we evaluate the current understanding regarding how mitoNEET regulates cellular bioenergetics as well as the structural requirements for drug compound association with mitoNEET. With a clear understanding of mitoNEET function, it might be possible to develop therapeutic agents useful in several different diseases including neurodegeneration, breast cancer, diabetes and inflammation. PMID- 24814436 TI - Celebrating four years. PMID- 24814437 TI - Alcohol consumption and reproductive health risks in rural Central Kenya. AB - OBJECTIVE: The goal of the current study is to explore the perceived reproductive health risks associated with alcoholism from the perspective of rural communities in Kenya where abuse of illicit liquor especially among men has become an epidemic. METHODS: Data for the study were gathered qualitatively through focus groups among community members and in-depth interviews with opinion leaders and key informants who were selected through a snowball method. All recorded data were analyzed through constructivist and interpretive techniques, which started with a line-by-line examination of transcripts for identification of emerging themes. RESULTS: Rural communities are aware of the lethal nature of the illicit liquor and the severe reproductive health problems associated with it among male consumers. Alcoholism also affects women's sexual and reproductive needs and is attributed to risky sexual behaviors in alcohol-discordant relationships, which puts them at a higher risk of HIV infection. CONCLUSIONS: Results indicate a need to address alcoholism in rural Kenya as a public health problem focusing on education and understanding of the long-term health consequences. Addressing the impact on male reproductive health is crucial because it impacts the wider community. Given the complex relationship between alcohol abuse and HIV/AIDS, it is also important for prevention interventions to target married women and non alcohol consumers. Furthermore, engaging communities will ensure development of culture- and gender-specific interventions. Such engagement requires facilitation of health practitioners for development of meaningful community-based initiatives. PMID- 24814438 TI - Ultrasound guidance of embryo transfer: a role for midwife. AB - OBJECTIVE: Evaluate the role of midwife with no experience in assisting ultrasound guided embryo transfer. METHODS: A prospective randomized study comparing results of IVF after ultrasound guided embryo transfer (ET) assisted either by a midwife with no formal training in US, or by a doctor trained to guide. ET procedure was performed on 553 patients undergoing ultrasound guided ET. The number of embryos transferred, the pregnancy rate (PR), the incidence of extrauterine pregnancy, ongoing pregnancy rate, the implantation rate (IR), difficulty of embryo transfer and quality of US assistance were compared among the groups. RESULTS: No significant differences were observed between the two groups regarding the number of embryos transferred (2.5+0.7 Group A vs 2.4+0.8 Group B) implantation rate (15.6% Group A vs 15.2% Group B), pregnancy rate (34.3% Group A vs 36.2% Group B), ongoing pregnancy rate (23.4% Group A vs 23.9% Group B), and rate of extrauterine pregnancies (1.4% Group A vs 1% Group B). Difficult transfers (2.9% Group A vs 3.6% Group B) and unsatisfactory visualization of uterus and catheter (6.2% Group A vs 7.3% Group B) were also similar in both groups of patients. DISCUSSION: Having an inexperienced nurse or midwife to perform ultrasound guidance during ET does not markedly affect the clinical results compared to using experienced clinicians for this purpose. PMID- 24814439 TI - Swedish women's expectations about antenatal care and change over time - a comparative study of two cohorts of women. AB - A decade ago a national cohort of Swedish-speaking women were surveyed about their expectations on antenatal care. Today, antenatal care in Sweden still operates under similar circumstances while changes have occurred in society and the pregnant population. OBJECTIVE: To compare expectations of antenatal care in pregnant women recruited 2009-2010 to those of pregnant women from a national cohort in 1999-2000. An additional aim was to compare antenatal expectations in women recruited to a clinical trial and subsequently received group based or standard antenatal care. METHODS: A cross-sectional pre-study of 700 women recruited to a clinical trial and a historical cohort of 3061 women from a Swedish national survey. Data was collected by a questionnaire in early pregnancy for both cohorts and before the clinical trial started. RESULTS: In early pregnancy 79% of the women in the study sample reported a preference for the recommended number of visits, which is slightly higher than in the national cohort (70%). Continuity of the caregiver was still important with 95% vs 97% of the women rated it important to meet the same midwife at subsequent antenatal visits. The content of care rank order showed a change over time with lower expectations in health check-ups and emotional content and higher expectations in information needs, respect and partner involvement. CONCLUSION: Women approached in early pregnancy had lower expectations about medical and emotional check-ups and parent education but higher expectations regarding information, being met with respect and the involvement of the partner compared to women 10 years ago. Continuity of a midwife caregiver was still important and women seem more willing to follow the recommended number of antenatal visits. CLINICAL IMPLICATIONS: Asking women about their expectations regarding antenatal care could be a means to individualize the care. PMID- 24814440 TI - Spatial analysis of choice of place of delivery in Nigeria. AB - OBJECTIVE: Access to quality healthcare during childbirth is a crucial factor for taming maternal and child mortality and morbidity. Increasing this access in developing countries depends on understanding the factors influencing maternal healthcare decision at a geographical location. This study analyzes spatial pattern in choice of place of delivery in Nigeria. METHOD: Data analyzed came from Nigerian Demographic and Health Survey data set. The choice of place delivery was considered a multi-categorical response and a multinomial logistic regression model used to evaluate spatial variations in choosing a particular place to deliver against home delivery. RESULTS: Results show a north-south divide in choosing health facilities against homes for delivery. The likelihood of institutional delivery was significantly lower for women residing in Bayelsa and the majority of the states in northern Nigeria. As women advance in age, they have more likelihood of having institutional deliveries. Other contributing factors that favor institutional deliveries include use of antenatal care services, urban dwelling, mass media and parity. CONCLUSION: Usage of mass media to campaign for institutional deliveries particularly in northern Nigeria, among younger women and those of higher parity; encouraging the use of antenatal services and even distribution of health facilities making them easily accessible to rural women are important for enhancing chances of institutional deliveries. Also, state-specific policies in this regard are indispensable. PMID- 24814441 TI - Fathers' experience of childbirth when non-progressive labour occurs and augmentation is established. A qualitative study. AB - OBJECTIVE: Augmentation with oxytocin during labour has increased in Western obstetrics over the last few decades. The aim of this study was to describe how fathers experienced childbirth when non-progressive labour occurred and augmentation was established. METHOD: A qualitative descriptive design. Ten fathers were interviewed 4-15 weeks post partum. The interviews were semi structured and were analyzed using Braun and Clarke's thematic analysis. RESULTS: The analysis revealed three themes and four sub-themes. The themes were: (1) A rational approach to own role, (2) Labour and birth as uncontrollable processes and (3) Relief about the decision of augmentation. The fathers had a rational approach and felt powerless when the process of labour was uncontrollable. They felt they were not able to help their partners in pain when non-progressive labour occurred. They experienced relief when augmentation was established because of the subsequent progression of labour, and because it was then easier to find a role as a helper. CONCLUSION: This study demonstrates that fathers feel relieved when augumentation is established. In addition, the study underlines that fathers, in order to regain control after experiencing the non-progressive labour, need directions from the midwives to carry out appropriate and usefull tasks. PMID- 24814442 TI - Swedish couples' attitudes towards birth, childbirth fear and birth preferences and relation to mode of birth - a longitudinal cohort study. AB - OBJECTIVE: Little is known if couples hold similar or different attitudes towards birth or what impact these have on the actual mode of birth. The aim of this study was to compare couples' personal and general attitudes towards birth. An additional aim was to study the relationship between attitudes, birth preferences, and fear of birth in relation to mode of birth. METHODS: This study is part of a longitudinal cohort study of 1074 pregnant women and their partners recruited during one year in three hospitals in the middle-north part of Sweden. Data was collected by questionnaires. Chi-square test, t-tests and multinominal regression analysis were used in the analyses. RESULTS: Women held stronger attitudes about the importance of a safe and less stressful birth for the baby, while their partners were most concerned about the woman's health. Women who preferred a caesarean section and reported childbirth fear often prioritized a safe and stressful birth for themselves, wanted to avoid pain, plan the date, and decide about birth themselves and did not view birth as natural. Some of these attitudes were also found in partners who preferred a caesarean section. Birth preference and fear were strongly associated with mode of birth. CONCLUSION: Special attention should be directed towards parents with a caesarean section preference and parents with childbirth related fear as they have certain attitudes to birth and are more likely to have caesarean section for the birth of the baby. PMID- 24814443 TI - Economic austerity, food poverty, and health. PMID- 24814444 TI - Human rights violations in Sri Lanka. PMID- 24814445 TI - Transient ischaemic attack: more than a stroke of bad luck. PMID- 24814446 TI - Influenza vaccine in pregnancy: policy and research strategies. PMID- 24814448 TI - Carl Hart: advocate for rational drug policy. PMID- 24814449 TI - Management of brain arteriovenous malformations. PMID- 24814450 TI - Management of brain arteriovenous malformations. PMID- 24814451 TI - Management of brain arteriovenous malformations. PMID- 24814452 TI - Management of brain arteriovenous malformations. PMID- 24814453 TI - Management of brain arteriovenous malformations. PMID- 24814454 TI - Management of brain arteriovenous malformations--authors' reply. PMID- 24814455 TI - Paroxysmal burning pain caused by erythromelalgia. PMID- 24814456 TI - [Pericardial effusion: An unknown expression of Graves' disease]. PMID- 24814457 TI - Anaphylactic shock induced by mephenesin. PMID- 24814458 TI - [A case of unusual allergy to champagne]. PMID- 24814459 TI - Psychometric properties of the disorders of consciousness scale. AB - OBJECTIVE: To provide evidence for psychometric properties of the Disorders of Consciousness Scale (DOCS). DESIGN: Prospective observational cohort. SETTINGS: Seven rehabilitation facilities. PARTICIPANTS: Patients (N=174) with severe brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE DOCS RESULTS: Initial analyses suggested eliminating 6 items to maximize psychometrics, resulting in the DOCS-25. The 25 items form a unidimensional hierarchy, rating scale categories are ordered, there are no misfitting items, and differential item functioning was not found according to sex, type of brain injury, veteran status, and days from onset. Person separation reliability (.91) indicates that the DOCS 25 is appropriate for individual patient measurement. Items are well targeted to the sample, with the difference between mean person and item calibrations less than 1 logit. DOCS-25 Rasch measures result in a 62% gain in relative precision over total raw scores. Internal consistency is very good (Cronbach alpha=.86); interrater agreement is excellent (intracIass correlation coefficient=.90) for both the DOCS-25 and the sensory subscales. The DOCS-25 total measure, but not subscale measures, correlates with the Glasgow Coma Scale and the Coma/Near-Coma Scales and distinguishes significantly between vegetative and minimally conscious states, indicating concurrent validity. CONCLUSIONS: The DOCS-25 is psychometrically strong. It has excellent measurement precision and captures a broad range of patient function, which is critical for capturing recovery of consciousness. The sensory subscales are clinically informative but should not be reported as separate measures. The Keyform synthesizes clinical observations to visualize response patterns with potential for informing clinical decision making. Future studies should determine sensitivity to change, examine issues of rater severity, and explore the usefulness of the Keyform in clinical practice. PMID- 24814460 TI - Psychometric properties of 2-minute walk test: a systematic review. AB - OBJECTIVE: To systematically review the psychometric evidence on the 2-minute walk test (2MWT). DATA SOURCES: Electronic searches of databases including MEDLINE, CINAHL, Academic Search Premier, SPORTDiscus, PsycINFO, EMBASE, the Cochrane Library, and DARE were done until February 2014 using a combination of subject headings and free texts. STUDY SELECTION: Studies were included if psychometric properties of the 2MWT were (1) evaluated; (2) written as full reports; and (3) published in English language peer-reviewed journals. DATA EXTRACTION: A modified consensus-based standard for the selection of health measurement instruments checklist was used to rate the methodological quality of the included studies. A quality assessment for statistical outcomes was used to assess the measurement properties of the 2MWT. DATA SYNTHESIS: Best-evidence synthesis was collated from 25 studies of 14 patient groups. Only 1 study was found that examined the 2MWT in the pediatric population. The testing procedures of the 2MWT varied across the included studies. Reliability, validity (construct and criterion), and responsiveness of the 2MWT also varied across different patient groups. Moderate to strong evidence was found for reliability, convergent validity, discriminative validity, and responsiveness of the 2MWT in frail elderly patients. Moderate to strong evidence for reliability, convergent validity, and responsiveness was found in adults with lower limb amputations. Moderate to strong evidence for validity (convergent and discriminative) was found in adults who received rehabilitation after hip fractures or cardiac surgery. Limited evidence for the psychometric properties of the 2MWT was found in other population groups because of methodological flaws. CONCLUSIONS: There is inadequate breadth and depth of psychometric evidence of the 2MWT for clinical and research purposes-specifically, minimal clinically important changes and responsiveness. More good-quality studies are needed, especially in the pediatric population. Consensus on standardized testing procedures of the 2MWT is also required. PMID- 24814461 TI - High-level mobility in chronic traumatic brain injury and its relationship with clinical variables and magnetic resonance imaging findings in the acute phase. AB - OBJECTIVES: To compare high-level mobility in individuals with chronic moderate to-severe traumatic brain injury (TBI) with matched healthy controls, and to investigate whether clinical variables and magnetic resonance imaging (MRI) findings in the acute phase can predict high-level motor performance in the chronic phase. DESIGN: A longitudinal follow-up study. SETTING: A level 1 trauma center. PARTICIPANTS: Individuals (N=136) with chronic TBI (n=65) and healthy matched peers (n=71). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: High Level Mobility Assessment Tool (HiMAT) and the revised version of the HiMAT performed at a mean of 2.8 years (range, 1.5-5.4y) after injury. RESULTS: Participants with chronic TBI had a mean HiMAT score of 42.7 (95% confidence interval [CI], 40.2-45.2) compared with 47.7 (95% CI, 46.1-49.2) in the control group (P<.01). Group differences were also evident using the revised HiMAT (P<.01). Acute-phase clinical variables and MRI findings explained 58.8% of the variance in the HiMAT score (P<.001) and 59.9% in the revised HiMAT score (P<.001). Lower HiMAT scores were associated with female sex (P=.031), higher age at injury (P<.001), motor vehicle collisions (P=.030), and posttraumatic amnesia >7 days (P=.048). There was a tendency toward an association between lower scores and diffuse axonal injury in the brainstem (P=.075). CONCLUSIONS: High-level mobility was reduced in participants with chronic, either moderate or severe TBI compared with matched peers. Clinical variables in the acute phase were significantly associated with high-level mobility performance in participants with TBI, but the role of early MRI findings needs to be further investigated. The findings of this study suggest that the clinical variables in the acute phase may be useful in predicting high-level mobility outcome in the chronic phase. PMID- 24814462 TI - Successful use of intravenous cyclophosphamide pulse therapy for interstitial lung disease in a patient with systemic sclerosis on hemodialysis. AB - Interstitial lung disease and scleroderma renal crisis are major complications of systemic sclerosis, which occasionally coexist in patients with the diffuse cutaneous subtype. We herein report a case of diffuse cutaneous systemic sclerosis under hemodialysis due to a previous history of scleroderma renal crisis, whose interstitial lung disease was effectively and safely treated with a half dose of i.v. cyclophosphamide pulse. The dose of cyclophosphamide and the timing of hemodialysis leading to efficacy and low toxicity are discussed. PMID- 24814463 TI - Sociodemographic risk and early environmental factors that contribute to resilience in executive control: A factor mixture model of 3-year-olds. AB - Young children at sociodemographic risk generally demonstrate lower executive control (EC), although with substantial heterogeneity across children. Given this marked variability, there may be some at-risk children who display higher EC and may be buffered from or resilient to the effects of sociodemographic risk who can be studied to identify the contributory factors. In this study, factor mixture modelling was used to determine whether subgroups of 3-year-old children existed based on their observed performance on a battery of EC tasks. Results indicated 2 latent groups: One characterized by lower EC and the other by higher EC. Both sociodemographically at-risk and low-risk children were represented in each group, yielding 4 risk-status-by-EC groups, where at-risk higher EC children were termed the resilient group. Proximal household enrichment (e.g., exposure to learning materials, varied enriching experiences, academic and language stimulation, parental responsivity) distinguished the resilient group from lower performing children of similar risk status, whereas distal financial resources and proximal social network resources did not distinguish these two groups. Results suggest potential intervention targets to promote optimal EC development, particularly among children at risk. PMID- 24814464 TI - Kaposi sarcoma in HIV-negative men who have sex with men. PMID- 24814465 TI - Clinal variation at phenology-related genes in spruce: parallel evolution in FTL2 and Gigantea? AB - Parallel clines in different species, or in different geographical regions of the same species, are an important source of information on the genetic basis of local adaptation. We recently detected latitudinal clines in SNPs frequencies and gene expression of candidate genes for growth cessation in Scandinavian populations of Norway spruce (Picea abies). Here we test whether the same clines are also present in Siberian spruce (P. obovata), a close relative of Norway spruce with a different Quaternary history. We sequenced nine candidate genes and 27 control loci and genotyped 14 SSR loci in six populations of P. obovata located along the Yenisei river from latitude 56 degrees N to latitude 67 degrees N. In contrast to Scandinavian Norway spruce that both departs from the standard neutral model (SNM) and shows a clear population structure, Siberian spruce populations along the Yenisei do not depart from the SNM and are genetically unstructured. Nonetheless, as in Norway spruce, growth cessation is significantly clinal. Polymorphisms in photoperiodic (FTL2) and circadian clock (Gigantea, GI, PRR3) genes also show significant clinal variation and/or evidence of local selection. In GI, one of the variants is the same as in Norway spruce. Finally, a strong cline in gene expression is observed for FTL2, but not for GI. These results, together with recent physiological studies, confirm the key role played by FTL2 and circadian clock genes in the control of growth cessation in spruce species and suggest the presence of parallel adaptation in these two species. PMID- 24814466 TI - Fitness is strongly influenced by rare mutations of large effect in a microbial mutation accumulation experiment. AB - Our understanding of the evolutionary consequences of mutation relies heavily on estimates of the rate and fitness effect of spontaneous mutations generated by mutation accumulation (MA) experiments. We performed a classic MA experiment in which frequent sampling of MA lines was combined with whole genome resequencing to develop a high-resolution picture of the effect of spontaneous mutations in a hypermutator (DeltamutS) strain of the bacterium Pseudomonas aeruginosa. After ~644 generations of mutation accumulation, MA lines had accumulated an average of 118 mutations, and we found that average fitness across all lines decayed linearly over time. Detailed analyses of the dynamics of fitness change in individual lines revealed that a large fraction of the total decay in fitness (42.3%) was attributable to the fixation of rare, highly deleterious mutations (comprising only 0.5% of fixed mutations). Furthermore, we found that at least 0.64% of mutations were beneficial and probably fixed due to positive selection. The majority of mutations that fixed (82.4%) were base substitutions and we failed to find any signatures of selection on nonsynonymous or intergenic mutations. Short indels made up a much smaller fraction of the mutations that were fixed (17.4%), but we found evidence of strong selection against indels that caused frameshift mutations in coding regions. These results help to quantify the amount of natural selection present in microbial MA experiments and demonstrate that changes in fitness are strongly influenced by rare mutations of large effect. PMID- 24814467 TI - Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type. AB - OBJECTIVE: Endometrial carcinomas of the endometrioid type (EEC) are associated with a good prognosis. However, about 20% of them recur and new prognostic markers are needed. Microsatellite instability (MSI), associated with mismatch repair (MMR) deficiency, is a frequent alteration in EECs that has been associated with prognosis. However, its prognostic impact on EECs remains unclear. The aim of the present study was to clarify the relationship between MMR deficiency and outcome in a large cohort of well classified EECs. METHODS: A total of 212 EEC samples were analyzed by immunohistochemistry for the MMR genes MLH-1, MSH-2, MSH-6 and PMS-2. Kaplan-Meier survival analysis and log-rank tests were performed to study the prognostic significance of dMMR taking into account clinical and pathological parameters. RESULTS: We observed no association between MMR deficiency and OS or PFS in our 212 EEC patients (p-value=0.6565 and 0.4380, respectively). When we performed the analysis in different FIGO-stage groups, we did not find association between MMR and OS or PFS in stages I, I/II or III/IV. When we analyzed the specific group of patients with lymphatic invasion separately, MMR expression was not associated with OS or PFS either. CONCLUSIONS: MMR deficiency does not seem to be a good prognostic marker in endometrioid type endometrial carcinomas. PMID- 24814468 TI - High rate of hepatitis C virus (HCV) recurrence in HIV-infected individuals with spontaneous HCV RNA clearance. AB - OBJECTIVES: Following resolution of hepatitis C virus (HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV 1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. METHODS: All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA >= 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. RESULTS: Of 191 eligible patients, 35 [18.3%; 95% confidence interval (CI) 12.8-23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users (IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0-5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio (OR) 0.44; 95% CI 0.20-0.99; P = 0.046] and older persons (OR 0.51 per 10 years older; 95% CI 0.28-0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non IDUs (OR 6.58; 95% CI 1.48-29.28; P = 0.013). CONCLUSIONS: Around 1 in 5 HIV infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early. PMID- 24814469 TI - Comment on 'The 60 most highly cited articles published in the Journal of Telemedicine and Telecare and Telemedicine Journal and E-health'. PMID- 24814470 TI - Authors' response to the letter of Nigel R Armfield on 'The 60 most highly cited articles published in the Journal of Telemedicine and Telecare and Telemedicine Journal and E-health'. PMID- 24814471 TI - Use of telepsychiatry in areas of conflict: the Syrian refugee crisis as an example. PMID- 24814472 TI - Group mindfulness-based therapy significantly improves sexual desire in women. AB - At least a third of women across reproductive ages experience low sexual desire and impaired arousal. There is increasing evidence that mindfulness, defined as non-judgmental present moment awareness, may improve women's sexual functioning. The goal of this study was to test the effectiveness of mindfulness-based therapy, either immediately or after a 3-month waiting period, in women seeking treatment for low sexual desire and arousal. Women participated in four 90-min group sessions that included mindfulness meditation, cognitive therapy, and education. A total of 117 women were assigned to either the immediate treatment (n = 68, mean age 40.8 yrs) or delayed treatment (n = 49, mean age 42.2 yrs) group, in which women had two pre-treatment baseline assessments followed by treatment. A total of 95 women completed assessments through to the 6-month follow-up period. Compared to the delayed treatment control group, treatment significantly improved sexual desire, sexual arousal, lubrication, sexual satisfaction, and overall sexual functioning. Sex-related distress significantly decreased in both conditions, regardless of treatment, as did orgasmic difficulties and depressive symptoms. Increases in mindfulness and a reduction in depressive symptoms predicted improvements in sexual desire. Mindfulness-based group therapy significantly improved sexual desire and other indices of sexual response, and should be considered in the treatment of women's sexual dysfunction. PMID- 24814473 TI - The role of hydrogen bonding in the decomposition of H2CO3 in water: mechanistic insights from ab initio metadynamics studies of aqueous clusters. AB - Both concerted and stepwise mechanisms have been proposed for the decomposition of H2CO3 in bulk water based on electronic structure and ab initio molecular dynamics calculations. To consistently determine which, if any, mechanism predominates in bulk water, we performed ab initio metadynamics simulations of the decomposition of H2CO3 in water clusters of increasing size. We found that, in the small clusters (containing six and nine water molecules), the decomposition occurs according to a concerted proton shuttle mechanism via a cyclic transition state, whereas, in the larger clusters (containing 20 and 45 water molecules), the decomposition occurs according to a two-step mechanism via a solvent-separated HCO3-/H3O+ ion pair intermediate. Due to the additional water molecules in the larger clusters, the dissociation of H2CO3 into the metastable solvent-separated ion pair was found to be energetically favorable, thereby preventing the formation of the cyclic transition state and committing the decomposition to the sequential route. An analysis of the solvation environment around the H2CO3 molecule in the various clusters revealed that the transition from the concerted mechanism to the stepwise mechanism precisely hinges upon the number of water molecules hydrogen bonded to the H3O+ intermediate, which changes as the size of the cluster increases. The larger clusters contain a sufficient number of water molecules to fully solvate the H3O+ intermediate, indicating that they can provide a bulk-like environment for this reaction. Therefore, these results strongly demonstrate that the decomposition of H2CO3 in bulk water occurs via the stepwise mechanism. PMID- 24814474 TI - Change of plans: an evaluation of the effectiveness and underlying mechanisms of successful talent transfer. AB - Talent transfer (TT) is a recently formalised process used to identify and develop talented athletes by selecting individuals who have already succeeded in one sport and transferring them to another. Despite the increasing popularity of TT amongst national organisations and sport governing body professionals, however, there is little empirical evidence as to its efficacy or how it may be most efficiently employed. Accordingly, this investigation was designed to gain a deeper understanding of the effectiveness and underlying mechanisms of TT, achieved through a two-part study. Stage 1 provided a quantitative analysis of the incidence and distribution or, in this respect, epidemiology of TT, finding the most popular transfer to be sprinting to bobsleigh, with an average transfer age of 19 years. Stage 2 scrutinised the TT process and explored the specific cases revealed in stage 1 by examining the perceptions of four sport science support specialists who had worked in TT settings, finding several emergent themes which, they felt, could explain the TT processes. The most prominent theme was the psychosocial mechanism of TT, an aspect currently missing from TT initiatives, suggesting that current TT systems are poorly structured and should redress their approach to develop a more integrated scheme that encompasses all potential mechanisms of transfer. PMID- 24814475 TI - Parental wellbeing of Iranian families with children who have developmental disabilities. AB - To date, most research with families who have a child with developmental disabilities has been undertaken in English speaking countries. Poorer health, allied with increased levels of stress has been commonly reported for mothers but less is known about the impact on fathers and on overall family functioning. This study aimed to document the correlates of these parental impacts with Iranian mothers and fathers who had children with either intellectual disabilities (ID) or with autism spectrum disorders (ASD). In all 121 parents (69 mothers and 52 fathers from 94 families) who had a child with a diagnosis of ADS, along with 115 parents of children with ID (83 mothers and 32 fathers from 101 families) volunteered to take part in the study. Each participant completed through interview standardised rating scales of parenting stress, emotional well-being, family functioning and satisfaction with caring role along with demographic information and details of informal supports. Structural Equation Modeling identified that family functioning was much poorer in families whose child had ASD and both mothers and fathers reported higher levels of stress. Poorer emotional well-being contributed to higher stress and was more frequent among mothers, single parents and those whose children had behaviour problems. Having other dependents living at home and more sources of informal support improved the emotional wellbeing of parents but not their stress or family functioning. Parents who derived greater satisfaction from their caring role tended to have better emotional health and less stress. Although the impact on Iranian parents of having a child with developmental disabilities is broadly similar to those of parents in other cultures, there are indications that children with ASD present distinct challenges to these families. The model derived in this study is a useful guide both for further research as well as family-centred interventions. PMID- 24814476 TI - Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings. AB - Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases. PMID- 24814477 TI - Life-threatening complications of posterior reversible encephalopathy syndrome in children. AB - BACKGROUND: Although the posterior reversible encephalopathy syndrome (PRES) is considered to have a benign clinical outcome, the presentation of PRES can be associated with life-threatening complications such as severe cerebral hemorrhage, cerebellar herniation and refractory status epilepticus (SE). The aim of this paper is to report incidence, clinical features and outcome of life threatening complications related to PRES in children. METHODS: Patients who suffered from life-threatening complications were retrospectively identified from a group composed by 27 consecutive children diagnosed with PRES in our hospital between 2000 and 2012. The clinical, radiological and EEG features and the outcome of these patients were evaluated and compared to the characteristics of patients with no complications. RESULTS: Five patients (18%) presented life threatening complications: 2 cerebral hemorrhages with mass effect and midline shift (1 massive intraparenchymal hemorrhage and 1 subdural hemorrhage and intraparenchymal hemorrhage), 2 transforaminal cerebellar herniations and 1 refractory SE. Two children died because of complications and 2 children required urgent neurosurgical intervention. The infratentorial involvement at onset of PRES and the observation of focal neurological deficits other than visual disturbances were significantly more frequent in children with life-threatening complications (p < 0.01). CONCLUSIONS: PRES is associated with a non-negligible incidence of life-threatening complications. A careful clinical, neuroradiological and EEG monitoring is necessary in order to improve the outcome especially in the case of focal neurological deficits and infratentorial involvement. PMID- 24814478 TI - A rapid qPCR method for genetic sex identification of Salmo salar and Salmo trutta including simultaneous elucidation of interspecies hybrid paternity by high-resolution melt analysis. AB - This study presents an improved duplex quantitative polymerase chain reaction (qPCR) method using the master sex-determining gene sdY as a marker for simultaneous genetic sex identification of salmonids of the Salmo genus and paternity elucidation for Salmo salar * Salmo trutta hybrids. This method will provide a new, simple and economical molecular tool for ecological studies of these species as well as for aquaculture purposes. PMID- 24814479 TI - Anti-oxidant N-acetylcysteine diminishes diesel exhaust-induced increased airway responsiveness in person with airway hyper-reactivity. AB - BACKGROUND: Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. OBJECTIVES: We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. METHODS: Participants took N acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 MUg/m(3) of particulate matter smaller than 2.5 microns). Twenty six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2 week washout between conditions. Methacholine challenge was performed pre exposure (baseline airway responsiveness) and post-exposure (effect of exposure). RESULTS: Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). CONCLUSIONS: Anti oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation. PMID- 24814480 TI - Social cognition, face processing, and oxytocin receptor single nucleotide polymorphisms in typically developing children. AB - Recent research has provided evidence of a link between behavioral measures of social cognition (SC) and neural and genetic correlates. Differences in face processing and variations in the oxytocin receptor (OXTR) gene have been associated with SC deficits and autism spectrum disorder (ASD) traits. Much work has examined the qualitative differences between those with ASD and typically developing (TD) individuals, but very little has been done to quantify the natural variation in ASD-like traits in the typical population. The present study examines this variation in TD children using a multidimensional perspective involving behavior assessment, neural electroencephalogram (EEG) testing, and OXTR genotyping. Children completed a series of neurocognitive assessments, provided saliva samples for sequencing, and completed a face processing task while connected to an EEG. No clear pattern emerged for EEG covariates or genotypes for individual OXTR single nucleotide polymorphisms (SNPs). However, SNPs rs2254298 and rs53576 consistently interacted such that the AG/GG allele combination of these SNPs was associated with poorer performance on neurocognitive measures. These results suggest that neither SNP in isolation is risk-conferring, but rather that the combination of rs2254298(A/G) and rs53576(G/G) confers a deleterious effect on SC across several neurocognitive measures. PMID- 24814481 TI - alpha/beta-Hydrolase domain-6-accessible monoacylglycerol controls glucose stimulated insulin secretion. AB - Glucose metabolism in pancreatic beta cells stimulates insulin granule exocytosis, and this process requires generation of a lipid signal. However, the signals involved in lipid amplification of glucose-stimulated insulin secretion (GSIS) are unknown. Here we show that in beta cells, glucose stimulates production of lipolysis-derived long-chain saturated monoacylglycerols, which further increase upon inhibition of the membrane-bound monoacylglycerol lipase alpha/beta-Hydrolase Domain-6 (ABHD6). ABHD6 expression in beta cells is inversely proportional to GSIS. Exogenous monoacylglycerols stimulate beta cell insulin secretion and restore GSIS suppressed by the pan-lipase inhibitor orlistat. Whole-body and beta-cell-specific ABHD6-KO mice exhibit enhanced GSIS, and their islets show elevated monoacylglycerol production and insulin secretion in response to glucose. Inhibition of ABHD6 in diabetic mice restores GSIS and improves glucose tolerance. Monoacylglycerol binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. We propose saturated monoacylglycerol as a signal for GSIS and ABHD6 as a negative modulator of insulin secretion. PMID- 24814482 TI - Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. AB - We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function. PMID- 24814483 TI - NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. AB - Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans. PMID- 24814485 TI - Frequency and practice-level variation in inappropriate and nonrecommended prasugrel prescribing: insights from the NCDR PINNACLE registry. PMID- 24814484 TI - Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response. AB - ATP-dependent chromatin remodeling is involved in all DNA transactions and is linked to numerous human diseases. We explored functions of chromatin remodelers during cellular aging. Deletion of ISW2, or mutations inactivating the Isw2 enzyme complex, extends yeast replicative lifespan. This extension by ISW2 deletion is epistatic to the longevity effect of calorie restriction (CR), and this mechanism is distinct from suppression of TOR signaling by CR. Transcriptome analysis indicates that isw2Delta partially mimics an upregulated stress response in CR cells. In particular, isw2Delta cells show an increased response to genotoxic stresses, and the DNA repair enzyme Rad51 is important for isw2Delta mediated longevity. We show that lifespan is also extended in C. elegans by reducing levels of athp-2, a putative ortholog of Itc1/ACF1, a critical subunit of the enzyme complex. Our findings demonstrate that the ISWI class of ATP dependent chromatin remodeling complexes plays a conserved role during aging and in CR. PMID- 24814486 TI - A randomized comparison of platinum chromium-based everolimus-eluting stents versus cobalt chromium-based Zotarolimus-Eluting stents in all-comers receiving percutaneous coronary intervention: HOST-ASSURE (harmonizing optimal strategy for treatment of coronary artery stenosis-safety & effectiveness of drug-eluting stents & anti-platelet regimen), a randomized, controlled, noninferiority trial. AB - OBJECTIVES: This study sought to test whether the newly developed platinum chromium (PtCr)-based everolimus-eluting stent (EES) is noninferior to the cobalt chromium (CoCr)-based zotarolimus-eluting stent (ZES) in all-comers receiving percutaneous coronary intervention (PCI). BACKGROUND: PtCr provides improved radial strength, conformability, and visibility compared with the CoCr alloy, but PtCr-based stents have not been tested in a wide range of patients receiving PCI. Also, recent case series have raised the issue of longitudinal stent deformation (LSD) with newer drug-eluting stents. METHODS: We randomly assigned 3,755 all comers receiving PCI to PtCr-EES or CoCr-ZES. The primary outcome was target lesion failure (TLF) at 1-year post-PCI, defined as the composite of cardiac death, nonfatal target vessel-related myocardial infarction, and ischemia-driven target lesion revascularization. Post-hoc angiographic analysis was performed to qualitatively and quantitatively analyze LSD. RESULTS: At 1 year, TLF occurred in 2.9% and 2.9% of the population in the PtCr-EES and CoCr-ZES groups, respectively (superiority p = 0.98, noninferiority p = 0.0247). There were no significant differences in the individual components of TLF as well as the patient-oriented clinical outcome. Of 5,010 stents analyzed, LSD occurred in 0.2% and 0% in the PtCr-EES and CoCr-ZES groups, respectively (p = 0.104). There was no significant difference in post-deployment stent length ratio between the 2 stents (p = 0.352). CONCLUSIONS: At 1 year, PtCr-EES was noninferior to CoCr-ZES in all comers receiving PCI. Although LSD was observed only in PtCr-EES, both the stent length ratio and the frequency of LSD were not significantly different between the 2 stent types, and PtCr-EES was not associated with adverse clinical outcomes. (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis SAfety & EffectiveneSS of Drug-ElUting Stents & Anti-platelet REgimen [HOST ASSURE]; NCT01267734). PMID- 24814487 TI - Headed in the right direction but at risk for miscalculation: a critical appraisal of the 2013 ACC/AHA risk assessment guidelines. AB - The newly released 2013 ACC/AHA Guidelines for Assessing Cardiovascular Risk makes progress compared with previous cardiovascular risk assessment algorithms. For example, the new focus on total atherosclerotic cardiovascular diseases (ASCVD) is now inclusive of stroke in addition to hard coronary events, and there are now separate equations to facilitate estimation of risk in non-Hispanic white and black individuals and separate equations for women. Physicians may now estimate lifetime risk in addition to 10-year risk. Despite this progress, the new risk equations do not appear to lead to significantly better discrimination than older models. Because the exact same risk factors are incorporated, using the new risk estimators may lead to inaccurate assessment of atherosclerotic cardiovascular risk in special groups such as younger individuals with unique ASCVD risk factors. In general, there appears to be an overestimation of risk when applied to modern populations with greater use of preventive therapy, although the magnitude of overestimation remains unclear. Because absolute risk estimates are directly used for treatment decisions in the new cholesterol guidelines, these issues could result in overuse of pharmacologic management. The guidelines could provide clearer direction on which individuals would benefit from additional testing, such as coronary calcium scores, for more personalized preventive therapies. We applaud the advances of these new guidelines, and we aim to critically appraise the applicability of the risk assessment tools so that future iterations of the estimators can be improved to more accurately assess risk in individual patients. PMID- 24814488 TI - Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. AB - The use of extracorporeal membrane oxygenation (ECMO) for both respiratory and cardiac failure in adults is evolving rapidly. Advances in technology and accumulating data are spurring greater interest and explosive growth in ECMO worldwide. Expanding indications and novel strategies are being used. Yet the use of ECMO outpaces the data. The promise of a major paradigm shift for the treatment of respiratory and cardiac failure is tempered by a need for evidence to support many current and potential future uses. The authors review cannulation strategies, indications, and evidence for ECMO in respiratory and cardiac failure in adults as well as potential applications and the impact they may have on current treatment paradigms. PMID- 24814489 TI - Curing atherosclerosis should be the next major cardiovascular prevention goal. AB - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in developed and developing countries. Despite decades of effort, unhealthy lifestyle habits and ASCVD risk factor levels remain high and are increasing in many population groups. A new approach to ASCVD prevention is needed. Multiple lines of evidence from animal and human studies suggest that atherosclerosis regression and normalization of vessel function can occur when low-density lipoprotein cholesterol (LDL-C) lowering occurs early in the course of atherosclerosis or when very aggressive LDL-C lowering occurs somewhat later. We propose a new paradigm focused on curing atherosclerosis early in the course of the disease. An approach that resets the vascular aging clock composed of initial regression therapy followed by periodic retreatment to suppress atherosclerosis development may be possible, with the ultimate goal of preventing subsequent ASCVD events. Proof-of-concept studies are needed to determine: 1) the optimal age and/or extent of atherosclerosis for intervention and LDL-C-lowering therapy; 2) the intensity and duration of therapy for inducing atherosclerosis regression; and 3) documenting the normalization of vascular function. Ultimately, this new paradigm will need to be evaluated in ASCVD outcomes trials. PMID- 24814490 TI - Application of the gompertz method for evaluating survival gains in patients receiving cardiac resynchronization therapy. PMID- 24814491 TI - Regarding the effect of dabigatran plasma concentrations. PMID- 24814492 TI - Reply: regarding the effect of dabigatran plasma concentrations. PMID- 24814493 TI - Reply: application of the gompertz method for evaluating survival gains in patients receiving cardiac resynchronization therapy. PMID- 24814494 TI - Peripartum cardiomyopathy: predictors of recovery and current state of implantable cardioverter-defibrillator use. AB - OBJECTIVES: The purpose of this study was to identify the predictors of left ventricular (LV) recovery in patients with peripartum cardiomyopathy (PPCM) and to record rates of implantable cardioverter-defibrillator (ICD) use. BACKGROUND: PPCM is a rare, life-threatening disease. The use of ICDs has not been clearly understood in this patient group. Identification of the predictors of persistent LV dysfunction can help select patients at risk for sudden cardiac death. METHODS: A retrospective study was conducted at 2 academic centers between January 1, 1999, and December 31, 2012. Clinical and demographic variables and delivery records of patients with a diagnosis of PPCM (International Classification of Diseases, 9th Revision code 674.5) were reviewed. Improvement in LV function was noted from echocardiography reports. RESULTS: The total sample comprised 100 patients, of whom 55% were African Americans, 39% were Caucasians, and 6% were Hispanic, with a mean age of 30 +/- 6 years. Mean left ventricular ejection fraction (LVEF) at diagnosis was 28 +/- 9%. Forty-two percent of patients showed improvement in LVEF over a mean duration of 33 +/- 21 months. Postpartum diagnosis (hazard ratio: 3.0; p = 0.01) and Caucasian/Hispanic race (hazard ratio: 2.2; p = 0.01) were predictors of improvement in LVEF. Only 7 of the 58 patients (12%) who did not have improvement in their LVEF had an ICD implanted. There were 11 deaths, with a trend toward higher mortality in those who did not display improved LV function (15% vs. 5%; p = 0.1). CONCLUSIONS: More than one-third of women with PPCM improve LV function with delayed recovery noted in the majority of these patients. Caucasians and those diagnosed in the postpartum period appear to be the most likely to recover. The rate of ICD implantation for primary prevention of sudden cardiac death in this patient group is low. PMID- 24814495 TI - Caval-aortic access to allow transcatheter aortic valve replacement in otherwise ineligible patients: initial human experience. AB - OBJECTIVES: This study describes the first use of caval-aortic access and closure to enable transcatheter aortic valve replacement (TAVR) in patients who lacked other access options. Caval-aortic access refers to percutaneous entry into the abdominal aorta from the femoral vein through the adjoining inferior vena cava. BACKGROUND: TAVR is attractive in high-risk or inoperable patients with severe aortic stenosis. Available transcatheter valves require large introducer sheaths, which are a risk for major vascular complications or preclude TAVR altogether. Caval-aortic access has been successful in animals. METHODS: We performed a single-center retrospective review of procedural and 30-day outcomes of prohibitive-risk patients who underwent TAVR via caval-aortic access. RESULTS: Between July 2013 and January 2014, 19 patients underwent TAVR via caval-aortic access; 79% were women. Caval-aortic access and tract closure were successful in all 19 patients; TAVR was successful in 17 patients. Six patients experienced modified VARC-2 major vascular complications, 2 (11%) of whom required intervention. Most (79%) required blood transfusion. There were no deaths attributable to caval-aortic access. Throughout the 111 (range 39 to 229) days of follow up, there were no post-discharge complications related to tract creation or closure. All patients had persistent aorto-caval flow immediately post procedure. Of the 16 patients who underwent repeat imaging after the first week, 15 (94%) had complete closure of the residual aorto-caval tract. CONCLUSIONS: Percutaneous transcaval venous access to the aorta allows TAVR in otherwise ineligible patients, and may offer a new access strategy for other applications requiring large transcatheter implants. PMID- 24814496 TI - The prevalence, incidence, progression, and risks of aortic valve sclerosis: a systematic review and meta-analysis. AB - OBJECTIVES: The aim of this study was to comprehensively review the epidemiology of aortic sclerosis (ASc) and its association with cardiovascular events. BACKGROUND: ASc, which is defined as thickening or calcification of the aortic valve without significant obstruction of blood flow, is a common finding on cardiac imaging. METHODS: We searched MEDLINE and EMBASE from inception to April 2013 for studies describing the epidemiology of ASc and performed a meta-analysis of the risk of adverse events using a random effects model. RESULTS: Twenty-two studies were identified from the systematic review. The prevalence of ASc increased in proportion to the average age of study participants, ranging from 9% in a study in which the mean age was 54 years to 42% in a study in which the mean age was 81 years. In total, 1.8% to 1.9% of participants with ASc had progression to clinical aortic stenosis per year. There was a 68% increased risk of coronary events in subjects with ASc (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.31 to 2.15), a 27% increased risk of stroke (HR: 1.27; 95% CI: 1.01 to 1.60), a 69% increased risk of cardiovascular mortality (HR: 1.69; 95% CI: 1.32 to 2.15), and a 36% increased risk of all-cause mortality (HR: 1.36; 95% CI: 1.17 to 1.59). CONCLUSIONS: ASc is a common finding that is more prevalent with older age. Despite low rates of progression to ASc, there is an independent increase in morbidity and mortality associated with the condition. PMID- 24814497 TI - Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with implantable devices. AB - OBJECTIVES: This study aimed to identify how accurately the current clinical atrial fibrillation (AF) classifications reflect its temporal persistence. BACKGROUND: Clinical classification of AF is employed to communicate its persistence, to select appropriate therapies, and as inclusion criterion for clinical trials. METHODS: Cardiac rhythm histories of 1,195 patients (age 73.0 +/ 10.1 years, follow-up: 349 +/- 40 days) with implantable devices were reconstructed and analyzed. Patients were classified as having paroxysmal or persistent AF by physicians at baseline in accordance with current guidelines. AF burden, measured as the proportion of time spent in AF, was obtained from the device. Additionally we evaluated the agreement between clinical and device derived AF classifications. RESULTS: Patients within the same clinical class were highly heterogeneous with regards to AF temporal persistence. Agreement between the clinical AF classification and the objective device-derived assessments of AF temporal persistence was poor (Cohen's kappa: 0.12 [95% CI: 0.05 to 0.18]). Patient characteristics influenced the clinical decision to classify AF as paroxysmal or persistent. Higher ejection fraction (odds ratio: 0.97/per unit [95% CI: 0.95 to 0.98/per unit]; p < 0.0001) and presence of coronary artery disease (odds ratio: 0.53 [95% CI: 0.32 to 0.88]; p = 0.01) were independently associated with a lower probability of being classified as persistent AF for the same AF burden level. CONCLUSIONS: The currently used clinical AF classifications poorly reflect AF temporal persistence. Patient characteristics significantly influence the physician's classification of AF. Patients classified in identical clinical categories may be inherently heterogeneous with regard to AF temporal persistence. Further study is required to determine if patient selection on the basis of objective criteria derived from rigorous AF monitoring can improve reported outcomes and better identify responders and non-responders to treatments. (OMNI Study-Assessing Therapies in Medtronic Pacemaker, Defibrillator, and Cardiac Resynchronization Therapy Devices; NCT00277524; TRENDS: A Prospective Study of the Clinical Significance of Atrial Arrhythmias Detected by Implanted Device Diagnostics; NCT00279981). PMID- 24814498 TI - Differentiating paroxysmal from persistent atrial fibrillation: long-term electrocardiographic monitoring is mightier than the clinician. PMID- 24814499 TI - Prevention of atherosclerotic cardiovascular disease: what is the best approach and how early should we start? PMID- 24814501 TI - Surgical perspectives: an introduction. PMID- 24814500 TI - Inflammation-induced hyperalgesia: effects of timing, dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia. AB - BACKGROUND: Inflammation-induced pain amplification and hypersensitivity play a role in the pathophysiology of numerous clinical conditions. Experimental endotoxemia has recently been implemented as model to analyze immune-mediated processes in human pain. In this study, we aimed to analyze dose- and time dependent effects of lipopolysaccharide (LPS) on clinically-relevant pain models for musculoskeletal and neuropathic pain as well as the interaction among LPS induced changes in inflammatory markers, pain sensitivity and negative affect. METHODS: In this randomized, double-blind, placebo-controlled study, healthy male subjects received an intravenous injection of either a moderate dose of LPS (0.8 ng/kg Escherichiacoli), low-dose LPS (0.4 ng/kg), or saline (placebo control group). Pressure pain thresholds (PPT), mechanical pain sensitivity (MPS), and cold pain sensitivity (CP) were assessed before and 1, 3, and 6h post injection to assess time-dependent LPS effects on pain sensitivity. Plasma cytokines (TNF alpha, IL-6, IL-8, IL-10) and state anxiety were repeatedly measured before, and 1, 2, 3, 4, and 6h after injection of LPS or placebo. RESULTS: LPS administration induced a systemic immune activation, reflected by significant increases in cytokine levels, body temperature, and negative mood with pronounced effects to the higher LPS dose. Significant decreases of PPTs were observed only 3h after injection of the moderate dose of LPS (0.8 ng/kg). MPS and CP were not affected by LPS-induced immune activation. Correlation analyses revealed that decreased PPTs were associated with peak IL-6 increases and negative mood. CONCLUSIONS: Our results revealed widespread increases in musculoskeletal pain sensitivity in response to a moderate dose of LPS (0.8 ng/kg), which correlate both with changes in IL-6 and negative mood. These data extend and refine existing knowledge about immune mechanisms mediating hyperalgesia with implications for the pathophysiology of chronic pain and neuropsychiatric conditions. PMID- 24814502 TI - Commentary on "Resident work-hour restrictions and responsibilities to patients". PMID- 24814503 TI - Epidural analgesia--the jury is in. PMID- 24814504 TI - Putting the patient first. PMID- 24814505 TI - The TNFSF15 gene single nucleotide polymorphism rs7848647 is associated with surgical diverticulitis. AB - OBJECTIVE: To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. BACKGROUND: A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy. METHODS: In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 +/- 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 +/- 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 +/- 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test. RESULTS: In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. CONCLUSIONS: The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making. PMID- 24814506 TI - Health-related quality of life (HRQOL) decreases independently of chronic conditions and geriatric syndromes in older adults with diabetes: the Fujiwara kyo Study. AB - BACKGROUND: Very few studies have investigated the association between diabetes and impaired health-related quality of life (HRQOL) in older adults, independent of chronic conditions and geriatric syndromes. METHODS: We conducted a self administered questionnaire survey and structured interviews with 3946 people aged 65 years or older to obtain medical histories of diabetes, chronic conditions, and geriatric syndromes. Blood tests were performed to measure glycated hemoglobin (HbA1c) and plasma glucose levels. HRQOL was evaluated using the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), and multiple logistic regression analysis was used to calculate adjusted odds ratios and 95% CIs for low HRQOL. RESULTS: A total of 3521 participants had not received a physician diagnosis of diabetes. Of these, 2345 participants with an HbA1c less than 5.7% were defined as the referent group. As compared with the referent group, 1029 participants with an HbA1c of at least 5.7% but less than 6.5% showed no significant decrease in QOL on the SF-36 physical, mental, and role component summaries, after adjustment for chronic conditions, geriatric syndromes, and other potential confounders. However, 572 patients who had received a physician diagnosis of diabetes and/or had an HbA1c of 6.5% or higher had a significantly higher adjusted odds ratio (1.48; 95% CI, 1.18-1.84) for the low physical component summary. No significant differences in relation to glycemic control, treatment regimen, or diabetes duration were found in any of the 3 component summaries among the 425 participants who were undergoing diabetes treatment. CONCLUSIONS: Older Japanese adults with diabetes had decreased physical QOL, independent of chronic conditions and geriatric syndromes. PMID- 24814507 TI - Japanese study on stratification, health, income, and neighborhood: study protocol and profiles of participants. AB - BACKGROUND: The Japanese Study on Stratification, Health, Income, and Neighborhood (J-SHINE) aims to clarify the complex associations between social factors and health from an interdisciplinary perspective and to provide a database for use in various health policy evaluations. METHODS: J-SHINE is an ongoing longitudinal panel study of households of adults aged 25-50 years. The wave 1 survey was carried out in 2010 among adults randomly selected from the resident registry of four urban and suburban municipalities in the greater Tokyo metropolitan area, Japan. In 2011, surveys for the participants' spouse/partner and child were additionally conducted. The wave 2 survey was conducted in 2012 for the wave 1 participants and will be followed by the wave 2 survey for spouse/partner and child in 2013. RESULTS: Wave 1 sample sizes were 4357 for wave 1 participants (valid response rate: 31.3%; cooperation rate: 51.8%), 1873 for spouse/partner (response rate: 61.9%), and 1520 for child (response rate: 67.7%). Wave 2 captured 69.0% of wave 1 participants. Information gathered covered socio demographics, household economy, self-reported health conditions and healthcare utilization, stress and psychological values, and developmental history. A subpopulation underwent physiological (n = 2468) and biomarker (n = 1205) measurements. CONCLUSIONS: Longitudinal survey data, including repeated measures of social factors evaluated based on theories and techniques of various disciplines, like J-SHINE, should contribute toward opening a web of causality for society and health, which may have important policy implications for recent global health promotion strategies such as the World Health Organization's Social Determinants of Health approach and the second round of Japan's Healthy Japan 21. PMID- 24814508 TI - Simplifying sample pretreatment: application of dried blood spot (DBS) method to blood samples, including postmortem, for UHPLC-MS/MS analysis of drugs of abuse. AB - The complexity of biological matrices, such as blood, requires the development of suitably selective and reliable sample pretreatment procedures prior to their instrumental analysis. A method has been developed for the analysis of drugs of abuse and their metabolites from different chemical classes (opiates, methadone, fentanyl and analogues, cocaine, amphetamines and amphetamine-like substances, ketamine, LSD) in human blood using dried blood spot (DBS) and subsequent UHPLC MS/MS analysis. DBS extraction required only 100MUL of sample, added with the internal standards and then three droplets (30MUL each) of this solution were spotted on the card, let dry for 1h, punched and extracted with methanol with 0.1% of formic acid. The supernatant was evaporated and the residue was then reconstituted in 100MUL of water with 0.1% of formic acid and injected in the UHPLC-MS/MS system. The method was validated considering the following parameters: LOD and LOQ, linearity, precision, accuracy, matrix effect and dilution integrity. LODs were 0.05-1ng/mL and LOQs were 0.2-2ng/mL. The method showed satisfactory linearity for all substances, with determination coefficients always higher than 0.99. Intra and inter day precision, accuracy, matrix effect and dilution integrity were acceptable for all the studied substances. The addition of internal standards before DBS extraction and the deposition of a fixed volume of blood on the filter cards ensured the accurate quantification of the analytes. The validated method was then applied to authentic postmortem blood samples. PMID- 24814509 TI - A survey of thickened fluid prescribing and monitoring practices of Australian health professionals. AB - RATIONALE, AIMS AND OBJECTIVES: This study aimed to describe (1) how thickened fluids are supplied to clients with dysphagia; (2) how clients' consumption of thickened fluids and hydration status is monitored; and (3) the impact of institutional factors on thickened fluid intake and hydration in Australian health care settings. METHODS: Speech pathologists, dietitians and nurses working in Australian health care settings were asked to voluntarily participate in an online survey that was advertised through their respective professional associations. The questions required a self-report of their practice with respect to thickened fluids. RESULTS: Few health care facilities (17%) monitored thickened fluid consumption routinely even though, in the opinion of 51% the respondents, clients on thickened fluids at their facility do not drink enough. Palatability of the thickened fluid products and patients' dependence on others for drinking were thought to have a major impact on fluid intake. Respondents also highlighted institutional factors such as inadequate assistance from staff and inconsistent systems for monitoring fluid intake and signs of dehydration. The most common way to address inadequate intake was for nurses to 'push fluids' (87%). Free water protocols were used only 14% of the time and setting small oral fluid targets throughout the day was the least common strategy (11%). CONCLUSIONS: There is a need for Australian health care facilities to educate all clinical staff about the risks of dehydration and develop clinical pathways for clients with dysphagia, which include routine monitoring of oral fluid consumption and dehydration and timely intervention. PMID- 24814510 TI - Justifying medical necessity for services ordered for Medicare beneficiaries. PMID- 24814511 TI - Alternative chelator for 89Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO). AB - Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for (89)Zr(4+); however, accumulation of (89)Zr in the bones of mice suggests that (89)Zr(4+) is released from DFO in vivo. An improved chelator for (89)Zr(4+) could eliminate the release of osteophilic (89)Zr(4+) and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of (89)Zr-HOPO matched or surpassed that of (89)Zr-DFO in every experiment. In healthy mice, (89)Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for (89)Zr-based PET imaging agents. PMID- 24814512 TI - Modelling the interaction between the host immune response, bacterial dynamics and inflammatory damage in comparison with immunomodulation and vaccination experiments. AB - The immune system is a complex system of chemical and cellular interactions that responds quickly to queues that signal infection and then reverts to a basal level once the challenge is eliminated. Here, we present a general, four component model of the immune system's response to a Staphylococcal aureus (S. aureus) infection, using ordinary differential equations. To incorporate both the infection and the immune system, we adopt the style of compartmenting the system to include bacterial dynamics, damage and inflammation to the host, and the host response. We incorporate interactions not previously represented including cross talk between inflammation/damage and the infection and the suppression of the anti-inflammatory pathway in response to inflammation/damage. As a result, the most relevant equilibrium of the system, representing the health state, is an all positive basal level. The model is able to capture eight different experimental outcomes for mice challenged with intratibial osteomyelitis due to S. aureus, primarily involving immunomodulation and vaccine therapies. For further validation and parameter exploration, we perform a parameter sensitivity analysis which suggests that the model is very stable with respect to variations in parameters, indicates potential immunomodulation strategies and provides a possible explanation for the difference in immune potential for different mouse strains. PMID- 24814513 TI - Kafkaesque. PMID- 24814514 TI - Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. AB - Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed 'field change'. However, it is not known how field change develops. Here we investigate this question using lineage tracing to track the behaviour of scattered single oesophageal epithelial progenitor cells expressing a mutation that inhibits the Notch signalling pathway. Notch is frequently subject to inactivating mutation in squamous cancers. Quantitative analysis reveals that cell divisions that produce two differentiated daughters are absent from mutant progenitors. As a result, mutant clones are no longer lost by differentiation and become functionally immortal. Furthermore, mutant cells promote the differentiation of neighbouring wild-type cells, which are then lost from the tissue. These effects lead to clonal expansion, with mutant cells eventually replacing the entire epithelium. Notch inhibition in progenitors carrying p53 stabilizing mutations creates large confluent regions of doubly mutant epithelium. Field change is thus a consequence of imbalanced differentiation in individual progenitor cells. PMID- 24814515 TI - ANCHR mediates Aurora-B-dependent abscission checkpoint control through retention of VPS4. AB - During the final stage of cell division, cytokinesis, the Aurora-B-dependent abscission checkpoint (NoCut) delays membrane abscission to avoid DNA damage and aneuploidy in cells with chromosome segregation defects. This arrest depends on Aurora-B-mediated phosphorylation of CHMP4C, a component of the endosomal sorting complex required for transport (ESCRT) machinery that mediates abscission, but the mechanism remains unknown. Here we describe ANCHR (Abscission/NoCut Checkpoint Regulator; ZFYVE19) as a key regulator of the abscission checkpoint, functioning through the most downstream component of the ESCRT machinery, the ATPase VPS4. In concert with CHMP4C, ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing and prevent multinucleation in an Aurora-B-dependent manner. This association prevents VPS4 relocalization to the abscission zone and is relieved following inactivation of Aurora B to allow abscission. We propose that the abscission checkpoint is mediated by ANCHR and CHMP4C through retention of VPS4 at the midbody ring. PMID- 24814516 TI - Anaplastic large cell lymphoma-propagating cells are detectable by side population analysis and possess an expression profile reflective of a primitive origin. AB - Cancer stem cells or tumour-propagating cells (TPCs) have been identified for a number of cancers, but data pertaining to their existence in lymphoma so far remain elusive. We show for the first time that a small subset of cells purified from human anaplastic lymphoma kinase (ALK)-positive and -negative, anaplastic large cell lymphoma cell lines and primary patient tumours using the side population (SP) technique have serial tumour-propagating capacity both in vitro and in vivo; they give rise to both themselves and the bulk tumour population as well as supporting growth of the latter through the production of soluble factors. In vivo serial dilution assays utilising a variety of model systems inclusive of human cell lines, primary human tumours and nucleophosmin (NPM)-ALK induced murine tumours demonstrate the TPC frequency to vary from as many as 1/54 to 1/1336 tumour cells. In addition, the SP cells express higher levels of pluripotency-associated transcription factors and are enriched for a gene expression profile consistent with early thymic progenitors. Finally, our data show that the SP cells express higher levels of the NPM-ALK oncogene and are sensitive to an ALK inhibitor. PMID- 24814517 TI - Neuropsychological function in children with primary complex motor stereotypies. AB - AIM: Complex motor stereotypies (CMS) are patterned, repetitive, rhythmic, and involuntary movements that persist over time. They are divided into two subgroups dependent on the presence of other developmental problems: 'primary' (development is otherwise typical) or 'secondary' (associated with autism, intellectual disability, or sensory deficits). There are no currently published studies that examine neuropsychological function in children with primary CMS. This case control study examines whether children with primary CMS manifest neurobehavioral deficits. METHOD: Fifty-seven children with primary CMS (32 males, 25 females; mean age 6y 8mo, SD 2y 4mo, range 4-12y) with negative screens for autism and 57 comparison participants (32 males, 25 females; mean age 6y 6mo, SD 2y 1mo) completed neuropsychological assessments of IQ, reading ability, attention, language, and motor and executive functions. Parents completed ratings of their child's repetitive movement severity. RESULTS: The CMS group performed significantly less well than comparison participants on motor skills and IQ tests (both p<0.01), although IQ was consistently in the average range. One-third of the CMS group showed signs of developmental motor coordination difficulties. Parent report of stereotypy severity was significantly associated with parent report of inattention and executive dysfunction. INTERPRETATION: Children with primary CMS were found to have largely intact neuropsychological profiles. Stereotypy severity appears to be associated with executive dysfunction. Although motor difficulties were observed in children with CMS, these were not correlated with parent report of symptom severity. PMID- 24814518 TI - Incidence of multiple primary cancers and interval between first and second primary cancers. AB - In this retrospective study, we aimed to clarify the risk of developing a second primary cancer and to determine the periods of high risk of second primary cancers. Subjects were all patients who had been diagnosed with a first primary cancer and registered with the Nagasaki Prefecture Cancer Registry between 1985 and 2007. We calculated the standardized incidence ratio (SIR) of second primary cancer according to site and years after diagnosis of the first primary cancer. A second primary cancer developed in 14 167 of 174 477 subjects (8.1%) during a median follow-up of 1.8 years. The SIR of all cancer was 1.10 (95% confidence interval, 1.08-1.11). Some specific relationships were observed between sites with risk factors in common, such as smoking, drinking, and hormone status. The SIRs were relatively high after approximately 10 years for all sites, and trends differ among cancer sites. We showed that cancer patients are at higher risk of a second primary cancer than the general population. In respect of the risk of a second primary cancer, physicians should be alert for cancers that have risk factors in common with the first primary cancer. PMID- 24814519 TI - Efficacy of standard (SLA) and modified sandblasted and acid-etched (SLActive) dental implants in promoting immediate and/or early occlusal loading protocols: a systematic review of prospective studies. AB - OBJECTIVE: To assess the survival percentage, clinical and radiographic outcomes of sandblasted and acid-etched (SLA) dental implants and its modified surface (SLActive) in protocols involving immediate and early occlusal loading. METHODS: MEDLINE, EMBASE and the Cochrane Oral Health Group's Trials Register CENTRAL were searched in duplicate up to, and including, June 2013 to include randomised controlled trials (RCTs) and prospective observational studies of at least 6 month duration published in all languages. Studies limited to patients treated with SLA and/or SLActive implants involving a treatment protocol describing immediate and early loading of these implants were eligible for inclusion. Data on clinical and/or radiographic outcomes following implant placement were considered for inclusion. RESULTS: Of the 447 potentially eligible publications identified by the search strategy, seven RCTs comprising a total of 853 implants (8% titanium plasma-sprayed, 41.5% SLA and 50.5% SLActive) and 12 prospective observational studies including 1394 SLA and 145 SLActive implants were included in this review. According to the Cochrane Collaboration's tool for assessing risk of bias, one of the studies was considered to be at a low risk of bias, whereas the remaining studies were considered to be at an unclear risk. Regarding the observational studies, all of them presented a medium methodological quality based on the Modified Newcastle-Ottawa scale. There were no significant differences reported in the studies in relation to implant loss or clinical parameters between the immediate/early loading and delayed loading protocols. Overall, 95% of SLA and 97% of SLActive implants still survive at the end of follow-up. CONCLUSIONS: Despite of the positive findings achieved by the included studies, few RCTs were available for analysis for SLActive implants. Study heterogeneity, scarcity of data and the lack of pooled estimates represent a limitation between studies' comparisons and should be considered when interpreting the present findings. PMID- 24814520 TI - Changes in the Factor VIII C2 domain upon membrane binding determined by hydrogen deuterium exchange MS. AB - Factor VIII enhances the catalytic activity of Factor IXa in a membrane-bound enzyme complex and both proteins are necessary to prevent haemophilia. Tandem lectin-like C domains mediate the membrane binding of Factor VIII and membrane interactive residues have been identified. However, the available data provide little insight into the dynamic changes that occur upon membrane binding. We used time-based hydrogen-deuterium exchange MS to evaluate the dynamics of FVIII-C2 (Factor VIII C2 domain) alone and when membrane bound. The results confirm the participation of previously identified membrane-interactive loops in the binding mechanism. In addition, they indicate that a long peptide segment, encompassing a membrane-interactive loop and strands of the beta-barrel core, is remarkably dynamic prior to membrane binding. The flexibility is reduced following membrane binding. In addition, regions that interact with the A1 and C1 domains have reduced solvent exchange. Thus the isolated C2 domain has extensive flexibility that is subject to stabilization and could be related to interactions between domains as well as between Factor VIII and Factor IXa or Factor X. These results confirm that the proposed membrane-binding loops of the FVIII-C2 interact with the membrane in a manner that leads to protection from solvent exposure. PMID- 24814521 TI - Erdheim-Chester disease: characteristics and management. AB - Erdheim-Chester disease is a rare CD68(+), CD1a(-) non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-alpha, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease. PMID- 24814523 TI - Anesthesia for interventional radiology. AB - Pediatric patients in the neurointerventional radiology setting pose the dual challenges of caring for relatively sick patients in the outfield environment. For safe and successful practice, the anesthesiologist must not only understand the nuances of pediatric anesthesia and the physiologic demands of the cerebral lesions. They must also help maintain a team-based approach to safe, compassionate care of the child in this challenging setting. In this review article, we summarize key aspects of success for several of these topics. PMID- 24814522 TI - Prognostic value of early magnetic resonance imaging in dogs after traumatic brain injury: 50 cases. AB - BACKGROUND: The prognostic value of early magnetic resonance imaging (MRI) in dogs after traumatic brain injury (TBI) remains unclear. OBJECTIVES: Determine whether MRI findings are associated with prognosis after TBI in dogs. ANIMALS: Fifty client-owned dogs. METHODS: Retrospective study of dogs with TBI that underwent 1.5T MRI within 14 days after head trauma. MRI evaluators were blinded to the clinical presentation, and all images were scored based on an MRI grading system (Grade I [normal brain parenchyma] to Grade VI [bilateral lesions affecting the brainstem with or without any lesions of lesser grade]). Skull fractures, percentage of intraparenchymal lesions, degree of midline shift, and type of brain herniation were evaluated. MGCS was assessed at presentation. The presence of seizures was recorded. Outcome was assessed at 48 h (alive or dead) and at 3, 6, 12, and 24 months after TBI. RESULTS: Sixty-six percent of the dogs had abnormal MRI findings. MRI grade was negatively correlated (P < .001) with MGCS. A significant negative correlation of MRI grade, degree of midline shift, and percentage of intraparenchymal lesions with follow-up scores was identified. The MGCS was lower in dogs with brain herniation (P = .0191). Follow-up scores were significantly lower in dogs that had brain herniation or skull fractures. The possibility of having seizures was associated with higher percentage of intraparenchymal lesions (P = 0.0054) and 10% developed PTE. CONCLUSIONS AND CLINICAL IMPORTANCE: Significant associations exist between MRI findings and prognosis in dogs with TBI. MRI can help to predict prognosis in dogs with TBI. PMID- 24814524 TI - Evaluating the potential risks and benefits of infant rotavirus vaccination in England. AB - Rotarix((r)), a vaccine for the prevention of gastroenteritis in young children, was introduced in England in July 2013. At around this time, an elevated risk of intussusception (a cause of bowel obstruction) was reported among infants vaccinated in Australia and the USA. A risk-benefit analysis compared potential vaccine-related risks (additional intussusception admissions and deaths) with estimated vaccine benefits (prevented rotavirus general practitioner visits, emergency visits, admissions and deaths) in the 2012 birth cohort. Detailed data from England included the incidence of intussusception events aged <2 years by week of age, the coverage of vaccination aged <2 years by week of age, and the incidence of rotavirus gastroenteritis (RVGE) events aged <5 years by week of age. Recent estimates of vaccine-related risk from Australia were applied during the 1-21 day period after the first and second dose of vaccination. Rotarix((r)) is estimated to cause one additional intussusception admission in every 18,551 vaccinated English infants (5th and 95th percentiles, 6728-93,952), equivalent to 35 (7-98) additional intussusception admissions each year. The vaccine is estimated to prevent three rotavirus deaths, 13,000 rotavirus admissions, 27,000 rotavirus emergency visits and 74,000 rotavirus GP consultations in children aged <5 years, and lead to annual savings of over L11 million, each year. We estimate 375 (136-1900) fewer RVGE admissions for every additional intussusception admission, and 88 (18-852) fewer RVGE deaths for every additional intussusception death. The estimated benefits of Rotarix((r)) vaccination would greatly exceed the potential risk in England. PMID- 24814525 TI - Leishmania genome analysis and high-throughput immunological screening identifies tuzin as a novel vaccine candidate against visceral leishmaniasis. AB - Leishmaniasis is a neglected tropical disease caused by Leishmania species. It is a major health concern affecting 88 countries and threatening 350 million people globally. Unfortunately, there are no vaccines and there are limitations associated with the current therapeutic regimens for leishmaniasis. The emerging cases of drug-resistance further aggravate the situation, demanding rapid drug and vaccine development. The genome sequence of Leishmania, provides access to novel genes that hold potential as chemotherapeutic targets or vaccine candidates. In this study, we selected 19 antigenic genes from about 8000 common Leishmania genes based on the Leishmania major and Leishmania infantum genome information available in the pathogen databases. Potential vaccine candidates thus identified were screened using an in vitro high throughput immunological platform developed in the laboratory. Four candidate genes coding for tuzin, flagellar glycoprotein-like protein (FGP), phospholipase A1-like protein (PLA1) and potassium voltage-gated channel protein (K VOLT) showed a predominant protective Th1 response over disease exacerbating Th2. We report the immunogenic properties and protective efficacy of one of the four antigens, tuzin, as a DNA vaccine against Leishmania donovani challenge. Our results show that administration of tuzin DNA protected BALB/c mice against L. donovani challenge and that protective immunity was associated with higher levels of IFN-gamma and IL-12 production in comparison to IL-4 and IL-10. Our study presents a simple approach to rapidly identify potential vaccine candidates using the exhaustive information stored in the genome and an in vitro high-throughput immunological platform. PMID- 24814526 TI - A reliable approach to distinguish between transient with and without HFOs using TQWT and MCA. AB - Recent studies have reported that discrete high frequency oscillations (HFOs) in the range of 80-500Hz may serve as promising biomarkers of the seizure focus in humans. Visual scoring of HFOs is tiring, time consuming, highly subjective and requires a great deal of mental concentration. Due to the recent explosion of HFOs research, development of a robust automated detector is expected to play a vital role in studying HFOs and their relationship to epileptogenesis. Therefore, a handful of automated detectors have been introduced in the literature over the past few years. In fact, all the proposed methods have been associated with high false-positive rates, which essentially arising from filtered sharp transients like spikes, sharp waves and artifacts. In order to specifically minimize false positive rates and improve the specificity of HFOs detection, we proposed a new approach, which is a combination of tunable Q-factor wavelet transform (TQWT), morphological component analysis (MCA) and complex Morlet wavelet (CMW). The main findings of this study can be summarized as follows: The proposed method results in a sensitivity of 96.77%, a specificity of 85.00% and a false discovery rate (FDR) of 07.41%. Compared to this, the classical CMW method applied directly on the signals without pre-processing by TQWT-MCA achieves a sensitivity of 98.71%, a specificity of 18.75%, and an FDR of 29.95%. The proposed method may be considered highly accurate to distinguish between transients with and without HFOs. Consequently, it is remarkably reliable and robust for the detection of HFOs. PMID- 24814527 TI - Ovarian torsion and bilateral? PMID- 24814528 TI - Effects of the insulin sensitizer pioglitazone on menstrual irregularity, insulin resistance and hyperandrogenism in young women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine cause of menstrual irregularities, hirsutism and acne. Women with PCOS present elevated plasma insulin levels, both fasting and after a glucose load, as an indirect evidence of insulin resistance. PCOS women may also present hypertension, low levels of HDL cholesterol, hypertriglyceridemia, visceral obesity and a higher level of CRP and fibrinogen that can predict an atherosclerotic risk. METHODS: This study was carried out on 15 young women with PCOS selected according to the 2003 diagnostic criteria of The Rotterdam Consensus Statement and 15 Control women. PCOS women were treated with pioglitazone 30 mg/day and at the beginning and after 6 months of treatment were evaluated: menstrual cycle trend, hirsutism and acne, total cholesterolemia and HDL, triglyceridemia, fibrinogenemia, C reactive protein, oral glucose tolerance test, glycated hemoglobin, FSH, LH, 17OH progesterone, 17beta-estradiol, free and total testosterone, SHBG, DHEA-S, Delta4 androstenedione and adiponectin. RESULTS AND DISCUSSION: Treatment with pioglitazone improves the irregularities of menses and hirsutism. Six months of treatment modify other parameters linked with a higher risk of type 2 diabetes mellitus and cardiovascular diseases: adiponectin increased with reduction of insulin resistance while fibrinogen and CRP levels decreased. PMID- 24814529 TI - Contraceptive need, counseling, and provision at the time of human papillomavirus vaccination on a catch-up schedule. AB - STUDY OBJECTIVE: Human papillomavirus vaccination may be given on a catch-up schedule to individuals between 13-26 years of age. Young women receiving human papillomavirus (HPV) vaccination during this time of adolescence and young adulthood may be at risk for pregnancy. We aimed to describe contraceptive need and contraceptive care for females at the time of HPV vaccination on a catch-up schedule. DESIGN: We performed a cross-sectional study of adolescents and young women who received HPV vaccination between June 2006 and May 2010. SETTING: University of Illinois Health Sciences Center. PARTICIPANTS: Females aged 13-26 years. MAIN OUTCOME MEASURES: Proportion of females receiving contraception counseling and provision at time of catch-up HPV vaccination. We used descriptive and chi-square statistics for analysis. RESULTS: 507 females, mean age 22 years, received HPV vaccination in the study period. Initiation of heterosexual activity was documented for 472 (94%). Of those who were currently sexually active, 316 (80%) were using contraception. The majority of all subjects (76%) were counseled on contraception at vaccination. Sexually active females were more likely to be counseled than those who had not initiated sexual activity (77% vs 54%, P = .002). Those vaccinated in primary care clinics were more likely to be counseled than in colposcopy clinics (87% vs 36%, P < .001). CONCLUSION: Young women presenting for HPV vaccination are often at risk of pregnancy. Onset of sexual activity and clinical site were associated with contraceptive care. HPV vaccination represents an opportunity to improve access to contraceptive care. PMID- 24814530 TI - Publication fate of abstracts presented at Society of British Neurological Surgeons meetings. AB - INTRODUCTION: Society of British Neurological Surgeons (SBNS) meetings are important national events which allow for the presentation of current academic work. The publication rate of presented abstracts is considered a proxy marker of the scientific strength of a conference. We aimed to determine the publication fate of presented abstracts at SBNS meetings over a 5-year period. METHODS: A retrospective review of SBNS conference proceedings between 2001 and 2005 was performed. To ascertain whether an abstract resulted in peer-reviewed publication, a range of databases (PubMed, Google Scholar, Medline and Ovid) were interrogated. Abstracts published in full were subsequently assessed for journal impact factor (IF), time of publication and number of citations received (per Google Scholar). RESULTS: A total of 494 abstracts were presented. Of these, 181 abstracts were subsequently published in full, giving the conference a publication rate of 36.6%. The mean time to publication from presentation was 22 months (range 35 months pre-presentation to 133 months afterwards). The top three journals for publication were the British Journal of Neurosurgery (23.2%), Neurosurgery (7.7%) and Journal of Neurosurgery (7.7%). The IF of journal destinations ranged from no IF to 38.28 (median=1.97). Number of citations ranged from 0 to 963 (median=22). Abstracts with positive results were significantly more likely to be published in full compared to those with negative results (p=0.0001). CONCLUSIONS: SBNS conferences have a respectable publication rate. Those abstracts that are published in full have gone on to gain a considerable number of citations reflecting their scientific relevance. However, studies presented at SBNS are susceptible to positive outcome bias. PMID- 24814531 TI - Small-molecule quadruplex-targeted drug discovery. AB - Repeated guanine tracts in human and other genomes can form higher-order four stranded structures, termed quadruplexes. In the human genome they have particular prevalence in telomeric and promoter regions and also in 5'-UTRs and introns. These structures, if unresolved and stabilised by small molecules, can form impediments to transcription and translation, and thus can be considered as a form of gene targeting. This Digest surveys the major types of quadruplex binding small molecules that have been designed and studied to date and directs attention to directions where future development of more drug-like compounds is likely to be most productive. PMID- 24814532 TI - Synthesis and biological effects of new hybrid compounds composed of benzylguanidines and the alkylating group of busulfan on neuroblastoma cells. AB - (131)Iodine-labelled (meta-iodobenzyl)guanidine ([(131)I]-mIBG) and busulfan [butane-1,4-diylbis(methanesulfonate)] are well-established pharmaceuticals in neuroblastoma therapy. We report the design, synthesis, and testing of hybrid molecules-mBBG and pBBG-which combine key structural features of (meta iodobenzyl)guanidine and busulfan: they contain a benzylguanidine moiety for accumulating in neuroblastoma cells via the noradrenaline transporter and, in the meta- or para-position, respectively, one of the two identical alkylating motives of busulfan for killing cells. Uptake and toxicity of hybrids mBBG and pBBG in human neuroblastoma cells compared favorably to their ancestors [(131)I]-mIBG and busulfan. PMID- 24814533 TI - Dietary adherence in children with chronic kidney disease: a review of the evidence. AB - BACKGROUND: In children with chronic kidney disease (CKD), a nutrition support plan is important to ensure optimal macro- and micro-nutrient intake in order to avoid malnutrition, disease-related complications and growth rate reduction. Children with CKD and their families encounter many difficulties in adjusting to the renal diet. Even though adherence to the recommended dietary plan is important in CKD, it is rarely measured partly due to the lack of robust, unbiased assessment methods. METHODS: In this review of 22 papers, the techniques used to assess adherence in children with CKD are reviewed, alongside their advantages and disadvantages. FINDINGS: Although dietary surveys, biochemical index assessment and clinician ratings have been found not to be efficient when used as a single tool, they should be used in combination in order to give the opportunity to the health providers to perceive adherence from as many angles as possible. PMID- 24814534 TI - Transcriptional regulation of enhancers active in protodomains of the developing cerebral cortex. AB - Elucidating the genetic control of cerebral cortical (pallial) development is essential for understanding function, evolution, and disorders of the brain. Transcription factors (TFs) that embryonically regulate pallial regionalization are expressed in gradients, raising the question of how discrete domains are generated. We provide evidence that small enhancer elements active in protodomains integrate broad transcriptional information. CreER(T2) and GFP expression from 14 different enhancer elements in stable transgenic mice allowed us to define a comprehensive regional fate map of the pallium. We explored transcriptional mechanisms that control the activity of the enhancers using informatics, in vivo occupancy by TFs that regulate cortical patterning (CoupTFI, Pax6, and Pbx1), and analysis of enhancer activity in Pax6 mutants. Overall, the results provide insights into how broadly expressed patterning TFs regulate the activity of small enhancer elements that drive gene expression in pallial protodomains that fate map to distinct cortical regions. PMID- 24814536 TI - Solvent/oxidant-switchable synthesis of multisubstituted quinazolines and benzimidazoles via metal-free selective oxidative annulation of arylamidines. AB - A fast and simple divergent synthesis of multisubstituted quinazolines and benzimidazoles was developed from readily available amidines, via iodine(III) promoted oxidative C(sp(3))-C(sp(2)) and C(sp(2))-N bond formation in nonpolar and polar solvents, respectively. Further selective synthesis of quinazolines in polar solvent was realized by TEMPO-catalyzed sp(3)C-H/sp(2)C-H direct coupling of the amidine with K2S2O8 as the oxidant. No metal, base, or other additives were needed. PMID- 24814535 TI - Directionality of temperature activation in mouse TRPA1 ion channel can be inverted by single-point mutations in ankyrin repeat six. AB - Several transient receptor potential (TRP) ion channels are activated with high sensitivity by either cold or hot temperatures. However, structures and mechanism that determine temperature directionality (cold versus heat) are not established. Here we screened 12,000 random mutant clones of the cold-activated mouse TRPA1 ion channel with a heat stimulus. We identified three single-point mutations that are individually sufficient to make mouse TRPA1 warm activated, while leaving sensitivity to chemicals unaffected. Mutant channels have high temperature sensitivity of voltage activation, specifically of channel opening, but not channel closing, which is reminiscent of other heat-activated TRP channels. All mutations are located in ankyrin repeat six, which identifies this domain as a sensitive modulator of thermal activation. We propose that a change in the coupling of temperature sensing to channel gating generates this sensitivity to warm temperatures. Our results demonstrate that minimal changes in protein sequence are sufficient to generate a wide diversity of thermal sensitivities in TRPA1. PMID- 24814537 TI - Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm. AB - This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm. PMID- 24814538 TI - Short stature and ischemic stroke in nonvalvular atrial fibrillation: new insight into the old observation. AB - BACKGROUND: For decades, repeated epidemiologic observations have been made regarding the inverse relationship between stature and cardiovascular disease, including stroke. However, the concept has not been fully evaluated in patients with atrial fibrillation (AF). We investigated whether patient's height is associated with ischemic stroke in patients with nonvalvular AF and attempted to ascertain a potential mechanism. METHODS: All 558 AF patients were enrolled: 211 patients with ischemic stroke (144 men, 68 +/- 10 years) and 347 no-stroke patients (275 men, 56 +/- 11 years) as a control group. Clinical characteristics and echocardiographic parameters were compared between the two groups. RESULTS: (1) Stroke patients were shorter than those in the control group (164 +/- 8, vs. 169 +/- 8 cm, p<0.001). However, body mass index failed to predict ischemic stroke; (2) Short stature (OR 0.93, 95% CI 0.91-0.95, p<0.001) along with left atrial (LA) anterior-posterior diameter and diastolic mitral inflow velocity (E) to diastolic mitral annuls velocity (E') (E/E') were independent predictor of stroke; (3) Height showed inverse correlation with E/E' independently, even after adjusting for other variables, including age, sex, and body weight, and comorbidities beta -0.20, p=0.003); (4) LA size showed no correlation with stature (R=-0.06, p=0.18), whereas left ventricular size increases according to height of patients. CONCLUSIONS: Short stature is associated with occurrence of ischemic stroke and diastolic dysfunction in patients with AF and preserved systolic function. Height is a non-modifiable risk factor of stroke and might be more important than obesity in Asian AF patients, who are relatively thinner than western populations. PMID- 24814539 TI - Maximum phonation time is related to disease severity in male chronic heart failure patients. PMID- 24814540 TI - Might ivabradine be useful in permanent atrial fibrillation? PMID- 24814541 TI - Brachial-brachial index of systolic blood pressure in the patients under anti hypertensive therapy. PMID- 24814542 TI - Reducing the avoidable time in the management of stroke patients. PMID- 24814543 TI - Bioresorbable vascular scaffold strut disruption after crossing with an optical coherence tomography imaging catheter. PMID- 24814544 TI - Febrile unilateral pulmonary edema: a potential misdiagnosis. PMID- 24814545 TI - Is systemic right ventricular function by cardiac MRI related to the degree of tricuspid regurgitation in congenitally corrected transposition of the great arteries? AB - BACKGROUND AND METHODS: Systemic right ventricular dysfunction and tricuspid regurgitation (TR) are frequently encountered in patients with congenitally corrected transposition of the great arteries (CCTGA). Studies using echocardiography have suggested a relationship between the degree of TR and systemic right ventricular dysfunction; however, assessment of systemic right ventricular function by echocardiography is limited. Cardiac MRI (CMR) is the gold standard for volumetric assessment of the systemic right ventricle. We performed a retrospective cohort study at our center evaluating all adult patients with CCTGA who underwent a CMR between 1/1999 and 1/2013 to determine the relationship between the degree of TR and systemic right ventricular function. RESULTS: Of the 33 patients identified, 12 had <= mild TR (37%), 13 had moderate TR (40%), and 8 had severe TR (24%). Mean age at CMR was 38 years (23 64). Mean right ventricular ejection fraction (45% vs. 41% vs. 42%, p=0.68) and mean indexed right ventricular end diastolic volume (122 ml/m(2) vs. 136 ml/m(2) vs. 138 ml/m(2)p=0.36) were not significantly different for patients with <= mild TR, moderate TR or severe TR. The degree of TR was not associated with additional congenital lesions, prior procedures, presence of an intraventricular conduction delay, or decreased left ventricular function. CONCLUSION: No association between the degree of TR and right ventricular volume or ejection fraction by CMR was identified. Failure to show worsening function or increased volume with greater degrees of TR suggests that the degree of regurgitation alone may not fully explain the heterogeneity in right ventricular size and function. PMID- 24814546 TI - Evolution of multi-well pad development and influence of well pads on environmental violations and wastewater volumes in the Marcellus shale (USA). AB - A majority of well pads for unconventional gas wells that are drilled into the Marcellus shale (northeastern USA) consist of multiple wells (in some cases as many as 12 wells per pad), yet the influence of the evolution of well pad development on the extent of environmental violations and wastewater production is unknown. Although the development of multi-well pads (MWP) at the expense of single well pads (SWP) has been mostly driven by economic factors, the concentrated nature of drilling activities from hydraulic fracturing and horizontal drilling operations on MWP suggests that MWP may create less surface disturbance, produce more volumes of wastewater, and generate more environmental violations than SWP. To explore these hypotheses, we use geospatial techniques and statistical analyses (i.e., regression and Mann-Whitney tests) to assess development of unconventional shale gas wells, and quantify environmental violations and wastewater volumes on SWP and MWP in Pennsylvania. The analyses include assessments of the influence of different types of well pads on potential, minor and major environmental events. Results reveal that (a) in recent years, a majority of pads on which new wells for unconventional gas were drilled are MWP, (b) on average, MWP have about five wells located on each pad and thus, had the transition to MWP not occurred, between two and four times as much land surface disturbance would have occurred per year if drilling was relegated to SWP, (c) there were more environmental violations on MWP than SWP, but when the number of wells were taken into account, fewer environmental violations per well were observed on MWP than on SWP, (d) there were more wastewater and recycled wastewater volumes per pad and per well produced on MWP than on SWP, and (e) the proportion of wastewater that was recycled was higher on MWP than SWP. This study sheds light on how the evolution from SWP to MWP has influenced environmental violations and wastewater production in a field that has undergone rapid development in recent years. PMID- 24814547 TI - The short-term effects of management changes on watertable position and nutrients in shallow groundwater in a harvested peatland forest. AB - Management changes such as drainage, fertilisation, afforestation and harvesting (clearfelling) of forested peatlands influence watertable (WT) position and groundwater concentrations of nutrients. This study investigated the impact of clearfelling of a peatland forest on WT and nutrient concentrations. Three areas were examined: (1) a regenerated riparian peatland buffer (RB) clearfelled four years prior to the present study (2) a recently clearfelled coniferous forest (CF) and (3) a standing, mature coniferous forest (SF), on which no harvesting took place. The WT remained consistently below 0.3 m during the pre-clearfelling period. Results showed there was an almost immediate rise in the WT after clearfelling and a rise to 0.15 m below ground level (bgl) within 10 months of clearfelling. Clearfelling of the forest increased dissolved reactive phosphorus concentrations (from an average of 28-230 MUg L(-1)) in the shallow groundwater, likely caused by leaching from degrading brash mats. PMID- 24814548 TI - Laboratory study of nitrification, denitrification and anammox processes in membrane bioreactors considering periodic aeration. AB - The possibility of using membrane bioreactors (MBRs) in simultaneous nitrification-anammox-denitrification (SNAD) by considering periodic aeration cycles was investigated. Two separate reactors were operated to investigate the effect of different anammox biomass in the presence of nitrifying and denitrifying biomass on the final nitrogen removal efficiency. The results illustrated that the reactor with higher anammox biomass was more robust to oxygen cycling. Around 98% Total Nitrogen (TN) and 83% Total Organic Carbon (TOC) removal efficiencies were observed by applying one hour aeration over a four-hour cycle. Decreasing the aeration time to 30, 15, and 2 min during a four-hour cycle affected the final TN removal efficiencies. However, the effect of decreasing aeration on the TN removal efficiencies in the reactor with higher anammox biomass was much lower compared to the regular reactor. The nitrous oxide (N2O) emission was a function of aeration as well, and was lower in the reactor with higher anammox biomass. The results of q-PCR analysis confirmed the simultaneous co-existence of nitrifiers, anammox, and denitrifiers in both of the reactors. To simulate the TN removal in these reactors as a function of the aeration time, a new model, based on first order reaction kinetics for both denitrification and anammox was developed and yielded a good agreement with the experimental observations. PMID- 24814549 TI - Determination of tissue levels of a neuroprotectant drug: the cell permeable JNK inhibitor peptide. AB - INTRODUCTION: Cell permeable peptides (CPPs) represent a novel tool for the delivery of bioactive molecules into scarcely accessible organs, such as the brain. CPPs have been successfully used in pre-clinical studies for a variety of diseases, ranging from cancer to neurological disorders. However, the mechanisms by which CPPs cross biological membranes, as well as their pharmacokinetic properties, have been poorly explored due to the lack of specific and sensitive analytical methods. METHODS: In this paper we describe a protocol to quantitatively determine the amount of CPPs in in vitro and in vivo experimental models. To this end we selected the peptide D-JNKI1 that was shown to prevent neurodegeneration in both acute and chronic degenerative disorders. This method allows an accurate quantitative analysis of D-JNKI1 in both neuronal lysates and tissue homogenates using mass spectrometry and stable isotope dilution approach. RESULTS: We found that D-JNKI1 crosses cellular membranes with fast kinetics, through an active and passive mechanism. After acute intraperitoneal (ip) administration of D-JNKI1 in mice, the peptide was found in the main organs with particular regard to the liver and kidney. Interestingly, D-JNKI1 crosses the blood brain barrier (BBB) and reaches the brain, where it remains for one week. DISCUSSION: The challenge lies in developing the clinical application of therapeutic cell permeable peptides. Discerning pharmacokinetic properties is a high priority to produce a powerful therapeutic strategy. Overall, our data shed light on the pharmacokinetic properties of D-JNKI1 and supports its powerful neuroprotective effect. PMID- 24814550 TI - The benefits of redesigning Benin's vaccine supply chain. AB - INTRODUCTION: New vaccine introductions have put strains on vaccine supply chains around the world. While increasing storage and transportation may be the most straightforward options, it is also important to consider what financial and operational benefits can be incurred. In 2012, suboptimal vaccine coverage and impending vaccine introductions prompted the Republic of Benin's Ministry of Health (MOH) to explore ways to improve their vaccine supply chain. METHODS: Working alongside the Beninese MOH, we utilized our computational model, HERMES, to explore the impact on cost and vaccine availability of three possible options: (1) consolidating the Commune level to a Health Zone level, (2) removing the Commune level completely, and (3) removing the Commune level and expanding to 12 Department Stores. We also analyzed the impact of adding shipping loops during delivery. RESULTS: At baseline, new vaccine introductions without any changes to the current system increased the logistics cost per dose ($0.23 to $0.26) and dropped the vaccine availability to 71%. While implementing the Commune level removal scenario had the same capital costs as implementing the Health Zone scenario, the Health Zone scenario had lower operating costs. This increased to an overall cost savings of $504,255 when implementing shipping loops. DISCUSSION: The best redesign option proved to be the synergistic approach of converting to the Health Zone design and using shipping loops (serving ten Health Posts/loop). While a transition to either redesign or only adding shipping loops was beneficial, implementing a redesign option and shipping loops can yield both lower capital expenditures and operating costs. PMID- 24814551 TI - Perceptions of personal belief vaccine exemption policy: a survey of Arizona vaccine providers. AB - BACKGROUND: As exemptions to school-entry requirements rise, vaccination rates in Arizona school children are approaching levels that may threaten public health. Understanding the interactions physicians have with vaccine-hesitant parents, as well as the opinions physicians hold regarding vaccination, exemption, and exemption policies, are critical to our understanding of, and ability to affect, vaccination exemption rates among children. METHODS: Survey responses were elicited from practitioners listed in The Arizona Partnership for Immunization and the Arizona Medical Association databases using a multi-pronged recruitment approach. Respondents provided data regarding their practice, comfort with parental refusal of individual vaccines, opinions about the beliefs held by parents that seek exemptions, parent education strategies, issues regarding providing care to unvaccinated children, and potential changes to Arizona policy. RESULTS: A total of 152 practitioners providing care to a wide geographic and economic population of Arizona responded to the survey. Respondents were generally strong advocates of all immunizations but were more accepting of parents' desires to refuse hepatitis B and rotavirus vaccines. Almost all providers indicated that they see patients whose parents request to refuse or delay from vaccinations at least occasionally (88% and 97%, respectively). Only 37% of respondents indicated that they would be supportive of a policy requiring them to sign off on a parent's decision to refuse vaccination. CONCLUSIONS: Vaccination providers in Arizona are generally very supportive of childhood immunizations but have varying comfort with exemption from individual vaccines. Responding providers tended to not support a requirement for a physician's signature for vaccine exemptions due to varying concerns regarding the implementation of such a practice. PMID- 24814552 TI - Protective humoral immune response induced by an inactivated porcine reproductive and respiratory syndrome virus expressing the hypo-glycosylated glycoprotein 5. AB - Porcine reproductive and respiratory syndrome (PRRS) causes significant economic losses to the swine industry worldwide. Although inactivated and live vaccines are commercially available for the control of PRRS, both types of vaccine have not always proven successful in terms of generating a protective immune response, particularly in the case of inactivated vaccines. In this study, we tested whether an inactivated vaccine could induce a humoral immune response to PRRS during a homologous challenge. Amino acid substitutions were introduced into glycoprotein (GP) 5 of the FL12 strain of the PRRS virus (PRRSV) using site directed mutagenesis with a pFL12 infectious clone. The substitutions led to double deglycosylation in the putative glycosylation moieties on GP5. The mutant virus was subsequently inactivated with binary ethylenimine. The efficacy of the inactivated mutant virus was compared with that of the inactivated wild-type PRRSV. Only the inactivated mutant PRRSV induced serum neutralizing antibodies at six weeks post-vaccination. The group that was administered the inactivated mutant virus twice exhibited a significantly increased neutralizing antibody titer after a challenge with the virulent homologous strain and exhibited more rapid clearing of viremia compared to other groups, including the groups that were administered either the inactivated mutant or wild-type virus only once and the group that was administered the inactivated wild-type virus twice. Histopathological examination of lung tissue sections revealed that the group that was administered the inactivated mutant virus twice exhibited significantly thinner alveolar septa, whereas the thickness of the alveolar septa of the other groups were markedly increased due to lymphocyte infiltration. These results indicated that the deglycosylation of GP5 enhanced the immunogenicity of the inactivated mutant PRRSV and that twice administrations of the inactivated mutant virus conferred better protection against the homologous challenge. These findings suggest that the inactivated PRRSV that expresses a hypo-glycosylated GP5 is a potential inactivated vaccine candidate and a valuable tool for controlling PRRS for the swine industry. PMID- 24814554 TI - Oral vaccination and protection of striped skunks (Mephitis mephitis) against rabies using ONRAB(r). AB - Skunks are one of the most important rabies vector species in North America due to their wide geographic distribution, high susceptibility to the rabies virus, and tendency to inhabit areas around human dwellings and domestic animals. Oral vaccination is a cost-effective, socially acceptable technique often used to control rabies in terrestrial wildlife; however, control of rabies in skunks has proven especially challenging due to the lack of a vaccine effective by the oral route in this species. In this study, we examined the antibody response of captive striped skunks (Mephitis mephitis) to ONRAB((r)) and tested the protection afforded by the vaccine against rabies virus. Thirty-one skunks were each offered one ONRAB((r)) vaccine bait, 25 skunks were administered ONRAB((r)) via direct instillation into the oral cavity (DIOC) and ten controls received no vaccine. A blood sample was collected from controls and vaccinates 6 weeks prior to treatment, and then 5 and 7 weeks post-vaccination (PV). A competitive ELISA was used to detect rabies antibody (RAb). Pre-vaccination sera for all skunks, and sera for all controls throughout the serology study, were negative for RAb. Fifty-eight percent (18/31) of skunks in the bait group and 100% (25/25) of skunks that received ONRAB((r)) DIOC had detectable RAb by 7 week PV. All 10 controls succumbed to experimental rabies infection. In the group of skunks administered ONRAB((r)) DIOC, 100% (23/23) survived challenge 247 days PV. Survival of skunks presented ONRAB((r)) baits was 81% (25/31). In the bait group, all 18 skunks that had detectable RAb by 7 week PV survived challenge. Seven additional skunks without detectable RAb prior to week 7 PV also survived. Lack of any remarkable pathology in study animals, together with positive serology and challenge results, supports that ONRAB((r)) is a safe and effective oral rabies vaccine for use in skunks. PMID- 24814553 TI - Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. AB - RATIONALE: Global tuberculosis (TB) control may require mass vaccination with a new TB vaccine, such as a recombinant bacille Calmette Guerin (BCG) or attenuated Mycobacterium tuberculosis (MTB). The safety profile of live mycobacterial vaccines in latently infected adults with prior infant BCG vaccination is unknown. OBJECTIVES: Evaluate safety and reactogenicity of BCG revaccination, with or without isoniazid (INH) pretreatment, in adults with latent MTB infection (LTBI). METHODS: Eighty-two healthy, HIV uninfected, South African adults, with a BCG scar and tuberculin skin test (TST) diameter >= 15 mm, were randomized to receive 6 months of INH, starting either before, or 6 months after, intradermal revaccination with BCG Vaccine SSI (Statens Serum Institut, Copenhagen). Safety and reactogenicity data are reported through 3 months post BCG revaccination. RESULTS: Baseline characteristics were similar between treatment arms. Mean baseline TST diameter was 20 +/- 4 mm. Seventy-two subjects received BCG revaccination. Injection site erythema (68%) and induration (86%) peaked 1 week after revaccination. Ulceration (76%) peaked at 2 weeks, and resolved by 3 months in all but 3 subjects. Diameter of ulceration was >10mm in only 8%, but a residual scar was common (85%). No regional lymphadenitis or serious morbidity related to BCG was seen. Reactogenicity was not affected by INH pretreatment. CONCLUSION: BCG revaccination of MTB infected adults is safe, well tolerated, and reactogenicity is similar to that of primary BCG vaccination. Clinical trials of live recombinant BCG or attenuated MTB vaccines may be considered in latently infected adults, with or without INH pretreatment (ClinicalTrials.gov identifier: NCT01119521). PMID- 24814555 TI - Effects of 7-valent pneumococcal conjugate 1 vaccine on the severity of adult 2 bacteremic pneumococcal pneumonia. AB - PURPOSE: The introduction of a 7-valent conjugate pneumococcal vaccine (PCV7) in children largely affected the prevalence of adult pneumococcal pneumonia. In this study we investigated whether the clinical severity of adult bacteremic pneumococcal pneumonia has also altered following the introduction of pediatric PCV7 vaccination. METHODS: Adults hospitalized with bacteremic pneumococcal pneumonia between 2001 and June 2011 at two Dutch hospitals were included retrospectively. Clinical data on patient characteristics, comorbidities and severity of disease were obtained and pneumococcal serotypes were determined. RESULTS: Among 343 patients investigated, those infected with PCV7 serotypes had a higher PSI score (p=0.0072) and mortality rate (p=0.0083) compared with the remainder of the cohort. Since the introduction of PCV7 the proportion of pneumococcal pneumonias caused by serotypes 1 and 7F (p-values 0.037 and 0.025) increased, as well as the rate of pleural effusion and empyema (p-values 0.011 and 0.049). Whilst de proportion of adults infected with PCV7 serotypes decreased after the introduction of PCV7 (p=0.015), PSI scores in these patients remained higher (p=0.030), although mortality rates between PCV7 and non PCV7 types equalized. After the introduction of PCV7 a marked shortening in hospital stay was observed only among patients infected with non PCV7 serotypes (p=0.019). CONCLUSIONS: The introduction of pediatric PCV7 vaccination was accompanied by subtle changes in clinical severity of adult bacteremic pneumococcal pneumonia. Expansion of serotypes covered by pneumococcal vaccination may again influence the clinical presentation of disease. PMID- 24814556 TI - Heat-killed yeast protects diabetic ketoacidotic-steroid treated mice from pulmonary mucormycosis. AB - Previous studies have shown that vaccination with heat-killed yeast, Saccharomyces cerevisiae (HKY), protects mice against systemic candidiasis, aspergillosis, cryptococcosis or coccidioidomycosis. Here we sought to define the potential use of HKY as a vaccine to protect mice from mucormycosis. Mice were vaccinated with different regimens of HKY prior to induction of diabetes. Diabetic ketoacidotic (DKA) mice were then treated with steroids prior to intratracheal challenge with Rhizopus oryzae. All regimens of HKY vaccine improved survival of DKA mice and reduced fungal burden in the primary target organ, lungs, as determined by qPCR. Furthermore, compared to mice vaccinated with diluent, vaccination with HKY substantially increased the mouse immune response as determined by detection of increased anti-Rhizopus antibody titers. Our results show that HKY protects steroid-treated DKA mice from pulmonary R. oryzae infection. Considering its demonstrated efficacy against other fungal infections, HKY is a promising candidate for development as a panfungal vaccine. PMID- 24814557 TI - Serological response of foals to polyvalent and monovalent live-attenuated African horse sickness virus vaccines. AB - African horse sickness (AHS) is typically a highly fatal disease in susceptible horses and vaccination is currently used to prevent the occurrence of disease in endemic areas. Similarly, vaccination has been central to the control of incursions of African horse sickness virus (AHSV) into previously unaffected areas and will likely play a significant role in any future incursions. Horses in the AHSV-infected area in South Africa are vaccinated annually with a live attenuated (modified-live virus [MLV]) vaccine, which includes a cocktail of serotypes 1, 3, 4 (bottle 1) and 2, 6-8 (bottle 2) delivered in two separate doses at least 21 days apart. In this study, the neutralising antibody response of foals immunized with this polyvalent MLV AHSV vaccine was evaluated and compared to the response elicited to monovalent MLV AHSV serotypes. Naive foals were immunized with either the polyvalent MLV AHSV vaccine, or a combination of monovalent MLV vaccines containing individual AHSV serotypes 1, 4, 7 or 8. There was a marked and consistent difference in the immunogenicity of individual virus serotypes contained in the MLV vaccines. Specifically, foals most consistently seroconverted to AHSV-1 and responses to other serotypes were highly variable, and often weak or not detected. The serotype-specific responses of foals given the monovalent MLV vaccines were similar to those of foals given the polyvalent MLV preparation suggesting that there is no obvious enhanced immune response through the administration of a monovalent vaccine as opposed to the polyvalent vaccine. PMID- 24814558 TI - Social inequalities in vaccination uptake among children aged 0-59 months living in Madagascar: an analysis of Demographic and Health Survey data from 2008 to 2009. AB - BACKGROUND: Socioeconomic inequalities in vaccination can reduce the ability and efficiency of global efforts to reduce the burden of disease. Vaccination is particularly critical because the poorest children are often at the greatest risk of contracting preventable infectious diseases, and unvaccinated children may be clustered geographically, jeopardizing herd immunity. Without herd immunity, these children are at even greater risk of contracting disease and social inequalities in associated morbidity and mortality are amplified. METHODS: Data on vaccination for children under five came from the most recent Demographic and Health Survey in Madagascar (2008-2009). Vaccination status was available for diptheria, pertussis, tetanus, hepatitis B, measles, tuberculosis, poliomyelitis, and H. influenza type-B. Multilevel logistic regression was used to analyze childhood vaccination by parental socioeconomic status while accounting for shared district, cluster, and household variation. Maps were created to serve as a roadmap for efforts to increase vaccination. FINDINGS: Geographic variation in vaccination rates was substantial. Districts that were less covered were near other districts with limited coverage. Most districts lacked herd immunity for diphtheria, pertussis, poliomyelitis and measles. Full herd immunity was reached in a small number of districts clustered near the capital. While within-district variation in coverage was substantial; parental education and wealth were independently associated with vaccination. INTERPRETATION: Socioeconomic inequalities in vaccination reduce herd immunity and perpetuate inequalities by allowing infectious diseases to disproportionately affect the most vulnerable populations. Findings indicated that most districts had low immunization coverage rates and unvaccinated children were geographically clustered. The result was inequalities in vaccination and reduced herd immunity. To further improve coverage, interventions must take a multilevel approach that focuses on both supply- and demand-side barriers to delivering vaccination to underserved regions, and to the poorest children in those regions. PMID- 24814559 TI - Vaccines are not associated with autism: an evidence-based meta-analysis of case control and cohort studies. AB - There has been enormous debate regarding the possibility of a link between childhood vaccinations and the subsequent development of autism. This has in recent times become a major public health issue with vaccine preventable diseases increasing in the community due to the fear of a 'link' between vaccinations and autism. We performed a meta-analysis to summarise available evidence from case control and cohort studies on this topic (MEDLINE, PubMed, EMBASE, Google Scholar up to April, 2014). Eligible studies assessed the relationship between vaccine administration and the subsequent development of autism or autism spectrum disorders (ASD). Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus with another author. Five cohort studies involving 1,256,407 children, and five case-control studies involving 9,920 children were included in this analysis. The cohort data revealed no relationship between vaccination and autism (OR: 0.99; 95% CI: 0.92 to 1.06) or ASD (OR: 0.91; 95% CI: 0.68 to 1.20), nor was there a relationship between autism and MMR (OR: 0.84; 95% CI: 0.70 to 1.01), or thimerosal (OR: 1.00; 95% CI: 0.77 to 1.31), or mercury (Hg) (OR: 1.00; 95% CI: 0.93 to 1.07). Similarly the case-control data found no evidence for increased risk of developing autism or ASD following MMR, Hg, or thimerosal exposure when grouped by condition (OR: 0.90, 95% CI: 0.83 to 0.98; p=0.02) or grouped by exposure type (OR: 0.85, 95% CI: 0.76 to 0.95; p=0.01). Findings of this meta-analysis suggest that vaccinations are not associated with the development of autism or autism spectrum disorder. Furthermore, the components of the vaccines (thimerosal or mercury) or multiple vaccines (MMR) are not associated with the development of autism or autism spectrum disorder. PMID- 24814560 TI - Lung mechanical changes following bronchoaspiration in a porcine model: differentiation of direct and indirect mechanisms. AB - Bronchoaspiration results in local deterioration of lung function through direct damage and/or indirect systemic effects related to neurohumoral pathways. We distinguished these effects by selectively intubating the two main bronchi in pigs while a PEEP of 4 or 10cm H2O was maintained. Gastric juice was instilled only into the right lung. Lung mechanical and ventilation defects were assessed by measuring unilateral pulmonary input impedance (ZL,s) and the third phase slope of the capnogram (SIII) for each lung side separately before the aspiration and for 120min thereafter. Marked transient elevations in ZL,s parameters and SIII were observed in the affected lung after aspiration. Elevating PEEP did not affect these responses in the ZL,s parameters, whereas it prevented the SIII increases. None of these indices changed in the intact left lung. These findings furnish evidence of the predominance of the local direct damage over the indirect systemic effects in the development of the deterioration of lung function, and demonstrate the benefit of an initially elevated PEEP following aspiration. PMID- 24814561 TI - Systematic review and meta-analysis of noninvasive cranial nerve neuromodulation for nervous system disorders. AB - OBJECTIVE: To systematically review the medical literature and comprehensively summarize clinical research done on rehabilitation with a novel portable and noninvasive electrical stimulation device called the cranial nerve noninvasive neuromodulator in patients suffering from nervous system disorders. DATA SOURCES: PubMed, MEDLINE, and Cochrane Database of Systematic Reviews from 1966 to March 2013. STUDY SELECTION: Studies were included if they recruited adult patients with peripheral and central nervous system disorders, were treated with the cranial nerve noninvasive neuromodulator device, and were assessed with objective measures of function. DATA EXTRACTION: After title and abstract screening of potential articles, full texts were independently reviewed to identify articles that met inclusion criteria. DATA SYNTHESIS: The search identified 12 publications: 5 were critically reviewed, and of these 5, 2 were combined in a meta-analysis. There were no randomized controlled studies identified, and the meta-analysis was based on pre-post studies. Most of the patients were individuals with a chronic balance dysfunction. The pooled results demonstrated significant improvements in the dynamic gait index postintervention with a mean difference of 3.45 (95% confidence interval, 1.75-5.15; P<.001), Activities specific Balance Confidence scale with a mean difference of 16.65 (95% confidence interval, 7.65-25.47; P<.001), and Dizziness Handicap Inventory with improvements of -26.07 (95% confidence interval, -35.78 to -16.35; P<.001). Included studies suffered from small sample sizes, lack of randomization, absence of blinding, use of referral populations, and variability in treatment schedules and follow-up rates. CONCLUSIONS: Given these limitations, the results of the meta-analysis must be interpreted cautiously. Further investigation using rigorous randomized controlled trials is needed to evaluate this promising rehabilitation tool for nervous system disorders. PMID- 24814562 TI - Conservative treatment of neuromuscular scoliosis in adult tetraplegia: a case report. AB - We report successful correction of new onset neuromuscular scoliosis without spinal surgery in a man who is 30-years post-American Spinal Injury Association Impairment Scale grade A C6 injury with new onset of left neuromuscular scoliosis (Cobb angle 45 degrees ) after a motor vehicle collision. Interventions included nightly low-load prolonged stretching (LLPS) (4h left side lying over bolster), a series of 6 botulinum toxin injections (BTIs) at 3-month intervals, and progressive seating adjustments to counteract the spinal curvature. Monthly seating adjustments included rear quadrant wedging, lateral supports, and hip blocking to promote erect and symmetrical posture. A normative Cobb angle (5 degrees ) was achieved after 8 months of treatment. Improvements in alignment were demonstrated in physical examination outcome measures at the final session and follow-up. LLPS, seating adjustments, and paraspinal BTI are nonsurgical options for treating neuromuscular scoliosis in adults with tetraplegia. Further studies are necessary to determine optimum protocols and examine generalizability of these treatment methods. PMID- 24814563 TI - Recalibration and validation of the Cumberland Ankle Instability Tool cutoff score for individuals with chronic ankle instability. AB - OBJECTIVE: To independently recalibrate and revalidate the Cumberland Ankle Instability Tool (CAIT) cutoff score for discriminating individuals with and without chronic ankle instability (CAI). There are concerns the original cutoff score (<=27) may be suboptimal for use in the CAI population. DESIGN: Case control. SETTING: Research laboratory. PARTICIPANTS: Two independent datasets were used (total N=200). Dataset 1 included 61 individuals with a history of >=1 ankle sprain and >=2 episodes of giving way in the last year (CAI group) and 57 participants with no history of ankle sprain or instability in their lifetime (uninjured group). Dataset 2 included 27 uninjured participants, 29 participants with CAI, and 26 individuals with a history of a single ankle sprain and no subsequent instability (copers). INTERVENTIONS: All participants completed the CAIT during a single session. In dataset 1, a receiver operating characteristic (ROC) curve was calculated using the CAIT score and group membership as test variables. The ideal cutoff score was identified using the Youden index. The recalibrated cutoff score was validated in dataset 2 using the ROC analysis and clinimetric characteristics. MAIN OUTCOME MEASURES: CAIT cutoff score and clinimetrics. RESULTS: In dataset 1, the optimal cutoff score was <=25, which is lower than previously reported. In dataset 2, the recalibrated cutoff score demonstrated a sensitivity of 96.6%, specificity of 86.8%, positive likelihood ratio of 7.318, and negative likelihood ratio of .039. There were 7 false positives and 1 false negative. CONCLUSIONS: The recalibrated CAIT score demonstrated very good clinimetric properties; all properties improved compared with the original cutoff score. Clinicians using the CAIT should use the recalibrated cutoff score to maximize test characteristics. Caution should be taken with copers, who had a high rate of false positives. PMID- 24814564 TI - Morphology versus function: the relationship between lumbar multifidus intramuscular adipose tissue and muscle function among patients with low back pain. AB - OBJECTIVE: To explore the bivariate and multivariate relations between fatty degeneration of the lumbar multifidus muscle (LMM) and LMM function among patients with low back pain (LBP). DESIGN: Cross-sectional clinical study. SETTING: Hospital. PARTICIPANTS: Patients with LBP (N=70) referred for lumbar spine magnetic resonance imaging. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: LMM morphology and function were measured at the L4/L5 and L5/S1 spinal levels bilaterally. Quantitative measures of LMM intramuscular adipose tissue (IMAT) were derived from T1-weighted magnetic resonance images. Function was assessed with ultrasound imaging by measuring change in LMM thickness during a submaximal contraction task. The study participants self-reported their level of LBP-related disability (Modified Oswestry Index), pain intensity (numerical pain rating scale), and physical activity (International Physical Activity Questionnaire). Bivariate and multivariate relations between LMM morphology and function were explored with correlational and hierarchical linear regression analyses, respectively. Additionally, we explored for possible covariates with potential to modify the relation between LMM IMAT and function. RESULTS: There were 70 participants (12 women) enrolled in the study (mean age, 45.4+/-11.9y). A high level of physical activity was reported by 45.5% of participates. Age, sex, and physical activity level demonstrated variable relations with LMM IMAT and LMM function. There were no significant bivariate or multivariate relations between LMM IMAT and LMM function. CONCLUSIONS: We observed higher levels of physical activity and LMM function and less LMM IMAT than previous studies involving patients with LBP. There was no relation between LMM morphology and function in this cohort of patients with LBP. Issues specific to LMM measurement and recommendations for future research are discussed. PMID- 24814565 TI - Are there income differences in the impact of a national reimbursement policy for smoking cessation treatment and accompanying media attention? Findings from the International Tobacco Control (ITC) Netherlands Survey. AB - BACKGROUND: This study examined possible income differences in the impact of a national reimbursement policy for smoking cessation treatment and accompanying media attention in the Netherlands in 2011. METHODS: We used three waves of the International Tobacco Control (ITC) Netherlands Survey, a nationally representative longitudinal sample of smokers aged 15 years and older (n=1912). The main analyses tested trends and income differences in outcome measures (smokers' quit attempt rates, use of behavioral counseling, use of cessation medications, and quit success) and awareness variables (awareness of reimbursement possibilities, the media campaign, medications advertisements and other media attention) with generalized estimating equations analyses. RESULTS: In the first half of 2011, there was a significant increase in quit attempts (odds ratio (OR)=2.02, p<0.001) and quit success (OR=1.47, p<0.001). Use of counseling and medications remained stable at 3% of all smokers in this period. Awareness of reimbursement possibilities increased from 11% to 42% (OR=6.38, p<0.001). Only awareness of the media campaign was associated with more quit attempts at the follow-up survey (OR=1.95, p<0.001). Results were not different according to smokers' income level. CONCLUSIONS: The Dutch reimbursement policy with accompanying media attention was followed by an increase in quit attempts and quit success, but use of cessation treatment remained stable. The impact of the policy and media attention did not seem to have decreased or increased socioeconomic inequalities in quit attempts, use of cessation treatment, or quit success. PMID- 24814567 TI - Water accommodation and desorption kinetics on ice. AB - The interaction of water vapor with ice remains incompletely understood despite its importance in environmental processes. A particular concern is the probability for water accommodation on the ice surface, for which results from earlier studies vary by more than 2 orders of magnitude. Here, we apply an environmental molecular beam method to directly determine water accommodation and desorption kinetics on ice. Short D2O gas pulses collide with H2O ice between 170 and 200 K, and a fraction of the adsorbed molecules desorbs within tens of milliseconds by first order kinetics. The bulk accommodation coefficient decreases nonlinearly with increasing temperature and reaches 0.41 +/- 0.18 at 200 K. The kinetics are well described by a model wherein water molecules adsorb in a surface state from which they either desorb or become incorporated into the bulk ice structure. The weakly bound surface state affects water accommodation on the ice surface with important implications for atmospheric cloud processes. PMID- 24814566 TI - Modulation of smoking and decision-making behaviors with transcranial direct current stimulation in tobacco smokers: a preliminary study. AB - BACKGROUND: Most tobacco smokers who wish to quit fail to reach their goal. One important, insufficiently emphasized aspect of addiction relates to the decision making system, often characterized by dysfunctional cognitive control and a powerful drive for reward. Recent proof-of-principle studies indicate that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) can transiently modulate processes involved in decision-making, and reduce substance intake and craving for various addictions. We previously proposed that this beneficial effect of stimulation for reducing addictive behaviors is in part mediated by more reflective decision-making. The goal of this study was to test whether nicotine intake and decision-making behaviors are modulated by tDCS over the DLPFC in tobacco smokers who wished to quit smoking. METHODS: Subjects received two five-day tDCS regimens (active or sham). Stimulation was delivered over the right DLPFC at a 2 mA during 30 min. Nicotine cravings, cigarette consumption and decision-making were assessed before and after each session. RESULTS: Main findings include a significant decrease in the number of cigarettes smoked when participants received active as compared to sham stimulation. This effect lasted up to four days after the end of the stimulation regimen. In regards to decision-making, smokers rejected more often offers of cigarettes, but not offers of money, after they received active as compared to sham stimulation at the Ultimatum Game. No significant change was observed at the Risk Task with cigarettes or money as rewards. CONCLUSION: Overall, these findings suggest that tDCS over the DLPFC may be beneficial for smoking reduction and induce reward sensitive effects. PMID- 24814568 TI - WITHDRAWN: The overall impact of COPD (CAT) and BODE index on COPD male patients: correlation? AB - This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.02.004. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24814570 TI - Assessment of the helical ventricular myocardial band using standard echocardiography. AB - BACKGROUND: The purpose of this study was to assess the feasibility of morphological and functional evaluation of the helical ventricular myocardial band using standard echocardiographic images. METHODS: Echocardiographic data were obtained from 132 normal children. We attempted to identify the echogenic bright line serving as the boundary between the ascending and descending segments in the ventricular septum, and between the left and ascending segments in the left ventricular inferior wall in the helical myocardial band model proposed by Torrent-Guasp. Myocardial deformations on both sides of the bright line were compared using speckle tracking echocardiography. RESULTS: The bright line separating the ascending from descending segment was visible in the mid ventricular septum in the four-chamber view in all subjects. This echogenic boundary was observed obliquely in the parasternal short-axis view in 116 subjects (87.9%). There was no significant difference in peak longitudinal or circumferential strain between the ascending and descending segments. However, the time from the QRS onset to peak circumferential strain was significantly lower in the descending than ascending segment (394.5 +/- 37.0 vs. 432.7 +/- 33.1 ms, P < 0.0001), whereas there was no significant difference in the time to peak longitudinal strain (394.4 +/- 26.4 vs. 393.2 +/- 24.1 ms). The bright line between the left and ascending segment was detected in the short-axis view from the subcostal region in 86 subjects (65.2%). The time to peak circumferential strain was significantly lower in the left than ascending segment (380.1 +/- 32.0 vs. 435.7 +/- 37.9 ms, P < 0.0001). CONCLUSION: There is a helical ventricular myocardial band that can be observed in standard echocardiographic images. PMID- 24814569 TI - Lithium: a promising treatment for fragile X syndrome. AB - Fragile X syndrome (FXS) is an inherited disorder that results in intellectual disability and a characteristic behavioral profile that includes autism spectrum disorder, attention deficit hyperactivity disorder, sensory hypersensitivity, hyperarousal, and anxiety. The epigenetic silencing of FMR1 and the consequent absence of its protein product, FMRP, is the most common cause of fragile X. The development of animal models of fragile X syndrome 20 years ago has produced a considerable increase in our understanding of the consequences of the absence of FMRP on the structure and function of the nervous system. Some of the insights gained have led to proposals of treatment strategies that are based on cellular and molecular changes observed in animals lacking FMRP. One such proposal is treatment with lithium, a drug with a long history of clinical efficacy in psychiatry and a drug with newly described uses in degenerative disorders of the nervous system. Lithium treatment has been studied extensively in both mouse and fruit fly models of FXS, and it has been shown to reverse numerous behavioral, physiological, cellular, and molecular phenotypes. A report of a pilot clinical trial on a limited number of adult FXS patients indicated that measurable improvements in behavior and function were seen after 2 months of lithium treatment. A double-blind clinical trial of lithium treatment in FXS patients is now needed. PMID- 24814571 TI - Newborn dried blood-spot screening of the p.V37I variant of GJB2 by high resolution melting analysis. AB - OBJECTIVES: To establish a high-throughput, low-cost method for neonatal genetic testing of the p.V37I of GJB2 gene, which is highly prevalent in East Asians and strongly associated with postnatal childhood hearing impairment. METHODS: A total of 6460 newborn blood-spot DNA samples were screened by high-resolution melting analysis (HRMA). RESULTS: The screening results were further verified by direct sequencing of 28 homozygous, 545 heterozygous and 200 wild-type samples. CONCLUSION: Our study indicated that the HRMA-based bloodspot screening method was of very high sensitivity and specificity and was suitable for large-scale screening of the p.V37I variants in newborns. PMID- 24814572 TI - A boy with mild mental retardation, mild sensorineural hearing loss and mild facial dysmorphism caused by a 19p13.2 deletion: a case report and review of the literature. AB - The investigation of patients with congenital anomalies and/or intellectual disability with modern genetic methods allows the recognition of an increasing number of cases with these chromosomal rearrangements. Here, we present a mildly mentally retarded boy with mild facial dysmorphism, language development delay, mild sensorineural hearing loss due to a deletion of 1,14 Mb on chromosome 19p 13.2. The deletion was de novo and familial history negative for this disorder. To our knowledge this is the first description of a patient with symptoms mentioned above associated with a 19p13.2-p13.2 deletion. PMID- 24814573 TI - Poroelastic response of articular cartilage by nanoindentation creep tests at different characteristic lengths. AB - Nanoindentation is an experimental technique which is attracting increasing interests for the mechanical characterization of articular cartilage. In particular, time dependent mechanical responses due to fluid flow through the porous matrix can be quantitatively investigated by nanoindentation experiments at different penetration depths and/or by using different probe sizes. The aim of this paper is to provide a framework for the quantitative interpretation of the poroelastic response of articular cartilage subjected to creep nanoindentation tests. To this purpose, multiload creep tests using spherical indenters have been carried out on saturated samples of mature bovine articular cartilage achieving two main quantitative results. First, the dependence of indentation modulus in the drained state (at equilibrium) on the tip radius: a value of 500 kPa has been found using the large tip (400 MUm radius) and of 1.7 MPa using the smaller one (25 MUm). Secon, the permeability at microscopic scale was estimated at values ranging from 4.5*10(-16) m(4)/N s to 0.1*10(-16) m(4)/N s, from low to high equivalent deformation. Consistently with a poroelastic behavior, the size dependent response of the indenter displacement disappears when characteristic size and permeability are accounted for. For comparison purposes, the same protocol was applied to intrinsically viscoelastic homogeneous samples of polydimethylsiloxane (PDMS): both indentation modulus and time response have been found size-independent. PMID- 24814574 TI - A role for Ral GTPase-activating protein subunit beta in mitotic regulation. AB - Ral proteins are small GTPases that play critical roles in normal physiology and in oncogenesis. There is little information on the GTPase-activating proteins (GAPs) that downregulate their activity. Here, we provide evidence that the noncatalytic beta subunit of RalGAPalpha1/2 beta complexes is involved in mitotic control. RalGAPbeta localizes to the Golgi and nucleus during interphase, and relocalizes to the mitotic spindle and cytokinetic intercellular bridge during mitosis. Depletion of RalGAPbeta causes chromosome misalignment and decreases the amount of mitotic cyclin B1, disturbing the metaphase-to-anaphase transition. Overexpression of RalGAPbeta interferes with cell division, leading to binucleation and multinucleation, and cell death. We propose that RalGAPbeta plays an essential role in the sequential progression of mitosis by controlling the spatial and temporal activation of Ral GTPases in the spindle assembly checkpoint (SAC) and cytokinesis. Deregulation of RalGAPbeta might cause genomic instability, leading to human carcinogenesis. PMID- 24814575 TI - Selenium-enriched probiotics improve antioxidant status, immune function, and selenoprotein gene expression of piglets raised under high ambient temperature. AB - This research was conducted to evaluate the effects of selenium-enriched probiotics (SP) on growth performance, antioxidant status, immune function, and selenoprotein gene expression of piglets under natural high ambient temperature in summer. Forty-eight crossbred weanling piglets randomly allocated to four groups were fed for 42 days ad libitum a basal diet without (Con, 0.16 mg Se/kg) and with supplementation of probiotics (P, 0.16 mg Se/kg), sodium selenite (SS, 0.46 mg Se/kg), and SP (0.46 mg Se/kg). From each group, three piglets were randomly selected for blood collection on days 0, 14, 28, and 42 and tissue collection on day 42. The SP improved growth performance of piglets. Both SS and SP increased blood glutathione peroxidase activity and tissue thioredoxin reductase 1 mRNA expression, with SP being higher than SS. All P, SS, and SP supplementation increased the superoxide dismutase activity (40.1, 53.0, and 64.5%), glutathione content (84.6, 104, and 165%), TCR-induced T lymphocyte proliferation (20.8, 26.4, and 50.0%), and IL-2 concentration (24.9, 27.2, and 46.2%) and decreased malondialdehyde content (25.1, 26.3, and 49.3%), respectively. The greatest effects of SP supplementation suggest that SP may serve as a better feed additive than P or SS for piglets under high-temperature environments. PMID- 24814576 TI - McKittrick-Wheelock syndrome may represent the extreme of a normally distributed continuum of secretory activity in colorectal villous adenomas. PMID- 24814577 TI - Verification of reference intervals by the C28 protocol--the alpha error/power trade-off. PMID- 24814578 TI - Telbivudine therapy may shape CD4(+) T-cell response to prevent liver fibrosis in patients with chronic hepatitis B. AB - BACKGROUND & AIMS: Nucleos(t)ide analogues (NAs) can indirectly restore host immunity against hepatitis B virus (HBV) by inhibiting virus replication. We aimed to investigate whether telbivudine could prevent HBV-related fibrosis progression by their influence on CD4(+) T-cell response. METHODS: Thirty-six HBeAg-positive patients with chronic hepatitis B (CHB) were enrolled for 52-week telbivudine monotherapy and were followed at treatment week (TW)-0, 4, 12, 24 and 52. By TW-52, the patients were classified into a complete-response group (CR, n = 10) with both negative HBV-DNA and HBeAg, or a part-response group (PR, n = 11) only with negative DNA, or a non-response group (NR, n = 15) still with positive DNA. The peripheral blood mononuclear cells (PBMCs) were prepared for further flow cytometric and real-time PCR analyses, and also for the in vitro experiments with primary hepatic stellate cells (HSCs). RESULTS: Peripherally, all chronic HBV-infected subjects showed the involvement of CD4(+) T-cell responses, among whom the inactive carriers (IC) had Th1 (CD4(+) IFNgamma(+) ) dominated, CHB had Th17 (CD4(+) IL-17(+) ) dominated, while the immune tolerant (IT) subjects had Treg (CD4(+) CD25(high) Foxp3(+) ) dominated. Besides, we found the therapeutic responses to telbivudine were especially associated with up-regulation of Th1 and Th17, and down-regulation of Treg. Furthermore, compared to CD4(+) cells from CR, those from NR could in vitro significantly exacerbate cell activation, proliferation and cytokine production of HSCs, which were partly mediated by IL-4 and TGF-beta1. CONCLUSIONS: Telbivudine might slow down HBV-related liver fibrosis progression by restoring CD4(+) T-cell responses against HBV. PMID- 24814579 TI - The role of visual representations during the lexical access of spoken words. AB - Do visual representations contribute to spoken word recognition? We examine, using MEG, the effects of sublexical and lexical variables at superior temporal (ST) areas and the posterior middle temporal gyrus (pMTG) compared with that of word imageability at visual cortices. Embodied accounts predict early modulation of visual areas by imageability--concurrently with or prior to modulation of pMTG by lexical variables. Participants responded to speech stimuli varying continuously in imageability during lexical decision with simultaneous MEG recording. We employed the linguistic variables in a new type of correlational time course analysis to assess trial-by-trial activation in occipital, ST, and pMTG regions of interest (ROIs). The linguistic variables modulated the ROIs during different time windows. Critically, visual regions reflected an imageability effect prior to effects of lexicality on pMTG. This surprising effect supports a view on which sensory aspects of a lexical item are not a consequence of lexical activation. PMID- 24814580 TI - Cross-language phonological activation: evidence from masked onset priming and ERPs. AB - The goal of the present research was to provide direct evidence for the cross language interaction of phonologies at the sub-lexical level by using the masked onset priming paradigm. More specifically, we investigated whether there is a cross-language masked onset priming effect (MOPE) with L2 (English) primes and L1 (Russian) targets and whether it is modulated by the orthographic similarity of primes and targets. Primes and targets had onsets that overlapped either only phonologically, only orthographically, both phonologically and orthographically, or did not have any overlap. Phonological overlap, but not orthographic overlap, between primes and targets led to faster naming latencies. In contrast, the ERP data provided evidence for effects of both phonological and orthographic overlap. Finally, the time-course of phonological and orthographic processing for our bilinguals mirrored the time-course previously reported for monolinguals in the ERP data. These results provide evidence for shared representations at the sub lexical level for a bilingual's two languages. PMID- 24814582 TI - Patient education after stoma creation may reduce health-care costs. AB - INTRODUCTION: Researchers are urged to include health-economic assessments when exploring the benefits and drawbacks of a new treatment. The aim of the study was to assess the costs associated with the establishment of a new patient education programme for patients with a stoma. MATERIAL AND METHODS: Following a previous case-control study that explored the effect of patient education for stoma patients, we set out to examine the costs related to such a patient education programme. The primary outcome was disease-specific health-related quality of life measured with the Ostomy Adjustment Scale six months after surgery. The secondary outcome was generic health-related quality of life measured with Short Form (SF)-36. In this secondary analysis, we calculated direct health-care costs for the first six months post-operatively from the perspective of the health-care system, including costs related to the hospital as well as primary health care. RESULTS: The overall cost related to establishing a patient education programme showed no significant increase in the overall average costs. However, we found a significant reduction in costs related to unplanned readmissions (p = 0.01) as well as a reduction in visits to the general practitioner (p = 0.05). CONCLUSION: Establishing a patient education programme - which increased quality of life - will probably not increase the overall costs associated with the patient course. FUNDING: The study received financial support from Soster Inge Marie Dahlgaards Fond, Diakonissestiftelsen, Denmark, and from Aase and Ejnar Danielsens Foundation, Denmark. TRIAL REGISTRATION: NCT01154725. PMID- 24814581 TI - Expression and nuclear translocation of glucocorticoid receptors in type 2 taste receptor cells. AB - Stress increases the secretion of glucocorticoids (GCs), potent steroid hormones that exert their effects on numerous target tissues by acting through glucocorticoid receptors (GRs). GC signaling significantly affects ingestive behavior and taste preferences in humans and rodent models, but far less is known about the hormonal modulation of the peripheral sensory system that detects and assesses nutrient content of foods. A previous study linked restraint stress in rats to diminished expression of mRNA for one subunit of the sweet taste receptor (Tas1r3) in taste tissue and reduced gustatory nerve excitation by sweet compounds. Using RT-PCR, we detected mRNAs for GRalpha in circumvallate taste papillae and in oral epithelium devoid of taste buds ("non-taste" tissue). Further, circumvallate tissue was significantly enriched in GR mRNA compared to non-taste tissue based on quantitative PCR. Histologically, GR protein was expressed in all taste bud populations examined (circumvallate, foliate and fungiform papillae). Using transgenic mice expressing green fluorescent protein, almost all (97%) Tas1r3-positive taste cells (sweet-/umami-sensitive) expressed GR compared to a significantly smaller percentage (89%) of TrpM5-positive taste cells (sweet-, umami- and bitter-sensitive). When mice (n=4) were restrain stressed, GR protein mobilized to the nucleus in Tas1r3-GFP taste cells (1.7-fold over controls). Our results suggest that GR can be activated in taste receptor cells and may play a role in specific taste qualities (e.g., sweet, umami, and bitter) to shape how the taste system responds to stress. PMID- 24814583 TI - Perioperative selective decontamination of the digestive tract and standard antibiotic prophylaxis versus standard antibiotic prophylaxis alone in elective colorectal cancer patients. AB - INTRODUCTION: Infectious complications and especially anastomotic leakage (AL) severely impede the recuperation of patients following colorectal cancer (CRC) surgery. When the normal gut barrier fails, as in AL, pathogenic microorganisms can enter the circulation and may cause severe sepsis which is associated with substantial mortality. Moreover, AL has a negative impact on the CRC prognosis. Selective decontamination of the digestive tract (SDD) employs oral nonabsorbable antibiotics to eradicate pathogenic microorganisms before elective tumour resection. METHODS: In this multicentre randomised clinical trial, perioperative SDD in addition to standard antibiotic prophylaxis is compared with standard antibiotic prophylaxis alone in patients with CRC who undergo elective surgical resection with a curative intent. The SDD regimen consists of colistin, tobramycin and amphotericin B. The primary objectives of this randomised clinical trial are to evaluate if perioperative SDD reduces the incidence of clinical AL and its septic consequences as well as other infectious complications. A main secondary objective is improvement of the cancer-free survival. A total of 762 patients will be included in total for sufficient power. CONCLUSION: It is hypothesised that SDD will reduce clinical AL thereby reducing the morbidity and the mortality in CRC patients. FUNDING: The trial is investigator-initiated, investigator-driven and supported by the Dutch Digestive Foundation (WO 11-06) and the private Posthumus Meyes Fund. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov: NCT01740947. PMID- 24814584 TI - Low incidence of children with acute epiglottis after introduction of vaccination. AB - INTRODUCTION: The aim of this retrospective case series is to describe the epidemiology, symptoms and findings of acute epiglottitis in hospitalized patients after the introduction of the Haemophilus influenzae type B (HIB) vaccine and to identify any symptoms or findings predictive of a prolonged hospital stay. MATERIAL AND METHODS: Medical records on all patients discharged with the International Classification of Diseases 10 diagnostic code DJ051, acute epiglottitis, from January 1997 to December 2012 were reviewed. A total of 41 patients were identified. RESULTS: In all, 37 patients were included, only one of whom was a child. The dominating symptom was a sore throat (97.2%). A hoarse voice was found in 20 patients (58.8%), and 14 patients (40.0%) were drooling. Thirteen patients (36.1%) had trouble breathing. Nine patients (24.3%) were diagnosed with abscess. Two adults tested positive for HIB. The average length of hospitalization was 6.1 days. The average stay in the intensive care unit was 1.2 days for patients who were not intubated and 4.0 days for patients who were intubated or tracheotomised. Six patients (16.2%) were intubated. One patient (2.7%) was directly tracheotomised. CONCLUSION: Our study shows that the incidence of adult acute epiglottis seems to remain unchanged compared with a previous investigation from the same geographical region. The disease is potentially life-threatening, and intubation or tracheostomy was required in 18.9% patients in this study. Respiratory distress had the largest impact on the length of hospitalization. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814585 TI - Onset symptoms in paediatric multiple sclerosis. AB - INTRODUCTION: Paediatric multiple sclerosis (MS) carries a relatively higher mortality and morbidity than adult MS. Paediatric MS symptoms and paraclinical findings at the first demyelinating event have never before been characterised in a Danish setting. The aim of this study was to compare symptoms and paraclinical findings at the first demyelinating event in paediatric MS with those of an adult MS population. MATERIAL AND METHODS: A total of 18 subjects with onset of MS relapse before 16 years of age were retrospectively included in the study. Case records were reviewed for symptoms at disease onset, cerebrospinal fluid findings, magnetic resonance imaging (MRI) and evoked potentials at the first demyelinating event. These data were compared with similar nationwide data from adults in Denmark. RESULTS: The median age was 14 (range 10-15) years at the first demyelinating event and the mean time to MS diagnosis was 1.7 years. The majority of children had sensory symptoms (47%; 95% confidence interval (CI): 23 72%) or optic neuritis (35%; CI: 14-62%) as their presenting symptoms. These results did not differ from the findings in adult MS subjects. Pleocytosis was present in 93% (CI: 66-100%) of paediatric MS subjects, 77% (CI: 46-95%) had an elevated IgG index and 85% (CI: 55-98%) had oligoclonal bands in the cerebrospinal fluid. MRI showed characteristic white matter lesions in all children (CI: 80-100%). CONCLUSION: MS symptoms at the first demyelinating event and diagnostic delay in paediatric MS subjects do not differ significantly from those seen in an adult MS population. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814586 TI - Unemployment under the flex job scheme increases the risk of permanent social security benefits. AB - INTRODUCTION: In Denmark, a flex job scheme was introduced in 1998 in the expectation that more people could remain in the workforce despite a reduced working capacity. The aim of this study was to characterise the group that did not obtain a flex job after having been included in the flex job scheme. MATERIAL AND METHODS: Persons included in the flex job scheme from 1 January 2001 to 30 March 2008 were identified via the Ministry of Employment's DREAM register. Data were linked to Statistics Denmark and The Danish National Patient Registry. Among the individuals who did not obtain employment in a flex job within the first three months, we identified those who did not obtain employment before they were transferred to disability pension or flex benefit. RESULTS: A total of 74,277 persons were included in the flex job scheme. Among these persons 33% received unemployment benefit for more than three months and the rest obtained a flex job within the first three months. Overall, 23% of the unemployment benefit recipients never entered the labour market, but were awarded early retirement pension or flex benefit. This percentage varied among different socio-demographic variables and regions. CONCLUSION: The present study demonstrates that attention should be paid to the flex job scheme, especially for those who do not obtain employment within the first three months. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814587 TI - Implementing video cases in clinical paediatric teaching increases medical students' self-assessed confidence. AB - INTRODUCTION: Use of video cases in clinical education is rarely used systematically. MATERIAL AND METHODS: Medical students (n = 127) reported by questionnaire whether they had or had not seen a bedside case of each of 22 specific clinical conditions during their five-week clinical course in paediatrics in seven centres. A video case library showing children with common clinical conditions was established, and a short video was added to the oral examination. We evaluated students' and internal and external examiners' perceptions by questionnaires. RESULTS: A total of 81% of the students reported having seen a child with asthma in the daily clinic. In contrast, respiratory syncytial virus infection was only seen by 20%. Students' self-reported confidence in the assessment of paediatric patients increased after the video case library was made available: Before the intervention, 41% (57/138) of the students reported confidence at a score of 5-7 on a seven-point Likert scale. This increased to 64% (186/289) (p < 0.0001) after the introduction of the video case library. Before, 84% (116/138) of the students judged the impact of video cases to be high (score 5-7 on a seven-point Likert scale) and after the intervention, this share was 75% (218/289) (p = 0.06). Furthermore, internal as well as external examiners found video cases valuable, but the use of videos did not change the average examination grade. CONCLUSION: A video case supplement to teaching in clinical paediatrics was considered to be of value for teaching. We were successful in establishing an educational resource that students considered useful. Internal and external examiners found that a short video case was a valuable supplementary tool during the oral examination. FUNDING: The University of Copenhagen funded the study. TRIAL REGISTRATION: not relevant. PMID- 24814588 TI - Assessment of palliative need in patients with chronic kidney disease by the new Three Levels of Need Questionnaire (3LNQ) is not exhaustive. AB - INTRODUCTION: The purpose of the study was to test and evaluate the Three Levels of Needs Questionnaire (3LNQ) as a method to clarify if help is needed and provided for 12 palliative problems in patients with chronic kidney disease stage 4 (CKD4). MATERIAL AND METHODS: A total of 33 patients from a consecutive sample of patients with CKD4 were given two questionnaires. The 3LNQ measures problem intensity and unmet needs for 12 palliative problems. An open question was added allowing the patients to describe additional symptoms not included in the 3LNQ. The EuroQol 5-Dimensional 3-Level Questionnaire was distributed in order to determine the patients' health-related quality of life. RESULTS: A total of 27 patients returned the two questionnaires (81.8%). Their average age was 69.3 years (range: 49-82 years). The prevalence of the 12 palliative problems ranged 19-89%, whereas the prevalence of unmet needs ranged 11-44%. The patients reported a median of seven problems and two unmet needs. Besides the 12 problems addressed by the 3LNQ, the following problems were mentioned by the patients: arthritis in the feet, morning cough, muscle cramps/pain, and nightly urination. The patients' mean health-related quality of life score was estimated to 0.791 (interval: 0.564-1). CONCLUSION: The 3LNQ is usable to indicate problem intensity and unmet needs in patients with chronic kidney disease stage 4. However, the questionnaire does not cover all the problems from which patients with chronic kidney disease suffer. Further research into the complexity of need of specialised palliative care for these patients is needed in order to help them optimally. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814589 TI - Validation of the Fatigue Severity Scale in Danish patients with systemic lupus erythematosus. AB - INTRODUCTION: Fatigue is a symptom of systemic lupus erythematosus (SLE), which has a substantial effect on the patients' quality of life and is a parameter that is difficult to quantify. The Fatigue Severity Scale (FSS) is a validated and reliable tool for quantifying fatigue. However, no Danish translation has yet been developed or validated. The aim of this study was to translate the FSS from English into Danish and subsequently to test and describe its validity and reliability in Danish SLE patients. MATERIAL AND METHODS: The FSS was translated from English into Danish and then back-translated. The translation agreed upon by medical professionals was tested for construct validity in an unselected group of SLE patients. The final version was tested for content validity, internal consistency and test-retest reliability in a second unselected group of SLE patients using the Danish version of the Short-Form Health Survey (SF-36). All patients included were outpatients with SLE of low to moderate disease activity, and low to moderate organ damage. RESULTS: Correlations were found between the Danish FSS and the main component scores of the SF-36. We found a high Cronbach's alpha as well as acceptable results of the intraclass correlation coefficient and the Bland-Altman plot. CONCLUSION: The Danish FSS translation is a valid and reliable measure of fatigue in the Danish SLE patients included in this study. FUNDING: Anne Voss reported a grant from The Danish Rheumatism Association (R33 A1836) and grants from The A.P. Moller Foundation for the Advancement of Medical Science and finally grants from the Region of South Denmark during the conduct of the study. TRIAL REGISTRATION: not relevant. PMID- 24814590 TI - Responsiveness of a Danish version of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. AB - INTRODUCTION: This prospective cohort study in consecutive shoulder patients sought to determine the minimal, clinically important difference of the Danish version of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and to evaluate patient responsiveness to it. The study was undertaken at the Outpatient Clinic of the Department of Orthopaedic Surgery, Viborg Regional Hospital, Denmark. MATERIAL AND METHODS: During clinical examination, patients completed a baseline questionnaire including the DASH questionnaire, the EuroQol 5D index and the EuroQol-VAS. A follow-up questionnaire concerning the patient's global impression of change was posted to the patients eight to nine weeks after the initial assessment. Responsiveness was analysed by correlation analysis and receiver-operating characteristic curve statistics. Using the optimal cut-off point of the receiver-operating characteristic curve, the minimal, clinically important difference was determined. RESULTS: A total of 81 patients with a variety of shoulder diagnoses were included. Only the DASH questionnaire demonstrated significant differences in change scores (p = 0.001). The area under the curve was 0.76 (95% confidence interval 0.62-0.90), and a minimal clinically important difference of 12 points was found. CONCLUSION: The DASH questionnaire provides a response outcome measure in Danish-speaking orthopaedic shoulder patients. FUNDING: This work was supported by the Regional Hospital of Central Jutland Research Foundation. TRIAL REGISTRATION: not relevant. PMID- 24814591 TI - General practitioners do not systematically adhere to regional recommendations on treatment of uncomplicated urinary tract infections. AB - INTRODUCTION: Uncomplicated urinary tract infection (uUTI) is a common reason for seeing a GP. In Denmark, it is debated if sulfamethizole or pivmecillinam should be recommended for empirical treatment of uUTIs. We evaluated sulfamethizole and pivmecillinam use in the five Danish regions from 2007 to 2011 and explored if the choice of antibiotic in primary care was in accordance with the regional recommendations for uUTI. MATERIAL AND METHODS: Regional drug use data on pivmecillinam and sulfamethizole from 2007 to 2011 were retrieved from the Registry of Medicinal Product Statistics. Regional recommendations from the same period were identified. We calculated differences in consumption based on defined daily doses per 1,000 inhabitants per day (DID) of pivmecillinam and sulfamethizole between the five regions, and intraregional developments. RESULTS: Four regions had recommendations on uUTI in 2011. From 2007 to 2009, sulfamethizole was the only antibiotic recommended. Pivmecillinam was recommended along with sulfametizole in one of four regions from 2010, which increased to two regions in 2011. During the five-year period, sulfamethizole consumption decreased in all regions. The absolute decrease ranged from 0.4 to 0.6 DID. Pivmecillinam consumption increased steadily; the absolute increase ranged from 1.5 to 2.5 DID. During the whole period, the total pivmecillinam consumption was higher than the total sulfamethizole consumption. CONCLUSION: Pivmecillinam dominated the treatment of uUTIs, whereas sulfamethizole prevailed in the regional recommendations, which suggests a lack of adherence to regional recommendations. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814592 TI - Specific antismoking advice after stroke. AB - INTRODUCTION: Many stroke survivors would benefit from modification of their lifestyle in order to reduce their risk of recurrent stroke. We investigated if tailored smoking cessation advice would yield a higher smoking cessation rate and a higher rate with sustained abstinence in ex-smokers in the intervention group than among controls. MATERIAL AND METHODS: Patients admitted with an acute stroke or a transient ischaemic attack were included in a randomised controlled trial focusing on control of lifestyle risk factors and hypertension. Here, we report the intervention focused on smoking cessation. We used multiple logistic regression analysis to identify patient characteristics associated with smoking cessation. Analyses were by intention to treat excluding those who died or suffered severe disease. RESULTS: We included 254 patients with a history of smoking. Two years after inclusion, 15 of 57 (26%) baseline smokers in the intervention group had stopped smoking versus eight of 56 (14%) among controls (p = 0.112). Living with a partner (p = 0.012), having at least ten years of education (p = 0.012), and not being exposed to smoking at home (p = 0.036) were independent predictors of smoking cessation. CONCLUSION: We did not achieve our aim of higher smoking cessation rates in the intervention group. Future smoking cessation interventions should be more intensive, focus on patients' social circumstances and, if possible, involve patients' relatives. FUNDING: This study was supported by the Ludvig and Sara Elsass Foundation, the Lundbeck Foundation and The Danish Heart Foundation (Grant 07-4-B703-A1378-22384F). TRIAL REGISTRATION: This protocol is registered with Clinical Trials.gov (NCT 00253097). PMID- 24814593 TI - Promising results after balloon dilatation of the Eustachian tube for obstructive dysfunction. AB - INTRODUCTION: As the first ear, nose and throat department in Denmark, we introduced balloon dilatation of the Eustachian tube as a treatment of obstructive dysfunction in the summer of 2012. We present our preliminary experiences with this new treatment in adults. MATERIAL AND METHODS: Preoperatively, several different tests were performed including otomicroscopy, audiometry, tympanometry and Toynbee's test. The patients were classified as Class 1 (if they could make a pressure equalisation of the middle ear by a normal Valsalva's test), Class 2 (if they needed an extended Valsalva's test), Class 3 (if only a test with the Otovent could make air flow to the middle ear), and Class 4 (if no passage of the Eustachian tube could be achieved). Furthermore, the patients filled out questionnaires using a visual analogue scale (VAS). RESULTS: A total of 50 treatments were performed in 34 patients (16 patients had bilateral problems). Four patients (six Eustachian tubes) had intermittent problems, while 30 patients had chronic dysfunction. A significant effect of the treatment was documented when measuring both audiometry, tympanometry, Toynbee's test, classification of Eustachian tube dysfunction and VAS questionnaires. Some patients (e.g. patients with atelectatic ear drums) were not helped by the treatment. Among the first 40 treatments, 10% were observed to have acute otitis media post-operatively. DISCUSSION: The majority of the patients experienced a positive effect of the treatment. Our results are comparable to those of other similar studies. We regard this new treatment as very promising, but look forward to more research. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814594 TI - Danish experiences with FOLFIRINOX as first-line therapy in patients with inoperable pancreatic cancer. AB - INTRODUCTION: Worldwide, pancreatic cancer (PC) ranks 13th in cancer incidence, but eighth as a cause of cancer death. For more than a decade, the reference regimen for palliative treatment of PC has been gemcitabine. In 2011, a randomised trial published by the PRODRIGE Intergroup showed an increase in median overall survival from 6.8 to 11.1 months in patients treated with FOLFIRINOX as compared with gemcitabine. MATERIAL AND METHODS: A total of 16 patients treated with FOLFIRINOX as first-line therapy for inoperable PC were included for this retrospective study. FOLFIRINOX was administered unmodified according to the PRODRIGE trial, and up to 12 cycles were planned with a computed tomography (CT) for every fourth cycle. RESULTS: Eleven patients completing at least four cycles of chemotherapy and therefore evaluable for response were assessed by review of CT. Partial response (PR) was shown after four cycles in four patients, whereas seven patients had stable disease, which resulted in an objective response rate of 36%. After eight cycles, one additional patient obtained a PR. No complete responders or patients with progressive disease were recorded. Toxicity was assessed by review of medical records with respect to toxic effects requiring interruption of therapy, admission of the patient or prolonged admission. CONCLUSION: Toxicity was shown to be a problem only during the first five cycles, and no patients were admitted to hospital due to toxicity after having received more than five cycles. The six-month-survival was 81%. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814595 TI - Prognosis and risk factors for intrauterine growth retardation. AB - INTRODUCTION: Intrauterine growth retardation (IUGR) is the term describing a foetus that has not reached its genetic growth potential. There is no international consensus on the definition of IUGR. The aim of this study was to describe a cohort of weight-restricted neonates and their mothers focusing on risk factors, catch up and neonatal outcome. MATERIAL AND METHODS: This was a retrospective descriptive study of IUGR neonates with a birth weight below 70% of the expected whose mothers were admitted to the Neonatal Ward at Hvidovre Hospital during 2007-2009. Obstetrical and maternal risk factors and neonatal growth and outcome at six weeks, five months and 12 months of age were collected. RESULTS: A total of 73 neonates and their mothers were included. Caesarean delivery was given in 78% of the cases. Maternal risk factors included gestational hypertension (33%), smoking (24%) and placental infarction (17%). Hypoglycaemic episodes developed in 31% of the neonates. At 12 months, 90% had caught up growth and 7% had a neurologically poor outcome. No infants died. CONCLUSION: Maternal smoking and gestational hypertension are important risk factors for the development of IUGR. Special attention must be given to reducing the risk of hypoglycaemia. More studies are needed. Our purpose was to underline the need for a consensus on the definition of IUGR, catch-up and follow-up programmes in order to compare results in the future. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814596 TI - Patients referred with type 2 diabetes remain in specialist care for a long period. AB - INTRODUCTION: Patients with uncomplicated type 2 diabetes are usually managed in general practice. The aim of this study was to describe the duration of contact for patients referred from primary care to a diabetes outpatient clinic. MATERIAL AND METHODS: The present study is a retrospective study with follow-up of at least 12 months or until discharged. Risk stratification was performed at referral and when patients were returned to primary care. A total of 154 patients with type 2 diabetes were referred to the clinic in the 2004-2009 period. The main outcome measure was the duration of contact with the diabetes clinic. RESULTS: In all, 105 patients were returned to primary care after a median of ten months (range 1-64 months) and six visits (1-25 visits). Half of the patients were returned to primary care after 18 months, and 20% were still in contact with the diabetes clinic after six years. The majority were classified as high-risk patients with no difference in risk level between patients followed <= 12 or > 12 months. CONCLUSION: The complication level was high even among discharged patients. The long duration of the contact for the patients who were returned to primary health care should stimulate initiatives leading to a faster course in the secondary care setting. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814597 TI - Contributions to the understanding of gait control. AB - This thesis is based on ten published articles. The experimental work was carried out at the Faculty of Health Sciences, University of Copenhagen. The aim was to investigate and describe a number of basic mechanical and physiological mechanisms behind human walking. The methodologies used were biomechanical movement analysis and electrophysiology. The walking experiments were carried out in a gait lab, where the subjects were video recorded while they walked across two force platforms, which measured the ground reaction forces. Net joint moments about the hip-, knee- and ankle joint were calculated by combining the movement data and the external reaction forces (inverse dynamics). Muscle activity and sensory input to the spinal cord were measured by electromyography (EMG) and electrical stimulation of peripheral nerves. The results showed that the gait pattern varies to a great degree between individuals. Some people choose to exert the highest forces about the ankle joint while others prefer to use the knee joint. By use of a cluster analysis, fifteen healthy subjects could be divided into two groups. The extensor moment about the knee joint was the main factor for separating the two gait patterns, but the group with the highest extensor moments about the knee joint also walked with more flexed knee joints, higher EMG activity in the quadriceps muscle and higher bone-on-bone forces. This may lead to development of osteoarthritis over the years. Walking on high-heeled shoes reduced the ankle joint moment significantly either because of reduced muscle fiber length and/or increased co-contraction about the joint. On the contrary, the extensor moment about the knee joint was almost doubled in the high-heeled condition compared to bare footed walking at the same velocity. Also the EMG activity increased in the leg muscles. This could be an explanation pertaining to the higher incidence of osteoarthritis in women than in men. Patients with a drop foot cannot put the foot to the ground with the heel first. Moreover, they have to increase flexion of the hip joint during the swing phase because the foot hangs in a plantar flexed position. It was shown that the ankle joint plantar flexor moment increased in the healthy leg and that the knee joint extensor moment increased significantly in both the affected and the healthy leg. The latter is most likely due to the patients trying to avoid an asymmetrical gait pattern. It is recommended to use an orthosis with drop-foot patients in order to keep the ankle joint dorsiflexed prior to touchdown, otherwise bone-on-bone forces in both knee joints will increase and probably lead to osteoarthritis. The hip joint moment varies less between individuals. However, both during walking and running an unexplained hip joint flexor moment is present during the last half of the stance phase. The moment appears to oppose the speed of progression and it has been suggested that it serves to balance the upper body. This was investigated in a group of healthy subjects who were asked to walk with their upper body in a reclined, inclined and normal position, respectively. It was shown that the hip joint flexor moment was similar in the reclined and the normal position but lower when walking in the inclined position and it can be concluded that the upper body is not balanced by hip joint flexor muscles but rather by accelerations of the pelvis and activity in abdominal and back muscles. These experiments also showed that the trailing leg is brought forward during the swing phase without activity in the flexor muscles about the hip joint. This was verified by the absence of EMG activity in the iliacus muscle measured by intramuscular wire electrodes. Instead the strong ligaments restricting hip joint extension are stretched during the first half of the swing phase thereby storing elastic energy, which is released during the last half of the stance phase and accelerating the leg into the swing phase. This is considered an important energy conserving feature of human walking. The gating of sensory input to the spinal cord during walking and running was investigated by use of the Hoffmann (H) reflex in m. soleus and m. gastrocnemius medialis. This reflex expresses the central component of the stretch reflex, i.e. the transmission from Ia afferents to alpha-motoneurones in the spinal cord. The soleus H-reflex was shown to be strongly modulated during the gait cycle. In general, it was facilitated in the stance phase and suppressed in the swing phase. However, as it was the case with the biomechanical parameters, inter-individual H-reflex modulations were found and they were highly reproducible between days. One group of subjects had an almost completely suppressed H-reflex during the entire swing phase, while another group showed a gradually increasing reflex excitability during the swing phase. This group also walked with a lower extensor moment about the knee joint and higher plantar flexor moment about the ankle joint and it is speculated that this gait pattern highly relies on reflexes to deal with unexpected perturbations. The subjects with the suppressed reflex during the swing phase also showed a higher EMG activity in the anterior tibial muscle, so it is likely that the suppression of the H-reflex was at least partly due to reciprocal antagonist inhibition. All subjects showed complete suppression of the H-reflex at toeoff. This seems necessary to avoid a stretch reflex being elicited in the soleus muscle as the ankle joint undergoes a fast dorsiflexion just after toeoff. The reflex modulation is clearly an integrated part of the human gait pattern and is absolutely necessary for normal gait function with smoothe movements. Furthermore, it is anticipated that the afferent input from the muscle spindles is used to drive the motor output from the alpha-motoneurones together with descending activity from the motor cortex. During running the H-reflex increased in both the soleus and the gastrocnemius already before heel strike and before the onset of EMG activity in the same two muscles and with a relatively high activity in the anterior tibial muscle, but this was most pronounced in the soleus. The H-reflex was always higher in the soleus also when expressed as percentage of the maximal M-wave. This is due to the difference in muscle fiber type distribution between the two muscles. The H-reflex increased from walking to running in both muscles and further with increasing running speed. Unexpectedly, there were no signs of the faster gastrocnemius becoming more important at higher running speed. During walking it is not possible to observe a stretch reflex in the form of a synchronized activation of a large number of muscle fibers as this would disturb the movement pattern. It is rather likely that the input from Ia afferents directly contributes to activate the alpha-motoneurones. However, during running the stance phase is much shorter, which enables the possibility of a stretch reflex to contribute to a strong contraction during push-off. EMG peaks in the soleus with an appropriate latency were observed in the soleus during running. This was not the case with the gastrocnemius and the explanation is most likely that the gastrocnemius is biarticular and not stretched to any great extent during running. PMID- 24814598 TI - Fatigue and acute/chronic anaemia. AB - Fatigue in patients with gastrointestinal (GI) diseases can be caused by several conditions and anaemia is one of them. Anaemia can be caused by acute GI bleeding, or it can appear in relation to more chronic conditions: iron deficiency anaemia (IDA) and/or anaemia of chronic disease (ACD). Acute anaemia due to acute upper GI bleedings (AUGIB) is often treated with blood transfusions and/or oral iron supplementations. The need for blood transfusions prior to endoscopic intervention has been well described in guidelines. However, guidelines for the monitoring and treatment of anaemia in patients after nonvariceal AUGIB are generally lacking. A retrospective study showed that more than 80% of patients were discharged from hospital with anaemia and less than 20% of them were recommended iron supplementations. Chronic anaemia in inflammatory bowel diseases (IBD) is well known. Anaemia can be caused by deficiency conditions (iron, folic acid or vitamin B12); chronic bleeding; inflammation or medication (or a combination of these). Fatigue in IBD is found in 40% of IBD patients, even with disease in remission. The PhD dissertation is based on two studies. 1. A randomised placebo controlled trial where patients were allocated to iron supplementation (oral or intravenous) or placebo. Patients with nonvariceal AUGIB and anaemia were included in the study (N = 97). The primary follow-up time was 13 weeks, followed by additional three months follow-up. 2. A cross-sectional study including Scandinavian outpatients with IBD. Five hospitals in Denmark, Norway and Sweden included consecutively 5% of their cohort of patients with IBD (N = 429). The aims were: 1. To investigate the effect of iron supplementation in patients who had anaemia after endoscopic intervention for AUGIB. Furthermore, to investigate the health-related quality of life (HRQoL) and fatigue in these patients. 2. To determine the prevalence and type of anaemia, iron deficiency (ID) and fatigue in an unselected group of Scandinavian IBD outpatients. RESULTS: 1. Using haemoglobin (Hb) as a marker, the results of the intervention study on anaemic AUGIB patients showed that iron supplementations were superior to no treatment and intravenous iron was more effective to fill the patients iron stores than was oral iron. No differences in the Hb levels were found between the oral and intravenous iron groups after 13 weeks. Data on HRQoL and fatigue showed in general an improvement during the follow-up period. The improvement was not solely linked to treatment of anaemia. 2. The overall prevalence of anaemia in the Scandinavian population of IBD outpatients was 19%. Most patients had both IDA and ACD. The prevalence of ID was 35%. Fatigue was found in 44% of patients, and the physical dimensions of fatigue were the most marked. Anaemia and/or ID were not associated with increased fatigue. CONCLUSIONS: 1. Treatment with iron supplementations of post-discharge anaemia after AUGIB had significant effect on Hb levels. Intravenous iron supplementation should be chosen if adherence to treatment is essential. The patients' HRQoL was not affected by anaemia. 2. Anaemia in IBD outpatients was present in one of five patients and only 20% had pure IDA. The remains had pure "ACD" or a combination between ACD and IDA. Fatigue was present in nearly half of the patients and was not associated with anaemia, but was related to gender and age. Physical fatigue was the most affected dimension of fatigue. PMID- 24814599 TI - Characterization of the vaginal microflora in health and disease. AB - BACKGROUND: Bacterial vaginosis (BV) is an imbalance of the vaginal bacterial microbiota and its aetiology is still unknown. Our aims were to investigate the diagnostic potential of species/genus specific quantitative PCR (qPCR) for bacteria present in swabs and first-void urine (FVU) samples using Nugent's and Claeys' criteria and 454 sequencing of the vaginal microbiome as reference. METHODS: Self-collected swabs, vaginal smears and FVU were obtained from 177 women from Greenland (Study I and III) and physician-collected vaginal swabs and smears were obtained from 163 Swedish women (Study II). BV was diagnosed by Nugent's criteria in Study I and III and by Amsel's criteria in Study II. The vaginal swabs and FVU samples were analysed by qPCR for selected vaginal bacteria in all three studies and for four sexually transmitted infections (STIs) in Study I. RESULTS: Study I: STIs were common in women from Greenland and BV was found in 45% of these women but was not associated with individual STIs. In multivariate logistic analysis, Atopobium vaginae and Prevotella spp. were both independently associated with BV in swabs. BV could be subdivided into clusters dominated by a single or a few species together. Seven vaginal bacteria (A. vaginae, Prevotella spp. Gardnerella vaginalis, Bacterial vaginosis associated bacterium (BVAB) 2, Eggerthella-like bacterium, Leptotrichia amnionii and Megasphaera type 1) had areas under the receiver operating characteristic (ROC) curve > 85% in swabs, suggesting that they were good predictors of BV according to Nugent. Study II: For the majority of species/genera, the kappa values indicated fair to good agreement when their presence was determined by 454 pyrosequencing versus real time PCR. The same seven vaginal bacteria as found in Study I, had areas under the ROC-curve > 85% in swabs from Swedish women, demonstrating a good diagnostic accuracy for BV according to Amsel. Study III: In a multivariate model, Megasphaera type 1 and Prevotella spp. remained significantly associated with BV in FVU samples. A linear regression analysis showed good agreement between bacterial load from swabs and FVU, but Prevotella spp. could be detected in high numbers in a few FVU samples without being present in swabs. After applying ROC curve analysis, the same seven vaginal bacteria as previously mentioned showed good prediction for BV according to Nugent in FVU. BV could be detected with comparable sensitivity in FVU and vaginal swabs. CONCLUSION: BV can be diagnosed by molecular methods performed either on swabs or urine but it is important to apply thresholds in order to improve the accuracy of the diagnosis. Furthers it was possible to identify clusters of BV dominated by single or paired bacteria, and these clusters could classify BV into subgroups, providing a more detailed understanding of the condition. Seven vaginal bacteria were highly accurate for BV diagnosis both in swabs and FVU. Finally a good agreement between Nugent and Claeys was found. PMID- 24814600 TI - Results of total joint arthroplasty and joint preserving surgery in younger patients evaluated by alternative outcome measures. AB - BACKGROUND: Knee and hip OA is the clinical and pathological outcome of a functional and structural failure of the joint, resulting in pain and physical dysfunction. Despite the similarity in clinical presentation the pathogenesis seems to differ. Where knee OA is associated with obesity and trauma, hip OA is associated with FAI covering three fundamentally different hip deformities, including acetabular dysplasia; all hypothesized to initiates OA development. Where PAO is used worldwide as a joint-preserving procedure in acetabular dysplasia, TKA and THA are the treatment of choice of end stage OA. Traditional main outcomes are clinically objective surgeon-reported endpoints. Patient perceived outcomes are known to differ from these and PROMs are now recommended as the core set of outcomes. When evaluating the outcome in younger patients, this high demanding group can show ceiling-effects of the scores. The overall aim of this thesis was to investigate the consequences of PAO, TKA, and THA in younger patients evaluated by alternative outcomes in relation to satisfaction, fulfillment of expectations, symptoms of depression, the socioeconomic effects, and abilities in sex-life; to improve patient information prior to PAO, TKA and THA surgery. MATERIAL AND METHODS: This PhD thesis is based on three studies. Study I is a cross-sectional survey of preserved hip joints with a mean follow-up of ten years after PAO. One hundred patients (121 PAO's) were eligible for inclusion. An inquiry to the National Patient registry identified 36 of PAO's (in 35 patients) being converted to THA. The 61 remaining patients (80 preserved hip joints) were asked to participate in this questionnaire based follow-up. Fifty five patients (70 preserved hip-joints) accepted and constituted the study population. All patients received a questionnaire concerning aspects of functional ability, patient satisfaction, expectations, and quality of life following PAO. Both Study II and Study III are prospective multicenter cohort studies. Consecutive patients less than 60 years of age scheduled for (study II) unilateral or bilateral simultaneous primary TKA or (study III) scheduled for unilateral or bilateral simultaneous primary THA or HR were eligible for inclusion. Study II consisted of 115 primary TKA patients; 103 unilateral and 12 simultaneous, and Study III consisted of 136 primary THA patients; 86 unilateral THA, six simultaneous bilateral THA, and 44 HR. The study groups received a paper format questionnaire within one month before surgery and at three, six, and 12 months postoperatively. RESULTS: Study I showed a high willingness to undergo PAO again with the experience and knowledge they have today and improvements were seen in all quality of life parameters except for ability in sex-life for males. Study II showed significantly improvements in joint function and HRQoL. Satisfaction and fulfillment of expectations do, however, not fully mirror the observed significant improvements in knee function and HRQoL. Patients with a depression preoperatively experience an inferior result evaluated by OKS and SF 36 PCS and MCS, but not concerning satisfaction, work-life, income or sex-life. In general TKA surgery in younger patients cannot be expected to change relation to work or annual income. Patients stay sexually active after TKA, but a decrease in frequency and a negative affection of sexual practice should be expected. Study III showed significantly improvements in joint function and HRQoL and a high degree of satisfaction and fulfillment of expectations. Only patients with major complications were not willing to repeat. THA surgery in younger patients cannot be expected to change the patient's relation to work or annual income. Patients stay sexually active after THA, and female patients experiences positive changes. CONCLUSION: Based on the findings in this thesis PAO patients are satisfied with the outcome at medium to long-term follow-up, and lasting improvements is seen in the patients' sex life, ability to do sports, and social life. TKA and THA are reliable surgical procedures in younger patients. In addition to significantly improving joint function and HRQoL, patients' stay employed and sexually active postoperatively. However, a decrease in frequency of sexual activities and negative affection of sexual practice patterns should be anticipated following TKA surgery, THA surgery have a positive influence on female THA patients sex-life. PMID- 24814601 TI - Achilles tendon rupture; assessment of nonoperative treatment. AB - BACKGROUND: Acute Achilles tendon rupture is a frequent and potentially disabling injury. Over the past decade a change in treatment of acute Achilles tendon rupture away from operative towards non-operative treatment has taken place. However, the optimal non-operative treatment protocol remains to be clarified, particularly the role of weight-bearing during early rehabilitation. Also, there is a need for a clinically applicable and accurate measurement to detect patients in risk of developing Achilles tendon elongation. PURPOSE: The aim of this PhD thesis was to evaluate non-operative treatment of acute Achilles tendon rupture. METHODS: In study I, a cross-sectional survey was performed investigating the chosen treatment protocols across Scandinavia. In study II, the effect of immediate weight-bearing on patient reported and functional outcomes was investigated in a randomized controlled trial (RCT). In study III, the effect of immediate weight-bearing on the biomechanical properties of the plantar flexor muscle-tendon complex was investigated in an RCT. In study IV, validity, reliability and agreement of a novel ultrasound measurement of Achilles tendon length and elongation was tested. RESULTS: Study I found surgery to be the preferred treatment in 83% of departments in Denmark, 92% in Norway, 65% in Sweden, and 30% in Finland (p < 0.001). Study II and III showed no statistically significant effects of controlled early weight-bearing at one year follow-up except from a better health-related quality of life in the weight-bearing group (p=0.009). Compared to the unaffected limb, the affected limb had decreased stiffness (77%, p < 0.001) and strength (93%, p = 0.009) of the plantar flexor muscle-tendon complex. Study IV showed excellent intra-rater reliability (ICC 0.96, SEM 3.7 mm and MDC 10.3 mm), inter-rater reliability (ICC 0.97, SEM 3.3 mm and MDC 9.3 mm) and validity (measurement error 2%). CONCLUSION: Treatment algorithms across Scandinavia showed considerable variation, though operative treatment and controlled early weight-bearing was the preferred treatment in Denmark, Norway and Sweden. Immediate weight-bearing was found to be safe and recommendable in non-operative treatment of acute Achilles tendon rupture. The novel ultrasound measurement showed excellent reliability and acceptable validity and agreement. PMID- 24814602 TI - Factors associated with resolution and progression of HIV/hepatitis C virus infection. AB - Coinfection with hepatitis C virus (HCV) is common in human immunodeficiency virus (HIV)-infected individuals as a result of shared routes of transmission, and this coinfection represents a special challenge. For HIV-HCV-coinfected individuals, the burden of disease is largely related to their HCV diseases, including a faster progression to liver fibrosis, cirrhosis and liver-related deaths. In the present thesis we investigated factors associated with spontaneous resolution and progression of HIV-HCV coinfection. In study I, we identified the study cohort of 327 individuals with HIV-HCV coinfection and a rate of spontaneous HCV resolution of 23%. We showed that female sex, coinfection with hepatitis B virus and individuals exposed through injecting drug use (IDU) or homosexual contact (MSM) had an increased rate of spontaneous HCV resolution. We speculate that differences in resolution rate may be caused by immunological memory induced by repeatedly being exposed to low-dose inoculum of HCV. In study II, we found three single-nucleotide-polymorphisms (SNPs) in the interleukin 28B (IL28B) gene associated with spontaneous HCV resolution in 208 Europeans of Caucasian origin with HIV-HCV coinfection. Further, we showed that the IL28B CC genotype favourable of HCV resolution was associated with a higher HCV viral load (VL) than non-CC genotypes. These results may indicate an influence of IL28B in viral control. In study III, we conducted a survival analysis in the 264 HIV-HCV coinfected individuals with chronic infection. We showed in a time-updated Poisson regression that HCV VL, HCV genotype 3 and IL28B CC genotype were predictors of increased mortality. This may indicate a need for closer observation in HIV-HCV-coinfected individuals with HCV genotype 3 and maybe even initiation of antiviral therapy. PMID- 24814603 TI - Danish guidelines for lipid-lowering treatment in patients with chronic renal failure. AB - Measurement of lipid profile in adults with CKD 1-5: We recommend measuring the lipid profile (T cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) in all adults with newly diagnosed CKD 1-5 (including patients in renal replacement therapy). Monitoring of lipid profile in adults with CKD 1-5: In many cases it is not necessary to regularly monitor the lipid profile. Patients >= 50 years with CKD 1-5 ND: We recommend that these patients be treated with a statin (CKD 1-2, evidence level B), and in CKD patients in stages 3-5 ND that a statin or the combination statin/ezetimibe be used (evidence level A). Patients aged 18 49 years with CKD 1-5 ND: We suggest treating these patients with a statin if they also have one or more of the following conditions (evidence level A): known CVD, DM, Prior ischaemic stroke, Estimated 10-year risk of coronary death or non fatal AMI > 10 % or risk of fatal cardiovascular disease > 5% (SCORE). Patients with CKD stage 5D: We suggest that these patients not be given a statin or started on statin/ezetimibe treatment (evidence level A). Patients who start dialysis and are already being treated with a statin or statin/ezetimibe: We suggest that treatment be continued (evidence level C). Adult kidney transplanted patients: We suggest that these patients be treated with a statin (evidence level B). PMID- 24814604 TI - Adverse signaling of scavenger receptor class B1 and PGC1s in alcoholic hepatosteatosis and steatohepatitis and protection by betaine in rat. AB - Because scavenger receptor class B type 1 is the cholesterol uptake liver receptor, whereas peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta) and PGC-1alpha are critical for lipid synthesis and degradation, we investigated the roles of these signaling molecules in the actions of ethanol-polyunsaturated fatty acids and betaine on hepatosteatosis and steatohepatitis. Ethanol-polyunsaturated fatty acid treatment caused the following: i) hepatosteatosis, as evidenced by increased liver cholesterol and triglycerides, lipid score, and decreased serum adiponectin; ii) marked inhibition of scavenger receptor class B type 1 glycosylation, its plasma membrane localization, and its hepatic cholesterol uptake function; and iii) moderate steatohepatitis, as evidenced by histopathological characteristics, increased liver tumor necrosis factor alpha and IL-6, decreased glutathione, and elevated serum alanine aminotransferase. These actions of ethanol involved up regulated PGC-1beta, sterol regulatory element-binding proteins 1c and 2, acetyl CoA carboxylase, and HMG-CoA reductase mRNAs/proteins and inactive non phosphorylated AMP kinase; and down-regulated silence regulator gene 1 and PGC 1alpha mRNA/proteins and hepatic fatty acid oxidation. Betaine markedly blunted all these actions of ethanol on hepatosteatosis and steatohepatitis. Therefore, we conclude that ethanol-mediated impaired post-translational modification, trafficking, and function of scavenger receptor class B type 1 may account for alcoholic hyperlipidemia. Up-regulation of PGC-1beta and lipid synthetic genes and down-regulation of silence regulator gene 1, PGC-1alpha, adiponectin, and lipid degradation genes account for alcoholic hepatosteatosis. Induction of proinflammatory cytokines and depletion of endogenous antioxidant, glutathione, account for alcoholic steatohepatitis. We suggest betaine as a potential therapeutic agent because it effectively protects against adverse actions of ethanol. PMID- 24814606 TI - Orthotopic animal model of pseudomyxoma peritonei: An in vivo model to test anti angiogenic drug effects. AB - Pseudomyxoma peritonei (PMP) is an uncommon peritoneal mucinous carcinomatosis confined to the peritoneal cavity. The rarity of PMP in humans makes evaluation of the disease biological features and new therapeutic strategies difficult. Accordingly, there is a need for animal models of PMP. Human PMP tissue was i.p. grafted and grown into nude mice, then constituted into reliable and reproducible orthotopic models. Histological and immunostaining analysis was performed. Bevacizumab was injected twice a week either during tumor growth or after cytoreductive surgery. In vivo imaging of tumor angiogenesis was performed using barium sulfate or isolectin microangiography and Doppler ultrasonography of the superior mesenteric artery. Tumor angiogenesis was confirmed by the presence of tortuous vascular networks with high levels of expression of CD31, vascular endothelial cadherin, and desmin. Doppler ultrasonography of the superior mesenteric artery revealed a twofold increase in blood flow velocity compared with tumor-free mice (P < 0.001). Bevacizumab administration was correlated with the normalization of tumor vascularity when injected during tumor growth and with the stabilization of the histological and hemodynamic findings when injected after cytoreductive surgery. Our PMP models mimic human PMP. Our results confirmed the presence of tumor angiogenesis related to PMP growth. Our murine model allows researchers to actually bench test and evaluate, in preclinical studies, the efficacy of new therapeutic strategies and anti-angiogenic therapies. PMID- 24814605 TI - Matrix metalloproteinase-9-null mice are resistant to TGF-beta-induced anterior subcapsular cataract formation. AB - Epithelial-mesenchymal transition (EMT) is associated with fibrotic diseases in the lens, such as anterior subcapsular cataract (ASC) formation. Often mediated by transforming growth factor (TGF)-beta, EMT in the lens involves the transformation of lens epithelial cells into a multilayering of myofibroblasts, which manifest as plaques beneath the lens capsule. TGF-beta-induced EMT and ASC have been associated with the up-regulation of two matrix metalloproteinases (MMPs): MMP-2 and MMP-9. The current study used MMP-2 and MMP-9 knockout (KO) mice to further determine their unique roles in TGF-beta-induced ASC formation. Adenoviral injection of active TGF-beta1 into the anterior chamber of all wild type and MMP-2 KO mice led to the formation of distinct ASC plaques that were positive for alpha-smooth muscle actin, a marker of EMT. In contrast, only a small proportion of the MMP-9 KO eyes injected with adenovirus-expressing TGF beta1 exhibited ASC plaques. Isolated lens epithelial explants from wild-type and MMP-2 KO mice that were treated with TGF-beta exhibited features indicative of EMT, whereas those from MMP-9 KO mice did not acquire a mesenchymal phenotype. MMP-9 KO mice were further bred onto a TGF-beta1 transgenic mouse line that exhibits severe ASC formation, but shows a resistance to ASC formation in the absence of MMP-9. These findings suggest that MMP-9 expression is more critical than MMP-2 in mediating TGF-beta-induced ASC formation. PMID- 24814608 TI - PIXE as a complement to ICP-OES trace metal analysis in Sudanese medicinal plants. AB - This paper compares trace element concentrations (Ca, K, Sr, Fe, Mn, Zn, Ni, Cu, Co and Cr) in 27 Sudanese medical plants determined in parallel by PIXE and ICP OES to get information on which technique is preferable at different matrices and element concentrations. PIXE correlates well to ICP-OES for Sr, Mn, Ca, K, Zn and Fe determinations. ICP-OES seems to be the superior technique over PIXE when measuring low concentrated elements (chromium, cobalt, nickel and copper) in the medicinal plants. PMID- 24814609 TI - Determination of a CR-39 detector response to neutrons from an Am-Be source. AB - A comparison of experimental and calculated responses of a CR-39 detector to neutron spectra from an Am-Be source is presented. Code named Neutron_CR-39.F90 has been used to calculate the neutron dose equivalent as well as the track density. Conversion coefficient (sensitivity), between track density in track/cm(2) and neutron dose equivalent in mSv, was calculated and good agreement with experimental data was found. Sensitivity increases linearly with removed layer in the range between 6 MUm and 24 MUm. PMID- 24814607 TI - Topiramate for cocaine dependence during methadone maintenance treatment: a randomized controlled trial. AB - BACKGROUND: Dual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a "positive signal" warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94). METHOD: In this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period. RESULTS: There was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups. CONCLUSION: Topiramate is not efficacious for increasing cocaine abstinence in methadone patients. PMID- 24814610 TI - Dose per unit cumulated activity (S-values) for e- and beta emitting radionuclides in cancer cell models calculated by Monte Carlo simulation. AB - Cell dosimetry is relevant regarding new efforts in specific molecular radiotherapy using Auger, CE and beta emitters. Absorbed dose in cells can be obtained by means of the dose per unit cumulated activity (S-values), together with the activity distribution. In this work, Monte Carlo simulation codes PENELOPE and MCNPX were used to obtain cellular S-values for point and extended sources of electrons and beta emitting radionuclides in the nucleus of breast (MDA-MB231, MCF7) and prostate (PC3) cancer cell models. PMID- 24814611 TI - Mesenchymal stromal cells from the human placenta promote neovascularization in a mouse model in vivo. AB - Cell transplantation is a promising strategy in regenerative medicine for revascularization of ischemic tissues. Based on our observation that placental mesenchymal stromal cells (PMSC) enhance endothelial cell viability in vitro via secretion of angiogenic factors, we asked whether PMSC support vascular growth in vivo. PMSC were isolated from amnion and placental endothelial cells (PLEC) from chorion and either separately or co-transplanted subcutaneously into immune deficient mice. Co-transplantation resulted in a higher number of perfused human vessels (CD31+/vimentin+) containing mouse glycophorin A+ erythrocytes. Results indicate positive effects of PMSC on neovascularization in vivo, making them attractive candidates to create autologous PMSC/PLEC pairs for research and transplantation. PMID- 24814612 TI - Urocortin 3 administration impairs fear motivated learning in mice is mediated by transmitters. AB - Urocortin 3 (Ucn 3) was found to impair passive avoidance learning in male and female mice. The possible involvement of transmitters in the action, the animals were pretreated with the following receptor antagonists in doses which alone could not influence the measurement. Haloperidol (a D2, dopamine receptor antagonist), phenoxybenzamine (a nonselective alpha1-adrenergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), bicuculline (a gamma-aminobutyric acid subunit A receptor antagonist), nitro-L-arginine (a nitric oxide synthase inhibitor), antalarmin (a CRF1 receptor antagonist) and astressin 2B (a CRF2 receptor antagonist). Haloperidol, phenoxybenzamine, bicuculline, atropine, nitro-L-arginine and astressin 2B prevented the action of Ucn 3, in both sexes, whereas antalarmin exerted no action in either male or female animals. PMID- 24814613 TI - The effects of neonatal cryoanaesthesia-induced hypothermia on adult emotional behaviour and stress markers in C57BL/6 mice. AB - Since the early 1930s, deep hypothermia (cryoanaesthesia) has been a useful anaesthetic in several types of surgery on neonatal rodents. Especially against the background of modern techniques in systems neuroscience, the method enjoys again increasing popularity. However, little is known about its effects on the subsequent adult behavioural and physiological profile. To systematically investigate the effects of neonatal cryoanaesthesia on adult basal and emotional behaviour as well as on physiological development, 59 C57BL/6 mouse pups were randomly assigned to one of three treatment groups: Pups of the first group were exposed to the hypothermia treatment (H) on postnatal day 3, while pups of the other two groups served as controls: These pups either remained in the home cage without any intervention (C), or were separated from the mother for 15 min (MS) to differentiate between effects of neonatal isolation alone versus hypothermia that inevitably goes along with neonatal isolation. Subsequent behavioural analyses were conducted during adulthood (P 84-P 130), including tests for exploratory, anxiety-like and depression-like behaviour. At the age of about 145 days mice were decapitated to record BDNF levels in the hippocampus and serum corticosterone. Altogether, H mice were found to display slightly increased anxiety levels on the O-Maze, but did not differ from the control animals in any other behavioural test. Subtle alterations in anxiety-like behaviour, however, were not accompanied by physiological changes in serum corticosterone and hippocampal BDNF levels, arguing against an overall long-lasting effect of neonatal hypothermia on the emotional profile of adult mice. PMID- 24814614 TI - Development of Australian clinical practice outcome standards for graduates of critical care nurse education. AB - AIMS AND OBJECTIVES: To develop critical care nurse education practice standards. BACKGROUND: Critical care specialist education for registered nurses in Australia is provided at graduate level. Considerable variation exists across courses with no framework to guide practice outcomes or evidence supporting the level of qualification. DESIGN: An eDelphi technique involved the iterative process of a national expert panel responding to three survey rounds. METHODS: For the first round, 84 statements, organised within six domains, were developed from earlier phases of the study that included a literature review, analysis of critical care courses and input from health consumers. The panel, which represented the perspectives of four stakeholder groups, responded to two rating scales: level of importance and level of practice. RESULTS: Of 105 experts who agreed to participate, 92 (88%) completed survey round I; 85 (92%) round II; and 73 (86%) round III. Of the 98 statements, 75 were rated as having a high level of importance - median 7 (IQR 6-7); 14 were rated as having a moderate level of importance - median 6 (IQR 5-7); and nine were rated as having a low level of importance - median 4 (IQR 4-6)-6 (IQR 4-6). The majority of the panel rated graduate level of practice as 'demonstrates independently' or 'teaches or supervises others' for 80 statements. For 18 statements, there was no category selected by 50% or more of the panel. The process resulted in the development of 98 practice standards, categorised into three levels, indicating a practice outcome level by the practitioner who can independently provide nursing care for a variety of critically ill patients in most contexts, using a patient- and family-focused approach. CONCLUSION/RELEVANCE TO CLINICAL PRACTICE: The graduate practice outcomes provide a critical care qualification definition for nursing workforce standards and can be used by course providers to achieve consistent practice outcomes. PMID- 24814616 TI - Chemotherapy mediates intestinal injury via p53/p53 upregulated modulator of apoptosis (PUMA) signaling pathway. AB - OBJECTIVE: The aim of this study was to investigate the potential mechanism and signaling pathway involved in chemotherapy-induced intestinal mucosal injury (CIMI), which is a common physiopathological problem in patients with cancer. METHODS: For the in vivo experiment, mice received intraperitoneal injection of 5 fluorouracil (5-FU) at a dose of 75 mg/kg/day for 1, 3 or 5 days. Villus height and crypt depth of the small intestine, cell apoptosis and proliferation were then examined to determine the extent of CIMI. The expressions of Akt, p53, PUMA and p21 were evaluated both in vivo in mice models and in vitro in the IEC-6 and HCT116 cell lines. RESULTS: After 5-FU therapy both the intestinal villus height (275.93 MUm vs 164.52 MUm, P < 0.001) and crypt depth (64.13 MUm vs 42.48 MUm, P < 0.001) were decreased. The apoptotic index was greatly increased from 0.32% to 15.84% (P < 0.001) and proliferation was suppressed (63.58% vs 39.15%, P < 0.001). Additionally, p53 expression was significantly increased in the intestinal crypt along with the expressions of PUMA and p21. Western blot showed that the administration of 5-FU induced p53/PUMA-mediated apoptosis and upregulated p21 expression to suppress cell proliferation. CONCLUSION: Chemotherapy might mediate intestinal injury via p53/PUMA-mediated apoptotic signaling and the suppression of proliferation in response to p21. PMID- 24814615 TI - Outcomes of renal transplant in patients with anti-complement factor H antibody associated hemolytic uremic syndrome. AB - Atypical HUS associated with anti-CFH autoantibodies is an uncommon illness associated with high risk of progression to end-stage renal disease. Disease relapses after transplantation, observed in one-third cases, often lead to graft loss. We report four patients with anti-CFH antibody-associated HUS who underwent renal transplantation 16-62 months from initial presentation. Two patients each received organs from deceased and living-related donors. Anti-CFH antibody titers were monitored during the illness and following transplantation. All patients received two doses of IV rituximab before or after transplantation; three patient each received 1-2 g/kg of IV immunoglobulin or underwent 2-5 sessions of plasma exchanges. The use of therapeutic plasma exchange, IV immunoglobulin, and rituximab in two cases enabled two-third reduction in anti-CFH antibody titers before transplantation. At 5- to 26-month follow-up, all patients showed satisfactory graft function without recurrence of HUS. This is the first report of patients with anti-CFH antibody-associated HUS who underwent living-related renal transplantation. Clearance of anti-CFH antibody by therapeutic plasma exchange and adjuvant immunosuppression aimed at decreasing antibody levels may enable successful transplantation and recurrence-free survival. PMID- 24814617 TI - The effect of propofol on intravenous glucose tolerance test in rhesus monkey. AB - BACKGROUND: Many anesthetics have been shown to impair glucose metabolism and cause hyperglycemia. The aim of this study was to evaluate the effects of propofol on glucose metabolism and insulin secretion during intravenous glucose tolerance test (IVGTT) in rhesus monkey. METHODS: Serum cortisol, blood glucose, insulin, and C-peptide concentrations during IVGTT were measured in four rhesus monkeys under either conscious state or propofol anesthesia. RESULTS AND CONCLUSIONS: The levels of serum cortisol significantly increased under conscious condition, whereas these levels remained constant under propofol anesthesia. In propofol group, the levels of serum insulin and C-peptide significantly increased compared with those in conscious group. Accordingly, glucose disposal capacity was significantly improved, and the time to return to basal glucose levels was shortened in propofol group. This study showed that propofol significantly increased insulin and C-peptide, and the corresponding improvement in glucose disposal may be related to reduction of serum cortisol in monkey. PMID- 24814619 TI - Prevention is better than Cure. AB - No abstract available. PMID- 24814618 TI - Deferiprone versus deferoxamine in sickle cell disease: results from a 5-year long-term Italian multi-center randomized clinical trial. AB - Blood transfusion and iron chelation currently represent a supportive therapy to manage anemia, vasculopathy and vaso-occlusion crises in Sickle-Cell-Disease. Here we describe the first 5-year long-term randomized clinical trial comparing Deferiprone versus Deferoxamine in patients with Sickle-Cell-Disease. The results of this study show that Deferiprone has the same effectiveness as Deferoxamine in decreasing body iron burden, measured as repeated measurements of serum ferritin concentrations on the same patient over 5-years and analyzed according to the linear mixed-effects model (LMM) (p=0.822). Both chelators are able to decrease, significantly, serum ferritin concentrations, during 5-years, without any effect on safety (p=0.005). Moreover, although the basal serum ferritin levels were higher in transfused compared with non-transfused group (p=0.031), the changes over time in serum ferritin levels were not statistically significantly different between transfused and non-transfused cohort of patients (p=0.389). Kaplan-Meier curve, during 5-years of study, suggests that Deferiprone does not alter survival in comparison with Deferoxamine (p=0.38). In conclusion, long-term iron chelation therapy with Deferiprone was associated with efficacy and safety similar to that of Deferoxamine. Therefore, in patients with Sickle-Cell-Disease, Deferiprone may represent an effective long-term treatment option. PMID- 24814620 TI - Immunogenicity and Safety of the AS04-adjuvanted Human Papillomavirus-16/18 Cervical Cancer Vaccine in Malaysian Women Aged 18-35 years: A Randomized Controlled Trial. AB - INTRODUCTION: Cervical cancer is the third most common cancer in women worldwide. The HPV-16/18 AS04- adjuvanted vaccine (Cervarix(c)) has previously been shown to be highly immunogenic with a clinically acceptable safety profile. This phase IIIb, double-blind, randomized (1:1) and placebo controlled trial (NCT00345878) was designed to evaluate the vaccine immunogenicity against HPV-16 and HPV-18 as well as its safety and reactogenicity in Malaysian women. METHODS: Healthy women aged 18-35 years received intramuscularly three doses of either the vaccine (HPV group) or aluminium hydroxide (ALU group) at 0, 1, and 6 months. Antibody titers were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 271 eligible subjects were enrolled and 266 subjects completed the study. Initially seronegative subjects in the HPV group showed 100% seroconversion one month post-dose-3 for anti HPV-16 and anti-HPV-18 antibodies with geometric mean titers of 11107.5 (95% CI: 9727.3-12683.4) EL.U/mL and 4273.5 (95% CI: 3771.8 4841.9) EL.U/mL, respectively. Over 96% of subjects in both groups received all three vaccine doses. Solicited local (pain) and general symptoms (myalgia, fatigue, arthralgia and headache) were commonly reported in both HPV and ALU groups. Eight serious adverse events were reported throughout the study (five in the HPV group; three in the ALU group), all considered by investigators to be unrelated to vaccination. CONCLUSION: The HPV-16/18 AS04-adjuvanted vaccine was immunogenic and generally well tolerated in Malaysian women aged 18-35 years. PMID- 24814621 TI - The Prevalence of Sensorineural Hearing Loss in beta-thalassaemia patient treated with Desferrioxamine. AB - OBJECTIVE: This study aimed to evaluate the prevalence of sensorineural hearing loss (SNHL) in beta-thalassaemia patients treated with Desferrioxamine (DFO) and determine the correlation of SNHL with average daily DFO dosage, serum ferritin level and Therapeutic index (T.I). METHODS: This is a cross sectional descriptive study carried out for a period of 14 months and 54 patients were recruited. The recruited patients are transfusion dependant beta- thalassaemia patient aged 3 years and above treated with DFO. An interview, clinical examination and hearing assessment, which included tympanogram, and Pure Tone Audiometry (PTA) or behaviour alaudiometry were performed. The data on age started on DFO, average daily DFO, duration of DFO intake, serum ferritin past 1 year and Therapeutic Index (T.I) were obtained from patients' case notes. RESULTS: The prevalence of SNHL was 57.4% and majority has mild hearing loss (93.6%). Fourteen patients (25.9%) have bilateral ear involvement and as many as 17 patients (31.5%) have SNHL in either ear. A total of 23 patients (42.6%) have normal hearing level. Although the prevalence of SNHL was 57.4%, only a small percentage of the patient noticed and complained of hearing loss (11.1%). There is no association between age started on DFO, average daily DFO and duration of DFO intake with normal hearing group and those patients with SNHL. Positive correlation was seen between average daily DFO with 2000 and 4000Hz on PTA in the left ear and between serum ferritin level past 1 year with 4000 and 8000Hz in the right ear and 8000Hz in the left ear. No significant correlation was seen between T.I on PTA. CONCLUSION: The prevalence of SNHL from hearing assessment is high in beta-thalassaemia patients in this study. However, it is manifested clinically in a smaller percentage. We suggest a baseline hearing assessment should be carried on all beta-thalassaemia patients prior to DFO chelation therapy. PMID- 24814622 TI - Partial Cricotracheal Resection (PCTR), a Rewarding Outcome for Paediatric Subglottic Stenosis: An Early Experience. AB - This is a retrospective study examining the outcome of paediatric patients with subglottic stenosis who underwent partial cricotracheal resection (PCTR) as a primary open procedure from 2004 to 2012. There were 5 patients identified aged from 3 to 18 years old. All the subglottic stenosis were acquired type. All of them were secondary to prolonged intubation. Three patients were classified as Myer-Cotton grade III and the other two were Myer-Cotton grade IV. Two of the patients had concomitant bilateral vocal cord immobility. All patients underwent two staged PCTR . All patients underwent two staged PCTR, and one patient underwent posterior cordectomy apart from partial CTR at different setting. All patients were successfully decannulated at various durations postoperatively. Although this is an early experience in our institution, PCTR has shown to be effective and safe procedure in patients with subglottic stenosis especially those with Myer-Cotton grade III and IV. PMID- 24814623 TI - A Pilot Randomized Control Cross over Study Evaluating the Effectiveness and Safety of Mechanical Percussor Compared with Conventional Chest Physiotherapy in Adults with Productive Cough. AB - INTRODUCTION: Conventional Chest Physiotherapy (CCPT) remains the mainstay of treatment for sputum mobilization in patients with productive cough such as bronchiectasis and "Chronic Obstructive Airway Disease" (COPD). However CCPT is time consuming requires the assistance of a physiotherapist and limits the independence of the patient. Mechanical percussors which are electrical devices used to provide percussion to the external chest wall might provide autonomy and greater compliance. We compared safety and efficacy of a mechanical chest percusser devised by Formedic Technology with conventional chest percussion. METHODS: Twenty patients (mean age 64years) were randomly assigned to receive either CCPT or mechanical percussor on the first day and crossed over by "Latin square randomisation" to alternative treatment for 6 consecutive days and the amount of sputum expectorated was compared by dry and wet weight. Adverse events and willingness to use was assessed by a home diary and a questionnaire. RESULTS: There were 13 males and 7 females, eight diagnosed as bronchiectasis and 12 COPD. The mean dry weight of sputum induced by CCPT (0.54g +/- 0.32) was significantly more compared with MP (0.40g + 0.11); p-value = 0.002. The mean wet weight of sputum with CCPT (10.71g +/- 8.70) was also significantly more compared with MP (5.99g +/- 4.5); p-value < 0.001. There were no significant difference in adverse events and majority of patients were willing to use the device by themselves. CONCLUSION: The mechanical percussor although produces less sputum is well tolerated and can be a useful adjunct to CCPT. PMID- 24814624 TI - Clinical presentation, severity and progression of primary angle closure in malays. AB - INTRODUCTION: There is limited knowledge on primary angle closure (PAC) in Malays. Understanding the clinical presentation and progression of PAC in Malays is important for prevention of blindness in Southeast Asia. MATERIAL AND METHODS: A retrospective record review study was conducted on Malay patients seen in the eye clinic of two tertiary hospitals in Kelantan, Malaysia. Based on the available data, Malay patients re-diagnosed as primary angle closure suspect (PACS), primary angle closure (PAC), and primary angle closure glaucoma (PACG) based on the International Society Geographical Epidemiological classification. Clinical data was collected from initial presentation including the presence of acute primary angle closure until at least 5 years follow up. Progression was defined based on gonioscopic changes, vertical cup to disc ratio (VCDR), intraocular pressure (IOP) and Humphrey visual field (HVF) analysis. Progression and severity of PACG was defined based Hodapp-Parrish-Anderson classification on reliable HVF central 24-2 or 30-2 analysis. RESULTS: A total of 100 patients (200 eyes) with at least 5 years follow up were included. 94 eyes (47%) presented with APAC. During initial presentation, 135 eyes (67.5%) were diagnosed with glaucomatous changes with 91 eyes already blind. After 5 years of follow up, 155 eyes (77.5%) progressed. There was 4 times risk of progression in eyes with PAC (p=0.071) and 16 times risk of progression in PACG (p=0.001). Absence of laser peripheral iridotomy was associated with 10 times the risk of progression. CONCLUSION: Angle closure is common in Malays. Majority presented with optic neuropathy at the initial presentation and progressed further. Preventive measures including promoting public awareness among Malay population is important to prevent blindness. PMID- 24814625 TI - Inherited Anti-Thrombin Deficiency in A Malay-Malaysian Family: A Missense Mutation at Nucleotide g.13267C>A aka anti-thrombin Budapest 5 (p.Pro439Thr) of the SERPINC 1 gene. AB - OBJECTIVE: Inherited anti-thrombin deficiency is an autosomal dominant disorder which is associated with increased risk for venous thromboembolism (VTE). This condition is very rare in Malaysia and there has been no documented report. Thus, the aim of the present study is to investigate the type of an inherited anti thrombin deficiency mutation in a 25-year-old Malay woman who presented with deep vein thrombosis in her first pregnancy. METHODS: DNA was extracted from the patient's blood sample and buccal mucosal swabs from family members. Polymerase chain reaction(PCR) assays were designed to cover all seven exons of the serpin peptidase inhibitor, clade C (antithrombin), member 1 (SERPINC1) gene; and the products were subjected to DNA sequencing. Sequences were referred to NCBI Reference Sequence: NG_012462.1. RESULTS: A heterozygous substitution mutation at nucleotide position 13267 (CCT->ACT) was identified in the patient and two other family members, giving a possible change of codon 439 (Pro->Thr) also known as anti-thrombin Budapest 5. The genotype was absent in 90 healthy controls. CONCLUSION: The study revealed a heterozygous antithrombin Budapest 5 mutation in SERPINC 1 giving rise to a possible anti-thrombin deficiency in a Malay-Malaysian family. PMID- 24814626 TI - Hyperplastic gastric polyps in an infant, mimicking infantile hypertrophic pyloric stenosis - a case report and review of the literature. AB - No abstract available. PMID- 24814627 TI - Psychosis induced by cefuroxime and metronidazole. AB - We report a case 35-year-old lady who developed acute psychosis following administration of cefuroxime and metronidazole. Earliest mood changes occurred on the second day of antibiotics therapy. She developed hallucinations, delusions and bizarre behavior 1 day after the completion of the antibiotic therapy. All the relevant investigations including CT brain were normal. The psychosis resolved completely within 5 days of antipsychotic treatment. PMID- 24814628 TI - Maternal Mortality Review: A Case of Pulmonary Haemorrhage Due to Ruptured Lung Haemangioma Secondary to Ghon's Focus Invasion. AB - Haemangioma can be present in the lung but rarely causes complications unless there is a bleed. Ghon's focus is a result of post primary tuberculosis. It is a caseating granuloma which invades the surrounding tissue. It is usually benign and may resolve spontaneously without causing complications or active tuberculosis. This case illustrates an unfortunate patient who had a pre-existing haemangioma in the lung which was in close proximity of a Ghon's focus that had invaded on to the haemangioma leading to haemorrhage causing death. This study seeks to highlight the importance of conducting a full post mortem in cases of maternal mortality. PMID- 24814629 TI - Case Report: A Patient with Acute Cardiac Tamponade Secondary to Complicated Stanford Type A Intramural Haematoma - the role of CT. AB - Chest pain is a common presenting complaint in the emergency room of which acute aortic syndrome is a sinister cause associated with high morbidity. A contrastenhanced CT aortogram is often performed for initial evaluation at the first instance of suspicion. We present a patient with Stanford Type A intramural haematoma complicated by haemopericardium and acute cardiac tamponade and highlight the relevant CT signs that would alert the managing physician to urgent echocardiogram correlation and emergent cardiothoracic intervention. PMID- 24814630 TI - A forgotten clinical sign making a comeback. AB - We report a case of Staphylococcus aureus infective endocarditis in a patient presenting with fever and rare cutaneous manifestations of Osler Nodes and Janeway Lesions. There had not been any distinct risk factors. His echocardiography subsequently revealed vegetation at the anterior mitral valve leaflet. As Staphylococcus aureus infective endocarditis is of utmost significance in morbidity and mortality, a sharp clinical acumen and follow up investigations is required alongside a prolonged course of antibiotics. Our patient was then started on intravenous cloxacillin for 28 days and gentamicin for 5 days to which he made good progress and recovery. PMID- 24814631 TI - Haemoglobin sickle d punjab: - a case report. AB - Haemoglobin S D-Punjab is a rare compound heterozygous haemoglobinopathy characterised by the presence of two beta globin gene variants: Beta6(GAG->GTG) and Beta121(GAA->CAA). These patients' clinical and haematological features mimic haemoglobin S disease. We describe the first case of doubly heterozygous HbSD Punjab from Malaysia managed with regular blood transfusion at the age of one. This case highlights the propensity for occurrence of rare phenotypes within our multi-ethnic population and emphasises the importance of accurate genotyping to avoid erroneous counselling, and to plan an effective patient management strategy before complication evolves. PMID- 24814632 TI - Spontaneous calf haematoma: case report. AB - Spontaneous calf haematoma is a rare condition and few case reports have been published in the English literature. Common conditions like deep vein thrombosis and traumatic gastrocnemius muscle tear need to be considered when a patient presents with unilateral calf swelling and tenderness. Ultrasound and Magnetic Resonance Imaging are essential for confirmation of diagnosis. The purpose of this paper is to report on a rare case of spontaneous calf hematoma and its diagnosis and management. PMID- 24814633 TI - Computed Tomography (CT) of Blunt Abdominal Trauma: The Frequency of Incidental Findings, how it was Documented in Radiology Report and the Implication of These Findings to Acute Trauma Care. AB - The wide use of computed tomography (CT) scanning for patients with blunt abdominal trauma can reveal incidental findings that vary in their importance. We evaluated these findings, how it was reported by radiologists and its implication on the trauma care. In 30 out of 154 patients, 32 incidental findings were discovered (19.5%). Out of these 32 findings, only 3 cases (9.4%) were considered significant and required immediate attention from the managing team. In all these 3 cases, the findings were described in the body of the report and highlighted in the conclusion section at the end of the radiology report. However, similar reporting style was used in only 58.4% of cases with moderate clinical concern and 23.5% of cases with little clinical concern. In 41.2% of cases with little concern, the incidental findings were not mentioned in the radiology report. In conclusion, incidental findings in CT scan performed for blunt abdominal trauma were common but many were clinically insignificant. There is little consistency in radiology reporting of these findings especially those with moderate and little clinical concern. PMID- 24814634 TI - Is there a Role for Routine Use of Calcium Scoring in Predicting Cardiovascular Event in Asymptomatic Adults in Primary Care? AB - No abstract available. PMID- 24814635 TI - Influenza season 2012-2013 in Europe: moderate intensity, mixed (sub)types. AB - This paper summarizes influenza activity in the European Union/European Economic Area (EU/EEA) in 2012-2013. The influenza season 2012-2013 in Europe lasted from early December to late April. Overall the severity of the season could be described as moderate, based on the ILI/ARI consultation rates and the percentage of sentinel specimens positive for influenza compared to previous seasons. Both influenza A and B viruses circulating accounted for 47% and 53% of positive sentinel specimens, respectively, with both A(H1) and A(H3) varying for dominance. Compared to outpatients, the proportion of laboratory-confirmed influenza hospitalized cases infected by A(H1N1)pdm09 was significantly higher in middle-aged patients (33% vs. 17%, chi 2 = 66.6, P < 0.01). Despite a relatively good match between vaccine and circulating strains, vaccine effectiveness was estimated to be moderate. PMID- 24814637 TI - In pre-school children, sleep objectively assessed via actigraphy remains stable over 12 months and is related to psychological functioning, but not to cortisol secretion. AB - STUDY OBJECTIVES: Studies of the long-term stability of sleep in pre-schoolers are scarce. The aim of the present study was to investigate objectively assessed sleep via actigraphy in pre-schoolers longitudinally, and to predict sleep, psychological functioning and cortisol secretion prospectively as a function of sleep 12 months earlier. METHOD: A total of 73 pre-schoolers (mean age: 5.45 years; 53% females) were assessed again after 12 (mean age: 6.4 years). Sleep actigraphy recordings were performed, saliva cortisol was analysed, and parents and experts rated children's psychological functioning. RESULTS: Longitudinally, poor sleep at age 5.45 years was associated with poor sleep and internalizing and peer problems but not with externalizing problems and hyperactivity, and cortisol secretion 12 months later. At age 6.4 years and cross-sectionally, poor sleep was concurrently associated with greater psychological difficulties and increased cortisol secretion. CONCLUSION: In pre-schoolers, poor sleep objectively assessed at age five was associated with psychological difficulties and poor sleep as assessed via actigraph and one year later. Results indicate that in pre-schoolers sleep remains stable over a 12-mont interval. Pre-schoolers with poor sleep appear to be at risk for developing further psychological difficulties. PMID- 24814638 TI - Drinking stories: a time in space and a space in time. PMID- 24814639 TI - Bad boys telling sexist stories? PMID- 24814640 TI - Overcoming barriers to effective early parenting interventions for attention deficit hyperactivity disorder (ADHD): parent and practitioner views. AB - BACKGROUND: The importance of early intervention approaches for the treatment of attention-deficit hyperactivity disorder (ADHD) has been increasingly acknowledged. Parenting programmes (PPs) are recommended for use with preschool children with ADHD. However, low 'take-up' and high 'drop-out' rates compromise the effectiveness of such programmes within the community. METHODS: This qualitative study examined the views of 25 parents and 18 practitioners regarding currently available PPs for preschool children with ADHD-type problems in the UK. Semi-structured interviews were undertaken to identify both barriers and facilitators associated with programme access, programme effectiveness, and continued engagement. RESULTS AND CONCLUSIONS: Many of the themes mirrored previous accounts relating to generic PPs for disruptive behaviour problems. There were also a number of ADHD-specific themes. Enhancing parental motivation to change parenting practice and providing an intervention that addresses the parents' own needs (e.g. in relation to self-confidence, depression or parental ADHD), in addition to those of the child, were considered of particular importance. Comparisons between the views of parents and practitioners highlighted a need to increase awareness of parental psychological barriers among practitioners and for better programme advertising generally. Clinical implications and specific recommendations drawn from these findings are discussed and presented. PMID- 24814641 TI - High-level expression, purification and characterization of active human C1q and tumour necrosis factor-related protein-1 in Escherichia coli. AB - C1q and tumour necrosis factor-related proteins (CTRPs) are a family of adiponectin paralogues. CTRP1 plays important biological functions in diabetes, obesity and hypertension. To further explore the physiological roles of human CTRP1 and its mechanisms of action, hCTRP1 gene was expressed in Escherichia coli. In the E. coli expression system, a large amount of soluble thioredoxin (Trx)-hCTRP1 fusion protein could be produced using the expression plasmid pET32a (+) and induction with IPTG at 18 degrees C, which accounts about 20% of the total soluble bacterial proteins. The recombinant Trx-hCTRP1 fusion protein was purified to an approx. 95% purity using Ni-NTA affinity chromatography and Superdex G-75 column with a yield of about 28-mg protein from 1-l bacterial cultures. The purified recombinant Trx-hCTRP1 was shown to be active under in vivo and in vitro assay conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: CTRP1 plays important biological functions and warrants further investigation. However, large-scale production of recombinant CTRP1 has been technically challenging, which becomes a major obstacle in the structural and functional analysis of this important family of proteins. To explore the possible clinical applications and mechanisms of its action, an efficient method to produce large amounts of active recombinant human CTRP1 is necessary. This study should facilitate basic functional and pharmacological studies of this important protein family. PMID- 24814642 TI - Enhanced performance of a glucose/O(2) biofuel cell assembled with laccase covalently immobilized three-dimensional macroporous gold film-based biocathode and bacterial surface displayed glucose dehydrogenase-based bioanode. AB - The power output and stability of enzyme-based biofuel cells (BFCs) is greatly dependent on the properties of both the biocathode and bioanode, which may be adapted for portable power production. In this paper, a novel highly uniform three-dimensional (3D) macroporous gold (MP-Au) film was prepared by heating the gold "supraspheres", which were synthesized by a bottom-up protein templating approach, and followed by modification of laccase on the MP-Au film by covalent immobilization. The as-prepared laccase/MP-Au biocathode exihibited an onset potential of 0.62 V versus saturated calomel electrode (SCE, or 0.86 V vs NHE, normal hydrogen electrode) toward O2 reduction and a high catalytic current of 0.61 mAcm(-2). On the other hand, mutated glucose dehydrogenase (GDH) surface displayed bacteria (GDH-bacteria) were used to improve the stability of the glucose oxidation at the bioanode. The as-assembled membraneless glucose/O2 fuel cell showed a high power output of 55.8 +/- 2.0 MUW cm(-2) and open circuit potential of 0.80 V, contributing to the improved electrocatalysis toward O2 reduction at the laccase/MP-Au biocathode. Moreover, the BFC retained 84% of its maximal power density even after continuous operation for 55 h because of the high stability of the bacterial surface displayed GDH mutant toward glucose oxidation. Our findings may be promising for the development of more efficient glucose BFC for portable battery or self-powered device applications. PMID- 24814643 TI - Mycetoma caused by Nocardia transvalensis with repeated local recurrences for 25 years without dissemination to viscera. PMID- 24814644 TI - Whole genome transcriptome analysis of rice seedling reveals alterations in Ca(2+) ion signaling and homeostasis in response to Ca(2+) deficiency. AB - Ca(2+) is an essential inorganic macronutrient, involved in regulating major physiological processes in plants. It has been well established as a second messenger and is predominantly stored in the cell wall, endoplasmic reticulum, mitochondria and vacuoles. In the cytosol, the concentration of this ion is maintained at nano-molar range. Upon requirement, Ca(2+) is released from intra cellular as well as extracellular compartments such as organelles and cell wall. In this study, we report for the first time, a whole genome transcriptome response to short (5 D) and long (14 D) term Ca(2+) starvation and restoration in rice. Our results manifest that short and long term Ca(2+) starvation involves a very different response in gene expression with respect to both the number and function of genes involved. A larger number of genes were up- or down-regulated after 14 D (5588 genes) than after 5 D (798 genes) of Ca(2+) starvation. The functional classification of these genes indicated their connection with various metabolic pathways, ion transport, signal transduction, transcriptional regulation, and other processes related to growth and development. The results obtained here will enable to understand how changes in Ca(2+) concentration or availability are interpreted into adaptive responses in plants. PMID- 24814645 TI - Viscoelastic properties of normal and infarcted myocardium measured by a multifrequency shear wave method: comparison with pressure-segment length method. AB - Our aims were (i) to compare in vivo measurements of myocardial elasticity by shear wave dispersion ultrasound vibrometry (SDUV) with those by the conventional pressure-segment length method, and (ii) to quantify changes in myocardial viscoelasticity during systole and diastole after reperfused acute myocardial infarction. The shear elastic modulus (MU1) and viscous coefficient (MU2) of left ventricular myocardium were measured by SDUV in 10 pigs. Young's elastic modulus was independently measured by the pressure-segment length method. Measurements made with the SDUV and pressure-segment length methods were strongly correlated. At reperfusion, MU1 and MU2 in end-diastole were increased. Less consistent changes were found during systole. In all animals, MU1 increased linearly with left ventricular pressure developed during systole. Preliminary results suggest that MU1 is preload dependent. This is the first study to validate in vivo measurements of myocardial elasticity by a shear wave method. In this animal model, the alterations in myocardial viscoelasticity after a myocardial infarction were most consistently detected during diastole. PMID- 24814646 TI - Neural correlates of the empathic perceptual processing of realistic social interaction scenarios displayed from a first-order perspective. AB - The neural processing of impulsive behavior is a central topic in various clinical and non-clinical contexts. To investigate neural and behavioral correlates of the empathic processing of complex social scenarios, especially considering ecological validity of the experimental procedure, we developed and investigated a video stimulus inventory. It includes realistic neutral, social positive, and reactive-aggressive action scenarios. Short video-clips showing these social scenarios from a first-person perspective triggering different emotional states were presented to a non-clinical sample of 20 young adult male participants during fMRI measurements. Both affective interaction conditions (social-positive and reactive-aggressive) were contrasted against a neutral baseline condition and against each other. Behavioral evaluation data largely confirmed the validity of the emotion-inducing stimulus material. Reactive aggressive and social-positive interaction scenarios produced widely overlapping fMRI activation patterns in hetero-modal association cortices, but also in subcortical regions, such as the peri-aqueductal gray. Reactive-aggressive compared to social-positive scenarios yielded a more anterior distribution of activations in pre-motor and inferior frontal brain regions associated to motor preparation and inhibitory control processing as well as in the insula associated to pain- and/or aversion-processing. We argue that there are both principally common neural networks recruited for the processing of reactive-aggressive and social-positive scenarios, but also exclusive network parts in particular involved depending on individual socialization. PMID- 24814647 TI - The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: High level of homocysteine induces injury of endothelial cells and predicts adverse cardiovascular events. The objective was to assess the effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease. METHODS AND RESULTS: We conducted a meta analysis of randomized controlled trials identified from PubMed, Embase, the Cochrane Library. Eight studies were included. Homocysteine-lowering therapy with folic acid in patients with coronary artery disease significantly improve FMD as compared with placebo using random-effect model (SMD = 1.65 with 95% CI 1.12 2.17, p < 0.001). Subgroup analysis of subjects revealed that lipid-lowering therapy, study duration, and Delphi criteria had no effects on FMD. CONCLUSION: Our meta-analysis demonstrated that folic acid supplementation can significantly improve endothelial dysfunction as assessed by FMD in the brachial artery in patients with coronary heart disease. PMID- 24814648 TI - Differential inflammasome activation by Porphyromonas gingivalis and cholesterol crystals in human macrophages and coronary artery endothelial cells. AB - OBJECTIVE: Observational evidence suggests association between periodontitis and atherosclerotic vascular disease (ASVD), however the cause-effect remains unclear. In this study, we investigated the mechanistic link of the two diseases by measuring production of interleukin (IL)-1beta, a potent inflammatory cytokine, induced via inflammasome activation by a key periodontal pathogen- Porphyromonas gingivalis LPS and cholesterol crystals (CC). METHODS: An in vitro model of primary human monocyte-derived macrophages (M1 and M2 macrophages) and coronary artery endothelial cells (HCAEC) was employed as a source of inflammasome product-IL-1beta. Both cell types are essential in initial inflammatory process of ASVD. As inflammasome activation requires 2 signals, P. gingivalis LPS was used as a signal1 and CC as a signal2. RESULTS: We found markedly release of IL-1beta from P. gingivalis LPS-primed M1 and M2 macrophages treated with CC. Unlike macrophages, HCAEC showed no release of IL-1beta in response to P. gingivalis LPS priming and subsequent treatment with either CC or extracellular danger molecule adenosine-5'-triphosphate (signal2). However, HCAEC, which were primed with pro-inflammatory cytokine TNF-alpha (signal1) and treated with adenosine-5'-triphosphate, consistently secreted minimal IL-1beta. The amount of IL-1beta released from activated HCAEC was much lower than that from M1 or M2 macrophages. CONCLUSIONS: P. gingivalis LPS and CC induced a differential activation of the inflammasome between human macrophages and HCAEC. The mechanistic role of periodontal infection in inflammasome activation as a cause of ASVD requires further investigation. PMID- 24814649 TI - BMP-2 and -4 produced by vascular smooth muscle cells from atherosclerotic lesions induce monocyte chemotaxis through direct BMPRII activation. AB - OBJECTIVE: Monocytes and macrophages, together with vascular smooth muscle cells (VSMCs), play key roles at all stages of atherogenesis. There is also growing evidence that BMP signaling is involved in vascular diseases, including atherosclerosis. Here we evaluate the role played by the BMP agonist/antagonist axis in monocyte recruitment during atherogenesis. METHODS AND RESULTS: Using ApoE-/- mice and BMPs, Gremlin and BMPRII siRNAs we show that BMPs (2 and 4) and their antagonist Gremlin are co-expressed in murine and human atherosclerotic vessels. Additionally, those genes are co-expressed and upregulated in cultured vascular smooth muscle cells early in atherosclerosis formation in ApoE-/- mice. Furthermore, we demonstrate that BMP-2 and -4 produced in atherosclerotic VSMCs promote, whereas Gremlin inhibits, monocyte chemoattraction. Finally, we demonstrate that chemotaxis induction occurs through direct BMP receptor II (BMPRII) activation. CONCLUSION: These findings suggest that the balance between BMPs (2 and 4) and Gremlin levels modulate crosstalk processes between vascular and immune cells and ultimately the homeostasis in normal vasculature. They also indicate that under pro-atherogenic conditions, BMP signaling prevails, favoring monocyte recruitment and inflammation. Manipulation of BMP signaling may enable the identification of novel molecular approaches for preventing, stabilizing, and reverting atherosclerosis. PMID- 24814650 TI - Spatial-simultaneous working memory and selective interference in Down syndrome. AB - Several studies have suggested that individuals with Down syndrome (DS) have impairments in some aspects of the visuospatial domain. It has been reported that they are particularly impaired in the spatial-simultaneous working memory (WM) even in advantageous conditions such as when information is grouped to form a configuration. This study aimed to assess the performance of individuals with DS carrying out a spatial-simultaneous WM task in single and dual selective interference conditions in order to better explore the characteristics of their impairment in this area. Groups of individuals with DS and mentally age-matched typically developing (TD) children were asked to carry out a spatial-simultaneous WM task in a single- and in two dual-task conditions. In the single condition, the participants were required to recall an increasing number of positions of red squares presented simultaneously in a matrix. In the dual-task conditions, together with the spatial-simultaneous WM task, the participants were asked to carry out an articulatory suppression task or a tapping task. As has already been shown in other studies, individuals with DS were found to be impaired in carrying out a spatial-simultaneous WM task and showed a worse performance with respect to the TD group in both the conditions. These findings indicate that individuals with DS use the same coding modality as TD children of the same mental age. Just as the TD children, they performed lower in the dual- than in the single-task condition and there was no difference between the verbal and visuospatial conditions. PMID- 24814651 TI - An assessment of the dynamic stability of microorganisms on patterned surfaces in relation to biofouling control. AB - Microstructure-based patterned surfaces with antifouling capabilities against a wide range of organisms are yet to be optimised. Several studies have shown that microtopographic features affect the settlement and the early stages of biofilm formation of microorganisms. It is speculated that the fluctuating stress-strain rates developed on patterned surfaces disrupt the stability of microorganisms. This study investigated the dynamic interactions of a motile bacterium (Escherichia coli) with microtopographies in relation to initial settlement. The trajectories of E. coli across a patterned surface of a microwell array within a microchannel-based flow cell system were assessed experimentally with a time lapse imaging module. The microwell array was composed of 256 circular wells, each with diameter 10 MUm, spacing 7 MUm and depth 5 MUm. The dynamics of E. coli over microwell-based patterned surfaces were compared with those over plain surfaces and an increased velocity of cell bodies was observed in the case of patterned surfaces. The experimental results were further verified and supported by computational fluid dynamic simulations. Finally, it was stated that the nature of solid boundaries and the associated microfluidic conditions play key roles in determining the dynamic stability of motile bacteria in the close vicinity over surfaces. PMID- 24814652 TI - Protection afforded by controlled application of a barrier cream: a study in a workplace setting. AB - BACKGROUND: Skin protective creams (PCs) are used widely in industrial work environments to prevent irritant contact dermatitis. However, workplace studies remain equivocal in terms of their effectiveness, which may be partly owing to whether the PC remains on the skin. OBJECTIVES: To assess the practicability of using skin occlusion testing in a workplace as a method to determine whether PCs applied under controlled conditions can reduce skin damage against known irritants. This study also compares two methods of skin evaluation: clinical dermatological assessment and bioengineering techniques. METHODS: Daily occlusion testing for 1 h (over two consecutive weeks) was conducted in an engineering company on the volar forearm of 21 healthy volunteer engineers with sodium lauryl sulfate (SLS) and a PC that was used on site. The engineers conducted their normal work activities during the occlusion testing period. The skin areas tested were assessed using transepidermal water loss (TEWL), Chroma Meter and by visual dermatological scoring. RESULTS: Testing with PC and SLS together showed that PC does not prevent irritant contact dermatitis but significantly reduced skin damage compared with SLS alone (P < 0.01). The changes in skin were evident earlier with the biophysical measurements when compared with the dermatological assessment. CONCLUSIONS: Occlusion testing is a useful method for assessing the potential effectiveness of protective creams and can be used in a workplace without affecting work practices. TEWL and the Chroma Meter provide useful objective information and should be used in combination with dermatological examinations. PMID- 24814653 TI - Dual effect of arginine on aggregation of phosphorylase kinase. AB - Arginine is widely used in biotechnology as a folding enhancer and aggregation suppressor. However, its action on the stability of complexly organized oligomeric proteins, on the one hand, and its role in the formation of supramolecular structures, on the other hand, are poorly known. The investigation is concerned with the effects of arginine on protein-protein interactions using phosphorylase kinase (PhK) as an example. PhK, a 1.3MDa (alphabetagammadelta)4 hexadecameric complex, is a Ca(2+)-dependent regulatory enzyme that catalyzes phosphorylation and activation of glycogen phosphorylase b. On the basis of light scattering measurements it was shown that arginine induced aggregation of Ca(2+) free PhK. On the contrary, when studying Ca(2+), Mg(2+)-induced aggregation of PhK at 37 degrees C, the protective effect of arginine was demonstrated. The data on analytical ultracentrifugation are indicative of disruption of PhK hexadecameric structure under the action of arginine. Though HspB6 and HspB5 suppress aggregation of PhK they do not block the disruption effect of arginine with respect to both forms of PhK (Ca(2+)-free and Ca(2+), Mg(2+)-bound conformers). The dual effect of arginine has been interpreted from view-point of dual behaviour of arginine, functioning both like an osmolyte and a protein denaturant. PMID- 24814654 TI - The relative discomfort of noise and vibration: effects of stimulus duration. AB - How noise discomfort and vibration discomfort depend on duration has not previously been compared. For five durations (2, 4, 8, 16 and 32 s), the subjective equivalence of noise and vibration was investigated with all 49 combinations of 7 levels of noise and 7 magnitudes of whole-body vertical vibration. The rates of increase in discomfort with increasing duration were similar for noise and vibration, whereas they are currently assumed to be 3 dB per doubling of noise duration and 1.5 dB per doubling of vibration duration. The discomfort caused by low levels of noise was masked by high magnitudes of vibration, and the discomfort caused by low magnitudes of vibration was masked by high levels of noise. As stimuli durations increased from 2 to 32 s, the influence of vibration on the judgement of noise discomfort decreased, whereas the influence of noise on the judgement of vibration discomfort was unchanged. PMID- 24814655 TI - Production and identification of mannosylerythritol lipid-A homologs from the ustilaginomycetous yeast Pseudozyma aphidis ZJUDM34. AB - Mannosylerythritol lipids (MELs) are mainly produced by strains of the genus Pseudozyma and by Ustilago maydis. These glycolipid biosurfactants exhibit not only excellent surface-active properties but also versatile bioactivities. Mannosylerythritol lipid-A (MEL-A) is worth investigating due to its self assembling property. In this work, crude MELs were produced by resting Pseudozyma aphidis ZJUDM34 cells using different culture media. MEL-A fractions were isolated and identified using high-performance liquid chromatography combined with mass spectrometry (HPLC-MS) and gas chromatography combined with mass spectrometry (GC-MS). The results showed that MEL-A homologs had long unsaturated fatty acid chains, and the chain lengths range from C8 to C20. Nuclear magnetic resonance (NMR) was employed to confirm the chemical structures of the MEL-A homologs. Fermentation medium without NaNO3 and medium with manganese ions enhanced MEL-A production by Pseudozyma aphidis ZJUDM34. PMID- 24814656 TI - Efficient synthesis of 2'-deoxyzebularine and its alpha-anomer by the silyl method of N-glycosylation. Crystal structures and conformational study in solution. AB - 2'-Deoxyzebularine and its alpha-anomer have been efficiently synthesized with relatively high stereoselectivity by a modified procedure of the silyl method of the N-glycosidic bond formation. An SnCl4-catalyzed condensation of silylated pyrimidin-2-one with 1-alpha-chloro-3,5-di-O-p-toluoyl-2-deoxy-d-ribofuranose under kinetic control condition (-33 degrees C, 1,2-dichloroethane) led to the mixture of beta- and alpha-anomeric nucleosides in 3:1 ratio. Analogous condensation at +35 degrees C (thermodynamic control conditions) provided mainly p-toluoyl protected alpha-2'-deoxyzebularine (alpha:beta=4:1), easily separated by crystallization from the anomeric mixture. The structures of both 2' deoxyzebularine anomers were confirmed by X-ray analysis of the crystals and conformational studies in solution performed using an NMR method. PMID- 24814657 TI - Simulated solvation of organic ions: protonated methylamines in water nanodroplets. Convergence toward bulk properties and the absolute proton solvation enthalpy. AB - We applied an alternative, purely theoretical route to estimate thermodynamical properties of organic ions in bulk solution. The method performs a large ensemble of simulations of ions solvated in water nanodroplets of different sizes, using a polarizable molecular dynamics approach. We consider protonated ammonia and methylamines, and K(+) for comparison, solvated in droplets of 50-1000 water molecules. The parameters of the model are assigned from high level quantum computations of small clusters. All the bulk phase results extrapolated from droplet simulations match, and confirm independently, the relative and absolute experiment-based ion solvation energies. Without using experiment-based parameters or assumptions, the results confirm independently the solvation enthalpy of the proton, as -270.3 +/- 1.1 kcal mol(-1). The calculated relative solvation enthalpies of these ions are constant from small water clusters, where only the ionic headgroups are solvated, up to bulk solution. This agrees with experimental thermochemistry, that the relative solvation energies of alkylammonium ions by only four H2O molecules reproduce the relative bulk solvation energies, although the small clusters lack major bulk solvation factors. The droplet results also show a slow convergence of ion solvation properties toward their bulk limit, and predict that the stepwise solvation enthalpies of ion/water droplets are very close to those of pure neutral water droplets already after 50 water molecules. Both the ionic and neutral clusters approach the bulk condensation energy very gradually up to 10,000 water molecules, consistent with the macroscopic liquid drop model for pure water droplets. Compared to standard computational methods based on infinite periodic systems, our protocol represents a new purely theoretical approach to investigate the solvation properties of ions. It is applicable to the solvation of organic ions, which are pivotal in environmental, industrial, and biophysical chemistry but have been little investigated theoretically up to the present. PMID- 24814658 TI - On the locality of asymmetric close relations: spatial proximity and health differences in a senior community. AB - OBJECTIVE: A long line of research maintains that physical proximity increases interpersonal contact and boosts the likelihood of voluntary relationships. Proximity effects, however, may be modified by additional, valued characteristics that distinguish people from one another, such as physical health. I examine this interaction between proximity and assortative mechanisms with a complete network of retirement community (RC) residents. METHODS: Descriptive statistics and an exponential random graph model (ERGM) are used to analyze ties between 123 RC residents. In addition to hypothesized variables, the ERGM approach accounts for structural network processes that generate ties. RESULTS: As expected, reports of close relationships were strongly influenced by physical proximity. Also consistent with hypotheses, close tie nominations tended to be asymmetric along a health gradient: People were less likely to identify those in worse health than themselves as a close tie. Physical proximity, moreover, intensified the health based asymmetries. DISCUSSION: Findings suggest that relational inequalities associated with health are most pronounced when they are most local. I conclude by noting broader implications for the study of social networks, health, and physical space among older adults. PMID- 24814659 TI - Prevalence and mitigation strategies of HIV/AIDS infection risks in Namibian tertiary education institutional hostels. AB - The purpose of this study was to investigate risk factors that could promote HIV infection amongst adolescents and young adults living in tertiary educational institutional hostels in Namibia. Employing structured questionnaires and focus group discussions, we sought to answer questions pertaining to factors, beliefs systems, values, traditions and sexual relations that could promote HIV infection in the student hostels. The data on these issues were gathered from 306 male and 314 female students aged 18-35 years living in eight hostels. Amongst other results, the data revealed that sexual promiscuity in the hostels was treated as the norm in the majority of cases, unauthorized access to hostel rooms by non hostel dwellers was rampant, sexual harassment of female students by men who were under the influence of alcohol was reported to be common and there was general lack of support for victims of sexual abuse in the hostels. In addition, there was a general sense of insecurity in the hostels where more than 50% of the participants were afraid of being sexually attacked, some female hostel residents engaged in sexual activities for monetary and material gain and there was a general practice of older men from the community having sexual relations with young female hostel dwellers. To mitigate these and other risks it is recommended that there be provision of more HIV/AIDS prevention services, enhanced security, non-toxic entertainment (e.g. participation in sport and social clubs) and the banning of the sale of alcohol in student residences and on tertiary institution campuses. These and other results are discussed in the article and ways of mitigating the risks are proposed. PMID- 24814660 TI - HIV and visceral leishmaniasis coinfection in Bihar, India: an underrecognized and underdiagnosed threat against elimination. AB - Although human immunodeficiency virus (HIV) and visceral leishmaniasis coinfection is recognized as a major public health challenge in Africa, data regarding the prevalence in India are very limited. Consecutive HIV screening of 2077 patients aged >=14 years with confirmed visceral leishmaniasis in Bihar, eastern India, found that 5.6% were HIV positive, including 2.4% with newly diagnosed HIV infection. PMID- 24814661 TI - Visceral leishmaniasis and HIV coinfection in Bihar, India: a wake-up call? PMID- 24814662 TI - Informed consent and nurses' roles: a survey of Indonesian practitioners. AB - BACKGROUND: In Southeast Asia, the process of obtaining informed consent is influenced by both culture and policy at the hospital and national level. Both physicians and nurses play vital roles in this process, but physicians influence the roles of nurses. OBJECTIVES: Since the physicians and nurses often have different perspectives, it is important to investigate their views about the informed consent process and nurses' roles therein and whether there is a difference between ideal and experienced practice (reality), and whether this differs across hospitals. METHODS: A questionnaire was developed and a survey was conducted among physicians and nurses. Using exploratory factor analysis a three factor structure was determined: 'nurses' roles', 'barriers in informed consent', and 'adequacy of information'. Non-parametric tests were applied to compare nurses and physicians, and hospital setting. PARTICIPANTS AND RESEARCH CONTEXT: Responses were obtained from 129 physicians and 616 nurses from two Indonesian hospitals. Those hospitals differ in ownership, location, and size. ETHICAL CONSIDERATION: The study was reviewed by the hospital ethical committee. Participation was voluntary and confidentiality was ensured by keeping the responses anonymous. FINDINGS: Physicians and nurses differ significantly on all three factors. The scores reflecting disparity between ideal and reality regarding nurses' roles varied across professions, while barriers in informed consent differed between hospitals. DISCUSSION: The differences between ideal and reality indicated that improvement in the informed consent process and nurses' roles therein is called for. Varying views between physicians and nurses on nurses' roles may hinder collaboration. The differences between hospital settings showed interventions may have to be customized for different settings. CONCLUSION: Views on nurses' roles vary across professions. Views on barriers in informed consent vary across hospitals. Therefore interprofessional education is needed to promote interprofessional collaboration and intervention to improve informed consent practice should be tailored to the hospital context. PMID- 24814663 TI - [Tobacco control and the reduccion in smoking-related premature deaths in the United States, 1964-2012]. PMID- 24814664 TI - Forensic informativity of ~3000 bp of coding sequence of domestic dog mtDNA. AB - The discriminatory power of the noncoding control region (CR) of domestic dog mitochondrial DNA alone is relatively low. The extent to which the discriminatory power could be increased by analyzing additional highly variable coding regions of the mitochondrial genome (mtGenome) was therefore investigated. Genetic variability across the mtGenome was evaluated by phylogenetic analysis, and the three most variable ~1 kb coding regions identified. We then sampled 100 Swedish dogs to represent breeds in accordance with their frequency in the Swedish population. A previously published dataset of 59 dog mtGenomes collected in the United States was also analyzed. Inclusion of the three coding regions increased the exclusion capacity considerably for the Swedish sample, from 0.920 for the CR alone to 0.964 for all four regions. The number of mtDNA types among all 159 dogs increased from 41 to 72, the four most frequent CR haplotypes being resolved into 22 different haplotypes. PMID- 24814665 TI - Social media use, body image, and psychological well-being: a cross-cultural comparison of Korea and the United States. AB - This study examined the relationships among social media use for information, self-status seeking and socializing, body image, self-esteem, and psychological well-being, and some cultural effects moderating these relationships. Americans (n = 502) and Koreans (n = 518) completed an online survey. The main findings showed that (a) social media use for information about body image is negatively related to body satisfaction in the United States and Korea, while social media use for self-status seeking regarding body image is positively related to body satisfaction only in Korea; and (b) body satisfaction has direct and indirect positive effects on psychological well-being manifested in similar ways in the United States and Korea. Implications and future research directions are discussed. PMID- 24814666 TI - Multiple functions are mediated by the miRNAs of Epstein-Barr virus. AB - Epstein-Barr virus is a gammaherpes virus that is causally associated with several malignancies and expresses multiple miRNAs in both normal and tumor cells. Since the identification of virally encoded miRNAs, various mRNAs have been identified as targets for regulation by EBV's miRNAs in host cells. We shall summarize these targets, the robustness of their identification, and examine how the regulation of these targets by EBV contributes to the successful infection of its host. PMID- 24814667 TI - Dynamic of neurochemical alterations in striatum, hippocampus and cortex after the 6-OHDA mesostriatal lesion. AB - Immediate neurochemical alterations produced by 6-OHDA could explain the general toxic pattern in the central nervous system. However, no evidences describe the effects of 6-OHDA on early changes of neurotransmitters in rats' striatum, cortex and hippocampus. In our study, unilateral 6-OHDA injection into medial forebrain bundle (MFB) was used in rats, then five neurotransmitters were analyzed at 3, 6, 12, 24, 48 and 72 h, respectively. Results showed that 6-OHDA injection caused a sharp decline of striatal dopamine (DA) levels in the first 12h followed by a further reduction between 12 and 48 h. However, striatal levels of homovanillic acid (HVA) were stable in the first 12h and showed a marked reduction between 12 and 24h. Striatal levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) decreased linearly for 72 h, whereas levels of norepinephrine (NE) showed a slight reduction in the first 48 h, and returned back to normal afterwards. Striatal HVA/DA ratio increased significantly in the first 12h, but 5 HIAA/5-HT ratio showed a sharp increase between 12 and 72 h. Besides, neurochemical alterations were also found in hippocampus and cortex, and the correlations of neurotransmitters were analyzed. Our study indicated that NE system had little influence in the early phase of 6-OHDA injection, moreover, early neurochemical alterations were involved with striatum, hippocampus and cortex. PMID- 24814668 TI - A qualitative exploration of factors that facilitate and impede adherence to child abuse prevention guidelines in Dutch preventive child health care. AB - RATIONALE, AIMS AND OBJECTIVES: In the Netherlands, evidence-based child abuse prevention (CAP) guidelines have been developed to support child health care professionals (CHPs) in recognizing and responding to suspected child abuse. The aim of this study was to identify factors related to characteristics of the guidelines, the user, the organization and the socio-political context that facilitate or impede adherence to the CAP guidelines. METHODS: Three semi structured focus groups including 14 CHPs working in one large Dutch child health care organization were conducted in January and February 2012. Participants were asked questions about the dissemination of the guidelines, adherence to their key recommendations and factors that impeded or facilitated desired working practices. The interviews were audiotaped and transcribed. Impeding and facilitating factors were identified and classified. An innovation framework was used to guide the research. RESULTS: CHPs mentioned 24 factors that facilitated or impeded adherence to the CAP guidelines. Most of these factors were related to characteristics of the user. Familiarity with the content of the guidelines, a supportive working environment and good inter-agency cooperation were identified as facilitating factors. Impeding factors included lack of willingness of caregivers to cooperate, low self-efficacy and poor inter-agency cooperation. CONCLUSIONS: The results indicate that a broad variety of factors may influence CHPs' (non-)adherence to the CAP guidelines. Efforts to improve implementation of the guidelines should focus on improving familiarity with their contents, enhancing self-efficacy, promoting intra-agency cooperation, supporting professionals in dealing with uncooperative parents and improving inter-agency cooperation. Recommendations for future research are provided. PMID- 24814669 TI - Awareness of disaster reduction frameworks and risk perception of natural disaster: a questionnaire survey among Philippine and Indonesian health care personnel and public health students. AB - As the impacts of natural disasters have grown more severe, the importance of education for disaster medicine gains greater recognition. We launched a project to establish an international educational program for disaster medicine. In the present study, we surveyed medical personnel and medical/public health students in the Philippines (n = 45) and Indonesia (n = 67) for their awareness of the international frameworks related to disaster medicine: the Human Security (securing individual life and health), the Sphere Project (international humanitarian response), and the Hyogo Framework for Action 2005-2015 (international strategy for disaster reduction). In both countries, more than 50% responders were aware of human security, but only 2 to 12% were aware of the latter two. The survey also contained questions about the preferred subjects in prospective educational program, and risk perception on disaster and disaster related infections. In the Philippines, significant disasters were geophysical (31.0%), hydrological (33.3%), or meteorological (24.8%), whereas in Indonesia, geophysical (63.0%) and hydrological (25.3%) were significant. Moreover, in the Philippines, leptospirosis (27.1%), dengue (18.6%), diarrhea (15.3%), and cholera (10.2%) were recognized common disaster-related infections. In Indonesia, diarrhea (22.0%) and respiratory infection (20.3%) are major disaster-related infections. Water-related infections were the major ones in both countries, but the profiles of risk perception were different (Pearson's chi-square test, p = 1.469e-05). The responders tended to overestimate the risk of low probability and high consequence such as geophysical disaster. These results are helpful for the development of a postgraduate course for disaster medicine in Asia Pacific countries. PMID- 24814670 TI - Assessing motor imagery using the hand rotation task: does performance change across childhood? AB - This study examined at what age children can engage in the hand rotation task (as a measure of motor imagery); whether engagement changes across development and; the influence of age and motor skill on performance. Children were aged 5-12 years (N=101; 52 girls), with no IQ or motor skill impairment. Less than 40% of 5 6 year olds completed the hand rotation with sufficient accuracy for further analysis, compared with 80% of 7-8 year olds, and 90% aged 9 and above. From age 7, either or both response time (RT) and accuracy conformed to the biomechanical constraints of corresponding physical movements. Although RT did not improve with age, accuracy did, with 11 year olds significantly more accurate than 7 and 8 year olds. Importantly, efficiency (RT/accuracy) improved with age and both age, in months, and motor skill level were significant predictors of efficiency, accounting for 35% and 8% of variability, respectively. Improvements in motor imagery ability during childhood are likely the result of increased neural efficiency, developing as the result of complex interactions between endogenous and exogenous factors. This highlights the need for a multidisciplinary approach to further our understanding of the emergence of motor imagery ability. PMID- 24814671 TI - Clostridium difficile spore biology: sporulation, germination, and spore structural proteins. AB - Clostridium difficile is a Gram-positive, spore-forming obligate anaerobe and a major nosocomial pathogen of worldwide concern. Owing to its strict anaerobic requirements, the infectious and transmissible morphotype is the dormant spore. In susceptible patients, C. difficile spores germinate in the colon to form the vegetative cells that initiate Clostridium difficile infections (CDI). During CDI, C. difficile induces a sporulation pathway that produces more spores; these spores are responsible for the persistence of C. difficile in patients and horizontal transmission between hospitalized patients. Although important to the C. difficile lifecycle, the C. difficile spore proteome is poorly conserved when compared to members of the Bacillus genus. Further, recent studies have revealed significant differences between C. difficile and Bacillus subtilis at the level of sporulation, germination, and spore coat and exosporium morphogenesis. In this review, the regulation of the sporulation and germination pathways and the morphogenesis of the spore coat and exosporium will be discussed. PMID- 24814673 TI - A multifunctional enzyme is involved in bacterial ether lipid biosynthesis. AB - Fatty acid-derived ether lipids are present not only in most vertebrates but also in some bacteria. Here we describe what is to our knowledge the first gene cluster involved in the biosynthesis of such lipids in myxobacteria that encodes the multifunctional enzyme ElbD, which shows similarity to polyketide synthases. Initial characterization of elbD mutants in Myxococcus xanthus and Stigmatella aurantiaca showed the importance of these ether lipids for fruiting body formation and sporulation. PMID- 24814672 TI - Microbial glycan microarrays define key features of host-microbial interactions. AB - Genomic approaches continue to provide unprecedented insight into the microbiome, yet host immune interactions with diverse microbiota can be difficult to study. We therefore generated a microbial microarray containing defined antigens isolated from a broad range of microbial flora to examine adaptive and innate immunity. Serological studies with this microarray show that immunoglobulins from multiple mammalian species have unique patterns of reactivity, whereas exposure of animals to distinct microbes induces specific serological recognition. Although adaptive immunity exhibited plasticity toward microbial antigens, immunological tolerance limits reactivity toward self. We discovered that several innate immune galectins show specific recognition of microbes that express self like antigens, leading to direct killing of a broad range of Gram-negative and Gram-positive microbes. Thus, host protection against microbes seems to represent a balance between adaptive and innate immunity to defend against evolving antigenic determinants while protecting against molecular mimicry. PMID- 24814674 TI - Author Impact Factor: tracking the dynamics of individual scientific impact. AB - The impact factor (IF) of scientific journals has acquired a major role in the evaluations of the output of scholars, departments and whole institutions. Typically papers appearing in journals with large values of the IF receive a high weight in such evaluations. However, at the end of the day one is interested in assessing the impact of individuals, rather than papers. Here we introduce Author Impact Factor (AIF), which is the extension of the IF to authors. The AIF of an author A in year t is the average number of citations given by papers published in year t to papers published by A in a period of Deltat years before year t. Due to its intrinsic dynamic character, AIF is capable to capture trends and variations of the impact of the scientific output of scholars in time, unlike the h-index, which is a growing measure taking into account the whole career path. PMID- 24814675 TI - Changes in whole-brain functional networks and memory performance in aging. AB - We used resting-functional magnetic resonance imaging data from 98 healthy older adults to analyze how local and global measures of functional brain connectivity are affected by age, and whether they are related to differences in memory performance. Whole-brain networks were created individually by parcellating the brain into 90 cerebral regions and obtaining pairwise connectivity. First, we studied age-associations in interregional connectivity and their relationship with the length of the connections. Aging was associated with less connectivity in the long-range connections of fronto-parietal and fronto-occipital systems and with higher connectivity of the short-range connections within frontal, parietal, and occipital lobes. We also used the graph theory to measure functional integration and segregation. The pattern of the overall age-related correlations presented positive correlations of average minimum path length (r = 0.380, p = 0.008) and of global clustering coefficients (r = 0.454, p < 0.001), leading to less integrated and more segregated global networks. Main correlations in clustering coefficients were located in the frontal and parietal lobes. Higher clustering coefficients of some areas were related to lower performance in verbal and visual memory functions. In conclusion, we found that older participants showed lower connectivity of long-range connections together with higher functional segregation of these same connections, which appeared to indicate a more local clustering of information processing. Higher local clustering in older participants was negatively related to memory performance. PMID- 24814676 TI - Age and CGG-repeat length are associated with neuromotor impairments in at-risk females with the FMR1 premutation. AB - Recent studies report a higher risk of dementia and motor symptoms in females with the fragile X mental retardation 1 premutation (PM-carriers) than has hitherto been appreciated. Here, we use dual-task gait paradigms to identify potential markers of cognitive and motor decline in female PM-carriers. Spatiotemporal gait characteristics and variability of gait were assessed during single- and dual-task conditions in 28 female PM-carriers (mean age 41.32 +/- 8.03 years) and 31 female controls with normal fragile X mental retardation 1 alleles (mean age 41.61 +/- 8.30 years). Despite comparable gait characteristics at baseline, gait performance was significantly poorer for PM-carriers when performing concurrent working memory tasks (counting backwards by 3's or 7's) when compared with controls. Correlational analyses showed that low working memory capacity was significantly associated with dual-task interference for the gait domains of pace (speed, step length) and variability (step time, swing time) in PM-carriers. Multiple regression analyses further showed that the interaction between age and CGG repeat length was strongly predictive of gait variability during dual-task performance. These findings indicate for the first time that vulnerability in specific domains of gait control may act as sensitive surrogate markers of future decline in female PM-carriers. PMID- 24814678 TI - Visible light-mediated C-H difluoromethylation of electron-rich heteroarenes. AB - A novel method for visible-light photoredox-catalyzed difluoromethylation of electron-rich N-, O-, and S-containingheteroarenes under mild reaction conditions is developed. Mechanistic investigation indicates that the net C-H difluoromethylation proceeds through an electrophilic radical-type pathway. PMID- 24814679 TI - Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. AB - Hyperargininaemia is a disorder of the last step of the urea cycle. It is an autosomal recessive disease caused by deficiency of liver arginase-1 and usually presents later in childhood with progressive neurological symptoms including marked spasticity. In contrast with other urea cycle disorders, hyperammonaemia is not usually present but can be a feature. A number of guanidine compounds may accumulate in the blood and cerebrospinal fluid of these patients, which could play an important pathophysiological role. Guanidinoacetate is of particular interest as a well-known potent epileptogenic compound in guanidinoacetate methyltransferase deficiency. We found markedly elevated guanidinoacetate levels in a patient with arginase deficiency, which dropped significantly in response to dietary and medical treatment. Measurement of guanidinoacetate and other guanidino compounds may, therefore, be important for therapeutic monitoring in arginase deficiency. PMID- 24814677 TI - Immunophenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma. AB - Patients with mediastinal lymph node metastasis (N2) in squamous cell carcinoma (SqCC) of the lung have poor prognosis after surgical resection of the primary tumor. The aim of this study was to clarify predictive factors of the recurrence of pathological lung SqCC with N2 focusing on the biological characteristics of both cancer cells and cancer-associated fibroblasts (CAFs) in primary and metastatic lymph node tumors. We selected 64 patients with pathological primary lung N2 SqCC who underwent surgical complete resection and investigated the expressions of four epithelial-mesenchymal transition-related markers (caveolin, clusterin, E-cadherin, ZEB2), three cancer stem cell-related markers (ALDH-1, CD44 variant6, podoplanin) of cancer cells, and four markers of CAFs (caveolin, CD90, clusterin, podoplanin) in both primary and matched metastatic lymph node tumors in the N2 area. In the primary tumors, the expressions of all the examined molecules were not related to recurrence. However, in the metastatic lymph node tumors, high clusterin and ZEB2 expressions in the cancer cells and high podoplanin expression in the CAFs were significantly correlated with recurrence (P = 0.03, 0.04, and 0.007, respectively). In a multivariate analysis, only podoplanin expression in the CAFs in metastatic lymph node tumors was identified as a significantly independent predictive factor of recurrence (P = 0.03). Our study indicated that the immunophenotypes of both cancer cells and CAFs in metastatic lymph node tumors, but not primary tumors, provide useful information for predicting the recurrence of pathological N2 lung SqCC. PMID- 24814680 TI - The unique characteristics of the placental transcriptome and the hormonal metabolism enzymes in placenta. AB - The placenta regulates the passage of both endogenous and xenobiotic compounds to the fetus during pregnancy. A small number of xenobiotic metabolizing CYP enzymes are constantly expressed in placenta, those include CYP19A1 which mainly converts androgens to estrogens, and CYP1A1 whose substrates include steroid hormones and xenobiotics. We performed an analysis of co-expression of xenobiotic metabolizing enzyme-coding genes and transcription factors in placenta and in 86 other tissues to discern the unique characteristics of the placental transcriptome. Transcription factors (TFs) driving the expression of proteins involved in phase I and II xenobiotic metabolism in the liver were not expressed in the placenta, nor were the bulk of xenobiotic metabolizing hepatic CYP enzymes. In contrast, TFs whose co-expression correlated with CYP1A1, i.e. AHR, PPARG, and CEBPB were highly expressed in placenta. The placenta is a hormonal tissue, and one needs to maintain the tissue-specific focus by removing the hepatic spectacles. PMID- 24814681 TI - Comparison of FaxitronTM versus MicroCT imaging of the skeleton of the suckling rat. AB - Currently, in pre and postnatal development studies or in juvenile rat studies, bone growth is assessed "for cause" by simple measurements of long bone length in vivo and at termination. This manuscript compares two radiographic methods for in vivo assessment of long bones in suckling rats; 2D imaging using a FaxitronTM and 3D imaging using MUCT. This paper illustrates that it is possible to image the unanaesthetised postnatal day 1 rat by FaxitronTM using a simple MicroporeTM tape restraint method. With isoflurane anaesthesia, it was possible to obtain high quality MUCT images of pups from day of birth. No pups were rejected by their mothers following either technique. The FaxitronTM was straightforward and fast, however the MUCT 3D images were of greater overall utility. Either method could be used for longitudinal investigation of long bone observations made previously in embryofetal development studies, or for other mechanistic work. PMID- 24814682 TI - Obesity and heart failure: epidemiology, pathophysiology, clinical manifestations, and management. AB - Obesity is a risk factor for heart failure (HF) in both men and women. The mortality risk of overweight and class I and II obese adults with HF is lower than that of normal weight or underweight adults with HF of comparable severity, a phenomenon referred to as the obesity paradox. Severe obesity produces hemodynamic alterations that predispose to changes in cardiac morphology and ventricular function, which may lead to the development of HF. The presence of systemic hypertension, sleep apnea, and hypoventilation, comorbidities that occur commonly with severe obesity, may contribute to HF in such patients. The resultant syndrome is known as obesity cardiomyopathy. Substantial weight loss in severely obese persons is capable of reversing most obesity-related abnormalities of cardiac performance and morphology and improving the clinical manifestations of obesity cardiomyopathy. PMID- 24814683 TI - Living kidney donation: considerations and decision-making. AB - BACKGROUND: When possible, renal transplantation is the treatment of choice for patients with end-stage kidney disease. Technological developments in immunology have made it possible to perform kidney transplants between donors and recipients despite antibodies against the donor organ. This allows for a wider range of relationships between recipient and donor. We investigated experiences of, and reflections on, kidney donation among genetic and non-genetic living donors before first consultation at the transplant centre. OBJECTIVE: The aim was to investigate early experiences in the process of becoming a living kidney donor (LKD). MATERIALS AND METHODS: The study was conducted within a phenomenological hermeneutic theoretical framework. Data were generated through semi-structured interviews with 18 potential donors. Data were interpreted and discussed in accordance with the Ricoeur's text interpretation theory on the three levels of naive reading, structural analysis and critical interpretation and discussion. RESULTS: Two themes emerged: the decision-making process and dilemmas in decision making. The study identifies that the decision about donation was made in relation to one's own life, family situation and in relation to the recipient considerations that demonstrate that a range of dilemmas can occur during the decision-making process. The desire to help was prominent and was of significance in decision-making. CONCLUSION: The study provides insight and knowledge for the health care professionals to meet and involve donors' narratives in reflections about and modifications to clinical nursing practice. It is essential that health care professionals have an understanding and appreciation of the experiences and concerns among LKDs, and this can help in planning and providing individual nursing care and support to donors. PMID- 24814684 TI - De novo lipogenesis in health and disease. AB - BACKGROUND: De novo lipogenesis (DNL) is a complex and highly regulated metabolic pathway. In normal conditions DNL converts excess carbohydrate into fatty acids that are then esterified to storage triacylglycerols (TGs). These TGs could later provide energy via beta-oxidation. In human body this pathway is primarily active in liver and adipose tissue. However, it is considered to be a minor contributor to the serum lipid homeostasis. Deregulations in the lipogenic pathway are associated with diverse pathological conditions. SCOPE OF REVIEW: The present review focuses on our current understanding of the lipogenic pathway with special reference to the causes and consequences of aberrant DNL. MAJOR CONCLUSIONS: The deregulation of DNL in the major lipogenic tissues of the human body is often observed in various metabolic anomalies - including obesity, non-alcoholic fatty liver disease and metabolic syndrome. In addition to that de novo lipogenesis is reported to be exacerbated in cancer tissues, virus infected cells etc. These observations suggest that inhibitors of the DNL pathway might serve as therapeutically significant compounds. The effectiveness of these inhibitors in treatment of cancer and obesity has been suggested by previous works. GENERAL SIGNIFICANCE: De novo lipogenesis - which is an intricate and highly regulated pathway - can lead to adverse metabolic consequences when deregulated. Therapeutic targeting of this pathway may open a new window of opportunity for combating various lipogenesis-driven pathological conditions - including obesity, cancer and certain viral infections. PMID- 24814685 TI - Irisin in response to acute and chronic whole-body vibration exercise in humans. AB - OBJECTIVE: Irisin is a recently identified myokine, suggested to mediate the beneficial effects of exercise by inducing browning of white adipocytes and thus increasing energy expenditure. In humans, the regulation of irisin by exercise is not completely understood. We investigated the effect of acute and chronic whole body vibration exercise, a moderate-intensity exercise that resembles shivering, on circulating irisin levels in young healthy subjects. MATERIALS/METHODS: Healthy untrained females participated in a 6-week program of whole-body vibration exercise training. Blood was drawn before and immediately after an acute bout of exercise at baseline (week 0) and after 6 weeks of training. RESULTS: The resting irisin levels were not different at baseline (week 0) and after 6 weeks of training. At both 0 and 6 weeks of training, an acute bout of vibration exercise significantly elevated circulating irisin levels by 9.5% and 18.1%, respectively (p=0.05 for the percent change of irisin levels). CONCLUSIONS: Acute bouts of whole-body vibration exercise are effective in increasing circulating irisin levels but chronic training does not change levels of baseline irisin levels in humans. PMID- 24814686 TI - The prevalence of and factors related to calcium pyrophosphate dihydrate crystal deposition in the knee joint. AB - OBJECTIVES: The purpose of this study was to reveal the accurate prevalence and related factors to the presence of calcium pyrophosphate dihydrate (CPPD) crystal deposition in cadaveric knee joints. DESIGN: Controlled laboratory study. METHODS: Six hundred and eight knees from 304 cadavers (332 male knees and 276 female knees, formalin fixed, Japanese anatomical specimens) were included in this study. The average age of the cadavers was 78.3 +/- 10.7 years. Knees were macroscopically evaluated for the existence of CPPD, and the depth of cartilage degeneration of the femoro-tibial joint following the Outerbridge's classification. CPPD crystal was confirmed under Fourier transform infrared spectroscopy (FTIR) analysis using light microscopy. Statistical analysis was performed to reveal the correlation between the occurrence of CPPD deposition in the knee joint and gender, age, and the depth of cartilage degeneration of the femoro-tibial joint. RESULTS: The prevalence of grossly visible CPPD crystal was 13% (79 knees). In all of these knees, CPPD crystal was confirmed under FTIR analysis. Statistical analysis showed significant correlation between the occurrence of CPPD deposition and gender (P < 0.001), and depth of cartilage degeneration in the femoro-tibial joint (P < 0.001). In the cartilage degeneration positive knees (Over grade 3 in Outerbridge's classification), average age of CPPD deposition knee was significantly higher than CPPD negative knees. CONCLUSIONS: In this study, the prevalence of CPPD deposition disease was evaluated in a relatively large sample size of cadaveric knees. The prevalence of CPPD deposition disease was 13%, and was significantly correlated with the subject's age, gender, and severity of cartilage degeneration in the femoro tibial joint. PMID- 24814687 TI - Functional ankle instability as a risk factor for osteoarthritis: using T2 mapping to analyze early cartilage degeneration in the ankle joint of young athletes. AB - OBJECTIVE: The aim of this study was to investigate, using T2-mapping, the impact of functional instability in the ankle joint on the development of early cartilage damage. METHODS: Ethical approval for this study was provided. Thirty six volunteers from the university sports program were divided into three groups according to their ankle status: functional ankle instability (FAI, initial ankle sprain with residual instability); ankle sprain Copers (initial sprain, without residual instability); and controls (without a history of ankle injuries). Quantitative T2-mapping magnetic resonance imaging (MRI) was performed at the beginning ('early-unloading') and at the end ('late-unloading') of the MR examination, with a mean time span of 27 min. Zonal region-of-interest T2-mapping was performed on the talar and tibial cartilage in the deep and superficial layers. The inter-group comparisons of T2-values were analyzed using paired and unpaired t-tests. Statistical analysis of variance was performed. RESULTS: T2 values showed significant to highly significant differences in 11 of 12 regions throughout the groups. In early-unloading, the FAI-group showed a significant increase in quantitative T2-values in the medial, talar regions (P = 0.008, P = 0.027), whereas the Coper-group showed this enhancement in the central-lateral regions (P = 0.05). Especially the comparison of early-loading to late-unloading values revealed significantly decreasing T2-values over time laterally and significantly increasing T2-values medially in the FAI-group, which were not present in the Coper- or control-group. CONCLUSION: Functional instability causes unbalanced loading in the ankle joint, resulting in cartilage alterations as assessed by quantitative T2-mapping. This approach can visualize and localize early cartilage abnormalities, possibly enabling specific treatment options to prevent osteoarthritis in young athletes. PMID- 24814689 TI - Lifelong exercise and locally produced insulin-like growth factor-1 (IGF-1) have a modest influence on reducing age-related muscle wasting in mice. AB - The age-related loss of skeletal muscle mass and function is termed sarcopenia and has been attributed to a decline in concentrations of insulin-like growth factor-1 (IGF-1). We hypothesized that constitutively expressed IGF-1 within skeletal muscles with or without exercise would prevent sarcopenia. Male transgenic mice that overexpress IGF-1 Ea in skeletal muscles were compared with wild-type littermates. Four-month-old mice were assigned to be sedentary, or had access to free-running wheels, until 18 or 28 months of age. In wild-type mice, the mass of the quadriceps muscles was reduced at 28 months and exercise prevented such loss, without affecting the diameter of myofibers. Conversely, increased IGF-1 alone was ineffective, whereas the combination of exercise and IGF-1 was additive in maintaining the diameter of myofibers in the quadriceps muscles. For other muscles, the combination of IGF-1 and exercise was variable and either increased or decreased the mass at 18 months of age, but was ineffective thereafter. Despite an increase in the diameter of myofibers, grip strength was not improved. In conclusion, our data show that exercise and IGF-1 have a modest effect on reducing aged-related wasting of skeletal muscle, but that there is no improvement in muscle function when assessed by grip strength. PMID- 24814690 TI - Noninvasive cardiac output measurement using bioreactance in postoperative pediatric patients. AB - BACKGROUND: Thoracic bioreactance is a noninvasive and continuous method of cardiac output (CO) measurement that is being developed in adult patients. Very little information is available on thoracic bioreactance use in children. OBJECTIVE: The aim of the study was to evaluate the ability of a bioreactance device (NICOM((r)) ; Cheetah Medical, Tel Aviv, Israel) to estimate CO and to track changes in CO induced by volume expansion (VE) in children. METHODS: Cardiac output values obtained using the NICOM((r)) device (CONICOM ) and measured by trans-thoracic echocardiography (COTTE ) were compared in pediatric neurosurgical patients during the postoperative period. RESULTS: Seventy-three pairs of measurements of CO obtained in 30 children were available for analysis. The bias (lower and upper limits of agreement) between CONICOM and COTTE was 0.11 (-1.4 to 1.2) l.min(-1). The percentage error (PE) was 55%. The precision of the NICOM((r)) device was 45%. A significant correlation was observed between the CO values obtained using the two methods (r = 0.89, <0.001). The concordance percentage between changes in COTTE and CON icom induced by VE was 84% following exclusion of patients with changes in CO <15% (n = 5). CONCLUSIONS: The PE observed is too large, and the limits of agreement too wide, to enable us to comment on the equivalence of the two techniques of CO measurements. However, the NICOM((r)) device performs well in tracking changes in CO following VE. PMID- 24814692 TI - Identified HLA class I epitopes can undergo conformational induced variation due to changes within HLA bound peptides. PMID- 24814691 TI - Proliferative index activity in oral squamous cell carcinoma: indication for postoperative radiotherapy? AB - The predictive value of the Ki-67 labelling index and its relationship with radiosensitivity in oral squamous cell carcinoma (SCC) remains controversial. We sought to evaluate whether the expression of Ki-67 antigen found in SCC of the tongue and the floor of the mouth is an indication for postoperative radiotherapy (PORT). The first study group included 34 patients who were treated only with primary surgery, while the second group included 26 patients who underwent primary surgery combined with PORT. The correlation between Ki-67 expression and loco-regional recurrence, as well as the 5-year disease-specific survival, was assessed in the two groups. Cases of high-proliferative tumours showed a significantly higher risk of loco-regional recurrence (P=0.018) and a poorer prognosis (P=0.001) only in the 34 patients treated with surgery alone. In multivariate Cox regression analysis, high Ki-67 expression was an independent predictor of loco-regional recurrence (HR 5.42, P=0.029) and disease-specific survival (HR 9.02, P=0.004). The correlation between Ki-67 expression and the risk of loco-regional recurrence in SCC of the tongue and the floor of the mouth may be useful in the selection of patients at a higher risk of recurrence who would benefit from PORT, despite adequate margins of resection and early stage of the disease. PMID- 24814688 TI - Advances in diagnostic and treatment modalities for intracranial tumors. AB - Intracranial neoplasia is a common clinical condition in domestic companion animals, particularly in dogs. Application of advances in standard diagnostic and therapeutic modalities together with a broad interest in the development of novel translational therapeutic strategies in dogs has resulted in clinically relevant improvements in outcome for many canine patients. This review highlights the status of current diagnostic and therapeutic approaches to intracranial neoplasia and areas of novel treatment currently in development. PMID- 24814693 TI - Death-associated protein kinase 3 mediates vascular structural remodelling via stimulating smooth muscle cell proliferation and migration. AB - Death-associated protein kinase 3 (DAPK3) also known as zipper-interacting kinase is a serine/threonine kinase that mainly regulates cell death and smooth muscle contraction. We have previously found that protein expression of DAPK3 increases in the mesenteric artery from spontaneously hypertensive rats (SHRs) and that DAPK3 mediates the development of hypertension in SHRs partly through promoting reactive oxygen species-dependent vascular inflammation. However, it remains to be clarified how DAPK3 controls smooth muscle cell (SMC) proliferation and migration, which are also important processes for hypertension development. We, therefore, sought to investigate whether DAPK3 affects SMC proliferation and migration. siRNA against DAPK3 significantly inhibited platelet-derived growth factor (PDGF)-BB-induced SMC proliferation and migration as determined by bromodeoxyuridine (BrdU) incorporation and a cell counting assay as well as a Boyden chamber assay respectively. DAPK3 siRNA or a pharmacological inhibitor of DAPK3 inhibited PDGF-BB-induced lamellipodia formation as determined by rhodamine phalloidin staining. DAPK3 siRNA or the DAPK inhibitor significantly reduced PDGF BB-induced activation of p38 and heat-shock protein 27 (HSP27) as determined by Western blotting. In ex vivo studies, PDGF-BB-induced SMC out-growth was significantly inhibited by the DAPK inhibitor. In vivo, the DAPK inhibitor significantly prevented carotid neointimal hyperplasia in a mouse ligation model. The present results, for the first time, revealed that DAPK3 mediates PDGF-BB induced SMC proliferation and migration through activation of p38/HSP27 signals, which may lead to vascular structural remodelling including neointimal hyperplasia. The present study suggests DAPK3 as a novel pharmaceutical target for the prevention of hypertensive cardiovascular diseases. PMID- 24814694 TI - Assessing the effect of a true-positive recall case in screening mammography: does perceptual priming alter radiologists' performance? AB - OBJECTIVE: To measure the effect of the insertion of less-difficult malignant cases on subsequent breast cancer detection by breast imaging radiologists. METHODS: The research comprises two studies. Study 1: 8 radiologists read 2 sets of images each consisting of 40 mammographic cases. Set A contained four abnormal cases, and Set B contained six abnormal cases, including two priming cases (less difficult malignancies) placed at intervals of three and five subsequent cases before a subtle cancer. Study 2: 16 radiologists read a third condition of the same cases, known as Set C, containing six abnormal cases and two priming cases immediately preceding the subtle cancer cases. The readers were asked to localize malignancies and give confidence ratings on decisions. RESULTS: Although not significant, a decrease in performance was observed in Set B compared with in Set A. There was a significant increase in the receiver operating characteristic (ROC) area under the curve (z = -2.532; p = 0.0114) and location sensitivity (z = -2.128; p = 0.0333) between the first and second halves of Set A and a marginal improvement in jackknife free-response ROC figure of merit (z = -1.89; p = 0.0587) between the first and second halves of Set B. In Study 2, Set C yielded no significant differences between the two halves of the study. CONCLUSION: Overall findings show no evidence that priming with lower difficulty malignant cases affects the detection of higher difficulty cancers; however, performance may decrease with priming. ADVANCES IN KNOWLEDGE: This research suggests that inserting additional malignant cases in screening mammography sets as an audit tool may potentially lead to a decrease in performance of experienced breast radiologists. PMID- 24814695 TI - Clinical observation and quality of life in terms of nasal sinusitis after radiotherapy for nasopharyngeal carcinoma: long-term results from different nasal irrigation techniques. AB - OBJECTIVE: The aim of our study was to investigate the relationship between nasal irrigation techniques (NIT) and the survival rate and the quality of life (QOL) in patients with nasal sinusitis (NS). METHODS: We studied data from 1134 patients with nasopharyngeal carcinoma (NPC) who received radical radiotherapy, which were randomly divided into three groups (A, B and C). Group A used nasal irrigator; Group B used homemade nasal irrigation (NI) connector combined with enemator; and Group C used nasal sprayer. The clinical effects, 5-year overall survival (OS) and progression-free survival (PFS) were observed. Furthermore, the QOL in patients with NS was evaluated using the Sino-Nasal Outcome Test 20. RESULTS: The median follow-up time was 69 months. The 5-year OS and PFS were 80.5% and 73.2%, respectively, for all patients. There was no significant difference in OS, PFS, xerostomia and neck skin toxicity grade 3 and greater among groups. There was no difference among groups. The incidence of NS was the highest in group C. CONCLUSION: The symptoms of NS seriously affected the QOL period of 1 year. Group C showed no improvement during the follow-up period, which for A and B, by contrast, had after 1 year. Although the exact mechanism remains to be explored in NIT, our findings suggest that patients with NPC should nasal irrigate for 2 years after radiotherapy. ADVANCES IN KNOWLEDGE: Our study shows that a nasal irrigator is necessary for patients with NPC for a high QOL in terms of NS. PMID- 24814696 TI - Air kerma and absorbed dose standards for reference dosimetry in brachytherapy. AB - This article reviews recent developments in primary standards for the calibration of brachytherapy sources, with an emphasis on the currently most common photon emitting radionuclides. The introduction discusses the need for reference dosimetry in brachytherapy in general. The following section focuses on the three main quantities, i.e. reference air kerma rate, air kerma strength and absorbed dose rate to water, which are currently used for the specification of brachytherapy photon sources and which can be realized with primary standards from first principles. An overview of different air kerma and absorbed dose standards, which have been independently developed by various national metrology institutes over the past two decades, is given in the next two sections. Other dosimetry techniques for brachytherapy will also be discussed. The review closes with an outlook on a possible transition from air kerma to absorbed dose to water based calibrations for brachytherapy sources in the future. PMID- 24814697 TI - A clinical trial testing the efficacy of PDT in preventing amputation in diabetic patients. AB - The feet of diabetic patients continue to be an unsolved problem in medicine. Uncontrolled neuropathy, ulceration and infection usually lead to amputation and presently there is no effective and reliable method that can be used to provide an efficient cure. Overall improvement in the salvage strategies, based on comprehensive pre-clinical evaluation, debridement, antibiotic therapy and follow up, has shown improvements in certain hospital settings, but the general picture for patients with diabetic foot is to have some sort of amputation, especially in underserved populations. It is clearly necessary to develop novel treatment strategies for this worldwide health problem. Photodynamic therapy (PDT) is a treatment modality that uses light to generate in situ reactive oxygen species, which can cause cell death. PDT can be used to treat several diseases, including foot infections that do not respond well to antibiotic therapy. There are several characteristics of PDT that make it potentially ideal to treat diabetic feet: the photosensitizer is non-toxic in the dark, but after illumination it becomes a very efficient antimicrobial agent with topical use, and it can regenerate small bones, such as the phalanges. However, PDT is still not used in clinical practice to treat diabetic feet. Therefore, we decided to perform a clinical study to prove that PDT is an effective method to avoid amputation of infected diabetic feet. An inexpensive PDT protocol was developed and applied to 18 patients with osteomyelitis, classified as Grade 3 on the Wagner scale. Only one of these patients suffered amputation. At least two of them were cured from resistant bacteria strains without intravenous antibiotic therapy. In the control group of 16 patients, all of them ended up suffering amputation. The rate of amputation in the PDT group was 0.029 times the rate in the control group and the difference is clearly statistically significant (p=0.002). PMID- 24814698 TI - Assessing the IQ-earnings link in environmental lead impacts on children: have hazard effects been overstated? AB - Studies in the 1990s by Schwartz and by Salkever provided the bases for measuring the earnings impacts of IQ decrements due to lead exposure for children, and many subsequent regulatory, policy guidance, and academic analyses adopted the estimates from these studies. Results by Salkever implied somewhat greater impacts of IQ decrements, but have been contested, in a series of more recent critical review articles, as overestimates of the negative impacts on children's future earnings caused by IQ decrements due to lead exposure. This paper examines the contentions of proponents of this overstatement hypothesis, the applicability of the evidence they offer, and the results from an additional important study from 1998 heretofore overlooked in the literature. Results of this examination indicate that the evidence for the overstatement hypothesis is seriously flawed. Studies cited to support this hypothesis (1) often report only evidence on wage impacts and thus ignore IQ impacts on hours of work and work participation rates, (2) give lesser weight to or completely exclude population groups that show relatively higher IQ impacts (e.g., women), and (3) give substantial weight to pre-1980 wage and earning data, thereby omitting the influence of recent upward trends in skill differentials in earnings and increasing returns to education. Because of these and other deficiencies, available evidence does not substantiate the overstatement hypothesis. In contrast, recent evidence overlooked by the proponents of this hypothesis suggests that the results reported by Salkever understate the actual strength of the negative IQ impacts from lead exposure. PMID- 24814699 TI - Diversity of diversity: conceptual and methodological differences in biodiversity estimates of eukaryotic microbes as compared to bacteria. AB - Recent advances such as high-throughput sequencing (HTS) have changed conceptions about the magnitude of diversity on Earth. This is especially true for microbial lineages, which have seen the discovery of great numbers of rare forms in places such as the human gut as well as diverse environments (e.g., freshwater, marine, and soil). Given the differences in perceptions of diversity for bacterial and eukaryotic microbes, including divergent species concepts, HTS tools used to eliminate errors and population-level variation in bacteria may not be appropriate for microbial eukaryotes and may eliminate valid species from the data. We discuss here how the nature of biodiversity varies among microbial groups and the extent to which HTS tools designed for bacteria are useful for eukaryotes. PMID- 24814701 TI - Magnetic-assisted rapid aptamer selection (MARAS) for generating high-affinity DNA aptamer using rotating magnetic fields. AB - A new SELEX protocol for the development of DNA aptamers has been demonstrated, referred to as magnetic-assisted rapid aptamer selection (MARAS). This method uses magnetic beads and an externally applied rotating magnetic field to provide the competitive mechanism for the selection aptamers with different affinities to the molecular target. The MARAS protocol efficiently generated aptamers with high affinity and specificity for C-reactive protein, a common cardiovascular disease indicator. The binding affinities of the selected aptamers could be varied by changing the frequency of the externally applied rotating magnetic field and optimal cases bound with low-nanomolar dissociation constants. PMID- 24814700 TI - Tuning the pore composition by two simultaneous interfacial self-assembly processes: breath figures and coffee stain. AB - In the current paper, we prepared microstructured porous films by the breath figures approach using polymer blends consisting of polystyrene as the major component and an amphiphilic additive, either a synthetic block copolymer {two different polystyrene-b-poly[poly(ethylene glycol) methyl ether methacrylate] copolymers} or a series of commercial surfactants. Tetrahydrofuran was employed as the solvent. Confocal micro-Raman spectroscopy demonstrated the preferential location of the amphiphilic additives in the cavities of the film as a consequence of the breath figures mechanism. However, the distribution of the copolymer within the cavities varies depending upon the structure and, more precisely, the surface properties of the additives, leading to three different situations. First of all, the copolymer with a larger polystyrene segment, insoluble in the condensed water droplets, is homogeneously distributed along the whole surface of the cavities. On the contrary, when the copolymer is soluble in water (shorter polystyrene segment), it migrates inside the droplet and a coffee stain phenomenon takes place during the water droplet evaporation, conducting to a ring-like deposition on the top edge of the cavities. Finally, when a water soluble surfactant with high surface activity is used, the surfactant is solubilized inside the water droplets, which provokes a decrease on the surface tension and the coffee-ring effect is modified. In this situation, the copolymer covers the bottom of the pore. PMID- 24814702 TI - The uniporter: from newly identified parts to function. PMID- 24814703 TI - Prophylactic angiotensin type 1 receptor antagonism confers neuroprotection in an aged rat model of postoperative cognitive dysfunction. AB - Postoperative cognitive dysfunction (POCD) is a common geriatric complication, although its exact neuropathogenesis remains elusive. Blockers of the renin angiotensin system (RAS) ameliorate cognitive deficits in inflammatory brain disorders, with its effects on POCD not yet fully elucidated. The aim of the present study was to investigate regulation of the brain RAS and the effect of angiotensin II receptor type 1 (AT1) inhibition on surgery-induced cognitive impairment in a well-established rat POCD model. We observed upregulation of angiotensin II protein expression and AT1 subtype B transcript levels in the hippocampus after laparotomy, suggesting surgical stress activates the hippocampal RAS in aged rats. Chronic pretreatment with 0.1 mg/kg/day candesartan, an AT1 antagonist, significantly attenuated surgery-induced cognitive deficits in the Morris water maze task without altering blood pressure. Candesartan also decreased hippocampal blood-brain barrier (BBB) permeability. Concomitant with these functional benefits, we observed significant inhibition of hippocampal neuroinflammation, evidenced by decreased glial reactivity and phosphorylation of the NF-kappaB p65 subunit, as well as marked reductions in interleukin-1beta, tumor necrosis factor-alpha, and cyclooxygenase-2. Our results are the first to show that activation of the brain RAS after surgery contributes to POCD in aged rats. Chronic treatment with low doses of candesartan may elicit blood pressure-independent neuroprotective effects in POCD by improving BBB function and promoting resolution of neuroinflammation. PMID- 24814704 TI - Apocynin attenuates isoproterenol-induced myocardial injury and fibrogenesis. AB - Oxidative stress is mechanistically implicated in the pathogenesis of myocardial injury and the subsequent fibrogenic tissue remodeling. Therapies targeting oxidative stress in the process of myocardial fibrogenesis are still lacking and thus remain as an active research area in myocardial injury management. The current study evaluated the effects of a NADPH oxidase inhibitor, apocynin, on the production of reactive oxygen species and the development of myocardial fibrogenesis in isoproterenol (ISO)-induced myocardial injury mouse model. The results revealed a remarkable effect of apocynin on attenuating the development of myocardial necrotic lesions, inflammation and fibrogenesis. Additionally, the protective effects of apocynin against myocardial injuries were associated with suppressed expression of an array of genes implicated in inflammatory and fibrogenic responses. Our study thus provided for the first time the histopathological and molecular evidence supporting the therapeutic value of apocynin against the development of myocardial injuries, in particular, myocardial fibrogenesis, which will benefit the mechanism-based drug development targeting oxidative stress in preventing and/or treating related myocardial disorders. PMID- 24814705 TI - Measurement of aberrant glycosylation of prostate specific antigen can improve specificity in early detection of prostate cancer. AB - INTRODUCTION: We previously identified prostate cancer (PCa)-associated aberrant glycosylation of PSA, where alpha2,3-linked sialylation is an additional terminal N-glycan on free PSA (S2,3PSA). We then developed a new assay system measuring S2,3PSA using a magnetic microbead-based immunoassay. We compared the diagnostic accuracy of conventional PSA and percent-free PSA (%fPSA) tests. METHODS: We used MagPlex beads to measure serum S2,3PSA levels using anti-human fPSA monoclonal antibody (8A6) for capture and anti-alpha2,3-linked sialic acid monoclonal antibody (HYB4) for detection. We determined the cutoff values in a training test and measured serum S2,3PSA levels in 314 patients who underwent biopsy, including 138 PCa and 176 non-PCa patients with PSA of <10.0 ng/ml. Serum S2,3PSA levels were presented as mean fluorescence intensity (MFI). Receiver operating characteristic curves were used to evaluate the diagnostic accuracy of total PSA, %fPSA, and S2,3PSA. RESULTS: We determined an MFI cutoff value of 1130 with a sensitivity of 95.0% and specificity of 72.0% for the diagnosis of PCa in the training test. In the validation study, the area under the curve for the detection of PCa with S2,3PSA was 0.84, which was significantly higher than that with PSA or %fPSA. CONCLUSIONS: Although the present study is small and preliminary, these results suggest that the measurement of serum S2,3PSA using a magnetic microbead-based immunoassay may improve the accuracy of early detection of PCa and reduce unnecessary prostate biopsy. PMID- 24814706 TI - Characterization of anticancer, DNase and antifungal activity of pumpkin 2S albumin. AB - The plant 2S albumins exhibit a spectrum of biotechnologically exploitable functions. Among them, pumpkin 2S albumin has been shown to possess RNase and cell-free translational inhibitory activities. The present study investigated the anticancer, DNase and antifungal activities of pumpkin 2S albumin. The protein exhibited a strong anticancer activity toward breast cancer (MCF-7), ovarian teratocarcinoma (PA-1), prostate cancer (PC-3 and DU-145) and hepatocellular carcinoma (HepG2) cell lines. Acridine orange staining and DNA fragmentation studies indicated that cytotoxic effect of pumpkin 2S albumin is mediated through induction of apoptosis. Pumpkin 2S albumin showed DNase activity against both supercoiled and linear DNA and exerted antifungal activity against Fusarium oxysporum. Secondary structure analysis by CD showed that protein is highly stable up to 90 degrees C and retains its alpha helical structure. These results demonstrated that pumpkin 2S albumin is a multifunctional protein with host of potential biotechnology applications. PMID- 24814707 TI - Expression of Dbn1 during mouse brain development and neural stem cell differentiation. AB - Dbn1 is a newly discovered gene in the drebrin gene family of mice. Previous studies have reported that Dbn1 is specifically expressed in the mouse brain suggesting its potential role in brain development. However, a detailed analysis of Dbn1 expression during mouse brain development has not been demonstrated. Here, we describe the expression pattern of Dbn1 and the coexpression of Dbn1 and actin during the development of the mouse brain from embryonic day 14 (E14) to adulthood and during the differentiation of neural stem cells (NSCs), as determined using immunohistochemistry, double-labeling immunofluorescence, and quantitative real-time polymerase chain reaction. During mouse brain development, Dbn1 expression level was high at E14, attenuated postnatally, reached its highest point at postnatal day 7 (P7), and showed a very low level at adulthood. Imaging data showed that Dbn1 was mainly expressed in the hippocampus, ventricular zone, and cortex, where NSCs are densely distributed, and that the intracellular distribution of Dbn1 was predominantly located in the cytoplasm edges and neurites. Moreover, the signal for colocalization of Dbn1 with actin was intense at E14, P0, and P7, but it was weak at adulthood. During NSC differentiation, Dbn1 mRNA expression increased after the onset of differentiation and reached its highest point at 3days, followed by a decrease in expression. The imaging data showed that Dbn1 was increasingly expressed in the extending neurites in accordance with the cell morphological changes that occur during differentiation. Furthermore, obvious colocalization signals of Dbn1 with actin were found in the neurites and dendritic spines. Collectively, these results suggest that Dbn1 may play a key role in mouse brain development and may regulate NSC differentiation by filamentous actin. PMID- 24814709 TI - RmKK, a tissue kallikrein inhibitor from Rhipicephalus microplus eggs. AB - Rhipicephalus microplus is an important ectoparasite that is responsible for transmission of anaplasmosis and babesiosis to cattle. Tissue kallikrein inhibitors might play an important role in R. microplus eggs. In the present work, we purified and characterized, a tissue kallikrein inhibitor presents in R. microplus eggs (RmKK), a protein which contains two Kunitz domain in tandem. Purified inhibitor was confirmed by amino terminal determination and its dissociation constant (Ki) for bovine trypsin and porcine pancreatic kallikrein were 0.6 nM and 91.5 nM, respectively. Using a cDNA library from R. microplus midgut, we cloned the cDNA fragment encoding mature RmKK and expressed the protein in Pichia pastoris system. Recombinant RmKK was purified by ion exchange chromatography and presented molecular mass of 16.3 kDa by MALDI-TOF analysis. Moreover, RmKK showed a tight binding inhibition for serine proteases as bovine trypsin (Ki=0.2 nM) and porcine pancreatic kallikrein (PPK) (Ki=300 nM). We performed, for the first time, the characterization of a tissue kallikrein inhibitor presents in R. microplus eggs, which the transcript is produced in the adult female gut. BmKK seems to be the strongest PPK inhibitor among all BmTIs present in the eggs and larvae (Andreotti et al., 2001; Sasaki et al., 2004). This data suggests that BmKK may participate in the development of tick egg and larvae phase. PMID- 24814708 TI - Biliverdin modulates the expression of C5aR in response to endotoxin in part via mTOR signaling. AB - Macrophages play a crucial role in the maintenance and resolution of inflammation and express a number of pro- and anti-inflammatory molecules in response to stressors. Among them, the complement receptor 5a (C5aR) plays an integral role in the development of inflammatory disorders. Biliverdin and bilirubin, products of heme catabolism, exert anti-inflammatory effects and inhibit complement activation. Here, we define the effects of biliverdin on C5aR expression in macrophages and the roles of Akt and mammalian target of rapamycin (mTOR) in these responses. Biliverdin administration inhibited lipopolysaccharide (LPS) induced C5aR expression (without altering basal expression), an effect partially blocked by rapamycin, an inhibitor of mTOR signaling. Biliverdin also reduced LPS dependent expression of the pro-inflammatory cytokines TNF-alpha and IL-6. Collectively, these data indicate that biliverdin regulates LPS-mediated expression of C5aR via the mTOR pathway, revealing an additional mechanism underlying biliverdin's anti-inflammatory effects. PMID- 24814710 TI - An unusual appearance of fibrin sheaths after implantable cardioverter defibrillator removal because of infective endocarditis. PMID- 24814711 TI - Home hemodialysis: beliefs, attitudes, and practice patterns. AB - There is increasing interest of the worldwide kidney community in home hemodialysis (HHD). This is due to emerging evidence of its superiority over conventional hemodialysis (HD), largely attributed to improved outcomes on intensive schedule HD, best deployed in patient's own homes. Despite published work in this area, universal uptake remains limited and reasons are poorly understood. All those who provide HD care were invited to participate in a survey on HHD, initiated to understand the beliefs, attitudes, and practice patterns of providers offering this therapy. The survey was developed and posted on the Nephrology Dialysis Transplantation-Educational (NDT-E) website. Two hundred and seventy-two responses were deemed suitable for complete analysis. It is apparent from the survey that there is great variability in the prevalence of HHD. Physicians have a great deal of interest in this modality, with majority viewing home as being the ideal location for the offer of intensive HD schedules (55%). A significant number (21%) feel intensive HD may be offered even outside the home setting. Those who offer this therapy do not see a financial disadvantage in it. Many units identify lack of appropriately trained personnel (35%) and funding for home adaptation (50.4%) as key barriers to widespread adoption of this therapy. Despite the interest and belief in this therapy among practitioners, HHD therapy is still not within reach of a majority of patients. Modifiable organizational, physician, and patient factors exist, which could potentially redefine the landscape of HHD provision. Well-designed systematic research of national and local barriers is needed to design interventions to help centers facilitate change. PMID- 24814712 TI - Hydrophobic noncovalent interactions of inosine-phenylalanine: a theoretical model for investigating the molecular recognition of nucleobases. AB - Understanding the molecular recognition process of nucleobases is one of the greatest challenges for both computational chemistry and biophysics fields. In fact, our results point out that it is a hard task to take into account the hydrophobic interactions, such as pi-pi and T-stacking interactions, by theoretical calculations using conventional force fields due to quantum effects of hyperconjugation and electronic correlation. In this line, our findings put in evidence that simple modifications in the Lennard-Jones potential can improve theoretical predictions in scenarios where hydrophobic interactions can drive the molecular recognition. PMID- 24814713 TI - Age-, and gender-specific incidence of vascular parkinsonism, progressive supranuclear palsy, and parkinsonian-type multiple system atrophy in North East Scotland: the PINE study. AB - INTRODUCTION: There have been few incidence studies of vascular parkinsonism (VP), progressive supranuclear palsy (PSP), and parkinsonian-type multiple system atrophy (MSA-P). We measured the age-, gender- and socioeconomic-specific incidence rates for these conditions in north-east Scotland. METHODS: Incident non drug-induced parkinsonian patients were identified prospectively over three years by several overlapping methods from a baseline primary care population of 311,357. Parkinsonism was diagnosed if patients had two or more cardinal motor signs. Patients had yearly follow-up to improve diagnostic accuracy. Incidence rates using the diagnosis by established research criteria at latest follow-up were calculated for each condition by age, gender, and socioeconomic status. RESULTS: Of 377 patients identified at baseline with possible or probable parkinsonism, 363 were confirmed as incident patients after median follow-up of 26 months (mean age 74.8 years, SD 9.8; 61% men). The crude annual incidence was 3.2 per 100,000 (95% confidence interval (CI) 2.2-4.3) for VP, 1.7 per 100,000 (95% CI 1.0-2.4) for PSP, and 1.4 per 100,000 (95% CI 0.8-2.1) for MSA-P. VP and MSA-P were more common in men (age-adjusted male to female ratios 2.58 (95% CI 1.65-3.83) and 8.65 (95% CI 4.73-14.5) respectively). Incidence did not vary with socioeconomic status. DISCUSSION: This is the first community-based, prospective study to report the incidence of vascular parkinsonism and the third to report the incidence of PSP and MSA-P. Further follow-up and comparison with similar studies in different populations will yield valuable prognostic and aetiological information on these conditions. PMID- 24814714 TI - Neuroimmunology of traumatic spinal cord injury: a brief history and overview. PMID- 24814715 TI - Commentary on Kaushik et al.: Prostaglandin D2 is crucial for seizure suppression and postictal sleep. Novel evidence supporting a role for prostanoid receptors in seizure control. AB - Accumulating clinical and experimental evidence suggests a role for prostaglandins (PGs) in epilepsy and isolated seizures. Prostaglandin levels are increased in the hippocampus of epileptic patients and in the cerebrospinal fluid of children with febrile seizures. Moreover, increased PGD2, PGE2 and PGF2alpha levels are found in the brain after chemically-induced seizures and in spontaneously epileptic mice. However, whether prostaglandins facilitate or decrease seizures has been a matter of debate in the literature. Both pro- and anticonvulsant activities have been described for most of prostaglandins, except for PGD2 and DP receptor agonists, for which a consistent anticonvulsant action has been reported. The study by Kaushik and colleagues elegantly extends this view by showing that hematopoietic PGD synthase (H-PGDS) and DP1 receptors are essential for seizure suppression and that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2/DP1 system regulates sleep that follows PTZ-induced seizures using knockout animals. This commentary discusses the experimental approach of the studies that have implicated prostaglandins and their receptors in seizures, the interesting approach and results of Kaushik and colleagues, and the challenges of considering PGD2 signaling as a therapeutic target in epilepsy. PMID- 24814716 TI - The homeobox transcription factor Irxl1 negatively regulates MyoD expression and myoblast differentiation. AB - Irxl1/Mkx (Iroquois homeobox-like 1/Mohawk) encodes a member of the TALE subfamily of homeodomain proteins. It is expressed in multiple mesoderm-derived tissues and has recently been shown to regulate tendon differentiation during mouse embryonic development. Previously we showed that knockdown of Irxl1 in zebrafish caused a deficit in neural crest cells which consequently resulted in deformation of craniofacial muscles and arch cartilages. Here, we further demonstrate that loss of Irxl1 function results in deformed somites with disordered muscle fibers and myotendinous junctions. Because expression of myoD is increased in the somites of Irxl1 knockdown morphants, we test whether Irxl1 negatively regulates myoD expression. When stable C2C12 myoblasts overexpressing Irxl1/Mkx were induced to differentiate, myotube formation was inhibited and protein levels of myoD and myosin heavy chain were decreased accordingly. A series of deletion constructs of myoD promoter fragments were tested by luciferase reporter assays, which identified a promoter fragment that is necessary and sufficient for Irxl1-mediated repression. Direct interaction of Irxl1 and myoD promoter was subsequently elucidated by yeast one-hybrid assays, electrophoretic mobility shift assays and chromatin immunoprecipitation analysis. Furthermore, mouse Mkx also binds to and represses myoD promoter. These results indicate that Irxl1/Mkx can repress myoD expression through direct binding to its promoter and may thus play a negative regulatory role in muscle differentiation. PMID- 24814718 TI - Why has the pedestrian death rate decreased in Spain between 1993 and 2011? An application of the decomposition method. AB - A decomposition procedure was used to estimate the percentage contributions of exposure, risk of collision and fatality to explain the decreases in pedestrian collision death rates observed in Spain from 1993 to 2011. Information was obtained from the Spanish National Institute of Statistics and the Spanish Register of Road Crashes with Victims. A quasi-induced method was used to obtain estimates of annual pedestrian exposure. Poisson regression was used to obtain age-adjusted and sex-adjusted estimates of the mean annual percentage decrease in pedestrian death rates attributable to exposure, collision and fatality; these values were +2.28%, -45.86% and -51.86%, respectively. The results suggest that the decrease in fatality rates and, to a lesser extent, collision rates were the most important determinants of the reduction in pedestrian collision death rates, whereas the contribution of exposure was irrelevant. PMID- 24814717 TI - Risky driving, mental health, and health-compromising behaviours: risk clustering in late adolescents and adults. AB - BACKGROUND: Health-compromising behaviours in adolescents and adults co-occur. Because motor vehicle crashes are the leading cause of death and disability for these age groups, understanding the association between risky driving and other health-compromising behaviours is critical. METHODS: We performed a secondary analysis of data from a randomised controlled trial of an intervention for participants who screened positive for risky driving and problem drinking. Using baseline data, we examined relationships among conduct behaviour problems before and after age 15 years, depressive symptoms, sleep, problem drinking, and risky driving (hostile, reckless and drinking and driving) in late adolescents ages 18 24 (n=110) years, and adults ages 25-44 (n=202) years. We developed a measurement model for the entire sample using confirmatory factor analysis, which was then specified as a multigroup structural equation model. RESULTS: Late adolescents and adults had some similar associations for pathways through problem drinking to drinking and driving; depression to reckless driving; and conduct behaviour problems after 15 years of age to hostile driving. Late adolescents, however, had more complex relationships: depressive symptoms and conduct behaviour problems before 15 years of age were associated with more risky driving behaviours through multiple pathways, and males reported more risky driving. CONCLUSIONS: Risky driving is associated with other health-compromising behaviours and mental health factors. It is a multidimensional phenomenon more pronounced in late adolescence than adulthood. In order to promote safe driving, the findings support the need to consider behaviours that are a health threat in the late adolescent population during driving training and licensure. TRIAL REGISTRATION NUMBER: NCT00164294. PMID- 24814719 TI - Diffusion and decay chain of radioisotopes in stagnant water in saturated porous media. AB - The analysis of the diffusion of radioisotopes in stagnant water in saturated porous media is important to validate the performance of barrier systems used in radioactive repositories. In this work a methodology is developed to determine the radioisotope concentration in a two-reservoir configuration: a saturated porous medium with stagnant water is surrounded by two reservoirs. The concentrations are obtained for all the radioisotopes of the decay chain using the concept of overvalued concentration. A methodology, based on the variable separation method, is proposed for the solution of the transport equation. The novelty of the proposed methodology involves the factorization of the overvalued concentration in two factors: one that describes the diffusion without decay and another one that describes the decay without diffusion. It is possible with the proposed methodology to determine the required time to obtain equal injective and diffusive concentrations in reservoirs. In fact, this time is inversely proportional to the diffusion coefficient. In addition, the proposed methodology allows finding the required time to get a linear and constant space distribution of the concentration in porous mediums. This time is inversely proportional to the diffusion coefficient. In order to validate the proposed methodology, the distributions in the radioisotope concentrations are compared with other experimental and numerical works. PMID- 24814720 TI - (210)Polonium and (210)lead content of marine birds from Southeastern Brazil. AB - In this study, we report the (210)Po and (210)Pb concentrations of bone, muscle and liver samples that were obtained from twelve different marine bird species stranded on beaches in the central-north region of Rio de Janeiro State. Both radionuclides were highly concentrated in the liver samples; however, the lowest mean (210)Po/(210)Pb activity ratio (1.3) was observed in bones compared with liver and muscle (16.8 and 13.8, respectively). Among the species that were studied, Fregata magnificens, with a diet based exclusively on fish, had the lowest (210)Pb and (210)Po concentrations and the lowest (210)Po/(210)Pb activity ratio. The (210)Po concentrations in Puffinus spp. liver samples followed a log normal distribution, with a geometric mean of 300 Bq kg(-1)wet weight. Only two references pertaining to (210)Po in marine birds were found in a Web of Science search of the literature, and each study reported a different concentration value. The values determined in this experiment are consistent with those in one of the previous studies, which also included one of the species studied in this work. No values for (210)Pb in marine birds have been published previously. PMID- 24814721 TI - Measurement of the tritium concentration in the fractionated distillate from environmental water samples. AB - Standard procedures for the measurement of tritium in water samples often require distillation of an appropriate sample aliquot. This distillation process may result in a fractionation of tritiated water and regular light water due to the vapor pressure isotope effect, introducing either a bias or an additional contribution to the total tritium measurement uncertainty. The current study investigates the relative change in vapor pressure isotope effect in the course of the distillation process, distinguishing it from and extending previously published measurements. The separation factor as a quantitative measure of the vapor pressure isotope effect is found to assume values of 1.04 +/- 0.036, 1.05 +/- 0.026, and 1.07 +/- 0.038, depending on the vigor of the boiling process during distillation of the sample. A lower heat setting in the experimental setup, and therefore a less vigorous boiling process, results in a larger value for the separation factor. For a tritium measurement in water samples where the first 5 mL are discarded, the tritium concentration could be underestimated by 4 7%. PMID- 24814722 TI - Soil-to-root vegetable transfer factors for (226)Ra, (232)Th, (40)K, and (88)Y in Malaysia. AB - Soil-to-plant transfer factors (TFs) are of fundamental importance in assessing the environmental impact due to the presence of radioactivity in soil and agricultural crops. Tapioca and sweet potato, both root crops, are popular foodstuffs for a significant fraction of the Malaysian population, and result in intake of radionuclides. For the natural field conditions experienced in production of these foodstuffs, TFs and the annual effective dose were evaluated for the natural radionuclides (226)Ra, (232)Th, (40)K, and for the anthropogenic radionuclide (88)Y, the latter being a component of fallout. An experimental tapioca field was developed for study of the time dependence of plant uptake. For soil samples from all study locations other than the experimental field, it has been shown that these contain the artificial radionuclide (88)Y, although the uptake of (88)Y has only been observed in the roots of the plant Manihot esculenta (from which tapioca is derived) grown in mining soil. The estimated TFs for (226)Ra and (232)Th for tapioca and sweet potato are very much higher than that reported by the IAEA. For all study areas, the annual effective dose from ingestion of tapioca and sweet potato are estimated to be lower than the world average (290 MUSv y(-1)). PMID- 24814723 TI - Evaluation of A Novel Information-Sharing Instrument for Home-Based Palliative Care: A Feasibility Study. AB - AIM: To examine the feasibility and usefulness of a novel region-based pathway: the Regional Referral Clinical Pathway for Home-Based Palliative Care. METHOD: This was a feasibility study to evaluate the frequency of variances and the perceived usefulness of pathway using in-depth interviews. All patients with cancer referred to the palliative care team between 2011 and 2013 and received home care services were enrolled. RESULT: A total of 44 patients were analyzed, and pathway was completed in all the patients. The target outcome was achieved in 61.4% while some variances occurred in 54.5%. Nine categories were identified as the usefulness of the pathway, such as reviewing and sharing information and promoting communication, education, motivation, and relationships. CONCLUSION: This novel pathway is feasible and seems to be useful. PMID- 24814724 TI - Vector-induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury. AB - Rewiring the injured corticospinal tract (CST) by promoting connections between CST axons and spared neurons is a strategy being explored experimentally to achieve improved recovery of motor function after spinal cord injury (SCI). Reliable interventions to promote and direct growth of collaterals from injured CST axons are in high demand to promote functionally relevant detour pathways. A promising tool is neurotrophin-3 (NT-3), which has shown growth-stimulating and chemo-attractive effects for spared CST axons caudal to a CST lesion. Yet, efforts to promote growth of injured CST axons rostral to a SCI with NT-3 have been less successful to date. Evidence indicates that immune activation in the local growth environment, either intrinsic or induced by the endotoxin lipopolysaccharide (LPS), can play a decisive role in the CST's responsiveness to NT-3. Here, we test the potential of NT-3 as a tool to enhance and direct collateral growth from the injured CST rostral to a SCI (1) using long-term expression of NT-3 by adeno-associated viral vectors, (2) with and without stimulating the immune system with LPS. Our results indicate that inducing a growth response from injured CST axons into a region of vector-mediated NT-3 expression is possible in the environment of the spinal cord rostral to a SCI, but seems dependent on the distance between the responding axon and the source of NT-3. Our findings also suggest that injured CST axons do not increase their growth response to NT-3 after immune activation with LPS in this environment. In conclusion, this is to our knowledge the first demonstration that NT-3 can be effective at promoting growth of injured CST collaterals far rostral to a SCI. Making NT-3 available in close proximity to CST target axons may be the key to success when using NT-3 to rewire the injured CST in future investigations. PMID- 24814725 TI - The impact of task demand on visual word recognition. AB - The left occipitotemporal cortex has been found sensitive to the hierarchy of increasingly complex features in visually presented words, from individual letters to bigrams and morphemes. However, whether this sensitivity is a stable property of the brain regions engaged by word recognition is still unclear. To address the issue, the current study investigated whether different task demands modify this sensitivity. Participants viewed real English words and stimuli with hierarchical word-likeness while performing a lexical decision task (i.e., to decide whether each presented stimulus is a real word) and a symbol detection task. General linear model and independent component analysis indicated strong activation in the fronto-parietal and temporal regions during the two tasks. Furthermore, the bilateral inferior frontal gyrus and insula showed significant interaction effects between task demand and stimulus type in the pseudoword condition. The occipitotemporal cortex showed strong main effects for task demand and stimulus type, but no sensitivity to the hierarchical word-likeness was found. These results suggest that different task demands on semantic, phonological and orthographic processes can influence the involvement of the relevant regions during visual word recognition. PMID- 24814727 TI - Alterations in phospholipidomic profile in the brain of mouse model of depression induced by chronic unpredictable stress. AB - Depression is a worldwide disability disease associated with high morbidity and has increased dramatically in the last few years. The differential diagnosis and the definition of an individualized therapy for depression are hampered by the absence of specific biomarkers. The aim of this study was to evaluate the phospholipidomic profile of the brain and myocardium in a mouse model of depression induced by chronic unpredictable stress (CUS). The lipidomic profile was evaluated by thin layer and liquid chromatography and mass spectrometry and lipid oxidation was estimated by FOX II assay. Antioxidant enzyme activity and the oxidized/reduced glutathione (GSH/GSSG) ratio were also evaluated. Results showed that chronic stress affects primarily the lipid profile of the brain, inducing an increase in lipid hydroperoxides, which was not detected in the myocardium. A significant decrease in phosphatidylinositol (PI) and in cardiolipin (CL) relative contents and also oxidation of CL and a significant increase of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were observed in the brain of mice after unpredictable chronic stress conditions. In the myocardium only an increase in PC content was observed. Nevertheless, both organs present a decreased GSH/GSSG ratio when compared to control groups, corroborating the occurrence of oxidative stress. The enzyme activities of catalase (CAT) and superoxide dismutase (SOD) were found to be decreased in the myocardium and increased in the brain, while glutathione reductase (GR) was decreased in the brain. Our results indicate that in a mouse model for studying depression induced by CUS, the modification of the expression of oxidative stress related enzymes did not prevent lipid oxidation in organs, particularly in the brain. These observations suggest that depression has an impact on the brain lipidome and that further studies are needed to better understand lipids role in depression and to evaluate their potential as future biomarkers. PMID- 24814728 TI - Individual differences in brain structure and resting-state functional connectivity associated with type A behavior pattern. AB - Type A behavior pattern (TABP) is characterized by competitiveness and hostility, time urgency and impatience. These traits can have a significant impact on physical and mental health. We have not found studies focusing on brain structure or functional connectivity correlates associated with individual differences in TABP. The present study used voxel-based morphometry (VBM) and resting-state functional connectivity (rsFC) analysis to examine the neural correlates of TABP. The results showed that TABP was positively correlated with regional gray matter volume (rGMV) in the left subgenual anterior cingulate cortex (sgACC), which might reflect immature functioning of this region related to impatience. In addition, TABP was positively correlated with the strength of rsFC between the left ventral striatum and areas in the left ventromedial prefrontal cortex (vmPFC) and the right rostral anterior cingulate cortex (rACC). These regions are associated with achievement striving related to impatience, aggressiveness, and worry under time pressure. In summary, the combination of morphometric results (increased rGMV of the left sgACC) and functional connectivity findings (increased rsFC between the left ventral caudate and the left vmPFC/right rACC in the fronto-striatal network) may provide a valuable basis for a comprehensive understanding of the neural circuitry underlying individual differences in TABP. PMID- 24814726 TI - Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus). AB - The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a receptor (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n=5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray (PAG), pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, PAG, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in the titi monkey brain, the OXTR antagonist ALS-II 69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood-brain barrier, these two compounds emerge as excellent candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primate species. PMID- 24814729 TI - Sulforaphane reduces the alterations induced by quinolinic acid: modulation of glutathione levels. AB - Glutamate-induced excitotoxicity involves a state of acute oxidative stress, which is a crucial event during neuronal degeneration and is part of the physiopathology of neurodegenerative diseases. In this work, we evaluated the ability of sulforaphane (SULF), a natural dietary isothiocyanate, to induce the activation of transcription factor Nrf2 (a master regulator of redox state in the cell) in a model of striatal degeneration in rats infused with quinolinic acid (QUIN). Male Wistar rats received SULF (5mg/kg, i.p.) 24h and 5min before the intrastriatal infusion of QUIN. SULF increased the reduced glutathione (GSH) levels 4h after QUIN infusion, which was associated with its ability to increase the activity of glutathione reductase (GR), an antioxidant enzyme capable to regenerate GSH levels at 24h. Moreover, SULF treatment increased glutathione peroxidase (GPx) activity, while no changes were observed in gamma-glutamyl cysteine ligase (GCL) activity. SULF treatment also prevented QUIN-induced oxidative stress (measured by oxidized proteins levels), the histological damage and the circling behavior. These results suggest that the protective effect of SULF could be related to its ability to preserve GSH levels and increase GPx and GR activities. PMID- 24814731 TI - Graphene materials and their use in dye-sensitized solar cells. PMID- 24814732 TI - Use of propofol infusion in alcohol withdrawal-induced refractory delirium tremens. AB - INTRODUCTION: Delirium tremens is a potentially fatal complication of alcohol withdrawal. In severe delirium, very large dosages of benzodiazepines can be required and in refractory cases, sedation with propofol can be used. Treatment of refractory delirium tremens with propofol is mainly described in case reports. We aimed to evaluate the treatment of delirium tremens with propofol infusion for 48 h. MATERIAL AND METHODS: This study was a single-centre retrospective cohort analysis of 15 patient journals covering the period from May 2012 to September 2013. RESULTS: Five women and ten men were included. Their mean age was 50.9 years. Prior to propofol treatment, conventional treatment with up to 1,500 mg of benzodiazepines, 2,000 mg of chlordiazepoxide or 1,200 mg of phenobarbital was attempted in the medical or psychiatric ward, without effect (sleep). Patients were sedated, intubated and mechanically ventilated in the intensive care unit. The mean propofol infusion rate was 4.22 mg/kg/h. Thirteen patients received supplemental infusion of opioids, whereas seven required concomitant vasopressor infusion. Once propofol infusion was discontinued after 48 h, 12 patients had a long awakening, displaying symptoms of prolonged sedation. Twelve of the 15 patients treated for delirium tremens with propofol for 48 h were successfully treated. Three patients needed further treatment. CONCLUSION: Our study suggests that treatment with propofol is viable. Establishing indication, dose, duration, and long-term effects of propofol treatment of delirium tremens requires further investigation. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814730 TI - GABA transport and neuroinflammation are coupled in multiple sclerosis: regulation of the GABA transporter-2 by ganaxolone. AB - Interactions between neurotransmitters and the immune system represent new prospects for understanding neuroinflammation and associated neurological disease. GABA is the chief inhibitory neurotransmitter but its actions on immune pathways in the brain are unclear. In the present study, we investigated GABAergic transport in conjunction with neuroinflammation in models of multiple sclerosis (MS). Protein and mRNA levels of gamma-amino butyric acid transporter 2 (GAT-2) were examined in cerebral white matter from MS and control (Non-MS) patients, in cultured human macrophages, microglia and astrocytes, and in spinal cords from mice with and without experimental autoimmune encephalomyelitis (EAE) using western blotting, immunocytochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). GABA levels were measured by HPLC. The GAT-2's expression was increased in MS patients' (n=6) white matter, particularly in macrophage lineage cells, compared to Non-MS patients (n=6) (p<0.05). Interferon gamma (IFN-gamma) stimulation of human macrophage lineage cells induced GAT-2 expression and reduced extracellular GABA levels (p<0.05) but soluble GABA treatment suppressed HLA-DRalpha, GAT-2 and XBP-1/s expression in stimulated macrophage lineage cells (p<0.05). Similarly, the synthetic allopregnanolone analog, ganaxolone (GNX), repressed GAT-2, JAK-1 and STAT-1 expression in activated macrophage lineage cells (p<0.05). In vivo GNX treatment reduced Gat-2, Cd3epsilon, MhcII, and Xbp-1/s expression in spinal cords following EAE induction (p<0.05), which was correlated with improved neurobehavioral outcomes and reduced neuroinflammation, demyelination and axonal injury. These findings highlight altered GABAergic transport through GAT-2 induction during neuroinflammation. GABA transport and neuroinflammation are closely coupled but regulated by GNX, pointing to GABAergic pathways as therapeutic targets in neuroinflammatory diseases. PMID- 24814733 TI - Work environment influences adverse events in an emergency department. AB - INTRODUCTION: The psychosocial work environment has been recognised as a factor that contributes to the occurrence of errors and adverse events at hospitals. There has been a strong focus on stress factors at intensive care units and emergency departments. The purpose of this study was to investigate the occurrence of adverse events and to examine the relationship between work-related stressors, safety culture and adverse events at an emergency department. MATERIAL AND METHODS: A total of 98 nurses and 26 doctors working in an emergency department at a Danish regional hospital filled out a questionnaire on the occurrence and pattern of adverse events, psychosocial work environment factors, safety climate and learning culture. RESULTS: The participants had experienced 742 adverse events during the previous month. The most frequent event types were lack of documents, referrals not performed, blood tests not available and lack of documentation. Problems related to reporting and learning and insufficient follow up and feedback after serious events were the most frequent complaints. A poor patient safety climate and increased cognitive demands were significantly correlated to adverse events. CONCLUSION: This study supports previous findings of severe underreporting to the mandatory national reporting system. The issue of reporting bias related to self-reported data should be born in mind. Among work environment issues, the patient safety climate and stress factors related to cognitive demands had the highest impact on the occurrence of adverse events. FUNDING: The project was funded by Trygfonden (grant no 7-10-0949). TRIAL REGISTRATION: not relevant. PMID- 24814734 TI - Genotyping increases the yield of angiotensin-converting enzyme in sarcoidosis--a systematic review. AB - INTRODUCTION: The diagnosis of sarcoidosis is challenging and involves radiological, clinical and paraclinical evaluation, the latter including the measurement of serum angiotensin-converting enzyme activity (s-ACE), which is elevated in about 60% of sarcoidosis patients. The normal inter-individual biological variation of s-ACE is large. Approximately 50% of the variation is due to a genomic insertion/deletion (I/D) polymorphism in the ACE gene. METHODS: We searched the MEDLINE library for articles presenting genotype-based reference intervals for s-ACE in healthy people. We summarised the results as weighted mean DD/II ratios of s-ACE. We also summarised the presented frequencies of the genotypes. RESULTS: We identified nine studies presenting genotype-based reference intervals. All studies found a significant difference between mean s ACE in the three genotype groups DD, ID and II. The mean DD/II ratio was 1.85 (range: 1.79-1.92) for all studies, 2.01 (1.92-2.10) for Caucasians and 1.64 (1.55-1.73) for Asians. The median frequencies of genotypes among Caucasians were 23% II, 45% ID and 30% DD, and 45% II, 49% ID and 14% DD among Asians. CONCLUSION: Genotyping for the I/D polymorphism increases the benefit of s-ACE since all studies found significantly different levels between genotype groups in healthy subjects. Genotyping is of special value if s-ACE is between the upper 97.5 percentile for genotype II and DD since values in this interval are at risk of being misclassified. Due to assay variation, genotype-specific reference levels should be verified locally. PMID- 24814735 TI - The use of shared medication record as part of medication reconciliation at hospital admission is feasible. AB - INTRODUCTION: Medication reconciliation improves congruence in cross sectional patient courses. Our regional electronic medical record (EMR) integrates the shared medication record (SMR) which provides full access to current medication and medication prescriptions for all citizens in Denmark. We studied whether our SMR integration could facilitate medication reconciliation. MATERIAL AND METHODS: Patients admitted to the emergency department for hospitalization were randomised to consultation using EMR with or without the integrated SMR access. Observed time used for medication reconciliation was the primary efficacy parameter. RESULTS: A total of 62 consecutive patient consultations were randomised including 39 with more than five prescriptions. EMR had data from previous consultations for 46 patients, 59 patients provided information on medication. In all, 18 junior physicians in early postgraduate medical training each participated with a median of three consultations (range 1-9). Time expenditure for medicine reconciliation was 5:27 min.:sec. (range: 2:00-15:37) with access to SMR integration and 4:15 min.:sec. (1:15-12:00) without SMR access. The number of active medicine prescriptions was eight and nine, respectively. Incorporating SMR did not increase the work load. Physicians judged the SMR integration and workflow as being useful. Patients unambiguously sup-ported physicians' use of SMR in this setting. CONCLUSION: Integration of information on individuals' medication from a national SMR into a hospital EMR was feasible and useful, and it did not increase time expenditure for medication reconciliation. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814736 TI - Acceptable results using small radio frequency ablation needle for liver parenchyma transection. AB - INTRODUCTION: The aim of this study was to investigate a single-electrode radio frequency ablation (RFA) needle as an instrument for liver resections with special emphasis on operation time, time of liver ischaemia, intra-operative blood loss and post-operative complications. MATERIAL AND METHODS: A total of 40 consecutive patients having a liver transection performed by an RFA single electrode from 1 September 2011 to 28 February 2012 were included in the study. Data concerning type of liver resection, liver parenchyma transection time, intraoperative bleeding and transfusions were prospectively recorded and registered. Furthermore, complications were recorded with special emphasis on bile fistulas and abscesses. RESULTS: In all, 20 females and 20 males had a liver resection performed by a single RFA electrode. The mean bleeding was 520 ml +/- 469 ml, and the mean liver parenchyma transection time was 52 min. +/- 22 min. Three patients, all of whom underwent major resections, received blood transfusions. Five patients developed bile fistulas and two abscesses. There were no re-operations for bleeding and no 30-day mortality. CONCLUSION: A single electrode RFA needle is a suitable tool for liver parenchyma transection with regard to operation time and intraoperative bleeding, but the frequency of bile leakage seems to be unacceptably high in cases of hemi-hepatectomies. FUNDING: The authors have no conflicts of interest or financial support to declare. TRIAL REGISTRATION: not relevant. PMID- 24814737 TI - Imported malaria is stable from Africa but declining from Asia. AB - INTRODUCTION: In this study, we describe patients with imported malaria seen at the Department of Infectious Diseases (DID), Hvidovre Hospital, Denmark. Our aim was to address possible risk factors for contracting malaria and risk factors for developing complicated malaria. MATERIAL AND METHODS: We searched patient databases for all cases of malaria seen at the DID from 1994 to 2012. Various parameters were registered. RESULTS: A total of 320 cases were identified. We found a significant 3.39 % decrease in the incidence of cases per year (p = 0.0008). Plasmodium falciparum infection was predominant (n = 217) followed by P. vivax infection (n = 76). 37% of all cases were Africans visiting relatives and friends (VRF). A total of 12 patients had one or more re-lapses of their P. vivax infection. In all, 53 (17%) cases were defined as severe malaria. 36% (n = 112) reported using some type of chemoprophylaxis. 14% (n = 26) of patients traveling to Africa in 1999-2012 reported taking chemoprophylaxis as recommended in the current guidelines. Complicated malaria was significantly associated with failure to take any chemoprophylaxis (p = 0.0317, chi(2)-test). CONCLUSION: Imported malaria is decreasing at the DID. The patients who carry the highest risk of imported malaria are ethnic Africans who travel as VRF without using chemoprophylaxis. Recrudescence from P. vivax malaria is a substantial risk. Complicated malaria is associated with failure to take any chemoprophylaxis. It is important that travelers receive expedient advice on the use of efficient chemoprophylaxis to bring down the number of imported malaria cases. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814738 TI - The Identification of Seniors at Risk screening tool is useful for predicting acute readmissions. AB - INTRODUCTION: Acutely ill elderly medical patients have a higher chance of survival if they are admitted to a specialised geriatric unit instead of a general medical unit. This was shown in a meta-analysis from 2011 which included more than 10,000 elderly patients. The best effect of geriatric intervention is seen when patients are selected carefully. The patients' need for geriatric intervention was assessed to determine if there was a relation between a screening tool and the assessment made by a specialist of geriatrics (SG). MATERIAL AND METHODS: A descriptive cohort study was conducted. Patients >= 65 years treated during a 14-day period were included. Their mean age was 78 years. Screening with the Identification of Seniors at Risk (ISAR) was performed (n = 198) by the Mobile Geriatric Team (MGT). The patients' medical journals were assessed retrospectively by the SG to determine any need for assessment and intervention. RESULTS: 53% of the admitted and 77% of the non-admitted patients would have benefitted from assessment by the MGT, and 22% would have benefitted from transfer directly to the Geriatric Unit. The readmitted patients and the patients who died during follow-up had a mean ISAR score of three compared with the non-readmitted patients who had a mean score of two. Patients with either nutritional or cognitive problems, or depression had a mean score of three. CONCLUSION: To identify elderly patients with a need for comprehensive geriatric assessment, we recommend that triage be supplemented with the ISAR screening. Furthermore, patients with a score of >= 2 should be assessed by the MGT so that a post-discharge plan including treatment/rehabilitation and follow-up may be drawn up. FUNDING: not relevant. TRIAL REGISTRATION: The study was approved and registered with the Danish Data Protection Agency under the Capital Region of Denmark's joint notification of health research (j. no.: 2007-58-0015, AMH-2013 003, I-Suite no.: 02495). PMID- 24814739 TI - Manifestations of Gorlin-Goltz syndrome. AB - INTRODUCTION: Gorlin-Goltz syndrome is an uncommon hereditary condition caused by mutations in the PTCH1 gene causing a wide range of developmental abnormalities. Multiple basal cell carcinomas, palmoplantar pits and jaw cysts are cardinal features. Many clinicians are unfamiliar with the different manifestations and the fact that patients are especially sensitive to ionizing radiation. MATERIAL AND METHODS: This was a retrospective analysis of patients with Gorlin-Goltz syndrome seen at the Department of Dermatology and Allergy Centre or at Department of Plastic Surgery, Odense University Hospital, Denmark, in the period from 1994 to 2013. RESULTS: A total of 17 patients from eight families fulfilled the diagnostic criteria. In all, 14 patients had basal cell carcinomas, 12 patients had jaw cysts and ten patients had calcification of the falx cerebri. Other clinical features were frontal bossing, kyphoscoliosis, rib anomalies, coalitio, cleft lip/palate, eye anomalies, milia and syndactyly. In one family, medulloblastoma and astrocytoma occurred. Traditional treatment principles of basal cell carcinomas were used including radiotherapy performed in six patients. PTCH1 mutations were identified in five families and none of these mutations had previously been described. CONCLUSION: The patient cohort illustrates classic and rare disease manifestations. It is necessary to remind clinicians that radiation therapy in Gorlin-Goltz syndrome is relatively contraindicated. Today, mutation analysis can be used for confirmation of the diagnosis and for predictive genetic testing. Patients should be offered genetic counselling and life-long surveillance. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814740 TI - Wrist arthroplasty--a systematic review. AB - INTRODUCTION: Severely painful or dysfunctional destroyed wrists can be reconstructed by fusion, interposition of soft-tissue or by arthroplasty using artificial materials. Total and partial wrist arthroplasty (T/PWA) has been used on a regular basis since the 1960's. The objective of this study was to review the literature on second, third and fourth generation implants. METHODS: The review was conducted according to the PRISMA-guidelines. A search was made using a protocolled strategy and well-defined criteria in PubMed, in the Cochrane Library and by screening reference lists. RESULTS: 37 publications describing a total of 18 implants were selected for analysis. 16 of the publications were useful for the evaluation of implant longevity. Despite methodological shortcomings in many of the source documents, a summary estimate was possible. CONCLUSION: It seems that T/PWA has a good potential to improve function through pain reduction and preservation of mobility. The risk of severe complications - deep infection and instability problems - is small with the available implants. Implant survival of 90-100% at five years are reported in most series - if not all - using newer second generation and third generation implants, but declines from five to eight years. Periprosthetic osteolysis/radiolucency is frequently reported. Its causes and consequences are not clarified. PMID- 24814741 TI - Insufficient pain management after spine surgery. AB - INTRODUCTION: A prospective observational quality assurance study was performed at Glostrup Hospital, Denmark, to describe patients undergoing spine surgery with regard to perioperative analgesic management, post-operative pain, opioid consumption and side effects. MATERIAL AND METHODS: Patients eligible for the study were identified consecutively from the operation chart. The following data were registered: post-operative visual analogue (VAS) pain score at rest and during mobilisation, opioid consumption for the first 24 h, other analgesics administered and side effects. RESULTS: A total of 87 patients were included. For instrumented lumbar fusion patients (n = 24), the VAS pain scores at 1, 4 and 24 h after surgery were (median (interquartile range)) 5 (0-7), 2.5 (0-8) and 5.5 (0 9) at rest and 5 (0-8), 3 (0-9) and 7 (3-9) during mobilisation, respectively. The other surgical subgroups generally experienced VAS <= 3. For instrumented lumbar fusion, the total 0-24 h consumption of intravenous morphine equivalents was 39.1 (27.5-62.7) mg. Only eight of 87 patients received the entire scheduled standard post-operative pain treatment. Adverse events were rare. CONCLUSION: Most patients experienced acceptable pain levels, but instrumented lumbar fusion leads to moderate to severe pain levels and a relatively high opioid consumption. The scheduled standard pain management protocols were sparsely followed. Challenges exist in post-operative pain management as observed in previous surveys, especially for instrumented lumbar fusion surgery. Future work should focus on optimising treatment plans. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814742 TI - Diabetes mortality differs between registers due to various disease definitions. AB - INTRODUCTION: We evaluated the impact of including haemolobbing A1c (HbA1c) measurements in a regional algorithm for identification of diabetics by comparing the population identified by the regional algorithm with diabetics registered in the National Danish Diabetes Register (NDR) relative to prevalence, co-morbidity and five-year mortality rate. MATERIAL AND METHODS: The regional (County of Vejle) and national diabetes populations were compared per the inclusion date of 31 December 2006 limited to persons residing in four municipalities in the County of Vejle, Denmark. RESULTS: A total of 14,998 diabetics were identified by the regional algorithm, of whom 11,499 (prevalence 4.1%) resided in the four municipalities. The total number of diabetics registered in the NDR was 227,621 in Denmark, of whom 10,976 (prevalence 4.0%) resided in the four municipalities. The regional diabetics (2,802 persons) not identified in the NDR population had a significantly lower mortality rate (57%) than the diabetics (2,279 persons) in the NDR population not identified by the regional algorithm. CONCLUSION: The significantly higher mortality in the NDR population not identified by the regional algorithm may stem from differences between the components of the two algorithms, i.e. frequency of glucose measurements in the NDR versus frequency of HbA1c measurements including elevated values in the regional algorithm. The NDR algorithm, which includes the use of frequency of glucose measurements without a value over the diagnostic threshold, identified about 21% of persons who probably had their glucose measured for other reasons than diabetes. FUNDING: The Danish Council for Research and Innovation, Region of Southern Denmark's PhD Fund, University of Southern Denmark and the Research Fund, Vejle Hospital. TRIAL REGISTRATION: not relevant. PMID- 24814743 TI - Self-reported quality of life and functional outcome in patients with rectal cancer--QoLiRECT. AB - INTRODUCTION: The treatment of rectal cancer has improved, and survival rates today exceed those of colon cancer, but functional impairments and other adverse effects of treatment are common among patients. The impact of treatment on patients' quality of life (QoL) remains unclear. Many of the common QoL instruments are brief and not sufficiently detailed to provide a deeper understanding of the factors that determine QoL. The aim of this study was to explore patients' experiences and long-term QoL in an unselected cohort of patients with rectal cancer. METHODS: This is a prospective international multicentre study based on a comprehensive, validated questionnaire on functional impairments and QoL administered to an unselected population of 1,500 patients with rectal cancer at diagnosis and after one, two and five years. The clinical characteristics are retrieved from the national quality registers. A total of 14 hospitals in Sweden and Denmark are currently involved in the study. Inclusion is ongoing, and new including hospitals are welcome to join. Full accrual is expected within two years. CONCLUSION: This study will provide detailed knowledge about the challenges that patients face following diagnosis and treatment of rectal cancer. It will investigate the nature, severity and perceived significance of constraints and symptoms, as well as the impact of a variety of clinical and patient-related factors on QoL. The study will probably identify areas where changes in care routines may improve patients' QoL. FUNDING: This study was supported by the Swedish Research Council, grant number 2012-1768; the Swedish Cancer Society CAN 2010/593 and CAN 2013/500; the Swedish Society of Medicine; the Gothenburg Medical Society; the Health & Medical Care Committee of the Regional Executive Board, Region Vastra Gotaland; ALF grant 138751 and 136151, "Agreement concerning research and education of doctors"; Anna-Lisa and Bror Bjornsson Foundation; Assar Gabrielsson Foundation; Mary von Sydow Foundation; Ruth and Richard Julin's Foundation and Lion's Cancer Research Foundation of Western Sweden. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01477229). PMID- 24814744 TI - Robot-assisted rectopexy is a safe and feasible option for treatment of rectal prolapse. AB - INTRODUCTION: Rectal prolapse is seen in up to one in 100 elderly women and results in symptoms such as incontinence, mucus secretion and constipation. The aim of this study was to present short- and longterm outcomes after robot assisted rectopexy in patients with rectal prolapse. MATERIAL AND METHODS: All patients diagnosed with rectal prolapse at our institution underwent robot assisted rectopexy. Data regarding the surgical procedure and post-operative morbidity were collected retrospectively. Patients were contacted to register long-term results regarding recurrence, incontinence and satisfaction. RESULTS: A total of 24 consecutive patients underwent robot-assisted rectopexy from October 2010 to July 2012. Data regarding their long-term outcome was available for 18 patients at follow-up (average ten months). 50% of the patients suffered from faecal incontinence before surgery (n = 9/18, 50%). The mean age at surgery was 72 years (28-93 years). The mean duration of surgery was 123 min. (70-245 min.). The median length of stay in hospital was 4.1 days (0-15 days). There was one procedure-related complication (small-bowel obstruction) resulting in reoperation. At the time of follow-up, two patients (11%) had a subjective recurrence of rectal prolapse, and three patients (17%) had faecal incontinence. 89% were satisfied with the operation, and 94% would recommend this operation to other patients with the same condition. CONCLUSION: Robot-assisted rectopexy is a safe procedure for patients with rectal prolapse and is associated with acceptable functional outcomes and recurrence rates. There is no evidence in the literature of advantages compared with the corresponding laparoscopic procedure. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814745 TI - Leakage and internal herniation are the most common complications after gastric bypass. AB - INTRODUCTION: The aim is to report the diagnostic strategy, clinical findings and treatment in patients admitted on suspicion of early or late complications associated with a previous laparoscopic Roux-en-Y gastric bypass (LRYGB). MATERIAL AND METHODS: Patients admitted in 2011-2012 to our department with the International Classification of Diseases 10 code DZ980C (condition with a gastric bypass) were identified using the Hospital register system. Patient data included co-morbidity, time between LRYGB and the actual admission, body mass index development, diagnostic strategy, clinical findings and treatment of complications. Early and late complications were defined as 30 days post operatively. RESULTS: Among 186 patients, the primary early complication was leakage or unexplained abdominal pain. Internal hernia or unexplained abdominal pain was observed most frequently as a late complication. The majority of patients had a computed tomography performed as their first diagnostic procedure. 19% of patients who were operated for internal hernia underwent a re-operation. Among patients undergoing laparoscopy, 72% had internal hernia and 20% had a leak. The length of stay was 18 days for patients with leakage compared to three days for patients with internal hernia. CONCLUSION: In conclusion, the primary early complication of LRYGB patients was leakage, and internal hernia was the most frequent late complication. A substantial number of the patients who are readmitted after LRYGB suffer from unexplained abdominal pain that should be managed by specialised centres. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814746 TI - A feasible method to study the Danish out-of-hours primary care service. AB - INTRODUCTION: The primary care out-of-hours (OOH) service is of considerable importance; it is the main provider of freely accessible medical advice outside daytime hours, and it covers 75% of the active time in the health-care system. Although the OOH handles three million contacts annually, only little is known about the reasons for encounter, the performed clinical work and the patient perspectives. MATERIAL AND METHODS: During a one-year period (2010-2011), data on patient contacts were collected using pop-up questionnaires integrated into the existing IT system. The questions explored the contents and characteristics of patient contacts. A paper-based questionnaire was sent to the included patients. RESULTS: Of all 700 general practitioners (GP) on duty, 383 (54.7%) participated at least once, and the participating GPs were representative of all GPs. In total, 21,457 contacts were registered; and the distribution of patient, contact and GP characteristics in OOH contacts was similar to the background contacts. Telephone consultations were most often offered to children and home visits primarily to elderly patients. The patient response rate was 51.2%. Females comprised the majority of the included contacts and of the respondents in the patient survey. CONCLUSION: The method was highly feasible for generating a representative sample of contacts to OOH services. The project has formed a substantial and valid basis for further studies and future research in the OOH service. FUNDING: Financed by the Region of Central Jutland, the Danish National Research Foundation for Primary Care and the Health Foundation. TRIAL REGISTRATION: not relevant. PMID- 24814747 TI - Patient reported outcomes in hip arthroplasty registries. AB - PROs are used increasingly in orthopedics and in joint registries, but still many aspects of use in this area have not been examined in depth. To be able to introduce PROs in the DHR in a scientific fashion, my studies were warranted; the feasibility of four often used PROs (OHS, HOOS, EQ-5D and SF-12) was examined in a registry context. Having the PROs in the target language is an absolute necessity, so I translated, cross-culturally adapted and validated a Danish language version of an often used PRO (OHS), since this PRO had no properly developed Danish language version. To minimize data loss and to maximize the data quality I validated our data capture procedure, an up to date AFP system, by comparing scannable, paper-based PROs, with manual single-key- and double-key entered data. To help further registry-PRO studies, I calculated the number of patients needed to discriminate between subgroups of age, sex, diagnosis, and prosthesis type for each of four often used PROs (OHS, HOOS, EQ-5D and SF-12), and to simplify the clinical interpretation of PRO scores and PRO change scores in PRO studies, I estimated MCII and PASS for two often used PROs (EQ-5D and HOOS). The feasibility study included 5,747 THA patients registered in the DHR, and I found only minor differences between the disease-specific and the generic PROs regarding ceiling and floor effects as well as discarded items. The HOOS, the OHS, the SF-12, and the EQ-5D are all appropriate PROs for administration in a hip registry. I found that group sizes from 51 to 1,566 were needed for subgroup analysis, depending on descriptive factors and choice of PRO. The AFP study included 200 THA patients (398 PROs, 4,875 items and 21,887 data fields), and gave excellent results provided use of highly structured questionnaires. OMR performed equally as well as manual double-key entering, and better than single key entering. The PRO translation and validation study included 2,278 patients (and 212 patients for the test-retest). I found that the translated PRO had good feasibility, an excellent response rate, no floor effect, but a high ceiling effect (as was expected with our postoperative patients) and few patients missed too many items to calculate a sum score. The translated PRO had high test-retest reliability and very high internal consistency, and appears to be a valid and reliable tool for outcome studies on THA patients in a hip registry setting. The MCII and PASS study included 1,335 patients, and I estimated that one year after THA, an improvement of 38-55% from mean baseline PRO score and absolute follow-up scores of 57-91% of the maximum score correspond to a minimal important improvement and acceptable symptom state, respectively. PMID- 24814748 TI - The epidemiology and risk factors for recurrence after inguinal hernia surgery. AB - BACKGROUND: Recurrence after inguinal hernia surgery is a considerable clinical problem, and several risk factors of recurrence such as surgical technique, re recurrence, and family history have been identified. Non-technical patient related factors that influence the risk of recurrence after inguinal hernia surgery are sparsely studied. The purpose of the studies included in this PhD thesis, was to describe the epidemiologic characteristics of inguinal hernia occurrence and recurrence, as well as investigating the patient related risk factors leading to recurrence after inguinal hernia surgery. Four studies were included in this thesis. METHODS AND RESULTS: Study 1: The study was a nationwide register-based study combining the Civil Registration System and the Danish National Hospital Register during a five-year period. We included a total of 46,717 persons operated for a groin hernia from the population of 5,639,885 people (2,799,105 males, 2,008,780 females). We found that 97% of all groin hernia repairs were inguinal hernias and 3% femoral hernias. Data showed that inguinal hernia surgery peaked during childhood and old age, whereas femoral hernia surgery increased throughout life. Study 2: Using data from the Danish Hernia Database (DHDB), we included all male patients operated for elective primary inguinal hernia during a 15-year period (n = 85,314). The overall inguinal hernia reoperation rate was 3.8%, and subdivided into indirect inguinal hernias and direct inguinal hernias, the reoperation rates were 2.7% and 5.2%, respectively (p <0.001, chi-square). In the multivariate Cox proportional hazards analysis of factors predicting reoperation, we found that a direct inguinal hernia at primary operation was a substantial risk factor for recurrence with a Hazard ratio of 1,90 (CI 95% 1.77-2.04) compared with an indirect inguinal hernia at primary operation (p < 0.001). We found that there was a significant relationship between the type of hernia at the primary operation and reoperation, when controlling for the effect of the operation method, r = 0.45 (p < 0.001). This corresponded to odds ratios (OR) of 7.1 (CI 95% 6.0-8.4) of being reoperated for a direct inguinal hernia if the hernia at the primary operation was a direct inguinal hernia, and an OR of 3.0 (CI 95% 2.7-3.3) of being reoperated for an indirect inguinal hernia if the primary operation was for an indirect inguinal hernia. As subsequent findings, we saw that the frequency of laparoscopic hernia repair increased during the study period and that the laparoscopic repair of indirect inguinal hernias recurred more often than indirect inguinal hernias operated by Lichtenstein's technique (p < 0.001). Study 3: Using data from the DHDB, we included all female patients operated for elective primary inguinal hernia during a 15-year period (n = 5,893). Of those, a total of 305 operations for recurrences were registered (61 % inguinal recurrences, 38 % femoral recurrences, 1 % no hernial), which corresponded to an overall crude reoperation rate of 5.2%. A noticeable difference was found in reoperation rates after primary operation for direct inguinal hernias (DIH), indirect inguinal hernias (IIH) and combined IIH+DIH of 11.0%, 3.0%, and 0.007% respectively (p < 0.001, chi-square). In the multivariate Cox proportional hazards analysis of factors predicting reoperation, we found that a direct inguinal hernia at primary operation was a substantial risk factor for recurrence with a Hazard ratio of 3.1 (CI 95% 2.4-3.9) compared with an indirect inguinal hernia at primary operation (p < 0.001). Laparoscopic operation was found to give a lower risk of recurrence with a Hazard ratio of 0.57 (CI 95% 0.43-0.75) compared with Lichtenstein's technique (p < 0.001). We found that all femoral recurrences (n = 116) occurred after Lichtenstein's procedure and none occurred after laparoscopic operation (p < 0.001, Log Rank test). Study 4: This study was a systematic review and meta analysis of non-technical patient-related risk factors for recurrence after inguinal hernia surgery. From a total of 5,061 potentially relevant records we included 40 studies in the review covering 719,901 procedures in 714,167 patients and of those 14 studies covering 378,824 procedures in 375,620 patients were included into meta-analysis of eight risk factors (gender, age, hernia type, hernia size, re-recurrence, bilaterality, mode of admission and smoking). We found that female gender (RR 1.38, 95% CI 1.28-1.48, I2 = 0%), direct inguinal hernias at primary procedure (RR 1.91, 95% CI 1.62-2.26, I2 = 10%), operation for a recurrent inguinal hernia (RR 2.2, 95% CI 2.0-2.42, I2 = 6%), and smoking (OR 2.53, 95% CI 1.43-4.47, I2 = 0%) were risk factors for recurrence after inguinal hernia surgery. Furthermore, emergency admission; connective tissue composition and degradation; and positive family history were found to have an impact on the risk of recurrence, while post-operative convalescence and age had no impact on the risk of recurrence. CONCLUSION: The studies included in the thesis have studies the natural history of groin hernias on a nationwide basis; have identified the epidemiologic distribution of groin hernias and the non-technical risk factors associated with recurrence. Data showed that non-technical patient related risk factors have great impact on the risk of recurrence after inguinal hernia surgery. The reason to why inguinal hernias recur is most likely multifactorial and lies in the span of technical and non-technical patient related risk factors and it is possible that the different groin hernia subtypes have different pathophysiology. This knowledge should be implemented into clinical practice in order to reduce the risk of recurrence and in future research design examining recurrence after inguinal hernia surgery as outcome. PMID- 24814749 TI - Influence of alkaline co-contaminants on technetium mobility in vadose zone sediments. AB - Pertechnetate was slowly reduced in a natural, untreated arid sediment under anaerobic conditions (0.02 nmolg(-1)h(-1)), which could occur in low permeability zones in the field, most of which was quickly oxidized. A small portion of the surface Tc may be incorporated into slowly dissolving surface phases, so was not readily oxidized/remobilized into pore water. In contrast, pertechnetate reduction in an anaerobic sediment containing adsorbed ferrous iron as the reductant was rapid (15-600 nmolg(-1)h(-1)), and nearly all (96-98%) was rapidly oxidized/remobilized (2.6-6.8 nmolg(-1)h(-1)) within hours. Tc reduction in an anaerobic sediment containing 0.5-10mM sulfide showed a relatively slow reduction rate (0.01-0.03 nmolg(-1)h(-1)) that was similar to observations in the natural sediment. Pertechnetate infiltration into sediment with a highly alkaline water resulted in rapid reduction (0.07-0.2 nmolg(-1)h(-1)) from ferrous iron released during biotite or magnetite dissolution. Oxidation of NaOH-treated sediments resulted in slow Tc oxidation (~0.05 nmolg(-1)h(-1)) of a small fraction of the surface Tc (13-23%). The Tc remaining on the surface was Tc(IV) (by XANES), and autoradiography and elemental maps of Tc (by electron microprobe) showed Tc was present associated with specific minerals, rather than being evenly distributed on the surface. Dissolution of quartz, montmorillonite, muscovite, and kaolinite also occurred in the alkaline water, resulting in significant aqueous silica and aluminum. Over time, aluminosilicates, cancrinite, zeolite and sodalite were precipitating. These precipitates may be coating surface Tc(IV) phases, limiting reoxidation. PMID- 24814750 TI - Water-stress-induced inhibition of alpha-tubulin gene expression during growth, and its implications for reproductive success in rice. AB - A drought-suppressed cDNA (RiP-3), encoding a putative alpha-tubulin protein was isolated from rice panicle at pollen-mother-cell meiosis stage. Analysis of its deduced amino acid sequence showed all the typical structural motifs for plant alpha-tubulins. The expression of alpha-tubulin transcripts was observed in all the reproductive organs of rice panicle, and in 5- or 15-day old seedlings, but not in mature leaves. Expression levels were positively correlated with the regions and periods of high growth, and the transcript level declined in parallel with drought-induced reduction in growth rates in all tissues examined. Immunoblot analysis of proteins separated by SDS-PAGE with anti-alpha-tubulin monoclonal antibody showed that the level of protein paralleled the changes in the transcript abundance in these organs. In situ immunolocalization of the alpha tubulin protein in sections of the basal part of 5-day old seedlings showed that the highest levels of the protein were associated with the fastest growing leaf whorls, and the protein level declined upon a brief episode of water stress. Given the known critical role of tubulin in cell division and elongation, the results indicate that the expression of alpha-tubulin gene may be part of the events that suppress panicle elongation during water deficit, which is in turn a suspected cause of male reproductive failure and yield reduction in rice. PMID- 24814751 TI - Intervention effects on negative affect of CPS-referred children: results of a randomized clinical trial. AB - Exposure to early adversity places young children at risk for behavioral, physiological, and emotional dysregulation, predisposing them to a range of long term problematic outcomes. Attachment and Biobehavioral Catch-up (ABC) is a 10 session intervention designed to enhance children's self-regulatory capabilities by helping parents to behave in nurturing, synchronous, and non-frightening ways. The effectiveness of the intervention was assessed in a randomized clinical trial, with parents who had been referred to Child Protective Services (CPS) for allegations of maltreatment. Parent-child dyads received either the ABC intervention or a control intervention. Following the intervention, children from the ABC intervention (n=56) expressed lower levels of negative affect during a challenging task compared to children from the control intervention (n=61). PMID- 24814752 TI - Enumeration of probiotic strains: Review of culture-dependent and alternative techniques to quantify viable bacteria. AB - Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Standard culture techniques are commonly used to quantify probiotic strains, but cell culture only measures replicating cells. In response to the stresses of processing and formulation, some fraction of the live probiotic microbes may enter a viable but non-culturable state (VBNC) in which they are dormant but metabolically active. These microbes are capable of replicating once acclimated to a more hospitable host environment. An operating definition of live probiotic bacteria that includes this range of metabolic states is needed for reliable enumeration. Alternative methods, such as fluorescent in situ hybridization (FISH), nucleic acid amplification techniques such as real-time quantitative PCR (RT-qPCR or qPCR), reverse transcriptase (RT PCR), propidium monoazide-PCR, and cell sorting techniques such as flow cytometry (FC)/fluorescent activated cell sorting (FACS) offer the potential to enumerate both culturable and VBNC bacteria. Modern cell sorting techniques have the power to determine probiotic strain abundance and metabolic activity with rapid throughput. Techniques such as visual imaging, cell culture, and cell sorting, could be used in combination to quantify the proportion of viable microbes in various metabolic states. Consensus on an operational definition of viability and systematic efforts to validate these alternative techniques ultimately will strengthen the accuracy and reliability of probiotic strain enumeration. PMID- 24814753 TI - A new method for rapid screening of ester-producing yeasts using in situ HS-SPME. AB - The selection of ester-producing yeasts is difficult because these molecules evaporate quickly, are extremely unstable and may be missed during analytical manipulation. We propose an easy, fast and efficient headspace-SPME method for screening of ester-producing yeasts directly at the extraction vials (in situ HS SPME). PMID- 24814755 TI - Efficacy of bortezomib for reducing donor-specific antibodies in children and adolescents on a steroid minimization regimen. AB - AMR is increasingly being recognized as an important cause of renal allograft injury, contributing to significant morbidity and graft loss. There are few controlled trials and no well-established treatment guidelines for AMR in renal transplant recipients. We retrospectively reviewed the outcome of four pediatric renal transplant recipients on a steroid minimization immunosuppression protocol treated with bortezomib for elevated DSA and acute AMR from 2012 to 2013. All patients received four doses of bortezomib 1.3 mg/m2 given on days one, four, eight, and 11. All patients also received other treatments prior to bortezomib, which may have included rituximab, methylprednisolone, plasmapheresis, and/or IVIg. While bortezomib in addition to other therapies significantly decreased DSA titers, DSA remained very elevated months after treatment. All four patients had immediate improvement or stabilization of renal function but one eventually lost her graft. There were no adverse events related to bortezomib six months after treatment. PMID- 24814756 TI - Temporal dynamics of prokaryotic communities in the marine sponge Sarcotragus spinosulus. AB - In spite of their putative relevance to host functioning, in-depth knowledge of sponge microbiome stability over time is scarce. This study tackles the temporal maintenance of bacterial and archaeal assemblages in the model host Sarcotragus spinosulus along three successive years. Prokaryotic communities were profiled by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and 454-pyrosequencing of S. spinosulus-derived 16S rRNA gene amplicons. Prevailing bacterial phyla were Actinobacteria, Acidobacteria, Proteobacteria, Poribacteria, PAUC34f, Chloroflexi and Bacteroidetes, with Bacteroidetes, Chloroflexi and Poribacteria showing different abundances over the years. At the approximate species level (operational taxonomic units, OTUs, defined at 97% sequence similarity), no major changes in bacterial richness and composition were found through time. Nearly 50% of all detected bacterial symbionts (96 in 205 OTUs) were recovered from all sampling years, whereas a taxonomically equivalent community of less dominant bacteria characterized the transient sponge microbiota. Despite the evidence for temporal symbiont maintenance, an intriguing cumulative degree of variation between individuals was unravelled, with all the surveyed sponge specimens sharing only 27 bacterial OTUs. Archaeal communities were dominated by one single symbiont of the candidate genus Nitrosopumilus (Thaumarchaeota), known for its ability to aerobically oxidize ammonia to nitrite. Only few bacterial ammonia oxidizers consistently occurred in S. spinosulus across the years as documented by PCR-DGGE fingerprinting. In conclusion, prokaryotic symbionts of S. spinosulus display a state of dynamic stability shaped by the interplay between the maintenance of dominant players and turnover of less prevalent community members, in time and across host individuals, with no apparent consequences to holobiont functioning. PMID- 24814757 TI - Safety of low- to medium-dose glucocorticoid treatment in rheumatoid arthritis: myths and reality over the years. AB - Low- to medium-dose glucocorticoids have been shown to have not only anti inflammatory but also disease-modifying properties in rheumatoid arthritis. The evidence for the benefit of its early use in combination with disease-modifying antirheumatic drugs underlines the need for a close evaluation of their risk benefit ratio. Over time, numerous myths and fears about glucocorticoid toxicity in rheumatoid arthritis have arisen from observational studies, and many concerns have been unduly extrapolated from observations with higher-dose treatment. Furthermore, we cannot exclude the possibility of a powerful effect of bias by indication in these studies. Low- to medium-dose glucocorticoid regimens continued to be evaluated in randomized clinical trials, particularly in early disease, but these studies also have relevant methodological limitations in assessing safety, particularly due to small size and/or short duration. At present, the evidence on which to support clear recommendations about glucocorticoid toxicity remains remarkably weak. A large prospective pragmatic trial dedicated to the toxicity of low-dose glucocorticoids is dearly needed. Meanwhile, adherence to recommendations on standardized methodologies for registration and report of glucocorticoid adverse events is essential for improving our knowledge and competence in the best management of these important medications. PMID- 24814758 TI - In vitro evaluation of nonconventional accessory devices for pressurized metered dose inhalers. AB - BACKGROUND: The selection of accessory devices for pressurized metered-dose inhalers (pMDIs) by health care professionals is typically cost driven without consideration of how the device modifies clinical outcomes. OBJECTIVE: To evaluate nonconventional accessory devices and the open-mouth technique with and without ideal coordination of actuation and inhalation to identify and understand the considerations for recommending potential inexpensive devices. METHODS: In vitro performance parameters of the beclomethasone dipropionate pMDI were evaluated with several devices (AeroChamber, toilet paper roll, paper towel roll, rolled paper, plastic bottle spacer, bottle-holding chamber, and nebulizer reservoir tubing). RESULTS: Compared with the pMDI alone, all the accessory devices evaluated have significantly lower drug exposure and throat deposition and higher respirable fractions, with the paper towel roll having the greatest effect of the devices evaluated (exposure decreased from a mean [SD] of 76.1 [4.8] MUg to 49.2 [2.0] MUg, throat deposition decreased from 32.0 [3.2] MUg to 0.8 [0.3] MUg, and respirable fraction increased from 49.8% [3.2%] to 96.4% [0.4%]). Introduction of a delay between actuation and inhalation resulted in greater variability in performance metrics for the devices evaluated, and the bottle-holding chamber and paper towel roll were most effective in mitigating the effect of the delay. The open-mouth technique was found to decrease throat deposition and respirable mass compared with the pMDI alone. CONCLUSION: In addition to cost, the amount of drug that deposits in the throat and the lungs and the effect of asynchronous actuation and inhalation can vary with the selection of an accessory device, which may affect the therapeutic benefits of the pMDI selected. PMID- 24814759 TI - Patient initiation and persistence with allergen immunotherapy. AB - BACKGROUND: Allergen immunotherapy (AIT) is advised for patients with allergic rhinitis who remain symptomatic despite the use of pharmacotherapy and allergen avoidance. Several factors influence the decision to initiate and complete the AIT regimen. OBJECTIVE: To evaluate patient initiation and persistence with subcutaneous and sublingual immunotherapies (SCIT and SLIT) according to physician recommendation. METHODS: A retrospective review of electronic health records of patients with allergic rhinitis for whom AIT was recommended was conducted in a large private allergy practice in Pennsylvania. RESULTS: Of 8,790 patients advised to consider AIT, 36.2% initiated AIT (57% adults, 43% children); 78% chose SCIT and 22% chose SLIT drops. Election of AIT was significantly associated with select comorbidities, specifically chronic sinusitis (8.1% for AIT vs 10% for no AIT), allergic conjunctivitis (12.5% for AIT vs 18.5% for no AIT), and asthma (33.8% for AIT vs 37.4% for no AIT; P < .05). Choice of SCIT vs SLIT drops was significantly associated with older age, female sex, select comorbidities, and more allergy medications at initiation (P < .05). Of adults, 30.2% completed at least 3 years of recommended treatment. Median time on treatment was longer for adults on SCIT vs SLIT drops (3 vs 1.6 years). Similarly, 35.4% of children completed treatment, with a longer median time on treatment for SCIT (4.7 years) vs SLIT drops (3.5 years). CONCLUSION: A minority of patients initiated AIT according to allergist recommendation and a subset of these patients completed therapy. AIT might be an underused option that could benefit patients unable to manage allergic rhinitis symptoms by other means. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01549340. PMID- 24814760 TI - Automated cytochemistry of acute promyelocytic leukemia: there's more than numbers. PMID- 24814762 TI - The role of vitamins and minerals in modulating the expression of microRNA. AB - A growing number of studies in recent years have highlighted the importance of molecular nutrition as a potential determinant of health and disease. In particular, the ability of micronutrients to regulate the final expression of gene products via modulation of transcription and translation is now being recognised. Modulation of microRNA (miRNA) by nutrients is one pathway by which nutrition may mediate gene expression. miRNA, a class of non-coding RNA, can directly regulate gene expression post-transcriptionally. In addition, miRNA are able to indirectly influence gene expression potential at the transcriptional level via modulation of the function of components of the epigenetic machinery (DNA methylation and histone modifications). These mechanisms interact to form a complex, bi-directional regulatory circuit modulating gene expression. Disease specific miRNA profiles have been identified in multiple disease states, including those with known dietary risk factors. Therefore, the role that nutritional components, in particular, vitamins and minerals, play in the modulation of miRNA profiles, and consequently health and disease, is increasingly being investigated, and as such is a timely subject for review. The recently posited potential for viable exogenous miRNA to enter human blood circulation from food sources adds another interesting dimension to the potential for dietary miRNA to contribute to gene modulation. PMID- 24814763 TI - Prevalence and risk factors of Giardia doudenalis in dogs from China. AB - The aim of this study was to carry out a survey for the presence of Giardia duodenalis infection in canine using ELISA and PCR and to identify risk factors for infection. Samples from 318 dogs' feces living in nine cities in China were used in the present study. Each sample was tested for the presence of G. duodenalis-specific antigens using ELISA and 197 out of 318 samples were further examined for the presence of G. duodenalis using PCR. The overall rate of canines infected with giardiasis in the present study was 16.04% and 15.22% using ELISA and PCR, respectively. No significant difference was found between sex and Giardia positivity. Young dogs (up to one year) and living in communities were identified as risk factors for infection by multivariate logistic regression analysis. In conclusion, giardiasis in dogs was present in nine cities in China; as risk factors, young dogs (up to one year) and living in communities were of great significance. Giardia-infected canine should be treated for hygienic management to prevent transmission of the infection from dog to human. PMID- 24814761 TI - Mcl-1 ubiquitination: unique regulation of an essential survival protein. AB - Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFbeta-TrCP, SCFFbw7 and Trim17) and one deubiquitinase (e.g., USP9X), that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system. PMID- 24814765 TI - Practicality of intraoperative teamwork assessments. AB - BACKGROUND: High-quality teamwork among operating room (OR) professionals is a key to efficient and safe practice. Quantification of teamwork facilitates feedback, assessment, and improvement. Several valid and reliable instruments are available for assessing separate OR disciplines and teams. We sought to determine the most feasible approach for routine documentation of teamwork in in-situ OR simulations. We compared rater agreement, hypothetical training costs, and feasibility ratings from five clinicians and two nonclinicians with instruments for assessment of separate OR groups and teams. MATERIALS AND METHODS: Five teams of anesthesia or surgery residents and OR nurses (RN) or surgical technicians were videotaped in simulations of an epigastric hernia repair where the patient develops malignant hyperthermia. Two anesthesiologists, one OR clinical RN specialist, one educational psychologist, one simulation specialist, and one general surgeon discussed and then independently completed Anesthesiologists' Non Technical Skills, Non-Technical Skills for Surgeons, Scrub Practitioners' List of Intraoperative Non-Technical Skills, and Observational Teamwork Assessment for Surgery forms to rate nontechnical performance of anesthesiologists, surgeons, nurses, technicians, and the whole team. RESULTS: Intraclass correlations of agreement ranged from 0.17-0.85. Clinicians' agreements were not different from nonclinicians'. Published rater training was 4 h for Anesthesiologists' Non Technical Skills and Scrub Practitioners' List of Intraoperative Non-Technical Skills, 2.5 h for Non-Technical Skills for Surgeons, and 15.5 h for Observational Teamwork Assessment for Surgery. Estimated costs to train one rater to use all instruments ranged from $442 for a simulation specialist to $6006 for a general surgeon. CONCLUSIONS: Additional training is needed to achieve higher levels of agreement; however, costs may be prohibitive. The most cost-effective model for real-time OR teamwork assessment may be to use a simulation technician combined with one clinical rater to allow complete documentation of all participants. PMID- 24814764 TI - Comparison of interleukin 10 homologs on dermal wound healing using a novel human skin ex vivo organ culture model. AB - BACKGROUND: Anti-inflammatory cytokine interleukin (IL)-10 has been shown to induce regenerative healing in postnatal wounds. A viral homolog of IL-10 produced by human cytomegalovirus (CMV IL-10) similarly generates potent immunoregulatory effects, but its effects on wound healing have not been investigated. Currently, there are limited cost-effective methods of screening vulnerary therapeutics. Taken together, we aim to develop and validate a novel human ex vivo dermal wound model and hypothesize that CMV IL-10 will enhance dermal wound healing. METHODS: Full-thickness circular (6-mm) explants were taken from surgical skin samples and 3-mm full-thickness wounds were created. Explants were embedded in collagen I matrix and maintained in specially formulated media with the epidermis at air-liquid interface, and treated with human IL-10 or CMV IL-10 (200 ng/mL). The viability of cultured explants was validated by histology and lactate dehydrogenase (LDH) activity. Epithelial gap, epithelial height, basal keratinocyte migration, vascular endothelial growth factor levels, and neovascularization were measured at days 3 and 7 to determine IL-10 effects on wound healing. RESULTS: Culture explants at day 7 appeared similar to fresh skin in morphology, cell, and vessel density. By day 14, the epidermis separated from the dermis and the cell density diminished. Day 7 wounds appeared viable with advancing epithelial and basal keratinocyte migration with no evidence of necrosis. Cytotoxicity analysis via the quantification of LDH revealed no differences between controls and treated groups. There was a slight increase in the quantity of LDH in media at day 3; however, this decreased at day 5 and continued to decline up to day 21. CMV IL-10 treatment resulted in a significant decrease in the epithelial gap and an increase in epithelial height. There were no differences in the rates of basal keratinocyte migration at day 7 between treated and control groups. Interestingly, human IL-10 increased vascular endothelial growth factor expression and neovascularization compared with controls. CONCLUSIONS: The human ex vivo wound model provides a simple and viable design to study dermal wound healing. Both IL-10 homologs demonstrate vulnerary effects. The viral homolog demonstrates enhanced effects on wound closure compared with human IL-10. These data represent a novel tool that can be used to screen therapeutics, such as CMV IL-10, before preclinical studies. PMID- 24814766 TI - A systematic review and meta-analysis comparing outcomes between robotic-assisted thyroidectomy and non-robotic endoscopic thyroidectomy. AB - BACKGROUND: Despite its feasibility, using the da Vinci robot in remote-access thyroidectomy remains controversial. This meta-analysis compared surgical and oncological outcomes between robotic-assisted thyroidectomy (RT) and non-robotic endoscopic thyroidectomy (ET). METHODS: A systematic review was performed to identify studies comparing outcomes between RT and ET. Outcomes included operating time, drain output, complications, number of central lymph nodes retrieved, and preablation stimulated thyroglobulin level. A random-effects model was used. RESULTS: Six studies were eligible. Of the 3510 patients, 2167 (61.7%) underwent RT whereas 1343 (38.3%) underwent ET. Despite a higher drain output (185.8 mLs versus 173.3 mLs, P = 0.019), RT had fewer temporary recurrent laryngeal nerve injury (2.6% versus 3.3%, P = 0.035) and shorter length of hospital stay (3.4 d versus 3.5 d, P = 0.030). In terms of oncological outcomes, despite higher incidence of multicentricity and larger tumors, the number of central lymph nodes retrieved during unilateral central neck dissection in RT was significantly greater than ET (4.5 +/- 2.6 and 3.4 +/- 2.5, P < 0.001) whereas the preablation stimulated thyroglobulin was comparable (0.8 ng/mL versus 1.1 ng/mL, P = 0.456). However, follow-up data were relatively scarce. CONCLUSIONS: Adding the robot in remote-access thyroidectomy was associated with a significantly lower risk of temporary recurrent laryngeal nerve injury and shorter length of hospital stay. However, despite achieving a comparable level of surgical completeness for low-risk differentiated thyroid carcinoma between RT and ET, this study highlighted the limitations with the current literature and the need for more prospective studies with adequate follow-up. PMID- 24814767 TI - Randomized clinical study evaluating the impact of mesh pore size on chronic pain after Lichtenstein hernioplasty. AB - BACKGROUND: The primary aim of this study was to determine whether mesh pore size influences the rate of chronic pain at 6-mo follow-up. Another aim was to evaluate the rate of foreign body feeling and quality of life after inguinal hernia repair. METHODS: The patients were randomized into two study groups: the UM group received Ultrapro mesh (pore size 3-4 mm) and the OM group received Optilene LP mesh (pore size 1 mm). Pain scores were measured on a visual analog scale. The feeling of a foreign body was a yes-or-no question. Quality of life was evaluated using the Medical Outcome Study Short-Form-36 questionnaire. RESULTS: A total of 67 patients in the UM group and 67 patients in the OM group were investigated 6 mo after operation. There were no significant differences in the results of the pain questionnaire between the study groups. Of the patients, 46.3% in the UM group reported pain during different activities at 6-mo follow-up versus 34.3% in the OM group (P = 0.165). The feeling of a foreign body in the inguinal region was experienced by 47.8% of the patients in the UM group and by 31.3% of the patients in the OM group at 6-mo follow-up (P = 0.052; risk ratio 1.52, 95% confidence interval: 1.00-2.37). There were no significant differences in the quality of life according to the Short-Form 36 questionnaire between the two study groups at 6-mo follow-up. In both study groups, the quality of life scores improved after operation by most dimensions. CONCLUSIONS: Differences in mesh pore size did not influence the rate of chronic pain. Although there was a trend for higher rate of foreign body feeling in the study group where a mesh with larger pores was used, we failed to find an explanation for this. The pore size of meshes investigated in this study did not affect the quality of life after inguinal hernia repair. Considering the fact that the quality of life improved significantly after operation, elective repair of symptomatic inguinal hernias should be undertaken as promptly as possible. PMID- 24814768 TI - The effects of different mixing intensities during anaerobic digestion of the organic fraction of municipal solid waste. AB - Mixing inside an anaerobic digester is often continuous and is not actively controlled. The selected mixing regime can however affect both gas production and the energy efficiency of the biogas plant. This study aims to evaluate these effects and compare three different mixing regimes, 150 RPM and 25 RPM continuous mixing and minimally intermittent mixing for both digestion of fresh substrate and post-digestion of the organic fraction of municipal solid waste. The results show that a lower mixing intensity leads to a higher biogas production rate and higher total biogas production in both cases. 25 RPM continuous mixing and minimally intermittent mixing resulted in similar biogas production after process stabilization, while 150 RPM continuous mixing resulted in lower production throughout the experiment. The lower gas production at 150 RPM could not be explained by the inhibition of volatile fatty acids. Cumulative biogas production until day 31 was 295 +/- 2.9, 317 +/- 1.9 and 304 +/- 2.8N ml/g VS added during digestion of fresh feed and 113 +/- 1.3, 134 +/- 1.1 and 130 +/- 2.3N ml/g VS added during post digestion for the 150 RPM, 25 RPM and minimally mixed intensities respectively. As well as increasing gas production, optimal mixing can improve the energy efficiency of the anaerobic digestion process. PMID- 24814769 TI - Importance of patient education on home medical care waste disposal in Japan. AB - To determine current practices in the disposal and handling of home medical care (HMC) waste, a questionnaire was mailed to 1965 offices nationwide. Of the office that responded, 1283 offices were analyzed. Offices were classified by management configuration: those attached to hospitals were classified as "attached offices" and others as "independent offices". More nurses from attached offices recovered medical waste from patients' homes than those from independent offices. Most nurses educated their patients on how to store HMC waste in their homes (79.3% of total) and on how to separate HMC waste (76.5% of total). On the other hand, only around half of nurses (47.3% from attached offices and 53.2% from independent offices) educated their patients on where to dispose of their HMC waste. 66.0% of offices replied that patients had separated their waste appropriately. The need for patient education has emerged in recent years, with education for nurses under the diverse conditions of HMC being a key factor in patient education. PMID- 24814770 TI - Characterization of Shredder Residues generated and deposited in Denmark. AB - This study presents a detailed characterization of Shredder residues (SR) generated and deposited in Denmark from 1990 to 2010. It represents approximately 85% of total Danish SR. A comprehensive sampling, size fractionation and chemical analysis was carried out on entire samples as well as on each individual size fraction. All significant elemental contents except oxygen were analyzed. The unexplained "balance" was subsequently explained by oxygen content in metal oxides, carbonates, sulphates and in organics, mainly cellulose. Using mass and calorific balance approaches, it was possible to balance the composition and, thereby, estimate the degree of oxidation of elements including metals. This revealed that larger fractions (>10mm, 10-4mm, 4-1mm) contain significant amount of valuable free metals for recovery. The fractionation revealed that the >10mm coarse fraction was the largest amount of SR being 35-40% (w/w) with a metal content constituting about 4-9% of the total SR by weight and the <1mm fine fraction constituted 27-37% (w/w) of the total weight. The lower heat value (LHV) of SR samples over different time periods (1990-2010) was between 7 and 17 MJ/kg, declining with decreasing particle size. The SR composition is greatly dependent on the applied shredding and post shredding processes at the shredding plants causing some variations. There are uncertainties related to sampling and preparation of samples for analyses due to its heterogeneous nature and uncertainties in the chemical analyses results (~15-25%). This exhaustive characterization is believed to constitute hitherto the best data platform for assessing potential value and feasibility of further resource recovery from SR. PMID- 24814771 TI - Endoscopic treatment of severe duodenal polyposis as an alternative to surgery for patients with familial adenomatous polyposis. AB - BACKGROUND: Patients with familial adenomatous polyposis (FAP) and severe (stage IV) duodenal polyposis are candidates for pancreaticoduodenectomy, which has high morbidity. Little information is available about the feasibility of therapeutic endoscopy for these patients. OBJECTIVE: To evaluate the long-term efficiency and risks of endoscopic therapy. DESIGN: Retrospective study. SETTING: A 2-referral center long-term cohort study. PATIENTS: Thirty-five FAP patients (15 men, mean age 48 years) presenting with stage IV duodenal polyposis were included. Patients had a mean Spigelman classification score of 9.8 points (range 9-12 points) at their first examination. INTERVENTIONS: Patients underwent a surveillance endoscopy, including lateral and axial viewing with chromoendoscopy while under sedation, along with 7 +/- 4.8 therapeutic endoscopic sessions during a follow-up period of 9 +/- 4.5 years (range 1-19 years) after their first endoscopy. MAIN OUTCOME MEASUREMENTS: Treatment modalities, adverse events, and efficiency (evolution of the Spigelman score) were reviewed. RESULTS: A total of 245 therapeutic endoscopies were performed and 15 adverse events (6%) occurred. During the follow-up period, Spigelman scores decreased in 95% of patients by 6 +/- 2.2 points (P = .002). Modeling analysis showed that the mean Spigelman score decreased by 60% after 150 months. LIMITATIONS: Retrospective study and the duration of the follow-up, even though this is the longest follow-up reported in medical literature. CONCLUSION: Endoscopic treatment of severe duodenal polyposis in patients with FAP produces few adverse events and allows efficient downstaging of the polyposis. Long-term follow-up data did not reveal a high risk of invasive duodenal cancer in these patients. PMID- 24814772 TI - Insulated-tip knife endoscopic resection of a giant pedunculated colon polyp. PMID- 24814773 TI - EUS-guided choledochoduodenostomy with lumen-apposing metal stent after failed rendezvous in synchronous malignant biliary and gastric outlet obstruction (with video). PMID- 24814774 TI - Screening colonoscopy versus sigmoidoscopy: implications of a negative examination for cancer prevention and racial disparities in average-risk patients. AB - BACKGROUND: Both colonoscopy and flexible sigmoidoscopy are accepted procedures for colorectal cancer (CRC) screening in the United States. OBJECTIVE: To compare risk of CRC after negative findings on screening colonoscopy versus sigmoidoscopy and to evaluate racial/ethnic disparities in postscreening CRC. DESIGN: Retrospective, comparative cohort study. SETTING: Integrated community-based health-care system. PATIENTS: Average-risk patients 50 to 75 years of age with negative findings on an initial endoscopic screening examination from January 2000 to December 2010. INTERVENTIONS: Colonoscopy versus sigmoidoscopy as the initial screening procedure. MAIN OUTCOME MEASUREMENTS: Incident cases of CRC identified via a prospective internal cancer registry, risk of CRC determined by Cox regression adjusted for age, sex, race/ethnicity, and comorbidity. RESULTS: The study cohort included 138,297 patients (42,938 patients with negative findings on colonoscopy and 95,359 with negative findings on sigmoidoscopy). The median age was 57.9 years (interquartile range 53.0-64.1 years). Women comprised 51.8% of the cohort with 42.2% non-Hispanic white patients, 24.1% Hispanic patients, 10.7% non-Hispanic black patients, 9.7% Asian patients, and 13.3% other/unknown. A total of 241 cases of CRC was detected during 553,543 person years of follow-up. The adjusted hazard ratio (HR) of postscreening CRC was 0.42 (95% confidence interval [CI], 0.28-0.64; P < .0001) for colonoscopy versus sigmoidoscopy. Risk reduction was primarily among proximal tumors (adjusted HR 0.30; 95% CI, 0.16-0.57). Non-Hispanic black patients were at higher risk of postscreening CRC compared with non-Hispanic white patients (adjusted HR 1.71; 95% CI, 1.20-2.42); however, this disparity was noted only in the sigmoidoscopy cohort. LIMITATIONS: Retrospective study with potential selection bias and residual confounding. CONCLUSIONS: Negative screening colonoscopy was associated with decreased incidence of subsequent CRC and a decrease in disparities compared with negative sigmoidoscopy findings in this large, community-based setting. PMID- 24814775 TI - Early precut fistulotomy for biliary access: time to change the paradigm of "the later, the better"? AB - BACKGROUND: The precut timing during the biliary cannulation algorithm is a subject of controversy. Some studies suggest that early institution of precut is a safe and effective strategy even though the extent to which this approach may affect the duration of the ERCP is seldom addressed. OBJECTIVE: To assess the success, safety, and procedure duration of an early precut fistulotomy (group A) versus a classic precut strategy after a difficult biliary cannulation (group B). DESIGN: Single-center, prospective cohort study. SETTING: University-affiliated hospital. PATIENTS: A total of 350 patients with a naive papilla. INTERVENTIONS: Standard biliary cannulation followed by needle-knife fistulotomy (NKF). MAIN OUTCOME MEASUREMENTS: Biliary cannulation rate, NKF success, adverse events, and ERCP duration. RESULTS: The overall cannulation rate was similar, at 96% and 94% for groups A and B, respectively. The adverse event rate was 6.2% and 6.4%, respectively, with pancreatitis as the most frequent adverse event (group A, 3.9%; group B, 5.2%). The mean ERCP duration was, however, significantly shorter in group A, both when biliary cannulation was achieved without precutting (14 minutes vs 25 minutes, P < .001) as well as when biliary cannulation was attempted after NKF (18 minutes vs 31 minutes, P < .0001). LIMITATIONS: Single center study design, referral center. CONCLUSIONS: If the endoscopist is experienced in ERCP and precut techniques, an early precut strategy should be the preferred cannulation strategy because this approach is as safe and effective as the late fistulotomy approach and substantially reduces ERCP duration. PMID- 24814776 TI - A premature stop codon in the TYRP1 gene is associated with brown coat colour in the European rabbit (Oryctolagus cuniculus). AB - Classical genetic studies in European rabbits (Oryctolagus cuniculus) suggested the presence of two alleles at the brown coat colour locus: a wild-type B allele that gives dense black pigment throughout the coat and a recessive b allele that in the homozygous condition (b/b genotype) produces brown rabbits that are unable to develop black pigmentation. In several other species, this locus is determined by mutations in the tyrosinase-related protein 1 (TYRP1) gene, encoding a melanocyte enzyme needed for the production of dark eumelanin. In this study, we investigated the rabbit TYRP1 gene as a strong candidate for the rabbit brown coat colour locus. A total of 3846 bp of the TYRP1 gene were sequenced in eight rabbits of different breeds and identified 23 single nucleotide polymorphisms (SNPs; 12 in intronic regions, five in exons and six in the 3'-untranslated region) and an insertion/deletion of 13 bp, in the 3'-untranslated region, organised in a few haplotypes. A mutation in exon 2 (g.41360196G>A) leads to a premature stop codon at position 190 of the deduced amino acid sequence (p.Trp190ter). Therefore, translation predicts a truncated TYRP1 protein lacking almost completely the tyrosinase domain. Genotyping 203 rabbits of 32 different breeds identified this mutation only in brown Havana rabbits. Its potential functional relevance in disrupting the TYRP1 protein and its presence only in brown animals strongly argue for this non-sense mutation being a causative mutation for the recessive b allele at the brown locus in Oryctolagus cuniculus. PMID- 24814777 TI - Adherence and proliferation of keratinocytes cultured with Candida albicans. PMID- 24814778 TI - A tailored galK counterselection system for efficient markerless gene deletion and chromosomal tagging in Magnetospirillum gryphiswaldense. AB - Magnetotactic bacteria have emerged as excellent model systems to study bacterial cell biology, biomineralization, vesicle formation, and protein targeting because of their ability to synthesize single-domain magnetite crystals within unique organelles (magnetosomes). However, only few species are amenable to genetic manipulation, and the limited methods for site-specific mutagenesis are tedious and time-consuming. Here, we report the adaptation and application of a fast and convenient technique for markerless chromosomal manipulation of Magnetospirillum gryphiswaldense using a single antibiotic resistance cassette and galK-based counterselection for marker recycling. We demonstrate the potential of this technique by genomic excision of the phbCAB operon, encoding enzymes for polyhydroxyalkanoate (PHA) synthesis, followed by chromosomal fusion of magnetosome-associated proteins to fluorescent proteins. Because of the absence of interfering PHA particles, these engineered strains are particularly suitable for microscopic analyses of cell biology and magnetosome biosynthesis. PMID- 24814779 TI - Functional heterologous production of reductive dehalogenases from Desulfitobacterium hafniense strains. AB - The anaerobic dehalogenation of organohalides is catalyzed by the reductive dehalogenase (RdhA) enzymes produced in phylogenetically diverse bacteria. These enzymes contain a cobamide cofactor at the active site and two iron-sulfur clusters. In this study, the tetrachloroethene (PCE) reductive dehalogenase (PceA) of the Gram-positive Desulfitobacterium hafniense strain Y51 was produced in a catalytically active form in the nondechlorinating, cobamide-producing bacterium Shimwellia blattae (ATCC 33430), a Gram-negative gammaproteobacterium. The formation of recombinant catalytically active PceA enzyme was significantly enhanced when its dedicated PceT chaperone was coproduced and when 5,6 dimethylbenzimidazole and hydroxocobalamin were added to the S. blattae cultures. The experiments were extended to D. hafniense DCB-2, a reductively dehalogenating bacterium harboring multiple rdhA genes. To elucidate the substrate spectrum of the rdhA3 gene product of this organism, the recombinant enzyme was tested for the conversion of different dichlorophenols (DCP) in crude extracts of an RdhA3 producing S. blattae strain. 3,5-DCP, 2,3-DCP, and 2,4-DCP, but not 2,6-DCP and 3,4-DCP, were reductively dechlorinated by the recombinant RdhA3. In addition, this enzyme dechlorinated PCE to trichloroethene at low rates. PMID- 24814780 TI - Microbial population dynamics in the hemolymph of Manduca sexta infected with Xenorhabdus nematophila and the entomopathogenic nematode Steinernema carpocapsae. AB - Xenorhabdus nematophila engages in a mutualistic association with the nematode Steinernema carpocapsae. The nematode invades and traverses the gut of susceptible insects. X. nematophila is released in the insect blood (hemolymph), where it suppresses host immune responses and functions as a pathogen. X. nematophila produces diverse antimicrobials in laboratory cultures. The natural competitors that X. nematophila encounters in the hemolymph and the role of antimicrobials in interspecies competition in the host are poorly understood. We show that gut microbes translocate into the hemolymph when the nematode penetrates the insect intestine. During natural infection, Staphylococcus saprophyticus was initially present and subsequently disappeared from the hemolymph, while Enterococcus faecalis proliferated. S. saprophyticus was sensitive to X. nematophila antibiotics and was eliminated from the hemolymph when coinjected with X. nematophila. In contrast, E. faecalis was relatively resistant to X. nematophila antibiotics. When injected by itself, E. faecalis persisted (~10(3) CFU/ml), but when coinjected with X. nematophila, it proliferated to ~10(9) CFU/ml. Injection of E. faecalis into the insect caused the upregulation of an insect antimicrobial peptide, while the transcript levels were suppressed when E. faecalis was coinjected with X. nematophila. Its relative antibiotic resistance together with suppression of the host immune system by X. nematophila may account for the growth of E. faecalis. At higher injected levels (10(6) CFU/insect), E. faecalis could kill insects, suggesting that it may contribute to virulence in an X. nematophila infection. These findings provide new insights into the competitive events that occur early in infection after S. carpocapsae invades the host hemocoel. PMID- 24814781 TI - The plasmid complement of Lactococcus lactis UC509.9 encodes multiple bacteriophage resistance systems. AB - Lactococcus lactis subsp. cremoris strains are used globally for the production of fermented dairy products, particularly hard cheeses. Believed to be of plant origin, L. lactis strains that are used as starter cultures have undergone extensive adaptation to the dairy environment, partially through the acquisition of extrachromosomal DNA in the form of plasmids that specify technologically important phenotypic traits. Here, we present a detailed analysis of the eight plasmids of L. lactis UC509.9, an Irish dairy starter strain. Key industrial phenotypes were mapped, and genes that are typically associated with lactococcal plasmids were identified. Four distinct, plasmid-borne bacteriophage resistance systems were identified, including two abortive infection systems, AbiB and AbiD1, thereby supporting the observed phage resistance of L. lactis UC509.9. AbiB escape mutants were generated for phage sk1, which were found to carry mutations in orf6, which encodes the major capsid protein of this phage. PMID- 24814782 TI - Abiotic stress resistance, a novel moonlighting function of ribosomal protein RPL44 in the halophilic fungus Aspergillus glaucus. AB - Ribosomal proteins are highly conserved components of basal cellular organelles, primarily involved in the translation of mRNA leading to protein synthesis. However, certain ribosomal proteins moonlight in the development and differentiation of organisms. In this study, the ribosomal protein L44 (RPL44), associated with salt resistance, was screened from the halophilic fungus Aspergillus glaucus (AgRPL44), and its activity was investigated in Saccharomyces cerevisiae and Nicotiana tabacum. Sequence alignment revealed that AgRPL44 is one of the proteins of the large ribosomal subunit 60S. Expression of AgRPL44 was upregulated via treatment with salt, sorbitol, or heavy metals to demonstrate its response to osmotic stress. A homologous sequence from the model fungus Magnaporthe oryzae, MoRPL44, was cloned and compared with AgRPL44 in a yeast expression system. The results indicated that yeast cells with overexpressed AgRPL44 were more resistant to salt, drought, and heavy metals than were yeast cells expressing MoRPL44 at a similar level of stress. When AgRPL44 was introduced into M. oryzae, the transformants displayed obviously enhanced tolerance to salt and drought, indicating the potential value of AgRPL44 for genetic applications. To verify the value of its application in plants, tobacco was transformed with AgRPL44, and the results were similar. Taken together, we conclude that AgRPL44 supports abiotic stress resistance and may have value for genetic application. PMID- 24814783 TI - Going wireless: Fe(III) oxide reduction without pili by Geobacter sulfurreducens strain JS-1. AB - Previous studies have suggested that the conductive pili of Geobacter sulfurreducens are essential for extracellular electron transfer to Fe(III) oxides and for optimal long-range electron transport through current-producing biofilms. The KN400 strain of G. sulfurreducens reduces poorly crystalline Fe(III) oxide more rapidly than the more extensively studied DL-1 strain. Deletion of the gene encoding PilA, the structural pilin protein, in strain KN400 inhibited Fe(III) oxide reduction. However, low rates of Fe(III) reduction were detected after extended incubation (>30 days) in the presence of Fe(III) oxide. After seven consecutive transfers, the PilA-deficient strain adapted to reduce Fe(III) oxide as fast as the wild type. Microarray, whole-genome resequencing, proteomic, and gene deletion studies indicated that this adaptation was associated with the production of larger amounts of the c-type cytochrome PgcA, which was released into the culture medium. It is proposed that the extracellular cytochrome acts as an electron shuttle, promoting electron transfer from the outer cell surface to Fe(III) oxides. The adapted PilA-deficient strain competed well with the wild-type strain when both were grown together on Fe(III) oxide. However, when 50% of the culture medium was replaced with fresh medium every 3 days, the wild-type strain outcompeted the adapted strain. A possible explanation for this is that the necessity to produce additional PgcA, to replace the PgcA being continually removed, put the adapted strain at a competitive disadvantage, similar to the apparent selection against electron shuttle-producing Fe(III) reducers in many anaerobic soils and sediments. Despite increased extracellular cytochrome production, the adapted PilA-deficient strain produced low levels of current, consistent with the concept that long-range electron transport through G. sulfurreducens biofilms is more effective via pili. PMID- 24814784 TI - Modulation of endogenous indole-3-acetic acid biosynthesis in bacteroids within Medicago sativa nodules. AB - To evaluate the dose-response effects of endogenous indole-3-acetic acid (IAA) on Medicago plant growth and dry weight production, we increased the synthesis of IAA in both free-living and symbiosis-stage rhizobial bacteroids during Rhizobium legume symbiosis. For this purpose, site-directed mutagenesis was applied to modify an 85-bp promoter sequence, driving the expression of iaaM and tms2 genes for IAA biosynthesis. A positive correlation was found between the higher expression of IAA biosynthetic genes in free-living bacteria and the increased production of IAA under both free-living and symbiotic conditions. Plants nodulated by RD65 and RD66 strains, synthetizing the highest IAA concentration, showed a significant (up to 73%) increase in the shoot fresh weight and upregulation of nitrogenase gene, nifH, compared to plants nodulated by the wild type strain. When these plants were analyzed by confocal microscopy, using an anti-IAA antibody, the strongest signal was observed in bacteroids of Medicago sativa RD66 (Ms-RD66) plants, even when they were located in the senescent nodule zone. We show here a simple system to modulate endogenous IAA biosynthesis in bacteria nodulating legumes suitable to investigate which is the maximum level of IAA biosynthesis, resulting in the maximal increase of plant growth. PMID- 24814786 TI - Modeling the infection dynamics of bacteriophages in enteric Escherichia coli: estimating the contribution of transduction to antimicrobial gene spread. AB - Animal-associated bacterial communities are infected by bacteriophages, although the dynamics of these infections are poorly understood. Transduction by bacteriophages may contribute to transfer of antimicrobial resistance genes, but the relative importance of transduction among other gene transfer mechanisms is unknown. We therefore developed a candidate deterministic mathematical model of the infection dynamics of enteric coliphages in commensal Escherichia coli in the large intestine of cattle. We assumed the phages were associated with the intestine and were predominantly temperate. Model simulations demonstrated how, given the bacterial ecology and infection dynamics, most (>90%) commensal enteric E. coli bacteria may become lysogens of enteric coliphages during intestinal transit. Using the model and the most liberal assumptions about transduction efficiency and resistance gene frequency, we approximated the upper numerical limits ("worst-case scenario") of gene transfer through specialized and generalized transduction in E. coli by enteric coliphages when the transduced genetic segment is picked at random. The estimates were consistent with a relatively small contribution of transduction to lateral gene spread; for example, generalized transduction delivered the chromosomal resistance gene to up to 8 E. coli bacteria/hour within the population of 1.47 * 10(8) E. coli bacteria/liter luminal contents. In comparison, the plasmidic blaCMY-2 gene carried by ~2% of enteric E. coli was transferred by conjugation at a rate at least 1.4 * 10(3) times greater than our generalized transduction estimate. The estimated numbers of transductants varied nonlinearly depending on the ecology of bacteria available for phages to infect, that is, on the assumed rates of turnover and replication of enteric E. coli. PMID- 24814785 TI - Analysis of multiple tsetse fly populations in Uganda reveals limited diversity and species-specific gut microbiota. AB - The invertebrate microbiome contributes to multiple aspects of host physiology, including nutrient supplementation and immune maturation processes. We identified and compared gut microbial abundance and diversity in natural tsetse flies from Uganda using five genetically distinct populations of Glossina fuscipes fuscipes and multiple tsetse species (Glossina morsitans morsitans, G. f. fuscipes, and Glossina pallidipes) that occur in sympatry in one location. We used multiple approaches, including deep sequencing of the V4 hypervariable region of the 16S rRNA gene, 16S rRNA gene clone libraries, and bacterium-specific quantitative PCR (qPCR), to investigate the levels and patterns of gut microbial diversity from a total of 151 individuals. Our results show extremely limited diversity in field flies of different tsetse species. The obligate endosymbiont Wigglesworthia dominated all samples (>99%), but we also observed wide prevalence of low-density Sodalis (tsetse's commensal endosymbiont) infections (<0.05%). There were also several individuals (22%) with high Sodalis density, which also carried coinfections with Serratia. Albeit in low density, we noted differences in microbiota composition among the genetically distinct G. f. fuscipes flies and between different sympatric species. Interestingly, Wigglesworthia density varied in different species (10(4) to 10(6) normalized genomes), with G. f. fuscipes having the highest levels. We describe the factors that may be responsible for the reduced diversity of tsetse's gut microbiota compared to those of other insects. Additionally, we discuss the implications of Wigglesworthia and Sodalis density variations as they relate to trypanosome transmission dynamics and vector competence variations associated with different tsetse species. PMID- 24814787 TI - Purine biosynthesis, biofilm formation, and persistence of an insect-microbe gut symbiosis. AB - The Riptortus-Burkholderia symbiotic system is an experimental model system for studying the molecular mechanisms of an insect-microbe gut symbiosis. When the symbiotic midgut of Riptortus pedestris was investigated by light and transmission electron microscopy, the lumens of the midgut crypts that harbor colonizing Burkholderia symbionts were occupied by an extracellular matrix consisting of polysaccharides. This observation prompted us to search for symbiont genes involved in the induction of biofilm formation and to examine whether the biofilms are necessary for the symbiont to establish a successful symbiotic association with the host. To answer these questions, we focused on purN and purT, which independently catalyze the same step of bacterial purine biosynthesis. When we disrupted purN and purT in the Burkholderia symbiont, the DeltapurN and DeltapurT mutants grew normally, and only the DeltapurT mutant failed to form biofilms. Notably, the DeltapurT mutant exhibited a significantly lower level of cyclic-di-GMP (c-di-GMP) than the wild type and the DeltapurN mutant, suggesting involvement of the secondary messenger c-di-GMP in the defect of biofilm formation in the DeltapurT mutant, which might operate via impaired purine biosynthesis. The host insects infected with the DeltapurT mutant exhibited a lower infection density, slower growth, and lighter body weight than the host insects infected with the wild type and the DeltapurN mutant. These results show that the function of purT of the gut symbiont is important for the persistence of the insect gut symbiont, suggesting the intricate biological relevance of purine biosynthesis, biofilm formation, and symbiosis. PMID- 24814788 TI - Investigating microbial eukaryotic diversity from a global census: insights from a comparison of pyrotag and full-length sequences of 18S rRNA genes. AB - Next-generation DNA sequencing (NGS) approaches are rapidly surpassing Sanger sequencing for characterizing the diversity of natural microbial communities. Despite this rapid transition, few comparisons exist between Sanger sequences and the generally much shorter reads of NGS. Operational taxonomic units (OTUs) derived from full-length (Sanger sequencing) and pyrotag (454 sequencing of the V9 hypervariable region) sequences of 18S rRNA genes from 10 global samples were analyzed in order to compare the resulting protistan community structures and species richness. Pyrotag OTUs called at 98% sequence similarity yielded numbers of OTUs that were similar overall to those for full-length sequences when the latter were called at 97% similarity. Singleton OTUs strongly influenced estimates of species richness but not the higher-level taxonomic composition of the community. The pyrotag and full-length sequence data sets had slightly different taxonomic compositions of rhizarians, stramenopiles, cryptophytes, and haptophytes, but the two data sets had similarly high compositions of alveolates. Pyrotag-based OTUs were often derived from sequences that mapped to multiple full length OTUs at 100% similarity. Thus, pyrotags sequenced from a single hypervariable region might not be appropriate for establishing protistan species level OTUs. However, nonmetric multidimensional scaling plots constructed with the two data sets yielded similar clusters, indicating that beta diversity analysis results were similar for the Sanger and NGS sequences. Short pyrotag sequences can provide holistic assessments of protistan communities, although care must be taken in interpreting the results. The longer reads (>500 bp) that are now becoming available through NGS should provide powerful tools for assessing the diversity of microbial eukaryotic assemblages. PMID- 24814789 TI - Effect of long-term starvation on the survival, recovery, and carbon utilization profiles of a bovine Escherichia coli O157:H7 isolate from New Zealand. AB - The ability to maintain a dual lifestyle of colonizing the ruminant gut and surviving in nonhost environments once shed is key to the success of Escherichia coli O157:H7 as a zoonotic pathogen. Both physical and biological conditions encountered by the bacteria are likely to change during the transition between host and nonhost environments. In this study, carbon starvation at suboptimal temperatures in nonhost environments was simulated by starving a New Zealand bovine E. coli O157:H7 isolate in phosphate-buffered saline at 4 and 15 degrees C for 84 days. Recovery of starved cells on media with different nutrient availabilities was monitored under aerobic and anaerobic conditions. We found that the New Zealand bovine E. coli O157:H7 isolate was able to maintain membrane integrity and viability over 84 days and that the level of recovery depended on the nutrient level of the recovery medium as well as the starvation temperature. In addition, a significant difference in carbon utilization was observed between starved and nonstarved cells. PMID- 24814790 TI - Metabolism of sialic acid by Bifidobacterium breve UCC2003. AB - Bifidobacteria constitute a specific group of commensal bacteria that inhabit the gastrointestinal tracts of humans and other mammals. Bifidobacterium breve UCC2003 has previously been shown to utilize several plant-derived carbohydrates that include cellodextrins, starch, and galactan. In the present study, we investigated the ability of this strain to utilize the mucin- and human milk oligosaccharide (HMO)-derived carbohydrate sialic acid. Using a combination of transcriptomic and functional genomic approaches, we identified a gene cluster dedicated to the uptake and metabolism of sialic acid. Furthermore, we demonstrate that B. breve UCC2003 can cross feed on sialic acid derived from the metabolism of 3'-sialyllactose, an abundant HMO, by another infant gut bifidobacterial strain, Bifidobacterium bifidum PRL2010. PMID- 24814791 TI - Murein lytic enzyme TgaA of Bifidobacterium bifidum MIMBb75 modulates dendritic cell maturation through its cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) amidase domain. AB - Bifidobacteria are Gram-positive inhabitants of the human gastrointestinal tract that have evolved close interaction with their host and especially with the host's immune system. The molecular mechanisms underlying such interactions, however, are largely unidentified. In this study, we investigated the immunomodulatory potential of Bifidobacterium bifidum MIMBb75, a bacterium of human intestinal origin commercially used as a probiotic. Particularly, we focused our attention on TgaA, a protein expressed on the outer surface of MIMBb75's cells and homologous to other known bacterial immunoactive proteins. TgaA is a peptidoglycan lytic enzyme containing two active domains: lytic murein transglycosylase (LT) and cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP). We ran immunological experiments stimulating dendritic cells (DCs) with the B. bifidum MIMBb75 and TgaA, with the result that both the bacterium and the protein activated DCs and triggered interleukin-2 (IL 2) production. In addition, we observed that the heterologous expression of TgaA in Bifidobacterium longum transferred to the bacterium the ability to induce IL 2. Subsequently, immunological experiments performed using two purified recombinant proteins corresponding to the single domains LT and CHAP demonstrated that the CHAP domain is the immune-reactive region of TgaA. Finally, we also showed that TgaA-dependent activation of DCs requires the protein CD14, marginally involves TRIF, and is independent of Toll-like receptor 4 (TLR4) and MyD88. In conclusion, our study suggests that the bacterial CHAP domain is a novel microbe-associated molecular pattern actively participating in the cross talk mechanisms between bifidobacteria and the host's immune system. PMID- 24814792 TI - Physiological and transcriptional responses of anaerobic chemostat cultures of Saccharomyces cerevisiae subjected to diurnal temperature cycles. AB - Diurnal temperature cycling is an intrinsic characteristic of many exposed microbial ecosystems. However, its influence on yeast physiology and the yeast transcriptome has not been studied in detail. In this study, 24-h sinusoidal temperature cycles, oscillating between 12 degrees C and 30 degrees C, were imposed on anaerobic, glucose-limited chemostat cultures of Saccharomyces cerevisiae. After three diurnal temperature cycles (DTC), concentrations of glucose and extracellular metabolites as well as CO2 production rates showed regular, reproducible circadian rhythms. DTC also led to waves of transcriptional activation and repression, which involved one-sixth of the yeast genome. A substantial fraction of these DTC-responsive genes appeared to respond primarily to changes in the glucose concentration. Elimination of known glucose-responsive genes revealed an overrepresentation of previously identified temperature responsive genes as well as genes involved in the cell cycle and de novo purine biosynthesis. In-depth analysis demonstrated that DTC led to a partial synchronization of the cell cycle of the yeast populations in chemostat cultures, which was lost upon release from DTC. Comparison of DTC results with data from steady-state cultures showed that the 24-h DTC was sufficiently slow to allow S. cerevisiae chemostat cultures to acclimate their transcriptome and physiology at the DTC temperature maximum and to approach acclimation at the DTC temperature minimum. Furthermore, this comparison and literature data on growth rate dependent cell cycle phase distribution indicated that cell cycle synchronization was most likely an effect of imposed fluctuations of the relative growth rate (MU/MUmax) rather than a direct effect of temperature. PMID- 24814794 TI - Discovery of bovine digital dermatitis-associated Treponema spp. in the dairy herd environment by a targeted deep-sequencing approach. AB - The bacteria associated with the infectious claw disease bovine digital dermatitis (DD) are spirochetes of the genus Treponema; however, their environmental reservoir remains unknown. To our knowledge, the current study is the first report of the discovery and phylogenetic characterization of rRNA gene sequences from DD-associated treponemes in the dairy herd environment. Although the spread of DD appears to be facilitated by wet floors covered with slurry, no DD-associated treponemes have been isolated from this environment previously. Consequently, there is a lack of knowledge about the spread of this disease among cows within a herd as well as between herds. To address the issue of DD infection reservoirs, we searched for evidence of DD-associated treponemes in fresh feces, in slurry, and in hoof lesions by deep sequencing of the V3 and V4 hypervariable regions of the 16S rRNA gene coupled with identification at the operational taxonomic-unit level. Using treponeme-specific primers in this high-throughput approach, we identified small amounts of DNA (on average 0.6% of the total amount of sequence reads) from DD-associated treponemes in 43 of 64 samples from slurry and cow feces collected from six geographically dispersed dairy herds. Species belonging to the Treponema denticola/Treponema pedis-like and Treponema phagedenis-like phylogenetic clusters were among the most prevalent treponemes in both the dairy herd environment and the DD lesions. By the high-throughput approach presented here, we have demonstrated that cow feces and environmental slurry are possible reservoirs of DD-associated treponemes. This method should enable further clarification of the etiopathogenesis of DD. PMID- 24814793 TI - Sporadic isolation of sabin-like polioviruses and high-level detection of non polio enteroviruses during sewage surveillance in seven Italian cities, after several years of inactivated poliovirus vaccination. AB - Sewage surveillance in seven Italian cities between 2005 and 2008, after the introduction of inactivated poliovirus vaccination (IPV) in 2002, showed rare polioviruses, none that were wild-type or circulating vaccine-derived poliovirus (cVDPV), and many other enteroviruses among 1,392 samples analyzed. Two of five polioviruses (PV) detected were Sabin-like PV2 and three PV3, based on enzyme linked immunosorbent assay (ELISA) and PCR results. Neurovirulence-related mutations were found in the 5'noncoding region (5'NCR) of all strains and, for a PV2, also in VP1 region 143 (Ile>Thr). Intertypic recombination in the 3D region was detected in a second PV2 (Sabin 2/Sabin 1) and a PV3 (Sabin 3/Sabin 2). The low mutation rate in VP1 for all PVs suggests limited interhuman virus passages, consistent with efficient polio immunization in Italy. Nonetheless, these findings highlight the risk of wild or Sabin poliovirus reintroduction from abroad. Non-polio enteroviruses (NPEVs) were detected, 448 of which were coxsackievirus B (CVB) and 294 of which were echoviruses (Echo). Fifty-six NPEVs failing serological typing were characterized by sequencing the VP1 region (nucleotides [nt] 2628 to 2976). A total of 448 CVB and 294 Echo strains were identified; among those strains, CVB2, CVB5, and Echo 11 predominated. Environmental CVB5 and CVB2 strains from this study showed high sequence identity with GenBank global strains. The high similarity between environmental NPEVs and clinical strains from the same areas of Italy and the same periods indicates that environmental strains reflect the viruses circulating in the population and highlights the potential risk of inefficient wastewater treatments. This study confirmed that sewage surveillance can be more sensitive than acute flaccid paralysis (AFP) surveillance in monitoring silent poliovirus circulation in the population as well as the suitability of molecular approaches to enterovirus typing. PMID- 24814795 TI - Wipes coated with a singlet-oxygen-producing photosensitizer are effective against human influenza virus but not against norovirus. AB - Transmission of enteric and respiratory viruses, including human norovirus (hNoV) and human influenza virus, may involve surfaces. In food preparation and health care settings, surfaces are cleaned with wipes; however, wiping may not efficiently reduce contamination or may even spread viruses, increasing a potential public health risk. The virucidal properties of wipes with a singlet oxygen-generating immobilized photosensitizer (IPS) coating were compared to those of similar but uncoated wipes (non-IPS) and of commonly used viscose wipes. Wipes were spiked with hNoV GI.4 and GII.4, murine norovirus 1 (MNV-1), human adenovirus type 5 (hAdV-5), and influenza virus H1N1 to study viral persistence. We also determined residual and transferred virus proportions on steel carriers after successively wiping a contaminated and an uncontaminated steel carrier. On IPS wipes only, influenza viruses were promptly inactivated with a 5-log10 reduction. D values of infectious MNV-1 and hAdV-5 were 8.7 and 7.0 h on IPS wipes, 11.6 and 9.3 h on non-IPS wipes, and 10.2 and 8.2 h on viscose wipes, respectively. Independently of the type of wipe, dry cleaning removed, or drastically reduced, initial spot contamination of hNoV on surfaces. All wipes transferred hNoV to an uncontaminated carrier; however, the risk of continued transmission by reuse of wipes after 6 and 24 h was limited for all viruses. We conclude that cleaning wet spots with dry wipes efficiently reduced spot contamination on surfaces but that cross-contamination with noroviruses by wiping may result in an increased public health risk at high initial virus loads. For influenza virus, IPS wipes present an efficient one-step procedure for cleaning and disinfecting contaminated surfaces. PMID- 24814796 TI - Assessing genetic diversity among Brettanomyces yeasts by DNA fingerprinting and whole-genome sequencing. AB - Brettanomyces yeasts, with the species Brettanomyces (Dekkera) bruxellensis being the most important one, are generally reported to be spoilage yeasts in the beer and wine industry due to the production of phenolic off flavors. However, B. bruxellensis is also known to be a beneficial contributor in certain fermentation processes, such as the production of certain specialty beers. Nevertheless, despite its economic importance, Brettanomyces yeasts remain poorly understood at the genetic and genomic levels. In this study, the genetic relationship between more than 50 Brettanomyces strains from all presently known species and from several sources was studied using a combination of DNA fingerprinting techniques. This revealed an intriguing correlation between the B. bruxellensis fingerprints and the respective isolation source. To further explore this relationship, we sequenced a (beneficial) beer isolate of B. bruxellensis (VIB X9085; ST05.12/22) and compared its genome sequence with the genome sequences of two wine spoilage strains (AWRI 1499 and CBS 2499). ST05.12/22 was found to be substantially different from both wine strains, especially at the level of single nucleotide polymorphisms (SNPs). In addition, there were major differences in the genome structures between the strains investigated, including the presence of large duplications and deletions. Gene content analysis revealed the presence of 20 genes which were present in both wine strains but absent in the beer strain, including many genes involved in carbon and nitrogen metabolism, and vice versa, no genes that were missing in both AWRI 1499 and CBS 2499 were found in ST05.12/22. Together, this study provides tools to discriminate Brettanomyces strains and provides a first glimpse at the genetic diversity and genome plasticity of B. bruxellensis. PMID- 24814797 TI - Host responses to the pathogen Mycobacterium avium subsp. paratuberculosis and beneficial microbes exhibit host sex specificity. AB - Differences between microbial pathogenesis in male and female hosts are well characterized in disease conditions connected to sexual transmission. However, limited biological insight is available on variances attributed to sex specificity in host-microbe interactions, and it is most often a minimized variable outside these transmission events. In this work, we studied two gut microbes-a pathogen, Mycobacterium avium subsp. paratuberculosis, and a probiotic, Lactobacillus animalis NP-51-and the interaction between each agent and the male and female gastrointestinal systems. This trial was conducted in BALB/c mice (n=5 per experimental group and per sex at a given time point), with analysis at four time points over 180 days. Host responses to M.avium subsp. paratuberculosis and L. animalis were sensitive to sex. Cytokines that were significantly different (P <= 0.05) betweenthe sexes included interleukin 1alpha/beta (IL-1alpha/beta), IL-17, IL-6, IL-10, IL-12, and gamma interferon (IFN-) and were dependent on experimental conditions. However, granulocyte macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and IL-13/23 showed no sex specificity. A metabolomics study indicated a 0.5- to 2.0-fold (log2 scale) increase in short-chain fatty acids (butyrate and acetate) in males and greater increases in o-phosphocholine or histidine from female colon tissues; variances distinct to each sex were observed with age or long-term probiotic consumption. Two genera, Staphylococcus and Roseburia, were consistently overrepresented in females compared to males; other species were specific to one sex but fluctuated depending on experimental conditions. The differences observed suggest that male and female gut tissues and microbiota respond to newly introduced microorganisms differently and that gut-associated microorganisms with host immune system responses and metabolic activity are supported by biology distinct to the host sex. PMID- 24814798 TI - Starter culture selection for making Chinese sesame-flavored liquor based on microbial metabolic activity in mixed-culture fermentation. AB - Selection of a starter culture with excellent viability and metabolic activity is important for inoculated fermentation of traditional food. To obtain a suitable starter culture for making Chinese sesame-flavored liquor, the yeast and bacterium community structures were investigated during spontaneous and solid state fermentations of this type of liquor. Five dominant species in spontaneous fermentation were identified: Saccharomyces cerevisiae, Pichia membranaefaciens, Issatchenkia orientalis, Bacillus licheniformis, and Bacillus amyloliquefaciens. The metabolic activity of each species in mixed and inoculated fermentations of liquor was investigated in 14 different cocultures that used different combinations of these species. The relationships between the microbial species and volatile metabolites were analyzed by partial least-squares (PLS) regression analysis. We found that S. cerevisiae was positively correlated to nonanal, and B. licheniformis was positively associated with 2,3-butanediol, isobutyric acid, guaiacol, and 4-vinyl guaiacol, while I. orientalis was positively correlated to butyric acid, isovaleric acid, hexanoic acid, and 2,3-butanediol. These three species are excellent flavor producers for Chinese liquor. Although P. membranaefaciens and B. amyloliquefaciens were not efficient flavor producers, the addition of them alleviated competition among the other three species and altered their growth rates and flavor production. As a result, the coculture of all five dominant species produced the largest amount of flavor compounds. The result indicates that flavor producers and microbial interaction regulators are important for inoculated fermentation of Chinese sesame-flavored liquor. PMID- 24814799 TI - A novel, rapid and automated conductometric method to evaluate surfactant-cells interactions by means of critical micellar concentration analysis. AB - Conductometry is widely used to determine critical micellar concentration and micellar aggregates surface properties of amphiphiles. Current conductivity experiments of surfactant solutions are typically carried out by manual pipetting, yielding some tens reading points within a couple of hours. In order to study the properties of surfactant-cells interactions, each amphiphile must be tested in different conditions against several types of cells. This calls for complex experimental designs making the application of current methods seriously time consuming, especially because long experiments risk to determine alterations of cells, independently of the surfactant action. In this paper we present a novel, accurate and rapid automated procedure to obtain conductometric curves with several hundreds reading points within tens of minutes. The method was validated with surfactant solutions alone and in combination with Saccharomyces cerevisiae cells. An easy-to use R script, calculates conductometric parameters and their statistical significance with a graphic interface to visualize data and results. The validations showed that indeed the procedure works in the same manner with surfactant alone or in combination with cells, yielding around 1000 reading points within 20 min and with high accuracy, as determined by the regression analysis. PMID- 24814800 TI - Lexical-semantic body knowledge in 5- to 11-year-old children: How spatial body representation influences body semantics. AB - This study addresses the relation between lexico-semantic body knowledge (i.e., body semantics) and spatial body representation (i.e., structural body representation) by analyzing naming performances as a function of body structural topography. One hundred and forty-one children ranging from 5 years 2 months to 10 years 5 months old were asked to provide a lexical label for isolated body part pictures. We compared the children's naming performances according to the location of the body parts (body parts vs. head features and also upper vs. lower limbs) or to their involvement in motor skills (distal segments, joints, and broader body parts). The results showed that the children's naming performance was better for facial body parts than for other body parts. Furthermore, it was found that the naming of body parts was better for body parts related to action. These findings suggest that the development of a spatial body representation shapes the elaboration of semantic body representation processing. Moreover, this influence was not limited to younger children. In our discussion of these results, we focus on the important role of action in the development of body representations and semantic organization. PMID- 24814801 TI - Molecular mapping of three male-sterile, female-fertile mutants and generation of a comprehensive map of all known male sterility genes in soybean. AB - In soybean, an environmentally stable male sterility system is vital for making hybrid seed production commercially viable. Eleven male-sterile, female-fertile mutants (ms1, ms2, ms3, ms4, ms5, ms6, ms7, ms8, ms9, msMOS, and msp) have been identified in soybean. Of these, eight (ms2, ms3, ms5, ms7, ms8, ms9, msMOS, and msp) have been mapped to soybean chromosomes. The objectives of this study were to (i) locate the ms1, ms4, and ms6 genes to soybean chromosomes; (ii) generate genetic linkage maps of the regions containing these genes; and (iii) develop a comprehensive map of all known male-sterile, female-fertile genes in soybean. The bulked segregant analysis technique was used to locate genes to soybean chromosomes. Microsatellite markers from the corresponding chromosomes were used on F2 populations to generate genetic linkage maps. The ms1 and ms6 genes were located on chromosome 13 (molecular linkage group F) and ms4 was present on chromosome 2 (molecular linkage group D1b). Molecular analyses revealed markers Satt516, BARCSOYSSR_02_1539, and AW186493 were located closest to ms1, ms4, and ms6, respectively. The ms1 and ms6 genes, although present on the same chromosome, were independently assorting with a genetic distance of 73.7 cM. Using information from this study and compiled information from previously published male sterility genes in soybean, a comprehensive genetic linkage map was generated. Eleven male sterility genes were present on seven soybean chromosomes. Four genes were present in two regions on chromosome 2 (molecular linkage group D1b) and two genes were present on chromosome 13 (molecular linkage group F). PMID- 24814802 TI - MicroRNA profiling reveals differentially expressed microRNA signatures from the skin of patients with nonsegmental vitiligo. PMID- 24814803 TI - VICKZ2 protein expression in ovarian serous carcinoma effusions is associated with poor survival. AB - The involvement of VICKZ proteins has been implicated in a large number of cancers. The aim of the present study was to investigate the biological and clinical role of VICKZ proteins in ovarian carcinoma (OC). VICKZ1-3 protein expression was analyzed in 82 serous OC specimens (51 effusions, 14 primary carcinomas, 17 solid metastases) by immunoblotting. Protein localization was studied using immunohistochemistry in 101 tumors (40 effusions, 25 primary carcinomas, 36 solid metastases). The effect of VICKZ silencing using short hairpin RNA on collagenolytic activity and invasion was assessed in ES-2 OC cells. VICKZ2 was the most frequently expressed family member in serous carcinomas. VICKZ levels measured by pan-VICKZ antibody were significantly higher in primary carcinomas and solid metastases compared to effusions (P < .001). In contrast, VICKZ1 and VICKZ2 were overexpressed in effusions compared to primary carcinomas and solid metastases (P = .016 and P = .024, respectively), and higher VICKZ2 expression in effusions was associated with shorter overall survival in univariate analysis (P = .01). All 3 proteins were localized to OC cells by immunohistochemistry, with tumor-specific expression observed for VICKZ1 and VICKZ2. VICKZ silencing in ES-2 cells led to reduced matrix metalloproteinase 9 activity and reduced invasion. In conclusion, VICKZ2 is the most frequently expressed VICKZ family member in serous OCs. VICKZ1 and VICKZ2 are overexpressed in effusions compared to primary carcinomas and solid metastases, suggesting a biological role at this anatomical site, and appear to have a role in proteolysis and invasion. VICKZ2 may be a prognostic marker in ovarian serous carcinoma effusions. PMID- 24814804 TI - Significance of signet ring cells in high-grade mucinous adenocarcinoma of the peritoneum from appendiceal origin. AB - Significance of signet ring cells in mucinous adenocarcinoma of the peritoneum from appendiceal origin has never been specifically studied. We retrospectively reviewed cases of mucinous adenocarcinoma of the peritoneum from appendiceal origin (n = 55) and collected clinical follow-up data. Signet ring cells were identified in 29 of 55 cases. No low-grade mucinous adenocarcinoma case (n = 11) had signet ring cells, whereas 29 of 44 high-grade mucinous adenocarcinoma cases did. Cases of high-grade mucinous adenocarcinoma were subdivided into 3 groups: (1) high-grade mucinous adenocarcinoma without signet ring cells (n = 15), (2) high-grade mucinous adenocarcinoma with signet ring cells only within mucin pools (n = 20), and (3) high-grade mucinous adenocarcinoma with signet ring cells invading tissue (n = 9). Overall survival (OS) and progression-free survival were subsequently evaluated. Five-year OS for cases of high-grade mucinous adenocarcinoma without signet ring cells and high-grade mucinous adenocarcinoma with signet ring cells within mucin pools were similar at 31.8% (SE, 14.4%) and 35.8% (SE, 13.9%), respectively. A significant survival difference was seen for cases of high-grade mucinous adenocarcinoma with signet ring cells invading tissue with a median OS of 0.5 years versus 2.9 and 2.4 years (P = .04 and P = .03), respectively, for cases of high-grade mucinous adenocarcinoma without signet ring cells and high-grade mucinous adenocarcinoma with signet ring cells within mucin pools. Finding signet ring cells floating in extracellular mucin pools made no prognostic difference when compared with cases of high-grade mucinous adenocarcinoma without signet ring cells. In contrast, high-grade mucinous adenocarcinoma with signet ring cells invading tissue was significant for worse survival, and thus, we propose reporting signet ring cell tissue invasion particularly when extensive. PMID- 24814805 TI - Pathogen recognition receptors in channel catfish: IV. Identification, phylogeny and expression analysis of peptidoglycan recognition proteins. AB - Peptidoglycan recognition proteins (PGRPs) can recognize bacterial cell wall (peptidoglycan) and activate innate immune system. In addition to its function as pathogen recognition receptors (PRRs), PGRPs are also involved in directly killing bacteria, and regulating multiple signaling pathways. Recently, we have reported catfish PRRs including nucleotide-binding domain, leucine-rich repeat containing receptors (NLRs), retinoic acid inducible gene I (RIG-I) like receptors (RLRs), and Toll-like receptors (TLRs). In this study, we identified and characterized the PGRP gene family in channel catfish which included two members, PGLYRP-5 and PGLYRP-6. Phylogenetic analysis, syntenic analysis and protein structural analysis were conducted to determine their identities and evolutionary relationships. In order to gain insight into the roles of PGRPs in catfish innate immune responses, quantitative real-time PCR was used to investigate the expression profiles in catfish healthy tissues and after bacterial infection. Both PGLYRP-5 and PGLYRP-6 were ubiquitously expressed in all 12 healthy tissues, and most highly expressed in gill and spleen, respectively. Distinct expression patterns were observed for PGRPs after infection with Edwardsiella ictaluri and Flavobacterium columnare, both Gram negative bacteria. After infection with E. ictaluri, both PGLYRP-5 and PGLYRP-6 were significantly down-regulated at a certain time-point, while both genes were generally up-regulated in the gill after infection with F. columnare. Collectively, these findings suggested that PGRPs may play complex roles in the host immune response to bacterial pathogens in catfish. PMID- 24814806 TI - Correlation between physician specific discharge costs, LOS, and 30-day readmission rates: an analysis of 1,831 cases. AB - There is currently wide variation in the use and cost of post acute care following total joint arthroplasty. Additionally the optimum setting to which patients should be discharged after surgery is controversial. Discharge patterns following joint replacement vary widely between physicians at our institution, however, only weak correlations were found between the cost of discharge and length of stay or readmission rates. The inter-physician variance in discharge cost did not correlate to a difference in quality, as measured by length of stay and readmission rates, but does imply there is significant opportunity to modify physician discharge practices without impacting patient outcomes and the quality of care. PMID- 24814807 TI - The relationship between work ability and oxidative stress in Japanese workers. AB - Work ability is based on the balance between personal resources and work demand. This study focused on the personal resources component of work ability. The aims of this study were to elucidate the association between work ability and cardiovascular (CV) risk factors, particularly oxidative stress, and to estimate the effect of a community-implemented lifestyle modification programme on work ability and CV risk factors. Urinary 8-iso-prostaglandin F2alpha (PGF2alpha), a biomarker of oxidative stress, was negatively correlated with psychological resources, as measured by the Work Ability Index (WAI). Overall WAI score was unchanged following the programme, while CV risk factors and antioxidative activity improved. A reduction in PGF2alpha levels was correlated with an improvement in subjective work ability relative to job demands, as assessed by a WAI item. Taken together, the results suggest that lifestyle modification programmes enhance the personal resources component of work ability and are associated with a reduction in oxidative stress. PMID- 24814814 TI - Comparison of isoflurane and propofol for maintenance of anesthesia in dogs with intracranial disease undergoing magnetic resonance imaging. AB - OBJECTIVE: To compare isoflurane and propofol for maintenance of anesthesia and quality of recovery in client-owned dogs with intracranial disease undergoing magnetic resonance imaging (MRI). STUDY DESIGN: Prospective, randomized, clinical trial. ANIMALS: Twenty-five client-owned dogs with intracranial pathology, 13 females and 12 males, ages 11 months to 13 years, weighing between 3.0 and 48.0 kg. METHODS: Each dog was randomly assigned to receive propofol or isoflurane for maintenance of anesthesia. All dogs were not premedicated, were administered propofol intravenously to effect for induction, intubated and mechanically ventilated to maintain an end-tidal carbon dioxide tension 30-35 mmHg (4.0-4.7 kPa). Temperature and cardiac output were measured pre- and post-MRI. Scores for mentation, neurological status, ease of maintenance, and recovery were obtained pre- and post-anesthesia. Pulse oximetry, end-tidal gases, arterial blood pressure, heart rate (HR) and requirements for dopamine administration to maintain mean arterial pressure (MAP) >60 mmHg were recorded throughout anesthesia. RESULTS: End-tidal isoflurane concentration was 0.73 +/- 0.35% and propofol infusion rate was 292 +/- 119 MUg kg(-1) minute(-1) . Cardiac index was higher, while HR was lower, with propofol than isoflurane in dogs younger than 5 years, but not in older dogs. Dogs maintained with isoflurane were 14.7 times more likely to require dopamine than propofol dogs. Mentation and maintenance scores and temperature were not different. MAP and diastolic arterial pressure were higher in the propofol group. Recovery scores were better with propofol, although times to extubation were similar. Change in neurological score from pre- to post-anesthesia was not different between treatments. CONCLUSIONS: Dogs maintained with propofol during MRI had higher arterial pressures, decreased requirements for dopamine, and better recovery scores, compared to dogs maintained with isoflurane. CLINICAL RELEVANCE: Propofol anesthesia offered cardiovascular and recovery advantages over isoflurane during MRI in dogs with intracranial disease in this study. PMID- 24814815 TI - Ion transport through a water-organic solvent liquid-liquid interface: a simulation study. AB - Ion interactions and partitioning at the water-organic solvent interface and the solvation characteristics have been characterized by molecular dynamics simulations. More precisely, we study sodium cation transport through water cyclohexane, water-1,2-dichloroethane, and water-pentanol interfaces, providing a systematic characterization of the ion interfacial behavior including barriers against entering the organic phase as well as characterization of the interfaces in the presence of the ions. We find a sodium depletion zone at the liquid-liquid interface and persistent hydration of the cation when entering the organic phase. The barrier against the cation entering the organic phase and ion hydration depend strongly on specific characteristics of the organic solvent. The strength of both barrier and hydration shell binding (persistence of the cation hydration) go with the polarity and the surface tension at the interface, that is, both decrease in order cyclohexane-water > 1,2-dichloroethane-water > pentanol-water. However, the size of the hydration shell measured in water molecules bound by the cation entering the less polar phase behaves oppositely, with the cation carrying most water to the pentanol phase and a much smaller in size, but very tightly bound water shell to cyclohexane. We discuss the implications of the observations for ion transport through the interface of immiscible or poorly miscible liquids and for materials of confined ion transport such as ion conduction membranes or biological ion channel activity. PMID- 24814816 TI - Parenting experiences of couples living with human immunodeficiency virus: a qualitative study from rural Southern Malawi. AB - The advent of antiretroviral therapy (ART) has allowed couples living with human immunodeficiency virus (HIV) to live longer and healthier lives. The reduction in the mother-to-child transmission of HIV has encouraged some people living with HIV (PLWH) to have children. However, little is known about the parenting experiences of couples living with HIV (CLWH). The aim of this qualitative study was to explore and describe parenting experiences of seroconcordant couples who have a child while living with HIV in Malawi. Data were collected using in-depth interviews with 14 couples purposively sampled in matrilineal Chiradzulu and patrilineal Chikhwawa communities from July to December 2010. The research findings shows that irrespective of kinship organization, economic hardships, food insecurity, gender-specific role expectations and conflicting information from health institutions and media about sources of support underpin their parenting roles. In addition, male spouses are directly involved in household activities, childcare and child feeding decisions, challenging the existing stereotyped gender norms. In the absence of widow inheritance, widows from patrilineal communities are not receiving the expected support from the deceased husband relatives. Finally, the study has shown that CLWH are able to find solutions for the challenges they encounter. Contrary to existing belief that such who have children depend solely on public aid. Such claims without proper knowledge of local social cultural contexts, may contribute to stigmatizing CLWH who continue to have children. The study is also relevant to PLWH who, although not parents themselves, are confronted with a situation where they have to accept responsibility for raising children from their kin. We suggest the longer-term vision for ART wide access in Malawi to be broadened beyond provision of ART to incorporate social and economic interventions that support the rebuilding of CLWH social and economic lives. The interventions must be designed using a holistic multi-sector approach. PMID- 24814817 TI - [Respiratory complications after transfusion]. AB - Respiratory complications of blood transfusion have several possible causes. Transfusion-Associated Circulatory Overload (TACO) is often the first mentioned. Transfusion-Related Acute Lung Injury (TRALI), better defined since the consensus conference of Toronto in 2004, is rarely mentioned. French incidence is low. Non hemolytic febrile reactions, allergies, infections and pulmonary embolism are also reported. The objective of this work was to determine the statistical importance of the different respiratory complications of blood transfusion. This work was conducted retrospectively on transfusion accidents in six health centers in Champagne-Ardenne, reported to Hemovigilance between 2000 and 2009 and having respiratory symptoms. The analysis of data was conducted by an expert committee. Eighty-three cases of respiratory complications are found (316,864 blood products). We have counted 26 TACO, 12 TRALI (only 6 cases were identified in the original investigation of Hemovigilance), 18 non-hemolytic febrile reactions, 16 cases of allergies, 5 transfusions transmitted bacterial infections and 2 pulmonary embolisms. Six new TRALI were diagnosed previously labeled TACO for 2 of them, allergy and infection in 2 other cases and diagnosis considered unknown for the last 2. Our study found an incidence of TRALI 2 times higher than that reported previously. Interpretation of the data by a multidisciplinary committee amended 20% of diagnoses. This study shows the imperfections of our system for reporting accidents of blood transfusion when a single observer analyses the medical records. PMID- 24814818 TI - [Ethics and transfusion--seminar report]. AB - This paper brings together the abstracts and proceedings of a seminar held on the topic of "ethics and transfusion", October 15, 2013 at the National Institute of Blood Transfusion, Paris. PMID- 24814819 TI - Neuronal influences are necessary to produce mitochondrial co-localization with glutamate transporters in astrocytes. AB - Recent evidence suggests that the predominant astrocyte glutamate transporter, GLT-1/ Excitatory Amino Acid Transporter 2 (EAAT2) is associated with mitochondria. We used primary cultures of mouse astrocytes to assess co localization of GLT-1 with mitochondria, and tested whether the interaction was dependent on neurons, actin polymerization or the kinesin adaptor, TRAK2. Mouse primary astrocytes were transfected with constructs expressing V5-tagged GLT-1, pDsRed1-Mito with and without dominant negative TRAK2. Astrocytes were visualized using confocal microscopy and co-localization was quantified using Volocity software. Image analysis of confocal z-stacks revealed no co-localization between mitochondria and GLT-1 in pure astrocyte cultures. Co-culture of astrocytes with primary mouse cortical neurons revealed more mitochondria in processes and a positive correlation between mitochondria and GLT-1. This co-localization was not further enhanced after neuronal depolarization induced by 1 h treatment with 15 mM K(+). In pure astrocytes, a rho kinase inhibitor, Y27632 caused the distribution of mitochondria to astrocyte processes without enhancing GLT 1/mitochondrial co-localization, however, in co-cultures, Y27632 abolished mitochondrial:GLT-1 co-localization. Disrupting potential mitochondrial: kinesin interactions using dominant negative TRAK2 did not alter GLT-1 distribution or GLT-1: mitochondrial co-localization. We conclude that the association between GLT-1 and mitochondria is modest, is driven by synaptic activity and dependent on polymerized actin filaments. Mitochondria have limited co-localization with the glutamate transporter GLT-1 in primary astrocytes in culture. Few mitochondria are in the fine processes where GLT-1 is abundant. It is necessary to culture astrocytes with neurones to drive a significant level of co-localization, but co localization is not further altered by depolarization, manipulating sodium ion gradients or Na/K ATPase activity. PMID- 24814822 TI - Statement of removal. PMID- 24814820 TI - Assessment of elastin deficit in a Marfan mouse aneurysm model using an elastin specific magnetic resonance imaging contrast agent. AB - BACKGROUND: Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome. The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using MRI with a gadolinium-based elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) mice. METHODS AND RESULTS: Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (n=9 and n=10, respectively) using 7-T MRI with a T1 mapping sequence. Significantly lower enhancement (ie, lower R1 values, where R1=1/T1) was detected post-elastin specific magnetic resonance contrast agent in Fbn1(C1039G/+) compared with wild type ascending aortas (1.15+/-0.07 versus 1.36+/-0.05; P<0.05). Post-elastin specific magnetic resonance contrast agent R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (P=0.006). CONCLUSIONS: Herein, we demonstrate that MRI with elastin specific magnetic resonance contrast agent accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared with wild-type controls. This approach has translational potential for noninvasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions. PMID- 24814823 TI - Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance. AB - Hepatitis B virus (HBV) polymerase and human immunodeficiency virus (HIV) reverse transcriptase are structurally related. However, the HBV enzyme has a protein priming activity absent in the HIV enzyme. Approved nucleoside/nucleotide inhibitors of the HBV polymerase include lamivudine, adefovir, telbivudine, entecavir and tenofovir. Although most of them target DNA elongation, guanosine and adenosine analogs (e.g. entecavir and tenofovir, respectively) also impair protein priming. Major mutational patterns conferring nucleoside/nucleotide analog resistance include the combinations rtL180M/rtM204(I/V) (for lamivudine, entecavir, telbivudine and clevudine) and rtA181V/rtN236T (for adefovir and tenofovir). However, development of drug resistance is very slow for entecavir and tenofovir. Novel nucleoside/nucleotide analogs in advanced clinical trials include phosphonates similar to adefovir or tenofovir, and new tenofovir derivatives with improved pharmacological properties. PMID- 24814824 TI - Molecular detection of bacteria associated to dental caries in 4-12-year-old Tunisian children. AB - The occurrence of several microbial species in the oral cavity of 4-12-year-old Tunisian children was investigated. Samples were taken from 158 children (81 caries actives and 77 caries free). Genomic DNA was extracted and analyzed for the presence of 17 microbial species using a polymerase chain reaction assay. All samples were positive for at least one of the target microbial strains. Streptococcus mutans was the most prevalent species (76.5%) detected in genomic DNA collected from carious lesions. Other prevalent species were Candida spp (63%), Streptococcus salivarius (59%) and Streptococcus oralis (42%). The frequency of Lactobacillus acidophilus, Lactobacillus plantarum, and Lactobacillus casei-group in caries lesions was 29.5%, 34.5% and 22% respectively. Pathogenic bacteria such as Staphylococcus aureus was found in 28.5% of carious lesion samples compared to 15.5% in the control. Frequency of Porphyromonas endodontali, Actinomyces radicidentis and Treponema denticola recovery did not differ significantly between origins of samples. PCR analysis of genomic DNA detect various oral bacteria that differ between caries actives and caries-free children. In addition, the association of same aciduric bacteria (S. mutans, S. salivarius, L. acidophilus) and caries formation was noticed. PMID- 24814825 TI - For every complex problem, there is an answer that is clear, simple and wrong: and other aphorisms about medical statistical fallacies. AB - RATIONALE, METHOD: This essay examines the notions of knowledge, truth and certainty as they apply to medical research and patient care. The human body does not behave in mechanistic but rather complex adaptive ways; thus, its behaviour to challenges is non-deterministic. This insight has important ramifications for experimental studies in health care and their statistical interrogation that are described in detail. RESULTS AND CONCLUSIONS: Four implications are highlighted: one, there is an urgent need to develop a greater awareness of uncertainties and how to respond to them in clinical practice, namely, what is important and what is not in the context of this patient; two, there is an equally urgent need for health professionals to understand some basic statistical terms and their meanings, specifically absolute risk, its reciprocal, numbers needed to treat and its inverse, index of therapeutic impotence, as well as seeking out the effect size of an intervention rather than blindly accepting P-values; three, there is an urgent need to accurately present the known in comprehensible ways through the use of visual tools; and four, there is a need to overcome the perception, that errors of commission are less troublesome than errors of omission as neither's consequences are predictable. PMID- 24814826 TI - The radiologist as direct public educator: impact of sessions demystifying select cancer screening imaging examinations. AB - PURPOSE: The aim of this report is to describe our early experience with radiologist-led direct public education about imaging-based cancer screening examinations, with a focus on the level of satisfaction and the educational impact reported by session participants. METHODS: Subspecialty radiologists provided 1-hour educational sessions to small lay public audiences covering breast, prostate, and lung cancer screening, focusing on key radiologic screening tests. Subsequently, session participants completed a survey pertaining to their levels of satisfaction and the perceived impact of the sessions on knowledge of the diseases and relevant screening tests; results from all topic sessions were pooled for analysis. RESULTS: One hundred nineteen participants attended a total of 144 sessions. The large majority of respondents agreed or strongly agreed that the sessions increased their understanding (95.4%), they gained information not obtained from clinic visit (88.1%), seeing radiology images helped their understanding (92.6%), they felt more involved in their own care (85.8%), they felt more prepared to undergo screening tests (87.4%), they were satisfied with the sessions' format (93.3%) and content (96.2%), their main questions were answered (88.3%), they would be interested in similar future radiologist-led sessions (88.5%), and they would recommend the sessions to friends (93.9%). The provided information (43.1%) and images (34.7%) were identified as the most helpful aspects of the sessions. CONCLUSION: Radiologist-led direct public education sessions about imaging-based cancer screening examinations yield high levels of audience satisfaction and add value to the public's understanding of the role of radiology and radiologists. Our experience may provide an encouraging model for other radiology practices in pursuing similar endeavors. PMID- 24814827 TI - Expression levels of eosinophil granule protein mRNAs in induced sputum reflect airway hyperresponsiveness and airflow limitation. AB - Eosinophils are regarded as the major effector cells that produce symptoms in allergic diseases. Activation of eosinophils induces extracellular release of a number of eosinophil granule proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil derived neurotoxin. The objective of this study was to evaluate the differences and significance of the sputum eosinophil% and expression levels of eosinophilic granule protein mRNAs in allergic airway disease. Induced sputum samples were obtained from non-smokers with 25 asthma, 54 eosinophilic bronchitis, 16 allergic rhinitis, and 19 healthy control subjects. The eosinophil granule protein mRNAs were measured with real time RT-PCR. There was no correlation between the sputum eosinophil% and the mRNA level of any of eosinophil granule proteins. However, the expression levels of MBP and ECP mRNAs were higher in subjects with each of the specified allergic diseases than those in control subjects (P < 0.05). Moreover, in the subjects with allergic sensitization, the expression levels of MBP and EPO mRNAs were significantly higher in those with airway hyperresponsiveness (13 subjects) than in those without airway hyperresponsiveness (32 subjects) (P = 0.004 and 0.010, respectively). In asthma patients, the FEV1% was negatively correlated with ECP mRNA levels (r = -0.510, P = 0.022), but showed no correlation with sputum eosinophil%. In conclusion, mRNA levels of eosinophil granule proteins, rather than sputum eosinophil%, may reflect airway hyperresponsiveness and airflow limitation. In practice, consideration for the eosinophil% as well as the eosinophil granule proteins levels in induced sputum is needed. PMID- 24814828 TI - Liposome electrokinetic chromatography based in vitro model for early screening of the drug-induced phospholipidosis risk. AB - Drug-induced phospholipidosis (PLD) is a storage disorder of lysosomes characterized by the excessive accumulation of phospholipids as a result of improper medical treatments. Although few evidences have supported that PLD can induce significant pathological consequences, this potential toxicity indeed can put off the drug discovery process. In this research, a high-throughput liposome electrokinetic chromatography (LEKC) method was validated to evaluate the PLD risk of drug candidates by screening drug-phospholipid interaction, which correlates to the phospholipidosis inducing risk. A statistical analysis based on the Spearman's correlation test showed that the retention factors (log k) of the tested drugs in the LEKC system and the literature reported in vivo and in vitro PLD data were highly correlated. In order to investigate the predictability of LEKC, the effect of liposome composition such as the molar ratio of phospholipids and the addition of cholesterol were also discussed in this study. The results indicated that the LEKC method could offer a fast, reliable and cost-effective screening tool for early prediction of the PLD inducing potential of drug candidates. PMID- 24814829 TI - "It Depends": Reasons Why Nursing Home Residents Change Their Minds About Care Preferences. AB - PURPOSE OF THE STUDY: Understanding and honoring preferences are fundamental in the promotion of well-being for frail elders. This study aims to understand and describe nursing home residents' perspectives on why the importance of their preferences may change in daily care. DESIGN AND METHODS: Secondary data analyses of cognitive interviews with 39 cognitively capable nursing home residents regarding their importance of preferences for everyday living were completed. Interviews were coded by 5 team members for reasons why residents may change their minds about the importance of their preferences or why their preferences may be restricted; discrepancies were reconciled through consensus. RESULTS: Content analysis revealed 4 major domains: within person (e.g., functional ability, personal schedule), facility environment (e.g., facility schedule, facility policy), social environment (e.g., quality and type of interactions), and global environment (e.g., weather, current events, special occasions). Residents reflected that the importance of their preferences fluctuated "depending upon" the circumstances related to these factors or their ability to perform the preference (i.e., barriers they encountered). A total of 27 themes for dependencies and barriers were identified. IMPLICATIONS: Findings indicate that nursing home residents' preferences may change in importance or fulfillment in relation to personal or environmental circumstances. In order to develop formal care that matches older adults' preferences, regular assessment of both elders' preferences and the contextual factors affecting preferences is needed. However, given the changing nature of preference importance, there is also a need to determine how to best balance older adults' changing preferences within care delivery environments. PMID- 24814830 TI - Successful aging and its discontents: a systematic review of the social gerontology literature. AB - PURPOSE OF THE STUDY: The purpose of this study was to analyze the range of critiques of successful aging models and the suggestions for improvement as expressed in the social gerontology literature. DESIGN AND METHODS: We conducted a systematic literature review using the following criteria: journal articles retrieved in the Abstracts in Social Gerontology, published 1987-2013, successful aging/ageing in the title or text (n = 453), a critique of successful aging models as a key component of the article. Sixty-seven articles met the criteria. Qualitative methods were used to identify key themes and inductively configure meanings across the range of critiques. RESULTS: The critiques and remedies fell into 4 categories. The Add and Stir group suggested a multidimensional expansion of successful aging criteria and offered an array of additions. The Missing Voices group advocated for adding older adults' subjective meanings of successful aging to established objective measures. The Hard Hitting Critiques group called for more just and inclusive frameworks that embrace diversity, avoid stigma and discrimination, and intervene at structural contexts of aging. The New Frames and Names group presented alternative ideal models often grounded in Eastern philosophies. IMPLICATIONS: The vast array of criteria that gerontologists collectively offered to expand Rowe and Kahn's original successful model is symptomatic of the problem that a normative model is by definition exclusionary. Greater reflexivity about gerontology's use of "successful aging" and other normative models is needed. PMID- 24814831 TI - Urea Rebound Assessment Based on UV Absorbance in Spent Dialysate. AB - The aim of the study was to examine the possibility of postdialysis urea rebound assessment using UV-absorbance measurements in spent dialysate. Twenty-six patients on chronic three-times-a-week hemodialysis (HD) were studied in two separate studies. Double-beam spectrophotometer was used for the determination of UV absorbance in the collected spent dialysate samples. Also, on-line UV absorbance was monitored. The equilibrium concentration (C(eq)) of urea at the end of the rebound phase was calculated based on urea concentration in blood and dialysate and UV absorbance in spent dialysate. Based on C(eq), urea rebound was expressed relative to urea concentration at the end of HD (R1) and relative to the decrease in urea concentration during HD (R2). Estimates based on UV absorbance values in spent dialysate (R(1_a), R(2_a)) slightly over assess postdialysis rebound compared with results based on the blood sample drawn 30 min after HD (R(1_30post), R(2_30post)), but R(1_a) and R(2_a) presented greater consistency and accuracy compared with the estimates based on the intradialytic blood sample (R(1_b), R(2_b)). In summary, the results show that it is possible to assess postdialysis urea rebound in blood based on UV-absorbance measurements in spent dialysate. PMID- 24814832 TI - High-Resolution Imaging Using the VisualSonics Vevo 2100 on Isolated, Perfused Porcine Kidneys on Mechanical Circulatory Support. AB - Despite many improvements in the field of renal transplantation, the key problem that persists is the lack of organs for all the patients who need kidneys. This problem continues despite the addition of extended criteria donors and donation after cardiac death. Compounding this issue is the high discard rate and there are no good means to truly predict renal function using current pretransplantation testing parameters. In an isolated renal perfusion model using porcine kidneys, we tested the proof of principle that a Vevo 2100 high-frequency high-resolution ultrasound system (Fujifilm VisualSonics, Inc., Toronto, Canada) could assess renal parenchymal perfusion and flow in the central renal vessels which could not assess by conventional ultrasound. Images and velocities were easily obtained during these studies. High-frequency ultrasound imaging may be a feasible and reproducible method for assessing renal parenchymal integrity and function pretransplantation. Further studies are required to determine the sensitivity and specificity of this approach in comparison with traditional renal biopsy pretransplantation with the goal of increasing the identification and use of donated kidneys for transplantation. PMID- 24814833 TI - Control of respiration-driven retrograde flow in the subdiaphragmatic venous return of the Fontan circulation. AB - Respiration influences the subdiaphragmatic venous return in the total cavopulmonary connection (TCPC) of the Fontan circulation whereby both the inferior vena cava (IVC) and hepatic vein flows can experience retrograde motion. Controlling retrograde flows could improve patient outcomes. Using a patient specific model within a Fontan mock circulatory system with respiration, we inserted a valve into the IVC to examine its effects on local hemodynamics while varying retrograde volumes by changing vascular impedances. A bovine valved conduit reduced IVC retrograde flow to within 3% of antegrade flow in all cases. The valve closed only under conditions supporting retrograde flow and its effects on local hemodynamics increased with larger retrograde volume. Liver and TCPC pressures improved only when the valve leaflets were closed whereas cycle averaged pressures improved only slightly (<1 mm Hg). Increased pulmonary vascular resistance raised mean circulation pressures, but the valve functioned and cardiac output improved and stabilized. Power loss across the TCPC improved by 12%-15% (p < 0.05) with a valve. The effectiveness of valve therapy is dependent on patient vascular impedance. PMID- 24814834 TI - Acoustic spectral analysis for determining pump thrombosis in rotary blood pumps. AB - Implantation of rotary blood pumps is an established treatment for end-stage heart failure. Anticoagulation is routinely used for reducing pump thrombosis, but this severe complication still occurs in 5-8% of patients. In 105 patients, the sound produced by the left ventricular assist device HeartWare HVAD was prospectively and sequentially recorded. The acoustic spectra calculated by runtime fast Fourier transformation were investigated. Results were compared with respect to patients without thrombotic complications (97 patients) and those with signs of pump thrombosis (8 patients). All eight pumps exchanged were opened and investigated. Thrombus formation was confirmed in all eight exchanged pumps. The existence of a sound peak with the threefold frequency of the pump speed correlated with the presence of thrombi inside the pump (p < 0.001). An increase in the sound amplitude of the rotary frequency of approximately 75% compared to previous measurements also denotes pump thrombosis. Analysis of the acoustic spectrum of the HVAD pump can be used as a reliable method to detect pump thrombosis. The appearance of third harmonics indicates the presence of thrombotic particles independently of previous baseline measurements. The goal of this study is to define and validate such a method. PMID- 24814835 TI - Insensible water loss through adult extracorporeal membrane oxygenation circuit: an in vitro study. AB - Patients on extracorporeal membrane oxygenation (ECMO) are critically ill, and fluid balance need to be managed as accurately as possible. Previous studies have focused on insensible water loss through neonatal ECMO circuit and showed that water loss through the ECMO circuit was correlated with the sweep-gas flow rates. Current study is the first study focusing on insensible water loss through adult ECMO circuit. An in vitro extracorporeal circuit consisting of Jostra Quadrox D membrane oxygenator and centrifugal pump was primed with normal saline. The amount of water loss through the ECMO circuit was found to be linearly correlated with the sweep-gas flow rate and fluid temperature. For every liter per minute of sweep-gas flow at 37 degrees C, 0.046 ml/min of water will be lost, and for every change of fluid temperature by 1 degrees C, water content loss will be changed by 0.0026 ml/min by multiple linear regression (R = 0.996). The average daily water loss for every liter per minute of sweep-gas flow at 33, 34, 35, 36, 37, 38, and 39 degrees C were 51.3, 55, 58.8, 62.5, 66.2, 70.0, and 73.7 ml/day, respectively. PMID- 24814836 TI - Administration of antithrombin concentrate in infants and children on extracorporeal life support improves anticoagulation efficacy. AB - Unfractionated heparin (UFH) is required in children on extracorporeal life support (ECLS) to maintain circuit patency. When high-dose UFH is inadequate to maintain an anticoagulant effect, the addition of antithrombin concentrate (ATC) is considered. The objective of this study was to review clinical experience giving 1,000 units (U) of ATC to patients on ECLS and UFH anticoagulation. Specifically, antithrombin (AT) levels pre- and post-administration of high-dose ATC, estimation of the efficacy of high-dose ATC administration as measured by the level of anticoagulation, and the incidence of adverse effects were determined. A retrospective chart review of all infants and children on ECLS who received ATC between June 2008 and May 2011 at Stollery Children's Hospital, Edmonton, Canada, was performed. A total of 78 doses of ATC were administered to 36 patients with a median age of 2.9 months (interquartile range, 0.6-12.6) on ECLS. Mean dose of ATC was 241 U/kg (95% confidence interval, 199-283). Mean AT level pre- and post-administration was 0.40 and 0.93 U/ml, respectively. Mean anti-Xa level pre- and post-AT administration was 0.23 and 0.41 U/ml, respectively. There were no associated acute adverse events. The administration of high-dose ATC decreases UFH dose requirements. PMID- 24814837 TI - Numerical simulation of compliant artery bypass grafts using fluid-structure interaction framework. AB - Early researches on the artery bypass graft (ABG) generally took the assumption of rigid vessel wall that ignored the wall compliancy. To obtain more realistic and physiological hemodynamic parameters, a fluid structure interaction study on a complete ABG was carried out. It was concluded: (1) a compliant vessel is able to expand its vessel diameter and decrease its anastomosis angle to achieve a buffer for the blood, thereby helping to reduce endothelial cell injury. (2) The vessel walls experienced their maximum deformation at the time of peak pressure while the deformation could be ignored during diastole. However, the consideration of wall compliance did not quantitatively change the flow characters compared to those of rigid walls. (3) Generally, the hemodynamic priority of helical-type ABG over a conventional one was further strengthened by adopting compliant vessel wall. (4) The consideration of the wall deformation revealed a hidden fact by the rigid wall assumption: Helical ABG aggravated the risk of intimal hyperplasia at its toe region due to its geometry and flow asymmetry. The present study may be useful for surgeons and graft designers to optimize the current and future ABG configurations and selection of materials. PMID- 24814838 TI - The presence of air bubbles in the aorta of a patient with a HeartMate II left ventricular assist device: a novel sign of outflow graft obstruction. AB - Microbubbles formed by cavitation have been frequently reported in patients with mechanical heart valves, but have not previously been described in patients with continuous-flow left-ventricular assist devices (LVADs). Obstruction of the LVAD circuit by thrombus, outflow graft kinking, or cannula malposition may cause high pressure gradients and turbulent flow, often resulting in hemolysis. The article is the first in the field to describe the presence of microbubbles in the ascending aorta of a patient with severe LVAD-associated hemolysis. It is proposed that these bubbles were formed by cavitation in the presence of a high pressure gradient due to LVAD outflow graft obstruction and suggested that this may be a novel imaging sign of LVAD obstruction in patients with continuous-flow LVADs. PMID- 24814839 TI - Six-year in-vitro reliability results of the HeartWare HVAD pump. AB - As a result of stagnant heart transplantation rates, ventricular assist devices (VADs) have become a widely accepted therapy for the treatment of advanced-stage heart failure. Long-term reliability of VADs will become increasingly vital as the population of destination therapy patients expands. In this study, eight HVAD pumps (n = 8) completed a 6-year reliability test in the HeartWare Life Cycle Testing System, an in-vitro mock circulatory loop that simulated physiologic pressures and flows. Cumulative runtime for the pumps was 2,408 +/- 60 days. During this time, no device failures of any type occurred. These results strongly support the durability of the pump design. PMID- 24814840 TI - Insufficient serum levels of antituberculosis agents during venovenous extracorporeal membrane oxygenation therapy for acute respiratory distress syndrome in a patient with miliary tuberculosis. AB - Prolonged cardiopulmonary support via extracorporeal membrane oxygenation (ECMO) is essential for patients with life-threatening respiratory or cardiac failure. Extracorporeal membrane oxygenation is known to be associated with conditions that potentially alter the distribution and elimination properties of drugs. However, little has been documented concerning pharmacokinetic changes of antibacterial agents in critically ill patients under oxygenation conditions. We describe a case of miliary tuberculosis with acute respiratory distress syndrome supported by venovenous ECMO. The patient had persistently positive acid-fast bacilli smears for respiratory specimens. Accordingly, standard doses of antituberculosis agents, including isoniazid, rifampicin, ethambutol, and pyrazinamide, were administered with appropriate therapeutic drug monitoring. Drug levels were found to be subtherapeutic. Therapeutic target levels were achieved after altering the route of administration and making dosage adjustments. Although this is a single case report, our observations indicate the need for therapeutic drug monitoring to achieve appropriate target concentrations for antituberculosis agents in patients with miliary tuberculosis under ECMO. PMID- 24814841 TI - Assessing thromboembolic risk on anticoagulation reversal in patients with left ventricular assist devices: a call to action for the mechanical circulatory support community. PMID- 24814842 TI - On-line dialysate infusion to estimate absolute blood volume in dialysis patients. AB - It was the aim to measure the distribution volume and the elimination of ultra pure dialysate in stable hemodialysis patients during on-line hemodiafiltration (HDF). Dialysate was automatically infused as a volume indicator using standard on-line HDF equipment. Indicator concentration was noninvasively measured in the arterial blood-line (using the blood volume monitor, Fresenius Medical Care, Bad Homburg vor der Hohe, Germany), and its time course was analyzed to obtain the elimination rate and the distribution volume V(t) at the time of dilution. Blood volume at treatment start (V0) was calculated accounting for the degree of intradialytic hemoconcentration. Five patients (two females) were studied during 15 treatments. Two to six measurements using indicator volumes ranging from 60 to 210 ml were done in each treatment. V0 was 4.59 +/- 1.15 L and larger than the volume of 4.08 +/- 0.48 L estimated from anthropometric relationships. The mean half-life of infused volume was 17.2 +/- 29.7 min. Given predialysis volume expansion V0 was consistent with blood volume determined from anthropometric measurements. Information on blood volume could substantially improve volume management in hemodialysis patients and fluid therapy in intensive care patients undergoing extracorporeal blood treatment. The system has the potential for complete automation using proper control inputs for BVM and HDF modules of the dialysis machine. PMID- 24814843 TI - Nutritional support and advanced heart failure. PMID- 24814844 TI - Gerstmann-Straussler-Scheinker disease: novel PRNP mutation and VGKC-complex antibodies. AB - OBJECTIVE: To describe a unique case of Gerstmann-Straussler-Scheinker (GSS) disease caused by a novel prion protein (PRNP) gene mutation and associated with strongly positive voltage-gated potassium channel (VGKC)-complex antibodies (Abs). METHODS: Clinical data were gathered from retrospective review of the case notes. Postmortem neuropathologic examination was performed, and DNA was extracted from frozen brain tissue for full sequence analysis of the PRNP gene. RESULTS: The patient was diagnosed in life with VGKC-complex Ab-associated encephalitis based on strongly positive VGKC-complex Ab titers but no detectable LGI1 or CASPR2 Abs. He died despite 1 year of aggressive immunosuppressive treatment. The neuropathologic diagnosis was GSS disease, and a novel mutation, P84S, in the PRNP gene was found. CONCLUSION: VGKC-complex Abs are described in an increasingly broad range of clinical syndromes, including progressive encephalopathies, and may be amenable to treatment with immunosuppression. However, the failure to respond to aggressive immunotherapy warns against VGKC complex Abs being pathogenic, and their presence does not preclude the possibility of prion disease. PMID- 24814845 TI - Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28. AB - OBJECTIVE: To identify the genetic cause of autosomal dominant spinocerebellar ataxia type 28 (SCA28) with ptosis in 2 Belgian families without AFG3L2 point mutations and further extend the clinical spectrum of SCA28 through the study of a brain autopsy, advanced MRI, and cell-based functional assays exploring the underlying disease mechanism. METHODS: Two large families were clinically examined in detail. Linkage analysis and multiplex amplicon quantification were performed. A brain autopsy was obtained. Brain MRI with voxel-based morphometry and diffusion tensor imaging was performed. RNA and Western blot analysis and blue native-polyacrylamide gel electrophoresis experiments were performed. RESULTS: MRI analysis demonstrated a significant cerebellar atrophy, as well as white matter degeneration in the cerebellar peduncles, corticospinal tracts, corpus callosum, and cingulum. A brain autopsy showed severe atrophy of the upper part of the cerebellar hemisphere. Ubiquitin and p62 immunoreactive intranuclear inclusions were found in cerebral and cerebellar cortical neurons, in neurons of the hippocampus, and in pontine and medullary nuclei. An identical heterozygous partial deletion of exons 14 to 16 of the AFG3L2 gene was found in both families. Additional functional assays in patient-derived cell lines revealed haploinsufficiency as the underlying disease mechanism. CONCLUSIONS: Our study expands the phenotypic characterization of SCA28 by means of brain pathology and diffusion tensor imaging/voxel-based morphometry MRIs. The identification of a partial AFG3L2 deletion and the subsequent functional studies reveal loss of function as the most likely disease mechanism. Specific testing for deletions in AFG3L2 is warranted because these escape standard sequencing. PMID- 24814846 TI - DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. AB - OBJECTIVE: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). METHODS: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells. RESULTS: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of a German family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant. CONCLUSIONS: DEPDC5 loss-of function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype. PMID- 24814847 TI - Abnormal thalamic function in patients with vestibular migraine. AB - OBJECTIVE: To investigate the functional response of neural pathways associated with vestibular stimulation in patients with vestibular migraine (VM). METHODS: Twelve patients with VM underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during ear irrigation with cold water. The functional response of neural pathways to this stimulation in patients with VM was compared with age- and sex matched patients with migraine without aura and healthy controls. Secondary analyses explored associations between BOLD signal change and clinical features of migraine in patients. RESULTS: We observed a robust cortical and subcortical pattern of BOLD signal change in response to ear irrigation across all participants. Patients with VM showed a significantly increased thalamic activation in comparison with both patients with migraine without aura and healthy controls. The magnitude of thalamic activation was positively correlated with the frequency of migraine attacks in patients with VM. CONCLUSIONS: We provide novel evidence for abnormal thalamic functional response to vestibular stimulation in patients with VM. These functional abnormalities in central vestibular processing may contribute to VM pathophysiology. PMID- 24814849 TI - Presence and progression of white matter hyperintensities and cognition: a meta analysis. AB - OBJECTIVE: We aimed to quantify the effects of white matter hyperintensities (WMHs) on specific cognitive functions with particular attention to WMH progression and localization. METHODS: PubMed (January 1990-July 2013) and bibliographies from included articles were used. Studies that were included (1) used MRI; (2) had a population-based or case-control design with a healthy control group that could be used for analysis; (3) matched/adjusted for age, sex, and education; and (4) addressed >=1 predefined cognitive domains with >=1 validated neuropsychological tests. Data were independently extracted by 2 investigators. Pearson r was extracted/calculated and used as the common metric for the effect size across studies. RESULTS: Twenty-three cross-sectional and 14 longitudinal studies were included with a total of 8,685 and 7,731 participants. Presence of WMHs was significantly associated with concurrent cognitive deficits in all examined domains: general intelligence (Fisher z -0.10, 95% confidence interval [CI] -0.19 to -0.04), memory (-0.08, -0.13 to -0.06), processing speed ( 0.11, -0.17 to -0.07), attention and executive functions (-0.11, -0.16 to -0.07), and perception/construction (-0.15, -0.21 to -0.07). Similar effect sizes were observed for cognitive decline over time. WMH progression was associated with greater cognitive decline, particularly for general intelligence (Fisher z -0.31, 95% CI -0.5 to -0.02) and attention and executive functions (-0.32, -0.34 to 0.28). CONCLUSIONS: The small but robust and consistent effects of WMHs on all cognitive domains suggest a more global effect on cognition than previously thought. Progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning. PMID- 24814850 TI - HIV and the neuropsychology of everyday life. PMID- 24814848 TI - Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. AB - OBJECTIVE: While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). METHODS: A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. RESULTS: The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2 10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. CONCLUSIONS: This longitudinal study demonstrates that ANI conveys a 2 fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression. PMID- 24814851 TI - Correlation of clinical and molecular features in spinal bulbar muscular atrophy. AB - OBJECTIVES: To characterize the clinical and genetic features of spinal bulbar muscular atrophy (SBMA), a rare neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene, in the United Kingdom. METHODS: We created a national register for SBMA in the United Kingdom and recruited 61 patients between 2005 and 2013. In our cross-sectional study, we assessed, by direct questioning, impairment of activities of daily living (ADL) milestones, functional rating, and subjective disease impact, and performed correlations with both CAG repeat size and degree of somatic mosaicism. Ten patients were deceased, 46 patients participated in the study, and 5 declined. RESULTS: Subjects had an average age at onset of 43.4 years, and weakness onset most frequently occurred in the lower limbs (87%). Impaired mobility was the most frequently reported problem by patients, followed by bulbar dysfunction. Age distribution of the impairment of ADL milestones showed remarkable overlap with a Japanese study. We have identified a significant correlation between the number of CAG repeats and both age at onset and ADL milestones. Somatic mosaicism also showed a correlation with CAG expansion size and age at onset. CONCLUSIONS: Clinical features in SBMA show a substantial overlap when comparing populations with different genetic backgrounds. This finding has major implications, because multicenter trials will be necessary to obtain sufficient power in future clinical trials. Clinical-genetic correlations are strong in SBMA and should inform any clinical research strategy in this condition. PMID- 24814852 TI - Unilateral versus bilateral pedicle screw instrumentation for single-level minimally invasive transforaminal lumbar interbody fusion. AB - Minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) has become an increasingly popular method of lumbar arthrodesis. However, there are few published studies comparing the clinical outcomes between unilateral and bilateral instrumented MIS TLIF. Sixty-five patients with degenerative lumbar spine disease were enrolled in this study. Thirty-one patients were randomized to the unilateral group and 34 to the bilateral group. Recorded demographic data included sex, age, preoperative diagnosis, and degenerated segment. Operative time, blood loss, hospital stay length, complication rates, and fusion rates were also evaluated. The Oswestry Disability Index (ODI) score and Visual Analog Scale (VAS) pain score data were obtained. All patients were asked to follow-up at 3 and 6 months after surgery, and once every 6 months thereafter. The mean follow up was 26.6 months (range 18-36 months). The two groups were similar in sex, age, preoperative diagnosis, and operated level. The unilateral group had significantly shorter operative time, lower blood loss, and shorter hospital time than the bilateral group. The average postoperative ODI and VAS scores improved significantly in each group. No significant differences were found between the two groups in relation to ODI and VAS. All patients showed evidence of fusion at 12 months postoperatively. The total fusion rate, screw failure, and general complication rate were not significantly different. Results showed that single level MIS TLIF with unilateral pedicle screw fixation would be sufficient in the management of preoperatively stable patients with lumbar degenerative disease. It seems that MIS TLIF with unilateral pedicle screw instrumentation is a better choice for single-level degenerative lumbar spine disease. PMID- 24814853 TI - Brain SPECT can differentiate between essential tremor and early-stage tremor dominant Parkinson's disease. AB - There are no confirmatory or diagnostic tests or tools to differentiate between essential tremor (ET) and tremor in idiopathic Parkinson's disease (PD). Although a number of imaging studies have indicated that there are differences between ET and PD, the functional imaging study findings are controversial. Therefore, we analyzed regional cerebral blood flow (CBF) by perfusion brain single-photon emission computed tomography (SPECT) to identify differences between ET and tremor-dominant Parkinson's disease (TPD). We recruited 33 patients with TPD, 16 patients with ET, and 33 healthy controls. We compared the severity of tremor symptoms by comparing the Fahn-Tolosa-Marin rating scale (FTM) score and the tremor score from Unified Parkinson's Disease Rating Scale (UPDRS) between TPD and ET patients. Subjects were evaluated by neuropsychological assessments, MRI and perfusion SPECT of the brain. Total FTM score was significantly higher in ET patients than TPD patients. However, there was no significant difference in FTM Part A scores between the two patient groups, while the scores for FTM Part B and C were significantly higher in ET patients than TPD patients. Brain SPECT analysis of the TPD group demonstrated significant hypoperfusion of both the lentiform nucleus and thalamus compared to the ET group. Brain perfusion SPECT may be a useful clinical method to differentiate between TPD and ET even during early-phase PD, because the lentiform nucleus and thalamus show differences in regional perfusion between these two groups during this time period. Additionally, we found evidence of cerebellar dysfunction in both TPT and ET. PMID- 24814854 TI - Increased cerebrospinal fluid concentrations of asymmetric dimethylarginine correlate with adverse clinical outcome in subarachnoid hemorrhage patients. AB - Elevated cerebrospinal fluid (CSF) concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been found in patients with subarachnoid hemorrhage (SAH). In addition, CSF levels of ADMA are associated with the severity of vasospasm. However, the relation between CSF ADMA levels and the clinical outcome of SAH patients is still unclear. We hypothesized that elevated ADMA levels in CSF might be related to the clinical outcome of SAH patients. CSF ADMA levels were measured in 20 SAH patients at days 3-5, days 7-9 and days 12-14 after SAH onset using high-performance liquid chromatography. Cerebral vasospasm was assessed by transcranial Doppler ultra sonography. Clinical outcome at 2year follow-up was evaluated using the Karnofsky Performance Status scale (KPS). CSF ADMA concentrations in all SAH patients were significantly increased at days 3-5 (p=0.002) after SAH, peaked on days 7-9 (p<0.001) and remained elevated until days 12-14 (p<0.001). In subgroup analysis, significant increases of CSF ADMA levels were found in patients both with and without vasospasm. The KPS scores significantly correlated with CSF levels of ADMA at days 7-9 (correlation coefficient=-0.55, p=0.012; 95% confidence interval -0.80 to -0.14). Binary logistic regression analysis indicated that higher ADMA level at days 7-9 predicted a poor clinical outcome at 2year follow-up after SAH (odds ratio=1.722, p=0.039, 95% confidence interval 1.029 to 2.882). ADMA may be directly involved in the pathological process and future adverse prognosis of SAH. PMID- 24814855 TI - Pain experience using conventional versus angled anterior posts during stereotactic head frame placement for radiosurgery. AB - Stereotactic frame placement for radiosurgery is assumed to be an uncomfortable experience. We developed angled anterior posts for the Leksell frame to avoid pin penetration of the temporalis muscle. This study aimed to determine the frequency of angled post requirement and quantify the patient pain experience from frame placement. We prospectively enrolled 63 patients undergoing radiosurgery. Angled posts were used when conventional post trajectory was posterior or within 3mm of the superior temporal line to avoid temporalis muscle penetration. Pain scores (0 to 10) were collected prior to frame placement, immediately after frame placement, before radiosurgery, after radiosurgery, and a day after radiosurgery. A total of 63 patients were enrolled: 33 (48%) patients required angled posts. Women were significantly more likely to require angled posts than men (60.0% versus 33.3%, respectively; p=0.034). Mean pain scores were very low, ranging from 0.33 to 2.23. There were no significant differences in pain outcomes between both groups at all time points. Stereotactic frame placement is not perceived to be a painful procedure. This information may be useful when counseling patients about the pain experience with frame application and the option of using angled anterior posts. PMID- 24814856 TI - Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage. AB - Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with mutations in SETX, which encodes the senataxin protein, a DNA/RNA helicase. We describe the clinical phenotype and molecular characterization of a Colombian AOA2 patient who is compound heterozygous for a c.994 C>T (p.R332W) missense mutation in exon 7 and a c.6848_6851delCAGA (p.T2283KfsX32) frameshift deletion in SETX exon 21. Immunocytochemistry of patient-derived fibroblasts revealed a normal cellular distribution of the senataxin protein, suggesting that these mutations do not lead to loss or mis localization of the protein, but rather that aberrant function of senataxin underlies the disease pathogenesis. Furthermore, we used the alkaline comet assay to demonstrate that patient-derived fibroblast cells exhibit an increased susceptibility to oxidative DNA damage. This assay provides a novel and additional means to establish pathogenicity of SETX mutations. PMID- 24814857 TI - Double filtration plasmapheresis benefits myasthenia gravis patients through an immunomodulatory action. AB - Double filtration plasmapheresis (DFPP) is used to treat myasthenia gravis (MG). However, the definite mechanism is unclear. This study investigated whether DFPP improves MG through an immunomodulatory action. Thirty-five MG patients were randomly divided into two treatment groups: Group A (DFPP combined with oral methylprednisolone) and Group B (oral methylprednisolone alone). Their antibody levels, clinical scores, cytokine levels, and CD4(+)CD25(high)Foxp3(+) (regulatory T cell [Treg]) levels were then determined. Anti-titin antibody levels were significantly lower in Group A compared with Group B after treatment. The clinical remission rate in Group A was significantly higher than in Group B. The changes in cytokine levels (interleukin [IL]-2, IL-4, IL-10, and interferon gamma) in sera and the peripheral blood mononuclear cell culture supernatants did not significantly differ before and after the treatments in both groups (p<0.05). The soluble intercellular adhesion molecule-1 (sICAM-1) levels were lower in Group A than in Group B (p<0.05). MG patients exhibited a lower percentage of Treg cells than normal patients. DFPP combined with methylprednisolone treatment increased the Treg cell percentage more than treatment with methylprednisolone alone (p<0.05). DFPP treatment more effectively lowers sICAM-1 and increases Treg cell expression, consequently benefiting MG patients. PMID- 24814858 TI - Supplementation of folic acid and vitamin B12 reduces plasma levels of asymmetric dimethylarginine in patients with acute ischemic stroke. AB - Increased levels of asymmetric dimethylarginine (ADMA) have been observed in patients with acute ischemic stroke. We aimed to investigate the correlation between ADMA and ischemic stroke, and evaluate the effect of supplementation of folic acid and vitamin B12 on concentrations of ADMA. Patients were randomized into intervention and non-intervention groups within 3 days after symptom onset. Intervention group patients were treated with folic acid (5mg daily) and vitamin B12 (500 MUg twice daily) for 12 weeks. ADMA and homocysteine (Hcy) concentrations were measured before treatment (baseline) and 2 and 12 weeks after treatment. The laboratory measures were also collected from healthy controls. Eighty five subjects were enrolled in this study, from whom 72 with complete baseline and follow-up laboratory data were included in the present analysis. Thirty four patients were assigned to the intervention group and 38 patients to the non-intervention group. Sixty people were enrolled as healthy controls. Levels of ADMA and Hcy were raised (p<0.05) in patients with acute ischemic stroke. With supplementation of both folic acid and vitamin B12, the levels of ADMA and Hcy decreased significantly at 2 and 12 weeks (p<0.05). The present study reconfirmed that ADMA can be regarded as a risk biomarker for acute ischemic stroke. We observed that with supplementation of folic acid and vitamin B12, levels of ADMA were decreased in patients with acute ischemic stroke. PMID- 24814859 TI - Generalized self-assembly of scalable two-dimensional transition metal oxide nanosheets. AB - Two-dimensional (2D) transition metal oxide systems present exotic electronic properties and high specific surface areas, and also demonstrate promising applications ranging from electronics to energy storage. Yet, in contrast to other types of nanostructures, the question as to whether we could assemble 2D nanomaterials with an atomic thickness from molecules in a general way, which may give them some interesting properties such as those of graphene, still remains unresolved. Herein, we report a generalized and fundamental approach to molecular self-assembly synthesis of ultrathin 2D nanosheets of transition metal oxides by rationally employing lamellar reverse micelles. It is worth emphasizing that the synthesized crystallized ultrathin transition metal oxide nanosheets possess confined thickness, high specific surface area and chemically reactive facets, so that they could have promising applications in nanostructured electronics, photonics, sensors, and energy conversion and storage devices. PMID- 24814860 TI - Re-envisioning global agricultural trade: time for a paradigm shift to ensure food security and population health in low-income countries. AB - In this commentary, we use examples from West Africa to highlight how the liberalization of global agricultural trade exacerbates population health inequalities by threatening the livelihoods and food security of communities in low-income settings. We highlight the exploitative nature of trade agreements with West African countries demonstrating how these agreements disincentivize local agricultural investment and take jobs away from small-scale farmers. Further, we link agricultural trade liberalization to increased food insecurity, malnutrition, and exposure to environmental contaminants. Finally, we propose a paradigm shift that advocates for food sovereignty and the right to food. PMID- 24814861 TI - Culture in salutogenesis: the scholarship of Aaron Antonovsky. AB - Aaron Antonovsky wrote extensively, although disjointedly, about the roles of culture in salutogenesis. This paper provides a synopsis of his work in this arena. A literature review identified those of his English language writings in which culture was a subject, and relevant text segments were analysed using an inductive followed by a deductive method. Using thematic network analysis, text segments were sorted inductively by open coding and then analysed. This was followed by deductive text segment coding guided by the constructs of the salutogenic model of health. The analysis revealed that Antonovsky had an expansive interest in the roles of culture in salutogenesis. His writings included attention to the role of culture in: (a) shaping life situations; (b) giving rise to stressors and resources; (c) contributing to life experiences of predictability, load balance and meaningful roles; (d) facilitating the development of the sense of coherence and (e) shaping perceptions of health and well-being. Antonovsky's writings about culture were sometimes conjectural, as well as being obviously influenced by his life experience in the USA and then in Israel, and by the spirit of the times in which he lived. However, he also drew extensively on his own and others' empiricism, leading him to view culture as an integral aspect of the salutogenic model of health. The present analysis provides salutogenesis scholars with a roadmap of Antonovsky's reflections, ponderings and conclusions about culture in the context of salutogenesis. It provides assistance in the form of an overview of Antonovsky's treatment of culture in the context of salutogenesis. PMID- 24814862 TI - Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma. AB - Brentuximab vedotin is an antibody-drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21-day cycle up to 16 cycles. In the phase I part of a dose-escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large-cell lymphoma). The median number of treatment cycles was 16 (range, 4-16). In the phase I part, no dose-limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large-cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111650). PMID- 24814863 TI - siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene. AB - The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications. PMID- 24814864 TI - Alkene-assisted nickel-catalyzed regioselective 1,4-addition of organoboronic acid to dienones: a direct route to all-carbon quaternary centers. AB - A nickel-catalyzed highly regioselective 1,4-addition reaction of boronic acids to dienones to form products with an all-carbon quaternary center is described. The 3-alkenyl group of dienones is the key for the reaction to proceed smoothly. A mechanism involving the coordination of the dienyl group to the nickel center is proposed. PMID- 24814865 TI - Horizontal head titubation in infants with Joubert syndrome: a new finding. AB - AIM: Head thrusts are well documented in Joubert syndrome and ocular motor apraxia. We provide a detailed clinical characterization of head titubation in 13 young children with Joubert syndrome. METHOD: Detailed characterization of head titubation was assessed by targeted clinical evaluation and/or analysis of videos. RESULTS: In 12 of 13 children (eight males, five females; median age 6y, range 2mo-15y) head titubation was first recognized in the first 2 months of age and decreased in severity until spontaneous resolution. In all children, the head titubation was horizontal, high frequency (~3Hz), had small amplitude (5-10 degrees ), was never present during sleep, and did not interfere with the neurodevelopment during infancy. In the majority of children, emotion, anxiety, and tiredness were worsening factors for head titubation. INTERPRETATION: Head titubation is a benign, early presentation of Joubert syndrome. Head titubation in hypotonic infants should prompt a careful search for Joubert syndrome. Awareness of its occurrence in Joubert syndrome may avoid unnecessary investigations. PMID- 24814866 TI - Management of hyperphosphataemia: practices and perspectives amongst the renal care community. AB - BACKGROUND: Protein-rich foods are a major source of dietary phosphorus; therefore, helping patients to increase their dietary protein intake, while simultaneously managing their hyperphosphataemia, poses a significant challenge for renal care professionals. OBJECTIVES: To examine the clinical recommendations and practice perceptions of renal care professionals providing nutrition and phosphate control advice to patients with chronic kidney disease (CKD). METHODS: Renal care professionals from four European countries completed an online survey on the clinical management of hyperphosphataemia. RESULTS: The majority of responders recommended a protein intake of less than 1.0 g/kg/day for pre dialysis patients, 1.2 g/kg/day for patients undergoing peritoneal dialysis (PD) and 1.1-1.2 g/kg/day for patients undergoing haemodialysis (HD). The most common perception was that maintaining dietary protein intake and reducing dietary phosphorus intake are equally important for hyperphosphataemia management. For patients in the pre-dialysis stage, the majority of responders (59%) reported that their first-line management recommendation would be reduction of dietary phosphorus. For patients undergoing PD and HD, the majority of responders (53% and 59%, respectively) reported a first-line management recommendation of both reduction of dietary phosphorus and phosphate binder therapy. More renal nurses than dietitians perceived reducing dietary phosphorus to be more important than maintaining protein intake (for patients undergoing PD, 23% vs. 0%, respectively; for patients undergoing HD, 34% vs. 0%, respectively). CONCLUSION: This renal care community followed professionally accepted guidelines for patient nutrition and management of hyperphosphataemia. There was disparity in the perceptions and recommendations between nurses and dietitians, highlighting the need to standardise management practices amongst renal care professionals. PMID- 24814867 TI - A peptide nucleic acid (PNA)-mediated polymerase chain reaction clamping allows the selective inhibition of the ERVWE1 gene amplification. AB - A new peptide nucleic acid (PNA) mediated QPCR technique for the detection and quantification of the Multiple Sclerosis-Associated Retrovirus (MSRV) belonging to the human endogenous retrovirus-W (HERV-W) family has been developed. The assay utilizes a PNA probe which is fully complementary to the ERVWE1 sequence, another member of the HERV-W family which is closely related to MSRV. Due to its excellent affinity to a completely matched template, PNA probe selectively blocks the amplification of ERVWE1 thus allowing the specific and exclusive detection and quantification of the MSRV as PNA does not interfere with the amplification of MSRV. Using this newly developed method we found that MSRV is predominantly expressed over ERWVE1 in astrocyte-derived U-87 MG cell line but not in human umbilical vein endothelial cells or human placental cells. PMID- 24814868 TI - Identification of Bartonella henselae in the liver of a thoroughbred foal with severe suppurative cholangiohepatitis. PMID- 24814869 TI - Patient and procedural characteristics for successful and failed immediate tracheal extubation in the operating room following cardiac surgery in infancy. AB - BACKGROUND: Immediate extubation in the operating room after congenital heart surgery is practiced with rising frequency at many cardiac institutions to decrease costs and complications. Infants less than one year of age are also increasingly selected for this 'fast track'. However, factors for patient selection, success, or failure of this practice have not been well defined in this population, yet are critical for patient safety. OBJECTIVE: To identify selection criteria, patient and procedural characteristics for successful or failed very early endotracheal extubation in the operating room immediately following infant heart surgery. METHODS: A retrospective analysis was performed for 326 consecutive patients undergoing neonatal and infant heart surgery from 2009 to 2012. Extubation and reintubation data were taken from the institutional Society of Thoracic Surgeons database and patients' charts. Patient characteristics were derived using multivariable logistic regression models. RESULTS: Very early extubation in the operating room was performed for 130 of 326 neonates and infants (40%). Weight >4 kg, lesser procedural complexity, and absence of trisomy 21 were identified as significant predictors for attempted very early extubation. Of these patients, 12% required reintubation within 48 h following surgery, predominantly due to respiratory failure or for mediastinal re exploration. Greater procedural complexity was associated with failed extubations. Reintubation was associated with prolonged hospitalization. CONCLUSIONS: Extubation immediately after infant heart surgery in the operating room can be safely achieved. However, our data suggest that patients undergoing more complex procedures should be selected more conservatively for immediate early extubation. PMID- 24814870 TI - SIRT2 as a new player in epigenetic programming of keratinocyte differentiation and a candidate tumor suppressor. AB - Epidermal keratinocytes undergo a continuous process of terminal differentiation, which is accompanied by a dramatic change in the expression and composition of keratins. This complex and carefully orchestrated process is regulated by a large number of signal transduction events and transcriptional factors as well as by epigenetic regulatory mechanisms, namely by histone methylation/acetylation and DNA methylation. In a recent issue of Exp Dermatol, Ming et al. provide evidence that sirtuin-2 (SIRT2), a NAD+-dependent deacetylase, inhibits the expression of keratin 15 and keratin 19, epidermal stem cell markers, while it stimulates the expression of loricrin, a marker of terminal keratinocyte differentiation. Human skin cancer cells show downregulation of SIRT2, and its deletion increases tumor growth in mice. Overall, these findings suggest that this deacetylase is involved in the epigenetic regulation of keratinocyte differentiation and exerts intracutaneous tumor suppressor functions. PMID- 24814871 TI - Acute heart failure in the African American patient. AB - BACKGROUND: African Americans (AAs) are disproportionately affected by acute heart failure (AHF) compared with other racial/ethnic groups. Disparities in AHF risk factors among AAs are attributed to higher rates of hypertension and diabetes mellitus, lower socioeconomic status, higher dietary caloric and salt intake, and biologic/genetic differences. However, AAs are frequently underrepresented in AHF clinical trials, and race-related differences in risks and clinical outcomes are not well understood. OBJECTIVE: The aim of this work was to review published data on AHF in the AA population, including management strategies that may differ based on race and common barriers to optimal care. METHODS: Publications were identified in Pubmed (through June 10, 2013) with the use of the search strategy terms (acute heart failure) AND (black OR African American OR racial). RESULTS: Racial disparities in the quality of AHF care are relatively uncommon; however, racial differences in pathophysiology have resulted in differing pharmacologic recommendations (eg, isosorbide dinitrate plus hydralazine is indicated only in AAs). Various socioeconomic factors influence disease progression, treatment compliance, and hospitalization/rehospitalization rates. CONCLUSIONS: Further research would enhance understanding of pathophysiologic heart failure differences between racial groups. Programs are needed that incorporate known clinical and cultural differences to improve quality of care and reduce the disease burden of AHF for all patients. PMID- 24814872 TI - Can natural language processing fulfill the promise of electronic medical records? PMID- 24814873 TI - Prolonged temporal interaction for peripheral visual processing in schizophrenia: evidence from a three-flash illusion. AB - BACKGROUND: Coherent perception of the visual world requires orderly processing of spatially and temporally distributed visual information across the visual field. The organization of this visual information is impaired in schizophrenia. We previously found that visual temporal integration in patients is prolonged, using flashes presented to the central fovea. In this study, we investigated this temporal interaction in both the fovea and fairly far out in the peripheral visual field. METHODS: We used a 'three-flash' illusion paradigm in which two spatially-coincident light pulses (of 1 ms each) are perceived by healthy individuals as one, two or three flashes depending on the time interval between the pulses. In each trial, two light pulses were presented in the fovea or 34 degrees out in the right visual field. The inter-stimulus pulse interval (ISI) ranged from 30 to 310 ms. The task for patients (n=28) and controls (n=26) was to indicate the number of flashes (one, two or three) perceived after each two-pulse presentation. RESULTS: For the controls, the peak of the three-flash illusion was shifted to longer ISIs (150 ms) in the periphery compared to the fovea (110 ms). For the patients, the three-flash illusion was greater and occurred at longer ISIs (270 ms in the periphery and 190 ms at the fovea). CONCLUSION: Compared to the central visual field, the range of temporal interactions in the periphery is prolonged to a greater extent in schizophrenia. This exacerbated temporal expansion in peripheral vision suggests a coarse temporal resolution for visual and cognitive organization in this mental disorder. PMID- 24814874 TI - Comparison of the clinical performances of the AdvanSure HPV Screening Real-Time PCR, the Abbott Real-Time High-Risk HPV Test, and the Hybrid Capture High-Risk HPV DNA Test for Cervical Cancer Screening. AB - The clinical performance of three human papillomavirus (HPV) DNA commercial assays for cervical cancer screening was evaluated; the AdvanSure HPV Screening Real-Time PCR (AdvanSure PCR; LG Life Sciences) that was developed recently for the detection of both high-risk and low-risk genotypes, the Abbott RealTime High Risk HPV Test (Abbott PCR; Abbott Molecular) and the Hybrid Capture High-Risk HPV DNA test (HC2; Qiagen). The three different HPV DNA tests were compared using cytology samples obtained from 619 women who underwent routine cervical cancer screening. The gold-standard assay was histopathological confirmation of cervical intraepithelial neoplasia of grade 2 or worse. The clinical sensitivities of the AdvanSure PCR, the Abbott PCR and the HC2 for the detection of cervical intraepithelial neoplasia of grade 2 or worse were 95.5%, 95.5% and 100%, respectively, while the clinical specificities were 61.6%, 86.4% and 83.3%, respectively. There were no significant differences in the clinical sensitivities of the Abbott PCR and the AdvanSure PCR compared to the HC2. The clinical specificities of the Abbott PCR and the AdvanSure PCR for the detection of HPV types 16/18 were 97.8% and 98.5%, respectively. For cervical cancer screening, all three tests showed relatively good clinical sensitivities, but the AdvanSure PCR had lower clinical specificity than the Abbott PCR and the HC2. The AdvanSure PCR and the Abbott PCR assays have the advantage of being automated and the ability to distinguish between HPV types 16/18 and other HPV types. The two real time PCR assays could be useful tools in HPV testing for cervical cancer screening. PMID- 24814875 TI - Targeting mitochondrial 18 kDa translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype. AB - The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically and by the use of selective TSPO ligands. Cellular responses were analysed by quantitative PCR (Q-PCR), immunoblotting and radiolabelling, including [3H]cholesterol efflux to (apo)lipoprotein A-I (apoA I), high-density lipoprotein (HDL) and human serum. Induction of macrophage cholesterol deposition by acetylated low-density lipoprotein (AcLDL) increased expression of TSPO mRNA and protein, reflecting findings in human carotid atherosclerosis. Transient overexpression of TSPO enhanced efflux (E%) of [3H]cholesterol to apoA-I, HDL and human serum compared with empty vector (EV) controls, whereas gene knockdown of TSPO achieved the converse. Ligation of TSPO (using PK11195, FGIN-1-27 and flunitrazepam) triggered increases in [3H]cholesterol efflux, an effect that was amplified in TSPO-overexpressing macrophages. Overexpression of TSPO induced the expression of genes [PPARA (peroxisome-proliferator-activated receptor alpha), NR1H3 (nuclear receptor 1H3/liver X receptor alpha), ABCA1 (ATP-binding cassette A1), ABCG4 (ATP-binding cassette G4) and APOE (apolipoprotein E)] and proteins (ABCA1 and PPARalpha) involved in cholesterol efflux, reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL. Thus, targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation, via enhanced cholesterol efflux to (apo)lipoprotein acceptors. PMID- 24814876 TI - Role of epigenetic mechanisms in the development of chronic complications of diabetes. AB - There is growing evidence that epigenetic regulation of gene expression including post-translational histone modifications (PTHMs), DNA methylation and microRNA (miRNA)-regulation of mRNA translation could play a crucial role in the development of chronic, diabetic complications. Hyperglycemia can induce an abnormal action of PTHMs and DNA methyltransferases as well as alter the levels of numerous miRNAs in endothelial cells, vascular smooth muscle cells, cardiomyocytes, retina, and renal cells. These epigenetic abnormalities result in changes in the expression of numerous genes contributing to effects such as development of chronic inflammation, impaired clearance of reactive oxygen species (ROS), endothelial cell dysfunction and/or the accumulation of extracellular matrix in the kidney, which causing the development of retinopathy, nephropathy or cardiomyopathy. Some epigenetic modifications, for example PTHMs and DNA methylation, become irreversible over time. Therefore, these processes have gained much attention in explaining the long-lasting detrimental consequences of hyperglycaemia causing the development of chronic complications even after improved glycaemic control is achieved. Our review suggests that the treatment of chronic complications should focus on erasing metabolic memory by targeting chromatin modification enzymes and by restoring miRNA levels. PMID- 24814877 TI - Cost-of-illness studies of diabetes mellitus: a systematic review. AB - BACKGROUND: Diabetes mellitus (DM) is recognised as a major health problem. OBJECTIVES: The aims of this study are two-fold: (1) to describe the methods used in the identified cost-of-illness (COI) studies of DM and (2) to summarise their study findings regarding the economic impact of DM. METHODS: This is a systematic review of MEDLINE and Scopus journal articles reporting the cost of type 1 and/or 2 DM that were published in English from 2007 to 2011. Costs reported in the included studies were converted to US dollars. RESULTS: The systematic search yielded 30 articles. The studies varied considerably in their study design, perspective and included cost categories. Estimates for the total annual costs of DM ranged from US$141.6 million to US$174 billion; direct costs ranged from US$150 to US$14,060 per patient per year (pppy) whereas indirect costs ranged from US$39.6 to US$7,164 pppy. Inpatient cost was the major contributor to direct cost in half of the studies that included inpatient costs, physician services and medications. CONCLUSION: There is a considerable economic burden associated with DM. Future research should focus on improving methods of estimating costs, enhancing the interpretation of study findings and facilitating comparisons between studies. PMID- 24814878 TI - A facile strategy to functionalize gold nanorods with polycation brushes for biomedical applications. AB - The fabrication of highly efficient nonviral gene carriers with low cytotoxicity remains a challenge in gene therapy. This paper reports a facile strategy to combine the advantages of gold nanorods (Au NRs) and polycations through surface functionalization. Different Au NR carriers with a controlled amount of poly(2 (N,N-dimethyl amino)ethyl methacrylate) (PDAEMA) brushes could be readily synthesized via surface-initiated atom transfer radical polymerization to achieve optimized nanohybrids for gene transfection. The obtained gene carriers demonstrate much higher gene transfection efficiency and lower cytotoxicity compared with polyethylenimine (~25kDa, gold standard of nonviral gene vector) in both COS7 and HepG2 cell lines. In addition, the potential of the PDMAEMA-grafted Au NR carriers to be utilized as a computed tomography contrast agent for the imaging of cancer cells has also been investigated. This strategy may realize the gene therapy and real-time imaging within one nanostructure and facilitate biomedical applications. PMID- 24814880 TI - Interfacial optimization of fiber-reinforced hydrogel composites for soft fibrous tissue applications. AB - Meniscal tears are the most common orthopedic injuries to the human body, yet the current treatment of choice is a partial meniscectomy, which is known to lead to joint degeneration and osteoarthritis. As a result, there is a significant clinical need to develop materials capable of restoring function to the meniscus following an injury. Fiber-reinforced hydrogel composites are particularly suited for replicating the mechanical function of native fibrous tissues due to their ability to mimic the native anisotropic property distribution present. A critical issue with these materials, however, is the potential for the fiber-matrix interfacial properties to severely limit composite performance. In this work, the interfacial properties of an ultra-high-molecular-weight polyethylene (UHMWPE) fiber-reinforced poly(vinyl alcohol) (PVA) hydrogel are studied. A novel chemical grafting technique, confirmed using X-ray photoelectron spectroscopy, is used to improve UHMWPE-PVA interfacial adhesion. Interfacial shear strength is quantified using fiber pull-out tests. Results indicate significantly improved fiber hydrogel interfacial adhesion after chemical grafting, where chemically grafted samples have an interfacial shear strength of 256.4+/-64.3kPa compared to 11.5+/ 2.9kPa for untreated samples. Additionally, scanning electron microscopy of fiber surfaces after fiber pull-out reveal cohesive failure within the hydrogel matrix for treated fiber samples, indicating that the UHMWPE-PVA interface has been successfully optimized. Lastly, inter-fiber spacing is observed to have a significant effect on interfacial adhesion. Fibers spaced further apart have significantly higher interfacial shear strengths, which is critical to consider when optimizing composite design. The results in this study are applicable in developing similar chemical grafting techniques and optimizing fiber-matrix interfacial properties for other hydrogel-based composite systems. PMID- 24814879 TI - Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-kappaB decoy oligodeoxynucleotide: a preliminary report. AB - Total joint replacement (TJR) is very cost-effective surgery for end-stage arthritis. One important goal is to decrease the revision rate, mainly because TJR has been extended to younger patients. Continuous production of ultra-high molecular weight polyethylene (UHMWPE) wear particles induces macrophage infiltration and chronic inflammation, which can lead to periprosthetic osteolysis. Targeting individual pro-inflammatory cytokines directly has not reversed the osteolytic process in clinical trials, owing to compensatory up regulation of other pro-inflammatory factors. It is hypothesized that targeting the important transcription factor NF-kappaB could mitigate the inflammatory response to wear particles, potentially diminishing osteolysis. In the current study, NF-kappaB activity in mouse RAW 264.7 and human THP1 macrophage cell lines, as well as primary mouse and human macrophages, was suppressed via competitive binding with double strand decoy oligodeoxynucleotide (ODN) containing an NF-kappaB binding element. It was found that macrophage exposure to UHMWPE particles induced multiple pro-inflammatory cytokine and chemokine expression, including TNF-alpha, MCP1, MIP1alpha and others. Importantly, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, and resulted in suppression of macrophage recruitment. The strategic use of decoy NF-kappaB ODN, delivered locally, could potentially diminish particle-induced periprosthetic osteolysis. PMID- 24814881 TI - Uptake, transport and peroral absorption of fatty glyceride grafted chitosan copolymer-enoxaparin nanocomplexes: influence of glyceride chain length. AB - The objective of this paper is to elucidate the influence of fatty glyceride chain length in chitosan copolymers on the peroral absorption of enoxaparin. First of all, a series of chitosan copolymers with glyceryl monocaprylate (GM8), glyceryl monolaurate (GM12) and glyceryl monostearate (GM18) as the hydrophobic part were synthesized. The structure of the copolymers was characterized using proton nuclear magnetic resonance. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay demonstrated that all the copolymers were non toxic. Enoxaparin nanocomplexes were prepared by self-assembly. Mucoadhesion of the nanocomplexes was characterized using the mucin particle method. Nanocomplex uptake and transport were quantified in Caco-2 cells and cellular localization was visualized by confocal laser scanning microscopy. Enoxaparin uptake was enhanced by nanocomplex formation, and was dependent on incubation time, concentration, temperature and glyceride chain length. The GM8 grafted chitosan enoxaparin nanocomplex exhibited the strongest bioadhesion and the best uptake and transport in both cell culture and in vivo absorption in rats. The uptake mechanism was assumed to be adsorptive endocytosis via clathrin- and caveolae mediated processes. In conclusion, oral absorption of enoxaparin can be further enhanced by using GM8 grafted chitosan copolymer as the carrier to form nanocomplexes. PMID- 24814882 TI - Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. AB - The objective of this research study is to develop a collagen (Col) and hyaluronic acid (HA) inter-stacking nanofibrous skin equivalent substitute with the programmable release of multiple angiogenic growth factors (vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and endothelial growth factor (EGF)) either directly embedded in the nanofibers or encapsulated in the gelatin nanoparticles (GNs) by electrospinning technology. The delivery of EGF and bFGF in the early stage is expected to accelerate epithelialization and vasculature sprouting, while the release of PDGF and VEGF in the late stage is with the aim of inducing blood vessels maturation. The physiochemical characterizations indicate that the Col-HA-GN nanofibrous membrane possesses mechanical properties similar to human native skin. The design of a particle-in-fiber structure allows growth factors for slow controlled release up to 1month. Cultured on biodegradable Col-HA membrane with four kinds of growth factors (Col-HA w/4GF), endothelial cells not only increase in growth rate but also form a better network with a thread-like tubular structure. The therapeutic effect of Col-HA w/4GF membrane on streptozotocin (STZ)-induced diabetic rats reveals an accelerated wound closure rate, together with elevated collagen deposition and enhanced maturation of vessels, as revealed by Masson's trichrome stain and immunohistochemical analysis, respectively. From the above, the electrospun Col-HA-GN composite nanofibrous skin substitute with a stage-wise release pattern of multiple angiogenic factors could be a promising bioengineered construct for chronic wound healing in skin tissue regeneration. PMID- 24814883 TI - Genetically engineered silk-collagen-like copolymer for biomedical applications: production, characterization and evaluation of cellular response. AB - Genetically engineered protein polymers (GEPP) are a class of multifunctional materials with precisely controlled molecular structure and property profile. Representing a promising alternative for currently used materials in biomedical applications, GEPP offer multiple benefits over natural and chemically synthesized polymers. However, producing them in sufficient quantities for preclinical research remains challenging. Here, we present results from an in vitro cellular response study of a recombinant protein polymer that is soluble at low pH but self-organizes into supramolecular fibers and physical hydrogels at neutral pH. It has a triblock structure denoted as C2S(H)48C2, which consists of hydrophilic collagen-inspired and histidine-rich silk-inspired blocks. The protein was successfully produced by the yeast Pichia pastoris in laboratory scale bioreactors, and it was purified by selective precipitation. This efficient and inexpensive production method provided material of sufficient quantities, purity and sterility for cell culture study. Rheology and erosion studies showed that it forms hydrogels exhibiting long-term stability, self-healing behavior and tunable mechanical properties. Primary rat bone marrow cells cultured in direct contact with these hydrogels remained fully viable; however, proliferation and mineralization were relatively low compared to collagen hydrogel controls, probably because of the absence of cell-adhesive motifs. As biofunctional factors can be readily incorporated to improve material performance, our approach provides a promising route towards biomedical applications. PMID- 24814884 TI - Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase. AB - The coenzyme A (CoA) biosynthetic enzymes have been used to produce various CoA analogues, including mechanistic probes of CoA-dependent enzymes such as those involved in fatty acid biosynthesis. These enzymes are also important for the activation of the pantothenamide class of antibacterial agents, and of a recently reported family of antibiotic resistance inhibitors. Herein we report a study on the selectivity of pantothenate kinase, the first and rate limiting step of CoA biosynthesis. A robust synthetic route was developed to allow rapid access to a small library of pantothenate analogs diversified at the beta-alanine moiety, the carboxylate or the geminal dimethyl group. All derivatives were tested as substrates of Escherichia coli pantothenate kinase (EcPanK). Four derivatives, all N-aromatic pantothenamides, proved to be equivalent to the benchmark N pentylpantothenamide (N5-pan) as substrates of EcPanK, while two others, also with N-aromatic groups, were some of the best substrates reported for this enzyme. This collection of data provides insight for the future design of PanK substrates in the production of useful CoA analogues. PMID- 24814885 TI - Development of a new class of proteasome inhibitors with an epoxyketone warhead: Rational hybridization of non-peptidic belactosin derivatives and peptide epoxyketones. AB - Proteasome inhibitors are currently a focus of increased attention as anticancer drug candidates. We recently performed systematic structure-activity relationship studies of the peptidic natural product belactosin A and identified non-peptidic derivative 2 as a highly potent proteasome inhibitor. However, the cell growth inhibitory effect of 2 is only moderate, probably due to the biologically unstable beta-lactone warhead. Peptide epoxyketones are an important class of proteasome inhibitors exhibit high potency in cellular systems based on the efficient alpha,beta-epoxyketone warhead. Importantly, belactosin derivatives bind primarily to the primed binding site, while peptide epoxyketones bind only to the non-primed binding site of proteasome, suggesting that hybridization of them might lead to the development of a new class of proteasome inhibitors. Thus, we successfully identified a novel chemotype of proteasome inhibitors 3 and 4 by rational structure-based design, which are expected to bind to both the primed and non-primed binding sites of proteasome. PMID- 24814886 TI - Deep eutectic solvents for the self-assembly of gold nanoparticles: a SAXS, UV Vis, and TEM investigation. AB - In this work, we report the formation and growth mechanisms of gold nanoparticles (AuNPs) in eco-friendly deep eutectic solvents (DES; choline chloride and urea). AuNPs are synthesized on the DES surface via a low-energy sputter deposition method. Detailed small angle X-ray scattering (SAXS), UV-Vis, and cryogenic transmission electron microscopy (cryo-TEM) investigations show the formation of AuNPs of 5 nm diameter. Data analysis reveals that for a prolonged gold sputtering time there is no change in the size of the particles. Only the concentration of AuNPs increases linearly in time. More surprisingly, the self assembly of AuNPs into a first and second shell ordered system is observed directly by in situ SAXS for prolonged gold-sputtering times. The self-assembly mechanism is explained by the templating nature of DES combined with the equilibrium between specific physical interaction forces between the AuNPs. A disulfide-based stabilizer, bis((2-mercaptoethyl)trimethylammonium) disulfide dichloride, was applied to suppress the self-assembly. Moreover, the stabilizer even reverses the self-assembled or agglomerated AuNPs back to stable 5 nm individual particles as directly evidenced by UV-Vis. The template behavior of DES is compared to that of nontemplating solvent castor oil. Our results will also pave the way to understand and control the self-assembly of metallic and bimetallic nanoparticles. PMID- 24814887 TI - Diethyl maleate inhibits MCA+TPA transformed cell growth via modulation of GSH, MAPK, and cancer pathways. AB - Murine or human cancer cells have high glutathione levels. Depletion of the elevated GSH inhibits proliferation of cancer cells. Molecular basis for this observation is little understood. In an attempt to find out the underlying mechanism, we reproduced these effects in transformed C3H10T1/2 and BALB/c 3T3 cells using diethyl maleate and studied cytogenomic changes in the whole mouse genome using spotted 8 * 60 K arrays. Transformed cells revealed an increase in GSH levels. GSH depletion by DEM inhibited the growth of transformed cells. The non-cytotoxic dose of DEM (0.25 mM) resulted in GSH depletion, ROS generation, cell cycle arrest, apoptosis, decrease in anchorage independent growth, gene expression changes and activation of all three members of the MAPK family. Increase in intracellular GSH levels by GSHe countered the effect of DEM. These results support the physiological importance of GSH in regulation of gene expression for transformed cell growth restraint. This study is of interest in not only understanding the molecular biology of the transformed cells, but also in identifying new targets for development of gene therapy together with the chemotherapy. PMID- 24814888 TI - Andrographolide inhibits tumor angiogenesis via blocking VEGFA/VEGFR2-MAPKs signaling cascade. AB - Traditional medicinal herb Andrographis paniculata is known to possess anti-tumor activity, and its potential active compound is the diterpenoid lactone andrographolide (ANGL). In this study, we have found that ANGL inhibits tumor growth in nude mice bearing xenografted Hep3B cancer cells, concomitant with a reduction in tumor vessel counts. ANGL inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenic responses in vitro and neoangiogenesis in vivo. We also found that ANGL inhibits VEGFA-induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream targets such as the mitogen-activated protein kinases (MAPKs). ANGL interferes with the binding of VEGFA to VEGFR2, but has no effect on VEGFR2 kinase activity in vitro. Taken together, our results indicate that ANGL possesses anti-angiogenic activity which is mediated by preventing VEGFA-induced phosphorylation and activation of VEGFR2 and MAPKs. The present study indicates that ANGL can block tumor angiogenesis and therefore represents therapeutic potential for cancer treatment. PMID- 24814889 TI - Real time three-dimensional transthoracic echocardiography of a supracristal ventricular septal defect associated with a bicuspid aortic valve. PMID- 24814890 TI - Comparison between intravenous and intra-articular regimens of tranexamic acid in reducing blood loss during total knee arthroplasty. AB - Tranexamic acid is an antifibrinolytic drug used widely to prevent bleeding. Its use in reducing bleeding during total knee arthroplasty surgery is well proven but there is no final consensus regarding the regimen. The purpose of our study was to compare the effectiveness of intravenous and intra-articular regimen of tranexamic acid during the total knee arthroplasty surgery. A total of 40 patients were received three doses of intravenous tranexamic acid during total knee arthroplasty surgery. Intra-articular tranexamic acid was used in 40 patients during the surgery. We concluded that intra-articular tranexamic acid is equally effective as three dose intravenous regimen in reducing blood loss during total knee arthroplasty surgery. PMID- 24814891 TI - Unicompartmental knee arthroplasty versus high tibial osteotomy: United States practice patterns for the surgical treatment of unicompartmental arthritis. AB - Both unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) produce satisfactory outcomes in the management of unicompartmental knee osteoarthritis (OA). The purpose of this study is to compare UKA and HTO practice patterns in a large US private payer insurance database. Utilization data for UKA and HTO were captured from the database between 2007 and 2011. Chi square analysis, parametric testing and Poisson regressions were performed where appropriate. Between 2007 and 2011, the compound annual growth rate in utilization of UKA was +4.7%, while that for HTO was -3.9%. Utilization of UKA and HTO were inversely correlated (P = 0.001). UKA utilization is increasing, while HTO utilization is decreasing in the management of OA. More work is required to understand specific indications and outcomes. PMID- 24814892 TI - Evaluation of Guided Bone Regeneration around Oral Implants over Different Healing Times Using Two Different Bovine Bone Materials: A Randomized, Controlled Clinical and Histological Investigation. AB - PURPOSE: To evaluate the potential of two bone substitute materials and the influence of different healing periods in guided bone regeneration therapy of osseous defects around implants. MATERIALS AND METHODS: Twenty-four edentulous patients received implants in the region of the lost lower incisors. Around two standardized osseous defects were created, treated either with a 50:50 mixture of PepGen P-15(r) and OsteoGraf(r)/N-700 (test group) or with BioOss(r) (control group), and covered with titanium membranes. After healing periods of 2, 4, 6, or 9 months, the implants were removed together with the surrounding bone and subsequently prepared for histological evaluations. RESULTS: Defect depths in both groups showed a clinical reduction after intervention. The histologically measured distance from the implant shoulder to the first point of bone-implant contact (BIC) after treatment did not differ between the two groups. The healing time influenced the level of the first point of BIC, with a longer healing period producing a more coronal first point of BIC. A greater percentage BIC and a higher fraction of mineralized bone were found in the pristine bone area compared with the augmented defect area. CONCLUSION: It can be concluded that in the treatment of osseous defects around oral implants, both materials were equally effective bone substitute materials when used in combination with guided bone regeneration. PMID- 24814893 TI - The use of direct oral anticoagulants for stroke prevention in atrial fibrillation: a study on physicians' perspective and preferences. PMID- 24814894 TI - Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. a systematic review. AB - BACKGROUND: The development of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is multifactorial with a number of biomarkers serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction [asymmetric dimethylarginine (ADMA)] and cellular proliferation [vascular endothelial growth factor (VEGF)]. METHODS: We systematically reviewed the literature for trials studying the role of these biomarkers in the clinical evaluation, prognosis and management of patients with PAH related to CHD (CHD PAH). RESULTS: Twenty-six studies were included in the systematic review, involving a total of 1113 patients with CHD-PAH. These patients had higher BNP, NT-proBNP and ADMA levels and higher VEGF expression when compared with healthy controls. Baseline and serial values of plasma levels of natriuretic peptides were shown to be significant predictors of survival. ADMA concentration was elevated in patients with CHD-PAH when compared with patients with simple CHD without PAH, whereas VEGF expression was particularly high in patients with CHD and persistent PAH after corrective surgery of the underlying heart disease. CONCLUSION: Right heart dysfunction, endothelial inflammation and proliferation are mirrored by plasma levels of the corresponding biomarkers among patients with CHD-PAH. There is early evidence to suggest that natriuretic peptides, in particular, may be a simple and effective tool for determining prognosis and timing for therapeutic interventions in patients with CHD-PAH. PMID- 24814895 TI - Prognostic performance of kinetic changes of high-sensitivity troponin T in acute coronary syndrome and in patients with increased troponin without acute coronary syndrome. AB - BACKGROUND: We sought to evaluate the prognostic impact of absolute and relative kinetic changes of high-sensitivity cardiac Troponin T (hs-cTnT) in comparison to baseline hs-cTnT elevations for risk stratification in acute coronary syndrome (ACS) and non-ACS conditions with increased hs-cTnT. METHODS: hs-cTnT was measured serially in patients presenting with acute symptoms to our emergency department. We assessed the prognostic performance of baseline and serial hs-cTnT concentrations in all consecutive patients with ACS (n=406) or hs-cTnT increases not due to ACS (n=442) within 3-6h after admission. RESULTS: Mortality rates were higher, albeit not statistically, in non-ACS (53/442=12.0%) than ACS patients (36/406=8.9%). In ACS patients, receiver operating characteristics (ROC) revealed optimized cut-off values of 12.2 ng/L for absolute delta-change (AUC=0.66, p<0.001), 31.2 ng/L for baseline hs-cTnT (AUC=0.71, p<0.001) and 45.2 ng/L for maximal hs-cTnT (AUC=0.68, p<0.001). C-statistics showed superiority of absolute delta-changes (p=0.0003), baseline hs-cTnT (p=0.04) and maximal hs-cTnT (p=0.02) compared to relative delta-changes. However, the combination of baseline hs-cTnT values with either absolute or relative delta-changes did not improve risk prediction compared to baseline hs-cTnT alone (p=n.s.). In non-ACS conditions, the ROC-optimized cut-off value of 46.2 ng/L for baseline hs-cTnT (AUC=0.661, p<0.001) was superior to absolute (p=0.007) and relative delta-changes regarding prognostication (p=0.045). CONCLUSIONS: Our data suggest that the magnitude of baseline hs-cTnT, and not acute dynamic changes, convey superior long-term prognostic information in ACS and non-ACS conditions. Moreover, absolute and relative kinetic delta-changes of hs-cTnT do not add significant incremental value in risk assessment in both conditions. PMID- 24814896 TI - Edwards Sapien XT valve implantation in CoreValve aortic prosthesis to treat severe paravalvular regurgitation. PMID- 24814897 TI - Unusual association of type A aortic dissection and aberrant right subclavian artery in Marfan syndrome. PMID- 24814898 TI - Using colors in anatomical figures: a novel method for medical education in Medieval Age. PMID- 24814899 TI - Survey on prevalence of hypertension in China: background, aim, method and design. PMID- 24814900 TI - Is off-pump coronary artery bypass grafting superior to drug-eluting stents for the treatment of coronary artery disease? A meta-analysis of randomized and nonrandomized studies. AB - BACKGROUND: As drug-eluting stent (DES) has almost overcome the disadvantage of frequent restenosis, off-pump coronary artery bypass grafting (OPCAB) has been introduced to avoid complications of cardiopulmonary bypass. However, which approach may promise better outcomes for patients with coronary artery disease remains controversial. METHODS: Three databases were searched. The outcomes of interest were major adverse cardiac and cerebrovascular events (MACCE), all-cause death, target vessel revascularization (TVR), repeat revascularization (RRV), myocardial infarction (MI), and cerebrovascular events (CVE). The relative risk (RR) was calculated as the summary statistic. RESULTS: 11,452 patients from 22 studies were included, of which 4949 patients underwent OPCAB and 6503 patients received DES. The cumulative rates of MACCE (RR [95% CI]=0.43 [0.34, 0.54], P<0.00001), all-cause death (RR [95% CI]=0.56 [0.33, 0.96], P=0.03), TVR (RR [95% CI]=0.33 [0.21, 0.53], P<0.00001), RRV (RR [95% CI]=0.22 [0.11, 0.42], P<0.00001) and MI (RR [95% CI]=0.13 [0.05, 0.29], P<0.00001) at 3 years were all lower in OPCAB group. The incidences of in-hospital death (RR [95% CI]=1.31 [0.81, 2.13], P=0.27) and MI (RR [95% CI]=1.03 [0.60, 1.78], P=0.92) were not different between groups, but the rate of in-hospital CVE was lower (RR [95% CI]=2.6355 [1.0033, 6.9228], P=0.05) in DES group. CONCLUSIONS: OPCAB presents better long-term outcomes of MACCE, all-cause mortality, TVR, RRV and MI but uncertain outcome of postoperative CVE without influencing the incidences of in-hospital death and MI. PMID- 24814902 TI - Photophysics of platinum tetrayne oligomers: delocalization of triplet exciton. AB - A series of platinum tetrayne oligomers, all-trans-Cl-Pt(P2)-[(C=C)4-Pt(P2)]n-Cl, where P = tri(p-tolyl)phosphine and n = 1-3, was subjected to a detailed photophysical investigation. The photoluminescence of each oligomer at low temperature (T < 140 K) in a 2-methyltetrahydrofuran (Me-THF) glass features an intense and narrow 0-0 phosphorescence band accompanied by a vibronic progression of sub-bands separated by ca. 2100 cm(-1). The emission arises from a (3)pi,pi* triplet state concentrated on the (C=C)4 carbon chain and the vibronic progression originates from coupling of the excitation to the nu(C=C) stretch. All of the experimental data including ambient temperature absorption, low temperature photoluminescence, and ambient temperature transient absorption spectroscopy provide clear evidence that the triplet state is localized on a chromophore consisting of approximately two -[(C=C)4-Pt(P2)]- repeat units. Density functional theory calculations support the hypothesis that the triplet triplet absorption arises from transitions that are delocalized over two repeat units. PMID- 24814901 TI - Effectiveness of combination therapy of atorvastatin and non lipid-modifying tanshinone IIA from Danshen in a mouse model of atherosclerosis. PMID- 24814903 TI - The effects of spinal mobilizations on the sympathetic nervous system: a systematic review. AB - The activity of the sympathetic nervous system is of importance to manual therapists, since the experience of pain is associated with sympathetic activity. There has been little exploration into the effects of mobilizing vertebral segments below the cervical spine. In addition to this, a synthesis of the evidence for changes in sympathetic outcome measures has not been completed. The primary aim of this review was to investigate the effects of spinal mobilizations compared to a control or placebo on sympathetic outcome measures. The secondary aim was to establish the level of change, either excitatory or inhibitory, in sympathetic outcome measures. Five electronic databases (Ovid Medline, Embase, AMED, PEDro, and the Cochrane library; from database inception to May 2012) were searched for randomized controlled trials. Two independent raters applied inclusion criteria and rated studies for methodological quality. Seven studies met the inclusion criteria. All studies demonstrated a consistent increase in sympathetic outcome measures, indicative of sympathetic excitation, irrespective of the segments mobilized. Synthesis of the results established strong evidence (multiple high-quality randomised controlled trials (RCTs) for a positive change in skin conductance, respiratory rate, blood pressure, and heart rate among the healthy population. As only one study investigated changes in a symptomatic population, there was limited evidence (one RCT) for an increase in skin conductance and decrease in skin temperature. Evidence from this systematic review supports a sympatho-excitatory response to spinal mobilizations irrespective of the segment mobilized. PMID- 24814904 TI - The portal fibroblast: not just a poor man's stellate cell. AB - Portal fibroblasts, the resident fibroblasts of the portal tract, are found in the mesenchyme surrounding the bile ducts. Their roles in liver homeostasis and response to injury are undefined and controversial. Although portal fibroblasts almost certainly give rise to myofibroblasts during the development of biliary fibrosis, recent lineage tracing studies suggest that their contribution to fibrogenesis is limited compared with that of hepatic stellate cells. Other functions of portal fibroblasts include participation in the peribiliary stem cell niche, regulation of cholangiocyte proliferation, and deposition of specific matrix proteins. Portal fibroblasts synthesize elastin and other components of microfibrils; these may serve structural roles, providing stability to ducts and the vasculature under conditions of increased ductal pressure, or could regulate the bioavailability of the fibrogenic transforming growth factor beta in response to injury. Viewing portal fibroblasts in the context of fibroblast populations throughout the body and studying their niche-specific roles in matrix deposition and epithelial regulation could yield new insights into their contributions in the normal and injured liver. Understanding the functions of portal fibroblasts will require us to view them as more than just an alternative to hepatic stellate cells in fibrosis. PMID- 24814905 TI - Effects of alginate on frozen-thawed boar spermatozoa quality, lipid peroxidation and antioxidant enzymes activities. AB - Although alginate was reported to play an important role as free radical scavengers in vitro and could be used as sources of natural antioxidants, there was no study about the cryoprotective effects of alginate on boar spermatozoa freezing. The objective of this research was to evaluate the effects of different concentrations of alginate added to the freezing extenders on boar spermatozoa motility, plasma membrane integrity, acrosomal integrity, mitochondrial activities, lipid peroxidation and antioxidative enzymes activities (SOD and GSH Px) after thawing. Alginate was added to the TCG extender to yield six different final concentrations: 0, 0.2, 0.4, 0.6, 0.8, and 1.0mg/mL. The semen extender supplemented with various doses of alginate increased (P<0.05) total motility. The spermatozoa plasma membrane integrity and mitochondrial activity were improved at four different concentrations: 0.4, 0.6, 0.8, 1.0mg/mL. The addition of alginate also provided significantly positive effect on post-thaw boar spermatozoa acrosomal integrity at concentrations of 0.6, 0.8, 1.0mg/mL, compared with that of the control (P<0.05). The freezing extenders with the presence of alginate led to higher SOD and GSH-Px activities and lower MDA levels, in comparison to the control (P<0.05). In summary, alginate exhibited a dose-related response on frozen-thawed boar spermatozoa motility, functional integrity and antioxidative capacity at appropriate concentrations. Therefore alginate could be employed as an effective cryoprotectant in boar spermatozoa cryopreservation. PMID- 24814906 TI - LMP1 stimulates the transcription of eIF4E to promote the proliferation, migration and invasion of human nasopharyngeal carcinoma. AB - Eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting translation initiation factor for many oncogenes. Previous studies have shown eIF4E overexpression in nasopharyngeal carcinoma (NPC). We aimed to study whether viral oncogene latent membrane protein 1 (LMP1) stimulates the transcription of eIF4E to promote NPC malignancy. In NPC cell lines (CNE1 and CNE2), ectopic LMP1 significantly increased the mRNA and protein levels of eIF4E and the transcriptional activity of the eIF4E promoter in a LMP1-plasmid-transfected dose dependent manner. As a backward experiment, knocking down of LMP1 significantly reduced eIF4E mRNA in B95-8 cells. In the high LMP1 expression condition, knocking down of c-Myc significantly reduced eIF4E mRNA in both NPC and B95-8 cells, and knocking down of eIF4E significantly inhibited the tumor proliferation, migration and invasion promoted by LMP1. The results indicated that LMP1 stimulates the transcription of eIF4E via c-Myc to promote NPC. To the best of our knowledge, this is the first evidence that LMP1 stimulates the transcription of eIF4E. This might be an important cause of the overexpression of eIF4E in NPC and be the novel mechanism by which LMP1 initiates cancer. LMP1 stimulated eIF4E initiates the translation of those oncogenes transcriptionally activated by LMP1 to amplify and pass down the carcinogenesis signals launched by LMP1. PMID- 24814907 TI - Mechanisms of water interaction with pore systems of hydrochar and pyrochar from poplar forestry waste. AB - The aim of this study was to understand the water-surface interactions of two chars obtained by gasification (pyrochar) and hydrothermal carbonization (hydrochar) of a poplar biomass. The two samples revealed different chemical compositions as evidenced by solid state (13)C NMR spectroscopy. In fact, hydrochar resulted in a lignin-like material still containing oxygenated functionalities. Pyrochar was a polyaromatic system in which no heteronuclei were detected. After saturation with water, hydrochar and pyrochar were analyzed by fast field cycling (FFC) NMR relaxometry. Results showed that water movement in hydrochar was mainly confined in very small pores. Conversely, water movement in pyrochar led to the conclusion that a larger number of transitional and very large pores were present. These results were confirmed by porosity evaluation derived from gas adsorption. Variable-temperature FFC NMR experiments confirmed a slow-motion regime due to a preferential diffusion of water on the solid surface. Conversely, the higher number of large pores in pyrochar allowed slow movement only up to 50 degrees C. As the temperature was raised to 80 degrees C, water interactions with the pore surface became weaker, thereby allowing a three dimensional water exchange with the bulk liquid. This paper has shown that pore size distribution was more important than chemical composition in affecting water movement in two chemically different charred systems. PMID- 24814908 TI - Longitudinal investigation on learned helplessness tested under negative and positive reinforcement involving stimulus control. AB - In this study, we investigated whether (a) animals demonstrating the learned helplessness effect during an escape contingency also show learning deficits under positive reinforcement contingencies involving stimulus control and (b) the exposure to positive reinforcement contingencies eliminates the learned helplessness effect under an escape contingency. Rats were initially exposed to controllable (C), uncontrollable (U) or no (N) shocks. After 24h, they were exposed to 60 escapable shocks delivered in a shuttlebox. In the following phase, we selected from each group the four subjects that presented the most typical group pattern: no escape learning (learned helplessness effect) in Group U and escape learning in Groups C and N. All subjects were then exposed to two phases, the (1) positive reinforcement for lever pressing under a multiple FR/Extinction schedule and (2) a re-test under negative reinforcement (escape). A fourth group (n=4) was exposed only to the positive reinforcement sessions. All subjects showed discrimination learning under multiple schedule. In the escape re-test, the learned helplessness effect was maintained for three of the animals in Group U. These results suggest that the learned helplessness effect did not extend to discriminative behavior that is positively reinforced and that the learned helplessness effect did not revert for most subjects after exposure to positive reinforcement. We discuss some theoretical implications as related to learned helplessness as an effect restricted to aversive contingencies and to the absence of reversion after positive reinforcement. This article is part of a Special Issue entitled: insert SI title. PMID- 24814909 TI - Scent-marking behaviour and social dynamics in a wild population of Eurasian lynx Lynx lynx. AB - Scent-marking is widespread among mammals and has been observed in many felid species. Although the behaviour is well-described, little is known about its function in wild felid populations. We investigated patterns of scent-marking and its role in intra- and intersexual communication among resident and non-resident Eurasian lynx Lynx lynx by observing interactions among wild lynx at natural marking sites by means of infrared camera traps. Marking activity of resident animals showed a peak during the mating season and was lowest during the time when females gave birth and lactated. Both sexes scent-marked, but male lynx visited marking sites much more often than females and marked relatively more often when visiting a site. Most visits to marking sites were by residents but we also observed scent-marking by non-residents. Juveniles were never observed marking. We found no evidence of lynx regularly renewing scent-marks after a certain 'expiry date' but the presence of a strange scent-mark triggered over marking. Males responded similarly to the presence of another individual's scent mark, irrespective of whether it was the top- or the underlying scent-mark in a mixture of scent-marks they encountered. Our results suggest that marking sites could serve as 'chemical bulletin boards', where male lynx advertise their presence and gain information on ownership relationships in a given area. Females placed their urine marks on top of the ones left by resident males, but further studies are needed to explain the functions of over-marking in females. PMID- 24814910 TI - Association between increased behavioral persistence and stereotypy in the pet dog. AB - The aim of the present study was to evaluate whether dogs that exhibit stereotypy also show higher behavioral persistence in an extinction-learning task. Thirteen pet dogs with stereotypy and 13 breed-matched control dogs were assessed on a resistance to extinction test. Each dog was trained for 40 trials using a food reinforcer to nose-touch the experimenter's hand on a continuous reinforcement schedule. After acquisition, the dogs entered an extinction phase, during which food was no longer delivered. The numbers of nose-touches as well as inter response times during this phase were recorded. A linear regression found that stereotypy status (t=-2.46, P=.027) and breed type (t=2.44, P=.023) were significant predictors of the number of responses in extinction. Dogs with stereotypy responded more in extinction than control dogs. The mean number of responses was 13.4 (SD=14.7) in the control group and 26.0 (SD=15.3) in the stereotypy group. These results suggest a link between previous laboratory and zoo animal findings on the neurophysiology of stereotypy and the pet dog population. They also have implications for the use of extinction procedures to reduce stereotypic behaviors in pet dogs, as these dogs show enhanced resistance to extinction. PMID- 24814911 TI - There are only minor changes in quality of life in patients with Scheuermann's disease. AB - INTRODUCTION: The impact of Scheuermannss disease (SD) on health-related quality of life (HRQoL) is unclear. The aim of this study was to study HRQoL based on The Medical Outcome Study Short Form-12 (SF-12) in adult life in a group of SD patients. MATERIAL AND METHODS: A total of 46,418 twins were sent a questionnaire. 75.3% answered. Included in the questionnaire were questions from the SF-12. We compared SF-12 values in SD patients and control patients. We also identified 259 "non-concordant" twin pairs and compared SF-12 values from the SD twin with values from the healthy twin. RESULTS: In all, 943 persons were identified to have SD, leaving 33,064 persons in the control group. SF-12 Physical Component Summary (PCS) (mean (standard deviation)) was found to be 50.50 (9.89) in SD and 53.21 (8.00) in controls (p < 0.001), and SF-12 Mental Component Summary (MCS) was found to be 51.52 (8.49) in SD and 51.81 (8.45) in controls (p = 0.71). In the non-concordant twin pairs, SF-12 PCS was found to be 50.74 (9.87) in SD and 52.74 (8.84) in controls (p < 0.001), and SF-12 MCS was found to be 53.91 (8.19) in SD and 53.72 (8.70) in controls (p = 0.64). CONCLUSION: SF-12 PCS is moderately, though highly statistically significantly worse in SD patients than in controls in this big group of twins. We found no statistical difference in SF-12 MCS between the two groups. SD patients evaluate their physical health worse and their mental health like controls. FUNDING: This study was funded by The Sahva Foundation. The sponsor had no influence on the study or its publication. No conflicts of interest exist between the sponsor and the authors. TRIAL REGISTRATION: Approved by the Scientific-ethical Committee in Denmark (no. 20010202). PMID- 24814912 TI - Dedicated emergency departments delay surgical treatment of acute appendicitis. AB - INTRODUCTION: A new emergency service has been introduced in Denmark. We aimed to assess the impact of the service change for the care of acute surgical emergencies, specifically a subset of patients treated with an appendectomy. MATERIAL AND METHODS: This was a retrospective review of all the patients who had an appendectomy in a surgical department during one year prior to and one year after the implementation of a new emergency service. Data collected included patients' demographics and information related to the care such as the number of doctors involved in diagnosing appendicitis, whether preoperative radiological investigation was used, time to operation, morbidity during the first 30 days, including readmission, type of complication and required intervention. RESULTS: A total of 314 patients had an appendectomy performed during the study period. After the implementation of the new emergency service, there was a significant delay in time to definitive treatment (457 minutes versus 593 minutes, p = 0.001). The total number of doctors involved in diagnosing appendicitis increased to a median of three doctors (range 1-6) from a median of two surgeons (range 1 6) (p < 0.0001). There was no difference in the number of readmissions or complications. CONCLUSION: Introducing a new emergency service required an extra doctor for diagnosing appendicitis which delayed the overall time to definitive treatment by nearly 2.5 hours. FUNDING: not relevant. TRIAL REGISTRATION: not applicable as this is an audit study. PMID- 24814913 TI - Tibial eminentia avulsion fracture in children - a systematic review of the current literature. AB - INTRODUCTION: Tibial eminentia avulsion fracture is the paediatric equivalent to a midsubstance anterior cruciate ligament injury. It is most common between the ages of 8 and 19 years of age. The incidence is three per 100,000 per year. We explored the clinical evaluation and classification of the fracture, indications for and methods of surgery and the possible sequelae. METHODS: We performed a systematic search in the PubMed database and retrieved 127 articles. A total of 16 articles met the defined inclusion criteria and were reviewed. Only studies on adolescents were included. RESULTS: No prospective studies were found. The Meyers & McKeever and Zaricznyj classifications were commonly used, also when evaluating fractures for surgery. X-ray in three views is often sufficient to establish a diagnosis, but computed topographies can be necessary to further evaluate the type of fracture. There is disagreement as to whether a type II-fracture needs surgery. The method of fixation varies greatly between different kinds of suture techniques and screw fixations, but arthroscopic surgery is preferred in the most recent literature. Whether to cross the physis when fixating the fracture is also a matter of dis-agreement, but there is a lack of literature on the subject. All authors describe low rates of subjective sequelae. CONCLUSION: Arthroscopic surgery is less invasive and allows for earlier mobilisation than other techniques. Pull-out suture seems to be a recommendable technique. There is a lack of literature on transphyseal fixation and a need for prospective studies evaluating the many different surgical techniques described and the indications for surgery. PMID- 24814914 TI - Daily number of fractures is associated with road temperature in an urban area. AB - INTRODUCTION: Different factors related to winter are known to influence the fracture incidence, but little is known about the effect of road surface temperature. This study examines the association between road surface temperature and the daily number of fractures in an urban area during two winters. MATERIAL AND METHODS: Retrospective data collection was conducted on all patients treated at Bispebjerg Hospital, Denmark, for a humeral, ankle, distal radius or hip fracture during the periods October to April 2009/2010 and 2010/2011. Patients were grouped according to age into the following categories: < 15, 15-30, 30-45, 45-60 and > 60 years. Data on road surface temperature (Tp.) were obtained from The Danish Road Directorate and grouped into the following categories: Days with Tp. > 0 degrees C, Tp. < 0 degrees C, Tp. > -5 degrees C, Tp. < -5 degrees C and ice alert (IA). RESULTS: A total of 4,892 patients (4,938 fractures) were treated during the study periods. The daily number of distal radius, humeral and ankle fractures increased significantly with decreasing road surface temperature and the presence of IA. For hip fractures no significant association was found. Decreasing temperature was associated with a significant decrease in the daily number of fractures for patients < 15 years, whereas patients > 30 years experienced a significant increase. CONCLUSION: Decreasing road temperature results in increased numbers of all fractures except hip fractures. Low temperatures is a risk factor for patients > 30 years and a protective factor for patients < 15 years. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814915 TI - In Denmark kidney transplantation is more cost-effective than dialysis. AB - INTRODUCTION: Approximately 5,000 Danish patients are being treated for end-stage renal disease, for which the two treatment options are dialysis and transplantation. The objective of this study was to estimate the cost effectiveness of kidney transplantation versus dialysis from a public health-care perspective. MATERIAL AND METHODS: A cost-utility analysis was conducted using a decision analytic model. The model was designed as a Markov model in which all relevant costs and effects of the two alternative treatments were included. Deterministic data were used alongside the best available evidence from the literature. To estimate the overall uncertainty concerning the incremental cost effectiveness ratio (ICER), a probabilistic sensitivity analysis with second order Monte Carlo simulations was carried out on a hypothetical cohort of 10,000 patients. RESULTS: The cost per quality-adjusted life year (QALY) was 1,032,934 DKK for dialysis compared with 810,516 DKK for transplantation. When comparing kidney transplantation with dialysis, kidney transplantation was cost-saving and resulted in additional QALYs. When taking the overall uncertainty associated with the ICER into account, an incremental cost-effectiveness scatter plot supported that transplantation was dominating and that the results were robust. In addition, a cost-effectiveness acceptability curve showed that transplantation had a 99.93% likelihood of being cost-effective at a willingness-to-pay value of 0 DKK. CONCLUSION: The cost-effectiveness ratio was favourable for kidney transplantation when compared with dialysis. In view of this, it was concluded that transplantation is preferable to dialysis when treating patients with end stage renal disease. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814916 TI - Non-invasive ventilation is less efficient in pneumonia than in chronic obstructive pulmonary disease exacerbation. AB - INTRODUCTION: Non-invasive ventilation (NIV) is especially valid for acute exacerbation in chronic obstructive pulmonary disease (COPD), but the trend has been to use it for all types of patients with acute respiratory failure (ARF). Recent data suggest that treatment failure occurs more often in patients with ARF from pneumonia than from COPD. MATERIAL AND METHODS: This was a retrospective study using data from patients with ARF admitted into the intensive care unit in a university-affiliated hospital in the period from 1 January 2009 to 31 December 2012 and treated with NIV. Patients with ARF due to acute exacerbation in COPD or ARF due to pneumonia were included. The primary end-point was treatment failure (intubation). The secondary end-point was in-hospital mortality. A total of 107 patients were included, 42 in the COPD group and 65 in the pneumonia group. RESULTS: We found no significant difference between the two groups with regard to age (mean 65 +/- 8 years (COPD) versus mean 64 +/- 16 years (pneumonia)), sex (male/female 23/19 (COPD) versus male/female 26/39 (pneumonia)) or New Simplified Acute Physiology Score (SAPS II) (mean 47 +/- 11 (COPD) versus mean 51 +/- 15 (pneumonia)). Treatment failure occurred in five patients in the COPD group (12%) and in 32 patients in the pneumonia group (49%), p < 0.00001. In-hospital mortality occurred in six patients in the COPD group (14%) and in 21 patients in the pneumonia group (32%), p = 0.01. CONCLUSION: NIV is less effective in the treatment of ARF due to pneumonia than in the treatment of ARF due to acute exacerbation in COPD. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814917 TI - Admissions to emergency department may be classified into specific complaint categories. AB - INTRODUCTION: In the emergency departments (ED), a heterogeneous mix of patients is seen. The aim of this study was to establish a limited number of categories of complaints and symptoms covering the majority of admissions in a Danish ED and to quantify the volume of cases in each category. MATERIAL AND METHODS: This was a cross-sectional study of all acute patients admitted to a Danish ED in 2010. Information was collected from electronic screens where the ED nurses registered the presenting symptoms or complaints according to the referring doctor or patient. A list of complaint categories covering all patient complaints was produced. Presumptive diagnoses and categories with frequencies less than 1% were pooled with other groups, unless keeping them was clinically relevant. RESULTS: Among the 9,863 patients, 49% were medical, 31% surgical, 15% orthopaedic and 5% vascular surgical patients. In 35% of cases, the patients were referred with a presumptive diagnosis, in 65% with a complaint or a symptom; and 11,031 complaints were placed in 13 main categories, 77 subcategories and 44 presumptive diagnoses. This aggregation resulted in 99 groups holding less than 1% of the patients' complaints. Further aggregation resulted in 31 categories covering 93% of the complaints. Of the complaints not covered, the largest groups were patients with post-operative complications and special examination for various diseases (5%). CONCLUSION: We have presented a first suggestion for complaint categories and distribution among admitted patients in a Danish ED setting. Further studies from other EDs are required. FUNDING: not relevant. TRIAL REGISTRATION: NCT01747434. PMID- 24814918 TI - Management of pneumothorax differs across Denmark. AB - INTRODUCTION: Pneumothorax is a common problem in Denmark. Guidelines recommend insertion of small-bore (<= 14 Fr) chest tubes or simple needle aspiration in spontaneous pneumothorax. Our objective was to investigate the management of pneumothorax in Danish hospitals. MATERIAL AND METHODS: We undertook a questionnaire survey at all Danish acute hospitals enquiring about current practice in the management of pneumothorax. A questionnaire was sent to 35 hospitals in May 2013. After follow-up in September 2013, a total of 32 completed questionnaires were assessed. RESULTS: We found that three hospitals (10.7%) used simple needle aspiration in primary spontaneous pneumothorax. The majority of the hospitals treated all types of pneumothorax by inserting chest tubes with a traditional small thoracotomy (75%), and most hospitals used large-bore (> 14 Fr) chest tubes (85.7%). There were no regional differences in the management of pneumothorax among the five regions in Denmark (p > 0.05), but we found a trend towards use of less invasive techniques in hospitals with departments of either Respiratory Medicine or Thoracic Surgery. CONCLUSION: Management of pneumothorax in Denmark is mainly based on insertion of a large-bore (> 14 Fr) chest tube by a traditional small thoracotomy. Only a few hospitals in Denmark use minimally invasive techniques in the management of spontaneous pneumothorax. We speculate that implementation of these techniques may reduce hospital admission time for patients with spontaneous pneumothorax in Denmark. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24814919 TI - First Danish experience with ex vivo lung perfusion of donor lungs before transplantation. AB - INTRODUCTION: The number of lung transplantations is limited by a general lack of donor organs. Ex vivo lung perfusion (EVLP) is a novel method to optimise and evaluate marginal donor lungs prior to transplantation. We describe our experiences with EVLP in Denmark during the first year after its introduction. MATERIAL AND METHODS: The study was conducted by prospective registration of donor offers and lung transplantations in Denmark from 1 May 2012 to 30 April 2013. Donor lungs without any contraindications were transplanted in the traditional manner. Taken for EVLP were donor lungs that were otherwise considered transplantable, but failed to meet the usual criteria due to possible contusions or because they were from donors with sepsis or unable to pass the oxygenation test. RESULTS: In the study period, seven of 33 Danish lung transplantations were made possible due to EVLP. One patient died of non-EVLP related causes, but all other recipients were alive with normal graft function at the end of our registration period. All lungs showed an improved PaO2/FiO2 ratio from a median 23.1 kPa (8.8-38.9) within the donor to 58.8 kPa (34.9-76.5) (FiO2 = 1.0) after EVLP, which corresponds to a 155% improved oxygenation. The median time to extubation, time in intensive care unit and the admission period were 1, 7 and 39 days, respectively. CONCLUSION: In the first year after the introduction of EVLP in Denmark, seven pairs of donor lungs that previously would have been rejected have been transplanted as a result of their improved function. EVLP seems to be a safe way to increase the use of marginal donor lungs. FUNDING: no funding was granted for the present paper. TRIAL REGISTRATION: not relevant. PMID- 24814920 TI - The role of CDX2 in inflammatory bowel disease. AB - BACKGROUND: High levels of pro-inflammatory cytokines are present in the gut of patients with inflammatory bowel disease (IBD) and have a crucial role in the dysfunction of mucosal homeostasis. Caudal-related homeobox transcription factor 2 (CDX2) is an essential regulator of intestinal epithelium homeostasis. When expressed, CDX2 modulates a diverse set of processes, including cell proliferation and differentiation, and cell adhesion and migration. In addition to these critical cellular processes, there is increasing indications (such as involvement in pro-inflammatory pathways and regulation of genes of importance for intestinal homeostasis) linking CDX2 to intestinal inflammation. AIM: The overall objective of this PhD thesis was to explore the role of CDX2 in the colonic epithelium of patients with IBD and to investigate the impact of pro inflammatory pathways on the expression of CDX2 and its target genes. METHODS: Initially, a literature research was conducted to review the importance of CDX2 in epithelial homeostasis and its potential role in mucosal inflammation. Expression of CDX2 was measured in colonic biopsies of patients with IBD, and the effects of pro-inflammatory cytokines and anti-TNF-alpha treatment (infliximab) were examined in Caco-2 cells. The role of CDX2 in the transcriptional regulation of MEP1A and the beta-catenin degradation complex genes APC, AXIN2, and GSK3beta were investigated in Caco-2 cells. Finally, the intracellular signalling pathways involved in the TNF-alpha-mediated down-regulation of CDX2 were investigated. RESULTS: The expression of CDX2 was decreased in the epithelium of patients with ulcerative colitis (UC), and the expression was inversely correlated with the level of TNF-alpha. The endogenous expression of CDX2 in Caco-2 cells was decreased by TNF-alpha through NF-kappaB and p38 MAPK pathways. High levels of TNF-alpha affected the expression of CDX2 target genes and reduced the binding of CDX2 to gene regulatory regions of these targets in Caco-2 cells. Finally, TNF alpha increased the expression of well-known Wnt target genes. CONCLUSIONS: These findings indicate that the CDX2 expression is decreased in UC, and moreover, the studies in Caco-2 cells have shed light on some of the molecular pathways of importance in the inhibitory effect of TNF-alpha. In addition, these studies have provided novel insight into the CDX2-mediated regulation of genes involved in the beta-catenin degradation complex and in response to the pro-inflammatory cytokine, TNF-alpha. In particular, these findings indicate that CDX2 is involved in the crosstalk between TNF-alpha and the Wnt signalling pathway, which might be of importance in understanding the link between intestinal inflammation and tumourigenesis. PMID- 24814921 TI - Experimental evaluation of clinical colon anastomotic leakage. AB - Colorectal anastomotic leakage remains a frequent and serious complication in gastrointestinal surgery. Patient and procedure related risk factors for anastomotic leakage have been identified. However, the responsible pathophysiological mechanisms are still unknown. Among these, ischemia and insufficient surgical technique have been suggested to play a central role. Animal models are valuable means to evaluate pathophysiological mechanisms and may be used to test preventive measures aiming at reducing the risk of anastomotic leakage, such as external anastomotic coating. The aim of this thesis was to: Clarify the best suited animal to model clinical anastomotic leakage in humans; Create animal models mimicking anastomotic leakage in humans induced by insufficient surgical technique and tissue ischemia; Determine the best suited coating materials to prevent anastomotic leakage. STUDY 1: This study is a systematic review using the databases MEDLINE and Rex. MEDLINE was searched up to October 2010 to identify studies on experimental animal models of clinical colon anastomotic leakage. From the Rex database, textbooks on surgical aspects as well as gastrointestinal physiology and anatomy of experimental animals were identified. The results indicated that the mouse and the pig are the best suited animals to evaluate clinical anastomotic leakage. However, the pig model is less validated and more costly to use compared with the mouse. Most frequently, rats are used as models. However, extreme interventions are needed to create clinical leakage in these animals. The knowledge from this study formed the basis for selecting the animal species most suited for the models in the next studies. STUDY 2: In this experimental study, technically insufficient colonic anastomoses were performed in 110 C57BL/6 mice. The number of sutures in the intervention group was reduced to produce a suitable leakage rate. Moreover, the analgesia and suture material were changed in order to optimize the model. In the final experiment, the four-suture anastomoses resulted in a 40% leakage rate in the intervention groups, whereas the eight-suture control anastomoses had a 0% leakage rate. Furthermore, the use of absorbable suture together with voluntarily ingested Temgesic in chocolate spread as analgesic regimen were feasible. This model may be used to test the leakage reducing potential of coating materials. STUDY 3: This experimental study used 53 C57BL/6 mice, in which sufficient eight suture anastomoses were created. By using bipolar electro-cautery, blood supply was reduced in a stepwise manner to create anastomotic leakage as a result of ischemia. The study showed that reduced blood supply led to large bowel obstruction instead of clinical leakage. However, anastomotic breaking strength was reduced in the ischemic anastomoses. STUDY 4: In this systematic review MEDLINE, Embase and Cinahl were searched up to September 2011 to identify studies evaluating external coating of colonic anastomoses. Most studies were experimental, in which designs were not comparable and many results were contradictory. In a clinical study, a non-significant benefit of fibrin sealant was found. Based on the available clinical and experimental data it was concluded that the fibrin-based sealants, such as Tisseel and Tachosil, and polyethylene glycols may be beneficial. However, further experimental and clinical studies are needed before routine clinical use can be recommended. DISCUSSION: The studies in this thesis may be valuable for the experimental research field of clinical anastomotic leakage. The model of technical insufficiency has been improved and is now thoroughly validated. If used by researchers worldwide, comparison of results is possible. Pure ischemia/anoxia may be too simple an approach to create a clinical leakage model. Thus, future models could focus on multiple risk factors. Conclusively, large-scale clinical multicenter studies are needed to definitively evaluate whether coating of colorectal anastomoses may reduce the leakage rate. PMID- 24814922 TI - Guideline for stress ulcer prophylaxis in the intensive care unit. AB - Stress ulcer prophylaxis (SUP) is commonly used in the intensive care unit (ICU), and is recommended in the Surviving Sepsis Campaign guidelines 2012. The present guideline from the Danish Society of Intensive Care Medicine and the Danish Society of Anesthesiology and Intensive Care Medicine sums up current evidence and gives clinical recommendations for SUP in the ICU. The GRADE approach was used for grading the evidence (www.gradeworkinggroup.org). In conclusion, existing meta-analyses have been underpowered to reach firm conclusions. We recommend not using SUP routinely for adult critically ill patients in the ICU outside the context of randomized controlled trials (GRADE 1C). No robust evidence supports recommendations for subpopulations in the ICU such as septic, burn, trauma, cardiothoracic or enterally fed patients. However, if SUP is considered clinically indicated in individual patients, we suggest using proton pump inhibitors over histamine-2-receptor antagonists (GRADE 2C). PMID- 24814923 TI - Disintegrin-like domain of glycoprotein B regulates Kaposi's sarcoma-associated herpesvirus infection of cells. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) glycoprotein B (gB) is a lytic structural protein expressed on the envelope of mature virions and on the membrane of cells supporting lytic infection. In addition to this viral glycoprotein's interaction with integrins via its RGD (Arg-Gly-Asp) motif, KSHV gB possesses a disintegrin-like domain (DLD), which binds integrins as well. Prior to this study, there has been minimal research involving the less common integrin-binding motif, DLD, of gB as it pertains to herpesvirus infection. By using phage display peptide library screening and molecular biology techniques, the DLD of KSHV gB was shown to interact specifically with non-RGD binding alpha9beta1 integrins. Similarly, monitoring wild-type infection confirmed alpha9beta1:DLD interactions to be critical to successful KSHV infection of human foreskin fibroblast (HFF) cells and human dermal microvascular endothelial cells (HMVEC-d) compared with 293 cells. To further demonstrate the importance of the DLD of gB in KSHV infection, two recombinant virus constructs were generated using a bacterial artificial chromosome (BAC) system harbouring the KSHV genome (BAC36): BAC36DeltaD-KSHV (lacking a functionally intact DLD of gB and containing an introduced tetracycline cassette) and BAC36.T-KSHV (containing an intact DLD sequence and an introduced tetracycline cassette). Accordingly, BAC36DeltaD-KSHV presented significantly lower infection rates in HFF and HMVEC-d cells compared with the comparable infection rates achieved by wild-type BAC36-KSHV and BAC36.T KSHV. Thus, the present report has delineated a critical role for the DLD of gB in KSHV infection, which may lead to a broader knowledge regarding the sophisticated mechanisms utilized by virus-encoded structural proteins in KSHV entry and infection. PMID- 24814924 TI - Viraemic frequencies and seroprevalence of non-primate hepacivirus and equine pegiviruses in horses and other mammalian species. AB - Non-primate hepacivirus (NPHV), equine pegivirus (EPgV) and Theiler's disease associated virus (TDAV) are newly discovered members of two genera in the Flaviviridae family, Hepacivirus and Pegivirus respectively, that include human hepatitis C virus (HCV) and human pegivirus (HPgV). To investigate their epidemiology, persistence and clinical features of infection, large cohorts of horses and other mammalian species were screened for NPHV, EPgV and TDAV viraemia and for past exposure through serological assays for NPHV and EPgV-specific antibodies. NPHV antibodies were detected in 43% of 328 horses screened for antibodies to NS3 and core antibodies, of which three were viraemic by PCR. All five horses that were stablemates of a viraemic horse were seropositive, as was a dog on the same farm. With this single exception, all other species were negative for NPHV antibodies and viraemia: donkeys (n=100), dogs (n=112), cats (n=131), non-human primates (n=164) and humans (n=362). EPgV antibodies to NS3 were detected in 66.5% of horses, including 10 of the 12 horses that had EPgV viraemia. All donkey samples were negative for EPgV antibody and RNA. All horse and donkey samples were negative for TDAV RNA. By comparing viraemia frequencies in horses with and without liver disease, no evidence was obtained that supported an association between active NPHV and EPgV infections with hepatopathy. The study demonstrates that NPHV and EPgV infections are widespread and enzootic in the study horse population and confirms that NPHV and potentially EPgV have higher frequencies of viral clearance than HCV and HPgV infections in humans. PMID- 24814925 TI - Pseudotyping of vesicular stomatitis virus with the envelope glycoproteins of highly pathogenic avian influenza viruses. AB - Pseudotype viruses are useful for studying the envelope proteins of harmful viruses. This work describes the pseudotyping of vesicular stomatitis virus (VSV) with the envelope glycoproteins of highly pathogenic avian influenza viruses. VSV lacking the homotypic glycoprotein (G) gene (VSVDeltaG) was used to express haemagglutinin (HA), neuraminidase (NA) or the combination of both. Propagation competent pseudotype viruses were only obtained when HA and NA were expressed from the same vector genome. Pseudotype viruses containing HA from different H5 clades were neutralized specifically by immune sera directed against the corresponding clade. Fast and sensitive reading of test results was achieved by vector-mediated expression of GFP. Pseudotype viruses expressing a mutant VSV matrix protein showed restricted spread in IFN-competent cells. This pseudotype system will facilitate the detection of neutralizing antibodies against virulent influenza viruses, circumventing the need for high-level biosafety containment. PMID- 24814926 TI - Differences in cellular function and viral protein expression between IgMhigh and IgMlow B-cells in bovine leukemia virus-infected cattle. AB - Bovine leukemia virus (BLV) induces abnormal B-cell proliferation and B-cell lymphoma in cattle, where the BLV provirus is integrated into the host genome. BLV-infected B-cells rarely express viral proteins in vivo, but short-term cultivation augments BLV expression in some, but not all, BLV-infected B-cells. This observation suggests that two subsets, i.e. BLV-silencing cells and BLV expressing cells, are present among BLV-infected B-cells, although the mechanisms of viral expression have not been determined. In this study, we examined B-cell markers and viral antigen expression in B-cells from BLV-infected cattle to identify markers that may discriminate BLV-expressing cells from BLV-silencing cells. The proportions of IgM(high) B-cells were increased in blood lymphocytes from BLV-infected cattle. IgM(high) B-cells mainly expressed BLV antigens, whereas IgM(low) B-cells did not, although the provirus load was equivalent in both subsets. Several parameters were investigated in these two subsets to characterize their cellular behaviour. Real-time PCR and microarray analyses detected higher expression levels of some proto-oncogenes (e.g. Maf, Jun and Fos) in IgM(low) B-cells than those in IgM(high) B-cells. Moreover, lymphoma cells obtained from the lymph nodes of 14 BLV-infected cattle contained IgM(low) or IgM(-) B-cells but no IgM(high) B-cells. To our knowledge, this is the first study to demonstrate that IgM(high) B-cells mainly comprise BLV-expressing cells, whereas IgM(low) B-cells comprise a high proportion of BLV-silencing B-cells in BLV-infected cattle. PMID- 24814927 TI - Rotavirus inhibits IFN-induced STAT nuclear translocation by a mechanism that acts after STAT binding to importin-alpha. AB - The importance of innate immunity to rotaviruses is exemplified by the range of strategies evolved by rotaviruses to interfere with the IFN response. We showed previously that rotaviruses block gene expression induced by type I and II IFNs, through a mechanism allowing activation of signal transducer and activator of transcription (STAT) 1 and STAT2 but preventing their nuclear accumulation. This normally occurs through activated STAT1/2 dimerization, enabling an interaction with importin alpha5 that mediates transport into the nucleus. In rotavirus infected cells, STAT1/2 inhibition may limit the antiviral actions of IFN produced early in infection. Here we further analysed the block to STAT1/2 nuclear accumulation, showing that activated STAT1 accumulates in the cytoplasm in rotavirus-infected cells. STAT1/2 nuclear accumulation was inhibited by rotavirus even in the presence of the nuclear export inhibitor Leptomycin B, demonstrating that enhanced nuclear export is not involved in STAT1/2 cytoplasmic retention. The ability to inhibit STAT nuclear translocation was completely conserved amongst the group A rotaviruses tested, including a divergent avian strain. Analysis of mutant rotaviruses indicated that residues after amino acid 47 of NSP1 are dispensable for STAT inhibition. Furthermore, expression of any of the 12 Rhesus monkey rotavirus proteins did not inhibit IFN-stimulated STAT1 nuclear translocation. Finally, co-immunoprecipitation experiments from transfected epithelial cells showed that STAT1/2 binds importin alpha5 normally following rotavirus infection. These findings demonstrate that rotavirus probably employs a novel strategy to inhibit IFN-induced STAT signalling, which acts after STAT activation and binding to the nuclear import machinery. PMID- 24814928 TI - Conservative surgical and microsurgical techniques for the management of dental implants that impinge on the inferior alveolar nerve. AB - Loss of sensation in the lip after insertion of an implant is annoying. The aim of this paper was to describe two techniques for management of osseointegrated dental implants that impinge on the mandibular nerve, the purpose of which is to improve sensation without unscrewing the dental implant. PMID- 24814929 TI - A novel siadenovirus detected in the kidneys and liver of Gouldian finches (Erythura gouldiae). AB - A novel siadenovirus was found in six captive Gouldian finches (Erythrura gouldiae) in the United States and Hungary. Histopathological examination revealed inclusions in the kidney of the captive Gouldian finch in the United States, and virions morphologically consistent with adenoviruses were seen by electron microscopy. Partial sequence of the DNA-dependent DNA polymerase gene was gained by consensus PCR and sequencing in all six finches, and all proved to be identical. In one Hungarian finch, additional sequence was obtained from the DNA polymerase gene, the pre-terminal protein (pTP) gene, the 52k gene, and the hexon gene. Bayesian, maximum likelihood, and distance-based analyses showed the novel virus clusters with the siadenoviruses, and is herein referred to as Gouldian finch adenovirus 1. The genes looked at in this study had low G+C percentages, which is common in the genus Siadenovirus, and suggestive of recent host switch. The significance of this virus' presence is unknown at this time as clinical signs of positive birds varied. PMID- 24814930 TI - Chronic disease prevalence and influencing factors among rural residents in Jiangxi, China. AB - BACKGROUND: This study assessed the prevalence of chronic disease among rural residents in Jiangxi, China, analyzed influencing factors and provided scientific rationale for chronic disease prevention and control. METHODS: Multi-stage stratified cluster random sampling was used to get a representative sample of rural residents in three counties across five time points from 2003 to 2012. Multivariate logistic regression and chi(2) analysis were performed to analyze the influencing factors. RESULTS: The average prevalence of chronic disease across the five surveys was 7.9%. A declining trend in chronic disease prevalence from 9.1% in the baseline year to 6.9% in 2012 was observed. Multivariate logistic regression analysis showed that age, gender, occupation, education, marital status and employment were related to the prevalence of chronic disease. CONCLUSION: The prevalence of chronic disease among rural residents in Jiangxi Province was lower than the national level, and declined over the course of the study. Strengthening health services and interventions for women, farmers, those who are divorced or widowed, the unemployed, and those with a low level of education or low income will help to improve the health status of the population. PMID- 24814931 TI - Risk of malaria among febrile patients: retrospective analysis of a hospital based study in an endemic area of northeast India. AB - BACKGROUND: Febrile illness is the most common symptom experienced by patients suspected of having malaria, especially in the malaria endemic areas of northeast India. Hospital-based data from two districts of upper Assam, namely Golaghat and Tinsukia, were analysed to assess the prevalence of malaria among inpatients who reported to health centres with febrile illness. METHODS: A total of 16 hospitals were selected for the study. These included six government hospitals (three in rural and three in urban areas) and 10 private hospitals, which included four tea garden hospitals. Selection was dependant on the availability of patients and inpatient treatment facilities. During the study, a total of 350 inpatients reported to the selected hospitals with fever; 324 were suspected of having malaria and were interviewed and included in the study. RESULTS: The average age of patients was 24.2+/-15.2 years and 63.3% (205/324) of them were male. The majority of patients (77.5%; 251/324) belonged to the lower household income category (<5000 Indian rupees) and travelled to the nearest town or city for treatment. Overall, the prevalence of malaria (as diagnosed by clinical examination and blood tests) across the different categories such as location, types of hospitals and household income was found to be 29.9% (97/324). Multivariate analysis revealed that the adjusted odds ratios (AOR) of malaria cases was higher based on location (2.13), type of health centre (1.75) and the distance travelled to a health centre (2.09). The mean duration of hospital treatment was 4.2+/-3.6 days and the delay in reporting to hospital was 3.9+/-2.6 days. CONCLUSION: The study emphasises the need to strengthen and improve the treatment facilities for malaria in government hospitals, and to create more awareness among people regarding early treatment, especially in the rural periphery villages of the endemic areas. PMID- 24814932 TI - Histological analysis of the periodontal ligament and alveolar bone during dental movement in diabetic rats subjected to low-level laser therapy. AB - OBJECTIVE: The purpose of this research was to evaluate the histological changes of the periodontal ligament and alveolar bone during dental movement in diabetic rats subjected to low level laser therapy (LLLT). METHODS: The movement of the upper molar was performed in 60 male Wistar rats divided into four groups (n=15): CTR (control), DBT (diabetic), CTR/LT (irradiated control) and DBT/LT (irradiated diabetic). Diabetes was induced with alloxan (150 mg/kg, i.p.). LLLT was applied with GaAlAs laser at 780 nm (35 J/cm(2)). After 7, 13 and 19 days, the periodontal ligament and alveolar bone were histologically analyzed. RESULTS: The mean of osteoblasts (p<0.01) and blood vessels (p<0.05) were significantly decreased in DBT compared with CTR at 7 days, whereas the mean of osteoclasts was lower at 7 (p<0.001) and 13 days (p<0.05). In DBT/LT, only the mean of osteoclasts was lower than in CTR (p<0.05) at 7 days, but no difference was observed at 13 and 19 days (p>0.05). The collagenization of the periodontal ligament was impaired in DBT, whereas DBT/LLT showed density/disposition of the collagen fibers similar to those observed in CTR. CONCLUSIONS: LLLT improved the periodontal ligament and alveolar bone remodeling activity in diabetic rats during dental movement. PMID- 24814933 TI - Higher dose of warfarin for patients with pulmonary embolism complicated by obstructive sleep apnea hypopnea syndrome. AB - BACKGROUND: The concomitant prevalence of obstructive sleep apnea hypopnea syndrome (OSAHS) and pulmonary embolism (PE) is strikingly high, and therefore we studied the patients with PE to determine whether those who had OSHAS required greater warfarin doses to achieve a therapeutic international normalized ratio (INR). METHODS: By using computer tomographic pulmonary angiography or pulmonary angiography, we identified and recruited 97 patients with PE and all underwent polysomnography. Warfarin was initiated at a dose of 3 mg/day and modified to adjust the INR to the range of 2.0-3.0. RESULTS: OSAHS patients (n = 32) required a significantly higher dose of warfarin than their non-OSAHS counterparts (5.01 mg vs 3.61 mg, P < .001). This difference still existed between the two groups after adjusting for covariates (achieved INR value and weight). Logistic analysis suggested that OSAHS was an independent risk factor for high dose warfarin (OR 5.715, P < .001). On admission, OSAHS patients had a lower mean value of INR and prothrombin time but higher plasminogen (PLG) activity compared to non-OSAHS patients. Other coagulation indices were not significantly different between the two groups. Except for the PLG activity (r = .273, P = .026), the correlation between the warfarin dose and the baseline coagulating indices wasn't significant. CONCLUSIONS: Our findings indicate that factors associated with OSAHS, such as hypercoagulation, may explain the need for higher doses of warfarin in treating patients with PE. PMID- 24814935 TI - Resting physiological arousal is associated with the experience of music-induced chills. AB - In the study of emotion and autonomic nervous system functioning, resting physiological arousal is usually considered a negative characteristic. The present study examined the relationship between resting physiological arousal and positive emotional experience linked to psychophysiological arousal. We assessed resting physiological arousal using markers as high skin conductance level and low respiratory sinus arrhythmia, measured just before participants listened to their favorite music. Participants reported the sensation of chills (goose bumps, shivers) by pressing a mouse button while listening. The results indicated that individuals with resting physiological arousal frequently experience music induced chills, which evoked unambiguous pleasurable feelings and an increase in skin conductance response. The current results, and the previously demonstrated relationship between resting physiological arousal and negative emotionality linked to psychophysiological arousal (e.g., anxiety, panic), suggest that resting physiological arousal may reflect sensitivity to psychophysiological arousal with both intense positive and negative emotions. PMID- 24814934 TI - Mood impact on effort-related cardiovascular reactivity depends on task context: evidence from a task with an unfixed performance standard. AB - Gendolla and colleagues have consistently found that negative mood leads to higher effort-related cardiovascular reactivity than positive mood if performers can choose their own performance standard (Gendolla et al., 2001; Gendolla and Krusken, 2001a, 2002a,b). However, an integration of motivational intensity theory with the mood literature suggests that the impact of mood on cardiovascular activity should vary with task context. In a 2 (task context: demand vs. reward)*2 (mood valence: negative vs. positive) between-persons design, participants performed a memory task without a fixed performance standard. The results showed the expected interaction. Positive mood led to higher effort mobilization-reflected by increased pre-ejection period and heart rate reactivity-than negative mood if participants had answered questions about task reward before performing the task. If participants had responded to questions about task demand, the pattern was reversed. These results extend and add to preceding research that has demonstrated that mood impact on effort related cardiovascular activity is not stable but depends on task context. PMID- 24814936 TI - An endobronchial inflammatory myofibroblastic tumor in a 10-yr-old child after allogeneic hematopoietic cell transplantation. AB - IMTs belong to the group of soft tissue tumor and could occur at any anatomical site; however, the causes and growth feature remain unclear. This case report documents a 10-yr-old male suffering from slowly developing dyspnea on exertion and cough around seven months post-HCT. He was diagnosed with an endobronchial tumor based on imaging, and histology confirmed ALK-positive submucosal spindle shaped cells with infiltrative cells, compatible with IMT. We should be aware that IMT is a potential complication of pediatric allogeneic HCT and can cause sudden airway obstruction. PMID- 24814938 TI - Diet, sun, and lifestyle as determinants of vitamin D status. AB - Vitamin D status can be assessed by measuring concentrations of 25-hydroxyvitamin D (25(OH)D). Sunlight is the most important source of vitamin D and stimulates the production of vitamin D3 in the skin during the summer, depending on age, skin pigmentation, clothing style, and sunscreen use. Seasonal variation in serum 25(OH)D is between 10 and 20 nmol/L in adults and almost absent in nursing home residents. Sunscreen use decreases, but does not abolish, vitamin D production in the skin. Clothing style has a large influence on vitamin D production. Furthermore, vitamin D status can be improved by ingestion of fatty fish and the fortification of milk or orange juice. A high dietary calcium intake has a vitamin D-sparing effect, because it increases the half-life of 25(OH)D. A combination of sunlight exposure, nutrition, food fortification, and supplements is desirable to obtain sufficient vitamin D status in the population of most countries throughout the year. PMID- 24814939 TI - The power of involving house staff in quality improvement: an interdisciplinary house staff-driven vaccination initiative. AB - Immunization for influenza and pneumococcal pneumonia were incorporated into The Joint Commission "global immunization" core measure January 1, 2012. The authors' hospital chose to adhere strictly to guidelines to avoid overvaccination. An immunization order set was created to aid appropriate ordering practices. In spite of this effort, compliance rates remained below the goal. The objective was to improve compliance with inpatient vaccination core measures to >96%. An educational slide set was created and distributed by the Housestaff Patient Safety and Quality Council (HPSQC). A competition was established among departments. Finally, the HPSQC partnered with quality improvement staff to improve communication and optimize concurrent review processes. The average compliance prior to the HPSQC vaccination initiative was 78% for pneumococcal pneumonia and 84% for influenza; average compliance in the months following the intervention was 96% and 97.5%, respectively. This project yielded significant improvement in compliance with vaccination core measures. PMID- 24814940 TI - Hospital variations in severe sepsis mortality. AB - This study sought to characterize variations in severe sepsis mortality between hospitals in the United States. Hospital discharge data (2012) were used from the University HealthSystem Consortium (UHC), a cooperative of US not-for-profit academic medical centers and affiliated hospitals. Discharge diagnosis codes were used to define severe sepsis as the presence of a serious infection with at least 1 organ dysfunction on hospital presentation. Expected mortality was determined from UHC risk adjustment mortality models. Among the 188 hospitals in the analysis, there were 256 509 patients with severe sepsis on admission. The median number of severe sepsis cases per hospital was 1202 (interquartile range [IQR] = 718-1940). Severe sepsis observed mortality (median = 8.6%; IQR = 6.8%-10.3%; range = 0.9%-18.2%) and observed-to-expected (O:E) mortality ratios (median = 0.91; IQR = 0.77-1.05; range = 0.16-1.95) varied across the hospitals. Variations in institutional severe sepsis observed mortality rates and O:E mortality ratios were observed in this national consortium of major medical centers. PMID- 24814941 TI - Intracellular neutrophil myeloperoxidase level in pediatric patients: significant age and gender variability. AB - INTRODUCTION: Myeloperoxidase (MPO) is an enzyme produced by neutrophil leukocytes and released upon activation, killing pathogens and causing tissue damage. As neutrophils in neonates are functionally immature, cellular MPO content in children may be age-related and different from adults. Hematological analyzer ADVIA 2120i (Siemens AG), while routinely assessing neutrophil count, measures their MPO content by means of myeloperoxidase index (MPXI). No pediatric reference range for MPXI has been published. METHODS: We performed a retrospective study of MPXI values in 51,303 consecutive routine blood tests of nonhematologic pediatric patients, looking for age- and gender-related variability. Nonparametric statistical analysis (Spearman rho and Mann-Whitney U test) was used for evaluation. RESULTS: Neutrophil MPO content was highly significantly lower during the first month of life (P << 0.001) and rose to average pediatric values by day 28. Unexpectedly, the study revealed a highly significant gender difference (P << 0.001), MPXI being lower in boys from birth to adulthood. CONCLUSIONS: We found previously unreported highly significant age- and gender-related variations of neutrophil MPO in children in hospital setting. There are possible clinical implications, particularly concerning neutrophil immunity of neonates and gender-related difference in vascular events in adults. The finding may be considered for refining automatic cell counting in infants. PMID- 24814942 TI - What was the role of nurses during the 2011 great East earthquake of Japan? An integrative review of the Japanese literature. AB - BACKGROUND: An earthquake and tsunami hit the east coast of Japan on March 11, 2011. Nurses were actively involved in the health response to this disaster and, subsequently, many authors have reported on the role nurses played in these efforts in Japanese nursing professional journals. Aim To describe the role of nurses who assisted in the 2011 Great East Earthquake of Japan by reviewing Japanese literature and reporting the findings in English. METHOD: This research used an integrative literature review methodology. Manuscripts were obtained from the Japanese database Ichushi Ver. 5 (Japan Medical Abstracts Society, Tokyo, Japan). A total of 44 manuscripts were identified and included in a thematic analysis. RESULTS: Three main themes were identified: (1) nursing roles, (2) specialized nursing roles, and (3) preparedness education. Nurses fulfilled different roles in the period after the disaster (ie, as a clinician, a communicator, a leader, and a provider of psychosocial support). Additionally, the specialized nurse role was identified, along with the need for preparedness education to support the nurse's role in a disaster. CONCLUSION: The understanding of the role of nurses in disasters is expanding. There is a need to further explore the roles of specialized nurses in disasters. Further disaster education opportunities should be available as a part of continuing education for all nurses. Radiation aspects of disaster assistance should be included in disaster education programs where there are radio-nuclear hazards present in the environment. PMID- 24814937 TI - Conservation implications of the evolutionary history and genetic diversity hotspots of the snowshoe hare. AB - With climate warming, the ranges of many boreal species are expected to shift northward and to fragment in southern peripheral ranges. To understand the conservation implications of losing southern populations, we examined range-wide genetic diversity of the snowshoe hare (Lepus americanus), an important prey species that drives boreal ecosystem dynamics. We analysed microsatellite (8 loci) and mitochondrial DNA sequence (cytochrome b and control region) variation in almost 1000 snowshoe hares. A hierarchical structure analysis of the microsatellite data suggests initial subdivision in two groups, Boreal and southwestern. The southwestern group further splits into Greater Pacific Northwest and U.S. Rockies. The genealogical information retrieved from mtDNA is congruent with the three highly differentiated and divergent groups of snowshoe hares. These groups can correspond with evolutionarily significant units that might have evolved in separate refugia south and east of the Pleistocene ice sheets. Genetic diversity was highest at mid-latitudes of the species' range, and genetic uniqueness was greatest in southern populations, consistent with substructuring inferred from both mtDNA and microsatellite analyses at finer levels of analysis. Surprisingly, snowshoe hares in the Greater Pacific Northwest mtDNA lineage were more closely related to black-tailed jackrabbits (Lepus californicus) than to other snowshoe hares, which may result from secondary introgression or shared ancestral polymorphism. Given the genetic distinctiveness of southern populations and minimal gene flow with their northern neighbours, fragmentation and loss of southern boreal habitats could mean loss of many unique alleles and reduced evolutionary potential. PMID- 24814943 TI - Development of a recombinase polymerase amplification assay for the detection of pathogenic Leptospira. AB - Detection of leptospires based on DNA amplification techniques is essential for the early diagnosis of leptospirosis when anti-Leptospira antibodies are below the detection limit of most serological tests. In middle and low income countries where leptospirosis is endemic, routine implementation of real-time PCR is financially and technically challenging due to the requirement of expensive thermocycler equipment. In this study we report the development and evaluation of a novel isothermal recombinase polymerase amplification assay (RPA) for detection of pathogenic Leptospira based on TwistAmp chemistry. RPA enabled the detection of less than two genome copies per reaction. Retrospective evaluation revealed a high diagnostic accuracy (sensitivity and specificity of 94.7% and 97.7%, respectively) compared to culturing as the reference standard. RPA presents a powerful tool for the early diagnosis of leptospirosis in humans and in animals. Furthermore, it enables the detection of the causative agent in reservoirs and environment, and as such is a valuable adjunct to current tools for surveillance and early outbreak warning. PMID- 24814944 TI - Effect of smoking abstinence and reduction in asthmatic smokers switching to electronic cigarettes: evidence for harm reversal. AB - Electronic cigarettes (e-cigs) are marketed as safer alternatives to tobacco cigarettes and have shown to reduce their consumption. Here we report for the first time the effects of e-cigs on subjective and objective asthma parameters as well as tolerability in asthmatic smokers who quit or reduced their tobacco consumption by switching to these products. We retrospectively reviewed changes in spirometry data, airway hyper-responsiveness (AHR), asthma exacerbations and subjective asthma control in smoking asthmatics who switched to regular e-cig use. Measurements were taken prior to switching (baseline) and at two consecutive visits (Follow-up/1 at 6 (+/-1) and Follow-up/2 at 12 (+/-2) months). Eighteen smoking asthmatics (10 single users, eight dual users) were identified. Overall there were significant improvements in spirometry data, asthma control and AHR. These positive outcomes were noted in single and dual users. Reduction in exacerbation rates was reported, but was not significant. No severe adverse events were noted. This small retrospective study indicates that regular use of e cigs to substitute smoking is associated with objective and subjective improvements in asthma outcomes. Considering that e-cig use is reportedly less harmful than conventional smoking and can lead to reduced cigarette consumption with subsequent improvements in asthma outcomes, this study shows that e-cigs can be a valid option for asthmatic patients who cannot quit smoking by other methods. PMID- 24814945 TI - Requiring pollutant discharge permits for pesticide applications that deposit residues in surface waters. AB - Agricultural producers and public health authorities apply pesticides to control pests that damage crops and carry diseases. Due to the toxic nature of most pesticides, they are regulated by governments. Regulatory provisions require pesticides to be registered and restrictions operate to safeguard human health and the environment. Yet pesticides used near surface waters pose dangers to non target species and drinking water supplies leading some governments to regulate discharges of pesticides under pollution discharge permits. The dual registration and discharge permitting provisions are burdensome. In the United States, agricultural interest groups are advancing new legislation that would exempt pesticide residues from water permitting requirements. An analysis of the dangers posed by pesticide residues in drinking water leads to a conclusion that both pesticide registration and pollutant discharge permitting provisions are needed to protect human health and aquatic species. PMID- 24814946 TI - Mental and behavioral disorders due to substance abuse and perinatal outcomes: a study based on linked population data in New South Wales, Australia. AB - BACKGROUND: The effects of mental and behavioral disorders (MBD) due to substance use during peri-conception and pregnancy on perinatal outcomes are unclear. The adverse perinatal outcomes of primiparous mothers admitted to hospital with MBD due to substance use before and/or during pregnancy were investigated. METHOD: This study linked birth and hospital records in NSW, Australia. Subjects included primiparous mothers admitted to hospital for MBD due to use of alcohol, opioids or cannabinoids during peri-conception and pregnancy. RESULTS: There were 304 primiparous mothers admitted to hospital for MBD due to alcohol use (MBDA), 306 for MBD due to opioids use (MBDO) and 497 for MBD due to cannabinoids (MBDC) between the 12 months peri-conception and the end of pregnancy. Primiparous mothers admitted to hospital for MBDA during pregnancy or during both peri conception and pregnancy were significantly more likely to give birth to a baby of low birthweight (AOR = 4.03, 95%CI: 1.97-8.24 for pregnancy; AOR = 9.21, 95%CI: 3.76-22.57 both periods); preterm birth (AOR = 3.26, 95% CI: 1.52-6.97 for pregnancy; AOR = 4.06, 95%CI: 1.50-11.01 both periods) and admission to SCN or NICU (AOR = 2.42, 95%CI: 1.31-4.49 for pregnancy; AOR = 4.03, 95%CI: 1.72-9.44 both periods). Primiparous mothers admitted to hospital for MBDO, MBDC or a combined diagnosis were almost three times as likely to give birth to preterm babies compared to mothers without hospital admissions for psychiatric or substance use disorders. Babies whose mothers were admitted to hospital with MBDO before and/or during pregnancy were six times more likely to be admitted to SCN or NICU (AOR = 6.29, 95%CI: 4.62-8.57). CONCLUSION: Consumption of alcohol, opioids or cannabinoids during peri-conception or pregnancy significantly increased the risk of adverse perinatal outcomes. PMID- 24814948 TI - The effect of playground- and nature-based playtime interventions on physical activity and self-esteem in UK school children. AB - School playtime provides opportunities for children to engage in physical activity (PA). Playground playtime interventions designed to increase PA have produced differing results. However, nature can also promote PA, through the provision of large open spaces for activity. The purpose of this study is to determine which playtime interventions are most effective at increasing moderate to-vigorous physical activity (MVPA) and if this varies by school location. Fifty two children from an urban and rural school participated in a playground sports (PS) and nature-based orienteering intervention during playtime for one week. MVPA was assessed the day before and on the final day of the interventions using accelerometers. Intervention type (p < 0.05) and school location (p < 0.001) significantly influenced MVPA; with PS increasing MVPA more than nature-based orienteering. Urban children seemed to respond to the interventions more positively; however, differences in baseline MVPA might influence these changes. There was a positive correlation for fitness and MVPA during PS (r = 0.32; p < 0.05), but not nature-based orienteering (p > 0.05). The provision of PS influences PA the most; however, a variety of interventions are required to engage less fit children in PA. PMID- 24814947 TI - Apolipoprotein A-I induces tubulin phosphorylation in association with cholesterol release in fetal rat astrocytes. AB - We previously identified cytosolic lipid-protein particles (CLPP) having size and density of HDL in rat astrocytes, to which apoA-I induces translocation of cholesterol, caveolin-1 and protein kinase Calpha (PKCalpha) following its association with microtubules prior to cholesterol release/biogenesis of HDL (JBC 277: 7929, 2002; JLR 45: 2269, 2004). To further understand the physiological relevance of these findings, we investigated the CLPP/microtubule association and its role in intracellular cholesterol trafficking by using a technique of reconstituted microtubule-like filaments (rMT) in rat astrocyte cytosol. When the cells were pretreated with apoA-I, alpha-tubulin as a 52-kDa protein in rMT was found phosphorylated while alpha-tubulin in a soluble monomeric form was little phosphorylated. The phosphorylation took place coincidentally to apoA-I-induced association with rMT of CLPP, a complex containing PKCalpha, and was suppressed by a PKC inhibitor, Bis indolylmaleimide 1 (BIM). alpha-Tubulin dissociated from CLPP when phosphorylated, and it poorly bound to CLPP once dissociated. BIM did not influence association of PKCalpha with rMT but suppressed apoA-I-induced cholesterol translocation to the cytosol from the ER/Golgi apparatus and apoA-I mediated cholesterol release. We thereby concluded that alpha-tubulin phosphorylation by PKCalpha on CLPP is involved in reversible CLPP association with the microtubules and intracellular cholesterol trafficking for apoA-I dependent HDL biogenesis/cholesterol release in rat astrocytes. PMID- 24814949 TI - Cranial imaging findings in dengue virus infection. AB - BACKGROUND: The aim of this study is to evaluate cranial CT or MRI changes in dengue encephalitis and their correlation with clinical and biochemical findings. METHODS: Twenty-one serologically confirmed patients with dengue with altered sensorium were included who underwent MRI (20)/CT (1) scan study. Their clinical details including seizure, hypotension, bleeding diathesis, focal neurologic deficit, and Glasgow Coma Scale (GCS) score were noted. Blood counts, hematocrit, renal and liver function tests, electrolytes, cerebrospinal fluid (CSF) and ECG were done. MRI findings on T1, T2, FLAIR, DWI and T1 gadolinium contrast were noted. RESULTS: The median age of the patients was 30 (5-69) years and 5 were females. MRI was abnormal in 9(45%) and CT scan in 1 patient with dengue shock syndrome revealed cerebellar and subdural hematoma. The MRI lesions were in thalamic and basal ganglia in 3, focal cortical areas in 3, white mater in 2 and meningeal enhancement in 3 patients. Seven of these patients had CSF pleocytosis. The presence of abnormal imaging was not related to outcome. One patient died, 1 was bed ridden and 19 had complete recovery on discharge. CONCLUSION: Cranial imaging reveals nonspecific changes and is not related to hematological and biochemical changes or outcome. PMID- 24814950 TI - Prevalence of migraine headache and its weight on neurological burden in Africa: a 43-year systematic review and meta-analysis of community-based studies. AB - BACKGROUND: Headache burden is not adequately explored in Africa. Here, we measured weighted migraine prevalence from community-based studies in Africa. METHODS: PubMed search was employed using terms 'headache in Africa' AND/OR 'migraine in Africa' for published literature from 1970 until January 31, 2014. PRISMA was applied for systematic review. Forest-plot meta-analysis, inter-study heterogeneity, and odds ratio were used to measure weighted prevalence, inter gender, and urban-rural differences. Disability adjusted life years (DALYs) for migraine and other neurologic disorders in Africa were extracted from Global Burden of Diseases (GBD) 2000-2030. RESULTS: Among 21 community-based studies included (n=137,277), pooled migraine prevalence was 5.61% (95% CI 4.61, 6.70; random effects) among general population; while 14.89% (14.06, 15.74; fixed effects) among student cohorts. Female students had weighted OR of 2.13 (1.34, 3.37; p=0.0013). Prevalence of migraine was higher among urban population compared to rural settings. Migraine burden is bound to increase by more than 10% DALYs within the next decade. CONCLUSION: Africa has a crude estimate of 56 million people suffering from migraine. By virtue of mainly afflicting the younger working-age group, migraine disability has wider socioeconomic implications. Improving early headache management access points at community level, training and research at facility-level, and healthy lifestyle modification among urban residents can help reduce this costly and disabling chronic progressive health problem. PMID- 24814951 TI - Clinical and MRI correlates of disease progression in a case of nonfluent/agrammatic variant of primary progressive aphasia due to progranulin (GRN) Cys157LysfsX97 mutation. AB - Little is known about the longitudinal changes of brain damage in patients with sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) and in progranulin (GRN) mutation carriers. This study reports the clinical and MRI longitudinal data of a patient with nfvPPA carrying GRN Cys157LysfsX97 mutation (GRN+). Voxel-based morphometry, tensor-based morphometry and diffusion tensor MRI were applied to evaluate gray matter (GM) and white matter (WM) changes over three years. The prominent clinical feature was motor speech impairment associated with only mild agrammatism. MRI demonstrated a progressive and severe GM atrophy of inferior fronto-insular-temporo-parietal regions with focal damage to frontotemporal and frontoparietal WM connections. This is the first report of longitudinal MRI data in a nfvPPA- GRN+ patient and this report offers new insights into the pathophysiology of the disease. PMID- 24814952 TI - Osteonecrosis of the metatarsal head with exuberant periostitis. AB - Idiopathic necrosis of the metatarsal head is unusual in adulthood. We report five cases of an atypical necrosis of the metatarsal head with a solid periosteal reaction in adults. Different imaging features are reported and diagnosis difficulties are highlighted. PMID- 24814953 TI - Genetic diversity in nine native Turkish sheep breeds based on microsatellite analysis. AB - The genetic variability of 204 sheep from nine breeds (Awassi, Cine Capari, Karakas, Karya, Karayaka, Morkaraman, Norduz, Sakiz and Tuj) growing in four different regions (western, northern, eastern and south-eastern Anatolia) was assessed using 18 microsatellite loci. High mean number of alleles, allelic richness and factorial correspondence analysis showed the degree of admixture between native sheep breeds of Turkey. The Karya and Cine Capari breeds were observed as the most distinct of the breeds, and possible introgressions were detected in other breeds. It was found that 8.9% of genetic variation resulted from the difference between the populations. The genetic variation in Turkish breeds was not much higher than that of European breeds, which might be a consequence of the recent sharp decrease in sheep numbers. PMID- 24814954 TI - Oral S-1 in advanced cutaneous squamous cell carcinoma. AB - Squamous cell carcinoma (SCC) is the second most common type of skin cancer in Japan, and its incidence has been increasing in recent years. Early diagnosis and complete excision can provide a high cure rate. However, advanced cases of SCC showing local invasion, regional lymph node metastasis or distant metastasis are not curative and are difficult to treat with surgery alone. Some chemotherapy regimens have been used for treating advanced cutaneous SCC. However, almost all these regimens require intravenous administration and result in serious toxicities in elderly people. We gave S-1, a novel oral chemotherapeutic agent, for six patients with advanced cutaneous SCC. Three patients achieved complete response and one achieved partial response. Two patients showed stable disease. The overall response rate was 66.7% (four of six patients), and the disease control rate was 100%. Two of six patients developed grade 3 anaemia. Oral S-1 treatment is safe and effective for treating advanced cutaneous SCC. However, a prospective trial is necessary to confirm the effectiveness of oral S-1 for advanced cutaneous SCC. PMID- 24814955 TI - Quantification of DAPK1 promoter methylation in bone marrow and peripheral blood as a follicular lymphoma biomarker. AB - Hypermethylation of DAPK1 promoter gene was found to be a frequent epigenetic alteration in follicular lymphoma (FL). We evaluated whether the quantification of DAPK1 methylation in the bone marrow (BM) and peripheral blood of FL patients at diagnosis and during follow-up provides important prognostic information. DAPK1 methylation was quantitated by real-time MethyLight PCR in 107 patients at diagnosis, at end of therapy, and during follow-up. Information on BCL2-IGH rearrangement and clinical characteristics were available for all patients. Aberrant DAPK1 methylation was found in 22 of 26 (85%) lymph node biopsy samples, 62 of 107 (58%) BM specimens, and 25 of 63 (40%) peripheral blood samples at diagnosis. DAPK1 methylation was greater in patients with BM infiltration and a higher Follicular Lymphoma International Prognostic Index score. The presence of aberrant DAPK1 methylation in BM significantly reduced progression-free survival following immunochemotherapy, independent of Follicular Lymphoma International Prognostic Index score. Residual or increased methylation after treatment was associated with an increased risk for relapse. With watchful waiting, greater DAPK1 methylation at diagnosis was associated with a shorter time to antilymphoma treatment. Our study indicates that quantification of DAPK1 methylation represents a prognostically relevant FL biomarker, with promising implications for risk assessment. PMID- 24814957 TI - Diagnosis of trypanosomatid infections: targeting the spliced leader RNA. AB - Trypanosomatids transcribe their genes in large polycistronic clusters that are further processed into mature mRNA molecules by trans-splicing. During this maturation process, a conserved spliced leader RNA (SL-RNA) sequence of 39 bp is physically linked to the 5' end of the pre-mRNA molecules. Trypanosomatid infections cause a series of devastating diseases in man (sleeping sickness, leishmaniasis, Chagas disease) and animals (nagana, surra, dourine). Here, we investigated the SL-RNA molecule for its diagnostic potential using reverse transcription followed by real-time PCR. As a model, we used Trypanosoma brucei gambiense, which causes sleeping sickness in west and central Africa. We showed that the copy number of the SL-RNA molecule in one single parasitic cell is at least 8600. We observed a lower detection limit of the SL-RNA assay in spiked blood samples of 100 trypanosomes per milliliter of blood. We also proved that we can detect the trypanosome's SL-RNA in the blood of sleeping sickness patients with a sensitivity of 92% (95% CI, 78%-97%) and a specificity of 96% (95% CI, 86% 99%). The SL-RNA is thus an attractive new molecular target for next-generation diagnostics in diseases caused by trypanosomatids. PMID- 24814956 TI - cDNA hybrid capture improves transcriptome analysis on low-input and archived samples. AB - The use of massively parallel sequencing for studying RNA expression has greatly enhanced our understanding of the transcriptome through the myriad ways these data can be characterized. In particular, clinical samples provide important insights about RNA expression in health and disease, yet these studies can be complicated by RNA degradation that results from the use of formalin as a clinical preservative and by the limited amounts of RNA often available from these precious samples. In this study we describe the combined use of RNA sequencing with an exome capture selection step to enhance the yield of on-exon sequencing read data when compared with RNA sequencing alone. In particular, the exome capture step preserves the dynamic range of expression, permitting differential comparisons and validation of expressed mutations from limited and FFPE preserved samples, while reducing the data generation requirement. We conclude that cDNA hybrid capture has the potential to significantly improve transcriptome analysis from low-yield FFPE material. PMID- 24814958 TI - Novel cationic polyene glycol phospholipids as DNA transfer reagents--lack of a structure-activity relationship due to uncontrolled self-assembling processes. AB - Cationic glycol phospholipids were synthesized introducing chromophoric, rigid polyenoic C20:5 and C30:9 chains next to saturated flexible alkyl chains of variable lengths C6-20:0. Surface properties and liposome formation of the amphiphilic compounds were determined, the properties of liposome/DNA complexes (lipoplexes) were established using three formulations (no co-lipid, DOPE as a co lipid, or cholesterol as a co-lipid), and the microstructure of the best transfecting compounds inspected using small angle X-ray diffraction to explore details of the partially ordered structures of the systems that constitute the series. Transfection and cytotoxicity of the lipoplexes were evaluated by DNA delivery to Chinese hamster ovary (CHO-K1) cells using the cationic glycerol phospholipid 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) as a reference compound. The uncontrollable self-association of the molecules in water resulted in aggregates and liposomes of quite different sizes without a structure-property relationship. Likewise, adding DNA to the liposomes gave rise to unpredictable sized lipoplexes, which, again, transfected without a structure-activity relationship. Nevertheless, one compound among the novel lipids (C30:9 chain paired with a C20:0 chain) exhibited comparable transfection efficiency and toxicity to the control cationic lipid EPC. Thus, the presence of a rigid polyene chain in this best performing achiral glycol lipid did not have an influence on transfection compared with the chiral glycerolipid reference ethyl phosphocholine EPC with two flexible saturated C14 chains. PMID- 24814959 TI - DNA theoretical modeling: Reply to comments on "Fluctuations in the DNA double helix: A critical review". PMID- 24814960 TI - Stroop interference in adults with dyslexia. AB - Prior research on developmental dyslexia using Stroop tasks with young participants has found increased interference in participants with dyslexia relative to controls. Here we extend these findings to adult participants, and introduce a novel test of Stroop incongruity, whereby the color names appeared on an object colored in the incongruent color. The results imply that impaired inhibitory and executive attentional mechanisms are still deficient in adults with dyslexia and that other forms of attentional mechanisms, such as object based attention, might also be impaired in dyslexia. Dyslexia arises not only from deficits in phonological processing, but from attentional mechanisms as well. PMID- 24814961 TI - More attention to pain management in community-dwelling older persons with chronic musculoskeletal pain. AB - BACKGROUND: persistent pain is a major problem in older people, but little is known about older persons' opinion about the treatment of persistent pain. OBJECTIVE: the objective of this study was to investigate the factors associated with older participants having chronic musculoskeletal pain and hoping persistently that physician would pay more attention to the pain management. METHODS: this 3-year follow-up study was a part of large population-based Geriatric Multidisciplinary Strategy for the Good Care of the Elderly (GeMS) study. The population sample (n = 1000) of the GeMS study was randomly selected from older inhabitants (>=75 years) of Kuopio city, Finland, and participants were interviewed annually in the municipal health centre or in the participant's current residence by three study nurses. The current substudy included participants with chronic musculoskeletal pain (n = 270). Participants were asked specifically whether they hoped that more attention would be paid to pain management by the physician. RESULTS: at baseline, 41% of the community-dwelling older participants with chronic musculoskeletal pain hoped the physician would pay more attention to pain management. Of those participants, 49% were still continuing to hope after 1 year and 31% after 2 years. A persistent hope to receive more attention to pain management was associated with poor self-rated health (OR: 2.94; 95% CI: 1.04-8.30), moderate-to-severe pain (OR: 3.46; 95% CI: 1.42-8.44), and the daily use of analgesics (OR: 4.16; 95% CI: 1.08-16.09). CONCLUSION: physicians need to take a more active role in the process of recognising, assessing and controlling persistent pain in older people. PMID- 24814962 TI - Chemoradiotherapy with taxane is superior to conventional surgery and radiotherapy in the management of cutaneous angiosarcoma: a multicentre, retrospective study. AB - BACKGROUND: The prognosis of cutaneous angiosarcoma (CAS), especially for patients with tumours > 5 cm has been reported to be dismal, even after conventional surgery and radiotherapy (S + RT). OBJECTIVES: To demonstrate the efficacy of chemoradiotherapy with taxane (T + RT) and maintenance chemotherapy. METHODS: We retrospectively reviewed 16 patients with CAS treated with T + RT and 12 patients treated with S + RT. None had distant metastasis. Tumour sites included the scalp (n = 25) and limbs (n = 3). The chemotherapy regimens used in T + RT were monthly docetaxel (n = 10), biweekly docetaxel (n = 1), weekly docetaxel (n = 5) and weekly paclitaxel (n = 1). The median radiation dose was 70 Gy. Nine patients receiving T + RT continued chemotherapy as maintenance therapy (monthly docetaxel in nine patients and monthly paclitaxel in two patients) and four patients receiving S + RT received adjuvant chemotherapy (weekly docetaxel). RESULTS: The response ratio of T + RT was 94% (14 complete remission and one partial remission). The 5-year overall survival (OS) rate of patients receiving T + RT was statistically higher than those receiving conventional S + RT (56% and 8%, respectively; P < 0.01). Moreover, patients who received T + RT with maintenance chemotherapy showed a significant improvement in OS than those receiving T + RT alone (P < 0.01). There was a strong trend for relapse-free survival, but it was not significant (P = 0.07). These data indicate that maintenance chemotherapy is crucial for long-term survival after T + RT. CONCLUSIONS: From these results, we suggest that T + RT followed by maintenance chemotherapy is a plausible method for managing CAS, especially large tumours that are difficult to manage with S + RT alone. PMID- 24814963 TI - Iris stromal imbrication oversewing for pigment epithelial defects. AB - We present a novel iris repair technique for the management of iris transillumination defects secondary to iris pigment epithelium (IPE) loss, which includes iris oversewing over the defect through partial iris stromal bites with 10-0 polypropylene. This technique provides a healthy layer of iris covering the transillumination defect without the creation of new defects on the contiguous IPE. PMID- 24814964 TI - Relationship between halo size and forward light scatter. AB - PURPOSE: To determine the relationship between the size of a halo induced by a glare source and forward scatter or visual acuity (VA) in healthy eyes. METHOD: Measurements were made in the right eyes of 51 healthy individuals of mean age 29.3 +/- 7.5 years. Halo radius was measured using the Vision Monitor and low luminance (1 cd/m(2)) optotypes presented at a distance of 2.5 m. The visual angle subtended by the radius of the halo was calculated in minutes of arc (arc min). Forward scatter or, straylight, was measured using the compensation comparison technique. Best-corrected distance VA was measured using high contrast (HC) (96%) and low contrast (LC) (10%) Bailey-Lovie logMAR letter charts under photopic (85 cd/m(2)) and mesopic (0.15 cd/m(2)) luminance conditions. RESULTS: Mean halo radius was 202 +/- 43 arc min (3.4 +/- 0.7 degrees ) and mean retinal straylight was 0.95 +/- 0.12 log units. Mean photopic distance HC-VA and LC-VA were -0.02 +/- 0.06 and 0.12 +/- 0.09 logMAR, respectively. Mean mesopic distance HC-VA and LC-VA were 0.35 +/- 0.11 and 0.74 +/- 0.11 logMAR, respectively. Forward stepwise regression analysis revealed that halo radius was significantly correlated with straylight (r=0.45) and mesopic LC-VA (r=0.48), but not with photopic HC-VA and/or LC-VA and mesopic HC-VA. CONCLUSIONS: In healthy eyes, the larger the halo size induced by a given glare source, the greater the forward scatter (straylight) and worse the mesopic LC-VA. Halo size seems to be independent of photopic HC-VA or LC-VA and mesopic HC-VA. PMID- 24814965 TI - Evaluation of choroidal thickness among patients with oculocutaneous albinism. PMID- 24814966 TI - Comparison between an in-house method and the ViroSeqTM method for determining mutations for drug resistance in the HIV-1 CRF01_AE subtype circulating in China. AB - Commercial products for determining the drug-resistance mutations of HIV-1 are expensive and usually focus on a particular HIV-1 subtype. In this study, a more cost-effective in-house method was compared side-by-side with the ViroSeqTM Genotyping System 2.0 for determining resistant mutations in China's most prevalent subtype, CRF01_AE. Plasma samples were obtained from 205 patients infected with HIV-1, and subtypes were verified using the Stanford calibrated population resistance tool. The capacity for determining positive samples was not significantly different between the in-house (93.8%) and ViroSeqTM (96.5%) methods. For the clade of subtype CRF01_AE in particular, complete concordance between the methods was observed for the protease and reverse-transcriptase regions of the HIV-1 pol gene, and concordance for overall DRRMs and HLDRMs was 99.5% and 100%, respectively. Although 51 discordant mutations were found, further analysis verified that most of mutations had minimal impact on antiviral drugs. Excellent overall concordance (97.7%) was achieved for the resistance reports between the two methods for CRF01_AE. Thus, the performance and effectiveness of determining resistance-associated mutations were nearly equivalent between the cost-effective in-house method and the ViroSeqTM system, the greatly potential application of the in-house method in China for many patients infected with HIV-1 located in resource-limited regions. PMID- 24814967 TI - An optimized expression vector for improving the yield of dengue virus-like particles from transfected insect cells. AB - Recombinant virus-like particles (rVLPs) of flaviviruses are non-infectious particles released from cells expressing the envelope glycoproteins prM and E. Dengue virus rVLPs are recognized as a potential vaccine candidate, but large scale production of these particles is hindered by low yields and the occurrence of cytopathic effects. In an approach to improve the yield of rVLPs from transfected insect cells, several components of a dengue serotype 2 virus prM+E expression cassette were modified and the effect of these modifications was assessed during transient expression. Enhancement of extracellular rVLP levels by simultaneous substitutions of the prM signal peptide and the stem-anchor region of E with homologous cellular and viral counterparts, respectively, was further augmented by codon optimization. Extensive formation of multinucleated cells following transfection with the codon-optimized expression cassette was abrogated by introducing an E fusion loop mutation. This mutation also helped restore the extracellular E levels affected negatively by alteration of a charged residue at the pr-M junction, which was intended to promote maturation of rVLPs during export. Optimized expression cassettes generated in this multiple add-on modification approach should be useful in the generation of stably expressing clones and production of dengue virus rVLPs for immunogenicity studies. PMID- 24814968 TI - Sustained high plasma plasminogen activator inhibitor-1 levels are associated with severity and mortality in septic patients. AB - BACKGROUND: Higher plasma plasminogen activator inhibitor-1 (PAI-1) levels have been reported in septic patients. However, some questions remain unanswered, such as whether there is an association between plasma PAI-1 levels and sepsis severity and mortality, and inflammation state during the first week. METHODS: Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units of 260 patients with severe sepsis. Circulating levels of PAI-1 and tumour necrosis factor (TNF)-alpha were measured at day 1, 4 and 8. End point was 30-day mortality. RESULTS: Nonsurviving septic patients (n=89) presented higher PAI-1 levels than surviving (n=171) at day 1 (58.4 (33.3-83.8) vs 36.5 (21.1-62.5) ng/mL; p<0.001), 4 (34.0 (14.7-53.3) vs 16.2 (10.2-27.4) ng/mL; p<0.001) and 8 (30.6 (16.2-47.8) vs 18.9 (10.4-29.5) ng/mL; p=0.004). We found a positive correlation of PAI-1 levels with SOFA, lactic acid, aPTT, INR and TNF-alpha, and negative with platelet count at day 1, 4 and 8. Logistic regression analyses showed that PAI-1 levels at day 1 (p<0.001), 4 (p<0.001) and 8 (p=0.001) were associated with 30-day mortality. On ROC curve analysis to predict 30- day survival, the area under the curve of PAI-1 levels at day 1, 4 and 8 were 0.65 (95% CI=0.58-0.72; p<0.001), 0.69 (95% CI=0.60-0.78; p<0.001) and 0.65 (95% CI=0.54-0.75; p=0.005) respectively. CONCLUSIONS: The most interesting findings of our study, to our knowledge the largest series reporting PAI-1 levels during follow-up in septic patients, were that plasma PAI-1 levels during the first week were associated with inflammation, severity and mortality. PMID- 24814969 TI - Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII. AB - INTRODUCTION: rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII SingleChain in comparison with full-length recombinant FVIII. MATERIALS AND METHODS: Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate((r))) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl3 induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200-250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice. RESULTS: rVIII-SingleChain displayed a high affinity for von Willebrand factor (KD=44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl3 induced arterial occlusion model. CONCLUSIONS: rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models. PMID- 24814970 TI - A comparative study of conventional versus new, magnesium-poor Vacutainer(r) Sodium Citrate blood collection tubes for determination of prothrombin time and INR. AB - INTRODUCTION: Conventional Vacutainer(r) Sodium Citrate blood collection tubes contain a relatively high concentration of contaminating magnesium ions, which may result in shortening of the prothrombin time (PT) and the International Normalized Ratio (INR). Recently the manufacturer of Vacutainer(r) Sodium Citrate tubes introduced new tubes with a magnesium-poor stopper. The magnesium concentration in the new low-Mg tubes is significantly lower than that in the conventional plastic tubes. The purpose of the present study was to compare PT and INR determined in specimens drawn with the new tubes to those drawn with the conventional tubes. MATERIALS AND METHODS: Venous blood specimens were collected from 22 healthy persons and 65 patients treated with vitamin K-antagonists using conventional Vacutainer(r) Sodium Citrate tubes and new, low-Mg Vacutainer(r) tubes. PT and INR were determined with four thromboplastin reagents, i.e., three brands of recombinant human tissue factor and one brand of combined rabbit brain reagent. Magnesium concentrations were determined in the citrate plasmas with a colorimetric method. RESULTS: The differences in PT, INR and International Sensitivity Index (ISI) between the two tubes were significant when using three recombinant human thromboplastin reagents, but were not significant when using the rabbit thromboplastin. The PT and INR differences between the tubes correlated with the magnesium concentration differences (P<0.001). The INR bias between the four reagents was greater for specimens drawn with conventional tubes than the INR bias for specimens drawn with the new tubes. CONCLUSION: Agreement of INR between reagents is improved by using magnesium-poor tubes. PMID- 24814971 TI - The role of thrombolysis for patients with hemodynamically stable acute pulmonary embolism. PMID- 24814972 TI - Incidence and predictors of new-onset atrial fibrillation in noncardiac intensive care unit patients. AB - BACKGROUND: Atrial fibrillation (AF) is thought to be a relatively common arrhythmia in the setting of noncardiac intensive care unit (ICU). However, data concerning AF deriving from such populations are scarce. In addition, it is unclear which of the wide spectrum of AF predictors are relevant to the ICU setting. OBJECTIVES: The aim of our study was to evaluate the incidence of new onset AF and investigate the factors that contribute to its occurrence in ICU patients. METHODS: We prospectively studied all patients admitted to our ICU during a 1-year period. Patients admitted for brief postoperative monitoring and patients with chronic or intermittent AF and AF present upon admission were excluded. A number of conditions incriminated as AF risk factors or "triggers" from demographics, medical history, present disease, and cardiac echocardiography as well as circumstances of AF onset were recorded. RESULTS: The study population consisted of 133 patients (90 males). Atrial fibrillation was observed in 15% of them. Age older than 65 years (P=.001), arterial hypertension (P=.03), systemic inflammatory response syndrome (P<.001), sepsis (P=.001), left atrial dilatation (P=.01), and diastolic dysfunction (P=.04) were significantly associated with the occurrence of AF. By multivariate analysis, it was demonstrated that only older than 65 years (odds ratio, 7.0; 95% confidence interval, 2.0-24.6; P=.003) and sepsis (odds ratio, 6.5; 95% confidence interval, 2.0-21.1; P=.002) independently predict new-onset AF. Patients manifesting AF were frequently hypovolemic (30%) and had electrolyte disorders (40%) as well as elevated and rising serum C reactive protein (70%). CONCLUSION: A significant fraction of ICU patients manifest AF. The predictors of interest for the ICU patients might be considerably different than those of the general population and other subgroups with systemic inflammation possibly having a pivotal role. PMID- 24814973 TI - The effect of high-frequency oscillatory ventilation combined with tracheal gas insufflation on extravascular lung water in patients with acute respiratory distress syndrome: a randomized, crossover, physiologic study. AB - PURPOSE: High-frequency oscillation combined with tracheal gas insufflation (HFO TGI) improves oxygenation in patients with acute respiratory distress syndrome (ARDS). There are limited physiologic data regarding the effects of HFO-TGI on hemodynamics and pulmonary edema during ARDS. The aim of this study was to investigate the effect of HFO-TGI on extravascular lung water (EVLW). MATERIALS AND METHODS: We conducted a prospective, randomized, crossover study. Consecutive eligible patients with ARDS received sessions of conventional mechanical ventilation with recruitment maneuvers (RMs), followed by HFO-TGI with RMs, or vice versa. Each ventilatory technique was administered for 8 hours. The order of administration was randomly assigned. Arterial/central venous blood gas analysis and measurement of hemodynamic parameters and EVLW were performed at baseline and after each 8-hour period using the single-indicator thermodilution technique. RESULTS: Twelve patients received 32 sessions. Pao2/fraction of inspired oxygen and respiratory system compliance were higher (P<.001 for both), whereas extravascular lung water index to predicted body weight and oxygenation index were lower (P=.021 and .029, respectively) in HFO-TGI compared with conventional mechanical ventilation. There was a significant correlation between Pao2/fraction of inspired oxygen improvement and extravascular lung water index drop during HFO TGI (Rs=-0.452, P=.009). CONCLUSIONS: High-frequency oscillation combined with tracheal gas insufflation improves gas exchange and lung mechanics in ARDS and potentially attenuates EVLW accumulation. PMID- 24814974 TI - Endovascular treatment of severe gastrointestinal bleeding due to a right hepatic artery aneurysm caused by erosion of an endoscopic biliary prosthesis. PMID- 24814975 TI - What is the definition of intraoperative hypotension in dogs? Results from a survey of diplomates of the ACVAA and ECVAA. AB - OBJECTIVE: Determine arterial blood pressure range that diplomates of the American College of Veterinary Anesthesia and Analgesia (ACVAA) and European College of Veterinary Anaesthesia and Analgesia (ECVAA) use to define intraoperative hypotension in dogs and identify the threshold values used for intervention. STUDY DESIGN: Survey of veterinary anesthesia specialists. POPULATION: Diplomates of the ACVAA and ECVAA. METHODS: ACVAA and ECVAA diplomates (n = 313) were invited to participate in an Internet-based survey regarding anesthetized healthy dogs undergoing two types of procedures (diagnostic or surgical). RESULTS: There were 151 respondents to the survey; 70.2% were ACVAA diplomates and 29.8% were ECVAA diplomates. The majority of the respondents (70.9%) worked in academia while the others were in private practice (19.2%), or research, diagnostic or pharmaceutical fields (9.9%). Hypotension was defined (mean +/- SD) by the respondents as systolic arterial blood pressure (SAP) <87 +/- 8 mmHg for surgical cases and <87 +/- 6 mmHg for diagnostic cases, or mean arterial pressure (MAP) <62 +/- 4 mmHg for both types of cases. Arterial pressures reported to prompt treatment were SAP 85 +/- 13 mmHg or MAP 61 +/- 4 mmHg in surgical cases, and SAP 84 +/- 11 mmHg or MAP 63 +/- 8 mmHg in diagnostic cases. CONCLUSIONS AND CLINICAL RELEVANCE: There was agreement between ACVAA and ECVAA diplomates on the definition of intraoperative hypotension in dogs during anesthesia. The blood pressures used to define hypotension were similar to the pressures that would prompt diplomates to start treatment. Readers could infer that diplomates define hypotension as a clinical condition that requires treatment at the time of diagnosis. PMID- 24814976 TI - Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study. AB - Chagas' disease, also known as American trypanosomiasis, is a lethal, chronic disease that currently affects more than 10 million people in Central and South America. The trans-sialidase from Trypanosoma cruzi (T. cruzi, TcTS) is a crucial enzyme for the survival of this parasite: sialic acids from the host are transferred to the cell surface glycoproteins of the trypanosome, thereby evading the host's immune system. On the other hand, the sialidase of T. rangeli (TrSA), which shares 70% sequence identity with TcTS, is a strict hydrolase and shows no trans-sialidase activity. Therefore, TcTS and TrSA represent an excellent framework to understand how different catalytic activities can be achieved with extremely similar structures. By means of combined quantum mechanics-molecular mechanics (QM/MM, SCC-DFTB/Amberff99SB) calculations and umbrella sampling simulations, we investigated the hydrolysis mechanisms of TcTS and TrSA and computed the free energy profiles of these reactions. The results, together with our previous computational investigations, are able to explain the catalytic mechanism of sialidases and describe how subtle differences in the active site make TrSA a strict hydrolase and TcTS a more efficient trans-sialidase. PMID- 24814978 TI - Longitudinal left ventricular strain impairment in type 1 diabetes children and adolescents: a 2D speckle strain imaging study. AB - AIM: Type 1 diabetes (T1D) involves complex metabolic disturbances in cardiomyocytes leading to morphological and functional abnormalities of the myocardium. The relationship between T1D and cardiac structure and function in children is not well established. Our study investigated whether T1D is associated with early subclinical myocardial disturbances in children and adolescents, and whether the state of metabolic control and diabetes duration are influential factors. METHODS: Standard echocardiography, tissue Doppler imaging (TDI) and two-dimensional (2D) strain imaging were prospectively performed in 100 T1D children (age: 11.3 +/- 3.6 years, 52 boys) and compared with 79 controls. RESULTS: The diabetic and control children were comparable with respect to age, gender, heart rate and blood pressure. There were no significant differences between the two groups in left ventricular (LV) ejection fraction, LV remodelling and TDI parameters. Conventional mitral Doppler demonstrated significantly fewer diastolic filling abnormalities with an early filling wave in the diabetes group. Global longitudinal strain (GLS) was also significantly lower in the T1D children, while circumferential strain and radial strain did not differ. GLS correlated with HbA1c (r=0.52; P<0.01), but there was no correlation with diabetes duration. CONCLUSION: Our results suggest that LV longitudinal myocardial deformation is decreased in young patients with T1D, and glycaemic control may be the main risk factor for these changes. Further follow-up is now necessary to precisely determine the clinical significance of these myocardial changes detected by 2D strain imaging in T1D children. PMID- 24814977 TI - Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice. AB - Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, FA elongase 5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic TGs and endoplasmic reticulum stress markers (X-box binding protein 1 and cAMP-dependent transcription factor 6alpha) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for beta-oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identification 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fibroblast growth factor 21), but not other cytochrome P450 4A10 (CYP4A10), PPAR-target genes. FA products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPARbeta-dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPARbeta agonist (GW0742) decreased (14)C-18:2,n-6 in TGs but did not affect beta oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPARbeta activity, ATGL expression, and TG catabolism, but not FA oxidation. PMID- 24814979 TI - Relationship between expression of human gingival beta-defensins and levels of periodontopathogens in subgingival plaque. AB - BACKGROUND AND OBJECTIVE: Human beta-defensins (hBDs) are a group of antimicrobial peptides important in epithelial innate immunity, and their differential expression is associated with periodontal diseases. The aim of this study was to explore relationships among hBDs, total subgingival bacteria and periodontopathogens in healthy subjects and in patients with chronic periodontitis. MATERIAL AND METHODS: The periodontal clinical parameters of 29 healthy subjects and 25 patients with chronic periodontitis were recorded. The relative expression of hBD1, hBD2 and hBD3 genes in gingival biopsies was measured using real-time PCR. The numbers of total bacteria and of Treponema denticola, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum and Tannerella forsythia in subgingival plaque were quantified by real-time PCR. Data were analyzed using the Mann-Whitney U-test and Spearman's rank correlation test. RESULTS: No significant differences in expression of the hBD genes were found between the group of healthy subjects and the group of patients with chronic periodontitis. Total bacteria and T. denticola were detected in all participants. F. nucleatum and T. forsythia were detected in all patients with chronic periodontitis and in 86.21% and 51.72%, respectively, of healthy volunteers. P. gingivalis and A. actinomycetemcomitans were detected in 24.14% and 17.24%, respectively, of the healthy group and in 84.00% and 12.00%, respectively, of the chronic periodontitis group. The prevalence of all bacteria, except A. actinomycetemcomitans, was significantly higher in the group of patients with chronic periodontitis than in the group of healthy subjects (p < 0.05). A significant, negative correlation was observed between total bacteria and hBD-2 (r = -0.384, p = 0.011). Upon analyzing the data in different groups, total bacteria and hBD-2 were significantly correlated (r = -0.492, p = 0.026) only in the group of healthy subjects. CONCLUSION: The negative correlations between hBD-2 and total bacteria, especially in the group of healthy subjects, indicate that hBDs may play an important role by limiting an increase of bacterial load at the initial stage of periodontitis. PMID- 24814980 TI - Sexual orientation change efforts through psychotherapy for LGBQ individuals affiliated with the Church of Jesus Christ of Latter-day Saints. AB - This study reports the results of a comprehensive online survey of 1,612 current or former members of the Church of Jesus Christ of Latter-day Saints, many of whom engaged in psychotherapy to cope with (i.e., understand, accept, or change) their same-sex attractions. Data obtained from written and quantitative responses showed that therapy was initiated over a very wide age range and continued for many years. However, counseling was largely ineffective; less than 4% reported any modification of core same-sex erotic attraction. Moreover, 42% reported that their change-oriented therapy was not at all effective, and 37% found it to be moderately to severely harmful. In contrast, affirming psychotherapeutic strategies were often found to be beneficial in reducing depression, increasing self-esteem, and improving family and other relationships. Results suggest that the very low likelihood of a modification of sexual orientation and the ambiguous nature of any such change should be important considerations for highly religious sexual minority individuals considering reorientation therapy. PMID- 24814981 TI - Regulation of SIRT2-dependent alpha-tubulin deacetylation by cellular NAD levels. AB - Acetylation of alpha-tubulin on lysine 40 is one of the major posttranslational modifications of microtubules. The acetylation reaction is catalyzed by alpha tubulin N-acetyltransferase and the modification can be reversed by either the NAD-independent class II histone deacetylase HDAC6 or the NAD-dependent deacetylase SIRT2. In this study, we assessed to what extent cellular NAD levels are involved in the regulation of the alpha-tubulin acetylation state. Cells were subjected to different treatments known to influence cellular NAD content. In response to NAD depletion caused by inhibition of NAD synthesis from nicotinamide, alpha-tubulin was hyperacetylated. Under these conditions, the normal tubulin acetylation state could be restored by providing the cells with alternative NAD precursors. Likewise, decreasing the rate of endogenous NAD consumption using an inhibitor of poly-ADP-ribosylation also stabilized the acetylation of alpha-tubulin. Conversely, the level of acetylated alpha-tubulin decreased when NAD synthesis was enhanced by overexpression of an NAD biosynthetic enzyme. Combined, these results show that the tubulin acetylation status is reciprocally regulated by cellular NAD levels. Furthermore, we provide evidence confirming that the NAD-dependent regulation of tubulin acetylation is mediated by SIRT2. PMID- 24814982 TI - Simple hepatic cyst causing inferior vena cava thrombus. AB - INTRODUCTION: Thrombosis of the inferior vena cava (IVC) is governed by Virchow's triad of stasis of blood flow, endothelial damage and hypercoagulability. Causes may be secondary to malignancy, congenital anomalies or other infrequent events such as external compression. We present a case of external compression of the IVC leading to extensive thrombus burden secondary to a benign hepatic cyst. PRESENTATION OF CASE: A 72 year old African American female presented to the emergency department with new onset shortness of breath, right lower extremity weakness and swelling. CT imaging demonstrated multiple hepatic cysts compressing the IVC, leading to extensive clot burden. Treatment with heparin drip was initiated without resolution of her symptoms. Transcatheter mechanical thrombectomy and tPA infusion was performed. After 24h, swelling and weakness were nearly resolved. The patient was bridged to therapeutic low molecular weight heparin in preparation for surgery. DISCUSSION: Management of IVC thrombosis has typically been with a heparin drip and transition to oral anticoagulants. Thrombolysis has been shown to promote complete clot lysis more often than compared to standard anticoagulant therapy. In addition, venous patency was better maintained. CONCLUSION: We feel that the added benefit of short term effects of improved venous patency and long term benefits of less post thrombotic syndrome, catheter based tPA administration and mechanical thrombectomy for thrombus offers an adjuvant treatment in the setting of large clot burden refractory to standard treatment. PMID- 24814983 TI - Chronic expanding hematoma, ruptured through the skin 53 years after buttock contusion. AB - INTRODUCTION: Chronic expanding hematoma is a relatively rare complication of soft tissue trauma and often clinically mistaken for a malignant neoplasm. PRESENTATION OF CASE: A 71-year-old female presented with a chronic expanding hematoma that ruptured through the buttock skin 53 years after the original contusion. The diagnosis of CEH was made based on the results of the biopsy, physical examination, and CT. The tumor was completely excised, and the defect was covered with a rhomboid flap. DISCUSSION: There are no reports of lesions rupturing through the skin. Almost all instances of chronic expanding hematoma previously reported in the English literature have a history ranging from 1 month to 20 years. There is a report of a thorax CEH that ruptured into the lung parenchyma after 24 years, so it is conceivable that other subcutaneous CEHs could break through the skin several decades after their inception. CONCLUSION: Once this lesion has ruptured, its differentiation from other entities becomes more complicated. PMID- 24814984 TI - Successful obturator nerve repairing: Intraoperative sural nerve graft harvesting in endometrium cancer patient. AB - INTRODUCTION: Intraoperative injury of obturator nerve is a rare complication of gynecologic surgeries, it has been reported especially in patients with endometriosis and genitourinary malignancies. Gynecologic patients undergoing open lymphadenectomy are at increased risk of obturator nerve injury. PRESENTATION OF CASE: A 60-year-old woman with FIGO stage II Grade II endometrial adenocarcinoma underwent bilateral pelvic paraaortic lymphadenectomy. During right obturator lymph node dissection, the right obturator nerve was inadvertently transected with Harmonic scalpel sealing system. The graft was used to anastomose epyneurium of distal segment of obturator nerve to its counterpart in the proximal segment with 10-0 prolen suture. DISCUSSION: In case of iatrogenic nerve transection, microsurgical end to end tension-free coaptation is advocated. In case of the obturator nerve is fixed and because of the thermal injury end to end alignment can not be achieved, nerve grafting is necessary. CONCLUSION: According to our knowledge, successful immediate grafting of iatrogenically damaged obturator nerve during pelvic lymphadenectomy in our patient is the third report of such a case, but also it has a unique feature of being the first obturator nerve repairing case after dissected with tissue sealing system which causes large sealed area that does not make it possible to make end-to-end anastomosis without nerve harvesting. PMID- 24814986 TI - Infected gluteal hydatid cyst. PMID- 24814985 TI - Xenobiotic transporter expression along the male genital tract. AB - The male genital tract plays an important role in protecting sperm by forming a distinct compartment separate from the body which limits exposure to potentially toxic substrates. Transporters along this tract can influence the distribution of xenobiotics into the male genital tract through efflux back into the blood or facilitating the accumulation of toxicants. The aim of this study was to quantitatively determine the constitutive mRNA expression of 30 xenobiotic transporters in caput and cauda regions of the epididymis, vas deferens, prostate, and seminal vesicles from adult Sprague-Dawley rats. The epididymis was found to express at least moderate levels of 18 transporters, vas deferens 15, seminal vesicles 23, and prostate 18. Constitutive expression of these xenobiotic transporters in the male genital tract may provide insight into the xenobiotics that can potentially be transported into these tissues and may provide the molecular mechanism for site specific toxicity of select agents. PMID- 24814987 TI - Therapeutic flexible endoscopy after bariatric surgery: a solution for complex clinical scenarios. PMID- 24814988 TI - Application of system thinking concepts in health system strengthening in low income settings: a proposed conceptual framework for the evaluation of a complex health system intervention: the case of the BHOMA intervention in Zambia. AB - BACKGROUND: The current drive to strengthen health systems provides an opportunity to develop new strategies that will enable countries to achieve targets for millennium development goals. In this paper, we present a proposed framework for evaluating a new health system strengthening intervention in Zambia known as Better Health Outcomes through Mentoring and Assessment. APPROACH: We briefly describe the intervention design and focus on the proposed evaluation approach through the lens of systems thinking. DISCUSSION: In this paper, we present a proposed framework to evaluate a complex health system intervention applying systems thinking concepts. We hope that lessons learnt from this process will help to adapt the intervention and limit unintended negative consequences while promoting positive effects. Emphasis will be paid to interaction and interdependence between health system building blocks, context and the community. PMID- 24814989 TI - Heart Rythm Society expert consensus statement on electrophysiology laboratory standards: process, protocols, equipment, personnel, and safety. PMID- 24814990 TI - Emerging novel concept of chaperone therapies for protein misfolding diseases. AB - Chaperone therapy is a newly developed molecular therapeutic approach to protein misfolding diseases. Among them we found unstable mutant enzyme proteins in a few lysosomal diseases, resulting in rapid intracellular degradation and loss of function. Active-site binding low molecular competitive inhibitors (chemical chaperones) paradoxically stabilized and enhanced the enzyme activity in somatic cells by correction of the misfolding of enzyme protein. They reached the brain through the blood-brain barrier after oral administration, and corrected pathophysiology of the disease. In addition to these inhibitory chaperones, non competitive chaperones without inhibitory bioactivity are being developed. Furthermore molecular chaperone therapy utilizing the heat shock protein and other chaperone proteins induced by small molecules has been experimentally tried to handle abnormally accumulated proteins as a new approach particularly to neurodegenerative diseases. These three types of chaperones are promising candidates for various types of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases. PMID- 24814991 TI - Functional zonation of the rat adrenal cortex: the development and maintenance. AB - The adrenal cortex of mammals consists of three concentric zones, i.e., the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), which secrete mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. In 1994, we identified immunohistochemically a new zone between zG and zF of the rat adrenal gland. The zone appeared to be devoid of any significant endocrine functions specific to adrenocortical zones, therefore, we designated the zone as "undifferentiated cell zone (zU)". Further, BrdU (5-bromo-2'-deoxyuridine) incorporating cells (cells in S-phase) were concentrated at the outer region and the inner region of zU, and these cells proliferated and migrated bidirectionally: toward zG centrifugally and toward zF centripetally. We proposed that cells in and around zU are stem/progenitor cells of the rat adrenal cortex, maintaining functional zonation of the adrenal cortex. The view is consistent with observations reported recently that Sonic hedgehog (Shh), an important factor in embryonic development and adult stem cell maintenance, exists in zU of the rat adrenal gland and the Shh-containing cells seem to migrate bidirectionally. PMID- 24814992 TI - In vitro fertilization in Japan - early days of in vitro fertilization and embryo transfer and future prospects for assisted reproductive technology. AB - Assisted reproductive technology (ART) such as in vitro fertilization (IVF) and embryo transfer (ET) has been essential in the treatment of infertility. The world's first IVF-ET baby was born in 1978 based on the technique developed by Dr. Robert Edwards and Dr. Patrick Steptoe. In Japan, the first IVF-ET birth was reported in 1983 by Prof. Masakuni Suzuki at Tohoku University School of Medicine. IVF-ET is a procedure used to achieve pregnancy that consists of extracting oocytes from an infertile woman, fertilizing them in vitro, and transferring fertilized eggs into the patient's uterine cavity (Fig. 1). Since the first report of successful IVF-ET, numerous techniques related to ART, such as cryopreservation of oocytes and embryos, gamete intrafallopian transfer (GIFT), and microinsemination, have been developed and refined (Table 1). Herein we describe the history of basic research in IVF-ET that led to human applications, how the birth of the first IVF-ET baby was achieved in Japan, the current status of ART in Japan, issues related to ART, and future prospects for ART. PMID- 24814993 TI - A LC/MS/MS micro-method for human plasma quantification of vemurafenib. Application to treated melanoma patients. AB - As previously shown for imatinib, therapeutic drug monitoring (TDM) of vemurafenib should be important to measure efficacy of the treatment in melanoma patient. A micro-method based on liquid chromatography coupled to triple quadrupole spectrometry detection using only 10MUL of plasma was validated. A simple protein precipitation with water/acetonitrile was used after addition of vemurafenib-(13)C6 as internal standard. The ion transitions used to monitor analytes were m/z 490.2->m/z 255.2 and m/z 383.3 for vemurafenib and m/z 496.2 >m/z 261.2 and m/z 389.3 for vemurafenib-(13)C6. Calibration curves were linear in the 0.1-100MUg/mL range, the limits of detection and quantification being 0.01MUg/mL and 0.1MUg/mL, respectively. The intra- and inter-assay precisions evaluated at 0.1, 0.3, 15, 45 and 80MUg/mL were lower than 13.3% and the accuracies were in the 93.7-105.8 range. No matrix effect was observed. At steady state, the results of TDM of vemurafenib in 26 patients treated by 960mg twice daily (n=60 samples), 13 patients with 740mg twice daily (n=13) and one with 1200mg twice daily (n=3) showed a great variability of the pharmacokinetics of this compound. PMID- 24814994 TI - NIR spectroscopy for the in-line monitoring of a multicomponent formulation during the entire freeze-drying process. AB - Freeze drying is a complex, time consuming and thus expensive process, hence creating a need for understanding the material behaviour in the process environment and for process optimization. Near-infrared (NIR) spectroscopy offers the opportunity to monitor physicochemical changes of the formulation during freeze-drying. The aim of this work was to examine whether NIR spectroscopy allows in-line monitoring of all components during the entire freeze-drying process of a multi-component pharmaceutical formulation (a solution of fenofibrate and mannitol in a mixture of tertiary-butyl alcohol, and water). To extract useful information of all components in the formulation from the large multivariate data-sets obtained during in-line spectroscopic monitoring, several spectral pre-processing techniques and spectral data analysis techniques such as the mean of selected wavenumbers (Mws), the correlation coefficient (CorrCoef) and principal component analysis (PCA) have been evaluated and compared. To find out whether these chemometric techniques are also able to differentiate between changes in the process settings influencing the freeze-drying process of the formulation, freeze-drying processes were performed at four different conditions. Results demonstrated that in-line measurements using NIR spectroscopy were possible in an icy environment and that a further process understanding could be obtained. Data-analysis revealed the crystallization behaviour of each of the four components. In addition, using the three pre-processing techniques allowed observe the sublimation of the solvents. Mws and CorrCoef have proven to be adequate methods for monitoring the main physicochemical changes of product during the processes; this affirmation was confirmed by observing the outputs of PCA for entire processes. PMID- 24814995 TI - The effect of hyperglycemia on the pharmacokinetics of valproic acid studied by high-performance liquid chromatography with electrochemical detection. AB - The effects of hyperglycemia on the pharmacokinetics of valproic acid (VPA) were examined by time-concentration profiles of plasma VPA accompanied with blood glucose (BG) changing. In addition, time-concentration profiles of plasma free fatty acids (FFAs) were also obtained to examine the interaction between VPA and FFAs in vivo. For the experiments in vivo, normal rats, given multiple doses of maltose orally, and diabetic rats, which were made to maintain hyperglycemia, were used. Plasma VPA and FFA were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) systems based on the reduction of quinone for the selective determination of acids, respectively. BG was determined by pocket-size glucose meter. The maximum plasma concentrations (Cmax) of VPA in normal rats given multiple doses of maltose orally and in diabetic rats were remarkably decreased in comparison with those in the control rats. From the present study, it was shown that the metabolism of plasma VPA is accelerated under hyperglycemia. Moreover, we also found that VPA was preferentially metabolized in comparison with the plasma FFA in vivo. PMID- 24814996 TI - Efficient purification of active bufadienolides by a class separation method based on hydrophilic solid-phase extraction and reversed-phase high performance liquid chromatography. AB - Traditional Chinese medicines (TCMs) have played a significant role in the process of discovering natural bioactive compounds, especially in anticancer therapeutics. However, the components of TCMs are complex mixtures with wide variation in polarity and content, which leads to inefficiency in the process of active compound discovery from TCMs. In this paper, the popular strategy of utilizing "pre-fractionated natural product libraries" has been improved by a new class separation approach to accelerate the process. As an example, the skin of Bufo bufo gargarizans Cantor, a well-known TCM, mainly contains two distinct bufadienolide classes: amino acid-conjugated bufadienolides (AACBs) and free form bufadienolides (AAUBs). We utilized hydrophilic interaction liquid chromatography solid-phase extraction (HILIC-SPE) to resolve the two types of bufadienolides, which co-eluted on C18 columns. By this strategy, twelve bufadienolides of the two types were purified via prep-HPLC from one active fraction, and eight of them were identified by (1)H NMR and (13)C NMR. These results indicated that the class separation method not only overcame the limited orthogonality in a 2D-RPLC*RPLC system but also accelerated the process of active compound discovery. PMID- 24814997 TI - Using a content analysis to identify study eligibility criteria concepts in cancer nursing research. AB - The aims of this study were to (1) identify and categorize study eligibility criteria concepts used in cancer nursing randomized controlled trials and (2) determine the extent to which a previously identified set of study eligibility criteria, based primarily on medical randomized controlled trials, were represented in cancer nursing randomized controlled trials. A total of 145 articles of cancer nursing randomized controlled trials indexed in PubMed or Cumulative Index to Nursing and Allied Health Literature and published in English from 1986 to 2010 were screened, and 114 were eligible. Directed content analysis was conducted until data saturation was achieved. Forty-three concepts categorized into eight domains were extracted from 49 articles published in 27 different journals. Most of the concepts identified were related to health status, treatment, and demographics domains. Although many concepts matched to the previously identified study eligibility concepts based on medical research, new concepts may need to be added to fully represent cancer nursing research. This study provides a solid foundation for future study of mapping the concepts to existing standardized terminologies to identify which systems can be adopted. Nursing researchers can use these eligibility criteria concepts as a guideline in structuring the eligibility criteria for their studies. PMID- 24814998 TI - The feasibility of using technology to enhance the transition of palliative care for rural patients. AB - Palliative care services for patients with life-limiting conditions enhance their quality of life. Most palliative care services, however, are located in hospitals with limited transitional care for patients who live in distant locations. The long-term goal of this program of research is to use existing technology for virtual visits to provide transitional care for patients initially hospitalized in an urban setting by a nurse practitioner located closer to patients' homes in distant, rural settings. The purpose of this proof-of-concept study was to determine the resources needed to use the system (efficiency) and the quality of the audio and visual components (effectiveness) to conduct virtual visits between a clinician at an academic center and community-dwelling adults living in rural locations. Guided by the Technology Acceptance Model, a mixed-methods field design was used. Because of the burden of testing technology with patients with life-limiting conditions, the sample included eight healthy adults. Participant satisfaction and perceptions of the ease of using the technology were also measured. Virtual visits were conducted using a 3G-enabled Apple iPad, cellular phone data service, and a Web-based video conference service. Participants and clinicians perceived the technology as easy to use. Observations revealed the importance of the visual cues provided by the technology to enhance communication, engagement, and satisfaction. Findings from this study will inform a subsequent study of technology-enhanced transitional care with palliative care patients. PMID- 24814999 TI - Evidence-based use of electronic clinical tracking systems in advanced practice registered nurse education: an integrative review. AB - Over the past decade, the federal government has mandated healthcare providers to incorporate electronic health records into practice by 2015. This technological update in healthcare documentation has generated a need for advanced practice RN programs to incorporate information technology into education. The National Organization of Nurse Practitioner Faculties created core competencies to guide program standards for advanced practice RN education. One core competency is Technology and Information Literacy. Educational programs are moving toward the utilization of electronic clinical tracking systems to capture students' clinical encounter data. The purpose of this integrative review was to evaluate current research on advanced practice RN students' documentation of clinical encounters utilizing electronic clinical tracking systems to meet advanced practice RN curriculum outcome goals in information technology as defined by the National Organization of Nurse Practitioner Faculties. The state of the science depicts student' and faculty attitudes, preferences, opinions, and data collections of students' clinical encounters. Although electronic clinical tracking systems were utilized to track students' clinical encounters, these systems have not been evaluated for meeting information technology core competency standards. Educational programs are utilizing electronic clinical tracking systems with limited evidence-based literature evaluating the ability of these systems to meet the core competencies in advanced practice RN programs. PMID- 24815000 TI - 8-Substituted 2-alkynyl-N(9)-propargyladenines as A2A adenosine receptor antagonists. AB - Structure-activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N(9)-propargyladenine derivatives exhibited potent antagonist activity, with IC50 values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3 mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson's disease. PMID- 24815001 TI - Inorganic hole conductor-based lead halide perovskite solar cells with 12.4% conversion efficiency. AB - Organo-lead halide perovskites have attracted much attention for solar cell applications due to their unique optical and electrical properties. With either low-temperature solution processing or vacuum evaporation, the overall conversion efficiencies of perovskite solar cells with organic hole-transporting material were quickly improved to over 15% during the last 2 years. However, the organic hole-transporting materials used are normally quite expensive due to complicated synthetic procedure or high-purity requirement. Here, we demonstrate the application of an effective and cheap inorganic p-type hole-transporting material, copper thiocyanate, on lead halide perovskite-based devices. With low temperature solution-process deposition method, a power conversion efficiency of 12.4% was achieved under full sun illumination. This work represents a well defined cell configuration with optimized perovskite morphology by two times of lead iodide deposition, and opens the door for integration of a class of abundant and inexpensive material for photovoltaic application. PMID- 24815002 TI - Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo. AB - Osteosarcoma typically arises in tissues of mesenchymal origin, and is the most malignant bone tumor characterized by high local aggressiveness, with poor therapeutic outcome. Busulfan has been widely used to treat CML. So far, there are no reports on the therapeutic effect of busulfan on osteosarcoma. Here, we showed that busulfan dose-dependently reduced the cell viability and proliferation, and induced cell apoptosis, senescence, and reactive oxygen species levels in two osteosarcoma cell lines. Moreover, a series of loss-of function and gain-of-function experiments further indicated that busulfan may have its anti-osteosarcoma effect by upregulating the microRNA-200 (miR-200) family which subsequently downregulated its target genes ZEB1 and ZEB2. Furthermore, treatment with busulfan potentially inhibited the growth of implanted osteosarcoma in nude mice. Taken together, our data suggest that busulfan may have an anti-osteosarcoma effect through downregulating ZEB1 and ZEB2 through activating the miR-200 family, highlighting a possibility of using busulfan as a novel therapy for osteosarcoma. PMID- 24815003 TI - Low thermal conductivity in ultrathin carbon nanotube (2, 1). AB - Molecular dynamic simulations reveal that the ultrathin carbon nanotube (CNT) (2, 1) with a reconstructed structure exhibits a surprisingly low thermal conductivity, which is only ~16-30% of those in regular CNTs, e.g. CNT (2, 2) and (5, 5). Detailed lattice dynamic calculations suggest that the acoustic phonon modes greatly soften in CNT (2, 1) as compared to regular CNTs. Moreover, both phonon group velocities and phonon lifetimes strikingly decrease in CNT (2, 1), which result in the remarkable reduction of thermal conductivity. Besides, isotope doping and chemical functionalization enable the further reduction of thermal conductivity in CNT (2, 1). PMID- 24815004 TI - Resuscitation decisions for patients dying in the community: a qualitative interview study of general practitioner perspectives. AB - BACKGROUND: Most patients dying at home do not have a Do Not Attempt Cardiopulmonary Resuscitation decision and may have inappropriate attempts at resuscitation made when they die. AIM: To investigate how general practitioners think and feel about making and communicating Do Not Attempt Cardiopulmonary Resuscitation decisions for patients dying in the community. DESIGN: Qualitative study using semi-structured interviews with general practitioners. The interviews were recorded and analysed using interpretative phenomenological analysis. SETTING/PARTICIPANTS: Purposive sampling was used to recruit 10 general practitioners from urban and rural practices in Southern England and of various ages and experience. Interviews were carried out either in their home or in their practice. RESULTS: General practitioners often wait until the patient has clearly deteriorated to communicate and document the Do Not Attempt Cardiopulmonary Resuscitation decision. They consider the chance of success of a resuscitation attempt, quality of life, dignity and the patient's and family's wishes. General practitioners feel they should discuss the decision with the patient but have anxieties about this. They vary widely in how much they guide patients and families in decision-making. Timing and the avoidance of conflict are important. Teamwork provides support in decision-making. CONCLUSION: Resuscitation decisions are important in facilitating a peaceful death, but can be difficult for general practitioners to discuss. General practitioners might benefit from clearer guidance on when an attempt at resuscitation is unlikely to be successful, especially in non-malignant disease. Team discussions including Gold Standards Framework meetings can give confidence and support in making difficult end-of life decisions. PMID- 24815005 TI - Total synthesis of biselyngbyolide A. AB - Biselyngbyolide A is an 18-membered macrolide that exhibits significant biological activities such as growth-inhibitory activity and apoptosis inducing activity against cancer cells. In this study, the first total synthesis of biselyngbyolide A by using an intramolecular Stille coupling reaction as a key step is achieved. PMID- 24815006 TI - [Recomendations for clinical use of food enriched phytosterols/phytostanols handling hypercholesterolemia]. AB - Raised low-density lipoprotein cholesterol (LDLc) plasma concentration is a major risk factor for atherosclerotic cardiovascular disease. Despite international recommendations on hypercholesterolemia management the percentage of individuals with LDLc plasma concentration above goals according to their global cardiovascular risk remains high, and additional therapeutic strategies should be evaluated. Consumption of functional foods enriched with phytosterols (PSRs) and phytostanols (PSNs) reduces LDLc concentrations by 10% as average. Although recommended as part of any lipid-lowering diet in the first intervention step, PSRs/PSNs maintain their LDL reduction capacity when administered with lipid lowering drugs; therefore, they can be also considered in some cases as an adjuvant to drug therapy. In this document we summarise the latest evidence regarding the LDL reducing effects of PSR/PSN supplementation, alone or as an add on to hipolipemic drugs and the international recommendations of its clinical use. PMID- 24815007 TI - Extensive motor axonal misrouting after conservative treatment of obstetric brachial plexus lesions. AB - AIM: The aim of this cross-sectional study was to assess systematically motor function and motor misrouting in adults with conservatively treated obstetric brachial plexus lesion (OBPL). METHOD: Seventeen adults with OBPL (median age 38y; five males, 12 females) and 16 comparison participants (median age 26y; eight males, eight females) were investigated. Motor function in the group with OBPL was assessed through passive and active motion, muscle strength of the deltoid, biceps, and triceps muscles, and Mallet aggregate score and five subscores. Motor misrouting was quantified by electrically stimulating each of 10 arm muscles and recording activity from the other nine in response to this. Motor function and motor misrouting were statistically analysed using the Mann-Whitney U test and Spearman's correlation coefficient. RESULTS: Motor function testing showed excellent strength but poor functional Mallet scores. Participants with OBPL had significantly more motor misrouting than comparison participants (Mann Whitney U=31.5 [df=28], p<0.001, median difference=-4.00, 95% confidence interval [CI]=-7.00 to -1.00). Most misrouting was observed when stimulating the biceps (Mann-Whitney U=38.5 [df=31], p<0.001, median difference=-3.00, 95% CI -3.00 to 1.00), deltoid (Mann-Whitney U=68.5 [df=31], p=0.003, median difference=-1.0, 95% CI=-4.00 to 0.00 <0.001) and brachioradialis muscles (Mann-Whitney U=72.0 [df=31], p=0.002, median difference <0.001, 95% CI=-3.00 to 0.00 <0.001). There were no significant correlations between the presence of motor misrouting and impairment of motor function. INTERPRETATION: There is extensive motor misrouting in conservatively treated OBPL. The presence of this, in addition to motor functional impairment, suggests that motor misrouting should be further studied in OBPL. PMID- 24815008 TI - Oleanane triterpenes as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Camellia japonica. AB - Protein tyrosine phosphatase 1B (PTP1B) plays a key role in metabolic signaling, thereby making it an exciting drug target for type 2 diabetes and obesity. Besides, there is substantial evidence that shows its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. As part of our continuous research on PTP1B inhibitors from medicinal plants, four oleanane-type triterpenes were isolated from an EtOAc-soluble extract of fruit peels of Camellia japonica (Theaceae), together with 6 previously known compounds of this class. Their structures were determined on the basis of spectroscopic data analysis (UV, IR, (1)H and (13)CNMR, HMBC, HSQC, NOESY, and MS). All isolates were evaluated for their inhibitory effects on PTP1B, as well as their cytotoxic effects against human breast cancer cell lines MCF7, MCF7/ADR, and MDA-MB-231. Several compounds with OH-3 or/and COOH-28 functionalities showed strong PTP1B inhibitory activity (IC50 values ranging from 3.77+/-0.11 to 6.40+/-0.81 MUM) as well as significant cytotoxicity (IC50 values ranging from 0.51+/-0.05 to 13.55+/-1.44 MUM). PMID- 24815009 TI - PhDAHP1 is required for floral volatile benzenoid/phenylpropanoid biosynthesis in Petunia * hybrida cv 'Mitchell Diploid'. AB - Floral volatile benzenoid/phenylpropanoid (FVBP) biosynthesis consists of numerous enzymatic and regulatory processes. The initial enzymatic step bridging primary metabolism to secondary metabolism is the condensation of phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P) carried out via 3-DEOXY D-ARABINO-HEPTULOSONATE-7-PHOSPHATE (DAHP) synthase. Here, identified, cloned, localized, and functionally characterized were two DAHP synthases from the model plant species Petunia * hybrida cv 'Mitchell Diploid' (MD). Full-length transcript sequences for PhDAHP1 and PhDAHP2 were identified and cloned using cDNA SMART libraries constructed from pooled MD corolla and leaf total RNA. Predicted amino acid sequence of PhDAHP1 and PhDAHP2 proteins were 76% and 80% identical to AtDAHP1 and AtDAHP2 from Arabidopsis, respectively. PhDAHP1 transcript accumulated to relatively highest levels in petal limb and tube tissues, while PhDAHP2 accumulated to highest levels in leaf and stem tissues. Through floral development, PhDAHP1 transcript accumulated to highest levels during open flower stages, and PhDAHP2 transcript remained constitutive throughout. Radiolabeled PhDAHP1 and PhDAHP2 proteins localized to plastids, however, PhDAHP2 localization appeared less efficient. PhDAHP1 RNAi knockdown petunia lines were reduced in total FVBP emission compared to MD, while PhDAHP2 RNAi lines emitted 'wildtype' FVBP levels. These results demonstrate that PhDAHP1 is the principal DAHP synthase protein responsible for the coupling of metabolites from primary metabolism to secondary metabolism, and the ultimate biosynthesis of FVBPs in the MD flower. PMID- 24815010 TI - A case of vemurafenib-induced polyarhritis in a patient with melanoma: how to manage it? AB - Vemurafenib is an inhibitor of the BRAF V600E mutation which is associated with tumor responses in patients with metastatic melanoma. Although it is generally well tolerated, common side effects of vemurafenib have been reported. Arthralgia is one of the more common adverse event associated with vemurafenib. We herein report a 49-year-old woman diagnosed with metastatic melanoma harboring the BRAF V600E mutation with severe polyarthritis associated with vemurafenib after 7 days of treatment. Sonographic examination of affected joints revealed synovitis and the patient's articular symptoms were improved by analgesic and anti-inflammatory treatment, including corticosteroids. During therapy with selective BRAF inhibitors, arthritis represents a new adverse event that can require dose reduction. In case of this adverse event, treatment with anti-inflammatory drugs, such as ibuprofen and prednisone, should be initiated early to keep patients on treatment and to avoid drug discontinuation and tumor progression. PMID- 24815011 TI - 100th anniversary of Physiotherapy. PMID- 24815012 TI - Protective effects of rutin on liver injury induced by biliary obstruction in rats. AB - Rutin has been shown to possess beneficial health effects, including hepatoprotection. However, to date, it has not been demonstrated to have a hepatoprotective effect against cholestatic liver injury. This is the first report to show a protective effect of rutin on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily oral administration of rutin was started 1 week before injury and was maintained for 4 weeks. In comparison with the control group, the BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation, and oxidative stress. These pathophysiological changes were attenuated by rutin supplementation. Rutin alleviated BDL-induced transforming growth factor beta1 (TGF-beta1), interleukin-1beta, connective tissue growth factor, and collagen expression. The antifibrotic effect of rutin was accompanied by reductions in alpha-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity critical to the fibrogenic potential of TGF-beta1. Rutin attenuated BDL-induced oxidative stress, leukocyte accumulation, NF-kappaB activation, and proinflammatory cytokine production. Further studies demonstrated an inhibitory effect of rutin on the redox-sensitive intracellular signaling molecule extracellular signal-regulated kinase (ERK). Rutin also attenuated BDL-induced reduction in NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and AMP activated protein kinase (AMPK). Taken together, the beneficial effects of rutin were shown to be associated with antioxidative and anti-inflammatory effects as well as the downregulation of NF-kappaB and TGF-beta/Smad signaling, probably via interference of ERK activation and/or enhancement of Nrf2, HO-1, and AMPK activity. PMID- 24815013 TI - Systematic domain swaps of iterative, nonreducing polyketide synthases provide a mechanistic understanding and rationale for catalytic reprogramming. AB - Iterative, nonreducing polyketide synthases (NR-PKSs) are multidomain enzymes responsible for the construction of the core architecture of aromatic polyketide natural products in fungi. Engineering these enzymes for the production of non native metabolites has been a long-standing goal. We conducted a systematic survey of in vitro "domain swapped" NR-PKSs using an enzyme deconstruction approach. The NR-PKSs were dissected into mono- to multidomain fragments and recombined as noncognate pairs in vitro, reconstituting enzymatic activity. The enzymes used in this study produce aromatic polyketides that are representative of the four main chemical features set by the individual NR-PKS: starter unit selection, chain-length control, cyclization register control, and product release mechanism. We found that boundary conditions limit successful chemistry, which are dependent on a set of underlying enzymatic mechanisms. Crucial for successful redirection of catalysis, the rate of productive chemistry must outpace the rate of spontaneous derailment and thioesterase-mediated editing. Additionally, all of the domains in a noncognate system must interact efficiently if chemical redirection is to proceed. These observations refine and further substantiate current understanding of the mechanisms governing NR-PKS catalysis. PMID- 24815015 TI - Matricryptins and matrikines: biologically active fragments of the extracellular matrix. AB - Numerous extracellular proteins and glycosaminoglycans (GAGs) undergo limited enzymatic cleavage resulting in the release of fragments exerting biological activities, which are usually different from those of the full-length molecules. In this review, we define matrikines and matricryptins, which are bioactive fragments released from the extracellular matrix proteins, proteoglycans and GAGs and report their major biological activities. These fragments regulate a number of physiopathological processes including angiogenesis, cancer, fibrosis, inflammation, neurodegenerative diseases and wound healing. The challenges to translate these fragments from molecules biologically active in vitro and in experimental models to potential drugs are discussed in the last part of the review. PMID- 24815014 TI - Update on the 2012 guidelines for the management of pediatric traumatic brain injury - information for the anesthesiologist. AB - Traumatic brain injury (TBI) is a significant contributor to death and disability in children. Considering the prevalence of pediatric TBI, it is important for the clinician to be aware of evidence-based recommendations for the care of these patients. The first edition of the Guidelines for the Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents was published in 2003. The Guidelines were updated in 2012, with significant changes in the recommendations for hyperosmolar therapy, temperature control, hyperventilation, corticosteroids, glucose therapy, and seizure prophylaxis. Many of these interventions have implications in the perioperative period, and it is the responsibility of the anesthesiologist to be familiar with these guidelines. PMID- 24815017 TI - Infinium monkeys: Infinium 450K array for the Cynomolgus macaque (Macaca fascicularis). AB - The Infinium Human Methylation450 BeadChip Array (Infinium 450K) is a robust and cost-efficient survey of genome-wide DNA methylation patterns. Macaca fascicularis (Cynomolgus macaque) is an important disease model; however, its genome sequence is only recently published, and few tools exist to interrogate the molecular state of Cynomolgus macaque tissues. Although the Infinium 450K is a hybridization array designed to the human genome, the relative conservation between the macaque and human genomes makes its use in macaques feasible. Here, we used the Infinium 450K array to assay DNA methylation in 11 macaque muscle biopsies. We showed that probe hybridization efficiency was related to the degree of sequence identity between the human probes and the macaque genome sequence. Approximately 61% of the Human Infinium 450K probes could be reliably mapped to the Cynomolgus macaque genome and contain a CpG site of interest. We also compared the Infinium 450K data to reduced representation bisulfite sequencing data generated on the same samples and found a high level of concordance between the two independent methodologies, which can be further improved by filtering for probe sequence identity and mismatch location. We conclude that the Infinium 450K array can be used to measure the DNA methylome of Cynomolgus macaque tissues using the provided filters. We also provide a pipeline for validation of the array in other species using a simple BLAST-based sequence identify filter. PMID- 24815018 TI - The roles of Frizzled-3 and Wnt3a on melanocyte development: in vitro studies on neural crest cells and melanocyte precursor cell lines. AB - BACKGROUND: Wnt3a and Frizzled-3 are both expressed in the dorsal neural tube that gives rise to the neural crest in Xenopus, zebrafish and mice. Melanocytes originate from the neural crest (NC) and postnatally, melanocyte stem cells reside in the hair follicle bulge and in the dermis. However, the roles of Wnt3a and Frizzled-3 in melanocyte development have not been clarified. OBJECTIVE: The aim of this study was to delineate the expression of Frizzled-3 in murine melanocyte lineage and human melanocytes, and to study the effects of Wnt3a on melanocyte development at various stages. METHODS: Murine NC explant cultures and three NC-derived melanocyte lineage cell lines, including NCCmelb4M5 (Kit(-) melanocyte precursors), NCCmelb4 (Kit(+) melanoblasts) and NCCmelan5 (differentiated melanocytes), and human epidermal melanocytes were treated with pure recombinant Wnt3a protein and their cell behaviors were analyzed including their proliferation, Kit expression, tyrosinase (Tyr) activity, melanin production, dendrite formation and migration. RESULTS: Frizzled-3 was expressed in Tyr-related protein (TRP)-1(+) cells in NC explant cultures, in all 3 melanocyte precursor cell lines and in human melanocytes. Wnt3a increased the population of TRP-1(+) cells, the number of L-3,4-dihydroxyphenylalanine (DOPA)(+) cells and dendrite formation in NC explant cultures. Wnt3a stimulated the proliferation of all 3 melanocyte precursor cell lines in a dose-dependent manner and also stimulated human melanocyte proliferation. Moreover, Wnt3a increased Tyr activity and melanin content of differentiated melanocytes, but did not activate Tyr activity in melanoblasts. Wnt3a stimulated dendrite formation in differentiated melanocytes, but not in melanoblasts. Wnt3a did not affect melanoblast or melanocyte migration. Wnt3a did not induce c-Kit expression in Kit(-) NCCmelb4M5 cells and did not affect c-Kit expression in any cell line tested. CONCLUSIONS: Frizzled-3 is constitutively expressed in murine melanocyte precursors, melanocytes and human melanocytes. Wnt3a and Frizzled-3 signalings play important roles in regulating the proliferation and differentiation of murine NCCs and various developmental stages of melanocyte precursors. The effect of Wnt3a on human melanocytes is similar to its effects on murine melanocytes. Therefore Wnt3a/Frizzled-3 signaling is a promising target for human melanocyte regeneration. PMID- 24815019 TI - Identification of two novel ATP6V0A2 mutations in an infant with cutis laxa by exome sequencing. PMID- 24815020 TI - Expression of osteopontin genotypes (T-4754-C and A-9138-C) in psoriasis and their relation to metabolic syndrome. PMID- 24815021 TI - Enhanced production of nitric oxide in A549 cells through activation of TRPA1 ion channel by cold stress. AB - The respiratory epithelium is exposed to the external environment, and inhalation of cold air is common during the season of winter. In addition, the lung is a major source of nitric oxide (NO). However, the effect of cold stress on the production of NO is still unclear. In the present work, We measured the change of NO in single cell with DACF-DA and the change in cytosolic Ca(2+) concentration ([Ca(2+)]c) in A549 cell. We observed that cold stress (from 20 degrees C to 5 degrees C) induced an increase of NO in A549 cell, which was completely abolished by applying an extracellular Ca(2+) free medium. Further experiments showed that cold-sensing transient receptor potential subfamily member 1 (TRPA1) channel agonist (allyl isothiocyanate, AITC) increased the production of NO and the level of [Ca(2+)]c in A549 cell. Additionally, TRPA1 inhibitor, Ruthenium red (RR) and camphor, significantly blocked the enhanced production of NO and the rise of [Ca(2+)]c induced by AITC or cold stimulation, respectively. Taken together, these data indicated that cold-induced TRPA1 activation was responsible for the enhanced production of NO in A549 cell. PMID- 24815022 TI - The dual effects of nitrite on hemoglobin-dependent redox reactions. AB - Evidence to support the role of heme proteins-dependent reactions as major inducers of oxidative damage is increasingly present. Nitrite (NO2(-)) is one of the major end products of NO metabolism, and from the daily consumption. Although the biological significance of heme proteins/NO2(-)-mediated protein tyrosine nitration is a subject of great interest, the important roles of NO2(-) on heme proteins-dependent redox reactions have been greatly underestimated. In this study, we investigated the influence of NO2(-) on met-hemoglobin (Hb)-dependent oxidative and nitrative stress. It was found that NO2(-) effectively reduced cytotoxic ferryl intermediate back to ferric Hb in a biphasic kinetic reaction. However, the presence of NO2(-) surprisingly exerted pro-oxidant effect on Hb H2O2-induced protein (bovine serum albumin, enolase) oxidation at low concentrations and enhanced the loss of HepG2 cell viability. In the reduction of ferryl Hb to ferric state, NO2(-) was decreased and oxidized to a nitrating agent NO2, Tyr12 and Tyr191 in enolase were subsequently nitrated. In contrast to the frequently inhibitive effect of nitrotyrosine, NO2(-)-triggered tyrosine nitration might play an important role in enolase activation. These data provided novel evidence that the dietary intake and potential therapeutic application of NO2(-) would possess anti- and pro-oxidant activities through interfering in hemoglobin-dependent redox reactions. Besides the classic role in protein tyrosine nitration, the dual effects on hemoglobin-triggered oxidative stress may provide new insights into the physiological and toxicological implications of NO2(-) with heme proteins. PMID- 24815023 TI - Hepatitis C virus polymerase-polymerase contact interface: significance for virus replication and antiviral design. AB - The hepatitis C virus (HCV) replicates its genome in replication complexes located in micro-vesicles derived from endoplasmic reticulum. The composition of these replication complexes indicates that proteins, both viral and cellular in origin, are at high concentrations. Under these conditions, protein-protein interactions must occur although their role in the replication pathways is unknown. HCV RNA-dependent RNA-polymerase (NS5B) initiates RNA synthesis in these vesicles by a de novo (DN) mechanism. After initiation, newly synthesized dsRNA could induce conformational changes that direct the transition from an initiating complex into a processive elongation complex. In this report, we analyze the role played by NS5B-NS5B intermolecular interactions controlling these conformational rearrangements. Based on NS5B protein-protein docking and molecular dynamics simulations, we constructed mutants of residues predicted to be involved in protein-protein interactions. Changes at these positions induced severe defects in both the activity of the enzyme and the replication of a subgenomic replicon. Thus, mutations at the interaction surface decreased both DN synthesis initiation and processive elongation activities. Based on this analysis, we define at an atomic level an NS5B homomeric interaction model that connects the T-helix in the thumb subdomain of one monomer, with the F-helix of the fingers subdomain in other monomer. Knowing the molecular determinants involved in viral replication could be helpful to delineate new and powerful antiviral strategies. PMID- 24815024 TI - Exposure to intrauterine inflammation leads to impaired function and altered structure in the preterm heart of fetal sheep. AB - Intrauterine inflammation is a major contributor to preterm birth and has adverse effects on preterm neonatal cardiovascular physiology. Cardiomyocyte maturation occurs in late gestation in species such as humans and sheep. We tested the hypothesis that intrauterine inflammation has deleterious effects on cardiac function in preterm sheep which might be explained by altered cardiomyocyte proliferation and maturation. Pregnant ewes received an ultrasound-guided intra amniotic injection of lipopolysaccharide (LPS) or saline 7 days prior to delivery at day 127 of pregnancy (term 147 days). Cardiac contractility was recorded in spontaneously beating hearts of the offspring, perfused in a Langendorff apparatus. Saline-filled latex balloons were inserted into the left ventricle (LV) and right ventricle (RV). Responsiveness to isoprenaline and stop flow/reperfusion was assessed. In other experiments, hearts were perfusion-fixed, and cardiomyocyte nuclearity, volume and number were determined. beta Adrenoceptor mRNA levels were determined in unfixed tissue. In hearts of LPS exposed fetuses, contractility in the LV and RV was suppressed by ~40% and cardiomyocyte numbers were reduced by ~25%. Immature mono-nucleated cardiomyocytes had lower volumes (~18%), whereas mature bi-nucleated cardiomyocyte volume was ~77% greater. Although basal coronary flow was significantly increased by 21+/-7% in LPS-exposed hearts, following ischaemia/reperfusion (IR), end-diastolic pressure was increased 2.4+/-0.3-fold and infarct area was increased 3.2+/-0.6-fold compared with those in controls. Maximum responsiveness to isoprenaline was enhanced by LPS, without an increase in beta-adrenoceptor mRNA, suggesting altered second messenger signalling. Intrauterine inflammation altered cardiac growth, suppressed contractile function and enhanced responsiveness to stress. Although these effects may ensure immediate survival, they probably contribute to the increased vulnerability of organ perfusion in preterm neonates. PMID- 24815025 TI - Raising the standard of applied dementia care research: addressing the implementation error. PMID- 24815026 TI - A novel approach for site-specific atom probe specimen preparation by focused ion beam and transmission electron backscatter diffraction. AB - Atom probe tomography (APT) is a suitable technique for chemical analyses with almost atomic resolution. However, the time-consuming site-specific specimen preparation can be improved. Recently, transmission electron backscatter diffraction (t-EBSD) has been established for high resolution crystallographic analyses of thin foils. In this paper we present the first successful application of a combined focused ion beam (FIB)/t-EBSD preparation of site-specific APT specimens using the example of grain boundary segregation in technically pure molybdenum. It will be shown that the preparation of a grain boundary can be substantially accelerated by t-EBSD analyses in-between the annular milling FIB procedure in the same microscope. With this combined method, a grain boundary can easily be recognized and positioned in the first 220nm of an APT sample much faster than e.g. with complementary investigations in a transmission electron microscope. Even more, the high resolution technique of t-EBSD gives the opportunity to get crystallographic information of the mapped area and, therefore, an analysis of the grain boundary character to support the interpretation of the APT data files. To optimize this newly developed technique for the application on needle-shaped APT specimens, a parameter study on enhanced background correction, acceleration voltage, and tilt angle was carried out. An acceleration voltage of 30kV at specimen surface tilt angles between -45 degrees and -35 degrees from horizontal plane leads to the best results. Even for molybdenum the observation of crystal orientation data up to about 200nm specimen thickness is possible. PMID- 24815027 TI - STXM goes 3D: digital reconstruction of focal stacks as novel approach towards confocal soft x-ray microscopy. AB - Fresnel zone plate based soft x-ray transmission microspectroscopy has developed into a routine technique for high-resolution elemental or chemical 2D imaging of thin film specimens. The availability of high resolution Fresnel lenses with short depth of focus offers the possibility of optical slicing (in the third dimension) by focus series with resolutions in the submicron regime. We introduce a 3D reconstruction algorithm that uses a variance-based metric to assign a focus measure as basis for volume rendering. The algorithm is applied to simulated geometries and opaque soft matter specimens thus enabling 3D visualization. These studies with z-resolution of few 100nm serve as important step towards the vision of a confocal transmission x-ray microscope. PMID- 24815028 TI - Sculpturing the electron wave function using nanoscale phase masks. AB - Electron beams are extensively used in lithography, microscopy, material studies and electronic chip inspection. Today, beams are mainly shaped using magnetic or electric forces, enabling only simple shaping tasks such as focusing or scanning. Recently, binary amplitude gratings achieved complex shapes. These, however, generate multiple diffraction orders, hence the desired shape, appearing only in one order, retains little of the beam energy. Here we demonstrate a method in electron-optics for arbitrarily shaping electron beams into a single desired shape, by precise patterning of a thin-membrane. It is conceptually similar to shaping light beams using refractive or diffractive glass elements such as lenses or holograms - rather than applying electromagnetic forces, the beam is controlled by spatially modulating its wavefront. Our method allows for nearly maximal energy transference to the designed shape, and may avoid physical damage and charging effects that are the scorn of commonly-used (e.g. Zernike and Hilbert) phase-plates. The experimental demonstrations presented here - on-axis Hermite-Gauss and Laguerre-Gauss (vortex) beams, and computer-generated holograms - are a first example of nearly-arbitrary manipulation of electron beams. Our results herald exciting prospects for microscopic material studies, enables electron lithography with fixed sample and beam and high resolution electronic chip inspection by structured electron illumination. PMID- 24815029 TI - Intraperitoneal curcumin decreased lung, renal and heart injury in abdominal aorta ischemia/reperfusion model in rat. AB - BACKGROUND: Previous studies have demonstrated that curcumin (CUR) has protective effects against ischemia reperfusion injury to various organs. We aimed to determine whether CUR has favorable effects on tissues and oxidative stress in abdominal aorta ischemia-reperfusion injury. MATERIALS AND METHODS: Thirty rats were divided into three groups as sham, control and treatment (CUR) group. Control and CUR groups underwent abdominal aorta ischemia for 60 min followed by a 120 min period of reperfusion. In the CUR group, CUR was given 5 min before reperfusion at a dose of 200 mg/kg via an intraperitoneal route. Total antioxidant capacity (TAC), total oxidative status (TOS), and oxidative stress index (OSI) in blood serum were measured, and lung, renal and heart tissue histopathology were evaluated with light microscopy. RESULTS: TOS and OSI activity in blood samples were statistically decreased in sham and CUR groups compared to the control group (p < 0.001 for TOS and OSI). Renal, lung, heart injury scores of sham and CUR groups were statistically decreased compared to control group (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in CUR group than in the control group. CONCLUSION: CUR administered intraperitoneally was effective in reducing oxidative stress and histopathologic injury in an acute abdominal aorta I/R rat model. PMID- 24815030 TI - Key interactions for clathrin coat stability. AB - Clathrin-coated vesicles are major carriers of vesicular traffic in eukaryotic cells. This endocytic pathway relies on cycles of clathrin coat assembly and Hsc70-mediated disassembly. Here we identify histidine residues as major determinants of lattice assembly and stability. They are located at the invariant interface between the proximal and distal segments of clathrin heavy chains, in triskelions centered on two adjacent vertices of the coated-vesicle lattice. Mutation of these histidine residues to glutamine alters the pH dependence of coat stability. We then describe single-particle fluorescence imaging experiments in which we follow the effect of these histidine mutations on susceptibility to Hsc70-dependent uncoating. Coats destabilized by these mutations require fewer Hsc70 molecules to initiate disassembly, as predicted by a model in which Hsc70 traps conformational distortions during the auxilin- and Hsc70:ATP-mediated uncoating reaction. PMID- 24815031 TI - Cancer-cell-targeted theranostic cubosomes. AB - This work was devoted to the development of a new type of lipid-based (cubosome) theranostic nanoparticle able to simultaneously host camptothecin, a potent anticancer drug, and a squarain-based NIR-emitting fluorescent probe. Furthermore, to confer targeting abilities on these nanoparticles, they were dispersed using mixtures of Pluronic F108 and folate-conjugated Pluronic F108 in appropriate ratios. The physicochemical characterization, performed via SAXS, DLS, and cryo-TEM techniques, proved that aqueous dispersions of such cubosomes can be effectively prepared, while the photophysical characterization demonstrated that these nanoparticles may be used for in vivo imaging purposes. The superior ability of these innovative nanoparticles in targeting cancer cells was emphasized by investigating the lipid droplet alterations induced in HeLa cells upon exposure to targeted and nontargeted cubosomes. PMID- 24815032 TI - Evaluation of an electrochemical biosensor for uric acid measurement in human whole blood samples. AB - BACKGROUND: Uric acid measurement has become increasingly important, and electrochemically modified detection method based portable devices hold a dominant position in the market for point of care and self-monitoring of uric acid blood levels. However, there has been a lack of detailed performance evaluation of the electrochemical detection devices that are currently being used in professional health care facilities and for home self-monitoring of uric acid. METHODS: A commercially available uric acid monitoring system that is chemically modified to reduce interference was evaluated via clinical evaluation for its performance and interference as compared to a centralized laboratory instrument. RESULTS: Precision was within +/-3.1% for 3 levels of control solutions and whole blood samples. A range from 30 to 55% was acceptable for the measurement of hematocrit levels in whole blood samples. There was no interference for the potential substances at their high therapeutic levels. Hemolyzed samples of up to 75 g/l showed no interference with test results obtained by the BeneCheck system, while a -45.9% bias% was obtained during testing of the same samples by a spectrophotometer. Clinical evaluation showed that >95% of tests were within +/ 20% bias% compared to a centralized instrument in hospitals. CONCLUSION: The uric acid monitoring system was suitable for use in monitoring or screening uric acid concentration for home users or professionals. PMID- 24815033 TI - Advancing the education in molecular diagnostics: the IFCC-Initiative "Clinical Molecular Biology Curriculum" (C-CMBC); a ten-year experience. AB - Molecular techniques are becoming commonplace in the diagnostic laboratory. Their applications influence all major phases of laboratory medicine including predisposition/genetic risk, primary diagnosis, therapy stratification and prognosis. Readily available laboratory hardware and wetware (i.e. consumables and reagents) foster rapid dissemination to countries that are just establishing molecular testing programs. Appropriate skill levels extending beyond the technical procedure are required for analytical and diagnostic proficiency that is mandatory in molecular genetic testing. An international committee (C-CMBC) of the International Federation for Clinical Chemistry (IFCC) was established to disseminate skills in molecular genetic testing in member countries embarking on the respective techniques. We report the ten-year experience with different teaching and workshop formats for beginners in molecular diagnostics. PMID- 24815034 TI - Investigation of potential breath biomarkers for the early diagnosis of breast cancer using gas chromatography-mass spectrometry. AB - BACKGROUND: Breast cancer (BC) remains the most commonly diagnosed malignancy in women. We investigated 4 straight aldehydes in the exhaled breath as potential early BC diagnostic biomarkers. METHODS: End-tailed breath were collected by Bio VOC(r) sampler and assayed by gas chromatography-mass spectrometry. Kruskal Wallis one-way analysis of variance test and binary logistic regression were used for data analysis. The diagnostic accuracies were evaluated by receiver operating characteristic curves. A predictive model/equation was generated using the 4 biomarkers and validated by leave-one-out cross-validation. RESULTS: All four potential biomarkers demonstrated significant differences in concentrations between BC and healthy controls (HC) (p<0.05). The areas under the curves (AUCs) in HC vs BCI-II model using hexanal, heptanal, octanal, and nonanal were 0.816, 0.809, 0.731, and 0.830, respectively. The AUC for their combined use was 0.934 (sensitivity 91.7%, specificity 95.8%) in the early diagnosis of BC. The predictive model/equation exhibited good sensitivity (72.7%) and specificity (91.7%) in distinguishing between HC and BC (cross-validation: sensitivity 68.2% and specificity 91.7%). CONCLUSIONS: The diagnostic values of 4 exhaled straight aldehydes as early diagnostic biomarkers for BC were successfully verified and the diagnostic accuracy improved in their combined use. PMID- 24815035 TI - Novel styrylbenzene derivatives for detecting amyloid deposits. AB - BACKGROUND: Various styrylbenzene compounds were synthesized and evaluated as mainly Abeta amyloid sensors. These compounds, however, cannot be used for detecting amyloid deposition in peripheral nerves because of the inherent sensitivity of the compounds. These compounds often generate false positives especially in the basement membrane of blood vessels in histochemical studies. To overcome these problems, we must first synthesize other styryl compounds for detecting amyloid fibrils in tissues. METHODS: A wide variety of symmetrical and unsymmetrical styrylbenzene derivatives were synthesized and then these compounds were used to detect amyloid fibrils in autopsy and biopsy samples from patients with various systemic and localized forms of amyloidosis such as familial amyloidotic polyneuropathy (FAP), senile systemic amyloidosis (SSA), amyloid A (AA) amyloidosis, localized AL amyloidosis, and Alzheimer's disease. RESULTS: 1 Methoxy-2,5-bis-styrylbenzene and 2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-2,5-bis styrylbenzene (EEEFSB) detected amyloid fibrils in both in vitro and in vivo histopathological studies. 1-Methoxy-2,5-bis-styrylbenzene also showed a high strength of fluorescence with amyloid deposition in peripheral nerves in a patient with FAP. CONCLUSIONS: 1-Methoxy-2,5-bis-styrylbenzene and EEEFSB may prove a useful tool for diagnosing amyloidosis, not only in a histochemical study but also in whole body amyloid positron emission tomography (PET) imaging. PMID- 24815036 TI - The association between aortic distensibility and coronary flow reserve in newly diagnosed diabetic patients. AB - INTRODUCTION: Aortic distensibility (AD) is an important parameter affecting coronary hemodynamics. Coronary flow velocity reserve (CFVR) is a reliable marker of coronary endothelial function in diabetic patients. The aim of this study was to investigate the association between AD and CFVR in newly diagnosed diabetic patients. METHOD: We studied 77 patients with newly diagnosed diabetes mellitus (DM) and 30 age- and sex-matched healthy control subjects. CFVR was calculated as the hyperemic to resting coronary diastolic velocities ratio by using transthoracic echocardiography. Pulse pressure (PP) and AD were calculated. RESULTS: Fasting blood glucose, HbA1c and PP were significantly higher in patients with diabetes (P < 0.001, P < 0.001 and P = 0.009, respectively). Other clinical and demographical characteristics, laboratory findings and echocardiographic findings were similar in both groups (P > 0.05, for all). The measurement of CFVR and AD in patients with diabetes were significantly lower compared with the controls (P < 0.001 and P = 0.001, respectively). CFVR was significantly negatively correlated with age, body mass index, HbA1c, systolic blood pressure, and PP, while significantly positively correlated with AD (P < 0.05, for all). Multivariate regression analysis showed that only AD (beta = 0.485, P < 0.0001) and HbA1c (beta = -0.362, P < 0.0001) were independently associated with CFVR. The cutoff value of AD obtained by the receiver operator characteristic (ROC) curve analysis was 2.44 for the prediction of impaired CFVR. CONCLUSION: Aortic distensibility and HbA1c were independently associated with CFVR. The decrease in AD may be used as a marker of impaired coronary microcirculation in asymptomatic diabetic patients. PMID- 24815037 TI - Impact of seasonal temperature environment on the neurologic prognosis of out-of hospital cardiac arrest: a nationwide, population-based cohort study. AB - OBJECTIVE: The relationship between environmental factors, such as winter or cold environments, and the onset of out-of-hospital cardiac arrest (OHCA) is well known. However, the association between environmental factors and the neurologic outcome of OHCA is poorly understood. This study aimed to assess the impact of the ambient temperature on the neurologic outcome of adult OHCA. METHODS: In a nationwide, population-based, observational study, we enrolled 121,081 adults 18 years or older who experienced an OHCA from January 1, 2010, to December 31, 2010. We used the All-Japan Utstein Registry database coupled with climate statistics data from the Japan Meteorological Agency. The primary end point was favorable neurologic outcome 1 month after OHCA. RESULTS: Of the eligible 120,721 adult patients with OHCA, 7747 cases of OHCA (6.4%) occurred during the cold season, 80,739 (66.9%) occurred during the midseason, and 32,235 (26.7%) occurred during the warm season. The adults who experienced an OHCA during the cold season exhibited a significantly lower rate of a favorable neurologic outcome than did those who experienced an OHCA during the warm season (2.4% vs 3.3%; odds ratio, 0.73; 95% confidence interval, 0.62-0.85; P < .0001). The adjusted odds ratio for favorable neurologic outcome per 1 degrees C increase in the monthly ambient temperature was 1.006 (95% confidence interval, 1.002-1.010; P = .0080). CONCLUSIONS: The seasonal ambient temperature is likely to affect favorable neurologic outcome. A lower seasonal ambient temperature may exacerbate the neurologic outcome of OHCA. PMID- 24815038 TI - A systematic review of pharmacoeconomic studies for pregabalin. AB - BACKGROUND: With anticonvulsant, anxiolytic, and analgesic properties, pregabalin has been evaluated for neuropathic pain and fibromyalgia (FM). These chronic conditions diminish patients' quality of life and increase healthcare utilization and costs. OBJECTIVE: To assess the current understanding of economic outcomes associated with pregabalin in neuropathic pain and FM. METHODS: Using keywords related to economic outcomes and pregabalin, we systematically searched MEDLINE- and EMBASE-indexed literature and nonindexed "grey" literature on neuropathic pain and FM published from March 2001 to October 2012. Included studies reported economic findings associated with pregabalin. RESULTS: In the past 11 years, 55 publications assessed the direct costs, resource use, or cost-effectiveness of pregabalin for neuropathic pain and FM. Studies generally lacked comparability due to heterogeneous patient populations, assumptions, time periods, and geographies. In the US, following treatment initiation, pregabalin resulted in similar or higher levels of healthcare use for FM compared with duloxetine. In contrast, medical costs for neuropathic pain did not significantly differ after initiation of pregabalin vs. duloxetine or other standard therapies in the US, but in Spain and Sweden, retrospective database studies suggested that pregabalin was cost-saving vs. gabapentin. Few economic analyses estimated indirect costs. CONCLUSIONS: Neuropathic pain and FM are associated with high healthcare resource use and costs. Economic studies of pregabalin in neuropathic pain and FM indicate some results favorable to other forms of care, but heterogeneity among study designs and populations hinder comparisons. Future economic analyses should aim to address data gaps regarding effects of pregabalin on productivity and resource use. PMID- 24815040 TI - Investigations on preferential Pu(IV) extraction over U(VI) by N,N dihexyloctanamide versus tri-n-butyl phosphate: evidence through small angle neutron scattering and DFT studies. AB - Straight chain amide N,N-dihexyloctanamide (DHOA) has been found to be a promising alternative extractant to tri-n-butyl phosphate (TBP) for the reprocessing of irradiated uranium- and thorium-based fuels. Unlike TBP, DHOA displays preferential extraction of Pu(IV) over U(VI) at higher acidities (>=3 M HNO3) and poor extraction at lower acidities. Density functional theory (DFT) based calculations have been carried out on the structures and relative binding energies of U(VI) and Pu(IV) with the extractant molecules. These calculations suggest that the differential hardness of the two extractants is responsible for the preferential binding/complexation of TBP to uranyl, whereas the softer DHOA and the bulky nature of the extractant lead to stronger binding/complexation of DHOA to Pu(IV). In conjunction with quantum chemical calculations, small angle neutron scattering (SANS) measurements have also been performed for understanding the stoichiometry of the complex formed that leads to relatively lower extraction of Th(IV) (a model for Pu(IV)) as compared to U(VI) using DHOA and TBP as the extractants. The combined experimental and theoretical studies helped us to understand the superior complexation/extraction behavior of Pu(IV) over U(VI) with DHOA. PMID- 24815039 TI - Model for ranking freshwater fish farms according to their risk of infection and illustration for viral haemorrhagic septicaemia. AB - We developed a model to calculate a quantitative risk score for individual aquaculture sites. The score indicates the risk of the site being infected with a specific fish pathogen (viral haemorrhagic septicaemia virus (VHSV); infectious haematopoietic necrosis virus, Koi herpes virus), and is intended to be used for risk ranking sites to support surveillance for demonstration of zone or member state freedom from these pathogens. The inputs to the model include a range of quantitative and qualitative estimates of risk factors organised into five risk themes (1) Live fish and egg movements; (2) Exposure via water; (3) On-site processing; (4) Short-distance mechanical transmission; (5) Distance-independent mechanical transmission. The calculated risk score for an individual aquaculture site is a value between zero and one and is intended to indicate the risk of a site relative to the risk of other sites (thereby allowing ranking). The model was applied to evaluate 76 rainbow trout farms in 3 countries (42 from England, 32 from Italy and 2 from Switzerland) with the aim to establish their risk of being infected with VHSV. Risk scores for farms in England and Italy showed great variation, clearly enabling ranking. Scores ranged from 0.002 to 0.254 (mean score 0.080) in England and 0.011 to 0.778 (mean of 0.130) for Italy, reflecting the diversity of infection status of farms in these countries. Requirements for broader application of the model are discussed. Cost efficient farm data collection is important to realise the benefits from a risk-based approach. PMID- 24815041 TI - Drowning out the protection racket: partner manipulation or drought can strengthen ant-plant mutualism. AB - Two recent reports discuss interactions between plants and ants that defend them from herbivores. Acacia trees provide their ant bodyguards with a diet that reduces their ability to benefit from alternate hosts. Provisioning of ants by Cordia trees during drought may buy insurance against extreme defoliation events, not just average-year benefits. PMID- 24815042 TI - Sex hormones alter sex ratios in the Indian skipper frog, Euphlyctis cyanophlyctis: Determining sensitive stages for gonadal sex reversal. AB - In amphibians, although genetic factors are involved in sex determination, gonadal sex differentiation can be modified by exogenous steroid hormones suggesting a possible role of sex steroids in regulating the process. We studied the effect of testosterone propionate (TP) and estradiol-17beta (E2) on gonadal differentiation and sex ratio at metamorphosis in the Indian skipper frog, Euphlyctis cyanophlyctis with undifferentiated type of gonadal differentiation. A series of experiments were carried out to determine the optimum dose and sensitive stages for gonadal sex reversal. Our results clearly indicate the importance of sex hormones in controlling gonadal differentiation of E. cyanophlyctis. Treatment of tadpoles with 10, 20, 40, and 80MUg/L TP throughout larval period resulted in the development of 100% males at metamorphosis at all concentrations. Similarly, treatment of tadpoles with 40MUg/L TP during ovarian and testicular differentiation resulted in the development of 90% males, 10% intersexes and 100% males respectively. Treatment of tadpoles with 10, 20, 40, and 80MUg/L E2 throughout larval period likewise produced 100% females at all concentrations. Furthermore, exposure to 40MUg/L E2 during ovarian and testicular differentiation produced 95% females, 5% intersexes and 91% females, 9% intersexes respectively. Both TP and E2 were also effective in advancing the stages of gonadal development. Present study shows the effectiveness of both T and E2 in inducing complete sex reversal in E. cyanophlyctis. Generally, exposure to E2 increased the larval period resulting in significantly larger females than control group while the larval period of control and TP treated groups was comparable. PMID- 24815043 TI - Editorial for perspectives in cichlid endocrinology. PMID- 24815044 TI - Cinnamtannin D-1 protects pancreatic beta-cells from palmitic acid-induced apoptosis by attenuating oxidative stress. AB - In previous studies, A-type procyanidin oligomers isolated from Cinnamomum tamala were proved to possess antidiabetic effect and protect pancreatic beta-cells in vivo. The aim of this study was to unveil the mechanisms of protecting pancreatic beta-cells from palmitic acid-induced apoptosis by cinnamtannin D-1 (CD1), one of the main A-type procyanidin oligomers in C. tamala. CD1 was discovered to dose dependently reduce palmitic acid- or H2O2-induced apoptosis and oxidative stress in INS-1 cells, MIN6 cells, and primary cultured murine islets. Moreover, CD1 could reverse palmitic acid-induced dysfunction of glucose-stimulated insulin secretion in primary cultured islets. These results indicate that reduction of apoptosis and oxidative stress might account for the protection effect of CD1, which provided a better understanding of the mechanisms of the antidiabetic effects of procyanidin oligomers. PMID- 24815045 TI - Face and location processing in children with early unilateral brain injury. AB - Human visuospatial functions are commonly divided into those dependent on the ventral visual stream (ventral occipitotemporal regions), which allows for processing the 'what' of an object, and the dorsal visual stream (dorsal occipitoparietal regions), which allows for processing 'where' an object is in space. Information about the development of each of the two streams has been accumulating, but very little is known about the effects of injury, particularly very early injury, on this developmental process. Using a set of computerized dorsal and ventral stream tasks matched for stimuli, required response, and difficulty (for typically-developing individuals), we sought to compare the differential effects of injury to the two systems by examining performance in individuals with perinatal brain injury (PBI), who present with selective deficits in visuospatial processing from a young age. Thirty participants (mean=15.1 years) with early unilateral brain injury (15 right hemisphere PBI, 15 left hemisphere PBI) and 16 matched controls participated. On our tasks children with PBI performed more poorly than controls (lower accuracy and longer response times), and this was particularly prominent for the ventral stream task. Lateralization of PBI was also a factor, as the dorsal stream task did not seem to be associated with lateralized deficits, with both PBI groups showing only subtle decrements in performance, while the ventral stream task elicited deficits from RPBI children that do not appear to improve with age. Our findings suggest that early injury results in lesion-specific visuospatial deficits that persist into adolescence. Further, as the stimuli used in our ventral stream task were faces, our findings are consistent with what is known about the neural systems for face processing, namely, that they are established relatively early, follow a comparatively rapid developmental trajectory (conferring a vulnerability to early insult), and are biased toward the right hemisphere. PMID- 24815046 TI - Body composition in patients with classical homocystinuria: body mass relates to homocysteine and choline metabolism. AB - INTRODUCTION: Classical homocystinuria is a rare genetic disease caused by cystathionine beta-synthase deficiency, resulting in homocysteine accumulation. Growing evidence suggests that reduced fat mass in patients with classical homocystinuria may be associated with alterations in choline and homocysteine pathways. This study aimed to evaluate the body composition of patients with classical homocystinuria, identifying changes in body fat percentage and correlating findings with biochemical markers of homocysteine and choline pathways, lipoprotein levels and bone mineral density (BMD) T-scores. METHODS: Nine patients with classical homocystinuria were included in the study. Levels of homocysteine, methionine, cysteine, choline, betaine, dimethylglycine and ethanolamine were determined. Body composition was assessed by bioelectrical impedance analysis (BIA) in patients and in 18 controls. Data on the last BMD measurement and lipoprotein profile were obtained from medical records. RESULTS: Of 9 patients, 4 (44%) had a low body fat percentage, but no statistically significant differences were found between patients and controls. Homocysteine and methionine levels were negatively correlated with body mass index (BMI), while cysteine showed a positive correlation with BMI (p<0.05). There was a trend between total choline levels and body fat percentage (r=0.439, p=0.07). HDL cholesterol correlated with choline and ethanolamine levels (r=0.757, p=0.049; r=0.847, p=0.016, respectively), and total cholesterol also correlated with choline levels (r=0.775, p=0.041). There was no association between BMD T-scores and body composition. CONCLUSIONS: These results suggest that reduced fat mass is common in patients with classical homocystinuria, and that alterations in homocysteine and choline pathways affect body mass and lipid metabolism. PMID- 24815047 TI - Genetic, historical and linguistic perspectives on the origin of the Kelantanese Malays. AB - The Kelantanese Malays who resided in the remote northeastern regions of the Malay Peninsula in the Kelantan state are believed to have a unique genetic signature. The objective of this review is to analyze the populational sub structure of the Kelantanese Malays from historical, genetic and linguistic perspectives. Historical data suggest that the Semang were composed of the Jahai, Bateq and Kensiu sub-tribes, whereas the Senoi were composed of only the Temiar sub-tribe. The Mendriq sub-tribe is believed to be the first group of aborigines to land in Kelantan. Subsequently, genetic analysis showed that the Kelantanese Malays are an independent clade at the base of the phylogenetic tree and contain genetic material similar to that of the Semang, specifically the Jahai and the Kensiu sub-tribes. The genetic data are supported by the fact that the Aslian language, a branch of the Austroasiatic languages that is widely spoken by the Semang, was potentially transmitted through agricultural activities. However, the potential limitation of this mini-review is the lack of primary reliable sources covering the historical, linguistic and genetic features of the Kelantanese Malays. PMID- 24815048 TI - Comparison of biosorption and phytoremediation of cadmium and methyl parathion, a case-study with live Lemna gibba and Lemna gibba powder. AB - Heavy metals and pesticides can be adsorbed by several biomasses such as living or non-living aquatic plants. In this study adsorption properties of live Lemna gibba and Lemna gibba powder were investigated with regard to cadmium and methyl parathion (MP). Toxicity data (IC50) on live L. gibba indicated that the period of four days was adequate for phytoremediation. Initial adsorption studies showed that both adsorbents were capable of removing cadmium and methyl parathion. Cadmium and methyl parathion adsorption onto L. gibba powder was fast and equilibrium was attained within 120min. The adsorption data could be well interpreted by the Freundlich model. The KF were: 7.8963 (Cd(2+)/ live Lemna); 0.7300 (MP/live Lemna); 11.5813 (Cd(2+)/Lemna powder); 1.1852 (MP/Lemna powder) indicating that Cd(2+) was more efficiently removed by both biosorbents than MP. Adsorption kinetics for cadmium and methyl parathion in both systems and rate constants were determined for each contaminant. It was found that the overall adsorption process was best described by pseudo-second-order kinetics. Boyd model and external mass-transfer expression were tested. It was concluded that cadmium and methyl parathion sorption onto Lemna powder is governed by film diffusion. PMID- 24815049 TI - Effects of limonene stress on the growth of and microcystin release by the freshwater cyanobacterium Microcystis aeruginosa FACHB-905. AB - The effects of limonene exposure on the growth of Microcystisaeruginosa and the release of toxic intracellular microcystin (MCY) were tested by evaluating the results obtained from the batch culture experiments with M. aeruginosa FACHB-905. The time series of cell as well as intracellular and extracellular MCY concentrations were evaluated during 5d of the incubation. After exposure to limonene, the number of cells gradually diminished; the net log cell reduction after 5d of the exposure was 3.0, 3.6, and 3.8log when the initial cell densities were set at 1.6*10(7), 1.1*10(6) and 4.1*10(5)cell/mL, respectively. Limonene was found to significantly influence the production and release of MCY. As the limonene exposure could inhibit the increase in the number of cells, the increase in the total MCY concentration in the medium was also inhibited. In the presence of limonene, the intracellular MCY was gradually released into the medium through a gradual reduction in the number of cells. The extracellular MCY concentration in the medium was significantly higher in the limonene-exposed samples than in the control samples, which confirmed that limonene cannot decompose the extracellular MCY. PMID- 24815050 TI - Electromagnetic compatibility and safety design of a patient compliance-free, inductive implant charger. AB - This article presents the design of a domestic, radiofrequency induction charger for implants toward compliance with the Federal Communications Commission safety and electromagnetic compatibility regulations. The suggested arrangement does not impose any patient compliance requirements other than the use of a designated bed for night sleep, and therefore can find a domestic use. The method can be applied to a number of applications; a rechargeable pacemaker is considered as a case study. The presented work has proven that it is possible to realize a fully compliant inductive charging system with minimal patient interaction, and has generated important information for consideration by the designers of inductive charging systems. Experimental results have verified the validity of the theoretical findings. PMID- 24815051 TI - Personnel-itis: a myth or a pathology? A retrospective analysis of obstetrical and perinatal outcomes for physicians and nurses. AB - OBJECTIVE: To evaluate whether medical personnel differ from the general population in obstetrical and perinatal outcomes. MATERIALS AND METHODS: The participants comprised 46 physicians and 116 nurses employed at one medical center who gave birth in its maternity hospital. General medical and obstetrical data on their latest ("index") pregnancy and delivery were extracted from real time computerized patient files. The control group included 162 women who gave birth during the same period in the same hospital. RESULTS: The study group had significantly more deliveries, cesarean sections, and terminations of pregnancy prior to the index pregnancy. The medical personnel conceived significantly more often with assisted reproductive technologies (ART) (18.8% vs. 8% for controls, P<0.05), and had significantly more obstetrical complications, i.e., premature contractions, gestational diabetes mellitus, preeclamptic toxemia, and 2nd/3rd trimester bleeding or chorioamnionitis (42.5% vs. 29% for controls, P<0.05). The rate of vaginal birth after cesarean delivery (VBAC) was lower in the study group (22.2% vs. 33.3% for controls, P=0.03). There was no difference in gestational age at delivery, birth weight, or adverse neonatal outcome. CONCLUSIONS: Medical personnel utilized ART more frequently and had more pregnancy complications as well as a lower incidence of VBAC than non-personnel. Neonatal outcomes were similar for both groups. PMID- 24815052 TI - Selection of an optimal method for co-isolation of circulating DNA and miRNA from the plasma of pregnant women. AB - BACKGROUND: Circulating nucleic acids acquired non-invasively have been confirmed as useful biomarkers in cancer and prenatal medicine. The most important molecules in the field of circulating nucleic acids research are circulating DNA and miRNA. In this study, the possibility of co-isolation of total circulating DNA, cell-free fetal DNA and miRNA from the plasma of pregnant women was tested, and the yields of co-isolated circulating nucleic acids using two commercial kits and three protocols were compared. METHODS: Cell-free fetal DNA and miRNA from the plasma of pregnant women carrying male fetuses were co-isolated with the miRCURY RNA Isolation Kit according to the original protocol and the QIAamp Circulating Nucleic Acid Kit (CNA kit) according to the manufacturer's protocol for DNA isolation and miRNA isolation. For comparison of DNA isolation, the AR and DYS14 gene-based assays were used for the detection and quantification of total circulating and cell-free fetal DNA. For miRNA detection and quantification, the miR-16 and miR-451 assays were used. RESULTS: Two different protocols for isolation using the CNA kit did not significantly differ in the yields of isolated tcDNA and cffDNA; however, the amount of isolated cffDNA using the miRCURY RNA Isolation Kit was significantly less (p<0.05, F=4.776). There was a statistically significant difference for miRNA isolation (p<0.0001, F=859 for miR-16 and p<0.0001, F=854.4 for miR-451), with the highest amount of isolated miRNA obtained using the miRCURY RNA Isolation Kit. CONCLUSIONS: All three methods used in our study were successful in the co-isolation of tcDNA, cffDNA and miRNA from the same sample. The best combined results were obtained with the miRCURY RNA Isolation Kit. PMID- 24815053 TI - Bleeding prevalence and transfusion requirement in patients with thrombocytopenia in the emergency department. AB - BACKGROUND: Thrombocytopenia is the most common coagulation disorder in critically ill patients. No studies have investigated the epidemiology and clinical impact of this condition in emergency department (ED) patients. We aimed to investigate epidemiological features, incidence of bleeding, and diagnostic and therapeutic requirements of patients with thrombocytopenia admitted to the ED. METHODS: We performed a retrospective observational study enrolling all patients admitted to the medical-surgical ED of the "Citta della Salute e della Scienza di Torino" Hospital with a platelet count <150*10(9) PLTs/L, during four non-consecutive months. There were no exclusion criteria. RESULTS: The study included 1218 patients. The percentage of patients with severe (<50*10(9) PLTs/L) or very severe (<20*10(9) PLTs/L) thrombocytopenia was about 12%. Thrombocytopenia associated with liver cirrhosis was the most represented etiology. On the contrary, the most frequent cause in patients with newly recognized low platelet count was disseminated intravascular coagulation/sepsis. The incidence of bleeding and hypovolemia, as well as the need of transfusional support and mechanical, surgical or endoscopic hemostasis progressively increased with the severity of thrombocytopenia. CONCLUSIONS: Our results suggest that the detection of a platelet count lower than 50*10(9) PLTs/L may help to identify patients with higher bleeding risk in the ED setting. Additional studies are required to evaluate whether, in this setting, thrombocytopenia may represent an independent risk factor for bleeding episodes and increased mortality. PMID- 24815054 TI - Semiparametric odds rate model for modeling short-term and long-term effects with application to a breast cancer genetic study. AB - The proportional odds model is commonly used in the analysis of failure time data. The assumption of constant odds ratios over time in the proportional odds model, however, can be violated in some applications. Motivated by a genetic study with breast cancer patients, we propose a novel semiparametric odds rate model for the analysis of right-censored survival data. The proposed model incorporates the short-term and long-term covariate effects on the failure time data and includes the proportional odds model as a nested model. We develop efficient likelihood-based inference procedures and establish the large sample properties of the proposed nonparametric maximum likelihood estimators. Simulation studies demonstrate that the proposed methods perform well in practical settings. An application to the motivating example is provided. PMID- 24815055 TI - Knee mechanics during landing in anterior cruciate ligament patients: A longitudinal study from pre- to 12 months post-reconstruction. AB - BACKGROUND: Patients with a history of anterior cruciate ligament rupture are at elevated risk of developing knee osteoarthritis. Altered knee kinematics and kinetics during functional activities have been viewed as risk factors for cartilage breakdown and, therefore, one of the primary goals of anterior cruciate ligament reconstruction is to restore knee joint function. METHODS: Patients' (n=18) knee mechanics while performing a single leg hop for distance were calculated for both legs using a soft-tissue artifact optimized rigid lower-body model at the pre-reconstruction state and six and twelve months after anterior cruciate ligament reconstruction. FINDINGS: Independent of the analyzed time point the involved leg showed a lower external flexion and adduction moment at the knee, and an increased anterior translation and external rotational offset of the shank with respect to the thigh compared to the uninvolved leg. There were no differences for any of the analyzed knee kinematic and kinetic parameters within the control subject group. INTERPRETATION: The identified kinematic changes can cause a shift in the normal load-bearing regions of the knee and may support the view that the risk of developing knee osteoarthritis in an anterior cruciate ligament ruptured joint while performing activities involving frequent landing and stopping actions is less likely to be associated with the knee adduction moment and is rather due to kinematic changes. Anterior cruciate ligament reconstruction surgery failed to restore normal knee kinematics during landing, potentially explaining the persistent risk for the development of knee osteoarthritis in patients who have returned to sports following reconstruction surgery. PMID- 24815056 TI - Developmental trajectories of children with birth asphyxia through 36 months of age in low/low-middle income countries. AB - BACKGROUND: Resuscitation following birth asphyxia reduces mortality, but may be argued to increase risk for neurodevelopmental disability in survivors. AIMS: To test the hypothesis that development of infants who received resuscitation following birth asphyxia is not significantly different through 36months of age from infants who had healthy births. STUDY DESIGN: Prospective observational cohort design comparing infants exposed to birth asphyxia with resuscitation or healthy birth. SUBJECTS: A random sample of infants with birth asphyxia who received bag-and-mask resuscitation was selected from birth records in selected communities in 3 countries. EXCLUSION CRITERIA: birth weight<1500g, severely abnormal neurological examination at 7days, mother<15years, unable to participate, or not expected to remain in the target area. A random sample of healthy-birth infants (no resuscitation, normal neurological exam) was also selected. Eligible=438, consented=407, and >=1 valid developmental assessment during the first 36months=376. OUTCOME MEASURE(S): Bayley Scales of Infant Development-II Mental (MDI) and Psychomotor (PDI) Development Index. RESULTS: Trajectories of MDI (p=.069) and PDI (p=.143) over 3 yearly assessments did not differ between children with birth asphyxia and healthy-birth children. Rather there was a trend for birth asphyxia children to improve more than healthy-birth children. CONCLUSIONS: The large majority of infants who are treated with resuscitation and survived birth asphyxia can be expected to evidence normal development at least until age 3. The risk for neurodevelopmental disability should not justify the restriction of effective therapies for birth asphyxia. PMID- 24815057 TI - Synthesis and characterization of new transition metal {Cu(II), Ni(II) and Co(II)} L-phenylalanine-DACH conjugate complexes: in vitro DNA binding, cleavage and molecular docking studies. AB - The novel metal-based molecular entities {Cu(II), Ni(II) and Co(II)} 1-3, respectively were synthesized and characterized by elemental analysis and spectroscopic methods (IR, (1)H and (13)C NMR, EPR, UV-vis, ESI-MS and XRPD). The interaction studies of 1-3 with CT DNA have been investigated by UV-vis titrations, fluorescence and circular dichroic studies which revealed the electrostatic mode of binding and on the basis of intrinsic binding constant Kb (5.30*10(4), 1; 3.41*10(4), 2; and 2.74*10(4), 3; M(-1)), the extent of DNA binding was ascertained, following the order 1>2>3. Specifically, 1 exhibited greater binding propensity with CT DNA, therefore the cleavage activity of 1 with pBR322 DNA was evaluated by agarose gel electrophoresis assay. Complex 1 presented an impressive nuclease activity generating single- and double-strand breaks. Further mechanistic investigation revealed the efficiency of 1 to cleave DNA strands by an oxidative pathway involving the generation of ROS and preferential selectivity towards the DNA minor groove. Moreover, complex 1 exhibited significant inhibitory effects on the catalytic activity of topoisomerase I at a very low concentration ~20 MUM. Additionally, computer-aided molecular docking techniques were carried out to correlate and rationalize the observed binding affinities with docking studies towards the molecular target DNA and Topo-I. PMID- 24815058 TI - Protective effects of citrus and rosemary extracts on UV-induced damage in skin cell model and human volunteers. AB - Ultraviolet radiation absorbed by the epidermis is the major cause of various cutaneous disorders, including photoaging and skin cancers. Although topical sunscreens may offer proper skin protection, dietary plant compounds may significantly contribute to lifelong protection of skin health, especially when unconsciously sun UV exposed. A combination of rosemary and citrus bioflavonoids extracts was used to inhibit UV harmful effects on human HaCaT keratinocytes and in human volunteers after oral intake. Survival of HaCaT cells after UVB radiation was higher in treatments using the combination of extracts than in those performed with individual extracts, indicating potential synergic effects. The combination of extracts also decreased UVB-induced intracellular radical oxygen species (ROS) and prevented DNA damage in HaCaT cells by comet assay and decreased chromosomal aberrations in X-irradiated human lymphocytes. The oral daily consumption of 250 mg of the combination by human volunteers revealed a significant minimal erythema dose (MED) increase after eight weeks (34%, p<0.05). Stronger protection was achieved after 12 weeks (56%, p<0.01). The combination of citrus flavonoids and rosemary polyphenols and diterpenes may be considered as an ingredient for oral photoprotection. Their mechanism of action may deserve further attention. PMID- 24815059 TI - Neurokinin B- and kisspeptin-positive fibers as well as tuberoinfundibular dopaminergic neurons directly innervate periventricular hypophyseal dopaminergic neurons in rats and mice. AB - Neurons co-expressing kisspeptin, neurokinin B (NKB), and dynorphin in the hypothalamic arcuate nucleus, named KNDy neurons, are directly affected by sex hormones, and are well known for regulating the secretion of gonadotropin releasing hormone. However, recent studies have shown that KNDy neurons also project and terminate to tuberoinfundibular dopaminergic (TIDA) neurons, suggesting a role in prolactin secretion. Moreover, there is a possibility that other neurosecretory dopaminergic neurons regulating prolactin secretion, such as periventricular hypophyseal dopaminergic (PHDA) neurons, may also be innervated by KNDy neurons. In the present study, by means of double immunohistochemistry and retrograde neural tracer, we examined whether KNDy neurons project directly to PHDA neurons that project to blood vessels, as well as to TIDA neurons. The results revealed that KNDy neurons are widely projecting to neurosecretory dopaminergic neurons of the PHDA and TIDA neurons in rats and mice. Secondary, presence of a major receptor for NKB, neurokinin-3 receptor (NK3R), in PHDA and TIDA neurons was examined and it appeared that most TIDA and PHDA neurons possess NK3R. These findings indicate that, in rodents, KNDy neurons widely project to neurosecretory dopaminergic neurons distributed in the hypothalamus, and may affect them via the NKB-NK3R signaling pathway. PMID- 24815060 TI - Effects of elevated magnesium and substrate on neuronal numbers and neurite outgrowth of neural stem/progenitor cells in vitro. AB - Because a potential treatment for brain injuries could be elevating magnesium ions (Mg(2+)) intracerebrally, we characterized the effects of elevating external Mg(2+) in cultures of neonatal murine brain-derived neural stem/progenitor cells (NSCs). Using a crystal violet assay, which avoids interference of Mg(2+) in the assay, it was determined that substrate influenced Mg(2+) effects on cell numbers. On uncoated plastic, elevating Mg(2+) levels to between 2.5 and 10mM above basal increased NSC numbers, and at higher concentrations numbers decreased to control or lower levels. Similar biphasic curves were observed with different plating densities, treatment durations and length of time in culture. When cells were plated on laminin-coated plastic, NSC numbers were higher even in basal medium and no further effects were observed with Mg(2+). NSC differentiation into neurons was not altered by either substrate or Mg(2+) supplementation. Some parameters of neurite outgrowth were increased by elevated Mg(2+) when NSCs differentiated into neurons on uncoated plastic. Differentiation on laminin resulted in increased neurites even in basal medium and no further effects were seen when Mg(2+) was elevated. This system can now be used to study the multiple mechanisms by which Mg(2+) influences neuronal biology. PMID- 24815061 TI - Three-year cost-effectiveness model for non-animal stabilized hyaluronic acid and dextranomer copolymer compared with sacral nerve stimulation after conservative therapy for the management of fecal incontinence. AB - BACKGROUND: Two new therapies for fecal incontinence (FI) are now available: non animal stabilized hyaluronic acid and dextranomer copolymer (NASHA/Dx) and sacral nerve stimulation (SNS). PURPOSE: This study aimed to determine the cost effectiveness of NASHA/Dx compared with SNS and conservative therapy (CT) for the treatment of FI after CT failure. METHODS: Decision tree models with Markov subbranches were developed to compare all direct costs and outcomes during a 3 year period from the viewpoint of the US third-party payer. Costs (in 2013 US dollars) of devices, medical and surgical care, and hospitalization were included. Outcomes included quality-adjusted life-years (QALYs) and incontinence free days (IFDs). Both costs and outcomes were discounted at an annual rate of 3%. The incremental cost-effectiveness ratio was calculated for each outcome. One way and probabilistic sensitivity analyses were performed to examine robustness of results and model stability. A budget impact analysis was also undertaken to estimate the potential cost and savings of NASHA/Dx for a payer with 1,000,000 covered lives. RESULTS: For the 3-year cost-effectiveness models, the expected cost was $9053 for CT, $14,962 for NASHA/Dx, and $33,201 for SNS. The numbers of QALYs were 1.769, 1.929, and 2.004, respectively. The numbers of IFDs were 128.8, 267.6, and 514.8, respectively. The incremental cost-effectiveness ratios per additional IFD gained were $42.60 for NASHA/Dx vs CT, $73.76 for SNS vs NASHA/Dx, and $62.55 for SNS vs CT. The incremental costs per QALY gained were $37,036 for NASHA/Dx vs CT, $244,509 for SNS vs NASHA/Dx, and $103,066 for SNS vs CT. The budget impact analysis evaluated the financial effect on the health care system of the use of NASHA/Dx and SNS. For the scenarios evaluated, when all of the patients receive NASHA/Dx, the net annual effect to the health care payer budget ranged from $571,455 to $2,857,275. When all of the patients receive SNS, the net annual effect to the health care payer budget ranged from $1,959,323 to $9,796,613. CONCLUSION: Both NASHA/Dx and SNS have produced significant improvements in FI symptoms for affected patients. NASHA/Dx is a cost-effective and more efficient use of resources for the treatment of FI when compared with SNS. The budget impact analysis suggests that although reimbursement for NASHA/Dx treatment initially adds costs to the health care system, it is significantly less expensive than SNS for patients who are candidates for either treatment. PMID- 24815062 TI - Efficacy of prophylactic additional cranial irradiation and intrathecal chemotherapy for the prevention of CNS relapse after allogeneic hematopoietic SCT for childhood ALL. AB - We evaluated the efficacy of CRT and IT chemotherapy, in addition to conditioning including TBI, for the prevention of CNS relapse, in allogeneic HSCT for childhood ALL. From January 1999 to December 2009, a total of 48 patients, without previous or presenting CNS involvement, underwent HSCT for ALL. All patients received myeloablative conditioning including TBI of 12 or 13.2 Gy and IT chemotherapy twice between days -10 and -2 prior to HSCT. Twenty-five patients received CRT prior to TBI (CRT+), and 23 patients did not (CRT-). CRT+ and CRT- patients had a seven-yr EFS rate of 40.0 +/- 9.8% and 41.7 +/- 10.6%, respectively (p = 0.8252). The seven-yr relapse rates for CRT+ and CRT- patients were 45.0 +/- 11.2% and 38.4 +/- 11.6%, respectively (p = 0.7460). CNS relapses were evident in 1 (4.0%) CRT+ patient and 1 (4.4%) CRT- patient (p = 1.000). There were no significant differences in EFS and the probability of CNS relapse between CRT+ and CRT- patients. These results demonstrate that CRT and IT chemotherapy, in addition to conditioning chemotherapy, may not be necessary in childhood ALL patients without previous or presenting CNS involvement. PMID- 24815063 TI - Is quality improvement sustainable? Findings of the American College of Cardiology's Guidelines Applied in Practice. AB - OBJECTIVE: (i) To examine the sustainability of an in-hospital quality improvement (QI) intervention, the American College of Cardiology's Guideline Applied to Practice (GAP) in acute myocardial infarction (AMI). (ii) To determine the predictors of physician adherence to AMI guidelines-recommended medication prescribing. DESIGN: Prospective observational study. SETTING: Five mid-Michigan community hospitals. PARTICIPANTS: 516 AMI patients admitted consecutively 1 year after the GAP intervention. These patients were compared with 499 post-GAP patients. MAIN OUTCOME MEASURES: The main outcome was adherence to medication use guidelines. Predictors of medication use were determined using multivariable logistic regression analysis. RESULTS: 1 year after GAP implementation, adherence to most medications remained high. We found a significant increase in beta blocker (BB) use in-hospital (87.9 vs. 72.1%, P < 0.001) whereas cholesterol assessment within 24 h (79.5 vs. 83.6%, P > 0.225) did not change significantly. However, discharge aspirin (83 vs. 90%, P < 0.018) and BB prescriptions (84 vs. 92%, P < 0.016) dropped to preintervention rates. Discharge angiotensin converting enzyme inhibitor and treatment of patients with low-density lipoprotein of >= 100 were unchanged. Predictors of receiving appropriate medications were male gender (for aspirin and BBs) and treatment with percutaneous coronary intervention compared with coronary artery bypass graft. Notably, prescription rates for discharge medications differed significantly by hospital. CONCLUSIONS: Early benefits of the Mid-Michigan GAP intervention on guideline use were only partially sustained at 1 year. Differences in guideline adherence by treatment modality and hospital demonstrate challenges for follow-up phases of GAP. Additional strategies to improve sustainability of QI efforts are urgently needed. PMID- 24815064 TI - Development and validation of a clinical prediction score (the SCOPE score) to predict sedation outcomes in patients undergoing endoscopic procedures. AB - BACKGROUND: Use of anaesthesia services during endoscopy has increased, increasing cost of endoscopy. AIM: To identify risk factors for and develop a clinical prediction score to predict difficult conscious sedation. METHODS: We performed a retrospective cross-sectional study of all patients who underwent oesophagogastroduodenoscopy (OGD) and colonoscopy with endoscopist-administered conscious sedation. The endpoint of difficult sedation was a composite of receipt of high doses (top quintile) of benzodiazepines and opioids, or the documentation of agitation or discomfort. Univariate and multivariate analyses were performed to measure association of the outcome with: age, sex, body mass index (BMI), procedure indication, tobacco use, self-reported psychiatric history, chronic use of benzodiazepines, opioids or other psychoactive medications, admission status and participation of a trainee. A clinical prediction score was constructed using statistically significant variables. RESULTS: We identified 13,711 OGDs and 21,763 colonoscopies, 1704 (12.4%) and 2299 (10.6%) of which met the primary endpoint, respectively. On multivariate analysis, factors associated with difficulty during OGD were younger age, procedure indication, male sex, presence of a trainee, psychiatric history and benzodiazepine and opioid use. Factors associated with difficulty during colonoscopy were younger age, female sex, BMI <25, procedure indication, tobacco, benzodiazepine, opioid and other psychoactive medication use. A clinical prediction score was developed and validated that may be used to risk-stratify patients undergoing OGD and colonoscopy across five risk classes. CONCLUSIONS: Using the Stratifying Clinical Outcomes Prior to Endoscopy (SCOPE) score, patients may be risk stratified for difficult sedation/high sedation requirement during OGD and colonoscopy. PMID- 24815065 TI - Analysis of catalytic gas products using electron energy-loss spectroscopy and residual gas analysis for operando transmission electron microscopy. AB - Operando transmission electron microscopy (TEM) of catalytic reactions requires that the gas composition inside the TEM be known during the in situ reaction. Two techniques for measuring gas composition inside the environmental TEM are described and compared here. First, electron energy-loss spectroscopy, both in the low-loss and core-loss regions of the spectrum was utilized. The data were quantified using a linear combination of reference spectra from individual gasses to fit a mixture spectrum. Mass spectrometry using a residual gas analyzer was also used to quantify the gas inside the environmental cell. Both electron energy loss spectroscopy and residual gas analysis were applied simultaneously to a known 50/50 mixture of CO and CO2, so the results from the two techniques could be compared and evaluated. An operando TEM experiment was performed using a Ru catalyst supported on silica spheres and loaded into the TEM on a specially developed porous pellet TEM sample. Both techniques were used to monitor the conversion of CO to CO2 over the catalyst, while simultaneous atomic resolution imaging of the catalyst was performed. PMID- 24815066 TI - SHSST cyclodextrin complex prevents the fibrosis effect on CCl4-induced cirrhotic cardiomyopathy in rats through TGF-beta pathway inhibition effects. AB - Patients with liver cirrhosis also have subtle cardiac structure or function abnormalities. This cardiac dysfunction commonly occurs in 56% of waiting orthotopic liver transplantation (OLT) patients and is defined as cirrhotic cardiomyopathy (CCM). Up to now, there is no standard treatment because CCM does not have a solidly established diagnosis and is based on high clinical suspicion. The liver function of CCM is particularly limited, making patients vulnerable to more drug treatments. Here, we use silymarin (100 mg/kg/day), baicalein (30 mg/kg/day), San Huang Shel Shin Tang (SHSST, 30 mg/kg/day) and beta-cyclodextrin modified SHSST (SHSSTc, 30 and 300 mg/kg/day) treatments for a CCl4-induced CCM rat model. The results show that silymarin, baicalein and SHSST treatments can only slightly reduce the collagen accumulation in CCM rat hearts. However, SHSSTc treatment protects the heart in CCM and significantly inhibits collagen acumination and the fibrosis regulating transforming growth factor-beta (TGF beta) pathway expression. SHSSTc treatments further reduced the heart weight and the ratio between left ventricular weight (LVW) and tibia length (TL). This experimental data show that water solubility improved beta-cyclodextrin modified Chinese herbal medicine formula (SHSSTc) can provide an excellent heart protection effect through TGF-beta pathway inhibition. PMID- 24815067 TI - MADS-box transcription factor SsMADS is involved in regulating growth and virulence in Sclerotinia sclerotiorum. AB - MADS-box proteins, a well-conserved family of transcription factors in eukaryotic organisms, specifically regulate a wide range of cellular functions, including primary metabolism, cell cycle, and cell identity. However, little is known about roles of the MADS-box protein family in the fungal pathogen Sclerotinia sclerotiorum. In this research, the S. sclerotiorum MADS-box gene SsMADS was cloned; it encodes a protein that is highly similar to Mcm1 orthologs from Saccharomyces cerevisiae and other fungi, and includes a highly conserved DNA binding domain. MADS is a member of the MADS box protein SRF (serum response factor) lineage. SsMADS function was investigated using RNA interference. Silenced strains were obtained using genetic transformation of the RNA interference vectors pS1-SsMADS and pSD-SsMADS. SsMADS expression levels in silenced strains were analyzed using RT-PCR. The results showed that SsMADS mRNA expression in these silenced strains was reduced to different degrees, and growth rate in these silenced strains was significantly decreased. Infecting tomato leaflets with silenced strains indicated that SsMADS was required for leaf pathogenesis in a susceptible host. Our results suggest that the MADS-box transcription factor SsMADS is involved in S. sclerotiorum growth and virulence. PMID- 24815068 TI - CB2 receptor activation inhibits melanoma cell transmigration through the blood brain barrier. AB - During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB). The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2); therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A), GPR18 (transcriptional variant 1) and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A), GPR18 (transcriptional variants 1 and 2), GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma. PMID- 24815069 TI - Microwave assistant synthesis, antifungal activity and DFT theoretical study of some novel 1,2,4-triazole derivatives containing pyridine moiety. AB - In order to investigate the biological activity of novel 1,2,4-triazole compounds, seventeen novel 1,2,4-triazole derivatives containing pyridine moiety were synthesized under microwave assistant condition by multi-step reactions. The structures were characterized by 1H NMR, MS and elemental analyses. The target compounds were evaluated for their fungicidal activities against Stemphylium lycopersici (Enjoji) Yamamoto, Fusarium oxysporum. sp. cucumebrium, and Botrytis cinerea in vivo, and the results indicated that some of the title compounds displayed excellent fungicidal activities. Theoretical calculation of the title compound was carried out with B3LYP/6-31G (d,p). The full geometry optimization was carried out using 6-31G (d,p) basis set, and the frontier orbital energy, atomic net charges were discussed, and the structure-activity relationship was also studied. PMID- 24815070 TI - Synthesis and characterization of novel purpurinimides as photosensitizers for photodynamic therapy. AB - A series of novel purpurinimides with long wavelength absorption were designed and synthesized to develop novel and potential photosensitizers. These compounds were investigated through reduction, oxidation, rearrangement reaction and amidation reactions of methyl pheophorbide a. They demonstrated a considerable bathochromic shift of the major absorption band in the red region of the optical spectrum (695-704 nm). Newly synthesized purpurinimides were screened for their antitumor activities, and showed higher photodynamic efficiency against A549 cell lines as compared to purpurin-18 methyl ester. The results revealed the novel purpurinimides could be potential photosensitizers. PMID- 24815071 TI - Inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death in human bladder cancer cells in vitro. AB - Statins are cholesterol reduction agents that exhibit anti-cancer activity in several human cancers. Because autophagy is a crucial survival mechanism for cancer cells under stress conditions, cooperative inhibition of autophagy acts synergistically with other anti-cancer drugs. Thus, this study investigates whether combined treatment of atorvastatin and autophagy inhibitors results in enhancing the cytotoxic effects of atorvastatin, upon human bladder cancer cells, T24 and J82, in vitro. To measure cell viability, we performed the EZ-Cytox cell viability assay. We examined apoptosis by flow cytometry using annexin V/propidium iodide (PI and western blot using procaspase-3 and poly (ADP-ribose) polymerase (PARP) antibodies. To examine autophagy activation, we evaluated the co-localization of LC3 and LysoTracker by immunocytochemistry, as well as the expression of LC3 and p62/sequestosome-1 (SQSTM1) by western blot. In addition, we assessed the survival and proliferation of T24 and J82 cells by a clonogenic assay. We found that atorvastatin reduced the cell viability of T24 and J82 cells via apoptotic cell death and induced autophagy activation, shown by the co localization of LC3 and LysoTracker. Moreover, pharmacologic inhibition of autophagy significantly enhanced atorvastatin-induced apoptosis in T24 and J82 cells. In sum, inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death in human bladder cancer cells in vitro, providing a potential therapeutic approach to treat bladder cancer. PMID- 24815072 TI - Ionic liquid electrolytes for Li-air batteries: lithium metal cycling. AB - In this work, the electrochemical stability and lithium plating/stripping performance of N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr14TFSI) are reported, by investigating the behavior of Li metal electrodes in symmetrical Li/electrolyte/Li cells. Electrochemical impedance spectroscopy measurements and galvanostatic cycling at different temperatures are performed to analyze the influence of temperature on the stabilization of the solid electrolyte interphase (SEI), showing that TFSI-based ionic liquids (ILs) rank among the best candidates for long-lasting Li-air cells. PMID- 24815073 TI - Rationale for the use of upfront whole brain irradiation in patients with brain metastases from breast cancer. AB - Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy. PMID- 24815074 TI - Phenotype profiling of patients with intellectual disability and copy number variations. AB - BACKGROUND: Nowadays the microarray technology allows whole-genome analysis with a high resolution and performance for the genetic diagnosis in any patient with intellectual disability or autism spectrum disorder. However in the immediate future, with the development of massive sequencing systems for application at clinical diagnosis, it will be necessary to have clinical criteria to guide studies. AIM: To perform an exhaustive clinical definition of patients with pathogenic copy number variations in order to establish the clinical criteria most suggestive of this kind of genomic rearrangements. METHOD: We designed and implemented a database to collect 190 different clinical variables (pregnancy, neonatal, facial dysmorphism, congenital anomalies, neurological features and family history) in a series of 246 patients, with developmental delay/intellectual disability. All cases were studied with array comparative genomic hybridization. RESULTS: We have found a pathogenic genomic imbalance in 73 patients. Frequency analysis of all clinical variables showed that growth disorder, abnormalities of hands, low-set ears and hypertelorism are the more frequent features among patients with genomic rearrangements. However other clinical features, such as genital abnormalities and aggressiveness, are more specifically associated with pathogenic copy number variations in spite of their low frequencies in the overall series, yielding higher statistical significance values than other traits. CONCLUSIONS: The genotype-phenotype comparison may be useful to set in the future the main clinical manifestations associated with deletions, duplications and unbalanced translocations. Theses analyses will improve the clinical indications and protocols to implement genomic arrays in the genetic study of patients with neurodevelopment disorders. PMID- 24815076 TI - Bone safety of low-dose glucocorticoids in rheumatic diseases. AB - Glucocorticoids are widely used internationally for the treatment of inflammatory disease, such as rheumatoid arthritis (RA). Although the benefit of glucocorticoids in RA on both disease activity and severity are well known, there remain unanswered questions about the overall bone safety of chronic low-dose glucocorticoids in RA. Debate exists about the merits of glucocorticoids for bone health on the basis of their benefits in promoting activity and reducing proinflammatory cytokines. Overall current evidence supports the view that bone loss is a disease related both to RA and to glucocorticoid use independently. Calcium and vitamin D, along with prescription antiosteoporosis therapies, particularly bisphosphonates and teriparatide, play an important role in stabilizing bone mineral density and potentially lowering spinal fracture risk at the spine. International guidelines provide pathways for appropriate prevention of glucocorticoid-induced osteoporosis (GIOP). Despite the evidence and these guidelines, many patients do not receive adequate management to prevent GIOP. PMID- 24815075 TI - Supervising community health workers in low-income countries--a review of impact and implementation issues. AB - BACKGROUND: Community health workers (CHWs) are an increasingly important component of health systems and programs. Despite the recognized role of supervision in ensuring CHWs are effective, supervision is often weak and under supported. Little is known about what constitutes adequate supervision and how different supervision strategies influence performance, motivation, and retention. OBJECTIVE: To determine the impact of supervision strategies used in low- and middle-income countries and discuss implementation and feasibility issues with a focus on CHWs. DESIGN: A search of peer-reviewed, English language articles evaluating health provider supervision strategies was conducted through November 2013. Included articles evaluated the impact of supervision in low- or middle-income countries using a controlled, pre-/post- or observational design. Implementation and feasibility literature included both peer-reviewed and gray literature. RESULTS: A total of 22 impact papers were identified. Papers were from a range of low- and middle-income countries addressing the supervision of a variety of health care providers. We classified interventions as testing supervision frequency, the supportive/facilitative supervision package, supervision mode (peer, group, and community), tools (self-assessment and checklists), focus (quality assurance/problem solving), and training. Outcomes included coverage, performance, and perception of quality but were not uniform across studies. Evidence suggests that improving supervision quality has a greater impact than increasing frequency of supervision alone. Supportive supervision packages, community monitoring, and quality improvement/problem solving approaches show the most promise; however, evaluation of all strategies was weak. CONCLUSION: Few supervision strategies have been rigorously tested and data on CHW supervision is particularly sparse. This review highlights the diversity of supervision approaches that policy makers have to choose from and, while choices should be context specific, our findings suggest that high-quality supervision that focuses on supportive approaches, community monitoring, and/or quality assurance/problem solving may be most effective. PMID- 24815077 TI - Clonal genetic structure and diversity in populations of an aquatic plant with combined vs. separate sexes. AB - Clonality is often implicated in models of the evolution of dioecy, but few studies have explicitly compared clonal structure between plant sexual systems, or between the sexes in dioecious populations. Here, we exploit the occurrence of monoecy and dioecy in clonal Sagittaria latifola (Alismataceae) to evaluate two main hypotheses: (i) clone sizes are smaller in monoecious than dioecious populations, because of constraints imposed on clone size by costs associated with geitonogamy; (ii) in dioecious populations, male clones are larger and flower more often than female clones because of sex-differential reproductive costs. Differences in clone size and flowering could result in discordance between ramet- and genet-based sex ratios. We used spatially explicit sampling to address these hypotheses in 10 monoecious and 11 dioecious populations of S. latifolia at the northern range limit in Eastern North America. In contrast to our predictions, monoecious clones were significantly larger than dioecious clones, probably due to their higher rates of vegetative growth and corm production, and in dioecious populations, there was no difference in clone size between females and males; ramet- and genet-based sex ratios were therefore highly correlated. Genotypic diversity declined with latitude for both sexual systems, but monoecious populations exhibited lower genotypic richness. Differences in life history between the sexual systems of S. latifolia appear to be the most important determinants of clonal structure and diversity. PMID- 24815078 TI - Does the presence of von Willebrand factor in FVIII-deficient plasma influences the measurement of FVIII inhibitor titres in haemophilia A patients? AB - INTRODUCTION: Reliable measurement of FVIII inhibitor is critical in the follow up of haemophilia A patients. We performed a multicentre study to evaluate whether the presence of von Willebrand factor (VWF) in FVIII-deficient plasma (FVIII-DP) influences FVIII inhibitor titres. METHODS: Six French haematology laboratories participated in this study. Three samples with varying FVIII inhibitor titres (1, 5 and 15 BU/mL) and one sample without any detectable FVIII inhibitor were tested using four different procedures for FVIII inhibitor assay. The Nijmegen method and a modified assay with imidazole were performed using FVIII-DP with and without VWF in the control mixture and as substrate plasma in the FVIII one stage assay (OSA). Each mixture (reference and test) was incubated for two hours at 37 degrees C with buffered normal pool plasma. RESULTS: Higher inhibitor titres were measured in 5 and 15 BU/mL samples when assays were performed with the Nijmegen method and FVIII-DP without VWF. When samples were diluted in imidazole buffer, similar inhibitor titres, close to expected values, were measured whether VWF was present in the FVIII-DP or not. The data obtained were also more accurate when residual FVIII activity levels between 40% and 60% were used to calculate inhibitor titres, despite a linear type I reaction kinetics. CONCLUSION: These results support the hypothesis that reliable FVIII inhibitor titres can be measured without the use of FVIII-DP containing VWF when an imidazole-modified assay is used. PMID- 24815080 TI - Statin therapy is associated with a reduced risk of non-alcoholic fatty liver in overweight individuals. AB - BACKGROUND: Non-alcoholic fatty liver or hepatic steatosis is considered the hepatic manifestation of the metabolic syndrome. Statins are often used by patients with metabolic syndrome, but their effect in steatosis is not well established. AIMS: To study the association between statins and the presence of steatosis. METHODS: In the population-based Rotterdam Study, 2578 subjects underwent liver ultrasonography and had prescription data available. In a cross sectional design, we investigated the effect of current, past, and duration of statin use. Logistic regression analyses were adjusted for age, sex, and other known risk factors. RESULTS: The prevalence of steatosis was 35.3%. We identified 631 current and 359 past statin users. In multivariable analyses, current statin use >2 years was associated with a significantly lower steatosis prevalence [OR 0.43, 95% CI 0.19-0.96]. Stratification by mean body mass index showed that this association was stronger in patients with body mass index >= 27.5 [OR 0.30, 95% CI 0.11-0.81 for current use >2 years], while in patients with body mass index <27.5 the association was non-significant. CONCLUSION: Within the Rotterdam study, in patients with body mass index >= 27.5 current use of statins for >2 years was associated with a lower prevalence of steatosis. PMID- 24815079 TI - Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. AB - The insular cortex (IC) and cingulate cortex (CC) are critically involved in pain perception. Previously we demonstrated that fibromyalgia (FM) patients have greater connectivity between the insula and default mode network at rest, and that changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain. In this study we more thoroughly evaluated the degree of resting-state connectivity to multiple regions of the IC in individuals with FM and healthy controls. We also investigated the relationship between connectivity, experimental pain, and current clinical chronic pain. Functional connectivity was assessed using resting-state functional magnetic resonance imaging in 18 FM patients and 18 age- and sex-matched healthy controls using predefined seed regions in the anterior, middle, and posterior IC. FM patients exhibited greater connectivity between 1) right mid IC and right mid/posterior CC and right mid IC, 2) right posterior IC and left CC, and 3) right anterior IC and left superior temporal gyrus. Healthy controls displayed greater connectivity between left anterior IC and bilateral medial frontal gyrus/anterior cingulate cortex; and left posterior IC and right superior frontal gyrus. Within the FM group, greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds. PERSPECTIVE: These data provide further support for altered resting-state connectivity between the IC and other brain regions known to participate in pain perception/modulation, which may play a pathogenic role in conditions such as FM. We speculate that altered IC connectivity is associated with the experience of chronic pain in individuals with FM. PMID- 24815081 TI - Comment on "No impact of interleukin-28B polymorphisms on spontaneous or drug induced hepatitis delta virus clearance" by Ubaldo Visco-Comandini et al. [Dig. Liver Dis. 2014;46:348-52]. PMID- 24815082 TI - Nonlinear gearshifts control of dual-clutch transmissions during inertia phase. AB - In this paper, a model-based nonlinear gearshift controller is designed by the backstepping method to improve the shift quality of vehicles with a dual-clutch transmission (DCT). Considering easy-implementation, the controller is rearranged into a concise structure which contains a feedforward control and a feedback control. Then, robustness of the closed-loop error system is discussed in the framework of the input to state stability (ISS) theory, where model uncertainties are considered as the additive disturbance inputs. Furthermore, due to the application of the backstepping method, the closed-loop error system is ordered as a linear system. Using the linear system theory, a guideline for selecting the controller parameters is deduced which could reduce the workload of parameters tuning. Finally, simulation results and Hardware in the Loop (HiL) simulation are presented to validate the effectiveness of the designed controller. PMID- 24815085 TI - Clinical profiles of Stevens-Johnson syndrome among Thai patients. AB - The objective of this study was to demonstrate the clinical profiles of Stevens Johnson syndrome (SJS) in Thai patients, and to compare those clinical features between younger and older patients. Medical records of all patients with SJS who were admitted to Srinagarind Hospital Medical School, Khon Kaen, Thailand, from January 2002 to December 2014 were reviewed. Epidemiological features, etiologies, treatment and clinical outcomes were collected. There were 45 patients with SJS during the 10-year period. Females were the majority (57.8%) and the median age was 49 years. Hepatitis was the most frequent complication (67.5%). Phenytoin (15.6%), sulfonamide drugs (15.6%) and allopurinol (13.3%) were implicated as leading causes of SJS. Steroids were prescribed in 37 cases (82.2%). The mortality rate was 4.4%. Comparing older patients to younger patients, allopurinol appeared to be the main instigating drug to develop SJS with an odds ratio of 5.6 (95% confidence interval, 2.8-10.6). In conclusion, clinical features of Thai patients with SJS were similar to other reports. Allopurinol had the strongest association with SJS in older patients as compared to the younger ones. PMID- 24815083 TI - Site-specific labeling of cysteine-tagged camelid single-domain antibody fragments for use in molecular imaging. AB - Site-specific labeling of molecular imaging probes allows the development of a homogeneous tracer population. The resulting batch-to-batch reproducible pharmacokinetic and pharmacodynamic properties are of great importance for clinical translation. Camelid single-domain antibody-fragments (sdAbs)-the recombinantly produced antigen-binding domains of heavy-chain antibodies, also called Nanobodies-are proficient probes for molecular imaging. To safeguard their intrinsically high binding specificity and affinity and to ensure the tracer's homogeneity, we developed a generic strategy for the site-specific labeling of sdAbs via a thio-ether bond. The unpaired cysteine was introduced at the carboxyl terminal end of the sdAb to eliminate the risk of antigen binding interference. The spontaneous dimerization and capping of the unpaired cysteine required a reduction step prior to conjugation. This was optimized with the mild reducing agent 2-mercaptoethylamine in order to preserve the domain's stability. As a proof-of-concept the reduced probe was subsequently conjugated to maleimide-DTPA, for labeling with indium-111. A single conjugated tracer was obtained and confirmed via mass spectrometry. The specificity and affinity of the new sdAb based imaging probe was validated in a mouse xenograft tumor model using a modified clinical lead compound targeting the human epidermal growth factor receptor 2 (HER2) cancer biomarker. These data provide a versatile and standardized strategy for the site-specific labeling of sdAbs. The conjugation to the unpaired cysteine results in the production of a homogeneous group of tracers and is a multimodal alternative to the technetium-99m labeling of sdAbs. PMID- 24815086 TI - The influence of apolipoprotein A5 T-1131C and apolipoprotein E common genetic variants on the levels of hemostatic markers in dyslipidemic patients. AB - OBJECTIVES: The aim of this study was to evaluate the relationships of the T 1131C (rs662799) polymorphism variants of apolipoprotein A5 (Apo A5) gene and variants of apolipoprotein E (Apo E) gene common polymorphism (rs429358, rs7412) to selected hemostatic markers. STUDY DESIGN AND METHODS: We examined 590 asymptomatic dyslipidemic patients, subsequently divided into MetS+ (n=146) and MetS- (n=444) groups according to the criteria for identification of the metabolic syndrome (MetS). We compared variant frequencies and differences in levels of hemostatic markers according to Apo A5, Apo E and Apo A5/Apo E common variants. RESULTS: The -1131C Apo A5 minor variant was associated with elevated tissue plasminogen activator (tPA) in comparison to TT genotype (p<0.001), but not in the MetS+ group. The analysis of Apo A5/Apo E common variants in all subjects revealed that the presence of -1131C minor allele has always been associated with higher levels of tPA in comparison with T allele, regardless of Apo E genotype. Also the presence of minor Apo E2 allele led to elevated tPA concentrations in both T and C carriers. In addition, common -1131C/E2 variant was associated with the highest tPA levels. CONCLUSION: We demonstrated a remarkable association especially between the -1131C Apo A5 variant and increased tPA levels in asymptomatic dyslipidemic patients. PMID- 24815088 TI - Role of self-assembled surfactant structure on the spreading of oil on flat solid surfaces. AB - Uniform spreading of oil on solid surfaces is important in many processes where proper lubrication is required and this can be controlled using surfactants. The role of oil-solid interfacial self-assembled surfactant structure (SASS) in oil spreading is examined in this study for the case of hexadecane-surfactant droplet spreading on a flat horizontal copper surface, with triphenyl phosphorothionate surfactants having varying chain lengths (0 to 9). It is shown that the frictional forces (F(SASS)) as determined by the SASS regulate droplet spreading rate according to surfactant chain length; surfactants with longer chains led to higher reduction in the spreading rate. The extent of such forces, F(SASS), depends on the surfactant density of the evolving SASS, and specific configuration the evolving SASS exhibit as per the orientations of the surfactant chains therein. Thus, F(SASS)=[k(1)+k(2(t))] Gamma(delta(t)), where Gamma(delta(t)) is the surfactant adsorption density of SASS at time 't' during evolution, and, k(1) and k(2(t)) are the force coefficients for Gamma(delta(t)) and orientations (as a function of spreading time) of the surfactant chains respectively. As a SASS evolves/grows along with adsorption of surfactants at the spreading induced fresh interface, the k1Gamma(delta(t)) component of F(SASS) increases and contributes to reduction in the net spreading force (S). With a decrease in the net spreading force, the existence of a cross-over period, during which the transition of the spatial dynamics of the chains from disordered to realignment/packing induced ordered orientation occurs, has been inferred from the F(SASS) vs. chain length relationships. Such relationships also suggested that the rate of realignment/packing is increased progressively particularly due the realignment/packing induced decrease in the net spreading force. Therefore, the realignment process is a self-induced process, which spans a measurable period of time (several minutes), the cross-over period, during which the net spreading force decreases essentially due to such self-induced process. PMID- 24815087 TI - Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells. AB - Antigen presenting cells (APCs), including macrophages and dendritic cells, are early and sustained targets of Ebola virus (EBOV) infection in vivo. Because EBOV activates mitogen-activated protein kinase (MAPK) signaling upon infection of APCs, we evaluated the effect of pyridinyl imidazole inhibitors of p38 MAPK on EBOV infection of human APCs and EBOV mediated cytokine production from human DCs. The p38 MAPK inhibitors reduced viral replication in PMA-differentiated macrophage-like human THP-1 cells with an IC50 of 4.73MUM (SB202190), 8.26MUM (p38kinhIII) and 8.21MUM (SB203580) and primary human monocyte-derived dendritic cells (MDDCs) with an IC50 of 2.67MUM (SB202190). Furthermore, cytokine production from EBOV-treated MDDCs was inhibited in a dose-dependent manner. A control pyridinyl imidazole compound failed to inhibit either EBOV infection or cytokine induction. Using an established EBOV virus-like particle (VLP) entry assay, we demonstrate that inhibitor pretreatment blocked VLP entry suggesting that the inhibitors blocked infection and replication at least in part by blocking EBOV entry. Taken together, our results indicate that pyridinyl imidazole p38 MAPK inhibitors may serve as leads for the development of therapeutics to treat EBOV infection. PMID- 24815089 TI - Retention of corneodesmosomes and increased expression of protease inhibitors in dandruff. AB - BACKGROUND: Dandruff is a common, relapsing and uncomfortable scalp condition affecting a large proportion of the global population. The appearance of flakes on the scalp and in the hair line, and associated itch are thought to be consequences of a damaged skin barrier, altered corneocyte cohesion and abnormal desquamation in dandruff. The balance between skin proteases and protease inhibitors is essential for driving the key events, including corneodesmosome degradation, in the desquamation process and to maintain stratum corneum (SC) barrier integrity. OBJECTIVES: To investigate the distribution of corneodesmosomes, the key component of the SC cohesivity and barrier function, and the protease inhibitors lympho-epithelial Kazal-type-related inhibitor (LEKTI 1) and squamous cell carcinoma antigen (SCCA1) in the scalp of dandruff-affected participants. METHODS: The methods utilized were immunohistochemistry, scanning immunoelectron microscopy, phase-contrast microscopy, Western blotting and serine protease activity assay on tape-stripped SC or scalp skin biopsies. RESULTS: In SC samples from healthy subjects, corneodesmosomes were peripherally located in the corneocytes. In samples of dandruff lesions, corneodesmosomes were located both peripherally and on the entire surface area of the corneocytes. LEKTI-1 and SCCA1 protein levels and parakeratosis were found to be highly elevated in the lesional samples. CONCLUSIONS: The persistence of nonperipheral corneodesmosomes is a characteristic feature of the perturbed desquamation seen in dandruff. The increased expression levels of LEKTI-1 and SCCA1 are consistent with the view that the dandruff condition is characterized by an imbalance in protease-protease inhibitor interaction in the SC. PMID- 24815090 TI - Safety of excisional inguinal lymph node biopsies performed for research purposes in HIV-1-infected women and men. AB - BACKGROUND: Most HIV-1 replication occurs in secondary lymphoid tissues, and evaluating these tissues is crucial to investigations of pathogenesis. Inguinal lymph nodes (LN) are obtained frequently for these studies as they are readily detectable in most individuals and provide abundant numbers of cells. Knowledge of the outcomes of inguinal LN excision for research purposes is important to inform accurately study participants and researchers of the potential risks. METHODS: Data on surgical complications were collected in real time in HIV-1 infected subjects who underwent excisional inguinal LN biopsies for research purposes from February 1997 through June 2011. Data were analyzed retrospectively to determine the frequency of surgical complications using the Fisher exact test and non-parametric testing. RESULTS: Eighty-seven research subjects underwent a total of 95 LN excisions. Thirty-six percent of subjects were female, 53% were white, 26% were black, 16% Hispanic, and 2% Native American. Median age was 36 y (22-52). The median CD4+ T cell count was 478 cell/mm(3) (range, 57-1117) and the median plasma HIV-1 RNA concentration was 4.1 log10copies/mL (range, 1.7-5.9). Minor complications including seroma, transient lymphedema, hematoma, and allergic reaction to surgical tape, occurred in 10% of procedures. Complications that required medical attention occurred in an additional 10% of procedures, and included cellulitis (5%), superficial incisional surgical site infection (3%), and seroma requiring aspiration (1%). Subjects with complications had a lower BMI (25; range, 16-38; n=12) than others (28; range, 19-57; n=40; p=0.05) and tended to have higher platelets, (median, 259*10(9)/L; range, 196-332; vs. 233*10(9)/L; range, 44-633; p=0.07). No other clinical or laboratory characteristics were associated with complications (p>=0.3). CONCLUSIONS: Lymph node excision for research purposes is generally safe in a diverse group of chronically HIV-1 infected women and men, but can result in complications in a minority of subjects. No predictors of complications were identified. PMID- 24815091 TI - Experience in judging intent to harm modulates parahippocampal activity: an fMRI study with experienced CCTV operators. AB - Does visual experience in judging intent to harm change our brain responses? And if it does, what are the mechanisms affected? We addressed these questions by studying the abilities of Closed Circuit Television (CCTV) operators, who must identify the presence of hostile intentions using only visual cues in complex scenes. We used functional magnetic resonance imaging to assess which brain processes are modulated by CCTV experience. To this end we scanned 15 CCTV operators and 15 age and gender matched novices while they watched CCTV videos of 16 sec, and asked them to report whether each clip would end in violence or not. We carried out four separate whole-brain analyses including 3 model-based analyses and one analysis of intersubject correlation to examine differences between the two groups. The three model analyses were based on 1) experimentally pre-defined clip activity labels of fight, confrontation, playful, and neutral behaviour, 2) participants' reports of violent outcomes during the scan, and 3) visual saliency within each clip, as pre-assessed using eye-tracking. The analyses identified greater activation in the right superior frontal gyrus for operators than novices when viewing playful behaviour, and reduced activity for operators in comparison with novices in the occipital and temporal regions, irrespective of the type of clips viewed. However, in the parahippocampal gyrus, all three model-based analyses consistently showed reduced activity for experienced CCTV operators. Activity in the anterior part of the parahippocampal gyrus (uncus) was found to increase with years of CCTV experience. The intersubject correlation analysis revealed a further effect of experience, with CCTV operators showing correlated activity in fewer brain regions (superior and middle temporal gyrus, inferior parietal lobule and the ventral striatum) than novices. Our results indicate that long visual experience in action observation, aimed to predict harmful behaviour, modulates brain mechanisms of intent recognition. PMID- 24815092 TI - Positron annihilation in cardo-based polymer membranes. AB - Positron annihilation lifetime spectroscopy (PALS) is applied to a series of bis(aniline)fluorene and bis(xylidine)fluorene-based cardo polyimide and bis(phenol)fluorene-based polysulfone membranes. It was found that favorable amounts of positronium (Ps, the positron-electron bound state) form in cardo polyimides with the 2,2-bis(3,4-dicarboxyphenyl) hexafluoropropane dianhydride (6FDA) moiety and bis(phenol)fluorene-based cardo polysulfone, but no Ps forms in most of the polyimides with pyromellitic dianhydride (PMDA) and 3,3',4,4' biphenyltetracarboxylic dianhydride (BTDA) moieties. A bis(xylidine)fluorene based polyimide membrane containing PMDA and BTDA moieties exhibits a little Ps formation but the ortho-positronium (o-Ps, the triplet state of Ps) lifetime of this membrane anomalously shortens with increasing temperature, which we attribute to chemical reaction of o-Ps. Correlation between the hole size (V(h)) deduced from the o-Ps lifetime and diffusion coefficients of O2 and N2 for polyimides with the 6FDA moiety and cardo polysulfone showing favorable Ps formation is discussed based on free volume theory of gas diffusion. It is suggested that o-Ps has a strong tendency to probe larger holes in rigid chain polymers with wide hole size distributions such as those containing cardo moieties, resulting in deviations from the previously reported correlations for common polymers such as polystyrene, polycarbonate, polysulfone, and so forth. PMID- 24815093 TI - Oligo(phenylene ethynylene) glucosides: modulation of cellular uptake capacity preserving light ON. AB - A new family of oligo(phenylene ethynylene) (OPE) glucosides has been prepared and characterized. Our results demonstrate that fine-tuning of their photophysical properties can be obtained by acting on the electronics of the core and molecular skeleton. Modulation of the hydrophobic chain length and substituents on the central moieties influences the bioaffinity too. In particular, introducing a NMe2 group on the aromatic central core affords a highly efficient biocompatible fluorescent probe that can be taken up in cytoplasmic vesicles of HEp-2 cells (cells from epidermoid carcinoma larynx tissue). The photophysical behavior, high quantum yield, and stability open the way to the use of the OPE family as stains for cellular imaging analysis by fluorescence microscopy. PMID- 24815094 TI - Inhaled versus nebulised tobramycin: a real world comparison in adult cystic fibrosis (CF). AB - BACKGROUND: There are no published data on real-life clinical experience comparing inhaled antibiotic therapy via new rapid delivery systems with nebulised antibiotic therapy in CF. This real world study compares safety, effectiveness and tolerability using tobramycin inhaled powder (TIP) versus tobramycin inhaled solution (TIS). METHODS: Adult patients with CF commencing TIP (n=78) completed a questionnaire assessing safety, efficacy, tolerability, patient-satisfaction and self-reported adherence to TIS at baseline and during 12 months of TIP therapy. FEV1% predicted and exacerbation rate were recorded at each visit. RESULTS: There was a significant improvement in adherence scores, with a significant decrease in the number of intravenous antibiotic courses received during 12 months of TIP compared with the preceding 12 months using TIS. 94% of patients who had previously used TIS preferred TIP therapy over TIS. CONCLUSIONS: Inhaled powder tobramycin in CF is associated with improved adherence, tolerability and decreased exacerbation rates compared to nebulised treatment in real-life practice. PMID- 24815095 TI - The use of a nerve stimulation test to confirm sacrococcygeal epidural needle placement in cats. AB - OBJECTIVE: To determine if a nerve stimulation test (NST) could act as a monitoring technique to confirm sacrococcygeal epidural needle placement in cats. STUDY DESIGN: Prospective experimental trial in a clinical setting. ANIMALS: Twenty-four adult cats, scheduled for a therapeutic procedure where epidural anesthesia was indicated. METHODS: Under general anesthesia, an insulated needle was inserted through the S3 -Cd1 intervertebral space guided by the application of a fixed electrical current (0.7 mA) until a motor response was obtained. The NST was considered positive when the epidural nerve stimulation produced a motor response of the muscles of the tail, whereas it was considered negative when no motor response was evoked. In the NST positive cases, 0.3 mL kg(-1) of 0.5% bupivacaine was administrated before needle withdrawal. Ten minutes after injection, epidural blockade was confirmed by the loss of perineal (anal), and pelvic limbs reflexes (patellar and withdrawal). RESULTS: The use of a fixed electrical stimulation current of 0.7 mA resulted in correct prediction of sacrococcygeal epidural injection, corroborated by post bupivacaine loss of perineal and pelvic limb reflexes, in 95.8% of the cases. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrates the feasibility of using, in a clinical setting, an electrical stimulation test as an objective and in real-time method to confirm sacrococcygeal epidural needle placement in cats. PMID- 24815096 TI - Measurement of tritium with high efficiency by using liquid scintillation counter with plastic scintillator. AB - The detection efficiencies of tritium samples by using liquid scintillation counter with hydrophilic plastic scintillator (PS) was approximately 48% when the sample of 20 MUL was held between 2 PS sheets treated by plasma. The activity and count rates showed a good relationship between 400 Bq to 410 KBq mL(-1). The calculated detection limit of 2 min measurement by the PS was 13 Bq mL(-1) when a confidence was 95%. The plasma method for PS produces no radioactive waste. PMID- 24815097 TI - Feasibility and acceptability of a computer-based tool to improve contraceptive counseling. AB - OBJECTIVE: The objective was to test the feasibility and acceptability of a computerized tool, Smart Choices, designed to enhance the quality of contraceptive counseling in family planning clinics. The tool includes (a) a questionnaire completed by patients and summarized in a printout for providers and (b) a birth control guide patients explore to learn about various contraceptive methods. STUDY DESIGN: In 2 family planning clinics, we conducted interviews with 125 women who used the Smart Choices computerized tool and 7 providers. RESULTS: Smart Choices integrated into clinic flow well in one clinic, but less well in the other, which had very short waiting times. Patients were generally enthusiastic about Smart Choices, including its helpfulness in preparing them and their providers for the counseling session and increasing their knowledge of contraceptive methods. Providers varied in how much they used the printout and in their opinions about its usefulness. Some felt its usefulness was limited because it overlapped with the clinic's intake forms or because it did not match with their concept of counseling needs. Others felt it provided valuable information not collected by intake forms and more honest information. Some found Smart Choices to be most helpful with patients who were unsure what method they wanted. CONCLUSIONS: Smart Choices is feasible to implement and well received by patients, but modifications are needed to increase provider enthusiasm for this tool. IMPLICATIONS: The Smart Choices tool requires refinement before widespread dissemination. PMID- 24815098 TI - RU OK? The acceptability and feasibility of remote technologies for follow-up after early medical abortion. AB - OBJECTIVES: We tested the effectiveness and feasibility of remote communication technologies to increase follow-up after early medical abortion. STUDY DESIGN: Women (n=999) were randomized to 'remote' follow-up incorporating a low sensitivity pregnancy test and standardized symptom questionnaire administered online, by text message or telephone by a non-clinical call center operator 2 weeks after treatment, or to 'clinic-based' follow-up with ultrasound at 1 week. Women in the clinic-based group who could not return performed a high-sensitivity pregnancy test at 3 weeks and had a telephone call with clinic staff. The primary outcome was completion of follow-up. Rates of complications, acceptability and preferences were compared. RESULTS: The overall follow-up rate did not differ by group {clinic-based, 73% vs. remote, 69%; risk ratio (RR) 1.0 [95% confidence interval (CI) 0.9-1.2]}. In the clinic-based group, 83% did not return for an ultrasound scan and were followed up by phone. In the remote group, follow-up by phone or text was more successful than online (text: 75.4%; phone: 73.7%; online: 46.5%, p<.001). The proportion of women receiving additional care was 9% in the clinic-based group and was 4% in the remote group [RR 1.8 (95% CI 1.1-3.1)]. Most women found their follow-up method acceptable but would prefer follow-up by phone or text message if needed in future. CONCLUSIONS: Follow-up after medical abortion using remote communication is feasible and, for most women, preferable to a clinic visit. IMPLICATIONS: Medical abortion protocols typically use follow up visits to ensure early identification of complications. This study demonstrates that follow-up can be achieved using remote communication technologies. This model may reduce the burden of multiple clinic visits on patients and providers. PMID- 24815099 TI - Extended use of the intrauterine device: a literature review and recommendations for clinical practice. PMID- 24815100 TI - Postpartum contraception: optimizing interpregnancy intervals. PMID- 24815101 TI - Side effects unrelated to disease activity and acceptability of highly effective contraceptive methods in women with systemic lupus erythematosus: a randomized, clinical trial. AB - OBJECTIVES: To assess the side effects unrelated to disease activity and the acceptability of combined oral contraceptives (COCs), progestin-only pills (POPs) and copper-releasing intrauterine devices (IUDs) in women with systemic lupus erythematosus (SLE). STUDY DESIGN: A randomized clinical trial including 162 women with SLE, assigned to COC (n=54), POP (n=54) or IUD (n=54). Follow-up visits were conducted after 1, 2, 3, 6, 9 and 12 months of treatment to monitor the presence of symptoms, changes in body weight and blood pressure as well as the development of health problems other than those relating to lupus. Reasons for discontinuation and satisfaction with the use of the assigned method were recorded at the end of treatment. Statistical analysis included descriptive statistics, repeated measure analyses and Kaplan-Meier curves. RESULTS: Significantly different discontinuation rates due to any reason [35%, 55%, 29% (p<0.01)] or nonmedical reasons [(11%, 31%, 4% (p<0.05)] were observed among the COC, POP and IUD groups. Nausea was most frequent among COC users, dysmenorrhea among IUD users and acne and hirsutism among POP users. Mean blood pressures remained unchanged. Mild increases in body weight were observed over time in all treatment groups. Most women were satisfied with the use of the assigned contraceptive method. CONCLUSIONS: Oral contraceptives and IUD are acceptable birth control methods for patients with lupus, when counseling and specialized health attention are provided; however, the acceptability of POP appears to be inferior. Side effects unrelated to lupus disease activity are not frequent reasons to discontinue the contraceptive methods. IMPLICATIONS: This study delves into an area that has not been explored among patients with lupus. Our findings on the associated side effects and reasons for discontinuing COCs, POPs or copper bearing IUDs may be useful in improving contraceptive counseling for women with lupus. Furthermore, they also heighten our knowledge on the reasons that may preclude the widespread use of effective contraceptives among lupus patients. PMID- 24815102 TI - Utilizing solar energy for the purification of olive mill wastewater using a pilot-scale photocatalytic reactor after coagulation-flocculation. AB - This study investigated the application of a solar-driven advanced oxidation process (solar Fenton) combined with previous coagulation/flocculation, for the treatment of olive mill wastewater (OMW) at a pilot scale. Pre-treatment by coagulation/flocculation using FeSO4.7H2O (6.67 g L(-1)) as the coagulant, and an anionic polyelectrolyte (FLOCAN 23, 0.287 g L(-1)) as the flocculant, was performed to remove the solid content of the OMW. The solar Fenton experiments were carried out in a compound parabolic collector pilot plant, in the presence of varying doses of H2O2 and Fe(2+). The optimization of the oxidation process, using reagents at low concentrations ([Fe(2+)] = 0.08 g L(-1); [H2O2] = 1 g L( 1)), led to a high COD removal (87%), while the polyphenolic fraction, which is responsible for the biorecalcitrant and/or toxic properties of OMW, was eliminated. A kinetic study using a modified pseudo first-order kinetic model was performed in order to determine the reaction rate constants. This work evidences also the potential use of the solar Fenton process at the inherent pH of the OMW, yielding only a slightly lower COD removal (81%) compared to that obtained under acidic conditions. Moreover, the results demonstrated the capacity of the applied advanced process to reduce the initial OMW toxicity against the examined plant species (Sorghum saccharatum, Lepidium sativum, Sinapis alba), and the water flea Daphnia magna. The OMW treated samples displayed a varying toxicity profile for each type of organism and plant examined in this study, a fact that can potentially be attributed to the varying oxidation products formed during the process applied. Finally, the overall cost of solar Fenton oxidation for the treatment of 50 m(3) of OMW per day was estimated to be 2.11 ? m(-3). PMID- 24815103 TI - Five-year clinical results for treatment of intrabony defects with EMD, guided tissue regeneration and open-flap debridement: a case series. AB - BACKGROUND AND OBJECTIVE: Although regenerative periodontal surgery with EMD or guided tissue regeneration (GTR) has been shown to enhance periodontal regeneration, there are limited data on the long-term results following these treatment modalities. The purpose of the present study was to investigate the long-term clinical outcomes in intrabony defects following regenerative periodontal surgery with EMD or GTR compared with open-flap debridement (OFD). MATERIAL AND METHODS: Data from 40 subjects (44 teeth), with no history of smoking or systemic diseases that could interfere with periodontal disease and who received one of three surgical procedures (EMD, GTR or OFD) for two- or three wall intrabony defects, were analyzed. Postoperative reduction in probing pocket depth, gain in clinical attachment level, gingival recession and percentage bone fill were compared at 1, 3 and 5 years. RESULTS: Reduction in probing pocket depth after GTR was significantly higher than after OFD at 1 and 3 years postoperatively, but there was no difference between the groups at 5 years. The gains in clinical attachment level for EMD (at 3 and 5 years) and for GTR (at 1, 3 and 5 years) were significantly greater than for OFD. Gingival recession after treatment with EMD and GTR showed a tendency toward positive results, whereas no such tendency was observed for OFD. Postoperative percentage bone fill for EMD and GTR was significantly greater than for OFD at 3 and 5 years. CONCLUSIONS: This is a retrospective study and an exploratory report with a high risk of bias. Within the limits of the current study, it may be concluded that superior gains in clinical attachment level and improved percentage bone fill can be obtained with EMD and GTR when compared with OFD, and these can be maintained over a period of 5 years. PMID- 24815104 TI - Production of particulates from transducer erosion: implications on food safety. AB - The formation of metallic particulates from erosion was investigated by running a series of transducers at various frequencies in water. Two low frequency transducer sonotrodes were run for 7.5h at 18kHz and 20kHz. Three high frequency plates operating at megasonic frequencies of 0.4MHz, 1MHz, and 2MHz were run over a 7days period. Electrical conductivity and pH of the solution were measured before and after each run. A portion of the non-sonicated and treated water was partially evaporated to achieve an 80-fold concentration of particles and then sieved through nano-filters of 0.1MUm, 0.05MUm, and 0.01MUm. An aliquot of the evaporated liquid was also completely dried on strips of carbon tape to determine the presence of finer particles post sieving. An aliquot was analyzed for detection of 11 trace elements by Inductively Coupled Plasma Mass Spectroscopy (ICPMS). The filters and carbon tapes were analyzed by FE-SEM imaging to track the presence of metals by EDS (Energy Dispersive Spectroscopy) and measure the particle size and approximate composition of individual particles detected. Light microscopy visualization was used to calculate the area occupied by the particles present in each filter and high resolution photography was used for visualization of sonotrode surfaces. The roughness of all transducers before and after sonication was tested through profilometry. No evidence of formation of nano particles was found at any tested frequency. High amounts of metallic micron sized particles at 18kHz and 20kHz formed within a day, while after 7day runs only a few metallic micro particles were detected above 0.4MHz. Erosion was corroborated by an increase in roughness in the 20kHz tip after ultrasound. The elemental analysis showed that metal leach occurred but values remained below accepted drinking water limits, even after excessively long exposure to ultrasound. With the proviso that the particles measured here were only characterized in two dimensions and could be nanoparticulate in terms of the third dimension, this research suggests that there are no serious health implications resulting from the formation of nanoparticles under the evaluation conditions. Therefore, high frequency transducer plates can be safely operated in direct contact with foods. However, due to significant production of metallic micro-particulates, redesign of lower frequency sonotrodes and reaction chambers is advised to enable operation in various food processing direct-contact applications. PMID- 24815105 TI - Morphology of the lingual papillae in the fishing cat. AB - We examined the dorsal lingual surface of an adult fishing cat (Prionailurus viverrinus) by scanning electron microscopy. The filiform papillae on the lingual apex had several pointed processes. The connective tissue core of the filiform papillae resembleda a well in shape. The filiform papillae on the anterior part of the lingual body were large and cylindrical in shape. The connective tissue core of the filiform papillae consisted of a large conical papilla. The filiform papillae on the central part of the lingual body were large and conical. The connective tissue core of the filiform papillae consisted of a large main process and some secondary processes. The connective tissue core of the fungiform papillae did not have processes. The vallate papillae were surrounded by a groove and a pad. The top of the connective tissue core of the vallate papillae had a rough surface with no spines. PMID- 24815106 TI - Morphology of the lingual papillae in the brush-tailed rat kangaroo. AB - We examined the dorsal lingual surface of an adult brush-tailed rat kangaroo (Bettongia penicillata) by scanning electron microscopy. The filiform and fungiform papillae on the lingual apex and body consisted of a main papilla and secondary papillae. The connective tissue core of the filiform papillae on the lingual apex was cylindrical in shape with a crushed top. The connective tissue core of the filiform papillae on the lingual body had one large and several small processes. The fungiform papillae were round in shape. The connective tissue core of the fungiform papillae had several depressions on its top. The surface of the vallate papillae was rough and the papillae were surrounded by a groove and a pad. Several long conical papillae derived from the posterolateral margin of the tongue where foliate papillae have been shown to be distributed in many other animal species. The long conical papillae were very similar to those of the koala and opossum. PMID- 24815107 TI - Variation of the subscapularis tendon at the fetal glenohumeral joint. AB - We examined the topohistology of the subscapularis tendon at the glenohumeral joint in 10 mid-term (15-16 weeks of gestation) and 10 late-stage (27-32 weeks) human fetuses. At both stages, there were two patterns of terminal course of the subscapularis tendon: 1) the tendon was tightly attached to the medial part of the joint capsule and extended anterosuperiorly along the capsule to the lesser tubercle (7/10 mid-term fetuses; 5/10 late-stage fetuses); 2) the tendon passed superiorly through the joint cavity for a long distance in combination with the subcoracoid bursa opening widely to the joint cavity (3/10 mid-term fetuses; 5/10 late-stage fetuses). The lower glenoid labrum tended to be well developed in the former pattern because the subscapularis tendon did not interfere with the superior extension of the labrum. With only one exception (late stage), the capsule-attaching tendon was seen in fetuses in which the coracoid process was located on the superior side of the lesser tubercle, whereas the intra-articular tendon accompanied the coracoid process at the same supero-inferior level of the tubercle. Thus, the topographical relationship between the coracoid process and lesser tubercle in fetuses seemed to determine the courses of the subscapularis tendon at the glenohumeral joint. The present variation in the subscapularis tendon was likely connected with the adult morphologies of the middle and inferior glenohumeral ligaments or folds, whose variations are well known. PMID- 24815108 TI - Electron microscopic identification of hydrogen peroxide detected in fixed human polymorphonuclear leukocytes during phagocytosis. AB - Polymorphonuclear leukocytes (PMNs) engaged in phagocytosis produce reactive oxygen species (ROS), such as those that occur in an activated NADPH oxidase reaction, to eliminate ingested microorganisms. The translocation of NADPH oxidase components to produce antimicrobial free radicals from the vesicles to the phagosomes may be important. Hydrogen peroxide (H2O2) derived from O2- has been observed by electron microscopy using a cerium method. However, 2'-7' dichlorofluorescin diacetate can also detect H2O2 through fluorescence. The main objective of the present study was to measure the H2O2-dependent fluorescence of PMNs after opsonized zymosan A (OPZ) phagocytosis using a microplate reader under different fixation conditions, including 0.5, 1, and 10% glutaraldehyde (GA) individually for 1, 5, 10, or 30 min. An additional objective was to visualize, through the use of electron microscopic cytochemistry, the process of H2O2 generation in OPZ phagocytic fixed PMNs. The fixed PMNs showed that the largest fluorescent value was produced by a concentration of 0.5% GA for all fixation times. This suggested that the fixation of PMNs with a high concentration of GA inhibited phagocytosis and produced ROS. In the fixed PMNs, electron microscopic results showed that after 1 min of mixing, some PMNs attached to particles and exhibited mild deposits in their secretory vesicles. When PMNs engulfed particles, free radical-producing vesicles had enhanced reaction deposits 10 min later and fused to the phagosomal membrane, releasing numerous free radicals into the lumen. Time-dependent H2O2 production was enhanced in the secretory vesicles, some of which were fused exactly to the phagosome membranes. PMID- 24815109 TI - GATA-dependent regulation of TPO-induced c-mpl gene expression during megakaryopoiesis. AB - Thrombopoietin (TPO) and its receptor, c-Mpl, play the crucial role during megakaryocytopoiesis. Previously, we have shown that the promoter activity of c mpl induced by TPO is modulated by transcription through a PKC-dependent pathway and that GATA(-77) is involved as a positive regulatory element in TPO-induced c mpl gene expression in the megakaryoblastic CMK cells. In this research, to examine participating possibility of GATA promoter element in TPO- induced c-mpl gene expression through a PKC-independent pathway, the promoter activity of site directed mutagenesis and the effect of potein kinase C modulator were measured by a transient transfection assay system. Together with our previous results on the TPO-induced c-mpl promoter, this study indicates destruction of -77GATA in c-mpl promoter decreased the activity by 47.3% under existence of GF109203. These results suggest that GATA promoter element plays significant role in TPO-induced c-mpl gene expression through a PKC-independent pathway. PMID- 24815111 TI - Superficial epithelial keratectomy, cautery, and amniotic membrane transplant for the treatment of painful bullous keratopathy in eyes with poor visual potential. AB - PURPOSE: The aim of this study was to report a new technique for the treatment of painful bullous keratopathy in eyes with poor visual potential. METHODS: Review of technique and outcomes of treated patients. RESULTS: The surgical technique involved superficial epithelial keratectomy, corneal cautery, amniotic membrane transplantation, and temporary bandage contact lens placement. Four patients were treated with this technique. All had significant pain due to bullous keratopathy before the surgery. After a mean follow-up of 16 months (1-42), 3 patients reported complete resolution of pain, and an examination disclosed a smoother corneal surface without bullae. One patient had recurrent pain after the removal of his bandage contact lens 1 month after the surgery. Separation of the amniotic membrane from the underlying cornea was noted. The patient underwent incision of the amniotic membrane with drainage of the fluid and is currently stable. CONCLUSIONS: Superficial epithelial keratectomy, cautery, and amniotic membrane transplantation can be used to treat painful bullous keratopathy in a minimally invasive fashion with improved cosmetic results. PMID- 24815112 TI - Topical cyclosporine A in the treatment of dry eye: a systematic review and meta analysis. AB - PURPOSE: Cyclosporine A (CsA) is considered a potentially effective treatment for dry eye syndrome (DES), which is now one of the most common ocular problems whose exact mechanism is unknown. Because randomized controlled trials (RCTs) reported to date have shown varying results in the efficacy and safety of CsA in different types of DES, we conducted a systematic review and meta-analysis of RCTs on CsA versus placebo in treating DES to evaluate the treatment efficacy and safety of CsA. METHODS: We searched for RCTs published after 1990, in MEDLINE, EMBASE, the Cochrane library, and ClinicalTrials.gov. The RCTs that were included compared topical CsA and placebo for DES treatment by evaluating scores of ocular surface disease index, tear break-up time, or Schirmer test. Cochrane risk of bias tool was used for assessing the risk of bias. RESULTS: We included 12 RCTs involving 3034 eyes of 1660 participants. We observed statistically significant improvements on scores of break-up time (standardized mean difference [SMD], 0.80; 95% confidence interval [CI], 0.13-1.46; I = 95%) and scores of Schirmer test with anesthesia (SMD, 0.78; 95% CI, 0.09-1.46; I = 97%) after treatment with topical CsA. Scores of ocular surface disease index (SMD, 0.77; 95% CI, -1.05 to 2.58; I = 98%) and scores of Schirmer test without anesthesia (SMD, 0.08; 95% CI, -0.11 to 0.27; I = 0%) were not improved. Adverse events (odds ratio [OR], 1.61; 95% CI, 1.28-2.02; I = 21%) were observed. CONCLUSIONS: Topical CsA could be an effective treatment for DES, especially for DES associated with conjunctival injury. Further RCTs with larger sample sizes for different clinical types of DES are warranted to determine the efficacy and limitation for different clinical types of DES. PMID- 24815115 TI - Needs for providing overseas organ transplant medical function and information with eHealth telecare systems-instrument development for health professionals in Taiwan. AB - BACKGROUND: The use of eHealth systems for facilitating overseas organ transplantation (OOT) between 2 medical parties has been discussed. Nevertheless, little information is available about organ transplant health professionals' (OTHPs') needs in using the eHealth telecare systems (eHTSs) for providing OOT medical service. This project attempted to answer this question. METHODS: A purposive sample including OT surgeons (OTSs), registered nurses (RNs), and organ transplant coordinating nurses (OTCNs) was obtained from 5 hospitals in Taiwan. A Delphi research method was used in this research. The subjects were invited to respond to a sequence of surveys to learn their appraisal of the needs in using eHTSs for providing OOT medical service. RESULTS: Twenty-two subjects including surgeons (n = 10), RNs (n = 9), and OTCNs (n = 3) participated in this research. Their years working in the field ranged from 3 to 45 (mean 15.77) years. To learn OTHPs' appraisals of their needs in using eHTSs for providing OOT medical service, system function requirements (SFR) and system information requirements (SIR) for telecare were produced. SFR were identified to encompass the following 9 aspects: (a) safety in the supervisor mechanism for protection of privacy including account, password, and unediting mode of medical prescriptions; (b) unlimited to particular software or hardware; (c) options of related medical term language in English and traditional and simplified Chinese; (d) available any time and anywhere; (e) being able to save print and export medical records by E mail systems under authorization; (f) friendly operation; (g) real-time and accurate information; (h) tape-recording functions (OTHPs may convey important medical information to others); and (i) online mutual communications between OTHPs and their clients. SIR included: (a) a comprehensive preoperative medical profile before departure for another country; (b) a comprehensive medical profile of OOT performed in another country; (c) a comprehensive postoperative treatment profile after return to original country; and (d) physiologic health indicators of long-term recovery in the community. CONCLUSIONS: In this project, OTHPs addressed their tangible needs for operating an eHTS to facilitate OOT. These findings would serve as a valuable reference for eHTS experts to continue to work with OTHPs to move to the next development stage. PMID- 24815113 TI - Catalytic antioxidant AEOL 10150 treatment ameliorates sulfur mustard analog 2 chloroethyl ethyl sulfide-associated cutaneous toxic effects. AB - Our previous studies and other published reports on the chemical warfare agent sulfur mustard (SM) and its analog 2-chloroethyl ethyl sulfide (CEES) have indicated a role of oxidative stress in skin injuries caused by these vesicating agents. We examined the effects of the catalytic antioxidant AEOL 10150 in the attenuation of CEES-induced toxicity using our established skin injury models (skin epidermal cells and SKH-1 hairless mice) to validate the role of oxidative stress in the pathophysiology of mustard vesicating agents. Treatment of mouse epidermal JB6 and human HaCaT cells with AEOL 10150 (50MUM) 1h post-CEES exposure resulted in significant (p < 0.05) reversal of CEES-induced decreases in both cell viability and DNA synthesis. Similarly, AEOL 10150 treatment 1h after CEES exposure attenuated CEES-induced DNA damage in these cells. Similar AEOL 10150 treatments also caused significant (p < 0.05) reversal of CEES-induced decreases in cell viability in normal human epidermal keratinocytes. Cytoplasmic and mitochondrial reactive oxygen species measurements showed that AEOL 10150 treatment drastically ameliorated the CEES-induced oxidative stress in both JB6 and HaCaT cells. Based on AEOL 10150 pharmacokinetic studies in SKH-1 mouse skin, mice were treated with a topical formulation plus subcutaneous injection (5mg/kg) of AEOL 10150 1h after CEES (4mg/mouse) exposure and every 4h thereafter for 12h. This AEOL 10150 treatment regimen resulted in over 50% (p < 0.05) reversal of CEES-induced skin bi-fold and epidermal thickness, myeloperoxidase activity, and DNA oxidation in mouse skin. Results from this study demonstrate the potential therapeutic efficacy of AEOL 10150 against CEES-mediated cutaneous lesions, supporting AEOL 10150 as a medical countermeasure against SM-induced skin injuries. PMID- 24815116 TI - Dilemma of applying telehealth for overseas organ transplantation: comparison on perspectives of health professionals and e-health information and communication technologists in Taiwan. AB - INTRODUCTION: Telehealth is one of the avenues of e-health; it is a voice, image, or document delivery system via the internet and aims to assist patients to prevent disease and to promote health, diagnosis, self-care, and treatment. The purpose of using telehealth for overseas organ transplantation (OOT) was debated. This study aimed to explore the dilemma in applying telehealth for OOT patients from the perspectives of health professionals and e-health information and communication technologists (eh-ICTs) in Taiwan. METHODS: An exploratory qualitative method was used, with a purposive sample of OT health professionals (OTHP) and eh-ICTs in Taiwan. Qualitative data were collected by face-to-face semistructured interviews, and were analyzed by content analysis. RESULTS: Fifty subjects including 10 OT surgeons (OTS), 30 registered nurses (RNs), and 10 eh ICTs participated in this study. Five dilemmas were identified: (1) medical law violation (80%, n = 40 of 50; 100% OTS [n = 10 of 10], 67% RNs [n = 20 of 30], 100% eh-ICTs [n = 10 of 10]); (2) integrating telecommunication and medical systems for OOT (74%, n = 37 of 50; 90% OTS [n = 9 of 10], 73% RNs [n = 22 of 30], 60% eh-ICTs [n = 6 of 10]); (3) the inconsistent caring protocols among medical parties (68%, n = 34 of 50; 80% OTS [n = 8 of 10], 70% RNs [n = 21 of 30], 50% eh-ICTs [n = 5 of 10]); (4) the uncertainty in quality of care in overseas medical institutes (62%, n = 31 of 50; 80% OTS [n = 8 of 10], 60% RNs [n = 18 of 30], 50% eh-ICTs [n = 5 of 10]); and (5) the uncertainty in cost effectiveness (36%, n = 18 of 50; 60% OTS [n = 6 of 10], 17% RNs [n = 5 of 30], 70% eh-ICTs [n = 7 of 10]). CONCLUSIONS: The use of telehealth for OOT is in its infancy. A systematic curriculum with advanced pilots targeted to develop telehealth for OOT will be needed for mutual communication between OTHPs and eh ICTs in the near future. PMID- 24815117 TI - Caring dilemmas and coping strategies for organ transplant recipients and their families: perspective of health professionals in Taiwan. AB - BACKGROUND: Organ transplant health professionals (OTHP) are challenged by more and more sophisticated caring dilemmas raised by organ transplant recipients (OTR) and their families. The purposes of this study were to explore caring dilemmas and the reliable coping strategies applied by OTHPs in Taiwan. METHODS: A qualitative design was used with a purposive sample of OT surgeons and nurses. Data were collected by face-to-face in-depth interviews and analyzed by content analysis. RESULTS: Sixty subjects (43 females, 17 male) participated in this project. They were 16 OT surgeons and 44 nurses, including RNs (n = 29), nurse practitioners (NP, n = 6), and assistant/head nurses (n = 9). Their ages ranged from 25 to 66 (mean = 38.2) years old. Their OT careers ranged from 3 to 40 (mean = 24.7) years for OT surgeons and 0.5 to 15 (years = 4.3) years for the nursing group. Five types of coping strategies for caring dilemmas were reported: (1) developing clinical paths for complex multiple-OT cases, (2) developing OT-expert training programs for interdisciplinary team members, (3) integrating acute and long-term care teams for difficult OT cases and families, (4) holding case conferences for successful and failed cases, and (5) implementing humanistic care training programs. CONCLUSIONS: The findings of this research provide important coping strategies that can help empower OTHPs to care for complex multiple-OT cases with humanitarian expressions. More discussion about cultivation of interdisciplinary OT experts programs, and integration of caring resources are needed in the near future. PMID- 24815118 TI - Holistic care for pediatric organ transplant recipients and their families during their dark postoperative recovery stage in the hospital. AB - INTRODUCTION: This study explored the difficulties in caring for pediatric organ transplant recipients (POTR) and their families during dark recovery experiences (DRE) in the hospital from the perspectives of Taiwan organ transplant health professionals (OTHP). METHODS: A qualitative design was used, with a purposive sample of OTHP including OT surgeons (OTS) and nursing groups. Data were collected by thorough face-to-face interviews and were analyzed using content analysis. RESULTS: Fifty-five subjects (39 female, 16 male) participated in this project. They included 15 OTS and 40 nurses. The nurses included registered nurses (n = 27), nurse practitioners (n = 5), and assistant or head nurses (n = 8). Their ages ranged from 25 to 66 (mean = 38.4) years old. Thirty-eight (69%) had college education, and 17 (31%) had graduate education. Their OT careers ranged from between 3 to 40 (mean = 23.8) years for OTS, and 0.5 to 15 (mean = 4.10) years for the OT nursing group. Five types of caring difficulties were reported: (1) threat of OT failure, (2) work overload, (3) insufficient collaboration within interdisciplinary teams due to incongruent surgical and nursing opinions, (4) poor communication between OTHP and POTR, and (5) lack of competent professional OT care. CONCLUSIONS: The following suggestions were made to help relieve the OTHPs' stress in providing holistic care for POTR and their families during DRE: (1) increasing the amount of experienced OT manpower and professional communication liaisons, (2) providing systematic on-the-job interdisciplinary case seminars and OT workshops, and (3) enhancing the POTR's mental health care and helping manage their distress of DRE. PMID- 24815119 TI - The existence of experience and frequency and severity of related concerns of ethical issues in nursing practice encountered in organ transplantation. AB - OBJECTIVES: The purpose of this study was to elucidate the existence of the experience of and the frequency and severity of related concerns of distressful ethical situations encountered by nursing professionals in organ transplantation. METHODS: An anonymous self-administered questionnaire was mailed to 569 nurses in 79 facilities that performed organ transplantation with living or brain-dead donors who provided approval for this study. The questionnaire, developed according to the Likert method, was composed of 12 items referring to the basic attributes of nursing professionals based on the results of previous studies and the scientific literature, as well as 27 items referring to the presence or absence and the frequency and severity of concerns regarding ethical situations. The data were analyzed using descriptive statistics. RESULTS: The questionnaire was distributed to 569 nursing professionals working in 79 facilities that had provided consent for study participation. Responses were obtained from 218 participants (recovery rate: 38.3%). Among the 3 highest-ranking items, those in the first and second positions in terms of the presence or absence and the frequency of worries were the same as those in the second and third positions in terms of the severity of concerns. In addition, the 3 lower-ranking items also were the same. Among the ethical situations encountered by nursing professionals, the ones most often experienced that caused the most concern were the following: "I have questioned whether it was better for the recipient, who could not do self care after the transplant, to undergo transplantation", and "I have felt that a recipient decided to receive a transplant without considering the importance of posttransplant self-management when making a decision about transplant surgery." CONCLUSIONS: The results indicate that most of the ethical issues related to organ transplantation in nursing practice were experienced because recipients, their families, and donors could not foresee the various problems that might occur after transplantation. PMID- 24815120 TI - A nationwide population-based study of the risk of tuberculosis in different solid organ transplantations in Taiwan. AB - Advances in immunosuppressants for solid organ transplantation (SOT) have improved prevention and treatment of acute rejection as well as reduced the risk of chronic graft damage. However, SOT recipients are prone to developing opportunistic infections because of their long-term immunosuppressed status. Tuberculosis (TB) is a serious opportunistic infection that is associated with increased morbidity and mortality in SOT recipients. However, nationwide population-based research specifically focused on the associations between kidney transplantation (KTx), liver transplantation (LTx), and heart transplantation (HTx), and subsequent TB infection is lacking. This study was conducted using Taiwan's National Health Insurance Research Database, which provided claims data for SOT recipients from 2000 to 2009. Clinical features, treatment, and outcomes were analyzed to determine the risk for TB after SOT. In total, 153 (3.2%) RTx, 19 (1.1%) LTx, and 26 (2.8%) HTx recipients became infected with TB. Compared with non-TB patients, HTx recipients with TB had significantly higher prevalence of older age (P = .037), hypertension (P < .001), and coronary artery disease (CAD) (P = .002). There were also greater percentages of male sex (P = .018), diabetes (P = .029), hyperlipidemia (P = .016), CAD (P < .001), and chronic obstructive pulmonary disease (COPD) (P < .001) in RTx recipients with TB than in those without. In conclusion, posttransplantation TB is a serious problem worldwide, and a high index of suspicion is warranted to ensure early diagnosis and prompt initiation of treatment for TB among SOT patients. In this preliminary study, KTx recipients had a higher risk of TB infection than LTx and HTx recipients, and the high-risk factors were male sex, diabetes, hyperlipidemia, CAD, and COPD. The use of optimal immunosuppressive agents to minimize acute rejection, monitoring of high-risk recipients, prompt diagnosis, and appropriate treatment are required for the management of TB infection in endemic areas such as Taiwan. PMID- 24815121 TI - Effects of an education program on intensive care unit nurses' attitudes and behavioral intentions to advocate deceased donor organ donation. AB - INTRODUCTION: Organ shortage limits the application of organ transplantation. The attitudes of intensive care unit (ICU) staff play an important role in organ advocating. The effects of an education program for ICU nurses on organ advocating were uncertain. The purpose of this study was to explore the effects of an education program based on the Theory of Planned Behavior (TPB) on ICU nurses' attitudes and behavioral intentions to advocate deceased organ donation. METHODS: Participants were recruited from 3 different ICU units in medical centers and were randomly assigned to either an experimental group (n = 61) or a control group (n = 62). The nurses in the experimental group received comprehensive education programs, and the control groups received a brochure only. The outcome parameters were measured by questionnaires at 3 different time points of pretest, posttests immediately after education, and 2 months later. RESULTS: Before education, there was no difference in attitude and behavior intentions between the control and experimental groups. After TPB training, the nurses significantly changed their attitudes and behavior intentions on organ advocating, both immediately (P < .01) and 2 months after the education program (P < .01). In addition, multivariate analysis indicated that TPB training is significantly associated with the change of attitude (P < .01) and behavior intention (P < .05) of organ donation advocacy. CONCLUSIONS: TPB education programs enhanced the ICU nurses' attitudes and behavioral intentions on advocating organ donation. Repeated education is advised to increase the participation of ICU nurses on organ advocacy. PMID- 24815122 TI - Hindering factors and suggestions related to organ donation decisions: perspective of the Taiwan Ali-Shan Tsou aboriginal tribe. AB - BACKGROUNDS AND AIMS: Ali-San Tsou (AST) is one of leading aboriginal tribes in Taiwan with traditional godly beliefs related to life and death. Lacking related knowledge, health professionals (HPs) often failed to help them reach good dying or organ donation (OD). This study aimed to explore hindering factors and suggestions related to OD for good dying from Taiwan AST's own perspective. METHODS: An explorative qualitative design was employed using a purposive sample of the AST tribes from Taiwan. Data were collected with AST residents by face-to face interviews and analyzed by content analysis. RESULTS: Thirty AST residents (16 females and 14 males) with ages ranging from 28 to 78 (mean, 54.5) years completed interviews. Of them, 85% reported various diseases. In this study 73% were Catholics and Christians, 17% held traditional godly believes, and 10% had no religious affiliation. Eight hindering factors were reported: (1) limited information about organs and OD; (2) no qualified organs for donation; (3) worry about lack of forgiveness by ancestors; (4) tribe elders who might not accept concept of OD; (5) intact bodies were required at home during spirit-companion rituals; (6) earth burial with intact bodies was preferred; (7) bodies due to accidental and bad death were impermissible for OD; and (8) worry about possession by the donor's spirit. Seven suggestions were also reported for HPs to enhance AST's OD decisions: (1) starting with friendship and a caring relationship; (2) providing spiritual support from reverent religions; (3) stressing good deeds and honoring tribe folks by OD; (4) avoiding accidental/bad death; (5) providing relevant modern medical knowledge of human organs and OD; (6) introducing OD as part of a good-dying care plan; and (7) demonstrating a respectful discussion mindset about OD. CONCLUSIONS: Eight hindering factors and 7 types of suggestions for enhancing AST aboriginal people's OD decisions were first explored in this project. In the future, HPs are encouraged to invite AST to share the concepts of OT and try to clarify the related concerns with respect for their cultural contexts. With mutual respect, the efforts of sharing and integrating OD into good-dying care would be more possible. PMID- 24815123 TI - International Registry in Organ Donation and Transplantation--2013. AB - OBJECTIVE: The International Registry in Organ Donation and Transplantation (IRODaT) presents final data on worldwide donation and transplantation activity to the community. The purpose of this report is not only to present raw data, but also to make organ donation effectiveness rates a useful tool to reveal similarities between countries on an international level. MATERIALS AND METHODS: The IRODaT Registry produced this report of 2013 statistics thanks to the collaboration of the official reporters, professionals in coordination and transplant services from national transplant organizations, and from the Ministries of Health of each reported country. RESULTS: The actual deceased donors and living donors rates, according to the total number of donors, from 72 countries can be analyzed using IRODaT tools, allowing the comparison and study of tendencies and rates of organ donation and transplantation activity at an international scale. IRODaT has been collecting and disseminating worldwide data since 1998. In this issue, it is shown that most of the countries that report the major activity in actual deceased donors are located in the European region. On the other hand, regarding living organ donation, the country location is more varied, including countries from Africa, Asia, and America. CONCLUSIONS: The results obtained through the IRODaT Registry provide a quick, clear, and illustrative view of worldwide organ donation activity. PMID- 24815124 TI - Correlation between donor age and organs transplanted per donor: our experience in Japan. AB - The shortage of available organs for transplantation is a worldwide issue. To maximize the number of transplantations, increasing the number of organs transplanted per donor (OTPD) is widely recognized as an important factor for improving the shortage. In Japan, we have had 211 donors, 1112 organs transplanted, and 924 recipients receiving the transplants, resulting in 4.4 +/- 1.4 recipients receiving transplants per donor and 5.3 +/- 1.6 OTPD as of February 2013. Because donor age is a well-recognized factor of donor suitability, we analyzed the correlation between donor age group and OTPD. Only the age group 60 to 69 years and the age group 70 to 79 years were significantly different (P < .05) from adjacent age groups. We estimate that a donor under age 70 years has the potential to donate 4.6 to 6.7 organs. PMID- 24815125 TI - Organ donation from brain-dead and circulatory-dead donors: single-institution experiences. AB - Although the number of organ donations is extremely small in Japan, organ donation from brain dead (DBD) donors is increasing since the revised Law for Organ Transplantation was enacted on July 17, 2010. In our institution, organ donations had so far been performed from 247 donors (DCD 242, DBD 5), which is the largest number in Japan. In this study, we analyzed the status of organ donation before and after the enforcement of the revised law. After the enforcement of the revised law, the option of organ donation was shown to the more families of potential donors by the doctors or donor coordinators. However, the final number of donors was almost the same. The frequency of DBD donors of all donors increased (33.3%) as compared to 9.1% before the enforcement of the revised law. Reasons for rejection of donation from donor families were mainly based on the lack of understanding of brain death. To increase organ donation, we should promote social recognition of brain death, having the Organ Donation Card, and discussion of organ donation in each family. PMID- 24815126 TI - Professionalism and human resource management of donor coordinators: results of an international comparison. AB - Through our earlier international survey on professionalism with donor coordinators in 38 countries, we identified 5 factors that comprise professionalism and demonstrated that, of these 5 factors, "pursuit of excellence" significantly affects job performance and sense of fulfillment among donor coordinators. In the present study we conducted an international comparison concerning professionalism and organizational actions to foster coordinators' professionalism and identify implications for Japan. Japan scored significantly lower than other countries in the "pursuit of excellence" factor of professionalism, feedback on the outcome of organ transplantation, peer recognition, and opportunities to educate other staff, which correspond with intrinsic motivation of organizational actions. These results suggested that each hospital must take steps to enhance intrinsic motivation, thereby increasing professionalism that will lead to successful outcomes in the years ahead. PMID- 24815127 TI - Kidney transplantation from cardiac death donors with terminal acute renal failure. AB - OBJECTIVES: Kidney transplantation from donation after cardiac death (DCD) donors with terminal acute renal failure (ARF) is not widely accepted due to concern about the organ quality. Here we report our initial clinical outcomes of kidney transplantation from DCD donors with ARF. MATERIALS AND METHODS: The results of 29 kidney transplants from ARF DCD donors were compared with those of 60 kidney transplants from non-ARF DCD donors performed at our center from August 2011 to March 2013. RESULTS: There was no difference in the incidence of delayed graft function and acute rejection between ARF and non-ARF kidneys (27.6% vs 16.7%, 10.3% vs 8.3%, respectively). Estimated glomerular filtration rate at 12 months was similar between ARF and non-ARF kidneys. With a mean follow-up of 18 months (range 7 to 26 months), actual patient and graft survival rates for ARF DCD recipients were 100% and 96.6%, respectively, which were similar to those of the control group of kidney transplants from non-ARF kidneys (98.3% and 95.0%). CONCLUSIONS: Kidneys from DCD donors with terminal ARF have excellent short-term outcomes and may represent another potential method to safely expand the donor pool. PMID- 24815128 TI - Short-term result of renal transplantation using extracorporeal membrane oxygenation-supported brain-dead donors. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is now widely used to maintain hemodynamic stability after traumatic events among medical centers. It remains unclear whether renal transplantation using ECMO-supported donors carries poorer outcomes. METHODS: From February 2010 to March 2013, we performed 9 renal transplantations (6 females and 3 males) from 5 ECMO-supported donors. Demographic data and clinical outcomes were retrospectively analyzed through medical chart review. RESULTS: The mean follow-up period was 15 +/- 9 months (range: 8-37). Eight of the 9 grafts remained functioning within the follow-up period. One (11.1%) graft loss was noted after repeated acute rejection. Acute rejection occurred in 3/9 (33%) of cases. Delayed graft function was also observed in 3/9 (33%) of cases. CONCLUSION: Renal transplantation using ECMO supported brain-dead donors was not associated with an unacceptably high rate of graft loss in this short-term follow-up. It might be an alternative way to expand donor pools. PMID- 24815129 TI - The impact of donor factors on early graft function in kidney transplantation from donation after cardiac death. AB - Donation after cardiac death (DCD) has the potential to significantly increase the number of organ donors. In this study, we investigate the influence of several donor parameters on the early graft function in kidney transplantation from DCD donors. We performed 58 kidney transplantations from DCD donors. Recipients were divided into 2 groups according to their graft function: normal graft function (NGF), patients who became be free of hemodialysis within 14 days post-transplantation) and delayed graft function (DGF) group, patients who required hemodialysis for longer than 15 days after transplantation). We compared donor age, sex, cause of death, warm and total ischemic time, duration of anuria (urine volume < 10 mL/h), and low blood pressure (systolic blood pressure < 60 mm Hg), usage of catecholamine and vasopressin, serum creatinine on the day of admission and graft retrieval, serum sodium concentration, and body temperature between 2 groups. The number of recipients in NGF and DGF group was 41 and 17. Univariate analysis revealed that duration of anuria (<24 vs >= 24 hours) and usage of catecholamine significantly influenced graft function. Duration of anuria was an independent risk factor for early graft function by multivariate analysis. In cadaveric kidney transplantation from DCD donors, there was a trend to poorer early graft function with donors who suffered from anuria for longer than 24 hours before kidney retrieval. PMID- 24815130 TI - Outcomes of expanded-criteria deceased donor kidney transplantation in a single center. AB - BACKGROUND: In an effort to expand the deceased donor pool, transplant centers have accepted expanded-criteria donors as appropriate for many of the patients in the deceased donor pool. We investigated expanded-criteria deceased donor kidney transplantation and compared the outcomes of kidney transplantation according to donor types. METHODS: We retrospectively analyzed 88 kidney transplantations performed between June 2006 and December 2012. We divided the patient into 4 groups: SCDD, standard-criteria deceased donor; ECDD, expanded-criteria deceased donor; ECMO, donor under extracorporeal membrane oxygenation support; living donor. RESULTS: Deceased and living donor kidney transplantations were performed in 52 (59.1%) and 36 (40.9%) cases, respectively. Among deceased donors, 31 (35.2%) were standard-criteria donors and 14 cases (15.9%) were expanded-criteria donors. Seven (8.0%) donors were under extracorporeal membrane oxygenation support. Mean follow-up was 26.1 +/- 20 months. Average number of HLA mismatches among the donor types was 3.39, 3.07, 3.0, and 2.94 in SCDD, ECDD, ECMO, and living donor groups, respectively (P = .708). Delayed graft function occurred in 2 (6.9%), 3 (21.4%), 3 (42.9%), and 3 (8.3%) patients in the SCDD, ECDD, ECMO, and living donor groups, respectively (P = .043). Episodes of acute rejection within a year occurred in 14 (45.2%), 2 (14.3%), 1 (14.3%), and 6 (16.7%) patients in the SCDD, ECDD, ECMO, and living donor groups, respectively (P = .029). Renal functions after kidney transplantation at 3 months, 6 months, 9 months, and 1 year were not significantly different according to donor types. Graft survival was not different among the different donor types (87.1%, 92.8%, 85.7%, 91.7% in SCDD, ECDD, ECMO, and living donor groups, respectively; P = .67). Patient survival was not different among the different donor types (87.1%, 92.9%, 100%, 97.2% in SCDD, ECDD, ECMO, and living donor group, respectively; P = .36). CONCLUSION: The use of expanded-criteria deceased donor had no impact on graft or patient survival after kidney transplantation. PMID- 24815131 TI - Establishment of educational program for multiorgan procurement from deceased donors. AB - INTRODUCTION: Multiorgan procurement is not an easy procedure and requires special technique and training. Since sufficient donors are not available for on site training in Japan, establishment of the educational program for multiorgan procurement is mandatory. MATERIALS AND METHODS: Development of e-learning and simulation using pigs are our main goals. E-learning contains three dimensional computer graphic (3DCG) animations of the multiorgan procurement, explanation of both donor criteria and procurement procedure, and self-assessment examination. To clarify the donor criteria, the risk factors to 3-month survival of the recipients were analyzed in 138 adult cases of liver transplantation. The 3DCG animation for liver procurement was developed, which was used in the lecture prior to the simulation on August 10, 2013. The results of the examination after this lecture (exam 2013) were compared with the results after the lecture without using animation in 2012 (exam 2012). The simulation was performed by 97 trainees divided into 9 teams, and the surveys were conducted. RESULTS: The risk factors for early outcome of the recipients were cold ischemia time (>= 10 hours), Model for End-stage Liver Disease score (>= 20), and donor age (>= 55 years). Results of examination showed that overall percentage of the correct answers was significantly higher in exam 2013 than in exam 2012 (48.3% vs 32.7%; P = .0001). The survey after the simulation of multiorgan procurement revealed that most trainees thought that the simulation was useful and should be continued. CONCLUSION: The novel educational program could allow young surgeons to make precise assessments and perform the exact procedure in the multiorgan procurement. PMID- 24815132 TI - Outcome of referrals for deceased organ donation to the government organ procurement organization. AB - BACKGROUND: The Human Organ Preservation Effort is a government organ procurement organization that pioneered the Deceased Organ Donation Program in the Philippines. Deceased organ donation comprises only 20% of kidney transplantation in the Philippines in the last 3 years. Various measures were implemented to improve deceased organ donor referrals and organ retrieval. OBJECTIVE: To compare outcome of deceased organ donor referrals from 2002 to 2008 and 2009 to 2012 in the Philippines. METHODS: This retrospective study reviewed the deceased organ donor referrals from 2002 to 2008 and 2009 to 2012. RESULTS: There were 437 referrals for potential deceased organ donors from 2009 to 2012, compared to 434 referrals from 2002 to 2008. Referrals were mainly trauma victims (76%) followed by those with cerebrovascular accidents (12%). In the recent cohort, 81% were approached and 60% consented for donation, but only 23% were retrieved and transplanted. Among those not retrieved, the majority (19%) were medically unsuitable and 6% retracted their consent. CONCLUSION: Although there was an increasing trend of organ donation referrals in the last 4 years, only 25% were procured. The reasons for nonprocurement should be addressed. PMID- 24815133 TI - Myocardial protection in donor heart preservation: a comparison between Bretschneider's histidine-tryptophan-ketoglutarate solution and cold blood cardioplegia. AB - BACKGROUND: Optimal myocardial protection for donated hearts is crucial to improve outcomes of heart transplantation and reduce morbidity and mortality. This study aimed to compare the efficacy of myocardial protection using single dose of Bretschneider's histidine-tryptophan-ketoglutarate (HTK) solution and repeated doses of cold blood cardioplegia (CBC) in donor heart preservation. METHODS: Sixty-seven patients undergoing heart transplantation in Tri-Service General Hospital, Taipei, Taiwan between 2002 and 2012 were enrolled in this study. Patients were divided into an HTK group and a CBC group based on the preservation solution used to protect the donated hearts. The perioperative variables and postoperative outcomes were retrospectively reviewed. RESULTS: There were no statistic differences about demographic data in donors and recipients between the 2 groups. There were no significant differences in postoperative cardiac enzymes, hemodynamic data, length of stay in intensive care, or 30-day mortality between the groups. The HTK group showed a trend of shorter pumping time (P = .091). Multivariate analyses reveal that the HTK group had higher postoperative inotropic score (P < .001) and shorter pumping time (P = .02). CONCLUSIONS: Single dose of Bretschneider's HTK solution could effectively reduce pumping time and afford similar myocardial protection compared with repeated doses of CBC in the preservation of donated hearts. PMID- 24815134 TI - Ischemic reperfusion injury-induced oxidative stress and pro-inflammatory mediators in liver transplantation recipients. AB - OBJECTIVE: Liver ischemic reperfusion injury is harmful to transplant recipients, and is associated with postoperative morbidity and mortality. Our study was designed to investigate the oxidative stress and pro-inflammatory mediators in liver transplant recipients. METHODS: We prospectively analyzed 14 recipients who underwent liver transplantation by measuring their blood levels of malondialdehyde (MDA) and cytokines, such as tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and IL-6, at nine time points perioperatively. We also evaluated the correlations between oxidative stress (MDA levels) and the characteristics of the recipient or the donated graft. RESULTS: These parameters significantly increased from 1 minute before reperfusion, and the values peaked within 3 to 30 minutes after reperfusion. On the time point at 5 minutes after reperfusion, the MDA levels which were the highest in the recipients correlated with the values of preoperative direct/and total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), model for end stage liver disease (MELD) score, international normalized ratio (INR), and surgical blood loss. CONCLUSION: The levels of MDA, TNF-alpha, IL-1beta, and IL-6 greatly increased with the ischemic reperfusion insult. Recipients with higher values of preoperative direct/and total bilirubin, AST, ALT, MELD score, INR, and surgical blood loss tended to have higher levels of MDA and may suffer more injury from this insult. PMID- 24815135 TI - Relationship between midgut malrotation and anatomy of the hepatoduodenal ligament: a rare anatomical variation in a deceased donor. AB - INTRODUCTION: Anatomical variations around the hepatoduodenal ligament greatly influence surgical procedures and the difficulty of operations. Here, we report the case of a deceased donor with midgut malrotation (MgM) and anatomical variation. We also present an anatomical comparison between MgM and normal cases. CASE REPORT: The donor, a male in his 60s, was diagnosed with MgM based on preoperative computed tomography. Intraoperatively, the liver graft was harvested from the proper hepatic artery (PHA), but its length was too short for reconstruction. Therefore, the hepatic artery was reconstructed at both the left and right hepatic arteries. METHODS: The length of the proper hepatic artery (l PHA) and main trunk of the portal vein (l-PV) was compared between MgM and control groups (n = 9) using computed tomography. The ratio of PHA (r-PHA) and PV (r-PV), which was calculated as the l-PHA or l-PV divided by the patient's height, was also compared. RESULTS: The r-PV was 1.3% in the MgM group and 1.6% in the control group (P = .09). The r-PHA was 0.23% in the MgM group and 0.92% in the control group (P < .01). Thus, the PHA was significantly shorter in the MgM group. Additionally, anatomical variations of the hepatic artery were confirmed in four cases. CONCLUSION: Preoperative radiological evaluation is not always adequate for identifying anatomical abnormalities in deceased donors. MgM is a rare but important anomaly because of the possibility of associated anatomical variations of the hepatic artery. PMID- 24815136 TI - Edaravone, a free radical scavenger, improves the graft viability on liver transplantation from non-heart-beating donors in pigs. AB - BACKGROUND: Although liver transplantation from non-heart-beating donors (NHBDs) is an effective way to overcome shortage of donors, primary graft nonfunction is often noted in these grafts. We have previously reported that edaravone, a free radical scavenger, has a cytoprotective effect on warm ischemia-reperfusion injury and improves the function of liver grafts from NHBDs in a rat model of ischemia-reperfusion. The purpose of this study was to investigate the effects of edaravone on liver transplantations from NHBDs. METHODS: Pigs were divided into three groups: (1) a heart-beating (HB) group (n = 5), in which liver grafts were retrieved from HB donors; (2) a non-heart-beating (NHB) group (n = 4), in which liver grafts were retrieved under apnea-induced NHB conditions; and (3) an edaravone-treated (ED) group (n = 5), in which liver grafts were retrieved in the same manner as the NHB group and treated with edaravone at the time of perfusion (3 mg/L in University of Wisconsin [UW] solution), cold preservation (1 mg/L in UW solution), and after surgery (1 mg/kg/d). The grafts from all groups were transplanted after 4 hours of cold preservation. RESULTS: In the ED group, the 7 day survival rate was significantly higher than that in the NHB group (80% versus 0%, P = .0042, Kaplan-Meier log-rank test). Furthermore, on histologic examination, the structure of sinusoids in the ED group was well preserved and similar to that in the HB group. CONCLUSIONS: Edaravone may improve the viability of liver grafts from NHBDs. PMID- 24815137 TI - Rewarming preservation by organ perfusion system for donation after cardiac death liver grafts in pigs. AB - BACKGROUND: Use of grafts from donors after cardiac death (DCD) would greatly contribute to the expansion of the donor organ pool. However, this requires the development of novel preservation methods to recover the organ from changes due to warm ischemia time (WIT). METHODS: Porcine livers were perfused with a newly developed machine perfusion (MP) system. The livers were perfused with modified University of Wisconsin solution (UW) - gluconate. All grafts were procured after acute hemorrhagic shock with the ventilator off. For group 1 (n = 6), grafts were procured after WIT of 60 minutes and preserved by hypothermic MP (HMP) for 3 hours. For group 2 (n = 5), grafts were preserved with 2 hours of simple cold storage (SCS) and HMP for 2 hours. For group 3 (n = 6), grafts were preserved with 2 hours of SCS and rewarming up to 25 degrees C by MP for 2 hours (RMP). The preserved liver grafts were transplanted orthotopically. RESULTS: The alanine aminotransferase level in perfusate in RMP during perfusion preservation was maintained at less than that of HMP. The levels of aspartate aminotransferase and lactate dehydrogenase in the 2 hours after reperfusion were significantly lower in group 3. Histologically, the necrosis of hepatocytes was less severe in group 3. The survival rate in group 3 was 2/4, but 0/4 in the other group. CONCLUSION: RMP is expected to facilitate the recovery of the DCD liver grafts. PMID- 24815138 TI - Impact of machine perfusion preservation of liver grafts from donation after cardiac death. AB - Because of the critical shortage of deceased donor grafts, using a donation after cardiac death (DCD) donor is an important resource. However, the ischemic damage of those DCD grafts jeopardizes organ viability during cold storage. Maintaining organ viability after donation until transplantation is important for optimal graft function and survival. This review describes the effective preservation in transplantation for DCD livers. Concepts and development of machine perfusion for DCD liver grafts to reduce ischemia/reperfusion injury are discussed. Despite the fact that hypothermic machine perfusion might be superior to static cold preservation, DCD livers are exposed to hypothermia-induced damage. Recently, some groups introduced the beneficial effects of normothermic or subnormothermic machine perfusion in DCD liver preservation and transplantation. PMID- 24815139 TI - Beneficial effects of hydrogen gas on porcine liver reperfusion injury with use of total vascular exclusion and active venous bypass. AB - BACKGROUND: Liver ischemia/reperfusion (I/R) injury is a high risk factor in liver transplantation and it influences graft survival. One of the major events during I/R injury is the generation of cytotoxic oxygen radicals. Recently, hydrogen gas has been reported to have antioxidant properties and protective effects against organ dysfunction induced by I/R injury. The aim of this study is to investigate effects of hydrogen on porcine liver reperfusion injury. MATERIALS AND METHODS: Six outbred pigs weighing 20 kg were used for the experiment. Under general anesthesia, the venous bypass between the left femoral vein and the splenic vein to the left jugular vein was made using a centrifugal pump. Then, we used a total vascular exclusion clamp (all in- and out-flow to the liver was clamped) for 60 minutes. Hydrogen (5 ppm) saturated with lactate Ringer's solution was prepared. This solution was infused through the portal vein just before reperfusion (hydrogen group). RESULTS: Aspartate aminotransferase levels in the control versus hydrogen group in 30, 60, and 120 minutes after reperfusion were 1560.3, 1925.3, and 2342.5 versus 175.3, 200.7, and 661.00 IU/L, respectively. Lactate dehydrogenase (LDH) levels in the control versus hydrogen groups in 30, 60, and 120 minutes after reperfusion were 23,235.0, 3496.7, and 4793.5 versus 663.3, 802.0, and 983.7 IU/L, respectively. The hydrogen gas level in liver tissue increased to 954.6 ppm immediately after reperfusion; however, it disappeared within 30 minutes. CONCLUSION: The solution containing hydrogen gas was safe and had remarkably protective effects on the porcine during liver I/R and may be applied in the clinical setting. PMID- 24815140 TI - Thrombomodulin administration attenuates ischemia-reperfusion injury of the remnant liver after 70% hepatectomy in rats: simulated model of small-for-size graft in living donor liver transplantation. AB - BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is a serious complication affecting liver function and postoperative course after liver transplantation. Thrombomodulin (TM) has been known to have anticoagulant and anti-inflammatory activities exerting a cytoprotective effect. We evaluated the cytoprotective effect of recombinant human soluble TM (rhsTM) on the remnant liver exposed to IRI after 70% hepatectomy in rats, which was the simulated model of small-for size graft in living donor liver transplantation. MATERIALS AND METHODS: A Wistar rat underwent 70% hepatectomy followed by 20-minute IRI for the remnant liver. rhsTM (1 mg/kg) (TM group) or saline (control group) was intravenously administered 30 minutes before operation. RESULTS: Alanine aminotransaminase levels were more significantly decreased during the 24 hours after operation in the TM group than in control group, especially at 6 hours. Intrahepatic infiltration of macrophages/monocytes (ED-1 immunohistochemical staining) at 6 hours was significantly decreased in the TM group compared to the control group. The number of proliferating cell nuclear antigen-positive cells at 12 hours (hepatocyte proliferation) was significantly higher in the TM group than in the control group; although liver weight 7 days after operation did not differ between the two groups. Hepatocyte apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, also known as TUNEL assay) at 24 hours was more significantly diminished in the TM group than in the control group. CONCLUSION: These results suggest that rshTM attenuates hepatocyte injury through its anti-inflammatory effect, and promotes hepatocyte proliferation in the reduced-size liver exposed to hepatic IRI. PMID- 24815141 TI - Inhibition of inducible nitric oxide synthesis ameliorates liver ischemia and reperfusion injury induced transient increase in arterial stiffness. AB - PURPOSE: Hemodynamic instability is a frequent scenario after reperfusion of ischemic liver due to major liver resection and liver transplantation. Previously, we showed that liver ischemia/reperfusion (I/R) injury induced increases in reactive oxygen/nitrogen species and inducible nitric oxide synthase (iNOS) expression impaired cardiac contractility. In addition, nitric oxide (NO) generated via iNOS may have impacts on large arterial smooth muscle tone, causing transient changes in arterial stiffness and ventricular afterload. In this study, we aim to investigate associations between iNOS and transient alternation in arterial stiffness during liver I/R injury, and effects of treatments with 1,400W, a selective iNOS inhibitor, and L-NG nitroarginine methyl ester (L-NAME), a non-specific NOS inhibitor. METHODS: The arterial stiffness is evaluated using the pulse wave velocity (PWV(2)), measured by finding the means of two high fidelity micromanometers positioned at the aortic root and left femoral artery. Liver ischemia was conducted by occluding both the hepatic artery and portal vein for 30 minutes, followed by 120 minutes of reperfusion. Studies were performed on male Sprague-Dawley rats in four groups: a sham-operated group, a liver I/R group, and those groups pretreated with 1,400W (N-[3 (aminomethyl)benzyl]acetamidine) or L-NAME. Serum NO metabolites, tumor necrosis factor-alpha (TNF-alpha) and methylguanidine (MG) were measured at baseline, 30 minutes of ischemia, and 120 minutes of reperfusion. RESULTS: Post-reperfusion arterial stiffness increased by ~14% as compared with the baseline, along with increases in serum NO metabolites, TNF-alpha, and MG level (P < .05); 1,400W and L-NAME treatment reduces post-reperfusion arterial stiffness by ~5% similarly. Treatments with 1,400W and L-NAME both attenuated I/R induced increases in serum TNF-alpha, MG, and NO metabolites level (P < .05). CONCLUSIONS: I/R-induced arterial stiffening was strongly associated with increased systemic inflammation. Comparable effects with treatments of 1,400W and L-NAME suggested that iNOS plays a dominant role in I/R-induced transient arterial stiffening. PMID- 24815142 TI - Protective effect of peptide GV1001 against renal ischemia-reperfusion injury in mice. AB - BACKGROUND: Ischemia reperfusion injury (IRI) is a common complication after kidney transplantation. Peptide GV1001 is a peptide vaccine representing a 16 amino acid human telomerase reverse transcriptase sequence, which has been reported to possess potential antineoplastic and anti-inflammatory activity. This study aimed to investigate the potential effects of peptide GV1001 on renal IRI. METHODS: Peptide GV1001 was subcutaneously administered to C57BL6/J mice 30 minutes before and 12 hours after bilateral IRI. Sham operation and phosphate buffered saline (PBS) injection were used as controls. Blood and renal tissues were harvested at 1 day after IRI. RESULTS: Peptide GV1001 treatment significantly attenuated renal functional deterioration after IRI (peptide GV1001 group vs PBS group; blood urea nitrogen, P < .05; creatinine, P < .05). Peptide GV1001 treatment also attenuated renal tissue injury (tubular injury score; the peptide GV1001 group vs PBS group; P < .001). Renal apoptosis was also lower in the peptide GV1001 group. Immunohistochemical studies showed that IRI increased perirenal infiltration of both neutrophils and macrophages, and that peptide GV1001 significantly attenuated this process. Expression of interleukin-6 and monocyte chemotactic protein-1 was significantly reduced by peptide GV1001 treatment. CONCLUSIONS: Peptide GV1001 ameliorates acute renal IRI by reducing inflammation and apoptosis; therefore, it is promising as a potential therapeutic agent for renal IRI. The mechanisms of protection should be explored in further studies. PMID- 24815143 TI - Inhibition of inducible nitric oxide synthase ameliorates myocardial ischemia/reperfusion injury - induced acute renal injury. AB - OBJECTIVES: Acute kidney injury occurs frequently in patients subsequent to coronary artery revascularization or myocardial ischemia and reperfusion (MIR). Hypotension and excessive nitric oxide (NO) production through inducible nitric oxide synthase (iNOS) were implicated in renal injury. On the other hand, NO may have a protective role during early reperfusion. In this study, we aim to compare protective effectiveness of 1,400W, a highly selective iNOS inhibitor, and L-NG nitroarginine methyl ester (L-NAME), a non-specific nitric oxide synthase (NOS) inhibitor, against MIR-induced hemodynamic stabilization and kidney injury. METHODS: Male Sprague-Dawley rats were evenly divided in four groups including sham-operated, MIR, and groups pretreated with 1,400W (20 mg/kg, intraperitoneally, [ip]) or L-NAME (30 mg/kg, ip) 15 minutes before MIR. Ischemia was conducted by occluding the left coronary artery for 30 minutes, followed by 120 minutes of reperfusion. We determined the measured aortic pressure (MAP) and assessed kidney injury through serum levels of blood urea nitrogen (BUN), methylguanidine (MG), malondialdehyde (MDA) and NO at different phases during the study. RESULTS: MAP, decreased during myocardial ischemia, increased during early reperfusion; however, that was abolished with L-NAME pretreatment, and the increase was moderate with 1,400W pretreatment. Serum MDA, MG and BUN levels, although relatively unaltered during ischemia, significantly increased after 120 minutes of reperfusion. Treatment with 1,400W reduced post-reperfusion MDA and MG levels (P < .05), but the improvement was not significant with L-NAME. CONCLUSIONS: 1,400W was effective in reducing MIR-induced hemodynamic instability and kidney injury, in contrast to no apparent protection with L-NAME administration. PMID- 24815144 TI - MK-571 attenuates kidney ischemia and reperfusion-induced airway hypersensitivity in rats. AB - OBJECTIVE: Reperfusion of the rat kidney has been shown to up-regulate cysteinyl leukotriene-1 receptor, an asthma-associated gene in human bronchioles, and increase expression of leukotriene D4. In this study, we aimed to investigate the efficacy of MK-571, a leukotriene D4 inhibitor, against hypersensitivity induced by kidney ischemia and reperfusion (I/R)-associated acute kidney injury. METHODS: Sprague-Dawley male rats were divided into 3 study groups: a sham-operated group, a kidney I/R group, and a group treated with MK-571 before the kidney I/R injury: MK-571 (5 mg/kg) was administered intraperitoneally 15 minutes before ischemia and every 12 hours after reperfusion up to 24 hours. Ischemia was conducted by bilateral occlusion of renal pedicles for 45 minutes, followed by releasing the clamps and closing the abdominal incision. Respiratory function was tested 24 hours after reperfusion, with the use of a 2-chamber whole body plethysmograph for conscious rats. Blood samples, pulmonary bronchoalveolar lavage fluid, and lung tissues were collected at the end of study. In 10 rats, urine was collected at baseline and the end of study. RESULTS: Compared with the sham group, kidney I/R injury markedly increased enhanced pause (Penh) index during methacholine challenge test (P < .05), suggesting airway hypersensitivity; it also increased in inflammatory response and levels of hydroxyl radical production and lipid peroxidation in the lungs. In contrast, in MK-571-treated rats, Penh was muted during methacholine challenge test (P < .05). CONCLUSIONS: Kidney I/R injury induces airway hypersensitivity to methacholine challenge test and inflammatory response and oxidative stress in the lungs. Treatment with MK-571, a leukotriene D4 inhibitor, effectively attenuates airway hypersensitivity, pulmonary inflammatory response, and lung and kidney injury. PMID- 24815145 TI - Resveratrol alleviates lung ischemia and reperfusion-induced pulmonary capillary injury through modulating pulmonary mitochondrial metabolism. AB - OBJECTIVE: Lung ischemia and reperfusion (I/R) injury is one of the major causes of postoperative pulmonary dysfunction after cardiopulmonary surgery and thoracic organ transplantation. Recent studies suggest that lung I/R injury may be associated with defects in pulmonary mitochondrial function, in addition to damage from reactive oxygen species. In this study, we examined effects of one lung I/R injury on the other lung, and the protective efficacy of resveratrol on mitochondrial biogenesis in lungs. METHODS: Studies were performed in male Sprague-Dawley rats in 3 groups: sham-operated, lung I/R injury, and treated with resveratrol before lung I/R injury (20 mg/kg/d, orally). Lung ischemia was established by occluding the lung left hilum for 60 minutes, followed by releasing the occlusion and closing the chest. Four days after ischemia, we assessed the lung water content and protein concentration in lung lavage of the nonischemic lung; lung inflammation and pulmonary oxidative stress were assessed by leukocyte counts and tissue content of malondialdehyde (MDA), respectively. The level of mitochondrial biogenesis was determined according to PGC1-alpha mRNA expression. RESULTS: The left lung I/R injury significantly suppressed right lung PGC1-alpha mRNA expression, increasing pulmonary oxidative stress, lung water content, and lavage leukocyte count and protein concentration (P < .05). Resveratrol treatment attenuated lung injury as well as increasing PGC1-alpha mRNA expression. CONCLUSIONS: Resveratrol treatment protects lung against I/R injury through improving mitochondrial biogenesis and reducing oxidative stress and leukocyte infiltration. PMID- 24815146 TI - Curcumin attenuates liver warm ischemia and reperfusion-induced combined restrictive and obstructive lung disease by reducing matrix metalloprotease 9 activity. AB - OBJECTIVE: Acute respiratory distress syndrome (ARDS) is a common scenario associated with hepatic warm ischemia and reperfusion (I/R) injury after shock or hemorrhage. Inflammation of lung parenchyma and increase in matrix metalloprotease 9 (MMP-9) activity have been implicated in ARDS. In this study, we aimed to investigate the protective efficacy of curcumin treatment against hepatic I/R-induced lung function impairment. METHODS: Thirty Sprague-Dawley male rats were evenly divided into 3 groups: a sham group, a hepatic I/R group, and a group treated with curcumin (15 mg/kg/d) 15 minutes before ischemia and every 24 hours for the next 48 hours. Ischemia was induced by occluding the hepatic artery and portal vein for 30 minutes. The clamps were then released and the abdominal incision was closed. Pulmonary function test was conducted after 48 hours of reperfusion. We also examined serum alanine transaminase (ALT) level and degrees of tumor necrosis factor alpha (TNF-alpha) and MMP-9 activity in the lung tissue. RESULTS: Hepatic I/R injury decreased the ratio of residual volume to total lung capacity (RV/TLC), chord compliance (Cchord), and maximum midexpiratory flow (MMEF; P < .05), and increased inspiratory resistance (RI; P < .05), characterized as combined obstructive and restrictive lung disease. Treatment with curcumin markedly improved RV/TLC, Cchord, and MMEF and decreased RI (P < .05). In addition, curcumin treatment reduced serum ALT level and degrees of TNF alpha level and MMP-9 activity in the lungs. CONCLUSIONS: Curcumin attenuated hepatic I/R-induced combined restrictive and obstructive lung disease by reducing lung inflammation and MMP-9 activity. PMID- 24815147 TI - Effect of preservation conditions on cartilage tissue for cell transplantation. AB - Autologous chondrocyte transplantation involves isolating chondrocytes from a patient's cartilage tissue. Storage conditions such as storage time and temperature are important for the quality of the isolated cells. However, few studies have focused on variables for optimum tissue preservation, and there is neither an established method for storing cartilage nor reliable reports on how different conditions affect the isolated chondrocytes. Therefore, in the present study, we stored cartilage in various preservation solutions, under different temperatures, and for varying durations and determined their effects on the characteristics and viability of isolated chondrocytes. We assessed chondrocyte viability with the use of a cell proliferation assay and determined their chondrogenic potential with the use of reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and glycosaminoglycan assays. Our results demonstrated that cartilage tissue stored in a preservation medium composed of dimethyl sulfoxide, fetal bovine serum, and Dulbecco Modified Eagle Medium at a ratio of 1:2:7 (v/v) or stored with a commercially available preservation solution generated greater numbers of chondrocytes when the storage temperature was -80 degrees C than when it was 4 degrees C. The viability of isolated cells decreased with time at 4 degrees C, whereas these values remained constant for tissues stored at -80 degrees C. Our data suggest that an optimal method for preserving cartilage tissue is required to ensure the quality of cells used for transplantation. PMID- 24815148 TI - Effect of cryopreservation and cell passage number on cell preparations destined for autologous chondrocyte transplantation. AB - Autologous chondrocyte transplantation (ACT) is an effective and safe therapy for repairing articular cartilage defects and requires cell preservation and subculture before transplantation. We compared the effects of cryopreservation and passaging on cell viability, proliferation, and maintenance of the function of chondrocytes and synovium-derived mesenchymal stem cells (MSCs) used as sources for ACT. These cells were isolated from the knee joints of rabbits and were cultured, passaged serially, and divided into 2 groups that were either cryopreserved or not. The morphology, viability, gene expression, and differentiation potential of the 2 groups were compared. Maintenance of the potential to undergo chondrogenic differentiation was determined with the use of a 3-dimensional culture method. Passaging and cryopreservation significantly affected the ability of chondrocytes to maintain their morphology, express chondrogenic genes, and differentiate. In contrast, synovium-derived cells were not affected by passaging and cryopreservation. Our results may serve as the foundation for the application of passaged and cryopreserved chondrocyte or other source cells of MSCs in ACT. PMID- 24815149 TI - Ginsenoside Rg3 enhances islet cell function and attenuates apoptosis in mouse islets. AB - BACKGROUND: The transplantation of isolated islets is thought to be an attractive approach for curative treatment of diabetes mellitus. Panax ginseng has been used in oriental countries for its pharmacologic effects, such as antidiabetic and antiinflammatory activities. 20(S)-ginsenoside Rg3 (Rg3), an active ingredient of ginseng saponins, has been reported to enhance insulin secretion-stimulating and antiapoptotic activities in pancreatic beta cells. We performed this study to examine the hypothesis that preoperative Rg3 administration can enhance islet cell function and antiapoptosis before islet transplantation. METHODS: Balb/c mice were randomly divided into 2 groups according to the administration of Rg3 after islet isolation. Mouse islets were cultured in medium supplemented with or without Rg3. In vitro, islet viability and function were assessed. After treatment of islets with a cytokine cocktail (tumor necrosis factor alpha, interferon-gamma, and interleukin-1beta), cell viability, function, and apoptosis were assessed. RESULTS: Cell viability was similar between the 2 groups. Islets cultured in medium supplemented with Rg3 showed 2.3-fold higher glucose-induced insulin secretion than islets cultured in medium without Rg3. After treatment with a cytokine cocktail, glucose-induced insulin release, total insulin content of islets, and apoptosis were significantly improved in Rg3-treated islets compared with cytokine-treated islets. Cytokine-treated islets produced significantly higher levels of nitric oxide (NO) than islets treated with Rg3. CONCLUSIONS: These results suggest that preoperative Rg3 administration enhanced islet function before islet transplantation and attenuated both cytokine-induced damage associated with NO production and apoptosis. Rg3 administration might be a prospective management to enhanced islet function and ameliorate early inflammation after transplantation. PMID- 24815150 TI - Artificial islets from hybrid spheroids of three pancreatic cell lines. AB - Pancreatic islets have been the focus of recent studies exploring the pathologic mechanisms of diabetes mellitus as well as more effective and radical treatments for this disease. Islet transplantation is a promising therapeutic strategy; however, isolation of pancreatic islets for this purpose has been challenging, because the technique is time consuming and technically difficult, and tissue handling can be variable. Pseudo-islets can be used as an alternative to naive islets, but require cellular sources or artificial materials. In this study, pancreas-derived cells were used to generate pseudo-islets. Because the pancreas is composed of a variety of cell types, namely alpha cells, beta cells, delta cells, and other pancreatic cells that perform different functions, we used 3 different cell lines-NIT-1 (a beta-cell line), alpha TC1 clone 6 (an alpha-cell line), and TGP52 (a pancreatic epithelial-like cell line)-which we cocultured in nonadhesive culture plates to produce hybrid cellular spheroids. These pseudo islets had an oval shape and were morphologically similar to naive islets; additionally, they expressed and secreted the pancreatic hormones insulin, glucagon, and somatostatin, as confirmed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The results demonstrate that pseudo-islets that mimic naive islets can be successfully generated by a coculture method. These artificial islets can potentially be used for in vitro tests related to diabetes mellitus, specifically, in drug discovery or for investigating pathology. Moreover, they can be useful for examining basic questions pertaining to cell-cell interactions and tissue development. PMID- 24815151 TI - Engineering of pseudoislets: effect on insulin secretion activity by cell number, cell population, and microchannel networks. AB - Engineered pseudoislets reconstituted from a suspension of pancreatic alpha and beta cells have the potential to relieve the shortage of donor islets for transplantation in the treatment of type 1 diabetes. However, the methods to fabricate pseudoislets are not well developed. In this study, we attempted to generate pseudoislets, which show a higher potential for glucose-induced insulin secretion, by altering total cell number, adjusting the cell ratio of pancreatic alpha and beta cells, and fabricating microchannel networks with the use of alginate hydrogel beads. To effectively aggregate alpha and beta cells and hydrogel beads, we used a previously established rapid aggregation method. When pseudoislets were reconstituted with 8,000 cells in a 1:8 alpha/beta-cell ratio, we observed that the glucose-induced insulin secretion was enhanced by 3.1 times compared with the pseudoislets formed with beta cells only. In addition, embedding of microchannel networks increased the insulin secretion rate by 4.4 times compared with the pseudoislets without the microstructures. These findings demonstrated that active modification was effective in reconstituting higher functional pseudoislets, which may be useful for islet transplantation. PMID- 24815152 TI - High-resolution intravital imaging for monitoring the transplanted islets in mice. AB - Intravital imaging techniques will be a valuable tool to monitor the post transplantation dynamics of the cells/tissues in regenerative medicine research. Among the conventional live imaging techniques, the cranial window model has various advantages regarding resolution, longevity, and easy manipulability. We describe the use of the cranial window model to visualize the post transplantation processes of primary pancreatic islets in the living mouse. Macroscopic or microscopic analyses were performed to evaluate the post transplantation dynamics of primary murine islets, including the revascularization process inside the cranium. Consistent with earlier literature on clinical outcomes of islet transplantation, marked loss of transplanted islets was observed within 7 days. Intravital confocal microscope analysis revealed that functional revascularization seldom occurred in the central regions of the transplants. Our results suggest that the cranial window model offers an ideal platform for understanding cellular dynamics, through the possibility of long term imaging studies over time scales. This platform is possibly applied not only for transplant studies of pancreatic islets, but also for other endodermal cell/tissue types in vivo. PMID- 24815153 TI - Pretreatment of transfused donor splenocytes and allografts with mitomycin C attenuates acute rejection in heart transplantation in mice. AB - OBJECTIVE: The aim of this study was to investigate the effect of pretreatment of donor splenocytes and grafts with mitomycin C (MMC) on heart allograft survival, as well as to demonstrate the mechanism of function. METHODS: Donor splenocytes from Balb/C mice were incubated with MMC (40 MUg/mL) in vitro and then transfused into recipients (C57BL/6 mice). The heart allograft was perfused with MMC before harvest. Graft survival and histopathology were examined. Lymphocyte activation, regulatory T cells, and donor splenocyte apoptosis were examined with the use of flow cytometry. RESULTS: MMC incubation in vitro induced apoptosis of donor splenocytes (15.5 +/- 2.3% vs 23.2 +/- 4.2%; P < .01). Either intravenous injection of MMC-treated donor splenocytes or transplantation of allograft pretreated with MMC prolonged heart allograft mean survival time from 7 +/- 0.8 days to 20.5 +/- 1.9 days or 10 +/- 0.9 days, respectively (both P < .01). A combination of MMC-pretreated donor splenocyte transfusion and allografts showed the best effect on prolongation of graft survival (28.5 +/- 1.8 days). Activation of CD4(+) T cells in spleen and peripheral lymph nodes of recipients was significantly inhibited by either MMC-splenocyte transfusion or the combination treatment. Meanwhile, the percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells in the spleen was increased in the MMC-splenocyte transfusion group (15.5 +/- 1.1% vs 18.2 +/- 0.9%; P < .05). CONCLUSIONS: Both injection of MMC-conditioned donor splenocytes and MMC-conditioned allograft have effects on prolongation of heart allograft survival in mice, and MMC-conditioned donor splenocytes might play an essential role. MMC pretreatment induced regulatory T cells likely through induction of donor splenocyte apoptosis, and thus it inhibited T-cell activation. PMID- 24815154 TI - Effect of 34 kinds of traditional Japanese herbal medicines on prolongation of cardiac allograft survival. AB - Herbal medicines have been used for over 3,000 years in Asian as alternative therapy for their variety effects and have recently become popular in Europe and the United States. In the last 30 years, Japanese herbal medicines were widely used for treatment of diseases after been recognized officially by Japanese government. In this study, we investigated the effect of 34 kinds of traditional Japanese herbal medicines on alloimmune responses in a murine model of cardiac allograft transplantation. CBA mice (H2(k)) underwent transplantation of a C57BL/6 (H2(b)) heart and received oral administration of 2 g/kg/d of the 34 kinds of herbal medicines from the day of transplantation until 7 days afterward. Naive CBA mice rejected B6 cardiac grafts acutely (median survival time [MST], 7 days). CBA transplant recipients given 2 g/kg/d of Sairei-to (TJ-114) and Tokishakuyaku-san (TJ-23) had prolonged C57BL/6 allograft survival indefinitely (both MSTs > 100 days). Moreover, CBA transplant recipients given Seisinrensiin (TJ-111), Tokishigyakukagoshuyushokyoto (TJ-38), Rikkunshito (TJ-43), Maobushisaishinto (TJ-127), Ninjin-yoei-to (TJ-108), Ryokan-kyomi-shinge-nin-to (TJ-119), Inchingorei-san (TJ-117), Hochuekkito (TJ-41), Kihi-to (TJ-65), and Sinbu-to (TJ-30) had also prolonged C57BL/6 allograft survival significantly (MSTs of 28, 22, 16, 14, 14, 13, 12, 9.5, 9 and 9 days, respectively). However, none of other 22 kinds of herbal medicines could prolong the allograft survival. Furthermore, oral administration of 2 g/kg/d of Daikenchuto (TJ-100) induced sudden death (within 1 minute) in CBA mice. In conclusion, 12 kinds of Japanese herbal medicines prolonged allograft survival and one showed toxic effect in mice. PMID- 24815155 TI - Gamma-glutamyl transferase as an early and sensitive marker in ethanol-induced liver injury of rats. AB - gamma-Glutamyl transferase (GGT) has been regarded as a biological marker of heavy alcohol consumption or hepatobiliary disease such as fatty liver. However, the role of GGT is unknown in the molecular pathway during alcohol-induced liver injury. To determine the role of GGT in alcohol-induced liver injury, Sprague Dawley rats were administered 22% and 38% ethanol for 3 days as acute and 5 weeks as subchronic model. In serologic analysis, the level of GGT was significantly increased and the level of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were not changed at 3 days and 5 weeks. In histologic analysis, ethanol exposure induced granular deposit formation and sinusoidal dilation in the acute model for 3 days. In the subchronic model for 5 weeks, ethanol exposure further increased the granular deposit formation, sinusoidal congestion, and mild fatty liver change. To determine whether ethanol-exposed liver is associated with changes of antioxidants levels, we performed reverse transcriptase polymerase chain reaction (RT-PCR) analysis on ethanol-exposed livers of rats. In RT-PCR analysis, the mRNA levels of GPX1 and SOD1 were significantly increased as well as up-regulation of CYP2E1. In the glutathione assay, the level of glutathione was significantly reduced in response to ethanol in rats. Therefore, in this study, ethanol increased the level of serum GGT but depleted the level of glutathione. Moreover, the CYP2E1 was rapidly reflected to ethanol in rats. Taken together, our findings suggest that the elevated GGT is associated with cellular antioxidant defense system, and the CYP2E1 can be used for early diagnosis in alcohol-related diseases. PMID- 24815156 TI - Generation of humanized liver mouse model by transplant of patient-derived fresh human hepatocytes. AB - Some research groups have produced immunodeficient mice with human liver tissue as a model system for the analysis of drug metabolism and liver regeneration. Mouse models are important for research and development of drugs and vaccines for viral infections. Recent progress in developing humanized mouse models permits studies of adaptive immune responses, innate host responses, and therapeutic approaches for several liver diseases of viral etiology. In this study, we generated a humanized liver mouse model by transplant with fresh patient-derived hepatocytes (1 * 10(6) cells/mouse, intrasplenic injection) into preconditioned (50 mg/kg ganciclovir, intraperitoneal injection) mice (herpes simplex virus type 1 thymidine kinase [TK] transgene expressed within the liver of a highly immunodeficient mouse strain [NOG]). Successful reconstitution of human hepatocytes in TK-NOG mouse liver tissues was observed with a strong proliferation of human cells in a time-dependent manner, using cytokeratin 8/18 stain. Similarly, we detected significantly increased human albumin levels in TK NOG mouse liver tissue and blood sera on immune staining and enzyme-linked immunosorbent assay. Therefore, this humanized liver mouse model provides a biomedical tool for studying human liver physiology, drug metabolism, and liver pathogenesis of viral etiology or liver regeneration. PMID- 24815157 TI - The development of humanized liver with Rag1 knockout rats. AB - BACKGROUND: The animal model with humanized liver is useful for testing drug metabolism and toxicity in preclinical studies. A mouse model has been reported in which the liver was repopulated more than 90% with human hepatocytes; however, in the rat, the target is far from being reached. In this study, we attempt to develop a humanized liver model with an immunodeficient rat. METHODS: Rag1 knockout rats were treated with neonatal thymectomy. At 3 and 4 weeks of age, they were injected with hepatotoxin retrorsine; 2 weeks after, the animals were subjected to 70% partial hepatectomy and transplanted with immature human hepatocytes via portal vein. The recipients were also treated with anti-asialo GM1 antibody weekly from the day before transplantation and were injected with FK506 every 3 days after transplantation. RESULTS: In Rag1 knockout rats, B lymphocytes were deleted almost completely in peripheral blood. However, T and natural killer (NK) lymphocytes were kept present. When they were treated additionally with neonatal thymectomy for T-lymphocyte deletion and suppressed neutralized NK lymphocytes with anti-asialo GM1, B, T, and NK cells in lymphocytes were reduced to very low levels of 0.75%, 1.58%, and 0.26%, respectively. After transplanting human donor hepatocytes into retrorsine-treated recipient livers, at week 3 the human cell-derived hepatic colonies were expanded in the recipient liver and the liver repopulation rate with human hepatocytes reached approximately 17%. The human hepatocyte-specific genes, albumin, CYP3A4, CYP2C18, and CYP2C9, also could be detected in the recipient rat. CONCLUSION: It is possible to generate a chimera animal with humanized liver in a novel severely immunodeficient rat model. PMID- 24815158 TI - Cardiac mesenchymal progenitors from postmortem cardiac tissues retained cellular characterization. AB - BACKGROUND AND OBJECTIVE: Currently, cells for transplantation in regenerative medicine are derived from either autologous or allogeneic tissue. The former has the drawbacks that the quality of donor cells may depend on the condition of the patient, while the quantity of the cells may also be limited. To solve these problems, we investigated the potential of allogeneic cardiac mesenchymal progenitors (CMPs) derived from postmortem hearts, which may be immunologically privileged similar to bone marrow-derived mesenchymal progenitors. MATERIALS AND METHODS: We examined whether viable CMPs could be isolated from C57/B6 murine cardiac tissues harvested at 24 hours postmortem. After 2- to 3-week propagation with a high dose of basic fibroblast growth factor, we performed cellular characteristics analyses, which included proliferation and differentiation property flow cytometry and microarray analyses. RESULTS: Postmortem CMPs had a longer lag phase after seeding than CMPs obtained from living tissues, but otherwise had similar characteristics in all the analyses. In addition, global gene expression analysis by microarray showed that cells derived from postmortem and living tissues had similar characteristics. CONCLUSION: These results indicate that allogeneic postmortem CMPs have potential for cell transplantation because they circumvent the issue of both the quality and quantity of donor cells. PMID- 24815159 TI - Regulation of heme oxygenase 1 expression by miR-27b with stem cell therapy for liver regeneration in rats. AB - Adipose-derived mesenchymal stem cells (ASCs) have been considered to be attractive and readily available adult mesenchymal stem cells (MSCs) and are becoming increasingly popular for use in regenerating cell therapy. However, recent evidence attributed a fibrotic potential to MSCs which differentiated into myofibroblasts with highly increased alpha-smooth muscle actin (alpha-SMA) expression while transplanted into an injured/regenerating liver in mice. In this study, we studied the role of miR-27b in ASCs and their regenerative potential after partial liver resection in rats. ASCs transfected with control siRNA or miR 27b were intravenously injected into autologous rats undergoing 70% partial hepatectomy (PH). Our data showed that the regenerative capacities of ASCs with overexpressed miR-27b were significantly higher compared with control ASCs. However, the enhanced regeneration, hepatic differentiation, and suppressed liver inflammation, as well as fibrotic activity, were significantly reverted by ZnPP coadministration (heme oxygenase-1 [HO-1] inhibitor) indicating an important role of HO-1 in the regenerating and cytoprotective activities of miR-27b-transfected ASCs. We demonstrated that administration of autologous ASCs overexpressed with miR-27b enhances rapid and early liver regeneration and, importantly, preserves function after PH. The ASCs with miR-27b overexpression might offer a viable therapeutic option to facilitate rapid recovery after liver resection. PMID- 24815160 TI - Identification of proliferating human hepatic cells from human induced pluripotent stem cells. AB - Mass-scale production of hepatocytes from human induced pluripotent stem cells (iPSCs) with functional properties of primary hepatocytes is of great value in clinical transplantation for liver failure as well as in facilitating drug development by predicting humanized drug metabolism profiles. In this report, we generated human hepatocyte-like cells from human iPSCs with the use of a stepwise protocol. Aiming at future clinical and industrial application, it is important to determine the suitable stage of iPSC-derived hepatic cells that possess high proliferative capacity to intensively expand the hepatic cells. Ki67 immunostaining showed that human iPSC-derived hepatic endoderm cells contained Ki67(+) cells at the highest level in the middle stage of hepatic differentiation, suggesting that the abundance of proliferating hepatic progenitor cells exists in this stage. Extensive expansion and differentiation of human iPSC-derived hepatic progenitors will provide future perspectives in transplantation therapy and drug development. PMID- 24815161 TI - Fluorescent labeling and visualization of human induced pluripotent stem cells with the use of transcription activator-like effector nucleases. AB - BACKGROUND: The visualization of induced pluripotent stem (iPS) cells with the use of fluorescent techniques is useful for the in vivo evaluation of iPS-derived functional cells following differentiation and distribution of the transplanted cells. The data obtained from the fluorescently labeled iPS cells would lead to amelioration and validation of protocols directing the differentiation of iPS cells into functional cells. In this study, we established enhanced green fluorescent protein (EGFP)-labeled iPS cells to enable their easy visualization. METHODS: Human iPS cells were transfected with (a) 2 transcription activator-like effector nuclease (TALEN) vectors targeted to the adeno-associated virus integration site 1 (AAVS1) locus and (b) the targeting vector carrying the homology arms, EGFP gene, and a drug-selection marker. RESULTS: Several puromycin resistant clones were obtained after transfection of the targeting vector and corresponding TALEN-expressing vectors. EGFP expression in these clones was observed with the use of a fluorescent microscope. Clones were examined for specific recombination, which revealed precise targeting at the AAVS1 locus. Furthermore, EGFP protein expression was sustained after directed differentiation into a hepatic lineage. CONCLUSIONS: We were successful in evaluating the behavior of iPS-derived hepatic cells. The data suggest that genomic knock-in at the AAVS1 locus is suitable for long-term observation of iPS-derived cells. Manipulation of the iPS genome can also be applied for the purification of hepatic cells during iPS cell differentiation by introducing the fluorescent protein under the regulation of a hepatic cell-specific promoter. Another application involves gene correction of iPS cells from patients with hepatic disease for regenerative medicine. PMID- 24815162 TI - Experimental canine facial transplantation. AB - OBJECTIVE: Facial allotransplantation represents a novel frontier in the reconstruction of complex human facial defects. To develop more refined surgical techniques and yield fine results, it is required to make a suitable animal model. The development of a model of composite facial and scalp allograft in canines is more appealing: In large animals, canine facial anatomy is the most similar to humans; its facial nerve anatomy also resembles humans'; and canines possess the most similar facial vascular anatomy to humans. These factors led to the development of a canine composite facial allograft model. METHODS: Two operative teams performed simultaneously on both donor and recipient to harvest the hemifacial/scalp flap and to prepare the recipient to shorten operative time. The flap was harvested with the common carotid artery and external jugular vein and transferred to the recipient. After insetting of the cartilage, skin, and muscles, the anastomosis of the external jugular vein and anastomosis between the external carotid artery and lingual artery were performed. RESULTS: The total mean time of transplantation was 5 hours +/- 30 minutes. All of the transplanted animals were wreated with FK-506 [tacrolimus, 2 mg/kg] for 7 days after surgery. Clinical rejection response was also identified by close monitoring. Most allografts survived with perfect viability without vascular problems in the early postoperative period. CONCLUSIONS: We documented that this model is well qualified in every aspect for use as a standard transplantation training model and future research work. PMID- 24815163 TI - Uterine transplantation in primates: a mini-review of the literature. AB - Assisted reproductive technology has improved markedly in recent years, and many infertile patients have had children with the use of this technology. However, women with infertility due to an absent or nonfunctional uterus currently have no option of having a genetically linked child other than gestational surrogacy. Uterus transplantation (UTx) is now a possible approach for women with uterine factor infertility to deliver a child. UTx studies have been performed in many animals, and accumulation of data from these studies has brought UTx within reach of clinical application. This has led to performance of UTx in humans in Saudi Arabia, Turkey, and Sweden. However, there has yet to be a delivery after allogeneic UTx in primates. More basic studies in primates are needed, and data from research in primates can provide important information for establishment of UTx in humans. In this review, we summarize the literature on UTx studies, with a focus on primates, both human and nonhuman. PMID- 24815164 TI - Elastic cartilage reconstruction by transplantation of cultured hyaline cartilage derived chondrocytes. AB - Current surgical intervention of craniofacial defects caused by injuries or abnormalities uses reconstructive materials, such as autologous cartilage grafts. Transplantation of autologous tissues, however, places a significant invasiveness on patients, and many efforts have been made for establishing an alternative graft. Recently, we and others have shown the potential use of reconstructed elastic cartilage from ear-derived chondrocytes or progenitors with the unique elastic properties. Here, we examined the differentiation potential of canine joint cartilage-derived chondrocytes into elastic cartilage for expanding the cell sources, such as hyaline cartilage. Articular chondrocytes are isolated from canine joint, cultivated, and compared regarding characteristic differences with auricular chondrocytes, including proliferation rates, gene expression, extracellular matrix production, and cartilage reconstruction capability after transplantation. Canine articular chondrocytes proliferated less robustly than auricular chondrocytes, but there was no significant difference in the amount of sulfated glycosaminoglycan produced from redifferentiated chondrocytes. Furthermore, in vitro expanded and redifferentiated articular chondrocytes have been shown to reconstruct elastic cartilage on transplantation that has histologic characteristics distinct from hyaline cartilage. Taken together, cultured hyaline cartilage-derived chondrocytes are a possible cell source for elastic cartilage reconstruction. PMID- 24815165 TI - Effect of FK506 ointment (Protopic) on rat skin allograft model. AB - OBJECTIVE: FK-506 (tacrolimus) is a well known immunosuppressive agent used to prevent allograft rejection. The need for chronic allograft immunosuppression and the consequent harmful systemic effects preclude the use of tissue allograft as a routine surgical reconstructive option. This study assessed the effects of FK-506 ointment (Protopic) therapy versus subcutaneous injection of FK-506 (Prograf) on rat skin graft model. METHODS: Donor Wistar rat dorsal skin was grafted to recipient Sprague-Dawley rats. Animals groups were divided into 2 groups: Group I was treated with intravenous injection of FK-506, and group II was treated with FK-506 ointment for 2 weeks after surgery. Graft appearance challenges were assessed. RESULTS: FK506 ointment could prolong the median allograft survival time (16.7 days) compared with group I (15.8). Hematoxylin-eosin staining performed on the allo-skin biopsy samples obtained from both group I and II animals at 2 weeks after graft revealed moderate degree of skin rejection accompanied by mixed lymphocyte infiltration. Tacrolimus mean blood levels were much lower in group II (<0.2 ng/mL) than in group I (0.45 ng/mL) CONCLUSIONS: Immunosuppressive FK506 ointment therapy has similar effect to intravenous injection and it could be a useful therapy in the prevention of skin allograft rejection. PMID- 24815166 TI - Rapamycin promotes podocyte migration through the up-regulation of urokinase receptor. AB - Conversion to rapamycin from calcineurin inhibitors may contribute to improvement of graft function in kidney transplant recipients, especially in patients with calcineurin inhibitor-related nephrotoxicity. The conversion from calcineurin inhibitors to rapamycin in kidney transplant recipients has been associated with a higher incidence of proteinuria. It could be explained by possible hemodynamic changes due to withdrawal of calcineurin inhibitors. Podocyte damage occurs commonly in rapamycin-related proteinuria. The vascular endothelial growth factor system has been suggested to be implicated in mammalian target of rapamycin inhibitor-associated proteinuria. However, induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein. In this study, we assessed the role of uPAR in primary cultured podocytes with rapamycin treatment. Our results indicate that 24-hour rapamycin treatment promotes podocyte migration on the wound scratch assay in a dose-dependent manner. Rapamycin treatment for 2 days does not increase the apoptosis of podocytes or affect the podocyte cell viability and morphology. The up-regulation of uPAR in podocytes was confirmed by immunofluorescence staining, real-time polymerase chain reaction (1.8 +/- 0.3-fold increase of relative quantification; P < .01) and Western blot analysis. Rapamycin treatment also causes the activation of FAK and ILK in a dose-dependent manner. In summary, rapamycin could promote podocyte migration through the up-regulation of uPAR. This finding provides a new mechanism of rapamycin-associated proteinuria. It also suggests that pharmacologic inhibition of uPAR signaling cascade may have therapeutic potential in the setting of rapamycin-related proteinuria. PMID- 24815167 TI - PRMT3: new binding molecule to RhoGDI-alpha during mycophenolic acid-induced beta cell death. AB - Mycophenolic acid (MPA)-induced beta cell toxicity limits islet graft survival. However, the signal transduction mechanisms underlying MPA-induced beta-cell toxicity have not been fully elucidated. Previously, we showed that MPA-induced pancreatic beta-cell apoptosis proceeds via RhoGDI-alpha down-regulation linked to Rac1 activation. In the present study, we investigated factors affecting RhoGDI-alpha during MPA-induced beta-cell apoptosis. The presence of RhoGDI-alpha related protein was determined with the use of yeast 2-hybrid (Y2H) analysis. Y2H screening of RhoGDI-alpha was performed in yeast PBN204 strain containing 3 reporters (URA3, lacZ, and ADE2) under the control of different GAL promoters. INS-1E cells (an insulin-secreting pancreatic beta-cell line) were treated with MPA for 12, 24, and 36 hours. Eighty-three real positives were obtained by Y2H analysis, and of these, arginine N-methyltransferase 3 (PRMT3) protein interacted with RhoGDI-alpha in INS-1E cells. PRMT3 gene expressions and its protein levels were significantly decreased during MPA-induced apoptosis. In summary, PRMT3 and RhoGDI-alpha were found to interact in INS-1E cells. Furthermore, MPA was found to regulate this interaction in INS-1E cells by down-regulating the gene expression of PRMT3. These findings suggest that control of the interaction between PRMT3 and RhoGDI-alpha could be used to prevent MPA-induced beta-cell death. PMID- 24815168 TI - Direct human mitochondrial transfer: a novel concept based on the endosymbiotic theory. AB - Mitochondria play an essential role in eukaryotes, and mitochondrial dysfunction is implicated in several diseases. Therefore, intercellular mitochondrial transfer has been proposed as a mechanism for cell-based therapy. In addition, internalization of isolated mitochondria cells by simple coincubation was reported to improve mitochondrial function in the recipient cells. However, substantial evidence for internalization of isolated mitochondria is still lacking, and its precise mechanism remains elusive. We tested whether enriched mitochondria can be internalized into cultured human cells by simple coincubation using fluorescence microscopy and flow cytometry. Mitochondria were isolated from endometrial gland-derived mesenchymal cells (EMCs) or EMCs stably expressing mitochondrial-targeted red fluorescent protein (EMCs-DsRed-mito), and enriched by anti-mitochondrial antibody-conjugated microbeads. They were coincubated with isogeneic EMCs stably expressing green fluorescent protein (GFP). Live fluorescence imaging clearly showed that DsRed-labeled mitochondria accumulated in the cytoplasm of EMCs stably expressing GFP around the nucleus. Flow cytometry confirmed the presence of a distinct population of GFP and DsRed double-positive cells within the recipient cells. In addition, transfer efficiency depended on mitochondrial concentration, indicating that human cells may possess the inherent ability to internalize mitochondria. Therefore, this study supports the application of direct transfer of isogeneic mitochondria as a novel approach for the treatment of diseases associated with mitochondrial dysfunction. PMID- 24815169 TI - CBRH-7919 cell supernate promotes fibroblasts to express cyclooxygenase-2 and hepatocyte growth factor. AB - BACKGROUND: Transplanted cells need a microenvironment for proliferation and neovascularization. As an important component of the microenvironment, fibroblasts play a role in the process of tumor growth. With that in mind, we planned to activate fibroblasts in vitro and investigate the expression of cyclooxygenase-2 (COX-2) and hepatocyte growth factor (HGF) which can promote the proliferation and neovascularization of the transplanted liver cells. METHODS: Fibroblasts were isolated from 20-day-old fetal Sprague-Dawley rats and incubated in the absence or presence of rat hepatoma CBRH-7919 cell supernate. On days 1, 2, 3, 5, and 7 the incubated fibroblasts were taken for detection of the levels of HGF and COX-2 by immunocytochemistry and the levels of HGF mRNA and COX-2 mRNA by reverse-transcription polymerase chain reaction. RESULTS: When incubated in the presence of CBRH-7919 cell supernate, the fibroblasts could be activated to myofibroblasts that expressed alpha-smooth muscle actin at a high level, and the fibroblasts expressed COX-2, COX-2 mRNA, HGF, and HGF mRNA at higher levels, reaching a peak on day 3 and maintained at high levels until on day 7. CONCLUSIONS: Fibroblasts can be activated by CBRH-7919 cell supernate. Activated fibroblasts can express COX-2 and HGF at higher levels. Maybe we can take advantage of the activated fibroblasts to promote the neovascularization and proliferation of transplanted liver cells. PMID- 24815170 TI - Anticancer benefits of early versus late use of rapamycin in a rat model of urothelial carcinoma. AB - BACKGROUND: We previously reported both in vivo and in vitro effects of rapamycin on urothelial carcinoma. Clinically, the use of rapamycin could not completely prevent the recurrence of urothelial carcinoma. Therefore, we designed this study to compare the difference of efficacy between early and late use of rapamycin in a rat model of urothelial carcinoma. METHODS: The rat model of urothelial carcinoma was induced by adding 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to the drinking water for up to 20 weeks in male Fisher-344 rats. Rapamycin was fed orally from the 1st day, 5th week, 9th week, 13th week, and 17th week. The antitumor effects of different periods of rapamycin treatment were assessed grossly and microscopically. RESULTS: Papillary tumors of urinary bladder were successfully induced in the BBN group. Simultaneous use of rapamycin and BBN from the 1st day of treatment significantly reduced the tumor growth in urinary bladder: 80% of the rats had no tumor and 20% had low-grade tumors. Adding rapamycin from the 5th week was associated with more tumor growth: 20% of the rats had no tumors, 20% had low-grade tumors, and 60% had high-grade tumors. Moreover, in the groups with rapamycin treatment from the 9th week, 13th week, and 17th week, all rats developed high-grade papillary tumors in urinary bladder, as did the control group that received no rapamycin. CONCLUSIONS: The study results suggest that the anticancer effect of rapamycin on urothelial carcinoma is stage dependent. Early use of rapamycin provides better anticancer effect, whereas late use of rapamycin fails to inhibit the cancer growth. PMID- 24815171 TI - Self-formation of vascularized hepatic tissue from human adult hepatocyte. AB - BACKGROUND: Recent study has demonstrated the important role of endothelial mesenchymal interactions in 3-dimensional self-organization of immature progenitor populations with the use of mimicking of organogenesis. Here, we show that the same principle can be applicable to adult mature cells, ie, human adult hepatocytes (hAHs). METHODS: We cultivated hAHs with fluorescence-labeled human mesenchymal cells (hMSCs) and human umbilical vein endothelial cells (HUVECs) in micro-well culture plates and observed them for 9 days. Fluorescence microscopy imaging analyses were performed to evaluate the internal structures of generated 3-dimensional tissues. Maintenance of in vitro protein production capacity was examined with the use of enzyme-linked immunosorbent assay (ELISA). RESULTS: hAHs started to self-organize into 3-dimensional tissue with the use of coculturing with hMSCs and HUVECs. Live imaging analyses showed that endothelial cells started sprouting inside the generated tissues after 2 days of culture. ELISA showed that human albumin production capacity was improved with the use of coculture compared with hAHs-only culture after 9 days. CONCLUSIONS: We demonstrated that 3-dimensional vascularized hepatic tissue could be generated from hAHs by reconstituting endothelial-mesenchymal interactions. Future studies are needed to evaluate the therapeutic potential of vascularized hepatic tissue transplantation, and this may pave a new way to establish a new transplantation modality as an alternative to hepatocyte transplantation. PMID- 24815172 TI - Effects of natural cartilaginous extracellular matrix on chondrogenic potential for cartilage cell transplantation. AB - Autologous chondrocyte transplantation (ACT) has been established to contribute cartilage regeneration over the past years; however, many obstacles need to be overcome. Recently, newer ACT technique involves cotransplantation of chondrocytes and biomaterial. Although various proposed intelligent biomaterials exist, many of them remain insufficient and controversial. In this study, we aimed to examine the effects of natural extracellular matrix (ECM) to the proliferation rate and differentiation on the chondrocytes. We first derived a natural ECM sheet from 10-MUm-thick frozen sections of porcine knee cartilages. We then cultured the chondrocytes derived from a rabbit's knee on a dish precoated with the natural ECM. Then we assessed differentiation and chondrogenic potential of the cells compared with those grown in untreated culture dishes. We characterized the gene expression of chondrogenic markers, such as collagen type II, SOX-9, and aggrecan, as well as the level of ECM protein with the use of reverse-transcription polymerase chain reaction analysis. The cells cultured with the ECM sheet showed highest chondrogenic potential and differentiation. Therefore, we can induce good chondrogenesis by with the use of a natural ECM sheet on the culture dish. The readily available and easy-to-handle thin ECM sheets create an environment that promotes efficient cartilage regeneration. Our data suggest that this natural ECM scaffold improved the chondrogenic differentiation of the cells in vitro by providing a favorable microenvironment. PMID- 24815173 TI - Evidence of a sophisticatedly heterogeneous population of human umbilical vein endothelial cells. AB - Induction and promotion of angiogenesis play a role in a diverse range of physiologic and pathophysiologic processes that are especially relevant to the field of regenerative medicine. For assessing vasculogenesis and neo angiogenesis, identifying angiogenic factors, angiocrine factors, and vascular niche, facilitating tissue-repair and tumor growth, efficiently generating induced pluripotent stem cells, and coculturing with organ-specific stem cells, isolation and characterization of the subpopulation of human umbilical vein endothelial cells (HUVECs) and their endothelial progenitor cells (EPCs) are needed. In this study, primary HUVECs were collected from fresh umbilical cords and fractionated and characterized with the use of flow cytometry. Clonal colony assay showed that endothelial colony-forming units in culture frequently existed in fresh HUVECs. Antigenic profiling demonstrated that undifferentiated EPCs in HUVECs had normal endothelial marker CD31 with a subpopulation of cells positive for hematopoietic stem cell marker CD34 and c-Kit. With continuing passages, EPC markers CD34 and vascular endothelial growth factor receptor 2 expression decreased dramatically. Moreover, a distinct subpopulation with different proliferative capability and angiogenesis from the early-passage HUVECs was shown. In conclusion, it is possible to isolate accurately and to enrich EPCs or hematoangioblast-like cells from a heterogeneous population of HUVECs, and to explore the differential process with flow cytometry for further investigations. PMID- 24815174 TI - Monocytic suppressor cells derived from peripheral blood suppress xenogenic natural killer cell lysis. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) were initially found to contribute to immunosuppression in tumor patients and have recently been recognized as a subset of innate immune cells that are capable of regulating adaptive immunity. A variety of innate immune stimuli, such as lipopolysaccharide, act as a double-edged sword, inducing both the maturation of dendritic cells and the expansion of MDSCs. METHODS: We isolated MDSCs from peripheral blood mononuclear cells (PBMCs) and examined the suppressive effect of MDSCs against xenocytotoxicity mediated by YT cells, a natural killer-like cell line, with the use of the lactate dehydrogenase assay method. RESULTS: Although primed MDSCs induced no significant suppression in YT cell-mediated cytotoxicity, activated MDSCs significantly suppressed the xenogenic cytotoxicity. CONCLUSIONS: These findings indicate that MDSCs have a great deal of potential as a therapeutic strategy for dealing with xenograft rejection. Further investigations of the underlying mechanisms will facilitate the development of this therapeutic strategy. PMID- 24815175 TI - Regulation of macrophage-mediated xenocytotoxicity by overexpression of alpha-2,6 sialyltransferase in swine endothelial cells. AB - Macrophages play an important role in xenogenic rejection and therefore may represent a major obstacle in clinical application of xenograft. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to the immunoglobulin superfamily and contain a cytoplasmic immunoreceptor tyrosine based inhibitory motif (ITIM) that is able to inhibit cytokine production. Because human macrophages express various CD33-related Siglecs, we hypothesized that overexpression of alpha-2,6-sialyltransferase (2,6-ST) in swine endothelial cells (SECs) might prevent the cytotoxicity mediated by macrophages. To confirm our hypothesis, the cytotoxicity of macrophages against 2,6-ST-overexpressing SECs was determined with the use of in vitro-generated macrophages as an effector and naive or 2,6-ST-overexpressing SECs as a target. The 2,6-ST-overexpressing SECs were established by transfection with the genes for 2,6-ST. Transfection of 2,6-ST led to significant reduction in cytotoxicity compared with naive SECs. These findings indicate that the sialylated ligands against CD33-related Siglecs may provide an effective therapeutic strategy to inhibit macrophage-mediated xenograft rejection in xenotransplantation. PMID- 24815176 TI - Solid-state NMR strategies for the structural characterization of paramagnetic NO adducts of Frustrated Lewis Pairs (FLPs). AB - By N,N addition of NO to the norbonane annulated borane-phosphane Frustrated Lewis pair (FLP) 1 a five-membered heterocyclic persistent aminoxyl radical 2 and its diamagnetic hydroxylamine reduction product 3 are prepared, and the comprehensive multinuclear solid state NMR characterization ((1)H, (11)B, (19)F, (31)P) of these FLP adducts is reported. Signal quantification experiments using a standard addition method reveal that the (11)B and (31)P NMR signals observed in 2 actually arise from molecular impurities of 3 embedded in the paramagnetic crystal. In contrast analogous quantification experiments reveal that the (1)H and (19)F MAS-NMR spectra originate from spin-carrying molecules. Peak assignments are based on DFT-calculated Mulliken spin densities, which lead to the surprising result that the largest paramagnetic shift affecting a proton NMR resonance in 2 originates from intermolecular interactions. For the (19)F nuclei, experiments and calculations indicate that paramagnetic shift effects are very small. In this case, assignments are based on DFT chemical shift calculations carried out on diamagnetic 3 and (19)F((11)B) Rotational Echo Adiabatic Passage DOuble Resonance (REAPDOR) experiments. The set of experiments described here defines an efficient strategy for the structural analysis of paramagnetic FLP adducts. PMID- 24815177 TI - Mental suffering and the DSM-5: a critical review. AB - The definition of mental disorder included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), indicates that mental disorders are usually associated with significant distress. However, the handbook is vague with respect to whether distress is crucial to the diagnosis of mental disorders, and a conceptual framework on the precise nature of distress is lacking. As a result, it remains vague how the term 'distress' is to be taken into account in actual diagnostic situations: the DSM-5 provides no operational framework for diagnosing distress. The authors argue that the work of Georges Canguilhem, who focuses on the topic of abnormality and pathology, and Paul Ricoeur's philosophical reflections on the theme of mental suffering may provide a structure for conceptualizing and evaluating distress. Ricoeur's phenomenological model of mental suffering is discussed. Here, mental suffering can be thought of in terms of the relationship between self and other, and also in terms of the continuum made up by, what he terms, languishing and acting. Ricoeur suggests that distress is not a quantity that can be measured, but a characteristic that should be studied qualitatively in interpersonal and narrative contexts. Consequently, diagnosticians should describe and document how individuals experience subjective distress. On a practical level, this means that clinicians' ideas about patients' distress should be embedded in case formulations. A detailed evaluation of an individual's pathos-experience should be made before conclusions are drawn with regard to diagnosis. PMID- 24815178 TI - Paravalvular regurgitation: the unconquered frontier in TAVR. PMID- 24815179 TI - Service user involvement in practitioner education: Movement politics and transformative change. AB - This paper will attempt to celebrate both key developments and best practice involving the users of health and social care services in programmes of practitioner education in a UK context, and offer a critical appraisal of the extent to which such initiatives meet some of the more transformative objectives sought by service user activists for change. The approach is largely that of a discussion paper but we will illustrate some of the themes relating to movement activism with selected data. These data relate to earlier research and two specially convened focus groups within the Comensus initiative at the University of Central Lancashire; itself constituted as a piece of participatory action research. We conclude that universities represent paradoxical sites for the facilitation of debate and learning relevant to key issues of social justice and change. As such, they are places that can impede or support movement aims. Particular strategic responses might be more likely to engender progressive outcomes. These ought to include the presence of critically engaged academic staff operating within a scholarly culture that fosters forms of deliberative democratic decision making. PMID- 24815180 TI - The evaluation of undergraduate nurses' attitudes, perspectives and perceptions toward older people. AB - OBJECTIVES: This literature review was undertaken to evaluate undergraduate nurses' attitudes and perspectives toward older people and perceptions of working with older people. The objectives were to (1) identify if undergraduate nurses hold positive or negative attitudes and perspectives toward older people and perceptions of working with older people, and (2) determine if positive attitudes, perspectives and perceptions can be established, maintained and improved with curriculum activities. DESIGN: Literature review. DATA SOURCES: For the period 2008-2013, the literature search included an electronic database search (Medline, CINAHL, Healthsource/Academic Edition, PsycINFO and PubMed) and a hand search of reference lists of the papers included. RESULTS AND CONCLUSIONS: The analysis of 32 studies revealed that undergraduate nurses' attitudes, perspectives and perceptions are positive and it is recommended that this be the starting point for the development of curriculum activities and future research to maintain and improve this result. Finally, the limitations of recent studies are identified and a research agenda for future studies is proposed. PMID- 24815181 TI - Midwifery students learning experiences in labor wards: a grounded theory. AB - BACKGROUND: The labor ward is an important and challenging learning area for midwifery students. It is there the students learn in authentic complex situations, in intimate situations, with potential risk for the life and health of mothers and their babies. OBJECTIVE: The aim of this study was to explore the main concern expressed by midwifery students in labor wards and how they handled this concern. DESIGN: A longitudinal study based on grounded theory methodology was used. The participants were 10 postgraduate midwifery students, from a University College in Norway. Data were gathered and analyzed throughout the 2 year postgraduate program, in the students first, third and fourth semesters. Every student was interviewed three times in a total of 15 single and three focus group sessions. FINDINGS: The grounded theory of "building relationships" explains how students dealt with their main concern: "how to gain access to learning experiences". This theory consisted of three strategies; a) controlling vulnerability, b) cultivating trust and c) obtaining acceptance. CONCLUSION: Clarifying discussions involving midwives and students may facilitate the process of building relationships and contribute to confident learning. Students appreciate it when the midwives initiate discussions about acute situations and state that a novice may perceive labor and childbirth as more frightening than an experienced midwife would. PMID- 24815182 TI - Cycloheximide and actiphenol production in Streptomyces sp. YIM56141 governed by single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase. AB - Cycloheximide (1) and actiphenol (2) have been isolated from numerous Streptomyces species. Cloning, sequencing, and characterization of a gene cluster from Streptomyces sp. YIM65141 now establish that 1 and 2 production is governed by single biosynthetic machinery. Biosynthesis of 1 features an acyltransferase less type I polyketide synthase to construct its carbon backbone but may proceed via 2 as a key intermediate, invoking a provocative reduction of a phenol to a cyclohexanone moiety in natural product biosynthesis. PMID- 24815184 TI - Regional strain determination and myocardial infarction detection by three dimensional echocardiography with varied temporal resolution. AB - BACKGROUND: Three-dimensional echocardiography (3DE) is a promising method for strain determination; however, there are temporal resolution concerns. This study aims to evaluate the feasibility and accuracy of 3DE on longitudinal and circumferential strain (LS, CS) determination and infarction detection under variable frame rates (FR) and "heart rates" (stroke rates [SR]) conditions. METHODS: Latex balloons were sewn into the left ventricle (LV) of 20 freshly harvested pig hearts which were then passively driven by a pulsatile pump apparatus at stroke volumes (SV) 30-70 mL. The hearts were pumped at 2 normal limits of human heart rate. Full-volume data were acquired before and after a simulated myocardial infarction (MI) at the 2 most commonly used FRs. LS and CS values were evaluated against sonomicrometry. RESULTS: Longitudinal strain and CS derived from high FR acquisitions showed statistically superior correlations with sonomicrometry data (LS: R(2) = 0.85, CS: R(2) = 0.84) than strain values from low FR (LS: R(2) = 0.78, CS: R(2) = 0.76) (all P < 0.01). After MI induction, LS and CS at different FRs were significantly decreased while maintaining excellent correlations with sonomicrometry data (all P < 0.001). There is no statistical difference of strain values between different SR acquisitions. CONCLUSION: Three dimensional wall-motion tracking has the ability to accurately determine regional myocardial deformation and detect MI. Different heart rates within a physiologically relevant range have no effect on 3D strain accuracy. Strain values calculated from higher frame rate acquisitions were found to have a slightly better accuracy. PMID- 24815183 TI - Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. AB - Mitochondrial function is an important determinant of the ageing process; however, the mitochondrial properties that enable longevity are not well understood. Here we show that optimal assembly of mitochondrial complex I predicts longevity in mice. Using an unbiased high-coverage high-confidence approach, we demonstrate that electron transport chain proteins, especially the matrix arm subunits of complex I, are decreased in young long-living mice, which is associated with improved complex I assembly, higher complex I-linked state 3 oxygen consumption rates and decreased superoxide production, whereas the opposite is seen in old mice. Disruption of complex I assembly reduces oxidative metabolism with concomitant increase in mitochondrial superoxide production. This is rescued by knockdown of the mitochondrial chaperone, prohibitin. Disrupted complex I assembly causes premature senescence in primary cells. We propose that lower abundance of free catalytic complex I components supports complex I assembly, efficacy of substrate utilization and minimal ROS production, enabling enhanced longevity. PMID- 24815185 TI - Protein kinase C (PKC) mediated interaction between conexin43 (Cx43) and K(+)(ATP) channel subunit (Kir6.1) in cardiomyocyte mitochondria: Implications in cytoprotection against hypoxia induced cell apoptosis. AB - PURPOSE OF RESEARCH: We have recently shown that adenosine-triphosphate-sensitive potassium [K(+)(ATP)] channel protein subunit, Kir6.1 is a phosphospecific interaction partner of the gap-junction protein connexin43 (Cx43). Since, both Cx43 and K(+)(ATP) are known to be involved in cell survival during hypoxia, we addressed the question, whether the interaction between Cx43 and K(+)(ATP) has a role in protecting cell against hypoxia-induced cell death. PRINCIPLE RESULTS: We report here that the Kir6.1 protein interacts, in a phosphospecific manner with Cx43 in the mitochondria of cardiomyocytic cell line H9C2. The hypoxia for 12-h resulted in the appreciable increase in the phosphorylation at the serine 262 (S262) of the Cx43 with the concomitant increase in the Cx43 and Kir6.1 interaction. Moreover, the increased interaction was mediated by a signaling pathway involving PKC and more specifically by PKC epsilon. Functional implications of the association between the Cx43 and Kir6.1 were found to prevent mitochondria mediated hypoxia induced cell apoptosis. MAJOR CONCLUSIONS: Our results demonstrate that PKC epsilon regulates the interaction between Cx43 and Kir6.1 in the cardiomyocyte mitochondria and this interaction prevents hypoxia induced cell death. Our results provide an interesting lead in developing effective strategies to protect cardiomyocytes from hypoxia/ischemia induced cell death. PMID- 24815186 TI - Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma. AB - BACKGROUND: Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage. Therefore, eIF4F translation initiation complex components are attractive therapeutic targets. METHODS: Protein lysates of myeloma cells (cell lines/patients' bone marrow samples) untreated/treated with bevacizumab were assayed for eIF4GI expression, regulation (NQO1/proteosome dependent fragmentation) (WB, Dicumarol, qPCR) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1. Cells were tested for viability (ELISA), death (FACS) and eIF4GI targets (WB). RESULTS: Previously, we have shown that manipulation of VEGF in myeloma cells attenuated eIF4E dependent translation initiation. Here we assessed the significance of eIF4GI to MM cells. We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon VEGF inhibition attributed to elevated NQO1/proteasome dependent fragmentation and diminished mRNA levels. Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets (SMAD5/ERalpha/HIF1alpha/c-Myc). Finally, we showed that the small molecule 4EGI 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma. CONCLUSION: Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI, critical to cell phenotype, and mark it as a viable target for pharmacological intervention. PMID- 24815187 TI - Regulation of contractile signaling and matrix remodeling by T-cadherin in vascular smooth muscle cells: constitutive and insulin-dependent effects. AB - Expression of GPI-anchored T-cadherin (T-cad) on vascular smooth muscle cells (VSMC) is elevated in vascular disorders such as atherosclerosis and restenosis which are associated with insulin resistance. Functions for T-cad and signal transduction pathway utilization by T-cad in VSMC are unknown. The present study examines the consequences of altered T-cad expression on VSMC for constitutive and insulin-induced Akt/mTOR axis signaling and contractile competence. Using viral vectors rat (WKY and SHR) and human aortic VSMCs were variously transduced with respect to T-cad-overexpression (Tcad+-VSMC) or T-cad-deficiency (shT-VSMC) and compared with their respective control transductants (E-VSMC or shC-VSMC). Tcad+-VSMC exhibited elevated constitutive levels of phosphorylated Akt(ser473), GSK3beta(ser9), S6RP(ser235/236) and IRS-1(ser636/639). Total IRS-1 levels were reduced. Contractile machinery was constitutively altered in a manner indicative of reduced intrinsic contractile competence, namely decreased phosphorylation of MYPT1(thr696 or thr853) and MLC20(thr18/ser19), reduced RhoA activity and increased iNOS expression. Tcad+-VSMC-populated collagen lattices exhibited greater compaction which was due to increased collagen fibril packing/reorganization. T-cad+-VSMC exhibited a state of insulin insensitivity as evidenced by attenuation of the ability of insulin to stimulate Akt/mTOR axis signaling, phosphorylation of MLC20 and MYPT1, compaction of free-floating lattices and collagen fibril reorganization in unreleased lattices. The effects of T-cad-deficiency on constitutive characteristics and insulin responsiveness of VSMC were opposite to those of T-cad-overexpression. The study reveals novel cadherin-based modalities to modulate VSMC sensitivity to insulin through Akt/mTOR axis signaling as well as vascular function and tissue architecture through the effects on contractile competence and organization of extracellular matrix. PMID- 24815188 TI - Mig-6 participates in the regulation of cell senescence and retinoblastoma protein phosphorylation. AB - Mitogen-inducible gene-6 (Mig-6) is a cytosolic multiadaptor protein that is best known for its role as a negative feedback regulator of epidermal growth factor receptor (EGFR) mediated signalling. Alternative roles of Mig-6 are becoming increasingly recognised. Consistently with this, Mig-6 was demonstrated to be involved in a broad spectrum of cellular events including tumour suppression which may include the induction of cellular senescence. Here, we investigated the mechanisms of Mig-6 induced premature cell senescence. Endogenous Mig-6 is poorly expressed in young fibroblasts, whilst its expression rises in cells presenting with typical features of senescence. Overexpression of Mig-6 is sufficient to trigger premature cellular senescence of early passage diploid lung fibroblasts (WI-38). Interestingly, Mig-6 overexpression reduced retinoblastoma protein (pRb) phosphorylation at the inactivating Ser249/Thr252 sites. We also found that phosphorylation of these sites in pRb is increased in the presence of the B-Raf V600E oncogenic mutation. We further show that Mig-6 overexpression reduces B-Raf V600E mediated pRb inactivation and preserves pRb function. PMID- 24815189 TI - Structural basis of Rad53 kinase activation by dimerization and activation segment exchange. AB - The protein kinase Rad53 is a key regulator of the DNA damage checkpoint in budding yeast. Its human ortholog, CHEK2, is mutated in familial breast cancer and mediates apoptosis in response to genotoxic stress. Autophosphorylation of Rad53 at residue Thr354 located in the kinase activation segment is essential for Rad53 activation. In this study, we assessed the requirement of kinase domain dimerization and the exchange of its activation segment during the Rad53 activation process. We solved the crystal structure of Rad53 in its dimeric form and found that disruption of the observed head-to-tail, face-to-face dimer structure decreased Rad53 autophosphorylation on Thr354 in vitro and impaired Rad53 function in vivo. Moreover, we provide critical functional evidence that Rad53 trans-autophosphorylation may involve the interkinase domain exchange of helix alphaEF via an invariant salt bridge. These findings suggest a mechanism of autophosphorylation that may be broadly applicable to other protein kinases. PMID- 24815190 TI - Spirulina-templated metal microcoils with controlled helical structures for THz electromagnetic responses. AB - Microstructures in nature are ultrafine and ordered in biological roles, which have attracted material scientists. Spirulina forms three-dimensional helical microstructure, one of remarkable features in nature beyond our current processing technology such as lithography in terms of mass-productivity and structural multiplicity. Spirulina varies its diameter, helical pitch, and/or length against growing environment. This unique helix is suggestive of a tiny electromagnetic coil, if composed of electro-conductive metal, which brought us main concept of this work. Here, we describe the biotemplating process onto Spirulina surface to fabricate metal microcoils. Structural parameters of the microcoil can be controlled by the cultivation conditions of Spirulina template and also purely one-handed microcoil can be fabricated. A microcoil dispersion sheet exhibited optically active response attributed to structural resonance in terahertz-wave region. PMID- 24815191 TI - Size- and shape-dependent pleural translocation, deposition, fibrogenesis, and mesothelial proliferation by multiwalled carbon nanotubes. AB - Multiwalled carbon nanotubes (MWCNT) have a fibrous structure similar to asbestos, raising concern that MWCNT exposure may lead to asbestos-like diseases. Previously we showed that MWCNT translocated from the lung alveoli into the pleural cavity and caused mesothelial proliferation and fibrosis in the visceral pleura. Multiwalled carbon nanotubes were not found in the parietal pleura, the initial site of development of asbestos-caused pleural diseases in humans, probably due to the short exposure period of the study. In the present study, we extended the exposure period to 24 weeks to determine whether the size and shape of MWCNT impact on deposition and lesion development in the pleura and lung. Two different MWCNTs were chosen for this study: a larger sized needle-like MWCNT (MWCNT-L; l = 8 MUm, d = 150 nm), and a smaller sized MWCNT (MWCNT-S; l = 3 MUm, d = 15 nm), which forms cotton candy-like aggregates. Both MWCNT-L and MWCNT-S suspensions were administered to the rat lung once every 2 weeks for 24 weeks by transtracheal intrapulmonary spraying. It was found that MWCNT-L, but not MWCNT S, translocated into the pleural cavity, deposited in the parietal pleura, and induced fibrosis and patchy parietal mesothelial proliferation lesions. In addition, MWCNT-L induced stronger inflammatory reactions including increased inflammatory cell number and cytokine/chemokine levels in the pleural cavity lavage than MWCNT-S. In contrast, MWCNT-S induced stronger inflammation and higher 8-hydroxydeoxyguanosine level in the lung tissue than MWCNT-L. These results suggest that MWCNT-L has higher risk of causing asbestos-like pleural lesions relevant to mesothelioma development. PMID- 24815192 TI - Bleeding management for pediatric craniotomies and craniofacial surgery. AB - Pediatric patients when undergoing craniotomies and craniofacial surgery may potentially have significant blood loss. The amount and extent will be dictated by the nature of the surgical procedure, the proximity to major blood vessels, and the age, and weight of the patient. The goals should be to maintain hemodynamic stability and oxygen carrying capacity and to prevent and treat hyperfibrinolysis and dilutional coagulopathy. Over transfusion and transfusion related side effects should be minimized. This article will highlight the pertinent considerations for managing massive blood loss in pediatric patients undergoing craniotomies and craniofacial surgery. North American and European guidelines for intraoperative administration of fluid and blood products will be discussed. PMID- 24815193 TI - N-acetylcysteine as treatment for self-injurious behavior in a child with autism. PMID- 24815194 TI - Metabolic model reconstruction and analysis of an artificial microbial ecosystem for vitamin C production. AB - An artificial microbial ecosystem (AME) consisting of Ketogulonicigenium vulgare and Bacillus megaterium is currently used in a two-step fermentation process for vitamin C production. In order to obtain a comprehensive understanding of the metabolic interactions between the two bacteria, a two-species stoichiometric metabolic model (iWZ-KV-663-BM-1055) consisting of 1718 genes, 1573 metabolites, and 1891 reactions (excluding exchange reactions) was constructed based on separate genome-scale metabolic models (GSMMs) of K. vulgare and B. megaterium. These two compartments (k and b) of iWZ-KV-663-BM-1055 shared 453 reactions and 548 metabolites. Compartment b was richer in subsystems than compartment k. In minimal media with glucose (MG), metabolite exchange between compartments was assessed by constraint-based analysis. Compartment b secreted essential amino acids, nucleic acids, vitamins and cofactors important for K. vulgare growth and biosynthesis of 2-keto-l-gulonic acid (2-KLG). Further research showed that when co-cultured with B. megaterium in l-sorbose-CSLP medium, the growth rate of K. vulgare and 2-KLG production were increased by 111.9% and 29.42%, respectively, under the constraints employed. Our study demonstrated that GSMMs and constraint based methods can be used to decode the physiological features and inter-species interactions of AMEs used in industrial biotechnology, which will be of benefit for improving regulation and refinement in future industrial processes. PMID- 24815195 TI - Luminescent hybrid materials based on zeolite L crystals and lanthanide complexes: host-guest assembly and ultraviolet-visible excitation. AB - Several kinds of host-guest hybrid materials have been synthesized employing a ship in a bottle method by loading 9-hydroxy-2-methylphenalenone (MHPO) or 9 hydroxyphenalen (HPNP) from gas phase into the nanochannels of Ln(3+)-exchanged zeolite L (ZL) crystals (Ln=Gd or Eu). The resulting hybrids without lanthanide ions, MHPO-ZL, HPNP-ZL and the hybrids with lanthanide ions Ln-MHPO-ZL and Ln HPNP-ZL are characterized with FT-IR, UV-vis DRS and photoluminescence spectroscopy. The photoluminescence properties of these hybrid materials have been analyzed and discussed, exhibiting the luminescence of Eu(3+) and ligands under the excitation at ultraviolet-visible region. These results provide useful data and can be expected to have potential application in the practical fields. PMID- 24815196 TI - Visualization of hormone binding proteins in vivo based on Mn-doped CdTe QDs. AB - Daminozide (B9) is a growth inhibitor with important regulatory roles in plant growth and development. Locating and quantifying B9-binding proteins in plant tissues will assist in investigating the mechanism behind the signal transduction of B9. In this study, red fluorescent Mn-doped CdTe quantum dots (CdTeMn QDs) were synthesized by a high-temperature hydrothermal process. Since CdTeMn QDs possess a maximum fluorescence emission peak at 610nm, their fluorescence properties are more stable than those of CdTe QDs. A B9-CdTeMn probe was synthesized by coupling B9 with CdTeMn QDs. The fluorescence intensity of the probe is double that of CdTeMn QDs; its fluorescence stability is also superior under different ambient conditions. The probe retains the biological activity of B9 and is unaffected by interference from the green fluorescent protein present in plants. Therefore, we used this probe to label B9-binding proteins selectively in root tissue sections of mung bean seedlings. These proteins were observed predominantly on the surfaces of the cell membranes of the cortex and epidermal parenchyma. PMID- 24815197 TI - Synthesis, spectral analysis, optical and thermal properties of new organic NLO crystal: N,N'-Diphenylguanidinium Nitrate (DPGN). AB - A new organic NLO material N,N'-Diphenylguanidinium Nitrate (DPGN) single crystal was grown by slow evaporation technique using methanol as solvent. Single crystal X-ray diffraction and powder X-ray diffraction experiments were carried out in order to confirm the structure and crystalline nature of DPGN crystal. Wide band gap of 3.9eV with transmittance of 57% up to 800nm is observed for the grown crystal using UV-vis spectral analysis. The chemical bonding and presence of various functional groups were confirmed by the FT-IR and FT-Raman spectral studies. The thermal behavior of DPGN crystal was analyzed by simultaneous TG-DTA studies. The second harmonic generation (SHG) nonlinearity of the grown crystal was measured by Kurtz and Perry powder technique and was found to be comparable with that of the standard reference material potassium dihydrogen phosphate (KDP) crystal. PMID- 24815198 TI - Porous membrane ultrafiltration-A novel method for enrichment of the active compounds from micro-plasma samples. AB - To enrich the active compounds from plasma samples, a novel and simple method has been developed using a porous membrane envelope based on the ultrafiltration technique combining with high-performance liquid chromatography. The ultrafiltration device is a sealed porous membrane envelope prepared with a polypropylene sheet to effectively separate the active small molecules and large biomolecules, and a sample carrier is held inside the envelope to load plasma samples. The enrichment of hyperoside and isoquercitrin from rat plasma was used as an example. Significant factors of this method, such as membrane types, the desorption solvent, and the desorption time were optimized for the ultrafiltration method. Under the optimal conditions, correlation coefficients of 0.999 and 0.998 were obtained for hyperoside and isoquercitrin, respectively, with a linear range between 0.5 and 100MUg/mL. The absolute extraction recoveries from 83.2% to 86.8% were achieved. The detection limits of the method for hyperoside and isoquercitrin were 0.22 and 0.20MUg/mL, respectively. Compared with protein precipitation, solid-phase extraction and commercial ultrafiltration membrane methods, our proposed method demonstrates lower detection limits and lower cost for extraction. Also, it consumes less plasma samples and is found to be applicable to biological samples. PMID- 24815200 TI - Social cognition in fishes. AB - Brain evolution has often been correlated with the cognitive demands of social life. Further progress depends on our ability to link cognitive processes to corresponding brain part sizes and structures, and, ultimately, to demonstrate causality. Recent research suggests that fishes are suitable to test general hypotheses about vertebrate social cognition and its evolution: brain structure and physiology are rather conserved among vertebrates, and fish are able to perform complex decisions in social context. Here, we outline the opportunities for experimentation and comparative studies using fish as model systems, as well as some current shortcomings in fish social cognition research. PMID- 24815199 TI - Efficacy and Tolerability of Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: A Responder Analysis of 2 Randomized, Placebo-Controlled Trials. AB - BACKGROUND: Subcutaneous methylnaltrexone is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); factors determining optimal responsiveness to OIC treatment, however, have not been elucidated. This post hoc responder analysis examined the influence of demographic and baseline characteristics on methylnaltrexone efficacy and tolerability in this population. METHODS: Data were pooled from 2 randomized, double-blind, placebo-controlled, phase 3 studies of subcutaneous methylnaltrexone (0.15 and 0.30 mg/kg) [ClinicalTrials.gov identifiers: Study 301 - NCT00401362; Study 302 - NCT00402038]. Subgroup analyses of the primary outcome, percentage of patients with rescue medication-free bowel movements (RFBM) within 4 hours of first dose, were conducted for age, sex, primary diagnosis, baseline constipation-related distress score, and baseline oral morphine equivalent dose. RESULTS: More than 50% of 165 patients treated with either methylnaltrexone dose experienced a RFBM within 4 hours vs. 14.6% of 123 placebo-treated patients (P < 0.0001 for both methylnaltrexone doses vs. placebo). Methylnaltrexone response was significantly greater than placebo response in all subgroups (P < 0.01). The largest differences vs. placebo were observed for patients taking methylnaltrexone 0.30 mg/kg with a noncancer primary diagnosis (70.0% [methylnaltrexone] vs. 12.8% [placebo]; P < 0.001) and for patients taking methylnaltrexone 0.30 mg/kg maintained on >= 150 mg/day baseline morphine equivalent doses (73.3% vs. 16.7%; P < 0.0001). Common adverse events were abdominal pain (pooled methylnaltrexone: 27.9%, placebo: 9.8%), flatulence (13.3%, 5.7%), and nausea (10.9%, 4.9%). Tolerability was comparable across subgroups. CONCLUSION: Subcutaneous methylnaltrexone provides a rapid, robust, and consistent RFBM response in patients with advanced illness and OIC. Methylnaltrexone 0.30 mg/kg may elicit particularly favorable responses in select patient populations. PMID- 24815201 TI - Introduction of the revised CENA Practice Standards for the emergency nursing specialist. PMID- 24815202 TI - Opportunistic immunisation in the emergency department: a survey of staff knowledge, opinion and practices. AB - OBJECTIVE: The aim of this study was to identify (a) emergency department staff knowledge, opinion and practices in relation to childhood vaccines and opportunistic immunisation in the emergency department and (b) differences between nursing and medical staff knowledge, opinion and self reported practices. METHODS: A self-administered, cross-sectional survey was offered to a convenience sample of medical and nursing staff (n=86) working in a tertiary paediatric emergency department. Variables of interest were described using frequencies and odds ratios to report differences between medical and nursing staff responses. RESULTS: An 87% survey response was achieved. The majority of staff agreed that childhood vaccines were safe (96%), effective (99%) and necessary (97%). Less than half (45%) of the staff correctly identified that there is no association between measles, mumps and rubella (MMR) vaccine and autism. Medical staff were more likely than nurses to disagree that giving multiple vaccines overloads the immune system (p<0.01), or that complementary therapies reduced the need for a child to be vaccinated (p<0.006). These knowledge deficits exist despite a reported awareness of immunisation resources. The majority (96%) of those surveyed reported that the Australian Immunisation Handbook was as a useful resource. CONCLUSION: Overall, the majority of staff agreed vaccines are safe, effective and necessary. This study highlighted that staff knowledge deficits and misconceptions about vaccines and vaccine management may be barriers to promoting opportunistic immunisation practices in ED. PMID- 24815203 TI - The Emergency Triage Education Kit: improving paediatric triage. AB - OBJECTIVES: The Emergency Triage Education Kit (ETEK) was published in 2007. To date, the impact of ETEK has not been measured. The purpose of this study was to measure the effectiveness of ETEK on paediatric triage. METHOD: A retrospective chart audit was undertaken in a tertiary paediatric hospital. Its' aim was to review the completeness of documentation recorded at the point of triage after a standardised documentation framework was introduced and to measure inter-rater agreement. Primary assessment and physiological discriminators documented at the point of triage were compared with those from the paediatric physiological discriminator table (PPDT) within ETEK. Using an audit tool developed by the researchers, a parallel decision-making pathway was used to ascertain whether the original ATS score could be substantiated by the PPDT. Improvement in documentation of the primary assessment and inter-rater agreement was measured over time. RESULTS: 600 triage records were selected; 200 each from 2007, 2008 and 2010. Triage documentation that did not support parallel decision-making decreased significantly according to the year of presentation (2007; 112 (56%), 2008; 106 (53%), 2010; 13 (7%), P<0.001). When parallel decision-making was facilitated by an improvement in triage documentation, there was improvement in matched triage scores (2007; 54%, 2008; 69%, 2010; 72%, P=0.01). CONCLUSION: The introduction of ETEK has had a significant impact in this ED, particularly when combined with education sessions. The use of the PPDT as a framework to guide documentation and triage language facilitated parallel decision-making and auditing, and led to an improvement in inter-rater agreement when applied to children. PMID- 24815204 TI - Recognising clinical deterioration in emergency department patients. AB - BACKGROUND: The use of rapid response systems such as Medical Emergency Team (MET) improves recognition and response to clinical deterioration in in-patient settings. However, few published studies have investigated use of rapid response systems in Australian emergency departments (ED). AIM: To examine the frequency, nature and outcomes of clinical deterioration in ED patients and compare the utility of hospital MET calling criteria with ED specific Clinical Instability Criteria (CIC) for recognition of deteriorating patients. The outcomes of interest were the prevalence of deterioration in ED patients, the utility of MET versus ED CIC, and the outcomes (MET activation, in-hospital mortality at 30 days) of patients who experienced deterioration during ED care. METHOD: An exploratory descriptive design was used. Vital sign data were prospectively collected from 200 patients receiving ED care in the general treatment areas of regional, publicly funded health service in Victoria, Australia, during May 2012. Outcome data were collected by follow up medical record audit. RESULTS: Of the 200 ED patients recruited, 2% fulfilled the study site MET criteria and 7.5% fulfilled ED CIC. The median age of patients fulfilling MET criteria was 85 years compared with a median age of 74 years for patients fulfilling the ED CIC criteria. Of the 136 ED patients admitted to in-patient wards, 5.9% required MET activation during admission and 3.7% of these MET activations occurred within 24h of emergency admission. Five percent of patients died in-hospital within 30 days of ED attendance. CONCLUSIONS: ED specific criteria for activation of a rapid response system identifies more ED patients at risk of clinical deterioration. The results of this study highlight a need for EDs to implement and evaluate systems to increase recognition of deteriorating patients designed specifically for the emergency care context. PMID- 24815205 TI - Participant evaluation of team-based learning using one-off teams in a hospital setting. AB - BACKGROUND: Team-based learning (TBL) is a highly structured educational strategy that improves student engagement, promotes deeper learning and builds professional skills but has had limited use in nursing education. AIMS: To examine participant experiences of TBL using one-off teams in a hospital setting. METHOD: A prospective exploratory design was used in an urban district hospital in Melbourne, Australia. The sample was 49 registered nurses. The intervention was a TBL-based education program focused on assessment and management of adult patients with isolated distal limb injuries. Data were collected using two instruments that evaluated participant experiences of the narrated slide presentation and participant experiences of learning of using TBL. Quantitative data were analysed using descriptive statistics and thematic analysis was used to analyse the qualitative data. RESULTS: The results revealed two key themes: "quality of learning" and "positive team experience". The presentation was accessed twice or more by 51% of participants. Participants perceived a high quality of learning: 95.5% stated that their learning expectations were met or exceeded. Three quarters of participants (77.5%) commented about the contribution of their team members. CONCLUSION: Participants in this study thought TBL provided them a positive learning experience, as individuals and as teams. Education methodologies that focus on professional attributes and behaviours in addition to clinical skill are well suited to emergency nursing whereby nurses have to be theoretically prepared for practice and work well in teams. RELEVANCE TO CLINICAL PRACTICE: TBL has a natural synergy with the requirements of advanced nursing practice and offers a positive learning experience that enhances clinical outcomes. PMID- 24815206 TI - Laparoscopic resection of synchronous colorectal cancers in separate specimens. AB - INTRODUCTION: Laparoscopic approaches are increasingly being used in patients with colorectal cancer, but the feasibility of laparoscopic resection of synchronous colorectal cancers in separate specimens remains unknown. In such cases, it is necessary to consider the site of port placement, sequence of dissection, choice of specimen extraction sites, specimen handling, and extracorporeal anastomosis sites. Moreover, the need for complete mesenteric dissection in two areas, removal of two separate specimens containing malignancies, and two anastomoses elicit unique questions related to technical considerations. The aim of this study was to determine the feasibility of laparoscopic resection of two separate specimens containing malignancies for multiple synchronous colorectal cancers. METHODS: Between June 2001 and January 2013, 1341 patients with colorectal cancer underwent laparoscopic surgery at our institution. Of them, 11 patients underwent laparoscopy-assisted combined resection of two separate colorectal specimens for multiple synchronous primary colorectal cancers. We retrospectively reviewed their surgical outcomes. RESULTS: All procedures were completed laparoscopically without perioperative mortality. Patients underwent right-sided colon resection for right-sided cancer and left sided or rectal resection for left-sided colon or rectal cancer. The median duration of surgery was 296 min, and the median blood loss was 65 mL. Median time to first postoperative liquid and solid intake was 1 day and 3 days, respectively. Most patients were discharged on postoperative day 8. With regard to postoperative complications, two patients had a surgical-site infection. CONCLUSION: Laparoscopic resection of two separate colorectal specimens for multiple synchronous primary colorectal cancers is a feasible and safe procedure. PMID- 24815207 TI - [Radiological reports and their structure]. PMID- 24815208 TI - Changing priority setting practice: the role of implementation in practice change. AB - BACKGROUND: Programme budgeting and marginal analysis (PBMA) is a priority setting approach that assists decision makers in choosing among resource demands. This paper describes and evaluates the process of implementing PBMA in a Canadian regional health authority, and draws out key lessons learned from this experience. METHODS: Qualitative data were collected through semi-structured participant interviews (twelve post year-1; nine post year-2), meeting attendance, and document review. Interview transcripts were analyzed using a constant comparison technique. Other data were analyzed to evaluate PBMA implementation. RESULTS: Desire for more clarity and for PBMA adaptations emerged as overarching themes. Participants desired greater clarity of their roles and how PBMA should be used to achieve PBMA's potential benefits. They argued that each PBMA stage should be useful independent of the others so that implementation could be adapted. To help improve clarity and ensure that resources were available to support PBMA, participants requested an organizational readiness and capacity assessment. CONCLUSION: We suggest tactics by which PBMA may be more closely aligned with real-world priority setting practice. Our results also contribute to the literature on PBMA use in various healthcare settings. Highlighting implementation issues and potential responses to these should be of interest to decision makers implementing PBMA and other evidence-informed practices. PMID- 24815211 TI - Tracheole investment does not vary with body size among bumblebee (Bombus impatiens) sisters. AB - Body size is a key organism trait with critical implications for the physiology, life history, and ecology of organisms. Modern insects vary in body mass by over 6 orders of magnitude, but are small by comparison to many other metazoan taxa. The small size of modern insects may reflect limitations imposed by their open respiratory systems which rely, in part, on diffusion. Diffusion rates decline with distance such that, absent compensation, the capacity for larger insects to deliver oxygen to their tissues may be compromised. To compensate, larger grasshoppers, beetles, and bumblebees devote proportionally more of their body volume to the respiratory system, as demonstrated by hypermetric scaling of tracheal volume with body mass(>1). Among bumblebee sisters, total respiratory volume scaled with mass(2.6), but it is unclear at what level or levels of the tracheal system (main tracheal trunks, air sacs, tracheoles) bumblebees express this extreme hypermetry. Here we use transmission electron microscopy to examine the morphology of tracheoles in bumblebee flight muscle among sister bumblebees varying nearly four-fold in body mass. Neither tracheole density nor tracheole diameter changed with body mass. The total cross-sectional area of tracheoles was also invariant with body mass. Together, these results reveal that bumblebees do not compensate for size-related limitations on oxygen delivery by increasing investment at the level of the tracheoles. PMID- 24815210 TI - Regulation of broad by the Notch pathway affects timing of follicle cell development. AB - During Drosophila oogenesis, activation of Notch signaling in the follicular epithelium (FE) around stage 6 of oogenesis is essential for entry into the endocycle and a series of other changes such as cell differentiation and migration of subsets of the follicle cells. Notch induces the expression of zinc finger protein Hindsight and suppresses homeodomain protein Cut to regulate the mitotic/endocycle (ME) switch. Here we report that broad (br), encoding a small group of zinc-finger transcription factors resulting from alternative splicing, is a transcriptional target of Notch nuclear effector Suppressor of Hairless (Su(H)). The early pattern of Br in the FE, uniformly expressed except in the polar cells, is established by Notch signaling around stage 6, through the binding of Su(H) to the br early enhancer (brE) region. Mutation of the Su(H) binding site leads to a significant reduction of brE reporter expression in follicle cells undergoing the endocycle. Chromatin immunoprecipitation results further confirm Su(H) binding to the br early enhancer. Consistent with its expression in follicle cells during midoogenesis, loss of br function results in a delayed entry into the endocycle. Our findings suggest an important role of br in the timing of follicle cell development, and its transcriptional regulation by the Notch pathway. PMID- 24815212 TI - Sex differences in diazepam effects and parvalbumin-positive GABA neurons in trait anxiety Long Evans rats. AB - In clinical populations, prevalence rates for a number of anxiety disorders differ between males and females and gonadal hormones are thought to contribute to these differences. While these hormones have been shown to modulate the anxiolytic effects of the benzodiazepine agonist diazepam in some models, findings are inconsistent. Here, we tested for sex differences in response to anxiogenic stimuli following a 30-min diazepam (1.0mg/kg) pre-treatment in male and female rats showing high (HAn) and low (LAn) anxiety-like behavior on the elevated plus maze. Acute diazepam administration resulted in decreased anxiety like behavior only in HAn males as demonstrated by a significant increase in percent open arm time in the elevated plus maze (EPM). Immunohistochemical analysis for parvalbumin (PV; a calcium-binding protein that selectively stains GABAergic neurons) in central amygdala (CeA), caudate putamen (CPu) and the hippocampus indicated the number of GABAergic interneurons in these areas differed across sex and anxiety trait. In the CPu, females had significantly more PV-immunoreactive (IR) cells than males, and LAn females had greater PV-IR neurons than HAn females. In the CeA, males displayed an increased number of PV IR neurons compared to females, with no differences found between LAn and HAn. Further, trait differences were evident in the CA2 region of the hippocampus, regardless of sex. Taken together, these data suggest that gonadal hormones and trait anxiety may influence the sensitivity to the anti-anxiety effects of diazepam and these differences may be due in part to the distribution of GABA containing interneurons. PMID- 24815213 TI - Activation of the serotonergic system by pedaling exercise changes anterior cingulate cortex activity and improves negative emotion. AB - Pedaling exercise (PE) of moderate intensity has been shown to ease anxiety and discomfort; however, little is known of the changes that occur in brain activities and in the serotonergic (5-HT) system after PE. Therefore, this study was conducted for the following reasons: (1) to localize the changes in the brain activities induced by PE using a distributed source localization algorithm, (2) to examine the changes in frontal asymmetry, as used in the Davidson model, with electroencephalography (EEG) activity, and (3) to examine the effect of PE on the 5-HT system. A 32-channel EEG was used to record before and after PE. Profile of Mood States tests indicated that there was a significant decrease in tension anxiety and a significant increase in vigor after PE. A standardized low resolution brain electromagnetic tomography analysis showed a significant decrease in brain activities after PE in the alpha-2 band (10-12.5 Hz) in the anterior cingulate cortex (ACC). Moreover, a significant increase in frontal EEG asymmetry was observed after PE in the alpha-1 band (7.5-10 Hz). Urine 5-HT levels significantly increased after PE. Urine 5-HT levels positively correlated with the degree of frontal EEG asymmetry in the alpha-1 band and negatively correlated with brain activity in ACC. Our results suggested that PE activates the 5-HT system and consequently induces increases in frontal EEG asymmetry in the alpha-1 band and reductions of brain activity in the alpha-2 band in the ACC region. PMID- 24815214 TI - Ageing and spatial reversal learning in humans: findings from a virtual water maze. AB - Deterioration in spatial memory with normal ageing is well accepted. Animal research has shown spatial reversal learning to be most vulnerable to pathological changes in the brain, but this has never been tested in humans. We studied ninety participants (52% females, 20-80 yrs) in a virtual water maze with a reversal learning procedure. Neuropsychological functioning, mood and personality were assessed to control moderator effects. For data analysis, participants were subdivided post hoc into groups aged 20-24, 25-34, 35-44, 45-64 and 65-80 yrs. Initial spatial learning occurred in all age groups but 65-80-yrs olds never reached the level of younger participants. When tested for delayed recall of spatial memory, younger people frequented the target area but those over 65 yrs did not. In spatial reversal learning, age groups over 45 yrs were deficient and the 65-80-yrs-olds showed no evidence of reversal. Spatial measures were associated with neuropsychological functioning. Extraversion and measures of depression moderated the age effect on the learning index with older introverted and non-depressed individuals showing better results. Measures of anxiety moderated the age effect on reversal learning with older people having higher anxiety scores showing a preserved reversal learning capability. Results confirmed age to be a major factor in spatial tasks but further showed neuropsychological functioning, psycho-affective determinants and personality traits to be significant predictors of individual differences. PMID- 24815215 TI - Intergroup Anxiety: Theory, Research, and Practice. AB - This article reviews studies of intergroup anxiety and places them in the context of a theoretical model that specifies categories of antecedents and consequences of intergroup anxiety. It is proposed that intergroup anxiety is comprised of three interrelated components: an affective component, a cognitive component, and a physiological component. The potential causes of intergroup anxiety include personality traits (e.g., social dominance orientation, attributional complexity), attitudes and related cognitions (e.g., negative expectations, stereotypes), personal experience (e.g., negative contact), and situational factors (e.g., the presence of linguistic barriers, structured vs. unstructured interactions). The potential consequences include attitudes and other cognitions (e.g., stereotypes, negative expectations), affect (e.g., fear, anger), and behavior (e.g., avoidance, negative behaviors). Theory and research on the reduction of intergroup anxiety (e.g., intergroup contact, direct or indirect cross-group friendships) are also presented. The discussion explores the implications of these studies for theory, research, and practice. PMID- 24815218 TI - Hyperbranched hydrocarbon surfactants give fluorocarbon-like low surface energies. AB - Two series of Aerosol-OT-analogue surfactants (sulfosuccinate-type di-BCnSS and sulfoglutarate-type di-BCnSG) with hyperbranched alkyl double tails (so-called "hedgehog" groups, carbon number n = 6, 9, 12, and 18) have been synthesized and shown to demonstrate interfacial properties comparable to those seen for related fluorocarbon (FC) systems. Critical micelle concentration (CMC), surface tension at the CMC (gammaCMC), and minimum area per molecule (Amin) were obtained from surface tension measurements of aqueous surfactant solutions. The results were examined for relationships between the structure of the hedgehog group and packing density at the interface. To evaluate A and B values in the Klevens equation for these hedgehog surfactants, log(CMC) was plotted as a function of the total carbon number in the surfactant double tail. A linear relationship was observed, producing B values of 0.20-0.25 for di-BCnSS and di-BCnSG, compared to a value of 0.31 for standard double-straight-tail sulfosuccinate surfactants. The lower B values of these hedgehog surfactants highlight their lower hydrophobicity compared to double-straight-tail surfactants. To clarify how hydrocarbon density in the surfactant-tail layer (rho(layer)) affects gammaCMC, the rho(layer) of each double-tail surfactant was calculated and the relationship between gammaCMC and rho(layer) examined. As expected for the design of low surface energy surfactant layers, rho(layer) was identified as an important property for controlling gammaCMC with higher rho(layer), leading to a lower gammaCMC. Interestingly, surfactants with BC9 and BC12 tails achieved much lower gammaCMC, even at low rho(layer) values of <0.55 g cm(-3). The lowest surface energy surfactant studied here was di-BC6SS, which had a gammaCMC of only 23.8 mN m(-1). Such a low gammaCMC is comparable to those obtained with short FC-tail surfactants (e.g., 22.0 mN m(-1) for the sulfosuccinate-type FC-surfactant with R = F(CF2)6CH2CH2-). PMID- 24815216 TI - The daily burden of acute kidney injury: a survey of U.S. nephrologists on World Kidney Day. AB - BACKGROUND: World Kidney Day 2013 focused on raising awareness of the impact and consequences of acute kidney injury (AKI). Although many studies have examined rates of AKI in hospitalized patients, we were interested in the impact of AKI on the workload of nephrologists. STUDY DESIGN: Cross-sectional forced-choice internet-based survey. SETTING & PARTICIPANTS: 598 survey respondents who were US based nephrologist members of the American Society of Nephrology. OUTCOMES: Numbers of inpatients and outpatients seen on World Kidney Day 2013 for the management of AKI or other conditions (and specifically in-hospital renal replacement therapies [RRTs]), based on self-report of number/percentage of patients seen on World Kidney Day and in the prior year. RESULTS: Of 598 physician respondents (response rate, 12%), 310 saw patients in the hospital on World Kidney Day. Of 3,285 patients seen by respondents, 1,500 were seen for AKI (46%); 1,233, for end-stage renal disease (37%); and 552, for non-AKI/end-stage renal disease-related problems (17%). Of patients with AKI, 688 (46%) were in the intensive care unit and 415 (28%) received RRT. Intermittent hemodialysis was performed in 315 patients (76%) who received RRT. Delivered dialysis dose was quantified in only 48 (15%) of those receiving intermittent hemodialysis. 260 respondents saw 2,380 patients in the ambulatory setting, of whom 207 (9%) were seen for follow-up of AKI. LIMITATIONS: There was a low response rate to the survey. Numbers of patients were self-reported. CONCLUSIONS: This is the first physician survey examining the care of patients and impact of AKI on current in hospital and ambulatory nephrology practices. In our sample, AKI was the most common reason for in-hospital nephrology consultation. Furthermore, our findings point to significant areas in which improvement is needed, including inadequate quantification of dialysis delivered dose. Finally, our survey highlights that AKI is a major public health issue. PMID- 24815217 TI - Cortical cartography reveals political and physical maps. AB - Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised. PMID- 24815219 TI - Er-Miao-San, a traditional herbal formula containing Rhizoma Atractylodis and Cortex Phellodendri inhibits inflammatory mediators in LPS-stimulated RAW264.7 macrophages through inhibition of NF-kappaB pathway and MAPKs activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Er-Miao-San (EMS) is a traditional Chinese herbal formulation that contains combinations of Rhizoma Atractylodis (RA) and Cortex Phellodendri (CP). It exhibits analgesic and anti-inflammatory activities and have been used for the treatment of various "Bi Zheng" for thousand years in China. The aims of the present study were to investigate the anti-inflammatory activities of EMS and elucidate the underlying mechanisms with regard to its molecular basis of action for the best combination. MATERIALS AND METHODS: The anti-inflammatory effects of EMS were studied by using lipopolysaccharide (LPS) stimulated activation of nitric oxide (NO) and pro-inflammatory cytokine production in mouse RAW264.7 macrophages. Expression of inducible NO synthase (iNOS), mitogen-activated protein kinases (MAPKs) phosphorylation, p65 phosphorylation, inhibitor-kappaBalpha (IkappaBalpha) degradation, and NF-kappaB DNA-binding activity were further investigated. RESULTS: The present study demonstrated that EMS could suppress the production of NO in LPS-stimulated RAW264.7 macrophages. However, CP and RA did not have significant inhibitory effect on them. EMS also inhibited the production of tumor necrosis factor-alpha, interleukin-1 beta and macrophage chemotactic protein-1. Further investigations showed EMS could suppress iNOs expression and p38 phosphorylation. EMS significantly decreased the content of IkappaBalpha, reduced the level of phosphorylated p65 and suppressed the NF-kappaB DNA-binding activity. All these results suggested the inhibitory effects of EMS on the production of inflammatory mediators through the inhibition of the NF-kappaB pathway. CONCLUSIONS: Our results indicated that EMS inhibited inflammatory events and iNOS expression in LPS-stimulated RAW264.7 cells through the inactivation of the MAPK and NF-kappaB pathway. This study gives scientific evidence validating the use of EMS in treatment of patients with "Bi Zheng" in clinical practice in traditional Chinese medicine. PMID- 24815220 TI - Integrated pharmacokinetics of five protoberberine-type alkaloids in normal and insomnic rats after single and multiple oral administration of Jiao-Tai-Wan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-Tai-Wan (JTW), an important herbal formula consists of Rhizoma coptidis and Cortex cinnamomi powder, is a famous prescription which has been used for centuries to treat insomnia in Traditional Chinese Medicine. The purpose of this study is to compare the pharmacokinetic properties of five protoberberine-type alkaloids (i.e. berberine, palmatine, coptisine, epiberberine and jatrorrhizine), the main bioactive constituents in JTW, between normal and insomnic rats. We also investigate the differences between single-dose and multiple-dose pharmacokinetics of five protoberberine type alkaloids. MATERIALS AND METHODS: The insomnic rat models were induced by intraperitoneal injection of one-dose para-chlorophenylalanine acid (PCPA). Quantification of five protoberberine-type alkaloids in rat plasma was achieved by using a rapid LC-MS/MS method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time and estimate pharmacokinetic parameters. An unpaired Student's t test was used for comparisons with SPSS 17.0. RESULTS: The five protoberberine-type alkaloids of single-dose normal groups had slow absorption and low bioavailability, as well as a delay of peak time. In the single-dose oral administration, the Cmax and Tmax of five ingredients in insomnic rats had significant differences compared with those of normal rats. In the multiple-dose oral administration, the pharmacokinetic parameters of five protoberberine-type alkaloids varied greatly in insomnic rats. In the normal rats, there were significant differences (P<0.05) in the principal pharmacokinetic parameters such as Cmax and Tmax between single-dose and multiple-dose oral administration. In the insomnic rats, the five ingredients of multiple-dose groups showed better absorption than the single-dose groups. Particularly, three peaks were observed in multiple-dose model group of plasma-concentration curves. CONCLUSIONS: The pharmacokinetic behavior of five protoberberine-type alkaloids was described in this paper. In both normal groups and model groups, the pharmacokinetic behavior of multiple-dose had significant differences comparing with the single-dose; either single-dose or multiple-dose, the pharmacokinetic behavior of insomnic rats had significant differences comparing the normal rats. Multiple dosing may improve the absorption of JTW in insomnic rats, which will increase the bioavailability and bring into active role in therapeutical effect. PMID- 24815221 TI - Estrous cycle fluctuations in sex and ingestive behavior are accentuated by exercise or cold ambient temperatures. AB - This article is part of a Special Issue "Energy Balance". In female Syrian hamsters (Mesocricetus auratus), low circulating levels of ovarian steroids are associated with increased food hoarding and decreased sexual motivation, but these effects are exaggerated in food-restricted females. To determine whether cold ambient temperature has the same effects as food restriction, groups of hamsters were fed ad libitum while they were housed at either 5 degrees C or 22 degrees C, and then tested for behavior for 90 min on each day of the estrous cycle. In females housed at 22 degrees C, high levels of sexual motivation and low levels of food hoarding were seen every day of the estrous cycle. In females housed at 5 degrees C, high levels of sexual motivation were restricted to the periovulatory day. On the three nonestrous days, these females showed high levels of food hoarding, but not food intake. A separate cohort of females were provided with access to running wheels and housed at 22 degrees C. They showed high levels of sexual motivation restricted to the periovulatory day, similar to the pattern of sexual motivation seen in cold-housed females. Unlike cold-housed females, those with running wheels showed low levels of food hoarding and high levels of food intake. Food restriction, cold housing, and access to wheels had no significant effect on plasma estradiol or progesterone concentrations, but significantly decreased plasma leptin concentrations. All three energetic challenges unmask estrous cycle fluctuations in sexual motivation that are obscured in laboratory conditions, i.e., isolation in a small cage with an overabundance of food. PMID- 24815222 TI - Structural and solvent control of nonadiabatic photochemical bond formation: photocyclization of o-terphenyl in solution. AB - Elucidating the molecular dynamics that underlie photoinduced electrocyclization is a critical step toward controlling nonadiabatic photochemistry that enables bond formation. Here we present a comprehensive examination of the photochemical dynamics of o-terphenyl (OTP) in solution. Ultrafast transient absorption measurements demonstrate that OTP cyclizes upon 266 nm photoexcitation to form 4a,4b-dihydrotriphenylene (DHT) on a solvent-dependent time scale of 1.5-4 ps, considerably slower than the nonadiabatic cyclization of related diarylethenes. Correlations in these time scales versus bulk solvent properties reveal that mechanical rather than electrostatic solvent-solute interactions impact the excited-state relaxation rate, impeding nuclear dynamics leading toward the conical intersection for cyclization. In contrast, solvent-dependent mechanical interactions are observed to facilitate vibrational relaxation of DHT on time scales of 10-25 ps. DHT decays via thermally activated ring-opening with a lifetime of ~46 ns in tetrahydrofuran, 12 orders of magnitude faster than dihydrophenanthrenes. We conclude that the differences in excited-state dynamics of OTP and diarylethenes and the relative stability of their cyclized products are determined by the relative strain induced by twisting the central carbon carbon bond that bridges the terminal phenyl rings in each to enable bond formation. We relate these structure-dynamics relationships to the feasibility of photoinduced cyclodehydrogenation of o-arenes and design considerations for molecular photoswitches. PMID- 24815223 TI - Melanoma's high C>T mutation rate: is deamination playing a role? AB - The majority of melanoma mutations are C>T transitions, and most bear UV signatures. However, other process may contribute to the high C>T mutation rate. Okura et al., have demonstrated immunohistochemical evidence of deaminating enzymes, activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B (APOBEC3B) in melanoma. Both have been implicated in cancer. While further validation is necessary, these findings warrant consideration of a role for deamination in melanomagenesis. Deamination primarily drives C>T transitions. Compared with trunk/extremity melanomas, acral melanomas display a significantly higher percentage of 'spontaneous' and 'AID' mutation signature events suggesting deamination may be particularly important in this subgroup. PMID- 24815224 TI - Application of human induced pluripotent stem cells for modeling and treating neurodegenerative diseases. AB - The advent of human induced pluripotent stem cells (hiPSCs), reprogrammed in vitro from both healthy and disease-state human somatic cells, has triggered an enormous global research effort to realize personalized regenerative medicine for numerous degenerative conditions. hiPSCs have been generated from cells of many tissue types and can be differentiated in vitro to most somatic lineages, not only for the establishment of disease models that can be utilized as novel drug screening platforms and to study the molecular and cellular processes leading to degeneration, but also for the in vivo cell-based repair or modulation of a patient's disease profile. hiPSCs derived from patients with the neurodegenerative diseases amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and multiple sclerosis have been successfully differentiated in vitro into disease-relevant cell types, including motor neurons, dopaminergic neurons and oligodendrocytes. However, the generation of functional iPSC-derived neural cells that are capable of engraftment in humans and the identification of robust disease phenotypes for modeling neurodegeneration still require several key challenges to be addressed. Here, we discuss these challenges and summarize recent progress toward the application of iPSC technology for these four common neurodegenerative diseases. PMID- 24815225 TI - Electron holographic visualization of collective motion of electrons through electric field variation. AB - This study demonstrates the accumulation of electron-induced secondary electrons by utilizing a simple geometrical configuration of two branches of a charged insulating biomaterial. The collective motion of these secondary electrons between the branches has been visualized by analyzing the reconstructed amplitude images obtained using in situ electron holography. In order to understand the collective motion of secondary electrons, the trajectories of these electrons around the branches have also been simulated by taking into account the electric field around the charged branches on the basis of Maxwell's equations. PMID- 24815226 TI - Preoperative somatostatin analogs treatment in acromegalic patients with macroadenomas. A meta-analysis. AB - BACKGROUND: Several studies have investigated the biochemical remission rate of presurgical somatostatin analogs treatment on acromegaly, but the remission criteria were diversed and the results were contradicting. OBJECTIVE: Aim of this paper is to provide enhanced evidence for the effectiveness of preoperative SSA treatment to improve on surgical results of macroadenomas in acromegaly. DATA SOURCE: Literature is cited from the PubMed, Embase and Cochrane Library, dating from December, 1985 to August, 2013. STUDY ELIGIBILITY CRITERIA: Eligibility criteria included patients with acromegaly caused by GH-secreting pituitary macroadenomas, patients pretreated with somatostatin analogs versus direct surgery and a stricter remission criteria defined as the GH nadir<1MUg/l during an oral glucose tolerance test (OGTT) and the age- and sex- adjusted IGF-1 concentration was normal. Primary end points included Short term and long term postoperative biochemical remission. STUDY APPRAISAL AND SYNTHESIS METHODS: A total of 1421 publications were found by the electronic search. After full-text review, 8 were included in our study. 7 of them focus on the postoperative remission in short term; 3 of them focus on the outcomes in long term. For the analysis of the postoperative biochemical remission, a random effect model was used to account for differences. RESULTS: The meta analysis shows that patients in the SSA pretreatment groups have had a more significantly cure rate than those in the direct surgery groups (RR=1.72, 95%CI: 1.14-2.60, P=0.009) with a short term follow-up. Subgroup analysis proves benefit from lanreotide pretreated groups (RR=2.27, 95%CI: 1.34-3.84, P=0.002) but not octreotide pretreated groups (RR=1.51, 95%CI: 0.82-2.75, P=0.183). No significant differences appeared between the two groups (RR=1.03, 95%CI: 0.86-1.24, P=0.751) with a long term follow-up. LIMITATIONS: 2 Retrospective trial was included and most of the trials included was designed as single-center study. CONCLUSIONS: Based on the analysis of this paper, the preoperative SSA treatment was beneficial in the group with short-term follow-up, while it was not advantageous in the group with long-term follow-up. For the limitations in this study, to drawn more solid conclusions, further large, randomized, multi-center, and long-term follow-up trials were required. PMID- 24815227 TI - Ontogeny of endothelin receptors in the brain, heart, and kidneys of neonatal rats. AB - BACKGROUND: Endothelin (ET) plays an important role in many physiological functions. It has been demonstrated that endogenous ET-1 concentration in the central nervous system (CNS) changes with age; however the ontogeny of ETA and ETB receptors in the brain, heart, and kidneys during postnatal development has not been studied. METHODS: Brains, hearts and kidneys of rats at postnatal days 1, 7, 14 and 28 were evaluated for the expression of ETA and ETB receptors via Western blot. ETB receptors within the developing brain were further accessed via immunofluorescence. RESULTS: The mean organ and body weights increased proportionally with advancing age demonstrating normal growth. The expression of ETA receptors in the brain, heart, and kidneys and ETB receptor expression in the heart and kidneys was similar in these rats at postnatal ages 1, 7, 14 and 28days. However, brain ETB receptor expression significantly (P<0.001) decreased by 72% on day 28 compared to the levels on postnatal day 1. Upon immunofluorescent analysis, the intensity of ETB staining in the cerebral cortex and subventricular zones of the developing rat brain decreased significantly from day 1 to day 7 (P<0.001) and from day 7 to day 14 (P<0.0001). There was no further decrease in ETB intensity noted in the cerebral cortex and subventricular zones between day 14 and day 28 of postnatal age. The intensity of ETB receptor staining within the cerebrovasculature, on the other hand, increased significantly (P<0.05) from days 1 and 7 to day 14. CONCLUSIONS: These results demonstrate that expression of ETA receptors does not change with postnatal development. On the other hand ETB receptors in the cerebral cortex and subventricular zones of the brain decrease with age, while ETB receptors in the cerebrovasculature increase with age, implicating ETB receptor involvement in the structural maturity and development of the CNS. PMID- 24815228 TI - Edible films from methylcellulose and nanoemulsions of clove bud (Syzygium aromaticum) and oregano (Origanum vulgare) essential oils as shelf life extenders for sliced bread. AB - Consumers are increasingly demanding foods with lower synthetic preservatives. Plant essential oils are natural compounds with remarkable antimicrobial properties and may be incorporated as emulsions into water-soluble polymers to form antimicrobial films. Coarse emulsions (diameters of 1.3-1.9 MUm) and nanoemulsions (diameters of 180-250 nm) of clove bud (Syzygium aromaticum) and oregano (Origanum vulgare) essential oils were produced through low-speed mixing and ultrasonication, respectively. Methylcellulose was added for film-forming purposes. Both essential oils reduced the rigidity and increased the extensibility of the methylcellulose films, effects that were even more pronounced for nanodroplets. Both essential oils lessened the counts of yeasts and molds in sliced bread during 15 days, and droplet size reduction provided a further improvement in antimicrobial properties. Due to increased bioavailability, less preservative content might be used and still deliver the same antimicrobial efficiency if encapsulated in smaller particles. PMID- 24815230 TI - Properties of Corprene, revisited. AB - Corprene has long been used in underwater projectors and receivers as an acoustic isolation material. Based on data initially reported by Higgs and Eriksson for type DC-100 Corprene [J. Acoust. Soc. Am. 46, 1254-1258 (1969)], a simple set of empirical relations is formulated that allow its density, sound speed, and acoustic attenuation to be estimated over a wide range of pressures. Laboratory measurements of the compressibility of recently manufactured material are also reported. One of the primary motivations behind this present study is to accurately determine the compressibility of Corprene. This information is needed to ascertain the variable ballast in a submersible as it goes to depth. This newly reported data, which additionally include measurement of hysteresis, agree with the results published by the aforementioned authors, indicating that this common material has remained unchanged over the past four decades. PMID- 24815229 TI - Sleep duration and history of stroke among adults from the USA. AB - Although short sleep duration is related to chronic conditions, such as hypertension, diabetes and obesity, the association with stroke is less well known. Using 2006-2011 National Health Interview Surveys, we assessed the association between self-reported duration of sleep and prevalence of stroke stratifying by age and sex. Of the 154 599 participants aged 18 years or older, 29.2%, 61.8% and 9.0% reported they sleep <=6, 7-8 and >=9 h per day, respectively. Corresponding age-standardized prevalence of stroke were 2.78%, 1.99% and 5.21% (P < 0.001). Logistic regression models showed a higher prevalence of stroke among those who slept <=6 or >=9 h a day compared with those who slept 7-8 h, after adjusting for sociodemographic, behavioural and health characteristics. Further stratifying by age and sex showed that the association of duration of sleep and stroke differed among different age or sex groups. Among young adults (18-44 years), a higher prevalence of stroke was found among women with short sleep. Higher prevalence of stroke was found among middle-aged men and women reporting short or long sleep duration. Among older adults (>=65 years), higher prevalence of stroke was found only among those who slept >=9 h. In this national sample of adults, the association between duration of sleep and stroke varied by sex and age. Although there was an association of short sleep duration with stroke, we also observed the association of long sleep duration with stroke, especially among those aged 65 years or older. PMID- 24815231 TI - The Jonker-Volgenant algorithm applied to click-train separation. AB - The problem of click-train separation is cast as a linear assignment problem to obtain a faster solution guaranteed to achieve the global minimum error. It is shown how the problem can be cast in a compact matrix form that is solvable by an off-the-shelf algorithm, the Jonker-Volgenant algorithm. PMID- 24815232 TI - Enhanced backscattering in water by partially exposed cylinders at free surfaces associated with an acoustic Franz wave. AB - When a smooth curved object is lowered into water, the initial specular contribution to high frequency backscattering of sound is weak before the specular point on the object becomes illuminated by incident sound. The associated transition in reflection from a metallic cylinder viewed at grazing incidence was previously studied [Baik and Marston, IEEE J. Ocean. Eng. 33, 386 396 (2008)]. The present research involves analogous measurements of backscattering performed using short tone bursts facilitating improved temporal resolution of distinct mechanisms contributing to the backscattering. The measurements reveal the presence of a delayed contribution to the backscattering that evolves in time in a way consistent with a scattering contribution of an acoustic Franz wave. The wave appears to be partially reflected at the free surface after having been excited on the cylinder by the incident acoustic wave. For slightly exposed cylinders viewed at grazing incidence, the Franz wave mechanism dominated the observed backscattering. PMID- 24815233 TI - Comment on "Wave model of the cat tympanic membrane" [J. Acoust. Soc. Am. 122(2), 918-931 (2007)]. AB - The tympanic membrane model as developed by Parent and Allen [(2007). J. Acoust. Soc. Am. 122(2), 918-931] is shown to have active, lossy, and non-reciprocal properties despite being described as lossless. These properties are traced back to its scattering junction formulations. Some impedance parameters are shown to have ambiguous values which complicate interpreting the physics of the model's internal wave propagation. Certain model parameters omitted from the original paper have been derived from the original computer simulation source code used by Parent and Allen. PMID- 24815234 TI - Three-dimensional coupled mode analysis of internal-wave acoustic ducts. AB - A fully three-dimensional coupled mode approach is used in this paper to describe the physics of low frequency acoustic signals propagating through a train of internal waves at an arbitrary azimuth. A three layer model of the shallow water waveguide is employed for studying the properties of normal modes and their coupled interaction due to the presence of nonlinear internal waves. Using a robust wave number integration technique for Fourier transform computation and a direct global matrix approach, an accurate three-dimensional coupled mode full field solution is obtained for the tonal signal propagation through straight and parallel internal waves. This approach provides accurate results for arbitrary azimuth and includes the effects of backscattering. This enables one to provide an azimuthal analysis of acoustic propagation and separate the effects of mode coupled transparent resonance, horizontal reflection and refraction, the horizontal Lloyd's mirror, horizontal ducting and anti-ducting, and horizontal tunneling and secondary ducting. PMID- 24815235 TI - Multiple scattering in porous media: comparison with water saturated double porosity media. AB - Multiple scattering in a poroelastic medium obeying Biot's theory is studied; the scatterers are parallel identical cylindrical holes pierced at random in the medium. The paper focuses first on the influence, on the effective wavenumbers, of the mode conversions that occur at each scattering event. The effect of the holes on the dispersion curves is then examined for two different values of the ratio of their radius to the pores mean radius. Depending on the latter, the dispersion curves of the pierced material are compared, for the fast and shear waves, with those of either a more porous medium or a double porosity medium. PMID- 24815236 TI - Modal radiation patterns of baffled circular plates and membranes. AB - The far field velocity potential and radiation pattern of baffled circular plates and membranes are found analytically using the full set of modal velocity profiles derived from the corresponding equation of motion. The derivation is valid for a plate or membrane subjected to an external excitation force, which is used as a sound receiver in any medium or as a sound transmitter in a gaseous medium. A general, concise expression is given for the radiation pattern of any mode of the membrane and the plate with arbitrary boundary conditions. Specific solutions are given for the four special cases of a plate with clamped, simply supported, and free edge boundary conditions as well as for the membrane. For all non-axisymmetric modes, the velocity potential along the axis of the radiator is found to be strictly zero. In the long wavelength limit, the radiation pattern of all axisymmetric modes approaches that of a monopole, while the non-axisymmetric modes exhibit multipole behavior. Numerical results are also given, demonstrating the implications of having non-axisymmetric excitation using both a point excitation with varying eccentricity and a homogeneous excitation acting on half of the circular radiator. PMID- 24815237 TI - Estimation of the low-frequency components of the head-related transfer functions of animals from photographs. AB - Reliable animal head-related transfer function (HRTF) estimation procedures are needed for several practical applications, for example, to investigate the neuronal mechanisms of sound localization using virtual acoustic spaces or to have a quantitative description of the different localization cues available to a given animal species. Here, two established techniques are combined to estimate an animal's HRTF from photographs by taking into account as much morphological detail as possible. The first step of the method consists in building a three dimensional-model of the animal from pictures taken with a standard camera. The HRTFs are then estimated by means of a rapid boundary-element-method implementation. This combined method is validated on a taxidermist model of a cat by comparing binaural and monaural localization cues extracted from estimated and measured HRTFs. It is shown that it provides a reliable way to estimate low frequency HRTF, which is difficult to obtain with standard acoustical measurements procedures because of reflections. PMID- 24815238 TI - Harmonic generation with a dual frequency pulse. AB - Nonlinear imaging was implemented in commercial ultrasound systems over the last 15 years offering major advantages in many clinical applications. In this work, pulsing schemes coupled with a dual frequency pulse are presented. The pulsing schemes considered were pulse inversion, power modulation, and power modulated pulse inversion. The pulse contains a fundamental frequency f and a specified amount of its second harmonic 2f. The advantages and limitations of this method were evaluated with both acoustic measurements of harmonic generation and theoretical simulations based on the KZK equation. The use of two frequencies in a pulse results in the generation of the sum and difference frequency components in addition to the other harmonic components. While with single frequency pulses, only power modulation and power modulated pulse inversion contained odd harmonic components, with the dual frequency pulse, pulse inversion now also contains odd harmonic components. PMID- 24815239 TI - Measurement and simulation of acoustic radiation force on a planar reflector. AB - The accurate calculation of the acoustic radiation force is important for ultrasonic application techniques. Usually, the acoustic radiation force can be divided into the near-field and the far-field force according to the ratio of the emitter-reflector distance to the wavelength. In this study, appropriate theories and methods are explored to simulate the far-field and the near-field acoustic radiation force exerted on a planar reflector. The comparison between simulation and experiment indicates that the far-field force is not sensitive to the boundary shape and size while the near-field force is highly sensitive to the boundary size. Only the acoustic model with the minimized boundary size could yield the near-field force consistent with the experiment. Further calculations reveal that the far-field force first increases and then decreases with the rise of the reflector radius, and that the near-field force fluctuates with the acoustic frequency, especially when the emitter-reflector distance is very small. The near-field repulsive force can be changed into the attractive force when the acoustic frequency is lowered. PMID- 24815240 TI - One-way approximation for the simulation of weak shock wave propagation in atmospheric flows. AB - A numerical scheme is developed to simulate the propagation of weak acoustic shock waves in the atmosphere with no absorption. It generalizes the method previously developed for a heterogeneous medium [Dagrau, Renier, Marchiano, and Coulouvrat, J. Acoust. Soc. Am. 130, 20-32 (2011)] to the case of a moving medium. It is based on an approximate scalar wave equation for potential, rewritten in a moving time frame, and separated into three parts: (i) the linear wave equation in a homogeneous and quiescent medium, (ii) the effects of atmospheric winds and of density and speed of sound heterogeneities, and (iii) nonlinearities. Each effect is then solved separately by an adapted method: angular spectrum for the wave equation, finite differences for the flow and heterogeneity corrections, and analytical method in time domain for nonlinearities. To keep a one-way formulation, only forward propagating waves are kept in the angular spectrum part, while a wide-angle parabolic approximation is performed on the correction terms. The numerical process is validated in the case of guided modal propagation with a shear flow. It is then applied to the case of blast wave propagation within a boundary layer flow over a flat and rigid ground. PMID- 24815241 TI - Analysis of scattering from an acoustic cloak in a moving fluid. AB - This work develops a theoretical framework for acoustic cloak scattering analysis in a low speed non-stationary fluid that is simply described as a potential flow. The equivalent sound source induced by the moving fluid local to the cloak is analytically constructed and is then estimated using Born approximation. The far field scattering can thereafter be obtained using the associated Green's function of the convected wave equation. The results demonstrate that the proposed analytical approach, which might be helpful in the design and evaluation of cloaking systems, effectively elucidates key characteristics of the relevant physics. In addition, it can be seen that, in a moving fluid, the so-called convected cloaking design achieves better cloaking performance than the classical cloaking design. PMID- 24815242 TI - Long-term, global-scale statistics of sound propagation. AB - The near-surface sound levels emitted due to a point source show a large variability caused by sound propagation through changing meteorological conditions. To assess this variability, this study uses a numerical model of sound propagation which accounts for ground reflection, atmospheric refraction, and turbulence effects. The atmospheric inputs to the model-including turbulence are calculated from Numerical Weather Prediction data. The method is used to investigate the relative sound levels at a range of 1.5 km from a 40 Hz sound source. The outstanding diversity of sound propagation conditions is illustrated over the globe. Over the long term, the sound propagation climates at selected sites are found to be modulated by the dominant wind regimes, the seasonal and diurnal cycles. The explored sensitivities stress the need for a careful assessment of sound scattering by turbulence and absorption by the surface. PMID- 24815243 TI - Measurement and analysis of radiated sound from a low speed fan with a large tip gap. AB - The wake flow field and radiated sound from a low speed axial fan is studied experimentally. The fan geometry uses controlled diffusion blades and is designed with a low aspect ratio (0.9). The fan is installed with a large tip gap, approximately 10% of the blade span. The radiated sound field is analyzed using a known trailing edge noise formulation. First, the model is compared to an experiment of a single airfoil in a wind tunnel to assess the predictive capabilities. Second, measurements of the fan are made at two different blade loading conditions. Hot wire measurements are made in the near wake of the fan to assess the extent of the tip leakage flow for each condition. The radiated sound fields are compared with the trailing edge noise theory. Use is made of the wake measurements as an input to a surface pressure model. When the fan is operated with the optimal blade loading, the influence of the tip leakage flow is found to be of secondary acoustic impact. When the fan is operated at a high loading condition for the blades, a more significant leakage flow develops and is found to be responsible for the dominant radiated sound. PMID- 24815244 TI - Resonant ultrasound spectroscopy for viscoelastic characterization of anisotropic attenuative solid materials. AB - Resonant ultrasound spectroscopy (RUS) is an accurate measurement method in which the full stiffness tensor of a material is assessed from the free resonant frequencies of a small sample, and the viscoelastic damping is measured from the resonant peaks width. High viscoelastic damping causes the resonant peaks to overlap and therefore complicate the measurement of the resonant frequencies and the inverse identification of material properties. For that reason, RUS has been known to be fully applicable only to low damping materials. The purpose of this work is to adapt RUS for the characterization of highly attenuating viscoelastic materials. Spectrum measurement using shear transducers combined with dedicated signal processing is employed to retrieve the resonant frequencies despite overlapping. A probabilistic (Bayesian) formulation of the inverse problem, tackling the problem of correctly pairing the measured and predicted frequencies, is proposed. Applications to polymethylmethacrylate (isotropic) and glass/epoxy transversely isotropic samples are presented. The full set of viscoelastic properties is obtained with good repeatability. Particularly, elastic moduli of the isotropic samples are obtained within 1%. PMID- 24815245 TI - Measuring the wavenumber of guided modes in waveguides with linearly varying thickness. AB - Measuring guided waves in cortical bone arouses a growing interest to assess skeletal status. In most studies, a model of waveguide is proposed to assist in the interpretation of the dispersion curves. In all the reported investigations, the bone is mimicked as a waveguide with a constant thickness, which only approximates the irregular geometry of cortical bone. In this study, guided mode propagation in cortical bone-mimicking wedged plates is investigated with the aim to document the influence on measured dispersion curves of a waveguide of varying thickness and to propose a method to overcome the measurement limitations induced by such thickness variations. The singular value decomposition-based signal processing method, previously introduced for the detection of guided modes in plates of constant thickness, is adapted to the case of waveguides of slowly linearly variable thickness. The modification consists in the compensation at each frequency of the wavenumber variations induced by the local variation in thickness. The modified method, tested on bone-mimicking wedged plates, allows an enhanced and more accurate detection of the wavenumbers. Moreover, the propagation in the directions of increasing and decreasing thickness along the waveguide is investigated. PMID- 24815246 TI - Pseudo-interface Rayleigh wave on a permeable porous medium/vacuum interface. AB - It is well known that the Rayleigh wave propagating along a permeable plane boundary of a poroelastic half-space may have a high-frequency cutoff beyond which the corresponding Rayleigh pole is absent. The present study investigates the specific features of the surface wave propagation during transition through this cut-off frequency. Using a set of experimentally determined mechanical parameter values for water-saturated sintered glass beads in the framework of Biot's theory, this theoretical investigation indicates the following. The Rayleigh wave upper cut-off frequency may occur within a physical frequency range over which the characteristic wavelength far exceeds typical pore size. Beyond the cut-off frequency, the Rayleigh pole migrates onto the non-principal, in other words, unphysical, Riemann sheet. As a consequence, during this transition, the Rayleigh wave transforms into a pseudo-interface wave and radiates part of its energy into the interior of the half-space in the form of P2-wave motion. PMID- 24815247 TI - A model for sound propagation between two adsorbing microporous plates. AB - A model describing the sound propagation between two infinite adsorbing plates is proposed in order to investigate the extension to the audible sound range of the Frequency Response method applied to the measurement of diffusion in micropores. The model relates adsorption parameters (i.e., diffusivity and equilibrium constant) to an acoustic quantity (i.e., propagation constant). The equations describing sound propagation in the presence of adsorbing boundaries are obtained on the basis of the classical Kirchhoff theory [(1868). Ann. Phys. (Leipzig) 134, 177-193]. The solution is derived using the Low Reduced Frequency Approximation method [Tijdeman, (1975). J. Sound Vib. 39, 1-33]. PMID- 24815248 TI - The interaction of Rayleigh waves with delaminations in composite laminates. AB - In the present work, the interaction of Rayleigh waves with a delamination in a fiber reinforced composite plate was analyzed. Rayleigh waves, upon interacting with delamination mode, convert into Lamb waves in the delamination zone. These guided Lamb modes have the capability to mode convert back into Rayleigh modes when they interact with the edge of the delamination. A unidirectional glass/epoxy laminate with a delamination of known size was fabricated and tested using air-coupled ultrasonics. Finite element models were developed to understand the mode conversions occurring at various sections of the delamination. Particle displacements along with numerical and experimental velocities were considered to identify each mode. Conclusions were drawn based on the velocity analysis. PMID- 24815249 TI - The effect of reverberation on personal audio devices. AB - Personal audio refers to the creation of a listening zone within which a person, or a group of people, hears a given sound program, without being annoyed by other sound programs being reproduced in the same space. Generally, these different sound zones are created by arrays of loudspeakers. Although these devices have the capacity to achieve different sound zones in an anechoic environment, they are ultimately used in normal rooms, which are reverberant environments. At high frequencies, reflections from the room surfaces create a diffuse pressure component which is uniform throughout the room volume and thus decreases the directional characteristics of the device. This paper shows how the reverberant performance of an array can be modeled, knowing the anechoic performance of the radiator and the acoustic characteristics of the room. A formulation is presented whose results are compared to practical measurements in reverberant environments. Due to reflections from the room surfaces, pressure variations are introduced in the transfer responses of the array. This aspect is assessed by means of simulations where random noise is added to create uncertainties, and by performing measurements in a real environment. These results show how the robustness of an array is increased when it is designed for use in a reverberant environment. PMID- 24815250 TI - Towards a sub 15-dBA optical micromachined microphone. AB - Micromachined microphones with grating-based optical-interferometric readout have been demonstrated previously. These microphones are similar in construction to bottom-inlet capacitive microelectromechanical-system (MEMS) microphones, with the exception that optoelectronic emitters and detectors are placed inside the microphone's front or back cavity. A potential advantage of optical microphones in designing for low noise level is the use of highly-perforated microphone backplates to enable low-damping and low thermal-mechanical noise levels. This work presents an experimental study of a microphone diaphragm and backplate designed for optical readout and low thermal-mechanical noise. The backplate is 1 mm * 1 mm and is fabricated in a 2-MUm-thick epitaxial silicon layer of a silicon on-insulator wafer and contains a diffraction grating with 4-MUm pitch etched at the center. The presented system has a measured thermal-mechanical noise level equal to 22.6 dBA. Through measurement of the electrostatic frequency response and measured noise spectra, a device model for the microphone system is verified. The model is in-turn used to identify design paths towards MEMS microphones with sub 15-dBA noise floors. PMID- 24815251 TI - Dynamic and acoustic response of a clamped rectangular plate in thermal environments: experiment and numerical simulation. AB - Experiments were performed to investigate the vibration and acoustic response characteristics of a clamped rectangular aluminum plate in thermal environments. Modal tests were carried out to study the influence of thermal environment on natural vibration. With the increment of structural temperature, natural frequencies of the plate decrease obviously. Mode shape interchange was observed for the modes with frequencies very close to each other. The thermally induced softening effect has unequal influences on the plate along the two in-plane directions. Numerical methods were also employed to study the experimental phenomena. Calculated results indicated that the initial deflection has a great influence on the natural vibration of the heated plate. Even a slight curvature can reduce the thermally induced softening effect obviously. Dynamic response tests were carried out under acoustic and mechanical excitations, and the measured results indicate that the variation in damping determines the response amplitudes at resonant peaks in the test. PMID- 24815252 TI - Wave propagation in sandwich panels with a poroelastic core. AB - Wave propagation in sandwich panels with a poroelastic core, which is modeled by Biot's theory, is investigated using the waveguide finite element method. A waveguide poroelastic element is developed based on a displacement-pressure weak form. The dispersion curves of the sandwich panel are first identified as propagating or evanescent waves by varying the damping in the panel, and wave characteristics are analyzed by examining their motions. The energy distributions are calculated to identify the dominant motions. Simplified analytical models are also devised to show the main physics of the corresponding waves. This wave propagation analysis provides insight into the vibro-acoustic behavior of sandwich panels lined with elastic porous materials. PMID- 24815253 TI - Assessment of a hybrid finite element-transfer matrix model for flat structures with homogeneous acoustic treatments. AB - Modeling complex vibroacoustic systems including poroelastic materials using finite element based methods can be unfeasible for practical applications. For this reason, analytical approaches such as the transfer matrix method are often preferred to obtain a quick estimation of the vibroacoustic parameters. However, the strong assumptions inherent within the transfer matrix method lead to a lack of accuracy in the description of the geometry of the system. As a result, the transfer matrix method is inherently limited to the high frequency range. Nowadays, hybrid substructuring procedures have become quite popular. Indeed, different modeling techniques are typically sought to describe complex vibroacoustic systems over the widest possible frequency range. As a result, the flexibility and accuracy of the finite element method and the efficiency of the transfer matrix method could be coupled in a hybrid technique to obtain a reduction of the computational burden. In this work, a hybrid methodology is proposed. The performances of the method in predicting the vibroacoutic indicators of flat structures with attached homogeneous acoustic treatments are assessed. The results prove that, under certain conditions, the hybrid model allows for a reduction of the computational effort while preserving enough accuracy with respect to the full finite element solution. PMID- 24815254 TI - Modal decomposition of exterior acoustic-structure interaction problems with model order reduction. AB - A numerical technique for modal decomposition of the acoustic responses of structures submerged in a heavy fluid medium using fluid-loaded structural modes is presented. A Krylov subspace model order reduction approach to reduce the computational effort required for a fully coupled finite element/boundary element model is described. By applying the Krylov subspace to only the structural part of the global system of equations for the fully coupled problem, only the frequency independent finite element matrices are reduced. A fluid-loaded cylindrical shell closed at each end by hemispherical end caps is examined. The cylinder is excited by a ring of axial or transverse forces acting at one end. The individual contributions of the cylinder circumferential modes to the sound power and directivity of the radiated sound pressure are observed. The technique presented here provides a tool for greater physical insight into exterior acoustic-structure interaction problems using fully coupled numerical models, with significantly reduced computational effort. PMID- 24815255 TI - A 2.5-dimensional method for the prediction of structure-borne low-frequency noise from concrete rail transit bridges. AB - Predicting structure-borne noise from bridges subjected to moving trains using the three-dimensional (3D) boundary element method (BEM) is a time consuming process. This paper presents a two-and-a-half dimensional (2.5D) BEM-based procedure for simulating bridge-borne low-frequency noise with higher efficiency, yet no loss of accuracy. The two-dimensional (2D) BEM of a bridge with a constant cross section along the track direction is adopted to calculate the spatial modal acoustic transfer vectors (MATVs) of the bridge using the space-wave number transforms of its 3D modal shapes. The MATVs calculated using the 2.5D method are then validated by those computed using the 3D BEM. The bridge-borne noise is finally obtained through the MATVs and modal coordinate responses of the bridge, considering time-varying vehicle-track-bridge dynamic interaction. The presented procedure is applied to predict the sound pressure radiating from a U-shaped concrete bridge, and the computed results are compared with those obtained from field tests on Shanghai rail transit line 8. The numerical results match well with the measured results in both time and frequency domains at near-field points. Nevertheless, the computed results are smaller than the measured ones for far-field points, mainly due to the sound radiation from adjacent spans neglected in the current model. PMID- 24815256 TI - A three dimensional investigation into the acoustic performance of dissipative splitter silencers. AB - Splitter silencers are found in ventilation and gas turbine systems and consist of parallel baffles of porous material placed within a duct so that they split the mean gas flow. Theoretical investigations into dissipative splitter silencers have generally been limited to two dimensions and this limits the analysis to finding the silencer eigenmodes or, for a finite length silencer, to rectangular baffles only. In this article a numerical point collocation approach is used to extend theoretical predictions to three dimensions. This facilitates the analysis of more complex silencer designs such as "bar" silencers and theoretical predictions are validated by comparison with experimental measurements. The insertion loss of different silencer designs is evaluated and the performance of a bar silencer is compared to traditional designs for rectangular and circular ducts. It is shown that a bar silencer with a volume of material identical to an equivalent parallel baffle design delivers a significant improvement in insertion loss at higher frequencies, although this is at the expense of a small reduction in performance at low frequencies. It is also shown that under most circumstances it is possible to get good agreement between prediction and experiment even for relatively large Helmholtz numbers. PMID- 24815257 TI - Thin broadband noise absorption through acoustic reactance control by electro mechanical coupling without sensor. AB - Broadband noise with profound low-frequency profile is prevalent and difficult to be controlled mechanically. This study demonstrates effective broadband sound absorption by reducing the mechanical reactance of a loudspeaker using a shunt circuit through electro-mechanical coupling, which induces reactance with different signs from that of loudspeaker. An RLC shunt circuit is connected to the moving coil to provide an electrically induced mechanical impedance which counters the cavity stiffness at low frequencies and reduces the system inertia above the resonance frequency. A sound absorption coefficient well above 0.5 is demonstrated across frequencies between 150 and 1200 Hz. The performance of the proposed device is superior to existing passive absorbers of the same depth (60 mm), which has lower frequency limits of around 300 Hz. A passive noise absorber is further proposed by paralleling a micro-perforated panel with shunted loudspeaker which shows potentials in absorbing band-limit impulse noise. PMID- 24815258 TI - A geospatial model of ambient sound pressure levels in the contiguous United States. AB - This paper presents a model that predicts measured sound pressure levels using geospatial features such as topography, climate, hydrology, and anthropogenic activity. The model utilizes random forest, a tree-based machine learning algorithm, which does not incorporate a priori knowledge of source characteristics or propagation mechanics. The response data encompasses 270 000 h of acoustical measurements from 190 sites located in National Parks across the contiguous United States. The explanatory variables were derived from national geospatial data layers and cross validation procedures were used to evaluate model performance and identify variables with predictive power. Using the model, the effects of individual explanatory variables on sound pressure level were isolated and quantified to reveal systematic trends across environmental gradients. Model performance varies by the acoustical metric of interest; the seasonal L50 can be predicted with a median absolute deviation of approximately 3 dB. The primary application for this model is to generalize point measurements to maps expressing spatial variation in ambient sound levels. An example of this mapping capability is presented for Zion National Park and Cedar Breaks National Monument in southwestern Utah. PMID- 24815259 TI - Sound energy decay in coupled spaces using a parametric analytical solution of a diffusion equation. AB - Sound field behavior in performance spaces is a complex phenomenon. Issues regarding coupled spaces present additional concerns due to sound energy exchanges. Coupled volume concert halls have been of increasing interest in recent decades because this architectural principle offers the possibility to modify the hall's acoustical environment in a passive way by modifying the coupling area. Under specific conditions, the use of coupled reverberation chambers can provide non-exponential sound energy decay in the main room, resulting in both high clarity and long reverberation which are antagonistic parameters in a single volume room. Previous studies have proposed various sound energy decay models based on statistical acoustics and diffusion theory. Statistical acoustics assumes a perfectly uniform sound field within a given room whereas measurements show an attenuation of energy with increasing source receiver distance. While previously proposed models based on diffusion theory use numerical solvers, the present study proposes a heuristic model of sound energy behavior based on an analytical solution of the commonly used diffusion equation and physically justified approximations. This model is validated by means of comparisons to scale model measurements and numerical geometrical acoustics simulations, both applied to the same simple concert hall geometry. PMID- 24815260 TI - The acoustic properties of panels with rectangular apertures. AB - A model for the acoustic properties of a plate perforated with slots of rectangular shape is proposed. The model is based on known expressions for the complex density and compressibility of a pore of rectangular shape together with the radiation impedance of a rectangular shaped piston in a baffle. For the so called end correction of a rectangular aperture in a plate, an approximate solution is shown to fit an exact solution for the imaginary part of the radiation impedance, the latter solution based on the work of Lindemann [J. Acoust. Soc. Am, 55, 708-717 (1974)]. Two different procedures are tested to calculate the mutual influence of the apertures on the end correction, the one calculating the mutual impedance of neighboring pistons in the plate, the other by calculating the end correction of a piston placed in the end of an infinitely long tube. The model is used calculating the input impedance and absorption coefficient of a Helmholtz resonator with such a plate, comparing with measurement results. The fit between predicted and measured results, using plates with narrow slits, is good, but it is believed that the model also cover a wider range of dimensions for such a slotted plate. PMID- 24815261 TI - On the modeling of sound transmission through a mixed separation of flexible structure with an aperture. AB - Modeling sound transmission among acoustic media through mixed separations, consisting of both rigid/flexible structures with apertures, is a challenging task. The coexistence of both structural and acoustic transmission paths through the same coupling surface adds system complexities, hampering the use of existing sub-structuring modeling techniques when the system configuration becomes complex. In the present work, a virtual panel treatment is proposed to model thin apertures involved in such complex vibroacoustic systems. The proposed virtual panel considers an aperture as an equivalent structural component, which can be integrated with the solid/flexible structure to form a unified compound interface. This allows handling the entire compound interface as a pure structural element, thus providing an efficient and versatile tool to tackle system complexities when using sub-structuring techniques. The accuracy and convergence of the method are investigated and validated, and the effective thickness range allowing for the virtual panel treatments is determined. The capability and the flexibility of the proposed formulation are demonstrated through several numerical examples, with underlying physics being explored. PMID- 24815262 TI - Comparison of multimicrophone probe design and processing methods in measuring acoustic intensity. AB - Three multimicrophone probe arrangements used to measure acoustic intensity are the four-microphone regular tetrahedral, the four-microphone orthogonal, and the six-microphone designs. Finite-sum and finite-difference processing methods can be used with such probes to estimate pressure and particle velocity, respectively. A numerical analysis is performed to investigate the bias inherent in each combination of probe design and processing method. Probes consisting of matched point sensor microphones both embedded and not embedded on the surface of a rigid sphere are considered. Results are given for plane wave fields in terms of root-mean-square average bias and maximum bias as a function of angle of incidence. An experimental verification of the analysis model is described. Of the combinations considered and under the stated conditions, the orthogonal probe using the origin microphone for the pressure estimate is shown to have the lowest amount of intensity magnitude bias. Lowest intensity direction bias comes from the six-microphone probe using an average of the 15 intensity components calculated using all microphone pairs. Also discussed are how multimicrophone probes can advantageously use correction factors calculated from a numerical analysis and how the results of such an analysis depend on the chosen definition of the dimensionless frequency. PMID- 24815263 TI - Regularization using Monte Carlo simulation to make optimal beamformers robust to system perturbations. AB - Design of optimal beamformers that withstand system perturbations such as channel mismatch, sensor position error, and pointing error has been a key issue in real world applications of arrays. This paper aims to characterize the array performance in relation to the random perturbations from a statistical perspective. In the synthesis stage, directivity index and front-to-back ratio are employed as the performance measures for beamformer optimization. Filter coefficients of the arrays are determined using the least-squares and convex optimization approaches using the preceding performance measures. Next, Monte Carlo sampling are conducted to simulate the stochastic system perturbations following either uniform distribution or normal distribution. Statistics including the sample mean, maximum, minimum, and the maximum likelihood (ML) of the preceding performance measures are calculated. Three regularization criteria based on max-mean, max-min, and max-ML of performance measures are proposed for choosing regularization parameters used in beamformer optimization. The max-mean criterion was found most useful to determine either a simple constant or a frequency-dependent regularization parameter. To validate the proposed methods, experiments of beam patterns and automatic speech recognition test were conducted for directional and diffuse noise suppression problems, where optimal beamformers designed with the regularization parameter selected by the preceding procedures were utilized. PMID- 24815264 TI - Subspace array processing using spatial time-frequency distributions: applications for denoising structural echoes of elastic targets. AB - Structural echoes of underwater elastic targets, used for detection and classification purposes, can be highly localized in the time-frequency domain and can be aspect-dependent. Hence such structural echoes recorded along a distributed (synthetic) aperture, e.g., using a moving receiver platform, would not meet the stationarity and multiple snapshots requirements of common subspace array processing methods used for denoising array data based on their estimated covariance matrix. To address this issue, this article introduces a subspace array processing method based on the space-time-frequency distribution (STFD) of single-snapshots of non-stationary signals. This STFD is obtained by computing Cohen's class time-frequency distributions between all pairwise combination of the recorded signals along an arbitrary aperture array. This STFD is interpreted as a generalized array covariance matrix which automatically accounts for the inherent coherence across the time-frequency plane of the received nonstationary echoes emanating from the same target. Hence, identifying the signal's subspace from the eigenstructure of this STFD provides a means for denoising these non stationary structural echoes by spreading the clutter and noise power in the time frequency domain; as demonstrated here numerically and experimentally using the structural echoes of a thin steel spherical shell measured along a synthetic aperture. PMID- 24815265 TI - Analysis and measurement of the modulation transfer function of harmonic shear wave induced phase encoding imaging. AB - Shear wave induced phase encoding (SWIPE) imaging generates ultrasound backscatter images of tissue-like elastic materials by using traveling shear waves to encode the lateral position of the scatters in the phase of the received echo. In contrast to conventional ultrasound B-scan imaging, SWIPE offers the potential advantages of image formation without beam focusing or steering from a single transducer element, lateral resolution independent of aperture size, and the potential to achieve relatively high lateral resolution with low frequency ultrasound. Here a Fourier series description of the phase modulated echo signal is developed, demonstrating that echo harmonics at multiples of the shear wave frequency reveal target k-space data at identical multiples of the shear wavenumber. Modulation transfer functions of SWIPE imaging systems are calculated for maximum shear wave acceleration and maximum shear constraints, and compared with a conventionally focused aperture. The relative signal-to-noise ratio of the SWIPE method versus a conventionally focused aperture is found through these calculations. Reconstructions of wire targets in a gelatin phantom using 1 and 3.5 MHz ultrasound and a cylindrical shear wave source are presented, generated from the fundamental and second harmonic of the shear wave modulation frequency, demonstrating weak dependence of lateral resolution with ultrasound frequency. PMID- 24815266 TI - Green's function retrieval from reflection data, in absence of a receiver at the virtual source position. AB - The methodology of Green's function retrieval by cross-correlation has led to many interesting applications for passive and controlled-source acoustic measurements. In all applications, a virtual source is created at the position of a receiver. Here a method is discussed for Green's function retrieval from controlled-source reflection data, which circumvents the requirement of having an actual receiver at the position of the virtual source. The method requires, apart from the reflection data, an estimate of the direct arrival of the Green's function. A single-sided three-dimensional (3D) Marchenko equation underlies the method. This equation relates the reflection response, measured at one side of the medium, to the scattering coda of a so-called focusing function. By iteratively solving the 3D Marchenko equation, this scattering coda is retrieved from the reflection response. Once the scattering coda has been resolved, the Green's function (including all multiple scattering) can be constructed from the reflection response and the focusing function. The proposed methodology has interesting applications in acoustic imaging, properly accounting for internal multiple scattering. PMID- 24815267 TI - Experimental evidence for the basal generation place of the short-latency transient-evoked otoacoustic emissions. AB - Time-frequency analysis of the transient-evoked otoacoustic emission response was performed on a population of subjects affected by sensory-neural hearing loss characterized by a sharp audiometric profile, caused by firearm noise exposure (42 ears), and on a control population of normal-hearing subjects (84 ears). Time frequency filtering permitted a careful evaluation of the relation between the audiometric profile and the spectral shape of the long- and short-latency otoacoustic components. Both filtered spectra closely follow the shape of the audiometric profile, with a frequency shift between them. The typical frequency shift was evaluated by averaging the otoacoustic spectra and the audiograms among groups of ears with the same cutoff frequency. Assuming that the otoacoustic emission source function depends on the local effectiveness of the cochlear amplifier, this experimental evidence suggests that the short-latency response is generated at a cochlear place displaced towards the base by about 0.5-1 mm with respect to the generation place of the long-latency component. The analysis of the control group demonstrates that, below 4 kHz, the observed effect is not dependent on the data acquisition and analysis procedure. These results confirm previous theoretical estimates and independent experimental evidence based on the measured latency difference between the two components. PMID- 24815268 TI - Speech recognition against harmonic and inharmonic complexes: spectral dips and periodicity. AB - Speech recognition in a complex masker usually benefits from masker harmonicity, but there are several factors at work. The present study focused on two of them, glimpsing spectrally in between masker partials and periodicity within individual frequency channels. Using both a theoretical and an experimental approach, it is demonstrated that when inharmonic complexes are generated by jittering partials from their harmonic positions, there are better opportunities for spectral glimpsing in inharmonic than in harmonic maskers, and this difference is enhanced as fundamental frequency (F0) increases. As a result, measurements of masking level difference between the two maskers can be reduced, particularly at higher F0s. Using inharmonic maskers that offer similar glimpsing opportunity to harmonic maskers, it was found that the masking level difference between the two maskers varied little with F0, was influenced by periodicity of the first four partials, and could occur in low-, mid-, or high-frequency regions. Overall, the present results suggested that both spectral glimpsing and periodicity contribute to speech recognition under masking by harmonic complexes, and these effects seem independent from one another. PMID- 24815269 TI - Robust fundamental frequency estimation in sustained vowels: detailed algorithmic comparisons and information fusion with adaptive Kalman filtering. AB - There has been consistent interest among speech signal processing researchers in the accurate estimation of the fundamental frequency (F(0)) of speech signals. This study examines ten F(0) estimation algorithms (some well-established and some proposed more recently) to determine which of these algorithms is, on average, better able to estimate F(0) in the sustained vowel /a/. Moreover, a robust method for adaptively weighting the estimates of individual F(0) estimation algorithms based on quality and performance measures is proposed, using an adaptive Kalman filter (KF) framework. The accuracy of the algorithms is validated using (a) a database of 117 synthetic realistic phonations obtained using a sophisticated physiological model of speech production and (b) a database of 65 recordings of human phonations where the glottal cycles are calculated from electroglottograph signals. On average, the sawtooth waveform inspired pitch estimator and the nearly defect-free algorithms provided the best individual F(0) estimates, and the proposed KF approach resulted in a ~16% improvement in accuracy over the best single F(0) estimation algorithm. These findings may be useful in speech signal processing applications where sustained vowels are used to assess vocal quality, when very accurate F(0) estimation is required. PMID- 24815270 TI - Effects of compression and onset/offset asynchronies on the detection of one tone in the presence of another. AB - The weaker of two temporally overlapping complex tones can be easier to hear when the tones are asynchronous than when they are synchronous. This study explored how the use of fast and slow five-channel amplitude compression, as might be used in hearing aids, affected the ability to use onset and offset asynchronies to detect one (signal) complex tone when another (masking) complex tone was presented almost simultaneously. A 2:1 compression ratio was used with normal hearing subjects, and individual compression ratios and gains recommended by the CAM2 hearing aid fitting method were used for hearing-impaired subjects. When the signal started before the masker, there was a benefit of compression for both normal-hearing and hearing-impaired subjects. When the signal finished after the masker, there was a benefit of fast compression for the normal-hearing subjects but no benefit for most of the hearing-impaired subjects, except when the offset asynchrony was relatively large (100 ms). The benefit of compression probably occurred because the compression improved the effective signal-to-masker ratio, hence reducing backward and forward masking. This apparently outweighed potential deleterious effects of distortions in envelope shape and the introduction of partially correlated envelopes of the signal and masker. PMID- 24815271 TI - Interpulse interval discrimination within and across channels: comparison of monopolar and tripolar mode of stimulation. AB - Perception of temporal patterns is crucial to speech understanding and music perception in normal hearing, and is fundamental in the design and implementation of processing strategies for cochlear implants. Two experiments described here investigated the effect of stimulation mode (monopolar versus tripolar) on interpulse interval discrimination using single-electrode stimulation (experiment 1) and dual-electrode stimulation (experiment 2). Experiment 1 required participants to discriminate stimuli containing different interpulse intervals and experiment 2 required listeners to discriminate between two dual-electrode stimuli that had the same temporal pattern on each electrode, but differed in inter-electrode timing. The hypotheses were that (i) stimulation mode would affect the ability to distinguish interpulse interval patterns on a single electrode and (ii) the electrode separation range in which subjects were sensitive to inter-electrode timing would be more restricted in tripolar than in monopolar stimulation. Results in nine cochlear implant users showed that mode did not have a significant mean effect on either the ability to discriminate interpulse intervals in single-electrode stimulation or the range of electrode separation in dual-electrode stimulation in which participants were sensitive to inter-electrode timing. In conclusion, tripolar stimulation did not show any advantage in delivering temporal information within or across channels in this group. PMID- 24815272 TI - Threshold of the precedence effect in noise. AB - Three effects that show a temporal asymmetry in the influence of interaural cues were studied through the addition of masking noise: (1) The transient precedence effect-the perceptual dominance of a leading transient over a similar lagging transient; (2) the ongoing precedence effect-lead dominance with lead and lag components that extend in time; and (3) the onset capture effect-determination by an onset transient of the lateral position of an otherwise ambiguous extended trailing sound. These three effects were evoked with noise-burst stimuli and were compared in the presence of masking noise. Using a diotic noise masker, detection thresholds for stimuli with lead/lag interaural delays of 0/500 MUs were compared to those with 500/0 MUs delays. None of the three effects showed a masking difference between those conditions, suggesting that none of the effects is operative at masked threshold. A task requiring the discrimination between stimuli with 500/0 and 0/500 MUs interaural delays was used to determine the threshold for each effect in noise. The results showed similar thresholds in noise (10-13 dB SL) for the transient and ongoing precedence effects, but a much higher threshold (33 dB SL) for onset capture of an ambiguous trailing sound. PMID- 24815273 TI - Effect of broadband and narrowband contralateral noise on psychophysical tuning curves and otoacoustic emissions. AB - The relative effectiveness of narrowband and broadband noises in activating the efferent system was assessed by comparing the effect of contralateral stimulation (CS) with such sounds on psychophysical tuning curves (PTCs) determined in simultaneous masking, using signal frequencies of 1000 or 2000 Hz. To check that the CS stimuli used did activate the efferent system, distortion product otoacoustic emissions (DPOAEs) were also measured in the absence and presence of narrowband and broadband CS. The CS had no consistent effect on the masker level at the tips of the PTCs. A broadband pink noise CS consistently reduced the masker level required for threshold on both the low- and high-frequency sides of the PTCs for the 2000-Hz signal frequency. However, there were no consistent effects of the CS for any other case. The broadband pink noise CS had a greater effect in reducing DPOAE levels than the narrowband CS. The results provide psychophysical evidence supporting the idea that the efferent system is activated more effectively by a broadband than by a narrowband CS, at least for a signal frequency of 2000 Hz. PMID- 24815274 TI - The influence of alcoholic intoxication on the short-time energy function of speech. AB - This study investigates rhythmic features based on the short-time energy function of speech signals with the aim of finding robust, speaker-independent features that indicate speaker intoxication. Data from the German Alcohol Language Corpus, which comprises read, spontaneous, and command&control speech uttered by 162 speakers of both genders and various age groups when sober and intoxicated, were analyzed. Energy contours are compared directly (Root Mean Squared Error, statistical correlation, or the Euclidean distance in the spectral space of the contour) and by parameterization of the contour using the Discrete Cosine Transform (DCT) and the first and second moments of the lower DCT spectrum. Contours are also analyzed by Principal Components Analysis aiming at fundamental "eigen contour" changes that might encode intoxication. Energy contours differ significantly with intoxication in terms of distance measures, the second and fourth DCT coefficients, and the first and second moments of the lower DCT spectrum. Principal Components Analysis did not yield interpretable "eigen contours" that could be used in distinguishing intoxicated from sober contours. PMID- 24815275 TI - The perceived clarity of children's speech varies as a function of their default articulation rate. AB - The current study investigated whether variation in children's default articulation rate might reflect individual differences in the development of articulatory timing control, which predicts a positive correlation between rate and perceived clarity (motor skills hypothesis), or whether such variation is better attributed to speech external factors, which predicts that faster rates result in poorer target attainment (undershoot hypothesis). Two different speech samples were obtained from 54 typically developing children (5;2 - 7;11). Six utterances were extracted from each sample and measured for articulation rate and segmental duration. Fourteen adult listeners rated the utterances for clarity (enunciation). Acoustic correlates of perceived clarity, pitch, and vowel quality were also measured. The findings were that age-dependent and individual differences in children's default articulation rates were due to segmental articulation and not to suprasegmental changes. The rating data indicated that utterances produced at faster rates were perceived as more clearly articulated than those produced at slower rates, regardless of a child's age. Vowel quality measures predicted perceived clarity independently of articulation rate. Overall, the results support the motor skills hypothesis: Faster default articulation rates emerge from better articulatory timing control. PMID- 24815276 TI - Acoustic characteristics of Greek fricatives. AB - The present study examined the acoustics of Greek fricative consonants in terms of temporal, spectral, and amplitude parameters. The effects of voicing, speaker's gender, place of articulation, and post-fricative vowel on the acoustic parameters were also investigated. The results indicated that first and second spectral moments (i.e., spectral mean and spectral variance), as well as second formant (F2) onset, and normalized amplitude values are the acoustic parameters most correlated with the Greek fricative place of articulation distinction. F2 onset and spectral mean were the parameters that distinguished all five places of articulation, while normalized amplitude differentiated sibilants from non sibilants. In addition, normalized duration and normalized amplitude are the parameters that distinguish Greek voiced from voiceless fricatives, with high classification accuracy. PMID- 24815277 TI - Comparison of voice relative fundamental frequency estimates derived from an accelerometer signal and low-pass filtered and unprocessed microphone signals. AB - The relative fundamental frequency (RFF) surrounding the production of a voiceless consonant has previously been estimated using unprocessed and low-pass filtered microphone signals, but it can also be estimated using a neck-placed accelerometer signal that is less affected by vocal tract formants. Determining the effects of signal type on RFF will allow for comparisons across studies and aid in establishing a standard protocol with minimal within-speaker variability. Here RFF was estimated in 12 speakers with healthy voices using unprocessed microphone, low-pass filtered microphone, and unprocessed accelerometer signals. Unprocessed microphone and accelerometer signals were recorded simultaneously using a microphone and neck-placed accelerometer. The unprocessed microphone signal was filtered at 350 Hz to construct the low-pass filtered microphone signal. Analyses of variance showed that signal type and the interaction of vocal cycle * signal type had significant effects on both RFF means and standard deviations, but with small effect sizes. The overall RFF trend was preserved regardless of signal type and the intra-speaker variability of RFF was similar among the signal types. Thus, RFF can be estimated using either a microphone or an accelerometer signal in individuals with healthy voices. Future work extending these findings to individuals with disordered voices is warranted. PMID- 24815279 TI - Tracking perception of the sounds of English. AB - Twenty American English listeners identified gated fragments of all 2288 possible English within-word and cross-word diphones, providing a total of 538,560 phoneme categorizations. The results show orderly uptake of acoustic information in the signal and provide a view of where information about segments occurs in time. Information locus depends on each speech sound's identity and phonological features. Affricates and diphthongs have highly localized information so that listeners' perceptual accuracy rises during a confined time range. Stops and sonorants have more distributed and gradually appearing information. The identity and phonological features (e.g., vowel vs consonant) of the neighboring segment also influences when acoustic information about a segment is available. Stressed vowels are perceived significantly more accurately than unstressed vowels, but this effect is greater for lax vowels than for tense vowels or diphthongs. The dataset charts the availability of perceptual cues to segment identity across time for the full phoneme repertoire of English in all attested phonetic contexts. PMID- 24815278 TI - Temporal control and compensation for perturbed voicing feedback. AB - Previous research employing a real-time auditory perturbation paradigm has shown that talkers monitor their own speech attributes such as fundamental frequency, vowel intensity, vowel formants, and fricative noise as part of speech motor control. In the case of vowel formants or fricative noise, what was manipulated is spectral information about the filter function of the vocal tract. However, segments can be contrasted by parameters other than spectral configuration. It is possible that the feedback system monitors phonation timing in the way it does spectral information. This study examined whether talkers exhibit a compensatory behavior when manipulating information about voicing. When talkers received feedback of the cognate of the intended voicing category (saying "tipper" while hearing "dipper" or vice versa), they changed the voice onset time and in some cases the following vowel. PMID- 24815280 TI - Evaluation of the importance of time-frequency contributions to speech intelligibility in noise. AB - Recent studies on binary masking techniques make the assumption that each time frequency (T-F) unit contributes an equal amount to the overall intelligibility of speech. The present study demonstrated that the importance of each T-F unit to speech intelligibility varies in accordance with speech content. Specifically, T F units are categorized into two classes, speech-present T-F units and speech absent T-F units. Results indicate that the importance of each speech-present T-F unit to speech intelligibility is highly related to the loudness of its target component, while the importance of each speech-absent T-F unit varies according to the loudness of its masker component. Two types of mask errors are also considered, which include miss and false alarm errors. Consistent with previous work, false alarm errors are shown to be more harmful to speech intelligibility than miss errors when the mixture signal-to-noise ratio (SNR) is below 0 dB. However, the relative importance between the two types of error is conditioned on the SNR level of the input speech signal. Based on these observations, a mask based objective measure, the loudness weighted hit-false, is proposed for predicting speech intelligibility. The proposed objective measure shows significantly higher correlation with intelligibility compared to two existing mask-based objective measures. PMID- 24815281 TI - Vowel discrimination by hearing infants as a function of number of spectral channels. AB - Reduced spectral resolution negatively impacts speech perception, particularly perception of vowels and consonant place. This study assessed impact of number of spectral channels on vowel discrimination by 6-month-old infants with normal hearing by comparing three listening conditions: Unprocessed speech, 32 channels, and 16 channels. Auditory stimuli (/ti/ and /ta/) were spectrally reduced using a noiseband vocoder and presented to infants with normal hearing via visual habituation. Results supported a significant effect of number of channels on vowel discrimination by 6-month-old infants. No differences emerged between unprocessed and 32-channel conditions in which infants looked longer during novel stimulus trials (i.e., discrimination). The 16-channel condition yielded a significantly different pattern: Infants demonstrated no significant difference in looking time to familiar vs novel stimulus trials, suggesting infants cannot discriminate /ti/ and /ta/ with only 16 channels. Results support effects of spectral resolution on vowel discrimination. Relative to published reports, young infants need more spectral detail than older children and adults to perceive spectrally degraded speech. Results have implications for development of perception by infants with hearing loss who receive auditory prostheses. PMID- 24815282 TI - Discrimination of foreign language speech contrasts by English monolinguals and French/English bilinguals. AB - The primary aim of this study was to determine whether late French/English bilinguals are able to utilize knowledge of bilabial stop contrasts that exist in each of their separate languages to discriminate bilabial stop contrasts from a new language (Thai). Secondary aims were to determine associations between bilabial stop consonant production in the L1 and the L2, between language learning factors and production and discrimination, and to compare English bilinguals' and monolinguals' discrimination. Three Thai bilabial stop consonant pairs differentiated by Voice Onset Time (VOT) (combinations of [b], [p], and [p(h)]) were presented to 28 French-English bilinguals, 25 English-French bilinguals, and 43 English monolinguals in an AX discrimination task. It was hypothesized that L2 experience would facilitate discrimination of contrasts that were phonemic in the L2 but not in the L1 for bilinguals. Only limited support for this hypothesis was found. However, results indicate that high production proficiency bilinguals had higher discrimination of the phonemic L2 contrasts (non-phonemic in L1). Discrimination patterns indicate lasting L1 influence, with similarity between unknown foreign language contrasts and L1 contrasts influencing discrimination rates. Production results show evidence for L2 influence in the L1. Results are discussed in the context of current speech perception models. PMID- 24815284 TI - Predicting the decay time of solid body electric guitar tones. AB - Although it can be transformed by various electronic devices, the sound of the solid body electric guitar originates from, and is strongly linked with, the string vibration. The coupling of the string with the guitar alters its vibration and can lead to decay time inhomogeneities. This paper implements and justifies a framework for the study of decay times of electric guitar tones. Two damping mechanisms are theoretically and experimentally identified: the string intrinsic damping and the damping due to mechanical coupling with the neck of the guitar. The electromagnetic pickup is shown to not provide any additional damping to the string. The pickup is also shown to be far more sensitive to the out-of-plane polarization of the string. Finally, an accurate prediction of the decay time of electric guitar tones is made possible, whose only requirements are the knowledge of the isolated string dampings and the out-of-plane conductance at the neck of the guitar. This prediction can be of great help for instrument makers and manufacturers. PMID- 24815283 TI - Understanding the mechanisms underlying voluntary responses to pitch-shifted auditory feedback. AB - Previous research has shown that vocal errors can be simulated using a pitch perturbation technique. Two types of responses are observed when subjects are asked to ignore changes in pitch during a steady vowel production, a compensatory response countering the direction of the perceived change in pitch and a following response in the same direction as the pitch perturbation. The present study investigated the nature of these responses by asking subjects to volitionally change their voice fundamental frequency either in the opposite direction ("opposing" group) or the same direction ("following" group) as the pitch shifts (+/-100 cents, 1000 ms) presented during the speaker's production of an /a/ vowel. Results showed that voluntary responses that followed the stimulus directions had significantly shorter latencies (150 ms) than opposing responses (360 ms). In addition, prior to the slower voluntary opposing responses, there were short latency involuntary responses that followed the stimulus direction. These following responses may involve mechanisms of imitation or vocal shadowing of acoustical stimuli when subjects are predisposed to respond to a change in frequency of a sound. The slower opposing responses may represent a control strategy that requires monitoring and correcting for errors between the feedback signal and the intended vocal goal. PMID- 24815285 TI - Acoustic behavior of tuning slots of labial organ pipes. AB - The effect of tuning slots on the sound characteristics of labial organ pipes is investigated in this paper by means of laboratory experiments. Besides changing the pitch of the pipe, the tuning slot also plays an important role in forming the timbre. The objectives of this contribution are to document the influence of tuning slots built with different geometries on the pipe sound and to validate the observed tendencies by means of reproducible experiments. It is found that the measured steady state sound spectra show unique characteristics, typical only for tuning slot organ pipes. By separately adjusting the geometrical parameters of the tuning slots on experimental pipes, the impact of each scaling parameter on the steady state spectrum is determined. It is shown that the scaling procedures used currently in organ building practice do not provide sufficient control over the sound characteristics, leaving the capabilities provided by the tuning slot unexploited. Subjective comparison made by organ builders of sound recordings of various setups confirms that the observed sound quality of tuning slot pipes is strongly dependent on the scaling of the slot. PMID- 24815291 TI - Non-song vocalizations of pygmy blue whales in Geographe Bay, Western Australia. AB - Non-song vocalizations of migrating pygmy blue whales (Balaenoptera musculus brevicauda) in Western Australia are described. Simultaneous land-based visual observations and underwater acoustic recordings detected 27 groups in Geographe Bay, WA over 2011 to 2012. Six different vocalizations were recorded that were not repeated in a pattern or in association with song, and thus were identified as non-song vocalizations. Five of these were not previously described for this population. Their acoustic characteristics and context are presented. Given that 56% of groups vocalized, 86% of which produced non-song vocalizations and 14% song units, the inclusion of non-song vocalizations in passive-acoustic monitoring is proposed. PMID- 24815292 TI - Reducing the impact of wind noise on cochlear implant processors with two microphones. AB - Behind-the-ear (BTE) processors of cochlear implant (CI) devices offer little to almost no protection from wind noise in most incidence angles. To assess speech intelligibility, eight CI recipients were tested in 3 and 9 m/s wind. Results indicated that speech intelligibility decreased substantially when the wind velocity, and in turn the wind sound pressure level, increased. A two-microphone wind noise suppression strategy was developed. Scores obtained with this strategy indicated substantial gains in speech intelligibility over other conventional noise reduction strategies tested. PMID- 24815293 TI - Arrival-time fluctuations of coherent reflections from surface gravity water waves. AB - Arrival time fluctuations of coherent reflections from surface gravity waves are examined. A two-dimensional ray model with an evolving rough sea surface is used to explain the mechanism and formation of the deterministic striation patterns due to the surface reflection. Arrival time predictions from the ray model match qualitatively well with the measurements from bidirectional acoustic transmissions in a water depth of 100 m. PMID- 24815294 TI - A 3-D elasticity theory based model for acoustic radiation from multilayered anisotropic plates. AB - A theoretical model built upon three-dimensional elasticity theory is developed to investigate the acoustic radiation from multilayered anisotropic plates subjected to a harmonic point force excitation. Fourier transform technique and stationary phase method are combined to predict the far-field radiated sound pressure of one-side water immersed plate. Compared to equivalent single-layer plate models, the present model based on elasticity theory can differentiate radiated sound pressure between dry-side and wet-side excited cases, as well as discrepancies induced by different layer sequences for multilayered anisotropic plates. These results highlight the superiority of the present theoretical model especially for handling multilayered anisotropic structures. PMID- 24815295 TI - Early recurrence of early stage endometrioid endometrial carcinoma: possible etiologic pathways and management options. AB - The majority of endometrial cancers is early stage and of the endometrioid histological type, as the symptoms (mainly vaginal bleeding) of the disease lead to an early diagnosis. Close follow-up is nevertheless essential in such cancers staged early on, in which the rate of recurrence is relatively low. We retrieved the studies included in our narrative review after performing a systematic electronic search in the PubMed, Scopus and Cochrane databases. The incidence or recurrence of disease in such patients could be up to 2.6%, with the main sites of recurrence being the vaginal vault or metastases in distant parts of the body. Genetic factors such as p53 overexpression, inactivation of 14-3-3-sigma, KRAS amplification and KRAS mRNA expression, microsatellite instability and Lynch syndrome genes could be associated with such a recurrence. Black race is also correlated, as well as lymphovascular space involvement, lower uterine segment involvement and DNA aneuploidy. Longer hysteroscopy duration was not found to be associated. Close follow-up is suggested for early detection of recurrences, while surgical excision of isolated disease or exenteration of local disease as well as radiotherapy and chemotherapy are the main treatment options. This narrative review investigated the possible mechanisms of early recurrence in patients with endometrioid endometrial cancer as well as the further management of them. PMID- 24815296 TI - Wnt signaling and osteoporosis. AB - Major advances in understanding basic bone biology and the cellular and molecular mechanisms responsible for the development of osteoporosis, over the last 20 years, have dramatically altered the management of this disease. The purpose of this mini-review is to highlight the seminal role of Wnt signaling in bone homeostasis and disease and the emergence of novel osteoporosis therapies by targeting Wnt signaling with drugs. PMID- 24815297 TI - Motor 'surround inhibition' is not correlated with activity in surround muscles. AB - Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively. PMID- 24815298 TI - Randomised clinical trial: A liquid multi-strain probiotic vs. placebo in the irritable bowel syndrome--a 12 week double-blind study. AB - BACKGROUND: The importance of interactions between the host and gut microbiota in the pathogenesis of irritable bowel syndrome (IBS) is becoming increasingly apparent. Probiotics offer a potential new treatment for IBS, but current results are conflicting, largely as a result of poorly designed trials and nonstandardisation of outcome measures. AIM: To assess the efficacy of a liquid, multi-strain probiotic (Symprove) in IBS. METHODS: A single-centre, randomised, double-blind, placebo-controlled trial of adult patients with symptomatic IBS. Patients received 12 weeks of treatment with the probiotic or placebo (1 mL/kg/day). The primary efficacy measure was the difference in change in the IBS symptom severity score (IBS-SSS) between probiotic vs. placebo at week 12. Secondary outcome measures included change in the IBS quality of life (IBS-QOL) score and change in the IBS-SSS symptom component scores. RESULTS: A total of 186 patients were randomised and 152 patients completed the study. The mean change in IBS-SSS was -63.3 probiotic vs. -28.3 placebo. The mean difference in the IBS-SSS was statistically significant [-35.0 (95% CI; -62.03, -7.87); P = 0.01]. There was no significant improvement in the IBS-QOL. No serious adverse events were reported. CONCLUSIONS: The multi-strain probiotic was associated with a statistically significant improvement in overall symptom severity in patients with IBS, and was well tolerated. These results suggest this probiotic confers benefit in IBS and deserves further investigation (ISRCTN identifier: 77512412). PMID- 24815299 TI - The p53/miR-34 axis in development and disease. AB - The tumor suppressor p53 is one of the most frequently mutated genes in human cancers. MicroRNAs (miRNAs) are small non-protein coding RNAs that regulate gene expression on the post-transcriptional level. Recently, it was shown that p53 regulates the expression of several miRNAs, thereby representing an important mechanism of p53 signaling. Several independent studies identified the members of the miR-34 family as the most prevalent p53-induced miRNAs. miR-34s are frequently silenced in variety of tumor entities, suggesting that they are important tumor suppressors. Indeed, ectopic expression of miR-34s inhibits proliferation, epithelial to mesenchymal transition, migration, invasion, and metastasis of various cancer cell entities. Moreover, delivery or re-expression of miR-34 leads to notable repression of tumor growth and metastasis in cancer mouse models, and may therefore represent an efficient strategy for future cancer therapeutics. Besides their crucial functions in cancer, members of the miR-34 family also play important roles in spermatogenesis, stem cell differentiation, neuronal development, aging, and cardiovascular functions. Consequently, miR-34 has also been implicated in various non-cancerous diseases, such as brain disorders, osteoporosis, and cardiovascular complications. PMID- 24815300 TI - Performance evaluation of the new hematology analyzer Sysmex XN-series. AB - INTRODUCTION: The Sysmex XN-series is a new automated hematology analyzer designed to improve the accuracy of cell counts and the specificity of the flagging events. METHODS: The basic characteristics and the performance of new measurement channels of the XN were evaluated and compared with the Sysmex XE 2100 and the manual method. Fluorescent platelet count (PLT-F) was compared with the flow cytometric method. The low WBC mode and body fluid mode were also evaluated. For workflow analysis, 1005 samples were analyzed on both the XN and the XE-2100, and manual review rates were compared. RESULTS: All parameters measured by the XN correlated well with the XE-2100. PLT-F showed better correlation with the flow cytometric method (r(2) = 0.80) compared with optical platelet count (r(2) = 0.73) for platelet counts <70 * 10(9) /L. The low WBC mode reported accurate leukocyte differentials for samples with a WBC count <0.5 * 10(9) /L. Relatively good correlation was found for WBC counts between the manual method and the body fluid mode (r = 0.88). The XN made less flags than the XE-2100, while the sensitivities of both instruments were comparable. CONCLUSION: The XN provided reliable results on low cell counts, as well as reduced manual blood film reviews, while maintaining a proper level of diagnostic sensitivity. PMID- 24815301 TI - Novel regulatory program for norepinephrine-induced epithelial-mesenchymal transition in gastric adenocarcinoma cell lines. AB - Norepinephrine and epinephrine, catecholamine hormones that are major mediators for chronic stress-induced cancers, are implicated in the progression of a number of cancer cells, including gastric adenocarcinoma. However, the underlying mechanisms of these hormones have not been well elucidated. Epithelial mesenchymal transition (EMT) is a crucial event responsible for cancer cell invasion and metastasis. The hypothesis regarding whether the promotive effects of norepinephrine (NE) on cancer are in part due to its ability to induce an EMT program has not been proven. In this study, we show that NE does not only obviously induce EMT alterations in the morphological characteristics of gastric adenocarcinoma cells, but also increases the markers of EMT, including vimentin expression, and decreases E-cadherin expression, further resulting in cell motility and invasiveness. We also reveal that these actions are mainly mediated through the activation of beta2 -AR-HIF-1alpha-Snail signaling pathways. In summary, this study implies that NE induces EMT in gastric adenocarcinoma through the regulation of beta2 -AR-HIF-1alpha-Snail activity. The data provide a new perspective on chronic stress in a negative social and psychological state, which may be a risk factor for cancer development and progression. PMID- 24815302 TI - Does exposure prediction bias health-effect estimation?: The relationship between confounding adjustment and exposure prediction. AB - In environmental epidemiology, we are often faced with 2 challenges. First, an exposure prediction model is needed to estimate the exposure to an agent of interest, ideally at the individual level. Second, when estimating the health effect associated with the exposure, confounding adjustment is needed in the health-effects regression model. The current literature addresses these 2 challenges separately. That is, methods that account for measurement error in the predicted exposure often fail to acknowledge the possibility of confounding, whereas methods designed to control confounding often fail to acknowledge that the exposure has been predicted. In this article, we consider exposure prediction and confounding adjustment in a health-effects regression model simultaneously. Using theoretical arguments and simulation studies, we show that the bias of a health-effect estimate is influenced by the exposure prediction model, the type of confounding adjustment used in the health-effects regression model, and the relationship between these 2. Moreover, we argue that even with a health-effects regression model that properly adjusts for confounding, the use of a predicted exposure can bias the health-effect estimate unless all confounders included in the health-effects regression model are also included in the exposure prediction model. While these results of this article were motivated by studies of environmental contaminants, they apply more broadly to any context where an exposure needs to be predicted. PMID- 24815303 TI - There goes the neighborhood effect: bias owing to nondifferential measurement error in the construction of neighborhood contextual measures. AB - BACKGROUND: Multilevel studies of neighborhood effects on health frequently aggregate individual-level data to create contextual measures. For example, percent of residents living in poverty and median household income are both aggregations of Census data on individual-level household income. Because household income is sensitive and complex, it is likely to be reported with error. METHODS: To assess the impact of such error on effect estimates for neighborhood contextual factors, we conducted simulation studies to relate neighborhood measures derived from Census data to individual body mass index, varying the extent of nondifferential misclassification/measurement error in the underlying Census data. We then explored the impact on the magnitude of bias owing to the form of variables chosen for neighborhood measure and outcome, modeling technique used, size and number of neighborhoods, and categorization of neighborhoods. RESULTS: For neighborhood contextual variables expressed as percentages (eg, percent of residents living in poverty), nondifferential misclassification in the underlying individual-level Census data always biases the parameter estimate for the neighborhood variable away from the null. However, estimates of differences between quantiles of neighborhoods using such contextual variables are unbiased. Aggregation of the same underlying individual-level Census income data into a continuous variable, such as median household income, also introduces bias into the regression parameter. Such bias is non-negligible if the sampled groups are small. CONCLUSIONS: Decisions regarding the construction and analysis of neighborhood contextual measures substantially alter the impact on study validity of measurement error in the data used to construct the contextual measure. PMID- 24815304 TI - Air pollution and risk of uterine leiomyomata. AB - BACKGROUND: Air pollution, particularly from vehicle exhaust, has been shown to influence hormonal activity. However, it is unknown whether air pollution exposure is associated with the occurrence of uterine leiomyomata, a hormonally sensitive tumor of the uterus. METHODS: For 85,251 women 25-42 years of age at enrollment in the Nurses' Health Study II, we examined proximity to major roadways and outdoor levels of particulate matter less than 10 microns (PM10) or 2.5 microns (PM2.5) or between 10 and 2.5 microns (PM10-2.5) in diameter for all residential addresses from September 1989 to May 2007. To be eligible for this analysis, a woman had to be alive and respond to questionnaires, premenopausal with an intact uterus, and without diagnoses of cancer or prevalent uterine leiomyomata. Incidence of ultrasound- or hysterectomy-confirmed uterine leiomyomata and covariates were reported on biennial questionnaires sent through May 2007. Multivariable time-varying Cox proportional hazard models were used to estimate the relationship between distance to road or PM exposures and uterine leiomyomata risk. RESULTS: During 837,573 person-years of follow-up, there were 7760 incident cases of uterine leiomyomata. Living close to a major road and exposures to PM10 or PM10-2.5 were not associated with an increased risk of uterine leiomyomata. However, each 10 MUg/m increase in 2-year average, 4-year average, or cumulative average PM2.5 was associated with an adjusted hazard ratio of 1.08 (95% confidence interval = 1.00-1.17), 1.09 (0.99-1.19), and 1.11 (1.03 1.19), respectively. CONCLUSIONS: Chronic exposure to PM2.5 may be associated with a modest increased risk of uterine leiomyomata. PMID- 24815305 TI - Hospital-acquired Clostridium difficile infections: estimating all-cause mortality and length of stay. AB - BACKGROUND: Clostridium difficile is a health care-associated infection of increasing importance. The purpose of this study was to estimate the time until death from any cause and time until release among patients with C. difficile, comparing the burden of those in the intensive care unit (ICU) with those in the general hospital population. METHODS: A parametric mixture model was used to estimate event times, as well as the case-fatality ratio in ICU and non-ICU patients within a cohort of 609 adult incident cases of C. difficile in the Southeastern United States between 1 July 2009 and 31 December 2010. RESULTS: ICU patients had twice the median time to death (relative time = 1.97 [95% confidence interval (CI) = 0.96-4.01]) and nearly twice the median time to release (1.88 [1.40-2.51]) compared with non-ICU patients. ICU patients also experienced 3.4 times the odds of mortality (95% CI = 1.8-6.2). Cause-specific competing risks analysis underestimated the relative survival time until death (0.65 [0.36-1.17]) compared with the mixture model. CONCLUSIONS: Patients with C. difficile in the ICU experienced higher mortality and longer lengths of stay within the hospital. ICU patients with C. difficile infection represent a population in need of particular attention, both to prevent adverse patient outcomes and to minimize transmission of C. difficile to other hospitalized patients. PMID- 24815306 TI - Comparison of bias analysis strategies applied to a large data set. AB - BACKGROUND: Epidemiologic data sets continue to grow larger. Probabilistic-bias analyses, which simulate hundreds of thousands of replications of the original data set, may challenge desktop computational resources. METHODS: We implemented a probabilistic-bias analysis to evaluate the direction, magnitude, and uncertainty of the bias arising from misclassification of prepregnancy body mass index when studying its association with early preterm birth in a cohort of 773,625 singleton births. We compared 3 bias analysis strategies: (1) using the full cohort, (2) using a case-cohort design, and (3) weighting records by their frequency in the full cohort. RESULTS: Underweight and overweight mothers were more likely to deliver early preterm. A validation substudy demonstrated misclassification of prepregnancy body mass index derived from birth certificates. Probabilistic-bias analyses suggested that the association between underweight and early preterm birth was overestimated by the conventional approach, whereas the associations between overweight categories and early preterm birth were underestimated. The 3 bias analyses yielded equivalent results and challenged our typical desktop computing environment. Analyses applied to the full cohort, case cohort, and weighted full cohort required 7.75 days and 4 terabytes, 15.8 hours and 287 gigabytes, and 8.5 hours and 202 gigabytes, respectively. CONCLUSIONS: Large epidemiologic data sets often include variables that are imperfectly measured, often because data were collected for other purposes. Probabilistic-bias analysis allows quantification of errors but may be difficult in a desktop computing environment. Solutions that allow these analyses in this environment can be achieved without new hardware and within reasonable computational time frames. PMID- 24815307 TI - First line treatment of chronic phase chronic myeloid leukaemia patients with the generic formulations of imatinib mesylate. PMID- 24815308 TI - Associations of fat mass and fat distribution with bone mineral density in Chinese obese population. AB - The purpose of the study was to investigate the associations of fat mass (FM) and fat distribution with bone mineral density (BMD) in Chinese obese population. Three hundred and forty-seven Chinese obese females and 339 males aged 20-39 years were analyzed. Lean mass (LM), FM, percent body fat (%BF), android FM, gynoid FM, and total and regional BMD were measured using dual-energy X-ray absorptiometry. Fat distribution was assessed by android-to-gynoid FM ratio (AOI). As a result, increased central body fat had an inverse association with total and leg BMD in females but not in males. Increased FM and %BF were positively associated with arm, trunk, and pelvic BMD in Chinese obese females. Increased FM was positively associated with total, rib, and trunk BMD in Chinese obese males. The results remained almost unchanged after adjusting for LM, and LM was significantly positively associated with spine BMD in female group. FM was positively associated with trunk BMD in male group after adjusting for LM. AOI was inversely associated with total and leg BMD, and %BF was positively associated with arm, trunk, and pelvic BMD when replacing FM with %BF in female group. The results remained almost unchanged after adjusting for LM. There is no significant association in male group when replacing FM with %BF. In conclusion, our findings demonstrate that there are different associations of FM and fat distribution with BMD, and AOI has a negative association with BMD. PMID- 24815309 TI - Hepatic venous outflow obstruction in pediatric liver transplantation: technical considerations in prevention, diagnosis, and management. AB - HVOO creates significant diagnostic and management dilemmas in pediatric liver transplant recipients, particularly with TVGs (split or reduced-size grafts). Numerous technical variations for the hepatic vein to IVC anastomosis have been described to minimize the incidence of this complication, but no consensus for an optimal anastomotic technique exists. One hundred and thirty-four liver transplants (70 TVGs) were performed in 124 patients between 1994 and 2011. These were divided into two cohorts. Group 1 (95 transplants, 41 TVGs) utilized a continuous running anastomosis. Group 2 (39 transplants, 29 TVGs) implemented a triangulated (three-stitch) anastomosis. All were reviewed for demographics, diagnostics, interventions, and outcome. The overall HVOO incidence was seven of 134 transplants (5.2%) and six of 70 transplants utilizing TVGs (8.6%). Group 1 incidence was five of 41 (12.2%) compared with one of 29 (3.4%; p = 0.20, OR 3.89) in Group 2. Liver Doppler was employed in all patients, and only three suggested HVOO. All patients with HVOO underwent venogram, at a median of 81 days post-transplant. All underwent percutaneous venoplasty and required 1-6 treatments, all resulting in HVOO resolution. Incidence of HVOO has improved since adopting the triangulated anastomosis, although not to a level of statistical significance. US is not adequately sensitive to exclude HVOO. Venogram is recommended in patients with prolonged ascites, and venoplasty has been highly successful in HVOO treatment. PMID- 24815310 TI - Hydrogen peroxide and nitric oxide are involved in salicylic acid-induced salvianolic acid B production in Salvia miltiorrhiza cell cultures. AB - Hydrogen peroxide (H2O2) and nitric oxide (NO) are key signaling molecules in cells whose levels are increased in response to various stimuli and are involved in plant secondary metabolite synthesis. In this paper, the roles of H2O2 and NO on salvianolic acid B (Sal B) production in salicylic acid (SA)-induced Salvia miltiorrhiza cell cultures were investigated. The results showed that H2O2 could be significantly elicited by SA, even though IMD (an inhibitor of NADPH oxidase) or DMTU (a quencher of H2O2) were employed to inhibit or quench intracellular H2O2. These elicited H2O2 levels significantly increased NO production by 1.6- and 1.46 fold in IMD+SA and DMTU+SA treatments, respectively, and induced 4.58- and 4.85-fold Sal B accumulation, respectively. NO was also markedly elicited by SA, in which L-NNA (an inhibitor of NO synthase) and cPTIO (a quencher of NO) were used to inhibit or quench NO within cells, and the induced NO could significantly enhance H2O2 production by 1.92- and 1.37-fold in L-NNA+SA and cPTIO+SA treatments, respectively, and 3.27- and 1.50-fold for Sal B accumulation, respectively. These results indicate that elicitation of SA for either H2O2 or NO was independent, and the elicited H2O2 or NO could act independently or synergistically to induce Sal B accumulation in SA-elicited cells. PMID- 24815311 TI - Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light. AB - Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite their direct correlation with the in vivo efficacy. In the current research, we have established and validated a stability-indicating HPLC method for the detection of TQ and its degradation products under different conditions. We then investigated the solubility and stability profiles of TQ in aqueous solutions. The stability study was aimed to determine the effect of pH, solvent type and light on the degradation process of TQ, along with the investigation of the kinetics of this degradation. The solubility of TQ varied in different aqueous solvents, and might be compromised due to stability issues. However, these findings confirm that the aqueous solubility is not the major obstacle for the drug formulations mainly due to the considerable water solubility (>500 MUg/mL) that may be enough to exert pharmacologic effects if administered via parenteral route. Stability study results showed a very low stability profile of TQ in all the aqueous solutions with rapid degradation that varied with solvent type. The study of the degradation kinetics showed a significant effect of pH on the degradation process. The process followed first order kinetics at more acidic and alkaline pH values, and second order kinetics at pH 5-7.4, regardless of the solvent type. The results also expressed that light has a greater impact on the stability of TQ as a shorter period of exposure led to severe degradation, independent of the solution pH and solvent type. Our results also addressed some discrepancies in previously published researches regarding the formulation and quantification of TQ with suggested solutions. Overall, the current study concludes that TQ is unstable in aqueous solutions, particularly at an alkaline pH, in addition to presenting severe light sensitivity. This data indicates the inappropriateness of aqueous solutions as pharmaceutical vehicles for TQ preparations. To the best of our knowledge, this is the first study describing TQ aqueous solubility and stability that may lead to the development of a stable and effective TQ formulation. PMID- 24815312 TI - Effect of zinc on anammox activity and performance of simultaneous partial nitrification, anammox and denitrification (SNAD) process. AB - In the present study, short-term effects of zinc on anammox activities and long term effect of zinc on the performance of simultaneous partial nitrification, anammox and denitrification (SNAD) process were evaluated. The anammox activity decreased with increasing zinc concentration and exposure time in short-term tests. The IC50 value of zinc was found to be 6.9mg/L. However, the presence of zinc (<10mg/L) in wastewater stimulated the microbial activities and nitrogen removal performance of SNAD process in sequencing batch biofilm reactor (SBBR). At first, inhibition of SNAD process was observed when influent zinc concentration increased to 20mg/L. The system recovered immediately, suggesting the acclimatization of microbial communities of SNAD process. The results showed that SBBR was well acclimatized under high zinc concentration (50-100mg/L) achieving 98% NH4(+)-N, 96% TN and 87% COD removal efficiencies. PMID- 24815314 TI - Hippocampus-dependent learning in SKAP-HOM deficient mice. AB - SKAP-HOM is an adapter protein which regulates the cross-talk between immunoreceptors and integrins and is involved in signal transduction. It is present in murine brain structures such as the hippocampus, frontal cortex, and cerebellum. In the present study we investigated types of hippocampus-dependent learning (fear conditioning, social memory, and the Morris Water Maze) and locomotor sensitization to amphetamine in transgenic SKAP-HOM deficient mice (-/ ) in comparison with respective controls (+/+). Animals from both groups showed comparable fear conditioning, and the extinction of conditioned fear was accelerated in -/-. In terms of sociability, there were no differences between the animals, but in -/- mice social memory was impaired. There was no difference between the two groups of mice in spatial learning and memory measured in the Morris Water Maze. Wild-type and deficient animals exhibited similar sensitization to amphetamine. In reaction to amphetamine challenge, the response in +/+ was enhanced. It was hypothesized that SKAP-HOM deficiency does not affect hippocampus-dependent learning in general, but that its effects on cognitive tasks seem to be dependent on the nature of the cognitive task, i.e. spatial vs. non-spatial. PMID- 24815313 TI - Role of D1 dopamine receptors of the ventral pallidum in inhibitory avoidance learning. AB - The mesolimbic dopaminergic system (MLDS) originating from the ventral tegmental area has important role in the regulation of motivation, learning and memory. The ventral pallidum (VP), innervated by the MLDS, is involved in the regulation of adaptive behavior, but its exact role is not known in inhibitory avoidance learning. The VP contains both D1 and D2 dopamine receptors, but the density of the former subtype is more excessive. Therefore, in our present experiments, the role of D1 dopamine receptors of the VP in one trial step-through inhibitory avoidance paradigm was investigated. In the conditioning trial, animals were shocked 3 times with 0.5 mA current for 1s, and subsequently were microinjected bilaterally with D1 dopamine receptor agonist SKF38393 into the VP in three doses (0.1 MUg, 1.0 MUg or 5.0 MUg in 0.4 MUl saline). To clarify whether the agonist effect was specific, we also applied the D1 dopamine receptor antagonist SCH23390 (5.0 MUg in 0.4 MUl saline) 15 min prior the agonist treatment. The D1 dopamine receptor agonist, in a dose-dependent manner, significantly increased the step through latency during the test trials: retention was significant relative to the controls even after 2 weeks of conditioning. The D1 dopamine receptor antagonist SCH23390 pretreatment eliminated SKF38393 effects in the ventral pallidum. Our results show that D1 dopamine receptor mediated mechanisms in the VP facilitate learning and memory in inhibitory avoidance paradigm and this facilitation is specific because it can be eliminated by D1 dopamine receptor antagonist. PMID- 24815315 TI - Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance? AB - Depression and diabetes are serious diseases with an increasing global prevalence. Intriguingly, recent meta-analyses have highlighted an asymmetrical relationship between the two conditions as depressed patients were found to display a higher risk of developing type 2 diabetes than those individuals suffering from diabetes are to become depressed. Based on recent findings, we favor a hypothesis where by decreased peripheral serotonin (5-HT) transporter (5 HTT) function is a reciprocal risk factor for the co-morbidity of depression and diabetes, as it can trigger inflammatory pathogenetic mechanisms of both conditions. Higher intestinal levels of 5-HT and 5-HT3 receptor stimulation lead to increased intestinal permeability in 5-HTT deficient mice, which is viewed one of the most relevant animal models of depression. We hypothesize that this leakage of bacterial endotoxins can activate both central and peripheral Toll like receptor 4 (TLR4), which inhibits insulin signaling and IRS1/PI3K/Akt and thus, contribute to the pathogenesis of diabetes and depression that are associated with this pathway. Antidepressant therapies, which also suppress intestinal 5-HTT, may have potentiating effects on the association between depression and diabetes. It is also of interest that high carbohydrate and fat intake ("cafeteria-type diet") increases intestinal 5-HT leading to TLR4 activation. Thus, endotoxaemia and inflammation owing to increased intestinal 5 HT may underpin the depression and diabetes association, where the risk of the latter pathology becomes particularly preeminent after the onset of depression and not vice versa. The evidence presented here shows the further investigation into peripheral mechanisms that linked diabetes to depression is clearly warranted. PMID- 24815316 TI - Adolescent rats are more prone to binge eating behavior: a study of age and obesity as risk factors. AB - Binge eating (BE) is characterized by repeated, intermittent over-consumption of food in a brief period of time. This study aims to advance the understanding of potential risk factors for BE such as obesity, overeating and adolescence as an age group. We used the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a genetic overeating-induced obesity model with increased preferences for sweet and fat. Adolescent and adult rats from both strains (OLETF and the lean control strain, Long Evans Tokushima Otsuka [LETO]) received limited access to a palatable liquid diet (Ensure vanilla) for three weeks. Water and chow were available throughout the study, but access to Ensure was limited to two hours, three times a week (3TW group) or every work day (5TW group). As expected, OLETF rats consumed more Ensure and were more BE-prone (BEP) than LETO rats at both ages. Adolescent rats showed a significantly larger binge size as demonstrated by a greater increase in Ensure intake, compared to adults. Furthermore, while the adults reduced their chow intake, compensating for increased Ensure intake, the adolescents increased their chow intake too. Finally, the adolescent rats showed binge like behavior earlier in the study and they tended to be BEP more than the adults. Our findings in rats suggest that adolescents and in particular obese adolescents are at risk for BE, and BE can lead to overweight, thus providing the basis for examination of biological mechanisms of this process in animal models. PMID- 24815317 TI - Phosphagen kinase in Schistosoma japonicum: II. Determination of amino acid residues essential for substrate catalysis using site-directed mutagenesis. AB - Phosphagen kinases (PKs) play major roles in the regulation of energy metabolism in animals. Creatine kinase (CK) is the sole PK in vertebrates, whereas several PKs are present in invertebrates. We previously identified a contiguous dimer taurocyamine kinase (TK) from the trematode Schistosoma japonicum (Sj), a causative agent of schistosomiasis. SjTK contiguous dimer is comprised of domain 1 (D1) and domain 2 (D2). In this study, we used SjTK contiguous dimer (SjTKD1D2) or truncated single-domain constructs (SjTKD1 or SjTKD2) and employed site directed mutagenesis to investigate the enzymatic properties of TK mutants. Mutation in SjTKD1 or SjTKD2 (D1E222G or D2E225G) caused complete loss of activity for the substrate taurocyamine. Likewise, a double mutant (D1E222GD2E225G) in the contiguous dimer (D1D2) exhibited complete loss of activity for the substrate taurocyamine. However, catalytic activity in the contiguous dimer remained in both of D1 inactive mutant (D1D2D1E222G) and D2 inactive mutant (D1D2D2E225G), suggesting that efficient catalysis of SjTKD1D2 is dependent on the activity of D1 and D2. The catalytic efficiency of the mixture of both single domains (WTD1+WTD2) showed same enzymatic properties (Km(Tauro)=0.68;Vmax/Km(Tauro)=137.04) to WTD1D2 (Km(Tauro)=0.47; Vmax/Km(Tauro)=144.30). This result suggests that the contiguous dimeric structure is not essential for the catalytic efficiencies of both domains of SjTK. Vmax/Km(Tauro) of the mixture of wild-type and inactivated domains (78.02 in WTD1+D2E225G and 128.24 in D1E222G+WTD2) were higher than the corresponding mutants (47.25 in D1D2D1E222G and 46.77 in D1D2D2E225G). To identify amino acid residues that are critical for taurocyamine binding, we performed alanine scanning mutagenesis at positions 57-63 on the guanidino specificity (GS) region of the SjTKD1, which is considered to be involved in guanidino-substrate recognition. R63A and R63Y mutants lost activity for taurocyamine, suggesting that these residues are associated with taurocyamine binding. In addition, we investigated the role of Tyr84 in D1 and found an association with substrate alignment. The Y84 residue was replaced with R, H, K, I, A, and G. Although the activities of each mutant were decreased (Vmax=2.36-67.50MUmolPi/min/mgprotein), Y84 mutants possess binding affinity for taurocyamine (Km(Tauro)=3.19-10.04mM). The D1Y84R, D1Y84H, D1Y84K, and D1Y84A mutants exhibited low activity for taurocyamine, whereas the D1Y84I and D1Y84G mutants exhibited slightly decreased activity compared with the other Y84 mutants. The D1Y84K mutant lost substrate synergy between taurocyamine and ATP, suggesting that this mutation moves the position of the GS loop, similar to that of lombricine kinase (LK), and interferes with taurocyamine binding. This is the first comprehensive investigation of essential amino acid residues for substrate catalysis in trematode TK. PMID- 24815319 TI - Mechanical tunability via hydrogen bonding in metal-organic frameworks with the perovskite architecture. AB - Two analogous metal-organic frameworks (MOFs) with the perovskite architecture, [C(NH2)3][Mn(HCOO)3] (1) and [(CH2)3NH2][Mn(HCOO)3] (2), exhibit significantly different mechanical properties. The marked difference is attributed to their distinct modes of hydrogen bonding between the A-site amine cation and the anionic framework. The stronger cross-linking hydrogen bonding in 1 gives rise to Young's moduli and hardnesses that are up to twice those in 2, while the thermal expansion is substantially smaller. This study presents clear evidence that the mechanical properties of MOF materials can be substantially tuned via hydrogen bonding interactions. PMID- 24815318 TI - Patch testing with a textile dye mix--a multicentre study. AB - BACKGROUND: Disperse dyes are well-known contact sensitizers. However, they are not included in the majority of commercially available baseline patch test series. OBJECTIVES: To investigate the outcome of patch testing with a textile dye mix (TDM) consisting of eight disperse dyes at dermatology clinics in various countries. PATIENTS/MATERIALS/METHODS: Two thousand nine hundred and seven consecutive dermatitis patients at 12 dermatology clinics representing nine countries were tested with a TDM at 6.6%, consisting of Disperse Blue 35, Disperse Yellow 3, Disperse Orange 1 and 3, and Disperse Red 1 and 17, all at 1.0%, and Disperse Blue 106 and Disperse Blue 124, each at 0.3%, provisionally included in the baseline series. Eighty-seven per cent of the patients allergic to the TDM were also tested with the eight separate dyes. RESULTS: Contact allergy to TDM was found in 108 patients (3.7%). The frequency of contact allergy varied from 2.1% to 6.9% in different centres. Simultaneous reactivity to p phenylenediamine was found in 57 of the TDM-positive patients (53%). The most frequent dye allergen among the TDM-positive patients was Disperse Orange 3. The contact allergy could have explained or contributed to the dermatitis in approximately one-third of the patients for whom clinical relevance of the TDM contact allergy was recorded. CONCLUSIONS: The TDM should be considered for inclusion in the European baseline series. PMID- 24815320 TI - cAMP protects acute promyelocytic leukemia cells from arsenic trioxide-induced caspase-3 activation and apoptosis. AB - More recently, arsenic trioxide (ATO), was integrated into acute promyelocytic leukemia (APL) treatment, showing high efficacy and tolerability in patients with both ATRA-sensitive and ATRA-resistant APL. ATO could induce apoptosis at relatively high concentrations (0.5 to 2.0 micromol/L) and partial differentiation at low concentrations (0.1 to 0.5 micromol/L) in leukemic promyelocytes. It is known that cAMP agonists enhance low-dose ATO-induced APL cells differentiation. Less well appreciated was the possible interaction between relatively high-doses of ATO and enhanced levels of cAMP in APL cells. Here, we show that elevation of cAMP levels by forskolin inhibited ATO-mediated apoptosis in APL-derived NB4 cells, and this inhibition could be averted by cell permeable cAMP-dependent protein kinase inhibitor (14-22) amide. Inactivating phosphorylation of the proapoptotic protein Bad at Ser118 and phosphorylation of the CREB proto-oncogene at Ser133 were observed upon elevation of cAMP levels in NB4 cells. Phosphorylation of these PKA target proteins is known to promote cell survival in AML cells. The ability of cAMP to endow the APL cells with survival advantage is of particular importance when cAMP agonists may be considered as adjuncts to APL therapy. PMID- 24815321 TI - Novel mixed NOP/MOP agonist BU08070 alleviates pain and inhibits gastrointestinal motility in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms. AB - The opioid and nociceptin systems play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of BU08070, a novel mixed MOP/NOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo in physiological conditions and in animal models mimicking symptoms of irritable bowel syndrome (IBS), including diarrhea and abdominal pain. The effect of BU08070 on muscle contractility in vitro was characterized in the ileum and colon. To assess the effect of BU08070 in vivo, the following parameters were assessed: whole GI transit, gastric emptying, geometric center, colonic bead expulsion, fecal pellet output and time to castor oil-induced diarrhea. The antinociceptive activity of BU08070 was characterized in the mustard oil (MO)-induced abdominal pain model and the writhing test, alone and in the presence of MOP and NOP antagonists. in vitro, BU08070 (10(-10)-10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent manner. in vivo, BU08070 prolonged the whole GI transit and inhibited colonic bead expulsion. The antitransit and antidiarrheal effects of BU08070 were observed already at the dose of 0.1 mg/kg (i.p.). BU08070 reversed hypermotility and reduced pain in mouse models mimicking IBS-D symptoms. Our results suggest that BU08070 has a potential of becoming an efficient drug in IBS-D therapy. Here we also validate mixed NOP/MOP receptor targeting as possible future treatment of functional GI diseases. PMID- 24815323 TI - Decreased thalamic volumes in adolescent inhalant users from Korea and Australia. AB - OBJECTIVES: Research investigating the impact of inhalant misuse on brain structure suggests abnormalities in subcortical regions. We investigated the association between inhalant misuse and subcortical brain volumes in adolescents. METHODS: Based on a collaborative dataset from South Korea (inhalant users: N = 15, mean age = 16.7, SD = 1.1; controls: N = 15, mean age = 15.4, SD = 1.2) and Australia (inhalant users: N = 7, mean age = 18.2, SD = 1.4; controls: N = 7, mean age = 18.9, SD = 2.6), the volumes of caudate nucleus, putamen, pallidum, amygdala, hippocampus, and thalamus were estimated in adolescent inhalant users and healthy adolescents using FreeSurfer. RESULTS: The results revealed a significantly decreased right thalamic volume in adolescent inhalant users (P = 0.042), along with a trend-level decrease in left thalamic volume (P = 0.061). A negative correlation (r = -0.544; P = 0.036) between thalamic volume and severity of inhalant use (i.e., reduced volumes associated with greater use) was identified among Korean participants. CONCLUSIONS: These findings suggest that compared with other subcortical structures, the thalamus is particularly sensitive to damage following chronic inhalant exposure during adolescence. PMID- 24815322 TI - Behavioral and cellular pharmacology characterization of 17-cyclopropylmethyl 3,14beta-dihydroxy-4,5alpha-epoxy-6alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) as a mu opioid receptor selective ligand. AB - Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14beta dihydroxy-4,5alpha-epoxy-6alpha-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) and the kappa opioid receptor (KOR). Its central nervous system penetration capacity together with marginal agonism in the MOR GTPgammaS binding assay made it a very interesting molecule for developing novel opioid abuse and addiction therapeutic agents. Therefore, further pharmacological characterization was conducted to fully understand its biological profile. At the molecular and cellular level, NAQ not only induced no translocation of beta arrestin2 to the MOR, but also efficaciously antagonized the effect of DAMGO in MOR-betaarr2eGFP-U2OS cells in the beta-arrestin2 recruitment assay. At the in vivo level, NAQ displayed a potent inhibition of the analgesic effect of morphine in the tail-flick assay (ID50=1.19 mg/kg). NAQ (10 mg/kg) also significantly decreased the hyper-locomotion induced by acute morphine without inducing any vertical jumps. Meanwhile NAQ precipitated lesser withdrawal symptoms in morphine dependent mice than naloxone. In conclusion, NAQ may represent a new chemical entity for opioid abuse and addiction treatment. PMID- 24815324 TI - The Medicago truncatula hypermycorrhizal B9 mutant displays an altered response to phosphate and is more susceptible to Aphanomyces euteiches. AB - Inorganic phosphate (Pi) plays a key role in the development of arbuscular mycorrhizal (AM) symbiosis, which is favoured when Pi is limiting in the environment. We have characterized the Medicago truncatula hypermycorrhizal B9 mutant for its response to limiting (P/10) and replete (P2) Pi. On P2, mycorrhization was significantly higher in B9 plants than in wild-type (WT). The B9 mutant displayed hallmarks of Pi-limited plants, including higher levels of anthocyanins and lower concentrations of Pi in shoots than WT plants. Transcriptome analyses of roots of WT and B9 plants cultivated on P2 or on P/10 confirmed the Pi-limited profile of the mutant on P2 and highlighted its altered response to Pi on P/10. Furthermore, the B9 mutant displayed a higher expression of defence/stress-related genes and was more susceptible to infection by the root oomycete pathogen Aphanomyces euteiches than WT plants. We propose that the hypermycorrhizal phenotype of the B9 mutant is linked to its Pi-limited status favouring AM symbiosis in contrast to WT plants in Pi-replete conditions, and discuss the possible links between the altered response of the B9 mutant to Pi, mycorrhization and infection by A. euteiches. PMID- 24815325 TI - Multiplex protein analysis to determine fibrosis stage and progression in patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Noninvasive tests cannot differentiate between adjacent stages of fibrosis, which limits assessment of disease progression and regression during therapy. We investigated whether levels of cytokines and extracellular matrix proteins in serum and biopsy samples can be used to determine actual stage of liver fibrosis in patients with chronic hepatitis C (CHC) and in prognosis. METHODS: We collected data from 383 treatment-naive patients with CHC from the Duke Hepatology Clinical Research Database and Biorepository, from 2006 through 2009, for use in the training set. Serum samples were obtained from 100 individuals without CHC (controls). We selected 37 serum biomarkers for customized array analysis by using the SearchLight multiplex sandwich enzyme linked immunosorbent assay. Data from 434 treatment-naive patients with CHC, which were obtained from the Trent HCV cohort, were used in the validation analysis. Multivariable modeling, marker selection, and validation included randomForest and Obuchowski measures, with independent comparison with FibroSURE. RESULTS: Four serum markers (levels of hyaluronic acid, vascular cell adhesion molecule 1, alpha-2 macroglobulin, and retinol-binding protein 4) and age associated with fibrosis stage (F0-1, F2-3, or F4); these had Obuchowski measures of 0.85-0.89, with misclassification rates of 38% and 29% in training and validation sets, compared with 50% for the FibroSURE test. In the training set, area under the curve values for the multiplex markers were similar to those from the FibroSURE test: stages F0 vs F1 (0.51 vs 0.53), F1 vs F2 (0.60 vs 0.59), F2 vs F3 (0.69 vs 0.72), and F3 vs F4 (0.51 vs 0.52). Area under the curve values were similar in the validation cohort. In longitudinal analyses of 133 paired biopsies, 9 markers (level of alanine aminotransferase, gamma glutamyltransferase, hyaluronic acid, intracellular adhesion molecule 1, interleukin 4, CXCL10, CXCL9, and vascular cell adhesion molecule 1) were associated with change in the histologic activity index (P values ranging from .000 to .049), and 4 (granulocyte-macrophage colony-stimulating factor, interleukin 12, interleukin 2, and matrix metalloproteinase 13) were associated with a change in fibrosis stage (P values ranging from .001 to .042). CONCLUSIONS: We identified serum biomarkers that can be measured by multiplex enzyme-linked immunosorbent assay to determine levels of fibrosis in patients with CHC, although misclassification is frequent and results are comparable with those from the FibroSURE test. Changes in protein levels in biopsy samples were associated with progression of fibrosis in patients. PMID- 24815327 TI - Risk of and factors associated with readmission after a sentinel attack of acute pancreatitis. AB - BACKGROUND & AIMS: Few data are available on how many patients are readmitted to the hospital after attacks of acute pancreatitis. We aimed to determine the risk and factors that determine early (within 30 days) and late (after 30 days) readmission of patients with acute pancreatitis. METHODS: In a retrospective study, we collected and analyzed data on 127 surviving patients (median age, 53 y; 52% male; 83% white) hospitalized at the University of Pittsburgh Medical Center for a sentinel attack of acute pancreatitis, enrolled in the Severe Acute Pancreatitis Study from June 2003 through April 2010, and who had follow-up data. Information was collected on demographics, clinical profile, risk score at discharge (based on a recently developed scoring system), and details of readmissions during the follow-up period (median, 36 mo). RESULTS: Of the 127 patients, 52% were transfers from another care center and 32% required admission to the intensive care unit. Etiologies for pancreatitis were biliary (47%), idiopathic (13%), alcohol associated (12%), and others (28%). Pancreatic necrosis (28%), persistent organ failure (27%), and peripancreatic fluid collections (19%) were common. The median length of stay was 9 days. A total of 108 readmissions occurred for 43 patients (34%). Early readmissions (n = 21) occurred more frequently for patients with smoldering (ongoing) symptoms or local complications than for those without. Late readmissions (n = 22) occurred more frequently for patients with recurrent pancreatitis than for those without. Male sex, alcohol associated disease, and severe disease increased the risks of readmission and recurrence. The risk for readmission was lower among nontransferred patients (23%) and patients without necrosis or organ failure (16%). Risk for readmission increased with the number of points on the weighted scoring system. CONCLUSIONS: Approximately one-third of patients hospitalized for acute pancreatitis are readmitted, usually as a result of smoldering symptoms, local complications, or recurrent attacks. Studies are needed to determine whether individualized discharge planning, with consideration of the etiology of acute pancreatitis, can reduce the risk for readmission. PMID- 24815326 TI - The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: We investigated the effects of the fatty acid-bile acid conjugate 3beta-arachidyl-amido, 7alpha-12alpha-dihydroxy, 5beta-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function. RESULTS: No serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% +/- 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% +/- 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% +/- 28.22%, but this change was nonsignificant (P = .35), indicating a dose-response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis. CONCLUSIONS: Three months' administration of the fatty acid-bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158. PMID- 24815328 TI - No decrease in the rate of early or missed colorectal cancers after colonoscopy with polypectomy over a 10-year period: a population-based analysis. AB - BACKGROUND & AIMS: It is not clear whether the incidence of missed or early colorectal cancers (CRCs) has decreased over time. We compared the rates of missed or early CRC after polypectomy between 1996 and 2006, and aimed to identify risk factors for these. METHODS: We performed a population-based, case control study linking data from the Dutch Pathology Registry with data from The Netherlands Cancer Registry. Of all patients with an incident CRC in 1996 and 2006, we identified whether colonic histology specimens were available in the preceding 3 years. Patients with early or missed CRC were defined as those with previous colonic histology in the 6 to 36 months preceding CRC diagnosis. We performed multivariate logistic regression analysis to identify factors associated with missed or early CRCs. RESULTS: CRC was diagnosed in 6941 patients in 1996 and in 10,963 patients in 2006. The proportion of patients with early or missed CRC was 1.7% of all CRC patients in 1996 and 2.3% in 2006 (P = .012). Early or missed CRCs had a lower tumor, nodal, and metastasis stage than regularly diagnosed CRCs (P < .001), but rate of survival, adjusted for TNM stage, did not differ. CRCs of the right colon and transverse colon and splenic flexure were associated with a missed or early CRC (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.80-3.05; and OR, 2.14; 95% CI, 1.49-3.08, respectively), as was male sex (OR, 1.31; 95% CI, 1.06-1.62). CONCLUSIONS: Based on an analysis of the Dutch population, there has been no decrease in the occurrence of missed or early CRCs over a 10-year period. Location in the right side of the colon was an independent risk factor for missed or early CRCs. PMID- 24815329 TI - Durability and predictors of successful radiofrequency ablation for Barrett's esophagus. AB - BACKGROUND & AIMS: After radiofrequency ablation (RFA), patients may experience recurrence of Barrett's esophagus (BE) after complete eradication of intestinal metaplasia (CEIM). Rates and predictors of recurrence after successful eradication have been poorly described. METHODS: We used the US RFA Registry, a nationwide registry of BE patients receiving RFA, to determine rates and factors that predicted recurrence of intestinal metaplasia (IM). We assessed recurrence by Kaplan-Meier analysis for the overall cohort and by worst pretreatment histology. Characteristics associated with recurrence were included in a logistic regression model to identify independent predictors. RESULTS: Among 5521 patients, 3728 had biopsies 12 months or more after initiation of RFA. Of these, 3169 (85%) achieved CEIM, and 1634 (30%) met inclusion criteria. The average follow-up period was 2.4 years after CEIM. IM recurred in 334 (20%) and was nondysplastic or indefinite for dysplasia in 86% (287 of 334); the average length of recurrent BE was 0.6 cm. In Kaplan-Meier analysis, more advanced pretreatment histology was associated with an increased yearly recurrence rate. Compared with patients without recurrence, patients with recurrence were more likely, based on bivariate analysis, to be older, have longer BE segments, be non-Caucasian, have dysplastic BE before treatment, and require more treatment sessions. In multivariate analysis, the likelihood for recurrence was associated with increasing age and BE length, and non-Caucasian race. CONCLUSIONS: BE recurred in 20% of patients followed up for an average of 2.4 years after CEIM. Most recurrences were short segments and were nondysplastic or indefinite for dysplasia. Older age, non-Caucasian race, and increasing length of BE length were all risk factors. These risk factors should be considered when planning post-RFA surveillance intervals. PMID- 24815330 TI - Effects of fatigue from sleep deprivation on experimental periodontitis in rats. AB - BACKGROUND AND OBJECTIVE: Factors such as vascularization of the periodontium, inflammatory reactions and immune response affect the oral environment and ecology, decreasing host resistance and promoting the development of symptoms and the advancement of periodontal disease. Fatigue also influences the hypothalamic pituitary-adrenal axis and reports relate it to systemic resistance. The aim of this study was to evaluate whether fatigue is a modifying factor for periodontal disease in rats. MATERIAL AND METHODS: We divided 24 3-wk-old male Sprague-Dawley rats randomly into the following four groups: control; fatigue (deep sleep deprivation for 7 d); infection (rats inoculated with carboxymethyl cellulose containing periodontopathic bacteria); and compound (combined fatigue and infection conditions). Weight, serum corticosterone levels, serum albumin levels, interleukin-1beta and tumor necrosis factor-alpha expression levels and distance from the cement-enamel junction to the alveolar bone crest were measured at baseline, and on the 36th (before sleep deprivation), 43rd (immediately after sleep deprivation) and 57th d (end of experiment). RESULTS: Immediately after sleep deprivation and at the end of the experiment, weight gain in the fatigue and compound groups was significantly lower than in controls (p < 0.05). Immediately after sleep deprivation, serum corticosterone levels were significantly higher in the fatigue and compound groups than in controls (p < 0.05). Moreover, serum albumin levels were significantly lower in the fatigue and compound groups than in controls (p < 0.05). Immediately after sleep deprivation, gene expression of interleukin-1beta was significantly higher in the infection and compound groups than in controls (p < 0.05). Moreover, gene expression of tumor necrosis factor-alpha was significantly higher in the compound group than in controls (p < 0.05). At the end of the experiment, the distance from the cement-enamel junction to the alveolar bone crest was significantly higher in the infection and compound groups than in controls (p < 0.05). Moreover, the distance was significantly higher in the compound group than in the infection group. CONCLUSIONS: Fatigue worsened systemic health in rats and increased gingival inflammation and alveolar bone loss in experimental periodontitis. In conclusion, our results suggest that fatigue is a modifying factor for periodontal disease in rats. PMID- 24815332 TI - Prevalence of methicillin resistant Staphylococcus aureus among Egyptian patients after surgical interventions. AB - BACKGROUND: Staphylococcus aureus (S. aureus) is isolated frequently from surgical site infections and other soft tissue infections. There are limited data examining the prevalence of methicillin resistant S. aureus (MRSA) among Egyptian patients after surgery. The current study determined the prevalence of MRSA isolated from surgical site and soft tissue infections at Minia University Hospital (MUH), determined their susceptibility to beta-lactams and other antimicrobials, and examined their mecA gene expression. METHODS: A total of 208 hospitalized patients attending the General Surgery Department at MUH were enrolled and all had skin and soft tissue infections (SSTIs) of different causes. These 208 patients (143 males and 65 females) were suffering from surgical site infection (SSI; n=82), diabetic foot (n=52), abscess (n=45), or burn (n=29) infections. Samples were cultured on different media for isolation and identification of S. aureus and the isolates were screened for antibiotic susceptibility. All MRSA isolates were tested by polymerase chain reaction to detect the mecA gene responsible for methicllin resistance. RESULTS: 241 Staphylococcal species represented the most common isolates (64.8%) among 371 collected isolates from the 208 patients. Out of the 241 staphylococcal isolates, 127 were S. aureus (61% of the total patients). The prevalence of S. aureus among SSI, diabetic foot, abscess, and burn patients were 59%, 75%, 56%, and 52%, whereas that of MRSA was 16%, 17%, 13%, and 10%, respectively. MRSA isolates (n=31; 15% of patients) showed multiple resistance to at least one member of the antimicrobial groups tested with an average resistance to 6.6+/-1.9 antimicrobial groups. Polymerase chain reaction data showed that only 29 isolates of the MRSA isolates (94%) were positive for mecA gene. CONCLUSIONS: Staphylococcus aureus isolates are the major pathogens responsible for wound and surgical site infections at MUH and MRSA are a potential threat for wound patients in Egypt. PMID- 24815331 TI - Hematopoietic not systemic impairment of Roquin expression accounts for intestinal inflammation in Roquin-deficient mice. AB - Roquin, an E3 ligase, is involved in curtailing autoimmune pathology as seen from studies using mice with mutated (Rc3h1(san/san)) or disrupted (Rc3h1(gt/gt)) Rc3h1 gene. The extent to which intestinal immunopathology is caused by insufficient Roquin expression in the immune system, or by Roquin impairment in non-hematopoietic cells, has not been determined. Using bone marrow cells from Rc3h1(gt/gt) mice transferred into irradiated normal mice (Rc3h1(gt/gt) -> NL chimeras), we show that inflammation developed in the small intestine, kidney, lung, liver, and spleen. Proinflammatory cytokine levels were elevated in lamina propria lymphocytes (LPLs). Inflammation in the liver was accompanied by areas of hepatocyte apoptosis. Lung inflammation consisted of an influx of both T cells and B cells. Small intestinal LPLs had increased numbers of CD44(hi), CD62L(lo), KLRG1(+), ICOS(+) short-lived effector cells, indicating an influx of activated T cells. Following oral infection with L. monocytogenes, Rc3h1(gt/gt) -> NL chimeras had more liver pathology and greater numbers of bacteria in the Peyer's patches than NL -> NL chimeras. These findings demonstrate that small intestinal inflammation in Rc3h1(san/san) and Rc3h1(gt/gt) mice is due to a failure of Roquin expression in the immune system and not to insufficient systemic Roquin expression. PMID- 24815333 TI - The effects of summer temperature and heat waves on heat-related illness in a coastal city of China, 2011-2013. AB - BACKGROUND: Devastating health effects from recent heat waves in China have highlighted the importance of understanding health consequences from extreme heat stress. Despite the increasing mortality from extreme heat, very limited studies have quantified the effects of summer extreme temperature on heat-related illnesses in China. METHODS: The associations between extreme heat and daily heat related illnesses that occurred in the summers of 2011-2013 in Ningbo, China, have been examined, using a distributed lag non-linear model (DLNM) based on 3862 cases. The excess morbidities of heat-related illness during each heat wave have been calculated separately and the cumulative heat wave effects on age-, sex-, and cause-specific illnesses in each year along lags have been estimated as well. RESULTS: After controlling the effect of relative humidity, it is found that maximum temperature, rather than heat index, was a better predictor of heat related illnesses in summers. A positive association between maximum temperatures and occurrence of heat-related diseases was apparent, especially at short lag effects. Six heat waves during the period of 2011-2013 were identified and all associated with excess heat-related illnesses. Relative to the average values for the corresponding periods in 2011 and 2012, a total estimated 679 extra heat related illnesses occurred during three heat waves in 2013. The significant prolonged heat wave effects on total heat-related illnesses during heat waves in three study years have also been identified. The strongest cumulative effect of heat waves was on severe heat diseases in 2013, with a 10-fold increased risk. More males than females, individuals with more severe forms of illness, were more affected by the heat. However, all age groups were vulnerable. CONCLUSIONS: Recent heat waves had a substantial and delayed effect on heat illnesses in Ningbo. Relevant active well-organized public health initiatives should be implemented to reduce the adverse effects of heat extremes on the illnesses. PMID- 24815334 TI - Sensitization to Asian dust and allergic rhinoconjunctivitis. AB - OBJECTIVE: Asian dust storms frequently occur in northeast Asia and the dust occasionally even spreads as far as North America during spring. Asian dust can be harmful to human health and the environment, and thus has become one of the most serious problems for Asian countries. In the present study, we evaluated sensitization to Asian dust in Japanese patients with rhinoconjunctivitis. METHODS: In March 2011, a prospective, non-randomized, cross-sectional study was conducted in 10 patients with allergic rhinoconjunctivitis (allergic group), 3 patients with atopic keratoconjunctivitis (atopic group), and 10 age- and sex matched healthy control subjects (control group). Skin prick tests (SPT) were performed with untreated Asian dust, Asian dust extract, heat-sterilized Asian dust, silicon dioxide (SiO2), and phosphate-buffered saline (PBS). A panel of 14 allergen extracts was also tested, comprising extracts of pollens (cedar, orchard grass, ragweed, and mugwort), house dust (house dust mixture and Dermatophagoides pteronyssinus), animal dander (cat and dog), fungi (Alternaria tenuis, Candida, and Aspergillus), and foods (milk, egg, and wheat). Then the SPT-positive rate and the mean wheal diameter for each allergen were compared among the three groups. RESULTS: The SPT-positive rates for untreated Asian dust, Asian dust extract, and sterilized Asian dust were significantly higher in the allergic and atopic groups than in the control group (all p<0.05). In the allergic group, there were a significant differences of the SPT-positive rates for untreated Asian dust (70%), Asian dust extract (50%), sterilized Asian dust (20%), SiO2 (20%), and PBS (0%) (p=0.0068). The SPT response to untreated Asian dust was correlated with the mean wheal diameters for four plant pollens (r=0.71, p=0.0104) and for three fungi (r=0.57, p=0.0426). Multivariate logistic regression analysis showed that significant predictors of the SPT reaction to untreated Asian dust were the mean wheal diameter for the four plant pollen (odds ratio=2.54, p=0.0138) and that for the three fungi (odds ratio=1.84, p=0.0273). CONCLUSIONS: Asian dust may act as an adjuvant to promote allergic disease induced by inhaled allergens such as pollen and fungi. PMID- 24815335 TI - Impact of urine concentration adjustment method on associations between urine metals and estimated glomerular filtration rates (eGFR) in adolescents. AB - Positive associations between urine toxicant levels and measures of glomerular filtration rate (GFR) have been reported recently in a range of populations. The explanation for these associations, in a direction opposite that of traditional nephrotoxicity, is uncertain. Variation in associations by urine concentration adjustment approach has also been observed. Associations of urine cadmium, thallium and uranium in models of serum creatinine- and cystatin-C-based estimated GFR (eGFR) were examined using multiple linear regression in a cross sectional study of adolescents residing near a lead smelter complex. Urine concentration adjustment approaches compared included urine creatinine, urine osmolality and no adjustment. Median age, blood lead and urine cadmium, thallium and uranium were 13.9 years, 4.0 MUg/dL, 0.22, 0.27 and 0.04 g/g creatinine, respectively, in 512 adolescents. Urine cadmium and thallium were positively associated with serum creatinine-based eGFR only when urine creatinine was used to adjust for urine concentration (beta coefficient=3.1 mL/min/1.73 m(2); 95% confidence interval=1.4, 4.8 per each doubling of urine cadmium). Weaker positive associations, also only with urine creatinine adjustment, were observed between these metals and serum cystatin-C-based eGFR and between urine uranium and serum creatinine-based eGFR. Additional research using non-creatinine-based methods of adjustment for urine concentration is necessary. PMID- 24815336 TI - The co-inertia approach in identification of specific microRNA in early and advanced atherosclerosis plaque. AB - MicroRNAs (miRs) are short, non-coding RNAs that regulate gene expression by absolute or partial binding to mRNA, which results in transcript degradation and translation blocking. Atherosclerosis, as a complex and progressive disease, represents one of the main causes of cardiovascular clinical complications and even death. We applied co-inertia analysis (CIA) as a novel computation method, to determine which miRs are potentially associated with differences in gene expression levels originating from microarray data of early and advanced atherosclerotic plaque. As the CIA has not been applied in the field of atherosclerosis yet, we hypothesized that using CIA we can get novel information about the miRs that have significant role in early phase of disease or in severe phase of disease. The characteristic split in the data along the axes of performed CIA showed the difference in the gene expression pattern between early atherosclerosis and advanced atherosclerotic plaque. The advanced atherosclerotic plaques showed more homogenous gene expression pattern than early atherosclerosis samples. In early carotid lesions five out of five algorithms predicted miR-24, four out of five predicted miR-155, miR-145, and miR-100 as early active miRs. These miRs could be "protective" in plaque evolution context because they were not active in advanced plaques according to our results. They were reported previously as atheroprotective, which in a way represents confirmation of CIA application in atherosclerosis. We detected 13 new miRs which could be active in early plaque phenotype according to CIA prediction. In the advanced plaques we predicted miR-221, miR-222, miR-127 and miR-146 which were previously revealed to have atherogenic properties. In addition to miRs that have literature support, we also found new 8 miRs that, with described function so far, could present a novelty in research of atherosclerotic plaque evolution. All of these examples show that CIA results have a great potential to be of interest in future research in atherosclerotic plaque progression. We validated the applicability of CIA in the field of atherosclerosis, but we also found new interesting miR competitors that have strong potential to serve as markers and plaque development factors. These results should be experimentally confirmed in further research with ultimate goal to discover new mediators and blood markers, which could improve the prevention and therapy of this complex disease. PMID- 24815337 TI - Risperidone treatment in a case of Tourette syndrome with factor V Leiden heterozygous mutation. PMID- 24815338 TI - Normative data for the Rappel libre/Rappel indice a 16 items (16-item Free and Cued Recall) in the elderly Quebec-French population. AB - Performance on verbal memory tests is generally associated with socio-demographic variables such as age, sex, and education level. Performance also varies between different cultural groups. The present study aimed to establish normative data for the Rappel libre/Rappel indice a 16 items (16-item Free and Cued Recall; RL/RI-16), a French adaptation of the Free and Cued Selective Reminding Test (Buschke, 1984; Grober, Buschke, Crystal, Bang, & Dresner, 1988). The sample consisted of 566 healthy French-speaking older adults (50-88 years old) from the province of Quebec, Canada. Normative data for the RL/RI-16 were derived from 80% of the total sample (normative sample) and cross-validated using the remaining participants (20%; validation sample). The effects of participants' age, sex, and education level were assessed on different indices of memory performance. Results indicated that these variables were independently associated with performance. Normative data are presented as regression equations with standard deviations (symmetric distributions) and percentiles (asymmetric distributions). PMID- 24815339 TI - Residential proximity to electromagnetic field sources and birth weight: Minimizing residual confounding using multiple imputation and propensity score matching. AB - Studies have suggested that residential exposure to extremely low frequency (50 Hz) electromagnetic fields (ELF-EMF) from high voltage cables, overhead power lines, electricity substations or towers are associated with reduced birth weight and may be associated with adverse birth outcomes or even miscarriages. We previously conducted a study of 140,356 singleton live births between 2004 and 2008 in Northwest England, which suggested that close residential proximity (<= 50 m) to ELF-EMF sources was associated with reduced average birth weight of 212 g (95%CI: -395 to -29 g) but not with statistically significant increased risks for other adverse perinatal outcomes. However, the cohort was limited by missing data for most potentially confounding variables including maternal smoking during pregnancy, which was only available for a small subgroup, while also residual confounding could not be excluded. This study, using the same cohort, was conducted to minimize the effects of these problems using multiple imputation to address missing data and propensity score matching to minimize residual confounding. Missing data were imputed using multiple imputation using chained equations to generate five datasets. For each dataset 115 exposed women (residing <= 50 m from a residential ELF-EMF source) were propensity score matched to 1150 unexposed women. After doubly robust confounder adjustment, close proximity to a residential ELF-EMF source remained associated with a reduction in birth weight of -116 g (95% confidence interval: -224:-7 g). No effect was found for proximity <= 100 m compared to women living further away. These results indicate that although the effect size was about half of the effect previously reported, close maternal residential proximity to sources of ELF-EMF remained associated with suboptimal fetal growth. PMID- 24815340 TI - Maternal serum concentrations of per- and polyfluoroalkyl substances and their predictors in years with reduced production and use. AB - Determining maternal concentrations of per- and polyfluoroalkyl substances (PFASs) and the relative impact of various demographic and dietary predictors is important for assessing fetal exposure and for developing proper lifestyle advisories for pregnant women. This study was conducted to investigate maternal PFAS concentrations and their predictors in years when the production and use of several PFASs declined, and to assess the relative importance of significant predictors. Blood from 391 pregnant women participating in The Northern Norway Mother-and-Child Contaminant Cohort Study (MISA) was collected in the period 2007 2009 and serum analyses of 26 PFASs were conducted. Associations between PFAS concentrations, sampling date, and demographic and dietary variables were evaluated by multivariate analyses and linear models including relevant covariates. Parity was the strongest significant predictor for all the investigated PFASs, and nulliparous women had higher concentrations compared to multiparous women (10 ng/mL versus 4.5 ng/mL in median PFOS, respectively). Serum concentrations of PFOS and PFOA of women recruited day 1-100 were 25% and 26% higher, respectively, compared to those women recruited in the last 167 days of the study (day 601-867), and the concentrations of PFNA, PFDA and PFUnDA increased with age. Dietary predictors explained 0-17% of the variation in concentrations for the different PFASs. Significantly elevated concentrations of PFOS, PFNA, PFDA and PFUnDA were found among high consumers of marine food. The concentrations of PFHxS, PFHpS and PFNA were also increased in high consumers of game and elevated concentrations of PFHpS and PFOS were detected in high consumers of white meat. Study subjects with a high intake of salty snacks and beef had significantly higher concentrations of PFOA. The present study demonstrates that parity, sampling date and birth year are the most important predictors for maternal PFAS concentrations in years following a decrease in production and use of several PFASs. Further, dietary predictors of PFAS concentrations were identified and varied in importance according to compound. PMID- 24815341 TI - Spatial analysis of toxic emissions in LCA: a sub-continental nested USEtox model with freshwater archetypes. AB - This paper develops continent-specific factors for the USEtox model and analyses the accuracy of different model architectures, spatial scales and archetypes in evaluating toxic impacts, with a focus on freshwater pathways. Inter-continental variation is analysed by comparing chemical fate and intake fractions between sub continental zones of two life cycle impact assessment models: (1) the nested USEtox model parameterized with sub-continental zones and (2) the spatially differentiated IMPACTWorld model with 17 interconnected sub-continental regions. Substance residence time in water varies by up to two orders of magnitude among the 17 zones assessed with IMPACTWorld and USEtox, and intake fraction varies by up to three orders of magnitude. Despite this variation, the nested USEtox model succeeds in mimicking the results of the spatially differentiated model, with the exception of very persistent volatile pollutants that can be transported to polar regions. Intra-continental variation is analysed by comparing fate and intake fractions modelled with the a-spatial (one box) IMPACT Europe continental model vs. the spatially differentiated version of the same model. Results show that the one box model might overestimate chemical fate and characterisation factors for freshwater eco-toxicity of persistent pollutants by up to three orders of magnitude for point source emissions. Subdividing Europe into three archetypes, based on freshwater residence time (how long it takes water to reach the sea), improves the prediction of fate and intake fractions for point source emissions, bringing them within a factor five compared to the spatial model. We demonstrated that a sub-continental nested model such as USEtox, with continent-specific parameterization complemented with freshwater archetypes, can thus represent inter- and intra-continental spatial variations, whilst minimizing model complexity. PMID- 24815342 TI - Evaluating the application of multipollutant exposure metrics in air pollution health studies. AB - BACKGROUND: Health effects associated with air pollution are typically evaluated using a single pollutant approach, yet people are exposed to mixtures consisting of multiple pollutants that may have independent or combined effects on human health. Development of exposure metrics that represent the multipollutant environment is important to understand the impact of ambient air pollution on human health. OBJECTIVES: We reviewed existing multipollutant exposure metrics to evaluate how they can be applied to understand associations between air pollution and health effects. METHODS: We conducted a literature search using both targeted search terms and a relational search in Web of Science and PubMed in April and December 2013. We focused on exposure metrics that are constructed from ambient pollutant concentrations and can be broadly applied to evaluate air pollution health effects. RESULTS: Multipollutant exposure metrics were identified in 57 eligible studies. Metrics reviewed can be categorized into broad pollutant grouping paradigms based on: 1) source emissions and atmospheric processes or 2) common health outcomes. DISCUSSION: When comparing metrics, it is apparent that no universal exposure metric exists; each type of metric addresses different research questions and provides unique information on human health effects. Key limitations of these metrics include the balance between complexity and simplicity as well as the lack of an existing "gold standard" for multipollutant health effects and exposure. CONCLUSIONS: Future work on characterizing multipollutant exposure error and joint effects will inform development of improved multipollutant metrics to advance air pollution health effects research and human health risk assessment. PMID- 24815343 TI - A simple method to reduce the risk of cadmium exposure from consumption of Iceland scallops (Chlamys islandica) fished in Greenland. AB - This paper studied the levels and organ distribution of the toxic heavy metal cadmium in scallops from unpolluted Greenlandic waters. The scallops had an average cadmium concentration of 2.93 +/- 0.94 MUg/g wet weight in the total soft tissues and no concentration dependent effect was found for gender or size (both p>0.05). The kidney was the primary organ for cadmium accumulation with a mean of 226.2 +/- 111.7 MUg/g wet weight, and despite the small weight of the kidney, it appeared as the principal contributor of cadmium with 92% of the total cadmium body burden. The cadmium concentrations in the total soft tissues far exceeded the EU-limit of 1 MUg/g wet weight for cadmium in bivalves. Based on this, selective evisceration of the cadmium-rich kidney and digestive gland during processing can be regarded as a reliable measure to be taken in order to reduce the cadmium content of scallops used for human consumption. PMID- 24815344 TI - Stimulation and analysis of the immune response in calves from vaccinated pregnant cows. AB - The effect of vaccinating pregnant cows with an inactivated vaccine against Mannheimia haemolytica, BRSV and PI3V infections on selected immune responses in their offspring was examined. Blood samples were collected weekly for 12 weeks from six newborn calves from each of vaccinated (experimental) and unvaccinated (control) dams. Specific antibodies to M. haemolytica, BRSV and PI3V and mean values of IgA, IgG concentrations were significantly higher in the experimental calves compared with the controls. However, specific antibody titres to adenovirus type 3, BHV1 and BVDV in the experimental calves had constant levels while the control group levels changed. The IgM, Hp and SAA concentrations generally increased until week 8 in the experimental group, but the control group titres became higher after week 9. This study demonstrates that specific immunisation of cows pre-partum significantly stimulated parameters associated with immunity and it also controlled the acute phase response intensity in their offspring. Therefore the vaccination of dams may provide additional antibody protection against infection to their offspring. PMID- 24815345 TI - Inhibition of p16 tumor suppressor gene expression via promoter hypermethylation in canine lymphoid tumor cells. AB - To investigate the epigenetic regulation of the p16 gene in canine lymphoid tumor cells, its methylation status was examined in four canine lymphoid tumor cell lines. In three canine lymphoid tumor cell lines (CLBL-1, GL-1, and UL-1) with low-level p16 mRNA expression, 20 CpG sites in the promoter region of p16 gene were consistently methylated although all of the CpG sites were not methylated in another cell line (CL-1) and normal lymph node cells. The expression level of p16 mRNA in these three cell lines was restored after cultivation in the presence of a methylation inhibitor, 5-Aza-2'-deoxycitidine, indicating inactivation of p16 gene via hypermethylation. This study revealed the inactivation of p16 gene through hypermethylation of its CpG island in a fraction of canine lymphoid tumor cells. PMID- 24815346 TI - Charge templates in aromatic plus ionic liquid systems revisited: NMR experiments and molecular dynamics simulations. AB - The mutual solubilities of [C2C1im][Ntf2] ionic liquid and aromatic molecules (benzene and its fluorinated derivatives) can be correlated to the dipolar and quadrupolar moments of the latter molecules. This fact can be interpreted as a consequence of the charge-induced structuration of the IL ions around the aromatic molecules. In this paper we demonstrate that we can follow the above mentioned structural changes in the mixtures using different NMR-based techniques, namely 1D (1)H and (13)C NMR and 2D (1)H-(1)H NOESY NMR spectroscopy. These have been complemented by more detailed structural analyses of the different (IL plus aromatic solute) mixtures using MD simulations. Such systematic studies included eight systems, namely mixtures of the 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid with benzene, fluorobenzene, 1,2-difluorobenzene, 1,4-difluorobenzene, 1,3,5-trifluorobenzene, 1,2,4,5-tetrafluorobenzene, penta-fluorobenzene, and hexafluorobenzene. PMID- 24815347 TI - Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. AB - BACKGROUND: Factor XI (FXI) deficiency is a rare autosomal recessive disorder. Many patients with even very low FXI levels (< 20 IU dL(-1) ) are asymptomatic or exhibit only mild bleeding, whereas others experience severe bleeding, usually following trauma. Neither FXI antigen nor activity predicts the risk of bleeding in FXI-deficient patients. OBJECTIVES: (i) Characterize the formation, structure and stability of plasma clots from patients with severe FXI deficiency and (ii) determine whether these assays can distinguish asymptomatic patients ('non bleeders') from those with a history of bleeding ('bleeders'). METHODS: Platelet poor plasmas were prepared from 16 severe FXI-deficient patients who were divided into bleeders or non-bleeders, based on bleeding associated with at least two tooth extractions without prophylaxis. Clot formation was triggered by recalcification and addition of tissue factor and phospholipids in the absence or presence of tissue plasminogen activator and/or thrombomodulin. Clot formation and fibrinolysis were measured by turbidity and fibrin network structure by laser scanning confocal microscopy. RESULTS: Non-bleeders and bleeders had similarly low FXI levels, normal prothrombin times, normal levels of fibrinogen, factor VIII, von Willebrand factor and factor XIII, and normal platelet number and function. Compared with non-bleeders, bleeders exhibited lower fibrin network density and lower clot stability in the presence of tissue plasminogen activator. In the presence of thrombomodulin, seven of eight bleeders failed to form a clot, whereas only three of eight non-bleeders did not clot. CONCLUSIONS: Plasma clot structure and stability assays distinguished non-bleeders from bleeders. These assays may reveal hemostatic mechanisms in FXI-deficient patients and have clinical utility for assessing the risk of bleeding. PMID- 24815348 TI - Isopropanol poisoning. AB - INTRODUCTION: Isopropanol is a clear, colorless liquid with a fruity odor and a mild bitter taste. Most commonly found domestically as rubbing alcohol, isopropanol is also found in numerous household and commercial products including cleaners, disinfectants, antifreezes, cosmetics, solvents, inks, and pharmaceuticals. AIM: The aim of this review is to critically review the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning. METHODS: OVID MEDLINE and ISI Web of Science were searched to November 2013 using the words "isopropanol", "isopropyl alcohol", "2-propanol", "propan-2-ol", and "rubbing alcohol" combined with the keywords "poisoning", "poison", "toxicity", "ingestion", "adverse effects", "overdose", or "intoxication". These searches identified 232 citations, which were then screened via their abstract to identify relevant articles referring specifically to the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning; 102 were relevant. Further information was obtained from book chapters, relevant news reports, and internet resources. These additional searches produced eight non-duplicate relevant citations. EPIDEMIOLOGY: The majority of isopropanol exposures are unintentional and occur in children less than 6 years of age. Although isopropanol poisoning appears to be a reasonably common occurrence, deaths are rare. TOXICOKINETICS: Isopropanol is rapidly absorbed following ingestion with peak plasma concentrations occurring within 30 min. It can also be absorbed following inhalation or dermal exposure. Isopropanol is widely distributed with a volume of distribution of 0.45-0.55 L/kg. Isopropanol is metabolized by alcohol dehydrogenase to acetone, acetol and methylglyoxal, propylene glycol, acetate, and formate with conversion of these metabolites to glucose and other products of intermediary metabolism. The elimination of isopropanol is predominantly renal, though some pulmonary excretion of isopropanol and acetone occurs. In one case 20% of the absorbed dose was eliminated unchanged in urine, with the remainder excreted as acetone and metabolites of acetone. The elimination half-life of isopropanol is between 2.5 and 8.0 h, whereas elimination of acetone is slower with a half-life following isopropanol ingestion of between 7.7 and 27 h. MECHANISMS OF TOXICITY: While the exact mechanism of action of isopropanol has not been fully elucidated, brain stem depression is thought to be the predominant mechanism. While the clinical effects are thought to be mostly due to isopropanol, acetone may also contribute. CLINICAL FEATURES: The major features of severe poisoning are due to CNS and respiratory depression, shock, and circulatory collapse. The most common metabolic effects are an increased osmol (osmolal) gap, ketonemia, and ketonuria. Diagnosis. Poisoning can be diagnosed using the measurement of isopropanol serum concentrations, though these may not be readily available. Diagnosis is therefore more typically made on the basis of the patient's history and clinical presentation. An osmol gap, ketonemia, and/or ketonuria without metabolic acidosis, along with a fruity or sweet odor on the breath and CNS depression support the diagnosis. Management. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Hemodialysis enhances elimination of isopropanol and acetone and should be considered in very severe poisoning. CONCLUSIONS: Severe isopropanol poisoning results in CNS and respiratory depression and circulatory collapse. Treatment primarily consists of symptom-directed supportive care. Although hemodialysis increases the elimination of isopropanol and acetone substantially, it should only be considered in severe life-threatening poisonings. Patients usually make a full recovery provided they receive prompt supportive care. PMID- 24815349 TI - [The blog Educacionpapps turns 3]. PMID- 24815350 TI - Molecular characterization, expression profiling, and binding properties of odorant binding protein genes in the whitebacked planthopper, Sogatella furcifera. AB - The whitebacked planthopper (WBPH) Sogatella furcifera is a notorious rice pest in Asia that utilizes chemoreception to help in locating and selecting host plants. In this study, we used a transcriptomic approach, based on the WBPH transcriptome, to identify genes encoding for proteins exhibiting OBP-like features. We discovered 12 important chemosensory genes, termed odorant binding protein (OBP) fragments. Subsequently, the entire open reading frames of these putative OBPs were obtained by RACE. The genes were classified into three groups of OBPs, eight "Classic OBPs", three "Plus-C OBPs", and one "Atypical OBP". The expression profiles of these 12 genes were investigated by real-time qPCR in different tissues (antennae, mouthparts, heads (without antennae and mouthparts), legs, and remaining bodies). Results revealed distinct tissue expression patterns of these OBPs, indicating their diverse functions in this species. Of note, SfurOBP2 and SfurOBP11 were the two highest expressing OBPs in antennae. We next used ligand-binding experiments to measure their binding spectrum in vitro. Results revealed that purified recombinant SfurOBP2 and SfurOBP11 bound several rice plant volatiles. Taken together, these findings will be helpful for determining the potential physiological functions of WBPH OBPs, which in turn may help to discover new targets for behavioral antagonists for use as control strategies. PMID- 24815351 TI - The effects of two non-steroidal anti-inflammatory drugs on the mobility of laying hens with keel bone fractures. AB - OBJECTIVE: Investigate the effects of administration of meloxicam and carprofen on the mobility of hens with and without keel fractures. STUDY DESIGN: Within each of two experiments a 'blinded' randomised cross over design whereby birds received either the test drug (carprofen or meloxicam) or saline. ANIMALS: Two groups of Lohman Brown hens with and without keel bone fractures. METHODS: The first group (n = 63) was treated with carprofen 25 mg kg(-1) and saline subcutaneously, twice. The second group (n = 40) was treated with meloxicam (5 mg kg(-1) ) and saline subcutaneously. The latency of birds to fly down from perches 50, 100 and 150 cm above the ground was measured after each treatment. Data from experiment 1 and 2 were analysed separately; the effects of drug treatment compared with saline on landing time for birds with and without keel bone fractures were evaluated using MLwiN. RESULTS: In both experiments latency to fly down from perches was longer in hens with keel fractures and there was a significant interaction between perch height and fracture status. For carprofen, at the 50 cm, 100 cm and 150 cm perch heights, birds with fractures took (mean +/ SD) 2.5 +/- 2.9, 6.8 +/- 9.7 and 11.5 +/- 13.2 seconds respectively to fly down compared with 1.3 +/- 0.5, 2.3 +/- 1.2 and 4.2 +/- 3.1 seconds for birds without fractures. For meloxicam, at the 50 cm, 100 cm and 150 cm perch heights, birds with fractures took 2.9 +/- 2.5, 49.8 +/- 85.4 and 100.3 +/- 123.6 seconds respectively compared with 0.7 +/- 0.5, 2.5 +/- 7.1 and 3.0 +/- 4.6 seconds to fly down for birds without fractures. There was no significant effect of carprofen or meloxicam treatment. CONCLUSION AND CLINICAL RELEVANCE: These data provide further confirmation that keel fractures reduce the willingness of birds to move from perches. PMID- 24815352 TI - Tubular obstruction leads to progressive proximal tubular injury and atubular glomeruli in polycystic kidney disease. AB - In polycystic kidney disease (PKD), renal parenchyma is destroyed by cysts, hypothesized to obstruct nephrons. A signature of unilateral ureteral obstruction, proximal tubular atrophy leads to formation of atubular glomeruli. To determine whether this process occurs in PKD, kidneys from pcy mice (moderately progressive PKD), kidneys from cpk mice (rapidly progressive PKD), and human autosomal dominant PKD were examined in early and late stages. Integrity of the glomerulotubular junction and proximal tubular mass were determined in sections stained with Lotus tetragonolobus lectin. Development of proximal tubular atrophy and atubular glomeruli was determined in serial sections of individual glomeruli. In pcy mice, most glomerulotubular junctions were normal at 20 weeks, but by 30 weeks, 56% were atrophic and 25% of glomeruli were atubular; glomerulotubular junction integrity decreased with increasing cyst area (r = 0.83, P < 0.05). In cpk mice, all glomerulotubular junctions were normal at 10 days, but by 19 days, 26% had become abnormal. In early-stage autosomal dominant PKD kidneys, 50% of glomeruli were atubular or attached to atrophic tubules; in advanced disease, 100% were abnormal. Thus, proximal tubular injury in cystic kidneys closely parallels that observed with ureteral obstruction. These findings support the hypothesis that, in renal cystic disorders, cyst dependent obstruction of medullary and cortical tubules initiates a process culminating in widespread destruction of proximal convoluted tubules at the glomerulotubular junction. PMID- 24815353 TI - Characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice. AB - We sought to develop and characterize a novel paucibacillary model in mice, which develops necrotic lung granulomas after infection with Mycobacterium tuberculosis. Six weeks after aerosol immunization with recombinant Mycobacterium bovis bacillus Calmette-Guerin overexpressing the 30-kDa antigen, C3HeB/FeJ mice were aerosol infected with M. tuberculosis H37Rv. Six weeks later, mice were treated with one of three standard regimens for latent tuberculosis infection or tumor necrosis factor (TNF)-neutralizing antibody. Mouse lungs were analyzed by histological features, positron emission tomography/computed tomography, whole genome microarrays, and RT-PCR. Lungs and sera were studied by multiplex enzyme linked immunosorbent assays. Paucibacillary infection was established, recapitulating the sterilizing activities of human latent tuberculosis infection regimens. TNF neutralization led to increased lung bacillary load, disrupted granuloma architecture with expanded necrotic foci and reduced tissue hypoxia, and accelerated animal mortality. TNF-neutralized mouse lungs and sera showed significant up-regulation of interferon gamma, IL-1beta, IL-6, IL-10, chemokine ligands 2 and 3, and matrix metalloproteinase genes. Clinical and microbiological reactivation of paucibacillary infection by TNF neutralization was associated with reduced hypoxia in lung granulomas and induction of matrix metalloproteinases and proinflammatory cytokines. This model may be useful for screening the sterilizing activity of novel anti-tuberculosis drugs, and identifying mycobacterial regulatory and metabolic pathways required for bacillary growth restriction and reactivation. PMID- 24815355 TI - Non-invasive and invasive predictors of paravalvular regurgitation post CoreValve(r) stent prosthesis implantation in aortic valves. AB - OBJECTIVES: The long-term success of CoreValve(r) stent prosthesis (Medtronic) implantation for severe aortic valve stenosis is limited by postprocedural paravalvular regurgitation (PVR). METHODS: We have retrospectively investigated preinterventional cardiac 256-slice computed tomography (CT) scans and aortography to define predictors for mild, moderate, or severe PVR, in a blinded fashion. RESULTS: We investigated 100 consecutive patients with a mean aortic valve area (AVA) of 0.69 cm(2) and a mean age of 79.4 years. PVR was defined by echocardiography as mild (63), moderate (18), or severe (19). We found no differences according to AVA, left ventricular function, deployed stent size, calcification rate of the aortic valve, and stent position. Anatomically, the annular size and the angle between the left ventricular outflow tract (LVOT) and the ascending aorta demonstrated significant (P < 0.05) differences in the severity of the PVR: an LVOT: ascending aorta angle >12.6 degrees , annulus area >8.9 cm(2) , and annulus diameter difference >3.9 mm. The multivariate analysis demonstrated that deviation angle, difference of aortic annulus (longitudinal orthogonal), and CoreValve size were independent predictors of PVR. CONCLUSION: Our data demonstrate the feasibility of cardiac CT to evaluate predictors of PVR post-CoreValve placement. We support the aortic annulus (the area as well as the diameter differences) and the deviation of the linear slope from LVOT to ascending aorta as predictors of severe paravalvular regurgitations poststent implantation. PMID- 24815354 TI - Endoplasmic reticulum stress mediates amyloid beta neurotoxicity via mitochondrial cholesterol trafficking. AB - Disrupted cholesterol homeostasis has been reported in Alzheimer disease and is thought to contribute to disease progression by promoting amyloid beta (Abeta) accumulation. In particular, mitochondrial cholesterol enrichment has been shown to sensitize to Abeta-induced neurotoxicity. However, the molecular mechanisms responsible for the increased cholesterol levels and its trafficking to mitochondria in Alzheimer disease remain poorly understood. Here, we show that endoplasmic reticulum (ER) stress triggered by Abeta promotes cholesterol synthesis and mitochondrial cholesterol influx, resulting in mitochondrial glutathione (mGSH) depletion in older age amyloid precursor protein/presenilin-1 (APP/PS1) mice. Mitochondrial cholesterol accumulation was associated with increased expression of mitochondrial-associated ER membrane proteins, which favor cholesterol translocation from ER to mitochondria along with specific cholesterol carriers, particularly the steroidogenic acute regulatory protein. In vivo treatment with the ER stress inhibitor 4-phenylbutyric acid prevented mitochondrial cholesterol loading and mGSH depletion, thereby protecting APP/PS1 mice against Abeta-induced neurotoxicity. Similar protection was observed with GSH ethyl ester administration, which replenishes mGSH without affecting the unfolded protein response, thus positioning mGSH depletion downstream of ER stress. Overall, these results indicate that Abeta-mediated ER stress and increased mitochondrial cholesterol trafficking contribute to the pathologic progression observed in old APP/PS1 mice, and that ER stress inhibitors may be explored as therapeutic agents for Alzheimer disease. PMID- 24815356 TI - Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging. AB - INTRODUCTION: Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with (99m)Tc by formulated kit for SPECT imaging of hepatic function. METHODS: p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for (99m)Tc labeling. Radiotracer (99m)Tc-p(VLA co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. RESULTS: (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (>99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49+/-10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1h and 4h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. CONCLUSION: (99m)Tc-p(VLA-co VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of (99m)Tc-labeling provides great potential for the evaluation of hepatocyte function in clinical application. PMID- 24815357 TI - Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome. AB - Ischemic stroke (IS) outcome predictors include clinical features, biochemical parameters and some risk factors. The relations between two main players in the ischemic brain, MMPs and HMGB1, were estimated in the plasma of ischemic stroke patients stratified according to the Glasgow Outcome Scale and the Oxfordshire Community Stroke Project classification. IS patients exhibited higher plasma concentration of MMP-9 and the inflammatory cytokine HMGB1 compared with healthy controls. A full-blown correlation between MMP-9 activation and increased plasma MMP-9 concentration was observed in case of IS patients. A similar activity of MMP-2 and MMP-12 was characteristic of healthy volunteers and IS patients. In patients with ischemic stroke increased plasma levels of MMP-9 and HMGB1 are associated with a poor functional outcome and are significantly correlated with each other (P=0.0054). We suggest that diagnostic benefits will be obtained if plasma HMGB1 levels are measured for IS patients in addition to MMP-9. PMID- 24815359 TI - Follicular microhemorrhage: a unique dermoscopic sign for the detection of coexisting trichotillomania in alopecia areata. AB - The diagnosis of trichotillomania (TT) is often difficult as it presents similar clinical manifestations with other hair loss diseases, especially alopecia areata (AA). As TT often coexists with AA, the methodology enabling reliable detection of TT in AA needs to be developed. Recently, characteristic dermoscopic findings of TT have been reported, yet, they were most clearly detectable by conventional immersion dermoscopy, not by dry dermoscopy, a technique more easily adoptable in daily practice. In addition, the usefulness of those signs for differentiating TT from AA has not been sufficiently assessed. Through intensive scanning of hair loss lesions by dry dermoscopy in AA patients with TT, we found a sign potentially useful for detecting hidden TT. The sign we named "follicular microhemorrhage" (FMH) represents a red dot corresponding to a follicular ostia capped or stuffed with blood clot and suggests a history of traumatic forced plucking. So far, we have detected FMH in four TT patients with moderate to severe AA. Although further accumulation of cases is necessary, FMH would be beneficial to dissect complicated pathophysiology of hair loss in AA patients with TT. PMID- 24815360 TI - Risk management--learning from the mistakes of others. PMID- 24815361 TI - [Specular microscopic analysis of endothelial wound healing after trauma from pine processionary caterpillar hairs: pediatric case report]. PMID- 24815362 TI - Progress in the characterization of bio-functionalized nanoparticles using NMR methods and their applications as MRI contrast agents. AB - Significant progress has been made over the last three decades in the field of NMR, a technique which has proven to have a variety of applications in many scientific disciplines, including nanotechnology. Herein we describe how NMR enables the characterization of nanosystems at different stages of their formation and modification (raw materials, bare or functionalized nanosystems), even making it possible to study in vivo nanoparticle interactions, thereby importantly contributing to nanoparticle design and subsequent optimization. Furthermore, the unique characteristics of nanosystems can open up new prospects for site-targeted, more specific contrast agents, contributing to the development of certain nuclear magnetic resonance applications such as MRI. PMID- 24815358 TI - Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications. AB - Cardiovascular disease is the leading cause of death in the U.S. and other developed countries. Metabolic syndrome, including obesity, diabetes/insulin resistance, hypertension and dyslipidemia is a major threat for public health in the modern society. It is well established that metabolic syndrome contributes to the development of cardiovascular disease collective called as cardiometabolic disease. Despite documented studies in the research field of cardiometabolic disease, the underlying mechanisms are far from clear. Proteases are enzymes that break down proteins, many of which have been implicated in various diseases including cardiac disease. Matrix metalloproteinase (MMP), calpain, cathepsin and caspase are among the major proteases involved in cardiac remodeling. Recent studies have also implicated proteases in the pathogenesis of cardiometabolic disease. Elevated expression and activities of proteases in atherosclerosis, coronary heart disease, obesity/insulin-associated heart disease as well as hypertensive heart disease have been documented. Furthermore, transgenic animals that are deficient in or over-express proteases allow scientists to understand the causal relationship between proteases and cardiometabolic disease. Mechanistically, MMPs and cathepsins exert their effect on cardiometabolic diseases mainly through modifying the extracellular matrix. However, MMP and cathepsin are also reported to affect intracellular proteins, by which they contribute to the development of cardiometabolic diseases. On the other hand, activation of calpain and caspases has been shown to influence intracellular signaling cascade including the NF-kappaB and apoptosis pathways. Clinically, proteases are reported to function as biomarkers of cardiometabolic diseases. More importantly, the inhibitors of proteases are credited with beneficial cardiometabolic profile, although the exact molecular mechanisms underlying these salutary effects are still under investigation. A better understanding of the role of MMPs, cathepsins, calpains and caspases in cardiometabolic diseases process may yield novel therapeutic targets for treating or controlling these diseases. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. PMID- 24815364 TI - NMR of glycans: shedding new light on old problems. AB - The diversity in molecular arrangements and dynamics displayed by glycans renders traditional NMR strategies, employed for proteins and nucleic acids, insufficient. Because of the unique properties of glycans, structural studies often require the adoption of a different repertoire of tailor-made experiments and protocols. We present an account of recent developments in NMR techniques that will deepen our understanding of structure-function relations in glycans. We open with a survey and comparison of methods utilized to determine the structure of proteins, nucleic acids and carbohydrates. Next, we discuss the structural information obtained from traditional NMR techniques like chemical shifts, NOEs/ROEs, and coupling-constants, along with the limitations imposed by the unique intrinsic characteristics of glycan structure on these approaches: flexibility, range of conformers, signal overlap, and non-first-order scalar (strong) coupling. Novel experiments taking advantage of isotopic labeling are presented as an option for overcoming spectral overlap and raising sensitivity. Computational tools used to explore conformational averaging in conjunction with NMR parameters are described. In addition, recent developments in hydroxyl detection and hydrogen bond detection in protonated solvents, in contrast to traditional sample preparations in D2O for carbohydrates, further increase the tools available for both structure information and chemical shift assignments. We also include previously unpublished data in this context. Accurate determination of couplings in carbohydrates has been historically challenging due to the common presence of strong-couplings. We present new strategies proposed for dealing with their influence on NMR signals. We close with a discussion of residual dipolar couplings (RDCs) and the advantages of using (13)C isotope labeling that allows gathering one-bond (13)C-(13)C couplings with a recently improved constant-time COSY technique, in addition to the commonly measured (1)H-(13)C RDCs. PMID- 24815365 TI - Annotation of the human serum metabolome by coupling three liquid chromatography methods to high-resolution mass spectrometry. AB - This work aims at evaluating the relevance and versatility of liquid chromatography coupled to high resolution mass spectrometry (LC/HRMS) for performing a qualitative and comprehensive study of the human serum metabolome. To this end, three different chromatographic systems based on a reversed phase (RP), hydrophilic interaction chromatography (HILIC) and a pentafluorophenylpropyl (PFPP) stationary phase were used, with detection in both positive and negative electrospray modes. LC/HRMS platforms were first assessed for their ability to detect, retain and separate 657 metabolite standards representative of the chemical families occurring in biological fluids. More than 75% were efficiently retained in either one LC-condition and less than 5% were exclusively retained by the RP column. These three LC/HRMS systems were then evaluated for their coverage of serum metabolome. The combination of RP, HILIC and PFPP based LC/HRMS methods resulted in the annotation of about 1328 features in the negative ionization mode, and 1358 in the positive ionization mode on the basis of their accurate mass and precise retention time in at least one chromatographic condition. Less than 12% of these annotations were shared by the three LC systems, which highlights their complementarity. HILIC column ensured the greatest metabolome coverage in the negative ionization mode, whereas PFPP column was the most effective in the positive ionization mode. Altogether, 192 annotations were confirmed using our spectral database and 74 others by performing MS/MS experiments. This resulted in the formal or putative identification of 266 metabolites, among which 59 are reported for the first time in human serum. PMID- 24815366 TI - Ultra high resolution SFC-MS as a high throughput platform for metabolic phenotyping: application to metabolic profiling of rat and dog bile. AB - Ultra high resolution SFC-MS (on sub-2MUm particles) coupled to mass spectrometry has been evaluated for the metabolic profiling of rat and dog bile. The selectivity of the SFC separation differed from that seen in previous reversed phase UPLC-MS studies on bile, with the order of elution for analytes such as e.g., the bile acids showing many differences. The chromatography system showed excellent stability, reproducibility and robustness with relative standard deviation of less than 1% for retention time obtained over the course of the analysis. SFC showed excellent chromatographic performance with chromatographic peak widths in the order of 3s at the base of the peak. The use of supercritical fluid carbon dioxide as a mobile phase solvent also reduced the overall consumption of organic solvent by a factor of 3 and also reduced the overall analysis time by a factor of 30% compared to reversed-phase gradient LC. SFC-MS appear complementary to RPLC for the metabolic profiling of complex samples such as bile. PMID- 24815363 TI - Sodium MRI: methods and applications. AB - Sodium NMR spectroscopy and MRI have become popular in recent years through the increased availability of high-field MRI scanners, advanced scanner hardware and improved methodology. Sodium MRI is being evaluated for stroke and tumor detection, for breast cancer studies, and for the assessment of osteoarthritis and muscle and kidney functions, to name just a few. In this article, we aim to present an up-to-date review of the theoretical background, the methodology, the challenges, limitations, and current and potential new applications of sodium MRI. PMID- 24815368 TI - A new parametric model-based technique in bone tumour analysis. AB - The study presents a new statistical model based segmentation technique dedicated to inhomogeneous bone tumours structure analysis. The presented 3-D segmentation procedure applies a statistic description of the structure based on Gaussian mixture model and an adaptive model-based relative fuzzy connectedness technique. It has been tested on 94 different MR series of 38 young patients. The final segmentation results have been evaluated using two different verification techniques and compared with other segmentation methods. The developed technique yields higher bone tumours segmentation accuracy compared to results obtained with conventional fuzzy connectedness approach and different segmentation methods presented in the literature, and based on active contour models or statistical analysis. PMID- 24815367 TI - Cortical shell unwrapping for vertebral body abnormality detection on computed tomography. AB - The vertebral body is the main axial load-bearing structure of the spinal vertebra. Assessment of acute injury and chronic deformity of the vertebral body is difficult to assess accurately and quantitatively by simple visual inspection. We propose a cortical shell unwrapping method to examine the vertebral body for injury such as fractures and degenerative osteophytes. The spine is first segmented and partitioned into vertebrae. Then the cortical shell of the vertebral body is extracted using deformable dual-surface models. The cortical shell is then unwrapped onto a 2D map and the complex 3D detection problem is effectively converted to a pattern recognition problem on a 2D plane. Characteristic features adapted for different applications are computed and sent to a committee of support vector machines for classification. The system was evaluated on two applications, one for fracture detection on trauma CT datasets and the other on degenerative osteophyte assessment on sodium fluoride PET/CT. The fracture CAD achieved 93.6% sensitivity at 3.2 false positive per patient and the degenerative osteophyte CAD achieved 82% sensitivity at 4.7 false positive per patient. PMID- 24815369 TI - Listeria monocytogenes Infection in a Sugar Glider (Petaurus breviceps) - New Mexico, 2011. AB - Listeria monocytogenes is a Gram-positive, facultative anaerobic, rod-shaped bacterium that can infect and cause disease in many species. In this case report, we describe a case of L. monocytogenes infection causing sepsis in a sugar glider (Petaurus breviceps). The sugar glider consumed a varied diet consisting of human food items, including cantaloupe. A nationwide outbreak of L. monocytogenes foodborne illness associated with cantaloupes occurred simultaneously with this incident case. In this case, the bacterial strains from the outbreak and glider were genetically distinct. Although rare, veterinarians should be aware of the emergence of foodborne pathogens' ability to infect exotic animals residing in domestic environments. PMID- 24815370 TI - Developmental validation of the EX20+4 system. AB - The EX20+4Y System is a polymerase chain reaction (PCR)-based amplification kit that enables typing of 19 autosomal short tandem repeat (STR) loci (i.e., CSF1PO, D13S317, D16S539, D18S51, D21S11, D3S1358, D5S818, D7S820, D8S1179, FGA, TH01, TPOX, vWA, Penta D, Penta E, D2S1338, D19S433, D12S391, D6S1043), four widely used Y chromosome-specific STR (Y-STR) loci (DYS458, DYS456, DYS391, DYS635), and amelogenin. In this study, this multiplex system was validated for sensitivity of detection, DNA mixtures, inhibitor tolerance, species specificity based on the Scientific Working Group on DNA Analysis methods (SWGDAM) developmental validation guidelines, and the Chinese criteria for the human fluorescent STR multiplex PCR reagent. The results show that the EX20+4 System is a robust and reliable amplification kit which can be used for human identification testing. PMID- 24815371 TI - A substantially lower frequency of uninformative matches between 23 versus 17 Y STR haplotypes in north Western Europe. AB - The analysis of human short tandem repeats of the Y-chromosome (Y-STRs) provides a powerful tool in forensic cases for male sex identification, male lineage identification and identification of the geographical origin of male lineages. As the commonly used 12 and 17 Y-STR multiplexes do not discriminate between some unrelated males, additional Y-STRs were implemented in the PowerPlex((r)) Y23 System to supplement the existing commercial Y-STR kits. Until today, the forensic value of a (near) 23 versus 17 Y-STR haplotype match between an unknown DNA donor and a certain biological sample in a database is not yet well studied. This will be of huge interest for cases where an autosomal DNA profile yields no match to a DNA database and the database is used for familial searching (male relative(s) of the offender) or for the estimation of the geographical origin of the offender. In order to value (near) 23 Y-STR haplotype matches in a local sample from Western Europe, we selected the region of Flanders (Belgium) due to the already present knowledge on its Y-chromosomal variants. Many Y-chromosomes of this region were previously genotyped with Y-SNPs at a high resolution of the most recently updated Y-chromosomal tree and the deep-rooted genealogy of each DNA donor was already established. By comparing (near) matches of 23 versus 17 Y STR haplotypes between patrilineal-unrelated males, a substantial lower number of uninformative (near) 23 Y-STR haplotype matches has been observed compared to 17 Y-STR haplotypes. Furthermore, the use of SNP data was informative to discriminate >60% of unrelated males with an (near) identical 17 Y-STR match while SNP data was only necessary to discriminate about 10% of unrelated males with a 23 Y-STR haplotype that differed at only two Y-STRs. This shows the higher value of the Y23 haplotype within familial DNA searching and the estimation of the geographical origin of a DNA donor. Therefore, the use of the PowerPlex((r)) Y23 System instead of the commonly used 12 and 17 Y-STRs by the forensic community is recommended as it will increase the efficiency of Y-STRs in forensic casework. PMID- 24815372 TI - Evidential evaluation of DNA profiles using a discrete statistical model implemented in the DNA LiRa software. AB - The high sensitivity of the technology for producing profiles means that it has become routine to produce profiles from relatively small quantities of DNA. The profiles obtained from low template DNA (LTDNA) are affected by several phenomena which must be taken into consideration when interpreting and evaluating this evidence. Furthermore, many of the same phenomena affect profiles from higher amounts of DNA (e.g. where complex mixtures has been revealed). In this article we present a statistical model, which forms the basis of software DNA LiRa, and that is able to calculate likelihood ratios where one to four donors are postulated and for any number of replicates. The model can take into account dropin and allelic dropout for different contributors, template degradation and uncertain allele designations. In this statistical model unknown parameters are treated following the Empirical Bayesian paradigm. The performance of LiRa is tested using examples and the outputs are compared with those generated using two other statistical software packages likeLTD and LRmix. The concept of ban efficiency is introduced as a measure for assessing model sensitivity. PMID- 24815373 TI - An investigation of the potential of DIP-STR markers for DNA mixture analyses. AB - The genetic characterization of unbalanced mixed stains remains an important area where improvement is imperative. In fact, using the standard tools of forensic DNA profiling (i.e., STR markers), the profile of the minor contributor in mixed DNA stains cannot be successfully detected if its quantitative share of DNA is less than 10% of the mixed trace. This is due to the fact that the major contributor's profile "masks" that of the minor contributor. Besides known remedies to this problem, such as Y-STR analysis, a new compound genetic marker that consists of a Deletion/Insertion Polymorphism (DIP) linked to a Short Tandem Repeat (STR) polymorphism, has recently been developed and proposed. These novel markers are called DIP-STR markers. This paper compares, from a statistical and forensic perspective, the potential usefulness of these novel DIP-STR markers (i) with traditional STR markers in cases of moderately unbalanced mixtures, and (ii) with Y-STR markers in cases of female-male mixtures. This is done through a comparison of the distribution of 100,000 likelihood ratio values obtained using each method on simulated mixtures. This procedure is performed assuming, in turn, the prosecution's and the defence's point of view. PMID- 24815374 TI - Neutrophil oxidative burst capacity for peri-operative immune monitoring in trauma patients. AB - BACKGROUND: Post injury immune dysfunction can result in serious complications. Measurement of biomarkers may guide the optimal timing of surgery in clinically borderline patients and therefore prevent complications. AIM: peri-operative measurement of neutrophil oxidative burst capacity as an indicator of the immune response to major orthopaedic surgical procedures. METHODS: Prospective cohort study of trauma patients aged >=16 yrs with pelvic, acetabular, femoral shaft or tibial shaft fractures requiring surgical intervention. Blood samples were taken immediately pre-op and at 30 min, 7, 24 and 72-9 6 h post-operatively. Neutrophil oxidative burst capacity was measured both with and without stimulation by formyl methionyl-leucyl-phenylalanine (fMLP, a chemotactic factor). Clinical outcomes measured were mortality, length of stay, MOF, pneumonia, acute respiratory distress syndrome (ARDS) and sepsis. RESULTS: 100 consecutive orthopaedic trauma patients were enrolled over a 16 month period. 78% were male, with a mean age of 42 +/- 18 years and an average ISS of 19 +/- 13. Neutrophil oxidative burst capacity was significantly elevated at 7 h (p = 0.006) and 24 h (p = 0.022) post operatively. Patients who developed infective complications (pneumonia and sepsis) had higher levels of oxidative burst capacity pre-operatively (pneumonia: 1.52 +/- 0.93 v 0.99 +/- 0.66 p = 0.032, sepsis: 1.39 +/- 0.86 v 0.97 +/- 0.56 p = 0.024) and at 24 h post op (pneumonia: 2.72 +/- 2.38 v 1.12 +/- 0.63 p = < 0.001, sepsis: 2.16 +/- 2.09 v 1.10 +/- 0.54 p = < 0.001). When analysed by operation type, no statistical difference was seen between major and minor operations. No correlation was found between length of stay, length of ICU stay, ISS or age and neutrophil oxidative burst capacity at any time point. CONCLUSIONS: Neutrophil oxidative burst capacity response to orthopaedic trauma surgery is associated with the infective post injury complications. There was no correlation between magnitude of injury or operation and oxidative burst capacity. These results are promising for the development of tools for prediction of post-operative complications and guidance for optimal timing for surgical intervention. PMID- 24815375 TI - Fractures of the posterior wall of the acetabulum: treatment using internal fixation of two parallel reconstruction plates. PMID- 24815376 TI - Central injection of L- and D-aspartate attenuates isolation-induced stress behavior in chicks possibly through different mechanisms. AB - Intracerebroventricular (i.c.v.) injection of L- and D-aspartate (L- and D-Asp) has been shown to have a sedative effect with and without a hypnotic effect, respectively, in neonatal chicks experiencing isolation stress. However, the mechanisms of the different stress-attenuating functions of L- and D-Asp have not yet been fully clarified. In the present study, we investigated the involvement of the N-methyl-D-aspartate (NMDA) receptor in order to reveal the receptor mediated function of L- and D-Asp. To reveal whether L-and D-Asp act through the NMDA receptor, (+)-MK-801, which is an antagonist of NMDA receptors, was used in the current study. In experiment 1, the chicks were injected i.c.v. with either saline, (+)-MK-801, L-Asp or L-Asp plus (+)-MK-801. The sedative and hypnotic effects induced by L-Asp were blocked by co-administration with (+)-MK-801. In experiment 2, the chicks were injected i.c.v. with either saline, (+)-MK-801, D Asp or D-Asp plus (+)-MK-801. Importantly, the sedative effects induced by D-Asp were shifted to hypnotic effects by co-administration with (+)-MK-801. Taken together, L-Asp could induce sedative and hypnotic effects for stress behaviors through the NMDA receptor, but the attenuation of stress behaviors by D-Asp might be via simultaneous involvement of other receptors besides the NMDA receptor in this process. These differences may explain the different functional mechanisms of L- and D-Asp in the central nervous system. PMID- 24815377 TI - The Spatial Power Motivation Scale: a semi-implicit measure of situational power motivation. AB - We introduce a new nonverbal and unobtrusive measure to assess power motive activation, the Spatial Power Motivation Scale (SPMS). The unique features of this instrument are that it is (a) very simple and economical, (b) reliable and valid, and (c) sensitive to situational changes. Study 1 demonstrates the instrument's convergent and discriminant validity with explicit measures. Study 2 demonstrates the instrument's responsiveness to situational power motive salience: anticipating and winning competition versus losing competition and watching television. Studies 3 and 4 demonstrate that thoughts of competition result in higher power motivation specifically for individuals with a high dispositional power motive. PMID- 24815378 TI - Advancing molecular diagnostics for trypanosomatid parasites. AB - This Commentary highlights the article by Gonzalez-Andrade et al who investigated a conserved spliced leader RNA as an attractive new molecular target for next generation diagnostics in diseases caused by trypanosomatids. PMID- 24815379 TI - Application of COLD-PCR for improved detection of NF2 mosaic mutations. AB - Somatic mosaicism represents the coexistence of two or more cell populations with different genotypes in one person, and it is involved in >30 monogenic disorders. Somatic mosaicism characterizes approximately 25% to 33% of patients with de novo neurofibromatosis type 2 (NF2). The identification of mosaicism is crucial to patients and their families because the clinical course of the disease and its transmission risk is influenced by the degree and distribution of mutated cells. Moreover, in NF2, the capability of discriminating patients with mosaicism is especially important to make differential diagnosis with schwannomatosis. However, the identification of mosaic variants is considerably difficult, and the development of specific molecular techniques to detect low levels of unknown molecular alterations is required. Co-amplification at lower denaturation temperature (COLD)-PCR has been described as a powerful method to selectively amplify minority alleles from mixtures of wild-type and mutation-containing sequences. Here, we applied COLD-PCR to molecular analysis of patients with NF2 mosaicism. With the use of COLD-PCR, followed by direct sequencing, we were able to detect NF2 mutations in blood DNA of three patients with NF2 mosaicism. Our study has shown the capability of COLD-PCR in enriching low-represented mutated allele in blood DNA sample, making it usable for molecular diagnosis of patients with mosaicism. PMID- 24815380 TI - Possibility of the existence of donor-acceptor interactions in bis(azole)amines: an electronic structure analysis. AB - Donor-stabilized divalent N(I) systems have recently gained attention in the field of organic chemistry. Existence of low-valent nitrogen(I) species with moderate nucleophilicities in several pharmacophoric functionalities is prompting extensive exploration in this field. Quantum chemical analysis on the imidazole, oxazole, and thiazole derivatives of thiazole-2-amine indicated that these species preferably exist in the iminic state. Electronic structure analysis of these systems suggested the existence of hidden divalent N(I) character in a neutral state (L -> N-R) and the explicit divalent N(I) character (L -> N <- L)(+) in the protonated state. The strength of L -> N interaction in these systems was analyzed, and the variations in the nucleophilicity trend at the coordinating nitrogen center were rationalized by estimating the electronic (TEP (Tolman electronic parameter) and MESP minimum (V(min))) as well as steric parameters (r-repulsiveness and DeltaH elimination of CO group, in L -> Ni(CO)3) of the coordinating ligands L. The importance of energetically preferred ionic and tautomeric representations of thiazol-2-amine derivatives in iminic and aminic forms was also demonstrated by carrying out comparative docking analysis with the enzyme lymphocyte-specific kinase (Lck). PMID- 24815382 TI - A tale of two label changes. PMID- 24815381 TI - Age and geographic variability of human papillomavirus high-risk genotype distribution in a large unvaccinated population and of vaccination impact on HPV prevalence. AB - BACKGROUND: The prevalence of infections with human papillomavirus (HPV) specific genotypes differs by age and areas. Knowledge of these differences will help predicting how prophylactic HPV vaccination and screening program could best be integrated. OBJECTIVES: To investigate variations in the HPV distribution between areas and ages in Italy and the impact of vaccination on HPV prevalence. STUDY DESIGN: 37,367 women aged 25-60 years who attended cervical screening in eight different areas in Northern and Central Italy were tested for HPV infection with the high-risk hybrid capture (hr-HC2) assay. hr-HC2 positive samples were genotyped by an intensive integrated strategy. RESULTS: hr-HPV types were detected in 79.1% of HC2 positive women. HPV16 was the most frequent type, followed by HPV31, HPV18 and HPV56. A statistically significant variability in HPV type distribution between centres (overall chi84df(2)=195.86p<0.001) was observed. No significant overall difference in the HPV type distribution was observed in the age groups 25-34, 35-44 and 45-60 years. Considering cross protection, overall 57.6% (95%CI 56.0-59.3) of all infections by hr-HPV types was preventable by vaccination with the bivalent vaccine and 49% (95%CI 46.9-51.1) with the quadrivalent vaccine. The variability between centres was statistically significant with both bivalent (chi7df(2)=43.8, p<0.0001) and quadrivalent vaccine (chi7df(2)=32.9, p<0.0001). CONCLUSIONS: We observed differences in HPV genotype distribution according to centres but not to age. Results suggest that the higher proportion of HPV16/18 related high grade CIN in younger women could be the result of faster progression and not of earlier infection by these types. PMID- 24815383 TI - The role of nerve growth factor and its receptors in tumorigenesis and cancer pain. AB - The nerve growth factor (NGF) is a growth factor that belongs to the neurotrophin family. NGF has two structurally different receptors, the p75 neurotrophin receptor (p75NTR) and the tropomyosin-related kinase A (TrkA). Interaction of NGF with its receptors regulates a variety of physiological processes of neuronal system. Recent studies have shown that NGF and its receptors were involved in the regulation of tumourigenesis by either supporting or suppressing tumor growth depending on the tumor types. This review summarizes the current views of NGF and its receptors in tumorigenesis and cancer pain. PMID- 24815384 TI - Performance of reversed transcription loop-mediated isothermal amplification technique detecting EV71: a systematic review with meta-analysis. AB - Human enterovirus 71 (EV71) is the major etiological agent of hand, foot and mouth disease (HFMD), which is a common infectious disease in young children. Studies in the past have shown that reversed transcription loop-mediated isothermal amplification (RT-LAMP) was a rapid approach for the detection of EV71 in HFMD. This meta-analysis study is to evaluate the diagnostic role of RT-LAMP in detecting EV71 infection. A comprehensive literature research of PubMed, Embase, Wan Fang Data, and Chinese National Knowledge Infrastructure databases was conducted on articles aiming at the diagnostic performance of RT-LAMP in EV71 detection published before February 10, 2014. Data from selected studies were pooled to yield the summary sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve by using STATA VERSION 12.0 software. Ten studies including a total of 907 clinical samples were of high quality in this meta analysis. Overall, the pooled sensitivity, specificity, PLR, NLR, DOR, and the area under the SROC curve was 0.99 (0.97, 1.00), 0.97 (0.94, 1.00), 5.90 (95% CI: 3.90-8.94), 0.20 (95% CI: 0.14-0.29), and 1.00 (95% CI: 0.99-1.00), respectively. The univariate analysis of potential variables showed some changes in the diagnostic performance, but none of the differences reached statistical significance. Despite inter-study variability, the test performance of RT-LAMP was consistent with real-time RT-PCR in detecting EV71. This meta-analysis suggests that RT-LAMP is a useful diagnostic tool with high sensitivity and specificity for detecting EV71. PMID- 24815385 TI - Overexpression of an ABC transporter and mutations of GyrA, GyrB, and ParC in contributing to high-level ciprofloxacin resistance in Streptococcus suis type 2. AB - Streptococcus suis is a pathogen of zoonotic diseases. Moreover, the emergence of fluoro-quinolones (FQs) resistance in this pathogen has severe consequences for pigs and human health. In this study, the molecular mechanism of FQs resistance in S. suis type 2 (SS2) sensitive strains isolated from pigs was assessed after in vitro induction of resistance against the most frequently used FQs: ciprofloxacin, norfloxacin, and enrofloxacin. Proteome analysis, sequencing and real-time RT-PCR results strongly established an overexpression of an ABC transporter protein (other than SatAB) and topoisomerase mutations in GyrA (Ser81Arg), GyrB (Glu354Lys), and ParC (Ser79Phe) in contributing to high level ciprofloxacin resistance in SS2. Due to the overexpression of the ABC transporter, intracellular ciprofloxacin concentrations were significantly lower in the resistant strains than those of sensitive strains after 20, 35, and 60 min exposures to ciprofloxacin (p < 0.05). It was concluded that improper use of FQs is one of the main causes of the emergence of this zoonotic pathogen as a multiresistant organism against commonly used antibiotics. The existence of an efflux-like protein is an incentive to find new drug targets to avoid the spread of FQs-resistant S. suis isolates in pigs and the human population. PMID- 24815386 TI - Defect of tropomyosin-related kinase B isotype expression in ovarian clear cell adenocarcinoma. AB - Tropomyosin-related kinase B (TrkB) is a functional signal molecule that correlates with cell survival and epithelial-mesenchymal transition (EMT), which is essential for the invasiveness of malignant cancer cells. While a truncated isoform of TrkB has a dominant negative effect, full-length TrkB with its tyrosine kinase domain is predicted to play a role in cancer progression. Because ovarian clear cell adenocarcinoma (CCA) shows worse prognosis compared to other cancer types, we investigated the correlation between TrkB isoforms and the progression of CCA. Ovarian adenocarcinoma and benign tumor samples were obtained from Tokai University Hospital and Juntendo University Hospital. These samples were examined for the TrkB expression of isotype-specific proteins and mRNAs by immunohistochemistry and domain-specific semi-quantitative reverse transcription polymerase chain reaction. While TrkB mRNA expression was detected in all of the ovarian tissues and TrkB protein expression was predominant in ovarian cancer tissues, the number of tissues expressing the tyrosine kinase-truncated isoforms (T-Shc or T1) decreased according to the clinical stage of CCA. Irregular isoforms were also observed in some CCA samples. The decrease in T-Shc and T1 were less obvious in mucinous adenocarcinoma and not observed in serous or endometrioid adenocarcinoma. Decreased expression of the truncated isoforms (T Shc and T1) was associated with CCA progression. These results demonstrate that irregular expression of TrkB isoforms is a characteristic of CCA tissues. The unique TrkB expression profile may be useful for the diagnosis of CCA subtypes. PMID- 24815387 TI - Expression of ankyrin repeat and SOCS box containing 4 (ASB4) confers migration and invasion properties of hepatocellular carcinoma cells. AB - Ankyrin repeat and SOCS box containing 4 (ASB4) involves in physiological process of ubiquitin-mediated proteasomal degradation. Our previous study demonstrated high expression of ASB4 in hepatocellular carcinoma (HCC) cell lines. This study further reveals its clinical implications and tumorigenic properties in HCC. Analysis of 217 HCC gene expression profiles followed by validation in a separate cohort of 50 cases illustrated high ASB4 in HCC. Among the 50 cases, 54% of tumors exhibited more than 2-fold up-regulation of ASB4. Elevated ASB4 associated with low serum level of a HCC serological marker alpha-fetoprotein (AFP), postulating of its use to differentiate AFP-negative HCC. Suppression of ASB4 in PLC and MHCC97-L HCC cells hindered the cell migration and invasion. Reciprocally, enhanced migration rate was measured when ASB4 was ectopically expressed in Hep3B HCC cells. Cross comparison of results derived from in silico predictions of seed-matched sequences and by analyzing human HCC databases with matched microRNA and gene expression profiles, microRNA-200 (miR-200) family members including miR-200a and miR-200b were predicted to regulate ASB4 expression in HCC. MiR-200a showed inversed expression level with ASB4 in several of studied HCC cell lines. Dual luciferase reporter assay confirmed the presence of miR-200a binding site on the 3' untranslated region of ASB4. Reduced ASB4 level was noticed under the influence of miR-200a mimic treatment, for which this mimic-induced effect was neutralized with miR-200a inhibitor. In conclusion, this study demonstrates for the first time on the involvement of ASB4 in HCC and that its level is regulated by miR-200a. PMID- 24815388 TI - Transplantation of bone marrow mesenchymal stem cells pretreated with valproic acid in rats with an acute spinal cord injury. AB - This study aimed to investigate whether valproic acid (VPA) pretreatment enhances the therapeutic effectiveness of mesenchymal stem cells derived from bone marrow (BMSCs) transplanted into rats with an acute spinal cord injury (SCI). BMSCs were pretreated with VPA before transplantation and then intravenously injected 1 week after SCI. Before transplantation, levels of CXC chemokine receptor 4 (CXCR4) expression in BMSCs were tested using quantitative real-time PCR and Western blotting. Stromal derived factor-1 (SDF-1), the unique ligand of CXCR4, was quantified using RT-PCR and immunofluorescence. The locomotor function of rats with an SCI was evaluated using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Fluorescence microscopy and hematoxylin-eosin (HE) staining were also performed to evaluate pathophysiological changes after transplantation. On day 7 after SCI, the level of SDF-1 expression peaked. CXCR4 expression increased significantly in BMSCs pretreated with VPA. After intravenous transplantation, BrdU-labeled BMSCs were noted at the spinal injury site, and this was especially true for BMSCs pretreated with VPA. More significant functional improvement was observed in rats receiving BMSCs pretreated with VPA than in other groups of rats. AMD3100 partially inhibited improvement. This study demonstrates that pretreatment with VPA before transplantation enhances the therapeutic benefits of BMSCs in terms of greater cell migration and better neurological outcomes after traumatic SCI. The mechanism of this enhancement may be related to the SDF 1/CXCR4 axis. Therefore, pretreatment of BMSCs with VPA warrants further study in relation to the treatment of traumatic SCI. PMID- 24815389 TI - EPA and DHA increased PPARgamma expression and deceased integrin-linked kinase and integrin beta1 expression in rat glomerular mesangial cells treated with lipopolysaccharide. AB - Fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is known to prevent the progression of nephropathy and retard the progression of kidney disease. This study sought to investigate the underlying mechanisms of EPA and DHA in terms of peroxisome proliferator-activated receptor gamma (PPARgamma), integrin-linked kinase (ILK), and integrin beta1 expression in glomerular mesangial cells (GMCs) because of their critical roles in the development and progression of nephropathy. Lipopolysaccharide (LPS) significantly reduced the expression of PPARgammaand increased the expression of ILK at the mRNA level and at the protein level in GMCs as indicated by real-time PCR and Western blotting. In addition, LPS increased integrin beta1 expression in GMCs at the mRNA level. Treatment with EPA and DHA significantly increased the expression of PPARgamma and decreased the expression of ILK and integrin beta1 in GMCs. These data suggest that the renoprotective effects of EPA and DHA may be related to their potential to increase the expression of PPARgamma and decrease the expression of ILK and integrin beta1. PMID- 24815390 TI - Substrate specificity of human granzyme 3: analyses of the P3-P2-P1 triplet using fluorescence resonance energy transfer substrate libraries. AB - Granzyme 3 (Gr3) is known as a tryptase-type member of the granzyme family and exists in the granules of immunocompetent cells. Granule proteases including granzymes, are transported into the cytoplasm of tumor cells or virus-infected cells by perforin function, degrade cytoplasmic or nuclear proteins and subsequently cause the death of the target cells. Recently, although several substrates of Gr3 in vivo have been reported, these hydrolyzed sites were unclear or lacked consistency. Our previous study investigated the optimal amino acid triplet (P3-P2-P1) as a substrate for Gr3 using a limited combination of amino acids at the P2 and P3 positions. In the present study, new fluorescence resonance energy transfer (FRET) substrate libraries to screen P2 and P3 positions were synthesized, respectively. Using these substrate libraries, the optimal amino acid triplet was shown to be Tyr-Phe-Arg as a substrate for human Gr3. Moreover, kinetic analyses also showed that the synthetic substrate FRETS YFR had the lowest Km value for human Gr3. A substantial number of membrane proteins possessed the triplet Tyr-Phe-Arg and some of them might be in vivo substrates for Gr3. The results might also be a great help for preparing specific inhibitors to manipulate Gr3 activity both in vitro and in vivo. PMID- 24815391 TI - A high-carbohydrate diet lowered blood pressure in healthy Chinese male adolescents. AB - Different diets consumed by individuals of different ethnicities, gender, and age may cause changes in blood pressure. The current study sought to investigate changes in blood pressures after consumption of a high-carbohydrate (high-CHO) diet by healthy Chinese adolescents. As a population, the Chinese consume a diet with a high carbohydrate content and they have a low incidence of hypertension and coronary artery disease. Dietary data were collected using a 3-day diet diary. Subjects were 672 high school students who were divided into a high-CHO diet group (>= 55% carbohydrates) and a non-high-CHO diet group (< 55% carbohydrates, < 40% fats). Plasma glucose levels, heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured. Body mass index (BMI), waist-to-hip ratio (WHR), pulse pressure (PP), and mean arterial pressure (MAP) were calculated. Results indicated that males had a higher BMI, glucose level, SBP, DBP, PP, and MAP than females. When diet was taken into account, males in the non-high-CHO diet group had a higher SBP and PP than females. Males in the high-CHO diet group had a higher glucose level than females. Males in the high-CHO diet group had a lower SBP (p = 0.004) and PP (p = 0.002) than males in the non-high-CHO diet group and females in the high-CHO diet group had a lower glucose level (p = 0.003) than females in the non-high-CHO diet group. After adjusting for age, BMI, WHR, heart rate, the total daily energy intake, and the intake of vitamin C, calcium, sodium, potassium and magnesium, significant differences in SBP and PP were noted in males. These results indicate that male adolescents consuming a high-CHO diet had a lower SBP and PP than males consuming a non-high-CHO diet. PMID- 24815392 TI - Appraising value: the role of universal core values and emotions in decision making. PMID- 24815393 TI - PMMA-N,N,N-trimethyl chitosan nanoparticles for fabrication of antibacterial natural rubber latex gloves. AB - This paper presents one-pot synthesis of N,N,N-trimethyl chitosan (TMC) stabilized poly(methyl methacrylate) (PMMA) latex particles via the miniemulsion polymerization technique. From (1)H NMR, synthesized TMC contains 52% degree of quaternization. Compared to native biopolymer chitosan, TMC possesses permanently positive charges as well as provides greater antibacterial activity. Combining properties of PMMA and TMC, PMMA-TMC latex nanoparticles (hydrodynamic size ~282 nm) could be used in place of inorganic lubricating powder in fabrication of latex gloves at pH >= 7. After immersing sulphur prevulcanized natural rubber (SPNR) film into 3 wt% of PMMA-TMC latex at pH 7, significant amount of nanoparticles uniformly deposited onto SPNR film was observed under SEM. A number of nanoparticles present on film surface would increase surface roughness of the rubber film and potentially inhibit the bacterial (Escherichia coli and Staphylococcus aureus) growth, which would be useful for fabrication of special gloves with antibacterial property. PMID- 24815394 TI - Electrospun chitosan-based nanocomposite mats reinforced with chitin nanocrystals for wound dressing. AB - The aim of this study was to develop electrospun chitosan/polyethylene oxide based randomly oriented fiber mats reinforced with chitin nanocrystals (ChNC) for wound dressing. Microscopy studies showed porous mats of smooth and beadless fibers with diameters between 223 and 966 nm. The addition of chitin nanocrystals as well as crosslinking had a positive impact on the mechanical properties of the mats, and the crosslinked nanocomposite mats with a tensile strength of 64.9 MPa and modulus of 10.2 GPa were considered the best candidate for wound dressing application. The high surface area of the mats (35 m(2)g(-1)) was also considered beneficial for wound healing. The water vapor transmission rate of the prepared mats was between 1290 and 1,548 gm(-2)day(-1), and was in the range for injured skin or wounds. The electrospun fiber mats showed compatibility toward adipose derived stem cells, further confirming their potential use as wound dressing materials. PMID- 24815395 TI - Process optimization for fabrication of gellan based electrospun nanofibers. AB - In this investigation, the nanofiber formation ability of gellan, a FDA approved low cost natural polysaccharide, has been achieved for the first time using electrospinning technique. The gellan based ultrafine nanofibers were fabricated by using a blend mixture of gellan with another biodegradable polymer polyvinyl alcohol (PVA). The morphology of resulting gellan-PVA nanofibers was analyzed using field emission scanning electron microscopy (FESEM). The mass ratio of 50:50 for gellan:PVA was recorded as an optimum solution ratio to obtain uniform bead free nanofibers with an average diameter of 40 +/- 15.8 nm. Data depicted that among different parameters evaluated, viscosity and the mass ratio of gellan:PVA were the key parameters that influence the nanofiber morphology and diameter. PMID- 24815396 TI - Ethyl cellulose nanoparticles: clarithomycin encapsulation and eradication of H. pylori. AB - The extreme acidic environment of the stomach, its regular voidance of contents and the restricted access to the mucus covered habitat combined with the antibiotic resistance of the bacteria, all contribute to the poor success in the treatment of Helicobacter pylori gastric infections. Here, we demonstrate that by encapsulating clarithromycin into ethyl cellulose (EC) nanoparticles, the efficiency of H. pylori clearance in C57BL/6 mice infected with these bacteria was significantly improved. Clarithomycin-loaded EC nanoparticles were prepared via a simple yet effective anti-solvent particle induction method, to yield sub micron sized particles with 22.3 +/- 0.17% (w/w) clarithromycin loading at 86 +/- 0.5% (w/w) encapsulation efficiency. The particles dispersed well in water and simulated gastric fluid and gave a minimum inhibitory concentration of 0.09-0.18 MUg/ml against four strains of H. pylori. Encapsulation into EC particles not only enhanced the anti-adhesion activity of clarithromycin when tested with H. pylori and Hep-2 cells, but also gave significant enhancement of H. pylori clearance in the stomach of C57BL/6 mice infected with the bacteria. PMID- 24815397 TI - Preparation and biological evaluation of a novel selenium-containing exopolysaccharide from Rhizobium sp. N613. AB - In order to obtain a low toxic antitumor agent and an organic selenium source, an exopolysaccharide obtained from Rhizobium sp. N613 (REPS) was modified by selenious acid using barium chloride as the catalyst. The reaction conditions were optimized by response surface methodology (RSM), and the optimal conditions for preparation of selenium-containing REPS (Se-REPS) were obtained. The selenium content of Se-REPS was 790 MUg/g under these conditions. The molecular structure of Se-REPS was confirmed by FTIR. In vitro antitumor activity of Se-REPS was evaluated by MTT assay, and the results indicated that Se-REPS could significantly inhibit the growth of S180 and HepG2 cells. Furthermore, Se-REPS exhibited comparable in vivo antitumor efficacy to cyclophosphamide at same concentrations. In addition, Se-REPS could substantially elevate the thymus and spleen indices in tumor-bearing mice. This study demonstrates that Se-REPS holds great potential to be a desirable antitumor agent for therapeutic and immunomodulatory applications. PMID- 24815398 TI - Cellulose nanofibrils aerogels generated from jute fibers. AB - In this work, we report the cellulose nanofibrils extracted from the pristine jute fibers via the pretreatments followed by the TEMPO (2,2,6,6 tetramethylpiperidine-1-oxyl radical)-mediated oxidation and mechanical disintegration. The effects of pretreatments by using the NaOH solution and dimethyl sulfoxide solvent on the fiber morphology and macro/micro-structures were investigated by polarizing microscope and synchrotron radiation wide/small angle X-ray scattering (WAXS/SAXS). The cellulose nanofibrils exhibit a diameter ranging from 5 nm to 20 nm and a length of several micrometers, which have been assembled into cellulose aerogels by the lyophilization of as-prepared nanofibrils dispersions with various concentrations. The results indicated that the hierarchical structures of as-prepared cellulose aerogels were dependent on the dispersion concentrations. The WAXS results show that the typical cellulose aerogels are coexistence of cellulose I and cellulose II, which has a great promise for many potential applications, such as pharmaceutical, liquid filtration, catalysts, bio-nanocomposites, and tissue engineering scaffolds. PMID- 24815399 TI - Self-scrolling ability of differentially acetylated chitosan film. AB - Chitosan film cast on a glass slide was exposed to acetic anhydride vapor, resulting in an acetylation gradient in the film, with preferential acetylation of the exposed surface. The difference in degree of acetylation between the two surfaces of the peeled film was confirmed by attenuated total reflection infrared spectroscopy. Upon immersion of the film in water, differential swelling occurred because the more highly acetylated surface absorbed less water, and the resulting bending moment caused self-scrolling with the more highly acetylated surface inside. Simultaneous peeling and scrolling of films with a thickness of micrometer order, using dilute aqueous hydrofluoric acid, afforded tightly rolled chitosan microtubes. This simple self-scrolling mechanism is potentially applicable for micro-scale design with various naturally occurring polymers. PMID- 24815400 TI - Effect of extraction media on preliminary characterizations and antioxidant activities of Phellinus linteus polysaccharides. AB - Three partially purified polysaccharides were extracted from Phellinus linteus mycelia using hot water, 1% (NH4)2C2O4, and 1.25M NaOH/0.05% NaBH4, and the extracts were named PL-W, PL-A, and, PL-N respectively. PL-N mainly comprised xylose and arabinose with a high molecular weight (Mw) and the highest carbohydrate and uronic acid contents. PL-W and PL-A were mainly composed of glucose with high and low Mw fractions in various ratios. All three polysaccharides existed as compact coils in aqueous solutions and exhibited strong scavenging capacity and antioxidant activities in a concentration dependent manner. The polysaccharides also had high uronic acid and carbohydrate contents and strong antioxidant activities. The Mws, monosaccharide compositions, and chemical structures of the polysaccharides also affected their antioxidant activities. PL-A and PL-N had better antioxidant activities and could thus be developed as potential natural antioxidant agents for applications in food additives and biomedical industries. PMID- 24815401 TI - Side selective surface modification of chitin nanofibers on anionically modified cotton fabrics. AB - Chitin nanofibers have been prepared from crab shell as a chitin source using ultrasound assisted fibrillation. Atomic force microscopy (AFM) study showed that the prepared nanofibers were having diameters and lengths primarily in the range of 2-20 nm and 0.3-4 MUm respectively. These nanofibers were selectively grafted on one side of a 100% cotton fabric using a special apparatus. Prior to the grafting, cotton fabrics were modified with partial carboxymethylation to encourage cotton fiber nanofiber interactions. The surface modification was confirmed by Fourier transform infrared spectroscopy (FT-IR) peaks at 1,594 cm( 1) and 1,735 cm(-1) due to the presence of carboxylic acid functionality in modified cotton fabrics. Scanning electron microscope (SEM) study of the nanofiber grafted cotton fabrics showed that nanofibers were adhered to the cotton fabrics. Elemental analysis confirmed that side selective grafting of nanofiber has taken place due to the peak at 0.394 keV which attributes to the presence of nitrogen element in chitin nanofibers. This peak was absent in the other side of the fabric which was not coated with chitin nanofibers. Amount of adhered nanofibers was seen to increase with the increase of nanofiber concentration used in grafting as confirmed by Kjeldahl analysis. A possible mechanism of cotton fiber-nanofiber interactions is introduced. PMID- 24815402 TI - Phase behavior of ovalbumin and carboxymethylcellulose composite system. AB - The phase behavior, rheological properties and microstructure of ovalbumin and carboxymethylcellulose (OVA-CMC) conjugates were studied and the influence parameters were investigated. The results showed that the phase behavior of OVA CMC conjugates was related to pH and concentration of CMC and NaCl. When pH was over 5.0, discrete phase separation occurred in the mixture system, which indicated that OVA and CMC were thermodynamic incompatible. The mixture system turned into uniform stable emulsion system when pH reduced below 5.0. The addition of NaCl can improve the stability of composite system against pH sensitivity. CLSM and particle size distribution and ultraviolet spectrum analysis results confirm that emptying interactions play a leading role in the separation system. PMID- 24815403 TI - Effects of polysaccharide on chicks co-infected with Bordetella avium and Avian leukosis virus. AB - Chicks' co-infection with immunosuppressive virus and bacteria seriously threaten the development of the poultry industry. In this study, a model was established in which chicks were injected with either subgroup B ALV (ALV-B)+Bordetella avium (B. avium), or ALV-B+B. avium+Taishan Pinus massoniana pollen polysaccharide (TPPPS), or B. avium only, or B. avium+TPPPS. The data showed that the group injected with ALV-B and B. avium exhibited significant inhibition of the immune function and therefore increased pathogenicity compared with the group injected with B. avium-only. Application of TPPPS effectively alleviated immunosuppression, and body weights increased sharply in the TPPPS groups compared with non-TPPPS groups. To some extent, TPPPS may reduce the proliferation of ALV-B. These results suggest that Pinus pollen polysaccharides are beneficial treating co-infections with immunosuppressive virus and bacteria and therefore have potential for development into safe and effective immunoregulator. PMID- 24815404 TI - Adjuvant effect of polysaccharide from fruits of Physalis alkekengi L. in DNA vaccine against systemic candidiasis. AB - Adjuvant effect mediated by polysaccharide (PPSB) isolated from the fruits of Physalis alkekengi L. in DNA vaccine was evaluated in mice. Recombinant plasmid containing epitope C (LKVIRK) from heat shock protein 90 (HSP90) of Candida albicans (C. albican) was used as DNA vaccine (pD-HSP90C). The results indicated that PPSB significantly enhanced specific antibody titers IgG, IgG1, IgG2b, and concentration of IL-2 and IL-4 in sera of mice immunized with pD-HSP90C (p<0.05). More importantly, it was found that the mice immunized with pD-HSP90C/PPSB not only had fewer CFU (colony forming unites) in the kidneys than mice immunized with pD-HSP90C, but also a statistically significant higher survival rate over PBS-injected group (p<0.05) when the immunized mice were challenged with living C. albican cells. However, no statistically significant difference in survival rate was observed between pD-HSP90C-immunized group and PBS-injected group. Therefore, PPSB can be considered as a promising adjuvant eliciting both Th1 and Th2 responses to enhance the efficacy of DNA vaccines. PMID- 24815405 TI - Formation of carbonyl groups on cellulose during ozone treatment of pulp: consequences for pulp bleaching. AB - The formation of carbonyl groups during the ozone treatment (Z) of eucalyptus (Eucalyptus grandis and Eucalyptus urophylla hybrid) kraft pulps and their behaviors during subsequent alkaline stages were investigated by the CCOA method with carbazole-9-carboxylic acid [2-(2-aminooxethoxy)-ethoxy] amide (CCOA) as the carbonyl-selective fluorescence label. Several pulp samples with or without lignin and hexenuronic acids (hexA) were used to elucidate the effects of these components when present in unbleached kraft pulp. Both hexA and lignin increased the formation of carbonyl groups on cellulose and hemicellulose during ozonation. It was concluded that radicals are likely formed when ozone reacts with either lignin or hexA. These carbonyl groups were involved in cellulose depolymerization during subsequent alkaline extraction stages with sodium hydroxide (E) and alkaline hydrogen peroxide (P, in ZEP or ZP). Their numbers decreased after E but increased during P when H2O2 was not stabilized enough. Several ways to minimize the occurrence of carbonyl group formation are suggested. PMID- 24815406 TI - Chitosan-glutaraldehyde copolymers and their sorption properties. AB - This study reports the preparation of chitosan-glutaraldehyde (Chi-Glu) copolymers at modified reaction conditions such as the temperature prior to gelation, pH, and reagent ratios. The chitosan copolymers were characterized using infrared spectroscopy (FT-IR), CHN elemental analysis, and thermal gravimetric analysis (TGA). Evidence of self-polymerized glutaraldehyde was supported by CHN and TGA results. The sorption properties of Chi-Glu copolymers were evaluated in aqueous solutions containing p-nitrophenol at variable pH (4.6, 6.6, and 9.0). The sorption properties of the copolymers correlated with the level of the accessibility of the sorption sites in accordance with the relative cross-linker content. The relative sorption capacity of the Chi-Glu copolymers increases as the level of cross-linking increases. Chitosan displays the lowest sorptive uptake while an optimal sorption capacity was concluded at the 4:1 glutaraldehyde:chitosan monomer mole ratio, in close agreement with the three reactive sites (i.e. OH/NH) per glucosamine monomer. The PNP dye probe was determined to bind to chitosan through an electrostatic interaction due to the increased sorption capacity of the phenolate anion, as evidenced by the change in pH from 4.6 to 9.0. PMID- 24815407 TI - Processing and characterization of natural cellulose fibers/thermoset polymer composites. AB - Recently natural cellulose fibers from different biorenewable resources have attracted the considerable attraction of research community all around the globe owing to their unique intrinsic properties such as biodegradability, easy availability, environmental friendliness, flexibility, easy processing and impressive physico-mechanical properties. Natural cellulose fibers based materials are finding their applications in a number of fields ranging from automotive to biomedical. Natural cellulose fibers have been frequently used as the reinforcement component in polymers to add the specific properties in the final product. A variety of cellulose fibers based polymer composite materials have been developed using various synthetic strategies. Seeing the immense advantages of cellulose fibers, in this article we discuss the processing of biorenewable natural cellulose fibers; chemical functionalization of cellulose fibers; synthesis of polymer resins; different strategies to prepare cellulose based green polymer composites, and diverse applications of natural cellulose fibers/polymer composite materials. The article provides an in depth analysis and comprehensive knowledge to the beginners in the field of natural cellulose fibers/polymer composites. The prime aim of this review article is to demonstrate the recent development and emerging applications of natural cellulose fibers and their polymer materials. PMID- 24815408 TI - The improvement of characteristics of biodegradable films made from kefiran-whey protein by nanoparticle incorporation. AB - Biodegradable kefiran-whey protein isolate (WPI) nanocomposites were produced using montmorillonite (MMT) and nano-TiO2 as nanoparticles in the percentage of 1, 3, and 5% (w/w) by a casting and solvent-evaporation method. Physical, mechanical, and water-vapor permeability (WVP) properties were determined as a function of nanoparticle concentration. The results revealed that the effect of these nanoparticles was different according to their nature and percentage. The films incorporated with 5% (w/w) MMT showed the highest tensile strength, Young's modulus, puncture strength, and the lowest WVP compared with the control and TiO2 added films. In contrast to MMT, addition of TiO2 nanoparticles due to the plasticizing effect led to a significant change in color and transparency of nanocomposite. Scanning electron microscopy (SEM) observations demonstrated the films' properties in relation to their microstructures. The surface topography results also showed a considerable increase in roughness parameters by incorporating the nanoparticles in kefiran-WPI matrix. PMID- 24815409 TI - Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. AB - Oral supplementation of chondroitin sulphate plus glucosamine helps repair the articular surface in osteoarthritis. Chondroitin-S reduces the concentration of the pro-inflammatory cytokines and transcription factor involved in inflammation. GlcN.S enhances cartilage specific matrix components and prevents collagen degeneration in chondrocytes by inhibiting hydrolytic enzymes, and preventing the oxidation of lipids and proteins. Chondroitin-S plus GlcN.S are slow-acting drugs that alleviate pain and partly restore joint function in OA patients. Orally administered pharmaceutical-grade chondroitin-S plus GlcN.S stabilize the joint space narrowing and significantly decrease the number of patients with new erosive OA. They are safe and no adverse events have ever been reported; they are recommended by EULAR and OARSI. The cost/effectiveness of the oral chondroitin-S plus GlcN.S therapy derives from the reduction of costs for physiotherapy, and for gastroprotective and non-steroidal drugs. The synergistic association of these two world-widely preferred nutraceuticals is a step forward in the management of OA. PMID- 24815410 TI - ZnO-modified cellulose fiber sheets for antibody immobilization. AB - Cellulose fiber sheets impregnated with saccharide capped-ZnO nanoparticles were used as bioactive materials for antibody immobilization. First, ZnO nanoparticles were synthesized in the presence of glucose (monosaccharide), sucrose (disaccharide) as well as alginic acid and starch (polysaccharides). The pine cellulose fibers were then modified by the obtained saccharide capped nanoparticles and further incorporated into the sheets. The presence of ZnO significantly improved the immobilization of the antibodies on the surface of the sheets. After rewetting the alginic acid-ZnO modified sheets with saline solution, the retention of antibodies was about 95%. A high degree of the immobilization of biomolecules is an important feature for possible fabrications of bioactive- or biosensing-papers and we successfully tested the sheets on the detection of blood types using (A, B, and D blood antibodies). The ZnO nanoparticles affected also the other properties of the sheets. The ZnO-modified fiber sheets showed higher values of tensile index (strength), smoothness and opacity, while the value of porosity was substantially lower than that of the unmodified sheet. The presence of ZnO nanoparticles provided also the antimicrobial activity to the sheets. They showed a strong activity against bacteria (Escherichia coli and Staphylococcus aureus) and strong resistance to the attack of cellulase producing fungus Gloeophyllum trabeum. PMID- 24815411 TI - Thermal and antimicrobial properties of chitosan-nanocellulose films for extending shelf life of ground meat. AB - Chitosan-nanocellulose biocomposites were prepared from chitosan having molecular weight of 600-800 kDa, nanocellulose with 20-50 nm diameters and various levels of 30, 60 and 90% (v/wCHT) for glycerol. Agitation and sonication were used to facilitate even dispersion of particles in the polymer matrix. The nanocomposites were examined by differential scanning calorimetry, X-ray diffraction and agar disc diffusion tests; finally, the film was applied on the surface of ground meat to evaluate its performance in real terms. Chitosan-nanocellulose nanocomposites showed high Tg range of 115-124 degrees C and were able to keep their solid state until the temperature (Tm) range of 97-99 degrees C. XRD photographs revealed that nanocellulose peak completely disappeared after their addition to chitosan context. Agar disc diffusion method proved that the nancomposite had inhibitory effects against both gram-positive (S. aureus) and gram-negative (E. coli and S. enteritidis) bacteria through its contact area. Application of chitosan nanocellulose nanocomposite on the ground meat decreased lactic acid bacteria population compared with nylon packaged samples up to 1.3 and 3.1 logarithmic cycles at 3 and 25 degrees C after 6 days of storage, respectively. PMID- 24815412 TI - Properties of starch-hydroxypropyl methylcellulose based films obtained by compression molding. AB - Corn starch-glycerol (1:0.3) films, containing or not citric acid (1g/100g starch) and HPMC (10 and 20g/100g starch), are obtained by compression molding. The microstructure of the films, the thermal behavior, the X-ray diffraction spectra and the physical properties (mechanical, barrier and optical) were analyzed after 1 and 5 storage weeks at 25 degrees C and 53% relative humidity. The bonded citric acid and film solubility were also determined. Starch-HPMC blend films showed a dispersed phase of HPMC in a continuous, starch-rich phase with lower glass transition than HPMC-free films. The addition of citric acid also provoked a decrease in glass transition in line with the partial hydrolysis of starch chains. Both components implied a decrease in the water vapour permeability while the oxygen permeability slightly increased. Although citric acid only provoked a small hardening effect in the films, it greatly decreased their extensibility (weak cross-linking effect), which seems to increase during film storage. Starch crystallization during storage was inhibited by both citric acid and HPMC. PMID- 24815413 TI - Effect of solvent transfer in agar gels on stress relaxation under large deformation. AB - We measured stress relaxation, volume of exuded water, and spatial distribution of stress in agar gels under large deformation. Gels with smaller sample size and lower concentration exuded water faster and had shorter stress relaxation time. Gels with the storage time of 3 days exuded more water and had shorter stress relaxation time than gels with the storage time of 1 day, and this tendency was remarkable for low-concentration gels. Examination of the spatial distribution of stress in a cylindrical gel under large deformation showed that the outer part of the gel had smaller stress than the inner part at an early stage, and the area with small stress gradually extended into the inner part. This result indicates that the inhomogeneity of water content caused by water exudation from the gel surface induces the stress distribution in the gel. PMID- 24815414 TI - Synthesis, characterization and antibacterial activity of biodegradable starch/PVA composite films reinforced with cellulosic fibre. AB - Cellulosic fibres reinforced composite blend films of starch/poly(vinyl alcohol) (PVA) were prepared by using citric acid as plasticizer and glutaraldehyde as the cross-linker. The mechanical properties of cellulosic fibres reinforced composite blend were compared with starch/PVA crossed linked blend films. The increase in the tensile strength, elongation percentage, degree of swelling and biodegradability of blend films was evaluated as compared to starch/PVA crosslinked blend films. The value of different evaluated parameters such as citric acid, glutaraldehyde and reinforced fibre to starch/PVA (5:5) was found to be 25 wt.%, 0.100 wt.% and 20 wt.%, respectively. The blend films were characterized using Fourier transform-infrared spectrophotometry (FTIR), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA/DTA/DTG). Scanning electron microscopy illustrated a good adhesion between starch/PVA blend and fibres. The blend films were also explored for antimicrobial activities against pathogenic bacteria like Staphylococcus aureus and Escherichia coli. The results confirmed that the blended films may be used as exceptional material for food packaging. PMID- 24815415 TI - HIV case reporting in the countries of North Africa and the Middle East. AB - The aim of the paper is to provide an overview of HIV case reporting data for the year 2011 from the countries of the World Health Organization Eastern Mediterranean Region (WHO EMR). Fourteen countries provided data for the year 2011 and reported a total of 4263 HIV cases of which 66.8% were men. The highest number of reported HIV cases in men per 100,000 population was in Oman (5.8), Somalia (5.5) and Iran (3.3), while in women in Somalia (7.6), Oman (3.9) and Morocco (2.4). In the majority of the countries, the most common reported mode of transmission was heterosexual. This could be due to under-reporting of male-to male transmission and more frequent testing of men than women. PMID- 24815416 TI - Relation of epicardial fat thickness to subclinical right ventricular dysfunction assessed by strain and strain rate imaging in subjects with metabolic syndrome: a two-dimensional speckle tracking echocardiography study. AB - BACKGROUND: Right ventricular (RV) function is known to be impaired in the presence of metabolic syndrome (MetS). Epicardial adipose tissue is a metabolically active organ that generates various bioactive molecules, which might affect cardiac function and morphology. Thus, we hypothesized that RV dysfunction in patients with MetS may be related to increased epicardial fat thickness (EFT) in these patients. In patients with MetS, we aimed to assess the relation of EFT with RV function using two-dimensional speckle tracking echocardiography (2DSTE)-derived strain and strain rate imaging. METHODS: The study involved 76 subjects with MetS and 61 subjects without MetS. Biventricular structure and function together with EFT were evaluated by conventional echocardiography. RV free and septal walls strain (RVFW-S & RVSW-S), systolic and early diastolic strain rates (RVSRs & RVSRe) were evaluated by 2DSTE. RESULTS: Epicardial fat thickness was significantly higher in subjects with MetS (6.45 +/- 1.48 mm vs. 5.49 +/- 1.05 mm, P < 0.001). RVFW-S (-22.95 +/- 4.97% vs. -24.96 +/- 3.63%; P = 0.007), RVSRs (1.53 +/- 0.33/sec vs. -1.70 +/- 0.33/sec; P = 0.002), and RVSRe (1.40 +/- 0.44/sec vs. 1.75 +/- 0.49/sec; P < 0.001) were all lower in subjects with MetS, while RVSW-S did not differ. Multiple regression analysis showed that EFT was independently associated with RVFW-S (beta = -0.547, P < 0.001), RVSRs (beta = -0.332, P = 0.001), and RVSRe (beta = -0.187, P = 0.019) in subjects with MetS. CONCLUSIONS: Metabolic syndrome is associated with subclinical RV systolic and diastolic dysfunction. In subjects with MetS, increased EFT is independently related to RV systolic and diastolic dysfunction. PMID- 24815417 TI - Postoperative analgesia using diclofenac and acetaminophen in children. AB - BACKGROUND: Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg.kg(-1) is recommended for children aged 1 12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown. METHODS: Children (n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg.kg(-1) before surgery and 20 mg.kg(-1) rectally at the end of surgery with diclofenac suspension 0.1 mg.kg(-1) , 0.5 mg.kg(-1) , or 2.0 mg.kg(-1) before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg.kg(-1) , 0.5 mg.kg(-1) , or 2.0 mg.kg(-1) only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout. RESULTS: Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect (EMAX ) was 4.9. The concentration resulting in 50% of EMAX (C50 ) was 1.23 mg.l(-1) for diclofenac and 13.3 mg.l(-1) for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg.kg(-1) with acetaminophen 15 mg.kg(-1) achieves equivalent analgesia to acetaminophen 30 mg.kg(-1) . CONCLUSIONS: Combination therapy can be used to achieve similar analgesia with lower doses of both drugs. PMID- 24815418 TI - Observation of quantum-tunnelling-modulated spin texture in ultrathin topological insulator Bi2Se3 films. AB - Understanding the spin-texture behaviour of boundary modes in ultrathin topological insulator films is critically essential for the design and fabrication of functional nanodevices. Here, by using spin-resolved photoemission spectroscopy with p-polarized light in topological insulator Bi2Se3 thin films, we report tunnelling-dependent evolution of spin configuration in topological insulator thin films across the metal-to-insulator transition. We report a systematic binding energy- and wavevector-dependent spin polarization for the topological surface electrons in the ultrathin gapped-Dirac-cone limit. The polarization decreases significantly with enhanced tunnelling realized systematically in thin insulating films, whereas magnitude of the polarization saturates to the bulk limit faster at larger wavevectors in thicker metallic films. We present a theoretical model that captures this delicate relationship between quantum tunnelling and Fermi surface spin polarization. Our high resolution spin-based spectroscopic results suggest that the polarization current can be tuned to zero in thin insulating films forming the basis for a future spin switch nanodevice. PMID- 24815419 TI - Freezing of gait in Parkinson's disease: the paradoxical interplay between gait and cognition. AB - BACKGROUND: Freezing of gait is a disabling episodic gait disturbance common in patients with Parkinson's disease. Recent evidences suggest a complex interplay between gait impairment and executive functions. Aim of our study was to evaluate whether specific motor conditions (sitting or walking) influence cognitive performance in patients with or without different types of freezing. METHODS: Eight healthy controls, eight patients without freezing, nine patients with levodopa-responsive and nine patients with levodopa-resistant freezing received a clinical and neuropsychological assessment during two randomly performed conditions: at rest and during walking. RESULTS: At rest, patients with levodopa resistant freezing performed worse than patients without freezing on tests of phonological fluency (p = 0.01). No differences among the four groups were detected during walking. When cognitive performances during walking were compared to the performance at rest, there was a significant decline of verbal episodic memory task (Rey Auditory Verbal Learning Test) in patients without freezing and with levodopa-responsive freezing. Interestingly, walking improved performance on the phonological fluency task in patients with levodopa-resistant freezing (p = 0.04). CONCLUSIONS: Compared to patients without freezing, patients with levodopa resistant freezing perform worse when tested while seated in tasks of phonological verbal fluency. Surprisingly, gait was associated with a paradoxical improvement of phonological verbal fluency in the patients with levodopa resistant freezing whilst walking determined a worsening of episodic memory in the other patient groups. PMID- 24815420 TI - Optimizing the bioavailability of small molecular optical imaging probes by conjugation to an albumin affinity tag. AB - Small molecular imaging probes are often found to be rapidly cleared from the circulation. In order to improve signal to noise ratio (SNR) by high probe accumulation in the target tissue we intended to prolong the presence of the probes in the circulation by exploiting inherent transport mechanisms. Human serum albumin (HSA) is playing an increasingly important role as a drug carrier in clinical settings and drugs directly bound to albumin or attached to albumin binding moieties have been successfully developed for treatment approaches. To optimize the bioavailability of existing fluorescent probes, a hydrophobic affinity tag is installed, which enhances albumin binding. In a first experiment an endothelin-A receptor (ETAR) probe is modified by inserting a trivalent linker, attaching an albumin affinity tag and labeling the conjugate with the fluorescent dye Cy 5.5. The spectroscopic properties of the conjugate are examined by photometer- and fluorometer measurements in comparison to a probe without albumin binding tag. Albumin binding was proven by agarose gel electrophoresis. The affinity towards ETAR was confirmed in vitro by cell binding assays on human fibrosarcoma cells (HT-1080) and in vivo by murine xenograft imaging studies. In vitro, the modified probe retains high target binding in the absence and presence of albumin. Binding could be blocked by predosing with ETAR antagonist atrasentan, proving specificity. The in vivo examinations in comparison to the established probe showed a reduced renal elimination and a prolonged circulation of the tracer resulting in significantly higher signal intensity (SI) at the target and a higher signal-to-noise ratio (SNR) between 3h and 96 h after injection. In summary, we designed a small molecular, non-peptidic fluorescent probe which targets ETAR and reversibly binds to serum albumins. The reversible binding to albumin enhances the biological half-life of the probe substantially and enables near infrared optical imaging of subcutaneous tumors for several days. This approach of reversibly attaching probes to serum albumin may serve as a tool to optimize tracer distribution for more precise target characterization in molecular imaging experiments. PMID- 24815421 TI - In situ gelling pH- and temperature-sensitive biodegradable block copolymer hydrogels for drug delivery. AB - Stimuli-sensitive injectable polymeric hydrogels have been extensively investigated during the past decade as bioactive agent delivery vehicles and for tissue engineering applications. An aqueous solution of these polymers undergoes a sol-to-gel phase transition in response to external stimuli such as pH, temperature, salt, light, biomolecules, electromagnetic field, etc. Bioactive molecules or cells can be mixed into the low-viscosity state of the polymer solution and injected into the body at a target site, forming an in situ hydrogel depot, which can then serve as bioactive-molecule-releasing carriers or a cell growing microenvironment. This review systematically summarizes the recent progress in biodegradable and injectable block copolymer hydrogels, giving special attention to the novel and promising pH- and temperature-sensitive injectable block copolymer hydrogels for biomedical applications. The gelation mechanism, formation of ionic complexes, and biodegradation are highlighted as key factors responsible for controlled protein/drug delivery. The advantages and perspectives of pH- and temperature-sensitive injectable block copolymer hydrogels are also highlighted. PMID- 24815422 TI - Functional and pathological improvements of the hearts in diabetes model by the combined therapy of bFGF-loaded nanoparticles with ultrasound-targeted microbubble destruction. AB - Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality among the diabetic patients and currently there is no effective means to reverse its pathological progress. Basic fibroblast growth factor (bFGF) has shown promise as a molecular therapy for DCM, but its delivery is inefficient and non specific. In the present study, a therapy combining nanoparticle (NP) carrier and ultrasound-targeted microbubble destruction (UTMD) was reported the first time for bFGF delivery to the heart of diabetic rats. bFGF-loaded NP (bFGF-NP) were prepared with Poloxamer 188-grafted heparin copolymer using water-in-water technique, and the morphology, encapsulation efficiency, and bioactivity of bFGF NP were studied. The cellular uptake and cytotoxicity of bFGF-NP were evaluated with primary cultures of the left ventricular (LV) cardiomyocytes in vitro. Therapeutic effects of bFGF-NP/UTMD on the heart of DCM rats were studied by measuring LV systolic and diastolic functions, hemodynamic characteristics and indicators of cardiac remodeling including myocardial collagen volume fraction and capillary density. Results demonstrated that bFGF-NP showed good round morphology, efficient bFGF encapsulation and stable bioactivity of bFGF in vitro. bFGF-NP/UTMD combined treatment significantly enhanced the efficiency of bFGF cellular uptake (P<0.05) without obvious cytotoxicity. Significant improvements (P<0.05) in both cardiac functions and tissue morphology in the DCM rats were observed in bFGF-NP/UTMD group. These were not achievable using free bFGF, bFGF NP or UTMD treatment alone. Our results show that combining a non-viral vector with UTMD technique is an effective strategy to deliver bFGF to the heart, and the resulting growth factor therapy has demonstrated potential to reverse the progress of DCM by restoring the cardiac functions and even the structure of damaged cardiac tissues. PMID- 24815423 TI - Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice. AB - Pregnancy-associated plasma protein-A (PAPP-A) is a novel zinc metalloproteinase that functions in many systems outside of pregnancy. Data in both humans and mice suggest a role for PAPP-A in aging and age-related diseases. However, our knowledge of tissue-specific PAPP-A expression and possible changes in this expression with age is limited. Thus, the aim of this study was to determine PAPP A mRNA expression in multiple tissues with age in both male and female mice using real-time PCR. These included the heart, liver, kidney, bone, fat, skeletal muscle, gonads, brain, thymus and spleen. In young mice, PAPP-A mRNA was expressed at relatively high levels in all tissues examined except for liver. The only difference in expression between males and females was seen in the kidney, subcutaneous fat and gonads. The highest PAPP-A mRNA expression levels were found in visceral fat and these were 10-fold higher than in subcutaneous fat. PAPP-A expression significantly increased with age in kidney, brain and gonads. PAPP-A expression significantly deceased with age in bone and skeletal muscle. In the thymus, PAPP-A mRNA showed a biphasic response with age. There were no age related changes in PAPP-A expression seen in any of the other tissues examined. Expression of IGFBP-5 mRNA, a marker of insulin-like growth factor-I (IGF-I) bioactivity known to be regulated by PAPP-A, paralleled the changes in PAPP-A expression with age in kidney, bone, skeletal muscle and thymus. Thus, tissue specific PAPP-A expression in mice is differentially affected during aging, and may regulate local IGF-I bioactivity in certain tissues. PMID- 24815424 TI - Mechanism of phosphatidylserine inhibition of IgE/FcepsilonRI-dependent anaphylactic human basophil degranulation via CD300a. PMID- 24815425 TI - Psoriasis: to treat or to manage? AB - The recognition of psoriasis as a systemic disorder with characteristic skin symptoms and associated diseases has changed treatment concepts substantially. The complexity of psoriasis disease not only requires appropriate therapy but also weight-loss and smoking cessation programmes as well as trigger factor elimination. The term 'management' may better reflect the aim for a holistic approach of disease control. Comorbidity and the presence of psoriatic arthritis are important denominators for drug selection. However, there is a lack of prospective data substantiating a benefit of associated diseases by antipsoriatic therapy. Securing success using treatment goals helps to establish an efficacious therapy and to control inflammation. A regular scoring of disease severity, patients' quality of life and assessment of other clinically relevant conditions are mandatory to closely follow the disease course. There is debate whether an early treatment may modulate the future course of psoriasis. Concepts of minimal disease activity have not been implemented in psoriasis yet. There is a lack of evidence how long any treatment should be given and when and how to terminate. Finally, outcome tools should specifically be tailored for psoriasis to evaluate disease-related items as well as the benefit of management from the patient's perspective. PMID- 24815426 TI - Phylogenetic characterisation of Taenia tapeworms in spotted hyenas and reconsideration of the "Out of Africa" hypothesis of Taenia in humans. AB - The African origin of hominins suggests that Taenia spp. in African carnivores are evolutionarily related to the human-infecting tapeworms Taenia solium, Taenia saginata and Taenia asiatica. Nevertheless, the hypothesis has not been verified through molecular phylogenetics of Taenia. This study aimed to perform phylogenetic comparisons between Taenia spp. from African hyenas and the congeneric human parasites. During 2010-2013, 233 adult specimens of Taenia spp. were collected from 11 spotted hyenas in Ethiopia. A screening based on short DNA sequences of the cytochrome c oxidase subunit 1 gene classified the samples into four mitochondrial lineages designated as I-IV. DNA profiles of nuclear genes for DNA polymerase delta (pold) and phosphoenolpyruvate carboxykinase (pepck) showed that lineages II and III can be assigned as two independent species. Common haplotypes of pold and pepck were frequently found in lineages I and IV, suggesting that they constitute a single species. Morphological observations suggested that lineage II is Taenia crocutae, but the other lineages were morphologically inconsistent with known species, suggesting the involvement of two new species. A phylogenetic tree of Taenia spp. was reconstructed by the maximum likelihood method using all protein-coding genes of their mitochondrial genomes. The tree clearly demonstrated that T. crocutae is sister to T. saginata and T. asiatica, whereas T. solium was confirmed to be sister to the brown bear tapeworm, Taenia arctos. The tree also suggested that T. solium and T. arctos are related to two species of Taenia in hyenas, corresponding to lineages I+IV and III. These results may partially support the African origin of human-infecting Taenia spp., but there remains a possibility that host switching of Taenia to hominins was not confined to Africa. Additional taxa from African carnivores are needed for further testing of the "Out of Africa" hypothesis of Taenia in humans. PMID- 24815428 TI - Impact of radiotherapy on background parenchymal enhancement in breast magnetic resonance imaging. AB - BACKGROUND: While many studies have shown that hormones can influence background parenchymal enhancement (BPE) in breast magnetic resonance imaging (MRI), only few have directly address the effect of radiotherapy. The purpose of this study was to evaluate the impact of radiotherapy on BPE in breast MRI. MATERIALS AND METHODS: A retrospective search identified 62 women with unilateral breast cancer who had a breast MRI both before and after radiotherapy following breast conserving surgery. In our study, we assumed that systemic therapy affected both breasts equivalently. We rated the level of BPE of both breasts using a four- point categorical scale. A change in the level of BPE prior to and after treatment was compared in the diseased and contralateral breasts. RESULTS: All patients received a 4256 to 6480 cGy dose of whole breast radiotherapy over 3-7 weeks. The mean timing of the follow-up study was 6.6 months after completion of radiotherapy. Although the BPE showed a decrease in both breasts after treatment, there was a significant reduction of BPE in the irradiated breast compared with the contralateral breast (1.18 versus 0.98 average reduction in BPE level, p=0.042). CONCLUSIONS: Radiotherapy is associated with decrease in BPE with MRI. PMID- 24815427 TI - Impact of the prevalence of different pathogens on the performance of sampling plans in lettuce products. AB - Prevalence and concentration of Listeria monocytogenes, Salmonella spp. and enteric pathogenic viruses (namely Hepatitis A-HAV, and noroviruses genogroup I NoVGI and genogroup II-NoVGII) were determined in raw and RTE lettuce from a Spanish processing premise. Fifteen samplings were made from September 2010 to February 2012 (n=600 samples). Sampling strategies for pathogen detection were suggested by the characterization of the uncertainty in prevalence associated with the performance of two-class attributes sampling plans (c=0). A probabilistic model was run (1000 iterations) using a Bayesian approach with a conjugate beta distribution considering the impact of taking different number of samples on the proportion of positive samples and lots (within- and between-lot prevalence). No enumeration results were obtained for the pathogens tested. Presence of L. monocytogenes and NoVGII in RTE lettuce (10%) and NoVGI and NoVGII in unprocessed lettuce (10%) was obtained in the tested lots during cold season. Results evidenced that, as the number of samples increased, the probability of rejecting a contaminated lot became higher, yielding right-skewed distributions with values close to 1. According to our results, 25 samples would result in 80% of rejected lots, while 95% confidence level would be reached with n>100. However, although those levels would imply a unrealistic high number of samples making the application of the sampling plan unfeasible, these results might be useful for food operators and risk managers to know the underlying distributions of microbial contamination together with potential control measures to be applied to assure a safer production of minimally processed vegetables. PMID- 24815429 TI - Depression and suicide ideas of cancer patients and influencing factors in South Korea. AB - BACKGROUND: This study compared risk factors for depression and suicidal ideas among cancer patients for comparison with the general population, and identified influencing factors. MATERIALS AND METHODS: We analyzed data from 2,472 cancer patients in the National Cancer Center and nine Regional Cancer Centers and frequency-matched data for age and sex from 2,349 members of the general population who completed the National Health and Nutrition Examination Survey in 2008. Logistic regression analysis was used to identify factors affecting depression and suicidal ideas. RESULTS: Cancer patients were not likely to have more depression (OR=0.96, 95%CI=0.79-1.18) and were less likely to have suicidal ideas (OR=0.64, 95%CI=0.53-0.79) compared to the general population. Female sex, more stress, and lower quality of life were influencing factors. The additional risk factors for suicidal ideas among cancer patients included income (OR=0.62, 95%CI=0.43-0.91), smoking (OR=1.63, 95% CI=1.06-2.50), recurrence (OR=1.50, 95%CI=1.15-1.95), and chemotherapy (OR=1.66, 95%CI=1.26-2.19). CONCLUSIONS: No differences appeared in depression rates between cancer patients and the general population, and cancer patients were less likely to have suicidal ideas. However, cancer patients were likely to have more risk factors than the general population, and those classified as being at high risk of suicide should receive distress management and social economic support, from early in the treatment process. PMID- 24815430 TI - Interleukin-4 and -8 gene polymorphisms and risk of gastric cancer in a population in Southwestern China. AB - BACKGROUND: Gastric carcinogenesis is a complicated process that involves environmental and genetic factors like interleukin-4 (IL-4) and IL-8. Single nucleotide polymorphisms in their genes are associated with changed levels of gene expression. Here, we investigated the association between IL4-590 C>T and IL8-251T>A and gastric cancer (GC) risk in Sichuan of Southwestern China. MATERIALS AND METHODS: We surveyed the research subjects using a self-designed questionnaire with questions on demographic factors and putative risk factors. Approximately 2-5ml of whole blood was collected after field survey to analyze IL4-590 C>T and IL8-251T>A genotypes using MALDI-TOF MS. RESULTS: Our study recruited 308 pairs of GC patients and controls, including 224 (72.7%) men and 84 (27.3%) women in each group. There were 99 cardia and 176 noncardia GC patients in the case group. The case and control groups had an average age of 57.7+/-10.6 (mean+/-SD) and 57.6+/-11.1 years. GC patients reported a significantly greater proportion of family history of cancer (29.9% vs 10.7%, p<0.01) and drinking (54.6% vs 43.2%, p<0.01) than did controls. Variant genotypes of IL-4-590 C>T and IL-8-251 T>A were not associated with overall GC risk (adjusted OR, 0.89; 95%CI, 0.61-1.28 for CT or CC vs TT; adjusted OR, 1.14; 95%CI, 0.86-1.79 for TA or AA vs TT). Stratification analysis of two SNPs for risk by subsites only found that variant IL-8-251 TA or AA genotype was associated with increased noncardia GC risk (adjusted OR, 2.58; 95%CI, 1.19-5.57). We did not observe interactions between the IL-8-251 T>A genotype and smoking (adjusted OR, 0.38; 95%CI, 0.08 1.79) or drinking (adjusted OR, 0.36; 95%CI, 0.08-1.65) for risk of noncardia GC. CONCLUSIONS: Our data indicate no association between the two SNPs of IL-4-590 and IL-8-251 with overall GC risk, while the IL-8-251 TA or AA genotype conferred risk of cardia GC. Our findings contribute to the evidence body for risk of SNPs associated with the development of gastric cancer in this region. PMID- 24815431 TI - Correlation of breast cancer incidence with the number of motor vehicles and consumption of gasoline in Korea. AB - While several reproductive and lifestyle-related factors are already well-known as established risk factors for breast cancer, environmental factors have attracted attention only recently. The objective of the current study was to assess the association between the breast cancer incidences in females, the mortality rate and the number of motor vehicles on the one side and the consumption of gasoline which could work as a major source of air pollution at the other side. The breast cancer incidences and the mortality trends were compared with various indices of westernization like dietary patterns or industrialization with 10 years lag of time. Geographical variations with 10, 15 and 20 years lag of time were assessed between the breast cancer incidence in 2010 and the number of motor vehicles as well as the consumption of gasoline. The upward trend of motor vehicle numbers proved to be comparable to those of breast cancer incidence and mortality. However, the consumption of gasoline started to decrease since the mid-1990s. The geographic distribution of motor vehicle numbers and gasoline consumption in 1990 is in a positive correlation with the breast cancer incidence rates in 2010 and the 20-year lag time (R2 0.379 with the number of motor vehicles and 0.345 with consumption of gasoline). In a linear relationship between the breast cancer incidences in 2010 and the log transformed number of motor vehicles, the log transformed consumption of gasoline in 2000 also showed a positive relationship (R2 0.367 with the number of motor vehicles and 0.329 with consumption of gasoline). The results of the current study indicate that there may be a positive relation between the number of vehicles, gasoline consumption and the incidence of breast cancer from the aspects of long term trends and geographical variation. PMID- 24815432 TI - Association of cadmium but not arsenic levels in lung cancer tumor tissue with smoking, histopathological type and stage. AB - BACKGROUND: To evaluate association of lung cancer with arsenic and cadmium levels measured in tumor tissue. MATERIALS AND METHODS: Ninety-five patients with lung cancer tumor tissue obtained surgically were included in this study. Arsenic and cadmium levels were measured and levels of metals were compared among types of lung cancer and with reference to patient data. RESULTS: The histopathologic diagnoses of the 95 cases were SCC, 49, adenocarcinoma, 28, large cell, 11 and SCLC, 1. Mean tumor arsenic and cadmium levels were 149.3+/-129.1MUg/kg and 276.3+/-219.3MUg/kg, respectively. Cadmium levels were significantly associated with smoking (p=0.02), histopathologic type (p=0.005), and TNM staging (r=0.325; p=0.001), although arsenic was not related to any parameter (p>0.05). There was no relation between metal levels and mortality (p>0.05). CONCLUSIONS: We found a significant association between tumor cadmium levels of patients with lung cancer and smoking, histopathologic type and staging, although there was no relation with arsenic levels. PMID- 24815433 TI - Expression and prognostic significance of lncRNA MALAT1 in pancreatic cancer tissues. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have been recently observed in various human cancers. However, the role of lncRNAs in pancreatic duct adenocarcinoma (PDAC) remains unclarified. The aim of this study was to detect the expression of lncRNA MALAT1 in PDAC formalin-fixed, paraffin embedded (FFPE) tissues and to investigate the clinical significance of the MALAT1 level. METHODS: The expression of MALAT1 was examined in 45 PDAC and 25 adjacent non-cancerous FFPE tissues, as well as in five PDAC cell lines and a normal pancreatic epithelium cell line HPDE6c-7, using qRT-PCR. The relationship between MALAT1 level and clinicopathological parameters of PDAC was analyzed with the Kaplan-Meier method and Cox proportional hazards model. RESULTS: The relative level of MALAT1 was significantly higher in PDAC compared to the adjacent normal pancreatic tissues (p=0.009). When comparing the MALAT1 level in the cultured cell lines, remarkably higher expression of MALAT1 was found in aspc-1 PDAC cells compared with the immortal pancreatic duct epithelial cell line HPDE6c-7 (q=7.573, p<0.05). Furthermore, MALAT1 expression level showed significant correlation with tumor size (r=0.35, p=0.018), tumor stage (r=0.439, p=0.003) and depth of invasion (r=0.334, p=0.025). Kaplan-Meier analysis revealed that patients with higher MALAT1 expression had a poorer disease free survival (p=0.043). Additionally, multivariate analysis indicated that overexpression of MALAT1, as well as the tumor location and nerve invasion, was an independent predictor of disease specific survival of PDAC. CONCLUSION: MALAT1 might be considered as a potential prognostic indicator and may be a target for diagnosis and gene therapy for PDAC. PMID- 24815435 TI - Pathological implications of Cx43 down-regulation in human colon cancer. AB - Connexin 43 is an important gap junction protein in vertebrates and is known for its tumor suppressive properties. Cx43 is abundantly expressed in the human intestinal epithelial cells and muscularis mucosae. To explore the role of Cx43 in the genesis of human colon cancer, we performed the expression analysis of Cx43 in 80 cases of histopathologically confirmed and clinically diagnosed human colon cancer samples and adjacent control tissue and assessed correlations with clinicopathological variables. Western blotting using anti-Cx43 antibody indicated that the expression of Cx43 was significantly down regulated (75%) in the cancer samples as compared to the adjacent control samples. Moreover, immunohistochemical analysis of the tissue samples confirmed the down regulation of the Cx43 in the intestinal epithelial cells. Cx43 down regulation showed significant association (p<0.05) with the histological type and tumor invasion properties of the cancer. Our data demonstrated that loss of Cx43 may be an important event in colon carcinogenesis and tumor progression, providing significant insights about the tumor suppressive properties of the Cx43 and its potential as a diagnostic marker for colon cancer. PMID- 24815434 TI - Serum peroxiredoxin3 is a useful biomarker for early diagnosis and assessemnt of prognosis of hepatocellular carcinoma in Chinese patients. AB - BACKGROUND: Recently, peroxiredoxin3 (PRDX3) was identified as a novel molecular marker for the progression of hepatocellular carcinoma (HCC). However, its potential clinical application as a serum marker for the early diagnosis and prognosis of HCC has not been investigated. METHODS: PRDX3, alpha-fetaprotein (AFP), and other biochemical parameters were measured in serum samples from 297 Chinese patients, including 96 with HCC, 98 with liver cirrhosis (LC), and 103 healthy controls (HCs). Correlations between serum PRDX3 expression and clinicopathological variables and the relationship between serum PRDX3 expression and prognosis were analyzed. RESULTS: Serum PRDX3 was significantly higher in HCC patients than in the LC and HC groups. The sensitivity and specificity of serum PRDX3 for the diagnosis of HCC were 85.9% and 75.3%, respectively, at a cutoff of 153.26 ng/mL, and the area under the curve was 0.865. Moreover, serum PRDX3 expression was strongly associated with AFP level, tumor diameter, TNM stage, and portal vein invasion. Kaplan-Meier curve analysis revealed that HCC patients with high serum PRDX3 expression had a shorter median survival time than those with low PRDX3 expression. Moreover, serum PRDX3 expression was an independent risk factor for overall survival. The inverse correlation between serum PRDX3 and patient survival remained significant in patients with early-stage HCC and in those with normal serum AFP levels. CONCLUSIONS: Serum PRDX3 can be used as a noninvasive biomarker for the diagnosis and/or prognosis of HCC. PMID- 24815436 TI - Extract of Saccharina japonica induces apoptosis companied by cell cycle arrest and endoplasmic reticulum stress in SK-Hep1 human hepatocellular carcinoma cells. AB - Saccharina japonica is a family member of Phaeophyceae (brown macro-alga) and extensively cultivated in China, Japan and Korea. Here, the potential anti-cancer effect of n-hexane fraction of S. japonica was evaluated in SK-Hep1 human hepatocellular carcinoma cells. The N-hexane fraction reduced cell viability and increased the numbers of apoptotic cells in a both dose- and time-dependent manner. Apoptosis was activated by both caspase-dependent and independent pathways. The caspase-dependent cell death pathway is mediated by cell surface death receptors and activated caspase-8 amplified the apoptotic signal either through direct activation of downstream caspase-3 or pro-apoptotic proteins (Bad, Bax and Bak) subsequently leading to the release of cytochrome c. On the other hand, caspase-independent apoptosis appeared mediated by disruption of mitochondrial membrane potential and translocation of AIF to the nucleus where they induced chromatin condensation and/or large-scale DNA fragmentation. In addition, the n-hexane fraction induced endoplasmic reticulum (ER)-stress and cell cycle arrest. The results suggested that potential anti-cancer effects of n hexane extract from S. japonica on SK-Hep1 cells. PMID- 24815437 TI - Expression of annexin A3 in gastric cancer and its correlation with proliferation and apoptosis. AB - Annexin A3 has been identified as a novel biomarker in different types of cancers. However, little is known about its clinical significances and and biological roles in gastric cancer. In this study, we assessed annexin A3 expression in 80 patients with gastric cancer and explore its correlation with prognosis Moreover, correlations with Ki-67, Bcl-2 and Bax were also investigated. Expression of annexin A3 was increased in gastric cancer compared with that in normal gastric tissues. Annexin A3 expression was significantly associated with tumor volume and TNM stage (p<0.05). and inversely correlation with prognosis of patients. More interestingly, expression of annexin A3 was positive correlated with Ki-67 and Bcl-2 expression. Our study showed annexin A3 might be a potential prognostic marker for gastric cancer and involved in tumorigenesis by regulating apoptosis and proliferation. PMID- 24815438 TI - Effects of ubiquitin-conjugating enzyme 2C on invasion, proliferation and cell cycling of lung cancer cells. AB - The aims of this study were to investigate the influence of ubiquitin- conjugating enzyme E2C (UBE2C) on biological behavior of lung cancer cells. Using MTT, flow cytometry and invasion assays, we detected UBE2C expression and evaluated its biological properties in these cells, including effects on proliferation, the cell cycle profile and invasive capability. Compared with control cells, the UBE2C transfected cells demonstrated increased cellular proliferation (p<0.05). UBE2C transfected cells also had a lower percentage in G1 phase and a higher percentage in S phase (p<0.05). Importantly, the UBE2C transfected cells had a notable enhancement of cell numbers penetrating the basement membrane compared with the control group (p<0.05). Ectopic up- regulation UBE2C promoted the growth of lung cancer cells in vivo. Furthermore, we found UBE2C increased the expression of cyclin D1 and MMP-2. These results show UBE2C may represent a potential therapeutic target for lung cancer. PMID- 24815439 TI - Differences in the level of knowledge on cervical cancer among health care students, midwives and patients in Serbia. AB - BACKGROUND: Level of midwife knowledge is particularly important because of their role in the cervical cancer prevention programme. The aim of this study was to examine differences in the level of knowledge among health care students, midwives and women in the general population of Serbia. MATERIALS AND METHODS: A cross-sectional approach was used with health care students of the medical shool, midwives in their practice, and women visiting a chosen general practitioner as respondents. RESULTS: In comparison with the students and midwives, women had lower level of knowledge of causative agents of the cervical cancer, genital warts, HPV types, screening for cervical cancer as well as about the target population for vaccine and its role. Differences in the numbers of right answers of respondents were statistically significant (p<0.001). Four or more correct answers were obtained from 22.7% women, 35.3% from midwives and 83.8% from students. CONCLUSIONS: Midwives should improve their own level of knowledge related to preventive practice for cervical cancer, as well as their personal compliance with recommended practices, in order to be qualified and credible promoters of cervical cancer control among women in Serbia. PMID- 24815440 TI - Oral cancer knowledge of senior dental students in Zahedan, South-East of Iran. AB - BACKGROUND: Oral carcinoma is one of the common types of cancer and one of the 10 leading causes of death around the world. This study was conducted to evaluate senior dental student knowledge about oral cancerous lesions in Zahedan Dental School. MATERIALS AND METHODS: In this cross-sectional research, all the students in the last academic year at the School of Dentistry were studied during year of 2013. The study questionnaire covered demographic data as well as 12 questions concerning the knowledge of oral cancer. Data were collected and analyzed with SPSS18 using independent t-test, one way ANOVA. Significance level was considered as p<=0.05. RESULTS: Of the 104 senior dental students, with an average age of 27.34+/- 7.79 years, who participated in this study, 32 (30.8%) were female and 72 (69.2%) were male. The mean score of the students regarding the knowledge of oral cancer was 7.24+/-2.61. 20 students (19.2%) had a weak knowledge, 45 students (43.3%) had a moderate knowledge, and 39 students (37.5%) had a good knowledge. CONCLUSIONS: The student knowledge of oral cancer is not satisfactory and they need to receive additional information and education. PMID- 24815441 TI - Lack of association of the MDR1 C3435T polymorphism with susceptibility to gastric cancer and peptic ulcer: a systemic review and meta-analysis. AB - BACKGROUND: The multidrug resistance 1 gene (MDR1) C3435T polymorphism has been demonstrated to influence the P-glycoprotein (P-gp) activity level which is related to inflammation and carcinogenesis. This meta-analysis was performed to estimate the association between the MDR1 C3435T polymorphism and the risk of gastric cancer (GC) and peptic ulcer (PU). MATERIALS AND METHODS: A literature search was conducted with PubMed, Embase and the Cochrane library up to November 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Data were analyzed using Review Manager (Version 5.2), and Stata package (version 12.0) for estimation of publication bias. RESULTS: Six case-control studies were included, of which five were for GC and two for PU. Overall, no evidence was found for any association between the MDR1 C3435T polymorphism and the susceptibility to GC and PU. In the stratified analysis by H. pylori infection status, stage and histology classification of GC, and PU type, there was still no significant association between them. CONCLUSIONS: This meta-analysis suggested that the MDR1 C3435T polymorphism is not associated with susceptibility to GC and PU. Large and well-designed studies are warranted to validate our findings. PMID- 24815442 TI - Longitudinal study of cancer-related fatigue in patients with colorectal cancer. AB - BACKGROUND: Dynamic changes of cancer-related fatigue (CRF) among hospitalized patients with colorectal cancer were determined. MATERIALS AND METHODS: This longitudinal, descriptive study involved 96 hospitalized patients with colorectal cancer, all recruited from a tertiary general hospital in Guangzhou, China. Patients completed questionnaires three times to assess the degree of fatigue, and measurement points were within one week of admission, at 2 to 3 days after surgery and 3 weeks after surgery. RESULTS: Significant differences among the three measurement points (p<0.01) were observed. The scores of fatigue in the second survey were the highest, followed by the third and first surveys. Colon cancer patient scores were higher than those of rectal cancer patients with a significant difference (p<0.05). Colorectal patients experienced different degrees of fatigue at different periods during hospitalization. CONCLUSIONS: This study highlights the importance of interventions that are carefully tailored to patients based on the characteristics at different periods to alleviate fatigue. PMID- 24815443 TI - Risk factors for lung cancer in the Pakistani population. AB - BACKGROUND: Lung cancer is one of the most prevalent malignancies in the world and both incidence and mortality rates are continuing to rise in Pakistan. However, epidemiological studies to identify common lung cancer determinants in the Pakistani population have been limited. MATERIALS AND METHODS: In this retrospective case-control study, 400 cases and 800 controls were enrolled from different hospitals of all provinces of Pakistan. Information about socio demographic, occupational, lifestyle and dietary variables was extracted by questionnaire from all subjects. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated. and dose-response associations were also assessed for suitable factors. RESULTS: Strong associations were observed for smoking (OR=9.4, 95%CI=6.9-12.8), pesticide exposure (OR=5.1, 95%CI=3.1-8.3), exposure to diesel exhaust (OR=3.1, 95%CI=2.1-4.5), red meat consumption (OR=2.9, 95%CI=1.8-4.7) and chicken consumption (OR=2.8, 95%CI=1.7-49). Other associated factors observed were welding fumes (OR=2.5, 95%CI=1.0-6.5), sedentary living (OR=2.0, 95%CI=1.6 2.6), family history (OR=2.0, 95%CI=0.8-4.9), wood dust (OR=1.9, 95%CI=1.2- 3.1), tea consumption (OR=1.8, 95%CI=1.2-2.6), coffee consumption (OR=1.8, 95%CI=1.1 2.8), alcoholism (OR=1.7, 95%CI=1.1-2.5) and asbestos exposure(OR=1.5, 95%CI=0.5 4.4). Consumption of vegetables (OR=0.3, 95%CI=0.2-0.4), juices (OR=0.3, 95%CI=0.3-0.4), fruits (OR=0.7, 95%CI=0.5-0.9) and milk (OR=0.6, 95%CI=0.5- 0.8) showed reduction in risk of lung cancer. Strongest dose-response relationships were observed for smoking (?2=333.8, p<=0.0000001), pesticide exposure (?2=50.9, p<=0.0000001) and exposure to diesel exhaust (?2=51.8, p<=0.0000001). CONCLUSIONS: Smoking, pesticide exposure, diesel exhaust and meat consumption are main lung cancer determinants in Pakistan. Consuming vegetables, fruits, milk and juices can reduce the risk of lung cancer risk, as in other countries. PMID- 24815444 TI - ESR1 and PGR gene promoter methylation and correlations with estrogen and progesterone receptors in ductal and lobular breast cancer. AB - The aim of this work was to analyze methylation of the promoter sites of the ESR1 and PGR genes and to determine correlations with immunohistochemical expression of estrogen and progesterone receptors in ductal and lobular breast cancers. An observational, descriptive, molecular study was conducted on 20 ductal and 20 lobular breast cancer samples with immunohistochemical determination of estrogen and progesterone receptor expression. The methylation analysis of ESR1 and PGR promoter sites was carried-out by methylation-specific PCR. For correlation analysis, Kendall's tau coefficient was determined. Positive correlations were found between estrogen and progesterone receptors, estrogen receptor and unmethylated progesterone receptor, progesterone receptor, and unmethylated progesterone receptor. Negative correlations were found between estrogen receptor and methylated progesterone receptor, progesterone receptor and methylated progesterone receptor, methylated and unmethylated estrogen receptor, and methylated and unmethylated progesterone receptor. The results suggest that methylation of promoter sites of ESR1 and PGR is a relatively uncommon event in ductal and lobular breast cancer, and also suggest that the determination of epigenetic states of ESR1 and PGR could represent an alternative or complement to the histopathological expression analysis. PMID- 24815445 TI - Targeting EGFL7 expression through RNA interference suppresses renal cell carcinoma growth by inhibiting angiogenesis. AB - Renal cell carcinoma (RCC) is the most lethal of all urological cancers and tumor angiogenesis is closely related with its growth, invasion, and metastasis. Recent studies have suggested that epidermal growth factor-like domain multiple 7 (EGFL7) is overexpressed by many tumors, such as colorectal cancer and hepatocellular carcinoma; it is also correlated with progression, metastasis, and a poor prognosis. However, the role of EGFL7 in RCC is not clear. In this study, we examined how EGFL7 contributes to the growth of RCC using a co-culture system in vitro and a xenograft model in vivo. Downregulated EGFL7 expression in RCC cells affected the migration and tubule formation of HMEC-1 cells, but not their growth and apoptosis in vitro. The level of focal adhesion kinase (FAK) phosphorylation in HMEC-1 cells decreased significantly when co-cultured with 786 0/iEGFL7 cells compared with 786-0 cells. After adding rhEGFL7, the level of FAK phosphorylation in HMEC-1 cells was significantly elevated compared with phosphate-buffered saline (PBS) control. However, FAK phosphorylation was abrogated by EGFR inhibition. The average size of RCC local tumors in the 786 0/iEGFL7 group was noticeably smaller than those in the 786-0 cell group and their vascular density was also significantly decreased. These data suggest that EGFL7 has an important function in the growth of RCC by facilitating angiogenesis. PMID- 24815446 TI - Expression and effects of JMJD2A histone demethylase in endometrial carcinoma. AB - Previous studies have demonstrated that JMJD2A is a potential oncogene and is overexpressed in human tumors. However, its role in the endometrial carcinoma remains largely unknown. In this study, we discovered that JMJD2A was overexpressed in endometrial carcinoma, using immunohistochemistry, quantitative real- time polymerase chain reaction, and western blotting. Downregulation of JMJD2A led to reduced endometrial carcinoma RL95-2 and ISK cell proliferation, invasion and metastasis as asessed with cell counting kit-8, cell migration and invasive assays. Collectively, our results support that JMJD2A is a promoter of endometrial carcinoma cell proliferation and survival, and is a potential novel drug target. PMID- 24815447 TI - Retrospective study of ALK rearrangement and clinicopathological implications in completely resected non- small cell lung cancer patients in Northern Thailand: role of screening with D5F3 antibodies. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) has been intensively studied. The gold standard for ALK detection is FISH, but this is not routinely conducted in clinical practice, so that the IHC method has a role. The aim of this study was to identify the incidence of ALK rearrangement and risk or prognostic factors for ALK positivity using both of IHC and FISH methods. MATERIALS AND METHODS: From January 2008 to December 2012, 267 completely resected NSCLC patients in Chiang Mai University Hospital were enrolled in this study. Clinical and pathological variables and outcomes of treatment were retrospectively reviewed. IHC and FISH were used to evaluate ALK rearrangement. Sensitivity and specificity of IHC were analyzed. Multivariable analysis was used to identify clinico-pathological correlations with positive results of IHC and clinical outcomes. RESULTS: Twenty-two (8.2%) of 267 specimens were IHC-positive for ALK with intense cytoplasmic staining, whereas only 10 (3.8%) were FISH-positive. Sensitivity, specificity and the positive likelihood ratio with IHC were 80.0%, 94.9%, and 15.8 respectively. Age less than 55 years (RR 4.4, 95%CI 1.78-10.73, p value=0.001) and presence of visceral pleural invasion (VPI) (RR 2.9, 95%CI 1.21-6.78, p value =0.017) were identified as risk factors for ALK rearrangement with FISH. There were no statistically significant differences in other clinical and pathological variables. ALK rearrangement was not a prognostic factor for tumor recurrence or overall survival. CONCLUSIONS: The incidences of ALK positivity in completely resected NSCLCs in northern Thailand were 8.2% by IHC and 3.8% by FISH. IHC with mouse monoclonal, Ventana D5F3 antibody can be used as a screening tool before FISH method because of high specificity and high positive likelihood ratio. Age less than 55 years and VPI are risk factors for ALK positivity. PMID- 24815448 TI - Expression of Ki-67, p53 and VEGF in pediatric neuroblastoma. AB - BACKGROUND: Neuroblastoma (NB), is a neuroectodermal tumor derived from neural crest cells, and it is the second most common pediatric malignant tumor. The biological and clinical behavior of NB is very heterogeneous. This study was conducted to evaluate the expression of Ki-67, p53 and VEGF markers in tissues obtained from NB patients with different histologic types and stage. MATERIALS AND METHODS: Tissue microarray (TMA) blocks were constructed from paraffin blocks of the NB tissues. Immunohistochemical staining was performed on TMA sections to detect the expression of Ki-67, p53 and VEGF markers. The association between the expression of these markers and clinicopathological parameters were then analyzed. RESULTS: We had 18 patients with NB, one patient with ganglioneuroblastoma (GNB) and one with ganglioneuroma. Ki-67 was expressed in 13 (65%) tumors, and negatively correlated with age, prognosis, histologic type and stage of NB (all p<0.05). High and moderate expression of VEGF was found in 5% (1/20) and 65% (13/20) of the tumors, respectively; and it was positively correlated with age, prognosis and histologic types (all p<0.05) and negatively correlated with MKI (mitosis-karyorrhexis index). p53 expression was observed in 10% (2/20) of the tumors, which showed a relative correlation with MKI (p value=0.07). CONCLUSIONS: VEGF as a candidate for anti-angiogenic targeted therapy was correlated with the development and progression of NB; therefore, VEGF along with Ki-67 can serve as a valuable marker for the prognosis of this tumor type. PMID- 24815449 TI - Risk factors of postoperative nosocomial pneumonia in stage I-IIIa lung cancer patients. AB - BACKGROUND: To investigate the related risk factors of postoperative nosocomial pneumonia (POP) in patients with I-IIIa lung cancer. METHODS: Medical records of 511 patients who underwent resection for lung cancer between January 2012 to December 2012 were retrospectively reviewed. Risk factors of postoperative pneumonia were identified and evaluated by univariate and multivariate analyses. RESULTS: The incidence of postoperative pneumonia in these lung cancer patients was 2.9% (15 cases). Compared with 496 patients who had no pneumonia infection after operation, older age (>60), histopathological type of squamous cell carcinoma and longer surgery time (>3h) were significant risk factors by univariate analysis. Other potential risk factors such as alcohol consumption, history of smoking, hypersensitivity, hypertension, diabetes mellitus and so on were not showed such significance in this study. Further, the multivariate analysis revealed that old age (>60 years) (OR 5.813, p=0.018) and histopathological type of squamous cell carcinoma (OR 5.831, p<0.001) were also statistically significant independent risk factors for postoperative pneumonia. CONCLUSIONS: This study demonstrated that being old aged (>60 years) and having squamous cell carcinoma histopathological type might be important factors in determining the risk of postoperative pneumonia in lung cancer patients after surgery. PMID- 24815450 TI - Lack of any prognostic value of body mass index for patients undergoing chemoradiotherapy for esophageal squamous cell carcinoma. AB - BACKGROUND: The relationship between body mass index(BMI) and outcomes after chemoradiotherapy(CRT) has not been systematically addressed. The purpose of this study was to evaluate the effect of BMI on survival in patients with esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Sixty ESCC cases were retrospectively reviewed in this study. Patient overall survival(OS) and disease free survival (DFS) were compared between two groups (BMI<24.00 kg/m2 and BMI>=24.00 kg/m2). RESULTS: There were 41 patients in the low/normal BMI group (BMI<24.00 kg/m2) and 19 in the high BMI group (BMI>=24.00 kg/m2). No significant differences were observed in patient characteristics between these. We found no difference in 2-year OS and DFS associated with BMI (p=0.763 for OS; p=0.818 for DFS) using the Kaplan-Meier method. Univariate analysis revealed that higher clinical stage was prognostic for worse 2-year OS and DFS, metastasis for 2-year OS, lymph node status for 2-year DFS, while age, gender, smoking, drinking, tumor location and BMI were not prognostic. There were no differences in the 2-year OS (hazard ratio=1.117; p=0.789) and DFS(hazard ratio=1.161; p=0.708) between BMI groups in multivariate analysis, whereas we found statistical differences in the 2-year OS and DFS associated with clinical stage, gender and tumor infiltration (p<0.04), independent of age, smoking, drinking, tumor location, the status of lymph node metastases and BMI. CONCLUSIONS: BMI was not associated with survival in patients with ESCC treated with CRT as primary therapy. BMI should not be considered a prognostic factor for patients undergoing CRT for ESCC. PMID- 24815451 TI - Social support and quality of life in Turkish patients with gynecologic cancer. AB - The aim of this study was to determine the level of social support and quality of life in Turkish patients with gynecologic cancer using a cross-sectional survey design. A total of 108 patients admitted to the gynecologic oncology clinic at a university hospital from September 2011 to January 2012 were included. Data were collected using patient information forms, the Multidimensional Scale of Perceived Social Support (MSPSS) and The Quality of Life-Cancer Survivors Instrument (QOL-CS). Average age was 54.5+/-10.8 years and it was determined that 65.7% of patients had ovarian cancer and 19.4% had cervical cancer. The total QOL CS mean score was 5.59+/-1.10. Average score of total MSPSS was found to be 69.7+/-14.64. Comparing socio-demographic and clinical characteristics of patients and average scores of QOL-CS and MSPSS, it was found that there was not a statisticaly significant corelation (p>0.05). Statistically significant relation was found between the average scores of QOL-CS and MSPSS. These results showed that quality of life was moderate and perceived social support was high in Turkish patients with gynecologic cancer. PMID- 24815452 TI - Utility of digital rectal examination, serum prostate specific antigen, and transrectal ultrasound in the detection of prostate cancer: a developing country perspective. AB - PURPOSE: To determine the utility of digital rectal examination (DRE), serum total prostate specific antigen (tPSA) estimation, and transrectal ultrasound (TRUS) for the detection of prostate cancer (PCa) in men with lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: All patients with abnormal DRE, TRUS, or serum tPSA >4ng/ml, in any combination, underwent TRUS-guided needle biopsy. Eight cores of prostatic tissue were obtained from different areas of the peripheral prostate and examined histopathologically for the nature of the pathology. RESULTS: PCa was detected in 151 (50.3%) patients, remaining 149 (49.7%) showed benign changes with or without active prostatitis. PCa was detected in 13 (56.5%), 9 (19.1%), 26 (28.3%), and 103 (74.6%) of patients with tPSA <4 ng/ml, 4-10 ng/ml, 10-20 ng/ml and >20 ng/ml respectively. Only 13 patients with PCa had abnormal DRE and TRUS with serum PSA <4 ng/ml. The detection rate was highest in patients with tPSA >20 ng/ml. The association between tPSA level and cancer detection was statistically significant (p<0.01). Among 209 patients with abnormal DRE and raised serum PSA, PCa was detected in 128 (61.2%). CONCLUSIONS: The incidence of PCa increases with increasing serum level of tPSA. The overall screening and detection rate can be further improved by using DRE, TRUS and TRUS-guided prostate needle biopsies. PMID- 24815453 TI - Effects of ribosomal protein l39-L on the drug resistance mechanisms of lung cancer A549 cells. AB - BACKGROUND: Cancer is a major threat to the public health whether in developed or in developing countries. As the most common primary malignant tumor, the morbidity and mortality rate of lung cancer continues to rise in recent ten years worldwide. Chemotherapy is one of the main methods in the treatment of lung cancer, but this is hampered by chemotherapy drug resistance, especially MDR. As a component of the 60S large ribosomal subunit, ribosomal protein L39-L gene was reported to be expressed specifically in the human testis and human cancer samples of various tissue origins. MATERIALS AND METHODS: Total RNA of cultured drug-resistant and susceptible A549 cells was isolated, and real time quantitative RT-PCR were used to indicate the transcribe difference between amycin resistant and susceptible strain of A549 cells. Viability assay were used to show the amycin resistance difference in RPL39-L transfected A549 cell line than control vector and null-transfected A549 cell line. RESULTS: The ribosomal protein L39-L transcription level was 8.2 times higher in drug-resistant human lung cancer A549 cell line than in susceptible A549 cell line by quantitative RT PCR analysis. The ribosomal protein L39-L transfected cells showed enhanced drug resistance compared to plasmid vector-transfected or null-transfected cells as determined by methyl tritiated thymidine (3H-TdR) incorporation. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The ribosomal protein L39-L gene may have effects on the drug resistance mechanism of lung cancer A549 cells. PMID- 24815454 TI - TMPRSS2:ETS fusions and clinicopathologic characteristics of prostate cancer patients from Eastern China. AB - TMPRSS2:ERG gene fusions in prostate cancer have a dominant prevalence of approximately 50.0%, but infomration is limited on differences among ethnic and geographical groups. Some studies focusing on Japanese and Korean patients reported a lower incidence. Investigations concerning Chinese revealed controversial results. We evaluated TMPRSS2:ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions in more than 100 Eastern Chinese prostate cancer patients. Paraffin blocks of needle biopsy and radical prostatectomy were collected from 91 and 18 patients respectively. All patients' clinicopathologic factors were gathered. TMPRSS2:ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions were tested by multi-probe fluorescence in situ hybridization (FISH) assay. TMPRSS2:ERG fusions was present in 14.3% biopsy specimens and 11.1% radical prostatectomy patients. Neither TMPRSS2:ETV1 nor TMPRSS2:ETV4 fusion was found in any case. Altogether, 13 (86.7%) TMPRSS2:ERG fusion positive cases possessed deletion pattern and 7 (46.6%) and insertion pattern. Some 5 cases had both deletion and insertion patterns. While 38.5% (5/13) patients with deletion pattern had distant metastasis, except for one metastatic case harboring both deletion and insertion, there were no patients with insertion pattern accompanied with metastasis. There were no differences between fusion positive and negative cases in the distribution of age, PSA, Gleason score and TNM stage. Eastern Chinese prostate cancer patients have a significantly low incidence of TMPRSS2:ERG fusion. They also lack TMPRSS2:ETV1 and TMPRSS2:ETV4 fusion. There are more deletion pattern than insertion pattern in TMPRSS2:ERG positive cases. Fusion positive and negative patients have no clinicopathologic factor differences. PMID- 24815455 TI - Influence of mammographic screening on breast cancer incidence trends in South Australia. AB - PURPOSE: To examine breast cancer (BC) incidence trends in relation to mammographic screening and risk factor prevalence in South Australia (SA). MATERIALS AND METHODS: Trends in annual BC incidence rates were calculated using direct standardisation and compared with projected incidence derived from Poisson regression analysis of pre-screening rates. Annual percentage change and change time points were estimated using Joinpoint software. Biennial mammography screening participation rates were calculated using data from BreastScreen SA. Trends in overweight/obesity, alcohol use and hormone replacement therapy (HRT) use were examined using 1991-2009 Health Omnibus Survey data. Trends in total fertility were examined using data from the Australian Bureau of Statistics. RESULTS: BC incidence increased around the time BreastScreen commenced and then stabilised in the mid-1990s. However rates have remained higher than projected, even though the proportion and age distribution of first time screening attendees stabilised around 1998. A decrease in BC incidence was observed among women aged 50-59yrs from the late-1990's but not among older women. Obesity and alcohol use have increased steadily in all age groups, while HRT use declined sharply from the late-1990s. CONCLUSIONS: BC incidence has remained higher than projected since mammography screening began. The sustained elevation is likely to be due to lead time effects, though over-diagnosis cannot be excluded. Declining HRT use has also impacted incidence trends. IMPLICATIONS: Studies using individual level data, which can account for changes in risk factor prevalence and lead time effects, are required to evaluate 'over-diagnosis' due to screening. PMID- 24815456 TI - Anticancer effect of COX-2 inhibitor DuP-697 alone and in combination with tyrosine kinase inhibitor (E7080) on colon cancer cell lines. AB - Colorectal cancer remains one of the most common types of cancer and a leading cause of cancer death worldwide. In this study, we aimed to investigate effects of DuP-697, an irreversible selective inhibitor of COX- 2 on colorectal cancer cells alone and in combination with a promising new multi-targeted kinase inhibitor E7080. The HT29 colorectal cancer cell line was used. Real time cell analysis (xCELLigence system) was conducted to determine effects on colorectal cell proliferation, angiogenesis was assessed with a chorioallantoic membrane model and apoptosis was determined with annexin V staining. We found that DuP-697 alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. For the antiproliferative effect the half maximum inhibition concentration (IC50) was 4.28?10-8 mol/L. Antiangiogenic scores were 1.2, 0.8 and 0.5 for 100, 10 and 1 nmol/L DuP-697 concentrations, respectively. We detected apoptosis in 52% of HT29 colorectal cancer cells after administration of 100 nmol/L DuP-697. Also in combination with the thyrosine kinase inhibitor E7080 strong antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells were observed. This study indicates that DuP-697 may be a promising agent in the treatment of colorectal cancer. Additionally the increased effects observed in the combination with thyrosine kinase inhibitor give the possibility to use lower doses of DuP-697 and E7080 which can avoid and/or minimize side effects. PMID- 24815457 TI - Insulin resistance reduces sensitivity to Cis-platinum and promotes adhesion, migration and invasion in HepG2 cells. AB - The liver is normally the major site of glucose metabolism in intact organisms and the most important target organ for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drug resistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubation with a high concentration of insulin. Once the insulin-resistant cell line was established, the instability of HepG2/ IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biological effects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells were determined. The results indicated that glucose consumption was reduced in insulin resistant cells. In addition, the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IR cells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited a lower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatment with the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drug resistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain the clinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasion and migration of cancer cells. PMID- 24815458 TI - rs10505474 and rs7837328 at 8q24 cumulatively confer risk of prostate cancer in Northern Han Chinese. AB - AIMS: Genome-wide association studies (GWAS) have identified several risk variants for prostate cancer (pCa) mainly in Europeans, which need to be further verified in other racial groups. We selected six previously identified variants as candidates and to define the association with PCa in Northern Han Chinese. METHODS: 749 subjects from Beijing and Tianjin in Northern China were included. Six variants (rs10505474, rs7837328, rs4242384, rs7813, rs486907 and rs1058205) were genotyped by high resolution melting (HRM) assays. The individual and cumulative contribution for of the risk of PCa and clinical covariates were analyzed. RESULTS: Among the six candidate variants, only rs10505474, and rs7837328, both locating at 8q24 region, were associated with PCa in our population.rs10505474 (A) was associated with PCa (ORrecessive= 1.56, p=0.006); and rs7837328 (A) was associated with PCa (ORdominant= 1.38, p=0.042/ORrecessive=1.99, p=0.003). Moreover, we observed a cumulative effects between them (ptrend=2.58?10-5). The joint population attributable risk showed the two variants might account for 71.85% of PCa risk. In addition, we found the homozygotes of rs10505474 (A) and rs7837328 (A) were associated with PCa clinical covariants (age at onset, tumor stage, respectively) (page=0.046, Ptumorstage =0.048). CONCLUSION: rs10505474 (A) and rs7387328 (A) at 8q24 are associated with PCa and cumulatively confer risk, suggesting the two variations could determine susceptibility to PCa in the Northern Chinese Han population. PMID- 24815459 TI - Histopathological features of colorectal cancer in Al-Madinah region of Saudi Arabia: 8 years experience. AB - BACKGROUND: To determine the histopathological pattern of colorectal cancer (CRC) among Saudi patients with a view to determine various epidemiological and histopathological features of the disease. MATERIALS AND METHODS: We retrospectively collected and analyzed the demographic and histopathological data of all the patients with CRC diagnosed at King Fahad Hospital, Madinah, Saudi Arabia over a period of 8 years from January 2006 to December 2013. RESULTS: Of 324 cases of CRC reviewed, 200 cases (61.7%) were males while 124 cases (38.3%) were females giving a male to female ratio of 1.6: 1. Age of the patients ranged from 20 to 100 years with a mean age 57.9 years. The rectosigmoid region was the most frequent anatomical site (13.6%) involved and adenocarcinoma (88.6%) was the most common histopathological type. The majority of adenocarcinomas (87.3%) were moderately differentiated. A total of 47.8% of patients were in stage B and 43.5% of patients were in stage C of the Aster-Coller classification. Most patients (75.7%) presented with large size tumors. Lymphovascular invasion and lymph node metastasis were recorded in 67.9% and 43.6% of cases, respectively. CONCLUSIONS: Colorectal cancer is common in our environment and the majority of patients present late with an advanced stage. Screening programs regarding CRC should be enhanced to improve the outcome of the patients. PMID- 24815460 TI - Acupuncture as a complementary treatment for cancer patients receiving chemotherapy. AB - BACKGROUND: Medical treatment for eliminating the side effects of cancer therapy may not always be efficacious. Acupuncture is one of the most widely accepted alternative and complementary therapies in use today. In this study, we investigated the efficacy of acupuncture in patients experiencing cancer treatment side effects, including nausea, vomiting, pain, poor sleep quality and anxiety. MATERIALS AND METHODS: A total of 45 inpatients who underwent chemotherapy between February and April 2013 in the Oncology Department of Numune Hospital were included in our study. Acupuncture was administered to the patients one day prior to chemotherapy, on the day of chemotherapy and one day after chemotherapy. The patients were evaluated on nausea, vomiting, pain, sleep quality and anxiety before the chemotherapy and on the 4th day of chemotherapy. RESULTS: Of the 45 patients included in the study, 18 (40%) were female and 27 (60%) were male. A total of 25 (55.6%) had an elementary school education; 32 patients (71%) had stage 4 cancer and were treated with palliative chemotherapy (the patient characteristics are shown in Table 1). Statistically significant decreases (p<0.001) in pain, nausea, vomiting, insomnia and anxiety scores were observed after the acupuncture treatment compared to baseline. There were no differences in the age, gender, education level, stage or metastasis levels between the patient groups whose symptoms improved or were unchanged. CONCLUSIONS: Our study showed that acupuncture has positive effects in cancer treatment patients who experience nausea, vomiting, pain, poor sleep quality and anxiety as side effects of chemotherapy. Chemotherapy-related side effects in cancer patients could be decreased by the concurrent use of acupuncture. PMID- 24815461 TI - Pathway and network analysis in glioma with the partial least squares method. AB - Gene expression profiling facilitates the understanding of biological characteristics of gliomas. Previous studies mainly used regression/variance analysis without considering various background biological and environmental factors. The aim of this study was to investigate gene expression differences between grade III and IV gliomas through partial least squares (PLS) based analysis. The expression data set was from the Gene Expression Omnibus database. PLS based analysis was performed with the R statistical software. A total of 1,378 differentially expressed genes were identified. Survival analysis identified four pathways, including Prion diseases, colorectal cancer, CAMs, and PI3K-Akt signaling, which may be related with the prognosis of the patients. Network analysis identified two hub genes, ELAVL1 and FN1, which have been reported to be related with glioma previously. Our results provide new understanding of glioma pathogenesis and prognosis with the hope to offer theoretical support for future therapeutic studies. PMID- 24815462 TI - Sorafenib continuation after first disease progression could reduce disease flares and provide survival benefits in patients with hepatocellular carcinoma: a pilot retrospective study. AB - BACKGROUND: Sorafenib is a promising drug for advanced hepatocellular carcinoma (HCC); however, treatment may be discontinued for multiple reasons, such as progressive disease, adverse events, or the cost of treatment. The consequences of sorafenib discontinuation and continuation are uncertain. MATERIALS AND METHODS: We retrospectively analyzed 88 HCC patients treated with sorafenib from July 2007 to January 2013. Overall survival (OS), post-disease progression overall survival (pOS), and time to disease progression (TTP) were compared for survival analysis. Cox proportional hazard regression was performed to assess the effect of important factors on OS in the overall patient population and on pOS in patients who continued sorafenib treatment. RESULTS: Sorafenib was discontinued and continued in 24 and 64 patients, respectively. The median OS (355 vs 517 days respectively; p=0.015) and median post-PD OS (260 vs 317 days, respectively; p=0.020) were statistically different between the discontinuation and continuation groups. Neither the median time to first PD nor the time to second PD were significantly different between the 2 groups. In the discontinuation group, 3 of the 24 patients (12.5%) suffered disease outbreaks. In Cox proportional hazard regression analysis after correction for confounding factors, BCLC stage (p=0.002) and PD site (p=0.024) were significantly correlated with pOS in patients who continued sorafenib treatment. CONCLUSIONS: Sorafenib discontinuation may cause HCC flares or outbreaks. It is advisable to continue sorafenib treatment after first PD, particularly in patients with Barcelona Clinic Liver Cancer stage B disease or only intrahepatic PD. PMID- 24815463 TI - First-line mono-chemotherapy in frail elderly patients with metastatic colorectal cancer. AB - BACKGROUND: Unlike for fit elderly metastatic colorectal cancer (mCRC) patients, general approaches to initial treatment for the frail older mCRC patients are not clear. Our aim was to evaluate the efficiency and safety of first-line single agent treatment in one such group. MATERIALS AND METHODS: We retrospectively evaluated mCRC patients aged 70 or older with an Eastern Cooperative Oncology Group performance score of 2. They had no prior treatment and underwent first line single-agent capecitabine or other monotherapies until disease progression or unacceptable toxicity. RESULTS: Thirty-six patients were included. Most (n:28, 77.8%) were treated with capecitabine. One patient achieved a complete response and 5 patients had a partial response for an overall response rate of 16.6%. Twelve patients (33.3%) remained stable. Median progression free survival was 5 months (confidence interval (CI), %; 3.59-6.40) and median overall survival was 10 months (95 CI%; 8.1-11.8). Grade 3-4 toxicity was found in 6 patients (16.6%). Febrile neutropenia was not observed and there were no toxicity-associated deaths. CONCLUSIONS: Capecitabine is a safe chemotherapeutic agent with moderate activity for first-line treatment of older metastatic colorectal cancer patients with limited performance status. PMID- 24815464 TI - Determinants of choice of surgery in Asian patients with early breast cancer in a middle income country. AB - BACKGROUND: Breast-conserving surgery (BCS) plus radiotherapy is equivalent to modified radical mastectomy (MRM) in terms of outcome. However there is wide variation in mastectomy rates dependent both on tumour and patient characteristics. OBJECTIVE: This study aimed to assess the determinants of surgery choice in Asian patients with early breast cancer in a middle-income country. MATERIALS AND METHODS: 184 patients with early breast cancer treated between Jan 2008 and Dec 2010 were recruited to complete a questionnaire. Chi square test was used to analyze the association between surgery choice and demographic and tumour factors, surgeon recommendation, family member and partner opinions, fear of recurrence, avoidance of second surgery, fear of disfigurement, interference with sex life, fear of radiation and loss of femininity. RESULTS: 85 (46%) had BCS while 99 (54%) had mastectomy. Age >60, Chinese ethnicity, lower education level, and larger tumour size were significantly associated with mastectomy. Surgeon recommendation was important in surgery choice. Although both groups did not place much importance on interference with sex life, 14.1% of the BCS group felt it was very important compared to 5.1% in the mastectomy group and this was statistically significant. There was no statistical difference between the two groups in terms of the other factors. When analyzed by ethnicity, significantly more Malay and Indian women considered partner and family member opinions very important and were more concerned about loss of femininity compared to Chinese women. There were no statistical differences between the three ethnic groups in terms of the other factors. CONCLUSIONS: When counseling on surgical options, the surgeon has to take into account the ethnicity, social background and education level, age and reliance on partner and family members. Decision making is usually a collective effort rather than just between the patient and surgeon, and involving the whole family into the process early is important. PMID- 24815465 TI - Prognostic factors on overall survival of newly diagnosed metastatic nasopharyngeal carcinoma. AB - BACKGROUND: To investigate factors associated with overall survival in patients with newly diagnosed metastatic nasopharyngeal carcinoma. MATERIALS AND METHODS: Two hundred and two consecutive patients with pathologically confirmed nasopharyngeal carcinoma with distant metastasis at diagnosis seen between December 2007 and May 2011 were reviewed. Patient, tumor and treatment factors were analyzed for their significance regarding overall survival. RESULTS: The median follow-up time was 22 months. At the time of this report, 116 patients had died. For 112 patients, cause of death was nasopharyngeal carcinoma. The 1, 2, 3, and 4-year overall survival rates were 75.6%, 50.2%, 39.2%, and 28.2%, respectively. Cox regression multivariate analysis showed that T-stage (p=0.045), N-stage (p=0.014), metastasis number (p<0.001) and radiotherapy for nasopharynx and neck (p<0.001) were significant factors for overall survival. CONCLUSIONS: Early T-stage and N-stage, solitary metastasis in a single organ were good prognostic factors for patients with newly diagnosed metastatic nasopharyngeal carcinoma. Radiotherapy should be strongly recommended in systemic treatment. PMID- 24815466 TI - Inhibitory effects of 3-bromopyruvate on human gastric cancer implant tumors in nude mice. AB - BACKGROUND: Gastric cancer is a common malignant tumor. Our previous study demonstrated inhibitory effects of 3-bromopyruvate (3-BrPA) on pleural mesothelioma. Moreover, we found that 3-BrPA could inhibit human gastric cancer cell line SGC-7901 proliferation in vitro, but whether similar effects might be exerted in vivo have remained unclear. AIM: To investigate the effect of 3-BrPA to human gastric cancer implant tumors in nude mice. MATERIALS AND METHODS: Animals were randomly divided into 6 groups: 3-BrPA low, medium and high dose groups, PBS negative control group 1 (PH7.4), control group 2 (PH 6.8-7.8) and positive control group receiving 5-FU. The TUNEL method was used to detect apoptosis, and cell morphology and structural changes of tumor tissue were observed under transmission electron microscopy (TEM). RESULTS: 3-BrPA low, medium, high dose group, and 5-FU group, the tumor volume inhibition rates were 34.5%, 40.2%, 45.1%, 47.3%, tumor volume of experimental group compared with 2 PBS groups (p<0.05), with no significant difference between the high dose and 5 FU groups (p>0.05). TEM showed typical characteristics of apoptosis. TUNEL demonstrated apoptosis indices of 28.7%, 39.7%, 48.7% for the 3-BrPA low, medium, high dose groups, 42.2% for the 5-FU group and 5% and 4.3% for the PBS1 (PH7.4) and PBS2 (PH6.8-7.8) groups. Compared each experimental group with 2 negative control groups, there was significant difference (p<0.05); there was no significant difference between 5-FU group and medium dose group (p>0.05), but there was between the 5-FU and high dose groups (p<0.05). CONCLUSIONS: This study indicated that 3-BrPA in vivo has strong inhibitory effects on human gastric cancer implant tumors in nude mice . PMID- 24815467 TI - US-guided 14G core needle biopsy: comparison between underestimated and correctly diagnosed breast cancers. AB - BACKGROUND: The purpose of study was to evaluate radiologic or clinical features of breast cancer undergoing ultrasound (US)-guided 14G core needle biopsy (CNB) and analyze the differences between underestimated and accurately diagnosed groups. MATERIALS AND METHODS: Of 1,898 cases of US-guided 14G CNB in our institute, 233 cases were proven to be cancer by surgical pathology. The pathologic results from CNB were invasive ductal carcinoma (IDC) (n=157), ductal carcinoma in situ (DCIS) (n=40), high-risk lesions in 22 cases, and benign in 14 cases. Among high-risk lesions, 7 cases of atypical ductal hyperplasia (ADH) were reported as cancer and 11 cases of DCIS were proven IDC in surgical pathology. Some 29 DCIS cases and 157 cases of IDC were correctly diagnosed with CNB. The clinical and imaging features between underestimated and accurately diagnosed breast cancers were compared. RESULTS: Of 233 cancer cases, underestimation occurred in 18 lesions (7.7%). Among underestimated cancers, CNB proven ADH (n=2) and DCIS (n=11) were diagnosed as IDC and CNB proven ADH (n=5) were diagnosed at DCIS finally. Among the 186 accurately diagnosed group, the CNB results were IDC (n=157) and DCIS (n=29). Comparison of underestimated and accurately diagnosed groups for BI-RADS category, margin of mass on mammography and US and orientation of lesion on US revealed statistically significant differences. CONCLUSIONS: Underestimation of US-guided 14G CNB occurred in 7.7% of breast cancers. Between underestimated and correctly diagnosed groups, BI-RADS category, margin of the mass on mammography and margin and orientation of the lesions on US were different. PMID- 24815469 TI - Regulatory mechanisms of annexin-induced chemotherapy resistance in cisplatin resistant lung adenocarcinoma. AB - Adenocarcinoma of lung has high incidence and a poor prognosis, woith chemotherapy as the main therapeutic tool, most commonly with cisplatin. However, chemotherapy resistance develops in the majority of patients during clinic treatment. Mechanisms of resistance are complex and still unclear. Although annexin play important roles in various tumor resistance mechanisms, their actions in cisplatin-resistant lung adenocarcinoma remain unclear. Preliminary studies by our group found that in cisplatin-resistant lung cancer A549 cells and lung adenocarcinoma tissues, both mRNA and protein expression of annexins A1, A2 and A3 is increased. Using a library of annexin A1, A2 and A3 targeting combined molecules already established by ourselves we found that specific targeting decreased cisplatin-resistance. Taken together, the underlined effects of annexins A1, A2 and A3 on drug resistance and suggest molecular mechanisms in cisplatin-resistant A549 cells both in vivo and in vitro. Furthermore, the study points to improved research on occurrence and development of lung adenocarcinoma, with provision of effective targets and programmes for lung adenocarcinoma therapy in the clinic. PMID- 24815468 TI - Investigation of antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. AB - BACKGROUND: Breast cancer evolution and tumor progression are controlled by complex interactions between steroid receptors and growth factor receptor signaling. Aberrant growth factor receptor signaling can augment or suppress estrogen receptor function in hormone-dependent breast cancer cells. Thus, we aimed to investigate antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. MATERIALS AND METHODS: Cytotoxicity of the sorafenib and lapatinib was tested in MCF-7 cells by XTT assays. 50, 25, 12.5 and 6.25MUM concentrations of sorafenib and 200, 100, 50 and 25MUM concentrations of lapatinib were administered alone and in combination. Results were evaluated as absorbance at 450nM and IC50 values are calculated according to the absorbance data RESULTS: Both sorafenib and lapatinib showed concentration dependent cytotoxic effects on MCF-7 cells. Sorafenib exerted cytotoxic effects with an IC50 value of 32.0MUM; in contrast with lapatinib the IC50 was 136.6MUM. When sorafenib and lapatinib combined, lapatinib increased cytotoxic effects of sorafenib at its ineffective concentrations. Also at the concentrations where both drugs had cytotoxic effects, combination show strong anticancer effects and killed approximately 70 percent of breast cancer cells. CONCLUSIONS: Combinations of tyrosine kinase inhibitors and cytotoxic agents or molecular targeted therapy has been successful for many types of cancer. The present study shows that both sorafenib and lapatinib alone are effective in the treatment of breast cancer. Also a combination of these two agents may be a promising therapeutic option in treatment of breast cancer. PMID- 24815470 TI - Inotodiol inhabits proliferation and induces apoptosis through modulating expression of cyclinE, p27, bcl-2, and bax in human cervical cancer HeLa cells. AB - Inonotus obliquus is a medicinal mushroom that has been used as an effective agent to treat various diseases such as diabetes, tuberculosis and cancer. Inotodiol, an included triterpenoid shows significant anti-tumor effect. However, the mechanisms have not been well documented. In this study, we aimed to explore the effect of inotodiol on proliferation and apoptosis in human cervical cancer HeLa cells and investigated the underlying molecular mechanisms. HeLa cells were treated with different concentrations of inotodiol. The MTT assay was used to evaluate cell proliferating ability, flow cytometry (FCM) was employed for cell cycle analysis and cell apoptosis, while expression of cyclinE, p27, bcl-2 and bax was detected by immunocytochemistry. Proliferation of HeLa cells was inhibited by inotodiolin a dose-dependent manner at 24h (r=0.9999, p<0.01). A sub G1 peak (apoptotic cells) of HeLa cells was detected after treatment and the apoptosis rate with the concentration and longer incubation time (r=1.0, p<0.01), while the percentage of cells in S phase and G2/M phase decreased significantly. Immunocytochemistry assay showed that the expression of cyclin E and bcl-2 in the treated cells significantly decreased, while the expression of p27 and bax obviously increased, compared with the control group (p<0.05). The results of our research indicate that inotodiol isolated from Inonotus obliquus inhibited the proliferation of HeLa cells and induced apoptosis in vitro. The mechanisms may be related to promoting apoptosis through increasing the expression of bax and cutting bcl-2 and affecting the cell cycle by down-regulation the expression of cyclin E and up-regulation of p27. The results further indicate the potential value of inotodiol for treatment of human cervical cancer. PMID- 24815471 TI - Glutathione S-transferase T1 and M1 polymorphisms and risk of uterine cervical lesions in women from central Serbia. AB - The aim of this study was to investigate the frequencies of GSTT1 and GSTM1 deletion polymorphisms in newly-diagnosed patients with uterine cervical lesions from central Serbia. Polymorphisms of GST genes were genotyped in 97 patients with cervical lesions and 50 healthy women using a multiplex polymerase chain reaction (PCR). The GSTM1 null genotype was significantly more prominent among the patients than in controls (74.2% vs 56.0%), the risk associated with lesions being almost 2.3-fold increased (OR=2.26, 95%CI=1.10-4.65, p=0.03) and 3.17-fold higher in patients above >45 years old (95%CI=1.02-9.79, p=0.04). The analysis of the two genotypes demonstrated that GSTM1 null genotype significantly increased risk only for low grade squamous intraepithelial lesion-LSIL (OR=2.81, 95%CI=1.03 7.68, p=0.04). GSTT1 null genotype or different genotype combinations were not found to be risk factors, irrespective to lesion stages, age or smoking. We found that the risk of cervical lesions might be significantly related to the GSTM1 null genotype, especially in women aged above 45 years. Furthermore, the GSTM1 polymorphism might have greater role in development of early stage lesions. PMID- 24815472 TI - Inflammatory breast cancer: a single centre analysis. AB - BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer characterized by rapidly progressive breast erythema, pain and tenderness, oedema and paeu d'orange appearance. It accounts for 1-3% of all newly diagnosed cases of breast cancer in the west. Data on IBC from India are lacking. The aim of our study was to assess the clinical-pathological parameters and outcome of IBC at, All India Institute of Medical Sciences, a large tertiary care centre. MATERIALS AND METHODS: We screened 3,650 breast cancer cases registered from January 2004 to December 2012 and found 41 cases of IBC. Data included demographics as well as clinical, radiological and histopathological characteristics, and were collected from clinical case records using the International Classification of Diseases code (C-50). Patients who presented with IBC as a recurrence, or who had a neglected and advanced breast cancer that simulated an IBC were excluded from this study. RESULTS: The median age was 45 years (range 23-66). The median duration of symptoms was 5 months. The American Joint Committee on Cancer stage (AJCC) distribution was Stage III - 26 and IV - 15 patients. Estrogen receptor (ER), progesterone receptor (PR) positivity and human epidermal growth factor receptor 2 (HER2/neu) positivity were 50%, 46% and 60%, respectively. Triple negativity was found in 15% of the cases. All the non metastatic IBC patients received anthracycline and/ or taxane based chemotherapy followed by modified radical mastectomy , radiotherapy and hormonal therapy as indicated. Pathological complete remission rate was 15%. At a median follow-up of 30 months, the 3 year relapse free survival and overall survival were 30% and 40%respectively. CONCLUSION: IBC constituted 1.1% of all breast cancer patients at our centre. One third of these had metastatic disease at presentation. Hormone positivity and Her2 neu positivity were found in 50% and 60% of the cases, respectively. PMID- 24815473 TI - Radio-sensitization by Piper longumine of human breast adenoma MDA-MB-231 cells in vitro. AB - BACKGROUND: The current study investigated the effects of Piper longumine on radio-sensitization of human breast cancer MDA-MB-231 cells and underlying mechanisms. MATERIALS AND METHODS: Human breast cancer MDA-MB-231 cells were cultured in vitro and those in logarithmic growth phase were selected for experiments divided into four groups: control, X-ray exposed, Piper longumine, and Piper longumine combined with X-rays. Conogenic assays were performed to determine the radio-sensitizing effects. Cell survival curves were fitted by single-hit multi-target model and then the survival fraction (SF), average lethal dose (D0), quasi-threshold dose (Dq) and sensitive enhancement ratio (SER) were calculated. Cell apoptosis was analyzed by flow cytometry (FCM).Western blot assays were employed for expression of apoptosis-related proteins (Bc1-2 and Bax) after treatment with Piper longumine and/or X-ray radiation. The intracellular reactive oxygen species (ROS) level was detected by FCM with a DCFH-DA probe. RESULTS: The cloning formation capacity was decreased in the group of piperlongumine plus radiation, which displayed the values of SF2, D0, Dq significantly lower than those of radiation alone group and the sensitive enhancement ratio (SER) of D0 was1.22 and 1.29, respectively. The cell apoptosis rate was increased by the combination treatment of Piper longumine and radiation. Piper longumine increased the radiation-induced intracellular levels of ROS. Compared with the control group and individual group, the combination group demonstrated significantly decreased expression of Bcl-2 with increased Bax. CONCLUSIONS: Piper longumine at a non-cytotoxic concentration can enhance the radio-sensitivity of MDA- MB-231cells, which may be related to its regulation of apoptosis-related protein expression and the increase of intracellular ROS level, thus increasing radiation-induced apoptosis. PMID- 24815475 TI - Effectiveness of online education in teaching breast self- examination. AB - BACKGROUND: This research evaluated the effectiveness of an online education model in teaching breast self- examination to university staff and students. MATERIALS AND METHODS: 1,679 women participated in a breast self-examination online training program. Breast self-examination knowledge evaluation forms developed by Maurer (1997) were used in the research and were evaluated on a 100 point scale. Paired t-test and McNemar's Test statistics were employed. RESULTS: The participants scored an average of 46.5 (14.0%) on knowledge on breast self examination before training, but 77.4 (11.0%) one month after education and 76.7 (9.52%) after six months. There was a clear significant difference between these knowledge levels (p<0.05). Similarly, while the rate for systematic practice of breast self-examination among women was 30.8% before training it increased to 47.8% afterwards. Again the difference was significant (p<0.05). CONCLUSIONS: Online education is an effective method for teaching breast self-examination to women. PMID- 24815474 TI - Alkylglyceronephosphate synthase (AGPS) alters lipid signaling pathways and supports chemotherapy resistance of glioma and hepatic carcinoma cell lines. AB - Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. beta-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells. PMID- 24815476 TI - Multivariate analysis of prognostic factors in male breast cancer in Serbia. AB - BACKGROUND: The aim of this study was to analyze the demographic and clinical characteristics of male breast cancer patients in Serbia, and furthermore to determine overall survival and predictive factors for prognosis. MATERIALS AND METHODS: In the period of 1996-2006 histopathological diagnosis of breast cancer was made in 84 males at the Institute for Oncology and Radiology of Serbia. For statistical analyses the Kaplan-Meier method, long-rank test and Cox proportional hazards regression model were used. RESULTS: The mean age at diagnosis with breast cancer was 64.3+/-10.5 years with a range from 35-84 years. Nearly 80% of the tumors showed ductal histology. About 44% had early tumor stages (I and II) whereas 46.4% and 9.5% of the male exhibited stages III and IV, respectively. Only 7.1% of male patients were grade one. One-fifth of all patients had tumors measuring <=2 cm, and 14.3% larger than 5 cm. Lymph node metastasis was recorded in 40.4% patients and 47% relapse. Estrogen and progesterone receptor expression was positive in 66.7% and 58.3%, respectively. Among 14.3% of individuals tumor was HER2 positive. About two-thirds of all male patients had radical mastectomy (66.7%). Adjuvant hormonal (tamoxifene), systematic chemotherapy (CMF or FAC) and adjuvant radiotherapy were given to 59.5%, 35.7% and 29.8% patients respectively. Overall survival rates at five and ten years for male breast cancer were 55.0% and 43.9%, respectively. According to the multivariate Cox regression predictive model, a lower initial disease stage, a lower tumor grade, application of adjuvant hormone therapy and no relapse occurrence were significant independent predictors for good overall survival. CONCLUSIONS: Results of the treatment would be better if disease is discovered earlier and therefore health education and screening are an imperative in solving this problem. PMID- 24815477 TI - Human papillomavirus vaccine awareness, acceptability, and decision-making factors among Chinese college students. AB - BACKGROUND: College students are recommended as the target groups for catch-up human papillomavirus (HPV) vaccination. Systematical exploration of awareness, acceptability, and decision-making factors of HPV vaccination among Chinese college students has been limited. MATERIALS AND METHODS: A multi-center survey was conducted in mainland China between November 2011 and May 2012. College students aged 18-22 years were stratified by their grade, gender, and major for sampling. Socio-demographic and HPV-related information such as knowledge, perceptions, acceptability, and attitudes were collected through a questionnaire. RESULTS: A total of 3,497 undergraduates completed the questionnaire, among which 1,686 were males. The acceptability of the HPV vaccine was high (70.8%). Undergraduates from high-level universities, at lower grade, or with greater prior knowledge of HPV vaccines showed higher acceptability of HPV vaccination (ptrend <0.001). Additionally, undergraduates with vaccination experience outside the National Expanded Program on Immunization (OR=1.29; 95%CI: 1.10-1.51) or fear of HPV-related diseases (OR=2.79; 95%CI: 2.28-3.41) were more willing to accept HPV vaccination. General knowledge of HPV vaccine was low among undergraduates, and safety was a major concern (71.05%). The majority of students wished to pay less than 300RMB for HPV vaccine and chose the Chinese Center for Disease Control and Prevention as the most appropriate venue for vaccination. CONCLUSIONS: Although most undergraduates demonstrate positive attitudes towards HPV vaccination, challenges pertaining to introduction exist in China. Corresponding proactive education and governmental subsidy to do so are urgently needed by this age-group population. Suggestions and potential strategies indicated may help shape the future HPV vaccination program in China. PMID- 24815478 TI - E-selectin S128R polymorphism is associated with cancer risk: a meta-analysis. AB - BACKGROUND: Genetic factors have been shown to play an important role in the development of cancers. However, individual studies may fail to completely demonstrate complicated genetic relationships because of small sample size. Therefore, we performed a meta-analysis to evaluate the association of E-selectin Ser128Arg (S128R) with cancer risk. MATERIALS AND METHODS: A literature search in PubMed, Embase, Web of Science, Science Direct, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure databases was carried out to identify studies of the association between E-selectin S128R polymorphism and cancer risk. The odds ratio (OR) with 95% confidence intervals (95%CIs) were used to assess the strength of association. RESULTS: A total of eight studies involving 1,675 cancer cases and 2,285 controls were included in the meta-analysis. In overall populations, S128R polymorphism seemed to be associated with cancer risk (Arg allele vs Ser allele: OR=1.65, 95%CI =1.33-2.04, p<0.01; Arg/Arg+Arg/Ser vs Ser/Ser: OR=1.87, 95%CI =1.48-2.36, p<0.01; Arg/Ser vs Ser/Ser: OR=1.80, 95%CI =1.51-2.14, p<0.01). Similarly, subgroup analysis by ethnicity and source of control also revealed that this polymorphism was related to cancer risk. CONCLUSIONS: Our meta-analysis revealed that there was association between the E selectin S128R polymorphism and the risk of cancer. Further large and well designed studies are needed to confirm this association. PMID- 24815479 TI - Role of household exposure, dietary habits and glutathione S-Transferases M1, T1 polymorphisms in susceptibility to lung cancer among women in Mizoram India. AB - BACKGROUND: A case-control study was conducted to evaluate the effect of household exposure, dietary habits, smoking and Glutathione S-Transferases M1, T1 polymorphisms on lung cancer among women in Mizoram, India. MATERIALS AND METHODS: We selected 230 newly diagnosed primary lung cases and 460 controls from women in Mizoram. Multivariate logistic regression analysis was performed to estimate adjusted odds ratio (OR). RESULTS: Exposure of cooking oil fumes (p<0.003), wood as heating source for cooking (p=0.004), kitchen inside living room (p=0.001), improper ventilated house (p=0.003), roasting of soda in kitchen (p=0.001), current smokers of tobacco (p=0.043), intake of smoked fish (p=0.006), smoked meat (p=0.001), Soda (p<0.001) and GSTM1 null genotype (p=0.003) were significantly associated with increased risk of lung cancer among women in Mizoram. Significantly protective effect was observed for intake of bamboo shoots (p=<0.001) and egg (p<0.001). A clear increase in dose response gradient was observed for total cooking dish years. Risk for lung cancer tends to increase with collegial effect of indoor environmental sources (p=0.022). Significant correlation was also observed for interaction of GST polymorphisms with some of dietary habits. CONCLUSIONS: We confirmed the important role of exposure of cooking oil emission and wood smoke, intake of smoked meat, smoked fish and soda (an alkali preparation used as food additives in Mizoram) and tobacco consumption for increase risk of lung cancer among Women in Mizoram. PMID- 24815480 TI - Serum vascular endothelial growth factor-A (VEGF-A) as a biomarker in squamous cell carcinoma of head and neck patients undergoing chemoradiotherapy. AB - BACKGROUND: To evaluate serum VEGF-A levels in squamous cell carcinoma of head and neck (SCCHN) patients and relationships with response to therapy. MATERIALS AND METHODS: Serum VEGF-A levels in patients (n=72) treated with radiotherapy (RT) or radio-chemotherapy (RCT) and controls (n=40) were measured by ELISA. RESULTS: Serum VEGF-A levels of the SCCHN cases were significantly higher (p=0.001) than in healthy controls, and in patients with positive as compared to negative lymph node status (p=0.004). Similarly, patients with advanced stage (Stage III-IV) disease had more greatly elevated levels of serum VEGF-A level than their early stage (Stage I-II) counterparts (p=0.001). In contrast, there was no significant difference (p=0.57) in serum level of VEGF-A in patients with advanced T-stage (T3-4) as compared to early stage (T1-2). Similarly, patients with distant metastasis had no significant (p=0.067) elevation in serum VEGF-A level as compared to non-metastatic disease. However, the non-responder patients had significantly higher serum VEGF-A level as compared to responders (p=0.001). CONCLUSIONS: Our results suggest that the serum VEGF-A level may be a useful biomarker for the prediction of response to therapy in SCCHN. PMID- 24815481 TI - Methionine synthase reductase A66G polymorphism is not associated with breast cancer susceptibility - a meta-analysis. AB - BACKGROUND: Several studies have investigated the association between methionine synthase reductase (MTRR) A66G polymorphism and breast cancer risk, but controversial results were yielded. Therefore, we performed a meta-analysis to provide a more robust estimate of the effect of this polymorphism on susceptibility to breast cancer. MATERIALS AND METHODS: Case-control studies investigating the relationship between MTRR A66G polymorphism and breast cancer risk were included by searching PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang Database. Either fixed-effects or random-effects models were applied to calculate odds ratios(ORs) and 95% confidence intervals (CIs) by RevMan5.2 software. RESULTS: A total of 9 studies bearing 7,097 cases and 7,710 controls were included in the meta-analysis. The results were that the combined ORs and 95%CIs of MTRR 66AG, GG, (AG+GG) genotypes were 0.98(0.91-1.05), 1.06(0.97-1.16) and 1.02(0.94-1.10), respectively with p=0.52, 0.19 and 0.65. We also performed subgroup analysis by specific ethnicity. The results of the combined analysis of MTRR 66AG, GG, (AG+GG) genotypes and breast cancer in Asian descent were Z=0.50, 0.53 and 0.21, with p all>0.05; for breast cancer in Caucasian descent, the results were Z=1.14, 1.65 and 0.43, with p all>0.05. CONCLUSIONS: Our findings suggested that MTRR A66G polymorphism was not associated with breast cancer susceptibility. PMID- 24815482 TI - An updated meta-analysis between the association of XRCC1 Arg399Gln polymorphism and hepatocellular carcinoma risk. AB - BACKGROUND: Various studies have evaluated the relationship between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and hepatocellular carcinoma (HCC) risk, but the conclusions have been inconsistent and underpowered. The purpose of this updated meta-analysis was to examine whether XRCC1 Arg399Gln polymorphism confers susceptibility to HCC. METHODS: Eligible studies extracted from PubMed, Embase, Cochrane Library, VIP (chinese) and CNKI (chinese) up to November 2013 were included in the study. Pooled odds ratio (OR) together with their 95% confidence interval (CI) were estimated to evaluate XRCC1 Arg399Gln polymorphism and HCC risk. RESULTS: Finally, 21 studies with 4,170 cases and 5,030 controls were involved in our meta-analysis. The results demonstrated that there was significant association between Arg399Gln polymorphism and HCC risk under two contrast models in overall populations (AG vs GG: OR=1.265, 95%CI=1.036-1.545, p=0.021; AA+AG vs GG: OR=1.240, 95%CI=1.021 1.506, p=0.030). In subgroup analyses, significant association was found in Asians (A vs G: OR=1.175, 95%CI=1.013-1.362, p=0.033; AG vs GG: OR=1.317, 95%CI=1.070-1.622, p=0.009; AA+AG vs GG: OR=1.289, 95%CI=1.055-1.575, p=0.013) and Caucasians (A vs G: OR=0.591, 95%CI=0.361-0.966, p=0.036; AA+AG vs GG: OR=0.468, 95%CI=0.234-0.934, p=0.031). CONCLUSIONS: The results suggest that XRCC1 Arg399Gln polymorphism may increase HCC risk especially among Asians. However, XRCC1 Arg399Gln polymorphism might act as a protective role against HCC among Caucasians. PMID- 24815483 TI - Factors associated with organized and opportunistic cancer screening: Results of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2011. AB - BACKGROUND: Cancer is one of the leading causes of death in Korea. To reduce cancer incidence, the Korean National Cancer Center (KNCC) has been expanding its organized cancer screening program. In addition, there are opportunistic screening programs that can be chosen by individuals or their healthcare providers. The purpose of this study was to investigate factors associated with participation in organized and opportunistic cancer screening programs, with a particular focus on socioeconomic factors. MATERIALS AND METHODS: We used data from the Korea National Health and Nutrition Examination Survey (KNHANES), a cross-sectional nationwide study conducted by the Korean Ministry of Health and Welfare from 2007 to 2011. The study included information from 9,708 men and 12,739 women aged 19 years or over. Multinomial logistic regression analysis was conducted, adjusting for age, year of data collection, residential region, current smoking status, current alcohol consumption status, exercise, marriage status, job status, perceived health status, stress level, BMI, limitation of activities, cancer history, health insurance type, and private insurance status, to investigate the association between education level, economic status, and cancer screening participation. RESULTS: In terms of education level, disparities in attendance were observed only for the opportunistic screening program. In contrast, there was no association between education level and participation in organized screening. In terms of economic status, disparities in opportunistic screening participation were observed at all income levels, but disparities in organized screening participation were observed only at the highest income level. CONCLUSIONS: Our findings reveal that socioeconomic factors, including educational level and economic status, were not significantly associated with participation in organized cancer screening, except at the highest level of income. PMID- 24815484 TI - Colorectal carcinoma in Malaysians: DNA mismatch repair pattern in a multiethnic population. AB - BACKGROUND: The interesting preponderance of Chinese with colorectal carcinoma (CRC) amongst the three major ethnic groups in Malaysia prompted a study to determine DNA mismatch repair (MMR) status in our CRC and attempt correlation with patient age, gender and ethnicity as well as location, grade, histological type and stage of tumour. Histologically re-confirmed CRC, diagnosed between 1st January 2005 and 31st December 2007 at the Department of Pathology, University of Malaya Medical Centre, were immunohistochemically stained with monoclonal antibodies to MMR proteins, MLH1, MSH2, MSH6 and PMS2 on the Ventana Benchmark XT autostainer. Of the 142 CRC cases entered into the study, there were 82 males and 60 females (M:F=1.4:1). Ethnically, 81 (57.0%) were Chinese, 32 (22.5%) Malays and 29 (20.4%) Indians. The patient ages ranged between 15-87 years (mean=62.4 years) with 21 cases <50-years and 121 >=50-years of age. 14 (9.9%) CRC showed deficient MMR (dMMR). Concurrent loss of MLH1 and PMS2 occurred in 10, MSH2 and MSH6 in 2 with isolated loss of MSH6 in 1 and PMS2 in 1. dMMR was noted less frequently amongst the Chinese (6.2%) in comparison with their combined Malay and Indian counterparts (14.8%), and was associated with right sided and poorly differentiated tumours (p<0.05). 3 of the 5 (60.0%) dMMR CRC cases amongst the Chinese and 1 of 9 cases (11.1%) amongst the combined Malay and Indian group were <50-years of age. No significant association of dMMR was noted with patient age and gender, tumour stage or mucinous type. PMID- 24815485 TI - Inhibitory effects of alpha-pinene on hepatoma carcinoma cell proliferation. AB - BACKGROUND: Pine needle oil from crude extract of pine needles has anti-tumor effects, but the effective component is not known. METHODS: In the present study, compounds from a steam distillation extract of pine needles were isolated and characterized. Alpha-pinene was identified as an active anti-proliferative compound on hepatoma carcinoma BEL-7402 cells using the MTT assay. RESULTS: Further experiments showed that alpha-pinene inhibited BEL-7402 cells by arresting cell growth in the G2/M phase of the cell cycle, downregulating Cdc25C mRNA and protein expression, and reducing cycle dependence on kinase 1(CDK1) activity. CONCLUSION: Taken together, these findings indicate that alpha-pinene may be useful as a potential anti-tumor drug. PMID- 24815486 TI - Identification of Homer1 as a potential prognostic marker for intrahepatic cholangiocarcinoma. AB - BACKGROUND: The aim of the present study was to analyze whether Homer1 is a potential prognostic marker for intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: The expression of Homer1 in ICC tissue was detected with immunohistochemistry and levels of protein in ICC and paratumor tissues were evaluated by Western blotting. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. RESULTS: Homer1 expression was high in 67.4% (58/86) of ICC samples, and there was significant difference between ICC and adjacent noncancerous tissues (p<0.001); high expression was associated with poor histologic differentiation (p=0.019), TNM stage (p=0.014), lymph node metastasis (p=0.040), and lymphatic invasion (p=0.025). On Kaplan-Meier analysis, a comparison of survival curves of low versus high expressors of Homer1 revealed a highly significant difference in OS (p=0.001) and DFS (p=0.006), indicating that high expression of Homer1 was linked with a worse prognosis. Multivariate analyses showed that Homer1 expression was an independent risk factor predicting overall survival[Hazard ratio(HR), 7.52; 95% confidence interval (CI), 2.63- 21.47; p=0.002] and disease-free survival (HR, 11.56; 95%CI, 5.17-25.96; p<0.001) in ICC. CONCLUSIONS: Homer1 promotes lymphatic invasion and associates with lymph node metastasis and poor prognosis of ICC. The current study shows that Homer1 may be an independent prognostic factor for ICC patients after curative resection, and it provides an important basis for screening/treating high-risk patients. PMID- 24815487 TI - Physical functions, health-related outcomes, nutritional status, and blood markers in community-dwelling cancer survivors aged 75 years and older. AB - BACKGROUND: A cancer survivor is defined as anyone who has been diagnosed with cancer, from the time of diagnosis through the rest of their life. The purpose of this study was to examine whether physical functions, health-related outcomes, nutritional status and blood markers in community-dwelling cancer survivors aged 75 years and older are different from those who do not have cancer MATERIALS AND METHODS: Two hundred seventy-five participants were asked by physicians, nurses, and physical therapists, questions regarding cancer history in a face-to-face interview. Data were collected for demographic information, physical functions, such as handgrip strength, knee extension power, abdominal muscle strength, static standing balance, walking speed and the timed-up-and-go test, health related outcomes, nutritional status, and blood markers. The measured parameters of survivor diagnosed with cancer were compared with those without a history of cancer. RESULTS: Thirty-seven older adults were previously diagnosed with cancer. Female cancer survivors had lower knee extension power (p<0.05), abdominal muscle strength (p<0.05), walking speed (p<0.05), timed-up-and-go test score (p<0.05), and time to spend on walking per day (p<0.05) than older women without a history of cancer. In men, none of the measured parameters were significantly different between cancer survivors and older men with no history of cancer. CONCLUSIONS: The present study shows that partial physical function of women cancer survivors aged 75 years and older differs from that in women with no history of cancer. PMID- 24815488 TI - Differentially expressed proteins in ER+ MCF7 and ER- MDA- MB-231 human breast cancer cells by RhoGDI-alpha silencing and overexpression. AB - BACKGROUND: The consequence of Rho GDP dissociation inhibitor alpha (RhoGDIalpha) activity on migration and invasion of estrogen receptor positive (ER+) and negative (ER-) breast cancer cells has not been studied using the proteomic approach. Changes in expression of RhoGDIalpha and other proteins interacting directly or indirectly with RhoGDIalpha in MCF7 and MDA-MB-231, with different metastatic potentials is of particular interest. MATERIALS AND METHODS: ER+ MCF7 and ER- MDA-MB-231 cell lines were subjected to two-dimensional electrophoresis (2-DE) and spots of interest were identified by matrix-assisted laser desorption/ionization time of- flight/time- of-flight (MALDI-TOF/TOF) mass spectrometry (MS) analysis after downregulation of RhoGDIalpha using short interfering RNA (siRNA) and upregulated using GFP-tagged ORF clone of RhoGDIalpha. RESULTS: The results showed a total of 35 proteins that were either up- or down-regulated in these cells. Here we identifed 9 and 15 proteins differentially expressed with silencing of RhoGDIalpha in MCF-7 and the MDA-MB 231 cells, respectively. In addition, 10 proteins were differentially expressed in the upregulation of RhoGDIalpha in MCF7, while only one protein was identified in the upregulation of RhoGDIalpha in MDA-MB-231. Based on the biological functions of these proteins, the results revealed that proteins involved in cell migration are more strongly altered with RhoGDI-alpha activity. Although several of these proteins have been previously indicated in tumorigenesis and invasiveness of breast cancer cells, some ohave not been previously reported to be involved in breast cancer migration. Hence, these proteins may serve as useful candidate biomarkers for tumorigenesis and invasiveness of breast cancer cells. CONCLUSIONS: Future studies are needed to determine the mechanisms by which these proteins regulate cell migration. The combination of RhoGDIalpha with other potential biomarkers may be a more promising approach in the inhibition of breast cancer cell migration. PMID- 24815489 TI - Clinicopathologic characteristics of breast cancer in Jamaica. AB - Breast cancer is the most common cancer in Jamaican women. This study assessed the clinicopathologic features of cases in a hospital-based specialist clinic in Kingston, Jamaica. A retrospective chart review was performed for the 2-year study period and relevant clinical and surgico-pathologic data were recorded and analyzed. Median age of the 121 breast cancer patients was 52 years (range 22-84, IQR 20) and there was 1 case of male breast cancer. Most patients (65%) were referred from the surgical service after definitive breast cancer surgery, 20% were referred for pre-operative systemic therapy, and 15% had a diagnosis of metastatic disease. The surgico-pathologic group comprised 78 women who were referred for adjuvant therapy. The majority had presented with a palpable breast lump (91%), with median tumour size 3.5cm (range 0.4-13, IQR 4). Most tumours were node positive (56%). Approximately one-third of patients had stage III disease (33%). Most women presented with large palpable tumours and had lymph node involvement confirmed on surgicopathological evaluation, indicative of limited early breast cancer detection. A national screening mammography programme is recommended for detection of earlier lesions. Pre-operative systemic therapy should be considered as an option for eligible patients. PMID- 24815490 TI - Locally advanced breast cancer in Jamaica: prevalence, disease characteristics and response to preoperative therapy. AB - Breast cancer is the most common cancer in Jamaican women. Locally advanced breast cancer (LABC) is associated with aggressive biology and poor prognosis, and has a predilection for African-American women. In this retrospective review, we assessed the prevalence of LABC as a breast cancer presentation in a population of mainly Afro-centric ethnicity, and determined disease characteristics and response to pre-operative chemotherapy. LABC was prevalent (20%), and had a low pathological response rate to pre-operative chemotherapy, with a high risk of disease recurrence. Increased utilization of breast cancer screening may help detect cancer at less advanced stages, and optimizing pre operative chemotherapy is recommended to improve response rates and ultimately survival. PMID- 24815491 TI - Clinicopathological evaluation of odontogenic tumours in Pakistan - a seven years retrospective study. AB - BACKGROUND: The purpose of the study was to analyse the clinicopathological spectrum of benign and malignant odontogenic tumours (OT) in Pakistan. MATERIALS AND METHODS: This retrospective study was carried out at the Armed Forces Institute of Pathology (AFIP) Rawalpindi. Seven years archival records of histologically diagnosed odontogenic tumours, both benign and malignant, were collected and the lesions re-diagnosed histologically in accordance with the WHO classification of head and neck tumours (2005). Clinical as well as histological data were analysed and frequency of each type of OT was calculated using computer software programme SPSS (version 17). Mean tumour size was calculated and Chi square test was applied to find associations of age, gender and site with each histological type of tumour. RESULTS: Only 1.7% of the odontogenic tumours diagnosed in this said period were malignant while the remaining 98.3% were benign. Amongst benign lesions, ameloblastoma was the most common (61.3%) type while primary intraosseous squamous cell carcinoma (1.7%) was the only reported malignant tumour. Mean age of the affected patients was 31.7+/-16.7 years with posterior mandible as the commonest site involved. CONCLUSIONS: Our study revealed ameloblastoma and primary intraosseous squamous cell carcinoma as the commonest diagnosed benign and malignant tumours respectively. There was a significant difference in age and site of origin of different types of OT at the time of their presentation. However, all the tumours showed male predominance. PMID- 24815492 TI - Genetic polymorphisms of TCF7L2 lack influence on risk of the polycystic ovary syndrome - a systemic analysis. AB - BACKGROUND: The results of previous researches that analyzed the association between genetic polymorphisms of transcription factor-7-like 2 (TCF7L2, rs7903146) and polycystic ovary syndrome (PCOS) were conflicting. Current systematic analysis was conducted to re-explore this association using updated materials. MATERIALS AND METHODS: The PubMed database was used for data collection and the final search was conducted on January 3, 2014. For TCF7L2 rs7903146, a non-significant slight increase in risk of PCOS development was observed under three genetic models (dominant model: OR=1.06, 95%CI: 0.93-1.21, p>0.05; recessive model: OR=1.12, 95%CI: 0.87-1.43, p> 0.05; homozygous model: OR=1.14, 95%CI: 0.87-1.47, p>0.05). In the subgroup analyses in Asian group, allele susceptibility of PCOS was calculated (allele model: OR=1.00, 95%CI: 0.74 1.35, p>0.05; dominant model: OR=0.98, 95%CI: 0.71-1.35, p>0.05; recessive model: OR=1.79, 95%CI: 0.33-9.84, p>0.05; homozygous model: OR=1.78, 95%CI: 0.32-9.80, p>0.05), the differences were again not statistically significant. CONCLUSIONS: The findings of this systemic analysis suggest that the polymorphism of TCF7L2 rs7903146 may not be associated with the susceptibility to PCOS. PMID- 24815493 TI - Clinical observations on associations between the UGT1A1 genotype and severe toxicity of irinotecan. AB - BACKGROUND: Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11). UDP glucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but the relationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guide clinical use of CPT-11. MATERIALS AND METHODS: 89 cancer patients with advanced disease received CPT-11-based chemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail and UGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variables and tumor response. RESULTS: The prevalence of grade III IV diarrhea was 10.1%, this being more common in patients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropenia was 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance (p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, 12.75MUmol/L) with compared to TA6/6 (mean, 9.92 MUmol/L) with p<0.05. CONCLUSIONS: Our study support the conclusion that patients with a UGT1A1*28 allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whether with mid-or low dosage. However, the UGT1A1*28 allele (s) did not increase severe neutropenia. Higher serum total bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usage of CPT-11. PMID- 24815494 TI - Long-term therapy of chronic delta hepatitis with peginterferon alfa. AB - BACKGROUND: Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response. AIM: To examine the efficacy and safety of long-term peginterferon in achieving a durable response. METHODS: Treatment was initiated with 180 MUg/week of peginterferon alfa-2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years. RESULTS: Thirteen patients were treated for a median of 140 weeks (6-260) with an average peginterferon dose of 180 MUg/week (90-270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 +/- 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05). CONCLUSION: Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection. PMID- 24815495 TI - Electrocardiographic precordial ST-segment deviations and the risk of cardiovascular death: results from the Copenhagen ECG Study. AB - BACKGROUND: We sought to perform a study assessing the association between electrocardiographic ST-segment deviations and cardiovascular death (CVD), in relation to sex and age (>= and <65 years), in a large primary care population without overt ischemic heart disease. METHODS AND RESULTS: Using computerized analysis of ECGs from 285 194 persons, we evaluated the association between precordial ST-segment deviations and the risk of CVD. All data on medication, comorbidity, and outcomes were retrieved from Danish registries. After a median follow-up period of 5.8 years, there were 6679 cardiovascular deaths. Increasing ST-depression was associated with an increased risk of CVD in almost all of the precordial leads, with the most robust association seen in lead V5 to V6. ST elevations in lead V2 to V6 were associated with increased risk of CVD in young women, but not in men. However, ST-elevations in V1 increased the risk for both genders and age groups, exemplified by a HR of 1.80 (95% CI [1.19 to 2.74], P=0.005) for men <65 years with ST-elevations >= 150 MUV versus a nondeviating ST segment (-50 MUV to +50 MUV). In contrast, for men <65 years, ST-elevations in lead V2 to V3 conferred a decreased risk of CVD with a HR of 0.77 (95% CI [0.62 to 0.96], P<0.001) for ST-elevations >= 150 MUV in V2. CONCLUSION: We found that ST-depressions were associated with a dose-responsive increased risk of CVD in nearly all the precordial leads. ST-elevations conferred an increased risk of CVD in women and with regard to lead V1 also in men. However, ST-elevations in V2 to V3 were associated with a decreased risk of CVD in young men. PMID- 24815496 TI - Carotid intima-media thickness is associated with incident heart failure among middle-aged whites and blacks: the Atherosclerosis Risk in Communities study. AB - BACKGROUND: Increased carotid intima-media thickness (IMT) is associated with subclinical left ventricular myocardial dysfunction, suggesting a possible role of carotid IMT in heart failure (HF) risk determination. METHODS AND RESULTS: Mean far wall carotid IMT, measured by B-mode ultrasound, was available for 13 590 Atherosclerosis Risk in Communities study participants aged 45 to 64 years and free of HF at baseline. HF was defined using ICD-9 428 and ICD-10 I-50 codes from hospitalization records and death certificates. The association between carotid IMT and incident HF was assessed using Cox proportional hazards analysis with models adjusted for demographic variables, major CVD risk factors, and interim CHD. There were 2008 incident HF cases over a median follow-up of 20.6 years (8.1 cases per 1000 person-years). Mean IMT was higher in those with HF than in those without (0.81 mm +/- 0.23 versus 0.71 mm +/- 0.17, P<0.001). Unadjusted rate of HF for the fourth compared with the first quartile of IMT was 15.4 versus 3.9 per 1000 person-years; P<0.001. In multivariable analysis, after adjustment, each standard deviation increase in IMT was associated with incident HF (HR 1.20 [95% CI: 1.16 to 1.25]). After adjustment, the top quartile of IMT was associated with HF (HR 1.60 [95% CI: 1.37 to 1.87]). Results were similar across race and gender groups. CONCLUSIONS: Increasing carotid IMT is associated with incident HF in middle-aged whites and blacks, beyond risks explained by major CVD risk factors and CHD. This suggests that carotid IMT may be associated with HF through mechanisms different from myocardial ischemia or infarction. PMID- 24815498 TI - Detection of malignant B lymphocytes by PCR clonality assay using direct lysis of cerebrospinal fluid and low volume specimens. AB - INTRODUCTION: The diagnosis of lymphoid malignancies is often challenging in paucicellular specimens. PCR may also be limited by insufficient cells for DNA isolation and incomplete coverage of gene rearrangements. This study aims to evaluate a PCR method for IgH clonality using direct cell lysates. METHODS: PCR amplification used cell lysate from detergent-based lysis and BIOMED-2 primers. CSF specimens were tested for 20 patients with primary CNS lymphoma or systemic lymphoma suspected for CNS involvement. Cytology and flow cytometry analysis was performed in parallel with PCR. RESULTS: Direct lysis produced a better yield than the column-based method for DNA isolation. PCR using lysate showed an efficiency of clonality detection from a minimum of 20 tumor cells. PCR clonality was found in nine of the 20 CSFs, and positive PCR was concordant with both cytology and flow cytometry in seven cases. There were two cases positive for PCR, but indeterminate for flow cytometry because of insufficient cell events. Of the eleven PCR-negative cases, two were considered as false negative, as flow cytometry showed positive for malignant cells. The PCR was also performed successfully with a specimen from the anterior chamber of the eye. CONCLUSION: PCR clonality with direct cell lysis of CSF is feasible, and it may overcome the limitation of DNA isolation. This PCR method may be particularly useful for small volume and low cell CSF when flow cytometry is inconclusive. PMID- 24815499 TI - Randomized, controlled trial to improve self-care in patients with heart failure living in rural areas. AB - BACKGROUND: Patients with heart failure (HF) who live in rural areas have less access to cardiac services than patients in urban areas. We conducted a randomized, clinical trial to determine the impact of an educational intervention on the composite end point of HF rehospitalization and cardiac death in this population. METHODS AND RESULTS: Patients (n=602; age, 66+/-13 years; 41% female; 51% with systolic HF) were randomized to 1 of 3 groups: control (usual care), Fluid Watchers LITE, or Fluid Watchers PLUS. Both intervention groups included a face-to-face education session delivered by a nurse focusing on self-care. The LITE group received 2 follow-up phone calls, whereas the PLUS group received biweekly calls (mean, 5.3+/-3.6; range, 1-19) until the nurse judged the patient to be adequately trained. Over 2 years of follow-up, 35% of patients (n=211) experienced cardiac death or hospitalization for HF, with no difference among the 3 groups in the proportion who experienced the combined clinical outcome (P=0.06). Although patients in the LITE group had reduced cardiac mortality compared with patients in the control group over the 2 years of follow-up (7.5% and 17.7%, respectively; P=0.003), there was no significant difference in cardiac mortality between patients in the PLUS group and the control group. CONCLUSIONS: A face-to-face education intervention did not significantly decrease the combined end point of cardiac death or hospitalization for HF. Increasing the number of contacts between the patient and nurse did not significantly improve outcome. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00415545. PMID- 24815497 TI - Cyclooxygenases 1 and 2 differentially regulate blood pressure and cerebrovascular responses to acute and chronic intermittent hypoxia: implications for sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)-induced inflammation. Cyclooxygenase (COX)-formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH. METHODS AND RESULTS: Twelve healthy, male participants underwent three, 6-hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex((r)) (selective COX-2 inhibitor) in a double-blind, randomized, crossover study design. Pre- and post-IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre-IH blood pressure (P <= 0.04) and decreased pre-IH CBF (P=0.04) while neither physiological variable was affected by COX-2 inhibition (P >= 0.90). Post-IH, MAP was elevated (P <= 0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX-2 inhibition abrogated the IH-induced MAP increase (P=0.19), but resulted in lower post-IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P <= 0.4) and COX-1 formed thromboxane A2 concentrations (P=0.02). CONCLUSIONS: COX-2 and COX-1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX-1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01280006. PMID- 24815500 TI - HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter defibrillator therapy in patients who are not included or not well represented in clinical trials. PMID- 24815501 TI - Evaluation of interval times from onset to reperfusion in patients undergoing endovascular therapy in the Interventional Management of Stroke III trial. AB - BACKGROUND: Meaningful delays occurred in the Interventional Management of Stroke (IMS) III trial. Analysis of the work flow will identify factors contributing to the in-hospital delays. METHODS AND RESULTS: In the endovascular arm of the IMS III trial, the following time intervals were calculated: stroke onset to emergency department arrival; emergency department to computed tomography (CT); CT to intravenous tissue plasminogen activator start; intravenous tissue plasminogen activator start to randomization; randomization to groin puncture; groin puncture to thrombus identification; thrombus identification to start of endovascular therapy; and start of endovascular therapy to reperfusion. The effects of enrollment time, CT angiography use, interhospital transfers, and intubation on work flow were evaluated. Delays occurred notably in the time intervals from intravenous tissue plasminogen activator initiation to groin puncture (median 84 minutes) and start of endovascular therapy to reperfusion (median 85 minutes). The CT to groin puncture time was significantly shorter during working hours than after. Times from emergency department to reperfusion and groin puncture to reperfusion decreased over the trial period. Patients with CT angiography had shorter emergency department to reperfusion and onset to reperfusion times. Transfer of patients resulted in a longer onset to reperfusion time compared with those treated in the same center. Age, sex, National Institutes of Health Stroke Scale score, and intubation did not affect delays. CONCLUSIONS: Important delays were identified before reperfusion in the IMS III trial. Delays decreased as the trial progressed. Use of CT angiography and endovascular treatment in the same center were associated with time savings. These data may help in optimizing work flow in current and future endovascular trials. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424. PMID- 24815502 TI - Clinicopathological analysis of 17 primary cutaneous T-cell lymphoma of the gammadelta phenotype from Japan. AB - Primary cutaneous gammadelta T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated gammadelta T-cells of a cytotoxic phenotype. Because primary cutaneous gammadelta T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) gammadelta cells are typically immunostained in frozen sections or determined by TCRbeta negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the gammadelta phenotype (CTCL-gammadelta) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-gammadelta without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-gammadelta with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-gammadelta patients with SPTCL features and SPTCL-gammadelta patients described in the previous literature. A univariate analysis of 17 CTCL-gammadelta patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-gammadelta patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-gammadelta with SPTCL features and CTCL gammadelta without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-gammadelta. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas. PMID- 24815503 TI - Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert((r)) HIT) for the diagnosis of heparin-induced thrombocytopenia. AB - A rapid lateral flow immunoassay (LFIA) (STic Expert((r)) HIT), recently developed for the diagnosis of heparin-induced thrombocytopenia (HIT), was evaluated in a prospective multicentre cohort of 334 consecutive patients. The risk of HIT was estimated by the 4Ts score as low, intermediate and high in 28.7%, 61.7% and 9.6% of patients, respectively. Definite HIT was diagnosed in 40 patients (12.0%) with positive results on both enzyme-linked immunosorbent assay (Asserachrom((r)) HPIA IgG) and serotonin release assay. The inter-reader reproducibility of results obtained was excellent (kappa ratio > 0.9). The negative predictive value of LFIA with plasma samples was 99.6% with a negative likelihood ratio (LR) of 0.03, and was comparable to those of the particle gel immunoassay (H/PF4-PaGIA((r)) ) performed in 124 cases. Positive predictive value and positive LR were 44.4% and 5.87, respectively, and the results were similar for serum samples. The probability of HIT in intermediate risk patients decreased from 11.2% to 0.4% when the LFIA result was negative and increased to 42.5% when it was positive. In conclusion, the STic Expert((r)) HIT combined with the 4Ts score is a reliable tool to rule out the diagnosis of HIT. PMID- 24815504 TI - Three-dimensional dosimetry of the full and empty bladder in high dose rate vaginal cuff brachytherapy. AB - OBJECTIVES: The objectives of the study were to assess the bladder doses during vaginal cuff brachytherapy and to examine the effect of bladder filling on normal tissue dosimetry by means of computed tomography. MATERIALS AND METHODS: A total number of 45 women were enrolled in a prospective clinical trial. Patients were treated with the application of a single-line source vaginal cylinder. All the patients were asked to consume 400 mL of water 40 minutes before computed tomography scans were taken. For each patient, 2 treatment plans were performed one with full bladder and the other one when the bladder was emptied. A dose volume histogram and the equivalent of 2-Gy dose for full and empty bladder were calculated. Doses to the bowels in 2 states of the bladder were estimated. RESULTS: Thirty-five patients received a lower dose to the empty bladder than to the filled organ. The average dose difference was 0.5 Gy. Ten patients received a lower dose to the full bladder than to the empty one. However, in this case, the difference amounted only to 0.2 Gy on average. Dose parameters (the maximal dose received by 0.1 cm of tissue and the maximal dose received by 2 cm of tissue) were lower in the empty state, but the volumetric parameters (the percent of bladder volume receiving >=50% of the prescribed dose and the percent of bladder volume receiving >=80% of the prescribed dose) were higher in the empty state of the bladder. Doses to the bowels seemed to be higher in the empty bladder. However, none of the doses exceeded the limitations. CONCLUSIONS: The results have shown that in most cases, the dose to the empty bladder is lower than when the bladder is full. Simultaneously, the doses to the bowels increase proportionally in the empty state of the bladder comparing to the full organ. Protection of the bowels, which are more radiosensitive, suggests treating the patients in the full state of the bladder. Early and late bowel toxicity should be investigated to establish clear standards of treatment. PMID- 24815505 TI - Alternative automatic alignment method for specimen tilt-series images based on back-projected volume data cross-correlations. AB - We devised a new automatic image alignment method for a specimen tilt series; this method is based on the volume data cross-correlation among 3-D cross sections reconstructed from different sets of projection images (including a single image) for tilt-series alignment or tilt-axis search purposes. This method requires neither markers nor image feature points traceable through the tilt series, and it was examined through simulations and applied to biological thin sections. The method automatically aligned tilt series centred at the correctly detected tilt axis with a precision sufficient for practical applications. PMID- 24815506 TI - Use of belatacept to maintain adequate early immunosuppression in calcineurin mediated microangiopathic hemolysis post-renal transplant. AB - We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group. PMID- 24815507 TI - Estimated intakes and sources of total and added sugars in the Canadian diet. AB - National food supply data and dietary surveys are essential to estimate nutrient intakes and monitor trends, yet there are few published studies estimating added sugars consumption. The purpose of this report was to estimate and trend added sugars intakes and their contribution to total energy intake among Canadians by, first, using Canadian Community Health Survey (CCHS) nutrition survey data of intakes of sugars in foods and beverages, and second, using Statistics Canada availability data and adjusting these for wastage to estimate intakes. Added sugars intakes were estimated from CCHS data by categorizing the sugars content of food groups as either added or naturally occurring. Added sugars accounted for approximately half of total sugars consumed. Annual availability data were obtained from Statistics Canada CANSIM database. Estimates for added sugars were obtained by summing the availability of "sugars and syrups" with availability of "soft drinks" (proxy for high fructose corn syrup) and adjusting for waste. Analysis of both survey and availability data suggests that added sugars average 11%-13% of total energy intake. Availability data indicate that added sugars intakes have been stable or modestly declining as a percent of total energy over the past three decades. Although these are best estimates based on available data, this analysis may encourage the development of better databases to help inform public policy recommendations. PMID- 24815508 TI - Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors. AB - The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC50s against PARP-1 enzyme. PMID- 24815509 TI - Discovery of camphor-derived pyrazolones as 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. AB - Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7 hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11betaHSD1. PMID- 24815510 TI - Synthesis of 2'-O,4'-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase. AB - The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'-C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2'-C methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay. PMID- 24815511 TI - Synthesis and antiproliferative studies of 5-aryl-2-(3-thienylamino)-1,3,4 thiadiazoles. AB - A series of 5-aryl-2-(3-thienylamino)-1,3,4-thiadiazoles 3a-m were synthesized in good yields in two steps starting from thiophen-3-isothiocyanates. Those compounds as well as the thiosemicarbazide intermediates 2a-m were screened for their antiproliferative activity against a panel of six cancer cell lines. Among them, two 5-aryl-2-(3-thienylamino)-1,3,4-thiadiazoles (3f and 3i) have shown very interesting results with IC50 <10MUM on three cell lines. PMID- 24815512 TI - Synthesis and radiolabeling of (111)In-core-cross linked polymeric micelle octreotide for near-infrared fluoroscopy and single photon emission computed tomography imaging. AB - The objective of this study was the development of a dual-modality imaging device, namely (111)In-core-cross-linked polymeric micelle (CCPM)-octreotide, for neuroendocrine tumor detection, using near-infrared fluoroscopy (NIRF) and single photon emission computed tomography (SPECT). The tumor targeting ability of the (111)In-labeled CCPM-octreotide was evaluated in a tumor mouse model. SPECT/CT, NIRF and gamma imaging results showed high tumor uptake of (111)In-labeled CCPM octreotide. In contrast, there was a much lower signal in the same mouse model injected with (111)In-labeled CCPM. The high accumulation of (111)In-labeled CCPM octreotide in U87 tumor was reduced after co-injection with an excess amount of CCPM-octreotide. These results suggested CCPM-octreotide's potential applications in tumor diagnosis, drug delivery and molecular imaging. PMID- 24815513 TI - Ruggedness and reproducibility of the MBEC biofilm disinfectant efficacy test. AB - The MBECTM Physiology & Genetics Assay recently became the first approved ASTM standardized biofilm disinfectant efficacy test method. This report summarizes the results of the standardization process using Pseudomonas aeruginosa biofilms. Initial ruggedness testing of the MBEC method suggests that the assay is rugged (i.e., insensitive) to small changes to the protocol with respect to 4 factors: incubation time of the bacteria (when varied from 16 to 18h), treatment temperature (20-24 degrees C), sonication duration (25-35min), and sonication power (130-480W). In order to assess the repeatability of MBEC results across multiple tests in the same laboratory and the reproducibility across multiple labs, an 8-lab study was conducted in which 8 concentrations of each of 3 disinfectants (a non-chlorine oxidizer, a phenolic, and a quaternary ammonium compound) were applied to biofilms using the MBEC method. The repeatability and reproducibility of the untreated control biofilms were acceptable, as indicated by small repeatability and reproducibility standard deviations (SD) (0.33 and 0.67 log10(CFU/mm(2)), respectively). The repeatability SDs of the biofilm log reductions after application of the 24 concentration and disinfectant combinations ranged from 0.22 to 1.61, and the reproducibility SDs ranged from 0.27 to 1.70. In addition, for each of the 3 disinfectant types considered, the assay was statistically significantly responsive to the increasing treatment concentrations. PMID- 24815514 TI - The restorative effect of intramuscular injection of tetanus toxin C-fragment in hemiparkinsonian rats. AB - The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a peptide that has a neuroprotective action against dopaminergic damage by MPP(+), both in vitro and in vivo. The trophic effects of Hc-TeTx have been related to its ability to activate the pathways of the tropomyosin receptor kinase, which are crucial for survival process. Our group had previously shown neuroprotective effect of intramuscular Hc-TeTx treatment on animals with a dopaminergic lesion; however, there is no evidence indicating its restorative effects on advanced dopaminergic neurodegeneration. The aim of our study was to examine the restorative effects of an intramuscular injection of the Hc-TeTx fragment on the nigrostriatal system of hemiparkinsonian rats. The animals were administered with a vehicle or Hc-TeTx (20MUg/kg) in the gastrocnemius muscle for three consecutive days post-dopaminergic lesion, which was made using 6-hydroxydopamine. Post-Hc TeTx treatment, the hemiparkinsonian rats showed constant motor asymmetry. Moreover, the ipsilateral striatum of the post-Hc-TeTx group had a lower number of argyrophilic structures and a major immunorreactivity to Tyrosine Hydroxylase in the striatum and the substantia nigra pars compacta compared to the 6-OHDA group. Our results show the restorative effect of the Hc-TeTx fragment during the dopaminergic neurodegeneration caused by 6-OHDA. PMID- 24815515 TI - Effects of pharmacological inhibition of AMP-activated protein kinase on GLUT3 expression and the development of ischemic tolerance in astrocytes. AB - Ischemic tolerance resulting from preconditioning ischemia is a neuroprotective mechanism. In cultured astrocytes, its development depends on regulation of the expression of glucose transporter 3 (GLUT3) by the stress sensor/effector AMP activated protein kinase (AMPK). Here we demonstrate that GLUT3 is upregulated during preconditioning and then downregulated during recovery. We also found that, although AMPK inhibition during preconditioning initially suppressed the upregulation of GLUT3 as shown previously, this was followed by a period of GLUT3 upregulation, enhanced glycogen accumulation, and enhanced tolerance to a subsequent ischemic challenge. These results reveal that AMPK has a complex influence on ischemic tolerance. PMID- 24815516 TI - The dramatic increase in the rate of methylisothiazolinone contact allergy in Belgium: a multicentre study. AB - BACKGROUND: The rate of contact allergy and allergic contact dermatitis caused by methylisothiazolinone (MI) is dramatically increasing throughout Europe. OBJECTIVES: To report on methylchloroisothiazolinone (MCI)/MI and MI allergy in Belgium. PATIENTS AND METHODS: Between January 2010 and December 2012, the medical charts of 6599 patients of the Belgian Contact and Environmental Dermatitis Group were retrospectively reviewed for MCI/MI and MI sensitization by use of a standardized questionnaire. Available data on sensitization in 2081 patients tested in 2013 were also included. RESULTS: In 2012, the sensitization rate for MCI/MI had increased to 4.5% and that for MI to 6.0%; the latter showed a further increase to 7.2% in 2013. The people mainly affected were women with a median age of 49 years with hand and/or facial dermatitis, most often resulting from the use of cosmetics. Simultaneous reactions to octylisothiazolinone were observed. CONCLUSION: A dramatic increase in the rate of contact allergy caused by MI in cosmetics is occurring in Belgium. Notwithstanding the recent recommendation to discontinue the use of MI in leave-on cosmetics, safer use concentrations should also be determined for rinse-off products. Close monitoring of MI sensitization in the near future will be necessary, and the highest test concentrations reported for MI and MCI/MI should be included in the baseline series. PMID- 24815517 TI - Quantitatively probing the Al distribution in zeolites. AB - The degree of substitution of Si(4+) by Al(3+) in the oxygen-terminated tetrahedra (Al T-sites) of zeolites determines the concentration of ion-exchange and Bronsted acid sites. Because the location of the tetrahedra and the associated subtle variations in bond angles influence the acid strength, quantitative information about Al T-sites in the framework is critical to rationalize catalytic properties and to design new catalysts. A quantitative analysis is reported that uses a combination of extended X-ray absorption fine structure (EXAFS) analysis and (27)Al MAS NMR spectroscopy supported by DFT-based molecular dynamics simulations. To discriminate individual Al atoms, sets of ab initio EXAFS spectra for various T-sites are generated from DFT-based molecular dynamics simulations, allowing quantitative treatment of the EXAFS single- and multiple-photoelectron scattering processes out to 3-4 atom shells surrounding the Al absorption center. It is observed that identical zeolite types show dramatically different Al distributions. A preference of Al for T-sites that are part of one or more 4-member rings in the framework over those T-sites that are part of only 5- and 6-member rings in an HBEA150 zeolite has been determined using this analysis. PMID- 24815518 TI - Unusual structural features revealed by the solution NMR structure of the NLRC5 caspase recruitment domain. AB - The cytosolic nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) are key sensors for bacterial and viral invaders and endogenous stress signals. NLRs contain a varying N-terminal effector domain that regulates the downstream signaling events upon its activation and determines the subclass to which a NLR member belongs. NLRC5 contains an unclassified N-terminal effector domain that has been reported to interact downstream with the tandem caspase recruitment domain (CARD) of retinoic acid-inducible gene I (RIG-I). Here we report the solution structure of the N-terminal effector domain of NLRC5 and in vitro interaction experiments with the tandem CARD of RIG-I. The N-terminal effector domain of NLRC5 adopts a six alpha-helix bundle with a general death fold, though it displays specific structural features that are strikingly different from the CARD. Notably, alpha-helix 3 is replaced by an ordered loop, and alpha-helix 1 is devoid of the characteristic interruption. Detailed structural alignments between the N-terminal effector domains of NLRC5 with a representative of each death-fold subfamily showed that NLRC5 fits best to the CARD subfamily and can be called an atypical CARD. Due to the specific structural features, the atypical CARD also displays a different electrostatic surface. Because the shape and charge of the surface is crucial for the establishment of a homotypic CARD-CARD interaction, these specific structural features seem to have a significant effect on the interaction between the atypical CARD of NLRC5 and the tandem RIG-I CARD. PMID- 24815519 TI - Polymorphisms in sodium-dependent vitamin C transporter genes and plasma, aqueous humor and lens nucleus ascorbate concentrations in an ascorbate depleted setting. AB - We have previously reported low concentrations of plasma ascorbate and low dietary vitamin C intake in the older Indian population and a strong inverse association of these with cataract. Little is known about ascorbate levels in aqueous humor and lens in populations habitually depleted of ascorbate and no studies in any setting have investigated whether genetic polymorphisms influence ascorbate levels in ocular tissues. Our objectives were to investigate relationships between ascorbate concentrations in plasma, aqueous humor and lens and whether these relationships are influenced by Single Nucleotide Polymorphisms (SNPs) in sodium-dependent vitamin C transporter genes (SLC23A1 and SLC23A2). We enrolled sixty patients (equal numbers of men and women, mean age 63 years) undergoing small incision cataract surgery in southern India. We measured ascorbate concentrations in plasma, aqueous humor and lens nucleus using high performance liquid chromatography. SLC23A1 SNPs (rs4257763, rs6596473) and SLC23A2 SNPs (rs1279683 and rs12479919) were genotyped using a TaqMan assay. Patients were interviewed for lifestyle factors which might influence ascorbate. Plasma vitamin C was normalized by a log10 transformation. Statistical analysis used linear regression with the slope of the within-subject associations estimated using beta (beta) coefficients. The ascorbate concentrations (MUmol/L) were: plasma ascorbate, median and inter-quartile range (IQR), 15.2 (7.8, 34.5), mean (SD) of aqueous humor ascorbate, 1074 (545) and lens nucleus ascorbate, 0.42 (0.16) (MUmol/g lens nucleus wet weight). Minimum allele frequencies were: rs1279683 (0.28), rs12479919 (0.30), rs659647 (0.48). Decreasing concentrations of ocular ascorbate from the common to the rare genotype were observed for rs6596473 and rs12479919. The per allele difference in aqueous humor ascorbate for rs6596473 was -217 MUmol/L, p < 0.04 and a per allele difference in lens nucleus ascorbate of -0.085 MUmol/g, p < 0.02 for rs12479919. The beta coefficients for the regression of log10 plasma ascorbate on aqueous humor ascorbate were higher for the GG genotype of rs6596473: GG, beta = 1460 compared to carriage of the C allele, CG, beta = 1059, CC, beta = 1132, p interaction = 0.1. In conclusion we found that compared to studies in well-nourished populations, ascorbate concentrations in the plasma, aqueous humor and lens nucleus were low. We present novel findings that polymorphisms in SLC23A1/2 genes influenced ascorbate concentration in aqueous humor and lens nucleus. PMID- 24815520 TI - Electrospun water-soluble polymer nanofibers for the dehydration and storage of sensitive reagents. AB - The ability to preserve and deliver reagents remains an obstacle for the successful deployment of self-contained diagnostic microdevices. In this study we investigated the ability of bacteriophage T7 to be encapsulated and preserved in water soluble nanofibers. The bacteriophage T7 was added to mixtures of polyvinylpyrrolidone and water and electrospun onto a grounded plate. Trehalose and magnesium salts were added to the mixtures to determine their effect on the infectivity of the bacteriophage following electrospinning and during storage. The loss of T7 infectivity was determined immediately following electrospinning and during storage using agar overlay plating and plaque counting. The results indicate that the addition of magnesium salts protects the bacteriophage during the relatively violent and high voltage electrospinning process, but is not as effective as a protectant during storage of the dried T7. Conversely, the addition of trehalose into the electrospinning mix has little effect on the electrospinning, but a more significant role as a protectant during storage. PMID- 24815521 TI - Therapeutic use of noninvasive brain stimulation methods, cognitive and biological characteristics in eating disorders as well as probable long-term effects of stress. Editorial. PMID- 24815522 TI - Prenatal stress and limbic-prefrontal white matter microstructure in children aged 6-9 years: a preliminary diffusion tensor imaging study. AB - OBJECTIVES: Maternal prenatal stress is associated with elevated risk of adverse behavioural outcomes in offspring. This association may involve developmental disruption to limbic-prefrontal white matter circuitry, of which the uncinate fasciculus is the major tract. One potential candidate for modulating brain development is maternal prenatal stress. We provide the first prospective study of prenatal stress and white matter microstructure in children. METHODS: A total of 22 healthy children (mean age 7 years) of mothers recruited in pregnancy underwent diffusion tensor magnetic resonance imaging. We examined correlations between prenatal stressful life events and white matter microstructural organisation indices (fractional anisotropy (FA) and perpendicular diffusivity (Dperp)) of the uncinate fasciculus and a "control" tract. RESULTS: Maternal prenatal stressful life events were correlated positively with right uncinate fasciculus FA, and negatively with right uncinate fasciculus Dperp in their child, with a similar trend with left uncinate fasciculus Dperp. Prenatal stress was not associated with control tract properties; sociodemographic/obstetric variables were not associated with FA/Dperp of either tract. CONCLUSIONS: Variation in maternal prenatal stress may be associated with differences in the development of white matter within brain networks underlying child social behaviour. PMID- 24815523 TI - Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy associated cardiomyopathy. AB - BACKGROUND: Mutations in SCN5A, which encodes the cardiac sodium channel NaV1.5, typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia. OBJECTIVE: The purpose of this study was to determine the clinical, genetic, and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain. METHODS: A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P expressed heterologously in tsA201 cells. RESULTS: Mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window and ramp currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current, and caused frequency-dependent inhibition of channel availability. CONCLUSION: We determined the functional consequences and pharmacologic responses of a novel SCN5A mutation associated with an arrhythmia associated cardiomyopathy. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation as a shared biophysical mechanism of the syndrome. PMID- 24815524 TI - Novel ICD therapy begets novel ICD detection: first look at the performance of the subcutaneous ICD discrimination algorithm. PMID- 24815525 TI - [Tako-tsubo syndrome: analysis of a series of 60 cases]. AB - BACKGROUND AND OBJECTIVE: The Tako-tsubo syndrome (TS) is a reversible acute cardiomyopathy simulating an infarction. We analyzed 60 patients admitted with TS in our center. PATIENTS AND METHOD: A percentage of 73.3 were women (mean age: 70.6 +/- 11.8 years); 83.3% had some cardiovascular risk factor, 25% had an anxiety-depressive disorder and in 58.3% a precipitating factor was identified, emotional stress being the most frequent. A percentage of 15.3 showed complete left bundle branch block (LBBB). In 23.3% of patients, contractile abnormalities respected the apex (mid ventricular or diaphragmatic types). RESULTS: The anterior descending artery showed no significant lesions in 35% of patients and in 68.3% it had a diaphragmatic segment. Forty percent of patients developed heart failure (HF) and 18.3% cardiogenic shock (CS). The overall in-hospital mortality was 3.3%, while it was 8.3% among those patients who developed HF. The incidence of CS was higher among patients with LBBB (44.4 vs. 13.7%, P=.05) and males (43.8 vs. 9.1%, P=.005). CONCLUSIONS: Although in-hospital mortality in patients admitted due to TS is low, a significant percentage of these patients develop HF with a high mortality in this subgroup. Males and patients with LBBB had higher in-hospital morbidity. PMID- 24815526 TI - Evaluation of a blended learning surgical skills course for rural surgeons. AB - BACKGROUND: Rural surgeons have unique learning needs not easily met by traditional continuing medical education courses. METHODS: A multidisciplinary team developed and implemented a skills curriculum focused on leadership and communication, advanced endoscopy, emergency urology, emergency gynecology, facial plastic surgery, ultrasound, and management of fingertip amputations. RESULTS: Twenty-five of 30 (89%) rural surgeons who completed a follow-up course evaluation reported that the knowledge acquired during the course had improved their practice and/or the quality of patient care, particularly by refining commonly used skills and expanding the care options they could offer to their patients. The surgeons reported incorporating changes in their communication and interaction with colleagues. CONCLUSIONS: This course was successful, from participants' perspectives, in providing hands-on mentored training for a variety of skills that reflect the broad scope of practice of surgeons in rural areas. Attendees felt that their participation resulted in important behavior and practice changes. PMID- 24815527 TI - Influence of medical students' past experiences and innate dexterity on suturing performance. AB - BACKGROUND: Medical students often cite their ability to excel at technical tasks as justification for choosing surgery as a career path. We sought to investigate how medical students' dexterity skills and past experiences correlated with suturing performance. METHODS: Sixty-four 3rd-year medical students were surveyed about previous experiences that involved manual dexterity. Technical skills were then measured using a validated test of manual dexterity and subcuticular closure of a pig's foot incision. Spearman's rank correlation coefficients determined correlation between variables. RESULTS: Previous experiences, self-assessment of dexterity, prior suturing, and current interest in surgery did not significantly correlate with manual dexterity or suturing skill scores. Innate manual dexterity score was the only significant correlating factor to suture skill score (Spearman's rank correlation coefficient = .336; P = .007). CONCLUSIONS: Innate manual dexterity skills are predictive of initial surgical suturing performance regardless of past student experiences. Interventions aimed at improving early surgical technique should be optimally focused on dexterity training. PMID- 24815528 TI - Effect of elective inguinal hernia repair on urinary symptom burden in men. AB - BACKGROUND: Our study sought to examine the prevalence of urinary symptoms in men undergoing hernia repair and whether there is an association between symptoms and short-term outcomes. METHODS: This is a prospective cohort study of male veterans consenting to inguinal hernia repair. The American Urological Association Symptom Score (AUASS) was administered preoperatively at 48 hours and again at 30 days after surgery. RESULTS: Median preoperative AUASS was 6 (interquartile range [IQR]: 3 to 12); at 48 hours, the median score increased significantly to 10 (IQR: 4 to 16, P < .01) and at 30 days, the median score dropped below baseline to 3 (IQR: 1 to 8, P < .0001). Multivariable linear regression modeling revealed that the use of an intraoperative urinary catheter was significantly associated with an increase in AUASS from preop to both 48 hours and 30 days. CONCLUSION: Elective repair of an inguinal hernia is associated with reduction in urinary symptom burden at 30 days, whereas the use of an intraoperative foley catheter is associated with no improvement at 30 days. PMID- 24815529 TI - Relationship between metabolic syndrome and periodontitis in 80-year-old Japanese subjects. AB - BACKGROUND AND OBJECTIVE: Potentially significant associations between metabolic syndrome (MetS) and periodontitis have been reported in recent studies; however, there are limited data on their association in the very old. The aim of this cross-sectional study was to investigate the association between MetS and periodontitis among 80-year-old Japanese subjects. MATERIAL AND METHODS: The subjects were 234 Japanese aged 80 years old who participated in a health and periodontal examination in June 2008 in Niigata city, Japan, and were classified into three groups: (i) severe periodontitis: having six or more interproximal sites with clinical attachment level >= 6 mm and three or more interproximal sites with probing pocket depth (PPD) >= 5 mm (not on the same tooth) (n = 19); (ii) moderate periodontitis: having six or more interproximal sites with clinical attachment level >= 4 mm or six or more interproximal sites with PPD >= 5 mm (not on the same tooth) (n = 162); and (iii) no or mild periodontitis: neither "moderate" nor "severe" periodontitis (n = 53). MetS was defined using the modified criteria of the guidelines for the diagnosis of MetS in Japan. An ordinal logistic regression model was used to evaluate the association between MetS and periodontitis. Adjustments for gender, income, education, smoking status, dental visiting patterns, brushing frequency, exercise habits and dietary energy and food intake were considered. RESULTS: Overall, 57 individuals (24.4%) were diagnosed as having MetS. MetS was associated with the presence and severity of periodontitis (crude odds ratio = 2.24, 95% confidence interval = 1.14-4.41). This association remained statistically significant after multivariate adjustments (adjusted odds ratio = 2.10, 95% confidence interval = 1.03-4.28). CONCLUSION: Our findings provide evidence of an association between MetS and periodontitis in elderly Japanese. PMID- 24815530 TI - Non-iridescent transmissive structural color filter featuring highly efficient transmission and high excitation purity. AB - Nanostructure based color filtering has been considered an attractive replacement for current colorant pigmentation in the display technologies, in view of its increased efficiencies, ease of fabrication and eco-friendliness. For such structural filtering, iridescence relevant to its angular dependency, which poses a detrimental barrier to the practical development of high performance display and sensing devices, should be mitigated. We report on a non-iridescent transmissive structural color filter, fabricated in a large area of 76.2 * 25.4 mm(2), taking advantage of a stack of three etalon resonators in dielectric films based on a high-index cavity in amorphous silicon. The proposed filter features a high transmission above 80%, a high excitation purity of 0.93 and non-iridescence over a range of 160 degrees , exhibiting no significant change in the center wavelength, dominant wavelength and excitation purity, which implies no change in hue and saturation of the output color. The proposed structure may find its potential applications to large-scale display and imaging sensor systems. PMID- 24815531 TI - Hepatic abscess caused by trans-gastric migration of a fishbone. PMID- 24815532 TI - Is it time to replace the Wada test and put awake craniotomy to sleep? AB - The question we address here is whether the invasive presurgical brain mapping approaches of direct cortical stimulation and of the Wada procedure can be replaced by noninvasive functional neuroimaging methods (functional magnetic resonance imaging [fMRI], magnetoencephalography [MEG], transcranial magnetic stimulation and [TMS]). First, we outline the reasons for contemplating such a replacement. Second, we present evidence to the effect that the efficacy of the invasive and noninvasive methods, while suboptimal, is comparable. Third, we discuss additional advantages of noninvasive presurgical brain mapping and conclude that there are no longer compelling reasons for opting for invasive mapping in many if not most cases provided that the non-invasive methods are available. PMID- 24815534 TI - In-stent restenosis is associated with neointimal angiogenesis and macrophage infiltrates. AB - Restenosis after stenting occurs secondary to the neointima formation. Neovessels have been found in the neointima within stents. However, there are few studies correlating neointimal angiogenesis and in-stent restenosis in humans. We analyzed 65 post-mortem stented arteries from 33 patients with duration >3 months. Cause of death was determined incidental to the coronary findings in every case. Stented segments were embedded in paraffin and stained immunohistochemically for CD68 (macrophages), and endothelial marker PECAM-1 (CD31). Computerized morphometry was performed to quantitate neovessel density for CD31, macrophage infiltrates, as well as plaque and neointimal area. In-stent restenosis was defined as luminal narrowing >= 75% cross-section of the stented area. Underlying plaque morphology was classified as fibrous or atheromatous. Neovessels were present in the neointima of 57 stented segments (88%). Mean neovessel density was greater in restenotic vs. non-restenotic neointimas (p = 0.009) and macrophage density was also greater (p = 0.006). Neointimal area correlated positively with density of neointimal vessels (p = 0.002), as well as neointimal macrophage density (p = 0.006), but not type of stent, underlying plaque type, or underlying plaque macrophage score. We conclude that in-stent restenosis is associated with neointimal angiogenesis which is accompanied by macrophage inflammation. The relevance of these findings to treatment and prevention of in-stent restenosis needs to be further explored. PMID- 24815533 TI - A double-blind efficacy and safety study of duloxetine fixed doses in children and adolescents with major depressive disorder. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of duloxetine fixed dose in the treatment of children (7-11 years) and adolescents (12-17 years) with major depressive disorder (MDD). METHODS: Patients (n=463) in this 36 week study (10 week acute and 26 week extension treatment) received duloxetine 60 mg QD (n=108), duloxetine 30 mg QD (n=116), fluoxetine 20 mg QD (n=117, active control), or placebo (n=122). Measures included: Children's Depression Rating Scale-Revised (CDRS-R), treatment-emergent adverse events (TEAEs), and Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: Neither active drug (duloxetine or fluoxetine) separated significantly (p<0.05) from placebo on mean change from baseline to end-point (10 weeks) on the CDRS-R total score. Total TEAEs and discontinuation for AEs were significantly (p<0.05) higher only for the duloxetine 60 mg group versus the placebo group during acute treatment. No clinically significant electrocardiogram (ECG) or laboratory abnormalities were observed, and no completed suicides or deaths occurred during the study. A total of 7 (6.7%) duloxetine 60 mg, 6 (5.2%) duloxetine 30 mg, 9 (8.0%) fluoxetine, and 11 (9.4%) placebo patients had worsening of suicidal ideation from baseline during acute treatment. Of the patients with suicidal ideation at baseline, 13/16 (81%) duloxetine 60 mg, 16/17 (94%) duloxetine 30 mg, 11/16 (69%) fluoxetine, and 13/15 (87%) placebo had improvement in suicidal ideation at end-point during acute treatment. One fluoxetine, one placebo, and six duloxetine patients had treatment-emergent suicidal behavior during the 36 week study. CONCLUSIONS: Trial results were inconclusive, as neither the investigational drug (duloxetine) nor the active control (fluoxetine) separated from placebo on the CDRS-R at 10 weeks. No new duloxetine safety signals were identified relative to those seen in adults. Clinical Trial Registry Number ( www.ClinicalTrials.gov ): NCT00849693. PMID- 24815536 TI - Renal mucinous tubular and spindle cell carcinoma and 18F-fluorodeoxyglucose PET/CT findings. PMID- 24815535 TI - Development of a psychometrically equivalent short form of the Face-Name Associative Memory Exam for use along the early Alzheimer's disease trajectory. AB - Neuropsychologists are developing more challenging and specific tests to detect early and subtle changes in cognition related to preclinical Alzheimer's disease (AD). The 16-item Face-Name Associative Memory Exam (FNAME-16) is a challenging paired associative memory test able to detect subtle memory changes associated with biomarker evidence of preclinical AD. However, as individuals progress along the AD trajectory, measures that are sensitive at the preclinical stage may become too challenging by the stage of Mild Cognitive Impairment (MCI). Our goal was to develop a modified version of the face-name and face-occupation paired associative memory task (FNAME-12) with fewer stimuli and additional learning trials suitable for use in MCI. We administered the FNAME-12A, an alternate version FNAME 12B, the original FNAME-16, and a series of other neuropsychological measures to 65 clinically normal (CN) older adults (aged 65 to 85) and a subsample characterized by MCI (n = 18). The FNAME-12 exhibited psychometric equivalence with the FNAME-16 (r = .77, p < .001) and was correlated with other measures of episodic and semantic memory. The alternate form, FNAME 12B, was highly correlated with FNAME-12A (r = .76, p < .001). Mean performance on the FNAME 12A, stratified by education, was generated. The task could be completed by our MCI group yet remained challenging in the CN group, providing evidence for its utility along the AD trajectory. PMID- 24815537 TI - Influence of subcutaneous fat in surface heating of ultrasonic diagnostic transducers. AB - The transducers of diagnostic ultrasonic equipment generate undesired local heating at the applied part of the transducer surface. The assessment of this heating is fundamental in warranting patient safety. On the standard IEC 60601-2 37, methods have been established for the reliable measurement of heating, where three tissue models based on tissue-mimicking materials are recommended: soft tissue mimic only, bone mimic close to the surface of soft tissue, and skin mimic at the surface of soft tissue. In the present work, we compared the last mentioned tissue model with a new one using a layer of porcine subcutaneous fat inserted between the soft tissue and skin-mimicking materials. We verify significant statistical differences between models, with the average temperature rise measured for the tests without subcutaneous fat at 6.7 degrees C+/-1.7 degrees C and for the ones with subcutaneous fat at 8.9 degrees C+/-1.8 degrees C (k=2; p=0.95). For each model, the procedure was performed 10 times in repeatability conditions of measurement. It has been suggested that the influence of subcutaneous fat for external transducers heating evaluation should be considered, as the presence of many millimeters of subcutaneous fat is a common condition in patients. Otherwise, the transducer surface heating and, therefore, the risk to the patient may be underestimated. PMID- 24815538 TI - Influence of low-intensity pulsed ultrasound on osteogenic tissue regeneration in a periodontal injury model: X-ray image alterations assessed by micro-computed tomography. AB - OBJECTIVE: This study was conducted to evaluate, with micro-computed tomography, the influence of low-intensity pulsed ultrasound on wound-healing in periodontal tissues. METHODS: Periodontal disease with Class II furcation involvement was surgically produced at the bilateral mandibular premolars in 8 adult male beagle dogs. Twenty-four teeth were randomly assigned among 4 groups (G): G1, periodontal flap surgery; G2, periodontal flap surgery+low-intensity pulsed ultrasound (LIPUS); G3, guided tissue regeneration (GTR) surgery; G4, GTR surgery plus LIPUS. The affected area in the experimental group was exposed to LIPUS. At 6 and 8weeks, the X-ray images of regenerated teeth were referred to micro-CT scanning for 3-D measurement. RESULTS: Bone volume (BV), bone surface (BS), and number of trabeculae (Tb) in G2 and G4 were higher than in G1 and G3 (p<0.05). BV, BS, and Tb.N of the GTR+LIPUS group were higher than in the GTR group. BV, BS, and Tb.N of the LIPUS group were higher than in the periodontal flap surgery group. CONCLUSION: LIPUS irradiation increased the number, volume, and area of new alveolar bone trabeculae. LIPUS has the potential to promote the repair of periodontal tissue, and may work effectively if combined with GTR. PMID- 24815540 TI - Replica-exchange molecular dynamics simulation of basic fibroblast growth factor adsorption on hydroxyapatite. AB - The adsorption of basic fibroblast growth factor (bFGF) on the hydroxyapatite (001) surface was investigated by a combination of replica-exchange molecular dynamics (REMD) and conventional molecular dynamics (CMD) methods. In CMD, the protein cannot readily cross the surface water layer, whereas in REMD, the protein can cross the adsorption barrier from the surface water layer and go through weak, medium, then strong adsorption states with three energetically preferred configurations: heparin-binding-up (HP-up), heparin-binding-middle (HP middle), and heparin-binding-down (HP-down). The HP-middle orientation, with the strongest adsorption energy (-1149 +/- 40 kJ.mol(-1)), has the largest adsorption population (52.1-52.6%) and exhibits the largest conformational charge (RMSD of 0.26 +/- 0.01 nm) among the three orientations. The HP-down and HP-up orientations, with smaller adsorption energies of -1022 +/- 55 and -894 +/- 70 kJ.mol(-1), respectively, have smaller adsorption populations of 27.4-27.7% and 19.7-20.5% and present smaller RMSD values of 0.21 +/- 0.01 and 0.19 +/- 0.01 nm, respectively. The convergent distribution indicates that nearly half of the population (in the HP-middle orientation) will support both FGF/FGFR and DGR integrin signaling and another half (in the HP-up and HP-down orientations) will support DGR-integrin signaling. The major population (~80%) has the protein dipole directed outward. In the strong adsorption state, there are usually 2 to 3 basic residues that form the anchoring interactions of 210-332 kJ.mol(-1) per residue or that are accompanied by an acidic residue with an adsorption energy of ~207 kJ.mol(-1). Together, the major bound residues form a triangle or a quadrilateral on the surface and stabilize the adsorption geometrically, which indicates topologic matching between the protein and HAP surfaces. PMID- 24815539 TI - Sinomenine inhibits microglia activation and attenuates brain injury in intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) causes morbidity and mortality and commonly follows the reperfusion after an ischemic event. Microglial activation mediated cytokine and protease secretion contributes to brain injury in ICH. Previous studies have shown that sinomenine possesses potent immunoregulatory properties. However, little is known about its exact role in ICH. In the present study, to investigate the effect of sinomenine on microglial cells inflammation, we treated ICH-challenged BV2 microglial cells with sinomenine in vitro, and explored its neuroprotection role in intracerebral hemorrhage in vivo. Changes in inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, reactive oxygen species (ROS) and NF-kappaB activation NF-kappaB were observed. In addition, the neurological deficit and cerebral water content of ICH mice were studied. The results demonstrated that sinomenine could inhibit the release of these cytokines and attenuate ROS production in a dose-dependent manner, and reduce NF-kappaB activation. Furthermore, sinomenine markedly inhibited cerebral water content and neurological deficit. In conclusion, our findings suggest that sinomenine played the protective effects through inhibition of microglial inflammation, and the findings also provided a novel therapy to treat ICH induced brain injury. PMID- 24815541 TI - gammaT -S195A thrombin reduces the anticoagulant effects of dabigatran in vitro and in vivo. AB - BACKGROUND: Dabigatran etexilate (DE) is an oral direct thrombin inhibitor used to prevent strokes in patients with atrial fibrillation. No licensed DE antidote is currently available. We hypothesized that active site-mutated S195A thrombin (S195A-IIa) and/or its trypsinized derivative (gammaT -S195A-IIa) would sequester dabigatran, the active form of DE, and reduce its anticoagulant effects. OBJECTIVE: To assess active site-mutated S195A or gammaT -S195A-IIa as dabigatran reversal agents in vitro and in vivo. METHODS: Diluted thrombin time (dTT) assays were performed using human or murine plasma containing dabigatran, combined with S195A-IIa, gammaT -S195A-IIa or FPR-chloromethyl ketone-treated thrombin (FPR IIa). Bleeding times were determined in anesthetized DE-treated mice also receiving gammaT -S195A-IIa or vehicle 15 min prior to tail transection. The time to occlusion of carotid arteries of DE-treated mice also receiving S195A-IIa, gammaT -S195A-IIa, prothrombin complex concentrate (PCC) or vehicle, 15 min prior to topical FeCl3 , was determined using Doppler ultrasound. RESULTS: gammaT-S195A IIa reduced dTT values of dabigatran-containing human and murine plasma more effectively than S195-IIa; FPR-IIa had no effect. A dose of 13 mg kg(-1) DE abrogated occlusive thrombus formation in the carotid arteries of FeCl3 -treated mice; gammaT -S195A-IIa (6 mg kg(-1) ) or PCC (14.3 IU kg(-1) ), but not saline vehicle or S195A-IIa (6 mg kg(-1) ), was equally effective in restoring thrombus formation. Bleeding times of mice treated with 60 mg kg(-1) DE and gammaT -S195A IIa (6 mg kg(-1) ) or saline vehicle did not differ. CONCLUSIONS: Our data suggest that gammaT -S195A-IIa decreases the anticoagulant effects of dabigatran in vitro and is partially effective at restoring hemostasis-related thrombus formation in DE-treated mice in vivo. PMID- 24815542 TI - Testing for cognitive function in animals in a regulatory context. AB - Superior cognitive functions have allowed the human species to proliferate in a world of incredible biological diversity. Threats to these essential capacities cannot be ignored, and a strategy is needed to evaluate the hazard posed by exposure to chemical and other agents. Because people exposed to chemicals often complain about confusion and forgetfulness, it is commonly thought that cognitive functions should be sensitive indicators of adverse consequences of chemical exposure. For these reasons, complex tests of cognitive function have been developed and deployed in experimental animal laboratories for decades. However, the results of these tests are rarely used as points of departure for chemical risk assessments. Due to their high cost in time, animals, and equipment, the efficacy and utility of these tests need to be evaluated in relation to cheaper and faster whole-animal screening methods. This review examines evidence for the assertions that cognitive functions represent uniquely sensitive indicators of chemical exposure, and that animal models of these functions are necessary to detect and quantify the neurotoxicity of chemicals. Studies conducted since the early 1980s to compare these approaches to assess the neurotoxicity of chemicals are reviewed for both adult and perinatal exposures in experimental rodents. Forty-one studies of 35 chemicals were found that directly compared acute effects using complex tests (i.e., tests that require training animals) with acute effects using screening tests (i.e., tests that do not require training animals) in adult rodents. Complex tests detected effects of three substances (bitertanol, iso-amyl nitrite, and Pfiesteria toxin) that had no effect on screening tests; for an additional five chemicals (carbaryl, deltamethrin, methyl mercury, tetraethyl tin, and Isopar-C), complex tests identified effects at lower doses than did screening tests. Fewer comparable cases were found for developmental exposures: screening and complex tests were found to be equivalent for trimethyltin, n-propylthiouracil (PTU), and elemental mercury. Analysis of two studies yielded an inconclusive case for lead. Evidence for the insufficiency of screening tests was found for PCBs and inhaled ethanol, though it is not clear that the measured effects of these chemicals reflected cognitive deficits per se. Whether these benefits are worth the additional time and expense of conducting complex tests is a matter for discussion in the research and risk management communities. PMID- 24815543 TI - Comparing fusion techniques for the ImageCLEF 2013 medical case retrieval task. AB - Retrieval systems can supply similar cases with a proven diagnosis to a new example case under observation to help clinicians during their work. The ImageCLEFmed evaluation campaign proposes a framework where research groups can compare case-based retrieval approaches. This paper focuses on the case-based task and adds results of the compound figure separation and modality classification tasks. Several fusion approaches are compared to identify the approaches best adapted to the heterogeneous data of the task. Fusion of visual and textual features is analyzed, demonstrating that the selection of the fusion strategy can improve the best performance on the case-based retrieval task. PMID- 24815544 TI - Intervening to reduce workplace sitting time: how and when do changes to sitting time occur? AB - OBJECTIVE: To investigate how and when changes in workplace sitting time occurred following a workplace intervention to inform evaluation of intervention success. METHOD: The 4-week Stand Up Comcare study (June-September 2011) aimed to reduce workplace sitting time via regularly interrupting and replacing sitting time throughout the day. Activity monitor (activPAL3) workplace data from control (n=22) and intervention participants (n=21) were analysed. Differences in the number and usual duration of sitting bouts were used to evaluate how change occurred. To examine when change occurred, intervention effects were compared by hour since starting work and hour of the workday. Change in workplace activity (sitting, standing, stepping) was examined to further inform alignment with intervention messages. Individual variability was examined in how and when the change occurred. RESULTS: Overall, behavioural changes aligned with intervention aims. All intervention participants reduced total workplace sitting time, though there was wide individual variability observed (range -29 to -262 min per 8 h workday). On average, intervention participants reduced number of sitting bouts ( 4.6 bouts (95% CI -10.1 to 1.0), p=0.106) and usual sitting bout duration (-5.6 min (95% CI -9.8 to -1.4, p=0.011)) relative to controls. Sitting time reductions were observed across the workday, though intervention effects varied by hour of the day (p=0.015). The intervention group successfully adopted the Stand Up and Sit Less intervention messages across the day. CONCLUSION: These analyses confirmed that this workplace intervention successfully modified sitting behaviour as intended (ie, fewer and shorter sitting bouts, with changes occurring throughout the day). PMID- 24815545 TI - Adding maps (GPS) to accelerometry data to improve study participants' recall of physical activity: a methodological advance in physical activity research. AB - OBJECTIVE: Obtaining the 'when, where and why' of healthy bouts of moderate-to vigorous physical activity (MVPA) provides insights into natural PA. DESIGN: In Salt Lake City, Utah, adults wore accelerometer and Global Positioning System (GPS) loggers for a week in a cross-sectional study to establish baseline travel and activity patterns near a planned Complete Street intervention involving a new rail line, new sidewalks and a bike path. RESULTS: At the end of the week, research assistants met with the 918 participants who had at least three 10 h days of good accelerometer readings. Accelerometer and GPS data were uploaded and integrated within a custom application, and participants were provided with maps and time information for past MVPA bouts of >=3 min to help them recall bout details. Participants said that 'getting someplace' was, on average, a more important motivation for their bouts than leisure or exercise. A series of recall tests showed that participants recalled most bouts they were asked about, regardless of the duration of the bout, suggesting that participant perceptions of their shorter lifestyle bouts can be studied with this methodology. Visual prompting with a map depicting where each bout took place yielded more accurate recall than prompting with time cues alone. CONCLUSIONS: These techniques provide a novel way to understand participant memories of the context and subjective assessments associated with healthy bouts of PA. Prompts with time-stamped maps that illustrate places of MVPA offer an effective method to improve understanding of activity and its supportive sociophysical contexts. PMID- 24815546 TI - Pulmonary toxicity following exposure to a tile coating product containing alkylsiloxanes. A clinical and toxicological evaluation. AB - CONTEXT: Coating products are widely used for making surfaces water and dirt repellent. However, on several occasions the use of these products has been associated with lung toxicity. OBJECTIVE: In the present study, we evaluated the toxic effects of an aerosolized tile-coating product. METHODS: Thirty-nine persons, who reported respiratory and systemic symptoms following exposure to the tile-coating product, were clinically examined. The product was analysed chemically and furthermore, the exposure scenario was reconstructed using a climate chamber and the toxicological properties of the product were studied using in vivo and by in vitro surfactometry. RESULTS: The symptoms developed within few hours and included coughing, tachypnoea, chest pain, general malaise and fever. The physical examination revealed perihilar lung infiltrates on chest radiograph and reduced blood oxygen saturation. The acute symptoms resolved gradually within 1-3 days and no delayed symptoms were observed. By means of mass spectrometry and X-ray spectroscopy, it was shown that the product contained non fluorinated alkylsiloxanes. The exposure conditions in the supermarket were reconstructed under controlled conditions in a climate chamber and particle and gas exposure levels were monitored over time allowing estimation of human exposure levels. Mice exposed to the product developed symptoms of acute pulmonary toxicity in a concentration-and time-dependent manner. The symptoms of acute pulmonary toxicity likely resulted from inhibition of the pulmonary surfactant function as demonstrated by in vitro surfactometry. Among these patients only a partial association between the level of exposure and the degree of respiratory symptoms was observed, which could be because of a high inter individual difference in sensitivity and time-dependent changes in the chemical composition of the aerosol. CONCLUSION: Workers need to cautiously apply surface coating products because the contents can be highly toxic through inhalation, and the aerosols can disperse to locations remote from the worksite and affect bystanders. PMID- 24815547 TI - Induction and dorsal restriction of Paired-box 3 (Pax3) gene expression in the caudal neuroectoderm is mediated by integration of multiple pathways on a short neural crest enhancer. AB - Pax3 encodes a paired-box transcription factor with key roles in neural crest and neural tube ontogenesis. Robust control of Pax3 neural expression is ensured by two redundant sets of cis-regulatory modules (CRMs) that integrate anterior posterior (such as Wnt-betaCatenin signaling) as well as dorsal-ventral (such as Shh-Gli signaling) instructive cues. In previous work, we sought to characterize the Wnt-mediated regulation of Pax3 expression and identified the Cdx transcription factors (Cdx1/2/4) as critical intermediates in this process. We identified the neural crest enhancer-2 (NCE2) from the 5'-flanking region of Pax3 as a Cdx-dependent CRM that recapitulates the restricted expression of Pax3 in the mouse caudal neuroectoderm. While this is consistent with a key role in relaying the inductive signal from posteriorizing Wnt ligands, the broad expression of Cdx proteins in the tailbud region is not consistent with the restricted activity of NCE2. This implies that other positive and/or negative inputs are required and, here, we report a novel role for the transcription factor Zic2 in this regulation. Our data strongly suggests that Zic2 is involved in the induction (as a direct Pax3NCE2 activator and Cdx neural cofactor) as well as the maintenance of Pax3 dorsal restriction (as a target of the ventral Shh repressive input). We also provide evidence that the inductive Cdx-Zic2 interaction is integrated on NCE2 with a positive input from the neural-specific transcription factor Sox2. Altogether, our data provide important mechanistic insights into the coordinated integration of different signaling pathways on a short Pax3 CRM. PMID- 24815548 TI - Dynamic behavior of tuning fork shear-force structures in a SNOM system. AB - Piezoelectric tuning fork shear-force structures are widely used as a distance control unit in a scanning near-field optical microscopy. However, the complex dynamic behavior among the micro-tuning forks (TFs), optical fiber probes, and the probe-surface interactions is still a crucial issue to achieve high resolution imaging or near-field interaction inspections. Based on nonlinear beam tension-bending vibration theory, vibration equations in both longitudinal and lateral directions have been established when the TF structure and the optical fiber are treated as deformable structures. The relationship of the probe-surface interaction induced by Van der Waals force has been analyzed and the corresponding numerical results used to describe the vibrational behavior of the probe approaching the sample surface are obtained. Meanwhile, the viscous resistance of the liquid film on the sample surface has also been investigated using linear beam-bending vibration theory. Experiments testing the interaction between the probe and the water film on a single crystal silicon wafer have been carried out and the viscous resistance of the water film was estimated using the established equations. Finally, to use the TF-probe structure as a force sensor, the relation between the dynamic response of the TF-probe system and an external force on the probe tip was obtained. PMID- 24815550 TI - Microstructural characterization of an Al-li-mg-cu alloy by correlative electron tomography and atom probe tomography. AB - Correlative electron tomography and atom probe tomography have been carried out successfully on the same region of a commercial 8090 aluminum alloy (Al-Li-Mg Cu). The combination of the two techniques allows accurate geometric reconstruction of the atom probe tomography data verified by crystallographic information retrieved from the reconstruction. Quantitative analysis of the precipitate phase compositions and volume fractions of each phase have been obtained from the atom probe tomography and electron tomography at various scales, showing strong agreement between both techniques. PMID- 24815549 TI - Spatial modulation of key pathway enzymes by DNA-guided scaffold system and respiration chain engineering for improved N-acetylglucosamine production by Bacillus subtilis. AB - Previously we constructed a Bacillus subtilis strain for efficient production of N-acetylglucosamine (GlcNAc) by engineering of GlcNAc synthetic and catabolic pathways. However, the further improvement of GlcNAc titer is limited by the intrinsic inefficiency of GlcNAc synthetic pathway and undesirable cellular properties including sporulation and high maintenance metabolism. In this work, we further improved GlcNAc titer through spatial modulation of key pathway enzymes and by blocking sporulation and decreasing maintenance metabolism. Specifically, a DNA-guided scaffold system was firstly used to modulate the activities of glucosamine-6-phosphate synthase and GlcNAc-6-phosphate N acetyltransferase, increasing the GlcNAc titer from 1.83g/L to 4.55g/L in a shake flask. Next, sporulation was blocked by respectively deleting spo0A (gene encoding the initiation regulon of sporulation) and sigE (gene encoding RNA polymerase sporulation-specific sigma factor). Deletion of sigE more effectively blocked sporulation without altering cell growth or GlcNAc production. The respiration chain was then engineered to decrease the maintenance metabolism of recombinant B. subtilis by deleting cydB and cydC, genes encoding cytochrome bd ubiquinol oxidase (subunit II) and ATP-binding protein for the expression of cytochrome bd, respectively. The respiration-engineered B. subtilis produced 6.15g/L GlcNAc in a shake flask and 20.58g/L GlcNAc in a 3-L fed-batch bioreactor. To the best of our knowledge, this report is the first to describe the modulation of pathway enzymes via a DNA-guided scaffold system in B. subtilis. The combination of spatial modulation of key pathway enzymes and optimization of cellular properties may be used to develop B. subtilis as a well organized cell factory for the production of the other industrially useful chemicals. PMID- 24815551 TI - Pore-size-dependent calcium carbonate precipitation controlled by surface chemistry. AB - Induced mineral precipitation is potentially important for the remediation of contaminants, such as during mineral trapping during carbon or toxic metal sequestration. The prediction of precipitation reactions is complicated by the porous nature of rocks and soils and their interaction with the precipitate, introducing transport and confinement effects. Here X-ray scattering measurements, modeling, and electron microscopies were used to measure the kinetics of calcium carbonate precipitation in a porous amorphous silica (CPG) that contained two discrete distributions of pore sizes: nanopores and macropores. To examine the role of the favorability of interaction between the substrate and precipitate, some of the CPG was functionalized with a self assembled monolayer (SAM) similar to those known to enhance nucleation densities on planar substrates. Precipitation was found to occur exclusively in macropores in the native CPG, while simultaneous precipitation in nanopores and macropores was observed in the functionalized CPG. The rate of precipitation in the nanopores estimated from the model of the X-ray scattering matched that measured on calcite single crystals. These results suggest that the pore-size distribution in which a precipitation reaction preferentially occurs depends on the favorability of interaction between substrate and precipitate, something not considered in most studies of precipitation in porous media. PMID- 24815552 TI - Influence of ketamine or xylazine supplementation on isoflurane anaesthetized horses--a controlled clinical trial. AB - OBJECTIVES: To determine the influence of ketamine or xylazine constant rate infusions on isoflurane requirements, cardiovascular parameters and quality of anaesthesia in horses undergoing elective surgery. STUDY DESIGN: Prospective, matched paired clinical trial. ANIMALS: Fifty four adult Warmblood horses. METHODS: After premedication with acepromazine, xylazine and butorphanol, anaesthesia was induced with ketamine-midazolam and maintained with isoflurane alone (I), isoflurane with either 1 mg kg(-1) hour(-1) ketamine (IK) or same dose of xylazine (IX). End tidal concentration of isoflurane (Fe'Iso) was adjusted by the same anaesthetist in all horses according to a scoring system. Dobutamine was infused to maintain mean arterial pressure (MAP) >=70 mmHg. Arterial blood gases, heart rate (HR), respiratory rate, MAP and cardiac output (lithium dilution) were measured. Groups I and IK received xylazine before recovery. Recovery quality was scored. RESULTS: Mean +/- SD averaged Fe'Iso (volume%) was significantly lower in IX (0.95 +/- 0.07) and IK (0.97 +/- 0.08) than in I (1.16 +/- 0.13). In group IX, HR was significantly lower and averaged MAP (90 +/- 13 mmHg) significantly higher than in groups I (71 +/- 7 mmHg) and IK (76 +/- 7 mm Hg). Differences in other cardiopulmonary variables did not reach statistical significance. All horses recovered well with best score in group IX. CONCLUSIONS: Both CRIs of xylazine and of ketamine resulted in pronounced reduction of isoflurane requirements and blood pressure support based on routinely monitored parameters. Cardiac output appeared well maintained in all three protocols, but lithium dilution induced errors mean the results are untrustworthy. The work requires repetition with another mode of measurement of cardiac output. CLINICAL RELEVANCE: All three protocols provided good clinical anaesthesia with clinically acceptable cardiovascular effects. PMID- 24815553 TI - Production of novel "functional oil" rich in diglycerides and phytosterol esters with "one-pot" enzymatic transesterification. AB - Diglycerides and phytosterol esters are two important functional lipids. Phytosterol esters mixed with dietary diglyceride could not only influence body weight but also prevent or reverse insulin resistance and hyperlipidemia. In this study, a kind of novel "functional oil" rich in both diglycerides and phytosterol esters was prepared with "one-pot" enzymatic transesterification. First, lipase AYS (Candida rugosa) was immobilized on the porous cross-linked polystyrene resin beads (NKA) via hydrophobic interaction. The resulting immobilized AYS showed much better transesterification activity and thermal stability to freeways. On the basis of the excellent biocatalyst prepared, a method for high-efficiency enzymatic esterification of phytosterols with different triglycerides to produce corresponding functional oils rich in both diglycerides and phytosterol esters was developed. Four functional oils rich in both diglycerides and phytosterol esters with conversions >92.1% and controllable fatty acid composition were obtained under the optimized conditions: 80 mmol/L phytosterols, 160 mmol/L triglycerides, and 25 mg/mL AYS@NKA at 180 rpm and 50 degrees C for 12 h in hexane. The prepared functional oil possessed low acid value (<=1.0 mgKOH/g), peroxide value (<=2.1 mmol/kg), and conjugated diene value (<=1.96 mmol/kg) and high diglyceride and phytosterol ester contents (>=10.4 and >=20.2%, respectively). All of the characteristics favored the wide application of the functional oil in different fields of functional food. PMID- 24815554 TI - Phthalates and alkylphenols in industrial and domestic effluents: case of Paris conurbation (France). AB - Phthalates and alkylphenols are toxics classified as endocrine disrupting compounds (EDCs). They are of particular concern due to their ubiquity and generally higher levels found in the environment comparatively to other EDCs. Industrial and domestic discharges might affect the quality of receiving waters by discharging organic matter and contaminants through treated waters and combined sewer overflows. Historically, industrial discharges are often considered as the principal vector of pollution in urban areas. If this observation was true in the past for some contaminants, no current data are today available to compare the quality of industrial and domestic discharges as regards EDCs. In this context, a total of 45 domestic samples as well as 101 industrial samples were collected from different sites, including 14 residential and 33 industrial facilities. This study focuses more specifically on 4 phthalates and 2 alkylphenols, among the most commonly studied congeners. A particular attention was also given to routine wastewater quality parameters. For most substances, wastewaters from the different sites were heavily contaminated; they display concentrations up to 1200 MUg/l for di-(2-ethylhexyl) phthalate and between 10 and 100 MUg/l for diethyl phthalate and nonylphenol. Overall, for the majority of compounds, the industrial contribution to the flux of contaminant reaching the wastewater treatment plants ranges between 1 and 3%. The data generated during this work constitutes one of the first studies conducted in Europe on industrial fluxes for a variety of sectors of activity. The study of the wastewater contribution was used to better predict the industrial and domestic contributions at the scale of a huge conurbation heavily urbanized but with a weak industrial cover, illustrated by Paris. Our results indicate that specific investigations on domestic discharges are necessary in order to reduce the release of phthalates and alkylphenols in the sewer systems for such conurbations. PMID- 24815555 TI - Anthropogenic land uses elevate metal levels in stream water in an urbanizing watershed. AB - Land use/cover change is a dominant factor affecting surface water quality in rapidly developing areas of Asia. In this study we examined relationships between land use and instream metal loadings in a rapidly developing mixed land use watershed in southeastern China. Five developing subwatersheds and one forested reference site (head water) were instrumented with timing- and rainfall-triggered autosampler and instream loadings of anthropogenic metals (Cu, Zn, Pb, Cr, Cd, and Mn) were monitored from March 2012 to December 2013. Farm land and urban land were positively, and forest and green land were negatively associated with metal loadings (except Cr) in stream water. All developing sites had higher loadings than the reference head water site. Assessed by Chinese surface water quality standard (GB3830-2002), instream loadings of Cu and Zn occasionally exceeded the Class I thresholds at monitoring points within farmland dominated subwatersheds while Mn loadings were greater than the limit for drinking water sources at all monitoring points. Farm land use highly and positively contributed to statistical models of instream loadings of Cu, Zn, Cd, and Mn while urban land use was the dominant contributor to models of Pb and Cd loadings. Rainfall played a crucial role in metal loadings in stream water as a direct source (there were significant levels of Cu and Zn in rain water) and as a driver of watershed processes (loadings were higher in wet years and seasons). Urbanization effects on metal loadings in this watershed are likely to change rapidly with development in future years. Further monitoring to characterize these changes is clearly warranted and should help to develop plans to avoid conflicts between economic development and water quality degradation in this watershed and in watersheds throughout rapidly developing areas of Asia. PMID- 24815556 TI - Characteristics of airborne bacteria in Mumbai urban environment. AB - Components of biological origin constitute small but a significant proportion of the ambient airborne particulate matter (PM). However, their diversity and role in proinflammatory responses of PM are not well understood. The present study characterizes airborne bacterial species diversity in Mumbai City and elucidates the role of bacterial endotoxin in PM induced proinflammatory response in ex vivo. Airborne bacteria and endotoxin samples were collected during April-May 2010 in Mumbai using six stage microbial impactor and biosampler. The culturable bacterial species concentration was measured and factors influencing the composition were identified by principal component analysis (PCA). The biosampler samples were used to stimulate immune cells in whole blood assay. A total of 28 species belonging to 17 genera were identified. Gram positive and spore forming groups of bacteria dominated the airborne culturable bacterial concentration. The study indicated the dominance of spore forming and human or animal flora derived pathogenic/opportunistic bacteria in the ambient air environment. Pathogenic and opportunistic species of bacteria were also present in the samples. TNF-alpha induction by PM was reduced (35%) by polymyxin B pretreatment and this result was corroborated with the results of blocking endotoxin receptor cluster differentiation (CD14). The study highlights the importance of airborne biological particles and suggests need of further studies on biological characterization of ambient PM. PMID- 24815557 TI - Variations in the structure of airborne bacterial communities in a downwind area during an Asian dust (Kosa) event. AB - Asian dust (Kosa) events transport airborne microorganisms that significantly impact biological ecosystems, human health, and ice-cloud formation in downwind areas. However, the composition and population dynamics of airborne bacteria have rarely been investigated in downwind areas during Kosa events. In this study, air samplings were sequentially performed at the top of a 10-m high building within the Kosa event arrival area (Kanazawa City, Japan) from May 1 to May 7, 2011, during a Kosa event. The particle concentrations of bacterial cells and mineral particles were ten-fold higher during the Kosa event than on non-Kosa event days. A 16S ribosomal DNA clone library prepared from the air samples primarily contained sequences from three phyla: Cyanobacteria, Firmicutes, and Alphaproteobacteria. The clones from Cyanobacteria were mainly from a marine type of Synechococcus species that was dominant during the first phase of the Kosa event and was continuously detected throughout the Kosa event. The clones from Alphaproteobacteria were mainly detected at the initial and final periods of the Kosa event, and phylogenetic analysis showed that their sequences clustered with those from a marine bacterial clade (the SAR clade) and Sphingomonas spp. During the middle of the Kosa event, the Firmicutes species Bacillus subtilis and Bacillus pumilus were predominant; these species are known to be predominant in the atmosphere above the Chinese desert, which is the source of the dust during Kosa events. The clones obtained after the Kosa event had finished were mainly from Bacillus megaterium, which is thought to originate from local terrestrial areas. Our results suggest that airborne bacterial communities at the ground level in areas affected by Kosa events change their species compositions during a Kosa event toward those containing terrestrial and pelagic bacteria transported from the Sea of Japan and the continental area of China by the Kosa event. PMID- 24815558 TI - Human health and safety risks management in underground coal mines using fuzzy TOPSIS. AB - The scrutiny of health and safety of personnel working in underground coal mines is heightened because of fatalities and disasters that occur every year worldwide. A methodology based on fuzzy TOPSIS was proposed to assess the risks associated with human health in order to manage control measures and support decision-making, which could provide the right balance between different concerns, such as safety and costs. For this purpose, information collected from three hazardous coal mines namely Hashouni, Hojedk and Babnizu located at the Kerman coal deposit, Iran, were used to manage the risks affecting the health and safety of their miners. Altogether 86 hazards were identified and classified under eight categories: geomechanical, geochemical, electrical, mechanical, chemical, environmental, personal, and social, cultural and managerial risks. Overcoming the uncertainty of qualitative data, the ranking process is accomplished by fuzzy TOPSIS. After running the model, twelve groups with different risks were obtained. Located in the first group, the most important risks with the highest negative effects are: materials falling, catastrophic failure, instability of coalface and immediate roof, firedamp explosion, gas emission, misfire, stopping of ventilation system, wagon separation at inclines, asphyxiation, inadequate training and poor site management system. According to the results, the proposed methodology can be a reliable technique for management of the minatory hazards and coping with uncertainties affecting the health and safety of miners when performance ratings are imprecise. The proposed model can be primarily designed to identify potential hazards and help in taking appropriate measures to minimize or remove the risks before accidents can occur. PMID- 24815559 TI - Strengthening the role of the ward manager: a review of the literature. AB - BACKGROUND: The role of the ward manager is integral to service delivery, however, they may lack the necessary authority and autonomy to achieve the organisation and delivery of patient care. AIM: To identify initiatives that have strengthened the ward manager role. METHODS: A review of published literature was undertaken. Data included were drawn from a variety of sources, including policy, professional literature and research studies. FINDINGS: Three policy initiatives were identified along with two innovations from ward managers and two recent professional organisation campaigns. One innovation was identified that could improve the process of care delivery thus empowering ward managers' decision making. The literature identified the need for a review of the role, and adequate administrative support and training for the role. CONCLUSION: The literature reviewed provided little evidence of initiatives to strengthen the role of the ward manager, highlighting the imperative to develop an evidence base. There was consensus on the importance of education and training before and during appointment to the position. IMPLICATIONS FOR NURSING MANAGEMENT: The role of the ward manager remains pivotal in care delivery. The focus should be on how best to support ward managers in achieving their role within health-care systems. PMID- 24815560 TI - Strategies to overcome hostile subclavian anatomy during transradial coronary angiography and interventions: impact on fluoroscopy, procedural time, complications, and radial patency. AB - BACKGROUND: Hostile anatomy of the subclavian artery (severe tortuosity and/or heavy calcification) remains a significant obstacle for the transradial approach during coronary angiography and interventions. OBJECTIVE: To assess impacts on fluoroscopy and procedural times, complications, and radial artery patency in patients with hostile subclavian anatomy by using multiple catheter-guide techniques. METHODS: We retrospectively reviewed the medical and equipment data of 4,580 consecutive patients (mean age 74.4 +/- 26.7 years, 49.5% females) who have been referred for transradial coronary angiography and/or interventions within the last 3 years (September 2010-September 2013). In order to overcome the strangling hold of a hostile subclavian artery, 2 techniques have been used: (1) for a coronary angiography-only procedure, a double mother and child technique; (2) for percutaneous coronary intervention, a triple mother and child technique. RESULTS: Ninety-five patients (2.1%) from the entire study population exhibited a hostile subclavian artery. Fifty-two patients (1.1%) underwent coronary angiography only and 43 patients (1%) underwent interventions requiring the use of the above double or triple mother and child techniques, respectively. The 2 techniques were successful in 94.7% of patients (90/95 patients). The procedural time was significantly longer in the patients with hostile subclavian artery while there were no differences in the fluoroscopy time. The radial artery was patent at 30 days in 92.6% of patients (88/95 patients). CONCLUSION: Our data showed that in the presence of hostile subclavian anatomy, the mother and child techniques appeared safe and effective, allowing for the completion of the intended procedure. PMID- 24815561 TI - Chelating polymeric beads as potential therapeutics for Wilson's disease. AB - Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease. PMID- 24815562 TI - Case of generalized pustular psoriasis with end-stage renal disease successfully treated with granulocyte monocyte apheresis in combination with hemodialysis. AB - Granulocyte monocyte apheresis (GMA) is an extracorporeal apheresis instrument that removes activated neutrophils and monocytes. Generalized pustular psoriasis (GPP) is characterized by neutrophil infiltration into the epidermis that causes Kogoj's spongiotic pustule. Thus, GMA is one of the useful therapies for GPP, and it was approved for the treatment in 2012 in Japan. Herein, we report a case of GPP with end-stage renal disease (ESRD) successfully treated with GMA in combination with hemodialysis (HD). A 54-year-old Japanese female visited our outpatient clinic because of erythema with pustules on her trunk and extremities over the past 4 months. Histopathological examination showed an intraepidermal pustule filled with numerous neutrophils and spongiosis. These findings led to the diagnosis of GPP. She had ESRD and had been treated with HD twice a week for approximately 4 years. During maintenance HD twice a week, weekly GMA was started at Tokai University Hospital. The skin symptoms disappeared after five administrations of GMA. We suggest that GMA is an effective therapy for GPP patients with ESRD who are treated with HD. PMID- 24815563 TI - The diverging perception among physiotherapists of how to work with the concept of evidence: a phenomenographic analysis. AB - RATIONALE, AIMS AND OBJECTIVES: Changes in Sweden's municipal care have impacted the situation of physiotherapists by the adoption of practice based on research evidence. Even if physiotherapists appear to be in favour of the idea of evidence based practice, barriers still exist that prevent many from keeping up with current research. The aim of this study was to identify and describe the different ways in which physiotherapists in municipal care perceive the concept of evidence in rehabilitation. METHODS: A phenomenographic design with semi structured interviews was carried out with physiotherapists working with frail older people in three municipal care units in two neighbouring municipalities in Sweden. The physiotherapists' perceptions of evidence were explored in 12 interviews. RESULTS: Distinct perceptions of the concept of evidence are identified in three categories: 'Confidence with the concept of evidence in relation to measurement instruments'; 'Perception of evidence-based practice as a duty, condition and demand of the profession'; and 'Evidence-based work as a separate rather than directly patient-oriented activity'. CONCLUSIONS: Physiotherapists take full responsibility to comply with what they perceive to be the demands of their profession. However, what evidence actually meant, and therefore what the practical element of this responsibility consisted of, was not as clear. PMID- 24815564 TI - Opportunistic infections in patients with pemphigus. AB - BACKGROUND: Opportunistic infections (OIs) can be defined as infections in immunosuppressed patients that are more frequent or severe because of immunosuppression. The literature on OIs in pemphigus is sparse. OBJECTIVE: We assessed the incidence, risk factors, and characteristics of OIs in patients with pemphigus. METHODS: This was a historical prospective study following a cohort of 172 patients with newly diagnosed pemphigus for the development of OIs. RESULTS: Fourteen patients developed OIs at a mean of 4 months from the time of diagnosis while taking a mean dose of 0.8 mg/kg/day of prednisone, 5 in conjunction with azathioprine. The risk of developing an OI in the first year after the diagnosis of pemphigus was 9.3%, subsequently dropping to 0. Advanced age and possibly diabetes were found to be risk factors for OI development. Infectious agents included Nocardia, cytomegalovirus, Legionella, and Listeria. Two patients died within 2 months of OI diagnosis, and 2 more had neurologic impairment. LIMITATIONS: Limitations include the extraction of historical data and the cohort originating from a single geographic region. CONCLUSION: OIs present in a significant number of patients with pemphigus during the first year after the diagnosis of pemphigus, with potential deleterious effects. Older and possibly diabetic patients are at increased risk. Physician vigilance and patient education on limiting pathogen exposure is recommended. PMID- 24815565 TI - Update on primary mucosal melanoma. AB - Mucosal melanomas are aggressive cancers of mucosal surfaces with clinical and pathologic characteristics distinct from cutaneous melanomas, warranting different staging systems and treatment approaches. Surgical resection is performed frequently for the primary tumor, although the utility of lymph node surgery and radiation therapy is not established. Therapies targeted against C KIT activating mutations, identified in many mucosal melanomas, are emerging as promising treatments. PMID- 24815566 TI - Community survey of rabies knowledge and exposure to bats in homes - Sumter County, South Carolina, USA. AB - Subsequent to a human rabies death in Sumter County, South Carolina, we assessed the frequency of exposures to bats in homes and citizens' rabies knowledge. A self-administered survey was mailed to 6033 randomly selected Sumter County addresses. The survey inquired about household exposures to bats and respondents' rabies knowledge. Surveys were returned by mail for descriptive analysis. Of 597 respondents, 3.5% (21/597) reported having bats living in (2.8% or 17/597) or entering their homes (2.5% or 15/597) during 2010-2012. Respondents generally understood that mammals transmit rabies virus through bites, but were less aware of the severity of rabies illness and modern post-exposure vaccine administration. Respondents were unsure about how to exclude bats from homes and ranked highly both healthcare and non-healthcare entities as preferred resources for obtaining assistance with bat-related concerns. We found potential for human exposures to bats in Sumter County households and gaps in citizen knowledge of rabies and bat exclusion. Public health officials should engage non-healthcare partners in assistance disseminating rabies educational materials and for providing appropriate referral for persons potentially exposed to bats. PMID- 24815567 TI - Alcohol consumption during pregnancy: cross-sectional survey. AB - OBJECTIVE: to assess the prevalence and pattern of alcohol consumption pre conception and/or during the first trimester using the Alcohol Use Disorders Identification Test (AUDIT), Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) and T-ACE (Tolerance, Annoyance, Cut Down and Eye-Opener) alcohol screening questionnaires, and determine the socio-demographic predictors of drinking in this time period. DESIGN: cross sectional survey of a consecutive sample of 500 pregnant women attending their first antenatal appointment at approximately 10-11 weeks gestation. SETTING: two antenatal clinics in the South West of England. FINDINGS: of the 409 women respondents, we found a quarter of women reported drinking alcohol despite being aware they are pregnant. Between two to three in every 100 women reported drinking six or more units on a single occasion (heavy episodic or 'binge' drinking) at least monthly or weekly in the past three months. A similar proportion reported exceeding the recommended drinking limits of one to two units, once or twice a week. The majority of heavy episodic drinkers were otherwise low risk drinkers. 5.4% of respondents had an AUDIT-C score of 3 or more, and 22.2% a T-ACE score of 2 or more, indicating risk drinking in the peri-conception period. Drinking pre-conception and/or during the first trimester was more likely if women were multiparous and of white ethnicity. KEY CONCLUSIONS: in this study pregnant women attending an antenatal appointment were willing to complete brief alcohol screening questionnaires. A minority of women reported drinking pre-conception and/or during the first trimester with a small percentage drinking at levels potentially harmful to the fetus. IMPLICATIONS FOR PRACTICE: use of these questionnaires would help midwives gather information about alcohol use to help identify women drinking at levels in excess of recommended limits in order that appropriate advice and support be offered. PMID- 24815568 TI - Symptomatic and functional remission of subjects at clinical high risk for psychosis: a 2-year naturalistic observational study. AB - BACKGROUND: The aim of this study was to assess the frequency and predictors of symptomatic and functional remission in individuals at clinical high risk (CHR) for psychosis at 1-2 years of follow-up. METHODS: Help-seeking CHR individuals with symptomatic (Scale of Prodromal Symptoms (SOPS) positive scores <3) and functional (Global Assessment of Functioning (GAF) score >60) (CHR-R) remission at 12-24 months were compared to non-remitted individuals (CHR-NR) regarding baseline and treatment characteristics, symptom changes and predictors. Time to full remission was compared with that of symptomatic remission only. RESULTS: Of 73 individuals, 29 (39.7%) achieved full remission; 44 (60.3%) did not. Compared to CHR-NR individuals, CHR-R individuals had lower baseline SOPS positive symptoms (p=0.017), antipsychotic use (p=0.004), antipsychotic chlorpromazine dose equivalents (p=0.001) and anxiolytic use (p=0.004). In survival analyses, the estimated full remission rate was 48.3% (95% confidence interval (CI)=36.2 61.9) and symptomatic remission rate was 67.5% (CI95=55.4-79.2). Time to full remission was longer than time to symptomatic remission (p=0.017). Linear mixed effect models revealed significantly greater improvements from 6 months onward in CHR-R subjects compared to CHR-NR subjects regarding SOPS positive symptoms (p=0.003), highest SOPS positive symptom (p<0.001) and GAF scores (p=0.004). Examining baseline predictors, time to full remission was significantly longer in patients with higher SOPS positive scores (p=0.017). CONCLUSIONS: More stringent remission criteria that include functional status in addition to attenuated positive symptom severity should be applied to CHR subjects. Furthermore, more attention should be given to CHR individuals with highly positive prodromal symptoms at baseline. PMID- 24815569 TI - Maternal prenatal infection, early susceptibility to illness and adult psychotic experiences: a birth cohort study. AB - BACKGROUND: Existing evidence has established that maternal infection during pregnancy and illness during early life are associated with later schizophrenia. No research has examined how the combination of these prenatal and postnatal exposures is linked to an increased risk to later schizophrenia and psychotic disorders. METHODS: Participants from the Mater University Study of Pregnancy (MUSP), an Australian based, pre-birth cohort study were examined for lifetime DSM-IV positive psychotic experiences at 21 years by a semi-structured interview. Structural equation modelling was used to derive a general factor of psychotic experiences at age 21. Next, we undertook a number of separate analyses to investigate how prenatal infections and infant illness susceptibility are related to positive psychotic experiences in early adulthood, allowing for tests of moderation and mediation between the two risk factors. RESULTS: After adjustment for important confounders, infant illness susceptibility was found to play a mediating role in the association between prenatal vaginal infection and later psychotic experiences. Whereby, infant illness susceptibility showed a direct association with psychotic experiences, while prenatal vaginal infection indirectly predicted psychotic experiences via infant illness susceptibility. CONCLUSION: Our findings suggest that illness susceptibility in early infancy may be central to the relationship between prenatal vaginal infection and later psychotic experiences. Further research is needed to establish the mechanisms that link these prenatal and postnatal exposures with psychotic illness in later life. PMID- 24815570 TI - [Case management: moving forward]. PMID- 24815571 TI - Community mobilization and service strengthening to increase awareness and use of postabortion care and family planning in Kenya. AB - OBJECTIVE: To evaluate whether a community engagement and service-strengthening intervention raised awareness of family planning (FP) and early pregnancy bleeding (EPB), and increased FP and postabortion care (PAC) use. METHODS: The intervention was carried out in 3 communities in Kenya over 18months; 3 additional communities served as the comparison group. A pre-post, contemporaneously controlled, quasi-experimental evaluation was conducted independently from the intervention. RESULTS: Baseline characteristics were similar. Awareness of FP methods increased (P<=0.001) in the intervention group. The incidence of reported EPB (before 5months of pregnancy) in the comparison group was 13.3% at baseline and 6.0% at endline (P=0.02); 79% at baseline and 100% at endline sought care (P>0.05). In the intervention group, recognition and reporting of EPB increased from 9.8% to 13.1% (P>0.05); 65% sought PAC at baseline and 80% at endline (P=0.11). The relative increase in EPB reports after the intervention was over 3 times greater in the intervention group (P<=0.01). CONCLUSION: The intervention raised FP and EPB awareness but not FP and PAC services use. As fewer comparison group respondents reported experiencing EPB, the PAC impact of the intervention is unclear. Mechanisms to improve EPB reporting are needed to avoid this reporting bias. PMID- 24815572 TI - The effect of albumin on podocytes: the role of the fatty acid moiety and the potential role of CD36 scavenger receptor. AB - Evidence is emerging that podocytes are able to endocytose proteins such as albumin using kinetics consistent with a receptor-mediated process. To date the role of the fatty acid moiety on albumin uptake kinetics has not been delineated and the receptor responsible for uptake is yet to be identified. Albumin uptake studies were carried out on cultured human podocytes exposed to FITC-labelled human serum albumin either carrying fatty acids (HSA+FA) or depleted of them (HSA FA). Receptor-mediated endocytosis of FITC-HSA+FA over 60 min was 5 times greater than that of FITC-HSA-FA. 24h exposure of podocytes to albumin up-regulated nephrin expression and induced the activation of caspase-3. These effects were more pronounced in response to HSA-FA. Individually, anti-CD36 antibodies had no effect upon endocytosis of FITC-HSA. However, a cocktail of 2 antibodies reduced uptake by nearly 50%. Albumin endocytosis was enhanced in the presence of the CD36 specific inhibitor sulfo-N-succinimidyl oleate (SSO) while knock-down of CD36 using CD36siRNA had no effect on uptake. These data suggest that receptor mediated endocytosis of albumin by podocytes is regulated by the fatty acid moiety, although, some of the detrimental effects are induced independently of it. CD36 does not play a direct role in the uptake of albumin. PMID- 24815573 TI - Assessment of implicit health attitudes: a multitrait-multimethod approach and a comparison between patients with hypochondriasis and patients with anxiety disorders. AB - Two adaptations of the Implicit Association Task were used to assess implicit anxiety (IAT-Anxiety) and implicit health attitudes (IAT-Hypochondriasis) in patients with hypochondriasis (n = 58) and anxiety patients (n = 71). Explicit anxieties and health attitudes were assessed using questionnaires. The analysis of several multitrait-multimethod models indicated that the low correlation between explicit and implicit measures of health attitudes is due to the substantial methodological differences between the IAT and the self-report questionnaire. Patients with hypochondriasis displayed significantly more dysfunctional explicit and implicit health attitudes than anxiety patients, but no differences were found regarding explicit and implicit anxieties. The study demonstrates the specificity of explicit and implicit dysfunctional health attitudes among patients with hypochondriasis. PMID- 24815574 TI - Physical activity is associated with decreased incidence of chronic kidney disease in type 2 diabetes patients: a retrospective cohort study in Taiwan. AB - AIMS: To assess the effect of physical activity in patients with type 2 diabetes mellitus on prevention of diabetes with chronic kidney disease. METHODS: This is a cohort study on stratified selected subjects in Taiwan from 2004/01/01 to 2005/12/31. Demographic data, lifestyle factors and clinical characteristics were analyzed for an association with the occurrence of chronic kidney disease. Applicable analysis weights, Stata 11.0, were applied to adjust the design variables for clustering and stratification. RESULTS: During the two year study period, the univariate Cox proportional hazards model showed significant associations of age, physical activity, and the Charlson comorbidity index (CCI) with chronic kidney disease. Physical activity had a beneficial effect in diabetic subjects with chronic kidney disease (HR: 0.31, p<0.01). Older age and a CCI greater than 2 were both harmful in diabetic subjects with chronic kidney disease (1.06 and 3.44, respectively). The results of a multivariate Cox proportional hazards evaluation model were similar to those of a univariate evaluation model, except that CCI was not significantly different. Moreover, medications for hypertension of diabetic subjects created an increased risk of chronic kidney disease (HR: 5.85 and 3.74, respectively), indicating that the presence of hypertension is a strong risk factor for the progression of chronic kidney disease. CONCLUSION: In this study, physical activity was not only a healthful lifestyle factor but also a treatment to decrease incidence of chronic kidney disease in diabetic patients. PMID- 24815575 TI - Effects of selected antidiabetics on weight loss--a retrospective database analysis. AB - AIMS: In published studies metformin was often associated with weight loss in type 2 diabetes patients. Until now, no epidemiological studies have directly compared the effects of DPP-4 and GLP-1 versus metformin on weight loss. Our study is a comparison of sulfonylurea, DPP-4 and GLP-1 with metformin regarding body weight in type 2 diabetes patients. METHODS: Data from 2641 patients initiated therapy with either metformin, sulfonylurea, DPP-inhibitors or GLP-1 with baseline BMI >30 were retrospectively analyzed (Disease Analyzer Germany: 11/2008-10/2012). Comparison was performed for the weight change after 1 year of therapy compared with the last value prior to therapy. Differences between SU, DPP-4, GLP-1 versus metformin were estimated using regression model adjusted for age, gender, health insurance status, defined co-diagnoses and body weight at baseline. RESULTS: In absolute values, metformin patients lost an average of 2.6 kg, subjects treated with SU gained 0.3 kg, body weight in the DPP-4 group decreased by 1.8 kg and GLP-1 patients lost 3.3 kg in body weight after 1 year. After adjustment for other variables, comparisons with metformin revealed the following results: SU +3.4 kg (p < 0.001), DPP-4 +1.0 kg (p = 0.003) and GLP-1 0.4 kg (p = 0.589). CONCLUSION: Our study showed that GLP-1 treatment was comparable to metformin regarding the weight reduction, while sulfonylurea and DPP-4 are inferior in this regard. PMID- 24815576 TI - Access to aryl mellitic acid esters through a surprising oxidative esterification reaction. AB - A serendipitously discovered oxidative esterification reaction of cyclohexane hexacarboxylic acid with phosphorus pentachloride and phenols provides one-pot access to previously unknown aryl mellitic acid esters. The reaction features a solvent-free digestion and chromatography-free purifications and demonstrates the possibility of cyclohexane-to-benzene conversions under relatively mild, metal free conditions. PMID- 24815578 TI - Understanding why landholders choose to participate or withdraw from conservation programs: a case study from a Queensland conservation auction. AB - Ensuring adequate participation by private landholders in a conservation scheme is a challenge for program managers around the world. This paper uses a case study of the Vegetation Incentives Program from Queensland, Australia, to contribute additional information to the literature on influences on participation in conservation, and to offer insight into ways to improve program design to optimise participation. The research is particularly of interest to programs that include a tender mechanism or conservation covenant in their designs. Participation in the Vegetation Incentives Program was limited outside two small geographic areas, with the result that the budget was not expended. A survey of participants revealed that a narrow subset of the rural population was attracted to participate, namely highly educated, experienced landholders with positive environmental attitudes and a low opportunity cost of participation. The research also investigated why some landholders chose to withdraw from the program before full participation. Both qualitative and quantitative methods were used in the analysis. There were a variety of reasons for making the decision to leave, including disliking the requirement for permanent protection, the tender mechanism employed, and not understanding the process well enough. This information can help improve conservation outcomes by understanding where to target limited efforts in a catchment, and clarifying the likely limitations of some aspects of scheme design. PMID- 24815577 TI - Gamma activity modulated by naming of ambiguous and unambiguous images: intracranial recording. AB - OBJECTIVE: Humans sometimes need to recognize objects based on vague and ambiguous silhouettes. Recognition of such images may require an intuitive guess. We determined the spatial-temporal characteristics of intracranially-recorded gamma activity (at 50-120Hz) augmented differentially by naming of ambiguous and unambiguous images. METHODS: We studied 10 patients who underwent epilepsy surgery. Ambiguous and unambiguous images were presented during extraoperative electrocorticography recording, and patients were instructed to overtly name the object as it is first perceived. RESULTS: Both naming tasks were commonly associated with gamma-augmentation sequentially involving the occipital and occipital-temporal regions, bilaterally, within 200ms after the onset of image presentation. Naming of ambiguous images elicited gamma-augmentation specifically involving portions of the inferior-frontal, orbitofrontal, and inferior-parietal regions at 400ms and after. Unambiguous images were associated with more intense gamma-augmentation in portions of the occipital and occipital-temporal regions. CONCLUSIONS: Frontal-parietal gamma-augmentation specific to ambiguous images may reflect the additional cortical processing involved in exerting intuitive guess. Occipital gamma-augmentation enhanced during naming of unambiguous images can be explained by visual processing of stimuli with richer detail. SIGNIFICANCE: Our results support the theoretical model that guessing processes in visual domain occur following the accumulation of sensory evidence resulting from the bottom-up processing in the occipital-temporal visual pathways. PMID- 24815579 TI - Medical countermeasures for national security: a new government role in the pharmaceuticalization of society. AB - How do governments contribute to the pharmaceuticalization of society? Whilst the pivotal role of industry is extensively documented, this article shows that governments too are accelerating, intensifying and opening up new trajectories of pharmaceuticalization in society. Governments are becoming more deeply invested in pharmaceuticals because their national security strategies now aspire to defend populations against health-based threats like bioterrorism and pandemics. To counter those threats, governments are acquiring and stockpiling a panoply of 'medical countermeasures' such as antivirals, next-generation vaccines, antibiotics and anti-toxins. More than that, governments are actively incentivizing the development of many new medical countermeasures--principally by marshaling the state's unique powers to introduce exceptional measures in the name of protecting national security. At least five extraordinary policy interventions have been introduced by governments with the aim of stimulating the commercial development of novel medical countermeasures: (1) allocating earmarked public funds, (2) granting comprehensive legal protections to pharmaceutical companies against injury compensation claims, (3) introducing bespoke pathways for regulatory approval, (4) instantiating extraordinary emergency use procedures allowing for the use of unapproved medicines, and (5) designing innovative logistical distribution systems for mass drug administration outside of clinical settings. Those combined efforts, the article argues, are spawning a new, government-led and quite exceptional medical countermeasure regime operating beyond the conventional boundaries of pharmaceutical development and regulation. In the first comprehensive analysis of the pharmaceuticalization dynamics at play in national security policy, this article unearths the detailed array of policy interventions through which governments too are becoming more deeply imbricated in the pharmaceuticalization of society. PMID- 24815580 TI - Systematic evidence-based clinical practice guidelines are ushering in a new stage of standardized management of hepatocellular carcinoma in Japan. AB - Since the European Association for the Study of the Liver published their guidelines for hepatocellular carcinoma HCC (EASL Guideline) in 2001, there have been many explorations of "transferring best current evidence into clinical decision-making" around the worldwide. Comparative analysis on current 17 characteristic guidelines for HCC indicated that evidence-based clinical practice guidelines for HCC are urgently needed and appropriate constructing approach is the factor most significantly influencing their implementation. The construction of evidence-based clinical practice guidelines for HCC in Japan made a good example of this practice. In accordance with evidence-based medicine (EBM), the first version of the J-HCC Guidelines was published in 2005, then revised in 2009, and the third version has just been published on October 15, 2013 with the incorporation of new evidence, which marks the construction of evidence-based clinical practice guidelines for HCC step into a systematic process in Japan. In order to make a more clear description on how to construct evidence-based clinical practice guidelines for HCC in Japan, the three versions of the J-HCC Guidelines were comparatively analyzed in this paper. Focus on methodology used to develop the updated version, the decision tree of 2013 J-HCC Guideline and its features were also revealed. It is expected that J-HCC Guidelines could be useful not only for Japanese physicians and patients in decision making at every clinical step, but also to benefit users internationally with the accumulated evidence and its interpretation in the guidelines. PMID- 24815581 TI - Daily hydroxyl radical scavenging capacity of mammals. AB - Both the formation and reactions of hydroxyl radical (*OH) are quantitative chemical reactions even in mammalians, and so we can reproduce such in vivo reactions in test tubes. Daily urinary excretions of some reaction products have been used to estimate the amount of *OH produced daily. Although urinary 8 hydroxydeoxyguanosine (8-OHdG) is a well-known marker of *OH, we have shown that creatol (CTL: 5-hydroxycreatinine), an *OH adduct of creatinine (Crn), and its metabolite, methylguanidine (MG), are better markers, because the amount of *OH scavenged by deoxyguanosine (dG) in the body is negligible. We measured CTL and MG together with Crn in 24-h urine, and calculated their molar sum, CTL + MG, providing a daily estimate of moles of *OH scavenged with Crn, and, from the molar ratio (CTL + MG)/Crn, we can calculate the percentage of Crn that was used to scavenge *OH. Healthy subjects and normal rats were indicated to use circa (ca.) 0.2 and 0.3% of Crn in order to scavenge *OH, respectively, because the corresponding ratios, scavenged *OH/Crn, were 2.2 and 3.0 mmole/mole (24-h urine) (Crn scavenged ca. 20-25 MUmole and ca. 200 pmole of *OH in healthy subjects and normal rats, respectively). Since 8-OHdG/Crn has been reported to be 1.9 MUmole/mole (24-h urine), the daily scavenging capacity with Crn is 10(3)-fold more than dG. In patients with chronic renal failure (CRF) or chronic kidney disease (CKD) at stages 3-5: glomerular filtration rate (GFR) < 60 mL/min/1.73 m(2), *OH levels increased in proportion to the severity of CKD: up to ca. 3% of Crn was used daily in order to scavenge *OH. Although the accumulation of MG in organs has not been reported except for the brain and skin tissues in normal animals, *OH increases markedly and MG becomes detectable in all organs such as the kidney, liver, and heart in CRF rats. PMID- 24815582 TI - Design, synthesis and biological evaluation of 4-chromanone derivatives as IKr inhibitors. AB - Cardiac arrhythmia is a major cause of death in the world. Among many delayed rectifier potassium currents, the rapid delayed rectifier K current (IKr) plays an important role in the repolarization of cardiac tissue. The inhibition of IKr can delay repolarization and lead to an increase in the QT interval of the electrocardiogram, which is the treatment mechanism of Class III antiarrhythmic agents. Therefore, IKr can be considered as the drug target for the treatment of cardiac arrhythmia. In the current study, a series of 4-chromanone compounds (WR1 WR12) were well designed and synthesized as IKr inhibitors. The results disclosed that two compounds displayed potent inhibitory activities against IKr. Moreover, our structure-activity relationship results might provide necessary information for the rational design of inhibitors for IKr. PMID- 24815583 TI - Metabolites from Aspergillus versicolor, an endolichenic fungus from the lichen Lobaria retigera. AB - Three new anthraquinone derivatives (1-3) and one new artifact (4) were isolated, along with six known anthraquinone derivatives (5-10) and three xanthones (11 13), from a culture of an endolichenic fungus, Aspergillus versicolor, that was isolated from the lichen Lobaria retigera. The structures of these substances were determined on the basis of 1D and 2D (COSY, HMQC, and HMBC) NMR and MS analyses. The substances 1-4 were also tested for their cytotoxic activity. PMID- 24815584 TI - Exploring the influence of renal dysfunction on the pharmacokinetics of ribavirin after oral and intravenous dosing. AB - Although ribavirin is minimally cleared by renal elimination, its pharmacokinetics are substantially altered in patients with chronic renal impairment. This open-label study assessed the pharmacokinetics of single 400-mg oral and intravenous (IV) doses of ribavirin in two healthy volunteers and 12 patients with varying degrees of chronic renal impairment. Blood and urine samples were collected pre-dose and up to 168 h post-dose for pharmacokinetic analyses. Ribavirin area under the plasma concentration-time curve from time zero to time of final quantifiable sample and maximum plasma concentration values were increased, and total plasma clearance (CL), renal clearance (CLr), non-renal clearance (CLnr), volume of distribution at steady state (Vdss), and amount excreted values were reduced in patients with renal dysfunction compared with those who had normal renal function. Following IV administration, mean CLr was 54%, 23%, and 10% in patients with mild, moderate, and severe renal dysfunction, respectively, relative to control subjects, and was 56%, 28%, and 9% of control values after oral dosing. After IV dosing, mean CLnr was 94%, 76%, and 75% of control values in patients with mild, moderate, and severe renal dysfunction, respectively, and was 54%, 48%, and 27% of control values after oral dosing. Mean oral bioavailability of ribavirin was 35%, 60%, 57%, and 71% in control subjects and patients with mild, moderate, and severe renal dysfunction, respectively. These data indicate that there are multiple mechanisms (increased oral bioavailability, reduced CLr and CLnr, reduced Vd) contributing to altered ribavirin pharmacokinetics in chronic renal impairment. PMID- 24815585 TI - Three-dimensional imaging technology offers promise in medicine. AB - Medical imaging plays an increasingly important role in the diagnosis and treatment of disease. Currently, medical equipment mainly has two-dimensional (2D) imaging systems. Although this conventional imaging largely satisfies clinical requirements, it cannot depict pathologic changes in 3 dimensions. The development of three-dimensional (3D) imaging technology has encouraged advances in medical imaging. Three-dimensional imaging technology offers doctors much more information on a pathology than 2D imaging, thus significantly improving diagnostic capability and the quality of treatment. Moreover, the combination of 3D imaging with augmented reality significantly improves surgical navigation process. The advantages of 3D imaging technology have made it an important component of technological progress in the field of medical imaging. PMID- 24815586 TI - Current clinical uses of the biomarkers for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a severe condition that is found worldwide. The current methods of HCC screening and diagnosis depend mainly on tumor imaging techniques. Using tumor biomarkers to detect cancer has helped to screen for disease and avoid wasting medical resources. Serum alpha-fetoprotein (AFP), a glycoform of AFP that reacts with Lens culinaris agglutinin (AFP-L3), and des gamma carboxyprothrombin (DCP) are biomarkers commonly used to detect HCC in medical practice around the world. However, each of these biomarkers is imperfect when used alone and each has limitations in terms of the sensitivity and specificity with which it detects HCC. Presumably, a combination of these biomarkers is a practical way to improve their performance. That said, novel biomarkers of HCC are being sought to diagnose the disease and also to optimize the treatment modality, to predict prognosis or recurrence, and to discover novel targets for therapeutic interventions. PMID- 24815587 TI - Suggestions to the media to help us cope with the A/H7N9 crisis in China. AB - The A/H7N9 avian influenza virus sparked global concerns about public health. The media published numerous reports about emerging infectious diseases, including their clinical characteristics and genomic information. However, outbreaks of A/H7N9 posed a real challenge to China's emergency management and especially its dealing with the media. This study analyzes ways to deal with the media during A/H7N9 crises and it proposes a shift in public emergency management from an "Impact-Responsive" approach to a "Prevention-Active" approach. A "Prevention Active" approach should be used when dealing with the media during subsequent outbreaks. PMID- 24815588 TI - Comparison of quantitative wall-motion analysis and strain for detection of coronary stenosis with three-dimensional dobutamine stress echocardiography. AB - BACKGROUND: Quantitative analysis of wall motion from three-dimensional (3D) dobutamine stress echocardiography (DSE) could provide additional diagnostic information not available from qualitative analysis. In this study, we compare the effectiveness of 3D fractional shortening (3DFS), a measure of wall motion computed from 3D echocardiography (3DE), to strain and strain rate measured with sonomicrometry for detecting critical stenoses during DSE. METHODS: Eleven open chest dogs underwent DSE both with and without a critical stenosis. 3DFS was measured from 3DE images acquired at peak stress. 3DFS was normalized by subtracting average 3DFS during control peak stress (?3DFS). Strains in the perfusion defect (PD) were measured from sonomicrometry, and PD size and location were measured with microspheres. RESULTS: A ?3DFS abnormality indicated the presence of a critical stenosis with high sensitivity and specificity (88% and 100%, respectively), and ?3DFS abnormality size correlated with PD size (R(2) = 0.54). The sensitivity and specificity for ?3DFS were similar to that for area strain (88%, 100%) and circumferential strain and strain rate (88%, 92% and 88%, 86%, respectively), while longitudinal strain and strain rate were less specific. ?3DFS correlated significantly with both coronary flow reserve (R(2) = 0.71) and PD size (R(2) = 0.97), while area strain correlated with PD size only (R(2) = 0.67), and other measures were not significantly correlated with flow reserve or PD size. CONCLUSION: Quantitative wall-motion analysis using ?3DFS is effective for detecting critical stenoses during DSE, performing similar to 3D strain, and provides potentially useful information on the size and location of a perfusion defect. PMID- 24815589 TI - Outpatient analgesia via paravertebral peripheral nerve block catheter and On-Q pump--a case series. AB - Outpatient pain management after iliac crest bone harvesting can be challenging. We report the use of home L2 paravertebral nerve block catheter (L2PVBC) in a series of five children. The pain scores were low, and analgesic medication consumption was minimal. No complications were reported related with these catheters, and the patients reported very high pain control satisfaction scores. Outpatient L2PVBC can be beneficial as part of a multimodal analgesia strategy in selected pediatric patients. PMID- 24815591 TI - Bloch oscillations in plasmonic waveguide arrays. AB - The combination of modern nanofabrication techniques and advanced computational tools has opened unprecedented opportunities to mold the flow of light. In particular, discrete photonic structures can be designed such that the resulting light dynamics mimics quantum mechanical condensed matter phenomena. By mapping the time-dependent probability distribution of an electronic wave packet to the spatial light intensity distribution in the corresponding photonic structure, the quantum mechanical evolution can be visualized directly in a coherent, yet classical wave environment. On the basis of this approach, several groups have recently observed discrete diffraction, Bloch oscillations and Zener tunnelling in different dielectric structures. Here we report the experimental observation of discrete diffraction and Bloch oscillations of surface plasmon polaritons in evanescently coupled plasmonic waveguide arrays. The effective external potential is tailored by introducing an appropriate transverse index gradient during nanofabrication of the arrays. Our experimental results are in excellent agreement with numerical calculations. PMID- 24815590 TI - Eating disorder symptoms and comorbid psychopathology among male and female veterans. AB - OBJECTIVE: Eating disorder (ED) symptoms have gone mostly unexamined among veterans. The current study assessed rates of bulimia nervosa (BN) and binge eating disorder (BED) symptoms and diagnoses and their associations with common comorbidities among male and female veterans. METHOD: Participants were US military veterans who screened positive for trauma histories and/or a probable Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) posttraumatic stress disorder (PTSD) diagnosis (n=499). Symptoms of PTSD were assessed using the Clinician-Administered PTSD Scale, and symptoms of EDs, mood, and substance use disorders were assessed using the Structured Clinical Interview for the DSM-IV. RESULTS: Lifetime rates of BN and BED diagnoses were comparable to civilian populations, and a considerable range of lifetime and current BN and BED symptoms were identified. In multivariate models, PTSD and depression severity were most consistently associated with BN and BED symptom severity, with depression most strongly associated with EDs for women. CONCLUSIONS: Findings highlight the importance of screening for ED symptoms among male and female veterans, particularly those that present with PTSD and depression symptomatology. Future examinations of the temporal order of such relationships and the degree to which ED symptoms and associated symptoms impact veteran functioning are warranted. PMID- 24815592 TI - Interrater and intrarater reliability of the pectoralis minor muscle length measurement in subjects with and without shoulder impingement symptoms. AB - Measuring the pectoralis minor muscle length (PML) is of clinical interest, as a short PML has been associated with a decrease of scapular posterior tilting and shoulder pain. However, as no reliability data are available at present, the objective of this study was to examine the inter- and intrarater reliability of the PML measurement in both subjects with and without shoulder impingement symptoms (SIS). Therefore, two assessors performed the PML measurement (3 times/shoulder) in 25 patients with SIS and 25 pain-free controls. Both assessors were blinded for each other's findings. For reliability testing, intra-class coefficients (ICCs; model 2,1) and standard errors of measurements were calculated. Intrarater reliability analysis resulted with ICCs ranging from 0.87 (Standard error of measurement (SEM) 0.21-0.27%) (symptomatic) to 0.93 (SEM 0.19 0.30%) (asymptomatic) in patients with SIS, representing excellent test-retest agreement. Healthy subjects presented with ICCs ranging from 0.76 (SEM 0.29 0.32%) (dominant side) to 0.87 (SEM 0.21-0.32%) (non-dominant side), representing good test-retest agreement. ICCs and SEMs on the symptomatic and asymptomatic side (0.48 and 0.46%; 0.56 and 0.61%) in SIS patients, and on the two sides (non dominant; 0.47 and 0.45%, dominant; 0.53 and 0.38% respectively) in healthy subjects showed moderate interrater reliability and low dispersion of the measurement errors. We concluded that the PML measurement has good to excellent intrarater reliability and poor to moderate interrater reliability. PMID- 24815593 TI - Cervical Spondylotic Myelopathy presenting as mechanical neck pain: a case report. AB - Cervical Spondylotic Myelopathy (CSM) is the most common type of myelopathy in adults over 55 years of age. In the early stages symptoms may include local neck pain and stiffness that might mimic the presentation of non-specific mechanical neck pain (NSMNP). The patient was a 79 year old male, who complained of eight weeks of neck pain. He had been referred for physiotherapy by his family physician with a diagnosis of NSMNP. Initial presentation was consistent with the referral, but further assessment by the physiotherapist revealed findings suggestive of CSM. He was referred for an urgent cervical MRI scan, which revealed myelomalacic changes at C3/4 due to spondylotic changes. The patient was unsuitable for manual therapy intervention and was referred to a spinal orthopaedic surgeon who performed a posterior decompression and stabilisation at C3-C5, 2 months after the initial presentation. This case report highlights the importance of considering CSM in adults over 55 years of age presenting with NSMNP, particularly as the prevalence of both increases with age. It demonstrates the need for health professionals to carry out detailed examination where CSM may be a potential differential diagnosis. Outcomes are less favourable for patients over the age of 70, therefore an urgent surgical opinion was required for this patient. Deterioration of symptoms whilst he awaited surgery demonstrates how missed diagnosis may lead to possible long term spinal cord damage, with potential medico-legal concerns for the therapist. PMID- 24815594 TI - The role of neuroplasticity in experimental neck pain: a study of potential mechanisms impeding clinical outcomes of training. AB - Training is a mainstay in the clinical management of neck pain, yet, effects of various training protocols are only small to moderate and improvements are required. Previous investigations of the nervous system indicate a correlation between neuroplastic adaptation to training and functional recovery. The interaction between neck pain and training thus needs further exploration. This was a randomized experimental study of the effects of experimental neck pain and training on corticomotor excitability. Healthy volunteers were randomized to training and experimental neck pain, training and no pain, and pain and no training. Primary endpoints were corticomotor excitability assessed by transcranial magnetic stimulation and electromyography measured as changes in amplitudes and latencies of motor evoked potentials (MEPs), recorded at baseline and after 30 min, 1 h, and 1 week. Additionally, correlations between changes in MEPs and motor learning, effects of pain and concomitant neck training on pain, muscle strength, and fatigue were investigated. Data were analyzed by repeated measurement ANOVA, paired t tests, Grubbs' outlier test and correlation coefficients. Results indicated that neck pain and training significantly enhanced the inhibition of the amplitudes of the MEPs for 1 week. The results indicate that moderate neck pain and training induce long-lasting inhibition of the corticomotor pathways. This inhibition may limit the outcome of neck training in painful conditions in contrast to pain-free training conditions. PMID- 24815595 TI - "I don't want financial support but verbal support." How do caregivers manage children's access to and retention in HIV care in urban Zimbabwe? AB - INTRODUCTION: Children living with HIV experience particular challenges in accessing HIV care. Children usually rely on adult caregivers for access to care, including timely diagnosis, initiation of treatment and sustained engagement with HIV services. The aim of this study was to inform the design of a community-based intervention to support caregivers of HIV-positive children to increase children's retention in care as part of a programme introducing decentralized HIV care in primary health facilities. METHODS: Using an existing conceptual framework, we conducted formative research to identify key local contextual factors affecting children's linkages to HIV care in Harare, Zimbabwe. We conducted semi-structured interviews with 15 primary caregivers of HIV-positive children aged 6-15 years enrolled at a hospital clinic for at least six months, followed by interviews with nine key informants from five community-based organizations providing adherence support or related services. RESULTS: We identified a range of facilitators and barriers that caregivers experience. Distance to the hospital, cost of transportation, fear of disclosing HIV status to the child or others, unstable family structure and institutional factors such as drug stock-outs, healthcare worker absenteeism and unsympathetic school environments proved the most salient limiting factors. Facilitators included openness within the family, availability of practical assistance and psychosocial support from community members. CONCLUSIONS: The proposed decentralization of HIV care will mitigate concerns about distance and transport costs but is likely to be insufficient to ensure children's sustained retention. Following this study, we developed a package of structured home visits by voluntary lay workers to proactively address other determinants such as disclosure within families, access to available services and support through caregivers' social networks. A randomized controlled trial is underway to assess impact on children's retention in care over two years. PMID- 24815596 TI - Generation of hazard indices for cumulative exposure to phthalates for use in cumulative risk assessment. AB - Exposures to multiple chemicals may contribute to increased risk of similar adverse effects. Cumulative risk may be estimated using a hazard index (HI), the sum of individual hazard quotients (HQ, ratio of exposure to the reference value). We demonstrate the HI approach for five phthalates: di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), diisobutyl phthalate (DiBP), diisononyl phthalate (DiNP), and butyl benzyl phthalate (BBP). Phthalate exposure for the US general population is estimated using urine metabolite levels from NHANES, extrapolating to ingested 'dose' using the creatinine correction approach. We used two sets of reference values: European Union Tolerable Daily Intakes and Denmark Environmental Protection Agency Derived No Effect Levels. We also investigated the use of an alternate reference value for DEHP, derived from a recent study on male reproductive system development. HQs and HIs were calculated for the total population ages 6years and older, as well as for men and women of approximate reproductive age (18-39 years), and children (6-11 years). Median HQs ranged from <0.01 for BBP, to ~0.1 (using established values) or ~2 (using an alternate value) for DEHP. Median HIs were <0.30 (95th percentiles just >1.0), and were driven by DEHP and DBP exposures. PMID- 24815597 TI - [From tic disorders to Tourette syndrome: current data, comorbidities, and therapeutic approach in children]. AB - Motor tics are frequently observed in children during development. Usually transient and benign, they can become chronic over time, join various morbid disorders (vocal tics, attention deficit and hyperactivity disorder, and obsessive-compulsive disorders) and move toward genuine Tourette syndrome. In this case, it will be necessary to prevent impacts - mainly in terms of quality of life and emotional and relational problems - using a global therapeutic strategy combining psychoeducational approaches with appropriate medication. PMID- 24815598 TI - [National French guidelines for management of infants with cystic fibrosis]. AB - These guidelines aim to standardize the care of infants diagnosed with a typical form of cystic fibrosis (CF) at neonatal screening. They have been implemented by the National Working Group for Neonatal Screening of the French Federation for CF and have been validated using the Delphi methodology by a large group of clinicians involved in the care of CF infants. These guidelines encompass management and organization of care at diagnosis and describe nutritional, digestive, and respiratory monitoring and treatment during the first 2 years of life. PMID- 24815599 TI - [Bariatric and plastic surgery in obese adolescents: an alternative treatment]. AB - The increased frequency of extreme forms of obesity in adolescents and the disappointing results of conventional treatments are now leading pediatricians to consider bariatric or cosmetic surgery as the only real long-term effective therapeutic alternative. The two main techniques currently used for bariatric surgery in adolescents are gastric bypass and adjustable gastric banding. Whatever the technique, weight loss is significant with improvement of comorbidities and quality of life. In addition, the complications are identical to those in adults and equally frequent. However, because of the particularities of this age, caution is still required. Adolescence is indeed characterized by specific nutritional needs, but also changes in body image in which surgery could have a negative effect. Currently, all obese teenagers making a request for bariatric surgery should have a comprehensive assessment with global care for at least 6 months. The indication is then discussed on a case-by-case basis by multidisciplinary teams and experts. To date, the type of surgery (gastric banding, gastric sleeve, or bypass) is still widely discussed. Based on experience with adults, we believe that gastric sleeve and bypass should be preferred. In addition, obesity in adolescents almost always involves psychosocial consequences, while somatic complications are rare. Thus, the care of adipo- or gynecomastia, abdominal fat excess, and concealed penis is essential and therefore justifies cosmetic surgery. PMID- 24815600 TI - [Hypnosis as an effective management of a child with posttraumatic stress disorder after perineal trauma]. AB - Children and teenagers may face trauma that threatens their life, but also their psychological integrity. These injuries can lead to posttraumatic stress disorder (PTSD), which is the most common psychopathological consequence after a trauma. Age is not a protective factor and this disorder can be severe and may last over a long-term period. Effective therapies on PTSD are scarce and research on this topic is rare in children. We report a case of a 12-year-old girl affected by PTSD after a carousel accident at the age of 4 years. A therapy based on hypnosis and psychological support was rapidly effective. This psychotherapeutic option was chosen on the basis of common features shared by hypnosis and the posttraumatic symptoms. Clinical manifestations of PTSD disappeared after 4 weeks of therapy and the patient remained symptom-free during a 1-year follow-up. Our report suggests that hypnosis could be an effective therapy for children with PTSD. Prospective studies on a larger number of patients are needed to validate this hypothesis. PMID- 24815601 TI - Finding ways to hope, seeing beauty. PMID- 24815602 TI - Exposure to stallion accelerates the onset of mares' cyclicity. AB - Horses (Equus caballus) belong to the group of seasonally polyestrous mammals. Estrous cycles typically start with increasing daylight length after winter, but mares can differ greatly in the timing of onset of regular estrus cycles. Here, we test whether spatial proximity to a stallion also plays a role. Twenty-two anestrous mares were either exposed to one of two stallions (without direct physical contact) or not exposed (controls) under experimental conditions during two consecutive springs (February to April). Ovarian activity was monitored via transrectal ultrasound and stallion's direct contact time with each mare was determined three times per week for one hour each. We found that mares exposed to a stallion ovulated earlier and more often during the observational period than mares that were not exposed to stallions. Neither stallion identity nor direct contact time, mare age, body condition, size of her largest follicle at the onset of the experiment, or parasite burden significantly affected the onset of cyclicity. In conclusion, the timing of estrous cycles and cycle frequency, i.e., crucial aspects of female reproductive strategy, strongly depend on how the mares perceive their social environment. Exposing mares to the proximity of a stallion can therefore be an alternative to, for example, light programs or elaborated hormonal therapies to start the breeding season earlier and increase the number of estrous cycles in horses. PMID- 24815603 TI - Animal models of Epstein Barr virus infection. AB - Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. PMID- 24815604 TI - Coming home at last: dermal white adipose tissue. AB - The upper part of subcutaneous white adipose tissue (SWAT) is closely associated with the reticular dermis, surrounds hair follicles and is of great importance for a range of skin functions. In this issue of Experimental Dermatology, Driskell and colleagues propose a nomenclature in which the upper SWAT layer is renamed dermal WAT (DWAT), and its cells intradermal adipocytes. Some pros and cons are discussed below. PMID- 24815605 TI - Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis. AB - OBJECTIVE: The impact of endogenous immunoglobulin isotypes on the prognosis of patients with severe sepsis has not been sufficiently explored. The aim of this study was to evaluate the association between immunoglobulin levels in plasma and survival in patients with this condition. DESIGN AND PATIENTS: A prospective multicentre cohort study was conducted. A total of 172 adult patients admitted to the intensive care unit (ICU) with severe sepsis or septic shock were recruited. Patients were classified based on deciles of immunoglobulin concentrations at diagnosis of sepsis. Categorical variables were created and tested for their association with survival during hospitalization in the ICU. RESULTS: Overall, 42 patients died in the ICU during the study. Kaplan-Meier analysis showed that immunoglobulin concentrations below 300 mg dL(-1) for IgG1, 35 mg dL(-1) for IgM and 150 mg dL(-1) for IgA were associated with shorter survival times. Multivariate regression analysis showed that IgG1 < 300 mg dL(-1) was a risk factor for mortality [odds ratio (OR) 2.50, 95% confidence interval (CI) 1.04 6.03; P = 0.042]. The combined presence of IgG1, IgM and IgA levels below the described thresholds had a synergistic impact on mortality risk (OR 5.27, 95% CI 1.41-19.69; P = 0.013). A similar effect was observed for combined low levels of IgG1 and IgA (OR 4.10, 95% CI 1.28-13.12; P = 0.018) and also of IgG1 and IgM (OR 3.10. 95% CI 1.13-8.49; P = 0.028). CONCLUSIONS: The combined presence of low levels of the endogenous immunoglobulins IgG1, IgM and IgA in plasma is associated with reduced survival in patients with severe sepsis or septic shock. Assessment of the concentrations of these immunoglobulins could improve the results of treatment with exogenous immunoglobulins in patients with sepsis. PMID- 24815606 TI - We take care of our own: caregiving salience increases out-group bias in response to out-group threat. AB - The parental caregiving motivational system leads people to behave selflessly. However, given that the purpose of this motivation is the protection of close kin, it might also lead to aggression toward distant, threatening others. In the present studies, we wished to investigate the effects of behaviorally activating the caregiving motivational system on out-group bias. On the basis of previous work in behavioral ecology, we predicted that activation of the caregiving system would enhance bias against out-groups whenever their members posed a salient threat. This prediction was confirmed in three studies (total N = 866) across different populations, manipulations, and measures. We discuss the possible importance of continued research into the behavioral consequences of caregiving salience. PMID- 24815607 TI - Forgiving you is hard, but forgetting seems easy: can forgiveness facilitate forgetting? AB - Forgiveness is considered to play a key role in the maintenance of social relationships, the avoidance of unnecessary conflict, and the ability to move forward with one's life. But why is it that some people find it easier to forgive and forget than others? In the current study, we explored the supposed relationship between forgiveness and forgetting. In an initial session, 30 participants imagined that they were the victim in a series of hypothetical incidents and indicated whether or not they would forgive the transgressor. Following a standard think/no-think procedure, in which participants were trained to think or not to think about some of these incidents, more forgetting was observed for incidents that had been forgiven following no-think instructions compared with either think or baseline instructions. In contrast, no such forgetting effects emerged for incidents that had not previously been forgiven. These findings have implications for goal-directed forgetting and the relationship between forgiveness and memory. PMID- 24815608 TI - We see more than we can report: "cost free" color phenomenality outside focal attention. AB - The distinction between access consciousness and phenomenal consciousness is a subject of intensive debate. According to one view, visual experience overflows the capacity of the attentional and working memory system: We see more than we can report. According to the opposed view, this perceived richness is an illusion we are aware only of information that we can subsequently report. This debate remains unresolved because of the inevitable reliance on report, which is limited in capacity. To bypass this limitation, this study utilized color diversity-a unique summary statistic-which is sensitive to detailed visual information. Participants were shown a Sperling-like array of colored letters, one row of which was precued. After reporting a letter from the cued row, participants estimated the color diversity of the noncued rows. Results showed that people could estimate the color diversity of the noncued array without a cost to letter report, which suggests that color diversity is registered automatically, outside focal attention, and without consuming additional working memory resources. PMID- 24815609 TI - Spatial orientation shrinks and expands psychological distance. AB - Being objectively close to or far from a place changes how people perceive the location of that place in a subjective, psychological sense. In the six studies reported here, we investigated whether people's spatial orientation (defined as moving toward or away from a place) will produce similar effects-by specifically influencing psychological closeness in each of its forms (i.e., spatial, temporal, probabilistic, and social distance). Orientation influenced subjective spatial distance at various levels of objective distance (Study 1), regardless of the direction people were facing (Study 2). In addition, when spatially oriented toward, rather than away from, a particular place, participants felt that events there had occurred more recently (Studies 3a and 3b) and that events there would be more likely to occur (Study 4). Finally, participants felt more similarity to people who were spatially oriented toward them than to people who were spatially oriented away from them (Study 5). Our investigation broadens the study of psychological distance from static spatial locations to dynamically moving points in space. PMID- 24815610 TI - Brief periods of auditory perceptual training can determine the sensory targets of speech motor learning. AB - The perception of speech is notably malleable in adults, yet alterations in perception seem to have little impact on speech production. However, we hypothesized that speech perceptual training might immediately influence speech motor learning. To test this, we paired a speech perceptual-training task with a speech motor-learning task. Subjects performed a series of perceptual tests designed to measure and then manipulate the perceptual distinction between the words head and had. Subjects then produced head with the sound of the vowel altered in real time so that they heard themselves through headphones producing a word that sounded more like had. In support of our hypothesis, the amount of motor learning in response to the voice alterations depended on the perceptual boundary acquired through perceptual training. The studies show that plasticity in adults' speech perception can have immediate consequences for speech production in the context of speech learning. PMID- 24815611 TI - Serotonin and social norms: tryptophan depletion impairs social comparison and leads to resource depletion in a multiplayer harvesting game. AB - How do people sustain resources for the benefit of individuals and communities and avoid the tragedy of the commons, in which shared resources become exhausted? In the present study, we examined the role of serotonin activity and social norms in the management of depletable resources. Healthy adults, alongside social partners, completed a multiplayer resource-dilemma game in which they repeatedly harvested from a partially replenishable monetary resource. Dietary tryptophan depletion, leading to reduced serotonin activity, was associated with aggressive harvesting strategies and disrupted use of the social norms given by distributions of other players' harvests. Tryptophan-depleted participants more frequently exhausted the resource completely and also accumulated fewer rewards than participants who were not tryptophan depleted. Our findings show that rank based social comparisons are crucial to the management of depletable resources, and that serotonin mediates responses to social norms. PMID- 24815612 TI - Purpose in life as a predictor of mortality across adulthood. AB - Having a purpose in life has been cited consistently as an indicator of healthy aging for several reasons, including its potential for reducing mortality risk. In the current study, we sought to extend previous findings by examining whether purpose in life promotes longevity across the adult years, using data from the longitudinal Midlife in the United States (MIDUS) sample. Proportional-hazards models demonstrated that purposeful individuals lived longer than their counterparts did during the 14 years after the baseline assessment, even when controlling for other markers of psychological and affective well-being. Moreover, these longevity benefits did not appear to be conditional on the participants' age, how long they lived during the follow-up period, or whether they had retired from the workforce. In other words, having a purpose in life appears to widely buffer against mortality risk across the adult years. PMID- 24815613 TI - Pre-crastination: hastening subgoal completion at the expense of extra physical effort. AB - In this article, we describe a phenomenon we discovered while conducting experiments on walking and reaching. We asked university students to pick up either of two buckets, one to the left of an alley and one to the right, and to carry the selected bucket to the alley's end. In most trials, one of the buckets was closer to the end point. We emphasized choosing the easier task, expecting participants to prefer the bucket that would be carried a shorter distance. Contrary to our expectation, participants chose the bucket that was closer to the start position, carrying it farther than the other bucket. On the basis of results from nine experiments and participants' reports, we concluded that this seemingly irrational choice reflected a tendency to pre-crastinate, a term we introduce to refer to the hastening of subgoal completion, even at the expense of extra physical effort. Other tasks also reveal this preference, which we ascribe to the desire to reduce working memory loads. PMID- 24815614 TI - Individual differences in infant fixation duration relate to attention and behavioral control in childhood. AB - Individual differences in fixation duration are considered a reliable measure of attentional control in adults. However, the degree to which individual differences in fixation duration in infancy (0-12 months) relate to temperament and behavior in childhood is largely unknown. In the present study, data were examined from 120 infants (mean age = 7.69 months, SD = 1.90) who previously participated in an eye-tracking study. At follow-up, parents completed age appropriate questionnaires about their child's temperament and behavior (mean age of children = 41.59 months, SD = 9.83). Mean fixation duration in infancy was positively associated with effortful control (beta = 0.20, R (2) = .02, p = .04) and negatively with surgency (beta = -0.37, R (2) = .07, p = .003) and hyperactivity-inattention (beta = -0.35, R (2) = .06, p = .005) in childhood. These findings suggest that individual differences in mean fixation duration in infancy are linked to attentional and behavioral control in childhood. PMID- 24815615 TI - Entering adulthood in a recession tempers later narcissism. AB - Despite widespread interest in narcissism, relatively little is known about the conditions that encourage or dampen it. Drawing on research showing that macroenvironmental conditions in emerging adulthood can leave a lasting imprint on attitudes and behaviors, I argue that people who enter adulthood during recessions are less likely to be narcissistic later in life than those who come of age in more prosperous times. Using large samples of American adults, Studies 1 and 2 showed that people who entered adulthood during worse economic times endorsed fewer narcissistic items as older adults. Study 3 extended these findings to a behavioral manifestation of narcissism: the relative pay of CEOs. CEOs who came of age in worse economic times paid themselves less relative to other top executives in their firms. These findings suggest that macroenvironmental experiences at a critical life stage can have lasting implications for how unique, special, and deserving people believe themselves to be. PMID- 24815616 TI - Sampling of illicit drugs for quantitative analysis--part III: sampling plans and sample preparations. AB - The findings in this paper are based on the results of our drug homogeneity studies and particle size investigations. Using that information, a general sampling plan (depicted in the form of a flow-chart) was devised that could be applied to the quantitative instrumental analysis of the most common illicit drugs: namely heroin, cocaine, amphetamine, cannabis resin, MDMA tablets and herbal cannabis in 'bud' form (type I). Other more heterogeneous forms of cannabis (type II) were found to require alternative, more traditional sampling methods. A table was constructed which shows the sampling uncertainty expected when a particular number of random increments are taken and combined to form a single primary sample. It also includes a recommended increment size; which is 1 g for powdered drugs and cannabis resin, 1 tablet for MDMA and 1 bud for herbal cannabis in bud form (type I). By referring to that table, individual laboratories can ensure that the sampling uncertainty for a particular drug seizure can be minimised, such that it lies in the same region as their analytical uncertainty for that drug. The table shows that assuming a laboratory wishes to quantitatively analyse a seizure of powdered drug or cannabis resin with a 'typical' heterogeneity, a primary sample of 15*1 g increments is generally appropriate. The appropriate primary sample for MDMA tablets is 20 tablets, while for herbal cannabis (in bud form) 50 buds were found to be appropriate. Our study also showed that, for a suitably homogenised primary sample of the most common powdered drugs, an analytical sample size of between 20 and 35 mg was appropriate and for herbal cannabis the appropriate amount was 200 mg. The need to ensure that the results from duplicate or multiple incremental sampling were compared, to demonstrate whether or not a particular seized material has a 'typical' heterogeneity and that the sampling procedure applied has resulted in a 'correct sample', was highlighted and the setting up of suitable control charts (R or S charts), for quality control purposes, was strongly recommended and examples given. Furthermore, although this particular study relates to the sampling of illicit drugs, it should be remembered that it is based on general sampling theory and therefore the same approach could be applied to other disciplines where 'correct sampling' of powders and solids is important. PMID- 24815617 TI - American alligator proximal pedal phalanges resemble human finger bones: Diagnostic criteria for forensic investigators. AB - A scientific approach to bone and tooth identification requires analysts to pursue the goal of empirical falsification. That is, they may attribute a questioned specimen to element and taxon only after having ruled out all other possible attributions. This requires analysts to possess a thorough understanding of both human and non-human osteology, particularly so for remains that may be morphologically similar across taxa. To date, forensic anthropologists have identified several potential 'mimics' for human skeletal remains, including pig teeth and bear paws. Here we document another possible mimic for isolated human skeletal elements--the proximal pedal phalanges of American alligators (Alligator mississippiensis) closely resemble the proximal and intermediate hand phalanges of adult humans. We detail morphological similarities and differences between these elements, with the goal of providing sufficient information for investigators to confidently falsify the hypothesis that a questioned phalanx is derived from an American alligator. PMID- 24815618 TI - Q-STAR: a perceptual video quality model considering impact of spatial, temporal, and amplitude resolutions. AB - In this paper, we investigate the impact of spatial, temporal, and amplitude resolution on the perceptual quality of a compressed video. Subjective quality tests were carried out on a mobile device and a total of 189 processed video sequences with 10 source sequences included in the test. Subjective data reveal that the impact of spatial resolution (SR), temporal resolution (TR), and quantization stepsize (QS) can each be captured by a function with a single content-dependent parameter, which indicates the decay rate of the quality with each resolution factor. The joint impact of SR, TR, and QS can be accurately modeled by the product of these three functions with only three parameters. The impact of SR and QS on the quality are independent of that of TR, but there are significant interactions between SR and QS. Furthermore, the model parameters can be predicted accurately from a few content features derived from the original video. The proposed model correlates well with the subjective ratings with a Pearson correlation coefficient of 0.985 when the model parameters are predicted from content features. The quality model is further validated on six other subjective rating data sets with very high accuracy and outperforms several well known quality models. PMID- 24815619 TI - Passive synthetic aperture hitchhiker imaging of ground moving targets--Part 1: image formation and velocity estimation. AB - In the Part 1 of this two-part study, we present a method of imaging and velocity estimation of ground moving targets using passive synthetic aperture radar. Such a system uses a network of small, mobile receivers that collect scattered waves due to transmitters of opportunity, such as commercial television, radio, and cell phone towers. Therefore, passive imaging systems have significant cost, manufacturing, and stealth advantages over active systems. We describe a novel generalized Radon transform-type forward model and a corresponding filtered backprojection-type image formation and velocity estimation method. We form a stack of position images over a range of hypothesized velocities, and show that the targets can be reconstructed at the correct position whenever the hypothesized velocity is equal to the true velocity of targets. We then use entropy to determine the most accurate velocity and image pair for each moving target. We present extensive numerical simulations to verify the reconstruction method. Our method does not require a priori knowledge of transmitter locations and transmitted waveforms. It can determine the location and velocity of multiple targets moving at different velocities. Furthermore, it can accommodate arbitrary imaging geometries. In Part 2, we present the resolution analysis and analysis of positioning errors in passive SAR images due to erroneous velocity estimation. PMID- 24815620 TI - A statistical prediction model based on sparse representations for single image super-resolution. AB - We address single image super-resolution using a statistical prediction model based on sparse representations of low- and high-resolution image patches. The suggested model allows us to avoid any invariance assumption, which is a common practice in sparsity-based approaches treating this task. Prediction of high resolution patches is obtained via MMSE estimation and the resulting scheme has the useful interpretation of a feedforward neural network. To further enhance performance, we suggest data clustering and cascading several levels of the basic algorithm. We suggest a training scheme for the resulting network and demonstrate the capabilities of our algorithm, showing its advantages over existing methods based on a low- and high-resolution dictionary pair, in terms of computational complexity, numerical criteria, and visual appearance. The suggested approach offers a desirable compromise between low computational complexity and reconstruction quality, when comparing it with state-of-the-art methods for single image super-resolution. PMID- 24815621 TI - Light illumination and detection patterns for fluorescence diffuse optical tomography based on compressive sensing. AB - Fluorescence diffuse optical tomography (FDOT) is an emerging molecular imaging modality that uses near infrared light to excite the fluorophore injected into tissue; and to reconstruct the fluorophore concentration from boundary measurements. The FDOT image reconstruction is a highly ill-posed inverse problem due to a large number of unknowns and limited number of measurements. However, the fluorophore distribution is often very sparse in the imaging domain since fluorophores are typically designed to accumulate in relatively small regions. In this paper, we use compressive sensing (CS) framework to design light illumination and detection patterns to improve the reconstruction of sparse fluorophore concentration. Unlike the conventional FDOT imaging where spatially distributed light sources illuminate the imaging domain one at a time and the corresponding boundary measurements are used for image reconstruction, we assume that the light sources illuminate the imaging domain simultaneously several times and the corresponding boundary measurements are linearly filtered prior to image reconstruction. We design a set of optical intensities (illumination patterns) and a linear filter (detection pattern) applied to the boundary measurements to improve the reconstruction of sparse fluorophore concentration maps. We show that the FDOT sensing matrix can be expressed as a columnwise Kronecker product of two matrices determined by the excitation and emission light fields. We derive relationships between the incoherence of the FDOT forward matrix and these two matrices, and use these results to reduce the incoherence of the FDOT forward matrix. We present extensive numerical simulation and the results of a real phantom experiment to demonstrate the improvements in image reconstruction due to the CS-based light illumination and detection patterns in conjunction with relaxation and greedy-type reconstruction algorithms. PMID- 24815622 TI - Systematic review: The epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease. AB - BACKGROUND: Extraintestinal manifestations are frequent in inflammatory bowel diseases (IBD). Most studies published so far focused on viral hepatitis and liver toxicity of IBD-related drugs. AIM: To conduct a systematic review of hepatobiliary manifestations associated with IBD. We excluded viral hepatitis and liver toxicity of IBD-related drugs. METHODS: Studies were identified through the electronic database of MEDLINE, EMBASE and the annual meetings of Digestive Disease Week, the American College of Gastroenterology, the United European Gastroenterology Week and the European Crohn's and Colitis Organization. RESULTS: One hundred and forty six articles were included in this systematic review. Cholelithiasis is more frequent in Crohn's disease (CD) than in general population. Prevalence of cholelithiasis in CD ranged from 11% to 34%, whereas it ranges from 5.5% to 15% in non-IBD patients. PSC is more frequent in UC than in CD. Prevalence of PSC ranges from 0.76% to 5.4% in UC and from 1.2% to 3.4% in CD. There is a male predominance when PSC is associated with UC, with a male/female ratio ranging from 65/35 to 70/30. No conclusion can be made on a possible increased risk of gall-bladder carcinoma. Mean prevalence of fatty liver is 23% (range, 1.5-55%). Hepatic amyloidosis occurs in less than 1% of IBD. Liver abscess is encountered mainly in CD. Portal vein thrombosis occurs in 39% to 45% of IBD patients undergoing proctocolectomy. CONCLUSIONS: Hepatobiliary manifestations associated with inflammatory bowel diseases are frequent and probably underdiagnosed. PMID- 24815623 TI - Integrin alphavbeta5 as a biomarker for the assessment of non-small cell lung cancer metastasis and overall survival. AB - BACKGROUND AND AIM: There is growing interest in how integrins play a role in cancer disease biology and what applications these may have in anti-cancer therapeutic development. This study investigates integrin alphavbeta5 expression in non-small cell lung carcinoma (NSCLC) and its correlations with clinical information. METHODS: Tumor human tissue microarrays of 147 radically operated Chinese NSCLC patients were retrieved from the pathology archive, and sections were autoimmune stained along with positive and negative controls. Integrin alphavbeta5 (P1F6) mouse monoclonal antibody were validated by both Western blotting and immunoreactivity on the same set of cell pellets, according to a precedent of expression levels in cell flow cytometry. The immunoreactivity of all patients' cases against integrin alphavbeta5 antibody was graded in a semi quantitative manner by two pathologists blind to any patient data. RESULTS: Overall survival significantly correlated to integrin alphavbeta5 immunoreactivity by Cox regression analysis with P = 0.032. When applying Kaplan Meier to analyze the comparison between positive and negative expression on lymph node metastasis patients, P = 0.082. Therefore, integrin alphavbeta5 expression emerges as a significant prognostic factor for NSCLC. In total, 39 of 147 (26.5%) showed an integrin alphavbeta5 immunoreactivity positive, as it ranged from 6.1% in squamous cell carcinoma to 19.7% in adenocarcinoma. This expression correlated significantly with histological subtypes (P = 0.007), tumor node metastasis classification of malignant tumors (P = 0.027) and lymph node metastases (P = 0.006). CONCLUSION: This study support the hypothesis that integrin alphavbeta5 is a prognostic biomarker and correlates to metastasis with therapeutic development potential in NSCLC. PMID- 24815624 TI - Obtaining a W state from a Greenberger-Horne-Zeilinger state via stochastic local operations and classical communication with a rate approaching unity. AB - We introduce a notion of the entanglement transformation rate to characterize the asymptotic comparability of two multipartite pure entangled states under stochastic local operations and classical communication (SLOCC). For two well known SLOCC inequivalent three-qubit states |GHZ?=(1/2)(|000?+|111?) and |W?=(1/3)(|100?+|010?+|001?), we show that the entanglement transformation rate from |GHZ? to |W? is exactly 1. That means that we can obtain one copy of the W state from one copy of the Greenberg-Horne-Zeilinger (GHZ) state by SLOCC, asymptotically. We then apply similar techniques to obtain a lower bound on the entanglement transformation rates from an N-partite GHZ state to a class of Dicke states, and prove the tightness of this bound for some special cases which naturally generalize the |W? state. A new lower bound on the tensor rank of the matrix permanent is also obtained by evaluating the tensor rank of Dicke states. PMID- 24815625 TI - Manifold mixing in the temporal evolution of a spin-1 spinor Bose-Einstein condensate. AB - Hydrodynamics of the spin-1 Bose-Einstein condensate is investigated without restriction of its allowed manifold to either the ferromagnetic or the antiferromagnetic phase. Mixing of the two manifolds is found to be a generic feature in the temporal evolution of the condensate, regardless of the sign and strength of the spin-dependent interaction. Hydrodynamic theory is developed based on a new representation of the spin-1 condensate wave function as a linear combination of the well-known wave functions specific to antiferromagnetic and ferromagnetic manifolds only. Dynamical constraints unique to each submanifold are derived for the first time, demonstrating that efforts to write down hydrodynamic theory in one specific manifold are generally invalid. Certain exceptions, such as a uniform spiral state in the antiferromagnetic manifold, are shown to sustain dynamical evolution within the same manifold over time. PMID- 24815626 TI - Scaling of Renyi entanglement entropies of the free fermi-gas ground state: a rigorous proof. AB - In a remarkable paper [Phys. Rev. Lett. 96, 100503 (2006)], Gioev and Klich conjectured an explicit formula for the leading asymptotic growth of the spatially bipartite von Neumann entanglement entropy of noninteracting fermions in multidimensional Euclidean space at zero temperature. Based on recent progress by one of us (A. V. S.) in semiclassical functional calculus for pseudodifferential operators with discontinuous symbols, we provide here a complete proof of that formula and of its generalization to Renyi entropies of all orders alpha>0. The special case alpha=1/2 is also known under the name logarithmic negativity and often considered to be a particularly useful quantification of entanglement. These formulas exhibiting a "logarithmically enhanced area law" have been used already in many publications. PMID- 24815627 TI - psi-Epistemic models are exponentially bad at explaining the distinguishability of quantum states. AB - The status of the quantum state is perhaps the most controversial issue in the foundations of quantum theory. Is it an epistemic state (state of knowledge) or an ontic state (state of reality)? In realist models of quantum theory, the epistemic view asserts that nonorthogonal quantum states correspond to overlapping probability measures over the true ontic states. This naturally accounts for a large number of otherwise puzzling quantum phenomena. For example, the indistinguishability of nonorthogonal states is explained by the fact that the ontic state sometimes lies in the overlap region, in which case there is nothing in reality that could distinguish the two states. For this to work, the amount of overlap of the probability measures should be comparable to the indistinguishability of the quantum states. In this Letter, I exhibit a family of states for which the ratio of these two quantities must be <=2de-cd in Hilbert spaces of dimension d that are divisible by 4. This implies that, for large Hilbert space dimension, the epistemic explanation of indistinguishability becomes implausible at an exponential rate as the Hilbert space dimension increases. PMID- 24815628 TI - Linear-optical simulation of the cooling of a cluster-state Hamiltonian system. AB - A measurement-based quantum computer could consist of a local-gapped Hamiltonian system, whose thermal states-at sufficiently low temperature-are universal resources for the computation. Initialization of the computer would correspond to cooling the system. We perform an experimental quantum simulation of such a cooling process with entangled photons. We prepare three-qubit thermal cluster states exploiting the equivalence between local dephasing and thermalization for these states. This allows us to tune the system's temperature by changing the dephasing strength. We monitor the entanglement as the system cools down and observe the transitions from separability to bound entanglement, and then to free entanglement. We also analyze the performance of the system for measurement-based single-qubit state preparation. These studies constitute a basic characterization of experimental cluster-state computation under imperfect conditions. PMID- 24815629 TI - Fluxon readout of a superconducting qubit. AB - An experiment demonstrating a link between classical single-flux quantum digital logic and a superconducting quantum circuit is reported. We implement coupling between a moving Josephson vortex (fluxon) and a flux qubit by reading out of a state of the flux qubit through a frequency shift of the fluxon oscillations in an annular Josephson junction. The energy spectrum of the flux qubit is measured using this technique. The implemented hybrid scheme opens an opportunity to readout quantum states of superconducting qubits with the classical fluxon logic circuits. PMID- 24815630 TI - Nano-Kelvin thermometry and temperature control: beyond the thermal noise limit. AB - We demonstrate thermometry with a resolution of 80 nK/Hz using an isotropic crystalline whispering-gallery mode resonator based on a dichroic dual-mode technique. We simultaneously excite two modes that have a mode frequency ratio that is very close to two (+/-0.3 ppm). The wavelength and temperature dependence of the refractive index means that the frequency difference between these modes is an ultrasensitive proxy of the resonator temperature. This approach to temperature sensing automatically suppresses sensitivity to thermal expansion and vibrationally induced changes of the resonator. We also demonstrate active suppression of temperature fluctuations in the resonator by controlling the intensity of the driving laser. The residual temperature fluctuations are shown to be below the limits set by fundamental thermodynamic fluctuations of the resonator material. PMID- 24815631 TI - Cavity-enhanced room-temperature magnetometry using absorption by nitrogen vacancy centers in diamond. AB - We demonstrate a cavity-enhanced room-temperature magnetic field sensor based on nitrogen-vacancy centers in diamond. Magnetic resonance is detected using absorption of light resonant with the 1042 nm spin-singlet transition. The diamond is placed in an external optical cavity to enhance the absorption, and significant absorption is observed even at room temperature. We demonstrate a magnetic field sensitivity of 2.5 nT/Hz, and project a photon shot-noise-limited sensitivity of 70 pT/Hz for a few mW of infrared light, and a quantum projection noise-limited sensitivity of 250 fT/Hz for the sensing volume of ~90 MUm*90 MUm*200 MUm. PMID- 24815632 TI - Strong binary pulsar constraints on Lorentz violation in gravity. AB - Binary pulsars are excellent laboratories to test the building blocks of Einstein's theory of general relativity. One of these is Lorentz symmetry, which states that physical phenomena appear the same for all inertially moving observers. We study the effect of violations of Lorentz symmetry in the orbital evolution of binary pulsars and find that it induces a much more rapid decay of the binary's orbital period due to the emission of dipolar radiation. The absence of such behavior in recent observations allows us to place the most stringent constraints on Lorentz violation in gravity, thus verifying one of the cornerstones of Einstein's theory much more accurately than any previous gravitational observation. PMID- 24815633 TI - Dark matter as a trigger for periodic comet impacts. AB - Although statistical evidence is not overwhelming, possible support for an approximately 35*106 yr periodicity in the crater record on Earth could indicate a nonrandom underlying enhancement of meteorite impacts at regular intervals. A proposed explanation in terms of tidal effects on Oort cloud comet perturbations as the Solar System passes through the galactic midplane is hampered by lack of an underlying cause for sufficiently enhanced gravitational effects over a sufficiently short time interval and by the time frame between such possible enhancements. We show that a smooth dark disk in the galactic midplane would address both these issues and create a periodic enhancement of the sort that has potentially been observed. Such a disk is motivated by a novel dark matter component with dissipative cooling that we considered in earlier work. We show how to evaluate the statistical evidence for periodicity by input of appropriate measured priors from the galactic model, justifying or ruling out periodic cratering with more confidence than by evaluating the data without an underlying model. We find that, marginalizing over astrophysical uncertainties, the likelihood ratio for such a model relative to one with a constant cratering rate is 3.0, which moderately favors the dark disk model. Our analysis furthermore yields a posterior distribution that, based on current crater data, singles out a dark matter disk surface density of approximately 10M?/pc2. The geological record thereby motivates a particular model of dark matter that will be probed in the near future. PMID- 24815634 TI - Simple predictions from multifield inflationary models. AB - We explore whether multifield inflationary models make unambiguous predictions for fundamental cosmological observables. Focusing on N-quadratic inflation, we numerically evaluate the full perturbation equations for models with 2, 3, and O(100) fields, using several distinct methods for specifying the initial values of the background fields. All scenarios are highly predictive, with the probability distribution functions of the cosmological observables becoming more sharply peaked as N increases. For N=100 fields, 95% of our Monte Carlo samples fall in the ranges ns?(0.9455,0.9534), alpha?(-9.741,-7.047)*10-4, r?(0.1445,0.1449), and riso?(0.02137,3.510)*10-3 for the spectral index, running, tensor-to-scalar ratio, and isocurvature-to-adiabatic ratio, respectively. The expected amplitude of isocurvature perturbations grows with N, raising the possibility that many-field models may be sensitive to postinflationary physics and suggesting new avenues for testing these scenarios. PMID- 24815635 TI - Resonantly produced 7 keV sterile neutrino dark matter models and the properties of Milky Way satellites. AB - Sterile neutrinos produced through a resonant Shi-Fuller mechanism are arguably the simplest model for a dark matter interpretation of the origin of the recent unidentified x-ray line seen toward a number of objects harboring dark matter. Here, I calculate the exact parameters required in this mechanism to produce the signal. The suppression of small-scale structure predicted by these models is consistent with Local Group and high-z galaxy count constraints. Very significantly, the parameters necessary in these models to produce the full dark matter density fulfill previously determined requirements to successfully match the Milky Way Galaxy's total satellite abundance, the satellites' radial distribution, and their mass density profile, or the "too-big-to-fail problem." I also discuss how further precision determinations of the detailed properties of the candidate sterile neutrino dark matter can probe the nature of the quark hadron transition, which takes place during the dark matter production. PMID- 24815638 TI - Lattice study of the jet quenching parameter. AB - We present a first-principle computation of the jet quenching parameter, which describes the momentum broadening of a high-energy parton moving through the deconfined state of QCD matter at high temperature. Following an idea originally proposed by Caron-Huot, we explain how one can evaluate the soft contribution to the collision kernel characterizing this real-time phenomenon, analyzing certain gauge-invariant operators in a dimensionally reduced effective theory (electrostatic QCD), which can be studied nonperturbatively via simulations on a Euclidean lattice. Our high-precision numerical computations at two different temperatures indicate that soft contributions to the jet quenching parameter are large. After discussing the systematic uncertainties involved, we present a quantitative estimate for the jet quenching parameter in the temperature range accessible at heavy-ion colliders, and compare it to results from phenomenological models as well as to strong-coupling computations based on the holographic correspondence. PMID- 24815639 TI - Lattice QCD with mismatched fermi surfaces. AB - We study two flavor fermions with mismatched chemical potentials in quenched lattice QCD. We first consider a large isospin chemical potential, where a charged pion is condensed, and then introduce a small mismatch between the chemical potentials of the up quark and the down antiquark. We find that the homogeneous pion condensate is destroyed by the mismatch of the chemical potentials. We also find that the two-point correlation function shows spatial oscillation, which indicates an inhomogeneous ground state, although it is not massless but massive in the present simulation setup. PMID- 24815641 TI - Observation of enhanced monopole strength and clustering in (12)Be. AB - In a recent breakup-reaction experiment using a Be12 beam at 29 MeV/nucleon, the 0+ band head of the expected He4+He8 molecular rotation was clearly identified at about 10.3 MeV, from which a large monopole matrix element of 7.0+/-1.0 fm2 and a large cluster-decay width were determined for the first time. These findings support the picture of strong clustering in Be12, which has been a subject of intense investigations over the past decade. The results were obtained thanks to a specially arranged detection system around zero degrees, which is essential in determining the newly emphasized monopole strengths to signal the cluster formation in a nucleus. PMID- 24815642 TI - Hyperfine structure constant of the neutron halo nucleus (11)Be(+). AB - The hyperfine splittings of ground state Be+11 have been measured precisely by laser-microwave double resonance spectroscopy for trapped and laser cooled beryllium ions. The ions were produced at relativistic energies and subsequently slowed down and trapped at mK temperatures. The magnetic hyperfine structure constant of Be+11 was determined to be A11=-2677.302 988(72) MHz from the measurements of the mF-mF'=0-0 field independent transition. This measurement provides essential data for the study of the distribution of the halo neutron in the single neutron halo nucleus Be11 through the Bohr-Weisskopf effect. PMID- 24815643 TI - Forging the link between nuclear reactions and nuclear structure. AB - A comprehensive description of all single-particle properties associated with the nucleus Ca40 is generated by employing a nonlocal dispersive optical potential capable of simultaneously reproducing all relevant data above and below the Fermi energy. The introduction of nonlocality in the absorptive potentials yields equivalent elastic differential cross sections as compared to local versions but changes the absorption profile as a function of angular momentum suggesting important consequences for the analysis of nuclear reactions. Below the Fermi energy, nonlocality is essential to allow for an accurate representation of particle number and the nuclear charge density. Spectral properties implied by (e, e'p) and (p, 2p) reactions are correctly incorporated, including the energy distribution of about 10% high-momentum nucleons, as experimentally determined by data from Jefferson Lab. These high-momentum nucleons provide a substantial contribution to the energy of the ground state, indicating a residual attractive contribution from higher-body interactions for Ca40 of about 0.64 MeV/A. PMID- 24815645 TI - Wireless network control of interacting Rydberg atoms. AB - We identify a relation between the dynamics of ultracold Rydberg gases in which atoms experience a strong dipole blockade and spontaneous emission, and a stochastic process that models certain wireless random-access networks. We then transfer insights and techniques initially developed for these wireless networks to the realm of Rydberg gases, and explain how the Rydberg gas can be driven into crystal formations using our understanding of wireless networks. Finally, we propose a method to determine Rabi frequencies (laser intensities) such that particles in the Rydberg gas are excited with specified target excitation probabilities, providing control over mixed-state populations. PMID- 24815646 TI - Zeeman-tuned rotational level-crossing spectroscopy in a diatomic free radical. AB - Rotational levels of molecular free radicals can be tuned to degeneracy by using laboratory-scale magnetic fields. Because of their intrinsically narrow width, these level crossings of opposite-parity states have been proposed for use in the study of parity-violating interactions and other applications. We experimentally study a typical manifestation of this system using BaF138. Using a Stark-mixing method for detection, we demonstrate level-crossing signals with spectral width as small as 6 kHz. We use our data to verify the predicted line shapes, transition dipole moments, and Stark shifts and to precisely determine molecular magnetic g factors. Our results constitute an initial proof of concept for use of this system to study nuclear spin-dependent parity-violating effects. PMID- 24815647 TI - Selective control over fragmentation reactions in polyatomic molecules using impulsive laser alignment. AB - We investigate the possibility of using molecular alignment for controlling the relative probability of individual reaction pathways in polyatomic molecules initiated by electronic processes on the few-femtosecond time scale. Using acetylene as an example, it is shown that aligning the molecular axis with respect to the polarization direction of the ionizing laser pulse does not only allow us to enhance or suppress the overall fragmentation yield of a certain fragmentation channel but, more importantly, to determine the relative probability of individual reaction pathways starting from the same parent molecular ion. We show that the achieved control over dissociation or isomerization pathways along specific nuclear degrees of freedom is based on a controlled population of associated excited dissociative electronic states in the molecular ion due to relatively enhanced ionization contributions from inner valence orbitals. PMID- 24815648 TI - Photoassociation of long-range nD Rydberg molecules. AB - We observe long-range homonuclear diatomic nD Rydberg molecules photoassociated out of an ultracold gas of Rb87 atoms for 34<=n<=40. The measured ground-state binding energies of Rb87(nD+5S1/2) molecular states are larger than those of their Rb87(nS+5S1/2) counterparts, which shows the dependence of the molecular bond on the angular momentum of the Rydberg atom. We exhibit the transition of Rb87(nD+5S1/2) molecules from a molecular-binding-dominant regime at low n to a fine-structure-dominant regime at high n [akin to Hund's cases (a) and (c), respectively]. In the analysis, the fine structure of the nD Rydberg atom and the hyperfine structure of the 5S1/2 atom are included. PMID- 24815644 TI - Shape coexistence in the neutron-deficient even-even (182-188)Hg isotopes studied via coulomb excitation. AB - Coulomb-excitation experiments to study electromagnetic properties of radioactive even-even Hg isotopes were performed with 2.85 MeV/nucleon mercury beams from REX-ISOLDE. Magnitudes and relative signs of the reduced E2 matrix elements that couple the ground state and low-lying excited states in Hg182-188 were extracted. Information on the deformation of the ground and the first excited 0+ states was deduced using the quadrupole sum rules approach. Results show that the ground state is slightly deformed and of oblate nature, while a larger deformation for the excited 0+ state was noted in Hg182,184. The results are compared to beyond mean field and interacting-boson based models and interpreted within a two-state mixing model. Partial agreement with the model calculations was obtained. The presence of two different structures in the light even-mass mercury isotopes that coexist at low excitation energy is firmly established. PMID- 24815649 TI - X-ray second harmonic generation. AB - We report clear experimental evidence for second harmonic generation at hard x ray wavelengths. Using a 1.7 A pumping beam generated by a free electron laser, we observe second harmonic generation in diamond. The generated second harmonic is of order 10 times the background radiation, scales quadratically with pump pulse energy, and is generated over a narrow phase-matching condition. Of importance for future experiments, our results indicate that it is possible to observe nonlinear x-ray processes in crystals at pump intensities exceeding 1016 W/cm2. PMID- 24815650 TI - Manipulation of high-order scattering processes in ultrasmall optical resonators to control far-field emission. AB - By imposing a set of harmonic perturbations to a microcavity boundary, we induce conversion and mixing of orbital angular momentum of light via surface scattering. Multiple scattering paths are available due to high-order scattering, which can be greatly enhanced by quasidegenerate resonances. By manipulating the relative strengths of these scattering processes, we theoretically synthesize the angular momentum spectra of individual modes so as to control their far-field patterns. We demonstrate experimentally that in wavelength-scale cavities of a fixed shape, the neighboring modes can have dramatically different emission directionality. This phenomenon is robust against slight shape deviation and surface roughness, and provides a general mechanism to control the emission direction of ultrasmall resonators. PMID- 24815651 TI - Dissipation-driven behavior of nonpropagating hydrodynamic solitons under confinement. AB - We have identified a physical mechanism that rules the confinement of nonpropagating hydrodynamic solitons. We show that thin boundary layers arising on walls are responsible for a jump in the local damping. The outcome is a weak dissipation-driven repulsion that determines decisively the solitons' long-time behavior. Numerical simulations of our model are consistent with experiments. Our results uncover how confinement can generate a localized distribution of dissipation in out-of-equilibrium systems. Moreover, they show the preponderance of such a subtle effect in the behavior of localized structures. The reported results should explain the dynamic behavior of other confined dissipative systems. PMID- 24815652 TI - Genesis of streamwise-localized solutions from globally periodic traveling waves in pipe flow. AB - The aim in the dynamical systems approach to transitional turbulence is to construct a scaffold in phase space for the dynamics using simple invariant sets (exact solutions) and their stable and unstable manifolds. In large (realistic) domains where turbulence can coexist with laminar flow, this requires identifying exact localized solutions. In wall-bounded shear flows, the first of these has recently been found in pipe flow, but questions remain as to how they are connected to the many known streamwise-periodic solutions. Here we demonstrate that the origin of the first localized solution is in a modulational symmetry breaking Hopf bifurcation from a known global traveling wave that has twofold rotational symmetry about the pipe axis. Similar behavior is found for a global wave of threefold rotational symmetry, this time leading to two localized relative periodic orbits. The clear implication is that many global solutions should be expected to lead to more realistic localized counterparts through such bifurcations, which provides a constructive route for their generation. PMID- 24815653 TI - Transverse spreading of electrons in high-intensity laser fields. AB - We show that for collisions of electrons with a high-intensity laser, discrete photon emissions introduce a transverse beam spread that is distinct from that due to classical (or beam shape) effects. Via numerical simulations, we show that this quantum induced transverse momentum gain of the electron is manifest in collisions with a realistic laser pulse of intensity within reach of current technology, and we propose it as a measurable signature of strong-field quantum electrodynamics. PMID- 24815654 TI - Experimental demonstration of a tunable microwave undulator. AB - Static magnetic undulators used by x-ray light sources are fundamentally too limited to achieve shorter undulator periods and dynamic control. To overcome these limitations, we report experimental demonstration of a novel short-period microwave undulator, essentially a Thomson scattering device, that has yielded tunable spontaneous emission and seeded coherent radiation. Its equivalent undulator period (lambdau) is 13.9 mm while it has achieved an equivalent magnetic field of 0.65 T. For future-generation light sources, this device promises a shorter undulator period, a large aperture, and fast dynamic control. PMID- 24815655 TI - Observation of turbulent intermittency scaling with magnetic helicity in an MHD plasma wind tunnel. AB - The intermittency in turbulent magnetic field fluctuations has been observed to scale with the amount of magnetic helicity injected into a laboratory plasma. An unstable spheromak injected into the MHD wind tunnel of the Swarthmore Spheromak Experiment displays turbulent magnetic and plasma fluctuations as it relaxes into a Taylor state. The level of intermittency of this turbulence is determined by finding the flatness of the probability distribution function of increments for magnetic pickup coil fluctuations B(t). The intermittency increases with the injected helicity, but spectral indices are unaffected by this variation. While evidence is provided which supports the hypothesis that current sheets and reconnection sites are related to the generation of this intermittent signal, the true nature of the observed intermittency remains unknown. PMID- 24815640 TI - Beam-energy dependence of the directed flow of protons, antiprotons, and pions in Au+Au collisions. AB - Rapidity-odd directed flow (v1) measurements for charged pions, protons, and antiprotons near midrapidity (y=0) are reported in sNN=7.7, 11.5, 19.6, 27, 39, 62.4, and 200 GeV Au+Au collisions as recorded by the STAR detector at the Relativistic Heavy Ion Collider. At intermediate impact parameters, the proton and net-proton slope parameter dv1/dy|y=0 shows a minimum between 11.5 and 19.6 GeV. In addition, the net-proton dv1/dy|y=0 changes sign twice between 7.7 and 39 GeV. The proton and net-proton results qualitatively resemble predictions of a hydrodynamic model with a first-order phase transition from hadronic matter to deconfined matter, and differ from hadronic transport calculations. PMID- 24815656 TI - Dissociation of high-pressure solid molecular hydrogen: a quantum Monte Carlo and anharmonic vibrational study. AB - A theoretical study is reported of the molecular-to-atomic transition in solid hydrogen at high pressure. We use the diffusion quantum Monte Carlo method to calculate the static lattice energies of the competing phases and a density functional-theory-based vibrational self-consistent field method to calculate anharmonic vibrational properties. We find a small but significant contribution to the vibrational energy from anharmonicity. A transition from the molecular Cmca-12 direct to the atomic I41/amd phase is found at 374 GPa. The vibrational contribution lowers the transition pressure by 91 GPa. The dissociation pressure is not very sensitive to the isotopic composition. Our results suggest that quantum melting occurs at finite temperature. PMID- 24815657 TI - Strain imaging of nanoscale semiconductor heterostructures with x-ray Bragg projection ptychography. AB - We report the imaging of nanoscale distributions of lattice strain and rotation in complementary components of lithographically engineered epitaxial thin film semiconductor heterostructures using synchrotron x-ray Bragg projection ptychography (BPP). We introduce a new analysis method that enables lattice rotation and out-of-plane strain to be determined independently from a single BPP phase reconstruction, and we apply it to two laterally adjacent, multiaxially stressed materials in a prototype channel device. These results quantitatively agree with mechanical modeling and demonstrate the ability of BPP to map out-of plane lattice dilatation, a parameter critical to the performance of electronic materials. PMID- 24815658 TI - Two-level systems and boson peak remain stable in 110-million-year-old amber glass. AB - The two most prominent and ubiquitous features of glasses at low temperatures, namely the presence of tunneling two-level systems and the so-called boson peak in the reduced vibrational density of states, are shown to persist essentially unchanged in highly stabilized glasses, contrary to what was usually envisaged. Specifically, we have measured the specific heat of 110 million-year-old amber samples from El Soplao (Spain), both at very low temperatures and around the glass transition Tg. In particular, the amount of two-level systems, assessed at the lowest temperatures, was surprisingly found to be exactly the same for the pristine hyperaged amber as for the, subsequently, partially and fully rejuvenated samples. PMID- 24815659 TI - Fast imaging with inelastically scattered electrons by off-axis chromatic confocal electron microscopy. AB - We introduce off-axis chromatic scanning confocal electron microscopy, a technique for fast mapping of inelastically scattered electrons in a scanning transmission electron microscope without a spectrometer. The off-axis confocal mode enables the inelastically scattered electrons to be chromatically dispersed both parallel and perpendicular to the optic axis. This enables electrons with different energy losses to be separated and detected in the image plane, enabling efficient energy filtering in a confocal mode with an integrating detector. We describe the experimental configuration and demonstrate the method with nanoscale core-loss chemical mapping of silver (M4,5) in an aluminium-silver alloy and atomic scale imaging of the low intensity core-loss La (M4,5@840 eV) signal in LaB6. Scan rates up to 2 orders of magnitude faster than conventional methods were used, enabling a corresponding reduction in radiation dose and increase in the field of view. If coupled with the enhanced depth and lateral resolution of the incoherent confocal configuration, this offers an approach for nanoscale three-dimensional chemical mapping. PMID- 24815660 TI - CO tip functionalization inverts atomic force microscopy contrast via short-range electrostatic forces. AB - We investigate insulating Cu2N islands grown on Cu(100) by means of combined scanning tunneling microscopy and atomic force microscopy with two vastly different tips: a bare metal tip and a CO-terminated tip. We use scanning tunneling microscopy data as proposed by Choi, Ruggiero, and Gupta to unambiguously identify atomic positions. Atomic force microscopy images taken with the two different tips show an inverted contrast over Cu2N. The observed force contrast can be explained with an electrostatic model, where the two tips have dipole moments of opposite directions. This highlights the importance of short-range electrostatic forces in the formation of atomic contrast on polar surfaces in noncontact atomic force microscopy. PMID- 24815636 TI - Observation of photon polarization in the b->sgamma transition. AB - This Letter presents a study of the flavor-changing neutral current radiative B+/ ->K+/-pi?pi+/-gamma decays performed using data collected in proton-proton collisions with the LHCb detector at 7 and 8 TeV center-of-mass energies. In this sample, corresponding to an integrated luminosity of 3 fb-1, nearly 14 000 signal events are reconstructed and selected, containing all possible intermediate resonances with a K+/-pi?pi+/- final state in the [1.1,1.9] GeV/c2 mass range. The distribution of the angle of the photon direction with respect to the plane defined by the final-state hadrons in their rest frame is studied in intervals of K+/-pi?pi+/- mass and the asymmetry between the number of signal events found on each side of the plane is obtained. The first direct observation of the photon polarization in the b->sgamma transition is reported with a significance of 5.2sigma. PMID- 24815661 TI - Field induced positional shift of Bloch electrons and its dynamical implications. AB - We derive the field correction to the Berry curvature of Bloch electrons, which can be traced back to a positional shift due to the interband mixing induced by external electromagnetic fields. The resulting semiclassical dynamics is accurate to second order in the fields, in the same form as before, provided that the wave packet energy is derived up to the same order. As applications, we discuss the orbital magnetoelectric polarizability and predict nonlinear anomalous Hall effects. PMID- 24815662 TI - Charge fractionalization in the integer quantum Hall effect. AB - We report an observation, via sensitive shot noise measurements, of charge fractionalization of chiral edge electrons in the integer quantum Hall effect regime. Such fractionalization results solely from interchannel Coulomb interaction, leading electrons to decompose to excitations carrying fractional charges. The experiment was performed by guiding a partitioned current carrying edge channel in proximity to another unbiased edge channel, leading to shot noise in the unbiased edge channel without net current, which exhibited an unconventional dependence on the partitioning. The determination of the fractional excitations, as well as the relative velocities of the two original (prior to the interaction) channels, relied on a recent theory pertaining to this measurement. Our result exemplifies the correlated nature of multiple chiral edge channels in the integer quantum Hall effect regime. PMID- 24815663 TI - Protected Josephson Rhombus chains. AB - We have studied the low-energy excitations in a minimalistic protected Josephson circuit which contains two basic elements (rhombi) characterized by the pi periodicity of the Josephson energy. Novel design of these elements, which reduces their sensitivity to the offset charge fluctuations, has been employed. We have observed that the lifetime T1 of the first excited state of this quantum circuit in the protected regime is increased up to 70 MUs, a factor of ~100 longer than that in the unprotected state. The quality factor omega01T1 of this qubit exceeds 106. Our results are in agreement with theoretical expectations; they demonstrate the feasibility of symmetry protection in the rhombus-based qubits fabricated with existing technology. PMID- 24815664 TI - Distinct magnetic phase transition at the surface of an antiferromagnet. AB - In the majority of magnetic systems the surface is required to order at the same temperature as the bulk. In the present Letter, we report a distinct and unexpected surface magnetic phase transition at a lower temperature than the Neel temperature. Employing grazing incidence x-ray resonant magnetic scattering, we have observed the near-surface behavior of uranium dioxide. UO2 is a noncollinear, triple-q, antiferromagnet with the U ions on a face-centered cubic lattice. Theoretical investigations establish that at the surface the energy increase-due to the lost bonds-is reduced when the spins near the surface rotate, gradually losing their component normal to the surface. At the surface the lowest energy spin configuration has a double-q (planar) structure. With increasing temperature, thermal fluctuations saturate the in-plane crystal field anisotropy at the surface, leading to soft excitations that have ferromagnetic XY character and are decoupled from the bulk. The structure factor of a finite two-dimensional XY model fits the experimental data well for several orders of magnitude of the scattered intensity. Our results support a distinct magnetic transition at the surface in the Kosterlitz-Thouless universality class. PMID- 24815665 TI - Coupled Skyrmion sublattices in Cu(2)OSeO(3). AB - We report the observation of a Skyrmion lattice in the chiral multiferroic insulator Cu2OSeO3 using Cu L3-edge resonant soft x-ray diffraction. We observe the unexpected existence of two distinct Skyrmion sublattices that arise from inequivalent Cu sites with chemically identical coordination numbers but different magnetically active orbitals. The Skyrmion sublattices are rotated with respect to each other, implying a long wavelength modulation of the lattice. The modulation vector is controlled with an applied magnetic field, associating this moirelike phase with a continuous phase transition. Our findings will open up a new class of science involving manipulation of quantum topological states. PMID- 24815666 TI - Quantum spin ices and topological phases from dipolar-octupolar doublets on the pyrochlore lattice. AB - We consider a class of d- and f-electron systems in which dipolar-octupolar Kramers doublets arise on the sites of the pyrochlore lattice. For such doublets, two components of the pseudospin transform like a magnetic dipole, while the other transforms like a component of the magnetic octupole tensor. Based on a symmetry analysis, we construct and study models of dipolar-octupolar doublets in itinerant and localized limits. In both limits, the resulting models are of surprisingly simple form. In the itinerant limit, we find topological insulating behavior. In the localized limit, the most general nearest-neighbor spin model is the XYZ model. We show that this XYZ model exhibits two distinct quantum spin ice (QSI) phases, that we dub dipolar QSI, and octupolar QSI. We conclude with a discussion of potential relevance to real material systems. PMID- 24815667 TI - Superconductivity of composite particles in a two-channel Kondo lattice. AB - Emergence of odd-frequency s-wave superconductivity is demonstrated in the two channel Kondo lattice by means of the dynamical mean-field theory combined with the continuous-time quantum Monte Carlo method. Around half filling of the conduction bands, divergence of an odd-frequency pairing susceptibility is found, which signals instability toward the superconductivity. The corresponding order parameter is equivalent to a staggered composite-pair amplitude with even frequencies, which involves both localized spins and conduction electrons. A model wave function is constructed for the composite order with the use of symmetry operations such as charge conjugation and channel rotations. Given a certain asymmetry of the conduction bands, another s-wave superconductivity is found that has a uniform order parameter. The Kondo effect in the presence of two channels is essential for both types of unconventional superconductivity. PMID- 24815668 TI - Completely stopped and dispersionless light in plasmonic waveguides. AB - We introduce a scheme where a time-dependent source excites "complex-frequency" modes in uniform plasmonic heterostructures, enabling complete and dispersionless stopping of light pulses, resilient to realistic levels of dissipative, radiative, and surface-roughness losses. Using transparent conducting oxides at telecommunication wavelengths we show how, without increasing optical losses, multiple light pulses can decay with time precisely at their injection points, unable to propagate despite the complete absence of barriers in front or behind them. Our results theoretically demonstrate extraordinary large light deceleration factors (of the order of 1.5*107) in integrated nanophotonic media, comparable only to those attainable with ultracold atomic vapors or with quantum coherence effects, such as coherent population oscillations, in ruby crystals. PMID- 24815669 TI - Josephson directional amplifier for quantum measurement of superconducting circuits. AB - We realize a microwave quantum-limited amplifier that is directional and can therefore function without the front circulator needed in many quantum measurements. The amplification takes place in only one direction between the input and output ports. Directionality is achieved by multipump parametric amplification combined with wave interference. We have verified the device noise performances by using it to read out a superconducting qubit and observed quantum jumps. With an improved version of this device, the qubit and preamplifer could be integrated on the same chip. PMID- 24815670 TI - Defect-mediated phase transitions in active soft matter. AB - How do topological defects affect the degree of order in active matter? To answer this question we investigate an agent-based model of self-propelled particles, which accounts for polar alignment and short-ranged repulsive interactions. For strong alignment forces we find collectively moving polycrystalline states with fluctuating networks of grain boundaries. In the regime where repulsive forces dominate, the fluctuations generated by the active system give rise to quasi-long range transitional order, but-unlike the thermal system-without creating topological defects. PMID- 24815671 TI - Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment. AB - Follicular helper T-cells (Tfh cells) are a subset of CD4(+) T-cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD-1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T-cell non Hodgkin lymphoma: angioimmunoblastic T-cell lymphoma (AITL) and ~20% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL-NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre-clinical development. PMID- 24815672 TI - Pharmacokinetics of olanzapine long-acting injection: the clinical perspective. AB - Olanzapine long-acting injection (OLAI) is a sustained-release depot antipsychotic for the treatment of schizophrenia in adults. Our objective was to explain the pharmacokinetics of OLAI to provide clinical insight. Simulation models and data from clinical trials are presented. Olanzapine concentrations were observed immediately upon injection. Half-life was ~30 days, controlled by the slow rate of intramuscular absorption rather than the 30-h elimination rate based half-life of oral olanzapine. As each injection builds on the drug still being released from previous injections, concentrations increase gradually until a steady state is reached after ~3 months. Concentrations were similar to oral olanzapine and proportional to the dose; the average steady-state concentrations (10th-90th percentile) for the 150, 210, and 300 mg/2-week doses were 16-32, 15 55, and 20-67 ng/ml, respectively, and those for the 300 and 405 mg/4-week doses were 19-48 and 19-62 ng/ml, respectively. Peak concentrations most often occurred at 2-4 days after injection. Peak-to-trough fluctuation was greater for the 4 week dosing interval than the 2-week one, with no apparent clinical ramifications for these differences. Trough concentrations were above the lower end of the therapeutic range, even at the first injection. Long-term use up to 6 years indicated no additional accumulation. The impact of smoking and sex was similar, but less pronounced than for oral olanzapine. PMID- 24815673 TI - Psychomotor symptoms and treatment outcomes of ziprasidone monotherapy in patients with major depressive disorder: a 12-week, randomized, double-blind, placebo-controlled, sequential parallel comparison trial. AB - The aim of this study was to evaluate efficacy of ziprasidone monotherapy for major depressive disorder (MDD) with and without psychomotor symptoms. In accordance with the sequential parallel comparison design, 106 MDD patients (age 44.0+/-10.7 years; female, 43.4%) were recruited and a post-hoc analysis was carried out on 12-week double-blind treatment with either ziprasidone (40-160 mg/day) or placebo, divided into two phases of 6 weeks each to the assigned treatment sequences, drug/drug, placebo/placebo, and placebo/drug. Psychomotor symptoms were evaluated on the basis of the Mini-International Neuropsychiatric Interview at baseline. Efficacy assessments, on the basis of the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Quick Inventory of Depressive Symptomatology Scale, Self-Rated (QIDS-SR), were performed every week throughout the trial. In phase I, ziprasidone monotherapy produced significant improvement in patients with psychomotor symptoms compared with placebo on the basis of HDRS 17 (F=5.95, P=0.017) and QIDS-SR (F=5.26, P=0.025) scores, whereas no significant changes were found in HDRS-17 (F=2.32, P=0.15) and QIDS-SR (F=3.70, P=0.074) scores in patients without psychomotor symptoms. In phase II, ziprasidone monotherapy produced no significant differences compared with placebo. In the pooled analysis, ziprasidone monotherapy showed significance according to QIDS-SR (Z=2.00, P=0.046) and a trend toward statistical significance according to the HDRS-17 (Z=1.66, P=0.10) in patients with psychomotor symptoms. Ziprasidone monotherapy may produce significant improvement compared with placebo in MDD patients with psychomotor symptoms. PMID- 24815674 TI - Endoscopic findings using narrow-band imaging to distinguish between basal cell hyperplasia and carcinoma of the pharynx. AB - Narrow-band imaging (NBI) has been reported to be useful for detecting superficial-type esophageal or head and neck squamous cell carcinoma (SCC), and in the present study we have used NBI to detect non-carcinomatous lesions, such as basal cell hyperplasia (BCH) accompanied by microvascular irregularities; these non-carcinomatous lesions were pathologically discriminated from squamous cell carcinoma of the pharynx. The aim of the present study was to clarify the endoscopic characteristics of BCH that contribute to the discrimination of superficial-type head and neck SCC (HNSCC). We examined the key endoscopic findings capable of distinguishing BCH from SCC using 26 BCH and 37 superficial type SCC of the pharynx that had been pathologically diagnosed at our institution between January 2008 and July 2012. The clinicopathological factors were also compared. The size of the BCH lesions was significantly smaller (P < 0.001), and their intervascular transparency was more clearly observed (P < 0.001). Intra epithelial papillary capillary loop (IPCL) shapes were less variable and monotonous (P < 0.001), and the distribution of the IPCL was more regular with an interval comparable to that of SCC (P < 0.001), although no significant differences in the sharpness of the lesion border, dilatation of IPCL and tortuosity of the IPCL were seen between the BCH and SCC lesions. This study revealed that BCH was an independent entity in terms of not only pathological findings, but also endoscopic findings observed using NBI, such as the regular distribution of IPCL and the preserved intervascular transparency. PMID- 24815675 TI - [Quality indicators in the storage and dispensing process in a Hospital Pharmacy]. AB - OBJECTIVE: To establish indicators for the evaluation of the quality of the storage and dispensing processes related to semiautomatic vertical (SAVCS) and horizontal (SAHCS) carousel systems. MATERIAL AND METHODS: Descriptive observational study conducted between January-December 2012. Definition of quality indicators, a target value is established and an obtained value is calculated for 2012. RESULTS: Five quality indicators in the process of storage and dispensing of drugs were defined and calculated: indicator 1, error filling unidose trolleys: target (<1.67%), obtained (1.03%); indicator 2, filling accuracy unidose trolleys by using an SAVCS: target (<15%), obtained (11.5%); indicator 3, reliability of drug inventory in the process of drug entries using an SAHCS: target (<15%), obtained (6.53%); indicator 4, reliability of drug inventory in the picking process of orders replacement stock of clinical units using an SAHCS: target (<10%), obtained (1.97%); indicator 5, accuracy of the picking process of drug orders using an SAHCS: target (<10%), obtained (10.41%). CONCLUSIONS: Establishing indicators has allowed the quality in terms of safety, precision and reliability of semiautomatic systems for storage and dispensing drugs to be assessed. PMID- 24815676 TI - Reliable prediction of clinical outcome in patients with chronic HCV infection and compensated advanced hepatic fibrosis: a validated model using objective and readily available clinical parameters. AB - OBJECTIVE: Reliable tools to predict long-term outcome among patients with well compensated advanced liver disease due to chronic HCV infection are lacking. DESIGN: Risk scores for mortality and for cirrhosis-related complications were constructed with Cox regression analysis in a derivation cohort and evaluated in a validation cohort, both including patients with chronic HCV infection and advanced fibrosis. RESULTS: In the derivation cohort, 100/405 patients died during a median 8.1 (IQR 5.7-11.1) years of follow-up. Multivariate Cox analyses showed age (HR=1.06, 95% CI 1.04 to 1.09, p<0.001), male sex (HR=1.91, 95% CI 1.10 to 3.29, p=0.021), platelet count (HR=0.91, 95% CI 0.87 to 0.95, p<0.001) and log10 aspartate aminotransferase/alanine aminotransferase ratio (HR=1.30, 95% CI 1.12 to 1.51, p=0.001) were independently associated with mortality (C statistic=0.78, 95% CI 0.72 to 0.83). In the validation cohort, 58/296 patients with cirrhosis died during a median of 6.6 (IQR 4.4-9.0) years. Among patients with estimated 5-year mortality risks <5%, 5-10% and >10%, the observed 5-year mortality rates in the derivation cohort and validation cohort were 0.9% (95% CI 0.0 to 2.7) and 2.6% (95% CI 0.0 to 6.1), 8.1% (95% CI 1.8 to 14.4) and 8.0% (95% CI 1.3 to 14.7), 21.8% (95% CI 13.2 to 30.4) and 20.9% (95% CI 13.6 to 28.1), respectively (C statistic in validation cohort = 0.76, 95% CI 0.69 to 0.83). The risk score for cirrhosis-related complications also incorporated HCV genotype (C statistic = 0.80, 95% CI 0.76 to 0.83 in the derivation cohort; and 0.74, 95% CI 0.68 to 0.79 in the validation cohort). CONCLUSIONS: Prognosis of patients with chronic HCV infection and compensated advanced liver disease can be accurately assessed with risk scores including readily available objective clinical parameters. PMID- 24815677 TI - Wave reflections, arterial stiffness, and orthostatic hypotension. AB - BACKGROUND: The effect of wave reflections on blood pressure change associated with posture remains unclear. We therefore applied a wave separation technique to investigate the relations of the backward pressure wave amplitude with orthostatic pressure changes and orthostatic hypotension (OH). METHODS: We analyzed data from 613 subjects who had participated in our hemodynamic studies. Measurements of brachial systolic (SBP) and diastolic blood pressures (DBP), carotid-femoral pulse wave velocity (cf-PWV), and backward pressure wave amplitude from a decomposed carotid pressure wave (Pb) were obtained at supine position. SBP and DBP were measured again 3 minutes after standing. OH was defined as a fall of >=20 mm Hg in SBP and/or >=10 mm Hg in DBP. RESULTS: Subjects with OH (n = 100) were characterized with significantly higher supine SBP and DBP and significantly lower standing SBP and DBP when compared with subjects without OH. Subjects with OH were also characterized with significantly higher cf-PWV and Pb. cf-PWV and Pb separately were significantly associated with the orthostatic SBP change in univariable and multivariable analyses. Also, cf PWV and Pb separately were significant predictors of OH in univariable and multivariable analyses. cf-PWV predicted OH in the younger but less so in the older subgroup, whereas Pb demonstrated similar prediction in both subgroups. In a final multivariable model, both cf-PWV and Pb were significant independent predictors of OH. CONCLUSIONS: Wave reflections are an independent determinant of orthostatic SBP change and OH in both younger and older subjects. PMID- 24815678 TI - A child with unresectable biliary rhabdomyosarcoma: 48-month disease-free survival after liver transplantation. AB - We describe here a two-yr-old boy with biliary RMS successfully treated by chemotherapy and LT. The child presented with obstructive jaundice at 20 months of age. A mildly vascularized, non-calcified, partially cystic lesion was visualized in the left hepatic lobe. Solid infiltration of the common bile duct and of both left and right hepatic ducts was suspected. Liver biopsy suggested a botryoid-type embryonal RMS originating from the biliary tract. After extrahepatic spread of the tumor was excluded, a biliary drain was applied and neoadjuvant chemotherapy was started. After the treatment, although reduced in volume, the mass was still unresectable without aggressive surgery and gross residual disease. LT with a reduced segment II/III graft was performed four months after diagnosis. The patient received six cycles of adjuvant chemotherapy, and he is alive and recurrence-free 48 months post-transplantation. A posteriori, the transplant might have possibly been avoided with an aggressive resection with biliary reconstruction. Nevertheless, although the risk of the transplant has to be balanced against the chemoresponsiveness of the tumor, the four-yr disease free survival of this patient suggests that, when coupled with effective chemotherapy, transplantation might be considered a potential treatment for unresectable biliary RMS. PMID- 24815679 TI - Dynamic compressed HRRP generation for random stepped-frequency radar based on complex-valued fast sequential homotopy. AB - Compressed sensing has been applied to achieve high resolution range profiles (HRRPs) using a stepped-frequency radar. In this new scheme, much fewer pulses are required to recover the target's strong scattering centers, which can greatly reduce the coherent processing interval (CPI) and improve the anti-jamming capability. For practical applications, however, the required number of pulses is difficult to determine in advance and any reduction of the transmitted pulses is attractive. In this paper, a dynamic compressed sensing strategy for HRRP generation is proposed, in which the estimated HRRP is updated with sequentially transmitted and received pulses until the proper stopping rules are satisfied. To efficiently implement the sequential update, a complex-valued fast sequential homotopy (CV-FSH) algorithm is developed based on group sparse recovery. This algorithm performs as an efficient recursive procedure of sparse recovery, thus avoiding solving a new optimization problem from scratch. Furthermore, the proper stopping rules are presented according to the special characteristics of HRRP. Therefore, the optimal number of pulses required in each CPI can be sought adapting to the echo signal. The results using simulated and real data show the effectiveness of the proposed approach and demonstrate that the established dynamic strategy is more suitable for uncooperative targets. PMID- 24815680 TI - Quorum sensing activity of a Kluyvera sp. isolated from a Malaysian waterfall. AB - In many species of bacteria, the quorum sensing mechanism is used as a unique communication system which allows them to regulate gene expression and behavior in accordance with their population density. N-Acylhomoserine lactones (AHLs) are known as diffusible autoinducer molecules involved in this communication network. This finding aimed to characterize the production of AHL of a bacterial strain ND04 isolated from a Malaysian waterfall. Strain ND04 was identified as Kluyvera sp. as confirmed by molecular analysis of its 16S ribosomal RNA gene sequence. Kluyvera sp. is closely related to the Enterobacteriaceae family. Chromobacterium violaceum CV026 was used as a biosensor to detect the production of AHL by strain ND04. High resolution triple quadrupole liquid chromatography-mass spectrometry analysis of strain ND04 showed our isolate produced two AHLs which are N-(3 oxohexanoyl)homoserine lactone (3-oxo-C6 HSL) and N-3-oxo-octanoyl-L-homoserine lactone (3-oxo-C8 HSL). PMID- 24815681 TI - Design of a base station for MEMS CCR localization in an optical sensor network. AB - This paper introduces a design and implementation of a base station, capable of positioning sensor nodes using an optical scheme. The base station consists of a pulse laser module, optical detectors and beam splitter, which are mounted on a rotation-stage, and a Time to Digital Converter (TDC). The optical pulse signal transmitted to the sensor node with a Corner Cube Retro-reflector (CCR) is reflected to the base station, and the Time of Flight (ToF) data can be obtained from the two detectors. With the angle and flight time data, the position of the sensor node can be calculated. The performance of the system is evaluated by using a commercial CCR. The sensor nodes are placed at different angles from the base station and scanned using the laser. We analyze the node position error caused by the rotation and propose error compensation methods, namely the outlier sample exception and decreasing the confidence factor steadily using the recursive least square (RLS) methods. Based on the commercial CCR results, the MEMS CCR is also tested to demonstrate the compatibility between the base station and the proposed methods. The result shows that the localization performance of the system can be enhanced with the proposed compensation method using the MEMS CCR. PMID- 24815682 TI - Inherited small RNAs: new insights into Darwin's cell theory. PMID- 24815683 TI - Immobilization of growing Sphingomonas sp. HXN-200 to gelatin microspheres: efficient biotransformation of N-Cbz-pyrrolidine and N-Boc-pyrrolidine into hydroxypyrrolidine derivatives. AB - Sphingomonas sp. HXN-200 bacteria were immobilized onto gelatin and poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microspheres in an aqueous system for industrial scale biohydroxylation. Scanning electron microscopy and confocal laser scanning microscopy were used to confirm the bacterial immobilization. The gelatin microsphere-immobilized cells successfully transformed N benzyloxycarbonyl-pyrrolidine and N-tert-butoxycarbonyl-pyrrolidine into R-N benzyloxycarbonyl-3-hydroxypyrrolidine and R-N-tert-butoxycarbonyl-3-pyrrolidinol at various substrate concentrations showing an improved conversion yield and product efficiency with respect to the freely suspended cells system at each reaction interval time. Additionally, in the immobilized cells system, it showed a faster reaction rate as compared to the freely suspended cells system for reaching the same product concentration. The inhibition effect due to substrate and product concentrations was significantly lower after immobilizing the bacteria onto the microspheres, which is beneficial for continuous reaction. The efficient whole-cell biocatalytic process was feasibly conducted in a 500mL preparative scale bioreactor and the conversion yield of N-benzyloxycarbonyl pyrrolidine did not decrease after consecutive repeated use, suggesting that the microsphere-cells immobilization system was stable and reusable. PMID- 24815684 TI - Chitosan/beta-1,3-glucan/calcium phosphate ceramics composites--novel cell scaffolds for bone tissue engineering application. AB - Bone tissue engineering put emphasis on fabrication three-dimensional biodegradable porous scaffolds that possess ability to enhance adhesion, proliferation and differentiation of osteoblast cells, therefore supporting bone regeneration and functional bone tissue formation. The aim of this work was to fabricate novel tri-component scaffolds composed of chitosan, beta-1,3-glucan, and bioceramics and to evaluate their basic structural, mechanical, and biological properties. It should be noted that we are the first who describe fabrication and characterization of tri-component composites containing beta-1,3 glucan. Microstructure of novel composites was visualized by computed tomography scanning and SEM. Compressive strength and Young's modulus of the composites were evaluated by compression testing. The biocompatibility was assessed in vitro by cytotoxicity, cell attachment and cell proliferation tests using human foetal osteoblast cell line. Our results demonstrated that novel composites possess good compressive strength as the effect of polysaccharide components of scaffolds, are very elastic, are non-toxic, favourable to cell adhesion and promote cell proliferation. However, novel biomaterials revealed relatively low Young's modulus values. Thus, we infer that fabricated novel composites are promising materials for bone tissue engineering application as cell scaffolds to fill small bone losses rather than as massive bone fillers exposed to mechanical load. PMID- 24815685 TI - The metagenome-derived enzyme RhaB opens a new subclass of bacterial B type alpha L-rhamnosidases. AB - A combined sequence- and function-based analysis of a metagenomic library DNA derived from elephant feces led to the identification of a novel bacterial alpha l-rhamnosidase belonging to glycoside hydrolase family 78 (GH78). The gene was designated rhaB (4095bp) and encoded for a putative protein of 1364 amino acids. The C-terminal part of the enzyme revealed an amino acid (AA) sequence identity of 58% to a predicted bacterial alpha-l-rhamnosidase from Bacteroides nordii. Interestingly, the N-terminal region of the deduced enzyme RhaB contained a GDSL like lipase motif and an acetyl-xylan esterase (DAP2) motif. While heterologous expression of the complete rhaB failed, subcloning of the gene identified the most active open reading frame (ORF) to be of 3081bp, which we designated rhaB1. The enzyme RhaB1 was overexpressed in Escherichia coli BL21 (DE3) and was purified to an amount of 75mg/L of culture medium. In accordance to the intestinal origin, RhaB1 showed a preference for mesophilic conditions with an optimum activity at a temperature TOpt of 40 degrees C and a pHOpt of 6.5, respectively. The recombinant protein had a Km value of 0.79mM and a specific activity vmax of 18.4U for pNP-alpha-l-rhamnose, a calculated Km of 6.36mM and vmax of 2.9*10(-3)U for naringin, and a Km of 6.75mM and specific activity vmax of 8.63*10(-2)U for rutin, respectively. Phylogenetic analysis and amino acid domain architecture comparison revealed that RhaB1 belongs to a new subclass of bacterial B type alpha-l-rhamnosidases of GH 78. To our knowledge RhaB1 is the first biochemically-characterized enzyme of this subclass. PMID- 24815686 TI - Spinel Mn-Co oxide in N-doped carbon nanotubes as a bifunctional electrocatalyst synthesized by oxidative cutting. AB - The notorious instability of non-precious-metal catalysts for oxygen reduction and evolution is by far the single unresolved impediment for their practical applications. We have designed highly stable and active bifunctional catalysts for reversible oxygen electrodes by oxidative thermal scission, where we concurrently rupture nitrogen-doped carbon nanotubes and oxidize Co and Mn nanoparticles buried inside them to form spinel Mn-Co oxide nanoparticles partially embedded in the nanotubes. Impressively high dual activity for oxygen reduction and evolution is achieved using these catalysts, surpassing those of Pt/C, RuO2, and IrO2 and thus raising the prospect of functional low-cost, non precious-metal bifunctional catalysts in metal-air batteries and reversible fuel cells, among others, for a sustainable and green energy future. PMID- 24815687 TI - Direct and selective small-molecule inhibition of photosynthetic PEP carboxylase: New approach to combat C4 weeds in arable crops. AB - Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme of C4 photosynthesis. Besides, non-photosynthetic isoforms of PEPC are found in bacteria and all types of plants, although not in animals or fungi. A single residue in the allosteric feedback inhibitor site of PEPC was shown to adjust the affinity of the photosynthetic and non-photosynthetic isoforms for feedback inhibition by metabolites of the C4 pathway. Here, we applied computational screening and biochemical analyses to identify molecules that selectively inhibit C4 PEPC, but have no effect on the activity of non-photosynthetic PEPCs. We found two types of selective inhibitors, catechins and quinoxalines. Binding constants in the lower MUM range and a strong preference for C4 PEPC qualify the quinoxaline compounds as potential selective herbicides to combat C4 weeds. PMID- 24815688 TI - Does a shift to limited glucose activate checkpoint control in fission yeast? AB - Here we review cell cycle control in the fission yeast, Schizosaccharomyces pombe, in response to an abrupt reduction of glucose concentration in culture media. S. pombe arrests cell cycle progression when transferred from media containing 2.0% glucose to media containing 0.1%. After a delay, S. pombe resumes cell division at a surprisingly fast rate, comparable to that observed in 2% glucose. We found that a number of genes, including zinc-finger transcription factor Scr1, CaMKK-like protein kinase Ssp1, and glucose transporter Ght5, enable rapid cell division in low glucose. In this article, we examine whether cell cycle checkpoint-like control operates during the delay and after resumption of cell division in limited-glucose. Using microarray analysis and genetic screening, we identified several candidate genes that may be involved in controlling this low-glucose adaptation. PMID- 24815689 TI - Fe deficiency induces phosphorylation and translocation of Lhcb1 in barley thylakoid membranes. AB - HvLhcb1 a major light-harvesting chlorophyll a/b-binding protein in barley, is a critical player in sustainable growth under Fe deficiency. Here, we demonstrate that Fe deficiency induces phosphorylation of HvLhcb1 proteins leading to their migration from grana stacks to stroma thylakoid membranes. HvLhcb1 remained phosphorylated even in the dark and apparently independently of state transition, which represents a mechanism for short-term acclimation. Our data suggest that the constitutive phosphorylation-triggered translocation of HvLhcb1 under Fe deficiency contributes to optimization of the excitation balance between photosystem II and photosystem I, the latter of which is a main target of Fe deficiency. PMID- 24815690 TI - Human Tudor staphylococcal nuclease (Tudor-SN) protein modulates the kinetics of AGTR1-3'UTR granule formation. AB - Human Tudor staphylococcal nuclease (Tudor-SN) interacts with the G3BP protein and is recruited into stress granules (SGs), the main type of discrete RNA containing cytoplasmic foci structure that is formed under stress conditions. Here, we further demonstrate that Tudor-SN binds and co-localizes with AGTR1 3'UTR (3'-untranslated region of angiotensin II receptor, type 1 mRNA) into SG. Tudor-SN plays an important role in the assembly of AGTR1-3'UTR granules. Moreover, endogenous Tudor-SN knockdown can decrease the recovery kinetics of AGTR1-3'UTR granules. Collectively, our data indicate that Tudor-SN modulates the kinetics of AGTR1-3'UTR granule formation, which provides an additional biological role of Tudor-SN in RNA metabolism during stress. PMID- 24815691 TI - MiR-718 represses VEGF and inhibits ovarian cancer cell progression. AB - Oncogenic activation of VEGF is found in various malignancies, including ovarian cancer. In this study, we investigate the role of microRNA (miRNA) in the regulation of VEGF in ovarian cancer. We find that miR-718 is expressed at low levels and inversely correlates with VEGF expression in ovarian cancer specimens. MiR-718 also directly targets and represses VEGF expression. In addition, miR-718 restoration inhibits ovarian cancer proliferation both in vitro and in vivo. Moreover, VEGF expression could reverse the effect of miR-718 on ovarian cancer by increasing the levels of phosphorylated AKT. These results suggest a new therapeutic strategy in ovarian cancer by restoring miR-718 expression, which is involved in VEGF regulation. PMID- 24815692 TI - Targeting Nrf2 by dihydro-CDDO-trifluoroethyl amide enhances autophagic clearance and viability of beta-cells in a setting of oxidative stress. AB - Nrf2 appears to be a critical regulator of diabetes in rodents. However, the underlying mechanisms as well as the clinical relevance of the Nrf2 signaling in human diabetes remain to be fully understood. Herein, we report that islet expression of Nrf2 is upregulated at an earlier stage of diabetes in both human and mice. Activation of Nrf2 suppresses oxidative stress and oxidative stress induced beta-cell apoptosis while enhancing autophagic clearance in isolated rat islets. Additionally, oxidative stress per se activated autophagy in beta-cells. Thus, these results reveal that Nrf2 drives a novel antioxidant independent autophagic clearance for beta-cell protection in the setting of diabetes. PMID- 24815693 TI - Identification of P2X2/P2X4/P2X6 heterotrimeric receptors using atomic force microscopy (AFM) imaging. AB - Seven P2X purinergic receptor subunits have been identified: P2X1-P2X7. The overlapping expression of P2X2, P2X4 and P2X6 subunits has been shown in different cell types, and functional analysis of P2X receptors in Leydig cells suggests that the three subunits might interact. Here, His6-tagged P2X2, HA tagged P2X4 and FLAG-tagged P2X6 subunits were co-expressed in tsA 201 cells. After sequential co-immunoprecipitation using anti-HA and anti-FLAG beads, all three subunits were present, demonstrating their interaction. Atomic force microscopy (AFM) imaging revealed receptors that were specifically decorated by both an anti-His6 antibody and an anti-HA Fab fragment, indicating the presence of a P2X2/4/6 heterotrimer. To our knowledge, this is the first report of a P2X receptor containing three different subunits. PMID- 24815694 TI - The mammalian AMP-activated protein kinase complex mediates glucose regulation of gene expression in the yeast Saccharomyces cerevisiae. AB - The AMP-activated protein kinase (AMPK) controls energy homeostasis in eukaryotic cells. Here we expressed hetero-trimeric mammalian AMPK complexes in a Saccharomyces cerevisiae mutant lacking all five genes encoding yeast AMPK/SNF1 components. Certain mammalian complexes complemented the growth defect of the yeast mutant on non-fermentable carbon sources. Phosphorylation of the AMPK alpha1-subunit was glucose-regulated, albeit not by the Glc7-Reg1/2 phosphatase, which performs this function on yeast AMPK/SNF1. AMPK could take over SNF1 function in glucose derepression. While indirectly acting anti-diabetic drugs had no effect on AMPK in yeast, compound 991 stimulated alpha1-subunit phosphorylation. Our results demonstrate a remarkable functional conservation of AMPK and that glucose regulation of AMPK may not be mediated by regulatory features of a specific phosphatase. PMID- 24815695 TI - Toll like receptor 2 knock-out attenuates carbon tetrachloride (CCl4)-induced liver fibrosis by downregulating MAPK and NF-kappaB signaling pathways. AB - Innate immune signaling associated with Toll-like receptors (TLRs) is a key pathway involved in the progression of liver fibrosis. In this study, we reported that TLR2 is required for hepatic fibrogenesis induced by carbon tetrachloride (CCl4). After CCl4 treatment, TLR2(-/-) mice had reduced liver enzyme levels, diminished collagen deposition, decreased inflammatory infiltration and impaired activation of hepatic stellate cells (HSCs) than wild type (WT) mice. Furthermore, after CCl4 treatment, TLR2(-/-) mice demonstrated downregulated expression of profibrotic and proinflammatory genes and impaired mitogen activated protein kinases (MAPK) and nuclear factor kappa B (NF-kappaB) activation than WT mice. Collectively, our data indicate that TLR2 deficiency protects against CCl4-induced liver fibrosis. PMID- 24815696 TI - Huaier suppresses proliferation and induces apoptosis in human pulmonary cancer cells via upregulation of miR-26b-5p. AB - Various studies have reported that Huaier possesses anti-tumor effects. However, the mechanisms are not completely elucidated. Here, we found 66 differentially expressed miRNAs in Huaier-treated pulmonary adenocarcinoma A549 cells, with upregulation of miR-26b-5p. Transfection of A549 cells with miR-26b-5p mimic inhibited proliferation and induced apoptosis, while transfection of Huaier treated A549 cells with a miR-26b-5p inhibitor reversed the effects of Huaier. EZH2 was verified as the target of miR-26b-5p. Thus, our findings indicate that Huaier might suppress proliferation and induce apoptosis in lung cancer cells via a miR-26b-5p-EZH2-mediated approach, which provides a new perspective for understanding the anti-tumor effects of Huaier. PMID- 24815697 TI - ERp57 modulates mitochondrial calcium uptake through the MCU. AB - ERp57 participates in the regulation of calcium homeostasis. Although ERp57 modulates calcium flux across the plasma membrane and the endoplasmic reticulum membrane, its functions on mitochondria are largely unknown. Here, we found that ERp57 can regulate the expression of the mitochondrial calcium uniporter (MCU) and modulate mitochondrial calcium uptake. In ERp57-silenced HeLa cells, MCU was downregulated, and the mitochondrial calcium uptake was inhibited, consistent with the effect of MCU knockdown. When MCU was re-expressed in the ERp57 knockdown cells, mitochondrial calcium uptake was restored. Thus, ERp57 is a potent regulator of mitochondrial calcium homeostasis. PMID- 24815698 TI - Identification of a Src kinase SH3 binding site in the C-terminal domain of the human ErbB2 receptor tyrosine kinase. AB - Overexpression of the ErbB2 receptor tyrosine kinase is associated with most aggressive tumors in breast cancer patients and is thus one of the main investigated therapeutic targets. Human ErbB2 C-terminal domain is an unstructured anchor that recruits specific adaptors for signaling cascades resulting in cell growth, differentiation and migration. Herein, we report the presence of a SH3 binding motif in the proline rich unfolded ErbB2 C-terminal region. NMR analysis of this motif supports a PPII helix conformation and the binding to Fyn-SH3 domain. The interaction of a kinase of the Src family with ErbB2 C-terminal domain could contribute to synergistic intracellular signaling and enhanced oncogenesis. PMID- 24815699 TI - Is chronic rhinosinusitis related to allergic rhinitis in adults and children? Applying epidemiological guidelines for causation. AB - The relationship between allergic rhinitis and chronic rhinosinusitis has been assessed in a number of observational and experimental studies. In this review, we attempt their synthesis and evaluation using the modified Bradford Hill guidelines for causation. Although there is no proof of causation, especially in the pediatric literature, an evaluation of underlying allergies is recommended at least as an initial measure of symptoms relief. PMID- 24815700 TI - A delicate subject: The impact of cultural factors on neonatal and perinatal decision making. AB - The neonatal intensive care unit (NICU) is a high-stress environment for both families and health care providers that can sometimes make appropriate medical decisions challenging. We present a review article of non-medical barriers to effective decision making in the NICU, including: miscommunication, mixed messages, denial, comparative social and cultural influences, and the possible influence of perceived legal issues and family reliance on information from the Internet. As examples of these barriers, we describe and discuss two cases that occurred simultaneously in the same NICU where decisions were influenced by social and cultural differences that were misunderstood by both medical staff and patients' families. The resulting stress and emotional discomfort created an environment with sub-optimal relationships between patients' families and health care providers. We provide background on the sources of conflict in these particular cases. We also offer suggestions for possible amelioration of similar conflicts with the twin goals of facilitating compassionate decision making in NICU settings and promoting enhanced well-being of both families and providers. PMID- 24815701 TI - Impact of umbilical catheterization on morbidity and mortality in extremely premature newborns. AB - OBJECTIVE: Investigate the benefit of umbilical catheterization upon survival and selected morbidities in extremely premature newborns (<28 weeks gestation). Outcomes of successfully catheterized extremely premature newborns are compared with others who cannot be successfully catheterized, and we hypothesize that umbilical catheterization promotes survival and reduces morbidities. STUDY DESIGN: Utilizing a retrospective, cohort study design, survival and outcomes of catheterized and non-catheterized newborns (n = 722) were compared by univariate and multiple logistic regression analyses. RESULTS: Of all newborns, 66.8% had both umbilical arterial catheter (UAC) and umbilical venous catheter (UVC) placements, 15.0% had only UAC, 13.7% had only UVC, and 4.6% had neither. Overall survival was 82.5%. Survivals with and without UAC were 82.5% and 82.6% (NS), but survival with UVC was 80.7% versus 90.1% without UVC (p = 0.012). Analysis of risk factors associated with death during umbilical catheterization reaffirmed that death remained significantly dependent upon UVC placement (OR = 35.7; 95% CI: 3.7-347.3, p = 0.002). CONCLUSION: Successful umbilical catheterization of extremely premature newborns does not provide benefit through promotion of survival or reduction of morbidities when compared to others who are not successfully catheterized at the umbilicus. PMID- 24815702 TI - Changes in hematocrit following a blood transfusion does not influence the risk for necrotizing enterocolitis: A case-control study. AB - OBJECTIVE: Transfusion Associated Necrotizing Enterocolitis (TANEC) is defined as the onset of necrotizing enterocolitis (NEC) within 48 hours of receiving a blood transfusion in preterm neonates. We wanted to determine if hematocrit changes following blood transfusions were associated with disease development. PATIENTS AND METHODS: This is a case-control analysis of inborn neonates <=32 weeks' gestational age, from January 1, 2007 and December 31, 2010, who were diagnosed with Bell stage II or greater NEC. Those meeting TANEC criteria were identified and an analysis completed to determine if beginning or ending hematocrit values were associated with an increased risk for disease development. RESULTS: Nineteen of forty-nine (39%) infants with NEC met the criteria for TANEC. We found no differences in gestational age at birth or birth weight in our experimental groups. The degree of illness including PDA, IVH, central line use, and respiratory support 48 hours prior to disease onset was also similar between groups. Those with TANEC had higher modified Bell staging of NEC and were more likely to be receiving full enteric feeds at the time of NEC onset. No statistically significant differences were found in hematocrit levels prior to or following the blood transfusion closest to NEC onset in the TANEC group, as compared to classic NEC (CNEC) or control infants. CONCLUSION: The onset of NEC following transfusion occurs with a frequency that invites investigation regarding causation. Our data indicates no association between the beginning and ending hematocrit values and TANEC in our patient population. PMID- 24815703 TI - Pneumothorax in neonates: Trends, predictors and outcomes. AB - OBJECTIVE: To examine rates, trends, predictive risk factors, and outcomes associated with pneumothorax in neonates. STUDY DESIGN: Retrospective analyses were used to estimate rates and assess trends in pneumothorax among early preterm (GA <32 weeks), moderate-late preterm (GA 32-36), and term (GA >=37 weeks) neonates admitted to neonatal intensive care units (NICUs) participating in the Canadian Neonatal NetworkTM from 2005 to 2011. For each GA group, multivariable logistic regression models were derived to predict pneumothorax using risk factors with known clinical relevance. Additional logistic regression analyses assessed associations between pneumothorax and mortality, bronchopulmonary dysplasia, and intraventricular hemorrhage. RESULTS: The study included 71,237 neonates; of them 16,985 (24%) early preterm, 27,709 (39%) moderate-late preterm, and 26,543 (37%) term neonates. The overall rate of pneumothorax by GA was bimodal with estimates of 4.0%, 2.6%, and 6.7% respectively. No significant temporal trends were detected. Risk factors for pneumothorax included: a) for the overall lpopulation- Score for Neonatal Acute Physiology, version II >20, surfactant use, and respiratory distress syndrome; b) for early preterm infants chorioamnionitis; c) for moderate-late preterm infants-higher birth weight, male sex, rupture of membranes >24 hours, and outborn status; and d) for term infants- male sex, outborn status, and meconium aspiration in term neonates. In early preterm neonates, pneumothorax was associated with mortality, bronchopulmonary dysplasia, severe intraventricular hemorrhage, and prolonged NICU stay. CONCLUSIONS: Pneumothorax rates were higher among term and early preterm neonates admitted to the NICU. Predictors of pneumothorax varied between GA groups. Pneumothorax-associated mortality and morbidity were significantly greater in early preterm infants. PMID- 24815704 TI - Right-sided congenital diaphragmatic hernia: A tertiary centre's experience over 25 years. AB - AIMS: To provide analysis on infants treated for right-sided congenital diaphragmatic hernia (RCDH) including mortality, neonatal morbidities, and associated congenital anomalies. METHODS: We reviewed records of infants admitted with RCDH from 1985 to 2010. RESULTS: A total of 160 infants with CDH were identified; of them 22 infants had RCDH, 14 (64%) were male and eight (36%) were female. Eleven of the 22 infants died (50%), of which seven (64%) were male, and four (36%) were female. Three infants (13.6%) were diagnosed prenatally, and 19 (86.4%) were diagnosed postnatally. A statistically significant association with mortality was observed for low five minute Apgar score (OR = 8; 95% CI: 1.24 51.5), and high alveolar-arterial gradient >400 (OR = 25.7; 95% CI: 2.2-298.5). Fourteen infants (64%) underwent surgical correction, three (21.4%) infants who underwent surgery died. Three infants were discharged with oxygen supplementation and tube feeding at home, and one on sildenafil. No statistical significance was observed between other variables and mortality/morbidity. We observed a change in practice in relation to timing of surgery allowing stabilisation of patient prior to surgery. Average in-patient stay for RCDH infants was 23.5 days (range: 0 112), compared with the total in-patient mean stay of 10.5 days. CONCLUSIONS: Low five minute Apgar score, and high alveolar-arterial gradient were significant predictors of mortality. RCDH is associated with high mortality (50%), prolonged length of stay and other anomalies. In recent years, we observed an improving trend for survival. PMID- 24815705 TI - Prenatal alcohol exposure and its repercussion on newborns. AB - BACKGROUND: Alcohol consumption during pregnancy, even when moderate, implies a risk of impaired neurodevelopment, physical impairments and malformations. Its early identification is essential for establishing preventive measures to diminish disabilities among newborns. METHODS: To determine the frequency of consumption of substance use in pregnant women, we have used the techniques of gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry to detect drugs and markers of chronic consumption of alcohol in meconium. We performed a prospective study during a period of 10 months among 110 infants in our hospital, assessing anthropometry, neuromuscular development and determination of toxic substances in urine and meconium. Furthermore, meconium analysis identified fatty acid ethyl esters (FAEEs) and ethyl glucuronide (Etg). We also conducted a survey regarding the obstetric history, toxic habits, and employment status of the mothers. RESULTS: According to early detection markers analyzed in meconium (FAEE >1000 ng/g and/or Etg >50 ng/g meconium), 34.65% of pregnant women consumed alcohol during pregnancy, and 17% were positive for both markers. Within the positive cases, 50% of those exceeding a FAEE's value of 5000 ng/g in meconium had low birth-weight children. Only 5/110 mothers (4.5%) admitted to occasional alcohol consumption during pregnancy. Nobody admitted to frequent intake. The cocaine test was positive in three cases; two of them were positive for alcohol as well. CONCLUSION: As expected, many screening devices do not accurately capture use during pregnancy and supplemental methods such as meconium analysis of biomarkers of chronic alcohol consumption may be warranted. PMID- 24815706 TI - In vitro measurement of flow rate variability in neonatal IV therapy with and without the use of check valves. AB - BACKGROUND: In multi-infusion IV therapy, the actual volume delivered to the neonate can vary over time. To reduce flow rate variability, check valves can be used. A check valve allows flow through the valve in only one direction. OBJECTIVE: To evaluate flow rate variability in a low flow dual-infusion setup with and without check valves. METHODS: The effect of changing the height of and adding syringes to the IV-administration set was tested with and without check valves in an in vitro dual-infusion setup with in-line flow meters. The pre programmed flow rates were 2.5 and 0.1 ml/h. RESULTS: Twenty-four tests of 90 minutes were performed. Time to reach 75% of the pre-programmed 0.1 ml/h flow rate was >20 minutes. The highest total delivered volume during a test was (mean +/- SD) 56 +/- 8% of the expected delivery for tests without check valves, and diminished to 12 +/- 24% of the expected delivery for check valves with a higher opening pressure. CONCLUSIONS: The actual flows and the total delivered volume in low flow dual-infusion setups are less than expected on the pre-programmed flow rate. These findings emphasize the need for the development of more accurate delivery systems for drugs and fluids in neonatology. Caregivers should be aware of these findings, and optimise the delivery of IV substances by making use of check valves with low opening pressures and by minimising compliance and volume of the IV-administration set. Furthermore, changes in the relative height between pumps and catheter tip should be minimized. PMID- 24815707 TI - Predicting fetal karyotype in fetuses with omphalocele: The current role of ultrasound. AB - OBJECTIVE: To assess the ability of ultrasound in predicting abnormal karyotype in pregnancies with prenatally diagnosed omphaloceles and to compare its test characteristics to previously published studies. METHODS: A retrospective case control study of omphaloceles diagnosed at one center was performed from 1995 2007. Cases were those with an abnormal karyotype and controls were those with a normal karyotype. Data collection included demographics, karyotype results, and ultrasound findings. The number and type of associated anomalies were compared between the cases and controls. The sensitivity, specificity, positive predictive value, and negative predictive value for predicting an abnormal karyotype were calculated from previously published studies. RESULTS: Of the 73 subjects, there were 12 cases and 61 controls. The majority of women were Caucasian and primigravida. The cases were less likely to have an isolated omphalocele [1 (8.3%) vs. 27 (42.6%), OR = 0.122; 95% CI: 0.02-0.08] but were more likely to have two or more major anomalies [8 (66.7%) vs. 17 (27.9%), OR = 5.18; 95% CI: 1.19-24.04)] compared to the controls. Cardiac anomalies and only one additional major anomaly were not different between the two groups, P > 0.05. The test characteristics for this study were similar to previously published studies. CONCLUSIONS: Isolated omphaloceles were more likely to have a normal karyotype; however fetuses with multiple anomalies were more likely to have an abnormal karyotype. Despite advances in ultrasound technology, its ability for predicting an abnormal karyotype in these fetuses has not improved. PMID- 24815708 TI - Fetal intestinal perforation and meconium peritonitis associated with maternal autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) in pregnancy can affect both fetal and maternal outcomes. Little is known regarding the fetal outcomes of AIH in pregnancy. The major risks include spontaneous abortions, fetal mortality, perinatal mortality and prematurity. Two common drugs used in the management of AIH, azathioprine and prednisone, may also be associated with adverse fetal outcomes. We present the case of perinatal focal intestinal perforation with a meconium pseudocyst in a preterm infant of a mother with autoimmune hepatitis on azathioprine and methylprednisone. PMID- 24815709 TI - Urinary ascites due to persistent urogenital sinus: A case report and review of literature. AB - BACKGROUND: Persistent urogenital sinus is one of the rare urogenital anomalies, which commonly presents as hydrometrocolpos. Fetal urinary ascites as a presentation of persistent urogenital sinus is extremely rare. CASE REPORT: We report on a preterm infant with antenatal diagnosis of hydrometrocolpos and massive urinary ascites secondary to urogenital sinus without any bladder or renal abnormalities. CONCLUSION: This case report emphasizes the importance of maintaining a high index of suspicion in the diagnosis of persistent urogenital sinus especially in infants presenting with urinary ascites along with hydrometrocolpos. PMID- 24815710 TI - Antenatal hemorrhage of a cervical lymphatic malformation presenting as a draining neck mass: An unusual presentation. AB - Lymphatic malformations in the neck can present as large fetal neck masses causing airway obstructions with potential perinatal demise and can pose a therapeutic challenge. We present a rare case of prenatally diagnosed large fetal neck mass with features of lymphatic malformation with intralesional hemorrhage of uncertain origin. Postnatal evaluation showed a complex cystic-solid lesion eroding through the skin with an open wound that made it clinically hard to differentiate from a teratoma. Given that malignancy could not be completely ruled out, surgery was favored. Final pathology showed a complex lymphatic malformation with intralesional hemorrhage, despite having no associated capillary, venous or arterial malformations. PMID- 24815711 TI - Traumatic victimization in the lives of lesbian and bisexual women. AB - SUMMARY This paper takes a contextual approach to understanding traumatic victimization experiences of lesbian and bisexual women over the life span. Expanding on feminist perspectives on violence against women, the concept of "cultural victimization" is used to explore the role of societal homophobia in shaping the experience of victimization for lesbian and bisexual women. An overview of the existing literature on the prevalence and impact of childhood abuse, domestic violence, sexual assault, and hate crimes among this population is provided. The relationship between sexual identity development and trauma is discussed. This article provides a framework for understanding lesbian and bisexual women's victimization, lends insight to clinicians working with lesbian/bisexual survivors, and provides direction for future research. PMID- 24815712 TI - The effects of sexual orientation on body image and attitudes about eating and weight. AB - SUMMARY We assessed the effect of sexual orientation on body image and attitudes toward eating and weight using data collected from lesbians and heterosexual women in three US cities. Data were analyzed using ordinary least squares regression controlling for a number of demographic characteristics. Findings indicate that while lesbian sexual orientation is predictive of positive body image and fewer negative attitudes toward eating and weight, the effects are modest. Body mass index (BMI), frequency of exercise, race, and self-image were the strongest predictors of body image; BMI, race, and city of residence were the strongest predictors of attitudes toward eating and weight. The authors conclude that while belonging to a lesbian subculture may provide some protection against the societal imperative toward thinness, it likely does not counter the larger societal preference that women be thin. PMID- 24815713 TI - No reflection in the mirror. AB - SUMMARY Lesbians with disabilities have atypical life experiences- they are virtually invisible within the mainstream culture. Both women with disabilities and lesbians experience societal, familial and economic pressures that directly impact their lives and the range of options available to them. When a lesbian is also a woman with a disability, the combination of these pressures has important mental health implications. This article explores the issues and barriers related to disabled lesbians accessing mental health services. Because no systematic research on the mental health needs and experiences of lesbians with disabilities exists, it is unknown how many of them are in need of, access, or are denied appropriate mental health services. The little research that exists on the mental health needs of women with disabilities has either excluded or ignored the particular experiences associated with lesbian identity. Like wise, lesbian mental health research has historically overlooked disabled women's identity and experiences. Shared experiences and other similarities, such as discriminatory attitudes in the health service system, social stigma, and self-devaluation, are discussed within the context of disabled lesbians' compounded risk for mental health problems. Service access and barriers, key therapeutic issues, and cultural competency are discussed as additional issues that emerge when addressing mental health services. We also examine how lesbians with disabilities have proactively networked, caring for each other through informal supports within their communities, and have creatively developed their own strategies and resources. The paper concludes with a discussion of new efforts toward gaining visibility, successful strategies for mental health practitioners in addressing issues and challenges associated with providing care to lesbians with disabilities, and recommendations for further research. PMID- 24815714 TI - Psychological distress in african american lesbian and heterosexual women. AB - SUMMARY Similarities and differences in indicators of psychological distress, risk factors for distress, and methods of coping were assessed in African American lesbians and heterosexual women. Despite similar rates of risk factors, lesbians reported more indicators of psychological distress and more frequent use of alcohol or other drugs in response to stress. In addition, findings reflect an overall trend toward higher rates of drinking, alcohol-related problems, and use of other legal and illegal drugs among lesbians. PMID- 24815715 TI - Self-reported sexual identity, sexual behaviors and health risks. AB - SUMMARY Data from a population-based survey of low-income young women (n = 2,438) was used to examine substance use patterns and exposure to coerced sexual activity among women who self-identify as lesbian (n = 34) or bisexual (n = 91), or who report sexual behavior exclusively with other women (n = 17) or with both women and men (n = 189). Findings for women classified by self-identity and by sexual behavior are compared. Women who identified as bisexual or lesbian reported higher rates of lifetime and recent substance use and were more likely to report experiences of coerced sex than women who identified as heterosexual. Women with both male and female sex partners reported higher rates of substance use and coerced sexual experiences than did women with male partners only. Heterosexual women with both male and female partners were more similar to self identified bisexuals, compared to heterosexual women with male partners only. The implications of assessing multiple dimensions of sexual orientation in research focusing on lesbians' mental health are discussed. PMID- 24815716 TI - Identity, stigma management, and well-being. AB - SUMMARY This study investigated and compared predictors of well-being in lesbians/bisexual women and gay/bisexual men. Well-being was assessed using measures of self-esteem, life satisfaction, and depression. Predictor variables included involvement in lesbian/gay/bisexual (LGB) culture, rejection of negative stereotypes of LGBs, positivity of gay/lesbian identity, and perceived acceptance by family, heterosexual friends, and work/school associates. A survey instrument was developed and distributed in the Greater Buffalo area in Spring and Summer of 1994, to which 168 lesbians and bisexual women and 152 gay and bisexual men responded. Overall, results were very similar for lesbian/bisexual women and gay/bisexual men. Having a positive LGB identity was the most robust predictor of psychological well-being in both women and men who participated in the study. In addition, rejection of negative stereotypes predicted positive LGB identity. Results are discussed within the context of lesbian/bisexual women's mental health and suggestions for research and practice are described. PMID- 24815717 TI - A comparative study of lesbian and heterosexual women in committed relationships. AB - SUMMARY Data from a diverse sample of lesbians and a demographi-cally matched group of heterosexual women were used to examine and compare lesbians' and heterosexual women's relationships. Findings suggest similarities in the broad relationship experiences of women in the sample including the importance of being in a committed relationship, shared values with partners on relationship issues, and division of labor. Contrary to previous research findings, lesbian and heterosexual women did not differ on overall frequency of sexual activity. Although relationship violence was uncommon among participants in this study, indicators of poor conflict resolution strategies were moderately high in both lesbian and heterosexual couples. Use of mental health services for relationship problems was low and did not differ by sexual orientation. Understanding relationship dynamics in general, and in lesbian couples in particular, is important in the provision of appropriate and effective mental health resources and services. PMID- 24815718 TI - Internalized homophobia in lesbians. AB - SUMMARY In this article we discuss the importance of studying internalized homophobia and provide a rationale for studying internalized homophobia in lesbians apart from gay men. We review published scales used to assess internalized homophobia in lesbians and describe recent studies on the correlates of internalized homophobia in lesbians. We discuss concepts of internalized homophobia as minority stress and identify variables that have been theoretically linked to internalized homophobia in lesbians but have not been empirically examined. Implications for practice and research are also discussed. PMID- 24815719 TI - Sexual minorities seeking services. AB - SUMMARY Understanding the mental health needs of lesbian and bisexual (sexual minority) women is an integral part of designing and providing appropriate mental health services and treatment for them. In an effort to understand the mental health needs of sexual minority women who seek community treatment, a chart review was conducted of the 223 lesbian and bisexual women who presented for services between July 1, 1997 and December 31, 2000 at Fenway Community Health in Boston, MA. Data are based on clients' self-reports and clinician assessments of clients' presenting problem, relevant developmental history, prior mental health and substance abuse treatment, current reports of emotional/psychological symptoms, and areas of impaired functioning. Although substance abuse and suicidal ideation were commonly reported problems, other concerns were more frequently reported. High percentages of lesbians and bisexual women reported relationship concerns and lack of adequate social networks; rates of depression and anxiety based on clinicians' assessments were also high. Overall, lesbians and bisexual women did not differ in the issues they brought to treatment or level or types of impairment. Compared with previous community survey samples, however, study participants appeared to be healthier than general, non-clinical samples of self-identified lesbians, possibly reflecting the special characteristics of sexual minority women who seek treatment in specialized community sites such as the Fenway. Although patients who come to these sites may not represent the more general population of sexual minority women, community health centers known to serve lesbian, gay, bisexual and transgender (LGBT) individuals may be fruitful access points for studying the mental health status and treatment needs of sexual minority women. PMID- 24815721 TI - [Lateral chest X-rays. Radiographic anatomy]. AB - Lateral chest views constitute an essential part of chest X-ray examinations, so it is fundamental to know the anatomy on these images and to be able to detect the variations manifested on these images in different diseases. The aim of this article is to review the normal anatomy and main normal variants seen on lateral chest views. For teaching purposes, we divide the thorax into different spaces and analyze each in an orderly way, especially emphasizing the anatomic details that are most helpful for locating lesions that have already been detected in the posteroanterior view or for detecting lesions that can be missed in the posteroanterior view. PMID- 24815720 TI - Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects. AB - BACKGROUND: Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic herpes simplex virus-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for antitumor efficacy. EXPERIMENTAL DESIGN: The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western blot assays were used to evaluate induction of estrogen receptor (ER) stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Antitumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log-rank test. RESULTS: Combination treatment with bortezomib and oHSV (34.5ENVE), displayed strong synergistic interaction in ovarian cancer, head and neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK, and IRE1alpha (Western blot analysis) and the UPR (induction of hsp40, 70, and 90). Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (P < 0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced antitumor efficacy in multiple different tumor models in vivo. CONCLUSIONS: The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib-induced UPR and warrants future clinical testing in patients. PMID- 24815723 TI - From the editors: Introducing Epilepsia's Controversy in Epilepsy series. PMID- 24815722 TI - Glycated albumin produced in diabetic hyperglycemia promotes monocyte secretion of inflammatory cytokines and bacterial adherence to epithelial cells. AB - BACKGROUND AND OBJECTIVE: The prevalence and severity of periodontal disease increase in patients with insulin-deficient or insulin-resistant forms of diabetes. A common characteristic of diabetes is the presence of hyperglycemia. A critical consequence of hyperglycemia is the nonenzymatic glycation and oxidation of proteins and lipids, resulting in the irreversible formation of advanced glycation end-products (AGEs). A central means by which AGEs are believed to impart their pathogenic effects is via interacting with specific cellular receptors; the best-characterized of these is receptor for AGE (RAGE). The major consequences of the AGE-RAGE interaction are the generation of enhanced cellular oxidant stress, hypersecretion of inflammatory mediators and altered subgingival flora. The aim of this study was to elucidate the influence of glycated albumin (G-alb), with or without lipopolysaccharide (LPS) isolated from periodontal pathogens, on the secretion of inflammatory cytokines by cultured monocytic cells and also to investigate the role of G-alb in adherence of bacteria to epithelial cells. MATERIAL AND METHODS: Activated THP-1 cells (1 * 10(6) cells) were incubated for 24 h with G-alb or normal albumin (N-alb), with or without LPS isolated from two periodontal pathogens. Supernatant fluids were collected and assayed for the cytokines interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) by ELISA. For bacterial adhesion assays, S-G epithelial cells were grown on cover slips and incubated with G-alb (10 MUg/mL) or N-alb (control) for 30 min. The cover slips were rinsed and then incubated with bacteria for 2 h. The number of adherent bacteria was determined by counting 20 epithelial cells chosen randomly under a light microscope. RESULTS: The secretion of IL-1beta, TNF-alpha and IL-6 by THP-1 cells was greater in the presence of G-alb than in the presence of N-alb. The amounts of cytokines secreted were even greater when THP-1 cells were incubated with G-alb and LPS of periodontal pathogens. The effect of G-alb and LPS was reduced when RAGE was blocked by its antibody. Coating the cultured epithelial cells with G-alb resulted in increased bacterial adherence. CONCLUSION: This study demonstrated the role of G-alb in stimulating cultured monocytic cells to secrete inflammatory cytokines. The stimulation was found to be greater when cells were incubated with LPS in addition to G-alb. The over-expression of inflammatory cytokines as a result of the combined effects of G-alb and bacterial LPS may contribute to the severity of periodontal disease in diabetic subjects. PMID- 24815724 TI - The other side of the bridge: exploring the sexual relationships of men who have sex with men and their female partners in Mumbai, India. AB - Behaviourally bisexual men have been identified as a 'bridge' population of HIV transmission to heterosexual women in India. Little is known about the sexual relationships that these men have with their female sex partners. The primary objective of this study was to explore the sexual practices and relationship dynamics between married and unmarried behaviourally bisexual men and their female sex partners in Mumbai, India. In 2009, semi-structured qualitative interviews were conducted with 32 men who reported sex with men and women. Participants discussed a variety of sexual practices and arrangements with female sex partners. Irrespective of marital status and sexual identity, many said that they had satisfying sexual experiences and feelings of affection for female sex partners. However, sexual incompatibility between married partners was also reported. Explanations of bisexual concurrency were discussed in terms of both sexual satisfaction and sexual preference. Self-perceived HIV risk related to same-sex sexual behaviour motivated many men to use condoms with female partners. Expectations of unprotected marital sex and perceptions of partner risk were barriers to condom use. HIV-prevention programmes for this population may benefit from tailored risk-reduction counselling that attends to the variations of these sexual and social relationship dynamics. PMID- 24815725 TI - Test-retest reliability of a continuous glucose monitoring system in individuals with type 2 diabetes. AB - AIMS: This study determined the test-retest reliability of a continuous glucose monitoring system (CGMS) (iProTM2; Medtronic, Northridge, CA) under standardized conditions in individuals with type 2 diabetes (T2D). SUBJECTS AND METHODS: Fourteen individuals with T2D spent two nonconsecutive days in a calorimetry unit. On both days, meals, medication, and exercise were standardized. Glucose concentrations were measured continuously by CGMS, from which daily mean glucose concentration (GLU(mean)), time spent in hyperglycemia (t(>10.0 mmol/L)), and meal, exercise, and nocturnal mean glucose concentrations, as well as glycemic variability (SD(w), percentage coefficient of variation [%cv(w)], mean amplitude of glycemic excursions [MAGEc, MAGE(ave), and MAGE(abs.gos)], and continuous overlapping net glycemic action [CONGA(n)]) were estimated. Absolute and relative reliabilities were investigated using coefficient of variation (CV) and intraclass correlation, respectively. RESULTS: Relative reliability ranged from 0.77 to 0.95 (P<0.05) for GLU(mean) and meal, exercise, and nocturnal glycemia with CV ranging from 3.9% to 11.7%. Despite significant relative reliability (R=0.93; P<0.01), t(>10.0 mmol/L) showed larger CV (54.7%). Among the different glycemic variability measures, a significant between-day difference was observed in MAGEc, MAGE(ave), CONGA6, and CONGA12. The remaining measures (i.e., SD(w), %cv(w), MAGE(abs.gos), and CONGA1-4) indicated no between-day differences and significant relative reliability. CONCLUSIONS: In individuals with T2D, CGMS estimated glycemic profiles were characterized by high relative and absolute reliability for both daily and shorter-term measurements as represented by GLUmean and meal, exercise, and nocturnal glycemia. Among the different methods to calculate glycemic variability, our results showed SD(w), %cv(w), MAGE(abs.gos), and CONGAn with n <= 4 were reliable measures. These results suggest the usefulness of CGMS in clinical trials utilizing repeated measured. PMID- 24815726 TI - Congenital hypogonadotropic hypogonadism and Kallmann syndrome as models for studying hormonal regulation of human testicular endocrine functions. AB - Men with Kallmann syndrome (KS) and those with congenital isolated hypogonadotropic hypogonadism with normal olfaction share a chronic, usually profound deficit, in FSH and LH, the two pituitary gonadotropins. Many studies indicate that this gonadotropin deficiency is already present during fetal life, thus explaining the micropenis, cryptorchidism and marked testicular hypotrophy already present at birth. In addition, neonatal activation of gonadotropin secretion is compromised in boys with severe CHH/Kallmann, preventing the first phase of postnatal testicular activation. Finally, CHH is characterized by the persistence, in the vast majority of cases, of gonadotropin deficiency at the time of puberty and during adulthood. This prevents the normal pubertal testicular reactivation required for physiological sex steroid and testicular peptide production, and for spermatogenesis. CHH/KS thus represents a pathological paradigm that can help to unravel, in vivo, the role of each gonadotropin in human testicular exocrine and endocrine functions at different stages of development. Recombinant gonadotropins with pure LH or FSH activity have been used to stimulate Leydig's cells and Sertoli's cells, respectively, and thereby to clarify their paracrine interaction in vivo. The effects of these pharmacological probes can be assessed by measuring the changes they provoke in circulating testicular hormone concentrations. This review discusses the impact of chronic gonadotropin deficiency on the endocrine functions of the interstitial compartment, which contains testosterone-, estradiol- and INSL3-secreting Leydig's cells. It also examines the regulation of inhibin B and anti-Mullerian hormone (AMH) secretion in the seminiferous tubules, and the insights provided by studies of human testicular stimulation with recombinant gonadotropins, used either individually or in combination. PMID- 24815727 TI - Investigation of mechanism and molecular epidemiology of linezolid-resistant Enterococcus faecalis in China. AB - Enterococcus is a major cause of important nosocomial infections. Linezolid, the first member of an entirely new class of antibiotics (oxazolidinones), is effective against serious infections caused by Enterococcus. However, resistance to linezolid has been discovered throughout the world rapidly. From 2011 to 2013, nine linezolid-resistant E. faecalis isolates were collected and the possible mechanisms of linezolid resistance, including mutations in domain V of 23S rRNA genes and in ribosomal proteins L3 and L4, and the multiresistance gene cfr, were investigated. Furthermore, an epidemiological survey of the nine linezolid resistant E. faecalis isolates was performed by pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and DiversiLab. The three methods were compared to evaluate their merits and demerits, respectively. We failed to find the resistance mechanisms that have been revealed in recent years by PCR and sequencing analysis in the linezolid-resistant E. faecalis. Epidemiological investigation suggested that a small-scale outbreak of linezolid-resistant E. faecalis emerged in neurosurgery ICU from March to May of 2013. DiversiLab was a reliable typing tool and a suitable alternative to PFGE because it was as discriminatory as PFGE and better than MLST. PMID- 24815728 TI - Genetic diversity evaluation on Portuguese Leishmania infantum strains by multilocus microsatellite typing. AB - Leishmania infantum is the main etiological agent of zoonotic visceral leishmaniasis in the Mediterranean region, including Portugal, but, given its low isoenzyme diversity in this country, the population structure is poorly known. A set of 14 polymorphic microsatellite markers was studied on 136 Portuguese Leishmania strains isolated from different hosts, geographic regions and different clinical forms. A total of 108 different genotypes were found, which is a degree of genetic diversity comparable to other regions, even within zymodeme MON-1. A single most common genotype was detected in 1:5 of all strains, which, with a greater number of multi-strain genotypes found in the Lisbon Metropolitan Region, particularly for human strains, was suggestive of the occurrence of clonal transmission. In addition, a high re-infection rate was found among HIV+ patients. Model based analysis by STRUCTURE uncovered two main populations (populations A and B, composed of MON-1 and non-MON-1 strains, respectively), with great genetic diversity between them, and two MON-1 sub-populations (A1 and A2). High inbreeding coefficients were found in these populations, although strains with mixed ancestry were identified, suggesting that recombination also plays a role in the epidemiology of this species in Portugal. Some but limited geographical differentiation was observed, with groups of strains from the same regions clustering together, particularly those from canine origin. Our results show that L. infantum isolates from Portugal present microsatellite diversity comparable to other regions and that different transmission models play a role in its epidemiology, from clonal transmission to recombination. In addition, although Portugal is a small country, mobility of people and animals is high and Leishmania can be probably easily disseminated between infected hosts throughout the country, two instances of seemingly local restricted transmission were identified. PMID- 24815729 TI - Spoligotyping of Mycobacterium tuberculosis complex isolates using hydrogel oligonucleotide microarrays. AB - Mycobacterium tuberculosis remains a leading cause of morbidity and mortality worldwide. This circumstance underscores the relevance of population studies of tuberculosis for transmission dynamics control. In this study, we describe a conversion of the spoligotyping of M.tuberculosis complex isolates on a platform of custom designed hydrogel microarrays (biochips). An algorithm of automated data processing and interpretation of hybridization results using online database was proposed. In total, the 445 samples were tested. Initially, 97 samples representing multiple species of M.tuberculosis complex and nontuberculous mycobacteria were used for protocol optimization and cut-off settings. The developed assay was further evaluated on the out-group of the 348 mycobacterial samples. Results showed high concordance with the conventional membrane-based spoligotyping method. Diagnostic sensitivity and diagnostic specificity of the spoligo-biochip assay were 99.1% and 100%, respectively. The analytical sensitivity was determined to be 500 genomic equivalents of mycobacterial DNA. The high sensitivity and specificity, ease of operation procedures, and the automatic processing of measured data make the developed assay a useful tool for the rapid and accurate genotyping of M. tuberculosis. PMID- 24815730 TI - HCV NS5A co-operates with PKR in modulating HCV IRES-dependent translation. AB - Translation initiation of the Hepatitis C virus (HCV) genome is driven by an internal ribosome entry site (IRES), located within the 5' non-coding region. Several studies have suggested that different cellular non canonical proteins or viral proteins can regulate the HCV IRES activity. However, the role of the viral proteins on HCV translation remains controversial. In this report, we confirmed previous studies showing that NS5A down-regulates IRES activity in HepG2 but not in Huh7 cells suggesting that the NS5A effect on HCV IRES is cell-type dependent. Additionally, we provide strong evidence that activated PKR up-regulates the IRES activity while silencing of endogenous PKR had the opposite effect. Furthermore, we present data indicating that the NS5A-mediated inhibitory effect on IRES dependent translation could be linked with the PKR inactivation. Finally, we show that NS5A from GBV-C but not from GBV-B down-regulates HCV IRES activity in the absence or the presence of PKR over expression. Notably, HCV and GBV-C but not GBV-B NS5A contains a previously identified PKR interacting protein domain. PMID- 24815731 TI - The metabotropic glutamate receptor subtype 7 rs3792452 polymorphism is associated with the response to methylphenidate in children with attention deficit/hyperactivity disorder. AB - OBJECTIVE: The purpose of this study was to investigate the association between the metabotropic glutamate receptor subtype 7 (mGluR7) gene (GRM7) polymorphism and treatment response to methylphenidate in Korean children with attention deficit/hyperactivity disorder (ADHD). METHODS: We enrolled 175 medication-naive children with ADHD in an open-label 8 week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impressions (CGI) Scale and the parent version of the ADHD Rating Scale-IV (ADHD-RS) before and after treatment. RESULTS: After the 8 week course of methylphenidate, children with the GRM7 rs37952452 polymorphism G/A genotype had a more pronounced response rate to the treatment than did children with the G/G genotype according to the ADHD-RS scores (72.2% vs. 55.4%, respectively; p=0.011) and the more stringent standard of combined ADHD-RS and CGI-Improvement (CGI-I) scores (50.0% vs. 35.3%, respectively; p=0.044). CONCLUSIONS: The present study suggests that the GRM7 rs37952452 polymorphism may play a role in the treatment response to methylphenidate in children with ADHD. Further studies to evaluate the association between glutamate genes and treatment response to methylphenidate in children with ADHD, including a replication of our findings using a control or comparative group in a larger sample, are warranted. PMID- 24815732 TI - Adverse events during the removal of impacted maxillary third molars. AB - The purpose of the present study was to estimate the frequency of the occurrence of intraoperative adverse events during the removal of impacted maxillary third molars and to correlate predictive variables. A prospective cohort study was carried out involving patients submitted to at least one surgical removal of an impacted maxillary third molar as part of a line of research on third molar surgery developed at the study university. Predictor variables indicative of the occurrence of adverse events during surgery were classified by their demographic, clinical, radiographic, and surgical features. Descriptive and bivariate statistics were computed. In total, 106 patients fulfilled the eligibility criteria, and 204 surgeries were performed. The mean patient age was 22.8 +/- 2.2 years and the ratio of women to men was 3:1. Nine different adverse events occurring during surgery were recorded. These events occurred in approximately 6.9% of cases and were significantly associated with the second molar relationship (P=0.008) and periodontal space (P=0.05). The study revealed a low frequency of adverse events during the surgical removal of an impacted maxillary third molar. The results suggest that adverse events during surgery are associated with the second molar relationship and periodontal space. PMID- 24815733 TI - Psychometric equivalence of a paper-based and computerized (iPad) version of the Memory Orientation Screening Test (MOST(r)). AB - The Memory Orientation Screening Test (MOST((r))) is a 29-point scale for identifying and following mild and major neurocognitive disorders in older patients. Previous research demonstrated validity in separating patients with normal vs. impaired cognition and high correlations with tests of memory and attention. This study compares the original paper-based MOST((r)) with a computerized (iPad app) version, the MOST((r))-96120, to determine the equivalence of formats. A total of 98 consecutive older patients were administered identical versions of the MOST and MOST-96120 in a random order, separated by 1 hour of interspersed testing, in a 3-hour neuropsychological evaluation. MOST and MOST-96120 scores were compared with each other, with global cognitive ratings, and with standardized tests of memory and attention. Both versions had equivalent means and standard deviations, very high inter-test correlation (r = .92, p < .001), and equal correlations with outcome measures. Both versions separated patients into normal vs. mild NCD vs. major NCD categories with equal accuracy. ANOVA showed no significant difference between versions or presentation order. Both versions correlated very highly with cognitive level and neuropsychological endpoints, confirming previous research. The MOST-96120 is a computerized neuropsychological assessment device that demonstrates equivalence with its paper-based original, allowing for confident reliance on the findings of previous research. PMID- 24815734 TI - Optical properties of secondary organic aerosols generated by photooxidation of aromatic hydrocarbons. AB - The refractive index (RI) is the fundamental characteristic that affects the optical properties of aerosols, which could be some of the most important factors influencing direct radiative forcing. The secondary organic aerosols (SOAs) generated by the photooxidation of benzene, toluene, ethylbenzene and m-xylene (BTEX) under low-NOx and high-NOx conditions are explored in this study. The particles generated in our experiments are considered to be spherical, based on atomic force microscopy (AFM) images, and nonabsorbent at a wavelength of 532 nm, as determined by ultraviolet-visible light (UV-Vis) spectroscopy. The retrieved RIs at 532 nm for the SOAs range from 1.38-1.59, depending on several factors, such as different precursors and NOx levels. The RIs of the SOAs are altered differently as the NOx concentration increases as follows: the RIs of the SOAs derived from benzene and toluene increase, whereas those of the SOAs derived from ethylbenzene and m-xylene decrease. Finally, by comparing the experimental data with the model values, we demonstrate that the models likely overestimate the RI values of the SOA particles to a certain extent, which in turn overestimates the global direct radiative forcing of the organic particles. PMID- 24815735 TI - The role of radiosurgery for infratentorial arteriovenous malformations. PMID- 24815736 TI - Delayed pedicle screw augmentation after spinal instrumentation for fractures in patients with multiple myeloma. PMID- 24815738 TI - Residue-specific force field based on the protein coil library. RSFF1: modification of OPLS-AA/L. AB - Traditional protein force fields use one set of parameters for most of the 20 amino acids (AAs), allowing transferability of the parameters. However, a significant shortcoming is the difficulty to fit the Ramachandran plots of all AA residues simultaneously, affecting the accuracy of the force field. In this Feature Article, we report a new strategy for protein force field parametrization. Backbone and side-chain conformational distributions of all 20 AA residues obtained from protein coil library were used as the target data. The dihedral angle (torsion) potentials and some local nonbonded (1-4/1-5/1-6) interactions in OPLS-AA/L force field were modified such that the target data can be excellently reproduced by molecular dynamics simulations of dipeptides (blocked AAs) in explicit water, resulting in a new force field with AA-specific parameters, RSFF1. An efficient free energy decomposition approach was developed to separate the corrections on phi and psi from the two-dimensional Ramachandran plots. RSFF1 is shown to reproduce the experimental NMR (3)J-coupling constants of AA dipeptides better than other force fields. It has a good balance between alpha-helical and beta-sheet secondary structures. It can successfully fold a set of alpha-helix proteins (Trp-cage and Homeodomain) and beta-hairpins (Trpzip-2, GB1 hairpin), which cannot be consistently stabilized by other state-of-the-art force fields. Interestingly, the RSFF1 force field systematically overestimates the melting temperature (and the stability of native state) of these peptides/proteins. It has a potential application in the simulation of protein folding and protein structure refinement. PMID- 24815737 TI - De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma cells at disease sites. OBJECTIVE: The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. METHODS: B-cell populations from the peripheral blood of 84 patients with active IgG4-RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy. RESULTS: Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG4(+), are increased in patients with active IgG4-RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive. CONCLUSIONS: Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive disease process. PMID- 24815739 TI - Evaluation of the effects of single-nucleotide polymorphisms in CYP3A4 and CYP4F2 on stable phenprocoumon and acenocoumarol maintenance doses: reply. PMID- 24815740 TI - Temporal lesions and widespread involvement of white matter associated with multi organ inflammatory disease in human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). AB - Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the spinal cord, characterized by spastic paraparesis, back pain, and sphincter disorders. Involvement of multiple organs and encephalopathy are uncommon in HAM/TSP. Nonspecific small white matter lesions of unknown etiology, mainly in the periventricular and subcortical regions, have been found on brain magnetic resonance imaging of HAM/TSP patients. Bitemporal lesions have rarely been described. We report the case of a 54-year-old woman diagnosed with HAM/TSP who presented subclinical cognitive deficits associated with bitemporal and widespread white matter lesions. The cerebrospinal fluid (CSF) was inflammatory (blood-CSF barrier dysfunction, intrathecal synthesis of total and HTLV-1 IgG). The proviral load was higher in cerebrospinal fluid than in peripheral blood mononuclear cells. The neurological picture was complicated by multi-organ inflammatory disease (Hashimoto's thyroiditis, uveitis, anemia, and chronic renal failure). This case highlights the potential multisystem inflammatory nature of HTLV-1 infection, with a wide spectrum of manifestations. In cases of HAM/TSP with multi-organ inflammatory disease, encephalic involvement should be investigated, even in the absence of clinical manifestations. Also bitemporal lesions can be the consequence of intense and diffuse inflammation associated with HTLV-1 infection. PMID- 24815742 TI - Canine eosinophilic gastrointestinal disorders. AB - Eosinophils play a crucial role in the inflammatory response in conjunction with both innate and adaptive immunity. Eosinophils have long been recognized as inflammatory leukocytes that are particularly important in patients with parasitic infestations. However, recent studies in veterinary medicine demonstrate a number of canine eosinophilic gastrointestinal (GI) disorders unrelated to a parasitic infestation. Although the underlying pathophysiology behind eosinophilic infiltration of the canine GI tract remains uncertain, medical intervention aiming to decrease the activation of eosinophils seems effective in reducing symptoms and preventing organ damage. This review focuses on the biology of eosinophils and their products. It describes, the composition of eosinophil granules, mechanisms of eosinophil activation, and eosinophil related disease processes leading to organ damage. Even though the main clinical signs of canine eosinophilic gastroenteritis, vomiting and diarrhea, are similar to those of other types of gastroenteritis, the clinical response and prognosis are worse for this condition. The clinical signs and diagnostic approach for eosinophilic GI disorders are described and compared between canine and human patients for each region of GI tract, from the esophagus to the colon. Moreover, the current treatments for this syndrome in canine and human patients are summarized and paralleled. The comparative study of canine and human patients with eosinophilic gastroenteritis will advance the understanding of this syndrome in both species and may lead to the development of novel treatment strategies. PMID- 24815741 TI - Comparison of the characteristics of elderly influenza patients in two consecutive seasons. AB - The seasonality of influenza infections can be affected by virus subtypes, climate, and social networking in populations. While these factors are well known, their relative influences in specific age groups have not been fully investigated. During 2010-2011, patients aged 65 years and above with influenza virus infections were recruited from a regional hospital in Hong Kong. They were either residents of homes for the elderly (n=60) or living with their family (n=75). Two seasons were distinguished, the summer season of 2010 dominated by H3N2 and the winter season of 2011 dominated by H1N1. The patients' clinical presentations and patterns of inter-personal connectivity were assessed. Overall, more elderly people living with their family were diagnosed with H1N1 compared to those in the homes for the elderly, and the former had visited a more diverse range of places 1 week prior to diagnosis. A higher proportion of patients living with family presented with lower respiratory tract symptoms, but these patients were less likely to have pre-existing chronic diseases. The results suggest that elderly patients infected during an influenza season could vary by virus subtype, which in turn is dependent on exposure locations and the pattern of social connectivity. PMID- 24815743 TI - Relative entropy minimizing noisy non-linear neural network to approximate stochastic processes. AB - A method is provided for designing and training noise-driven recurrent neural networks as models of stochastic processes. The method unifies and generalizes two known separate modeling approaches, Echo State Networks (ESN) and Linear Inverse Modeling (LIM), under the common principle of relative entropy minimization. The power of the new method is demonstrated on a stochastic approximation of the El Nino phenomenon studied in climate research. PMID- 24815744 TI - Identifying crystallization- and incorporation-limited regimes during vapor liquid-solid growth of Si nanowires. AB - The vapor-liquid-solid (VLS) mechanism is widely used for the synthesis of semiconductor nanowires (NWs), yet several aspects of the mechanism are not fully understood. Here, we present comprehensive experimental measurements on the growth rate of Au-catalyzed Si NWs over a range of temperatures (365-480 degrees C), diameters (30-200 nm), and pressures (0.1-1.6 Torr SiH4). We develop a kinetic model of VLS growth that includes (1) Si incorporation into the liquid Au Si catalyst, (2) Si evaporation from the catalyst surface, and (3) Si crystallization at the catalyst-NW interface. This simple model quantitatively explains growth rate data collected over more than 65 distinct synthetic conditions. Surprisingly, upon increasing the temperature and/or pressure, the analysis reveals an abrupt transition from a diameter-independent growth rate that is limited by incorporation to a diameter-dependent growth rate that is limited by crystallization. The identification of two distinct growth regimes provides insight into the synthetic conditions needed for specific NW-based technologies, and our kinetic model provides a straightforward framework for understanding VLS growth with a range of metal catalysts and semiconductor materials. PMID- 24815745 TI - Plutonium desorption from mineral surfaces at environmental concentrations of hydrogen peroxide. AB - Knowledge of Pu adsorption and desorption behavior on mineral surfaces is crucial for understanding its environmental mobility. Here we demonstrate that environmental concentrations of H2O2 can affect the stability of Pu adsorbed to goethite, montmorillonite, and quartz across a wide range of pH values. In batch experiments where Pu(IV) was adsorbed to goethite for 21 days at pH 4, 6, and 8, the addition of 5-500 MUM H2O2 resulted in significant Pu desorption. At pH 6 and 8 this desorption was transient with readsorption of the Pu to goethite within 30 days. At pH 4, no Pu readsorption was observed. Experiments with both quartz and montmorillonite at 5 MUM H2O2 desorbed far less Pu than in the goethite experiments highlighting the contribution of Fe redox couples in controlling Pu desorption at low H2O2 concentrations. Plutonium(IV) adsorbed to quartz and subsequently spiked with 500 MUM H2O2 resulted in significant desorption of Pu, demonstrating the complexity of the desorption process. Our results provide the first evidence of H2O2-driven desorption of Pu(IV) from mineral surfaces. We suggest that this reaction pathway coupled with environmental levels of hydrogen peroxide may contribute to Pu mobility in the environment. PMID- 24815746 TI - Quantification of myocardial perfusion using cardiac magnetic resonance imaging correlates significantly to rubidium-82 positron emission tomography in patients with severe coronary artery disease: a preliminary study. AB - INTRODUCTION: Aim was to compare absolute myocardial perfusion using cardiac magnetic resonance imaging (CMRI) based on Tikhonov's procedure of deconvolution and rubidium-82 positron emission tomography (Rb-82 PET). MATERIALS AND METHODS: Fourteen patients with coronary artery stenosis underwent rest and adenosine stress imaging by 1.5-Tesla MR Scanner and a mCT/PET 64-slice Scanner. CMRI were analyzed based on Tikhonov's procedure of deconvolution without specifying an explicit compartment model using our own software. PET images were analyzed using standard clinical software. CMRI and PET data was compared with Spearman's rho and Bland-Altman analysis. RESULTS: CMRI results were strongly and significantly correlated with PET results for the absolute global myocardial perfusion differences (r=0.805, p=0.001) and for global myocardial perfusion reserve (MPR) (r=0.886, p<0.001). At vessel territorial level, CMRI results were also significantly correlated with absolute PET myocardial perfusion differences (r=0.737, p<0.001) and MPR (r=0.818, p<0.001). Each vessel territory had similar strong correlation for absolute myocardial perfusion differences (right coronary artery (RCA): r=0.787, p=0.001; left anterior descending artery (LAD): r=0.796, p=0.001; left circumflex artery (LCX): r=0.880, p<0.001) and for MPR (RCA: r=0.895, p<0.001; LAD: r=0.886, p<0.001; LCX: r=0.886, p<0.001). CONCLUSION: On a global and vessel territorial basis, CMRI-measured absolute myocardial perfusion differences and MPR were strongly and significantly correlated with the Rb-82 PET findings. PMID- 24815747 TI - Placement of hemoparin-coated stents in the iliac arteries: early experience and midterm results in 28 patients. AB - PURPOSE: Aim was to determine immediate results and mid-term outcome of the hemoparin-coated (HC) stainless-steel stent (camouflage coating) in the treatment of occlusive lesions of the iliac arteries. MATERIALS AND METHODS: Twenty-eight patients were prospectively treated with the use of a HC stent between January 2007 and March 2010. Clinical examination and color-doppler ultrasound were performed at 1, 3, 6 and 12 months, CT angiography (CTA) or MR angiography (MRA) at 12 months. Indication for treatment was a high-grade stenosis of the common iliac and/or external iliac artery. RESULTS: Successful placement was achieved in all patients. Significant decrease in translesional pressure gradient (>10 mm Hg) was measured in 27 patients (96%). In one patient, proximal dissection occurred without flow limitation. A minor complication (small access site hematoma) occurred in one patient (4%). Two patients (7%) were lost to follow-up. After 12 months, stent patency in CTA, MRA and ultrasound was 100%. 20 patients (77%) experienced an initial improvement of at least one clinical stage. In one patient (4%), mild intimal hyperplasia without significant stenosis was observed. In three patients (12%), proximal or distal stenosis occurred. A non-significant increase of mean ankle-brachial index (ABI) after treatment was measured (0.85 +/ 0.27 vs. 0.75 +/- 0.22, respectively; p=0.328). CONCLUSIONS: The use of HC stents in patients with iliac artery occlusive disease may lead to a lower rate of intimal hyperplasia and thus to increased patency rates even in heavily calcified vessels. However, large-scale prospective trials have to be performed to evaluate the long-term patency rates of the HC coated stents. PMID- 24815748 TI - Oocyte and sperm donors' opinions on the acceptable number of offspring. AB - OBJECTIVE: To investigate opinions on the acceptable number of donation offspring in a national cohort of oocyte and sperm donors. DESIGN: A prospective follow-up study on a national cohort of gamete donors. SETTING: Sweden. METHODS: Study specific questionnaire. MAIN OUTCOME MEASURES: Opinion on the acceptable number of offspring from one donor. RESULTS: About half of both oocyte and sperm donors expressed an opinion that the number of offspring from one donor should be limited to between one and 10, and many donors reported having no firm opinion. When controlling for age, educational level, marital status and biological children, oocyte donors were four times more likely than sperm donors to support an upper limit of five offspring. For many sperm and oocyte donors the number of offspring resulting from their donations was unknown (43.2% oocyte, 47.1% sperm). CONCLUSION: Oocyte donors have more restrictive opinions compared with sperm donors on the acceptable number of offspring from one donor. Donors perform a very humanitarian and societal act when donating their gametes. In the ambition to have safe and trustworthy clinics we need to have well known regulations to be able to recruit donors in the future. PMID- 24815749 TI - Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression. AB - In Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; cAMP) and in the activity of cAMP activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in cAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In Schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of cAMP and PKA activity that characterise mitosis are due to enhanced cAMP degradation by PDE4D9. PDE4D9, was found to locate primarily not only in the perinuclear region of Rat-1 cells but also at the cell margins. We propose that the sequestration of PDE4D9 in a specific complex together with AMPK, ERK, MK2 and the H2O2-activatable 'switch' kinase allows for its selective multi-site phosphorylation, activation and regulation in mitosis. PMID- 24815750 TI - Partial intravenous anaesthesia in the horse: a review of intravenous agents used to supplement equine inhalation anaesthesia. Part 1: lidocaine and ketamine. AB - OBJECTIVE: To review the literature with regard to the use of different intravenous agents as supplements to inhalational anaesthesia in horses. These drugs include lidocaine, ketamine, opioids and alpha2 -agonists. The Part 1 of this review will focus in the use of lidocaine and ketamine. DATABASES USED: Pubmed & Web of Science. Search terms: horse, inhalant anaesthesia, balanced anaesthesia, partial intravenous anaesthesia, lidocaine, ketamine. CONCLUSIONS: Different drugs and their combinations can be administered systemically in anaesthetized horses, with the aim of reducing the amount of the volatile agent whilst improving the recovery qualities and providing a multimodal analgesic approach. However, full studies as to whether these techniques improve cardiopulmonary status are not always available and potential disadvantages should also be considered. PMID- 24815751 TI - Characterization of barley serpin Z7 that plays multiple roles in malt and beer. AB - Barley protein Z7 (BSZ7) is a well-known serine protease inhibitor that was regarded as a major effector of beer foam stability. Moreover, it has also been suggested to participate in haze formation and affect wort filterability. The present study purified BSZ7 from barley malt and characterized its secondary structure and modification, as well as its relationship with peroxidase, to elucidate the molecular base of BSZ7 that supports its multiple roles in malt and beer. It was found that after 30 min of heating, the secondary structure was not affected. BSZ7 has no inhibiting effect on nonspecific protease originated from malt, suggesting its negative role in wort filterability was accomplished by other means. Furthermore, the glycation of BSZ7 by the Maillard reaction may make some contribution to its survival during wort boiling. The interaction of BSZ7 with polysaccharides and polyphenols found by adding experiment may explain how it acts as a negative factor on wort filterability. Greater understanding of BSZ7 and other proteins of malts will lead to better improvements in brewing quality. PMID- 24815752 TI - Guidelines for culturally effective psychiatric-mental health nursing worldwide. PMID- 24815753 TI - Recognizing real-life restraint use. PMID- 24815756 TI - Drugs to treat anxiety disorders. PMID- 24815757 TI - Delirium and its prevention with melatonergic drugs. AB - Delirium is a complex neurobehavioral syndrome caused by dysregulation of brain activity, characterized by an alteration in the level of attention and awareness, which develops over a short period of time and is seen as a change from the patient's baseline. Dysregulation of 24-hour circadian cycles, including melatonin secretion or activity, has suggested the potential therapeutic use of melatonergic drugs for delirium. Melatonin and the melatonin analog drug ramelteon have been shown to be effective in the prevention of delirium in three controlled studies. Additional studies using these drugs are warranted. PMID- 24815758 TI - Psychogenic non-epileptic seizures in the older adult. AB - Psychogenic non-epileptic seizures (PNES) are classified in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, as a functional neurological symptom disorder. This disorder is often misdiagnosed as epilepsy, with the consequence that older adults may have been treated for years for epilepsy before they learn their seizures are non-epileptic. Video electroencephalography monitoring, which is the standardized approach for ruling out epilepsy, is often performed in a specialized epilepsy monitoring unit where the patient lies in bed 24 hours per day waiting for a seizure to be recorded. The immobility, loss of independence, and anxiety that occurs during the monitoring process can be difficult for older adults. It is important for all nurses to be aware of PNES and to be sensitive to the unique needs of older adults who are experiencing these seizures. PMID- 24815761 TI - Long-term vascular responses to Resolute(r) and Xience V(r) polymer-based drug eluting stents in a rabbit model of atherosclerosis. AB - OBJECTIVES: To assess the late postinterventional response to iliac stenting in atheromatous rabbits using the Xience V everolimus-eluting stent (Xience V EES; Abbott Vascular) and the Resolute zotarolimus-eluting stent (Resolute ZES; Medtronic Vascular) with the MultiLink Vision bare metal stent (BMS; Abbott Vascular) as a reference. BACKGROUND: Xience V EES and Resolute ZES were developed to overcome shortcomings of first-generation DES. METHODS: Functional and microscopic changes were assessed by organ bath experiments and histopathologic examination. Gene expression was investigated using RT-PCR. RESULTS: After 91 days, re-endothelialization was nearly complete (BMS: 93 +/- 3%; Resolute ZES: 92 +/- 2%; Xience V EES: 94 +/- 3%; P = 0.10). Neointima thickness was similar in Resolute ZES (0.17 +/- 0.08 mm) and BMS (0.17 +/- 0.09 mm), and reduced in Xience V EES (0.03 +/- 0.01 mm; P < 0.0001). Xience V EES had less peri-strut inflammation compared with BMS (P = 0.001) and Resolute ZES (P = 0.0001), while arterial segments distal to Xience V EES were more sensitive to acetylcholine than those distal to BMS and Resolute ZES (P = 0.02). Lectin-like oxidized receptor-1 was overexpressed in stented arteries (P < 0.001), whereas thrombomodulin was downregulated in Resolute ZES (P = 0.01) and BMS (P = 0.02) compared to unstented arteries of rabbits on regular chow. No significant changes were seen for vascular cell adhesion molecule-1, nitric oxide synthase 3, or endothelin-1. CONCLUSIONS: At 3-month follow-up, nearly complete re endothelialization was achieved for all stent groups. Xience V EES induced greater suppression of neointimal growth and peri-strut inflammation, higher vasorelaxation to acetylcholine, and expression of thrombomodulin at the level of unstented controls. PMID- 24815762 TI - Use of bioresorbable plating systems in paediatric mandible fractures. AB - AIM: The aim of this study is to retrospectively evaluate the use of bioresorbable plating systems in the rigid fixation of paediatric mandible fractures. PATIENTS AND METHODS: Our series consists of fifteen paediatric patients (11 male, 4 female, average age 8.13 years) with mandible fractures of varying severity treated with bioresorbable plates over a 54-month period at our institution. Fractures of the ramus, body, parasymphysis, and symphysis were treated by one surgeon with open reduction and internal fixation with 1.5 mm and 2 mm resorbable plates and monocortical screws, using 3 different plating systems, each with differing polymer concentrations of polyglycolic and poly-L lactic acid. The patients were followed with respect to the following clinical categories: fracture location, postoperative occlusion, maximum interincisal opening (MIO), segmental mobility at the fracture site, and any abnormal swelling at the operative site. RESULTS: Our data shows a stable occlusion and maximum interincisal opening of thirty millimetres or greater was achieved in 14 of 15 patients seen in follow up, with 8 patients having an MIO of 40 mm or greater. No segmental mobility noted at any of the fracture sites. Thirteen patients had no postoperative sequelae or implant related complications. Two patients developed a seroma-like collection at the operative site. Postoperative films starting at 1 year showed significant bony osseous fill where the previous screw sites were located. CONCLUSIONS: In our case series we found that the use of resorbable polyglycolic and poly-L-lactic acid plating systems when combined with a brief postoperative period of intermaxillary fixation is an effective method of internal fixation for mandibular fractures in the paediatric population. PMID- 24815763 TI - Non-syndromic and syndromic keratocystic odontogenic tumors: systematic review and meta-analysis of recurrences. AB - BACKGROUND: Keratocystic odontogenic tumors (KCOTs) are locally aggressive benign tumors which occur in the bones of both jaws with a high recurrence rate. The aim of the present study was to define and evaluate the post-treatment recurrence of KCOT lesions in non-syndromic and syndromic patients. METHODS: A systematic review of the literature and meta-analysis was conducted according to the PRISMA statement. Seven electronic databases were searched from their start up to August 2013 for clinical studies on human patients without limitation to year, language or publication status. RESULTS: A total of five case series studies with 323 treated KCOT lesions were included in the quantitative synthesis. The recurrence rate of KCOTs for three treatment forms ranged from 7% to 28%. Comparisons among the various treatments suggest that resection or marsupialization might be associated with fewer recurrences. However, high risk of bias and effect imprecision preclude the making of clinical recommendation. Existing evidence regarding nevoid basal cell carcinoma patients was likewise scarce. CONCLUSIONS: The absence of studies with low risk of bias precludes the making of safe recommendations about the optimal management of KCOTs. PMID- 24815637 TI - Search for top squark and Higgsino production using diphoton Higgs boson decays. AB - Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top quark (the top squark) and the Higgs boson (Higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 fb-1 of proton-proton collision data at s=8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the top squark mass below 360 to 410 GeV, depending on the Higgsino mass. PMID- 24815764 TI - In vitro combinatorial anticancer effects of 5-fluorouracil and curcumin loaded N,O-carboxymethyl chitosan nanoparticles toward colon cancer and in vivo pharmacokinetic studies. AB - Colon cancer is the third most leading causes of death due to cancer worldwide and the chemo drug 5-fluorouracil's (5-FU) applicability is limited due to its non-specificity, low bioavailability and overdose. The efficacy of 5-FU in colon cancer chemo treatment could be improved by nanoencapsulation and combinatorial approach. In the present study curcumin (CUR), a known anticancer phytochemical, was used in combination with 5-FU and the work focuses on the development of a combinatorial nanomedicine based on 5-FU and CUR in N,O-carboxymethyl chitosan nanoparticles (N,O-CMC NPs). The developed 5-FU-N,O-CMC NPs and CUR-N,O-CMC NPs were found to be blood compatible. The in vitro drug release profile in pH 4.5 and 7.4 showed a sustained release profile over a period of 4 days. The combined exposure of the nanoformulations in colon cancer cells (HT 29) proved the enhanced anticancer effects. In addition, the in vivo pharmacokinetic data in mouse model revealed the improved plasma concentrations of 5-FU and CUR which prolonged up to 72 h unlike the bare drugs. In conclusion, the 5-FU and CUR released from the N,O-CMC NPs produced enhanced anticancer effects in vitro and improved plasma concentrations under in vivo conditions. PMID- 24815765 TI - Blepharochalasis: possibly associated with matrix metalloproteinases. AB - Blepharochalasis is a rare disorder characterized by recurrent episodic swelling of eyelids, eventually leading to atrophy of skin. Although immunological mechanisms may be involved in the degradation of elastic fibers, the pathogenesis is not well characterized. We report a 10-year-old Japanese boy with an 11-month history of the swelling of bilateral upper eyelids with atrophic skin. Attacks of non-painful swelling in eyelids with erythema have recurred several times a month and lasted for 2-3 days. Histological examination revealed perivascular and interstitial infiltration of lymphocytes in the dermis. Elastica Van Gieson staining showed a marked decrease of elastic fibers throughout the dermis. Results of direct and indirect immunofluorescence analyses were negative. Staining of matrix metalloproteinase (MMP)-3 and MMP-9 was observed in and around infiltrating cells in the dermis, suggesting that MMP-3 and MMP-9 may play, in part, roles in the development of blepharochalasis, and that inhibitor of MMP may have a possibility of therapeutic application. PMID- 24815771 TI - What is the optimal treatment for patients with atherosclerotic renal artery stenosis? PMID- 24815770 TI - Topographical and nano-mechanical characterization of native corneocytes using atomic force microscopy. PMID- 24815767 TI - Funding healthcare-associated infection research: a systematic analysis of UK research investments, 1997-2010. AB - BACKGROUND: Healthcare-associated infections (HCAIs) are a cause of high health and economic burden in the UK. The number of HCAI research studies funded in the UK, and the associated amount of investment, has not previously been analysed. AIM: To assess the level of research funding awarded to UK institutions for HCAI research and the relationship of funded research to clinical and public health burden of HCAIs. METHODS: Databases and websites were systematically searched for information on how infectious disease research studies were funded for the period 1997-2010. Studies specifically related to HCAI research were identified and categorized in terms of funding by pathogen, disease, and by a research and development value chain describing the type of science. FINDINGS: The overall dataset included 6165 studies (total investment L2.6 billion) of which L57.7 million was clearly directed towards HCAI research across 297 studies (2.2% of total spend, 2.1% of total studies). Of the HCAI-related projects, 45 studies had a specific focus on MRSA (L10.3 million), 14 towards Clostridium difficile (L10.7 million), two towards pneumonia (L0.3 million) and 103 studies related to surgical infections (L14.1 million). Mean and median study funding was L194,129 (standard deviation: L429,723) and L52,684 (interquartile range: L9,168 to L201,658) respectively. Award size ranged from L108 to L50.0 million. CONCLUSIONS: Research investment for HCAIs has gradually increased in the study period, but remains low due to the health, economic, and social burden of HCAI. Research for hospital-acquired pneumonia, behavioural interventions, economic analyses, and research on emerging pathogens exhibiting antimicrobial resistance remain underfunded. PMID- 24815768 TI - [Left vocal cord paralysis after patent ductus arteriosus surgery]. AB - INTRODUCTION: Patent ductus arteriosus (PDA) is a common problem in preterm newborns. Left vocal cord paralysis (LVCP) can complicate surgical closure if the recurrent nerve is damaged. MATERIALS AND METHODS: A retrospective case series study was conducted on preterm babies diagnosed with PDA in our unit from 1999 to 2013. Their clinical features and treatment complications were reviewed. In those patients that received surgical treatment a telephone questionnaire on the symptoms of LVCP symptoms was completed, and laryncoscopy examination offered. RESULTS: A total of 88 subjects diagnosed with PDA were found, of whom 13.64% (12/88) needed surgery. These patients had a lower gestational age and birth weight. They required mechanical ventilation more frequently, and they had more complications such as, diaphragmatic paralysis, bronchopulmonary dysplasia and intraventricular hemorrhage. One third (3/9) of the surgically treated patients had LVCP, and all of them had dysphonia (100% vs. 16.7%, p=.05). DISCUSSION: LVCP is a common complication of PDA surgery. Further studies are needed to determine its risk factors and its short and long-term consequences. PMID- 24815772 TI - Resident outcomes of person-centered care in long-term care: a narrative review of interventional research. AB - BACKGROUND: Person-centered care has been widely promoted in long-term care settings. It is commonly referred to as a core concept that guides the care philosophy change in long-term care settings from a traditional medical model to a more humanistic approach to care. Current person-centered practice in long-term care settings is guided by multiple person-centered care models. However, evidence regarding the effects of person-centered practice guided by multiple models on residents' outcomes has not been well established or synthesized. OBJECTIVES: To outline and compare the principal models and to synthesize current evidence of the effects of multiple person-centered care models on resident outcomes. METHOD: Systematic searches were conducted using CINAHL, MEDLINE, PsychoINFO, Evidence Based Medicine Reviews, Cochrane Review databases, and ProQuest Dissertations and Theses using the following keywords (UK and US spellings) individually and in multiple combinations: person-centered care, resident-centered care, client-centered care, individualized care, patient centered care, culture change, Eden Alternative, Wellspring, Green House, Pioneer Network, dementia, nursing home, assisted living and long-term care. The searches were limited to articles written in English and published from January 1990 to April 2013. Then a manual search of the reference lists of selected relevant articles was conducted. RESULTS: Twenty-four studies from three countries were reviewed and compared in terms of person-centered interventions, measurement, and resident outcomes. 15 culture change studies for residents who were cognitively intact or with minor cognitive impairment and 9 studies for residents with dementia were reviewed. Across the studies, culture change models had some beneficial effects on residents' psychological wellbeing. Person-centered dementia care had significant effects on decreasing behavioral symptoms and psychotropic medication use in dementia residents in long-term care. CONCLUSION: An agreed upon definition of person-centered care is essential for researchers and clinicians to guide person-centered care development and implementation. Rigorous study design and objective and subjective measurement use are needed for future studies, especially those guided by culture change models. The effectiveness of person-centered care on residents' bio-psycho-social outcomes like sleep, stress, and physical wellbeing need to be addressed and systematically examined with subjective and objective measures in future studies. PMID- 24815769 TI - Angiopoietin-like 4, a protein strongly induced during sebocyte differentiation, regulates sebaceous lipogenesis but is dispensable for sebaceous gland function in vivo. PMID- 24815766 TI - From lists of behaviour change techniques (BCTs) to structured hierarchies: comparison of two methods of developing a hierarchy of BCTs. AB - OBJECTIVES: Behaviour change technique (BCT) Taxonomy v1 is a hierarchically grouped, consensus-based taxonomy of 93 BCTs for reporting intervention content. To enhance the use and understanding of BCTs, the aims of the present study were to (1) quantitatively examine the 'bottom-up' hierarchical structure of Taxonomy v1, (2) identify whether BCTs can be reliably mapped to theoretical domains using a 'top-down' theoretically driven approach, and (3) identify any overlap between the 'bottom-up' and 'top-down' groupings. METHODS AND DESIGN: The 'bottom-up' structure was examined for higher-order groupings using a dendrogram derived from hierarchical cluster analysis. For the theory-based 'top-down' structure, 18 experts sorted BCTs into 14 theoretical domains. Discriminant Content Validity was used to identify groupings, and chi-square tests and Pearson's residuals were used to examine the overlap between groupings. RESULTS: Behaviour change techniques relating to 'Reward and Punishment' and 'Cues and Cue Responses' were perceived as markedly different to other BCTs. Fifty-nine of the BCTs were reliably allocated to 12 of the 14 theoretical domains; 47 were significant and 12 were of borderline significance. Thirty-four of 208 'bottom-up' * 'top-down' pairings showed greater overlap than expected by chance. However, only six combinations achieved satisfactory evidence of similarity. CONCLUSIONS: The moderate overlap between the groupings indicates some tendency to implicitly conceptualize BCTs in terms of the same theoretical domains. Understanding the nature of the overlap will aid the conceptualization of BCTs in terms of theory and application. Further research into different methods of developing a hierarchical taxonomic structure of BCTs for international, interdisciplinary work is now required. Statement of contribution What is already known on this subject? Behaviour change interventions are effective in improving health care and health outcomes. The 'active' components of these interventions are behaviour change techniques and over 93 have been identified. Taxonomies of behaviour change techniques require structure to enable potential applications. What does this study add? This study identifies groups of BCTs to aid the recall of BCTs for intervention coding and design. It compares two methods of grouping--'bottom up' and theory-based 'top-down'--and finds a moderate overlap. Building on identified BCT groups, it examines relationships between theoretical domains and BCTs. PMID- 24815773 TI - Development and preliminary validation of the Neonatal Infant Acute Pain Assessment Scale (NIAPAS). AB - BACKGROUND: Several pain scales are available for neonates, but, unfortunately they are only rarely used in clinical practice. To help with the current situation of unrecognized and under-treated pain in neonatal intensive care units (NICUs), we developed an assessment tool in close collaboration with clinical staff. OBJECTIVES: To develop a multidimensional scale, NIAPAS (the Neonatal Infant Acute Pain Assessment Scale), that is sensitive to the needs of infants in neonatal intensive care units, and to test the validity, reliability, feasibility and clinical utility of the scale for this population. DESIGN: Instrument development and psychometric analysis. METHODS: Pain assessments (n=180) were made of 34 neonates born between 23 and 42 weeks gestational age who were undergoing 60 painful procedures (heel lance 77%, tracheal suctioning 23%) in the NICU. Using bedside video recordings, each neonate was observed through three phases of the procedure: 1 min before the procedure, during the procedure (lasting from 0.6 to 11.2 min, mean 2.6), and 1 min after the procedure. In addition, an expert panel (n=5) and nurses (n=26) participated in the validation of the scale. RESULTS: A pool of 8 pain indicators (5 behavioral and 3 physiological indicators), including the gestational age of neonates as a contextual factor, was identified based on the nurses' expertise in neonatal intensive care. Scores on the NIAPAS changed significantly across the phases (p<0.001), indicating a good construct validity of the scale. Correlations between the NIAPAS and NIPS (the Neonatal Infant Pain Score) were high (0.751 0.873). The study also demonstrated high coefficients for inter-rater (r=0.991 0.997) and intra-rater reliability (r=0.992-1.00), with an internal consistency of 0.723. The content validity was very good (Mean I-CVI 1.00), as evaluated by the expert group. The nurses agreed that the scale was easy to administer and that it helped decision-making in the pain management of infants. CONCLUSIONS: The NIAPAS was shown to be a valid and reliable scale for assessing acute pain in preterm and full-term infants in the NICU. It allows nurses to evaluate infants' acute pain especially during painful procedures and help to provide pain relief for the infants. PMID- 24815774 TI - Analysis of humoral immune response and cytokines in chickens vaccinated with Eimeria brunetti apical membrane antigen-1 (EbAMA1) DNA vaccine. AB - This study aimed to determine the changes of cytokines, specific serum IgG and several parameters in chickens vaccinated with DNA vaccine encoding Eimeria brunetti apical membrane antigen-1 (EbAMA1) antigen. Two-week-old chickens were divided into five groups (four groups for experiment) randomly. Experimental groups of chickens were immunized with DNA vaccine while control group of chickens were injected with pVAX1 plasmid alone or TE buffer solution. All immunizations were boosted 2 weeks later. The EbAMA1 specific IgG antibody responses were measured at weeks 1-6 post-second immunizations and several parameters were also identified. The result showed that the antibody titers in chickens vaccinated with DNA vaccines were significantly different from those of the control groups 1 week after the second immunization and reached the maximum values 3 weeks post-second immunization. IFN-gamma concentration was increased the highest level against EbAMA1 of all chickens vaccinated with vaccines up to 56-fold, follow by the specific IgG antibody levels were increased 10-17-fold compared with those of TE solution and plasmid (pVAX1) control chickens 1-6 weeks post-second immunization. In case of the levels of IL-10 and IL-17 was increased in experimental chickens with 4-5-fold. Even though it was statistically significant, TGF-beta and IL-4 levels were higher in vaccinated than unvaccinated chickens. The results suggested that DNA vaccines encoding E. brunetti apical membrane antigen-1 (EbAMA1) could increase serum specific IgG antibody and cytokines concentration and could give protection against E. brunetti infection. PMID- 24815775 TI - Immunotherapy for human TB: evidence for adjuvant activities of some host defense peptides against TB. PMID- 24815777 TI - Could bystander killing contribute significantly to the antitumor activity of brentuximab vedotin given with standard first-line chemotherapy for Hodgkin lymphoma? AB - Evaluation of: Younes A, Connors JM, Park SI et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a Phase 1, open-label, dose-escalation study. Lancet Oncol. 14(13), 1348-1356 (2013). With exceptionally high response rates, the CD30-directed antibody-drug conjugate brentuximab vedotin (BV) was US FDA approved for treatment of patients with relapsed/refractory Hodgkin lymphoma (HL). Now in Phase I clinical trial, it has been shown that combining BV with multiagent chemotherapy (excluding bleomycin) as first-line treatment in HL patients with high-risk disease is feasible. Complete response rates were over 90% and toxicity was manageable. Given that the malignant cell population comprises a minority of HL lesions, and that BV releases a diffusible cytotoxin via a cathepsin B-cleavable linker, we argue that a significant proportion of the antitumor activity of BV can be attributed to bystander cytotoxicity in addition to direct killing of CD30-expressing malignant cells. PMID- 24815779 TI - The role of RixubisTM in the treatment of hemophilia B. AB - Hemophilia B is an inherited coagulopathy caused by the partial or complete deficiency of factor (F) IX. Factor replacement therapy, involving the intravenous infusion of plasma-derived or recombinant (r) FIX concentrate, is the cornerstone of treatment, used to control and prevent bleeding episodes. Although several plasma-derived FIX products are available, until recently, only a single rFIX concentrate was on the market. The aim of this paper is to review the pharmacokinetics, hemostatic efficacy, and safety of RixubisTM (Baxter Healthcare Corporation, CA, USA), a newly licensed rFIX product. PMID- 24815778 TI - Akt2 deficiency as a therapeutic strategy protects against acute lung injury. AB - Evaluation of: Vergadi E, Vaporidi K, Theodorakis EE et al. Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR 146a induction in mice. J. Immunol. 192, 394-406 (2013). Acute respiratory distress syndrome currently has limited effective treatments; however, recent evidence suggests that modulation of alveolar macrophage responses may be an effective method for protection or repair of lung injury. Vergadi et al. are the first to demonstrate that depletion of Akt2 kinase and microRNA-146a induction in mice resulted in polarization of alveolar macrophages towards an M2 activation phenotype and resulted in less severe injury following acid-induced lung injury. However, this M2 polarization also resulted in increased lung bacterial load following infection with Pseudomonas aeruginosa. PMID- 24815780 TI - Use of a multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) for bacterial meningitis prevention. AB - Developing effective vaccines against Neisseria meningitidis serogroup B has been challenging for several reasons, including the fact that the capsular polysaccharide of N. meningitidis serogroup B is a poor antigen. Therefore, studies have focused on developing vaccines that target capsular protein meningococcal antigens using reverse vaccinology, a technique that predicts likely vaccine candidates using computational analysis of the whole bacterial genome. This has resulted in a multicomponent, recombinant, meningococcal serogroup B vaccine: 4CMenB (Bexsero((r)), Novartis Vaccines & Diagnostics, NC, USA), containing four main immunogenic components: two recombinant fusion proteins (Neisseria heparin-binding antigen-GNA1030 and factor H-binding protein GNA2091); recombinant Neisserial adhesion A; and detergent-treated outer membrane vesicles derived from the meningococcal NZ98/254 strain, where porin A 1.4 is the major immunodominant antigen. In this article, we summarize the available clinical data on 4CMenB in healthy infants, adolescents and adults, and discuss the methods available for assessing vaccine efficacy. PMID- 24815781 TI - Irradiated mononuclear cells express significant in vitro cytotoxic activity: promise for in vivo clinical efficacy of irradiated mismatched donor lymphocytes infusion. AB - BACKGROUND: Relapse of the original disease remains the most common cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo SCT). Patients who relapse post-allo-SCT can achieve prolonged remission after donor lymphocyte infusion. Donor lymphocyte infusion as well as other immunotherapeutic strategies are usually complicated by severe graft versus host disease. AIM: In the present study, we examined the effect of irradiation on the cytotoxic activity of mononuclear cells (MNCs). MATERIALS & METHODS: Cytotoxic activity of fresh and irradiated MNCs from healthy donors was tested against the leukemic cell line K562 and against fresh leukemic cells from patients with acute myeloid leukemia. Cytotoxicity was assessed by using a flow-cytometry assay. RESULTS & DISCUSSION: Interestingly, we observed that 25 Gy irradiated MNCs retain significant cytotoxic activity against K562. Based on these in vitro data, the safety and efficacy of irradiated haploidentical, IL-2-activated lymphocytes were tested in six patients after allo-SCT. Acute skin graft versus host disease developed in two patients and was resolved after a short course of steroids. One patient with mixed chimera converted to full donor chimera after infusion of irradiated donor cells. CONCLUSION: The efficacy of irradiated haploidentical lymphocytes should be further tested in a larger number of patients. PMID- 24815782 TI - Minimizing immunosuppression in islet xenotransplantation. AB - Pancreatic islet transplantation is a promising treatment option for Type 1 diabetes, but organ supply shortage limits its wide adoption. Pig islets are the most promising alternative source and many important measures such as donor animal selection, pig islet production release criteria, preclinical data and zoonosis surveillance prior to human clinical trials have been put forward as a consensus through the efforts of the International Xenotransplantation Association. To bring pig islet transplantation to clinical reality, the development of clinically applicable immunosuppression regimens and methods to minimize immunosuppression to reduce side effects should be established. This review encompasses immune rejection mechanisms in islet xenotransplantation, immunosuppression regimens that have enabled long-term graft survival in pig-to nonhuman primate experiments and strategies for minimizing immunosuppression in islet xenotransplantation. By thoroughly examining the drugs that are currently available and in development and their individual targets within the immune response, the best strategy for enabling clinical trials of pig islets for Type 1 diabetes will be proposed. PMID- 24815783 TI - Radioimmunotherapy with alpha-particle-emitting radionuclides. AB - alpha-particle-emitting radionuclides are highly cytotoxic and are thus promising candidates for use in targeted radioimmunotherapy of cancer. Due to their high linear energy transfer (LET) combined with a short path length in tissue, alpha particles cause severe DNA double-strand breaks that are repaired inaccurately and finally trigger cell death. For radioimmunotherapy, alpha-emitters such as (225)Ac, (211)At, (212)Bi/(212)Pb, (213)Bi and (227)Th are coupled to antibodies via appropriate chelating agents. The alpha-emitter immunoconjugates preferably target proteins that are overexpressed or exclusively expressed on cancer cells. Application of alpha-emitter immunoconjugates seems particularly promising in treatment of disseminated cancer cells and small tumor cell clusters that are released during the resection of a primary tumor. alpha-emitter immunoconjugates have been successfully administered in numerous experimental studies for therapy of ovarian, colon, gastric, blood, breast and bladder cancer. Initial clinical trials evaluating alpha-emitter immunoconjugates in terms of toxicity and therapeutic efficacy have also shown positive results in patients with melanoma, ovarian cancer, acute myeloid lymphoma and glioma. The present problems in terms of availability of therapeutically effiective alpha-emitters will presumably be solved by use of alternative production routes and installation of additional production facilities in the near future. Therefore, clinical establishment of targeted alpha-emitter radioimmunotherapy as one part of a multimodal concept for therapy of cancer is a promising, middle-term concept. PMID- 24815785 TI - Immunosuppressive drugs for the treatment of autoimmune pancreatitis. AB - Autoimmune pancreatitis is one of the few diseases of the pancreas characterized by the possibility of curing the illness using immunosuppressant drugs. In this paper, the therapeutic approach used to treat autoimmune pancreatitis patients and the clinical outcome related to each treatment modality were reviewed. Steroids are useful in alleviating the symptoms of the acute presentation of autoimmune pancreatitis, but some questions remain open, such as a shared definition of the disease's remission as well as autoimmune pancreatitis relapse, the dosage of steroids in the symptomatic phase of the disease and the duration of steroid therapy. Finally, it should be determined if other immunosuppressive nonsteroidal drugs could become first-line therapy in patients with autoimmune pancreatitis without jaundice and without atrophic pancreas. PMID- 24815784 TI - Harnessing the power of the immune system via blockade of PD-1 and PD-L1: a promising new anticancer strategy. AB - Cancer cells employ several mechanisms to evade the immune system of their host, thus escaping immune recognition and elimination. Of particular interest is a cancer cell's ability to co-opt the immune system's innate ligands and inhibitory receptors (also known as checkpoints), thus creating an immunosuppressive microenvironment that downregulates T-cell activation and cell signaling. The recent development of the checkpoint inhibitors anti-programmed death-1 and anti programmed death ligand-1 has generated an enormous amount of interest as a potential new anticancer strategy in solid tumors, particularly in non-small-cell lung cancer, renal cell carcinoma and melanoma. Data suggest significant disease response rates using anti-programmed death-1 and anti-programmed death ligand-1 antibodies, even in heavily pretreated patients. Future directions include optimization of drug delivery sequence and combination of immunotherapy with other therapies including cytotoxic chemotherapy, radiation, antiangiogenic agents and small-molecule tyrosine kinase inhibitors. PMID- 24815786 TI - Dendritic cell vaccine against leukemia: advances and perspectives. AB - As with many other types of malignancies, sustainable eradication of leukemia has been a challenge. This is related to the inevitable failure of conventional chemotherapeutic agents and radiation therapy to target the relatively quiescent leukemia stem cells, which are believed to have multidrug resistance, antiapoptotic capacity and enhanced DNA repair mechanisms allowing them to evade the immune system. Considering other therapeutic options that are minimally toxic to normal cells and effectively target not only the majority and more differentiated cancer cells, but also the rare residual leukemia cells, is of paramount importance. A number of immunotherapeutic options have been proposed to counter this challenge. One of the remarkable achievements in the field of immunotherapy has been the successful use of antigen presenting cells as vehicles of tumor/pathogenic antigens to the T-cell compartments. This review will focus on advances and perspectives of this arm of immunotherapy against leukemia. PMID- 24815787 TI - Topical tacrolimus for recurrent penile Crohn's disease. PMID- 24815788 TI - Mechanism, reactivity, and selectivity in Rh(III)-catalyzed phosphoryl-directed oxidative C-H activation/cyclization: a DFT study. AB - Density functional theory calculations (DFT) have been performed on Rh(III) catalyzed phosphoryl-directed oxidative C-H activation/cyclization to investigate the detailed mechanism, including four basic steps: C-H activation, alkyne insertion, reductive elimination, and catalyst recycling, each of which consists of different steps. Interestingly, the Rh(III)-AgOAc catalyst system was found to be more favorable in the C-H activation step in comparison with the Rh(III) Ag2CO3 system, whereas the Rh(I)-Ag2CO3 catalyst system was more efficient for catalyst recycling. Importantly, our calculations suggest that the alkyne insertion process is a reversible step. Reductive elimination is the rate determining step with an activation energy of 25.0 kcal/mol. In addition, the origin of the reactivity and selectivity difference between diarylacetylenes and dialkylacetylenes or electron-rich and electron-deficient diarylacetylenes was probed by means of comparative DFT calculations. The calculation results show that the electronic effects of alkynes play a key role in the reactivity and selectivity, in line with the experimental observations that diarylacetylenes and electron-rich diarylacetylenes are more reactive than dialkylacetylenes and electron-deficient diarylacetylenes, respectively. Our findings should be useful for further developments of transition-metal-catalyzed C-H activation reactions. PMID- 24815789 TI - Hypnic jerks: neurophysiological characterization of a new motor pattern. PMID- 24815790 TI - [Influence of resistance to voices on depression]. AB - OBJECTIVE: Beliefs about voices and reactions to voices have been proposed as important variables influencing the course of depression in schizophrenia. Consequences of auditory hallucinations are different according to identity, goals, omnipotence, omniscience, and meanings attributed to voices by the client. Ten to 15 % of the general population experience auditory hallucinations during lifetime without any distress or need for medical care. In addition, neither frequency of voices, nor their topography, influence the emotional consequences of auditory hallucinations experiences, but the relationships to voices. The Revised Belief about Voices Questionnaire analyzes voices along 5 dimensions: malevolence, benevolence, omnipotence, resistance, and engagement. Malevolent voices are related to depression, whereas benevolent voices engender more positive emotions. Subjects usually engage with benevolent voices, and resist to malevolent voices. But resistance strategies are barely efficient and often backfire. Patients resisting to their voices consider them more malevolent and present with more depressive symptoms. This research aims at studying the influence of resistance to auditory hallucinations on depression in a group of patients suffering from schizophrenia and experiencing auditory hallucinations, using the Revised Beliefs About Voices Questionnaire (BAVQ-R). It also provides a study of the psychometrics properties of the French language version of the BAVQ R. METHOD: Thirty-eight patients suffering from paranoid schizophrenia, undifferentiated schizophrenia or schizoaffective disorder, have been tested with the French versions of the Revised Beliefs About Voices Questionnaire (BAVQ-R), the Positive and Negative Syndrome Scale (PANSS), and the Calgary Depression Scale for Schizophrenia (CDSS). Each patient presented with auditory hallucinations during the week before evaluation, with a minimum score of 3 on P3 item of PANSS. Mean age was 39.39 years (SD 11.33); mean duration of symptoms was 13.92 years (SD 10.81), and patients' mean history of hospitalizations was 7.66 (SD 9.24). Each patient was receiving an antipsychotic medication at the time of evaluation, with a mean chlorpromazine equivalent dose of 806.69 mg/d (ET 539.51); 18.5 % of patients were receiving serotonin reuptake inhibitor, and 31.57 % once committed a suicide attempt. RESULTS: The French version of the BAVQ R presents with a satisfying internal consistency (Cronbach's alpha=0.74). Similar to the original version, Malevolence and Resistance, and Benevolence and Engagement dimensions are strongly correlated (r=0.73, and r=0.90, P<0.05, respectively). The BAVQ-R scores correlate with the CDSS (r=0.40, P<0.05) and the PANSS General Psychopathology subscale scores (r=0.44, P<0.05), but not with the Positive and Negative subscales. (r=0.17, and r=0.13, P>0.05, respectively). Correlations and forced entry multiple regressions analyses show that Resistance and Malevolence are both strongly correlated to depression, but Resistance is the only dimension that influences depression. Moreover, clients presenting with depressive symptoms resist more to their auditory hallucinations. Finally, emotional resistance, in comparison to behavioral resistance, is responsible for depression in people suffering from auditory hallucinations. CONCLUSION: Emotional resistance to auditory hallucinations constitutes the most important variable influencing depression in schizophrenia comparing to what the voices say or are supposed to know, their malevolence or benevolence. Demonstration of the influence of resistance to voices on depression would help the development of new therapeutic practices. PMID- 24815791 TI - [Should hospitalization be required after the emergency discharge of patients with borderline personality disorder who have attempted suicide (FRENCH CRISIS cohort)?]. AB - BACKGROUND: Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability and impulsivity. There is a high prevalence of BPD patients among those admitted to the emergency department for suicide attempts. However, little empirical research exists to assist clinicians in deciding whether to hospitalize a suicidal patient. Some authors have argued that hospitalization does not prevent suicide and could actually harm these patients, thereby leading to psychosocial regression. Parasuicidal behaviors could be reinforced by the attention given during hospitalization. OBJECTIVE: Our purpose was to determine whether the hospitalization of suicidal patients who have a high risk of BPD after discharge from the emergency department is associated with a recurrence of suicidal behavior at 6months. METHOD: We designed a prospective study, acquiring patients from three emergency hospitals. The participants were suicidal subjects admitted for voluntary drug intoxication and were 18years of age or older. The participants completed the Personality Disorder Questionnaire (PDQ-4+) to assess BPD symptomatology. Information on the recurrence of suicidal behavior at 6months was obtained by interview of patients and the review of the charts from the 3 hospitals involved in the study. Other assessments included the BDI-13 (severity of depression), the Hopelessness Scale (hopelessness), the TAS 20 (alexythymia), the AUDIT (alcohol disorder) and the MINI (axis I disorders). RESULTS: A total of 606 subjects admitted for a suicide attempt participated in this study. A total of 320 (52.8 %) of the subjects completed the PDQ-4+. The sample was divided into three groups: participants at high risk of having at least one BPD (n=197), a group at high risk of having at least one non-BPD PD (n=84) and a group with low risk of having a PD (n=39). Hospitalization following an emergency was not associated with a recurrence of suicide attempts at 6months among patients at high risk of BPD. A logistical regression analysis showed pre hospitalization antidepressant prescription to be associated with recidivism (OR=2.1, P=.037). CONCLUSION: Our exploratory study suggests that hospitalization may not increase suicide attempts among patients with BPD when the health organization does not include a specific device such as DBT. PMID- 24815792 TI - [Cannabis use and antisocial behaviors in high-school students]. AB - OBJECTIVE: The aim of the study was to evaluate the contribution of cannabis to the prediction of delinquent behaviors. METHOD: Participants were 312 high-school students who completed self-report questionnaires measuring antisocial behaviors, the frequency of cannabis and alcohol use, psychopathic traits using the Youth Psychopathic traits Inventory, borderline traits, depressive symptoms, socio economic status, life events, attachment to parents, and low academic achievement. Hierarchical multiple regression analyses were conducted to investigate the contribution of cannabis use and potential confounding variables to antisocial behaviors. RESULTS: Boys reported a greater number of delinquent behaviors than girls (10.2+/-9.2 vs. 5.4+/-5.3, t=9.2, P<0.001). Thirty-seven percent of boys and 24 % of girls reported having used cannabis at least once during the last six months (P<0.001). Among cannabis users, boys reported a greater frequency of use than girls: average use for boys was 2-3 times per month whereas average use for girls was once a month (3.4+/-2.3 vs. 2.6+/-2, t=2.9, P=0.004). Cannabis users reported a greater number of antisocial behaviors than non-users (13.2+/-9.9 vs. 6.1+/-6.3, t=13.6, P<0.001). Multiple regression analyses showed that cannabis use was a significant independent predictor of antisocial behaviors in both gender (beta=.35, P<.001 in boys, beta=.29, P<.001 in girls) after adjustment for alcohol use, psychopathological and sociofamilial variables. DISCUSSION: The unique and independent association between frequency of cannabis use and antisocial behaviors does not indicate the causal direction of the relationship. It may be that cannabis use induces antisocial behaviors by enhancing impulsivity or irritability or by the need for money to buy cannabis. Conversely, antisocial behaviors may lead to cannabis use either through becoming used to transgressions or through the influence of delinquent peers using cannabis. This link is probably bidirectional, cannabis use and antisocial behaviors influencing mutually in a negative interactive spiral. This association suggests that these two problems are to be jointly approached when treating adolescents using cannabis or having antisocial behaviors. PMID- 24815793 TI - Establishing a critical-size mandibular defect model in growing pigs: characterization of spontaneous healing. AB - PURPOSE: A large animal model is desired for preclinical studies aimed at reconstructing severe mandibular skeletal defects using tissue engineering techniques. To identify the size and location requirements for a mandibular critical-size bone defect in growing pigs, the present study investigated the spontaneous healing of surgically created mandibular defects. MATERIALS AND METHODS: Six 4-month-old domestic pigs were used. In pigs 1 and 2, a 3-, 5-, or 7 cm(3) subperiosteal mandibular defect was created. In pigs 3 to 6, 3- to 5-cm(3) bilateral defects were randomly created at the anterior (apical to the molars) and posterior (mandibular angle) mandibular regions. Spontaneous healing of these defects was assessed by serial computed tomography scans (postoperative week 1, 6, and 12) and histologic analyses. RESULTS: In pigs 1 and 2, regardless of defect size, the anterior, but not posterior, defects had largely healed. Systematic analyses of pigs 3 to 6 revealed, first, the extent of defect regeneration from spontaneous healing was significantly less in the posterior than in the anterior defects, with about two thirds and one third of the original defect volume remaining, respectively. Second, histologically, the posterior defects had considerably less regeneration and more evident tapering of the new bone than did the anterior defects. Finally, the buccal periosteum had completely regenerated in the anterior defects, but had only partially done so in the posterior defects. Also, the buccal surface contour was moderately concave in the anterior defects, but it was severely concave in the posterior defects. CONCLUSIONS: Despite robust spontaneous healing of mandibular defects in growing pigs, 5-cm(3) defects in the mandibular angle region without buccal periosteum would be a reasonable critical-size defect model relevant to mandibular defects in adolescent humans. PMID- 24815794 TI - Facial abnormalities in Nablus mask-like facial syndrome: multidetector computed tomography findings. AB - Nablus mask-like facial syndrome (NMLFS) is a rare microdeletion syndrome characterized by a mask-like facial appearance. NMLFS has been reported in only 6 patients and has a recognizable facial appearance, along with other clinical features. The first case of NMLFS has been described by Teebi in 2000, in a 4 year-old Palestinian boy. Three years later, Salpietro et al reported a second example of NMLFS in a 21-month-old girl. The same patient recently came to our hospital to undergo a computed tomography (CT) study to evaluate the degree of development of the zygomatic-maxillary region for orthodontic treatment and orthognathic surgery. To the best of our knowledge, no reports have previously illustrated the maxillofacial CT findings of NMLFS in the radiologic data. We report the multidetector CT (MDCT) facial characteristics/abnormalities of this syndrome, emphasizing the usefulness of multiplanar reformations (MPRs) in preoperative planning. PMID- 24815795 TI - Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension. AB - BACKGROUND: In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous epoprostenol improved 6-minute walk distance (6MWD) and hemodynamics and delayed time to clinical worsening in a 16-week randomized, placebo controlled trial (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil [PACES-1]). METHODS: Patients completing PACES-1 could receive sildenafil (titrated to 80 mg, three times daily, as tolerated) in an open-label extension study (PACES-2) for >= 3 years; additional therapy was added according to investigator judgment. Survival and changes from PACES-1 baseline in World Health Organization Functional Class and 6MWD were captured. RESULTS: In an open-label setting, 6MWD, an effort-dependent outcome measure, was known to have improved or to have been maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively; functional class was known to have improved or to have been maintained in 73%, 59%, and 46%. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD < 325 meters without 6MWD improvement during the first 20 weeks of sildenafil treatment subsequently had poorer survival. CONCLUSIONS: Although reliable assessments of safety and efficacy require a long-term randomized trial, the addition of sildenafil to background intravenous epoprostenol therapy appeared generally to be well tolerated in PAH patients. PMID- 24815796 TI - A little bit of leak goes a long way. PMID- 24815798 TI - Somatic symptoms in survivors of critical illness. PMID- 24815799 TI - Do we know the real benefits of PCV13? PMID- 24815800 TI - Effectiveness of neuraminidase inhibitors for severe influenza. PMID- 24815801 TI - Pulmonary hypertension: smaller kids, smaller steps. PMID- 24815802 TI - Extracorporeal lung support for COPD reaches a crossroad. PMID- 24815803 TI - Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study. AB - BACKGROUND: Critical illness is associated with cognitive impairment, but mental health and functional disabilities in survivors of intensive care are inadequately characterised. We aimed to assess associations of age and duration of delirium with mental health and functional disabilities in this group. METHODS: In this prospective, multicentre cohort study, we enrolled patients with respiratory failure or shock who were undergoing treatment in medical or surgical ICUs in Nashville, TN, USA. We obtained data for baseline demographics and in hospital variables, and assessed survivors at 3 months and 12 months with measures of depression (Beck Depression Inventory II), post-traumatic stress disorder (PTSD, Post-Traumatic Stress Disorder Checklist-Event Specific Version), and functional disability (activities of daily living scales, Pfeffer Functional Activities Questionnaire, and Katz Activities of Daily Living Scale). We used linear and proportional odds logistic regression to assess the independent associations between age and duration of delirium with mental health and functional disabilities. This study is registered with ClinicalTrials.gov, number NCT00392795. FINDINGS: We enrolled 821 patients with a median age of 61 years (IQR 51-71), assessing 448 patients at 3 months and 382 patients at 12 months after discharge. At 3 months, 149 (37%) of 406 patients with available data reported at least mild depression, as did 116 (33%) of 347 patients at 12 months; this depression was mainly due to somatic rather than cognitive-affective symptoms. Depressive symptoms were common even among individuals without a history of depression (as reported by a proxy), occurring in 76 (30%) of 255 patients with data at 3 months and 62 (29%) of 217 individuals at 12 months. Only 7% of patients (27 of 415 at 3 months and 24 of 361 at 12 months) had symptoms consistent with post-traumatic distress disorder. Disabilities in basic activities of daily living (ADL) were present in 139 (32%) of 428 patients at 3 months and 102 (27%) of 374 at 12 months, as were disabilities in instrumental ADL in 108 (26%) of 422 individuals at 3 months and 87 (23%) of 372 at 12 months. Mental health and functional difficulties were prevalent in patients of all ages. Although old age was frequently associated with mental health problems and functional disabilities, we observed no consistent association between the presence of delirium and these outcomes. INTERPRETATION: Poor mental health and functional disability is common in patients treated in intensive-care units. Depression is five times more common than is post-traumatic distress disorder after critical illness and is driven by somatic symptoms, suggesting approaches targeting physical rather than cognitive causes could benefit patients leaving critical care. FUNDING: National Institutes of Health AG027472 and the Geriatric Research, Education and Clinical Center (GRECC), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System. PMID- 24815804 TI - Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: a time series analysis. AB - BACKGROUND: In March 2010, 13-valent pneumococcal conjugate vaccine (PCV13) replaced the seven-valent vaccine in the USA. We assessed the effect of PCV13 use on pneumococcus-related admissions to hospital 2 years after the vaccine was introduced, when coverage in children younger than age 5 years had reached 54%. METHODS: We used data from a private inpatient discharge record database. We extracted age-specific data for admissions to hospital per month (July 1-June 30) for all-cause pneumonia, invasive pneumococcal disease, non-invasive pneumococcal pneumonia, and empyema (all coded by International Classification of Diseases 9) for 2005-12. We also extracted data for urinary tract infection and hospital admission for any reason as control outcomes. We assessed incidences of hospital admission before and after the introduction of PCV13 and used a negative binomial multiple regression model to estimate how much of the change in hospital admissions could be attributed to the vaccine. FINDINGS: Our model results showed that PCV13 was associated with significant reductions in hospital admissions for all-cause pneumonia for some children (21% [95% CI 14-28] in children aged <2 years, 17% [7-27] in those aged 2-4 years) and for empyema (50% [95% CI 22-68] for children age <2 years, 46% [21-64] for 2-4 years, and 37% [13-54] for 5-17 years). All-cause pneumonia was significantly reduced in adults aged 18-39 years (12% (6-17) but not for other adult age groups. The vaccine also reduced admissions for invasive pneumococcal pneumonia and non-invasive pneumococcal or lobar pneumonia in children and adults, indicating herd protection, although the reduction was only significant in some age groups. INTERPRETATION: Only 2 years into the US programme, PCV13 significantly reduced residual invasive and non invasive pneumococcal hospital admissions in children younger than 5 years, as well as in some adult age groups. Our study design captured the total prevented hospital burden (directly and indirectly by herd protection) and also showed a reversal of the PCV7 era increase in paediatric empyema related to strain replacement. FUNDING: Pfizer. PMID- 24815806 TI - Genetic determinants of pulmonary fibrosis: evolving concepts. AB - Interstitial lung diseases encompass a wide range of diffuse lung disorders that are often complicated by the development of pulmonary fibrosis and that can occur in isolation or in systemic diseases. In the past decade, availability of high throughput genotyping and large collaborative clinical networks has led to the identification of many genetic variants associated with sporadic and familial fibrotic interstitial pneumonias. Susceptibility to idiopathic pulmonary fibrosis seems to involve a combination of polymorphisms related to epithelial cell injury and dysfunction and abnormal wound healing, whereas chronic inflammation seems important in the development of pulmonary fibrosis in sarcoidosis or collagen vascular diseases such as systemic sclerosis or rheumatoid arthritis; however, each of the disease-associated variants typically has a small effect and they are therefore not helpful in prediction of risk. Genetic studies have substantially expanded understanding of the pathogenesis of pulmonary fibrosis. Future challenges will be to assess how multiple susceptibility alleles interact with each other and environmental factors to determine disease risk and several different phenotypes, to define the mechanism of action and cellular pathways involving susceptibility alleles, and to identify which of the gene products and molecular mechanisms implicated in disease pathobiology are good therapeutic targets. PMID- 24815807 TI - Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT--authors' reply. PMID- 24815808 TI - Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT. PMID- 24815809 TI - Analysis of left atrial performance in patients with type 2 diabetes mellitus without overt cardiac disease and inducible ischemia: high prevalence of increased systolic force related to enhanced left ventricular systolic longitudinal function. AB - OBJECTIVES: In patients with chronic pressure overload, higher left atrial systolic force (LASF) is associated with high-risk cardiovascular (CV) phenotype, with increased left ventricular (LV) mass, concentric hypertrophy, and diastolic dysfunction. In hypertension and aortic stenosis, LASF predicts increased rate of CV events independent of traditional risk factors. Moreover, LASF is an independent predictor of heart failure in diabetic and nondiabetic patients. Limited data are available about LASF and its relationship with LV systolic function in type 2 diabetes mellitus (T2DM). METHODS: We used baseline clinic and echocardiographic data from 333 patients recruited in the SHORTWAVE study evaluating LV and left atrial performance in T2DM patients without cardiac disease. LASF was calculated by Manning's method and defined high when exceeded 16 Kdynes (90th percentile of LASF found in 120 healthy subjects used as controls). RESULTS: Mean LASF was 15.8 A +/- 9.4 Kdynes/cm(2) and showed a close positive correlation with peak mitral annular systolic velocity (function of LV longitudinal fibers), independent of E/E', age, systolic blood pressure, heart rate, and concentric geometry (multiple R = 0.57, P < 0.0001). Such independent correlation (tested in patients with and without concomitant hypertension) was confirmed at multiple logistic regression analysis where patients were dichotomized for having high (119 = 36%) or normal LASF. CONCLUSIONS: High LASF is present in one third of T2DM patients without overt cardiac disease and is positively and independently related to an increased LV longitudinal shortening function, suggesting a close interaction between LV systolic and diastolic function. PMID- 24815805 TI - Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. AB - BACKGROUND: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0.81; 95% CI 0.70-0.93; p=0.0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0.48; 95% CI 0.41-0.56; p<0.0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0.50; 95% CI 0.37-0.67; p<0.0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1.23] [95% CI 1.18-1.28]; p<0.0001 for the increasing HR with each day's delay). INTERPRETATION: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING: F Hoffmann-La Roche. PMID- 24815810 TI - Evaluation of the auditory evoked potentials derived aepEX(TM) as a measure of hypnotic depth in pediatric patients receiving sevoflurane-remifentanil anesthesia. AB - BACKGROUND: The aepEX is a measure of depth of hypnosis (DoH), derived from processed mid-latency auditory evoked potentials. OBJECTIVES: To evaluate the aepEX as a measure of DoH in children receiving sevoflurane-remifentanil anesthesia. METHODS: aepEX and bispectral index (BIS) were recorded simultaneously in 75 children, (1-3, 3-6, and 6-18 years), receiving sevoflurane at endtidal concentrations (ETsevo ) between 1.5 and 0.5 MAC. The ETsevo at which the aepEX and BIS had a value of 50 (EC50aep EX and EC50BIS ) was calculated by nonlinear regression analysis. The accuracy of aepEX and BIS to predict the DoH was assessed by prediction probability (Pk ) and receiver operating characteristics (ROC) analysis. RESULTS: Seventy-four children were included for analysis. The EC50aep EX (2.68%) and EC50BIS (2.10%) were comparable; the same accounts for the EC50aep EX of the different age groups and the EC50aep EX and EC50BIS of corresponding age groups. The EC50BIS in children aged 1-3 years was lower than in the older age groups (P < 0.05). Pk values of the aepEX (0.32, CI 95% 0.08-0.56) and BIS (0.47, CI 95% 0.19-0.75) were comparable. The area under the ROC curve was 0.72 (CI 95%: 0.62-0.82) and 0.67 (CI95%: 0.56-0.77) for the aepEX and BIS, respectively (P = 0.54). Optimal cutoff values were >60 (aepEX) and >68 (BIS), with corresponding specificities 91%, CI 95%: 80-97% (aepEX) and 66%, CI 95%: 52-77% (BIS). CONCLUSIONS: In this study with children receiving sevoflurane anesthesia, the aepEX outperformed the BIS in distinguishing unconsciousness from consciousness. Both indices performed equally bad in differentiating different levels of DoH. PMID- 24815811 TI - Cell-free nucleic acids in (maternal) blood: any relevance to (reproductive) immunologists? AB - Cell-free foetal DNA recently hit the international headlines by facilitating the non-invasive prenatal testing (NIPT) of foetal chromosomal anomalies directly from maternal blood samples. Being largely of placental origin, cell-free foetal DNA may also, however, provide insight into underlying pathological changes in preeclampsia, or the influences of external stresses, such as hypoxia. This analysis may be enhanced by the simultaneous assessment of placenta-derived, cell free mRNA species. The source of maternal cell-free DNA is not readily apparent, but may involve neutrophil extracellular traps (NETs). The rapid rise in this material following removal of the placenta, especially in preeclampsia, may indicate a rapid transient maternal inflammatory response to placenta-derived debris. Since NETs have recently been shown to promote coagulation, this may provide a link to pregnancy-associated thrombosis or placental infarction. The presence of cell-free, placenta-derived DNA may not be as innocuous as commonly assumed, as it is largely hypomethylated and could, like bacterial DNA, trigger the activation of maternal immune effector cells via interaction with toll-like receptor 9 (TLR9), thereby contributing to an excessive inflammatory response in preeclampsia or preterm labour. Possibly the most fascinating aspect concerning placenta-derived, cell-free nucleic acids is the recent report that placental exosomes loaded with placenta-specific C19MC miRNA species may modulate the antiviral response of maternal immune cells, thereby ensuring foetal well-being. PMID- 24815812 TI - Parallel evolution of cox genes in H2S-tolerant fish as key adaptation to a toxic environment. AB - Populations that repeatedly adapt to the same environmental stressor offer a unique opportunity to study adaptation, especially if there are a priori predictions about the genetic basis underlying phenotypic evolution. Hydrogen sulphide (H2S) blocks the cytochrome-c oxidase complex (COX), predicting the evolution of decreased H2S susceptibility of the COX in three populations in the Poecilia mexicana complex that have colonized H2S-containing springs. Here, we demonstrate that decreased H2S susceptibility of COX evolved in parallel in two sulphide lineages, as evidenced by shared amino acid substitutions in cox1 and cox3 genes. One of the shared substitutions likely triggers conformational changes in COX1 blocking the access of H2S. In a third sulphide population, we detect no decreased H2S susceptibility of COX, suggesting that H2S resistance is achieved through another mechanism. Our study thus demonstrates that even closely related lineages follow both parallel and disparate molecular evolutionary paths to adaptation in response to the same selection pressure. PMID- 24815813 TI - The spectroscopic (FT-IR, FT-Raman and NMR), first order hyperpolarizability and HOMO-LUMO analysis of 2-mercapto-4(3H)-quinazolinone. AB - The FTIR and FT-Raman spectra of 2-mercapto-4(3H) quinazolinone have been recorded in the region 4000-450 and 4000-100 cm(-1), respectively. The optimized geometry, frequency and intensity of the vibrational bands of 2-mercapto-4(3H) quinazolinone (2MQ) were obtained by the density functional theory (DFT) using 6 311++G(d,p) basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. The (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method. The theoretical UV-VIS spectrum of the compound and the electronic properties, such as HOMO (highest occupied molecular orbital) and LUMO (lowest occupied molecular orbital) energies were performed by time-dependent DFT (TD-DFT) approach. The change in electron density (ED) in the sigma(*) antibonding orbitals and stabilization energies E((2)) have been calculated by natural bond (NBO) analysis, to give clear evidence of stabilization originating in the hyper conjugation of hydrogen-bonded interactions. Information about the size, shape, charge density distribution and site of chemical reactivity of the molecule has been obtained by mapping electron density isosurface with molecular electrostatic potential (MESP). PMID- 24815814 TI - Voids in mixed-cation silicate glasses: Studies by positron annihilation lifetime and Fourier transform infrared spectroscopies. AB - PALS in comparison with FTIR studies have been applied to investigate the structure of different oxide glasses. Three components of the positron lifetime tau (tau1 para- and tau3 ortho-positronium and tau2 intermediate lifetime component) and their intensities were obtained. The results of the calculation of mean values of positron lifetimes for the investigated glasses showed the existence of a long-living component on the positron annihilation lifetime spectra. From the Tao-Eldrup formula we can estimate the size of free volume. On the basis of the measurements we can conclude that the size and fraction of free volume reaches the biggest value for the fused silica glass. The degree of network polymerisation increases void size. PMID- 24815815 TI - Iron bioavailability of common beans (Phaseolus vulgaris L.) intrinsically labeled with (59)Fe. AB - A radiobioassay was performed in rats with or without iron depletion to evaluate the iron bioavailability of diets enriched with common beans and with "multimixture", a nutritional supplement based on parts of foods that are not usually eaten. The full-body (59)Fe level was determined after 5h, the absorbed (59)Fe level was determined after 48 h, and the amount of (59)Fe retained was determined after 7 days. Iron bioavailability was assessed by the full-body radioactivity of the animals, determined using a solid scintillation detector. The iron bioavailability of common beans was higher in the iron-depleted animals (55.7%) than in the non-depleted animals (25.12%) because of the higher absorption rate in the iron-depleted animals. The multimixture did not influence dietary iron bioavailability. In addition, the iron bioavailability of common beans was similar to that observed in the standard source of iron for Wistar rats. Hence, common beans may be considered an adequate dietary iron source because of its high bioavailability. PMID- 24815816 TI - Effects of different sources of copper on Ctr1, ATP7A, ATP7B, MT and DMT1 protein and gene expression in Caco-2 cells. AB - Copper sulfate (CuSO4), micron copper oxide (micron CuO) and nano copper oxide (nano CuO) at different concentrations were, respectively, added to culture media containing Caco-2 cells and their effects on Ctr1, ATP7A/7B, MT and DMT1 gene expression and protein expression were investigated and compared. The results showed that nano CuO promoted mRNA expression of Ctr1 in Caco-2 cells, and the difference was significant compared with micron CuO and CuSO4. Nano CuO was more effective in promoting the expression of Ctr1 protein than CuSO4 and micron CuO at the same concentration. Nano CuO at a concentration of 62.5 MUM increased the mRNA expression levels of ATP7A and ATP7B, and the difference was significant compared with CuSO4. The addition of CuSO4 and nano CuO to the culture media promoted the expression of ATP7B proteins. CuSO4 at a concentration of 125 MUM increased the mRNA expression level of MT in Caco-2 cells, and the difference was significant compared with nano CuO and micron CuO. Nano CuO at a concentration of 62.5 MUM inhibited the mRNA expression of DMT1, and the difference was significant compared with CuSO4 and micron CuO. Thus, the effects of CuSO4, micron CuO and nano CuO on the expression of copper transport proteins and the genes encoding these proteins differed considerably. Nano CuO has a different uptake and transport mechanism in Caco-2 cells to those of CuSO4 and micron CuO. PMID- 24815817 TI - Evaluation of potential endocrine activity of 2,4-dichlorophenoxyacetic acid using in vitro assays. AB - The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was evaluated in five in vitro screening assays to assess the potential for interaction with the androgen, estrogen and steroidogenesis pathways in the endocrine system. The assays were conducted to meet the requirements of the in vitro component of Tier 1 of the United States Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP), and included assays for estrogen receptor (ER) binding (rat uterine cytosol ER binding assay), ER-mediated transcriptional activation (HeLa 9903-ERalpha transactivation assay), androgen receptor (AR) binding (rat prostate cytosol AR binding assay), aromatase enzymatic activity inhibition (recombinant human CYP19 aromatase inhibition assay), and interference with steroidogenesis (H295R steroidogenesis assay). Results from these five assays demonstrated that 2,4-D does not have the potential to interact in vitro with the estrogen, androgen, or steroidogenesis pathways. These in vitro data are consistent with a corresponding lack of endocrine effects observed in apical in vivo animal studies, and thus provide important supporting data valuable in a comprehensive weight of evidence evaluation indicating a low potential of 2,4-D to interact with the endocrine system. PMID- 24815818 TI - First description of French V. tubiashii strains pathogenic to mollusk: I. Characterization of isolates and detection during mortality events. AB - Nine dominant bacterial isolates were obtained from different batches of Crassostrea gigas spat experiencing high mortality rates in a French experimental hatchery/nursery in 2007. Using phenotypic analysis combined with multilocus sequence analysis, the isolates were shown to be genetically close to the Vibrio tubiashii type strain. Based on (1) analyses of the recA gene sequences; (2) the results of DNA-DNA hybridization assays between 07/118 T2 (LMG 27884=CECT 8426), which is a representative strain, and the V. tubiashii type strain (69%); and (3) phenotypic traits, the bacteria were classified in a group close to American V. tubiashii strain. Its virulence (70% of mortalities) and the toxicity of the extracellular products of 07/118 T2 was demonstrated (41% of mortalities). Moreover, a QPCR diagnostic tool targeting the gyrB gene was developed to investigate the epidemiological significance of V. tubiashii in French oyster mortality outbreaks recorded by the national surveillance network. Of the 21 batches originating from hatcheries, only two were positive, whereas V. tubiashii DNA could not be detected in any of the batches of moribund animals collected in field/outdoor facilities. These results demonstrate the existence of a group of virulent V. tubiashii in France that episodically infect C. gigas. PMID- 24815819 TI - Food survey: levels and potential health risks of chromium, lead, zinc and copper content in fruits and vegetables consumed in Algeria. AB - A food survey was carried out with the aim to investigate the levels of lead (Pb), zinc (Zn), copper (Cu) and chromium (Cr) in various fruits and vegetables sold in Algeria. Concentrations (mg/kgdry wt.) in selected foodstuffs were detected within the following ranges: 4-29.49, 11.17-49, 12.33-39.33 and 3-16.33 for Cu, Zn, Pb and Cr respectively. The food ingestion rate of the selected items was investigated by self-administered questionnaires which were filled by a total of 843 people randomly recruited at the exit of markets. The potential health risk for consumers was investigated by estimating the daily intake (EDI) and the target hazard quotient (THQ) for each heavy metal. For all foodstuffs, the EDI and the THQ were below the threshold values for Cu, Zn and Cr while they exceeded the thresholds for Pb (EDI: 15.66MUgPb/kg body weight/day; THQ: 4.37), indicating an obvious health risk over a life time of exposure. PMID- 24815820 TI - Drug metabolism enzymes in a steatotic model of rat treated with a high fat diet and a low dose of streptozotocin. AB - Herein we have characterized CYPs and antioxidant enzymes in a new steatotic rat model induced with a high fat diet (HFD) combined with a low dose of streptozotocin (STZ). This model was recently put forward in order to better replicate the NAFLD human pathology. HFD/STZ rats developed hyperglycemia, hypercholesterolemia and overt steatosis. The treatment also caused liver damage, but not lipid peroxidation, suggesting this damage was due to hepatic fat deposition and excess formation of toxic free fatty acids, rather than to oxidative stress. In the HFD/STZ group, a significant rise in total CYP content was found, in conjunction with increased activity and protein levels of CYP2E1 and CYP4A, the latter also up-regulated at the transcriptional level. A significant decrease of CYP2C11 was observed at the transcriptional and protein level, whereas CYP3A2 did not change in response to HFD/STZ treatment. In our experimental conditions, the activity of the HO-1 and NQO1 enzymes, whose genes are regulated by Nrf2, were not affected, and nor were the antioxidant enzymes SOD and CAT, confirming the lack of oxidative stress. Our HFD/STZ treatment, which established overt steatosis and changes in CYPs expression, but not oxidative stress, likely reflects an early stage of NAFLD. PMID- 24815821 TI - Food allergy population thresholds: an evaluation of the number of oral food challenges and dosing schemes on the accuracy of threshold dose distribution modeling. AB - For most allergenic foods, limited availability of threshold dose information within the population restricts the advice on action levels of unintended allergenic foods which should trigger advisory labeling on packaged foods. The objective of this paper is to provide guidance for selecting an optimal sample size for threshold dosing studies for major allergenic foods and to identify factors influencing the accuracy of estimation. A simulation study was performed to evaluate the effects of sample size and dosing schemes on the accuracy of the threshold distribution curve. The relationships between sample size, dosing scheme and the employed statistical distribution on the one hand and accuracy of estimation on the other hand were obtained. It showed that the largest relative gains in accuracy are obtained when sample size increases from N=20 to N=60. Moreover, it showed that the EuroPrevall dosing scheme is a useful start, but that it may need revision for a specific allergen as more data become available, because a proper allocation of the dosing steps is important. The results may guide risk assessors in minimum sample sizes for new studies and in the allocation of proper dosing schemes for allergens in provocation studies. PMID- 24815822 TI - Effect of commercially available green and black tea beverages on drug metabolizing enzymes and oxidative stress in Wistar rats. AB - The effect of commercially available green tea (GT) and black tea (BT) drinks on drug metabolizing enzymes (DME) and oxidative stress in rats was investigated. Male Wistar rats were fed a laboratory chow diet and GT or BT drink for 5 weeks. Control rats received de-ionized water instead of the tea drinks. Rats received the GT and BT drinks treatment for 5 weeks showed a significant increase in hepatic microsomal cytochrome P450 (CYP) 1A1 and CYP1A2, and a significant decrease in CYP2C, CYP2E1 and CYP3A enzyme activities. Results of immunoblot analyses of enzyme protein contents showed the same trend with enzyme activity. Significant increase in UDP-glucuronosyltransferase activity and reduced glutathione content in liver and lungs were observed in rats treated with both tea drinks. A lower lipid peroxide level in lungs was observed in rats treated with GT drink. Electrophoretic mobility shift assay revealed that both tea drinks decreased pregnane X receptor binding to DNA and increased nuclear factor erythroid 2 p45-related factor 2 binding to DNA. These results suggest that feeding of both tea drinks to rats modulated DME activities and reduced oxidative stress in liver and lungs. GT drink is more effective on reducing oxidative stress than BT drink. PMID- 24815824 TI - CD109, a novel TGF-beta antagonist, decreases fibrotic responses in a hypoxic wound model. AB - Excessive extracellular matrix deposition that occurs in many fibrotic skin disorders such as hypertrophic scarring and scleroderma is often associated with hypoxia. CD109 is a novel TGF-beta co-receptor and TGF-beta antagonist shown to inhibit TGF-beta-induced extracellular matrix protein production in vitro. We examined whether CD109 is able to regulate extracellular matrix deposition under low oxygen tension in vivo using transgenic mice overexpressing CD109 in the epidermis. By creating dorsal bipedicle skin flaps with centrally located excisional wounds in these mice and their wild-type littermates, we generated a novel murine hypoxic wound model. Mice were sacrificed on 7 or 14 days post wounding, and tissues were harvested for histological and biochemical analysis. Hypoxic wounds in both transgenic and wild-type mice showed increased levels of HIF-1alpha and delayed wound closure, validating this model in mice. Hypoxic wounds in CD109 transgenic mice demonstrated decreased collagen type 1 and fibronectin expression, and reduced dermal thickness on day 7 post-wounding as compared to those in wild-type mice and to non-hypoxic control wounds. These results suggest that CD109 decreases extracellular matrix production and fibrotic responses during hypoxic wound healing. Manipulating CD109 levels may have potential therapeutic value for the treatment of fibrotic skin disorders associated with poor oxygen delivery. PMID- 24815823 TI - Can 1% chlorhexidine diacetate and ethanol stabilize resin-dentin bonds? AB - OBJECTIVES: To examine the effects of the combined use of chlorhexidine and ethanol on the durability of resin-dentin bonds. METHODS: Forty-eight flat dentin surfaces were etched (32% phosphoric acid), rinsed (15 s) and kept wet until bonding procedures. Dentin surfaces were blot-dried with absorbent paper and re wetted with water (water, control), 1% chlorhexidine diacetate in water (CHD/water), 100% ethanol (ethanol), or 1% chlorhexidine diacetate in ethanol (CHD/ethanol) solutions for 30 s. They were then bonded with All Bond 3 (AB3, Bisco) or Excite (EX, Ivoclar-Vivadent) using a smooth, continuous rubbing application (10 s), followed by 15 s gentle air stream to evaporate solvents. The adhesives were light-cured (20 s) and resin composite build-ups constructed for the microtensile method. Bonded beams were obtained and tested after 24-h, 6 months and 15-months of water storage at 37 degrees C. Storage water was changed every month. Effects of treatment and testing periods were analyzed (ANOVA, Holm Sidak, p<0.05) for each adhesive. RESULTS: There were no interactions between factors for both etch-and-rinse adhesives. AB3 was significantly affected only by storage (p=0.003). Excite was significantly affected only by treatments (p=0.048). AB3 treated either with ethanol or CHD/ethanol resulted in reduced bond strengths after 15 months. The use of CHD/ethanol resulted in higher bond strengths values for Excite. CONCLUSIONS: Combined use of ethanol/1% chlorhexidine diacetate did not stabilize bond strengths after 15 months. PMID- 24815825 TI - Trends in 28-day and 1-year mortality rates in patients hospitalized for a first acute myocardial infarction in Norway during 2001-2009: a "Cardiovascular disease in Norway" (CVDNOR) project. AB - OBJECTIVE: The aim of this study was to investigate the trends in 28-day and 1 year mortality rates in patients hospitalized for a first acute myocardial infarction (AMI) in Norway during the period 2001-2009. Potential age group and gender differences in these trends were also examined. DESIGN, SUBJECTS AND SETTING: In this retrospective nationwide cohort study, patients hospitalized for a first AMI between 2001 and 2009 were identified in the Cardiovascular Disease in Norway 1994-2009 (CVDNOR) project and followed for 1 year. MAIN OUTCOME MEASURES: Trends in 28-day and 1-year mortality [both all-cause and cardiovascular disease (CVD) mortality] were investigated. RESULTS: A total of 115,608 patients (60.6% men) were hospitalized for a first AMI during the study period. Mortality at 28 days was reduced annually by 3.8% overall and by 6.7%, 4.1% and 2.6% in patients aged 25-64, 65-84 and >=85 years, respectively (all Ptrend < 0.001). In addition, 1-year all-cause mortality was reduced annually by 2.0% overall (Ptrend < 0.001) and by 3.7% (Ptrend = 0.02), 2.5% (Ptrend < 0.001) and 1.1% (Ptrend < 0.001) in patients aged 25-64, 65-84 and >=85 years, respectively. Furthermore, 1-year CVD mortality was reduced overall by 6.2% annually; a reduction was observed in all age groups. Finally, 1-year non-CVD mortality increased annually overall by 3.9% due to an increase in patients aged >=65 years. CONCLUSION: Mortaity at 28 days after the first AMI declinedin Norway between 2001 and 2009 in both men and women and in all age groups. All-cause mortality at 1 year also declined both in men and women due to decreases in CVD mortality rates, whilst non-CVD mortality rates increased amongst patients >=65 years of age. PMID- 24815826 TI - Electrical status epilepticus during sleep: a study of 22 patients. AB - OBJECTIVE: The aim of this study was to evaluate the clinical and imaging characteristics, treatment results, and prognosis of patients with electrical status epilepticus during sleep (ESES). METHOD: A total of 22 patients with ESES pattern on EEG were retrospectively studied. RESULTS: The first neurological symptoms were seen at a mean age of 4.4years. The first symptoms in 77% of the patients were seizures. Other symptoms were hyperactivity, restlessness, insomnia, disinhibition, autistic behavior, speech retardation and deterioration in school performance. Diagnosis of ESES was made at a mean age of 7.45years, approximately 3years after the first symptom. Magnetic resonance imaging (MRI) was abnormal in 36% of the patients. Single photon emission computed tomography (SPECT) showed focal hypoperfusion after resolution of ESES involving left temporoparietal and right posterior temporal areas in four patients including three with normal MRI, and one with periventricular leukomalacia without focal cortical lesion. First line treatment with valproic acid monotherapy was not effective. Electrical status epilepticus during sleep disappeared in 82% of the patients on clobazam and 70% of the patients on clonazepam in combination with valproic acid within a few months. Topiramate was not found to be effective. A significant decrease in intelligence quotient (IQ) scores was found in 66% of the patients compared to the baseline. CONCLUSIONS: ESES should be considered in children with new onset behavioral, cognitive, and speech problems with or without seizures. The high frequency of focal seizures and focal findings on SPECT suggest a focal origin. Clonazepam and clobazam were most effective in our cohort. PMID- 24815827 TI - Melanoma m1: diagnosis and therapy. AB - This article reviews the epidemiology, pathogenesis, diagnosis, prognostic factors and treatment of metastatic melanoma, including the most recent developments in the specific field. It examines the sequential and non-linear models of development and progression of melanoma and the main molecular disorder involved in these processes. Clinical and diagnostic aspects have been divided according to clinical staging. Surgical resectability, the site and number of metastases, the number of involved organs, the duration of remission, serum lactate dehydrogenase levels and tumor doubling-time have the greatest prognostic value. Surgical treatment has been analyzed considering its rational function and examining all sites involved in metastasis. We also discuss the palliative role of radiotherapy in relation to various metastatic sites, chemotherapy and recently introduced targeted-therapy. The association of newer drugs and new biological therapies such as ipilimumab and verumafenib have improved the treatment landscape of stage IV melanoma. PMID- 24815828 TI - Post-translational histone modifications in circulating nucleosomes as new biomarkers in colorectal cancer. AB - Although many potential biomarkers for colorectal cancer (CRC) have been detected, rarely do they have usage in clinical practice. New biomarkers are needed to detect CRC at an early phase, to detect recurrence and monitor therapeutic response. It has become increasingly evident that altered epigenetic control of gene expression plays an important role in carcinogenesis. In addition to DNA methylation and non-coding RNAs, post-translational histone modifications play an important role in gene regulation and carcinogenesis. Knowledge regarding the patterns of histone modifications in CRC is accumulating. Additionally, histone modification alterations can be detected in nucleosomes circulating in the blood of patients with cancer offering the possibility to use them as biomarkers in CRC and other types of cancer. In the present review, we discuss the potential clinical utility of histone modifications in circulating nucleosomes for the diagnosis and estimation of prognosis in patients with CRC. PMID- 24815829 TI - Circulating miR-18a: a sensitive cancer screening biomarker in human cancer. AB - MicroRNAs have been reported to be stably detectable in plasma/serum and to exhibit resistance to endogenous ribonuclease activity because of binding to proteins such as Argonaute-2 and high-density lipoprotein, or being packed by secretory particles such as exosomes. These secretory particles include specific microRNAs and can function as intercellular transmitters. These findings could open-up a new and promising field in the use of circulating microRNAs for cancer treatment. In particular, miR-18a, which is located in the potentially oncogenic miR-17-92 cluster, is a highly expressed microRNAs in several types of cancers. The concentration of miR-18a in plasma/serum of patients with cancer such as esophageal (AUC=0.944), pancreatic (AUC=0.936), hepatocellular (AUC=0.881), colorectal and other types of cancers is much higher than that of healthy volunteers. Such reports provide evidence that circulating miR-18 might be a next generation biomarker and contribute to cancer screening in non-invasive liquid biopsy, to a clinically-satisfactory degree of sensitivity and specificity. PMID- 24815830 TI - Increased DNA integrity in colorectal cancer. AB - BACKGROUND: Blood-based DNA integrity, defined as the relation of long to small fragments of cell-free circulating DNA, is known to be increased in various types of cancers. Since different DNA fragments and formulae are used by different researchers, conflicting results on the relevance of this marker for cancer diagnosis have been reported. PATIENTS AND METHODS: Sera from 24 patients with colorectal cancer, 11 patients with benign gastrointestinal diseases, and 24 healthy individuals were investigated. After DNA isolation, ALU repeats with 115 bp and 247 bp length were measured using quantitative polymerase chain reaction and resulting DNA integrities were calculated by the two formulae of Umetani et al. (DNA Int 1) and Wang et al. (DNA Int 2) RESULTS: DNA integrity by both formulae correlated strongly with each other. DNA integrity was significantly higher in patients with colorectal cancer when compared with healthy controls (p=0.005 and p=0.006, respectively), while there was no significant difference from those with benign colorectal diseases. In receiver operating characteristic curve analysis, areas under the curve of 0.74 and 0.73 and sensitivities of 71% at 75% specificity (DNA Int 1 and 2, respectively) were achieved for the discrimination between patients with colorectal cancer and healthy controls. CONCLUSION: DNA integrity is significantly increased in patients with colorectal cancer and may be useful in prospective trials. PMID- 24815831 TI - The need for surgery in acute abdominal pain: a randomized study of abdominal computed tomography. AB - AIM: To assess the need for surgical treatment in patients with acute abdominal pain in a prospective randomized study. PATIENTS AND METHODS: Initially 203 patients with acute abdominal pain were randomized to the routine abdominal computed tomography CT (rCT, n=118), or selective abdominal CT group (sCT, n=85) over a period of 16 months. Ninety-three of the randomized patients (45.8%) underwent the study design and were reached for follow-up at three months. RESULTS: Diagnostic accuracy improved significantly in the rCT group (p<0.001). The surgeon's assessment of the need for surgery changed more often in the rCT group than in the sCT group (78.7% vs. 46.9%, p=0.002). The confidence to treat operatively increased significantly in the rCT vs. the sCT group (65.6% vs. 40.6%, p=0.028). The rCT was the only independent parameter for the change of the assessment of surgery. CONCLUSION: Routine CT allows for more confidence in decision making for the surgical treatment of patients with acute abdominal pain. PMID- 24815832 TI - Medullary carcinoma of the colon: a case series and review of the literature. AB - BACKGROUND: Most colon cancers are adenocarcinoma of the colon, which present with a typical histological type. However, a relatively newly-recognized subtype, called medullary carcinoma of the colon, has been characterized. This type is generally divided into subtypes of poorly-differentiated and undifferentiated medullary carcinoma. Only a handful of studies have been conducted thus far, mostly focusing on immunohistochemical and clinical characteristics of the disease. PATIENTS AND METHODS: Herein we present two cases seen at our hospital within one academic year. The first is the case of a 79-year-old African-American woman, who presented with generalized weakness and gait unsteadiness ultimately diagnosed with a Stage IIIB medullary carcinoma of the proximal colon at the time of surgery, but later found to have metastases to a single paraesophageal lymph node. The second is a case of a 79-year-old Caucasian woman, who presented with several weeks of malaise, nausea, and diarrhea leading to diagnosis of a stage IIB medullary colon carcinoma now receiving chemotherapy. CONCLUSION: Although these tumors tend to be right-sided and therefore present at an advanced stage, distant metastasis is rare at presentation and is primarily to the liver or regional lymph nodes. Only one study has been performed regarding short-term outcomes, which failed to reach statistical significance, but trended towards better prognosis compared to poorly-differentiated and undifferentiated colonic adenocarcinomas. PMID- 24815833 TI - Expression of claudins-1, -4, -5, -7 and occludin in hepatocellular carcinoma and their relation with classic clinicopathological features and patients' survival. AB - BACKGROUND: Occludin and claudins are integral constituents of tight junction proteins and are de-regulated in various malignancies, including hepatocellular carcinoma (HCC). This study investigated whether expression of claudins 1, 4, 5, 7 and occludin may be used as prognostic markers for overall and disease-free survival in patients with HCC after hepatectomy. PATIENTS AND METHODS: The study included 67 hepatectomy specimens obtained from an equal number of patients with HCC who underwent partial hepatectomy at the Patras University Hospital for therapeutic reasons. Ten normal liver tissues were used as controls. Expression of claudins 1, 4, 5, 7 and occludin in liver tissues was assessed by immunochemistry. Clinicopathological features were also available for each case. RESULTS: Expression of claudins 1, 4, 5, 7 and occludin was significantly increased in HCC specimens compared to non-neoplastic liver tissues and normal controls (p<0.001 in each case) Moreover, there was a statistically significant association between low level of claudin-4 and advanced tumor grade (p=0.03). Down-regulation of claudin-1 was associated with low overall survival in univariate survival analysis (p=0.049) and Kaplan-Meier analysis (p=0.04). Multivariate analysis showed that the claudin-4 level was an independent factor for survival prognosis (p=0.01). In addition, down-regulation of claudin-4 expression was associated with increased recurrence rate and low disease-free survival rate in univariate analysis (p=0.038), Kaplan-Meier plot (p=0.013) and multivariate analysis (p=0.013). A low level of claudin-5 and high level of claudin-7 levels were independent negative prognostic factors according to multivariate analysis (p=0.015 and 0.009, respectively). CONCLUSION: The present study demonstrates that high expression of claudins 1, 4, 5 and down-regulation of claudin-7 are positive prognostic markers and are associated with good outcome and increased survival rates. Moreover, an increase in claudin-4 expression may serve as an independent positive prognostic factor for low recurrence rate after hepatectomy. PMID- 24815834 TI - Paraneoplastic phenomena and diagnostic challenges in angioimmunoblastic T-cell lymphoma (AITL): report of two cases and review of the literature. AB - BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma with unique clinical, pathological and genetic features. Clinical diagnosis is often hampered as typical lymphoma-associated symptoms may not be found at the time of first presentation and only occur later during disease progression. However, as AITL leads to a de-regulated immune system, various paraneoplastic syndromes or autoimmune reactions may represent the first clinical signs, resulting in delayed diagnosis and treatment. CASE REPORT: We herein describe two AITL cases characterized by a fatal clinical course and the occurrence of unusual paraneoplastic phenomena, including fluid retention and disseminated intravascular coagulation, respectively. Despite multiple diagnostic procedures, both patients died of rapid disease progression and definitive diagnoses could only be established post-mortem. CONCLUSION: These cases underscore the complex diagnostic challenges of AITL and illustrate the requirement for careful clinical evaluation and prompt integration of different diagnostic parameters, including immunohistochemistry, flow cytometry, conventional cytogenetics and molecular genetics, to enable adequate and prompt therapeutic interventions. PMID- 24815835 TI - Inflammatory paradental cyst of the first molar (buccal bifurcation cyst) in a 6 year-old boy: case report with respect to immunohistochemical findings. AB - The inflammatory paradental cyst (IPC) is a relatively rarely reported lesion arising from the lateral periodontium of vital teeth. However, IPC appear to be under-represented in registers of odontogenic cysts due to the misinterpretation of IPC as infected dentigerous cysts, in particular IPC originating from third molars. IPCs exhibit some temporospatial associations with tooth eruptions and occur almost exclusively in the mandible. The IPC of the first molar is predominantly diagnosed in children younger than 10 years. Bony bulging in the area of cyst formation may alert parents to seek medical advice. This case report details the characteristic clinical and radiological features of a first molar IPC arising in a child. The features of the presented cyst correspond well to the attributes qualifying for a so-called buccal bifurcation cyst. A conservative treatment regimen proved to be successful. Certain immunohistochemical markers are reported to further characterize this entirely benign lesion. PMID- 24815836 TI - Dual role of podoplanin in oral cancer development. AB - Podoplanin plays a crucial role for normal and pathological tissue development. Known as a lymphatic endothelial marker, podoplanin has been found to be overexpressed in tumor cells of various cancers with a certified involvement in tumor progression, invasion and metastasis. Oral cancer includes a heterogeneous group of malignancies with unpredictable behaviour and sometimes poor prognosis. Based on these facts, development of new molecular markers with a more reliable impact on therapy and prognosis is required. The present study was designed to characterize podoplanin expression in tumor cells of lip, oral cavity, tongue and pharynx squamous cell carcinomas, together with lymphatic vessels distribution, morphology, density and their impact on tumor progression. Evaluation of podoplanin by D2-40 immunohistochemistry assessement on 56 cases of oral cancers, revealed two different expression patterns in tumor cells depending on their location. Peri-tumor and intra-tumor lymphatic vessels density, morphology and distribution were correlated with lymph node status but not with tumor stage. The highest number of lymphatic vessels was observed in grade 3 squamous cell carcinomas. Dual expression of podoplanin in tumor cells and lymphatics with particular patterns correlated with histopathology and lymph node status in oral cancer, representing the molecular basis for testing podoplanin as a potential target for anti D2-40 antibody based therapy. PMID- 24815837 TI - Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency. AB - While sporadic cases of colorectal cancer (CRC) most commonly arise via the well characterized chromosomal instability pathway (CIN), most other cases develop via a serrated neoplasia pathway (CIMP), in which methylation of CpG islands results in silencing of DNA nucleotide mismatch repair (MMR)-related genes, and a high level of microsatellite instability (MSI). MSI-high tumors typically show proximal location, mucinous histology, poor differentiation, and lymphocytic infiltration. Cell-free circulating DNA (CFD) may become elevated in CRC patients compared to healthy individuals. Because of these biological differences, we hypothesized that compared to MMR-proficient tumors MMR-deficient CRCs may produce higher CFD blood levels. PATIENTS AND METHODS: Forty-one patients with newly-diagnosed CRC from all stages were studied for MMR-proficiency status, and CFD and carcinoembryonic antigen (CEA) blood levels. MMR proficiency was evaluated in formalin-fixed, paraffin-embedded tissues by immunohistochemistry (IHC) for MLH1/MSH2. CFD plasma levels were measured with SYBR gold nucleic acid gel staining on fluorometry. MMR-proficiency status was studied by clinicopathological parameters, CFD and CEA blood levels. RESULTS: Tumors were MMR-proficient, and -deficient in 16 patients (39%), and 25 patients (61%), respectively. The mean age of MMR-deficient patients was approximately 10 years higher than that of MMR-proficient patients (61.2+/-8.4 years versus 71.9+/-9.7 years, p=0.07). MMR-deficient tumors were more often proximally-located, (p=0.018). The mean CFD plasma levels in MMR-proficient, and MMR-deficient patients were 795+/-431 ng/ml, and 906+/-494 ng/ml, respectively (p=0.68). The mean CEA serum levels in MMR-proficient and MMR-deficient patients were 10.4+/ 17.6 MUg/l, and 15+/-48 MUg/l, respectively (p=0.46). CONCLUSION: Compared to MMR proficient CRCs, MMR-deficient tumors occurred in older patients, and were more commonly proximally-located. Despite the presence of distinct biological and histopathological characteristics, both tumor types produced similar CFD blood levels. PMID- 24815838 TI - Effect of dutasteride on microvessel density in benign prostatic hyperplasia. AB - AIM: Dutasteride, a dual 5alpha-reductase inhibitor, is used to treat benign prostatic hyperplasia (BPH). However, its histopathological effects on the morphometrics of blood vessels and glands are still controversial. This study aimed to assess the histopathological effects of dutasteride in cases of BPH in a retrospective manner. PATIENTS AND METHODS: Patients with BPH were administered 0.5 mg of dutasteride daily or left untreated prior to undergoing holmium laser enucleation of the prostate (HoLEP). After HoLEP, remaining prostatic peripheral tissue at the bladder neck and the apex was resected. Each specimen was subjected to hematoxylin/eosin and immunohistochemical staining for CD31, and microvessel density (MVD) was analyzed. RESULTS: In the dutasteride-treated group (n=14), the mean duration of administration was 7.07+/-2.46 weeks. MVD was significantly lower at the bladder neck side in the dutasteride-treated group than in the control group (p=0.018). CONCLUSION: The present study, to our knowledge for the first time, assessed MVD by evaluating the bladder neck and apex sides of the remaining prostatic peripheral tissue after HoLEP, allowing evaluation of MVD in more detail without intraoperative damage of the peripheral tissue, such as through heat denaturation. Dutasteride reduces MVD in the bladder neck side of the prostate among patients with BPH and may lead to decreased risk of perioperative prostatic urethral bleeding. PMID- 24815839 TI - Tropism of cancer stem cells to a specific distant organ. AB - BACKGROUND: Patients diagnosed with pancreatic cancer have a high mortality rate relating to the highly malignant and refractory nature of their disease, and reputedly linked to the presence of cancerous pancreatic stem cells. These stem cells are believed to be deeply involved in distant metastasis. Therefore, the present study examined whether pancreatic cancer stem cells (CSCs) exhibit organ specific migration patterns during metastasis. MATERIALS AND METHODS: Pancreatic cancer cells derived from primary tumors isolated from a mouse model of pancreatic cancer were subcutaneously injected into wild-type mice to form tumor allografts. Allografts were isolated and dissociated into single cells prior to cell sorting using flow cytometry. Sorted cancer cells were injected into the tail vein or spleen of recipient wild-type mice, and analyzed for engraftment three weeks post-transplantation. RESULTS: Pancreatic cancer cells metastasized either to the liver or lungs. Furthermore, we compared the number and size of metastatic foci in the liver and lungs; metastatic liver foci were larger compared with those in the lungs. CONCLUSION: Our results showed that pancreatic CSCs metastasize to distinct organs with direct access to the transplantation site via the circulation. Clarifying the interaction between pancreatic CSCs and the liver microenvironment will lead to improved prognosis and treatments for pancreatic cancer. PMID- 24815840 TI - Lymphangiogenesis as a prerequisite in the pathogenesis of lung fibrosis. AB - Despite increasing knowledge on the cellular and molecular mechanisms involved in pulmonary fibrosis, its therapeutic options are still limited. The study of lymphangiogenesis has contributed to a better understanding of tumor growth and metastasis, with a major impact upon changes in therapeutic strategies and this was followed by the research of lymphatic vessels in other pathological conditions. Some data support the possible role of lymphangiogenesis in the pathogenesis of lung fibrosis. However, at the time of diagnosis for each patient with a fibrotic interstitial lung disease, it is necessary to predict the prognosis and to choose for individual targeted-therapy. Our aim was the characterization of lymphangiogenesis as a useful tool to stratify patients with lung fibrosis. We evaluated the presence, morphology and density of D2-40 positive lymphatic vessels and co-localization of D2-40/Ki67 in pulmonary fibrosis with different degrees of severity and without a specific etiology. Lymphatic vessel density did not correlate with severity grade and ranged between 4.66 to 38.33 vessels/*40 field, with the highest value in degree III of fibrosis. An intense proliferative activity of lymphatic endothelial cells was found in 24% (6 out of 25) of cases. The morphology of lymphatics and the presence of splitting combined with the proliferative activity of endothelial cell pillars suggested two different mechanisms in the formation new lymphatic vessels. Our results support the hypothesis that the activity and ongoing evolution of fibrosis can be predicted through the characterization of lymphangiogenesis but its presence or absence cannot predict the severity of fibrosis. PMID- 24815841 TI - The clinical and pathological significance of RCAS1 expression as a prognostic biomarker in non-small cell lung cancer. AB - BACKGROUND: Lung cancer remains a major health problem due to its incidence and mortality. Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a protein that can be expressed in cancer cells and is involved in tumor cell escape from immune system surveillance. AIM: The aim of this study was to evaluate the clinical significance of immunohistochemical staining for RCAS1 in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Tissue microarrays of tumor specimens from 112 consecutive patients with newly diagnosed primary NSCLC were constructed. RCAS1 and Ki-67 immunohistochemistry were studied through computerized image analysis. Associations between RCAS1 and Ki-67 expression and clinico-pathological variables and survival were analyzed. RESULTS: RCAS1 expression was higher in grade III tumors (p=0.009), regardless of the histological type, and in adenocarcinomas with lymphovascular invasion (p=0.014). A positive correlation between RCAS1 and Ki-67 levels was observed (p=0.002). Moreover, there was an inverse correlation of overall survival with RCAS1 (hazard ratio=0.99, p<0.001) and Ki-67 (hazard ratio=1.05, p=0.003) levels. Particularly, patients with higher expression of RCAS1 or Ki-67 had a significantly shorter survival than those with lower expression. CONCLUSION: RCAS1 could be a useful immunohistochemical biomarker, indicating not only tumor aggressiveness but also a poorer prognosis for patients with NSCLC. PMID- 24815842 TI - A novel caveolin-1 biomarker for clinical outcome of sarcopenia. AB - Sarcopenia, defined by the European Working Group on Sarcopenia in Older People as leading to significantly decreased muscle mass and function, contributes to increased risk of adverse health outcomes among older people. Caveolin-1 (CAV1) is a main structural protein playing a regulatory role in signaling pathways and muscle normality. However, the role of CAV1 in the development of sarcopenia is largely unknown. In this study, we aimed to investigate the contribution of CAV1 genotype to sarcopenia in a Taiwanese population. We enrolled 175 patients with sarcopenia (56 pre-sarcopenia, 63 sarcopenia and 56 severe sarcopenia) and 327 age- and gender-matched controls in this community-based case control study. The associations of six single nucleotide polymorphisms of the CAV1 gene at C521A (rs1997623), G14713A (rs3807987), G21985A (12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992) with sarcopenia risk were evaluated. After grouping the sarcopenia patients together, the results showed that there was a significant differential distribution among the cases and controls in their CAV1 G14713A genotype (p=0.0235), and those carrying the AG and AA genotypes had 1.65- and 1.78-fold higher odds ratios for sarcopenia compared to those with the GG genotype (95% confidence interval=1.09-2.49 and 0.96-3.31, respectively). Furthermore, the carriers with CAV1 G14713A AG or AA genotype had a higher risk for sarcopenia and severe sarcopenia, but not pre-sarcopenia, compared to those with the GG genotype. Our findings suggest that Cav1 may play a critical role in the etiology of sarcopenia, and the A allele of Cav1 G14713A may serve as an early marker for detection of sarcopenia and severe sarcopenia. PMID- 24815843 TI - IL18 production and IL18 promoter polymorphisms correlate with mortality in ICU patients. AB - BACKGROUND: Single nucleotide polymorphisms in the promoter of interleukin (IL) 18 (-607C/A and -137G/C) may affect the clinical course of inflammatory diseases. This study examined the relationship between the plasma IL18 levels, IL18 promoter polymorphism, and outcomes in the intensive care unit (ICU) setting. PATIENTS AND METHODS: Plasma IL18 levels, IL18 promoter genotype, clinical variables, including APACHE II score, and mortality were examined in 70 ICU patients. RESULTS: Plasma IL18 levels were significantly higher in patients who did not survive the ICU stay than in patients who survived, and were correlated with APACHE II score. When examined by IL18 promoter genotype, only patients with the -607CA genotype exhibited differences in IL18 expression between survivors and non-survivors. CONCLUSION: Plasma IL18 levels may predict outcome in patients with sepsis. IL18 promoter polymorphism, especially at -607, may increase IL18 production in some patients and might be useful in predicting the outcome of patients with sepsis in the ICU. PMID- 24815845 TI - Survival and prognostic factors in adult patients with recurrent or refractory ewing sarcoma family tumours: a 13-years retrospective study in Turkey. AB - AIM: The aim of the present study was to evaluate the results of treatment and prognostic factors in adult patients with recurrent or refractory Ewing's sarcoma family tumors (ESFT). PATIENTS AND METHODS: We retrospectively evaluated treatment outcomes of 54 consecutive patients with ESFT (aged 15 years or more) with complete medical records, who were treated with multimodal therapies after recurrence at the Istanbul University, Institute of Oncology. RESULTS: The commonly used chemotherapy regimens at relapse were ifosfamide and etoposide (IE), ifosfamide and etoposide plus carboplatin (ICE), and oral etoposide. The median progression-free survival and overall survival for the entire group were 6.3 (95% confidence interval, 3.08-9.60) and 8.6 (95% confidence interval CI, 4.7 12.4) months, respectively. Multivariate analysis using a Cox proportional hazards model showed that non-IE/ICE chemotherapy regimens (p=0.003, hazard ratio=2.38) and the presence extrapulmonary metastases (p=0.045, hazard ratio=2.15) were associated with worse overall survival. CONCLUSION: In primary refractory or relapsed ESFT, the presence of extrapulmonary metastases and treatment with salvage regimens other than ifosfamide and etoposide and/or carboplatin correlate with a poor prognosis. PMID- 24815844 TI - Functional genetic variants in apoptosis-associated FAS and FASL genes and risk of bladder cancer in a Turkish population. AB - BACKGROUND: The present study aimed to evaluate the role of functional polymorphisms of apoptosis-associated Fatty acid synthase (FAS) and fatty acid synthase ligand (FASL) genes in bladder cancer susceptibility as first presentation in a Turkish population. PATIENTS AND METHODS: Genotypes of 91 patients with bladder cancer and 101 healthy controls were evaluated for the polymorphism of FAS-1377 G/A and FASL-844 T/C genes by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The frequency of the FAS-1377 G allele was significantly higher in patients with bladder cancer compared to controls (p<0.001). A significantly increased risk for developing bladder cancer was found for the group bearing a T allele for FASL-844 compared to the homozygous FASL-844 CC genotype (p=0.027). FAS-1377 GG genotype and FASL 844 T allele were found to be independently associated with an increased risk of bladder cancer. Additionally, gene-gene interaction analysis revealed that the frequency of FAS-1377AA with FASL-844TC was significantly lower in patients with bladder cancer in comparison to those of controls (p<0.001). Extensive studies for gene-gene interaction are still needed. CONCLUSION: Our study provides new evidence that FAS-1377 G and FASL-844 T alleles may be used as low-penetrant risk factors for bladder cancer development in a Turkish population. PMID- 24815846 TI - Rotation thromboelastometry and the hypercoagulable state in Cushing's syndrome. AB - INTRODUCTION: Rotation thromboelastometry (ROTEM(r)) can be used for hypercoagulability evaluation. Cushing's syndrome (CS) is associated with hypercoagulability; however, ROTEM(r) has never been evaluated in this setting. OBJECTIVE: To evaluate hypercoagulability in CS using ROTEM(r) and to correlate these parameters with coagulation markers and with the presence of deep vein thrombosis. DESIGN AND METHODS: Thirty patients with active CS (26 women) and 30 controls matched for age, sex, body mass index, diabetes mellitus, arterial hypertension, ABO blood group and smoking were included. We measured levels of activated partial thromboplastin time (aPTT), platelets, fibrinogen, D-dimer, factor VIII (FVIII), von Willebrand factor (vWF) and C-reactive protein. ROTEM(r) was used to evaluate the intrinsic (INTEM), extrinsic (EXTEM) and fibrinogen (FIBTEM) pathways. Doppler ultrasonography was performed to search for lower limbs deep vein thrombosis. RESULTS: INTEM clotting time using ROTEM(r) was shorter in patients than in controls (P = 0.04). Other ROTEM(r) parameters were not different. Mean aPTT was shorter in patients than in controls (P = 0.001). The FVIII, vWF and D-dimer levels were higher in patients than in controls (P = 0.001, 0.001 and 0.02, respectively). Obese CS patients presented higher levels of platelets and alterations in maximum clot formation (MCF), alpha angle and maximum speed of clot formation of INTEM (P = 0.03, 0.02 and 0.02, respectively) and an increase in the MCF of FIBTEM (P = 0.02). No deep vein thrombosis was found. CONCLUSIONS: Although FVIII and vWF were abnormal in CS patients, only the initiation clot formation was different in the ROTEM(r) methodology and no deep vein thrombosis was found. PMID- 24815847 TI - Abstracts of the HIV Drug Therapy in the Americas 8-10 May 2014, Rio de Janeiro, Brazil. PMID- 24815848 TI - Hypermethylation of p15 gene in diffuse - large B-cell lymphoma: association with less aggressiveness of the disease. AB - In this study, methylation-specific polymerase chain reaction was used to investigate the potential prognostic significance of the methylation status of p15, p16, MGMT, and DAPK genes in 51 specimens of diffuse large B-cell lymphoma (DLBCL). Hypermethylation of p15 gene was significantly more prevalent in patients without relapse (p = 0.001) and there was a trend toward more frequent presence of p15 methylation in patients without death outcome within 5-year follow-up period (p = 0.086) Also, there was a trend toward accumulation of p15 methylation with favorable clinicopathological parameters including: age <= 60 years (p = 0.091), normal levels of lactate dehydrogenase (p = 0.090), Eastern Cooperative Oncology Group performance status < 2 (p = 0.095), and low/intermediate low International Prognostic Index (p = 0.076). In the female group and group of the patients without bulky tumor mass, treated with chemotherapeutic regimens including rituximab, methylation of p15 was significantly related to longer overall survival (p = 0.036 and 0.027, respectively). Our results suggest that promoter methylation of p15 gene could have prognostic value in DLBCL patients treated with rituximab when used in combination with gender and tumor size. PMID- 24815849 TI - Tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer. AB - Our recent studies of the microRNA (miRNA) expression signature in prostate cancer (PCa) indicated that miRNA-218 (miR-218) was significantly downregulated in clinical specimens, suggesting that miR-218 might act as a tumor-suppressive miRNA in PCa. The aim of the present study was to investigate the functional significance of miR-218 in PCa and to identify novel miR-218-regulated cancer pathways and target genes involved in PCa oncogenesis and metastasis. Restoration of miR-218 in PCa cell lines (PC3 and DU145) revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that LIM and SH3 protein 1 (LASP1) is a potential target of miR-218 regulation. LASP1 is a cytoskeletal scaffold protein that plays critical roles in cytoskeletal organization and cell migration. Luciferase reporter assays showed that miR-218 directly regulated expression of LASP1. Moreover, downregulating the LASP1 gene significantly inhibited cell migration and invasion in cancer cells, and the expression of LASP1 was upregulated in cancer tissues. We conclude that loss of tumor-suppressive miR-218 enhanced cancer cell migration and invasion in PCa through direct regulation of LASP1. Our data on pathways regulated by tumor-suppressive miR-218 provide new insight into the potential mechanisms of PCa oncogenesis and metastasis. PMID- 24815850 TI - Long-chain peer referral to recruit black MSM and black transgender women for an HIV vaccine efficacy trial. PMID- 24815852 TI - Low prevalence of transmitted drug resistance of HIV-1 during 2008-2012 antiretroviral therapy scaling up in Southern Vietnam. AB - BACKGROUND: The recent expansion of antiretroviral therapy (ART) program in resource-limited setting has raised concern about possible transmission of drug resistance (TDR). We assessed the prevalence of TDR over a 5-year period among treatment-naive individuals in Southern Vietnam during rapid ART scale-up. METHODS: Drug resistance mutations among antiretroviral-naive HIV-1-infected patients in Ho Chi Minh City were evaluated prospectively from 2008 to 2012 by HIV-1 pol gene sequencing. TDR was defined according to the World Health Organization list for surveillance of transmitted HIV-1 drug resistance in 2009. RESULTS: Pol sequence was obtained in 1389 individuals (median age: 30 years, males: 52.3%). Risks of HIV-1 infection included heterosexual contact in 60.7%, injection drug use in 22.4% and both 5.2%. The majority was infected with CRF01_AE (97%), whereas 19 were infected with subtype B. Over the 5-year study period, TDR was detected in 58 individuals (4.18%): 28 (2.02%) against nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 19 (1.37%) against nonnucleoside reverse transcriptase inhibitors (NNRTIs), and 15 (1.08%) against protease inhibitors (PIs), including 4 (0.29%) against both NRTIs and NNRTIs. The most common TDR was K103N (0.5%) for NNRTI. The annual prevalence of TDR remained low to moderate (2008: 2.4%; 2009: 5.2%; 2010: 5.48%; 2011: 2.72%; 2012: 5.36%), and there was no clear trend over time. CONCLUSIONS: There was no increase in TDR prevalence in Southern Vietnam during and after the 2008-2012 rapid scale up of ART. PMID- 24815851 TI - A randomized controlled trial of palifermin (recombinant human keratinocyte growth factor) for the treatment of inadequate CD4+ T-lymphocyte recovery in patients with HIV-1 infection on antiretroviral therapy. AB - BACKGROUND: Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease. METHODS: In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels <=200 copies per milliliter for >=6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 MUg/kg of palifermin on 3 consecutive days. RESULTS: The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-MUg/kg dose [11 (2, 32) cells/mm], the 40-MUg/kg dose [12 (-2, 25) cells/mm], or the 60-MUg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants. CONCLUSIONS: Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART. PMID- 24815853 TI - Symptomatic HIV-positive persons in rural Mozambique who first consult a traditional healer have delays in HIV testing: a cross-sectional study. AB - OBJECTIVE: Delays in HIV diagnosis and initiation of antiretroviral therapy are common even among symptomatic individuals in Africa. We hypothesized that antiretroviral therapy delays might be more common if traditional healers (THs) were the first practitioners consulted. DESIGN: Cross-sectional study. METHODS: We interviewed 530 newly diagnosed HIV-infected adults (>=18 years of age) who were clinically symptomatic at the time of HIV testing in 2 rural districts in Zambezia Province, Mozambique. We ascertained their previous health care seeking behavior, duration of their symptoms, CD4 cell counts at the time of entry into care, and treatment provided by TH(s). RESULTS: Of 517 patients (97.5%) with complete histories, 62% sought care from a healer before presenting to the local health facility. The median time to first health facility visit from first relevant symptom was 2 months [interquartile range (IQR): 1-4.5] for persons who had not visited a healer, 3 months (IQR: 2-6) for persons visiting 1 healer, and 9 months (IQR: 5-12) for persons visiting >1 healer (P < 0.001). Healers diagnosed 56% of patients with a social or ancestral curse and treated 66% with subcutaneous herbal remedies. A nonsignificant trend toward lower CD4 cells for persons who had seen multiple healers was noted. CONCLUSIONS: Seeking initial care from healers was associated with delays in HIV testing among symptomatic HIV seropositive persons. We had no CD4 evidence that sicker patients bypass THs, a potential inferential bias. Engaging THs in a therapeutic alliance may facilitate the earlier diagnosis of HIV/AIDS. PMID- 24815854 TI - Do age-disparate relationships drive HIV incidence in young women? Evidence from a population cohort in rural KwaZulu-Natal, South Africa. AB - BACKGROUND: Based on ethnographic investigations and mathematical models, older sexual partners are often considered a major risk factor for HIV for young women in sub-Saharan Africa. Numerous public health campaigns have been conducted to discourage young women from relationships with older men. However, longitudinal evidence relating sex partner age disparity to HIV acquisition in women is limited. METHODS: Using data from a population-based open cohort in rural KwaZulu Natal, South Africa, we studied 15- to 29-year-old women who were HIV seronegative at first interview between January 2003 and June 2012 (n = 2444). We conducted proportional hazards analysis to establish whether the age disparity of women's most recent sexual partner, updated at each surveillance round, was associated with subsequent HIV acquisition. RESULTS: A total of 458 HIV seroconversions occurred over 5913 person-years of follow-up (incidence rate: 7.75 per 100 person-years). Age disparate relationships were common in this cohort; 37.7% of women reported a partner 5 or more years older than themselves. The age disparity of women's partners was not associated with HIV acquisition when measured either continuously [hazard ratio (HR) for 1-year increase in partner's age: 1.00, 95% confidence interval (CI): 0.97 to 1.03] or categorically (man >=5 years older: HR, 0.98; 95% CI: 0.81 to 1.20; man >=10 years older: HR, 0.98; 95% CI: 0.67 to 1.43). These results were robust to adjustment for known sociodemographic and behavioral HIV risk factors and did not vary significantly by women's age, marital status, education attainment, or household wealth. CONCLUSIONS: HIV incidence in young women was very high in this rural community in KwaZulu-Natal. Partner age disparity did not predict HIV acquistion. Campaigns to reduce age-disparate sexual relationships may not be a cost-effective use of HIV prevention resources in this setting. PMID- 24815855 TI - Social integration and the mental health of Black adolescents. AB - The influence of family, school, and religious social contexts on the mental health of Black adolescents has been understudied. This study used Durkheim's social integration theory to examine these associations in a nationally representative sample of 1,170 Black adolescents, ages 13-17. Mental health was represented by positive and negative psychosocial well-being indicators. Results showed that adolescents' integration into family and school were related to better mental health. In addition, commitment to religious involvement positively influenced mental health. Although the direct effect of religious involvement was inversely related to mental health, mediation analyses revealed a positive influence through religious commitment. Findings suggest a greater emphasis on all three social contexts when designing strategies to improve the mental health of Black adolescents. PMID- 24815856 TI - A qualitative study: potential benefits and challenges of traditional healers in providing aspects of palliative care in rural South Africa. AB - INTRODUCTION: This article draws on selected palliative care providers' views and experiences to reflect on the potential benefits and possible challenges of involving traditional healers in palliative care in rural areas of South Africa. There is increasing consensus that palliative care should be offered by a range of professional and non-professional healthcare givers. Including non professionals such as traditional healers in a palliative care team may strengthen care provisioning as they have intimate knowledge of patients' local culture and spiritual beliefs. METHODS: Employing the qualitative method of photo elicitation, one-on-one discussions about the photographs taken by participants were conducted. The participants - 4 palliative care nurses and 17 home-based care workers - were purposively selected to provide in-depth information about their experiences as palliative caregivers in rural homes. RESULTS: Healthcare workers' experiences revealed that the patients they cared for valued traditional rituals connected to illness, dying, death and bereavement. Participants suggested that traditional healers should be included in palliative care training programs as they could offer appropriate psychological, cultural and spiritual care. A challenge identified by participants was the potential of traditional healers to foster a false sense of longevity in patients facing death. DISCUSSION: The importance of recognising the value of traditional practices in palliative care should not be underrated in rural South Africa. Traditional healers could enhance palliative care services as they have deep, insider knowledge of patients' spiritual needs and awareness of cultural practices relating to illness, death, dying and bereavement. Incorporating traditional healers into healthcare services where there are differences in the worldviews of healthcare providers and patients, and a sensitivity to mediate cultural differences between caregivers and patients, could have the benefit of providing appropriate care in rural spaces. CONCLUSIONS: Considering the influences of cultural and spiritual beliefs on the wellbeing of patients living in rural areas, the inclusion of traditional healers in a palliative care team is a sensible move. It is, nevertheless, important to note that unanticipated challenges may arise with respect to power differentials within the palliative care team and to beliefs that contradict medical prognosis. PMID- 24815858 TI - The organisation of the cell membrane: do proteins rule lipids? AB - Cell membranes are a complex adaptive system: they are constantly re-organised in response to extra- and intracellular inputs and their local and global structure ultimately determines how, where and when these inputs are processed. This requires a tight coupling of signalling and membranes in localised and specialised compartments. While lipids are essential components of cell membranes, they mostly lack a direct link to the input signals. Here we review how proteins can deform locally membranes, modify and reorganise lipids to form membrane domains and regulate properties like membrane charges and diffusion. From this point-of-view, it appears that proteins play a central role in regulating membrane organisation. PMID- 24815857 TI - Faster fluorescence microscopy: advances in high speed biological imaging. AB - The past decade has seen explosive growth in new high speed imaging methods. These can broadly be classified as either point-scanning (which offer better depth penetration) or parallelized systems (which offer higher speed). We discuss each class generally, and cover specific advances in diffraction-limited microscopes (laser-scanning confocal, spinning-disk, and light-sheet) and superresolution microscopes (single-molecule imaging, stimulated emission depletion, and structured illumination). A theme of our review is that there is no free lunch: each technique has strengths and weaknesses, and an advance in speed usually comes at the expense of either spatial resolution or depth penetration. PMID- 24815859 TI - Lactobacillus plantarum CLP-0611 ameliorates colitis in mice by polarizing M1 to M2-like macrophages. AB - The TNF-alpha expression-inhibitory effect of lactic acid bacteria (LAB) isolated from kimchi were measured in lipopolysaccharide (LPS)-stimulated peritoneal macrophages. Among the LAB evaluated, Lactobacillus plantarum CLP-0611 inhibited the IL-1beta and IL-6 expression, as well as the NF-kappaB and AP1 activation in LPS-stimulated peritoneal macrophages. Therefore, we investigated its inhibitory effect on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. TNBS significantly induced colon shortening, as well as myeloperoxidase activity and macroscopic score. Oral administration of CLP-0611 significantly reduced TNBS induced body weight loss, colon shortening, myeloperoxidase activity, IRAK-1 phosphorylation, NF-kappaB and MAP kinase (p38, ERK, JNK) activation, and iNOS and COX-2 expression. CLP-0611 also inhibited TNBS-induced expression of TNF alpha, IL-1beta, and IL-6. However, IL-10 expression was induced. CLP-0611 also induced the production of M2 macrophage markers (IL-10, arginase I and CD206). Based on these findings, CLP-0611 inhibits TLR-4-linked NF-kappaB and MAPK signaling pathways and polarizes M1 to M2-like macrophages, thus ameliorating colitis. PMID- 24815860 TI - The evaluation of endothelin 1 (EDN1) and endothelin receptor type A (EDNRA) gene polymorphisms in Hashimoto's thyroiditis. AB - PURPOSE: Endothelin1 (EDN1) is well established marker of inflammation. The functions of EDN1 are mediated mainly by endothelin receptors type A (EDNRA). The etiopathogenesis of Hashimoto's thyroiditis (HT) remains still elusive although the role of chronic inflammation and subsequent endothelial dysfunction has been established. This study examined firstly the possible association of EDN1 (G5665Tand T-1370G) and EDNRA (C+70G and G-231A) single nucleotide polymorphisms (SNPs) with the occurrence of HT, and evaluates the relationship between genotypes and clinical/laboratory manifestation of HT. MATERIALS AND METHODS: We analyzed genotype and allele distributions of above mentioned polymorphisms in 163 patients with HT and 181 healthy controls by real-time PCR combined with melting curve analysis. RESULTS: No significant associations between HT and variant alleles of EDN1 5665 and -1370, as well as EDNRA +70 and -231 SNPs were found. Haplotype analysis demonstrated that there was a strong (D'=0.76, r(2)=0.487) and weak (D'=0.403, r(2)=0.086) linkage disequilibrium (LD) between EDN1 -1370 and 5665, and between EDNRA -231 and +70 SNPs, respectively. However, haplotype frequencies in patients were similar to those in controls. In addition, it was observed that the EDNRA +70 G allele had protective effect against early (at age before 40 years) disease onset of HT (OR: 0.51, 95% CI=0.32-0.79, p=0.003). CONCLUSION: Although no significant associations between susceptibility to HT with EDN1 5665 and -1370, as well as with EDNRA+70 and -231 SNPs were found, EDNRA +70 polymorphism was related with decreased risk for early onset HT. PMID- 24815861 TI - [Ethical issues in health care of gender violence]. AB - Gender violence is a health problem that occasionally gives rise to ethical dilemmas for the family doctor. One of the most important conflict is probably when a patient admits to being abused by her partner, but appeals to keep the information confidential, and refuses to present an injury report. There also other problematic situations. This essay attempts to reflect on these issues and help professionals in making decisions. PMID- 24815862 TI - Brachyury: a new player in promoting breast cancer aggressiveness. PMID- 24815863 TI - Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma. AB - BACKGROUND: Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy. METHODS: We retrospectively tested plasma IGF 1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50 ng/mL = 1 point; 26 to 50 ng/mL = 2 points; and less than 26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell's C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided. RESULTS: Patients' stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively). CONCLUSIONS: The IGF-CTP score is simple, blood based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted. PMID- 24815865 TI - Storytelling's power in cancer treatment. PMID- 24815864 TI - Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) has been implicated as an important process in tumor cell invasion, metastasis, and drug resistance. The transcription factor brachyury has recently been described as a driver of EMT of human carcinoma cells. METHODS: Brachyury mRNA and protein expression was analyzed in human breast carcinomas and benign tissues. The role of brachyury in breast tumor prognosis and drug resistance and the ability of brachyury-specific T cells to lyse human breast carcinoma cells were also evaluated. Kaplan-Meier analyses were used to evaluate the association between brachyury expression and survival. All statistical tests were two-sided. RESULTS: The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel. A comparison of survival among breast cancer patients treated with tamoxifen in the adjuvant setting who had tumors with high vs low brachyury mRNA expression demonstrated that high expression of brachyury is associated as an independent variable with higher risk of recurrence (hazard ratio [HR] = 7.5; 95% confidence interval [CI] = 2.4 to 23.5; P = 5.14*10(-4)) and distant metastasis (HR = 15.2; 95% CI = 3.5 to 66.3; P = 3.01*10(-4)). We also demonstrated that brachyury-specific T cells can lyse human breast carcinoma cells. CONCLUSIONS: The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies. PMID- 24815868 TI - TERT promoter eyed with suspicion and hope. PMID- 24815869 TI - Treating multiple myeloma: the cause for optimism. PMID- 24815870 TI - Why is breast cancer chemoprevention such a hard sell? PMID- 24815871 TI - Successful living donor liver transplantation for giant extensive venous malformation. AB - We report our success in employing LDLT as a course of treatment for extensive hepatic VM. A 14-yr-old pediatric patient presented at our hospital with nosebleed, fatigability, orthopnea, and abdominal distension. He had a history of right hemicolectomy with primary anastomosis due to VM of the transverse colon at age seven. Coagulation abnormalities were apparent, characterized by high international normalized ratio of prothrombin time, decreased fibrinogen level, increased FDPs, and D-dimer. T2-weighted magnetic resonance imaging revealed numerous, variable-sized high signal intensity nodules. Abdominal ultrasonography and CT scan showed hepatomegaly with multiple hypo-echogenic lesions and arteriovenous shunting in the liver. Doppler ultrasound showed hypokinetic flow in the hypo-echogenic lesions of liver. Immediate LDLT was performed to avoid spontaneous rupture and DIC. The right lobe of the liver was implanted with temporary portocaval shunt to prevent intestinal congestion and bleeding. Pathologic examination of the explanted liver confirmed the presence of an extensive hepatic VM. The postoperative course was uneventful, and the patient remained symptom-free with normal liver function throughout the 12-month follow up period. PMID- 24815872 TI - Immunosuppressive protocol with delayed use of low-dose tacrolimus after aortic transplantation suppresses donor-specific anti-MHC class I and class II antibody production in rats. AB - BACKGROUND: Arterial allografts are used as vascular conduits in the treatment of prosthetic graft infection. Immunosuppression decreases their rupture risk rate. However, immunosuppression can be unprofitable in florid infection. Previously, we confirmed inhibition of cell-mediated destruction of rat aortic grafts by delayed use of tacrolimus. In this work, we studied the influence of this protocol on the antibody-mediated rejection. MATERIAL AND METHODS: Flow cytometry was used for the retrospective analysis of day 0, 14, and 30 sera obtained from Lewis rat recipients of isogeneic fresh infrarenal aortic grafts (group A) or Brown-Norway rat aortic grafts (group B,C,D) for the presence of donor-specific anti-MHC class I and II antibodies. Tacrolimus in daily dose of 0.2 mg/kg was administered from day 1 to day 30 (group C) or from day 7 to day 30 (group D). RESULTS: Inhibition of fluorescence-labeled anti-BN MHC class I and MHC class II antibodies binding to BN-splenocytes was observed only by day 14 and day 30 sera of allogeneic non-immunosuppressed Lewis rats (group B). The day 30 sera significantly decreased anti-MHC I (42+/-3%) and anti-MHC II antibody binding (56+/-3%) compared to day 0 (76+/-9%, p=0.005 and 79+/-5%, p=0.003, respectively). Deposition of immunoglobulins G into the tunica media was observed only in non-immunosuppressed aortic allografts on day 30. CONCLUSIONS: Fresh aortic allografts induce donor-specific anti-MHC class I and anti-MHC class II antibody production. Delayed administration of tacrolimus completely suppressed antibody production and antibody-mediated destruction of aortic allografts. PMID- 24815873 TI - Experiences of donor families after consenting to organ donation: a qualitative study. AB - AIM: The aim of this study was to investigate the experience of Norwegian donor families during organ donation after brain death. METHODS: This was a qualitative study using personal interviews. Twenty donor-family members from thirteen different situations were interviewed about their experience of being a close relative in an organ donation situation. The principles of qualitative content analysis were used. FINDINGS: An experience of strain caused by the organ donation situation was identified. Lack of comprehension and awareness of the process of organ donation contributed to this, and continuing information after the consent was given appeared to be necessary. Reconciliation with the decision of organ donation and the subsequent situation was gained through understanding the organ donation process, through recognition of the increased strain and through satisfaction resulting from the contribution made by organ donation. Healthcare personnel were key persons in contributing to such understanding and recognition. CONCLUSION: When attending to families in an organ donation situation, the focus must be on ensuring comprehension of the situation both through information provided in the hospital and during follow-up. It seems essential to arrange for a period of parting that can contribute to reconciliation, and to offer follow-up according to individual needs. PMID- 24815874 TI - Steatosis affects the performance of liver stiffness measurement for fibrosis assessment in patients with genotype 1 chronic hepatitis C. AB - BACKGROUND & AIMS: In Chronic Hepatitis C (CHC), the influence of steatosis on liver stiffness measurement (LSM) is still debated. We assessed the impact of steatosis and its ultrasonographical sign - bright liver echo pattern (BLEP) - on LSM values and on transient elastography (TE) accuracy for the diagnosis of liver fibrosis, in a cohort of consecutive patients with Genotype 1 (G1) CHC. METHODS: Patients (n=618) were assessed by clinical, ultrasonographic and histological (Scheuer score) features. TE was performed using the M probe. RESULTS: Male gender (p=0.04), steatosis as continuous variable (p<0.001), severity of necroinflammation (p=0.02) and stage of fibrosis (p<0.001) were associated with LSM by multivariate linear regression analysis. Among patients within the same fibrosis stages (F0-F2 and F3-F4; F0-F3 and F4), mean LSM values, expressed in kPa, were significantly higher in subjects with moderate-severe steatosis (?20% at liver biopsy) compared with those without, as well as in patients with BLEP on US compared with their counterpart. In subjects without severe fibrosis (F0-F2) and without cirrhosis (F0-F3), a higher rate of false-positive LSM results was observed in patients with steatosis ?20% compared with those without (F0-F2: 35.3% vs. 17.9%; F0-F3: 38.9% vs. 16.6%), and in patients with BLEP on US (F0-F2: 28.0% vs. 18.3%; F0-F3: 29.7% vs. 17.8%) compared with their counterpart. CONCLUSIONS: In patients with G1 CHC, the presence of moderate-severe steatosis, detected by histology or by US, should always be taken into account in order to avoid overestimations of liver fibrosis assessed by TE. PMID- 24815875 TI - Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. AB - BACKGROUND & AIMS: Autophagy is an intracellular lysosomal degradation process that plays an important role in regulating normal physiological functions of the liver. The purpose of the present study was to investigate the mechanism(s) by which the loss of hepatic autophagy leads to liver inflammation, fibrosis and tumorigenesis. METHODS: Hepatocyte-specific Atg5 knockout mice were generated by crossing Atg5 Flox/Flox mice with albumin Cre mice. These mice were also crossed with Nrf2 knockout mice to generate Atg5 Flox/Flox, Albumin Cre(+)/Nrf2(-/-) double knockout mice. These mice were housed for various time points up to 15 months, and blood and liver tissues were harvested for biochemical and histological analysis. RESULTS: Hepatocyte-specific deletion of Atg5 resulted in increased apoptosis, inflammation and fibrosis in the liver. Increased apoptosis in hepatocyte-specific Atg5 knockout mice was likely due to accumulation of aberrant polyubiquitinated proteins (proteotoxicity) and disruption of the homeostasis of pro-and anti-apoptotic proteins. All of these pathological changes started as early as one month and persisted for 12-15 months. At 9-15 months of age, these mice also developed hepatocellular adenomas. Interestingly, deletion of Nrf2 in Atg5 liver-specific knockout mice markedly abolished these pathological changes, indicating a key role for this transcription factor in the mechanism of hepatic pathology. CONCLUSIONS: Our results provide genetic evidence that loss of autophagy in hepatocytes causes cell death resulting in liver inflammation, fibrosis and tumorigenesis. We also demonstrate that persistent activation of Nrf2 is critical for liver inflammation, fibrosis and eventual tumorigenesis that occur in mice with defects in hepatocyte autophagy. PMID- 24815876 TI - Non-invasive assessment of liver fibrosis with impulse elastography: comparison of Supersonic Shear Imaging with ARFI and FibroScan(r). AB - BACKGROUND & AIMS: Non-invasive assessment of liver fibrosis by elastography is a rapidly developing field with frequent technological innovations. The aim of this study was to assess the diagnostic performances of Supersonic Shear Imaging (SSI) for the diagnosis of liver fibrosis in chronic liver disease. METHODS: A total of 349 consecutive patients with chronic liver diseases who underwent liver biopsy from November 2011 to October 2013 were prospectively enrolled. For each patient, liver stiffness was assessed by SSI, ARFI, FibroScan(r) (M probe for patients with BMI <30 kg/m(2), and XL probe for patients with BMI ?30 kg/m(2)), performed within two weeks of liver biopsy. Areas under the receiver operating curves (AUROCs) were performed and compared for each degree of liver fibrosis. RESULTS: SSI, FibroScan(r), and ARFI correlated significantly with histological fibrosis score (r=0.79, p<0.00001; r=0.70, p<0.00001; r=0.64, p<0.00001, respectively). AUROCs of SSI, FibroScan(r), and ARFI were 0.89, 0.86, and 0.84 for the diagnosis of mild fibrosis; 0.88, 0.84, and 0.81 for the diagnosis of significant fibrosis; 0.93, 0.87, and 0.89, for the diagnosis of severe fibrosis; 0.93, 0.90, and 0.90 for the diagnosis of cirrhosis, respectively. SSI had a higher accuracy than FibroScan(r) for the diagnosis of severe fibrosis (?F3) (p=0.0016), and a higher accuracy than ARFI for the diagnosis of significant fibrosis (?F2) (p=0.0003). No significant difference was observed for the diagnosis of mild fibrosis and cirrhosis. CONCLUSIONS: SSI is an efficient method for the assessment of liver fibrosis in chronic liver diseases, comparing favourably to FibroScan(r) and ARFI. PMID- 24815877 TI - What level of sodium intake worsens renal outcomes? PMID- 24815878 TI - Rapid detection of encephalomyocarditis virus by one-step reverse transcription loop-mediated isothermal amplification method. AB - The encephalomyocarditis virus (EMCV) can cause acute myocarditis in young pigs or reproductive failure in sows. In this study, a reverse transcription loop mediated isothermal amplification (RT-LAMP) assay was developed to detect EMCV RNA. The RT-LAMP assay was highly sensitive and able to detect 2.2 * 10(-5)ng of EMCV RNA, as no cross-reaction was observed with other viruses. The RT-LAMP assay was conducted in isothermal (62 degrees C) conditions within 50 min. The amplified products of EMCV could be detected as ladder-like bands using agarose gel electrophoresis. This is the first report to demonstrate the application of a one-step RT-LAMP assay for the detection of EMCV. The sensitive, specific and rapid RT-LAMP assay developed in this study can be applied widely in clinical diagnosis and field surveillance of EMCV. PMID- 24815879 TI - Visualization of the Npro protein in living cells using biarsenically labeling tetracysteine-tagged classical swine fever virus. AB - Real-time fluorescence imaging of viral proteins in living cells is a valuable means to study virus-host interactions, and tetracysteine (TC)-biarsenical technology has been used in several viruses but not in classical swine fever virus (CSFV). Here, we generated CSFV mutants vSMTC385 or vSMTC412 bearing the small TC tag (CCPGCC) in the N-terminal region of the N(pro) protein. The mutants showed growth characteristics indistinguishable from that of the wild-type virus, and retained similar N(pro) subcellular localization to that of the parent virus. Furthermore, labeling with membrane-permeable biarsenical dye resulted in the fluorescent N(pro) protein in the context of virus infection. Finally, we showed that N(pro) was localized in the cytoplasm of CSFV-infected cells at 27 h post infection (hpi) and present in the nucleus at 48 hpi, and the nuclear import and export was clearly observed from 36.5 to 37 hpi. Interestingly, our results demonstrated that N(pro) transported across the nuclear pores by passive diffusion, which might be prevented by exogenous interferon regulatory factor 3 interacting with N(pro). Taken together, biarsenical labeling allows real-time visualization of the nucleus import and export of the fluorescent N(pro) protein in CSFV-infected living cells. PMID- 24815881 TI - European Society of Endodontology: position statements. PMID- 24815880 TI - Palladium(II)-catalyzed enantioselective C(sp3)-H activation using a chiral hydroxamic acid ligand. AB - An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene beta C(sp(3))-H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected alpha-amino-O-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing alpha-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective beta C(sp(3))-H activation of acyclic amides. PMID- 24815882 TI - European Society of Endodontology position statement: the use of CBCT in endodontics. AB - This Position Statement represents a consensus of an expert committee convened by the European Society of Endodontology (ESE) on the use of Cone Beam Computed Tomography (CBCT). The statement is based on the current scientific evidence, and provides the clinician with evidence-based criteria on when to use CBCT in Endodontics. Given the dynamic and changing nature of research, development of new devices and clinical practice relating to CBCT, this Position Statement will be updated within 3 years, or before that time should new evidence become available. PMID- 24815883 TI - Letter to the editor. PMID- 24815884 TI - Regulation of gene expression of vasotocin and corticotropin-releasing hormone receptors in the avian anterior pituitary by corticosterone. AB - The effect of chronic stress (CS) on gene expression of the chicken arginine vasotocin (AVT) and corticotropin-releasing hormone (CRH) receptors [VT2R, VT4R, CRH-R1, and CRH-R2] was examined by measuring receptor mRNA levels in the anterior pituitary gland of the chicken after chronic immobilization stress compared to acute stress (AS). Radioimmunoassay results showed that blood circulating corticosterone (CORT) levels in the CS group were significantly decreased compared to that of birds in the AS group (P<0.05). The VT2R and CRH-R2 mRNA in CS birds were significantly decreased to that of controls. The VT4R mRNA was significantly decreased compared to controls in AC birds and was further decreased in the CS group compared to controls (P<0.05). The CRH-R1 mRNA was significantly decreased in the AS birds compared to controls. However, there was no significant difference of CRH-R1 mRNA between acute stress and chronic stress birds. Using primary anterior pituitary cell cultures, the effect of exogenous CORT on VT/CRH receptor gene expression was examined. Receptor mRNA levels were measured after treatment of CORT followed by AVT/CRH administration. The CORT pretreatment resulted in a dose-dependent decrease of proopiomelanocortin heteronuclear RNA, a molecular marker of a stress-induced anterior pituitary. Without CORT pretreatment of anterior pituitary cell cultures, the VT2R, VT4R and CRH-R1mRNA levels were significantly increased within 15 min and then decreased at 1 h and 6 h by AVT/CRH administration (P<0.05). Pretreatment of CORT in anterior pituitary cells induced a dose-dependent increase of VT2R, VT4R and CRH R2 mRNA levels, and a significant decrease of CRH-R1 mRNA levels at only the high dose (10 ng/ml) of CORT (P<0.05).Taken together, results suggest a modulatory role of CORT on the regulation of VT/CRH receptor gene expression in the avian anterior pituitary gland dependent upon CORT levels. PMID- 24815885 TI - Calcitonin receptor family evolution and fishing for function using in silico promoter analysis. AB - In the present study the calcitonin receptor (CTR) sub-family of family B G protein coupled receptors (GPCRs) in teleosts is evaluated and put in the context of the families overall evolution from echinodermates to vertebrates. Echinodermates, hemichordates, cephalochordates and tunicates have a single gene that encodes a receptor that bears similarity to the vertebrate calcitonin receptor (CTR) and calcitonin-like receptor (CTR/CLR). In tetrapods one gene encodes the calcitonin receptor (CALCR) and another gene the calcitonin receptor like receptor (CALCRL). The evolution of CALCR has been under strong conservative pressure and a single copy is also found in fishes and high conservation of gene organisation and synteny exits from teleosts to human. A teleost specific CTR innovation that occurred after their divergence from holostei is the presence of several HBDs in the N-terminus. CALCRL had a different evolutionary trajectory from CALCR and although a single gene copy is present in tetrapods the sarcopterygii fish, the coelacanth, has 1 copy of CALCRL but also a fish specific form CALCRL3. The ray-finned fish, the spotted gar, has 1 copy of CALCRL and 1 of CALCRL3 but the teleost specific whole genome duplication has resulted in a CALCRL1 and CALCRL2 in addition to the fish specific CALCRL3. Strong conservation of CALCRL gene structure exists from human to fish. Promoter analysis in silico reveals that the duplicated CALCRL genes in the teleosts, zebrafish, takifugu, tetraodon and medaka, have divergent promoters and different putative co regulated gene partners suggesting their function is different. PMID- 24815886 TI - OB-RL silencing inhibits the thermoregulatory ability of Great Roundleaf Bats (Hipposideros armiger). AB - Previous studies have shown that the hormone Leptin has an important role in mammalian heterothermy by regulating metabolism and food intake via lipolysis, as well as adaptive evolution of Leptin in heterothermic bats driven by selected pressure. However, the mechanism of Leptin in heterothermic regulation in mammals is unknown. By combining previous results, we speculated that the Leptin signaling pathway mediated by OB-RL (Leptin receptor long form) in the hypothalamus is important. OB-RL is one of the products of db gene and mainly distributed in the hypothalamus. In this study, we used OB-RL as a molecular marker, combining with the RNA interference technology and physiological/molecular analyses with Hipposideros armiger (a hibernating bat species) as an animal model, to explore the mechanism of Leptin in heterothermic regulation. Our data showed that all of four anti-OB-RL shRNA lentivirus significantly inhibited OB-RL expression (>90%), and the interference efficiency of PSC1742 lentivirus reached the highest value. In situ hybridization proved that PSC1742 lentivirus significantly decreased the OB-RL expression in the hypothalamus, especially in the ventromedial hypothalamic nucleus (VHM, 86.6%). Physiological analysis demonstrated that the thermoregulatory ability of bats (e.g., reducing core body temperature and heart rate) was significantly depressed after OB-RL silencing in the hypothalamus, and animals could not enter torpor state. Our study for the first time proved that the knock-down of OB-RL expression in hypothalamus inhibits heterothermic regulation of bats, and also provided the clues for further analyzing the mechanism of Leptin in the heterothermic regulation of mammals. PMID- 24815887 TI - Artificial masculinization in tilapia involves androgen receptor activation. AB - Estrogens have a pivotal role in natural female sexual differentiation of tilapia while lack of steroids results in testicular development. Despite the fact that androgens do not participate in natural sex differentiation, synthetic androgens, mainly 17-alpha-methyltestosterone (MT) are effective in the production of all male fish in aquaculture. The sex inversion potency of synthetic androgens may arise from their androgenic activity or else as inhibitors of aromatase activity. The current study is an attempt to differentiate between the two alleged activities in order to evaluate their contribution to the sex inversion process and aid the search for novel sex inversion agents. In the present study, MT inhibited aromatase activity, when applied in vitro as did the non-aromatizable androgen dihydrotestosterone (DHT). In comparison, exposure to fadrozole, a specific aromatase inhibitor, was considerably more effective. Androgenic activity of MT was evaluated by exposure of Sciaenochromis fryeri fry to the substance and testing for the appearance of blue color. Flutamide, an androgen antagonist, administered concomitantly with MT, reduced the appearance of the blue color and the sex inversion potency of MT in a dose-dependent manner. In tilapia, administration of MT, fadrozole or DHT resulted in efficient sex inversion while flutamide reduced the sex inversion potency of all three compounds. In the case of MT and DHT the decrease in sex inversion efficiency caused by flutamide is most likely due to the direct blocking of the androgen binding to its cognate receptor. The negative effect of flutamide on the efficiency of the fadrozole treatment may indicate that the masculinizing activity of fadrozole may be attributed to excess, un-aromatized, androgens accumulated in the differentiating gonad. The present study shows that when androgen receptors are blocked, there is a reduction in the efficiency of sex inversion treatments. Our results suggest that in contrast to natural sex differentiation, during sex inversion treatments, androgens, either endogenous or exogenous, participate in inducing testicular differentiation. PMID- 24815888 TI - Ligand-induced internalization, recycling, and resensitization of adrenomedullin receptors depend not on CLR or RAMP alone but on the receptor complex as a whole. AB - Adrenomedullins (AM) is a multifaceted distinct subfamily of peptides that belongs to the calcitonin gene-related peptide (CGRP) superfamily. These peptides exert their functional activities via associations of calcitonin receptor-like receptors (CLRs) and receptor activity-modifying proteins (RAMPs) RAMP2 and RAMP3. Recent studies established that RAMPs and CLRs can modify biochemical properties such as trafficking and glycosylation of each other. However there is very little or no understanding regarding how RAMP or CLR influence ligand induced events of AM-receptor complex. In this study, using pufferfish homologs of CLR (mfCLR1-3) and RAMP (mfRAMP2 and mfRAMP3), we revealed that all combinations of CLR and RAMP quickly underwent ligand-induced internalization; however, their recycling rates were different as follows: mfCLR1-mfRAMP3>mfCLR2 mfRAMP3>mfCLR3-mfRAMP3. Functional receptor assay confirmed that the recycled receptors were resensitized on the plasma membrane. In contrast, a negligible amount of mfCLR1-mfRAMP2 was recycled and reconstituted. Immunocytochemistry results indicated that the lower recovery rate of mfCLR3-mfRAMP3 and mfCLR1 mfRAMP2 was correlated with higher proportion of lysosomal localization of these receptor complexes compared to the other combinations. Collectively our results indicate, for the first time, that the ligand-induced internalization, recycling, and reconstitution properties of RAMP-CLR receptor complexes depend on the receptor-complex as a whole, and not on individual CLR or RAMP alone. PMID- 24815889 TI - Allergic rhinitis is a risk factor for traffic safety. AB - BACKGROUND: Allergic rhinitis (AR) affects up to 30% of the adult population and symptomatic patients continue to engage in daily life activities, including car driving. Previous studies have shown that AR can impair cognitive functions, especially during longer-lasting tasks. Other reports suggest negative effects on psychomotor functions such as driving, but no clear evidence has been presented yet. OBJECTIVES: Primary objective was to determine the effect of AR per se on actual driving performance and compare it with the effects of treated AR. METHODS: Nineteen patients with documented AR history underwent a unique and validated 1-h on-the-road driving test outside the pollen season. In a 4-leg repeated measures design, patients underwent a nasal provocation test with either pollen or inactive control prior to the driving test. In the three conditions with pollen provocation, patients were pretreated with either cetirizine 10 mg, fluticasone furoate 27.5 MUg, or placebo to alleviate the provoked AR symptoms. RESULTS: The driving performance of patients when symptomatic and not treated was significantly impaired compared to the placebo condition. When engaging in a secondary memory task during driving, their performance deteriorated further. The magnitude of impairment was relevant and comparable to that seen at a blood alcohol level of 0.05%, the legal limit in many countries. Treatment of AR symptoms partially counteracted the effect of AR on driving. CONCLUSIONS: Untreated AR can impair driving ability and put patients at risk. Drug therapy reduces this impairment, and AR patients should therefore be advised to always treat their condition. PMID- 24815890 TI - Introduction. AB - SUMMARY In this introduction to the Oswald volume, it is argued that there is no politically correct way to design lesbian ritual. Lesbians create their own and participate in rituals that may be punctuated with traditional family of origin, religious, and cultural symbols as well as symbols and practices drawn from lesbian cultures. Lesbians, like everyone else, need to review their ritual lives, to construct rituals that are empowering rather than inhibiting or bereft of meaning, and to delete those that do not express their meanings. The authors herein richly describe and deconstruct a range of rituals participated in by lesbians, speculating on the ways they may be transforming and the ways they may be disaffirming. PMID- 24815891 TI - Death's Midwife. AB - SUMMARY Ritual provided a way for Nance, her lesbian family, and her birth family to care for each other during Nance's diagnosis and death of cancer. "Death's Midwife" tells of the Tuesday night healing rituals and some of the rituals during Nance's dying days. The survivors used ritual in grief and in the memorial service; however, once Nance died the ritual circle fragmented. This short memoir examines how lesbian-created ritual centered, for a while, a lesbian family and community. PMID- 24815892 TI - Lesbian rituals and dianic tradition. AB - SUMMARY In her article, "Lesbian Rituals and Dianic Tradition," Dianic priestess Ruth Rhiannon Barrett, provides a herstorical perspective of the feminist Dianic Wiccan Goddess tradition and its contributions to lesbian culture. The article describes the cosmology of this Goddess-centered and women-identified magical denomination, and the figure of the Goddess Diana as a symbol of women free from patriarchal influences. Barrett's position is that lesbians can heal from, and challenge, internalized and externalized homophobia by creating and sharing in rituals that celebrate significant passages in their lives. Barrett discusses the personal and political importance of ritual-making as a way to honoring and valuing lesbian lives, otherwise invisible in the dominant culture. Drawing upon 30 years of experience, Barrett provides examples from a spectrum of rituals that have been created: coming out, preparing to enter the circle of mothers, and honoring women's conscious choice not to have children. PMID- 24815893 TI - Ritual encounters of the queer kind: a political analysis of jewish lesbian ritual innovation. AB - SUMMARY Jewish feminist and queer engagement in Jewish life and Judaism are transforming the practices and foundational orientations of traditional modes. Jewish feminist, queer ritual innovation in particular is inspired by an array of secular and radical critical theories as much as it is by the historic concrete experiences of a diversity of Jews in different Jewish communities. It is important to hold all of us who are involved in religious ritual innovation responsible to the knowledges we have developed and learned in critical theory or we risk, even with the best of intentions and creativity, re-inscribing some of the very problems of traditional ontological norms that we might have originally sought to disrupt and subvert. This article looks specifically at examples of new "coming out" rituals for Jewish queers explored over time in the Jewish Queer Think Tank: honoring them as well as offering tools from secular critical theory to assist our work in keeping them accountable to our aspirations to both love and fundamentally transform Jewishness. Here I redefine the function of religious ritual itself in political terms as an identity-producing performance. As such I utilize social constructionist queer theories (i.e., Shane Phelan and Judith Butler), anarchists (i.e., Emma Goldman), and those involved in radical theatre (i.e., Augusto Boal) to articulate the revolutionary potential of ritual innovation. PMID- 24815894 TI - The new religious rite: a symbolic interactionist case study of lesbian commitment rituals. AB - SUMMARY Despite the legal and religious establishment's denial of rights and recognition to same-gender couples, many lesbians and gay men are adapting and/or creating their own rituals to affirm their commitments to each other. This article uses participant observation of a black lesbian couple's shower and holy union ceremony to explore the multiple and competing meanings attached to the ritualistic symbols and narratives they incorporated. I seek to complicate the existing framework, in which rituals are held to produce feelings of belonging for participants and serve as vehicles for the social transformation of marginalized groups (e.g., Driver, 1991). By adapting and appropriating ritualistic elements often used in heterosexual weddings, I argue that this couple and their ritual coordinators succeeded in creating a sense of social order, "communitas" (Turner, 1969), and personal and social transformation for some participants. However, I also suggest that the achievement of these functions hinged on the creation of symbolic out-groups and the reproduction of social conventions around gender, the family, and the "appropriate" expression of sex in marriage, which diminished the experience of communitas and social transformation for other participants. Future research should focus on the competing expectations and interpretations participants bring to their experiences of rituals and the ways in which existing structures of power and authority may limit rituals' social functionality, creation of communitas, and revolutionary potential. PMID- 24815895 TI - Do lesbians change their last names in the context of a committed relationship? AB - SUMMARY This exploratory study begins to redress a critical gap in the literature on committed same-sex relationships and last name practices. Data were gathered from an Internet survey, which included 16 lesbian respondents currently in a same-sex relationship. Analyses explored individual, couple, and family of origin factors associated with changing or not changing one's name. Name-changing was cited as a strategy for securing external recognition and acceptance of family status by outsiders. Not changing was cited as a strategy to preserve each partner's individual identity. Contrary to our expectations, changing one's last name was not associated with having a commitment ceremony. Instead, name-changing was ritualized on other occasions, special to the individual couple, such as an anniversary, a partner's birthday, or an intimate dinner party among friends. PMID- 24815896 TI - Fear and loathing in Mississippi: the attack on cAMP sister spirit. AB - SUMMARY In 1993, the small rural community of Ovett, Miss., and a group of self described radical lesbian feminists clashed over the establishment by the women of a feminist educational retreat known as Camp Sister Spirit. This dispute took the form of physical and psychological harassment of the women, wide-open public debate in the community, in the press, and on television, federal mediation efforts, and two lawsuits. This article analyzes this dispute using Mary Daly's seven patterns of the sado-ritual syndrome (Daly, 1978). The analysis examines the ideological and moral standpoints of the participants, the issues of "blaming the victim" and scapegoating, the development of the conflict from a dispute between neighbors to the involvement of international media, national activists and the Clinton Administration, the transformation of the conflict from a political to legal dispute, the representations of the groups within the community and the media, the effect of public opinion on the dispute, and the politics of the media in the dispute. PMID- 24815897 TI - A member of the wedding? Heterosexism and family ritual. AB - SUMMARY Heterosexism as an interpersonal dynamic at weddings was examined using feminist critical science. Data were collected from 45 gay, lesbian, bisexual, and transgender people who attended focus groups. Gay, lesbian, bisexual, and transgender participants described multiple interactions in which they were devalued or hidden while het-erosexuality was elevated, as well as interactions in which they or another family member resisted heterosexism. Weddings were perceived to be difficult, and participation in them was questioned. As part of their critique of weddings, participants offered a vision of relationships that was based on commitment, rather than heterosexuality or material benefits. Results of this study were used to create a brochure and Website for educating heterosexual people planning weddings. PMID- 24815898 TI - Preface. PMID- 24815899 TI - Critical points in the evaluation of analytical methods based on liquid chromatography separation for the determination of doramectin in different environmental samples. AB - In recent years, the number of analytical methods of target compound residues (such as pharmaceuticals) has grown rapidly. Most of them are based on high performance liquid chromatography (HPLC). From the economic point of view, it is usual to apply the conditions of available HPLC methods or to design extraction and chromatographic separation conditions using HPLC and transfer them subsequently to a more sensitive technique like liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). However, if such a transfer is planned, it is important to assess the quality of the newly-designed LC-MS/MS method. The determination of parameters like matrix effects (ME), extraction efficiency (EE) and absolute recovery (AR) is mandatory. These parameters can visualise the weakest step in the analytical method and enable methods based on different techniques to be compared. The aim of this work was to show how quality assessment should be carried out in order to transfer an optimised method from one technique to another. The representative compound used in our investigation was doramectin (DOR), an anthelmintic drug used in veterinary medicine. The quality of the suggested methods for determining this drug in three environmental matrices (water, sediment and fish tissue) using HPLC-UV and LC-MS/MS was evaluated on the basis of known values of absolute recovery (HPLC-UV) and matrix effect, extraction efficiency and absolute recovery (all LC-MS/MS). Finally, the suggested methods for determining DOR in water, sediment and fish tissue based on LC-MS/MS measurements were validated and applied to the analysis of real environmental samples. PMID- 24815900 TI - Perfluoroalkyl and polyfluoroalkyl substances in entire clutches of Audouin's gulls from the Ebro Delta. AB - The aim of the present study was to determine the distribution of per- and polyfluoroalkyl substances (PFASs) in three-egg clutches of Audouin's gull (Larus audouinii) breeding in Ebro Delta's colony according to the laying order (a, b and c eggs). Five PFASs were analyzed in 30 eggs (yolk and albumen separately), corresponding to 10 three-egg clutches. Carbon and nitrogen stable isotopes were measured as dietary tracers. PFASs were not detected in albumen. In egg yolks, perfluorooctane sulfonate (PFOS) was the main compound detected followed by perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHS) and perfluorooctanoic acid (PFOA). Perfluorooctane sulfonate (PFBS) was not detected. Mean SigmaPFASs for a-eggs was of 236+/-57 ng g(-1) yolk wet weight (ww), for b eggs was of 140+/-56 ng g(-1) yolk ww and for c-eggs, 133+/-54 ng g(-1) yolk ww. PFOS concentration decreased according to the laying order of the eggs, showing significant differences between consecutive eggs. In addition, significant correlation (rs2=0.7-0.9) was observed for PFOS concentration within the eggs from the same clutch. No relationship was found between PFOS levels and stable isotopes signatures. Capsule: In Audouin gull's eggs, PFOS was the main PFASs detected and its concentration decreased according to the laying sequence. PMID- 24815901 TI - The photolytic activity of poly-arginine cell penetrating peptides conjugated to carboxy-tetramethylrhodamine is modulated by arginine residue content and fluorophore conjugation site. AB - Upon light irradiation, Fluorophore-cell-penetrating peptide (Fl-CPP) conjugates can disrupt the integrity of biological membranes. This activity can in turn be used to photoinduce the disruption of endocytic organelles and promote the delivery of entrapped macromolecules such as proteins or RNAs into live cells. Recent mechanistic studies have shown that ROS production by the fluorophore and a latent lytic ability of CPPs act in synergy to elicit photolysis. However, how the structure of fluorophore-CPP conjugates impacts this synergistic activity remains unclear. Herein, using red blood cells (RBCs) as a model of biological membranes, we show that the number of arginine residues in a CPP as well as the position of fluorophore with respect to the CPP dramatically affect the photolytic activity of a fluorophore-CPP conjugate. These factors should therefore be considered for the development of effective photoinducible delivery agents. PMID- 24815902 TI - Seizures in fetal alcohol spectrum disorders: evaluation of clinical, electroencephalographic, and neuroradiologic features in a pediatric case series. AB - Seizures are observed with a frequency of 3-21% in children with fetal alcohol spectrum disorders (FASD). However, clinical, neuroradiologic, and electroencephalography (EEG) features are poorly described. In this study, 13 patients with FASD and epilepsy or seizures were identified retrospectively from the databases of seven Italian pediatric neurology divisions. Eleven children were affected by epilepsy, and two had at least one documented seizure. Both generalized and focal seizures were observed. EEG showed diffuse or focal epileptic activity; two children developed electric status epilepticus during sleep (ESES). Structural brain anomalies, including polymicrogyria, nodular heterotopia, atrophy, and Arnold-Chiari type 1 malformation, were discovered in almost 50% of patients. Control of seizures was not difficult to obtain in 11 cases; one patient showed pharmacoresistant epilepsy. EEG and clinical follow-up are recommended in children with FASD and epilepsy, since severe conditions requiring aggressive treatment, such as in ESES, may develop. Neuroradiological evaluation is warranted because several types of brain anomalies could be associated with maternal alcohol consumption during pregnancy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24815903 TI - Prevention of involuntary admission through Family Group Conferencing: a qualitative case study in community mental health nursing. AB - AIM: To understand whether and how Family Group Conferencing might contribute to the social embedding of clients with mental illness. BACKGROUND: Ensuring the social integration of psychiatric clients is a key aspect of community mental health nursing. Family Group Conferencing has potency to create conditions for clients' social embedding and subsequently can prevent coercive measures. DESIGN: A naturalistic qualitative case study on the process of one conference that was part of 41 conferences that had been organized and studied from January 2011 September 2013 in a public mental health care setting in the north of the Netherlands. METHODS: Semi-structured interviews (N = 20) were conducted with four stakeholder groups (N = 13) involved in a conference on liveability problems in a local neighbourhood wherein a man with schizophrenia resides. FINDINGS: To prevent an involuntary admission to a psychiatric ward of a man with schizophrenia, neighbourhood residents requested a family group conference between themselves, the sister of the man and the mental health organization. As a possible conference aggravated psychotic problems, it was decided to organize it without the client. Nine months after the conference, liveability problems in the neighbourhood had been reduced and coercive measures adverted. The conference strengthened the community and resulted in a plan countering liveability problems. CONCLUSION: The case indicates that social embedding of clients with severe psychiatric problems can be strengthened by Family Group Conferencing and that hence coercive measures can be prevented. A shift is required from working with the individual client to a community driven approach. PMID- 24815904 TI - Desire for fertility among HIV-seroconcordant and -discordant couples in Lusaka, Zambia. AB - Pregnancy rates and the desire to conceive are increasing among women living with HIV in Africa. However, attempts to conceive may increase the risk of HIV transmission or reinfection. A better understanding of factors influencing fertility desires would significantly contribute to programmes to meet the reproductive needs of women living with HIV. Using a couples-based approach, this paper explored fertility desires among HIV-seroconcordant and -discordant couples in Lusaka, Zambia. Participants were 208 heterosexual couples recruited from community health clinics and their respective catchment areas. Couples completed assessments on demographics, condom use, relationship quality and communication. Desire for children was often shared among couple members, and the strongest predictor of participants' desire for children was having a partner who wanted children. Additionally, the number of children participants had, their own reports of positive communication, and their partner's HIV serostatus influenced reproductive desires. Results support the involvement of both couple members in pre-conception counselling and pregnancy planning interventions. The inclusion of both partners may be a more effective strategy to respond to the reproductive needs of couples affected by HIV, enabling them to safeguard the health of both partners and infants. PMID- 24815905 TI - Cu(II)-catalyzed oxidation of dopamine in aqueous solutions: mechanism and kinetics. AB - Spontaneous oxidation of dopamine (DA) and the resultant formation of free radical species within dopamine neurons of the substantia nigra (SN) is thought to bestow a considerable oxidative load upon these neurons and may contribute to their vulnerability to degeneration in Parkinson's disease (PD). An understanding of DA oxidation under physiological conditions is thus critical to understanding the relatively selective vulnerability of these dopaminergic neurons in PD and may support the development of novel neuro-protective approaches for this disorder. In this study, the oxidation of dopamine (0.2-10MUM) was investigated both in the absence and the presence of copper (0.01-0.4MUM), a redox active metal that is present at considerable concentrations in the SN, over a range of background chloride concentrations (0.01-0.7M), different oxygen concentrations and at physiological pH7.4. DA was observed to oxidize extremely slowly in the absence of copper and at moderate rates only in the presence of copper but without chloride. The oxidation of DA however was significantly enhanced in the presence of both copper and chloride with the rate of DA oxidation greatest at intermediate chloride concentrations (0.05-0.2M). The variability of the catalytic effect of Cu(II) on DA oxidation at different chloride concentrations can be explained and successfully modeled by appropriate consideration of the reaction of Cu(II) species with DA and the conversion of Cu(I) to Cu(II) through oxygenation. This model suggests that the speciation of Cu(II) and Cu(I) is critically important to the kinetics of DA oxidation and thus the vulnerability to degradation of dopaminergic neuron in the brain milieu. PMID- 24815906 TI - Preparation, transportation mechanisms and brain-targeting evaluation in vivo of a chemical delivery system exploiting the blood-cerebrospinal fluid barrier. AB - In recent years, specific transportation mechanisms on the blood-brain barrier (BBB) are extensively employed for brain-targeted drug delivery via colloidal nanocarriers. However, in this study, we purposed to exploit the sodium-dependent vitamin C transporter 2 (SVCT2)-mediated transportation on the blood cerebrospinal fluid barrier to enhance central nervous system penetration of the highly hydrophilic ibuprofen (IBU) by synthesizing a SVCT2-targeted chemical delivery system (CDS), ibuprofen-C6-O-ascorbic acid (IAA). The physicochemical parameters of IAA were determined, and the transporter-mediated transportation mechanism of IAA was explored on a BBB monolayer mode. The overall brain targeting effect of IAA was assayed on mice by measuring the biodistribution of IBU after i.v. administration and calculating the pharmacokinetic parameters and targeting indexes. Results showed that lipophilicity and solubility of IAA was conspicuously improved compared with IBU. At the physiological pH, IAA was stable while in brain homogenates it was easily degraded. Transport studies on the BBB monolayer mode revealed that IAA displayed higher transepithelial permeability than IBU via SVCT2. The biodistribution study in vivo demonstrated that the overall targeting efficiency of IAA was 1.77-fold greater than that of the IBU. In conclusion, the synthetic IAA might be a promising brain-targeted CDS for smuggling small-molecule hydrophilic pharmaceuticals into the brain. PMID- 24815907 TI - Utilization of assay performance characteristics to estimate hemoglobin A1c result reliability. AB - BACKGROUND: Allowable total error (TE(a)) goals for hemoglobin (Hb) A(1c) require minimal assay imprecision and bias and implementation of a robust QC monitoring program. Here, we compare the combined influence on the risk of reporting unreliable results of TE(a) goals, a routine QC practice, and assay performance characteristics of 6 Hb A(1c) instruments across 4 academic medical centers. METHODS: The CLSI protocols EP-5 and EP-9 were applied to investigate Hb A(1c) result imprecision and bias on the Variant II Turbo and Variant II (Bio-Rad), G8 (Tosoh), Capillarys 2 Flex Piercing (Sebia), COBAS Integra 800 (Roche), and DCA Vantage (Siemens). Patient-weighted sigma values and the risk of reporting unreliable Hb A(1c) results were determined for each assay at TE(a) specifications of 5%, 6%, and 7%. RESULTS: A large range of patient-weighted sigma values spanning 0.5 orders of magnitude at a 6% TE(a) was observed. Although imprecision for all instruments was <3%, bias impacted the majority of the sigma changes observed. Estimates for reporting unreliable results varied almost 500-fold based on analytical performance alone. CONCLUSIONS: Considerable differences in the probability of reporting unreliable Hb A(1c) results between different NGSP (formerly the National Glycohemoglobin Standardization Program) certified platforms were observed. At a 6% TE(a), our study indicates all but the Capillarys 2 Flex Piercing requires that the maximum affordable QC be run. Risk estimates for individual laboratories' Hb A(1c) methods can be used to assess QC practices and residual risk of an unreliable Hb A(1c) result. PMID- 24815908 TI - Mortality predicted by preinduction cerebral oxygen saturation after cardiac operation. AB - BACKGROUND: An intraoperative decline in regional cerebral oxygen saturation (rSO2) has been associated with postoperative injury to the central nervous system. Wide individual variation in steady-state cerebral oxygen saturation limits the clinical use of rSO2 to monitoring during anesthesia and surgical procedures. Recently, low preoperative rSO2 has been proposed as a predictor of adverse postoperative outcomes in cardiovascular operations. We compared the sensitivity and specificity of preinduction rSO2 as a predictor of adverse operative events and compared this to the widely accepted risk index developed by the Society for Thoracic Surgeons. METHODS: 2,097 consecutive white patients who underwent cardiac operations from 2010 through 2012 were included. In 1,496 patients (group 1) the preinduction rSO2 was equal to or greater than 60%, whereas in the remaining 601 patients (group 2) it was below 60%. We compared the predictive accuracy of preinduction rSO2 with that of the STS mortality risk score by means of standard statistical techniques, including a receiver operating curve characteristic analysis. RESULTS: Patients with a preinduction rSO2 below 60% had significantly higher STS mortality risk scores than did patients with an rSO2 equal to or greater than 60% (2.0 vs 4.0, p<0.001). Those with an rSO2 below 60% experienced higher operative mortality (p<0.001) and after adjustment this determination emerged as an independent predictor of increased mortality (p<0.001). Receiver operating characteristic curve analysis demonstrated that the rSO2 was slightly less accurate as a mortality predictor (area under the curve: 0.71 vs 0.85). CONCLUSIONS: Measurement of rSO2 is considerably less complex than calculation of the STS score and is only slightly less accurate as a predictor of operative mortality. It may be useful when the STS mortality risk score cannot be calculated. PMID- 24815909 TI - Potential roles for interactions between the mitochondrial and nuclear DNA throughout the cell cycle of Schizosaccharomyces pombe. AB - Over the course of mitochondrial evolution, the majority of genes required for its function have been transferred and integrated into nuclear chromosomes. Ongoing transfer of mitochondrial DNA to the nucleus has been detected, but its functional significance has not been fully elucidated. Here by Genome Conformation Capture, we identify DNA-DNA interactions between the mitochondrial and nuclear chromosomes (mt-nDNA interactions) that vary in strength and number between the G1, G2 and M phases of the fission yeast cell cycle. Mt-nDNA interactions captured in mitotic anaphase were associated with nuclear genes required for the regulation of cell growth and energy availability. Furthermore, mt-nDNA interactions captured in the G1 phase involved high efficiency, early firing origins of DNA replication. Collectively, these results suggest functional roles for the ongoing transfer of regions of the mitochondrial genome to the nucleus. PMID- 24815910 TI - Participant-perceived quality of life in a long-term, open-label trial of lisdexamfetamine dimesylate in adolescents with attention-deficit/hyperactivity disorder. AB - OBJECTIVES: The purpose of this study was to assess long-term improvement in quality of life (QOL) in adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with lisdexamfetamine dimesylate (LDX). METHODS: Adolescents with ADHD treated for >=3 weeks in a 4 week, placebo-controlled study entered a 1 year, open-label study. After the 4 week dose optimization (30, 50, and 70 mg/day LDX) period, treatment was maintained for 48 additional weeks. Change from baseline (of prior study) to week 52/early termination (ET) (of open label study) in ADHD Rating Scale IV (ADHD-RS-IV) assessed effectiveness, and the Youth QOL-Research Version (YQOL-R) assessed participant-perceived QOL. Post-hoc analyses described effectiveness and QOL for participants with self-perceived poor QOL at baseline (>=1 SD below the mean) versus all others, and for study completers versus study noncompleters. RESULTS: These post-hoc analyses included 265 participants. Participants with baseline self-perceived poor QOL (n=32) versus all others (n=232) exhibited robust YQOL-R perceptual score changes (improvement) with LDX, emerging by week 28 and maintained to week 52/ET. Week 52/ET mean change score ranged from +9.8 to +17.6 for participants with baseline self-perceived poor QOL and +0.4 to +5.1 for all others; week 52/ET improvements in ADHD-RS-IV total scores were similar, regardless of baseline YQOL-R total score. At week 52/ET, study completers had greater YQOL-R improvements than did noncompleters; ADHD-RS-IV total score changes were also numerically larger at week 52/ET for completers than for noncompleters. CONCLUSION: Participant perceived QOL and ADHD symptoms improved from baseline with LDX in adolescents with ADHD; greatest improvements occurred among participants with baseline self perceived poor QOL. PMID- 24815912 TI - Metabolism of DNA secondary structures at the eukaryotic replication fork. AB - DNA secondary structures are largely advantageous for numerous cellular processes but can pose specific threats to the progression of the replication machinery and therefore genome duplication and cell division. A number of specialized enzymes dismantle these structures to allow replication fork progression to proceed faithfully. In this review, we discuss the in vitro and in vivo data that has lead to the identification of these enzymes in eukaryotes, and the evidence that suggests that they act specifically at replication forks to resolve secondary structures. We focus on the role of helicases, which catalyze the dissociation of nucleotide complexes, and on the role of nucleases, which cleave secondary structures to allow replication fork progression at the expense of local rearrangements. Finally, we discuss outstanding questions in terms of dismantling DNA secondary structures, as well as the interplay between diverse enzymes that act upon specific types of structures. PMID- 24815911 TI - Intraobserver and interobserver variability in diagnosing scapholunate dissociation by cineradiography. AB - PURPOSE: To evaluate the intraobserver and interobserver variability in diagnosing scapholunate dissociation (SLD) by wrist cineradiography. METHODS: A musculoskeletal radiologist, hand surgeon, and trauma surgeon assessed the records of 50 consecutive wrist cineradiographies performed in 25 patients. Fluoroscopy was performed on the unaffected and affected wrist and consisted of radiographer-controlled passive flexion-extension and passive radial-ulnar deviation in both posteroanterior and lateral projections. To determine the intraobserver variability, the 3 reviewers reassessed all wrist cineradiographies 6 months after their first assessment. The kappa coefficient for interobserver agreement was calculated using the jackknife method. The Cohen kappa was used to assess intraobserver variability. RESULTS: The interobserver variability for diagnosing SLD by cineradiography was excellent (kappa = 0.84). The intraobserver variability for the hand surgeon was excellent (kappa = 0.80), and was good for the radiologist (kappa = 0.72) and the trauma surgeon (kappa = 0.76). CONCLUSIONS: Cineradiography is a promising and helpful, noninvasive tool for diagnosing SLD. It is widely available and has relatively low costs. Conventional radiographs remain essential in the primary workup for suspected SLD. However, we recommend cineradiography when an SLD is clinically suspected. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 24815913 TI - Hemispherotomy in Rasmussen encephalitis: long-term outcome in an Italian series of 16 patients. AB - Surgical disconnection of the affected hemisphere is considered the treatment of choice for Rasmussen encephalitis (RE), however few data on long-term outcomes after disconnective surgery are available. We report on long-term seizure, cognitive and motor outcomes after disconnective surgery in 16 (8 M, 8 F) RE patients. Pre- and post-operative evaluations included long-term video-EEG monitoring, MRI, assessment of motor function, and cognitive evaluation. Hemispherotomy, by various techniques was used to obtain functional disconnection of the affected hemisphere. The patients, of median current age 23.5 years, range 12-33, were operated on between 1993 and 2009. Median age at disease onset was 5.8 years (range 3-11.4). Median time from seizure onset to surgery was 3.8 years, range 8 months to 21 years. Post-surgical follow-up was a median of 9.5 years, range 3-20. At surgery all patients were receiving two or more antiepileptic drugs (AEDs). All but three patients were seizure-free at latest follow-up. AEDs had been stopped in ten patients; in the remaining six AEDs were markedly reduced. Postural control improved in all patients. Gain in cognitive functioning was significantly (p=0.002) related to disease duration. The long term outcomes, in terms of seizure control, motor improvement, and cognitive improvement provide important support for disconnective surgery as first choice treatment for RE. PMID- 24815914 TI - Effects of light activated in-office bleaching on permeability, microhardness, and mineral content of enamel. AB - The aim of this study was to evaluate the permeability (PE), microhardness (KHN), and mineral change in enamel after LED/laser activated in-office bleaching. For PE, the coronal portion of premolars (n=51) was subjected to bleaching with 35% hydrogen peroxide (Whiteness HP Maxx, FGM Dental Products, Joinville, SC, Brazil). The samples were stained via the histochemical method, which involves a copper sulphate solution and rubeanic acid. The penetration of dye into the enamel was measured. The KHN of enamel was assessed before treatment, immediately after the bleaching treatment, and again after one week. The calcium and phosphorus content were analyzed with a scanning electron microscope with energy dispersive X-ray (JSM 6360LV, Jeol Ltd, Tokyo, Japan). The data set from each test was subjected to appropriate parametric statistical analysis (alpha=0.05). No significant differences were observed for PE in NLA and LA compared to the control group (p=0.98), as well as for calcium (p=0.16) and phosphorus (p=0.80) content. Significant reduction of KHN after bleaching occurred for both groups (p<0.001). After immersion in artificial saliva, the KHN of the enamel for all groups was similar to that seen before bleaching. Light activation during in office bleaching does not produce significant changes in the enamel compared to a non-light-activated technique. PMID- 24815915 TI - Effect of different matrix metalloproteinase inhibitors on microtensile bond strength of an etch-and-rinse and a self-etching adhesive to dentin. AB - AIM: This study aimed to analyze the effect of different matrix metalloproteinase (MMP) inhibitors on the microtensile bond strength (microTBS) of an etch-and rinse and a self-etching adhesive after 9 months of aging. METHODS AND MATERIALS: Flat human dentin surfaces were bonded either with an etch-and-rinse adhesive (Optibond FL) or a self-etching adhesive (Clearfil SE Bond). Dentin surfaces were left untreated or were pretreated with MMP inhibitors (2% chlorhexidine digluconate [CHX], 0.05% green tea extract, 1 mM ferrous sulfate, or 0.2 mM galardin) prior to application of the adhesive. Composite buildups were made incrementally. Pretreated groups were tested after 9 months of storage in artificial saliva (37 degrees C) and compared with untreated groups, which were tested immediately (initial microTBS) and upon aging (9-month microTBS). Data were analyzed by linear mixed-model regression. Failure mode analysis was performed microscopically and statistically analyzed by repeated-measures analysis of variance (p<0.05). RESULTS: MicroTBS of the etch-and-rinse adhesive but not of the self-etching adhesive was significantly decreased by aging. For Optibond FL, pretreatment with 2% CHX, 0.05% green tea extract, and 0.2 mM galardin revealed bond strength values (MPa) similar to the initial microTBS (32.1+/-14.8) and significantly higher compared with the microTBS (20.3+/-13.6) of aged untreated dentin. No significant differences were observed between groups bonded with Clearfil SE Bond (initial microTBS: 28.3+/-12.4; 9-month microTBS: 25.3+/-11.8). Application of the MMP inhibitors decreased the number of adhesive failures compared with untreated controls after 9 months of aging, but this effect was not significant. CONCLUSION: The MMP inhibitors prevented the decrease in microTBS upon aging of the etch-and-rinse but not of the self-etching adhesive. PMID- 24815916 TI - Dissecting the cell to nucleus, perinucleus and cytosol. AB - Cells have been described under the microscope as organelles containing cytoplasm and the nucleus. However, an unnoted structure exists between the cytoplasm and the nucleoplasm of eukaryotic cells. In addition to the nuclear envelope, there exists a perinuclear region (PNR or perinucleus) with unknown composition and function. Until now, an investigation of the role of the perinucleus has been restricted by the absence of a PNR isolation method. This manuscript describes a perinucleus isolation technique on the basis of its unique compact organization. The perinucleus was found to contain approximately 15 to 18% of the total proteins of the mammalian cell, almost half of the proteins of nuclei. Using four different normal and cancer cell lines, it was shown that the composition of PNR is highly dynamic. Application of the method showed that translocation of the p53 tumor-suppressor protein to the perinucleus in immortalized MEF cells is correlated with the translocation of p53-stabilizing protein, nucleophosmin (B23), to the PNR. Herein, the concept of the perinuclear region is advanced as a formal, identifiable structure. The roles of the perinucleus in maintaining genome integrity, regulation of gene expression and understanding of malignant transformation are discussed. PMID- 24815917 TI - Indirubin-3'-oxime, an activator of Wnt/beta-catenin signaling, enhances osteogenic commitment of ST2 cells and restores bone loss in high-fat diet induced obese male mice. AB - Obesity is a growing issue of the modern world, and its negative impact on bones in obese male patients has been recently reported. The Wnt/beta-catenin pathway has an established role in the regulation of body fat content and bone density. We investigated the effects of indirubin-3'-oxime (I3O), the GSK3beta inhibitor that activates Wnt/beta-catenin signaling, on trabecular bone in high-fat diet (HFD)-induced obese male mice. I3O reverses the downregulating effect of fatty acid (FA) on Wnt/beta-catenin signaling and enhances the osteogenic commitment of the bone marrow-derived stromal cell line ST2. FA induces the adipogenic differentiation of bone marrow stromal cells in vitro. In a male mouse model of HFD-induced obesity, trabecular bone loss was observed in the femora, with a gross increase in abdominal fat; however, the HFD effects were rescued with the activation of Wnt/beta-catenin signaling by I3O treatment. I3O administration also reversed the increase in the number of HFD-induced adipocytes in the femur bone marrow in trabecular bone. Overall, our results indicate that I3O could be a potential therapeutic agent for obese male patients through downregulation of abdominal fat and net increment in trabecular bone density. PMID- 24815918 TI - Gene expression profile induced by ovariectomy in bone marrow of mice: a functional approach to identify new candidate genes associated to osteoporosis risk in women. AB - Osteoporosis is a multifactorial skeletal pathology with a main genetic component. To date, however, the majority of genes associated with this pathology remain unknown since genes cataloged to date only explain a part of the heritability of bone phenotypes. In the present study, we have used a genome-wide gene expression approach by means of microarrays to identify new candidate genes involved in the physiopathology of osteoporosis, using as a model the ovariectomized (OVX) mice by comparing global bone marrow gene expression of the OVX mice with those of SHAM operated mice. One hundred and eighty transcripts were found to be differentially expressed between groups. The analysis showed 23 significant regulatory networks, of which the top five canonical pathways included B-cell development, primary immunodeficiency signaling, PI3K signaling in B-cells, phospholipase C signaling, and FcgRIIB signaling in B-cells. Twelve differentially expressed genes were validated by MALDI-TOF mass spectrometry with good reproducibility. Finally, the association to bone phenotypes of SNPs in genes whose expression was increased (IL7R and CD79A) or decreased (GPX3 and IRAK3) by OVX in mice was analyzed in a cohort of 706 postmenopausal women. We detected an association of a SNP in a gene involved in the detoxification of free radicals like glutathione peroxidase 3 (GPX3) with femoral neck BMD (rs8177447, P=0.043) and two SNPs in the Ig-alpha protein of the B-cell antigen component gene (CD79A) with lumbar spine BMD (rs3810153 and rs1428922, P=0.016 and P=0.001, respectively). These results reinforce the role of antioxidant pathways and of B cells in bone metabolism. Furthermore, it shows that a genome-wide gene expression approach in animal models is a useful method for detecting genes associated to BMD and osteoporosis risk in humans. PMID- 24815919 TI - Insulinogenic sucrose+amino acid mixture ingestion immediately after resistance exercise has an anabolic effect on bone compared with non-insulinogenic fructose+amino acid mixture in growing rats. AB - Maximizing peak bone mass is an important factor in osteoporosis prevention. Resistance exercise increases bone mass and strength, while nutritional supplements have beneficial effects on bone loss reduction. We have previously shown that the combined intake of sucrose and amino acids (AA), which is strongly insulinogenic, efficiently increased muscle protein synthesis. To investigate the effects of sugar and an AA solution immediately after resistance exercise, we compared insulinogenic sucrose and non-insulinogenic fructose combined with an AA solution with or without resistance exercise. Sucrose intake immediately after resistance exercise increased the trabecular bone mass and compressive maximum load compared with fructose+AA intake after exercise. Additionally, combined sucrose+AA and exercise increased trabecular bone formation and decreased bone resorption more than combined fructose and exercise. Serum insulin levels were greatly increased by sucrose+AA intake with exercise. In culture experiments, neither sugar+AA affected osteoblast and osteoclast differentiation. In a gene expression study, sucrose+AA intake after resistance exercise was shown to upregulate the Runx2 expression level and decrease RANKL/OPG ratio. These results suggest that the combined intake of sucrose and an AA solution immediately after resistance exercise exerts anabolic effects on bone by altering gene expression related to bone remodeling. Although translation of our bone remodeling findings from animal to human studies has been challenging, our findings suggest that exercise with sugar+AA intake may contribute to improved bone health. PMID- 24815920 TI - Validation of a heterologous fertilization assay and comparison of fertilization rates of equine oocytes using in vitro fertilization, perivitelline, and intracytoplasmic sperm injections. AB - IVF in horses is rarely successful. One reason for this could be the failure of sperm to fully capacitate or exhibit hyperactive motility. We hypothesized that the zona pellucida (ZP) of equine oocytes prevents fertilization in vitro, and bypassing the ZP would increase fertilization rates. Limited availability of equine oocytes for research has necessitated the use of heterologous oocyte binding assays using bovine oocytes. We sought to validate an assay using bovine oocytes and equine sperm and then to demonstrate that bypassing the ZP using perivitelline sperm injections (PVIs) with equine sperm capacitated with dilauroyl phosphatidylcholine would result in higher fertilization rates than standard IVF in bovine and equine oocytes. In experiment 1, bovine oocytes were used for (1) IVF with bovine sperm, (2) IVF with equine sperm, and (3) intracytoplasmic sperm injections (ICSIs) with equine sperm. Presumptive zygotes were either stained with 4',6-diamidino-2-phenylindole from 18 to 26 hours at 2 hour intervals or evaluated for cleavage at 56 hours after addition of sperm. Equine sperm fertilized bovine oocytes; however, pronuclei formation was delayed compared with bovine sperm after IVF. The delayed pronuclear formation was not seen after ICSI. In experiment 2, bovine oocytes were assigned to the following five groups: (1) cumulus oocyte complexes (COCs) coincubated with bovine sperm; (2) COC exposed to sucrose then coincubated with bovine sperm; (3) COC coincubated with equine sperm; (4) COC exposed to sucrose, and coincubated with equine sperm; and (5) oocytes exposed to sucrose, and 10 to 15 equine sperm injected into the perivitelline (PV) space. Equine sperm tended (P = 0.08) to fertilize more bovine oocytes when injected into the PV space than after IVF. In experiment 3, oocytes were assigned to the following four groups: (1) IVF, equine, and bovine COC coincubated with equine sperm; (2) PVI of equine and bovine oocytes; (3) PVI with equine oocytes pretreated with sucrose; and (4) ICSI of equine oocytes. Oocytes were examined at 24 hours for cleavage. No equine oocytes cleaved after IVF or PVI. However, ICSI conducted with equine sperm treated with dilauroyl phosphatidylcholine resulted in 85% of the oocytes cleaving. Sperm injected into the PV space of equine oocytes did not appear to enter the ooplasm. This study validated the use of bovine oocytes for equine sperm studies and indicates that failure of equine IVF is more than an inability of equine sperm to penetrate the ZP. PMID- 24815921 TI - Protein inference using Peptide quantification patterns. AB - Determining the list of proteins present in a sample, based on the list of identified peptides, is a crucial step in the untargeted proteomics LC-MS/MS data processing pipeline. This step, commonly referred to as protein inference, turns out to be a very challenging problem because many peptide sequences are found across multiple proteins. Current protein inference engines typically use peptide to spectrum match (PSM) quality measures and spectral count information to score protein identifications in LC-MS/MS data sets. This is, however, not enough to confidently validate or otherwise rule out many of the proteins. Here we introduce the basis for a new way of performing protein inference based on accurate quantification patterns of identified peptides using the correlation of these patterns to validate peptide to protein matches. For the first implementation of this new approach, we focused on (1) distinguishing between unambiguously and ambiguously identified proteins and (2) generating hypotheses for the discrimination of subsets of the ambiguously identified proteins. Our preprocessing pipelines support both labeled LC-MS/MS or label-free LC-MS followed by LC-MS/MS providing the peptide quantification. We apply our procedure to two published data sets and show that it is able to detect and infer proteins that would otherwise not be confidently inferred. PMID- 24815922 TI - Epstein-Barr virus infection in adult renal transplant recipients. AB - Epstein-Barr virus (EBV) DNAemia in the first year posttransplantation has been studied extensively. There is a paucity of information on prevalence and sequelae of EBV infection in adult renal transplantation beyond the first year. This single-center study examines the relationship between EBV DNAemia and demographic, immunosuppressive, hematologic and infection-related parameters in 499 renal transplant recipients between 1 month and 33 years posttransplant. Participants were tested repeatedly for EBV DNAemia detection over 12 months and clinical progress followed for 3 years. Prevalence of DNAemia at recruitment increased significantly with time from transplant. In multivariate adjusted analyses, variables associated with DNAemia included EBV seronegative status at transplant (p = 0.045), non-White ethnicity (p = 0.014) and previous posttransplant lymphoproliferative disease (PTLD) diagnosis (p = 0.006), while low DNAemia rates were associated with mycophenolate mofetil use (p < 0.0001) and EBV viral capsid antigen positive Epstein-Barr nuclear antigen-1 positive serostatus at transplant (p = 0.044). Patient and graft survival, rate of kidney function decline and patient reported symptoms were not significantly different between EBV DNAemia positive and negative groups. EBV DNAemia is common posttransplant and increases with time from transplantation, but EBV DNAemia detection in low-risk (seropositive) patients has poor specificity as a biomarker for future PTLD risk. PMID- 24815923 TI - Changing role of formulation in biologics drug development. PMID- 24815924 TI - Delivering the promise of SFC: a case study. AB - During the past years there has been a rapid development in supercritical fluid chromatography (SFC) instrumentation making it a highly efficient and robust technique. Although much is written about the advantages of SFC over liquid chromatography (LC), there are not many direct comparisons detailing the gain in purification throughput, the savings in solvent consumption and the reduced environmental impact for large-scale SFC applications. We will show that a research scale separation laboratory built to handle multigram amounts can be used for kilogram separations when moving from LC to SFC. PMID- 24815925 TI - Effects of herbage allowance of native grasslands in purebred and crossbred beef cows: metabolic, endocrine and hepatic gene expression profiles through the gestation-lactation cycle. AB - Our objective was to evaluate the metabolic, endocrine and hepatic mRNA profiles through the gestation-lactation cycle in purebred (PU: Angus and Hereford) and crossbred (CR: reciprocal F1 crosses) mutliparous beef cows (n=32), grazing on two herbage allowances of native pastures (2.5 v. 4 kg dry matter/kg BW; LO v. HI) and their associations with cow's productive performance (calf birth weight, milk production and commencement of luteal activity). Cow BW, body condition score (BCS) and blood samples were collected monthly, starting at -165 days relative to calving (days), and every 2 weeks after calving until +60 days of lactation. Liver biopsies were collected at -165, -75, -45, -15+/-10, and +15 and +60+/-3 days. Metabolic, endocrine and hepatic gene expression profiles, and calf birth weight, milk yield and postpartum commencement of luteal activity were evaluated. Overall, the most pronounced changes in metabolic, endocrine and hepatic gene expression occurred during winter gestation (-165 to -45 days), when all cows experienced the onset of a negative energy balance (decreased BCS, glucose and insulin, and increased non-esterified fatty acid concentrations, P<0.008). Concentrations of insulin and IGF-I were greater (P<0.037) in HI than in LO cows. However, serum IGF-I concentrations and hepatic growth hormone receptor (GHR) and IGF1 mRNA decreased (P<0.05) during the winter gestation period only in HI cows. Although IGF-I concentrations decreased (P<0.05) during the early postpartum (-15 v.+15 days) for all cows, the typical molecular mechanism that control the uncoupling of the growth hormone-IGF1 axis during the transition period of the dairy cattle (reduced hepatic GHR1A and IGF-I mRNA) was not observed in this study. The hepatic mRNA expression of key transcripts involved in gluconeogenesis and fatty-acid oxidation were upregulated (P<0.05) during winter gestation (from -165 to -45, -15 or +15 days, depending on the cow groups). Particularly, acyl-CoA oxidase-1 mRNA was greater for CR than for PU cows during winter gestation (-75 and -45 days), and fibroblast growth factor-21 mRNA was downregulated (P<0.01) only for HI cows during the transition (-15 v. 15 days) and lactation period (+15 to +60 days, P<0.01). These results, together with the greater BCS, estimated energy intake, increased milk yield and shorter commencement of luteal activity in HI than in LO, and in CR than in PU cows (P<0.018), would indicate that HI and CR cows were able to adapt more efficiently to changes in nutrient and energy supply through the gestation-lactation cycle. PMID- 24815926 TI - The quest to reduce the risk of adverse medical events in exercising individuals: introducing the SAFER (Strategies to reduce Adverse medical events For the ExerciseR) studies. PMID- 24815927 TI - Older females are at higher risk for medical complications during 21 km road race running: a prospective study in 39 511 race starters--SAFER study III. AB - BACKGROUND: The half-marathon (21 km) race is a very popular mass community-based distance running event. It is important to determine risk factors for medical complications during these events, so that prevention programmes can be developed. OBJECTIVE: To determine risk factors associated with medical complications during 21 km road running events. DESIGN: Prospective study. SETTING: Two Oceans half-marathon (21 km) races. PARTICIPANTS: 39 511 starters in the 21 km race. METHODS: Medical complications (defined as any runner requiring assessment by a doctor at the race medical facility or a local hospital on race day) were recorded over a 4-year study period. Medical complications were subdivided according to the system affected and by final diagnosis. A Poisson regression model was used to determine risk factors for any medical complication and more common specific complications. RESULTS: Independent risk factors for medical complication during 21 km running were older female runners (women >50 vs <=50 years; p<0.0001) and year of observation (2008 vs 2011; p=0.0201: 2009 vs 2011: p=0.0019; 2010 vs 2011: p=0.0096). Independent risk factors for specific common medical complications were: postural hypotension (women, slow running pace), musculoskeletal complications (less running experience, slower running pace) and dermatological complications (women). CONCLUSIONS: Older female runners are at higher risk of developing medical complications during 21 km road running races. Environmental conditions in a particularly cold climate may also play a role. Less running experience and slower running pace are associated with specific medical complications. Medical staff can now plan appropriate care on race days, and interventions can be developed to reduce the risk of medical complications in 21 km races. PMID- 24815928 TI - Less experience and running pace are potential risk factors for medical complications during a 56 km road running race: a prospective study in 26 354 race starters--SAFER study II. AB - BACKGROUND: It is important to identify risk factors associated with medical complications during ultra-marathons so that prevention programmes can be developed. OBJECTIVE: To determine risk factors for medical complications during ultra-marathons. DESIGN: Prospective study. SETTING: Two Oceans ultra-marathon (56 km) races. PARTICIPANTS: 26 354 race starters. METHODS: Medical complications (defined as any runner requiring assessment by a doctor at the race medical facility or a local hospital on race day) were recorded over 4 years. Complications were subdivided according to the system that was affected and by final diagnosis. A Poisson regression model was used to determine risk factors for any medical complication and for more common specific complications. RESULTS: Risk factors for medical complications during 56 km road races were less running experience (<=1 medal vs 2-4 medals, p=0.0097), and both fastest (<6 vs 6-7 min/km, p=0.0051) and slowest (>7 vs 6-7 min/km, p<0.0001) running pace category. Year of observation was also associated with risk of complications (2009 vs 2008, p=0.0176; 2009 vs 2010, p=0.0007; 2010 vs 2011, p=0.0112). Risk factors for specific common medical complications were: postural hypotension (slowest pace), serious exercise-associated muscle cramping (older age, fastest pace), gastrointestinal complications (slowest pace) and dermatological complications (fastest pace). CONCLUSIONS: Less experience and running at either a slow or a fast pace were risk factors for complications during 56 km road running. Annual variation may also affect risk. Risk factors for specific medical complications were also identified. These data form the basis of further studies to assist medical staff to plan appropriate care at races. PMID- 24815929 TI - Characterization of the cell surface properties of drinking water pathogens by microbial adhesion to hydrocarbon and electrophoretic mobility measurements. AB - The surface characteristics of microbial cells directly influence their mobility and behavior within aqueous environments. The cell surface hydrophobicity (CSH) and electrophoretic mobility (EPM) of microbial cells impact a number of interactions and processes including aggregation, adhesion to surfaces, and stability of the cells within the aqueous environments. These cell characteristics are unique to the bacterial species and are a reflection of the large diversity of surface structures, proteins, and appendages of microorganisms. CSH and EPM of bacterial cells contribute substantially to the effectiveness of drinking water treatment to remove them, and therefore an investigation of these properties will be useful in predicting their removal through drinking water treatment processes and transport through drinking water distribution systems. EPM and CSH measurements of six microbiological pathogen or surrogate species suspended in phosphate-buffered water are reported in this work. Two strains of Vibrio cholerae were hydrophobic, while three strains of Escherichia coli were hydrophilic. Bacillus cereus was categorized as moderately hydrophobic. The strains of E. coli had the highest (most negative) EPM. Based on the measurements, E. coli species is predicted to be most difficult to remove from water while V. cholerae will be the easiest to remove. PMID- 24815931 TI - Mapping orientational order of charge-probed domains in a semiconducting polymer. AB - Structure-property relationships are of fundamental importance to develop quantitative models describing charge transport in organic semiconductor based electronic devices, which are among the best candidates for future portable and lightweight electronic applications. While microstructural investigations, such as those based on X-rays, electron microscopy, or polarized optical probes, provide necessary information for the rationalization of transport in macromolecular solids, a general model predicting how charge accommodates within structural maps is not yet available. Therefore, techniques capable of directly monitoring how charge is distributed when injected into a polymer film and how it correlates to structural domains can help fill this gap. Supported by density functional theory calculations, here we show that polarized charge modulation microscopy (p-CMM) can unambiguously and selectively map the orientational order of the only conjugated segments that are probed by mobile charge in the few nanometer thick accumulation layer of a high-mobility polymer-based field-effect transistor . Depending on the specific solvent-induced microstructure within the accumulation layer, we show that p-CMM can image charge-probed domains that extend from submicrometer to tens of micrometers size, with markedly different degrees of alignment. Wider and more ordered p-CMM domains are associated with improved carrier mobility, as extracted from device characteristics. This observation evidences the unprecedented opportunity to correlate, directly in a working device, electronic properties with structural information on those conjugated segments involved in charge transport at the buried semiconductor dielectric interface of a field-effect device. PMID- 24815930 TI - Poly(basic red 9) doped functionalized multi-walled carbon nanotubes as composite films for neurotransmitters biosensors. AB - This paper discusses the electrochemical polymerization of basic dye films, which are composed of basic red 9 (BR9), on various electrodes and the enhancement of the electropolymerization by functionalized multiwall carbon nanotubes (f-MWCNTs) modification of the electrode surface. The presence of f-MWCNTs enhances the surface coverage (Gamma) and stability. Poly(BR9) films were electrocatalytically active for epinephrine and serotonin oxidation. The electrocatalytic oxidation current developed from the anodic peak of the redox couple. Electrochemical impedance spectroscopy (EIS) was applied to monitor the whole process of the electrode modification. EIS can provide useful information regarding the impedance changes on the electrode surface between each step. We studied the surface morphology of the composite film using scanning electron microscopy (SEM) and atomic force microscopy (AFM), which revealed that BR9 is doped on f-MWCNTs. Cyclic voltammetry (CV) was used for the measurement of the electroanalytical properties of the analytes. The sensitivity values for the f-MWCNTs/BR9 composite film were higher than the poly(BR9) and f-MWCNTs composite film. Finally, differential pulse voltammetry (DPV) was used for the detection of a mixture of analytes at the f-MWCNTs/BR9 composite film. We simulated a more complex system with both serotonin and epinephrine present simultaneously. This system also exhibited oxidation peaks for serotonin in bovine calf serum (BCS) and epinephrine injection for real samples determination at pH 7.0 at the f MWCNTs/BR9 composite film. PMID- 24815932 TI - Reconstruction of adsorption potential in Polanyi-based models and application to various adsorbents. AB - The equilibrium Polanyi adsorption potential was reconstructed as epsilon = -RT ln(Ca(or H)/delta) to correlate the characteristic energy (E) of Polanyi-based models (qe = f[epsilon/E]) with the properties or structures of absorbates, where qe is the equilibriumn adsorption capacity, Ca(or H) is the converted concentration from the equilibrium aqueous concentration at the same activity and corresponds to the adsorption from the gas or n-hexadecane (HD) phase by the water-wet adsorbent, and "delta" is an arbitrary divisor to converge the model fitting. Subsequently, the modified Dubinin-Astakhov model based on the reconstructed epsilon was applied to aqueous adsorption on activated carbon, black carbon, multiwalled carbon nanotubes, and polymeric resin. The fitting results yielded intrinsic characteristic energies Ea, derived from aqueous-to-gas phase conversion, or EH, derived from aqueous-to-HD phase conversion, which reflect the contributions of the overall or specific adsorbate-adsorbent interactions to the adsorption. Effects of the adsorbate and adsorbent properties on Ea or EH then emerge that are unrevealed by the original characteristic energy (Eo), i.e., adsorbates with tendency to form stronger interactions with an adsorbent have larger Ea and EH. Additionally, comparison of Ea and EH allows quantitative analysis of the contributions of nonspecific interactions, that is, a significant relationship was established between the nonspecific interactions and Abraham's descriptors for the adsorption of all 32 solutes on the four different adsorbents: (Ea - EH) = 24.7 * V + 9.7 * S - 19.3 (R(2) = 0.97), where V is McGowan's characteristic volume for adsorbates, and S reflects the adsorbate's polarity/polarizability. PMID- 24815933 TI - Utility of antimicrobial susceptibility testing of multiple Haemophilus influenzae isolates from throat swabs of children with adenoid hypertrophy. AB - Eleven out of 40 children with adenoiditis were colonized with multiple genotypes of Haemophilus influenzae. Heterogeneous antibiotic susceptibility to ampicillin and cotrimoxazole was observed in 6 children. A multiple-colony methodology may potentially help to find the resistant strains of H. influenzae in patients who do not respond to the antibiotic treatment. PMID- 24815935 TI - Non-reflux esophagitis: a review of inflammatory diseases of the esophagus exclusive of reflux esophagitis. AB - Esophagitis is a frequent cause of clinical symptoms and is often an indication for upper endoscopy. Mucosal biopsies are procured for diagnostic purposes and may be used to assess the efficacy of treatment, as in patients with eosinophilic esophagitis. This article outlines salient clinical and pathologic features of diseases that cause esophagitis exclusive of reflux esophagitis. PMID- 24815934 TI - Association between fetal abdominal circumference and birthweight in maternal hyperglycemia. AB - OBJECTIVES: To compare fetal abdominal circumference and its relationship with birthweight at increasing gestational ages in the context of maternal hyperglycemia of varying severity. DESIGN: Retrospective cohort study. SETTING: Two centers participated in building one database. POPULATION: A total of 1538 Korean pregnant women were subjected to a two-step approach to diagnose gestational diabetes mellitus. METHODS: Pregnant women were classified into gestational diabetes mellitus, borderline gestational diabetes mellitus, and normal groups. Fetal abdominal circumferences, which were measured with ultrasound at 4-week intervals starting at 16 weeks of gestation and ending prior to delivery, were evaluated in the groups. MAIN OUTCOME MEASURE: The significance of fetal abdominal circumferences as predictors or risk factors of macrosomia/large-for-gestational age. RESULTS: Fetal abdominal circumferences measured from 16 weeks of gestation until prior to delivery predicted birthweight in all groups with some exceptions. Fetal abdominal circumferences measured from 32 weeks of gestation until prior to delivery were predictive of macrosomia in all groups. Fetal abdominal circumferences measured from 28 weeks of gestation until prior to delivery were predictive of neonates being large-for-gestational age in all groups. Fetal abdominal circumferences measured at 16 and 24 weeks of gestation were also predictive of large-for-gestational age in the borderline gestational diabetes mellitus group. Fetal abdominal circumference measured at 24 weeks of gestation was also a predictor of macrosomia/large-for-gestational age in normal women. CONCLUSIONS: Fetal abdominal circumferences measured during the second and especially third trimesters were significantly associated with excessive birthweight, irrespective of the severity of maternal glucose intolerance. PMID- 24815936 TI - Barrett esophagus: diagnostic challenges. AB - The incidence of esophageal adenocarcinoma and associated mortality has risen dramatically over the past several decades, and, thus, it is increasingly important to understand its pathogenesis and risk factors. Barrett esophagus is the established precursor to esophageal adenocarcinoma that progresses through a metaplasia-dysplasia-carcinoma sequence. Its risk of transforming to carcinoma is not as high as previously reported and there appears to be a biological heterogeneity among patients with this disease. The overall prevalence of Barrett esophagus in the United States ranges from 1% to 25% and is closer to 5% in patients with gastroesophageal reflux disease. Because of the frequency of Barrett esophagus and associated implications, it is important for the practicing pathologist to have a thorough understanding of this disease and its diagnostic pitfalls. In this review, we will discuss issues associated with the diagnosis of Barrett esophagus, including the definition of Barrett esophagus and its distinction from carditis with intestinal metaplasia. We will also discuss challenges in the grading of dysplasia and new variants of dysplasia, including crypt dysplasia and foveolar-type dysplasia. Finally, we will touch upon the evaluation of dysplasia in endoscopic mucosal resection specimens. PMID- 24815938 TI - A practical approach to small bowel biopsy interpretation: celiac disease and its mimics. AB - While celiac disease is the most common cause of villous remodeling and intraepithelial lymphocytosis in the proximal small bowel, there are many entities that can mimic its histologic appearance. The purpose of this review is to discuss normal small bowel histology and the differential diagnosis of celiac disease. Approaches to evaluate increased intraepithelial lymphocytes are presented, followed by a detailed discussion of the pathology of celiac disease. Particular emphasis is given to those conditions that cause intraepithelial lymphocytosis in the setting of preserved villous architecture, although other important entities, such as peptic injury, idiopathic inflammatory bowel disease, medication injury, eosinophilic (allergic) gastroenteritis, autoimmune enteropathy, common variable immunodeficiency, and infections are also reviewed. PMID- 24815937 TI - Pathology and differential diagnosis of chronic, noninfectious gastritis. AB - The histologic finding of chronic inflammation in an endoscopic mucosal biopsy of the stomach (chronic gastritis) is very common and usually reflects the presence of Helicobacter pylori infection. However, infectious organisms are not always present in biopsy material, and some cases of chronic gastritis do not result from H. pylori infection. Thus, the differential diagnosis of this finding is an important one for pathologists to keep in mind. This review presents the three most common and clinically significant causes of chronic, noninfectious gastritis, namely, autoimmune atrophic gastritis, lymphocytic gastritis, and gastric involvement in the setting of inflammatory bowel disease, especially Crohn disease. For each entity, a brief discussion of its etiology and pathogenesis, a review of the clinical and endoscopic features, and a description of the microscopic findings are presented in the context of the differential diagnosis of chronic gastritis with emphasis on helpful histopathologic hints and long-term sequelae. PMID- 24815939 TI - Histologic mimics of inflammatory bowel disease. AB - This review summarizes a variety of clinical and histologic mimics of idiopathic inflammatory bowel disease. All the entities that are included demonstrate one or more histologic features typical of idiopathic inflammatory bowel disease that may lead to potential diagnostic confusion and misinterpretation by the pathologist. The elements of the clinical history, laboratory test results, and endoscopic findings that are helpful to the surgical pathologist in considering a diagnosis other than idiopathic inflammatory bowel disease are emphasized. On occasion, a poor response to standard treatment for idiopathic inflammatory bowel disease is the clue that prompts reconsideration of the initial diagnosis. Subtle histologic features, special stains, or other diagnostic methodologies that can aid in proper diagnosis are also discussed. PMID- 24815940 TI - Ischemic enterocolitis and its differential diagnosis. AB - Ischemia is a common type of gastrointestinal injury that can be clinically misdiagnosed due to its often mild and transient clinical presentation as well as a tendency to masquerade as other disorders. A wide range of etiologies can contribute to the development of ischemia. These include hypovolemic states, systemic diseases such as vasculitis and hypercoagulable states, mechanical obstruction, therapeutic drug effects, infection, and a host of other diseases. An accurate diagnosis of ischemia relies on a strong clinical suspicion in combination with endoscopic and pathologic findings. Most cases show histologic features that are diagnostic of ischemia, but do not point to a specific differential diagnosis, whereas the cause of ischemia can be recognized or suspected based on careful review of vascular changes in others. This review is focused on providing an overview of ischemic enterocolitis and its differential diagnosis. PMID- 24815941 TI - Drug-induced injury in the gastrointestinal tract. AB - Abnormalities of the gastrointestinal tract due to drug-induced injuries are common and often have important clinical consequences. Medications may cause damage by direct corrosive effects on mucosae or by alter processes, mucosal immunity, and local environmental conditions. The aim of this review is to guide practicing pathologists in the identification of drug-related injuries in gastrointestinal mucosal biopsies and resection specimens. Common causes of injury and their gross, endoscopic, and microscopic features are presented. PMID- 24815942 TI - Enterocolitis in immunocompromised patients. AB - Diarrhea is a very common complaint among immunocompromised patients, and the most common causes of this and other gastrointestinal complaints in this population differ from those commonly seen in immunocompetent patients. Underlying immunodeficiencies may be associated with particular patterns of gastrointestinal tract injury, and particular immunodeficiencies may lead to increased susceptibility to infection by specific organisms depending upon the etiology of the immune compromise. It is important to become familiar with the causes of gastrointestinal disease in the immunocompromised patient population because prompt and proper treatment is of the essence in this patient group. This review focuses on common causes of enterocolitis in the immunocompromised with attention to primary immunodeficiency disorders, the post-transplant setting, chemotherapy-related injury, and a select group of common or emerging infections. PMID- 24815943 TI - Novel hydrophobin-coated docetaxel nanoparticles for intravenous delivery: in vitro characteristics and in vivo performance. AB - Novel hydrophobin (H star Protein(r) B, HPB)-coated docetaxel (DTX) nanoparticles were designed for intravenous delivery. DTX-HPB nanoparticles (DTX-HPB-NPs) were prepared using a nanoprecipitation-ultrasonication technique. The physicochemical properties in terms of particle size, size distribution, zeta potential, morphology, crystalline state of the drug, in vitro release and plasma stability were evaluated. To investigate the drug-hydrophobin interaction, FTIR analysis was carried out. The pharmacokinetics of DTX-HPB-NPs and Taxotere were compared after i.v. administration to rats. The optimized formulations have a high drug loading (>25%) and nanoparticle yield (>93%), small particle size with a narrow distribution, and exhibit delayed release. X-ray diffraction (XRD) demonstrated that the drug is present in a crystalline state. FTIR analysis suggested that the interaction of DTX and HPB involved hydrogen bonding. In vitro hemolysis study confirmed the safety of these nanoparticles. In plasma, DTX-HPB nanoparticles exhibited a significantly enhanced Cmax (1300.618+/-405.045 ng/mL vs 453.174+/ 164.437 ng/mL, p<0.05), and AUC0-t (409.602+/-70.267 vs 314.924+/-57.426 MUg/Lh, p<0.05), and a significantly reduced volume of distribution (36.635+/-15.189 vs 95.199+/-40.972 L/kg, p<0.05) compared with the Taxotere. These results demonstrated that hydrophobin has the potential to be used as a novel biocompatible biomaterial for drug delivery. PMID- 24815945 TI - Is there a relationship between red or processed meat intake and obesity? A systematic review and meta-analysis of observational studies. AB - A body of literature exists regarding the association of red and processed meats with obesity; however, the nature and extent of this relation has not been clearly established. The aim of this study is to conduct a systematic review and meta-analysis of the relationship between red and processed meat intake and obesity. We searched multiple electronic databases for observational studies on the relationship between red and processed meat intake and obesity published until July 2013. Odds ratios (ORs) and means for obesity-related indices and for variables that may contribute to heterogeneity were calculated. A systematic review and a meta-analysis were conducted with 21 and 18 studies, respectively (n = 1,135,661). The meta-analysis (n = 113,477) showed that consumption of higher quantities of red and processed meats was a risk factor for obesity (OR: 1.37; 95% CI: 1.14-1.64). Pooled mean body mass index (BMI) and waist circumference (WC) trends showed that in comparison to those in the lowest ntile, subjects in the highest ntile of red and processed meat consumption had higher BMI (mean difference: 1.37; 95% CI: 0.90-1.84 for red meat; mean difference: 1.32; 95% CI: 0.64-2.00 for processed meat) and WC (mean difference: 2.79; 95% CI: 1.86-3.70 for red meat; mean difference: 2.77; 95% CI: 1.87-2.66 for processed meat). The current analysis revealed that red and processed meat intake is directly associated with risk of obesity, and higher BMI and WC. However, the heterogeneity among studies is significant. These findings suggest a decrease in red and processed meat intake. PMID- 24815944 TI - Parenteral thermo-sensitive organogel for schizophrenia therapy, in vitro and in vivo evaluation. AB - Novel biodegradable in situ forming organogel, obtained via the self-assembly of long chain fatty acid in pharmaceutical oil, was prepared and characterized. Different from traditional organogels, the use of organic solvent was avoided in this gel system, in consideration of its tissue irritation. Four kinds of fatty acids were employed as organogelators, which could successfully gel with injectable soybean oil. The gelation procedure was thermo-reversible. Phase transition temperature and time were depended on carbon chain length and concentration of gelators. Optimized formulations containing drug were then injected subcutaneously in rats for pharmacokinetic study. Results showed the steady drug release for one week with the well-controlled burst, which fitted well with the drug release mechanism of both drug diffusion and frame erosion. In vivo imaging of the organogel with fluorescence in live animals suggested that the organogel matrix was gradually absorbed and completely up-taken in nine days. Histopathological analysis of the surrounding tissues was carried out and revealed an overall good biocompatibility property of the implants over drug release period. This research demonstrates that this thermo-sensitive in situ forming organogel system represents a potentially promising platform for sustained drug delivery. PMID- 24815946 TI - p-Coumaric acid and ursolic acid from Corni fructus attenuated beta-amyloid(25 35)-induced toxicity through regulation of the NF-kappaB signaling pathway in PC12 cells. AB - Neuroinflammatory responses induced by amyloid-beta peptide (Abeta) are important causes in the pathogenesis of Alzheimer's disease (AD). Blockade of Abeta has emerged as a possible therapeutic approach to control the onset of AD. This study investigated the neuroprotective effects and molecular mechanisms of p-coumaric acid (p-CA) and ursolic acid (UA) from Corni fructus against Abeta(25-35)-induced toxicity in PC12 cells. p-CA and UA significantly inhibited the expression of iNOS and COX-2 in Abeta(25-35)-injured PC12 cells. Blockade of nuclear translocation of the p65 subunit of nuclear factor kappaB (NF-kappaB) and phosphorylation of IkappaB-alpha was also observed after p-CA and UA treatment. For the upstream kinases, UA exclusively reduced ERK1/2, p-38, and JNK phosphorylation, but p-CA suppressed ERK1/2 and JNK phosphorylation. Both compounds comprehensively inhibited NF-kappaB activity, but possibly with different upstream pathways. The results provide new insight into the pharmacological modes of p-CA and UA and their potential therapeutic application to AD. PMID- 24815947 TI - Differential effects of deep brain stimulation on verbal fluency. AB - We aimed at gaining insights into principles of subcortical lexical processing. Therefore, effects of deep brain stimulation (DBS) in different target structures on verbal fluency (VF) were tested. VF was assessed with active vs. inactivated DBS in 13 and 14 patients with DBS in the vicinity of the thalamic ventral intermediate nucleus (VIM) and, respectively, of the subthalamic nucleus (STN). Results were correlated to electrode localizations in postoperative MRI, and compared to those of 12 age-matched healthy controls. Patients' VF performance was generally below normal. However, while activation of DBS in the vicinity of VIM provoked marked VF decline, it induced subtle phonemic VF enhancement in the vicinity of STN. The effects correlated with electrode localizations in left hemispheric stimulation sites. The results show distinct dependencies of VF on DBS in the vicinity of VIM vs. STN. Particular risks for deterioration occur in patients with relatively ventromedial thalamic electrodes. PMID- 24815948 TI - On pleasure and thrill: the interplay between arousal and valence during visual word recognition. AB - We investigated the interplay between arousal and valence in the early processing of affective words. Event-related potentials (ERPs) were recorded while participants read words organized in an orthogonal design with the factors valence (positive, negative, neutral) and arousal (low, medium, high) in a lexical decision task. We observed faster reaction times for words of positive valence and for those of high arousal. Data from ERPs showed increased early posterior negativity (EPN) suggesting improved visual processing of these conditions. Valence effects appeared for medium and low arousal and were absent for high arousal. Arousal effects were obtained for neutral and negative words but were absent for positive words. These results suggest independent contributions of arousal and valence at early attentional stages of processing. Arousal effects preceded valence effects in the ERP data suggesting that arousal serves as an early alert system preparing a subsequent evaluation in terms of valence. PMID- 24815949 TI - The anatomical foundations of acquired reading disorders: a neuropsychological verification of the dual-route model of reading. AB - In this study we investigated the neural correlates of acquired reading disorders through an anatomo-correlative procedure of the lesions of 59 focal brain damaged patients suffering from acquired surface, phonological, deep, undifferentiated dyslexia and pure alexia. Two reading tasks, one of words and nonwords and one of words with unpredictable stress position, were used for this study. We found that surface dyslexia was predominantly associated with left temporal lesions, while in phonological dyslexia the lesions overlapped in the left insula and the left inferior frontal gyrus (pars opercularis) and that pure alexia was associated with lesions in the left fusiform gyrus. A number of areas and white matter tracts, which seemed to involve processing along both the lexical and the sublexical routes, were identified for undifferentiated dyslexia. Two cases of deep dyslexia with relatively dissimilar anatomical correlates were studied, one compatible with Coltheart's right-hemisphere hypothesis (1980) whereas the other could be interpreted in the context of Morton and Patterson's (1980), multiply damaged left-hemisphere hypothesis. In brief, the results of this study are only partially consistent with the current state of the art, and propose new and stimulating challenges; indeed, based on these results we suggest that different types of acquired dyslexia may ensue after different cortical damage, but white matter disconnection may play a crucial role in some cases. PMID- 24815950 TI - E-cigarettes: a rising trend among youth. AB - Electronic cigarettes, known as "e-cigarettes," were designed as a smoking cessation tool for adults. An unintended audience for the product has been found with adolescents, many of whom have never used conventional cigarettes. Broad consequences of e-cigarettes on adolescent health include nicotine addiction-and later nicotine withdrawal-and potential for nicotine overdose. U.S. Food and Drug Administration regulations are non-existent; empirical evidence regarding e cigarettes is limited; and studies conducted with adolescent e-cigarette use are even less common. Prevention measures must target the manufacturers and retailers of these devices as well as adolescents, parents, schools, and health care professionals. Psychiatricmental health nurses are well positioned to raise awareness of the dangerous consequences of e-cigarette use in teens. PMID- 24815951 TI - Drug-eluting balloon in the treatment of in-stent restenosis and diffuse coronary artery disease: real-world experience from our registry. AB - OBJECTIVES: To report a single-center experience of drug-eluting balloons (DEB) in the treatment of in-stent restenosis (ISR) and de novo coronary artery disease. BACKGROUND: DEB are emerging as an alternative treatment for coronary stenosis especially when metal scaffolding is undesirable (in-stent restenosis and small-vessel de novo disease). Although there are various randomized trials and registry studies, the data from real-world cohorts are lacking. METHODS: Consecutive patients treated with the In.Pact FalconTM (Medtronic Inc., Minneapolis, MN, USA) paclitaxel-eluting balloon between January 2009 and December 2011 were retrospectively studied. The measured end-points were cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR), and major adverse cardiac events (MACE) defined as combination of cardiac death, MI, and TVR. RESULTS: A total of 275 lesions were successfully treated in 184 patients. The mean age was 66.2 +/- 9.6 years, and 87% were males. The predominant indication for DEB use was ISR (62%), with de novo lesions accounting for the remainder (38%). A mean of 1.48 +/- 0.9 DEB were used per patient. Bailout stenting was required in 24% of lesions. The median clinical follow-up was 14.6 months (IQR 12-23). The overall rates of cardiac death, MI, TLR, TVR, and MACE were 3.8%, 1.6%, 16.8%, 17.9%, and 21.7%, respectively. The overall rate of stent thrombosis was 0.5% (n = 1). CONCLUSION: Our results suggests that DEB can be considered in lesions where the use of stents is not desirable, especially restenotic lesions. Further long-term follow up of these patients will provide us more insights on the long-term outcomes. PMID- 24815954 TI - Prevalence of Chagas disease in pregnant women and congenital transmission of Trypanosoma cruzi in Brazil: a systematic review and meta-analysis. AB - OBJECTIVE: To estimate the prevalence of Chagas disease in pregnant women and the risk of congenital transmission of Trypanosoma cruzi infection in Brazil, through a systematic review and meta-analysis. METHODS: We searched electronic databases, grey literature and reference lists of included publications to identify epidemiological studies on the prevalence of Chagas disease in pregnant women and on the congenital transmission rate of T. cruzi infection in Brazil published between January 1980 and June 2013. Pooled estimates and 95% confidence intervals (95% CIs) were calculated using fixed- and random-effects models. RESULTS: Sixteen articles were included - 12 studies on the prevalence of Chagas disease in pregnant women (549,359 pregnant women) and nine on congenital transmission rates (1687 children born to infected mothers). Prevalence of Chagas disease in pregnant women ranged from 0.1% to 8.5%, and congenital transmission rates from 0% to 5.2%. The pooled prevalence of Chagas disease among pregnant women across studies was 1.1% (95% CI: 0.6-2.0); the pooled congenital transmission rate was 1.7% (95% CI: 0.9-3.1). In 2010, 34,629 pregnant women were estimated to be infected with T. cruzi, and 312-1073 children born (mean: 589 cases) with congenital infection. CONCLUSION: Congenital Chagas disease is a neglected public health problem in Brazil. Systematic congenital Chagas disease control programs through routine prenatal screening for T. cruzi should be widely implemented in Brazil's endemic areas, to identify infected pregnant women and newborns at risk of congenital infection. PMID- 24815953 TI - Measurement of the frequency and source of interruptions occurring during bedside nursing handover in the intensive care unit: An observational study. AB - BACKGROUND: Effective clinical handover involves the communication of relevant patient information from one care provider to another and is critical in ensuring patient safety. Interruptions may contribute to errors and are potentially a significant barrier to the delivery of effective handovers. OBJECTIVES: The study objective was to measure the frequency and source of interruptions during intensive care (ICU) bedside nursing handover. METHODS: Twenty observations of bedside handover in an ICU were performed and the frequency and source of interruptions were recorded by the observer for each handover. Observations occurred Monday to Friday during shift change; night to day shift and day to evening shift. Interruptions were defined as a break in performance of an activity. RESULTS: The mean handover time was 11 (+/- 4)min with a range of 5-22 min. The mean number of interruptions was 2 (+/- 2) per handover with a range of 0-7. The most frequent number of interruptions was seven, occurring during a 15 min handover. Doctors, nurses and alarming intravenous pumps were the most frequent source of interruptions, with administration staff and wards people also disrupting handovers. CONCLUSION: Nurses, doctors and alarming intravenous pumps frequently interrupt ICU bedside handovers, which may lead to loss of critical information and result in adverse patient events. Increased knowledge in this area will ensure appropriate strategies are developed and implemented in healthcare areas to manage interruptions effectively and improve patient safety. PMID- 24815952 TI - Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia. AB - Selective estrogen receptor modulators (SERMs) have been reported to enhance synaptic plasticity and improve cognitive performance in adult rats. SERMs have also been shown to induce neuroprotection against cerebral ischemia and other CNS insults. In this study, we sought to determine whether acute regulation of neurogenesis and spine remodeling could be a novel mechanism associated with neuroprotection induced by SERMs following cerebral ischemia. Toward this end, ovariectomized adult female rats were either implanted with pellets of 17beta estradiol (estrogen) or tamoxifen, or injected with raloxifene. After one week, cerebral ischemia was induced by the transient middle-cerebral artery occlusion (MCAO) method. Bromodeoxyuridine (BrdU) was injected to label dividing cells in brain. We analyzed neurogenesis and spine density at day-1 and day-5 post MCAO. In agreement with earlier findings, we observed a robust induction of neurogenesis in the ipsilateral subventricular zone (SVZ) of both the intact as well as ovariectomized female rats following MCAO. Interestingly, neurogenesis in the ipsilateral SVZ following ischemia was significantly higher in estrogen and raloxifene-treated animals compared to placebo-treated rats. In contrast, this enhancing effect on neurogenesis was not observed in tamoxifen-treated rats. Finally, both SERMs, as well as estrogen significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia. Taken, together these results reveal a profound structural remodeling potential of SERMs in the brain following cerebral ischemia. This article is part of a Special Issue entitled "Sex steroids and brain disorders". PMID- 24815955 TI - Anti-Mullerian hormone in reproductive age women with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an inflammatory autoimmune systemic and chronic disease. Fertility in SLE patients is considered normal; factors that have been associated in these patients with ovarian failure are: disease activity, autoantibodies, and the use of cytotoxic agents. The anti-Mullerian hormone (AMH) is a marker that helps to determine the follicular reserve. OBJECTIVE: Determinate the objective was to determine AMH levels in women of reproductive age with SLE. MATERIAL AND METHODS: We included 65 women with SLE classified according to the 1997 ACR criteria, 18- to 40-years old. We obtained demographic, clinical, obstetric, and gynecological characteristics as well as serum levels of AMH. We performed a bivariate analysis among patients with low ovarian reserve and those with normal ovarian reserve. We also performed a correlation analysis between activity and damage index and between the cumulative cyclophosphamide dose and AMH levels. RESULTS: We found a median of serum AMH in SLE patients of .61 ng/mL. The prevalence of low ovarian reserve in our study was 3.07%. We found a median MEX-SLEDAI score of 1 point and the median SLICC score was 2 points. Twenty-five patients (38.4%) had used cyclophosphamide and their cumulative average dose was 7.5 grams. CONCLUSIONS: We found a median of AMH of .61 ng/mL in our population. The prevalence of low ovarian reserve in SLE patients was 3.07%. We did not find a correlation between AMH levels, the use of cyclophosphamide, and disease activity. PMID- 24815956 TI - Commentary on "How to avoid mucocele formation under pedicled nasoseptal flap". PMID- 24815957 TI - Immediate reconstruction of soft palate defects after ablative surgery and evaluation of postoperative function: an analysis of 45 consecutive patients. AB - PURPOSE: The aim of the present study was to estimate the effect of different defect sizes and flaps used on the postoperative soft palate functional outcomes. PATIENTS AND METHODS: The study included 45 consecutive patients who were treated by 3 different reconstructive flaps for their soft palate defect. Postoperative speech and swallowing functions were assessed to measure the relationships between the defect size and postoperative function of the soft palate, the different flap reconstructions, and postoperative function. The 1-way analysis of variance test was computed. P < .05 was considered significant. RESULTS: The postoperative evaluation revealed that both speech and swallowing functions were normal or near normal in patients with type II defects, but they were poor in the patients with type III and IV defects. No significant changes in postoperative soft palate function using different flap sizes for the same defect type were found. CONCLUSIONS: The study results have confirmed that the size of the defect, rather than the type of the flap, will have the most critical influence on soft palate postoperative function. A defect size of 50% or less will have a better outcome than defect sizes greater than 50%. PMID- 24815958 TI - Adolescent and young adult health in the United States in the past decade: little improvement and young adults remain worse off than adolescents. AB - Adolescence and young adulthood are unique developmental periods that present opportunities and challenges for improving health. Health at this age can affect health throughout the lifespan. This review has two aims: (1) to examine trends in key indicators in outcomes, behaviors, and health care over the past decade for U.S. adolescents and young adults; and (2) to compare U.S. adolescents and young adults on these indicators. The review also assesses sociodemographic differences in trends and current indicators. Guided by our aims, previous reviews, and national priorities, the present review identified 21 sources of nationally representative data to examine trends in 53 areas and comparisons of adolescents and young adults in 42 areas. Most health and health care indicators have changed little over the past decade. Encouraging exceptions were found for adolescents and young adults in unintentional injury, assault, and tobacco use, and, for adolescents, in sexual/reproductive health. Trends in violence and chronic disease and related behaviors were mixed. Review of current indicators demonstrates that young adulthood continues to entail greater risk and worse outcomes than adolescence. Young adults fared worse on about two-thirds of the indicators examined. Differences among sociodemographic subgroups persisted for both trends and current indicators. PMID- 24815959 TI - Psychosocial burden and glycemic control during the first 6 years of diabetes: results from the SEARCH for Diabetes in Youth study. AB - PURPOSE: To evaluate the psychosocial burden of adolescents with diabetes, determine the trajectory of psychosocial burden, and examine the interdependent relationships between psychosocial burden and glycemic control across the first 6 years of diabetes. METHODS: Data from SEARCH for Diabetes in Youth, an observational study of U.S. children diagnosed with diabetes before the age of 20, were collected during study visits conducted at baseline and then at 12, 24, and 60 months after baseline. Blood was drawn, clinical and demographic information was collected, and psychosocial burden was evaluated using standardized depression and generic and diabetes-specific health-related quality of life (QOL) surveys. RESULTS: Among the 1,307 adolescents (mean age, 14.1+/-2.5 years) with baseline data, 1,026 had type 1 diabetes and 281 had type 2 diabetes. For those with a 60-month follow-up visit, glycated hemoglobin (A1c) values rose 1.5% from baseline (type 1, 7.7%-9.3% and type 2, 7.3%-8.8%). Adolescents with type 2 diabetes reported more depression and poorer QOL than adolescents with type 1 diabetes. For each diabetes type, there were similar baseline risk factors for higher A1c values: longer diabetes duration, ethnic minority status, and declining diabetes QOL (p < .05). However, youth with type 2 diabetes had higher A1c values with increasing generic QOL, an unexpected finding. Younger adolescents with type 1 diabetes had higher A1c values at the end of the study. CONCLUSIONS: Significant deterioration in glycemic control marks the first 6 years of diabetes for adolescents. Psychosocial burden, particularly poor diabetes-specific QOL, is a contributor to suboptimal glycemic outcomes. PMID- 24815962 TI - Advances in perioperative analgesia: current challenges. PMID- 24815960 TI - Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease. AB - Treponema denticola, a periopathogen, evades complement-mediated killing by binding the negative complement regulatory protein factor H (FH) to its surface via the FhbB protein. Paradoxically, bound FH is cleaved by T. denticola's dentilisin protease, a process hypothesized to trigger localized dysregulation of complement activation in periodontal pockets. The ability of other oral treponemes to evade complement-mediated killing and bind and cleave FH has not been assessed. In this report, we demonstrate that representative isolates of Treponema socranskii, Treponema medium, Treponema pectinovorum and Treponema maltophilum are also serum resistant, whereas Treponema vincentii and Treponema amylovorum are serum sensitive. Although T. denticola's ability to evade complement-mediated killing is strictly dependent on FH binding, other serum resistant treponemal species lack FhbB and do not bind FH, indicating an FH independent mechanism of complement evasion. To assess the influence of FhbB sequence variation on FH binding and cleavage by T. denticola, fhbB sequences were determined for 30 isolates. Three distinct phyletic types were identified. All T. denticola strains bound FH and were serum resistant, but differences in binding kinetics, dentilisin activity and FH cleavage ability were observed. Based on these analyses, we hypothesize that the composition of the T. denticola population is a determining factor that influences the progression and severity of periodontal disease. PMID- 24815961 TI - Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. AB - Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however, which Tlr4-expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity and ameliorated hepatic steatosis despite the development of obesity after a high-fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes. PMID- 24815963 TI - Perioperative analgesia: ever-changing technology and pharmacology. AB - Our understanding of pain and its long-term implications have dramatically changed with the advent of advancements in molecular mechanisms involved in acute or postoperative pain and chronic pain. This better understanding has led to multiple pharmacologic advancements to better treat pain with minimal side effects. Currently, we are still struggling to find the right balance between all of the different modalities that we have at our leisure. In order to best take care of postoperative pain, we are improving patient satisfaction, decreasing hospital stays, and decreasing the development of long-term pain and its related complications. However, despite using a multimodal approach that includes newer technologies, we still have a long way to go before we can guarantee a pain-free postoperative course or a comfortable end for a terminally ill patient. These arms of anesthesiology are ever changing. Anesthesiologists have taken a leadership role in perioperative pain management and clinical research designed for the improvement of pain. PMID- 24815964 TI - Liposomal bupivacaine and clinical outcomes. AB - In the multimodal approach to the management of postoperative pain, local infiltration and regional blocks have been increasingly utilized for pain control. One of the limitations of local anesthetics in the postoperative setting is its relatively short duration of action. Multivesicular liposomes containing bupivacaine have been increasingly utilized for their increased duration of action. Compared with bupivacaine HCl, local infiltration of liposomal bupivacaine has shown to have an increase in duration of action and causes delay in peak plasma concentration. In this article, we attempt to review the clinical literature surrounding liposomal bupivacaine and its evolving role in perioperative analgesia. This new bupivacaine formation may have promising implications in postoperative pain control, resulting in increased patient satisfaction and a decrease in both hospital stay and opioid-induced adverse events (AEs). Although more studies are needed, the preliminary clinical trials suggest that liposomal bupivacaine has predictable pharmacokinetics, a similar side effect profile compared with bupivacaine HCl, and is effective in providing increased postoperative pain control. PMID- 24815965 TI - Ultrasound and its evolution in perioperative regional anesthesia and analgesia. AB - Perioperative regional anesthetic and analgesic techniques have evolved considerably over the past four decades. Perhaps, the most impressive development in recent years has been the rapid adoption and widespread utilization of ultrasound (US) guidance to perform targeted delivery of local anesthetics and catheters in a consistent manner for postoperative pain control. This article briefly reviews the history of US in regional anesthesia and perioperative analgesia, the evidence basis for this practice, the clinical application of novel techniques and imaging modalities, and possible future technology and research directions. PMID- 24815966 TI - Peripheral nerve catheters and local anesthetic infiltration in perioperative analgesia. AB - Peripheral nerve catheters (PNCs) and local infiltration analgesia (LIA) represent valuable options for controlling perioperative pain. PNCs have been increasingly utilized to provide both surgical anesthesia and prolonged postoperative analgesia for a wide variety of procedures. PNCs can be more technically challenging to place than typical single-injection nerve blocks (SINB), and familiarity with the indications, contraindications, relevant anatomy, and appropriate technical skills is a prerequisite for the placement of any PNC. PNCs include risks of peripheral nerve injury, damage to adjacent anatomic structures, local anesthetic toxicity, intravascular injection, risks associated with motor block, risks of unnoticed injury to the insensate limb, and risks of sedation associated with PNC placement. In addition to these common risks, there are specific risks unique to each PNC insertion site. LIA strategies have emerged that seek to provide the benefit of targeted local anesthesia while minimizing collateral motor block and increasing the applicability of durable local anesthesia beyond the extremities. LIA involves the injection and/or infusion of a local anesthetic near the site of surgical incision to provide targeted analgesia. A wide variety of techniques have been described, including single-injection intraoperative wound infiltration, indwelling wound infusion catheters, and the recent high-volume LIA technique associated with joint replacement surgery. The efficacy of these techniques varies depending on specific procedures and anatomic locations. The recent incorporation of ultra long-acting liposomal bupivacaine preparations has the potential to dramatically increase the utility of single-injection LIA. LIA represents a promising yet under-investigated method of postoperative pain control. PMID- 24815967 TI - Multimodal therapy in perioperative analgesia. AB - This article reviews the current evidence for multimodal analgesic options for common surgical procedures. As perioperative physicians, we have come a long way from using only opioids for postoperative pain to combinations of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), selective Cyclo-oxygenase (COX-2) inhibitors, local anesthetics, N-methyl-d-aspartate (NMDA) receptor antagonists, and regional anesthetics. As discussed in this article, many of these agents have decreased narcotic requirements, improved patient satisfaction, and decreased postanesthesia care unit (PACU) times, as well as morbidity in the perioperative period. PMID- 24815968 TI - Novel delivery systems for postoperative analgesia. AB - Moderate-to-severe postoperative pain is usually controlled using a multimodal approach, including opioids. Intravenously administered patient-controlled analgesia (IV PCA) with opioids, popular for over 40 years, enables patients to control their level of analgesia and has advantages over a nurse-administered approach, including more satisfied patients and improved pain relief. Unfortunately, IV PCA has drawbacks such as device programming errors, medication prescribing errors, pump malfunction, limitations on patient mobility, IV patency issues, and transmission of infection. Furthermore, the setup of an infusion pump is often complex, time-consuming, and requires witnessed confirmation. Complicating IV PCA is the problem of commonly used compounds, morphine and hydromorphone, having significantly reduced brain/effector-site permeability and active metabolites, both of which create the risk of delayed adverse events. Novel patient-controlled modalities that incorporate rapid effector site permeating opioids and non-invasive routes of administration offer great promise to enhance both patient and caregiver experiences with postoperative analgesia systems. PMID- 24815969 TI - Perioperative analgesia and challenges in the drug-addicted and drug-dependent patient. AB - The epidemic use of illicit drugs has led to an increasing number of patients with drug addiction and dependence presenting for perioperative care. There are a wide variety of drugs commonly abused including opioids, such as heroin and prescription drugs; stimulants, such as amphetamine and cocaine; depressant drugs, such as alprazolam and diazepam; and hallucinogens, such as lysergic acid diethylamide, phencyclidine, and marijuana. Treatment of opioid dependence by office-based buprenorphine and methadone maintenance programs has expanded opportunities for therapy. Treatment of these patients in the perioperative period is challenging. In addition to pain control, management of anxiety, psychological states, and hemodynamic control are the factors to be considered to provide optimum treatment. Although opioids are the mainstay for the control of acute pain, other therapeutic options include alternative routes of administration of local anesthetic, ketamine infusion, and the use of regional anesthesia. We discuss optimum perioperative management, the role of perioperative urine testing, and special considerations in patients on methadone and buprenorphine. PMID- 24815970 TI - Polyhedra, complexes, nets and symmetry. AB - Skeletal polyhedra and polygonal complexes in ordinary Euclidean 3-space are finite or infinite 3-periodic structures with interesting geometric, combinatorial and algebraic properties. They can be viewed as finite or infinite 3-periodic graphs (nets) equipped with additional structure imposed by the faces, allowed to be skew, zigzag or helical. A polyhedron or complex is regular if its geometric symmetry group is transitive on the flags (incident vertex-edge-face triples). There are 48 regular polyhedra (18 finite polyhedra and 30 infinite apeirohedra), as well as 25 regular polygonal complexes, all infinite, which are not polyhedra. Their edge graphs are nets well known to crystallographers and they are identified explicitly. There are also six infinite families of chiral apeirohedra, which have two orbits on the flags such that adjacent flags lie in different orbits. PMID- 24815971 TI - Non-crystallographic nets: characterization and first steps towards a classification. AB - Non-crystallographic (NC) nets are periodic nets characterized by the existence of non-trivial bounded automorphisms. Such automorphisms cannot be associated with any crystallographic symmetry in realizations of the net by crystal structures. It is shown that bounded automorphisms of finite order form a normal subgroup F(N) of the automorphism group of NC nets (N, T). As a consequence, NC nets are unstable nets (they display vertex collisions in any barycentric representation) and, conversely, stable nets are crystallographic nets. The labelled quotient graphs of NC nets are characterized by the existence of an equivoltage partition (a partition of the vertex set that preserves label vectors over edges between cells). A classification of NC nets is proposed on the basis of (i) their relationship to the crystallographic net with a homeomorphic barycentric representation and (ii) the structure of the subgroup F(N). PMID- 24815972 TI - Atomic clusters and atomic surfaces in icosahedral quasicrystals. AB - This paper presents the basic tools commonly used to describe the atomic structures of quasicrystals with a specific focus on the icosahedral phases. After a brief recall of the main properties of quasiperiodic objects, two simple physical rules are discussed that lead one to eventually obtain a surprisingly small number of atomic structures as ideal quasiperiodic models for real quasicrystals. This is due to the fact that the atomic surfaces (ASs) used to describe all known icosahedral phases are located on high-symmetry special points in six-dimensional space. The first rule is maximizing the density using simple polyhedral ASs that leads to two possible sets of ASs according to the value of the six-dimensional lattice parameter A between 0.63 and 0.79 nm. The second rule is maximizing the number of complete orbits of high symmetry to construct as large as possible atomic clusters similar to those observed in complex intermetallic structures and approximant phases. The practical use of these two rules together is demonstrated on two typical examples of icosahedral phases, i AlMnSi and i-CdRE (RE = Gd, Ho, Tm). PMID- 24815973 TI - Applications of direct methods in protein crystallography for dealing with diffraction data down to 5 A resolution. AB - Apart from solving the heavy-atom substructure in proteins and ab initio phasing of protein diffraction data at atomic resolution, direct methods have also been successfully combined with other protein crystallographic methods in dealing with diffraction data far below atomic resolution, leading to significantly improved results. In this respect, direct methods provide phase constraints in reciprocal space within a dual-space iterative framework rather than solve the phase problem independently. Applications of this type of direct methods to difficult SAD phasing, model completion and low-resolution phase extension will be described in detail. PMID- 24815974 TI - About systematic errors in charge-density studies. AB - The formerly introduced theoretical R values [Henn & Schonleber (2013). Acta Cryst. A69, 549-558] are used to develop a relative indicator of systematic errors in model refinements, R(meta), and applied to published charge-density data. The counter of R(meta) gives an absolute measure of systematic errors in percentage points. The residuals (Io - Ic)/sigma(Io) of published data are examined. It is found that most published models correspond to residual distributions that are not consistent with the assumption of a Gaussian distribution. The consistency with a Gaussian distribution, however, is important, as the model parameter estimates and their standard uncertainties from a least-squares procedure are valid only under this assumption. The effect of correlations introduced by the structure model is briefly discussed with the help of artificial data and discarded as a source of serious correlations in the examined example. Intensity and significance cutoffs applied in the refinement procedure are found to be mechanisms preventing residual distributions from becoming Gaussian. Model refinements against artificial data yield zero or close to-zero values for R(meta) when the data are not truncated and small negative values in the case of application of a moderate cutoff Io > 0. It is well known from the literature that the application of cutoff values leads to model bias [Hirshfeld & Rabinovich (1973). Acta Cryst. A29, 510-513]. PMID- 24815975 TI - A new theory for X-ray diffraction. AB - This article proposes a new theory of X-ray scattering that has particular relevance to powder diffraction. The underlying concept of this theory is that the scattering from a crystal or crystallite is distributed throughout space: this leads to the effect that enhanced scatter can be observed at the 'Bragg position' even if the 'Bragg condition' is not satisfied. The scatter from a single crystal or crystallite, in any fixed orientation, has the fascinating property of contributing simultaneously to many 'Bragg positions'. It also explains why diffraction peaks are obtained from samples with very few crystallites, which cannot be explained with the conventional theory. The intensity ratios for an Si powder sample are predicted with greater accuracy and the temperature factors are more realistic. Another consequence is that this new theory predicts a reliability in the intensity measurements which agrees much more closely with experimental observations compared to conventional theory that is based on 'Bragg-type' scatter. The role of dynamical effects (extinction etc.) is discussed and how they are suppressed with diffuse scattering. An alternative explanation for the Lorentz factor is presented that is more general and based on the capture volume in diffraction space. This theory, when applied to the scattering from powders, will evaluate the full scattering profile, including peak widths and the 'background'. The theory should provide an increased understanding of the reliability of powder diffraction measurements, and may also have wider implications for the analysis of powder diffraction data, by increasing the accuracy of intensities predicted from structural models. PMID- 24815976 TI - Unified approach for determining tetragonal tungsten bronze crystal structures. AB - Tetragonal tungsten bronze (TTB) oxides are one of the most important classes of ferroelectrics. Many of these framework structures undergo ferroelastic transformations related to octahedron tilting deformations. Such tilting deformations are closely related to the rigid unit modes (RUMs). This paper discusses the whole set of RUMs in an ideal TTB lattice and possible crystal structures which can emerge owing to the condensation of some of them. Analysis of available experimental data for the TTB-like niobates lends credence to the obtained theoretical predictions. PMID- 24815977 TI - On the assessment of time-resolved diffraction results. AB - Data collected during dynamic structure pump-probe crystallography experiments require appropriate indicators of agreement and tools to visualize the electron density distribution changes. Agreement factors based on the ratio of intensities R with and without the external perturbation are shown to be analogous to the R1 and wR2 R factors widely used in standard crystallographic refinements. The eta based R factors, normalized by the average relative intensity change, are significantly larger than R-based values. It is shown that the relative intensity change eta-based R factors are not suitable for comparing different data sets. Fourier photodifference maps allow the visualization of the externally induced structural changes in the crystal, but also can be used during refinement to observe residual peaks not yet accounted for by the model and thus monitor the progress of the refinement. The photodeformation maps are a complementary tool to confirm the validity of the final model. Photodeformation maps with equalized laser-on and laser-off thermal motion are used to highlight the structural changes. PMID- 24815978 TI - Seitz symbols for crystallographic symmetry operations. AB - The aim of this report is to describe the Seitz notation for symmetry operations adopted by the Commission on Crystallographic Nomenclature as the standard convention for Seitz symbolism of the International Union of Crystallography. The established notation follows the existing crystallographic conventions in the descriptions of symmetry operations. PMID- 24815981 TI - The protective effect of CD40 ligand-CD40 signalling is limited during the early phase of Plasmodium infection. AB - gammadelta T cells are essential for eliminating Plasmodium berghei XAT. Because administration of the agonistic anti-CD40 antibody can induce elimination of P. berghei XAT parasites in gammadelta T cell-deficient mice, we considered that gammadelta T cells might activate dendritic cells via CD40 signalling during infection. Here we report that administration of the anti-CD40 antibody to gammadelta T cell-deficient mice 3-10 days post-P. berghei XAT infection could eliminate the parasites. Our data suggest that dendritic cell activation via gammadelta T cells expressing CD40 ligand is critical during the early phase of infection. PMID- 24815982 TI - Peri-aortic fluid: a critical finding in acute aortic syndrome. PMID- 24815983 TI - Alteration of bioelectrically-controlled processes in the embryo: a teratogenic mechanism for anticonvulsants. AB - Maternal use of anticonvulsants during the first trimester of pregnancy has been associated with an elevated risk of major congenital malformations in the offspring. Whether the increased risk is caused by the specific pharmacological mechanisms of certain anticonvulsants, the underlying epilepsy, or common genetic or environmental risk factors shared by epilepsy and malformations has been controversial. We hypothesize that anticonvulsant therapies during pregnancy that attain more successful inhibition of neurotransmission might lead to both better seizure control in the mother and stronger alteration of bioelectrically controlled processes in the embryo that result in structural malformations. We propose that development of pharmaceuticals that do not alter cell resting transmembrane voltage levels could result in safer drugs. PMID- 24815985 TI - Physical chemical effects of zinc on in vitro enamel demineralization. AB - OBJECTIVES: Zinc salts are formulated into oral health products as antibacterial agents, yet their interaction with enamel is not clearly understood. The aim was to investigate the effect of zinc concentration [Zn(2+)] on the in vitro demineralization of enamel during exposure to caries-simulating conditions. Furthermore, the possible mechanism of zinc's action for reducing demineralization was determined. METHODS: Enamel blocks and synthetic hydroxyapatite (HAp) were demineralized in a range of zinc-containing acidic solutions (0-3565ppm [Zn(2+)]) at pH 4.0 and 37 degrees C. Inductively coupled plasma optical emission spectroscopy (ICP-OES) was used to measure ion release into solution. Enamel blocks were analysed by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR), and HAp by X-ray diffraction (XRD) and neutron diffraction (ND). RESULTS: ICP-OES analysis of the acidic solutions showed a decrease in [Ca(2+)] and [PO4(3-)] release with increasing [Zn(2+)]. FTIR revealed a alpha-hopeite (alpha-Zn3(PO4)2.4H2O)-like phase on the enamel surfaces at >107ppm [Zn(2+)]. XRD and ND analysis confirmed a zinc phosphate phase present alongside the HAp. CONCLUSIONS: This study confirms that zinc reduces enamel demineralization. Under the conditions studied, zinc acts predominantly on enamel surfaces at PO4(3-) sites in the HAp lattice to possibly form an alpha-hopeite-like phase. CLINICAL SIGNIFICANCE: These results have a significant implication on the understanding of the fundamental chemistry of zinc in toothpastes and demonstrate its therapeutic potential in preventing tooth mineral loss. PMID- 24815984 TI - EEG functional connectivity, axon delays and white matter disease. AB - OBJECTIVE: Both structural and functional brain connectivities are closely linked to white matter disease. We discuss several such links of potential interest to neurologists, neurosurgeons, radiologists, and non-clinical neuroscientists. METHODS: Treatment of brains as genuine complex systems suggests major emphasis on the multi-scale nature of brain connectivity and dynamic behavior. Cross-scale interactions of local, regional, and global networks are apparently responsible for much of EEG's oscillatory behaviors. Finite axon propagation speed, often assumed to be infinite in local network models, is central to our conceptual framework. RESULTS: Myelin controls axon speed, and the synchrony of impulse traffic between distant cortical regions appears to be critical for optimal mental performance and learning. Several experiments suggest that axon conduction speed is plastic, thereby altering the regional and global white matter connections that facilitate binding of remote local networks. CONCLUSIONS: Combined EEG and high resolution EEG can provide distinct multi-scale estimates of functional connectivity in both healthy and diseased brains with measures like frequency and phase spectra, covariance, and coherence. SIGNIFICANCE: White matter disease may profoundly disrupt normal EEG coherence patterns, but currently these kinds of studies are rare in scientific labs and essentially missing from clinical environments. PMID- 24815986 TI - Safety of bilateral intravitreal injections delivered in a teaching institution. AB - Intravitreal injection is one of the most common in-office procedures performed in ophthalmic practices. In teaching institutions such as the Veterans Affairs (VA) Hospitals, patient care is delivered by physicians-in-training, while mastering intravitreal injection technique. Infectious endophthalmitis and visual loss are the most feared complications of intravitreal injections, especially in the context of recent outbreaks caused by contaminated compounded medications. Ophthalmologists and ophthalmic educators increasingly face the dilemma of timing as well as balancing the risks and benefits of bilateral treatments required by many patients. In this editorial, we discuss published reports of bilateral injections, summarize our experience with bilateral intravitreal injections in a teaching setting at the Miami VA Hospital and list our recommendations for minimizing the risk of infectious endophthalmitis. PMID- 24815987 TI - Polarization-sensitive hyperspectral imaging in vivo: a multimode dermoscope for skin analysis. AB - Attempts to understand the changes in the structure and physiology of human skin abnormalities by non-invasive optical imaging are aided by spectroscopic methods that quantify, at the molecular level, variations in tissue oxygenation and melanin distribution. However, current commercial and research systems to map hemoglobin and melanin do not correlate well with pathology for pigmented lesions or darker skin. We developed a multimode dermoscope that combines polarization and hyperspectral imaging with an efficient analytical model to map the distribution of specific skin bio-molecules. This corrects for the melanin hemoglobin misestimation common to other systems, without resorting to complex and computationally intensive tissue optical models. For this system's proof of concept, human skin measurements on melanocytic nevus, vitiligo, and venous occlusion conditions were performed in volunteers. The resulting molecular distribution maps matched physiological and anatomical expectations, confirming a technologic approach that can be applied to next generation dermoscopes and having biological plausibility that is likely to appeal to dermatologists. PMID- 24815988 TI - Stability of sugar solutions: a novel study of the epimerization kinetics of lactose in water. AB - This article reports on the stereochemical aspects of the chemical stability of lactose solutions stored between 25 and 60 degrees C. The lactose used for the preparation of the aqueous solutions was alpha-lactose monohydrate with an anomer purity of 96% alpha and 4% beta based on the supplied certificate of analysis (using a GC analytical protocol), which was further confirmed here by nuclear magnetic resonance (NMR) analysis. Aliquots of lactose solutions were collected at different time points after the solutions were prepared and freeze-dried to remove water and halt epimerization for subsequent analysis by NMR. Epimerization was also monitored by polarimetry and infrared spectroscopy using a specially adapted Fourier transform infrared attenuated total reflectance (FTIR-ATR) method. Hydrolysis was analyzed by ion chromatography. The three different analytical approaches unambiguously showed that the epimerization of lactose in aqueous solution follows first order reversible kinetics between 25 to 60 degrees C. The overall rate constant was 4.4 * 10(-4) s(-1) +/- 0.9 (+/- standard deviation (SD)) at 25 degrees C. The forward rate constant was 1.6 times greater than the reverse rate constant, leading to an equilibrium constant of 1.6 +/- 0.1 (+/-SD) at 25 degrees C. The rate of epimerization for lactose increased with temperature and an Arrhenius plot yielded an activation energy of +52.3 kJ/mol supporting the hypothesis that the mechanism of lactose epimerization involves the formation of extremely short-lived intermediate structures. The main mechanism affecting lactose stability is epimerization, as no permanent hydrolysis or chemical degradation was observed. When preparing aqueous solutions of lactose, immediate storage in an ice bath at 0 degrees C will allow approximately 3 min (180 s) of analysis time before the anomeric ratio alters significantly (greater than 1%) from the solid state composition of the starting material. In contrast a controlled anomeric composition (~38% alpha and ~62% beta) will be achieved if an aqueous solution is left to equilibrate for over 4 h at 25 degrees C, while increasing the temperature up to 60 degrees C rapidly reduces the required equilibration time. PMID- 24815989 TI - Cross-reactivity and neutralization of Indian King cobra (Ophiophagus hannah) venom by polyvalent and monovalent antivenoms. AB - The venom of the largest venomous snake, the king cobra (Ophiophagus hannah), is still out of league for the production of therapeutic polyvalent antivenom nor it is characterized immunologically in the Indian subcontinent. In the present study, the king cobra venom is comparatively studied for the cross reactivity/reactivity and toxicity neutralization by the locally available equine therapeutic polyvalent BSV and VB antivenoms, and monovalent antivenom (OH-IgG) prepared in rabbit. None of the two therapeutic antivenoms procured from two different firms showed any signs of cross-reactivity in terms of antigen-antibody precipitin lines in immunodouble diffusion assay; however, a weak and an insignificant cross-reactivity pattern was observed in ELISA and Western blot studies. Further, both BSV and VB antivenoms failed to neutralize proteolytic, hyaluronidase and phospholipase activities as well as toxic properties such as edema, myotoxicity and lethality of the venom. As expected, OH-IgG showed strong reactivity in immunodouble diffusion, ELISA and in Western blot analysis and also neutralized both enzyme activities as well as the toxic properties of the venom. Thus, the study provides insight into the likely measures that are to be taken in cases of accidental king cobra bites for which the Indian subcontinent is still not prepared for. PMID- 24815990 TI - [Generic drugs: what do patients really know about them?]. PMID- 24815992 TI - Identifying 1st instar larvae for three forensically important blowfly species using "fingerprint" cuticular hydrocarbon analysis. AB - Calliphoridae are known to be the most forensically important insects when it comes to establishing the minimum post mortem interval (PMImin) in criminal investigations. The first step in calculating the PMImin is to identify the larvae present to species level. Accurate identification which is conventionally carried out by morphological analysis is crucial because different insects have different life stage timings. Rapid identification in the immature larvae stages would drastically cut time in criminal investigations as it would eliminate the need to rear larvae to adult flies to determine the species. Cuticular hydrocarbon analysis on 1st instar larvae has been applied to three forensically important blowflies; Lucilia sericata, Calliphora vicina and Calliphora vomitoria, using gas chromatography-mass spectrometry (GC-MS) and principal component analysis (PCA). The results show that each species holds a distinct "fingerprint" hydrocarbon profile, allowing for accurate identification to be established in 1-day old larvae, when it can be challenging to apply morphological criteria. Consequently, this GC-MS based technique could accelerate and strengthen the identification process, not only for forensically important species, but also for other entomological samples which are hard to identify using morphological features. PMID- 24815991 TI - Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis. AB - Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B-cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity. PMID- 24815993 TI - Chronology of the development of the deciduous dentition in Mediterranean population. AB - The objective of this study of the maturation of deciduous dentition was to offer a novel age-estimation method for Mediterranean populations, using the osteological collection of fetuses, infants, and young children in the Anthropology Laboratory of Granada University (Spain) as study material. After excluding premature newborns and infants with disease, the final study sample comprised 1303 deciduous teeth suitable for analysis from 138 individuals (80 male, 58 female) aged between 24 weeks in utero and 6 years. Eleven mineralization stages were defined for the dental maturation analysis, and the alveolar emergence was also studied. The criteria published by Demirjian et al. (Hum. Biol. 45 (1973) 211), Moorrees et al. (J. Dent. Res. 42 (1963a) 490), and Liversidge et al. (Am. J. Phys. Anthropol. 123 (2004) 172) were combined and modified for this purpose. The reproducibility of the proposed method is supported by the low intra- and inter-observer error in the identification of these development stages. The results provide information on the mean age of attainment of each of 11 mineralization stages and on the average age for each stage in each deciduous tooth type, considering each sex separately and both sexes combined. PMID- 24815994 TI - Characterization of microsatellite loci in Phormia regina towards expanding molecular applications in forensic entomology. AB - Forensic entomology involves the use of insects and arthropods to assist a spectrum of medico-criminal investigations that range from identifying cases of abuse, corpse movements, and most commonly, post mortem interval estimates. Many of these applications focus on the use of blowflies given their predicable life history characteristics in their larval stages. Molecular tools have become increasingly important in the unambiguous identification of larval blowfly species, however, these same tools have the potential to broaden the array of molecular applications in forensic entomology to include individual identifications and population assignments. Herein, we establish a microsatellite profiling system for the blowfly, Phormiaregina (Diptera: Calliphoridae). The goal being to create a system to identify the population genetic structure of this species and subsequently establish if these data are amenable to identifying corpse movements based on the geographic distribution of specific genetic clusters of blowflies. Using next generation sequencing technology, we screened a partial genomic DNA sequence library of P.regina, searching for di-, tetra-, and penta-nucleotide microsatellite loci. We identified and developed primers for 84 highly repetitive segments of DNA, of which 14 revealed consistent genotypes and reasonable levels of genetic variation (4-26 alleles/locus; heterozygosity ranged from 0.385 to 0.909). This study provides the first step in assessing the utility of microsatellite markers to track the movements and sources of corpses via blowflies. PMID- 24815995 TI - Morita-Baylis-Hillman reaction: ESI-MS(/MS) investigation with charge tags and ionic liquid effect origin revealed by DFT calculations. AB - The use of a charge-tagged acrylate derivative bearing an imidazolium tag to study the Morita-Baylis-Hillman reaction via ESI-MS(/MS) monitoring and the effect of such tag (imidazolium cations and ion pairs) over TSs is described. The ionic nature of the substrate was meant to facilitate ESI transfer to the gas phase for direct mass spectrometric analysis. The detection and characterization of charged intermediates has suggested major reaction pathways. DFT calculations considering the effect of a polar and protic solvent (methanol), of a polar and aprotic solvent (acetonitrile), and of no solvent (gas phase) were used to predict possible TSs through a common accepted intermediate. The controversial proton transfer step, which may proceed via Aggarwal's or McQuade's proposals, was evaluated. Calculations predicted the formation of electrostatic intermediate complexes with both the cation and anion when charge-tagged reagents are used. These complexes contribute to the positive ionic liquid effect, and based on the formation of these unique complexes, a rationale for the ionic liquid effect is proposed. These complexes also pointed to a plausible explanation for the positive ionic liquid effect observed in several reactions that are difficult to be carried out in organic solvents but have shown a beneficial effect when performed in ionic liquids. PMID- 24815996 TI - Mechanisms of oligozoospermia: an oxidative stress perspective. AB - Infertile patients presenting with poor semen concentration, motility, and morphology have significantly higher levels of reactive oxygen species (ROS). In this cross-sectional study, our goal was to: 1) determine how semen parameters such as concentration, motility, morphology, as well as ROS are altered in oligozoospermic men alone and those in combination with poor sperm concentration, motility, morphology, and compare these with three control groups; unproven donors, donors with proven fertility <2 years, and proven donors with fertility established >2 years; 2) establish the cutoff, sensitivity, specificity for ROS, and see how it compared in the three donor groups compared to the patient groups, and 3) establish the reference range for the various semen parameters in these three donor groups compared to the oligozoospermic group by generating receiver operating characteristic (ROC) curves for each parameter. Fifty-six donors and 101 infertile men were included in this study. The patient group included: oligozoospermia: n = 16; oligoasthenozoospermia (OA): n = 12; oligoteratozoospermia (OT): n = 19; oligoasthenoteratozoospermia (OAT): n = 54. The patient group was compared with the three donor groups. Proven donors who had established a pregnancy in the past or recently (<2 years) had significantly improved semen motility and morphology compared to the OAT and OT groups (p < 0.001). In the OAT group, normal morphology was positively correlated with concentration and negatively with levels of ROS. Compared to the three donor groups, oligozoospermic patients in the OAT, OT, and OA groups had significantly elevated ROS levels. The cutoff for ROS in the proven donors < 2 years was significantly lower with a higher sensitivity and specificity compared to the unproven donors and donors who had not established a recent pregnancy. These results indicate a positive association between semen parameters and ROS suggesting a common underlying mechanism in these infertile patient groups. PMID- 24815997 TI - [An overview of the history of electro-vectorcardiography. Tribute to the memory of the unforgettable Dr. Gustavo A. Medrano Castro]. AB - The history of the investigations about of the so-called irritability of animal tissues showed by English physician Francis Glisson in the 17th century, is summarized. During the 18th century, reliable studies on the bioelectric properties of these tissues began, due to the Swiss scientist Albrecht von Haller and continuated by the Italian naturalist Felice Fontana. In the second half of this century, multiple controversies of the partisans of the animal electricity against the partisans of the contact electricity took place. The Danish scientist Oersted in 1820 proved the close relation of magnetism to electricity, which led to construction of electrometers. These instruments allowed to register and measure record of the electric current. On this way, at middle 21st century, the true animal electricity was identified as the injury current. Later it was possible to record the electric current, risen in the myocardium, out the thorax first by means of the Lippmann' capillary electrometer and later thanks to the Einthoven's string galvanometer at the beginning of the 20th century. So the modern electro-vectorcardiography took off, due to English Thomas Lewis, the North-American Frank N. Wilson and the Mexican Demetrio Sodi Pallares. The last one allowed to rationalize the electro-vectorcardiographic exploration on experimental bases. PMID- 24815998 TI - Increased concentration of T-cell receptor rearrangement excision circles (TREC) in peripheral blood in Graves' disease. AB - BACKGROUND: T-cell receptor rearrangement excision circles (TREC) are circular DNA molecules generated during T-cell maturation in the thymus. Recent studies suggested that a decreased TREC concentration in peripheral blood may be a general feature of autoimmunity. Our purpose was to assess the TREC concentration in Graves' disease (GD). METHODS: TREC concentration was assessed by real time PCR in DNA samples isolated from peripheral blood leucocytes among younger (n = 94, age range 6-29 years) and older patients with GD (n = 93, age range 57-80 years) and age-matched controls (n = 206). RESULTS: TREC concentration decreased with age in all subjects, but it was significantly higher in GD compared with controls (P = 9.4 * 10(-10) ). TREC concentration was higher (P = 0.0038) in hyperthyroid (n = 78) than euthyroid (n = 82) patients with GD, but in both groups, it remained increased relative to controls (P = 2.2 * 10(-11) and P = 4.4 *10(-7) , respectively). CONCLUSIONS: Patients with GD, particularly those with hyperthyroidism, have increased concentration of TREC which may suggest increased rather than decreased thymic activity. Thus, GD does not follow the paradigm suggested for other autoimmune disorders which links autoimmunity with thymic senescence. PMID- 24816000 TI - A dimer is the minimal proton-conducting unit of the influenza a virus M2 channel. AB - When influenza A virus infects host cells, its integral matrix protein M2 forms a proton-selective channel in the viral envelope. Although X-ray crystallography and NMR studies using fragment peptides have suggested that M2 stably forms a tetrameric channel irrespective of pH, the oligomeric states of the full-length protein in the living cells have not yet been assessed directly. In the present study, we utilized recently developed stoichiometric analytical methods based on fluorescence resonance energy transfer using coiled-coil labeling technique and spectral imaging, and we examined the relationship between the oligomeric states of full-length M2 and its channel activities in living cells. In contrast to previous models, M2 formed proton-conducting dimers at neutral pH and these dimers were converted to tetramers at acidic pH. The antiviral drug amantadine hydrochloride inhibited both tetramerization and channel activity. The removal of cholesterol resulted in a significant decrease in the activity of the dimer. These results indicate that the minimum functional unit of the M2 protein is a dimer, which forms a complex with cholesterol for its function. PMID- 24815999 TI - The inhalation characteristics of patients when they use different dry powder inhalers. AB - BACKGROUND: The characteristics of each inhalation maneuver when patients use dry powder inhalers (DPIs) are important, because they control the quality of the emitted dose. METHODS: We have measured the inhalation profiles of asthmatic children [CHILD; n=16, mean forced expiratory volume in 1 sec (FEV1) 79% predicted], asthmatic adults (ADULT; n=53, mean predicted FEV1 72%), and chronic obstructive pulmonary disease (COPD; n=29, mean predicted FEV1 42%) patients when they inhaled through an Aerolizer, Diskus, Turbuhaler, and Easyhaler using their "real-life" DPI inhalation technique. These are low-, medium-, medium/high-, and high-resistance DPIs, respectively. The inhalation flow against time was recorded to provide the peak inhalation flow (PIF; in L/min), the maximum pressure change (DeltaP; in kPa), acceleration rates (ACCEL; in kPa/sec), time to maximum inhalation, the length of each inhalation (in sec), and the inhalation volume (IV; in liters) of each inhalation maneuver. RESULTS: PIF, DeltaP, and ACCEL values were consistent with the order of the inhaler's resistance. For each device, the inhalation characteristics were in the order ADULT>COPD>CHILD for PIF, DeltaP, and ACCEL (p<0.001). The results showed a large variability in inhalation characteristics and demonstrate the advantages of DeltaP and ACCEL rather than PIFs. Overall inhaled volumes were low, and only one patient achieved an IV >4 L and DeltaP >4 kPa. CONCLUSION: The large variability of these inhalation characteristics and their range highlights that if inhalation profiles were used with compendial in vitro dose emission measurements, then the results would provide useful information about the dose patients inhale during routine use. The inhalation characteristics highlight that adults with asthma have greater inspiratory capacity than patients with COPD, whereas children with asthma have the lowest. The significance of the inhaled volume to empty doses from each device requires investigation. PMID- 24816001 TI - Atypical Friedreich ataxia in patients with FXN p.R165P point mutation or comorbid hemochromatosis. AB - BACKGROUND: Compound heterozygosity for a trinucleotide repeat expansion and a point mutation in the FXN gene is a rare cause of Friedreich ataxia (FRDA). METHODS: We identified three Swedish FRDA patients with an FXN p.R165P missense mutation and compared their clinical features with six homozygote trinucleotide repeat expansion carriers. Patients were assessed clinically. Trinucleotide expansion length was determined and lymphocyte frataxin levels measured. RESULTS: p.R165P mutation carriers became wheelchair bound early, but had retained reflexes, better arm function, milder dysarthria, and were more independent in activities of daily living. One p.R165P mutation carrier developed psychosis. Frataxin levels were higher than in homozygous trinucleotide expansion patients. One patient with homozygous trinucleotide repeat expansions and comorbid hemochromatosis had more severe FRDA symptoms than his sibling without hemochromatosis. CONCLUSION: p.R165P patients progress to a less disabling disease state than typical FRDA. Comorbid hemochromatosis may worsen FRDA symptoms through additive effects on iron metabolism. PMID- 24816002 TI - Diagnostic accuracy of parkinsonism syndromes by general neurologists. AB - INTRODUCTION: Movement disorder specialists can achieve a high level of accuracy when clinically diagnosing parkinsonism syndromes. However, data about the diagnostic accuracy among general neurologists is limited. OBJECTIVES: This study investigated the recent diagnostic accuracy of parkinsonism syndromes by general neurologists. METHODS: A retrospective examination of 1362 post-mortem cases diagnosed in the years 2000-2012 by neuropathologists was performed. Out of these cases, we identified 111 patients who received a clinical parkinsonism diagnosis during life and 122 patients who received a neuropathological diagnosis of a parkinsonism syndrome post-mortem including 11 incidental cases. RESULTS: Fifty eight (75.3%) of the 77 patients who had received clinical Parkinson's disease (PD) diagnoses were confirmed after the neuropathological examination. The sensitivity of the clinical diagnosis for idiopathic Parkinson's disease (PD) was 89.2% and the specificity was 57.8%. The corresponding numbers for progressive supranuclear palsy (PSP) were 52.9% and 100%, and for multiple system atrophy (MSA) were 64.3% and 99.0%, respectively. CONCLUSIONS: Parkinson's disease is heavily overdiagnosed by general neurologists, whereas parkinsonism plus syndromes are underdiagnosed. Despite improvements in the diagnostic methods during recent decades and the development of diagnostic clinical criteria for parkinsonian syndromes, the diagnostic accuracy of Parkinson's disease remains relatively low, and 1/4 of diagnoses are incorrect. PMID- 24816003 TI - LRRK2 mutations in Parkinson's disease: confirmation of a gender effect in the Italian population. AB - BACKGROUND: The relative risk of developing idiopathic PD is 1.5 times greater in men than in women, but an increased female prevalence in LRRK2-carriers has been described in the Ashkenazi Jewish population. We report an update about the frequency of major LRRK2 mutations in a large series of consecutive patients with Parkinson's disease (PD), including extensive characterization of clinical features. In particular, we investigated gender-related differences in motor and non-motor symptoms in the LRRK2 population. METHODS: 2976 unrelated consecutive Italian patients with degenerative Parkinsonism were screened for mutations on exon 41 (G2019S, I2020T) and a subgroup of 1190 patients for mutations on exon 31 (R1441C/G/H). Demographic and clinical features were compared between LRRK2 carriers and non-carriers, and between male and female LRRK2 mutation carriers. RESULTS: LRRK2 mutations were identified in 40 of 2523 PD patients (1.6%) and not in other primary parkinsonian syndromes. No major clinical differences were found between LRRK2-carriers and non-carriers. We found a novel I2020L missense variant, predicted to be pathogenic. Female gender was more common amongst carriers than non-carriers (57% vs. 40%; p = 0.01), without any gender-related difference in clinical features. Family history of PD was more common in women in the whole PD group, regardless of their LRRK2 status. CONCLUSIONS: PD patients with LRRK2 mutations are more likely to be women, suggesting a stronger genetic load compared to idiopathic PD. Further studies are needed to elucidate whether there is a different effect of gender on the balance between genetic and environmental factors in the pathogenesis of PD. PMID- 24816004 TI - Metabolic effects of antipsychotics in prepubertal children: a retrospective chart review. AB - OBJECTIVE: Antipsychotics, especially atypical ones, are in common use in children and adolescents with psychotic or affective spectrum disorders, as well as in various other psychopathologies. The adverse effects of atypical antipsychotics in children and adolescents are similar to those seen in adults, and include weight gain, elevated blood glucose levels, and hyperlipidemia. In this retrospective chart review, we compared these adverse events in children who were treated with typical, atypical, or no antipsychotic treatment. METHODS: The medical charts of 72 children, 65 boys and 7 girls, were reviewed. All children were 6-13 years old (mean age 9.5+/-1.7 years). In total, 48 children received antipsychotic treatment, and 24 children were in the control group. Data were extracted from the medical charts, including weight, height, body mass index (BMI), blood pressure, aspartate transaminase (AST), alanine transaminase (ALT), triglycerides, total cholesterol, and glucose blood levels. We examined the values in the beginning of the antipsychotic treatment and at release from the hospital in the study group, and at admission and in the end of the drug-free period or at release from the hospital (a duration of at least 4 weeks) in the control group. RESULTS: The average weight gain was 3.9+/-3.8 kg in the atypical antipsychotic treatment (AAT) group, 1.1+/-4.4 kg in the typical antipsychotic treatment (TAT) group, and 0.23+/-2.9 kg in the control group. The average increase in BMI was 15.1+/-22.0 percentiles in the AAT group, 6.4+/-14.2 percentiles in the TAT group, and 1.6+/-12.5 percentiles in the control group. No statistically significant difference was found in the increase in height percentile. There were no significant differences in the rates of elevated values of serum triglycerides, cholesterol, AST, ALT, or fasting blood glucose. CONCLUSIONS: We found a significant increase in both absolute weight gain and BMI percentile following atypical antipsychotic treatment. In contrast, typical antipsychotic treatment did not affect weight gain significantly, and the same was true for the control group. In addition, the rates of elevated values of biochemical parameters (AST, ALT, total cholesterol, triglycerides, and fasting blood glucose levels) were very low at the beginning of the study, and were not significantly altered by the various treatments. PMID- 24816005 TI - Soft scorpionate coordination at alkali metals. AB - Reported here are the single-crystal X-ray structure analyses of bis-MU-methanol kappa(4)O:O-bis{[hydrotris(3-phenyl-2-sulfanylidene-2,3-dihydro-1H-1,3-imidazol-1 yl)borato-kappa(3)H,S,S'](methanol-kappaO)sodium(I)}, [Na2(C27H22BN6S3)2(CH4O)4] (NaTm(Ph)), bis-MU-methanol-kappa(4)O:O-bis{[hydrotris(3-isopropyl-2 sulfanylidene-2,3-dihydro-1H-1,3-imidazol-1-yl)borato-kappa(3)H,S,S'](methanol kappaO)sodium(I)}-diethyl ether-methanol (1/0.3333/0.0833), [Na2(C18H28BN6S3)2(CH4O)4].0.3333C4H10O.0.0833CH3OH (NaTm(iPr)), and a novel anhydrous form of sodium hydrotris(methylthioimidazolyl)borate, poly[[MU hydrotris(3-methyl-2-sulfanylidene-2,3-dihydro-1H-1,3-imidazol-1 yl)borato]sodium(I)], [Na(C12H16BN6S3)] ([NaTm(Me)]n). NaTm(iPr) and NaTm(Ph) have similar dimeric molecular structures with kappa(3)H,S,S'-bonding, but they differ in that NaTm(Ph) is crystallographically centrosymmetric (Z' = 0.5) while NaTm(iPr) contains one crystallographically centrosymmetric dimer and one dimer positioned on a general position (Z' = 1.5). [NaTm(Me)]n is a one-dimensional coordination polymer that extends along the a direction and which contains a hitherto unseen side-on eta(2)-C=S-to-Na bond type. An overview of the structural preferences of alkali metal soft scorpionate complexes is presented. This analysis suggests that these thione-based ligands will continue to be a rich source of interesting alkali metal motifs worthy of isolation and characterization. PMID- 24816006 TI - A one-dimensional lead(II) coordination polymer with terminal and bridging 5 carboxy-2-(pyridin-3-yl)-1H-imidazole-4-carboxylate ligands. AB - In the coordination polymer catena-poly[[[diaqua[5-carboxy-2-(pyridin-3-yl)-1H imidazole-4-carboxylato-kappa(2)N(3),O(4)]lead(II)]-MU-5-carboxy-2-(pyridin-3-yl) 1H-imidazole-4-carboxylato-kappa(3)N(3),O(4):N(2)] dihydrate], {[Pb(C10H6N3O4)(H2O)2].2H2O}n, the two 5-carboxy-2-(pyridin-3-yl)-1H-imidazole-4 carboxylate ligands have different coordination modes, one being terminal and the other bridging. The bridging ligand links Pb(II) cations into one-dimensional coordination polymer chains. The structure is also stabilized by intra- and interchain pi-pi stacking interactions between the pyridine rings, resulting in the formation of a two-dimensional network. Extensive hydrogen-bonding interactions lead to the formation of a three-dimensional supramolecular network. PMID- 24816007 TI - Low-dimensional compounds containing cyanide groups. XXV. Synthesis, spectroscopic properties and crystal structures of two ionic iron(II) complexes with tricyanomethanide: tris(1,10-phenanthroline-kappa(2)N,N')iron(II) bis(tricyanomethanide) and tris(2,2'-bipyridine-kappa(2)N,N')iron(II) bis(tricyanomethanide) sesquihydrate. AB - Two new diamagnetic coordination compounds, [Fe(phen)3][C(CN)3]2, (I), and [Fe(bpy)3][C(CN)3]2.1.5H2O, (II), have been synthesized and characterized by single-crystal X-ray diffraction analysis, and IR and UV-Vis spectroscopy (phen is 1,10-phenanthroline, C12H8N2, and bpy is 2,2'-bipyridine, C10H8N2). Both compounds are ionic with distorted octahedral [Fe(phen)3](2+) or [Fe(bpy)3](2+) complex cations, with average Fe-N distances of 1.977 (2) and 1.971 (3) A, respectively, and two uncoordinated planar tricyanomethanide, or [C(CN)3](-), counter-anions balancing the positive charges of the cations. Solvent water molecules and tcm anions in (II) are linked via O-H...N hydrogen bonds into negatively charged layers and the interlayer space is filled by [Fe(bpy)3](2+) cations. The structures of (I) and (II) are stabilized by pi-pi interactions between the stacked aromatic rings of the phen ligands of two adjacent cations and by O-H...N hydrogen bonds, respectively, and also by pi-pi stacking interactions between phen and tcm units in (I). PMID- 24816008 TI - An iron(III) complex salt containing pyrazole as both ligand and counter-ion: bis(1H-pyrazol-2-ium) pentacyanido(1H-pyrazole-kappaN(2))ferrate(III). AB - The title compound, (C3H5N2)2[Fe(CN)5(C3H4N2)], is composed of a mononuclear [Fe(CN)5(pyrazole)](2-) dianion and two 1H-pyrazol-2-ium cations. A three dimensional supramolecular network is formed through a rich scheme of N-H...N hydrogen bonds and C-H...pi interactions among the cations and anions. PMID- 24816009 TI - The structure of {[Co(pht)(bpy)(H2O)].3H2O}n (pht is phthalate and bpy is 4,4' bipyridine) and the role of solvent water clusters in structure stability. AB - The Co(II) cation in poly[[aqua(MU-benzene-1,2-dicarboxylato kappa(3)O(1),O(2):O(1))(MU-4,4'-bipyridine-kappa(2)N:N')cobalt(II)] trihydrate], {[Co(C8H4O4)(C10H8N2)(H2O)].3H2O}n, is octahedrally coordinated by two N atoms of two 4,4'-bipyridine ligands, three O atoms from phthalate anions and a fourth O atom from a coordinated water molecule. The packing consists of planes of coordination polymers linked by hydrogen bonds mediated by three solvent water molecules; the linkage is achieved by the water molecules forming intricate oligomeric clusters which also involve the O atoms of the phthalate ligands. PMID- 24816010 TI - A one-dimensional ladder-like six-coordinate cadmium polymer: catena-poly[bis[(S) 2-methylpiperazine-1,4-diium] [bis[trichloridocadmium(II)]-di-MU3-chlorido]]. AB - The crystal structure of the title compound {(C5H14N2)2[Cd2Cl8]}n, (I), consists of hydrogen-bonded 2-methylpiperazinediium (H2MPPA(2+)) cations in the presence of one-dimensional polymeric {[CdCl3(MU3-Cl)](2-)}n anions. The Cd(II) centres are hexacoordinated by three terminal chlorides and three bridging chlorides and have a slightly distorted octahedral CdCl3(MU3-Cl)3 arrangement. The alternating CdCl6 octahedra form four-membered Cd2Cl2 rings by the sharing of neighbouring Cd Cl edges to give rise to extended one-dimensional ladder-like chains parallel to the b axis, with a Cd...Cd distance of 4.094 (2) A and a Cd...Cd...Cd angle of 91.264 (8) degrees . The H2MPPA(2+) cations crosslink the [CdCl3(MU3-Cl)]n chains by the formation of two N-H...Cl hydrogen bonds to each chain, giving rise to one dimensional ladder-like H2MPPA(2+)-Cl2 hydrogen-bonded chains [graph set R4(2)(14)]. The [CdCl3(MU3-Cl)]n chains are interwoven with the H2MPPA(2+)-Cl2 hydrogen-bonded chains, giving rise to a three-dimensional supramolecular network. PMID- 24816011 TI - The molecular structure of high-spin (S = 5/2) manganese(II) phthalocyanine in tetrabutylammonium bromido(phthalocyaninato)manganese(II). AB - The title complex salt, (C16H36N)[MnBr(C32H16N8)] or (TBA)[Mn(II)Br(Pc)] (TBA is tetrabutylammonium and Pc is phthalocyaninate), has been obtained as single crystals by the diffusion technique and its crystal structure was determined using X-ray diffraction. The high-spin (S = 5/2) [Mn(II)Br(Pc)](-) macrocycle has a concave conformation, with an average equatorial Mn-N(Pc) bond length of 2.1187 (19) A, an axial Mn-Br bond length of 2.5493 (7) A and with the Mn(II) cation displaced out of the 24-atom Pc plane by 0.894 (2) A. The geometry of the Mn(II)N4 fragment in [Mn(II)Br(Pc)](-) is similar to that of the high-spin (S = 5/2) manganese(II) tetraphenylporphyrin (TPP) in [Mn(II)(1-MeIm)(TPP)] (1-MeIm is 1-methylimidazole). PMID- 24816012 TI - Substitutional disorder in Sr2-yEuyB2-2xSi2+3xAl2-xN8+x (x ? 0.12, y ? 0.10). AB - A novel nitride, Sr2-yEuyB2-2xSi2+3xAl2-xN8+x (x ? 0.12, y ? 0.10) (distrontium europium diboron disilicon dialuminium octanitride), with the space group P62c, was synthesized from Sr3N2, EuN, Si3N4, AlN and BN under nitrogen gas pressure. The structure consists of a host framework with Sr/Eu atoms accommodated in the cavities. The host framework is constructed by the linkage of MN4 tetrahedra (M = Si, Al) and BN3 triangles, and contains substitutional disorder described by the alternative occupation of B2 or Si2N on the (0, 0, z) axis. The B2:Si2N ratio contained in an entire crystal is about 9:1. PMID- 24816013 TI - Two crown-ether-coordinated caesium halogen salts. AB - The crystal structures of two crown-ether-coordinated caesium halogen salt hydrates, namely di-MU-bromido-bis[aqua(1,4,7,10,13,16 hexaoxacyclooctadecane)caesium(I)] dihydrate, [Cs2Br2(C12H24O6)2(H2O)2].2H2O, (I), and poly[[diaquadi-MU-chlorido-MU-(1,4,7,10,13,16 hexaoxacyclooctadecane)dicaesium(I)] dihydrate], {[Cs2Cl2(C12H24O6)(H2O)2].2H2O}n, (II), are reported. In (I), all atoms are located on general positions. In (II), the Cs(+) cation is located on a mirror plane perpendicular to the a axis, the chloride anion is located on a mirror plane perpendicular to the c axis and the crown-ether ring is located around a special position with site symmetry 2/m, with two opposite O atoms exactly on the mirror plane perpendicular to the a axis; of one water molecule, only the O atom is located on a mirror plane perpendicular on the a axis, while the other water molecule is completely located on a mirror plane perpendicular to the c axis. Whereas in (I), hydrogen bonds between bromide ligands and water molecules lead to one-dimensional chains running along the b axis, in (II) two-dimensional sheets of water molecules and chloride ligands are formed which combine with the polymeric caesium-crown polymer to give a three-dimensional network. Although both compounds have a similar composition, i.e. a Cs(+) cation with a halogen, an 18-crown-6 ether and a water ligand, the crystal structures are rather different. On the other hand, it is remarkable that (I) is isomorphous with the already published iodide compound. PMID- 24816014 TI - A new P,S-coordinating ferrocenyl ligand: synthesis of a precursor and its coordination compounds with Pd(II) and Pt(II). AB - In our ongoing development of ferrocene ligands, 1-dimethylamino-2 (diphenylphosphinothioyl)ferrocene is being used as a convenient building block to obtain racemic or enantiomerically pure ligands. Using this building block in large excess allowed the formation of several by-products, two of which have already been reported; the structure of a third by-product, namely 1 (diphenylphosphinothioyl)-2-{[(diphenylphosphinothioyl)sulfanyl]methyl}ferrocene, [Fe(C5H5)(C30H25P2S3)], is presented here. The crystal structure is built up from a ferrocene unit, with one of the cyclopentadienyl (Cp) rings substituted in the 1- and 2-positions by a protected diphenylphosphinothioyl group and a [(diphenylphosphinothioyl)sulfanyl]methyl fragment, -CH2SP(=S)Ph2. There are C H...S interactions which result in the formation of chains parallel to the c axis. After desulfurization, the crude material was then reacted with Pd and Pt (M) precursors [MCl2(CH3CN)2] to yield two isostructural dinuclear complexes arranged around twofold axes, namely (R,R/S,S)-bis{MU-[2 (diphenylphosphanyl)ferrocen-1-yl]methanethiolato kappa(3)P,S:S}bis[chloridopalladium(II)] pentane disolvate, [Pd2{Fe(C5H5)(C18H15PS)}2Cl2].2C5H12, and the platinum(II) analogue, (R,R/S,S) bis{MU-[2-(diphenylphosphanyl)ferrocen-1-yl]methanethiolato kappa(3)P,S:S}bis[chloridoplatinum(II)] toluene monosolvate, [Pt2{Fe(C5H5)(C18H15PS)}2Cl2].C7H8, in which the two metal atoms present a slightly distorted square-planar geometry formed by two bridging S atoms and P and Cl atoms. The P,S-chelating ligand results from the rupture of one of the P-S bonds in the starting ligand. These dinuclear complexes display a butterfly geometry. Surprisingly, only the (R,R/S,S) diastereoisomer has been isolated. PMID- 24816015 TI - Tris(2,2'-bipyridine)iron(II) bis(1,1,3,3-tetracyano-2-ethoxypropenide) dihydrate: chiral hydrogen-bonded frameworks interpenetrate in three dimensions. AB - In the title compound, [Fe(C10H8N2)3](C9H5N4O)2.2H2O, the chiral cations lie across twofold rotation axes in the space group C2/c. The anions and the water molecules are linked by two independent O-H...N hydrogen bonds to form C2(2)(8) chains, and these chains are linked by the cations via C-H...N and C-H...O hydrogen bonds to form two interpenetrating three-dimensional frameworks, each of which contains only one enantiomeric form of the chiral cation. PMID- 24816016 TI - Phase transitions and twinned low-temperature structures of tetraethylammonium tetrachloridoferrate(III). AB - The title compound, [(C2H5)4N][FeCl4], has at room temperature a disordered structure in the high-hexagonal space group P63mc. At 230 K, the structure is merohedrally twinned in the low-hexagonal space group P63. The volume has increased by a factor of 9 with respect to the room-temperature structure. At 170 and 110 K, the structure is identical in the orthorhombic space group Pca21 and twinned by reticular pseudomerohedry. The volume has doubled with respect to the room-temperature structure. All three space groups, viz. P63mc, P63 and Pca21, are polar and the direction of the polar axis is not affected by the twinning. In the P63 and Pca21 structures, all cations and anions are well ordered. PMID- 24816017 TI - Synthesis, characterization and crystal structure of the new pentahydrate of bis(2,2'-bipyridine-kappa(2)N,N')(oxalato-kappa(2)O(1),O(2))nickel(II). AB - The reaction of NiCl2, K2C2O4.H2O and 2,2'-bipyridine (bpy) in water-ethanol solution at 281 K yields light-purple needles of the new pentahydrate of bis(2,2' bipyridine)oxalatonickel(II), [Ni(C2O4)(C10H8N2)2].5H2O or [Ni(ox)(bpy)2].5H2O, while at room temperature, deep-pink prisms of the previously reported tetrahydrate [Ni(ox)(bpy)2].4H2O [Roman, Luque, Guzman-Miralles & Beitia (1995), Polyhedron, 14, 2863-2869] were gathered. The asymmetric unit in the crystal structure of the new pentahydrate incorporates the discrete molecular complex [Ni(ox)(bpy)2] and five solvent water molecules. Within the complex molecule, all three ligands are bonded as chelates. The complex molecules are involved in an extended system of hydrogen bonds with the solvent water molecules. Additionally, pi-pi interactions also contribute to the stabilization of the extended structure. The dehydration of the pentahydrate starts at 323 K and proceeds in at least two steps as determined by thermal analysis. PMID- 24816018 TI - Intra- and intermolecular Se...X (X = Se, O) interactions in selenium-containing heterocycles: 3-benzoylimino-5-(morpholin-4-yl)-1,2,4-diselenazole. AB - In the selenium-containing heterocyclic title compound {systematic name: N-[5 (morpholin-4-yl)-3H-1,2,4-diselenazol-3-ylidene]benzamide}, C13H13N3O2Se2, the five-membered 1,2,4-diselenazole ring and the amide group form a planar unit, but the phenyl ring plane is twisted by 22.12 (19) degrees relative to this plane. The five consecutive N-C bond lengths are all of similar lengths [1.316 (6)-1.358 (6) A], indicating substantial delocalization along these bonds. The Se...O distance of 2.302 (3) A, combined with a longer than usual amide C=O bond of 2.252 (5) A, suggest a significant interaction between the amide O atom and its adjacent Se atom. An analysis of related structures containing an Se-Se...X unit (X = Se, S, O) shows a strong correlation between the Se-Se bond length and the strength of the Se...X interaction. When X = O, the strength of the Se...O interaction also correlates with the carbonyl C=O bond length. Weak intermolecular Se...Se, Se...O, C-H...O, C-H...pi and pi-pi interactions each serve to link the molecules into ribbons or chains, with the C-H...O motif being a double helix, while the combination of all interactions generates the overall three-dimensional supramolecular framework. PMID- 24816019 TI - Cd(II) and Co(II) coordination polymers constructed from benzene-1,4-dicarboxylic acid and 2-(pyridin-3-yl)-1H-benzimidazole ligands. AB - In poly[aqua(MU3-benzene-1,4-dicarboxylato-kappa(5)O(1),O(1'):O(1):O(4),O(4'))[2 (pyridin-3-yl-kappaN)-1H-benzimidazole]cadmium(II)], [Cd(C8H4O4)(C12H9N3)(H2O)]n, (I), each Cd(II) ion is seven-coordinated by the pyridine N atom from a 2 (pyridin-3-yl)benzimidazole (3-PyBIm) ligand, five O atoms from three benzene-1,4 dicarboxylate (1,4-bdc) ligands and one O atom from a coordinated water molecule. The complex forms an extended two-dimensional carboxylate layer structure, which is further extended into a three-dimensional network by hydrogen-bonding interactions. In catena-poly[[diaquabis[2-(pyridin-3-yl-kappaN)-1H benzimidazole]cobalt(II)]-MU2-benzene-1,4-dicarboxylato-kappa(2)O(1):O(4)], [Co(C8H4O4)(C12H9N3)2(H2O)2]n, (II), each Co(II) ion is six-coordinated by two pyridine N atoms from two 3-PyBIm ligands, two O atoms from two 1,4-bdc ligands and two O atoms from two coordinated water molecules. The complex forms a one dimensional chain-like coordination polymer and is further assembled by hydrogen bonding interactions to form a three-dimensional network. PMID- 24816020 TI - syn and anti conformations in 2-hydroxy-5-[(E)-(4-nitrophenyl)diazenyl]benzoic acid and two related salts. AB - The crystal structures of 2-hydroxy-5-[(E)-(4-nitrophenyl)diazenyl]benzoic acid, C13H9N3O5, (I), ammonium 2-hydroxy-5-[(E)-phenyldiazenyl]benzoate, NH4(+).C13H9N2O3(-), (II), and sodium 2-hydroxy-5-[(E)-(4 nitrophenyl)diazenyl]benzoate trihydrate, Na(+).C13H8N3O5(-).3H2O, (III), have been determined using single-crystal X-ray diffraction. In (I) and (III), the phenyldiazenyl and carboxylic acid/carboxylate groups are in an anti orientation with respect to each other, which is in accord with the results of density functional theory (DFT) calculations, whereas in (II), the anion adopts a syn conformation. In (I), molecules form slanted stacks along the [100] direction. In (II), anions form bilayers parallel to (010), the inner part of the bilayers being formed by the benzene rings, with the -OH and -COO(-) substituents on the bilayer surface. The NH4(+) cations in (II) are located between the bilayers and are engaged in numerous N-H...O hydrogen bonds. In (III), anions form layers parallel to (001). Both Na(+) cations have a distorted octahedral environment, with four octahedra edge-shared by bridging water O atoms, forming [Na4(H2O)12](4+) units. PMID- 24816021 TI - A twofold interpenetrating three-dimensional zinc-organic framework built from naphthalene-1,4-dicarboxylate and 4,4'-bipyridine ligands. AB - A novel three-dimensional Zn(II) complex, poly[[(MU2-4,4'-bipyridine)(MU4 naphthalene-1,4-dicarboxylato)(MU2-naphthalene-1,4-dicarboxylato)dizinc(II)] dimethylformamide monosolvate monohydrate], {[Zn2(C12H6O4)2(C10H8N2)].2C3H7NO.H2O)}n, has been prepared by the solvothermal assembly of Zn(NO3).6H2O, naphthalene-1,4-dicarboxylic acid and 4,4'-bipyridine. The two crystallographically independent Zn atoms adopt the same four-coordinated tetrahedral geometry (ZnO3N) by bonding to three O atoms from three different naphthalene-1,4-dicarboxylate (1,4-ndc) ligands and one N atom from a 4,4' bipyridine (bpy) ligand. The supramolecular secondary building unit (SBU) is a distorted paddle-wheel-like {Zn2(COO)2N2O2} unit and these units are linked by 1,4-ndc ligands within the layer to form a two-dimensional net parallel to the ab plane, which is further connected by bpy ligands to form the three-dimensional framework. The single net leaves voids that are filled by mutual interpenetration of an independent equivalent framework in a twofold interpenetrating architecture. The title compound is stable up to 673 K. Excitation and luminescence data observed at room temperature show that it emits bright-blue fluorescence. PMID- 24816022 TI - Zn/Mn-MOFs with 'S-shaped' packing modes. AB - Two novel polymers exhibiting metal-organic frameworks (MOFs) have been synthesized by the combination of a metal ion with a benzene-1,3,5-tricarboxylate ligand (BTC) and 1,10-phenanthroline (phen) under hydrothermal conditions. The first compound, poly[[(MU4-benzene-1,3,5-tricarboxylato-kappa(4)O:O':O'':O''')(MU hydroxido-kappa(2)O:O)bis(1,10-phenanthroline-kappa(2)N,N')dizinc(II)] 0.32 hydrate], {[Zn2(C9H3O6)(OH)(C12H8N2)2].0.32H2O}n, denoted Zn-MOF, forms a two dimensional network in which a binuclear Zn2 cluster serves as a 3-connecting node; the BTC trianion also acts as a 3-connecting centre. The overall topology is that of a 6(3) net. The phen ligands serve as appendages to the network and interdigitate with phen ligands belonging to adjacent parallel sheets. The second compound, poly[[(MU6-benzene-1,3,5-tricarboxylato kappa(7)O(1),O(1'):O(1):O(3):O(3'):O(5):O(5'))(MU3-hydroxido-kappa(2)O:O:O)(1,10 phenanthroline-kappa(2)N,N')dimanganese(II)] 1.26-hydrate], {[Mn2(C9H3O6)(OH)(C12H8N2)].1.26H2O}n, denoted Mn-MOF, exists as a three dimensional network in which an Mn4 cluster serves as a 6-connecting unit, while the BTC trianion again plays the role of a 3-connecting centre. The overall topology is that of the rutile net. Phen ligands act as appendages to the network and form the 'S-shaped' packing mode. PMID- 24816023 TI - Two molybdenum pentacarbonyl complexes with electroneutral phosphane ligands: [bis(morpholin-4-yl)(pentafluoroethyl)phosphane-kappaP]pentacarbonylmolybdenum(0) and pentacarbonyl[(pentafluoroethyl)bis(piperidin-1-yl)phosphane kappaP]molybdenum(0). AB - The crystal structures of the title compounds, [Mo{(C4H8NO)2P(C2F5)}(CO)5], (1a), and [Mo{(C5H10N)2P(C2F5)}(CO)5], (2a), were determined as part of a larger project that focuses on the synthesis and coordination chemistry of phosphane ligands possessing moderate (electroneutral, i.e. neither electron-rich nor electron-deficient) electronic characteristics. Both complexes feature a slightly distorted octahedral geometry at the metal center, due to the electronic and steric repulsions between two of the four equatorial CO groups and the pentafluoroethyl group attached to the phosphane ligand. Bond length and angle data for (1a) and (2a) support the conclusion that the free phosphane ligands are electroneutral. For complex (1a), the Mo-P, Mo-Cax and Mo-Ceq(ave) bond lengths are 2.5063 (5), 2.018 (2) and 2.048 (2) A, respectively, and for complex (2a) these values are 2.5274 (5), 2.009 (3) and 2.050 (3) A, respectively. Geometric data for (1a) and (2a) are compared with similar data reported for analogous Mo(CO)5 complexes. PMID- 24816024 TI - (H3O)2NaAl3F12, isostructural with A2NaAl3F12 (A = K(+), Rb(+), Cs(+)) fluorides having HTB-type sheets. AB - The title compound, (H3O)2NaAl3F12 [dihydronium sodium trialuminum(III) dodecafluoride], was obtained by solvothermal synthesis from the reaction of aluminium hydroxide, sodium hydroxide, 1,2,4-triazole and aqueous HF in ethanol at 463 K for 48 h. The structure consists of AlF6 octahedra organized in [AlF4( )]n HTB-type sheets (HTB is hexagonal tungsten bronze) separated by H3O(+) and Na(+) cations. PMID- 24816025 TI - A two-dimensional Cd(II) coordination polymer with 2,2'-(disulfanediyl)dibenzoate and 1,10-phenanthroline ligands. AB - In poly[[MU3-2,2'-(disulfanediyl)dibenzoato-kappa(5)O:O,O':O'',O'''](1,10 phenanthroline-kappa(2)N,N')cadmium(II)], [Cd(C14H8O4S2)(C12H8N2)]n, the asymmetric unit contains one Cd(II) cation, one 2,2'-(disulfanediyl)dibenzoate anion (denoted dtdb(2-)) and one 1,10-phenanthroline ligand (denoted phen). Each Cd(II) centre is seven-coordinated by five O atoms of bridging/chelating carboxylate groups from three dtdb(2-) ligands and by two N atoms from one phen ligand, forming a distorted pentagonal-bipyramidal geometry. The Cd(II) cations are bridged by dtdb(2-) anions to give a two-dimensional (4,4) layer. The layers are stacked to generate a three-dimensional supramolecular architecture via a combination of aromatic C-H...pi and pi-pi interactions. The thermogravimetric and luminescence properties of this compound were also investigated. PMID- 24816026 TI - Two different one-dimensional supramolecular chains formed from the reaction of 2 [1-(pyridin-4-ylmethyl)-1H-benzimidazol-2-yl]quinoline with two different precursors, Co(NO3)2 and CoCl2. AB - Two different one-dimensional supramolecular chains with Co(II) cations have been synthesized based on the semi-rigid ligand 2-[1-(pyridin-4-ylmethyl)-1H benzimidazol-2-yl]quinoline (L), obtained by condensation of 2-(1H-benzimidazol-2 yl)quinoline and 4-(chloromethyl)pyridine hydrochloride. Starting from different Co(II) salts, two new compounds have been obtained, viz. catena poly[[[dinitratocobalt(II)]-MU-2-[1-(pyridin-4-ylmethyl)-1H-benzimidazol-2 yl]quinoline] dichloromethane monosolvate acetonitrile monosolvate], {[Co(NO3)2(C22H16N4)].CH2Cl2.CH3CN}n, (I) and catena-poly[[[dichloridocobalt(II)] MU-2-[1-(pyridin-4-ylmethyl)-1H-benzimidazol-2-yl]quinoline] methanol disolvate], {[CoCl2(C22H16N4)].2CH3OH}n, (II). In (I), the Co(II) centres lie in a distorted octahedral [CoN3O3] coordination environment. {Co(NO3)2L}n units form one dimensional helical chains, where the L ligand has different directions of twist. The helical chains stack together via interchain pi-pi interactions to form a two dimensional sheet, and another type of pi-pi interaction further connects neighbouring sheets into a three-dimensional framework with hexagonal channels, in which the acetonitrile molecules and disordered dichloromethane molecules are located. In (II), the Co(II) centres lie in a distorted trigonal-bipyramidal [CoCl2N3] coordination environment. {CoCl2L}n units form one-dimensional chains. The chains interact via C-H...pi and C-H...Cl interactions. The result is that two-dimensional sheets are generated, which are further linked into a three dimensional framework via interlayer C-H...Cl interactions. When viewed down the crystallographic b axis, the methanol solvent molecules are located in an orderly manner in wave-like channels. PMID- 24816027 TI - The efficacy and safety of microvascular decompression for idiopathic trigeminal neuralgia in patients older than 65 years. AB - OBJECTIVE: The aim of this study was to review the efficacy and safety of microvascular decompression (MVD) for idiopathic trigeminal neuralgia (ITN) in elderly patients older than 65 years. METHODS: From June 2006 to June 2011, a total of 59 elderly patients with ITN underwent MVD. We performed a retrospective study of the medical records and compared the outcome data with those from 164 patients younger than 64 years during the same period. RESULTS: The mean age of the elderly and younger patient groups was 72 and 55 years. The pain was completely relieved in 93.2% and partially relieved in another 5.1% of the elderly patient group after surgery. The mean follow-up period was 42 months (range, 16-75 mo). A total of 8.9% of the patients in the elderly patient group experienced recurrence. Headaches, nausea, and vomiting were more frequent complications. There were no mortalities and severe morbidities after surgery. Between the elderly and younger patient groups, no statistically significant differences existed in the outcomes. CONCLUSIONS: Microvascular decompression is a safe and effective procedure for elderly patients with ITN. It is recommended that any patients with ITN should have the opportunity to choose MVD, unless their condition cannot tolerate general anesthesia. PMID- 24816028 TI - Photophysics, excited-state double-proton transfer and hydrogen-bonding properties of 5-deazaalloxazines. AB - The photophysical properties of 5-deazaalloxazine and 1,3-dimethyl-5 deazaalloxazine were studied in different solvents. These compounds have higher values of fluorescence quantum yields and longer fluorescence lifetimes, compared to those obtained for their alloxazine analogs. Electronic structure and S0 -Si transitions were investigated using the ab initio methods [MP2, CIS(D), EOM-CCSD] with the correlation-consistent basis sets. Also the time-dependent density functional theory (TD-DFT) has been employed. The lowest singlet excited states of 5-deazaalloxazine and 1,3-dimethyl-5-deazaalloxazine are predicted to have the pi, pi* character, whereas similar alloxazines have two close-lying pi, pi* and n, pi* transitions. Experimental steady-state and time-resolved spectral studies indicate formation of an isoalloxazinic excited state via excited-state double proton transfer (ESDPT) catalyzed by an acetic acid molecule that forms a hydrogen bond complex with the 5-deazaalloxazine molecule. Solvatochromism of both 5-deazaalloxazine and its 1,3-dimethyl substituted derivative was analyzed using the Kamlet-Taft scale and four-parameter Catalan solvent scale. The most significant result of our studies is that the both scales show a strong influence of solvent acidity (hydrogen bond donating ability) on the emission properties of these compounds, indicating the importance of intermolecular solute-solvent hydrogen-bonding interactions in their excited state. PMID- 24816029 TI - Stabilizing autism: A Fleckian account of the rise of a neurodevelopmental spectrum disorder. AB - Using the conceptual tools of philosopher of science Ludwik Fleck, I argue that the reframing of autism as a neurodevelopmental spectrum disorder is constrained by two governing 'styles of thought' of contemporary psychiatry. The first is the historically conditioned 'readiness for directed perception' of, and thinking in terms of, ontologically distinct diseases. The clinical gaze of mental health professionals, the bureaucratic needs of health administration, the clinical and scientific utility of disease categories, and the practices of autism-oriented advocacy groups all imply a bias toward thinking about autism and related disorders as ontologically distinct psychiatric and scientific entities. Second, within the 'neuromolecular style of thought', mental disorders are more and more located at the neurobiological levels of the brain. In autism research, one of the biggest challenges is the identification of autism's neurobiological singularity. However, at a moment when biological and categorical approaches toward autism face serious empirical difficulties, a balance is established that holds together these two styles of thought. With a need to account for some of the most persistent uncertainties and conflicts in autism research, namely ubiquitous heterogeneity and a failure to identify disease specific biomarkers, the reframing of autism as a neurodevelopmental spectrum disorder satisfies the scientific, institutional and socio-political needs for stability and homogenization. PMID- 24816030 TI - Scurvy: a new problem for patients with chronic GVHD involving mucous membranes; an easy problem to resolve. AB - Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 +/- 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat. PMID- 24816031 TI - A single-component molecular superconductor. AB - The pressure dependence of the resistivities of a single-component molecular conductor, [Ni(hfdt)2] (hfdt = bis(trifluoromethyl)tetrathiafulvalenedithiolate) with semiconducting properties at ambient pressure was examined. The four-probe resistivity measurements were performed up to ~10 GPa using a diamond anvil cell. The low-temperature insulating phase was suppressed above 7.5 GPa and the resistivity dropped, indicating the superconducting transition occurred around 7.5-8.7 GPa with a maximum Tc (onset temperature) of 5.5 K. The high-pressure crystal and electronic band structures were derived by the first-principle calculations at 6-11 GPa. The crystal was found to retain the semiconducting band structure up to 6 GPa. But the electron and hole Fermi surfaces appear at 8 GPa. These results of the calculations agree well with the observation that the pressure-induced superconducting phase of [Ni(hfdt)2] appeared just above the critical pressure where the low-temperature insulating phase was suppressed. PMID- 24816033 TI - Domiciliary respiratory therapies SEPAR year 2014. A real health challenge. PMID- 24816032 TI - Tracking the pharmaceutical pipeline: clinical trials and global disease burden. AB - Aggregate data about pharmaceutical research and development (R&D) tend to examine Phase III trials. Hence, there are few published data about investigational drugs in earlier phases of clinical development that might fail. It is also unclear how well R&D corresponds to disease burden. We track the pharmaceutical pipeline using data from industry publications that provide otherwise unreported information about industry-sponsored clinical trials. The sample includes 2,477 unique drug entities in 4,182 clinical trials. The majority of drugs targeted neoplasms (26.20%), neurological diseases/diseases of the sense organs (13.48%), infectious and parasitic diseases (10.5%), and endocrine, metabolic, nutrition, and immunity disorders (9.45%). Less than 6% of drugs targeted diseases of the circulatory system, which represent the most prevalent causes of global mortality. Detailing the pharmaceutical pipeline, our findings suggest that pharmaceutical development does not adequately address global disease burden. Future research on the under-reported details of Phase I and II clinical trials is needed to understand how the industry operates and how its resource-allocation matches global health concerns. PMID- 24816034 TI - Chronic obstructive pulmonary disease and left ventricle. AB - Several studies have shown that the interaction between chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidity is complex and bidirectional, since each of these diseases complicates the prognosis of the other. Recent advances in imaging technology have led to better characterization of cardiac chambers and allowed the relationship between certain cardiac function parameters and COPD clinical and functional variables to be explored. Although cardiac abnormalities in COPD have been mainly associated with the right ventricle, several studies have reported that the left ventricle may also be affected in this disease. A better understanding of the mechanisms involved and their clinical implications will establish diagnostic and therapeutic strategies for patients with both these conditions. PMID- 24816035 TI - Inter-regional changes in the performance and interpretation of spirometry in Spain: 3E study. AB - OBJECTIVES: This report shows the results of a nation-wide survey on spirometry to assess regional differences. METHODS: Observational cross-sectional study conducted by means of a telephone survey in 805 primary care (PC) and specialized centers (SC) in all regions. The survey contacted technicians in charge of spirometry and consisted of 36 questions related to the test. RESULTS: The results showed major differences between regions. Most centers had 1-2 spirometers. The number of spirometry tests per week ranged from 2 to 8.9 in PC and between 34.3 and 98.3 in SC. Some training had been given in most centers (63.6-100% in PC and 60.0-100% in SC) but not on a regular basis. Most centers used several short-acting bronchodilators for the bronchodilation test, but with insufficient inhalations (2.0-3.8 in PC and 2.0-3.3 in SC) and frequently incorrect waiting time (29.4-83.3% PC and 33.3-87.5% in SC). Daily calibration was not performed in all centers (0-100% in PC and 66.7-100% in SC). Significant inter-regional differences in spirometry quality criteria were observed, with 6 or more criteria met in 9.1-84.6% of PC centers and 37.5-100% in SC. CONCLUSIONS: Our results show the current situation of spirometry in primary and specialized care in Spain, highlighting considerable variability and areas for improvement. This information should be considered by health officials to improve the quality and accessibility of such tests. PMID- 24816037 TI - The endothelial glycocalyx: scratching the surface for cardiovascular disease in kidney failure. PMID- 24816036 TI - COPD screening in primary care in four Latin American countries: methodology of the PUMA Study. AB - INTRODUCTION: The prevalence of COPD among patients treated in the healthcare system in Latin America is unknown. The PUMA study (Prevalencia y practica habitUal -diagnostico y tratamiento- en poblacion de riesgo de EPOC en Medicos generalistas de 4 paises de America Latina) screened at-risk patients attending primary care centers to evaluate the prevalence, diagnosis and treatment of COPD in this setting. The aim of this report is to describe the study methodology. METHODS: Multicenter, observational, cross-sectional study conducted in Argentina, Colombia, Uruguay and Venezuela. Subjects were>=40 years, smokers, former smokers and/or exposed to fossil fuels attending primary care centers. Eligible patients underwent pre- and post- bronchodilator spirometry and completed standardized questionnaires on demographics, smoking, exposure to environmental/domestic pollution, symptoms/history and management of respiratory diseases, comorbidities, and use of healthcare resources. RESULTS: A total of 57 centers in 4 countries participated; 1,907 patients were included, 1,743 completed the PUMA questionnaire and 1,540 patients underwent validated spirometry. CONCLUSIONS: We describe the methodology used in the PUMA study, the first systematic multicenter study in four Latin American countries aimed at detecting COPD cases confirmed by spirometry in primary care. Approximately 90% of patients who completed the PUMA questionnaire underwent valid spirometry tests. This gives room for reflection on the feasibility of opportunistic screening at the primary care level to detect patients in the early stages of COPD or with undiagnosed COPD, and improve the diagnosis and management of this disease. PMID- 24816038 TI - In search for genetic determinants of clinically meaningful differential cardiovascular event reduction by pravastatin in the PHArmacogenetic study of Statins in the Elderly at risk (PHASE)/PROSPER study. AB - BACKGROUND: Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response. METHODS AND RESULTS: We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease--PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n = 5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1 * 10(-4) were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n = 711) and WOSCOPS (n = 522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p = 0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing. CONCLUSIONS: We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited. PMID- 24816039 TI - Relationship between nitroglycerine-induced vasodilation and clinical severity of peripheral artery disease. AB - OBJECTIVE: Nitroglycerine-induced vasodilation is usually used as a control test for flow-mediated vasodilation (FMD). However, nitroglycerine-induced vasodilation per se has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationship between nitroglycerine-induced vasodilation and the clinical severity of peripheral artery disease (PAD). METHODS AND RESULTS: We measured nitroglycerine induced vasodilation and FMD in 144 subjects (mean age: 63.8 +/- 15.1 years), including 32 PAD patients with critical limb ischemia (CLI group), 28 PAD patients without CLI (non-CLI group), 60 age- and sex-matched patients without established cardiovascular disease (at-risk group), and 24 healthy subjects (healthy group). Nitroglycerine-induced vasodilation was significantly impaired in the CLI group compared to that in the other three groups (healthy group, 16.0 +/- 5.3%; at-risk group, 12.9 +/- 3.8%; non-CLI group, 10.3 +/- 5.1%; CLI group, 6.7 +/- 3.9%; P < 0.05, respectively). Even after multivariate adjustment, the differences remained significant. On the other hand, FMD was significantly impaired in the at-risk, non-CLI, and CLI group compared with that in the healthy group (healthy group, 7.1 +/- 2.9%; at-risk group, 3.4 +/- 2.3%; non-CLI group, 3.5 +/- 2.7%; CLI group, 3.0 +/- 2.8%; P < 0.001, respectively), but the differences among the at-risk, non-CLI, and CLI groups were not significant. Multivariate analysis revealed that nitroglycerine-induced vasodilation (odds ratio: 0.77, 95% confidence interval [CI]: 0.61-0.97) and diabetes mellitus (odds ratio: 8.75, 95% CI: 1.74-44.2) were independent variables for CLI in PAD patients. CONCLUSIONS: There was no significant difference in FMD between PAD patients with and those without CLI, but nitroglycerine-induced vasodilation was significantly smaller in PAD patients with CLI compared with those without CLI. PMID- 24816040 TI - Increased atherosclerosis in mice with increased vascular biglycan content. AB - OBJECTIVE: The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. METHODS: Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4-12 weeks. RESULTS: LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. CONCLUSION: Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. PMID- 24816041 TI - Shared and additional risk factors for decrease of toe-brachial index compared to ankle-brachial index in Japanese patients with diabetes mellitus. AB - OBJECTIVE: Some diabetic patients have a low toe-brachial index (TBI) despite their normal ankle-brachial index (ABI). We statistically investigated whether the impact of risk factors on TBI would be different compared to ABI. RESEARCH DESIGN AND METHODS: We used a database of 1738 limbs of consecutive 869 Japanese diabetic patients whose ABI and TBI were simultaneously evaluated. We developed a common regression model to ABI and TBI by extending the linear mixed model, and statistically detected the difference in the impact of risk factors between the two indices. RESULTS: Sex, smoking, proteinuria, hypertension, and history of stroke and coronary artery disease were common independent risk factors for the decrease of ABI and TBI; their impacts on ABI and TBI were not significantly different. On the other hand, the impact of age, diabetic duration, and body mass index was significantly different between the two indices (all p < 0.05). Age and body mass index were significantly associated with TBI but not with ABI. Diabetic duration had a significant impact both on TBI and ABI, but the impact on TBI was significantly greater than that on ABI (beta = -0.144 vs. -0.087; p < 0.05). In the population with normal ABI, patients with these risk factors had a higher prevalence of decreased TBI. CONCLUSIONS: The risk factors for the decrease of ABI and TBI were not identical in Japanese diabetic patients. Age, diabetic duration and body mass index were associated with reduced TBI in patients with normal ABI. PMID- 24816042 TI - Treatment compliance in chronic illness: Current situation and future perspectives. AB - Long-term chronic diseases have a high mortality rate around the world, affecting both genders equally. Despite improvements in the diagnosis and treatment of various health problems, lack of treatment compliance remains an obstacle to improving health and patient quality of life, and it carries a high associated socio-healthcare cost. The objectives of this study were to develop the concept of "therapeutic adherence", which includes both pharmacological compliance as well as non-pharmacological (level of agreement and patient involvement, lifestyle changes, etc.) treatments. The study also aimed to establish the clinical and socio-health impact of non-compliance, the reasons for non compliance, and methods and strategies to improve compliance. The results of this study support therapeutic adherence as an essential goal of the healthcare system that encompasses all stakeholders involved in patient health. PMID- 24816044 TI - The link between middle school mathematics course placement and achievement. AB - The proportion of eighth graders in United States public schools enrolled in algebra or a more advanced mathematics course doubled between 1990 and 2011. This article uses Early Childhood Longitudinal Study's Kindergarten Cohort data to consider the selection process into advanced middle school mathematics courses and estimate the effects of advanced courses on students' mathematics achievement (n = 6,425; mean age at eighth grade = 13.7). Eighth-grade algebra and geometry course placements are academically selective, but considerable between-school variation exists in students' odds of taking these advanced courses. While analyses indicate that advanced middle school mathematics courses boost student achievement, these effects are most pronounced in content areas closely related to class content and may be contingent on student academic readiness. PMID- 24816043 TI - Absence of PO2 change in fetal brain despite PO2 increase in placenta in response to maternal oxygen challenge. AB - OBJECTIVE: Magnetic resonance imaging allows the noninvasive observation of PO2 changes between air breathing and oxygen breathing through quantification of the magnetic longitudinal relaxation time T1. Changes in PO2 are proportional to changes in the longitudinal relaxation rate DeltaR1 (where DeltaR1=1/T1oxygen 1/T1air). Knowledge of this response could inform clinical interventions using maternal oxygen administration antenatally to treat fetal growth restriction. We present in vivo measurements of the response of the fetal-placental unit to maternal hyperoxia. DESIGN: Prospective cohort. SETTING: Large tertiary maternity hospital. SAMPLE: Nine women undergoing low-risk pregnancy (21-33 weeks of gestation) and five nonpregnant adults. METHODS: During imaging the air supply to mothers was changed from medical air (21% oxygen) to medical oxygen (100% oxygen) and T1 was monitored over time in both the placenta and fetal brain using a periodically repeated magnetic resonance imaging sequence. To demonstrate that the method could detect a brain response, brain responses from five normal adult volunteers were measured using a similar imaging protocol. MAIN OUTCOME MEASURE: Changes in T1 following oxygen challenge. RESULTS: No significant DeltaR1 (P=0.42, paired t-test) was observed in fetal brains. A significant placental DeltaR1 (P=0.0002, paired t-test) of 0.02+/-0.01/s (mean+/-SD) was simultaneously observed in the same participants. In the brains of the nonpregnant adults, a significant DeltaR1 (P=0.01, paired t-test) of 0.005+/-0.002/s was observed. CONCLUSION: Short-term maternal oxygen administration does not improve fetal brain oxygenation, in contrast to the response observed in the adult brain. PMID- 24816045 TI - Chronic pulmonary penicilliosis due to Penicillium marneffei: late presentation in a french traveler. AB - We report a case of pulmonary penicilliosis due to Penicillium marneffei in an immunocompetent French patient with chronic obstructive pulmonary disease, who had traveled in endemic countries several years before. The long interval between exposure and initial symptoms of infection, and relapse despite prolonged voriconazole treatment are unusual features. PMID- 24816047 TI - Antipsychotics, mood stabilisers, and reductions in violence. PMID- 24816046 TI - Antipsychotics, mood stabilisers, and risk of violent crime. AB - BACKGROUND: Antipsychotics and mood stabilisers are prescribed widely to patients with psychiatric disorders worldwide. Despite clear evidence for their efficacy in relapse prevention and symptom relief, their effect on some adverse outcomes, including the perpetration of violent crime, is unclear. We aimed to establish the effect of antipsychotics and mood stabilisers on the rate of violent crime committed by patients with psychiatric disorders in Sweden. METHODS: We used linked Swedish national registers to study 82,647 patients who were prescribed antipsychotics or mood stabilisers, their psychiatric diagnoses, and subsequent criminal convictions in 2006-09. We did within-individual analyses to compare the rate of violent criminality during the time that patients were prescribed these medications versus the rate for the same patients while they were not receiving the drugs to adjust for all confounders that remained constant within each participant during follow-up. The primary outcome was the occurrence of violent crime, according to Sweden's national crime register. FINDINGS: In 2006-09, 40,937 men in Sweden were prescribed antipsychotics or mood stabilisers, of whom 2657 (6.5%) were convicted of a violent crime during the study period. In the same period, 41,710 women were prescribed these drugs, of whom 604 (1.4 %) had convictions for violent crime. Compared with periods when participants were not on medication, violent crime fell by 45% in patients receiving antipsychotics (hazard ratio [HR] 0.55, 95% CI 0.47-0.64) and by 24% in patients prescribed mood stabilisers (0.76, 0.62-0.93). However, we identified potentially important differences by diagnosis-mood stabilisers were associated with a reduced rate of violent crime only in patients with bipolar disorder. The rate of violence reduction for antipsychotics remained between 22% and 29% in sensitivity analyses that used different outcomes (any crime, drug-related crime, less severe crime, and violent arrest), and was stronger in patients who were prescribed higher drug doses than in those prescribed low doses. Notable reductions in violent crime were also recorded for depot medication (HR adjusted for concomitant oral medications 0.60, 95% CI 0.39-0.92). INTERPRETATION: In addition to relapse prevention and psychiatric symptom relief, the benefits of antipsychotics and mood stabilisers might also include reductions in the rates of violent crime. The potential effects of these drugs on violence and crime should be taken into account when treatment options for patients with psychiatric disorders are being considered. FUNDING: The Wellcome Trust, the Swedish Prison and Probation Service, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare. PMID- 24816048 TI - Green chiral HPLC study of the stability of Chiralcel OD under high temperature liquid chromatography and subcritical water conditions. AB - We report here the study of the stability under subcritical water conditions of one of the most popular polysaccharide chiral stationary phase (CSP): Chiralcel OD. This CSP was used under high temperature and reversed phase conditions with acetonitrile and 2-propanol as modifier, respectively. The evolution of selectivity and resolution was investigated both in normal and reversed mode conditions with five racemates after packing, heating at 150 degrees C and separations of some racemic compounds under different high temperatures and mobile phase conditions. The results show that after using at high temperature and subcritical water conditions the selectivity was only moderately affected while the resolution fell dramatically especially in reversed mode due to the creation of a void at the head of the columns which reflects the dissolution of the silica matrix. PMID- 24816050 TI - Introduction. PMID- 24816051 TI - Latina lesbian writers and performers. AB - ABSTRACT This article introduces the most significant contemporary Latina lesbian writers and performers in the United States, Latin America, and Spain, giving us a panoramic view of the Latina lesbian canon of the late twentieth and early twenty-first centuries. PMID- 24816049 TI - Psychometric properties of the questionnaire about the process of recovery (QPR). AB - The latent structure, reliability and validity of the Questionnaire about the Process of Recovery (QPR) (Neil et al., 2009) were examined in a sample of participants with experience of psychosis (N=335). The original two factor model proposed by Neil et al. (2009) was examined using exploratory factor analysis followed by a further independent exploratory factor analysis to test revised solutions. Model fit statistics indicated that the most interpretable solution was a one factor model using 15 items from the original measure. Internal consistency, test re-test reliability and convergent validity of this new 15 item version were found to be high. Recommendations for the utility of the QPR in routine clinical practice along with suggestions for future research are discussed. PMID- 24816052 TI - Tortilleras on the prairie. AB - ABSTRACT This article argues that there is a considerable, distinctive Latina lesbian cultural presence in the Midwest that cannot be sufficiently accounted for using prevalent East or West Coast models of Latina lesbian artistic representation. By examining the literary productions of Latina lesbians in and/or from the Great Plains, we can arrive at a new concept of the border and of what it means to be a Chicana or Latina lesbian. PMID- 24816053 TI - The role of carmelita tropicana in the performance art of alina troyano. AB - ABSTRACT This article maps out the development and cultural meanings in the performance art of Alina Troyano, better known by her stage name, Carmelita Tropicana. Through such strategies as code switching, the avoidance of commodification, the development of alter egos, the breaking of heterosexist norms, and the creation of an intercultural discourse, Troyano has created a hybrid identity as an artist and performer. PMID- 24816054 TI - Moving La Frontera Towards a Genuine Radical Democracy in Gloria Anzaldua's Work. AB - ABSTRACT This article situates Gloria Anzaldua's work Borderlands/La Fronterain the context of staid, heterosexist academia and conventional readings of the Latin American mestizaje to show how the book has subverted both. By examining how Borderlandshas been received and how it ironically anticipates these hierarchical readings, we can see the functioning of the elitist, exclusionary processes that manufacture subaltern identities within societies and within academia. PMID- 24816055 TI - Como sabes, depresion. PMID- 24816056 TI - To sor juana. PMID- 24816057 TI - Lesbianism and Caricature in Griselda Gambaro's Lo impenetrable. AB - ABSTRACT This article explores the work of novelist Griselda Gambaro as a lesbian discourse that counters the prevailing patriarchal discourse of the Latin American dictatorships. Gambaro's work is placed in the context of other Latin American "lesbian" texts that also challenge the political status quo by providing deviant models of female sexuality. PMID- 24816058 TI - The (In)visible Lesbian. AB - ABSTRACT This article positions lesbian literature within post-Franco Spanish literature, demonstrating how works by Spanish lesbian authors and/or with lesbian themes have been marginalized publicly and academically, even after the liberalizations that have dramatically transformed Spanish society since the death of Franco. The article calls for a more thoughtful reading of lesbian literature in particular, and women's literature in general, providing a model with its encapsulated readings of works by Marosa Gomez Pereira, Ana Maria Moix, and Lucia Etxebarria. PMID- 24816059 TI - Black South african lesbians. AB - ABSTRACT In South Africa there is virtually no research that documents the lives of Black lesbians. The research reported here is part of a larger study which, to date, is the first and only in-depth study that focuses on the lives of Black South African lesbians. The study was located within a feminist social constructionist paradigm. The aim of the research was to explore the positions from which Black lesbians speak, as well as to explore how their discourse(s) replicate, challenge and contradict the dominant societal discourses on what it means to be Black and lesbian within South African society. The data was collected by means of nine (9) individual interviews and ten (10) focus groups. The total number of women in the study was sixty-three. The data was analysed using discourse analysis. A range of discourses emerged which illustrates how they both replicate and challenge traditional roles and discourses. The discourses explored in this article relate to their views on motherhood and women's roles. Although certain of their "choices" may be interpreted as not falling within a feminist paradigm in terms of western feminism(s), this could be viewed as feminist and strategic given the current reality in which they live. PMID- 24816061 TI - A dangerous exercise lessons from food-dependent anaphylaxis for the physician. AB - Exercise-induced anaphylaxis (EIA) and its subtype, food dependent exercise induced anaphylaxis are uncommon and therefore underdiagnosed forms of physical allergy. Triggers include various degrees of exercise in combination with ingestion of specific food products. Treatment remains identical to that of IgE mediated allergic reactions. The presentation is commonly underdiagnosed and caries significant fatality risk, and this case should raise the awareness of the attending physician. PMID- 24816062 TI - Obesity and seatbelt use: a fatal relationship. AB - BACKGROUND: Seatbelts significantly reduce the risk of death in motor vehicle accidents, but a certain number of individuals from some subgroups tend not to wear their seatbelts. OBJECTIVES: In this study, we hypothesized that obese drivers (in fatal crashes) were less likely to wear seatbelts than their normal weight counterparts. METHODS: A retrospective study was conducted on the drivers in motor vehicle crashes entered into the Fatality Analysis Reporting System database between 2003 and 2009. A number of precrash variables were found to be significantly associated with seatbelt use. These were entered into a multivariate logistic regression model using stepwise selection. Drivers were grouped into weight categories based on the World Health Organization definitions of obesity by body mass index. Seatbelt use was then examined by body mass index, adjusted for precrash variables that were significantly associated with seatbelt use. RESULTS: The odds of seatbelt use for normal-weight individuals were found to be 67% higher than the odds of seatbelt use in the morbidly obese. The relationship of seatbelt use between the different weight groups and the morbidly obese is as follows (odds ratios [ORs] for each comparison are listed with 95% confidence limits [CL]): underweight vs morbidly obese (OR, 1.62; CL, 1.47-1.79), normal weight vs morbidly obese (OR, 1.67; CL, 1.54-1.81), overweight vs morbidly obese (OR, 1.60; CL, 1.48-1.74), slightly obese vs morbidly obese (OR, 1.40; CL, 1.29-1.52), and moderately obese vs morbidly obese (OR, 1.24; CL, 1.13-1.36). CONCLUSION: Seatbelt use is significantly less likely in obese individuals compared with their normal-weight counterparts. PMID- 24816063 TI - [Lacrimal sac tumors presenting as lacrimal obstruction. Retrospective study in Mexican patients 2007-2012]. AB - OBJECTIVE: To determine the demographic and clinical data of primary tumors of the lacrimal sac presenting as lacrimal obstruction. METHODS: Retrospective and descriptive study was conducted between the years 2007 to 2012 on all patients undergoing surgery for low lacrimal obstruction at Dr. Luis Sanchez Bulnes Hospital, an Association for the prevention of blindness in Mexico IAP. RESULTS: Primary tumors of the lacrimal sac represented 2.5% of all lacrimal obstructions, being more common in women than in men (8:1). The large majority (89%) of the cases were non-epithelial, with lymphoid lesions being the most frequent. Benign tumors were presented at a younger age (50 years old) than malignant (70 years old). One-third (33%) of cases were unexpected findings during surgery (100% benign). Just over half (55%) were malignant tumors (1.4% of obstructions), all of them lymphoproliferative lesions. The most frequent clinical tumor was in the inner edge, either with or without epiphora. The progression time varied according to the degree of aggressiveness of the lymphoma (3 months-10 years). CONCLUSIONS: Lacrimal sac tumors are rare, but they must be taken into account in patients with an unusual clinical presentation of lacrimal obstruction. PMID- 24816064 TI - In vitro modeling of the prostate cancer microenvironment. AB - Prostate cancer is the most commonly diagnosed malignancy in men and advanced disease is incurable. Model systems are a fundamental tool for research and many in vitro models of prostate cancer use cancer cell lines in monoculture. Although these have yielded significant insight they are inherently limited by virtue of their two-dimensional (2D) growth and inability to include the influence of tumour microenvironment. These major limitations can be overcome with the development of newer systems that more faithfully recreate and mimic the complex in vivo multi-cellular, three-dimensional (3D) microenvironment. This article presents the current state of in vitro models for prostate cancer, with particular emphasis on 3D systems and the challenges that remain before their potential to advance our understanding of prostate disease and aid in the development and testing of new therapeutic agents can be realised. PMID- 24816065 TI - Speckle strain echocardiography predicts outcome in patients with heart failure with both depressed and preserved left ventricular ejection fraction. AB - BACKGROUND: While speckle imaging has been shown to predict outcome in patients with heart failure (HF), it remains unclear whether speckle strain predicts outcome in patients with HF with preserved ejection fraction (HFPEF). METHODS: Four hundred twenty patients with HF by Framingham criteria and either: left ventricular (LV) EF <50%, or elevated LV filling pressure by comprehensive echo Doppler study in the setting of left ventricular ejection fraction (LVEF) >=50%, were enrolled. Speckle tracking was used to measure strain and strain rate in multiple vectors. The primary endpoint was HF hospitalization or cardiovascular death. RESULTS: Follow-up was completed in 380/420 patients (90%). The mean age was 55.7 +/- 0.8 years, 191/380 (50%) were male, 319/380 (84%) were hypertensive, 183/380 (48%) were diabetic, and 152/380 (40%) had known coronary artery disease. At a mean follow-up of 369 +/- 30 days, 107/380 patients (28%) reached the primary endpoint: 97 HF rehospitalizations and 10 cardiac deaths. The best univariate predictors of outcome were global longitudinal peak strain (GLPS) (chi(2) = 25.6, P < 0.001), mitral DT (chi(2) = 16.8, P < 0.001), LVEF (chi(2) = 16.7, P < 0.0001), longitudinal early diastolic strain (chi(2) = 8.7, P = 0.003), and circumferential peak strain (chi(2) = 7.9, P = 0.005). On multivariate analysis, GLPS (P < 0.0001), LVEF (P = 0.0002), and mitral DT (P = 0.005) were independent predictors of outcome. In the 100 HF patients with preserved LVEF, there were 17 events. Patients with GPLS <=-15 had significantly better event free survival than patients with GPLS >-15 (chi(2) = 4.1, P = 0.04), whereas LVEF did not predict event-free survival. CONCLUSION: Speckle strain echocardiography is an important predictor of outcome in HF patients with both depressed and preserved LVEF. PMID- 24816067 TI - Large non-functioning parathyroid cysts: our institutional experience of a rare entity and a possible pitfall in thyroid cytology. AB - OBJECTIVE: Large non-functioning parathyroid cysts represent a rare entity with a benign clinical course. They may be misdiagnosed as thyroid cystic neoplasms on fine needle aspiration cytology (FNAC), resulting in inappropriate surgical treatment. We evaluated our institutional experience in the diagnosis of large parathyroid cystic lesions underlining all the differential diagnoses and pitfalls. METHODS: In the period between 1998 and 2012, we reported the cytology of eight large (>2.5 cm) parathyroid cystic lesions (all female patients) with histological control. The aspirations were performed with a 25-gauge needle with ultrasonographic guidance. The aspirated material was processed with liquid-based cytology (LBC). All the patients had normal serum parathyroid hormone (PTH) and calcium. RESULTS: The cytological samples showed a fluid watery component without colloid and few or absent epithelial cells. The resulting negativity for thyroglobulin and positivity for PTH, carried out on the cystic fluids, suggested parathyroid lesions rather than either thyroid cystic lesions (including follicular thyroid neoplasm) or cystic malignant lesions. All the patients underwent surgery without complications. CONCLUSIONS: To the best of our knowledge, this is one of the largest series with cytohistological evaluation of large parathyroid cysts. The incidence of large parathyroid cysts remains controversial as most patients are asymptomatic. FNAC may be performed with conclusive results in the majority of cystic cases. The detection of PTH and calcium on the cystic liquid is likely to achieve a correct cytological diagnosis, allowing adequate treatment and ruling out a more frequent thyroid lesion. PMID- 24816066 TI - Synthesis, biological evaluation and molecular docking studies of trans-indole-3 acrylamide derivatives, a new class of tubulin polymerization inhibitors. AB - In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a-k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1 MUM, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC50=17 MUM). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL 60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin. PMID- 24816068 TI - Diagnostic utility of immunohistochemistry in distinguishing between epithelioid pleural mesotheliomas and breast carcinomas: a comparative study. AB - Epithelioid mesotheliomas and breast carcinomas can present a variety of morphologic patterns. Because of this, breast carcinomas that metastasize to the pleura and lung may be confused with mesotheliomas. The aim of the present study is to compare the immunohistochemical markers currently available for the diagnosis of these 2 malignancies and to determine the best panel of markers that can be used to assist in discriminating between them. Sixty epithelioid mesotheliomas and 80 breast carcinomas (40 triple negative and 40 estrogen receptor positive) were investigated for expression of the positive mesothelioma markers calretinin, keratin 5/6, mesothelin, podoplanin, thrombomodulin, and WT1; the positive carcinoma marker claudin 4; and the breast-associated markers gross cystic disease fluid protein 15 (GCDFP-15), mammaglobin, and GATA3. All of the epithelioid mesotheliomas reacted for calretinin and keratin 5/6, 93% for WT1; 88% for podoplanin; 77% for thrombomodulin; 23% for GATA3; and 0% for claudin 4, GCDFP-15, and mammaglobin, respectively. Of the triple-negative breast carcinomas, 100% expressed claudin 4; 5%, keratin 5/6; 30%, GATA3; 18%, mammaglobin; 15%, GCDFP-15; 56%, mesothelin; 38%, calretinin; 18%, thrombomodulin; 5%, WT1; and 3%, podoplanin. Among the estrogen receptor-positive breast carcinomas, 100% were claudin 4 and GATA3 positive; 70% expressed GCDFP 15; 63%, mammaglobin; 13%, calretinin; 13%, thrombomodulin; 8%, WT1; 5%, keratin 5/6; 3%, mesothelin; and 0%, podoplanin. It is concluded that podoplanin and WT1 are the best positive mesothelioma markers for differentiating epithelioid mesotheliomas from breast carcinomas. An accurate differential diagnosis can be reached with the use of these two markers in combination with the breast associated markers GCDFP-15, mammaglobin, and GATA3. PMID- 24816070 TI - Particle designs for the stabilization and controlled-delivery of protein drugs by biopolymers: a case study on insulin. AB - Natural biopolymers have attracted considerable interest for the development of delivery systems for protein drugs owing to their biocompatibility, non-toxicity, renewability and mild processing conditions. This paper offers an overview of the current status and future perspectives of particle designs using biopolymers for the stabilization and controlled-delivery of a model protein drug--insulin. We first describe the design criteria for polymeric encapsulation and subsequently classify the basic principles of particle fabrication as well as the existing particle designs for oral insulin encapsulation. The performances of these existing particle designs in terms of insulin stability and in vitro release behavior in acidic and alkaline media, as well as their in vivo performance are compared and reviewed. This review forms the basis for future works on the optimization of particle design and material formulation for the development of an improved oral delivery system for protein drugs. PMID- 24816071 TI - Development of RNAi technology for targeted therapy--a track of siRNA based agents to RNAi therapeutics. AB - RNA interference (RNAi) was intensively studied in the past decades due to its potential in therapy of diseases. The target specificity and universal treatment spectrum endowed siRNA advantages over traditional small molecules and protein drugs. However, barriers exist in the blood circulation system and the diseased tissues blocked the actualization of RNAi effect, which raised function versatility requirements to siRNA therapeutic agents. Appropriate functionalization of siRNAs is necessary to break through these barriers and target diseased tissues in local or systemic targeted application. In this review, we summarized that barriers exist in the delivery process and popular functionalized technologies for siRNA such as chemical modification and physical encapsulation. Preclinical targeted siRNA delivery and the current status of siRNA based RNAi therapeutic agents in clinical trial were reviewed and finally the future of siRNA delivery was proposed. The valuable experience from the siRNA agent delivery study and the RNAi therapeutic agents in clinical trial paved ways for practical RNAi therapeutics to emerge early. PMID- 24816072 TI - The central place of psychiatry in health care worldwide. PMID- 24816069 TI - Designer lipids for drug delivery: from heads to tails. AB - For four decades, liposomes composed of both naturally occurring and synthetic lipids have been investigated as delivery vehicles for low molecular weight and macromolecular drugs. These studies paved the way for the clinical and commercial success of a number of liposomal drugs, each of which required a tailored formulation; one liposome size does not fit all drugs! Instead, the physicochemical properties of the liposome must be matched to the pharmacology of the drug. An extensive biophysical literature demonstrates that varying lipid composition can influence the size, membrane stability, in vivo interactions, and drug release properties of a liposome. In this review we focus on recently described synthetic lipid headgroups, linkers and hydrophobic domains that can provide control over the intermolecular forces, phase preference, and macroscopic behavior of liposomes. These synthetic lipids further our understanding of lipid biophysics, promote targeted drug delivery and improve liposome stability. We further highlight the immune reactivity of novel synthetic headgroups as a key design consideration. For instance it was originally thought that synthetic PEGylated lipids were immunologically inert; however, it's been observed that under certain conditions PEGylated lipids induce humoral immunity. Such immune activation may be a limitation to the use of other engineered lipid headgroups for drug delivery. In addition to the potential immunogenicity of engineered lipids, future investigations on liposome drugs in vivo should pay particular attention to the location and dynamics of payload release. PMID- 24816073 TI - Biography. Professor Helen Herrman. PMID- 24816074 TI - Layered compounds BaM2Ge4Ch6 (M = Rh, Ir and Ch = S, Se) with pyrite-type building blocks and Ge-Ch heteromolecule-like anions. AB - The structures and chemical features of layered compounds BaM2Ge4Ch6 (M = Rh, Ir; Ch = S, Se) synthesized by high-pressure and high-temperature methods have been systematically studied. These compounds crystallize in an orthorhombic phase with space group Pbca (No. 61). These compounds have the remarkable structural feature of M-Ge-Ch pyrite-type building units, stacking with Ba-Ch layers alternatively along the c axis. It is very rare and novel that pyrite-type subunits are the building blocks in layered compounds. Theoretical calculations and experimental results indicate that there are strongly polarized covalent bonds between Ge and Ch atoms, forming heteromolecule-like anions in these compounds. Moreover, Ge atoms in this structure exhibit an unusual valence state (~+1) due to the tetrahedral coordination environment of Ge atoms along with M and Ch atoms simultaneously. PMID- 24816075 TI - Gender differences, clinical correlates, and longitudinal outcome of bipolar disorder with comorbid migraine. AB - OBJECTIVE: Migraine is a common comorbidity of bipolar disorder and is more prevalent in women than men. We hypothesized comorbid migraine would be associated with features of illness and psychosocial risk factors that would differ by gender and impact outcome. METHOD: A retrospective analysis was conducted to assess association between self-reported, physician-diagnosed migraine, clinical variables of interest, and mood outcome in subjects with DSM IV bipolar disorder (N = 412) and healthy controls (N = 157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005-2010. Informed consent was obtained from all participants. RESULTS: Migraine was more common in subjects with bipolar disorder (31%) than in healthy controls (6%) and had elevated risk in bipolar disorder women compared to men (OR = 3.5; 95% CI, 2.1-5.8). In men, migraine was associated with bipolar II disorder (OR = 9.9; 95% CI, 2.3-41.9) and mixed symptoms (OR = 3.5; 95% CI, 1.0-11.9). In comparison to absence of migraine, presence of migraine was associated with an earlier age at onset of bipolar disorder by 2 years, more severe depression (beta = .13, P = .03), and more frequent depression longitudinally (beta = .13, P = .03). Migraine was correlated with childhood emotional abuse (P = .01), sexual abuse (P = 4 * 10-3), emotional neglect (P = .01), and high neuroticism (P = 2 * 10-3). Protective factors included high extraversion (P = .02) and high family adaptability at the trend level (P = .08). CONCLUSIONS: Migraine is a common comorbidity with bipolar disorder and may impact long-term outcome of bipolar disorder, particularly depression. Clinicians should be alert for migraine comorbidity in women and in men with bipolar II disorder. Effective treatment of migraine may impact mood outcome in bipolar disorder as well as headache outcome. Joint pathophysiologic mechanisms between migraine and bipolar disorder may be important pathways for future study of treatments for both disorders. PMID- 24816076 TI - Benefits of adding fluticasone propionate/salmeterol to tiotropium in COPD: a meta-analysis. AB - OBJECTIVE: This meta-analysis was performed to evaluate the efficacy and safety of adding fluticasone propionate/salmeterol (FSC) to tiotropium (Tio) in COPD patients. METHODS: A systematic search was made of MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases, and a hand search of leading respiratory journals. Randomized clinical trials on treatment of stable COPD with the addition of FSC, compared with tiotropium alone, were reviewed. Studies were pooled to odds ratio (OR) and weighted mean differences (WMD), with 95% confidence interval (CI). RESULTS: Six trials met the inclusion criteria. Compared with tiotropium, addition of FSC presented significant effects on trough forced expiratory volume in 1s (FEV1) (WMD 54.64 mL; 95% CI 51.76 to 57.52 mL; P<0.001), COPD exacerbations (OR 0.73; 95% CI 0.55 to 0.96; p=0.03), and health-related quality of life (WMD 4.63; 95% CI 4.26 to 5.01; P<0.001). No significant increase was noticed in adverse events in the Tio+FSC group (OR 1.24; 95% CI 0.98 to 1.57; p=0.07). CONCLUSIONS: The addition of FSC to subjects with COPD treated with tiotropium significantly improves lung function, quality of life and COPD exacerbations without increasing the risk of adverse events. PMID- 24816078 TI - Our bodies are our own: resistance to ABC-based HIV-prevention programmes in northern Tanzanian conservation organisations. AB - ABC-based HIV-prevention programmes have been widely employed in northern Tanzanian wildlife conservation settings in an attempt to (re)shape the sexual behaviours of conservation actors. Utilising findings from 66 semi-structured interviews conducted in 2009-2010, this paper examines ABC prevention as a form of Foucauldian governmentality--circulating technologies of power that mobilise disciplinary technologies and attempt to transform such efforts into technologies of the self--and explores how individuals understand and respond to attempts to govern their behaviour. ABC regimes attempt to rework subjectivity, positioning HIV-related behaviours within a risk-based neoliberal rationality. However, efforts to use ABC as a technology to govern populations and individual bodies are largely incommensurate with existing Tanzanian sociocultural formations, including economic and gendered inequalities, and local understandings of sexuality. The language research participants used to talk about ABC and the justifications they offered for non-compliance illuminate this discrepancy. Data reveal that the recipients of ABC campaigns are active producers of understandings that work for them in their lives, but may not produce the behavioural shifts envisioned by programme goals. These findings corroborate previous research, which questions the continued plausibility of ABC as a stand alone HIV- prevention framework. PMID- 24816077 TI - Influence of inadequate antimicrobial therapy on prognosis in elderly patients with severe urinary tract infections. AB - BACKGROUND: Inadequate empirical antimicrobial therapy (IEAT) in intensive care unit (ICU) is associated with adverse outcomes. However, the influence of IEAT on prognosis for elderly patients with urinary tract infection (UTI) in non-ICU settings is unknown. METHODS: A retrospective cross-sectional study of elderly patients admitted to a non-ICU ward in a university hospital with a primary diagnosis of UTI over a 3-year period was done. Data relating to age, sex, background comorbidities, severity of infection, bacteremia, microorganisms isolated in urine, treatment given, length of stay and prognosis were obtained using chart review. Cases were segregated according to the adequacy of empirical antimicrobial therapy. In-hospital mortality rate was the main outcome variable evaluated. RESULTS: A total of 270 patients with a mean age of 83.7years were studied. Sixty-eight percent were health-care associated infections. Seventy-nine (29.3%) cases received IEAT. IEAT was associated with previous hospitalization, urinary catheter and previous antibiotic. A Gram stain of urine with a gram positive cocci was predictive of IEAT by multivariate analysis (OR, 6.29; 95% CI, 1.05-37.49). In-hospital mortality rate was 8.9%. IEAT (OR, 3.47; 95% CI, 1.42 8.48) was an independent risk factor for mortality along with APACHE II >=15 (OR, 3.14; 95% CI, 1.24-7.90), dementia (OR, 3.10; 95% CI, 1.19-8.07) and neoplasia (OR, 3.49; 95% CI, 1.13-10.77). IEAT was not associated with length of stay in hospital. CONCLUSION: IEAT is associated with mortality in elderly patients with UTI admitted to a non-ICU ward, suggesting that improving empirical antimicrobial therapy could have a favorable impact on prognosis. PMID- 24816079 TI - Effects and mechanisms of acetyl-L-cysteine in rats with chronic mountain sickness with H1-NMR metabolomics methods. AB - BACKGROUND: We established a rat model of chronic mountain sickness using acetyl L-cysteine. Then we studied the effects and mechanisms of acetyl-L-cysteine (Da) in rats with chronic mountain sickness using nuclear magnetic resonance (H1-NMR) metabolomics methods. MATERIAL AND METHODS: Using NMR spectroscopy combined with pattern recognition and orthogonal partial least squares discriminant analysis, we analyzed the impact of Da on blood metabolism in rats with chronic mountain sickness by determining different metabolites and changes in metabolic network in the blood of rats with mountain sickness after the intragastric administration of different doses of Da suspension. RESULTS: Increased levels of amino acids (valine, tyrosine, 1-methyl-histidine, leucine, phenylalanine, and methionine) were detected in the blood of rats in the chronic mountain sickness group, yet significantly decreased levels were detected in control rats. At the same time, beta-glucose and alpha-glucose levels were markedly elevated in the blood of rats in the model group but decreased in the chronic mountain sickness group, which indicated a statistically significant difference compared with the chronic altitude sickness model group (P<0.05). CONCLUSIONS: Da has a significant impact on the metabolism of rats with chronic mountain sickness. Da may act on the disturbed glucose metabolism and amino acid metabolism in rats triggered by chronic mountain sickness, resulting in the treatment and prevention of this disease. PMID- 24816081 TI - Effect of driving experience on anticipatory look-ahead fixations in real curve driving. AB - Anticipatory skills are a potential factor for novice drivers' curve accidents. Behavioural data show that steering and speed regulation are affected by forward planning of the trajectory. When approaching a curve, the relevant visual information for online steering control and for planning is located at different eccentricities, creating a need to disengage the gaze from the guidance of steering to anticipatory look-ahead fixations over curves. With experience, peripheral vision can be increasingly used in the visual guidance of steering. This could leave experienced drivers more gaze time to invest on look-ahead fixations over curves, facilitating the trajectory planning. Eighteen drivers (nine novices, nine experienced) drove an instrumented vehicle on a rural road four times in both directions. Their eye movements were analyzed in six curves. The trajectory of the car was modelled and divided to approach, entry and exit phases. Experienced drivers spent less time on the road-ahead and more time on the look-ahead fixations over the curves. Look-ahead fixations were also more common in the approach than in the entry phase of the curve. The results suggest that with experience drivers allocate greater part of their visual attention to trajectory planning. PMID- 24816080 TI - Pre-pubertal gonadectomy and the social consequences of acute ethanol in adolescent male and female rats. AB - It has previously been shown that pre-pubertal or adult gonadectomy (GX) increases ethanol intake in male rats. This study examined whether this sex selective increase reflects a GX-induced maintenance in males of more adolescent typical responsiveness to ethanol characterized by enhanced sensitivity to positive (e.g., socially facilitating) and a decreased sensitivity to adverse (e.g., socially inhibitory) effects of ethanol. Male and female Sprague-Dawley rats were pre-pubertally GX, sham (SH)-operated, or non-manipulated (NM) at postnatal day (P) 25. During the late adolescent transition into adulthood (P48 - baseline day), rats were given a saline injection, placed alone into a familiar test apparatus for 30min and then exposed for 10min to an unfamiliar partner of the same age and sex. On the following day (P49), similar testing occurred after administration of 0.5, 0.75, 1.0 or 1.25g/kg ethanol. At baseline, GX males and females displayed higher levels of social activity (especially adolescent-typical play and contact behavior) than SH and NM animals, with GX females displaying greater social activity than GX males. Neither males nor females demonstrated social facilitation at lower ethanol doses, regardless of hormonal status. Whereas the social inhibitory effects of higher doses of ethanol were similar across groups among females, SH males were less sensitive than both GX and NM males to ethanol-induced social inhibition. These results suggest that enhanced ethanol intake in GX males is not related to alterations in sensitivity to ethanol's social inhibitory effects. GX, however, results in retention of adolescent-typical social behaviors, with older GX adolescent rats resembling early adolescents in exhibiting elevated social activity-particularly play and contact behavior. PMID- 24816082 TI - Peripheral blood mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio as a marker of mitochondrial toxicities of stavudine containing antiretroviral therapy in HIV infected Malawian patients. AB - Mitochondrial toxicity is a major concern related to nucleoside reverse transcriptase inhibitors. Common manifestations are peripheral neuropathy and lipodystrophy. Depletion of mitochondria has been associated with mitochondrial dysfunction. We investigated whether mitochondria DNA (mtDNA) levels in peripheral blood can be used as biomarker of stavudine-associated mitochondrial toxicities. We enrolled 203 HIV-infected Malawian adult patients on stavudine containing ART and 64 healthy controls of Bantu origin in a cross-sectional study. Total DNA was extracted from whole blood.The glyceraldehyde-3-phosphate dehydrogenase gene was used to estimate nuclear DNA (nDNA) levels and the ATP synthase-8 mitochondrial DNA gene to estimate mtDNA levels, from which mtDNA/nDNA ratios were determined. MtDNA subhaplogroups were established by sequencing. Among patients, peripheral neuropathy was present in 21% (43/203), lipodystrophy in 18% (20/112), elevated lactate level (>2.5 mmol/L) in 17% (19/113). Healthy controls had a higher median mtDNA/nDNA ratio when compared to HIV/AIDS patients (6.64 vs. 5.08; p=0.05), patients presenting with peripheral neuropathy (6.64 vs. 3.40, p=0.039), and patients with high lactate levels (6.64 vs. 0.68, p=0.024), respectively. Significant differences in median mtDNA/nDNA ratios were observed between patients with high and normal lactate levels (5.88 vs. 0.68, p=0.018). The median mtDNA/nDNA ratio of patients in subhaplogroup L0a2 was much lower (0.62 vs. 8.50, p=0.01) than that of those in subhaplogroup L2a. Our data indicate that peripheral blood mtDNA/nDNA ratio is a marker of mitochondrial toxicities of stavudine and is associated with elevated lactate levels and mtDNA subhaplogroups. This could open the prospect to select a substantial group of patients who will not have problematic side effects from stavudine, an affordable and effective antiretroviral drug that is being phased out in Africa due to its toxicity. PMID- 24816083 TI - Extraoperative neurostimulation mapping: results from an international survey of epilepsy surgery programs. AB - OBJECTIVE: Extraoperative electrical stimulation mapping (ESM) to identify functional cortex is performed prior to neurosurgical resection at epilepsy surgery programs worldwide. However, the procedure remains unstandardized, with no established clinical guidelines. We sought to determine the current range in ESM practice parameters across established epilepsy surgery centers. METHODS: We developed and distributed a 31-question survey to 220 epilepsy centers worldwide regarding current practice parameters of ESM. Questions addressed preoperative assessment, technical stimulation parameters, language testing protocols, criteria for identification of positive or negative functional sites, management of mapping complications, and postoperative functional outcome. RESULTS: Survey responses were obtained from 56 centers. These revealed marked practice variability in virtually all aspects of the ESM procedure. These aspects included critical procedure components such as electrical stimulation settings, the types of language functions tested, the operational definition of a language error, size of surgical resection margin, cortical locations mapped for language, testing in the presence of afterdischarges, and medical management of mapping complications. Forty-one percent of centers reported at least one persistent adverse language outcome despite preserving all eloquent sites defined by their stimulation mapping procedure. SIGNIFICANCE: The striking variations in practice across centers are likely to influence mapping results, which directly affect the boundaries of cortical resection and, consequently, might worsen either seizure or functional outcomes. Clearly, adverse functional outcomes occur despite mapping procedures that were perceived to be adequate. Investigation of critical technical and procedural aspects of stimulation mapping is warranted, with the ultimate goal of establishing empirically based practice guidelines to improve the safety and efficacy of ESM and resective epilepsy surgery. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24816084 TI - Geographic and temporal variations in pollen exposure across Europe. AB - BACKGROUND: The EC-funded EuroPrevall project examined the prevalence of food allergy across Europe. A well-established factor in the occurrence of food allergy is primary sensitization to pollen. OBJECTIVE: To analyse geographic and temporal variations in pollen exposure, allowing the investigation of how these variations influence the prevalence and incidence of food allergies across Europe. METHODS: Airborne pollen data for two decades (1990-2009) were obtained from 13 monitoring sites located as close as possible to the EuroPrevall survey centres. Start dates, intensity and duration of Betulaceae, Oleaceae, Poaceae and Asteraceae pollen seasons were examined. Mean, slope of the regression, probability level (P) and dominant taxa (%) were calculated. Trends were considered significant at P < 0.05. RESULTS: On a European scale, Betulaceae, in particular Betula, is the most dominant pollen exposure, two folds higher than to Poaceae, and greater than five folds higher than to Oleaceae and Asteraceae. Only in Reykjavik, Madrid and Derby was Poaceae the dominant pollen, as was Oleaceae in Thessaloniki. Weed pollen (Asteraceae) was never dominant, exposure accounted for >10% of total pollen exposure only in Siauliai (Artemisia) and Legnano (Ambrosia). Consistent trends towards changing intensity or duration of exposure were not observed, possibly with the exception of (not significant) decreased exposure to Artemisia and increased exposure to Ambrosia. CONCLUSIONS: This is the first comprehensive study quantifying exposure to the major allergenic pollen families Betulaceae, Oleaceae, Poaceae and Asteraceae across Europe. These data can now be used for studies into patterns of sensitization and allergy to pollen and foods. PMID- 24816085 TI - MRI for characterization of primary tumors in the non-cirrhotic liver: added value of Gd-EOB-DTPA enhanced hepatospecific phase. AB - PURPOSE: To evaluate the added value of hepatospecific phase in Gd-EOB-DTPA enhanced magnetic resonance imaging (MRI) in patients with primary tumors in non cirrhotic liver. METHODS: Twenty-nine patients (median, 39 years; range, 18-81 years; 11 male) underwent preoperative Gd-EOB-DTPA enhanced MRI including hepatospecific phase after 10 and 20 min of contrast injection at four institutions in Europe, North America and New Zealand. Images were evaluated by three different readers (R1-R3) who characterized liver tumors with and without consultation of the hepatospecific phase images. Confidence in diagnosis was scored on a visual analog scale from 1 to 10. Histopathology (adenoma, n=5; focal nodular hyperplasia, n=11 and hepatocellular carcinoma, n=13) in all patients served as the standard of reference. Differences were evaluated using the McNemar and Wilcoxon signed rank test. RESULTS: Without hepatospecific phase images available, 22 (76%), 19 (66%) and 19 (66%) of 29 tumors were characterized correctly by the three readers respectively. Mean confidence in diagnosis was 6.1, 5.7 and 5.8. With the hepatospecific phase included, characterization of liver tumors did not change significantly with 21 (72%), 23 (79%) and 19 (66%) of 29 tumors diagnosed correctly (p>0.05). According confidence ratings increased to 6.3, 6.5 and 7.7, respectively. Increase in diagnostic confidence was significant for R2 and R3 (p<0.05) and independent of reader's experience. CONCLUSION: The additional hepatospecific phase in Gd-EOB-DTPA enhanced MRI did not significantly increase diagnostic accuracy in characterization of primary tumors in the non cirrhotic liver. However, 2/3 readers showed a significant increase in diagnostic confidence after consultation of the hepatospecific phase. PMID- 24816086 TI - Age determination of subdural hematomas with CT and MRI: a systematic review. AB - OBJECTIVES: To systematically review the literature on dating subdural hematomas (SDHs) on CT and MRI scans. METHODS: We performed a systematic review in MEDLINE, EMBASE and Cochrane to search for articles that described the appearance of SDHs on CT or MRI in relation to time between trauma and scanning. Two researchers independently screened the articles, assessed methodological quality and performed data extraction. Medians with interquartile ranges were calculated. Differences were tested with a Mann-Whitney U or Kruskal-Wallis H test. RESULTS: We included 22 studies describing 973 SDHs on CT and 4 studies describing 83 SDHs on MRI. Data from 17 studies (413 SDHs) could be pooled. There were significant differences between time intervals for the different densities on CT (p<0.001). Time interval differed significantly between children and adults for iso- and hypodensity (p=0.000) and hyperdensity (p=0.046). Time interval did not differ significantly between abused and non-abused children. On MRI, time intervals for different signal intensities on T1 and T2 did not differ significantly (p=0.108 and p=0.194, respectively). CONCLUSIONS: Most time intervals of the different appearances of SDHs on CT and MRI are broad and overlapping. Therefore CT or MRI findings cannot be used to accurately date SDHs. PMID- 24816087 TI - Less is better? Intraindividual and interindividual comparison between 0.075 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadoterate meglumine for cranial MRI. AB - PURPOSE: To retrospectively compare a reduced dose (RD) (0.075 mmol/kg) of gadobenate dimeglumine (RD-gadobenate) with standard single dose (SSD) (0.1 mmol/kg) of gadoterate meglumine (SSD-gadoterate) for cranial MRI. MATERIALS AND METHODS: Thirty-one patients (12 males; aged 52 +/- 16 years) underwent cranial MRI with SSD-gadoterate and repeated the examination with RD-gadobenate after a median interval of 10 months. Signal-to-noise ratio (SNR) was obtained on contrast-enhanced images for enhancing lesions (n=10) as well as for right and left transverse venous sinuses, internal carotid arteries, and parotid glands. Moreover, a consecutive series of 100 cranial MRI with SSD-gadoterate (49 males; aged 51 +/- 19 years) was compared with a consecutive series of 100 cranial MRI with RD-gadobenate (45 males; aged 54 +/- 18 years). Two blinded neuroradiologists (R1, R2) judged contrast enhancement as sufficient, good, or optimal. Wilcoxon, Mann-Whitney, chi(2), and Cohen kappa statistics were used. RESULTS: At intraindividual analysis, median SNR ranged 57-88 for SSD-gadoterate and 79-99 for RD-gadobenate, the latter being systematically higher, the difference being significant for both transverse venous sinuses (p <= 0.011), not significant for both internal carotid arteries and both parotid glands, and enhancing lesions (p <= 0.101). The two series of interindividual analysis were not significantly different for gender/age (p>0.415). Contrast enhancement was optimal in 59% (R1) and 76% (R2) of patients using RD-gadobenate, in 39% (R1) and 49% (R2) of patients using SSD-gadoterate (p <= 0.016), with substantial reproducibility (kappa >= 0.606). CONCLUSION: Both analyses showed an equal or better contrast enhancement when using RD-gadobenate compared to SSD-gadoterate for routine cranial MRI. The high relaxivity of gadobenate allowed for a 25% dose reduction. PMID- 24816088 TI - Hitting the target: fragment screening with acoustic in situ co-crystallization of proteins plus fragment libraries on pin-mounted data-collection micromeshes. AB - Acoustic droplet ejection (ADE) is a powerful technology that supports crystallographic applications such as growing, improving and manipulating protein crystals. A fragment-screening strategy is described that uses ADE to co crystallize proteins with fragment libraries directly on MiTeGen MicroMeshes. Co crystallization trials can be prepared rapidly and economically. The high speed of specimen preparation and the low consumption of fragment and protein allow the use of individual rather than pooled fragments. The Echo 550 liquid-handling instrument (Labcyte Inc., Sunnyvale, California, USA) generates droplets with accurate trajectories, which allows multiple co-crystallization experiments to be discretely positioned on a single data-collection micromesh. This accuracy also allows all components to be transferred through small apertures. Consequently, the crystallization tray is in equilibrium with the reservoir before, during and after the transfer of protein, precipitant and fragment to the micromesh on which crystallization will occur. This strict control of the specimen environment means that the crystallography experiments remain identical as the working volumes are decreased from the few microlitres level to the few nanolitres level. Using this system, lysozyme, thermolysin, trypsin and stachydrine demethylase crystals were co-crystallized with a small 33-compound mini-library to search for fragment hits. This technology pushes towards a much faster, more automated and more flexible strategy for structure-based drug discovery using as little as 2.5 nl of each major component. PMID- 24816090 TI - An improved integration method in serial femtosecond crystallography. AB - Recent experiments in serial femtosecond crystallography (SFX) have demonstrated the feasibility of obtaining structural information from nanoscale crystals using X-ray free-electron lasers (XFELs). However, millions of crystals are required to determine one reliable structure. Here, an improved integration algorithm for SFX data processing is reported. By evaluating the dimensions of each crystal and correcting for the geometric factors of single patterns, the effective diffraction intensities, as opposed to the directly measured single-shot pattern diffraction intensities, can be merged to acquire more accurate integrated intensities which can be used for structure determination. This improvement enhances the quality of electron-density maps and decreases the number of diffraction patterns that are needed to solve the crystal structure in SFX experiments. PMID- 24816089 TI - A slow-forming isopeptide bond in the structure of the major pilin SpaD from Corynebacterium diphtheriae has implications for pilus assembly. AB - The Gram-positive organism Corynebacterium diphtheriae, the cause of diphtheria in humans, expresses pili on its surface which it uses for adhesion and colonization of its host. These pili are covalent protein polymers composed of three types of pilin subunit that are assembled by specific sortase enzymes. A structural analysis of the major pilin SpaD, which forms the polymeric backbone of one of the three types of pilus expressed by C. diphtheriae, is reported. Mass spectral and crystallographic analysis shows that SpaD contains three internal Lys-Asn isopeptide bonds. One of these, shown by mass spectrometry to be located in the N-terminal D1 domain of the protein, only forms slowly, implying an energy barrier to bond formation. Two crystal structures, of the full-length three domain protein at 2.5 A resolution and of a two-domain (D2-D3) construct at 1.87 A resolution, show that each of the three Ig-like domains contains a single Lys Asn isopeptide-bond cross-link, assumed to give mechanical stability as in other such pili. Additional stabilizing features include a disulfide bond in the D3 domain and a calcium-binding loop in D2. The N-terminal D1 domain is more flexible than the others and, by analogy with other major pilins of this type, the slow formation of its isopeptide bond can be attributed to its location adjacent to the lysine used in sortase-mediated polymerization during pilus assembly. PMID- 24816091 TI - Structural basis of a novel activity of bacterial 6-pyruvoyltetrahydropterin synthase homologues distinct from mammalian 6-pyruvoyltetrahydropterin synthase activity. AB - Escherichia coli 6-carboxytetrahydropterin synthase (eCTPS), a homologue of 6 pyruvoyltetrahydropterin synthase (PTPS), possesses a much stronger catalytic activity to cleave the side chain of sepiapterin in vitro compared with genuine PTPS activity and catalyzes the conversion of dihydroneopterin triphosphate to 6 carboxy-5,6,7,8-tetrahydropterin in vivo. Crystal structures of wild-type apo eCTPS and of a Cys27Ala mutant eCTPS complexed with sepiapterin have been determined to 2.3 and 2.5 A resolution, respectively. The structures are highly conserved at the active site and the Zn(2+) binding site. However, comparison of the eCTPS structures with those of mammalian PTPS homologues revealed that two specific residues, Trp51 and Phe55, that are not found in mammalian PTPS keep the substrate bound by stacking it with their side chains. Replacement of these two residues by site-directed mutagenesis to the residues Met and Leu, which are only found in mammalian PTPS, converted eCTPS to the mammalian PTPS activity. These studies confirm that these two aromatic residues in eCTPS play an essential role in stabilizing the substrate and in the specific enzyme activity that differs from the original PTPS activity. These aromatic residues Trp51 and Phe55 are a key signature of bacterial PTPS enzymes that distinguish them from mammalian PTPS homologues. PMID- 24816092 TI - IR laser-induced protein crystal transformation. AB - A method and the design of instrumentation, and its preliminary practical realisation, including test experiments, with the object of inducing phase changes of biomolecular crystals by controlled dehydration through heating with infrared (IR) light are described. The aim is to generate and select crystalline phases through transformation in the solid state which have improved order (higher resolution in X-ray diffraction experiments) and reduced mosaic spread (more uniformly aligned mosaic blocks) for diffraction data collection and analysis. The crystal is heated by pulsed and/or constant IR laser irradiation. Loss of crystal water following heating and its reabsorption through equilibration with the environment is measured optically by a video system. Heating proved superior to traditional controlled dehydration by humidity change for the test cases CODH (carbon monoxide dehydrogenase) and CLK2 (a protein kinase). Heating with IR light is experimentally simple and offers an exploration of a much broader parameter space than the traditional method, as it allows the option of varying the rate of phase changes through modification of the IR pulse strength, width and repeat frequency. It impacts the crystal instantaneously, isotropically and homogeneously, and is therefore expected to cause less mechanical stress. PMID- 24816093 TI - Accurate macromolecular crystallographic refinement: incorporation of the linear scaling, semiempirical quantum-mechanics program DivCon into the PHENIX refinement package. AB - Macromolecular crystallographic refinement relies on sometimes dubious stereochemical restraints and rudimentary energy functionals to ensure the correct geometry of the model of the macromolecule and any covalently bound ligand(s). The ligand stereochemical restraint file (CIF) requires a priori understanding of the ligand geometry within the active site, and creation of the CIF is often an error-prone process owing to the great variety of potential ligand chemistry and structure. Stereochemical restraints have been replaced with more robust functionals through the integration of the linear-scaling, semiempirical quantum-mechanics (SE-QM) program DivCon with the PHENIX X-ray refinement engine. The PHENIX/DivCon package has been thoroughly validated on a population of 50 protein-ligand Protein Data Bank (PDB) structures with a range of resolutions and chemistry. The PDB structures used for the validation were originally refined utilizing various refinement packages and were published within the past five years. PHENIX/DivCon does not utilize CIF(s), link restraints and other parameters for refinement and hence it does not make as many a priori assumptions about the model. Across the entire population, the method results in reasonable ligand geometries and low ligand strains, even when the original refinement exhibited difficulties, indicating that PHENIX/DivCon is applicable to both single-structure and high-throughput crystallography. PMID- 24816094 TI - Exploiting fast detectors to enter a new dimension in room-temperature crystallography. AB - A departure from a linear or an exponential intensity decay in the diffracting power of protein crystals as a function of absorbed dose is reported. The observation of a lag phase raises the possibility of collecting significantly more data from crystals held at room temperature before an intolerable intensity decay is reached. A simple model accounting for the form of the intensity decay is reintroduced and is applied for the first time to high frame-rate room temperature data collection. PMID- 24816095 TI - Sunitinib: from charge-density studies to interaction with proteins. AB - Protein kinases are targets for the treatment of a number of diseases. Sunitinib malate is a type I inhibitor of tyrosine kinases and was approved as a drug in 2006. This contribution constitutes the first comprehensive analysis of the crystal structures of sunitinib malate and of complexes of sunitinib with a series of protein kinases. The high-resolution single-crystal X-ray measurement and aspherical atom databank approach served as a basis for reconstruction of the charge-density distribution of sunitinib and its protein complexes. Hirshfeld surface and topological analyses revealed a similar interaction pattern in the sunitinib malate crystal structure to that in the protein binding pockets. Sunitinib forms nine preserved bond paths corresponding to hydrogen bonds and also to the C-H...O and C-H...pi contacts common to the VEGRF2, CDK2, G2, KIT and IT kinases. In general, sunitinib interacts with the studied proteins with a similar electrostatic interaction energy and can adjust its conformation to fit the binding pocket in such a way as to enhance the electrostatic interactions, e.g. hydrogen bonds in ligand-kinase complexes. Such behaviour may be responsible for the broad spectrum of action of sunitinib as a kinase inhibitor. PMID- 24816096 TI - Structural insight into glucose dehydrogenase from the thermoacidophilic archaeon Thermoplasma volcanium. AB - Glucose dehydrogenase from the thermoacidophilic archaeon Thermoplasma volcanium (tvGlcDH) is highly active towards D-glucose and D-galactose, but does not utilize aldopentoses such as D-xylose as substrates. In the present study, the crystal structures of substrate/cofactor-free tvGlcDH and of a tvGlcDH T277F mutant in a binary complex with NADP and in a ternary complex with D-glucose and nicotinic acid adenine dinucleotide phosphate, an NADP analogue, were determined at resolutions of 2.6, 2.25 and 2.33 A, respectively. The overall structure of each monomer showed notable similarity to that of the enzyme from Sulfolobus solfataricus (ssGlcDH-1), which accepts a broad range of C5 and C6 sugars as substrates. However, the amino-acid residues of tvGlcDH involved in substrate binding markedly differed from those of ssGlcDH-1. Structural comparison revealed that a decreased number of interactions between the C3-hydroxyl group of the sugar and the enzyme are likely to be responsible for the lack of reactivity of tvGlcDH towards D-xylose. PMID- 24816097 TI - Structural analysis and insight into metal-ion activation of the iron-dependent regulator from Thermoplasma acidophilum. AB - The iron-dependent regulator (IdeR) is a metal ion-activated transcriptional repressor that regulates the expression of genes encoding proteins involved in iron uptake to maintain metal-ion homeostasis. IdeR is a functional homologue of the diphtheria toxin repressor (DtxR), and both belong to the DtxR/MntR family of metalloregulators. The structure of Fe(2+)-bound IdeR (TA0872) from Themoplasma acidophilum was determined at 2.1 A resolution by X-ray crystallography using single-wavelength anomalous diffraction. The presence of Fe(2+), which is the true biological activator of IdeR, in the metal-binding site was ascertained by the use of anomalous difference electron-density maps using diffraction data collected at the Fe absorption edge. Each DtxR/IdeR subunit contains two metal ion-binding sites separated by 9 A, labelled the primary and ancillary sites, whereas the crystal structures of IdeR from T. acidophilum show a binuclear iron cluster separated by 3.2 A, which is novel to T. acidophilum IdeR. The metal binding site analogous to the primary site in DtxR was unoccupied, and the ancillary site was occupied by binuclear clustered ions. This difference suggests that T. acidophilum IdeR and its closely related homologues are regulated by a mechanism distinct from that of either DtxR or MntR. T. acidophilum IdeR was also shown to have a metal-dependent DNA-binding property by electrophoretic mobility shift assay. PMID- 24816098 TI - Fingerprinting redox and ligand states in haemprotein crystal structures using resonance Raman spectroscopy. AB - It is crucial to assign the correct redox and ligand states to crystal structures of proteins with an active redox centre to gain valid functional information and prevent the misinterpretation of structures. Single-crystal spectroscopies, particularly when applied in situ at macromolecular crystallography beamlines, allow spectroscopic investigations of redox and ligand states and the identification of reaction intermediates in protein crystals during the collection of structural data. Single-crystal resonance Raman spectroscopy was carried out in combination with macromolecular crystallography on Swiss Light Source beamline X10SA using cytochrome c' from Alcaligenes xylosoxidans. This allowed the fingerprinting and validation of different redox and ligand states, identification of vibrational modes and identification of intermediates together with monitoring of radiation-induced changes. This combined approach provides a powerful tool to obtain complementary data and correctly assign the true oxidation and ligand state(s) in redox-protein crystals. PMID- 24816099 TI - Divalent metal ion-based catalytic mechanism of the Nudix hydrolase Orf153 (YmfB) from Escherichia coli. AB - YmfB from Escherichia coli is the Nudix hydrolase involved in the metabolism of thiamine pyrophosphate, an important compound in primary metabolism and a cofactor of many enzymes. In addition, it hydrolyzes (d)NTPs to (d)NMPs and inorganic orthophosphates in a stepwise manner. The structures of YmfB alone and in complex with three sulfates and two manganese ions determined by X-ray crystallography, when compared with the structures of other Nudix hydrolases such as MutT, Ap4Aase and DR1025, provide insight into the unique hydrolysis mechanism of YmfB. Mass-spectrometric analysis confirmed that water attacks the terminal phosphates of GTP and GDP sequentially. Kinetic analysis of binding-site mutants showed that no individual residue is absolutely required for catalytic activity, suggesting that protein residues do not participate in the deprotonation of the attacking water. Thermodynamic integration calculations show that a hydroxyl ion bound to two divalent metal ions attacks the phosphate directly without the help of a nearby catalytic base. PMID- 24816100 TI - Structure of the ubiquitin-activating enzyme loaded with two ubiquitin molecules. AB - The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. Here, a ubiquitin E1 structure loaded with two ubiquitin molecules is presented for the first time. While one ubiquitin is bound in its adenylated form to the active adenylation domain of E1, the second ubiquitin represents the status after transfer and is covalently linked to the active-site cysteine. The covalently linked ubiquitin enables binding of the E2 enzyme without further modification of the ternary Uba1-ubiquitin2 arrangement. This doubly loaded E1 structure constitutes a missing link in the structural analysis of the ubiquitin-transfer cascade. PMID- 24816102 TI - Bacteriophage P22 tailspike: structure of the complete protein and function of the interdomain linker. AB - Attachment of phages to host cells, followed by phage DNA ejection, represents the first stage of viral infection of bacteria. Salmonella phage P22 has been extensively studied, serving as an experimental model for bacterial infection by phages. P22 engages bacteria by binding to the sugar moiety of lipopolysaccharides using the viral tailspike protein for attachment. While the structures of the N-terminal particle-binding domain and the major receptor binding domain of the tailspike have been analyzed individually, the three dimensional organization of the intact protein, including the highly conserved linker region between the two domains, remained unknown. A single amino-acid exchange in the linker sequence made it possible to crystallize the full-length protein. Two crystal structures of the linker region are presented: one attached to the N-terminal domain and the other present within the complete tailspike protein. Both retain their biological function, but the mutated full-length tailspike displays a retarded folding pathway. Fitting of the full-length tailspike into a published cryo-electron microscopy map of the P22 virion requires an elastic distortion of the crystal structure. The conservation of the linker suggests a role in signal transmission from the distal tip of the molecule to the phage head, eventually leading to DNA ejection. PMID- 24816101 TI - Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. AB - Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), a fatal childhood-onset neurodegenerative disease with mild facial, visceral and skeletal abnormalities, is caused by an inherited deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH; sulfamidase). More than 100 mutations in the SGSH gene have been found to reduce or eliminate its enzymatic activity. However, the molecular understanding of the effect of these mutations has been confined by a lack of structural data for this enzyme. Here, the crystal structure of glycosylated SGSH is presented at 2 A resolution. Despite the low sequence identity between this unique N-sulfatase and the group of O-sulfatases, they share a similar overall fold and active-site architecture, including a catalytic formylglycine, a divalent metal-binding site and a sulfate-binding site. However, a highly conserved lysine in O-sulfatases is replaced in SGSH by an arginine (Arg282) that is positioned to bind the N-linked sulfate substrate. The structure also provides insight into the diverse effects of pathogenic mutations on SGSH function in mucopolysaccharidosis type IIIA and convincing evidence for the molecular consequences of many missense mutations. Further, the molecular characterization of SGSH mutations will lay the groundwork for the development of structure-based drug design for this devastating neurodegenerative disorder. PMID- 24816103 TI - Flexible torsion-angle noncrystallographic symmetry restraints for improved macromolecular structure refinement. AB - One of the great challenges in refining macromolecular crystal structures is a low data-to-parameter ratio. Historically, knowledge from chemistry has been used to help to improve this ratio. When a macromolecule crystallizes with more than one copy in the asymmetric unit, the noncrystallographic symmetry relationships can be exploited to provide additional restraints when refining the working model. However, although globally similar, NCS-related chains often have local differences. To allow for local differences between NCS-related molecules, flexible torsion-based NCS restraints have been introduced, coupled with intelligent rotamer handling for protein chains, and are available in phenix.refine for refinement of models at all resolutions. PMID- 24816104 TI - Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors. AB - Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects against Cp-NanI, a sialidase from Clostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of the Cp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme-inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents. PMID- 24816105 TI - A novel beta-xylosidase structure from Geobacillus thermoglucosidasius: the first crystal structure of a glycoside hydrolase family GH52 enzyme reveals unpredicted similarity to other glycoside hydrolase folds. AB - Geobacillus thermoglucosidasius is a thermophilic bacterium that is able to ferment both C6 and C5 sugars to produce ethanol. During growth on hemicellulose biomass, an intracellular beta-xylosidase catalyses the hydrolysis of xylo oligosaccharides to the monosaccharide xylose, which can then enter the pathways of central metabolism. The gene encoding a G. thermoglucosidasius beta-xylosidase belonging to CAZy glycoside hydrolase family GH52 has been cloned and expressed in Escherichia coli. The recombinant enzyme has been characterized and a high resolution (1.7 A) crystal structure has been determined, resulting in the first reported structure of a GH52 family member. A lower resolution (2.6 A) structure of the enzyme-substrate complex shows the positioning of the xylobiose substrate to be consistent with the proposed retaining mechanism of the family; additionally, the deep cleft of the active-site pocket, plus the proximity of the neighbouring subunit, afford an explanation for the lack of catalytic activity towards the polymer xylan. Whilst the fold of the G. thermoglucosidasius beta xylosidase is completely different from xylosidases in other CAZy families, the enzyme surprisingly shares structural similarities with other glycoside hydrolases, despite having no more than 13% sequence identity. PMID- 24816107 TI - Structure of a three-dimensional domain-swapped dimer of the Helicobacter pylori type IV secretion system pilus protein CagL. AB - A new crystal form of the Helicobacter pylori type IV secretion system (T4SS) pilus protein CagL is described here. In contrast to two previously reported monomeric structures, CagL forms a three-dimensional domain-swapped dimer. CagL dimers can arise during refolding from inclusion bodies or can form spontaneously from purified monomeric CagL in the crystallization conditions. Monomeric CagL forms a three-helix bundle, with which the N-terminal helix is only loosely associated. In the new crystal form, the N-terminal helix is missing. The domain swap is owing to exchange of the C-terminal helix between the two protomers of a dimer. A loop-to-helix transition results in a long helix of 108 amino acids comprising the penultimate and the last helix of the monomer. The RGD motif of dimeric CagL adopts an alpha-helical conformation. In contrast to the previously reported structures, the conserved and functionally important C-terminal hexapeptide is resolved. It extends beyond the three-helix bundle as an exposed helical appendage. This new crystal form contributes to the molecular understanding of CagL by highlighting rigid and flexible regions in the protein and by providing the first view of the C-terminus. Based on the structural features, a previously unrecognized homology between CagL and CagI is discussed. PMID- 24816106 TI - An arginine tetrad as mediator of input-dependent and input-independent ATPases in the clock protein KaiC. AB - A post-translational oscillator (PTO) composed of the proteins KaiA, KaiB and KaiC is at the heart of the cyanobacterial circadian clock. KaiC interacts with KaiA and KaiB over the daily cycle, and CII domains undergo rhythmic phosphorylation/dephosphorylation with a 24 h period. Both the N-terminal (CI) and C-terminal (CII) rings of KaiC exhibit ATPase activity. The CI ATPase proceeds in an input-independent fashion, but the CII ATPase is subject to metabolic input signals. The crystal structure of KaiC from Thermosynechococcus elongatus allows insight into the different anatomies of the CI and CII ATPases. Four consecutive arginines in CI (Arg linker) that connect the P-loop, CI subunits and CI and CII at the ring interface are primary candidates for the coordination of the CI and CII activities. The mutation of linker residues alters the period or triggers arhythmic behavior. Comparison between the CI and CII structures also reveals differences in loop regions that are key to KaiA and KaiB binding and activation of CII ATPase and kinase. Common packing features in KaiC crystals shed light on the KaiB-KaiC interaction. PMID- 24816108 TI - Insights into the binding specificity and catalytic mechanism of N acetylhexosamine 1-phosphate kinases through multiple reaction complexes. AB - Utilization of N-acetylhexosamine in bifidobacteria requires the specific lacto-N biose/galacto-N-biose pathway, a pathway differing from the Leloir pathway while establishing symbiosis between humans and bifidobacteria. The gene lnpB in the pathway encodes a novel hexosamine kinase NahK, which catalyzes the formation of N-acetylhexosamine 1-phosphate (GlcNAc-1P/GalNAc-1P). In this report, seven three dimensional structures of NahK in complex with GlcNAc, GalNAc, GlcNAc-1P, GlcNAc/AMPPNP and GlcNAc-1P/ADP from both Bifidobacterium longum (JCM1217) and B. infantis (ATCC15697) were solved at resolutions of 1.5-2.2 A. NahK is a monomer in solution, and its polypeptide folds in a crescent-like architecture subdivided into two domains by a deep cleft. The NahK structures presented here represent the first multiple reaction complexes of the enzyme. This structural information reveals the molecular basis for the recognition of the given substrates and products, GlcNAc/GalNAc, GlcNAc-1P/GalNAc-1P, ATP/ADP and Mg(2+), and provides insights into the catalytic mechanism, enabling NahK and mutants thereof to form a choice of biocatalysts for enzymatic and chemoenzymatic synthesis of carbohydrates. PMID- 24816109 TI - The structure of a class 3 nonsymbiotic plant haemoglobin from Arabidopsis thaliana reveals a novel N-terminal helical extension. AB - Plant nonsymbiotic haemoglobins fall into three classes, each with distinct properties but all with largely unresolved physiological functions. Here, the first crystal structure of a class 3 nonsymbiotic plant haemoglobin, that from Arabidopsis thaliana, is reported to 1.77 A resolution. The protein forms a homodimer, with each monomer containing a two-over-two alpha-helical domain similar to that observed in bacterial truncated haemoglobins. A novel N-terminal extension comprising two alpha-helices plays a major role in the dimer interface, which occupies the periphery of the dimer-dimer face, surrounding an open central cavity. The haem pocket contains a proximal histidine ligand and an open sixth iron-coordination site with potential for a ligand, in this structure hydroxide, to form hydrogen bonds to a tyrosine or a tryptophan residue. The haem pocket appears to be unusually open to the external environment, with another cavity spanning the entrance of the two haem pockets. The final 23 residues of the C terminal domain are disordered in the structure; however, these domains in the functional dimer are adjacent and include the only two cysteine residues in the protein sequence. It is likely that these residues form disulfide bonds in vitro and it is conceivable that this C-terminal region may act in a putative complex with a partner molecule in vivo. PMID- 24816111 TI - In cellulo structure determination of a novel cypovirus polyhedrin. AB - This work demonstrates that with the use of a microfocus synchrotron beam the structure of a novel viral polyhedrin could be successfully determined from microcrystals within cells, removing the preparatory step of sample isolation and maintaining a favourable biological environment. The data obtained are of high quality, comparable to that obtained from isolated crystals, and enabled a facile structure determination. A small but significant difference is observed between the unit-cell parameters and the mosaic spread of in cellulo and isolated crystals, suggesting that even these robust crystals are adversely affected by removal from the cell. PMID- 24816110 TI - Crystallographic and kinetic study of riboflavin synthase from Brucella abortus, a chemotherapeutic target with an enhanced intrinsic flexibility. AB - Riboflavin synthase (RS) catalyzes the last step of riboflavin biosynthesis in microorganisms and plants, which corresponds to the dismutation of two molecules of 6,7-dimethyl-8-ribityllumazine to yield one molecule of riboflavin and one molecule of 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione. Owing to the absence of this enzyme in animals and the fact that most pathogenic bacteria show a strict dependence on riboflavin biosynthesis, RS has been proposed as a potential target for antimicrobial drug development. Eubacterial, fungal and plant RSs assemble as homotrimers lacking C3 symmetry. Each monomer can bind two substrate molecules, yet there is only one active site for the whole enzyme, which is located at the interface between two neighbouring chains. This work reports the crystallographic structure of RS from the pathogenic bacterium Brucella abortus (the aetiological agent of the disease brucellosis) in its apo form, in complex with riboflavin and in complex with two different product analogues, being the first time that the structure of an intact RS trimer with bound ligands has been solved. These crystal models support the hypothesis of enhanced flexibility in the particle and also highlight the role of the ligands in assembling the unique active site. Kinetic and binding studies were also performed to complement these findings. The structural and biochemical information generated may be useful for the rational design of novel RS inhibitors with antimicrobial activity. PMID- 24816112 TI - Structure of the epimerization domain of tyrocidine synthetase A. AB - Tyrocidine, a macrocyclic decapeptide from Bacillus brevis, is nonribosomally assembled by a set of multimodular peptide synthetases, which condense two D amino acids and eight L-amino acids to produce this membrane-disturbing antibiotic. D-Phenylalanine, the first amino acid incorporated into tyrocidine, is catalytically derived from enzyme-bound L-Phe by the C-terminal epimerization (E) domain of tyrocidine synthetase A (TycA). The 1.5 A resolution structure of the cofactor-independent TycA E domain reveals an intimate relationship to the condensation (C) domains of peptide synthetases. In contrast to the latter, the TycA E domain uses an enlarged bridge region to plug the active-site canyon from the acceptor side, whereas at the donor side a latch-like floor loop is suitably extended to accommodate the alphaIII helix of the preceding peptide-carrier domain. Additionally, E domains exclusively harbour a conserved glutamate residue, Glu882, that is opposite the active-site residue His743. This active site topology implies Glu882 as a candidate acid-base catalyst, whereas His743 stabilizes in the protonated state a transient enolate intermediate of the L<->D isomerization. PMID- 24816113 TI - The structure of a novel electron-transfer ferredoxin from Rhodopseudomonas palustris HaA2 which contains a histidine residue in its iron-sulfur cluster binding motif. AB - Rhodopseudomonas palustris HaA2 contains a gene, RPB3630, encoding a ferredoxin, HaPuxC, with an atypical CXXHXXC(X)nCP iron-sulfur cluster-binding motif. The ferredoxin gene is associated with a cytochrome P450 (CYP) monooxygenase-encoding gene, CYP194A3, an arrangement which is conserved in several strains of bacteria. Similar ferredoxin genes are found in other bacteria, such as Mycobacterium tuberculosis, where they are also associated with CYP genes. The crystal structure of HaPuxC has been solved at 2.3 A resolution. The overall fold of this [3Fe-4S] cluster-containing ferredoxin is similar to other [3Fe-4S] and [4Fe-4S] species, with the loop around the iron-sulfur cluster more closely resembling those of [3Fe-4S] ferredoxins. The side chain of His17 from the cluster-binding motif in HaPuxC points away from the vacant site of the cluster and interacts with Glu61 and one of the sulfide ions of the cluster. This is the first cytochrome P450 electron-transfer partner of this type to be structurally characterized and will provide a better understanding of the electron-transfer processes between these ferredoxins and their CYP enzymes. PMID- 24816114 TI - Structure of human Bloom's syndrome helicase in complex with ADP and duplex DNA. AB - Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3'-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640-1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome. PMID- 24816115 TI - Structure of the unique SEFIR domain from human interleukin 17 receptor A reveals a composite ligand-binding site containing a conserved alpha-helix for Act1 binding and IL-17 signaling. AB - Interleukin 17 (IL-17) cytokines play a crucial role in mediating inflammatory and autoimmune diseases. A unique intracellular signaling domain termed SEFIR is found within all IL-17 receptors (IL-17Rs) as well as the key adaptor protein Act1. SEFIR-mediated protein-protein interaction is a crucial step in IL-17 cytokine signaling. Here, the 2.3 A resolution crystal structure of the SEFIR domain of IL-17RA, the most commonly shared receptor for IL-17 cytokine signaling, is reported. The structure includes the complete SEFIR domain and an additional alpha-helical C-terminal extension, which pack tightly together to form a compact unit. Structural comparison between the SEFIR domains of IL-17RA and IL-17RB reveals substantial differences in protein topology and folding. The uniquely long insertion between strand betaC and helix alphaC in IL-17RA SEFIR is mostly well ordered, displaying a helix (alphaCC'ins) and a flexible loop (CC'). The DD' loop in the IL-17RA SEFIR structure is much shorter; it rotates nearly 90 degrees with respect to the counterpart in the IL-17RB SEFIR structure and shifts about 12 A to accommodate the alphaCC'ins helix without forming any knots. Helix alphaC was identified as critical for its interaction with Act1 and IL-17 stimulated gene expression. The data suggest that the heterotypic SEFIR-SEFIR association via helix alphaC is a conserved and signature mechanism specific for IL-17 signaling. The structure also suggests that the downstream motif of IL-17RA SEFIR together with helix alphaC could provide a composite ligand-binding surface for recruiting Act1 during IL-17 signaling. PMID- 24816116 TI - Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase. AB - Lactate dehydrogenase A (LDH-A) is a key enzyme in anaerobic respiration that is predominantly found in skeletal muscle and catalyses the reversible conversion of pyruvate to lactate in the presence of NADH. LDH-A is overexpressed in many tumours and has therefore emerged as an attractive target for anticancer drug discovery. Crystal structures of human LDH-A in the presence of inhibitors have been described, but currently no structures of the apo or binary NADH-bound forms are available for any mammalian LDH-A. Here, the apo structure of human LDH-A was solved at a resolution of 2.1 A in space group P4122. The active-site loop adopts an open conformation and the packing and crystallization conditions suggest that the crystal form is suitable for soaking experiments. The soaking potential was assessed with the cofactor NADH, which yielded a ligand-bound crystal structure in the absence of any inhibitors. The structures show that NADH binding induces small conformational changes in the active-site loop and an adjacent helix. A comparison with other eukaryotic apo LDH structures reveals the conservation of intra-loop interactions. The structures provide novel insight into cofactor binding and provide the foundation for soaking experiments with fragments and inhibitors. PMID- 24816117 TI - Diamonds in the rough: a strong case for the inclusion of weak-intensity X-ray diffraction data. AB - Overwhelming evidence exists to show that the inclusion of weak-intensity, high resolution X-ray diffraction data helps improve the refinement of atomic models by imposing strong constraints on individual and overall temperature B factors and thus the quality of crystal structures. Some researchers consider these data to be of little value and opt to discard them during data processing, particularly at medium and low resolution, at which individual B factors of atomic models cannot be refined. Here, new evidence is provided to show that the inclusion of these data helps to improve the quality of experimental phases by imposing proper constraints on electron-density models during noncrystallographic symmetry (NCS) averaging. Using electron-density correlation coefficients as criteria, the resolution of data has successfully been extended from 3.1 to 2.5 A resolution with redundancy-independent merging R factors from below 100% to about 310%. It is further demonstrated that phase information can be fully extracted from observed amplitudes through de novo NCS averaging. Averaging starts with uniform density inside double-shelled spherical masks and NCS matrices that are derived from bound heavy-atom clusters at the vertices of cuboctahedrally symmetric protein particles. PMID- 24816119 TI - Investigating biases of attention and memory for alcohol-related and negative words in alcohol-dependents with and without major depression after day-clinic treatment. AB - This study aimed to investigate attentional and memory biases in alcohol dependents with and without major depression compared to healthy controls. We assumed that both groups of alcohol-dependents would show attentional and memory biases for alcohol-related words. For the alcohol-dependents with depression, we additionally expected both types of biases for negative words. Alcohol-dependents without co-morbidity (Alc) and alcohol-dependents with major depression (D-Alc) as well as control participants with a moderate consumption of alcohol (Con) completed an alcohol Stroop task and a directed forgetting paradigm using word stimuli from three categories: neutral, negative, and alcohol-related. Stroop effects showed that not only alcohol-dependents but also control participants were more distracted by alcohol-related than by negative words. In the directed forgetting procedure, all participants showed a significant effect for each word category, including alcohol-related and negative words. The D-Alc-group memorized more alcohol-related than negative to-be-remembered words. The results do not corroborate the hypothesis of more pronounced attentional and memory biases in alcohol-dependents. However, in alcohol-dependents with depression a memory bias for alcohol-related material was found, suggesting that this group may be more pre-occupied with alcohol than patients without such co-morbidity. PMID- 24816120 TI - Using implicit association tests for the assessment of implicit personality self concepts of extraversion and neuroticism in schizophrenia. AB - There is evidence from research based on self-report personality measures that schizophrenia patients tend to be lower in extraversion and higher in neuroticism than healthy individuals. Self-report personality measures assess aspects of the explicit self-concept. The Implicit Association Test (IAT) has been developed to assess aspects of implicit cognition such as implicit attitudes and implicit personality traits. The present study was conducted to investigate the applicability and reliability of the IAT in schizophrenia patients and test whether they differ from healthy individuals on implicitly measured extraversion and neuroticism. The IAT and the NEO-FFI were administered as implicit and explicit measures of extraversion and neuroticism to 34 schizophrenia patients and 45 healthy subjects. For all IAT scores satisfactory to good reliabilities were observed in the patient sample. In both study groups, IAT scores were not related to NEO-FFI scores. Schizophrenia patients were lower in implicit and explicit extraversion and higher in implicit and explicit neuroticism than healthy individuals. Our data show that the IAT can be reliably applied to schizophrenia patients and suggest that they differ from healthy individuals not only in their conscious representation but also in their implicit representation of the self with regard to neuroticism and extraversion-related characteristics. PMID- 24816121 TI - Glucose biosensor based on a glassy carbon electrode modified with polythionine and multiwalled carbon nanotubes. AB - A novel glucose biosensor was fabricated. The first layer of the biosensor was polythionine, which was formed by the electrochemical polymerisation of the thionine monomer on a glassy carbon electrode. The remaining layers were coated with chitosan-MWCNTs, GOx, and the chitosan-PTFE film in sequence. The MWCNTs embedded in FAD were like "conductive wires" connecting FAD with electrode, reduced the distance between them and were propitious to fast direct electron transfer. Combining with good electrical conductivity of PTH and MWCNTs, the current response was enlarged. The sensor was a parallel multi-component reaction system (PMRS) and excellent electrocatalytic performance for glucose could be obtained without a mediator. The glucose sensor had a working voltage of -0.42 V, an optimum working temperature of 25 degrees C, an optimum working pH of 7.0, and the best percentage of polytetrafluoroethylene emulsion (PTFE) in the outer composite film was 2%. Under the optimised conditions, the biosensor displayed a high sensitivity of 2.80 uA mM(-1) cm(-2) and a low detection limit of 5 uM (S/N = 3), with a response time of less than 15 s and a linear range of 0.04 mM to 2.5 mM. Furthermore, the fabricated biosensor had a good selectivity, reproducibility, and long-term stability, indicating that the novel CTS+PTFE/GOx/MWCNTs/PTH composite is a promising material for immobilization of biomolecules and fabrication of third generation biosensors. PMID- 24816122 TI - P2Y2 R activation by nucleotides promotes skin wound-healing process. AB - P2Y2 R has been shown to be upregulated in a variety of tissues in response to stress or injury and to mediate tissue regeneration through its ability to activate multiple signalling pathways. This study aimed to investigate the role of P2Y2 R in the wound-healing process and the mechanisms by which P2Y2 R activation promotes wound healing in fibroblasts. The role of P2Y2 R in skin wound healing was examined using a full-thickness skin wound model in wildtype (WT) and P2Y2 R(-/-) mice and an in vitro scratch wound model in control or P2Y2 R siRNA-transfected fibroblasts. WT mice showed significantly decreased wound size compared with P2Y2 R(-/-) mice at day 14 post-wounding, and immunohistochemical analysis showed that a proliferation marker Ki67 and extracellular matrix (ECM)-related proteins VEGF, collagen I, fibronectin and alpha-SMA were overexpressed in WT mice, which were reduced in P2Y2 R(-/-) mice. Scratch-wounded fibroblasts increased ATP release, which peaked at 5 min. In addition, scratch wounding increased the level of P2Y2 R mRNA. Activation of P2Y2 R by ATP or UTP enhanced proliferation and migration of fibroblasts in in vitro scratch wound assays and were blocked by P2Y2 R siRNA. Finally, ATP or UTP also increased the levels of ECM-related proteins through the activation of P2Y2 R in fibroblasts. This study suggests that P2Y2 R may be a potential therapeutic target to promote wound healing in chronic wound diseases. PMID- 24816124 TI - Mycobacterium interjectum lung infection: a case report. PMID- 24816123 TI - Socioeconomic and psychosocial adversity in midlife and depressive symptoms post retirement: a 21-year follow-up of the Whitehall II study. AB - OBJECTIVE: We examined whether socioeconomic and psychosocial adversity in midlife predicts post-retirement depressive symptoms. DESIGN AND SETTING: A prospective cohort study of British civil servants who responded to a self administered questionnaire in middle-age and at older ages, 21 years later. PARTICIPANTS: The study sample consisted of 3,939 Whitehall II Study participants (2,789 men, 1,150 women; mean age 67.6 years at follow-up) who were employed at baseline and retired at follow-up. MEASUREMENTS: Midlife adversity was assessed by self-reported socioeconomic adversity (low occupational position; poor standard of living) and psychosocial adversity (high job strain; few close relationships). Symptoms of depression post-retirement were measured by the Center for Epidemiologic Studies Depression scale. RESULTS: After adjustment for sociodemographic and health-related covariates at baseline and follow-up, there were strong associations between midlife adversities and post-retirement depressive symptoms: low occupational position (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.15-2.51), poor standard of living (OR: 2.37, 95% CI: 1.66-3.39), high job strain (OR: 1.52, 95% CI: 1.09-2.14), and few close relationships (OR: 1.51, 95% CI: 1.12-2.03). The strength of the associations between socioeconomic, psychosocial, work-related, or non-work related exposures and depressive symptoms was similar. CONCLUSIONS: Robust associations from observational data suggest that several socioeconomic and psychosocial risk factors for symptoms of depression post-retirement can be detected already in midlife. PMID- 24816125 TI - Atypical deep venous thrombosis as the first manifestation of pulmonary neoplasm. PMID- 24816126 TI - Cardiogenic shock and pulmonary embolism. PMID- 24816127 TI - Diagnosis of peritoneal-pleural communication by peritoneography with (99m)Tc sulfur colloid in a 3-year-old girl with congenital nephrotic syndrome of the Finnish type. PMID- 24816128 TI - In vitro permeability of a model protein across ocular tissues and effect of iontophoresis on the transscleral delivery. AB - The aim of this work was to study the penetration of cytochrome c, a positively charged model protein (MW 12.4 kDa, charge at pH 8.2: +9), across different ocular tissues, and to evaluate the potential of iontophoresis to enhance and control the transscleral transport. The passive transport of cytochrome c across the sclera and across the bilayer choroid-Bruch's membrane was evaluated using Franz diffusion cells and porcine tissues. The affinity of cytochrome c for melanin was measured by means of in vitro binding experiments. The iontophoretic (anodal) permeation was studied as a function of donor concentration (from 5 to 70 mg/ml) and current intensity (from 0.9 to 3.5 mA; density from 1.5 to 5.8 mA/cm(2)), and the contribution of electroosmosis on cytochrome c transport was evaluated by using a high molecular weight fluorescent dextran (FD-150, 149 kDa) as neutral marker. Finally, the possibility of tuning cytochrome c permeation rate was investigated on a 70 mg/ml cytochrome c solution, by alternating passive permeation and iontophoresis at different intensities. Cytochrome c permeated the sclera with a passive permeability coefficient of about 2.5 * 10(-6)cm/s, comparable to molecules of similar molecular radius. The choroid-Bruch's layer was an important barrier to penetration, since its presence reduced 5-7 times the amount permeated after 5h, also because of the presence of melanin that binds cytochrome. Iontophoresis (2.9 mA/cm(2)) enhanced cytochrome c penetration across the sclera at all the concentrations tested, increasing about ten times the amount permeated after 2h. The effect was proportional to current density: the enhancement factor (measured on a 10mg/ml solution), resulted 6.0 +/- 4.3 (i=0.9 mA; density=1.5 mA/cm(2)), 10.6 +/- 4.1 (i=1.75 mA; density=2.9 mA/cm(2)), 33.2 +/- 8.3 (i=1.75 mA; density=5.8 mA/cm(2)). Iontophoretic (density=2.9 mA/cm(2)) experiments performed with FD-150, an electroosmotic flow (EO) marker, demonstrated that cytochrome c, at concentration higher that 1mg/ml, dramatically reduced the EO flow and that, despite the high MW, the main mechanism for cytochrome c iontophoretic permeation is electrorepulsion. Finally, by alternating in the same experiment passive permeation and iontophoresis at different current intensities, a precise modulation of cytochrome c release was obtained, thus indicating the possibility of tuning the release as a function of specific therapeutic needs. PMID- 24816129 TI - A new nanostructured carrier design including oil to enhance the pharmaceutical properties of retinoid therapy and its therapeutic effects on chemo-resistant ovarian cancer. AB - All-trans retinoic acid (ATRA) is an appealing alternative drug for the cancers that have failed the conventional chemotherapy and become chemo-resistant and more tumorigenic. In this study, we specifically addressed two issues commonly associated with ATRA nanotherapeutics: (1) insufficient, unstable entrapment and uncontrolled release of the highly lipophilic ATRA and (2) lack of studies in therapeutically relevant chemo-resistant cancer cell models. A polymer-oil nanostructured carrier (PONC) composed of oil and PLGA was designed and studied in an ovarian cancer cell subline SKOV-3PR that could withstand up to 300 nM paclitaxel and expressed high levels of multidrug resistance transporter ABCB1 and tumorigenic marker CD133. Differential scanning calorimetry of PONC revealed superior polymer amorphosity and dispersion of the entrapped ATRA in a manner comparable to nanostructured lipid carriers. With this design, the ATRA encapsulation efficiency was increased up to 8.5-fold and a 5-day controlled release profile was obtained. ATRA-PONC was able to induce extensive apoptotic cell death and exert substantially higher long-term anti-tumorigenic effects (IC50 of ATRA-PONC: 2 MUg/ml versus free ATRA: 17.5 MUg/ml; p<0.05) in SKOV-3PR cells. Mechanistic studies indicated that these enhanced anticancer effects were likely attributable to higher cell permeation by the well-dispersed drug/oil steadily released from PONC. To conclude, a nanostructured, oil-in-polymer hybrid carrier design has been developed for efficient ATRA delivery and treatment of the chemo-exposed, chemo-resistant sub-population of ovarian cancer, exemplifying a convenient strategy to vastly improve the pharmaceutical and therapeutic properties of tough-to-deliver lipophilic, poorly water-soluble anticancer compounds. PMID- 24816130 TI - Impact of lipid dynamic behavior on physical stability, in vitro release and skin permeation of genistein-loaded lipid nanoparticles. AB - The aim of this study was to develop lipid nanoparticles to deliver genistein (GEN) to deeper skin layers. To do so, the impact of lipid dynamic behavior (nanoparticle flexibility) on stability, release and skin permeation studies was verified. GEN-loaded solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were obtained and characterization was undertaken. Freshly prepared nanoparticles were produced with similar features (i.e., drug loading). However, a higher level of crystallization in GEN-SLN formulation was observed in differential scanning calorimetry experiments. Electron paramagnetic resonance measurements showed a lower mobility of the spin labels in the SLN, which would indicate that NLC could be more flexible than SLN. Despite the fact that NLC demonstrated more fluidity, GEN was released more slowly from NLC than from SLN. Skin permeation studies demonstrated that lipid nanoparticles increased GEN skin retention. More flexible particles (NLC) also favored drug penetration into deeper skin layers. GEN-NLC would seem to be a promising formulation for GEN topical delivery. PMID- 24816131 TI - Fractionation of extracts from paper and board food contact materials for in vitro screening of toxicity. AB - Paper and board used as food contact materials (FCMs) are chemically complex matrices, partly due to the naturally occurring substances in paper and board, but also due to the chemical treatment of the paper used to make it suitable for food contact. In order to assure the safety of packaging materials, information on the exposure as well as on the toxicity of substances in the packaging must be obtained. This study describes a comprehensive method for the extraction and fractionation of substances present in paper and board FCMs for further investigation by in vitro testing and chemical analysis. The extraction efficiency and the fractionation process were validated by determining recoveries in extracts from paper and board fortified with five surrogates of known concentration. The recoveries for the five surrogates were between 20% and 104% in the raw extract and between 21% and 109% after extraction and fractionation. The fractionation both reduces the number of compounds to be identified and works as a sample clean-up by reducing matrix effects. Raw extracts and fractions from two paper and board FCMs were furthermore tested in the aryl hydrocarbon receptor (AhR) reporter gene assay. Both raw extracts and two of the fractions of the raw extracts gave a positive response in the AhR assay. The strategy of extraction followed by fractionation offers a powerful tool in order to make the workflow for screening FCMs for potentially adverse effects more efficient. PMID- 24816132 TI - Self-efficacy to avoid suicidal action: factor structure and convergent validity among adults in substance use disorder treatment. AB - Individuals with substance use disorders (SUDs) are at high risk of suicidal behaviors, highlighting the need for an improved understanding of potentially influential factors. One such domain is self-efficacy to manage suicidal thoughts and impulses. Psychometric data about the Self-Efficacy to Avoid Suicidal Action (SEASA) Scale within a sample of adults seeking SUD treatment (N = 464) is provided. Exploratory factor analysis supported a single self-efficacy construct. Lower SEASA scores, or lower self-efficacy, were reported in those with more severe suicidal ideation and those with more suicide attempts, providing evidence for convergent validity. Implications of measuring self-efficacy in the context of suicide risk assessment are discussed. PMID- 24816134 TI - Oral peptide and protein delivery: intestinal obstacles and commercial prospects. AB - INTRODUCTION: Pharmaceutical research and development is increasingly focussed on biopharmaceuticals including peptide and protein drugs. Despite their growing importance and almost 100 years of research, the vast majority are still only available by injection. Oral bioavailabilities of peptide and protein drugs are very low mainly because of the stability and permeability barriers of the gastrointestinal (GI) tract. AREAS COVERED: Data from studies of peptide/protein drug oral bioavailability, stability and permeability in the stomach, small intestine and large intestine have been compiled to make comparisons between the various regions of the GI tract and peptides/proteins with differing characteristics. Assessment of the oral formulation strategies that have progressed farthest in clinical trials has been conducted to identify which have the best potential for future success. EXPERT OPINION: Oral delivery of peptides and small proteins is increasingly achieved by utilising formulations that combat the stability challenges of the GI tract and disrupt the intestinal cell membranes to enable absorption. However, oral bioavailabilities remain low and variable therefore high, potentially toxic doses of peptide/protein drugs are needed to elicit a therapeutic effect leading to high cost of the final product. There is very little research into larger proteins, making their oral delivery unlikely in the near future. PMID- 24816133 TI - Predicting protein aggregation during storage in lyophilized solids using solid state amide hydrogen/deuterium exchange with mass spectrometric analysis (ssHDX MS). AB - Solid state amide hydrogen/deuterium exchange with mass spectrometric analysis (ssHDX-MS) was used to assess the conformation of myoglobin (Mb) in lyophilized formulations, and the results correlated with the extent of aggregation during storage. Mb was colyophilized with sucrose (1:1 or 1:8 w/w), mannitol (1:1 w/w), or NaCl (1:1 w/w) or in the absence of excipients. Immediately after lyophilization, samples of each formulation were analyzed by ssHDX-MS and Fourier transform infrared spectroscopy (FTIR) to assess Mb conformation, and by dynamic light scattering (DLS) and size exclusion chromatography (SEC) to determine the extent of aggregation. The remaining samples were then placed on stability at 25 degrees C and 60% RH or 40 degrees C and 75% RH for up to 1 year, withdrawn at intervals, and analyzed for aggregate content by SEC and DLS. In ssHDX-MS of samples immediately after lyophilization (t = 0), Mb was less deuterated in solids containing sucrose (1:1 and 1:8 w/w) than in those containing mannitol (1:1 w/w), NaCl (1:1 w/w), or Mb alone. Deuterium uptake kinetics and peptide mass envelopes also indicated greater Mb structural perturbation in mannitol, NaCl, or Mb-alone samples at t = 0. The extent of deuterium incorporation and kinetic parameters related to rapidly and slowly exchanging amide pools (Nfast, Nslow), measured at t = 0, were highly correlated with the extent of aggregation on storage as measured by SEC. In contrast, the extent of aggregation was weakly correlated with FTIR band intensity and peak position measured at t = 0. The results support the use of ssHDX-MS as a formulation screening tool in developing lyophilized protein drug products. PMID- 24816135 TI - Are racemic crystals favored over homochiral crystals by higher stability or by kinetics? Insights from comparative studies of crystalline stereoisomers. AB - The crystal and molecular structures of 134 pairs of diastereoisomers and of 279 racemic-homochiral pairs were retrieved from the Cambridge Structural Database. Lattice and intramolecular energies are calculated. Density differences between crystals of stereoisomers of all kind are mostly within 5%, as observed also for crystal polymorphs. Racemic crystals are predominantly, but not exclusively, more stable and more dense. Denser crystals are predominantly more stable, but there is no quantitative correlation between density and energy differences between partners in the chosen pairs. Second-order symmetry operators are neither ubiquitous in the racemic nor patently superior to first-order operators in promoting crystal cohesion. Thermodynamic, energetic factors in the final crystalline products are not enough to explain the (largely) predominant occurrence of racemic crystallization from racemic solution. At least for homogeneous nucleation, a probabilistic factor, from kinetics or from statistical predominance of mixed versus enantiopure aggregates, must be in action during the early separation of liquid-like particles, which are thought to be the precursors of crystal nucleation. PMID- 24816136 TI - Physicians' perceptions of the value of prognostic models: the benefits and risks of prognostic confidence. AB - BACKGROUND: The communication of prognosis in end-of-life (EOL) care is a challenging task that is limited by prognostic uncertainty and physicians' lack of confidence in their prognostic estimates. Clinical prediction models (CPMs) are increasingly common evidence-based tools that may mitigate these problems and facilitate the communication and use of prognostic information in EOL care; however, little is known about physicians' perceptions of the value of these tools. OBJECTIVE: To explore physicians' perceptions of the value of CPMs in EOL care. DESIGN: Qualitative study using semi-structured individual interviews which were analysed using a constant comparative method. SETTING AND PARTICIPANTS: Convenience sample of 17 attending physicians representing five different medical specialties at a single large tertiary care medical centre. RESULTS: Physicians perceived CPMs as having three main benefits in EOL care: (i) enhancing their prognostic confidence; (ii) increasing their prognostic authority; and (iii) enabling patient persuasion in circumstances of low prognostic and therapeutic uncertainty. However, physicians also perceived CPMs as having potential risks, which include producing emotional distress in patients and promoting prognostic overconfidence in EOL care. DISCUSSION AND CONCLUSIONS: Physicians perceive CPMs as a potentially valuable means of increasing their prognostic confidence, communication and explicit use of prognostic information in EOL care. However, physicians' perceptions of CPMs also indicate a need to establish broad and consistent implementation processes to engage patients in shared decision making in EOL care, to effectively communicate uncertainty in prognostic information and to help both patients and physicians manage uncertainty in EOL care decisions. PMID- 24816137 TI - The effect of pre-warming on performance during simulated firefighting exercise. AB - This study examined the effect of active pre-warming on speed and quality of performance during simulated firefighting exercise. Twelve male firefighters performed two trials in counterbalanced order. They were either pre-warmed by 20 min cycling at 1.5 Watt kg(-)(1) body mass (WARM) or remained thermoneutral (CON) prior to a simulated firefighting activity. After the pre-warming, gastrointestinal temperature (P < 0.001), skin temperature (P = 0.002), and heart rate (P < 0.001) were higher in WARM than in CON. During the firefighting activity, rating of perceived exertion, thermal sensation and discomfort were higher for WARM than for CON. Finish time of the firefighting activity was similar, but the last task of the activity was completed slower in WARM than in CON (P = 0.04). In WARM, self-reported performance quality was lower than in CON (P = 0.04). It is concluded that pre-warming reduces the speed during the last part of simulated firefighting activity and reduces self-reported quality of performance. PMID- 24816138 TI - Patterns without patches: hierarchical self-assembly of complex structures from simple building blocks. AB - Nanoparticles with "sticky patches" have long been proposed as building blocks for the self-assembly of complex structures. The synthetic realizability of such patchy particles, however, greatly lags behind predictions of patterns they could form. Using computer simulations, we show that structures of the same genre can be obtained from a solution of simple isotropic spheres, with control only over their sizes and a small number of binding affinities. In a first step, finite clusters of well-defined structure and composition emerge from natural dynamics with high yield. In effect a kind of patchy particle, these clusters can further assemble into a variety of complex superstructures, including filamentous networks, ordered sheets, and highly porous crystals. PMID- 24816139 TI - Genetic trends of conformation traits and genetic correlations to osteochondrosis in boars. AB - The objective of our study was to investigate the heritabilities and genetic correlations between traits from a linear exterior assessment system and osteochondrosis (OC) measured by computed tomography (CT), and in addition, to study the genetic trend in a population where the conformation traits have been included in the breeding goal. The data material consisted of phenotypes from a total of 4571 Norsvin Landrace test boars. At the end of the test period, all boars were subjected to a detailed exterior assessment system. Within 10 days of the assessment, the boars were CT scanned for measuring OC. The total score of osteochondrosis (OCT), used in this study, is the sum of phenotypes from the assessment on the medial and lateral condyles at the distal end of both the humerus and the femur of the right and the left leg of the boar based on images from CT. The exterior assessment traits included in the study were; 'front leg knee' (FKNE), 'front leg pasterns' (FPAS), 'front leg stance' (FSTA), 'front leg twisted pasterns' (FFLK), 'hind leg stance', 'hind leg pasterns' (HPAS), 'hind leg standing under' (HSTU), 'hind leg small inner toe', 'dipped back', 'arched back' (ARCH) and 'waddling hindquarters' (WADL). The estimation of (co)variance components and breeding values were performed using bivariate animal genetic models. Breeding values for HSTU, HPAS, FPAS, WADL and OCT traits were additional outputs from the same bivariate analyses. The lowest heritability was found for FFLK (h 2 FFLK=0.05), whereas FPAS was estimated to have the highest heritability (h 2 FPAS=0.36), and OCT demonstrating a heritability of 0.29. Significant genetic correlations were found between several traits; the strongest correlation was between FSTA and FFLK (0.94), which was followed by the correlation between FPAS and FKNE (0.69). The traits ARCH and FSTA had significant genetic correlations to OCT, whereas all other genetic correlations between OCT and the conformation traits were low and not significantly different from 0. Our study shows positive genetic trends for the conformation traits included in the breeding goal. In general, low genetic correlations between conformation traits and OC were observed in our study. PMID- 24816140 TI - Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. AB - Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging-related neurodegenerative diseases, such as Parkinson's disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, we studied LC neurons using electrophysiological and optical approaches in ex vivo mouse brain slices. We found that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca(2+) concentration that were attributable to the opening of L-type Ca(2+) channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide increased the spike rate but differentially affected mitochondrial oxidant stress. Oxidant stress was also increased in an animal model of PD. Thus, our results point to activity-dependent Ca(2+) entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons. PMID- 24816141 TI - Induction of self awareness in dreams through frontal low current stimulation of gamma activity. AB - Recent findings link fronto-temporal gamma electroencephalographic (EEG) activity to conscious awareness in dreams, but a causal relationship has not yet been established. We found that current stimulation in the lower gamma band during REM sleep influences ongoing brain activity and induces self-reflective awareness in dreams. Other stimulation frequencies were not effective, suggesting that higher order consciousness is indeed related to synchronous oscillations around 25 and 40 Hz. PMID- 24816142 TI - Embolisation of perimembranous ventricular septal defect occluder and transcatheter retrieval. AB - AIMS: In this study, we aim to summarise our experience with techniques used for the transcatheter retrieval of embolised devices. METHODS: We retrospectively reviewed the transcatheter retrieval of embolised devices in seven patients who underwent an attempted transcatheter closure of perimembranous ventricular septal defects (PMVSDs) between October 2002 and October 2013. The incidence, the main causes for the device's embolisation, and the techniques for transcatheter retrieval of the embolised device are discussed. RESULTS: The incidence of device embolisation in our centre was 0.82% (seven embolisations in 852 device placements). The main causes for device embolisation included undersized devices and inadequate subaortic rims. Among the seven embolisations, six of the devices were retrieved percutaneously without mortality, while one was retrieved during surgery. Of these patients, five had a HeartR(TM) Membranous VSD occluder of their PMVSDs, and the remaining two had surgical PMVSD closures. CONCLUSIONS: Our approach to the transcatheter retrieval of the embolised devices is associated with good results. PMID- 24816143 TI - The effects of respiratory muscle training on respiratory mechanics and energy cost. AB - Resistance respiratory muscle training (RRMT) increases respiratory muscle strength and can increase swimming endurance time by as much as 85%. The purpose of this study was to examine potential mechanisms by which RRMT improves exercise endurance. Eight healthy adult male scuba divers underwent experiments in a hyperbaric chamber at sea level (1 atmosphere absolute (ATA)), 2.7 ATA and 4.6 ATA, both dry and fully submersed. Subjects rested, exercised, and rested while mimicking their own exercise breathing (ISEV). Airway resistance (R(aw)), exhaled nitric oxide output (V(NO)), and respiratory duty cycle (T(I)/T(Tot)) were determined before and after four weeks of RRMT. RRMT decreased T(I)/T(Tot) (-10% at rest at 1 ATA), V(O2) (-17% at 2.7 ATA during submersed exercise), V(E) (-6% at 2.7 ATA during submersed exercise), and R(aw) (-34% inspiratory at 4.6 ATA submersed, -38% expiratory at 2.7 ATA dry), independent of changes in V(NO). Most importantly, respiratory muscle efficiency increased (+83% at 2.7 ATA submersed). PMID- 24816144 TI - Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study. AB - BACKGROUND: Growth hormone deficiency (GHD) in adulthood may be associated with a decreased bone mineral density (BMD), a decreased bone mineral content (BMC) and an increased fracture risk. Recombinant human GH (rhGH) replacement induces a progressive increase in BMD for up to 5-7 years of treatment. Data on longer follow-up are, however, scarce. METHODS: Two hundred and thirty-adult GHD patients (mean age 47.1 years, 52.6% female), of whom 88% patients had adult onset (AO) GHD, receiving rhGH replacement for >=5 years were included in the study. Most patients had multiple pituitary hormone deficiencies. Bone turnover markers, BMC and BMD and T-scores at the lumbar spine and femoral neck were evaluated at baseline, and after 5, 10 and 15 years of rhGH replacement. In addition, clinical fracture incidence was assessed. RESULTS: Mean lumbar spine BMD, lumbar spine BMC and T-scores gradually increased during the first 10 years of rhGH replacement and remained stable thereafter. Largest effects of rhGH supplementation were found in men. In the small subset of patients using bisphosphonates, use of bisphosphonates did not impact additional beneficial effects in the long term. Low baseline BMD positively affected the change in BMD and BMC over time, but there was a negative effect of high GH dose at 1 year on the change in BMD and BMC over time. Clinical fracture incidence during long-term rhGH replacement was 20.1/1000 py. CONCLUSIONS: Fifteen years of rhGH replacement in GHD adults resulted in a sustained increase in BMD values at the lumbar spine, particularly in men, and stabilization of BMD values at the femoral neck. Clinical fracture incidence was suggested not to be increased during long-term rhGH replacement. PMID- 24816145 TI - A COFRADIC protocol to study protein ubiquitination. AB - Here, we apply the COmbined FRActional DIagonal Chromatography (COFRADIC) technology to enrich for ubiquitinated peptides and to identify sites of ubiquitination by mass spectrometry. Our technology bypasses the need to overexpress tagged variants of ubiquitin and the use of sequence-biased antibodies recognizing ubiquitin remnants. In brief, all protein primary amino groups are blocked by chemical acetylation, after which ubiquitin chains are proteolytically and specifically removed by the catalytic core domain of the USP2 deubiquitinase (USP2cc). Because USP2cc cleaves the isopeptidyl bond between the ubiquitin C-terminus and the epsilon-amino group of the ubiquitinated lysine, this enzyme reintroduces primary epsilon-amino groups in proteins. These amino groups are then chemically modified with a handle that allows specific isolation of ubiquitinated peptides during subsequent COFRADIC chromatographic runs. This method led to the identification of over 7500 endogenous ubiquitination sites in more than 3300 different proteins in a native human Jurkat cell lysate. PMID- 24816146 TI - Confocal laser endomicroscopy guided endoscopic myotomy. PMID- 24816147 TI - Alcohol and dilution water characteristics in distilled anis (ouzo). AB - The authenticity of some mixed drinks such as vodka or rum was correlated to the conductivity of the dilution water. Authentic drinks demonstrated low conductivity, suggesting the use of treated water, whereas fraud drinks were mixed with regular tap water. The objective of the present study was to test if this criterion is valid for distilled anis, also known as ouzo. Several Greek distilled anis samples, mostly ouzo samples, were tested for different parameters including conductivity, pH, and percentage of different alcohol constituents. Because ouzo in Greece is commonly produced by small enterprises, no correlation between conductivity and the size of the producer was possible. Neither was it possible to correlate the price or high consumption with conductivity and, thus, prior water treatment. Alcohol quality in terms of undesirable constituents, such as methanol content, was good and comparable among samples. In ouzo, water is related to the producer quality goal for the final product and, thus, it is treated and used accordingly. PMID- 24816149 TI - Microgel-modified surfaces enhance short-term osteoblast response. AB - Modulations of surface structure or chemistry over various length scales are able to control the interactions of cells with biomaterials surfaces. This effect has been extensively studied using a number of top-down lithographic patterning processes. We create a modulated surface using a simple, bottom-up, self-assembly method involving the electrostatic deposition of microgels onto surfaces. We copolymerize acrylic acid (AA) with poly(ethylene glycol) (PEG) by suspension polymerization to form negatively charged, submicron-sized PEG-AA microgels and electrostatically deposit these onto cationic poly-l-lysine (PLL) primed substrates. The PEG-AA microgels resist fibronectin adsorption while the exposed PLL between adjacent microgels adsorbs fibronectin, thus producing a disordered array of submicron sized non-adhesive features separated from each other by microscale distances on an otherwise cell-adhesive surface. Relative to continuously adhesive surfaces, microgel-modulated adhesiveness increases both short-term cell spreading and cell proliferation (MTS) while maintaining the same differentiation behavior (ALP). Scanning electron microscopy indicates that osteoblasts grow over the microgels while adhering to the exposed adhesive surface between the microgels. Time-resolved optical microscopy shows that microgel-modified surfaces induce higher cell motility than the unmodified controls. These findings are consistent with the idea that cell-surface interactions are regulated by the spatial distribution of cell-adhesive sites on a surface, and they furthermore suggest a simple method by which to influence cellular processes associated with healing after the implantation of a tissue contacting biomedical device. PMID- 24816148 TI - Establishment and genetic characterization of six unique tumor cell lines as preclinical models for sinonasal squamous cell carcinoma. AB - Sinonasal squamous cell carcinomas (SCC) are rare tumors, etiologically related to occupational exposure to wood and leather dust. In spite of surgical and radiotherapeutic advances, the 5 year survival is still 30-50%. Therefore, alternative treatment options are needed. We report the establishment and characterization of six unique human sinonasal SCC cell lines, named SCCNC1, 2, 4, 5, 6 and 7. In vitro growth and invasion characteristics were evaluated and genetic profiles were compared to those of the original primary tumors. The population doubling times ranged from 21 to 34 hours. Cell lines SCCNC2 and 7 were highly invasive in matrigel. Five cell lines carried a high number of copy number alterations, including amplifications and homozygous deletions, while one showed only three abnormalities. Sequence analysis revealed three cell lines with TP53 mutation and none with KRAS or BRAF. Overexpression of p53 was observed in five, and of EGFR in four cell lines. None of the cell lines showed strong immunopositivity of p16 or presence of human papilloma virus. In conclusion, we have created six new cell lines that are clinically and genetically representative of sinonasal SCC and that will be a useful tool for the preclinical testing of new therapeutic agents. PMID- 24816150 TI - Resveratrol-loaded nanocarriers: formulation, optimization, characterization and in vitro toxicity on cochlear cells. AB - The present work aimed to investigate the suitability of polymeric nanoparticles (NPs) loaded with resveratrol (RES) for drug delivery to cochlear cells. RES loaded NPs were prepared by a solvent-diffusion method without surfactant. The Box-Behnken design was used to study the effect of the formulation variables on the particle mean diameter (PMD), polydispersity index (PDI), zeta-potential (zeta), percent drug encapsulation efficiency (EE%), and ratio between NP size before and after freeze-drying (Sf/Si). The physicochemical stability of the RES loaded NPs during freeze-drying was investigated using four well-known cryoprotectants (i.e., lactose, mannitol, sucrose, and trehalose) at different concentrations. The RES-loaded NPs were also characterized by powder X-ray diffraction (PXRD) and in vitro drug release studies. Finally, the in vitro toxicity of the synthesized NPs was evaluated on two cochlear cell lines: HEI-OC1 and SVK-1 cells. The optimal formulation (desirability: 0.86) had 135.5+/-37.3nm as PMD, 0.126+/-0.080 as PDI, -26.84+/-3.31mV as zeta, 99.83+/-17.59% as EE%, and 3.30+/-0.92 as Sf/Si ratio. The PMD and PDI of the RES-loaded NPs were maintained within the model space only when trehalose was used at concentrations higher than 15% (w/v). Results from the in vitro cytotoxicity studies showed that blank NPs did not alter the viability of both cells lines, except for concentrations higher than 600MUg/mL. However, the cell viability was significantly decreased at high concentrations of native RES (>50MUM, p<0.05) in both cell lines. Overall, the results suggested that the RES-loaded polymeric NPs could be a suitable template for cochlea antioxidant delivery and otoproctection. PMID- 24816151 TI - Configuring retroreflective markings to enhance the night-time conspicuity of road workers. AB - This study investigated whether the night-time conspicuity of road workers can be enhanced by positioning retroreflective strips on the moveable joints in patterns that convey varying degrees of biological motion. Participants were 24 visually normal adults (12 young M=26.8 years; 12 older M=72.9 years). Visual acuity, contrast sensitivity and glare sensitivity were recorded for each participant. Experimenters acting as road workers walked in place on a closed road circuit within simulated road work sites, facing either the oncoming driver or the roadway (presenting sideways to the driver) and wearing one of four clothing conditions: (i) standard road worker vest; (ii) standard vest plus thigh-mounted retroreflective strips; (iii) standard vest plus retroreflective strips on ankles and knees; (iv) standard vest plus retroreflective strips positioned on the extremities in a configuration that conveyed biological motion ("biomotion"). As they drove along the closed road participants were instructed to press a button to indicate when they first recognized that a road worker was present. The results demonstrated that regardless of the direction of walking, road workers wearing biomotion clothing were recognized at significantly (p<0.05) longer distances (3*), relative to the standard vest alone. Response distances were significantly shorter for the older drivers. Contrast sensitivity was a better predictor of the ability to recognize road workers than was visual acuity or glare sensitivity. We conclude that adding retroreflective strips in the biomotion configuration can significantly improve road worker conspicuity regardless of the road worker's orientation and the age of the driver. PMID- 24816152 TI - Phase I study of olaratumab in Japanese patients with advanced solid tumors. AB - Olaratumab (IMC-3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet-derived growth factor receptor-alpha with high affinity and blocks ligand binding. This was a single-center, dose escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose-limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab-related treatment-emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab-related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab-related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 MUg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated. PMID- 24816153 TI - Medical evaluation before electroconvulsive therapy: A task for the internist. PMID- 24816155 TI - Predicting Posttraumatic Stress Symptoms Following Mild, Moderate, and Severe Traumatic Brain Injury: The Role of Posttraumatic Amnesia. AB - OBJECTIVE: To explore the relation between posttraumatic amnesia (PTA) and posttraumatic stress symptoms in traumatic brain injury. DESIGN: Single-site prospective cohort study. PARTICIPANTS: A total of 1114 individuals between the ages of 18 and 65 years with a traumatic brain injury seen on average 3 months following injury. Participants were divided into 4 groups according to their duration of PTA: less than 1 hour; 1 to 24 hours; 24 hours to 1 week; and more than 1 week. MAIN MEASURES: Glasgow Coma Scale, PTA, computed tomographic brain scan abnormalities, Impact of Event Scale, the 28-item General Health Questionnaire, and Rivermead Postconcussion Disorder Questionnaire. RESULTS: The duration of PTA less than 1 hour was associated with more avoidant (P < .01) and intrusive (P < .001) posttraumatic stress symptoms and more anxiety according to the General Health Questionnaire (P < .01) than other groups. Regression analysis identified PTA and 3 concussive symptoms (light sensitivity, noise intolerance, and difficulties concentrating) as independent predictors of intrusive posttraumatic stress symptoms. CONCLUSION: Our data, representative of the full range of traumatic brain injury severity, indicate that a brief duration of PTA is a significant risk factor for the development of posttraumatic stress disorder symptoms. The persistence of certain symptoms of postconcussion disorder adds to the risk by possibly acting as a trigger for reminders of the traumatic event. PMID- 24816154 TI - Dual-transmitter neurons: functional implications of co-release and co transmission. AB - Co-transmission, the ability of a neuron to release multiple transmitters, has long been recognized in selected circuits. However, the release of multiple primary neurotransmitters from a single neuron is only beginning to be appreciated. Here we consider recent examples of co-transmission as well as co release-the packaging of multiple neurotransmitters into a single vesicle. The properties associated with each mode of release greatly enhance the possible action of such neurons within circuits. The functional importance of dual- (or multi-) transmitter neurons extends beyond actions on postsynaptic receptors, due in part to differential spatial and temporal profiles of each neurotransmitter. Recent evidence also suggests that the dual-transmitter phenotype can be dynamically regulated during development and following injury or disease. PMID- 24816156 TI - Stroke incidence following traumatic brain injury in older adults. AB - OBJECTIVE: Following traumatic brain injury (TBI), older adults are at an increased risk of hemorrhagic and thromboembolic events, but it is unclear whether the increased risk continues after hospital discharge. We estimated incidence rates of hemorrhagic and ischemic stroke following hospital discharge for TBI among adults 65 years or older and compared them with pre-TBI rates. PARTICIPANTS: A total of 16 936 Medicare beneficiaries 65 years or older with a diagnosis of TBI in any position on an inpatient claim between June 1, 2006, and December 31, 2009, who survived to hospital discharge. DESIGN: Retrospective analysis of a random 5% sample of Medicare claims data. MAIN MEASURES: Hemorrhagic stroke was defined as ICD-9 (International Classification of Diseases, Ninth Revision) codes 430.xx-432.xx. Ischemic stroke was defined as ICD 9 codes 433.xx-435.xx, 437.0x, and 437.1x. RESULTS: There was a 6-fold increase in the rate of hemorrhagic stroke following TBI compared with the pre-TBI period (adjusted rate ratio, 6.5; 95% confidence interval, 5.3-7.8), controlling for age and sex. A smaller increase in the rate of ischemic stroke was observed (adjusted rate ratio, 1.3; 95% CI, 1.2-1.4). CONCLUSION: Future studies should investigate causes of increased stroke risk post-TBI as well as effective treatment options to reduce stroke risk and improve outcomes post-TBI among older adults. PMID- 24816157 TI - Stability of employment over the first 3 years following traumatic brain injury. AB - OBJECTIVE: To examine the stability of employment between 1 and 3 years following traumatic brain injury (TBI) and to identify the variables associated with continued employment throughout this time span. PARTICIPANTS: This study included 236 individuals with predominantly moderate to very severe TBI, who had received rehabilitation in the context of a no-fault accident compensation system. Participants were eligible for the current study if they were employed before injury and reported their employment status at 1, 2, and 3 years following their injury as part of a longitudinal head injury outcome study. RESULTS: Only 44% of participants remained employed at each of the 3 years following TBI. There was also substantial transition into and out of employment across the 3 years. Significantly greater instability in employment was reported by individuals who were machinery operators or laborers before injury, had a longer duration of posttraumatic amnesia, reported more cognitive difficulties, and were less mobile 1 year following their injury. CONCLUSION: A number of important factors determine the likelihood of achieving stability in employment following TBI. Findings from the current study support the continued need to identify ways in which physical as well as cognitive changes contribute to employment following TBI. Further examination is needed to identify possible compensatory strategies or job modifications to maximize the likelihood of job retention. PMID- 24816158 TI - Effects of multiple congruent cues on concurrent sound segregation during passive and active listening: an event-related potential (ERP) study. AB - In two experiments, we assessed the effects of combining different cues of concurrent sound segregation on the object-related negativity (ORN) and the P400 event-related potential components. Participants were presented with sequences of complex tones, half of which contained some manipulation: one or two harmonic partials were mistuned, delayed, or presented from a different location than the rest. In separate conditions, one, two, or three of these manipulations were combined. Participants watched a silent movie (passive listening) or reported after each tone whether they perceived one or two concurrent sounds (active listening). ORN was found in almost all conditions except for location difference alone during passive listening. Combining several cues or manipulating more than one partial consistently led to sub-additive effects on the ORN amplitude. These results support the view that ORN reflects a combined, feature-unspecific assessment of the auditory system regarding the contribution of two sources to the incoming sound. PMID- 24816159 TI - Study of in vitro metabolism of m-nisoldipine in human liver microsomes and recombinant cytochrome P450 enzymes by liquid chromatography-mass spectrometry. AB - This is a report about the investigation of the metabolic fate of m-nisoldipine in human liver microsomes and the recombinant cytochrome P450 enzymes by using LC MS/MS. A sensitive and reliable LC-MS/MS method was developed to obtain a rapid and complete characterization of new metabolites and the metabolism pathways. The analytes were separated on a reversed phase C18 column with acetonitrile and 0.1% aqueous formic acid as the mobile phase. Tandem mass spectrometry with positive electrospray ionization was used to enable the structural characterization of the metabolites. A total of 10 metabolites were characterized with proposed structures in the incubation of human liver microsomes by comparing their retention times and spectral patterns with those of the parent drug. Dehydrogenation of the dihydropyridine core and reactions of side chains such as hydroxylation and hydrolysis of ester bonds were the major metabolic pathways. The specific cytochrome P450 (CYP) enzymes responsible for m-nisoldipine metabolites were identified using chemical inhibition and cDNA expressed CYP enzymes. The results indicated that CYP2C19 and CYP3A4 might play major roles in the metabolism of m-nisoldipine in human liver microsomes. PMID- 24816160 TI - Chromatographic and electrophoretic assessment of Filgrastim biosimilars in pharmaceutical formulations. AB - An orthogonal testing protocol was developed and validated to assess the quality of Filgrastim biosimilars. Results were compared to those obtained from the innovator product. Initial screening was carried out using reducing and non reducing gel electrophoresis. RP-LC was employed for the determination of Filgrastim in the presence of its oxidative degradation products. SEC and CIEF were used under non-denaturing conditions to reveal high molecular weight and charged impurities, respectively. RP-LC assay was found accurate (99.78+/-0.89) and precise over a linear concentration range of 9.38-300.00MUg/ml with a LOD of 8.26MUg/ml (0.44mM). SEC was carried out over a molecular weight range of 5.0 150.0kDa. CIEF was optimized using neutrally coated capillaries over a wide-range pH gradient (pH 3.0-10.0). Differences between the studied products were revealed using all these techniques. Impurities above the acceptable limits were detected in both biosimilar products. CIEF revealed heterogeneity in the active ingredient that has not been investigated by the manufacturers. Correlation of the obtained results indicated the presence of not only product-related impurities, but also process-related impurities. Results confirmed the need for in-house validated orthogonal testing protocols to be developed by local regulatory authorities. This should prevent access of substandard biosimilars to price-sensitive markets. PMID- 24816161 TI - Differential regulation of pancreatic digestive enzymes during chronic high-fat diet-induced obesity in C57BL/6J mice. AB - Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The aim of the present study was to investigate the effects of chronic HF diet feeding on exocrine pancreatic digestive enzyme transcript levels in DIO C57BL/6J mice. C57BL/6J mice were fed diets containing either 10 or 45% energy (E%) derived from fat for 12 weeks (n 10 mice per diet group). Pancreatic tissue and blood samples were collected at 0, 4 and 12 weeks. The expression of a panel of exocrine pancreatic digestive enzymes was analysed using quantitative RT-PCR and Western blot analysis. The HF (45 E%) diet-fed C57BL/6J mice developed obesity, hyperleptinaemia, hyperglycaemia and hyperinsulinaemia. The transcript levels of pancreatic lipase (PL), pancreatic lipase-related protein 2 (PLRP2) and pancreatic phospholipase A2 (PLA2) were initially elevated; however, they were down-regulated to basal control levels at week 12. The transcript levels of colipase were significantly affected by diet and time. The protein levels of PL and PLRP2 responded to HF diet feeding. The transcript levels of amylase and proteases were not significantly affected by diet and time. The transcript levels of specific lipases in hyperinsulinaemic, hyperleptinaemic and hyperglycaemic DIO C57BL/6J mice are down-regulated. However, these mice compensate for this by the post-transcriptional regulation of the levels of proteins that respond to dietary fat. This suggests a complex regulatory mechanism involved in the modulation of fat digestion. PMID- 24816163 TI - Personality dynamics in adolescence. PMID- 24816162 TI - Diacetyl induces amphiregulin shedding in pulmonary epithelial cells and in experimental bronchiolitis obliterans. AB - Diacetyl (DA), a component of artificial butter flavoring, has been linked to the development of bronchiolitis obliterans (BO), a disease of airway epithelial injury and airway fibrosis. The epidermal growth factor receptor ligand, amphiregulin (AREG), has been implicated in other types of epithelial injury and lung fibrosis. We investigated the effects of DA directly on the pulmonary epithelium, and we hypothesized that DA exposure would result in epithelial cell shedding of AREG. Consistent with this hypothesis, we demonstrate that DA increases AREG by the pulmonary epithelial cell line NCI-H292 and by multiple independent primary human airway epithelial donors grown under physiologically relevant conditions at the air-liquid interface. Furthermore, we demonstrate that AREG shedding occurs through a TNF-alpha-converting enzyme (TACE)-dependent mechanism via inhibition of TACE activity in epithelial cells using the small molecule inhibitor, TNF-alpha protease inhibitor-1, as well as TACE-specific small inhibitor RNA. Finally, we demonstrate supportive in vivo results showing increased AREG transcript and protein levels in the lungs of rodents with DA induced BO. In summary, our novel in vitro and in vivo observations suggest that further study of AREG is warranted in the pathogenesis of DA-induced BO. PMID- 24816164 TI - Improvements on neuromuscular performance with caffeine ingestion depend on the time-of-day. AB - OBJECTIVES: To determine whether the ergogenic effects of caffeine ingestion on neuromuscular performance are similar when ingestion takes place in the morning and in the afternoon. DESIGN: Double blind, cross-over, randomized, placebo controlled design. METHODS: Thirteen resistance-trained males carried out bench press and full squat exercises against four incremental loads (25%, 50%, 75% and 90% 1RM), at maximal velocity. Trials took place 60 min after ingesting either 6 mg kg(-1) of caffeine or placebo. Two trials took place in the morning (AMPLAC and AMCAFF) and two in the afternoon (PMPLAC and PMCAFF), all separated by 36-48 h. Tympanic temperature, plasma caffeine concentration and side-effects were measured. RESULTS: Plasma caffeine increased similarly during AMCAFF and PMCAFF. Tympanic temperature was lower in the mornings without caffeine effects (36.7+/ 0.4 vs. 37.0+/-0.5 degrees C for AM vs. PM; p<0.05). AMCAFF increased propulsive velocity above AMPLAC to levels similar to those found in the PM trials for the 25%, 50%, 75% 1RM loads in the SQ exercise (5.4-8.1%; p<0.05). However, in the PM trials, caffeine ingestion did not improve propulsive velocity at any load during BP or SQ. The negative side effects of caffeine were more prevalent in the afternoon trials (13 vs. 26%). CONCLUSIONS: The ingestion of a moderate dose of caffeine counteracts the muscle contraction velocity declines observed in the morning against a wide range of loads. Caffeine effects are more evident in the lower body musculature. Evening caffeine ingestion not only has little effect on neuromuscular performance, but increases the rate of negative side-effects reported. PMID- 24816165 TI - The independent association between diet quality and body composition. AB - Excess body weight is associated with an imbalance between energy expenditure and dietary intake but evidence on the association between diet quality and body composition remains equivocal. Rather than relying on differences in diet quality between overweight/obese and normal weight adults, this study examined the association between the Healthy Eating Index 2010 (HEI-2010) and body fatness on a continuous scale, independent of physical activity (PA). Further the association between components of the HEI-2010 and risk for overweight/obesity was explored. 407 adults (27.6 +/- 3.7 years) provided at least two 24-hour diet recalls over a period of 14 days, which were used to calculate the HEI-2010. Percent body fat (BF) was assessed via dual X-ray absorptiometry and PA was determined via a multi-sensor device, worn over a period of 10 days. PA was a stronger contributor to the variability in BF than the HEI-2010 and the association between HEI-2010 and BF was significant only in men. Particularly a high consumption of protein, sodium and empty calories increased the risk for overweight/obesity. Adherence to dietary guidelines positively affects body fatness in men, independent of PA. In contrast to current dietary recommendations, the risk for overweight/obesity was increased with a higher protein intake. PMID- 24816166 TI - The cocaine- and amphetamine-regulated transcript, calbindin, calretinin and parvalbumin immunoreactivity in the medial geniculate body of the guinea pig. AB - The purpose of this study was to describe the distribution and colocalization of cocaine- and amphetamine-regulated transcript (CART) and three calcium-binding proteins (calbindin, calretinin and parvalbumin) in each main division of the medial geniculate body (MGB) in the guinea pig. From low to moderate CART immunoreactivity was observed in all divisions of the MGB, although in most of its length only fibers and neuropil were labeled. A small number of CART immunoreactive somata were observed in the caudal segment of the MGB. The central parts of all divisions contained a distinctly smaller number of CART immunoreactive fibers relative to their outer borders, where CART fibers formed patchy clusters. As a whole, the intense CART immunoreactive borders formed a shell around the weakly CART labeled core. Double-labeling immunofluorescence showed that CART did not colocalize with either calbindin, calretinin or parvalbumin, whose immunoreactivity was predominantly restricted to perikarya. The distribution pattern of calretinin was more similar to that of calbindin than to that of parvalbumin. Calretinin and calbindin exhibited higher immunoreactivity in the medial and dorsal divisions of the MGB, where parvalbumin staining was low. In general, although parvalbumin exhibited the weakest immunoreactivity of all studied Ca(2+) binding proteins, it was most highly expressed in the ventral division of the MGB. Our results indicate that CART could be involved in hearing, although its immunoreactivity in the medial geniculate complex was not as intense as in other sensory brain regions. In the guinea pig the heterogeneous and complementary pattern of calbindin, calretinin and parvalbumin is evident, however, the overlap in staining appears to be more extensive than that seen in other rodents. PMID- 24816167 TI - Intracellular guest exchange between dynamic supramolecular hosts. AB - Decyl and oligo(ethylene glycol) chains were appended to the same poly(methacrylate) backbone to generate an amphiphilic polymer with a ratio between hydrophobic and hydrophilic segments of 2.5. At concentrations greater than 10 MUg mL(-1) in neutral buffer, multiple copies of this particular macromolecule assemble into nanoparticles with a hydrodynamic diameter of 15 nm. In the process of assembling, these nanoparticles can capture anthracene donors and borondipyrromethene acceptors within their hydrophobic interior and permit the transfer of excitation energy with an efficiency of 95%. Energy transfer is observed also if nanocarriers containing exclusively the donors are mixed with nanoparticles preloaded separately with the acceptors in aqueous media. The two sets of supramolecular assemblies exchange their guests with fast kinetics upon mixing to co-localize complementary chromophores within the same nanostructured container and enable energy transfer. After guest exchange, the nanoparticles can cross the membrane of cervical cancer cells and bring the co-entrapped donors and acceptors within the intracellular environment. Alternatively, intracellular energy transfer is also established after sequential cell incubation with nanoparticles containing the donors first and then with nanocarriers preloaded with the acceptors or vice versa. Under these conditions, the nanoparticles exchange their cargo only after internalization and allow energy transfer exclusively within the cell interior. Thus, the dynamic character of such supramolecular containers offers the opportunity to transport independently complementary species inside cells and permit their interaction only within the intracellular space. PMID- 24816168 TI - High prevalence of erythromycin-resistant Bordetella pertussis in Xi'an, China. AB - Resistance of Bordetella pertussis, the causative agent of pertussis, to erythromycin is rare. Recently, several Chinese isolates were found to be erythromycin resistant. This study aimed to investigate the occurrence of pertussis in children suffering persistent cough and the prevalence of B. pertussis resistance to erythromycin in Xi'an, China. Three hundred and thirteen patients with suspected pertussis admitted to Xi'an Children's Hospital from January 2012 through to December 2013 were included and their nasopharyngeal (NP) swabs were taken for culture and PCRs (targeting IS481 and ptx-Pr). PCR-based sequencing was used to identify the A2047G mutation of B. pertussis 23S rRNA directly from the NP samples. Sixteen (5.1%) and 168 (53.7%) patients were positive for culture and IS481 PCR. Of the 168 samples positive for IS481 PCR, 122 (72.6%) and 100 (59.5%) were positive for ptx-Pr and 23S rRNA PCRs, respectively. All culture-positive samples were also positive for the three PCRs. Fourteen (87.5%) of the 16 B. pertussis isolates were found to be resistant to erythromycin (MICs>256 mg/L). All the 14 isolates were confirmed to have a homogeneous A2047G mutation of 23S rRNA. Of the 100 samples positive for 23S rRNA PCR, 85 (85.0%) were found to have the A2047G mutation by sequencing. Our results indicate that in Xi'an, China, pertussis remains endemic in young children, and the circulating B. pertussis strains are mostly erythromycin resistant. PMID- 24816169 TI - 'Direct PCR' optimization yields a rapid, cost-effective, nondestructive and efficient method for obtaining DNA barcodes without DNA extraction. AB - Macroinvertebrates that are collected in large numbers pose major problems in basic and applied biodiversity research: identification to species via morphology is often difficult, slow and/or expensive. DNA barcodes are an attractive alternative or complementary source of information. Unfortunately, obtaining DNA barcodes from specimens requires many steps and thus time and money. Here, we promote a short cut to DNA barcoding, that is, a nondestructive PCR method that skips DNA extraction ('direct PCR') and that can be used for a broad range of invertebrate taxa. We demonstrate how direct PCR can be optimized for the larvae and adults of nonbiting midges (Diptera: Chironomidae), a typical invertebrate group that is abundant, contains important bioindicator species, but is difficult to identify based on morphological features. After optimization, direct PCR yields high PCR success rates (>90%), preserves delicate morphological features (e.g. details of genitalia, and larval head capsules) while allowing for the recovery of genomic DNA. We also document that direct PCR can be successfully optimized for a wide range of other invertebrate taxa that need routine barcoding (flies: Culicidae, Drosophilidae, Dolichopodidae, Sepsidae; sea stars: Oreasteridae). Key for obtaining high PCR success rates is optimizing (i) tissue quantity, (ii) body part, (iii) primer pair and (iv) type of Taq polymerase. Unfortunately, not all invertebrates appear suitable because direct PCR has low success rates for other taxa that were tested (e.g. Coleoptera: Dytiscidae, Copepoda, Hymenoptera: Formicidae and Odonata). It appears that the technique is less successful for heavily sclerotized insects and/or those with many exocrine glands. PMID- 24816170 TI - Iterative breakthrough invasive aspergillosis due to TR(34) /L98H azole-resistant Aspergillus fumigatus and Emericella sublata in a single hematopoietic stem cell transplant patient. AB - We report 3 consecutive episodes of invasive aspergillosis in a single hematopoietic stem cell transplant patient successively attributed to TR(34) /L98H azole-resistant Aspergillus fumigatus and to a first occurrence of invasive Emericella sublata infection. This case illustrates potential selection of resistant molds during antifungal therapy in hematological patient. PMID- 24816171 TI - Dengue virus-infected human dendritic cells reveal hierarchies of naturally expressed novel NS3 CD8 T cell epitopes. AB - Detailed knowledge of dengue virus (DENV) cell-mediated immunity is limited. In this study we characterize CD8(+) T lymphocytes recognizing three novel and two known non-structural protein 3 peptide epitopes in DENV-infected dendritic cells. Three epitopes displayed high conservation (75-100%), compared to the others (0 50%). A hierarchy ranking based on magnitude and polyfunctionality of the antigen specific response showed that dominant epitopes were both highly conserved and cross-reactive against multiple DENV serotypes. These results are relevant to DENV pathogenesis and vaccine design. PMID- 24816172 TI - BOLD-MRI to explore the oxygenation of fetal organs and of the placenta. PMID- 24816173 TI - Daclatasvir plus sofosbuvir for HCV infection: an oral combination therapy with high antiviral efficacy. PMID- 24816174 TI - Hepcidin knockout mice fed with iron-rich diet develop chronic liver injury and liver fibrosis due to lysosomal iron overload. AB - BACKGROUND & AIMS: Hepcidin is the central regulator of iron homeostasis and altered hepcidin signalling results in both hereditary and acquired iron overload. While the association between iron overload and development of end stage liver disease is well established, the underlying mechanisms are largely unknown. To improve that, we analysed hepcidin knockout (KO) mice as a model of iron overload-associated liver disease. METHODS: Hepcidin wild type (WT) and KO mice fed with 3% carbonyl iron-containing diet starting at one month of age were compared to age-matched animals kept on standard chow. Liver histology and serum parameters were used to assess the extent of liver injury and fibrosis. Iron distribution was determined by subcellular fractionation and electron microscopy. RESULTS: Among mice kept on iron-rich diet, 6 months old hepcidin KO mice (vs. WT) displayed profound hepatic iron overload (3,186 +/- 411 vs. 1,045 +/- 159 MUg/mg tissue, p<0.005), elevated liver enzymes (ALT: KO 128 +/- 6, WT 56 +/- 5 IU/L, p<0.05), mild hepatic inflammation and hepatocellular apoptosis. Twelve, but not six months old KO mice fed with iron-rich diet developed moderate liver fibrosis. The liver injury was accompanied by a marked lysosomal iron overload and lysosomal fragility with release of cathepsin B into the cytoplasm. Increased p62 levels and autofluorescent iron complexes suggested impaired protein degradation. As a mechanism leading to lysosomal iron overload, the autophagy (lysosomal influx) was increased. CONCLUSIONS: Hepcidin KO mice represent a novel model of iron overload-related liver diseases and implicate lysosomal injury as a crucial event in iron toxicity. PMID- 24816175 TI - Determination of (210)Pb and (210)Po in water using the extractive scintillation cocktail PolexTM. AB - Method validation was performed to achieve the accreditation for our determination method of (210)Pb and (210)Po in water. A Pb(NO3)2 carrier is added to the sample and lead is precipitated with Na2SxH2O. (210)Po is co-precipitated and the extractive scintillation cocktail Polex(TM) is used to determine (210)Po and (210)Pb. Uranium is also extracted by Polex(TM). It can be removed by washing the precipitate with 1% HNO3. The ingrowth of (210)Pb from (222)Rn during transportation time must be calculated. It has to be subtracted from the original (210)Pb in the sample and taken into account for the calculation of the lower limit of detection. PMID- 24816176 TI - Tetrachlorobenzoquinone induces acute liver injury, up-regulates HO-1 and NQO1 expression in mice model: the protective role of chlorogenic acid. AB - Tetrachlorobenzoquinone (TCBQ) is an active metabolite of pentachlorophenol (PCP). Although PCP has been investigated extensively, there are only a few reports describing the toxicity effect of TCBQ, and no report regarding TCBQ induced liver injury in vivo. In the current study, we aimed to examine the acute hepatic toxicity of TCBQ in the mice model. Chlorogenic acid (CGA) exhibits promising antioxidant activity in the past studies, thus, the second aim of this study was to evaluate the protective effect of CGA on TCBQ-induced liver injury. Our results indicated TCBQ-intoxication caused marked liver cell necrosis and inflammation but not apoptosis, and this damage was alleviated by CGA treatment. Meantime, TCBQ-intoxication enhanced serum ALT, AST activities, TBIL content, hepatic oxidative stress and lipid peroxidation, decreased GSH content and inhibited the activities of antioxidant enzymes. Western blot and immunohistochemical analysis showed that TCBQ marked up-regulated HO-1 and NQO1 expression. On the other hand, pretreatment of CGA reduced TCBQ-induced liver damage remarkably. Taking together, these results revealed that TCBQ has strong hepatic toxic effect, and at least a part of this effect is initiated by free radical and relieved with CGA administration. PMID- 24816178 TI - Theoretical study of the water oxidation mechanism with non-heme Fe(Pytacn) iron complexes. Evidence that the Fe(IV)(O)(Pytacn) species cannot react with the water molecule to form the O-O bond. AB - Recent studies have shown that non-heme iron complexes [Fe(L(N4))X2], where L(N4) stands for a tetradentate nitrogen based aminopyridine ligand (L(N4) = Pytacn, mcp or mep, Pytacn = 1-(2-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane, mcp = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)cyclohexane-trans-1,2-diamine, mep = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)ethylendiamine), and X are monodentate ligands (X = Cl, CH3CN, CF3SO3(-), or H2O), catalyze the oxidation of water using cerium(IV) ammonium nitrate (CAN) as oxidant. Spectroscopic monitoring of catalytic water oxidation with [Fe(CF3SO3)2(Pytacn)] established [Fe(IV)(O)(OH2)(Pytacn)](2+) as an intermediate along the catalytic pathway, raising the question if these high valent species could be directly responsible for the O-O bond formation event. Herein, this question is addressed by a computational analysis of the thermodynamic and kinetic parameters associated with the reaction of non-heme iron complexes [Fe(IV)(O)(OH)(Pytacn)](+), [Fe(IV)(O)(OH2)(Pytacn)](2+), and [Fe(IV)(OH)(OH)(Pytacn)](2+) with water. Two different mechanisms have been studied for [Fe(IV)(O)(OH)(Pytacn)](+); the nucleophilic water attack assisted by the hydroxyl group as internal base, which is the lowest energy path, and the external nucleophilic water attack. For [Fe(IV)(OH)(OH)(Pytacn)](2+), only the attack assisted by the internal base has been studied, while in the case of [Fe(IV)(O)(OH2)(Pytacn)](2+), the only viable mechanism is the external nucleophilic water attack. Up to four water molecules were needed to be included in modeling of the O-O bond formation event for a proper description of the external nucleophilic water attack. The lowest Gibbs energy barrier and reaction free energy found for the direct water nucleophilic attack to the oxo ligand are of 32.2 and 28.3 kcal.mol(-1) for [Fe(IV)(O)(OH)(Pytacn)](+), 52.0 and 40.5 kcal.mol(-1) for [Fe(IV)(O)(OH2)(Pytacn)](2+), and 28.3 and 28.3 kcal.mol(-1) for [Fe(IV)(OH)(OH)(Pytacn)](2+), respectively. These energy barriers and endergonic reaction energies are too high for the reaction to proceed and inconsistent with the relatively rapid reaction rates determined experimentally (DeltaG(?)(exp.) = 17.6 kcal.mol(-1)). Therefore, this study provides strong evidence against the O O bond formation by these species. The energetic accessibilities of Fe(V)(O) and Fe(VI)(O) intermediates have also been investigated, showing that Fe(V) is the higher oxidation state accessible under catalytic conditions, consistent with our previous results. PMID- 24816177 TI - Effect of acetaminophen exposure in Oncorhynchus mykiss gills and liver: detoxification mechanisms, oxidative defence system and peroxidative damage. AB - The increasing presence of pharmaceutical drugs in nature is cause of concern due to the occurrence of oxidative stress in non-target species. Acetaminophen is widely used in human medicine as an analgesic and antipyretic drug, and it is one of the most sold non-prescription drugs. The present study aimed to assess the toxic effects of acetaminophen (APAP) in Oncorhynchus mykiss following acute and chronic exposures in realistic levels. In order to evaluate the APAP effects in the rainbow trout, gills and liver were analyzed with biochemical biomarkers, such as catalase (CAT), total and selenium-dependent glutathione peroxidase (GPx), glutathione reductase (GRed) and glutathione-S-transferases (GSTs) activity and also lipid peroxidation levels (TBARS). The results obtained in all tests indicate that a significant response of oxidative stress was established, along with the increase of APAP concentrations. The establishment of an oxidative stress scenario occurred with the involvement of all tested biomarkers, sustaining a generalized set of pro-oxidative effects elicited by APAP. Additionally, the occurrence of oxidative damage strongly suggests the impairment of the antioxidant defense mechanism of O. mykiss. It is important to note that the occurrence of oxidative deleterious effects and peroxidative damages occurred for concentrations similar to those already reported for several freshwater ecosystems. The importance of these assumptions is further discussed under the scope of ecological relevance of the assessment of effects caused by pharmaceuticals in non-target organisms. PMID- 24816179 TI - Echocardiography and cardiac MRI in mutation-negative hypertrophic cardiomyopathy in an older patient: a case defining the need for ICD. AB - We report the case of a 67-year-old man with hypertrophic cardiomyopathy who presented for a second opinion about implantable cardio-defibrillator (ICD) placement after a witnessed syncopal episode. Despite his older age, being mutation-negative, and having a maximal septal thickness of 2.2 cm on echocardiography, he demonstrated rapid progression of myocardial fibrosis on cardiac MRI, correlating to ventricular tachyarrhythmias and syncope. We review the role of echocardiography and cardiac MRI in optimizing medical care for such patients who may not otherwise meet criteria for an ICD placement or further interventions. PMID- 24816180 TI - Headache, hand clumsiness, and "involuntary serial sevens" in a young person. PMID- 24816181 TI - The benefits of diversity: heterogenous DC populations allow for both immunity and tolerance. AB - The immune system must simultaneously mount a response against foreign antigens while tolerating self. How this happens is still unclear as many mechanisms of immune tolerance are antigen non-specific. Antigen specific immune cells called T cells must first bind to Immunogenic Dendritic Cells (iDCs) before activating and proliferating. These iDCs present both self and foreign antigens during infection, so it is unclear how the immune response can be limited to primarily foreign reactive T-cells. Regulatory T-cells (Tregs) are known to play a key role in self-tolerance. Although they are antigen specific, they also act in an antigen non-specific manner by competing for space and growth factors as well as modifying DC behavior to help kill or deactivate other T-cells. In prior models, the lack of antigen specific control has made simultaneous foreign-immunity and self-tolerance extremely unlikely. We include a heterogeneous DC population, in which different DCs present antigens at different levels. In addition, we include Tolerogenic DC (tDCs) which can delete self-reactive T-cells under normal physiological conditions. We compare different mathematical models of immune tolerance with and without Tregs and heterogenous antigen presentation. For each model, we compute the final number of foreign-reactive and self-reactive T-cells, under a variety of different situations. We find that even if iDCs present more self-antigen than foreign antigen, the immune response will be primarily foreign reactive as long as there is sufficient presentation of self-antigen on tDCs. Tregs are required primarily for rare or cryptic self-antigens that do not appear frequently on tDCs. We also find that Tregs can only be effective when we include heterogenous antigen presentation, as this allows Tregs and T-cells of the same antigen-specificity to colocalize to the same set of DCs. Tregs better aid immune tolerance when they can both compete for space and growth factors and directly eliminate other T-cells. Our results show the importance of the structure of the DC population in immune tolerance as well as the relative contribution of different cellular mechanisms. PMID- 24816182 TI - Modeling the effects of covalently closed circular DNA and dendritic cells in chronic HBV infection. AB - The contribution of covalently closed circular DNA (cccDNA) and dendritic cells (DCs) to the progression of chronic hepatitis B virus (HBV) infection remains largely unknown. A dynamic model with seven cell types was proposed based on the biological mechanisms of viral replication and the host immune response. The cccDNA self-amplification rate was found to be closely related to both the basic reproduction number of the virus and the immune response. The combination of the cccDNA self-amplification rate and the initial activated DC count induces rich dynamics. Applying our model to the clinical data of untreated patients, we found that chronic patients have a high cccDNA self-amplification rate. For antiviral treatment, an overall drug effectiveness was introduced and the critical drug effectiveness was obtained. The model predicts that timely long-term therapy is needed to reduce the symptoms of HBV and to maintain the benefits of treatment. PMID- 24816183 TI - TuberQ: a Mycobacterium tuberculosis protein druggability database. AB - In 2012 an estimated 8.6 million people developed tuberculosis (TB) and 1.3 million died from the disease [including 320 000 deaths among human immunodeficiency virus (HIV)-positive people]. There is an urgent need for new anti-TB drugs owing to the following: the fact that current treatments have severe side effects, the increasing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the negative drug-drug interactions with certain HIV (or other disease) treatments and the ineffectiveness against dormant Mtb. In this context we present here the TuberQ database, a novel resource for all researchers working in the field of drug development in TB. The main feature of TuberQ is to provide a druggability analysis of Mtb proteins in a consistent and effective manner, contributing to a better selection of potential drug targets for screening campaigns and the analysis of targets for structure-based drug design projects. The structural druggability analysis is combined with features related to the characteristics of putative inhibitor binding pockets and with functional and biological data of proteins. The structural analysis is performed on all available unique Mtb structures and high-quality structural homology-based models. This information is shown in an interactive manner, depicting the protein structure, the pockets and the associated characteristics for each protein. TuberQ also provides information about gene essentiality information, as determined from whole cell-based knockout experiments, and expression information obtained from microarray experiments done in different stress-related conditions. We hope that TuberQ will be a powerful tool for researchers working in TB and eventually will lead to the identification of novel putative targets and progresses in therapeutic activities. Database URL: http://tuberq.proteinq.com.ar/ PMID- 24816184 TI - Concerns about identity and services among people with autism and Asperger's regarding DSM-5 changes. AB - The Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2012 ) now includes a new autism spectrum diagnosis (ASD) with previous separate diagnoses of autism removed. This study explores the concerns of people with Asperger's syndrome (AS) and autistic disorder (AD). Discussion forum data of people with AS and AD (N = 76) were analyzed using phenomenological, inductive-content analysis to gather qualitative data about the concerns of people with AS and AD regarding the changes in the DSM 5. People with AS and AD were concerned about identity, community, the cure movement, and services. They also discussed using advocacy and solidarity to address their concerns. PMID- 24816185 TI - Chromosomal location of blaCTX-M genes in clinical isolates of Escherichia coli from Germany, The Netherlands and the UK. AB - This study aimed to detect and characterise clinical Escherichia coli isolates suspected of carrying chromosomally encoded CTX-M enzymes. Escherichia coli (n=356) obtained in Germany, The Netherlands and the UK (2005-2009) and resistant to third-generation cephalosporins were analysed for the presence of ESBL-/AmpC encoding genes within the European SAFEFOODERA-ESBL project. beta-Lactamases and their association with IS26 and ISEcp1 were investigated by PCR. Isolates were typed by phylogenetic grouping, MLST and PFGE. Plasmids were visualised by S1 nuclease PFGE, and the location of blaCTX-M genes was determined by Southern hybridisation of XbaI-, S1- and I-CeuI-digested DNA. ESBL enzymes could not be located on plasmids in 17/356 isolates (4.8%). These 17 isolates, from different countries and years, were ascribed to phylogenetic groups D (9), B2 (6) and B1 (2), and to seven sequence types, with ST38 being the most frequent (7 phylogroup D isolates). Eleven isolates produced CTX-M-15. blaCTX-M-15 genes were associated with ISEcp1. The remaining isolates expressed the CTX-M group 9 beta-lactamases CTX-M-14 (4), CTX-M-9 (1) and CTX-M-51 (1). blaCTX-M probes hybridised with I CeuI- and/or XbaI-digested DNA, but not with S1-digested DNA, corroborating their chromosomal location. To summarise, only 4.8% of a large collection of ESBL producing E. coli isolates harboured chromosomal blaCTX-M genes. These isolates were of human origin and belonged predominantly to ST38 and ST131, which possibly indicates the role of these sequence types in this phenomenon. However, heterogeneity among isolates was found, suggesting that their spread is not only due to the dispersion of successful E. coli clones. PMID- 24816186 TI - The first clinical case of intermediate ex vivo normothermic perfusion in renal transplantation. AB - A short period of ex vivo normothermic perfusion (EVNP) immediately before transplantation can revive the kidney and reduce the effects of cold ischemic (CI) injury. Herein, we report a clinical case of EVNP carried out at an intermediate period of the preservation interval. The kidney was retrieved from a 63-year-old extended criteria donor. After 10 h 29 min of CI the kidney underwent EVNP with 1 unit of compatible packed red blood cells mixed with a priming solution at 35.0 degrees C while the recipient was being prepared for surgery. The mean renal blood flow was 93.6 mL/min/100 g and the kidney produced 60 mL of urine. Shortly after the start of surgery the first intended recipient became unfit for transplantation. After 60 min EVNP the kidney was flushed with cold preservation solution and re-packed in ice. The second period of CI was 5 h and 21 min. The kidney was transplanted without any complications into a 54-year-old predialysis patient. The recipient had immediate graft function with serum creatinine levels falling from 315 to 105 umol/L by day 7. This is the first report of an intermediate period of EVNP in clinical renal transplantation. This case demonstrates the feasibility and safety of the technique. PMID- 24816187 TI - Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. AB - Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non-MDR paclitaxel resistant ovarian cancer lines ES-2/TP, MES OV/TP and OVCAR-3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti-human CCL2 antibody CNTO 888 and the anti-mouse MCP-1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer. PMID- 24816188 TI - Caspase-8 mutations in head and neck cancer confer resistance to death receptor mediated apoptosis and enhance migration, invasion, and tumor growth. AB - Little is known regarding molecular markers in head and neck squamous cell carcinoma (HNSCC) that predict responsiveness to different therapeutic regimens or predict HNSCC progression. Mutations in procaspase-8 occur in 9% of HNSCC primary tumors, but the functional consequences of these mutations are poorly understood. In this study, we examined the impact of four, representative, HNSCC associated procaspase-8 mutations on activation of the extrinsic apoptosis pathway, as well as cellular migration and invasion, and in vivo tumor growth. All four mutant proteins acted to potently inhibit activation of apoptosis following treatment with TRAIL or agonistic anti-Fas. In contrast to wild-type procaspase-8, the mutant proteins were not recruited to FADD following treatment with TRAIL or anti-Fas, but may be constitutively bound by FADD. Three of the four procaspase-8 mutants promoted enhanced cellular migration and invasion through matrigel, relative to that seen with the wild-type procaspase-8 protein. Procaspase-8 mutation also stimulated the growth of HNSCC xenograft tumors. These findings indicate that HNSCC-associated procaspase-8 mutations inhibit activation of the extrinsic apoptosis pathway and are likely to represent markers for resistance to therapeutic regimens incorporating death receptor activators. Moreover, procaspase-8 mutations may serve as markers of HNSCC tumor progression, as exemplified by enhanced migration, invasion, and tumor growth. PMID- 24816190 TI - Impaired orofacial motor functions on chronic temporomandibular disorders. AB - Because temporomandibular disorders (TMDs) rehabilitation continues to be a challenge, a more comprehensive picture of the orofacial functions in patients with chronic pain is required. This study assessed the orofacial functions, including surface electromyography (EMG) of dynamic rhythmic activities, in patients with moderate-severe signs and symptoms of chronic TMD. It was hypothesized that orofacial motor control differs between patients with moderate severe chronic TMD and healthy subjects. Seventy-six subjects (46 with TMD and 30 control) answered questionnaires of severity of TMD and chewing difficulties. Orofacial functions and EMG during chewing were assessed. Standardized EMG indices were obtained by quantitative analysis of the differential EMG signals of the paired masseter and temporal muscles, and used to describe muscular action during chewing. TMD patients showed significant greater difficulty in chewing; worse orofacial scores; longer time for free mastication; a less accurate recruitment of the muscles on the working and balancing sides, reduced symmetrical mastication index (SMI) and increased standardized activity during EMG test than healthy subjects. SMI, TMD severity and orofacial myofunctional scores were correlated (P<0.01). Impaired orofacial functions and increased activity of the muscles of balancing sides during unilateral chewing characterized the altered orofacial motor control in patients with moderate severe chronic TMD. Implications for rehabilitation are discussed. PMID- 24816189 TI - Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity. AB - The tumor suppressor p53 regulates the expression of genes involved in cell cycle progression, senescence and apoptosis. Here, we investigated the effect of single point mutations in the oligomerization domain (OD) on tetramerization, transcription, ubiquitylation and stability of p53. As predicted by docking and molecular dynamics simulations, p53 OD mutants show functional defects on transcription, Mdm2-dependent ubiquitylation and 26S proteasome-mediated degradation. However, mutants unable to form tetramers are well degraded by the 20S proteasome. Unexpectedly, despite the lower structural stability compared to WT p53, p53 OD mutants form heterotetramers with WT p53 when expressed transiently or stably in cells wild type or null for p53. In consequence, p53 OD mutants interfere with the capacity of WT p53 tetramers to be properly ubiquitylated and result in changes of p53-dependent protein expression patterns, including the pro-apoptotic proteins Bax and PUMA under basal and adriamycin induced conditions. Importantly, the patient derived p53 OD mutant L330R (OD1) showed the more severe changes in p53-dependent gene expression. Thus, in addition to the well-known effects on p53 stability, ubiquitylation defects promote changes in p53-dependent gene expression with implications on some of its functions. PMID- 24816192 TI - Artificial structures in sediment-dominated estuaries and their possible influences on the ecosystem. AB - Artificial substrates are omnipresent today in most estuaries mostly in form of massive rip-rap used for groynes and jetties. In the Weser estuary, Germany, 60% of the shoreline is covered with such artificial substrates while, natural rocky substrate is lacking, as in all Wadden Sea estuaries. This large quantity of artificial substrates may be colonized by a benthic hard-substrate community which differs from the local natural soft-substrate assemblage. In this study we examined species compositions, abundances, biomass, and numbers of species of subtidal benthic communities on groynes and in the natural habitat, the sediment, along the salinity gradient of the Weser estuary. Species composition changed on both substrates significantly with salinity and was also significantly different between the substrates. In a comparison with the sediment, the groynes did not provide any benefit for non-indigenous nor for endangered species in terms of abundance, biomass, and number of species, but represent habitats with higher total abundances and biomass; though some non-indigenous species even occurred exclusively on groynes. In particular, groynes supported filter-feeding organisms which play an important role by linking benthic and pelagic food webs. The dominance of the suspension feeders affects crucial estuarine ecosystem services and may have important implications for the estuarine management by altering the estuarine ecological quality status. Hence, artificial substrates should be considered in future conservation planning and in ecological quality monitoring of the benthic fauna according to the European Water Framework Directive. PMID- 24816191 TI - Developmental toxicity and DNA damage from exposure to parking lot runoff retention pond samples in the Japanese medaka (Oryzias latipes). AB - Parking lot runoff retention ponds (PLRRP) receive significant chemical input, but the biological effects of parking lot runoff are not well understood. We used the Japanese medaka (Oryzias latipes) as a model to study the toxicity of water and sediment samples from a PLRRP in Morehead City, NC. Medaka exposed in ovo to a dilution series of PLRRP water had increased odds of death before hatching, but not teratogenesis or delayed hatching. Next, we adapted a long-amplicon quantitative PCR (LA-QPCR) assay for DNA damage for use with the Japanese medaka. We employed LA-QPCR to test the hypotheses that PLRRP water and sediments would cause nuclear and mitochondrial DNA damage with and without full-spectrum, natural solar radiation. Fluoranthene with and without natural sunlight was a positive control for phototoxic polycyclic aromatic hydrocarbon-induced DNA damage. Fluoranthene exposure did not result in detectable DNA damage by itself, but in combination with sunlight caused significant DNA damage to both genomes. PLRRP samples caused DNA damage to both genomes, and this was not increased by sunlight exposure, suggesting the DNA damage was unlikely the result of PAH phototoxicity. We report for the first time that PLRRP-associated pollutants cause both nuclear and mitochondrial DNA damage, and that fluoranthene-mediated phototoxicity results in similar levels of damage to the nuclear and mitochondrial genomes. These effects may be especially significant in sensitive marine ecosystems. PMID- 24816193 TI - Piperine reverses the effects of corticosterone on behavior and hippocampal BDNF expression in mice. AB - A mouse model of depression has been recently developed by exogenous corticosterone administration. The present study aimed to examine the antidepressant-like effect and the possible mechanisms of piperine, a major alkaloid of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.), in corticosterone-induced depression in mice. The results showed that 3 weeks corticosterone injections caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test and tail suspension test. Moreover, it was found that brain-derived neurotrophic factor protein and mRNA levels in the hippocampus were significantly decreased in corticosterone-treated mice. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by corticosterone. The results suggest that piperine produces an antidepressant-like effect in corticosterone-treated mice, which is possibly mediated by increasing brain-derived neurotrophic factor expression in the hippocampus. PMID- 24816194 TI - Expression and immunogenic analysis of recombinant polypeptides derived from capsid protein VP1 for developing subunit vaccine material against hepatitis A virus. AB - Three recombinant polypeptides, VP1-His, VP1-3N-His, and 3D2-His, were produced by Escherichia coli expression system. Recombinant VP1-His, VP1-3N-His, and 3D2 His were expressed as bands with molecular weights of 32, 38, and 30 kDa, respectively. These were purified by affinity chromatography using Ni-NTA Fast flow resin and/or ion-exchange chromatography using DEAE-Sepharose Fast-flow resin. Intraperitoneal immunizations of recombinant polypeptides successfully elicited the productions of VP1-His, VP1-3N-His, and 3D2-His specific IgG antibodies (IgG subclass distribution of IgG1>IgG2a>IgG2b>IgG3) in sera and induced the secretions of cytokines IFN-gamma and IL-6 in spleen cells. Sera from recombinant VP1-His-, VP1-3N-His-, and 3D2-His-immunized mice neutralized the propagation of HAV. The highest neutralizing activity was shown in sera from recombinant VP1-3N-His-immunized mice. These results suggest that recombinant VP1 3N-His can be a useful source for developing hepatitis A virus (HAV) subunit vaccine candidates. PMID- 24816195 TI - Disease burden, disease manifestations and current treatment regimen of the SAPHO syndrome in Germany: results from a nationwide patient survey. AB - BACKGROUND: Due to diagnostic and therapeutic advances, quality of life of patients with spondyloarthritides (SpA) has improved substantially in recent years. However, little is known about how patients with the SAPHO syndrome, a heterogeneous disease counted among the SpAs, profit from these advances. OBJECTIVE: To investigate current aspects of patient care in a nationwide SAPHO cohort. METHODS: Patients were recruited in a university centre and via a nationwide SAPHO patient support group. Medical records were reviewed and patients were asked to complete a questionnaire on the course of diagnosis, disease burden and treatment regimen. RESULTS: A total of 64 patients were included in the analysis. The mean time from disease onset to diagnosis was 3.8 +/- 5.3 years. The patients' overall satisfaction with the course of diagnosis was 23.0 +/- 28.9 on a visual analogue scale (VAS) from 0 to 100. Musculoskeletal symptoms had the highest impact on the patients' wellbeing. The mean overall disease burden on a VAS for pain was 45.4 +/- 25.9. Limitations in the quality of life were reported mainly in the general health, bodily pain and vitality dimensions of the SF-36 questionnaire. Current treatments consisted of NSAIDs (77%), DMARDs (27%), glucocorticoids (23%), TNF-inhibitors (16%) and bisphosphonates (11%). CONCLUSIONS: The SAPHO syndrome has a high impact on the patients' general health and quality of life. Establishing the diagnosis still takes years and expends multiple medical resources. Effective treatments such as TNF-inhibitors are rarely prescribed and current disease burden is not acceptable. PMID- 24816196 TI - An examination of expectations for rheumatoid arthritis disability in Germany: comparison with Canadian data. PMID- 24816197 TI - Comment on: Th17 cells and IL-17A--focus on immunopathogenesis and immunotherapeutics. PMID- 24816198 TI - Extended release quetiapine fumarate in patients with major depressive disorder: suicidality data from acute and maintenance studies. AB - OBJECTIVE: To prospectively analyze effects of extended release quetiapine fumarate (quetiapine XR) on suicidality in major depressive disorder (MDD). METHOD: Data were pooled from randomized, acute studies (4 monotherapy; 2 adjunct therapy) in adult patients with a DSM-IV diagnosis of MDD who were considered not to be at high risk of suicide at baseline and were receiving quetiapine XR 50 mg/d (n = 181), 150 mg/d (n = 910), or 300 mg/d (n = 685) or placebo (n = 957). Data from 1 acute monotherapy study in elderly patients receiving quetiapine XR (50-300 mg/d; n = 166) or placebo (n = 172) and maintenance data (up to 52 weeks) for patients receiving quetiapine XR (50-300 mg/d; n = 391) or placebo (n = 385) were also evaluated. Overall incidences and relative risks for suicidality (suicidal behavior/ideation) were assessed by Columbia-type review and classification. The proportion of patients with Montgomery-Asberg Depression Rating Scale (MADRS) item 10 (suicidal thoughts) score >= 4 was analyzed. RESULTS: Incidence of suicidality during acute treatment in adults was 1.1%, 0.7%, 0.7%, and 0.7% with quetiapine XR 50 mg/d, 150 mg/d, and 300 mg/d and placebo, respectively. The proportion of patients with MADRS item 10 score >= 4 during acute treatment in adults was 1.8% with quetiapine XR (all doses combined) and 2.4% with placebo. In elderly patients, the incidence of suicidality during acute treatment was 0.6% in both treatment groups; the proportion of patients with MADRS item 10 score >= 4 was 0% with quetiapine XR (all doses combined) and 1.2% with placebo. During maintenance treatment, the incidence of suicidality was 0.3% (n = 1) and 0.5% (n = 2) for quetiapine XR and placebo, respectively. The proportion of patients with MADRS item 10 score >= 4 was 4.1% with quetiapine XR in the open-label stabilization period and 0.3% with quetiapine XR and 0.5% with placebo during the randomized period. CONCLUSIONS: This analysis suggests that there is no evidence of treatment-emergent suicidality with quetiapine XR therapy in patients with MDD considered not to be at high suicide risk at baseline. PMID- 24816200 TI - AQUATOX coupled foodweb model for ecosystem risk assessment of Polybrominated diphenyl ethers (PBDEs) in lake ecosystems. AB - The AQUATOX model considers the direct toxic effects of chemicals and their indirect effects through foodwebs. For this study, the AQUATOX model was applied to evaluating the ecological risk of Polybrominated diphenyl ethers (PBDEs) in a highly anthropogenically disturbed lake-Baiyangdian Lake. Calibration and validation results indicated that the model can adequately describe the dynamics of 18 biological populations. Sensitivity analysis results suggested that the model is highly sensitive to temperature limitation. PBDEs risk estimate results demonstrate that estimated risk for natural ecosystems cannot be fully explained by single species toxicity data alone. The AQUATOX model could provide a good basis in ascertaining ecological protection levels of "chemicals of concern" for aquatic ecosystems. Therefore, AQUATOX can potentially be used to provide necessary information corresponding to early warning and rapid forecasting of pollutant transport and fate in the management of chemicals that put aquatic ecosystems at risk. PMID- 24816199 TI - Urban and rural safety net health care system clinics: no disparity in HPV4 vaccine completion rates. AB - OBJECTIVE: Safety net health care centers in the US serve vulnerable and underinsured females. The primary aim of this work was to determine if HPV4 dosing compliance differs between females who receive doses at rural vs. urban core safety net health care locations. METHODS: Females exclusively receiving health care in the Truman Medical Center (TMC) safety net system at the urban core and rural locations were identified by their HPV4 vaccine records. Dates and number of HPV4 doses as well as age, gravidity, parity and race/ethnicity were recorded from the electronic medical record (EMR). Appropriate HPV4 dosing intervals were referenced from the literature. RESULTS: 1259 females, 10-26 years of age, received HPV4 vaccination at either the rural (23%) or urban core location (77%). At the rural location, 23% received three doses on time, equal to the 24% at the urban core. Females seen in the urban core were more likely to receive on-time doublet dosing than on-time triplet dosing (82% vs. 67%, p<0.001). Mistimed doses occurred equally often among females receiving only two doses, as well as those receiving three doses. CONCLUSIONS: Compliance with on time HPV4 triplet dose completion was low at rural and urban core safety net health clinics, but did not differ by location. PMID- 24816201 TI - Mercury loads into the sea associated with extreme flood. AB - Floods are an important factor determining riverine pollution loads, including toxic mercury (Hg). The impact of the Vistula River flood in 2010, which was the biggest one recorded in 160 years and its influence on marine environment was studied. Mercury concentration was analyzed in river and sea water, suspended matter, phytoplankton and sea surface sediment. Flood and gulf water contained several times higher concentration of Hg (exceeded reference values safe for aquatic organisms) than before or after the flood. In 2010 the Vistula introduced into the Baltic ca. 1576 kg of Hg, of which 75% can be attributed to the flood water. Increase of water temperature, decrease of oxygen content contended increasing of dissolved mercury concentration, which was transported far into the Baltic. This phenomenon led to an increase of Hg concentration in phytoplankton and during many months in surface sediments. It is a potential threat to marine organisms. PMID- 24816202 TI - Effects of subtle pollution at different levels of biological organisation on species-rich assemblages. AB - We investigated effects of subtle nutrient enrichment and metal pollution on different levels of biological organization (i.e. whole assemblage, population and individual) of species-rich assemblages. We used rockpools as model system, applying a multi-factorial sampling design to test hypotheses on differences between disturbed and reference locations. Results indicated that disturbed and reference locations supported similar assemblages, as well as individual fitness related life-traits were ineffective to discriminate between the two conditions. In contrast, assemblages responded to pollution through a reduction of the abundance of sensitive species and a proliferation of tolerant species, although these alterations were detectable only once the influence of dominant taxa was down-weighed by data transformation. Present findings suggest that, contrarily to individual level variables, assemblage structure after data transformation and patterns of distribution and abundance of differently sensitive taxa would be a powerful tool to detect effects of subtle pollution on species-rich assemblages. PMID- 24816203 TI - Comparative cancer survival in European countries. AB - BACKGROUND: Survival for patients with cancer varies widely across Europe. This review is an attempt to explore some of the factors that influence this variation. SOURCES OF DATA: The data on cancer survival come from EUROCARE-5 and a recent OECD report. These figures have been analysed together with data from a variety of other sources: other OECD data sets; EUROSTAT; The World Bank; Gallup and the World Health Organisation. AREAS OF AGREEMENT: This study confirms the importance of national socio-economic factors in influencing the outcomes for patients with cancer. AREAS OF CONTROVERSY: The usual suspects (limited access to expensive new cancer drugs; delayed diagnosis and late presentation) may have less influence on cancer survival than is usually assumed. GROWING POINTS: Disparities in outcomes challenge systems of health care to re-evaluate their strategies. The key point is that these new strategies need to be informed by facts, rather than suppositions. AREAS TIMELY FOR DEVELOPING RESEARCH: The role and scope of national cancer registries should be enhanced. We need to record more detailed information on each patient with cancer and, in an era of linked data, cancer registries are ideally placed to collect and curate such information. PMID- 24816204 TI - Clinical aspects of portopulmonary hypertension. AB - Portopulmonary hypertension (PoPH) is an often neglected form of pulmonary hypertension where pulmonary hypertension occurs in the presence of portal hypertension. PoPH is important to diagnose and treat as it may improve the patient's quality of life and improve the outcome after liver transplantation. In this review, we discuss the clinical aspects of PoPH including its pathophysiology, diagnosis, treatment, and prognosis. PMID- 24816205 TI - Comparing mammographic measures across populations. PMID- 24816207 TI - Evaluation of factors influencing the remaining astigmatism after toric intraocular lens implantation. AB - PURPOSE: To evaluate the influencing factors on remaining astigmatism after implanting a toric intraocular lens during cataract surgery. METHODS: In this observational study, consecutive patients with cataract from three different centers who received toric intraocular lenses were included. Keratometry was performed with an optical biometry device preoperatively. The IOLMaster 500 (Carl Zeiss Meditec AG, Jena, Germany) was used in Vienna, Lenstar (Haag-Streit, Koniz, Switzerland) in Castrop-Rauxel, and IOLMaster (Carl Zeiss Meditec AG) in London. Partial least squares regression was used to detect the influence of different parameters on remaining astigmatism. RESULTS: In total, 235 eyes of 200 patients were included. Mean corneal astigmatism measured preoperatively with the optical biometry device was -2.24 +/- 0.87 diopters (D) (range: -5.75 to -1.00 D). Mean absolute and vector difference between the aimed for and the postoperatively measured astigmatism were 0.48 +/- 0.37 D (range: 0.00 to 2.05 D) and 0.73 +/- 0.46 D (range: 0.031 to -2.20 D), respectively (P = .576). Partial least squares regression showed a significant effect of preoperatively measured corneal astigmatism and deviation between preoperative measurements of the cornea on the postoperative (unintended) remaining astigmatism. CONCLUSIONS: The main source of error when using toric intraocular lenses is the preoperative measurement of corneal astigmatism, especially in eyes with low astigmatism. The influence of the postoperative anterior chamber depth on the cylindrical power of toric intraocular lenses and the effect of misalignment on the reduction of the astigmatism-reducing effect can be easily calculated. PMID- 24816208 TI - Current options in the management of pellucid marginal degeneration. AB - PURPOSE: To review and evaluate current and future directions in the diagnosis and surgical management of pellucid marginal degeneration (PMD), including penetrating keratoplasty, full-thickness crescentic wedge resection (FTCWR), deep anterior lamellar keratoplasty (DALK), crescentic lamellar wedge resection (CLWR), crescentic lamellar keratoplasty, tuck-in lamellar keratoplasty (TILK), toric phakic intraocular lens (PIOL) implantation, intrastromal corneal ring segment implantation (ICRS), corneal collagen cross-linking (CXL), and combined therapies. This is the first review article looking at the literature specific to PMD. METHODS: Review of published studies. RESULTS: Reported data for each treatment is presented. Penetrating keratoplasty is the treatment of last resort in PMD and is effective, but with considerable complications. DALK provides visual outcomes similar to penetrating keratoplasty without the risk of immune mediated graft rejection, but its complexity and relative novelty limit its acceptance. FTCWR has good visual outcomes, but with significant astigmatic drift. CLWR is effective, but lacks long-term results. Crescentic lamellar keratoplasty and TILK are effective, but technically difficult and without long term results. Toric PIOL implantation is effective, but ectasia progression is a concern. ICRS implantation can delay penetrating keratoplasty and improve contact lens tolerance, but does not treat the underlying process. CXL demonstrates effectiveness without complications, although data are limited and long-term results are needed. Combining treatments such as ICRS, CXL, toric PIOL implantation, and refractive surgery is promising, but additional studies are needed to investigate their efficacy and safety. CONCLUSIONS: Although little is understood about the etiology, pathophysiology, epidemiology, and genetics of PMD, new treatments are improving visual outcomes and reducing complications. Corneal collagen cross-linking is especially exciting because it halts disease progression. Combined treatments and improved screening could eliminate the need for surgical management in most cases of PMD. PMID- 24816206 TI - Mammographic density phenotypes and risk of breast cancer: a meta-analysis. AB - BACKGROUND: Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. METHODS: We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. RESULTS: Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. CONCLUSIONS: The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area. PMID- 24816209 TI - Oseltamivir Dosing in Critically Ill Patients With Severe Influenza. AB - OBJECTIVE: To evaluate the literature for published reports regarding the efficacy of standard versus higher dosing of oseltamivir in critically ill patients with severe influenza. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1966-February 2014) using the terms oseltamivir and influenza limited to humans and adults older than 19 years. Additional articles were identified through a manual search of the references obtained from the MEDLINE search. STUDY SELECTION AND DATA EXTRACTION: Articles were manually screened for inclusion related to pharmacokinetic or clinical studies comparing varying doses of oseltamivir, particularly in the critically ill patient population. Studies investigating the pharmacokinetics of oseltamivir in continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) were also included. DATA SYNTHESIS: During the 2009 H1N1 influenza pandemic, the World Health Organization suggested 150 mg twice daily as a consideration in critically ill patients with severe influenza. The basis for the recommendation can be traced back to animal studies investigating the H5N1 virus. Three different studies in humans investigating higher doses in severe influenza have found no differences in clinical outcomes between standard and higher dosing. Pharmacokinetic studies suggest adequate absorption in critically ill patients. Although no dosage adjustment appears to be needed for ECMO patients, reduction may berequired for CRRT.. CONCLUSIONS: . Although additional data are needed for a definitive conclusion, the small body of literature available in humans does not support routine use of high-dose oseltamivir in critically ill patients. PMID- 24816211 TI - Efficacy of surotomycin in an in vitro gut model of Clostridium difficile infection. AB - OBJECTIVES: We investigated the efficacy of the cyclic lipopeptide surotomycin in treating clindamycin-induced Clostridium difficile infection (CDI) using an in vitro gut model. METHODS: Two three-stage chemostat gut models were inoculated with human faeces, spiked with C. difficile spores (~10(7) cfu/mL, PCR ribotype 027 or 001). Clindamycin (33.9 mg/L, four times daily for 7 days) was dosed to induce CDI. Following high-level toxin production, surotomycin (250 mg/L, twice daily for 7 days) was instilled. Microflora populations, C. difficile vegetative cells and spores, cytotoxin titres and antimicrobial levels (LC-MS/MS and bioassay) were determined. The emergence of C. difficile and enterococci with reduced susceptibility to surotomycin was monitored on breakpoint agar (4 * MIC). RESULTS: Counts of viable C. difficile were reduced to near the limit of detection on Days 1 and 3 of surotomycin instillation, and cytotoxin was undetectable on Days 3 and 4 of surotomycin instillation in the 027 and 001 models, respectively. Recurrence of vegetative growth and toxin production occurred 11 days (001 model) and 15 days (027 model) after surotomycin instillation had ceased, and remained for the duration of the experiment. Surotomycin instillation decreased populations of bifidobacteria, clostridia, enterococci and lactobacilli, but was sparing of Bacteroides fragilis group populations. All enumerated organisms had recovered to steady-state levels by 3 weeks post-surotomycin instillation. No evidence of the emergence of reduced susceptibility to surotomycin was observed. CONCLUSIONS: Surotomycin successfully reduced C. difficile vegetative cell counts and toxin levels in the gut model and was sparing of B. fragilis group populations. There was no evidence of decreased susceptibility to surotomycin during exposure or post-exposure. PMID- 24816210 TI - Effect of Anticholinergic Medications on Falls, Fracture Risk, and Bone Mineral Density Over a 10-Year Period. AB - BACKGROUND: Many medications used in older adults have strong anticholinergic (ACH) properties, which may increase the risk of falls and fractures. Use of these medications was identified in a population-based Canadian cohort. OBJECTIVE: To identify the fall and fracture risk associated with ACH medication use. METHODS: Data collection and analysis were conducted at baseline, year 5, and year 10. Cross-sectional analyses were performed to examine associations between ACH medication use and falls. Time-dependent Cox regression was used to examine time to first nontraumatic fracture. Finally, change in bone mineral density (BMD) over 10 years was compared in ACH medication users versus nonusers. RESULTS: Strongly ACH medications were used by 618 of 7753 participants (8.0%) at study baseline, 592 (9.5%) at year 5, and 334 (7.7%) at year 10. Unadjusted ACH medication use was associated with falls at baseline (odds ratio = 1.50; 95% CI = 1.14-1.98; P = 0.004), but the association was no longer significant after covariate adjustment. Similar results occurred at years 5 and 10. ACH medication use was associated with increased incident fracture risk before (hazard ratio = 1.22; CI = 1.13-1.32; P < 0.001) but not after covariate adjustment. Mean (SD) change in femoral neck BMD T-score over 10 years, in those using ACH medications at both years 0 and 5, was -0.60 (0.63) in ACH users versus -0.49 (0.45) in nonusers (P = 0.041), but this was not significant after covariate adjustment. CONCLUSIONS: ACH medications were not found to be independently associated with an increased risk of falling, fractures, or BMD loss. Rather, factors associated with ACH medication use explained the apparent associations. PMID- 24816212 TI - Bile-mediated activation of the acrAB and tolC multidrug efflux genes occurs mainly through transcriptional derepression of ramA in Salmonella enterica serovar Typhimurium. AB - OBJECTIVES: In Salmonella Typhimurium, the genes encoding the AcrAB-TolC multidrug efflux system are mainly regulated by the ramRA locus, composed of the divergently transcribed ramA and ramR genes. The acrAB and tolC genes are transcriptionally activated by RamA, the gene for which is itself transcriptionally repressed by RamR. Previous studies have reported that bile induces acrAB in a ramA-dependent manner, but none provided evidence for an induction of ramA expression by bile. Therefore, the objective of this study was to clarify the regulatory mechanism by which bile activates acrAB and tolC. METHODS: qRT-PCR was used to address the effects of bile (using choleate, an ox bile extract) on the expression of ramA, ramR, acrB and tolC. Electrophoretic mobility shift assays and surface plasmon resonance experiments were used to measure the effect of bile on RamR binding to the ramA promoter (PramA) region. RESULTS: We show that ramA is transcriptionally activated by bile and is strictly required for the bile-mediated activation of acrB and tolC. Additionally, bile is shown to specifically inhibit the binding of RamR to the PramA region, which overlaps the putative divergent ramR promoter, thereby explaining our observation that bile also activates ramR transcription. CONCLUSIONS: We propose a regulation model whereby the bile-mediated activation of the acrAB and tolC multidrug efflux genes occurs mainly through the transcriptional derepression of the ramA activator gene. PMID- 24816213 TI - Change in HIV-1 DNA tropism despite virological success in patients receiving an enfuvirtide-based regimen. PMID- 24816214 TI - Lung diffusion capacity in children with respiratory symptoms and untreated GERD. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is associated with many respiratory disorders, among which, chronic cough, laryngitis, and asthma are among the most common. We investigated lung function, including gas diffusion capacity, in children with poor asthma control or chronic laryngitis with untreated GERD. MATERIAL AND METHODS: A total of 71 children, aged 6-17 years, with chronic respiratory and other symptoms suggestive for GERD, were enrolled and divided into 2 groups: chronic laryngitis and asthma. Participants underwent 24-hour pH monitoring and lung function assessment, measurement of single-breath diffusing capacity of the lung for carbon monoxide (DLCO), and fraction of exhaled nitric oxide (FENO) measurement. RESULTS: 24-hour pH monitoring was positive for GERD in 92.1% of preselected children with asthma and 90.1% of children with chronic recurrent laryngitis. All flows (PEF, MEF75, MEF50, and MEF25) were significantly lower in the asthma group, while FENO and DLCO were significantly lower in the laryngitis group. A significant inverse relationship was found between DLCO and all reflux indexes in the laryngitis group. Each unit change of Johnson-DeMeester score and Boix-Ochoa score increased the odds for significantly lower DLCO in laryngitis patients by 3.9% and 5.5%, respectively. CONCLUSIONS: In children with uncontrolled asthma and chronic laryngitis, the regurgitation of gastric contents due to GERD contributes to poor asthma control and aggravation of chronic laryngitis. Despite having normal lung function, the gas diffusion capacity should be controlled in patients with GERD and chronic laryngitis, and it might be the very first abnormality in distal airways. PMID- 24816215 TI - Concerns about partner infidelity are a barrier to adoption of HIV-prevention strategies among young South African couples. AB - As part of a larger study to examine the feasibility and acceptability of a couples-based HIV-prevention intervention, we conducted formative in-depth interviews with 10 couples to explore topics such as challenges in practising safer sex, HIV-prevention strategies, gender power and violence, and issues of trust and infidelity. In this study, both men and women perceived infidelity as ubiquitous in their social context and were therefore unable to discuss HIV risk and prevention without suspicions of infidelity in their own relationship. This impacted couples' ability openly and effectively to discuss strategies to prevent HIV and thus may have contributed to the limited uptake of HIV-prevention strategies, such as condom use and HIV testing. The contentious nature of safe sex discussions placed both members of the couple at a higher risk for HIV acquisition within the partnership. This study sheds light on how existing relationship norms in South Africa influence HIV-prevention communication within couples and suggests that new ways of approaching conflictual issues such as mistrust and infidelity are vital in order for HIV-prevention programmes to succeed. PMID- 24816216 TI - Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes. AB - Recent work has identified missense mutations in calmodulin (CaM) that are associated with severe early-onset long-QT syndrome (LQTS), leading to the proposition that altered CaM function may contribute to the molecular etiology of this subset of LQTS. To date, however, no experimental evidence has established these mutations as directly causative of LQTS substrates, nor have the molecular targets of CaM mutants been identified. Here, therefore, we test whether expression of CaM mutants in adult guinea-pig ventricular myocytes (aGPVM) induces action-potential prolongation, and whether affiliated alterations in the Ca(2+) regulation of L-type Ca(2+) channels (LTCC) might contribute to such prolongation. In particular, we first overexpressed CaM mutants in aGPVMs, and observed both increased action potential duration (APD) and heightened Ca(2+) transients. Next, we demonstrated that all LQTS CaM mutants have the potential to strongly suppress Ca(2+)/CaM-dependent inactivation (CDI) of LTCCs, whether channels were heterologously expressed in HEK293 cells, or present in native form within myocytes. This attenuation of CDI is predicted to promote action-potential prolongation and boost Ca(2+) influx. Finally, we demonstrated how a small fraction of LQTS CaM mutants (as in heterozygous patients) would nonetheless suffice to substantially diminish CDI, and derange electrical and Ca(2+) profiles. In all, these results highlight LTCCs as a molecular locus for understanding and treating CaM-related LQTS in this group of patients. PMID- 24816218 TI - Efficacy of IgE-targeted vs empiric six-food elimination diets for adult eosinophilic oesophagitis. AB - BACKGROUND: Skin testing-guided elimination diet has proved unsuccessful for adult eosinophilic oesophagitis (EoE), whereas empiric six-food elimination diet (SFED) achieves an efficacy of 70%. OBJECTIVE: To compare the efficacy of food specific serum IgE-targeted elimination diet (sIgE-ED) and SFED. METHODS: Prospective study in adult patients with EoE. Food-specific serum IgE, skin prick test (SPT) and atopy patch test (APT) to foods included in SFED were performed. Those with >=1 positive IgE test, defined by >=0.1 kU/l, followed a 6-week sIgE ED, whereas non-IgE-sensitized patients underwent a 6-week SFED. Responders to diet (<15 eos/HPF) underwent individual reintroduction of foods followed by histological assessment. RESULTS: Forty-three EoE patients were included (26 sIgE ED and 17 SFED). Regarding sIgE-ED, the mean number of eliminated foods per patient was significantly lower than in SFED (3.81 vs 6; P < 0.001), being wheat (85%), nuts (73%) and cow's milk (61%) the most commonly foods withdrawn. No difference in histological response was observed between sIgE-ED and SFED (73% vs 53%, P = 0.17). Causative foods identified by food challenge were cow's milk (64%), wheat (28%), egg (21%) and legumes (7%), with a single food trigger in 71% of patients. sIgE exhibited the higher accuracy to predict offending foods in IgE sensitized patients (sensitivity 87.5%, specificity 68% (kappa = 0.43)), with k values of 1 for cow's milk. APT results were all negative. CONCLUSIONS: Histological remission was accomplished in 73% of patients undergoing sIgE-ED, which was nonsignificantly superior to SFED. sIgE effectively identified cow's milk as a food trigger in IgE-sensitized patients. PMID- 24816219 TI - Fragmentation of the paced QRS complex: a marker of antitachycardia pacing effectiveness among ICD patients. AB - INTRODUCTION: The presence of notches in the paced QRS complex (P-QRS) from the right ventricular apex (RVA) reflects delays in the activation of the left ventricle and may therefore be associated with longer times of stimulus conduction. Our objective was to determine prospectively the relationship between the duration of a notch >=0.1 mV in the P-QRS (DN) and the effectiveness of antitachycardia pacing (ATP). METHODS AND RESULTS: We followed 286 implantable cardioverter-defibrillator (ICD) patients with left ventricular dysfunction (pacing site: RVA) for 41 +/- 27 months. ICD programming was standardized. P-QRS (100 bpm) was obtained at implant (50 mm/s). A total of 955 monomorphic ventricular tachycardias (VTs) with a cycle length of 335 +/- 32 milliseconds occurred consecutively in 108 patients. ATP was successful in 84% of VTs. DN correlated with the probability of ineffective ATP (C = 0.67; P < 0.001), the cutoff point with the best sensitivity and specificity being 50 milliseconds. The adjusted mean ATP effectiveness per patient was 76% (95% CI: 72-85). Patients with a DN >= 50 milliseconds had a lower ATP efficiency: 67% (56-77) versus 92% (87-97) and a higher proportion of VTs terminated with shocks (SH): 31% (21-42) versus 8% (2-14); P < 0.001 for both. Although the occurrence of VT was similar (41% vs. 40%), the incidence of VT-related SH was higher in patients with a DN >= 50 (25% vs. 14%; P = 0.01) in the overall study population (n = 286). CONCLUSIONS: When ATP is applied to the RVA, a DN >= 50 milliseconds is associated with a lower ATP effectiveness and a higher risk of SH due to VT. PMID- 24816217 TI - CXCR4 blockade induces atherosclerosis by affecting neutrophil function. AB - AIMS: The SDF-1alpha/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. METHODS AND RESULTS: Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr(-/-) mice with autologous bone marrow infected with lentivirus encoding SDF-1alpha antagonist or CXCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. CONCLUSION: In conclusion, CXCR4 contributes to later stages of plaque progression by perturbing neutrophil function. PMID- 24816221 TI - Replicated origin of female-biased adult sex ratio in introduced populations of the trinidadian guppy (Poecilia reticulata). AB - There are many theoretical and empirical studies explaining variation in offspring sex ratio but relatively few that explain variation in adult sex ratio. Adult sex ratios are important because biased sex ratios can be a driver of sexual selection and will reduce effective population size, affecting population persistence and shapes how populations respond to natural selection. Previous work on guppies (Poecilia reticulata) gives mixed results, usually showing a female-biased adult sex ratio. However, a detailed analysis showed that this bias varied dramatically throughout a year and with no consistent sex bias. We used a mark-recapture approach to examine the origin and consistency of female-biased sex ratio in four replicated introductions. We show that female-biased sex ratio arises predictably and is a consequence of higher male mortality and longer female life spans with little effect of offspring sex ratio. Inconsistencies with previous studies are likely due to sampling methods and sampling design, which should be less of an issue with mark-recapture techniques. Together with other long-term mark-recapture studies, our study suggests that bias in offspring sex ratio rarely contributes to adult sex ratio in vertebrates. Rather, sex differences in adult survival rates and longevity determine vertebrate adult sex ratio. PMID- 24816220 TI - Fetal alcohol syndrome, chemo-biology and OMICS: ethanol effects on vitamin metabolism during neurodevelopment as measured by systems biology analysis. AB - Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment. PMID- 24816222 TI - Acute myocardial infarction in sub-Saharan Africa: the need for data. AB - BACKGROUND: Trends in the prevalence of acute myocardial infarction in sub Saharan Africa have not been well described, despite growing recognition of the increasing burden of cardiovascular disease in low- and middle-income countries. The aim of this systematic review was to describe the prevalence of acute myocardial infarction in sub-Saharan Africa. METHODS: We searched PubMed, EMBASE, Global Health Archive, CINAHL, and Web of Science, and conducted reference and citation analyses. Inclusion criteria were: observational studies, studies that reported incidence or prevalence of acute myocardial infarction, studies conducted in sub-Saharan Africa, and studies that defined acute myocardial infarction by EKG changes or elevation of cardiac biomarkers. Studies conducted prior to 1992 were excluded. Two independent reviewers analyzed titles and abstracts, full-texts, and references and citations. These reviewers also performed quality assessment and data extraction. Quality assessment was conducted with a validated scale for observational studies. FINDINGS: Of 2292 records retrieved, seven studies met all inclusion criteria. These studies included a total of 92,378 participants from highly heterogeneous study populations in five different countries. Methodological quality assessment demonstrated scores ranging from 3 to 7 points (on an 8-point scale). Prevalence of acute myocardial infarction ranged from 0.1 to 10.4% among the included studies. INTERPRETATION: There is insufficient population-based data describing the prevalence of acute myocardial infarction in sub-Saharan Africa. Well designed registries and surveillance studies that capture the broad and diverse population with acute myocardial infarction in sub-Saharan Africa using common diagnostic criteria are critical in order to guide prevention and treatment strategies. REGISTRATION: Registered in International Prospective Register of Systematic Reviews (PROSPERO) Database #CRD42012003161. PMID- 24816223 TI - Theory and practice of size exclusion chromatography for the analysis of protein aggregates. AB - Size exclusion chromatography (SEC) is a historical technique widely employed for the detailed characterization of therapeutic proteins and can be considered as a reference and powerful technique for the qualitative and quantitative evaluation of aggregates. The main advantage of this approach is the mild mobile phase conditions that permit the characterization of proteins with minimal impact on the conformational structure and local environment. Despite the fact that the chromatographic behavior and peak shape are hardly predictable in SEC, some generic rules can be applied for SEC method development, which are described in this review. During recent years, some improvements were introduced to conventional SEC that will also be discussed. Of these new SEC characteristics, we discuss (i) the commercialization of shorter and narrower columns packed with reduced particle sizes allowing an improvement in the resolution and throughput; (ii) the possibility of combining SEC with various detectors, including refractive index (RI), ultraviolet (UV), multi-angle laser light scattering (MALLS) and viscometer (IV), for extensive characterization of protein samples and (iii) the possibility of hyphenating SEC with mass spectrometry (MS) detectors using an adapted mobile phase containing a small proportion of organic modifiers and ion-pairing reagents. PMID- 24816224 TI - Endoscopic versus microscopic approach to type 1 tympanoplasty in children. AB - OBJECTIVES: We investigated the outcomes of the endoscopic versus microscopic approach to type 1 tympanoplasty in pediatric patients. METHODS: In this retrospective study, the outcomes of 61 ears of 60 pediatric patients (33 male and 27 female) who underwent type 1 tympanoplasty were evaluated. One patient underwent a bilateral operation. The age range of the patients was 7-16 years. Group 1 underwent tympanoplasty with an endoscopic technique (n=32), and Group 2 underwent tympanoplasty with the conventional microscopic technique (n=29). A boomerang-shaped chondroperichondrial graft was used in both groups. The outcomes were analyzed in terms of the hearing gain, duration of surgery, and graft success rate. RESULTS: In both groups, the postoperative air-bone gap (ABG) was significantly lower than the preoperative ABG. There were no significant differences between the preoperative and postoperative ABG values (in dB) in either group. The mean operative duration in Group 1 was significantly lower than that in Group 2 (51.37 vs. 67.03 min, respectively). In the preoperative evaluation, 65.6% of patients in Group 1 had larger perforations and 34.4% had smaller perforations. In Group 2, 58.6% and 41.3% of patients had larger and smaller perforations, respectively. Perforations were detected in two (6.25%), four (12.50%), and four (12.50%) of the patients in Group 1 at postoperative months 1, 6, and 12, respectively. Perforations were detected in two (5.71%) patients in Group 2 at postoperative months 1, 6, and 12. At 12 months postoperatively, there were smaller perforations in four (12.5%) of the children in Group 1 and in two (5.71%) of the children in Group 2. The difference between the perforation conditions (larger vs. smaller) was not significant in either group. The preoperative and postoperative increases in the ABG were associated. The operative duration was shorter in Group 1 than in Group 2. CONCLUSION: In pediatric patients undergoing type 1 tympanoplasty, especially if the external ear canal is narrow and the anterior canal wall is prominent, the endoscopic and microscopic approaches appear to give equal results in terms of easy visualization of the entire tympanic membrane and no requirement for extra intervention to evaluate the ossicular system. A shorter operative duration is an advantage of the endoscopic tympanoplasty technique. PMID- 24816225 TI - The primary-secondary care interface: does provision of more services in primary care reduce referrals to medical specialists? AB - Great variation in referral rates between primary care physicians has been the main reason to influence physician's referral behaviour, by for example, stimulating extra services. This study investigated the extent to which the number of therapeutic and diagnostic services performed by primary care physicians influenced referrals. Data was derived from electronic medical records of 70 general practices for the period 2006 until 2010. For the total patient population (N=651,089 patient years) and specific patients groups for whom specific services were performed mostly (28 groups; 10 services), logistic multilevel regression analyses were conducted to determine associations between the number of services performed in a practice and referrals to medical specialists. The total number of services performed in a practice was not associated with the referral rate (OR: 1.00). Only for two specific services was a significant association found: a lower referral rate for minor surgery for patient with sebaceous cysts (OR: 0.98) and a higher rate for Doppler diagnostic tests for patients with other peripheral arterial diseases (OR: 1.04). As the number of services in general practice was rarely associated with referrals, other measures might be more effective in changing referral behaviour. Another explanation for our results could be that certain preconditions have not been met. PMID- 24816226 TI - Expression of decorin throughout the murine hair follicle cycle: hair cycle dependence and anagen phase prolongation. AB - Decorin is a prototypical member of the small leucine-rich proteoglycan (SLRP) family, which is involved in numerous biological processes. The role of decorin, as a representative SLRP, in hair follicle morphogenesis has not been elucidated. We present our initial findings on decorin expression patterns during induced murine hair follicle (HF) cycles. It was found that decorin expression is exclusively restricted to the epidermis, outer root sheath and sebaceous glands during the anagen phase, which correlates with the upregulation of decorin mRNA and protein expression in depilated murine dorsal skin. Furthermore, we used a functional approach to investigate the effects of recombinant human decorin (rhDecorin) via cutaneous injection into HFs at various murine hair cycle stages. The local injection of rhDecorin (100 MUg/ml) into the hypodermis of depilated C57BL/6 mice at anagen delayed catagen progression. In contrast, rhDecorin injection during the telogen phase caused the premature onset of anagen, as demonstrated by the assessment of the following parameters: (i) hair shaft length, (ii) follicular bulbar diameter, (iii) hair follicle cycling score and (iv) follicular phase percentage. Taken together, our results suggest that decorin may modulate follicular cycling and morphogenesis. In addition, this study also provides insight into the molecular control mechanisms governing hair follicular epithelial-mesenchymal interactions. PMID- 24816227 TI - Terrein biosynthesis in Aspergillus terreus and its impact on phytotoxicity. AB - Terrein is a fungal metabolite with ecological, antimicrobial, antiproliferative, and antioxidative activities. Although it is produced by Aspergillus terreus as one of its major secondary metabolites, not much is known about its biosynthetic pathway. Here, we describe an unexpected discovery of the terrein biosynthesis gene locus made while we were looking for a PKS gene involved in production of conidia coloration pigments common for Aspergilli. The gene, ATEG_00145, here named terA, is essential for terrein biosynthesis and heterologous production of TerA in Aspergillus niger revealed an unusual plasticity in the products formed, yielding a mixture of 4-hydroxy-6-methylpyranone, orsellinic acid, and 6,7 dihydroxymellein. Biochemical and molecular genetic analyses indicate a low extension cycle specificity of TerA. Furthermore, 6-hydroxymellein was identified as a key intermediate in terrein biosynthesis. We find that terrein production is highly induced on plant-derived media, that terrein has phytotoxic activity on plant growth, and induces lesions on fruit surfaces. PMID- 24816229 TI - Natural product proteomining, a quantitative proteomics platform, allows rapid discovery of biosynthetic gene clusters for different classes of natural products. AB - Information on gene clusters for natural product biosynthesis is accumulating rapidly because of the current boom of available genome sequencing data. However, linking a natural product to a specific gene cluster remains challenging. Here, we present a widely applicable strategy for the identification of gene clusters for specific natural products, which we name natural product proteomining. The method is based on using fluctuating growth conditions that ensure differential biosynthesis of the bioactivity of interest. Subsequent combination of metabolomics and quantitative proteomics establishes correlations between abundance of natural products and concomitant changes in the protein pool, which allows identification of the relevant biosynthetic gene cluster. We used this approach to elucidate gene clusters for different natural products in Bacillus and Streptomyces, including a novel juglomycin-type antibiotic. Natural product proteomining does not require prior knowledge of the gene cluster or secondary metabolite and therefore represents a general strategy for identification of all types of gene clusters. PMID- 24816230 TI - Synthesis of diosgenin analogues as potential anti-inflammatory agents. AB - We herein report the synthesis of diosgenin analogues from commercially available diosgenin as the starting material. The structures of newly synthesised compounds were confirmed by (1)H NMR, (13)C NMR and mass spectrometry. All analogues were evaluated for in-vitro anti-inflammatory profile against LPS-induced inflammation in primary peritoneal macrophages isolated from mice by quantification of pro inflammatory (TNF-alpha, IL-6 and IL-1beta) cytokines in cell culture supernatant using the ELISA technique followed by in-vitro cytotoxicity study. Among the synthesised analogues, analogue 15 [(E) 26-(3',4',5'-trimethoxybenzylidene) furost-5en-3beta-acetate)] showed significant anti-inflammatory activity by inhibiting LPS-induced pro-inflammatory cytokines in a dose-dependent manner without any cytotoxicity. Efficacy and safety of analogue 15 were further validated in an in-vivo system using LPS-induced sepsis model and acute oral toxicity in mice. Oral administration of analogue 15 inhibited the pro inflammatory cytokines in serum, attenuated the liver and lung injury and reduced the mortality rate in sepsis mice. Acute oral toxicity study showed that analogue 15 is non-toxic at higher dose in BALB/c mice. Molecular docking study revealed the strong binding affinity of diosgenin analogues to the active site of the pro inflammatory proteins. These findings suggested that analogue 15 may be a useful therapeutic candidate for the treatment of inflammatory diseases. PMID- 24816228 TI - In vivo photoswitchable flow cytometry for direct tracking of single circulating tumor cells. AB - Photoswitchable fluorescent proteins (PSFPs) that change their color in response to light have led to breakthroughs in studying static cells. However, using PSFPs to study cells in dynamic conditions is challenging. Here we introduce a method for in vivo ultrafast photoswitching of PSFPs that provides labeling and tracking of single circulating cells. Using in vivo multicolor flow cytometry, this method demonstrated the capability for studying recirculation, migration, and distribution of circulating tumor cells (CTCs) during metastasis progression. In tumor-bearing mice, it enabled monitoring of real-time dynamics of CTCs released from primary tumor, identifying dormant cells, and imaging of CTCs colonizing a primary tumor (self-seeding) or existing metastasis (reseeding). Integration of genetically encoded PSFPs, fast photoswitching, flow cytometry, and imaging makes in vivo single cell analysis in the circulation feasible to provide insights into the behavior of CTCs and potentially immune-related and bacterial cells in circulation. PMID- 24816231 TI - Steroids and endocrine disruptors--History, recent state of art and open questions. AB - This introductory chapter provides an overview of the levels and sites at which endocrine disruptors (EDs) affect steroid actions. In contrast to the special issue of Journal of Steroid Biochemistry and Molecular Biology published three years ago and devoted to EDs as such, this paper focuses on steroids. We tried to point to more recent findings and opened questions. EDs interfere with steroid biosynthesis and metabolism either as inhibitors of relevant enzymes, or at the level of their expression. Particular attention was paid to enzymes metabolizing steroid hormones to biologically active products in target cells, such as aromatase, 5alpha-reductase and 3beta-, 11beta- and 17beta-hydroxysteroid dehydrogenases. An important target for EDs is also steroid acute regulatory protein (StAR), responsible for steroid precursor trafficking to mitochondria. EDs influence receptor-mediated steroid actions at both genomic and non-genomic levels. The remarkable differences in response to various steroid-receptor ligands led to a more detailed investigation of events following steroid/disruptor binding to the receptors and to the mapping of the signaling cascades and nuclear factors involved. A virtual screening of a large array of EDs with steroid receptors, known as in silico methods (=computer simulation), is another promising approach for studying quantitative structure activity relationships and docking. New data may be expected on the effect of EDs on steroid hormone binding to selective plasma transport proteins, namely transcortin and sex hormone-binding globulin. Little information is available so far on the effects of EDs on the major hypothalamo-pituitary-adrenal/gonadal axes, of which the kisspeptin/GPR54 system is of particular importance. Kisspeptins act as stimulators for hormone-induced gonadotropin secretion and their expression is regulated by sex steroids via a feed-back mechanism. Kisspeptin is now believed to be one of the key factors triggering puberty in mammals, and various EDs affect its expression and function. Finally, advances in analytics of EDs, especially those persisting in the environment, in various body fluids (plasma, urine, seminal fluid, and follicular fluid) are mentioned. Surprisingly, relatively scarce information is available on the simultaneous determination of EDs and steroids in the same biological material. This article is part of a Special Issue entitled 'Endocrine disruptors & steroids'. PMID- 24816232 TI - Skeletal development of mice lacking bone sialoprotein (BSP)--impairment of long bone growth and progressive establishment of high trabecular bone mass. AB - Adult Ibsp-knockout mice (BSP-/-) display shorter stature, lower bone turnover and higher trabecular bone mass than wild type, the latter resulting from impaired bone resorption. Unexpectedly, BSP knockout also affects reproductive behavior, as female mice do not construct a proper "nest" for their offsprings. Multiple crossing experiments nonetheless indicated that the shorter stature and lower weight of BSP-/- mice, since birth and throughout life, as well as their shorter femur and tibia bones are independent of the genotype of the mothers, and thus reflect genetic inheritance. In BSP-/- newborns, uCT analysis revealed a delay in membranous primary ossification, with wider cranial sutures, as well as thinner femoral cortical bone and lower tissue mineral density, reflected in lower expression of bone formation markers. However, trabecular bone volume and osteoclast parameters of long bones do not differ between genotypes. Three weeks after birth, osteoclast number and surface drop in the mutants, concomitant with trabecular bone accumulation. The growth plates present a thinner hypertrophic zone in newborns with lower whole bone expression of IGF-1 and higher IHH in 6 days old BSP-/- mice. At 3 weeks the proliferating zone is thinner and the hypertrophic zone thicker in BSP-/- than in BSP+/+ mice of either sex, maybe reflecting a combination of lower chondrocyte proliferation and impaired cartilage resorption. Six days old BSP-/- mice display lower osteoblast marker expression but higher MEPE and higher osteopontin(Opn)/Runx2 ratio. Serum Opn is higher in mutants at day 6 and in adults. Thus, lack of BSP alters long bone growth and membranous/cortical primary bone formation and mineralization. Endochondral development is however normal in mutant mice and the accumulation of trabecular bone observed in adults develops progressively in the weeks following birth. Compensatory high Opn may allow normal endochondral development in BSP-/- mice, while impairing primary mineralization. PMID- 24816233 TI - Meta-analysis of randomized controlled trials comparing latanoprost with timolol in the treatment of Asian populations with chronic angle-closure glaucoma. AB - BACKGROUND: To evaluate the efficacy and safety of latanoprost compared with timolol in the treatment of Asian patients with chronic angle-closure glaucoma (CACG). METHODS: Relevant trials were identified through systematic searches of Medline, EMBASE, PubMed, Cochrane Library, Google Scholar and several Chinese databases. The main outcome measures included absolute and relative reduction of intraocular pressure (IOP) at mean, peak and trough from baseline, ocular adverse effects and systemic adverse events. RESULTS: Seven randomized controlled trials with 685 patients were included. In comparison with timolol, latanoprost reduced absolute IOP in CACG patients by more than 2.3 mmHg (95%CI, 1.8~2.9, P<0.01), 2.4 mmHg (95%CI, 1.9~2.9, P<0.01) and 2.5 mmHg (95%CI, 1.6~3.3, P<0.01) at mean, peak and trough, respectively. As for relative IOP, there is 9.0% (95%CI, 6.6~11.4, P<0.01), 9.7% (95%CI, 7.6~11.8, P<0.01), and 10.8% (95%CI, 7.4~14.3, P<0.01) greater reduction among latanoprost users than among timolol users. The differences were statistically significant at all time points (1, 2, 4, 8, 12, and 24 weeks). More ocular adverse effects (OR = 1.49, 95% CI, 1.05~2.10, P = 0.02) and less systemic adverse events (OR = 0.46, 95% CI, 0.25~0.84, P = 0.01) were observed in latanoprost group in comparison with timolol group. CONCLUSION: Compared with timolol, latanoprost was significantly more effective in lowering IOP of Asian patients with CACG, with higher risk of ocular adverse effects but lower risk of systemic adverse events, and might be a good substitute for CACG patients. PMID- 24816234 TI - IGH@ translocations co-exist with other primary rearrangements in B-cell precursor acute lymphoblastic leukemia. AB - Primary established genetic abnormalities in B-cell precursor acute lymphoblastic leukemia include high hyperdiploidy (51-65 chromosomes), the translocations t(12;21)(p13;q22)/ETV6-RUNX1 fusion and t(9;22)(q34;q11)/BCR-ABL1 fusion, MLL rearrangements and intrachromosomal amplification of chromosome 21. These rearrangements are of prognostic and therapeutic relevance and are usually mutually exclusive. We identified 28 patients at diagnosis with both a primary genetic rearrangement and an immunoglobulin heavy chain locus translocation using chromosomal analysis and fluorescence in situ hybridization. Among these patients, the immunoglobulin heavy chain locus translocation partner gene was identified in six (CRLF2, CEBPA, CEBPB, TRA/D@, IGF2BP1 and IGK@). Clonal architecture was investigated in 17 patients using multiple color interphase fluorescence in situ hybridization analysis, which showed that the translocation was acquired as a secondary abnormality in ten patients, in four patients the etiology was undetermined and in three patients it was observed in a separate clone from the primary chromosomal rearrangement. These findings demonstrate the co-existence of immunoglobulin heavy chain locus translocations with other primary chromosomal rearrangements either in the same or separate clones, which may have prognostic significance in B-cell precursor acute lymphoblastic leukemia. Clinical trials: UKALLXII: Study ID n. ISRCTN77346223 and ALL2003: Study ID n. ISRCTN07355119. PMID- 24816235 TI - No evidence of hypermutability in red cells from patients with paroxysmal nocturnal hemoglobinuria using the XK gene. PMID- 24816236 TI - Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - Oral busulfan is the historical backbone of the busulfan+cyclophosphamide regimen for autologous stem cell transplantation. However intravenous busulfan has more predictable pharmacokinetics and less toxicity than oral busulfan; we, therefore, retrospectively analyzed data from 952 patients with acute myeloid leukemia who received intravenous busulfan for autologous stem cell transplantation. Most patients were male (n=531, 56%), and the median age at transplantation was 50.5 years. Two-year overall survival, leukemia-free survival, and relapse incidence were 67+/-2%, 53+/-2%, and 40+/-2%, respectively. The non-relapse mortality rate at 2 years was 7+/-1%. Five patients died from veno-occlusive disease. Overall leukemia-free survival and relapse incidence at 2 years did not differ significantly between the 815 patients transplanted in first complete remission (52+/-2% and 40+/-2%, respectively) and the 137 patients transplanted in second complete remission (58+/-5% and 35+/-5%, respectively). Cytogenetic risk classification and age were significant prognostic factors: the 2-year leukemia free survival was 63+/-4% in patients with good risk cytogenetics, 52+/-3% in those with intermediate risk cytogenetics, and 37 +/- 10% in those with poor risk cytogenetics (P=0.01); patients <=50 years old had better overall survival (77+/ 2% versus 56+/-3%; P<0.001), leukemia-free survival (61+/-3% versus 45+/-3%; P<0.001), relapse incidence (35+/-2% versus 45+/-3%; P<0.005), and non-relapse mortality (4+/-1% versus 10+/-2%; P<0.001) than older patients. The combination of intravenous busulfan and high-dose melphalan was associated with the best overall survival (75+/-4%). Our results suggest that the use of intravenous busulfan simplifies the autograft procedure and confirm the usefulness of autologous stem cell transplantation in acute myeloid leukemia. As in allogeneic transplantation, veno-occlusive disease is an uncommon complication after an autograft using intravenous busulfan. PMID- 24816237 TI - Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients. AB - Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic transplantation in recipients aged 50 years and over. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. A total of 203 patients completed geriatric assessment and underwent transplant. Median age was 58 years (range 50-73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95%CI: 1.59-3.56; P<0.001), slow walk speed (HR 1.80, 95%CI: 1.14-2.83; P=0.01), high comorbidity by hematopoietic cell transplantation specific comorbidity index (HR 1.56, 95%CI: 1.07-2.28; P=0.02), low mental health by short-form-36 mental component summary (HR 1.67, 95%CI: 1.13-2.48; P=0.01), and elevated serum C-reactive protein (HR 2.51, 95%CI: 1.54-4.09; P<0.001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and over. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid appropriate selection of older adults. PMID- 24816238 TI - Therapeutic effects of induced pluripotent stem cells in chimeric mice with beta thalassemia. AB - Although beta-thalassemia is one of the most common human genetic diseases, there is still no effective treatment other than bone marrow transplantation. Induced pluripotent stem cells have been considered good candidates for the future repair or replacement of malfunctioning organs. As a basis for developing transgenic induced pluripotent stem cell therapies for thalassemia, beta(654) induced pluripotent stem cells from a beta(654) -thalassemia mouse transduced with the normal human beta-globin gene, and the induced pluripotent stem cells with an erythroid-expressing reporter GFP were used to produce chimeric mice. Using these chimera models, we investigated changes in various pathological indices including hematologic parameters and tissue pathology. Our data showed that when the chimerism of beta(654) induced pluripotent stem cells with the normal human beta globin gene in beta(654) mice is over 30%, the pathology of anemia appeared to be reversed, while chimerism ranging from 8% to 16% provided little improvement in the typical beta-thalassemia phenotype. Effective alleviation of thalassemia related phenotypes was observed when chimerism with the induced pluripotent stem cells owning the erythroid-expressing reporter GFP in beta(654) mouse was greater than 10%. Thus, 10% or more expression of the exogenous normal beta-globin gene reduces the degree of anemia in our beta-thalassemia mouse model, whereas treatment with beta(654) induced pluripotent stem cells which had the normal human beta-globin gene had stable therapeutic effects but in a more dose dependent manner. PMID- 24816239 TI - Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies. AB - A multistep model has been proposed of disease progression starting in monoclonal gammopathy of undetermined significance continuing through multiple myeloma, sometimes with an intermediate entity called smoldering myeloma, and ending in extramedullary disease. To gain further insights into the role of the transcriptome deregulation in the transition from a normal plasma cell to a clonal plasma cell, and from an indolent clonal plasma cell to a malignant plasma cell, we performed gene expression profiling in 20 patients with monoclonal gammopathy of undetermined significance, 33 with high-risk smoldering myeloma and 41 with multiple myeloma. The analysis showed that 126 genes were differentially expressed in monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma as compared to normal plasma cell. Interestingly, 17 and 9 out of the 126 significant differentially expressed genes were small nucleolar RNA molecules and zinc finger proteins. Several proapoptotic genes (AKT1 and AKT2) were down-regulated and antiapoptotic genes (APAF1 and BCL2L1) were up-regulated in multiple myeloma, both symptomatic and asymptomatic, compared to monoclonal gammopathy of undetermined significance. When we looked for those genes progressively modulated through the evolving stages of monoclonal gammopathies, eight snoRNA showed a progressive increase while APAF1, VCAN and MEGF9 exhibited a progressive downregulation. In conclusion, our data show that although monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma are not clearly distinguishable groups according to their gene expression profiling, several signaling pathways and genes were significantly deregulated at different steps of the transformation process. PMID- 24816241 TI - Adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia is associated with glucocorticoid receptor polymorphisms ER22/23EK and BclI. PMID- 24816240 TI - Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. AB - Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10(-6)). One hundred and twenty-seven patients (80.4%) achieved complete remission after induction therapy and, of these, 56 patients (44.1%) relapsed. At each checkpoint, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 was associated with a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for patients with ratios above the cut-off versus 26.4% for those with ratios below the cut-off. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separated the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the course of minimal residual disease in an individual is an important prognostic factor and could be included in clinical trials for the guidance of post-remission therapy. The trials from which data were obtained were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230). PMID- 24816242 TI - Mapping epigenetic regulator gene mutations in cytogenetically normal pediatric acute myeloid leukemia. PMID- 24816243 TI - Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. AB - Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25*10(9)/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia. PMID- 24816244 TI - Knowledge, perceptions, and environmental risk factors among Jamaican households with a history of leptospirosis. AB - BACKGROUND: Leptospirosis is a globally important zoonotic disease caused by pathogenic Leptospira, and outbreaks typically follow heavy rainfall and flooding. This study examined the knowledge and perceptions concerning leptospirosis, factors associated with environmental hygiene and sanitation, and the presence of Leptospira in water samples from households with or without a history of the disease in the parish of St. Mary, Jamaica. METHODS: The study employed a cross-sectional design in 43 communities within the parish of St. Mary, Jamaica between September 2008 and March 2009. Households that had at least one confirmed case of leptospirosis during the 2005 or 2007 outbreaks were assessed for living conditions, environmental hygiene, and for knowledge and risk perceptions about leptospirosis. A parallel sampling scheme was used for households with no reported cases during the outbreak years. RESULTS: Almost 97% of the participants reported having heard of leptospirosis; however, less than 40% of respondents from households with a history of leptospirosis agreed that leptospirosis was a problem in the parish. Among households without a history of leptospirosis, this perception was greater in urban/peri-urban households than in rural households (59% vs. 21%; p=0.04). Risk behaviors or living conditions were common; however, there was a high level of awareness about the health risks associated with flooding. Among households with history of leptospirosis, the perception that nothing can be done to control rodents was significantly higher (p<0.04) in rural (50%) than in urban/peri-urban (17.6%) households. Nine (4%) water samples were positive for Leptospira; 56% of these were from water stored for domestic purposes. Overall, residence in rural communities, presence of a garbage dump, and leptospiral DNA in water samples correlated with households with the history of the disease (p<0.01). CONCLUSIONS: Education of rural communities regarding leptospirosis and its prevention through proper waste disposal and rodent control should be urgently initiated. PMID- 24816245 TI - Effect of the meso-substituent in the Huckel-to-Mobius topological switches. AB - Expanded porphyrins have emerged as a new promising class of molecules for the creation of new Huckel-to-Mobius topological switches with distinct aromaticities and magnetic and electric properties. In this work, we report a theoretical investigation of the conformational switch between the Huckel planar and the singly twisted Mobius structure for eight different meso-substituted [28] hexaphyrins (with different steric effects and electron-withdrawing and releasing character). Our results show how a change in the nature of the meso substituent is able to turn an endothermic interconversion process with a high energy barrier into an exothermic and almost barrierless Huckel-Mobius transition. We also provide a thorough analysis of the main factors (aromaticity, intramolecular hydrogen bonds, ring strain, and steric effects) that play a role in this interconversion process. Overall, these results are very relevant to find new ways to control the thermochemistry and kinetics of these topological switches and even "freeze" the switch in the desired Mobius or Huckel conformation. PMID- 24816247 TI - Developments in treatments for amyotrophic lateral sclerosis via intracerebroventricular or intrathecal delivery. AB - INTRODUCTION: Amyotrophic lateral scleroses (ALS) are neurodegenerative disorders primarily affecting the motor system. These incurable disorders are relentlessly progressive and typically limit survival to 2 - 5 years after disease onset. An improved knowledge about disease-causing genes, disease proteins and pathways has revealed considerable heterogeneity in ALS. Novel targeted therapies are being developed, but getting these beyond the BBB remains a challenge. AREAS COVERED: The authors review the intracerebroventricular and intrathecal delivery of drugs for the treatment of ALS in preclinical and clinical studies. EXPERT OPINION: Lack of BBB permeability should not hold back the development of promising treatments for ALS, as the available evidence suggest that direct intrathecal or intracerebroventricular administration of drug is a feasible delivery route in patients with ALS. PMID- 24816246 TI - Barriers to patient portal access among veterans receiving home-based primary care: a qualitative study. AB - BACKGROUND: Electronic, or web-based, patient portals can improve patient satisfaction, engagement and health outcomes and are becoming more prevalent with the advent of meaningful use incentives. However, adoption rates are low, particularly among vulnerable patient populations, such as those patients who are home-bound with multiple comorbidities. Little is known about how these patients view patient portals or their barriers to using them. OBJECTIVE: To identify barriers to and facilitators of using My HealtheVet (MHV), the United States Department of Veterans Affairs (VA) patient portal, among Veterans using home based primary care services. DESIGN: Qualitative study using in-depth semi structured interviews. We conducted a content analysis informed by grounded theory. PARTICIPANTS: Fourteen Veterans receiving home-based primary care, surrogates of two of these Veterans, and three home-based primary care (HBPC) staff members. KEY RESULTS: We identified five themes related to the use of MHV: limited knowledge; satisfaction with current HBPC care; limited computer and Internet access; desire to learn more about MHV and its potential use; and value of surrogates acting as intermediaries between Veterans and MHV. CONCLUSIONS: Despite their limited knowledge of MHV and computer access, home-bound Veterans are interested in accessing MHV and using it as an additional point of care. Surrogates are also potential users of MHV on behalf of these Veterans and may have different barriers to and benefits from use. PMID- 24816248 TI - The associations of race/ethnicity and suicidal ideation among college students: a latent class analysis examining precipitating events and disclosure patterns. AB - The aim of this paper was to examine precipitating events for suicidal ideation and how these experiences relate to disclosure in a diverse sample of college students were examined. Among non-Hispanic White students, relationship/academic problems were most associated with ideation. A romantic break-up increased the odds of getting help. Among racial/ethnic minority students, family/academic problems were most associated with ideation and students who reported multiple events were less likely to get help compared with those not reporting events. Future research should examine the reasons for interpersonal conflict among this high-risk group and their attitudes about help-seeking, and identify cultural norms associated with disclosure. PMID- 24816250 TI - Skill training for swallowing rehabilitation in patients with Parkinson's disease. AB - OBJECTIVE: To examine the effects of skill training on swallowing in individuals with dysphagia secondary to Parkinson's disease (PD) and to explore skill retention after treatment termination. DESIGN: Within-subject pilot study with follow-up after 2 weeks of treatment and after a 2-week nontreatment period. SETTING: Clinic in a research institute. PARTICIPANTS: Patients (N=10; mean age, 67.4y) included 3 women (mean Hoehn and Yahr score, 2.6) and 7 men (mean Hoehn and Yahr score, 2.4). INTERVENTION: Patients underwent 10 daily sessions of skill training therapy focused on increasing precision in muscle contraction during swallowing using visual feedback. MAIN OUTCOME MEASURES: Data from the timed water swallow test, Test of Mastication and Swallowing Solids, surface electromyography (sEMG) of submental muscles, and swallowing-related quality of life questionnaire were collected at 2 baseline sessions (conducted 2wk apart) at the end of treatment and after 2 nontreatment weeks to assess skill retention. RESULTS: Immediately after posttreatment, the swallowing rate for liquids (P=.034), sEMG durational parameters of premotor time (P=.003), and preswallow time (P<.001) improved. A functional carryover effect was seen from dry to water swallows (P=.009). Additionally, swallowing-related quality of life improved (P=.018). Reassessment at 2 weeks after treatment termination revealed short-term retention of treatment effects. CONCLUSIONS: A skill-based training approach produced functional, biomechanical, and swallowing-related quality of life improvements in this cohort indicating compelling evidence for the effectiveness of this novel approach for dysphagia rehabilitation in PD. PMID- 24816249 TI - Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERalpha expression in initially ERalpha+ breast cancer cells. AB - Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERalpha) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross talk' between ERalpha and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERalpha+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERalpha signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERalpha expression in initially ERalpha+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERalphalow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients. PMID- 24816251 TI - Basal ganglia and restricted and repetitive behaviours in Autism Spectrum Disorders: current status and future perspectives. AB - This editorial offers a concise overview of the recent structural magnetic resonance imaging studies that evaluate the basal ganglia (BG) volumes in autism spectrum disorders (ASD). The putative relationship between the repetitive or stereotyped behaviours of ASD and BG volumes is also explored, with a focus on possible translational approaches. PMID- 24816252 TI - An atlas of genetic influences on human blood metabolites. AB - Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease. Here we report the most comprehensive exploration of genetic loci influencing human metabolism thus far, comprising 7,824 adult individuals from 2 European population studies. We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity with more than 400 metabolites in human blood. We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information on gene expression, heritability and overlap with known loci for complex disorders, inborn errors of metabolism and pharmacological targets. We further developed a database and web-based resources for data mining and results visualization. Our findings provide new insights into the role of inherited variation in blood metabolic diversity and identify potential new opportunities for drug development and for understanding disease. PMID- 24816253 TI - Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. AB - Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy. PMID- 24816254 TI - The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome. AB - Parental imprinting is a form of epigenetic regulation that results in parent-of origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1-DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region. PMID- 24816255 TI - Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. AB - Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction. We performed whole exome sequencing on 30 DGC cases and found recurrent RHOA nonsynonymous mutations. With validation sequencing of an additional 57 cases, RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein. These positions are highly conserved among RHO family members, and Tyr42 and Arg5 are located outside the guanine nucleotide-binding pocket. Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner. Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs, the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa. Our findings identify a potential therapeutic target for this poor-prognosis subtype of gastric cancer with no available molecularly targeted drugs. PMID- 24816256 TI - Spermatid count as a predictor of response to FSH therapy. AB - This study evaluated the predictive power of spermatid count and cytology for assisted reproduction outcome after FSH therapy. A total of 174 men with severe oligozoospermia and normal plasma FSH concentration underwent semen analysis including spermatid count, TUNEL test, FISH analysis for sperm aneuploidies and testicular fine-needle aspiration cytology. Ninety-two men with hypospermatogenesis received FSH therapy for 3 months and 82 patients with maturative disturbance or partial obstruction served as controls. Semen was analysed at baseline, after FSH therapy and after 3- and 9-month follow up, and pregnancies were recorded. Subjects not reaching pregnancy at 3-month follow up were recommended assisted reproduction treatment. Spermatid count was related to testicular cytology: spermatid concentrations <0.01, 0.01-0.3 and >0.3 * 10(6)/ml were predictive of partial obstruction, hypospermatogenesis and maturative disturbance. FSH therapy patients showed increases in sperm number and motility (both P < 0.001), allowing some couples to undergo intrauterine insemination instead of IVF. Cumulative pregnancy rate after 12 months was higher with FSH therapy (44.6%) than without (22.0%; P = 0.002). FSH therapy improved pregnancy rate and sometimes allowed less invasive assisted reproduction treatment in well selected patients. Spermatid count could represent a new parameter to predict response to FSH therapy. One-hundred seventy-four patients with severe reduction of sperm count and normal sex hormones plasma levels underwent semen analysis with spermatid count, and testicular fine needle aspiration cytologiy (FNAC). Ninety-two men infertile men with reduced sperm production (hypospermatogenesis) were treated with highly purified urofollitropin and 82 patients with sperm maturative defects or partial obstruction of the seminal tract served as controls. After treatment and after the following 3 and 9 months all subjects performed a new semen analysis and pregnancies were recorded. Subjects who had not reached spontaneous pregnancy were suggested to undergo assisted reproductive techniques (ARTs). Spermatid count was strongly related to testicular cytology: spermatid concentrations were predictive of partial obstruction, hypospermatogenesis and maturative disturbance respectively. Treated patients showed significant increase in sperm number and motility allowing some couples to undergo easier and less invasive assisted reproductive techniques. The number of pregnancies was significantly higher among treated (44.6%) than untreated couples (22.0%). Our data confirmed that FSH treatment can induce a significant improvemet of pergnancy rate and sometimes allows less invasive ARTs use in well selected severe oligozoospermic patients. Moreover, we suggest that spermatid count can be useful to define tubular status and could represent a new parameter to predict response to FSH therapy. PMID- 24816257 TI - Coronary responses to cold air inhalation following afferent and efferent blockade. AB - Cardiac ischemia and angina pectoris are commonly experienced during exertion in a cold environment. In the current study we tested the hypotheses that oropharyngeal afferent blockade (i.e., local anesthesia of the upper airway with lidocaine) as well as systemic beta-adrenergic receptor blockade (i.e., intravenous propranolol) would improve the balance between myocardial oxygen supply and demand in response to the combined stimulus of cold air inhalation ( 15 to -30 degrees C) and isometric handgrip exercise (Cold + Grip). Young healthy subjects underwent Cold + Grip following lidocaine, propranolol, and control (no drug). Heart rate, blood pressure, and coronary blood flow velocity (CBV, from Doppler echocardiography) were continuously measured. Rate-pressure product (RPP) was calculated, and changes from baseline were compared between treatments. The change in RPP at the end of Cold + Grip was not different between lidocaine (2,441 +/- 376) and control conditions (3,159 +/- 626); CBV responses were also not different between treatments. With propranolol, heart rate (8 +/- 1 vs. 14 +/ 3 beats/min) and RPP responses to Cold + Grip were significantly attenuated. However, at peak exercise propranolol also resulted in a smaller DeltaCBV (1.4 +/ 0.8 vs. 5.3 +/- 1.4 cm/s, P = 0.035), such that the relationship between coronary flow and cardiac metabolism was impaired under propranolol (0.43 +/- 0.37 vs. 2.1 +/- 0.63 arbitrary units). These data suggest that cold air breathing and isometric exercise significantly influence efferent control of coronary blood flow. Additionally, beta-adrenergic vasodilation may play a significant role in coronary regulation during exercise. PMID- 24816258 TI - Systemic vascular effects of acute electrical baroreflex stimulation. AB - We intended to determine if acute baroreflex activation therapy (BAT) increases venous capacitance and aortic conductance. BAT is effective in resistant hypertension, but its effect on the systemic vasculature is poorly understood. Left ventricular (LV) and aortic pressures and subdiaphragmatic aortic and caval flows (ultrasonic) were measured in six anesthetized dogs. Changes in abdominal blood volume (Vabdominal) were estimated as the integrated difference in abdominal aortic inflow and caval outflow. An electrode was implanted on the right carotid sinus. Data were measured during control and BAT. Next, sodium nitroprusside (SNP) was infused and BAT was subsequently added. Finally, angiotensin II (ANG II) was infused, and three increased BAT currents were added. We found that BAT decreased mean aortic pressure (PAo) by 22.5 +/- 1.3 mmHg (P < 0.001) and increased aortic conductance by 16.2 +/- 4.9% (P < 0.01) and Vabdominal at a rate of 2.2 +/- 0.6 ml.kg(-1).min(-1) (P < 0.01). SNP decreased PAo by 17.4 +/- 0.7 mmHg (P < 0.001) and increased Vabdominal at a rate of 2.2 +/ 0.7 ml.kg(-1).min(-1) (P < 0.05). During the SNP infusion, BAT decreased PAo further, by 26.0 +/- 2.1 mmHg (P < 0.001). ANG II increased PAo by 40.4 +/- 3.5 mmHg (P = 0.001). When an increased BAT current was added, PAo decreased to baseline (P < 0.01) while aortic conductance increased from 62.3 +/- 5.2% to 80.2 +/- 3.3% (P < 0.05) of control. Vabdominal increased at a rate of 1.8 +/- 0.9 ml.kg(-1).min(-1) (P < 0.01), reversing the ANG II effects. In conclusion, BAT increases arterial conductance, decreases PAo, and increases venous capacitance even in the presence of powerful vasoactive drugs. Increasing venous capacitance may be an important effect of BAT in hypertension. PMID- 24816259 TI - Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries. AB - The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in the maternal environment during pregnancy. We hypothesized that maternal nutrient restriction during pregnancy alters vasodilator responses in fetal coronary arteries. Pregnant ewes were fed a control [100% U.S. National Research Council (NRC)] or nutrient-restricted (60% NRC) diet from days 50 to 130 of gestation (term = 145 days); fetal tissues were collected at day 130. In coronary arteries isolated from control fetal lambs, relaxation to bradykinin was unaffected by nitro-l-arginine (NLA). Iberiotoxin or contraction with KCl abolished the NLA resistant response to bradykinin. In fetal coronary arteries from nutrient restricted ewes, relaxation to bradykinin was fully suppressed by NLA. Large conductance, calcium-activated potassium channel (BKCa) currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa openers, BMS 191011 and NS1619, and 14,15-epoxyeicosatrienoic acid [a putative endothelium-derived hyperpolarizing factor (EDHF)] each caused fetal coronary artery relaxation and BKCa current activation that was unaffected by maternal nutrient restriction. Expression of BKCa-channel subunits did not differ in fetal coronary arteries from control or undernourished ewes. The results indicate that maternal undernutrition during pregnancy results in loss of the EDHF-like pathway in fetal coronary arteries in response to bradykinin, an effect that cannot be explained by a decreased number or activity of BKCa channels or by decreased sensitivity to mediators that activate BKCa channels in vascular smooth muscle cells. Under these conditions, bradykinin-induced relaxation is completely dependent on nitric oxide, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway. PMID- 24816260 TI - Exercise training improves functional sympatholysis in spontaneously hypertensive rats through a nitric oxide-dependent mechanism. AB - Functional sympatholysis is impaired in hypertensive animals and patients. Exercise training (ET) improves functional sympatholysis through a nitric oxide (NO)-dependent mechanism in normotensive rats. However, whether ET has similar physiological benefits in hypertension remains to be elucidated. Thus we tested the hypothesis that the impairment in functional sympatholysis in hypertension is reversed by ET through a NO-dependent mechanism. In untrained normotensive Wistar Kyoto rats (WKYUT; n = 13), untrained spontaneously hypertensive rats (SHRUT; n = 13), and exercise-trained SHR (SHRET; n = 6), changes in femoral vascular conductance (FVC) were examined during lumbar sympathetic nerve stimulation (1, 2.5, and 5 Hz) at rest and during muscle contraction. The magnitude of functional sympatholysis (Delta%FVC = Delta%FVC muscle contraction - Delta%FVC rest) in SHRUT was significantly lower than WKYUT (1 Hz: -2 +/- 4 vs. 13 +/- 3%; 2.5 Hz: 9 +/- 3 vs. 21 +/- 3%; and 5 Hz: 12 +/- 3 vs. 26 +/- 3%, respectively; P < 0.05). Three months of voluntary wheel running significantly increased maximal oxygen uptake in SHRET compared with nontrained SHRUT (78 +/- 6 vs. 62 +/- 4 ml.kg( 1).min(-1), respectively; P < 0.05) and restored the magnitude of functional sympatholysis in SHRET (1 Hz: 9 +/- 2%; 2.5 Hz: 20 +/- 4%; and 5 Hz: 34 +/- 5%). Blockade of NO synthase (NOS) by N(G)-nitro-l-arginine methyl ester attenuated functional sympatholysis in WKYUT but not SHRUT. Furthermore, NOS inhibition significantly diminished the improvements in functional sympatholysis in SHRET. These data demonstrate that impairments in functional sympatholysis are normalized via a NO mechanism by voluntary wheel running in hypertensive rats. PMID- 24816261 TI - Gi proteins mediate activation of the canonical hedgehog pathway in the myocardium. AB - During myocardial ischemia, upregulation of the hedgehog (Hh) pathway promotes neovascularization and increases cardiomyocyte survival. The canonical Hh pathway activates a transcriptional program through the Gli family of transcription factors by derepression of the seven-transmembrane protein smoothened (Smo). The mechanisms linking Smo to Gli are complex and, in some cell types, involve coupling of Smo to Gi proteins. In the present study, we investigated, for the first time, the transcriptional response of cardiomyocytes to sonic hedgehog (Shh) and the role of Gi protein utilization. Our results show that Shh strongly activates Gli1 expression by quantitative PCR in a Smo-dependent manner in neonatal rat ventricular cardiomyocytes. Microarray analysis of gene expression changes elicited by Shh and sensitive to a Smo inhibitor identified a small subset of 37 cardiomyocyte-specific genes regulated by Shh, including some in the PKA and purinergic signaling pathways. In addition, neonatal rat ventricular cardiomyocytes infected with an adenovirus encoding GiCT, a peptide that impairs receptor-Gi protein coupling, showed reduced activation of Hh targets. In vitro data were confirmed in transgenic mice with cardiomyocyte-inducible GiCT expression. Transgenic GiCT mice showed specific reduction of Gli1 expression in the heart under basal conditions and failed to upregulate the Hh pathway upon ischemia and reperfusion injury, unlike their littermate controls. This study characterizes, for the first time, the transcriptional response of cardiomyocytes to Shh and establishes a critical role for Smo coupling to Gi in Hh signaling in the normal and ischemic myocardium. PMID- 24816262 TI - Cell-generated traction forces and the resulting matrix deformation modulate microvascular alignment and growth during angiogenesis. AB - The details of the mechanical factors that modulate angiogenesis remain poorly understood. Previous in vitro studies of angiogenesis using microvessel fragments cultured within collagen constructs demonstrated that neovessel alignment can be induced via mechanical constraint of the boundaries (i.e., boundary conditions). The objective of this study was to investigate the role of mechanical boundary conditions in the regulation of angiogenic alignment and growth in an in vitro model of angiogenesis. Angiogenic microvessels within three-dimensional constructs were subjected to different boundary conditions, thus producing different stress and strain fields during growth. Neovessel outgrowth and orientation were quantified from confocal image data after 6 days. Vascularity and branching decreased as the amount of constraint imposed on the culture increased. In long-axis constrained hexahedral constructs, microvessels aligned parallel to the constrained axis. In contrast, constructs that were constrained along the short axis had random microvessel orientation. Finite element models were used to simulate the contraction of gels under the various boundary conditions and to predict the local strain field experienced by microvessels. Results from the experiments and simulations demonstrated that microvessels aligned perpendicular to directions of compressive strain. Alignment was due to anisotropic deformation of the matrix from cell-generated traction forces interacting with the mechanical boundary conditions. These findings demonstrate that boundary conditions and thus the effective stiffness of the matrix regulate angiogenesis. This study offers a potential explanation for the oriented vascular beds that occur in native tissues and provides the basis for improved control of tissue vascularization in both native tissues and tissue-engineered constructs. PMID- 24816264 TI - Protective role of Arapaima gigas fish scales: structure and mechanical behavior. AB - The scales of the arapaima (Arapaima gigas), one of the largest freshwater fish in the world, can serve as inspiration for the design of flexible dermal armor. Each scale is composed of two layers: a laminate composite of parallel collagen fibrils and a hard, highly mineralized surface layer. We review the structure of the arapaima scales and examine the functions of the different layers, focusing on the mechanical behavior, including tension and penetration of the scales, with and without the highly mineralized outer layer. We show that the fracture of the mineral and the stretching, rotation and delamination of collagen fibrils dissipate a significant amount of energy prior to catastrophic failure, providing high toughness and resistance to penetration by predator teeth. We show that the arapaima's scale has evolved to minimize damage from penetration by predator teeth through a Bouligand-like arrangement of successive layers, each consisting of parallel collagen fibrils with different orientations. This inhibits crack propagation and restricts damage to an area adjoining the penetration. The flexibility of the lamellae is instrumental to the redistribution of the compressive stresses in the underlying tissue, decreasing the severity of the concentrated load produced by the action of a tooth. The experimental results, combined with small-angle X-ray scattering characterization and molecular dynamics simulations, provide a complete picture of the mechanisms of deformation, delamination and rotation of the lamellae during tensile extension of the scale. PMID- 24816266 TI - Endothelin modulates the circadian expression of non-visual opsins. AB - The non-visual opsin, melanopsin, expressed in the mammalian retina, is considered a circadian photopigment because it is responsible to entrain the endogenous biological clock. This photopigment is also present in the melanophores of Xenopus laevis, where it was first described, but its role in these cells is not fully understood. X. laevis melanophores respond to light with melanin granule dispersion, the maximal response being achieved at the wavelength of melanopsin maximal excitation. Pigment dispersion can also be triggered by endothelin-3 (ET-3). Here we show that melanin translocation is greater when a blue light pulse was applied in the presence of ET-3. In addition, we demonstrated that mRNA levels of the melanopsins Opn4x and Opn4m exhibit temporal variation in melanophores under light/dark (LD) cycles or constant darkness, suggesting that this variation is clock-driven. Moreover, under LD cycles the oscillations of both melanopsins show a circadian profile suggesting a role for these opsins in the photoentrainment mechanism. Blue-light pulse decreased Opn4x expression, but had no effect on Opn4m. ET-3 abolishes the circadian rhythm of expression of both opsins; in addition the hormone increases Opn4x expression in a dose-, circadian time- and light-dependent way. ET-3 also increases the expression of its own receptor, in a dose-dependent manner. The variation of melanopsin levels may represent an adaptive mechanism to ensure greater melanophore sensitivity in response to environmental light conditions with ideal magnitude in terms of melanin granule dispersion, and consequently color change. PMID- 24816267 TI - Infection of corn ears by Fusarium spp. induces the emission of volatile sesquiterpenes. AB - Infection of corn (Zea mays L.) ears with fungal pathogens of the Fusarium genus might result in yield losses and in the accumulation of mycotoxins. The aim of this study was to investigate whether volatile profiles could be used to identify Fusarium-infected corn ears. The volatiles released by corn ears infected by Fusarium graminearum, Fusarium verticillioides, and Fusarium subglutinans were studied. Volatile emission was recorded at 24 days postinoculation (dpi) and in a time series (from 4 to 24 dpi). Twenty-two volatiles were differentially emitted from Fusarium-infected versus healthy corn ears. These included C6-C8 compounds and sesquiterpenoids. All volatiles indicative of Fusarium infection were detectable as early as 4-8 dpi and continued to be produced to the final sampling time (early milk maturity stage). The induced emission of beta-macrocarpene and beta-bisabolene correlated with an increased transcript accumulation of corn terpene synthase 6/11 (tps6/11). Additionally, the modification of volatile profiles after Fusarium infection was accompanied by the induction of plant defense compounds such as zealexins and oxylipins. Together, these results reveal a broad metabolic response of the plant to pathogen attack. Volatile biomarkers of Fusarium infection are promising indicators for the early detection of fungal infection before disease symptoms become visible. PMID- 24816265 TI - Post-transcriptional regulation in osteoblasts using localized delivery of miR 29a inhibitor from nanofibers to enhance extracellular matrix deposition. AB - MicroRNAs are important post-transcriptional regulators of skeletal biology, and miRNA-based therapeutics have the potential to aid bone repair. However, efficient tools for delivering miRNA mimics or inhibitors to specific target tissues are limited. Polymeric nanofibers closely mimic natural extracellular matrix (ECM) morphology, and are attractive candidates for supporting delivery of cells and bone-anabolic reagents. It is hypothesized that gelatin nanofibers could be used for the localized transient delivery of miRNA-based therapeutics, using miR-29a inhibitor as a prototype to increase ECM deposition. miR-29 family members are negative regulators of ECM synthesis, targeting the mRNAs of selected collagens and osteonectin/SPARC. Inhibiting miR-29 activity may therefore increase ECM production by cells. miR-29a inhibitor-loaded gelatin nanofibers, prepared by electrospinning, demonstrated continuous release of miRNA inhibitor over 72h. Pre-osteoblastic murine MC3T3-E1 cell line seeded on miR-29a inhibitor loaded nanofibers synthesized more osteonectin, indicating efficient inhibitor delivery. These cells also displayed increased Igf1 and Tgfb1 mRNA. Moreover, primary bone marrow stromal cells from transgenic pOBCol3.6cyan reporter mice, grown on miR-29a inhibitor scaffolds, displayed increased col3.6 cyan expression as well as collagen production. This study demonstrates that ECM mimicking nanostructured scaffolds, in conjunction with bioactive miRNA-based therapeutics, may serve as a novel platform for developing biologically active localized cell delivery systems. PMID- 24816268 TI - Optical trapping and binding of particles in an optofluidic stable Fabry-Perot resonator with single-sided injection. AB - In this article, microparticles are manipulated inside an optofluidic Fabry-Perot cylindrical cavity embedding a fluidic capillary tube, taking advantage of field enhancement and multiple reflections within the optically-resonant cavity. This enables trapping of suspended particles with single-side injection of light and with low optical power. A Hermite-Gaussian standing wave is developed inside the cavity, forming trapping spots at the locations of the electromagnetic field maxima with a strong intensity gradient. The particles get arranged in a pattern related to the mechanism affecting them: either optical trapping or optical binding. This is proven to eventually translate into either an axial one dimensional (1D) particle array or a cluster of particles. Numerical simulations are performed to model the field distributions inside the cavity allowing a behavioral understanding of the phenomena involved in each case. PMID- 24816269 TI - Parallel processing of shape and texture in haptic search. AB - In a haptic search task, one has to determine the presence of a target among distractors. It has been shown that if the target differs from the distractors in two properties, shape and texture, performance is better than in both single property conditions (Van Polanen, Bergmann Tiest, & Kappers, 2013). The search for a smooth sphere among rough cubical distractors was faster than both the searches for a rough sphere (shape information only) and for a smooth cube (texture information only). This effect was replicated in this study as a baseline. The main focus here was to further investigate the nature of this integration. It was shown that performance is better when the two properties are combined in a single target (smooth sphere), than when located in two separate targets (rough sphere and smooth cube) that are simultaneously present. A race model that assumes independent parallel processing of the two properties could explain the enhanced performance with two properties, but this could only take place effectively when the two properties were located in a single target. PMID- 24816270 TI - Individual differences in perspective taking and field-independence mediate structural persistence in dialog. AB - Speakers often reuse syntactic constructions recently produced by an interlocutor. As a form of conversational repetition, evidence for such structural persistence may depend on the extent to which different people are sensitive to the linguistic contributions of others. To investigate how individual differences might mediate the likelihood of structural persistence in dialog, two potential measures of such sensitivity - a measure of self-reported perspective taking and a measure of field-dependence/independence - were collected from participants who also worked with a confederate partner on a picture description task adopted from Branigan, Pickering, and Cleland (2000). Following prime descriptions produced by the confederate, participants produced target descriptions of ditransitive events that could be described with either prepositional dative (PD) or double object (DO) constructions. In general, participants who rated themselves higher in perspective taking and who were identified as more field-independent showed more evidence of repeating the partner's syntax; however, these patterns were limited to PD primes. Variability in sensitivity to others' perspectives, and variability in one's ability to attend to local structure, may shape the likelihood that interlocutors will display evidence for structural persistence in dialog. PMID- 24816271 TI - The role of effect grouping in free-choice response selection. AB - Which motor actions are preferred to replace an initially planned but momentary not executable action? Previous research (Khan, Mourton, Buckolz, Adams, & Hayes, 2010, Acta Psychologica) suggests that anatomical constraints seem to be a major determinant for such choices: For example, participants more frequently chose to respond with the finger homologous to the prepared one. We argue that in this case finger homology is confounded with action effect similarity, and action effects have been ascribed a crucial role in action selection. We report two experiments. Experiment 1 replicated the results obtained by Khan et al. In Experiment 2, we introduced visual action effects in the paradigm. Results from this experiment clearly point to a role of effect similarity in addition to mere finger homology status for the choice frequency effect. PMID- 24816272 TI - Crystal structure of Escherichia coli SsuE: defining a general catalytic cycle for FMN reductases of the flavodoxin-like superfamily. AB - The Escherichia coli sulfur starvation utilization (ssu) operon includes a two component monooxygenase system consisting of a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase, SsuE, and a monooxygenase, SsuD. SsuE is part of the flavodoxin-like superfamily, and we report here the crystal structures of its apo, FMN-bound, and FMNH2-bound forms at ~2 A resolution. In the crystals, SsuE forms a tetramer that is a dimer of dimers similar to those seen for homologous FMN reductases, quinone reductases, and the WrbA family of enzymes. A pi-helix present at the tetramer building interface is unique to the reductases from two-component monooxygenase systems. Analytical ultracentrifugation studies of SsuE confirm a dimer-tetramer equilibrium exists in solution, with FMN binding favoring the dimer. As the active site includes residues from both subunits, at least a dimeric association is required for the function of SsuE. The structures show that one FMN binds tightly in a deeply held site, which makes available a second binding site, in which either a second FMN or the nicotinamide of NADPH can bind. The FMNH2-bound structure shows subtle changes consistent with its binding being weaker than that of FMN. Combining this information with published kinetic studies, we propose a general catalytic cycle for two-component reductases of the flavodoxin-like superfamily, by which the enzyme can potentially provide FMNH2 to its partner monooxygenase by different routes depending on the FMN concentration and the presence of a partner monooxygenase. PMID- 24816273 TI - A synthetic model for the oxygen-evolving complex in Sr(2+)-containing photosystem II. AB - A novel heterometallic MnSr complex containing the Mn3SrO4 cuboidal moiety and all types of MU-O(2-) moieties observed in the oxygen-evolving complex (OEC) in Sr(2+)-containing photosystem II (PSII) has been synthesized and characterized, which provides a new synthetic model of the OEC. PMID- 24816276 TI - Diversity of the molecular responses to separate wastewater effluents in freshwater mussels. AB - The environmental safety of pharmaceutical and personal care products (PPCPs) requires a crucial examination. The aim of this study was to evaluate the responses of biomarkers of stress and toxicity in freshwater mussels to the effect of commonly found PPCPs in wastewater. We treated male mussels Unio tumidus, from an undisturbed site with ibuprofen (IBU, 250 ng L(-1)), triclosan (TCS, 500 ng L(-1)), or estrone (E1, 100 ng L(-1)) for 14 days. Untreated mussels from this site (C) and mussels inhabiting a polluted area (P) were also examined after a similar time of being kept in the laboratory. The consequences of chronic exposure of the mussels in the P-group were reflected in elevated concentrations of oxyradicals (1.4 times), oxidized glutathione (4.3 times), lipofuscin (2.2 times), and DNA-strand breaks in the digestive gland (DG) in comparison to the C group, higher levels of caspase-3 activity in the DG, and vitellogenin-like proteins in gonads among all studied groups. Exposed mussels demonstrated some common responses with mussels in the P-group: elevated levels of lactate/pyruvate ratio, lipofuscin (IBU and E1), DNA fragmentation (TCS and E1), and caspase-3 activity (TCS and E1). Exposed to PPCPs mussels also showed elevation of ethoxyresorufin-O-deethylase and/or glutathione-S-transferase activity in the DG and a decrease in lysosomal stability in hemocytes (TCS and E1). The TCS group was distinguished by having the highest level of DNA-fragmentation and the lowest concentrations of total glutathione, oxyradicals, lipofuscin, pyruvate, and lactate, reflecting total metabolic depression. These results show that selected PPCPs at low concentrations alter a variety of physiological processes in this animal model system. PMID- 24816275 TI - Oceans of opportunity: exploring vertebrate hematopoiesis in zebrafish. AB - Exploitation of the zebrafish model in hematology research has surged in recent years, becoming one of the most useful and tractable systems for understanding regulation of hematopoietic development, homeostasis, and malignancy. Despite the evolutionary distance between zebrafish and humans, remarkable genetic and phenotypic conservation in the hematopoietic system has enabled significant advancements in our understanding of blood stem and progenitor cell biology. The strengths of zebrafish in hematology research lie in the ability to perform real time in vivo observations of hematopoietic stem, progenitor, and effector cell emergence, expansion, and function, as well as the ease with which novel genetic and chemical modifiers of specific hematopoietic processes or cell types can be identified and characterized. Further, myriad transgenic lines have been developed including fluorescent reporter systems to aid in the visualization and quantification of specified cell types of interest and cell-lineage relationships, as well as effector lines that can be used to implement a wide range of experimental manipulations. As our understanding of the complex nature of blood stem and progenitor cell biology during development, in response to infection or injury, or in the setting of hematologic malignancy continues to deepen, zebrafish will remain essential for exploring the spatiotemporal organization and integration of these fundamental processes, as well as the identification of efficacious small molecule modifiers of hematopoietic activity. In this review, we discuss the biology of the zebrafish hematopoietic system, including similarities and differences from mammals, and highlight important tools currently utilized in zebrafish embryos and adults to enhance our understanding of vertebrate hematology, with emphasis on findings that have impacted our understanding of the onset or treatment of human hematologic disorders and disease. PMID- 24816277 TI - Partner accommodation in posttraumatic stress disorder: initial testing of the Significant Others' Responses to Trauma Scale (SORTS). AB - Posttraumatic stress disorder (PTSD) is associated with myriad relationship problems and psychological distress in partners of individuals with PTSD. This study sought to develop a self-report measure of partner accommodation to PTSD (i.e., ways in which partners alter their behavior in response to patient PTSD symptoms), the Significant Others' Responses to Trauma Scale (SORTS), and to investigate its reliability and construct validity in 46 treatment-seeking couples. The SORTS demonstrated strong internal consistency and associations with individual and relationship distress. Accommodation was positively correlated with partners' ratings of patients' PTSD symptoms, patient self-reported depressive and trait anger severity, and partner self-reported depressive and state anger severity. Accommodation was negatively correlated with patient and partner relationship satisfaction and partners' perceived social support received from patients. Findings suggest that accommodation may be an attempt to adapt to living with a partner with PTSD but may have negative implications for patient and partner well-being. PMID- 24816274 TI - Hematopoietic transcriptional mechanisms: from locus-specific to genome-wide vantage points. AB - Hematopoiesis is an exquisitely regulated process in which stem cells in the developing embryo and the adult generate progenitor cells that give rise to all blood lineages. Master regulatory transcription factors control hematopoiesis by integrating signals from the microenvironment and dynamically establishing and maintaining genetic networks. One of the most rudimentary aspects of cell type specific transcription factor function, how they occupy a highly restricted cohort of cis-elements in chromatin, remains poorly understood. Transformative technologic advances involving the coupling of next-generation DNA sequencing technology with the chromatin immunoprecipitation assay (ChIP-seq) have enabled genome-wide mapping of factor occupancy patterns. However, formidable problems remain; notably, ChIP-seq analysis yields hundreds to thousands of chromatin sites occupied by a given transcription factor, and only a fraction of the sites appear to be endowed with critical, non-redundant function. It has become en vogue to map transcription factor occupancy patterns genome-wide, while using powerful statistical tools to establish correlations to inform biology and mechanisms. With the advent of revolutionary genome editing technologies, one can now reach beyond correlations to conduct definitive hypothesis testing. This review focuses on key discoveries that have emerged during the path from single loci to genome-wide analyses, specifically in the context of hematopoietic transcriptional mechanisms. PMID- 24816279 TI - Amorphous Fe2+-rich FeOx loaded in mesoporous silica as a highly efficient heterogeneous Fenton catalyst. AB - A simple physical-vapor-infiltration (PVI) method using ferrocene as the iron source, has been developed to load FeOx into the pore channels of mesoporous silica SBA-15. The obtained FeOx/SBA-15 composite has a high loading amount of FeOx (e.g. 26.64 wt% Fe content obtained at PVI duration 17 h and calcination temperature 450 degrees C) but unblocked pore channels thanks to the unique preparation strategy. The FeOx species are amorphous, rich of Fe(2+) and have been highly dispersed as a nanocoating onto the pore channel surface. The FeOx/SBA-15 composite was used as a heterogeneous Fenton catalyst to degrade Acid orange 7 (AO7). It showed a high catalytic activity and degradation efficiency, which was attributed to the high proportion of Fe(2+) in the amorphous FeOx and their favorable adsorption capability for the dye. The influences of the PVI duration, the calcination temperature and the Fenton reaction conditions (FeOx/SBA-15 dosages, H2O2 dosages and initial pH value) on the catalytic activity were investigated in detail. PMID- 24816278 TI - Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model. AB - Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome. PMID- 24816280 TI - Are the Antarctic dipteran, Eretmoptera murphyi, and Arctic collembolan, Megaphorura arctica, vulnerable to rising temperatures? AB - Polar terrestrial invertebrates are suggested as being vulnerable to temperature change relative to lower latitude species, and hence possibly also to climate warming. Previous studies have shown Antarctic and Arctic Collembola and Acari to possess good heat tolerance and survive temperature exposures above 30 degrees C. To test this feature further, the heat tolerance and physiological plasticity of heat stress were explored in the Arctic collembolan, Megaphorura arctica, from Svalbard and the Antarctic midge, Eretmoptera murphyi, from Signy Island. The data obtained demonstrate considerable heat tolerance in both species, with upper lethal temperatures >=35 degrees C (1 h exposures), and tolerance of exposure to 10 and 15 degrees C exceeding 56 days. This tolerance is far beyond that required in their current environment. Average microhabitat temperatures in August 2011 ranged between 5.1 and 8.1 degrees C, and rarely rose above 10 degrees C, in Ny-Alesund, Svalbard. Summer soil microhabitat temperatures on Signy Island have previously been shown to range between 0 and 10 degrees C. There was also evidence to suggest that E. murphyi can recover from high temperature exposure and that M. arctica is capable of rapid heat hardening. M. arctica and E. murphyi therefore have the physiological capacity to tolerate current environmental conditions, as well as future warming. If the features they express are characteristically more general, such polar terrestrial invertebrates will likely fare well under climate warming scenarios. PMID- 24816282 TI - Controlled release and gradient formation of human glial-cell derived neurotrophic factor from heparinated poly(ethylene glycol) microsphere-based scaffolds. AB - Introduction of spatial patterning of proteins, while retaining activity and releasability, is critical for the field of regenerative medicine. Reversible binding to heparin, which many biological molecules exhibit, is one potential pathway to achieve this goal. We have covalently bound heparin to poly(ethylene glycol) (PEG) microspheres to create useful spatial patterns of glial-cell derived human neurotrophic factor (GDNF) in scaffolds to promote peripheral nerve regeneration. Labeled GDNF was incubated with heparinated microspheres that were subsequently centrifuged into cylindrical scaffolds in distinct layers containing different concentrations of GDNF. The GDNF was then allowed to diffuse out of the scaffold, and release was tracked via fluorescent scanning confocal microscopy. The measured release profile was compared to predicted Fickian models. Solutions of reaction-diffusion equations suggested the concentrations of GDNF in each discrete layer that would result in a nearly linear concentration gradient over much of the length of the scaffold. The agreement between the predicted and measured GDNF concentration gradients was high. Multilayer scaffolds with different amounts of heparin and GDNF and different crosslinking densities allow the design of a wide variety of gradients and release kinetics. Additionally, fabrication is much simpler and more robust than typical gradient-forming systems due to the low viscosity of the microsphere solutions compared to gelating solutions, which can easily result in premature gelation or the trapping of air bubbles with a nerve guidance conduit. The microsphere-based method provides a framework for producing specific growth factor gradients in conduits designed to enhance nerve regeneration. PMID- 24816283 TI - A nanocarrier system for the delivery of nucleic acids targeted to a pancreatic beta cell line. AB - Pancreatic beta cells secrete insulin in response to glucose levels and thus are involved in controlling blood glucose levels. A line of pancreatic beta cells "MIN6" has been used in studies related to the function of beta cells and diabetes therapy. Regulating gene expression in MIN6 cells could accelerate these studies, but an efficient method for the transfection of nucleic acids targeted to MIN6 cells is required. We report here on a liposome-based carrier targeted to pancreatic beta cells (Multifunctional envelope-type nano device for pancreatic beta cells, beta-MEND). We identified a lipid composition for use in preparing the beta-MEND, which permits the particles to be efficiently internalized into MIN6, as evidenced by flow cytometry analyses. Intracellular observation by confocal laser scanning microscopy showed that the beta-MEND efficiently delivered the oligo nucleic acids to the cytosol of MIN6 cells. Moreover, using a beta-MEND encapsulating a 2'-O-Methyl RNA complementary to a microRNA that suppresses insulin secretion, the knockdown of the targeted microRNA and an up regulation of insulin secretion were observed in MIN6. Thus, the beta-MEND holds promise as an efficient system for delivering nucleic acids targeted to MIN6 and can contribute to research and therapy aimed at diabetes. PMID- 24816281 TI - Secreted phosphoprotein 1 is a determinant of lung function development in mice. AB - Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14-P28) as compared with C3H/HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose-dependent mouse lung epithelial-15 cell proliferation. Spp1((-/-)) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (Lm) compared with Spp1((+/+)) mice. Microarray analysis revealed enriched gene ontogeny categories, with numerous genes associated with lung development and/or respiratory disease. Insulin-like growth factor 1, Hedgehog-interacting protein, wingless-related mouse mammary tumor virus integration site 5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1((-/ )) mice as determined by quantitative RT-PCR analysis. SPP1 promotes pneumocyte growth, and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (i.e., increased Lm). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene-targeted Spp1((-/-)) mice, particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice. PMID- 24816284 TI - Contrasting effects of cysteine modification on the transfection efficiency of amphipathic peptides. AB - Delivery of DNA to cells remains a key challenge towards development of gene therapy. A better understanding of the properties involved in stability and transfection efficiency of the vector could critically contribute to the improvement of delivery vehicles. In the present work we have chosen two peptides differing only in amphipathicity and explored how presence of cysteine affects DNA uptake and transfection efficiency. We report an unusual observation that addition of cysteine selectively increases transfection efficiency of secondary amphipathic peptide (Mgpe-9) and causes a drop in the primary amphipathic peptide (Mgpe-10). Our results point the effect of cysteine is dictated by the importance of physicochemical properties of the carrier peptide. We also report a DNA delivery agent Mgpe-9 exhibiting high transfection efficiency in multiple cell lines (including hard-to-transfect cell lines) with minimal cytotoxicity which can be further explored for in vivo applications. PMID- 24816285 TI - The effect of metallic magnesium degradation products on osteoclast-induced osteolysis and attenuation of NF-kappaB and NFATc1 signaling. AB - Wear particle-induced aseptic prosthetic loosening is one of the most common reasons for total joint arthroplasty (TJA). Extensive bone destruction (osteolysis) by osteoclasts plays an important role in wear particle-induced peri implant loosening. Thus, strategies for inhibiting osteoclast function may have therapeutic benefit for prosthetic loosening. Here, we mimicked the process of magnesium (Mg) degradation in vivo and obtained Mg leach liquor (MLL) by immersing pure Mg in culture medium. For the first time, we demonstrated that MLL suppresses osteoclast formation, polarization, and osteoclast bone resorption in vitro. An in vivo assay demonstrated that MLL attenuates wear particle-induced osteolysis. Furthermore, we found that MLL significantly inhibits nuclear factor kappaB (NF-kappaB) activation by retarding inhibitor-kappaB degradation and subsequent NF-kappaB nuclear translocation. We also found that MLL attenuates the expression of NFATc1 at both the protein and mRNA levels. These results demonstrate that MLL has anti-osteoclast activity in vitro and prevents wear particle-induced osteolysis in vivo. Collectively, our study suggests that metallic magnesium, one of the orthopedic implants with superior properties, has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and function. PMID- 24816287 TI - Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid. AB - Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight heparin derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3 +/- 2.89%) and prolonged the mean residence time (7.5 +/- 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2 +/- 3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor. PMID- 24816286 TI - The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles. AB - A key attribute for nanoparticles (NPs) that are used in medicine is the ability to avoid rapid uptake by phagocytic cells in the liver and other tissues. Poly(ethylene glycol) (PEG) coatings has been the gold standard in this regard for several decades. Here, we examined hyperbranched polyglycerols (HPG) as an alternate coating on NPs. In earlier work, HPG was modified with amines and subsequently conjugated to poly(lactic acid) (PLA), but that approach compromised the ability of HPG to resist non-specific adsorption of biomolecules. Instead, we synthesized a copolymer of PLA-HPG by a one-step esterification. NPs were produced from a single emulsion using PLA-HPG: fluorescent dye or the anti-tumor agent camptothecin (CPT) were encapsulated at high efficiency in the NPs. PLA-HPG NPs were quantitatively compared to PLA-PEG NPs, produced using approaches that have been extensively optimized for drug delivery in humans. Despite being similar in size, drug release profile and in vitro cytotoxicity, the PLA-HPG NPs showed significantly longer blood circulation and significantly less liver accumulation than PLA-PEG. CPT-loaded PLA-HPG NPs showed higher stability in suspension and better therapeutic effectiveness against tumors in vivo than CPT loaded PLA-PEG NPs. Our results suggest that HPG is superior to PEG as a surface coating for NPs in drug delivery. PMID- 24816288 TI - The effect of surface charge of functionalized Fe3O4 nanoparticles on protein adsorption and cell uptake. AB - Nanoparticles engineered for biomedical applications are meant to be in contact with protein-rich physiological fluids. These proteins are usually adsorbed onto the nanoparticle's surface, forming a swaddling layer that has been described as a 'protein corona', the nature of which is expected to influence not only the physicochemical properties of the particles but also the internalization into a given cell type. We have investigated the process of protein adsorption onto different magnetic nanoparticles (MNPs) when immersed in cell culture medium, and how these changes affect the cellular uptake. The role of the MNPs surface charge has been assessed by synthesizing two colloids with the same hydrodynamic size and opposite surface charge: magnetite (Fe3O4) cores of 25-30 nm were in situ functionalized with (a) positive polyethyleneimine (PEI-MNPs) and (b) negative poly(acrylic acid) (PAA-MNPs). After few minutes of incubation in cell culture medium the wrapping of the MNPs by protein adsorption resulted in a 5-fold increase of the hydrodynamic size. After 24 h of incubation large MNP-protein aggregates with hydrodynamic sizes of ~1500 nm (PAA-MNPs) and ~3000 nm (PEI-MNPs) were observed, each one containing an estimated number of magnetic cores between 450 and 1000. These results are consistent with the formation of large protein MNPs aggregate units having a 'plum pudding' structure of MNPs embedded into a protein network that results in a negative surface charge, irrespective of the MNP-core charge. In spite of the similar negative zeta-potential for both MNPs within cell culture, we demonstrated that PEI-MNPs are incorporated in much larger amounts than the PAA-MNPs units. Quantitative analysis showed that SH-SY5Y cells can incorporate 100% of the added PEI-MNPs up to ~100 pg/cell, whereas for PAA-MNPs the uptake was less than 50%. The final cellular distribution showed also notable differences regarding partial attachment to the cell membrane. These results highlight the need to characterize the final properties of MNPs after protein adsorption in biological media, and demonstrate the impact of these properties on the internalization mechanisms in neural cells. PMID- 24816289 TI - Salutary effects of melatonin combined with treadmill exercise on cartilage damage. AB - Osteoarthritis (OA) is a major cause of disability in the adult population. The purpose of this study was to evaluate the effects of melatonin with graded dosage on extracellular matrix synthesis and cellular death in response to cartilage damage in vitro and in vivo. TNF-alpha reduced the viability of primary cultured chondrocytes and extracellular matrix protein, but melatonin at concentrations of 1 MUm and 1 nm restored them. Rats with knee instability induced by intra articular collagenase were used for the in vivo study. Joint parameters were significantly augmented in the collagenase injection-only group but not in the melatonin-alone or melatonin+exercise groups, as cartilage degeneration progressed. Serum TNF-alpha and IL-6 were upregulated by collagenase injection, which was attenuated by melatonin with and without exercise in the early phase. TGF-beta1 mRNA was either conserved or enhanced by melatonin with and without exercise at the early phase. In particular, melatonin combined with exercise dramatically decreased the expression of not only catabolic mediators but also cellular death markers with lower mineralization. At the advanced phase, prolonged melatonin treatment promoted mineralization through caspase-3-mediated chondrocyte apoptosis. However, co-intervention induced extracellular matrix remodeling through increases in IL-6, EPAS-1, and MMP-13. Reconstructed micro-CT images showed that collagenase injection induced subchondral bone erosion, formation of parameniscal osteophytes, and reduction of trabecular bone thickness regardless of the intervention, which was minimized by combined intervention. In conclusion, we suggest that melatonin with treadmill exercise may have both preventive and synergistic effects on rescue from cartilage degeneration and is more effective in the initial phase. PMID- 24816290 TI - Bacterial mural endocarditis. A case series. AB - Mural endocarditis represents a rare subset of intracardiac infections, with potentially life threatening sequelae. Clinically alike, with many shared aetiologies, substrates and risk factors such as valvular endocarditis, it can be difficult to differentiate without the use of sophisticated cardiovascular imaging techniques. Despite high rates of complications, there are no definite strategies for management. Herein we present three interesting cases of left ventricular mural endocarditis, without valvular involvement, due to staphylococcus aureus. PMID- 24816291 TI - Estimating the number and size of phloem sieve plate pores using longitudinal views and geometric reconstruction. AB - Because it is difficult to obtain transverse views of the plant phloem sieve plate pores, which are short tubes, to estimate their number and diameters, a method based on longitudinal views is proposed. This method uses recent methods to estimate the number and the sizes of approximately circular objects from their images, given by slices perpendicular to the objects. Moreover, because such longitudinal views are obtained from slices that are rather close to the plate centres whereas the pore size may vary with the pore distance from the plate edge, a sieve plate reconstruction model was developed and incorporated in the method to consider this bias. The method was successfully tested with published longitudinal views of phloem of Soybean and an exceptional entire transverse view from the same tissue. The method was also validated with simulated slices in two sieve plates from Cucurbita and Phaseolus. This method will likely be useful to estimate and to model the hydraulic conductivity and the architecture of the plant phloem, and it could have applications for other materials with approximately cylindrical structures. PMID- 24816293 TI - Purified NADH-cytochrome b5 reductase is a novel superoxide anion source inhibited by apocynin: sensitivity to nitric oxide and peroxynitrite. AB - Cytochrome b5 reductase (Cb5R) is a pleiotropic flavoprotein that catalyzes multiple one-electron reduction reactions with various redox partners in cells. In earlier work from our laboratory, we have shown its implication in the generation of reactive oxygen species (ROS), primarily a superoxide anion overshoot peak, which plays a major role as a triggering event for the acceleration of apoptosis in cerebellar granule neurons in culture. However, the results obtained in that work did not allow us to exclude the possibility that this superoxide anion production could be derived from Cb5R acting in concert with other cellular components. In this work, we have purified Cb5R from pig liver and we have experimentally shown that this enzyme catalyzed NADH-dependent production of superoxide anion, assayed with cytochrome c and nitroblue tetrazolium as detection reagents for this particular ROS. The basic kinetic parameters for this novel NADH-dependent activity of Cb5R at 37 degrees C are Vmax = 3.0 +/- 0.5 MUmol/min/mg of purified Cb5R and KM(NADH) = 2.8 +/- 0.3 MUM NADH. In addition, we report that apocynin, a widely used inhibitor of nonmitochondrial ROS production in mammalian cell cultures and tissues, is a potent inhibitor of purified Cb5R activity at the concentrations used in the experiments done with cell cultures. In the presence of apocynin the KM(NADH) value of Cb5R increases, and docking simulations indicate that apocynin can bind to a site near to or partially overlapping the NADH binding site of Cb5R. Other ROS, such as nitric oxide and peroxynitrite, have inhibitory effects on purified Cb5R, providing the basis for a feedback cellular protection mechanism through modulation of excessive extramitochondrial superoxide anion production by Cb5R. Both kinetic assays and docking simulations suggest that nitric oxide-induced nitrosylation (including covalent adduction of nitroso functional groups) of Cb5R cysteines and peroxynitrite-induced tyrosine nitration and cysteine oxidation modified the conformation of the NADH binding domain leading to a decreased affinity of Cb5R for NADH. PMID- 24816292 TI - The glutaredoxin/S-glutathionylation axis regulates interleukin-17A-induced proinflammatory responses in lung epithelial cells in association with S glutathionylation of nuclear factor kappaB family proteins. AB - Interleukin-17A (IL-17A) is a newly emerging player in the pathogenesis of chronic lung diseases that amplifies inflammatory responses and promotes tissue remodeling. Stimulation of lung epithelial cells with IL-17A leads to activation of the transcription factor nuclear factor kappaB (NF-kappaB), a key player in the orchestration of lung inflammation. We have previously demonstrated the importance of the redox-dependent posttranslational modification S glutathionylation in limiting activation of NF-kappaB and downstream gene induction. Under physiological conditions, the enzyme glutaredoxin 1 (Grx1) acts to deglutathionylate NF-kappaB proteins, which restores functional activity. In this study, we sought to determine the impact of S-glutathionylation on IL-17A induced NF-kappaB activation and expression of proinflammatory mediators. C10 mouse lung alveolar epithelial cells or primary mouse tracheal epithelial cells exposed to IL-17A show rapid activation of NF-kappaB and the induction of proinflammatory genes. Upon IL-17A exposure, sulfenic acid formation and S glutathionylated proteins increased. Assessment of S-glutathionylation of NF kappaB pathway components revealed S-glutathionylation of RelA (RelA-SSG) and inhibitory kappaB kinase alpha (IKKalpha-SSG) after stimulation with IL-17A. SiRNA-mediated ablation of Grx1 increased both RelA-SSG and IKKalpha-SSG and acutely increased nuclear content of RelA and tended to decrease nuclear RelB. SiRNA-mediated ablation or genetic ablation of Glrx1 decreased the expression of the NF-kappaB-regulated genes KC and CCL20 in response to IL-17A, but conversely increased the expression of IL-6. Last, siRNA-mediated ablation of IKKalpha attenuated nuclear RelA and RelB content and decreased expression of KC and CCL20 in response to IL-17A. Together, these data demonstrate a critical role for the S glutathionylation/Grx1 redox axis in regulating IKKalpha and RelA S glutathionylation and the responsiveness of epithelial cells to IL-17A. PMID- 24816294 TI - In vivo detection of a novel endogenous etheno-DNA adduct derived from arachidonic acid and the effects of antioxidants on its formation. AB - Previous studies showed that 7-(1',2'-dihydroxyheptyl)-substituted etheno DNA adducts are products of reactions with the epoxide of (E)-4-hydroxy-2-nonenal, an oxidation product of omega-6 polyunsaturated fatty acids (PUFAs). In this work, we report the detection of 7-(1',2'-dihydroxyheptyl)-1,N(6)-ethenodeoxyadenosine (DHHedA) in rodent and human tissues by two independent methods: a (32)P postlabeling/HPLC method and an isotope dilution liquid chromatography electrospray ionization-tandem mass spectrometry method, demonstrating for the first time that DHHedA is a background DNA lesion in vivo. We showed that DHHedA can be formed upon incubation of arachidonic acid with deoxyadenosine, supporting the notion that omega-6 PUFAs are the endogenous source of DHHedA formation. Because cyclic adducts are derived from the oxidation of PUFAs, we subsequently examined the effects of antioxidants, alpha-lipoic acid, Polyphenon E, and vitamin E, on the formation of DHHedA and gamma-hydroxy-1,N(2) propanodeoxyguanosine (gamma-OHPdG), a widely studied acrolein-derived adduct arising from oxidized PUFAs, in the livers of Long Evans Cinnamon (LEC) rats. LEC rats are afflicted with elevated lipid peroxidation and prone to the development of hepatocellular carcinomas. The results showed that although the survival of LEC rats was increased significantly by alpha-lipoic acid, none of the antioxidants inhibited the formation of DHHedA, and only Polyphenon E decreased the formation of gamma-OHPdG. In contrast, vitamin E caused a significant increase in the formation of both gamma-OHPdG and DHHedA in the livers of LEC rats. PMID- 24816295 TI - The formation of DNA single-strand breaks and alkali-labile sites in human blood lymphocytes exposed to 365-nm UVA radiation. AB - The potency of UVA radiation, representing 90% of solar UV light reaching the earth's surface, to induce human skin cancer is the subject of continuing controversy. This study was undertaken to investigate the role of reactive oxygen species in DNA damage produced by the exposure of human cells to UVA radiation. This knowledge is important for better understanding of UV-induced carcinogenesis. We measured DNA single-strand breaks and alkali-labile sites in human lymphocytes exposed ex vivo to various doses of 365-nm UV photons compared to X-rays and hydrogen peroxide using the comet assay. We demonstrated that the UVA-induced DNA damage increased in a linear dose-dependent manner. The rate of DNA single-strand breaks and alkali-labile sites after exposure to 1J/cm(2) was similar to the rate induced by exposure to 1 Gy of X-rays or 25 MUM hydrogen peroxide. The presence of either the hydroxyl radical scavenger dimethyl sulfoxide or the singlet oxygen quencher sodium azide resulted in a significant reduction in the UVA-induced DNA damage, suggesting a role for these reactive oxygen species in mediating UVA-induced DNA single-strand breaks and alkali labile sites. We also showed that chromatin relaxation due to hypertonic conditions resulted in increased damage in both untreated and UVA-treated cells. The effect was the most significant in the presence of 0.5M Na(+), implying a role for histone H1. Our data suggest that the majority of DNA single-strand breaks and alkali-labile sites after exposure of human lymphocytes to UVA are produced by reactive oxygen species (the hydroxyl radical and singlet oxygen) and that the state of chromatin may substantially contribute to the outcome of such exposures. PMID- 24816296 TI - Mitochondrial thioredoxin reductase inhibition, selenium status, and Nrf-2 activation are determinant factors modulating the toxicity of mercury compounds. AB - The thioredoxin system has essential functions in the maintenance of cellular redox homeostasis in the cytosol, nucleus, and mitochondria. Thioredoxin (Trx) and thioredoxin reductase (TrxR) are targets for mercury compounds in vitro and in vivo. This study aimed at understanding mechanistically how the mitochondrial and cytosolic thioredoxin systems were affected by mercurials, including the regulation of TrxR transcription. The effects of coexposure to selenite and mercurials on the thioredoxin system were also addressed. Results in HepG2 cells showed that TrxR1 expression was enhanced by Hg(2+), whereas exposure to MeHg decreased expression. Selenite exposure also increased the expression of TrxR1 and resulted in higher specific activity. Coexposure to 2 uM selenite and up to 5 uM Hg(2+) increased even further TrxR1 expression. This synergistic effect was not verified for MeHg, because TrxR1 expression and activity were reduced. Analysis of Nrf-2 translocation to the nucleus and TrxR mRNA suggests that induction of TrxR1 transcription was slower upon exposure to MeHg in comparison to Hg(2+). Subcellular fractions showed that MeHg affected the activity of the thioredoxin system equally in the mitochondria and cytosol, whereas Hg(2+) inhibited primarily the activity of TrxR2. The expression of TrxR2 was not upregulated by any treatment. These results show important differences between the mechanisms of toxicity of Hg(2+) and MeHg and stress the narrow range of selenite concentrations capable of antagonizing mercury toxicity. The results also highlight the relevance of the mitochondrial thioredoxin system (TrxR2 and Trx2) in the development of mercury toxicity. PMID- 24816302 TI - A crystalline porous coordination polymer decorated with nitroxyl radicals catalyzes aerobic oxidation of alcohols. AB - A porous coordination polymer (PCP) has been synthesized employing an organic ligand in which a stable free radical, isoindoline nitroxide, is incorporated. The crystalline PCP possesses one-dimensional channels decorated with the nitroxyl catalytic sites. When O2 gas or air was used as the oxidant, this PCP was verified to be an efficient, recyclable, and widely applicable catalyst for selective oxidation of various alcohols to the corresponding aldehydes or ketones. PMID- 24816303 TI - Statins use and risk of mortality in patient with Clostridium difficile infection. AB - Current evidence suggests that statins may improve outcome in infectious diseases. This study aims to assess whether statins use is associated with reduced risk of 30-day mortality in Clostridium difficile infection (CDI). Using the computerized database of Clalit, the largest healthcare provider in Israel, we identified a cohort of adult subjects (age >=40 years) who tested positive on a C. difficile toxin assay performed between January 2011 and December 2012. Subjects were defined as current statins users if they filled at least one prescription during the 90 days before the laboratory assay date. Current users were classified into long-term users if at least one additional prescription was filled during the previous 91-180 days; otherwise they were defined as short-term users. A total 1888 patients with CDI were included. Of them, 340 (18.0%) died during the first 30 days after diagnosis. The 30-day mortality rate was lower among current statins users 89/669 (13.3%) compared with 251/1219 (20.6%) in non users (p <0.001). A significant reduced risk of 30-day mortality existed after adjustment for potential confounders; adjusted OR = 0.57 (95% CI 0.42-0.79) and was unique to long-term users; 0.53 (0.38-0.73) but not short-term users; 1.15 (0.56-2.34). The risk of 30-day mortality decreased with increasing number of filled statins prescriptions; adjusted OR = 0.77 (95% CI 0.67-0.89) for each additional prescription. Current aspirin use was also independently associated with reduced mortality; adjusted OR = 0.64 (95% CI 0.43-0.88). In conclusion, current statins use, particularly long-term use, has a dose-response protective effect on mortality in patients with CDI. PMID- 24816304 TI - An oligonucleotide-based label-free luminescent switch-on probe for RNA detection utilizing a G-quadruplex-selective iridium(III) complex. AB - We report herein the synthesis and application of a novel G-quadruplex-selective luminescent iridium(iii) complex for the construction of an oligonucleotide based, label-free, rapid and convenient luminescent RNA detection platform. PMID- 24816305 TI - Treatment outcomes of rapid desensitisation protocols. PMID- 24816307 TI - A journal's progress. PMID- 24816306 TI - Prostate cancer: measuring PSA. AB - Population screening with prostate-specific antigen (PSA) for detection of prostate cancer is a topic associated with ongoing dissent and confusion within the oncology and wider medical community. The PSA blood test has been used in various stages of prostate cancer management, including screening and the assessment of future risk of prostate cancer development, detection of recurrent disease after local therapy and in the management of advanced disease. However, PSA-based decision-making in prostate cancer has significant shortcomings. This review will summarise the evidence and current recommendations for the use of PSA in detection and management of prostate cancer. PMID- 24816297 TI - Oxidative stress and hepatic Nox proteins in chronic hepatitis C and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common liver cancer and a leading cause of cancer-related mortality in the world. Hepatitis C virus (HCV) is a major etiologic agent of HCC. A majority of HCV infections lead to chronic infection that can progress to cirrhosis and, eventually, HCC and liver failure. A common pathogenic feature present in HCV infection, and other conditions leading to HCC, is oxidative stress. HCV directly increases superoxide and H2O2 formation in hepatocytes by elevating Nox protein expression and sensitizing mitochondria to reactive oxygen species generation while decreasing glutathione. Nitric oxide synthesis and hepatic iron are also elevated. Furthermore, activation of phagocytic NADPH oxidase (Nox) 2 of host immune cells is likely to exacerbate oxidative stress in HCV-infected patients. Key mechanisms of HCC include genome instability, epigenetic regulation, inflammation with chronic tissue injury and sustained cell proliferation, and modulation of cell growth and death. Oxidative stress, or Nox proteins, plays various roles in these mechanisms. Nox proteins also function in hepatic fibrosis, which commonly precedes HCC, and Nox4 elevation by HCV is mediated by transforming growth factor beta. This review summarizes mechanisms of oncogenesis by HCV, highlighting the roles of oxidative stress and hepatic Nox enzymes in HCC. PMID- 24816309 TI - Physical activity levels and patients' expectations of physical activity during acute general medical admission. AB - Bedrest during hospital admission is common and might be harmful. There is scarce published evidence that quantifies physical activity levels and expectations regarding physical activity of general medical patients during an acute inpatient stay. The current study aimed to investigate physical activity levels and expectations regarding physical activity in general medical patients at a large Australian teaching hospital. A convenience sample of 24 general medical patients was observed at 10-min intervals in one day between 8:00 and 17:00 and their physical activity status recorded. Participants completed a questionnaire regarding their expectations of physical activity during illness and hospital admission. Patients were observed to be in bed 51% of the time, were sitting out of bed 43% of the time, were standing 1% of the time and were walking 5% of the time. One third of participants (n = 8) were not observed to walk during the observation period. Questionnaire data indicated that nine (38%) participants expected to remain in bed while in hospital. General medical patients had low levels of physical activity during their hospital stay, which was consistent with many participants' expectations of appropriate activity when in hospital. If physical activity is an important part of acute general medical patient management, then patient expectations of the appropriateness of physical activity need to be addressed and methods to increase physical activity implemented. PMID- 24816308 TI - Low-molecular-weight heparin biosimilars: potential implications for clinical practice. Australian Low-Molecular-Weight Heparin Biosimilar Working Group (ALBW). AB - A working group of clinicians and scientists was formed to review the clinical considerations for use of low-molecular-weight heparin (LMWH) biosimilars. LMWH are biological molecules of significant complexity; the full complexity of chemical structure is still to be elucidated. LMWH biosimilars are products that are biologically similar to their reference product and rely on clinical data from a reference product to establish safety and efficacy. The complex nature of LMWH molecules means that it is uncertain whether a LMWH biosimilar is chemically identical to its reference product; this introduces the possibility of differences in activity and immunogenicity. The challenge for regulators and clinicians is to evaluate the level of evidence required to demonstrate that a LMWH is sufficiently similar to the reference product. The consensus opinion of the working group is that prior to clinical use a LMWH biosimilar should have proven efficacy and safety, similar to the reference product with prospective studies, which should be confirmed with a proactive post-marketing pharmacovigilance programme. PMID- 24816310 TI - Twenty-eight day Holter monitoring is poorly tolerated and insensitive for paroxysmal atrial fibrillation detection in cryptogenic stroke. AB - This pilot study in a prospective cohort of 20 cryptogenic stroke patients showed that a significant proportion has paroxysmal atrial fibrillation undetected by 24 h Holter monitoring. However, longer monitoring with 28-day Holter was poorly tolerated and still insufficiently sensitive for paroxysmal atrial fibrillation detection. Further studies are urgently needed to elucidate the optimal timing, method and duration of cardiac rhythm monitoring following ischaemic stroke. PMID- 24816311 TI - Non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population. AB - This retrospective case series identifies the largest cohort of non-O1, non-O139 Vibrio cholerae bacteraemia in an Australian population from 2000 to 2013. We examine the risk factors, epidemiology, clinical presentations and mortality of non-O1, non-O139 V. cholerae bacteraemia in Victoria and compare them with published cases in the literature. This case series highlights the pathogenic potential of non-O1, non-O139 V. cholerae and identifies possible associations with host (underlying chronic liver disease and malignancy) and environmental factors (contaminated water supply and raw seafood). Clinicians should be aware of the morbidity and mortality associated with invasive non-O1, non-O139 V. cholerae infections, particularly in immunocompromised patients. PMID- 24816312 TI - Refeeding syndrome is uncommon in alcoholics admitted to a hospital detoxification unit. AB - The refeeding syndrome is increasingly recognised. It is a serious change in electrolytes when nutrition is reintroduced to malnourished patients. Alcohol dependence is a risk factor for the refeeding syndrome. We report a prospective cohort study of 36 alcoholics hospitalised for withdrawal management. We found no evidence of refeeding syndrome in any patient after 3 days of hospitalisation, despite hypomagnesaemia, a risk factor for the refeeding syndrome being prevalent (44% of subjects). Low thiamine levels were infrequent affecting 3/29 (10%). We recommend that in alcoholics admitted for managed withdrawal, risk of refeeding syndrome appears to be low, and routine testing of repeat electrolytes appears unnecessary. PMID- 24816313 TI - Are suspected stroke patients identified by paramedics transported to appropriate stroke centres in Victoria, Australia? AB - Emergency medical services (EMS) are vital to ensuring acute stroke patients are transported to thrombolysis and/or stroke unit centres. This 6-month audit of Victorian EMS cases found the majority of suspected acute strokes are transported to appropriate stroke centres. However, there is still room for improvement, in particular, strategies to improve access to stroke services in some rural regions and to ensure patients/relatives are fully informed when requesting transport to a non-stroke service hospital. PMID- 24816314 TI - Thrombopoietin receptor agonists in immune thrombocytopenia of less than 6 months duration. PMID- 24816315 TI - Hyponatraemic seizure following arginine vasopressin for von Willebrand disease: pernicious, predictable and preventable. PMID- 24816317 TI - Detailed characterisation of circulatory nitric oxide and free radical indices- is there evidence for abnormal cardiovascular homeostasis in young women with polycystic ovary syndrome? AB - OBJECTIVE: To assess circulating biochemical indices of endothelial function and nitro-oxidative stress in women with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. POPULATION: Seventeen women with PCOS and eighteen age- and body mass index-matched healthy volunteers. METHODS: Nitric oxide (NO) metabolite levels were assessed by chemiluminescence. Electron paramagnetic resonance spectroscopy with spin trapping was used to assess oxidative stress ex vivo and in vitro. Antioxidant capacity was measured using oxygen radical absorbance. MAIN OUTCOME MEASURES: Biochemical indices of endothelial function, including NO metabolites, lipid-derived radicals and antioxidant capacity. RESULTS: Plasma NO metabolites were similar in the two groups (nitrite: 257+/-116 nmol/l [PCOS], 261+/-135 nmol/l [controls] P=0.93; nitrate: 27+/-7 MUmol/l [PCOS], 26+/-6 MUmol/l [controls] P=0.89). Alkoxyl free radicals (lipid-derived) were detected as the dominant species, but levels were not different between women with PCOS and controls whether measured directly ex vivo (median 7.2 [range 0.17-16.73]e6 arbitrary units [a.u.] and 7.2 [1.7-11.9]e6 a.u., respectively, P=0.57) or when stimulated in vitro to test radical generation capacity (1.23 [0.3-5.62]e7 a.u. and 1.1 [0.48-15.7]e7 a.u. respectively, P=0.71). In regression analysis, visceral fat area was independently associated with in vitro oxidative potential (beta=0.6, P=0.002). Total plasma antioxidant capacity (94+/-30% [PCOS], 79+/-24% [controls], P=0.09) and plasma hydroperoxides (7.5+/-4 MUmol/l [PCOS], 6.7+/-5 MUmol/l [controls], P=0.21) were not different between groups. However, lipophilic antioxidant capacity was lower in women with PCOS compared with controls (92+/-32 and 125+/-48%, respectively, P=0.02). CONCLUSIONS: Young overweight women with PCOS display a reduced lipophilic antioxidant capacity compared with healthy volunteers, but no change in circulating free radicals or nitro-oxidative stress. PMID- 24816316 TI - Increased miR-223 expression in T cells from patients with rheumatoid arthritis leads to decreased insulin-like growth factor-1-mediated interleukin-10 production. AB - We hypothesized that the aberrant expression of microRNAs (miRNAs) in rheumatoid arthritis (RA) T cells was involved in the pathogenesis of RA. The expression profile of 270 human miRNAs in T cells from the first five RA patients and five controls were analysed by real-time polymerase chain reaction. Twelve miRNAs exhibited potentially aberrant expression in RA T cells compared to normal T cells. After validation with another 22 RA patients and 19 controls, miR-223 and miR-34b were over-expressed in RA T cells. The expression levels of miR-223 were correlated positively with the titre of rheumatoid factor (RF) in RA patients. Transfection of Jurkat cells with miR-223 mimic suppressed insulin-like growth factor-1 receptor (IGF-1R) and transfection with miR-34b mimic suppressed cAMP response element binding protein (CREB) protein expression by Western blotting. The protein expression of IGF-1R but not CREB was decreased in RA T cells. The addition of recombinant IGF-1-stimulated interleukin (IL)-10 production by activated normal T cells, but not RA T cells. The transfection of miR-223 mimic impaired IGF-1-mediated IL-10 production in activated normal T cells. The expression levels of SCD5, targeted by miR-34b, were decreased in RA T cells after microarray analysis. In conclusion, both miR-223 and miR-34b were over expressed in RA T cells, but only the miR-223 expression levels were correlated positively with RF titre in RA patients. Functionally, the increased miR-223 expression could impair the IGF-1-mediated IL-10 production in activated RA T cells in vivo, which might contribute to the imbalance between proinflammatory and anti-inflammatory cytokines. PMID- 24816319 TI - Attentional bias for food cues in binge eating disorder. AB - The aim of the present study was to investigate an attentional bias toward food stimuli in binge eating disorder (BED). To this end, a BED and a weight-matched control group (CG) completed a clarification task and a spatial cueing paradigm. The clarification task revealed that food stimuli were faster detected than neutral stimuli, and that this difference was more pronounced in BED than in the CG. The spatial cueing paradigm indicated a stimulus engagement effect in the BED group but not in the CG, suggesting that an early locus in stimulus processing contributes to differences between BED patients and obese controls. Both groups experienced difficulty disengaging attention from food stimuli, and this effect was only descriptively larger in the BED group. The effects obtained in both paradigms were found to be correlated with reported severity of BED symptoms. Of note, this relationship was partially mediated by the arousal associated with food stimuli relative to neutral stimuli, as predicted by an account on incentive sensitization. PMID- 24816318 TI - The role of impulsivity traits and delayed reward discounting in dysregulated eating and drinking among heavy drinkers. AB - Impulsivity is a multifaceted construct that has been linked to dysregulated eating and problematic alcohol use. The UPPS model identifies five personality based impulsivity traits that have unique predictive utility: Negative Urgency, Perseverance, Premeditation, Sensation Seeking, and Positive Urgency. Delayed reward discounting (DRD) is an index of impulsive decision making characterized by preference for smaller immediate gains at the cost of larger delayed gains. In the current study, we sought to refine the influence of impulsive personality traits and DRD on disordered eating patterns and problematic drinking. One hundred and eight treatment-seeking heavy drinkers were assessed for UPPS impulsivity traits, DRD, disordered eating, alcohol use, and demographic information. With regard to disordered eating patterns, DRD predicted higher levels of Dietary Restraint and Weight and Shape Concerns. Negative Urgency predicted binge eating and Weight and Shape Concerns. Positive Urgency predicted Eating Concerns. Female sex predicted Eating, Weight, and Shape Concerns. When considering problematic alcohol use, only Negative Urgency and Sensation Seeking were predictive. This is the first study to examine both personality-based impulsivity and DRD in relation to pathological eating and drinking behavior. The results suggest the importance of disentangling the contributions of various impulsivity constructs on dysregulated eating. PMID- 24816320 TI - I take therefore I choose? The impact of active vs. passive acquisition on food consumption. AB - This research investigates the consequences of physically taking (actively acquiring) vs. receiving (passively acquiring) food items. Specifically, we demonstrate that the act of physically taking food can generate a false impression of choice, an effect we term "embodied illusion of choice." Across two studies, we document the mediating effect of this embodied illusion of choice on food evaluation and actual consumption, and show that these effects are moderated by an individual's need-for-control. PMID- 24816321 TI - Feeding beliefs and practices of Chinese immigrant mothers. Validation of a modified version of the child feeding questionnaire. AB - The Child Feeding Questionnaire (CFQ) developed by Birch et al. (2001) is a widely used tool for measuring parental feeding beliefs, attitudes and practices. However, the appropriateness of the CFQ for use with Chinese populations is unknown. This study tested the construct validity of a novel Chinese version of the CFQ using confirmatory factor analysis (CFA). Participants included a convenience sample of 254 Chinese-Australian mothers of children aged 1-4 years. Prior to testing, the questionnaire was translated into Chinese using a translation-back-translation method, one item was reworded to be culturally appropriate, a new item was added (monitoring), and five items that were not age appropriate for the sample were removed. Based on previous literature, both a seven-factor and an eight-factor model were assessed via CFA. Results showed that the eight-factor model, which separated restriction and use of food rewards, improved the conceptual clarity of the constructs and provided a good fit to the data. Internal consistency of all eight factors was acceptable (Cronbach's alpha: .60-.93). This modified eight-factor CFQ appears to be a linguistically and culturally appropriate instrument for assessing feeding beliefs and practices in Chinese-Australian mothers of young children. PMID- 24816322 TI - Parental perceptions, feeding practices, feeding styles, and level of acculturation of Chinese Americans in relation to their school-age child's weight status. AB - Parents influence their child's eating behavior and attitudes directly as food providers and indirectly through their parental feeding styles and feeding concerns and practices. Chinese American parents' practices are likely influenced by culture. The objective of this study was to explore the relationships between parental perceptions, feeding practices, feeding styles, level of parental acculturation (LPA), and child weight status via a self-administered questionnaire. This survey study involved a convenience sample of 712 individuals who were parents of 5- to 10-year old children attending Chinese language after school programs. The prevalence of overweight was 11.5% and obesity was 11.1%. LPA was not directly predictive of child overweight in multiple regression but from categorical data, Chinese American parents tended to use indulgent (33.2%) and authoritarian (27.9%) feeding styles, with the former increasing with acculturation and the latter decreasing. Indulgent parents had more than expected overweight and obese children, and authoritarian and authoritative parents, fewer. LPA was negatively predictive of pressure to eat healthy foods (p < .01), which was negatively correlated with child weight status (p < .01). LPA was also independently positively correlated to responsiveness to child needs (p < .01), monitoring of child intake (p < .01), and perceived responsibility for child feeding. Parental perceptions and concerns about child weight were predictors of child weight. Consequently, parental concerns and responsiveness to child needs without also encouragement (demandingness) to eat healthy foods (indulgent feeding style) may promote overweight. The authoritative parental feeding style may contribute to children having healthy weights and therefore healthy lives. PMID- 24816323 TI - Cognitive and behavioural effects of sugar consumption in rodents. A review. AB - The pronounced global rise in sugar consumption in recent years has been driven largely by increased consumption of sugar-sweetened beverages. Although high sugar intakes are recognised to increase the risk of obesity and related metabolic disturbances, less is known about how sugar might also impair cognition and learned behaviour. This review considers the effects of sugar in rodents on measures of learning and memory, reward processing, anxiety and mood. The parallels between sugar consumption and addictive behaviours are also discussed. The available evidence clearly indicates that sugar consumption can induce cognitive dysfunction. Deficits have been found most consistently on tasks measuring spatial learning and memory. Younger animals appear to be particularly sensitive to the effects of sugar on reward processing, yet results vary according to what reward-related behaviour is assessed. Sugar does not appear to produce long-term effects on anxiety or mood. Importantly, cognitive impairments have been found when intake approximates levels of sugar consumption in people and without changes to weight gain. There remain several caveats when extrapolating from animal models to putative effects of sugar on cognitive function in people. These issues are discussed in conjunction with potential underlying neural mechanisms and directions for future research. PMID- 24816324 TI - Perceptions of parental pressure to eat and eating behaviours in preadolescents: the mediating role of anxiety. AB - Previous research suggests that parental controlling feeding practices are associated with children's overeating and undereating behaviours. However, there is limited research addressing the link between children's mental health symptoms (specifically anxiety and depression) and their reports of eating behaviours, despite knowledge that these psychopathologies often co-exist. The current study aimed to identify the relationships between preadolescents' perceptions of their parents' feeding practices with reports of their own anxiety, depression and eating behaviours. Three hundred and fifty-six children (mean age 8.75 years) completed questionnaires measuring their dietary restraint, emotional eating and external eating, as well as their perceptions of their parents' use of pressure to eat and restriction of food. Children also completed measures of general anxiety, social anxiety and depression symptomology. Results indicated that preadolescents' eating behaviours were associated with their perceptions of the controlling feeding practices their parents used with them. Preadolescents' dietary restraint, emotional eating and external eating behaviours were positively associated with their reports of general and social anxiety, and depression symptomology. In addition, perceptions of parental pressure to eat were positively related to preadolescents' anxiety and depression levels. Child anxiety (general and social) was found to mediate the relationship between perceptions of parental pressure to eat and preadolescents' eating behaviours (dietary restraint, emotional eating and external eating). The results suggest that greater anxiety in preadolescents may explain why children who perceive greater pressure to eat by their parents are more likely to exhibit maladaptive eating behaviours. PMID- 24816325 TI - Endoscopic endonasal transcavernous posterior clinoidectomy with interdural pituitary transposition. AB - OBJECT.: The object of this paper was to describe the surgical anatomy and technical nuances of the endonasal transcavernous posterior clinoidectomy approach with interdural pituitary transposition and to report the clinical outcome of this technical modification. METHODS: The surgical anatomy of the proposed approach was studied in 10 colored silicon-injected anatomical specimens. The medical records of 12 patients that underwent removal of the posterior clinoid(s) with this technique were reviewed. RESULTS: The natural anatomical corridor provided by the cavernous sinus is used to get access to the posterior clinoid by mobilizing the pituitary gland in an interdural fashion. The medial wall of the cavernous sinus is preserved intact and attached to the gland during its medial and superior mobilization. This provides protection to the gland, allowing for preservation of its venous drainage pathways. The inferior hypophyseal artery is transected to facilitate the manipulation of the medial wall of the cavernous sinus and pituitary gland. This approach was successfully performed in all patients, including 6 with chordomas, 5 with petroclival meningiomas, and 1 with an epidermoid tumor. No patient in this series had neurovascular injury related to the posterior clinoidectomy. There were no instances of permanent hypopituitarism or diabetes insipidus. CONCLUSIONS: The authors introduce a surgical variant of the endoscopic endonasal posterior clinoidectomy approach that does not require intradural pituitary transposition and is more effective than the purely extradural approach. The endoscopic endonasal transcavernous approach facilitates the removal of prominent posterior clinoids increasing the working space at the lateral recess of the interpeduncular cistern, while preserving the pituitary function. PMID- 24816326 TI - Internal carotid artery anterior wall aneurysms. PMID- 24816327 TI - The effect of stem cells in bridging peripheral nerve defects: a meta-analysis. AB - OBJECT.: For decades the gold standard for reconstructing a large peripheral nerve defect has been, and remains, the nerve autograft. Alternatives to the nerve autograft include biological conduits and vessels. Adding stem cells in the lumen of a nerve conduit has been the subject of multiple studies. The purpose of the present meta-analysis was to summarize animal experimental studies on the effect of stem cells as a luminal additive when reconstructing a peripheral nerve defect with a nerve graft. METHODS: A literature search of the MEDLINE and Embase databases was performed from inception to April 2012, searching for animal experiments on peripheral nerve reconstruction models in which a nerve conduit was used with and without the support of 3 different types of stem cells. Stem cells were analyzed according to their origin: bone marrow, adipose tissue, and other origins. Included studies had consistent outcome measurements: walking track analysis, muscle mass ratio, and electrophysiology. RESULTS: Forty-four studies were included in the final analysis. Forest plots of the 3 outcome measurements (walking track analysis, muscle mass ratio, and electrophysiology) showed positive effects of stem cells on the regeneration of peripheral nerves at different time points. Almost all comparisons showed significant differences for all 3 stem cells groups compared with a control group in which stem cells were not used. CONCLUSIONS: The present report systematically analyzed the different studies that used stem cells as a luminal additive when bridging a large peripheral nerve defect. All 3 different stem cell groups showed a beneficial effect when used in the reconstruction compared with control groups in which stem cells were not used. PMID- 24816328 TI - Double-chambered left ventricle in a cat. AB - Double-chambered left ventricle is a rare congenital disorder in which the left ventricular cavity is subdivided into two cavities by an anomalous septum or muscle band. We describe a case of double-chambered left ventricle, most likely caused by the presence of excessive left ventricular bands, in an asymptomatic cat. PMID- 24816329 TI - Training brain networks and states. AB - Brain training refers to practices that alter the brain in a way that improves cognition, and performance in domains beyond those involved in the training. We argue that brain training includes network training through repetitive practice that exercises specific brain networks and state training, which changes the brain state in a way that influences many networks. This opinion article considers two widely used methods - working memory training (WMT) and meditation training (MT) - to demonstrate the similarities and differences between network and state training. These two forms of training involve different areas of the brain and different forms of generalization. We propose a distinction between network and state training methods to improve understanding of the most effective brain training. PMID- 24816330 TI - Comparison of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid (anti [18F]FACBC) accumulation in lymph node prostate cancer metastasis and lymphadenitis in rats. AB - INTRODUCTION: Trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid (anti [(18)F]FACBC) is a positron emission tomography (PET) tracer used to visualize prostate cancer (PCa). In this study, we investigated the differences in anti [(18)F]FACBC accumulation between metastatic and inflamed lymph node (LN) lesions. METHODS: A PCa LN metastasis (PLM) model was developed by inoculating a rat PCa cell line, MAT-Ly-Lu-B2, into popliteal LNs of Copenhagen rats. Acute lymphadenitis (AL) was induced by injecting concanavalin A (Con A) into the hind footpad, and chronic lymphadenitis (CL) was induced by daily injection of Con A into the tissues surrounding the popliteal LNs for 2weeks. Main lesions of all animal models were established in lumbar and/or inguinal LNs. Biodistribution and dynamic PET imaging data were acquired after tracer injection. T2-weighted magnetic resonance (MR) images were registered with PET images. RESULTS: In the biodistribution study, the uptake ratios of PLM-to-lymphadenitis in lesional lumbar and inguinal LNs were 0.97-1.57 and 1.47-2.08 at 15 and 60min post-anti [(18)F]FACBC injection respectively. In PET imaging, the lesional lumbar LNs of CL and PLM, but not of AL, were visualized on anti-[(18)F]FACBC-PET/MR fusion images without disturbance from radioactivity from urine, and the rank order of anti-[(18)F]FACBC accumulation at 50-60 post-injection in lesional lumbar LNs was PLM>CL>AL. CONCLUSIONS: Anti-[(18)F]FACBC accumulation in LNs with PLM was higher than that in inflamed LNs. ADVANCES IN KNOWLEDGE: The study showed that although low but significant levels of anti-[(18)F]FACBC uptake by chronic inflamed lesions might cause false-positives in anti-[(18)F]FACBC-PET in some PCa patients, uptake of the tracer at acutely inflamed sites was minimal. IMPLICATIONS FOR PATIENT CARE: The findings of this study suggest the potential of Anti-[(18)F]FACBC for distinguishing between tumors and acute inflammation in clinical practice. PMID- 24816331 TI - Magnetic properties of 1:2 mixed cobalt(II) salicylaldehyde Schiff-base complexes with pyridine ligands carrying high-spin carbenes (Scar = 2/2, 4/2, 6/2, and 8/2) in dilute frozen solutions: role of organic spin in heterospin single-molecule magnets. AB - The 1:2 mixtures of Co(p-tolsal)2, p-tolsal = N-p-tolylsalicylideniminato, and diazo-pyridine ligands, DXpy; X = 1, 2, 3l, 3b, and 4, in MTHF solutions were irradiated at cryogenic temperature to form the corresponding 1:2 cobalt-carbene complexes Co(p-tolsal)2(CXpy)2, with Stotal = 5/2, 9/2, 13/2, 13/2, and 17/2, respectively. The resulting Co(p-tolsal)2(CXpy)2, X = 1, 2, 3l, 3b, and 4, showed magnetic behaviors characteristic of heterospin single-molecule magnets with effective activation barriers, Ueff/kB, of 40, 65, 73, 72, and 74 K, for reorientation of the magnetic moment and temperature-dependent hysteresis loops with a coercive force, Hc, of ~0, 6.2, 10, 6.5, and 9.0 kOe at 1.9 K, respectively. The relaxation times, tauQ, due to a quantum tunneling of magnetization (QTM) were estimated to be 1.6 s for Co(p-tolsal)2(C1py)2, ~2.0 * 10(3) s for Co(p-tolsal)2(C2py)2, and >10(5) s for Co(p-tolsal)2(CXpy)2; X = 3b, 3l, and 4. In heterospin complexes, organic spins, carbenes interacted with the cobalt ion to suppress the QTM pathway, and the tauQ value increased with increasing the Stotal values. PMID- 24816332 TI - Cardioprotective effect of embelin on isoproterenol-induced myocardial injury in rats: possible involvement of mitochondrial dysfunction and apoptosis. AB - AIMS: Preventive and/or therapeutic interventions using natural products for ischemic heart disease have gained considerable attention worldwide. This study investigated the cardioprotective effect and possible mechanism of embelin, a major constituent of Embelia ribes Burm, using isoproterenol (ISO)-induced myocardial infarction model in rats. MATERIALS AND METHODS: Rats were pretreated for three days with embelin (50mg/kg, p.o) before inducing myocardial injury by administration of ISO (85 mg/kg) subcutaneously at an interval of 24h for 2 consecutive days. Serum was analyzed for cardiac specific injury biomarkers, lipids and lipoprotein content. Heart tissues were isolated and were used for histopathology, antioxidant and mitochondrial respiratory enzyme activity assays and western blot analysis. KEY FINDINGS: Results showed that pretreatment with embelin significantly decreased the elevated levels of serum specific cardiac injury biomarkers (CK-MB, LDH and AST), serum levels of lipids and lipoproteins and histopathological changes when compared to ISO-induced controls. Exploration of the underlying mechanisms of embelin action revealed that embelin pretreatment restored the myocardial mitochondrial respiratory enzyme activities (NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity), strengthened antioxidant status and attenuated ISO-induced myocardial lipid peroxidation. Immunoblot analysis revealed that embelin interrupted mitochondria dependent apoptotic damage by increasing the myocardial expression of Bcl-2 and downregulating the expression of Bax, cytochrome c, cleaved-caspase-3 & 9 and PARP. Histopathology findings further strengthened the cardioprotective findings of embelin. SIGNIFICANCE: Result suggested that embelin may have a potential benefit in preventing ischemic heart disease like myocardial infarction. PMID- 24816333 TI - Individual Thresholding of Voxel-based Functional Connectivity Maps. Estimation of Random Errors by Means of Surrogate Time Series. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Neural Signals and Images". BACKGROUND: Voxel-based functional connectivity analysis is a common method for resting state fMRI data. However, correlations between the seed and other brain voxels are corrupted by random estimate errors yielding false connections within the functional connectivity map (FCmap). These errors must be taken into account for a correct interpretation of single-subject results. OBJECTIVES: We estimated the statistical range of random errors and propose two methods for an individual setting of correlation threshold for FCmaps. METHODS: We assessed the amount of random errors by means of surrogate time series and described its distribution within the brain. On the basis of these results, the FCmaps of the posterior cingulate cortex (PCC) from 15 healthy subjects were thresholded with two innovative methods: the first one consisted in the computation of a unique (global) threshold value to be applied to all brain voxels, while the second method is to set a different (local) threshold of each voxel of the FCmap. RESULTS: The distribution of random errors within the brain was observed to be homogeneous and, after thresholding with both methods, the default mode network areas were well identifiable. The two methods yielded similar results, however the application of a global threshold to all brain voxels requires a reduced computational load. The inter-subject variability of the global threshold was observed to be very low and not correlated with age. Global threshold values are also almost independent from the number of surrogates used for their computation, so the analyses can be optimized using a reduced number of surrogate time series. CONCLUSIONS: We demonstrated the efficacy of FCmaps thresholding based on random error estimation. This method can be used for a reliable single-subject analysis and could also be applied in clinical setting, to compute individual measures of disease progression or quantitative response to pharmacological or rehabilitation treatments. PMID- 24816334 TI - Motor strategy patterns study of diabetic neuropathic individuals while walking. A wavelet approach. AB - The aim of this study was to investigate muscle's energy patterns and spectral properties of diabetic neuropathic individuals during gait cycle using wavelet approach. Twenty-one diabetic patients diagnosed with peripheral neuropathy, and 21 non-diabetic individuals were assessed during the whole gait cycle. Activation patterns of vastus lateralis, medial gastrocnemius and tibialis anterior were studied by means of bipolar surface EMG. The signal's energy and frequency were compared between groups using t-test. The energy was compared in each frequency band (7-542 Hz) using ANOVAs for repeated measures for each group and each muscle. The diabetic individuals displayed lower energies in lower frequency bands for all muscles and higher energies in higher frequency bands for the extensors' muscles. They also showed lower total energy of gastrocnemius and a higher total energy of vastus, considering the whole gait cycle. The overall results suggest a change in the neuromuscular strategy of the main extensor muscles of the lower limb of diabetic patients to compensate the ankle extensor deficit to propel the body forward and accomplish the walking task. PMID- 24816335 TI - Leukemia during pregnancy: long term follow up of 32 cases from a single institution. AB - BACKGROUND AND OBJECTIVES: There is limited information regarding the outcome of patients treated for leukemia during pregnancy. This study was performed on all cases of leukemia during pregnancy identified in our institution leukemia database. PATIENTS AND METHODS: It is a retrospective study from our existing database. Thirty two cases were identified among the cohort of patients treated for acute and chronic leukemia between January 1991 and July 2003. RESULTS: Among the acute leukemia patients (n=21), 10 patients (47.6%) received chemotherapy during pregnancy, seven had live birth and three had spontaneous abortion. No teratogenicity or congenital malformations or postnatal complication were reported. The remaining 11 (52.4%) were not given chemotherapy while pregnant; three patients presented after 34 weeks of gestation ending in normal live births and then received chemotherapy and eight patients had abortion before starting chemotherapy. Among the chronic myeloid leukemia (CML) patients (n=11), nine patients received hydroxyurea, one patient received alfa-interferon and one patient was treated with leukapheresis. Eight patients had normal live births and three patients had abortion. Out of the 32 patients, 18 patients (56.2%) subsequently underwent HLA matched sibling allogeneic stem cell transplantation, seven for acute myeloid leukemia (AML), two for acute lymphocytic leukemia (ALL) and nine for CML. After a median follow up of 16 years, five patients (15.6%) are alive in remission (one from chemotherapy group and four from SCT group). CONCLUSIONS: Our report lends credence to the safety and feasibility of administering anti-leukemic therapy in acute and chronic leukemias during pregnancy although acute leukemia patients had possibly a poor long term outcome compared to non-pregnant patients. PMID- 24816336 TI - Number of people in the United States experiencing ambulatory and independent living difficulties. AB - Estimating the characteristics of the "disabled" population is necessary for some governments and of interest to health researchers concerned with producing disability prevalence rates. Because generating easy-to-understand estimates of disability in the population is important, this article provides U.S. population estimates for two disability-related measures by using the 2009 to 2011 American Community Survey Public Use Microdata Sample file. The number of people who have "independent living" and "ambulatory" difficulties is calculated from a sample of 9,204,437 (representing >309 million people). The percentage for "disabled" is found to vary by racial and ethnic category, sex, age, citizenship status, educational attainment, and state-level regions divided by weather. PMID- 24816337 TI - Structural connectivity of the default mode network and cognition in Alzheimer's disease. AB - Disconnectivity between the Default Mode Network (DMN) nodes can cause clinical symptoms and cognitive deficits in Alzheimer's disease (AD). We aimed to examine the structural connectivity between DMN nodes, to verify the extent in which white matter disconnection affects cognitive performance. MRI data of 76 subjects (25 mild AD, 21 amnestic Mild Cognitive Impairment subjects and 30 controls) were acquired on a 3.0T scanner. ExploreDTI software (fractional Anisotropy threshold=0.25 and the angular threshold=60 degrees ) calculated axial, radial, and mean diffusivities, fractional anisotropy and streamline count. AD patients showed lower fractional anisotropy (P=0.01) and streamline count (P=0.029), and higher radial diffusivity (P=0.014) than controls in the cingulum. After correction for white matter atrophy, only fractional anisotropy and radial diffusivity remained significantly lower in AD compared to controls (P=0.003 and P=0.05). In the parahippocampal bundle, AD patients had lower mean and radial diffusivities (P=0.048 and P=0.013) compared to controls, from which only radial diffusivity survived for white matter adjustment (P=0.05). Regression models revealed that cognitive performance is also accounted for by white matter microstructural values. Structural connectivity within the DMN is important to the execution of high-complexity tasks, probably due to its relevant role in the integration of the network. PMID- 24816339 TI - One kidney for life. PMID- 24816338 TI - Microstructural abnormalities in white matter and their effect on depressive symptoms after stroke. AB - The aim of the study was to investigate the existence of microstructural abnormalities in the white matter of the brain in stroke patients, as well as the relationship between these microstructural abnormalities and changes in depressive symptoms over 6 months. Participants were 29 acute ischemic stroke patients and 37 healthy control subjects. Depressive symptoms were assessed in all subjects using the Hamilton Rating Scale for Depression and the Zung Self rating Depression Scale. Whole brain voxel-based analysis was used to compare diffusion tensor imaging measures of Fractional Anisotropy (FA) between the groups. Six-month follow-up examinations were conducted. Patients showed significantly lower white matter FA values in the left and right anterior limbs of the internal capsule, and 6 months after the stroke they showed significantly increased FA values in these regions. We found a significant negative correlation between the increased ratio of the FA values and the change in depression scale scores at 6-month follow-up. Regional white matter damage may reflect abnormalities in neuroanatomical pathways related to the pathophysiology of depression. PMID- 24816340 TI - Multicentric prevalence study of anti P ribosomal autoantibodies in juvenile onset systemic lupus erythematosus compared with adult onset systemic lupus erythematosus. AB - OBJECTIVE: To investigate the prevalence and associations with clinical manifestations of anti- P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). METHODS: Clinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years old) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti- P ribosomal antibodies were tested by ELISA. RESULTS: Anti- P ribosomal antibodies were found significantly more often in pediatric-onset SLE patients (26.7% vs. 6.5%; OR=5.21 [CI95%=1.6-16.5], p=0.003). Alopecia (OR=10.11, CI 95%=1.25-97) and skin rash (non discoid) (OR=4.1, CI 95%=1.25-13.89) were significantly associated with anti- P ribosomal antibodies. CONCLUSION: Anti-ribosomal P antibodies are more often found in patients with juvenile SLE. Alopecia and skin rash were the only clinical manifestations associated to anti-ribosomal P antibodies. PMID- 24816341 TI - Health related quality of life in rheumatoid arthritis, osteoarthritis, diabetes mellitus, end stage renal disease and geriatric subjects. Experience from a General Hospital in Mexico. AB - INTRODUCTION: Chronic diseases have a great impact in the morbidity and mortality and in the health-related quality of life (HRQoL) of patients around the world. The impact of rheumatic diseases has not been fully recognized. We conducted a comparative study to evaluate the HRQoL in different chronic diseases. OBJECTIVES: The aim of the present study was to assess the HRQoL and identify specific areas affected in patients with rheumatoid arthritis (RA), osteoarthritis (OA), diabetes mellitus, end-stage renal disease, geriatric subjects and a control group. PATIENTS AND METHODS: We conducted a cross sectional study, in a General Hospital in Morelia, Mexico. All patients met classification criteria for RA, OA, diabetes mellitus, end-stage renal disease; the geriatric subjects group was>=65 years, and the control group>=30 years. Demographic characteristics were recorded, different instruments were applied: SF 36, visual analogue scale for pain, patient's and physician's global assessments, Beck Depression Inventory and specific instruments (DAS-28, HAQ-Di, WOMAC, Diabetes Quality of Life [DQOL] and Kidney Disease Questionnaire of Life [KDQOL]). Biochemical measures: erythrocyte sedimentation rate, blood count, glucose, HbA1C, serum creatinine and urea. RESULTS: We evaluated 290 subjects (control group: 100; geriatric subjects: 30 and 160 for the rest of groups). Differences were detected in baseline characteristics (P<.0001). The SF-36 scores were different between control group and others groups (P=0.007). The worst HRQoL was in end-stage renal disease group (+/-SD: 48.06+/-18.84 x/SD). The general health was the principal affected area in RA. The pain was higher in rheumatic diseases: OA (5.2+/-2.4) and RA (5.1+/-3). HAQ was higher in OA compared to RA (1.12+/-0.76 vs 0.82+/-0.82, respectively; P=.001). Forty five percent of all subjects had depression. CONCLUSIONS: The HRQoL in RA patients is poor and comparable to other chronic diseases (end-stage renal disease and diabetes mellitus). Rheumatic diseases should be considered high impact diseases and therefore should receive more attention. PMID- 24816342 TI - dbCRY: a Web-based comparative and evolutionary genomics platform for blue-light receptors. AB - Cryptochromes are flavoproteins that play a central role in the circadian oscillations of all living organisms except archaea. Cryptochromes are clustered into three subfamilies: plant-type cryptochromes, animal-type cryptochromes and cryptochrome-DASH proteins. These subfamilies are composed of photolyase/cryptochrome superfamily with 6-4 photolyase and cyclobutane pyrimidine dimer photolyase. Cryptochromes have conserved domain architectures with two distinct domains, an N-terminal photolyase-related domain and a C terminal domain. Although the molecular function and domain architecture of cryptochromes are conserved, their molecular mechanisms differ between plants and animals. Thus, cryptochromes are one of the best candidates for comparative and evolutionary studies. Here, we have developed a Web-based platform for comparative and evolutionary studies of cryptochromes, dbCRY (http://www.dbcryptochrome.org/). A pipeline built upon the consensus domain profile was applied to 1438 genomes and identified 1309 genes. To support comparative and evolutionary genomics studies, the Web interface provides diverse functions such as (i) browsing by species, (ii) protein domain analysis, (iii) multiple sequence alignment, (iv) homology search and (v) extended analysis opportunities through the implementation of 'Favorite Browser' powered by the Comparative Fungal Genomics Platform 2.0 (CFGP 2.0; http://cfgp.snu.ac.kr/). dbCRY would serve as a standardized and systematic solution for cryptochrome genomics studies. Database URL: http://www.dbcryptochrome.org/ PMID- 24816345 TI - Elevated salicylic acid levels conferred by increased expression of ISOCHORISMATE SYNTHASE 1 contribute to hyperaccumulation of SUMO1 conjugates in the Arabidopsis mutant early in short days 4. AB - Post-translational modification of proteins by attachment of small ubiquitin-like modifier (SUMO) is essential for plant growth and development. Mutations in the SUMO protease early in short days 4 (ESD4) cause hyperaccumulation of conjugates formed between SUMO and its substrates, and phenotypically are associated with extreme early flowering and impaired growth. We performed a suppressor mutagenesis screen of esd4 and identified a series of mutants called suppressor of esd4 (sed), which delay flowering, enhance growth and reduce hyperaccumulation of SUMO conjugates. Genetic mapping and genome sequencing indicated that one of these mutations (sed111) is in the gene salicylic acid induction-deficient 2 (SID2), which encodes ISOCHORISMATE SYNTHASE I, an enzyme required for biosynthesis of salicylic acid (SA). Analyses showed that compared with wild-type plants, esd4 contains higher levels of SID2 mRNA and about threefold more SA, whereas sed111 contains lower SA levels. Other sed mutants also contain lower SA levels but are not mutant for SID2, although most reduce SID2 mRNA levels. Therefore, higher SA levels contribute to the small size, early flowering and elevated SUMO conjugate levels of esd4. Our results support previous data indicating that SUMO homeostasis influences SA biosynthesis in wild-type plants, and also demonstrate that elevated levels of SA strongly increase the abundance of SUMO conjugates. PMID- 24816346 TI - A call for improved vaccine error reporting by pharmacists. PMID- 24816347 TI - Pharmacists and public health: other opportunities. PMID- 24816348 TI - Pharmacists' roles in patient-centered medical homes. PMID- 24816349 TI - Promoting the proper disposal of unused, unwanted, or expired medications. PMID- 24816350 TI - Pharmacists' training, perceived roles, and actions associated with dispensing controlled substance prescriptions. AB - OBJECTIVES: To examine situations that prompt pharmacists to access a prescription drug monitoring program (PDMP) database and management of opioid abuse/addiction; assess pharmacists' actions when abuse is suspected; describe pharmacists' tasks when dispensing controlled substance prescriptions (CSPs); and their continuing pharmacy education (CPE). DESIGN Cross-sectional mail survey of 1,000 randomly selected pharmacists. SETTING: Texas from February 2012 to April 2012. PARTICIPANTS: 1,000 Texas community pharmacists. INTERVENTION: Mail survey instrument. MAIN OUTCOME MEASURES: Prompts to use a PDMP and pharmacists' views actions, and related CPE programs. RESULTS The usable response rate was 26.2%. Pharmacists were more supportive of mandated PDMP use by physicians than by pharmacists (mean +/- SD 4.1 +/- 1.2 versus 3.2 +/- 1.5; P <0.001), based on a 5 point Likert scale (1, strongly disagree, to 5, strongly agree). Most pharmacists would be prompted to use a PDMP if the prescription contains mistakes (68.1%) or the patient requests an early refill (66.3%). Bivariate statistics showed that men pharmacists, those with BSPharm degrees, and pharmacists >=50 years of age reported a greater number of CPE hours related to prescription opioid abuse and pain management. An analysis of variance showed that pharmacy owners reported significantly more (P <0.05) CPE compared with manager and staff pharmacists. CONCLUSION: Older pharmacists with a BSPharm degree may be more willing to provide counseling to patients with opioid addiction based on their work experience and additional CPE related to controlled substances. As PDMP use becomes more prevalent, pharmacists should be prepared to interact and counsel patients identified with aberrant controlled prescription drug use and properly deliver pain management care. Additionally, schools of pharmacy curricula must prepare new pharmacists to prevent abuse and diversion, as well as intervene when aberrant use is identified. PMID- 24816351 TI - Discussions between medical providers and children/caregivers about the benefits of asthma-control medications. AB - OBJECTIVES: To describe the content of discussions between general pediatric providers and children and their caregivers about the benefits of asthma-control medication; describe the extent to which these discussions occur; and examine factors that are associated with medication benefit discussions. DESIGN: Cross sectional secondary analysis of audiotaped medical visits. SETTING: Five primary care pediatric clinics in North Carolina. PARTICIPANTS: 35 pediatric providers and 248 children with persistent asthma and their caregivers. MAIN OUTCOME MEASURES: Presence of discussion about benefits associated with asthma-control medications. RESULTS: Providers discussed benefits associated with asthma-control medications during 56% of medical visits. Benefits were more likely to be discussed when the child was younger and when medication adherence was discussed during the visit. When providers discussed benefits of asthma-control medications, they were most likely to ask questions and make statements regarding symptom control/prevention. CONCLUSION: General pediatric medical providers often do not discuss the benefits of asthma-control medications. Pharmacists could fill this information gap by counseling both children and their caregivers about benefits that a child with asthma can expect as a result of treatment. PMID- 24816352 TI - Adoption of a biometric screening service in community pharmacies: a qualitative study. AB - OBJECTIVE: To explore differences in perceived attributes of biometric screening services and organization characteristics among community pharmacies that adopt, outsource, or do not adopt biometric screening services that assess patients' blood pressure, blood glucose, serum cholesterol, and body mass index. DESIGN: Qualitative, comparative analysis. SETTING: Independently owned community pharmacies in Alabama. PARTICIPANTS: 25 key informants from community pharmacies were classified as adopters, outsourced adopters, and nonadopters of biometric screening services. Pharmacies using in-house staff to conduct screenings are referred to as adopters; those using external staff are referred to as outsourced adopters. MAIN OUTCOME MEASURES: Perceived attributes of the screening service and organizational characteristics identified through emergent theme analysis based on the Diffusion of Innovations Model and Model of Innovation Assimilation. RESULTS: The screening service was perceived differently by adopters, outsourced adopters, and nonadopters. Adopters saw the opportunity to increase revenue and expand the role of the pharmacist in health care by offering the service. Adopters also perceived the service to be compatible with their pharmacy layout and organizational identity; simple to implement; modifiable in terms of experimentation with models of service delivery; and visible by external constituencies (which positively affects pharmacy image). In contrast, nonadopters felt the amount of time, investment, and lack of potential patients associated with the service influenced their decision not to adopt it. Adopters and nonadopters differed in regard to their innovativeness in patient care services, their connectedness in professional networks, and how they make sense of and deal with the uncertainty of new programs. Outsourced adopters were similar to adopters but were more cautious in their decision making. CONCLUSION: Perceived attributes of the screening service and organizational characteristics differed among adopters, outsourced adopters, and nonadopters. PMID- 24816353 TI - Improving prescription auxiliary labels to increase patient understanding. AB - OBJECTIVES: To develop new, easy-to-understand prescription auxiliary labels, assess patient understanding of both new and existing labels, and compare the effectiveness of existing labels with the newly developed ones. DESIGN: Cross sectional study. SETTING: Semistructured interviews. PARTICIPANTS: Convenience sample of adults from minority populations who were currently taking or had previously taken a prescription medication and could understand English. INTERVENTION: Easy-to-understand prescription auxiliary labels were developed. Both these newly created labels and existing labels were shown to participants. Participants' health literacy levels and understanding of the information provided on the labels were determined. The reading difficulty of the auxiliary labels was determined using a Lexile Score. MAIN OUTCOME MEASURES: Interpretation and understanding of prescription auxiliary labels. RESULTS: The study included 120 participants with a mean age of 40 years (SD = 14). All existing prescription auxiliary labels yielded less than 50% "excellent" interpretations except for those indicating "Take with food" and "Do not chew or crush." The newly designed labels were better understood compared with existing labels. Some existing labels yielded Lexile scores above the sixth-grade reading level. There was an association between higher levels of education (chi2 = 20.86, P = 0.02) or higher REALM-R (Rapid Estimate of Adult Literacy in Medicine, Revised) scores (chi2 = 26.79, P = 0.02) and better interpretation of auxiliary labels. CONCLUSION: Simpler auxiliary labels with improved patient comprehension can be developed. Auxiliary label understanding and interpretation is low for commonly used labels. Pharmacies should consider using existing manufacturer auxiliary labels that meet the criteria for patients with low literacy. PMID- 24816354 TI - Quantification of an ongoing community-based medication take-back program. AB - OBJECTIVE: To develop a medication take-back program to evaluate current medication disposal practices and to quantify medication waste. METHODS: Seven medication take-back days have been held in a local community. The University of Findlay College of Pharmacy, local law enforcement, and municipal officials have collaborated to develop and sustain the events. All medications returned were quantified by documenting the drug name, dose, quantity, type, source, and estimated cost. Additionally, a participant survey was administered to determine demographics, prior disposal habits, and reason for disposal. RESULTS: A total of 786,882 dosing units estimated to be worth $1,118,020 were collected. Participant surveys (n = 818) suggest common reasons for disposal were expired (50%) or discontinued (40%) medications. The average community pharmacy prescription contained 35 dosing units worth approximately $68, and the average mail-service prescription contained 95 dosing units worth approximately $205. Antihypertensive agents, gastrointestinal agents, and analgesics were the most common therapeutic categories returned. CONCLUSION: Ongoing, collaborative medication take-back events are an effective method of removing unused medications from the community. Although the majority of medications collected were originally dispensed in community pharmacies, the average unused prescription from mail-service sources contained almost three times as many dosage units. These data suggest that the larger quantities more typically dispensed by mail-service pharmacies may contribute considerably to the problems associated with surplus medications. Further studies are needed to investigate this association. PMID- 24816355 TI - Patient participation in a clinic-based community pharmacy medication take-back program. AB - OBJECTIVES: To describe patient interest and involvement in participating in a clinic-based community pharmacy drug take-back program to dispose of unused, unwanted, or expired (UUE) medications and to identify patients' reasons for participating in the program. METHODS: A convenience sample of patients at the University of Oklahoma Family Medicine Pharmacy was recruited to complete a needs assessment survey regarding interest in drug take-back programs and current practices for handling UUE medications. Participants who purchased a postage-paid drug disposal envelope were asked to complete a program survey identifying sources of UUE medications, experience with drug take-back programs, and reasons for participation. These participants were later contacted for a follow-up telephone survey regarding their experience with the program and medications sent back. RESULTS: 62 needs assessment surveys were collected. 61% of patients reported interest in a drug take-back program. 57% reported having no UUE medications at home. Commonly reported UUE handling practices included disposal in the garbage (53.2%) or sewer (29.0%) and home storage (17.7%). 15 disposal envelopes were sold to 10 participants whose most common reasons for participation included concern about the safety of household members, accidental or intentional ingestion, and environmental impact. For 4 patients who returned a median of 9.5 prescriptions, the most common class of returned drugs was antibiotics (19.0%). CONCLUSION: Interest in drug take-back programs exists, but awareness and availability of continuous programs is limited. Programs may be more successful if offered at no cost to patients. Future studies are needed on the types of medications sent back and specific reasons for accumulation. PMID- 24816356 TI - Characteristics of online pharmacy users in a nationally representative sample. AB - OBJECTIVE: To identify health care-related factors associated with online pharmacy use by considering patients' prescription drug insurance coverage, number of prescriptions, health care expenditures, types of medications purchased, and health status. METHODS: Data were obtained from the Agency for Healthcare Research and Quality's 2002-2010 Medical Expenditure Panel Survey. Online pharmacy users were compared with nonusers across study variables in unadjusted and adjusted comparisons using logistic regression. Survey weights were applied to generate nationally representative estimates. RESULTS: A total of 443 online pharmacy users were identified, representing an average of 1.5 million individuals per year. Online users were found to be older and to have more prescriptions compared with nonusers, as well as to have higher health care expenditures and higher Charlson comorbidity index scores. Online users were also more likely to be privately insured, white, and married, and to be more educated. In logistic regression models, higher prescription expenditures (odds ratio [OR] 1.17 [1.05-1.32]), higher number of prescriptions (OR 5.13 [1.4-19]), medium to high income (OR 1.82 (1.3-2.5)], and use of erectile dysfunction drugs (OR 2.09 [1.06-4.10]) were associated with greater odds of online pharmacy use. Black race (OR 0.47 [0.3-0.72]), Medicaid insurance coverage (OR 0.23 [0.1-0.5]), and use of narcotic medications (OR 0.72 [0.53-0.97]) were associated with decreased odds of online pharmacy use. CONCLUSION: This study showed that age, race, income level, insurance coverage, high health care expenditures, and higher number of prescriptions are predictors for online pharmacy use. PMID- 24816357 TI - Evaluation of a pharmacist-led, 6-month weight loss program in obese patients. AB - OBJECTIVE: To evaluate a pharmacist-led weight loss program based on the general requirements set forth by the Centers for Medicare & Medicaid Services' (CMS) Decision Memo for Intensive Behavioral Therapy for Obesity. SETTING: Onsite Walgreens pharmacy located inside the main administration building of Maricopa County in downtown Phoenix, AZ. PRACTICE DESCRIPTION: A prevention and wellness behavioral therapy weight loss program was developed for patients of the Maricopa County on-site Walgreens. PRACTICE INNOVATION: Current pharmacy patients were recruited to attend 14 one-on-one, pharmacist-led, face-to-face behavioral therapy sessions during a 6-month period that addressed diet, exercise, and nutrition. Interactive PowerPoint presentations were used throughout the sessions. MAIN OUTCOME MEASURES: The primary outcome was mean weight loss from baseline to the end of the study. Secondary outcomes included changes in body composition, changes in nutritional intake, and participant satisfaction. RESULTS: Of 12 enrolled participants, 11 (92%) completed the program. The mean weight loss from baseline to the end of the program was 5 kg (P <0.001), representing an average 4.5% weight loss. There was a statistically significant decrease in body mass index (BMI), waist circumference, and percent visceral fat from baseline to the end of the study; however, the increase in percent muscle mass, decrease in percent body fat, and change in nutrition intake was not statistically significant. Overall, the participants rated the program highly. CONCLUSION: Pharmacists are accessible health care providers who can effectively provide intensive behavioral therapy for obesity in a manner consistent with the CMS guidelines. PMID- 24816358 TI - Measles, mumps, and rubella (MMR) vaccination: an update. PMID- 24816359 TI - Dapagliflozin propanediol, avanafil, and conjugated estrogens/bazedoxifene. PMID- 24816360 TI - Using pharmacists to improve outcomes: perceived versus proven results. PMID- 24816361 TI - PEGylated PAMAM dendrimer-doxorubicin conjugate-hybridized gold nanorod for combined photothermal-chemotherapy. AB - We prepared pH-sensitive drug-dendrimer conjugate-hybridized gold nanorod as a promising platform for combined cancer photothermal-chemotherapy under in vitro and in vivo conditions. Poly(ethylene glycol)-attached PAMAM G4 dendrimers (PEG PAMAM) were first covalently linked on the surface of mercaptohexadecanoic acid functionalized gold nanorod (MHA-AuNR), with subsequent conjugation of anti cancer drug doxorubicin (DOX) to dendrimer layer using an acid-labile-hydrazone linkage to afford PEG-DOX-PAMAM-AuNR particles. The particles with a high PEG PAMAM dendrimer coverage density (0.28 per nm(2) AuNR) showed uniform sizes and excellent colloidal stability. In vitro drug release studies demonstrated that DOX released from PEG-DOX-PAMAM-AuNR was negligible under normal physiological pH, but it was enhanced significantly at a weak acidic pH value. The efficient intracellular acid-triggered DOX release inside of lysosomes was confirmed using confocal laser scanning microscopy analysis. Furthermore, the combined photothermal-chemo treatment of cancer cells using PEG-DOX-PAMAM-AuNR for synergistic hyperthermia ablation and chemotherapy was demonstrated both in vitro and in vivo to exhibit higher therapeutic efficacy than either single treatment alone, underscoring the great potential of PEG-DOX-PAMAM-AuNR particles for cancer therapy. PMID- 24816362 TI - Intermittent electrical stimuli for guidance of human mesenchymal stem cell lineage commitment towards neural-like cells on electroconductive substrates. AB - In the context of the role of multiple physical factors in dictating stem cell fate, the present paper demonstrates the effectiveness of the intermittently delivered external electric field stimulation towards switching the stem cell fate to specific lineage, when cultured in the absence of biochemical growth factors. In particular, our findings present the ability of human mesenchymal stem cells (hMSCs) to respond to the electric stimuli by adopting extended neural like morphology on conducting polymeric substrates. Polyaniline (PANI) is selected as the model system to demonstrate this effect, as the electrical conductivity of the polymeric substrates can be systematically tailored over a broad range (10(-9) to 10 S/cm) from highly insulating to conducting by doping with varying concentrations (10(-5) to 1 m) of HCl. On the basis of the culture protocol involving the systematic delivery of intermittent electric field (dc) stimulation, the parametric window of substrate conductivity and electric field strength was established to promote significant morphological extensions, with minimal cellular damage. A time dependent morphological change in hMSCs with significant filopodial elongation was observed after 7 days of electrically stimulated culture. Concomitant with morphological changes, a commensurate increase in the expression of neural lineage commitment markers such as nestin and betaIII tubulin was recorded from hMSCs grown on highly conducting substrates, as revealed from the mRNA expression analysis using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) as well as by immune fluorescence imaging. Therefore, the present work establishes the key role of intermittent and systematic delivery of electric stimuli as guidance cues in promoting neural-like differentiation of hMSCs, when grown on electroconductive substrates. PMID- 24816363 TI - Magnetic hyperthermia efficiency in the cellular environment for different nanoparticle designs. AB - Magnetic hyperthermia mediated by magnetic nanomaterials is one promising antitumoral nanotherapy, particularly for its ability to remotely destroy deep tumors. More and more new nanomaterials are being developed for this purpose, with improved heat-generating properties in solution. However, although the ultimate target of these treatments is the tumor cell, the heating efficiency, and the underlying mechanisms, are rarely studied in the cellular environment. Here we attempt to fill this gap by making systematic measurements of both hyperthermia and magnetism in controlled cell environments, using a wide range of nanomaterials. In particular, we report a systematic fall in the heating efficiency for nanomaterials associated with tumour cells. Real-time measurements showed that this loss of heat-generating power occurred very rapidly, within a matter of minutes. The fall in heating correlated with the magnetic characterization of the samples, demonstrating a complete inhibition of the Brownian relaxation in cellular conditions. PMID- 24816364 TI - Gelatin-encapsulated iron oxide nanoparticles for platinum (IV) prodrug delivery, enzyme-stimulated release and MRI. AB - A facile method for transferring hydrophobic iron oxide nanoparticles (IONPs) from chloroform to aqueous solution via encapsulation of FITC-modified gelatin based on the hydrophobic-hydrophobic interaction is described in this report. Due to the existence of large amount of active groups such as amine groups in gelatin, the fluorescent labeling molecules of fluorescein isothiocyanate (FITC) and platinum (IV) prodrug functionalized with carboxylic groups can be conveniently conjugated on the IONPs. The nanoparticles carrying Pt(IV) prodrug exhibit good anticancer activities when the Pt(IV) complexes are reduced to Pt(II) in the intracellular environment, while the pure Pt(IV) prodrug only presents lower cytotoxicity on cancer cells. Meanwhile, fluorescence of FITC on the surface of nanoparticles was completely quenched due to the possible Forster Resonance Energy Transfer (FRET) mechanism and showed a fluorescence recovery after gelatin release and detachment from IONPs. Therefore FITC as a fluorescence probe can be used for identification, tracking and monitoring the drug release. In addition, adding pancreatic enzyme can effectively promote the gelatin release from IONPs owing to the degradation of gelatin. Noticeable darkening in magnetic resonance image (MRI) was observed at the tumor site after in situ injection of nanoparticles, indicating the IONPs-enhanced T2-weighted imaging. Our results suggest that the gelatin encapsulated Fe3O4 nanoparticles have potential applications in multi-functional drug delivery system for disease therapy, MR imaging and fluorescence sensor. PMID- 24816365 TI - The performance of cross-linked acellular arterial scaffolds as vascular grafts; pre-clinical testing in direct and isolation loop circulatory models. AB - There is a significant need for small diameter vascular grafts to be used in peripheral vascular surgery; however autologous grafts are not always available, synthetic grafts perform poorly and allografts and xenografts degenerate, dilate and calcify after implantation. We hypothesized that chemical stabilization of acellular xenogenic arteries would generate off-the-shelf grafts resistant to thrombosis, dilatation and calcification. To test this hypothesis, we decellularized porcine renal arteries, stabilized elastin with penta-galloyl glucose and collagen with carbodiimide/activated heparin and implanted them as transposition grafts in the abdominal aorta of rats as direct implants and separately as indirect, isolation-loop implants. All implants resulted in high patency and animal survival rates, ubiquitous encapsulation within a vascularized collagenous capsule, and exhibited lack of lumen thrombogenicity and no graft wall calcification. Peri-anastomotic neo-intimal tissue overgrowth was a normal occurrence in direct implants; however this reaction was circumvented in indirect implants. Notably, implantation of non-treated control scaffolds exhibited marked graft dilatation and elastin degeneration; however PGG significantly reduced elastin degradation and prevented aneurismal dilatation of vascular grafts. Overall these results point to the outstanding potential of crosslinked arterial scaffolds as small diameter vascular grafts. PMID- 24816366 TI - Experimental and modeling study on removal of pharmaceutically active compounds in rotating biological contactors. AB - The aim of this work was to study the biological removal of pharmaceutical compounds in rotating biological contactors (RBCs) under continuous operation. A two-stage RBC was used, providing a total surface area of 1.41 m(2). Four pharmaceuticals of different therapeutic classes; caffeine, sulfamethoxazole, ranitidine and carbamazepine, were studied. Six experimental scenarios were applied to the RBC-system by varying substrates' loadings (12-54 gCOD/d), volumetric flow rate (2-5L/d), and pharmaceuticals' concentration (20-50 MUg/L). The different conditions resulted to different solid retention times (SRT: 7-21 d) in each scenario. The increase of SRT due to variations of the operating conditions seemed to have a positive effect on pharmaceuticals' removal. Likewise, a negative correlation was observed between substrates' loading and pharmaceuticals' removal. An increase of initial pharmaceuticals' concentration resulted to decrease of SRT and pharmaceuticals' removal, suggesting a toxic effect to the biofilm. The maximum removals achieved were greater than 85% for all pharmaceuticals. Finally, a mathematical model which includes biofilm growth, substrates' utilization and pharmaceuticals' elimination was developed. The model predicts the contribution of sorption and biodegradation on pharmaceuticals' elimination taking into account the diffusion of pharmaceuticals inside biofilm. PMID- 24816367 TI - TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6. AB - AIMS/HYPOTHESIS: Inflammation contributes to pancreatic beta cell dysfunction in type 2 diabetes. Toll-like receptor (TLR)-2 and -4 ligands are increased systemically in recently diagnosed type 2 diabetes patients, and TLR2- and TLR4 deficient mice are protected from the metabolic consequences of a high-fat diet. Here we investigated the role of macrophages in TLR2/6- and TLR4-mediated effects on islet inflammation and beta cell function. METHODS: Genetic and pharmacological approaches were used to determine the effects of TLR2/6 and TLR4 ligands on mouse islets, human islets and purified rat beta cells. Islet macrophages were depleted and sorted by flow cytometry and the effects of TLR2/6- and TLR4-activated bone-marrow-derived macrophages (BMDMs) on beta cell function were assessed. RESULTS: Macrophages contributed to TLR2/6- and TLR4-induced islet Il1a/IL1A and Il1b/IL1B mRNA expression in mouse and human islets and IL-1beta secretion from human islets. TLR2/6 and TLR4 ligands also reduced insulin gene expression; however, this occurred in a non-beta cell autonomous manner. TLR2/6- and TLR4-activated BMDMs reduced beta cell insulin secretion partly via reducing Ins1, Ins2, and Pdx1 mRNA expression. Antagonism of the IL-1 receptor and neutralisation of IL-6 completely reversed the effects of activated macrophages on beta cell gene expression. CONCLUSIONS/INTERPRETATION: We conclude that islet macrophages are major contributors to islet IL-1beta secretion in response to TLR2/6 and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin secretion from pancreatic beta cells, partly via IL-1beta- and IL-6 mediated decreased insulin gene expression. PMID- 24816369 TI - Oxygen-aromatic contacts in intra-strand base pairs: analysis of high-resolution DNA crystal structures and quantum chemical calculations. AB - Three-dimensional structures of biomolecules are stabilized by a large number of non-covalent interactions and some of them such as van der Waals, electrostatic and hydrogen bond interactions are well characterized. Delocalized pi-electron clouds of aromatic residues are known to be involved in cation-pi, CH-pi, OH-pi and pi-pi interactions. In proteins, many examples have been found in which the backbone carbonyl oxygen of one residue makes close contact with the aromatic center of aromatic residues. Quantum chemical calculations suggest that such contacts may provide stability to the protein secondary structures. In this study, we have systematically analyzed the experimentally determined high resolution DNA crystal structures and identified 91 examples in which the aromatic center of one base is in close contact (<3.5A) with the oxygen atom of preceding (Group-I) or succeeding base (Group-II). Examples from Group-I are overwhelmingly observed and cytosine or thymine is the preferred base contributing oxygen atom in Group-I base pairs. A similar analysis of high resolution RNA structures surprisingly did not yield many examples of oxygen aromatic contact of similar type between bases. Ab initio quantum chemical calculations on compounds based on DNA crystal structures and model compounds show that interactions between the bases in base pairs with oxygen-aromatic contacts are energetically favorable. Decomposition of interaction energies indicates that dispersion forces are the major cause for energetically stable interaction in these base pairs. We speculate that oxygen-aromatic contacts in intra-strand base pairs in a DNA structure may have biological significance. PMID- 24816368 TI - Impaired proteostasis: role in the pathogenesis of diabetes mellitus. AB - In living organisms, proteins are regularly exposed to 'molecular ageing', which corresponds to a set of non-enzymatic modifications that progressively cause irreversible damage to proteins. This phenomenon is greatly amplified under pathological conditions, such as diabetes mellitus. For their survival and optimal functioning, cells have to maintain protein homeostasis, also called 'proteostasis'. This process acts to maintain a high proportion of functional and undamaged proteins. Different mechanisms are involved in proteostasis, among them degradation systems (the main intracellular proteolytic systems being proteasome and lysosomes), folding systems (including molecular chaperones), and enzymatic mechanisms of protein repair. There is growing evidence that the disruption of proteostasis may constitute a determining event in pathophysiology. The aim of this review is to demonstrate how such a dysregulation may be involved in the pathogenesis of diabetes mellitus and in the onset of its long-term complications. PMID- 24816370 TI - Combination of antithrombin and recombinant thrombomodulin modulates neutrophil cell-death and decreases circulating DAMPs levels in endotoxemic rats. AB - INTRODUCTION: The activation of coagulation is recognized as a universal event in severe sepsis. Both antithrombin and thrombomodulin play pivotal roles as suppressors of coagulation. Since the levels of both anticoagulants decrease significantly, we hypothesized that a combination therapy would be beneficial. METHODS: A sepsis model was established using the intravenous infusion of lipopolysaccharide (LPS). Either 125 IU/kg of antithrombin, 0.25mg/kg of recombinant thrombomodulin, or a combination of both agents was injected immediately after LPS infusion (n=7 each), while only a physiological saline was injected in the control group (n=7). Blood samples were obtained at eight hours after LPS infusion, and organ damage markers and the plasma levels of damage associated molecular patterns (DAMPs), such as histone H3 and cell-free DNA (cf DNA), were measured. In another series, the leukocytes harvested from normal rats were cultured in plasma obtained from each group (n=7). Eight hours later, the leukocytes were stained with green fluorescent protein, Annexin V and 7-AAD, and the proportion of alive+apoptic/necrotic cells was calculated. RESULTS: Organ damage markers such as ALT and BUN were maintained best in the combination group (P<0.05). The circulating levels of histone H3 and cf-DNA were both significantly lower in the combination therapy group (P<0.01, 0.05, respectively). The proportion of alive+apoptic/necrotic cells was significantly higher in the combination therapy group (P<0.05). CONCLUSION: The coadministration of antithrombin and recombinant thrombomodulin can modulate cell death and decrease the circulating levels of histone H3 and cf-DNA, leading to protection against organ damage in a rat model of sepsis. PMID- 24816371 TI - New insights in heparin-induced thrombocytopenia by the use of fluid-phase assays to detect specifically platelet factor 4/heparin complex antibodies and antibody secreting cells. AB - INTRODUCTION: The key feature of heparin-induced thrombocytopenia (HIT) is the production of antibodies (Ab) against the platelet factor 4 (PF4)/heparin complex. These Ab are directed against neoepitopes of the PF4 tetramer, which are induced by the complex formation with heparin. To study this humoral immune response in greater detail, either in a murine immunization model or in human blood samples, reliable and specific immune assays to detect specifically Ab against the PF4/heparin complexes, but not PF4 alone are required. MATERIALS AND METHODS: We established fluid-phase enzyme-immunoassays in which the soluble biotinylated antigen, PF4/heparin, is firstly captured by specific Ab, and secondly directly detected with enzyme-conjugated streptavidin. RESULTS: The use of this fluid-phase principle allowed a higher specificity than the traditional solid-phase enzyme-immunoassays in terms of Ab binding to murine PF4/heparin compared to murine PF4 alone. This fluid-phase approach applied to the detection of specific murine PF4/heparin Ab-secreting cells (ASC) identified the spleen as the main lymphatic organ that contributes to the PF4/heparin Ab response in mice. IgG ASC specific for PF4/heparin are very transiently detectable in mice, which might explain why anti-PF4/heparin IgG Ab typically disappear within 100 days in humans. Furthermore, this fluid-phase approach was successfully transferred to detect human PF4/heparin-specific Ab. CONCLUSION: The fluid-phase principle for the specific detection of anti-PF4/heparin IgG and IgM Ab enables new and improved assays for HIT research in men and mice. At least in mice PF4/heparin antibodies are produced by transient B cells. PMID- 24816372 TI - The Gini coefficient: a methodological pilot study to assess fetal brain development employing postmortem diffusion MRI. AB - BACKGROUND: Diffusion-weighted imaging (DWI) is important in the assessment of fetal brain development. However, it is clinically challenging and time-consuming to prepare neuromorphological examinations to assess real brain age and to detect abnormalities. OBJECTIVE: To demonstrate that the Gini coefficient can be a simple, intuitive parameter for modelling fetal brain development. MATERIALS AND METHODS: Postmortem fetal specimens(n = 28) were evaluated by diffusion-weighted imaging (DWI) on a 3-T MRI scanner using 60 directions, 0.7-mm isotropic voxels and b-values of 0, 150, 1,600 s/mm(2). Constrained spherical deconvolution (CSD) was used as the local diffusion model. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and complexity (CX) maps were generated. CX was defined as a novel diffusion metric. On the basis of those three parameters, the Gini coefficient was calculated. RESULTS: Study of fetal brain development in postmortem specimens was feasible using DWI. The Gini coefficient could be calculated for the combination of the three diffusion parameters. This multidimensional Gini coefficient correlated well with age (Adjusted R(2) = 0.59) between the ages of 17 and 26 gestational weeks. CONCLUSIONS: We propose a new method that uses an economics concept, the Gini coefficient, to describe the whole brain with one simple and intuitive measure, which can be used to assess the brain's developmental state. PMID- 24816373 TI - The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. AB - OBJECTIVE: To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials. METHOD: We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. RESULTS: The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). CONCLUSIONS: We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches. PMID- 24816374 TI - Integration host factor is required for the induction of acid resistance in Escherichia coli. AB - Integration host factor (IHF) is a heterodimeric histone-like DNA-binding protein that participates in many cellular functions. Many systems and global regulators of acid resistance (AR) under strongly acidic conditions have been reported, but the role of IHF has not been examined. In the present study, we report that IHF is necessary for the induction of AR in Escherichia coli. At acidic pH, a ?ihfA?ifhB-mutant strain was found to have significantly depressed levels of transcription of the arginine decarboxylase gene (adiA) and of translation of the lysine/cadaverine antiporter gene (cadB), when compared with wild-type strain. Thus, IHF induces the arginine- and lysine-dependent AR. These results indicate that in E. coli, by combined transcriptional and translational controls of gene expression, IHF activates expression of a specific set of genes required for survival at extremely acidic pH. PMID- 24816375 TI - Harm, tangible or feared: young Victorians' adverse experiences from others' drinking or drug use. AB - BACKGROUND: Harms from alcohol experienced by someone other than the drinker have received increasing attention of late, but have not been compared to harms from others' drug use. The aim of the current study is to compare the reported harms that are attributable to the alcohol use of others to those attributable to drugs, distinguishing between different types of harm in order to highlight how reported harms may be influenced by perception and social standing of use of the substance. METHOD: Respondents aged 16-24 from Victoria, Australia, completed the Victorian Youth Alcohol and Drug Survey (n=5001), including questions on demographics, drug and alcohol consumption, on the types of harms they experienced attributable to drugs and alcohol, as well as harms they perpetrated after using drugs or alcohol. RESULTS: For both drug and alcohol related harms, reports of harms loaded into two groups using multiple correspondence analysis: tangible harms such as assault, and amenity impacts such as being annoyed by people under the influence. Amenity impacts attributed to alcohol were more likely to be experienced by those who reported drug use and vice versa, while the tangible impacts were more likely to be reported by those who used both drugs and alcohol. CONCLUSIONS: Reports of amenity impacts from others appear to be influenced by the perception of the drug in question more than tangible impacts such as assault. Particularly for amenity impacts, the greater stigma attached to drug use may make respondents more likely to consider themselves harmed by drugs than they would when compared to alcohol, something that needs to be taken into account when assessing harms by either alcohol or drugs. PMID- 24816377 TI - Lack of exercise outweighs obesity among heart disease risk factors, says Australian study. PMID- 24816376 TI - Mexicans' use of illicit drugs in an era of drug reform: national comparative analysis by migrant status. AB - BACKGROUND: Although rates of illicit drug use are considerably lower in Mexico than in the United States, rates in Mexico have risen significantly. This increase has particular implications for Mexican women and US migrants, who are considered at increased risk of drug use. Due to drug reforms enacted in Mexico in 2008, it is critical to evaluate patterns of drug use among migrants who reside in both regions. METHODS: We analysed a sample of Mexicans (N=16,249) surveyed during a national household survey in 2011, the Encuesta Nacional de Adicciones (National Survey of Addictions). Comparative analyses based on Mexicans' migrant status - (1) never in the United States, (2) visited the United States, or (3) lived in the United States (transnationals) - featured analysis of variance and Chi-square global tests. Two multilevel regressions were conducted to determine the relationships among migrant status, women, and illicit drug use. RESULTS: Comparative findings showed significant differences in type and number of drugs used among Mexicans by migrant status. The regression models showed that compared with Mexicans who had never visited the United States, Mexican transnationals were more likely to report having used drugs (OR=2.453, 95% CI=1.933, 3.113) and using more illicit drugs (IRR=2.061, 95% CI=1.626, 2.613). Women were less likely than men to report having used drugs (OR=0.187, 95% CI=0.146, 0.239) and using more illicit drugs (IRR=0.153, 95% CI=0.116, 0.202). CONCLUSIONS: Overall, the findings support further exploration of risk factors for illicit drug use among Mexican transnationals, who exhibit greater drug use behaviours than Mexicans never in the United States. Because drug reform mandates referrals to treatment for those with recurrent issues of drug use, it is critical for the Mexican government and civic society to develop the capacity to offer evidence-based substance abuse treatment for returning migrants with high risk drug behaviours. PMID- 24816378 TI - [Mega aorta: Borst operation or Kouchoukos operation?]. AB - It was done 163 operations on aortic arch in terms 2000 to December 2011. All patients were operated in the department of aortic surgery of acad. B.V. Petrovskogo RSCS of RAMS. 36 operations were performed by using of Borst's technique and 9 operations - by using of Kouchoukos technique in case of extended aneurysms of thoracic aorta. All patients did not differ in the severity of primary state, concomitant diseases and age. Duration of cardiopulmonary bypass and internal organs ischemia were 189+/-55/190+/-47 and 55+/-8/77+/-20 min respectively. Complication frequency was 27% and 22% in case of cardiovascular failure. Respiratory failure was 16.7% and 33%. Liver and renal failure was observed in 27% and 11% of cases. Encephalopathy was detected 33% and 22% of cases. Mortality was 22% and 11% of cases. It was concluded that Kouchoukos technique is alternative and safe method in thoracic aorta aneurysm treatment. PMID- 24816380 TI - [The method of duodenal bulb plasty in case of complicated chronic ulcer of back wall of the duodenal bulb]. AB - It was proposed the method of organ-preserving surgical treatment of chronic ulcers of back wall of duodenal bulb complicated by decompensated stenosis and penetration in intrapancreatic part of common bile duct (RF patent number 2476164 from 27.02.2013). 12 patients were operated by using of this technique. One patient had post-operative pancreatitis. There were not lethal outcomes. PMID- 24816379 TI - [Laparoscopic resection of stomach in case of stomach ulcer]. AB - Laparoscopic resection of stomach was done in 84 patients with complicated peptic ulcer of stomach and duodenum. There were 1.2% post-operative complications in case of laparoscopic resection of stomach in comparison with open resection, which had 33.3% complications. There were not deaths in case of laparoscopic resection of stomach. This indication was about 4% in patients after open resection. It was determined that functionalefficiency afterlaparoscopic resection was in 1.6-1.8 times higher than afteropen resectionof stomach. PMID- 24816381 TI - [Decision of the indications for relaparotomy in case of widespread peritonitis]. AB - Use of trending analysis of multiple organ failure points in 40 patients with widespread peritonitis allowed to determine the features of its formation and regression. It was detected 4 stages of multiple organ failure. The first stage is origin and development. The second stage is slowdown of development. The third stage is regression. And the fourth stage is final. The definition of multiple organ failure stage and number of stab neutrophiles allows to determine the indications for relaparotomy timely. Sensitivity of such method was 0.9, specificity was 0.8. So, it was obtained a tool for determination of the indications for relaparotomy "on demand". It was able to identify need for surgery on the early stages objectively. PMID- 24816382 TI - [Discussion about therapeutic tactics in case of acute appendicitis]. AB - The authors' opinion about conservative treatment of acute appendicitis is presented in the article. Conservative treatment of acute appendicitiswas proposed by K. Varadhan, etc. (2009). It was presented the examination results of 7216 patients who werehospitalized with suspected acute appendicitis. Also it was analyzed the results of appendectomy, which were performed in 5172 patients. Validity of diagnostic laparoscopy, informational content of ultrasonic scanning and Alvarado scale were discussed in the article. The authors propose that wide application of conservative treatment of acute appendicitis is premature in Russian Federation. Technique approbation is necessary on base of several medical organizations with discussion of its results within the Russian Society of Surgeons. PMID- 24816383 TI - [ALPPS in case of massive liver metastases]. AB - It was presented the first experience of ALPPS technique using in treatment of massive liver metastases in the Urals. The technique allows to carry out surgical treatment without danger of development of post-operative liver failure. Also it permits to complete treatment during one hospitalization without stretching the therapeutic process in time. PMID- 24816384 TI - [Surgical treatment of patients with severe fecal incontinence]. AB - The objective of the study is improvement of clinical and functional results of surgical treatment of patients with severe fecal incontinence. 79 patients with complete fecal incontinence were included in the study. The technique of surgical intervention was choosed in depending on the localization of structural and functional disorders of the rectum closing apparatus. Complex treatment in pre operative and post-operative periods was directed on the improvement of functional results. Long-term results (6-24 months) were traced in 63 patients after surgical treatment and complex post-operative rehabilitation. Good and satisfactory results were identified in 57 (90.5%) patients, unsatisfactory results - in 6 (9.5%) patients. Choice of surgical technique in depending on the localization of structural and functional disorders of the rectum closing apparatus and combination of surgical correction with complex functional rehabilitation allow to increase treatment efficiency. Also it improves closing function in the most patients. PMID- 24816385 TI - [Fournie's disease in the light of modern ideas]. AB - The results of treatment of scrotum gangrene (Fournier's disease) in 25 patients aged from 34 to 82 years are presented in the article. The diseases of colorectal zone were nosological reasons of Fournier's disease in 13 patients, the diseases of urogenital tract - in 10 cases. Development of Fournier's disease was associated with closed trauma in 1 patient, and 1 case was associated with gunshot wound of perineum and scrotum. Slowly progressing forms of the disease were detected in 14 patients, fulminant and rapidly progressing variants - in 11 patients. Diabetes mellitus of different severity were identified in 6 patients. Clinical picture and laboratory data evidenced about systemic infection in all patients. Non-clostridial anaerobic microbes were the main exciters of pio necrotic process (92%). 6 patients died. Mortality was about 24%. Toxic shock was the reason of death in 1 patient, progressing endotoxemia - in 3 cases, pulmonary embolism - in 2 cases. The authors consider that early diagnosis and active tactics of radical treatment of pio-necrotic hearth in combination with programmed (phased) remedial necrectomy are effective methods for improvement of treatment results. Also such ways as complex system of local wound treatment, focused and multicomponent therapy of systemic and metabolic disorders of homeostasis are very important in complex treatment of patients. PMID- 24816386 TI - [The opportunities for genic therapy of chronic obliterating diseases of lower limbs arteries]. PMID- 24816387 TI - [Locally common inflammatory miofibroblastis tumor of stomach]. PMID- 24816388 TI - [Surgical treatment of abdominal aorta aneurysm in combination with Leriche's syndrome in patient with fused kidney]. PMID- 24816389 TI - [A one-time intervention in case of combination of biliary strictures with extrahepatic portal hypertension and a large aneurysm of the splenic artery]. PMID- 24816390 TI - [Purulent paraproctitis combined with retroperitoneal abscess]. PMID- 24816391 TI - Active cage mechanism of chaperonin-assisted protein folding demonstrated at single-molecule level. AB - The cylindrical chaperonin GroEL and its lid-shaped cofactor GroES of Escherichia coli have an essential role in assisting protein folding by transiently encapsulating non-native substrate in an ATP-regulated mechanism. It remains controversial whether the chaperonin system functions solely as an infinite dilution chamber, preventing off-pathway aggregation, or actively enhances folding kinetics by modulating the folding energy landscape. Here we developed single-molecule approaches to distinguish between passive and active chaperonin mechanisms. Using low protein concentrations (100pM) to exclude aggregation, we measured the spontaneous and GroEL/ES-assisted folding of double-mutant maltose binding protein (DM-MBP) by single-pair fluorescence resonance energy transfer and fluorescence correlation spectroscopy. We find that GroEL/ES accelerates folding of DM-MBP up to 8-fold over the spontaneous folding rate. Accelerated folding is achieved by encapsulation of folding intermediate in the GroEL/ES cage, independent of repetitive cycles of protein binding and release from GroEL. Moreover, photoinduced electron transfer experiments provided direct physical evidence that the confining environment of the chaperonin restricts polypeptide chain dynamics. This effect is mediated by the net-negatively charged wall of the GroEL/ES cavity, as shown using the GroEL mutant EL(KKK2) in which the net negative charge is removed. EL(KKK2)/ES functions as a passive cage in which folding occurs at the slow spontaneous rate. Taken together our findings suggest that protein encapsulation can accelerate folding by entropically destabilizing folding intermediates, in strong support of an active chaperonin mechanism in the folding of some proteins. Accelerated folding is biologically significant as it adjusts folding rates relative to the speed of protein synthesis. PMID- 24816392 TI - Intestinal MUC2 mucin supramolecular topology by packing and release resting on D3 domain assembly. AB - MUC2 is the major gel-forming mucin of the colon forming a protective gel barrier organized into an inner stratified and an outer loose layer. The MUC2 N-terminus (D1-D2-D'D3 domains) has a dual function in building a net-like structure by disulfide-bonded trimerization and packing the MUC2 polymer into an N-terminal concatenated polygonal platform with the C-termini extending perpendicularly by pH- and calcium-dependent interactions. We studied the N-terminal D'D3 domain by producing three recombinant variants, with or without Myc tag and GFP (green fluorescent protein), and analyzed these by gel filtration, electron microscopy and single particle image processing. The three variants were all trimers when analyzed upon denaturing conditions but eluted as hexamers upon gel filtration under native conditions. Studies by electron microscopy and three-dimensional maps revealed cage-like structures with 2- and 3-fold symmetries. The structure of the MUC2 D3 domain confirms that the MUC2 mucin forms branched net-like structures. This suggests that the MUC2 mucin is stored with two N-terminal concatenated ring platforms turned by 180 degrees against each other, implicating that every second unfolded MUC2 net in mature mucus is turned upside down. PMID- 24816393 TI - Stable DNA methylation boundaries and expanded trinucleotide repeats: role of DNA insertions. AB - The human genome segment upstream of the FMR1 (fragile X mental retardation 1) gene (Xq27.3) contains several genetic signals, among them is a DNA methylation boundary that is located 65-70 CpGs upstream of the CGG repeat. In fragile X syndrome (FXS), the boundary is lost, and the promoter is inactivated by methylation spreading. Here we document boundary stability in spite of critical expansions of the CGG trinucleotide repeat in male or female premutation carriers and in high functioning males (HFMs). HFMs carry a full CGG repeat expansion but exhibit an unmethylated promoter and lack the FXS phenotype. The boundary is also stable in Turner (45, X) females. A CTCF-binding site is located slightly upstream of the methylation boundary and carries a unique G-to-A polymorphism (single nucleotide polymorphism), which occurs 3.6 times more frequently in genomes with CGG expansions. The increased frequency of this single nucleotide polymorphism might have functional significance. In CGG expansions, the CTCF region does not harbor additional mutations. In FXS individuals and often in cells transgenomic for EBV (Epstein Barr Virus) DNA or for the telomerase gene, the large number of normally methylated CpGs in the far-upstream region of the boundary is decreased about 4-fold. A methylation boundary is also present in the human genome segment upstream of the HTT (huntingtin) promoter (4p16.3) and is stable both in normal and Huntington disease chromosomes. Hence, the vicinity of an expanded repeat does not per se compromise methylation boundaries. Methylation boundaries exert an important function as promoter safeguards. PMID- 24816395 TI - Basophil response to peanut allergens in Mediterranean peanut-allergic patients. AB - Ara h 1, Ara h 2, and Ara h 3 are important sensitizers in peanut allergy. Ara h 9 has also been shown to be relevant in the Mediterranean area. We evaluated the basophil response to peanut allergens and Pru p 3 in Mediterranean patients: Group 1, peanut and peach allergy; Group 2, peanut allergy and tolerance to peach; Group 3, peach allergy and tolerance to peanut; Group 4, nonallergic subjects that tolerate both peanut and peach. Compared to controls (Group 4), there was an increased basophil activation with Ara h 2 (P = 0.031) and Pru p 3 (P = 0.009) in Group 1 and with Ara h 1 (P = 0.016), Ara h 2 (P = 0.001), and Ara h 9 (P = 0.016) in Group 2. Importantly, only Ara h 2 showed an increased activation (P = 0.009) in Group 2 compared to Group 3. Ara h 2 is the best discriminating allergen for peanut allergy diagnosis in a Mediterranean population showing two patterns: patients also allergic to peach, responding to Ara h 2 and Pru p 3, and patients allergic only to peanut, responding to Ara h 1, Ara h 2, and Ara h 9. PMID- 24816394 TI - Corpus callosum atrophy correlates with gray matter atrophy in patients with multiple sclerosis. AB - OBJECTIVE: Atrophy of the corpus callosum is a recognized characteristic of multiple sclerosis (MS). We describe a new reliable method for measuring corpus callosum atrophy and correlate this with global cerebral atrophy measures. METHODS: Whole brain 3T MRI was performed in 38 relapsing-remitting MS subjects and 21 healthy controls (HC). Brain global gray and white matter volumes were segmented with SPM8. The contour of the corpus callosum was outlined on the midline of 3-D T1-weighted images by a semiautomated edge-detection technique to determine the corpus callosum area (CCA). Normalized CCA was correlated with other brain atrophy measures in MS subjects. RESULTS: CCA was disproportionately lower in MS subjects vs. HC (20.1% mean decrease; P < .001), with a large effect size (d = .62) when compared with global atrophy measures. In MS subjects, CCA correlated with brain parenchymal fraction (r = .55; P < .001) and gray matter fraction (r = .45; P = .005) but not white matter fraction (r = .18; P = .29). An inverse correlation with FLAIR hyperintense lesion volume (r = -.40; P = .01) was detected for CCA. CONCLUSION: Measurement of atrophy of the corpus callosum can have sensitivity as a useful imaging biomarker in patients with MS, even in patients with low disability levels. Both gray and white matter involvement in MS contribute to corpus callosum atrophy. PMID- 24816396 TI - Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway. AB - Hypoxic preconditioning (HPC) protects rat hearts against ischemia-reperfusion (IR) injury. However, the role of transient receptor potential vanilloid 1 (TRPV1) in HPC-mediated cardioprotection remains unknown. TRPV1 is activated by endovanilloid 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which is synthesized by arachidonate 12-lipoxygenase (ALOX12). Therefore, we examined whether HPC protects the myocardium against IR via the ALOX12/TRPV1 pathway. Compared to hearts of rats kept in room air, the hearts of rats kept in air with 10 % oxygen for 4 weeks had better post-ischemic recovery and less tissue damage when subjected to 30-min global ischemia and 4-h reflow in a Langendorff apparatus. Capsazepine, a specific TRPV1 blocker, administered 5 min before reperfusion markedly attenuated the effects of HPC, confirming that TRPV1 is a downstream effector in HPC-mediated cardioprotection. HPC resulted in the upregulation of ALOX12 and myocardial 12(S)-HETE, and prevented IR-induced 12(S) HETE reduction. In addition, sarcolemmal ALOX12 expression in HPC hearts mainly co-localized with TRPV1 expression. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy alpha-cyanocinnamate or baicalein abrogated the effects of HPC, baicalein also decreased 12(S)-HETE expression. Mimicking HPC by given 12(S)-HETE or capsaicin to baicalien-treated hearts enhanced cardiac recovery during reperfusion. The cardiac protein kinase C (PKC) isoforms alpha, delta, epsilon, and zeta were preferentially expressed in the sarcolemmal membrane of HPC-treated hearts, indicating their high intrinsic activation state. Capsazepine or co-treatment with baicalein attenuated translocation of PKCalpha, PKCdelta and PKCepsilon, but not that of PKCzeta. We conclude that HPC reduces heart susceptibly to IR via ALOX12/TRPV1/PKC pathway, as shown by increased 12(S)-HETE expression in HPC hearts. PMID- 24816397 TI - Degradation of AIMP1/p43 induced by hepatitis C virus E2 leads to upregulation of TGF-beta signaling and increase in surface expression of gp96. AB - Hepatitis C virus (HCV) causes chronic hepatitis leading to liver fibrosis and autoimmune diseases. AIMP1/p43 is a multifunctional protein initially known as a cofactor of aminoacyl tRNA synthetase complex. Its function includes negative regulation of TGF-beta signaling and suppression of Lupus-like autoimmune disease by inhibition of surface expression of gp96. HCV E2 was shown to directly interact with AIMP1/p43 by GST pulldown assay and coimmunoprecipitation. Their subcellular colocalization was observed in an immunofluorescence confocal microscopy. We showed that HCV E2 led to degradation of AIMP1/p43 in two ways. First, in the presence of HCV E2, endogenous AIMP1/p43 was shown to be degraded in an ubiquitin-dependent proteasome pathway. Second, grp78, an ER chaperone, was shown to interact with and stabilize AIMP1/p43. And HCV E2 inhibited this interaction leading to reduction of cellular AIMP1/p43. The degradation of AIMP1/p43 by HCV E2 resulted in increase of TGF-beta signaling and cell surface expression of gp96. Thus we suggest that these are novel mechanisms responsible for liver fibrosis and autoimmune diseases caused by HCV. PMID- 24816398 TI - Development of a high-performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of CP-47,497, CP-47,497-C8 and JWH-250 in mouse brain. AB - While Marijuana continues to be the most widely used illicit drug, abuse of synthetic cannabinoid (SCB) compounds in 'Spice' or 'K2' herbal incense products has emerged as a significant public health concern in many European countries and in the USA. Several of these SCBs have been declared Schedule I controlled substances but detection and quantification in biological samples remain a challenge. Therefore, we present a liquid chromatography-tandem mass spectrometry method after liquid-liquid extraction for the quantitation of CP-47,497, CP 47,497-C8 and JWH-250 in mouse brain. We report data for linearity, limit of quantification, accuracy/bias, precision, recovery, selectivity, carryover, matrix effects and stability experiments which were developed and fully validated based on Scientific Working Group for Forensic Toxicology guidelines for forensic toxicology method validation. Acceptable coefficients of variation for accuracy/bias, within- and between-run precision and selectivity were determined, with all values within +/-15% of the target concentration. Validation experiments revealed degradation of CP-47, 497 and CP-47,497-C8 at different temperatures, and significant ion suppression was produced in brain for all compounds tested. The method was successfully applied to detect and quantify CP-47,497 in brains from mice demonstrating significant cannabimimetic behavioral effects as assessed by the classical tetrad paradigm. PMID- 24816400 TI - The relation between migraine, typical migraine aura and "visual snow". AB - OBJECTIVE: To assess the relationship between the phenotype of the "visual snow" syndrome, comorbid migraine, and typical migraine aura on a clinical basis and using functional brain imaging. BACKGROUND: Patients with "visual snow" suffer from continuous TV-static-like tiny flickering dots in the entire visual field. Most patients describe a syndrome with additional visual symptoms of the following categories: palinopsia ("afterimages" and "trailing"), entopic phenomena arising from the optic apparatus itself (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye), photophobia, nyctalopia (impaired night vision), as well as the non-visual symptom tinnitus. The high prevalence of migraine and typical migraine aura in this population has led to the assumption that "visual snow" is caused by persistent migraine aura. Due to the lack of objective measures, alternative diagnoses are malingering or a psychogenic disorder. METHODS: (1) The prevalence of additional visual symptoms, tinnitus, and comorbid migraine as well as typical migraine aura was assessed in a prospective semi-structured telephone interview of patients with "visual snow." Correlations were calculated using standard statistics with P < .05 being considered statistically significant. (2) Areas with increased brain metabolism in a group of "visual snow" patients in comparison to healthy controls were identified using [(18) F]-2-fluoro-2-deoxy-D-glucose positron emission tomography and statistical parametric mapping (SPM8 with whole brain analysis; statistical significance was defined by P < .001 uncorrected for multiple comparisons). RESULTS: (1) Of 120 patients with "visual snow," 70 patients also had migraine and 37 had typical migraine aura. Having comorbid migraine was associated with an increased likelihood of having palinopsia (odds ratio [OR] 2.8; P = .04 for "afterimages" and OR 2.6; P = .01 for "trailing"), spontaneous photopsia (OR 2.9; P = .004), photophobia (OR 3.2; P = .005), nyctalopia (OR 2.7; P = .01), and tinnitus (OR 2.9; P = .006). Typical migraine aura was associated with an increased likelihood of spontaneous photopsia (OR 2.4; P = .04). (2) After adjusting for typical migraine aura, comparison of 17 "visual snow" patients with 17 age and gender matched controls showed brain hypermetabolism in the right lingual gyrus (Montreal Neurological Institute coordinates 16-78-5; kE = 101; ZE = 3.41; P < .001) and the left cerebellar anterior lobe adjacent to the left lingual gyrus (Montreal Neurological Institute coordinates -12-62-9; kE = 152; ZE = 3.28; P = .001). CONCLUSIONS: -Comorbid migraine aggravates the clinical phenotype of the "visual snow" syndrome by worsening some of the additional visual symptoms and tinnitus. This might bias studies on "visual snow" by migraineurs offering study participation more likely than non-migraineurs due to a more severe clinical presentation. The independence of entoptic phenomena from comorbid migraine indicates "visual snow" is the main determinant. The hypermetabolic lingual gyrus confirms a brain dysfunction in patients with "visual snow." The metabolic pattern differs from interictal migraine with some similarities to migrainous photophobia. The findings support the view that "visual snow," migraine, and typical migraine aura are distinct syndromes with shared pathophysiological mechanisms that need to be addressed in order to develop rational treatment strategies for this disabling condition. PMID- 24816399 TI - Imaging changes associated with cognitive abnormalities in Parkinson's disease. AB - The current study investigates both gray and white matter changes in non-demented Parkinson's disease (PD) patients with varying degrees of mild cognitive deficits and elucidates the relationships between the structural changes and clinical sequelae of PD. Twenty-six PD patients and 15 healthy controls (HCs) were enrolled in the study. Participants underwent T1-weighted and diffusion tensor imaging (DTI) scans. Their cognition was assessed using a neuropsychological battery. Compared with HCs, PD patients showed significant cortical thinning in sensorimotor (left pre- and postcentral gyri) and cognitive (left dorsolateral superior frontal gyrus [DLSFG]) regions. The DLSFG cortical thinning correlated with executive and global cognitive impairment in PD patients. PD patients showed white matter abnormalities as well, primarily in bilateral frontal and temporal regions, which also correlated with executive and global cognitive impairment. These results seem to suggest that both gray and white matter changes in the frontal regions may constitute an early pathological substrate of cognitive impairment of PD providing a sensitive biomarker for brain changes in PD. PMID- 24816402 TI - Working together: basal ganglia pathways in action selection. AB - Jin, Tecuapetla, and Costa combined in vivo electrophysiology with optogenetic identification to examine firing in multiple basal ganglia nuclei during rapid motor sequences. Their results support a model of basal ganglia function in which co-activation of the direct and indirect pathways facilitate appropriate, while inhibiting competing, motor programs. PMID- 24816401 TI - Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology. AB - We developed a three-dimensional (3D) cellular microarray platform for the high throughput (HT) analysis of human neural stem cell (hNSC) growth and differentiation. The growth of an immortalized hNSC line, ReNcell VM, was evaluated on a miniaturized cell culture chip consisting of 60nl spots of cells encapsulated in alginate, and compared to standard 2D well plate culture conditions. Using a live/dead cell viability assay, we demonstrated that the hNSCs are able to expand on-chip, albeit with lower proliferation rates and viabilities than in conventional 2D culture platforms. Using an in-cell, on-chip immunofluorescence assay, which provides quantitative information on cellular levels of proteins involved in neural fate, we demonstrated that ReNcell VM can preserve its multipotent state during on-chip expansion. Moreover, differentiation of the hNSCs into glial progeny was achieved both off- and on chip six days after growth factor removal, accompanied by a decrease in the neural progenitor markers. The versatility of the platform was further demonstrated by complementing the cell culture chip with a chamber system that allowed us to screen for differential toxicity of small molecules to hNSCs. Using this approach, we showed differential toxicity when evaluating three neurotoxic compounds and one antiproliferative compound, and the null effect of a non-toxic compound at relevant concentrations. Thus, our 3D high-throughput microarray platform may help predict, in vitro, which compounds pose an increased threat to neural development and should therefore be prioritized for further screening and evaluation. PMID- 24816403 TI - Role of Ets-1 in fibronectin-derived heparin-binding domain polypeptides alleviating melanoma cell invasiveness and chemoresistance. AB - In this study, we observed that rhFNHN29 and rhFNHC36, two recombinant heparin binding domain polypeptides of fibronectin, suppressed adhesion and invasion of B16F10 and A375 melanoma cells mediated by integrin alphav and alpha2 in a dose dependent manner. Combined with low-concentration epirubicin (EPI), rhFNHN29 or rhFNHC36 exhibited a synergistic inhibition on the viability and metastasis of B16F10 cells. Moreover, in the presence of high-concentration rhFNHN29 or rhFNHC36, the Ets-1 activity and the expression of p-FAK, p-Erk1/2 and Ets-1 were notably downregulated in B16F10 cells. Ets-1 is one of the central regulatory links for rhFNHN29 and rhFNHC36 to suppress the adhesion and invasion of melanoma cells. Combining rhFNHN29 or rhFNHC36 with EPI may be a good way to alleviate invasiveness or chemoresistance in melanoma. PMID- 24816406 TI - Disaster management and emergency planning. PMID- 24816404 TI - gammadeltaT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. AB - Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate gammadeltaT (gammadeltaT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and gammadeltaT17 polarization in human tumors. Activated inf-DCs induced gammadeltaT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, gammadeltaT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC gammadeltaT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC meditated immunosuppression with tumor-elicited inflammation. These findings suggest that gammadeltaT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction. PMID- 24816409 TI - The public health impact of hay fever: is it time to look at prevention through environmental modification? PMID- 24816405 TI - IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. AB - Little is known about how the immune system impacts human colorectal cancer invasiveness and stemness. Here we detected interleukin-22 (IL-22) in patient colorectal cancer tissues that was produced predominantly by CD4(+) T cells. In a mouse model, migration of these cells into the colon cancer microenvironment required the chemokine receptor CCR6 and its ligand CCL20. IL-22 acted on cancer cells to promote activation of the transcription factor STAT3 and expression of the histone 3 lysine 79 (H3K79) methytransferase DOT1L. The DOT1L complex induced the core stem cell genes NANOG, SOX2, and Pou5F1, resulting in increased cancer stemness and tumorigenic potential. Furthermore, high DOT1L expression and H3K79me2 in colorectal cancer tissues was a predictor of poor patient survival. Thus, IL-22(+) cells promote colon cancer stemness via regulation of stemness genes that negatively affects patient outcome. Efforts to target this network might be a strategy in treating colorectal cancer patients. PMID- 24816410 TI - Putting 'the public' back into public health - building the experience of citizens into public health evidence: 16th January 2014, Leeds Metropolitan University, Leeds, UK. PMID- 24816411 TI - How should public health teams engage in area planning? PMID- 24816412 TI - Disaster management: a case study. PMID- 24816413 TI - A Health in All Policies response to disaster recovery. PMID- 24816414 TI - Disaster issues and management in farm and urban crop production. PMID- 24816415 TI - Developing and implementing a robust asset-based approach to public health. PMID- 24816416 TI - Sedentary behaviour and chronic disease. PMID- 24816417 TI - Addressing health inequalities: five practical approaches for local authorities. PMID- 24816419 TI - Electrophysiological diagnosis of Guillain-Barre syndrome subtype: could a single study suffice? AB - BACKGROUND: Serial electrophysiology has been suggested as essential for accurate diagnosis in Guillain-Barre syndrome (GBS). However, whether more adapted electrophysiological criteria may allow a single study to be sufficient is unknown. METHODS: We retrospectively reviewed records of 365 consecutive patients with GBS from Birmingham, U.K., and Garches, France, admitted between 1998 and 2013. Electrophysiology was analysed using existing criteria as well as a set of modified criteria, developed using sensitive and specific cut-off values for demyelination and incorporating new knowledge on electrophysiology of axonal GBS. We compared diagnostic rates and classification changes using modified criteria with published literature relating to serial studies. RESULTS: With existing criteria, we found similar proportions of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (71.5% vs. 72%; p=1), axonal GBS (17.5% vs. 14.7%; p=0.62) and equivocal forms (9.9% vs. 13.3%; p=0.41) to the previous studies considered. With modified criteria, we identified comparable rates of AIDP (56.2% vs. 58.7%; p=0.70), axonal GBS (35.1% vs. 36%; p=0.89) and equivocal forms (7.7% vs. 5.3%; p=0.63) with a single nerve conduction study as compared with when serial electrophysiology was used in previous analyses. We observed an identical diagnostic shift from AIDP to axonal GBS with modified criteria as that described with serial studies (21.5% vs. 18.5%; p=0.72). Classification changes with modified criteria correlated significantly with performing of electrophysiology <=7 days after symptom onset (p=0.045), indicating their greater usefulness in earlier disease stages. CONCLUSIONS: A single electrophysiological study may suffice to establish the ultimate electrodiagnosis of GBS subtype if the proposed modified electrodiagnostic criteria are used. PMID- 24816420 TI - Parkin western blotting is useful for identification of patients with Parkin related Parkinson's disease. PMID- 24816421 TI - The effect of insomnia on tinnitus. AB - OBJECTIVE: The objective is to see how chronic tinnitus sufferers who are unmanageable to maximized medical therapy can benefit by decreasing their subjective complaints from a sleep evaluation and treatment. However, the proper identification of these particular patients has not been described well in the literature when attempting to correlate these 2 diagnoses. Thus, tinnitus patients with and without insomnia, based on ICD-9 diagnosis, were evaluated using the Tinnitus Reaction Questionnaire and Insomnia Severity Index to determine correlations between insomnia and tinnitus. METHODS: Patients with a diagnosis of tinnitus and tinnitus along with insomnia who were treated at our institution from 2009 to 2011 were identified. Tinnitus Reaction Questionnaire and Insomnia Severity Index responses were obtained through written and telephone interviews. A Pearson product moment correlation was used to determine the effect of insomnia on tinnitus. Additional analyses identified whether Tinnitus Reaction Questionnaire scores were associated with a possible benefit from an evaluation for insomnia in tinnitus patients. RESULTS: A total of 117 patients met inclusion criteria. A significant correlation was found between the Insomnia Severity Index score and Tinnitus Reaction Questionnaire severity (r = 0.64; P = .001). Tinnitus Reaction Questionnaire severity was shown to be a good predictor of sleep disturbance and good in predicting group association, especially the "emotional" subscore component (sensitivity 96.9% and specificity 55.3% for identifying tinnitus patients with insomnia). The greater the insomnia disability as exhibited by an elevated Insomnia Severity Index score, the more severe the patient's complaints were regarding the tinnitus. CONCLUSION: Results suggest that if the emotional score on the Tinnitus Reaction Questionnaire is >= 15, the Insomnia Severity Index may be useful to identify patients who may benefit from further treatment and evaluation of insomnia. The robust correlation between the Tinnitus Reaction Questionnaire and Insomnia Severity Index objectively showed that patients with insomnia have an increased emotional distress associated with their tinnitus. Both questionnaires can be used together with a high degree of specificity and sensitivity in predicting tinnitus patients with an underlying sleep disturbance. PMID- 24816422 TI - UM-SCC-103: a unique tongue cancer cell line that recapitulates the tumorigenic stem cell population of the primary tumor. AB - OBJECTIVE: A new head and neck cancer cell line was developed from a highly aggressive HNSCC of the oral cavity diagnosed in a 26-year-old pregnant woman. METHODS: Cells from the primary tumor were passaged in culture and genotyped as a unique cell line. The resultant cell line was assessed for its ability to replicate the primary tumor. RESULTS: The primary tumor and cell line contained 19.03% and 19.62% CD44(high) cells, respectively. CD44(high) cancer stem cells from UM-SCC-103 formed tumors after flank injections in mice that reconstituted the heterogeneity of the primary tumor. CD44 staining and histology in the primary tumor and tumors grown in vivo from the cell line were similar. CD44(high) cells from the primary tumor resulted in lung colony formation in 2 out of 2 tail vein injections in mice, whereas CD44(low) cells did not. Similarly, CD44(high) cells from UM-SCC-103 formed lung tumors in 2 out of 4 mice, whereas CD44(low) cells did not. CONCLUSION: The similarity in marker expression and tumorigenic behavior between the primary tumor and the resulting cell line strongly suggests that the cell line resembles the primary tumor that it was derived from and provides an important new research tool for the study of head and neck carcinomas in young patients. PMID- 24816423 TI - Cloning, expression, purification and characterization of a bispecific single chain diabody against fluoroquinolones and sulfonamides in Escherichia coli. AB - A recombinant bispecific single-chain diabody (scDb), recognizing fluoroquinolones (FQs) and sulfonamides (SAs), was successfully constructed with two single-chain variable fragment antibodies (scFvs). The scDb gene was cloned into the expression vector pJB33, and 6*His-tagged scDb was expressed as soluble bodies in Escherichia coli RV308 host, then purified by one step affinity chromatography of immobilized metal ion affinity chromatography (IMAC). SDS-PAGE and Western blotting analysis of the purified scDb indicated that the prepared scDb was successfully expressed as a ~60 kDa and the final purity of the scDb protein was up to 95% with yields of approximately 6 mg/L of bacterial culture. The scDb was further characterized by indirect competitive enzyme linked immunosorbent assay (icELISA), showing that the affinity and specificity of scDb were fully retained from the two parental scFvs, capable of simultaneously binding FQs and SAs. The 50% inhibition concentration (IC50) values of the optimized immunoassay were 0.45 ng mL(-1) for FQs and 0.75 ng mL(-1) for SAs, respectively. The scDb exhibited high affinity to 20 FQs and 14 SAs. Taken together, these findings suggested that the prepared scDb could be used to develop future novel immunoassay for simultaneous determination of 20 FQs and 14 SAs. PMID- 24816424 TI - The value of speed mentoring in a pediatric academic organization. AB - OBJECTIVE: A reliable and supportive mentor is indispensable to the career development of successful academic professionals. The Academic Pediatric Association (APA) utilized a speed mentoring format at the 2012 Pediatric Academic Societies meeting to enhance mentoring potential. We sought to evaluate the structure of the speed mentoring event and to determine the benefits and impact from the perspectives of the mentors and mentees. METHODS: Sixty mentees were matched with 60 mentors within various tracks. Each mentee met with 6 mentors for 10 minutes for each dyad. Participants were then asked to complete a survey 1 to 4 weeks after the event. Survey items included expectation, impact, and value of the experience along with potential for ongoing mentoring relationships. RESULTS: Fifty-four (90%) of the 60 mentees and 52 (87%) of 60 of the mentors completed the evaluation. Mentees stated that the event allowed them to receive advice from multiple mentors in a short time period. Mentors appreciated that they gained new insights, reflected on their own careers, and were able to give back to their field. Both mentees and mentors agreed that the time was well spent, would participate again, and identified chemistry as a major factor in pursuing an ongoing relationship. CONCLUSIONS: This national speed mentoring event provided an innovative, fun, and time-efficient mechanism to establish connections, network, and determine whether chemistry existed for potential mentor-mentee relationships. Further study should evaluate whether it can be used in other venues and lead to the development of lasting mentor-mentee relationships. PMID- 24816425 TI - Differing perceptions regarding quality of life and inpatient treatment goals for children with severe disabilities. AB - OBJECTIVE: To describe and compare during an acute hospitalization the perceptions of parents, pediatric interns, and pediatric hospitalists regarding the long-term health-related quality of life (HRQoL) of children with severe disabilities when not hospitalized and to identify treatment goals. METHODS: Parents of children with severe disabilities aged 5 to 18 years, as well as the intern and hospitalist caring for the child during acute hospitalizations at a tertiary care center in Salt Lake City, Utah, participated in this study. All participants completed the KIDSCREEN-10 and an investigator-developed survey; a subset was interviewed to qualitatively ascertain perceptions of the child's HRQoL before the current acute illness. Responses were summarized with descriptive statistics and content analysis. RESULTS: We enrolled 115 subjects. Overall, parents rated the HRQoL of their children significantly higher than did either group of physicians on both the KIDSCREEN-10 (37.4 +/- 3.9 vs 29.6 +/- 5.5, P < .001) and the investigator-developed survey (30.3 +/- 5.9 vs 26.3 +/- 5.5, P < .001). Parents described the HRQoL of their children more positively and broadly than did physicians. Parents and physicians also expressed different goals for treatment. Parents expressed optimism despite uncertainty regarding their child's future, whereas physicians anticipated increased medical complications and focused on caregiver burden. CONCLUSIONS: Parents of children with severe disabilities rated their children's long-term HRQoL higher than physicians did. Such discrepancies may increase tensions and hinder shared decision-making efforts during acute hospitalizations. Explicit discussions between parents and physicians regarding the HRQoL of children with severe disabilities and treatment goals may facilitate care processes for everyone involved. PMID- 24816426 TI - Parents' obesity-related behavior and confidence to support behavioral change in their obese child: data from the STAR study. AB - OBJECTIVE: Successful childhood obesity interventions frequently focus on behavioral modification and involve parents or family members. Parental confidence in supporting behavior change may be an element of successful family based prevention efforts. We aimed to determine whether parents' own obesity related behaviors were related to their confidence in supporting their child's achievement of obesity-related behavioral goals. METHODS: Cross-sectional analyses of data collected at baseline of a randomized control trial testing a treatment intervention for obese children (n = 787) in primary care settings (n = 14). Five obesity-related behaviors (physical activity, screen time, sugar sweetened beverage, sleep duration, fast food) were self-reported by parents for themselves and their child. Behaviors were dichotomized on the basis of achievement of behavioral goals. Five confidence questions asked how confident the parent was in helping their child achieve each goal. Logistic regression modeling high confidence was conducted with goal achievement and demographics as independent variables. RESULTS: Parents achieving physical activity or sleep duration goals were significantly more likely to be highly confident in supporting their child's achievement of those goals (physical activity, odds ratio 1.76; 95% confidence interval 1.19-2.60; sleep, odds ratio 1.74; 95% confidence interval 1.09-2.79) independent of sociodemographic variables and child's current behavior. Parental achievements of TV watching and fast food goals were also associated with confidence, but significance was attenuated after child's behavior was included in models. CONCLUSIONS: Parents' own obesity related behaviors are factors that may affect their confidence to support their child's behavior change. Providers seeking to prevent childhood obesity should address parent/family behaviors as part of their obesity prevention strategies. PMID- 24816427 TI - Generation of anti-idiotype scFv for pharmacokinetic measurement in lymphoma patients treated with chimera anti-CD22 antibody SM03. AB - Pre-clinical and clinical studies of therapeutic antibodies require highly specific reagents to examine their immune responses, bio-distributions, immunogenicity, and pharmacodynamics in patients. Selective antigen-mimicking anti-idiotype antibody facilitates the assessment of therapeutic antibody in the detection, quantitation and characterization of antibody immune responses. Using mouse specific degenerate primer pairs and splenocytic RNA, we generated an idiotype antibody-immunized phage-displayed scFv library in which an anti idiotype antibody against the therapeutic chimera anti-CD22 antibody SM03 was isolated. The anti-idiotype scFv recognized the idiotype of anti-CD22 antibody and inhibited binding of SM03 to CD22 on Raji cell surface. The anti-idiotype scFv was subsequently classified as Ab2gamma type. Moreover, our results also demonstrated firstly that the anti-idiotype scFv could be used for pharmacokinetic measurement of circulating residual antibody in lymphoma patients treated with chimera anti-CD22 monoclonal antibody SM03. Of important, the present approach could be easily adopted to generate anti-idiotype antibodies for therapeutic antibodies targeting membrane proteins, saving the cost and time for producing a soluble antigen. PMID- 24816428 TI - Selective preparation of diamondoid phosphonates. AB - We present an effective sequence for the preparation of phosphonic acid derivatives of the diamondoids diamantane, triamantane, [121]tetramantane, and [1(2,3)4]pentamantane. The reactions of the corresponding diamondoid hydroxy derivatives with PCl3 in sulfuric or trifluoroacetic acid give mono- as well as didichlorophosphorylated diamondoids in high preparative yields. PMID- 24816429 TI - Factors that affect the decision to undergo amniocentesis in women with normal Down syndrome screening results: it is all about the age. AB - BACKGROUND: Risk for foetal Down syndrome (DS) increases as maternal age increases. Non-invasive screening (maternal serum triple test) for DS is routinely offered to pregnant women to provide risk estimates and suggest invasive amniocentesis for definitive pre-natal diagnosis to high-risk women. OBJECTIVE: We examined women's decision process with regard to pre-natal screening, and specifically, the degree to which they take into account triple serum screening results when considering whether or not to undergo amniocentesis. DESIGN: Semi-structured phone interviews were conducted to assess recall of DS screening results, understanding of risk estimates and their effect on women's decision whether to undergo amniocentesis. The study included 60 pregnant Israeli women (half younger than 35 and half advanced maternal age - AMA), with normal DS screening results and no known ultrasound abnormalities. RESULTS: Age appeared to determine the decision process. The vast majority of AMA women had amniocentesis, many of them before receiving their DS screening results. Most AMA participants knew that their risk estimate was 'normal', but still considered themselves at high risk due to their age. Procedure-related risk (miscarriage) and other factors only had a minor effect on their decision. A minority of younger women had amniocentesis. Younger women mentioned procedure-related risk and having normal screening results as the main factors affecting their decision not to have amniocentesis. CONCLUSION: Age 35 is an anchor for the pre-determination regarding performing or avoiding amniocentesis. AMA women mention 'age' as their main reason to have amniocentesis and considered it an independent risk factor. PMID- 24816430 TI - Chromosomal aneuploidies and combinational fluorescence in situ hybridization probe panels are useful for predicting prognosis for esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common cancer type in China. In this study, we aimed to develop aneuploidy markers for diagnosis and prognosis of ESCC. METHODS: Chromosomal aneuploidies were detected in 493 primary tumors and 61 precancerous lesions by fluorescence in situ hybridization with chromosome enumeration probes (CEP), and cut-off values were set by receiver operating characteristic (ROC) curves. RESULTS: According to the cut-off values, chromosomes 3, 8, 10, 12, 17 and 20 presented frequent gains, with rates of 70.1, 69.7, 58.9, 66.9, 67.5 and 77.2 % in tumors and of 32.1, 26.8, 33.9, 41.2, 44.0 and 42.0 % in precancerous lesions. Loss of chromosome Y was detected in 72.0 % of male patients. An optimal four-probe panel CEP3/12/17/20 was established for detecting ESCC (sensitivity: 86.1 %), and CEP3/10/12/20 for precancerous lesions (sensitivity: 48.0 %). Gain of CEP8 was significantly correlated with lymph node metastasis (LNM) and late stages (P = 0.002 and 0.001), and loss of CEPY with age (P = 0.002, male). Kaplan-Meier survival curves indicated that patients with positive CEP10/17 (pT1 + T2, P = 0.041) and CEP8/17 (stages IIb + III + IV, P = 0.002) had poor overall survival. Combinations of LNM/stage and CEP panels could divide patients into more subgroups, including LNM + CEP3/17, LNM + CEP10/17, LNM + CEP3/10/17, stage + CEP3/17, stage + CEP10/17 and stage + CEP3/10/17 (P = 0.0004, 0.0003, 0.0001, 0.005, 0.001 and 0.0008, respectively). Multivariate Cox regression analysis confirmed that the above combinational models were independent prognostic factors. CONCLUSIONS: Our data suggest that the combinational probe sets may have potential for detection and prognostic prediction of ESCC. PMID- 24816431 TI - Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy. AB - Recessive mutations in chromosome 10 open reading frame 2 (C10orf2) are relevant in infantile-onset spinocerebellar ataxia (IOSCA). In this study, we investigated the causative mutation in a Korean family with combined phenotypes of IOSCA, sensorimotor polyneuropathy, and myopathy. We investigated recessive mutations in a Korean family with two individuals affected by IOSCA. Causative mutations were investigated using whole exome sequencing. Electrophysiological analyses and muscle and nerve biopsies were performed, along with magnetic resonance imaging (MRI) of the brain and lower extremities. Compound heterozygous mutations c.1460C>T and c.1485-1G>A in C10orf2 were identified as causative of IOSCA. Skeletal muscle showed mitochondrial DNA (mtDNA) deletions. Both patients showed a period of normal development until 12-15 months, followed by ataxia, athetosis, hearing loss, and intellectual disability. Electrophysiological findings indicated motor and sensory polyneuropathies. Muscle biopsy revealed variations in the size and shape of myofibers with scattered, small, and angulated degenerating myofibers containing abnormal mitochondria; these observations are consistent with myopathy and may be the result of mtDNA deletions. Sural nerve biopsy revealed an axonal neuropathy. High-signal-intensity lesions in the middle cerebellar peduncles were correlated with clinical severity, and MRI of the lower legs was compatible with the hypothesis of length-dependent axonal degeneration. We identified novel compound heterozygous mutations of the C10orf2 gene as the cause of IOSCA with sensorimotor polyneuropathy and myopathy. Signs of motor neuropathy and myopathy were discovered for the first time in IOSCA patients with C10orf2 mutations. These results suggest that the clinical spectrum of IOSCA caused by C10orf2 mutations may be more variable than previously reported. PMID- 24816432 TI - PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family. AB - SYNJ1 has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were initially reported (one of Sicilian and one of Iranian origins), with the same SYNJ1 homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same SYNJ1 homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the SYNJ1 homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the SYNJ1 p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20. PMID- 24816433 TI - Lindon J. Eaves, Ph.D., M.A. (Oxon), D.Sc. Theory-model-data. AB - We begin this special issue by providing a glimpse into the career of Dr. Lindon J. Eaves, from the perspectives of a student, postdoc, instructor, assistant to associate and full professor over the last 20 odd years. We focus primarily on Lindon's contributions to methodological issues and research designs to address them, in particular those related to models for extended twin-family designs, for the development of adolescent behavior, for genotype-environment covariation and interaction, and their application to the Virginia 30,000 and the Virginia Twin Study of Adolescent Behavioral Development. We then introduce the collection of papers in this special festschrift issue of Behavior Genetics, celebrating Dr. Eaves achievements over the last 40 years. PMID- 24816434 TI - Cilostazol renoprotective effect: modulation of PPAR-gamma, NGAL, KIM-1 and IL-18 underlies its novel effect in a model of ischemia-reperfusion. AB - Cilostazol, a phosphodiesterase-III inhibitor, reportedly exhibits positive effects against ischemia/reperfusion (I/R)-induced injury in several models. However, its potential role against the renal I/R insult has not been elucidated. To test whether the PPAR-gamma (of peroxisome proliferator activated receptor gamma) pathway is involved in the cilostazol effect, rats were randomized into sham, I/R, cilostazol (50 and 100 mg/kg per day, orally), pioglitazone (3 and 10 mg/kg per day, orally) and their combination at the low dose levels. Drugs regimens were administered for 14 days prior to the I/R induction. Pretreatment with cilostazol or pioglitazone provided significant protection against the I/R induced renal injury as manifested by the attenuated serum levels of creatinine, blood urea nitrogen and cystatin C. Both drugs have also opposed the I/R-induced elevation in tissue contents/activity of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kappaim-1), nuclear factor-kappaB, interleukappain-18, caspase-1, as well as malondialdehyde, iNOS, myeloperoxidase, ICAM-1 and VCAM-1. Nevertheless, the drugs increased both the PPAR-gamma transcriptional activity and the content of glutathione. Furthermore, combining the two low doses of both drugs produced effects comparable to that of the high dose level of either drug, advocating the fortification of pioglitazone renoprotective effect when given concomitantly with cilostazol. In conclusion, cilostazol purveyed conceivable novel renoprotective mechanisms and alleviated incidents associated with acute renal injury either alone or in combination with pioglitazone partially via the elevation of PPAR-gamma besides the amendment of the aforementioned biomarkers. PMID- 24816435 TI - Quantification assays for total and polyglutamine-expanded huntingtin proteins. AB - The expansion of a CAG trinucleotide repeat in the huntingtin gene, which produces huntingtin protein with an expanded polyglutamine tract, is the cause of Huntington's disease (HD). Recent studies have reported that RNAi suppression of polyglutamine-expanded huntingtin (mutant HTT) in HD animal models can ameliorate disease phenotypes. A key requirement for such preclinical studies, as well as eventual clinical trials, aimed to reduce mutant HTT exposure is a robust method to measure HTT protein levels in select tissues. We have developed several sensitive and selective assays that measure either total human HTT or polyglutamine-expanded human HTT proteins on the electrochemiluminescence Meso Scale Discovery detection platform with an increased dynamic range over other methods. In addition, we have developed an assay to detect endogenous mouse and rat HTT proteins in pre-clinical models of HD to monitor effects on the wild type protein of both allele selective and non-selective interventions. We demonstrate the application of these assays to measure HTT protein in several HD in vitro cellular and in vivo animal model systems as well as in HD patient biosamples. Furthermore, we used purified recombinant HTT proteins as standards to quantitate the absolute amount of HTT protein in such biosamples. PMID- 24816437 TI - Miscellaneous indications for extracorporeal photochemotherapy (ECP). AB - Extracorporeal photochemotherapy (ECP) has been applied to many T-cell mediated diseases where immunosuppressive drugs are insufficient or not tolerated. As ECP is mainly used in rare indications after failure of other therapies, controlled studies are hardly possible. In addition, the importance of the extracorporeal circuit imposes ethical doubts in organising sham ECP procedure, which explains the rarity of controlled double-blind studies. However, encouraging and even successful results have been reported in newly developed diabetes mellitus, erosive lichen planus, Crohn's disease, systemic sclerosis, nephrogenic fibrosing dermopathy, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematodes, psoriasis arthritis, cutaneous mucinosis, scleromyxoedema, pemphigus vulgaris, multiple sclerosis, eosinophilic fasciitis and in the prevention of percutaneous transluminal coronary angioplasty (PTCA) restenosis. This article discusses the various levels of evidence in the above cited indications. PMID- 24816436 TI - Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism. AB - The mechanism of antihypertensive and lipid-lowering drugs on the human organism is still not fully understood. New insights on the drugs' action can be provided by a metabolomics-driven approach, which offers a detailed view of the physiological state of an organism. Here, we report a metabolome-wide association study with 295 metabolites in human serum from 1,762 participants of the KORA F4 (Cooperative Health Research in the Region of Augsburg) study population. Our intent was to find variations of metabolite concentrations related to the intake of various drug classes and--based on the associations found--to generate new hypotheses about on-target as well as off-target effects of these drugs. In total, we found 41 significant associations for the drug classes investigated: For beta-blockers (11 associations), angiotensin-converting enzyme (ACE) inhibitors (four assoc.), diuretics (seven assoc.), statins (ten assoc.), and fibrates (nine assoc.) the top hits were pyroglutamine, phenylalanylphenylalanine, pseudouridine, 1-arachidonoylglycerophosphocholine, and 2-hydroxyisobutyrate, respectively. For beta-blockers we observed significant associations with metabolite concentrations that are indicative of drug side effects, such as increased serotonin and decreased free fatty acid levels. Intake of ACE inhibitors and statins associated with metabolites that provide insight into the action of the drug itself on its target, such as an association of ACE inhibitors with des-Arg(9)-bradykinin and aspartylphenylalanine, a substrate and a product of the drug-inhibited ACE. The intake of statins which reduce blood cholesterol levels, resulted in changes in the concentration of metabolites of the biosynthesis as well as of the degradation of cholesterol. Fibrates showed the strongest association with 2-hydroxyisobutyrate which might be a breakdown product of fenofibrate and, thus, a possible marker for the degradation of this drug in the human organism. The analysis of diuretics showed a heterogeneous picture that is difficult to interpret. Taken together, our results provide a basis for a deeper functional understanding of the action and side-effects of antihypertensive and lipid-lowering drugs in the general population. PMID- 24816438 TI - Transfusion therapy and alloimmunization in Thalassemia Intermedia: a 10 year experience at a tertiary care university hospital. AB - BACKGROUND: Thalassemia Intermedia (TI) has a wide clinical profile with many patients requiring only occasional transfusions. To prevent alloimmunization, we adopted a policy of issuing phenotype matched red blood cells in 2009. We examined transfusion indications and alloimmunization rate in TI patients. STUDY DESIGN AND METHODS: Clinical and blood bank records of 37 TI patients were reviewed. RESULTS: 23 Patients required transfusion for pregnancy (26), splenectomy (8) and anemia (11). Since 2009, total of 335 units were transfused with only one antibody developing after transfusing a non-phenotype matched unit. CONCLUSION: The commonest indication for blood transfusion was pregnancy. Providing phenotype matched blood has successfully reduced the rate of alloimmunization. PMID- 24816439 TI - The Forgotten Asclepieion of Peparithos and the Islander Worshippers of the Snake God. AB - The ancient Asclepieion of the island of Peparithos, modern Skopelos, had been build in an ideal position, one kilometer from the ancient city of Peparithos. The angry north Aegean Sea brought in the surface its north wall at the beginning of the 60s decade. The monument was identified as an Asclepieion from one partially saved ceramic inscription "ASCL..." (Greek: AlphaSigmaKappaLambda...). The sanctuary was surrounded by covered walkway (Greek: sigmatauomicronalpha) and it is dated at the early years of the fourth century BC. It is possible that god Apollo and goddess Artemis were worshiped in parallel. The monument reflects the culture of Peparitheans and the importance given toward the holistic treatment for the patients. PMID- 24816440 TI - Cure the incurable: stem cells an introduction to the special issue of Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC). PMID- 24816441 TI - Improved human mesenchymal stem cell isolation. AB - Human mesenchymal stem cells (hMSCs) are currently available for a range of applications and benefits and have become a good material for regenerative medicine, tissue engineering, and disease therapy. Before ex vivo expansion, isolation and characterization of primary hMSCs from peripheral tissues are key steps for obtaining adequate materials for clinical application. The proportion of peripheral stem cells is very low in surrounding tissues and organs; thus the recovery ratio will be a limiting factor. In this review, we summarized current common methods used to isolate peripheral stem cells, as well as the new insights revealed to improve the quantity of stem cells and their stemness. These strategies offer alternative ways to acquire hMSCs in a convenient and/or effective manner, which is important for clinical treatments. Improved isolation and mass amplification of the hMSCs while ensuring their stemness and quantity will be an important step for clinical use. Enlarged suitable hMSCs are more clinically applicable for therapeutic transplants and may help people live longer and better. PMID- 24816442 TI - Plasma-depleted versus red cell-reduced umbilical cord blood. AB - Umbilical cord blood banks use two methods to store frozen umbilical cord blood (UCB): red cell reduction (RCR) or plasma depletion (PD). The RCR method centrifuges cord blood in hetastarch or albumin to isolate 21 ml of cord blood containing mostly white blood cells, adds 4 ml of 50% dimethyl sulfoxide (DMSO), and then freezes the resulting 25 ml of cell suspension. The PD method removes plasma, saves all the cells, and freezes the cells in 10% DMSO. PD UCB units are cheaper to process but more expensive to store and somewhat more troublesome to thaw. However, when properly thawed and washed, PD UCB units have as many or more total nucleated cells (TNCs), CD34(+) cells, and colony-forming units (CFU) than RCR units. Two studies suggest that PD units have 20-25% more TNCs, MNCs, and CD34(+) cells, as well as two to three times more CFU than RCR units. Higher TNC, CD34(+), and CFU counts predict engraftment rate with faster neutrophil and platelet recovery. PD units have high engraftment rates with low mortality and high disease-free survival, comparable with clinical results of treatments with RCR units. One recent series of studies suggests that PD units are more effective for treating thalassemia with 2-year survival rates of 88%, disease-free survival rates of 74%, and 100% cure rate for children under age 7, compared to only 61% overall survival and 23% disease-free survival rate in thalassemic children treated with RCR units. These findings suggest that PD units not only have more TNCs, CD34(+) cells, and CFU than RCR units but also have high engraftment rates and may be more effective for treating certain conditions such as beta thalassemia. PMID- 24816443 TI - Polyglutamine (PolyQ) diseases: genetics to treatments. AB - The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases. PMID- 24816444 TI - Therapeutic potential of microRNA let-7: tumor suppression or impeding normal stemness. AB - The first microRNA, let-7, and its family were discovered in Caenorhabditis elegans and are functionally conserved from worms to humans in the regulation of embryonic development and stemness. The let-7 family has been shown to have an essential role in stem cell differentiation and tumor-suppressive activity. Deregulating expression of let-7 is commonly reported in many human cancers. Emerging evidence has accumulated and suggests that reestablishment of let-7 in tumor cells is a valuable therapeutic strategy. However, findings reach beyond tumor therapeutics and may impinge on stemness and differentiation of stem cells. In this review, we discuss the role of let-7 in development and differentiation of normal adult stem/progenitor cells and offer a viewpoint of the association between deregulated let-7 expression and tumorigenesis. The regulation of let-7 expression, cancer-relevant let-7 targets, and the application of let-7 are highlighted. PMID- 24816445 TI - Sustained running in rats administered corticosterone prevents the development of depressive behaviors and enhances hippocampal neurogenesis and synaptic plasticity without increasing neurotrophic factor levels. AB - We have previously shown that voluntary running acts as an anxiolytic and ameliorates deficits in hippocampal neurogenesis and spatial learning. It also reduces depression-like behaviors that are normally observed in rats that were administered either low (30 mg/kg) or moderate (40 mg/kg) doses of corticosterone (CORT). However, the protective effects of running were absent in rats treated with a high (50 mg/kg) dose of CORT. We examined whether allowing animals to exercise for 2 weeks prior and/or concurrently with the administration of 50 mg/kg CORT treatment could have similar protective effects. We examined hippocampal neurogenesis using immunohistochemical staining of proliferative and survival cells with the thymidine analogs (BrdU, CIdU, and IdU). In addition, we monitored synaptic protein expression and quantified the levels of neurotrophic factors in these animals as well as performing behavioral analyses (forced swim test and sucrose preference test). Our results indicate that the depressive phenotype and reductions in neurogenesis that normally accompany high CORT administration could only be prevented by allowing animals to exercise both prior to and concurrently with the CORT administration period. These animals also showed increases in both synaptophysin and PSD-95 protein levels, but surprisingly, neither brain-derived neurotrophic factor (BDNF) nor insulin-like growth factor 1 (IGF-1) levels were increased in these animals. The results suggest that persistent exercise can strengthen resilience to stress by promoting hippocampal neurogenesis and increasing synaptic protein levels, thereby reducing the deleterious effects of stress. PMID- 24816446 TI - Umbilical cord blood: a trustworthy source of multipotent stem cells for regenerative medicine. AB - It is conservatively estimated that one in three individuals in the US might benefit from regenerative medicine therapy. However, the relation of embryonic stem cells (ESCs) to human blastocysts always stirs ethical, political, moral, and emotional debate over their use in research. Thus, for the reasonably foreseeable future, the march of regenerative medicine to the clinic will depend upon the development of non-ESC therapies. Current sources of non-ESCs easily available in large numbers can be found in the bone marrow, adipose tissue, and umbilical cord blood (UCB). UCB provides an immune-compatible source of stem cells for regenerative medicine. Owing to inconsistent results, it is certainly an important and clinically relevant question whether UCB will prove to be therapeutically effective. This review will show that UCB contains multiple populations of multipotent stem cells, capable of giving rise to hematopoietic, epithelial, endothelial, and neural tissues both in vitro and in vivo. Here we raise the possibility that due to unique immunological properties of both the stem cell and non-stem cell components of cord blood, it may be possible to utilize allogeneic cells for regenerative applications without needing to influence or compromise the recipient immune system. PMID- 24816447 TI - Mesenchymal stem cells in regenerative medicine for musculoskeletal diseases: bench, bedside, and industry. AB - Human bone marrow-derived mesenchymal stem cells (MSCs) can self-renew and differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs have effectively emerged as a promising tool for clinical applications, specifically in musculoskeletal diseases. This article reviews the status of preclinical animal studies, clinical trials, and the efforts of the industry in using MSCs to treat musculoskeletal diseases such as bone fractures, bone defects, focal chondral lesions, osteoarthritis, spinal diseases, and tendon injuries. We also discuss the current problems encountered and potential of using MSCs in future clinical studies. PMID- 24816448 TI - Mesenchymal stem cell insights: prospects in cardiovascular therapy. AB - Ischemic heart damage usually triggers cardiomyopathological remodeling and fibrosis, thus promoting the development of heart functional failure. Mesenchymal stem cells (MSCs) are a heterogeneous group of cells in culture, with multipotent and hypoimmunogenic characters to aid tissue repair and avoid immune responses, respectively. Numerous experimental findings have proven the feasibility, safety, and efficiency of MSC therapy for cardiac regeneration. Despite that the exact mechanism remains unclear, the therapeutic ability of MSCs to treat ischemia heart diseases has been tested in phase I/II clinical trials. Based on encouraging preliminary findings, MSCs might become a potentially efficacious tool in the therapeutic options available to treat ischemic and nonischemic cardiovascular disorders. The molecular mechanism behind the efficacy of MSCs on promoting engraftment and accelerating the speed of heart functional recovery is still waiting for clarification. It is hypothesized that cardiomyocyte regeneration, paracrine mechanisms for cardiac repair, optimization of the niche for cell survival, and cardiac remodeling by inflammatory control are involved in the interaction between MSCs and the damaged myocardial environment. This review focuses on recent experimental and clinical findings related to cellular cardiomyoplasticity. We focus on MSCs, highlighting their roles in cardiac tissue repair, transdifferentiation, the MSC niche in myocardial tissues, discuss their therapeutic efficacy that has been tested for cardiac therapy, and the current bottleneck of MSC-based cardiac therapies. PMID- 24816449 TI - The use of ADSCs as a treatment for chronic stroke. AB - Stroke is one of the disorders for which clinically effective therapeutic modalities are most needed, and numerous ways have been explored to attempt to investigate their feasibilities. However, ischemic- or hemorrhagic-induced inflammatory neuron death causes irreversible injuries and infarction regions, and there are currently no truly effective drugs available as therapy. It is therefore urgent to be able to provide a fundamental treatment method to regenerate neuronal brain cells, and therefore, the use of stem cells for curing chronic stroke could be a major breakthrough development. In this review, we describe the features and classification of stroke and focus on the benefits of adipose tissue-derived stem cells and their applications in stroke animal models. The results show that cell-based therapies have resulted in significant improvements in neuronal behaviors and functions through different molecular mechanisms, and no safety problems have so far arisen after transplantation. Further, we propose a clinical possibility to create a homing niche by reducing the degree of invasive intracerebroventricular transplantation and combining it with continuous intravenous administration to achieve a complete cure. PMID- 24816450 TI - ADSC therapy in neurodegenerative disorders. AB - Neurodegenerative disorders, chronic diseases that can severely affect the patient's daily life, include amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. However, these diseases all have the common characteristic that they are due to degenerative irreversibility, and thus no efficient drugs or therapy methods can mitigate symptoms completely. Stem cell therapy, such as adipose tissue-derived stem cells (ADSCs), is a promising treatment for incurable disorders. In this review, we summarized the previous studies using ADSCs to treat neurodegenerative disorders, as well as their therapeutic mechanisms. We also suggested possible expectations for future human clinical trials involving minimized intracerebroventricular combined with intravenous administration, using different cell lineages to finish complementary therapy as well as change the extracellular matrix to create a homing niche. Depending on successful experiments in relevant neurodegenerative disorders models, this could form the theoretical basis for future human clinical trials. PMID- 24816451 TI - The potential therapeutic applications of olfactory ensheathing cells in regenerative medicine. AB - Olfactory ensheathing cells (OECs) are unique glia cells restricted to the primary olfactory system including the olfactory mucosa, olfactory nerve, and the outer nerve layer of the olfactory bulb. OECs guide growing olfactory axons from the neurons of the nasal cavity olfactory mucosa to the olfactory bulb to connect both the peripheral nervous system (PNS) and central nervous system (CNS). Based on these specialized abilities of OECs, transplantation of OECs to injury sites has been widely investigated for their potential therapeutic applications in neural repair in different injuries. In this article, we reviewed the properties of OECs and their roles in olfactory regeneration and in treatment of different injuries including spinal cord injury, PNS injury, and stroke and neurodegenerative diseases. PMID- 24816452 TI - Spinal cord regeneration. AB - Three theories of regeneration dominate neuroscience today, all purporting to explain why the adult central nervous system (CNS) cannot regenerate. One theory proposes that Nogo, a molecule expressed by myelin, prevents axonal growth. The second theory emphasizes the role of glial scars. The third theory proposes that chondroitin sulfate proteoglycans (CSPGs) prevent axon growth. Blockade of Nogo, CSPG, and their receptors indeed can stop axon growth in vitro and improve functional recovery in animal spinal cord injury (SCI) models. These therapies also increase sprouting of surviving axons and plasticity. However, many investigators have reported regenerating spinal tracts without eliminating Nogo, glial scar, or CSPG. For example, many motor and sensory axons grow spontaneously in contused spinal cords, crossing gliotic tissue and white matter surrounding the injury site. Sensory axons grow long distances in injured dorsal columns after peripheral nerve lesions. Cell transplants and treatments that increase cAMP and neurotrophins stimulate motor and sensory axons to cross glial scars and to grow long distances in white matter. Genetic studies deleting all members of the Nogo family and even the Nogo receptor do not always improve regeneration in mice. A recent study reported that suppressing the phosphatase and tensin homolog (PTEN) gene promotes prolific corticospinal tract regeneration. These findings cannot be explained by the current theories proposing that Nogo and glial scars prevent regeneration. Spinal axons clearly can and will grow through glial scars and Nogo-expressing tissue under some circumstances. The observation that deleting PTEN allows corticospinal tract regeneration indicates that the PTEN/AKT/mTOR pathway regulates axonal growth. Finally, many other factors stimulate spinal axonal growth, including conditioning lesions, cAMP, glycogen synthetase kinase inhibition, and neurotrophins. To explain these disparate regenerative phenomena, I propose that the spinal cord has evolved regenerative mechanisms that are normally suppressed by multiple extrinsic and intrinsic factors but can be activated by injury, mediated by the PTEN/AKT/mTOR, cAMP, and GSK3b pathways, to stimulate neural growth and proliferation. PMID- 24816453 TI - Tai Chi intervention increases progenitor CD34(+) cells in young adults. AB - Tai Chi has been shown to have many great health benefits. However, few research attempts have been made to explore the effects of practicing TCC on life span. This study provides direct evidence of Tai Chi's antiaging effects. We conducted a retrospective cross-sectional study to compare the rejuvenating and antiaging effects among Tai Chi group (TCC) and brisk walking group (BW) and no exercise habit group (NEH). Thirty-two participants were selected out of a possible 60 based on a survey, and they were separated into three groups: the TCC group (practicing for more than 1 year), the BW group (practicing for more than 1 year), and the NEH group. The CD34(+) cell counts in peripheral blood of the participants was determined, and the Kruskal-Wallis test was used to evaluate and compare the antiaging effects of the three groups. Of the 32 participants in this study, the participants in the TCC group (N = 10) outperformed the NEH group (N = 12) with respect to the number of CD34(+) progenitor cells. No significant difference was found between the TCC group and the BW group. TCC practice sustained for more than 1 year may be an intervention against aging as effective as BW in terms of its benefits on the improvement of CD34(+) number. PMID- 24816454 TI - Decellularization and recellularization technologies in tissue engineering. AB - Decellularization is the process by which cells are discharged from tissues/organs, but all of the essential cues for cell preservation and homeostasis are retained in a three-dimensional structure of the organ and its extracellular matrix components. During tissue decellularization, maintenance of the native ultrastructure and composition of the extracellular matrix (ECM) is extremely acceptable. For recellularization, the scaffold/matrix is seeded with cells, the final goal being to form a practical organ. In this review, we focus on the biological properties of the ECM that remains when a variety of decellularization methods are used, comparing recellularization technologies, including bioreactor expansion for perfusion-based bioartificial organs, and we discuss cell sources. In the future, decellularization-recellularization procedures may solve the problem of organ assembly on demand. PMID- 24816455 TI - The therapeutic potential of anti-interleukin-20 monoclonal antibody. AB - Interleukin (IL)-20, a member of the IL-10 family of cytokines, was discovered in 2001. IL-20 acts on multiple cell types by activating on a heterodimer receptor complex of either IL-20R1-IL-20R2 or IL-22R1-IL-20R2. Recent evidence indicates that IL-20's interaction with its receptors might have proinflammatory effects on chronic inflammatory diseases, particularly rheumatoid arthritis (RA), osteoporosis, and breast cancer. Updated information about IL-20, such as its identification, expression, receptors, signaling, and biological activities, is illustrated in this review based on our research and the data available in the literature. IL-20 is a pleiotropic cytokine, which promotes inflammation, angiogenesis, and chemotaxis. IL-20 also regulates osteoclast differentiation by altering the receptor activator of NF-kappaB (RANK) and RANK ligand (RANKL) axis. Inflammation, angiogenesis, and osteoclastogenesis are critical for the pathogenesis of RA, osteoporosis, and breast cancer-induced osteolysis. Based on the in vitro and in vivo data and clinical samples, we demonstrated that IL-20 plays pivotal roles in these three diseases. In experimental models, anti-IL-20 monoclonal antibody ameliorates arthritis severity, protects against ovariectomized-induced bone loss, and inhibits breast tumor-induced osteolysis. This review presents the clinical implications of IL-20, which will lead to a better understanding of the biological functions of IL-20 in these diseases and provide new therapeutic options in the future. PMID- 24816456 TI - Dryocrassin suppresses immunostimulatory function of dendritic cells and prolongs skin allograft survival. AB - Dendritic cells (DCs) are the major specialized antigen-presenting cells for the development of optimal T-cell immunity. DCs can be used as pharmacological targets to monitor novel biological modifiers for the cure of harmful immune responses, such as transplantation rejection. Dryopteris crassirhizoma Nakai (Aspiadaceae) is used for traditional herbal medicine in the region of East Asia. The root of this fern plant has been listed for treating inflammatory diseases. Dryocrassin is the tetrameric phlorophenone component derived from Dryopteris. Here we tested the immunomodulatory potential of dryocrassin on lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs in vitro and in skin allograft transplantation in vivo. Results demonstrated that dryocrassin reduced the emission of tumor necrosis factor-alpha, interleukin-6, and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility complex class II, CD40, and CD86 on DCs was also blocked by dryocrassin. Moreover, LPS-stimulated DC-elicited allogeneic T-cell proliferation was alleviated by dryocrassin. In addition, dryocrassin inhibited LPS-induced activation of IkappaB kinase, JNK/p38 mitogen-activated protein kinase, and the translocation of NF-kappaB. Treatment with dryocrassin noticeably diminished 2,4 dinitro-1-fluorobenzene-reduced delayed-type hypersensitivity and extended skin allograft survival. Dryocrassin may be one of the potent immunosuppressive agents for transplant rejection via the destruction of DC maturation and function. PMID- 24816457 TI - Salvianolic acid B maintained stem cell pluripotency and increased proliferation rate by activating Jak2-Stat3 combined with EGFR-Erk1/2 pathways. AB - Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are considered the most powerful in terms of differentiating into three-germ-layer cells. However, maintaining self-renewing ESCs and iPSCs in vitro requires leukemia-induced factor (LIF), an expensive reagent. Here we describe a less expensive compound that may serve as a LIF substitute-salvianolic acid B (Sal B), a Salvia miltiorrhiza extract. We found that Sal B is capable of upregulating Oct4 and Sox2, two genes considered important for the maintenance of ESC pluripotency. Our MTT data indicate that instead of triggering cell death, Sal B induced cell proliferation, especially at optimum concentrations of 0.01 nM and 0.1 nM. Other results indicate that compared to non-LIF controls, Sal B-treated ESCs expressed higher levels of several stem cell markers while still maintaining differentiation into three-germ-layer cells after six passages. Further, we found that Sal B triggers the Jak2-Stat3 and EGFR-ERK1/2 signaling pathways. Following Sal B treatment, (a) levels of phosphorylated (p)-Jak2, p-Stat3, p-EGFR, and p ERK proteins all increased; (b) these increases were suppressed by AG490 (a Jak2 inhibitor) and ZD1839 (an EGFR inhibitor); and (c) cytokines associated with the Jak2-Stat3 signaling pathway were upregulated. Our findings suggest that Sal B can be used as a LIF replacement for maintaining ESC pluripotency while increasing cell proliferation. PMID- 24816458 TI - MicroRNA142-3p promotes tumor-initiating and radioresistant properties in malignant pediatric brain tumors. AB - Primary central nervous system (CNS) atypical teratoid/rhabdoid tumor (ATRT) is an extremely malignant pediatric brain tumor observed in infancy and childhood. It has been reported that a subpopulation of CD133(+) cells isolated from ATRT tumors present with cancer stem-like and radioresistant properties. However, the exact biomolecular mechanisms of ATRT or CD133-positive ATRT (ATRT-CD133(+)) cells are still unclear. We have previously shown that ATRT-CD133(+) cells have pluripotent differentiation ability and the capability of malignant cells to be highly resistant to ionizing radiation (IR). By using microRNA array and quantitative RT-PCR in this study, we showed that expression of miR142-3p was lower in ATRT-CD133(+) cells than in ATRT-CD133(-) cells. miR142-3p overexpression significantly inhibited the self-renewal and tumorigenicity of ATRT-CD133(+) cells. On the contrary, silencing of endogenous miR142-3p dramatically increased the tumor-initiating and stem-like cell capacities in ATRT cells or ATRT-CD133(-) cells and further promoted the mesenchymal transitional and radioresistant properties of ATRT cells. Most importantly, therapeutic delivery of miR142-3p in ATRT cells effectively reduced its lethality by blocking tumor growth, repressing invasiveness, increasing radiosensitivity, and prolonging survival time in orthotropic-transplanted immunocompromised mice. These results demonstrate the prospect of developing novel miRNA-based strategies to block the stem-like and radioresistant properties of malignant pediatric brain cancer stem cells. PMID- 24816459 TI - Fasting whole blood fatty acid profile and risk of type 2 diabetes in adults: a nested case control study. AB - OBJECTIVE: to determine the association of fasting whole blood fatty acid concentrations with incidence of type 2 diabetes in adults. METHODS: A nested case-control study of 187 subjects from a cohort of men and women aged 55-85 years from the Hunter Region, New South Wales, Australia. Fasting whole blood fatty acids were measured using gas chromatography and incidence of type 2 diabetes was ascertained by self-reported questionnaire at the study follow-up. RESULTS: After adjustment for potential confounding variables, positive associations with type 2 diabetes were seen for dihomo-gamma-linolenic acid (DGLA) (OR = 1.04, 95% CI:1.01-1.07, P = 0.01); arachidonic acid (ARA) (OR = 1.01, 95% CI:1.00-1.01, P = 0.002); alpha-linolenic acid (ALA) (OR = 1.10, 95% CI: 1.03-1.18, P = 0.01); eicosapentaenoic acid (EPA) (OR = 1.05, 95% CI:1.02 1.08, P = 0.001); and docosahexaenoic acid (DHA) (OR = 1.03, 95% CI:1.02-1.05, P<0.0001). Lignoceric acid is significantly associated with lower type 2 diabetes risk (OR = 0.95, 95% CI: 0.92-0.99, P = 0.01). CONCLUSION: These data suggest that higher fasting whole blood concentrations of omega-6 polyunsaturated fatty acids (n-6PUFA) (ARA and DGLA) as well as omega-3 polyunsaturated fatty acid (n 3PUFA) (ALA, EPA, and DHA) are associated with an increased risk of diabetes, whereas increased fasting whole blood concentrations of lignoceric acid is inversely associated with diabetes risk. PMID- 24816460 TI - Synthetic mRNAs for manipulating cellular phenotypes: an overview. AB - Availability of high quality synthetic mRNAs (syn-mRNAs) has enabled progress in their applications. Important structural features and quality requirements are discussed. Developments in the application of mRNA-mediated manipulation of cells are presented (i) mRNA-directed expression of antigens in dendritic cells for vaccination projects in oncogenesis, infectious disease and allergy prevention; (ii) reprogramming of human fibroblasts to induced pluripotent stem cells with their subsequent differentiation to the desired cell type; (iii) applications in gene therapy. PMID- 24816461 TI - Oesophageal manometry: 10-year audit from a specialist centre, and early experience with high-resolution manometry. AB - BACKGROUND: Manometry is the gold standard investigation of innate or acquired motility disorders in the oesophagus. New technology in the form of high resolution manometry (HRM) may supplant traditional water-perfused manometry and enhance standardisation of manometric interpretation and reporting. This study reports on a 10-year experience of 5,184 consecutive patients using the traditional methods, and an early experience with HRM. RESULTS: Of 5,184 patients assessed, 4,509 (87%) had both pH and manometry and 675 (13%) had manometry only. 3,523 (78%) of the pH /manometry group had normal motility, 635 (14%) showed ineffective motility (IM), 213 (5%) a non-specific motility disturbance (NSMD), 42 (0.9%) achalasia, 58 (1.3%) nutcracker oesophagus, 22 (0.5%) hypertensive LOS (HLOS), 8 (0.2%) diffuse oesophageal spasm (DOS) and 8 (0.2 %) had scleroderma. For those referred solely for manometry only, 324 (48%) had normal motility, 72 (11%) IM, 51 (8%) NSMD, 175 (26%) achalasia, 16 (2%) nutcracker oesophagus, 32 (5%) HLOS, 1 (0.1%) DOS and 4 (0.6%) had scleroderma. 92 patients to date have been studied with HRM, with enhanced definition of lower oesophageal sphincter (LOS) function. CONCLUSION: For patients referred for reflux related symptoms, motility disorders are present in 22% of the cases. Conversely, of the patients referred for dysphagia, motility disturbances are detected in 52% of the cases sent for manometry. Our initial experience shows that HRM technology is adding a valuable dimension and clearer understanding of motility patterns in the dysphagic patient. PMID- 24816462 TI - Impact of clay mineral on air oxidation of PAH-contaminated soils. AB - This work investigated the impact of a clay mineral (bentonite) on the air oxidation of the solvent extractable organic matters (EOMs) and the PAHs from contaminated soils. EOMs were isolated from two coking plant soils and mixed with silica sand or bentonite. These samples, as well as raw soils and bentonite/soil mixtures, were oxidized in air at 60 and 100 degrees C for 160 days. Mineralization was followed by measuring the CO2 produced over the experiments. EOM, polycyclic aromatic compound (PAC), including PAH, contents were also determined. Oxidation led to a decrease in EOM contents and PAH concentrations, these diminutions were enhanced by the presence of bentonite. Transfer of carbon from EOM to insoluble organic matter pointed out a condensation phenomenon leading to a stabilization of the contamination. Higher mineralization rates, observed during the oxidation of the soil/bentonite mixtures, seem to indicate that this clay mineral had a positive influence on the transformation of PAC into CO2. PMID- 24816463 TI - Reproductive toxicity of lead, cadmium, and phthalate exposure in men. AB - Environmental toxicants viz lead or cadmium and phthalate esters (di(2 ethylhexyl) phthalate [DEHP], dibutyl phthalate [DBP], and diethyl phthalate [DEP]) widely found in different environmental strata are linked to deteriorating male reproductive health. The objective was to assess the relationships between the seminal lead, cadmium, and phthalate (DEHP, DBP, DEP) concentrations at environmental level and serum hormone levels and semen quality in non occupationally exposed men and specify the effect of individual and combined exposure of toxicants on semen quality. A study of 60 male partners of couples attending the Andrology Laboratory of the Reproductive Biology Department, All India Institute of Medical Sciences (AIIMS), New Delhi, India for semen analysis to assess their inability to achieve a pregnancy was selected for the study. The results of univariate and stepwise multiple regression analysis in the unadjusted model showed a significant correlation between lead or cadmium and phthalates DEHP/DBP/DEP and sperm motility, sperm concentration, and DNA damage. After adjusting for potential confounders, an association with lead or DEHP was only observed. The present data shows that lead (Pb) or cadmium (Cd) or phthalates might independently contribute to decline in semen quality and induce DNA damage. Phthalates might influence reproductive hormone testosterone. These findings are significant in light of the fact that men are exposed to a volley of chemicals; however, due to the small sample size, our finding needs to be confirmed in a larger population. PMID- 24816464 TI - Photonic efficiency of the photodegradation of paracetamol in water by the photo Fenton process. AB - An experimental study of the homogeneous Fenton and photo-Fenton degradation of 4 amidophenol (paracetamol, PCT) is presented. For all the operation conditions evaluated, PCT degradation is efficiently attained by both Fenton and photo Fenton processes. Also, photonic efficiencies of PCT degradation and mineralization are determined under different experimental conditions, characterizing the influence of hydrogen peroxide (H2O2) and Fe(II) on both contaminant degradation and sample mineralization. The maximum photonic degradation efficiencies for 5 and 10 mg L(-1) Fe(II) were 3.9 (H2O2 = 189 mg L( 1)) and 5 (H2O2 = 378 mg L(-1)), respectively. For higher concentrations of oxidant, H2O2 acts as a "scavenger" radical, competing in pollutant degradation and reducing the reaction rate. Moreover, in order to quantify the consumption of the oxidizing agent, the specific consumption of the hydrogen peroxide was also evaluated. For all operating conditions of both hydrogen peroxide and Fe(II) concentration, the consumption values obtained for Fenton process were always higher than the corresponding values observed for photo-Fenton. This implies a less efficient use of the oxidizing agent for dark conditions. PMID- 24816465 TI - Phytoremediating a copper mine soil with Brassica juncea L., compost and biochar. AB - The soils at a depleted copper mine in Touro (Galicia, Spain) are chemically degraded. In order to determine the effect of amendments and vegetation on the chemical characteristics of a mine soil and on the plant uptake of metals, a greenhouse experiment was carried out for 3 months. A settling pond soil was amended with different percentages of a compost and biochar mixture and vegetated with Brassica juncea L. The results showed that the untreated settling pond soil was polluted by Cu. Amendments and planting mustards decreased the pseudototal concentration of this metal, reduced the extreme soil acidity and increased the soil concentrations of C and TN. Both treatments also decreased the CaCl2 extractable Co, Cu and Ni concentrations. However, the amendments increased the pseudototal concentration of Zn in the soil, provided by the compost that was used. The results also showed that mustards extracted Ni efficiently from soils, suggesting that B. juncea L. is a good phytoextractor of Ni in mine soils. PMID- 24816466 TI - The role of the reporting framework MIATA within current efforts to advance immune monitoring. PMID- 24816467 TI - New method for isolation of rat lamina propria macrophages in colonic tissue. AB - Studies on intestinal cells in the lamina propria are important for understanding the cellular and immune responses in the gut. There is a lack of specific isolating procedures of macrophage cells in rats. Two different procedures of macrophage isolation of the lamina propria in rats are compared: a standard mice protocol for lymphocyte isolation (A) adapted to rat samples and a new protocol developed specifically for rats (B). Significant differences are observed when analyzing the effect of the isolation method on the cell number, viability and phenotype. This has important implications when further functional studies are required. PMID- 24816468 TI - Quantitative detection of epidermal growth factor and interleukin-8 in whole saliva of healthy individuals. AB - OBJECTIVES: This study aims to create consensus concerning the use of a methodology by which the handling of saliva is standardized and quantitative detection of IL-8 and EGF in whole saliva is achieved. Our study involves evaluating the extent to which the pre-treatment of saliva samples with an anionic detergent - sodium dodecyl sulphate (SDS) - improved detection levels for IL-8 and EGF. METHODS: Whole saliva samples (n=28) were collected from healthy individuals and a protease inhibitor cocktail was added immediately. They were treated with either SDS or PBS for 20min and were then applied to a sandwich ELISA. RESULTS AND CONCLUSIONS: Saliva is a complex viscous fluid that requires degrading before the analysis of salivary biomarkers. We found that pre-treatment of samples with SDS significantly increased the detection levels for both EGF (293%) and IL-8 (346%) when compared with PBS-treated pairs (***P<0.001). According to the results we recommend: (i) pre-treatment of whole saliva samples with SDS for quantitative analysis (ii) using secretory output instead of concentration in the presentation of results to avoid individual variations and (iii) taking into consideration gender, age and meal intake since these have an impact on the secretory output of salivary proteins. PMID- 24816470 TI - A special phase detector for magnetic inductive measurement of cerebral hemorrhage. AB - Cerebral hemorrhage is an important clinical problem that is often monitored and studied with expensive techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). These devices are not readily available in economically underdeveloped regions of the world and in emergency departments and emergency zones. The magnetic inductive method is an emerging technology that may become a new tool to detect cerebral hemorrhage. In this study, a special phase detector (PD) was developed and used for cerebral hemorrhage detection with the magnetic inductive method. The performance indicated that the PD can achieve phase noise as low as 6 m degrees and a 4-hour phase drift as low as 30 m degrees at 21.4 MHz. The noise and drift decreased as the frequency decreased. The performance at 10.7 MHz was slightly better than that of other recently developed phase detection systems. To test the practicality of the system, the PD was used to detect the volume change in a self made physical model of the brain. The measured phase shift was approximately proportional to the volume change of physiological saline inside the model. The change of the phase shift increased as the volume change and frequency increased. The results are in agreement with those from previous reports. To verify the feasibility of in vivo detection, an autologous blood injection model was established in rabbit brain. The results from the injection group showed a similar trend of increasing phase shift change with increasing injection volume. The average phase shift change induced by a 3-ml injection of blood was 0.502 degrees +/-0.119 degrees , which was much larger than that of the control group. The measurement system can distinguish a minimal cerebral hemorrhage volume of approximately 0.5 ml. All of the results demonstrated that the PD used with this method can detect cerebral hemorrhage. PMID- 24816469 TI - Unusual effects of GH deficiency in adults: a review about the effects of GH on skin, sleep, and coagulation. AB - Based on the literature data in the last two decades, growth hormone deficiency (GHD) in adults has been accepted as a clinical entity. Due to the presence of GH and IGF-I receptors throughout the body, the physiological effects of the GH-IGF I axis are still under investigation. The effects of GH on skin, sleep, and coagulation parameters in adults have only been investigated in detail only in the recent years. In this review, our aim was to summarize the literature regarding the effects of GHD and GH replacement treatment on the skin, sleep, and coagulation parameters in adults. PMID- 24816471 TI - False and true pre-treatment predictors of weight loss in obese patients starting a program for lifestyle change. AB - PURPOSE: Weight loss treatment effectiveness and cost-effectiveness may be improved by the identification of patients who are more prone to participate and gain benefit from specific interventions. Aim of the present study is to identify easily available additional predictors of weight loss among data usually present in the medical records of obese/overweight patients attending an outpatient clinic for a non-pharmacological lifestyle change program. RESULTS: 268 patients, 74 men and 195 women (age 43.2 +/- 11.9 years, BMI 38.9 +/- 6.8 kg/m(2)) were enrolled. Among these patients, only 35.6 % men and 22.7 % women completed the 6 month protocol. Among participants, 50.7 % lost at least 5 % initial body weight after 6 months (SUCCESSES), while 49.3 % failed (FAILURES). Baseline nutritional parameters (total Kcal, lipid, carbohydrate, protein and alcohol intake) were not significantly different in successes when compared to failures, while a significant difference between groups was observed for baseline diastolic blood pressure (DBP); free fat mass (FFM); muscle mass (MM); total body water (TBW); HDL cholesterol; ALT; AST; gammaGT. After dividing into quartiles the not normally distributed variables, successes had AST values above median (3rd and 4th quartiles; chi (2) = 0.003). At multivariate analysis (linear regression), the OR was 3.34 (1.42-7.85; p = 0.006). CONCLUSIONS: In our patients, baseline liver enzyme levels (AST in particular), but not baseline quantitative and qualitative dietary intake, were significantly different in successes versus failures and could therefore represent a predictor of success. In conclusion, AST could represent a usually available biomarker that could be used as a predictor of outcome (weight loss) in obese patients starting a lifestyle change program. PMID- 24816473 TI - Tissue Doppler imaging optical flow (TDIOF): a combined B-mode and tissue Doppler approach for cardiac motion estimation in echocardiographic images. AB - The quantitative analysis of cardiac motion from echocardiographic images helps clinicians in the diagnosis and therapy of patients suffering from heart disease. Quantitative analysis is usually based on tissue Doppler imaging (TDI) or speckle tracking. These methods are based on two techniques which to a large degree are independent: the Doppler phenomenon and image sequence processing. Herein, to increase the accuracy of the speckle tracking technique and to cope with the angle dependence of TDI, a combined approach dubbed tissue Doppler imaging optical flow (TDIOF) is proposed. TDIOF is formulated based on the combination of B-mode and Doppler energy terms minimized using algebraic equations and is validated on simulated images, and in vivo data. It was observed that the additional Doppler term is able to increase the accuracy of speckle tracking, compared to two popular motion estimation and speckle tracking techniques (Horn Schunck and block matching methods). This observation was more pronounced when noise was present. The magnitude and angular error for TDIOF applied to simulated images, when comparing estimated motion with ground-truth motion, were 15% and 9.2 degrees /frame, respectively. As an additional validation, echocardiography derived strains were compared to tagged MRI-derived myocardial strains in the same subjects. The correlation coefficient (r) between the TDIOF-derived radial strains and tagged MRI-derived radial strains value was 0.83 (P < 0.001). The correlation coefficient ( r) for the TDIOF-derived circumferential strains compared to the tagged MRI-derived circumferential strains was 0.86 (P < 0.001). The comparison of TDIOF-derived and block matching speckle tracking and Horn Schunck optical flow strain values using student t-test demonstrated superiority of TDIOF (95% confidence interval, P < 0.001). PMID- 24816472 TI - Decisional conflict in economically disadvantaged men with newly diagnosed prostate cancer: baseline results from a shared decision-making trial. AB - BACKGROUND: Decisional conflict is a source of anxiety and stress for men diagnosed with prostate cancer given uncertainty surrounding myriad treatment options. Few data exist to help clinicians identify which patients are at risk for decisional conflict. The purpose of this study was to examine factors associated with decisional conflict in economically disadvantaged men diagnosed with prostate cancer before any treatment choices were made. METHODS: A total of 70 men were surveyed at a Veterans Administration clinic with newly diagnosed localized prostate cancer enrolled in a randomized trial testing a novel shared decision-making tool. Baseline demographic, clinical, and functional data were collected. Independent variables included age, race, education, comorbidity, relationship status, urinary/sexual dysfunction, and prostate cancer knowledge. Tested outcomes were Decisional Conflict Scale, Uncertainty Subscale, and Perceived Effectiveness Subscale. Multiple linear regression modeling was used to identify factors associated with decisional conflict. RESULTS: Mean age was 63 years, 49% were African American, and 70% reported an income less than $30,000. Poor prostate cancer knowledge was associated with increased decisional conflict and higher uncertainty (P < .001 and P = 0.001, respectively). Poor knowledge was also associated with lower perceived effectiveness (P = 0.003) whereas being in a relationship was associated with higher decisional conflict (P = 0.03). CONCLUSIONS: Decreased patient knowledge about prostate cancer is associated with increased decisional conflict and lower perceived effective decision-making. Interventions to increase comprehension of prostate cancer and its treatments may reduce decisional conflict. Further work is needed to better characterize this relationship and identify effective targeted interventions. PMID- 24816474 TI - Characterization of radiofrequency ablation lesion development based on simulated and measured intracardiac electrograms. AB - Radiofrequency ablation (RFA) therapy is the gold standard in interventional treatment of many cardiac arrhythmias. A major obstacle is nontransmural lesions, leading to recurrence of arrhythmias. Recent clinical studies have suggested intracardiac electrogram (EGM) criteria as a promising marker to evaluate lesion development. Seeking for a deeper understanding of underlying mechanisms, we established a simulation approach for acute RFA lesions. Ablation lesions were modeled by a passive necrotic core surrounded by a borderzone with properties of heated myocardium. Herein, conduction velocity and electrophysiological properties were altered. We simulated EGMs during RFA to study the relation between lesion formation and EGM changes using the bidomain model. Simulations were performed on a three-dimensional setup including a geometrically detailed representation of the catheter with highly conductive electrodes. For validation, EGMs recorded during RFA procedures in five patients were analyzed and compared to simulation results. Clinical data showed major changes in the distal unipolar EGM. During RFA, the negative peak amplitude decreased up to 104% and maximum negative deflection was up to 88% smaller at the end of the ablation sequence. These changes mainly occurred in the first 10 s after ablation onset. Simulated unipolar EGMs reproduced the clinical changes, reaching up to 83% negative peak amplitude reduction and 80% decrease in maximum negative deflection for transmural lesions. In future studies, the established model may enable the development of further EGM criteria for transmural lesions even for complex geometries in order to support clinical therapy. PMID- 24816475 TI - An optimized HPLC/MS/MS method for quantification of excitatory amino acids in rat hippocampus and its application in brain ischemia/reperfusion research. AB - An optimized HPLC/MS/MS method was established to quantify glutamate (Glu) and aspartic acid (Asp) in rat hippocampus with glutamate-d5 (Glu-d5) as internal standard. The mass spectrometry was operated under the multiple reaction monitoring mode using electrospray ionization in the positive ion mode for Glu and negative ion mode for Asp. The retention times of Glu, Asp and Glu-d5 were 1.53, 2.07 and 1.52 min, respectively. The linearity of calibration curves was good, with r(2) > 0.99 and a lower limit of quantitation of 10 ng/mL. The intra day precisions (relative standard deviation, RSD) of Glu and Asp were in the range of 3.61-8.17 and 4.22-10.09%, respectively; the inter-day precisions (RSD) of Glu and Asp were in the range of 3.57-5.19 and 2.49-5.04%, respectively. The accuracies of Glu and Asp were in the range of -2.10-6.20 and -0.90-10.00%, respectively. The recovery rates of 10, 100 and 1000 ng/mL were found to be 0.89 +/- 0.24, 1.01 +/- 0.10 and 0.90 +/- 0.12 for Glu and 0.99 +/- 0.26, 0.93 +/- 0.07 and 1.13 +/- 0.13 for Asp, respectively. This optimized method was successfully applied to quantify the concentration of Glu and Asp in rat hippocampus in brain ischemia/reperfusion research. PMID- 24816477 TI - Visual rating and volumetric measurement of medial temporal atrophy in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort: baseline diagnosis and the prediction of MCI outcome. AB - OBJECTIVE: This study aims to determine the clinical utility of visual ratings and volumetric measurements of medial temporal atrophy among subjects from the Alzheimer's Disease Neurorimaging Initiative (ADNI) cohort. METHODS: A sample of 189 subjects from the ADNI, Phase 1 (ADNI-1), was chosen as follows: 49 cognitively normal (CN), 89 with mild cognitive impairment (MCI), and 50 with Alzheimer's disease (AD). Structural MRI images were downloaded from the ADNI website, and a visual rating system (VRS) was used to obtain semi-quantitative ratings of the hippocampus (HPC) and entorhinal cortex (ERC). VRS ratings and FreeSurfer measures of the HPC and ERC were used to predict (i) baseline diagnosis and (ii) progression to AD among subjects with MCI at baseline. RESULTS: VRS and FreeSurfer measures of ERC were equivalent in classifying subjects at baseline, but FreeSurfer measures of HPC were superior to VRS measures for classifying CN versus MCI subjects. VRS and FreeSurfer measures of both HPC and ERC were significant predictors of progression from MCI to AD. However, VRS ratings of ERC were superior to other MRI measures. MCI subjects with minimal ERC atrophy by VRS had a threefold lower progression rate to AD at 3.2 years compared with those with mild, moderate, or severe atrophy (23% vs 63%, 69%, and 87%, respectively). CONCLUSIONS: Visual ratings of HPC and ERC provide useful information to a physician in a clinical setting. Visual ratings of ERC may be especially useful in following patients with MCI. PMID- 24816478 TI - 3D MRI of impaired hyperpolarized 129Xe uptake in a rat model of pulmonary fibrosis. AB - A variety of pulmonary pathologies, in particular interstitial lung diseases, are characterized by thickening of the pulmonary blood-gas barrier, and this thickening results in reduced gas exchange. Such diffusive impairment is challenging to quantify spatially, because the distributions of the metabolically relevant gases (CO2 and O2) cannot be detected directly within the lungs. Hyperpolarized (HP) (129)Xe is a promising surrogate for these metabolic gases, because MR spectroscopy and imaging allow gaseous alveolar (129)Xe to be detected separately from (129)Xe dissolved in the red blood cells (RBCs) and the adjacent tissues, which comprise blood plasma and lung interstitium. Because (129)Xe reaches the RBCs by diffusing across the same barrier tissues (blood plasma and interstitium) as O2, barrier thickening will delay (129)Xe transit and, thus, reduce RBC-specific (129)Xe MR signal. Here we have exploited these properties to generate 3D, MR images of (129)Xe uptake by the RBCs in two groups of rats. In the experimental group, unilateral fibrotic injury was generated prior to imaging by instilling bleomycin into one lung. In the control group, a unilateral sham instillation of saline was performed. Uptake of (129)Xe by the RBCs, quantified as the fraction of RBC signal relative to total dissolved (129)Xe signal, was significantly reduced (P = 0.03) in the injured lungs of bleomycin-treated animals. In contrast, no significant difference (P = 0.56) was observed between the saline-treated and untreated lungs of control animals. Together, these results indicate that 3D MRI of HP (129)Xe dissolved in the pulmonary tissues can provide useful biomarkers of impaired diffusive gas exchange resulting from fibrotic thickening. PMID- 24816479 TI - The effect of maternal prenatal smoking and alcohol consumption on the placenta to-birth weight ratio. AB - BACKGROUND: Maternal influence on fetal growth is mediated through the placenta and this influence may have an implication for the offspring's long-term health. The placenta-to-birth weight ratio has been regarded as an indicator of placental function. However, few studies have examined the effect of maternal lifestyle exposures on the placenta-to-birth weight ratio. This study aims to examine the associations of maternal prenatal smoking and alcohol consumption with the placenta-to-birth weight ratio. METHODS: Data for 7945 term singletons, gestation>=37 weeks, were selected from the Tasmanian Infant Health Survey; a 1988-1995 Australian cohort study. Placenta and birth weight were extracted from birth notification records. RESULTS: Maternal smoking during pregnancy was strongly associated with a 6.77 g/kg higher (95% CI 4.83-8.71) placenta-to-birth weight ratio when compared to non-smoking mothers. Maternal prenatal smoking was associated with lower placental (beta = -15.37 g; 95% CI -23.43 to -7.31) and birth weights (beta = -205.49 g; 95% CI -232.91 to -178.08). Mothers who consumed alcohol during pregnancy had a lower placenta-to-birth weight ratio (beta = -2.07 g/kg; 95% CI -4.01 to -0.12) than mothers who did not consume alcohol. The associations of maternal alcohol consumption during pregnancy with placental and birth weight did not reach statistical significance. DISCUSSION: Maternal prenatal smoking and alcohol consumption may influence fetal growth by either directly or indirectly altering the function of the placenta. CONCLUSIONS: The alteration of the in utero environment induced by smoking and alcohol consumption appears to affect placental and fetal growth in differing ways. Further studies are needed to elucidate the mechanism. PMID- 24816480 TI - Transoral robotic surgery versus conventional surgery in treatment for squamous cell carcinoma of the upper aerodigestive tract. AB - BACKGROUND: The purpose of our work was to compare a group of patients undergoing transoral robotic surgery (TORS group) for squamous cell carcinoma of the upper aerodigestive tract and a matched group of patients undergoing conventional surgery (conventional surgery group) for the same indication. METHODS: In this retrospective single-center study, 26 patients were included in each group. RESULTS: There were significantly fewer tracheotomies in the TORS group (p < .001). The mean durations of feeding by nasogastric tube and hospitalization were shorter for the TORS group (p = .001). There was no significant difference in disease-free survival at 3 years (p = .76). Mean treatment cost was $7124 lower for the TORS group (p = .03). CONCLUSION: This comparative study shows that robotic technology can be used to treat selected squamous cell carcinomas of the upper aerodigestive tract, reducing morbidity and treatment costs while providing equivalent cancer control at 3 years. PMID- 24816481 TI - Family caregivers' awareness of illness and attitude toward disclosure during chemotherapy for advanced cancer. AB - OBJECTIVE: We investigated family caregivers' awareness of disease status and attitude toward disclosure of disease progression compared with those of cancer patients and explored the potential association between family caregivers' attitudes and patients' quality of life (QOL). METHODS: We carried out a survey using self-administered questionnaires answered by pairs of family caregivers and patients diagnosed with advanced cancer (n = 136 pairs). To assess patients' QOL, we used the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire. RESULTS: More than half of family caregivers (54%) did not have full knowledge of patients' advanced stage and goal of therapy. Positive attitudes toward disclosure were less common in family caregivers than in patients (59.4% and 85.4%, respectively; p < 0.01). The family caregivers' positive attitudes toward disclosure were inversely associated with patients' low functional scores (emotion [p = 0.04] and cognition [p = 0.02]) and high symptom scores (nausea and vomiting, pain, and insomnia; p < 0.05). However, in most QOL scales, patients' attitudes were not significantly associated with functioning and symptom scores. CONCLUSIONS: A large portion of family caregivers may not know the patients' exact status. This study also suggests that the family caregivers' attitudes may differ from patients' and may be associated with patients' QOL. PMID- 24816482 TI - Congenital microcephaly. AB - The underlying etiologies of genetic congenital microcephaly are complex and multifactorial. Recently, with the exponential growth in the identification and characterization of novel genetic causes of congenital microcephaly, there has been a consolidation and emergence of certain themes concerning underlying pathomechanisms. These include abnormal mitotic microtubule spindle structure, numerical and structural abnormalities of the centrosome, altered cilia function, impaired DNA repair, DNA Damage Response signaling and DNA replication, along with attenuated cell cycle checkpoint proficiency. Many of these processes are highly interconnected. Interestingly, a defect in a gene whose encoded protein has a canonical function in one of these processes can often have multiple impacts at the cellular level involving several of these pathways. Here, we overview the key pathomechanistic themes underlying profound congenital microcephaly, and emphasize their interconnected nature. PMID- 24816483 TI - Key residues in octyl-tridecaptin A1 analogues linked to stable secondary structures in the membrane. AB - Tridecaptin A1 is a linear antimicrobial lipopeptide comprised of 13 amino acids, including three diaminobutyric acid (Dab) residues. It displays potent activity against Gram-negative bacteria, including multidrug-resistant strains. Using solid-phase peptide synthesis, we performed an alanine scan of a fully active analogue, octyl-tridecaptin A1 , to determine key residues responsible for activity. The synthetic analogues were tested against ten organisms, both Gram positive and Gram-negative bacteria. Modification of D-Dab8 abolished activity, and marked decreases were observed with substitution of D-allo-Ile12 and D-Trp5. Circular dichroism showed that octyl-tridecaptin A1 adopts a secondary structure in the presence of model phospholipid membranes, which was weakened by D-Dab8-D Ala, D-allo-Ile12-D-Ala, and D-Trp5-D-Ala substitutions. The antimicrobial activity of the analogues is directly correlated to their ability to adopt a stable secondary structure in a membrane environment. PMID- 24816484 TI - Probing the non-locality of Majorana fermions via quantum correlations. AB - Majorana fermions (MFs) are exotic particles that are their own anti-particles. Recently, the search for the MFs occurring as quasi-particle excitations in solid state systems has attracted widespread interest, because of their fundamental importance in fundamental physics and potential applications in topological quantum computation based on solid-state devices. Here we study the quantum correlations between two spatially separate quantum dots induced by a pair of MFs emerging at the two ends of a semiconductor nanowire, in order to develop a new method for probing the MFs. We find that without the tunnel coupling between these paired MFs, quantum entanglement cannot be induced from an unentangled (i.e., product) state, but quantum discord is observed due to the intrinsic nonlocal correlations of the paired MFs. This finding reveals that quantum discord can indeed demonstrate the intrinsic non-locality of the MFs formed in the nanowire. Also, quantum discord can be employed to discriminate the MFs from the regular fermions. Furthermore, we propose an experimental setup to measure the onset of quantum discord due to the nonlocal correlations. Our approach provides a new, and experimentally accessible, method to study the Majorana bound states by probing their intrinsic non-locality signature. PMID- 24816485 TI - Retrospective cohort analysis of chest injury characteristics and concurrent injuries in patients admitted to hospital in the Wenchuan and Lushan earthquakes in Sichuan, China. AB - BACKGROUND: The aim of this study was to compare retrospectively the characteristics of chest injuries and frequencies of other, concurrent injuries in patients after earthquakes of different seismic intensity. METHODS: We compared the cause, type, and body location of chest injuries as well as the frequencies of other, concurrent injuries in patients admitted to our hospital after the Wenchuan and Lushan earthquakes in Sichuan, China. We explored possible relationships between seismic intensity and the causes and types of injuries, and we assessed the ability of the Injury Severity Score, New Injury Severity Score, and Chest Injury Index to predict respiratory failure in chest injury patients. RESULTS: The incidence of chest injuries was 9.9% in the stronger Wenchuan earthquake and 22.2% in the less intensive Lushan earthquake. The most frequent cause of chest injuries in both earthquakes was being accidentally struck. Injuries due to falls were less prevalent in the stronger Wenchuan earthquake, while injuries due to burial were more prevalent. The distribution of types of chest injury did not vary significantly between the two earthquakes, with rib fractures and pulmonary contusions the most frequent types. Spinal and head injuries concurrent with chest injuries were more prevalent in the less violent Lushan earthquake. All three trauma scoring systems showed poor ability to predict respiratory failure in patients with earthquake-related chest injuries. CONCLUSIONS: Previous studies may have underestimated the incidence of chest injury in violent earthquakes. The distributions of types of chest injury did not differ between these two earthquakes of different seismic intensity. Earthquake severity and interval between rescue and treatment may influence the prevalence and types of injuries that co-occur with the chest injury. Trauma evaluation scores on their own are inadequate predictors of respiratory failure in patients with earthquake-related chest injuries. PMID- 24816486 TI - Mechanical ventilation causes airway distension with proinflammatory sequelae in mice. AB - The pathogenesis of ventilator-induced lung injury has predominantly been attributed to overdistension or mechanical opening and collapse of alveoli, whereas mechanical strain on the airways is rarely taken into consideration. Here, we hypothesized that mechanical ventilation may cause significant airway distension, which may contribute to the pathological features of ventilator induced lung injury. C57BL/6J mice were anesthetized and mechanically ventilated at tidal volumes of 6, 10, or 15 ml/kg body wt. Mice were imaged by flat-panel volume computer tomography, and central airways were segmented and rendered in 3D for quantitative assessment of airway distension. Alveolar distension was imaged by intravital microscopy. Functional dead space was analyzed in vivo, and proinflammatory cytokine release was analyzed in isolated, ventilated tracheae. CT scans revealed a reversible, up to 2.5-fold increase in upper airway volume during mechanical ventilation compared with spontaneous breathing. Airway distension was most pronounced in main bronchi, which showed the largest volumes at tidal volumes of 10 ml/kg body wt. Conversely, airway distension in segmental bronchi and functional dead space increased almost linearly, and alveolar distension increased even disproportionately with higher tidal volumes. In isolated tracheae, mechanical ventilation stimulated the release of the early response cytokines TNF-alpha and IL-1beta. Mechanical ventilation causes a rapid, pronounced, and reversible distension of upper airways in mice that is associated with an increase in functional dead space. Upper airway distension is most pronounced at moderate tidal volumes, whereas higher tidal volumes redistribute preferentially to the alveolar compartment. Airway distension triggers proinflammatory responses and may thus contribute relevantly to ventilator induced pathologies. PMID- 24816488 TI - Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation. AB - Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial cells to CS induced damage, thereby protecting the airways against inflammation upon CS exposure. Here, we tested whether Pim survival kinases could protect from CS induced inflammation. We determined expression of Pim kinases in lung tissue, airway inflammation, and levels of keratinocyte-derived cytokine (KC) and several damage-associated molecular patterns in bronchoalveolar lavage in mice exposed to CS or air. Human bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) in the presence or absence of Pim1 inhibitor and assessed for loss of mitochondrial membrane potential, induction of cell death, and release of heat shock protein 70 (HSP70). We observed increased expression of Pim1, but not of Pim2 and Pim3, in lung tissue after exposure to CS. Pim1-deficient mice displayed a strongly enhanced neutrophilic airway inflammation upon CS exposure compared with wild-type controls. Inhibition of Pim1 activity in BEAS-2B cells increased the loss of mitochondrial membrane potential and reduced cell viability upon CSE treatment, whereas release of HSP70 was enhanced. Interestingly, we observed release of S100A8 but not of double-strand DNA or HSP70 in Pim1-deficient mice compared with wild-type controls upon CS exposure. In conclusion, we show that expression of Pim1 protects against CS-induced cell death in vitro and neutrophilic airway inflammation in vivo. Our data suggest that the underlying mechanism involves CS-induced release of S100A8 and KC. PMID- 24816487 TI - Progress in solving the sex hormone paradox in pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with marked morbidity and mortality. Even though being female represents one of the most powerful risk factors for PAH, multiple questions about the underlying mechanisms remain, and two "estrogen paradoxes" in PAH exist. First, it is puzzling why estrogens have been found to be protective in various animal models of PAH, whereas PAH registries uniformly demonstrate a female susceptibility to the disease. Second, despite the pronounced tendency for the disease to develop in women, female PAH patients exhibit better survival than men. Recent mechanistic studies in classical and in novel animal models of PAH, as well as recent studies in PAH patients, have significantly advanced the field. In particular, it is now accepted that estrogen metabolism and receptor signaling, as well as estrogen interactions with key pathways in PAH development, appear to be potent disease modifiers. A better understanding of these interactions may lead to novel PAH therapies. It is the purpose of this review to 1) review sex hormone synthesis, metabolism, and receptor physiology; 2) assess the context in which sex hormones affect PAH pathogenesis; 3) provide a potential explanation for the observed estrogen paradoxes and gender differences in PAH; and 4) identify knowledge gaps and future research opportunities. Because the majority of published studies investigated 17beta-estradiol and/or its metabolites, this review will primarily focus on pulmonary vascular and right ventricular effects of estrogens. Data for other sex hormones will be discussed very briefly. PMID- 24816489 TI - Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) carrying the F508del mutation is retained in endoplasmic reticulum and fails to traffic to the cell surface where it functions as a protein kinase A (PKA)-activated chloride channel. Pharmacological correctors that rescue the trafficking of F508del CFTR may overcome this defect; however, the rescued F508del CFTR still displays reduced chloride permeability. Therefore, a combined administration of correctors and potentiators of the gating defect is ideal. We recently found that 4,6,4' trimethylangelicin (TMA), besides inhibiting the expression of the IL-8 gene in airway cells in which the inflammatory response was challenged with Pseudomonas aeruginosa, also potentiates the cAMP/PKA-dependent activation of wild-type CFTR or F508del CFTR that has been restored to the plasma membrane. Here, we demonstrate that long preincubation with nanomolar concentrations of TMA is able to effectively rescue both F508del CFTR-dependent chloride secretion and F508del CFTR cell surface expression in both primary or secondary airway cell monolayers homozygous for F508del mutation. The correction effect of TMA seems to be selective for CFTR and persisted for 24 h after washout. Altogether, the results suggest that TMA, besides its anti-inflammatory and potentiator activities, also displays corrector properties. PMID- 24816492 TI - Efficient and persistent cold cathode emission from CuPc nanotubes: a joint experimental and simulation investigation. AB - In the current report, chemically synthesized copper phthalocyanine (CuPc) nanotubes are shown to exhibit unprecedentedly well cold cathode emission characteristics with turn-on field (3.2 V MU m(-1)) and stable emission during long intervals (200 min). Simulation of electric field distribution via finite element method around an isolated nanotube emitter in a manner parallel to the experimental setup (inter-electrode distance = 180 MUm) exhibits good corroboration of theoretical premises with experimental findings. Obtained results strongly indicate CuPc nanotubes to be potential candidate as cold cathode emitter for electron emission based applications such as field emission displays and vacuum nano-electronic devices. PMID- 24816490 TI - PdhR, the pyruvate dehydrogenase repressor, does not regulate lipoic acid synthesis. AB - Lipoic acid is a covalently-bound enzyme cofactor required for central metabolism all three domains of life. In the last 20 years the pathway of lipoic acid synthesis and metabolism has been established in Escherichia coli. Expression of the genes of the lipoic acid biosynthesis pathway was believed to be constitutive. However, in 2010 Kaleta and coworkers (BMC Syst. Biol. 4:116) predicted a binding site for the pyruvate dehydrogenase operon repressor, PdhR (referred to lipA site 1) upstream of lipA, the gene encoding lipoic acid synthase and concluded that PdhR regulates lipA transcription. We report in vivo and in vitro evidence that lipA is not controlled by PdhR and that the putative regulatory site deduced by the prior workers is nonfunctional and physiologically irrelevant. E. coli PdhR was purified to homogeneity and used for electrophoretic mobility shift assays. The lipA site 1 of Kaleta and coworkers failed to bind PdhR. The binding detected by these workers is due to another site (lipA site 3) located far upstream of the lipA promoter. Relative to the canonical PdhR binding site lipA site 3 is a half-palindrome and as expected had only weak PdhR binding ability. Manipulation of lipA site 3 to construct a palindrome gave significantly enhanced PdhR binding affinity. The native lipA promoter and the version carrying the artificial lipA3 palindrome were transcriptionally fused to a LacZ reporter gene to directly assay lipA expression. Deletion of pdhR gave no significant change in lipA promoter-driven beta-galactosidase activity with either the native or constructed palindrome upstream sequences, indicating that PdhR plays no physiological role in regulation of lipA expression. PMID- 24816493 TI - From ionic-liquid@metal-organic framework composites to heteroatom-decorated large-surface area carbons: superior CO2 and H2 uptake. AB - For the first time, high surface area uniformly nitrogen (N)- and boron-nitrogen (BN)-decorated nanoporous carbons have been successfully fabricated by impregnation of ionic liquids (ILs) within a metal-organic framework (MOF), MIL 100(Al), followed by carbonization, which exhibit remarkable CO2 and H2 adsorption capacities. PMID- 24816491 TI - Epidithiodioxopiperazines. occurrence, synthesis and biogenesis. AB - Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines. PMID- 24816494 TI - Marburg haemorrhagic fever in returning travellers: an overview aimed at clinicians. AB - Marburg virus haemorrhagic fever (MARV HF) is a dramatic disease that can occur in a traveller returning from an area where the virus is endemic. In this article, we provide an overview of MARV HF as an imported infection with an emphasis on clinical aspects. Although late features such as rash, signs of haemorrhagic diathesis and liver necrosis may point to the diagnosis, the initial clinical picture is non-specific. If in this early phase the patient's epidemiological exposure history is compatible with MARV HF, the patient should be isolated and managed according to viral haemorrhagic fever protocol and RT-PCR should be performed on the patient's blood as soon as possible to rule out MARV HF (or other possible viral haemorrhagic fevers). In severe cases, direct electron microscopy of blood in specialized centres (e.g. Bernhard-Nocht Institute in Hamburg, Germany) may be considered if the result of the RT-PCR is not readily available. Adequate diagnostics and empirical treatment for other acute life-threatening illnesses should not be withheld while test results are awaited, but all management and diagnostics should be weighed against the risks of nosocomial transmission. PMID- 24816496 TI - Enhanced photoelectrochemical water splitting performance of TiO2 nanotube arrays coated with an ultrathin nitrogen-doped carbon film by molecular layer deposition. AB - Vertically oriented TiO2 nanotube arrays (TNTAs) were conformally coated with an ultrathin nitrogen-doped (N-doped) carbon film via the carbonization of a polyimide film deposited by molecular layer deposition and simultaneously hydrogenated, thereby creating a core/shell nanostructure with a precisely controllable shell thickness. The core/shell nanostructure provides a larger heterojunction interface to substantially reduce the recombination of photogenerated electron-hole pairs, and hydrogenation enhances solar absorption of TNTAs. In addition, the N-doped carbon film coating acts as a high catalytic active surface for oxygen evolution reaction, as well as a protective film to prevent hydrogen-treated TiO2 nanotube oxidation by electrolyte or air. As a result, the N-doped carbon film coated TNTAs displayed remarkably improved photocurrent and photostability. The TNTAs with a N-doped carbon film of ~ 1 nm produces a current density of 3.6 mA cm(-2) at 0 V vs. Ag/AgCl under the illumination of AM 1.5 G (100 mW cm(-2)), which represents one of the highest values achieved with modified TNTAs. Therefore, we propose that ultrathin N-doped carbon film coating on materials is a viable approach to enhance their PEC water splitting performance. PMID- 24816495 TI - After the feature presentation: technologies bridging untargeted metabolomics and biology. AB - Liquid chromatography/mass spectrometry-based untargeted metabolomics is now an established experimental approach that is being broadly applied by many laboratories worldwide. Interpreting untargeted metabolomic data, however, remains a challenge and limits the translation of results into biologically relevant conclusions. Here we review emerging technologies that can be applied after untargeted profiling to extend biological interpretation of metabolomic data. These technologies include advances in bioinformatic software that enable identification of isotopes and adducts, comprehensive pathway mapping, deconvolution of MS(2) data, and tracking of isotopically labeled compounds. There are also opportunities to gain additional biological insight by complementing the metabolomic analysis of homogenized samples with recently developed technologies for metabolite imaging of intact tissues. To maximize the value of these emerging technologies, a unified workflow is discussed that builds on the traditional untargeted metabolomic pipeline. Particularly when integrated together, the combination of the advances highlighted in this review helps transform lists of masses and fold changes characteristic of untargeted profiling results into structures, absolute concentrations, pathway fluxes, and localization patterns that are typically needed to understand biology. PMID- 24816498 TI - The Current Perception Threshold Test Differentiates Categories of Mechanical Neck Disorder. AB - Study Design Cross-sectional discriminative analysis. Objective To determine whether current perception threshold (CPT) can differentiate between categories of patients with mechanical neck disorders (MNDs). Background Neck pain is the third most common musculoskeletal disorder, affecting a third of all adults each year. It can present as neck pain without musculoskeletal signs; neck pain with musculoskeletal signs but no neurological signs; neck pain with neurological signs. CPT testing can assess altered sensory perception that may reflect neurological changes. Methods Patients with MNDs (n=106) were classified into 3 groups based on a standardized musculoskeletal examination process performed by an experienced physiotherapist blinded to CPT scores. The 3 groups were defined as: MND-I, neck pain without musculoskeletal signs (n=60); MND-II, neck pain with musculoskeletal signs (n=29); MND-III, neck pain with neurological signs (n=17). A rapid protocol of CPT testing was performed at 3 frequencies (5, 250, 2000 Hz), using 3 dermatomal locations on the hand. A 1-way ANOVA with post hoc comparison and effect sizes were calculated to compare the mean CPT score between the groups. A binary logistic regression model was used to predict probability of higher CPT in MND-III and used to create a receiver operating characteristic (ROC) curve. Results Mean CPT differed significantly across the 3 MND groups (MND I, 9.7; MND-II, 10.6; and MND-III, 11.8; P < .001, eta2 = .6). Post hoc comparisons indicated differences between MND-I and MND-II (P = .05) and between MND-II and MND-III (P = .01), that were large effect sizes (MND I versus II, d = 1 and MND II versus III, d = 2.2). CPT testing was able to distinguish between MND II and III when a threshold value of greater than 11 was used to indicate MND III. The predicted probability of abnormal CPT in MND-III had an estimated 73% sensitivity and 81% specificity; the odds ratio was 11.5 (P =.001) for the differentiation capacity of CPT between MND-II and III with a cut-off of 11. The area under the ROC curve (AUC) was .84 (95% CI =.72 to .96, P < .001). Conclusions CPT testing has moderate discriminatory accuracy, specificity, and sensitivity for classification of MND categories into neck pain with or without neurological signs. J Orthop Sports Phys Ther, Epub 10 May 2014. doi:10.2519/jospt.2014.5691. PMID- 24816497 TI - Infliximab therapy increases the frequency of circulating CD16(+) monocytes and modifies macrophage cytokine response to bacterial infection. AB - Crohn's disease (CD) has been correlated with altered macrophage response to microorganisms. Considering the efficacy of infliximab treatment on CD remission, we investigated infliximab effects on circulating monocyte subsets and on macrophage cytokine response to bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, treated or not with infliximab. Macrophages were infected with Escherichia coli, Enterococcus faecalis, Mycobacterium avium subsp. paratuberculosis (MAP) or M. avium subsp avium, and cytokine levels [tumour necrosis factor (TNF) and interleukin (IL)-10] were evaluated at different time-points. To evaluate infliximab-dependent effects on monocyte subsets, we studied CD14 and CD16 expression by peripheral blood monocytes before and after different infliximab administrations. We also investigated TNF secretion by macrophages obtained from CD16(+) and CD16(-) monocytes and the frequency of TNF(+) cells among CD16(+) and CD16(-) monocyte derived macrophages from CD patients. Infliximab treatment resulted in elevated TNF and IL-10 macrophage response to bacteria. An infliximab-dependent increase in the frequency of circulating CD16(+) monocytes (particularly the CD14(++) CD16(+) subset) was also observed (before infliximab: 4.65 +/- 0.58%; after three administrations: 10.68 +/- 2.23%). In response to MAP infection, macrophages obtained from CD16(+) monocytes were higher TNF producers and CD16(+) macrophages from infliximab-treated CD patients showed increased frequency of TNF(+) cells. In conclusion, infliximab treatment increased the TNF production of CD macrophages in response to bacteria, which seemed to depend upon enrichment of CD16(+) circulating monocytes, particularly of the CD14(++) CD16(+) subset. Infliximab treatment of CD patients also resulted in increased macrophage IL-10 production in response to bacteria, suggesting an infliximab-induced shift to M2 macrophages. PMID- 24816499 TI - Normalization considerations for using the unilateral seated shot put test in rehabilitation. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To examine the effect of different normalization methods on unilateral seated shot put test results. BACKGROUND: The unilateral seated shot put test could assist clinical decision making in upper extremity rehabilitation, but test results must be normalized to compare across patients. The effect of normalization methods based on body size and upper-limb dominance is unknown. METHODS: One hundred twenty-five collegiate athletes (63 males) performed the unilateral seated shot put test with each upper extremity. Anthropometric measures (height, body mass, arm length) and distance thrown were recorded. Normalization based on body size included ratio scaling and allometric scaling. Ratio scaling was performed with the anthropometric measure having the highest correlation to distance thrown (distance/anthropometric measure). Allometric scaling was performed with body mass raised to the theoretical exponent 0.67 (distance/body mass(0.67)) and a derived exponent. Correlations of nonnormalized and normalized values with body mass were then determined. The limb symmetry index [(dominant-side distance/nondominantside distance) * 100] was used for normalization based on limb dominance. Sex differences were examined. RESULTS: Body mass was selected for ratio scaling, and 0.35 was the derived allometric-scaling exponent. Across sexes, only allometric scaling with the exponent 0.35 removed the correlation with body mass. The mean limb symmetry index exceeded 100% in males (108.7%) and females (104.4%). All normalized test results were higher in males. CONCLUSION: When using the unilateral seated shot put test in rehabilitation, allometric scaling with the exponent 0.35 is preferable, limb comparisons should account for 5% to 10% better performance on the dominant side, and performance benchmarks should be set within sex. J Orthop Sports Phys Ther 2014;44(7):518-524. Epub 10 May 2014. doi:10.2519/jospt.2014.5004. PMID- 24816500 TI - The influence of hip strength on lower-limb, pelvis, and trunk kinematics and coordination patterns during walking and hopping in healthy women. AB - STUDY DESIGN: Cross-sectional laboratory study. OBJECTIVES: To compare peak lower limb, pelvis, and trunk kinematics and interjoint and intersegmental coordination in women with strong and weak hip muscle performance. BACKGROUND: Persons with lower extremity musculoskeletal disorders often demonstrate a combination of weak hip musculature and altered kinematics during weight-bearing dynamic tasks. However, the association between hip strength and kinematics independent of pathology or pain is unclear. METHODS: Peak hip extensor and abductor torques were measured in 150 healthy young women. Of these, 10 fit the criteria for the strong group and 9 for the weak group, representing those with the strongest and weakest hip musculature, respectively, of the 150 screened individuals. Kinematics of the hip, knee, pelvis, and trunk were measured during the stance phases of walking and rate-controlled hopping. Hip/knee and pelvis/trunk coordination were calculated using the vector coding technique. RESULTS: There were no group differences in peak hip, knee, or pelvis kinematics. Participants in the weak group demonstrated greater trunk lateral bend toward the stance limb during hopping (P = .002, effect size [d] = 1.88). In the transverse plane, those in the weak group utilized less inphase coordination between the hip and the knee during walking (P = .036, d = 1.45) and more antiphase coordination between the hip and knee during hopping (P = .03, d = 1.47). CONCLUSION: In the absence of pain or pathology, poor hip muscle performance does not affect peak hip or knee joint kinematics in young women, but is associated with significantly different lower-limb and trunk/pelvis coordination during weight-bearing dynamic tasks. J Orthop Sports Phys Ther 2014;44(7):525-531. Epub 10 May 2014. doi:10.2519/jospt.2014.5028. PMID- 24816501 TI - Ulnar nerve neurodynamic test: study of the normal sensory response in asymptomatic individuals. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To describe and analyze normal sensory responses to the ulnar upper-limb neurodynamic test (ULNT3) and to investigate the influence of sex and arm dominance. BACKGROUND: Neurodynamic tests are commonly used in the clinical evaluation of patients with musculoskeletal pain disorders. While the normal responses of other upper-limb neurodynamic tests have been previously investigated, there are no studies that have reported the normal responses for the ULNT3. METHODS: A total of 68 asymptomatic individuals between 18 and 50 years of age volunteered to participate in the study. Of these, 57 (29 women, 28 men) were eligible for the study. The variables measured were pain intensity using a numeric rating scale, shoulder abduction angle, and quality and distribution of symptoms at the point of pain tolerance of the ULNT3. RESULTS: There were statistically significant differences in pain intensity and shoulder abduction angle between the sexes, with women having higher perceived pain and lower shoulder angle than men (P<.05). There was a significant difference of 6.6 degrees (95% confidence interval: 1.1 degrees , 12.1 degrees ) in shoulder abduction angle during the ULNT3 (P<.05) between the dominant arm and nondominant arm. The symptoms most often described during application of the ULNT3 were stretching (90%), followed by pain, and the most frequent location of symptoms was the anteromedial half of the forearm. CONCLUSION: The results of this study provide the normal shoulder abduction angle and quality and distribution of symptoms for the ULNT3. These data can be used by clinicians as a reference when using the ULNT3 in their clinical reasoning and decision making. PMID- 24816502 TI - Use of thoracic spine thrust manipulation for neck pain and headache in a patient following multiple-level anterior cervical discectomy and fusion: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: Thoracic spine thrust manipulation has been shown to be an effective intervention for individuals experiencing mechanical neck pain. CASE DESCRIPTION: The patient was a 46-year-old woman referred to outpatient physical therapy 2 months following multiple-level anterior cervical discectomy and fusion. At initial evaluation, primary symptoms consisted of frequent headaches, neck pain, intermittent referred right elbow pain, and muscle fatigue localized to the right cervical and upper thoracic spine regions. Initial examination findings included decreased passive joint mobility of the thoracic spine, limited cervical range of motion, and limited right shoulder strength. Outcome measures consisted of the numeric pain rating scale, the Neck Disability Index, and the global rating of change scale. Treatment consisted of a combination of manual therapy techniques aimed at the thoracic spine, therapeutic exercises for the upper quarter, and patient education, including a home exercise program, over a 6-week episode of care. OUTCOMES: Immediate reductions in cervical-region pain (mean +/- SD, 2.0 +/- 1.1) and headache (2.0 +/- 1.3) intensity were reported every treatment session immediately following thoracic spine thrust manipulation. At discharge, the patient reported 0/10 cervical pain and headache symptoms during all work-related activities. From initial assessment to discharge, Neck Disability Index scores improved from 46% to 16%, with an associated global rating of change scale score of +7 ("a very great deal better"). DISCUSSION: This case report describes the immediate and short-term clinical outcomes for a patient presenting with symptoms of neck pain and headache following anterior cervical discectomy and fusion surgical intervention. Clinical rationale and patient preference aided the decision to incorporate thoracic spine thrust manipulation as a treatment for this patient. Level of Evidence Therapy, level 4. PMID- 24816503 TI - Recommendations for physical therapists on the treatment of lumbopelvic pain during pregnancy: a systematic review. AB - STUDY DESIGN: Systematic review of the literature. OBJECTIVES: To review and assess the peer-reviewed literature on the effectiveness of physical therapy interventions in treating lumbopelvic pain during pregnancy. BACKGROUND: Current guidelines on interventions for lumbopelvic pain during pregnancy differ in their recommendations for assessment and intervention. Recent publications may allow revising current recommendations for the treatment of this complex problem. METHODS: An electronic search strategy was conducted in PubMed, PEDro, Scopus, and CINAHL of literature published from January 1992 to November 2013. Two authors independently assessed all abstracts for eligibility. Articles were independently rated for quality by 2 authors, using the Cochrane Back Review Group criteria for methodological quality. Where possible, effect sizes were calculated for the different interventions. RESULTS: A total of 22 articles (all randomized controlled trials) reporting on 22 independent studies were included. Overall, the methodological quality of the studies was moderate. Data for 4 types of interventions were considered: a combination of interventions (7 studies, n = 1202), exercise therapy (9 studies, n = 2149), manual therapy (5 studies, n = 360), and material support (1 study, n = 115). CONCLUSION: All included studies on exercise therapy, and most of the studies on interventions combined with patient education, reported a positive effect on pain, disability, and/or sick leave. Evidence-based recommendations can be made for the use of exercise therapy for the treatment of lumbopelvic pain during pregnancy. LEVEL OF EVIDENCE: Therapy, level 1a-. J Orthop Sports Phys Ther 2014;44(7):464-473. Epub 10 May 2014. doi:10.2519/jospt.2014.5098. PMID- 24816504 TI - The relevance of scapular dysfunction in neck pain: a brief commentary. AB - Synopsis Though our understanding of motor disorders and mechanical neck pain has advanced, the role of scapular dysfunction in mechanical neck pain remains enigmatic. The biomechanical interdependence between the neck and scapula and the potentially deleterious consequences of scapular dysfunction in the cervical region are biomechanically plausible. Yet the relevance of observed scapular dysfunction in patients with neck pain is still inadequately explained by research. However, studies investigating the association between scapular function and neck pain are beginning to emerge. The purpose of this paper was to review the current knowledge of this topic and consider the implications for clinical practice. Level of Evidence Therapy, level 5. PMID- 24816505 TI - Syntheses and magnetic properties of new tellurite-sulfate compounds M2(TeO3)(SO4).H2O (M = Co, Mn) with a layer structure showing a distorted honeycomb spin-lattice. AB - New tellurite-sulfate compounds M2(TeO3)(SO4).H2O (M = Co, Mn) are synthesized by a conventional hydrothermal method. Two compounds are found to exhibit a similar structure, which both crystallize in the orthorhombic system of space group Pbcm. Te(4+) ions are coordinated by three O atoms, forming a quite distorted TeO3 trigonal pyramid with lone-pair electrons, while magnetic Co(2+) or Mn(2+) ions construct a wavelike layer with a distorted honeycomb spin-lattice. Magnetic measurements confirm that two isostructural compounds display different magnetic behaviors, in which Co2(TeO3)(SO4).H2O shows a canted antiferromagnetic ordering at ~15 K, while Mn2(TeO3)(SO4).H2O shows a collinear antiferromagnetic ordering at ~28 K. The nature of different magnetic behaviors between two isostructural compounds is also discussed. PMID- 24816506 TI - Auditory and Nociceptive Stimuli Responses in the Electroencephalogram. A Non linear Measures and Time-frequency Representation Based Analysis. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Neural Signals and Images". OBJECTIVES: An efficient way to investigate the neural basis of nociceptive responses is the analysis of the event-related brain potentials (ERPs). The main objective of this work was to study how adaptation and fatigue affect the ERPs to stimuli of different modalities, by characterizing the responses to infrequent and frequent stimulation in different recording periods. METHODS: In this work, series of averaged EEG epochs recorded after thermal, electrical and auditory stimulation were analyzed with time-frequency representation and non-linear measures as spectral entropy and auto-mutual information function. The study was performed by considering the traditional EEG frequency bands. RESULTS: The defined measures presented a statistical significance p-value < 0.01 and accuracy higher than 60% by differentiating windows of response to infrequent (I) and frequent (F) stimuli between the start and end of the EEG recording. CONCLUSIONS: These measures permitted to observe some aspects of the subject's adaptation and the nociceptive response. PMID- 24816507 TI - High-throughput screening of pesticide and veterinary drug residues in baby food by liquid chromatography coupled to quadrupole Orbitrap mass spectrometry. AB - A new analytical method was developed and validated for simultaneous analysis of 333 pesticide and veterinary drug residues in baby food. Response surface methodology was employed to optimize a generic extraction method. Ultrahigh performance liquid chromatography and electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-ESI Q-Orbitrap) was used for the separation and detection of all the analytes. The method was validated by taking into consideration the guidelines specified in Commission Decision 2002/657/EC and SANCO/12571/2013. The extraction recoveries were in a range of 79.8-110.7%, with coefficient of variation <8.3%. The 333 compounds behave dynamic in the range 0.1-1000MUgkg(-1) concentration, with correlation coefficient >0.99. The limits of detection for the analytes are in the range 0.01-5.35MUgkg(-1). The limits of quantification for the analytes are in the range 0.01-9.27MUgkg(-1). This method has been successfully applied on screening of pesticide and veterinary drugs in ninety-three commercial baby food samples, and tilmicosin, fenbendazole, tylosin tartrate and thiabendazole were detected in some samples tested in this study. The present study is very useful for fast screening of different food contaminants. PMID- 24816508 TI - Capillary gas chromatography using a gamma-cyclodextrin for enantiomeric separation of methylamphetamine, its precursors and chloro intermediates after optimization of the derivatization reaction. AB - The enantiomeric ratio of methylamphetamine (MAMP) is closely related to the optical activity of precursors and reagents used for the synthesis and this knowledge can provide useful information concerning the origins and synthetic methods used for illicit manufacture. The information can be utilized for regulation of the precursors and investigation of the manufacturing sources but this requires analytical procedures to determine purity of drug substances, impurity profiling and enantiomeric composition. In this study, a gas chromatography (GC) coupled with mass spectrometry (MS) method using a gamma cyclodextrin chiral stationary phase was developed and optimized for the simultaneous enantiomeric separations of MAMP and its common precursors, ephedrine, and pseudoephedrine, as well as its chlorointermediates formed during MAMP synthesis by the Emde method, after derivatization with trifluoroacetic anhydride. The optimization was performed using multivariate statistics (cluster analysis and principal components analysis) in order to select and compare optimal experimental conditions. Under the optimized experimental conditions, the calculated calibration curves showed good linearity range up to 0.1MUg/mL for all tested analytes. The limits of detection were in the range of 0.002-0.008MUg/mL and the coefficient of variability was between 1.0 and 3.9%. The method has the advantage of achieving excellent precision under repeatability and reproducibility conditions while detection by MS allows for the identity of analytes to be confirmed in a single analysis. The method was therefore applied satisfactory to MAMP analysis. PMID- 24816509 TI - Structural and thermodynamic characterization of doxycycline/beta-cyclodextrin supramolecular complex and its bacterial membrane interactions. AB - Doxycycline is a semi-synthetic antibiotic commonly used for the treatment of many aerobic and anaerobic bacteria. It inhibits the activity of matrix metalloproteinases (MMPs) and affects cell proliferation. In this study, the structural and thermodynamic parameters of free DOX and a DOX/betaCD complex were investigated, as well as their interactions and effects on Staphylococcus aureus cells and cellular cytotoxicity. Complexation of DOX and betaCD was confirmed to be an enthalpy- and entropy-driven process, and a low equilibrium constant was obtained. Treatment of S. aureus with higher concentrations of DOX or DOX/betaCD resulted in an exponential decrease in S. aureus cell size, as well as a gradual neutralization of zeta potential. These thermodynamic profiles suggest that ion pairing and hydrogen bonding interactions occur between DOX and the membrane of S. aureus. In addition, the adhesion of betaCD to the cell membrane via hydrogen bonding is hypothesized to mediate a synergistic effect which accounts for the higher activity of DOX/betaCD against S. aureus compared to pure DOX. Lower cytotoxicity and induction of osteoblast proliferation was also associated with DOX/betaCD compared with free DOX. These promising findings demonstrate the potential for DOX/betaCD to mediate antimicrobial activity at lower concentrations, and provides a strategy for the development of other antimicrobial formulations. PMID- 24816510 TI - Neutrophil-lymphocyte ratio as a prognostic marker of outcome in infrapopliteal percutaneous interventions for critical limb ischemia. AB - BACKGROUND: Endovascular intervention has become a frequently used treatment of critical limb ischemia (CLI) in recent times. The recent Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL) trial consensus recommended endovascular treatment as a first-line treatment in patients who have a life expectancy that was limited to <2 years. Despite these recommendations, there still remains limited data available to clinicians when seeking to risk stratify patients who present with CLI. The neutrophil-lymphocyte ratio (NLR) has been suggested to be a marker for predicting mortality and patency. This study aimed to investigate the use of the NLR as a prognostic marker for primary patency and mortality after an infrapopliteal endovascular intervention in patients with CLI. METHODS: All patients who underwent tibial angioplasty for CLI were retrospectively analyzed. Demographics, degrees of stenosis, vessel patency rates, mortality, and comorbidities were recorded. NLRs were calculated from preoperative blood samples. Primary end points were all-cause mortality, primary patency, and amputation-free survival (AFS) within the follow-up period of 12 months. Multivariate Cox proportional hazard models were used to identify independent predictors. Overall survival, AFS, and the probability of a vessel remaining patent were evaluated by standard Kaplan-Meier survival curves and groups compared by the log-rank test. RESULTS: Eighty-three patients were monitored for 12 months. Ninety limbs were identified, with 104 procedural events and 127 vessels undergoing successful angioplasty. The technical success rate was 86%, and patency at 1 year was 19%. Survival at 1 year was 76% and AFS was 61%. Patients with a NLR >=5.25 had an increased risk of death (hazard ratio, 1.97; 95% confidence interval, 1.08-3.62; P = .03) compared with those with a NLR of <5.25. Furthermore, those with lymphocytes counts of <1.5 * 10(9)/L had higher mortality (hazard ratio, 1.88; 95% confidence interval, 1.02-3.70; P = .045) than those with lymphocyte counts >1.5 * 10(9)/L. CONCLUSIONS: The NLR and absolute lymphocyte counts are potentially valuable prognostic indicators for risk stratification of patient's presenting with CLI undergoing infrapopliteal angioplasty. PMID- 24816512 TI - Aortic remodeling after thoracic endovascular aortic repair for intramural hematoma. AB - BACKGROUND: Intramural hematoma (IMH), penetrating atherosclerotic ulcer (PAU), and aortic dissection comprise a spectrum of acute aortic pathologies. Although thoracic endovascular aortic repair (TEVAR) has increasingly been applied to aortic dissection, there is a paucity of data on the anatomic effect of TEVAR for IMH. Our goal was to investigate the extent of aortic remodeling after TEVAR. METHODS: A retrospective chart review from 2006 to 2012 was conducted on patients who underwent TEVAR for IMH. Data were collected from the electronic medical record. Radiology images were reviewed and primary data points included diameter (TLD) and volume measurements for aortic true lumen and total aortic diameter (TAD) and volume at the site of maximal pathology. Aortic remodeling was evidenced by a TAD/TLD ratio closest to 1.0. Patients with no imaging beyond 30 days postoperatively were excluded. RESULTS: During the 6-year period, 44 patients underwent TEVAR for IMH. Twenty-five patients had an IMH with concomitant PAU. There were 25 (57%) female patients. Mean age was 71 +/- 11 years, and 40 (91%) patients had hypertension. Operative indications included intractable pain in 31 (70%), rapidly progressing IMH or conversion to dissection in 13 (30%), rupture in 10 (23%), and uncontrolled hypertension in 6 (14%). Technically successful TEVAR was performed in all patients with 42 (95%) reporting complete relief of symptoms. The 30-day mortality rate was 5% with a 5% rate of permanent paraplegia or paraparesis. At a mean follow-up of 26 months, there were no additional aortic-related deaths and overall survival was 80% with a reintervention rate of 11%. For our imaging analysis, 10 patients were excluded because of lack of follow-up imaging beyond 30 days. At a mean follow-up of 13 months, all measured data points were statistically improved from before to after TEVAR: thickness of IMH (12 mm vs. 4 mm; P = .01), mean TLD (35 mm vs. 37 mm; P = .04), mean TAD (47 mm vs 42 mm; P = .02), TAD/TLD ratio (1.35 vs. 1.14; P < .01), and IMH volume (103 cm3 vs. 14 cm3; P < .01). The mean Delta in TAD/TLD ratio from before to after TEVAR for the reintervention group was Delta0.14, and the mean Delta in TAD/TLD ratio for the nonreintervention group was Delta0.29 (P = .05). Analysis of patients with isolated IMH and those with concomitant PAU revealed no statistical differences. CONCLUSIONS: TEVAR is safe and effective in treating IMH and based on longitudinal computed tomography scan analysis, aortic remodeling is evidenced by normalization of all measured indices. PMID- 24816514 TI - Critical analysis of results after chimney endovascular aortic aneurysm repair raises cause for concern. AB - OBJECTIVE: "Chimney" techniques used to extend landing zones for endovascular aortic repair (chEVAR) have been increasingly reported; however, concerns about durability and patency remain. The purpose of this analysis was to examine midterm outcomes of chEVAR. METHODS: All patients at the University of Florida treated with chEVAR were reviewed. Major adverse events (MAEs) were recorded and defined as any chimney stent thrombosis, type Ia endoleak in follow-up, reintervention, 30-day/in-hospital death, or >=25% decrease in estimated glomerular filtration rate after discharge. Primary end points included chimney stent patency and freedom from MAE. Secondary end points included complications and long-term survival. RESULTS: From 2008 to 2012, 41 patients (age +/- standard deviation, 73 +/- 8 years; male, 66% [n = 27]) were treated with a total of 76 chimney stents (renal, n = 51; superior mesenteric artery, n = 16; celiac artery, n = 9) for a variety of indications: juxtarenal, 42% (n = 17, one rupture), suprarenal, 17% (n = 7), and thoracoabdominal aneurysm, 17% (n = 7); aortic anastomotic pseudoaneurysm, 15% (n = 6; three ruptures); type Ia endoleak after EVAR, 7% (n = 3); and atheromatous disease, 2% (n = 1). Two patients had a single target vessel abandoned because of cannulation failure, and one had a type Ia endoleak at case completion (technical success, 93%). Intraoperative complications occurred in seven patients (17%), including graft maldeployment with unplanned mesenteric chimney (n = 2) and access vessel injury requiring repair (n = 5). Major postoperative complications developed in 20% (n = 8). The 30-day mortality and in-hospital mortality were 5% (n = 2) and 7% (n = 3), respectively. At median follow-up of 18.2 months (range, 1.4-41.5 months), 28 of 33 patients (85%) with available postoperative imaging experienced stabilization or reduction of abdominal aortic aneurysm sac diameters. Nine patients (32%) developed endoleak at some point during follow-up (type Ia, 7% [n = 3]; type II, 10% [n = 4]; indeterminate, 7% [n = 3]), and one patient underwent open, surgical conversion. The estimated probability of freedom from reintervention (+/-standard error mean) was 96% +/- 4% at both 1 year and 3 years. Primary patency of all chimney stents was 88% +/- 5% and 85% +/- 5% at 1 year and 3 years, respectively. Corresponding freedom from MAEs was 83% +/- 7% and 57% +/- 10% at 1 year and 3 years. The actuarial estimated survival for all patients at 1 year and 5 years was 85% +/- 6% and 65% +/- 8%, respectively. CONCLUSIONS: These results demonstrate that chEVAR can be completed with a high degree of success; however, perioperative complications and MAEs during follow-up, including loss of chimney patency and endoleak, may occur at a higher rate than previously reported. Elective use of chEVAR should be performed with caution, and comparison to open and fenestrated EVAR is needed to determine long-term efficacy of this technique. PMID- 24816515 TI - Effect of maternal nutrient restriction and melatonin supplementation from mid to late gestation on vascular reactivity of maternal and fetal placental arteries. AB - INTRODUCTION: Maternal nutrient restriction and decreased scotophase concentrations of melatonin have been associated with severely compromised pregnancies. We hypothesized that melatonin supplementation in a compromised pregnancy enhances the bradykinin (BK)-induced relaxations of placental arteries thereby ensuring sufficient umbilical blood flow to the developing fetus. METHODS: Pregnant ewes (n = 31) were fed an adequate (ADQ) or nutrient restricted (RES) diet supplemented with 5 mg of melatonin (MEL) or without melatonin (CON) from day 50 to 130 of gestation. On day 130 of gestation, the maternal (caruncular; CAR) and fetal (cotyledonary; COT) placental arteries were suspended in organ chambers for isometric tension recording. RESULTS: There were no treatment or dietary effects on CAR arteries for any vasoactive agent. However, in COT arteries, MEL ewes were more sensitive (P < 0.01) to bradykinin-induced relaxation than CON ewes. There was a melatonin by nutritional level interaction (P < 0.01) with sodium nitroprusside-induced relaxation of COT arteries where CON RES were more sensitive to sodium nitroprusside compared to CON-ADQ, which was in contrast to when ewes were fed MEL. There was a significant melatonin by nutritional interaction (P = 0.04) for responsiveness to norepinephrine. The sensitivity of the COT arteries to norepinephrine in CON-RES ewes was decreased compared to CON-ADQ. Melatonin supplementation, regardless of maternal dietary intake, resulted in COT arteries having similar responsiveness to CON-RES ewes. CONCLUSION: An increase in placental vessel sensitivity to bradykinin-induced relaxation may contribute to melatonin-induced increases in umbilical artery blood flow. PMID- 24816516 TI - If it's not counted it didn't happen! PMID- 24816517 TI - Mobile phone use and brain tumours in the CERENAT case-control study. AB - The carcinogenic effect of radiofrequency electromagnetic fields in humans remains controversial. However, it has been suggested that they could be involved in the aetiology of some types of brain tumours. OBJECTIVES: The objective was to analyse the association between mobile phone exposure and primary central nervous system tumours (gliomas and meningiomas) in adults. METHODS: CERENAT is a multicenter case-control study carried out in four areas in France in 2004-2006. Data about mobile phone use were collected through a detailed questionnaire delivered in a face-to-face manner. Conditional logistic regression for matched sets was used to estimate adjusted ORs and 95% CIs. RESULTS: A total of 253 gliomas, 194 meningiomas and 892 matched controls selected from the local electoral rolls were analysed. No association with brain tumours was observed when comparing regular mobile phone users with non-users (OR=1.24; 95% CI 0.86 to 1.77 for gliomas, OR=0.90; 95% CI 0.61 to 1.34 for meningiomas). However, the positive association was statistically significant in the heaviest users when considering life-long cumulative duration (>=896 h, OR=2.89; 95% CI 1.41 to 5.93 for gliomas; OR=2.57; 95% CI 1.02 to 6.44 for meningiomas) and number of calls for gliomas (>=18,360 calls, OR=2.10, 95% CI 1.03 to 4.31). Risks were higher for gliomas, temporal tumours, occupational and urban mobile phone use. CONCLUSIONS: These additional data support previous findings concerning a possible association between heavy mobile phone use and brain tumours. PMID- 24816518 TI - Mortality experience among Minnesota taconite mining industry workers. AB - OBJECTIVE: To evaluate the mortality experience of Minnesota taconite mining industry workers. METHODS: Mortality was evaluated between 1960 and 2010 in a cohort of Minnesota taconite mining workers employed by any of the seven companies in operation in 1983. Standardised mortality ratios (SMR) were estimated by comparing observed deaths in the cohort with expected frequencies in the Minnesota population. Standardised rate ratios (SRR) were estimated using an internal analysis to compare mortality by employment duration. RESULTS: The cohort included 31,067 workers with at least 1 year of documented employment. Among those, there were 9094 deaths, of which 949 were from lung cancer, and 30 from mesothelioma. Mortality from all causes was greater than expected in the Minnesota population (SMR=1.04, 95% CI 1.02 to 1.04). Mortality from lung cancer and mesothelioma was higher than expected with SMRs of 1.16 for lung cancer (95% CI 1.09 to 1.23) and 2.77 for mesothelioma (95% CI 1.87 to 3.96). Other elevated SMRs included those for cardiovascular disease (SMR=1.10, 95% CI 1.06 to 1.14), specifically for hypertensive heart disease (SMR=1.81, 95% CI 1.39 to 2.33) and ischemic heart disease (SMR=1.11, 95% CI 1.07 to 1.16). Results of the SRR analysis did not show variation in risk by duration of employment. CONCLUSIONS: This study provides evidence that taconite workers may be at increased risk for mortality from lung cancer, mesothelioma, and some cardiovascular disease. Occupational exposures during taconite mining operations may be associated with these increased risks, but non-occupational exposures may also be important contributors. PMID- 24816519 TI - Exposure to dexamethasone reduces pituitary volume and gonadotropic cell number in rat fetuses. AB - Overexposure to glucocorticoids during the fetal period induces changes in developmental processes in various fetal tissues. The aim of this study was to investigate the effects of the synthetic glucocorticoid, dexamethasone (Dx), on pituitary volume and gonadotropic cells during a critical period of pituitary development. The effects of Dx on stereological parameters of the pituitary gland and FSH and LH cells were investigated in 19 and 21-day old fetuses. On day 16 of pregnancy, the experimental dams received 1.0 mg Dx/kg b.w. subcutaneously, followed by 0. 5mg Dx/kg b.w./day on days 17 and 18 of gestation. The control gravid females received the same volume of saline. FSH and LH cells were stained immunohistochemically by the peroxidase-antiperoxidase method (PAP). In 19-day old fetuses, exposure to Dx caused a significant decrease of pituitary volume, estimated by Cavalieri's principle. Also, the total number of FSH and LH cells per pituitary, determined by physical fractionator counting technique, was significantly reduced. These changes persisted until fetal day 21. Volume densities and numerical densities of FSH and LH cells after exposure to Dx in 19 and 21-day old fetuses remained unaffected. Our results suggest that altered stereological parameters in pituitary gland after exposure to dexamethasone in fetal period could be long-lasting. PMID- 24816520 TI - Hemodynamic ranges during daily activities and exercise testing in patients with pulmonary arterial hypertension. AB - BACKGROUND: In patients with pulmonary arterial hypertension (PAH) the relationship between hemodynamic impairment experienced during daily activity and that during exercise testing is not known. METHODS AND RESULTS: Ten PAH patients received an implantable hemodynamic monitor that continuously recorded and stored right ventricular systolic (RVSP) and mean pulmonary arterial (MPAP) pressures. Before starting a new PAH treatment (baseline) and after 12 weeks on treatment, a 6-minute walk test (6MWT) and a maximal walk test (MAXWT) were performed. Exercise pressure range was measured as the difference between rest before exercise and maximal pressure during 6MWT or MAXWT. Ambulatory range (AMB) was measured as the difference between the lowest (4th percentile) and highest (96th percentile) values recorded over 24 hours. One week of AMBs were averaged for each patient before each exercise test. Mean age was 54 +/-18 years, 9 were female, and all were in World Health Organization functional class III. At baseline, RVSP and MPAP increased, respectively, 136 +/- 49% and 164 +/- 49% during AMB, 63 +/- 26% and 79 +/- 30% during MAXWT, and 59 +/- 32% and 69 +/- 33% during 6MWT. There was no difference in pressure change at 12 weeks. CONCLUSIONS: Changes in RV and PA pressures during exercise tests were relatively small compared with the range seen during ambulatory conditions. PMID- 24816521 TI - Assessment of toxic metals in waste personal computers. AB - Considering the enormous production of waste personal computers nowadays, it is obvious that the study of their composition is necessary in order to regulate their management and prevent any environmental contamination caused by their inappropriate disposal. This study aimed at determining the toxic metals content of motherboards (printed circuit boards), monitor glass and monitor plastic housing of two Cathode Ray Tube (CRT) monitors, three Liquid Crystal Display (LCD) monitors, one LCD touch screen monitor and six motherboards, all of which were discarded. In addition, concentrations of chromium (Cr), cadmium (Cd), lead (Pb) and mercury (Hg) were compared with the respective limits set by the RoHS 2002/95/EC Directive, that was recently renewed by the 2012/19/EU recast, in order to verify manufacturers' compliance with the regulation. The research included disassembly, pulverization, digestion and chemical analyses of all the aforementioned devices. The toxic metals content of all samples was determined using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). The results demonstrated that concentrations of Pb in motherboards and funnel glass of devices with release dates before 2006, that is when the RoHS Directive came into force, exceeded the permissible limit. In general, except from Pb, higher metal concentrations were detected in motherboards in comparison with plastic housing and glass samples. Finally, the results of this work were encouraging, since concentrations of metals referred in the RoHS Directive were found in lower levels than the legislative limits. PMID- 24816522 TI - Reduction-melting combined with a Na2CO3 flux recycling process for lead recovery from cathode ray tube funnel glass. AB - With large quantity of flux (Na2CO3), lead can be recovered from the funnel glass of waste cathode-ray tubes via reduction-melting at 1000 degrees C. To reduce flux cost, a technique to recover added flux from the generated oxide phase is also important in order to recycle the flux recovered from the reduction-melting process. In this study, the phase separation of sodium and the crystallization of water-soluble sodium silicates were induced after the reduction-melting process to enhance the leachability of sodium in the oxide phase and to extract the sodium from the phase for the recovery of Na2CO3 as flux. A reductive atmosphere promoted the phase separation and crystallization, and the leachability of sodium from the oxide phase was enhanced. The optimum temperature and treatment time for increasing the leachability were 700 degrees C and 2h, respectively. After treatment, more than 90% of the sodium in the oxide phase was extracted in water. NaHCO3 can be recovered by carbonization of the solution containing sodium ions using carbon dioxide gas, decomposed to Na2CO3 at 50 degrees C and recycled for use in the reduction-melting process. PMID- 24816523 TI - Prevalence of common food allergies in Europe: a systematic review and meta analysis. AB - Allergy to cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish constitutes the majority of food allergy reactions, but reliable estimates of their prevalence are lacking. This systematic review aimed to provide up-to-date estimates of their prevalence in Europe.Studies published in Europe from January 1, 2000, to September 30, 2012, were identified from searches of four electronic databases. Two independent reviewers appraised the studies and extracted the estimates of interest. Data were pooled using random-effects meta-analyses. Fifty studies were included in a narrative synthesis and 42 studies in the meta analyses. Although there were significant heterogeneity between the studies, the overall pooled estimates for all age groups of self-reported lifetime prevalence of allergy to cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish were 6.0% (95% confidence interval: 5.7-6.4), 2.5% (2.3-2.7), 3.6% (3.0-4.2), 0.4% (0.3-0.6), 1.3% (1.2-1.5), 2.2% (1.8-2.5), and 1.3% (0.9-1.7), respectively. The prevalence of food-challenge-defined allergy to cow's milk, egg, wheat, soy, peanut, tree nuts, fish, and shellfish was 0.6% (0.5-0.8), 0.2% (0.2-0.3), 0.1% (0.01-0.2), 0.3% (0.1-0.4), 0.2% (0.2-0.3), 0.5% (0.08-0.8), 0.1% (0.02-0.2), and 0.1% (0.06-0.3), respectively. Allergy to cow's milk and egg was more common among younger children, while allergy to peanut, tree nuts, fish, and shellfish was more common among the older ones. There were insufficient data to compare the estimates of soy and wheat allergy between the age groups. Allergy to most foods, except soy and peanut, appeared to be more common in Northern Europe. In summary, the lifetime self-reported prevalence of allergy to common foods in Europe ranged from 0.1 to 6.0%. The heterogeneity between studies was high, and participation rates varied across studies reaching as low as <20% in some studies. Standardizing the methods of assessment of food allergies and initiating strategies to increase participation will advance this evidence base. PMID- 24816524 TI - Frequent arguments are linked to premature death, Danish study says. PMID- 24816525 TI - Three-dimensional imaging of the aortic valve geometry for prosthesis sizing prior to transcatheter aortic valve replacement. PMID- 24816526 TI - Predictors of health care use among patients with or at high risk of atherothrombotic disease: two-year follow-up data. AB - BACKGROUND: Atherothrombotic diseases are the leading health problems in the world, both in terms of morbidity and mortality. This study aimed to identify and quantify the predictors of medication, hospital and outpatient service use among patients with or at high risk of atherothrombotic disease. METHODS: Two-year follow-up data were analyzed for 2873 Australian participants of the Reduction of Atherothrombosis for Continued Health (REACH) registry. The analysis was performed using generalized linear models with Poisson and Gamma distributions and log link function. RESULTS: Participants with hypercholesterolemia, diabetes, hypertension, atrial fibrillation (AF), and history of coronary artery disease (CAD) used more medications (p<0.0001). The presence of diabetes predicted higher number of outpatient visits (RR=1.09, 95% CI: 1.07-1.11), as did AF (RR=1.10, 95% CI: 1.08-1.12). The presence of peripheral artery disease (PAD) regardless of ankle brachial index (ABI) status (abnormal or normal) increased the use of outpatient visits (RR=1.24, 95% CI: 1.20-1.29 and RR=1.12, 95% CI: 1.08-1.15), compared to those without PAD. Similarly, the presence of PAD regardless of ABI status increased the risk of vascular interventions, including coronary angioplasty, carotid surgery, amputation affecting lower-limb and peripheral bypass graft (RR=3.64, 95% CI: 2.01-6.60) (RR=2.8, 95% CI: 1.6-4.92) compared to patients without PAD. CONCLUSIONS: The presence of PAD regardless of ABI status predicts a higher number of outpatient visits, non-fatal cardiovascular endpoints and vascular-interventions, while diabetes predicts higher pharmaceutical use and outpatient visits. AF predicts the higher number of outpatient visits and non fatal cardiovascular events. PMID- 24816527 TI - Unusual cause of chest pain in a 13 year-old young child: left ventricular hydatid cyst. PMID- 24816528 TI - Co-occurrence of autoantibodies in healthy blood donors. AB - Autoimmune diseases are rare, but their incidence has increased over the past decades. Interestingly, the co-occurrence of autoimmune diseases is well documented; however, data on the presence of more than one specific autoantibody in healthy individuals are not available. Here, we investigated the prevalence of several autoantibodies in a cohort of over 6000 healthy persons. While individual autoantibodies were rarely detected (i.e. ranging from 0.3% for ANCA to 4.6% for anti-TPO), the cumulative prevalence of the tested autoantibodies was as high as 10%. Furthermore, our results demonstrate co-occurrence of ANA with specific autoantibodies that target TPO, CCP and Dsg1/3, while ANCA and autoantibodies to PCA and BP180/BP230 were not more frequent in ANA-positive compared to ANA negative samples. This indicates that shared and independent mechanisms influence loss of tolerance to distinct sets of self-antigens. PMID- 24816530 TI - Relationship Between Hematologic Indices and Global Registry of Acute Coronary Events Risk Score in Patients With ST-Segment Elevation Myocardial Infarction. AB - The aim of this study was to evaluate the relationship between hematologic indices and the Global Registry of Acute Coronary Events (GRACE) score in patients with ST-segment elevation myocardial infarction (STEMI). A total of 800 patients who consecutively and retrospectively presented with STEMI within 12 hours of symptom onset. After accounting for exclusion criteria, a total of 379 patients remained in the study. We enrolled 379 patients with STEMI (mean age 61.7 +/- 13.6 years; men 73%). Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), red cell distribution width (RDW), and monocyte count were associated with increased worse GRACE risk score (P = .008, P = .012, P = .005, P = .022, respectively). In multivariate linear regression analysis, NLR, PLR, RDW, and monocyte count were found to be independent predictors of GRACE risk score. We demonstrate for the first time that PLR, RDW, and monocyte were associated with the GRACE score in patients with STEMI. PMID- 24816529 TI - Lipid profiling and transcriptomic analysis reveals a functional interplay between estradiol and growth hormone in liver. AB - 17beta-estradiol (E2) may interfere with endocrine, metabolic, and gender differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPARalpha. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a marked influence on GH physiology, with implications in human therapy. PMID- 24816531 TI - Towards quantitative connectivity analysis: reducing tractography biases. AB - Diffusion MRI tractography is often used to estimate structural connections between brain areas and there is a fast-growing interest in quantifying these connections based on their position, shape, size and length. However, a portion of the connections reconstructed with tractography is biased by their position, shape, size and length. Thus, connections reconstructed are not equally distributed in all white matter bundles. Quantitative measures of connectivity based on the streamline distribution in the brain such as streamline count (density), average length and spatial extent (volume) are biased by erroneous streamlines produced by tractography algorithms. In this paper, solutions are proposed to reduce biases in the streamline distribution. First, we propose to optimize tractography parameters in terms of connectivity. Then, we propose to relax the tractography stopping criterion with a novel probabilistic stopping criterion and a particle filtering method, both based on tissue partial volume estimation maps calculated from a T1-weighted image. We show that optimizing tractography parameters, stopping and seeding strategies can reduce the biases in position, shape, size and length of the streamline distribution. These tractography biases are quantitatively reported using in-vivo and synthetic data. This is a critical step towards producing tractography results for quantitative structural connectivity analysis. PMID- 24816532 TI - Regional gray matter volume increases following 7days of voluntary wheel running exercise: a longitudinal VBM study in rats. AB - The effects of physical exercise on brain morphology in rodents have been well documented in histological studies. However, to further understand when and where morphological changes occur in the whole brain, a noninvasive neuroimaging method allowing an unbiased, comprehensive, and longitudinal investigation of brain morphology should be used. In this study, we investigated the effects of 7days of voluntary wheel running exercise on regional gray matter volume (rGMV) using longitudinal voxel-based morphometry (VBM) in rats. Eighteen pairs of adult male naive Wistar rats were randomized to the exercise or control condition (one rat for each condition from each pair). Each rat was scanned in a 7.0-T MRI scanner at three time points: before exercise, after 7days of exercise, and after 7days of follow-up. The T2-weighted MRI images were segmented using the rat brain tissue priors that were recently published by our laboratory, and the intra- and inter-subject template creation steps were followed. Longitudinal VBM analysis revealed significant increases in rGMV in the motor, somatosensory, association, and visual cortices in the exercise group. Among these brain regions, rGMV changes in the motor cortex were positively correlated with the total distance that was run during the 7days of exercise. In addition, the effects of 7days of exercise on rGMV persisted after 7days of follow-up. These results support the utility of a longitudinal VBM study in rats and provide new insights into experience-dependent structural brain plasticity in naive adult animals. PMID- 24816534 TI - Heritability of brain volume change and its relation to intelligence. AB - Human brain volumes change throughout life, are highly heritable, and have been associated with general cognitive functioning. Cross-sectionally, this association between volume and cognition can largely be attributed to the same genes influencing both traits. We address the question whether longitudinal changes in brain volume or in surface area in young adults are under genetic control and whether these changes are also related to general cognitive functioning. We measured change in brain volume and surface area over a 5-year interval in 176 monozygotic and dizygotic twins and their non-twin siblings aged 19 to 56, using magnetic resonance imaging. Results show that changes in volumes of total brain (mean = -6.4 ml; 0.5% loss), cerebellum (1.4 ml, 1.0% increase), cerebral white matter (4.4 ml, 0.9% increase), lateral ventricles (0.6 ml; 4.8% increase) and in surface area (-19.7 cm(2),1.1% contraction) are heritable (h(2) = 43%; 52%; 29%; 31%; and 33%, respectively). An association between IQ (available for 91 participants) and brain volume change was observed, which was attributed to genes involved in both the variation in change in brain volume and in intelligence. Thus, dynamic changes in brain structure are heritable and may have cognitive significance in adulthood. PMID- 24816533 TI - Contributions of the cerebellum and the motor cortex to acquisition and retention of motor memories. AB - We investigated the contributions of the cerebellum and the motor cortex (M1) to acquisition and retention of human motor memories in a force field reaching task. We found that anodal transcranial direct current stimulation (tDCS) of the cerebellum, a technique that is thought to increase neuronal excitability, increased the ability to learn from error and form an internal model of the field, while cathodal cerebellar stimulation reduced this error-dependent learning. In addition, cathodal cerebellar stimulation disrupted the ability to respond to error within a reaching movement, reducing the gain of the sensory motor feedback loop. By contrast, anodal M1 stimulation had no significant effects on these variables. During sham stimulation, early in training the acquired motor memory exhibited rapid decay in error-clamp trials. With further training the rate of decay decreased, suggesting that with training the motor memory was transformed from a labile to a more stable state. Surprisingly, neither cerebellar nor M1 stimulation altered these decay patterns. Participants returned 24hours later and were re-tested in error-clamp trials without stimulation. The cerebellar group that had learned the task with cathodal stimulation exhibited significantly impaired retention, and retention was not improved by M1 anodal stimulation. In summary, non-invasive cerebellar stimulation resulted in polarity-dependent up- or down-regulation of error dependent motor learning. In addition, cathodal cerebellar stimulation during acquisition impaired the ability to retain the motor memory overnight. Thus, in the force field task we found a critical role for the cerebellum in both formation of motor memory and its retention. PMID- 24816535 TI - Olfactory short-term memory encoding and maintenance - an event-related potential study. AB - This study examined whether the memory encoding and short term maintenance of olfactory stimuli is associated with neurophysiological activation patterns which parallel those described for sensory modalities such as vision and auditory. We examined olfactory event-related potentials in an olfactory change detection task in twenty-four healthy adults and compared the measured activation to that found during passive olfactory stimulation. During the early olfactory post-processing phase, we found a sustained negativity over bilateral frontotemporal areas in the passive perception condition which was enhanced in the active memory task. There was no significant lateralization in either experimental condition. During the maintenance interval at the end of the delay period, we still found sustained activation over bilateral frontotemporal areas which was more negative in trials with correct - as compared to incorrect - behavioural responses. This was complemented by a general significantly stronger frontocentral activation. Summarizing, we were able to show that olfactory short term memory involves a parallel sequence of activation as found in other sensory modalities. In addition to olfactory-specific frontotemporal activations in the memory encoding phase, we found slow cortical potentials over frontocentral areas during the memory maintenance phase indicating the activation of a supramodal memory maintenance system. These findings could represent the neurophysiological underpinning of the 'olfactory flacon', the olfactory counter-part to the visual sketchpad and phonological loop embedded in Baddeley's working memory model. PMID- 24816536 TI - Pretreatment with remifentanil, fentanyl, or lidocaine to prevent withdrawal after rocuronium using venous occlusion technique in children and adolescents: a prospective randomized placebo-controlled double-blind study. AB - BACKGROUND: Pain caused by intravenous injection of the muscle relaxant rocuronium bromide is common in children and adolescents. The cause of this unwanted effect is still unclear, and different pretreatment drugs have been administered in attempts to alleviate this side effect, with varying degrees of success. PURPOSE: This study used a 60-s venous occlusion technique to evaluate the effectiveness of pretreatment with lidocaine, fentanyl, or remifentanil in preventing pain-induced withdrawal caused by intravenous injection of rocuronium bromide during the induction of general anesthesia. METHOD: One hundred and one child and adolescent patients, ASA Iota-II, requiring various surgical procedures under general anesthesia with muscle relaxation and mechanical ventilation, were enrolled. Patients were allocated randomly using computer-generated randomization into one of four pretreatment groups: a remifentanil group (1 ug/kg, n = 25), fentanyl group (1 ug/kg, n = 26), lidocaine 1% group (0.5 mg/kg, n = 25), and normal saline group (n = 25). Drug doses were prepared in normal saline to a total volume of 5 ml. Venous occlusion was applied 10 cm above the venous access site. Pretreatment drugs were injected and retained for 60 s at the site of injection by an anesthetist blinded to group allocation. After release of the tourniquet, rocuronium (0.5 mg/kg) was then injected over 5 s, and withdrawal was recorded by another anesthetist blinded to group allocation. Descriptive statistics, analysis of variance, and a chi-squared test were used to statistically analyze the results as appropriate. RESULTS: Compared to normal saline, all other pretreatment groups scored a significantly lower mean of withdrawal response (P < 0.001). Lidocaine was superior to both remifentanil (P < 0.05) and fentanyl (P < 0.05) in suppressing the withdrawal response to rocuronium injection. Remifentanil was superior to fentanyl in suppressing the withdrawal response caused by rocuronium injection (P < 0.001). CONCLUSION: Using a venous occlusion technique for 60 s, lidocaine was found to be most effective in preventing the withdrawal effect caused by rocuronium injection in children and adolescents. Lidocaine was superior to remifentanil which, in turn, was more effective than fentanyl. PMID- 24816537 TI - Characterization of Staphylococcus aureus responses to spermine stress. AB - Spermine (Spm), a potent bactericidal polyamine, exerts a strong synergistic effect with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA). To explore the Spm-based antibacterial targets in S. aureus, time course dependent transcriptome analysis was conducted on Mu50 (MRSA) in the absence and presence of Spm. Genes in the sigB regulon and most ATP-producing pathways were found down-regulated when exposure to high dose Spm. In contrast, a number of genes for iron acquisition and regulation showed significant induction, indicating a specific connection between Spm and iron-depletion. The tetM gene for tetracycline (Tc) resistance exhibited most significant fold change among the listed genes. It was specifically upregulated by Tc and Spm but not by other ribosome-targeted drugs or other polyamines; however, such induction of tetM cannot confer resistance to Spm. A set of genes for osmotic balance, including kdpABCDE for potassium ion uptake and regulation, was also induced by Spm stress. Addition of KCl or NaCl, but not high concentration sucrose, was found to increase Spm MIC over 30-fold. In summary, transcriptome analysis demonstrated a specific pattern of response upon Spm exposure, suggesting Spm may alter the intracellular iron status and suppress the SigB regulon to exert its toxicity. PMID- 24816538 TI - Persistence and effect of processing on reduction of fipronil and its metabolites in chilli pepper (Capsicum annum L.) fruits. AB - A single laboratory UPLC-MS/MS method was developed and validated for the estimation of fipronil and its metabolites in fresh and dry chilli pepper fruits. Dissipation of fipronil on chilli fruits was studied following the application of fipronil (Jump 80 WG) at 40 and 80 g active ingredient (a.i.) ha(-1) in the fruiting stage of the crop. The initial deposits of total fipronil on fresh chilli fruits at single and double dose application were 0.69 and 1.43 MUg g(-1), respectively, and were dissipated to below quantitation level at 27 days after application. The half-life of fipronil at single and double dose in fresh chilli pepper was 4.22 and 4.32 days and the waiting period was 25.9 and 30.6 days, respectively. Processing factor due to sun drying was calculated by measuring fipronil residues in dry chilli fruits, and it ranged from 2.96 to 3.50 during 0 to 21st day after application. Among the metabolites of fipronil, fipronil desulfenyl and fipronil sulfone had maximum residues in fresh and dried chilli, respectively, followed by fipronil sulfide. Dipping in solutions of tamarind, turmeric, vinegar and slaked lime and wet scrubbing could remove more than 90% of fipronil residues in fruits. PMID- 24816539 TI - Water use sources of desert riparian Populus euphratica forests. AB - Desert riparian forests are the main body of natural oases in the lower reaches of inland rivers; its growth and distribution are closely related to water use sources. However, how does the desert riparian forest obtains a stable water source and which water sources it uses to effectively avoid or overcome water stress to survive? This paper describes an analysis of the water sources, using the stable oxygen isotope technique and the linear mixed model of the isotopic values and of desert riparian Populus euphratica forests growing at sites with different groundwater depths and conditions. The results showed that the main water source of Populus euphratica changes from water in a single soil layer or groundwater to deep subsoil water and groundwater as the depth of groundwater increases. This appears to be an adaptive selection to arid and water-deficient conditions and is a primary reason for the long-term survival of P. euphratica in the desert riparian forest of an extremely arid region. Water contributions from the various soil layers and from groundwater differed and the desert riparian P. euphratica forests in different habitats had dissimilar water use strategies. PMID- 24816540 TI - Visually determined stream mesohabitats influence benthic macroinvertebrate assessments in headwater streams. AB - Mesohabitat components such as substrate and surface flow types are intimately related to benthic macroinvertebrate assemblages in streams. Visual assessments of the distribution of these components provide a means of evaluating physical habitat heterogeneity and aid biodiversity surveys and monitoring. We determined the degree to which stream site and visually assessed mesohabitat variables explain variability (i.e., beta-diversity) in the relative abundance and presence absence of all macroinvertebrate families and of Ephemeroptera, Plecoptera, and Trichoptera (EPT) genera. We systematically sampled a wide variety of mesohabitat arrangements as they occured in stream sites. We also estimated how much of the explanation given by mesohabitat was associated with substrate or surface flow types. We performed variation partitioning to determine fractions of explained variance through use of partial redundancy analysis (pRDA). Mesohabitats and stream sites explained together from 23 to 32% of the variation in the four analyses. Stream site explained 8-11% of that variation, and mesohabitat variables explained 13-20%. Surface flow types accounted for >60% of the variation provided by the mesohabitat component. These patterns are in accordance with those obtained in previous studies that showed the predominance of environmental variables over spatial location in explaining macroinvertebrate distribution. We conclude that visually assessed mesohabitat components are important predictors of assemblage composition, explaining significant amounts of beta-diversity. Therefore, they are critical to consider in ecological and biodiversity assessments involving macroinvertebrates. PMID- 24816541 TI - Analysis of methylated patterns and quality-related genes in tobacco (Nicotiana tabacum) cultivars. AB - Methylation-sensitive amplified polymorphism was used in this study to investigate epigenetic information of four tobacco cultivars: Yunyan 85, NC89, K326, and Yunyan 87. The DNA fragments with methylated information were cloned by reamplified PCR and sequenced. The results of Blast alignments showed that the genes with methylation information included chitinase, nitrate reductase, chloroplast DNA, mitochondrial DNA, ornithine decarboxylase, ribulose carboxylase, and promoter sequences. Homologous comparison in three cloned gene sequences (nitrate reductase, ornithine decarboxylase, and ribulose decarboxylase) indicated that geographic factors had significant influence on the whole genome methylation. Introns also contained different information in different tobacco cultivars. These findings suggest that synthetic mechanisms for tobacco aromatic components could be affected by different environmental factors leading to variation of noncoding regions in the genome, which finally results in different fragrance and taste in different tobacco cultivars. PMID- 24816542 TI - Development and validation of a real-time PCR for Chlamydia suis diagnosis in swine and humans. AB - Pigs are the natural host for Chlamydia suis, a pathogen which is phylogenetically highly related to the human pathogen C. trachomatis. Chlamydia suis infections are generally treated with tetracyclines. In 1998, tetracyline resistant C. suis strains emerged on U.S. pig farms and they are currently present in the Belgian, Cypriote, German, Israeli, Italian and Swiss pig industry. Infections with tetracycline resistant C. suis strains are mainly associated with severe reproductive failure leading to marked economical loss. We developed a sensitive and specific TaqMan probe-based C. suis real-time PCR for examining clinical samples of both pigs and humans. The analytical sensitivity of the real-time PCR is 10 rDNA copies/reaction without cross-amplifying DNA of other Chlamydia species. The PCR was successfully validated using conjunctival, pharyngeal and stool samples of slaughterhouse employees, as well as porcine samples from two farms with evidence of reproductive failure and one farm without clinical disease. Chlamydia suis was only detected in diseased pigs and in the eyes of humans. Positive humans had no clinical complaints. PCR results were confirmed by culture in McCoy cells. In addition, Chlamydia suis isolates were also examined by the tet(C) PCR, designed for demonstrating the tetracycline resistance gene tet(C). The tet(C) gene was only present in porcine C. suis isolates. PMID- 24816543 TI - Th1 and Th2 immune response to P30 and ROP18 peptides in human toxoplasmosis. AB - We determined the specific lymphocyte proliferative response and cytokine profile production regarding Toxoplasma P30 (2017 from virulent and non-virulent strain) and ROP18 protein-derived peptides (from clonal lineages I, II and III) in 19 patients having ocular toxoplasmosis, five suffering chronic asymptomatic infection, nine with congenital toxoplasmosis and eight Toxoplasma negative people. A Beckman Coulter FC500 flow cytometer was used for determining antigen specific T cells (CD3+ CD4+ or CD3+ CD8+ cells) in peripheral blood culture. IFN gamma and IL10 levels were determined in culture supernatants. Specific CD4+ and CD8+ T cell response to total antigen and P30- and ROP18-derived peptides was observed in infected people. Ocular toxoplasmosis patients had a preferential Th2 response after antigenic stimulation. Non-virulent peptide 2017 was able to shift response toward Th1 in congenitally infected children and virulent peptide 2017 induced a Th2 response in chronically infected, asymptomatic people. An immune response in human toxoplasmosis after ex vivo antigenic stimulation was Th1- or Th2-skewed, depending on a patient's clinical condition. Colombian ocular toxoplasmosis patients' immune response was Th2-skewed, regardless of the nature of antigen stimulus. PMID- 24816544 TI - Membrane-induced changes in the holomyoglobin tertiary structure: interplay with function. AB - The effect of anionic phospholipid membranes on holomyoglobin (holoMb) conformation and deoxygenation was studied. HoloMb structural changes and behavior in the presence of membranes were monitored by a variety of techniques including far UV and near UV circular dichroism, tryptophan (Trp) fluorescence, absorbance in the Soret region, differential scanning calorimetry, (1)H-NMR spectroscopy, size exclusion chromatography, and macroscopic diffusion. Kinetics of deoxygenation was monitored by absorption at 581 nm. The results gave evidence that proximity to a negatively charged membrane surface can cause destabilization of the structure of holomyoglobin, which delivers oxygen (O2) to mitochondria. It was shown that holoMb undergoes the native-to-intermediate-state transition in the presence of anionic phospholipid membranes at neutral pH, and that in this state it is able to interact with the membranes. When in the intermediate state, holoMb loses its rigid tertiary structure but preserves a pronounced secondary one. The presence of anionic phospholipid membranes substantially accelerates the process of deoxygenation. A possible functional role of the more flexible protein structure acquired in immediate proximity to the membrane surface is discussed. PMID- 24816545 TI - The relationship between disease activity and depression and sleep quality in Behcet's disease patients. AB - Like many chronic illnesses, Behcet's disease (BD) has been reported to negatively affect the quality of life and mental health of the individuals diagnosed with this disease. This study aims to investigate the relationship between disease activity and depression and sleep quality in BD. Forty patients with BD and 30 healthy subjects (controls), aged 18-65, were included in this study, and all of the subjects enrolled in this study were assessed in terms of depression and sleep quality using the Beck depression index (BDI) and Pittsburg sleep quality index (PSQI). Additionally, the subjects with BD were also assessed using the Behcet's disease current activity form (BDCAF). It was determined that the depression and sleep quality scores were significantly higher in the BD group compared to those in the control group (p = 0.012 and p = 0.020, respectively), and in the BD group, significant positive correlations were determined between the BDCAF and depression and sleep quality scores (r = 0.559, p < 0.001 and r = 0.462, p = 0.003, respectively). We believe that the assessment of BD patients for depressive symptoms and sleep quality, and providing medical support to those who need it, will contribute to the treatment and follow-up processes of BD. PMID- 24816546 TI - Caecal ligation and puncture induced sepsis in the rat results in increased brain water content and perimicrovessel oedema. AB - To investigate brain water content and ultrastructure in a rat caecal ligation and puncture (CLP) model of sepsis, adult male Wistar rats were assigned to one of the following experimental groups: CLP, Un-operated or Sham. CLP was performed under anaesthesia, Sham rats were exposed to anaesthesia, laparotomy and caecal mobilisation and Un-operated rats did not experience anaesthesia or surgery. CLP and Sham rats were sacrificed 18-20 h following recovery from surgery and Un operated rats were sacrificed at the same time. Frontal cortex samples (CLP n = 9; Un-operated n = 10; Sham n = 8) were taken immediately post mortem and their water content determined using gravimetry. Similar samples were taken from other rats (CLP n = 8; Un-operated n = 8; Sham n = 8), processed for electron microscopy and subjected to morphometric analysis. There was significantly more brain water in CLP than Un-operated (P < 0.01) and Sham (P < 0.05) rats. Electron microscopy revealed significantly more peri-microvessel oedema in CLP than Un operated (P < 0.001) and Sham rats (P < 0.05). Microvessel endothelial cell lumen cross-sectional area was significantly smaller in CLP than Un-operated (P < 0.001) and Sham (P < 0.05) rats and microvessel endothelial cell cross-sectional area was significantly smaller in CLP than Un-operated (P < 0.05) rats. Significantly more endothelial cell cytoplasmic area was occupied by mitochondria in CLP than Un-operated (P < 0.05) and Sham (P < 0.05) rats. However, experimental group did not affect the number of mitochondria present in endothelial cell profiles, or their cross-sectional area. Therefore, sepsis induced cerebral oedema involves an increase in and a redistribution of brain water, together with ultrastructural changes to cerebral microvessels and adjacent tissue. PMID- 24816547 TI - Electromagnetic tracking in medicine--a review of technology, validation, and applications. AB - Object tracking is a key enabling technology in the context of computer-assisted medical interventions. Allowing the continuous localization of medical instruments and patient anatomy, it is a prerequisite for providing instrument guidance to subsurface anatomical structures. The only widely used technique that enables real-time tracking of small objects without line-of-sight restrictions is electromagnetic (EM) tracking. While EM tracking has been the subject of many research efforts, clinical applications have been slow to emerge. The aim of this review paper is therefore to provide insight into the future potential and limitations of EM tracking for medical use. We describe the basic working principles of EM tracking systems, list the main sources of error, and summarize the published studies on tracking accuracy, precision and robustness along with the corresponding validation protocols proposed. State-of-the-art approaches to error compensation are also reviewed in depth. Finally, an overview of the clinical applications addressed with EM tracking is given. Throughout the paper, we report not only on scientific progress, but also provide a review on commercial systems. Given the continuous debate on the applicability of EM tracking in medicine, this paper provides a timely overview of the state-of-the art in the field. PMID- 24816548 TI - Automatic whole brain MRI segmentation of the developing neonatal brain. AB - Magnetic resonance (MR) imaging is increasingly being used to assess brain growth and development in infants. Such studies are often based on quantitative analysis of anatomical segmentations of brain MR images. However, the large changes in brain shape and appearance associated with development, the lower signal to noise ratio and partial volume effects in the neonatal brain present challenges for automatic segmentation of neonatal MR imaging data. In this study, we propose a framework for accurate intensity-based segmentation of the developing neonatal brain, from the early preterm period to term-equivalent age, into 50 brain regions. We present a novel segmentation algorithm that models the intensities across the whole brain by introducing a structural hierarchy and anatomical constraints. The proposed method is compared to standard atlas-based techniques and improves label overlaps with respect to manual reference segmentations. We demonstrate that the proposed technique achieves highly accurate results and is very robust across a wide range of gestational ages, from 24 weeks gestational age to term-equivalent age. PMID- 24816549 TI - False discovery rate control in magnetic resonance imaging studies via Markov random fields. AB - Magnetic resonance imaging (MRI) is widely used to study population effects of factors on brain morphometry. Inference from such studies often require the simultaneous testing of millions of statistical hypotheses. Such scale of inference is known to lead to large numbers of false positive results. Control of the false discovery rate (FDR) is commonly employed to mitigate against such outcomes. However, current methodologies in FDR control only account for the marginal significance of hypotheses, and are not able to explicitly account for spatial relationships, such as those between MRI voxels. In this article, we present novel methods that incorporate spatial dependencies into the process of controlling FDR through the use of Markov random fields. Our method is able to automatically estimate the relationships between spatially dependent hypotheses by means of maximum pseudo-likelihood estimation and the pseudo-likelihood information criterion. We show that our methods have desirable statistical properties with regards to FDR control and are able to outperform noncontexual methods in simulations of dependent hypothesis scenarios. Our method is applied to investigate the effects of aging on brain morphometry using data from the PATH study. Evidence of whole brain and component level effects that correspond to similar findings in the literature is found in our investigation. PMID- 24816550 TI - Accelerating parallel transmit array B1 mapping in high field MRI with slice undersampling and interpolation by kriging. AB - Transmit arrays have been developed to mitigate the RF field inhomogeneity commonly observed in high field magnetic resonance imaging (MRI), typically above 3T. To this end, the knowledge of the RF complex-valued B1 transmit-sensitivities of each independent radiating element has become essential. This paper details a method to speed up a currently available B1-calibration method. The principle relies on slice undersampling, slice and channel interleaving and kriging, an interpolation method developed in geostatistics and applicable in many domains. It has been demonstrated that, under certain conditions, kriging gives the best estimator of a field in a region of interest. The resulting accelerated sequence allows mapping a complete set of eight volumetric field maps of the human head in about 1 min. For validation, the accuracy of kriging is first evaluated against a well-known interpolation technique based on Fourier transform as well as to a B1 maps interpolation method presented in the literature. This analysis is carried out on simulated and decimated experimental B1 maps. Finally, the accelerated sequence is compared to the standard sequence on a phantom and a volunteer. The new sequence provides B1 maps three times faster with a loss of accuracy limited potentially to about 5%. PMID- 24816551 TI - The T box riboswitch: A novel regulatory RNA that utilizes tRNA as its ligand. AB - The T box riboswitch is a cis-acting regulatory RNA that controls expression of amino acid-related genes in response to the aminoacylation state of a specific tRNA. Multiple genes in the same organism can utilize this mechanism, with each gene responding independently to its cognate tRNA. The uncharged tRNA interacts directly with the regulatory RNA element, and this interaction promotes readthrough of an intrinsic transcriptional termination site upstream of the regulated coding sequence. A second class of T box elements uses a similar tRNA dependent response to regulate translation initiation. This review will describe the current state of our knowledge about this regulatory system. This article is part of a Special Issue entitled: Riboswitches. PMID- 24816552 TI - Complement deficiencies in systemic lupus erythematosus. AB - The complement system is a major, multifunctional part of innate immunity and serves as a bridge between the innate and adaptive immune systems. It consists of more than 30 distinct proteins that interact with one another in a specific sequence. There are three pathways of complement activation: the classical, the lectin, and the alternative pathways. The three pathways are initiated by distinct mechanisms, but they all generate the same core set of effector molecules. Inherited complete deficiencies in complement components are generally very rare and predispose to infections and autoimmune disease. One of the better described associations is between deficiencies in early classical pathway components and the development of systemic lupus erythematosus. The goal of this review will be to discuss the associations between and the causal mechanisms of complement deficiencies and systemic lupus erythematosus. PMID- 24816553 TI - Dietary supplementation with Lovaza and krill oil shortens the life span of long lived F1 mice. AB - Marine oils rich in omega-3 polyunsaturated fatty acids have been recommended as a preventive treatment for patients at risk for cardiovascular diseases. These oils also are the third most consumed dietary supplement in the USA. However, evidence for their health benefits is equivocal. We tested the daily, isocaloric administration of krill oil (1.17 g oil/kg diet) and Lovaza (Omacor; 4.40 g/kg diet), a pharmaceutical grade fish oil, beginning at 12 months of age, on the life span and mortality-related pathologies of long-lived, male, B6C3F1 mice. The oils were incorporated into the chemically defined American Institute of Nutrition (AIN)-93 M diet. An equivalent volume of soybean oil was removed. Krill oil was 3 % and Lovaza 11 % of the oil in the diets. When their effects were analyzed together, the marine oils significantly shortened life span by 6.6 % (P = 0.0321; log-rank test) relative to controls. Individually, Lovaza and krill oil non-significantly shortened median life span by 9.8 and 4.7 %, respectively. Lovaza increased the number of enlarged seminal vesicles (7.1-fold). Lovaza and krill oil significantly increased lung tumors (4.1- and 8.2-fold) and hemorrhagic diathesis (3.9- and 3.1-fold). Analysis of serum from treated mice found that Lovaza slightly increased blood urea nitrogen, while krill oil modestly increased bilirubin, triglycerides, and blood glucose levels. Taken together, the results do not support the idea that the consumption of isolated omega-3 fatty acid-rich oils will increase the life span or health of initially healthy individuals. PMID- 24816554 TI - Prevalence of consanguineous marriages and associated factors among Israeli Bedouins. AB - The Bedouin population in Israel is a semi-nomadic traditional patriarchal society. Consanguineous marriages are very common, contributing to high rates of congenital malformations and genetic diseases, resulting in high infant mortality. Data on consanguineous marriages among Bedouins in Israel are limited. This study examined the current prevalence of consanguineous marriages and their determinants among Israeli Bedouins. One thousand two hundred ninety Bedouin women who delivered in the maternity wards of the only hospital serving the Bedouin population were interviewed between November 2009 and January 2010. The prevalence of consanguineous marriages was 44.8 %. The most common type of spousal relationship was first cousins (65.7 % of all consanguineous marriages). The mean inbreeding coefficient was 0.0238. Factors significantly associated with consanguinity were less years of schooling (OR 0.94, 95 % CI (0.88-0.99), p = 0.02) and younger age at marriage of the wife (OR 0.90, 95 % CI (0.80-0.96), p = 0.0002). In conclusion, the rate of consanguineous marriages among Bedouins is very high, making this population at risk for congenital malformations and genetic diseases. Efforts should be directed at better education and provision of premarital and prenatal counseling on the health consequences of consanguineous marriages and the possibilities to lower those risks. PMID- 24816555 TI - Genetic architecture of palm oil fatty acid composition in cultivated oil palm (Elaeis guineensis Jacq.) compared to its wild relative E. oleifera (H.B.K) Cortes. AB - We searched for quantitative trait loci (QTL) associated with the palm oil fatty acid composition of mature fruits of the oil palm E. guineensis Jacq. in comparison with its wild relative E. oleifera (H.B.K) Cortes. The oil palm cross LM2T x DA10D between two heterozygous parents was considered in our experiment as an intraspecific representative of E. guineensis. Its QTLs were compared to QTLs published for the same traits in an interspecific Elaeis pseudo-backcross used as an indirect representative of E. oleifera. Few correlations were found in E. guineensis between pulp fatty acid proportions and yield traits, allowing for the rather independent selection of both types of traits. Sixteen QTLs affecting palm oil fatty acid proportions and iodine value were identified in oil palm. The phenotypic variation explained by the detected QTLs was low to medium in E. guineensis, ranging between 10% and 36%. The explained cumulative variation was 29% for palmitic acid C16:0 (one QTL), 68% for stearic acid C18:0 (two QTLs), 50% for oleic acid C18:1 (three QTLs), 25% for linoleic acid C18:2 (one QTL), and 40% (two QTLs) for the iodine value. Good marker co-linearity was observed between the intraspecific and interspecific Simple Sequence Repeat (SSR) linkage maps. Specific QTL regions for several traits were found in each mapping population. Our comparative QTL results in both E. guineensis and interspecific materials strongly suggest that, apart from two common QTL zones, there are two specific QTL regions with major effects, which might be one in E. guineensis, the other in E. oleifera, which are independent of each other and harbor QTLs for several traits, indicating either pleiotropic effects or linkage. Using QTL maps connected by highly transferable SSR markers, our study established a good basis to decipher in the future such hypothesis at the Elaeis genus level. PMID- 24816558 TI - Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients. AB - BACKGROUND: The aim of this study is to investigate the expression profile of multiple epithelial mesenchymal transition (EMT)-related molecules in intrahepatic cholangiocarcinoma (ICC) and the related prognostic significance. METHODS: Immunohistochemistry was performed to determine the expression of E cadherin, Vimentin, Snail, slug and beta-catenin in a tissue microarray consisting of tumor tissues of 140 ICC patients undergoing curative resection. The correlation between the expression of these molecules and the clinicopathological characteristics of ICC patients was analyzed, and their prognostic implication was evaluated. RESULTS: Reduced E-cadherin and increased Vimentin expression, the characteristic changes of EMT, identified in 55.0% and 55.7% of primary ICCs, respectively, were correlated with lymphatic metastasis and poorer overall survival (OS) and disease-free survival (DFS) of ICCs. The overexpression of snail and nonmembranous beta-catenin, which are the major regulators of the EMT, were identified in 49.2% and 45.7% of primary ICCs, while little slug expression was detected in ICCs. Cytoplasmic/nuclear beta-catenin did not significantly predict worse DFS and was not related with E-cadherin loss. The overexpression of snail predicted worse OS and DFS. Snail overexpression correlated with the down-regulation of E-cadherin and the up-regulation of Vimentin. Inhibition of snail in an ICC cell line decreased the expression of E cadherin, enhanced the expression of Vimentin and impaired the invasion and migration ability of ICC cells. CONCLUSIONS: These data support the hypothesis that EMT plays vital roles in ICC progression and suggest that snail but not slug and beta-catenin plays a crucial role in the EMT induction of ICC. PMID- 24816556 TI - Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. AB - T cells control the focus and extent of adaptive immunity in infectious and pathological diseases. The activation of T cells occurs when the T cell antigen receptor (TCR) and costimulatory and/or adhesion receptors are engaged by their ligands. This process drives signaling that promotes cytoskeletal rearrangement and transcription factor activation, both of which regulate the quality and magnitude of the T cell response. However, it is not fully understood how different receptor-induced signals combine to alter T cell activation. The related non-receptor tyrosine kinases focal adhesion kinase (FAK) and proline rich tyrosine kinase 2 (Pyk2) are phosphorylated downstream of the TCR and several costimulatory and adhesion receptors. FAK family proteins integrate receptor-mediated signals that influence actin cytoskeletal rearrangement and effector T cell responses. In this review, we summarize the receptor-specific roles that FAK and Pyk2 control to influence T cell development and activation. PMID- 24816557 TI - Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression. AB - Infectious diseases caused by Staphylococcus aureus present a significant clinical and public health problem. S. aureus causes some of the most severe hospital-associated and community-acquired illnesses. Specifically, it is the leading cause of infective endocarditis and osteomyelitis, and the second leading cause of sepsis in the USA. While pathogenesis of S. aureus infections is at the center of current research, many questions remain about the mechanisms underlying staphylococcal toxic shock syndrome (TSS) and associated adaptive immune suppression. Both conditions are mediated by staphylococcal superantigens (SAgs) secreted staphylococcal toxins that are major S. aureus virulence factors. Toxic shock syndrome toxin-1 (TSST-1) is the SAg responsible for almost all menstrual TSS cases in the USA. TSST-1, staphylococcal enterotoxin B and C are also responsible for most cases of non-menstrual TSS. While SAgs mediate all of the hallmark features of TSS, such as fever, rash, hypotension, and multi-organ dysfunction, they are also capable of enhancing the toxic effects of endogenous endotoxin. This interaction appears to be critical in mediating the severity of TSS and related mortality. In addition, interaction between SAgs and the host immune system has been recognized to result in a unique form of adaptive immune suppression, contributing to poor outcomes of S. aureus infections. Utilizing rabbit models of S. aureus infective endocarditis, pneumonia and sepsis, and molecular genetics techniques, we aim to elucidate the mechanisms of SAg and endotoxin synergism in the pathogenesis of TSS, and examine the cellular and molecular mechanisms underlying SAg-mediated immune dysfunction. PMID- 24816559 TI - RasGAP mediates neuronal survival in Drosophila through direct regulation of Rab5 dependent endocytosis. AB - The GTPase Ras can either promote or inhibit cell survival. Inactivating mutations in Drosophila RasGAP (encoded by vap), a Ras GTPase-activating protein, lead to age-related brain degeneration. Genetic interactions implicate the epidermal growth factor receptor (EGFR)-Ras pathway in promoting neurodegeneration but the mechanism is not known. Here, we show that the Src homology 2 (SH2) domains of RasGAP are essential for its neuroprotective function. By using affinity purification and mass spectrometry, we identify a complex containing RasGAP together with Sprint, which is a Ras effector and putative activator of the endocytic GTPase Rab5. Formation of the RasGAP-Sprint complex requires the SH2 domains of RasGAP and tyrosine phosphorylation of Sprint. RasGAP and Sprint colocalize with Rab5-positive early endosomes but not with Rab7-positive late endosomes. We demonstrate a key role for this interaction in neurodegeneration: mutation of Sprint (or Rab5) suppresses neuronal cell death caused by the loss of RasGAP. These results indicate that the long-term survival of adult neurons in Drosophila is crucially dependent on the activities of two GTPases, Ras and Rab5, regulated by the interplay of RasGAP and Sprint. PMID- 24816561 TI - Ccdc13 is a novel human centriolar satellite protein required for ciliogenesis and genome stability. AB - Here, we identify coiled-coil domain-containing protein 13 (Ccdc13) in a genome wide RNA interference screen for regulators of genome stability. We establish that Ccdc13 is a newly identified centriolar satellite protein that interacts with PCM1, Cep290 and pericentrin and prevents the accumulation of DNA damage during mitotic transit. Depletion of Ccdc13 results in the loss of microtubule organisation in a manner similar to PCM1 and Cep290 depletion, although Ccdc13 is not required for satellite integrity. We show that microtubule regrowth is enhanced in Ccdc13-depleted cells, but slowed in cells that overexpress Ccdc13. Furthermore, in serum-starved cells, Ccdc13 localises to the basal body, is required for primary cilia formation and promotes the localisation of the ciliopathy protein BBS4 to both centriolar satellites and cilia. These data highlight the emerging link between DNA damage response factors, centriolar and peri-centriolar satellites and cilia-associated proteins and implicate Ccdc13 as a centriolar satellite protein that functions to promote both genome stability and cilia formation. PMID- 24816560 TI - A novel bidirectional positive-feedback loop between Wnt-beta-catenin and EGFR ERK plays a role in context-specific modulation of epithelial tissue regeneration. AB - By operating as both a subunit of the cadherin complex and a key component of Wnt signalling, beta-catenin acts as the lynchpin between cell-cell contact and transcriptional regulation of proliferation, coordinating epithelial tissue homeostasis and regeneration. The integration of multiple growth-regulatory inputs with beta-catenin signalling has been observed in cancer-derived cells, yet the existence of pathway crosstalk in normal cells is unknown. Using a highly regenerative normal human epithelial culture system that displays contact inhibition, we demonstrate that the receptor tyrosine kinase (RTK)-driven MAPK and Wnt-beta-catenin signalling axes form a bidirectional positive-feedback loop to drive cellular proliferation. We show that beta-catenin both drives and is regulated by proliferative signalling cues, and its downregulation coincides with the switch from proliferation to contact-inhibited quiescence. We reveal a novel contextual interrelationship whereby positive and negative feedback between three major signalling pathways - EGFR-ERK, PI3K-AKT and Wnt-beta-catenin - enable autocrine-regulated tissue homeostasis as an emergent property of physical interactions between cells. Our work has direct implications for normal epithelial tissue homeostasis and provides insight as to how dysregulation of these pathways could drive excessive and sustained cellular growth in disease. PMID- 24816562 TI - Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors. AB - It is well documented that statins protect atherosclerotic patients from inflammatory changes and plaque instability in coronary arteries. However, the underlying mechanisms are not fully understood. Using a previously established mouse model for vulnerable atherosclerotic plaque, we investigated the effect of atorvastatin (10 mg/kg/day) on plaque morphology. Atorvastatin did not lower plasma total cholesterol levels or affect plaque progression at this dosage; however, vulnerable plaque numbers were significantly reduced in the atorvastatin treated group compared to control. Detailed examinations revealed that atorvastatin significantly decreased macrophage infiltration and subendothelial lipid deposition, reduced intimal collagen content, and elevated collagenase activity and expression of matrix metalloproteinases (MMPs). Because vascular inflammation is largely driven by changes in monocyte/macrophage numbers in the vessel wall, we speculated that the anti-inflammatory effect of atorvastatin may partially result from decreased monocyte recruitment to the endothelium. Further experiments showed that atorvastatin downregulated expression of the chemokines monocyte chemoattractant protein (MCP)-1, chemokine (C-X3-C motif) ligand 1 (CX3CL1) and their receptors CCR2 and, CX3CR1, which are mainly responsible for monocyte recruitment. In addition, levels of the plasma inflammatory markers C reactive protein (CRP) and tumor necrosis factor (TNF)-alpha were also significantly decrease in atorvastatin-treated mice. Collectively, our results demonstrate that atorvastatin can improve plaque stability in mice independent of plasma cholesterol levels. Given the profound inhibition of macrophage infiltration into atherosclerotic plaques, we propose that statins may partly exert protective effects by modulating levels of chemokines and their receptors. These findings elucidate yet another atheroprotective mechanism of statins. PMID- 24816563 TI - Proton-pump inhibitors do not influence serum magnesium levels in renal transplant recipients. AB - Severe hypomagnesemia has been reported with use of proton-pump inhibitors (PPIs). We assessed the effect, if any, of PPI use on serum magnesium level in a cross-sectional analysis of a large published cohort of renal transplant recipients (RTRs). Between February 2004 and February 2006, 512 consecutive prevalent RTRs were enrolled at two university hospitals in Belgium (Brussels and Ghent). Serum creatinine was 1.5 +/- 0.7 mg/dl, and estimated glomerular filtration rate (eGFR) 53 +/- 19 ml/min/1.73 m(2). Mean (and median) magnesium level was 1.91 +/- 0.23 mg/dl. PPIs were prescribed in 20 % (n = 101) of cases. At multivariable analysis, PPI use was not an independent predictor of serum magnesium level or hypomagnesemia. The independent predictors of a lower serum magnesium level were the use of tacrolimus, cyclosporin and sirolimus, the absence of use of mycophenolate mofetil, lower levels of parathyroid hormone and higher eGFR. This study is the first to analyze the potential impact of PPIs on magnesium level in a large, representative cohort of RTR patients. Our results suggest that PPIs may be used without particular fear of favoring hypomagnesemia related side effects in RTRs, an important finding in a population at high risk of hypomagnesemia. PMID- 24816564 TI - Near-complete genome sequencing of swine vesicular disease virus using the Roche GS FLX sequencing platform. AB - Swine vesicular disease virus (SVDV) is an enterovirus that is both genetically and antigenically closely related to human coxsackievirus B5 within the Picornaviridae family. SVDV is the causative agent of a highly contagious (though rarely fatal) vesicular disease in pigs. We report a rapid method that is suitable for sequencing the complete protein-encoding sequences of SVDV isolates in which the RNA is relatively intact. The approach couples a single PCR amplification reaction, using only a single PCR primer set to amplify the near complete SVDV genome, with deep-sequencing using a small fraction of the capacity of a Roche GS FLX sequencing platform. Sequences were initially verified through one of two criteria; either a match between a de novo assembly and a reference mapping, or a match between all of five different reference mappings performed against a fixed set of starting reference genomes with significant genetic distances within the same species of viruses. All reference mappings used an iterative method to avoid bias. Further verification was achieved through phylogenetic analysis against published SVDV genomes and additional Enterovirus B sequences. This approach allows high confidence in the obtained consensus sequences, as well as provides sufficiently high and evenly dispersed sequence coverage to allow future studies of intra-host variation. PMID- 24816566 TI - Separation-dependence evolution of inter-particle interaction in the oriented attachment growth of nanorods: a case of hexagonal nanocrystals. AB - Previous reports only evaluated the correlation between oriented-attachment growth and part of the interaction, i.e., either van der Waals interaction or Coulombic interaction. By focusing on hexagonal nanorods, a relatively complex form of 1D nanocrystals, this article takes into account both dominant interactions and systematically investigates their countering effects on the separation dependence of the inter-particle interaction in the oriented attachment growth of 1D nanocrystals. As elucidated by the Arrhenius equation, the growth kinetics and thermodynamics of oriented-attachment nanocrystals can thus be evaluated with such quantitatively resolved inter-particle interactions between the attaching objects. PMID- 24816565 TI - Antinociceptive effects of curcumin in a rat model of postoperative pain. AB - Curcumin is a principal ingredient of traditional Chinese medicine, Curcuma Longa, which possesses a variety of pharmacological activities including pain relief. Preclinical studies have demonstrated that curcumin has antinociceptive effects for inflammatory and neuropathic pain. This study examined the effects of curcumin in a rat model of postoperative pain. A surgical incision on the right hind paw induced a sustained mechanical hyperalgesia that lasted for 5 days. Acute curcumin treatment (10-40 mg/kg, p.o) significantly and dose dependently reversed mechanical hyperalgesia. In addition, repeated curcumin treatment significantly facilitated the recovery from surgery. In contrast, repeated treatment with curcumin before surgery did not impact the postoperative pain threshold and recovery rate. All the doses of curcumin did not significantly alter the spontaneous locomotor activity. Combined, these results suggested that curcumin could alleviate postoperative pain and promote recovery from the surgery, although there was no significant preventive value. This study extends previous findings and supports the application of curcumin alone or as an adjunct therapy for the management of peri-operative pain. PMID- 24816567 TI - Metal-free oxidative synthesis of quinazolinones via dual amination of sp3 C-H bonds. AB - A novel metal-free synthesis of quinazolinones via dual amination of sp(3) C-H bonds was developed. The sp(3) carbon in methylarenes or adjacent to a heteroatom in DMSO, DMF or DMA was used as the one carbon synthon. PMID- 24816568 TI - Narrowing the gap between the promise and reality of polyketide synthases as a synthetic biology platform. AB - Engineering modular polyketide synthases (PKSs) has the potential to be an effective methodology to produce existing and novel chemicals. However, this potential has only just begun to be realized. We propose the adoption of an iterative design-build-test-learn paradigm to improve PKS engineering. We suggest methods to improve engineered PKS design by learning from laboratory-based selection; adoption of DNA design software and automation to build constructs and libraries more easily; tools for the expression of engineered proteins in a variety of heterologous hosts; and mass spectrometry-based high-throughput screening methods. Finally, lessons learned during iterations of the design-build test-learn cycle can serve as a knowledge base for the development of a single retrosynthesis algorithm usable by both PKS experts and non-experts alike. PMID- 24816569 TI - The 'global interconnectedness' of dentist migration: a qualitative study of the life-stories of international dental graduates in Australia. AB - The migration of dentists is a major challenge contributing to the oral health system crisis in many countries. This paper explores the origins of the dentist migration problem through a study on international dental graduates, who had migrated to Australia. Life-stories of 49 international dental graduates from 22 countries were analysed in order to discern significant themes and patterns. We focused on their home country experience, including stories on early life and career choice; dental student life; professional life; social and political life; travels; and coming to Australia. Our participants exhibited a commitment to excellence in earlier stages of life and had cultivated a desire to learn more and be involved with the latest technology. Dentists from low- and middle-income countries were also disappointed by the lack of opportunity and were unhappy with the local ethos. Some pointed towards political unrest. Interestingly, participants also carried prior travel learnings and unforgettable memories contributing to their migration. Family members and peers had also influenced participants. These considerations were brought together in four themes explaining the desire to migrate: 'Being good at something', 'Feelings of being let down', 'A novel experience' and 'Influenced by someone'. Even if one of these four themes dominated the narrative, we found that more than one theme, however, coexisted for most participants. We refer to this worldview as 'Global interconnectedness', and identify the development of migration desire as a historical process, stimulated by a priori knowledge (and interactions) of people, place and things. This qualitative study has enriched our understanding on the complexity of the dental migration experience. It supports efforts to achieve greater technical co-operation in issues such as dental education, workforce surveillance and oral health service planning within the context of ongoing global efforts on health professional migration by the World Health Organization and member states. PMID- 24816570 TI - Removing user fees for facility-based delivery services: a difference-in differences evaluation from ten sub-Saharan African countries. AB - BACKGROUND: Several countries in sub-Saharan Africa have recently adopted policies that remove user fees for facility-based delivery services. There is little rigorous evidence of the impact of these policies on utilization of delivery services and no evaluations have examined effects on neonatal mortality rates (NMR). In this article, we estimate the causal effect of removing user fees on the proportion of births delivered in facilities, the proportion of births delivered by Caesarean section, and NMR. METHODS: We used data from Demographic and Health Surveys conducted in 10 African countries between 1997 and 2012. Kenya, Ghana and Senegal adopted policies removing user fees for facility-based deliveries between 2003 and 2007, while seven other countries not changing user fee policies were used as controls. We used a difference-in-differences (DD) regression approach to control for secular trends in the outcomes that are common across countries and for time invariant differences between countries. RESULTS: According to covariate-adjusted DD models, the policy change was consistent with an increase of 3.1 facility-based deliveries per 100 live births (95% confidence interval (CI): 0.9, 5.2) and an estimated reduction of 2.9 neonatal deaths per 1000 births (95% CI: -6.8, 1.0). In relative terms, this corresponds to a 5% increase in facility deliveries and a 9% reduction in NMR. There was no evidence of an increase in Caesarean deliveries. We examined lead and lag-time effects, finding evidence that facility deliveries continued to increase following fee removal. CONCLUSIONS: Our findings suggest removing user fees increased facility based deliveries and possibly contributed to a reduction in NMR. Evidence from this evaluation may be useful to governments weighing the potential benefits of removing user fees. PMID- 24816571 TI - Strengthening the implementation of Health in All Policies: a methodology for realist explanatory case studies. AB - To address macro-social and economic determinants of health and equity, there has been growing use of intersectoral action by governments around the world. Health in All Policies (HiAP) initiatives are a special case where governments use cross sectoral structures and relationships to systematically address health in policymaking by targeting broad health determinants rather than health services alone. Although many examples of HiAP have emerged in recent decades, the reasons for their successful implementation--and for implementation failures--have not been systematically studied. Consequently, rigorous evidence based on systematic research of the social mechanisms that have regularly enabled or hindered implementation in different jurisdictions is sparse. We describe a novel methodology for explanatory case studies that use a scientific realist perspective to study the implementation of HiAP. Our methodology begins with the formulation of a conceptual framework to describe contexts, social mechanisms and outcomes of relevance to the sustainable implementation of HiAP. We then describe the process of systematically explaining phenomena of interest using evidence from literature and key informant interviews, and looking for patterns and themes. Finally, we present a comparative example of how Health Impact Assessment tools have been utilized in Sweden and Quebec to illustrate how this methodology uses evidence to first describe successful practices for implementation of HiAP and then refine the initial framework. The methodology that we describe helps researchers to identify and triangulate rich evidence describing social mechanisms and salient contextual factors that characterize successful practices in implementing HiAP in specific jurisdictions. This methodology can be applied to study the implementation of HiAP and other forms of intersectoral action to reduce health inequities involving multiple geographic levels of government in diverse settings. PMID- 24816573 TI - Hierarchical interfaces induce high dielectric permittivity in nanocomposites containing TiO2@BaTiO3 nanofibers. AB - Interface issues are common and crucial in nanocomposites or nanohybrid systems since the interface area is enormous on the nanoscale. In the 0-3 dimensional polymer nanocomposites, in which nano-inclusions (0-dimension) are embedded in a 3-dimensionally connected polymer matrix, enhanced dielectric permittivity could be induced by the interfacial polarization at the interfaces between the nano inclusions and the polymer matrix. In this contribution, we propose and demonstrate that the topological structure of the interface plays an equally important role as the area of the interface in determining the dielectric polarization of polymer nanocomposites. TiO2 nanofibers embedded with BaTiO3 nanoparticles are prepared via electrospinning and then fused with polyvinyl difluoride (PVDF) into polymer nanocomposite films. Modulation of hierarchical interfaces is thus achieved for these nanocomposites. The confinement of these additional interfaces inside the TiO2 nanofibers leads to percolated networks formed by the interfacial regions. The dielectric permittivity of the polymer nanocomposites is thus enhanced by ~300% over the PVDF matrix at a low filler loading of 11 vol%. A phase-field simulation study indicates that the enhanced dielectric permittivity could be attributed to the increased polarization in the percolated interfacial regions inside the TiO2 nanofibers. The instantaneous electrical breakdown of the TiO2@BaTiO3 nanofibers studied by the in situ transmission electron microscopy method further reveals the striking feature that the breakdown behavior of the nanofibers changes from semiconductive to metallic with the incorporation of insulating BaTiO3 nanoparticles. PMID- 24816572 TI - Community case management of malaria: exploring support, capacity and motivation of community medicine distributors in Uganda. AB - BACKGROUND: In Uganda, community services for febrile children are expanding from presumptive treatment of fever with anti-malarials through the home-based management of fever (HBMF) programme, to include treatment for malaria, diarrhoea and pneumonia through Integrated Community Case Management (ICCM). To understand the level of support available, and the capacity and motivation of community health workers to deliver these expanded services, we interviewed community medicine distributors (CMDs), who had been involved in the HBMF programme in Tororo district, shortly before ICCM was adopted. METHODS: Between October 2009 and April 2010, 100 CMDs were recruited to participate by convenience sampling. The survey included questionnaires to gather information about the CMDs' work experience and to assess knowledge of fever case management, and in-depth interviews to discuss experiences as CMDs including motivation, supervision and relationships with the community. All questionnaires and knowledge assessments were analysed. Summary contact sheets were made for each of the 100 interviews and 35 were chosen for full transcription and analysis. RESULTS: CMDs faced multiple challenges including high patient load, limited knowledge and supervision, lack of compensation, limited drugs and supplies, and unrealistic expectations of community members. CMDs described being motivated to volunteer for altruistic reasons; however, the main benefits of their work appeared related to 'becoming someone important', with the potential for social mobility for self and family, including building relationships with health workers. At the time of the survey, over half of CMDs felt demotivated due to limited support from communities and the health system. CONCLUSIONS: Community health worker programmes rely on the support of communities and health systems to operate sustainably. When this support falls short, motivation of volunteers can wane. If community interventions, in increasingly complex forms, are to become the solution to improving access to primary health care, greater attention to what motivates individuals, and ways to strengthen health system support are required. PMID- 24816575 TI - The mechanism of the Cu2+[12-MCCu(Alaha)-4] metallacrown formation and lanthanum(III) encapsulation. AB - A kinetic, calorimetric, mass spectrometry and EPR study has been performed on the formation of the metallacrown Cu(2+)[12-MCCu(Alaha)-4] from Cu(ii) and alpha alaninehydroxamic acid (H2L). The acidity range where Cu(2+)[12-MCCu(Alaha)-4] is stable lies between pH 3.5 and 6.0. For pH values below that range the complex CuHL(+) is the prevailing species. This species plays a fundamental role in the formation of Cu(2+)[12-MCCu(Alaha)-4]. Actually, depending on the Cu(II)/H2L ratio and on pH, it can originate a dimer Cu2(HL)2(2+) or a dinuclear complex Cu2L(2+). Both species constitute the nuclei necessary for a further oligomerisation reaction which ends when the crown is formed. The kinetics of Cu(2+)[12-MCCu(Alaha)-4] formation is biphasic. Under conditions of Cu(II) excess the fast phase leads to formation of Cu2L(2+). The slow phase is interpreted in terms of a sequential addition of monomers (CuHL(+)) to the Cu2L(2+) nucleus to form the crown. The interaction of La(III) with Cu(2+)[12-MCCu(Alaha)-4] has also been investigated. The system displays a biphasic behaviour; in the first phase the intermediate complex Cu[12-MCCu(Alaha)-4]La is formed which, in excess of ligand, evolves towards the larger metallacrown La(3+)[15-MCCu(Alaha)-5]. The reaction mechanisms of the two investigated systems are discussed. PMID- 24816574 TI - Alcoholic liver disease: a synopsis of the Charles Lieber's Memorial Symposia 2009-2012. AB - This paper is based upon the 'Charles Lieber Satellite Symposia' organized by Manuela G. Neuman at each of the 2009-2012 Research Society on Alcoholism (RSA) Annual Meetings. The presentations represent a broad spectrum dealing with alcoholic liver disease (ALD). In addition, a literature search (2008-2013) in the discussed area was performed in order to obtain updated data. The presentations are focused on genetic polymorphisms of ethanol metabolizing enzymes and the role of cytochrome P4502E1 (CYP2E1) in ALD. In addition, alcohol mediated hepatocarcinogenesis, immune response to alcohol and fibrogenesis in alcoholic hepatitis as well as its co-morbidities with chronic viral hepatitis infections in the presence or absence of human deficiency virus are discussed. Finally, emphasis was led on alcohol and drug interactions as well as liver transplantation for end-stage ALD. PMID- 24816577 TI - [Renal complications after hematopoietic stem cell transplantation]. AB - Hematopoietic stem cell transplantation is a widely used therapeutic modality for many, mainly malignant, diseases. Toxicities of this procedure include acute and chronic renal dysfunction. Acute renal failure, generally reversible is due to acute tubular necrosis (tumor lysis syndrome, marrow-infusion toxicity, sepsis, nephrotoxins), hepatic veno-occlusive disease or acute graft-versus-host disease. Chronic renal failure is often multifactorial, caused by conditioning-associated endothelial cell toxicity (bone marrow transplant nephropathy) and calcineurin inhibitors toxicity. Renal pathologic findings are somewhat similar to thrombotic microangiopathy, with sometimes systemic disease. Rare cases of nephrotic syndrome have been described after hematopoietic stem cell transplantation, mainly membranous nephropathy, associated with graft-versus-host disease. Therapeutic options for renal dysfunction after hematopoietic stem cell transplantation are limited but kidney transplantation is possible in case of end stage renal disease. PMID- 24816576 TI - Tuberculin skin testing and treatment modulates interferon-gamma release assay results for latent tuberculosis in migrants. AB - BACKGROUND: Identifying latent tuberculosis infection (LTBI) in people migrating from TB endemic regions to low incidence countries is an important control measure. However, no prospective longitudinal comparisons between diagnostic tests used in such migrant populations are available. OBJECTIVES: To compare commercial interferon (IFN)-gamma release assays (IGRAs) and the tuberculin skin test (TST) for diagnosing LTBI in a migrant population, and the influence of antecedent TST and LTBI treatment on IGRA performance. MATERIALS AND METHODS: This cohort study, performed from February to September 2012, assessed longitudinal IGRA and TST responses in Nepalese military recruits recently arrived in the UK. Concomitant T-SPOT.TB, QFT-GIT and TST were performed on day 0, with IGRAs repeated 7 and 200 days later, following treatment for LTBI if necessary. RESULTS: 166 Nepalese recruits were prospectively assessed. At entry, 21 individuals were positive by T-SPOT.TB and 8 individuals by QFT-GIT. There was substantial agreement between TST and T-SPOT.TB positives at baseline (71.4% agreement; kappa = 0.62; 95% CI:0.44-0.79), but only moderate concordance between positive IGRAs (38.1% agreement; kappa = 0.46; 95% CI:0.25-0.67). When reassessed 7 days following TST, numbers of IGRA-positive individuals changed from 8 to 23 for QFT-GIT (p = 0.0074) and from 21 to 23 for T-SPOT.TB (p = 0.87). This resulted in an increase in IGRA concordance to substantial (64.3% agreement; kappa = 0.73; 95% CI:0.58-0.88). Thus, in total on day 0 and day 7 after testing, 29 out of 166 participants (17.5%) provided a positive IGRA and of these 13 were TST negative. Two hundred days after the study commenced and three months after treatment for LTBI was completed by those who were given chemoprophylaxis, 23 and 21 participants were positive by T-SPOT.TB or QFT-GIT respectively. When individual responses were examined longitudinally within this population 35% of the day 7 QFT-GIT-positive, and 19% T-SPOT.TB-positive individuals, were negative by IGRA. When the change in the levels of secreted IFN-gamma was examined after chemoprophylaxis the median levels were found to have fallen dramatically by 77.3% from a pre-treatment median concentration of IFN-gamma 2.73 IU/ml to a post treatment median concentration IFN-gamma 0.62 (p = 0.0002). CONCLUSIONS: This study suggests differences in the capacity of commercially available IGRAs to identify LTBI in the absence of antecedent TST and that IGRAs, in the time periods examined, may not be the optimal tests to determine the success of chemoprophylaxis for LTBI. PMID- 24816578 TI - Viewpoint: "underutilisation of novel antiplatelet agents--myths, generics, and economics". AB - Two oral antiplatelet agents have been recently introduced for acute coronary syndromes indication providing alternatives for dual therapy with aspirin and clopidogrel. In fact, worldwide prasugrel has been on the market for four years, and ticagrelor for over two years. Despite declared benefits over clopidogrel, including hypothetical cost saving advantages, in real life, the clinical utilisation of both agents is small. Generic clopidogrel, and price differences are claimed as major obstacles to prevent broader prasugrel and ticagrelor use. However, these economic difficulties are barely supported by available evidence, and served mostly to protect questionable management spending, as an exuse to explain why in reality cardiologists are so sceptical about both novel agents, and to convince the sharehoders that their money is not wasted, misleading the owners with regard to future success. Importantly, brand Plavix(r) is used worldwide 5-10 times more often than new agents, despite heavy generic competition. The future of prasugrel outside Japan, where much lower reasonable dose will be used is not impressive due to lack of further outcome studies, negative results of the latest trials, and less than four years left before patent expiration. The fate of ticagrelor will depend on verification of deaths numbers in the ongoing United States Department of Justice PLATO investigation, and confirmation of the mortality benefit in the PEGASUS TIMI-54 trial. PMID- 24816579 TI - A feasible computer-based evaluation tool for reduction mammaplasty patients: indications for operation and monitoring of guidelines. AB - In Sweden, evidence-based national guidelines for the indication for reduction mammaplasty in the public health-care system have been developed by a group of experts. They were defined as breast volume>=800 ml at normal weight. Furthermore, a volume asymmetry of 25% or at least 200 ml or an extreme ptosis may be an indication in some cases. The aim of the present paper was to describe an easy-to-use computer-based tool that has been developed to assure that patients with mammary hyperplasia are evaluated and offered care in a standardized fashion and that the adherence to the guidelines is monitored. Included variables were based on a model for priority grouping originally presented by Strombeck and Malm in 1986 and comprise body mass index (BMI), BMI corrected breast volume, ptosis, asymmetry, and general breast-related factors preoperatively and 1 year postoperatively and complications postoperatively. Between June 2007 and January 2013, 377 patients were evaluated. Of which, 275 qualified for operation. With the help of the computer-based tool, compliance to the indications for operation can be easily followed, and hence the intended patients offered a reduction mammaplasty in the public health-care system. PMID- 24816580 TI - The emerging role of gemcitabine in conditioning regimens for hematopoietic stem cell transplantation. AB - The specific combination for conditioning regimens in hematopoietic stem cell transplantation continues to be a premier area of focus in research. Although conditioning regimens have significantly evolved over time, obstacles continue to persist, including regimen-related toxicities, graft-versus-host disease, and disease relapse. Gemcitabine (2',2'-difluoro 2'-deoxycytidine, dFdC) is a pyrimidine nucleoside analog that distinguishes itself from other agents in the class by possessing a favorable pharmacokinetic and cytotoxic profile, while maintaining acceptable toxicities. Given the desirable properties, gemcitabine has garnered much attention and been assessed in several conditioning regimens. In this article, we review the pharmacology of gemcitabine with other nucleoside analogs and report the findings of pivotal trials conducted in both autologous and allogeneic transplantation. The positive results suggest a potential future role for gemcitabine and necessitate the need to conduct studies to further define its role. PMID- 24816581 TI - Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. AB - Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation. PMID- 24816583 TI - Recurring axillary, abdominal and genitofemoral nodules and abscesses. Hereditary steatocystoma multiplex. PMID- 24816584 TI - A new formula for bivariate Hermite interpolation on variable step grids and its application to image interpolation. AB - In this paper, we present a novel formula of the bivariate Hermite interpolating (BHI) polynomial in the case of support points arranged on a grid with variable step. This expression is applicable when interpolation of a bivariate function is required, given its value and the values of its partial derivatives of arbitrarily high order, at the support points. The proposed formula is a generalization of an existing formula for the bivariate Hermite polynomial. It is also algebraically much simpler, thus can be computed more efficiently. In order to apply Hermite interpolation to image interpolation, we simplify the proposed (BHI) to handle support points on a regular unit-step grid. The values of image partial derivatives are arithmetically approximated using compact finite differences. The proposed method is being assessed in a number of image interpolation experiments that include a synthetic image, for which the values of the partial derivatives are computed analytically, as well as a collection of images from different medical modalities. The proposed BHI with up to second order image partial derivatives, outperforms the convolution-based interpolation methods, as well as generalized interpolation methods with the same number of support points that was compared with, in the majority of image interpolation experiments. The computational load of the proposed BHI is calculated and its behaviour with respect to its controlling parameters is investigated. PMID- 24816582 TI - Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy. AB - Natural killer (NK) cell efficacy correlates with in vivo proliferation, and we hypothesize that NK cell product manipulations may optimize this endpoint. Xenotransplantation was used to compare good manufacturing practice (GMP) grade freshly activated NK cells (FA-NK) and ex vivo expanded NK cells (Ex-NK). Cells were infused into NOD scid IL2 receptor gamma chain knockout (NSG) mice followed by IL-2, IL-15, or no cytokines. Evaluation of blood, spleen, and marrow showed that persistence and expansion was cytokine dependent, IL-15 being superior to IL 2. Cryopreservation and immediate infusion resulted in less cytotoxicity and fewer NK cells in vivo, and this could be rescued in FA-NK by overnight culture and testing the next day. Marked differences in the kinetics and homing of FA-NK versus Ex-NK were apparent: FA-NK cells preferentially homed to spleen and persisted longer after cytokine withdrawal. These data suggest that cryopreservation of FA-NK and Ex-NK is detrimental and that culture conditions profoundly affect homing, persistence, and expansion of NK cells in vivo. The NSG mouse model is an adjuvant to in vitro assays before clinical testing. PMID- 24816585 TI - Max-margin multiattribute learning with low-rank constraint. AB - Attribute learning has attracted a lot of interests in recent years for its advantage of being able to model high-level concepts with a compact set of midlevel attributes. Real-world objects often demand multiple attributes for effective modeling. Most existing methods learn attributes independently without explicitly considering their intrinsic relatedness. In this paper, we propose max margin multiattribute learning with low-rank constraint, which learns a set of attributes simultaneously, using only relative ranking of the attributes for the data. By learning all the attributes simultaneously through low-rank constraint, the proposed method is able to capture their intrinsic correlation for improved learning; by requiring only relative ranking, the method avoids restrictive binary labels of attributes that are often assumed by many existing techniques. The proposed method is evaluated on both synthetic data and real visual data including a challenging video data set. Experimental results demonstrate the effectiveness of the proposed method. PMID- 24816586 TI - Simultaneous segmentation and multiresolution nonrigid atlas registration. AB - In this paper, a novel Markov random field (MRF)-based approach is presented for segmenting medical images while simultaneously registering an atlas nonrigidly. In the literature, both segmentation and registration have been studied extensively. For applications that involve both, such as segmentation via atlas based registration, earlier studies proposed addressing these problems iteratively by feeding the output of each to initialize the other. This scheme, however, cannot guarantee an optimal solution for the combined task at hand, since these two individual problems are then treated separately. In this paper, we formulate simultaneous registration and segmentation (SRS) as a maximum a posteriori (MAP) problem. We decompose the resulting probabilities such that the MAP inference can be done using MRFs. An efficient hierarchical implementation is employed, allowing coarse-to-fine registration while estimating segmentation at pixel level. The method is evaluated on two clinical data sets: 1) mandibular bone segmentation in 3D CT and 2) corpus callosum segmentation in 2D midsaggital slices of brain MRI. A video tracking example is also given. Our implementation allows us to directly compare the proposed method with the individual segmentation/registration and the iterative approach using the exact same potential functions. In a leave-one-out evaluation, SRS demonstrated more accurate results in terms of dice overlap and surface distance metrics for both data sets. We also show quantitatively that the SRS method is less sensitive to the errors in the registration as opposed to the iterative approach. PMID- 24816587 TI - Phase-based binarization of ancient document images: model and applications. AB - In this paper, a phase-based binarization model for ancient document images is proposed, as well as a postprocessing method that can improve any binarization method and a ground truth generation tool. Three feature maps derived from the phase information of an input document image constitute the core of this binarization model. These features are the maximum moment of phase congruency covariance, a locally weighted mean phase angle, and a phase preserved denoised image. The proposed model consists of three standard steps: 1) preprocessing; 2) main binarization; and 3) postprocessing. In the preprocessing and main binarization steps, the features used are mainly phase derived, while in the postprocessing step, specialized adaptive Gaussian and median filters are considered. One of the outputs of the binarization step, which shows high recall performance, is used in a proposed postprocessing method to improve the performance of other binarization methodologies. Finally, we develop a ground truth generation tool, called PhaseGT, to simplify and speed up the ground truth generation process for ancient document images. The comprehensive experimental results on the DIBCO'09, H-DIBCO'10, DIBCO'11, H-DIBCO'12, DIBCO'13, PHIBD'12, and BICKLEY DIARY data sets show the robustness of the proposed binarization method on various types of degradation and document images. PMID- 24816588 TI - Tacrolimus increases Nox4 expression in human renal fibroblasts and induces fibrosis-related genes by aberrant TGF-beta receptor signalling. AB - Chronic nephrotoxicity of immunosuppressives is one of the main limiting factors in the long-term outcome of kidney transplants, leading to tissue fibrosis and ultimate organ failure. The cytokine TGF-beta is considered a key factor in this process. In the human renal fibroblast cell line TK-173, the macrolide calcineurin inhibitor tacrolimus (FK-506) induced TGF-beta-like effects, manifested by increased expression of NAD(P)H-oxidase 4 (Nox4), transgelin, tropomyosin 1, and procollagen alpha1(V) mRNA after three days. The macrolide mTOR inhibitor rapamycin had similar effects, while cyclosporine A did not induce fibrose-related genes. Concentration dependence curves were sigmoid, where mRNA expression was induced already at low nanomolar levels of tacrolimus, and reached saturation at 100-300 nM. The effects were independent of extracellular TGF-beta as confirmed by the use of neutralizing antibodies, and thus most likely caused by aberrant TGF-beta receptor signaling, where binding of tacrolimus to the regulatory FKBP12 protein results in a "leaky" TGF-beta receptor. The myofibroblast marker alpha-smooth muscle actin was neither induced by tacrolimus nor by TGF-beta1, indicating an incomplete activation of TK-173 fibroblasts under culture conditions. Tacrolimus- and TGF-beta1-induced Nox4 protein upregulation was confirmed by Western blotting, and was accompanied by a rise in intracellular H2O2 concentration. Si-RNA mediated knock-down of Nox4 expression prevented up regulation of procollagen alpha1(V) mRNA in tacrolimus-treated cells, but induced procollagen alpha1(V) expression in control cells. Nox4 knock-down had no significant effect on the other genes tested. TGF-beta is a key molecule in fibrosis, and the constant activation of aberrant receptor signaling by tacrolimus might contribute to the long-term development of interstitial kidney fibrosis in immunosuppressed patients. Nox4 levels possibly play a regulatory role in these processes. PMID- 24816589 TI - Characterization of pore structure in biologically functional poly(2-hydroxyethyl methacrylate)-poly(ethylene glycol) diacrylate (PHEMA-PEGDA). AB - A copolymer composed of poly(2-hydroxyethyl methacrylate) (PHEMA) and poly(ethylene glycol) diacrylate (PEGDA) (PHEMA-PEGDA) is structurally versatile. Its structure can be adjusted using the following porogens: water, sucrose, and benzyl alcohol. Using phase separation technique, a variety of surface architectures and pore morphologies were developed by adjusting porogen volume and type. The water and sucrose porogens were effective in creating porous and cytocompatible PHEMA-PEGDA scaffolds. When coated with collagen, the PHEMA-PEGDA scaffolds accommodated cell migration. The PHEMA-PEGDA scaffolds are easy to produce, non-toxic, and mechanically stable enough to resist fracture during routine handling. The PHEMA-PEGDA structures presented in this study may expedite the current research effort to engineer tissue scaffolds that provide both structural stability and biological activity. PMID- 24816590 TI - Hydrologic modelling for Lake Basaka: development and application of a conceptual water budget model. AB - Quantification of fluxes of water into and out of terminal lakes like Basaka has fundamental challenges. This is due to the fact that accurate measurement and quantification of most of the parameters of a lake's hydrologic cycle are difficult. Furthermore, quantitative understanding of the hydrologic systems and hence, the data-intensive modelling is difficult in developing countries like Ethiopia due to limitation of sufficient recorded data. Therefore, formulation of a conceptual water balance model is extremely important as it presents a convenient analytical tool with simplified assumptions to simulate the magnitude of unknown fluxes. In the current study, a conceptual lake water balance model was systematically formulated, solved, calibrated, and validated successfully. Then, the surface water and groundwater interaction was quantified, and a mathematical relationship developed. The overall agreement between the observed and simulated lake stage at monthly time step was confirmed based on the standard performance parameters (R(2), MAE, RMSE, E(f)). The result showed that hydrological water balance of the lake is dominated by the groundwater (GW) component. The net GW flux in recent period (post-2000s) accounts about 56% of the total water inflow. Hence, GW plays a leading role in the hydrodynamics and existence of Lake Basaka and is mostly responsible for the expansion of the lake. Thus, identification of the potential sources/causes for the GW flux plays a leading role in order to limit the further expansion of the lake. Measurement of GW movement and exchange in the area is a high priority for future research. PMID- 24816591 TI - Hidden sources of mercury in clinical laboratories. AB - The healthcare sector is an important contributor to mercury (Hg) pollution because of the potential presence of mercury in thermometers, blood pressure cuffs, amalgams, etc. There are also other potential sources of mercury in this sector which are used frequently and in high volumes where the presence of the metal is not obvious and which might be collectively contributing to pollution. For instance, some chemicals used for the clinical diagnosis of illness may contain mercury. The goal of this study was to investigate potential sources of mercury pollution, which originate from clinical laboratory discharges, using an exploratory approach. The focus was on the residue generated during automatic analysis of patients' bodily fluids at a medical center in Hermosillo, Sonora, Mexico. This study shows an overview of what might be happening in the region or the country related to non-obvious sources of mercury in the healthcare sector. The results showed measurable levels of mercury in the residues coming from urine sediment analysis. These amounts do not exceed the maximum allowed by Mexican environmental regulations; nevertheless, the frequency and cumulative volume of residues generated, combined with the potential for persistence and the bioaccumulation of mercury in the environment, warrant attention. The work carried out in this study is being taken as a model for future studies for pollution prevention in the healthcare sector with the goal of measuring mercury emissions to the environment from clinical laboratory wastewater, including identifying sources which--while not obvious--could be important given the frequency and volume of their use in the clinical diagnosis. PMID- 24816592 TI - Fucus spiralis as monitoring tool of metal contamination in the northwest coast of Portugal under the European Water Framework Directives. AB - Metals (Cd, Cr, Cu, Fe, Mn and Zn) in coastal seawaters and soft tissues of macroalga Fucus spiralis from the northwest coast of Portugal were determined to assess spatial variations of metal bioavailabilities and bioaccumulation factors to compare different ecological quality classifications. Both coastal seawaters and soft tissues of F. spiralis showed significant spatial variations in their metal concentrations along the coast. The macroalgae F. spiralis accumulated more efficiently Cd, Mn and Zn and showed low bioaccumulation factors to Cr, Cu and Fe. Regarding the metal guidelines of the Norwegian Pollution Control Authority, the entire northwest (NW) coast of Portugal in April 2013 should be classified as 'class I--unpolluted' for all metals, except in Ave for Cu ('class II--moderately polluted') and Cavado for Cd and Cu ('class II-moderately polluted'), revealing the low metal bioavailabilities of these seawaters. As there were always significant positive correlations between all metals in seawaters and F. spiralis, this macroalga species was considered a suitable monitoring tool of metal contamination in the NW coast of Portugal and a useful aquatic organism to be included in the European Environmental Specimen Banks in order to establish a real-time environmental monitoring network under the European Water Framework Directives. PMID- 24816594 TI - Implementation of water safety plan for a large-piped water supply system. AB - A water safety plan for the city of Nagpur was developed by the National Environmental Engineering Research Institute (NEERI) and Nagpur Municipal Corporation (NMC). Possible hazards were identified through field visits. Based on this, an improvement plan was drawn up to suggest corrective actions and a time frame for implementation. The findings of this study are being used to modify or repair components of the water supply system and upgrade management procedures. This paper highlights the lessons learnt during implementation of the WSP and the key challenges faced. PMID- 24816593 TI - A landscape-based reconnaissance survey of estrogenic activity in streams of the upper Potomac, upper James, and Shenandoah Rivers, USA. AB - Endocrine-disrupting compounds (EDCs) are becoming of increasing concern in waterways of the USA and worldwide. What remains poorly understood, however, is how prevalent these emerging contaminants are in the environment and what methods are best able to determine landscape sources of EDCs. We describe the development of a spatially structured sampling design and a reconnaissance survey of estrogenic activity along gradients of land use within sub-watersheds. We present this example as a useful approach for state and federal agencies with an interest in identifying locations potentially impacted by EDCs that warrant more intensive, focused research. Our study confirms the importance of agricultural activities on levels of a measured estrogenic equivalent (E2Eq) and also highlights the importance of other potential sources of E2Eq in areas where intensive agriculture is not the dominant land use. Through application of readily available geographic information system (GIS) data, coupled with spatial statistical analysis, we demonstrate the correlation of specific land use types to levels of estrogenic activity across a large area in a consistent and unbiased manner. PMID- 24816595 TI - Glutaredoxin1 protects neuronal cells from copper-induced toxicity. AB - Glutaredoxin1 (GRX1) is a glutathione (GSH)-dependent thiol oxidoreductase. The GRX1/GSH system is important for the protection of proteins from oxidative damage and in the regulation of protein function. Previously we demonstrated that GRX1/GSH regulates the activity of the essential copper-transporting P1B-Type ATPases (ATP7A, ATP7B) in a copper-responsive manner. It has also been established that GRX1 binds copper with high affinity and regulates the redox chemistry of the metallochaperone ATOX1, which delivers copper to the copper ATPases. In this study, to further define the role of GRX1 in copper homeostasis, we examined the effects of manipulating GRX1 expression on copper homeostasis and cell survival in mouse embryonic fibroblasts and in human neuroblastoma cells (SH SY5Y). GRX1 knockout led to cellular copper retention (especially when cultured with elevated copper) and reduced copper tolerance, while in GRX1-overexpressing cells challenged with elevated copper, there was a reduction in both intracellular copper levels and copper-induced reactive oxygen species, coupled with enhanced cell proliferation. These effects are consistent with a role for GRX1 in regulating ATP7A-mediated copper export, and further support a new function for GRX1 in neuronal copper homeostasis and in protection from copper mediated oxidative injury. PMID- 24816596 TI - Biological characteristics and gene expression pattern of bone marrow mesenchymal stem cells in patients with psoriasis. AB - Mesenchymal stem cells (MSCs) have immunoregulatory and proangiogenic effects and are suggested to be involved in the pathological processes of immune-related diseases, including psoriasis. Biological characteristics of bone marrow MSCs (BMSCs) from patients with autoimmune diseases, such as systemic lupus erythematosus or rheumatoid arthritis, but not psoriasis, have been characterized. We compared the gene expression profile and biological characteristics of BMSCs from patients with psoriasis and healthy controls. Although the phenotype, differentiation potential and ability to support CD34(+) cell proliferation were similar to those of normal BMSCs, psoriatic BMSCs showed aberrant proliferative activity, increased apoptosis rate and a characteristic gene expression profile. These aberrations may develop after the abnormal immune response in psoriasis and result in BMSC dysfunction. The functionally deficient BMSCs may then fail to suppress overactive immune cells, thereby contributing to the pathogenesis of psoriasis. PMID- 24816597 TI - Trastuzumab (herceptin): a retrospective analysis of the effects of long-term application in a series of patients with breast cancer. AB - INTRODUCTION: About 20 % of all mamma carcinomas are HER2 positive. The overexpression of HER2 is considered to be a negative prognostic factor. Trastuzumab is a monoclonal anti-HER2 antibody developed to target HER2 overexpressing tumor cells. So far, there is only little data available on long term effects of trastuzumab. This is why we analyzed the medical records of our patient collective with respect to tolerability and oncological outcomes of long term trastuzumab treatment. MATERIALS AND METHODS: Our retrospective observational study included all patients of the Saarland University Hospital with breast cancer who received trastuzumab for more than 18 months between 2003 and 2012. We analyzed the medical records with respect to oncological outcome, tolerability and cardiac side effects. RESULTS: A total of n = 15 patients had been treated with trastuzumab for over 18 months with a mean therapy duration of 57.2 months (range 18-119 months). The mean follow-up time was 113.5 months (range 50-240 months). Three of the patients had a treatment interruption for an average of 2.6 months (range 3-5), which was not due to side effects. The left ventricular ejection fraction (LVEF) was controlled at regular intervals in all of the patients. Upon the beginning of the trastuzumab treatment, the mean LVEF was 68 %. In one patient, the trastuzumab treatment was discontinued after 41 months because of a decrease of the LVEF below normal levels. CONCLUSION: Trastuzumab is well tolerated even during long-term use. Patients with HER2 overexpression and metastases can be treated well with trastuzumab for up to 119 months. PMID- 24816598 TI - Hemostatic gelatine-thrombin matrix (Floseal(r)) facilitates hemostasis and organ preservation in laparoscopic treatment of tubal pregnancy. AB - PURPOSE: Laparoscopic salpingotomy has become the gold standard for the treatment of tubal ectopic pregnancy (TEP). Limitations for organ preservation in TEP can result from intra-operative bleeding or potential tubal damage due to application of thermal coagulation. Hemostatic gelatine-thrombin matrix Floseal(r) allows effective local hemostasis when sutures or thermal coagulation are inadequate or impossible. METHODS: We demonstrate in two cases how tubal preservation following effective hemostasis can be achieved by local application of gelatine-thrombin matrix. RESULTS: In both cases, the ectopic pregnancy was localized in the ampullar part of the right tube, with gestational sac diameter of 38 and 15 mm, respectively, and visible embryos of 25 and 6.5 mm, respectively. After laparoscopic salpingotomy and evacuation of TEP, diffuse bleeding from the implantation site at the tubal wall was treated with the hemostatic matrix. Punctual bipolar coagulation was used only in Case 1 for striking bleeding from incision margins. Both patients were discharged without complications within 24 48 h after operation. CONCLUSIONS: Hemostatic gelatine-thrombin matrix Floseal(r) minimizes tissue damage and optimizes local hemostasis. The use of Floseal(r) enhances the chance of organ preservation in the laparoscopic treatment of TEP. PMID- 24816600 TI - How many initiator tRNA genes does Escherichia coli need? AB - Multiple copies of a gene require enhanced investment on the part of the cell and, as such, call for an explanation. The observation that Escherichia coli has four copies of initiator tRNA (tRNAi) genes, encoding a special tRNA (tRNA(fMet)) required to start protein synthesis, is puzzling particularly because the cell appears to be unaffected by the removal of one copy. However, the fitness of an organism has both absolute and relative connotations. Thus, we carried out growth competition experiments between E. coli strains that differ in the number of tRNAi genes they contain. This has enabled us to uncover an unexpected link between the number of tRNAi genes and protein synthesis, nutritional status, and fitness. Wild-type strains with the canonical four tRNAi genes are favored in nutrient-rich environments, and those carrying fewer are favored in nutrient-poor environments. Auxotrophs behave as if they have a nutritionally poor internal environment. A heuristic model that links tRNAi gene copy number, genetic stress, and growth rate accounts for the findings. Our observations provide strong evidence that natural selection can work through seemingly minor quantitative variations in gene copy number and thereby impact organismal fitness. PMID- 24816599 TI - Traumatic event exposure and depression severity over time: results from a prospective cohort study in an urban area. AB - PURPOSE: A substantial proportion of adults experience traumatic events each year, yet little is known about the effects of different types of traumatic events on depression severity over time. We prospectively assessed the effects of traumatic event exposure during a 1-year period on changes in depression severity during that period among a representative sample of adults living in Detroit, Michigan in the United States. METHODS: We used data from 1,054 participants in the first two waves of the Detroit Neighborhood Health Study (2008-2010). Depression severity was measured with the Patient Health Questionnaire-9 (PHQ-9). Negative binomial regression was used to estimate the effect of traumatic event exposure on depression severity at Wave 2, adjusting for Wave 1 PHQ-9 score and potential confounders. RESULTS: The mean depression severity score at Wave 2 among those exposed to at least one traumatic event during follow-up was 1.71 times higher than among those with no traumatic event exposure [95 % confidence interval (CI) 1.27-2.29]. Also positively associated with depression severity at Wave 2 (vs. no traumatic events) were assaultive violence (mean ratio 2.49, 95 % CI 1.41-4.38), injuries and other directly experienced shocking events (mean ratio 2.59, 95 % CI 1.62-3.82), and three or more traumatic events (mean ratio 2.58, 95 % CI 1.62-4.09). CONCLUSIONS: Violence, injuries, and other directly experienced traumatic events increase depression severity and may be useful targets for interventions to alleviate the burden of depression in urban areas. PMID- 24816601 TI - Identification and characterization of glycoproteins on the spore surface of Clostridium difficile. AB - In this study, we identify a major spore surface protein, BclA, and provide evidence that this protein is glycosylated. Following extraction of the spore surface, solubilized proteins were separated by one-dimensional PAGE and stained with glycostain to reveal a reactive high-molecular-mass region of approximately 600 kDa. Tandem mass spectrometry analysis of in-gel digests showed this band to contain peptides corresponding to a putative exosporangial glycoprotein (BclA3) and identified a number of glycopeptides modified with multiple N-acetyl hexosamine moieties and, in some cases, capped with novel glycans. In addition, we demonstrate that the glycosyltransferase gene sgtA (gene CD3350 in strain 630 and CDR3194 in strain R20291), which is located immediately upstream of the bclA3 homolog, is involved in the glycosylation of the spore surface, and is cotranscribed with bclA3. The presence of anti-beta-O-GlcNAc-reactive material was demonstrated on the surface of spores by immunofluorescence and in surface extracts by Western blotting, although each strain produced a distinct pattern of reactivity. Reactivity of the spore surface with the anti-beta-O-GlcNAc antibody was abolished in the 630 and R20291 glycosyltransferase mutant strains, while complementation with a wild-type copy of the gene restored the beta-O-GlcNAc reactivity. Phenotypic testing of R20291 glycosyltransferase mutant spores revealed no significant change in sensitivity to ethanol or lysozyme. However, a change in the resistance to heat of R20291 glycosyltransferase mutant spores compared to R20291 spores was observed, as was the ability to adhere to and be internalized by macrophages. PMID- 24816602 TI - HupB, a nucleoid-associated protein of Mycobacterium tuberculosis, is modified by serine/threonine protein kinases in vivo. AB - HU, a widely conserved bacterial histone-like protein, regulates many genes, including those involved in stress response and virulence. Whereas ample data are available on HU-DNA communication, the knowledge on how HU perceives a signal and transmit it to DNA remains limited. In this study, we identify HupB, the HU homolog of the human pathogen Mycobacterium tuberculosis, as a component of serine/threonine protein kinase (STPK) signaling. HupB is extracted in its native state from the exponentially growing cells of M. tuberculosis H37Ra and is shown to be phosphorylated on both serine and threonine residues. The STPKs capable of modifying HupB are determined in vitro and the residues modified by the STPKs are identified for both in vivo and the in vitro proteins through mass spectrometry. Of the identified phosphosites, Thr(65) and Thr(74) in the DNA-embracing beta strand of the N-terminal domain of HupB (N-HupB) are shown to be crucial for its interaction with DNA. In addition, Arg(55) is also identified as an important residue for N-HupB-DNA interaction. N-HupB is shown to have a diminished interaction with DNA after phosphorylation. Furthermore, hupB is shown to be maximally expressed during the stationary phase in M. tuberculosis H37Ra, while HupB kinases were found to be constitutively expressed (PknE and PknF) or most abundant during the exponential phase (PknB). In conclusion, HupB, a DNA-binding protein, with an ability to modulate chromatin structure is proposed to work in a growth-phase-dependent manner through its phosphorylation carried out by the mycobacterial STPKs. PMID- 24816604 TI - Tolerance of a phage element by Streptococcus pneumoniae leads to a fitness defect during colonization. AB - The pathogenesis of the disease caused by Streptococcus pneumoniae begins with colonization of the upper respiratory tract. Temperate phages have been identified in the genomes of up to 70% of clinical isolates. How these phages affect the bacterial host during colonization is unknown. Here, we examined a clinical isolate that carries a novel prophage element, designated Spn1, which was detected in both integrated and episomal forms. Surprisingly, both lytic and lysogenic Spn1 genes were expressed under routine growth conditions. Using a mouse model of asymptomatic colonization, we demonstrate that the Spn1(-) strain outcompeted the Spn1(+) strain >70-fold. To determine if Spn1 causes a fitness defect through a trans-acting factor, we constructed an Spn1(+) mutant that does not become an episome or express phage genes. This mutant competed equally with the Spn1(-) strain, indicating that expression of phage genes or phage lytic activity is required to confer this fitness defect. In vitro, we demonstrate that the presence of Spn1 correlated with a defect in LytA-mediated autolysis. Furthermore, the Spn1(+) strain displayed increased chain length and resistance to lysis by penicillin compared to the Spn(-) strain, indicating that Spn1 alters the cell wall physiology of its host strain. We posit that these changes in cell wall physiology allow for tolerance of phage gene products and are responsible for the relative defect of the Spn1(+) strain during colonization. This study provides new insight into how bacteria and prophages interact and affect bacterial fitness in vivo. PMID- 24816603 TI - Acinetobacter baumannii response to host-mediated zinc limitation requires the transcriptional regulator Zur. AB - Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia in intensive care units, and the increasing rates of antibiotic resistance make treating these infections challenging. Consequently, there is an urgent need to develop new antimicrobials to treat A. baumannii infections. One potential therapeutic option is to target bacterial systems involved in maintaining appropriate metal homeostasis, processes that are critical for the growth of pathogens within the host. The A. baumannii inner membrane zinc transporter ZnuABC is required for growth under low-zinc conditions and for A. baumannii pathogenesis. The expression of znuABC is regulated by the transcriptional repressor Zur. To investigate the role of Zur during the A. baumannii response to zinc limitation, a zur deletion mutant was generated, and transcriptional changes were analyzed using RNA sequencing. A number of Zur-regulated genes were identified that exhibit increased expression both when zur is absent and under low-zinc conditions, and Zur binds to predicted Zur box sequences of several genes affected by zinc levels or the zur mutation. Furthermore, the zur mutant is impaired for growth in the presence of both high and low zinc levels compared to wild-type A. baumannii. Finally, the zur mutant exhibits a defect in dissemination in a mouse model of A. baumannii pneumonia, establishing zinc sensing as a critical process during A. baumannii infection. These results define Zur-regulated genes within A. baumannii and demonstrate a requirement for Zur in the A. baumannii response to the various zinc levels experienced within the vertebrate host. PMID- 24816605 TI - Genetic dissection of the mamAB and mms6 operons reveals a gene set essential for magnetosome biogenesis in Magnetospirillum gryphiswaldense. AB - Biosynthesis of bacterial magnetosomes, which are intracellular membrane enclosed, nanosized magnetic crystals, is controlled by a set of >30 specific genes. In Magnetospirillum gryphiswaldense, these are clustered mostly within a large conserved genomic magnetosome island (MAI) comprising the mms6, mamGFDC, mamAB, and mamXY operons. Here, we demonstrate that the five previously uncharacterized genes of the mms6 operon have crucial functions in the regulation of magnetosome biomineralization that partially overlap MamF and other proteins encoded by the adjacent mamGFDC operon. While all other deletions resulted in size reduction, elimination of either mms36 or mms48 caused the synthesis of magnetite crystals larger than those in the wild type (WT). Whereas the mms6 operon encodes accessory factors for crystal maturation, the large mamAB operon contains several essential and nonessential genes involved in various other steps of magnetosome biosynthesis, as shown by single deletions of all mamAB genes. While single deletions of mamL, -P, -Q, -R, -B, -S, -T, and -U showed phenotypes similar to those of their orthologs in a previous study in the related M. magneticum, we found mamI and mamN to be not required for at least rudimentary iron biomineralization in M. gryphiswaldense. Thus, only mamE, -L, -M, -O, -Q, and -B were essential for formation of magnetite, whereas a mamI mutant still biomineralized tiny particles which, however, consisted of the nonmagnetic iron oxide hematite, as shown by high-resolution transmission electron microscopy (HRTEM) and the X-ray absorption near-edge structure (XANES). Based on this and previous studies, we propose an extended model for magnetosome biosynthesis in M. gryphiswaldense. PMID- 24816606 TI - PvdP is a tyrosinase that drives maturation of the pyoverdine chromophore in Pseudomonas aeruginosa. AB - The iron binding siderophore pyoverdine constitutes a major adaptive factor contributing to both virulence and survival in fluorescent pseudomonads. For decades, pyoverdine production has allowed the identification and classification of fluorescent and nonfluorescent pseudomonads. Here, we demonstrate that PvdP, a periplasmic enzyme of previously unknown function, is a tyrosinase required for the maturation of the pyoverdine chromophore in Pseudomonas aeruginosa. PvdP converts the nonfluorescent ferribactin, containing two iron binding groups, into a fluorescent pyoverdine, forming a strong hexadentate complex with ferrous iron, by three consecutive oxidation steps. PvdP represents the first characterized member of a small family of tyrosinases present in fluorescent pseudomonads that are required for siderophore maturation and are capable of acting on large peptidic substrates. PMID- 24816607 TI - Alginate-dependent gene expression mechanism in Sphingomonas sp. strain A1. AB - Sphingomonas sp. strain A1, a Gram-negative bacterium, directly incorporates alginate polysaccharide into the cytoplasm through a periplasmic alginate-binding protein-dependent ATP-binding cassette transporter. The polysaccharide is degraded to monosaccharides via the formation of oligosaccharides by endo- and exotype alginate lyases. The strain A1 proteins for alginate uptake and degradation are encoded in both strands of a genetic cluster in the bacterial genome and inducibly expressed in the presence of alginate. Here we show the function of the alginate-dependent transcription factor AlgO and its mode of action on the genetic cluster and alginate oligosaccharides. A putative gene within the genetic cluster seems to encode a transcription factor-like protein (AlgO). Mutant strain A1 (DeltaAlgO mutant) cells with a disrupted algO gene constitutively produced alginate-related proteins. DNA microarray analysis indicated that wild-type cells inducibly transcribed the genetic cluster only in the presence of alginate, while DeltaAlgO mutant cells constitutively expressed the genetic cluster. A gel mobility shift assay showed that AlgO binds to the specific intergenic region between algO and algS (algO-algS). Binding of AlgO to the algO-algS intergenic region diminished with increasing alginate oligosaccharides. These results demonstrated a novel alginate-dependent gene expression mechanism. In the absence of alginate, AlgO binds to the algO-algS intergenic region and represses the expression of both strands of the genetic cluster, while in the presence of alginate, AlgO dissociates from the algO-algS intergenic region via binding to alginate oligosaccharides produced through the lyase reaction and subsequently initiates transcription of the genetic cluster. This is the first report on the mechanism by which alginate regulates the expression of the gene cluster. PMID- 24816608 TI - The Rip1 protease of Mycobacterium tuberculosis controls the SigD regulon. AB - Regulated intramembrane proteolysis of membrane-embedded substrates by site-2 proteases (S2Ps) is a widespread mechanism of transmembrane signal transduction in bacteria and bacterial pathogens. We previously demonstrated that the Mycobacterium tuberculosis S2P Rip1 is required for full virulence in the mouse model of infection. Rip1 controls transcription in part through proteolysis of three transmembrane anti-sigma factors, anti-SigK, -L, and -M, but there are also Rip1-dependent, SigKLM-independent pathways. To determine the contribution of the sigma factors K, L, and M to the Deltarip1 attenuation phenotype, we constructed an M. tuberculosis DeltasigKDelta sigL DeltasigM mutant and found that this strain fails to recapitulate the marked attenuation of Deltarip1 in mice. In a search for additional pathways controlled by Rip1, we demonstrated that the SigD regulon is positively regulated by the Rip1 pathway. Rip1 cleavage of transmembrane anti-SigD is required for expression of SigD target genes. In the absence of Rip1, proteolytic maturation of RsdA is impaired. These findings identify RsdA/SigD as a fourth arm of the branched pathway controlled by Rip1 in M. tuberculosis. PMID- 24816609 TI - Non-invasive positive pressure ventilation to facilitate the post-operative respiratory outcome of spine surgery in neuromuscular children. AB - PURPOSE: Scoliosis surgery may be associated with a high morbidity and even mortality in children with non-idiopathic scoliosis. The aim of the study was to report our experience with a pre-operative training to non-invasive positive pressure ventilation (NPPV) and a mechanical insufflator-exsufflator (MI-E) device to improve the post-operative respiratory outcome of children scheduled for scoliosis surgery. METHODS: Consecutive patients with non-idiopathic scoliosis undergoing posterior arthrodesis were trained to NPPV and MI-E before intervention. NPPV and MI-E were performed immediately after extubation. Length of intubation and intensive care unit (ICU) stay, duration of NPPV, and respiratory complications were assessed. RESULTS: Thirteen patients participated in the training (mean age 13.9 +/- 2.6, mean vital capacity 52.3 +/- 15.4% predicted). The patients had severe respiratory muscle weakness with a mean sniff oesophageal pressure of 35.8 +/- 14.2 cmH2O (50% predicted) and a mean gastric pressure during a cough of 31.9 +/- 7.8 cmH2O (30% predicted). The mean length of intubation was 19.9 +/- 12.3 h with a mean length of ICU stay of 2.5 +/- 2.5 days. NPPV was used during a mean of 2.7 +/- 1.9 days after surgery. No respiratory complication was observed. One patient died 3 months after surgery from multi-organ failure of non-respiratory origin. CONCLUSIONS: No respiratory complications were observed after scoliosis correction surgery in children with non-idiopathic scoliosis after pre-operative training and post-operative use of NPPV and MI-E, underlying the interest of this management in these high-risk patients. PMID- 24816610 TI - Circumferential fusion using a custom-made screw in the management of high-grade spondylolisthesis. AB - PURPOSE: Management of high-grade spondylolisthesis is challenging and to date no therapeutic consensus is available. Various surgical procedures have been described using unique or double approach. The aim of the study is to describe an original technique using a posterior-only approach to achieve a circumferential lumbosacral fusion with a custom-made screw. METHODS: In our experience, eight patients (mean age 15 years old) were treated for grade III or IV slipping without instrumental reduction. Surgical technique included a laminectomy from L5 to S2, then after mobilization of neural elements a guide wire was inserted from the posterior side of S2 to the antero-superior corner of L5. A specific drill was used and the 10-mm screw was then inserted under fluoroscopic guidance. Further steps included a discectomy, lumbosacral interbody graft and posterolateral graft to obtain a circumferential fusion. Clinical and radiological evaluations were obtained. RESULTS: On the whole series, solid fusion was achieved after 6 months on average. Sagittal realignment was observed with a regression of pelvic retroversion and hip flessum, a lumbarization of the lumbar lordosis and an improvement of the thoracic kyphosis. For one patient, a postoperative S1 deficit was observed. CONCLUSION: This technique provides satisfactory results in the management of high-grade spondylolisthesis. This concept is based on a double spine instability considering viscoelastic properties of the disc and postoperative sagittal reciprocal changes as prerequisite. This posterior-only approach represents a valuable alternative to other procedures. PMID- 24816611 TI - A randomized controlled trial of a multiple health behavior change intervention delivered to colorectal cancer survivors: effects on sedentary behavior. AB - BACKGROUND: Sedentary behavior may independently contribute to morbidity and mortality among survivors of colorectal cancer. In the current study, the authors assessed whether a telephone-delivered multiple health behavior change intervention had an effect on the sedentary behavior of recently diagnosed colorectal cancer survivors. METHODS: A total of 410 participants were recruited through the Queensland Cancer Registry and randomized to the health coaching (intervention) or usual-care (control) group. Eleven health coaching sessions addressing multiple health behaviors, including sedentary behavior, were delivered over a period of 6 months. Data were collected at baseline (before randomization), at 6 months, and at 12 months via a telephone interview. RESULTS: At 12 months, there was a significant decrease noted in the hours per day of sedentary time in both the health coaching (-1.21; 95% confidence interval [95% CI], -1.71 to -0.70) and usual-care groups (-0.55; 95% CI, -1.06 to -0.05), but the between-group difference was not found to be statistically significant ( 0.65; 95% CI, -1.37 to 0.06 [P = .07]). In stratified subgroup analyses, the multiple health behavior change intervention was found to have a significant effect on total sedentary time (hours/day) at 12 months in survivors of colorectal cancer who were aged > 60 years (-0.90; 95% CI, -1.80 to -0.01 [P = .05]), male (-1.33; 95% CI, -2.44 to -0.21 [P = .02]), and nonobese (-1.10; 95% CI, -1.96 to -0.25; [P = .01]). CONCLUSIONS: Incorporating simple messages about limiting sedentary behaviors into a multiple health behavior change intervention was found to have modest effects on sedentary behavior. A sedentary behavior specific intervention strategy may be required to achieve substantial changes in sedentary behavior among colorectal cancer survivors. PMID- 24816612 TI - Cell cycle dynamics: clustering is universal in negative feedback systems. AB - We study a model of cell cycle ensemble dynamics with cell-cell feedback in which cells in one fixed phase of the cycle S (Signaling) produce chemical agents that affect the growth and development rate of cells that are in another phase R (Responsive). For this type of system there are special periodic solutions that we call k-cyclic or clustered. Biologically, a k-cyclic solution represents k cohorts of synchronized cells spaced nearly evenly around the cell cycle. We show, under very general nonlinear feedback, that for a fixed k the stability of the k-cyclic solutions can be characterized completely in parameter space, a 2 dimensional triangle T. We show that T is naturally partitioned into k(2) sub triangles on each of which the k-cyclic solutions all have the same stability type. For negative feedback we observe that while the synchronous solution (k = 1) is unstable, regions of stability of k >= 2 clustered solutions seem to occupy all of T. We also observe bi-stability or multi-stability for many parameter values in negative feedback systems. Thus in systems with negative feedback we should expect to observe cyclic solutions for some k. This is in contrast to the case of positive feedback, where we observe that the only asymptotically stable periodic orbit is the synchronous solution. PMID- 24816613 TI - LC-MS/MS determination of cinacalcet enantiomers in rat plasma on Chirobiotic V column in polar ionic mode: application to a pharmacokinetic study. AB - A simple and selective polar ionic liquid chromatography-tandem mass spectrometric method for separation and determination of cinacalcet enantiomers in rat plasma was developed and validated. The chromatographic separation was accomplished on a Chirobiotic V column packed with vancomycin as a chiral stationary phase using 2.5 mm ammonium formate in 100% methanol as a mobile phase in an isocratic mode of elution at a flow rate of 1.0 mL/min. The analytes were extracted from rat plasma by precipitating the proteins with acetonitrile. The developed method exhibited a linear dynamic range over 0.5-500 ng/mL in rat plasma for both enantiomers. The method was successfully applied to study the pharmacokinetics after a single dose by oral administration of 10 mg/kg of cinacalcet enantiomers to healthy male Wistar rats. PMID- 24816614 TI - Service-oriented medical system for supporting decisions with missing and imbalanced data. AB - In this paper, we propose a service-oriented support decision system (SOSDS) for diagnostic problems that is insensitive to the problems of the imbalanced data and missing values of the attributes, which are widely observed in the medical domain. The system is composed of distributed Web services, which implement machine-learning solutions dedicated to constructing the decision models directly from the datasets impaired by the high percentage of missing values of the attributes and imbalanced class distribution. The issue of the imbalanced data is solved by the application of a cost-sensitive support vector machine and the problem of missing values of attributes is handled by proposing the novel ensemble-based approach that splits the incomplete data space into complete subspaces that are further used to construct base learners. We evaluate the quality of the SOSDS components using three ontological datasets. PMID- 24816615 TI - Aerial obstacle detection with 3-D mobile devices. AB - In this paper, we present a novel approach for aerial obstacle detection (e.g., branches or awnings) using a 3-D smartphone in the context of the visually impaired (VI) people assistance. This kind of obstacles are especially challenging because they cannot be detected by the walking stick or the guide dog.The algorithm captures the 3-D data of the scene through stereo vision. To our knowledge, this is the first work that presents a technology able to obtain real 3-D measures with smartphones in real time. The orientation sensors of the device (magnetometer and accelerometer) are used to approximate the walking direction of the user, in order to look for the obstacles only in such a direction. The obtained 3-D data are compressed and then linearized for detecting the potential obstacles. Potential obstacles are tracked in order to accumulate enough evidence to alert the user only when a real obstacle is found.In the experimental section, we show the results of the algorithm in several situations using real data and helped by VI users. PMID- 24816616 TI - Carbon monoxide may be an important molecule in migraine and other headaches. AB - INTRODUCTION: Carbon monoxide was previously considered to just be a toxic gas. A wealth of recent information has, however, shown that it is also an important endogenously produced signalling molecule involved in multiple biological processes. Endogenously produced carbon monoxide may thus play an important role in nociceptive processing and in regulation of cerebral arterial tone. DISCUSSION: Carbon monoxide-induced headache shares many characteristics with migraine and other headaches. The mechanisms whereby carbon monoxide causes headache may include hypoxia, nitric oxide signalling and activation of cyclic guanosine monophosphate pathways. Here, we review the literature about carbon monoxide-induced headache and its possible mechanisms. CONCLUSION: We suggest, for the first time, that carbon monoxide may play an important role in the mechanisms of migraine and other headaches. PMID- 24816617 TI - Sorption characteristics and mechanisms of Pb(II) from aqueous solution by using bioflocculant MBFR10543. AB - This paper focuses on the effectiveness of removing Pb(II) from aqueous solution using bioflocculant MBFR10543 and a series of experimental parameters including MBFR10543 dose, calcium ions concentration, solution pH, and temperature on Pb(II) uptake was evaluated. Meanwhile, the flocculation mechanism of MBFR10543 was discussed. Results have demonstrated that the removal efficiency of Pb(II) reached 94.7 % (with the sorption capacity of 81.2 mg . g(-1)) by adding MBFR10543 in two stages, separately, 3 * 10(-2) % (w/w) in the 1.0 min's rapid mixing (180 rpm) and 4 * 10(-2) % (w/w) after 2.0 min's slow mixing (80 rpm) with pH value fixed at 6. Pb(II) flocculation process could be described by the Langmuir isotherms model and pseudo-second-order kinetic model. The negative Gibbs free energy change indicated the spontaneous nature of the flocculation. Fourier transform infrared spectra analysis indicated that functional groups, such as -OH, C=O, and C-N, were existed in MBFR10543 molecular chains, which had strong capacity for removing Pb(II). Furthermore, both charge neutralization and bridging being the main mechanisms involved in Pb(II) removal by MBFR10543. PMID- 24816618 TI - Microalgal symbiosis in biotechnology. AB - This review provides an analysis of recent published work on interactions between microorganisms, especially the ones involving mainly nutrient exchanges and at least with one microalga species. Examples of microbial partners are given, with a remark to the potential application of cultures of an autotroph and a heterotroph, which grow simultaneously, taking advantage of the complementary metabolisms. These are particularly interesting, either due to economic or sustainable aspects, and some applications have already reached the commercial stage of development. The added advantages of these symbiotic cultures are biomass, lipid, and other products productivity enhancement a better utilization of resources and the reduction or even elimination of process residues (including carbon dioxide and other greenhouse gases) to conduct an increasingly greener biotechnology. Among the several symbiotic partners referred, the microalgae and yeast cultures are the most used. The interaction between these two microorganisms shows how to enhance the lipid production for biodiesel purposes compared with separated (stand-alone) cultures. PMID- 24816619 TI - Succinic acid-producing biofilms of Actinobacillus succinogenes: reproducibility, stability and productivity. AB - Continuous anaerobic fermentations were performed in a biofilm reactor packed with Poraver(r) beads. Dilution rates (D) varied between 0.054 and 0.72 h(-1), and D-glucose and CO2 gas were used as carbon substrates. Steady-state conditions were shown to be repeatable and independent of the operational history. Production stability was achieved over periods exceeding 80 h at values of D below 0.32 h(-1). In these situations, steady-state variation (expressed as fluctuations in NaOH neutralisation flow rates) exhibited a standard deviation of less than 5 % while no indication of biofilm deactivation was detected. The total biomass amount was found to be independent of the dilution rate with an average dry concentration of 23.8 +/- 2.9 g L(-1) obtained for all runs. This suggests that the attachment area controls the extent of biofilm accumulation. Specific succinic acid (SA) productivities, based on the total biomass amount, exhibited a substantial decrease with decreasing D. An SA volumetric productivity of 10.8 g L(-1) h(-1) was obtained at D = 0.7 h(-1)-the highest value reported to date in Actinobacillus succinogenes fermentations. SA yields on glucose increased with decreasing D, with a yield of 0.90 +/- 0.01 g g(-1) obtained at a D of 0.054 h( 1). Production of formic acid approached zero with decreasing D, while the succinic to acetic acid ratio increased with decreasing D, resulting in an increasing SA yield on glucose. PMID- 24816620 TI - Impact of protein uptake and degradation on recombinant protein secretion in yeast. AB - Protein titers, a key bioprocessing metric, depend both on the synthesis of protein and the degradation of protein. Secreted recombinant protein production in Saccharomyces cerevisiae is an attractive platform as minimal media can be used for cultivation, thus reducing fermentation costs and simplifying downstream purification, compared to other systems that require complex media. As such, engineering S. cerevisiae to improve titers has been then the subject of significant attention, but the majority of previous efforts have been focused on improving protein synthesis. Here, we characterize the protein uptake and degradation pathways of S. cerevisiae to better understand its impact on protein secretion titers. We do find that S. cerevisiae can consume significant (in the range of 1 g/L/day) quantities of whole proteins. Characterizing the physiological state and combining metabolomics and transcriptomics, we identify metabolic and regulatory markers that are consistent with uptake of whole proteins by endocytosis, followed by intracellular degradation and catabolism of substituent amino acids. Uptake and degradation of recombinant protein products may be common in S. cerevisiae protein secretion systems, and the current data should help formulate strategies to mitigate product loss. PMID- 24816621 TI - Application of new metabolic engineering tools for Clostridium acetobutylicum. AB - The renewed interests in clostridial acetone-butanol-ethanol (ABE) fermentation as a next-generation biofuel source led to significantly intensified research in the past few years. This mini-review focuses on the current status of metabolic engineering techniques available for the model organism of ABE fermentation, Clostridium acetobutylicum. A comprehensive survey of various application examples covers two general issues related to both basic and applied research questions: (i) how to improve biofuel production and (ii) what information can be deduced from respective genotype/phenotype manipulations. Recently developed strategies to engineer C. acetobutylicum are summarized including the current portfolio of altered gene expression methodologies, as well as systematic (rational) and explorative (combinatorial) metabolic engineering approaches. PMID- 24816622 TI - Production and applications of engineered viral capsids. AB - As biological agents, viruses come in an astounding range of sizes, with varied shapes and surface morphologies. The structures of viral capsids are generally assemblies of hundreds of copies of one or a few proteins which can be harnessed for use in a wide variety of applications in biotechnology, nanotechnology, and medicine. Despite their complexity, many capsid types form as homogenous populations of precise geometrical assemblies. This is important in both medicine, where well-defined therapeutics are critical for drug performance and federal approval, and nanotechnology, where precise placement affects the properties of the desired material. Here we review the production of viruses and virus-like particles with methods for selecting and manipulating the size, surface chemistry, assembly state, and interior cargo of capsid. We then discuss many of the applications used in research today and the potential commercial and therapeutic products from engineered viral capsids. PMID- 24816623 TI - Structure-based rational design and introduction of arginines on the surface of an alkaline alpha-amylase from Alkalimonas amylolytica for improved thermostability. AB - In this study, the thermostability of an alkaline alpha-amylase from Alkalimonas amylolytica was significantly improved through structure-based rational and the introduction of multiple arginines (Arg) on the protein surface. Based on an analysis of the tertiary structure, seven residues (glutamine (Gln) 166, Gln 169, serine (Ser) 270, lysine (Lys) 315, Gln 327, asparagine (Asn) 346, and Asn 423) were selected as engineering targets and individually replaced with arginine. Five of the seven single-mutated enzymes-S270R, K315R, Q327R, N346R, and N423R showed enhanced thermostability. Multiple arginines were subsequently introduced on the protein surface, and the quintuple-mutated enzyme S270R/K315R/Q327R/N346R/N423R showed a 6.4-fold improvement in half-life at 60 and a 5.4 degrees C increase in melting temperature (T m) compared with those of wild-type enzyme. Concomitantly, the optimal temperature, optimal pH, and catalytic efficiency of this mutated enzyme also improved. The mutated enzyme displayed a large shift in optimal pH from 9.5 to 11.0. In addition, the optimum temperature increased from 50 to 55 degrees C, and the catalytic efficiency (k cat/K m) increased from 1.8 * 10(4) to 3.6 * 10(4) L/(g . min). The intramolecular interactions of mutated enzymes that contributed to increased thermostability were examined through comparative analysis of the model structures of wild-type and mutated enzymes. The thermostable mutated enzymes generated in this study have potential applications in the textile industry. PMID- 24816624 TI - Overall functional gene diversity of microbial communities in three full-scale activated sludge bioreactors. AB - Understanding microbial community composition is thought to be crucial for improving process functioning and stabilities of full-scale activated sludge reactors in wastewater treatment plants (WWTPs). However, functional gene compositions of microbial communities within them have not been clearly elucidated. To gain a complete picture of microbial community, in this study, GeoChip 4.2 was used to profile the overall functional genes of three full-scale activated sludge bioreactors, the 16S rRNA gene diversities of which had been unveiled by 454-pyrosequencing in our previous investigation. Triplicate activated sludge samples from each system were analyzed, with the detection of 38,507 to 40,654 functional genes. A high similarity of 77.3-81.2 % shared functional genes was noted among the nine samples, verified by the high 16S rRNA gene similarity with shared operational taxonomic units (OTUs) constituting 66.4 70.0 % of the detected sequences in each system. Correlation analyses showed that the abundances of a wide array of functional genes were associated with system performances. For example, the abundances of carbon degradation genes were strongly correlated to chemical oxygen demand (COD) removal efficiencies (r = 0.8697, P < 0.01). Lastly, we found that sludge retention time (SRT), influent total nitrogen concentrations (TN inf), and dissolved oxygen (DO) concentrations were key environmental factors shaping the overall functional genes. Together, the results revealed vast functional gene diversity and some links between the functional gene compositions and microbe-mediated processes. PMID- 24816625 TI - Gaze-following behind barriers in domestic dogs. AB - Although gaze-following abilities have been demonstrated in a wide range of species, so far no clear evidence has been available for dogs. In the current study, we examined whether dogs follow human gaze behind an opaque barrier in two different contexts, in a foraging situation and in a non-foraging situation (food involved vs. food not involved in the situation). We assumed that dogs will spontaneously follow the human gaze and that the foraging context will have a positive effect on dogs' gaze-following behaviour by causing an expectation in the dogs that food might be hidden somewhere in the room and might be communicated by the experimenter. This expectation presumably positively affects their motivational and attentional state. Here, we report that dogs show evidence of spontaneous gaze-following behind barriers in both situations. According to our findings, the dogs gazed earlier at the barrier in the indicated direction in both contexts. However, as we expected, the context also has some effect on dogs' gaze-following behaviour, as more dogs gazed behind the barrier in the indicated direction in the foraging situation. The present results also support the idea that gaze-following is a characteristic skill in mammals which may more easily emerge in certain functional contexts. PMID- 24816626 TI - Cognitive inhibition in older high-lethality suicide attempters. AB - BACKGROUND: People who attempt suicide often display cognitive impairments, particularly poor cognitive control. Could poor cognitive control contribute to high suicide rates in old age? A component of cognitive control, cognitive inhibition-active suppression of task-irrelevant processing-is very sensitive to aging and has been linked to attempted suicide. We investigated cognitive inhibition in older high-lethality suicide attempters, closely resembling suicide victims, as well as low-lethality attempters, and control groups with and without depression and suicidal ideation. METHODS: A total of 102 participants aged 60 years and older (17 psychiatrically healthy control subjects, 38 depressed control subjects, 16 suicide ideators, 14 low-lethality suicide attempters, and 17 high-lethality suicide attempters) underwent comprehensive clinical and cognitive assessments. They completed the Delis-Kaplan Executive Function System Color-Word Interference Test, a validated modification of the Stroop test. RESULTS: High-lethality suicide attempters demonstrated a distinct pattern of cognitive inhibition deficits. Compared with psychiatrically healthy control subjects and suicide ideators, high-lethality attempters took longer to complete inhibition trials, even after accounting for potential confounding factors (age, education, Mini mental state examination score, information processing speed, and accuracy). Compared with non-suicidal depressed and healthy control subjects, low lethality suicide attempters committed more uncorrected errors; however, this difference was not specific to the inhibition condition. CONCLUSIONS: Older suicide attempters are a cognitively heterogeneous group. Poor cognitive control in high-lethality attempters may undermine their ability to solve real-life problems, precipitating a catastrophic accumulation of stressors. Meanwhile, low lethality attempters' poor performance may reflect a careless approach to the task or faulty monitoring. PMID- 24816627 TI - A framework for biodynamic feedthrough analysis--part I: theoretical foundations. AB - Biodynamic feedthrough (BDFT) is a complex phenomenon, which has been studied for several decades. However, there is little consensus on how to approach the BDFT problem in terms of definitions, nomenclature, and mathematical descriptions. In this paper, a framework for biodynamic feedthrough analysis is presented. The goal of this framework is two-fold. First, it provides some common ground between the seemingly large range of different approaches existing in the BDFT literature. Second, the framework itself allows for gaining new insights into BDFT phenomena. It will be shown how relevant signals can be obtained from measurement, how different BDFT dynamics can be derived from them, and how these different dynamics are related. Using the framework, BDFT can be dissected into several dynamical relationships, each relevant in understanding BDFT phenomena in more detail. The presentation of the BDFT framework is divided into two parts. This paper, Part I, addresses the theoretical foundations of the framework. Part II, which is also published in this issue, addresses the validation of the framework. The work is presented in two separate papers to allow for a detailed discussion of both the framework's theoretical background and its validation. PMID- 24816628 TI - Resilient monitoring systems: architecture, design, and application to boiler/turbine plant. AB - Resilient monitoring systems, considered in this paper, are sensor networks that degrade gracefully under malicious attacks on their sensors, causing them to project misleading information. The goal of this paper is to design, analyze, and evaluate the performance of a resilient monitoring system intended to monitor plant conditions (normal or anomalous). The architecture developed consists of four layers: data quality assessment, process variable assessment, plant condition assessment, and sensor network adaptation. Each of these layers is analyzed by either analytical or numerical tools. The performance of the overall system is evaluated using a simplified boiler/turbine plant. The measure of resiliency is quantified based on the Kullback-Leibler divergence and shown to be sufficiently high in all scenarios considered. PMID- 24816629 TI - Projected gradients for subclass discriminant nonnegative subspace learning. AB - Current discriminant nonnegative matrix factorization (NMF) methods either do not guarantee convergence to a stationary limit point or assume a compact data distribution inside classes, thus ignoring intra class variance in extracting discriminant data samples representations. To address both limitations, we regard that data inside each class has a multimodal distribution, forming various subclasses and perform optimization using a projected gradients framework to ensure limit point stationarity. The proposed method combines appropriate clustering-based discriminant criteria in the NMF decomposition cost function, in order to find discriminant projections that enhance class separability in the reduced dimensional projection space, thus improving classification performance. The developed algorithms have been applied to facial expression, face and object recognition, and experimental results verified that they successfully identified discriminant parts, thus enhancing recognition performance. PMID- 24816630 TI - Optimal classification by mixed-initiative nested thresholding. AB - We propose a novel architecture for a team of machine and human classifiers (i.e., a mixed-initiative team). We adopt a model of performance that is workload dependent for the human and workload-independent for the machine. The team is structured in a nested architecture that exploits a primary trichotomous classifier (returning true, false, or unknown) with workload-independent performance that turns over the data classified as unknown to a secondary dichotomous classifier (returning true or false) with workload-dependent performance. The novel classifier architecture outperforms other classifiers, such as a single dichotomous classifier or a simple nested two-classifier team. PMID- 24816631 TI - ASMiGA: an archive-based steady-state micro genetic algorithm. AB - We propose a new archive-based steady-state micro genetic algorithm (ASMiGA). In this context, a new archive maintenance strategy is proposed, which maintains a set of nondominated solutions in the archive unless the archive size falls below a minimum allowable size. It makes the archive size adaptive and dynamic. We have proposed a new environmental selection strategy and a new mating selection strategy. The environmental selection strategy reduces the exploration in less probable objective spaces. The mating selection increases searching in more probable search regions by enhancing the exploitation of existing solutions. A new crossover strategy DE-3 is proposed here. ASMiGA is compared with five well known multiobjective optimization algorithms of different types-generational evolutionary algorithms (SPEA2 and NSGA-II), archive-based hybrid scatter search, decomposition-based evolutionary approach, and archive-based micro genetic algorithm. For comparison purposes, four performance measures (HV, GD, IGD, and GS) are used on 33 test problems, of which seven problems are constrained. The proposed algorithm outperforms the other five algorithms. PMID- 24816632 TI - An incremental and distributed inference method for large-scale ontologies based on MapReduce paradigm. AB - With the upcoming data deluge of semantic data, the fast growth of ontology bases has brought significant challenges in performing efficient and scalable reasoning. Traditional centralized reasoning methods are not sufficient to process large ontologies. Distributed reasoning methods are thus required to improve the scalability and performance of inferences. This paper proposes an incremental and distributed inference method for large-scale ontologies by using MapReduce, which realizes high-performance reasoning and runtime searching, especially for incremental knowledge base. By constructing transfer inference forest and effective assertional triples, the storage is largely reduced and the reasoning process is simplified and accelerated. Finally, a prototype system is implemented on a Hadoop framework and the experimental results validate the usability and effectiveness of the proposed approach. PMID- 24816633 TI - A cross-sectional analysis of otitis media with effusion in children with Down syndrome. AB - Children with Down syndrome are at risk to develop otitis media with effusion (OME). We performed a retrospective and cross-sectional analysis to evaluate the prevalence of OME in children with Down syndrome (DS) for consecutive age categories between 6 months and 12 years. Clinical and audiometric data were available for 107 children followed in a multidisciplinary Down team. A high prevalence of OME was found at the age of 1 year (66.7 %), with a second peak prevalence of 60 % at 6-7 years. A declining trend was observed in children >=8 years. Overall, 52.3 % of DS children had either OME or ventilation tubes at the time of evaluation. Hearing thresholds were significantly higher in children with bilateral OME (median 36.7 decibel hearing level (dB HL), range 26.7-46.1) compared to those with at least one normally ventilated middle ear (median 28.3 dB HL, range 22.8-3.3), p = 0.013. CONCLUSION: We found a high prevalence of OME in children with Down syndrome, with a peak of >=60 % around 1 and 6-7 years. A declining trend is seen in older children. Mild to moderate hearing loss was present in children with bilateral OME. PMID- 24816634 TI - Modification of treatment strategy after FFR measurement: CVIT-DEFER registry. AB - The impact of the fractional flow reserve (FFR) on clinical decision-making remains unclear in daily practice. The CVIT-DEFER registry is a prospective multicenter registry enrolling consecutive patients with angiographically intermediate coronary stenosis for whom FFR measurement is clinically indicated. The treatment strategy determined from angiographic findings alone and the strategy selected after FFR measurement were compared. Data on the treatment strategy were obtained for 3093 subjects. The average age of these subjects was 69.5 +/- 10.2 years and 73.8 % were men. The majority had stable coronary artery disease, including 60.4 % with stable angina pectoris. The treatment strategy based on angiographic findings was medical management in 34.5 %, percutaneous coronary intervention (PCI) in 63.5 %, and coronary artery bypass grafting in 2.1 %. The FFR was <=0.8 in 1566 lesions (42.2 %). After FFR measurement, medical treatment was changed to revascularization in 19.7 %, while PCI was switched to medical treatment in 57.4 % at the lesion level. As a result, reclassification of the treatment strategy at the patient level was done in 39.0 % of the patients. Revascularization was frequently switched to medical treatment after FFR measurement. These findings support the clinical utility of employing FFR data to guide selection of PCI. PMID- 24816635 TI - An exploration of computer game-based instruction in the "world history" class in secondary education: a comparative study in China. AB - So far, many studies on educational games have been carried out in America and Europe. Very few related empirical studies, however, have been conducted in China. This study, combining both quantitative with qualitative research methods, possibly compensated for this regret. The study compared data collected from two randomly selected classes (out of 13 classes) under computer game-based instruction (CGBI) and non-computer game-based instruction (NCGBI), respectively, in a senior high school located in Nanjing, Capital of Jiangsu Province, in China. The participants were 103 students, composed of 52 boys and 51 girls (aged 17-18 years old). The following conclusion was reached: (1) participants under CGBI obtained significantly greater learning achievement than those under NCGBI; (2) participants were significantly more motivated by CGBI compared with NCGBI; (3) there were no significant differences in learning achievement between boys and girls; although (4) boys were significantly more motivated by CGBI than girls. Both disadvantages and advantages were discussed, together with directions for future research. PMID- 24816636 TI - Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naive and memory T-cell subsets. AB - BACKGROUND: Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naive CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T cell subsets and CD4+/CD8+ ratio have not been well described. METHODS: A cross sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO CD62L+(naive) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated. RESULTS: We recruited 190 subjects, age 42(36-48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6-10.2) years. Nadir and current CD4+ counts were 200(112-309) and 465(335-607) cells/mm3 respectively. Median CD4+/CD8+ ratio was 0.6(0.4-1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3)% were naive, 36.8(29.0-40.0)% central memory and 27.4(20.0-38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naive, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001. CONCLUSIONS: Study suggests important role for naive CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study. PMID- 24816637 TI - Can Italian healthcare administrative databases be used to compare regions with respect to compliance with standards of care for chronic diseases? AB - BACKGROUND: Italy has a population of 60 million and a universal coverage single payer healthcare system, which mandates collection of healthcare administrative data in a uniform fashion throughout the country. On the other hand, organization of the health system takes place at the regional level, and local initiatives generate natural experiments. This is happening in particular in primary care, due to the need to face the growing burden of chronic diseases. Health services research can compare and evaluate local initiatives on the basis of the common healthcare administrative data.However reliability of such data in this context needs to be assessed, especially when comparing different regions of the country. In this paper we investigated the validity of healthcare administrative databases to compute indicators of compliance with standards of care for diabetes, ischaemic heart disease (IHD) and heart failure (HF). METHODS: We compared indicators estimated from healthcare administrative data collected by Local Health Authorities in five Italian regions with corresponding estimates from clinical data collected by General Practitioners (GPs). Four indicators of diagnostic follow-up (two for diabetes, one for IHD and one for HF) and four indicators of appropriate therapy (two each for IHD and HF) were considered. RESULTS: Agreement between the two data sources was very good, except for indicators of laboratory diagnostic follow-up in one region and for the indicator of bioimaging diagnostic follow-up in all regions, where measurement with administrative data underestimated quality. CONCLUSION: According to evidence presented in this study, estimating compliance with standards of care for diabetes, ischaemic heart disease and heart failure from healthcare databases is likely to produce reliable results, even though completeness of data on diagnostic procedures should be assessed first. Performing studies comparing regions using such indicators as outcomes is a promising development with potential to improve quality governance in the Italian healthcare system. PMID- 24816638 TI - The synergistic in vitro and in vivo antitumor effect of combination therapy with salinomycin and 5-fluorouracil against hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the few cancers in which a continuous increase in incidence has been observed over several years. Drug resistance is a major problem in the treatment of HCC. In the present study, we used salinomycin (Sal) and 5-fluorouracil (5-FU) combination therapy on HCC cell lines Huh7, LM3 and SMMC-7721 and nude mice subcutaneously tumor model to study whether Sal could increase the sensitivity of hepatoma cells to the traditional chemotherapeutic agent such as 5-FU. The combination of Sal and 5-FU resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. Sal reversed the 5-FU-induced increase in CD133(+) EPCAM(+) cells, epithelial-mesenchymal transition and activation of the Wnt/beta-catenin signaling pathway. The combination of Sal and 5-FU may provide us with a new approach to reverse drug resistant for the treatment of patients with HCC. PMID- 24816640 TI - Yeast homologous recombination cloning leading to the novel peptides ambactin and xenolindicin. AB - Heterologous production of GameXPeptide A (1), as well as of the novel peptide natural products ambactin (2) and xenolindicins A-C (3 a-c), was achieved by using the "overlap extension PCR-yeast homologous recombination" (ExRec) method. ExRec cloning is based on the ability of yeast to assemble overlapping DNA fragments into functional plasmids. Here we used this technique to clone a total of 15 biosynthesis gene clusters from Photorhabdus and Xenorhabdus with sizes of up to 45 kb. The structures of the novel compounds 2 and 3 a, which were produced in Escherichia coli, were elucidated by detailed MS and bioinformatics analysis, and additionally confirmed by their chemical synthesis. PMID- 24816639 TI - Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid arthritis fibroblast-like synoviocytes by down-regulating the PI3K/AKT activation and MMP-2/9 production in vitro. AB - To investigate the potential regulation of sphingosine kinase 1 (SPHK1) on the migration, invasion, and matrix metalloproteinase (MMP) expression in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were transfected control siRNA or SPHK1 siRNA. The migration and invasion of unmanipulated control, control siRNA or SPHK1 siRNA- transfected RA-FLS in vitro were measured by the transwell system. The relative levels of SPHK1, PI3K, and AKT as well as AKT phosphorylation in RA-FLS were determined by Western blot. The levels of MMP-2/9 secreted by RA-FLS were detected by ELISA. Knockdown of SPHK1 significantly inhibited the spontaneous migration and invasion of RA-FLS, accompanied by significantly reduced levels of PI3K expression and AKT phosphorylation. Similarly, treatment with LY294002, an inhibitor of the PI3K/AKT pathway, inhibited the migration and invasion of RA-FLS. Knockdown of SPHK1 and treatment with the inhibitor synergistically inhibited the migration and invasion of RA-FLS, by further reducing the levels of PI3K expression and AKT phosphorylation. In addition, knockdown of SPHK1 or treatment with LY294002 inhibited the secretion of MMP-2 and MMP-9, and both synergistically reduced the production of MMP-2 and MMP-9 in RA-FLS in vitro. Knockdown of SPHK1 expression inhibits the PI3K/AKT activation, MMP-2 and MMP-9 expression, and human RA-FLS migration and invasion in vitro. Potentially, SPHK1 may be a novel therapeutic target for RA. PMID- 24816641 TI - Altered cerebral blood flow one month after systemic chemotherapy for breast cancer: a prospective study using pulsed arterial spin labeling MRI perfusion. AB - Cerebral structural and functional alterations have been reported after chemotherapy for non-CNS cancers, yet the causative mechanism behind these changes remains unclear. This study employed a novel, non-invasive, MRI-based neuroimaging measure to provide the first direct longitudinal measurement of resting cerebral perfusion in breast cancer patients, which was tested for association with changes in cognitive function and gray matter density. Perfusion was measured using pulsed arterial spin labeling MRI in women with breast cancer treated with (N = 27) or without (N = 26) chemotherapy and matched healthy controls (N = 26) after surgery before other treatments (baseline), and one month after chemotherapy completion or yoked intervals. Voxel-based analysis was employed to assess perfusion in gray matter; changes were examined in relation to overall neuropsychological test performance and frontal gray matter density changes measured by structural MRI. Baseline perfusion was not significantly different across groups. Unlike control groups, chemotherapy-treated patients demonstrated significantly increased perfusion post-treatment relative to baseline, which was statistically significant relative to controls in the right precentral gyrus. This perfusion increase was negatively correlated with baseline overall neuropsychological performance, but was not associated with frontal gray matter density reduction. However, decreased frontal gray matter density was associated with decreased perfusion in bilateral frontal and parietal lobes in the chemotherapy-treated group. These findings indicate that chemotherapy is associated with alterations in cerebral perfusion which are both related to and independent of gray matter changes. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. Additionally, lower baseline cognitive function may be a risk factor for treatment-associated perfusion dysregulation. Future research is needed to clarify these mechanisms, identify individual differences in susceptibility to treatment-associated changes, and further examine perfusion change over time in survivors. PMID- 24816642 TI - Comparing screening instruments to predict posttraumatic stress disorder. AB - BACKGROUND: Following traumatic exposure, a proportion of trauma victims develops posttraumatic stress disorder (PTSD). Early PTSD risk screening requires sensitive instruments to identify everyone at risk for developing PTSD in need of diagnostic follow-up. AIMS: This study compares the accuracy of the 4-item SPAN, 10-item Trauma Screening Questionnaire (TSQ) and 22-item Impact of Event Scale Revised (IES-R) in predicting chronic PTSD at a minimum sensitivity of 80%. METHOD: Injury patients admitted to a level-I trauma centre (N = 311) completed the instruments at a median of 23 days and were clinically assessed for PTSD at 6 months. Areas under the curve and specificities at 80% sensitivity were compared between instruments. RESULTS: Areas under the curve in all instruments were adequate (SPAN: 0.83; TSQ: 0.82; IES-R: 0.83) with no significant differences. At 80% sensitivity, specificities were 64% for SPAN, 59% for TSQ and 72% for IES-R. CONCLUSION: The SPAN, TSQ and IES-R show similar accuracy in early detection of individuals at risk for PTSD, despite differences in number of items. The modest specificities and low positive predictive values found for all instruments could lead to relatively many false positive cases, when applied in clinical practice. PMID- 24816643 TI - Anti-HLA alloantibodies in surgical patients refractory to platelet transfusion. AB - Alloimmune platelet refractoriness (alloPR) among actively bleeding surgical patients with thrombocytopenia represents a life-threatening problem. Here we present three cases in which surgical bleeding was complicated by life threatening thrombocytopenia and alloPR. We demonstrate that the human leukocyte antigens (HLA) antibodies associated with alloPR are broadly reactive and in high concentration, are not removed by hemodilution, and are not absorbed by transfusion of multiple doses of platelet concentrates. HLA alloPR may be under recognized among surgical patients. Research is needed to develop pre-operative screening methods that will identify patients in need of specialized platelet support using HLA compatible donor products. PMID- 24816644 TI - Trajectory and risk factors for chemotherapy-induced nausea and vomiting in Asian patients with head and neck cancer. AB - BACKGROUND: The purpose of this study was to analyze the trajectory of and risk factors for chemotherapy-induced nausea and vomiting in Asian patients with head and neck cancer. METHODS: Adult patients with head and neck cancer scheduled to receive cisplatin-based chemotherapy were recruited for the study. Clinical events were collated from standardized diaries. RESULTS: Two hundred thirty-five patients were included in the analyses. The majority (75.7%) was men, Chinese (81.7%), and manifested nasopharyngeal cancer (83.4%). The overall incidence of significant nausea and vomiting was 73.7% and 24.7%, respectively, with single day cisplatin regimens of 48.9% and 28.9%, respectively, with the multiple-day cisplatin regimen. Patients using complementary alternative medicine were less likely than others to achieve a complete response to antiemetics. CONCLUSION: Although postchemotherapy vomiting is relatively well controlled in Asian patients with head and neck cancer, postchemotherapy nausea remains problematic in this population. PMID- 24816645 TI - A random forest based risk model for reliable and accurate prediction of receipt of transfusion in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Transfusion is a common complication of Percutaneous Coronary Intervention (PCI) and is associated with adverse short and long term outcomes. There is no risk model for identifying patients most likely to receive transfusion after PCI. The objective of our study was to develop and validate a tool for predicting receipt of blood transfusion in patients undergoing contemporary PCI. METHODS: Random forest models were developed utilizing 45 pre procedural clinical and laboratory variables to estimate the receipt of transfusion in patients undergoing PCI. The most influential variables were selected for inclusion in an abbreviated model. Model performance estimating transfusion was evaluated in an independent validation dataset using area under the ROC curve (AUC), with net reclassification improvement (NRI) used to compare full and reduced model prediction after grouping in low, intermediate, and high risk categories. The impact of procedural anticoagulation on observed versus predicted transfusion rates were assessed for the different risk categories. RESULTS: Our study cohort was comprised of 103,294 PCI procedures performed at 46 hospitals between July 2009 through December 2012 in Michigan of which 72,328 (70%) were randomly selected for training the models, and 30,966 (30%) for validation. The models demonstrated excellent calibration and discrimination (AUC: full model = 0.888 (95% CI 0.877-0.899), reduced model AUC = 0.880 (95% CI, 0.868-0.892), p for difference 0.003, NRI = 2.77%, p = 0.007). Procedural anticoagulation and radial access significantly influenced transfusion rates in the intermediate and high risk patients but no clinically relevant impact was noted in low risk patients, who made up 70% of the total cohort. CONCLUSIONS: The risk of transfusion among patients undergoing PCI can be reliably calculated using a novel easy to use computational tool (https://bmc2.org/calculators/transfusion). This risk prediction algorithm may prove useful for both bed side clinical decision making and risk adjustment for assessment of quality. PMID- 24816646 TI - Structure of constituents isolated from the flower buds of Cananga odorata and their inhibitory effects on aldose reductase. AB - Three new terpenoid derivatives, canangaterpenes IV-VI, were isolated from the flower buds of Cananga odorata, cultivated in Thailand, together with eight known flavonoids. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects of the isolated compounds on aldose reductase were also investigated. Several terpenoid derivatives and flavonoids were shown to inhibit aldose reductase. PMID- 24816647 TI - A pilot study to examine the correlation between cognition and blood biomarkers in a Singapore Chinese male cohort with type 2 diabetes mellitus. AB - BACKGROUND: Diabetes is reported to be linked to poorer cognitive function. The purpose of this study is to examine (a) clinical correlation between cognitive function and the biochemical perturbations in T2DM, and (b) the impact of statin treatment on cognitive function in diabetic subjects. METHODS: Forty Singaporean Chinese males with diabetes and twenty Singaporean Chinese males without diabetes were recruited for this study. Twenty-two of the diabetic subjects were on statin therapy and all subjects were non-demented. This was a 2-period non interventional case-control study in which subjects were assessed for cognitive function in period 1 and blood samples taken over 2 periods, approximately 1 week apart. Blood was collected to determine the level of total cholesterol, high density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, glucose and insulin. Cognitive performance was measured by a neuropsychological battery covering domains of attention, language, verbal and visual memory, visuomotor speed and executive function. Z-scores were derived for each cognitive domain using the mean and standard deviations (SDs), and they were used to compare between (a) diabetic and non-diabetic groups, and (b) diabetic subjects with and without statin treatment. ANCOVAs with age, education, BMI, and the duration of diabetes as covariates were employed to examine differences in mean score of cognitive domains and subtests between the two groups. RESULTS: Overall cognitive function was similar among diabetics and age matched non-diabetic controls. Among diabetic statin users, HDL, LDL and total cholesterol were negatively correlated with executive function, whereas peripheral insulin levels and insulin resistance were negatively associated with attention. CONCLUSION: Diabetic statin users were likely to have poorer performance in attention and executive function. Increasing levels of the peripheral biomarkers are likely to contribute to poorer cognitive performance. PMID- 24816648 TI - Novel approach to activity evaluation for release-active forms of anti-interferon gamma antibodies based on enzyme-linked immunoassay. AB - Selection of a suitable assay to measure the activity of drug agents based on release-active forms of anti-interferon-gamma antibodies (RA forms of Abs) is an important step forward in the investigation of such agents. In this study, the enzyme-linked immunosorbent assay was utilized to examine the effect of RA forms of Abs specific for human interferon gamma on the interaction between monoclonal anti-interferon gamma antibodies and recombinant human interferon gamma. The experimental data and the results obtained by using relevant mathematical analysis showed that such RA forms of Abs are able to modulate the monoclonal antibody interaction with both soluble and immobilized (to the assay plate well) interferon gamma. These data demonstrated the importance of using relatively low concentrations of both soluble and plate-immobilized interferon gamma to detect the effects of RA forms of Abs to interferon gamma on the binding of monoclonal antibodies to interferon gamma. It has been suggested that the observed influence of RA forms of Abs on 'antibody-antigen' interaction could be used to detect and analyze the activity of drugs containing RA forms of Abs. PMID- 24816649 TI - Has Tanzania embraced the green leaf? Results from outlet and household surveys before and after implementation of the Affordable Medicines Facility-malaria. AB - BACKGROUND: The Affordable Medicines Facility-malaria (AMFm) is primarily an artemisinin combination therapy (ACT) subsidy, aimed at increasing availability, affordability, market share and use of quality-assured ACTs (QAACTs). Mainland Tanzania was one of eight national scale programmes where AMFm was introduced in 2010. Here we present findings from outlet and household surveys before and after AMFm implementation to evaluate its impact from both the supply and demand side. METHODS: Outlet surveys were conducted in 49 randomly selected wards throughout mainland Tanzania in 2010 and 2011, and data on outlet characteristics and stocking patterns were collected from outlets stocking antimalarials. Household surveys were conducted in 240 randomly selected enumeration areas in three regions in 2010 and 2012. Questions about treatment seeking for fever and drugs obtained were asked of individuals reporting fever in the previous two weeks. RESULTS: The availability of QAACTs increased from 25.5% to 69.5% among all outlet types, with the greatest increase among pharmacies and drug stores, together termed specialised drug sellers (SDSs), where the median QAACT price fell from $5.63 to $0.94. The market share of QAACTs increased from 26.2% to 42.2%, again with the greatest increase in SDSs. Household survey results showed a shift in treatment seeking away from the public sector towards SDSs. Overall, there was no change in the proportion of people with fever obtaining an antimalarial or ACT from baseline to endline. However, when broken down by treatment source, ACT use increased significantly among clients visiting SDSs. DISCUSSION: Unchanged ACT use overall, despite increases in QAACT availability, affordability and market share in the private sector, reflected a shift in treatment seeking towards private providers. The reasons for this shift are unclear, but likely reflect both persistent stockouts in public facilities, and the increased availability of subsidised ACTs in the private sector. PMID- 24816650 TI - An optimized triple modality reporter for quantitative in vivo tumor imaging and therapy evaluation. AB - We present an optimized triple modality reporter construct combining a far-red fluorescent protein (E2-Crimson), enhanced firefly luciferase enzyme (Luc2), and truncated wild type herpes simplex virus I thymidine kinase (wttk) that allows for sensitive, long-term tracking of tumor growth in vivo by fluorescence, bioluminescence, and positron emission tomography. Two human cancer cell lines (MDA-MB-231 breast cancer and HT-1080 fibrosarcoma cancer) were successfully transduced to express this triple modality reporter. Fluorescence and bioluminescence imaging of the triple modality reporter were used to accurately quantify the therapeutic responses of MDA-MB-231 tumors to the chemotherapeutic agent monomethyl auristatin E in vivo in athymic nude mice. Positive correlation was observed between the fluorescence and bioluminescence signals, and these signals were also positively correlated with the ex vivo tumor weights. This is the first reported use of both fluorescence and bioluminescence signals from a multi-modality reporter construct to measure drug efficacy in vivo. PMID- 24816651 TI - Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice. AB - Clinicopathological paradox has hampered significantly the effective assessment of the efficacy of therapeutic intervention for multiple sclerosis. Neuroimaging biomarkers of tissue injury could guide more effective treatment by accurately reflecting the underlying subclinical pathologies. Diffusion tensor imaging derived directional diffusivity and anisotropy indices have been applied to characterize white matter disorders. However, these biomarkers are sometimes confounded by the complex pathologies seen in multiple sclerosis and its animal models. Recently, a novel technique of diffusion basis spectrum imaging has been developed to quantitatively assess axonal injury, demyelination and inflammation in a mouse model of inflammatory demyelination. Lenaldekar, which inhibits T-cell expansion in a non-cytolytic manner, has been shown to suppress relapses and preserve white matter integrity in mice with experimental autoimmune encephalomyelitis. In this study, relapsing-remitting experimental autoimmune encephalomyelitis was induced through active immunization of SJL/J mice with a myelin proteolipid protein peptide. The therapeutic efficacy of Lenaldekar treatment was evaluated via daily clinical score, cross-sectional ex vivo diffusion basis spectrum imaging examination and histological analysis. Lenaldekar greatly reduced relapse severity and protected white matter integrity in these experimental autoimmune encephalomyelitis mice. Diffusion basis spectrum imaging-derived axial diffusivity, radial diffusivity and restricted diffusion tensor fraction accurately reflected axonal injury, myelin integrity and inflammation-associated cellularity change, respectively. These results support the potential use of diffusion basis spectrum imaging as an effective outcome measure for preclinical drug evaluation. PMID- 24816652 TI - What does tympanostomy tube placement in children teach us about the association between atopic conditions and otitis media? AB - Otitis media is the most common infection second only to viral upper respiratory infection in the outpatient setting. Tympanostomy tube insertion (TTI) is the most common ambulatory surgical procedure in the USA. While many risk factors for otitis media have been identified, atopic conditions have been underrecognized as risk factors for recurrent and persistent otitis media. Given that asthma and other atopic conditions are the most common chronic conditions during childhood, it is worth examining the association between atopic conditions and risk of otitis media, which can provide insight into how atopic conditions influence the risk of microbial infections. This paper focuses its discussion on otitis media; however, it is important that the association between atopic conditions and risk of otitis media be interpreted in the context of the association of atopic conditions with increased risks of various microbial infections. PMID- 24816653 TI - Mutational screening of NOTCH3 gene reveals two novel mutations: complexity of CADASIL diagnosis. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary vascular disease with neurological manifestations. The classical clinical course is relentlessly progressive with early transient ischaemic attacks (TIA) or strokes, dementia and finally death in the mid-1960s. The disorder is inherited in an autosomal dominant fashion, with high penetrance and broad variable clinical course even within family. It is caused by mutations in the NOTCH3 gene; all causative mutations result in gain or loss of a cysteine residue within the extracellular domain, with exons 3 and 4 reported as hot spot mutational sites. Mutation analysis of the NOTCH3 gene was performed through direct sequencing of the 2-23 exons containing all EGF-like domains. Patients underwent genetic counselling pre and post testing. Here, we report two novel mutations located in exons 6 and 15 of the NOTCH3 gene; clinical description for the probands and for available relatives is enclosed. No reliable data on incidence or prevalence rates of this disease are available: it is therefore essential that the diagnosis is obtained in all suspected cases through the extensive analysis of the NOTCH3 gene and that all cases are brought to the attention of the scientific community. PMID- 24816655 TI - Defining a genetic ideotype for crop improvement. AB - While plant breeders traditionally base selection on phenotype, the development of genetic ideotypes can help focus the selection process. This chapter provides a road map for the establishment of a refined genetic ideotype. The first step is an accurate definition of the target environment including the underlying constraints, their probability of occurrence, and impact on phenotype. Once the environmental constraints are established, the wealth of information on plant physiological responses to stresses, known gene information, and knowledge of genotype *environment and gene * environment interaction help refine the target ideotype and form a basis for cross prediction.Once a genetic ideotype is defined the challenge remains to build the ideotype in a plant breeding program. A number of strategies including marker-assisted recurrent selection and genomic selection can be used that also provide valuable information for the optimization of genetic ideotype. However, the informatics required to underpin the realization of the genetic ideotype then becomes crucial. The reduced cost of genotyping and the need to combine pedigree, phenotypic, and genetic data in a structured way for analysis and interpretation often become the rate-limiting steps, thus reducing genetic gain. Systems for managing these data and an example of ideotype construction for a defined environment type are discussed. PMID- 24816656 TI - From genes to markers: exploiting gene sequence information to develop tools for plant breeding. AB - Once the sequence is known for a gene of interest, it is usually possible to design markers to detect polymorphisms within the gene. Such markers can be particularly useful in plant breeding, especially if they detect the causal polymorphism within the gene and are diagnostic of the phenotype. In this chapter, we (1) discuss how gene sequences are obtained and aligned and how polymorphic sites can be identified or predicted; (2) explain the principles of PCR primer design and PCR amplification and provide guidelines for their application in the design and testing of markers; (3) discuss detection methods for presence/absence (dominant) polymorphisms, length polymorphisms and single nucleotide polymorphisms (SNPs); and (4) outline some of the factors that affect the utility of markers in plant breeding and explain how markers can be evaluated (validated) for use in plant breeding. PMID- 24816654 TI - A hydrophobic area of the GABA rho1 receptor containing phenylalanine 124 influences both receptor activation and deactivation. AB - Experimental evidence suggests that GABA rho1 receptors are potential therapeutic targets for the treatment of a range of neurological conditions, including anxiety and sleep disorders. Homology modelling of the GABA rho1 extracellular N terminal domain has revealed a novel hydrophobic area that extends beyond, but not including the GABA-binding site. Phenylalanine 124 (F124) is predicted to be involved in maintaining the structural integrity of the orthosteric-binding site. We have assessed the activity of a series of GABA rho1 receptors that incorporate a mutation at F124. Wild-type and mutant human GABA rho1 subunits were expressed in Xenopus laevis oocytes and AD293 cells, and the pharmacology and kinetic properties of the receptors were measured using electrophysiological analysis. Mutation of F124 had minimal effect on receptor pharmacology. However, the rate of deactivation was significantly increased compared to wild type. This study provides further information about the role of residues within a novel hydrophobic area of the GABA rho1 receptor. This knowledge can help future studies into the design of potent and subtype-selective ligands with therapeutic value. PMID- 24816657 TI - Temperature switch PCR (TSP): a gel-based molecular marker technique for investigating single nucleotide polymorphisms. AB - Temperature Switch PCR (TSP) is a robust single-marker single nucleotide polymorphism (SNP) genotyping technique with broad applications in genetic studies of various organisms. The technique consists of a biphasic PCR with two sets of primers, a locus-specific set and a nested locus-specific set. The PCR products can be easily assessed for polymorphism based on different band sizes using agarose gel electrophoresis. PMID- 24816658 TI - Multiplex-Ready Technology for mid-throughput genotyping of molecular markers. AB - Screening molecular markers across large populations in breeding programs is generally time consuming and expensive. The Multiplex-Ready Technology (MRT) (Hayden et al., BMC genomics 9:80, 2008) was created to optimize polymorphism screening and genotyping using standardized PCR reaction conditions. The flexibility of this method maximizes the number of markers (up to 24 markers SSR or SNP, ideally small PCR product <500 bp and highly polymorphic) by using fluorescent dye (VIC, FAM, NED, and PET) and a semiautomated DNA fragment analyzer (ABI3730) capillary electrophoresis for large numbers of DNA samples (96 or 384 samples). PMID- 24816659 TI - Genotyping by high-resolution melting analysis. AB - High-resolution melting (HRM) analysis is a simple, closed tube, post-PCR method used to identify genetic variation. The method is highly sensitive and can discriminate DNA sequence variants based on length (such as insertions or deletions), composition (such as single nucleotide polymorphisms, i.e., SNP) or strand complementarity (such as heterozygous or homozygous material). The technique involves PCR amplification of a target sequence in the presence of a fluorescent double-stranded DNA (dsDNA) binding dye, melting of the fluorescent amplicons, and subsequent interpretation of melt curve profiles. Here, we describe general considerations for assay design, PCR amplification, and HRM analysis. PMID- 24816660 TI - Bi-allelic SNP genotyping using the TaqMan(r) assay. AB - With TaqMan((r)) technology allele-specific probes are utilized for quick and reliable genotyping of known polymorphic sites. TaqMan assays are robust in genotyping multiple variant types, including single nucleotide polymorphisms, insertions/deletions, and presence/absence variants. To query a single bi-allelic polymorphism, two TaqMan probes labeled with distinct fluorophores are designed such that they hybridize to different alleles during PCR-based amplification of a surrounding target region. During the primer extension phase of PCR, the 5'-3' exonuclease activity of Taq polymerase cleaves and releases the fluorophores from bound probes. At the end of PCR, the emission intensity of each fluorophore is measured and allele determination at the queried site can be made. PMID- 24816661 TI - SNP genotyping: the KASP assay. AB - The KASP genotyping assay utilizes a unique form of competitive allele-specific PCR combined with a novel, homogeneous, fluorescence-based reporting system for the identification and measurement of genetic variation occurring at the nucleotide level to detect single nucleotide polymorphisms (SNPs) or inserts and deletions (InDels). The KASP technology is suitable for use on a variety of equipment platforms and provides flexibility in terms of the number of SNPs and the number of samples able to be analyzed. The KASP chemistry functions equally well in 96-, 384-, and 1,536-well microtiter plate formats and has been utilized over many years in large and small laboratories by users across the fields of human, animal, and plant genetics. PMID- 24816662 TI - Rindsel: an R package for phenotypic and molecular selection indices used in plant breeding. AB - Selection indices are estimates of the net genetic merit of the individual candidates for selection and are calculated based on phenotyping and molecular marker information collected on plants under selection in a breeding program. They reflect the breeding value of the plants and help breeders to choose the best ones for next generation. Rindsel is an R package that calculates phenotypic and molecular selection indices. PMID- 24816663 TI - OptiMAS: a decision support tool to conduct marker-assisted selection programs. AB - Ongoing major advances in plant genotyping and phenotyping lead to a better understanding of genetic architecture of agronomical traits. In this context, it is important to develop decision support tools to help breeders in implementing marker-assisted selection (MAS) projects to assemble new allele combinations. Algorithms have been developed within an interactive graphical interface to (a) trace parental QTL alleles throughout selection generations, (b) propose strategies to select the best plants based on estimated molecular scores, and (c) efficiently intermate them depending on the expected value of their progenies. By investigating multi-allelic context and diverse pedigree structure, OptiMAS enables to assemble favorable alleles issued from diverse parents and further accelerate genetic gain. PMID- 24816664 TI - Genomic selection in plant breeding. AB - Genomic selection (GS) is a method to predict the genetic value of selection candidates based on the genomic estimated breeding value (GEBV) predicted from high-density markers positioned throughout the genome. Unlike marker-assisted selection, the GEBV is based on all markers including both minor and major marker effects. Thus, the GEBV may capture more of the genetic variation for the particular trait under selection. PMID- 24816665 TI - Simulated breeding with QU-GENE graphical user interface. AB - Comparing the efficiencies of breeding methods with field experiments is a costly, long-term process. QU-GENE is a highly flexible genetic and breeding simulation platform capable of simulating the performance of a range of different breeding strategies and for a continuum of genetic models ranging from simple to complex. In this chapter we describe some of the basic mechanics behind the QU GENE user interface and give a simplified example of how it works. PMID- 24816666 TI - The control of recombination in wheat by Ph1 and its use in breeding. AB - Two meiotic processes have a major influence on the plant breeding, namely, the independent assortment of chromosomes, and recombination. The major chromosome pairing locus in hexaploid and tetraploid wheat, Ph1, has a significant effect on both these processes. This chapter reviews our current understanding of this locus and how mutants of it can be exploited for breeding purposes. PMID- 24816667 TI - TILLING for plant breeding. AB - TILLING is widely used in plant functional genomics. Mutagenesis and SNP detection is combined to allow for the isolation of mutations in genes of interest. It can also be used as a plant breeding tool, whereby variation in known or candidate genes of interest to breeding programs is generated. Here we describe a simple low-cost TILLING procedure. PMID- 24816668 TI - In vitro culture for doubled haploids: tools for molecular breeding. AB - Doubled haploid (DH) techniques using immature microspores or embryos rescued in vitro following interspecific hybridization are important tools for breeding wheat and barley and for generating populations for gene mapping purposes. Here, we describe methods being used for the successful production of spring wheat and barley DHs in Australia. PMID- 24816669 TI - Biolistic transformation of wheat with centrophenoxine as a synthetic auxin. AB - Cereal crops, including bread wheat (Triticum aestivum L.), are an important staple food worldwide. With a growing global population, it is evident that current crop production will not meet the rising demands being placed on modern agriculture. Efforts to improve crop yield and stress-tolerance by traditional breeding are labor intensive, time consuming, and highly dependent upon the ability to capture existing and novel genetic variation from a restricted genetic pool. Genetic engineering of crop species is one of several alternatives to traditional breeding for the introduction of novel genetic variation. This recently established technology has proved useful for the introduction of novel traits like pest resistance and herbicide tolerance. As a universal tool for genetic transformation, the Biolistic Gene Gun allows for the genomic integration of novel gene sequences from various sources into a whole host of living organisms.In this chapter, we present a novel and detailed protocol for the Biolistic Transformation of bread wheat that uses the pharmaceutical compound, Centrophenoxine (CPX). The application of CPX as the main auxin-like plant growth regulator in cereal genetic transformation replaces the potent but more toxic herbicide 2,4-D. PMID- 24816670 TI - Agrobacterium-mediated transformation of barley (Hordeum vulgare L.). AB - Barley biotechnology requires efficient genetic engineering tools for producing transgenic plants necessary for conducting reverse genetics analyses in breeding and functional genomics research. Agrobacterium-mediated genetic transformation is an important technique for producing barley transgenics with simple low-copy number transgenes. This chapter reports a refined protocol for the systematic high-throughput transformation of the advanced Australian spring barley breeding line WI4330. PMID- 24816671 TI - qPCR for quantification of transgene expression and determination of transgene copy number. AB - Quantitative real-time PCR (qPCR) is a mature technology that can be used to accurately quantify the number of copies of a target nucleic acid in a sample. Here, we describe a method for using this technology to determine the copy number of a transgene stably integrated into a plant's genome and to ascertain the level of transgene expression. PMID- 24816672 TI - High-throughput analysis pipeline for achieving simple low-copy wheat and barley transgenics. AB - Transgenic (or genetically modified-GM) plant breeding is increasingly being used as a supplementary tool to many classical plant-breeding programs. Currently the range of transgenic traits accepted for commercial use is largely restricted to herbicide and pest resistance. Given the fact that transgenics can offer an alternative and novel source of genetic variation, pre-breeding research is now increasingly exploiting this technology to tackle a greater spectrum of traits. These traits range from abiotic stress tolerance to improved product quality and nutritional characteristics. Likewise there is an increasing demand for high throughput methodologies for transgenic plant generation, characterization and phenotyping. Selecting simple low-copy number transgenic events that are both heritable and stably expressed "in planta" is considered a prerequisite to systematic phenotyping for traits of interest. Furthermore, this assessment relies heavily on comparisons to appropriate control plants, in the case of wheat and barley transgenics this is both wild-type and null siblings. This chapter presents a general scheme on which to base selection of transgenics and respective null siblings using wheat and barley as an example. This scheme can be adapted to other similar crop species. Overall this strategy reduces the total number of plants to be genotyped and phenotyped at each generational step, and therefore resulting in significant savings in time, effort, and resources. PMID- 24816673 TI - Arterial stiffness in patients with non-classic Pompe disease: role of antihypertensive drugs and statins. PMID- 24816674 TI - Bacteria-material surface interactions: methodological development for the assessment of implant surface induced antibacterial effects. AB - The choice of material for implanted prostheses is of great importance concerning bacterial colonization and biofilm formation. Consequently, methods to investigate bacterial behavior are needed in order to develop new infection resistant surfaces. In this study, different methodological setups were used to evaluate the antimicrobial effect of photocatalytic titanium oxide and silver surfaces. Biofilm formation and eradication under static and dynamic culture conditions were studied with the use of the following analytical techniques: viable colony-forming unit (CFU) counting, imprinting, fluorescence, and bioluminescence. The present study demonstrates that different methods are needed in order to evaluate the prophylactic and treatment effects on planktonic and biofilm bacteria and to assess the antimicrobial effect of different surface treatments/coatings. Choosing the right antibacterial testing model for the specific application is also of great importance. Both in situ approaches and indirect methods provide valuable complementary information. PMID- 24816675 TI - Evalution of DNA extraction methods in order to monitor genetically modified materials in soy foodstuffs and feeds commercialised in Turkey by multiplex real time PCR. AB - BACKGROUND: Soybean is one of the most important biotech crops, widely used as an ingredient in both foodstuffs and feed. DNA extraction methods have been evaluated to detect the presence of genetically modified (GM) materials in soya containing food and feed products commercialised in Turkey. RESULTS: All extraction methods performed well for the majority of soya foods and feed products analysed. However, the most successful method varied between different products; the Foodproof, Genespin and the cetyltrimethylammonium bromide (CTAB) methods each produced the highest DNA yield and purity for different soya foodstuffs and feeds. Of the samples tested, 20% were positive for the presence of at least two GM elements (35S/NOS) while 11% contained an additional GM element (35S/NOS/FMV). Of the tested products, animal feeds showed a larger prevalence of GM material (50%) than the soya-containing foodstuffs (13%). CONCLUSION: The best performing extraction methods proved to be the Foodproof, Genespin and CTAB methods for soya-containing food and feed products. The results obtained herein clearly demonstrate the presence of GM soybean in the Turkish market, and that the Foodproof GMO Screening Kit provides reliable screening of soy-containing food and feed products. PMID- 24816676 TI - Circulating microparticles in carriers of prothrombin G20210A mutation. AB - Factor V Leiden (FVL) and prothrombin gene mutation G20210A (PTM) are the two most common genetic polymorphisms known to predispose carriers to venous thromboembolism (VTE). A recent study in FVL carriers showed that circulating levels of microparticles (MP) may contribute to their thrombogenic profile. To further elucidate the prothrombotic state linked to genetic thrombophilia, we extended this study to carriers of PTM. The plasma level of annexin V-MP, endothelial-MP (EMP), platelet-MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) was measured in 124 carriers of PTM (105 heterozygous and 19 homozygous) and in 120 age- and gender-matched healthy individuals. Heterozygous and homozygous carriers of PTM showed significantly increased levels of annexin V-MP (2930 [1440-4646] MP/ul and 3064 [2412-4906] MP/ul, respectively) and significantly shorter PPL clotting time (54 [46-67] sec and 55 [46-64] sec) compared to controls (1728 [782-2122] MP/ul and 71 [61-75] sec, respectively; p<0.01). Similarly, heterozygous and homozygous subjects presented with significantly higher levels of EMP, PMP and TF+ than controls (p<0.05). PTM carriers with a VTE history had significantly higher MP numbers and activity than controls. No significant difference was seen between carriers with and without a VTE history. We conclude that the higher levels of circulating MP found in PTM carriers may play a role in the development of VTE possibly by increasing thrombin generation. Further studies are needed to better define the role of MP as triggering factors for the thrombotic complications characterizing mild genetic thrombophilic defects. PMID- 24816677 TI - Usefulness of diffusion tensor MR imaging in the assessment of intramedullary changes of the cervical spinal cord in different stages of degenerative spine disease. AB - PURPOSE: The aim of this study was to evaluate the usefulness of diffusion tensor imaging (DTI) in the detection of cervical spinal cord integrity alterations in different stages of degenerative spine disease, as well as to compare DTI parameters with selected cervical spinal stenosis measurements. METHODS: One hundred and thirty-two symptomatic patients (mean age 53.58 years) with different stages of cervical spondylosis and twenty-five control subjects (mean age 45.78 years) were enrolled in the study. DTI was performed with a 1.5 T MR scanner. Three hundred and forty-nine spine segments from C2/C3 to C5/C6 were evaluated and divided into five groups according to the degree of spinal cord compression. The values of fractional anisotropy (FA) and apparent diffusion coefficient at each level were calculated and their correlations with the degree of stenosis were analyzed. RESULTS: FA values differed significantly (p < 0.0001) at all levels between the control group and patients with cervical degenerative disease, including subjects without spinal cord compression visible on plain MR images. A significant (p < 0.01) positive correlation between the mean FA values and anteroposterior diameter of the spinal canal as well as space available for the spinal cord index was demonstrated at all investigated levels. CONCLUSION: DTI is capable of revealing impairment of the cervical spinal cord microstructure at the very early stage of degenerative spine disease, even prior to spinal cord compression visible on plain MR. Anteroposterior spinal canal diameter as well as space available for the cord index is well related to spinal cord tissue integrity defined by DTI. PMID- 24816678 TI - Recent applications and developments of capacitively coupled contactless conductivity detection (CE-C4D) in capillary electrophoresis. AB - Capacitively coupled contactless conductivity detection (C4D) has emerged as a powerful technique for the detection of compounds lacking any distinct chromophores or fluorophores. This review provides an update of the most recent application in CE-C4D for pharmaceutical, biomedical and food covering the period from January 2012 to January 2014. The present review is an update of two previous review papers covering the years 2000-2010 (Biomedical Chromatography 2010; 24: 1038-1044 and Biomedical Chromatography 2012; 26: 990-1000). Representative examples illustrate the applicability of CE-C4D in the fields of pharmaceutical, biomedical and food. Finally, general conclusions and perspectives are provided. PMID- 24816679 TI - Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population. AB - Neural tube defects (NTDs) are the most common and severe malformations of the central nervous system. The association of single nucleotide polymorphisms (SNPs) of the Frizzled 3 (FZD3) and Frizzled 6 (FZD6) genes and NTDs in the Han population of northern China was principally studied. One synonymous SNP (rs2241802) in FZD3 gene and three nonsynonymous SNPs (rs827528, rs3808553 and rs12549394) in FZD6 gene were analyzed by polymerase chain reaction (PCR) and sequencing methods in 135 NTD patients and 135 normal controls. The allele, genotype and haplotype frequencies were calculated and analyzed to examine the relationship between FZD3/FZD6 SNPs and NTDs. Both T allele and TT genotype frequencies of the FZD6 rs3808553 loci in the NTDs group were significantly higher than those in the controls, and children with T allele and TT genotype were associated with increased NTDs risk (OR = 1.575, 95 % CI 1.112-2.230, P = 0.010 and OR = 2.811, 95 % CI 1.325-5.967, P = 0.023, respectively). There were no differences among different genotypes or alleles in other three SNPs. Haplotypes A-G-C and A-T-C in FZD6 were found associated with NTDs in the case control study (OR = 0.560, 95 % CI 0.378-0.830, P = 0.004 and OR = 1.670, 95 % CI 1.126-2.475, P = 0.011, respectively). The rs3808553 of FZD6 is obviously associated with NTDs in Han population of northern China. The TT genotype may increase risk for NTDs. PMID- 24816680 TI - A water-soluble sulfonate-BODIPY based fluorescent probe for selective detection of HOCl/OCl- in aqueous media. AB - A new, water-soluble BODIPY dye 1, bearing sulfonate groups at the 2- and 6 positions was found to be a sensitive and selective fluorescent probe for the detection of HOCl/OCl(-) in aqueous buffer solution. The probe, which displays extremely weak fluorescence owing to efficient singlet excited state quenching by photoinduced electron transfer (PeT) from an electron-rich catechol group at a meso-position, responds to HOCl/OCl(-) through a dramatic enhancement of its fluorescence intensity. PMID- 24816682 TI - Exploration of the slow relaxation behavior in the manganese phosphate network. AB - Our endeavors are devoted to the explanation of the nature of the magnetic relaxation phenomena in the herein prepared [Mn(II)5(HPO4)2(PO4)2(H2O)4]n (1). The behavior investigation indicates the prominence of the half-occupied magnetic centers and the competence of the antiferromagnetic interactions and non-zero magnetic moments. The investigation suggests that the design and synthesis of unusual magnetic center materials with innate unquenched magnetic moments could provide a new route for the production of molecular magnets with magnetic relaxation. PMID- 24816681 TI - The revised human liver cytochrome P450 "Pie": absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics. AB - The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds (arachidonic acid and leukotriene B4), nutrients (vitamins K1 and E), and xenobiotics (pafuramidine and fingolimod). CYP4F2 and CYP4F3B are reported to be expressed in the human liver. However, absolute concentrations of these enzymes in human liver microsomes (HLMs) and their interindividual variability have yet to be determined because of the lack of specific antibodies. Here, an liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of CYP4F2 and CYP4F3B compared with CYP3A in two panels of HLMs (n = 31). As a result, the human hepatic cytochrome P450 (P450) "pie" has been revised to include the contribution of CYP4F enzymes, which amounts to 15% of the total hepatic cytochrome P450 enzymes. CYP4F3B displayed low interindividual variability (3.3-fold) in the HLM panels whereas CYP4F2 displayed large variability (21-fold). However, CYP4F2 variability decreased to 3.4-fold if the two donors with the lowest expression were excluded. In contrast, CYP3A exhibited 29-fold interindividual variability in the same HLM panels. The proposed marker reaction for CYP4F enzymes pafuramidine/DB289 M1 formation did not correlate with CYP4F protein content, suggesting alternate metabolic pathways for DB289 M1 formation in HLMs. In conclusion, CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation. PMID- 24816684 TI - Aluminum based sulfide solid lithium ionic conductors for all solid state batteries. AB - The present work focuses on the synthesis of lithium ionic conductors based on a Li2S-Al2S3-GeS-P2S5 system due to the high ionic conductivity exhibited by the constituents of this system. Mechanical milling for a short duration and a single step heat treatment at a moderate temperature of 550 degrees C resulted in crystalline powders with high lithium ionic conductivity at room temperature that are comparable to the organic liquid electrolytes. The effect of various aluminum to germanium ratios was studied. Among the samples containing Al : Ge, the ratio of 30 : 70 was found to show high ionic conductivities of 1.7 * 10(-3) S cm(-1) at 25 degrees C and ~ 6 * 10(-3) S cm(-1) at 100 degrees C equivalent. The activation energy of this material was significantly less (Ea = 17 kJ mol(-1)), which can be considered to be the best value among solid electrolytes. The electrochemical stability was analyzed using cyclic voltammetry between -0.3 and 5.0 V and it was found that the voltammetric profile was smooth without any additional current response, due to electrolyte decomposition, or any other side reaction, except a pair of lithium deposition and stripping peaks. PMID- 24816685 TI - Somatization in refugees: a review. AB - PURPOSE: To present a review of the literature concerning medically unexplained physical symptoms in refugees. METHODS: We outline a variety of definitions and explanations of somatization, as well as the role of culture in the concept of disease. In addition, we present a review of the epidemiological literature about somatization in refugees. RESULTS: Refugees from non-Western countries exhibit more unexplained somatic symptoms than the general Western population. Although different studies have employed different methodologies and are therefore difficult to compare, it can be concluded that refugees form a particular population in which somatization is prominent. CONCLUSIONS: Potential, not mutually exclusive, explanations of the high number of somatic symptoms in the refugee population include general psychopathology, specifically traumatisation, results of torture, and stigmatisation of psychiatric care. There are implications for assessment, clinical treatment and further research concerning somatization in refugees. PMID- 24816686 TI - Positional isomers of cyanostilbene: two-component molecular assembly and multiple-stimuli responsive luminescence. AB - An understanding of the aggregates and properties of positional isomers can not only uncover how a slight difference in molecular structure alter crystal packing and bulk solid-state properties, but also plays an important role in developing new types of molecule-based functional materials. Herein, we report a study of the molecular packing and static/dynamic luminescence properties of three cyanostilbene (CS)-based isomers (CS1, CS2, CS3) within their single- and two component molecular solids. Changing the positions of the cyano substitutents in the CS isomers has a marked influence on their packing modes and luminescent properties. Moreover, two-component CS-based materials have been constructed, which exhibit tunable conformations and packing fashions, as well as fluorescence properties, which differ from the pristine CS solids. The CS-based two-component molecular materials show solvent-responsive luminescence due to the dynamic disassembly of the samples. Moreover, it was found that the system based on CS2 and octafluoronaphthalene shows reversible photochromic fluorescence upon alternating light illumination and grinding. Such co-assembly procedures provide a facile way to fabricate patterned luminescent film materials. Therefore, this work not only affords new insight into the relationship between isomers and luminescence from molecular and supramolecular perspectives, but provides an effective strategy to develop multiple-stimuli-responsive luminescent materials. PMID- 24816688 TI - The diagnostic accuracy of pelvic measurements: threshold values and fetal size. AB - PURPOSE: This study aimed to correlate pelvic dimensions and fetal size to the risk for cesarean section caused by protracted labor. METHODS: This is an observational, retrospective cohort study on pregnant women with an increased risk of labor dystocia. After pelvimetry, pelvic adequacy was clinically tested in a trial of labor. A multivariable regression analysis was made to identify the risk factors for cesarean section. Two subgroups were established according to the size of the estimated fetal head circumference (HC) (arbitrary cutoffs of <=340 and >340 mm), and the pelvic measurements were compared by the mode of delivery. Receiver operating characteristic (ROC) curves were evaluated. RESULTS: Altogether, 274 patients were ultimately included. The mean size of the maternal inlet was 1.0 cm larger in fetal HC >340 mm group compared with <=340 mm. In the vaginal delivery group, the difference was 1.3 cm. In the multivariable modeling, maternal age (odds ratio [OR] 1.09, 95 % confidence interval [CI] 1.02-1.17), fetal HC (OR 1.05, 95 % CI 1.02-1.09), and maternal inlet circumference (OR 0.95, 95 % CI 0.92-0.97) had significance for the risk of cesarean section. In the ROC analysis, the area under the curve (AUC) value for the pelvic inlet was 0.736 (p < 0.001, 95 % CI 0.656-0.816), and in the subgroups with fetal HC <=340 and >340 mm, AUCs were 0.634 (p < 0.11, 95 % CI 0.493-0.775) and 0.836 (p < 0.001, 95 % CI 0.751-0921), respectively. CONCLUSIONS: Labor arrest was associated with the linear relationship between the maternal pelvic dimensions and the fetal size. Therefore, the approach should be changed from standardized pelvimetric threshold values to passenger-passageway ratio analyzed by multivariable modeling to find more accurate methods to predict cephalopelvic disproportion. PMID- 24816687 TI - MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer. AB - Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and beta catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and beta-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and beta-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention. PMID- 24816689 TI - A randomized controlled trial comparing cosmetic outcome after skin closure with 'staples' or 'subcuticular sutures' in emergency cesarean section. AB - OBJECTIVE: To compare staples with subcuticular sutures for skin closure in emergency Cesarean sections (CS). METHODS: One hundred and thirty women (undergoing emergency CS without previous abdominal delivery) were randomly assigned to either staples or subcuticular skin closure (monocryl 3-0). Primary outcome of the study was cosmetic outcome [as assessed by patient and independent observer: Patient Scar Assessment Scale (PSAS) and Observer Scar Assessment Scale (OSAS), respectively], 6 weeks post-operative. Secondary outcomes were wound complications, operating time, post-operative pain (visual analogue scale day 3 post-operative and patient assessment of pain in scar 6 weeks post-operative), and duration of hospital stay. RESULTS: 112 women were available for evaluation of scar 6 weeks post-operative. Cosmetic result of staples was significantly better than subcuticular sutures (PSAS and OSAS: p value 0.022 and 0.000, respectively), with significantly lesser duration of surgery (24 vs. 32 min: p value 0.000) and comparable post-operative pain (pain on day 3 and 6 weeks post operatively: p value 0.474 and 0.179, respectively) and wound complications (p value 0.737). However, duration of stay in hospital was increased (6 vs. 3 days: p value 0.001). CONCLUSION: Staples are the method of choice for skin closure in emergency CS as they are significantly better than subcuticular sutures with respect to cosmesis and duration of surgery. Post-operative pain and wound complications are comparable in two groups. However, staples are associated with significantly increased duration of hospital stay. Trial registered in clinical trial registry CTRI: REF/2013/05/005087. PMID- 24816690 TI - A highly sensitive nucleic acid stain based on amino-modified tetraphenylethene: the influence of configuration. AB - We designed and synthesized a new amino-functionalized tetraphenylethene (TPE) derivative as a highly sensitive dye for the detection of dsDNA and oligonucleotide in both solution and a gel matrix. We further revealed that the cis configuration dye showed a much higher sensitivity than its trans isomer for the first time. PMID- 24816691 TI - Comparative effects of snoring sound between two minimally invasive surgeries in the treatment of snoring: a randomized controlled trial. AB - BACKGROUND: Minimally invasive surgeries of the soft palate have emerged as a less-invasive treatment for habitual snoring. To date, there is only limited information available comparing the effects of snoring sound between different minimally invasive surgeries in the treatment of habitual snoring. OBJECTIVE: To compare the efficacy of palatal implant and radiofrequency surgery, in the reduction of snoring through subjective evaluation of snoring and objective snoring sound analysis. PATIENTS AND METHOD: Thirty patients with habitual snoring due to palatal obstruction (apnea-hypopnea index <=15, body max index <=30) were prospectively enrolled and randomized to undergo a single session of palatal implant or temperature-controlled radiofrequency surgery of the soft palate under local anesthesia. Snoring was primarily evaluated by the patient with a 10 cm visual analogue scale (VAS) at baseline and at a 3-month follow-up visit and the change in VAS was the primary outcome. Moreover, life qualities, measured by snore outcomes survey, and full-night snoring sounds, analyzed by a sound analytic program (Snore Map), were also investigated at the same time. RESULTS: Twenty-eight patients completed the study; 14 received palatal implant surgery and 14 underwent radiofrequency surgery. The VAS and snore outcomes survey scores were significantly improved in both groups. However, the good response (postoperative VAS <=3 or postoperative VAS <=5 plus snore outcomes survey score >=60) rate of the palatal implant group was significantly higher than that of the radiofrequency group (79% vs. 29%, P = 0.021). The maximal loudness of low-frequency (40-300 Hz) snores was reduced significantly in the palatal implant group. In addition, the snoring index was significantly reduced in the radiofrequency group. CONCLUSIONS: Both palatal implants and a single stage radiofrequency surgery improve subjective snoring outcomes, but palatal implants have a greater effect on most measures of subjective and objective snoring. Multi-stage radiofrequency surgery was not tested. TRIAL REGISTRATION: ClinicalTrials.gov NCT01955083. PMID- 24816692 TI - Population-level impact of shorter-course regimens for tuberculosis: a model based analysis. AB - Despite current control efforts, global tuberculosis (TB) incidence is decreasing slowly. New regimens that can shorten treatment hold promise for improving treatment completion and success, but their impact on population-level transmission remains unclear. Earlier models projected that a four-month regimen could reduce TB incidence by 10% but assumed that an entire course of therapy must be completed to derive any benefit. We constructed a dynamic transmission model of TB disease calibrated to global estimates of incidence, prevalence, mortality, and treatment success. To account for the efficacy of partial treatment, we used data from clinical trials of early short-course regimens to estimate relapse rates among TB patients who completed one-third, one-half, two thirds, and all of their first-line treatment regimens. We projected population level incidence and mortality over 10 years, comparing standard six-month therapy to hypothetical shorter-course regimens with equivalent treatment success but fewer defaults. The impact of hypothetical four-month regimens on TB incidence after 10 years was smaller than estimated in previous modeling analyses (1.9% [95% uncertainty range 0.6-3.1%] vs. 10%). Impact on TB mortality was larger (3.5% at 10 years) but still modest. Transmission impact was most sensitive to the proportion of patients completing therapy: four-month therapy led to greater incidence reductions in settings where 25% of patients leave care ("default") over six months. Our findings remained robust under one-way variation of model parameters. These findings suggest that novel regimens that shorten treatment duration may have only a modest effect on TB transmission except in settings of very low treatment completion. PMID- 24816693 TI - The surface protease ompT serves as Escherichia coli K1 adhesin in binding to human brain micro vascular endothelial cells. AB - Escherichia coli (E. coli) K1 is the most common bacteria that cause meningitis in the neonatal period. But it's not entirely clear about how E. coli crosses the blood-brain barrier. The features of the ompT deletion in meningitic E. coli infection were texted in vitro. In comparison with the parent strain, the isogenic ompT deletion mutant was significantly less adhesive to human brain microvascular endothelial cells (HBMEC). The adhesion-deficient phenotype of the mutant was restored to the level of the wild-type by complementing with low-level OmpT expression plasmid. Interestingly, the adhesion was enhanced by point mutation at the OmpT proposed catalytic residue D85. Compared with the poor adhesive activity of bovine serum albumin-coated fluorescent beads, recombinant OmpT or catalytically inactive variant of OmpT-coated beads bound to HBMEC monolayer effectively. Our study suggests that OmpT is important for bacterial adhesion while entering into central nervous system, and the adhesion does not involve in the proteolytic activity of OmpT. PMID- 24816694 TI - Impact of Cr3+ pollution on microbial characteristics in purple paddy soil. AB - Impact of Cr(3+) pollution on soil microbial quantity, enzyme activity and biological activity in purple paddy soil were studied under incubation conditions. The results showed that amounts of all tested microbes and enzyme activities in soil were inhibited by low Cr(3+) concentration (200mg/kg). After 7 day incubation, sulfate-reducing activity, methanogen activity, denitrifying activity and anaerobic nitrogen-fixing activity in soil were reduced by 34%, 66%, 98% and 65% respectively. Amounts of soil microbes were remarkably inhibited with medium Cr(3+) concentration (400mg/kg), all with reduction of more than 50%; and all tested soil biological activity was almost recovered in the fourth week except soil denitrifying activity. Activities of urease, invertase, neutral phosphatase and catalase were decreased by 60%, 21%, 59% and 42%, respectively. With high Cr(3+) concentration (1600mg/kg), amounts and activities of tested microbes had only about 1% of that with control. As calculated from the regression equation, the ED50 (ecological dose) values of activities of soil urease, invertase and catalase were around 800mg/kg; the ED50 values of soil sulfate-reducing activity, methanogen activity and anaerobic nitrogen-fixing activity were also around 800mg/kg with an exception of soil denitrifying activity which ranged 35 to 39 mg/kg. According to the Standards of National Soil Environmental Quality in China and their sensitivities to 400mg/kg Cr(3+) concentration, quantity of denitrifying bacteria, urease activity and denitrifying activity could be selected as indicators of early warning for Cr(3+) pollution in purple paddy soil. PMID- 24816695 TI - Microbial characteristics of purple paddy soil in response to Pb pollution. AB - The study focused on the change of microbial characteristics affected by Plumbum pollution with purple paddy soil in an incubation experiment. The results showed that low concentration of Plumbum had little effect on most of microbial amounts, biological activity and enzymatic activity. However, denitrifying activity was inhibited severely, and inhibition rate was up to 98%. Medium and high concentration of Plumbum significantly reduced the amounts and activity of all microorganisms and enzymatic activity, which increased with incubation time. Negative correlations were found between Plumbum concentrations and microbial amounts, biological activity and enzymatic activities except fungi and actinomyces. Thus they can be used to indicate the Plumbum pollution levels to some extent. LD(50) of denitrifying bacteria (DB) and ED50 of denitrifying activity were 852mg/kg and 33.5mg/kg. Across all test soil microbes, denitrifying bacteria was most sensitive to Plumbum pollution in purple paddy soil. Value of early warning showed that anaerobic cellulose-decomposing bacteria (ACDB) and actinomyces were also sensitive to Plumbum pollution. We concluded that denitrifying activity, actinomyces, ACDB or DB can be chosen as predictor of Plumbum contamination in purple paddy soil. PMID- 24816696 TI - Mutagenic breeding of Quambalaria cyanescens strain for the production of milk clotting enzymes. AB - A strain for producing rennet was screened from red kojic rice and identified as Quambalaria cyanescens. In the current work, various mutagenic treatments, such as UV, diethyl sulfate and their combinations were applied for improving the production of milk-clotting enzymes. The mutagenic conditions were optimized based on the fatality rate of the strain. A significant increasing in the productivity of the fungal rennet produced from the strain Quambalaria cyanescens was achieved and its milk-clotting activity (MCA) was increased from 57 to 117 (SU mL(-1)) through the mutagenic breeding. Further study showed that MCA was greatly inhibited (P < 0.0001) by pepstain A, indicating it belongs to an aspartic acid protease, but absence of serine protease, metalloproteinase and cysteine protease. The mutated strain with the highest activity of milk-clotting enzymes showed a stable capacity to produce rennet through the test of its heritability. This is the first report of the breeding study of Quambalaria cyanescens for its capacity to produce microbial rennet. PMID- 24816697 TI - Expression of trehalose synthase gene from Pseudomonas putida P06 in Pichia pastoris. AB - The trehalose synthase (TreS) gene from Pseudomonas putida P06 was successfully ligated with pPICZaA expression vector by the EcoRI and XbaI and was transformed into Pichia pastoris GS115 by electrotransformation. The trehalose synthase gene was fused to the genome of Pichia pastoris GS115 and was controlled by AOX1 promoter. The TreS protein was successfully expressed in intracellularly. SDS PAGE results illustrated that a specificity protein band was observed at about 76 kDa. The cell lysates could convert 60% maltose into trehalose at 50 degrees C and pH 7.5 in 10% maltose substrate for 24 h. The Pichia pastorisas exogenous gene expression host is safer to produce endotoxin free TreS than E.coli. PMID- 24816698 TI - Preparation of a low-cost minimal medium for engineered Escherichia coli with high yield of human-like collagen II. AB - In order to reduce the production cost of human-like collagen (HLC), a minimal medium was introduced. On the base of Design of experiments (DOE), especially Plackett-Burman design and central composite design, a modified minimal medium that could give a high yield of HLC was developed. The optimum minimal medium for engineered E. coli BL21 DeltaptsG contained 6.11g/L of glucose, 5.82g/L of (NH(4))(2)SO(4), 1.80'10(-4)g/L of thiamine and 3.00'10(-2)L of trace element solution, the other ingredients were same to that in M9 medium. And the HLC production of ptsG mutant reached to 0.26g/L in this optimized minimal medium, which approached to 0.27g/L produced by the strain without deleting ptsG gene in an optimized complex medium. PMID- 24816699 TI - The Study on the factors affecting transformation efficiency of E. coli competent cells. AB - The preparation of competent cell is the central step of bacteria transformation and has a great impact on transformation efficiency of nucleic acid. The aim of the research was to study the factors such as ionic species, strain types, plasmid concentration, ice-bath time and incubation time. The result shows that ionic species is fatal to the transformation efficiency, preparation of competent cells by monovalent ions (Li(+),Na(+),K(+)) and tervalent ion (Al(3+)) do not have capacity of transformation, preparation of competent cells by bivalent ion (Ba(2+),Ca(2+),Mn(2+),Mg(2+),Sr(2+)) has capacity of transformation. On the whole, the efficiency of Ca(2+) was found to be the optimum bivalent ion, following by Sr(2+),Mn(2+),Mg(2+),Ba(2+). On the other factors that affecting transformation efficiency, the transformation efficiency was the best when plasmid concentration was 100ng/mL, and ice-bath time should be controlled at about 30 min and incubate time selected as 60 min. Experiment of natural transformation later proves the existence of the phenomenon of natural transformation and it's also related to factors such as calcium chloride concentration, plasmid concentration and others. PMID- 24816700 TI - In vitro study of antigrowth capacity and antiacid capacity on Sreptococcus sobrinus 6715 of sorghum procyanidin dimers. AB - The bacteria grow in oral cavity and product acids, which could induce dental caries. In this study, in order to obtain the relationship between procyanidin dimers from sorghum episperm (sorghum procyanidins, SPC) and its anticaries effect. The extract of SPC purified by macroporous resin was divided into three parts by gel chromatography, marked as GPC-1, GPC-2, and GPC-3 in order. The ESI MS and MS/MS analysis indicated that the main composition of GPC-2 was procyanidin dimers. In addition, the capacities of antigrowth and antiacid on Sreptococcus sobrinus 6715 were analysised to investigate the effect of SPC dimers in protecting against dental caries. The results indicated that the minimum inhibitory concentration (MIC) of SPC dimers was 16 mg/mL. Furthermore, the SPC dimers had notable preventive effect < against the acid production of Sreptococcus sobrinus 6715 compared with the control group, which suppressed in a dose-dependent manner by pH decline. These findings indicated that SPC dimers had potential to be used as anticaries preventive medicine due to its strong capacity of antigrowth and antiacid. PMID- 24816701 TI - Identification and characterization of a helicase-like protein encoded by a Thermus siphoviridae phage 4 gene. AB - DNA helicases are essential motor proteins that unwind duplex DNA to yield the transient single-stranded DNA intermediates required for replication, recombination, and repair. As laboratory model strains of thermostable bacteria, the roles of Thermus have been studied and discussed extensively. In this study, one gene (ORF42) encoding a helicase-like protein of TSP4 (Thermus Siphoviridae phage 4) was identified and characterized. The results showed that ORF42 protein shared a higher homology to the DnaB helicases of Thermus bacteriophages P74-26 and P24-46. DNA helicase assay and atomic force microscopy (AFM) revealed that ORF42 protein was an Mg(2+)-dependent helicase with ATPase activity and involved in DNA unwinding. These evidences indicated that ORF42 protein, homologue of DnaB, probably acts as a helicase in TSP4. This study will not only contribute to explore the co-evolution of Thermus phages and their hosts but also shed a new light on the "arm-race" pattern between Thermus and its predator (TSP4), providing a basis for the theoretical investigations of new generation bacteriophage therapy. PMID- 24816702 TI - Cytotoxicity of hollow silica nanoparticles loaded with photosensitizes on huh-7 cells. AB - To observe the cytotoxic effect of the photodynamic therapy mediated by the traditional photosensitizer polyhematoporphyrin (C(34)H(38)N(4)NaO(5), Photosan II Photosan-II was loaded into HSNP by one-step wet chemical, PS) and hollow silica nanoparticles (HSNP) loaded PS on Huh-7 cells and compare the cytotoxic effects. -based synthetic route. The cellular viability was determined by 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Apoptotic and necrotic cells were measured by flow cytometry. The suitable drug concentrations of free PS and HSNP loaded PS on Huh-7 cells were 20mg/L and 5mg/L respectively, and the suitable incubation time were 4 h and 2 h respectively. Under the same drug concentration, the survival rates of free PS and HSNP loaded PS were 62.46%+/-1.93% and 6.54%+/-1.24% <. Under the same drug concentration and incubation time, the total rates of apoptosis necrosis caused by free PS and HSNP loaded PS mediated PDT were respectively 22.00% +/- 2.24% and 87.23% +/- 2.1% <. PS-loaded HSNP mediated PDT can inhibit proliferation of cancer cells and induce apoptosis more quickly and effectively. As the loading system of PS, HSNP can make the photosensitizer have stronger solubility and drug concentration efficiency, which can significantly improve the therapeutic effect of PDT. PMID- 24816703 TI - Separation characteristics of lignin from Eucalyptus camaldulensis lignin celluloses for biomedical cellulose. AB - The separation characteristics of Eucalyptus camaldulensis biomass cell wall were investigated and analyzed by FTIR, UV and XRD. The result showed that the crystallinity of untreated sample were lower than ones of treated samples at 10 degrees C, 20 degrees C and 30 degrees C. Effect of temperature was very notable so as to use the lower temperature if cellulose would be kept natural structure during lignin separation from lignincellulose. Treatment time and temperature had a notably significant effect on SLR of E. camaldulensis lignin cellulose, and the SLR increased gradually with the temperature increment, and SLR were 73.35% at 10 degrees C, 80.14% at 20 degrees C, 83.73% at 30 degrees C. The maximum of SLR increased with the rising of temperature 10 degrees C, 20 degrees C and 30 degrees C. Consequently, the best separation conditions of lignin were 24h and 30 degrees C. During hemicelluloses separation, the peak of C=O disappeared, and the peak of CO-OR, O-H and C-O abated, resulting that acetyl in hemicelluloses were mainly broken by the dehydration, heat decomposition reaction and mild thermal degradation. During lignin separation, the side chain and benzene ring of lignin of E. urophynis lignin cellulose reached the largest bond breaking characteristics under the temperature of 10 degrees C at 7h, 20 degrees C at 7h and 30 degrees C at 24h. PMID- 24816704 TI - Web-based e-learning and virtual lab of human-artificial immune system. AB - Human immune system is as important in keeping the body healthy as the brain in supporting the intelligence. However, the traditional models of the human immune system are built on the mathematics equations, which are not easy for students to understand. To help the students to understand the immune systems, a web-based e learning approach with virtual lab is designed for the intelligent system control course by using new intelligent educational technology. Comparing the traditional graduate educational model within the classroom, the web-based e-learning with the virtual lab shows the higher inspiration in guiding the graduate students to think independently and innovatively, as the students said. It has been found that this web-based immune e-learning system with the online virtual lab is useful for teaching the graduate students to understand the immune systems in an easier way and design their simulations more creatively and cooperatively. The teaching practice shows that the optimum web-based e-learning system can be used to increase the learning effectiveness of the students. PMID- 24816705 TI - Plasmid mediated kallistain gene expression via intramuscular electroporation delivery in vivo for treatment of NCI-H446 subcutaneous xenograft tumor. AB - Kallistatin (KAL) is a novel anti-tumor protein with anti-angiogenic activity. The aim of this study was to investigate whether intramuscular injection of KAL plasmid DNA by electroporation could inhibit NCI-H446 subcutaneous xenograft tumor growth in mice. The tumor model of BALB/c nude mice was induced by subcutaneous inoculation of 5*10(6) NCI-H446 cells into the mice right flank. The next day, naked plasmid pEGFP or pKAL was electrotransfered into the skeletal muscle of nude mice (n=6 for each group), with the optimized electroporation conditions. Tumor cells migration was assessed by E-cadherin staining; Proliferation was determined by anti-Ki-67 staining; and apoptosis was assayed via TUNEL, tumor microvessel density (MVD) was examined by anti-CD34 staining to evaluate the angiogenesis of tumor. Compared to the pEGFP treating group, tumor growth was inhibited by 85% (pEGFP group: 486 +/- 187 mm(3), pKAL group: 71+/-33 mm(3)) at day 42, the MVD of tumor tissues was significantly decreased, and tumor cellular proliferation was also inhibited. The results indicate that this therapeutic strategy might serve as a promising approach for cancer clinical therapy. PMID- 24816706 TI - High-level expression of fusion peptide Dybowskin-2CDYa and hEGF in E. coli and its dual function. AB - Dybowskin-2CDYa (Dy2), with a broad antimicrobial spectrum and low hemolytic feature, is a newly discovered type of antimicrobial peptides from Rana dybowskii. In order to get a dual function peptide which inhibits bacterial growth and promotes cell proliferation, we cloned the gene of Dy2and hEGF (human epidermal growth factor) into the prokaryotic expression vector pET-30a(+). With isopropyl-beta-D-thiogalactoside (IPTG) induction, a 13.7KDa peptide with a 6*His tag was highly expressed in the form of inclusion in E. coli BL2l (DE3). SDS-PAGE and western-blot confirmed the expression of the fusion peptide hEGF-Dy2. Under the optimized condition of 1.0mmol/L IPTG induction and incubation time 4h at 37o, the yield of hEGF-Dy2reached 30mg/L following purification on nickel nitrilotriacetic acid (Ni-NTA) metal affinity chromatography matrices. The purified fusion peptide showed significant antibacterial activities against Staphylococcus aureus, Escherichia coli O157, Pseudomonas aeruginosa and proliferating activities on NIH3T3. These results indicated that the fusion peptide might have a good prospect in therapy of trauma and burns. PMID- 24816707 TI - Design of a microbial contamination detector and analysis of error sources in its optical path. AB - Microbial contamination is a growing concern in the food safety today. To effectively control the types and degree of microbial contamination during food production, this paper introduces a design for a microbial contamination detector that can be used for quick in-situ examination. The designed detector can identify the category of microbial contamination by locating its characteristic absorption peak and then can calculate the concentration of the microbial contamination by fitting the absorbance vs. concentration lines of standard samples with gradient concentrations. Based on traditional scanning grating detection system, this design improves the light splitting unit to expand the scanning range and enhance the accuracy of output wavelength. The motor rotation angle phi is designed to have a linear relationship with the output wavelength angle lambda, which simplifies the conversion of output spectral curves into wavelength vs. light intensity curves. In this study, we also derive the relationship between the device's major sources of errors and cumulative error of the output wavelengths, and suggest a simple correction for these errors. The proposed design was applied to test pigments and volatile basic nitrogen (VBN) which evaluated microbial contamination degrees of meats, and the deviations between the measured values and the pre-set values were only in a low range of 1.15% - 1.27%. PMID- 24816708 TI - Performance improvement of a microbial fuel cell based on adaptive fuzzy control. AB - Microbial fuel cells have been obtaining more and more attention with the associated abilities of continuous electrical power supply and wastewater treatment. Because of its complicated reaction mechanism and its inherent characteristics of time varying, uncertainty, strong coupling and nonlinearity, there are complex control challenges in microbial fuel cells. In this paper, an adaptive fuzzy control scheme is proposed for the microbial fuel cell system to achieve constant voltage output under different loads. A main fuzzy controller is used to track the set value, and an auxiliary fuzzy controller is applied to adjust the factors of the main controller. Simulation results show that the output voltage can track the given value well. The proposed adaptive fuzzy controller can give better steady-state behavior and faster response, and it improves the running performance of the microbial fuel cell. PMID- 24816709 TI - The effect of enzyme digestion time on the detection of diatom species. AB - This study is aimed at detecting diatom in lung, liver and kidney tissues using PCR - DHPLC technology after different periods of enzyme digestion to assess the effect of enzyme digestion on the detection of diatom species. Twenty Randomly selected experimental rabbits were drowned at the same place. Their liver, kidney, and lung tissues were removed for sampling. After the extraction of DNA from the samples, amplification was conducted with specific primers of the SSU gene of diatom. Then, an analysis was performed with agarose gel electrophoresis and DHPLC. Within 2 h-8 h, the amount of the diatom species found in the lung gradually increased over time and was statistically significant <. After 8 h, with enzyme digestion, the amount of the diatom species found in lung showed no significant increase (>). However, as for the liver and kidney, within 2h-6h, the amount of the diatom species gradually increased over time and was statistically significant <. After 6h, the fig. did not present significant growth (>). The amount of the diatom species found in the organs after different periods of digestion time had significant differences, which provides a reference for the detection of diatoms and also, has a good application prospect in the forensic identification of drowning. PMID- 24816710 TI - Effects of probiotics on the growth performance and intestinal micro flora of broiler chickens. AB - Antibiotics have been used in poultry industry for decades to promote growth and protect animals from diseases, followed by various side effects. In efforts of searching for a better alternative, probiotic is of extensive attention. We investigated the effects of Bacillus subtitles, Rhodopseudomonas palustris, Candida utilis and Lactobacillus acidophilus as 0.1% (W/W) feed additives on broiler growth performance and intestinal microflora. The results showed the probiotics treatments significantly improved growth of broilers. Broilers supplemented with B. subtilis and L. acidophilus weighed 18.4% and 10.1% more than birds in control group at 42 days of age. Furthermore the feed conversion ratios of the birds in the two groups were also improved, decreasing 9.1% and 12.9%, respectively. Further study indicated a significant increase of cecal Lactobacilli concentration in briolers supplemented with probiotics, expecially in L. acidophilus treatment group. Meanwhile, the count of cecal Actinomyces in birds treated with probiotics was significantly lower compared with the control group. In conclusion, probiotics such as B. subtitles and L. acidophilus are good alternatives to antibiotics in promoting growth resulting from a beneficial modulation of the intestinal micro flora, which leads to increased efficiency of intestinal digestion in the host animal. PMID- 24816711 TI - 3D protein structure prediction of influenza A virus based on optimization genetic algorithm. AB - The 3D structure of close polymer is constituted by the interaction of close contact couples among amino acid residues. In this paper, 3D protein structure of influenza A virus was predicted. Twenty kinds of amino acid residues were divided into four categories according to the number of close contact couples. The stable structure with minimum energy was obtained by using optimization genetic algorithm. The HNXP 3D lattice model was established to predict the 3D protein structure. It can be concluded that the two kinds of structures are significantly similar by computing the similarity. PMID- 24816712 TI - Therapeutic effects of Chinese herbal medicine against neuroendocrinological diseases especially related to hypothalamus-pituitary-adrenal and hypothalamus pituitary-gonadal axis. AB - This is a systemic review of plants used traditionally for neuroendocrinological diseases related to hypothalamus-pitutary-adrenal (HPA) and hypothalamus-pitutary gland (HPG) axis. By searching from PubMed literature search system (1950-2013), Medline (1950-2013) and CNKI (China Journals of Full-text database; 1989-2013), 105 papers met the inclusion criteria were displayed in this review. 96 herbal drugs were classified into two parts which include hormones mainly related to HPA and HPG axis. The full scientific name of each herbal medicine, dose ranges and routes, models or diseases, affect on hormones and pertinent references are presented via synoptic tables. Herbal remedies that have demonstrable the activities of hormones have provided a potential to various diseases related to neunoendocrine and deserve increased attention in future studies. This review provides a basis for herbs use in neuroendocrinological diseases. The data collected here will benefit to further research associated to herbal medicines and hormones. PMID- 24816713 TI - Endogenous RNAi pathways in C. elegans. AB - In addition to several hundred microRNAs, C. elegans produces thousands of other small RNAs targeting coding genes, pseudogenes, transposons, and other noncoding RNAs. Here we review what is currently known about these endogenous small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs), providing an overview of their biogenesis, their associated protein factors, and their effects on mRNA dynamics and chromatin structure. Additionally, we describe how the molecular actions of these classes of endogenous small RNAs connect to their physiological roles in the organism. PMID- 24816714 TI - Role of HIV in amyloid metabolism. AB - HIV infection has changed from an acute devastating disease to a more chronic illness due to combination anti-retroviral treatment (cART). In the cART era, the life expectancy of HIV-infected (HIV+) individuals has increased. More HIV + individuals are aging with current projections suggesting that 50% of HIV + individuals will be over 50 years old by 2015. With advancing age, HIV + individuals may be at increased risk of developing other potential neurodegenerative disorders [especially Alzheimer's disease (AD)]. Pathology studies have shown that HIV increases intra and possibly extracellular amyloid beta (Abeta42), a hallmark of AD. We review the synthesis and clearance of Abeta42; the effects of HIV on the amyloid pathway; and contrast the impact of AD and HIV on Abeta42 metabolism. Biomarker studies (cerebrospinal fluid AB and amyloid imaging) in HIV + participants have shown mixed results. CSF Abeta42 has been shown to be either normal or diminished in with HIV associated neurocognitive disorders (HAND). Amyloid imaging using [(11)C] PiB has also not demonstrated increased extracellular amyloid fibrillar deposits in HAND. We further demonstrate that Abeta42 deposition is not increased in older HIV + participants using [(11)C] PiB amyloid imaging. Together, these results suggest that HIV and aging each independently affect Abeta42 deposition with no significant interaction present. Older HIV + individuals are probably not at increased risk for developing AD. However, future longitudinal studies of older HIV + individuals using multiple modalities (including the combination of CSF markers and amyloid imaging) are necessary for investigating the effects of HIV on Abeta42 metabolism. PMID- 24816716 TI - The oriental fruitfly Bactrocera dorsalis s.s. in East Asia: disentangling the different forces promoting the invasion and shaping the genetic make-up of populations. AB - The Oriental fruit fly, Bactrocera dorsalis sensu stricto, is one of the most economically destructive pests of fruits and vegetables especially in East Asia. Based on its phytophagous life style, this species dispersed with the diffusion and implementation of agriculture, while globalization allowed it to establish adventive populations in different tropical and subtropical areas of the world. We used nine SSR loci over twelve samples collected across East Asia, i.e. an area that, in relatively few years, has become a theatre of intensive agriculture and a lively fruit trade. Our aim is to disentangle the different forces that have affected the invasion pattern and shaped the genetic make-up of populations of this fruit fly. Our data suggest that the considered samples probably represent well established populations in terms of genetic variability and population structuring. The human influence on the genetic shape of populations and diffusion is evident, but factors such as breeding/habitat size and life history traits of the species may have determined the post introduction phases and expansion. In East Asia the origin of diffusion can most probably be allocated in the oriental coastal provinces of China, from where this fruit fly spread into Southeast Asia. The spread of this species deserves attention for the development and implementation of risk assessment and control measures. PMID- 24816715 TI - Practical application of acid dissociation in monitoring patients treated with adalimumab. AB - Patients treated with adalimumab (ADL) can induce anti-ADL antibodies (AAA) formation that is associated with low drug levels and clinical non-response. But, in the majority of the assays, the measurement of AAA is hampered by the presence of the drug itself. In support of immunogenicity assessment in clinical samples with subtherapeutic ADL levels, we proved acid pre-treatment for AAA detection with the Promonitor-enzyme-linked immunosorbent assay (ELISA). Were measured AAA after acidification in 32 serum samples with a subtherapeutic ADL trough level. ADL and AAA concentrations were measured by ELISA (Promonitor). The impact of drug concentration on AAA recovery (with or without acidification) was also evaluated by mixing known amounts of ADL (0.25, 0.5 and 1 mg/L) and AAA (100, 200, 300 and 400 AU/mL) from clinical samples in pooled serum. The drug significantly inhibited the detection of AAA in untreated samples. And progressively higher levels of ADL cause increasing inhibition of signal. Acid pre-treatment carried a significant increase in assay response, particularly at lower free ADL concentrations. AAA were detected in the 53 % of the samples after acid dissociation. In seven patients, the positive AAA after dissociation was detected in the first monitoring of ADL and five patients were positive 3 months later for AAA with the standard assay. Monitoring AAA using acid dissociation in patients with subtherapeutic circulating level of ADL could detect precocious problems of bioavailability, assess the immunogenicity of ADL and may be used to optimise dose regimens, thereby preventing prolonged use of inadequate therapy and guide change of treatment. PMID- 24816717 TI - Impact of host plant connectivity, crop border and patch size on adult Colorado potato beetle retention. AB - Tagged Colorado potato beetles (CPB), Leptinotarsa decemlineata (Say), were released on potato plants, Solanum tuberosum L., and tracked using a portable harmonic radar system to determine the impact of host plant spatial distribution on the tendency of the pest to remain on the colonized host plant or patch. Results confirmed the long residency time on the host plant and showed that close connection of the plant to neighboring plants hastened dispersal between plants. Tracking walking CPB for over 6 h in small potato plots revealed that all types of mixed borders tested (potato/bare ground, potato/timothy and potato/woodland) acted as a strong barrier and retained beetles within the patch. In another experiment in potato patches surrounded by bare ground borders, tracked walking CPB displayed similar behaviour for up to four days. The distribution of turning angles in the CPB walking paths was not uniform and corresponded to beetles following the edge rows of potato patches in response to the crop border barrier or reversing their direction as they reached the end of a row and therefore a border. Patch size had no or little effect on beetle retention in the patch. The relative distribution of counts of tagged beetles detected among small (16 m2), medium (64 m2) and large size (256 m2) patches of potato four days after initial release remained similar to that of numbers released. Even though mixed crop borders were a strong barrier to walking CPB emigrating from potato patches, the departure rate of beetles over time was high. Results suggest that the effect of mixed borders is largely limited to dispersal by walking and does not apply to beetles leaving host patches by flight. The manipulation of crop borders and patch size seem to have limited potential for the management of CPB emigrating from potato fields. PMID- 24816718 TI - Integration of molecular profiling and chemical imaging to elucidate fibroblast microenvironment impact on cancer cell phenotype and endocrine resistance in breast cancer. AB - The tumor microenvironment is known to play a key role in altering the properties and behavior of nearby cancer cells. Its influence on resistance to endocrine therapy and cancer relapse, however, is poorly understood. Here we investigate the interaction of mammary fibroblasts and estrogen receptor-positive breast cancer cells in three-dimensional culture models in order to characterize gene expression, cellular changes, and the secreted protein factors involved in the cellular cross-talk. We show that fibroblasts, which are the predominant cell type found in the stroma adjacent to the cancer cells in a tumor, induce an epithelial-to-mesenchymal transition in the cancer cells, leading to hormone independent growth, a more invasive phenotype, and resistance to endocrine therapy. Here, we applied a label-free chemical imaging modality, Fourier transform infrared (FT-IR) spectroscopic imaging, to identify cells that had transitioned to hormone-independent growth. Both the molecular and chemical profiles identified here were translated from cell culture to patient samples: a secreted protein signature was used to stratify patient populations based on gene expression and FT-IR was used to characterize breast tumor patient biopsies. Our findings underscore the role of mammary fibroblasts in promoting aggressiveness and endocrine therapy resistance in ER-positive breast cancers and highlight the utility of FT-IR for the further characterization of breast cancer samples. PMID- 24816719 TI - Bioinformatics study of delta-12 fatty acid desaturase 2 (FAD2) gene in oilseeds. AB - Fatty acid desaturases constitute a group of enzymes that introduce double bonds into the hydrocarbon chains of fatty acids to produce unsaturated fatty acids. In plants, seed-specific delta-12 fatty acid desaturase 2 (FAD2) is responsible for the high content of linoleic acid by inserting a double bond at the delta-12 (omega-6) position of oleic acid. In this study, sixteen FAD2 and FAD2-2 protein sequences from oilseeds were analyzed by computational tools including two databases of the NCBI and EXPASY and data management tools such as SignalP, TMHMM, Psort, ProtParam, TargetP, PLACE and PlantCARE. These services were used to predict the protein properties such as molecular mass, pI, signal peptide, transmembrane and conserved domains, secondary and spatial structures. The polypeptide sequences were aligned and a neighbour-joining tree was constructed using MEGA5.1 to elucidate phylogenetic relationships among FAD2 genes. Based on the phylogenetic analysis species with high similarity in FAD2 sequence grouped together. FAD2 proteins include highly conserved histidine-rich motifs (HECGHH, HRRHH and HV[A/C/T]HH) that are located by three to five transmembrane anchors. For further investigations Sesamum indicum FAD2 was selected and analyzed by bioinformatics tools. Analysis showed no N-terminal signal peptide for probable localization of FAD2 protein in cytoplasmic organelles such as chloroplast, mitochondria and Golgi. Instead the C-terminal signaling motif YNNKL, Y(K/N)NKF or YRNKI allows FAD2 protein to selectively bind to and embed in the endoplasmic reticulum. FAD2 promoter contains different cis-regulatory elements involve in the biotic and abiotic stresses response or control of gene expression specifically in seeds. PMID- 24816720 TI - The suppressive role of SOX7 in hepatocarcinogenesis. AB - SOX7 is a transcription factor mediating various developmental processes. However, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we assessed the role of SOX7 in hepatocarcinogenesis. We found HCC samples exhibited lower levels of SOX7 mRNA and protein expression than non-tumor samples, and the expression of SOX7 was negatively correlated with tumor size. SOX7 expression was also reduced in four HCC cell lines (SMMC-7721, Hep3B, HepG2 and Huh 7). Overexpression of SOX7 could inhibit HCC cell growth, with G1to S phase arrest. In SOX7-overexpression cells, cyclin D1 and c-myc, two cell cycle promoters, were down-regulated. Moreover, ectopic expression of cyclin D1 or c-myc could override G1 to S pahse arrest induced by SOX7. Furthermore, overexpression of SOX7 suppressed tumor formation with down-regulation of cyclin D1 and c-myc in vivo. The expression of Ki-67, a proliferation marker, was also reduced in SOX7 overexpression tumors. Taken together, our study suggests that SOX7 plays an important inhibitory role in hepatocarcinogenesis, and might be a novel target for HCC therapy. PMID- 24816722 TI - Application of metabolic engineering for the biotechnological production of L valine. AB - The branched chain amino acid L-valine is an essential nutrient for higher organisms, such as animals and humans. Besides the pharmaceutical application in parenteral nutrition and as synthon for the chemical synthesis of e.g. herbicides or anti-viral drugs, L-valine is now emerging into the feed market, and significant increase of sales and world production is expected. In accordance, well-known microbial production bacteria, such as Escherichia coli and Corynebacterium glutamicum strains, have recently been metabolically engineered for efficient L-valine production under aerobic or anaerobic conditions, and the respective cultivation and production conditions have been optimized. This review summarizes the state of the art in L-valine biosynthesis and its regulation in E. coli and C. glutamicum with respect to optimal metabolic network for microbial L valine production, genetic strain engineering and bioprocess development for L valine production, and finally, it will shed light on emerging technologies that have the potential to accelerate strain and bioprocess engineering in the near future. PMID- 24816721 TI - Serological cross-reactivity between Merkel cell polyomavirus and two closely related chimpanzee polyomaviruses. AB - Phylogenetic analyses based on the major capsid protein sequence indicate that Merkel cell polyomavirus (MCPyV) and chimpanzee polyomaviruses (PtvPyV1, PtvPyV2), and similarly Trichodysplasia spinulosa-associated polyomavirus (TSPyV) and the orangutan polyomavirus (OraPyV1) are closely related. The existence of cross-reactivity between these polyomaviruses was therefore investigated. The findings indicated serological identity between the two chimpanzee polyomaviruses investigated and a high level of cross-reactivity with Merkel cell polyomavirus. In contrast, cross-reactivity was not observed between TSPyV and OraPyV1. Furthermore, specific antibodies to chimpanzee polyomaviruses were detected in chimpanzee sera by pre-incubation of sera with the different antigens, but not in human sera. PMID- 24816723 TI - ItchyQoL bands: pilot clinical interpretation of scores. PMID- 24816724 TI - Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial. AB - PURPOSE: AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients. PATIENTS AND METHODS: Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation. RESULTS: Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed. CONCLUSION: Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy. PMID- 24816725 TI - Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial. AB - PURPOSE: This phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC). METHODS: Fifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16). RESULTS: The hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29-1.08; P = 0.07) and 0.55 (95 % CI 0.3-1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26-0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31 1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3 1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells >=3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation. CONCLUSIONS: MGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703. PMID- 24816726 TI - Trop2 gene: a novel target for cervical cancer treatment. AB - OBJECT: Trop2 plays an important role in proliferation and invasion of tumors. Extensive research has shown that the expression level of Trop2 is closely related to the progress of cervical diseases. This study was to explore the effects of Trop2 on cell proliferation and apoptosis in cervical cancer. METHODS: Trop2 was knocked down by shRNA in CaSki cells. The expression level of mRNA and protein was detected by real-time PCR and western blot, respectively. Cell proliferation was determined by CCK-8 and clone formation assay; apoptosis was measured by flow cytometry; cell cycle and apoptosis-related proteins cyclinD1, P53, bcl-2, bax, caspase 3, 8 and 9 were analyzed as well to investigate possible mechanism. RESULTS: Trop2 expression was effectively repressed in CaSki cells by Trop2 shRNA, which resulted in inhibition of proliferation and colony formation, whereas apoptosis rate was significantly increased. Furthermore, in Trop2 knockdown CaSki cells, the expression of cyclinD1 and bcl-2 was significantly down-regulated, while that of P53 and bax was up-regulated accompanied by increased activities of caspase 9 and 3 but not caspase 8. CONCLUSIONS: Trop2 is important in proliferation and apoptosis regulation in CaSki cells, which may become a novel target for cervical cancer treatment. PMID- 24816728 TI - Reconstructive strategies for dermatofibrosarcomas of the face: role of regenerative dermal templates. AB - BACKGROUND: Dermatofibrosarcomas protuberans is a challenging cutaneous tumor from an oncologic and reconstructive surgical point of view. Involvement of functionally and aesthetically sensitive areas, such as facial units, in young patients accounts for more demanding cases. An updated evaluation of most beneficial excisional/reconstructive strategies in these cases is still lacking. METHODS: We investigated the potential of regenerative dermal templates in staged postoncologic reconstructive management of a young woman affected by a dermatofibrosarcomas protuberans of the forehead involving the frontal bone. RESULTS: Final result was optimal in terms of cosmetic and functional recovery, obtaining a pliability, softness, and color similar to surrounding healthy skin. CONCLUSION: In facial dermatofibrosarcomas protuberans, staged reconstruction with regenerative dermal templates provides a conservative yet safe and effective management, achieving optimal aesthetic outcomes. We suggest its adoption as first-line treatment in facial dermatofibrosarcomas protuberans that cannot be repaired by direct suture and in equivalent benign yet challenging cases. PMID- 24816727 TI - Bile acid supplementation improves established liver steatosis in obese mice independently of glucagon-like peptide-1 secretion. AB - Bile acids or its derivatives may influence non-alcoholic fatty liver disease development through multiple mechanisms. Intestinal L-cells secrete glucagon-like peptide-1 (GLP-1) and can be activated by bile acids (BA) influencing insulin resistance and hepatic steatosis development and progression. The aim of the present study was to assess the effects of cholic acid (CA) or ursodeoxycholic acid (UDCA) administration on portal and systemic levels of GLP-1 in genetically obese mice with established hepatic steatosis. Eight-week-old ob/ob mice were fed CA or UDCA during 4 weeks. Systemic and portal GLP-1 levels were measured as well as glucose tolerance test, serum and biliary parameters, hepatic triglyceride content, liver histology, and hepatic gene expression of relevant genes related to bile secretion. Eight-week-old ob/ob mice exhibited marked obesity, hyperinsulinemia, and fasting hyperglycemia. Administration of both CA and UDCA was associated to decreased hepatic triglyceride content and complete reversion of histological steatosis. BA-fed animals did not exhibit significant differences in glucose tolerance. In addition, neither CA nor UDCA administration significantly influenced portal or systemic GLP-1 levels. CA and UDCA strongly ameliorated established fatty liver in ob/ob mice independently of the GLP-1 incretin pathway. Thus, the anti-steatotic action of these bile acids is likely related to direct hepatic effects. PMID- 24816729 TI - Structural control of hierarchically-ordered TiO2 films by water for dye sensitized solar cells. AB - A facile way of controlling the structure of TiO(2) by changing the amount of water to improve the efficiency of dye-sensitized solar cells (DSSCs) is reported. Hierarchically ordered TiO(2) films with high porosity and good interconnectivity are synthesized in a well-defined morphological confinement arising from a one-step self-assembly of preformed TiO(2) (pre-TiO(2)) nanocrystals and a graft copolymer, namely poly(vinyl chloride)-g poly(oxyethylene methacrylate). The polymer-solvent interactions in solution, which are tuned by the amount of water, are shown to be a decisive factor in determining TiO(2) morphology and device performance. Systematic control of wall and pore size is achieved and enables the bifunctionality of excellent light scattering properties and easy electron transport through the film. These properties are characterized by reflectance spectroscopy, incident photon-to electron conversion efficiency, and electrochemical impedance spectroscopy analyses. The TiO(2) photoanode that is prepared with a higher water ratio, [pre TiO(2)]:[H(2)O]=1:0.3, shows a larger surface area, greater light scattering, and better electron transport, which result in a high efficiency (7.7 %) DSSC with a solid polymerized ionic liquid. This efficiency is much greater than that of commercially available TiO(2) paste (4.0 %). PMID- 24816730 TI - Curdlan beta-1,3-glucooligosaccharides induce the defense responses against Phytophthora infestans infection of potato (Solanum tuberosum L. cv. McCain G1) leaf cells. AB - Activation of the innate immune system before the invasion of pathogens is a promising way to improve the resistance of plant against infection while reducing the use of agricultural chemicals. Although several elicitors were used to induce the resistance of potato plant to microbial pathogen infection, the role of curdlan oligosaccharide (CurdO) has not been established. In the current study, the defense responses were investigated at biochemical and proteomic levels to elucidate the elicitation effect of CurdOs in foliar tissues of potato (Solanum tuberosum L. cv. McCain G1). The results indicate that the CurdOs exhibit activation effect on the early- and late-defense responses in potato leaves. In addition, glucopentaose was proved to be the shortest active curdlan molecule based on the accumulation of H2O2 and salicylic acid and the activities of phenylalanine amino-lyase, beta-1,3-glucanase and chitinase. The 2D-PAGE analysis reveals that CurdOs activate the integrated response reactions in potato cells, as a number of proteins with various functions are up-regulated including disease/defense, metabolism, transcription, and cell structure. The pathogenesis assay shows that the ratio of lesion area of potato leaf decreased from 15.82%+/ 5.44% to 7.79%+/-3.03% when the plants were treated with CurdOs 1 day before the infection of Phytophthora infestans. Furthermore, the results on potato yield and induction reactions indicate that the defense responses induced by CurdOs lasted for short period of time but disappeared gradually. PMID- 24816731 TI - Confidentiality in the digital age. PMID- 24816732 TI - How the UK drug regulator became the herbalists' marketeer. PMID- 24816733 TI - A cognitive model for aggregating people's rankings. AB - We develop a cognitive modeling approach, motivated by classic theories of knowledge representation and judgment from psychology, for combining people's rankings of items. The model makes simple assumptions about how individual differences in knowledge lead to observed ranking data in behavioral tasks. We implement the cognitive model as a Bayesian graphical model, and use computational sampling to infer an aggregate ranking and measures of the individual expertise. Applications of the model to 23 data sets, dealing with general knowledge and prediction tasks, show that the model performs well in producing an aggregate ranking that is often close to the ground truth and, as in the "wisdom of the crowd" effect, usually performs better than most of individuals. We also present some evidence that the model outperforms the traditional statistical Borda count method, and that the model is able to infer people's relative expertise surprisingly well without knowing the ground truth. We discuss the advantages of the cognitive modeling approach to combining ranking data, and in wisdom of the crowd research generally, as well as highlighting a number of potential directions for future model development. PMID- 24816734 TI - Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia. AB - Glioblastoma is the most malignant and lethal form of astrocytoma, with patients having a median survival time of approximately 15 months with current therapeutic modalities. It is therefore important to identify novel therapeutics. There is mounting evidence that microglia (specialized brain-resident macrophages) play a significant role in the development and progression of glioblastoma tumors. In this paper we show that microglia, in addition to stimulating glioblastoma cell invasion, also promote glioblastoma cell proliferation and resistance to ionizing radiation in vitro. We found that semapimod, a drug that selectively interferes with the function of macrophages and microglia, potently inhibits microglia stimulated GL261 invasion, without affecting serum-stimulated glioblastoma cell invasion. Semapimod also inhibits microglia-stimulated resistance of glioblastoma cells to radiation, but has no significant effect on microglia-stimulated glioblastoma cell proliferation. We also found that intracranially administered semapimod strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In conclusion, our observations indicate that semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia and/or infiltrating macrophages. PMID- 24816736 TI - A stochastic model correctly predicts changes in budding yeast cell cycle dynamics upon periodic expression of CLN2. AB - In this study, we focus on a recent stochastic budding yeast cell cycle model. First, we estimate the model parameters using extensive data sets: phenotypes of 110 genetic strains, single cell statistics of wild type and cln3 strains. Optimization of stochastic model parameters is achieved by an automated algorithm we recently used for a deterministic cell cycle model. Next, in order to test the predictive ability of the stochastic model, we focus on a recent experimental study in which forced periodic expression of CLN2 cyclin (driven by MET3 promoter in cln3 background) has been used to synchronize budding yeast cell colonies. We demonstrate that the model correctly predicts the experimentally observed synchronization levels and cell cycle statistics of mother and daughter cells under various experimental conditions (numerical data that is not enforced in parameter optimization), in addition to correctly predicting the qualitative changes in size control due to forced CLN2 expression. Our model also generates a novel prediction: under frequent CLN2 expression pulses, G1 phase duration is bimodal among small-born cells. These cells originate from daughters with extended budded periods due to size control during the budded period. This novel prediction and the experimental trends captured by the model illustrate the interplay between cell cycle dynamics, synchronization of cell colonies, and size control in budding yeast. PMID- 24816735 TI - Amygdala perfusion is predicted by its functional connectivity with the ventromedial prefrontal cortex and negative affect. AB - BACKGROUND: Previous studies have shown that the activity of the amygdala is elevated in people experiencing clinical and subclinical levels of anxiety and depression (negative affect). It has been proposed that a reduction in inhibitory input to the amygdala from the prefrontal cortex and resultant over-activity of the amygdala underlies this association. Prior studies have found relationships between negative affect and 1) amygdala over-activity and 2) reduced amygdala prefrontal connectivity. However, it is not known whether elevated amygdala activity is associated with decreased amygdala-prefrontal connectivity during negative affect states. METHODS: Here we used resting-state arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in combination to test this model, measuring the activity (regional cerebral blood flow, rCBF) and functional connectivity (correlated fluctuations in the BOLD signal) of one subregion of the amygdala with strong connections with the prefrontal cortex, the basolateral nucleus (BLA), and subsyndromal anxiety levels in 38 healthy subjects. RESULTS: BLA rCBF was strongly correlated with anxiety levels. Moreover, both BLA rCBF and anxiety were inversely correlated with the strength of the functional coupling of the BLA with the caudal ventromedial prefrontal cortex. Lastly, BLA perfusion was found to be a mediator of the relationship between BLA-prefrontal connectivity and anxiety. CONCLUSIONS: These results show that both perfusion of the BLA and a measure of its functional coupling with the prefrontal cortex directly index anxiety levels in healthy subjects, and that low BLA-prefrontal connectivity may lead to increased BLA activity and resulting anxiety. Thus, these data provide key evidence for an often-cited circuitry model of negative affect, using a novel, multi-modal imaging approach. PMID- 24816737 TI - Clinicopathological significance of SIRT1 expression in colorectal adenocarcinoma. AB - Sirtuin 1 (SIRT1) has been reported to have diverse roles in various biological processes through deacetylation of histone and nonhistone proteins. However, the correlations between SIRT1 protein expression, clinicopathological parameters, and survival of colorectal cancer patients remain unclear. SIRT1 protein expression in a paraffin-embedded tissue microarray, including 13 benign adenomas, nine liver metastasis tissues, and 120 paired colorectal cancer and normal mucosa tissues, was measured by immunohistochemistry. SIRT1 mRNA and protein expression in colon cancer cell lines with different metastatic potential and normal colon cells were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. The correlations between SIRT1 protein expression, clinicopathological features, and prognosis were analyzed. All samples (100 %) were positive for SIRT1, with variable staining in the cytoplasm rather than the nucleus. There was significant difference in SIRT1 overexpression between adenocarcinomas and normal mucosal tissues (P < 0.01, chi(2) test). SIRT1 overexpression was more frequently observed in advanced-stage tumors and lymph node or liver metastases (P = 0.046, 0.002, and 0.004, respectively, chi(2) test). SIRT1 expression was also significantly elevated in the more aggressive colon cancer cell line SW620. SIRT1 overexpression was significantly correlated with poor overall survival (P = 0.013, log-rank test) and disease-free survival (P = 0.012, log-rank test). SIRT1 overexpression was correlated with advanced-stage and poor prognosis. SIRT1 may play an important role in the progression of colorectal cancer. PMID- 24816738 TI - p16 Methylation is associated with chemosensitivity to fluorouracil in patients with advanced gastric cancer. AB - No effective biomarkers have been confirmed to predict chemosensitivity for patients with gastric cancer. The purpose of this study was to investigate whether DNA methylation is associated with chemosensitivity in patients with gastric cancer. Tumors and matched non-tumor biopsy tissues collected from 134 advanced gastric cancer (AGC) patients prior to fluorouracil-based chemotherapy were retrospectively analyzed. The methylation status of p16, E-cadherin (CDH1), MGMT (O-6-methylguanine-DNA methyltransferase), and human mutL homolog 1 (hMLH1) was evaluated using a Methylight assay, and the association between p16 methylation and the sensitivity of 5-fluorouracil in cell lines was determined by in vitro assay. The methylation of p16 (17.9 vs. 0 %, P = 0.002), CDH1 (20.9 vs. 2.2 %, P < 0.001), MGMT (17.9 vs. 0 %, P = 0.052), and hMLH1 (14.9 vs. 2.2 %, P = 0.024) was more common in gastric cancer tissues (n = 134) than in non-tumor tissues (n = 46). For all patients, a reverse correlation was only found between p16 methylation and clinical response (P = 0.017), which suggested that p16 methylation might be associated with chemosensitivity of fluorouracil in gastric cancer patients. Results from in vitro experiments demonstrated that p16 methylation was closely correlated with the sensitivity of 5-fluorouracil in gastric cancer cells. The present results indicated that the methylation of p16, CDH1, MGMT, and hMLH1 was both frequent and specific in gastric cancer tissues. p16 Methylation might be used to predict chemosensitivity of fluorouracil for patients with AGC when validated in large samples in the future. PMID- 24816739 TI - COX2 expression in high-grade breast cancer: evidence for prognostic significance in the subset of triple-negative breast cancer patients. AB - COX2 expression correlates with high-grade breast cancer, but the clinical significance and possible prognostic influence in these patients have not been studied in depth. Our goal was to evaluate the significance of COX2 expression in a group of patients with high-grade breast cancer. Three hundred and three patients (median age 55; age range 25-95 years) with high-grade breast cancer entered this retrospective study. Mean follow-up was 65.2 months (4-179 months). COX2 expression was studied by immunohistochemistry. The distribution of patients with high-grade tumors according to staining for COX2 was as follows: score 0 28/303 (9.3 %); score 1-101/303 (33.3 %); score 2-114/303 (37.6 %); score 3 60/303 (19.8 %). Patients with score 2 and 3 were classified as COX2 positive (174 of 303 patients (57.4 %). There was no correlation between any clinicopathological pattern, ER, PR, Her2 status and COX2 expression. In the group of patients with triple-negative breast cancer, the 5-year disease-free survival rate was 58.3 % for patients with COX2 expression compared with 83.9 % for patients without COX2 expression (P = 0.042). COX2 expression did not provide any prognostic significance for the other biological subtypes of breast cancer with high-grade histological features. PMID- 24816740 TI - Comparative pharmacokinetics of cyclophosphamide administration alone and combination with vitamin B6 in rats. AB - A fast and sensitive high performance liquid chromatography coupled with mass spectrometry (LC-MS) method was developed and validated for the determination of cyclophosphamide in rat plasma with and without the combination of vitamin B6. After addition of digoxin used as the internal standard (IS), plasma samples were extracted by protein precipitation with acetonitrile (1:1, v/v), and the analytes were separated by a Kromasil C18 column (150 * 4.6 mm, 5 um) with a mobile phase of acetonitrile-0.1% formic acid water (40:60, v/v). The detection of the analyte was monitored in positive electrospray ionization by selected ion monitoringmode. The linear range was 0.01-40 ug/mL for cyclophosphamide. The intra- and inter-day precision and accuracy were all <15%. The extraction recoveries and matrix effects of the analyte and IS were all within acceptable range. The selectivity of the method was satisfactory with no endogenous interference. The results for stabilities of cyclophosphamide and IS under various conditions were all within the acceptance criteria. The validated method was successfully applied to evaluate the drug-drug interaction of cyclophosphamide and vitamin B6 in rat plasma. The results showed no differences of pharmacokinetic behaviors between cyclophosphamide administration with and without vitamin B6. PMID- 24816741 TI - Mapping intravascular ultrasound controversies in interventional cardiology practice. AB - Intravascular ultrasound is a catheter-based imaging modality that was developed to investigate the condition of coronary arteries and assess the vulnerability of coronary atherosclerotic plaques in particular. Since its introduction in the clinic 20 years ago, use of intravascular ultrasound innovation has been relatively limited. Intravascular ultrasound remains a niche technology; its clinical practice did not vastly expand, except in Japan, where intravascular ultrasound is an appraised tool for guiding percutaneous coronary interventions. In this qualitative research study, we follow scholarship on the sociology of innovation in exploring both the current adoption practices and perspectives on the future of intravascular ultrasound. We conducted a survey of biomedical experts with experience in the technology, the practice, and the commercialization of intravascular ultrasound. The collected information enabled us to map intravascular ultrasound controversies as well as to outline the dynamics of the international network of experts that generates intravascular ultrasound innovations and uses intravascular ultrasound technologies. While the technology is praised for its capacity to measure coronary atherosclerotic plaque morphology and is steadily used in clinical research, the lack of demonstrated benefits of intravascular ultrasound guided coronary interventions emerges as the strongest factor that prevents its expansion. Furthermore, most of the controversies identified were external to intravascular ultrasound technology itself, meaning that decision making at the industrial, financial and regulatory levels are likely to determine the future of intravascular ultrasound. In light of opinions from the responding experts', a wider adoption of intravascular ultrasound as a stand-alone imaging modality seems rather uncertain, but the appeal for this technology may be renewed by improving image quality and through combination with complementary imaging modalities. PMID- 24816742 TI - Feasibility, acceptability, and potential effectiveness of dignity therapy for people with motor neurone disease. AB - BACKGROUND: Motor neurone disease (MND) practice guidelines suggest developing interventions that will promote hope, meaning, and dignity to alleviate psychological distress, but very little research has been done. This study begins to address this need by exploring the use of dignity therapy with people with MND. Dignity therapy is a brief psychotherapy that promotes hope, meaning and dignity, and enhances the end of life for people with advanced cancer. The aims of this study are to assess the feasibility, acceptability, and potential effectiveness of dignity therapy for people with MND. METHODS/DESIGN: This cross sectional feasibility study used a one-group pre-test post-test design with 29 people diagnosed with MND. Study participants completed the following self-report questionnaires: Herth Hope Index, FACIT-sp, Patient Dignity Inventory, ALS Assessment Questionnaire, ALS Cognitive Behavioural Screen, and a demographic and health history questionnaire. Acceptability was measured with a 25-item feedback questionnaire. Feasibility was assessed by examining the length of time taken to complete dignity therapy and how symptoms common in MND affected the intervention. Generalised linear mixed models and reliable change scores were used to analyse the data. RESULTS: There were no significant pre-test post-test changes for hopefulness, spirituality or dignity on the group level, but there were changes in hopefulness on the individual level. The results of the feedback questionnaire indicates dignity therapy is highly acceptable to people with MND, who report benefits similar to those in the international randomised controlled trial on dignity therapy, a population who primarily had end-stage cancer. Benefits include better family relationships, improved sense of self and greater acceptance. Dignity therapy with people with MND is feasible if the therapist can overcome time and communication difficulties. CONCLUSIONS: Dignity therapy for people with MND is feasible and acceptable. Further research is warranted to explore its ability to diminish distress. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12611000410954. PMID- 24816743 TI - Whole-exome sequencing identifies a novel genotype-phenotype correlation in the entactin domain of the known deafness gene TECTA. AB - Postlingual progressive hearing loss, affecting primarily the high frequencies, is the clinical finding in most cases of autosomal dominant nonsyndromic hearing loss (ADNSHL). The molecular genetic etiology of ADNSHL is extremely heterogeneous. We applied whole-exome sequencing to reveal the genetic etiology of high-frequency hearing loss in a mid-sized Korean family without any prior linkage data. Whole-exome sequencing of four family members (two affected and two unaffected), together with our filtering strategy based on comprehensive bioinformatics analyses, identified 21 potential pathogenic candidates. Sanger validation of an additional five family members excluded 20 variants, leaving only one novel variant, TECTA c.710C>T (p.T237I), as the strongest candidate. This variant resides in the entactin (ENT) domain and co-segregated perfectly with non-progressive high-frequency hearing loss in the family. It was absent among 700 ethnically matched control chromosomes, and the T237 residue is conserved among species, which supports its pathogenicity. Interestingly, this finding contrasted with a previously proposed genotype-phenotype correlation in which variants of the ENT domain of TECTA were associated with mid-frequency hearing loss. Based upon what we observed, we propose a novel "genotype to phenotype" correlation in the ENT domain of TECTA. Our results shed light on another important application of whole-exome sequencing: the establishment of a novel genotype-phenotype in the molecular genetic diagnosis of autosomal dominant hearing loss. PMID- 24816745 TI - Step-by-step surgical technique for mandibular reconstruction with fibular free flap: application of digital technology in virtual surgical planning. AB - At present, mandibular reconstruction with a fibular free flap is the gold standard for functional and esthetic rehabilitation after oncological surgery. The purpose of this study was to describe the computer-assisted mandibular reconstruction procedure adopting the customized solution Synthes ProPlan CMF. The study reports five consecutive patients with benign or malignant disease requiring mandibular reconstruction using a microvascular fibular free flap, pre operative virtual planning, construction of cutting guides and customized laser pre-bent titanium plates. The surgical technique is discussed in a step-by-step fashion. The average post-operative hospital stay was 18 +/- 3 days. Ischemia time was recorded in all five cases, with an average of 75 +/- 8 min. No problems were encountered in any surgical step and there were no major complications. Excellent precision of cutting guides and a good fit of pre-bent plates were found on both the mandible and fibula. There was excellent precision in bone to bone contact and position between mandible and fibula graft. Measurement data from the pre-operative and post-operative CT scans were compared. The average difference (Delta) between programed segment lengths and CT control segment lengths was 0.098 +/- 0.077 cm. Microsurgical mandibular reconstruction using a virtual surgical planning yields significantly shorter ischemia times and allows more precise osteotomies. The technology is becoming increasingly recognized for its ability to optimize surgical outcomes and minimize operating time. Considering that the extent of resection can be wider than predicted, this results in safer modeling of the fibula only after frozen sections have demonstrated the radicality of resection. PMID- 24816744 TI - Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. AB - Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 uM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis. PMID- 24816746 TI - Sensorineural hearing loss in pediatric patients with celiac disease. AB - Sensorineural hearing loss (SNHL) as an extraintestinal manifestation of celiac disease (CD) has been reported in several studies. The aim of this study was to determine presence of subclinical sensorineural hearing loss associated with CD in pediatric patients. Otoscopy, tympanometry and pure tone audiometry were performed in 44 patients with CD and 20 healthy age and sex-matched controls. Pure tone audiometry did not show significant sensorineural hearing loss over all frequencies in patients with CD compared with controls (P > 0.05). SNHL was detected in only three (6.8 %) patients with CD. In conclusion, subclinical sensorineural hearing loss was demonstrated in adult patients with CD; therefore, we recommend to perform audiometric examinations in pediatric patients for recognizing hearing loss early during the course of the disease. PMID- 24816749 TI - Patient empowerment in cancer pain management: an integrative literature review. AB - OBJECTIVE: More than 50% of patients with cancer experience pain. Patient empowerment has been highlighted as central to success in pain management. Up to now, no clear model for this patient group exists, yet several strategies to empower patients have been used in clinical practice. This review examines how empowerment or related concepts have been described in relation to pain management in patients with cancer. With the help of a conceptual model, recommendations for clinical practice are provided. METHODS: An integrative review was conducted, using the databases PubMed, CINAHL and PsycINFO. We evaluated papers discussing empowerment or related concepts in relation to pain management in patients with cancer. We analyzed the term 'empowerment' semantically. RESULTS: From a total of 5984 identified papers, 34 were included for analysis. Empowerment has been described with the concepts self-efficacy, active patient participation, increasing abilities, and control of life. Most papers focus on pain treatment induced by the professional caregiver or on the active involvement of the patient, and not on the combination of both. The following elements of empowerment could be discriminated: role of the patient, role of the professional, resources, self-efficacy, active coping, and shared decision making. CONCLUSIONS: On the basis of these findings, we propose a conceptual model to empower patients in controlling cancer pain. We recommend focusing on pain treatment given by the professional, on the active involvement of the patient, and on the interaction of both. Our model might also be useful for other patient groups or specific contexts, especially in symptom management. PMID- 24816748 TI - IncA/C plasmid-mediated spread of CMY-2 in multidrug-resistant Escherichia coli from food animals in China. AB - OBJECTIVES: To obtain a broad molecular epidemiological characterization of plasmid-mediated AmpC beta-lactamase CMY-2 in Escherichia coli isolates from food animals in China. METHODS: A total of 1083 E. coli isolates from feces, viscera, blood, drinking water, and sub-surface soil were examined for the presence of CMY 2 beta-lactamases. CMY-2-producing isolates were characterized as follows: the blaCMY-2 genotype was determined using PCR and sequencing, characterization of the blaCMY-2 genetic environment, plasmid sizing using S1 nuclease pulsed-field gel electrophoresis (PFGE), PCR-based replicon typing, phylogenetic grouping, XbaI-PFGE, and multi-locus sequence typing (MLST). RESULTS: All 31 CMY-2 producers were only detected in feces, and presented with multidrug resistant phenotypes. All CMY-2 strains also co-harbored genes conferring resistance to other antimicrobials, including extended spectrum beta-lactamases genes (blaCTX-M 14 or blaCTX-M-55), plasmid-mediated quinolone resistance determinants (qnr, oqxA, and aac-(6')-Ib-cr), floR and rmtB. The co-transferring of blaCMY-2 with qnrS1 and floR (alone and together) was mainly driven by the Inc A/C type plasmid, with sizes of 160 or 200 kb. Gene cassette arrays inserted in the class 1 or class 2 integron were amplified among 12 CMY-2 producers. CMY-2 producers belonged to avirulent groups B1 (n = 12) and A (n = 11), and virulent group D (n = 8). There was a good correlation between phylogenetic groups and sequence types (ST). Twenty-four STs were identified, of which the ST complexes (STC) 101/B1 (n = 6), STC10/A (n = 5), and STC155/B1 (n = 3) were dominant. CONCLUSIONS: CMY-2 is the dominant AmpC beta-lactamase in food animals and is associated with a transferable replicon IncA/C plasmid in the STC101, STC10, and STC155 strains. PMID- 24816750 TI - Mild hypothermia alleviates excessive autophagy and mitophagy in a rat model of asphyxial cardiac arrest. AB - Mild hypothermia is an effective therapeutic strategy to improve poor neurological outcomes in patients following cardiac arrest (CA). However, the underlying mechanism remains unclear. The aim of the study was to evaluate the effect of mild hypothermia on intracellular autophagy and mitophagy in hippocampal neurons in a rat model of CA. CA was induced in Sprague-Dawley (SD) rats by asphyxia for 5 min. After successful resuscitation, the surviving rats were randomly divided into two groups, the normothermia (NT) group and the hypothermia (HT) group. Mild hypothermia (32 degrees C) was induced following CA for 4 h, and animals were rewarmed at a rate of 0.5 degrees C/h. Neurologic deficit scores (NDS) were used to determine the status of neurological function. Cytoplasmic and mitochondrial protein from the hippocampus was extracted, and the expression of LC3B-II/I and Parkin were measured as markers of intracellular autophagy and mitophagy, respectively. Of the 60 rats that underwent CA, 44 were successfully resuscitated (73 %), and 33 survived until the end of the experiment (55 %). Mild hypothermia maintained eumorphism of nuclear and mitochondrial structures and significantly improved NDS (p < 0.05). Expression of LC3B-II/I and Parkin in hippocampal nerve cells were significantly increased (p < 0.05) in the NT group relative to the control. Meanwhile, mild hypothermia reduced the level of LC3B-II/I and Parkin (p < 0.05) relative to the NT group. Mild hypothermia protected mitochondria and improved neurological function following CA and resuscitation after ischemia/reperfusion (I/R) injury, likely by reducing excessive autophagy and mitophagy in neurons. PMID- 24816751 TI - A review of recent literature - nurse case managers in diabetes care: equivalent or better outcomes compared to primary care providers. AB - Primary care has changed remarkably with chronic disease burden growth. Nurse case managers assist with this chronic disease by providing if not significantly better care, than equivalent care to that provided by usual primary care providers. Chronic disease management requires patient-centered skills and tools, such as registries, panel management, review of home data, communicating with patients outside of face-to-face care, and coordinating multiple services. Evidence reviewed in this article demonstrates that registered nurse care managers (RNCM) perform many actions required for diabetes chronic disease management including initiation and titration of medications with similar or improved physiologic and patient satisfaction outcomes over usual care providers. Selection and training of the nurse case managers is of utmost importance for implementation of a successful chronic disease management program. Evidence based guidelines, algorithms, protocols, and adequate ongoing education and mentoring are generally cited as necessary support tools for the nurse case managers. PMID- 24816754 TI - Consensus Statement by the American Association of Clinical Endocrinologists/American College of Endocrinology insulin pump management task force. PMID- 24816752 TI - Metabolic consequences of sleep and circadian disorders. AB - Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome, and sleep related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance, and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed. PMID- 24816755 TI - Solution of a Diagnostic Problem upon Visiting the Patient at Home and Reading their Medication Leaflet. PMID- 24816756 TI - A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the most common gynecologic malignancy. To identify the micro-ribonucleic acids (miRNAs) expression profile in EOC tissues that may serve as a novel diagnostic biomarker for EOC detection, the expression of 1722 miRNAs from 15 normal ovarian tissue samples and 48 ovarian cancer samples was profiled by using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. A ten-microRNA signature (hsa-miR-1271-5p, hsa-miR-574-3p, hsa miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-15b-5p, hsa-miR-182-3p, hsa miR-141-5p, hsa-miR-130b-5p, and hsa-miR-135b-3p) was identified to be able to distinguish human ovarian cancer tissues from normal tissues with 97% sensitivity and 92% specificity. Two miRNA clusters of miR183-96-183 (miR-96-5p, and miR-182, miR183) and miR200 (miR-141-5p, miR200a, b, c and miR429) are significantly up regulated in ovarian cancer tissue samples compared to those of normal tissue samples, suggesting theses miRNAs may be involved in ovarian cancer development. PMID- 24816758 TI - Theoretical morphology and development of flight feather vane asymmetry with experimental tests in parrots. AB - Asymmetry in flight feather vane width is a major functional innovation associated with the evolution of flight in the ancestors of birds. However, the developmental and morphological basis of feather shape is not simple, and the developmental processes involved in vane width asymmetry are poorly understood. We present a theoretical model of feather morphology and development that describes the possible ways to modify feather development and produce vane asymmetry. Our model finds that the theoretical morphospace of feather shape is redundant, and that many different combinations of parameters could be responsible for vane asymmetry in a given feather. Next, we empirically measured morphological and developmental model parameters in asymmetric and symmetric feathers from two species of parrots to identify which combinations of parameters create vane asymmetry in real feathers. We found that both longer barbs, and larger barb angles in the relatively wider trailing vane drove asymmetry in tail feathers. Developmentally, longer barbs were the result of an offset of the radial position of the new barb locus, whereas larger barb angles were produced by differential expansion of barbs as the feather unfurls from the tubular feather germ. In contrast, the helical angle of barb ridge development did not contribute to vane asymmetry and could be indicative of a constraint. This research provides the first comprehensive description of both the morphological and developmental modifications responsible for vane asymmetry within real feathers, and identifies key steps that must have occurred during the evolution of vane asymmetry. PMID- 24816757 TI - Whole-body mapping of spatial acuity for pain and touch. AB - OBJECTIVE: Tactile spatial acuity is routinely tested in neurology to assess the state of the dorsal column system. In contrast, spatial acuity for pain is not assessed, having never been systematically characterized. More than a century after the initial description of tactile acuity across the body, we provide the first systematic whole-body mapping of spatial acuity for pain. METHODS: We evaluated the 2-point discrimination thresholds for both nociceptive-selective and tactile stimuli across several skin regions. Thresholds were estimated using pairs of simultaneous stimuli, and also using successive stimuli. RESULTS AND INTERPRETATION: These two approaches produced convergent results. The fingertip was the area of highest spatial acuity, for both pain and touch. On the glabrous skin of the hand, the gradient of spatial acuity for pain followed that observed for touch. On the hairy skin of the upper limb, spatial acuity for pain and touch followed opposite proximal-distal gradients, consistent with the known innervation density of this body territory. Finally, by testing spatial acuity for pain in a rare participant completely lacking Abeta fibers, we demonstrate that spatial acuity for pain does not rely on a functioning system of tactile primary afferents. This study represents the first systematic characterization of spatial acuity for pain across multiple regions of the body surface. PMID- 24816759 TI - Effect of fructose and 3,5-diiodothyronine (3,5-T(2)) on lipid accumulation and insulin signalling in non-alcoholic fatty liver disease (NAFLD)-like rat primary hepatocytes. AB - Non-alcoholic fatty liver disease (NAFLD) is nowadays considered as one of the most serious pathological conditions affecting the liver. NAFLD is supposed to be initiated by the accumulation of lipids in the liver, which finally results in an impaired hepatic insulin signalling. Many researchers have recently focused their attention on the role played by fructose as a NAFLD-triggering agent, because of the increased diffusion of fructose-sweetened food. However, epidemiological data do not permit to evaluate the role of fructose per se, because these foods are often associated with elevated energy intake and unhealthy lifestyle. In the present work, we analysed the effects of fructose on the accumulation of lipids and insulin signalling in rat primary hepatocytes. Moreover, we investigated the effect of the thyroid hormone metabolite, devoid of thyrotoxic effects, 3,5 diiodothyronine (3,5-T2) over the same parameters. To evaluate the effect on insulin signalling we took into consideration three key proteins, such as p85 subunit of phosphatidylinositol 3-kinase (PI3K), phosphatase and tensin homolog (PTEN), and Akt. Our results show that fructose in vitro, in the range of physiological concentrations, was not able to stimulate either lipid accumulation or to impair insulin signalling in our NAFLD-like rat primary hepatocytes. Our data thus support the idea that fructose per se may exert detrimental effects mainly triggering systemic effects, rather than directly affecting isolated hepatocytes. Moreover, we demonstrated that 3,5-T2, at physiological levels, reduces lipid content and triggers phosphorylation of Akt in an insulin receptor independent manner, revealing new interesting properties as a biologically active molecule. PMID- 24816760 TI - The reduction in blood loss with intra-articular injection of tranexamic acid in unilateral total knee arthroplasty without operative drains: a randomized controlled trial. AB - The objective of this randomized controlled trial was to evaluate the efficacy and safety of intra-articular injections of tranexamic acid (TXA) on perioperative blood loss and transfusion in primary unilateral total knee arthroplasty (TKA) without drainage. Primary TKA was performed on a total of 80 patients (80 knees) affected to various degrees by knee osteoarthritis. The patients were randomized to receive 500 mg of TXA in 20 mL of normal saline solution (n = 40) or an equivalent volume of normal saline solution (n = 40), applied into the joint for 5 min at the end of surgery. Data on routine blood examination, blood loss and blood transfusion after TKA were compared between the two groups. The results showed no significant difference between the two groups in intra-operative blood loss (P = 0.136). The mean postoperative visible blood loss, hidden blood loss and transfusion requests were significantly different between the two groups (P < 0.05). The values of postoperative hemoglobin and hematocrit were lower in the control group compared with those in the treatment group (P < 0.05). No deep vein thrombosis was detected through Doppler ultrasound examination. Three hour postoperative D-dimer in the control group was higher than the treatment group (P = 0.02). There was no statistically significant difference between the coagulation indicators and range of motion in the two groups. We conclude that intra-articular TXA in patients undergoing unilateral TKA could significantly reduce postoperative blood loss and blood transfusion and avoid perioperative anemia-related complications without increased risk of venous thrombosis. PMID- 24816761 TI - A comparison of four tibial-fixation systems in hamstring-graft anterior ligament reconstruction. AB - The aim of this study was to evaluate at time-zero four tibial fixations on four major criteria: the elongation and cyclic stiffness of the hamstring graft construct under cyclic loading, the yield load and pullout stiffness under load at failure. Four fixation systems were tested: the Delta screw, the WasherLoc, the TightRope Reverse and the tape locking screw on 32 tibiae of adult pigs using 32 pairs of human semitendinosus and gracilis tendons. Two tests were performed: cyclic tests using loads at 70-220 N, to measure the elongation at the end of the cycles, followed by load-to-failure testing to measure the yield load and the cyclic stiffness. The mean elongation was 1.23 mm for the TLS, 3.81 mm for the Delta, 3.59 mm for the WasherLoc and 3.91 mm for the TightRope. The mean yield loads and SD were 1,015 +/- 129 N for the TLS, 844 +/- 394 N for the Delta, 511 +/- 95 N for the WasherLoc and 567 +/- 112 N for the TightRope. The results showed the significant superiority of TLS and Delta over WasherLoc and tibial TightRope in regard to yield load. The results showed the significant superiority of TLS over the other fixations in regard to slippage. The TLS system and the Delta screw provide a better quality of primary fixation to the tibia, but further in vitro studies are needed. PMID- 24816762 TI - T helper responses are maintained by basal-like breast cancer cells and confer to immune modulation via upregulation of PD-1 ligands. AB - A conspicuous T cell infiltration is frequently observed in triple-negative and/or basal-like breast cancers. Since the immunological course of breast cancer is explicitly directed by helper T cells, this study aims to determine the influence of basal-like breast cancer (BLBC) cells on CD4(+) T cell responses. Co cultures were established with breast cancer cell lines and CD4(+) T cells under stimulatory conditions. Helper T cell activation, proliferation, cytokine secretion, and differentiation were assessed. Protein and mRNA expression of PD-1 ligands were determined on breast cancer cell lines. Blockade assays were performed in order to determine the functional assets of PD-1 ligation. In contrast to luminal breast cancer cells, BLBC cells allowed CD4(+) T cell activation, proliferation, and IFN-gamma secretion, but only to a certain extent. A substantial population of CD25(+)CD127(low/-) regulatory T (Treg) cells was also induced in BLBC co-cultures. In return, IFN-gamma stimulated the upregulation of PD-L1 (B7-H1) and/or PD-L2 (B7-DC) inhibitory molecules on the basal-like cells. In prolonged periods of co-culturing, blockade of PD-1 ligands on BLBC cell lines impaired Treg differentiation, restored IL-2 secretion, and increased CD8(+) T cell activation. In conclusion, T helper responses were maintained by BLBC cells. On the other hand, IFN-gamma secreted from Th1 and other immune cells upregulated the expression of PD-1 ligands on BLBC cells and modulated the immune reactions. Our results indicate the capacity of BLBCs to adapt to IFN-gamma-mediated anti-tumor immune responses and to evade immunity via upregulation of PD-1 ligands. PMID- 24816763 TI - Metabolic characterization of all-trans-retinoic acid (ATRA)-induced craniofacial development of murine embryos using in vivo proton magnetic resonance spectroscopy. AB - AIM: To characterize the abnormal metabolic profile of all-trans-retinoic acid (ATRA)-induced craniofacial development in mouse embryos using proton magnetic resonance spectroscopy (1H-MRS). METHODS: Timed-pregnant mice were treated by oral gavage on the morning of embryonic gestation day 11 (E11) with all-trans retinoic acid (ATRA). Dosing solutions were adjusted by maternal body weight to provide 30, 70, or 100 mg/kg RA. The control group was given an equivalent volume of the carrier alone. Using an Agilent 7.0 T MR system and a combination of surface coil coils, a 3 mm*3 mm*3 mm 1H-MRS voxel was selected along the embryonic craniofacial tissue. 1H-MRS was performed with a single-voxel method using PRESS sequence and analyzed using LCModel software. Hematoxylin and eosin was used to detect and confirm cleft palate. RESULT: 1H-MRS revealed elevated choline levels in embryonic craniofacial tissue in the RA70 and RA100 groups compared to controls (P<0.05). Increased choline levels were also found in the RA70 and RA100 groups compared with the RA30 group (P<0.01). High intra myocellular lipids at 1.30 ppm (IMCL13) in the RA100 group compared to the RA30 group were found (P<0.01). There were no significant changes in taurine, intra myocellular lipids at 2.10 ppm (IMCL21), and extra-myocellular lipids at 2.30 ppm (EMCL23). Cleft palate formation was observed in all fetuses carried by mice administered 70 and 100 mg/kg RA. CONCLUSIONS: This novel study suggests that the elevated choline and lipid levels found by 1H-MRS may represent early biomarkers of craniofacial defects. Further studies will determine performance of this test and pathogenetic mechanisms of craniofacial malformation. PMID- 24816765 TI - Sensations experienced and patients' perceptions of osteopathy in the cranial field treatment. AB - Osteopathy in the cranial field is an approach used by manual and physical therapists. However, there is minimal information in the literature about patient experiences of this treatment. The present study was undertaken to explore patients' experiences of osteopathy in the cranial field. Patients completed the Patient Perception Measure-Osteopathy in the Cranial Field and identified sensations they experienced during treatment. Additional measures of anxiety, depression, Satisfaction With Life, and Meaningfulness of Daily Activity were completed. The Patient Perception Measure-Osteopathy in the Cranial Field was internally consistent (Cronbach's alpha = .85). The most frequently experienced sensations of osteopathy in the cranial field patients were "relaxed," "releasing," and "unwinding." Satisfaction With Life and Meaningfulness of Daily Activity were positively associated with Patient Perception Measure-Osteopathy in the Cranial Field scores. Negative associations were observed between the Patient Perception Measure-Osteopathy in the Cranial Field and depression. Psychometric properties of the Patient Perception Measure-Osteopathy in the Cranial Field require further testing. The observed associations of Satisfaction With Life and depression with patients' perceptions of osteopathy in the cranial field treatment needs to be tested in larger clinical manual therapy cohorts. PMID- 24816764 TI - Risk of psychiatric disorders following polycystic ovary syndrome: a nationwide population-based cohort study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. A higher prevalence of psychiatric comorbidities, including depressive disorder, anxiety disorder, and bipolar disorder has been proved in patients with PCOS. However, a clear temporal causal relationship between PCOS and psychiatric disorders has not been well established. OBJECTIVE: We explored the relationship between PCOS and the subsequent development of psychiatric disorders including schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. METHODS: We identified patients who were diagnosed with PCOS by an obstetrician-gynecologist in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed of patients without PCOS who were matched according to age and sex. The occurrence of subsequent new-onset psychiatric disorders was evaluated in both cohorts based on diagnoses made by psychiatrists. RESULTS: The PCOS cohort consisted of 5431 patients, and the comparison cohort consisted of 21,724 matched control patients without PCOS. The incidence of depressive disorder (hazard ratio [HR] 1.296, 95% confidence interval [CI] 1.084-.550), anxiety disorder (HR 1.392, 95% CI 1.121-1.729), and sleep disorder (HR 1.495, 95% CI 1.176-1.899) were higher among the PCOS patients than among the patients in the comparison cohort. In addition, a higher incidence of newly diagnosed depressive disorder, anxiety disorder, and sleep disorder remained significantly increased in all of the stratified follow-up durations (0-1, 1-5, >=5 y). CONCLUSIONS: PCOS might increase the risk of subsequent newly diagnosed depressive disorder, anxiety disorder, and sleep disorder. The risk of newly diagnosed bipolar disorder, which has often been reported in the literature to be comorbid with PCOS, was not significantly elevated. PMID- 24816766 TI - Commentary: pediatric eHealth interventions: common challenges during development, implementation, and dissemination. AB - OBJECTIVE: To provide an overview of common challenges that pediatric eHealth researchers may encounter when planning, developing, testing, and disseminating eHealth interventions along with proposed solutions for addressing these challenges. METHODS: The article draws on the existing eHealth literature and the authors' collective experience in pediatric eHealth research. RESULTS AND CONCLUSIONS: The challenges associated with eHealth interventions and their proposed solutions are multifaceted and cut across a number of areas from eHealth program development through dissemination. Collaboration with a range of individuals (e.g., multidisciplinary colleagues, commercial entities, primary stakeholders) is the key to eHealth intervention success. To ensure adequate resources for design, development, and planning for sustainability, a number of public and private sources of funding are available. A study design that addresses ethical concerns and security issues is critical to ensure scientific integrity and intervention dissemination. Table I summarizes key issues to consider during eHealth intervention development, testing, and dissemination. PMID- 24816767 TI - Naevoid basal cell carcinoma syndrome in a 22-month-old child presenting with multiple basal cell carcinomas and a fetal rhabdomyoma. PMID- 24816768 TI - Post-functionalization of graphitic carbon nitrides by grafting organic molecules: toward C-H bond oxidation using atmospheric oxygen. AB - Described here is the feasible modification of a graphitic carbon nitride polymer using Prato's reaction with in situ formed azomethine ylides. These novel carbon nitrides with designable organic functional groups, and tailorable surface and structure properties illustrated excellent performance in the selective oxidation of 3,5,5-trimethylcyclohex-3-en-1-one using atmospheric oxygen. PMID- 24816769 TI - Semi-automated separation of the epimeric dehydropyrrolizidine alkaloids lycopsamine and intermedine: preparation of their N-oxides and NMR comparison with diastereoisomeric rinderine and echinatine. AB - INTRODUCTION: The diversity of structure and, particularly, stereochemical variation of the dehydropyrrolizidine alkaloids can present challenges for analysis and the isolation of pure compounds for the preparation of analytical standards and for toxicology studies. OBJECTIVE: To investigate methods for the separation of gram-scale quantities of the epimeric dehydropyrrolizidine alkaloids lycopsamine and intermedine and to compare their NMR spectroscopic data with those of their heliotridine-based analogues echinatine and rinderine. METHODS: Lycopsamine and intermedine were extracted, predominantly as their N oxides and along with their acetylated derivatives, from commercial samples of comfrey (Symphytum officinale) root. Alkaloid enrichment involved liquid-liquid partitioning of the crude methanol extract between dilute aqueous acid and n butanol, reduction of N-oxides and subsequent continuous liquid-liquid extraction of free base alkaloids into CHCl3 . The alkaloid-rich fraction was further subjected to semi-automated flash chromatography using boronated soda glass beads or boronated quartz sand. RESULTS: Boronated soda glass beads (or quartz sand) chromatography adapted to a Biotage Isolera Flash Chromatography System enabled large-scale separation (at least up to 1-2 g quantities) of lycopsamine and intermedine. The structures were confirmed using one- and two-dimensional (1) H- and (13) C-NMR spectroscopy. Examination of the NMR data for lycopsamine, intermedine and their heliotridine-based analogues echinatine and rinderine allowed for some amendments of literature data and provided useful comparisons for determining relative configurations in monoester dehydropyrrolizidine alkaloids. A similar NMR comparison of lycopsamine and intermedine with their N oxides showed the effects of N-oxidation on some key chemical shifts. A levorotatory shift in specific rotation from +3.29 degrees to -1.5 degrees was observed for lycopsamine when dissolved in ethanol or methanol respectively. CONCLUSION: A semi-automated flash chromatographic process using boronated soda glass beads was standardised and confirmed as a useful, larger scale preparative approach for separating the epimers lycopsamine and intermedine. The useful NMR correlations to stereochemical arrangements within this specific class of dehydropyrrolizidine alkaloid cannot be confidently extrapolated to other similar dehydropyrrolizidine alkaloids. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 24816770 TI - Understanding gluten-free dough for reaching breads with physical quality and nutritional balance. AB - In the last decade the development of gluten-free foodstuffs has attracted great attention as a result of better diagnoses of coeliac disease and a greater knowledge of the relationship between gluten-free products and health. The increasing interest has prompted extensive research into the development of gluten-free foodstuffs that resemble gluten-containing foods. This review aims to provide some insights on dough functionality and process conditions regarding bread quality and to point out recent research dealing with the nutritional composition of those products. Gluten-free dough results from the combination of different ingredients, additives, and the processing aids required for building up network structures responsible for bread quality. Some relationships between dough rheology and bread characteristics were established to identify possible predictor parameters. Regarding bread-making processes, the impact of mixing, dough treatment and baking is stated. Nutritional quality is an important asset when developing gluten-free breads, and different strategies for improving it are reviewed. Gluten-free bread quality is dependent on ingredients and additives combination, but also processing can provide a way to improve bread quality. Nutritive value of the gluten-free breads must be always in mind when setting up recipes, for obtaining nutritionally balanced bread with adequate glycaemic index. PMID- 24816772 TI - Apolipoprotein B100 danger-associated signal 1 (ApoBDS-1) triggers platelet activation and boosts platelet-leukocyte proinflammatory responses. AB - Low-density lipoproteins (LDL), occurring in vivo in both their native and oxidative form, modulate platelet function and thereby contribute to atherothrombosis. We recently identified and demonstrated that 'ApoB100 danger associated signal 1' (ApoBDS-1), a native peptide derived from Apolipoprotein B 100 (ApoB100) of LDL, induces inflammatory responses in innate immune cells. Platelets are critically involved in the development as well as in the lethal consequences of atherothrombotic diseases, but whether ApoBDS-1 has also an impact on platelet function is unknown. In this study we examined the effect of ApoBDS-1 on human platelet function and platelet-leukocyte interactions in vitro. Stimulation with ApoBDS-1 induced platelet activation, degranulation, adhesion and release of proinflammatory cytokines. ApoBDS-1-stimulated platelets triggered innate immune responses by augmenting leukocyte activation, adhesion and transmigration to/through activated HUVEC monolayers, under flow conditions. These platelet-activating effects were sequence-specific, and stimulation of platelets with ApoBDS-1 activated intracellular signalling pathways, including Ca2+, PI3K/Akt, PLC, and p38- and ERK-MAPK. Moreover, our data indicates that ApoBDS-1-induced platelet activation is partially dependent of positive feedback from ADP on P2Y1 and P2Y12, and TxA2. In conclusion, we demonstrate that ApoBDS-1 is an effective platelet agonist, boosting platelet-leukocyte's proinflammatory responses, and potentially contributing to the multifaceted inflammatory promoting effects of LDL in the pathogenesis of atherothrombosis. PMID- 24816773 TI - Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization. AB - Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition. PMID- 24816774 TI - Treatment related impairments in arm and shoulder in patients with breast cancer: a systematic review. AB - BACKGROUND: Breast cancer is the most common type of cancer in women in the developed world. As a result of breast cancer treatment, many patients suffer from serious complaints in their arm and shoulder, leading to limitations in activities of daily living and participation. In this systematic literature review we present an overview of the adverse effects of the integrated breast cancer treatment related to impairment in functions and structures in the upper extremity and upper body and limitations in daily activities. Patients at highest risk were defined. METHODS AND FINDINGS: We conducted a systematic literature search using the databases of PubMed, Embase, CINAHL and Cochrane from 2000 to October 2012, according to the PRISMA guidelines. Included were studies with patients with stage I-III breast cancer, treated with surgery and additional treatments (radiotherapy, chemotherapy and hormonal therapy). The following health outcomes were extracted: reduced joint mobility, reduced muscle strength, pain, lymphedema and limitations in daily activities. Outcomes were divided in within the first 12 months and >12 months post-operatively. Patients treated with ALND are at the highest risk of developing impairments of the arm and shoulder. Reduced ROM and muscle strength, pain, lymphedema and decreased degree of activities in daily living were reported most frequently in relation to ALND. Lumpectomy was related to a decline in the level of activities of daily living. Radiotherapy and hormonal therapy were the main risk factors for pain. CONCLUSIONS: Patients treated with ALND require special attention to detect and consequently address impairments in the arm and shoulder. Patients with pain should be monitored carefully, because pain limits the degree of daily activities. Future research has to describe a complete overview of the medical treatment and analyze outcome in relation to the treatment. Utilization of uniform validated measurement instruments has to be encouraged. PMID- 24816775 TI - Early oral feeding after total laryngectomy: A systematic review. AB - BACKGROUND: Early oral feeding for patients who underwent total laryngectomy is still controversial. The purpose of this study was to evaluate the safety of initiating early oral feeding after total laryngectomy regarding pharyngocutaneous fistula. The survey included research in MEDLINE, EMBASE, and LILACS. METHODS: The intervention analyzed was early oral feeding (<5 days), whereas the control group received late oral feeding (>7 days) after total laryngectomy. RESULTS: From 304 studies, 4 randomized clinical trials with 180 patients were selected. In the early oral feeding group, the incidence was 6.7%, whereas in the late oral feeding group it was 10%, with no statistically significant difference (IC95% -0.11 to 0.05; p = .42; I(2) = 0%). Four cohort studies with 490 patients were also selected. In the early oral feeding group, the incidence was 12.2%, whereas in the other group, it was 10.1%, with no statistically significant difference (IC95% -0.05 to 0.08; p = .67; I2 = 0%). CONCLUSION: There is no increase in pharyngocutaneous fistula rates in patients who receive early oral feeding after total laryngectomy. PMID- 24816776 TI - Target-initiated impedimetric proximity ligation assay with DNAzyme design for in situ amplified biocatalytic precipitation. AB - A target-initiated proximity ligation assay (PLA) protocol accompanying DNAzyme formation was for the first time designed for ultrasensitive impedimetric monitoring of heavy metal ions (silver ions were used in this case) by coupling with enzymatic biocatalytic precipitation. PMID- 24816778 TI - PQQ-dependent methanol dehydrogenases: rare-earth elements make a difference. AB - Methanol dehydrogenase (MDH) catalyzes the first step in methanol use by methylotrophic bacteria and the second step in methane conversion by methanotrophs. Gram-negative bacteria possess an MDH with pyrroloquinoline quinone (PQQ) as its catalytic center. This MDH belongs to the broad class of eight-bladed beta propeller quinoproteins, which comprise a range of other alcohol and aldehyde dehydrogenases. A well-investigated MDH is the heterotetrameric MxaFI-MDH, which is composed of two large catalytic subunits (MxaF) and two small subunits (MxaI). MxaFI-MDHs bind calcium as a cofactor that assists PQQ in catalysis. Genomic analyses indicated the existence of another MDH distantly related to the MxaFI-MDHs. Recently, several of these so-called XoxF MDHs have been isolated. XoxF-MDHs described thus far are homodimeric proteins lacking the small subunit and possess a rare-earth element (REE) instead of calcium. The presence of such REE may confer XoxF-MDHs a superior catalytic efficiency. Moreover, XoxF-MDHs are able to oxidize methanol to formate, rather than to formaldehyde as MxaFI-MDHs do. While structures of MxaFI- and XoxF-MDH are conserved, also regarding the binding of PQQ, the accommodation of a REE requires the presence of a specific aspartate residue near the catalytic site. XoxF-MDHs containing such REE-binding motif are abundantly present in genomes of methylotrophic and methanotrophic microorganisms and also in organisms that hitherto are not known for such lifestyle. Moreover, sequence analyses suggest that XoxF-MDHs represent only a small part of putative REE-containing quinoproteins, together covering an unexploited potential of metabolic functions. PMID- 24816777 TI - Fc receptors for immunoglobulins and their appearance during vertebrate evolution. AB - Receptors interacting with the constant domain of immunoglobulins (Igs) have a number of important functions in vertebrates. They facilitate phagocytosis by opsonization, are key components in antibody-dependent cellular cytotoxicity as well as activating cells to release granules. In mammals, four major types of classical Fc receptors (FcRs) for IgG have been identified, one high-affinity receptor for IgE, one for both IgM and IgA, one for IgM and one for IgA. All of these receptors are related in structure and all of them, except the IgA receptor, are found in primates on chromosome 1, indicating that they originate from a common ancestor by successive gene duplications. The number of Ig isotypes has increased gradually during vertebrate evolution and this increase has likely been accompanied by a similar increase in isotype-specific receptors. To test this hypothesis we have performed a detailed bioinformatics analysis of a panel of vertebrate genomes. The first components to appear are the poly-Ig receptors (PIGRs), receptors similar to the classic FcRs in mammals, so called FcRL receptors, and the FcR gamma chain. These molecules are not found in cartilagous fish and may first appear within bony fishes, indicating a major step in Fc receptor evolution at the appearance of bony fish. In contrast, the receptor for IgA is only found in placental mammals, indicating a relatively late appearance. The IgM and IgA/M receptors are first observed in the monotremes, exemplified by the platypus, indicating an appearance during early mammalian evolution. Clearly identifiable classical receptors for IgG and IgE are found only in marsupials and placental mammals, but closely related receptors are found in the platypus, indicating a second major step in Fc receptor evolution during early mammalian evolution, involving the appearance of classical IgG and IgE receptors from FcRL molecules and IgM and IgA/M receptors from PIGR. PMID- 24816779 TI - Candidacidal mechanism of the arenicin-3-derived peptide NZ17074 from Arenicola marina. AB - The candidacidal mechanisms of NZ17074, which is a variant of arenicin-3 from Arenicola marina, against human pathogenic fungus Candida albicans are reported in this work. The minimum inhibitory concentration (MIC) of NZ17074 toward C. albicans was 4 MUg/ml, and this peptide exerted marked candidacidal activity in an energy-dependent and salt-sensitive manner. The flow cytometric analysis using propidium iodide (PI) showed that the plasma membrane of cells treated with NZ17074 was perturbed and that the cells were arrested in the G2/M phase. The dihydrorhodamine-123 (DHR-123) staining showed that the reactive oxygen species (ROS) production of C. albicans increased after exposure to NZ17074. Typical cellular disruption events, such as mitochondrial degradation, nuclear fragmentation, nuclear membrane disruption, and chromatin condensation, were further revealed through rhodamine 123 (RH123) staining, 4',6-diamidino-2 phenylindole (DAPI) staining, and transmission electron microscopy. In addition, the intracellular localization of this peptide was concentration dependent: it was located in the membrane at low concentrations (4 to 8 MUg/ml) and penetrated into the cytoplasm at high concentrations (16 to 32 MUg/ml). Our results suggested that NZ17074 exerts its candidacidal effects by disrupting the cell membrane, inducing apoptosis, and interrupting the cell cycle. These findings showed the potential of NZ17074 as a new candidacidal peptide, in addition to its antibacterial activities. PMID- 24816780 TI - Novel bacterial bioassay for a high-throughput screening of 4 hydroxyphenylpyruvate dioxygenase inhibitors. AB - Plant 4-hydroxyphenylpyruvate dioxygenase (HPPD) is the molecular target of a range of synthetic beta-triketone herbicides that are currently used commercially. Their mode of action is based on an irreversible inhibition of HPPD. Therefore, this inhibitory capacity was used to develop a whole-cell colorimetric bioassay with a recombinant Escherichia coli expressing a plant HPPD for the herbicide analysis of beta-triketones. The principle of the bioassay is based on the ability of the recombinant E. coli clone to produce a soluble melanin-like pigment, from tyrosine catabolism through p-hydroxyphenylpyruvate and homogentisate. The addition of sulcotrione, a HPPD inhibitor, decreased the pigment production. With the aim to optimize the assay, the E. coli recombinant clone was immobilized in sol-gel or agarose matrix in a 96-well microplate format. The limit of detection for mesotrione, tembotrione, sulcotrione, and leptospermone was 0.069, 0.051, 0.038, and 20 MUM, respectively, allowing to validate the whole-cell colorimetric bioassay as a simple and cost-effective alternative tool for laboratory use. The bioassay results from sulcotrione-spiked soil samples were confirmed with high-performance liquid chromatography. PMID- 24816781 TI - Redox and complexation chemistry of the CrVI/CrV-D-glucaric acid system. AB - When an excess of uronic acid over Cr(VI) is used, the oxidation of D-glucaric acid (Glucar) by Cr(VI) yields D-arabinaric acid, CO2 and Cr(III)-Glucar complex as final redox products. The redox reaction involves the formation of intermediate Cr(IV) and Cr(V) species. The reaction rate increases with [H(+)] and [substrate]. The experimental results indicated that Cr(IV) and Cr(V) are very reactive intermediates since their disappearance rates are much faster than Cr(VI). Cr(IV) and Cr(V) intermediates are involved in fast steps and do not accumulate in the redox reaction of the mixture Cr(VI)-Glucar. Kinetic studies show that the redox reaction between Glucar and Cr(VI) proceeds through a mechanism combining one- and two-electron pathways: Cr(VI) -> Cr(IV) -> Cr(II) and Cr(VI) -> Cr(IV) -> Cr(III). After the redox reaction, results show a slow hydrolysis of the Cr(III)-Glucar complex into [Cr(OH2)6](3+). The proposed mechanism is supported by the observation of free radicals, CrO2(2+) (superoxo Cr(III) ion) and oxo-Cr(V)-Glucar species as reaction intermediates. The continuous-wave electron paramagnetic resonance, CW-EPR, spectra show that five coordinate oxo-Cr(V) bischelates are formed at pH <= 4 with the aldaric acid bound to oxo-Cr(V) through the carboxylate and the alpha-OH group. A different oxo-Cr(V) species with Glucar was detected at pH 6.0. The high g(iso) value for the last species suggests a mixed coordination species, a five-coordinated oxo Cr(V) bischelate with one molecule of Glucar acting as a bi-dentate ligand, using the 2-hydroxycarboxylate group, and a second molecule of Glucar with any vic diolate sites. At pH 7.5 only a very weak EPR signal was observed, which may point to instability of these complexes. This behaviour contrasts with oxo-Cr(V) uronic species, and must thus be related to the Glucar acyclic structure. In vitro, our studies on the chemistry of oxo-Cr(V)-Glucar complexes can provide information on the nature of the species that are likely to be stabilized in vivo. PMID- 24816782 TI - Monodispersed mesoporous Li4Ti5O12 submicrospheres as anode materials for lithium ion batteries: morphology and electrochemical performances. AB - Although nanosizing Li4Ti5O12 (LTO) materials is an effective way to improve their rate performances, their low tap density and first cycle coulombic efficiency limit their practical applications. To tackle these problems while preserving the advanced rate performances, monodispersed mesoporous LTO submicrospheres are developed here. These submicrospheres are synthesized via a solvothermal method using TiO2 submicrospheres and LiOH as precursors followed by a mild calcinations. The roles of the solvent used in the solvothermal process and calcination temperature are systematically investigated and optimized. The LTO submicrospheres fabricated by the solvothermal process using a water-ethanol (60 vol%) solvent followed by a calcination process at 600 degrees C reveal a large sphere size of 660 +/- 30 nm with a small primary particle size of 20-100 nm, a large specific surface area of 15.5 m(2) g(-1), an appropriate pore size of 4.5 nm and an ultra-high tap density of 1.62 g cm(-3). Furthermore, they show high crystallinity and no blockage of Li(+) ion transportation pathways. Due to the novel morphology and ideal crystal structure, these submicrospheres exhibit outstanding electrochemical performances. They display a high first cycle coulombic efficiency of 93.5% and a high charge capacity of 179 mA h g(-1) at 0.5 C between 1.0 and 2.5 V (vs. Li/Li(+)), surpassing the theoretical capacity of LTO. Their charge capacity at 10 C is as high as 109 mA h g(-1) with a capacity retention of 97.8% over 100 cycles. Therefore, this LTO material can be a superior and practical candidate for the anodes of high-power lithium-ion batteries. PMID- 24816783 TI - Onco-epidemiology of domestic animals and targeted therapeutic attempts: perspectives on human oncology. AB - The spontaneous tumor biology has been investigated with the support of animalists using animals as a preclinical model allowing translation of results in clinical practice. This review provides an insight into the field of comparative oncology. Evidence shows that companion animal health care is impressively growing in terms of development of new therapies and diagnostic tools, nutrition and disease prevention. However, even if most animal tumors might be a reliable model to study human carcinomas, many open questions, related to the opportunities to select and recruit new models in oncology, along with their legal and ethical implications, remain unanswered. PMID- 24816784 TI - Re-evaluation of cytostatic therapies for meningiomas in vitro. AB - PURPOSE: The purpose was to re-evaluate in cell culture models the therapeutic usefulness of some discussed chemotherapies or targeted therapies for meningiomas with a special emphasis on the role of the neurofibromatosis type 2 (NF2) tumor suppressor, which had been neglected so far. In addition, the study intended to evaluate a potential benefit from a treatment with drugs which are well established in other fields of medicine and have been linked recently with tumor disease by epidemiological studies. METHODS: Meningioma cell lines corresponding to various subtypes and pairs of syngenic meningioma cell lines with or without shRNA-induced NF2 knockdown were analyzed for their dose-dependent response to the drugs in microtiter tetrazolium assays, BrdU assays and for selected cases in ELISAs measuring nucleosome liberation to specifically separate cell death from pure inhibition of cell proliferation. RESULTS: We confirmed a moderate efficacy of hydroxyurea (HU) in clinically relevant concentrations. Under appropriate dosing, we neither detected major responses to the alkylating compound temozolomide nor to various drugs targeting membrane receptors or enzymes (tamoxifen, erlotinib, mifepristone, losartan, metformin and verapamil). Only concentrations far beyond achievable serum levels generated significant effects with the exception of losartan, which showed no effects at all. Chemosensitivity varied markedly among meningioma cell lines. Importantly, cells with NF2 loss exhibited a significantly higher induction of cell death by HU. CONCLUSIONS: Alternative chemotherapeutic or targeted approaches besides HU have still to be evaluated in further studies, and the role of NF2 must be taken into account. PMID- 24816785 TI - An emerging understanding of long noncoding RNAs in kidney cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome and are emerging as new players in tumorigenesis. METHODS: An electronic search of all relevant publications in peer-reviewed journals before April 2014 was performed on PubMed, Google scholar databases. The keywords of long-coding RNAs, lncRNAs, kidney tumor, renal cancers were used for searching. RESULTS: The lncRNA biology was introduced into cancer biology from contemporary research, and the regulatory mechanisms of lncRNAs was highlighted at transcriptional, post transcriptional and epigenetic levels. The kidney cancer-associated onco-lncRNAs (e.g., KCQN1OT1, MALAT-1 and HOTAIT) and tumor suppressive lncRNAs (e.g., H19, GAS5 and MEG3) were summarized and their possible regulatory network was depicted in a comprehensive diagram. CONCLUSION: LncRNAs are deregulated in various cancers including kidney cancer, demonstrating both oncogenic and tumor suppressive roles, thus suggesting their aberrant expression may be a substantial contributor in cancer development. LncRNAs could serve as potential diagnostics biomarkers and/or therapeutic targets. PMID- 24816786 TI - A polyoxovanadate as an advanced electrode material for supercapacitors. AB - Polyoxovanadate Na(6)V(10)O(28) is investigated for the first time as electrode material for supercapacitors (SCs). The electrochemical properties of Na(6)V(10)O(28) electrodes are studied in Li(+) -containing organic electrolyte (1 M LiClO(4) in propylene carbonate) by galvanostatic charge/discharge and cyclic voltammetry in a three-electrode configuration. Na(6)V(10)O(28) electrodes exhibit high specific capacitances of up to 354 F g(-1). An asymmetric SC with activated carbon as positive electrode and Na(6)V(10)O(28) as negative electrode is fabricated and exhibits a high energy density of 73 Wh kg(-1) with a power density of 312 W kg(-1), which successfully demonstrates that Na(6)V(10)O(28) is a promising electrode material for high-energy SC applications. PMID- 24816787 TI - Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion. AB - Changes in endothelial glycocalyx are one of the earliest changes in development of cardiovascular disease. The endothelial glycocalyx is both an important biological modifier of interactions between flowing blood and the vessel wall, and a determinant of organ perfusion. We hypothesize that deeper penetration of erythrocytes into the glycocalyx is associated with reduced microvascular perfusion. The population-based prospective cohort study (the Netherlands Epidemiology of Obesity [NEO] study) includes 6,673 middle-aged individuals (oversampling of overweight and obese individuals). Within this cohort, we have imaged the sublingual microvasculature of 915 participants using sidestream darkfield (SDF) imaging together with a recently developed automated acquisition and analysis approach. Presence of RBC (as a marker of microvascular perfusion) and perfused boundary region (PBR), a marker for endothelial glycocalyx barrier properties for RBC accessibility, were assessed in vessels between 5 and 25 um RBC column width. A wide range of variability in PBR measurements, with a mean PBR of 2.14 um (range: 1.43-2.86 um), was observed. Linear regression analysis showed a marked association between PBR and microvascular perfusion, reflected by RBC filling percentage (regression coefficient beta: -0.034; 95% confidence interval: -0.037 to -0.031). We conclude that microvascular beds with a thick ("healthy") glycocalyx (low PBR), reflects efficient perfusion of the microvascular bed. In contrast, a thin ("risk") glycocalyx (high PBR) is associated with a less efficient and defective microvascular perfusion. PMID- 24816788 TI - Dietary fiber and amyotrophic lateral sclerosis: results from 5 large cohort studies. AB - Amyotrophic lateral sclerosis (ALS) is a fast-progressing neurodegenerative disease with a median survival time from diagnosis of 1.5-3 years. The cause of ALS is unknown, but inflammation may play a role. Fiber has been shown to lower inflammatory markers, and a high fiber intake was associated with a lower risk of ALS in a case-control study; however, prospective studies are lacking. We explored the relation between dietary intake of fiber and the risk of ALS in 5 large prospective cohort studies comprising over 1,050,000 US citizens who contributed 1,133 ALS cases during a mean of 15 years of follow-up (1980-2008). Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. We found that intakes of total fiber, cereal fiber, vegetable fiber, and fruit fiber were not associated with ALS risk when comparing the highest quintile of intake with the lowest (for total fiber, pooled multivariable relative risk (RR) = 0.99, 95% confidence interval (CI): 0.80, 1.24; for cereal fiber, RR = 1.13, 95% CI: 0.94, 1.37; for vegetable fiber, RR = 0.97, 95% CI: 0.77, 1.23; and for fruit fiber, RR = 1.05, 95% CI: 0.86, 1.29). These findings do not support the hypothesis that fiber intake is a major determinant of ALS risk. PMID- 24816789 TI - Evolution of tertiary structure of viral RNA dependent polymerases. AB - Viral RNA dependent polymerases (vRdPs) are present in all RNA viruses; unfortunately, their sequence similarity is too low for phylogenetic studies. Nevertheless, vRdP protein structures are remarkably conserved. In this study, we used the structural similarity of vRdPs to reconstruct their evolutionary history. The major strength of this work is in unifying sequence and structural data into a single quantitative phylogenetic analysis, using powerful a Bayesian approach. The resulting phylogram of vRdPs demonstrates that RNA-dependent DNA polymerases (RdDPs) of viruses within Retroviridae family cluster in a clearly separated group of vRdPs, while RNA-dependent RNA polymerases (RdRPs) of dsRNA and +ssRNA viruses are mixed together. This evidence supports the hypothesis that RdRPs replicating +ssRNA viruses evolved multiple times from RdRPs replicating +dsRNA viruses, and vice versa. Moreover, our phylogram may be presented as a scheme for RNA virus evolution. The results are in concordance with the actual concept of RNA virus evolution. Finally, the methods used in our work provide a new direction for studying ancient virus evolution. PMID- 24816790 TI - High-level cross-resistance to didanosine observed in South African children failing an abacavir- or stavudine-based 1st-line regimen. AB - BACKGROUND: The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure. METHODS: A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions. RESULTS: Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%). CONCLUSION: Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens. PMID- 24816791 TI - The process from symptom onset to rheumatology clinic in polymyalgia rheumatica. AB - Polymyalgia rheumatica (PMR) is an inflammatory disease of individuals aged over 50 years. Because of the concomitant malignancy possibility and the high prevalence of constitutional symptoms seen in this condition, patients with classical clinical picture often experience delay in diagnosis and treatment and are exposed to a wide list of laboratory and imaging procedures. In this study, we aimed to explore the adventure these patients experience from symptom onset to rheumatology clinic. A total of 106 PMR patients (84 women, 22 men) mean age 70.1 +/- 8 were analyzed retrospectively. The time period from the onset of symptoms and referral to rheumatology specialists was explored. Diagnostic methods applied to these patients, antibiotic use and hospitalization during this period were recorded. The interval between the onset of the symptoms and admission to rheumatology unit was 13 +/- 13 months. In this period, abdominal computed tomography (29.2 %), chest computed tomography (21.7 %), cranial magnetic resonance imaging (18.9 %) and whole-body scintigraphy (3.8 %) were applied to the patients. About 30 % of the patients were hospitalized for a mean period of 7 +/- 3 days before referral to rheumatology unit, and 30 % of the patients were given antibiotics. In order to reduce the delay in the diagnosis of PMR and prevent unnecessary and expensive diagnostic methods, education of clinicians about the diagnosis of PMR may be beneficial. PMID- 24816793 TI - Prevalent drug resistance among oral yeasts from asymptomatic patients in Hainan, China. AB - The oral cavity is a significant niche of the human microbiome and a gateway for the microbiota in many other human body sites. As a result, understanding the oral microbiota has broad implications for the prevention and management of human infectious diseases. Opportunistic yeast infections are among the most prevalent fungal infections of humans, and most opportunistic yeast pathogens are common residents of the oral mucosa. However, relatively little is known about the drug susceptibility profiles of oral yeasts. Here, we report the species distribution and patterns of antifungal susceptibility profiles among 313 yeasts isolated from the oral cavities of 301 asymptomatic hospitalized patients in Hainan Province in southern China. These yeasts were tested for their susceptibilities to the following five drugs: amphotericin B, fluconazole, itraconazole, ketoconazole, and fluorocytosine. Since none of the sampled hosts had taken any antifungal drugs at least 3 months before samples were taken, we hypothesized that little or no drug resistance should be observed. Contrary to our expectations, our analyses identified that 29 % (91/313) of the isolates were resistant to at least one drug and 14.3 % (45/313) were resistant to two or more of the five common drugs. The potential sources of the observed resistance were discussed. PMID- 24816792 TI - Label-free cell phenotypic profiling decodes the composition and signaling of an endogenous ATP-sensitive potassium channel. AB - Current technologies for studying ion channels are fundamentally limited because of their inability to functionally link ion channel activity to cellular pathways. Herein, we report the use of label-free cell phenotypic profiling to decode the composition and signaling of an endogenous ATP-sensitive potassium ion channel (KATP) in HepG2C3A, a hepatocellular carcinoma cell line. Label-free cell phenotypic agonist profiling showed that pinacidil triggered characteristically similar dynamic mass redistribution (DMR) signals in A431, A549, HT29 and HepG2C3A, but not in HepG2 cells. Reverse transcriptase PCR, RNAi knockdown, and KATP blocker profiling showed that the pinacidil DMR is due to the activation of SUR2/Kir6.2 KATP channels in HepG2C3A cells. Kinase inhibition and RNAi knockdown showed that the pinacidil activated KATP channels trigger signaling through Rho kinase and Janus kinase-3, and cause actin remodeling. The results are the first demonstration of a label-free methodology to characterize the composition and signaling of an endogenous ATP-sensitive potassium ion channel. PMID- 24816795 TI - [Elimination or control of the onchocerciasis in Africa? Case of Gami village in Central African Republic]. AB - The authors return the results of a transverse prospective survey whose goal was to value the impact of struggle against the onchocerciasis after 20 years of distribution of ivermectin in a village of the Central African Republic. A transverse prospective survey with a descriptive and analytic aim of a sample of 393 topics aged of more than 5 years residing in Gami Village since more of 2 years and having benefitted the ivermectine in the last distribution that took place 10 months before. The epidemiological, clinical and parasitologic data introverted have been compared to the results of the previous investigations in the village. The parameters improved distinctly during the 20 years (1990-2010) notably the microfilarian indication (88% in 1990 against 19% in 2010), the middle microfilarian density (54 against 0,7), the CMFL Indication (39 against 0,67), the Knuttgen indication moved of the trance of age of 5-9 years to the one of more than 45 years since 1998), the cystic indication (36% against 8%), the ocular lesions (31% against 4%) of which onchocercian (28% against 2%), serious ocular lesions (16% against 1,3%), rate of blindness (9% against 0,8%), rate of meadow-blindness (9% against 0,8), important loss of vision (3% against 0,0%), ocular lesions in children of 6-10 years old (6% against 0,3%). These data permit to speak of control but not of elimination of the onchocerciasis in the grouping villager of Gami because of the persistence of the microfilarian indications susceptible to maintain the transmission of where necessity to pursue the struggle. PMID- 24816794 TI - Impact of inhibitors and L2 antibodies upon the infectivity of diverse alpha and beta human papillomavirus types. AB - The licensed human papillomavirus (HPV) vaccines elicit type-restricted immunity but do not target cutaneous HPV types of the beta genus that are associated with non-melanoma skin cancer in immune-compromised patients, and it is unclear if these diverse types share a common mechanism of infection. Residues 11-88 of minor capsid protein L2 contain cross-protective epitopes, and vaccination with concatamers of this region derived from as many as eight alpha HPV (L2 alpha11 88x8) is being developed as an alternative prophylactic vaccine with potentially broader efficacy. There is also interest in developing broadly protective topical microbicides, such as carrageenan or heparin that block HPV receptor interactions, or small molecule inhibitors of infection. Here we have examined several inhibitors of HPV infection and antisera to L2 alpha11-88x8 for their breadth of activity against infection by 34 HPV types from within both the alpha and beta families using pseudovirions (PsV) carrying a luciferase reporter as surrogates for native virus. We observed that both heparin and carrageenan prevented infection by mucosatropic HPV types, but surprisingly PsV of several epidermotropic alpha4 and beta HPV types exhibited increased infectivity especially at low inhibitor concentrations. Furin and gamma-secretase inhibitors and L2 alpha11-88x8 antiserum blocked infection by all HPV PsV types tested. These findings suggest that the distinct tropism of mucosal and cutaneous HPV may reflect distinct cell surface receptor interactions, but a common uptake mechanism dependent upon furin and gamma-secretase proteolytic activities. Carrageenan, which is being tested as a vaginal microbicide, broadly inhibited infection by the high-risk mucosatropic HPV PsV, but not most skin tropic alpha and beta HPV. Vaccination with an L2 multimer derived exclusively from alpha papillomavirus sequences induced antibodies that broadly neutralized PsV of all 34 HPVs from within both the alpha and beta families, suggesting each displays conserved L2 neutralizing epitopes. PMID- 24816796 TI - Diagnostic accuracy of transient hepatic attenuation differences on computed tomography scans for acute cholangitis in patients with malignant disease. AB - BACKGROUND: Few reports have assessed the accuracy of transient hepatic attenuation differences (THAD) in the arterial phase of computed tomography (CT) in diagnosing acute cholangitis (AC). We examined the diagnostic accuracy of THAD in AC in patients with malignant disease. METHODS: We retrospectively examined the records of 123 consecutive patients (73 men, 50 women; mean age, 69 [range, 43-91] years) who underwent dynamic CT 3 days before biliary drainage for malignant hepatobiliary disease between 2006 and 2011. We examined the diagnostic ability of THAD for AC and assessed the relationship between THAD and AC severity. RESULTS: Acute cholangitis was present in 45% of patients. The sensitivity and specificity of THAD for AC were 93% and 39%, respectively. Diffuse, hemi-hepatic, and segmental THAD for AC were seen in 84%, 4%, and 9%, respectively. In all, 64% of patients were diagnosed with severe AC and 29% with mild AC, depending on the intensity of THAD, but the patterns and degree of intensity of THAD and AC severity were not related. CONCLUSION: Although the pattern and the degree of intensity of THAD and AC severity were not related, THAD might be useful in diagnosing AC. Thus, THAD should be considered a diagnostic criterion for AC. PMID- 24816797 TI - Association of nuclear-localized Nemo-like kinase with heat-shock protein 27 inhibits apoptosis in human breast cancer cells. AB - Nemo-like kinase (NLK), a proline-directed serine/threonine kinase regulated by phosphorylation, can be localized in the cytosol or in the nucleus. Whether the localization of NLK can affect cell survival or cell apoptosis is yet to be disclosed. In the present study we found that NLK was mainly localized in the nuclei of breast cancer cells, in contrast to a cytosolic localization in non cancerous breast epithelial cells. The nuclear localization of NLK was mediated through direct interaction with Heat shock protein 27 (HSP27) which further protected cancer cells from apoptosis. The present study provides evidence of a novel mechanism by which HSP27 recognizes NLK in the breast cancer cells and prevents NLK-mediated cell apoptosis. PMID- 24816798 TI - The prognostic value of osteopontin expression in non-small cell lung cancer: a meta-analysis. AB - To investigate the association of Osteopontin (OPN) expression in tumor tissue with clinicopathological features of non-small cell lung carcinoma (NSCLC) patients. Publications assessing the clinicopathological characteristics and prognostic significance of OPN in expression NSCLC were identified up to March 2014. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between OPN expression and these clinical parameters. A total of eleven studies met the inclusion criteria, and included 1536 cases of NSCLC tumor tissue and 340 cases of normal lung tissue. The OPN expression rate in NSCLC tissue was higher than normal tissue [Odds ratio (OR) 6.427; 95% confidence interval (CI) 4.689-8.808; P = 0.000]. Simultaneously, we also found that OPN expression was positively associated with stage (OR 0.332; 95% CI 0.250-0.440; P = 0.000), lymph node metastasis (OR 3.094; 95% CI 2.295 4.172; P = 0.000), tumor size (tumor size <3 cm vs. >=3 cm; OR 0.484; 95% CI 0.303-0.773; P = 0.002) and pathology (OR 0.611; 95% CI 0.466-0.800; P = 0.000). It was unrelated that OPN expression in NSCLC tissue with and degree of differentiation and other clinical features (P > 0.05). Experimental findings indicate that, OPN plays a crucial role in the development of NSCLC. PMID- 24816799 TI - Inhibition of K+ transport through Na+, K+-ATPase by capsazepine: role of membrane span 10 of the alpha-subunit in the modulation of ion gating. AB - Capsazepine (CPZ) inhibits Na+,K+-ATPase-mediated K+-dependent ATP hydrolysis with no effect on Na+-ATPase activity. In this study we have investigated the functional effects of CPZ on Na+,K+-ATPase in intact cells. We have also used well established biochemical and biophysical techniques to understand how CPZ modifies the catalytic subunit of Na+,K+-ATPase. In isolated rat cardiomyocytes, CPZ abolished Na+,K+-ATPase current in the presence of extracellular K+. In contrast, CPZ stimulated pump current in the absence of extracellular K+. Similar conclusions were attained using HEK293 cells loaded with the Na+ sensitive dye Asante NaTRIUM green. Proteolytic cleavage of pig kidney Na+,K+-ATPase indicated that CPZ stabilizes ion interaction with the K+ sites. The distal part of membrane span 10 (M10) of the alpha-subunit was exposed to trypsin cleavage in the presence of guanidinum ions, which function as Na+ congener at the Na+ specific site. This effect of guanidinium was amplified by treatment with CPZ. Fluorescence of the membrane potential sensitive dye, oxonol VI, was measured following addition of substrates to reconstituted inside-out Na+,K+-ATPase. CPZ increased oxonol VI fluorescence in the absence of K+, reflecting increased Na+ efflux through the pump. Surprisingly, CPZ induced an ATP-independent increase in fluorescence in the presence of high extravesicular K+, likely indicating opening of an intracellular pathway selective for K+. As revealed by the recent crystal structure of the E1.AlF4-.ADP.3Na+ form of the pig kidney Na+,K+-ATPase, movements of M5 of the alpha-subunit, which regulate ion selectivity, are controlled by the C-terminal tail that extends from M10. We propose that movements of M10 and its cytoplasmic extension is affected by CPZ, thereby regulating ion selectivity and transport through the K+ sites in Na+,K+-ATPase. PMID- 24816800 TI - Paraoxonase 2 protein is spatially expressed in the human placenta and selectively reduced in labour. AB - Humans parturition involves interaction of hormonal, neurological, mechanical stretch and inflammatory pathways and the placenta plays a crucial role. The paraoxonases (PONs 1-3) protect against oxidative damage and lipid peroxidation, modulation of endoplasmic reticulum stress and regulation of apoptosis. Nothing is known about the role of PON2 in the placenta and labour. Since PON2 plays a role in oxidative stress and inflammation, both features of labour, we hypothesised that placental PON2 expression would alter during labour. PON2 was examined in placentas obtained from women who delivered by cesarean section and were not in labour and compared to the equivalent zone of placentas obtained from women who delivered vaginally following an uncomplicated labour. Samples were obtained from 12 sites within each placenta: 4 equally spaced apart pieces were sampled from the inner, middle and outer placental regions. PON2 expression was investigated by Western blotting and real time PCR. Two PON2 forms, one at 62 kDa and one at 43 kDa were found in all samples. No difference in protein expression of either isoform was found between the three sites in either the labour or non labour group. At the middle site there was a highly significant decrease in PON2 expression in the labour group when compared to the non-labour group for both the 62 kDa form (p = 0.02) and the 43 kDa form (p = 0.006). No spatial differences were found within placentas at the mRNA level in either labour or non-labour. There was, paradoxically, an increase in PON2 mRNA in the labour group at the middle site only. This is the first report to describe changes in PON2 in the placenta in labour. The physiological and pathological significance of these remains to be elucidated but since PON2 is anti-inflammatory further studies are warranted to understand its role. PMID- 24816801 TI - Relation between belief and performance in perceptual decision making. AB - In an uncertain and ambiguous world, effective decision making requires that subjects form and maintain a belief about the correctness of their choices, a process called meta-cognition. Prediction of future outcomes and self-monitoring are only effective if belief closely matches behavioral performance. Equality between belief and performance is also critical for experimentalists to gain insight into the subjects' belief by simply measuring their performance. Assuming that the decision maker holds the correct model of the world, one might indeed expect that belief and performance should go hand in hand. Unfortunately, we show here that this is rarely the case when performance is defined as the percentage of correct responses for a fixed stimulus, a standard definition in psychophysics. In this case, belief equals performance only for a very narrow family of tasks, whereas in others they will only be very weakly correlated. As we will see it is possible to restore this equality in specific circumstances but this remedy is only effective for a decision-maker, not for an experimenter. We furthermore show that belief and performance do not match when conditioned on task difficulty--as is common practice when plotting the psychometric curve- highlighting common pitfalls in previous neuroscience work. Finally, we demonstrate that miscalibration and the hard-easy effect observed in humans' and other animals' certainty judgments could be explained by a mismatch between the experimenter's and decision maker's expected distribution of task difficulties. These results have important implications for experimental design and are of relevance for theories that aim to unravel the nature of meta-cognition. PMID- 24816802 TI - Acrolein and asthma attack prevalence in a representative sample of the United States adult population 2000-2009. AB - BACKGROUND: Acrolein is an air toxic and highly potent respiratory irritant. There is little epidemiology available, but US EPA estimates that outdoor acrolein is responsible for about 75 percent of non-cancer respiratory health effects attributable to air toxics in the United States, based on the Agency's 2005 NATA (National-Scale Air Toxics Assessment) and acrolein's comparatively potent inhalation reference concentration of 0.02 ug/m3. OBJECTIVES: Assess the association between estimated outdoor acrolein exposure and asthma attack reported by a representative cross-sectional sample of the adult United States population. METHODS: NATA 2005 chronic outdoor acrolein exposure estimates at the census tract were linked with residences oif adults (>=18 years old) in the NHIS (National Health Interview Survey) 2000-2009 (n = 271,348 subjects). A sample weighted logistic regression model characterized the association between the prevalence of reporting at least one asthma attack in the 12 months prior to survey interview and quintiles of exposure to outdoor acrolein, controlling for potential confounders. RESULTS: In the highest quintile of outdoor acrolein exposure (0.05-0.46 ug/m3), there was a marginally significant increase in the asthma attack pOR (prevalence-odds ratio [95% CI] = 1.08 [0.98?1.19]) relative to the lowest quintile. The highest quintile was also associated with a marginally significant increase in prevalence-odds (1.13 [0.98?1.29]) in a model limited to never smokers (n = 153,820). CONCLUSIONS: Chronic exposure to outdoor acrolein of 0.05-0.46 ug/m3 appears to increase the prevalence-odds of having at least one asthma attack in the previous year by 8 percent in a representative cross-sectional sample of the adult United States population. PMID- 24816803 TI - Successful conversion of the Bacillus subtilis BirA Group II biotin protein ligase into a Group I ligase. AB - Group II biotin protein ligases (BPLs) are characterized by the presence of an N terminal DNA binding domain that allows transcriptional regulation of biotin biosynthetic and transport genes whereas Group I BPLs lack this N-terminal domain. The Bacillus subtilis BPL, BirA, is classified as a Group II BPL based on sequence predictions of an N-terminal helix-turn-helix motif and mutational alteration of its regulatory properties. We report evidence that B. subtilis BirA is a Group II BPL that regulates transcription at three genomic sites: bioWAFDBI, yuiG and yhfUTS. Moreover, unlike the paradigm Group II BPL, E. coli BirA, the N terminal DNA binding domain can be deleted from Bacillus subtilis BirA without adverse effects on its ligase function. This is the first example of successful conversion of a Group II BPL to a Group I BPL with retention of full ligase activity. PMID- 24816804 TI - Seasonal variability of mercury contents in street dust in Brno, Czech Republic. AB - Environmental contamination by mercury carries serious risks to the biosphere. Urban agglomerations burdened with traffic are characterized by substantial dust levels, including high concentrations of pollutants bound to particulate matter. In this research, the content of particulate mercury in street dust was investigated in relation to the season and traffic intensity. In total, 80 street dust samples were collected in the centre of Brno (Czech Republic) in which total and bioaccessible mercury contents were determined. Total mercury content in the samples ranged from 0.03 to 2.67 mg/kg. The content of bioaccessible mercury was below the limit of quantification in all samples. Thus, street dust did not increase the daily mercury intake by the population in studied area. A clear trend of mercury accumulation in street dust depending on traffic intensity in the investigated streets was not observed over the whole year. PMID- 24816805 TI - Metformin may reduce breast cancer risk in Taiwanese women with type 2 diabetes. AB - Whether metformin therapy affects breast cancer risk in Asian patients with type 2 diabetes mellitus (T2DM) has not been investigated. The reimbursement databases of Taiwanese female patients with a new diagnosis of T2DM between 1998 and 2002 (n = 476,282) were retrieved from the National Health Insurance for follow-up of breast cancer until the end of 2009. Metformin was treated as a time-dependent variable; and of these patients, 285,087 were never-users and 191,195 were ever users. A time-dependent approach was used to calculate breast cancer incidence and estimate hazard ratios by Cox regression for ever-users, never-users, and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). During follow-up, 2,412 (1.26 %) metformin ever-users and 9,322 (2.10 %) never-users developed breast cancer, representing an incidence of 201.08 and 535.88 per 100,000 person-years, respectively. The overall multivariable-adjusted hazard ratio (95 % confidence intervals) for ever- versus never-users was 0.630 (0.597-0.665). The multivariable-adjusted hazard ratios for the first, second, and third tertiles of cumulative duration of metformin therapy were 1.122 (1.043 1.207), 0.754 (0.692-0.820), and 0.280 (0.253-0.310), respectively, (P-trend <0.0001); and 1.099 (1.021-1.182), 0.664 (0.611-0.723), and 0.311 (0.281-0.344), respectively, (P-trend <0.0001), for cumulative dose of metformin. Metformin use is associated with a decreased risk of breast cancer. PMID- 24816806 TI - A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI. AB - Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12 months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74 % of AI-users reported new/worsened musculoskeletal complaints compared with 37 % in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p = 0.0002). 15 % of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p = 0.0107). Young age (p = 0.0135), taxane-based chemotherapy (p = 0.0223), and baseline VAS score >4 (p = 0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p = 0.0090) and probability of discontinuation was observed (p = 0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients. PMID- 24816807 TI - Probable ankylosaur ossicles from the middle Cenomanian Dunvegan formation of northwestern Alberta, Canada. AB - A sample of six probable fragmentary ankylosaur ossicles, collected from Cenomanian deposits of the Dunvegan Formation along the Peace River, represent one of the first dinosaurian skeletal fossils reported from pre-Santonian deposits in Alberta. Specimens were identified as ankylosaur by means of a palaeohistological analysis. The primary tissue is composed of zonal interwoven structural fibre bundles with irregularly-shaped lacunae, unlike the elongate lacunae of the secondary lamellar bone. The locality represents the most northerly Cenomanian occurrence of ankylosaur skeletal remains. Further fieldwork in under-examined areas of the province carries potential for additional finds. PMID- 24816808 TI - N-acetyl-heparin attenuates acute lung injury caused by acid aspiration mainly by antagonizing histones in mice. AB - Acute lung injury (ALI) is the leading cause of death in intensive care units. Extracellular histones have recently been recognized to be pivotal inflammatory mediators. Heparin and its derivatives can bind histones through electrostatic interaction. The purpose of this study was to investigate 1) the role of extracellular histones in the pathogenesis of ALI caused by acid aspiration and 2) whether N-acetyl-heparin (NAH) provides more protection than heparin against histones at the high dose. ALI was induced in mice via intratracheal instillation of hydrochloric acid (HCl). Lethality rate, blood gas, myeloperoxidase (MPO) activity, lung edema and pathological changes were used to evaluate the degree of ALI. Heparin/NAH was administered intraperitoneally, twice a day, for 3 days or until death. Acid aspiration caused an obvious increase in extracellular histones. A significant correlation existed between the concentration of HCl aspirated and the circulating histones. Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score. At a dose of 20 mg/kg, NAH still provided protection, however heparin tended to aggravate the injury due to hemorrhagic complications. The specific interaction between heparin and histones was verified by the binding assay. In summary, high levels of extracellular histones can be pathogenic in ALI caused by acid aspiration. By neutralizing extracellular histones, heparin/NAH can offer similar protection at the moderate doses. At the high dose, NAH provides better protection than heparin. PMID- 24816810 TI - Facile method to stain the bacterial cell surface for super-resolution fluorescence microscopy. AB - A method to fluorescently stain the surfaces of both Gram-negative and Gram positive bacterial cells compatible with super-resolution fluorescence microscopy is presented. This method utilizes a commercially-available fluorescent probe to label primary amines at the surface of the cell. We demonstrate efficient staining of two bacterial strains, the Gram-negative Shewanella oneidensis MR-1 and the Gram-positive Bacillus subtilis 168. Using structured illumination microscopy and stochastic optical reconstruction microscopy, which require high quantum yield or specialized dyes, we show that this staining method may be used to resolve the bacterial cell surface with sub-diffraction-limited resolution. We further use this method to identify localization patterns of nanomaterials, specifically cadmium selenide quantum dots, following interaction with bacterial cells. PMID- 24816811 TI - Roosting and foraging social structure of the endangered Indiana bat (Myotis sodalis). AB - Social dynamics are an important but poorly understood aspect of bat ecology. Herein we use a combination of graph theoretic and spatial approaches to describe the roost and social network characteristics and foraging associations of an Indiana bat (Myotis sodalis) maternity colony in an agricultural landscape in Ohio, USA. We tracked 46 bats to 50 roosts (423 total relocations) and collected 2,306 foraging locations for 40 bats during the summers of 2009 and 2010. We found the colony roosting network was highly centralized in both years and that roost and social networks differed significantly from random networks. Roost and social network structure also differed substantially between years. Social network structure appeared to be unrelated to segregation of roosts between age classes. For bats whose individual foraging ranges were calculated, many shared foraging space with at least one other bat. Compared across all possible bat dyads, 47% and 43% of the dyads showed more than expected overlap of foraging areas in 2009 and 2010 respectively. Colony roosting area differed between years, but the roosting area centroid shifted only 332 m. In contrast, whole colony foraging area use was similar between years. Random roost removal simulations suggest that Indiana bat colonies may be robust to loss of a limited number of roosts but may respond differently from year to year. Our study emphasizes the utility of graphic theoretic and spatial approaches for examining the sociality and roosting behavior of bats. Detailed knowledge of the relationships between social and spatial aspects of bat ecology could greatly increase conservation effectiveness by allowing more structured approaches to roost and habitat retention for tree-roosting, socially-aggregating bat species. PMID- 24816809 TI - Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST segment elevation myocardial infarction. AB - AIMS: Whether prasugrel plus bivalirudin is a superior strategy to unfractionated heparin plus clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has never been assessed in specifically designed randomized trials. METHODS AND RESULTS: The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study is an investigator-initiated, randomized, open-label, multicentre trial, designed to test the hypothesis that in STEMI patients with planned primary PCI a strategy based on prasugrel plus bivalirudin is superior to a strategy based on clopidogrel plus heparin in terms of net clinical outcome. Owing to slow recruitment, the trial was stopped prematurely after enrolment of 548 of 1240 planned patients. At 30 days, the primary composite endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stent thrombosis, stroke, or bleeding was observed in 42 patients (15.6%) randomized to prasugrel plus bivalirudin and 40 patients (14.5%) randomized to clopidogrel plus heparin [relative risk, 1.09; one-sided 97.5% confidence interval (CI) 0-1.79, P = 0.680]. The composite ischaemic endpoint of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, or stroke occurred in 13 patients (4.8%) in the prasugrel plus bivalirudin group and 15 patients (5.5%) in the clopidogrel plus heparin group (relative risk, 0.89; 95% CI 0.40-1.96, P = 0.894). Bleeding according to the HORIZONS-AMI definition was observed in 38 patients (14.1%) in the prasugrel plus bivalirudin group and 33 patients (12.0%) in the clopidogrel plus heparin group (relative risk, 1.18; 95% CI 0.74-1.88, P = 0.543). Results were consistent across various subgroups of patients. CONCLUSION: In this randomized trial of STEMI patients, we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus heparin. Neither the composite of ischaemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with a regimen of clopidogrel plus unfractionated heparin. However, the results must be interpreted in view of the premature termination of the trial. CLINICAL TRIAL REGISTRATION INFORMATION: Unique identifier NCT00976092 (www.clinicaltrials.gov). PMID- 24816812 TI - Motor axon synapses on renshaw cells contain higher levels of aspartate than glutamate. AB - Motoneuron synapses on spinal cord interneurons known as Renshaw cells activate nicotinic, AMPA and NMDA receptors consistent with co-release of acetylcholine and excitatory amino acids (EAA). However, whether these synapses express vesicular glutamate transporters (VGLUTs) capable of accumulating glutamate into synaptic vesicles is controversial. An alternative possibility is that these synapses release other EAAs, like aspartate, not dependent on VGLUTs. To clarify the exact EAA concentrated at motor axon synapses we performed a quantitative postembedding colloidal gold immunoelectron analysis for aspartate and glutamate on motor axon synapses (identified by immunoreactivity to the vesicular acetylcholine transporter; VAChT) contacting calbindin-immunoreactive (-IR) Renshaw cell dendrites. The results show that 71% to 80% of motor axon synaptic boutons on Renshaw cells contained aspartate immunolabeling two standard deviations above average neuropil labeling. Moreover, VAChT-IR synapses on Renshaw cells contained, on average, aspartate immunolabeling at 2.5 to 2.8 times above the average neuropil level. In contrast, glutamate enrichment was lower; 21% to 44% of VAChT-IR synapses showed glutamate-IR two standard deviations above average neuropil labeling and average glutamate immunogold density was 1.7 to 2.0 times the neuropil level. The results were not influenced by antibody affinities because glutamate antibodies detected glutamate-enriched brain homogenates more efficiently than aspartate antibodies detecting aspartate-enriched brain homogenates. Furthermore, synaptic boutons with ultrastructural features of Type I excitatory synapses were always labeled by glutamate antibodies at higher density than motor axon synapses. We conclude that motor axon synapses co-express aspartate and glutamate, but aspartate is concentrated at higher levels than glutamate. PMID- 24816813 TI - MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma. AB - Non-small cell lung cancers (NSCLCs) cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R), TGF-beta receptor type-1 (TGFBR1), and epidermal growth factor receptor (EGFR), are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer. PMID- 24816814 TI - Application of dual phase imaging of 11C-acetate positron emission tomography on differential diagnosis of small hepatic lesions. AB - OBJECTIVE: Previously we observed that dual phase 11C-acetate positron emission tomography (AC-PET) could be employed for differential diagnosis of liver malignancies. In this study, we prospectively evaluated the effect of dual phase AC-PET on differential diagnosis of primary hepatic lesions of 1-3 cm in size. METHODS: 33 patients having primary hepatic lesions with size of 1-3 cm in diameter undertook dual phase AC-PET scans. Procedure included an early upper abdomen scan immediately after tracer injection and a conventional scan in 11-18 min. The standardized uptake value (SUV) was calculated for tumor (SUVT) and normal tissue (SUVB), from which 11C-acetate uptake ratio (as lesion against normal liver tissue, SUVT/SUVB) in early imaging (R1), conventional imaging (R2), and variance between R2 and R1 (DeltaR) were derived. Diagnoses based on AC-PET data and histology were compared. Statistical analysis was performed with SPSS 19.0. RESULTS: 20 patients were found to have HCC and 13 patients had benign tumors. Using DeltaR>0 as criterion for malignancy, the accuracy and specificity were significantly increased comparing with conventional method. The area under ROC curve (AUC) for R1, R2, and DeltaR were 0.417, 0.683 and 0.831 respectively. Differential diagnosis between well-differentiated HCCs and benign lesions of FNHs and hemangiomas achieved 100% correct. Strong positive correlation was also found between R1 and R2 in HCC (r2 = 0.55, P<0.001). CONCLUSIONS: Dual phase AC PET scan is a useful procedure for differential diagnosis of well-differentiated hepatocellular carcinoma and benign lesions. The dynamic changes of 11C-acetate uptake in dual phase imaging provided key information for final diagnosis. PMID- 24816815 TI - Molecular analysis of the relationship between specific vaginal bacteria and bacterial vaginosis metronidazole therapy failure. AB - Bacterial vaginosis frequently persists, even after treatment. The role of some strains of bacteria associated with bacterial vaginosis treatment failure remains poorly defined. The aim of our study was to define the risk of bacterial vaginosis treatment failure, including pre-treatment detection of specific vaginal bacteria. Bacterial vaginosis is present when the Nugent score is >=7 and the modified Amsel criteria is positive. Women with bacterial vaginosis were treated with intravaginal metronidazole gel nightly for 5 nights. The 454 pyrosequencing method was used to detect bacteria in vaginal fluid. By univariate analysis, a history of bacterial vaginosis, intrauterine device use and the presence of Facklamia, Corynebacterium and Veillonella were significantly associated with bacterial vaginosis treatment failure. Lactobacillus crispatus, Lactobacillus pentosus and Megasphaera were significantly associated with curing bacterial vaginosis. After logistic regression analysis and detection of these bacteria for test-of-cure, we found that women who had a history of bacterial vaginosis had a higher incidence of bacterial vaginosis treatment failure, whereas women with L. crispatus had a lower incidence of treatment failure. Post treatment sexual activity was not associated with the treatment effect. Our data suggested that treatment failure may be not caused by drug resistance. Rather, it has a closer relationship with the failed restoration of lactobacilli. PMID- 24816816 TI - Allograft inflammatory factor-1 alleviates liver disease of BALB/c mice infected with Schistosoma japonicum. AB - Allograft inflammatory factor-1 (AIF-1) plays an important role in various inflammatory conditions. Our previous study demonstrated that AIF-1 was over expressed in the liver of BALB/c mice infected with Schistosoma japonicum and played significant role in the pathogenesis of schistosomiasis. The aim of this study was to focus on the effect of AIF-1 treatment on liver fibrosis and necrosis of BALB/c mice infected with S. japonicum. Seventy-two BALB/c mice were infected with cercariae of S. japonicum and then divided into three groups: AIF-1 treated group, saline-treated group, and control group. The vital signs, liver function, egg load, and hepatic pathological changes of the mice were assessed, and the levels of AIF-1 and TNF-alpha in the liver and spleen were measured at 5, 8, and 14 weeks postinfection. The treatment of AIF-1 on the mice infected with S. japonicum suppressed the expression of TNF-alpha and increased the effectiveness of AIF-1 in the liver and spleen at 14 weeks postinfection. Histopathological analysis and Masson trichrome staining for the liver tissues showed that the liver fibrosis and necrosis were alleviated previously compared with other infected mice at 14 weeks postinfection. The treatment of AIF-1 on the mice infected with S. japonicum can alleviate hepatic fibrosis and necrosis which indicate that AIF-1 use may prevent and cure the liver fibrosis. PMID- 24816817 TI - Massively parallel sequencing of human urinary exosome/microvesicle RNA reveals a predominance of non-coding RNA. AB - Intact RNA from exosomes/microvesicles (collectively referred to as microvesicles) has sparked much interest as potential biomarkers for the non invasive analysis of disease. Here we use the Illumina Genome Analyzer to determine the comprehensive array of nucleic acid reads present in urinary microvesicles. Extraneous nucleic acids were digested using RNase and DNase treatment and the microvesicle inner nucleic acid cargo was analyzed with and without DNase digestion to examine both DNA and RNA sequences contained in microvesicles. Results revealed that a substantial proportion (~87%) of reads aligned to ribosomal RNA. Of the non-ribosomal RNA sequences, ~60% aligned to non coding RNA and repeat sequences including LINE, SINE, satellite repeats, and RNA repeats (tRNA, snRNA, scRNA and srpRNA). The remaining ~40% of non-ribosomal RNA reads aligned to protein coding genes and splice sites encompassing approximately 13,500 of the known 21,892 protein coding genes of the human genome. Analysis of protein coding genes specific to the renal and genitourinary tract revealed that complete segments of the renal nephron and collecting duct as well as genes indicative of the bladder and prostate could be identified. This study reveals that the entire genitourinary system may be mapped using microvesicle transcript analysis and that the majority of non-ribosomal RNA sequences contained in microvesicles is potentially functional non-coding RNA, which play an emerging role in cell regulation. PMID- 24816818 TI - Tal2 expression is induced by all-trans retinoic acid in P19 cells prior to acquisition of neural fate. AB - TAL2 is a member of the basic helix-loop-helix family and is essential for the normal development of the mouse brain. However, the function of TAL2 during brain development is unclear. P19 cells are pluripotent mouse embryonal carcinoma cells that adopt neural fates upon exposure to all-trans retinoic acid (atRA) and culture in suspension. We found that the expression of Tal2 gene was induced in P19 cells after addition of atRA in suspension culture. Tal2 expression was detected within 3 h after the induction, and had nearly returned to basal levels by 24 h. When GFP-tagged TAL2 (GFP-TAL2) was expressed in P19 cells, we observed GFP-TAL2 in the nucleus. Moreover, we showed that atRA and retinoic acid receptor alpha regulated Tal2 expression. These results demonstrate for the first time that atRA induces Tal2 expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development. PMID- 24816819 TI - Small juxtacortical hemorrhages in cerebral venous thrombosis. AB - OBJECTIVE: Intracerebral hemorrhages (ICHs) are common in patients with cerebral venous thrombosis (CVT). We examined whether small juxtacortical hemorrhages (JCHs) are characteristic for CVT and studied their radiological and pathological properties. METHODS: We identified all patients with CVT and an ICH at baseline admitted between 2000 and 2011 (prospectively from July 2006). JCH was defined as a hemorrhage (diameter < 20mm) located in the white matter just below the cortex. To determine the specificity of JCHs for CVT, we examined the frequency of JCHs in a control group of patients of similar age with an ICH not related to CVT. RESULTS: Of 114 patients with CVT, 53 had an ICH. JCHs were present in 14 of the 53 (26%). The remaining 39 had other kinds of hemorrhages. Papilledema was more common among patients with a JCH compared to patients with other types of ICHs (44% vs 9%, p = 0.01). All patients with a JCH except 1 had thrombosis of the superior sagittal sinus, compared to 49% of patients with CVT and other kinds of hemorrhages (p = 0.004). Reanalysis of all imaging data and histopathologic analysis in 1 patient showed that JCHs are located near the U-fibers and that they follow the curvature of the cortex. Among 196 control patients (spontaneous ICH, not caused by CVT), only 3 patients had a JCH. One of these 3 appeared on re examination of all imaging results to have had CVT. INTERPRETATION: Small nontraumatic JCHs are a characteristic feature of CVT and are rarely encountered in other conditions. PMID- 24816820 TI - Evaluation of Salacia species as anti-diabetic natural resources based on quantitative analysis of eight sulphonium constituents: a new class of alpha glucosidase inhibitors. AB - INTRODUCTION: Stems and roots of Salacia genus plants have been used in Ayurveda as a specific remedy for early stage diabetes. Previous investigations identified four sulphonium sulphates, that is, salacinol (1), kotalanol (3), ponkoranol (5) and salaprinol (7), as the compounds responsible for the anti-diabetic activity. Their desulphonates (2, 4, 6 and 8) were also isolated as active constituents. Two separate quantitative analytical protocols, that is, for 1 and 3 and for 2 and 4, have been developed recently. OBJECTIVE: To: validate the two analytical protocols with respect to all eight sulphoniums; evaluate the quality of a variety of Salacia samples collected in different geographical regions, that is, Thailand, Sri Lanka and India; and determine their distribution in each part of the plant, that is, stems/roots, leaves and fruits. METHODS: Analyses of four sulphonium sulphates in 32 Salacia extracts were carried out on an Asahipak NH2P 50 column, and those of the corresponding desulphonates were conducted on an Inertsil ODS-3 column. RESULTS: Neokotalanol (4) was the major constituent in Salacia samples from Thailand, whereas 1 was the primary constituent in extracts of the stems/roots of plants from Sri Lanka and India. These sulphoniums were only present in trace amounts in leaves and fruits of the plants. CONCLUSION: Two analytical protocols were successfully applied to analyse 32 Salacia samples, and revealed that sulphoniums (1-8) had characteristic distributions due to the plant part and/or due to geographical region. PMID- 24816821 TI - Factor structure of the parent perception of uncertainty scale in parents of children with cancer. PMID- 24816822 TI - Ensemble positive unlabeled learning for disease gene identification. AB - An increasing number of genes have been experimentally confirmed in recent years as causative genes to various human diseases. The newly available knowledge can be exploited by machine learning methods to discover additional unknown genes that are likely to be associated with diseases. In particular, positive unlabeled learning (PU learning) methods, which require only a positive training set P (confirmed disease genes) and an unlabeled set U (the unknown candidate genes) instead of a negative training set N, have been shown to be effective in uncovering new disease genes in the current scenario. Using only a single source of data for prediction can be susceptible to bias due to incompleteness and noise in the genomic data and a single machine learning predictor prone to bias caused by inherent limitations of individual methods. In this paper, we propose an effective PU learning framework that integrates multiple biological data sources and an ensemble of powerful machine learning classifiers for disease gene identification. Our proposed method integrates data from multiple biological sources for training PU learning classifiers. A novel ensemble-based PU learning method EPU is then used to integrate multiple PU learning classifiers to achieve accurate and robust disease gene predictions. Our evaluation experiments across six disease groups showed that EPU achieved significantly better results compared with various state-of-the-art prediction methods as well as ensemble learning classifiers. Through integrating multiple biological data sources for training and the outputs of an ensemble of PU learning classifiers for prediction, we are able to minimize the potential bias and errors in individual data sources and machine learning algorithms to achieve more accurate and robust disease gene predictions. In the future, our EPU method provides an effective framework to integrate the additional biological and computational resources for better disease gene predictions. PMID- 24816823 TI - Osteotomies in the treatment of spinal deformities: indications, classification, and surgical planning. AB - The surgical treatment of adult spinal deformity has been shown to offer superior clinical and radiographic outcomes compared with nonoperative approaches; furthermore, osteotomies are increasingly applied for treating spinal deformities. Establishing a plan for a patient suffering from marked spinal deformity is a matter of consideration of certain radiographic parameters which correlate with health-related quality of life scores, adherence to consistent principles of alignment and established formulas, and selecting the appropriate osteotomies. This is a review of the most recent work on vertebral osteotomies and includes a summary of a systematic and anatomically based osteotomy classification. A universal classification will facilitate communication, standardize outcomes research, and establish a framework upon which indications can be properly studied and described. Ongoing multicenter collaboration is certain to drive a more evidence-based approach to the complex clinical scenarios of patients suffering from spinal deformity. PMID- 24816824 TI - Phosphocalcium ceramics are efficient in the management of severe acetabular loss in revision hip arthroplasties. A 22 cases long-term follow-up study. AB - Management of bone loss in revision total hip replacement remains a challenge. To eliminate any immunological or infectious problem and so to try to improve the long-term results obtained with allografts, the authors used synthetic ceramics as bone substitutes since 1995. We reviewed 13 of the patients of our study, we previously reported in 2005 (Schwartz and Bordei in Eur J Orthop Surg Traumatol 15: 191 2005), which was a prospective cohort of thirty-two cases of acetabular revision reconstruction, with a mean follow-up of 14.4 years yet (from 9 to 16 years). Clinical results were assessed according to Oxford scale and Postel and Merle d'Aubigne (PMA) scale. Since 2005, no specific complications were noted. The average PMA functional hip score was 14.9 (vs. 9.2 before revision) at follow up over 9 years. Nine patients still alive in 2013 were seen again by a surgeon, which was not the operator, with a mean follow-up of 15.3 years: Their Oxford average score was 40.3. Radiological assessment affirmed a good integration of the substitutes in bone without any edging in all cases. A progressive invasion of the ceramics by bone can be seen on the X-ray. We conclude that about 15 years of average delay, which is a significant follow-up in orthopedic surgery, the outcomes without specific complications are satisfactory and allow one to go with these materials in total hip revision surgery. PMID- 24816825 TI - Synthesis of the 18th ArgoSpine Symposium. AB - The subject of this 18th Symposium of ArgoSpine Association was the space of the intervertebral discs. Space of the intervertebral discs must be initially defined anatomically and histologically. A geometrical rebuilding in 3D is possible and must allow a modeling of the intervertebral discs. The physiology of the disc, its nutrition, must be known, in particular that of the center of the disc. The disc constitutes the base of the balance of the rachis, balances which can be only dynamic. The degenerative cascade by the loss of the proteoglycans involves the loss of the biomechanical properties of the disc. The consequences of this degenerative cascade are the base of all the vertebral pathology of origin of the intervertebral discs and even of the posterior articular facets. The origin of the pains and the diagnosis, especially at the lumbar level, are studied by the speakers. Traumatology of the intervertebral discs is the object of a particular chapter. Finally, the average therapeutic ones, that is, decompression of the intervertebral discs, fusion of the intervertebral discs, the recovery of mobility of the intervertebral discs, and the capacity of restoration of space of the intervertebral discs, are studied in detail. The infection of the disc is studied in detail. PMID- 24816826 TI - Characterisation of large F9 deletions in seven unrelated patients with severe haemophilia B. AB - Large deletions in the F9 gene are detected in approximately 5% of patients with severe haemophilia B, but only a few deletion breakpoints have been characterised precisely until now. In this study we identified a total of seven large F9 deletions in the index patients and nine female carriers by the AccuCopy technique. We also successfully characterised the exact breakpoints for each large deletion including four deletions encompassing the entire F9 gene by the genome walking method combined with primer walking strategy. The extents of deletion regions ranged from 11.1 to 884 kb. Microhomologies ranged from 2 to 6 bp were identified in the breakpoint junctions of six deletions. The other deletion occurred between two highly homologous sequences of the same long interspersed nuclear element 1 (LINE/L1). Non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) may be the main causative mechanisms for the six large deletions with microhomologies. Non allelic homologous recombination (NAHR) may mediate the deletion occurred between the two tandem LINEs in the other large deletion. Repetitive elements and non-B DNA forming motifs identified in the junction regions may contribute to DNA breakage leading to large deletions. PMID- 24816827 TI - Examining why ethics is taught to veterinary students: a qualitative study of veterinary educators' perspectives. AB - Although it is widely agreed that veterinary students need to be introduced to ethics, there is limited empirical research investigating the reasons why veterinary ethics is being taught. This study presents the first extensive investigation into the reasons for teaching veterinary ethics and reports data collected in semi-structured interviews with educators involved in teaching undergraduate veterinary ethics at three European schools: the University of Copenhagen, the University of Nottingham, and the Technical University of Lisbon (curricular year 2010-2011). The content of the interview transcripts were analyzed using Toulmin's argumentative model. Ten objectives in teaching veterinary ethics were identified, which can be grouped into four overarching themes: ethical awareness, ethical knowledge, ethical skills, and individual and professional qualities. These objectives include recognizing values and ethical viewpoints, identifying norms and regulations, developing skills of communication and decision making, and contributing to a professional identity. Whereas many of the objectives complement each other, there is tension between the view that ethics teaching should promote knowledge of professional rules and the view that ethics teaching should emphasize critical reasoning skills. The wide range of objectives and the possible tensions between them highlight the challenges faced by educators as they attempt to prioritize among these goals of ethics teaching within a crowded veterinary curriculum. PMID- 24816828 TI - Pillar[5]arene-based nonionic polyrotaxanes and a topological gel prepared from cyclic host liquids. AB - We synthesize nonionic polymer-based polyrotaxanes in solvent systems based on pillar[5]arene cyclic host liquids. Using a reactive liquid, pillar[5]arene enabled synthesis of a nonionic topological gel. PMID- 24816829 TI - Intraperitoneal delivery of paclitaxel by poly(ether-anhydride) microspheres effectively suppresses tumor growth in a murine metastatic ovarian cancer model. AB - Intraperitoneal (IP) chemotherapy is more effective than systemic chemotherapy for treating advanced ovarian cancer, but is typically associated with severe complications due to high dose, frequent administration schedule, and use of non biocompatible excipients/delivery vehicles. Here, we developed paclitaxel (PTX) loaded microspheres composed of di-block copolymers of poly(ethylene glycol) and poly(sebacic acid) (PEG-PSA) for safe and sustained IP chemotherapy. PEG-PSA microspheres provided efficient loading (~ 13% w/w) and prolonged release (~ 13 days) of PTX. In a murine ovarian cancer model, a single dose of IP PTX/PEG-PSA particles effectively suppressed tumor growth for more than 40 days and extended the median survival time to 75 days compared to treatments with Taxol((r)) (47 days) or IP placebo particles (34 days). IP PTX/PEG-PSA was well tolerated, with only minimal to mild inflammation. Our findings support PTX/PEG-PSA microspheres as a promising drug delivery platform for IP therapy of ovarian cancer, and potentially other metastatic peritoneal cancers. PMID- 24816830 TI - Modeling the pharyngeal anatomical effects on breathing resistance and aerodynamically generated sound. AB - The objective of this study was to systematically assess the effects of pharyngeal anatomical details on breathing resistance and acoustic characteristics by means of computational modeling. A physiologically realistic nose-throat airway was reconstructed from medical images. Individual airway anatomy such as the uvula, pharynx, and larynx was then isolated for examination by gradually simplifying this image-based model geometry. Large eddy simulations with the FW-H acoustics model were used to simulate airflows and acoustic sound generation with constant flow inhalations in rigid-walled airway geometries. Results showed that pharyngeal anatomical details exerted a significant impact on breathing resistance and energy distribution of acoustic sound. The uvula constriction induced considerably increased levels of pressure drop and acoustic power in the pharynx, which could start and worsen snoring symptoms. Each source anatomy was observed to generate a unique spectrum with signature peak frequencies and energy distribution. Moreover, severe pharyngeal airway narrowing led to an upward shift of sound energy in the high-frequency range. Results indicated that computational aeroacoustic modeling appeared to be a practical tool to study breathing-related disorders. Specifically, high-frequency acoustic signals might disclose additional clues to the mechanism of apneic snoring and should be included in future acoustic studies. PMID- 24816831 TI - Serum prolactin in advanced chronic liver disease. AB - Hyperprolactinemia is a frequent endocrine disorder with well known harmful effects on the reproductive system and bone metabolism. Besides prolactinomas several drugs and disorders such as renal failure and hypothyroidism have been shown to cause hyperprolactinemia. Based on former studies, liver cirrhosis has also been suggested to cause hyperprolactinemia, while mechanisms have not been identified yet. In this study, we set out to investigate the prevalence and predictors of hyperprolactinemia in 178 patients with liver cirrhosis of different etio-logies. Eighteen out of 178 patients - 7 females and 11 males - displayed elevated serum pro-lactin levels. When patients were excluded who suffered from co-morbidities or took medication that are discussed to potentially interfere with prolactin metabolism, only 3 males displayed increased serum prolactin levels. Prolactin levels were similar in patients with liver cirrhosis of different etiologies. Our data suggest that hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or presence of comorbidites which are known to potentially cause hyperprolactinemia. We thus hypothesize that in contrast to former studies liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that are known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis. PMID- 24816832 TI - Suppression of mesangial cell proliferation and extracellular matrix production in streptozotocin-induced diabetic mice by adiponectin in vitro and in vivo. AB - Renal growth, particularly hypertrophy, is a feature of diabetic nephropathy (DN). Adiponectin, an adipocyte-derived hormone, is an important regulator of cell proliferation. Recent studies have suggested that adiponectin has a protective effect in the kidney. The purpose of this study was to investigate the therapeutic effects and the underlying mechanisms of adiponectin in early DN. Mouse mesangial cells (MMCs) were cultured in media containing different concentrations of platelet-derived growth factor-BB (PDGF-BB) with or without adiponectin. MMC proliferation and expression of type IV collagen, laminin, and fibronectin were investigated. Streptozotocin-induced diabetic mice were injected intravenously with recombinant lentivirus encoding the mouse adiponectin gene (Lenti-Acdc-IRES-EGFP). Urinary microalbumin, serum adiponectin level, and expression of proliferating cell nuclear antigen, type IV collagen, laminin, and fibronectin were determined. Adiponectin inhibited the increases in MMC proliferation and expression of type IV collagen, laminin, and fibronectin induced by PDGF-BB. Adiponectin also effectively reduced renal cell proliferation and expression of type IV collagen, laminin, and fibronectin when it was introduced in vivo by lentivirus-mediated gene transfer. These findings suggest that adiponectin exerts renoprotective effects by inhibiting renal cell proliferation and reducing synthesis of extracellular matrix proteins, thus suppressing the development and progression of DN. PMID- 24816833 TI - Re-operative thyroid surgery: a 20-year prospective cohort study at a tertiary referral centre. AB - Re-operative thyroid surgery is a relatively uncommon procedure complicated by distorted anatomy and post-operative tissue changes. Surgery may follow initial benign or malignant pathology. Published outcomes vary widely in the literature. This study aims to report our outcomes from re-operative thyroid surgery. Patient demographics and complication rates for consecutive thyroidectomies performed by a single surgeon at a tertiary centre were collected between 1993 and 2013. Outcomes in re-operative surgery are analysed and compared with local and national data. Cases of re-operative surgery following benign disease are further analysed for histology, re-presenting symptoms and time between procedures. Our cohort comprised 1,657 cases including 164 re-operative procedures (101 malignant, 63 benign). Within our cohort re-operative cases were on average 4 years older (mean 49.9 vs 45.9 years, p = 0.001) and had a higher incidence of haematoma formation (4.3 vs 1.7 %, p = 0.033) and transient recurrent laryngeal nerve palsy (5.5 vs 2.5 %, p = 0.044) compared to primary surgery. Rates of permanent hypocalcaemia (2.4 vs 1.8 %, p = 0.540) and permanent RLN palsy (1.8 vs 0.4 %, p = 0.051) were higher in the re-operative group but did not reach significance. Comparison of complications following re-operation for benign and malignant disease revealed no significant differences. Mean interval to re operation for benign cases was 17.4 years with 74.6 % found to have multinodular goitre at repeat procedure. Re-operative procedures comprised around 10 % of thyroid surgery at our centre. Re-operative cases experienced more complications than primary surgery but permanent rates were low. Re-operative surgery may therefore be safely considered in experienced hands. PMID- 24816834 TI - Preoperative serum pattern analysis to predict the outcome of tonsillectomy in adults with chronic tonsillitis. AB - The method of classification and tree analysis (CART) was used to predict the outcome of tonsillectomy for chronic tonsillitis (CHT) analyzing patterns of serological markers. In a prospective case study of 24 adult patients with CHT in comparison to 24 patients with acute peritonsillar abscess (PTA) blood samples were assessed 1 day before (T-1) and 3 days after tonsillectomy. Outcome 6 months later (T180) was documented using the Glasgow Benefit Inventory (GBI) and the Specific Benefits from Tonsillectomy Inventory (SBTI). In comparison to PTA, patients with CHT were at best classified by C-reactive protein with a cut-off value of <16.735 mg/dl. For CHT, immunoglobulin E <= 144.65 kU/l and the combination of monocytes <= 0.565 Gpt/l plus leucocytes >5.855 Gpt/l at T-1 were the best classificators for higher SBTI overall score and symptom score symptom score, respectively, at T180. A higher benefit subscore at T180 was associated to gamma-globulin >15.85 % plus alpha2-globulin >8.950% at T-1. The best classificator for better GBI overall score at T180 was an ASL titer >169.0 IU/ml or the combination of an ASL titer <= 169.0 IU/ml with lymphocytes <= 2.195 Gpt/l. Lymphocytes <= 2.195 Gpt/l were associated with higher GBI general subscore. Leukocytes <= 6.780 Gpt/l were related to higher GBI social support subscore. The combination of immunoglobulin A >1.360 g/l with procalcitonin level >0.058 ng/ml was the best combination to classify for higher physical health score. Instead of looking on isolated serologic markers, CART of multiple parameters seems to be more effective to predict the outcome of tonsillectomy for CHT. PMID- 24816835 TI - Assessment of modularity in the urodele skull: an exploratory analysis using ossification sequence data. AB - The potential presence of developmental modules is studied in the urodele skull using several classical statistical methods that have not previously been used in this context. Principal component analysis (PCA) of ossification sequence data on 21 bones in 21 extant urodele species suggests the presence of up to four developmental modules, but examination of statistically significant correlations using phylogenetic independent contrasts (PIC) and correcting for multiple tests using the false discovery rate suggests the presence of only two modules of uneven size and of two bones that may not be part of these modules. Thus, PCA does not appear to be a reliable method to investigate modularity; direct investigation of statistically significant correlations using PIC or other phylogeny-informed methods is recommended. A binomial test of the distribution of significant correlations between characters shows significant heterogeneity, which suggests that modularity is indeed present in the data. A cluster analysis gives inconsistent results that apparently do not reflect developmental modules. The data include a phylogenetic signal, as shown by a permutation-based test with squared change parsimony, but this is detectable only when the whole matrix is analyzed, and a plot of the tree onto developmental space through Evolutionary PCA shows that homoplasy is pervasive. Evolutionary rates between characters vary about 90-fold. Canonical variates analyses suggest that obligatorily neotenic urodeles may be discriminated from other urodeles on the basis of cranial ossification sequence data. PMID- 24816836 TI - A role for ultrasonic vocalisation in social communication and divergence of natural populations of the house mouse (Mus musculus domesticus). AB - It has long been known that rodents emit signals in the ultrasonic range, but their role in social communication and mating is still under active exploration. While inbred strains of house mice have emerged as a favourite model to study ultrasonic vocalisation (USV) patterns, studies in wild animals and natural situations are still rare. We focus here on two wild derived mouse populations. We recorded them in dyadic encounters for extended periods of time to assess possible roles of USVs and their divergence between allopatric populations. We have analysed song frequency and duration, as well as spectral features of songs and syllables. We show that the populations have indeed diverged in several of these aspects and that USV patterns emitted in a mating context differ from those emitted in same sex encounters. We find that females vocalize not less, in encounters with another female even more than males. This implies that the current focus of USVs being emitted mainly by males within the mating context needs to be reconsidered. Using a statistical syntax analysis we find complex temporal sequencing patterns that could suggest that the syntax conveys meaningful information to the receivers. We conclude that wild mice use USV for complex social interactions and that USV patterns can diverge fast between populations. PMID- 24816838 TI - A new family of Ln7 clusters with an ideal D(3h) metal-centered trigonal prismatic geometry, and SMM and photoluminescence behaviors. AB - The first use of the flexible Schiff base ligand N-salicylidene-2 aminocyclohexanol in metal cluster chemistry has afforded a new family of Ln7 clusters with ideal D(3h) point group symmetry and metal-centered trigonal prismatic topology; solid-state and solution studies revealed SMM and photoluminescence behaviors. PMID- 24816837 TI - Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations. AB - Bone morphogenetic proteins (BMPs) are highly conserved signaling molecules that are part of the transforming growth factor (TGF)-beta superfamily, and function in the patterning and morphogenesis of many organs including development of the dentition. The functions of the BMPs are controlled by certain classes of molecules that are recognized as BMP antagonists that inhibit BMP binding to their cognate receptors. In this study we tested the hypothesis that USAG-1 (uterine sensitization-associated gene-1) suppresses deciduous incisors by inhibition of BMP-7 function. We learned that USAG-1 and BMP-7 were expressed within odontogenic epithelium as well as mesenchyme during the late bud and early cap stages of tooth development. USAG-1 is a BMP antagonist, and also modulates Wnt signaling. USAG-1 abrogation rescued apoptotic elimination of odontogenic mesenchymal cells. BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced. Using explant culture and subsequent subrenal capsule transplantation of E15 USAG-1 mutant maxillary incisor tooth primordia supplemented with BMP-7 demonstrated in USAG-1+/- as well as USAG-1-/- rescue and supernumerary tooth development. Based upon these results, we conclude that USAG 1 functions as an antagonist of BMP-7 in this model system. These results further suggest that the phenotypes of USAG-1 and BMP-7 mutant mice reported provide opportunities for regenerative medicine and dentistry. PMID- 24816839 TI - Secretarybird Sagittarius serpentarius population trends and ecology: insights from South African citizen science data. AB - Data from two long-term citizen science projects were used to examine the status and ecology of a Red List species, the Secretarybird Sagittarius serpentarius (Vulnerable), in South Africa. The first phase of the Southern African Bird Atlas Project operated from 1987 until 1992, and the second phase began in 2007. The Coordinated Avifaunal Roadcounts (CAR) project began in 1993 and by 1998 had expanded to cover much of the south-eastern half of the country. Data submitted up until April 2013 were used. A new method of comparing reporting rates between atlas projects was developed. Changing reporting rates are likely to reflect changes in abundance; in this instance the data suggest that the Secretarybird population decreased across much of South Africa between the two atlas projects, with a widespread important decrease in the Kruger National Park. Habitat data from the CAR project were analysed to gain insight into the ecology of the species. Secretarybirds tended to avoid transformed habitats across much of the area covered by the CAR project. In the winter rainfall region of the Western Cape, which is characterised by heavily transformed fynbos vegetation, at least 50% of Secretarybirds recorded were in transformed environments. This implies that in the Fynbos biome, at least, Secretarybirds have adapted to transformed environments to some degree. However, in the rest of the country it is likely that habitat loss, largely through widespread bush encroachment but also through agriculture, afforestation, and urbanisation, is a major threat to the species. The methods developed here represent a new approach to analysing data from long term citizen science projects, which can provide important insights into a species' conservation status and ecology. PMID- 24816840 TI - Gibberellin overproduction promotes sucrose synthase expression and secondary cell wall deposition in cotton fibers. AB - Bioactive gibberellins (GAs) comprise an important class of natural plant growth regulators and play essential roles in cotton fiber development. To date, the molecular base of GAs' functions in fiber development is largely unclear. To address this question, the endogenous bioactive GA levels in cotton developing fibers were elevated by specifically up-regulating GA 20-oxidase and suppressing GA 2-oxidase via transgenic methods. Higher GA levels in transgenic cotton fibers significantly increased micronaire values, 1000-fiber weight, cell wall thickness and cellulose contents of mature fibers. Quantitative RT-PCR and biochemical analysis revealed that the transcription of sucrose synthase gene GhSusA1 and sucrose synthase activities were significantly enhanced in GA overproducing transgenic fibers, compared to the wild-type cotton. In addition, exogenous application of bioactive GA could promote GhSusA1 expression in cultured fibers, as well as in cotton hypocotyls. Our results suggested that bioactive GAs promoted secondary cell wall deposition in cotton fibers by enhancing sucrose synthase expression. PMID- 24816841 TI - Overexpression of LAPTM4B is correlated with tumor angiogenesis and poor prognosis in non-small cell lung cancer. AB - Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is a novel oncogene, which has been indicated to be dramatically overexpressed in various malignant tumors. The aims of this study were to detect LAPTM4B protein expression in patients with non-small cell lung cancer (NSCLC) and then analyze the relationships of LAPTM4B protein with clinicopathologic factors, tumor angiogenesis and prognosis with SPSS statistical software. Immunohistochemistry was used to examine the expression of LAPTM4B and CD34 proteins in NSCLC tissues, and its results showed that LAPTM4B protein expression in NSCLC tissues was significantly higher than that in normal lung tissues (P < 0.001). Of the186 NSCLC cases, 129 (69.35 %) had strong expression of LAPTM4B protein, which was associated with histopathologic differentiation (P = 0.017), lymph node metastasis (P = 0.001) and TNM stage (P = 0.046), as well as the microvessel density (MVD) (P = 0.019). Kaplan-Meier survival analysis revealed that patients with strong LAPM4B protein expression and high MVD might have poor overall survival (OS; P = 0.001, P = 0.002, respectively) and disease-free survival (DFS; P = 0.002, P = 0.038, respectively). Multivariate analysis demonstrated that LAPTM4B protein was an independent prognostic marker for OS and DFS of NSCLC patients (P = 0.037, P = 0.046, respectively). These findings illustrated that LAPTM4B protein was closely associated with NSCLC progression, angiogenesis and poor prognosis, suggesting that LAPTM4B protein could be applied not only in predicting patient's outcome, but also in antiangiogenic therapy as a possible novel target molecule. PMID- 24816842 TI - Variation in N-acetyltransferase 2 (NAT2), smoking and risk of prostate cancer in the Slovak population. AB - N-acetyltransferase 2 (NAT2) is an enzyme involved in the biotransformation of xenobiotics, mainly aromatic and heterocyclic amines and hydrazines, all of which represent an important class of carcinogens found in tobacco smoke. Polymorphism in NAT2 gene is reported to be associated with susceptibility to various types of cancer. This study investigated the relationship between the NAT2 polymorphism and the risk of prostate cancer with reference to the link between cigarette smoking and the xenobiotic-metabolizing enzyme NAT2. Overall, 281 cases and 395 controls from Slovakia were studied using polymerase chain reaction-restriction fragment length polymorphism assay. We found no statistically significant association between NAT2 genotypes and prostate cancer risk (slow acetylation vs. rapid acetylation: OR 1.13; 95 % CI 0.83-1.55). We report here a statistically significant correlation between the NAT2*5C/NAT2*6A slow acetylator genotype and the risk for developing prostate cancer (OR 2.91; 95 % CI 1.43-5.94; p = 0.003) when compared with the rapid phenotype. Smokers with NAT2 rapid phenotype had a five percent (5 %) reduced risk of prostate cancer compared with non-smokers carrying the rapid acetylator genotype. The association was reversed among smokers and non-smokers with NAT2 slow phenotype. On the basis of the foregoing, we conclude that the NAT2 phenotypes whether alone or in association with smoking do not correlate with susceptibility to prostate cancer within the Slovak population. PMID- 24816844 TI - Associations of atherosclerosis in the descending thoracic aorta on CTA with arterial stiffness and chronic kidney disease in asymptomatic patients with diabetes mellitus. AB - The relation between atherosclerosis in the descending thoracic aortic (DTA), arterial stiffness and chronic kidney disease (CKD) in patients with diabetes mellitus (DM) remains unclear. The current aim was to evaluate associations of DTA atherosclerosis with arterial stiffness and parameters of CKD in asymptomatic patients with DM. A total of 213 asymptomatic patients with diabetes (mean age 52 years, 56% men) underwent cardiovascular risk assessment including multi-slice computed tomography (for non-invasive coronary angiography, from which DTA atherosclerosis can be derived), non-invasive assessment of arterial stiffness with applanation tonometry and assessment of renal function. Measurements of DTA atherosclerosis included assessment of DTA thickening and calcium score. Arterial stiffness was determined by the carotid-femoral pulse wave velocity (PWV), parameters of CKD included estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). DTA atherosclerosis was present in 180 (84%) patients. Patients with DTA atherosclerosis had increased arterial stiffness, lower eGFR and higher UACR values. After multivariate correction, DTA calcium score was independently associated with PWV (beta = 0.18, p = 0.04). Furthermore, both DTA maximal wall thickness and DTA calcium score were independently associated with eGFR (beta = -7.37, p < 0.001 and beta = -1.99, p < 0.003, respectively), but not with UACR. The increase in arterial stiffness by atherosclerosis seemed to be mediated by arterial calcification, while the DTA calcium score was independently associated with arterial stiffness, but not DTA maximal wall thickness. Furthermore, parameters of CKD in patients with DM had a distinct relationship with DTA atherosclerosis: DTA atherosclerosis was associated with eGFR but not with UACR. PMID- 24816843 TI - Overexpression of HSBP1 is associated with resistance to radiotherapy in oral squamous epithelial carcinoma. AB - Heat shock factor binding protein 1 (HSBP1) has been recognized to regulate early embryonic development. However, HSBP1 expression and function in oral squamous carcinoma (OSCC) have not been studied. We found that HSBP1 expression was elevated in OSCC tissues compared to adjacent normal tissue. Although increased HSBP1 expression was not associated with clinical stage of the disease, it significantly related to outcome after radiotherapy (P < 0.01). Overexpression of HSBP1 enhanced sensitivity of OSCC cells in radiation. Moreover, HSBP1 elevated expression of stem cell markers such as CD44, CD133, ALDH and SOX2, and subsequently enhanced mammosphere formation ability, indicating it drives stem cell-like status in OSCC cells. Furthermore, in mice xenograft tumor model, HSBP1 increased sensitivity of OSCC to radiotherapy. Above all, HSBP1 is a potential marker for prognosis of OSCC after radiotherapy. PMID- 24816847 TI - Information seeking and avoidance throughout the cancer patient journey: two sides of the same coin? A synthesis of qualitative studies. AB - OBJECTIVE: Understanding what motivates patients to seek or avoid information beyond the medical consultation is essential for effective information provision that will be relevant to patients' needs and preferences. We conducted a synthesis of published qualitative research to provide insight into patients' motivations for cancer information seeking and avoidance. METHODS: We searched five electronic databases: Medline, CINAHL, PsycINFO, Communication and Mass Media Complete, and Sociological Abstracts. We complemented this process by reviewing reference lists of relevant articles and searching in Google Scholar. We independently assessed the quality of selected studies and used the technique of meta-ethnography to synthesize available findings. RESULTS: Eighteen articles that reported the information-seeking experiences of 650 patients diagnosed with more than 20 different types of cancer were included. Key concepts were experience of diagnosis, sense of control, trust in medical expertise, hope and fear, and need to resume normality. The synthesis revealed the fluid boundaries existing between information seeking and avoidance throughout the cancer journey and pointed toward the exploration of factors that could influence patients' motivations to engage in information seeking. Patient characteristics, disease characteristics, characteristics of incoming information, and the context of cancer care were found to facilitate or hinder individuals' willingness and potential to assume the role of 'informed patient'. CONCLUSIONS: This meta ethnography suggests that information seeking and avoidance should not be necessarily considered as two distinct behaviors pertaining to different groups of patients; rather, a number of personal and contextual characteristics should be taken into account when evaluating patient desire for information. PMID- 24816848 TI - 18 FDG-PET/CT computer-assisted biopsies for suspected persistent or recurrent malignant skull base disease. AB - Background: FDG-PET/CT is increasingly used for the evaluation of regional or distant metastasis in head and neck oncology. However, positive PET findings lack specificity, which is especially challenging for localized disease at the skull base. Methods: An optically tracked navigation system for multimodal image-guided biopsies was tested to evaluate PET-positive skull base lesions between 2009 and 2013. Results: FDG-PET/CT navigated biopsies of patients with suspected persistence or recurrence of carcinoma (sinonasal, n=3; nasopharyngeal, n=1; adenocarcinoma, n=2; and carcinoma of unknown primary origin, n=1) have been safely performed. Histology confirmed local persistent or recurrent malignant disease (n=5), radio-osteonecrosis (n=1) and super-infection (n=1). Conclusions: In the follow-up of tumor patients, FDG-PET/CT-navigated biopsies are a valid tool to evaluate PET-positive skull base lesions. This is an especially useful technique if functional anomalous areas in FDG-PET/CT do not cause structural alterations in MRI/CT, and if endoscopic visualization is impossible because of post-treatment alterations. Head Neck, 2014. PMID- 24816846 TI - c-FLIP-Short reduces type I interferon production and increases viremia with coxsackievirus B3. AB - Cellular FLIP (c-FLIP) is an enzymatically inactive paralogue of caspase-8 and as such can block death receptor-induced apoptosis. However, independent of death receptors, c-FLIP-Long (c-FLIPL) can heterodimerize with and activate caspase-8. This is critical for promoting the growth and survival of T lymphocytes as well as the regulation of the RIG-I helicase pathway for type I interferon production in response to viral infections. Truncated forms of FLIP also exist in mammalian cells (c-FLIPS) and certain viruses (v-FLIP), which lack the C-terminal domain that activates caspase-8. Thus, the ratio of c-FLIPL to these short forms of FLIP may greatly influence the outcome of an immune response. We examined this model in mice transgenically expressing c-FLIPS in T cells during infection with Coxsackievirus B3 (CVB3). In contrast to our earlier findings of reduced myocarditis and mortality with CVB3 infection of c-FLIPL-transgenic mice, c-FLIPS transgenic mice were highly sensitive to CVB3 infection as manifested by increased cardiac virus titers, myocarditis score, and mortality compared to wild type C57BL/6 mice. This observation was paralleled by a reduction in serum levels of IL-10 and IFN-alpha in CVB3-infected c-FLIPS mice. In vitro infection of c FLIPS T cells with CVB3 confirmed these results. Furthermore, molecular studies revealed that following infection of cells with CVB3, c-FLIPL associates with mitochondrial antiviral signaling protein (MAVS), increases caspase-8 activity and type I IFN production, and reduces viral replication, whereas c-FLIPS promotes the opposite phenotype. PMID- 24816849 TI - An invasive clonal plant benefits from clonal integration more than a co occurring native plant in nutrient-patchy and competitive environments. AB - Many notorious invasive plants are clonal, however, little is known about the different roles of clonal integration effects between invasive and native plants. Here, we hypothesize that clonal integration affect growth, photosynthetic performance, biomass allocation and thus competitive ability of invasive and native clonal plants, and invasive clonal plants benefit from clonal integration more than co-occurring native plants in heterogeneous habitats. To test these hypotheses, two stoloniferous clonal plants, Alternanthera philoxeroides (invasive), Jussiaea repens (native) were studied in China. The apical parts of both species were grown either with or without neighboring vegetation and the basal parts without competitors were in nutrient- rich or -poor habitats, with stolon connections were either severed or kept intact. Competition significantly reduced growth and photosynthetic performance of the apical ramets in both species, but not the biomass of neighboring vegetation. Without competition, clonal integration greatly improved the growth and photosynthetic performance of both species, especially when the basal parts were in nutrient-rich habitats. When grown with neighboring vegetation, growth of J. repens and photosynthetic performance of both species were significantly enhanced by clonal integration with the basal parts in both nutrient-rich and -poor habitats, while growth and relative neighbor effect (RNE) of A. philoxeroides were greatly improved by clonal integration only when the basal parts were in nutrient-rich habitats. Moreover, clonal integration increased A. philoxeroides's biomass allocation to roots without competition, but decreased it with competition, especially when the basal ramets were in nutrient-rich sections. Effects of clonal integration on biomass allocation of J. repens was similar to that of A. philoxeroides but with less significance. These results supported our hypothesis that invasive clonal plants A. philoxeroides benefits from clonal integration more than co-occurring native J. repens, suggesting that the invasiveness of A. philoxeroides may be closely related to clonal integration in heterogeneous environments. PMID- 24816850 TI - Yeast modulation of human dendritic cell cytokine secretion: an in vitro study. AB - Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. The concept of individual microorganisms influencing the makeup of T cell subsets via interactions with intestinal dendritic cells (DCs) appears to constitute the foundation for immunoregulatory effects of probiotics, and several studies have reported probiotic strains resulting in reduction of intestinal inflammation through modulation of DC function. Consequent to a focus on Saccharomyces boulardii as the fundamental probiotic yeast, very little is known about hundreds of non-Saccharomyces yeasts in terms of their interaction with the human gastrointestinal immune system. The aim of the present study was to evaluate 170 yeast strains representing 75 diverse species for modulation of inflammatory cytokine secretion by human DCs in vitro, as compared to cytokine responses induced by a S. boulardii reference strain with probiotic properties documented in clinical trials. Furthermore, we investigated whether cytokine inducing interactions between yeasts and human DCs are dependent upon yeast viability or rather a product of membrane interactions regardless of yeast metabolic function. We demonstrate high diversity in yeast induced cytokine profiles and employ multivariate data analysis to reveal distinct clustering of yeasts inducing similar cytokine profiles in DCs, highlighting clear species distinction within specific yeast genera. The observed differences in induced DC cytokine profiles add to the currently very limited knowledge of the cross-talk between yeasts and human immune cells and provide a foundation for selecting yeast strains for further characterization and development toward potentially novel yeast probiotics. Additionally, we present data to support a hypothesis that the interaction between yeasts and human DCs does not solely depend on yeast viability, a concept which may suggest a need for further classifications beyond the current definition of a probiotic. PMID- 24816851 TI - In vitro synergistic antioxidant activity and identification of antioxidant components from Astragalus membranaceus and Paeonia lactiflora. AB - Many traditionally used herbs demonstrate significantly better pharmacological effects when used in combination than when used alone. However, the mechanism underlying this synergism is still poorly understood. This study aimed to investigate the synergistic antioxidant activity of Astragalus membranaceus (AME) and Paeonia Lactiflora (PL), and identify the potential antioxidant components by 1,1-diphenyl-2-picrylhydrazine (DPPH) radical spiking test followed by a high performance liquid chromatography separation combined with diode array detection and tandem mass spectrometry analysis (DPPH-HPLC-DAD-MS/MS). Eight AME-PL combined extracts (E1-E8) were prepared based on bioactivity-guided fractionation. Among them, E1 exhibited the strongest synergistic effect in scavenging DPPH radicals and reducing ferric ions (P<0.05). Moreover, E1 presented strong cytoprotection against H2O2-induced oxidative damage in MRC-5 cells by suppressing the decrease of the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities. A strong correlation between the increment of total phenolic/flavonoid and synergistic antioxidant activity, especially between the increment of total flavonoid and the increase in ferric reducing power was observed. Finally, seven antioxidant substances were identified in E1 as oxypaeoniflora, catechin, calycosin-7-O-beta-D glucopyranoside, fomononetin-7-O-beta-D-glucopyranoside, 9,10-dimethoxy pterocarpan-3-O-beta-D-glucopyranoside, quercetin and 2'-dihydroxy-3',4'-dimethyl isoflavan-7-O-beta-D-glucopyranoside. PMID- 24816852 TI - Phosphorylated dendronized poly(amido amine)s as protein analogues for directing hydroxylapatite biomineralization. AB - Dendronized poly(amido amine)s (DPs) bearing tri-phosphate or bis-phosphonate peripheral groups are synthesized. These worm-like DPs can template the formation of BMSCs adhesive hydroxylapatite (HA) on the nano-scale, or self-assemble into mineral-collecting microfibers on the micro-scale, exhibiting similar functions of non-collagenous proteins (NCPs) in the natural biomineralization process of HA. PMID- 24816853 TI - PD-L1 gene polymorphisms and low serum level of PD-L1 protein are associated to type 1 diabetes in Chile. AB - INTRODUCTION: Type 1 diabetes (T1D) has a complex etiology in which genetic and environmental factors are involved, whose interactions have not yet been completely clarified. In this context, the role in PD-1 pathway and its ligands 1 and 2 (PD-L1 and PD-L2) have been proposed as candidates in several autoimmune diseases. The aim of this work was to determine the allele and haplotype frequency of six gene polymorphisms of PD-ligands (PD-L1 and PD-L2) in Chilean T1D patients and their effect on serum levels of PD-L1 and autoantibody profile (GAD65 and IA2). METHODS: This study cohort comprised 205 T1D patients and 205 normal children. We performed genotypic analysis of PD-L1 and PD-L2 genes by TaqMan method. Determination of anti-GAD65 and anti-IA-2 autoantibodies was performed by ELISA. The PD-L1 serum levels were measured. RESULTS: The allelic distribution of PD-L1 variants (rs2297137 and rs4143815) showed differences between T1D patients and controls (p = 0.035 and p = 0.022, respectively). No differences were detected among the PD-L2 polymorphisms, and only the rs16923189 showed genetic variation. T1D patients showed decreased serum levels of PD-L1 compared to controls: 1.42 [0.23-7.45] ng/mL versus 3.35 [0.49-5.89] ng/mL (p < 0.025). In addition, the CGG haplotype in PD-L1 associated with T1D (constructed from rs822342, rs2297137 and rs4143815 polymorphisms) showed an OR = 1.44 [1.08 to 1.93]. Finally, no association of these genetic variants was observed with serum concentrations of PD ligands or auto-antibody profile, although a correlation between PD-L1 ligand serum concentration and the age at disease onset was detected. CONCLUSION: Two polymorphism of PD-L1 are presented in different allelic variants between T1D and healthy subjects, also PDL-1 serum levels are significantly lowered in diabetics patients. Moreover, the age of onset of the disease determine differences between serum ligand levels in diabetics, being lower in younger. These results points to a possible establishment of PDL-1 as a genetic and biochemical marker for T1D onset, at least in Chilean population. PMID- 24816854 TI - A syndrome of leukonychia, koilonychia and multiple pilar cysts. PMID- 24816855 TI - Technical and clinical outcome of percutaneous CT fluoroscopy-guided screw placement in unstable injuries of the posterior pelvic ring. AB - PURPOSE: To evaluate technical success, complications, and effective dose in patients undergoing CT fluoroscopy-guided iliosacral screw placement for the fixation of unstable posterior pelvic ring injuries. MATERIALS AND METHODS: Our retrospective analysis includes all consecutive patients with vertical sacral fractures and/or injury of the iliosacral joint treated with CT fluoroscopy guided screw placement in our department from 11/2005 to 03/2013. Interventions were carried out under general anesthesia and CT fluoroscopy (10-20 mAs; 120 kV; 16- or 128-row scanner, Siemens Healthcare, Erlangen, Germany). Technical outcome, major and minor complications, and effective patient dose were analyzed. RESULTS: We treated 99 consecutive patients (mean age 53.1 +/- 21.7 years, 50 male, 49 female) with posterior pelvic ring instability with CT fluoroscopy guided screw placement. Intervention was technically successful in all patients (n = 99). No major and one minor local complication occurred (1 %, secondary screw dislocation). General complications included three cases of death (3 %) due to pulmonary embolism (n = 1), hemorrhagic shock (n = 1), or cardiac event (n = 1) during a follow-up period of 30 days. General complications were not related to the intervention. Mean effective patient radiation dose per intervention was 12.28 mSv +/- 7.25 mSv. Mean procedural time was 72.1 +/- 37.4 min. CONCLUSIONS: CT fluoroscopy-guided screw placement for the treatment of posterior pelvic ring instabilities can be performed with high technical success and a low complication rate. This method provides excellent intrainterventional visualization of iliac and sacral bones, as well as the sacral neuroforamina for precise screw placement by applying an acceptable effective patient dose. PMID- 24816857 TI - Sample presentation, sources of error and future perspectives on the application of vibrational spectroscopy in the wine industry. AB - Vibrational spectroscopy encompasses a number of techniques and methods including ultra-violet, visible, Fourier transform infrared or mid infrared, near infrared and Raman spectroscopy. The use and application of spectroscopy generates spectra containing hundreds of variables (absorbances at each wavenumbers or wavelengths), resulting in the production of large data sets representing the chemical and biochemical wine fingerprint. Multivariate data analysis techniques are then required to handle the large amount of data generated in order to interpret the spectra in a meaningful way in order to develop a specific application. This paper focuses on the developments of sample presentation and main sources of error when vibrational spectroscopy methods are applied in wine analysis. Recent and novel applications will be discussed as examples of these developments. PMID- 24816856 TI - Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat. AB - OBJECTIVE: Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). MATERIALS AND METHODS: Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18-55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. RESULTS: Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9% (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of -1.6 (1.1) to -0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56%) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42%) patients had focal bone lesions, which remained stable, and 7/19 (37%) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. CONCLUSIONS: Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1. PMID- 24816858 TI - Analysis of predictors influencing indeterminate whole-blood interferon-gamma release assay results in patients with rheumatic diseases. AB - Triggers of indeterminate results from interferon-gamma release assays (IGRA) in patients with rheumatic diseases are still elusive. The aim of the present study was to describe predictors of indeterminate results from IGRA in the field of rheumatology. This cross-sectional study was retrospectively performed by using a database of patients with a request for QuantiFERON-TB Gold-In Tube test (QFT GIT) for screening of latent tuberculosis infection. The study cohort included 631 patients with rheumatic diseases. All variables influencing indeterminate QFT GIT results were investigated by logistic regression analysis. The overall frequency of indeterminate IGRA results was 6.8 % (43/631). Those with indeterminate results were more likely to be aged >=70 years, female, visitors in winter, suffering from systemic lupus erythematosus (SLE), and using sulfasalazine or a tumor necrosis factor (TNF)-alpha inhibitor. In addition, a longer incubation time of >6 h increased the odds ratio of indeterminate IGRA results. In contrast, the automated ELISA processor, ankylosing spondylitis, and the use of a non-steroidal anti-inflammatory drug decreased the likelihood of indeterminate IGRA results. Lymphopenia, thrombocytopenia, anemia, and hypoalbuminemia were significantly associated with indeterminate IGRA results. Multivariate analysis revealed that SLE, use of sulfasalazine or a TNF-alpha inhibitor, and a manual ELISA system were significantly independent predictors of indeterminate IGRA results. The proportion of indeterminate results in patients with rheumatic diseases is not infrequent. Careful attention to the pre analytical conditions should minimize the indeterminate results. Automation of the ELISA process seems to be a promising solution to decrease the rate of indeterminate response. PMID- 24816859 TI - Primary hypertrophic osteoarthropathy caused by homozygous deletion in HPGD gene in a family: changing clinical and radiological findings with long-term follow up. AB - Autosomal recessive primary hypertrophic osteoarthropathy1 (PHOAR1) is characterized by delayed closure of the fontanels, digital clubbing, arthropathy and periostosis. Homozygous mutations in hydroxyprostaglandin dehydrogenase (HPGD) gene are the underlying pathology of PHOAR1. The aim of this study was to analyze the HPGD gene and the changing clinical and radiological findings with advancing age of two siblings with the diagnosis of PHOAR1. A novel 2-bp homozygous deletion was found in exon 3 (c.310-311delCT) of HPGD gene in the patients. Clinical and radiological findings of the siblings were evaluated between 4 months and 8 years and 6 months of age. The painful swelling and sweating of the hands and feet, cranial ossification defect and expanded diaphyses were evident at infantile period and gradually showed improvement until 4 years of age. After the age of 4 years, digital clubbing and swelling of knees persisted, palmoplantar hyperkeratosis developed and acro-osteolysis became evident on hand radiographs. In conclusion, we suggest that the clinical findings of the patients with PHOAR1 should be classified in two periods as early and late childhood. We also observed that there was intrafamilial variability of clinical findings. PMID- 24816861 TI - Association of mTOR polymorphisms with cancer risk and clinical outcomes: a meta analysis. AB - Genetic polymorphisms in mTOR gene may be associated with cancer risk and clinical outcomes of cancer patients by affecting mTOR gene expression or its activation. However, inconsistent results have been reported. The aim of this study is to systematically evaluate the association between mTOR polymorphisms (rs2295080, rs2536 and rs11121704) and cancer risk as well as clinical outcome by a meta-analysis. We identified 10 eligible studies and extracted data by two investigators. Based on dominant and recessive models, odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by using Stata, version 11 to evaluate the association strength. Our meta-analysis results showed that the wild genotype TT of rs2295080 polymorphism was associated with increased cancer risk under dominant model (OR = 1.24, 95%CI: 1.12-1.36, p<0.0005) in Chinese but not with clinical outcome parameters, while the TT genotype of rs11121704 was associated with poor clinical outcome parameters (OR = 1.53, 95%CI: 1.01-2.32, p = 0.044), such as death, metastasis and resistance to chemotherapy. However, rs2536 may not influence cancer susceptibility. In conclusion, this meta-analysis indicated the common polymorphisms in mTOR gene might be genetic risk factors for the carcinogenesis and clinical outcomes of cancer patients. However, further investigation on large population and different ethnicities are warranted. PMID- 24816860 TI - Biotic and abiotic properties mediating plant diversity effects on soil microbial communities in an experimental grassland. AB - Plant diversity drives changes in the soil microbial community which may result in alterations in ecosystem functions. However, the governing factors between the composition of soil microbial communities and plant diversity are not well understood. We investigated the impact of plant diversity (plant species richness and functional group richness) and plant functional group identity on soil microbial biomass and soil microbial community structure in experimental grassland ecosystems. Total microbial biomass and community structure were determined by phospholipid fatty acid (PLFA) analysis. The diversity gradient covered 1, 2, 4, 8, 16 and 60 plant species and 1, 2, 3 and 4 plant functional groups (grasses, legumes, small herbs and tall herbs). In May 2007, soil samples were taken from experimental plots and from nearby fields and meadows. Beside soil texture, plant species richness was the main driver of soil microbial biomass. Structural equation modeling revealed that the positive plant diversity effect was mainly mediated by higher leaf area index resulting in higher soil moisture in the top soil layer. The fungal-to-bacterial biomass ratio was positively affected by plant functional group richness and negatively by the presence of legumes. Bacteria were more closely related to abiotic differences caused by plant diversity, while fungi were more affected by plant-derived organic matter inputs. We found diverse plant communities promoted faster transition of soil microbial communities typical for arable land towards grassland communities. Although some mechanisms underlying the plant diversity effect on soil microorganisms could be identified, future studies have to determine plant traits shaping soil microbial community structure. We suspect differences in root traits among different plant communities, such as root turnover rates and chemical composition of root exudates, to structure soil microbial communities. PMID- 24816863 TI - Portal vein embolization using absolute ethanol: evaluation of its safety and efficacy. AB - BACKGROUND: Previously, we reported on the clinical efficacy and safety of portal vein embolization (PVE) with fibrin glue. Our embolic materials for PVE changed from fibrin glue to absolute ethanol (EOH) after 2001 due to prohibition of using fibrin glue for PVE. With introducing our technique of PVE with EOH, we evaluated its safety and efficacy with attention to the amount of EOH. METHODS: The medical records of 154 patients who underwent PVE using EOH were retrospectively reviewed. RESULTS: Changes with time in both the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) after PVE returned to the initial condition within 7 days after PVE. In the 96 patients who underwent CT volumerty 14 to 21 days after PVE, the volume of the embolized lobe decreased from 701 +/- 165 cm(3) to 549 +/- 148 cm(3) (P < 0.0001). Meanwhile, the volume of the non-embolized lobe increased from 388 +/- 105 cm(3) to 481 +/- 113 cm(3) (P < 0.0001). On simple linear regression, the amount of EOH was positively correlated with both the maximum of AST and that of ALT after PVE; however, it never correlated with changes in liver volume after PVE. CONCLUSIONS: Portal vein embolization with EOH has a substantial effect on both hypertrophy of the non embolized lobe and atrophy of the embolized lobe. Quick recoveries of changes with time in AST and ALT after PVE proved that PVE with EOH is a safe procedure. The amount of EOH affected the extent of liver damage but had no clinical effects on changes in liver volume after PVE. PMID- 24816862 TI - A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis. AB - BACKGROUND: Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and has emerged as an important candidate susceptibility factor for a number of immune-related diseases. This study aimed to examine the predisposition of PTPN22 SNPs to Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS). METHODS: A total of 1005 VKH syndrome, 302 AAU+AS+ patients and 2010 normal controls among the Chinese Han population were enrolled in the study. Genotyping, PTPN22 expression, cell proliferation, cytokine production and cell activation were examined by PCR-RFLP, Real-time PCR, CCK8, ELISA and Flow cytometry. RESULTS: The results showed significantly increased frequencies of the rs2488457 CC genotype and C allele but a decreased frequency of the GG genotype in VKH syndrome patients (PBonferroni correction (Pc) = 3.47*10(-7), OR = 1.54; Pc = 3.83*10(-8), OR = 1.40; Pc = 6.35*10(-4), OR = 0.62; respectively). No significant association of the tested SNPs with AAU+AS+ patients was observed. Functional studies showed a decreased PTPN22 expression, impaired cell proliferation and lower production of IL-10 in rs2488457 CC cases compared to GG cases (Pc = 0.009, Pc = 0.015 and Pc = 0.048 respectively). No significant association was observed concerning T cell activation and rs2488457 genotype. CONCLUSIONS: The study showed that a functional variant of PTPN22 confers risk for VKH syndrome but not for AAU+AS+ in a Chinese Han population, which may be due to a modulation of the PTPN22 expression, PBMC proliferation and IL-10 production. PMID- 24816864 TI - There's life in the old dog yet: clopidogrel competing with prasugrel and ticagrelor for treatment of ACS patients. PMID- 24816865 TI - Prognostic importance of baseline and serial glycated hemoglobin levels in high risk patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study. AB - The prognostic importance of baseline and serial glycated hemoglobin (HbA1c) changes for cardiovascular outcomes is still debated. We aimed to evaluate it in 620 high-risk individuals with type 2 diabetes (mean age 60.4 years, 37 % males, 55 % Caucasians). Patients had HbA1c levels measured at study entry and serially during follow-up. Primary end points were total cardiovascular events (CVEs), major CVEs (non-fatal myocardial infarctions and strokes plus cardiovascular deaths) and all-cause mortality. Cardiovascular and non-cardiovascular mortalities were secondary end points. HbA1c was evaluated either as a continuous variable and categorized at clinically relevant cutoffs. Multivariate Cox regressions assessed the associations with end points. After a median follow-up of 6.6 years, 125 total CVEs occurred (90 major CVEs), and 111 patients died (64 from cardiovascular diseases). After statistical adjustments for other cardiovascular risk factors, baseline and mean first-year HbA1c predicted all end points, except non-cardiovascular deaths; and hazard ratios tended to be higher for mean first year than for baseline HbA1c. Each 1 % (10.9 mmol/mol) increase in mean first-year HbA1c increased 27 % the risk of major CVEs occurrence (95 % CI 11-45 %). Updating HbA1c for values obtained beyond the second year of follow-up did not improve its predictive performance. The cardiovascular protection was observed until HbA1c values lower than 6.5 % (48 mmol/mol). Moreover, the magnitude of HbA1c reduction during the first year of follow-up was predictive of better cardiovascular outcomes, independent of baseline HbA1c levels. In conclusion, better glycemic control, especially during the first year of follow up, is determinant of better cardiovascular outcomes in high-risk patients with type 2 diabetes, without any detectable lower threshold level of HbA1c. PMID- 24816866 TI - Mechanisms in the solution growth of free-standing two-dimensional inorganic nanomaterials. AB - Free-standing two-dimensional (2D) nanomaterials have attracted extensive and growing research interest owing to their exotic physical and mechanical properties, which have enabled their applications in electronics, optoelectronics, electrochemical and biomedical devices. Current synthesis strategies rely largely on top-down approaches such as etching and exfoliation. Among bottom-up approaches in literature, there lacks a systematic understanding of the mechanisms of 2D crystal growth, unlike one-dimensional nanomaterials whose growth mechanisms have been well documented. To date, the growth design of free-standing 2D nanomaterials has remained a case-by-case practice. This review focuses on the bottom-up solution synthesis of free-standing 2D nanomaterials and summarizes the general mechanisms and empirical methodologies that can lead to 2D crystal growth. A brief outlook on the development of synthesis and application of solution-grown 2D nanomaterials is also presented. PMID- 24816867 TI - Assessment of heavy metal contents in surface soil in the Lhasa-Shigatse-Nam Co area of the Tibetan Plateau, China. AB - Eight important heavy metals (As, Cr, Cu, Ni, Pb, Zn, Mn, and Hg) were investigated in surface soil samples collected from the Lhasa-Shigatse-Nam Co region, Tibetan Plateau, China. The mean contents of As, Cr, Cu, Ni, Pb, Zn, Mn, and Hg in the samples were 39.5, 57.4, 28.5, 48.2, 15.7, 79.2, 637 and 0.0175 mg/kg, respectively. All metals were divided into three clusters by cluster analysis. The results of geoaccumulation index indicated that no samples were polluted by Cr, Pb, Zn, and Mn, and samples were polluted with As, Cu, Ni, and Hg to different degrees. All surface soils had a low ecological risk with potential ecological risk index below 150, indicating a low ecological risk. As, Pb, and Hg were the primary contributors to potential ecological risk. PMID- 24816868 TI - On the complementarity of ECD and VCD techniques. AB - An unprecedented complementarity of electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopic techniques is demonstrated by showing that each technique reveals the structure of a different molecular segment. Using a flexible molecule of biological significance we show that the synergetic use of ECD and VCD yields more complete structural characterization as it provides improved and more reliable conformer resolution. PMID- 24816869 TI - Classification of behaviorally defined disorders: biology versus the DSM. AB - Three levels of investigation underlie all biologically based attempts at classification of behaviorally defined developmental and psychiatric disorders: Level A, pseudo-categorical classification of mostly dimensional descriptions of behaviors and their disorders included in the 2013 American Psychiatric Association's Fifth Edition of the Diagnostic and Statistical Manual (DSM-5); Level C, mostly categorical classification of genetic and environmental causes (etiologies) of Level A disorders; and Level B, the pathophysiologic--both categorical and dimensional--biologic mechanisms underlying Level A "diagnoses" which comprise hierarchically interacting molecular, cellular, and neural networks and major brain pathways orchestrated by Level C etiologies. Besides modest numbers of effective psychotropic medications and their derivatives, major advances in treatment have addressed the behavioral symptoms of Level A-defined developmental and psychiatric disorders. The National Institute of Mental Health proposes support for a new biologically based Research Domain Criteria (RDoC) classification; its goal is to apply to behaviorally defined Level A developmental and psychiatric disorders the biologically based Level C and Level B research strategies that have greatly accelerated treatment and prevention of medical disorders. It plans to supplement effective educational and behavioral symptom-based interventions with faster, more potent and specific biologic therapies and, hopefully, to discover how effective behavioral interventions alter brain function. This commentary raises the question of whether a hybrid nosology that maps biology onto behavior is attainable. At a minimum, such a nosologic effort requires greater in-depth and better informed dialog between investigators of behavior and biology than occurs typically, and more realistic communication of the implications of research results to the public. PMID- 24816870 TI - Promoting peer acceptance of females with higher-functioning autism in a mainstream education setting: a replication and extension of the effects of an autism anti-stigma program. AB - This study evaluated the effects of an eight-session female higher-functioning autism anti-stigma program on the knowledge, attitudes and behavioural intentions of adolescent girls. Participants were seventh-, eighth- and ninth-grade students (N = 273) in a mainstream school. Two-eighth-grade classes were randomly allocated to the intervention condition. The remaining students were either allocated to the no-intervention peer or no-intervention non-peer condition. The anti-stigma program positively influenced knowledge, attitudes and to a lesser extent behavioural intentions towards peers with higher-functioning autism within the intervention condition. Some degree of attitudinal improvement occurred across all conditions following the program suggesting some spill over effects. Overall, findings provide preliminary evidence supporting the efficacy of an anti stigma program tailored to support females with higher-functioning autism. PMID- 24816871 TI - Nurses: leading the way. PMID- 24816872 TI - Improving family-centered care practices in the NICU. AB - Family presence and participation in care in the NICU is fundamental to the recovery and well-being of the sick neonate and family. However, some NICU visitation policies are not supportive of families. A new visitor-management program was initiated at a local hospital. The program included open visitation for parents and others chosen by parents to be a support during their hospital stay. This quality-improvement project evaluated if there was any improvement in parents' perceptions and experiences of family-centered care after the implementation of the new visitor-management program. The NICU parent survey data revealed a modest positive difference in parent responses after the implementation of the program. PMID- 24816873 TI - The effect of in-line infusion filtering on in-line pressure monitoring in an experimental infusion system for newborns. AB - AIM: To study the effect of in-line filtering on in-line pressure measurement in a simulated infusion system. METHODS: The experimental setup consisted of a syringe pump, syringe, intravenous (IV) line, and extension line. For aqueous fluids, a 0.2-MUm infusion filter was used, and for lipid emulsions, a 1.2-MUm filter. Infusion speed varied from 0.5 to 10.0 mL/h. First, the effect of clamping the extension line was studied on reaching alarm threshold. Second, the effect of aqueous and lipid fluids was evaluated on in-line pressure measurements. RESULTS: In-line placement of an infusion filter did not prolong the time to alarm threshold after occlusion. During 24 hours of monitoring, lipid emulsions and all-in-one admixture only caused a moderate increase in in-line pressure. CONCLUSION: Placement of an infusion filter does not have a significant effect on the in-line pressure monitoring and has no adverse effect on detecting pressure-related complications of IV administration. PMID- 24816874 TI - Comparison of two transcutaneous bilirubinometers in term and near-term neonates. AB - PURPOSE: Determination of bilirubin levels is performed for many newborns in the first days of life, and several different transcutaneous bilirubinometers are available. We aimed to determine whether transcutaneous bilirubin measurement, as performed using Jaundice Detector JH20-1C, a new device, correlates with Minolta/Hill-Rom Air-Shields Transcutaneous Jaundice Meter model JM-103. DESIGN AND SAMPLE: The study was performed on term or near-term newborn infants who underwent transcutaneous bilirubin measurements as part of their normal care. The study group consisted of 585 newborn infants with gestational ages ranging from 35 to 42 weeks, coming from an uneventful pregnancy. In this prospective study, bilirubin concentrations were determined with two different transcutaneous bilirubinometers. MAIN OUTCOME VARIABLE: In 585 infants, the correlation coefficient for Jaundice Detector JH20-1C versus Minolta Air-Shields Jaundice Meter model JM-103 was .965 (p < .0001). The mean (+/- standard deviation) difference between the Jaundice Detector JH20-1C versus Minolta Air-Shields Jaundice Meter model JM-103 was 0.26 +/- 0.95 mg/dL. Results showed the Jaundice Detector JH20-1C to have an acceptable level of intradevice imprecision (r = .978, p < .0001, mean differences .0158 +/- .871 mg/dL). RESULTS: Jaundice Detector JH20-1C showed the good performances of intradevice and interdevice imprecision in comparison with Minolta/Hill-Rom Air-Shields Transcutaneous Jaundice Meter model JM-103. Jaundice Detector JH20-1C may be suitable for screening term or near-term newborn infants for jaundice in the well-baby nursery or maternity ward. PMID- 24816875 TI - Preventing admission hypothermia in very low birth weight neonates. AB - Neonatal hypothermia, temperature < 36.5 degrees C, is a major contributor to neonatal mortality and morbidity. hypothermia of preterm infants remains a challenge in the NiCU for many reasons. preterm very low birth weight (VlBW) infants, those infants born <1,500 g, are prone to very rapid heat losses through mechanisms of convection, evaporation, conduction, and radiation. this article reviews current research to reduce and prevent mortality and morbidity from hypothermia in preterm VlBW infants by implementing interventions in the delivery room to minimize heat loss and maintain core body temperatures. PMID- 24816876 TI - Who is Billy Reuben? Health literacy and patient education. AB - The issue of health literacy is focused on whether health consumers understand and are able to apply the information provided to them. In the neonatal setting, limited parent and caregiver health literacy can result in increased stress and poor compliance with instructions. Health literacy and patient education go hand in hand. This article includes an overview of health literacy and how it applies to the neonatal setting. Information is provided to assist with assessing for health literacy. Hints and resources are also provided for improving patient and family education. PMID- 24816877 TI - Review of micronutrients in parenteral nutrition for the NICU population. AB - A recent review of macronutrients in parenteral nutrition (PN) in the NICU population summarized the carbohydrate, protein, and fat nutrients in PN.1 The purpose of this article is to review the other nutrients in PN that are important for growth and homeostasis including minerals or electrolytes, vitamins, and trace elements. Although the macronutrients contribute more dramatically to adequate nutrition and growth, the other components in PN have significant impact on use of macronutrients as well as targeted organ and cellular function. PMID- 24816878 TI - Understanding triglyceride levels related to intravenous fat administration. AB - Lipid is an essential macronutrient in parenteral nutrition (PN) support. intravenous (IV) lipid provides essential fatty acids and a concentrated calorie source. Preterm infants are at risk for essential fatty deficiency early in life. Lipid administration is associated with some risks, and there are guidelines for administration to minimize complications. Lipid emulsions in the United States are derived from soybean oil. Outside of the United States, lipid emulsions made from fish oil or combinations of fish, soybean, olive, and medium-chain triglycerides (MCTs) are under investigation for improved tolerance, lower plasma lipid levels, and improved fatty acid profiles, all of which are considered beneficial. Triglyceride levels are an important measurement to assess patient tolerance. PMID- 24816879 TI - Why NICU nurses mean so much to parents. AB - Parents of premature infants are grateful for their child's NICU nurse. Take a step onto the parent's side and see the top ten reasons parents are grateful for the nurses, and you might see some surprises. PMID- 24816883 TI - The association between exercise enjoyment and physical activity in women with fibromyalgia. AB - Evidence suggests the role of physical activity (PA) in management of clinical symptoms of fibromyalgia. However, very little is known regarding the psychological correlates of PA in patients with fibromyalgia. Therefore, this study examined the association between exercise enjoyment (EE) and PA in women with fibromyalgia. 19 women with fibromyalgia completed a laboratory session, where EE was assessed using a self-report questionnaire immediately after 20 min of light-intensity biking. Muscle pain ratings (MPR) in the legs were assessed during exercise, and changes in clinical pain intensity after exercise were computed. PA was assessed subjectively using a self-report questionnaire and objectively using an accelerometer for one week. Results from correlation analyses indicated that EE was associated with the self-reported amount of PA (rs=0.61, R(2)=0.37, p<0.01) and the minutes spent for moderate intensity PA (rs=0.48, R(2)=0.23, p<0.05). However, neither MPR nor changes in clinical pain intensity were associated with PA. These results suggest that EE may serve as a determinant of PA in women with fibromyalgia. Future research is needed to develop interventions to maximize EE to promote PA in this clinical population. PMID- 24816884 TI - Effects of high-intensity interval vs. continuous moderate exercise on intraocular pressure. AB - Our purpose was to compare the acute effects of high-intensity interval training (HIT) vs. continuous moderate exercise (CME) on intraocular pressure (IOP) in healthy subjects. Fifteen young men (age=22.1+/-6 years) underwent 30 min of HIT (2 min of walking at 50% of reserve heart rate (HR) alternated with 1 min of running at 80% of reserve HR) and CME sessions (30 min of jogging/running at 60% of reserve HR) in random order (2-5 days between sessions). IOP was measured before (baseline), immediately after (post--exercise), 5 min after (Rec5) and 10 min after (Rec10) each exercise session. IOP was reduced post-exercise and remained reduced at Rec5 during both HIT and CME session, with no significant difference between interventions (~16% between 23%). However, IOP remained reduced at Rec10 only after HIT intervention (~19%), whereas IOP at Rec10 returned to levels similar to the observed at baseline during CME intervention. In summary, both HIT and CME equally reduced IOP immediately and 5 min after exercise session. However, only HIT was able to remain IOP reduced 10 min after exercise. These results suggest that HIT may be more effective than CME for reducing IOP in young healthy men. PMID- 24816885 TI - The acute response of apoptosis and migration to resistance exercise is protocol dependent. AB - The aim of the present study was to compare the acute effects of resistance exercise (RE) designed for hypertrophy or local muscle endurance (LME) on CD4+ and CD8+ T cell apoptosis and migration. 14 untrained subjects (age 20.5+/-0.8 years, body mass 70.0+/-12.8 kg, body mass index 24.0+/-3.2 kg/m(2)), women (N=11) and men (N=3) completed 2 RE sessions (3 sets of 9 exercises) designed for hypertrophy at 10 repetitions maximum (RM) and LME at 60% of 10RM with 1-min rest intervals between sets and exercises. The investigated lymphocytes were: CD4+, CD4+/CD69RA+, CD8+ and CD8+/CD69RA+ with cell surface markers annexin V and CX3CR1 analyzed by flow cytometry. Percentage of CD4+ positive for annexin V+ were higher immediately following and 24 h after the hypertrophy protocol as compared with LME, while CD4+ positive for CX3CR1 were higher immediately after and lower at the 24 h time point after LME as compared with the hypertrophy session. CD8+ lymphocytes responded similarly to the hypertrophy and LME protocols with elevations in both cellular migration and cell death immediately following and 24 h after the bouts (p<=0.05). Considering that the acute response of CD4+ lymphocytes to RE is protocol-dependent, a gradual adaptation to a hypertrophy program could minimize the effect on CD4+ lymphocytes and reduce the potential susceptibility to antigens during this timeframe. This would also be interesting for a RE program designed for LME based on the observed CD8+ lymphocyte response. PMID- 24816886 TI - Does heat acclimation improve exercise capacity at altitude? A cross-tolerance model. AB - New approaches to inducing altitude acclimation in a relatively short timeframe are needed, as it is not practical for many soldiers and athletes to gain access to specialized training facilities. Acclimation to one environmental stressor could enhance adaptation to various other stressors in animals and humans. This phenomenon has been described as cross-tolerance and involves the activation of common protective pathways. The purpose of this review is to discuss possible mechanisms involved in the cross-tolerance between heat and hypoxia. Future data could potentially support the use of a cross-tolerance model as a means for military personnel to prepare for deployment to high-altitude environments, as well as for athletes competing at high altitude. PMID- 24816887 TI - Accuracy of energy expenditure estimation by activity monitors differs with ethnicity. AB - The aim of this project is to explore the accuracy of 2 activity monitors (SenseWear Armband & Actical) to estimate energy expenditure during rest and light to moderate intensity exercises in 2 ethnic groups. 18 Caucasian and 20 Black adults (age: 26.8+/-5.2 years; body mass index: 23.9+/-3.0 kg/m(2)) wore the 2 devices simultaneously during 3 standardised activities: 30-min rest, 45 min of treadmill at 40% of their VO2peak and 45-min of stationary cycling at 50% of their VO2peak. Energy estimated with the 2 devices was compared to indirect calorimetry measurements. Both devices overestimated energy expenditure during rest (SenseWear: 36% in Black vs. 16% in Caucasian; Actical: 26% vs. 11%, p<0.01 between groups) and treadmill (SenseWear: 50% vs. 25%; Actical: 67% vs. 32%, p<0.01 between groups). Both devices significantly underestimated energy expenditure during stationary cycling (SenseWear: 24% vs. 26%; Actical: 58% vs. 70%, p=NS between groups). Equations used to estimate energy expenditure from accelerometer data is less precise among Black adults than Caucasian adults. Ethnic-specific formulas are probably required. PMID- 24816888 TI - Seasonal changes in multiple indices of body composition in professional football players. AB - We examined the seasonal variability of indicators of adiposity and generic and population-specific equations of estimating body fat in professional football players. Anthropometric data of 35 outfield players (age, 20+/-4 years; stature, 1.82+/-0.06 m; body mass 77.1+/-7.3 kg) were collected over a playing season. There were a significant main effects for time for all indicators (p<0.001). Post hoc analysis revealed significant changes in body composition between July and mid-August (?4SF-DW: 1.6 mm, p<0.001; ?4SF-R: 2.4 mm, p=0.002; ?5SF: 2.0 mm, p<0.002; ?8SF: 3.8 mm, p=0.001; Reilly et al.: 0.4%, p=0.001; Durnin and Wormsley: 0.7%, p<0.001). Although all indicators were sensitive to detect small changes in body composition between training mesocycles, we advocate the use of the sum of 4 skinfolds by Reilly et al. to monitor changes in body composition in professional football players; if an estimate of percent body fat is required, the population-specific equation by Reilly et al. may be utilised. PMID- 24816889 TI - Autonomic modulation in resistance-trained individuals after acute resistance exercise. AB - The effects of different types of acute bouts of resistance exercise on autonomic modulation in individuals that are resistance-trained compared to untrained individuals are unknown. Seventeen untrained and 17 resistance-trained participants were assessed for autonomic modulation after various acute resistance exercise bouts. Electrocardiogram readings were collected at rest and 25 min after a control period, whole-, lower-, or upper-body acute bouts of resistance exercise. Heart rate variability and heart rate complexity were used to assess autonomic modulation. Participants were similar for age, height, weight and measures of body composition (p>0.05) and were different for measures of maximal strength (p<0.05). There were no differences (p>0.05) in autonomic modulation at rest between groups. Significant decreases (p<0.05) in parasympathetic modulation after the acute bouts of resistance exercise were noted. Sample entropy was not affected in the untrained group, but was significantly decreased after whole- (-17.5%) and upper-body exercise (-13.5%) in the resistance training group. The changes in sample entropy after lower-body resistance exercise were not significant (-15.7%; p=0.06). These data suggest that resistance exercise training further attenuates the parasympathetic responses to an acute bout of resistance training regardless of the modality compared to the untrained state. PMID- 24816890 TI - Effect of defensive pressure on movement behaviour during an under-18 basketball game. AB - The aim of this study was to examine the effect of defensive pressure on movement behaviour during an under-18 basketball game. 20 international male players (age: M=16.05, SD=2.09 years old; weekly practice: M=10.9, SD=1.94 h; playing experience: M=7.1, SD=1.1 years) played two 10-min basketball quarters, using man to-man 1/4-court for the first 4 min (F1/4), man-to-man full court defence for the next 3 min (FULL), and man-to-man 1/4-court defence for the last 3 min (S1/4). The positional data were captured by the Ubisense Real Time Location System and analysed with non-linear signal processing methods (approximate entropy) and repeated measures ANOVA. There were differences in the regularity values between F1/4 and FULL in distance to the basket and to the opponents' basket. A stronger in-phase attraction in both lateral and longitudinal directions was identified; however, the centroids (i. e., the mean position from all team players) were closer and revealed higher values of irregularity in lateral displacements for all defensive systems. The individual speed displacements became more coordinated with teammates, particularly in the offensive court. Overall, this study provided evidence on how changing the level of defensive pressure promotes different collective behaviours. PMID- 24816891 TI - LONGITUDINAL INTENSITY NORMALIZATION IN THE PRESENCE OF MULTIPLE SCLEROSIS LESIONS. AB - This paper proposes a longitudinal intensity normalization algorithm for T1 weighted magnetic resonance images of human brains in the presence of multiple sclerosis lesions, aiming towards stable and consistent longitudinal segmentations. Unlike previous longitudinal segmentation methods, we propose a 4D intensity normalization that can be used as a preprocessing step to any segmentation method. The variability in intensities arising from the relapsing and remitting nature of the multiple sclerosis lesions is modeled into an otherwise smooth intensity transform based on first order autoregressive models, resulting in smooth changes in segmentation statistics of normal tissues, while keeping the lesion information unaffected. We validated our method on both simulated and real longitudinal normal subjects and on multiple sclerosis subjects. PMID- 24816892 TI - OTX2 duplication is implicated in hemifacial microsomia. AB - Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma. PMID- 24816893 TI - Co-expression network analysis identifies transcriptional modules in the mouse liver. AB - The mouse liver transcriptome has been extensively studied but little is known about the global hepatic gene network of the mouse under normal physiological conditions. Understanding this will help reveal the transcriptional organization of the liver and elucidate its functional complexity. Here, weighted gene co expression network analysis (WGCNA) was carried out to explore gene co-expression networks using large-scale microarray data from normal mouse livers. A total of 7,203 genes were parsed into 16 gene modules associated with protein catabolism, RNA processing, muscle contraction, transcriptional regulation, oxidation reduction, sterol biosynthesis, translation, fatty acid metabolism, immune response and others. The modules were organized into higher order co-expression groups. Hub genes in each module were found to be critical for module function. In sum, the analyses revealed the gene modular map of the mouse liver under normal physiological condition. These results provide a systems-level framework to help understand the complexity of the mouse liver at the molecular level, and should be beneficial in annotating uncharacterized genes. PMID- 24816894 TI - Optimizing online social networks for information propagation. AB - Online users nowadays are facing serious information overload problem. In recent years, recommender systems have been widely studied to help people find relevant information. Adaptive social recommendation is one of these systems in which the connections in the online social networks are optimized for the information propagation so that users can receive interesting news or stories from their leaders. Validation of such adaptive social recommendation methods in the literature assumes uniform distribution of users' activity frequency. In this paper, our empirical analysis shows that the distribution of online users' activity is actually heterogenous. Accordingly, we propose a more realistic multi agent model in which users' activity frequency are drawn from a power-law distribution. We find that previous social recommendation methods lead to serious delay of information propagation since many users are connected to inactive leaders. To solve this problem, we design a new similarity measure which takes into account users' activity frequencies. With this similarity measure, the average delay is significantly shortened and the recommendation accuracy is largely improved. PMID- 24816896 TI - (1)H, (15)N and (13)C resonance assignments for 3rC and 3rCWP: amyloidogenic variants of imunoglobulin lambda 3 light-chain. AB - Primary amyloidosis (AL) is the most common amyloid systemic disease and it is characterized by the deposition of immunoglobulin light-chain amyloid fibers in different organs, causing organ failure. The germ-line lambda 3 immunoglobulin light-chain proteins have been correlated with the AL condition. Two mutants have been derived from this germ-line, the single mutant C34Y (3rC) and the triple mutant C34Y, W35A and P7D (3rCWP), presenting a remarkable difference in amyloid fibril formation propensities in vitro. Here we report the (1)H, (13)C and (15)N resonance assignments of these proteins, as the first step to use solution nuclear magnetic resonance spectroscopy to get a better understanding of the amyloid fibril formation differences between these two mutants. PMID- 24816895 TI - Effect of a selective cyclooxygenase type 2 inhibitor celecoxib on depression associated with obesity in mice: an approach using behavioral tests. AB - The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain ambiguous. In the present study the potential of a selective cyclooxygenase inhibitor celecoxib (15 mg/kg p.o.) was investigated in depression associated with obesity in mice. Behavioral tests used to assess depressive-like behavior were sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM). The basal locomotor score in obese mice was not altered. Furthermore, estimation of biochemical parameters was performed for plasma glucose, total cholesterol, triglycerides and total proteins. Escitalopram (10 mg/kg p.o.) served as reference standard drug. In the results, chronic treatment with celecoxib for 28 days significantly attenuated the behavioral alterations as indicated by increased the sucrose consumption, reduced the immobility time in FST and TST, increased the percent open arm time and entries in EPM in obese mice. In the biochemical parameters celecoxib significantly reversed the increased plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. In conclusion, celecoxib exhibited potential antidepressant-like effect in depression associated with obesity, which to some extent is mediated by reversing the altered plasma glucose in obese mice. PMID- 24816897 TI - Resonance assignment and secondary structure determination of full length human Dickkopf 4 (hDkk4), a secreted, disulphide-rich Wnt inhibitor protein. AB - A number of proteins have been shown to modulate canonical Wnt signalling at the cell surface, including members of the Dickkopf (Dkk) family (Baron and Rawadi in J Endocrinol 148:2635-2643, 2007; Cruciat and Niehrs in Cold Spring Harb Perspect Biol 5:a015081, 2013). The Dkk family includes four secreted proteins (Dkk1-4), which are characterised by two highly conserved cysteine-rich regions corresponding to C24-C73 and C128-C201 in human Dkk4 (hDkk4). Here we report essentially complete backbone and comprehensive side chain (15)N, (13)C and (1)H NMR assignments for full length mature hDkk4 (M1-L207) containing a short C terminal hexa-histidine tag (E208-H222). Analysis of the backbone chemical shift data obtained indicates that there is a very limited amount of regular secondary structure, with only small stretches of beta-strand identified in both cysteine rich regions. The N-terminal region of hDkk4 (M1-G21) and the relatively long linker between the two cysteine-rich regions (E77-Q123) appear to be unstructured and relatively mobile. PMID- 24816898 TI - Enhanced creative thinking under dopaminergic therapy in Parkinson disease. AB - OBJECTIVE: Creative thinking requires a combination of originality, flexibility, and usefulness. Several reports described enhanced artistic creativity in Parkinson disease (PD) patients treated with dopaminergic agents. We aimed to examine PD patients' ability to perform creativity tasks compared to healthy controls and to verify whether creativity is related to an impulse control disorder (ICD) as a complication of dopaminergic therapy. METHODS: Right-handed PD patients treated with dopamine agonists and/or levodopa, and age- and education- matched neurologically healthy controls were assessed using the Montreal Cognitive Assessment, semantic verbal fluency, Beck Depression Inventory, and Questionnaire for Impulsive-Compulsive Disorders in Parkinson Disease Rating Scale (QUIP-RS). Creativity assessment included Comprehension of Novel Metaphors (CNM), Remote Association Test, and Tel Aviv Creativity Test (TACT). Groups were compared using analyses of variance, t tests, and correlation analyses. RESULTS: Twenty-seven PD patients (age, mean +/- standard deviation = 62 +/- 7 years; education = 16 +/- 3 years; disease duration = 5.8 +/- 3.9 years) and 27 controls (age = 59 +/- 9 years; education 17 +/- 3 years) participated. PD patients performed significantly better than controls in divergent thinking tasks; specifically, the TACT-Visual for both fluency (33.48 +/- 11.83 vs 25.59 +/- 10.27, p = 0.034) and quality (15.78 +/- 7.6 vs 11.19 +/- 6.22, p = 0.025). Comprehension of Novel Metaphors was better in PD patients vs controls (0.71 +/- 0.23 vs 0.55 +/- 0.29, p = 0.04). QUIP-RS scores did not correlate with creativity measures. INTERPRETATION: PD patients treated with dopaminergic drugs demonstrated enhanced verbal and visual creativity as compared to neurologically healthy controls. This feature was unrelated to ICD. Dopaminergic agents might act through the reduction of latent inhibition, resulting in widening of the associative network and enriched divergent thinking. PMID- 24816899 TI - Security of modified Ping-Pong protocol in noisy and lossy channel. AB - The "Ping-Pong" (PP) protocol is a two-way quantum key protocol based on entanglement. In this protocol, Bob prepares one maximally entangled pair of qubits, and sends one qubit to Alice. Then, Alice performs some necessary operations on this qubit and sends it back to Bob. Although this protocol was proposed in 2002, its security in the noisy and lossy channel has not been proven. In this report, we add a simple and experimentally feasible modification to the original PP protocol, and prove the security of this modified PP protocol against collective attacks when the noisy and lossy channel is taken into account. Simulation results show that our protocol is practical. PMID- 24816900 TI - First outbreak of community-acquired MRSA USA300 in France: failure to suppress prolonged MRSA carriage despite decontamination procedures. AB - The first French outbreak of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 clone was investigated. After outbreak investigation, hygiene measures were implemented in all family households and childminders' homes. Several decontamination procedures were performed, which used a combination of topical mupirocin, total body application of chlorhexidine, chlorhexidine gargle (if >6 years old) and a course of antibiotic therapy in cases of infection or decontamination failure. Patients were followed up for MRSA skin and soft tissue infections (SSTIs) and carriage. Strains were characterised by antimicrobial drug resistance profile, pulsed-field gel electrophoresis (PFGE) and DNA microarrays. Between June 2011 and June 2012, six children and six adults among the ten corresponding relatives developed 28 SSTIs. None of the family members, including the index case, had any contact with foreigners or individuals known to have SSTIs. After infection control measures and prolonged decontamination have been implemented with a high adherence, six patients remained sustained CA-MRSA USA300 carriers, including one who developed mupirocin resistance and six who experienced minor CA-MRSA-related SSTIs. A baby was identified as an MRSA carrier 2 months after delivery. CA-MRSA decontamination using mupirocin and chlorhexidine in the community setting may also be a questionable strategy, associated with failure and resistance to both agents. Close monitoring of CA-MRSA SSTIs is required in France and in other European countries where MRSA USA300 has recently emerged. We showed that a closed management based on hygiene measures reinforcement, decolonisation and extended screening may fail to suppress CA-MRSA carriage and subsequent infections. PMID- 24816901 TI - Aspirated bile: a major host trigger modulating respiratory pathogen colonisation in cystic fibrosis patients. AB - Chronic respiratory infections are a leading global cause of morbidity and mortality. However, the molecular triggers that cause respiratory pathogens to adopt persistent and often untreatable lifestyles during infection remain largely uncharacterised. Recently, bile aspiration caused by gastro-oesophageal reflux (GOR) has emerged as a significant complication associated with respiratory disease, and cystic fibrosis (CF) in particular. Based on our previous finding that the physiological concentrations of bile influence respiratory pathogens towards a chronic lifestyle in vitro, we investigated the impact of bile aspiration on the lung microbiome of respiratory patients. Sputum samples (n = 25) obtained from a cohort of paediatric CF patients were profiled for the presence of bile acids using high-resolution liquid chromatography-mass spectrometry (LC-MS). Pyrosequencing was performed on a set of ten DNA samples that were isolated from bile aspirating (n = 5) and non-bile aspirating (n = 5) patients. Both denaturing gradient gel electrophoresis (DGGE) and pyrosequencing revealed significantly reduced biodiversity and richness in the sputum samples from bile aspirating patients when compared with non-aspirating patients. Families and genera associated with the pervasive CF microbiome dominated aspirating patients, while bacteria associated with the healthy lung were most abundant in non-aspirating patients. Bile aspiration linked to GOR is emerging as a major host trigger of chronic bacterial infections. The markedly reduced biodiversity and increased colonisation by dominant proteobacterial CF-associated pathogens observed in the sputum of bile aspirating patients suggest that bile may play a major role in disease progression in CF and other respiratory diseases. PMID- 24816902 TI - The effect of quitting smoking on costs and healthcare utilization in patients with chronic obstructive pulmonary disease: a comparison of current smokers versus ex-smokers in routine clinical practice. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is a prevalent condition mainly related to smoking, which is associated with a substantial economic burden. The purpose was to compare healthcare resource utilization and costs according to smoking status in patients with COPD in routine clinical practice. METHODS: A retrospective cohort nested case-control study was designed. The cohort was composed of male and female COPD outpatients, 40 years or older, covered by the Badalona Serveis Assistencials (a health provider) health plan. Cases were current smokers with COPD and controls (two per case) were former smokers with COPD (at least 12 months without smoking), matched for age, sex, duration of COPD, and burden of comorbidity. The index date was the last visit recorded in the database, and the analysis was performed retrospectively on healthcare resource utilization data for the 12 months before the index date. RESULTS: A total of 930 COPD records were analyzed: 310 current and 620 former smokers [mean age 69.4 years (84.6 % male)]. Cases had more exacerbations, physician visits of any type, and drug therapies related to COPD were more common. As a consequence, current smokers had higher average annual healthcare costs: ?3,784 (1,888) versus ?2,302 (2,451), p < 0.001. This difference persisted after adjusting for severity of COPD. CONCLUSIONS: Current smokers with COPD had significantly higher use of healthcare resources, mainly COPD drugs and physician visits, compared with former smokers who had abstained for at least 12 months. As a consequence, current smokers had higher healthcare costs to the National Health System in Spain than ex-smokers. PMID- 24816903 TI - Extracorporeal membrane oxygenation and retransplantation in lung transplantation: an analysis of the UNOS registry. AB - BACKGROUND: Despite limited organ availability, extracorporeal membrane oxygenation (ECMO) and retransplantation are becoming more commonplace. METHODS: Using the United Network for Organ Sharing (UNOS) database, we evaluated survival of patients treated with ECMO before lung transplantation and undergoing retransplantation. A query identified cadaveric recipients from 2001 to 2012 over the age of 6 years. RESULTS: Of 15,772 lung recipients, 15 583 never received ECMO, whereas 189 did. Mean age was 52.1 +/- 14.4 versus 46.8 +/- 16.5 years for non-ECMO and ECMO groups, respectively (p < 0.0001). Using Kaplan-Meier method, there were survival differences between ECMO and non-ECMO groups (p < 0.0001) and first-time transplants with and without ECMO to retransplants with and without ECMO (p < 0.0001). The proportional hazards model identified higher risk with ECMO use in idiopathic pulmonary fibrosis (hazard ratio [HR] 1.09; 95 % confidence interval (CI), 1.02-1.17; p = 0.014) and retransplants (HR 1.77; 95 % CI, 1.55-2.03; p < 0.0001). CONCLUSIONS: Survival for retransplantation was similar to ECMO as a primary option with significant mortality associated with ECMO use in patients with idiopathic pulmonary fibrosis and retransplants. PMID- 24816904 TI - Partial monochorionic and monoamniotic twin pregnancies: a report of two cases. AB - Monochorionic (MC) twin pregnancies are at increased risk of adverse outcome because of the vascular anastomoses that connect the two fetal circulations. MC monoamniotic (MA) twins are at an even higher risk because of their almost universal cord entanglement and possible compression, which can cause an acute transfusion imbalance between the twins. Chorionicity and amnionicity should be determined during the first-trimester ultrasound examination to identify high risk MC and MA twin pregnancies for which a fortnightly follow-up may improve outcome. Although this can be achieved readily by assessing and counting the membranes that separate the twins, some pitfalls may occur. We present our observations of two monozygotic twin pairs with an intermediate type of monodichorionic and monodiamniotic twin pregnancy. The first was recognized during the first-trimester scan and the second during the second-trimester scan. PMID- 24816906 TI - Comment on "radioactive fallout in the United States due to the Fukushima nuclear plant accident" by P. Thakur, S. Ballard and R. Nelson, J. Environ. Monit., 2012, 14, 1317-1324. AB - The May 2012 paper "Radioactive fallout in the United States due to the Fukushima nuclear plant accident" (P. Thakur, S. Ballard and R. Nelson, J. Environ. Monit., 2012, 14, 1317-1324), does not address medical patient excreta as a source of (131)I (t1/2 = 8.04 d) to the environment. While (131)I is generated during fission reactions and may be released to the environment from nuclear power plants, nuclear weapons tests, nuclear fuel reprocessing and weapons production facilities, it is also produced for medical use. Iodine-131 administered to patients, excreted and discharged to sewer systems is readily measureable in sewage and the environment; the patient-to-sewage pathway is the only source of (131)I in many locations. PMID- 24816905 TI - Single nucleotide variants in the protein C pathway and mortality in dialysis patients. AB - BACKGROUND: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. METHODS: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. RESULTS: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. CONCLUSION: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients. PMID- 24816907 TI - Ossified soft tissue recurrence of giant cell tumor of the bone: four case reports with follow-up radiographs, CT, ultrasound, and MR images. AB - Giant cell tumor (GCT) of the bone is a benign tumor with a high incidence of recurrence. The majority of recurrence occurs in the bone, typically where curettage was performed previously. Soft tissue recurrence is much less common and often shows ossification at the periphery of the soft tissue mass. We report four cases of ossified soft tissue recurrence of giant cell tumor of the bone after surgery at follow-up examination using plain radiography, ultrasound, CT, and MR imagings. Imaging findings of soft tissue recurrence with peripheral or central ossification were reviewed with pathologic correlation. To the best of our knowledge, this is the first report to describe soft tissue tumor recurrence with ossification illustrated and monitored at various imaging modalities over an extended follow-up period. PMID- 24816908 TI - Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab. AB - Agents targeting the insulin-like growth factor receptor type 1 (IGF1R) have shown antitumor activity. Based on the evidence for interaction between the IGF-1 and TRAIL pathways, we hypothesized that the combination of ganitumab (monoclonal antibody to IGF1R) with the pro-apoptotic death receptor 5 agonist, conatumumab, might increase antitumor response. Ganitumab and conatumumab were tested in combination in a Colo-205 xenograft model. Part 1 of the clinical study was a phase Ib program of three doses of conatumumab (1, 3, 15 mg/kg) in combination with 18 mg/kg ganitumab to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. Part 2 was conducted in six cohorts with advanced non small cell lung cancer (squamous or non-squamous histology), colorectal cancer, sarcoma, pancreatic cancer, or ovarian cancer, treated at the recommended doses of the combination. The combination was significantly more active in the Colo-205 xenograft model than either single agent alone (p < 0.0015). In part 1 of the clinical study, no dose-limiting toxicities were observed and the MTD of conatumumab was 15 mg/kg in combination with 18 mg/kg ganitumab. In part 2, 78 patients were treated and there were no objective responses but 28 patients (36 %) had stable disease (median 46 days, range 0-261). The combination was well tolerated with no new toxicities. In conclusion, the combination of ganitumab and conatumumab was well-tolerated but had no objective responses in the population tested. The successful future application of this combination of antitumor mechanisms may rely on the identification of predictive biomarkers. PMID- 24816909 TI - Microcirculatory significance of periprocedural myocardial necrosis after percutaneous coronary intervention assessed by the index of microcirculatory resistance. AB - This study sought to investigate the relationship between the index of microcirculatory resistance (IMR) and periprocedural myocardial necrosis in patients with unstable angina pectoris (UAP). Fifty-seven UAP patients undergoing elective percutaneous coronary intervention (PCI) of a single lesion were recruited. A pressure-temperature sensor wire was used to measure IMR immediately after PCI. Total creatine kinase-MB (CK-MB) and troponin I (TNI) were measured every 8 h after PCI until they began to decline. Of the 57 patients studied, 22 had periprocedural myocardial infarction (MI) according to TNI. Post-PCI IMR >31 U had 86% sensitivity and 91% specificity for predicting periprocedural MI. There are a strong positive correlation between IMR and peak TNI (r = 0.805, p = 0.001), and a moderate positive correlation between IMR and peak CK-MB (r = 0.608, p = 0.003). Periprocedural myocardial injury, even in small area, during reperfusion is associated with impaired microcirculatory integrity as evaluated by IMR. Post-PCI IMR is independent predictive of developing periprocedural MI in patients with UAP, and, therefore, potentially enables a triage of higher risk patients to more intensive therapy. PMID- 24816910 TI - High-pitch coronary CT angiography with third generation dual-source CT: limits of heart rate. AB - To determine the average heart rate (HR) and heart rate variability (HRV) required for diagnostic imaging of the coronary arteries in patients undergoing high-pitch CT-angiography (CTA) with third-generation dual-source CT. Fifty consecutive patients underwent CTA of the thoracic (n = 8) and thoracoabdominal (n = 42) aorta with third-generation dual-source 192-slice CT with prospective electrocardiography (ECG)-gating at a pitch of 3.2. No beta-blockers were administered. Motion artifacts of coronary arteries were graded on a 4-point scale. Average HR and HRV were noted. The average HR was 66 +/- 11 beats per minute (bpm) (range 45-96 bpm); the HRV was 7.3 +/- 4.4 bpm (range 3-20 bpm). Interobserver agreement on grade of image quality for the 642 coronary segments evaluated by both observers was good (kappa = 0.71). Diagnostic image quality was found for 608 of the 642 segments (95%) in 43 of 50 patients (86%). In 14% of the patients, image quality was nondiagnostic for at least one segment. HR (p = 0.001) was significantly higher in patients with at least one non-diagnostic segment compared to those without. There was no significant difference (p > 0.05) in HRV between patients with nondiagnostic segments and those with diagnostic images of all segments. All patients with a HR < 70 bpm had diagnostic image quality in all coronary segments. The effective radiation dose and scan time for the heart were 0.4 +/- 0.1 mSv and 0.17 +/- 0.02 s, respectively. Third generation dual-source 192-slice CT allows for coronary angiography in the prospectively ECG-gated high-pitch mode with diagnostic image quality at HR up to 70 bpm. HRV is not significantly related to image quality of coronary CTA. PMID- 24816911 TI - 3,3'-(Ethane-1,2-diylidene)bis(indolin-2-one) based conjugated polymers for organic thin film transistors. AB - 3,3'-(Ethane-1,2-diylidene)bis(indolin-2-one) (EBI) was used as a new electron acceptor building block for conjugated polymers. Copolymers of EBI and bithiophene exhibited p-type semiconductor performance with hole mobility of up to 0.044 cm(2) V(-1) s(-1) in organic thin film transistors. PMID- 24816912 TI - Transoral robotic excision of ectopic lingual thyroid: Case series and literature review. AB - BACKGROUND: Surgical excision of an ectopic lingual thyroid has traditionally been associated with significant morbidity and has therefore been reserved for patients with severe obstructive symptoms or suspected malignancy. Transoral robotic surgery (TORS) has provided a minimally invasive approach to completely and safely excise ectopic lingual thyroid. METHODS: Three index cases were identified from the detailed clinical database of TORS patients. A systematic review of the management of ectopic lingual thyroid in the English literature was performed. RESULTS: TORS-assisted excision of a lingual thyroid gland was successfully performed in 3 patients with excellent functional outcomes CONCLUSION: TORS-assisted excision of an ectopic lingual thyroid is a safe and feasible treatment modality with minimal morbidity, and, in experienced hands, should be offered as a valid treatment for this pathology. PMID- 24816913 TI - No association between mean telomere length and life stress observed in a 30 year birth cohort. AB - Telomeres are specialised structures that cap the ends of chromosomes. They shorten with each cell division and have been proposed as a marker of cellular aging. Previous studies suggest that early life stressors increase the rate of telomere shortening with potential impact on disease states and mortality later in life. This study examined the associations between telomere length and exposure to a number of stressors that arise during development from the antenatal/perinatal period through to young adulthood. Participants were from the Christchurch Health and Development Study (CHDS), a New Zealand longitudinal birth cohort which has followed participants from birth until age 30. Telomere length was obtained on DNA from peripheral blood samples collected from consenting participants (n = 677) at age 28-30, using a quantitative PCR assay. These data were assessed for associations with 26 measures of life course adversity or stress which occurred prior to 25 years of age. No associations were found between telomere length measured at age 28-30 years and life course adversity or stress for specific measures and for the summary risk scores for each developmental domain. The correlations were very small ranging from -0.06 to 0.06 with a median of 0.01, and none were statistically significant. Our results in this well-studied birth cohort do not support prior reports of such associations, and underscore the need for more extensive replication of proposed links between stress and telomere biology in larger cohorts with appropriate phenotypic data. PMID- 24816914 TI - Bidirectional functions of arsenic as a carcinogen and an anti-cancer agent in human squamous cell carcinoma. AB - Bidirectional cancer-promoting and anti-cancer effects of arsenic for cancer cells have been revealed in previous studies. However, each of these effects (cancer-promoting or anti-cancer) was found in different cells at different treated-concentration of arsenic. In this study, we for the first time indicated that arsenic at concentration of 3 uM, equal to average concentration in drinking water in cancer-prone areas in Bangladesh, simultaneously expressed its bidirectional effects on human squamous cell carcinoma HSC5 cells with distinct pathways. Treatment with 3 uM of arsenic promoted cell invasion via upregulation of expression of MT1-MMP and downregulation of expression of p14ARF and simultaneously induced cell apoptosis through inhibition of expression of N cadherin and increase of expression of p21(WAF1/CIP1) at both transcript and protein levels in HSC5 cells. We also showed that inhibition of MT1-MMP expression by NSC405020 resulted in decrease of arsenic-mediated invasion of HSC5 cells involving decrease in phosphorylated extracellular signal-regulated kinases (pERK). Taken together, our biological and biochemical findings suggested that arsenic expressed bidirectional effects as a carcinogen and an anti-cancer agent in human squamous cell carcinoma HSC5 cells with distinct pathways. Our results might play an important scientific evident for further studies to find out a better way in treatment of arsenic-induced cancers, especially in squamous cell carcinoma. PMID- 24816915 TI - Design of a zinc-finger hydrolase with a synthetic alphabetabeta protein. AB - Recent advances in protein design have opened avenues for the creation of artificial enzymes needed for biotechnological and pharmaceutical applications. However, designing efficient enzymes remains an unrealized ambition, as the design must incorporate a catalytic apparatus specific for the desired reaction. Here we present a de novo design approach to evolve a minimal carbonic anhydrase mimic. We followed a step-by-step design of first folding the main chain followed by sequence variation for substrate binding and catalysis. To optimize the fold, we designed an alphabetabeta protein based on a Zn-finger. We then inverse designed the sequences to provide stability to the fold along with flexibility of linker regions to optimize Zn binding and substrate hydrolysis. The resultant peptides were synthesized and assessed for Zn and substrate binding affinity by fluorescence and ITC followed by evaluation of catalytic efficiency with UV-based enzyme kinetic assays. We were successful in mimicking carbonic anhydrase activity in a peptide of twenty two residues, using p-nitrophenyl acetate as a CO2 surrogate. Although our design had modest activity, being a simple structure is an advantage for further improvement in efficiency. Our approach opens a way forward to evolving an efficient biocatalyst for any industrial reaction of interest. PMID- 24816916 TI - Human IP10-scFv and DC-induced CTL synergistically inhibit the growth of glioma in a xenograft model. AB - The epidermal growth factor receptor (EGFR) mutant of EGFRvIII is highly expressed in glioma cells, and the EGFRvIII-specific dendritic cell (DC)-induced tumor antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) may hold promise in cancer immunotherapy. Interferon (IFN)-gamma-inducible protein (IP)-10 (IP-10) is a potent inhibitor of angiogenesis and can recruit CXCR3(+) T cells, including CD8(+) T cells, which are important for the control of tumor growth. In this study, we assessed if the combination of IP10-EGFRvIIIscFv with DC-induced CTLs would improve the therapeutic antitumor efficacy. IP10-scFv was generated by linking the human IP-10 gene with the DNA fragment for anti-EGFRvIIIscFv with a (Gly4Ser)3 flexible linker, purified by affinity chromatography, and characterized for its anti-EGFRvIII immunoreactivity and chemotactic activity. DCs were isolated from human peripheral blood monocyte cells and pulsed with EGFRvIII-peptide, then co-cultured with autologous CD8(+) T cells. BALB/c-nu mice were inoculated with human glioma U87-EGFRvIII cells in the brain and treated intracranially with IP10-scFv and/or intravenously with DC-induced CTLs for evaluating the therapeutic effect. Treatment with both IP10-scFv and EGFRvIII peptide-pulsed, DC-induced CTL synergistically inhibited the growth of glioma and prolonged the survival of tumor-bearing mice, which was accompanied by the inhibition of tumor angiogenesis and enhancement of cytotoxicity, thereby increasing the numbers of brain-infiltrating lymphocytes (BILs) and prolonging the residence time of CTLs in the tumor. PMID- 24816917 TI - Cytoglobin in tumor hypoxia: novel insights into cancer suppression. AB - Emerging new and intriguing roles of cytoglobin (Cygb) have attracted considerable attention of cancer researchers in recent years. Hypoxic upregulation of Cygb as well as its altered expression in various human cancers suggest another possible role of this newly discovered globin in tumor cell response under low oxygen tension. Since tumor hypoxia is strongly associated with malignant progression of disease and poor treatment response, it constitutes an area of paramount importance for rational design of cancer selective therapies. However, the mechanisms involved during this process are still elusive. This review outlines the current understanding of Cygb's involvement in tumor hypoxia and discusses its role in tumorigenesis. A better perception of Cygb in tumor hypoxia response is likely to open novel perspectives for future tumor therapy. PMID- 24816918 TI - Vascular endothelial growth factor gene polymorphism (-634G/C) and breast cancer risk. AB - The aim of this meta-analysis was to assess if the -634G/C polymorphism represents a predisposition factor for the risk of breast cancer. We included eight published case-control studies, in which a total of 6,175 cancer cases and 6,421 cancer-free controls were included. Pooled ORs and 95 % CIs were calculated by the fixed effects model to evaluate the association of the -634G/C polymorphism and breast cancer risk. When all studies were pooled, we did not find statistical evidence of any significant association with overall breast cancer risk (ORBB vs. bb = 1.00, 95 % CI = 0.93-1.07, P = 0.999; ORBB + Bb vs. bb = 1.00, 95 % CI = 0.95-1.05, P = 0.999; ORBB vs. Bb + bb = 1.03, 95 % CI = 0.96 1.09, P = 0.984; ORallele B vs. allele b = 1.01, 95 % CI = 0.97-1.05, P = 0.998; ORBb vs. bb = 0.99, 95 % CI = 0.92-1.06, P = 0.992). In further stratified analyses by ethnicity and control source, no significant association was revealed. This study suggests that the -634G/C polymorphism does not appear to represent a risk factor for breast cancer. PMID- 24816919 TI - Association between miR-146aG>C and miR-196a2C>T polymorphisms and the risk of hepatocellular carcinoma in a Chinese population. AB - MicroRNAs have been demonstrated to have a role in susceptibility and prognosis of various types of human cancer. We investigated the association between polymorphisms in miR-146aG>C, miR-196a2C>T, and miR-499A>G and hepatocellular carcinoma (HCC) risk and interaction with HCC and hepatitis B virus (HBV) infection. Two hundred sixty-six cases with HCC and 281 health controls were enrolled in the present study. Genotyping of the miR-146aG>C, miR-196a2C>T, and miR-499A>G genotypes was conducted by duplex polymerase chain reaction with the confronting two-pair primer (PCR-RFLP). Subjects with miR-146a GG and G allele had an increased risk of HCC compared with the homozygote CC genotype. Similarly, HCC patients carrying microRNA (miRNA)-196a2 computed tomography, TT, and T allele significantly decreased the risk of HCC relative to the CC genotype. Stratified analysis indicated that miR-196a2C>T polymorphism was associated with reduced risk of HBV-related HCC, but not in hepatitis C virus- and nonviral related HCC cases. In conclusion, miR-146aG>C and miR-196a2C>T polymorphism are associated with risk of HCC patients in China, especially in patients with HBV infection. SNPs in miRNA sequences can be used as a diagnostic biomarker for HCC. PMID- 24816920 TI - Letter regarding the article of Jiao G. J. et al. entitled "Prognostic significance of cyclooxygenase-2 in osteosarcoma: a meta-analysis". PMID- 24816921 TI - Heart rate variability and the metabolic syndrome: a systematic review of the literature. AB - BACKGROUND: A number of cross-sectional studies have examined associations between heart rate variability and metabolic syndrome, but differences in study populations, data collection and analysis methodologies make synthesis difficult. The purpose of this study was to systematically review published primary research examining associations between heart rate variability and metabolic syndrome or its individual risk factors. METHODS: A systematic literature search of PubMed and EMBASE was conducted to identify relevant articles published from January 1999 to December 2012. Studies were included if they examined associations between heart rate variability analysed by standard protocols and metabolic syndrome risk factors according to published definitions. All papers were scored with a modified Downs and Black instrument, and data were extracted. RESULTS: Fourteen studies were included. Heart rate variability generally was reduced in women with metabolic syndrome compared to those without, while results in men were inconsistent. Time and frequency domain heart rate variability parameters were associated with individual metabolic syndrome risk factors, though sex differences exist. Only two studies considered nonlinear and Poincare plot heart rate variability parameters, which were reduced in metabolic syndrome. CONCLUSIONS: Heart rate variability is altered differently in men and women with metabolic syndrome. Future studies should follow consistent heart rate variability analysis protocols and metabolic syndrome definitions and include more comprehensive analyses to investigate potential mechanisms. PMID- 24816922 TI - Interleukin-27 is differentially associated with HIV viral load and CD4+ T cell counts in therapy-naive HIV-mono-infected and HIV/HCV-co-infected Chinese. AB - Human Immunodeficiency Virus (HIV) infection and the resultant Acquired Immunodeficiency Syndrome (AIDS) epidemic are major global health challenges; hepatitis C virus (HCV) co-infection has made the HIV/AIDS epidemic even worse. Interleukin-27 (IL-27), a cytokine which inhibits HIV and HCV replication in vitro, associates with HIV infection and HIV/HCV co-infection in clinical settings. However, the impact of HIV and HCV viral loads on plasma IL-27 expression levels has not been well characterized. In this study, 155 antiretroviral therapy-naive Chinese were recruited. Among them 80 were HIV- and HCV-negative healthy controls, 45 were HIV-mono-infected and 30 were HIV/HCV-co infected. Plasma level HIV, HCV, IL-27 and CD4+ number were counted and their correlation, regression relationships were explored. We show that: plasma IL-27 level was significantly upregulated in HIV-mono-infected and HIV/HCV-co-infected Chinese; HIV viral load was negatively correlated with IL-27 titer in HIV-mono infected subjects whereas the relationship was opposite in HIV/HCV-co-infected subjects; and the relationships between HIV viral loads, IL-27 titers and CD4+ T cell counts in the HIV mono-infection and HIV/HCV co-infection groups were dramatically different. Overall, our results suggest that IL-27 differs in treatment-naive groups with HIV mono-infections and HIV/HCV co-infections, thereby providing critical information to be considered when caring and treating those with HIV mono-infection and HIV/HCV co-infection. PMID- 24816924 TI - The antidepressant tranylcypromine alters cellular proliferation and migration in the adult goldfish brain. AB - The goldfish (Carassius auratus) is a widely studied vertebrate model organism for studying cell proliferation in the adult brain, and provide the experimental advantage of growing their body and brain throughout their ~30-year life time. Cell proliferation occurs in the teleost brain in widespread proliferation zones. Increased cell proliferation in the brain has been linked to the actions of certain antidepressants, including tranylcypromine (TCP), which is used in the treatment of depression. We hypothesized that proliferation zones in the adult goldfish brain can be used to determine the antidepressant effects on cellular proliferation. Here, we report that bromodeoxyuridine (BrdU) labeling over a 24 hr period can be used to rapidly identify the proliferation zones throughout the goldfish brain, including the telencephalon, diencephalon, optic tectal lobes, cerebellum, and facial and vagal lobes. In the first 24 hr of BrdU administration, TCP caused an approximate and significant doubling of labeled cells in the combined brain regions examined, as detected by BrdU immunohistochemistry. TCP caused the greatest increase in cell proliferation in the cerebellum. The normal migratory paths of the proliferating cells within the cerebellum were not affected by TCP treatment. These results indicate that the goldfish provide significant advantages as a vertebrate model for rapidly investigating the effects of antidepressant drugs on cellular proliferation and migration in the normal and injured brain. PMID- 24816923 TI - Analysis of the effects of five factors relevant to in vitro chondrogenesis of human mesenchymal stem cells using factorial design and high throughput mRNA profiling. AB - The in vitro process of chondrogenic differentiation of mesenchymal stem cells for tissue engineering has been shown to require three-dimensional culture along with the addition of differentiation factors to the culture medium. In general, this leads to a phenotype lacking some of the cardinal features of native articular chondrocytes and their extracellular matrix. The factors used vary, but regularly include members of the transforming growth factor beta superfamily and dexamethasone, sometimes in conjunction with fibroblast growth factor 2 and insulin-like growth factor 1, however the use of soluble factors to induce chondrogenesis has largely been studied on a single factor basis. In the present study we combined a factorial quality-by-design experiment with high-throughput mRNA profiling of a customized chondrogenesis related gene set as a tool to study in vitro chondrogenesis of human bone marrow derived mesenchymal stem cells in alginate. 48 different conditions of transforming growth factor beta 1, 2 and 3, bone morphogenetic protein 2, 4 and 6, dexamethasone, insulin-like growth factor 1, fibroblast growth factor 2 and cell seeding density were included in the experiment. The analysis revealed that the best of the tested differentiation cocktails included transforming growth factor beta 1 and dexamethasone. Dexamethasone acted in synergy with transforming growth factor beta 1 by increasing many chondrogenic markers while directly downregulating expression of the pro-osteogenic gene osteocalcin. However, all factors beneficial to the expression of desirable hyaline cartilage markers also induced undesirable molecules, indicating that perfect chondrogenic differentiation is not achievable with the current differentiation protocols. PMID- 24816925 TI - The role of precision agriculture for improved nutrient management on farms. AB - Precision agriculture uses proximal and remote sensor surveys to delineate and monitor within-field variations in soil and crop attributes, guiding variable rate control of inputs, so that in-season management can be responsive, e.g. matching strategic nitrogen fertiliser application to site-specific field conditions. It has the potential to improve production and nutrient use efficiency, ensuring that nutrients do not leach from or accumulate in excessive concentrations in parts of the field, which creates environmental problems. The discipline emerged in the 1980s with the advent of affordable geographic positioning systems (GPS), and has further developed with access to an array of affordable soil and crop sensors, improved computer power and software, and equipment with precision application control, e.g. variable rate fertiliser and irrigation systems. Precision agriculture focusses on improving nutrient use efficiency at the appropriate scale requiring (1) appropriate decision support systems (e.g. digital prescription maps), and (2) equipment capable of varying application at these different scales, e.g. the footprint of a one-irrigation sprinkler or a fertiliser top-dressing aircraft. This article reviews the rapid development of this discipline, and uses New Zealand as a case study example, as it is a country where agriculture drives economic growth. Here, the high yield potentials on often young, variable soils provide opportunities for effective financial return from investment in these new technologies. PMID- 24816926 TI - Lanthanide based tuning of luminescence in MOFs and dense frameworks--from mono- and multimetal systems to sensors and films. AB - This feature article focuses on tuning options of photoluminescence properties of lanthanide containing Metal-Organic Frameworks (MOFs) and Dense Frameworks by selection of an appropriate set of metal ions together with suitable ligands. In addition to lanthanide-only systems, frameworks with main group and transition metal ions that are heterometallic or co-doped with variable lanthanide content offer excellent tuning options for luminescence. The MOF feature porosity enables further applications such as sensors for a large number of chemical analytes by selective influences on the luminescence upon contact. The application of functional thin films marks the most recent development of this amazingly growing field, involving processing and structuring. PMID- 24816927 TI - The self-assembly of a cyclic lipopeptides mixture secreted by a B. megaterium strain and its implications on activity against a sensitive Bacillus species. AB - Cyclic lipopeptides are produced by a soil Bacillus megaterium strain and several other Bacillus species. In this work, they are detected both in the Bacillus intact cells and the cells culture medium by MALDI-TOF mass spectrometry. The cyclic lipopeptides self-assemble in water media producing negatively charged and large aggregates (300-800 nm of mean hydrodynamic radius) as evaluated by dynamic light scattering and zeta-potential analysis. The aggregate size depends on pH and ionic strength. However, it is not affected by changes in the osmolarity of the outer medium suggesting the absence of an internal aqueous compartment despite the occurrence of low molecular weight phospholipids in their composition as determined from inorganic phosphorus analysis. The activity against a sensitive Bacillus cereus strain was evaluated from inhibition halos and B. cereus lysis. Essential features determining the antibiotic activity on susceptible Bacillus cereus cells are the preserved cyclic moiety conferring cyclic lipopeptides resistance to proteases and the medium pH. The aggregates are inactive per se at the pH of the culture medium which is around 6 or below. The knock out of the sensitive cells only takes place when the aggregates are disassembled due to a high negative charge at pH above 6. PMID- 24816928 TI - Excess salt increases infarct size produced by photothrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats. AB - Cerebral circulation is known to be vulnerable to high salt loading. However, no study has investigated the effects of excess salt on focal ischemic brain injury. After 14 days of salt loading (0.9% saline) or water, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to photothrombotic middle cerebral artery occlusion (MCAO), and infarct volume was determined at 48 h after MCAO: albumin and hemoglobin contents in discrete brain regions were also determined in SHR. Salt loading did not affect blood pressure levels in SHR and WKY. After MCAO, regional cerebral blood flow (CBF), determined with two ways of laser-Doppler flowmetry (one-point measurement or manual scanning), was more steeply decreased in the salt-loaded group than in the control group. In SHR/Izm, infarct volume in the salt-loaded group was 112+/-27 mm3, which was significantly larger than 77+/-12 mm3 in the control group (p = 0.002), while the extents of blood-brain barrier disruption (brain albumin and hemoglobin levels) were not affected by excess salt. In WKY, salt loading did not significantly increase infarct size. These results show the detrimental effects of salt loading on intra-ischemic CBF and subsequent brain infarction produced by phototrhombotic MCAO in hypertensive rats. PMID- 24816930 TI - Feasibility of in vivo diffusion tensor imaging of articular cartilage with coverage of all cartilage regions. AB - OBJECTIVES: To investigate the value of diffusion tensor imaging (DTI) of articular cartilage to differentiate healthy from osteoarthritis (OA) subjects in all cartilage regions. METHODS: DTI was acquired sagittally at 7 T in ten healthy and five OA (Kellgren-Lawrence grade 2) subjects with a line scan diffusion tensor sequence (LSDTI). Three healthy volunteers and two OA subjects were examined twice to assess the test-retest reproducibility. Averaged mean diffusivity (MD) and fractional anisotropy (FA) were calculated in each cartilage region (femoral trochlea, lateral and medial femoral condyles, patella, and lateral and medial tibia). RESULTS: The test-retest reproducibility was 2.9% for MD and 5.6% for FA. Averaged MD was significantly increased (+20%, p < 0.05) in the OA subjects in the lateral femoral condyle, lateral tibia and the femoral trochlea compartments. Averaged FA presented a trend of lower values in the OA subjects (-12%), which was only significant for the lateral tibia. CONCLUSIONS: In vivo DTI of articular cartilage with coverage of all cartilage regions using an LSDTI sequence is feasible, shows excellent reproducibility for MD and FA, and holds potential for the diagnosis of OA. KEY POINTS: * DTI of articular cartilage is feasible at 7 T in all cartilage regions * DTI of articular cartilage can potentially differentiate healthy and OA subjects. PMID- 24816929 TI - Genome-wide transcriptome analysis reveals that cadmium stress signaling controls the expression of genes in drought stress signal pathways in rice. AB - Plant growth is severely affected by toxic concentrations of the non-essential heavy metal cadmium (Cd). Comprehensive transcriptome analysis by RNA-Seq following cadmium exposure is required to further understand plant responses to Cd and facilitate future systems-based analyses of the underlying regulatory networks. In this study, rice plants were hydroponically treated with 50 uM Cd for 24 hours and ~60,000 expressed transcripts, including transcripts that could not be characterized by microarray-based approaches, were evaluated. Upregulation of various ROS-scavenging enzymes, chelators and metal transporters demonstrated the appropriate expression profiles to Cd exposure. Gene Ontology enrichment analysis of the responsive transcripts indicated the upregulation of many drought stress-related genes under Cd exposure. Further investigation into the expression of drought stress marker genes such as DREB suggested that expression of genes in several drought stress signal pathways was activated under Cd exposure. Furthermore, qRT-PCR analyses of randomly selected Cd-responsive metal transporter transcripts under various metal ion stresses suggested that the expression of Cd-responsive transcripts might be easily affected by other ions. Our transcriptome analysis demonstrated a new transcriptional network linking Cd and drought stresses in rice. Considering our data and that Cd is a non-essential metal, the network underlying Cd stress responses and tolerance, which plants have developed to adapt to other stresses, could help to acclimate to Cd exposure. Our examination of this transcriptional network provides useful information for further studies of the molecular mechanisms of plant adaptation to Cd exposure and the improvement of tolerance in crop species. PMID- 24816931 TI - CT colonography: effect of computer-aided detection of colonic polyps as a second and concurrent reader for general radiologists with moderate experience in CT colonography. AB - OBJECTIVES: To assess the effectiveness of computer-aided detection (CAD) as a second reader or concurrent reader in helping radiologists who are moderately experienced in computed tomographic colonography (CTC) to detect colorectal polyps. METHODS: Seventy CTC datasets (34 patients: 66 polyps >=6 mm; 36 patients: no abnormalities) were retrospectively reviewed by seven radiologists with moderate CTC experience. After primary unassisted evaluation, a CAD second read and, after a time interval of >=4 weeks, a CAD concurrent read were performed. Areas under the receiver operating characteristic (ROC) curve (AUC), along with per-segment, per-polyp and per-patient sensitivities, and also reading times, were calculated for each reader with and without CAD. RESULTS: Of seven readers, 86% and 71% achieved a higher accuracy (segment-level AUC) when using CAD as second and concurrent reader respectively. Average segment-level AUCs with second and concurrent CAD (0.853 and 0.864) were significantly greater (p < 0.0001) than average AUC in the unaided evaluation (0.781). Per-segment, per polyp, and per-patient sensitivities for polyps >=6 mm were significantly higher in both CAD reading paradigms compared with unaided evaluation. Second-read CAD reduced readers' average segment and patient specificity by 0.007 and 0.036 (p = 0.005 and 0.011), respectively. CONCLUSIONS: CAD significantly improves the sensitivities of radiologists moderately experienced in CTC for polyp detection, both as second reader and concurrent reader. KEY POINTS: * CAD helps radiologists with moderate CTC experience to detect polyps >=6 mm. * Second and concurrent read CAD increase the radiologist's sensitivity for detecting polyps >=6 mm. * Second read CAD slightly decreases specificity compared with an unassisted read. * Concurrent read CAD is significantly more time-efficient than second read CAD. PMID- 24816933 TI - Short-term side-effects of brain MR examination at 7 T: a single-centre experience. AB - OBJECTIVE: To study patient tolerability of brain imaging that employs an ultrahigh field (7 T) MR system METHODS: We examined 180 subjects that underwent brain MR examination at 7 T. A tolerability test consisting of two parts (during patient table motion and during the examination) was administered to all subjects in order to monitor their discomfort. The scores range from 0 to 5 for the first part, and from 0 to 10 for the second part, the total score of each subject therefore ranging from 0 (no side effects reported) to 15 (lowest tolerability) RESULTS: A total of 51% of subjects reported at least one side effect but all were mild in intensity and did not require examination interruption. No serious adverse event was reported. The total score (mean +/- standard deviation) was 1.1 +/- 1.5 out of 15 (mean score 0.4 +/- 0.7 out of 5 during patient table motion and 0.7 +/- 1.1 out of 10 during MR). Patient discomfort was not related to gender or health status, but it was reduced with time after system installation with increasing operator experience in performing UHF MR examinations. CONCLUSIONS: Ultrahigh field MRI is well tolerated without excessive discomfort to subjects. KEY POINTS: * 7-T MRI is well tolerated with low incidence of side effects * The subjects' discomfort during 7-T MRI is reduced as the operators' experience increases * 7-T MRI is practicable in healthy subjects and patients with neurodegenerative diseases. PMID- 24816932 TI - Impact of the digitalisation of mammography on performance parameters and breast dose in the Flemish Breast Cancer Screening Programme. AB - OBJECTIVES: To investigate the impact of digitalisation on performance parameters and breast dose of the Flemish Breast Cancer Screening Programme. Both computed (CR) and direct radiography (DR) are compared with screen-film mammography (SFM). METHODS: Data from 975,673 mammographic examinations were collected from units which underwent digitalisation from SFM to CR (41 units) or DR (72 units) in the period 2005-2011. Performance indicators were obtained by consulting the Screening Programme database. Phantom and patient dosimetry data were acquired from the physical technical quality assurance of the programme. RESULTS: Digitalisation induced no significant change in cancer detection rate (CDR), percentage of ductal carcinomas in situ and percentage of breast cancers smaller than 1 cm. A decrease in false-positive results and third readings was observed, which was a time-related observation. After digitalisation, positive predictive value (PPV) increased and recall rates decreased. Compared with SFM, an increase of 30% in mean glandular dose (MGD) was found for CR, while a similar change in the opposite direction was found for DR. CONCLUSIONS: No major differences in performance parameters after digitalisation were found. Transition of SFM to CR resulted in a higher MGD and associated lower detection-over-induction ratio (DIR), while the change to DR induced an improvement of DIR. KEY POINTS: * Performance parameters showed no major differences after digitalisation to CR or DR. * Transition from SFM to CR results in a higher mean glandular dose. * Transition from SFM to DR results in a lower mean glandular dose. PMID- 24816934 TI - MRI-based determination of reference values of thoracic aortic wall thickness in a general population. AB - OBJECTIVES: To provide age- and sex-specific reference values for MRI-derived wall thickness of the ascending and descending aorta in the general population. MATERIALS AND METHODS: Data of 753 subjects (311 females) aged 21-81 years were analysed. MRI was used to determine the aortic wall thickness (AWT). Equations for reference value calculation according to age were established for females and males. RESULTS: Median wall thickness of the ascending aorta was 1.46 mm (5th 95th range: 1.15-1.88 mm) for females and 1.56 mm (1.22-1.99 mm) for males. Median wall thickness of the descending aorta was 1.26 mm (0.97-1.58 mm) in females and 1.36 mm (1.04-1.75 mm) in males. While median and 5th and 95th percentiles for the ascending and descending aorta increased with age in both sexes, the association between age and median AWT was stronger in males than in females for both the ascending and descending aorta. CONCLUSIONS: Reference values for the ascending and descending AWT are provided. In a healthy sample from the general population, the wall of the ascending aorta is thicker than the wall of the descending aorta, and both walls are thicker in males than females. The increase in wall thickness with age is greater in males. KEY POINTS: Ascending aortic wall thickness is greater than descending aortic wall thickness. Ascending and descending aortic wall thickness is greater in males. Thoracic aortic wall thickness increases with age in both sexes. The age-related increase in aortic wall thickness is stronger in males. PMID- 24816935 TI - Perforation rate in CT colonography: a systematic review of the literature and meta-analysis. AB - PURPOSE: The primary aim was to assess the perforation rate of CTC; the secondary aim was to identify potential clinical/technical predictors of this complication. METHODS: Methods for analysis were based on PRISMA (preferred reporting items for systematic reviews and meta-analyses). From the selected studies, the rate of CTC perforation and patient/technical characteristics potentially associated with this event were extracted. Forest plots showing individual and pooled estimates of the perforation rate were obtained for all analyses. I(2) was used to evaluate heterogeneity between studies. RESULTS: Eleven articles out of the 187 initially identified were selected for the analysis (103,399 patients). There were 29,048 (28%) asymptomatic individuals and 30,773 (30%) symptomatic patients; this characteristic was not reported in the remaining subjects (42%). Colon distension was obtained manually in 69,222 (67%) and using an automated carbon dioxide insufflator in 26,479 (26%) patients; in the remaining 7% of patients, this information was missing. Twenty-eight colonic perforations were reported, with the CTC perforation rate estimated to be 0.04% (95% CI. 0.00-0.10), 19-fold higher in symptomatic than in screening subjects (OR: 19.2, CI 3.3-108 and P = 0.001). The surgical rate was 0.008%. No CTC-related deaths were reported. CONCLUSIONS: The perforation rate in CTC is very low, particularly considering asymptomatic individuals. KEY POINTS: * This is the first meta-analysis on this topic, based on 100,000 patients. * The CTC-related colorectal perforation rate is 0.04%, 0.02% in asymptomatic subjects. * The CTC-induced surgery rate is 0.008% (1:12,500). * The perforation rate in CTC is low, particularly in average risk, asymptomatic individuals. PMID- 24816936 TI - Cardiac valve calcifications on low-dose unenhanced ungated chest computed tomography: inter-observer and inter-examination reliability, agreement and variability. AB - OBJECTIVES: To determine inter-observer and inter-examination variability for aortic valve calcification (AVC) and mitral valve and annulus calcification (MC) in low-dose unenhanced ungated lung cancer screening chest computed tomography (CT). METHODS: We included 578 lung cancer screening trial participants who were examined by CT twice within 3 months to follow indeterminate pulmonary nodules. On these CTs, AVC and MC were measured in cubic millimetres. One hundred CTs were examined by five observers to determine the inter-observer variability. Reliability was assessed by kappa statistics (kappa) and intra-class correlation coefficients (ICCs). Variability was expressed as the mean difference +/- standard deviation (SD). RESULTS: Inter-examination reliability was excellent for AVC (kappa = 0.94, ICC = 0.96) and MC (kappa = 0.95, ICC = 0.90). Inter examination variability was 12.7 +/- 118.2 mm(3) for AVC and 31.5 +/- 219.2 mm(3) for MC. Inter-observer reliability ranged from kappa = 0.68 to kappa = 0.92 for AVC and from kappa = 0.20 to kappa = 0.66 for MC. Inter-observer ICC was 0.94 for AVC and ranged from 0.56 to 0.97 for MC. Inter-observer variability ranged from 30.5 +/- 252.0 mm(3) to 84.0 +/- 240.5 mm(3) for AVC and from -95.2 +/- 210.0 mm(3) to 303.7 +/- 501.6 mm(3) for MC. CONCLUSIONS: AVC can be quantified with excellent reliability on ungated unenhanced low-dose chest CT, but manual detection of MC can be subject to substantial inter-observer variability. Lung cancer screening CT may be used for detection and quantification of cardiac valve calcifications. KEY POINTS: * Low-dose unenhanced ungated chest computed tomography can detect cardiac valve calcifications. * However, calcified cardiac valves are not reported by most radiologists. * Inter-observer and inter examination variability of aortic valve calcifications is sufficient for longitudinal studies. * Volumetric measurement variability of mitral valve and annulus calcifications is substantial. PMID- 24816937 TI - Image quality and radiation dose of low tube voltage 3rd generation dual-source coronary CT angiography in obese patients: a phantom study. AB - OBJECTIVES: To assess the influence of tube potential on radiation dose and image quality of third-generation dual-source coronary CT angiography (CTA) in a phantom simulating an obese patient. METHODS: A thoracic phantom was equipped with tubular inserts containing iodine solution and water. A soft-tissue equivalent ring around the phantom simulated an obese patient. Images were acquired at tube potentials of 80, 100, 120 and 140 kV with second-generation dual-source CT (DSCT) and 70-150 kV (in 10-kV increments) with third-generation DSCT. Contrast-to-noise ratio (CNR) was calculated and CT dose index was recorded. RESULTS: With second-generation DSCT, CNR was highest for 120 kV (19.0) and decreased with lower tube potential (12.0 at 80 kV) owing to disproportionately increased image noise. With third-generation DSCT, 70- and 80 kV acquisitions showed a smaller increase in noise. CNRs for third-generation DSCT were highest for 70 and 80 kV (21.1 and 21.2, respectively). Compared to 120 kV, radiation dose was 68% and 49% lower at 70 kV and 80 kV, respectively. CONCLUSION: Third-generation DSCT enables one to perform coronary CTA at 70-80 kV in obese patients without compromising CNR and thus reduces radiation dose by 49 68%. KEY POINTS: * Low tube potential CT angiography is currently not suitable for obese patients. * Third-generation DSCT offers substantially increased tube power at low tube potential. * This enables one to perform coronary CT angiography at 70-80 kV in obese patients. * Signal-to-noise ratio is maintained owing to increased tube current. * This approach can be expected to reduce radiation dose by 49-68%. PMID- 24816938 TI - Evaluating the agreement between tumour volumetry and the estimated volumes of tumour lesions using an algorithm. AB - OBJECTIVES: To evaluate the agreement between tumour volume derived from semiautomated volumetry (SaV) and tumor volume defined by spherical volume using longest lesion diameter (LD) according to Response Evaluation Criteria In Solid Tumors (RECIST) or ellipsoid volume using LD and longest orthogonal diameter (LOD) according to World Health Organization (WHO) criteria. MATERIALS AND METHODS: Twenty patients with metastatic colorectal cancer from the CIOX trial were included. A total of 151 target lesions were defined by baseline computed tomography and followed until disease progression. All assessments were performed by a single reader. A variance component model was used to compare the three volume versions. RESULTS: There was a significant difference between the SaV and RECIST-based tumour volumes. The same model showed no significant difference between the SaV and WHO-based volumes. Scatter plots showed that the RECIST-based volumes overestimate lesion volume. The agreement between the SaV and WHO-based relative changes in tumour volume, evaluated by intraclass correlation, showed nearly perfect agreement. CONCLUSIONS: Estimating the volume of metastatic lesions using both the LD and LOD (WHO) is more accurate than those based on LD only (RECIST), which overestimates lesion volume. The good agreement between the SaV and WHO-based relative changes in tumour volume enables a reasonable approximation of three-dimensional tumour burden. KEY POINTS: * Tumour response in patients undergoing chemotherapy is assessed using CT images * Measurements are based on RECIST (unidimensional)-based or WHO (bidimensional)-based criteria * We calculated tumour volume from bidimensional target lesion measurements * This formula provides good tumour volume approximation, based on semiautomated volumetry. PMID- 24816939 TI - Quantitative magnetic resonance imaging (MRI) evaluation of cartilage repair after microfracture (MF) treatment for adult unstable osteochondritis dissecans (OCD) in the ankle: correlations with clinical outcome. AB - OBJECTIVES: To quantitatively evaluate cartilage repair after microfracture (MF) for ankle osteochondritis dissecans (OCD) using MRI and analyse correlations between MRI and clinical outcome. METHODS: Forty-eight patients were recruited and underwent MR imaging, including 3D-DESS, T2-mapping and T2-STIR sequences, and completed American Orthopaedic Foot and Ankle Society (AOFAS) scoring. Thickness index, T2 index of repair tissue (RT) and volume of subchondral bone marrow oedema (BME) were calculated. Subjects were divided into two groups: group A (3-12 months post-op), and group B (12-24 months post-op). Student's t test was used to compare the MRI and AOFAS score between two groups and Pearson's correlation coefficient to analyse correlations between them. RESULTS: Thickness index and AOFAS score of group B were higher than group A (P < 0.001, P < 0.001). T2 index and BME of group B were lower than group A (P < 0.001, P = 0.012). Thickness index, T2 index and BME were all correlated with AOFAS score (r = 0.416, r = -0.475, r = -0.353), but BME was correlated with neither thickness index nor T2 index. CONCLUSIONS: Significant improvement from MF can be expected on the basis of the outcomes of quantitative MRI and AOFAS score. MRI was correlated with AOFAS score. BME is insufficient as an independent predictor to evaluate repair quality, but reduction of BME can improve the patient's clinical outcome. KEY POINTS: * Patients with unstable ankle OCD had satisfactory clinical outcome after MF. * Quantitative MRI correlates with clinical outcome after MF for ankle OCD. * The reduction of subchondral BME will improve the patient's clinical outcome. * Quantitative MRI can monitor the process of cartilage repair over time. PMID- 24816940 TI - Topogram-based automated selection of the tube potential and current in thoraco abdominal trauma CT - a comparison to fixed kV with mAs modulation alone. AB - OBJECTIVE: To investigate the impact of automated attenuation-based tube potential selection on image quality and exposure parameters in polytrauma patients undergoing contrast-enhanced thoraco-abdominal CT. METHODS: One hundred patients were examined on a 16-slice device at 120 kV with 190 ref.mAs and automated mA modulation only. Another 100 patients underwent 128-slice CT with automated mA modulation and topogram-based automated tube potential selection (autokV) at 100, 120 or 140 kV. Volume CT dose index (CTDI(vol)), dose-length product (DLP), body diameters, noise, signal-to-noise ratio (SNR) and subjective image quality were compared. RESULTS: In the autokV group, 100 kV was automatically selected in 82 patients, 120 kV in 12 patients and 140 kV in 6 patients. Patient diameters increased with higher kV settings. The median CTDI(vol) (8.3 vs. 12.4 mGy; -33%) and DLP (594 vs. 909 mGy cm; -35%) in the entire autokV group were significantly lower than in the group with fixed 120 kV (p < 0.05 for both). Image quality remained at a constantly high level at any selected kV level. CONCLUSION: Topogram-based automated selection of the tube potential allows for significant dose savings in thoraco-abdominal trauma CT while image quality remains at a constantly high level. KEY POINTS: * Automated kV selection in thoraco-abdominal trauma CT results in significant dose savings * Most patients benefit from a 100-kV protocol with relevant DLP reduction * Constantly good image quality is ensured * Image quality benefits from higher kV when arms are positioned downward. PMID- 24816941 TI - Delayed gadolinium-enhanced MRI of the meniscus (dGEMRIM) in patients with knee osteoarthritis: relation with meniscal degeneration on conventional MRI, reproducibility, and correlation with dGEMRIC. AB - OBJECTIVES: To assess (1) whether normal and degenerated menisci exhibit different T1GD on delayed gadolinium-enhanced MRI of the meniscus (dGEMRIM), (2) the reproducibility of dGEMRIM and (3) the correlation between meniscus and cartilage T1GD in knee osteoarthritis (OA) patients. METHODS: In 17 OA patients who underwent dGEMRIM twice within 7 days, meniscus and cartilage T1GD was calculated. Meniscus pathology was evaluated on conventional MRI. T1GD in normal and degenerated menisci were compared using a Student's t-test. Reproducibility was assessed using ICCs. Pearson's correlation was calculated between meniscus and cartilage T1GD. RESULTS: A trend towards lower T1GD in degenerated menisci (mean: 402 ms; 95% CI: 359-444 ms) compared to normal menisci (mean: 448 ms; 95% CI: 423-473 ms) was observed (p = 0.05). Meniscus T1GD ICCs were 0.85-0.90. The correlation between meniscus and cartilage T1GD was moderate in the lateral (r = 0.52-0.75) and strong in the medial compartment (r = 0.78-0.94). CONCLUSIONS: Our results show that degenerated menisci have a clear trend towards lower T1GD compared to normal menisci. Since these results are highly reproducible, meniscus degeneration may be assessed within one delayed gadolinium-enhanced MRI simultaneously with cartilage. The strong correlation between meniscus and cartilage T1GD suggests concomitant degeneration in both tissues in OA, but also suggests that dGEMRIC may not be regarded entirely as sulphated glycosaminoglycan specific. KEY POINTS: dGEMRIM T1 GD can possibly be used to assess meniscal degeneration; dGEMRIM yields highly reproducible meniscal T1 GD in early stage osteoarthritic patients; Concomitant degeneration of cartilage and meniscus tissue occurs in early stage osteoarthritis; dGEMRIC cannot be regarded as entirely sulphated glycosaminoglycan specific. PMID- 24816942 TI - Emotion potentiated startle in fragile X syndrome. AB - Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We investigated the relationship between social avoidance and emotion-potentiated startle, a probe of amygdala activation, in children and adolescents with FXS, developmental disability without FXS (DD), and typical development. Individuals with FXS or DD demonstrated significantly reduced potentiation to fearful faces than a typically developing control group (p < .05). However, among individuals with FXS, social avoidance correlated positively with fearful-face potentiation (p < .05). This suggests that general intellectual disability blunts amygdalar response, but differential amygdala responsiveness to social stimuli contributes to phenotypic variability among individuals with FXS. PMID- 24816943 TI - Systematic review of articles describing experience and supports of individuals with autism enrolled in college and university programs. AB - The increase in the number of higher-functioning individuals with autism spectrum disorders (ASD) is likely to lead to an increased interest in postsecondary opportunities including degree-granting college and university programs. To provide an understanding of the current evidence-base for supporting individuals with ASD in higher education, this article reports the results of a systematic review of the literature concerning college students with ASD. Overall, 20 articles describing 69 individuals met the inclusion criteria. This small number of articles and participants indicates the scarcity of research on this topic and only two of these studies were experimental in nature. These studies described a video-self modeling intervention and a counseling intervention respectively. Eighteen "case studies" were also present in the literature that described difficulties ranging from anxiety to housing concerns. This review deliniates the limitation of our understanding of effective college programming for individuals with ASD. PMID- 24816944 TI - Facile functional analysis of insect odorant receptors expressed in the fruit fly: validation with receptors from taxonomically distant and closely related species. AB - With the advent of genomic sequences and next-generation sequencing technologies (RNA-Seq), multiple repertoires of olfactory proteins in various insect species are being unraveled. However, functional analyses are lagging behind due in part to the lack of simple and reliable methods for heterologous expression of odorant receptors (ORs). While the Xenopus oocyte recording system fulfills some of this lacuna, this system is devoid of other olfactory proteins, thus testing only the "naked" ORs. Recently, a moth OR was expressed in the majority of neurons in the antennae of the fruit fly using Orco-GAL4 to drive expression of the moth OR. Electroantennogram (EAG) was used to de-orphanize the moth OR, but generic application of this approach was brought to question. Here, we describe that this system works with ORs not only from taxonomically distant insect species (moth), but also closely related species (mosquito), even when the fruit fly has highly sensitive innate ORs for the odorant being tested. We demonstrate that Orco-GAL4 flies expressing the silkworm pheromone receptor, BmorOR1, showed significantly higher responses to the sex pheromone bombykol than the control lines used to drive expression. Additionally, we show that flies expressing an OR from the Southern house mosquito, CquiOR2, gave significantly stronger responses to the cognate odorants indole and 2-methylphenol than the "background noise" recorder from control lines. In summary, we validate the use of Orco-GAL4 driven UAS-OR lines along with EAG analysis as a simple alternative for de-orphanization and functional studies of insect ORs in an intact olfactory system. PMID- 24816946 TI - alpha-synuclein in the inner retina in parkinson disease. AB - Behavioral, electrophysiological, and imaging data reveal impaired visual processing and altered retinal morphology in Parkinson disease. Are visual changes epiphenomena? We report the presence of misfolded alpha-synuclein in the retina, not hitherto shown, in discrete retinal neurons within the inner retina. They demonstrate the histopathology that may underlie impaired vision and retinal remodeling in Parkinson disease. Furthermore, the histological localization of alpha-synuclein gives clues to the nonsynaptic mode of alpha-synuclein propagation. PMID- 24816945 TI - The pro-oxidant buthionine sulfoximine (BSO) reduces tumor growth of implanted Lewis lung carcinoma in mice associated with increased protein carbonyl, tubulin abundance, and aminopeptidase activity. AB - This study evaluated the effects of the pro-oxidant buthionine sulfoximine (BSO) and of the interaction between BSO and TETRAC, an antagonist of alphavbeta3 integrin, on tumor development and aminopeptidase (AP) activity in a murine model of implanted Lewis's carcinoma. Male CBA-C57 mice were untreated (controls) or treated with BSO (222 mg/100 mL in drinking water), TETRAC (10 mg/kg/day, i.p.), or BSO + TETRAC. BSO for 28 days and TETRAC were given for the last 20 days. Mice were subcutaneously inoculated with 1 * 10(6) Lewis carcinoma 3LL cells into the dorsum. Study variables were tumor weight (TW); Hb, as index of tumor-mediated angiogenesis; vascular endothelial growth factor (VEGF) protein abundance; protein carbonyl content; alpha-tubulin abundance; and GluAp, AlaAp, and AspAp activities. BSO produced a major decrease in TW (203 +/- 18 mg) with respect to controls (365 +/- 26) and a reduction in Hb content. The TETRAC group also showed marked reductions in TW (129 +/- 15) and Hb concentration associated with a reduced VEGF content. The BSO + TETRAC group showed a major TW reduction (125 +/- 13); although, the difference with the TETRAC group was not significant. BSO treatment increased protein carbonyl and tubulin abundance in comparison to controls. The activity of all APs was increased in the three experimental groups and was strongly and negatively correlated with TW. In conclusion, administration of BSO reduced the TW, which inversely correlated with protein carbonyl content, suggesting a loss of microtubule polymerization. The finding of a negative correlation between TW and AP activity opens up new perspectives for the study of APs as tumor growth modulators. PMID- 24816947 TI - Comparison of various adiposity indexes in women with polycystic ovary syndrome and normo-ovulatory non-hirsute women: a population-based study. AB - OBJECTIVE: Insulin resistance (IR) and metabolic disorders are common in polycystic ovary syndrome (PCOS). However, it is still not clear which adiposity marker could precisely predict metabolic syndrome (MetS) in women with PCOS and whether these indexes are different in normo-ovulatory non-hirsute women. DESIGN: A case-control study was conducted on a total of 175 Iranian subjects with PCOS and 525 normal control subjects, aged 18-45 years. METHODS: Waist circumference (WC), BMI, waist-to-hip ratio, lipid accumulation product (LAP) index, and visceral adiposity index (VAI) were examined and the homeostasis model assessment index was calculated. MetS was defined according to the joint interim statement. The receiver operating characteristic curves were used to evaluate the extent to which measures of adiposity can predict IR and MetS risk. RESULTS: LAP index and VAI are two indicators (sensitivity and PPV of 70% (LAP index) and 60% (VAI), and 80% (LAP index) and 83% (VAI) respectively) that best predict IR in women with PCOS. Among healthy women, the LAP index and WC were better markers (sensitivity and PPV of 78% (LAP index) and 75% (VAI), and 82% (LAP index) and 81% (VAI) respectively). The two most reliable indicators for prediction of MetS among PCOS and normal women were the WC and VAI (sensitivity and PPV of 83% (WC) and 81% (VAI), and 97% (WC) and 95% (VAI) respectively) and the VAI and LAP index (sensitivity and PPV of 88% (VAI) and 83% (LAP index), and 98% (VAI) and 98% (LAP index) respectively) respectively. CONCLUSIONS: While the appropriate adiposity indicators and their optimum cutoff values vary in women with PCOS, compared with the normal control subjects, the LAP index is an easily obtainable index that might be useful for screening of cardiometabolic complications among both groups. PMID- 24816948 TI - Optimal radiation shielding for beta and bremsstrahlung radiation emitted by (89)Sr and (90)Y: validation by empirical approach and Monte Carlo simulations. AB - OBJECTIVE: High-energy beta emitters such as Strontium-89 ((89)Sr) and Yttrium-90 ((90)Y) are becoming increasingly popular nuclear therapy sources in Japan for treating cancer. Various characteristics of materials must be considered when designing radiation protection device for high-energy beta emitters. We empirically measured and simulated dose equivalents of beta and bremsstrahlung radiation arising from (89)Sr and (90)Y radiation shielded with various materials and determined optimal shielding materials against these sources. METHODS: The dose equivalents of (89)Sr and (90)Y determined experimentally using an ionization chamber survey meter were compared with those of Monte Carlo simulations. The relative dose equivalents of beta and bremsstrahlung radiation separately transmitted by changing the thickness of acrylic, aluminum, iron, lead and tungsten shielding materials were simulated. RESULTS: Dose equivalents were consistent between the empirical measurements and the simulation to within +/-5%. Shielding ability was more effective in the order of tungsten, lead, iron, aluminum and acrylic against both (89)Sr and (90)Y. The amount of beta and bremsstrahlung radiation transmitted through tungsten and lead was relatively small. Although such high-density material generates much bremsstrahlung radiation, it absorbs the bremsstrahlung radiations. CONCLUSIONS: Tungsten was the optimal material for efficient shielding against (89)Sr and (90)Y radiation and preferable among operators. The present findings provide useful information about how to define an appropriate shielding strategy for high-energy beta emitters. PMID- 24816949 TI - Utilisation of novel anti-platelet agents: evidence, guidelines and proven patients' value. PMID- 24816950 TI - Utility of algorithm-based chemoradioselection in the treatment for advanced hypopharyngeal carcinoma. AB - BACKGROUND: Current organ-preserving dose-intensified modalities have apparently reached the limit of human tolerance. To optimize the therapeutic ratio, we evaluated the utility of a chemoradioselection strategy for the treatment of advanced hypopharyngeal carcinoma. METHODS: Fifty-five patients with advanced hypopharyngeal carcinoma were enrolled in our algorithm-based protocol. After 40 Gy of concurrent chemoradiation therapy (CCRT), patients who were chemoradioselected (chemoradioselected group, complete response [CR] at the primary site) received further 30 Gy of CCRT up to 70 Gy, whereas the remaining nonchemoradioselected (nonchemoradioselected group) patients underwent radical surgery. RESULTS: Based on this algorithm, 27 patients were chemoradioselected and 28 nonchemoradioselected. The 5-year cumulative disease-specific and overall survival (OS) rates were 76% and 65%, respectively. The chemoradioselected group demonstrated favorable laryngoesophageal dysfunction-free survival (77% at 3 years). CONCLUSION: Although preliminary, our results indicate that algorithm based chemoradioselection may provide a novel platform for improving the treatment of advanced hypopharyngeal carcinoma by providing the complete advantages of CCRT and radical surgical resection. PMID- 24816951 TI - Ongoing leadership and effort needed to keep the focus on improving Maori health. PMID- 24816952 TI - A Maori cultural reluctance to present for care, or a systems and quality failure? How we pose the issue, informs our solutions. PMID- 24816953 TI - Health system costs by sex, age and proximity to death, and implications for estimation of future expenditure. AB - AIMS: Health expenditure increases with age, but some of this increase is due to costs proximal to death. We used linked health datasets (HealthTracker) to determine health expenditure by proximity to death. We then determined the impact on future health expenditure projections of accounting for proximity to death in costs. METHODS: 2007 to 2009 national health event data were linked for hospitalisations, inpatient procedures, outpatient events, pharmaceuticals, laboratory tests, and primary care consultations. Each event was assigned a cost. Health expenditure by sex, age and whether in last 6 or 12 months of life or not were calculated. Future health expenditure trends were then estimated for the Statistics New Zealand median projection population counts, with 2010-12 mortality rates reducing by 2% per annum into the future. RESULTS: A total of $8.1, $8.8 and $9.2 billion dollars (inflation-adjusted to 2011 NZ$) was allocated to individual health events in HealthTracker in 2007, 2008 and 2009, respectively. Citizen costs for people not within 6 months of death ranged from $498 per person-year (10-14 year old females) to $6900 per person-year (90-94 year old males). Per person-year costs in the last 6 months of life were 10-fold higher on average, being maximal at $30,000 or more among infants and the older elderly (80+ years). Similar patterns were apparent for costs within 12 months of death. For people hypothetically exposed to these 2007-09 health system costs over their full life, the cumulative costs for a person dying at age 70 years was $113,000, and doubled to $223,000 for a person dying at age 90. The proportion of cumulative health expenditure in the last year of life declined with increasing age of death: e.g. 24%, 13% and 10% for someone aged 40, 70 and 90 respectively. Projections of future health system expenditure were overestimated by 2.3% to 3.5% in 2041 when not accounting for proximity to death in costs. CONCLUSIONS: New Zealand is fortunate to have access to rich data on health system costs. The age-specific health system costs per citizen we have calculated can be used in health expenditure projections, for cost-effectiveness analyses, and for considering how public health expenditure is distributed across the life course. PMID- 24816954 TI - Retrospective epidemiology of acute rheumatic fever: a 10-year review in the Waikato District Health Board area of New Zealand. AB - BACKGROUND: Acute rheumatic fever (ARF) is a preventable disease which remains a prominent burden of health in New Zealand, with an annual incidence comparable to that of developing countries. AIM: The aim of this study was to describe the epidemiology of ARF and recurrent ARF cases in the Waikato District Health Board (DHB) area of New Zealand from 1 January 2002 to 31 December 2011. METHODS: A total of 106 cases of ARF and four cases of recurrent ARF were identified through the Public Health Database - EpiSurv and the Hospital coding system, ICD-10. RESULTS: The overall Waikato DHB annual incidence of ARF was 3.1 per 100,000 population with Maori children aged 5-14 years experiencing higher rates of 46.1 per 100,000 population. Eighty-five percent of the cases were of Maori ethnicity, and 10% Pacific. Almost three-quarters of all cases lived in areas of the three most deprived deciles as described by the New Zealand Deprivation Index 2006. DISCUSSION: The rates of ARF seen in the Waikato DHB are comparable to that seen previously locally and nationally. High risk groups have been identified as children aged 5-14 years, Maori and Pacific ethnicity, and those living in lower socioeconomic areas which could be targeted by the Rheumatic Fever Prevention Programme (RFPP) with the intention to reduce the incidence of ARF nationally to 0.4 cases per 100,000 population by 2017. PMID- 24816955 TI - Ethnicity and revascularisation following acute coronary syndromes: a 5-year cohort study (ANZACS-QI-3). AB - BACKGROUND: Prior studies have reported higher rates of coronary revascularisation in European compared with Maori and Pacific patients. Our aim was to define the current variation by ethnicity in investigation, revascularisation and pharmacotherapy after admission with an acute coronary syndrome (ACS). METHODS: Data from consecutive New Zealand residents <80 years of age admitted to the Middlemore Hospital coronary care unit with ACS (2007 to 2012) were collected prospectively. RESULTS: Of 2666 ACS patients <80y, 51.5% were European/Other, 14.2% Maori, 16.0% Pacific, 14.8% Indian, and 3.5% Asian. Cardiac risk factors and comorbidity varied markedly by ethnicity. The overall coronary angiography rate was high (89%). After adjustment for clinical factors which influence the decision to perform angiography, European/Other patients were about 5% more likely than Maori and Pacific patients to have angiography. Overall revascularisation was highest in Asian, Indian and European/Other (76.1%, 69.1% and 68.6%), and lower in Maori and Pacific patients (58.2% and 52.9%). Non obstructive coronary disease was more common in Maori and Pacific (20.6 and 18.6%, respectively), than in European/Other, Indian and Asian patients (13.3%, 8.7% and 6.1%). After adjustment, Maori, Indian and Asian patients were as likely to receive revascularisation as European/Others, but revascularisation in Pacific patients was 13% lower. Discharge prescribing of triple preventive therapy was uniformly high across ethnic groups (overall 91%). CONCLUSIONS: There is a small unexplained variation in angiography rates across ethnic groups. Much of the observed variation in revascularisation may be due to differences in the coronary artery disease phenotype. PMID- 24816956 TI - Initiation of maternity care for young Maori women under 20 years of age. AB - AIM: To explore the lived realities of pregnant Maori women <20 years through pregnancy and motherhood, to identify barriers to, and facilitators of, access to maternity care. METHOD: Using a Kaupapa Maori research paradigm, 44 pregnant or recently pregnant Maori woman <20 years of age were recruited in two case study sites. Participants completed a series of interviews during different stages of pregnancy and motherhood. Interview transcripts were read, re-read and cross compared by the two interviewing researchers to identify emergent themes, and organised using the software programme Nvivo. Thematic data was grouped, and re grouped into topic areas for further analysis. RESULTS: Participants engaged early with health care services both to confirm their pregnancy and to initiate maternity care. Barriers to access occurred at the first contact with a lack of information, and support along the maternity care pathway to mainly community based midwifery care. Many participants felt inadequately supported to be able to identify, confirm, and enrol with a midwife or hospital care. Participants who received proactive support at the first interaction with health services had an appropriate maternity care pathway toward obtaining early and seamless maternity care. CONCLUSION: Interviews with participants identified that contrary to published literature young Maori women are engaging early with health services (GP services, school and community based youth health services) for maternity care, but system barriers from this first health contact lead to avoidable delays to them accessing a seamless maternity care pathway. There is a lack of sufficient and appropriate information and support for this young population group who have limited resources and experience to navigate through health services. These inequities in access to maternity care could be reduced through an integrated model of care that sees maternity care beginning at the first interaction with health care services. The service, primarily general practitioners, would then take responsibility for first trimester screening and navigation to a lead maternity carer. PMID- 24816957 TI - Cultural and social factors and quality of life of Maori in advanced age. Te puawaitanga o nga tapuwae kia ora tonu - Life and living in advanced age: a cohort study in New Zealand (LiLACS NZ). AB - AIM: To establish 1) the socioeconomic and cultural profile and 2) correlates of quality of life (QOL) of Maori in advanced age. METHOD: A cross sectional survey of a population based cohort of Maori aged 80-90 years, participants in LiLACS NZ, in the Rotorua and Bay of Plenty region of New Zealand. Socioeconomic and cultural engagement characteristics were established by personal interview and QOL was assessed by the SF-12. RESULTS: In total 421 (56%) participated and 267 (63%) completed the comprehensive interview. Maori lived with high deprivation areas and had received a poor education in the public system. Home ownership was high (81%), 64% had more than 3 children still living and social support was present for practical tasks and emotional support in 82%. A need for more practical help was reported by 21%. Fifty-two percent of the participants used te reo Maori me nga tikanga (Maori language and culture) daily. One in five had experienced discrimination and one in five reported colonisation affecting their life today. Greater frequency of visits to marae/sacred gathering places was associated with higher physical health-related QOL. Unmet need for practical help was associated with lower physical health-related QOL. Lower mental health related QOL was associated with having experienced discrimination. CONCLUSION: Greater language and cultural engagement is associated with higher QOL for older Maori and unmet social needs and discrimination are associated with lower QOL. PMID- 24816958 TI - Botulinum toxin versus botulinum toxin with low-dose glyceryltrinitrate for healing of chronic anal fissure: a prospective, randomised trial. AB - BACKGROUND: Chronic anal fissure (CAF) is perpetuated by high sphincter pressures and secondary local ischemia. Pharmacological approaches include topical nitrates and botulinum toxin (BT), which both help to decrease the sphincter pressure. AIMS & OBJECTIVES: The aims of the present study were to assess the efficacy and safety of BT injection and combined treatment with BT injection and lowered dose glyceryltrinitrate (GTN) cream for the treatment of CAF. We hypothesised that combined treatment would have a synergistic effect on healing. METHODS: Forty-one consecutive patients with CAF were randomly assigned to receive one of the following treatments: Group A, injection of BT (20 U into internal anal sphincter) and Group B, BT injection (20 units) and subsequent thrice daily topical applications of half-dose 0.2% GTN cream for 6 weeks. Patients were followed up at 6 and 12 weeks and were assessed for healing of anal fissure, by means of visual inspection using fissure grades; for faecal incontinence, using Cleveland Clinic incontinence scores; and for fissure pain and headache using a numeric pain rating scale. RESULTS: Fissure healing was similar in the two groups at both 6 (30% in BT and GTN and 33% in BT only) and 12 weeks (50% in BT and GTN vs 57% in BT-only group). Neither the change in pain score from 6 to 12 weeks, nor the overall level of pain was significantly different in the 2 groups. Moderate or severe headaches were suffered by 58% of patients using GTN. CONCLUSION: Single-agent treatment by means of BT injection alone was well tolerated compared with combination treatment with BT injection and GTN cream, with no significant differences in healing of CAF observed in this small study. PMID- 24816959 TI - Attitudes towards smokefree campus policies in New Zealand. AB - AIM: This study examines the level of support for a completely smokefree campus policy and other smokefree policy initiatives amongst staff and students at a New Zealand University. METHODS: Attitudes to smoking on campus, smokefree campus policies, implementation and enforcement of smokefree policies were assessed using an online survey of 332 staff and 268 students; giving a response rate of 51% from staff and 41% from students. RESULTS: Most participants had never smoked, or were past smokers; few reported being current smokers. Participants agreed that exposure to second-hand smoke is harmful, disliked being exposed to second-hand smoke on campus, and felt the university should promote a healthy work and study environment. Results indicated strong support for smokefree policies, and participants made several recommendations regarding smokefree policies. Most disagreed that compliance with a smokefree policy should be voluntary, but felt that campus security should warn people who breach the policy. CONCLUSIONS: These results provide a sound basis for university administrators to implement smokefree policies. While around half of the tertiary education institutions in New Zealand already have a completely smokefree campus policy, greater adoption of this policy by tertiary education institutions would foster realisation of the government's goal that New Zealand become a smokefree nation by 2025. A potential barrier preventing tertiary education institutions working towards a smokefree campus is a perceived risk of opposition from staff and students. Our study found strong support for smokefree campus policies; these findings should encourage other universities, polytechnics and other tertiary education providers to adopt full campus smokefree policies. PMID- 24816960 TI - Will New Zealand be smokefree by 2025? Smoking prevalence amongst a cohort of Pacific adults. AB - AIM: To examine the prevalence of smoking amongst a cohort of Pacific fathers and mothers from birth up to 11 years after the birth of their child. METHODS: Within the context of broader interviews, 1073 Pacific fathers and 1434 Pacific mothers participating in the longitudinal Pacific Islands Families (PIF) Study were surveyed about their smoking at multiple time-points of the study from 2000 until 2012. Prevalence rates of any and heavy smoking were calculated and analysed. RESULTS: Maternal prevalence rates showed a sharp decline during pregnancy and immediately postpartum, yet rates then increased gradually to pre-birth levels within one to four years. Prevalence rates for mothers showed little change between 4 and 11 years postpartum, maintaining a steady 32% for mothers. While prevalence rates for fathers show a decline from initial levels (40.3%), they still remain extremely high (37.5%) at 11 years postpartum. CONCLUSION: The minimal decline in smoking prevalence amongst this cohort is of alarming concern for Pacific families and their communities. Given the New Zealand Government's Aotearoa Smokefree 2025 goal, innovative approaches must be implemented to discover effective solutions to help Pacific communities reduce their smoking. PMID- 24816961 TI - Improving Maori health through clinical assessment: Waikare o te Waka o Meihana. AB - Health professionals play an important role in addressing indigenous health inequalities. This paper describes the further development and a new conceptualisation of the Meihana model (2007) and the Hui process (2011), which together have formed the indigenous health framework in the University of Otago, Christchurch undergraduate medical education programme for 4th-6th year medical students over the past 5 years. The components of the framework are defined followed by description of their application to clinical assessment. The indigenous health framework has been evaluated by medical students, health practitioners, Maori patients and whanau over this time and has been rated favourably as a clinically relevant framework that supports health practitioners to work effectively with Maori patients and whanau. PMID- 24816962 TI - Metronidazole-induced encephalopathy: an uncommon scenario. AB - Metronidazole can produce neurological complications although it is not a common scenario. We present a case where a patient developed features of encephalopathy following prolonged metronidazole intake. Magnetic resonance imaging (MRI) brain showed abnormal signal intensity involving both dentate nuclei of cerebellum and splenium of corpus callosum. The diagnosis of metronidazole toxicity was made by the MRI findings and supported clinically. PMID- 24816963 TI - Medical image. Button battery ingestion. PMID- 24816964 TI - The future prospects of regulating in the interest of public health under the Trans Pacific Partnership Agreement: the example of agricultural antibiotic use. PMID- 24816965 TI - Managing meningococcal disease. PMID- 24816966 TI - Heat stress is associated with reduced health status in pulmonary arterial hypertension: a prospective study cohort. AB - BACKGROUND: Summer heat waves with temperature extremes are becoming more frequent with growing numbers in morbidity and mortality in patients with respiratory diseases. The aim of this study was to evaluate the ramifications of heat stress (temperature >25 degrees C) on the health status of patients with pulmonary arterial hypertension (PAH). METHODS: Fifteen patients with PAH (mean age = 66.7 +/- 5.2 years) continuously wore an accelerometer from April 1 to September 30, 2011, and their daily step count was recorded. In addition, patients kept a diary to record data on seven standardized questions regarding their daily symptoms. Echocardiography, 6-minute walk test, NTproBNP, and Modified Medical Research Council Scale (MMRC) were assessed at baseline and at the end of the study after 6 months. RESULTS: On heat-stress days, patients showed significantly more symptoms and lower total steps/day compared to thermal comfort days (3,995 +/- 2,013 steps/day vs. 5,567 +/- 2,434 steps/day, respectively; P < 0.001). There was a significant negative correlation between total steps/day and Temp(max) (R = -0.47; P < 0.001) and humidity (R = -0.34; P < 0.001). A significant positive correlation was found between daily symptoms and Temp(max) (R = +0.79; P < 0.001) and humidity (R = +0.23; P < 0.001). CONCLUSIONS: Heat stress is associated with a compromised clinical status in patients with PAH. Adaptation strategies must be implemented to prevent heart related morbidity, including therapeutic adjustments and adequate room cooling in the patient's home and at the hospital. PMID- 24816967 TI - Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation may represent a unique phenotype, possibly with shared features of COPD and asthma. The role of exhaled nitric oxide (eNO) in identifying COPD patients with sputum eosinophilia was examined in this study. METHODS: Ninety COPD patients without past medical history of asthma or allergic diseases were prospectively enrolled, and their eNO, lung function, and cellular profile of induced sputum were measured. Eosinophil cationic protein and IgE in sputum and venous blood also were determined. Subjects with and without sputum eosinophilia (>3 %) were compared. The role of eNO in the prediction of sputum eosinophilia was assessed in a logistic regression model. RESULTS: Patients with sputum eosinophilia had significantly higher levels of eNO (29 vs. 18 ppb, p = 0.01) than those without. The difference in serum total IgE (168 vs. 84.9 IU/ml, p = 0.057) and percentages of positive allergen test results (48.3 vs. 29.5 %, p = 0.082) showed a trend toward significance. The sputum eosinophil level was significantly correlated to the eNO level (r = 0.485, p < 0.001). The eNO level at the cutoff of 23.5 ppb had the maximum sum of sensitivity (62.1 %) and specificity (70.5 %). The unadjusted and adjusted odds ratios of a higher eNO level (>23.5 ppb) in the prediction of sputum eosinophilia were 3.909 (confidence interval (CI) 1.542-9.91, p = 0.004) and 4.329 (CI 1.306-14.356, p = 0.017), respectively. CONCLUSIONS: eNO is a good marker to identify COPD patients with eosinophilic airway inflammation. PMID- 24816968 TI - Collateral damage: depressive symptoms in the partners of COPD patients. AB - BACKGROUND: Depression is a frequent comorbidity in COPD patients and is associated with greater physical impairment, increased health-care utilization, and worse outcomes. The presence of depressive symptoms in the partners of COPD patients has not been evaluated. METHODS: We evaluated the partners of 230 consecutive COPD patients included in a prospective study. Depressive symptoms were evaluated using Beck's Depression Inventory (BDI) on the first day of admission for COPD exacerbation. Patients were followed-up for 1 year. RESULTS: Significant depressive symptoms were present in 39.6 % of the COPD patients and in 40.9 % of their partners. Beck scores were higher in the partners of patients with severe airflow obstruction and in those with >=2 exacerbations and >=1 hospitalizations for COPD exacerbation during the 1-year follow-up. The BDI score of the patients' partners was significantly correlated with the BDI score of the COPD patients (r s = 0.422). In multivariate analysis, depressive symptoms in the COPD patients were an independent predictor of depressive symptoms in their partners (OR 4.136, 95 % CI 1.991-8.594; p < 0.001). CONCLUSIONS: A large proportion of the partners of COPD patients present significant depressive symptoms. The identification of those patients and their partners represents a possible target for intervention. PMID- 24816969 TI - Neutrophil elastase gene polymorphisms: modulators of response to therapy in childhood bronchiectasis? AB - BACKGROUND: The aim of this study was to investigate polymorphisms in the promoter region of the neutrophil elastase (ELANE) gene as potential modulators of the therapeutic response in children with idiopathic bronchiectasis. METHODS: The study included 48 children between 5 and 17 years old who were diagnosed with idiopathic bronchiectasis based on high-resolution computed tomography of the thorax. In all patients therapy included administration of antibiotics, anti inflammatory drugs, expectorants, and postural drainage. Response to therapy was evaluated by the change in FeNO levels before and after administration of therapy. The ELANE promoter region polymorphisms were analyzed by PCR-direct DNA sequencing. RESULTS: According to the predicted activity of ELANE genotypes, subjects were divided into two groups: low/intermediate activity (n = 18) and high activity (n = 30). Subjects in the group with high-activity genotype had higher initial FeNO levels and this difference was statistically significant (t = 2.906; p = 0.006). The difference between FeNO levels before and after therapy was also statistically significantly higher in children with high-activity genotype (t = 3.329; p = 0.002). Statistically significant correlation was observed between the change in FeNO levels and ELANE genotypes (r = 0.350; p = 0.015). CONCLUSION: Children with high-activity genotype had higher initial FeNO levels and showed better response to therapy than children with low/intermediate activity genotypes. PMID- 24816970 TI - Inherited thrombotic thrombocytopenic purpura in children. AB - Congenital thrombotic thrombocytopenic purpura (TTP) or Upshaw-Schulman syndrome is caused by homozygous or compound heterozygous mutations in the ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) gene. We investigated 30 patients with congenital TTP and analyzed clinical data and underlying ADAMTS-13 mutations. All patients showed virtually no ADAMTS-13 activity in plasma. Individual disease burden ranged from mild courses with rare episodes of mild thrombocytopenia to severe courses with chronic kidney disease and central nervous system (CNS) lesions. Two patients died due to complications of TTP. If initiated in a timely manner, plasma transfusions offer a reliable treatment to prevent organ damage. We identified 30 different causative mutations in the ADAMTS-13 gene. Our data do not support the idea of a tight correlation between ADAMTS-13 genotype and severity of disease. The type and magnitude of exogenous triggers for acute bouts of TTP as well as endogenous individual factors participating in the inflammatory response likely represent the foremost determinants of individual clinical courses. Future developments should aim at improving early diagnosis of TTP. To improve feasibility of prophylaxis and treatment of congenital TTP, recombinant ADAMTS-13 therapeutics are highly anticipated. PMID- 24816971 TI - Reassembly of JIP1 scaffold complex in JNK MAP kinase pathway using heterologous protein interactions. AB - Formation of signaling protein complexes is crucial for proper signal transduction. Scaffold proteins in MAP kinase pathways are thought to facilitate complex assembly, thereby promoting efficient and specific signaling. To elucidate the assembly mechanism of scaffold complexes in mammals, we attempted to rationally rewire JIP1-dependent JNK MAP kinase pathway via alternative assembly of JIP1 complex. When JIP1-JNK docking interaction in the complex was replaced with heterologous protein interaction domains, such as PDZ domains and JNK-binding domains, a functional scaffold complex was reconstituted, and JNK signaling was rescued. Reassembly of JIP1 complex using heterologous protein interactions was sufficient for restoring of JNK MAP kinase pathway to induce signaling responses, including JNK activation and cell death. These results suggest a simple yet modular mechanism for JIP1 scaffold assembly in mammals. PMID- 24816972 TI - EELS tomography in multiferroic nanocomposites: from spectrum images to the spectrum volume. AB - Electron Energy Loss Spectroscopy (EELS) in a transmission electron microscope offers the possibility of extracting high accuracy maps of composition and electronic properties through EELS spectrum images (EELS-SI). Acquiring EELS-SI for different tilt angles, a 3D tomographic reconstruction of EELS information can be achieved. In the present work we show that an EELS spectrum volume (EELS SV), a 4D dataset where every voxel contains a full EELS spectrum, can be reconstructed from the EELS-SI tilt series by the application of multivariate analysis. We apply this novel approach to characterize a nanocomposite material consisting of CoFe2O4 nanocolumns embedded in a BiFeO3 matrix grown on a LaNiO3 buffered LaAlO3 (001) substrate. PMID- 24816975 TI - Interobserver agreement in assigning IOTA color score to adnexal masses using three-dimensional volumes or digital videoclips: potential implications for training. AB - OBJECTIVE: To estimate the interobserver agreement between a trainer and trainees in assigning the International Ovarian Tumor Analysis (IOTA) color score to adnexal masses using three-dimensional (3D) volumes and videoclips. METHODS: Fifty-one digital videoclips and 3D volumes of a non-consecutive series of adnexal masses were used for this study. One trainer and four trainees evaluated first the 3D volume and 1 week later a videoclip from the same mass. They had to assign IOTA color scores according to their impression of the amount of color content in each case. Interobserver agreement between trainer and trainees was assessed using Cohen's weighted kappa index with 95% CIs and percentage of agreement. RESULTS: When using 3D volumes, interobserver agreement was good for three out of four pairs of comparisons and very good for one (kappa values of 0.70, 0.68, 0.81 and 0.71 for trainees A, B, C and D, respectively). When using videoclips, interobserver agreement was very good for two out of four pairs of comparisons and good for two (kappa values of 0.84, 0.80, 0.68 and 0.86 for Trainees A, B, C and D, respectively). CONCLUSION: Evaluation of IOTA color scores in adnexal masses using either videoclips or 3D volumes is reproducible even in the hands of trainees after a short training program. PMID- 24816974 TI - The protective arms of the renin-angiontensin system in stroke. AB - It is quite well established that activation of the so-called protective arms of the renin-angiotensin system (RAS), involving both AT2 and Mas receptors, provides a counter-regulatory role to AT1 receptor overactivity that may drive pathological changes in the cardiovascular system. In this brief review, we will focus on recent evidence that identifies at least three different pathways that may be effective in the setting of stroke and may be complementary with AT1 receptor blockade. Such mechanisms include AT2 receptor stimulation, Mas receptor stimulation and insulin-regulated aminopeptidase blockade. This report highlights recent data demonstrating striking neuroprotective effects in preclinical models of stroke targeting each of these pathways, which may pave the way for translational opportunities in this field. PMID- 24816976 TI - [Influence of surgeon experience in total hip arthroplasty. Dependence on operating time and complication risk]. AB - BACKGROUND: As a consequence of limited personnel and financial resources, the increase in total hip arthroplasties places higher demands on orthopedic surgeons. OBJECTIVES: In order to maintain high quality treatment, the correlation between surgical experience, duration of surgery and risk of complications was examined. MATERIAL AND METHODS: The surgery time and, if applicable, complications (until discharge from hospital) of 1129 total hip arthroplasties over a period of 4 years were evaluated retrospectively. RESULTS: The group of most experienced surgeons needed an average time of 53.2 +/- 17.6 min for each implantation, followed by moderately experienced surgeons (74.5 +/- 25.5 min) and less experienced surgeons (80.8 +/- 21.9 min). Of all included cases, a total of 41 complications until discharge from hospital occurred. The number of complications increased with duration of surgery, whereby the risk of complications was significantly lower for shorter surgery times conducted by the most experienced surgeons as well as moderately experienced surgeons. The complication risk of less experienced surgeons remained constant independent of surgery duration. CONCLUSION: These results underline the recommendations of the German Endocert system, which determine a minimum number of total joint arthroplasties as a quality indicator not only for hospitals but also for individual surgeons. PMID- 24816977 TI - [Computer-assisted systems in total knee arthroplasty. Useful aid or only additional costs]. AB - BACKGROUND: The primary goal of computer-assisted surgery (CAS) in total knee arthroplasty is to increase the accuracy in terms of prosthesis positioning. In theory, this would lead to longer implant survival and a reduction of malpositioning. Thus, a better clinical outcome and lower revision rates would be expected. However, the necessary technical equipment represents significant additional effort and cost factors which are not included in the current diagnosis-related groups (DRG) system. OBJECTIVE: The objective of this article is a critical review of the current literature to examine whether these costs are reasonable by taking the additional benefits of the technology into account. METHODS: This review is based on a selective PubMed search on CAS and navigation in primary total knee arthroplasty. RESULTS: The current evidence base on CAS suggests that at least the primary outcome parameter, the improvement of the radiological alignment, is achieved by the technique. However, the claimed secondary effects are not yet proven. In particular, an improvement of clinical outcome and patient satisfaction has not been demonstrated so far. Furthermore, there is some evidence of increased complication rates by the use of CAS. CONCLUSION: Against this background and with respect to further cost-benefit analyses, the technology has to be reviewed critically. In particular, low-volume units do not seem to benefit from the use of CAS. However, the assessment of long term effects is still pending. PMID- 24816978 TI - [Risk factors for failure of osteosynthesis. After periprosthetic fractures of the knee joint]. AB - BACKGROUND: The increasing number of implantations of total knee endoprostheses shows a correlation with an increase in revision operations and periprosthetic fractures. OBJECTIVE: This article presents strategies for prevention of complications after open reduction internal fixation (ORIF) of periprosthetic fractures in addition to the classification of periprosthetic fractures of the knee joint. THERAPY STRATEGIES: Osteosynthetic treatment is only applicable in some of the cases. Although special periprosthetic, angle locking plates are available for osteosynthesis, treatment of periprosthetic fractures of the knee joint remains a challenge with a high complication rate. If the prosthesis becomes loosened, the prosthesis should be replaced and ORIF should not be performed. RISK FACTORS: The risk factors for failure of osteosynthesis include the prosthesis model and the associated reduction of residual bone and the mostly osteoporotic bone structures. PMID- 24816979 TI - [Failure analysis as basis for quality assurance strategies in implant technology]. AB - BACKGROUND: Implant safety is a topic gaining more and more public interest. Implants are safety relevant medical devices which in the case of failure can lead to life-threatening situations. OBJECTIVES: A well-founded failure analysis requires expert knowledge not only of materials and implant design but also a qualified explantation procedure and storage conditions. METHODS: A selective literature search was carried out putting the main emphasis on implant failure analysis supplemented with own investigations. RESULTS: The reasons for implant breakdown are mostly failures of materials and in the manufacturing process. In some cases false material combinations can lead to tribocorrosion effects under cyclic loading. CONCLUSION: The increased level of knowledge gained from complex analyses of failed implants produces valuable evidence for better quality management. PMID- 24816980 TI - [E-learning in orthopedics and traumatology. A comparative pilot study on acceptance and knowledge acquisition among users and non-users]. AB - BACKGROUND: Additional internet-based learning tools (e-learning) are successfully used in the curricula of many disciplines and are highly accepted among students. However, in orthopedics and traumatology e-learning is underrepresented and scientific papers are rare. The aim of the present pilot study was to evaluate the acceptance of the e-learning module network for students in traumatology and orthopedics (NESTOR) among users and non-users and to analyze the effect of this additional learning tool on knowledge acquisition. MATERIAL AND METHODS: A total of 544 students were asked to complete evaluation questionnaires at the end of two semesters using different ones for NESTOR users and non-users. The gain of knowledge was analyzed by two written knowledge tests (pre-post test, 20 multiple choice questions) at the beginning and end of the semester comparing these two groups. RESULTS: A total of 191 students took part in the evaluation and 152 completed both written tests. The NESTOR users showed a high acceptance of the e-learning system and non-users considered e-learning beneficial as well. Reasons given for not using NESTOR were lack of time, lack of information about the existence of NESTOR and a lack of interest in this discipline and e-learning in general. Both groups significantly increased their level of knowledge during the course of the semester (p < 0.01), whereas users scored significantly higher in the post-test (p < 0.05). CONCLUSION: The presented data support the high acceptance among users and the benefit of the e learning project NESTOR in teaching students in orthopedics and traumatology. Based on experience and these results the permanent implementation of an additional e-learning module in the curriculum can be recommended for other faculties. In this process the critical comments of the non-users determined in the present study should be addressed. PMID- 24816981 TI - [Long-term results of reconstructive surgery in infantile cerebral palsy patients with high hip dislocation: is hip screening necessary?]. AB - BACKGROUND: Hip dislocation as a result of neurogenic hip displacement is a common focal motor symptom in children with infantile cerebral palsy (ICP). In addition to contracture of the hip joint, in up to 65 % of cases patients suffer from pain which leads to further loss of function and often to limitations in important basic functions, such as lying, care, sitting, standing and transfer. METHODS: In order to avoid hip dislocation and to be able to implement therapy at an early stage, screening programs have been developed in recent years which clearly demonstrate the risks of hip displacement in ICP depending on the ability to walk. An investigation of the natural course is practically impossible because as a rule patients with painful neurogenic hip displacement receive surgical therapy. PATIENTS: In this study 96 patients with high hip dislocation grade IV on the Tonnis classification were included and 68 could be followed up. The average age at the time of surgery was 10.9 years and the mean follow-up period was 7.7 years. In the postoperative course 6 out of 91 reconstructed hips became redislocated and a proximal femoral resection was carried out in one female patient. The migration index according to Reimers was 14.0 % at the time of the follow-up examination. CONCLUSION: Revision procedures can be avoided by screening programs. These should be strived for so that the neuro-orthopedic treatment on operation planning is not first initiated when pain occurs and revision procedures, such as angulation osteotomy or proximal femoral resection can be avoided. The reconstruction should also involve minimal deformation of the femoral head. In order to implement this, the interdisciplinary cooperation between neuropediatricians, social pediatriatricians and neuro-orthopedists should be intensified in the future. PMID- 24816982 TI - NDRG2 as a marker protein for brain astrocytes. AB - The protein NDRG2 (N-myc downregulated gene 2) is expressed in astrocytes. We show here that NDRG2 is located in the cytosol of protoplasmic and fibrous astrocytes throughout the mammalian brain, including Bergmann glia as observed in mouse, rat, tree shrew, marmoset and human. NDRG2 immunoreactivity is detectable in the astrocytic cell bodies and excrescencies including fine distal processes. Glutamatergic and GABAergic nerve terminals are associated with NDRG2 immunopositive astrocytic processes. Muller glia in the retina displays no NDRG2 immunoreactivity. NDRG2 positive astrocytes are more abundant and more evenly distributed in the brain than GFAP (glial fibrillary acidic protein) immunoreactive cells. Some regions with very little GFAP such as the caudate nucleus show pronounced NDRG2 immunoreactivity. In white matter areas, NDRG2 is less strong than GFAP labeling. Most NDRG2 positive somata are immunoreactive for S100beta but not all S100beta cells express NDRG2. NDRG2 positive astrocytes do not express nestin and NG2 (chondroitin sulfate proteoglycan 4). The localization of NDRG2 overlaps only partially with that of aquaporin 4, the membrane-bound water channel that is concentrated in the astrocytic endfeet. Reactive astrocytes at a cortical lesion display very little NDRG2, which indicates that expression of the protein is reduced in reactive astrocytes. In conclusion, our data show that NDRG2 is a specific marker for a large population of mature, non-reactive brain astrocytes. Visualization of NDRG2 immunoreactive structures may serve as a reliable tool for quantitative studies on numbers of astrocytes in distinct brain regions and for high-resolution microscopy studies on distal astrocytic processes. PMID- 24816983 TI - Regulation of osteoarthritis-associated key mediators by TNFalpha and IL-10: effects of IL-10 overexpression in human synovial fibroblasts and a synovial cell line. AB - Synovial fibroblasts (SF) contribute to the pathogenesis of osteoarthritis (OA), but the effects of intra-articular cytokines on SF are not completely understood. The aim of this study was to characterize the interplay between tumor necrosis factor (TNF)alpha and the anti-inflammatory interleukin (IL)-10. Non-immortalized human SF and SF of the human cell line K4IM were stimulated with recombinant TNFalpha, IL-10, or TNFalpha + IL-10 (10 ng/ml each) for 24 h or transduced with an adenoviral vector overexpressing human IL-10 (hIL-10) and subsequently treated with 10 ng/ml TNFalpha for 24 h. Effects on the gene expression and protein synthesis of IL-6, IL-10, matrix metalloproteinases (MMP)-1, -3, type I collagen, beta1-integrin, and CD44 were investigated via real-time detection polymerase chain reaction, immunofluorescence labeling, flow cytometry, and Western blotting. IL-10 release by transduced SF was confirmed with enzyme-linked immunosorbent assay. Both cell populations were activated by TNFalpha and by TNFalpha + IL-10, increasing their gene expression and protein synthesis of IL-6, IL-10, MMP-1, and MMP-3 and altering the synthesis of type I collagen, beta1 integrin, and CD44. hIL-10 overexpression greatly elevated the gene expression and protein synthesis of IL-10. However, transduction did not significantly affect the gene expression of IL-6, MMP-1, and MMP-3 in SF. The increased expression of pro-inflammatory and catabolic mediators in TNFalpha-activated SF indicates their role in OA pathogenesis, suggesting they are a potential therapeutic target. Although the vigorousness of the responses of non immortalized SF and K4IM clearly differ, the K4IM cell line seems to be a suitable model for non-immortalized human SF. PMID- 24816984 TI - Chromatin dynamics from S-phase to mitosis: contributions of histone modifications. AB - This review focuses on the major protein moiety of chromosomes, i.e., the histone proteins, on the contribution of their posttranslational modification to structural and functional chromatin dynamics, on the acetylation and methylation of lysine residues, and on the phosphorylation of serine or threonine with respect to various steps during the cell cycle. PMID- 24816985 TI - Changes in PTTG1 by human TERT gene expression modulate the self-renewal of placenta-derived mesenchymal stem cells. AB - In addition to their differentiation potential, self-renewal capability is an important characteristic of stem cells. The limited self-renewal activity of mesenchymal stem cells is the greatest obstacle to the application of stem cell therapy in regenerative medicine. The human TERT gene enhances the self-renewal of MSCs, but the mechanism of self-renewal and the interactions among TERT-gene related molecules remain unknown. The objectives of this study were to generate immortalized MSCs derived from MSCs isolated from placenta (naive) by human TERT gene transfection with the AMAXA gene delivery system, to compare their characteristics, and to investigate whether increased TERT expression affected the pituitary tumor transforming gene (PTTG1; also known as securin), which is involved in chromosome segregation during mitosis. TERT-immortalized cells (TERT+) with a prolonged life span displayed high PTTG1 expression. TERT+ cells also retained the stemness capacity and multipotency of naive cells and displayed high PTTG1 expression. However, down-regulation of PTTG1 by treatment with short interfering RNA induced cell senescence and decreased telomerase activity. Moreover, TERT bound to PTTG1 formed complexes with chaperones such as Ku70 and heat shock protein 90. Thus, placental MSCs immortalized by TERT gene transfection display differentiation potential and exhibit enhanced self-renewal through a balanced interaction of PTTG1 and chaperones. The interaction between TERT and PTTG1 by association of Ku70 might be important for the enhancement of the limited self-renewal activity of MSCs and for understanding the regulatory mechanisms of self-renewal. PMID- 24816986 TI - In situ hybridization analysis of the temporospatial expression of the midkine/pleiotrophin family in rat embryonic pituitary gland. AB - Pituitary gland development is controlled by numerous signaling molecules, which are produced in the oral ectoderm and diencephalon. A newly described family of heparin-binding growth factors, namely midkine (MK)/pleiotrophin (PTN), is involved in regulating the growth and differentiation of many tissues and organs. Using in situ hybridization with digoxigenin-labeled cRNA probes, we detected cells expressing MK and PTN in the developing rat pituitary gland. At embryonic day 12.5 (E12.5), MK expression was localized in Rathke's pouch (derived from the oral ectoderm) and in the neurohypophyseal bud (derived from the diencephalon). From E12.5 to E19.5, MK mRNA was expressed in the developing neurohypophysis, and expression gradually decreased in the developing adenohypophysis. To characterize MK-expressing cells, we performed double-staining of MK mRNA and anterior pituitary hormones. At E19.5, no MK-expressing cells were stained with any hormone. In contrast, PTN was expressed only in the neurohypophysis primordium during all embryonic stages. In situ hybridization clearly showed that MK was expressed in primitive (immature/undifferentiated) adenohypophyseal cells and neurohypophyseal cells, whereas PTN was expressed only in neurohypophyseal cells. Thus, MK and PTN might play roles as signaling molecules during pituitary development. PMID- 24816987 TI - Epigenetics in esophageal cancers. AB - Esophageal cancers are a challenging upper gastrointestinal tract tumor entity for interdisciplinary oncology. For the two main histotypes, namely esophageal squamous cell carcinomas and Barrett's adenocarcinomas, several genetic aberrations have been shown to contribute to carcinogenesis and progression as well as to represent potential novel targets for therapeutic intervention. This is paralleled by growing insight into epigenetic alterations of esophageal cancers. Studies involving the analyses of human tissue specimens predominantly describe altered patterns of miRNA expression, DNA methylation patterns, and histone marks levels. This review provides a critical update on this increasing knowledge of epigenetic alteration in esophageal cancers by specifically focusing on the translational aspects of epigenetic analyses from human tissue specimens. PMID- 24816988 TI - Dexamethasone-related osteogenic differentiation of dental follicle cells depends on ZBTB16 but not Runx2. AB - Dental follicle cells (DFCs) can be artificially differentiated into mineralizing cells. With a dexamethasone-based differentiation protocol, transcription factors ZBTB16 and NR4A3 are highly upregulated but Runx2 and other osteogenic marker genes are not. Previous studies have suggested the involvement of a Runx2 independent differentiation pathway. The objective of this study is to further elucidate this mechanism. Differentiation of DFCs was examined by alkaline phosphatase (ALP) staining and ALP activity measurement, by Alizarin Red S staining and by real-time reverse transcription plus the polymerase chain reaction. ZBTB16 was overexpressed by using a transient transfection method. Resulting genome-wide gene expression changes were assessed by microarray. ZBTB16 and Runx2 were inhibited by short interfering RNA transfection. Promoter binding of ZBTB16 was evaluated by chromatin immunoprecipitation. Downregulation of Runx2 had no effect on dexamethasone-induced differentiation but was effective on BMP2 induced differentiation. Downregulation of ZBTB16, however, impaired dexamethasone-induced differentiation. Genes that were upregulated by dexamethasone induction were also upregulated by ZBTB16 overexpression. Genes that were not upregulated during dexamethasone-induced differentiation were also not regulated by ZBTB16 overexpression. ZBTB16 bound directly to the promoter regions of osterix and NR4A3 but not that of Runx2. Overexpression of ZBTB16 led to changes in the gene expression profile, whereby upregulated genes were overrepresented in osteogenesis-associated biological processes. Our findings suggest that, in DFCs, a Runx2-independent differentiation mechanism exists that is regulated by ZBTB16. PMID- 24816990 TI - Chirality and chiroptical properties of amyloid fibrils. AB - Chirality of amyloid fibrils-linear beta-sheet-rich aggregates of misfolded protein chains-often manifests in morphological traits such as helical twist visible in atomic force microscopy and in chiroptical properties accessible to vibrational circular dichroism (VCD). According to recent studies the relationship between molecular chirality of polypeptide building blocks and superstructural chirality of amyloid fibrils may be more intricate and less deterministic than previously assumed. Several puzzling experimental findings have put into question earlier intuitive ideas on: 1) the bottom-up chirality transfer upon amyloidogenic self-assembly, and 2) the structural origins of chiroptical properties of protein aggregates. For example, removal of a single amino acid residue from an amyloidogenic all-L peptide was shown to reverse handedness of fibrils. On the other hand, certain types of amyloid aggregates revealed surprisingly strong VCD spectra with the sign and shape dependent on the conditions of fibrillation. Hence, microscopic and chiroptical studies have highlighted chirality as one more aspect of polymorphism of amyloid fibrils. This brief review is intended to outline the current state of research on amyloid-like fibrils from the perspective of their structural and superstructural chirality and chiroptical properties. PMID- 24816989 TI - The role of 5-hydroxymethylcytosine in human cancer. AB - The patterns of DNA methylation in human cancer cells are highly abnormal and often involve the acquisition of DNA hypermethylation at hundreds or thousands of CpG islands that are usually unmethylated in normal tissues. The recent discovery of 5-hydroxymethylcytosine (5hmC) as an enzymatic oxidation product of 5 methylcytosine (5mC) has led to models and experimental data in which the hypermethylation and 5mC oxidation pathways seem to be connected. Key discoveries in this setting include the findings that several genes coding for proteins involved in the 5mC oxidation reaction are mutated in human tumors, and that a broad loss of 5hmC occurs across many types of cancer. In this review, we will summarize current knowledge and discuss models of the potential roles of 5hmC in human cancer biology. PMID- 24816991 TI - An upstream open reading frame regulates LST1 expression during monocyte differentiation. AB - The regulation of gene expression depends on the interplay of multiple factors at the transcriptional and translational level. Upstream open reading frames (uORFs) play an important role as translational repressors of main ORFs and their presence or usage in transcripts can be regulated by different mechanisms. The main objective of the present study was to assess whether uORFs regulate the expression of the MHC class III gene LST1. We report that expression of LST1 is tightly regulated by alternative transcription initiation and the presence of an uORF in the 5'-UTR of transcripts. Specifically, using EGFP reporter constructs in human HeLa and HEK-293T cells and flow cytometry as well as western blot analysis we found the uORF to reduce the expression of the main ORF by roughly two-thirds. Furthermore, we were able to correlate a previously detected increase in LST1 protein expression during monocyte differentiation with an increase of transcription initiation at an alternative exon that does not contain an uORF. PMID- 24816992 TI - Microbes versus microbes: control of pathogens in the food chain. AB - Foodborne illness continues as a considerable threat to public health. Despite improved hygiene management systems and increased regulation, pathogenic bacteria still contaminate food, causing sporadic cases of illness and disease outbreaks worldwide. For many centuries, microbial antagonism has been used in food processing to improve food safety. An understanding of the mode of action of this microbial antagonism has been gained in recent years and potential applications in food and feed safety are now being explored. This review focuses on the potential opportunities presented, and the limitations, of using microbial antagonism as a biocontrol mechanism to reduce contamination along the food chain; including animal feed as its first link. (c) 2014 Society of Chemical Industry. PMID- 24816993 TI - Segmental analysis of congenital heart disease: putting the "puzzle" together with computed tomography. AB - Advances in surgical and medical treatment for congenital heart disease have resulted in greater life expectancy. As a result, there has been an increase in the utilization of cross-sectional imaging for diagnosis and management of complex congenital heart disease. This manuscript describes a morphological and sequential segmental approach to deciphering the code of complex congenital heart defects in cross-sectional imaging, mostly computed tomography. This manuscript will review approaches to differentiate types of transposition, the anatomic relationships of cardiac structures, and the application of these relationships in the description of complex congenital heart disease. PMID- 24816994 TI - Confined H2O molecules as local probes of pressure-induced amorphisation in faujasite. AB - Confined H2O molecules act as local probes for depressurization phenomena during the pressure induced amorphisation of faujasite NaX at which the OH stretching frequency first decreases and then increases almost to its room pressure value upon further compression. Pair distribution function (PDF) analysis provides evidence that amorphisation corresponds to a collapse of the structure around hydrated sodium cations with strong distortion of the secondary building units (double six-membered rings, sodalite cages). Both the use of guest molecules as local probes in far- and mid-infrared spectroscopy, where we correlate intermolecular water H bonding vibrations and internal mode behaviour under confinement, and PDF analysis could be of great use to study the mechanical behaviour of other hydrated materials. PMID- 24816995 TI - Less is more: development and evaluation of an interactive e-atlas to support anatomy learning. AB - An Interactive electronic Atlas (IeA) was developed to assist first-year nursing students with interpretation of laboratory-based prosected cadaveric material. It was designed, using pedagogically sound principles, as a student-centered resource accessible to students from a wide range of learning backgrounds. It consisted of a highly simplified interactive interface limited to essential anatomical structures and was intended for use in a blended learning situation. The IeA's nine modules mirrored the body systems covered in a Nursing Biosciences course, with each module comprising a maximum of 10 pages using the same template: an image displaying a cadaveric specimen and, in most cases, a corresponding anatomical model with navigation panes (menus) on one side. Cursor movement over the image or clicking the menu highlighted the structure with a transparent overlay and revealed a succinct functional description. The atlas was complemented by a multiple-choice database of nearly 1,000 questions using IeA images. Students' perceptions of usability and utility were measured by survey (n = 115; 57% of the class) revealing mean access of 2.3 times per week during the 12-week semester and a median time of three hours of use. Ratings for usability and utility were high, with means ranging between 4.24 and 4.54 (five-point Likert scale; 5 = strongly agree). Written responses told a similar story for both usability and utility. The role of providing basic computer-assisted learning support for a large first-year class is discussed in the context of current research into student-centered resources and blended learning in human anatomy. PMID- 24816996 TI - Apolipoprotein B and non-HDL cholesterol are more powerful predictors for incident type 2 diabetes than fasting glucose or glycated hemoglobin in subjects with normal glucose tolerance: a 3.3-year retrospective longitudinal study. AB - The association between atherogenic dyslipidemia (AD) and incident type 2 diabetes (T2D) in the low-risk group for T2D has not yet been determined. The aims of this study were to investigate whether AD, characterized by increased serum apoB and non-HDL cholesterol, could predict the development of T2D in subjects with normal glucose tolerance (NGT). A total of 84,394 subjects with NGT (48,906 men and 35,488 women), aged 20-89 years (mean age 38.4 years), were enrolled in this study and were followed for a mean duration of 3.3 years. ApoB and non-HDL cholesterol levels showed stronger associations with the development of T2D compared with conventional lipid measurements and their ratios (HR per 1 SD (95 % CI) 1.27 (1.23-1.30) and 1.27 (1.24-1.29), respectively, both P < 0.001). In multivariate Cox regression models, both apoB and non-HDL cholesterol were associated with the development of T2D, independent of other risk factors for T2D, fasting serum glucose, HbA1c, and conventional lipid measurements such as triglycerides and HDL cholesterol (HR per 1-SD (95 % CI) 1.16 (1.11-1.21) and 1.15 (1.11-1.19), respectively, both P < 0.001). However, fasting serum glucose was not associated with the development of T2D in these models. In conclusion, AD was more closely associated with the development of T2D than fasting glucose or glycated hemoglobin in subjects with NGT. PMID- 24816997 TI - Efficacy of real-time continuous glucose monitoring on glycaemic control and glucose variability in type 1 diabetic patients treated with either insulin pumps or multiple insulin injection therapy: a randomized controlled crossover trial. AB - BACKGROUND: The aim of this study was to determine the efficacy of real-time continuous glucose monitoring in T1D patients treated with insulin pump therapy or multiple daily insulin therapy. METHODS: Twenty adult patients (ten insulin pump therapy and ten multiple daily insulin) with poor glycaemic control (HbA1c > 8.0%) were randomized into two groups for 6 months: the continuous glucose monitoring arm (using real-time continuous glucose monitoring) and the SMBG arm. After 2 months of wash-out, the participants crossed over. The primary outcome was HbA1c reduction. The secondary outcomes were hypoglycaemia and hyperglycaemia risk assessment (area under the curve < 70 mg/dL/day and AUC > 200 mg/dL/day, respectively) and glucose variability. RESULTS: Fourteen patients (eight multiple daily insulin, six insulin pump therapy) used continuous glucose monitoring appropriately (at least 40% of the time). In these patients, the improvement in glycaemic control was more evident during the real-time continuous glucose monitoring period (7.76% +/- 0.4 vs 8.54% +/- 0.4, p < 0.05) than during the self monitoring of blood glucose period (8.42% +/- 0.4 vs 8.56% +/- 0.5, p = 0.2). Better results with continuous glucose monitoring were observed in patients using multiple daily insulin with greater improvement in both glycaemic control (7.71% +/- 0.2 vs 8.58% +/- 0.2, p < 0.05) and glucose variability and with a marked reduction in the risk of both hypoglycaemia and hyperglycaemia. CONCLUSIONS: Appropriate use of real-time continuous glucose monitoring improved glycometabolic control in T1D patients. The effects of continuous glucose monitoring were more evident in patients under multiple daily insulin treatment, compared with insulin pump therapy. Glucose variability, in addition to glycaemic control, was improved in compliant diabetic patients. PMID- 24816998 TI - A cooperative system of two species with bidirectional interactions. AB - Cooperation between species is often regarded to mean that the increase of each species promotes the growth of the other. The well-known cooperative model is the Lotka-Volterra equations (LVEs). In the LVEs, population densities of species increase infinitely as the cooperation is strong, which is called the divergence problem. Moreover, LVEs never exhibit an Allee effect in the case of obligate cooperation. In order to avoid these problems, several models have been established although most of them are rather complex. In this paper, we consider a cooperative system of two species with bidirectional interactions, in which each species also has negative feedback on the other. Population densities of the species will not increase infinitely because of the limited resource and negative feedback. Then, we focus on an extended lattice model of cooperation, which is deduced from reactions on lattice and has the same form as that of LVEs. In the case of obligate cooperation, the model predicts an Allee effect. Global dynamics of the system exhibit essential features of cooperation and basic mechanisms by which the cooperation can lead to coexistence/extinction of species. Intermediate cooperation is shown to be beneficial in cooperation under certain conditions, while extremely strong cooperation is demonstrated to lead to extinction of one/both species. Numerical simulations confirm and extend our results. PMID- 24816999 TI - Unconventional oil and gas extraction and animal health. AB - The extraction of hydrocarbons from shale formations using horizontal drilling with high volume hydraulic fracturing (unconventional shale gas and tight oil extraction), while derived from methods that have been used for decades, is a relatively new innovation that was introduced first in the United States and has more recently spread worldwide. Although this has led to the availability of new sources of fossil fuels for domestic consumption and export, important issues have been raised concerning the safety of the process relative to public health, animal health, and our food supply. Because of the multiple toxicants used and generated, and because of the complexity of the drilling, hydraulic fracturing, and completion processes including associated infrastructure such as pipelines, compressor stations and processing plants, impacts on the health of humans and animals are difficult to assess definitively. We discuss here findings concerning the safety of unconventional oil and gas extraction from the perspectives of public health, veterinary medicine, and food safety. PMID- 24817000 TI - The Utrecht Pharmacy Practice network for Education and Research: a network of community and hospital pharmacies in the Netherlands. AB - Practice-based networks can serve as effective mechanisms for the development of the profession of pharmacists, on the one hand by supporting student internships and on the other hand by collection of research data and implementation of research outcomes among public health practice settings. This paper presents the characteristics and benefits of the Utrecht Pharmacy Practice network for Education and Research, a practice based research network affiliated with the Department of Pharmaceutical Sciences of Utrecht University. Yearly, this network is used to realize approximately 600 student internships (in hospital and community pharmacies) and 20 research projects. To date, most research has been performed in community pharmacy and research questions frequently concerned prescribing behavior or adherence and subjects related to uptake of regulations in the pharmacy setting. Researchers gain access to different types of data from daily practice, pharmacists receive feedback on the functioning of their own pharmacy and students get in depth insight into pharmacy practice. PMID- 24817001 TI - The rational design of a highly sensitive and selective fluorogenic probe for detecting nitric oxide. AB - A rationally designed small-molecule fluorogenic probe for nitric oxide (NO) detection based on a new switching mechanism has been developed. Attaching a NO responsive dihydropyridine pendant group to a fluorophore led to a probe that displays a very high sensitivity to NO concentrations down to the low nM range and a very high specificity to NO while being insensitive to other oxidative oxygen/nitrogen species that often interfere with the sensing of NO. PMID- 24817002 TI - Sorafenib combined with transarterial chemoembolization versus transarterial chemoembolization alone for advanced-stage hepatocellular carcinoma: a propensity score matching study. AB - AIMS: The purpose of the present study was to compare the efficacies of transarterial chemoembolization (TACE) combined with sorafenib versus TACE monotherapy for treating patients with advanced hepatocellular carcinoma (HCC). METHODS: We enrolled 321 patients and selected 280 with advanced HCC (Barcelona Clinic Liver Cancer stage C) who underwent TACE therapy between February 2009 and February 2013. TACE alone (monotherapy group) was administered to 198 patients (70.7%), and the remaining 82 (29.3%) underwent repeat combined TACE and sorafenib therapy (combined group). To minimize selection bias, these latter 82 patients were matched using propensity-score matching at a 1?2 ratio with 164 patients who received TACE monotherapy. The primary endpoints were overall survival (OS) and related subgroup analysis. The secondary endpoints were time to progression (TTP) and treatment-related adverse events. RESULTS: Of the respective patients in the combined and monotherapy groups, 64.6% and 49.2% had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. In the propensity-score-matched cohort, the OS survival of the combined group was significantly higher compared with the monotherapy group (7.0 months vs. 4.9 months, respectively, P = 0.003). The TTP was significantly longer in the combined group (2.6 months vs. 1.9 months, respectively, P = 0.001). Subgroup analysis showed that the outcomes of patients with advanced HCC without main portal vein invasion who were treated with combined therapy were significantly better compared with those who received monotherapy (P<0.05). Univariate and subsequent multivariate analyses revealed that the addition of sorafenib was an independent predictor of favorable OS and TTP (adjusted hazard ratios, 0.63 and 0.62, respectively; P<0.05 for both). CONCLUSION: Sorafenib plus TACE was more effective than TACE monotherapy for treating patients with advanced HCC without main portal vein invasion. Future trials with larger samples are required to validate these preliminary findings. PMID- 24817003 TI - Effects of temperature and carbon-nitrogen (C/N) ratio on the performance of anaerobic co-digestion of dairy manure, chicken manure and rice straw: focusing on ammonia inhibition. AB - Anaerobic digestion is a promising alternative to disposal organic waste and co digestion of mixed organic wastes has recently attracted more interest. This study investigated the effects of temperature and carbon-nitrogen (C/N) ratio on the performance of anaerobic co-digestion of dairy manure (DM), chicken manure (CM) and rice straw (RS). We found that increased temperature improved the methane potential, but the rate was reduced from mesophilic (30~40 degrees C) to thermophilic conditions (50~60 degrees C), due to the accumulation of ammonium nitrogen and free ammonia and the occurrence of ammonia inhibition. Significant ammonia inhibition was observed with a C/N ratio of 15 at 35 degrees C and at a C/N ratio of 20 at 55 degrees C. The increase of C/N ratios reduced the negative effects of ammonia and maximum methane potentials were achieved with C/N ratios of 25 and 30 at 35 degrees C and 55 degrees C, respectively. When temperature increased, an increase was required in the feed C/N ratio, in order to reduce the risk of ammonia inhibition. Our results revealed an interactive effect between temperature and C/N on digestion performance. PMID- 24817004 TI - Abdominal aortic aneurysm calcification and thrombus volume are not associated with outcome following endovascular abdominal aortic aneurysm repair. AB - OBJECTIVES: Aortic calcification and thrombus have been postulated to worsen outcome following endovascular abdominal aortic aneurysm repair (EVAR). The purpose of this study was to assess the association of abdominal aortic aneurysm (AAA) calcification and thrombus volume with outcome following EVAR using a reproducible, quantifiable computed tomography (CT) assessment protocol. METHODS: Patients with elective EVAR performed between January 2002 and 2012 at the Townsville Hospital, Mater Private Hospital (Townsville) and Royal Brisbane and Women's Hospital (RBWH) were included if preoperative CTAs were available for analysis. AAA calcification and thrombus volume were measured using a semiautomated workstation protocol. Outcomes were assessed in terms of clinical failure, endoleak (type I, type II) and reintervention. Univariate and multivariate analyses were performed. Median follow-up was 1.7 years and the interquartile range 1.0-3.8 years. RESULTS: One hundred thirty-four patients undergoing elective EVAR were included in the study. Rates of primary clinical success and freedom from reintervention were 82.8% and 88.9% at the 24-month follow-up. AAA calcification and thrombus volume were not associated with clinical failure, type I endoleak, type II endoleak or reintervention. CONCLUSIONS: AAA calcification and thrombus volume were not associated with poorer outcome after EVAR in this study. KEY POINTS: * The association of calcification and thrombus volumes with EVAR outcome is unclear * Quantifiable methods for assessing calcification and thrombus were not used previously * This study used reproducible methods for assessing AAA calcification and thrombus volumes. PMID- 24817005 TI - Association of MOV10L1 gene polymorphisms and male infertility in azoospermic men with complete maturation arrest. AB - PURPOSE: The present research was undertaken to study probable genetic variations of MOV10L1 in 30 infertile men that had complete maturation arrest in their spermatocyte levels and 70 fertile men as the control group. METHODS: We performed polymerase chain reaction single strand conformation polymorphism (PCR SSCP) on extracted DNAs and sequencing was used to confirm the results. Identified polymorphisms in the MOV10L1 were further subjected to a haplotype analysis. RESULTS: We identified eight single nucleotide polymorphisms (SNPs): one missense (rs2272837) and four nonsense polymorphisms (rs2272836, rs11704548, rs2272838, rs138271) in the exonic sequences and three polymorphisms (rs12170772, rs2272840, rs17248147) in the intronic regions. With the exception of rs2272838, there was a statistically significant association in all polymorphisms between study population (P < 0.05). The result of haplotyping analysis showed ten possible haplotypes, from which five were significantly increased in infertile patients compared with the control group. CONCLUSIONS: Our results suggest that MOV10L1 gene polymorphisms in the studied infertile males with complete maturation arrest are linked to infertility. PMID- 24817006 TI - Magnetic Resonance Imaging Staging to Evaluate the Stability of Capitellar Osteochondritis Dissecans Lesions. AB - BACKGROUND: Treatment for capitellar osteochondritis dissecans (COCD) lesions is usually based on their stability from the bony floor after arthroscopic or open direct observation. Thus, a noninvasive means of lesion stability assessment by use of imaging is desirable to preoperatively determine treatment strategy. PURPOSE: To evaluate our modified MRI staging system for COCD, we compared the results of MRI staging with the International Cartilage Repair Society (ICRS) classification for lesion stability. Intra- and interrater reliability for MRI staging was examined as well. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Fifty-two COCD lesions were preoperatively evaluated by T2 weighted MRI and classified into 5 stages: stage 1 = normally shaped capitellum with several spotted areas of high signal intensity that is lower than that of cartilage; stage 2 = as with stage 1 but with several spotted areas of higher intensity than that of cartilage; stage 3 = as with stage 2 but with both discontinuity and noncircularity of the chondral surface signal of the capitellum and no high signal interface apparent between the lesion and the floor; stage 4 = lesion separated by a high intensity line in comparison with cartilage; and stage 5 = capitellar lesion displaced from the floor or defect of the capitellar lesion noted. The MRI staging results were compared with the intraoperative ICRS classification for lesion stability of each patient. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were all determined for fragment instability. Intra- and interrater correlations for our MRI staging were calculated among 3 examiners. RESULTS: Preoperative MRI grading correctly matched ICRS classification in 49 of 52 patients (94%), with a sensitivity of 100% and a specificity of 80%. The PPV and NPV were 93% and 100%, respectively, for diagnosing lesion instability. Intrarater reliability (intraclass correlation coefficient [ICC]) for MRI staging was high at ICC(1, 1) = 0.86 and ICC(1, 2) = 0.90, as was interrater reliability at ICC(2, 1) = 0.82 and ICC(2, 3) = 0.88. CONCLUSION: The MRI staging system provides accurate and reliable evidence for estimating ICRS classification and instability of COCD and is useful to decide appropriate treatment. PMID- 24817007 TI - Results 2 Years After Matrix-Associated Autologous Chondrocyte Transplantation Using the Novocart 3D Scaffold: An Analysis of Clinical and Radiological Data. AB - BACKGROUND: A range of scaffolds is available from various manufacturers for cartilage repair through matrix-associated autologous chondrocyte transplantation (MACT), with good medium- to long-term results. PURPOSE: To evaluate clinical and magnetic resonance imaging (MRI) outcomes 2 years after MACT on the knee joint using the Novocart 3D scaffold based on a bilayered collagen type I sponge. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Of 28 initial patients, 23 were clinically and radiologically evaluated 24 months after transplantation. Indications for MACT were chondral or osteochondral lesions on the knee joint with a defect size >2 cm2, no instability, and no malalignment (axis deviation <5 degrees ). Then, MRI was performed on a 3-T scanner to assess the magnetic resonance observation of cartilage repair tissue (MOCART) and 3-dimensional (3D) MOCART scores. A variety of subjective scores (International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS], Noyes sports activity rating scale, Tegner activity scale, and visual analog scale [VAS] for pain) were used for clinical evaluation. RESULTS: Two years after MACT, the MRI evaluation showed a mean MOCART score of 73.2 +/- 12.4 and a 3D MOCART score of 73.4 +/- 9.7. Clinical results showed mean values of 69.8 +/- 15.2 for the IKDC; 51.6 +/- 21.2, 86.5 +/- 13.9, 54.5 +/- 23.6, 65.0 +/- 8.0, and 91.5 +/- 10.6 for the KOOS subscales (Quality of Life, Pain, Sports and Recreation, Symptoms, and Activities of Daily Living, respectively); 77.5 +/- 12.7 for the Noyes scale; 4.4 +/- 1.6 for the Tegner activity scale; and 1.8 +/- 1.7 for the VAS, with statistically significant improvement in all scores other than KOOS Symptoms. CONCLUSION: Undergoing MACT using the Novocart 3D scaffold is an applicable method to treat large focal chondral and osteochondral defects, with good short-term clinical and radiological results. PMID- 24817009 TI - Health policy analysis for prevention and control of cardiovascular diseases and diabetes mellitus in Turkey. AB - OBJECTIVES: Current capacity of the Turkish health system is reviewed to evaluate and develop appropriate policies for cardiovascular diseases (CVD), diabetes mellitus (DM) and related risk factors. METHODS: This paper qualitatively evaluates existing policies; interviews with key informants (KIs); and rapid appraisal fieldwork in clinical settings about CVD-DM through the framework of Walt and Gilson (Health Policy Plan 9:353-370, 1994). RESULTS: Document review shows that prevention and control of CVD-DM were strongly addressed in Turkey, yet no document mentioned country-wide early detection or screening programs. KIs indicated over-fragmented management of CVD-DM by the Ministry of Health (MoH). Coordination among the MoH, organizational structure at provincial level and civil society organizations are poor where mutual trust is a significant problem according to KIs. Clinical setting findings point to a complete lack of a referral structure and a lack of follow-up, compounding the absence of functioning health information systems for patient records. CONCLUSIONS: Primary care services for CVD-DM require urgent attention, focusing particularly on the training of staff in public facilities, the integration of patient data, referrals and follow-up across all levels of the health system. PMID- 24817008 TI - The effectiveness of extracorporeal shock wave therapy in lower limb tendinopathy: a systematic review. AB - BACKGROUND: There is accumulating evidence for the effectiveness of extracorporeal shock wave therapy (ESWT) when treating lower limb tendinopathies including greater trochanteric pain syndrome (GTPS), patellar tendinopathy (PT), and Achilles tendinopathy (AT). PURPOSE: To evaluate the effectiveness of ESWT for lower limb tendinopathies. STUDY DESIGN: Systematic review and meta-analysis. METHODS: PubMed (Medline), Embase, Web of Knowledge, Cochrane, and CINAHL were searched from inception to February 2013 for studies of any design investigating the effectiveness of ESWT in GTPS, PT, and AT. Citation tracking was performed using PubMed and Google Scholar. Animal and non-English language studies were excluded. A quality assessment was performed by 2 independent reviewers, and effect size calculations were computed when sufficient data were provided. RESULTS: A total of 20 studies were identified, with 13 providing sufficient data to compute effect size calculations. The energy level, number of impulses, number of sessions, and use of a local anesthetic varied between studies. Additionally, current evidence is limited by low participant numbers and a number of methodological weaknesses including inadequate randomization. Moderate evidence indicates that ESWT is more effective than home training and corticosteroid injection in the short (<12 months) and long (>12 months) term for GTPS. Limited evidence indicates that ESWT is more effective than alternative nonoperative treatments including nonsteroidal anti-inflammatory drugs, physical therapy, and an exercise program and equal to patellar tenotomy surgery in the long term for PT. Moderate evidence indicates that ESWT is more effective than eccentric loading for insertional AT and equal to eccentric loading for midportion AT in the short term. Additionally, there is moderate evidence that combining ESWT and eccentric loading in midportion AT may produce superior outcomes to eccentric loading alone. CONCLUSION: Extracorporeal shock wave therapy is an effective intervention and should be considered for GTPS, PT, and AT particularly when other nonoperative treatments have failed. PMID- 24817010 TI - Steroid-responsive, progressive, focal measles virus brain infection. AB - Chronic measles virus infection of the brain causes subacute sclerosing panencephalitis (SSPE), a progressive, relentless fatal disorder. We report a 52 year-old male who developed focal, chronic persistent measles virus infection of the brain following interferon and ribavirin therapy for hepatitis C, and who responded to steroid therapy. This case, diametrically different from SSPE, has 2 unique features, its focal nature and its permissive response to steroids, that may add to the understanding of the pathogenesis of SSPE and the mechanism enabling viruses to evade the immune response and establish persistent brain infection. PMID- 24817011 TI - MicroRNA-21 regulates hTERT via PTEN in hypertrophic scar fibroblasts. AB - BACKGROUND: As an important oncogenic miRNA, microRNA-21 (miR-21) is associated with various malignant diseases. However, the precise biological function of miR 21 and its molecular mechanism in hypertrophic scar fibroblast cells has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT PCR) analysis revealed significant upregulation of miR-21 in hypertrophic scar fibroblast cells compared with that in normal skin fibroblast cells. The effects of miR-21 were then assessed in MTT and apoptosis assays through in vitro transfection with a miR-21 mimic or inhibitor. Next, PTEN (phosphatase and tensin homologue deleted on chromosome ten) was identified as a target gene of miR-21 in hypertrophic scar fibroblast cells. Furthermore, Western-blot and qRT-PCR analyses revealed that miR-21 increased the expression of human telomerase reverse transcriptase (hTERT) via the PTEN/PI3K/AKT pathway. Introduction of PTEN cDNA led to a remarkable depletion of hTERT and PI3K/AKT at the protein level as well as inhibition of miR-21-induced proliferation. In addition, Western-blot and qRT-PCR analyses confirmed that hTERT was the downstream target of PTEN. Finally, miR-21 and PTEN RNA expression levels in hypertrophic scar tissue samples were examined. Immunohistochemistry assays revealed an inverse correlation between PTEN and hTERT levels in high miR-21 RNA expressing-hypertrophic scar tissues. CONCLUSIONS/SIGNIFICANCE: These data indicate that miR-21 regulates hTERT expression via the PTEN/PI3K/AKT signaling pathway by directly targeting PTEN, therefore controlling hypertrophic scar fibroblast cell growth. MiR-21 may be a potential novel molecular target for the treatment of hypertrophic scarring. PMID- 24817012 TI - Cell cycle association and hypoxia regulation of excision repair cross complementation group 1 protein (ERCC1) in tumor cells of head and neck cancer. AB - Excision repair cross complementation group 1 (ERCC1) is a key component of homologous recombination-based repair of interstrand DNA cross-links (ICLs). As a consequence, ERCC1 mediates resistance to mitomycin C (MMC) and platinum chemotherapeutic agents and may predict treatment failure. Clinical response to MMC or cisplatin (CDDP)-based radiochemotherapy (RCT) was assessed in 106 head and neck squamous cell carcinoma (HNSCC) patients and correlated with cell nuclear immunoreactivity of the mouse monoclonal (clone: 8 F1) ERCC1 antibody in tumor tissue samples. BEAS-2B epithelial and Detroit 562 pharyngeal squamous carcinoma cells were treated with CDDP, MMC, and 5-fluorouracil (5-FU) at 50 % growth inhibitory (IC-50) concentrations. ERCC1 protein synthesis was compared with cell cycle distribution using combined immunocytochemistry and flow cytometry. ERCC1 messenger RNA (mRNA) and protein expression was investigated in normoxic and hypoxic conditions in Detroit 562 cells. Clinically, the nonresponder revealed significantly lower HNSCC tissue ERCC1 immunoreactivity than the responder (p = 0.0064) or control normal mucosa, which led to further mechanistic investigations. In vitro, control cells and cells treated with cytotoxic agents showed increasing ERCC1 levels from the G1 through S and G2 phases of the cell cycle. In CDDP-treated cells, ERCC1 mRNA and protein expression increased. Under hypoxic conditions, ERCC1 gene expression significantly decreased. Although ERCC1(+) cells show increased chemoresistance, they might be particularly radiosensitive, representing G2 cell cycle phase and less hypoxic. ERCC1 expression might be indirectly related with some conditions important for RCT treatment, but it is not a clear predictor for its failure in HNSCC patients. PMID- 24817013 TI - ncRuPAR inhibits gastric cancer progression by down-regulating protease-activated receptor-1. AB - ncRuPAR is a newly discovered long noncoding RNA molecule that can upregulate protease-activated receptor-1 (PAR-1) during embryonic growth; however, its role in cancer has not been elucidated. Here, we conducted a study to investigate the role of ncRuPAR in gastric cancer. Significant downregulation of ncRuPAR was detected in gastric cancer tissues compared with paired adjacent nontumor tissues; however, both PAR-1 and vascular endothelial growth factor (VEGF) messenger RNA (mRNA) levels were significantly higher in cancerous tissues compared with adjacent normal tissues. Additionally, the expression level of ncRuPAR was found to be significantly correlated with tumor invasion depth, lymph node metastasis, distant metastasis, tumor size, and tumor-nodes-metastasis (TNM) stage and inversely associated with the mRNA levels and extent (E) * intensity (I) scores of PAR-1 and VEGF. The protein level of PAR-1 was significantly correlated with tumor size only, while the VEGF protein level was significantly correlated with invasion depth and tumor size. The area under the receiver operating characteristic (ROC) curve of ncRuPAR was 0.84 (95 % CI 0.79-0.88) at a cutoff value of 4.97; ncRuPAR had a sensitivity of 88.41 %, a specificity of 73.91 %, and an accuracy of 81.16 % for the prediction of gastric cancer. These results suggest that ncRuPAR inhibits gastric cancer development, and its underlying mechanism involves the inhibition of PAR-1. In addition, ncRuPAR could be regarded as a marker for gastric cancer in the future. PMID- 24817014 TI - Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease. AB - Chronic kidney disease (CKD) is part of a number of systemic and renal diseases and may reach epidemic proportions over the next decade. Efforts have been made to improve diagnosis and management of CKD. We hypothesised that combining metabolomic and proteomic approaches could generate a more systemic and complete view of the disease mechanisms. To test this approach, we examined samples from a cohort of 49 patients representing different stages of CKD. Urine samples were analysed for proteomic changes using capillary electrophoresis-mass spectrometry and urine and plasma samples for metabolomic changes using different mass spectrometry-based techniques. The training set included 20 CKD patients selected according to their estimated glomerular filtration rate (eGFR) at mild (59.9+/ 16.5 mL/min/1.73 m2; n = 10) or advanced (8.9+/-4.5 mL/min/1.73 m2; n = 10) CKD and the remaining 29 patients left for the test set. We identified a panel of 76 statistically significant metabolites and peptides that correlated with CKD in the training set. We combined these biomarkers in different classifiers and then performed correlation analyses with eGFR at baseline and follow-up after 2.8+/ 0.8 years in the test set. A solely plasma metabolite biomarker-based classifier significantly correlated with the loss of kidney function in the test set at baseline and follow-up (rho = -0.8031; p<0.0001 and rho = -0.6009; p = 0.0019, respectively). Similarly, a urinary metabolite biomarker-based classifier did reveal significant association to kidney function (rho = -0.6557; p = 0.0001 and rho = -0.6574; p = 0.0005). A classifier utilising 46 identified urinary peptide biomarkers performed statistically equivalent to the urinary and plasma metabolite classifier (rho = -0.7752; p<0.0001 and rho = -0.8400; p<0.0001). The combination of both urinary proteomic and urinary and plasma metabolic biomarkers did not improve the correlation with eGFR. In conclusion, we found excellent association of plasma and urinary metabolites and urinary peptides with kidney function, and disease progression, but no added value in combining the different biomarkers data. PMID- 24817016 TI - An informative failure to replicate--the type D is distressed: a comment on Meyer et al. PMID- 24817015 TI - Testing negative means I'm lucky, making good choices, or immune: diverse reactions to HIV test results are associated with risk behaviors. AB - BACKGROUND: HIV testing may lead to behavioral changes among some individuals, but no scale has been developed to assess potential mechanisms. PURPOSE: We aimed to develop and evaluate the psychometric properties of a scale to measure psychological reactions to the receipt of a negative HIV test and explore the scale's associations with unprotected anal intercourse (UAI). METHODS: Two focus groups were conducted to develop the Inventory of Reactions to Testing HIV Negative, which was subsequently tested on 725 men who have sex with men in the New York City area. RESULTS: Factor analyses confirmed the presence of three subscales-Reinforced Safety, Invulnerability, and Luck. Regression analyses demonstrated that the subscales interacted with HIV testing behavior to influence UAI. CONCLUSIONS: These findings support the notion that there is heterogeneity in how individuals respond to a negative HIV test, with some individuals subsequently being influenced towards increased engagement in HIV risk behaviors. PMID- 24817017 TI - Shoulder joint hemiarthroplasty for treatment of a severe osteochondritis dissecans lesion in a dog. AB - INTRODUCTION: Partial resurfacing of the humeral head has been reported in humans to treat humeral osteochondritis dissecans. The aim is to describe a custom-made humeral resurfacing prosthesis for treatment of severe humeral head osteochondritis disse-cans in a dog. CASE REPORT: A seven-month-old female entire St. Bernard dog was presented with a 10 week history of severe left thoracic limb lameness. Radiography, arthroscopy and magnetic resonance imaging confirmed an extensive osteochondritis dissecans lesion affecting the caudal, medial and central regions of the humeral head. A prosthesis designed from computed tomography (CT) images was manufactured in polished stainless steel alloy with a hydroxyapatite coated base and central finned humeral stem for cementless insertion. A standard caudal approach to the shoulder was used to place the prosthesis following reaming of the caudal humeral head. RESULTS: Radiography and CT imaging revealed appropriate topographical placement on the humerus. Force plate analysis demonstrated initial reduction in ground reaction force at six weeks, followed by gradual improvement at three months. There was no radiographic evidence of implant loosening and the range of shoulder joint motion was comparable to the contralateral joint at three months; these findings were maintained to final follow-up at 24 months. CLINICAL SIGNIFICANCE: Placement of a humeral head resurfacing prosthesis was an effective technique for the management of severe osteochondritis dissecans-related shoulder lameness. To the authors' knowledge, this is the first report of the clinical use of shoulder hemiarthroplasty in a dog. PMID- 24817018 TI - Posttraumatic stress disorder symptoms in newly diagnosed patients with head and neck cancer and their partners. AB - BACKGROUND: Head and neck cancer is a life-threatening illness requiring aversive treatments. Despite clear potential for posttraumatic stress disorder (PTSD) symptoms in both patients and their partners, research is scant. METHODS: Newly diagnosed patients and partners (number of dyads = 42) completed questionnaires to assess symptoms of PTSD, anxiety, and depression, as well as demographic, medical, and attitudinal variables. RESULTS: Partners had higher average levels of PTSD symptoms than patients (p = .023). More partners (28.6%) met criteria for estimated PTSD caseness than did patients (11.9%). There were no significant differences in levels of other anxiety or depression symptoms. Perceived threat of disease appeared to be a stronger correlate of PTSD symptom levels than medical variables in patients and partners. CONCLUSION: A diagnosis of head and neck cancer elicits significant levels of PTSD symptoms in patients, and even higher levels among partners. Identified correlates of distress, including perceived threat of disease, are potential intervention targets. PMID- 24817019 TI - Carbon isotope labelling in graphene research. AB - The large scale production of graphene for any potential application relies on catalytic chemical vapour deposition (CVD). Despite much effort put into the graphene CVD research, there are still many challenges to be solved, not only concerning the growth itself, but also the subsequent treatment, i.e. transfer from the catalyst to a desired substrate. The need for fast progress naturally necessitates easy-to-use, versatile and efficient characterization methods. This perspective reviews the recent advances and potential of probably the most prospective one--Raman spectroscopy in connection with carbon isotope labelling of the CVD grown graphene layers. We discuss its use for the explanation and optimization of the growth process, followed by examples of employing isotope engineering in the studies of fundamental properties of graphene, not only by Raman spectroscopy. PMID- 24817021 TI - External fixators and sudden-onset disasters: Medecins Sans Frontieres experience. AB - PURPOSE: Carrying out osteosynthesis is challenging, and controlling for results and complications is necessary to define the limits of acceptable complications. Within the context of sudden-onset disasters, comparing internal with external osteosynthesis remains controversial. METHODS: The most recent and significant Medecins Sans Frontieres (MSF) experience with osteosynthesis was following the earthquake in Haiti in 2010: 353 external fixators were used in the 12 months following the catastrophe, 62 of which were used in the first month. Carrying out internal osteosynthesis was possible two weeks following the earthquake. RESULTS: The most common indication for open tibial fracture was Gustillo grade 2 or 3. Conversion rate from external to internal osteosynthesis remains anecdotal for several practical reasons. Advantages and drawbacks of external fixators are discussed in the context of precarious situations frequently encountered by MSF. CONCLUSIONS: External osteosynthesis as a primary and definitive treatment for open fractures, especially of the leg, remains the most frequently used and best adapted procedure in the context of sudden-onset disasters, even though not ideal. PMID- 24817020 TI - Assembly and nuclear export of pre-ribosomal particles in budding yeast. AB - The ribosome is responsible for the final step of decoding genetic information into proteins. Therefore, correct assembly of ribosomes is a fundamental task for all living cells. In eukaryotes, the construction of the ribosome which begins in the nucleolus requires coordinated efforts of >350 specialized factors that associate with pre-ribosomal particles at distinct stages to perform specific assembly steps. On their way through the nucleus, diverse energy-consuming enzymes are thought to release assembly factors from maturing pre-ribosomal particles after accomplishing their task(s). Subsequently, recruitment of export factors prepares pre-ribosomal particles for transport through nuclear pore complexes. Pre-ribosomes are exported into the cytoplasm in a functionally inactive state, where they undergo final maturation before initiating translation. Accumulating evidence indicates a tight coupling between nuclear export, cytoplasmic maturation, and final proofreading of the ribosome. In this review, we summarize our current understanding of nuclear export of pre-ribosomal subunits and cytoplasmic maturation steps that render pre-ribosomal subunits translation-competent. PMID- 24817022 TI - Meta-analysis of randomised controlled trials comparing unipolar with bipolar hemiarthroplasty for displaced femoral-neck fractures. AB - PURPOSE: Unipolar and bipolar hemiarthroplasty (HA) are used to treat displaced femoral-neck fractures. However, which type is best for treating displaced femoral-neck fractures in elderly patients remains a subject for debate. Our aim was to review randomised controlled trials to establish which type provides superior clinical outcome for this patient population. METHODS: We searched PubMed, Embase and Cochrane Register of Controlled Trials databases and Web of Science for randomised controlled trials (RCTs) comparing unipolar with bipolar HA to treat femoral-neck fracture in the elderly. Risk ratios (RRs) and mean differences (MDs) from each trial were pooled using random-effects or fixed effects models depending on study heterogeneity. Analysis was performed using RevMan5.2 from the Cochrane Collaboration. RESULTS: A total of 1,100 patients from nine studies were assessed in this meta-analysis. Results showed no significant differences in function score [MD = -0.14, 95% confidence interval (CI) -2.42-2.13], mortality (RR = 0.97, 95% CI 0.65-1.46), dislocation (RR = 1.33, 95% CI 0.53-3.34), deep infection (RR = 0.79, 95% CI 0.35-1.79), acetabular erosion (RR = 1.99, 95% CI 0.61-6.52), operating time (MD = 2.14, 95% CI -9.85 to14.14), blood loss (MD = 13.40, 95% CI -49.60 to 76.39) and length of hospital stay (MD = 0.12, 95% CI -0.49 to 0.73) between unipolar and bipolar HA. CONCLUSIONS: Unipolar and bipolar HA achieved similar clinical outcomes in patients with displaced femoral-neck fractures. PMID- 24817023 TI - Medial patellofemoral ligament anatomy: is it a predisposing factor for lateral patellar dislocation? AB - PURPOSE: Because the medial patellofemoral ligament (MPFL) is the primary restraint to lateral dislocation of the patella, we aimed, in this controlled study, to verify whether the MPFL with different measurements could be considered another predisposing factor for patellar dislocation. METHODS: A group of 100 consecutive individuals without the criteria for patellar dislocation (trochlear dysplasia, patella alta and lateral patellar tilt) was recruited as a control group and underwent magnetic resonance imaging (MRI) study and another group of 50 patients with patellar instability. Femoral condyles, interepicondylar distance, length and thickness of the MPFL were measured. RESULTS: In the control group, the MPFL was 38-60 mm long. Individuals with patellar instability who had no episode of patellar dislocation had a 4.11-mm longer ligament than controls (p = 0.032), while patients with instability with a previous history of dislocation had a 13.54-mm longer MPFL than controls (p < 0.001). Thickness of the MPFL at the patellar insertion was lower in individuals with patellar instability with a history of dislocation (p < 0.001). An instability coefficient (IC) less than 1.3 indicates that the MPFL is insufficient. CONCLUSIONS: Individuals with patellar instability and previous patellar dislocation present with longer MPFL when compared to controls, and an associated IC less than 1.3 can be considered a predisposing factor for patellar dislocation. Treatment of patellar instability is a challenge, and it is difficult to identify what is the predisposing factor. This study has verified the measurements of the MPFL for the first time and presents values of thickness and length that can be considered as indications for surgical reconstruction. LEVEL OF EVIDENCE: III. PMID- 24817024 TI - Bacterial adherence to different components of total hip prosthesis in patients with prosthetic joint infection. AB - PURPOSE: The purpose of our study was to evaluate and quantify the bacterial adherence to the different components of total hip prosthesis. METHODS: The bacterial load of 80 retrieved hip components from 24 patients was evaluated by counting of colony-forming units (CFU) dislodged from component surfaces using the sonication culture method. RESULTS: Micro-organisms were detected in 68 of 80 explanted components. The highest bacterial load was detected on the polyethylene liners, showing a significant difference in distribution of CFU between the liner and metal components (stem and cup). Staphylococcus epidermidis was identified as the pathogen causing the highest CFU count, especially from the polyethylene liner. CONCLUSIONS: Results of our study confirm that sonicate culture of the retrieved liners and heads, which revealed the highest bacterial loads, are reliable and sufficient for pathogen detection in the clinical diagnostic routine. PMID- 24817026 TI - Corticosteroids in the treatment of severe community-acquired pneumonia. AB - Controversy surrounds the use of adjunctive corticosteroids in severe community acquired pneumonia (CAP) as current guidelines either do not address or discourage their use. Double-blind, placebo-controlled, randomized controlled trials examining systemic corticosteroids in the treatment of severe CAP were summarized and their impacts on patient-important outcomes assessed. Four trials describing systemic corticosteroid use in adults with severe CAP were identified. One trial had a significant mortality difference favoring corticosteroids. However, this may be the result of a CAP severity imbalance within the trial and the mortality benefit was not confirmed in a larger trial conducted in a similar critical care setting. Pneumonia severity, mortality assessment timing, comorbidities, corticosteroid and antibiotic choice and timing in the CAP disease course, and bias risks varied across the four trials. Because of the clinical heterogeneity of available studies and the unknowns pertaining to clinical efficacy and safety, we do not recommend the use of adjunctive corticosteroids in severe CAP. PMID- 24817027 TI - Urological fistulas after fetal cystoscopic laser ablation of posterior urethral valves: surgical technical aspects. AB - OBJECTIVE: To describe the surgical technical aspects associated with the development of urological fistulas after fetal antegrade cystoscopic laser fulguration of the posterior urethral valves (PUV). METHODS: The perioperative data for all fetal cystoscopies performed between January 2004 and August 2013 at three institutions in the USA, France and Brazil were reviewed, with particular emphasis on surgical technical aspects of the procedure and the complications encountered. RESULTS: A total of 40 fetal cystoscopies were performed at the three institutions. Laser fulguration of the PUV was performed in 23 of these cases, with a survival rate of 60.9% (14/23) and normal renal function in 85.7% (12/14) of these infants. Urological fistulas were diagnosed postnatally in four (10%) newborns. The presence of fistulas was associated with a higher gestational age at diagnosis of PUV (P < 0.01) and with the use of semi-curved rather than curved sheaths (P < 0.01), the use of a diode laser (P < 0.01) and the use of higher laser power and energy (P < 0.01 and P < 0.01, respectively), as well as with less operator experience (P < 0.01) and with absence of fetal anesthesia/immobilization (P = 0.02). CONCLUSION: Urological fistulas are a severe complication of fetal cystoscopic laser fulguration of PUV and are associated with type, energy and power settings of the laser and instrumentation. The use of appropriate technique and proper training of the operator are necessary to perform this fetal intervention safely. PMID- 24817028 TI - Incidence in ICU populations: how to measure and report it? AB - Incidence of ICU events is mostly measured in one of two ways which differ by the denominator only. Either the number of incident events divided by the number of ICU patients is reported or the number of incident events per 1,000 ICU days is calculated. The difference is relevant, but a connection is rarely made. We give an example where pneumonia diagnosis on admission has no effect on one measure of mortality incidence, but increases the other. We demonstrate how to connect the two measures of incidence. The conclusion is that so-called 'competing incidences' should also be reported. PMID- 24817029 TI - Amikacin dosing in the ICU: we now know more, but still not enough.... PMID- 24817030 TI - Helmet CPAP vs. oxygen therapy in severe hypoxemic respiratory failure due to pneumonia. AB - PURPOSE: The efficacy of noninvasive continuous positive airway pressure (CPAP) to improve outcomes in severe hypoxemic acute respiratory failure (hARF) due to pneumonia has not been clearly established. The aim of this study was to compare CPAP vs. oxygen therapy to reduce the risk of meeting criteria for endotracheal intubation (ETI). METHODS: In a multicenter randomized controlled trial conducted in four Italian centers patients with severe hARF due to pneumonia were randomized to receive helmet CPAP (CPAP group) or oxygen delivered with a Venturi mask (control group). The primary endpoint was the percentage of patients meeting criteria for ETI, including either one or more major criteria (respiratory arrest, respiratory pauses with unconsciousness, severe hemodynamic instability, intolerance) or at least two minor criteria (reduction of at least 30% of basal PaO2/FiO2 ratio, increase of 20% of PaCO2, worsening of alertness, respiratory distress, SpO2 less than 90%, exhaustion). RESULTS: Between February 2010 and 2013, 40 patients were randomized to CPAP and 41 to Venturi mask. The proportion of patients meeting ETI criteria in the CPAP group was significantly lower compared to those in the control group (6/40 = 15% vs. 26/41 = 63%, respectively, p < 0.001; relative risk 0.24, 95% CI 0.11-0.51; number needed to treat, 2) two patients were intubated in the CPAP group and one in the control group. The CPAP group showed a faster and greater improvement in oxygenation in comparison to controls (p < 0.001). In either study group, no relevant adverse events were detected. CONCLUSIONS: Helmet CPAP reduces the risk of meeting ETI criteria compared to oxygen therapy in patients with severe hARF due to pneumonia. PMID- 24817031 TI - Combined effects of dentin sialoprotein and bone morphogenetic protein-2 on differentiation in human cementoblasts. AB - The aim of this study is to determine the effects of the combination of recombinant human BMP-2 (rh-BMP-2) and dentin sialoprotein (rh-DSP) on growth and differentiation in human cementoblasts and determine the underlying signal transduction mechanism. Compared to treatment of cementoblasts with either rh-BMP 2 or rh-DSP alone, the combination of rh-BMP-2 and rh-DSP synergistically increased cell growth, ALP activity, nodule formation and expression of differentiation markers. The differentiation-promoting effect was also observed in periodontal ligament cells and an osteoblastic cell line. Likewise, combination of rh-DSP and rh-BMP-2 increased BMP-2 mRNA expression and Smad1/5/8 phosphorylation, which was blocked by the BMP antagonist noggin. The expression levels of alpha2beta1 integrin and RhoA, as well as the phosphorylation status of FAK and Akt, were increased by the combination of rh-BMP-2 and rh-DSP in a time dependent manner. In addition, rh-BMP-2 and rh-DSP enhanced expression of Wnt ligands, beta-catenin activation and GSK-3beta phosphorylation, all of which were inhibited by the Wnt receptor antagonist DKK1. Furthermore, treatment with rh-DSP plus rh-BMP-2 resulted in phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 and also induced the nuclear translocation of the NF-kappaB p65 subunit, which was blocked by noggin. This study demonstrates for the first time that rh-DSP and rh-BMP-2 act synergistically, enhancing each other's ability to stimulate cementoblastic cell growth and differentiation in vitro via autocrine BMP, integrin, Wnt/beta catenin, MAP kinase and NF-kappaB pathways. These results support the therapeutic potential of a combination strategy for aiding periodontal regeneration. PMID- 24817032 TI - Role of microRNAs in resveratrol-mediated mitigation of colitis-associated tumorigenesis in Apc(Min/+) mice. AB - The pleiotropic effects of resveratrol include anti-inflammatory, antioxidant, and anticancer activities, and thus unique possibilities exist to explore mechanistic pathways of chemoprevention. The aim of this study was to investigate the role of microRNA (miRNA) alterations induced by resveratrol in the context of chemopreventive mechanisms against dextran sodium sulfate (DSS)-induced colitis associated tumorigenesis in the Apc(Min/+) mouse. To that end, Apc(Min/+) mice were exposed to 2% DSS to enhance intestinal inflammation and polyp development. Concurrently, mice received either vehicle or resveratrol treatment via oral gavage for 5 weeks. Interestingly, treatment of DSS-exposed mice with resveratrol resulted in decreased number and size of polyps, fewer histologic signs of cell damage, and decreased proliferating epithelial cells in intestinal mucosa compared with vehicle. Resveratrol treatment dramatically reversed the effects of DSS on the numbers of specific inflammatory CD4(+) T cells, CD8(+) T cells, B cells, natural killer T cells, and myeloid-derived suppressor cells in mesenteric lymph nodes. Resveratrol treatment also decreased interleukin-6 (IL-6) and tumor necrosis factor-alpha protein levels and reduced IL-6 and cyclooxygenase-2 mRNA expression. Microarray analysis revealed 104 miRNAs exhibiting >1.5-fold differences in expression in the intestinal tissue of resveratrol-treated mice. Among them, two miRNAs with anti-inflammatory properties, miRNA-101b and miRNA 455, were validated to be upregulated with resveratrol treatment by reverse transcription polymerase chain reaction. Pathway analysis revealed that numerous differentially regulated miRNAs targeted mRNAs associated with inflammatory processes with known roles in intestinal tumorigenesis. These results suggest that resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis through miRNA modulation. PMID- 24817033 TI - Potent inhibition of alcohol self-administration in alcohol-preferring rats by a kappa-opioid receptor antagonist. AB - A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl 3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[(4'-trimethylfluoro)benzamido]morphinan hydrochloride--(compound 5), previously shown to be a potent kappa-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other kappa-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 MUg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 MUg/kg. The results suggest that compound 5 is a potent drug-like kappa-opioid receptor antagonist of utility in alcohol cessation medications development. PMID- 24817035 TI - The histamine H4 receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects. AB - The histamine H4 receptor (H4R) is a promising target for the treatment of pruritus. A clinical study was conducted to evaluate the safety and efficacy of the H4R antagonist, JNJ 39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl pyrimidin-2-ylamine], on histamine-induced pruritus in healthy subjects. A single oral dose of 600 mg JNJ 39758979, 10 mg cetirizine, or placebo was administered in a randomized, three-period, double-blind, crossover study. Treatment periods were separated by 22-day washout periods. A histamine challenge was administered on day -1 and at 2 and 6 hours postdose on day 1 of each treatment period. The primary efficacy endpoint was the area under the curve (AUC) of pruritus score 0 10 minutes after the histamine challenge. Secondary efficacy endpoints included wheal and flare areas assessed 10 minutes after the histamine challenge. Safety was assessed for all subjects. Of the 24 enrolled subjects, 23 individuals completed the study. One subject withdrew after completing two treatment periods. Due to a carryover effect of JNJ 39758979, only treatment period 1 was used for pruritus-related evaluations. Compared with placebo, the reduction of the AUC of pruritus score was significant for JNJ 39758979 at 2 hours (P = 0.0248) and 6 hours (P = 0.0060), and for cetirizine at 6 hours (P = 0.0417). In all treatment periods, JNJ 39758979 did not demonstrate a significant decrease in wheal or flare at either time point, although a significant reduction was achieved with cetirizine at 2 and 6 hours (P < 0.0001). Adverse eventss reported in >1 patient with JNJ 39758979 were headache (9%) and nausea (13%). In conclusion, JNJ 39758979 was effective in inhibiting histamine-induced pruritus in healthy subjects. PMID- 24817034 TI - Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-alpha by macrophages: role of the DNA damage response. AB - Trovafloxacin (TVX) is a drug that has caused idiosyncratic, drug-induced liver injury (IDILI) in humans. In a murine model of IDILI, otherwise nontoxic doses of TVX and the inflammagen lipopolysaccharide (LPS) interacted to produce pronounced hepatocellular injury. The liver injury depended on a TVX-induced, small but significant prolongation of tumor necrosis factor-alpha (TNF) appearance in the plasma. The enhancement of TNF expression by TVX was reproduced in vitro in RAW 264.7 murine macrophages (RAW cells) stimulated with LPS. The current study was designed to identify the molecular target of TVX responsible for this response in RAW cells. An in silico analysis suggested a favorable binding profile of TVX to eukaryotic topoisomerase II-alpha (TopIIalpha), and a cell-free assay revealed that TVX inhibited eukaryotic TopIIalpha activity. Topoisomerase inhibition is known to lead to DNA damage, and TVX increased the DNA damage marker phosphorylated histone 2A.X in RAW cells. Moreover, TVX induced activation of the DNA damage sensor kinases, ataxia telangiectasia mutated (ATM) and Rad3-related (ATR). The ATR inhibitor NU6027 [6-(cyclohexylmethoxy)-5-nitrosopyrimidine-2,4 diamine] prevented the TVX-mediated increases in LPS-induced TNF mRNA and protein release, whereas a selective ATM inhibitor [2-(4-morpholinyl)-6-(1-thianthrenyl) 4H-pyran-4-one (KU55933)] was without effect. TVX prolonged TNF mRNA stability, and this effect was largely attenuated by NU6027. These results suggest that TVX can inhibit eukaryotic topoisomerase, leading to activation of ATR and potentiation of TNF release by macrophages, at least in part through increased mRNA stability. This off-target effect might contribute to the ability of TVX to precipitate IDILI in humans. PMID- 24817037 TI - HOXA9 inhibits migration of lung cancer cells and its hypermethylation is associated with recurrence in non-small cell lung cancer. AB - This study was aimed at understanding the clinicopathological significance of HOXA9 hypermethylation in non-small cell lung cancer (NSCLC). HOXA9 hypermethylation was characterized in six lung cancer cell lines, and its clinicopathological significance was analyzed using methylation-specific PCR in 271 formalin-fixed paraffin-embedded tissues and 27 fresh-frozen tumor and matched normal tissues from 298 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA9 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC). Transient transfection of HOXA9 into H23 lung cancer cells resulted in the inhibition of cell migration but not proliferation. Conversely, sequence-specific siRNA-mediated knockdown of HOXA9 enhanced cell migration. The mRNA levels of HOXA9 in 27 fresh-frozen tumor tissues were significantly lower than in matched normal tissues (P<0.0001; Wilcoxon signed-rank test). HOXA9 hypermethylation was found in 191 (70%) of 271 primary NSCLCs. HOXA9 hypermethylation was not associated with tumor size (P=0.12) and Ki-67 proliferation index (P=0.15). However, patients with HOXA9 hypermethylation had poor recurrence-free survival (hazard ratio=3.98, 95% confidence interval = 1.07-17.09, P=0.01) in never-smokers, after adjusting for age, sex, tumor size, adjuvant therapy, pathologic stage, and histology. In conclusion, the present study suggests that HOXA9 inhibits migration of lung cancer cells and its hypermethylation is an independent prognostic factor for recurrence-free survival in never-smokers with NSCLC. PMID- 24817036 TI - Effects of pharmacologic dopamine beta-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. AB - Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor nepicastat block cocaine primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine were pretreated with disulfiram or nepicastat prior to cocaine-induced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in accumbal DA neurochemistry was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies. PMID- 24817038 TI - Development of a point-of-use fortification technology for delivery of micronutrients in Honduras. AB - BACKGROUND: Micronutrient deficiencies continue to afflict children rural populations around the world. A micronutrient delivery vehicle (MDV) was developed as a point-of-use technology for fortification of meals for school-age children beneficiaries of the Healthy Schools Program (HSP) in Honduras. RESULTS: MDV combines micronutrient powder through a traditional dough-making process, using staple flours (wheat and nixtamalized corn), oil and water as ingredients. After mixing the ingredients and kneading, dough is extruded through a specially designed hand press into noodles. After drying (overnight, 23 degrees C), noodles are broken into small pieces, mixed (1:100 w/w) with rice and cooked as customary. Dispersion studies with NaFeEDTA showed adequate distribution (<10% RSD) and recovery (>90%) in white rice. Color changes in MDV due to addition of vitamin A and iron (NaFeEDTA) carried forward into cooked rice. In Honduras, children from two rural schools (N = 47, 6-12 years) were not able to differentiate (triangle test) between control and unfortified MDV mixed (1:100 w/w) with white rice. Children from four schools (N = 83, 7-12 years) accepted control and iron fortified rice (3 mg Fe per serving) based on color and flavor similarly. CONCLUSION: This is a feasible point-of-use fortification technology for improvement of meals provided by the HSP in Honduras. PMID- 24817039 TI - Circulating tumour cells--a bona fide cause of metastatic cancer. AB - Circulating tumour cells (CTCs) are emerging as important prognostic markers and have potential clinical utility as tumour biomarkers for targeted cancer therapy. Although CTCs were proposed more than 100 years ago as potential precursors that may form metastatic lesions, formal evidence that CTCs are indeed capable of initiating metastases is limited. Moreover, the process of CTCs shedding into the circulation, relocating to distant organ sites and initiating metastatic foci is complex and intrinsically inefficient. To partially explain the metastatic process, the concepts of CTCs as metastatic precursors or pre-metastatic conditioners have been proposed; however, it is questionable as to whether these are both variable pathways to metastasis or just markers of metastatic burden. This review explores the evidence for CTCs in the initiation and progression of metastatic cancer and the data supporting these different concepts in an attempt to better understand the role of CTCs in metastasis. A greater understanding of the metastatic potential of CTCs will open new avenues for therapeutic interventions in the future. PMID- 24817040 TI - A new assisted molecular cycloaddition on boron doped silicon surfaces: a predictive DFT-D study. AB - In the framework of the Density Functional Theory (DFT-D), we investigate the phthalocyanine (H2Pc) molecule adsorption on SiC(0001)3 * 3 and Si(111)?3 * ?3R30 degrees -B (SiB) surfaces, and particularly compare the involved molecular adsorptions. In the H2Pc-SiC(0001)3 * 3 system, the molecular adsorption can be ascribed to a [10+2] cycloaddition. The H2Pc-SiB system is considered in three cases: defectless SiB surface (denoted SiB-0D) and SiB surfaces presenting one or two boron defects (denoted SiB-1D and SiB-2D respectively). The SiB-0D surface is passivated by a charge transfer from the Si adatoms to the boron atoms and therefore no chemical bond between the molecule and the substrate is observed. A similar molecular adsorption as already evidenced in the H2Pc-SiC(0001)3 * 3 system is involved in the SiB-2D case. In the case of the SiB-1D surface, two Si N bonds (Si1-N1 and Si2-N2) are observed. One of them, Si1-N1, is nearly similar to that found in the H2Pc-SiB-2D system, but the Si2-N2 bond is unexpected. The Bader charge analysis suggests that, in the presence of the H2Pc molecule, the boron atoms behave like an electron reservoir whose availability varies following the involved molecular adsorption process. In the SiB-1D case, charges are transferred from the substrate to the molecule, allowing the Si2-N2 bond formation. Such a kind of molecular adsorption, not yet observed, could be designed by "assisted pseudo cycloaddition". PMID- 24817041 TI - The 18th congress of the Society of Hair Testing (SoHT) in Geneva. PMID- 24817042 TI - Is one hair lock really representative? AB - When investigating someone's hair a single lock is cut, washed, extracted and analysed. The forensic institutes in Switzerland agreed to retain a second lock for a possible reassessment. We were interested in the reproducibility of the concentrations of analytes in hair locks taken from different areas of the head of the same person covering the same time period. Therefore we analysed ethyl glucuronide and caffeine as model substances in 10 hair locks from three individuals categorised as social drinkers. The individual coefficients of variation varied between 14% and 28% for ethyl glucuronide and between 13% and 62% for caffeine corresponding to factors of 1.6 to 4.2 for the highest to the lowest concentrations between the hair locks. This finding has a significant importance both when the second hair lock has to be analysed in a forensic case and if the interpretation of the result is depending on a cut-off value. PMID- 24817043 TI - Development and application of GC-MS method for monitoring of long-term exposure to the pesticide cypermethrin. AB - Cypermethrin (CPMN) is a synthetic pyrethroid used as an insecticide in large scale commercial agricultural applications as well as for domestic purposes. In the present study a gas chromatography-mass spectrometry (GC-MS) based method was developed and validated for the quantitation of CPMN metabolites, 3 phenoxybenzoic acid (3-PBA) and cis- and trans- 3-(2,2-dichlorovinyl)-2,2 dimethyl-1-cyclopropane (cis- and trans- Cl2 CA). The developed method was applied for the monitoring of CPMN metabolites in hair of laboratory animals (rabbits) intentionally exposed per os to CPMN at 40 (low dose) and 80 (high dose) mg/kg weight/day for 16 weeks. The analytical method comprises three main steps: isolation of analytes from hair, analytes derivatization, and subsequent instrumental analysis by GC-MS. The limits of detection ensured by the method are 4.0, 3.9 and 1.0 pg/mg hair for cis-Cl2 CA, trans-Cl2 CA and 3-PBA, respectively. The instrument responce is linear (r(2) > 0.99) in the investigated concentrations range from 25 to 1000 pg/mg. With and between-run precision as well as accuracy were estimated and found satisfactory. Analytes were efficiently isolated by solid-liquid extraction from hair with recoveries greater than 84.8% for cis-Cl2 CA, 87.2% for trans-Cl2 CA and 96.4% for 3-PBA. Rabbit's hair showed increasing levels for all metabolites (metabolites accumulation in a time and dose dependent manner) over time and in a dose-dependent manner. The developed experimental procedure could be used for biomonitoring of population exposure to CPMN. PMID- 24817044 TI - Synthetic phosphodiesterase-5-inhibitors use/abuse and interest of hair testing: reporting of a rape case. AB - If classic phosphodiesterase-5 (PDE-5) inhibitors are well known, new synthetic PDE-5 analogues are of more recent introduction. Some of them have already been tested in dietary supplements. We describe here a rape case following the consumption of pills bought on the Internet and containing new synthetic PDE-5 inhibitors. The assailant declared that he lost control after ingesting these pills for the first time. Analyses of conventional matrices (blood, urine) don't allow us to highlight the intake of any substances in relation to this offence due to late sampling (5 days after the offence). Therefore, we have developed an analytical approach to test for PDE-5 inhibitors in hair including the two new synthetic PDE-5 inhibitors analogues - thiosildenafil and hydroxythiohomosildenafil - previously identified in the pills. This new method was validated and applied to the hair samples of the victim and the suspect. Analyses were conducted using a liquid/liquid extraction followed by liquid chromatography coupled with a mass spectrometer in multiple reaction monitoring mode detection. The 2-centimetre proximal hair section of the suspect revealed the presence of thiosildenafil (48 pg/mg), hydroxythiohomosildenafil (24 pg/mg), and sildenafil (7.5 pg/mg). To our knowledge, it is the first time that these two new synthetic PDE-5 inhibitors were detected in biological samples and especially in hair. Complementary investigations showed that a single pill taken by a volunteer provided similar levels in thiosildenafil (35 pg/mg), hydroxythiohomosildenafil (17 pg/mg), and sildenafil (8 pg/mg) to those found in the previous case described here. PMID- 24817045 TI - Segmental analysis of amphetamines in hair using a sensitive UHPLC-MS/MS method. AB - A sensitive and robust ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine and 3,4 methylenedioxy methamphetamine in hair samples. Segmented hair (10 mg) was incubated in 2M sodium hydroxide (80 degrees C, 10 min) before liquid-liquid extraction with isooctane followed by centrifugation and evaporation of the organic phase to dryness. The residue was reconstituted in methanol:formate buffer pH 3 (20:80). The total run time was 4 min and after optimization of UHPLC MS/MS-parameters validation included selectivity, matrix effects, recovery, process efficiency, calibration model and range, lower limit of quantification, precision and bias. The calibration curve ranged from 0.02 to 12.5 ng/mg, and the recovery was between 62 and 83%. During validation the bias was less than +/-7% and the imprecision was less than 5% for all analytes. In routine analysis, fortified control samples demonstrated an imprecision <13% and control samples made from authentic hair demonstrated an imprecision <26%. The method was applied to samples from a controlled study of amphetamine intake as well as forensic hair samples previously analyzed with an ultra high performance liquid chromatography time of flight mass spectrometry (UHPLC-TOF-MS) screening method. The proposed method was suitable for quantification of these drugs in forensic cases including violent crimes, autopsy cases, drug testing and re-granting of driving licences. This study also demonstrated that if hair samples are divided into several short segments, the time point for intake of a small dose of amphetamine can be estimated, which might be useful when drug facilitated crimes are investigated. PMID- 24817046 TI - Examination of sex differences in fatty acid ethyl ester and ethyl glucuronide hair analysis. AB - Clinical studies examining performance of fatty acid ethyl esters (FAEE) and ethyl glucuronide (EtG) in identifying excessive alcohol consumption have been primarily conducted in male populations. An impact of hair cosmetics in producing both false-negative EtG results and false-positive FAEE results has been demonstrated, suggesting a possible bias in female populations. This study evaluates FAEE-positive hair samples (>0.50 ng/mg) from n = 199 female and n = 73 male subjects for EtG. Higher FAEE/EtG concordance was observed amongst male over female subjects. Performance of multiple proposed EtG cut-off levels were assessed; amongst female samples, FAEE/EtG concordance was 36.2% (30 pg/mg), 36.7% (27 pg/mg), and 43.7% (20 pg/mg). Non-coloured hair demonstrated a two-fold increase in concordance (41.8 v. 20.8%) over coloured hair in the female cohort. FAEE levels did not differ between male and female subjects; however they were lower in coloured samples (p = 0.046). EtG was lower in female subjects (p = 0.019) and coloured samples (p = 0.026). A total of n = 111 female samples were discordant. Amongst discordant samples (EtG-negative), 26% had evidence of recent alcohol use including consultation histories (n = 20) and detectable cocaethylene (n = 9); 29% of discordant samples were coloured. False-negative risk with ethyl glucuronide analysis in females was mediated by cosmetic colouring. These findings suggest that combined analysis of FAEE and EtG is optimal when assessing a female population and an EtG cut-off of 20 pg/mg is warranted when using combined analysis. While concordant FAEE/EtG-positive findings constitute clear evidence, discordant FAEE/EtG findings should still be considered suggestive evidence of chronic excessive alcohol consumption. PMID- 24817047 TI - Differentiation between consumption and external contamination when testing for cocaine and cannabis in hair samples. AB - It is possible for hair to be externally contaminated by drugs like cannabis or cocaine, which are smoked or snorted. Three steps are commonly employed to minimize the chance of external contamination causing misinterpretation of the results of a hair test. The first consists of decontamination of hair samples by washing the hair before analysis, the second is the use of cut-off levels, and the third is the detection of both the parent drugs and appropriate levels of their metabolite(s) in the hair sample. We propose an additional step for the assessment of drug use using hair samples combined with decontamination data. Hair samples from 186 drug users were analyzed along with their wash residues by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results of the hair analysis of the 140 samples for cocaine showed that 85.5% (N=89) of the samples passed 'cocaine use' criteria for metabolites ratios and 12.5% (N=13) for wash residue criteria (<10% of cocaine in the wash residue) leading to conclusive interpretation. Only two cases (1.9%) had an uncertain conclusion of drug consumption because cocaine levels in the wash residue were >10% of the levels in the hair. The results of the cannabis set of samples (N=46) were not as clear cut, as a comparatively large number of samples (15.2%) had relatively high levels of THC in the wash residues. To use this approach, it is important that laboratories testing drugs in hair samples can demonstrate that the method utilized does not generate significant levels of the cocaine metabolites. PMID- 24817048 TI - Identification and analysis of damaged or porous hair. AB - Cosmetic hair treatments have been referred to as 'the pitfall' of hair analysis. However, most cosmetic treatments, when applied to the hair as instructed by the product vendors, do not interfere with analysis, provided such treatments can be identified by the laboratory and the samples analyzed and reported appropriately for the condition of the hair. This paper provides methods for identifying damaged or porous hair samples using digestion rates of hair in dithiothreitol with and without proteinase K, as well as a protein measurement method applied to dithiothreitol-digested samples. Extremely damaged samples may be unsuitable for analysis. Aggressive and extended aqueous washing of hair samples is a proven method for removing or identifying externally derived drug contamination of hair. In addition to this wash procedure, we have developed an alternative wash procedure using 90% ethanol for washing damaged or porous hair. The procedure, like the aqueous wash procedure, requires analysis of the last of five washes to evaluate the effectiveness of the washing procedure. This evaluation, termed the Wash Criterion, is derived from studies of the kinetics of washing of hair samples that have been experimentally contaminated and of hair from drug users. To study decontamination methods, in vitro contaminated drug-negative hair samples were washed by both the aqueous buffer method and a 90% ethanol method. Analysis of cocaine and methamphetamine was by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Porous hair samples from drug users, when washed in 90% ethanol, pass the wash criterion although they may fail the aqueous wash criterion. Those samples that fail both the ethanolic and aqueous wash criterion are not reported as positive for ingestion. Similar ratios of the metabolite amphetamine relative to methamphetamine in the last wash and the hair is an additional criterion for assessing contamination vs. ingestion of methamphetamine. PMID- 24817049 TI - Hair decontamination procedure prior to multi-class pesticide analysis. AB - Although increasing interest is being observed in hair analysis for the biomonitoring of human exposure to pesticides, some limitations still have to be addressed for optimum use of this matrix in that specific context. One main possible issue concerns the need to differentiate chemicals biologically incorporated into hair from those externally deposited on hair surface from contaminated air or dust. The present study focuses on the development of a washing procedure for the decontamination of hair before analysis of pesticides from different chemical classes. For this purpose, three different procedures of artificial contamination (with silica, cellulose, and aqueous solution) were used to simulate pesticides deposition on hair surface. Several washing solvents (four organic: acetone, dichloromethane, methanol, acetonitrile; and four aqueous: water, phosphate buffer, shampoo, sodium dodecylsulfate) were evaluated for their capacity to remove artificially deposited pesticides from hair surface. The most effective washing solvents were sodium dodecylsulfate and methanol for aqueous and organic solvents, respectively. Moreover, after a first washing with sodium dodecylsulfate or methanol, the majority of externally deposited pesticides was removed and a steady-state was reached since significantly lower amounts were removed by additional second and third washings. Finally, the effectiveness of a decontamination procedure comprising washing with sodium dodecylsulfate and methanol was successively demonstrated. In parallel, it was determined that the final procedure did not affect the chemicals biologically incorporated, as hair strands naturally containing pesticides were used. Such a procedure appears to remove in one-shot the fraction of chemicals located on hair surface and does not require repeated washing steps. PMID- 24817050 TI - Hair analysis as a useful procedure for detection of vapour exposure to chemical warfare agents: simulation of sulphur mustard with methyl salicylate. AB - Chemical warfare agents (CWA) are highly toxic compounds which have been produced to kill or hurt people during conflicts or terrorist attacks. Despite the fact that their use is strictly prohibited according to international convention, populations' exposure still recently occurred. Development of markers of exposure to CWA is necessary to distinguish exposed victims from unexposed ones. We present the first study of hair usage as passive sampler to assess contamination by chemicals in vapour form. This work presents more particularly the hair adsorption capacity for methyl salicylate used as a surrogate of the vesicant sulphur mustard. Chemical vapours toxicity through the respiratory route has historically been defined through Haber's law's concentration-time (Ct) product, and vapour exposure of hair to methyl salicylate was conducted with various times or doses of exposure in the range of incapacitating and lethal Ct products corresponding to sulphur mustard. Following exposure, extraction of methyl salicylate from hair was conducted by simple soaking in dichloromethane. Methyl salicylate could be detected on hair for vapour concentration corresponding to about one fifth of the sulphur mustard concentration that would kill 50% of exposed individuals (LCt50). The amount of methyl salicylate recovered from hair increased with time or dose of exposure. It showed a good correlation with the concentration-time product, suggesting that hair could be used like a passive sampler to assess vapour exposure to chemical compounds. It introduces great perspectives concerning the use of hair as a marker of exposure to CWA. PMID- 24817051 TI - Influence of thermal hair straightening on ethyl glucuronide content in hair. AB - Hair analysis of ethyl glucuronide (EtG) has become a valuable marker for the detection of moderate and chronic alcohol consumption. It has been shown that bleaching and perming may decrease EtG content in hair. So far, no studies exist about the influence of thermal hair straightening on EtG content in hair. Forty one positive EtG hair samples were treated in vitro with a hair straightener at 200 degrees C. Duration of treatment of 1 min was chosen for this study. After washing, pulverization, incubation in ultrasonic bath, solid-phase extraction, and derivatization with heptafluorobutyric anhydride, EtG was determined by gas chromatography-mass spectrometry - negative ion chemical ionization (GC-MS-NICI). The EtG contents in straightened hair strands were then compared with those in the corresponding untreated strands. In 20 of 41 hair samples, a decrease of EtG content was found ranging from 0.7% to 79.3% (average 20%) whereas in 21 cases an increase was shown ranging from 2.0% to 50.9% (average 15%). The variation of the results seems to depend on hair colour. The decrease may be explained by thermic in vitro destruction of EtG. The increase may be explained by denaturation of the hair matrix by thermal treatment possibly causing a better extraction of EtG during incubation in ultrasonic bath. This in vitro study indicates that thermal hair straightening has an impact on the EtG content in hair. This has to be considered for a correct interpretation of EtG results in hair. However, these results should be confirmed by in vivo studies. PMID- 24817052 TI - A study on photodegradation of methadone, EDDP, and other drugs of abuse in hair exposed to controlled UVB radiation. AB - The drug content of hair may be affected by washing, chemical or thermal treatments, the use of cosmetics, or exposure to the environment. Knowledge concerning the effect of natural or artificial light on drug content in hair can be helpful to the forensic toxicologist, in particular when investigating drug concentrations above or below pre-determined cut-offs. The photodegradation of methadone and its metabolite, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was studied in authentic positive hair samples by comparing drug concentrations determined by liquid chromatrography-high resolution mass spectrometry before and after exposure to UVB light (in vivo study). The same approach was applied in order to investigate the light sensitivity of opiates (6-monoacetylmorphine and morphine) and cocainics (cocaine and benzoylecgonine) in true positive hair. The yields of photodegradation were calculated for each drug class in eight different positive hair samples irradiated by UVB at 300 J/cm(2) obtaining averages, ranges and standard deviations. In parallel, the photostability of all the compounds as 10(-5) -10(-4) M standard solutions in methanol were examined by means of UVB light irradiation in the range 0-100 J/cm(2) followed by UV/Vis spectroscopic analysis and direct infusion electrospray ionization-high resolution mass spectrometry (in vitro study). In hair, methadone was shown to be significantly affected by light (photodegradation of 55% on average), while its metabolite EDDP proved to be more photostable (17%). 6-monoacetylmorphine, morphine, benzoylecgonine, and cocaine were more photostable than methadone in vivo (on average, 21%, 17%, 20%, and 11% of degradation, respectively). When irradiated in standard solutions, the target molecules exhibited a larger photodegradation than in vivo with the exception of cocaine (photodegradation for methadone up to 70%, 6-monoacetylmorphine and morphine up to 90%, benzoylecgonine up to 67%, cocaine up to 15%). Some factors possibly affecting the yields of photodegradation in hair and partially explaining the differences observed between the in vivo and the in vitro studies were also investigated, such as the colour of hair (the role of melanin) and the integrity of the keratin matrix. PMID- 24817053 TI - Rapid method for the simultaneous determination of DDTs and PCBs in hair of children by headspace solid phase microextraction and gas chromatography-mass spectrometry (HSSPME/GC-MS). AB - The purpose of this study was to develop a rapid and cost efficient hair extraction method, using the headspace solid phase microextraction (HSSPME) technique for the simultaneous determination and biomonitoring of 1,1,1-trichloro 2,2-bis(4-chlorophenyl)ethane) (DDT) and its isomers/metabolites and polychlorinated biphenyls (PCBs) in hair samples. A total of 72 head hair samples were collected from children living in urban and rural regions of the island of Crete. Two hundred milligrams of hair were digested under alkaline conditions and thermostated for 30 min at 90 degrees C while a 65 um PDMS/DVB fibre was exposed into the headspace of the vial. Analytical parameters of the method (time of incubation, agitation speed, recovery, precision, accuracy, carry over, matrix effect, linearity, and selectivity) were examined. Recoveries of the DDTs in the spiked hair samples were calculated from 42.3% for opDDD to 87.1% for opDDE, while recoveries for PCB congeners were from 52.6% for PCB138 to 96.6 % for PCB28. The method was applied for the analysis of authentic hair samples. Significant differences (p=0.001) of the burden to total DDTs (sumDDTs) as well as of the frequencies of detection of positive samples (p=0.020) were observed between the examined regions. Moreover, significant differences in the detected concentrations of PCB congeners were observed for PCB52 (p<0.001) and PCB28 (p=0.017) as well for their prevalence between urban and rural regions. Application of HSSPME for the biomonitoring of DDTs and PCBs biomarkers in hair was tested and successfully applied to the analysis of spiked and authentic hair samples. HSSPME was found to be substantially simpler and faster procedure than previous reported sample treatment procedures. PMID- 24817054 TI - Buprenorphine and nor-buprenorphine levels in head hair samples from former heroin users under Suboxone(r) treatment. AB - In the current study, buprenorphine (BUP) and its major metabolite, nor buprenorphine (NBUP), were determined in hair samples from former heroin users following Suboxone(r) treatment. Hair samples from 36 subjects were analyzed. The drugs of interest were isolated from hair by solid-liquid extraction with methanol and were determined by liquid chromatography-mass spectrometry, using an electrospray ionization interface. The analytical parameters of the method (such as linearity, limits of quantification, recovery, accuracy, and precision) were determined. The inter-quartile range of BUP levels was from 11.4 to 37.4 pg/mg (mean value 56.6 pg/mg) for the proximal hair segment, from 5.8 to 43.3 pg/mg for the middle hair segment (mean value 25.3 pg/mg), while a range from 4.3 to 33.9 pg/mg (mean value 105.2 pg/mg) for the distant to the root hair segment was determined. For NBUP the corresponding inter-quartile range was from 27.0 to 147.6 for the proximal segment (mean value 95.4 pg/mg), from 21.5 to 164.7 pg/mg for the middle segment (mean value 102.0 pg/mg) and from 20.4 to 103.6 pg/mg for the distant segment (mean value 156.8 pg/mg). The mean BUP/NBUP concentration ratio was 0.5. The daily dose of Suboxone(r) correlated significantly with BUP and NBUP levels in hair (p = 0.001 and p = 0.023) as well as with the BUP/NBUP ratio (p = 0.010). No significant correlation was found between the levels of BUP and NBUP and the duration of Suboxone(r) administration. The developed and validated method was successfully used for the determination of BUP and NBUP in hair samples collected from former heroin users under Suboxone(r) treatment. PMID- 24817055 TI - Utility of ELISA screening for the monitoring of abstinence from illegal and legal drugs in hair and urine. AB - Amphetamines, cannabinoids, cocaine, opiates, methadone, and benzodiazepines in authentic hair samples with drug concentrations around the medical and psychological assessment (MPA) guidelines cut-offs were screened by LUCIO-direct ELISA kits. Following confirmation of all positive and a significant number of negatively screened samples with gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods accredited for forensic purposes. Receiver operating characteristics (ROC) were plotted and the area under the curve (AUC) and overall misclassification rate (OMR) were calculated and compared to those obtained for the same drug classes in urine. While fulfilling the validation criteria of the German forensic guidelines, for almost all screening tests in hair and urine the AUC were greater than 0.8, indicating good to excellent performance. Moreover the AUC calculated for the detection of drugs in hair did not differ significantly to the AUC calculated for the detection of the same drug classes in urine, thus showing a comparable screening performance to the well accepted, previously published application of the same ELISAs for the detection of drugs at unconventionally low cut-offs in urine. For the first time, the validation of the immunoassay tests for the complete 6-drug panel MPA profile in hair and urine using a large population of authentic hair and urine samples with drug concentrations around MPA cut-offs, lower than conventional clinical or workplace drug testing guidelines cut-offs as well as those suggested by the Society of hair testing (SoHT) is presented. PMID- 24817056 TI - Utility of coloured hair for the detection of drugs and alcohol. AB - The aim of this paper is to assess the utility of coloured hair for the detection of drugs and alcohol in a large statistically significant population. The positivity rate, the 1st, 5th, 50th, 95th, and 99th percentiles of five amphetamines, cannabinoids, cocaine, four opiates, methadone, buprenorphine, seven benzodiazepines, and ethyl glucuronide (EtG) in 9488 non-treated and 1026 cosmetically treated (dyed or bleached) authentic hair samples was compared. Analytical methods used were accredited for forensic purposes at the cut-offs defined by the German driving licence re-granting medical and psychological assessment (MPA) guidelines. Considering only the drug classes for which at least 10 positive samples were detected, the positivity rate in non-treated hair was highest for alcohol (4.50%; measured using EtG at concentrations >= 7 pg/mg hair), followed by THC (2.00%), cocaine (1.75%), and amphetamine (0.59%). While the 1st to 99th percentile range was significantly lower for drugs in treated, compared to non-treated hair, no significant change was observed for EtG. Additionally, no significant difference in the positivity rate was observed between treated hair and non-treated hair for both drugs and EtG. This study is the first attempt to evaluate the influence of cosmetic treatment, mainly dying, on the positivity rate for both drugs and EtG in hair samples submitted routinely for abstinence testing and the first to indicate that dyed and eventually bleached hair is not necessarily useless in detecting drugs and/or alcohol consumption, thus making coloured hair analysis still useful, often being the only possibility to prove such misuse. PMID- 24817057 TI - Is urine an alternative to cosmetically treated hair for the detection of drugs and alcohol? AB - This study attempts to assess the utility of the urine matrix as an alternative to cosmetically treated hair for the detection of drugs and alcohol for driving licence re-granting in 1026 cosmetically treated hair samples and 33 262 urine routine samples. No significant difference was observed between the percentage positive samples in cosmetically treated hair to those in urine at both the 95% and 99% significance level for amphetamines, cocaine, opiates, benzodiazepines, and methadone. Significant difference was found between the positivity rates of cannabinoids in cosmetically treated hair and that in urine indicating urine to be a better alternative to the use of the hair matrix even when cosmetically treated. The opposite was observed for the alcohol consumption marker ethyl glucuronide (EtG) for which the positivity rate in cosmetically treated hair was twice that in urine samples. Particularly for alcohol abstinence monitoring, as for the rehabilitative driving licence re-granting medical and psychological assessment (MPA) programme in Germany, it seems that ethyl glucuronide (EtG) in hair presents a much better alternative than urine testing, even when cosmetically treated hair is analyzed. Moreover, segmentation is an additional advantage of hair testing which can provide additional useful information. PMID- 24817058 TI - External sphincter resection for lower rectal and anal canal adenocarcinoma: achieving anal preservation with oncological and functional satisfaction. AB - Intersphincteric resection (ISR) has recently been performed for very low rectal cancer, whereas abdominoperineal resection (APR) is typically reserved for cancers extremely close to the anal verge and/or when the depth of tumor invasion is suspected to involve the intersphincteric space. This is because impairment of anal function is considered unavoidable if the external sphincter (ES) is excised. We describe our technique of ISR with ES resection and discuss its outcomes. This surgical technique may offer major clinical advantages to selected patients and should be considered as an alternative to APR, although careful consideration of anal function is required. PMID- 24817059 TI - Prognostic significance of the preoperative serum C-reactive protein level in patients with stage IV colorectal cancer. AB - PURPOSE: Previous studies have revealed that an elevated preoperative serum C reactive protein (CRP) level is associated with a poor prognosis in patients with various malignant tumors. The aim of this study was to determine the clinical significance of the preoperative serum CRP level in patients with stage IV colorectal cancer. METHODS: We enrolled 144 patients who underwent surgery for stage IV colorectal cancer. A total of 53 patients with a serum CRP level of >= 1.0 mg/dl were classified as the high CRP individuals. The association between the preoperative serum CRP level and survival was retrospectively assessed. RESULTS: The cancer-specific survival of the patients with a high CRP level was significantly worse than that of the patients with a low CRP level. A multivariate analysis indicated that the curability (non-curative surgery), the number of organs with metastasis (more than one organ), the tumor diameter (>= 5 cm), lymphatic involvement, histological differentiation (non-differentiated) and a high CRP level (>= 1.0 mg/dl) were independent risk factors for a poor survival. CONCLUSIONS: A high preoperative serum CRP level is a convenient biomarker for identifying patients with a poor prognosis for stage IV colorectal cancer. PMID- 24817060 TI - Pleural lavage cytology predicts recurrence and survival, even in early non-small cell lung cancer. AB - PURPOSE: The TNM staging remains the best prognostic descriptor of lung cancer; however, new independent prognostic factors are needed, particularly for early stage disease. METHODS: An evaluation of the pleural lavage cytology (PLC) was performed in 436 consecutive NSCLC patients who underwent surgical resection; clinical, pathological and follow-up data were available for 414 patients. RESULTS: The PLC was positive in 15 patients (3.6 %). The overall five-year survival was 35.9 % in PLC-positive and 57.8 % in PLC-negative patients (p = 0.004). To compare groups with the same prognostic characteristics, the analysis was restricted to p-stage I patients, but the survival remained worse in the PLC positive patients (42.9 vs 69.4 %; p = 0.001). Recurrence was also observed more frequently in PLC-positive cases: 69.2 vs 34.5 %, OR 4.28 (95 % CI 1.29-14.18; p = 0.01). Among the PLC-positive patients, no difference between the local (44.4 %) and distant (55.6 %) relapse patterns was found (p = 0.82). The multivariate analysis identified four independent prognostic factors: age (p < 0.001), disease stage (p < 0.001), gender (p = 0.025) and PLC status (p = 0.012). CONCLUSIONS: PLC is an independent prognostic factor for NSCLC. PLC-positive NSCLC patients have a worse overall survival and a higher recurrence rate, even in stage I disease. PLC-positive patients should be considered a high risk category, who should potentially be eligible for adjuvant therapy regardless of their p-stage. PMID- 24817061 TI - Computer-assisted fracture reduction: a new approach for repositioning femoral fractures and planning reduction paths. AB - PURPOSE: Reduction is a crucial step in the surgical treatment of bone fractures to achieve anatomical alignment and facilitate healing. Surgical planning for treatment of simple femoral fractures requires suitable gentle reduction paths. A plan with optimal movement of fracture fragments from the initial to the desired target position should improve the reduction procedure. A virtual environment which repositions the fracture fragments automatically and provides the ability to plan reduction paths was developed and tested. METHODS: Virtual 3D osseous fragments are created from CT scans. Based on the computed surface curvatures, strongly curved edges are selected and fracture lines are generated. After assignment of matching points, the lines are compared and the desired target position is calculated. Planning of reduction paths was achieved using a reference-coordinate-system for the computation of reduction parameters. The fracture is reduced by changing the reduction parameters step by step until the target position is reached. To test this system, nine different fractured SYNBONE models and one human fracture were reduced, based on CT scans with varying resolution. RESULTS: The highest mean translational error is 1.2 +/- 0.9 (mm), and the rotational error is 2.6? +/- 2.8 ( degrees ), both of which are considered as clinically acceptable. The reduction paths can be planned manually or semi-automatically for each fracture. CONCLUSIONS: Automated fracture reduction was achieved using a system based on preoperative CT scans. The automated system provides a clinically feasible basis for planning optimal reduction paths that may be augmented by further computer- or robot-assisted applications. PMID- 24817062 TI - Fusion of coronary angiography and stress echocardiography for myocardial viability evaluation. AB - PURPOSE: Identification of viable myocardial tissue is important for patients with a low left ventricular ejection fraction, since revascularization is effective only if the affected region is viable. After cineangiographic identification of occluded coronary vessels, the myocardial viability is usually determined using cardiac MRI or SPECT. Alternatively, myocardial deformation imaging by echocardiography has been introduced that allows detection of viable myocardium directly within the catheterization laboratory. Multimodality fusion of coronary angiograms and echocardiograms was developed to match viable regions with areas affected by occluded vessels. METHODS: Identification of corresponding myocardial regions in both coronary angiograms and ultrasound scans was performed using multimodality image fusion. Geometrically correct superposition of these images was done to allow direct identification of the involved myocardial regions. An electromagnetic tracking system was used as a common base for co registration of the images. The system was tested using a phantom test device in a cardiac catheterization laboratory. RESULTS: A 2D projection error of 3.8+/-1.1 mm was achieved in trials using a cardiac phantom test object. CONCLUSIONS: Superimposition of the occluded coronary artery and the regional myocardial viability was achieved using automated multimodality fusion of coronary angiograms and stress echocardiograms with in vitro experiments. This system is promising for integrated single step angiography and angioplasty that may reduce procedure time, cost and length of hospitalization. Further testing in vivo is needed to verify and validate the system in a clinical setting. PMID- 24817063 TI - Are changes in glycaemic control associated with diabetes-specific quality of life and health status in screen-detected type 2 diabetes patients? Four-year follow up of the ADDITION-Cambridge cohort. AB - BACKGROUND: Interventions that improve HbA1c levels do not necessarily improve health-related quality of life (QoL). This issue may be particularly relevant in asymptomatic diabetes patients detected earlier in the course of the disease. METHODS: HbA1c , diabetes-specific QoL (ADDQoL) and health status were measured in 510 screen-detected diabetes patients from the ADDITION-Cambridge trial at 1 and 5 years post diagnosis. Multivariable logistic/linear regression was used to quantify the longitudinal association between change in HbA1c from 1 to 5 years and ADDQoL and health status at 5 years, adjusting for age, sex, education and trial group; alcohol consumption, smoking, physical activity, plasma vitamin C, HbA1c , ADDQoL or health status at 1 year, and glucose-lowering medication at 5 years. RESULTS: From 1 to 5 years, median HbA1c interquartile range increased from 6.3% (5.9-6.8) to 6.8% (6.4-7.4); the median ADDQoL score and mean health status physical health summary score decreased from -0.4 (-1 to -0.08) to -0.5 ( 1.08 to -0.09) (suggesting an adverse impact of diabetes on QoL) and by -0.79 (8.94) points, respectively. Increases in HbA1c were independently associated with reporting a negative impact of diabetes on QoL (OR = 1.38, 95% CI: 1.03 to 1.85) but not with the health status summary scores. CONCLUSIONS: Increases in HbA1c from 1 to 5 years post-diagnosis were independently associated with increased odds of reporting a negative impact of diabetes on QoL. While our results suggest that efforts to reduce HbA1c do not adversely affect health related QoL, large numbers of participants still report a negative impact of diabetes on their QoL 5 years post-diagnosis. PMID- 24817064 TI - Wushen, a food mixture containing 55 different natural ingredients, inhibits S180 tumor growth in vivo. AB - As cancer has become a worldwide threat to human life and health, developing a safe and effective tumor-inhibiting agent is presently a major scientific challenge. In this study, a food mixture produced from 55 different natural ingredients called wushen was fed to S180 tumor-bearing mice, and the antitumor effects were investigated in vivo. Kunming mice were implanted subcutaneously in the armpit with murine sarcoma S180 cells to construct the S180 tumor-bearing mouse model. The mice were randomly divided into three groups: control, wushen and 5-fluorouracil (5-Fu). 5-Fu was used as the positive drug treatment to confirm the reliability of the model. The food intake, antitumor rate, and spleen and thymus indices were recorded. Tumor histopathology was conducted using hematoxylin and eosin (H&E) staining. The catalase, glutathione peroxidase, and superoxide dismutase activities and the malondialdehyde concentration were measured to evaluate the antioxidative effects of the treatments. The antitumor rate of the mice fed wushen was 48.52%. Wushen-treated mice exhibited alterations in antioxidative enzyme activity and reduced liver lipid peroxidation. The results demonstrated that wushen has antitumor effects on S180 tumor-bearing mice in vivo, and the underlying mechanism is partially due to its antioxidant activity. Wushen, which contains various natural products, can be eaten directly and may be beneficial to human health. PMID- 24817066 TI - KISS1 receptor is preferentially expressed in clinically non-functioning pituitary tumors. AB - OBJECTIVE: KISS1 is a metastasis suppressor gene involved in cancer biology. Given the high expression levels of KISS1 and KISS1R in the hypothalamus and the pituitary respectively, we hypothesized that this system could possibly affect tumor invasiveness and clinical behavior of pituitary tumors. METHODS: Expression levels of KISS1 and KISS1R mRNA were evaluated by RT-PCR. Clinical information pertaining tumor characteristics was extracted from patients' charts. RESULTS: Tumors from 39 patients (21 females, mean age 47.5 years) were examined. KISS1R was expressed in 26 (67%) of samples (94% of NFPA, 42% of GH-, 67% of ACTH-, and 25% of PRL-secreting adenomas) and was found more often in female patients (81 vs. 50% males, p < 0.05); and in NFPA (94 vs. 45.5% in secreting tumors; p = 0.003). Patients expressing KISS1R were older at presentation (50.5 +/- 1.4 vs. 38.1 +/- 1.3 years; p = 0.008). In the multivariate analysis, factors significantly associated with KISS1R expression included female gender (OR 13.8, 95 % CI 1.22-155.9; p = 0.03) and having a NFPA (OR 24.7, 95% CI 1.50-406.4; p = 0.02). Tumor size, invasiveness and age at presentation were not independently associated with KISS1R expression. Pituitary tumors and normal pituitary were negative for KISS1 mRNA expression. CONCLUSIONS: The majority of human NFPA expressed KISS1R with lower rates of expression in other types of pituitary tumors. KISS1R expression did not impart a clinical beneficial tumor phenotype, as it was not associated with tumor size or invasiveness. Additional studies are required to elucidate the role of KISS1 receptor in pituitary gland physiology and pathology. PMID- 24817068 TI - Lifetime achievement award 2014: Sir Iain Chalmers. PMID- 24817067 TI - Prevalence of dyslipidemia in urban and rural India: the ICMR-INDIAB study. AB - AIM: To study the pattern and prevalence of dyslipidemia in a large representative sample of four selected regions in India. METHODS: Phase I of the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study was conducted in a representative population of three states of India [Tamil Nadu, Maharashtra and Jharkhand] and one Union Territory [Chandigarh], and covered a population of 213 million people using stratified multistage sampling design to recruit individuals >=20 years of age. All the study subjects (n = 16,607) underwent anthropometric measurements and oral glucose tolerance tests were done using capillary blood (except in self-reported diabetes). In addition, in every 5th subject (n = 2042), a fasting venous sample was collected and assayed for lipids. Dyslipidemia was diagnosed using National Cholesterol Education Programme (NCEP) guidelines. RESULTS: Of the subjects studied, 13.9% had hypercholesterolemia, 29.5% had hypertriglyceridemia, 72.3% had low HDL-C, 11.8% had high LDL-C levels and 79% had abnormalities in one of the lipid parameters. Regional disparity exists with the highest rates of hypercholesterolemia observed in Tamilnadu (18.3%), highest rates of hypertriglyceridemia in Chandigarh (38.6%), highest rates of low HDL-C in Jharkhand (76.8%) and highest rates of high LDL-C in Tamilnadu (15.8%). Except for low HDL-C and in the state of Maharashtra, in all other states, urban residents had the highest prevalence of lipid abnormalities compared to rural residents. Low HDL-C was the most common lipid abnormality (72.3%) in all the four regions studied; in 44.9% of subjects, it was present as an isolated abnormality. Common significant risk factors for dyslipidemia included obesity, diabetes, and dysglycemia. CONCLUSION: The prevalence of dyslipidemia is very high in India, which calls for urgent lifestyle intervention strategies to prevent and manage this important cardiovascular risk factor. PMID- 24817069 TI - Is the prevalence of autism increasing in the United States? PMID- 24817070 TI - NHS in England has no obligation to provide free abortions to women from Northern Ireland, judge rules. PMID- 24817071 TI - Executions should use a single drug and be overseen by medical personnel, expert panel says. PMID- 24817072 TI - Waste in medical academia must be addressed, Chalmers urges in The BMJ Awards acceptance speech. PMID- 24817073 TI - Labile alkoxyamines: past, present, and future. AB - Alkoxyamines--per-alkylated derivatives of hydroxylamine R(1)R(2)NO-R(3)--can undergo C-ON bond homolysis to release a persistent nitroxyl radical R(1)R(2)NO and a transient alkyl radical R(3). Although they were considered as an oddity when discovered in 1974, their properties have been extensively studied since the seminal work of Solomon, Rizzardo and Cacioli (Chem. Abstr., 102, 221335q), who patented the key role of alkoxyamines in nitroxide-mediated polymerization (NMP) in 1985. This feature article surveys and assesses the various applications of alkoxyamines: in tin-free radical chemistry, e.g., for the elaboration of carbo- or hetero-cycles, for the development of new reactions, for total synthesis of natural products; in polymerization under thermal conditions (NMP) or photochemical conditions (nitroxide-mediated photo-polymerization, NMP2); and in the design of smart materials. In this feature article, we also describe our recent findings concerning the chemical triggering of the C-ON bond homolysis in alkoxyamines, affording the controlled generation of alkyl radicals at room temperature. Based on these results, we describe herein some new opportunities for applications in the field of smart materials, and of course, some possible developments as new initiators for NMP as well as an entirely new field of application: the use of alkoxyamines as theranostic agents. Indeed, each of the radicals released after homolysis can play an appealing role: the nitroxide, through dynamic nuclear polarization (DNP), can be used for imagery purposes (diagnostic properties), while the alkyl radical can be used to induce cellular disorders in abnormal cells (therapeutic activity). PMID- 24817074 TI - Palliative care is critical to the changing face of child mortality and morbidity in the United States. PMID- 24817075 TI - Fifteen-year-old girl with severe obstructive lung disease, pansinusitis, and failure to thrive. PMID- 24817076 TI - Neuroblastoma presenting as facial nerve palsy and bulging tympanic membrane. PMID- 24817077 TI - Payment analysis of two diagnosis and management approaches of acute otitis media. AB - We determined the cost of care for 2 diagnosis and management approaches for acute otitis media (AOM) among children 6 to 30 months old. A case-control design was used. Cases included 208 children diagnosed with AOM based on a bulging tympanic membrane (TM) and treated with amoxicillin/clavulanate. Controls (5:1 ratio) included 1020 children with AOM diagnosed not requiring bulging of the TM and treated with amoxicillin. Fewer cases (49%) than controls (69%) were diagnosed with AOM (P < .001), fewer were diagnosed with recurrent AOM or AOM treatment failure (0.34 vs 1.6/child; P < .0001), and fewer had insertion of tympanostomy tubes (6.3% vs 14.8%) due to recurrent AOM (P < .0001). The combined direct payments and indirect costs for management of AOM were $539/case versus $1,023/control. Using Rochester NY payments generalized to the US birth cohort, this case diagnosis and treatment strategy could save $1.008 billion per year. PMID- 24817078 TI - The obesity quotient: a new tool to measure childhood obesity. PMID- 24817079 TI - Response to Eculizumab in Escherichia coli O157: H7-induced hemolytic uremic syndrome with severe neurological manifestations. PMID- 24817080 TI - Anterior petroclinoid fold fenestration: an adjunct to clipping of postero laterally projecting posterior communicating aneurysms. AB - Proximally located posterior communicating artery (PCoA) aneurysms, projecting postero-laterally in proximity to the tentorium, may pose a technical challenge for microsurgical clipping due to obscuration of the proximal aneurysmal neck by the anterior petroclinoid fold. We describe an efficacious technique utilizing fenestration of the anterior petroclinoid fold to facilitate visualization and clipping of PCoA aneurysms abutting this aspect of the tentorium. Of 86 cases of PCoA aneurysms treated between 2003 and 2013, the technique was used in nine (10.5 %) patients to allow for adequate clipping. A 3 mm fenestration in the anterior petroclinoid ligament is created adjacent and lateral to the anterior clinoid process. This fenestration is then widened into a small wedge corridor by bipolar coagulation. In all cases, the proximal aneurysm neck was visualized after the wedge fenestration. Additionally, an adequate corridor for placement of the proximal clip blade was uniformly established. All cases were adequately clipped, with complete occlusion of the aneurysm neck and fundus with preservation of the PCoA. There were two intraoperative ruptures not related to creation of the wedge fenestration. One patient experienced post-operative partial third nerve palsy, which resolved during follow-up. We describe a technique of fenestration of the anterior petroclinoid fold to establish a critical and safe corridor for both visualization and clipping of PCoA aneurysms. PMID- 24817082 TI - Megakaryocytic differentiation of K562 cells induced by PMA reduced the activity of respiratory chain complex IV. AB - Mitochondria are involved in the regulation of cell differentiation processes, but its function changes and molecular mechanisms are not yet clear. In this study, we found that mitochondrial functions changed obviously when K562 cells were induced to megakaryocytic differentiation by phorbol 12-myristate 13-acetate (PMA). During the cell differentiation, the reactive oxygen species (ROS) level was increased, mitochondrial membrane potential declined and respiratory chain complex IV activity was decreased. Treatment with specific inhibitor of mitochondrial respiratory chain complex IV led to a significant inhibition in mitochondrial membrane potential and reduction of PMA-induced cell differentiation. However, treatment with cyclosporine A, a stabilization reagent of mitochondrial membrane potential, did not improve the down-regulation of mitochondrial respiratory chain complex IV induced by PMA. Furthermore, we found that the level of the complex IV core subunit COX3 and mitochondrial transport related proteins Tim9 and Tim10 were decreased during the differentiation of K562 cells induced by PMA, suggesting an important role of these factors in mitochondrial functional changes. Our results suggest that changes in mitochondrial functions are involved in the PMA-induced K562 cell differentiation process, and the maintenance of the steady-state of mitochondrial functions plays a critical role in the regulation of cell differentiation. PMID- 24817083 TI - Perfusion CT best predicts outcome after radioembolization of liver metastases: a comparison of radionuclide and CT imaging techniques. AB - OBJECTIVE: To determine the best predictor for the response to and survival with transarterial radioembolisation (RE) with (90)yttrium microspheres in patients with liver metastases. METHODS: Forty consecutive patients with liver metastases undergoing RE were evaluated with multiphase CT, perfusion CT and (99m)Tc-MAA SPECT. Arterial perfusion (AP) from perfusion CT, HU values from the arterial (aHU) and portal venous phase (pvHU) CT, and (99m)Tc-MAA uptake ratio of metastases were determined. Morphologic response was evaluated after 4 months and available in 30 patients. One-year survival was calculated with Kaplan-Meier curves. RESULTS: We found significant differences between responders and non responders for AP (P < 0.001) and aHU (P = 0.001) of metastases, while no differences were found for pvHU (P = 0.07) and the (99m)Tc-MAA uptake ratio (P = 0.40). AP had a significantly higher specificity than aHU (P = 0.003) for determining responders to RE. Patients with an AP >20 ml/100 ml/min had a significantly (P = 0.01) higher 1-year survival, whereas an aHU value >55 HU did not discriminate survival (P = 0.12). The Cox proportional hazard model revealed AP as the only significant (P = 0.02) independent predictor of survival. CONCLUSION: Compared to arterial and portal venous enhancement and the (99m)Tc MAA uptake ratio of liver metastases, the AP from perfusion CT is the best predictor of morphologic response to and 1-year survival with RE. KEY POINTS: * Perfusion CT allows for calculation of the liver arterial perfusion. * Arterial perfusion of liver metastases differs between responders and non-responders to RE. * Arterial perfusion can be used to select patients responding to RE. PMID- 24817085 TI - Eco-taxonomic insights into actinomycete symbionts of termites for discovery of novel bioactive compounds. AB - Termites play a major role in foraging and degradation of plant biomass as well as cultivating bioactive microorganisms for their defense. Current advances in "omics" sciences are revealing insights into function-related presence of these symbionts, and their related biosynthetic activities and genes identified in gut symbiotic bacteria might offer a significant potential for biotechnology and biodiscovery. Actinomycetes have been the major producers of bioactive compounds with an extraordinary range of biological activities. These metabolites have been in use as anticancer agents, immune suppressants, and most notably, as antibiotics. Insect-associated actinomycetes have also been reported to produce a range of antibiotics such as dentigerumycin and mycangimycin. Advances in genomics targeting a single species of the unculturable microbial members are currently aiding an improved understanding of the symbiotic interrelationships among the gut microorganisms as well as revealing the taxonomical identity and functions of the complex multilayered symbiotic actinofloral layers. If combined with target-directed approaches, these molecular advances can provide guidance towards the design of highly selective culturing methods to generate further information related to the physiology and growth requirements of these bioactive actinomycetes associated with the termite guts. This chapter provides an overview on the termite gut symbiotic actinoflora in the light of current advances in the "omics" science, with examples of their detection and selective isolation from the guts of the Sunshine Coast regional termite Coptotermes lacteus in Queensland, Australia. PMID- 24817084 TI - Non- or full-laxative CT colonography vs. endoscopic tests for colorectal cancer screening: a randomised survey comparing public perceptions and intentions to undergo testing. AB - OBJECTIVES: Compare public perceptions and intentions to undergo colorectal cancer screening tests following detailed information regarding CT colonography (CTC; after non-laxative preparation or full-laxative preparation), optical colonoscopy (OC) or flexible sigmoidoscopy (FS). METHODS: A total of 3,100 invitees approaching screening age (45-54 years) were randomly allocated to receive detailed information on a single test and asked to return a questionnaire. Outcomes included perceptions of preparation and test tolerability, health benefits, sensitivity and specificity, and intention to undergo the test. RESULTS: Six hundred three invitees responded with valid questionnaire data. Non-laxative preparation was rated more positively than enema or full-laxative preparations [effect size (r) = 0.13 to 0.54; p < 0.0005 to 0.036]; both forms of CTC and FS were rated more positively than OC in terms of test experience (r = 0.26 to 0.28; all p-values < 0.0005). Perceptions of health benefits, sensitivity and specificity (p = 0.250 to 0.901), and intention to undergo the test (p = 0.213) did not differ between tests (n = 144-155 for each test). CONCLUSIONS: Despite non-laxative CTC being rated more favourably, this study did not find evidence that offering it would lead to substantially higher uptake than full-laxative CTC or other methods. However, this study was limited by a lower than anticipated response rate. KEY POINTS: * Improving uptake of colorectal cancer screening tests could improve health benefits * Potential invitees rate CTC and flexible sigmoidoscopy more positively than colonoscopy * Non-laxative bowel preparation is rated better than enema or full-laxative preparations * These positive perceptions alone may not be sufficient to improve uptake * Health benefits and accuracy are rated similarly for preventative screening tests. PMID- 24817086 TI - Ecological roles and biotechnological applications of marine and intertidal microbial biofilms. AB - This review is a retrospective of ecological effects of bioactivities produced by biofilms of surface-dwelling marine/intertidal microbes as well as of the industrial and environmental biotechnologies developed exploiting the knowledge of biofilm formation. Some examples of significant interest pertaining to the ecological aspects of biofilm-forming species belonging to the Roseobacter clade include autochthonous bacteria from turbot larvae-rearing units with potential application as a probiotic as well as production of tropodithietic acid and indigoidine. Species of the Pseudoalteromonas genus are important examples of successful surface colonizers through elaboration of the AlpP protein and antimicrobial agents possessing broad-spectrum antagonistic activity against medical and environmental isolates. Further examples of significance comprise antiprotozoan activity of Pseudoalteromonas tunicata elicited by violacein, inhibition of fungal colonization, antifouling activities, inhibition of algal spore germination, and 2-n-pentyl-4-quinolinol production. Nitrous oxide, an important greenhouse gas, emanates from surface-attached microbial activity of marine animals. Marine and intertidal biofilms have been applied in the biotechnological production of violacein, phenylnannolones, and exopolysaccharides from marine and tropical intertidal environments. More examples of importance encompass production of protease, cellulase, and xylanase, melanin, and riboflavin. Antifouling activity of Bacillus sp. and application of anammox bacterial biofilms in bioremediation are described. Marine biofilms have been used as anodes and cathodes in microbial fuel cells. Some of the reaction vessels for biofilm cultivation reviewed are roller bottle, rotating disc bioreactor, polymethylmethacrylate conico-cylindrical flask, fixed bed reactor, artificial microbial mats, packed-bed bioreactors, and the Tanaka photobioreactor. PMID- 24817087 TI - Community-based technology transfer in rural aquaculture: the case of mudcrab Scylla serrata nursery in ponds in Northern Samar, Central Philippines. AB - Finding aquaculture development approaches to open up livelihood opportunities for the rural poor and in mainstreaming smallholder fish farmers to reduce poverty remain a challenge. This paper examines the community-based technology transfer mechanism of mudcrab nursery in ponds and its socioeconomic impacts on smallholder mudcrab growers in Northern Samar, Philippines. Results indicated that the technology is a viable enterprise done by a straight culture system method, which is the rearing of crablets from <1.0 to 4.0 cm for 42 days, or by phases. However, technology adoption hinges on many factors like area ownership, farm distance from household, and market including the type of strategy needed to enhance technology uptake. Collaboration among research and development institutions and local partners is critical in training and empowering rural communities to adopt aquaculture technologies. PMID- 24817088 TI - Turning the tide: how blue carbon and payments for ecosystem services (PES) might help save mangrove forests. AB - In this review paper, we aim to describe the potential for, and the key challenges to, applying PES projects to mangroves. By adopting a "carbocentric approach," we show that mangrove forests are strong candidates for PES projects. They are particularly well suited to the generation of carbon credits because of their unrivaled potential as carbon sinks, their resistance and resilience to natural hazards, and their extensive provision of Ecosystem Services other than carbon sequestration, primarily nursery areas for fish, water purification and coastal protection, to the benefit of local communities as well as to the global population. The voluntary carbon market provides opportunities for the development of appropriate protocols and good practice case studies for mangroves at a small scale, and these may influence larger compliance schemes in the future. Mangrove habitats are mostly located in developing countries on communally or state-owned land. This means that issues of national and local governance, land ownership and management, and environmental justice are the main challenges that require careful planning at the early stages of mangrove PES projects to ensure successful outcomes and equitable benefit sharing within local communities. PMID- 24817089 TI - Prognostic value of S100/CD31 and S100/podoplanin double immunostaining in mucosal malignant melanoma of the head and neck. AB - BACKGROUND: In uncommon mucosal melanomas of the head and neck established prognostic factors are rare and controversially discussed. The purpose of this study was to evaluate outcome and value of S100/podoplanin and S100/CD31 double immunostaining in head and neck mucosal melanomas. METHODS: Retrospectively, patients with head and neck mucosal melanomas treated between 1973 and 2008 were analyzed. S100/podoplanin and S100/CD31 immunostaining were performed to detect lymph vessel invasion (LVI) and blood vessel invasion (BVI). Predictive parameters for disease-specific survival (DSS) were identified using univariate and multivariate statistics. RESULTS: Forty-two patients with head and neck mucosal melanoma were included. Three-year, 5-year, and 10-year DSS rates were 59%, 44%, and 20%, respectively. Age above 70 years, occurrence of distant metastasis, LVI, and BVI were significantly associated with shorter DSS time (p < .05), whereas localization at the conjunctiva showed better outcome. CONCLUSION: S100/podoplanin and S100/CD31 double immunostaining detect reliable LVI and BVI in head and neck mucosal melanoma and both are associated significantly with worse prognosis. PMID- 24817090 TI - Major complications and risk factors associated with surgical correction of congenital medial patellar luxation in 124 dogs. AB - Dogs treated for congenital medial patellar luxation were reviewed for the purpose of determining the incidence of postoperative major complications requiring surgical revision and the risk factors for their occurrence. Major complications occurred in 18.5% of the patellar luxation stabilization procedures with implant associated complications being the most frequent, patellar reluxation the second, and tibial tuberosity avulsion the third most common major complication. Other complications included patellar ligament rupture and trochlear wedge displacement. When recession trochleoplasty was performed in addition to tibial tuberosity transposition, a 5.1-fold reduction in the rate of patellar reluxation was observed. Release of the cranial belly of the sartorius muscle further reduced the incidence of patellar reluxation, while patella alta (pre- or postoperative) and patellar luxation grade were not found to influence the rate of reluxation. Tibial tuberosity avulsion was 11.1-times more likely when using a single Kirschner wire to stabilize a transposition, compared with two Kirschner wires. Independent to the number of Kirschner wires used, the more caudodistally the Kirschner wires were directed, the higher the risk for tibial tuberosity avulsion. Tension bands were used in 24.4% of the transpositions with no tuberosity avulsion occurring in stifles stabilized with a tension band. Overall, grade 1 luxations had a significantly lower incidence of major complications than other grades, while body weight, age, sex, and bilateral patellar stabilization were not associated with risk of major complication development. PMID- 24817091 TI - CD49f-positive testicular cells in Saanen dairy goat were identified as spermatogonia-like cells by miRNA profiling analysis. AB - miRNAs, a type of small RNA, play critical roles in mammalian spermatogenesis. Spermatogonia are the foundation of spermatogenesis and are valuable for the study of spermatogenesis. However, the expression profiling of the miRNAs in spermatogonia of dairy goats remains unclear. CD49f has been one of the surface markers used for spermatogonia enrichment by magnetic activated cell sorting (MACS). Therefore, we used a CD49f microbead antibody to purify CD49f-positive and -negative cells of dairy goat testicular cells by MACS and then analysed the miRNA expression in these cells in depth using Illumina sequencing technology. The results of miRNA expression profiling in purified CD49f-positive and negative testicular cells showed that 933 miRNAs were upregulated in CD49f positive cells and 916 miRNAs were upregulated in CD49f-negative cells with a twofold increase, respectively; several miRNAs and marker genes specific for spermatogonial stem cells (SSCs) in testis had a higher expression level in CD49f positive testicular cells, including miR-221, miR-23a, miR-29b, miR-24, miR-29a, miR-199b, miR-199a, miR-27a, and miR-21 and CD90, Gfra1, and Plzf. The bioinformatics analysis of differently expressed miRNAs indicated that the target genes of these miRNAs in CD49f-positive cells were involved in cell-cycle biological processes and the cell-cycle KEGG pathway. In conclusion, our comparative miRNAome data provide useful miRNA profiling data of dairy goat spermatogonia cells and suggest that CD49f could be used to enrich dairy goat spermatogonia-like cells, including SSCs. PMID- 24817092 TI - Variability of polychaete secondary production in intertidal creek networks along a stream-order gradient. AB - Dendritic tidal creek networks are important habitats for sustaining biodiversity and ecosystem functioning in salt marsh wetlands. To evaluate the importance of creek heterogeneity in supporting benthic secondary production, we assess the spatial distribution and secondary production of a representative polychaete species (Dentinephtys glabra) in creek networks along a stream-order gradient in a Yangtze River estuarine marsh. Density, biomass, and secondary production of polychaetes were found to be highest in intermediate order creeks. In high order (3rd and 4th) creeks, the density and biomass of D. glabra were higher in creek edge sites than in creek bottom sites, whereas the reverse was true for low order (1st and 2nd) creeks. Secondary production was highest in 2nd order creeks (559.7 mg AFDM m-2 year-1) and was ca. 2 folds higher than in 1st and 4th order creeks. Top fitting AIC models indicated that the secondary production of D. glabra was mainly associated with geomorphological characters including cross-sectional area and bank slope. This suggests that hydrodynamic forces are essential factors influencing secondary production of macrobenthos in salt marshes. This study emphasizes the importance of microhabitat variability when evaluating secondary production and ecosystem functions. PMID- 24817094 TI - Crystal structure and electronic properties of a thiolate-protected Au24 nanocluster. AB - Solving the total structures of gold nanoclusters is of critical importance for understanding their electronic, optical and catalytic properties. Herein, we report the X-ray structure of a charge-neutral Au24(SCH2Ph-(t)Bu)20 nanocluster. This structure features a bi-tetrahedral Au8 kernel protected by four tetrameric staple-like motifs. Electronic structure analysis is further carried out and the optical absorption spectrum is interpreted. The Au24(SCH2Ph-(t)Bu)20, Au23(S-c C6H11)16 and Au25(SCH2CH2Ph)18 nanoclusters constitute the first crystallographically characterized "trio". PMID- 24817093 TI - Interplay of sequence, topology and termini charge in determining the stability of the aggregates of GNNQQNY mutants: a molecular dynamics study. AB - This study explores the stabilities of single sheet parallel systems of three sequence variants of 1GNNQQNY7, N2D, N2S and N6D, with variations in aggregate size (5-8) and termini charge (charged or neutral). The aggregates were simulated at 300 and 330 K. These mutations decrease amyloid formation in the yeast prion protein Sup35. The present study finds that these mutations cause instability even in the peptide context. The protonation status of termini is found to be a key determinant of stabilities; other determinants are sequence, position of mutation and aggregate size. All systems with charged termini are unstable, whereas both stable and unstable systems are found when the termini are neutral. When termini are charged, the largest stable aggregate for the N2S and N6D systems has 3 to 4 peptides whereas N2D mutation supports oligomers of larger size (5-and 6-mers) as well. Mutation at 2nd position (N2S and N2D) results in fewer H-bonds at the mutated as well as neighboring (Gly1/Gln4) positions. However, no such effect is found if mutation is at 6th position (N6D). The effect of Asn->Asp mutation depends on the position and termini charge: it is more destabilizing at the 2nd position than at the 6th in case of neutral termini, however, the opposite is true in case of charged termini. Appearance of twist in stable systems and in smaller aggregates formed in unstable systems suggests that twist is integral to amyloid arrangement. Disorder, dissociation or rearrangement of peptides, disintegration or collapse of aggregates and formation of amorphous aggregates observed in these simulations are likely to occur during the early stages of aggregation also. The smaller aggregates formed due to such events have a variety of arrangements of peptides. This suggests polymorphic nature of oligomers and presence of a heterogeneous mixture of oligomers during early stages of aggregation. PMID- 24817095 TI - Dinitrogen fixation associated with shoots of aquatic carnivorous plants: is it ecologically important? AB - BACKGROUND AND AIMS: Rootless carnivorous plants of the genus Utricularia are important components of many standing waters worldwide, as well as suitable model organisms for studying plant-microbe interactions. In this study, an investigation was made of the importance of microbial dinitrogen (N2) fixation in the N acquisition of four aquatic Utricularia species and another aquatic carnivorous plant, Aldrovanda vesiculosa. METHODS: 16S rRNA amplicon sequencing was used to assess the presence of micro-organisms with known ability to fix N2. Next-generation sequencing provided information on the expression of N2 fixation associated genes. N2 fixation rates were measured following (15)N2-labelling and were used to calculate the plant assimilation rate of microbially fixed N2. KEY RESULTS: Utricularia traps were confirmed as primary sites of N2 fixation, with up to 16 % of the plant-associated microbial community consisting of bacteria capable of fixing N2. Of these, rhizobia were the most abundant group. Nitrogen fixation rates increased with increasing shoot age, but never exceeded 1.3 MUmol N g(-1) d. mass d(-1). Plant assimilation rates of fixed N2 were detectable and significant, but this fraction formed less than 1 % of daily plant N gain. Although trap fluid provides conditions favourable for microbial N2 fixation, levels of nif gene transcription comprised <0.01 % of the total prokaryotic transcripts. CONCLUSIONS: It is hypothesized that the reason for limited N2 fixation in aquatic Utricularia, despite the large potential capacity, is the high concentration of NH4-N (2.0-4.3 mg L(-1)) in the trap fluid. Resulting from fast turnover of organic detritus, it probably inhibits N2 fixation in most of the microorganisms present. Nitrogen fixation is not expected to contribute significantly to N nutrition of aquatic carnivorous plants under their typical growth conditions; however, on an annual basis the plant-microbe system can supply nitrogen in the order of hundreds of mg m(-2) into the nutrient-limited littoral zone, where it may thus represent an important N source. PMID- 24817096 TI - X chromosome regulation of autosomal gene expression in bovine blastocysts. AB - Although X chromosome inactivation in female mammals evolved to balance the expression of X chromosome and autosomal genes in the two sexes, female embryos pass through developmental stages in which both X chromosomes are active in somatic cells. Bovine blastocysts show higher expression of many X genes in XX than XY embryos, suggesting that X inactivation is not complete. Here, we reanalyzed bovine blastocyst microarray expression data from a network perspective with a focus on interactions between X chromosome and autosomal genes. Whereas male-to-female ratios of expression of autosomal genes were distributed around a mean of 1, X chromosome genes were clearly shifted towards higher expression in females. We generated gene coexpression networks and identified a major module of genes with correlated gene expression that includes female-biased X genes and sexually dimorphic autosomal genes for which the sexual dimorphism is likely driven by the X genes. In this module, expression of X chromosome genes correlates with autosome genes, more than the expression of autosomal genes with each other. Our study identifies correlated patterns of autosomal and X-linked genes that are likely influenced by the sexual imbalance of X gene expression when X inactivation is inefficient. PMID- 24817097 TI - Neurologic complications of diabetes. AB - Neuropathy as a complication of diabetes is common and presents in a wide variety of clinical scenarios. Often the work-up is one of exclusion tempered with monitoring the response of symptoms to treatment options. The collaboration of a neurologist is often crucial to determining the best course of action for the patient. This review will address proposed pathogenic mechanisms and potential therapeutic interventions, both pharmacologic and nonpharmacologic. PMID- 24817098 TI - Biparietal/transverse abdominal diameter ratio <= 1: potential marker for open spina bifida at 11-13-week scan. AB - OBJECTIVE: In the first trimester of pregnancy, a biparietal diameter (BPD) below the 5(th) percentile is a simple marker that enables the prenatal detection of half of all cases of open spina bifida. We hypothesized that relating the BPD measurement to the transverse abdominal diameter (TAD) might be another simple and effective screening method. In this study we assessed the performance of using the BPD/TAD ratio during the first trimester of pregnancy in screening for open spina bifida. METHODS: A total of 20,551 first-trimester ultrasound scans (11-13 weeks' gestation), performed between 2000 and 2013, were analyzed retrospectively; there were 26 cases of open spina bifida and 17,665 unaffected pregnancies with a crown-rump length of 45-84 mm and a record of both BPD and TAD measurements. RESULTS: The mean (+/- SD) BPD/TAD ratio was 1.00 +/- 0.06 for fetuses with spina bifida and 1.13 +/- 0.06 for those without (P < 0.0001). A BPD <= 5(th) percentile enabled the prenatal detection of 46.2% of spina bifida cases, while a BPD/TAD ratio of <= 1.00 detected 69.2%. If we considered cases in which either BPD was <= 5(th) percentile or BPD/TAD ratio was <= 1, we identified 76.9% of cases. In the latter case, the false-positive rate was 5.1%, while that for using a combination of both BPD <= 5th percentile and BPD/TAD ratio <= 1 was 0.6%, with a sensitivity of 38.5%. The positive predictive value of using a combination of BPD <= 5th percentile and BPD/TAD ratio <= 1 for detecting spina bifida was 8.5%. CONCLUSIONS: Between 11 and 13 weeks' gestation, relating BPD to TAD improves considerably the diagnostic performance of using BPD measurement alone in screening for open spina bifida. Screening using this marker is simple and applicable to a large population. PMID- 24817100 TI - Histone methylation during neural development. AB - Post-translational modification of histone proteins, such as the methylation of lysine and arginine residues, influences the higher order of chromatin and leads to gene activation or silencing. Histone methyltransferases or demethylases actively add or remove various methylation marks in a cell-type-specific and context-dependent way. They are therefore important players in regulating the transcriptional program of a cell. Some control of the various cellular programs is necessary during the differentiation of stem cells along a specific lineage, when differentiation to alternative lineages needs to be suppressed. One example is the development of neurons from neural stem cells during neurogenesis. Neurogenesis is a highly organized process that requires the proper coordination of survival, proliferation, differentiation and migration signals. This holds true for both embryonic and neural stem cells that give rise to the various cell types of the central nervous system. The control of embryonic and neural stem cell self-renewal and differentiation is achieved by both extrinsic and intrinsic signals that regulate gene expression precisely. Recent advances in neuroscience support the importance of epigenetic modifications, such as the methylation and acetylation of histones, as an important intrinsic mechanism for the regulation of central nervous system development. This review summarizes our current knowledge of histone methylation processes during neural development and provides insights into the function of histone methylation enzymes and their role during central nervous system development. PMID- 24817099 TI - Effectiveness of an autologous transfusion system following cemented and non cemented revisions of total hip arthroplasty. AB - PURPOSE: The goal of this study was to analyse the efficacy of blood autotransfusion using a continuous autologous transfusion system in revisions of total hip arthroplasty (THA). We looked at whether administration of allogeneic blood units was reduced in these cases and if there is a difference between cemented and non-cemented revisions. METHODS: Between January 2011 and December 2011, patients being treated with revision THA were included (n = 411). The following parameters were analysed: patient age, gender, weight (kg), height (cm), body mass index (BMI, kg/m(2)), surgical diagnosis, treatment and American Society of Anesthesiologists (ASA) classification score. The difference between pre- and post-operative haemoglobin (Hb, g/dl), amount of peri-operative blood loss (ml), amount of retransfused washed shed blood and amount of allogeneic and/or autologous transfusion (ml) were recorded. RESULTS: In both the cemented and non-cemented revision THA groups, there was no significant difference between pre- and post-operative Hb with or without using an autotransfusion system. In 92 of 186 cemented cases using an autologous transfusion system (49.5%) and 38 of 117 non-cemented cases using an autologous transfusion system (32.5%), allogeneic blood transfusion (ABT) was required. Cemented procedures using an autologous transfusion system got significantly more ABTs than non-cemented procedures using an autologous transfusion system (p = 0.0042, odds ratio = 2.035). CONCLUSIONS: Use of an autologous transfusion system did not reduce the amount of ABT in revision THA in the patient cohort reported here. In our opinion, general blood management is required before and during surgery to reduce administration of ABT. PMID- 24817101 TI - Chromatin dynamics in kidney development and function. AB - Epigenetic mechanisms are fundamental key features of developing cells connecting developmental regulatory factors to chromatin modification. Changes in the environment during renal development can have long-lasting effects on the permanent tissue structure and the level of expression of important functional genes. These changes are believed to contribute to kidney disease occurrence and progression. Although the mechanisms of early patterning and cell fate have been well described for renal development, little is known about associated epigenetic modifications and their impact on how genes interact to specify the renal epithelial cells of nephrons and how this specification is relevant to maintaining normal renal function. A better understanding of the renal cell specific epigenetic modifications and the interaction of different cell types to form this highly complex organ will not only help to better understand developmental defects and early loss of kidney function in children, but also help to understand and improve chronic disease progression, cell regeneration and renal aging. PMID- 24817102 TI - Epigenetics in cardiac development, function, and disease. AB - Substantial new knowledge has accrued, over the past few years, concerning the epigenetic regulation of heart development and disease. Epigenetic mechanisms comprise DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and non-coding RNAs. Many of these processes have been ascertained to influence the tight spatiotemporal control of gene expression during cardiac development. Nevertheless, the relative contribution of each mechanism and their potentially complex interplay remain largely unexplored. Cardiac development and disease are linked through the reactivation of fetal genes upon cardiac hypertrophy and failure. In cardiac disease, changes in gene expression are accompanied and influenced by distinct changes in histone modifications. Detailed knowledge about the epigenetic pathways of cardiac development and function is expected ultimately to lead to novel therapeutic strategies for heart disease and regenerative medicine. PMID- 24817103 TI - Olfactory subsystems in the honeybee: sensory supply and sex specificity. AB - The antennae of honeybee (Apis mellifera) workers and drones differ in various aspects. One striking difference is the presence of Sensilla basiconica in (female) workers and their absence in (male) drones. We investigate the axonal projection patterns of olfactory receptor neurons (ORNs) housed in S. basiconica in honeybee workers by using selective anterograde labeling with fluorescent tracers and confocal-microscopy analysis of axonal projections in antennal lobe glomeruli. Axons of S. basiconica-associated ORNs preferentially projected into a specific glomerular cluster in the antennal lobe, namely the sensory input-tract three (T3) cluster. T3-associated glomeruli had previously been shown to be innervated by uniglomerular projection (output) neurons of the medial antennal lobe tract (mALT). As the number of T3 glomeruli is reduced in drones, we wished to determine whether this was associated with the reduction of glomeruli innervated by medial-tract projection neurons. We retrogradely traced mALT projection neurons in drones and counted the innervated glomeruli. The number of mALT-associated glomeruli was strongly reduced in drones compared with workers. The preferential projections of S. basiconica-associated ORNs in T3 glomeruli together with the reduction of mALT-associated glomeruli support the presence of a female (worker)-specific olfactory subsystem that is partly innervated by ORNs from S. basiconica and is associated with the T3 cluster of glomeruli and mALT projection neurons. We propose that this olfactory subsystem supports parallel olfactory processing related to worker-specific olfactory tasks such as the coding of colony odors, colony pheromones and/or odorants associated with foraging on floral resources. PMID- 24817104 TI - Advances in total knee arthroplasty. PMID- 24817105 TI - A quantitative analysis of hip capsular thickness. AB - PURPOSE: The purpose of this study was to provide a comprehensive quantitative analysis of capsular thickness adjacent to the acetabular rim in clinically relevant locations. METHODS: Dissections were performed and hip capsular measurements were recorded on 13 non-paired, fresh-frozen cadaveric hemi-pelvises using a coordinate measuring device. Measurements were taken for each clock-face position at 0, 5, 10 and 15 mm distances from the labral edge. RESULTS: The capsule was consistently thickest at 2 o'clock for each interval from the labrum with a maximum thickness of 8.3 at 10 mm [95 % CI 6.8, 9.8] and 15 mm [95 % CI 6.8, 9.7]. The capsule was noticeably thinner between 4 and 11 o'clock with a minimum thickness of 4.1 mm [95 % CI 3.3, 4.9] at 10 o'clock at the labral edge. Direct comparison between 0 and 5 mm between 9 and 3 o'clock showed that the hip capsule was significantly thicker at 5 mm from the labrum at 9 o'clock (p = 0.027), 10 o'clock (p = 0.032), 1 o'clock (p = 0.003), 2 o'clock (p = 0.001) and 3 o'clock (p = 0.001). CONCLUSIONS: The hip capsule was thickest between the 1 and 2 o'clock positions for all measured distances from the acetabular labrum and reached its maximum thickness at 2 o'clock, which corresponds to the location of the iliofemoral ligament. PMID- 24817106 TI - Technical guide and tips on the all-arthroscopic Latarjet procedure. AB - Shoulder dislocation and subsequent anterior instability is a common problem in young athletes. The arthroscopic Bankart repair was originally described by Morgan et al. in 1987. The procedure has benefited from many technical advancements over the past 25 years and currently remains the most commonly utilized procedure in the treatment of anterior glenohumeral instability without glenoid bone loss. Capsulolabral repair alone may not be sufficient for treatment of patients with poor capsular tissue quality and significant bony defects. In the presence of chronic anterior glenoid bony defects, a bony reconstruction should be considered. The treatment of anterior shoulder instability with transfer of the coracoid and attached conjoint tendon such as the Latarjet procedure has provided reliable results. The arthroscopic Latarjet procedure was described in 2007 by the senior author, who has now performed the procedure over 450 times. The initial surgical technique has evolved considerably since its introduction, and this article presents a comprehensive update on this demanding but well-defined procedure. This article reviews technical tips to help the surgeon perform the surgery more smoothly, navigate through challenging situations, and avoid potential complications. Level of evidence V. PMID- 24817107 TI - An analysis of normative data on the knee rotatory profile and the usefulness of the Rotatometer, a new instrument for measuring tibiofemoral rotation: the reliability of the knee Rotatometer. AB - PURPOSE: This study proposes a simple and noninvasive instrument called the "Rotatometer" to measure tibiofemoral rotation and investigates its clinical applicability to the assessment of static rotational knee laxity. METHODS: The degree of tibiofemoral rotation was measured for a sample of 94 healthy volunteers with 188 knees by using the Rotatometer. The measurement was made by two independent and blinded examiners in three sessions at one-month intervals. The normative rotational profile and its relationship with gender and age were evaluated, and inter-observer reliability and intra-observer reliability were calculated. RESULTS: Males showed 62 degrees +/- 5 degrees of external rotation, whereas females, 64 degrees +/- 5 degrees . Males showed 44 degrees +/- 5 degrees of internal rotation, whereas females, 49 degrees +/- 4 degrees . Females showed significantly higher degrees of rotation than males. Tibiofemoral rotation was not correlated with age, and external rotation and internal rotation had a moderate positive relationship. Inter-observer reliability ranged from 0.84 to 0.91 for external rotation and 0.90 to 0.95 for internal rotation, and intra observer reliability ranged from 0.69 to 0.89 for external rotation and 0.87 to 0.95 for internal rotation. CONCLUSIONS: The results suggest the Rotatometer to be a simple and noninvasive device with high inter- and intra-observer reliability. The device can provide a normative rotational profile for reference purposes and thus can be used to determine the preoperative and postoperative rotational status of knees with anterior cruciate ligament injuries and compare results from different reconstruction techniques. PMID- 24817108 TI - Anatomy of the anterior cruciate ligament insertion sites: comparison of plain radiography and three-dimensional computed tomographic imaging to anatomic dissection. AB - PURPOSE: The aim of this study was to provide quantitative data on insertion sites of anterior cruciate ligament (ACL) and to assess the correlation among measurements of anatomic dissection, plain radiographs, and 3D CT images to determine whether radiologic data can accurately reflect real anatomic measurements. METHODS: Fifteen cadaveric knees were assessed using the three measurement modalities. Lengths of the long and short axis, area, and centre position of each bundle insertion sites by quadrant method were examined on both the femur and tibia. Distances from the insertion centre to distal cortical and posterior cortical margins of condyle on femur, and distance between insertion centres on tibia were also inspected. RESULTS: The average ACL insertion position in the three measurement modalities was at 33.9 % in deep-shallow position and at 26.5 % in high-low position for anteromedial (AM) bundle and at 39.2 and 54.8 %, respectively, for posterolateral (PL) bundle in femur. For tibia, it was at 36.9 % in anterior-posterior position and 47.1 % in medial-lateral position for AM bundle and at 43.1 and 53.5 %, respectively, for PL bundle. The slight differences in various measurements among the three modalities were not statistically significant. CONCLUSIONS: The femoral insertion positions were considerably shallow and low, whereas tibial insertion positions were near the average compared to those in previous studies. Plain radiographic and 3D CT measurements showed a reliable correlation with anatomic dissection measurements. The clinical relevance is that plain radiographs rather than 3D CT can be used as a post-operative evaluation tool after ACL reconstruction. PMID- 24817109 TI - The Turkish version of the Achilles tendon Total Rupture Score: cross-cultural adaptation, reliability and validity. AB - PURPOSE: The Achilles tendon Total Rupture Score (ATRS) is a questionnaire designed to evaluate pain, symptoms, function and physical activity after Achilles tendon rupture. The purpose of this study was to translate and culturally adapt the ATRS into Turkish and to determine its reliability and validity. METHODS: The ATRS was translated into Turkish in accordance with the stages recommended by Beaton. Seventy-four patients (73 male; average age: 42.3 +/- 7.6; range 27-63 years) suffering from previous Achilles tendon ruptures were included for the study. The ATRS-Turkish was administered twice at 7-14 days intervals with 52 of the 74 patients (51 male, average age: 41.8 +/- 7.8) to assess the test-retest reliability. Cronbach's alpha was used for internal consistency, and the inter-rater correlation coefficient (ICC) was used to calculate the test-retest reliability. The Turkish Short-Form-12 (SF-12) and the Foot and Ankle Outcome Score (FAOS) were employed for validity estimation. RESULTS: The internal consistency (Cronbach's alpha = 0.95) and the test-retest reliability (ICC = 0.98) were excellent. The mean interval between the two tests was 7.1 +/- 3.1 days. The mean and standard deviation of the first and second assessment of the ATRS were 78.1 +/- 23.1 and 79.1 +/- 22.5, respectively. The correlation coefficient between the ATRS-Turkish and the FAOS subscales (pain, symptoms, activities of daily living, sports and recreational activities, and quality of life) were determined (r = 0.82, r = 0.66, r = 0.79, r = 0.83 and r = 0.60, respectively, p < 0.0001). The ATRS-Turkish displayed good correlation with the SF-12 physical component score (r = 0.63, p < 0.001) and no correlation with the SF-12 mental component score (r = 0.22, p = 0.06). CONCLUSION: The ATRS Turkish was found to be reliable and valid for outcome evaluation after Achilles tendon ruptures. LEVEL OF EVIDENCE: II. PMID- 24817110 TI - How to improve femoral component rotational alignment in computer-assisted TKA. AB - PURPOSE: Although several anatomical landmarks have been proposed to obtain adequate femoral component alignment in total knee arthroplasty (TKA), there is still no consensus regarding the best way to correctly position the prosthetic component on the horizontal plane. A previous computed tomography (CT)-based study has demonstrated anatomical transepicondylar axis (aTEA) to be externally rotated relative to surgical transepicondylar axis (sTEA) of approximately 4.5 degrees . In this study, it is described a new methodological approach to femoral component rotational positioning through the use of previously reported CT scan information and navigation. METHODS: Eight consecutive patients scheduled for navigated TKA were selected. Rotational placement of the femoral component was performed using navigation system. The femoral component was implanted setting 4.5 degrees of internal rotation relative to the aTEA. Within 1 week from surgery, all patients underwent a CT scan, and the posterior condylar angle (PCA) was measured. A PCA of 0.0 degrees , meaning component placement parallel to sTEA, was set as femoral rotational alignment target. Clinical evaluation was performed at a mean 14.3 months of follow-up with KOOS questionnaire. RESULTS: The mean PCA measured on post-operative CT images was 0.4 degrees (SD 1.3 degrees ), meaning that the femoral component was averagely implanted with 0.4 degrees of internal rotation relative to the sTEA. Seven out of eight cases (87.5 %) resulted to have within 1 degrees deviation from the rotational alignment target. All patients but one reported good clinical results. CONCLUSIONS: Relevant finding of the present study was that the use of navigation and aTEA as a reference demonstrated to be accurate to set up femoral component rotational positioning on the horizontal plane in TKA. Further study should be performed to confirm this conclusion. PMID- 24817111 TI - Surface engineering of ZnO nanostructures for semiconductor-sensitized solar cells. AB - Semiconductor-sensitized solar cells (SSCs) are emerging as promising devices for achieving efficient and low-cost solar-energy conversion. The recent progress in the development of ZnO-nanostructure-based SSCs is reviewed here, and the key issues for their efficiency improvement, such as enhancing light harvesting and increasing carrier generation, separation, and collection, are highlighted from aspects of surface-engineering techniques. The impact of other factors such as electrolyte and counter electrodes on the photovoltaic performance is also addressed. The current challenges and perspectives for the further advance of ZnO based SSCs are discussed. PMID- 24817112 TI - Anti-diabetic effects of the ethanol extract of a functional formula diet in mice fed with a fructose/fat-rich combination diet. AB - BACKGROUND: Rhizoma dioscorea, Lycium barbarum, Prunella vulgaris and hawthorn are well known in both traditional food and folk medicine. Each of these plants reportedly possesses beneficial effects in the treatment of diabetes. In this study an anti-diabetic health-promoting diet was formulated by mixing the herbs in a ratio of 6:4:2:3, and the anti-diabetic effect and underlying mechanism were elucidated in vivo. RESULTS: Compared with the model control group, the formula, especially its ethanol extract (EF), could improve glucose intolerance and normalize the lipid profile. The mechanisms responsible for the amelioration of glucose and lipid metabolism in mice were an increase in peripheral and hepatic insulin sensitivity, a decrease in serum free fatty acid level, enhanced hepatic glucokinase activity and glycogen content and improved serum antioxidant activity. Hepatic histopathological examination also showed that EF administration markedly decreased fatty deposits in the liver of mice. CONCLUSION: The results of the present study demonstrated that the prepared functional formula diet is a potent alternative as an anti-diabetic health promoting diet. PMID- 24817113 TI - Food grade titanium dioxide disrupts intestinal brush border microvilli in vitro independent of sedimentation. AB - Bulk- and nano-scale titanium dioxide (TiO2) has found use in human food products for controlling color, texture, and moisture. Once ingested, and because of their small size, nano-scale TiO2 can interact with a number of epithelia that line the human gastrointestinal tract. One such epithelium responsible for nutrient absorption is the small intestine, whose constituent cells contain microvilli to increase the total surface area of the gut. Using a combination of scanning and transmission electron microscopy it was found that food grade TiO2 (E171 food additive coded) included ~25% of the TiO2 as nanoparticles (NPs; <100 nm), and disrupted the normal organization of the microvilli as a consequence of TiO2 sedimentation. It was found that TiO2 isolated from the candy coating of chewing gum and a commercially available TiO2 food grade additive samples were of the anatase crystal structure. Exposure to food grade TiO2 additives, containing nanoparticles, at the lowest concentration tested within this experimental paradigm to date at 350 ng/mL (i.e., 100 ng/cm(2) cell surface area) resulted in disruption of the brush border. Through the use of two independent techniques to remove the effects of gravity, and subsequent TiO2 sedimentation, it was found that disruption of the microvilli was independent of sedimentation. These data indicate that food grade TiO2 exposure resulted in the loss of microvilli from the Caco-2BBe1 cell system due to a biological response, and not simply a physical artifact of in vitro exposure. PMID- 24817114 TI - Hexamethylcyclopentadiene: time-resolved photoelectron spectroscopy and ab initio multiple spawning simulations. AB - Progress in our understanding of ultrafast light-induced processes in molecules is best achieved through a close combination of experimental and theoretical approaches. Direct comparison is obtained if theory is able to directly reproduce experimental observables. Here, we present a joint approach comparing time resolved photoelectron spectroscopy (TRPES) with ab initio multiple spawning (AIMS) simulations on the MS-MR-CASPT2 level of theory. We disentangle the relationship between two phenomena that dominate the immediate molecular response upon light absorption: a spectrally dependent delay of the photoelectron signal and an induction time prior to excited state depopulation in dynamics simulations. As a benchmark molecule, we have chosen hexamethylcyclopentadiene, which shows an unprecedentedly large spectral delay of (310 +/- 20) fs in TRPES experiments. For the dynamics simulations, methyl groups were replaced by "hydrogen atoms" having mass 15 and TRPES spectra were calculated. These showed an induction time of (108 +/- 10) fs which could directly be assigned to progress along a torsional mode leading to the intersection seam with the molecular ground state. In a stepladder-type approach, the close connection between the two phenomena could be elucidated, allowing for a comparison with other polyenes and supporting the general validity of this finding for their excited state dynamics. Thus, the combination of TRPES and AIMS proves to be a powerful tool for a thorough understanding of ultrafast excited state dynamics in polyenes. PMID- 24817115 TI - Reduction of proteinuria through podocyte alkalinization. AB - Podocytes are highly differentiated cells and critical elements for the filtration barrier of the kidney. Loss of their foot process (FP) architecture (FP effacement) results in urinary protein loss. Here we show a novel role for the neutral amino acid glutamine in structural and functional regulation of the kidney filtration barrier. Metabolic flux analysis of cultured podocytes using genetic, toxic, and immunologic injury models identified increased glutamine utilization pathways. We show that glutamine uptake is increased in diseased podocytes to couple nutrient support to increased demand during the disease state of FP effacement. This feature can be utilized to transport increased amounts of glutamine into damaged podocytes. The availability of glutamine determines the regulation of podocyte intracellular pH (pHi). Podocyte alkalinization reduces cytosolic cathepsin L protease activity and protects the podocyte cytoskeleton. Podocyte glutamine supplementation reduces proteinuria in LPS-treated mice, whereas acidification increases glomerular injury. In summary, our data provide a metabolic opportunity to combat urinary protein loss through modulation of podocyte amino acid utilization and pHi. PMID- 24817116 TI - T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling. AB - Natural killer (NK) cell activation is well orchestrated by a wide array of NK cell receptor repertoire. T-cell immunoglobulin and ITIM domain (TIGIT) receptor was recently defined as an inhibitory receptor that is expressed on NK cells and T cells. TIGIT receptor/poliovirus receptor (PVR) ligand engagement signaling inhibits cytotoxicity mediated by NK and CD8(+) T cells. However, it is unclear how TIGIT/PVR signaling regulates cytokine secretion in NK cells. Here we show that TIGIT/PVR engagement suppresses interferon-gamma (IFN-gamma) production of NK cells. TIGIT transgenic NK cells generate less IFN-gamma undergoing TIGIT/PVR ligation. Moreover, TIGIT knock-out NK cells produce much more IFN-gamma. TIGIT/PVR ligation signaling mediates suppression of IFN-gamma production via the NF-kappaB pathway. We identified a novel adaptor beta-arrestin 2 that associates with phosphorylated TIGIT for further recruitment of SHIP1 (SH2-containing inositol phosphatase 1) through the ITT-like motif. Importantly, SHIP1, but not other phosphatases, impairs the TNF receptor-associated factor 6 (TRAF6) autoubiquitination to abolish NF-kappaB activation, leading to suppression of IFN gamma production in NK cells. PMID- 24817117 TI - In vitro biosynthesis and chemical identification of UDP-N-acetyl-d-quinovosamine (UDP-d-QuiNAc). AB - N-acetyl-d-quinovosamine (2-acetamido-2,6-dideoxy-d-glucose, QuiNAc) occurs in the polysaccharide structures of many Gram-negative bacteria. In the biosynthesis of QuiNAc-containing polysaccharides, UDP-QuiNAc is the hypothetical donor of the QuiNAc residue. Biosynthesis of UDP-QuiNAc has been proposed to occur by 4,6 dehydration of UDP-N-acetyl-d-glucosamine (UDP-GlcNAc) to UDP-2-acetamido-2,6 dideoxy-d-xylo-4-hexulose followed by reduction of this 4-keto intermediate to UDP-QuiNAc. Several specific dehydratases are known to catalyze the first proposed step. A specific reductase for the last step has not been demonstrated in vitro, but previous mutant analysis suggested that Rhizobium etli gene wreQ might encode this reductase. Therefore, this gene was cloned and expressed in Escherichia coli, and the resulting His6-tagged WreQ protein was purified. It was tested for 4-reductase activity by adding it and NAD(P)H to reaction mixtures in which 4,6-dehydratase WbpM had acted on the precursor substrate UDP-GlcNAc. Thin layer chromatography of the nucleotide sugars in the mixture at various stages of the reaction showed that WbpM converted UDP-GlcNAc completely to what was shown to be its 4-keto-6-deoxy derivative by NMR and that addition of WreQ and NADH led to formation of a third compound. Combined gas chromatography-mass spectrometry analysis of acid hydrolysates of the final reaction mixture showed that a quinovosamine moiety had been synthesized after WreQ addition. The two-step reaction progress also was monitored in real time by NMR. The final UDP-sugar product after WreQ addition was purified and determined to be UDP-d-QuiNAc by one dimensional and two-dimensional NMR experiments. These results confirmed that WreQ has UDP-2-acetamido-2,6-dideoxy-d-xylo-4-hexulose 4-reductase activity, completing a pathway for UDP-d-QuiNAc synthesis in vitro. PMID- 24817118 TI - Casein kinase 1delta-dependent Wee1 protein degradation. AB - Eukaryotic mitotic entry is controlled by Cdk1, which is activated by the Cdc25 phosphatase and inhibited by Wee1 tyrosine kinase, a target of the ubiquitin proteasome pathway. Here we use a reporter of Wee1 degradation, K328M-Wee1 luciferase, to screen a kinase-directed chemical library. Hit profiling identified CK1delta-dependent Wee1 degradation. Small-molecule CK1delta inhibitors specifically disrupted Wee1 destruction and arrested HeLa cell proliferation. Pharmacological inhibition, siRNA knockdown, or conditional deletion of CK1delta also reduced Wee1 turnover. Thus, these studies define a previously unappreciated role for CK1delta in controlling the cell cycle. PMID- 24817119 TI - Glucocorticoid receptor beta stimulates Akt1 growth pathway by attenuation of PTEN. AB - Glucocorticoids (GCs) are known inhibitors of proliferation and are commonly prescribed to cancer patients to inhibit tumor growth and induce apoptosis via the glucocorticoid receptor (GR). Because of alternative splicing, the GR exists as two isoforms, GRalpha and GRbeta. The growth inhibitory actions of GCs are mediated via GRalpha, a hormone-induced transcription factor. The GRbeta isoform, however, lacks helix 12 of the ligand-binding domain and cannot bind GCs. While we have previously shown that GRbeta mRNA is responsive to insulin, the role of GRbeta in insulin signaling and growth pathways is unknown. In the present study, we show that GRbeta suppresses PTEN expression, leading to enhanced insulin stimulated growth. These characteristics were independent of the inhibitory qualities that have been reported for GRbeta on GRalpha. Additionally, we found that GRbeta increased phosphorylation of Akt basally, which was further amplified following insulin treatment. In particular, GRbeta specifically targets Akt1 in growth pathways. Our results demonstrate that the GRbeta/Akt1 axis is a major player in insulin-stimulated growth. PMID- 24817120 TI - Casein kinase II regulation of the Hot1 transcription factor promotes stochastic gene expression. AB - In Saccharomyces cerevisiae, Hog1 MAPK is activated and induces a transcriptional program in response to hyperosmotic stress. Several Hog1-responsive genes exhibit stochastic transcription, resulting in cell-to-cell variability in mRNA and protein levels. However, the mechanisms governing stochastic gene activity are not fully defined. Here we uncover a novel role for casein kinase II (CK2) in the cellular response to hyperosmotic stress. CK2 interacts with and phosphorylates the Hot1 transcription factor; however, Hot1 phosphorylation is not sufficient for controlling the stochastic response. The CK2 protein itself is required to negatively regulate mRNA expression of Hot1-responsive genes and Hot1 enrichment at target promoters. Single-cell gene expression analysis reveals altered activation of Hot1-targeted STL1 in ck2 mutants, resulting in a bimodal to unimodal shift in expression. Together, this work reveals a novel CK2 function during the hyperosmotic stress response that promotes cell-to-cell variability in gene expression. PMID- 24817121 TI - The photoinitiated reaction pathway of full-length cyanobacteriochrome Tlr0924 monitored over 12 orders of magnitude. AB - The coupling of photochemistry to protein chemical and structural change is crucial to biological light-activated signaling mechanisms. This is typified by cyanobacteriochromes (CBCRs), members of the phytochrome superfamily of photoreceptors that exhibit a high degree of spectral diversity, collectively spanning the entire visible spectrum. CBCRs utilize a basic E/Z isomerization of the bilin chromophore as the primary step in their photocycle, which consists of reversible photoconversion between two photostates. Despite intense interest in these photoreceptors as signal transduction modules a complete description of light-activated chemical and structural changes has not been reported. The CBCR Tlr0924 contains both phycocyanobilin and phycoviolobilin chromophores, and these two species photoisomerize in parallel via spectrally and kinetically equivalent intermediates before the second step of the photoreaction where the reaction pathways diverge, the loss of a thioether linkage to a conserved cysteine residue occurs, and the phycocyanobilin reaction terminates in a red-absorbing state, whereas the phycoviolobilin reaction proceeds more rapidly to a final green absorbing state. Here time-resolved visible transient absorption spectroscopy (femtosecond to second) has been used, in conjunction with time-resolved IR spectroscopy (femtosecond to nanosecond) and cryotrapping techniques, to follow the entire photoconversion of the blue-absorbing states to the green- and red absorbing states of the full-length form of Tlr0924 CBCR. Our analysis shows that Tlr0924 undergoes an unprecedented long photoreaction that spans from picoseconds to seconds. We show that the thermally driven, long timescale changes are less complex than those reported for the red/far-red photocycles of the related phytochrome photoreceptors. PMID- 24817122 TI - Concomitant action of structural elements and receptor phosphorylation determines arrestin-3 interaction with the free fatty acid receptor FFA4. AB - In addition to being nutrients, free fatty acids act as signaling molecules by activating a family of G protein-coupled receptors. Among these is FFA4, previously called GPR120, which responds to medium and long chain fatty acids, including health-promoting omega-3 fatty acids, which have been implicated in the regulation of metabolic and inflammatory responses. Here we show, using mass spectrometry, mutagenesis, and phosphospecific antibodies, that agonist-regulated phosphorylation of the human FFA4 receptor occurred primarily at five residues (Thr(347), Thr(349), Ser(350), Ser(357), and Ser(360)) in the C-terminal tail. Mutation of these residues reduced both the efficacy and potency of ligand mediated arrestin-3 recruitment as well as affecting recruitment kinetics. Combined mutagenesis of all five of these residues was insufficient to fully abrogate interaction with arrestin-3, but further mutagenesis of negatively charged residues revealed additional structural components for the interaction with arrestin-3 within the C-terminal tail of the receptor. These elements consist of the acidic residues Glu(341), Asp(348), and Asp(355) located close to the phosphorylation sites. Receptor phosphorylation thus operates in concert with structural elements within the C-terminal tail of FFA4 to allow for the recruitment of arrestin-3. Importantly, these mechanisms of arrestin-3 recruitment operate independently from Gq/11 coupling, thereby offering the possibility that ligands showing stimulus bias could be developed that exploit these differential coupling mechanisms. Furthermore, this provides a strategy for the design of biased receptors to probe physiologically relevant signaling. PMID- 24817124 TI - The interim regulated legal market for NPS ('legal high') products in New Zealand: The impact of new retail restrictions and product licensing. AB - New Zealand has recently established the world's first regulated legal market for new psychoactive products (NPS) (i.e. 'legal highs'). While the new regime is currently in a transitional phase, a range of retail restrictions and an interim licensing regime for NPS products and operators has been introduced. A product safety assessment framework has been developed to determine if a product should receive an interim licence. As a result of the licensing requirements, the number of NPS retail outlets fell from 3000- 4000 largely convenience stores to 156 specialty stores, and the number of legally available NPS products fell from 200 to fewer than 46. Some of the licensed products contain potent cannabinoid compounds. The licensing system provided, for the first time, information on all the products and operators involved in the sector, and this will assist future monitoring. The effectiveness of the new product safety assessment framework will depend on the quality of the data available on adverse cases. This is a challenge as self-reported information from users is often unreliable, and some emergency department cases do not have all the information required to make an accurate assessment. These data limitations indicate the need for retrospective studies of NPS adverse cases and additional test data. While the new legislation initially reduced the number of NPS retailers by prohibiting convenience outlets, new specialized NPS retail outlets may emerge as the new sector expands. Empirical research is required to measure the impact of the reduction in retail outlets and products on NPS availability. PMID- 24817123 TI - P2X4 forms functional ATP-activated cation channels on lysosomal membranes regulated by luminal pH. AB - P2X receptors are commonly known as plasma membrane cation channels involved in a wide variety of cell functions. The properties of these channels have been extensively studied on the plasma membrane. However, studies in amoeba suggest that P2X receptors are also present intracellularly and involved in vesicle fusion with the plasma membrane. Recently, it was shown that in addition to plasma membrane expression, mammalian P2X4 was also localized intracellularly in lysosomes. However, it was not clear whether the lysosomal P2X4 receptors function as channels and how they are activated and regulated. In this paper, we show that both P2X4 and its natural ligand, ATP, are enriched in lysosomes of COS1 and HEK293 cells. By directly recording membrane currents from enlarged lysosomal vacuoles, we demonstrated that lysosomal P2X4 formed channels activated by ATP from the luminal side in a pH-dependent manner. While the acidic pH at the luminal side inhibited P2X4 activity, increasing the luminal pH in the presence of ATP caused P2X4 activation. We further showed that, as for the plasma membrane P2X4, the lysosomal P2X4 was potentiated by ivermectin but insensitive to suramin and PPADS, and it permeated the large cation N-methyl-d-glucamine upon activation. Our data suggest that P2X4 forms functional ATP-activated cation channels on lysosomal membranes regulated by luminal pH. Together with the reported fusion effect of intracellular P2X in lower organisms, we speculate that the lysosome-localized P2X4 may play specific roles in membrane trafficking of acidic organelles in mammalian cells. PMID- 24817126 TI - Pulmonary artery rupture after bilateral pulmonary artery banding in a neonate with Loeys-Dietz syndrome and an interrupted aortic arch complex: report of a case. AB - Loeys-Dietz syndrome (LDS) is a recognized connective tissue disorder characterized by progressive aortic aneurysm and dissection. Patients are at high risk of aortic dissection or rupture at an early age, but to our knowledge, surgery on the great arteries has never been attempted in the neonatal period. We report a case of LDS with dilated pulmonary arteries and an interrupted aortic arch complex in a neonate. We performed bilateral pulmonary artery banding, but 12 days after the procedure, the infant died of rupture of the distal portion of the banding sites following massive dilatation. PMID- 24817125 TI - Intermediate-type vancomycin resistance (VISA) in genetically-distinct Staphylococcus aureus isolates is linked to specific, reversible metabolic alterations. AB - Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype. PMID- 24817127 TI - Serum aluminum levels in dialysis patients after sclerotherapy of internal hemorrhoids with aluminum potassium sulfate and tannic acid. AB - PURPOSE: Aluminum potassium sulfate and tannic acid (ALTA) is an effective sclerosing agent for internal hemorrhoids. However, it is contraindicated for patients with chronic renal failure on dialysis, because the aluminum in ALTA can cause aluminum encephalopathy when it is not excreted effectively. We conducted this study to measure the serum aluminum concentrations and observe for symptoms relating to aluminum encephalopathy in dialysis patients after ALTA therapy. METHODS: Ten dialysis patients underwent ALTA therapy for hemorrhoids. We measured their serum aluminum concentrations and observed them for possible symptoms of aluminum encephalopathy. RESULTS: The total injection volume of ALTA solution was 31 mL (24-37). The median serum aluminum concentration before ALTA therapy was 9 MUg/L, which increased to 741, 377, and 103 MUg/L, respectively, 1 h, 1 day, and 1 week after ALTA therapy. These levels decreased rapidly, to 33 MUg/L by 1 month and 11 MUg/L by 3 months after ALTA therapy. No patient suffered symptoms related to aluminum encephalopathy. CONCLUSIONS: Although the aluminum concentrations increased temporarily after ALTA therapy, dialysis patients with levels below 150 MUg/L by 1 week and thereafter are considered to be at low risk of the development of aluminum encephalopathy. PMID- 24817129 TI - An algorithm for noise correction of dual-energy computed tomography material density images. AB - PURPOSE: Dual-energy computed tomography (DECT) images can undergo a two-material decomposition process which results in two images containing material density information. Material density images obtained by that process result in images with increased pixel noise. Noise reduction in those images is desirable in order to improve image quality. METHODS: A noise reduction algorithm for material density images was developed and tested. A three-level wavelet approach combined with the application of an anisotropic diffusion filter was used. During each level, the resulting noise maps are further processed, until the original resolution is reached and the final noise maps obtained. Our method works in image space and, therefore, can be applied to any type of material density images obtained from any DECT vendor. A quantitative evaluation of the noise-reduced images using the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and 2D noise power spectrum was done to quantify the improvements. RESULTS: The noise reduction algorithm was applied to a set of images resulting in images with higher SNR and CNR than the raw density images obtained by the decomposition process. The average improvement in terms of SNR gain was about 49 % while CNR gain was about 52 %. The difference between the raw and filtered regions of interest mean values was far from reaching statistical significance (minimum [Formula: see text], average [Formula: see text]). CONCLUSION: We have demonstrated through a series of quantitative analyses that our novel noise reduction algorithm improves the image quality of DECT material density images. PMID- 24817128 TI - First functional and mutational analysis of group 3 N-acetylneuraminate lyases from Lactobacillus antri and Lactobacillus sakei 23K. AB - N-acetyl neuraminate lyases (NALs) catalyze the reversible aldol cleavage of N acetyl neuraminic acid (Neu5Ac) to pyruvate and N-acetyl-D-mannosamine (ManNAc). Previous phylogenetic studies divided NALs into four different groups. Groups 1 and 2 have been well characterized at both kinetic and molecular levels, but no NAL from group 3 has been studied to date. In this work, a functional characterization of two group 3 members was performed using the recombinant NALs from Lactobacillus antri and Lactobacillus sakei 23K, revealing an optimal pH of between 6.0 and 7.0, low stability at basic pHs (>8.0), low optimal temperatures and, especially, low catalytic efficiency compared with their counterparts in group 1 and 2. The mutational analysis carried out showed that a plausible molecular reason for the low activity shown by Lactobacillus antri and Lactobacillus sakei 23k NALs compared with group 1 and 2 NALs could be the relatively small sugar-binding pocket they contain. A functional divergence analysis concluding that group 3 is more closely related to group 2 than to group 1. PMID- 24817130 TI - Microfluidic chip for plasma separation from undiluted human whole blood samples using low voltage contactless dielectrophoresis and capillary force. AB - A plasma separating biochip is demonstrated using a capillary-driven contactless dielectrophoresis method with low voltage (~1 V) and high frequency induced electrostatics between red blood cells. The polarized red blood cells were aggregated and separated from plasma with a 69.8% volume separation and an 89.4% removal rate of red blood cells. PMID- 24817132 TI - Antidiabetic activity of Sedum dendroideum: metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin. AB - The aim of this study was to evaluate the antidiabetic potential of a leaf extract and flavonoids from Sedum dendroideum (SD). Additionally, our goals were to establish a possible structure/activity relationship between these flavonoids and to assess the most active flavonoid on the glycolytic enzyme 6-phosphofructo 1-kinase (PFK). SD juice (LJ), a flavonoid-rich fraction (BF), and separately five flavonoids were evaluated intraperitoneally for their acute hypoglycemic activity in normal and streptozotocin-induced diabetic mice. First, the major flavonoids kaempferol 3,7-dirhamnoside or kaempferitrin (1), kaempferol 3 glucoside-7-rhamnoside (2), and kaempferol 3-neohesperidoside-7-rhamnoside (3) were tested. Then, the monoglycosides kaempferol 7-rhamnoside (5) and kaempferol 3-rhamnoside (6) were assayed to establish their structure/activity relationship. The effect of 1 on PFK was evaluated in skeletal muscle, liver, and adipose tissue from treated mice. LJ (400 mg/kg), BF (40 mg/kg), and flavonoid 1 (4 mg/kg) reduced glycemia in diabetic mice (120 min) by 52, 53, and 61%, respectively. Flavonoids 2, 3, 5, and 6 were inactive or showed little activity, suggesting that the two rhamnosyl moieties in kaempferitrin are important requirements. Kaempferitrin enhanced the PFK activity chiefly in hepatic tissue, suggesting that it is able to stimulate tissue glucose utilization. This result is confirmed testing kaempferitrin on C2C12 cell line, where it enhanced glucose consumption, lactate production, and the key regulatory glycolytic enzymes. The hypoglycemic activity of kaempferitrin depends on the presence of both rhamnosyl residues in the flavonoid structure when intraperitoneally administered. Our findings show for the first time that a flavonoid is capable of stimulating PFK in a model of diabetes and that kaempferitrin stimulates glucose-metabolizing enzymes. This study contributes to the knowledge of the mechanisms by which this flavonoid exerts its hypoglycemic activity. PMID- 24817131 TI - Expression of Arabidopsis sugar transport protein STP13 differentially affects glucose transport activity and basal resistance to Botrytis cinerea. AB - Botrytis cinerea is the causing agent of the grey mold disease in more than 200 crop species. While signaling pathways leading to the basal resistance against this fungus are well described, the role of the import of sugars into host cells remains to be investigated. In Arabidopsis thaliana, apoplastic hexose retrieval is mediated by the activity of sugar transport proteins (STPs). Expression analysis of the 14 STP genes revealed that only STP13 was induced in leaves challenged with B. cinerea. STP13-modified plants were produced and assayed for their resistance to B. cinerea and glucose transport activity. We report that STP13-deficient plants exhibited an enhanced susceptibility and a reduced rate of glucose uptake. Conversely, plants with a high constitutive level of STP13 protein displayed an improved capacity to absorb glucose and an enhanced resistance phenotype. The correlation between STP13 transcripts, protein accumulation, glucose uptake rate and resistance level indicates that STP13 contributes to the basal resistance to B. cinerea by limiting symptom development and points out the importance of the host intracellular sugar uptake in this process. We postulate that STP13 would participate in the active resorption of hexoses to support the increased energy demand to trigger plant defense reactions and to deprive the fungus by changing sugar fluxes toward host cells. PMID- 24817133 TI - Cationic heterooligopeptides by ficain-catalyzed co-oligomerization of lysine and methionine ethylesters. AB - Oligopeptides are of high importance for various industrial applications, e.g. cosmetical or medical. Homooligomerizations and co-oligomerizations with anionic amino acid esters are well described but a successful synthesis of cationic heterooligopeptides has been missing so far. The present study reports the ficain catalyzed heterooligomerizations of LysOEt with MetOEt, leading to cationic heterooligopeptides with a yield up to 49.5% (w/w). MALDI-ToF/ToF-MS analyses proved successful syntheses of cationic heterooligopeptides with a DP between 7 and 10 amino acid residues, with the enzyme exhibiting a clear preference for methionine. PMID- 24817134 TI - B(C6F5)3 promoted cyclisation of internal propargyl esters: structural characterisation of 1,3-dioxolium compounds. AB - The reactions of internal propargyl esters with B(C6F5)3 provide access to stable zwitterionic 1,3-dioxolium compounds which are characterised by X-ray diffraction. These 6pi-electron systems show no significant aromatic stabilisation. PMID- 24817136 TI - Preface: evidence-based clinical practice guidelines for CKD: an abridged English version. PMID- 24817135 TI - Impact of mental and physical stress on blood pressure and pulse pressure under normobaric versus hypoxic conditions. AB - OBJECTIVE: Hypobaric hypoxia, physical and psychosocial stress may influence key cardiovascular parameters including blood pressure (BP) and pulse pressure (PP). We investigated the effects of mild hypobaric hypoxia exposure on BP and PP reactivity to mental and physical stress and to passive elevation by cable car. METHODS: 36 healthy volunteers participated in a defined test procedure consisting of a period of rest 1, mental stress task (KLT-R), period of rest 2, combined mental (KLT-R) and physical task (bicycle ergometry) and a last period of rest both at Graz, Austria (353 m asl) and at the top station Dachstein (2700 m asl). Beat-to-beat heart rate and BP were analysed both during the test procedures at Graz and at Dachstein and during passive 1000 m elevation by cable car (from 1702 m to 2700 m). RESULTS: A significant interaction of kind of stress (mental vs. combined mental and physical) and study location (Graz vs. Dachstein) was found in the systolic BP (p = .007) and PP (p = .002) changes indicating that during the combined mental and physical stress task sBP was significantly higher under hypoxic conditions whereas sBP and PP were similar during mental stress both under normobaric normoxia (Graz) and under hypobaric hypoxia (Dachstein). During the passive ascent in cable car less trivialization (psychological coping strategy) was associated with an increase in PP (p = .004). CONCLUSION: Our data show that combined mental and physical stress causes a significant higher raise in sBP and PP under hypoxic conditions whereas isolated mental stress did not affect sBP and PP under hypoxic conditions. PP-reaction to ascent in healthy subjects is not uniform. BP reactions to ascent that represents an accumulation of physical (mild hypobaric hypoxia) and psychological stressors depend on predetermined psychological traits (stress coping strategies). Thus divergent cardiovascular reactions can be explained by applying the multidimensional aspects of the biopsychosocial concept. PMID- 24817138 TI - Role of intrarenal (pro)renin receptor in ischemic acute kidney injury in rats. AB - BACKGROUND: (Pro)renin receptor [(P)RR], a trans-membrane receptor for renin and prorenin, is involved in the local activation of renin-angiotensin system (RAS) in the kidney. However, it remains to be determined whether (P)RR plays a role in the development of ischemic acute kidney injury (AKI). METHODS: We examined the abundance of (P)RR, renin/prorenin, angiotensinogen (AGT), AT1 receptor (AT1R), phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and nuclear factor-kappaB (NF-kappaB) by Western blots at 6, 24 and 48 h, and at 7 days after 45-min ischemic injury in rats. Intrarenal angiotensin II (Ang II) levels were determined by radioimmunoassay. We then tested whether the beneficial effects of oral loading of saline solution (1.0 % NaCl) for 7 days prior to ischemic injury were associated with changes in RAS components and ERK 1/2 and NF kappaB phosphorylation in the kidney. We also examined the effect of AT1R blocker, olmesartan, on ischemia-induced changes of (P)RR downstream such as AGT and phosphorylation of ERK 1/2. RESULTS: Renal ischemia increased the abundance of (P)RR protein at 24 h, and peaked at 48 h. (P)RR was mainly stained in the connecting tubules and collecting ducts in control rats, while ischemia increased its immunointensity in the damaged proximal tubules. Renal ischemia increased phosphorylation of ERK 1/2 and NF-kappaB proteins as early as at 6 h. There was a significant increase in AGT and Ang II levels at 24 and 48 h. Prior saline loading prevented the increase in serum creatinine at 48 h (5.36 +/- 1.26 vs. 3.38 +/- 1.74 mg/dL, p < 0.05), and suppressed the increases in renal (P)RR, AGT and Ang II contents. Saline drinking also significantly blocked the ischemia induced increases in phosphorylation of ERK 1/2 and NF-kappaB. In contrast, although treatment with olmesartan (10 mg/kg/day) for 14 days suppressed an increase of intrarenal AGT, olmesartan did not alleviate ischemic AKI, along with no change of (P)RR and phosphorylated ERK 1/2. CONCLUSIONS: These findings suggest that increased (P)RR is associated with activation of RAS-independent downstream such as ERK 1/2 and NF-kappaB phosphorylation in the ischemic kidney. PMID- 24817139 TI - Differential influence of hippocampal subfields to memory formation: insights from patients with temporal lobe epilepsy. AB - To clarify the anatomical organization of human memory remains a major challenge in clinical neuroscience. Experimental data suggest dentate gyrus granule cells play a major role in memory acquisition, i.e. pattern separation and rapid pattern completion, whereas hippocampal CA1 neurons are implicated in place memory and autobiographical memory retrieval. Patients with temporal lobe epilepsy present with a broad spectrum of memory impairment, which can be assessed during clinical examination. Although long seizure histories may contribute to a pathophysiological reorganization of functional connectivity, surgical resection of the epileptic hippocampus offers a unique possibility to anatomically study the differential contribution of hippocampal subfields to compromised learning and memory in humans. Herein, we tested the hypothesis of hippocampal subfield specialization in a series of 100 consecutive patients with temporal lobe epilepsy submitted to epilepsy surgery. Memory profiles were obtained from intracarotid amobarbital testing and non-invasive verbal memory assessment before surgery, and correlated with histopathologically quantified cell loss pattern in hippocampal subfields obtained from the same patients using the new international consensus classification for hippocampal sclerosis proposed by the International League against Epilepsy (HS ILAE). Interestingly, patients with CA1 predominant cell loss (HS ILAE Type 2; n = 13) did not show declarative memory impairment and were indistinguishable from patients without any hippocampal cell loss (n = 19). In contrast, 63 patients with neuronal loss affecting all hippocampal subfields including CA1, CA4 and dentate gyrus (HS ILAE Type 1), or predominant cell loss in CA4 and partially affecting also CA3 and dentate gyrus (HS ILAE Type 3, n = 5) showed significantly reduced declarative memory capacities (intracarotid amobarbital testing: P < 0.001; verbal memory: P < 0.05). Our results suggested an alternative model of how memory processing can be organized amongst hippocampal subfields, and that CA1 pyramidal cells are less critically involved in declarative human memory acquisition compared to dentate gyrus granule cells or CA4/CA3 pyramidal cells. PMID- 24817140 TI - Prognostic impact of infiltration of the vagina and/or uterus in women undergoing anterior pelvic exenteration for urothelial carcinoma of the bladder: results of a contemporary multicentre series. AB - PURPOSE: To evaluate for the first time the prognostic significance of female invasive patterns in stage pT4a urothelial carcinoma of the bladder in a large series of women undergoing anterior pelvic exenteration. PATIENTS AND METHODS: Our series comprised of 92 female patients in total of whom 87 with known invasion patterns were eligible for final analysis. Median follow-up for evaluation of cancer-specific mortality (CSM) was 38 months (interquartile ranges, 21-82 months). The impact on CSM was evaluated using multivariable Cox proportional-hazards regression analysis; predictive accuracy (PA) was assessed by receiver operating characteristic analysis. RESULTS: Vaginal invasion was noted in 33 patients (37.9 %; group VAG), uterine invasion in 20 patients (23 %; group UT), and infiltration of both vagina and uterus in 34 patients (39.1 %; group VAG + UT). Groups VAG and UT significantly differed from group VAG + UT with regard to the presence of positive soft tissue margins (STM) only. Five-year cancer-specific survival probabilities in the groups VAG, UT, and VAG + UT were 21, 20, and 21 %, respectively (p = 0.955). On multivariable analysis, only STM status (HR = 2.02, p = 0.023) independently influenced CSM. C-indices of multivariable models for CSM with and without integration of invasive patterns were 0.570 and 0.567, respectively (PA gain 0.3 %, p = 0.526). CONCLUSIONS: Infiltration of the vagina, the uterus or both is associated with poor 5-year survival rates. With regard to CSM, no difference was detectable between patients with different invasion patterns, thus justifying further collectively including these invasive patterns as stage pT4a. PMID- 24817141 TI - Transperitoneal versus retroperitoneal robotic partial nephrectomy: matched-pair comparisons by nephrometry scores. AB - PURPOSE: The purpose of this study was to compare perioperative outcomes of transperitoneal (TP) and retroperitoneal (RP) robot-assisted partial nephrectomy (RPN) by matched analysis using nephrometry systems. METHODS: A total of 107 patients who underwent RPN by a single surgeon from December 2008 to June 2012 were analyzed; 57 patients underwent TP RPN and 50 patients underwent RP RPN. Baseline demographic characteristics, perioperative outcomes and changes in renal function were collected by retrospective review of medical records. Matched-pair comparisons were done using RENAL score and C-index. RESULTS: No significant difference was observed between TP and RP RPN in patient age, body mass index, gender, laterality, clinical stage, tumor size, RENAL score or ASA score. The TP RPN had more cystic renal masses (TP vs. RP = 33 vs. 12 %, p = 0.012) and RP RPN had shorter median operation times (150 vs. 120 min, p = 0.015) and shorter mean warm ischemic times (26.2 vs. 22.6 min, p = 0.040) than TP RPN. In the matched pair analysis, RP RPN showed shorter operation times with similar warm ischemic times. Estimated blood loss and visual analog pain scales showed no significant differences between groups. A total of 12 (11.4 %) postoperative complications occurred, all Clavien class I or II with no significant difference in incidence. CONCLUSIONS: Retroperitoneal robot-assisted partial nephrectomy showed shorter operation time and generally equivalent perioperative results to TP RPN. RP RPN is a viable treatment option for treating posterior or lateral renal masses. PMID- 24817143 TI - [Epidemics and pandemics in general practice. What can we learn from the swine flu (H1N1) and EHEC outbreak?]. AB - BACKGROUND: As primary care givers with a coordinating function, general practitioners (GP) play a key role in dealing with epidemics and pandemics. As of yet, there are no studies in Germany describing the difficulties experienced by GPs in patient care during epidemics/pandemics. OBJECTIVES: This study aimed at identifying the problem areas in GPs' patient care during the H1N1 and EHEC (enterohemorrhagic strain of Escherichia coli) outbreaks. With this information, recommendations for guaranteeing proper patient care during future epidemics/pandemics can be derived. MATERIALS AND METHODS: In all, 12 qualitative, semi-structured, open guideline interviews with GPs in Hamburg and Lubeck were conducted, transcribed, and evaluated with qualitative content analysis. RESULTS: Five areas in ambulatory patient care were identified in which changes are needed from the primary care perspective: provision of information for GPs, workload, financing of epidemic-related measures, organization of the practices, care of those taken ill. CONCLUSIONS: The workload of GPs in particular can and should be reduced through successful, centralized information distribution during epidemics/pandemics. The GP's function as a coordinator should be supported and consolidated, in order to relieve the in-patient sector in cases of an epidemic/pandemic. Secured financing of epidemic-associated measures can help ensure patient care. PMID- 24817142 TI - Impact of warm versus cold ischemia on renal function following partial nephrectomy. AB - INTRODUCTION: We evaluated renal function following partial nephrectomy with cold ischemia (CI) versus warm ischemia (WI). METHODS: Data were collected from 1,396 patients at six institutions who underwent partial nephrectomy for a renal mass with normal contralateral kidney to evaluate percent change in glomerular filtration rate (GFR) at 3-18 months. A multivariate linear regression model tested the association of percent change GFR with clinical, operative, and pathologic factors. RESULTS: A total of 874 patients (63 %) underwent PN with CI and 522 (37 %) with WI. All patients undergoing laparoscopic and robotic-assisted partial nephrectomy (n = 443) had WI, whereas 92 % of open partial nephrectomy patients (n = 953) had CI. The CI group had a lower mean baseline GFR (72 vs. 80 ml/min/1.73 m(2)), longer median ischemia time (33 vs. 29 min), and larger mean tumor size (3.2 vs. 2.9 cm) with more advanced pathologic stage (T1b-T3: 25 vs. 16 %) (all p values <0.001). Patients with CI and WI demonstrated 12.3 and 10.1 % reductions in renal function from baseline, respectively (p = 0.067). Increasing age, female gender, and increasing tumor size were associated with reduction in renal function (all p values <0.001). Neither renal hypothermia nor operative technique independently predicted reduced renal function. Sensitivity analyses limited to ischemia time >30 min, baseline estimated glomerular filtration rate <60 ml/min/1.73 m(2), or tumors >4 cm did not significantly alter the findings. CONCLUSIONS: Increasing age, female gender, and larger tumor size independently predict a decrease in renal function following partial nephrectomy with a normal contralateral kidney. Within the limitations of a non-randomized comparison, including lack of parenchymal preservation percentage, neither surgical approach (open or laparoscopic) nor presence of hypothermia appears to be associated with long-term renal function. PMID- 24817144 TI - Simultaneous analysis of the gene expression profiles of cancer and stromal cells in endometrial cancer. AB - To address the role of cancer-stroma interactions, we performed gene expression profiling of both cancer and stroma, using matching samples of endometrial cancer (EC), and analyzed the relationship between the gene expression pattern and prognosis in EC. Sixty EC cases were included in this study (38 nonrecurrent and 22 recurrent). Cancer and stroma were separated by performing laser capture microdissection, and microarray analysis was performed separately on cancer and stromal cells. Genes related with progression-free survival (PFS) in cancer and stroma were analyzed using the Cox regression model, and we established a formula, based on the gene expression pattern of cancer and stroma, to predict recurrence using logistic regression. We estimated the accuracy of the formula using the 0.632 method. All cases were classified based on the 79 selected genes of cancer and stroma related to PFS, based on unsupervised clustering. A total of 143 genes in cancer, and 79 genes in stroma were significantly related with PFS. The estimated area under the curve of receiver operating characteristics curve in cancer and stroma to predict recurrence were 0.800 and 0.758, respectively. Based on the 79 genes of cancer, the 22 recurrent cases were divided into two groups, which generally correlated with the histological grade. In contrast, based on the 79 genes of stroma, the 22 recurrent cases displayed homogeneous gene expression, unrelated to the histological grade. We conclude that gene expression profiles of cancer and stroma can predict the recurrence of EC and stromal that gene expression does not depend on the cancer grade. PMID- 24817146 TI - Exploration of pharmacological interventions to prevent isoproterenol-induced myocardial infarction in experimental models. AB - High incidences of myocardial infarction associated with high morbidity and mortality, are a major concern and economic burden on industrialized nations. Persistent beta-adrenergic receptor stimulation with isoproterenol leads to the development of oxidative stress, myocardial inflammation, thrombosis, platelet aggregation and calcium overload, which ultimately cause myocardial infarction. Therapeutic agents that are presently employed for the prevention and management of myocardial infarction are beta-blockers, antithrombotics, thrombolytics, statins, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, calcium channel blockers and nitrovasodilators. In spite of effective available interventions, the mortality rate of myocardial infarction is progressively increasing. Thus, there has been a regular need to develop effective therapies for the prevention and management of this insidious disease. In this review, the authors give an overview of the consequences of isoproterenol in the pathogenesis of cardiac disorders and various therapeutic possibilities to prevent these disorders. PMID- 24817145 TI - Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count. AB - Several studies report associations between the particularly interesting new cysteine histidine-rich (PINCH) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients, and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy or before and after a change in the treatment regimen. The intervals were approximately 1 (T2) and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4 T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold changes in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm(3) at T2 compared to those with CD4 counts <200 cells/mm(3) at T2. This trend persisted irrespective of plasma or CSF viral burden or antiretroviral therapy CPE scores. The fold changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation coefficient = 0.69, p < 0.001; correlation coefficient = 0.83, p < 0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, WBC, or antiretroviral regimen CPE. PMID- 24817147 TI - Modification of the contact area of a standard force platform and runway for small breed dogs. AB - OBJECTIVES: To develop a platform that used standard size force plates for large breed dogs to capture ground reaction force data from any size dog. METHODS: A walkway platform was constructed to accommodate two force plates (60 cm x 40 cm) positioned in series to a variety of smaller sizes. It was constructed from a custom wood frame with thick aluminium sheet force plate covers that prevented transfer of load to the force plate, except for rectangular windows of three different dimensions. A friction study was performed to ensure plates did not translate relative to one another during gait trials. A prospective, observational, single crossover study design was used to compare the effect of force platform configuration (full plate size [original plate], half plate size [modified plate]) on ground reaction forces using eight adult healthy Labrador Retriever dogs. RESULTS: Slippage of the steel plate on the force plate did not occur. Peak propulsion force was the only kinetic variable statistically different between the full size and half sized platforms. There were no clinically significant differences between the full and half force platforms for the variables and dogs studied. DISCUSSION AND CONCLUSION: The modified force platform allows the original 60 x 40 cm force plate to be adjusted effectively to a 30 x 40 cm, 20 x 40 cm and 15 x 40 cm sized plate with no clinically significant change in kinetic variables. This modification that worked for large breed dogs will potentially allow kinetic analysis of a large variety of dogs with different stride lengths. PMID- 24817149 TI - Versatile post-functionalization of the external shell of cowpea chlorotic mottle virus by using click chemistry. AB - We present the modification of the outer protein shell of cowpea chlorotic mottle virus (CCMV) with linear and strained alkyne groups. These functionalized protein capsids constitute valuable platforms for post-functionalization via click chemistry. After modification, the integrity of the capsid and the reversible disassembly behavior are preserved. PMID- 24817148 TI - Novel polyglutamine model uncouples proteotoxicity from aging. AB - Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia. In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins. We are interested in elucidating the underlying mechanisms of toxicity of the protein ataxin-3, in which a polyglutamine expansion is the genetic determinant for Machado-Joseph Disease (MJD), also referred to as spinocerebellar ataxia 3 (SCA3). To this end, we have developed a novel model for ataxin-3 protein aggregation, by expressing a disease-related polyglutamine-containing fragment of ataxin-3 in the genetically tractable body wall muscle cells of the model system C. elegans. Here, we demonstrate that this ataxin-3 fragment aggregates in a polyQ length-dependent manner in C. elegans muscle cells and that this aggregation is associated with cellular dysfunction. However, surprisingly, this aggregation and resultant toxicity was not influenced by aging. This is in contrast to polyglutamine peptides alone whose aggregation/toxicity is highly dependent on age. Thus, the data presented here not only describe a new polyglutamine model, but also suggest that protein context likely influences the cellular interactions of the polyglutamine-containing protein and thereby modulates its toxic properties. PMID- 24817150 TI - Species identification from hair by means of spectral library searches. AB - Species identification from hair has been performed in the past by several techniques, such as scanning electron microscopy and polymerase chain reaction. Despite the great promise of mass spectrometry herein, the repetitive glycine stretches and the evolutionary conserved sequences of keratins make the results from conventional database search algorithms on MSMS fragmentation data very ambiguous. Here, we present a new method based on electron spray quadrupole time of-flight (ESI-Q-TOF) mass spectrometry and spectral library searching. By comparing different sets of data processing parameters, spectral libraries for human, cat, and dog were constructed with the highest possible specificity and sensitivity. This proof of principle was confirmed by the annotation of blind samples. In addition, by providing a step-by-step roadmap for creating such libraries, more species can be included in the future as demonstrated here by the inclusion of sheep and rabbit. Additionally, we illustrate that this approach allows for species identification of a single hair, making this an interesting approach in a forensic setting. PMID- 24817151 TI - Guest editorial: hematopoietic regulators in the marrow: new players in inter organ communication. PMID- 24817152 TI - Bone marrow Schwann cells induce hematopoietic stem cell hibernation. AB - Hematopoietic stem cells (HSCs) are clonogenic cells capable of both self-renewal and multilineage differentiation. In adult mouse bone marrow (BM), most HSCs remain in the non-dividing G0-phase of cell cycle, in close contact with supporting cells known as the HSC "niche". In the present study, we focused on signaling mechanisms that regulate stem cell dormancy in the BM niche. We show that TGF-beta type II receptor deficiency causes reduced phosphorylation of Smad2/3 and impairs long-term repopulating activity in HSCs, suggesting a significant role for TGF-beta/Smad signaling in hematopoiesis. Furthermore, we aimed at defining the candidate BM niche responsible for homeostasis of hematopoiesis, and revealed that non-myelinating Schwann cells sustain HSC hibernation by converting TGF-beta from its latent to its active form. PMID- 24817153 TI - The structural and functional basis of catalysis mediated by NAD(P)H:acceptor Oxidoreductase (FerB) of Paracoccus denitrificans. AB - FerB from Paracoccus denitrificans is a soluble cytoplasmic flavoprotein that accepts redox equivalents from NADH or NADPH and transfers them to various acceptors such as quinones, ferric complexes and chromate. The crystal structure and small-angle X-ray scattering measurements in solution reported here reveal a head-to-tail dimer with two flavin mononucleotide groups bound at the opposite sides of the subunit interface. The dimers tend to self-associate to a tetrameric form at higher protein concentrations. Amino acid residues important for the binding of FMN and NADH and for the catalytic activity are identified and verified by site-directed mutagenesis. In particular, we show that Glu77 anchors a conserved water molecule in close proximity to the O2 of FMN, with the probable role of facilitating flavin reduction. Hydride transfer is shown to occur from the 4-pro-S position of NADH to the solvent-accessible si side of the flavin ring. When using deuterated NADH, this process exhibits a kinetic isotope effect of about 6 just as does the NADH-dependent quinone reductase activity of FerB; the first, reductive half-reaction of flavin cofactor is thus rate-limiting. Replacing the bulky Arg95 in the vicinity of the active site with alanine substantially enhances the activity towards external flavins that obeys the standard bi-bi ping-pong reaction mechanism. The new evidence for a cryptic flavin reductase activity of FerB justifies the previous inclusion of this enzyme in the protein family of NADPH-dependent FMN reductases. PMID- 24817154 TI - Deep brain and motor cortex stimulation. AB - Deep brain stimulation (DBS) and motor cortex stimulation (MCS) are established surgical modalities that have been successfully used over the last several decades for treatment of numerous chronic pain disorders. Most often, these approaches are reserved for severe, disabling, and medically refractory syndromes after less invasive approaches have been tried and have failed. Although the exact mechanism of action for DBS and MCS remains unknown, it appears that these central neuromodulation processes have multifactorial effects on central pain processing and descending pain inhibition. Clinical studies and laboratory reports have shed some light on stimulation details and optimal parameters, as well as the choice of stimulation targets, best surgical indications, and expected long-term outcomes. Based on the worldwide published experience, it appears that additional data is needed to obtain regulatory approval for both MCS and DBS for the treatment of pain. Following approval, further clinical research will shape the ability to initiate, implement, and update comprehensive patient and procedure selection paradigms. PMID- 24817155 TI - Cervical length in late second and third trimesters: a mixture model for predicting delivery. AB - OBJECTIVES: To examine the distribution of cervical length (CL) in the late second and third trimesters of pregnancy and construct survival models for spontaneous delivery. METHODS: This cross-sectional study included 647 women with a singleton pregnancy who had routine CL measurements taken by transvaginal ultrasonography between 24 and 40 weeks' gestation. Only one measurement per patient was included in the analysis. Exploratory data analysis revealed that the distribution of CL measurements was a mixture of two Gaussian distributions, and subsequently a mixture model was applied to describe the distribution of CL. Changes in CL in relation to gestational age were examined by regression analysis and measurements were converted to Z-scores. Survival analysis was applied to the subgroups identified, to describe the probability of delivery throughout gestation. RESULTS: CL was best described by a mixture model of two subgroups with Gaussian distribution, one including women with a long cervix (73.85% of the study population, mean CL of 28.2 +/- 4.45 mm) and the other including women with a short cervix (26.15% of the study population, mean CL of 12.3 +/- 5.14 mm). CL was dependent on gestational age (GA), therefore conversion to Z-scores was employed in the analysis. Women with a short cervix had a higher probability for spontaneous delivery (hazard ratio (HR), 1.807; P < 0.001) than did women with a long cervix, after adjustment for GA at the time of measurement (GA HR, 1.115; P < 0.001). In both subgroups, the probability of spontaneous delivery was predicted by the GA and CL Z-scores. Survival models for the prediction of spontaneous delivery were constructed separately for the short-cervix subgroup (GA HR, 1.085; P < 0.001 and CL Z-score HR, 0.819; P = 0.003) and the long-cervix subgroup (GA HR, 1.130; P < 0.001 and CL Z-score HR, 0.864; P = 0.005). CONCLUSIONS: CL follows a mixture of two Gaussian distributions, one for a short and one for a long cervix. Late second-trimester/third-trimester CL measurement may be of value in estimating the probability for spontaneous delivery at any given gestational age. PMID- 24817156 TI - Do we need to do overcorrection in Blount's disease? AB - PURPOSE: In order to prevent recurrent deformity, overcorrection in Blount's disease has been a common practice by most paediatric orthopaedic surgeons. However, some patients have persistent valgus alignment resulting in awkward deformity. The femoro-tibial angle (FTA) was measured in this series of cases to determine the necessity of such practice. METHOD: During 1998-2010, patients with Blount's disease stage 2 by Langenskiold, aged from 30 to 40 months who had failed from bracing and underwent valgus osteotomy were included. Seventeen legs had postoperative FTA 7-13 degrees (group 1) and 48 legs had postoperative FTA more than 13 degrees (group 2). ROC curve was used to determine the appropriate FTA that was suitable to prevent recurrence. RESULTS: Four legs had recurrence (28.6%) in group 1 and six legs (12.5%) had recurrence in group 2. Chi-square test between two groups were not statistically significant in recurrence (p = 0.434). Age and BMI were not statistically significant between recurrent and non recurrent groups. The ROC curve shows that overcorrection more than 15 degrees did not show benefit to prevent the recurrence in Blount's stage 2. CONCLUSION: Our study showed that the overcorrection group had non-statistically significant recurrence compared to the non-overcorrection group, and overcorrection more than valgus 15 degrees has no benefit to prevent recurrence. PMID- 24817157 TI - Heavy browsing affects the hydraulic capacity of Ceanothus rigidus (Rhamnaceae). AB - Defoliation by herbivores can reduce carbon assimilation, change plant water relations, and even shift the biotic structure of plant communities. In this study, we took advantage of a long-term deer exclosure experiment to examine the consequences of persistent deer herbivory on plant water relations and the xylem structure-function relationships in Ceanothus rigidus, a maritime chaparral shrub in coastal California. Browsed plants had thicker stems with many intertwined short distal twigs, and significantly higher sapwood-to-leaf area ratios than their non-browsed counterparts. Leaf area-specific hydraulic conductivity was similar in both browsed and non-browsed plants, but xylem area-specific conductivity was significantly lower in the browsed plants. Vessel diameters were equivalent in both plant groups, but the number of vessels on a transverse area basis was nearly 40% lower in the browsed plants, accounting for their lower transport efficiency. Mid-day in situ water potentials and losses of hydraulic conductivity due to embolism were similar in both groups of plants but stomatal conductance was higher in the browsed shrubs in the early part of the growing season. We discuss our findings in the context of whole-plant ecophysiology, and explore the consequences of herbivory on hormonal signals, wood anatomy, and xylem function. PMID- 24817158 TI - Slow lifelong growth predisposes Populus tremuloides trees to mortality. AB - Widespread dieback of aspen forests, sometimes called sudden aspen decline, has been observed throughout much of western North America, with the highest mortality rates in the southwestern United States. Recent aspen mortality has been linked to drought stress and elevated temperatures characteristic of conditions expected under climate change, but the role of individual aspen tree growth patterns in contributing to recent tree mortality is less well known. We used tree-ring data to investigate the relationship between an individual aspen tree's lifetime growth patterns and mortality. Surviving aspen trees had consistently higher average growth rates for at least 100 years than dead trees. Contrary to observations from late successional species, slow initial growth rates were not associated with a longer lifespan in aspen. Aspen trees that died had slower lifetime growth and slower growth at various stages of their lives than those that survived. Differences in average diameter growth between live and dead trees were significant (alpha = 0.05) across all time periods tested. Our best logistical model of aspen mortality indicates that younger aspen trees with lower recent growth rates and higher frequencies of abrupt growth declines had an increased risk of mortality. Our findings highlight the need for species-specific mortality functions in forest succession models. Size-dependent mortality functions suitable for late successional species may not be appropriate for species with different life history strategies. For some early successional species, like aspen, slow growth at various stages of the tree's life is associated with increased mortality risk. PMID- 24817159 TI - Metrological assessment of a portable analyzer for monitoring the particle size distribution of ultrafine particles. AB - Adverse health effects caused by worker exposure to ultrafine particles have been detected in recent years. The scientific community focuses on the assessment of ultrafine aerosols in different microenvironments in order to determine the related worker exposure/dose levels. To this end, particle size distribution measurements have to be taken along with total particle number concentrations. The latter are obtainable through hand-held monitors. A portable particle size distribution analyzer (Nanoscan SMPS 3910, TSI Inc.) was recently commercialized, but so far no metrological assessment has been performed to characterize its performance with respect to well-established laboratory-based instruments such as the scanning mobility particle sizer (SMPS) spectrometer. The present paper compares the aerosol monitoring capability of the Nanoscan SMPS to the laboratory SMPS in order to evaluate whether the Nanoscan SMPS is suitable for field experiments designed to characterize particle exposure in different microenvironments. Tests were performed both in a Marple calm air chamber, where fresh diesel particulate matter and atomized dioctyl phthalate particles were monitored, and in microenvironments, where outdoor, urban, indoor aged, and indoor fresh aerosols were measured. Results show that the Nanoscan SMPS is able to properly measure the particle size distribution for each type of aerosol investigated, but it overestimates the total particle number concentration in the case of fresh aerosols. In particular, the test performed in the Marple chamber showed total concentrations up to twice those measured by the laboratory SMPS likely because of the inability of the Nanoscan SMPS unipolar charger to properly charge aerosols made up of aggregated particles. Based on these findings, when field test exposure studies are conducted, the Nanoscan SMPS should be used in tandem with a condensation particle counter in order to verify and correct the particle size distribution data. PMID- 24817160 TI - A novel maize homeodomain-leucine zipper (HD-Zip) I gene, Zmhdz10, positively regulates drought and salt tolerance in both rice and Arabidopsis. AB - Increasing evidence suggests that homeodomain-leucine zipper I (HD-Zip) I transcription factors play important roles in abiotic stress responses, but no HD Zip I proteins have been reported in maize. Here, a drought-induced HD-Zip I gene, Zmhdz10, was isolated from maize and characterized for its role in stress responses. Real-time quantitative PCR showed that expression of Zmhdz10 was also induced by salt stress and ABA. Transient expression of Zmhdz10-green fluorescent protein (GFP) fusion proteins in onion cells showed a nuclear localization of Zmhdz10. Yeast hybrid assays demonstrated that Zmhdz10 has transactivation and DNA-binding activity in yeast cells. Overexpression of Zmhdz10 in rice led to enhanced tolerance to drought and salt stresses and increased sensitivity to ABA. Moreover, Zmhdz10 transgenic plants had lower relative electrolyte leakage (REL), lower malondialdehyde (MDA) and increased proline content relative to wild-type plants under stress conditions, which may contribute to enhanced stress tolerance. Zmhdz10 transgenic Arabidopsis plants also exhibited enhanced tolerance to drought and salt stresses that was concomitant with altered expression of stress/ABA-responsive genes, including Delta1-Pyrroline-5 carboxylate synthetase 1 (P5CS1), Responsive to dehydration 22 (RD22), Responsive to dehydration 29B (RD29B) and ABA-insensitive 1 (ABI1). Taken together, these results suggest that Zmhdz10 functions as a transcriptional regulator that can positively regulate drought and salt tolerance in plants through an ABA-dependent signaling pathway. PMID- 24817161 TI - Measurements of tibial rotation during a simulated pivot shift manoeuvre using a gyroscopic sensor. AB - PURPOSE: The pivot shift has been correlated with patient-reported outcomes and knee function following ACL injury and reconstruction. Tibial rotation has been recognized as an important component to the pivot shift motion path. However, few methodologies exist to quantify tibial rotation in the clinical setting. The purpose of this study was to validate the use of a wireless gyroscopic sensor to measure axial rotation of the tibia during a manually simulated pivot shift manoeuvre in cadaveric specimens. We hypothesized that integrated gyroscopic measurements of tibial rotation velocity (tibial rotation) would be highly correlated with tibial rotations simultaneously recorded with a rotary potentiometer during a simulated pivot shift motion under intact and ACL deficient conditions. METHODS: Gyroscopic measurements of rotational velocity were integrated and calibrated to a known arc of rotation. The gyroscope was mounted on the distal tibia with its axis aligned to the tibial shaft. Ten simulations of a pivot shift motion pathway were performed on nine cadaveric knees under intact and ACL-deficient conditions. Logistic regression was used to compare gyroscopic and potentiometer measurements of tibial rotation for both test conditions. RESULTS: Gyroscopic measurements of maximum external tibial rotation during the simulated pivot shift motion pathway were strongly correlated with potentiometer measurements of external tibial rotation in both the intact and ACL-deficient states (R (2) = 0.984). CONCLUSION: The gyroscope evaluated in this cadaveric study was capable of accurately recording tibial rotation during a simulated pivot shift motion pathway. PMID- 24817162 TI - Variability of tunnel positioning in fluoroscopic-assisted ACL reconstruction. AB - PURPOSE: Intraoperative fluoroscopy has been proposed as a feasible method to improve the accuracy of anatomical tunnel positioning. However, it has so far not been determined, whether this technique reduces the variability of tunnel positioning in a clinical set-up. Therefore, the purpose of this study was to determine the variability of tunnel positions applying intraoperative fluoroscopy. METHODS: Femoral and tibial tunnel positions of 112 fluoroscopic ACL reconstruction cases were determined according to validated radiological measurement methods. Mean positions, standard deviations and ranges were calculated to determine the variability of the tunnel positions. Subgroup variability analysis was performed to analyse cases in which tunnel positions were corrected. RESULTS: Applying intraoperative fluoroscopy, the variability of tunnel positions was found to be 3 % at the femur (range 15.4 %) and 2.3 % at the tibia (9.7 %). In 34 cases (30.0 %), non-satisfactory tunnel positions were identified and could be corrected achieving more accurate positions regarding to radiological parameters (14* femur, 16* tibia, 4* femur and tibia). CONCLUSIONS: The results of the presented study indicate that intraoperative fluoroscopy allows to identify non-accurate tunnel positions regarding to radiological criteria. The determined low variability indicates that fluoroscopic-based ACL reconstruction can be recommended as a feasible, easy and effective adjunct that enables surgeons to create more consistent and reliable tunnel positions in ACL reconstruction. LEVEL OF EVIDENCE: IV. PMID- 24817163 TI - Endoscopic decompression for chronic compartment syndrome of the forearm in motocross racers. AB - PURPOSE: Sporting activities that involve repetitive stress to muscle compartments can elicit chronic exertional compartment syndrome. Its occurrence in the lower leg muscle compartments is most common, but other locations are less well known and the pathophysiology is not completely understood. In motocross racers, chronic exertional compartment syndrome can occur in the muscles of the lower arm. Currently, the only accepted treatment of correctly diagnosed chronic exertional compartment syndrome is surgical release of the fascia, which successfully relieves pain and allows patients to return to full activity. Open decompression is considered as the gold standard of treatment. This clinical paper describes our new endoscopic technique and investigates the functional outcome after surgery. METHODS: We report on a series of 154 chronic exertional compartment syndromes afflicted motocross racers treated with an endoscopic release of the lower arm muscles. An MRI scan before and after strenuous exercise of the hand flexors (repetitive grip until exhaustion for 15 min) was performed to confirm the clinical diagnosis of chronic exertional compartment syndrome. Symptom severity before and after surgery was assessed using a visual analogue scale. RESULTS: Preoperative symptom severity scores were 1.1 +/- 0.3 before exercise and 7.4 +/- 1.5 after exercise. Post-operatively, these were 1.0 +/- 0.2 and 1.7 +/- 0.9. The pre- versus post-operative symptom scores after exercise were significantly different (p < 0.0001). No perioperative complications occurred, and at 6 weeks, all of the racers resumed their sportive activities. CONCLUSION: It can be concluded that endoscopic release of the superficial compartment of the forearms of motocross racers diagnosed with chronic exertional compartment syndrome is a valuable treatment option, with mild post-operative pain and fast recovery. PMID- 24817164 TI - Matrix-induced autologous chondrocyte implantation (MACI) for chondral defects in the patellofemoral joint. AB - PURPOSE: Both autologous chondrocyte implantation (ACI) and tibial tubercle transfer (TTT) have been used to treat chondral defects in the patellofemoral joint resulting in clinical improvement. Our study investigates the magnetic resonance imaging (MRI) appearance of the matrix-induced autologous chondrocyte implantation (MACI) graft at 5-year follow-up to determine if it provides a durable treatment option in patients with an average age of 42 (standard deviation 11.6). METHODS: Twenty-three patients were available for follow-up. Nine patients required realignment of the extensor mechanism with lateral release and TTT. The MRI magnetic resonance observation of cartilage repair tissue (MOCART) scoring system was used to assess the graft status. Clinical outcomes were assessed at these time periods. RESULTS: The mean weighted MOCART composite score improved from 2.87 at 3 months to 3.39 at 5 years, indicating an intact appearance in most grafts. Graft height measured >50% of the adjacent native cartilage in 82% of patients. Clinical improvement assessed by the Knee Injury and Osteoarthritis Outcome Score, SF-36 (PCS) and the 6-minute walk test was demonstrated between pre-operative scores and final 5-year follow-up. 91% of patients would undergo MACI again. Correlation between MOCART and clinical scores were low in MACI to the patellofemoral joint. No significant difference was found in outcome between those that required realignment surgery compared with those that did not. CONCLUSION: Patellofemoral MACI provides a durable graft on MRI assessment at 5 years with resultant clinical improvement. Further work is needed to determine which defect locations may benefit most from this procedure. LEVEL OF EVIDENCE: IV. PMID- 24817165 TI - Lower limb clinical and radiographic osteoarthritis in former elite male athletes. AB - PURPOSE: To investigate the prevalence of lower extremities clinical and radiographic OA in former elite male athletes and referents from the general population and to examine its association with the participants' demographic characteristics. METHODS: Two hundred and eighteen former elite male athletes (soccer, volleyball, martial arts, track and field and basketball players, and skiers) and 181 male controls that reported no systematic athletic activity were examined by means of questionnaire, clinical and radiographic evaluation. Exclusion criteria were age younger than 40 years and a positive history of lower extremity surgery, bone or soft tissue trauma and inflammatory arthropathy. RESULTS: Overall, the prevalence of clinical OA between former elite athletes (15.6 %) and controls (14.4 %) was similar (n.s.). The prevalence of radiographic OA was significantly higher (p = 0.03) in former elite athletes (36.6 %) compared with controls (23.9 %). All the participants with clinical OA who underwent radiographic examination also had radiographic OA. The prevalence of clinical and radiographic OA was similar (n.s.) between former athletes of different sports. Age, body mass index (BMI) and occupation variably predicted the prevalence of hip, knee and ankle OA in both study groups. CONCLUSIONS: In the absence of major bone and soft tissue lower limb trauma during their athletic career, former elite athletes may not be at increased risk of developing clinical OA. Radiographic signs of OA present at a significantly higher incidence and possibly precede the clinical onset of OA. Age, BMI and occupation are identified as strong predictors of the development of OA in former elite athletes. PMID- 24817166 TI - Effect of high tibial osteotomy on joint loading in symptomatic patients with varus aligned knees: a study using SPECT/CT. AB - PURPOSE: The purpose was to prospectively evaluate the outcome, in particular the SPECT/CT bone tracer uptake (BTU) after high tibial osteotomy (HTO) due to symptomatic varus malalignment. It was the hypothesis that the BTU after HTO decreases in the medial compartment, clinical outcome and the degree of correction correlates with BTU and asymptomatic patients after HTO reveals a significantly decreased BTU in the medial subchondral areas. METHODS: Twenty-two consecutive patients with 23 knees undergoing medial opening-wedge HTO for medial compartment overloading were assessed pre- and postoperatively (12 and/or 24 months) using Tc-99m-HDP-SPECT/CT including our 4D-SPECT/CT protocol. BTU was quantified and localized to specific biomechanically relevant joint areas. Maximum absolute and relative values (mean +/- standard deviation, median and range) for each area were recorded. Pre- and postoperative mechanical alignment was measured. At 24 months after HTO, the WOMAC score was used. RESULTS: A significant decrease of BTU in the medial subchondral zones after HTO was found (preoperatively to 12 and 24 months postoperatively, p < 0.01). BTU normalized in all asymptomatic patients within 24 months. This decrease was partly seen in the lateral compartments, but significantly higher in the medial compartments (p < 0.0001). A significant increase of the BTU was noted in zones directly adjacent to the plate or within the osteotomy zone (p < 0.01). Decreased BTU was observed in osteotomy zones at 24 months postoperatively following higher uptake values at 12 months postoperatively. The average valgus correction of the tibiofemoral angle was 5.9 degrees +/- 2.8 degrees . Less stiffness correlated significantly with a higher decrease in BTU (p < 0.05). Higher postoperative BTU significantly correlated with more pain (p < 0.05). No statistical significant associations between BTU and alignment correction were found. CONCLUSION: In patients with medial compartment, overloading due to varus malalignment HTO led to a significant decrease in BTU in the medial joint compartments. SPECT/CT BTU patterns and intensity in these patients pre- to 12 and 24 months postoperatively were seen. These correlated significantly with pain and stiffness. Hence, SPECT/CT could be used for assessment of adequate correction and healing after HTO. SPECT/CT could be further used to identify the optimal individualized correction for each patient and clinical scenario. CLINICAL EVIDENCE: Diagnostic prospective study, Level II. PMID- 24817167 TI - Costing hospital surgery services: the method matters. AB - BACKGROUND: Accurate hospital costs are required for policy-makers, hospital managers and clinicians to improve efficiency and transparency. However, different methods are used to allocate direct costs, and their agreement is poorly understood. The aim of this study was to assess the agreement between bottom-up and top-down unit costs of a large sample of surgical operations in a French tertiary centre. METHODS: Two thousand one hundred and thirty consecutive procedures performed between January and October 2010 were analysed. Top-down costs were based on pre-determined weights, while bottom-up costs were calculated through an activity-based costing (ABC) model. The agreement was assessed using correlation coefficients and the Bland and Altman method. Variables associated with the difference between methods were identified with bivariate and multivariate linear regressions. RESULTS: The correlation coefficient amounted to 0.73 (95%CI: 0.72; 0.76). The overall agreement between methods was poor. In a multivariate analysis, the cost difference was independently associated with age (Beta = -2.4; p = 0.02), ASA score (Beta = 76.3; p<0.001), RCI (Beta = 5.5; p<0.001), staffing level (Beta = 437.0; p<0.001) and intervention duration (Beta = -10.5; p<0.001). CONCLUSIONS: The ability of the current method to provide relevant information to managers, clinicians and payers is questionable. As in other European countries, a shift towards time-driven activity-based costing should be advocated. PMID- 24817168 TI - "Cancer--Educate to Prevent"--high-school teachers, the new promoters of cancer prevention education campaigns. AB - Cancer is one of the leading causes of death worldwide, and thus represents a priority for national public health programs. Prevention has been assumed as the best strategy to reduce cancer burden, however most cancer prevention programs are implemented by healthcare professionals, which constrain range and educational impacts. We developed an innovative approach for cancer prevention education focused on high-school biology teachers, considered privileged mediators in the socialization processes. A training program, "Cancer, Educate to Prevent" was applied, so that the teachers were able to independently develop and implement prevention campaigns focused on students and school-related communities. The program encompassed different educational modules, ranging from cancer biology to prevention campaigns design. Fifty-four teachers were empowered to develop and implement their own cancer prevention campaigns in a population up to five thousands students. The success of the training program was assessed through quantitative evaluation--questionnaires focused on teachers' cancer knowledge and perceptions, before the intervention (pre-test) and immediately after (post-test). The projects developed and implemented by teachers were also evaluated regarding the intervention design, educational contents and impact on the students' knowledge about cancer. This study presents and discusses the results concerning the training program "Cancer, Educate to Prevent" and clearly shows a significant increase in teacher's cancer literacy (knowledge and perceptions) and teachers' acquired proficiency to develop and deliver cancer prevention campaigns with direct impact on students' knowledge about cancer. This pilot study reinforces the potential of high-school teachers and schools as cancer prevention promoters and opens a new perspective for the development and validation of cancer prevention education strategies, based upon focused interventions in restricted targets (students) through non-health professionals (teachers). PMID- 24817169 TI - Ultrasmall Au(10-12)(SG)(10-12) nanomolecules for high tumor specificity and cancer radiotherapy. AB - Radiosensitizers can increase local treatment efficacy under a relatively low and safe radiation dose, thereby facilitating tumor eradication and minimizing side effects. Here, a new class of radiosensitizers is reported, which contain several gold (Au) atoms embedded inside a peptide shell (e.g., Au10-12 (SG)10-12 ) and can achieve ultrahigh tumor uptake (10.86 SUV at 24 h post injection) and targeting specificity, efficient renal clearance, and high radiotherapy enhancement. PMID- 24817171 TI - Characterization of RotaTeq(r) vaccine-derived rotaviruses in South Korean infants with rotavirus gastroenteritis. AB - Genotyping of human rotaviruses was performed in 191 rotavirus-positive fecal samples collected from infants with acute gastroenteritis, 3 years after the introduction of two rotavirus vaccines in South Korea. Among these samples, the most prevalent rotavirus genotype was G3P[8] (30.9%), followed by G1P[8] (27.7%), G4P[6] (15.2%), and G9P[8] (5.8%). Sequence analysis identified RotaTeq(r) vaccine-derived strains in 12 samples (6.3%), comprising 11 G1P[8] human-bovine double reassortant rotaviruses and 1 G1P[5] human-bovine single reassortant rotavirus. It is of note that cross-reactivity between the current G4-specific typing primer and RotaTeq(r)-specific G1 genotypes was found. A trace of the clinical and environmental routes of the rotavirus vaccine strains revealed unexpected complexity, and the diagnostic protocol for rotaviruses may require modification by using either another typing primer set or nucleotide sequence analysis. PMID- 24817170 TI - Raised by depressed parents: is it an environmental risk? AB - The mechanisms explaining how parental depression compromises healthy child development are complex and multifaceted, with genetic and environmental pathways intertwined. Reexamination of whether and how maternal and paternal depression serve as environmental risk factors is important because such an investigation can be helpful to identify modifiable mechanisms that are accessible to interventions. We review studies that have employed designs that isolate the effects of the environment from genetic influences, including adoption studies and children of twins studies. Findings indicate that maternal depression is an environmental risk factor for the emotional, behavioral, and neurobiological development of children. Although more studies are needed, preliminary findings suggest that paternal depression appears to be a weaker environmental risk as compared to maternal depression, at least during infancy and toddlerhood. Implications for theory and future research are discussed. PMID- 24817172 TI - The protective effect of the mesoporous host on the photo oxidation of fluorescent guests: a UV-Vis spectroscopy study. AB - The inclusion of fluorescent molecules within the pores of an inorganic host system is one of the most common ways used for the preparation of highly fluorescent nanosystems. The confinement of labile molecules usually leads to better performances mainly due to their protection against environmental parameters which can concur with the deactivation of the fluorescent ones. In this work the protective effect of the siliceous mesoporous host on photo oxidation of fluorescent guest molecules has been investigated under different experimental conditions, highlighting an outstanding photostability if compared to the performances exerted by the fluorescent dye in solution. PMID- 24817173 TI - Evaluation of degradation kinetics and physicochemical stability of tenofovir. AB - Tenofovir (TFV) has been proven to prevent the transmission of the Human Immunodeficiency Virus (HIV) through the vagina. But, there is little information available about its stability under various storage and stress conditions. Hence, this study aimed to investigate the degradation behavior and physicochemical stability of TFV using liquid chromatography coupled mass spectrometry (LC-MS) and solid state X-ray diffraction (XRD) analyses. The LC-MS analysis was performed on a QTrap mass spectrometer with an enhanced mass spectrum (EMS) scan in positive mode. A reversed phase C18 column was used as the stationary phase. TFV exhibited degradation under acidic and alkaline hydrolytic conditions. The degradation products with m/z 289.2 and 170 amu have been proposed as 6-Hydroxy adenine derivative of TFV, and (2-hydroxypropan-2-yloxy) methylphosphonic acid, respectively. A pseudo-first-order degradation kinetic allowed for estimating the shelf-life, half-life, and time required for 90% degradation of 3.84, 25.34, and 84.22 h in acidic conditions, and 58.26, 384.49, and 1277.75 h in alkaline conditions, respectively. No significant degradation was observed at pH 4.5 (normal cervicovaginal pH) and oxidative stress conditions of 3% and 30% v/v hydrogen peroxide solutions. The shelf life of TFV powder at room temperature was 23 months as calculated by using an Arrhenius plot. The XRD pattern showed that the drug was stable and maintained its original crystallinity under the accelerated and thermal stress conditions applied. Stability analyses revealed that the TFV was stable in various stress conditions; however, formulation strategies should be implemented to protect it in strong acidic and alkaline environments. PMID- 24817174 TI - An approach to objective analysis of cerebrospinal fluid flow dynamics with phase contrast magnetic resonance imaging. PMID- 24817175 TI - The usefulness of the awake-awake-awake technique. PMID- 24817177 TI - Magnetic microreactors for efficient and reliable magnetic nanoparticle surface functionalization. AB - Microreactors have attracted wide attention in the nano- and biotechnology fields because they offer many advantages over standard liquid phase reactions. We report the development of a magnetic microreactor for reliable, fast and efficient surface functionalization of superparamagnetic iron oxide nanoparticles (SPIONs). A comprehensive study of the development process in terms of setup, loading capacity and efficiency is described. We performed experimental and computational studies in order to evaluate the trapping efficiencies, maximum loading capacity and magnetic alignment of the nanoparticles. The results showed that capacity and trapping efficiencies are directly related to the flow rate, elution time and reactor type. Based on our results and the developed magnetic microreactor, we describe a model multistep surface derivatization procedure of SPIONs. PMID- 24817176 TI - Semi-automatic MRI segmentation and volume quantification of intra-plaque hemorrhage. AB - PURPOSE: Intra-plaque hemorrhage (IPH) is associated with plaque instability. Therefore, the presence and volume of IPH in carotid arteries may be relevant in predicting the progression of atherosclerotic disease and the occurrence of clinical events. The aim of our work was to develop and evaluate a method for semi-automatic IPH segmentation in T1-weighted (T1w)-magnetic resonance imaging (MRI). MATERIAL AND METHODS: IPH segmentation is performed by a regional level set method that models the intensity of the IPH and the background in T1w-MRI to be smoothly varying. The method only requires minimal user interaction, i.e., one or more mouse clicks inside the hemorrhage serve as initialization. The parameters of the method are optimized using a leave-one-out strategy by maximizing the Dice similarity coefficient (DSC) between manual and semi automatic segmentations. We evaluated the IPH segmentation method on 22 carotid arteries; 10 of which were annotated by two observers and 12 were scanned twice within a 2 week period. RESULTS: We obtained a DSC of 0.52 between the manual and level set segmentations on all 22 carotids. The inter-observer DSC on 10 arteries is 0.57, which is comparable to the DSC between the method and the manual segmentation (0.55). The correlation between the IPH volumes extracted from the level set segmentation and the manual segmentation is 0.88, which is close to the inter-observer volume correlation of 0.92. The reproducibility after rescanning 12 carotids yield an IPH volume correlation of 0.97. The robustness with respect to the initialization by manually clicking two sets of seed points in these 12 carotid artery pairs yields a volume correlation of 0.99. CONCLUSION: Semi automatic segmentation and quantification of IPHs are feasible with an accuracy in the range of the inter-observer variability. The method has excellent reproducibility with respect to rescanning and manual initialization. PMID- 24817178 TI - Effect of prior exercise training and myocardial infarction-induced heart failure on the neuronal and glial densities and the GFAP-immunoreactivity in the posterodorsal medial amygdala of rats. AB - Exercise training has neuroprotective effects whereas myocardial infarction (MI) and heart failure (HF) can cause neuronal death and reactive gliosis in the whole amygdala. The posterodorsal medial amygdala (MePD) is involved with cardiovascular reflexes and the central control of sympathetic/parasympathetic responses. Our aim was to study the effects of prior exercise training and of MI induced HF on the neuronal and glial densities and the glial fibrillary acidic protein-immunoreactivity (GFAP-ir) in the MePD of adult male rats. Animals (n= 5/group) were: control, sedentary submitted to a sham MI (Sed Sham), sedentary submitted to MI/HF (Sed HF), trained on a treadmill and submitted to a sham MI (T Sham) or trained on a treadmill and submitted to MI/HF (T HF). The number of neurons and glial cells in the MePD was estimated using the optical fractionator and the GFAP-ir was quantified by optical densitometry. In the respective groups, treadmill training improved physical performance and MI damaged near 40% of the left ventricle. There was a hemispheric lateralization effect on the density of neurons (higher in the right MePD), but no significant difference in either the neuronal or the glial densities due to experimental condition. Regional GFAP-ir results revealed that the Sed HF group had a higher expression in the left MePD compared to the control and the Sed Sham rats (p?0.01). The present data did not evidence the effects of training or MI/HF in the MePD cellular density, but indicate a possible local restructuring of astrocytic cytoskeleton after MI/HF in rats. PMID- 24817179 TI - Antiplasmodial activity study of angiotensin II via Ala scan analogs. AB - Angiotensin II (AII) as well as analog peptides shows antimalarial activity against Plasmodium gallinaceum and Plasmodium falciparum, but the exact mechanism of action is still unknown. This work presents the solid-phase synthesis and characterization of eight peptides corresponding to the alanine scanning series of AII plus the amide-capped derivative and the evaluation of the antiplasmodial activity of these peptides against mature P. gallinaceum sporozoites. The Ala screening data indicates that the replacement of either the Ile(5) or the His(6) residues causes minor effects on the in vitro antiplasmodial activity compared with AII, i.e. AII (88%), [Ala(6) ]-AII (79%), and [Ala(5) ]-AII (75%). Analogs [Ala(3) ]-AII, [Ala(1) ]-AII, and AII-NH2 showed antiplasmodial activity around 65%, whereas the activity of the [Ala(8) ]-AII, [Ala(7) ]-AII, [Ala(4) ]-AII, and [Ala(2) ]-AII analogs is lower than 45%. Circular dichroism data suggest that AII and the most active analogs adopt a beta-fold conformation in different solutions. All AII analogs, except [Ala(4) ]-AII and [Ala(8) ]-AII, show contractile responses and interact with the AT1 receptor, [Ala(5) ]-AII and [Ala(6) ]-AII. In conclusion, this approach is helpful to understand the contribution of each amino acid residue to the bioactivity of AII, opening new perspectives toward the design of new sporozoiticidal compounds. PMID- 24817181 TI - Entrapment into charge transfer complexes for resonant Raman scattering enhancement. AB - This communication suggests a new approach expanding the range of important analytes becoming available for Raman scattering enhancement due to entrapping them into charge-transfer complexes immobilized onto nanostructured substrates. PMID- 24817180 TI - Fluorescence F 0 of photosystems II and I in developing C3 and C 4 leaves, and implications on regulation of excitation balance. AB - This work addresses the question of occurrence and function of photosystem II (PSII) in bundle sheath (BS) cells of leaves possessing NADP-malic enzyme-type C4 photosynthesis (Zea mays). Although no requirement for PSII activity in the BS has been established, several component proteins of PSII have been detected in BS cells of developing maize leaves exhibiting O2-insensitive photosynthesis. We used the basal fluorescence emissions of PSI (F 0I) and PSII (F 0II) as quantitative indicators of the respective relative photosystem densities. Chl fluorescence induction was measured simultaneously at 680 and 750 nm. In mature leaves, the F m(680)/F 0(680) ratio was 10.5 but less in immature leaves. We propose that the lower ratio was caused by the presence of a distinct non variable component, F c, emitting at 680 and 750 nm. After F c was subtracted, the fluorescence of PSI (F 0I) was detected as a non-variable component at 750 nm and was undetectably low at 680 nm. Contents of Chls a and b were measured in addition to Chl fluorescence. The Chl b/(a + b) was relatively stable in developing sunflower leaves (0.25-0.26), but in maize it increased from 0.09 to 0.21 with leaf tissue age. In sunflower, the F 0I/(F 0I + F 0II) was 0.39 +/- 0.01 independent of leaf age, but in maize, this parameter was 0.65 in young tissue of very low Chl content (20-50 mg m(-2)) falling to a stable level of 0.53 +/- 0.01 at Chl contents >100 mg m(-2). The values of F 0I/(F 0I + F 0II) showed that in sunflower, excitation was partitioned between PSII and PSI in a ratio of 2:1, but the same ratio was 1:1 in the C4 plant. The latter is consistent with a PSII:PSI ratio of 2:1 in maize mesophyll cells and PSI only in BS cells (2:1:1 distribution). We suggest, moreover, that redox mediation of Chl synthesis, rather than protein accumulation, regulates photosystem assembly to ensure optimum excitation balance between functional PSII and PSI. Indeed, the apparent necessity for two Chls (a and b) may reside in their targeted functions in influencing accumulation of PSI and PSII, respectively, as opposed to their spectral differences. PMID- 24817182 TI - Extension of Murray's law including nonlinear mechanics of a composite artery wall. AB - A goal function approach is used to derive an extension of Murray's law that includes effects of nonlinear mechanics of the artery wall. The artery is modeled as a thin-walled tube composed of different species of nonlinear elastic materials that deform together. These materials grow and remodel in a process that is governed by a target state defined by a homeostatic radius and a homeostatic material composition. Following Murray's original idea, this target state is defined by a principle of minimum work. We take this work to include that of pumping and maintaining blood, as well as maintaining the materials of the artery wall. The minimization is performed under a constraint imposed by mechanical equilibrium. We derive a condition for the existence of a cost-optimal homeostatic state. We also conduct parametric studies using this novel theoretical frame to investigate how the cost-optimal radius and composition of the artery wall depend on flow rate, blood pressure, and elastin content. PMID- 24817184 TI - No major effect of the CDH1 c.2440-6C>G mutation on splicing detected in last exon-specific splicing minigene assay. PMID- 24817183 TI - The role of MRI-targeted and confirmatory biopsies for cancer upstaging at selection in patients considered for active surveillance for clinically low-risk prostate cancer. AB - PURPOSE: The purpose of this study was to assess the roles of MRI-targeted biopsies (TB) and confirmatory biopsies for cancer upstaging at selection in patients considered for active surveillance (AS) for low-risk prostate cancer (PCa) based on the first systematic biopsy (SB) series in another centre. METHODS: From 2009 to 2012, 41 patients with PCa diagnosed within the last 4 months and eligible for AS [clinical stage <=T2a, prostate-specific antigen (PSA) <10 ng/ml, <=2 positive biopsy cores with no Gleason pattern 4 or 5 and <=5 mm involvement of any biopsy core] underwent pre-biopsy MRI, confirmatory transrectal ultrasound 12-core SB and MRI-TB of suspicious lesions. A contingency table assessed the accuracy of MRI to predict cancer upstaging. RESULTS: Median age and PSA were 63.5 years and 5.3 ng/ml, respectively. Overall, 24 patients (59 %) were upstaged. This upstaging was obtained at a confirmatory SB in 16 patients (39 %) based on the Gleason score (9), on cancer length (8) or both (7) and at MRI-TB in 17 patients (41 %) based on the Gleason score (14), cancer length (9) or both (6). Nine patients were upstaged at both SB and TB (22 %). The added value of MRI-TB was 20 % (8/41). The positive and negative predictive values of MRI for predicting cancer upstaging were 79 and 70.5 %, respectively. CONCLUSION: MRI-TB and confirmatory SB upstaged 59 % of cases, improving the selection of patients considered for AS at the first series of SB. Variation in histologic grade assignation between centres and better cancer sampling may explain this high upstaging rate. PMID- 24817185 TI - [Importance of PET in surgery of esophageal cancer]. AB - Perioperative or preoperative radiochemotherapy (RCTx) is nowadays standard for locally advanced esophageal cancer in Europe, as randomized studies have shown a significant survival benefit for patients with multimodal treatment. As responders and nonresponders have a significantly different prognosis, a response based tailored preoperative treatment would be of utmost interest. An established method is a metabolic response evaluation by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). The level of metabolic response is known to be dependent on the localization, tumor entity and type of preoperative treatment. Association of FDG-PET with later response and prognosis was shown for absolute standardized uptake values (SUV) or a decrease of SUV levels before and after therapy but there are also contradictory findings in the literature and no prospective validation. However, neither time points nor cut-off for metabolic response evaluation have been defined so far. The most interesting approach seems to be early response monitoring during preoperative chemotherapy, which has shown promising results in prospective single center trials (MUNICON I/II) during chemotherapy of adenocarcinoma of the esophagogastric junction (AEG), but needs to be validated in prospective multicenter trails. PMID- 24817186 TI - Competing with lower level opponents decreases intra-team movement synchronization and time-motion demands during pre-season soccer matches. AB - This study aimed to quantify the time-motion demands and intra-team movement synchronization during the pre-season matches of a professional soccer team according to the opposition level. Positional data from 20 players were captured during the first half of six pre-season matches of a Portuguese first league team. Time-motion demands were measured by the total distance covered and distance covered at different speed categories. Intra-team coordination was measured by calculating the relative phase of all pairs of outfield players. Afterwards, the percentage of time spent in the -30 degrees to 30 degrees bin (near-in-phase mode of coordination) was calculated for each dyad as a measure of space-time movement synchronization. Movement synchronization data were analyzed for the whole team, according to each dyad average speed and by groups of similar dyadic synchronization tendencies. Then, these data were compared according to the opponent team level (first league; second league; amateurs). Time-motion demands showed no differences in total distance covered per opposition levels, while matches opposing teams of superior level revealed more distance covered at very high intensity. Competing against superior level teams implied more time in synchronized behavior for the overall displacements and displacements at higher intensities. These findings suggest that playing against higher-level opponents (1st league teams) increased time-motion demands at high intensities in tandem with intra-team movement synchronization tendencies. PMID- 24817187 TI - Automated classification of oral premalignant lesions using image cytometry and Random Forests-based algorithms. AB - PURPOSE: A major challenge for the early diagnosis of oral cancer is the ability to differentiate oral premalignant lesions (OPL) at high risk of progressing into invasive squamous cell carcinoma (SCC) from those at low risk. Our group has previously used high-resolution image analysis algorithms to quantify the nuclear phenotypic changes occurring in OPLs. This approach, however, requires a manual selection of nuclei images. Here, we investigated a new, semi-automated algorithm to identify OPLs at high risk of progressing into invasive SCC from those at low risk using Random Forests, a tree-based ensemble classifier. METHODS: We trained a sequence of classifiers using morphometric data calculated on nuclei from 29 normal, 5 carcinoma in situ (CIS) and 28 SCC specimens. After automated discrimination of nuclei from other objects (i.e., debris, clusters, etc.), a nuclei classifier was trained to discriminate abnormal nuclei (8,841) from normal nuclei (5,762). We extracted voting scores from this trained classifier and created an automated nuclear phenotypic score (aNPS) to identify OPLs at high risk of progression. RESULTS: The new algorithm showed a correct classification rate of 80% (80.6% sensitivity, 79.3% specificity) at the cellular level for the test set, and a correct classification rate of 75% (77.8% sensitivity, 71.4% specificity) at the tissue level with a negative predictive value of 76% and a positive predictive value of 74% for predicting progression among 71 OPLs, performed on par with the manual method in our previous study. CONCLUSIONS: We conclude that the newly developed aNPS algorithm serves as a crucial asset in the implementation of high-resolution image analysis in routine clinical pathology practice to identify lesions that require molecular evaluation or more frequent follow-up. PMID- 24817188 TI - Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. AB - Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness. PMID- 24817189 TI - Examining effects of anticipated stigma, centrality, salience, internalization, and outness on psychological distress for people with concealable stigmatized identities. AB - Understanding how stigmatized identities contribute to increased rates of depression and anxiety is critical to stigma reduction and mental health treatment. There has been little research testing multiple aspects of stigmatized identities simultaneously. In the current study, we collected data from a diverse, urban, adult community sample of people with a concealed stigmatized identity (CSI). We targeted 5 specific CSIs--mental illness, substance abuse, experience of domestic violence, experience of sexual assault, and experience of childhood abuse--that have been shown to put people at risk for increased psychological distress. We collected measures of the anticipation of being devalued by others if the identity became known (anticipated stigma), the level of defining oneself by the stigmatized identity (centrality), the frequency of thinking about the identity (salience), the extent of agreement with negative stereotypes about the identity (internalized stigma), and extent to which other people currently know about the identity (outness). Results showed that greater anticipated stigma, greater identity salience, and lower levels of outness each uniquely and significantly predicted variance in increased psychological distress (a composite of depression and anxiety). In examining communalities and differences across the five identities, we found that mean levels of the stigma variables differed across the identities, with people with substance abuse and mental illness reporting greater anticipated and internalized stigma. However, the prediction pattern of the variables for psychological distress was similar across the substance abuse, mental illness, domestic violence, and childhood abuse identities (but not sexual assault). Understanding which components of stigmatized identities predict distress can lead to more effective treatment for people experiencing psychological distress. PMID- 24817190 TI - Automated robust and accurate assignment of protein resonances for solid state NMR. AB - The process of resonance assignment represents a time-consuming and potentially error-prone bottleneck in structural studies of proteins by solid-state NMR (ssNMR). Software for the automation of this process is therefore of high interest. Procedures developed through the last decades for solution-state NMR are not directly applicable for ssNMR due to the inherently lower data quality caused by lower sensitivity and broader lines, leading to overlap between peaks. Recently, the first efforts towards procedures specifically aimed for ssNMR have been realized (Schmidt et al. in J Biomol NMR 56(3):243-254, 2013). Here we present a robust automatic method, which can accurately assign protein resonances using peak lists from a small set of simple 2D and 3D ssNMR experiments, applicable in cases with low sensitivity. The method is demonstrated on three uniformly (13)C, (15)N labeled biomolecules with different challenges on the assignments. In particular, for the immunoglobulin binding domain B1 of streptococcal protein G automatic assignment shows 100% accuracy for the backbone resonances and 91.8% when including all side chain carbons. It is demonstrated, by using a procedure for generating artificial spectra with increasing line widths, that our method, GAMES_ASSIGN can handle a significant amount of overlapping peaks in the assignment. The impact of including different ssNMR experiments is evaluated as well. PMID- 24817191 TI - Convergent and enantioselective syntheses of cytosolic phospholipase A(2)alpha inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates. AB - Cytosolic phospholipase A2alpha (cPLA2alpha) is an important enzyme of the inflammation cascade. Therefore, inhibitors of cPLA2alpha are assumed to be promising drug candidates for the treatment of inflammatory disorders. Recently we have found that indole-5-carboxylic acid with a 3-(4-octylphenoxy)-2 (phenoxycarbonylamino)propyl substituent in position 1 is an inhibitor of cPLA2alpha. We have now synthesized a corresponding derivative with the indole heterocycle replaced by an indazole (4) employing an analogous reaction sequence as for the synthesis of the indole derivative. Besides, a more convergent synthesis for 4 was established using an aziridine as central intermediate. Furthermore, a chiral-pool based enantioselective synthesis was developed for the synthesis of (R)- and (S)-4. Starting compound for both enantiomers was the (R) serine derived oxazolidine (R)-25. Compound 4 proved to be a moderate inhibitor of cPLA2alpha, with the S-enantiomer being twice as active as the R-enantiomer. The racemate 4 and the enantiomers (R)- and (S)-4 showed a high in vitro metabolic stability in rat liver S9 fractions. PMID- 24817192 TI - Health services utilization of patients with vertigo in primary care: a retrospective cohort study. AB - Vertigo and dizziness count among the most frequent symptoms in outpatient practices. Although most vestibular disorders are manageable, they are often under- and misdiagnosed in primary care. This may result in prolonged absence from work, increased resource use and, potentially, in chronification. Reliable information on health services utilization of patients with vertigo in primary care is scarce. Retrospective cohort study in patients referred to a tertiary care balance clinic. Included patients had a confirmed diagnosis of benign paroxysmal positional vertigo (BPPV), Meniere's disease (MD), vestibular paroxysmia (VP), bilateral vestibulopathy (BVP), vestibular migraine (VM), or psychogenic vertigo (PSY). All previous diagnostic and therapeutic measures prior to the first visit to the clinic were recorded. 2,374 patients were included (19.7 % BPPV, 12.7 % MD, 5.8 % VP, 7.2 % BVP, 14.1 % VM, 40.6 % PSY), 61.3 % with more than two consultations. Most frequent diagnostic measures were magnetic resonance imaging (MRI, 76.2 %, 71 % in BPPV) and electrocardiography (53.5 %). Most frequent therapies were medication (61.0 %) and physical therapy (41.3 %). 37.3 % had received homoeopathic medication (39 % in BPPV), and 25.9 % were treated with betahistine (20 % in BPPV). Patients had undergone on average 3.2 (median 3.0, maximum 6) diagnostic measures, had received 1.8 (median 2.0, maximum 8) therapies and 1.8 (median 1.0, maximum 17) different drugs. Diagnostic subgroups differed significantly regarding number of diagnostic measures, therapies and drugs. The results emphasize the need for establishing systematic training to improve oto-neurological skills in primary care services not specialized on the treatment of dizzy patients. PMID- 24817193 TI - Discordance between perceived and actual cancer stage among cancer patients in Korea: a nationwide survey. AB - PURPOSE: We assessed the accuracy of communication between doctors and patients by evaluating the consistency between patient perception of cancer stage and the medical records, and analyzed the most influential factors of incongruence among cancer patients at 10 cancer centers across Korea. METHODS: Information was gathered from cancer patients at the National Cancer Center and nine regional cancer centers located in every province of Korea between 1 July 2008 and 31 August 2008. Data were analyzed using Pearson's chi2 test and multivariate logistic regression analysis. RESULTS: The stages of cancer reported by the 1,854 patients showed a low degree of congruence with the stages given in medical records (k = 0.35, P<0.001). Only 57.1% of the patients had accurate knowledge of their cancer stage. In total, 18.5% underestimated their stage of disease, and the more advanced the cancer stage, the more likely they were to underestimate it, in order of local (14.2%), regional (23.7%), and distant (51.6%). Logistic regression analysis showed that congruence was lower in patients with cervical cancer (odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.30-0.87), recurrence (OR = 0.64, 95% CI = 0.50-0.83), and treatment at the National Cancer Center (OR = 0.53, 95% CI = 0.39-0.72). CONCLUSION: There are knowledge gaps between patients' perceived and actual stage of cancer. Patients with cervical cancer, recurrence, and who received treatment at a regional cancer center showed less understanding of their cancer stage. PMID- 24817194 TI - The oxidation of HSP70 is associated with functional impairment and lack of stimulatory capacity. AB - Expression of intracellular HSP70 is associated with cytoprotective effects against a wide range of stressful stimuli, such as inflammation, oxidative stress, hypoxia, endotoxins, infections, and fever. This cytoprotective effect is mainly attributed to their ability to stabilize protein structures through chaperone-like reversible interactions. HSP70 was recently detected in the extracellular medium, and its presence in serum is commonly associated with pathological situations, where it exerts modulatory effects on cells of the immune system. Previously, we have described the relationship between serum HSP70 levels, oxidant status, and clinical outcome of septic patients; the group of patients with higher prooxidant status and higher serum HSP70 had also higher mortality. To investigate the possible association between oxidized HSP70 and cytoprotection or cell death, we incubated RAW 264.7 macrophages with oxidized HSP70 and evaluated nitrite production, cell proliferation, cell viability, TNF alpha release, and phagocytic activity. We also evaluated structural modifications caused by oxidation in purified HSP70. Oxidation of HSP70 altered its protein structure; besides, the modulatory effect of oxidized HSP70 on RAW264.7 cells was different from that of native HSP70. Macrophages treated with oxidized HSP70 presented lower proliferation and viability, lower phagocytic activity, and lower TNF-alpha release. These results indicate that oxidation of extracellular HSP70 modified its signaling properties, causing alterations on its modulatory effects on macrophage function and viability. PMID- 24817195 TI - Prenatal echocardiographic diagnosis of double aortic arch. AB - A double aortic arch is a congenital anomaly associated with the formation of a vascular ring, which can cause varying degrees of airway compression. This can be subclinical or clinical, manifesting as acute stridor, severe respiratory compromise or symptoms of chronic airway compression. An accurate diagnosis of double aortic arch can be made prenatally by fetal echocardiography. In this report, we describe two infants with normal karyotypes in whom a prenatal diagnosis of double aortic arch was made at our fetal cardiology center, between July 2012 and August 2013. The diagnosis was confirmed postnatally by two dimensional echocardiography and cardiac magnetic resonance imaging (MRI). The presence of a right aortic arch should prompt more careful evaluation to exclude a double aortic arch. Postnatal assessment should comprise echocardiography and cross-sectional imaging in the form of cardiac MRI/computed tomography. Bronchoscopy may be considered to exclude subclinical airway compression and reduce potential long-term respiratory sequelae. PMID- 24817196 TI - Nutritional regulation in mixotrophic plants: new insights from Limodorum abortivum. AB - Partially mycoheterotrophic (mixotrophic) plants gain carbon from both photosynthesis and their mycorrhizal fungi. This is considered an ancestral state in the evolution of full mycoheterotrophy, but little is known about this nutrition, and especially about the physiological balance between photosynthesis and fungal C gain. To investigate possible compensation between photosynthesis and mycoheterotrophy in the Mediterranean mixotrophic orchid Limodorum abortivum, fungal colonization was experimentally reduced in situ by fungicide treatment. We measured photosynthetic pigments of leaves, stems, and ovaries, as well as the stable C isotope compositions (a proxy for photosynthetic C gain) of seeds and the sizes of ovaries and seeds. We demonstrate that (1) in natural conditions, photosynthetic pigments are most concentrated in ovaries; (2) pigments and photosynthetic C increase in ovaries when fungal C supply is impaired, buffering C limitations and allowing the same development of ovaries and seeds as in natural conditions; and (3) responses to light of pigment and (13)C contents in ovaries shift from null responses in natural conditions to responses typical of autotrophic plants in treated L. abortivum, demonstrating photoadaptation and enhanced use of light in the latter. L. abortivum thus preferentially feeds on fungi in natural conditions, but employs compensatory photosynthesis to buffer fungal C limitations and allow seed development. PMID- 24817197 TI - Ecological functioning in grass-shrub Mediterranean ecosystems measured by eddy covariance. AB - Climate change may alter ecosystem functioning, as assessed via the net carbon (C) exchange (NEE) with the atmosphere, composed of the biological processes photosynthesis (GPP) and respiration (R(eco)). In addition, in semi-arid Mediterranean ecosystems, a significant fraction of respired CO2 is stored in the vadose zone and emitted afterwards by subsoil ventilation (VE), contributing also to NEE. Such conditions complicate the prediction of NEE for future change scenarios. To evaluate the possible effects of climate change on annual NEE and its underlying processes (GPP, R(eco) and VE) we present, over a climate/altitude range, the annual and interannual variability of NEE, GPP, R(eco) and VE in three Mediterranean sites. We found that annual NEE varied from a net source of around 130 gC m(-2) in hot and arid lowlands to a net sink of similar magnitude for alpine meadows (above 2,000 m a.s.l) that are less water stressed. Annual net C fixation increased because of increased GPP during intermittent and several growth periods occurring even during winter, as well as due to decreased VE. In terms of interannual variability, the studied subalpine site behaved as a neutral C sink (from emission of 49 to fixation of 30 gC m(-2) year(-1)), with precipitation as the main factor controlling annual GPP and R(eco). Finally, the importance of VE as 0-23% of annual NEE is highlighted, indicating that this process could shift some Mediterranean ecosystems from annual C sinks to sources. PMID- 24817198 TI - Climate conditions and resource availability drive return elevational migrations in a single-brooded insect. AB - Seasonal elevational migrations have important implications for life-history evolution and ecological responses to environmental change. However, for most species, particularly invertebrates, evidence is still scarce for the existence of such migrations, as well as for the potential causes. We tested the extent to which seasonal abundance patterns in central Spain for overwintering (breeding) and summer (non-breeding) individuals of the butterfly Gonepteryx rhamni were consistent with three hypotheses explaining elevational migration: resource limitation (host plant and flower availability), physiological constraints of weather (maximum temperatures) and habitat limitation (forest cover for overwintering). For overwintering adults, abundance was positively associated with host plant density during two intensive survey seasons (2007-2008), and the elevational distribution was relatively stable over a 7-year period (2006-2012). The elevational distribution of summer adults was highly variable, apparently related both to temperature and habitat type. Sites occupied by adults in the summer were on average 3 degrees C cooler than their breeding sites, and abundance showed negative associations with summer temperature, and positive associations with forest cover and host plant density in 2007 and 2008. The results suggest that the extent of uphill migration in summer could be driven by different factors, depending on the year, and are mostly consistent with the physiological constraint and habitat limitation hypotheses. In contrast, the patterns for overwintering adults suggest that downhill migration can be explained by resource availability. Climate change could generate bottlenecks in the populations of elevational migrant species by constraining the area of specific seasonal habitat networks or by reducing the proximity of environments used at different times of year. PMID- 24817199 TI - Labiopexy and labioplasty for labium majus rejuvenation in light of a newly discovered anatomic structure. AB - BACKGROUND: Currently, removal of excessive cutis with subdermal adipose tissues is done for labium majus rejuvenation. The objectives of this study were to determine the accurate labium majus anatomy, to develop new labiopexy and labioplasty techniques, to attest to the applicability of these two new operations, and to determine the impact of the operations on self-perceived body image and sensation of nerve endings. METHODS: A prospective case series study was conducted. Eleven fresh human female cadavers and three living subjects were studied. Living subjects were healthy women and presented with labium majus deformities. The study was conducted in three phases: phase I, the labium majus anatomy of the cadavers was studied; phase II, anatomic findings from phase I were used to develop and standardize new stepwise surgical interventions; and phase III, newly developed operations were implemented on living subjects. Labial sensation tests of nerve endings were performed preoperatively and at 6 months postoperatively. The primary outcome measured the labial anatomy and applicability of the new operations. The secondary outcome measured the self perceived body image and sensation of nerve endings before and after surgery. RESULTS: A new anatomic feature, the labium majus adipose sac, was discovered and was present in each subject. Labium majus labiopexy and labioplasty were executed without technical difficulties or complications. Postoperatively, the self perceived body image improved and sensation of nerve endings was intact. CONCLUSIONS: The labium majus adipose sac is present in each woman. Intraoperatively, newly developed labium majus labiopexy and/or labioplasty do not create technical problems. Self-perceived body image improves and sensation of the nerve endings is intact after labiopexy or labioplasty. EVIDENCE-BASED MEDICINE LEVEL II: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 24817201 TI - The economics of eating disorder treatment. AB - Illness-associated costs are a major concern in eating disorders (ED). Economic aspects of (ED) have been an area receiving research attention. In the last three years a number of studies have been completed, including studies examining national costs of ED; third party payer costs for ED treatment; societal costs of ED; and cost effectiveness analysis of specific treatments. Additionally, some work has been done to model costs associated with ED prevention efforts. A number of further cost effectiveness analyses are planned. This area will be a fertile one for continued study. PMID- 24817202 TI - Interferon gamma (IFN-gamma)-mediated inflammation and the kynurenine pathway in relation to risk of hip fractures: the Hordaland Health Study. AB - The cytokine interferon gamma (IFN-gamma) stimulates neopterin release and tryptophan degradation into kynurenines through the kynurenine pathway. High levels of neopterin were associated with increased hip fracture risk, as were some of the kynurenines, suggesting a role of IFN-gamma-mediated inflammation in the processes leading to hip fracture. INTRODUCTION: Low-grade systemic inflammation has been associated with bone loss and risk of fractures. Interferon gamma (IFN-gamma) initiates macrophage release of neopterin and also stimulates degradation of tryptophan along the kynurenine pathway as part of cell-mediated immune activation. Plasma neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-gamma-mediated inflammation. Risk of hip fracture was investigated in relation to markers of inflammation and metabolites in the kynurenine pathway (kynurenines). METHODS: Participants (71 to 74 years, N = 3,311) in the community-based Hordaland Health Study (HUSK) were followed for hip fractures from enrolment (1998-2000) until 31 December 2009. Plasma C-reactive protein (CRP), neopterin, KTR, and six kynurenines were investigated as predictors of hip fracture, using Cox proportional hazards regression analyses. RESULTS: A hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.3-2.7) for hip fracture was found in the highest compared to the lowest quartile of neopterin (p trend across quartiles <0.001). CRP and KTR were not related to hip fracture risk. Among the kynurenines, a higher risk of fracture was found in the highest compared to the lowest quartiles of anthranilic acid and 3 hydroxykynurenine. For subjects in the highest quartiles of neopterin, CRP, and KTR compared to those in no top quartiles, HR was 2.5 (95% CI 1.6-4.0). CONCLUSIONS: This may indicate a role for low-grade immune activation in the pathogenic processes leading to hip fracture. PMID- 24817203 TI - Racial/ethnic match and treatment outcomes for women with PTSD and substance use disorders receiving community-based treatment. AB - This study examined the relationship between racial/ethnic match and treatment outcomes for 224 women who participated in a clinical trial of group treatments for posttraumatic stress disorder (PTSD) and substance use disorders. Generalized estimating equations were used to examine the effect of client-therapist racial/ethnic match on outcomes. Results revealed racial/ethnic match was not significantly associated with session attendance. There was a significant three way interaction between client race/ethnicity, baseline level of PTSD symptoms, and racial/ethnic match on PTSD outcomes. White clients, with severe PTSD symptoms at baseline, who attended treatment groups where they were matched with their therapist, had greater reductions in PTSD symptoms at follow-up than their counterparts who were racially/ethnically mismatched with their group therapist. Racial/ethnic match did not confer additional benefits for Black clients in terms of PTSD outcomes. Racial/ethnic match interacted with baseline substance use to differentially influence substance use outcomes at follow-up for all women. Clinical implications are discussed. PMID- 24817205 TI - The Protective Effects of Adolescent Motherhood in South Central Appalachia: Salvation From Drugs and Emptiness. AB - This study qualitatively explored the meaning of teenage motherhood to young Appalachian mothers. Fourteen in-depth interviews at the homes of mothers between the ages of 18 and 22 from the South Central Appalachian region were conducted. Findings indicate that teenage motherhood is symbolically reproduced by filling a void and providing escape from the drug culture. Analysis of these findings indicates that the meaning of motherhood is characterized by salvation. This salvation is shaped by the emotional chasm that motherhood fills, as well as the protective barrier it provides between the mother and the surrounding drug culture. Implications of these findings might include a need to examine the protective effects of motherhood from negative sociocultural forces among other subcultures. Also, the pervasive drug culture that surrounds young people in Appalachia should be taken into consideration when shaping policy and interventions for teenage pregnancy prevention. PMID- 24817204 TI - Comparison of lower genital tract microbiota in HIV-infected and uninfected women from Rwanda and the US. AB - INTRODUCTION: Previous studies have shown that alterations of the bacterial microbiota in the lower female genital tract influence susceptibility to HIV infection and shedding. We assessed geographic differences in types of genital microbiota between HIV-infected and uninfected women from Rwanda and the United States. METHODS: Genera of lower genital tract bacterial microbiota were identified by high-throughput pyrosequencing of the 16S rRNA gene from 46 US women (36 HIV-infected, 10 HIV-uninfected) and 40 Rwandan women (18 HIV-infected, 22 HIV-uninfected) with similar proportions of low (0-3) Nugent scores. Species of Lactobacillus were identified by assembling sequences along with reference sequences into phylogenetic trees. Prevalence of genera and Lactobacillus species were compared using Fisher's exact tests. RESULTS: Overall the seven most prevalent genera were Lactobacillus (74%), Prevotella (56%), Gardnerella (55%), Atopobium (42%), Sneathia (37%), Megasphaera (30%), and Parvimonas (26%), observed at similar prevalences comparing Rwandan to US women, except for Megasphaera (20% vs. 39%, p = 0.06). Additionally, Rwandan women had higher frequencies of Mycoplasma (23% vs. 7%, p = 0.06) and Eggerthella (13% vs. 0%, p = 0.02), and lower frequencies of Lachnobacterium (8% vs. 35%, p<0.01) and Allisonella (5% vs. 30%, p<0.01), compared with US women. The prevalence of Mycoplasma was highest (p<0.05) in HIV-infected Rwandan women (39%), compared to HIV-infected US women (6%), HIV-uninfected Rwandan (9%) and US (10%) women. The most prevalent lactobacillus species in both Rwandan and US women was L. iners (58% vs. 76%, p = 0.11), followed by L. crispatus (28% vs. 30%, p = 0.82), L. jensenii (20% vs. 24%, p = 0.80), L. gasseri (20% vs. 11%, p = 0.37) and L. vaginalis (20% vs. 7%, p = 0.10). DISCUSSION: We found similar prevalence of most major bacterial genera and Lactobacillus species in Rwandan and US women. Further work will be needed to establish whether observed differences differentially impact lower genital tract health or susceptibility to genital infections. PMID- 24817206 TI - Cultural competence models and cultural competence assessment instruments in nursing: a literature review. AB - The author reviewed cultural competence models and cultural competence assessment instruments developed and published by nurse researchers since 1982. Both models and instruments were examined in terms of their components, theoretical backgrounds, empirical validation, and psychometric evaluation. Most models were not empirically tested; only a few models developed model-based instruments. About half of the instruments were tested with varying levels of psychometric properties. Other related issues were discussed, including the definition of cultural competence and its significance in model and instrument development, limitations of existing models and instruments, impact of cultural competence on health disparities, and further work in cultural competence research and practice. PMID- 24817207 TI - C9ORF72-ALS: P62- and ubiquitin-aggregation pathology in skeletal muscle. PMID- 24817208 TI - Large-area freestanding graphene paper for superior thermal management. AB - Large-area freestanding graphene papers (GPs) are fabricated by electrospray deposition integrated with a continuous roll-to-roll process. Upon mechanical compaction and thermal annealing, GPs can achieve a thermal conductivity of as high as 1238.3-1434 W m(-1) K(-1) . The super-thermally conductive GPs display an outstanding heat-spread ability and are more efficient in removing hot spots than Cu and Al foils. PMID- 24817209 TI - Where does the water go? A computational study on the reactivity of a ruthenium(V) oxo complex (bpc)(bpy)Ru(V)O. AB - Two possible reactive sites (the oxo site and the Ru site) for water on a high valent ruthenium(V) oxo complex were examined. Our results suggest that the reaction on the ruthenium (via a seven coordinate intermediate) has both a lower barrier and a product with a lower free energy than the product of addition at the oxo. PMID- 24817210 TI - Does CSF p-tau181 help to discriminate Alzheimer's disease from other dementias and mild cognitive impairment? A meta-analysis of the literature. AB - To evaluate the clinical importance of cerebrospinal fluid (CSF) phosphorylated tau 181 (p-tau181) in mild cognitive impairment (MCI), Alzheimer's disease (AD) and other dementias, more specifically: frontotemporal degeneration (FTD), dementia with Lewy bodies (DLB), vascular dementia (VaD) and Parkinson's disease (PD) with dementia (PDD). Fifty eligible articles were identified by search of databases including PubMed, EMBASE, Elsevier, Springer Link and the Cochrane Library, up to December 2013. The random effects model was used to calculate the standardized mean difference (SMD) with corresponding 95% CI by STATA 9.0 software. The subgroup analyses were made on the methods or PD with dementia. We found that CSF p-tau181 concentrations were significantly higher in AD compared to MCI [SMD: 0.61, 95% CI: (0.46, 0.76), z = 8.07, P < 0.001], FTD [SMD: 1.23, 95% CI: (0.89, 1.56), z = 7.19, P < 0.001], DLB [SMD: 1.08, 95% CI: (0.80, 1.37), z = 7.41, P < 0.001], PDD [SMD: 1.05, 95% CI: (0.02, 2.07), z = 2.00, P = 0.045] and VaD [SMD: 1.28, 95% CI: (0.68, 1.88), z = 4.19, P < 0.001]. Results from this meta-analysis implied that CSF p-tau181 is a good biomarker for discriminating Alzheimer's disease from other dementias and mild cognitive impairment. PMID- 24817211 TI - Form and function remixed: developmental physiology in the evolution of vertebrate body plans. AB - The most widely accepted model of evolutionary change, the Modern Evolutionary Synthesis, is based on the gradualism of Darwin and Wallace. They, in turn, developed their ideas in the context of 19th century concepts of how matter, including the tissues of animals and plants, could be reshaped and repatterned. A new physics of condensed, chemically, electrically and mechanically excitable materials formulated in the 20th century was, however, readily taken up by physiologists, who applied it to the understanding of dynamical, external condition-dependent and homeostatic properties of individual organisms. Nerve conduction, vascular and airway dynamics, and propagation of electrical excitations in heart and brain tissue all benefited from theories of biochemical oscillation, fluid dynamics, reaction-diffusion-based pattern instability and allied dissipative processes. When, in the late 20th century, the development of body and organ form was increasingly seen to involve dynamical, frequently non linear processes similar to those that had become standard in physiology, a strong challenge to the evolutionary synthesis emerged. In particular, large scale changes in organismal form now had a scientific basis other than gradualistic natural selection based on adaptive advantage. Moreover, heritable morphological changes were seen to be capable of occurring abruptly with little or no genetic change, with involvement of the external environment, and in preferred directions. This paper discusses three examples of morphological motifs of vertebrate bodies and organs, the somites, the skeletons of the paired limbs, and musculoskeletal novelties distinctive to birds, for which evolutionary origination and transformation can be understood on the basis of the physiological and biophysical determinants of their development. PMID- 24817212 TI - Changes in microbial communities, including both uncultured and culturable bacteria, with mid-ocean ballast-water exchange during a voyage from Japan to Australia. AB - We assessed changes in the microbial communities in ballast water during a trans Pacific voyage from Japan to Australia that included a mid-ocean ballast-water exchange. Uncultured (i.e., total) and culturable bacteria were counted and were characterized by using denaturing gradient gel electrophoresis (DGGE). There was a clear decrease over time in numbers of uncultured microorganisms, except for heterotrophic nanoflagellates, whereas the abundance of culturable bacteria initially decreased after the ballast-water exchange but then increased. The increase, however, was only up to 5.34% of the total number of uncultured bacteria. Cluster analysis showed that the DGGE profiles of uncultured bacteria clearly changed after the exchange. In contrast, there was no clear change in the DGGE profiles of culturable bacteria after the exchange. Multidimensional scaling analysis showed changes in microbial communities over the course of the voyage. Although indicator microbes as defined by the International Convention for the Control and Management of Ships' Ballast Water and Sediments were occasionally detected, no coliform bacteria were detected after the exchange. PMID- 24817213 TI - Bridging stent placement through the superior vena cava to the inferior vena cava in a patient with malignant superior vena cava syndrome and an iodinated contrast material allergy. AB - Positioning is critical during the placement of superior vena cava (SVC) stents in patients with malignant SVC syndrome. Although SVC stents effectively relieve various symptoms of SVC syndrome, improper stent positioning may cause life threatening complications such as migration that result in fatal cardiac failure. Here we describe a patient with an allergy to iodinated contrast material (ICM) who presented with SVC syndrome owing to mediastinal lymph node metastases from hepatocellular carcinoma, which was successfully treated with an SVC stent. Secure stent placement was achieved by bridging the stent through the SVC to the inferior vena cava with venography using carbon dioxide instead of ICM. PMID- 24817214 TI - Prostate-supplying arteriogram created by multidetector-row CT during pelvic arteriography: contribution to the treatment strategy of prostatic artery embolization for prostatic hyperplasia. AB - We describe an 85-year-old man suffering lower urinary tract symptoms, who underwent prostatic artery embolization (PAE) based on a prostate-supplying arteriogram created with multidetector-row computed tomography during pelvic arteriography. This arteriogram was synthesized from a background bone volume rendered (VR) image, an aorta-pelvic artery VR image, and a prostate-supplying artery VR image. Because the bone background VR image is combined with the aorta pelvic artery VR image, the prostate-supplying arteriogram can simultaneously show the pelvic branch arteries present on the ventral side, inside, and the dorsal side of the pelvic bone. It showed that the left prostatic artery supplied the urethra at the outlet of the urinary bladder. PAE of the left prostatic artery was performed with catheter navigation based on the prostate-supplying arteriogram. There was marked relief of the lower urinary tract symptoms at the 12-month follow-up. PMID- 24817215 TI - Cell patterning with a heptagon acoustic tweezer--application in neurite guidance. AB - Accurate control over positioning of cells is a highly desirable feature in tissue engineering applications since it allows, for example, population of substrates in a controlled fashion, rather than relying on random seeding. Current methods to achieve a differential distribution of cells mostly use passive patterning methods to change chemical, mechanical or topographic properties of surfaces, making areas differentially permissive to the adhesion of cells. However, these methods have no ad hoc control over the actual deposition of cells. Direct patterning methods like bioprinting offer good control over cell position, but require sophisticated instrumentation and are often cost- and time intensive. Here, we present a novel electronically controlled method of generating dynamic cell patterns by acoustic trapping of cells at a user determined position, with a heptagonal acoustic tweezer device. We demonstrate the capability of the device to create complex patterns of cells using the device's ability to re-position acoustic traps by using a phase shift in the acoustic wave, and by switching the configuration of active piezoelectric transducers. Furthermore, we show that by arranging Schwann cells from neonatal rats in a linear pattern we are able to create Bands of Bungner-like structures on a non-structured surface and demonstrate that these features are able to guide neurite outgrowth from neonatal rat dorsal root ganglia. PMID- 24817216 TI - Reliable LC-MS/MS assay for the estimation of rilpivirine in human plasma: application to a bioequivalence study and incurred sample reanalysis. AB - A simple, precise, and rapid stable isotope dilution liquid chromatography-tandem mass spectrometry method has been developed and validated for the quantification of rilpivirine, a non-nucleoside reverse transcriptase inhibitor in human plasma. Rilpivirine and its deuterated analogue, rilpivirine-d6, used as an internal standard (IS) were quantitatively extracted by liquid-liquid extraction with methyl-tert-butyl ether and diethyl ether solvent mixture from 50 MUL plasma. The chromatography was achieved on Gemini C18 (150 * 4.6 mm, 5 um) analytical column in a run time of 2.2 min. The precursor -> product ion transitions for rilpivirine (m/z 367.1 -> 128.0) and IS (m/z 373.2 -> 134.2) were monitored on a triple quadrupole mass spectrometer in the positive ionization mode. The linearity of the method was established in the concentration range of 0.5-200 ng/mL. The mean extraction recovery for rilpivirine (94.9%) and IS (99.9%) from spiked plasma samples was consistent and reproducible. The IS-normalized matrix factors for rilpivirine ranged from 0.98 to 1.02 across three quality controls. Bench top, freeze-thaw, wet extract, and long-term stability of rilpivirine was examined in spiked plasma samples. The application of the method was demonstrated by a bioequivalence study with 25 mg rilpivirine tablet formulation in 40 healthy subjects. The assay reproducibility was shown by reanalysis of 200 study samples and the % change in the concentration of repeat values from the original values was within +/-15%. PMID- 24817217 TI - Prevalence of psychiatric disorders and functional impairment after loss of a family member: a longitudinal study after the 2004 Tsunami. AB - BACKGROUND: Bereavement following disasters is a devastating experience for family members. The aim of this study was to examine the long-term mental health effects of losing a loved one in a natural disaster. METHODS: Ninety-four Norwegians aged 18-80 years who lost close family members in the 2004 Southeast Asian tsunami were evaluated 2 and 6 years after the disaster. The participants were either staying in an affected area at the time of the disaster (i.e., directly exposed) or not (i.e., not directly exposed). The prevalence of psychiatric disorders was assessed by the MINI International Neuropsychiatric Interview (M.I.N.I). Prolonged grief disorder (PGD) was self-reported using the Inventory of Complicated Grief (ICG), and functional impairment was self-reported using the Work and Social Adjustment Scale (WSAS). RESULTS: We did not identify a significant decrease in the prevalence of PGD, posttraumatic stress disorder (PTSD), or major depressive disorder (MDD) from 2 to 6 years. Approximately, one third of the bereaved (36%) had a psychiatric disorder 6 years after the tsunami. The most common disorder was PGD (12%) followed by general anxiety disorder (GAD, 11%), agoraphobia (11%), and MDD (10%). The prevalence of PTSD and MDD was higher among family members who were directly exposed to the disaster compared to those who were not (21 vs. 0%, and 25 vs. 3%). PGD was associated with functional impairment independent of other disorders. CONCLUSIONS: Loss of a close family member in a natural disaster can have a substantial adverse long-term effect on mental health and everyday functioning. PMID- 24817218 TI - Bee species diversity enhances productivity and stability in a perennial crop. AB - Wild bees provide important pollination services to agroecoystems, but the mechanisms which underlie their contribution to ecosystem functioning--and, therefore, their importance in maintaining and enhancing these services-remain unclear. We evaluated several mechanisms through which wild bees contribute to crop productivity, the stability of pollinator visitation, and the efficiency of individual pollinators in a highly bee-pollination dependent plant, highbush blueberry. We surveyed the bee community (through transect sampling and pan trapping) and measured pollination of both open- and singly-visited flowers. We found that the abundance of managed honey bees, Apis mellifera, and wild-bee richness were equally important in describing resulting open pollination. Wild bee richness was a better predictor of pollination than wild-bee abundance. We also found evidence suggesting pollinator visitation (and subsequent pollination) are stabilized through the differential response of bee taxa to weather (i.e., response diversity). Variation in the individual visit efficiency of A. mellifera and the southeastern blueberry bee, Habropoda laboriosa, a wild specialist, was not associated with changes in the pollinator community. Our findings add to a growing literature that diverse pollinator communities provide more stable and productive ecosystem services. PMID- 24817220 TI - Evaluating occupational hearing loss: the value of the AMA's Guides to the Evaluation of Permanent Impairment. PMID- 24817219 TI - Copper amine oxidase and phospholipase D act independently in abscisic acid (ABA) induced stomatal closure in Vicia faba and Arabidopsis. AB - Recent evidence has demonstrated that both copper amine oxidase (CuAO; EC 1.4.3.6) and phospholipase D (PLD; EC 3.1.4.4) are involved in abscisic acid (ABA)-induced stomatal closure. In this study, we investigated the interaction between CuAO and PLD in the ABA response. Pretreatment with either CuAO or PLD inhibitors alone or that with both additively led to impairment of ABA-induced H2O2 production and stomatal closure in Vicia faba. ABA-stimulated PLD activation could not be inhibited by the CuAO inhibitor, and CuAO activity was not affected by the PLD inhibitor. These data suggest that CuAO and PLD act independently in the ABA response. To further examine PLD and CuAO activities in ABA responses, we used the Arabidopsis mutants cuaozeta and pldalpha1. Ablation of guard cell expressed CuAOzeta or PLDalpha1 gene retarded ABA-induced H2O2 generation and stomatal closure. As a product of PLD, phosphatidic acid (PA) substantially enhanced H2O2 production and stomatal closure in wide type, pldalpha1, and cuaozeta. Moreover, putrescine (Put), a substrate of CuAO as well as an activator of PLD, induced H2O2 production and stomatal closure in WT but not in both mutants. These results suggest that CuAO and PLD act independently in ABA-induced stomatal closure. PMID- 24817221 TI - Tympanic paraganglioma. PMID- 24817222 TI - Endoscopic view of a concha bullosa of the inferior nasal turbinate. PMID- 24817223 TI - Complex posterior arytenoid dislocation. PMID- 24817224 TI - Ceruminous adenocarcinoma of the ear. PMID- 24817226 TI - Massive pleomorphic adenoma of the parotid gland: surgical considerations. PMID- 24817227 TI - Chronic lymphocytic thyroiditis (Hashimoto thyroiditis). PMID- 24817228 TI - A "nail-biting" case of an airway foreign body. PMID- 24817229 TI - Parathyroid adenoma in a woman with secondary hyperparathyroidism. PMID- 24817230 TI - Dizziness in the elderly: diagnosing its causes in a multidisciplinary dizziness unit. AB - We conducted a study to determine the causes of dizziness in patients aged 70 years and older who had been referred to our multidisciplinary dizziness clinic between Nov. 1, 2000, and Dec. 31, 2008. This population was made up of 731 patients--254 men (34.7%) and 477 women (65.3%). During their consultations, all of these patients were evaluated simultaneously by an ENT surgeon and a neurologist. We were able to identify the cause of dizziness in 620 of these patients (84.8%). The two most common causes were benign paroxysmal positional vertigo (BPPV), which was found in 202 patients (27.6%), and hyperventilation/anxiety, which was diagnosed in 112 patients (15.3%). Based on our findings, we conclude that the cause of dizziness can be established in the vast majority of elderly patients. We also compare our findings in these older patients with those of a group of 2,556 younger patients who were seen at our hospital and with the findings reported in other studies. PMID- 24817231 TI - Evaluating the role of single-photon emission computed tomography in the assessment of neurotologic complaints. AB - We conducted a retrospective study to reexamine the value of single-photon emission computed tomography (SPECT) in the evaluation of patients with neurotologic complaints, and to assess the intra- and inter-radiologist variability of SPECT readings. Our study population was made up of 63 patients- 23 men and 40 women, aged 34 to 91 years (mean: 59)--who had presented to a tertiary care otolaryngology practice and university hospital for evaluation of head trauma, sensorineural hearing loss, tinnitus, and/or vertigo. All patients had undergone brain scanning with SPECT during their evaluation, and almost all had also undergone magnetic resonance imaging (MRI) and standard computed tomography (CT). We compared the findings of all three imaging modalities in terms of their ability to detect neurotologic abnormalities. We found that detection rates were very similar among the three modalities; abnormalities were found in 24% of SPECT scans, 26% of MRIs, and 23% of CTs. Nevertheless, we did find that among 60 patients who underwent all three types of imaging, 13 (22%) exhibited areas of cerebral hypoperfusion on SPECT while their MRIs and CTs were read as either normal or nonspecific. In all, 18 of these 60 patients (30%) exhibited normal or nonspecific findings on all three types of imaging. In addition, when SPECT scans were read by the same radiologist at different times, different results were reported for 17 of the 63 scans (27%). Likewise, when SPECT scans were read by different radiologists, different results were reported for 21 of 63 scans (33%). We conclude that SPECT may be a valuable complementary diagnostic modality for making a comprehensive neurotologic evaluation and that it may detect abnormalities in some patients whose other imaging is read as normal. However, we did not find that SPECT was the most sensitive of the three modalities in neurotologic evaluation, as we had previously found in a preliminary study that the senior author (R.T.S.) published in 1996. In addition, with respect to our radiologists, both their intra- and inter-reader reliability was low, and we recommend additional study on this matter. PMID- 24817232 TI - Nasal valve surgery: assessment of quality of life with the Glasgow Benefit Inventory. AB - We used the 18-question Glasgow Benefit Inventory (GBI) to conduct a retrospective assessment of quality of life following nasal valve surgery. We telephoned 53 patients who had undergone open rhinoplasty for the treatment of nasal valve collapse over a 2-year period. A total of 39 patients--24 men and 15 women, aged 20 to 50 years (mean: 38)--agreed to participate and answer the questions. Follow-up ranged from 3 to 12 months (mean: 8). The spectrum of possible GBI scores ranges from -100 (maximum negative outcome) to 0 (no change) to +100 (maximum benefit); in our group, the median total score was +56 (interquartile range: +32 to +90.5) and the overall total score was +58. The three subscale components of the GBI--general benefit, physical benefit, and social benefit--were analyzed individually; the respective median scores were +46 (+21 to +71), +67 (+25 to +91.5), and +50 (+17 to +100), and the respective overall scores were +60, +59, and +50. Based on these findings, we conclude that nasal valve surgery significantly improves quality of life. PMID- 24817233 TI - The role of contact endoscopy in screening for premalignant laryngeal lesions: a study of 141 patients. AB - At their earliest stage, pathologic lesions of the laryngeal epithelium are macroscopically invisible. Ideally, these lesions should be detected before their clinical manifestations appear so that prompt management can be initiated. However, most diagnostic modalities are unable to detect early premalignant lesions. We conducted a retrospective study of the use of contact endoscopy in analyzing the vocal fold mucosal epithelium in adults who had been operated on at our hospital under general anesthesia for various nonlaryngeal diseases. After we identified 71 such patients who were smokers, we chose an almost equal number of nonsmokers (n = 70) for comparison purposes. In all, our study population was made up of 141 patients--51 men and 90 women, aged 21 to 78 years (mean: 52). All patients had normal findings on preoperative laryngeal endoscopy. Our goal was to determine if the routine use of this diagnostic modality is justified in selected cases. Contact endoscopy identified dysplastic vocal fold lesions in 4 patients and chronic laryngitis in 3; all 7 of these patients were smokers. Since early laryngeal lesions are not macroscopically evident, early detection of these changes by other means is associated with a better prognosis and easier management. Our study demonstrates that the use of contact endoscopy during general anesthesia as a standard diagnostic method in long-time cigarette smokers is fully justified. PMID- 24817234 TI - Metastatic cervical carcinoma from an unknown primary: literature review. AB - Carcinoma of an unknown primary (CUP) encompasses a heterogeneous group of tumors for which no primary site can be detected following a thorough history, physical examination, and noninvasive and invasive testing. CUP presenting with metastasis to the neck (metastatic cervical carcinoma from an unknown primary [MCCUP]) has been an enigma since von Volkmann first described it in 1882 as a cancer arising in a branchial cleft cyst. Genetic studies have shed some light on this unusual entity. In most cases, clinical features, imaging studies, and a meticulous assessment of the upper aerodigestive tract should assist in identifying the source of disease. Molecular testing of cytologic specimens for Epstein-Barr virus and human papillomavirus (HPV) can facilitate identification of the primary site in the nasopharynx and oropharynx. At least 25% of MCCUPs are directly attributable to HPV-related malignancies, and this number can be expected to increase. Minimally invasive transoral mucosal sampling can identify an otherwise clinically and radiologically occult cancer. We performed a literature review with the objective of discussing the history, epidemiology, clinical presentation, diagnostic workup, and management of MCCUP. PMID- 24817235 TI - Anatomic measurements of the anterior and posterior ethmoid arteries in cadaveric heads using endoscopic sinus instrumentation. AB - The challenges of endoscopic sinus surgery lie in the complexity of the anatomy of the nasal vault and side walls and the proximity to critical structures. Additionally, operating in a three-dimensional space while relying on a two dimensional image for surgical navigation can be a disorienting task. Successful sinus surgery relies on the surgeon having a clear understanding of the anatomy and relationships within the operative field. We performed a study of 8 adult cadaveric heads to better elucidate the location of the ethmoid arteries in relation to an accessible external landmark, the nasal sill. Sinus endoscopy was performed on the heads to identify and measure the distance from the nasal sill to the anterior and posterior ethmoid arteries. We found that the distance from the nasal sill to the anterior ethmoid artery was approximately 6.0 cm, and the distance to the posterior ethmoid artery was approximately 6.7 cm. The interarterial distance was approximately 1.2 cm. With a better understanding of these vessels, surgeons will be better able to avoid them during surgery and thereby minimize the risk of excessive intraoperative bleeding and perioperative orbital hematoma. PMID- 24817236 TI - Endoscopic transnasal transsphenoidal approach for craniopharyngioma: report of 6 cases. AB - We conducted a retrospective study to evaluate outcomes in patients with a craniopharyngioma who were managed via a transnasal transsphenoidal approach. Craniopharyngiomas exhibit histologically benign but "clinically malignant" features. Our study group was made up of 5 patients who underwent a total of 6 operations. The study population included 1 female and 5 males, aged 14 to 50 years (mean: 29.2). The overall rate of near-total tumor removal was 67%, but all patients eventually experienced a recurrence. Revision surgery to correct any severe postoperative complications was not required in any case. We found that the endoscopic transnasal transsphenoidal approach could be a safe and less invasive surgical option for the removal of craniopharyngiomas, although we were unable to remove all tumor or prevent recurrences. PMID- 24817237 TI - Postoperative shoulder function after different types of neck dissection in head and neck cancer. AB - Reported complications of neck dissection surgery have included decreases in shoulder muscle power and range of motion, drooping shoulder, and shoulder pain. We conducted a cross-sectional study to assess postoperative shoulder function following three different types of neck dissection surgery that were performed at Aga Khan University Hospital and to determine how various treatment factors and patient characteristics affected postoperative shoulder function. Our study population included 70 patients--51 men and 19 women, aged 18 to 70 years (mean: 48.6 +/- 11.6)--who had undergone a total of 92 neck dissections (22 patients underwent bilateral procedures). Patients were assessed by physical examination and questionnaire responses. The physical examination included objective assessments of shoulder muscle power against resistance, active range of motion, maximum possible forward flexion, the length of time needed to repeat active shoulder flexion 5 times, and shoulder abduction. The questionnaire covered shoulder mobility during activities of daily living, the results of physiotherapy (and exercise), postoperative radiation status, and shoulder pain. Of the 92 neck dissections, 17 were selective (18.5%), 64 were modified radical (69.6%), and 11 were radical (12.0%). We found that patients who had undergone a nerve-sparing procedure (i.e., selective neck dissection or a modified radical neck dissection) exhibited significantly better shoulder function than did patients who had undergone radical neck dissections (p < 0.01). In addition, increasing age (p < 0.001) and a history of diabetes (p = 0.003) were associated with worse shoulder function, and postoperative physiotherapy was associated with better shoulder function (p = 0.002). Neither sex, weight, the side of the neck operated on (left or right), the administration of postoperative radiation, the length of time between surgery and shoulder function assessment, comorbidities such as hypertension and ischemic heart disease, nor the status of the level V lymph nodes had any statistically significant association with shoulder function. PMID- 24817238 TI - Retropharyngeal pseudoabscess manifesting in nephrotic syndrome. AB - We describe a case of nephrotic syndrome that manifested as a retropharyngeal pseudoabscess. The patient was a 32-year-old man who presented with a short history of throat discomfort and a choking sensation. Laryngoscopy identified bulging of the posterior pharyngeal wall that partially occluded the laryngeal inlet. A lateral neck x-ray revealed that the prevertebral space was widened, and computed tomography detected fluid in the retropharyngeal and parapharyngeal spaces. Neck exploration revealed that the edema had been caused by nonsuppurative fluid. Biochemical analyses revealed marked hypoalbuminemia and heavy proteinuria suggestive of nephrotic syndrome. Following surgery, the patient's symptoms resolved. Aseptic effusion into the retropharyngeal space is rare; reported etiologies include internal jugular vein thrombosis, neoplasia, radiation therapy, trauma, acute calcific tendinitis, hereditary angioedema, and myxedema of hypothyroidism. To the best of our knowledge, this is the first case of nephrotic syndrome initially manifesting as retropharyngeal pseudoabscess to be reported in the literature. Thrombotic occlusion of the pharyngeal venous plexus secondary to hypercoagulability is a plausible explanation for such isolated retropharyngeal effusion. PMID- 24817239 TI - Modified radical mastoidectomy and its complications--12 years' experience. AB - To find the incidence of complications of modified radical mastoidectomy and to evaluate different parameters that play a role in their causation, we conducted a retrospective study spanning a period of 12 years. Included were 210 patients who underwent primary modified radical mastoidectomies performed by one senior surgeon; of these patients, 163 fulfilled the inclusion criteria. The charts were evaluated for patients' age and sex, laterality, intraoperative pathology, and complications. The complications were grouped into nine categories for analysis of their etiology. The results in this study were compared with those from other published reports. Complications were documented in 46 of 163 (28.2%) operated ears; 21 (45.7%) of them were noted in children <15 years of age, and 25 (54.3%) were found in adults. Sex and laterality were of no significance. The most common complication recorded was residual/recurrent cholesteatoma (20 [12.3%]), followed by meatal stenosis (11 [6.7%]). A moist cavity with discharging ear was noted in only 4 (2.5%) patients. No facial nerve palsies or dead ears were observed. Eleven (6.7%) patients had more than one complication. The parameters evaluated were size of the meatus, tympanic membrane appearance, status of the mastoid cavity, height of the facial ridge, and extent of the disease process. Complications can be caused by a number of factors, such as congenital anomalies, disease process, and the surgeon's skill. Each complication must be thoroughly evaluated for immediate management and to learn how to avoid it in the future. PMID- 24817240 TI - Prevalence and correlates of dizziness in the Ibadan Study of Ageing. AB - Dizziness is common among older people, but little is known about its prevalence and risk factors in the sub-Saharan population. We conducted a cross-sectional study to determine the prevalence of dizziness and its sociodemographic, lifestyle, and clinical correlates in 1,299 subjects--551 men (42.4%) and 748 women (57.6%), aged 65 years and older (mean: 77.3 +/- 6.3)--who lived in the Yoruba-speaking areas of Nigeria. Among this group, 318 persons reported dizziness, which represents a prevalence of 24.5%. Univariate analysis of sociodemographic and lifestyle variables revealed that low economic status (p = 0.05) and smoking (p = 0.01) were significantly correlated with dizziness; however, on logistic regression analysis, only smoking (p = 0.01) was found to be significant. Neither sex (p = 0.07), age (p = 0.71), area of residence (p = 0.34), education level (p = 0.74), nor alcohol consumption (p = 0.44) had a significant correlation with dizziness. On multivariate modeling, significant clinical correlates in patients with dizziness included self-reports of a history of suppurative otitis media (p = 0.01), head injury (p = 0.03), and recurrent rhinosinusitis (p = 0.01); no significant correlation was seen between dizziness and hypertension, transient ischemic attack, and diabetes. Finally, balance testing conducted in a subset of 1,006 subjects revealed poor balance in 93 of 250 persons with dizziness (37.2%) and in 189 of 756 subjects without dizziness (25.0%) (p = 0.01). Logistic regression analysis of sex and age revealed that the probability of poor balance was 1.5 times greater among those persons with dizziness. We conclude that the high incidence of dizziness among community dwelling elderly and its significant correlations with remediable medical conditions suggest the need for policy formulation for the care of the elderly in Nigeria. PMID- 24817241 TI - Saddle-nose deformities in the rheumatology clinic. AB - Saddle-nose deformity can occur as a result of trauma to the nose, but it has also been well described in the setting of infections such as leprosy and syphilis and idiopathic inflammatory conditions such as granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) and relapsing polychondritis. Since these deformities may also arise without an evident precipitating cause, they can pose a diagnostic conundrum. We review 2 cases of saddle-nose deformity that were treated at Northwick Park Hospital in Middlesex, England. The first patient was a 53-year-old woman who presented with epistaxis and deviation of the nasal septum. She subsequently developed a saddle-nose deformity and a septal ulcer. An autoimmune screen was negative, and histologic findings were nonspecific. She underwent successful reconstruction with a polyethylene implant. The second patient was a 21-year-old woman who presented with nasal obstruction and a nasal septal deviation. Two years later, she was diagnosed with Crohn disease and treatment with azathioprine was commenced. Eventually, the cartilaginous dorsum of her nose collapsed. A biopsy of the area revealed nonspecific, active, chronic inflammation. A polyethylene implant was placed to correct the deformity, but part of the implant became dislodged, and revision surgery was not successful. A subsequent revision was performed, and the early results were encouraging. Saddle-nose deformity may be a manifestation of underlying connective tissue disease, so it is important to detect and treat any such condition before embarking on surgical repair of the deformity. Our 2 cases indicate that this very deforming condition is poorly understood and treatment can be unsatisfactory. PMID- 24817242 TI - Rhinotopic therapy for refractory chronic rhinosinusitis: a study of 20 cases. AB - The management of refractory chronic rhinosinusitis (CRS) after endoscopic sinus surgery is complex and challenging. We conducted a prospective clinical pilot study to evaluate the effectiveness of a rhinotopic protocol for the treatment of refractory CRS. Our study population was made up of 20 patients--8 men and 12 women, aged 31 to 76 years (mean: 50.1)--who were treated in our tertiary care rhinology fellowship training program. The rhinotopic protocol consisted of twice daily saline rinses, each of which was followed by the administration of a nebulized corticosteroid and then a nebulized antibiotic. This regimen was administered for 6 weeks. Thereafter, patients underwent a once-weekly endoscopic sinus debridement followed by topical intrasinus installation of a corticosteroid and antibiotic. The duration of follow-up was 24 weeks, and thus the total study duration was 30 weeks. Treatment outcomes were based on Lund-Kennedy symptom scores and Lund-Kennedy endoscopic appearance scores. We found a 56% improvement in the mean symptom score after 3 weeks of therapy and 77% after 6 weeks. Subsequent follow-up revealed 90% improvement 4 weeks following the completion of therapy and 95% at 8 weeks post-therapy. Thereafter, we saw a small decrease in improvement: 73% at 16 weeks of follow-up and 65% at 24 weeks. Analysis of endoscopic appearance scores revealed a 55% improvement at 3 weeks of therapy and 84% at 6 weeks. The same general pattern emerged during follow-up, with 94% improvement 4 weeks after the cessation of therapy, 96% at 8 weeks, 76% at 16 weeks, and 75% at 24 weeks. Sinus cultures performed 4 weeks after the cessation of therapy found no growth in 13 patients (65%), normal respiratory flora in 5 patients (25%), a persistent pathogen in 1 patient (5%), and the emergence of a new pathogen in another (5%). Analysis of symptom scores and endoscopic appearance scores revealed that the rhinotopic protocol resulted in statistically significant improvement (p < 0.001) throughout the treatment period and follow-up period, although the improvement gradually declined over time. We therefore conclude that a rhinotopic protocol can be an effective treatment for refractory CRS. PMID- 24817243 TI - The cosmetic Z-plasty: restoring and refining an old technique for neck rejuvenation. AB - Direct excision of the "turkey neck" skin fold with Z-plasty closure was introduced in the 1970s, but it has fallen out of favor in an era in which much emphasis is placed on minimizing visible scars. Although the newer techniques may effectively improve the aesthetic contour of the neck without leaving visible scars, they may not be optimal for selected patients who want a quick, "no hassle" correction of their neck contour without changing the overall appearance of their face. We conducted a retrospective study of 50 patients--47 men and 3 women, aged 59 to 80 years (mean: 70)--who had undergone cosmetic Z-plasty performed by the senior author (A.N.L.) over a 9-year period. These patients either did not want or were not candidates for a face-lift or other procedure. Patients' charts were examined for demographic data, complications, and overall satisfaction with the procedure. In 46 of the 50 cases, the initial cosmetic result was acceptable to both the patient and the surgeon. The only complications were recurrent or residual areas of skin redundancy or dissatisfaction with the scar, but these were easily corrected with a second procedure using local anesthesia in the office setting. We conclude that cosmetic Z-plasty is a safe and effective means of correcting turkey neck deformity in patients who desire a procedure with a short operating time, a brief recovery period, a low complication rate, and a minimal effect on the overall appearance of their face. Although cosmetic Z-plasty is frequently considered to be antiquated, we believe refined versions of this procedure can still be of value to the plastic surgeon. In addition to describing our study results, we also describe in detail our surgical technique, including several contemporary refinements. PMID- 24817244 TI - Resolution of laryngeal granuloma with high-dose prednisone. PMID- 24817245 TI - Chondroid syringoma of the ear lobule: a unique case. PMID- 24817246 TI - Endoscopic view of an edematous uncinate process. PMID- 24817247 TI - An integrated map of HIV-human protein complexes that facilitate viral infection. AB - Recent proteomic and genetic studies have aimed to identify a complete network of interactions between HIV and human proteins and genes. This HIV-human interaction network provides invaluable information as to how HIV exploits the host machinery and can be used as a starting point for further functional analyses. We integrated this network with complementary datasets of protein function and interaction to nominate human protein complexes with likely roles in viral infection. Based on our approach we identified a global map of 40 HIV-human protein complexes with putative roles in HIV infection, some of which are involved in DNA replication and repair, transcription, translation, and cytoskeletal regulation. Targeted RNAi screens were used to validate several proteins and complexes for functional impact on viral infection. Thus, our HIV human protein complex map provides a significant resource of potential HIV-host interactions for further study. PMID- 24817248 TI - Quality of life and psychological functioning in pediatric obesity: the role of body image dissatisfaction between girls and boys of different ages. AB - PURPOSE: This study aims to explore the associations between weight status, body image dissatisfaction (BID), and psychosocial adjustment [quality of life (QOL), internalizing and externalizing problems] of normal-weight and obese youth. It aims to explore whether the associations between weight status and psychosocial adjustment are mediated by BID as well as the moderating role of youth's age and gender on these associations. METHODS: The sample comprised 260 children and adolescents aged 8-18 years with normal weight (n = 128) and obesity (n = 132). All of the participants completed self-report instruments, including the KIDSCREEN-10, Strengths and Difficulties Questionnaire, and Collins Body Image scale. RESULTS: Obese youth, regardless of gender, reported poorer QOL, more internalizing/externalizing problems, and higher rates of BID compared with their normal-weight counterparts. BID mediated the relationship between weight status and QOL, but only for youth above 12-year old. The relationship between weight status and internalizing/externalizing problems was direct and independent of youth's age and gender. CONCLUSIONS: Pediatric obesity is associated with poorer psychosocial outcomes, which underlines the need for preventive and early interventions. An important target in psychological interventions seems to be BID, which proved to be an important mechanism linking obesity and decreased QOL among adolescents. PMID- 24817249 TI - Rhodium(III)-catalyzed C2-selective carbenoid functionalization and subsequent C7 alkenylation of indoles. AB - Here a new, mild and versatile method for efficient synthesis of a diverse range of 2-acetate substituted indoles via Rh(III)-catalyzed and alcohol-mediated C2 selective carbenoid insertion functionalization of indoles by alpha-diazotized Meldrum's acid has been developed. Furthermore, for the first time, a Rh(III)/Cu(II)-catalyzed direct C7-alkenylation of such functionalized products has also been demonstrated. PMID- 24817251 TI - Spectrofluorimetric analysis of ethopabate in veterinary formulations with application to residue determination in chicken muscles and liver. AB - Ethopabate is a veterinary drug used in the prophylaxis and treatment of coccidiosis in chickens. The presence of drug residues in edible tissues can be dangerous to human consumers. It may cause direct toxic effects, allergic reactions and increased bacterial resistance. A highly sensitive, simple and rapid spectrofluorimetric method was developed for the determination of ethopabate in its veterinary formulations. The proposed method is based on measuring the native fluorescence of ethopabate in water at 364 nm after excitation at 270 nm. The fluorescence-concentration plot was rectilinear over the range of 2-100 ng/mL, with a limit of detection of 2.9 ng/g and a limit of quantification of 9.8 ng/g for ethopabate. The method was successfully applied to the analysis of ethopabate in its commercial veterinary formulations and the results were in good agreement with those obtained with the reference method. The method was extended to the determination of ethopabate residues in chicken muscles and liver, and the results were satisfactory. The recoveries obtained were in the 108.36-113.42% range. No organic solvents are used in the procedure, so it can be considered a type of 'green' chemistry. PMID- 24817250 TI - Responses of a pair of flying locusts to lateral looming visual stimuli. AB - We presented a pair of locusts flying loosely tethered with laterally looming discs. Two experiments tested whether looming-evoked flight behaviour was affected by the presence (1) or relative position (2) of a conspecific. We recorded: the type of behavioural response, motion within 6 degrees of freedom, behavioural onset time and duration, distance between individuals and relative direction of motion. Response distributions of the locust furthest from the stimulus (L1) were not affected by the presence or relative position of a conspecific, whereas distributions of the closer locust (L2) were affected by its position relative to the stimulus. Motion tracks of L1 were affected by the presence of L2, which generated relatively robust responses directed forward and away from the stimulus. Translational and rotational motion of L1 differed across treatments in both experiments, whereas L2 motion was less sensitive to the presence or position of a conspecific. The start and duration of the behaviour were invariant to the presence or position of a conspecific and locust pairs maintained a fixed distance during responses to looming. Results suggest that looming-evoked behaviour is influenced by visual cues from a conspecific in the vicinity. PMID- 24817252 TI - Principles of T2 *-weighted dynamic susceptibility contrast MRI technique in brain tumor imaging. AB - Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is used to track the first pass of an exogenous, paramagnetic, nondiffusible contrast agent through brain tissue, and has emerged as a powerful tool in the characterization of brain tumor hemodynamics. DSC-MRI parameters can be helpful in many aspects, including tumor grading, prediction of treatment response, likelihood of malignant transformation, discrimination between tumor recurrence and radiation necrosis, and differentiation between true early progression and pseudoprogression. This review aims to provide a conceptual overview of the underlying principles of DSC-MRI of the brain for clinical neuroradiologists, scientists, or students wishing to improve their understanding of the technical aspects, pitfalls, and controversies of DSC perfusion MRI of the brain. Future consensus on image acquisition parameters and postprocessing of DSC-MRI will most likely allow this technique to be evaluated and used in high-quality multicenter studies and ultimately help guide clinical care. PMID- 24817253 TI - [Trichophyton rubrum onychomycosis with secondary Aspergillus versicolor infection in a 12-year-old girl: successful topical therapy with terbinafine-urea ointment]. AB - CASE REPORT: A 12-year-old with a functional circulatory disturbance had toe nail onychomycosis caused by Trichophyton rubrum. There were no other underlying diseases. THERAPY AND OUTCOME: Oral therapy with terbinafine 125 mg once weekly in addition to ciclopirox nail lacquer was ineffective. Two years later the disease worsened and A. versicolor was found in pure culture. A preparation of 10% terbinafine HCl in a 20% urea ointment (Onychomal(r)) applied daily for 4 weeks, then once weekly resulted in complete cure after 7 months. PMID- 24817255 TI - Copper-catalyzed bis-arylations of alkenes leading to oxindole derivatives. AB - A simple and practical copper-catalyzed approach to oxindole derivatives by copper-catalyzed bis-arylation of N-alkyl-N-phenylacrylamides with diaryliodonium triflates has been developed under mild conditions, and the method is of tolerance towards some functional groups in the substrates. PMID- 24817254 TI - Elevated intraocular pressure in patients with acromegaly. AB - PURPOSE: To evaluate central corneal thickness (CCT) and intraocular pressure (IOP) in a cohort of acromegalic patients, and to correlate CCT with serum levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). METHODS: Consecutive patients affected by acromegaly underwent a comprehensive endocrinological and ophthalmological evaluation, including serum GH and IGF-1 levels, CCT measured with ultrasonic pachymetry and IOP assessed with Goldmann applanation tonometry. RESULTS: Fourteen patients with acromegaly and 28 healthy controls were included in the study. Acromegalic patients had a statistically higher median CCT (570 MUm [range 551.5-638] vs 542.7 MUm [range 461.5-610]; p < 0.01) and higher median IOP (17.2 mm Hg [range 14-21] vs 13.7 mm Hg [range 10.5 19]; p < 0.01) than healthy controls. No statistically significant correlation was found among CCT and GH, CCT and IGF-1, IOP and GH, IOP and IGF-1 in the acromegalic group, whereas a statistically significant correlation was documented between CCT and IOP in the entire cohort (Spearman's correlation coefficient: 0.56, p < 0.01). However, when IOP was corrected for CCT no significant difference was found between the two study groups (p = 0.07). CONCLUSIONS: Our results suggest that acromegaly is associated with an increased CCT, which could lead to an overestimation of IOP readings as determined with Goldmann applanation tonometry. PMID- 24817256 TI - Measuring echogenicity and area of the puborectalis muscle: method and reliability. AB - OBJECTIVES: To develop a semi-automated method to assess puborectalis muscle echogenicity on three-dimensional/four-dimensional (3D/4D) volume transperineal ultrasound images using 4D View and Matlab(r) software and evaluate its intra- and interobserver reliability. METHOD: The data of 23 women in their first trimester were included. 3D/4D volume datasets were obtained at rest. Two inexperienced observers were trained by an experienced observer to construct tomographic ultrasound images (TUI) from the original data and to delineate all structures. Puborectalis muscle area (PMA) and the mean echogenicity of the puborectalis muscle (MEP) were calculated offline. Intra- and interobserver reliability were determined by intraclass correlation coefficients (ICC) and their 95% CIs. RESULTS: The development of a semi-automated method to calculate puborectalis area and echogenicity is described in detail. PMA and MEP measurements in pregnant women demonstrated almost perfect intraobserver reliability for both inexperienced observers, with ICC values ranging from 0.88 to 0.99. The interobserver reliability showed ICCs of 0.63 for PMA and almost perfect ICC values, of 0.96-0.98, for echogenicity. The majority of intraobserver mismatch between two delineations of PMA occurred near the borders. CONCLUSIONS: Matlab software can be used to provide reliable measurements of the area and echogenicity of the puborectalis muscle. As the latter can be used to assess structural changes in the puborectalis muscle, it appears a promising new tool for studying pelvic floor structural anatomy. PMID- 24817257 TI - Author's reply to Ruo Redda MG et al. concerning "Dosimetric comparison between intensity-modulated radiotherapy and standard wedged tangential technique for whole-breast radiotherapy in Asian women with relatively small breast volumes". PMID- 24817258 TI - RAG1 reversion mosaicism in a patient with Omenn syndrome. AB - PURPOSE: To identify mechanisms of disease in a child born to consanguineous parents, who presented with Omenn syndrome (OS) and was found to carry a heterozygous RAG1 mutation in peripheral blood DNA. METHODS: Mutation analysis was performed on whole blood and buccal swab DNA. Recombination activity of the mutant RAG1 protein and diversity of T cell repertoire were tested. RESULTS: Apparent heterozygosity for a novel, functionally null RAG1 mutation in peripheral blood DNA from a patient with OS was shown to be secondary to true somatic reversion. Analysis of T cell repertoire demonstrated expression of various TCRBV families, but an overall restricted pattern. CONCLUSIONS: This is the first case of true somatic reversion of a RAG1 mutation in a patient with OS. The reversion event likely occurred at a stage where only a limited pool of T cell progenitors capable of performing V(D)J recombination could be generated. This work emphasizes the importance of performing functional studies to investigate the significance of novel genetic variants, and to consider somatic reversion as a possible disease modifier in SCID. PMID- 24817259 TI - Intervention to reduce inpatient psychiatric admission in a metropolitan city. AB - When psychiatric hospitalization is over-used, it represents a financial drain and failure of care. We evaluated implementation and cessation of transporting people medically certified for psychiatric hospitalization to a central psychiatric emergency service for management and re-evaluation of hospitalization need. After implementation, the hospitalization rate declined 89% for 346 transported patients; only four of the nonhospitalized patients presented in crisis again in the next 30 days. Following cessation, the hospitalization rate jumped 59% compared to the preceding year. Costs declined 78.7% per diverted patient. The findings indicate that it is possible to reduce hospitalization and costs, and maintain quality care. PMID- 24817260 TI - Alternative treatment modalities for the hypogonadal patient. AB - Testosterone (T) deficiency syndrome (TDS) is a prevalent condition, commonly managed with exogenous T. Despite an abundance of T formulations, alternative treatments are often sought for various reasons. To evaluate outcomes of alternative therapies, a PubMed search was performed of all publications that included men with TDS from 1990 through October 2013, with results summarized. Proposed mechanisms of action were also reviewed to provide a pathophysiologic basis for reported outcomes. Nonpharmacologic therapies that increase endogenous T are weight loss, exercise, and varicocelectomy, while medications used off label include aromatase inhibitors, human chorionic gonadotropin, and selective estrogen receptor modulators. All reported therapies increase T, while changes in estradiol and adverse events vary by therapeutic class. Although limited data preclude direct comparisons between therapies, exercise and weight loss alone or in combination with medications may be considered first line. The role for surgical therapy in TDS remains undefined and requires further study. PMID- 24817261 TI - Management of advanced prostate cancer - role of the urologist. AB - There now exists an enhanced opportunity for urologists to continue to successfully identify, treat, and manage advanced prostate cancer patients in partnership with our medical oncology and radiation oncology colleagues. For urologists and their supporting staff who are dedicated to caring for patients with advanced prostate cancer, there are novel therapies that delay disease progression, maintain - and oftentimes improve - quality-of-life metrics, and prolong overall survival. These therapies are not unusually difficult to manage, nor are they too intimidating with regard to understanding their mechanisms of action and respective safety profiles. They provide the opportunity to improve and enhance patient care, as well as to further augment the urological role in both the academic and community multidisciplinary prostate cancer clinic. PMID- 24817262 TI - Effects of molten-salt/ionic-liquid mixture on extraction of docosahexaenoic acid (DHA)-rich lipids from Aurantiochytrium sp. KRS101. AB - In this study, lipid extraction from Aurantiochytrium sp. was performed using a molten-salt/ionic-liquid mixture. The total fatty acid content of Aurantiochytrium sp. was 478.8 mg/g cell, from which 145 mg/g cell (30.3% of total fatty acids) of docosahexaenoic acid (DHA) was obtained. FeCl3.6H2O showed a high lipid extraction yield (207.9 mg/g cell), when compared with that of [Emim]OAc, which was only 118.1 mg/g cell; notably however, when FeCl3.6H2O was mixed with [Emim]OAc (5:1, w/w), the yield was increased to 478.6 mg/g cell. When lipid was extracted by the FeCl3.6H2O/[Emim]OAc mixture at a 5:1 (w/w) blending ratio under 90 degrees C, 30 min reaction conditions, the fatty acid content of the extracted lipid was a high purity 997.7 mg/g lipid, with most of the DHA having been extracted (30.2% of total fatty acids). Overall, lipid extraction from Aurantiochytrium sp. was enhanced by the synergistic effects of the molten salt/ionic-liquid mixture with different ions. PMID- 24817263 TI - Pilot-scale experiment of down-flow hanging sponge for direct treatment of low strength municipal wastewater in Bangkok, Thailand. AB - A pilot-scale experiment of a down-flow hanging sponge (DHS) reactor for treatment of low-strength municipal wastewater was conducted over 1 year in Bangkok, Thailand, to establish an appropriate method for treatment under tropical climate conditions. Municipal wastewater with an average BOD of 19 mg/L was fed directly into the DHS reactor. Superior effluent quality (5.1 +/- 3.4 mg/L TSS, 21.1 +/- 9.0 mg/L COD, 2.8 +/- 1.4 mg/L BOD, and 4.1 +/- 1.0 mg/L TN) was achieved at a hydraulic retention time (HRT) of 1 h under an average temperature of 30 degrees C. The DHS reactor reached an actual HRT of 19.0 min, indicating good contact efficiency between wastewater and retained sludge. The DHS reactor retained dense sludge at 15.3-26.4 g VSS/L based on the sponge media volume. The sludge activity in terms of specific oxygen uptake rate was good. Excess sludge was produced as 0.051 g TSS/g COD removed (0.11 g TSS/g BOD removed), and a good SVI of 28 mL/g was observed. The sufficient performance was attributed to dense sludge with high activity, regardless of the low-strength wastewater. Overall, the DHS was advantageous owing to its simple operation, lack of operational problems, and low power consumption. PMID- 24817264 TI - Shining a spotlight on intact proteins. PMID- 24817268 TI - Design and fabrication of a biomimetic nanochannel for highly sensitive arginine response in serum samples. AB - Inspired from their biological counterparts, chemical modification of the interior surface of nanochannels with functional molecules may provide a highly efficient means to control ionic or molecular transport through nanochannels. Herein, we have designed and prepared a aldehyde calix[4]arene (C4AH), which was attached to the interior surface of a single nanochannel by using a click reaction, and that showed a high response for arginine (Arg). Furthermore, the nanofluidic sensing system has been challenged with complex matrices containing a high concentration of interfering sequences and serum. Based on this finding, we believe that the artificial nanochannel can be used for practical Arg-sensing devices, and be applied in a biological environment. PMID- 24817269 TI - Ultrasound of the cervical roots and brachial plexus in neonates. AB - INTRODUCTION: In this exploratory study we investigated whether ultrasound can visualize the neonatal cervical roots and brachial plexus. METHODS: In 12 healthy neonates <2 days old, the neck region was studied unilaterally with ultrasound using a small-footprint 15-7-MHz transducer. RESULTS: The C5-C8 nerve roots and brachial plexus could be imaged with sufficient delineation of the root exits to assess their integrity. The brachial plexus was more difficult to discern from the surrounding area in neonates compared with adults, especially in the interscalene region because of the smaller amount of connective tissue in and surrounding muscles and nerves. In addition, the large deposits of brown fat make for a different ultrasound appearance of the neonatal neck compared with adults. CONCLUSIONS: Ultrasound of the neonatal cervical nerve roots is feasible and may be used as a non-invasive screening technique to assess nerve root integrity in obstetric brachial plexus injury. PMID- 24817270 TI - Reaction rate constants of H-abstraction by OH from large ketones: measurements and site-specific rate rules. AB - Reaction rate constants of the reaction of four large ketones with hydroxyl (OH) are investigated behind reflected shock waves using OH laser absorption. The studied ketones are isomers of hexanone and include 2-hexanone, 3-hexanone, 3 methyl-2-pentanone, and 4-methl-2-pentanone. Rate constants are measured under pseudo-first-order kinetics at temperatures ranging from 866 K to 1375 K and pressures near 1.5 atm. The reported high-temperature rate constant measurements are the first direct measurements for these ketones under combustion-relevant conditions. The effects of the position of the carbonyl group (C=O) and methyl (CH3) branching on the overall rate constant with OH are examined. Using previously published data, rate constant expressions covering, low-to-high temperatures, are developed for acetone, 2-butanone, 3-pentanone, and the hexanone isomers studied here. These Arrhenius expressions are used to devise rate rules for H-abstraction from various sites. Specifically, the current scheme is applied with good success to H-abstraction by OH from a series of n-ketones. Finally, general expressions for primary and secondary site-specific H abstraction by OH from ketones are proposed as follows (the subscript numbers indicate the number of carbon atoms bonded to the next-nearest-neighbor carbon atom, the subscript CO indicates that the abstraction is from a site next to the carbonyl group (C=O), and the prime is used to differentiate different neighboring environments of a methylene group): PMID- 24817271 TI - The dopaminergic stabilizers pridopidine and ordopidine enhance cortico-striatal Arc gene expression. AB - The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1 propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3 (methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4 dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine. PMID- 24817272 TI - Agrobacterium-mediated transformation of tomato with rolB gene results in enhancement of fruit quality and foliar resistance against fungal pathogens. AB - Tomato (Solanum lycopersicum L.) is the second most important cultivated crop next to potato, worldwide. Tomato serves as an important source of antioxidants in human diet. Alternaria solani and Fusarium oxysporum cause early blight and vascular wilt of tomato, respectively, resulting in severe crop losses. The foremost objective of the present study was to generate transgenic tomato plants with rolB gene and evaluate its effect on plant morphology, nutritional contents, yield and resistance against fungal infection. Tomato cv. Rio Grande was transformed via Agrobacterium tumefaciens harbouring rolB gene of Agrobacterium rhizogenes. rolB. Biochemical analyses showed considerable improvement in nutritional quality of transgenic tomato fruits as indicated by 62% increase in lycopene content, 225% in ascorbic acid content, 58% in total phenolics and 26% in free radical scavenging activity. Furthermore, rolB gene significantly improved the defence response of leaves of transgenic plants against two pathogenic fungal strains A. solani and F. oxysporum. Contrarily, transformed plants exhibited altered morphology and reduced fruit yield. In conclusion, rolB gene from A. rhizogenes can be used to generate transgenic tomato with increased nutritional contents of fruits as well as improved foliar tolerance against fungal pathogens. PMID- 24817273 TI - The chromatin "landscape" of a murine adult beta-globin gene is unaffected by deletion of either the gene promoter or a downstream enhancer. AB - In mammals, the complex tissue- and developmental-specific expression of genes within the beta-globin cluster is known to be subject to control by the gene promoters, by a locus control region (LCR) located upstream of the cluster, and by sequence elements located across the intergenic regions. Despite extensive investigation, however, the complement of sequences that is required for normal regulation of chromatin structure and gene expression within the cluster is not fully defined. To further elucidate regulation of the adult beta-globin genes, we investigate the effects of two deletions engineered within the endogenous murine beta-globin locus. First, we find that deletion of the beta2-globin gene promoter, while eliminating beta2-globin gene expression, results in no additional effects on chromatin structure or gene expression within the cluster. Notably, our observations are not consistent with competition among the beta globin genes for LCR activity. Second, we characterize a novel enhancer located 3' of the beta2-globin gene, but find that deletion of this sequence has no effect whatsoever on gene expression or chromatin structure. This observation highlights the difficulty in assigning function to enhancer sequences identified by the chromatin "landscape" or even by functional assays. PMID- 24817275 TI - Purification, characterization and antibacterial activity of L-amino acid oxidase from Cerastes cerastes. AB - Antibiotic resistance presents a real problem in which new antibacterial molecules from natural secretions could be beneficial in the development of new drugs. In this study, Cerastes cerastes venom was investigated for its antibacterial activity against Gram-positive and Gram-negative bacteria. The antibacterial activity was evaluated by measuring the halo inhibition and minimum inhibitory concentration (MIC). An L-amino acid oxidase (CcLAAO) was purified from this venom using three chromatographic steps; its homogeneity (60 kDa) was confirmed by SDS-PAGE. LC-MS/MS analysis of CcLAAO showed similarities with other LAAO enzymes from Echis ocellatus and Viridovipera stejnegeri venoms. CcLAAO presents an antibacterial activity against three bacterial strains (Staphylococcus aureus, Methicillin-resistant S. aureus, and Pseudomonas aeruginosa) with MIC values of 10, 10, and 20 MUg/mL, respectively. However, no effect was observed against Escherichia coli and yeast strains. Kinetic parameters of CcLAAO evaluated on L-leucine at pH 8.0 and 20 degrees C were Km = 0.06 mmol and Vmax = 164 mmol/min. PMID- 24817274 TI - Mycobacterium tuberculosis proteins involved in mycolic acid synthesis and transport localize dynamically to the old growing pole and septum. AB - Understanding the mechanism that controls space-time coordination of elongation and division of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is critical for fighting the tubercle bacillus. Most of the numerous enzymes involved in the synthesis of Mycolic acid - Arabinogalactan Peptidoglycan complex (MAPc) in the cell wall are essential in vivo. Using a dynamic approach, we localized Mtb enzymes belonging to the fatty acid synthase II (FAS-II) complexes and involved in mycolic acid (MA) biosynthesis in a mycobacterial model of Mtb: M. smegmatis. Results also showed that the MA transporter MmpL3 was present in the mycobacterial envelope and was specifically and dynamically accumulated at the poles and septa during bacterial growth. This localization was due to its C-terminal domain. Moreover, the FAS-II enzymes were co-localized at the poles and septum with Wag31, the protein responsible for the polar localization of mycobacterial peptidoglycan biosynthesis. The dynamic localization of FAS-II and of the MA transporter with Wag31, at the old-growing poles and at the septum suggests that the main components of the mycomembrane may potentially be synthesized at these precise foci. This finding highlights a major difference between mycobacteria and other rod-shaped bacteria studied to date. Based on the already known polar activities of envelope biosynthesis in mycobacteria, we propose the existence of complex polar machinery devoted to the biogenesis of the entire envelope. As a result, the mycobacterial pole would represent the Achilles' heel of the bacillus at all its growing stages. PMID- 24817276 TI - Dynamics matter: differences and similarities between alternatively designed mechanisms. AB - Cells selectively respond to external stimuli to maintain cellular homeostasis by making use of different regulatory mechanisms. We studied two classes of signal dependent regulatory inhibition and activation mechanisms in this study. Inhibition mechanisms assume that inhibition can occur in two different ways: either by increasing the degradation rate or decreasing the production rate. Similarly, it is assumed that signal-triggered activation can occur either through increasing production rate or decreasing degradation rate. We devised mathematical models (deterministic and stochastic) to compare and contrast responses of these activation and inhibition mechanisms to a time dependent discrete signal. Our simulation results show that the signal-dependent increased degradation mechanism is a more effective, noisier and quicker way to inhibit the protein abundance compared to the signal-dependent decreased activation mechanism. On the other hand, the signal-dependent increased production mechanism can produce a much stronger and faster response than the signal-dependent decreased degradation mechanism. However, our simulations predict that both of the activation mechanisms have roughly similar noise structures. Our analysis exemplifies the importance of mathematical modeling in the analysis of biological regulatory networks. PMID- 24817277 TI - Hard-diet feeding recovers neurogenesis in the subventricular zone and olfactory functions of mice impaired by soft-diet feeding. AB - The subventricular zone (SVZ) generates an immense number of neurons even during adulthood. These neurons migrate to the olfactory bulb (OB) and differentiate into granule cells and periglomerular cells. The information broadcast by general odorants is received by the olfactory sensory neurons and transmitted to the OB. Recent studies have shown that a reduction of mastication impairs both neurogenesis in the hippocampus and brain functions. To examine these effects, we first measured the difference in Fos-immunoreactivity (Fos-ir) at the principal sensory trigeminal nucleus (Pr5), which receives intraoral touch information via the trigeminal nerve, when female adult mice ingested a hard or soft diet to explore whether soft-diet feeding could mimic impaired mastication. Ingestion of a hard diet induced greater expression of Fos-ir cells at the Pr5 than did a soft diet or no diet. Bromodeoxyuridine-immunoreactive (BrdU-ir) structures in sagittal sections of the SVZ and in the OB of mice fed a soft or hard diet were studied to explore the effects of changes in mastication on newly generated neurons. After 1 month, the density of BrdU-ir cells in the SVZ and OB was lower in the soft-diet-fed mice than in the hard-diet-fed mice. The odor preferences of individual female mice to butyric acid were tested in a Y-maze apparatus. Avoidance of butyric acid was reduced by the soft-diet feeding. We then explored the effects of the hard-diet feeding on olfactory functions and neurogenesis in the SVZ of mice impaired by soft-diet feeding. At 3 months of hard-diet feeding, avoidance of butyric acid was reversed and responses to odors and neurogenesis were recovered in the SVZ. The present results suggest that feeding with a hard diet improves neurogenesis in the SVZ, which in turn enhances olfactory function at the OB. PMID- 24817278 TI - Genetic characterization and structure of the endemic Colombian silvery brown bare-face tamarin, Saguinus leucopus (Callitrichinae, Cebidae, Primates). AB - We analyzed 115 Saguinus leucopus, from four Colombian departments (Antioquia, Bolivar, Caldas and Tolima ), for 701 bp of the mt COII gene and at 10 microsatellite loci to estimate gene diversity levels, possible molecular subspecies and historical demographic changes in this species. This endemic Colombian species showed an elevated gene diversity in this gene, although its geographical distribution is very restrictive and extremely threatened by habitat fragmentation. The mt COII gene did not show any geographical structure in the distribution of the haplotypes within this species, but it did show a noteworthy population expansion throughout the history of this species. A Bayesian analysis showed that the haplotype diversification of this species began around 1.6 million years ago (MYA), whilst a haplotype network gave the beginning of this diversification at around 0.5-0.6 MYA. Forty-seven individuals out of the 115 were analyzed for 10 DNA microsatellites. The genetic diversity was relatively elevated for this kind of marker too, and comparable to that found in other Neotropical monkeys with a wider geographical distribution. Two gene pools were detected with the microsatellites, one in the northern distribution area (Antioquia) and the other in the southern distribution area (Tolima). No tests detected any bottleneck affecting this population; however, two procedures (k test and Kimmel et al. 1998 test) detected significant population expansion for the microsatellite markers, like that seen with the mt COII gene. PMID- 24817279 TI - Recurrent melanoma presenting as a very large cardiac mass with concurrent pancreatic involvement. PMID- 24817280 TI - Increased hospital and emergency department utilization by individuals with recent criminal justice involvement: results of a national survey. AB - BACKGROUND: Individuals involved with the criminal justice system have increased health needs and poor access to primary care. OBJECTIVE: To examine hospital and emergency department (ED) utilization and related costs by individuals with recent criminal justice involvement. DESIGN: Cross-sectional survey. PARTICIPANTS: Non-institutionalized, civilian U.S. adult participants (n = 154,356) of the National Survey on Drug Use and Health (2008-2011). MAIN MEASURES: Estimated proportion of adults who reported past year 1) hospitalization or 2) ED utilization according to past year criminal justice involvement, defined as 1) parole or probation, 2) arrest without subsequent correctional supervision, or 3) no criminal justice involvement; estimated annual expenditures using unlinked data from the Medical Expenditure Panel Survey. KEY RESULTS: An estimated 5.7 million adults reported parole or probation and an additional 3.9 million adults reported an arrest in the past year. Adults with recent parole or probation and those with a recent arrest, compared with the general population, had higher rates of hospitalization (12.3 %, 14.3 %, 10.5 %; P < 0.001) and higher rates of ED utilization (39.3 %, 47.2 %, 26.9 %; P < 0.001). Recent parole or probation was an independent predictor of hospitalization (adjusted odds ratio [AOR], 1.21; 95 % confidence interval [CI], 1.02-1.44) and ED utilization (AOR, 1.35; 95 % CI, 1.12-1.63); Recent arrest was an independent predictor of hospitalization (AOR, 1.26; 95 % CI, 1.08-1.47) and ED utilization (AOR, 1.81; 95 % CI, 1.53-2.15). Individuals with recent criminal justice involvement make up 4.2 % of the U.S. adult population, yet account for an estimated 7.2 % of hospital expenditures and 8.5 % of ED expenditures. CONCLUSIONS: Recent criminal justice involvement is associated with increased hospital and ED utilization and costs. The criminal justice system may offer an important point of contact for efforts to improve the healthcare utilization patterns of a large and vulnerable population. PMID- 24817281 TI - Internet support groups for health: ready for the Affordable Care Act. PMID- 24817282 TI - Evolution of hospital medicine and the impact on residents' career choices. PMID- 24817283 TI - In vitro test system for evaluation of immune activation potential of new single stranded DNA-based therapeutics. AB - Aptamers are synthetic single-stranded DNA (ssDNA) molecules with the ability to fold into complex three-dimensional structures. They can bind their targets with a high selectivity and affinity, thus they have an enormous potential as therapeutic agents. However, since aptamers are synthetic and especially since certain sequences can increasingly bind to the pattern recognition receptors of the immune cells when applied in vivo, they can induce an immune activation. Here, we established a real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) based assay to evaluate aptamers-induced immune activation prior to in vivo studies. Human whole blood or plasmacytoid dendritic cell line (PMDC05) were incubated with CpG, R10-60 aptamer, start library, or a CpG containing aptamer. After 2 and 4 h, cytokine expression was measured using qRT-PCR to determine immune reaction against different aptamers. CpG containing a phosphorothioate backbone led to a significant up-regulation of CCL-7, IFN 1alpha, IFN-1beta in whole blood after 4 h. Compared to the samples without ssDNA, significantly higher TNF-alpha expression was detected after the R10-60 aptamer incubation for 4 h. The stimulation of PMDC05 cells with different ssDNA enabled more sensitive detection of aptamer sequence specific immune activation. After 4 h, CpG led to a significantly higher expression of CCL-8, CXCL-10, IL 1beta, IL-6, IL-8, IFN-1beta, and TNF-alpha. R10-60 aptamer caused a significant up-regulation of IL-1beta, IFN-1beta, and TNF-alpha. Negative control aptamers did not induce an immune activation. The use of this assay before starting with in vivo studies will facilitate the in vitro prediction of immune activation potential of aptamers. PMID- 24817284 TI - Statins excert neuroprotection on cerebral ischemia independent of their lipid lowering action: the potential molecular mechanisms. AB - Cerebral ischemia is a major neurological disorder and a leading cause of death and disability in the world. Statins are a widely used group of cholesterol lowering agents that act by inhibiting the enzyme 3-hydroxy 3-methylglutaryl CoA (HMG CoA) reductase, which catalyses the rate-limiting step of cholesterol biosynthesis. In addition to their cholesterol-lowering properties, however, statins exert a number of so-called 'pleiotropic' actions. Data has emerged largely from thromboembolic animal models of stroke and cultivated cells. It is suggested that statins which have efficacy in preventing the stroke pretreatedly may have a positive effect even given post ischemia possibly through their pleiotropic effects. Mechanisms of the protective actions on cerebral ischemia include the inhibition of inflammatory responses, the improvement of endothelial dysfunction, the regulation of apoptosis proteins, the reduction of oxidative damage and the control of other relative endogenous signal pathways. Attempting to review these properties of statins is an exciting work that will improve our understanding on stroke and thus enable us to better use clinically this type of drugs. The present review summarizes available evidences on the effects and the potential molecular mechanisms of statins on cerebral ischemia. PMID- 24817285 TI - Optimization of in vitro cell labeling methods for human umbilical cord-derived mesenchymal stem cells. AB - BACKGROUND AND OBJECTIVES: Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) are a novel source of seed cells for cell therapy and tissue engineering. However, in vitro labeling methods for hUCMSCs need to be optimized for better detection of transplanted cells. AIM OF THE STUDY: To identify the most stable and efficient method for labeling hUCMSCs in vitro. MATERIALS AND METHODS: hUCMSCs were isolated using a modified enzymatic digestion procedure and cultured. hUCMSCs of passage three (P3) were then labeled with BrdU, PKH26, or lentivirus-GFP and passaged further. Cells from the first labeled passage (LP1), the fourth labeled passage (LP4) and later passages were observed using a fluorescence microscope. The differentiation potential of LP4 cells was assessed by induction with adipogenic and osteogenic medium. Flow cytometry was used to measure the percentage of labeled cells and the percentage of apoptotic or dead cells. The labeling efficiencies of the three hUCMSC-labeling methods were compared in vitro. RESULTS: BrdU, PKH26, and lentivirus-GFP all labeled LP1 cells with high intensity and clarity. However, the BrdU labeling of the LP4 cells was vague and not localized to the cell nuclei; LP9 cells were not detected under a fluorescence microscope. There was also a significant decrease in the fluorescence intensity of PKH26-labeled LP4 cells, and LP11 cells were not detected under a fluorescence microscope. However, the fluorescence of LP4 cells labeled with lentivirus-GFP remained strong, and cells labeled with lentivirus GFP were detected up to LP14 under a fluorescence microscope. Statistical analyses indicated that percentages of LP1 cells labeled with PKH26 and lentivirus-GFP were significantly higher than that of cells labeled with BrdU (p < 0.05), and that the LP4 cells were more efficiently labeled with lentivirus-GFP than with PKH26 or BrdU (p < 0.05). BrdU-, PKH26-, and lentivirus-GFP labeled LP4 cells were all differentiated to adipocytes or osteoblasts with adipogenic and osteogenic medium. No statistical significance (p > 0.05) was observed between the death rates of labeled and unlabeled cells. CONCLUSIONS: Lentivirus-GFP is a valid method for long-term in vitro labeling, and it may be used as a long-term hUCMSC tracker following transplantation in vivo. PMID- 24817286 TI - Role of reactive oxygen species in p53 activation during cisplatin-induced apoptosis of rat mesangial cells. AB - BACKGROUND AND OBJECTIVES: Nephrotoxicity is one of the main side effects of the anticancer drug cisplatin, and one of its main therapeutic limitations. It has been suggested that p53 activation plays important roles in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study examined whether reactive oxygen species (ROS) production by cisplatin would be linked to p53 activation in rat mesangial cells. MATERIALS AND METHODS: Renal cells were incubated with cisplatin in the absence or presence of pifithrin a (PFT), N-acetyl-cysteine (NAC), or dimethylthiourea (DMT). Cell viability was evaluated by 3-(4,5-dimethyl-2-thiazol yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis was evaluated by caspase-3 activity and cleavage of poly (ADP ribose) polymerase (PARP). The relative levels of ROS and p53 phosphorylation were determined by fluorometric assay and Western blot analysis, respectively. RESULTS: Cisplatin induced apoptotic cell death via caspase-3 activation and PARP cleavage, and also increased p53 activation and ROS production. The p53 inhibitor PFT inhibited cisplatin-induced apoptosis. NAC and DMT, two antioxidants, also inhibited cisplatin-induced apoptosis. Interestingly, NAC and DMT reduced ROS production and suppressed p53 activation in renal cells exposed to cisplatin. CONCLUSIONS: Our results suggest that the ability of cisplatin to induce apoptosis of rat mesangial cells requires ROS-dependent p53 activation, thus, supporting the potential therapeutic role of antioxidants in preventing the cisplatin nephrotoxicity. PMID- 24817287 TI - Comparison of the effects of the pretreatment and treatment with RhIL-11 on acute liver failure induced by D-galactosamine. AB - OBJECTIVE: To compare the effects of the pretreatment and treatment with recombinant human interleukin-11 (rhIL-11) on acute liver failure induced by D galactosamine (D-GalN). METHODS: The Sprague Dawley (SD) male rats were randomly divided into five groups: control, model, pretreatment, treatment and repeated treatment groups. The acute liver failure model was established by intraperitoneal injections with D-GalN (1400 mg/kg). The pretreatment, treatment and repeated treatment groups were injected subcutaneously with rhIL-11 (500 ug/kg). The rats were killed 24, 48, or 72 h after the D-GalN injection. The symptoms and survival rate of the rats were analysed. Liver injury was assessed by serum ALT and AST levels and by histological analysis. The percentage of Proliferating Cell Nuclear Antigen (PCNA+) cells in the liver tissue was evaluated by immunohistochemistry. RESULTS: Compared with the model group, the survival rate of the pretreatment group improved markedly, and these rats were protected from severe hepatic injury, as shown by the decreased serum ALT and AST levels and improved histological results. In the pretreatment group, the percentage of PCNA+ cells was significantly increased in the late stage. In contrast, the treatment and repeated treatment groups did not show improved survival rates or the prevention of severe hepatic injury, as shown by the absence of any decrease in the serum ALT and AST levels and the lack of any improvement in the histological results.The treatment and repeated treatment groups also have a significant increase in the percentage of PCNA+ cells in the late stage. CONCLUSIONS: The pretreatment with rhIL-11 can reduce acute liver failure and protect the liver. In contrast, the treatment with rhIL-11 cannot reduce acute liver failure or protect the liver. PMID- 24817288 TI - Influence of lactuside B on the expression of AQP4 and TRPM7 mRNAs in the cerebral cortex after cerebral ischemia injury. AB - AIM: This study aimed to determine the effect of Lactuside B isolated from Pterocypsela alata on the expression of AQP4 and TRPM7 mRNAs after cerebral ischemic injury. MATERIALS AND METHODS: Brain ischemia injury was established by occluding the MCA (middle cerebral artery) for 2 h, followed by reperfusion in rats. The neurologic deficit scores were used to determine the success of the model. All drugs were intraperitoneally administered once a day (5 ml/kg). Eight animals from each group were investigated for the Na+ level, and the others were examined for AQP4 and TRPM7 mRNA changes. RESULTS: Compared with the model group, the neurologic deficit scores and Na+ levels decreased in the lactuside B groups (p < 0.05 vs. p < 0.01). All lactuside B groups had significantly decreased AQP4 and TRPM7 mRNA expression compared with the model group (p < 0.05 vs. < 0.01). Dose dependence was observed between low and medium doses. CONCLUSIONS: Lactuside B protected against cerebral edema and nerve cell damage caused by cerebral ischemic injury by decreasing the expression of AQP4 and TRPM7 mRNAs in the cerebral cortex of rats. PMID- 24817289 TI - Effect of urokinase on cerebral perfusion after cardiopulmonary resuscitation in rabbits. AB - BACKGROUND: Cerebral resuscitation after cardiac arrest (CA) is always an unresolved problem in medical field. The decreased cerebral perfusion or nonperfusion caused by coagulation and fibrinolytic system function disorder and cerebral microthrombosis after CA and cardiopulmonary resuscitation (CPR) is one of the important reasons. MATERIALS AND METHODS: TTo investigate the effect of urokinase on cerebral microcirculatory perfusion after CA and CPR in rabbits. 20 rabbits were randomly divided into experimental group and control group, 10 rabbits in each group. Potassium chloride injection combined with asphyxia method was conducted to establish the CA models. CPR and basic life-support were performed on experimental group. Based on above treatments, intervention with urokinase was conducted on experimental group. Dual-slice spiral CT cerebral perfusion imaging was performed to observe the cerebral blood flow (CBF), cerebral blood volume (CBV) and top teep time (TTP). RESULTS: CBF and CBV in experimental group were significantly higher than those in control group, respectively (p < 0.01), and TTP in experimental group was significantly shorter than control group (p < 0.01). The cerebral perfusion in experimental group was better than control group. CONCLUSIONS: Thrombolytic therapy with urokinase in CPR after CA can improve the cerebral microcirculatory perfusion in rabbits. PMID- 24817290 TI - Phospholipases A-II (PLA2-II) induces acute pancreatitis through activation of the transcription factor NF-kappaB. AB - OBJECTIVES: Acute pancreatitis (AP) is an inflammatory disease of the pancreas characterized by local inflammation. Secretory phospholipases A-II (sPLA2-II) have been implicated in triggering AP, but their exact role to evoke AP is largely unknown. NF-kB activation has previously been shown to induce acute pancreatitis. The aim of this study is to explore that PLA2-II triggers AP by activation of NF-kB and the expression of inducible inflammatory mediators. MATERIALS AND METHODS: Acute pancreatitis in vivo was induced in Wistar rats by retrograde infusion of 4% sodium taurocholate (TAC) into the pancreatic duct. Then the Wistar rats were devided into 2 groups: (1) PLA2 II-specific siRNA was subsequently administrated subcapsularly after infusion of TAC. (2) One hour before the intraductal injection of TCA, the rats were treated with PDTC 100 mg/kg twice i.p. in 1 h interval. Induction of pancreatitis was confirmed by histopathology, NF-kB activity and expression in pancreas was detected by EMSA and immunohistochemistry. Inflammatory mediators such as the tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, intercellular adhesion molecule 1 (ICAM-1), IL-6 and IL-8 in blood was detected by ELISA. The severity of the disease and the mortality were observed. RESULTS: We demonstrated that TAC specifically induces pancreatitis, induces PLA2-II expression and activates NF kappaB and proinflammatory cytokine synthesis in the pancreas of rats. sPLA2-II siRNA transfection blocked NF-kappaB activation and proinflammatory cytokine expression and relieved pancreatitis severity. PDTC treatment blocked NF-kappaB activation and proinflammatory cytokine expression. Pretreatment with PDTC or PLA2 II-specific siRNA transfection improved the survival of the rats. CONCLUSIONS: These findings suggest that PLA2-II induces acute pancreatitis through activation of the transcription factor NF-kappaB. siRNA mediated gene knockdown of PLA2-II relieves pancreatitis severity at least partly mediated by the inhibition of NF-kappaB activation and proinflammatory cytokine synthesis. PMID- 24817291 TI - Diagnosis and treatment of xanthogranulomatous cholecystitis. AB - BACKGROUND: The aim of this study was to review our case load of the treatment and outcomes of patients with xanthogranulomatous cholecystitis (XGC). PATIENTS AND METHODS: Data about 21 patients were reviewed retrospectively to determine age, clinical symptoms and findings, preoperative screening, operative findings, surgical history, length of hospital stay, and postoperative complications. RESULTS: There were 14 men and 7 women (mean age, 65 +/- 11.3 yr). Preoperative ultrasonography of 17 patients showed a gallbladder stone in 14 patients, adenomyomatosis plus stones in 2 patients, and a polyp in 1 patient. There were 5 patients with acute cholecystitis and 16 patients with chronic cholecystitis. Gallbladder wall thickening was noted in 3 of the 12 patients who had abdominal computed tomography. Frozen section examinations were done in 5 patients. Radical cholecystectomy was done in 1 patient because of suspected carcinoma. CONCLUSIONS: It is difficult to diagnose XGC preoperatively or intraoperatively, and the definitive diagnosis depends exclusively on pathologic examination. PMID- 24817292 TI - Neurological symptoms associated with cerebral hyperperfusion syndrome after CEA and CAS--one centre study. AB - BACKGROUND: There are two equivalent in efficacy methods of the treatment of carotid artery stenosis: endarterectomy (CEA) and stenting (CAS), in which the blood flow increases in most patients by 20-40% over baseline, in some exceeding 100% and being symptomatic and leading to cerebral hyperperfusion syndrome (CHS). AIM: The aim of this study is to analyze the structure of neurological symptoms associated with CHS in patients with carotid artery revascularization. PATIENTS AND METHODS: Retrospective analysis included 1386 consecutive patients treated in the Department of General and Vascular Surgery between 2005 and 2011, with 625 of them were subjected to CEA and 761 to CAS. If neurological symptoms occurred, patients were consulted by a neurologist and ultrasonography (USG) examination and CT were performed. Neurological symptoms in patients with new onset of headache ipsilateral to the carotid revascularization were extracted from medical records and nursing documentation. RESULTS: Neurological symptoms attributed to CHS were observed in 66 (10.6%) of CEA and 61 (8.0 %) of CAS group. The frequency was similar in both groups (p = 0.43). The occurrence of epileptic attacks was similar in both study groups. The only difference was the less frequent falling of the lip in CAS group. Transient bradycardia and/or hypotension were observed in CAS (8.8% vs. 10.4% and 1.3% vs. 1.3%, respectively). No difference in stroke appearance between groups were found. CONCLUSIONS: The occurrence of neurological symptoms attributable to cerebral hyperperfusion syndrome after carotid artery revascularization in short term observation is similar regardless of the method used. PMID- 24817293 TI - Screening of differentially expressed genes related to ischemic stroke and functional analysis with DNA microarray. AB - BACKGROUND: Prognostic blood biomarkers in the setting of acute ischemic stroke have become increasingly relevant for risk stratification, monitoring disease and response to therapies, developing targets for neuroprotective treatment and as surrogate end points for treatment trials. AIM: We aim to find the feature genes which can accurately detect acute ischemic stroke and perform function analysis of these crucial genes in peripheral blood mononuclear cells. MATERIALS AND METHODS: The gene expression profile GSE22255 was downloaded from Gene Expression Omnibus (GEO) database which includes 20 ischemic stroke patients and 20 controls. The differentially expressed genes between patients and controls samples were identified with packages in R language. The selected differentially expressed genes were further analyzed using bioinformatics methods. Software STRING (Search Tool for the Retrieval of Interacting Genes) was used to establish co-expression network. GOTM (General Ocean Turbulence Model) software was used to obtain differentially expressed gene enriched modules. The functions of genes in modules were analyzed by using software GeneCodis. RESULTS: A total of 37 genes were identified as differentially expressed genes by comparing peripheral blood mononuclear cells gene expression of ischemic stroke patients and 20 controls. A co-expression network was constructed within 30 differentially expressed genes, among which gene interleukin-8 (IL-8) and tumor necrosis factor (TNF) showed the highest node degree. Genes in the module containing IL-8 and TNF were significantly enriched in 6 biological functions, and the most significant function was respond to stimulation. CONCLUSIONS: Our results highlight that genes IL-8 and TNF have close relationship with acute ischemic stroke, and the expression patterns of these genes may be valid targets for new medications able to modify the ischemic stroke process. PMID- 24817294 TI - Evaluation of the effectiveness of home based or hospital based calisthenic exercises in patients with multiple sclerosis. AB - OBJECTIVES: The aim of this study is to evaluate the effects of calisthenic exercises on balance, walking speed, fatigue, quality of life, and psychological status in patients with Multiple Sclerosis (MS). PATIENTS AND METHODS: Forty patients diagnosed with MS were randomized into two exercise groups (group 1 = hospital-based, group 2 = home-based). Outcome measures including the MS International Quality of Life Scale, 10-meter walking test, Berg Balance Scale, Fatigue Severity Scale and the Hospital Anxiety Depression Inventory were assessed at the baseline and at 12-weeks. RESULTS: Thirty-six participants completed the exercise programme (hospital based = 16, home based = 20). The mean age was 32.83 +/- 3.64 years. The mean duration of disease was 6.97 +/- 3.15 years. Hospital-based and home-based exercise groups had significant improvements in the balance, 10-meter walking test, anxiety, and the quality of life after the 12-week exercise programme. There was a significant improvement in the hospital based patients in terms of the depression scores. No significant improvement was observed in terms of fatigue in any of the groups. When both groups were compared, the improvement in the balance and depression scores of the hospital based patients was significantly higher than the home-based patients. CONCLUSIONS: Calisthenic exercises can be easily performed both at home and in hospital setting. In patients with MS, calisthenic exercises performed at home or at the hospital may improve the balance, quality of life, and the functional and psychological status, while no significant effect has been observed on fatigue. PMID- 24817295 TI - Evaluation of some antioxidant enzyme activities (SOD and GPX) and their polymorphisms (MnSOD2 Ala9Val, GPX1 Pro198Leu) in fibromyalgia. AB - OBJECTIVE: Fibromyalgia syndrome (FMS) is a pain syndrome in which common pain in muscle-skeletal system, sleeping disorder and fatigue symptoms coexist. The aim of the present study was to determine SOD and GPX enzyme levels in FMS as well as to investigate possible associations between FMS and Ala9Val polymorphism of MnSOD2 and Pro198Leu polymorphism of GPX1. PATIENTS AND METHODS: The study included 127 women FMS patients and 56 healthy subjects. Total SOD and total GPX enzyme activities were determined in patient and control groups. In addition, frequencies of Ala9Val polymorphism of MnSOD2 and Pro198Leu polymorphism of GPX1 were also detected. RESULTS: SOD enzyme activity was higher in FMS group compared to control (p < 0.001). GPX enzyme activity, on the other hand, was not different between FMS and control groups. No significant differences were found between genotype and allele frequencies of GPX1 and MnSOD2 polymorphisms. CONCLUSIONS: Elevated total SOD and unchanging total GPX1 activities in FMS patients could be the reason for increased oxidative stress and lipid peroxidation in FMS. Genotype and allele frequencies of Ala9Val polymorphism of MnSOD2 and Pro198Leu polymorphism of GPX1 in FMS have been studied first time in the present study, and no associations were found between them and FMS. PMID- 24817296 TI - Prediction of difficulties in laparoscopic cholecystectomy on the base of routinely available parameters in a smaller regional hospital. AB - BACKGROUND: Identification of preoperative factors that indicate difficulties in the operation are in the function of primary prevention of intraoperative complications and require selection of an experienced surgical team, planning of operating program and timely provision of information to patients about the increased likelihood of conversion. AIM: Identification of preoperative factors of operative difficulties by analysis of routine clinical parameters. PATIENTS AND METHODS: A prospective cohort study of patients who underwent laparoscopic cholecystectomy from February 2005 to December 2009. All patients were operated by the same surgeon. There were 369 operated patients. Conversion was done in 10 patients. Main outcome measures were: duration of stages of laparoscopic cholecystectomy and conversion; identification of predictive parameters; assessment of their predictive value; assessment of the predictive value of individual parameters in respect to the duration of stages of laparoscopic cholecystectomy; correlation of parameter predictive value and duration of laparoscopic cholecystectomy stage. RESULTS: Multivariate stepwise linear regression analysis showed that previous history of acute cholecystitis, gallbladder wall thickness ? 4 mm, acute cholecystitis to admission, size of calculus > 2 cm, > 5 attacks of pain that lasted longer of 4 hours, diabetes mellitus, duration of symptoms longer then 36 months and pericholecystic fluid collection were significant for prediction of difficulties of laparoscopic cholecystectomy. CONCLUSIONS: Based on clinical, laboratory and ultrasonographic parameters without the use of highly sophisticated diagnostic procedures and increasing medical costs it is possible to predict difficulties in the laparoscopic cholecystectomy. PMID- 24817297 TI - Surgical treatment of T1b glottic tumor, 10-years follow-up. AB - BACKGROUND: The TNM classification of glottic tumors defined T1b as a tumor involving both vocal cords with normal mobility of such. In the last fifteen years, in the medical literature, the role of open surgery for management of laringeal cancer has decreased considerably owing to the development of transoral laser microsurgery which is an oncologically and functionally reliable treatment particularly for early glottic cancers. AIM: Report the efficacy of different surgical techniques (laser CO2 cordectomy or supracricoid partial laryngectomy) in T1b glottic cancers treatment with a 10-years follow-up. PATIENTS AND METHODS: 92 patients with T1b glottic cancer undergoing surgery between 1986 and 2002, of which 39 were treated with CO2 laser cordectomy while 53 with supracricoid partial laryngectomy (14 crico-hyoid-pexy and 39 crico-hyoid-epiglotto-pexy). Each of the three groups was recalled and evalued with the aim to calculate the survival, initially at 3 and 5 years and thereafter, provide a 10 years follow up, including local recurrence. RESULTS: 10 years absolute survival of the 39 patient treated with CO2 laser was 56.25%, while that of the two groups subjected to supracricoid partial laryngectomy was respectively of 66.6% for crico-hyoid pexy and 58.82% for crico-hyoid-epiglotto-pexy. CONCLUSIONS: Our data suggest an excellent absolute survival also after 10 years follow-up. Since both the CO2 laser and supracricoid partial laryngectomy show similar local control and survival rates we can't determine with certainty the best therapeutic approach as claimed by a great number of literature studies. PMID- 24817298 TI - The health status of Roma children--a medical or social issue? AB - BACKGROUND: Most studies dealing with health problems of the Roma population suggests that a low economic status significantly contributes to their overall poor health. In Serbia, Roma people are members of a marginalized ethnic group with a low socioeconomic status which contributes to their much higher morbidity and mortality rate compared with the majority population. The questions we asked in this paper were: Are Roma children discriminated during hospital care? Do they get the same treatment as the non-Roma children? PATIENTS AND METHODS: To answer these questions, we examined medical records of 59 Roma children and compared with 59 records of non-Roma children in order to determine whether there are any differences in the health status, as well as the length, course, outcome, and cost of treatment. RESULTS: Roma children have statistically significant more comorbidity, more malnutritions, more skin diseases (especially parasitic and fungal infections) and were more frequently anemic. Also, the length of hospitalization of Roma children was significantly higher, as well as the number of laboratory tests performed and number of drugs prescribed, which contribute to the significantly higher costs of treatment for Roma children compared to non Roma children. However, a significantly lower number of Roma children were discharged as "completely cured". CONCLUSIONS: The results of our study does not support hypothesis of discrimination of Roma children concerning medical treatment in observed hospital. At the same time, our results suggests that social interventions (e.g. hygienic housing, water supply, etc.) and prevention measures could prevent necessity of hospitalized treatment of Roma children and could diminish the drain on the health budget spent on treating the consequences of social neglect. PMID- 24817299 TI - Densitometric kneecap changes after unilateral knee arthroplasty. AB - PURPOSE: To assess bone density of kneecaps in subjects with femoro-tibial prosthesis before and after surgery by means of DEXA examination. SUBJECTS AND METHODS: We examined 34 patients with unilateral femoro-tibial prosthesis, 20 healthy subjects of the same age and non-carriers of knee replacement and 14 healthy young adult subjects. All the data sets were analysed by two radiologists (AS and AM). The coincidence of the results between the two specialists was evaluated by means of Cohen's Kappa index and the results were considered statistically significative if p value is < of 0.05. RESULTS: The values of patellar BMD in the group of 34 patients, were: a minimum of 0.386 g/cm(2) (K = 0.879, p = 0.0012), a maximum 1.707 g/cm(2) (K = 0.886, p = 0.0016). The comparison between the left and right knee showed the following data: minimum difference 0.034 g/cm2 (K = 0.901, p = 0.0015), maximum difference of 0.622 g/cm(2) (K = 0.908, p = 0.0017), the average was found to be of 0.277 g/cm(2) (K = 0.894, p = 0.0018). But this difference tends to decrease 6 months after surgery. In the group of healthy young adults, we obtained the following values: a minimum of 0.782 g/cm(2) (K = 0.907, p = 0.0025), maximum 1.503 g/cm(2) (K = 0.932, p = 0.0012). Between both knees, the difference was minimal 0.006 g/cm(2) (K = 0.951, p = 0.0035) and maximum 0.096 g/cm(2) (K = 0.926, p = 0.0007) with an average difference of 0.058 g/cm(2) (K = 0.954, p = 0.0026). In the group of healthy subjects of the same age and non-carriers of knee replacement the values were average higher. A maximum value of 1.134 g/cm(2) (K = 0.894, p = 0.0028) and a minimum value of 0.944 g/cm(2) (K = 0.892, p = 0.0023) were found; between both knees a minimum difference of 0.010 g/cm(2) (K = 0.918, p = 0.0047) and a maximum of 0.090 g/cm(2) (K = 0.937, p = 0.0017) were found, with an average difference of 0.052 g/cm(2) (K = 0.956, p = 0.0024). CONCLUSIONS: DEXA examination of the patellar is recommended as a supplementary study to the clinical and radiological standard exams because it is able to provide additional information to determine when to intervene surgically, on the basis of patellar bone density values. PMID- 24817300 TI - Composite artificial semi-knee joint system. AB - OBJECTIVES: The purpose of the study was to investigate the clinical implantation protocol of custom-made artificial semi-knee joint based on computer-aided design so as to improve the limb salvage efficiency. MATERIALS AND METHODS: The custom made artificial semi-knee joint was designed and manufactured based on rapid prototyping technology. The repeated modifications were carried out in the design and manufacture of the semi-knee joint, together with the operation protocol. Clinical trial was conducted on 2 cases of osteosarcoma, one receiving allograft prosthesis composite transplantation, and the other receiving synthetic bone graft prosthesis composite transplantation. The clinical outcomes of the 2 patients were evaluated. RESULTS: The custom-made artificial semi-knee joint met the clinical customization needs. In clinical trial, 18-month follow-up demonstrated the satisfactory knee joint function recovery in near future. CONCLUSIONS: The custom-made artificial semi-knee joint based on computer-aided design can afford satisfactory knee joint function recovery following allograft bone transplantation. PMID- 24817301 TI - Castleman's disease mimicking a parotid gland tumor: report of a case and review of the literature. AB - Castleman's disease (giant lymph node hyperplasia, angiofollicular hyperplasia, lymphoid hamartoma, benign giant lymphoma), is a quite rare and complex disease of lymphoid tissue that causes progressive lymph node enlargement, typically presenting as a solitary mediastinal mass. It was first described by Castleman et al in 1956. The head and neck regions are the second, less common site for this lesion. The preoperative diagnosis is very often extremely difficult and the routine investigations are often inconclusive. A multicentric extension of this disease shows poorer prognosis compared to the unifocal Histologically, three types do exist: the hyaline-vascular type, the plasma cell type and the mixed type. The etiology and pathogenesis is still unclear. In the literature, to our knowledge, only 112 cases have been reported involving head and neck, and only 22, including our own, interesting the parotid gland. In this report we describe a rare singular of Castleman's disease presenting as a tumor of the inferior pole of the parotid gland extending in the submandibular region, in a 35-year-old woman. The patient undergone a surgical treatment and, therefore, the mass was successfully totally removed. PMID- 24817302 TI - The role of IVS14+1 G > A genotype detection in the dihydropyrimidine dehydrogenase gene and pharmacokinetic monitoring of 5-fluorouracil in the individualized adjustment of 5-fluorouracil for patients with local advanced and metastatic colorectal cancer: a preliminary report. AB - AIM: We retrospectively investigated the relationship between IVS14+1 G > A genotype of the dihydropyrimidine dehydrogenase (DPD) gene with plasma concentration of 5-fluorouracil (5-FU) as well as adverse reactions in 80 patients with locally advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Eighty patients with un-resectable locally advanced or metastatic colorectal cancer were treated with Folfox-6 regimen, which repeated every two weeks for at least three cycles. Single nucleotide polymorphisms for DPD gene were analyzed before chemotherapy by high-resolution melting (HRM) analysis. The plasma concentration of fluorouracil was measured by high performance liquid chromatography (HPLC) after continuous infusion of fluorouracil over 12 h in each cycle. The average values of plasma concentrations in each cycle were calculated, and the factors related to plasma concentration of 5-FU were screened by stepwise regression. RESULTS: All patients were divided into three groups according to the predictive confidence interval of plasma concentration of 5-FU, and the average plasma concentrations of fluorouracil in each cycle of these three groups were less than or equal to 26.83 mg/L, 26.83-40.62 mg/L, and more than 40.62 mg/L, respectively. Stepwise regression analysis showed that the plasma concentration of fluorouracil was associated with myelosuppression, hand-foot syndrome, diarrhea, overall survival (OS) and DPD genotype. In efficacy, the median progression-free survival PFS (mPFS) and OS (mOS) of group 2 and group 3 were both significantly higher than those of group 1. CONCLUSIONS: Among the advanced colorectal cancer patients receiving fluorouracil-based chemotherapy, those with plasma concentration of 5-FU above 26.83 mg/L can obtain better survival; for patients with heterozygous DPD IVS14+1 mutation, 5-FU dose should be appropriately reduced according to last plasma concentration to reduce adverse reactions, while the homozygous ones should avoid application of 5-FU and its derivatives. PMID- 24817303 TI - Cystic pancreatic neoplasms: diagnosis and management emphasizing their imaging features. AB - The incidence of cystic pancreatic neoplasms increased in the past decade, due to the recent advances in multidetector computed tomography and magnetic resonance imaging; several pancreatic cysts are incidentally encountered during diagnostic exams performed for non-pancreatic diseases. Indeed, cystic pancreatic tumors are currently considered relatively rare, accounting for approximately 10% of all pancreatic neoplasms. Serous cystadenoma, mucinous cystadenoma, intraductal papillary mucinous neoplasms and solid-pseudopapillary tumor represent about 90% of all pancreatic primary cystic tumours. The non-optimal diagnostic preoperative accuracy in distinguishing benign from malignant cystic lesions ensures that up till now there are no well-defined guidelines regarding the management of cystic pancreatic neoplasms. Imaging findings often do not allow the diagnosis, because there is a considerable overlap among the cystic lesions; the best pre-operative characterization is obtained by the association of all diagnostic procedures available. For their different histology and behavior, cystic pancreatic neoplasms need to be managed according to various factors. In this review, the main elements necessary for their management are assessed--radiological features, tumour dimensions, patients' characteristics, the mode of clinical presentation and the associated oncologic markers. A multidisciplinary approach--including gastroenterologists, radiologists and surgeons--should be adopted in order to perform a differential diagnosis and a correct management. PMID- 24817304 TI - Aryl hydrocarbon receptor exogenous ligand 3-methylchoranthrene inhibited endometrial cancer cells proliferation. AB - OBJECTIVE: Endometrial cancer (EC) is the most prevalent gynecologic malignancy among women worldwide. Increasing evidence has disclosed the potential role of aryl hydrocarbon receptor (AhR) in the cancer development; however, little is known about its roles in the EC development. In the present study, we evaluated AhR expression in EC tissues as well as cell lines, and investigated the effects of AhR knockdown and exogenous ligand 3-methylchoranthrene (3-MC) on EC cells proliferation and invasion using Ishikawa and ECC-1 cells lines. MATERIALS AND METHODS: In this study, tissue microarray and immunohistochemistry were used to investigate the expression and localization of AhR in EC tissues. RT-PCR and Western blot were performed to detect the AhR expression. AhR specific siRNA was used to knockdown the AhR expression. MTT and transwell assay were carried out to study the EC cells proliferation and invasion, respectively. RESULTS: Our results showed that AhR was highly expressed in the EC tissues and cell lines when compared with its expression in the normal endometrial tissues. AhR siRNA significantly decreased (p < 0.05) AhR protein expression in both Ishikawa and ECC-1 cells. Knockdown of AhR did not alter EC cells proliferation and invasion. However, 3-MC dose-dependently inhibited (p < 0.05) EC cells proliferation via AhR-mediated pathway. CONCLUSIONS: The results from the current application will provide critical information on roles of 3-MC/AhR pathway in mediating EC growth, which could be useful for future therapeutic intervention in this lethal human disease. PMID- 24817305 TI - HPV infection in HIV-positive females: the need for cervical cancer screening including HPV-DNA detection despite successful HAART. AB - PURPOSE: To identify the presence of Human Papilloma Virus (HPV) infection and evaluate the role of Highly Active Antiretroviral Treatment (HAART) in patients with HIV-HPV co-infection. We also compared cytological screening results with HPV-DNA detection to implement screening programs and prevention of invasive cervical cancer (ICC) in HIV-infected females. PATIENTS AND METHODS: We enrolled HIV-infected females presenting for routine clinical evaluation. HPV-DNA of high/intermediate and low-risk types was detected from cervical specimens by nucleic acid hybridization assay with signal-amplification. Patients were divided into two groups according to the presence of HPV co-infection (HPV+) or not (HPV ). RESULTS: We enrolled 57 HIV-infected females. Median age was 40 (IQR 35-44) years, mean CD4 count was 547 +/- 227 cells/mm(3), 45 (78.9%) had undetectable HIV-RNA and 52 (91.2%) received HAART. Globally, 19/57 (33.3%) patients were HPV infected, 16/57 (28.1%) with high/intermediate and 3/57 (5.3%) with low-risk types. Five of the 19 (26.3%) HPV+ patients carried both types. Correlating high risk genotype HPV-DNA detection with cytology, 17.5% of women with negative cytology, 36.4% with ASCUS (Atypical Squamous Cells of Uncertain Significance) and 83.4% of women with positive cytology (50% of LSIL: low-grade squamous intraepithelial lesion and 100% of HSIL: high grade SIL) were HPV positive. No statistical difference when comparing HPV+ and HPV-patients in age, CD4 cell count, in the proportion of previous intravenous-drug use, previous AIDS and of those receiving HAART with undetectable HIV-RNA was observed. CONCLUSIONS: Cervical cancer screening including HPV-DNA detection should be implemented in HIV infected females across Europe, also when receiving successful HAART, to early identify the HIV patients at risk for ICC to be submitted to more frequent follow up and proper treatment. PMID- 24817306 TI - Lung cancer in HIV positive patients: the GICAT experience. PMID- 24817307 TI - Combining site occupancy, breeding population sizes and reproductive success to calculate time-averaged reproductive output of different habitat types: an application to Tricolored Blackbirds. AB - In metapopulations in which habitat patches vary in quality and occupancy it can be complicated to calculate the net time-averaged contribution to reproduction of particular populations. Surprisingly, few indices have been proposed for this purpose. We combined occupancy, abundance, frequency of occurrence, and reproductive success to determine the net value of different sites through time and applied this method to a bird of conservation concern. The Tricolored Blackbird (Agelaius tricolor) has experienced large population declines, is the most colonial songbird in North America, is largely confined to California, and breeds itinerantly in multiple habitat types. It has had chronically low reproductive success in recent years. Although young produced per nest have previously been compared across habitats, no study has simultaneously considered site occupancy and reproductive success. Combining occupancy, abundance, frequency of occurrence, reproductive success and nest failure rate we found that that large colonies in grain fields fail frequently because of nest destruction due to harvest prior to fledging. Consequently, net time-averaged reproductive output is low compared to colonies in non-native Himalayan blackberry or thistles, and native stinging nettles. Cattail marshes have intermediate reproductive output, but their reproductive output might be improved by active management. Harvest of grain-field colonies necessitates either promoting delay of harvest or creating alternative, more secure nesting habitats. Stinging nettle and marsh colonies offer the main potential sources for restoration or native habitat creation. From 2005-2011 breeding site occupancy declined 3x faster than new breeding colonies were formed, indicating a rapid decline in occupancy. Total abundance showed a similar decline. Causes of variation in the value for reproduction of nesting substrates and factors behind continuing population declines merit urgent investigation. The method we employ should be useful in other metapopulation studies for calculating time-averaged reproductive output for different sites. PMID- 24817308 TI - Electrical wave propagation in an anisotropic model of the left ventricle based on analytical description of cardiac architecture. AB - We develop a numerical approach based on our recent analytical model of fiber structure in the left ventricle of the human heart. A special curvilinear coordinate system is proposed to analytically include realistic ventricular shape and myofiber directions. With this anatomical model, electrophysiological simulations can be performed on a rectangular coordinate grid. We apply our method to study the effect of fiber rotation and electrical anisotropy of cardiac tissue (i.e., the ratio of the conductivity coefficients along and across the myocardial fibers) on wave propagation using the ten Tusscher-Panfilov (2006) ionic model for human ventricular cells. We show that fiber rotation increases the speed of cardiac activation and attenuates the effects of anisotropy. Our results show that the fiber rotation in the heart is an important factor underlying cardiac excitation. We also study scroll wave dynamics in our model and show the drift of a scroll wave filament whose velocity depends non monotonically on the fiber rotation angle; the period of scroll wave rotation decreases with an increase of the fiber rotation angle; an increase in anisotropy may cause the breakup of a scroll wave, similar to the mother rotor mechanism of ventricular fibrillation. PMID- 24817309 TI - Nf2/Merlin controls spinal cord neural progenitor function in a Rac1/ErbB2 dependent manner. AB - OBJECTIVE: Individuals with the neurofibromatosis type 2 (NF2) cancer predisposition syndrome develop spinal cord glial tumors (ependymomas) that likely originate from neural progenitor cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural progenitor cells (NPCs). METHODS: To identify potential therapeutic targets for these tumors, we leveraged primary mouse Nf2-deficient spinal cord neural progenitor cells. RESULTS: We demonstrate that the Nf2 protein, merlin, negatively regulates spinal neural progenitor cell survival and glial differentiation in an ErbB2-dependent manner, and that NF2 associated spinal ependymomas exhibit increased ErbB2 activation. Moreover, we show that Nf2-deficient SC NPC ErbB2 activation results from Rac1-mediated ErbB2 retention at the plasma membrane. SIGNIFICANCE: Collectively, these findings establish ErbB2 as a potential rational therapeutic target for NF2-associated spinal ependymoma. PMID- 24817310 TI - Mechanical basis of otoacoustic emissions in tympanal hearing organs. AB - Tympanal hearing organs of insects emit distortion-product otoacoustic emissions (DPOAEs), which in mammals are used as indicator for nonlinear cochlear amplification, and which are highly vulnerable to manipulations interfering with the animal's physiological state. Although in previous studies, evidence was provided for the involvement of auditory mechanoreceptors, the source of DPOAE generation and possible active mechanisms in tympanal organs remained unknown. Using laser Doppler vibrometry in the locust ear, we show that DPOAEs mechanically emerge at the tympanum region where the auditory mechanoreceptors are attached. Those emission-coupled vibrations differed remarkably from tympanum waves evoked by external pure tones of the same frequency, in terms of wave propagation, energy distribution, and location of amplitude maxima. Selective inactivation of the auditory receptor cells by mechanical lesions did not affect the tympanum's response to external pure tones, but abolished the emission's displacement amplitude peak. These findings provide evidence that tympanal auditory receptors, comparable to the situation in mammals, comprise the required nonlinear response characteristics, which during two-tone stimulation lead to additional, highly localized deflections of the tympanum. PMID- 24817312 TI - Air space proportion in pterosaur limb bones using computed tomography and its implications for previous estimates of pneumaticity. AB - Air Space Proportion (ASP) is a measure of how much air is present within a bone, which allows for a quantifiable comparison of pneumaticity between specimens and species. Measured from zero to one, higher ASP means more air and less bone. Conventionally, it is estimated from measurements of the internal and external bone diameter, or by analyzing cross-sections. To date, the only pterosaur ASP study has been carried out by visual inspection of sectioned bones within matrix. Here, computed tomography (CT) scans are used to calculate ASP in a small sample of pterosaur wing bones (mainly phalanges) and to assess how the values change throughout the bone. These results show higher ASPs than previous pterosaur pneumaticity studies, and more significantly, higher ASP values in the heads of wing bones than the shaft. This suggests that pneumaticity has been underestimated previously in pterosaurs, birds, and other archosaurs when shaft cross-sections are used to estimate ASP. Furthermore, ASP in pterosaurs is higher than those found in birds and most sauropod dinosaurs, giving them among the highest ASP values of animals studied so far, supporting the view that pterosaurs were some of the most pneumatized animals to have lived. The high degree of pneumaticity found in pterosaurs is proposed to be a response to the wing bone bending stiffness requirements of flight rather than a means to reduce mass, as is often suggested. Mass reduction may be a secondary result of pneumaticity that subsequently aids flight. PMID- 24817311 TI - A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression. AB - PURPOSE: The goal of this study was to develop an immunodeficient rat model of retinal degeneration (RD nude rats) that will not reject transplanted human cells. METHODS: SD-Tg(S334ter)3Lav females homozygous for a mutated mouse rhodopsin transgene were mated with NTac:NIH-Whn (NIH nude) males homozygous for the Foxn1 (rnu) allele. Through selective breeding, a new stock, SD-Foxn1 Tg(S334ter)3Lav (RD nude) was generated such that all animals were homozygous for the Foxn1 (rnu) allele and either homo- or hemizygous for the S334ter transgene. PCR-based assays for both the Foxn1 (rnu) mutation and the S334ter transgene were developed for accurate genotyping. Immunodeficiency was tested by transplanting sheets of hESC-derived neural progenitor cells to the subretinal space of RD nude rats, and, as a control, NIH nude rats. Rats were killed between 8 and 184 days after surgery, and eye sections were analyzed for human, neuronal, and glial markers. RESULTS: After transplantation to RD nude and to NIH nude rats, hESC derived neural progenitor cells differentiated to neuronal and glial cells, and migrated extensively from the transplant sheets throughout the host retina. Migration was more extensive in RD nude than in NIH nude rats. Already 8 days after transplantation, donor neuronal processes were found in the host inner plexiform layer. In addition, host glial cells extended processes into the transplants. The host retina showed the same photoreceptor degeneration pattern as in the immunocompetent SD-Tg(S334ter)3Lav rats. Recipients survived well after surgery. CONCLUSIONS: This new rat model is useful for testing the effect of human cell transplantation on the restoration of vision without interference of immunosuppression. PMID- 24817313 TI - Impact of age, sex, and indexation method on MR left ventricular reference values in the Framingham Heart Study offspring cohort. AB - PURPOSE: To determine normative values for left ventricular (LV) volumes, mass, concentricity, and ejection fraction (EF) and investigate associations between sex, age, and body size with LV parameters in community-dwelling adults. MATERIALS AND METHODS: In all, 1794 Framingham Heart Study Offspring cohort members underwent LV short-axis oriented, contiguous multislice cine steady-state free precession MR of the left ventricle; from these a healthy referent group (n = 852, 61 +/- 9 years, 40% men) free of clinical cardiac disease and hypertension (SBP < 140, DBP < 90 mmHg, never used antihypertensive medication >=30 years prior to scanning) was identified. Referent participants were stratified by sex and age group (<=55, 56-65, >65 years); LV parameters were indexed to measures of body size. RESULTS: Men have greater LV volumes and mass than women both before and after indexation to height, powers of height, and body surface area (P < 0.01 all), but indexation to fat-free mass yielded greater LV volume and mass in women. In both sexes, LV volumes and mass decrease with advancing age, although indexation attenuates this association. LVEF is greater in women than men (68 +/- 5% vs. 66 +/- 5%, P < 0.01) and increases with age in both sexes (P < 0.05). CONCLUSION: Among nonhypertensive adults free of cardiac disease, men have greater LV volumes and mass with sex differences generally persisting after indexation to body size. LV volumes and mass tend to decrease with greater age in both sexes. Female sex and advanced age were both associated with greater LVEF. J. Magn. Reson. Imaging 2015;41:1038-1045. (c) 2014 Wiley Periodicals, Inc. PMID- 24817314 TI - Probing recursion. AB - The experimental probing of recursion in human performance is faced with non trivial problems. Here, I analyse three case studies from the literature and argue that they tell us little about the underlying mental processes at play within each of these domains: (a) the question of whether experimental participants employ recursive rules in parsing artificial strings of nonsense syllables; (b) the role of self-embedded structures in reasoning and general cognition; and (c) the reputed connection between structural features of a given object and the corresponding, recursive rules needed to represent/generate it. I then outline what a recursive process would actually look like and how one could go about probing its presence in human behaviour, concluding, however, that recursive processes in performance are very unlikely, at least as far as fast, mandatory, and automatic modular processes are concerned. PMID- 24817315 TI - Effect of Chaiqin Chengqi Decoction on cholecystokinin receptor 1-mediated signal transduction of pancreatic acinar cells in acute necrotizing pancreatitis rats. AB - OBJECTIVE: To investigate the effect of Chaiqin Chengqi Decoction (,CQCQD) on cholecystokinin receptor 1 (CCKR1)-mediated signal transduction of pancreatic acinar cell in rats with acute necrotic pancreatitis (ANP). METHODS: Twenty-seven Sprague-Dawley rats were randomized into three groups: the control group, the ANP group, and the CQCQD group (9 in each group). ANP rats were induced by two intraperitoneal injections of 8% L-arginine (pH=7.0, 4.4 g/kg) over a 2-h period. Rats were treated with 1.5 mL/100 g body weight of CQCQD (CQCQD group) or physiological saline (control and ANP groups) at 2 h interval. And 6 h after induction, pancreatic tissues were collected for histopathological examination. Pancreatic acinar cells were isolated for determination of CCKR1 mRNA and protein expression, phospholipase C (PLC) and inositol-1,4,5-triphosphate (IP3), and determination of fluorescence intensity (FI) as a measure of intracellular calcium ion concentration [Ca(2+)]i. RESULTS: The pancreatic histopathological score (6.2 +/- 1.1) and the levels of PLC (1,187.2 +/- 228.2 MUg/mL) and IP3 (872.2 +/- 88.4 MUg/mL) of acinar cells in the ANP group were higher than those in the control (2.8 +/- 0.4, 682.5 +/- 121.8 MUg/mL, 518.4 +/- 115.8 MUg/mL) and the CQCQD (3.8 +/- 0.8, 905.3 +/- 78.5 MUg/mL, 611.0 +/- 42.5 MUg/mL) groups (P<0.05). [Ca(2+)]i FI for the ANP group (34.8+/-27.0) was higher than that in the control (5.1 +/- 2.2) and CQCQD (12.6 +/- 2.5) groups (P<0.05). The expression of pancreatic acinar cell CCKR1 mRNA in the ANP group was up-regulated (expression ratio=1.761; P=0.024) compared with the control group. The expression of pancreatic acinar cell CCKR1 mRNA in the CQCQD group was down-regulated (expression ratio=0.311; P=0.035) compared with the ANP group. The ratio of gray values of the CCKR1 and beta-actin in the ANP group (1.43 +/- 0.17) was higher than those in the control (0.70 +/- 0.15) and CQCQD (0.79 +/- 0.11) groups (P<0.05). CONCLUSIONS: Pancreatic acinar cell calcium overload of ANP induced by L-arginine was related to the up-regulated expressions of pancreatic acinar cell CCKR1 mRNA and protein. CQCQD can down-regulate expressions of pancreatic acinar cell CCKR1 mRNA and protein to reduce the PLC and IP3 of pancreatic acinar cells, relieving the calcium overload and reducing the pathological changes in rats with ANP. PMID- 24817316 TI - Protective effects of Jiashen Prescription () on myocardial infarction in rats. AB - OBJECTIVE: To evaluate the effects of Jiashen Prescription (, JSP) on myocardial infarction (MI) size and cardiac function at the early stage of MI in rats. METHODS: One hundred male Sprague-Dawley rats were subjected to sham-operation or MI induced by ligating the left anterior descending coronary artery. The rats with MI were treated with vehicle, JSP 3 and 6 g/(kg.d), or losartan 10 mg/(kg.d) for 1 week. RESULTS: Compared with the vehicle-treated MI rats, 6 g/(kg.d) JSP reduced MI size 3 days after MI (P<0.05), and attenuated the MI-induced increases in left ventricular end-diastolic and end-systolic dimension and decreases in fractional shortening and ejection fraction 1 week after MI (P<0.05). In addition, 6 g/(kg.d) JSP and losartan were equally effective in reducing MI size and enhancing cardiac functional recovery. CONCLUSION: JSP reduces MI size and improves cardiac function after MI, suggesting that JSP has potential as a therapy for MI. PMID- 24817317 TI - Exploring the outcomes in studies of primary frozen shoulder: is there a need for a core outcome set? AB - PURPOSE: In our study we explored the need to define a core outcome set for primary frozen shoulder. METHODS: We investigated the outcomes used by studies included in a systematic review of the management of primary frozen shoulder; surveyed which primary outcome measures health care professionals considered important; and re-examined papers previously obtained for a systematic review of patients' views of interventions for frozen shoulder to investigate their views on outcomes. RESULTS: Thirty-one studies investigated the outcomes range of movement (28 studies), pain (22), function and disability (22), adverse events (13), quality of life (7) and other outcomes (5). Many different types of pain and ranges of movement were measured. Function and disability was measured using fifteen instruments, the content of which varied considerably. Function and disability, pain and range of movement (132, 108 and 104 respondents, respectively) were most often cited by health care professionals as the primary outcome measure that should be used. Searches identified one paper that included patients' views. Outcomes of importance to patients were pain at night, general pain, reduced mobility (resulting in modification of activities) and the emotional impact of frozen shoulder. CONCLUSIONS: We identified a diverse range of outcomes that have been used or are considered to be important. The development of a core outcome set would improve the design and reporting of studies and availability of data for evidence synthesis. Methods used to develop a core outcome set should be robust, transparent and reflect the views of all stakeholders. PMID- 24817319 TI - Cardiac complications of chemotherapy: role of prevention. AB - OPINION STATEMENT: With recent novel therapies, cancer survival has improved and chemotherapy-induced cardiac toxicity including left ventricular dysfunction and heart failure has a greater potential impact on long-term outcomes. Hence, the prevention of cardiotoxicity should be an important objective when planning the therapy of cancer patients. Different pharmacologic and nonpharmacologic approaches have been shown to be effective in small trials, most of them in patients treated with anthracyclines. Treatment of cardiovascular risk factors, the implementation of a healthy lifestyle, and changes in the administration of anthracyclines have been shown to be effective to prevent cardiotoxicity, as is the administration of antioxidants such as dexrazoxane, and some cardiovascular drugs such as ACE-inhibitors and beta-blockers. Ongoing studies are analyzing the effects of these drugs on anthracycline- and trastuzumab-induced cardiotoxicity. Nevertheless, the future of the prevention of cardiac toxicity should include the study of the exact mechanism of toxicity of each cardiotoxic drug and the genetic individual susceptibility of each patient. With this information, correct risk stratification could be performed when planning the initial therapy and new drugs with less cardiotoxicity could be developed. Also, the diagnostic and prognostic value of different cardiac biomarkers and of imaging techniques for each cardiotoxic drug should be established. Finally, further large randomized studies are needed to confirm the results of prior pilot studies on the effects of cardioprotective drugs. PMID- 24817318 TI - Impact of psychological and cancer-related factors on HRQoL for Korean childhood cancer survivors. AB - PURPOSE: The purposes of this study were (1) to compare health-related quality of life (HRQoL) between Korean childhood cancer survivors and healthy controls and (2) to examine the impact of demographic, diagnosis/treatment, and psychological variables on physical and psychosocial health in survivors. METHODS: The HRQoL (PedsQL), Self-Concept Inventory, and Child Behavior Checklist were administered to childhood cancer survivors, age/gender-matched healthy counterparts, and their parents. Independent-samples t tests and hierarchical multiple regression analyses were conducted. RESULTS: Compared with healthy controls, childhood cancer survivors reported significantly lower scores across physical and psychosocial HRQoL. For survivors, demographic, diagnosis/treatment, current health status, and psychological variables explained more than 50 % of the variance in both subscales of HRQoL. Especially, self-concept, a psychological variable, explained a significant portion of the variance in physical and psychosocial HRQoL after controlling for cancer-related factors. Several cancer related factors including time since treatment completion, having a history of allogeneic hematopoietic stem cell transplantation, multiple treatment modalities, and suffering from severe late effects also associated with specific dimension of HRQoL. CONCLUSIONS: Childhood cancer survivors do experience lower level of QoL and psychological factors, especially self-concept, should be considered when supporting the well-being of childhood cancer survivors. PMID- 24817321 TI - Management of complex abdominal wall defects associated with penetrating abdominal trauma. AB - INTRODUCTION: The paradigm of Damage Control Surgery (DCS) has radically improved the management of abdominal trauma, but less well described are the options for managing the abdominal wall itself in an austere environment. This article describes a series of patients with complex abdominal wall problems managed at the UK-led Role 3 Medical Treatment Facility (MTF) in Camp Bastion, Afghanistan. METHOD: Contemporaneous review of a series of patients with complex abdominal wall injuries who presented to the Role 3 MTF between July and November 2012. RESULTS: Five patients with penetrating abdominal trauma associated with significant damage to the abdominal wall were included. All patients were managed using DCS principles, leaving the abdominal wall open at the end of the first procedure. Subsequent management of the abdominal wall was determined by a multidisciplinary team of general and plastic surgeons, intensivists and specialist nurses. The principles of management identified included minimising tissue loss on initial laparotomy by joining adjacent wounds and marginal debridement of dead tissue; contraction of the abdominal wall was minimised by using topical negative pressure dressing and dermal-holding sutures. Definitive closure was timed to allow oedema to settle and sepsis to be controlled. Closure techniques include delayed primary closure with traction sutures, components separation, and mesh closure with skin grafting. DISCUSSION: A daily multidisciplinary team discussion was invaluable for optimal decision making regarding the most appropriate means of abdominal closure. Dermal-holding sutures were particularly useful in preventing myostatic contraction of the abdominal wall. A simple flow chart was developed to aid decision making in these patients. This flow chart may prove especially useful in a resource-limited environment in which returning months or years later for closure of a large ventral hernia may not be possible. PMID- 24817320 TI - Antifungal activity of naphthoquinoidal compounds in vitro against fluconazole resistant strains of different Candida species: a special emphasis on mechanisms of action on Candida tropicalis. AB - In recent decades, the incidence of candidemia in tertiary hospitals worldwide has substantially increased. These infections are a major cause of morbidity and mortality; in addition, they prolong hospital stays and raise the costs associated with treatment. Studies have reported a significant increase in infections by non-albicans Candida species, especially C. tropicalis. The number of antifungal drugs on the market is small in comparison to the number of antibacterial agents available. The limited number of treatment options, coupled with the increasing frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. The objective of this study was to evaluate and compare the antifungal activities of three semisynthetic naphthofuranquinone molecules against fluconazole-resistant Candida spp. strains. These results allowed to us to evaluate the antifungal effects of three naphthofuranquinones on fluconazole-resistant C. tropicalis. The toxicity of these compounds was manifested as increased intracellular ROS, which resulted in membrane damage and changes in cell size/granularity, mitochondrial membrane depolarization, and DNA damage (including oxidation and strand breakage). In conclusion, the tested naphthofuranquinones (compounds 1-3) exhibited in vitro cytotoxicity against fluconazole-resistant Candida spp. strains. PMID- 24817322 TI - Facilitation and interference in the color-naming task. AB - Two experiments were conducted to evaluate the phonological activation of the name of pictures when participants had to name the color in which these pictures were depicted. In Experiment 1, participants named the color of pictures whose names and color names shared the phonological beginning (phonologically related condition), the color of pictures whose names and color names did not share phonology (phonologically unrelated condition), and the color of abstract forms (neutral condition). A facilitatory effect was obtained, so participants were faster in the related condition than in the unrelated condition. However, naming latencies were similar in the neutral condition and the unrelated condition. In Experiment 2, the unrelated condition was replaced by a phonologically incongruent condition in which the name of the picture was phonologically unrelated to its color name but related to the name of other response color names. The results showed again a facilitatory effect when the related condition was compared with the incongruent condition. Importantly, an interference effect was also observed, so naming latencies were longer in the incongruent condition than in the neutral condition. These results are discussed in terms of language production models. PMID- 24817323 TI - A comprehensive biological insight of trinuclear copper(II)-tin(IV) chemotherapeutic anticancer drug entity: in vitro cytotoxicity and in vivo systemic toxicity studies. AB - Cisplatin (cis-diamminedichloroplatinum(II), CDDP) causes severe systemic toxicity, which limits its application in cancer treatment. Nevertheless, incorporation of endogenously present essential metal ions (copper) in anticancer drug regimes in a heterometallic ligand scaffold can substantially modulate the toxic effects of non-essential metals (platinum), thereby reducing unwanted toxic side effects. A chiral l-tryptophan derived [bis(1,2-diaminobenzene) copper(II)] chloride complex [CuSn2(Trp)] was previously synthesized by us as an active chemotherapeutic agent. Furthermore, we have explored CuSn2(Trp) induced in vitro cytotoxicity in a panel of human cancer cell lines and in vivo acute and systemic toxicities in healthy female Rattus norvegicus (Wistar) rats. MTT assay showed that CuSn2(Trp) exhibits strong anticancer potency against ovarian (PA-1) and prostate carcinomas (PC-3) but lower potency towards liver (HepG2) and breast carcinomas (MCF-7). Further, flow cytometric analysis demonstrated that CuSn2(Trp) kills PA-1 cells dose-dependently after 48 h treatment. Fluorescence microscopy and western blotting revealed that the plausible mechanism behind CuSn2(Trp) cytotoxicity was apoptosis, which was substantiated by cleavage of caspase-3 and poly-(ADP-ribose) polymerase (PARP). Furthermore, it has lower toxicity than CDDP in rats as evident from its eight fold (98.11 mg kg(-1)) more medial lethal dose (LD50) than CDDP (12 mg kg(-1)). Besides, the safety profile of CuSn2(Trp) was also established and no measurable DNA damage, nephrotoxicity, hepatotoxicity and neurotoxicity were observed when assessed as a function of oxidative stress markers in contrast to CDDP at equivalent lower doses. Our findings are of high importance in the context of further in vivo cancer studies on the CuSn2(Trp) drug entity. PMID- 24817324 TI - Three-dimensional NiFe layered double hydroxide film for high-efficiency oxygen evolution reaction. AB - Fabricating active materials into specific macrostructures is critical in the pursuit of high electro-catalytic activity. Herein we demonstrate that a three dimensional (3D) architecture of NiFe layered double hydroxide (NiFe-LDH) significantly reduced the onset potential, yielded high current density at small overpotentials, and showed outstanding stability in electrochemical oxygen evolution reaction. PMID- 24817325 TI - An invasive plant promotes its arbuscular mycorrhizal symbioses and competitiveness through its secondary metabolites: indirect evidence from activated carbon. AB - Secondary metabolites released by invasive plants can increase their competitive ability by affecting native plants, herbivores, and pathogens at the invaded land. Whether these secondary metabolites affect the invasive plant itself, directly or indirectly through microorganisms, however, has not been well documented. Here we tested whether activated carbon (AC), a well-known absorbent for secondary metabolites, affect arbuscular mycorrhizal (AM) symbioses and competitive ability in an invasive plant. We conducted three experiments (experiments 1-3) with the invasive forb Solidago canadensis and the native Kummerowia striata. Experiment 1 determined whether AC altered soil properties, levels of the main secondary metabolites in the soil, plant growth, and AMF communities associated with S. canadensis and K. striata. Experiment 2 determined whether AC affected colonization of S. canadensis by five AMF, which were added to sterilized soil. Experiment 3 determined the competitive ability of S. canadensis in the presence and absence of AMF and AC. In experiment 1, AC greatly decreased the concentrations of the main secondary metabolites in soil, and the changes in concentrations were closely related with the changes of AMF in S. canadensis roots. In experiment 2, AC inhibited the AMF Glomus versiforme and G. geosporum but promoted G. mosseae and G. diaphanum in the soil and also in S. canadensis roots. In experiment 3, AC reduced S. canadensis competitive ability in the presence but not in the absence of AMF. Our results provided indirect evidence that the secondary metabolites (which can be absorbed by AC) of the invasive plant S. canadensis may promote S. canadensis competitiveness by enhancing its own AMF symbionts. PMID- 24817326 TI - Putative pathway of sex pheromone biosynthesis and degradation by expression patterns of genes identified from female pheromone gland and adult antenna of Sesamia inferens (Walker). AB - The general pathway of biosynthesis and degradation for Type-I sex pheromones in moths is well established, but some genes involved in this pathway remain to be characterized. The purple stem borer, Sesamia inferens, employs a pheromone blend containing components with three different terminal functional groups (Z11 16:OAc, Z11-16:OH, and Z11-16:Ald) of Type-I sex pheromones. Thus, it provides a good model to study the diversity of genes involved in pheromone biosynthesis and degradation pathways. By analyzing previously obtained transcriptomic data of the sex pheromone glands and antennae, we identified 73 novel genes that are possibly related to pheromone biosynthesis (46 genes) or degradation (27 genes). Gene expression patterns and phylogenetic analysis revealed that one desaturase (SinfDes4), one fatty acid reductase (SinfFAR2), and one fatty acid xtransport protein (SinfFATP1) genes were predominantly expressed in pheromone glands, and clustered with genes involved in pheromone synthesis in other moth species. Ten genes including five carboxylesterases (SinfCXE10, 13, 14, 18, and 20), three aldehyde oxidases (SinfAOX1, 2 and 3), and two alcohol dehydrogenases (SinfAD1 and 3) were expressed specifically or predominantly in antennae, and could be candidate genes involved in pheromone degradation. SinfAD1 and 3 are the first reported alcohol dehydrogenase genes with antennae-biased expression. Based on these results we propose a pathway involving these potential enzyme-encoding gene candidates in sex pheromone biosynthesis and degradation in S. inferens. This study provides robust background information for further elucidation of the genetic basis of sex pheromone biosynthesis and degradation, and ultimately provides potential targets to disrupt sexual communication in S. inferens for control purposes. PMID- 24817327 TI - Single flexible nanofiber to achieve simultaneous photoluminescence-electrical conductivity bifunctionality. AB - In order to develop new-type multifunctional composite nanofibers, Eu(BA)3 phen/PANI/PVP bifunctional composite nanofibers with simultaneous photoluminescence and electrical conductivity have been successfully fabricated via electrospinning technology. Polyvinyl pyrrolidone (PVP) is used as a matrix to construct composite nanofibers containing different amounts of Eu(BA)3 phen and polyaniline (PANI). X-Ray diffractometry (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), fluorescence spectroscopy and a Hall effect measurement system are used to characterize the morphology and properties of the composite nanofibers. The results indicate that the bifunctional composite nanofibers simultaneously possess excellent photoluminescence and electrical conductivity. Fluorescence emission peaks of Eu(3+) ions are observed in the Eu(BA)3 phen/PANI/PVP photoluminescence-electrical conductivity bifunctional composite nanofibers. The electrical conductivity reaches up to the order of 10(-3) S/cm. The luminescent intensity and electrical conductivity of the composite nanofibers can be tuned by adjusting the amounts of Eu(BA)3 phen and PANI. The obtained photoluminescence electrical conductivity bifunctional composite nanofibers are expected to possess many potential applications in areas such as microwave absorption, molecular electronics, biomedicine and future nanomechanics. More importantly, the design concept and construction technique are of universal significance to fabricate other bifunctional one-dimensional naonomaterials. PMID- 24817328 TI - Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity. AB - A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram-positive bacteria and features self-assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2-chlorotrityl chloride resin through ether formation with the side-chain alcohol. Subsequent elongation proceeds through Fmoc solid-phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)-3-hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on-resin head-to tail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self-assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A D-Asn8 analogue developed en route retains self assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self-assembling properties and structure-activity relationships. PMID- 24817329 TI - The association between aortic calcification and fracture risk in postmenopausal women in China: the prospective Chongqing osteoporosis study. AB - PURPOSE: Fractures are associated with cardiovascular diseases in the elderly. The purpose of the present study was to investigate the association between aortic calcification (AC) and the risk of vertebral fractures in postmenopausal Chinese women. METHODS: A prospective study with 5 years of follow-up in 1724 postmenopausal women (aged 50 years old and older) was conducted from July 2005 to June 2010. Dual energy X-ray absorptiometry was utilized to evaluate bone mineral density (BMD). Aortic calcification score (ACS) was determined by a semi quantitative method and was further categorized into four groups. Cox proportional hazards models were established to assess the association between AC and the risk of vertebral fractures. RESULTS: For subjects with AC, the incidence of vertebral fractures was higher than that of those without AC (p<0.01). After adjustment for age and other potential confounders, it was found that severe AC (G4, ACS>6; G3, ACS = 3-6) was associated with vertebral fractures. Severe AC (G4) was associated with non-vertebral fractures. There were higher risk for the vertebral fractures in two groups and higher risk for non-vertebral fractures in one group. CONCLUSIONS: The results of the current study indicate that severe AC is associated with a significantly increased risk of vertebral fractures and non vertebral fractures in postmenopausal women in China. PMID- 24817330 TI - Detection of viral protein-protein interaction by microplate-format luminescence based mammalian interactome mapping (LUMIER). PMID- 24817331 TI - Old diseases for new nightmares: distemper strikes back in Italy. AB - This article analyses the distemper outbreak that affected the population of Apennine wolves (Canis lupus) in Italy during 2013. Distemper, as rabies, is a well-known viral infectious disease that concerns the canine population worldwide and represents a threat for wild species too. Implementation of vaccination and legislation for compulsory vaccination strategies should be achieved in areas with endangered wild species. PMID- 24817332 TI - Severe, diffuse fibrinonecrotic pleuropneumonia in a cat affected by multiple viral infection. AB - This communication describes the coinfection with feline panleukopenia virus (FPV), feline herpesvirus 1 (FeHV-1), feline calicivirus (FCV) and feline coronavirus (FCoV) in a 1 year-old domestic cat living in a feline shelter. The cat was referred to veterinary hospital with clinical signs related to diffuse gastro-intestinal inflammation, it had developed a severe pneumopathy with fibrinous exudation in all body cavities and died 8 days after initial presentation. Pathological findings and biomolecular diagnostic test results were compatible with an initial FPV infection that, in consequence of the lymphoid depletion, has fostered coinfection or reactivation of chronic-latent infections with FeHV-1, FCV, and FCoV. In the reported case, the simultaneous presence of different viruses exacerbated the clinical status of the host, resulting in multiple organ damage and leading it to its death. PMID- 24817334 TI - Integrating satellite imagery with simulation modeling to improve burn severity mapping. AB - Both satellite imagery and spatial fire effects models are valuable tools for generating burn severity maps that are useful to fire scientists and resource managers. The purpose of this study was to test a new mapping approach that integrates imagery and modeling to create more accurate burn severity maps. We developed and assessed a statistical model that combines the Relative differenced Normalized Burn Ratio, a satellite image-based change detection procedure commonly used to map burn severity, with output from the Fire Hazard and Risk Model, a simulation model that estimates fire effects at a landscape scale. Using 285 Composite Burn Index (CBI) plots in Washington and Montana as ground reference, we found that an integrated model explained more variability in CBI (R (2) = 0.47) and had lower mean squared error (MSE = 0.28) than image (R (2) = 0.42 and MSE = 0.30) or simulation-based models (R (2) = 0.07 and MSE = 0.49) alone. Overall map accuracy was also highest for maps created with the Integrated Model (63 %). We suspect that Simulation Model performance would greatly improve with higher quality and more accurate spatial input data. Results of this study indicate the potential benefit of combining satellite image-based methods with a fire effects simulation model to create improved burn severity maps. PMID- 24817333 TI - Toward the functional oligomerization state of tryptophan-rich sensory proteins. AB - A conserved family of tryptophan-rich sensory proteins (TspO) mediates the transport of heme degradation intermediates across membranes. In eukaryotes, the homologous mitochondrial translocator protein (TSPO) binds cholesterol and radioligands as monomer. On the basis of the mammalian TSPO structure, bioinformatic analysis, and a 10 A resolution electron microscopy map of TspO from Rhodobacter sphaeroides, we developed a model of the tertiary and quaternary structure of TspO that is in agreement with available mutagenesis data. Our study provides insight into the conformational basis for the restricted interaction of bacterial TspO with radioligands and the functional oligomerization state of bacterial TspO proteins. PMID- 24817335 TI - Spatial and temporal assessment of cumulative disturbance impacts due to military training, burning, haying, and their interactions on land condition of Fort Riley. AB - The effects of military training activities on the land condition of Army installations vary spatially and temporally. Training activities observably degrade land condition while also increasing biodiversity and stabilizing ecosystems. Moreover, other anthropogenic activities regularly occur on military lands such as prescribed burns and agricultural haying-adding to the dynamics of land condition. Thus, spatially and temporally assessing the impacts of military training, prescribed burning, agricultural haying, and their interactions is critical to the management of military lands. In this study, the spatial distributions and patterns of military training-induced disturbance frequency were derived using plot observation and point observation-based method, at Fort Riley, Kansas from 1989 to 2001. Moreover, spatial and variance analysis of cumulative impacts due to military training, burning, haying, and their interactions on the land condition of Fort Riley were conducted. The results showed that: (1) low disturbance intensity dominated the majority of the study area with exception of concentrated training within centralized areas; (2) high and low values of disturbance frequency were spatially clustered and had spatial patterns that differed significantly from a random distribution; and (3) interactions between prescribed burning and agricultural haying were not significant in terms of either soil erosion or disturbance intensity although their means and variances differed significantly between the burned and non burned areas and between the hayed and non-hayed areas. PMID- 24817336 TI - Efficacy of three irrigation agitation techniques on bacterial elimination: a microbiologic and microscopic evaluation. AB - The aim of this study was to compare in vitro reduction of Enterococcus faecalis by using three agitation methods. Fifty-five mandibular premolar teeth were used. The root canals were prepared by using ProTaper instruments to size F4. Fresh bacterial suspensions were inoculated into each canal and the teeth were incubated at 37 degrees C under aerobic conditions for 3 weeks. The specimens in negative control group were not contaminated and the teeth in positive control receive no further instrumentation or irrigation after contamination. The contaminated teeth were divided into three experimental groups and two control groups. The experimental groups were as follows according to agitation of NaOCl irrigation solution; group 1, the brush-covered NaviTip FX needle; group 2, EndoVac apical negative pressure irrigation system; and group 3, self-adjusting file (SAF). Following the final irrigation, samples obtained with sterile #40 H file from teeth and the file used were placed into sterile microcentrifuge tubes. After the incubation period, bacterial colony numbers were noted as CFU/ml. Three teeths were randomly selected from each group for scanning electron microscope evaluation. The three groups were compared with the Kruskal-Wallis test. Comparisons between three groups were made with the Mann-Whitney U-test with Bonferroni correction. SAF was significantly effective in elimination of E. faecalis when compared to EndoVac (p < 0.05). There was no difference between NaviTip FX needle and other two methods (p > 0.05). In conclusion, agitation of NaOCl with SAF for 2 min may be an effective alternative approach. PMID- 24817337 TI - The new digital pathology: just say NLO. PMID- 24817338 TI - Accuracy of diagnostic codes for identifying patients with ulcerative colitis and Crohn's disease in the Veterans Affairs Health Care System. AB - BACKGROUND: International Classification of Diseases-9 (ICD-9) codes are useful in clinical research; however, the validity of ICD-9 codes for inflammatory bowel disease (IBD) patients in multiple centers in the Veterans Affairs Health Care Systems (VA) has not been established. Our aim was to determine the accuracy of ICD-9 codes for Crohn's disease (CD) and ulcerative colitis (UC) in the VA. METHODS: Patients with a diagnosis of IBD during 1999-2009 were identified by at least one ICD-9 code for CD (555.x) or UC (556.x) at the Houston and Ann Arbor VA Medical Centers and confirmed by chart review. A diagnosis of CD, UC, and IBD, unspecified (IBDU) was determined based on structured review of data in the VA medical records. Positive predictive values (PPV) were calculated for the codes using previously published ICD-9 algorithms. RESULTS: A total of 1,871 patients were identified with ICD-9 codes for IBD. Of these patients, 1,298 (69 %) were confirmed to have IBD, with 541 CD (41 %), 707 UC (55 %), and 50 IBDU (4 %) patients. An algorithm of 2 or more codes with at least one from an outpatient encounter improved the PPV (0.83 and 0.89 for CD and UC, respectively) compared a single code algorithm (PPV 0.59 and 0.66, respectively). CONCLUSION: Single ICD-9 codes are inadequate to accurately define IBD patients; however, ICD-9 code algorithms can be used to identify patients with UC or CD with high positive predictive value. The 2 code, at least 1 outpatient code algorithm was observed to have a high PPV and low miss rate. PMID- 24817339 TI - Hodgkin lymphoma following adalimumab for the treatment of Crohn's disease in an adolescent. PMID- 24817340 TI - An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome. AB - BACKGROUND: In 2009, the European Paediatric Study Group for Haemolytic Uraemic Syndrome (HUS) published a clinical practice guideline for the investigation and initial therapy of diarrhea-negative HUS (now more widely referred to as atypical HUS, aHUS). The therapeutic component of the guideline (comprising early, high volume plasmapheresis) was derived from anecdotal evidence and expert consensus, and the authors committed to auditing outcome. METHODS: Questionnaires were distributed to pediatric nephrologists across Europe, North America, and the Middle East, who were asked to complete one questionnaire per patient episode of aHUS between July 1, 2009 and December 31, 2010. Comprehensive, anonymous demographic and clinical data were collected. RESULTS: Seventy-one children were reported with an episode of aHUS during the audit period. Six cases occurred on a background of influenza A H1N1 infection. Of 71 patients, 59 (83 %) received plasma therapy within the first 33 days, of whom ten received plasma infusion only. Complications of central venous catheters occurred in 16 out of 51 patients with a catheter in-situ (31 %). Median time to enter hematological remission was 11.5 days, and eight of 71 (11 %) patients did not enter hematological remission by day 33. Twelve patients (17 %) remained dialysis dependent at day 33. CONCLUSIONS: This audit provides a snapshot of the early outcome of a group of children with aHUS in the months prior to more widespread use of eculizumab. PMID- 24817341 TI - Malcolm A. Holliday, M.D, January 12, 1924 - March 26, 2014. PMID- 24817342 TI - CD80 and suPAR in patients with minimal change disease and focal segmental glomerulosclerosis: diagnostic and pathogenic significance: response. PMID- 24817343 TI - Investigating peptide sequence variations for 'double-click' stapled p53 peptides. AB - Stapling peptides for inhibiting the p53/MDM2 interaction is a promising strategy for developing anti-cancer therapeutic leads. We evaluate double-click stapled peptides formed from p53-based diazidopeptides with different staple positions and azido amino acid side-chain lengths, determining the impact of these variations on MDM2 binding and cellular activity. We also demonstrate a K24R mutation, necessary for cellular activity in hydrocarbon-stapled p53 peptides, is not required for analogous 'double-click' peptides. PMID- 24817344 TI - Enable, mediate and advocate: a tribute to the refined health promotion leadership of John Catford. PMID- 24817345 TI - New in-capillary electrophoretic kinase assays to evaluate inhibitors of the PI3k/Akt/mTOR signaling pathway. AB - Human kinases are one of the most promising targets for cancer therapy. Methods able to measure the effects of drugs on these cell agents remain crucial for biologists and medicinal chemists. The current work therefore sought to develop an in-capillary enzymatic assay based on capillary electrophoresis (CE) to evaluate the inhibition of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR). These kinases belong to the same signaling pathway PI3K/Akt/mTOR. For this proposal, the capillary was used as a nanoreactor in which a few nanoliters of the kinase, its substrate, adenosine triphosphate (ATP), and the potent inhibitor were separately injected. A transverse diffusion of laminar flow profiles (TDLFP) approach was employed to mix the reactants. Adenosine diphosphate (ADP ) was detected online at 254 nm. The CE assay was first developed on the alpha isoform of PI3K. It was compared to five commercial kits frequently used to assess kinase inhibition, based on time resolved fluorescence resonance energy transfer (TR-FRET) and bioluminescence. Each assay was evaluated in terms of sensitivity (S/B), reproducibility (Z'), and variability (r (2)). This CE method was easily extended to assay the inhibition of the beta, gamma, and delta isoforms of PI3K, and of the other kinases of the pathway, Akt1 and mTOR, since it is based on in-capillary mixing by TDLFP and on ADP quantification by simple UV absorption. This work shows for the first time the evaluation of inhibitors of the kinases of the PI3K/Akt/mTOR pathway using a common in-capillary CE assay. Several inhibitors with a wide range of affinity toward these enzymes were tested. PMID- 24817346 TI - Simultaneous chromatographic analysis of photoinitiators and amine synergists in food contact materials. AB - Photoinitiators (PIs) are components of UV-cured inks widely used in printing of food packaging. These substances can migrate into food and may be a hazard to human health. High-performance liquid chromatography with diode-array detection (HPLC-DAD) has been used for analysis of PIs and amine synergists in food packaging. Analysis was performed with a Kromasil C18 column (250 mm * 3.2 mm i.d., 5 MUm particle size) with a binary mobile phase gradient prepared from acetonitrile and Milli-Q water. The flow rate was 0.5 mL min(-1). The method enables separation of fourteen PIs and amine synergists in a single run. The method was validated for linearity, repeatability, and limits of detection and quantification. Excellent sensitivity (LODs <= 1.56 MUg dm(2)) and appropriate repeatability (RSD (n = 10) <0.9%) were achieved. Different types of food packaging material including plastic films, cardboard, and cans were analyzed and PIs were detected in 47% of the samples tested (n = 17). Positive samples were confirmed by use of LC-MS-MS in positive electrospray ionization (ESI) mode. PMID- 24817347 TI - The need for external validation in machine olfaction: emphasis on health-related applications. AB - Over the last two decades, electronic nose research has produced thousands of research works. Many of them were describing the ability of the e-nose technology to solve diverse applications in domains ranging from food technology to safety, security, or health. It is, in fact, in the biomedical field where e-nose technology is finding a research niche in the last years. Although few success stories exist, most described applications never found the road to industrial or clinical exploitation. Most described methodologies were not reliable and were plagued by numerous problems that prevented practical application beyond the lab. This work emphasizes the need of external validation in machine olfaction. I describe some statistical and methodological pitfalls of the e-nose practice and I give some best practice recommendations for researchers in the field. PMID- 24817348 TI - Development and validation of a sensitive thermal desorption-gas chromatography mass spectrometry (TD-GC-MS) method for the determination of phosgene in air samples. AB - A new rapid, sensitive and reliable method was developed for the determination of phosgene in air samples using thermal desorption (TD) followed by gas chromatography-mass spectrometry (GC-MS). The method is based on a fast (10 min) active sampling of only 1 L of air onto a Tenax(r) GR tube doped with 0.5 mL of derivatizing mixture containing dimercaptotoluene and triethylamine in hexane solution. Validation of the TD-GC-MS method showed a low limit of detection (40 ppbv), acceptable repeatability, intermediate fidelity (relative standard deviation within 12 %) and excellent accuracy (>95%). Linearity was demonstrated for two concentration ranges (0.04 to 2.5 ppmv and 2.5 to 10 ppmv) owing to variation of derivatization recovery between low and high concentration levels. Due to its simple on-site implementation and its close similarity with recommended operating procedure (ROP) for chemical warfare agents vapour sampling, the method is particularly useful in the process of verification of the Chemical Weapons Convention. PMID- 24817349 TI - Monitoring bisphenol A and estrogenic chemicals in thermal paper with yeast-based bioreporter assay. AB - Bioluminescent Saccharomyces cerevisiae yeast-based bioreporters were used to monitor bisphenol A and other estrogenic chemicals in thermal paper samples collected mainly from Finland on two occasions in 2010/2011, and 2013. The bisphenol A-targeted (BPA-R) and the human oestrogen receptor (hERalpha) bioreporters were applied to analyse both non-treated and extracted paper samples. Bisphenol A was readily bioavailable to the yeast bioreporters on the non-treated paper samples without any pre-treatment. Detected concentrations ranged from a detection limit of 9-142 MUg/g to over 20 mg/g of bisphenol A equivalents in the thermal papers. Low bisphenol A like activities were detected in many samples, and were considered to be caused by residual bisphenol A or other types of bisphenols, such as bisphenol S. Most of the thermal paper samples were toxic to the yeast bioreporters. The toxicity did not, however, depend on the bisphenol A concentration of the samples. The yeast bioreporters were demonstrated to be a robust and cost-efficient method to monitor thermal paper samples for their bisphenol A content and estrogenicity. Thermal paper was considered as a potential BPA source for both human exposure and environmental emission. PMID- 24817350 TI - Determination of phthalate esters in edible oils by use of QuEChERS coupled with ionic-liquid-based dispersive liquid-liquid microextraction before high performance liquid chromatography. AB - A selective and low organic-solvent-consuming method of sample preparation combined with high-performance liquid chromatography with diode-array detection is introduced for analysis of phthalic acid esters in edible oils. Sample treatment involves initial liquid-liquid partitioning with acetonitrile, then QuEChERS cleanup by dispersive solid-phase extraction with primary secondary amine as sorbent. Preconcentration of the analytes is performed by ionic-liquid based dispersive liquid-liquid microextraction, with the cleaned-up extract as disperser solvent and 1-hexyl-3-methylimidazolium hexafluorophosphate as extraction solvent. Under the optimized conditions, correlation coefficients (r) were 0.998-0.999 and standard errors (S y/x ) were 2.67-3.37 * 10(3) for calibration curves in the range 50-1000 ng g(-1). Detection limits, at a signal to-noise ratio of 3, ranged from 6 to 9 ng g(-1). Intra-day and inter-day repeatability, expressed as relative standard deviation, were in the ranges 1.0 6.9 % and 2.4-9.4 %, respectively. Recovery varied between 84 % and 106 %. The developed method was successfully used for analysis of the analytes in 28 edible oils. The dibutyl phthalate content of four of the 28 samples (14 %) exceeded the specific migration limit established by domestic and international regulations. PMID- 24817351 TI - A sensitive and accurate quantitative method to determine N-arachidonoyldopamine and N-oleoyldopamine in the mouse striatum using column-switching LC-MS-MS: use of a surrogate matrix to quantify endogenous compounds. AB - The transient receptor potential vanilloid 1 (TRPV1) channel, a nonselective Ca(2+) and Na(+) channel, is a molecular transducer of nociceptive stimuli. N Arachidonoyl dopamine (NADA) and N-oleoyldopamine (OLDA), two unsaturated N acyldopamines, are major activating endogenous TRPV1 ligands and their presence in mammalian brain tissue has been reported. However, the biological significance of NADA and OLDA remains unknown. To investigate their biological function in the nervous system, a sensitive and accurate quantitative method for determining endogenous NADA and OLDA in the brain is necessary. Thus, a column-switching liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed to quantify NADA and OLDA in mouse striatum. Mouse cerebellum tissue in which neither NADA nor OLDA were detected was used as a surrogate matrix to prepare calibrators. NADA and OLDA were extracted from mouse brain tissue by solid-phase extraction and then filtered and analyzed by LC-MS-MS with electrospray ionization in the positive ion mode. The selectivity results and comparison of calibration curves prepared with mouse cerebellum and striatum established that the former was acceptable as the surrogate matrix of the latter for analyzing NADA and OLDA. The validation results of the matrix effect, linearity, precision, accuracy, and stability were satisfactory. The limits of detection and limits of quantification were 0.125 pg mg(-1) for both analytes. This method was sensitive and accurate enough to determine endogenous concentrations of these compounds in mouse striatum and will be very useful for further study of the biological functions of NADA and OLDA and other related factors in vivo. PMID- 24817352 TI - Analysis of lipid peroxidation biomarkers in extremely low gestational age neonate urines by UPLC-MS/MS. AB - Extremely low gestational age neonates (ELGAN) frequently require the use of oxygen supply in the delivery room leading to systemic inflammation and oxidative stress that are responsible for increased morbidity and mortality. The objective of this study was to establish reference ranges of a set of representative isoprostanes and prostaglandins, which are stable biomarkers of lipid peroxidation often correlated with oxidative stress-related disorders. First, a quantitative ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated. The proposed analytical method was tailored for its application in the field of neonatology, enabling multi analyte detection in non-invasive, small-volume urine samples. Then, the lipid peroxidation product concentrations in a total of 536 urine samples collected within the framework of two clinical trials including extremely low gestational age neonates (ELGAN) were analyzed. The access to a substantially large number of samples from this very vulnerable population provided the chance to establish reference ranges of the studied biomarkers. Up to the present, and for this population, this is the biggest reference data set reported in literature. Results obtained should assist researchers and pediatricians in interpreting test results in future studies involving isoprostanes and prostaglandins, and could help assessing morbidities and evaluate effectiveness of treatment strategies (e.g., different resuscitation conditions) in the neonatal field. PMID- 24817353 TI - Dynamics of GDOES-induced surface roughening in metal interfaces. AB - The roughness induced during glow-discharge optical-emission spectroscopy (GDOES) measurements has been reported to cause a loss of resolution during GDOES depth profiling analysis. In this paper, we undertake for the first time a study of the dynamics of the surface morphology of chromium and titanium thin films (designed in mono and multilayer structures) under the impinging of GDOES incoming ions. We performed this study under the theoretical framework of the dynamic scaling theory, by analysing surface morphology changes, as measured ex-situ by AFM, with irradiation time. For single metal layers it was found that, after an initial surface smoothening, the surface undergoes a rapid steep roughening for both systems, with quite similar quantitative dynamics. Once this roughening ends a second temporal scaling regime arises, operating for long length scales with dynamics depending on the sputtering rate of the material. For the chromium layer, with a very high sputtering rate of 5.5 MUm min(-1), this regime is consistent with the KPZ model, whereas for the titanium layer an EW scaling regime is indicated. These different scaling regimes are consistent with the development of larger surface slopes for the Cr system. In the multilayer systems, the initial roughness induced on the top Cr layer by GDOES has similar dynamics to that for single-layer Cr. However, a clear decrease in the roughness was observed once the underlying Ti layer, with a lower sputtering rate, was reached. This decrease in the induced roughness is maintained while the Ti layer is eroded. Therefore, choice of appropriate material (i.e. sputtering yield values) combinations and of their depth of location can enable tuning of GDOES induced roughness and achieve substantial control over the depth profiling process. PMID- 24817354 TI - Quantitative determination of free and total bisphenol A in human urine using labeled BPA glucuronide and isotope dilution mass spectrometry. AB - Bisphenol A (BPA) is a widely used industrial chemical in the manufacturing of polycarbonate plastic bottles, food and beverage can linings, thermal receipts, and dental sealants. Animal and human studies suggest that BPA may disrupt normal hormonal function and hence, potentially, have negative effects on the human health. While total BPA is frequently reported, it is recognized that free BPA is the biologically active form and is rarely reported in the literature. The objective of this study was to develop a sensitive and improved method for the measurement of free and total BPA in human urine. Use of a labeled conjugated BPA (bisphenol A-d6 beta-D-glucuronide) allowed for the optimization of the enzymatic reaction and permitted an accurate determination of the conjugated BPA concentration in urine samples. In addition, a (13)C12-BPA internal standard was used to account for the analytical recoveries and performance of the isotope dilution method. Solid-phase extraction (SPE) combined with derivatization and analysis using a triple quadrupole GC-EI/MS/MS system achieved very low method detection limit of 0.027 ng/mL. BPA concentrations were measured in urine samples collected during the second and third trimesters of pregnancy in 36 Canadian women. Total maternal BPA concentrations in urine samples ranged from not detected to 9.40 ng/mL (median, 1.21 ng/mL), and free BPA concentrations ranged from not detected to 0.950 ng/mL (median, 0.185 ng/mL). Eighty-six percent of the women had detectable levels of conjugated BPA, whereas only 22 % had detectable levels of free BPA in their urine. BPA levels measured in this study agreed well with data reported internationally. PMID- 24817355 TI - The potential of asymmetric flow field-flow fractionation hyphenated to multiple detectors for the quantification and size estimation of silica nanoparticles in a food matrix. AB - This work represents a first systematic approach to the size-based elemental quantification and size estimation of metal(loid) oxide nanoparticles such as silica (SiO2) in a real food matrix using asymmetric flow field-flow fractionation coupled online with inductively coupled plasma mass spectrometry (ICP-MS) and multi-angle light scattering (MALS) and offline with transmission electron microscopy (TEM) with energy-dispersive X-ray analysis (EDAX). Coffee creamer was selected as the model sample since it is known to contain silica as well as metal oxides such as titania at the milligramme per kilogramme levels. Optimisation of sample preparation conditions such as matrix-to-solvent ratio, defatting with organic solvents and sonication time that may affect nanoparticle size and size distribution in suspensions was investigated. Special attention was paid to the selection of conditions that minimise particle transformation during sample preparation and analysis. The coffee creamer matrix components were found to stabilise food grade SiO2 particles in comparison with water suspensions whilst no significant effect of defatting using hexane was found. The use of sample preparation procedures that mimic food cooking in real life was also investigated regarding their effect on particle size and particle size distribution of silica nanoparticles in the investigated food matrix; no significant effect of the water temperature ranging from ambient temperature to 60 degrees C was observed. Field-flow fractionation coupled to inductively coupled plasma-mass spectrometry (FFF-ICP-MS) analysis of extracts of both unspiked coffee creamer and coffee creamer spiked with food grade silicon dioxide, using different approaches for size estimation, enabled determination of SiO2 size-based speciation. Element-specific detection by ICP-MS and post-FFF calibration with elemental calibration standards was used to determine the elemental composition of size fractions separated online by FFF. Quantitative data on mass balance is provided for the size-based speciation of the investigated inorganic nano-objects in the complex matrix. The combination of FFF with offline fractionation by filtration and with detection by ICP-MS and TEM/EDAX has been proven essential to provide reliable information of nanoparticle size in the complex food matrix. PMID- 24817356 TI - Size does matter! Label-free detection of small molecule-protein interaction. AB - This review is focused on methods for detecting small molecules and, in particular, the characterisation of their interaction with natural proteins (e.g. receptors, ion channels). Because there are intrinsic advantages to using label free methods over labelled methods (e.g. fluorescence, radioactivity), this review only covers label-free techniques. We briefly discuss available techniques and their advantages and disadvantages, especially as related to investigating the interaction between small molecules and proteins. The reviewed techniques include well-known and widely used standard analytical methods (e.g. HPLC-MS, NMR, calorimetry, and X-ray diffraction), newer and more specialised analytical methods (e.g. biosensors), biological systems (e.g. cell lines and animal models), and in-silico approaches. PMID- 24817357 TI - Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedure for screening of urine specimens for 100 analytes relevant in drug-facilitated crime (DFC). AB - In recent years, drug-facilitated crime (DFC) has become an increasing problem. A minimum list of 80 analytes to be monitored in such cases has been proposed by the Society of Forensic Toxicologists (SOFT) including the recommended minimum performance limits (RMPL). In the present study, two liquid chromatography-tandem mass spectrometry-based screening procedures, one in positive (method I) and one in negative (method II) electrospray ionization mode were developed and validated. Gradient elution was performed on a ZORBAX Eclipse XDB-C18 column after protein precipitation of the urine samples. Detection was carried out in the scheduled multiple reaction monitoring (MRM) mode monitoring two transitions per compound. A total of 100 analytes (91 basic in method I and nine acidic in method II) could be identified using the described procedure. No interferences were observed in 30 tested blank urine samples. The RMPLs were achieved for all analytes and ranged from 1 ng/mL for fentanyl to 10 MUg/mL for gamma hydroxybutyrate (GHB). Matrix effects (ME) were evaluated using the same 30 urine samples and ranged from -90 % for tetrazepam to >6,000 % for the 11-nor-9-carboxy tetrahydrocannabinol (THC-COOH). The relative standard deviations of ME were below 25 % for the vast majority of analytes. Results for urine specimens from nine authentic DFC cases were always negative with exception of drugs prescribed to the victims. Reanalysis with the developed procedure of 24 urine samples, with a positive screening result during routine clinical toxicology analysis, confirmed the routine findings. In an excretion study after a single oral doxylamine dose (30 mg), the parent drug and its nor metabolite could be detected in urine specimens from a young female volunteer for 10 days. The developed procedure allows a selective and sensitive screening of urine samples for almost all recommended analytes relevant in DFC cases. PMID- 24817358 TI - Study of urinary steroid hormone disorders: difference between hepatocellular carcinoma in early stage and cirrhosis. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Discovery of novel biomarkers for early HCC from other liver diseases such as cirrhosis is of great clinical benefit. In this study, a novel steroid hormone metabolomic method based on liquid chromatography-mass spectrometry combined with logistic regression analysis was applied to study the steroid hormone disorders and to screen potential urinary steroid hormone biomarkers of early HCC. Thirty six urinary steroid hormones were detected and quantified in healthy controls, cirrhotic patients, and early HCC patients. Heat map analysis and multivariate statistical analysis suggested severe disorders of steroid hormone network and holistically decreased urinary steroid hormone pattern in cirrhotic and early HCC patients. Logistic regression analysis reveals that a panel of two urinary steroid hormones (epitestosterone and allotetrahydrocortisol) displayed excellent diagnostic capability for distinguishing early HCC from cirrhosis with area under the curve (AUC) = 0.938 of receiver operating characteristic (ROC) analysis. These results help to overcome the disadvantage of lower sensitivity and specificity of alpha-fetoprotein for distinguishing early HCC from cirrhosis. Our work shows that steroid hormone metabolomics is a promising biomarker tool for biomarker study of early HCC. PMID- 24817359 TI - Effect of downscaling on the linearity range of a calibration curve in spectrofluorimetry. AB - Interest in the microfluidic environment, owing to its unique physical properties, is increasing in much innovative chemical, biological, or medicinal research. The possibility of exploiting and using new phenomena makes the microscale a powerful tool to improve currently used macroscopic methods and approaches. Previously, we reported that an increase in the surface area to volume ratio of a measuring cell could provide a wider linear range for fluorescein (Kwapiszewski et al., Anal. Bioanal. Chem. 403:151-155, 2012). Here, we present a broader study in this field to confirm the assumptions we presented before. We studied fluorophores with a large and a small Stokes shift using a standard cuvette and fabricated microfluidic detection cells having different surface area to volume ratios. We analyzed the effect of different configurations of the detection cell on the measured fluorescence signal. We also took into consideration the effect of concentration on the emission spectrum, and the effect of the surface area to volume ratio on the limit of linearity of the response of the selected fluorophores. We observed that downscaling, leading to an increase in the probability of collisions between molecules and cell walls with no energy transfer, results in an increase in the limit of linearity of the calibration curve of fluorophores. The results obtained suggest that microfluidic systems can be an alternative to the currently used approaches for widening the linearity of a calibration curve. Therefore, microsystems can be useful for studies of optically dense samples and samples that should not be diluted. PMID- 24817360 TI - Comprehensive two-dimensional liquid chromatography coupled to the ABTS radical scavenging assay: a powerful method for the analysis of phenolic antioxidants. AB - The on-line combination of comprehensive two-dimensional liquid chromatography (LC * LC) with the 2,2'-azino-bis(3-ethylbenzothiazoline)-6 sulphonic acid (ABTS) radical scavenging assay was investigated as a powerful method to determine the free radical scavenging activities of individual phenolics in natural products. The combination of hydrophilic interaction chromatography (HILIC) separation according to polarity and reversed-phase liquid chromatography (RP-LC) separation according to hydrophobicity is shown to provide much higher resolving power than one-dimensional separations, which, combined with on-line ABTS detection, allows the detailed characterisation of antioxidants in complex samples. Careful optimisation of the ABTS reaction conditions was required to maintain the chromatographic separation in the antioxidant detection process. Both on-line and off-line HILIC * RP-LC-ABTS methods were developed, with the former offering higher throughput and the latter higher resolution. Even for the fast analyses used in the second dimension of on-line HILIC * RP-LC, good performance for the ABTS assay was obtained. The combination of LC * LC separation with an on-line radical scavenging assay increases the likelihood of identifying individual radical scavenging species compared to conventional LC-ABTS assays. The applicability of the approach was demonstrated for cocoa, red grape seed and green tea phenolics. PMID- 24817361 TI - Ultrasound-assisted temperature-controlled ionic-liquid dispersive liquid-phase microextraction method for simultaneous determination of anethole, estragole, and para-anisaldehyde in different plant extracts and human urine: a comparative study. AB - In this study, the performances of four ionic-liquid-based microextraction methods, ionic-liquid-based dispersive liquid-liquid microextraction (IL-DLLME), ionic-liquid-based ultrasound-assisted emulsification microextraction (IL-USA ME), temperature-controlled ionic-liquid dispersive liquid-phase microextraction (TC-IL-DLME), and ultrasound-assisted temperature-controlled ionic-liquid dispersive liquid-phase microextraction (USA-TC-IL-DLME), were investigated for extraction of three bioactive compounds (anethole, estragole, and anisaldehyde) from different plant extracts and human urine. Anethole and estragole were chosen because they can alter cellular processes positively or negatively, and an efficient method is needed for their extraction and sensitive determination in the samples mentioned. Because there is no previous report on the separation of anethole and estragole (structural isomers), first, simultaneous gradient elution and flow programming were used. The microextraction methods were then applied and compared for analysis of these compounds in plant extracts and human urine by use of high-performance liquid chromatography (HPLC). The effect of conditions on extraction efficiency was studied and under the optimum conditions, the best enrichment factors (58-64), limits of detection (14-18 ng mL(-1)), limits of quantification (47-60 ng mL(-1)), and recovery (94.4-101.7 %) were obtained by use of USA-TC-IL-DLME. The optimized conditions were used to determine anethole, estragole, and para-anisaldehyde in fennel, anise, and tarragon extracts and in human urine. PMID- 24817362 TI - Simultaneous determination of NNK and its metabolites in mouse tissue for evaluating the effects of chronic alcohol consumption on the metabolism of NNK in mouse liver and lung. AB - A hydrophilic-interaction liquid chromatography-tandem mass spectrometry (HILIC MS-MS) method was developed for the determination of 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) and its metabolites in mouse liver and lung. The limits of detection of all analytes were in the range 0.017-0.057 ng mL(-1), and recovery ranged from 88.4-119.8 % with intra and inter-day precision in the range 0.89-6.03 % and 1.01-6.97 %, respectively. This simple and accurate method was used to evaluate the effect of chronic alcohol consumption on NNK bioactivation in mouse tissue. Time-course curves for NNK and its metabolites were generated, and the areas under the curves (AUCs) were compared. It was found that target tissues of NNK carcinogenesis in C57BL/6 mice contained high levels of alpha hydroxylation metabolites of NNK and its carbonyl reduction metabolite, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). The most pronounced effect of alcohol was to enhance alpha-hydroxylation of NNK in mouse lung and liver, which suggests that chronic alcohol consumption may increase the risk of carcinogenicity associated with NNK in mice. PMID- 24817363 TI - Infrared microspectroscopic identification of marker ingredients in the finished herbal products based on the inherent heterogeneity of natural medicines. AB - Finished herbal products (FHPs) are preparations made from one or more herbs. The first stage in assuring the quality, safety, and efficacy of FHPs is to identify the herbs in the products. A new simple and quick method is developed in this research to detect the marker ingredients in FHPs. The inherent chemical heterogeneity of herbs and FHPs makes it possible to resolve different ingredients, without any additional separation or labeling, by infrared microspectroscopic imaging. Therefore, multiple marker ingredients in FHPs can be recognized directly and simultaneously by the infrared microspectroscopic identification method. As an example, all six kinds of herbs in Liuwei Dihuang Wan are identified through the following steps: (1) Each herb is characterized by infrared spectroscopic imaging, then the spectra of the main ingredients are calculated by the combination of principal component analysis, independent component analysis, and alternating least squares. (2) One marker ingredient is chosen for each herb. Ten typical pixels, the spectra of which best match the calculated spectrum of the marker ingredient, are selected by partial least squares target. The average spectrum of the typical pixels is taken as the marker spectrum. (3) Correlation coefficients between the typical pixel spectra and the marker spectrum are calculated. The acceptance correlation threshold is determined through the beta distribution function and then validated by positive and negative samples. (4) Using the above marker spectra and correlation criteria, herbs in the model mixture and the commercial product are identified. Good recognition results reveal the potential of the infrared microspectroscopic identification method in the quality control of herbs and FHPs. PMID- 24817364 TI - Capillary electrophoresis for total glycosaminoglycan analysis. AB - A capillary zone electrophoresis-laser-induced fluorescence detection (CZE-LIF) method was developed for the simultaneous analysis of disaccharides derived from heparan sulfate, chondroitin sulfate/dermatan sulfate, hyaluronan, and keratan sulfate. Glycosaminoglycans (GAGs) were first depolymerized with the mixture of GAG lyases (heparinase I, II, III and chondroitinase ABC and chondroitinase AC II) and GAG endohydrolase (keratinase II) and the resulting disaccharides were derivatized by reductive amination with 2-aminoacridone. Nineteen fluorescently labeled disaccharides were separated using 50 mM phosphate buffer (pH 3.3) under reversed polarity at 25 kV. Using these conditions, all the disaccharides examined were baseline separated in less then 25 min. This CZE-LIF method gave good reproducibility for both migration time (<=1.03% for intraday and <=4.4% for interday) and the peak area values (<=5.6% for intra- and <=8.69% for interday). This CZE-LIF method was used for profiling and quantification of GAG derivative disaccharides in bovine cornea. The results show that the current CZE-LIF method offers fast, simple, sensitive, reproducible determination of disaccharides derived from total GAGs in a single run. PMID- 24817365 TI - Development of an immunosensor for the detection of Francisella tularensis antibodies. AB - Tularemia, also known as rabbit fever, is a highly infectious zoonotic disease caused by a non-motile and non-spore-forming Gram-negative coccoid rod bacterium, Francisella tularensis. It occurs naturally in lagomorphs (rabbits and hares), but many animals have been reported to be susceptible. Transmission to humans is mostly caused by inhalation of aerosolised bacteria, handling of infected animals, arthropod stings, and ingestion of contaminated foods and water. At present, pathogenic isolation, molecular detection, and serology are the most commonly used methods to confirm the diagnosis of tularemia. In this work, an electrochemical immunosensor for the detection of anti-F. tularensis antibodies was developed, consisting of gold-based self-assembled monolayers of a carboxylic group-terminated bipodal alkanethiol that is covalently linked to a lipopolysaccharide (LPS) that can be found in the outer membrane of the bacteria F. tularensis. The presence of anti-F. tularensis antibodies was measured using horseradish peroxidase-labelled protein A (HRP-protein A) from Staphylococcus aureus, and the developed immunosensor gave a stable quantitative response to different anti-F. tularensis FB11 antibody concentrations after 30 min with a limit of detection of 15 ng/mL, RSD of 9%, n = 3. The developed immunosensor was tested with serum from animals infected with tularemia and was compared to the results obtained using ELISA showing an excellent degree of correlation. PMID- 24817366 TI - Presence of a glycine-cysteine-rich beta-protein in the oberhautchen layer of snake epidermis marks the formation of the shedding layer. AB - The complex differentiation of snake epidermis largely depends on the variation in the production of glycine-cysteine-rich versus glycine-rich beta-proteins (beta-keratins) that are deposited on a framework of alpha-keratins. The knowledge of the amino acid sequences of beta-proteins in the snake Pantherophis guttatus has allowed the localization of a glycine-cysteine-rich beta-protein in the spinulated oberhautchen layer of the differentiating shedding complex before molting takes place. This protein decreases in the beta-layer and disappears in mesos and alpha-layers. Conversely, while the mRNA for a glycine-rich beta protein is highly expressed in differentiating beta-cells, the immunolocalization for this protein is low in these cells. This discrepancy between expression and localization suggests that the epitope in glycine-rich beta-proteins is cleaved or modified by posttranslational processes that take place during the differentiation and maturation of the beta-layer. The present study suggests that among the numerous beta-proteins coded in the snake genome to produce epidermal layers with different textures, the glycine-cysteine-rich beta-protein marks the shedding complex formed between alpha- and beta-layers that allows for molting while its disappearance between the beta- and alpha-layers (mesos region for scale growth) is connected to the formation of the alpha-layers. PMID- 24817367 TI - Electrochemical properties of oxygenated cup-stacked carbon nanofiber-modified electrodes. AB - Oxygenated cup-stacked carbon nanofibers (CSCNFs), the surface of which provides highly ordered graphene edges and oxygen-containing functional groups, were investigated as electrode materials by using typical redox species in electrochemistry, Fe(2+/3+), [Fe(CN)6](3-/4-), and dopamine. The electron transfer rates for these redox species at oxygenated CSCNF electrodes were higher than those at edge-oriented pyrolytic graphite and glassy carbon electrodes. In addition, the oxygen-containing functional groups also contributed to the electron transfer kinetics at the oxygenated CSCNF surface. The electron transfer rate of Fe(2+/3+) was accelerated and that of [Fe(CN)6](3-/4-) was decelerated by the oxygen-containing groups, mainly due to the electrostatic attraction and repulsion, respectively. The electrochemical reaction selectivities at the oxygenated CSCNF surface were tunable by controlling the amount of nanofibers and the oxygen/carbon atomic ratio at the nanofiber surface. Thus, the oxygenated CSCNFs would be useful electrode materials for energy-conversion, biosensing, and other electrochemical devices. PMID- 24817368 TI - The JSGS president's message: for the development of the cooperation between the JSGS and the SSO. PMID- 24817369 TI - Efficacy of hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced intrahepatic cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The prognosis of ICC is far worse than that of ECC. In this pilot trial, the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) combined with subcutaneous administration of pegylated interferon (PEG-IFN) alpha 2b in patients with advanced ICC was evaluated. METHODS: The subjects were 20 advanced ICC patients treated using subcutaneous PEG-IFNalpha-2b (50-100 MUg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). One treatment cycle lasted 4 weeks. Therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for >=1 cycle. RESULTS: The objective early response rate was 60.0 %. Cumulative survival rates were 71.6 % at 6 months, 53.7 % at 12 months, 28.6 % at 18 months, and 14.3 % at 24 months. Median survival time was 14.6 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment-related deaths were not observed. CONCLUSIONS: The combination therapy of PEG-IFNalpha-2b and 5-FU for advanced ICC seems not to be worse than the results of the previous studies. Furthermore, most adverse effects are transient and well tolerated. Based on the present findings, this combination therapy may be useful for patients with advanced ICC as one of the therapeutic option. PMID- 24817370 TI - Improving the nutritive value of wheat straw with urea and yeast culture for dry season feeding of dairy cows. AB - The study evaluated the effects of feeding urea treated/supplemented wheat straw based diets with addition of yeast culture (YC) as a dry season feed for dairy cows. Wheat straw diets with 3.6% urea and 5.8% molasses were formulated to upgrade nonprotein nitrogen levels and fibre degradation in the rumen. Yeast culture was included at 0 and 10 g/cow/day in mixer with commercial dairy meal to improve on fibre degradation and milk yield. Two experiments were conducted. Firstly, an in sacco dry matter degradability (DMD) trial with three steers in a completely randomized design (CRD) with a 3 * 2 factorial arrangement to determine the effects on intake and rumen degradation parameters. Secondly, feeding trial with 18 lactating cows in a 3 * 2 factorial arrangement at two levels of yeast culture (0 and 10 g/cow/day) and three types of urea interventions: No intervention (WS); addition of urea to straw at the time of feeding (USWS); and 7 days incubation of straw with urea (UTWS). Yeast cultures addition had no effect on rumen pH and NH3-N, but urea intervention showed an effect on rumen pH with USWS being lowest (p < 0.05). Both urea interventions and yeast culture addition had no effect (p > 0.05) on dry matter intake, milk yield, and milk composition but they increased (p < 0.05) propionate yields. PMID- 24817371 TI - Reproductive performance of sows with and without PRRS modified live virus vaccination in PRRS-virus-seropositive herds. AB - Porcine reproductive and respiratory syndrome (PRRS) virus infection causes reproductive failures including return to oestrus, abortion, mummified foetuses, stillborn, and weak-born piglets. The objective of the present study was to investigate reproductive performance of sows in PRRS-virus-seropositive herds with and without PRRS modified live virus (PRRS-MLV) vaccination. The study was conducted in 20 PRRS-virus-seropositive commercial swine herds in Thailand. The data included 211,009 mating and 180,935 farrowing records. The analysed variables included farrowing rate (FR), return rate (RR), abortion rate (AR), total number of piglets born per litter (TB), number of piglets born alive per litter (BA), percentage of stillborn (SB), percentage of mummified foetuses (MM), and number of piglets weaned per litter (WP). The results revealed that FR in non vaccinated sows was lower than that in vaccinated sows (85.0 vs 89.7%, respectively, P < 0.001), and RR in non-vaccinated sows was higher than that in vaccinated sows (6.9 vs 3.7%, respectively, P < 0.001). AR did not differ significantly between non-vaccinated and vaccinated sows (1.6 and 2.0%, respectively, P = 0.964). TB (11.2 and 11.5, respectively, P < 0.001), BA (10.0 and 10.6, respectively, P < 0.001), and WP (9.2 and 9.6, respectively, P < 0.001) in non-vaccinated sows were lower than those in vaccinated sows. SB (6.9 and 5.1%, respectively, P < 0.001) and MM (3.2 and 2.2%, respectively, P < 0.001) in PRRS-MLV-vaccinated sows were higher than those in non-vaccinated sows. The improvement in sow reproductive performance in PRRS-MLV-vaccinated herds was most pronounced in gilts and primiparous sows. PMID- 24817372 TI - Asymptomatic gastric bacterial overgrowth after bariatric surgery: are long-term metabolic consequences possible? AB - BACKGROUND: Patients with postbariatric bacterial overgrowth were reinvestigated after a follow-up of 15 years. It was hypothesized that systemic associations analogous to those reported for whole gut microbiome would be revealed. METHODS: Patients (n = 37, 70.3 % females, 42.4 +/- 9.9 years old, preoperative BMI 53.5 +/- 10.6 kg/m(2), current BMI 32.8 +/- 10.8 kg/m(2)), all submitted to RYGB on account of morbid obesity, were followed during 176.8 +/- 25.7 months. Blood tests included fasting blood glucose, HbA1c, liver and pancreatic enzymes, and lipid fractions. Bacterial overgrowth was diagnosed by quantitative culture of gastric fluid in both the excluded remnant and the gastric pouch, with the help of double-balloon enteroscopy. Absolute counts of aerobes and anaerobes in both gastric reservoirs were correlated with nutritional and biochemical measurements, aiming to identify clinically meaningful associations. RESULTS: Patients denied diarrhea, abdominal pain, weight loss, or other symptoms related to bacterial overgrowth. Biochemical profile including enzymes was also acceptable, indicating a stable condition. Positive correlation of bacterial count in either segment of the stomach was demonstrated for BMI and gamma-glutamyl transferase, whereas negative correlation occurred regarding fasting blood glucose. CONCLUSIONS: An antidiabetic role along with deleterious consequences for weight loss and liver function are possible in such circumstances. Such phenotype is broadly consistent with reported effects for the whole gut microbiome. Prospective controlled studies including molecular analysis of gastrointestinal fluid, and simultaneous profiling of the entire microbiome, are necessary to shed more light on these findings. PMID- 24817373 TI - Bariatric surgery decreases monocyte-platelet aggregates in blood: a pilot study. AB - Morbid obesity is accompanied by platelet hyperactivity, leading to thrombotic events including myocardial infarction and stroke. Bariatric surgery is an effective intervention to reduce cardiovascular risk in obesity. However, the effect of bariatric surgery on platelet function is largely unknown. This study investigated the effects of laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) on prothrombotic monocyte-platelet aggregates (MPAs), markers of platelet activation in vivo. MPA were measured in whole blood by flow cytometry before surgery and 1 and 3 months after surgery. In non-obese healthy controls, MPA level is 13 +/- 2 %. MPAs are elevated in morbidly obese subjects. RYGB (n = 12 patients) decreases MPAs 1 month after surgery by a weight-independent mechanism (56 +/- 6 % presurgically vs 26 +/- 8 % at 1 month, p <0.01). LAGB (n = 5 patients) has a smaller weight-dependent effect (49 +/- 8 % presurgically vs 32 +/- 6 % at 1 month, p > 0.05). Bariatric surgery may reduce thrombotic events by alleviation of platelet overactivity. PMID- 24817374 TI - Laparoscopic bariatric surgery can be performed through a single incision: a comparative study. AB - BACKGROUND: The application of single-incision laparoscopic surgery (SILS) in bariatric patients has been limited to less complex procedures. We evaluated the short-term outcomes of SILS sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), compared to a group of well-established minimally invasive techniques. METHODS: Twenty-eight morbidly obese patients who underwent SILS SG (n = 14) and RYGB (n = 14) were compared to a matched control group composed of 28 cases of conventional laparoscopic surgery (CLS). A single vertical 2.5-3-cm intra umbilical incision, three-ports placed trans-fascially, and a liver suspension technique were used to perform SILS. RESULTS: Both groups were comparable in terms of age (p = 0.96), gender (p = 1.0), type of procedure (p = 1.0), and number of comorbidities (p = 0.63). Two (7%) SILS patients required placement of one additional port, and no conversions to CLS or open surgery were needed. The estimated blood loss (p = 0.48), operative time (p = 0.33), length of hospital stay (p = 0.79), overall 90-day perioperative complication rate (p = 1.0), and short-term weight loss (p = 0.53) were comparable between the two groups. In terms of pain control, the frequency of patient-controlled analgesia use in both groups was similar. However, the pain score (assessed by visual analog scale) was significantly less for SILS patients on postoperative days 1 (5.0 +/- 2.1 vs. 6.5 +/- 1.8; p = 0.007) and 2 (4.0 +/- 2.0 vs. 5.1 +/- 2.4; p = 0.49). Cosmetic satisfaction with the scar was high in the SILS group. No patients required reoperation or readmission during the 90 days after surgery. CONCLUSION: SILS is feasible in carefully selected bariatric patients and results in short-term outcomes comparable to those observed after CLS. Improved pain and cosmesis are potential benefits of SILS. PMID- 24817376 TI - A novel bioassay to monitor fungicide sensitivity in Mycosphaerella fijiensis. AB - BACKGROUND: Black leaf streak disease (BLSD) is the most important disease of bananas for export. The successful control of BLSD requires an intensive use of systemic fungicides, leading to the build-up of resistance and failure of control. Early detection of fungicide resistance is crucial to drive rational chemical strategies. Present methods relying on ascospore germination bioassays have several drawbacks that could be overcome using conidia. RESULTS: Generally, a single genotype is present on the conidial population derived from one lesion. Conidial germination tests with thiabendazole (5 mg L(-1)) enable a clear detection of strains resistant to methyl benzimidazole carbamates. Germination bioassays on azoxystrobin (10 mg L(-1)) enable the detection of most QoI resistant strains, but their proportion might be underestimated with cut-off limits of germ tube length (L > 120 um) or growth inhibition (GI < 50%). The level of fungicide resistance differs at different canopy levels of a banana tree, which should be considered for sampling. The ascospore germination bioassay provided more variable estimations of the level of resistance by comparison with the new conidial germination bioassay. CONCLUSION: Germination bioassays performed with conidia obtained from young lesions overcome most drawbacks encountered with ascospore germination bioassays and could be considered as a new reference method for fungicide resistance monitoring in this species. Different steps are proposed, from sampling to microscopic examinations, for the implementation of this technique. PMID- 24817377 TI - Tuning the surface charge of graphene for self-assembly synthesis of a SnNb2O6 nanosheet-graphene (2D-2D) nanocomposite with enhanced visible light photoactivity. AB - A two-dimensional (2D) SnNb2O6 nanosheet-graphene (SnNb2O6-GR) nanocomposite featuring a typical 2D-2D structure has been synthesized via a simple surface charge modified self-assembly approach. The method is afforded by electrostatic attractive interaction between negatively charged SnNb2O6 nanosheets and modified graphene nanosheets with a positively charged surface in an aqueous solution. The SnNb2O6-GR nanocomposite exhibits a distinctly enhanced visible light photocatalytic performance toward degradation of organic dye in water as compared to blank SnNb2O6 nanosheets. The enhanced photoactivity is attributed to the integrated factors of the intimate interfacial contact and unique 2D-2D morphology associated with SnNbO6 and GR, which are beneficial for harnessing the electron conductivity of GR, facilitating the transfer and separation of photogenerated charge carriers over SnNbO6-GR upon visible light irradiation, and thereby contributing to the photoactivity enhancement. It is hoped that this work could enrich the facile, efficient fabrication of various 2D-2D semiconductor nanosheet-graphene composite photocatalysts toward target photocatalytic applications. PMID- 24817375 TI - A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8 -/- embryos. AB - PURPOSE: Maternal folate intake has reduced the incidence of human neural tube defects by 60-70 %. However, 30-40 % of cases remain nonresponsive to folate intake. The main purpose of this study was to understand the molecular mechanism of folate nonresponsiveness in a mouse model of neural tube defect. METHODS: We used a folate-nonresponsive Fkbp8 knockout mouse model to elucidate the molecular mechanism(s) of folate nonresponsiveness. Neurospheres were grown from neural stem cells isolated from the lumbar neural tube of E9.5 Fkbp8 (-/-) and wild-type embryos. Immunostaining was used to determine the protein levels of oligodendrocyte transcription factor 2 (Olig2), Nkx6.1, class III beta-tubulin (TuJ1), O4, glial fibrillary acidic protein (GFAP), histone H3 Lys27 trimethylation (H3K27me3), ubiquitously transcribed tetratricopeptide repeat (UTX), and Msx2, and quantitative real-time (RT)-PCR was used to determine the message levels of Olig2, Nkx6.1, Msx2, and noggin in neural stem cells differentiated in the presence and absence of folic acid. RESULTS: Fkbp8 (-/-) derived neural stem cells showed (i) increased noggin expression; (ii) decreased Msx2 expression; (iii) premature differentiation--neurogenesis, oligodendrogenesis (Olig2 expression), and gliogenesis (GFAP expression); and (iv) increased UTX expression and decreased H3K27me3 polycomb modification. Exogenous folic acid did not reverse these markers. CONCLUSIONS: Folate nonresponsiveness could be attributed in part to increased noggin expression in Fkbp8 (-/-) embryos, resulting in decreased Msx2 expression. Folate treatment further increases Olig2 and noggin expression, thereby exacerbating ventralization. PMID- 24817378 TI - Diagnostic value of T1 and T2 * relaxation times and off-resonance saturation effects in the evaluation of Achilles tendinopathy by MRI at 3T. AB - PURPOSE: To evaluate and compare the diagnostic value of T1 , T2 * relaxation times and off-resonance saturation ratios (OSR) in healthy controls and patients with different clinical and morphological stages of Achilles tendinopathy. MATERIAL AND METHODS: Forty-two healthy Achilles tendons and 34 tendons of 17 patients with symptomatic and asymptomatic tendinopathy were investigated clinically with conventional magnetic resonance imaging (MRI) sequences on a 3T whole-body MR scanner and a dynamic ultrasound examination. In addition, T1 and T2 * relaxation times were assessed using an ultrashort echo time (UTE) imaging sequence with flip angle and echo time variation. For the calculation of OSR values a Gaussian off-resonance saturation pulse (frequency offset: 750-5000 Hz) was used. The diagnostic value of the derived MR values was assessed and compared using receiver operating characteristic (ROC) curves. RESULTS: ROC curves demonstrate the highest overall test performance for OSR values at 2000 Hz off resonance in differentiating slightly (OSR-2000 [AUC: 0.930] > T2 * [AUC: 0.884] > T1 [AUC: 0.737]) and more severe pathologically altered tendon areas (OSR-2000 [AUC: 0.964] > T2 * [AUC: 0.917] > T1 [AUC: 0.819]) from healthy ones. CONCLUSION: OSR values at a frequency offset of 2000 Hz demonstrated a better sensitivity and specificity for detecting mild and severe stages of tendinopathy compared to T2 * and particularly when compared to T1 relaxation times. PMID- 24817379 TI - How does ankle-foot orthosis stiffness affect gait in patients with lower limb salvage? AB - BACKGROUND: Ankle-foot orthoses (AFOs) are commonly prescribed during rehabilitation after limb salvage. AFO stiffness is selected to help mitigate gait deficiencies. A new custom dynamic AFO, the Intrepid Dynamic Exoskeletal Orthosis (IDEO), is available to injured service members but prescription guidelines are limited. QUESTIONS/PURPOSES: In this study we ask (1) does dynamic AFO stiffness affect gait parameters such as joint angles, moments, and powers; and (2) can a given dynamic AFO stiffness normalize gait mechanics to noninjured control subjects? METHODS: Thirteen patients with lower limb salvage (ankle arthrodesis, neuropathy, foot/ankle reconstruction, etc) after major lower extremity trauma and 13 control subjects who had no lower extremity trauma and wore no orthosis underwent gait analysis at a standardized speed. Patients wore their custom IDEO with posterior struts of three different stiffnesses: nominal (clinically prescribed stiffness), compliant (20% less stiff), and stiff (20% stiffer). Joint angles, moments, powers, and ground reaction forces were compared across the varying stiffnesses of the orthoses tested and between the patient and control groups. RESULTS: An increase in AFO compliance resulted in 20% to 26% less knee flexion relative to the nominal (p = 0.003) and stiff (p = 0.001) conditions, respectively. Ankle range of motion and power generation were, on average, 56% (p < 0.001) and 63% (p < 0.001), respectively, less than controls as a result of the relatively fixed ankle position. CONCLUSIONS: Patients with limb salvage readily adapted to different dynamic AFO stiffnesses and demonstrated few biomechanical differences among conditions during walking. None of the stiffness conditions normalized gait to controls. CLINICAL RELEVANCE: The general lack of differences across a 40% range of strut stiffness suggests that orthotists do not need to invest large amounts of time identifying optimal device stiffness for patients who use dynamic AFOs for low-impact activities such as walking. However, choosing a stiffer strut may more readily translate to higher-impact activities and offer less chance of mechanical failure. PMID- 24817380 TI - What is the minimum clinically important difference in grip strength? AB - BACKGROUND: Grip strength reflects functional status of the upper extremity and has been used in many of the clinical studies regarding upper extremity disease or fracture. However, the smallest difference in grip strength that a patient would notice as an improvement resulting from treatment (defined as the minimum clinically important difference [MCID]), to our knowledge has not been determined. QUESTIONS/PURPOSES: We asked (1) how 1-year postsurgery grip strength compares with preinjury values; (2) if grip strength correlated with patient's ratings; (3) what the MCID is in the grip strength; and (4) if these values are equivalent to or greater than what can be explained by measurement errors in patients treated for distal radius fracture. METHODS: Fifty patients treated by volar locking plate fixation for a distal radius fracture constituted the study cohort. Grip strengths were measured 1 year after surgery on the injured and uninjured sides using a dynamometer. Grip strengths before injury were estimated using the grip strengths of the uninjured side with consideration of hand dominance. Patients were asked to rate their subjective level of grip strength weakness at 1 year postoperatively. Receiver operator characteristic curve analysis was used to determine MCIDs. Minimal detectable change in grip strength, which is a statistical estimate of the smallest change between two measurement points expected by measurement error or chance alone, also was determined using the formula 1.65 * ?2 * standard error of measurement. RESULTS: One year after surgery, grip strength (23 kg; 95% CI, 20-27) was less compared with calculated preinjury values (28 kg; 95% CI, 25-31; p < 0.001). Patients' rating of grip strength and measured grip strength changes correlated well (p = 0.56). MCIDs were 6.5 kg for grip strength and 19.5% for percentage grip strength. The MCID was not less than the minimum detectable change for grip strength (also 6.5 kg). CONCLUSIONS: The MCID of the grip strength was a decrease of 6.5 kg (19.5%). We believe the MCID of grip strength is useful for evaluating effectiveness of new treatments and for determining appropriate sample size in clinical trials of distal radius fractures. LEVEL OF EVIDENCE: Level III diagnostic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24817382 TI - Painful legs and moving toes syndrome: responsive to dopaminergic treatment. PMID- 24817381 TI - Human papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. AB - Knowledge about human papillomaviruses (HPV) types involved in anal cancers in some world regions is scanty. Here, we describe the HPV DNA prevalence and type distribution in a series of invasive anal cancers and anal intraepithelial neoplasias (AIN) grades 2/3 from 24 countries. We analyzed 43 AIN 2/3 cases and 496 anal cancers diagnosed from 1986 to 2011. After histopathological evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping was performed using SPF-10/DEIA/LiPA25 system (version 1). A subset of 116 cancers was further tested for p16(INK4a) expression, a cellular surrogate marker for HPV associated transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance in the anal cancer data set. HPV DNA was detected in 88.3% of anal cancers (95% confidence interval [CI]: 85.1-91.0%) and in 95.3% of AIN 2/3 (95% CI: 84.2-99.4%). Among cancers, the highest prevalence was observed in warty-basaloid subtype of squamous cell carcinomas, in younger patients and in North American geographical region. There were no statistically significant differences in prevalence by gender. HPV16 was the most frequent HPV type detected in both cancers (80.7%) and AIN 2/3 lesions (75.4%). HPV18 was the second most common type in invasive cancers (3.6%). p16(INK4a) overexpression was found in 95% of HPV DNA-positive anal cancers. In view of the results of HPV DNA and high proportion of p16(INK4a) overexpression, infection by HPV is most likely to be a necessary cause for anal cancers in both men and women. The large contribution of HPV16 reinforces the potential impact of HPV vaccines in the prevention of these lesions. PMID- 24817383 TI - Beneficial effects of serial contractions on muscle performance after a brief period of rest. AB - PURPOSE: The study investigated potential mechanisms underlying the beneficial effects of performing serial contractions for increasing muscle performance. METHODS: Thirteen men performed maximal isometric dorsiflexion contractions to a limited amount of fatigue. The recovery pattern was monitored over 15 min. Force, surface electromyography (sEMG) of the agonist and antagonist, and skin temperature were observed. Evoked potentials were elicited. RESULTS: Force decreased to 206 +/- 40 N and recovered to 243 +/- 55 N (102 % of initial value). While full recovery is noteworthy, it was not significant (p = 0.24). Surface EMG root-mean-square (RMS) amplitude did not fully recover: tibialis anterior (219 +/ 46 versus 242 +/- 63 MUV, 91 %) and soleus (13 +/- 5 versus 16 +/- 6 MUV, 82 %). The result was an 11 % decrease in the co-activation ratio during recovery. Tibialis anterior and soleus mean power frequency (MPF) "over-recovered" to 117 % (144 +/- 25 versus 124 +/- 27 Hz) and 118 % (80 +/- 14 versus 68 +/- 11 Hz) of initial value, respectively. Peak rate of force development (RFD) during recovery was 146 % of initial (743 +/- 246 versus 509 +/- 271 N). Skin temperature increased 0.6 degrees C over the test session. Potentiation was not present during recovery, as assessed by twitch force. CONCLUSIONS: The return of force to initial values, rather than a persistent decrement was a result of several mechanisms operating simultaneously. The sEMG data indicate an increase in conduction velocity, while an increase in peak RFD suggests contraction-induced facilitation of ATPase pump activity. However, alterations in muscle coordination were observed as a reduction in antagonist co-activity. PMID- 24817384 TI - Selective muscle contraction during plantarflexion is incompatible with maximal voluntary torque assessment. AB - OBJECTIVE: Large variations in maximal voluntary torque are reported in the literature during isometric plantarflexion contractions. We propose that these differences, which could reach 40 % across similar studies, could be explained by differences in the instructions provided, and notably by instructions as to favoring or not multi-joint contractions. METHOD: Sixteen participants were placed on an isokinetic ergometer in 3 different positions, supine, prone and seated, with the ankle in the neutral position, and instructed to create maximal force on the footplate by conforming to instructions that favored either isolated (ISOL) or multi-joint (ALL) isometric contractions. Torque, foot kinematics and the electromyographic activity of seven muscles of the lower limb have been recorded. RESULTS: Joint torques were greater in ALL compared to ISOL (p < 0.05) with gains of 43.5 (25.4-170.6) %, 42.5 (1.4-194.6) % and 15.3 (9.3-71.9) % in the supine, prone and seated position, respectively [values are given as median (range)]. The results of this study suggested that forces created by muscles that do not span over the ankle joint significantly influenced the measured joint torque. Nevertheless, the observed gains in torque were associated with greater plantarflexor muscles activation, showing that the ISOL condition may have induced a form of inhibition of these muscles. CONCLUSIONS: The results of this study suggest that using isolated contractions, hence constrained testing protocols, cannot provide optimal conditions for MVC testing, notably for plantarflexor muscles, which seem to be extremely sensitive to such constrained conditions. PMID- 24817385 TI - Antennal olfactory sensilla responses to insect chemical repellents in the common bed bug, Cimex lectularius. AB - Populations of the common bed bug Cimex lectularius (Hemiptera; Cimicidae), a temporary ectoparasite on both humans and animals, have surged in many developed countries. Similar to other haematophagous arthropods, C. lectularius relies on its olfactory system to detect semiochemicals in the environment, including both attractants and repellents. To elucidate the olfactory responses of the common bed bug to commonly used insect chemical repellents, particularly haematophagous repellents, we investigated the neuronal responses of individual olfactory sensilla in C. lectularius' antennae to 52 insect chemical repellents, both synthetic and botanic. Different types of sensilla displayed highly distinctive response profiles. While C sensilla did not respond to any of the insect chemical repellents, Dgamma sensilla proved to be the most sensitive in response to terpene-derived insect chemical repellents. Different chemical repellents elicited neuronal responses with differing temporal characteristics, and the responses of the olfactory sensilla to the insect chemical repellents were dose dependent, with an olfactory response to the terpene-derived chemical repellent, but not to the non-terpene-derived chemical repellents. Overall, this study furnishes a comprehensive map of the olfactory response of bed bugs to commonly used insect chemical repellents, providing useful information for those developing new agents (attractants or repellents) for bed bug control. PMID- 24817386 TI - N-(18-hydroxylinolenoyl)-L-glutamine: a newly discovered analog of volicitin in Manduca sexta and its elicitor activity in plants. AB - Plants attacked by insect herbivores release a blend of volatile organic compounds (VOCs) that serve as chemical cues for host location by parasitic wasps, natural enemies of the herbivores. Volicitin, N-(17-hydroxylinolenoyl)-L glutamine, is one of the most active VOC elicitors found in herbivore regurgitants. Our previous study revealed that hydroxylation on the 17th position of the linolenic acid moiety of N-linolenoyl-L-glutamine increases by more than three times the elicitor activity in corn plants. Here, we identified N-(18 hydroxylinolenoyl)-L-glutamine (18OH-volicitin) from larval gut contents of tobacco hornworm (THW), Manduca sexta. Eggplant and tobacco, two solanaceous host plants of THW larvae, and corn, a non-host plant, responded differently to this new elicitor. Eggplant and tobacco seedlings emitted twice the amount of VOCs when 18OH-volicitin was applied to damaged leaf surfaces compared to N-linolenoyl L-glutamine, while both these fatty acid amino acid conjugates (FACs) elicited a similar response in corn seedlings. In both solanaceous plants, there was no significant difference in the elicitor activity of 17OH- and 18OH-volicitin. Interestingly, other lepidopteran species that have 17OH-type volicitin also attack solanaceous plants. These data suggest that plants have developed herbivory-detection systems customized to their herbivorous enemies. PMID- 24817387 TI - Cognitive and other predictors of change in quality of life one year after treatment for chronic myelogenous leukemia or myelodysplastic syndrome. AB - The role of cognitive function in quality of life is important among the growing numbers of survivors after cancer treatment. The authors conducted a prospective cohort study of 106 adults evaluated 5.6 months (median) after diagnosis and 77 of 83 (93%) survivors 12 months later with neuropsychological assessments yielding information about simple reaction time to stimuli and other aspects of cognitive function and with two quality of life measures. The two most consistent predictors of change in quality of life were baseline quality of life ratings and simple reaction time. This novel finding about simple reaction time warrants further confirmation. PMID- 24817388 TI - Bone marrow stromal cells as a therapeutic treatment for ischemic stroke. AB - Cerebral ischemia remains the most frequent cause of death and quality-of-life impairments due to neurological deficits, and accounts for the majority of total healthcare costs. However, treatments for cerebral ischemia are limited. Over the last decade, bone marrow stromal cell (BMSC) therapy has emerged as a particularly appealing option, as it is possible to help patients even when initiated days or even weeks after the ischemic insult. BMSCs are a class of multipotent, self-renewing cells that give rise to differentiated progeny when implanted into appropriate tissues. Therapeutic effects of BMSC treatment for ischemic stroke, including sensory and motor recovery, have been reported in pre clinical studies and clinical trials. In this article, we review the recent progress in BMSC-based therapy for ischemic stroke, focusing on the route of delivery and pre-processing of BMSCs. Selecting an optimal delivery route is of particular importance. The ideal approach, as well as the least risky, for translational applications still requires further identification. Appropriate preprocessing of BMSCs or combination therapy has the benefit of achieving the maximum possible restoration. Further pre-clinical studies are required to determine the time-window for transplantation and the appropriate dosage of cells. PMID- 24817390 TI - Oxidizing elemental platinum with oleum under harsh conditions: the unique tris(disulfato)platinate(IV) [Pt(S2O7)3]2- anion. AB - For the first time, direct oxidation of elemental platinum by a mineral acid to its tetravalent state was observed in course of the reaction of platinum with oleum (65 % SO3) in the presence of barium carbonate. The reaction has been carried out in torch-sealed glass ampoules at 160 degrees C and gave yellow single crystals of Ba[Pt(S2O7)3](H2SO4)0.5(H2S O7)0.5 (triclinic, P1, Z=2, a=992.05(2), b=1069.07(3), c=1114.22(3) pm, alpha=69.49(7), beta=72.96(2), gamma=72.93(1) degrees , V=1033.95(5) A(3)). The structure of Ba[Pt(S2O7)3](H2SO4)0.5(H2S2O7)0.5 exhibits the unique tris-(disulfato)-platinate anion [Pt(S2O7)3](2-) with three chelating disulfate groups coordinated to the platinum atom. Charge balance is achieved by the Ba(2+) ions, which are coordinated by (S2O7)(2-) groups from the platinate complex and by disordered sulfuric acids and disulfuric acid molecules. Thermal decomposition of the bulk material revealed elemental platinum and barium sulfate as decomposition residual. PMID- 24817389 TI - Current status of cell-mediated regenerative therapies for human spinal cord injury. AB - During the past decade, significant advances have been made in refinements for regenerative therapies following human spinal cord injury (SCI). Positive results have been achieved with different types of cells in various clinical studies of SCI. In this review, we summarize recently-completed clinical trials using cell mediated regenerative therapies for human SCI, together with ongoing trials using neural stem cells. Specifically, clinical studies published in Chinese journals are included. These studies show that current transplantation therapies are relatively safe, and have provided varying degrees of neurological recovery. However, many obstacles exist, hindering the introduction of a specific clinical therapy, including complications and their causes, selection of the target population, and optimization of transplantation material. Despite these and other challenges, with the collaboration of research groups and strong support from various organizations, cell-mediated regenerative therapies will open new perspectives for SCI treatment. PMID- 24817391 TI - Size-controlled synthesis of hierarchical nanoporous iron based fluorides and their high performances in rechargeable lithium ion batteries. AB - High performance nanostructured iron fluorides with controllable sizes were successfully synthesized using oleylamine as a size tuning agent for the first time. They exhibited excellent cathode performances with large retensive capacities exceeding 200 mA h g(-1) after 50 cycles and outstanding rate performances of nearly 100 mA h g(-1) even at 10 C. PMID- 24817392 TI - Metal ion release: also a concern for ceramic-on-ceramic couplings? AB - BIOLOX delta is the newest ceramic composite material of the BIOLOX family and its use in hip devices represents a good alternative to Metal-on-Metal or Metal on-Polyethylene coupling. Some Metal-on-Metal hip devices have shown chromium and cobalt release, which promoted toxic effects. Furthermore, the ceramic composite contains trivalent chromium, even if strongly bound to the alumina lattice. The present study is aimed at detecting any 'in vivo' release of chromium ions from BIOLOX delta bearings in the blood, erythrocytes and urine of patients. Twenty patients implanted with total hip arthroplasty (THA) with BIOLOX delta-BIOLOX delta couplings and 21 subjects with no implanted prostheses were studied. Inductively coupled plasma mass spectrometry equipped with dynamic reaction cell was used for analysis. In the THA group the Cr ions values were; in blood mean 0.21 ug/l (+/-0.09), in serum 0.21 ug/l (+/-0.12), in normalized erythrocytes 0.13 ug/l (+/-0.09), in normalized urine 0.12 ug/g creatinine (+/-0.13). In the control group the Cr ions values were; in blood mean 0.22 ug/l (st dev 0.14), in serum 0.17 ug/l (+/-0.08), in normalized erythrocytes 0.13 ug/l (+/-0.11), in normalized urine 0.07 ug/g creatinine (+/-0.08). The Lab reference values were 0.1-5.0 ug/l for blood, 0.1-0.5 ug/l for serum, 0.14-4.58 ug/l for normalised erythrocytes and 0.05-2.2 ug/l for urine. All samples in both groups resulted in chromium levels within the normal reference range and the safety of BIOLOX delta ceramics, in terms of chromium ions release, has been demonstrated. PMID- 24817393 TI - Factors affecting squeaking in metal on metal hip resurfacings. AB - We reviewed 380 hip resurfacings cases between December 1999 and Dec 2012. 11 cases (2.89%) squeaked postoperatively. Mean follow-up was 88.6 months (19-130 months). Mean time to squeak was 11.3 months (3-22 months). Ten (91%) cases were male and nine (81%) cases had a Birmingham hip resurfacing. Cases were matched for age, gender, BMI and implant to three controls. Radiographs were analysed using EBRA (Einzel-Bild-Roentgen-Analysis, University of Innsbruck, Austria) software to evaluate cup orientation. There was no significant difference between the mean inclination angle of the cups (p = 0.26) or the mean anteversion angle (p = 0.29). There was no difference in serum cobalt (p = 0.20) or serum chromium (p = 0.45) levels at latest follow-up. Three of the 11 (27.3%) cases had revision surgery at a mean follow-up of 101 months (72-117 months). Squeaking was not influenced by patient demographic parameters and resolved in all cases that did not undergo revision surgery. Males with a resurfacing head size <50 mm had significantly increased odds of squeaking when compared to controls (odds ratio = 26.6; 95% CI = 1.2-573.3; p<0.05). Based on our findings, we do not recommend that squeaking on its own should be an indication for revision of hip resurfacing components. PMID- 24817394 TI - Primary total hip arthroplasty (THA) in patients with incomplete hip abductor tears: does hip abductor repair improve outcome? AB - INTRODUCTION: Incomplete tears of the hip abductor insertion can coexist with primary hip osteoarthritis. The aim of this investigation was to test the hypotheses that: (1) the outcome of patients undergoing primary THA using a direct anterior approach would be inferior when hip abductor pathology was present; and (2) in the presence of incomplete tears, the transgluteal approach with hip abductor repair delivers a superior outcome compared to the direct anterior approach. PATIENTS AND METHODS: Forty patients underwent MR imaging of the hip abductor insertion prior to THA. The grade of abductor tears was assessed, the approach used for THA was recorded, and pre- and postoperative one year outcome scores (WOMAC, HHS) were recorded. RESULTS: Twenty patients showed a normal appearance of the hip abductor insertion and THA was performed using the direct anterior approach (group 1). In 20 patients partial tears of the hip abductor insertion were recognized. Eight of them had THA through a direct anterior approach (group 2) and twelve through a transgluteal approach with repair (group 3).All patients improved after surgery. Overall the WOMAC improved from 6.1 to 2.1 points and the HHS from 46 to 87 points. A significantly higher benefit in terms of the HHS was achieved in patients of group 1 (p = 0.045). No significant differences were recorded between group 2 and group 3. CONCLUSIONS: Improvement in outcome scores after THA using the direct anterior approach was inferior in the presence of partial hip abductor tears. The repair of partial hip abductor tears was not associated with superior clinical results. PMID- 24817395 TI - Patient satisfaction and clinical results at a mean eight years following BHR arthroplasty: results from a district general hospital. AB - We present the clinical and radiological results of a prospective study of a consecutive series of patients treated with the Birmingham Hip Resurfacing (BHR) prosthesis between 1999 and 2006 and followed for six to 12 years. Patients were reviewed preoperatively and six, 12, 26 and 52 weeks postoperatively and annually thereafter. They were assessed clinically and radiographically and the Merle d'Aubigne Postel and Oxford Hip scores were calculated at each visit. A SF-36 form assessed general health. Patient satisfaction was assessed by a Visual Analogue Score. Kaplan Meier survival analysis was performed.One hundred and seven patients (109 hips) were included (45 males, 62 females). Median age was 44 years. Mean follow-up was 97.4 months. Median preoperative Merle d'Aubigne Postel and Oxford hip scores were 10 (3-14) and 42 (26-55) respectively. Median SF36 score was 29 (0-65) and patients rated their level of pain as 7.7 on a scale of 0 10 (10 being the worst score). At final follow-up, median MDP and OHS scores were 17 (16-18) and 25 (12-46). Median SF36 score was 72 (27-97). Seven revisions were performed in six females and one male patient. Survival was 96.2% with revision for any reason as the end point. No revisions were performed in the group with hip dysplasia.The BHR prosthesis provides pain relief, high levels of patient satisfaction and improvement of function and well being in the medium-term. Failures occurred primarily in the female group. PMID- 24817396 TI - The case for ceramic-on-polyethylene as the preferred bearing for a young adult hip replacement. AB - The optimum choice of bearing surfaces in total hip arthroplasty, particularly in the younger and more active patient, remains controversial. Despite several studies demonstrating good long-term results for the metal-on-polyethylene articulation, there has been a recent vogue towards the utilisation of hard-on hard bearings for younger patients due, in part, to concerns regarding polyethylene induced osteolysis. However, well-documented complications concerning metal-on-metal bearings and the risk of fracture in ceramic-on-ceramic bearings have raised concerns regarding the principle of the hard-on-hard bearing in the active patient. With recent technological advancements in the manufacture of both polyethylene and alumina ceramics, the in vitro properties of each material with regards to strength and toughness have been significantly improved. In addition, ceramic femoral heads have consistently been shown to produce less in vivo polyethylene wear than similar sized metal heads. This paper aims to critically review the biomechanical, in vivo and clinical studies related to the use of the ceramic on polyethylene bearing, and highlights its potential use as the preferred bearing for a young adult hip replacement. PMID- 24817397 TI - Clinical and radiological outcome after periacetabular osteotomy: a cross sectional study of 127 hips operated on from 1999-2008. AB - PURPOSE: Few papers have described results after periacetabular osteotomy (PAO) and risk factors for conversion to total hip arthroplasty (THA). The aim of the present paper was to analyse clinical and radiographic outcome, survival of the hip joint and risk factors of early conversion to THA in patients with PAO. BASIC PROCEDURES: In the period 1999-2008, 93 patients (127 hips, median patient age 31, range 13-49 years) were operated on with PAO. Median follow-up was 7 (SD 2.1) years. Analyses of clinical and radiographic examinations, including WOMAC, were performed. Osteoarthritis was measured using Tonnis grade. Survival was assessed by the Kaplan-Meier method and predictors of conversion to THA were calculated using Cox regression analysis with THA as defined endpoint. MAIN FINDINGS: Centre edge angle improved significantly with a mean of 8.7 (95% CI: 7.1; 10.3) preoperatively to a mean of 24.6 (95% CI: 22.6; 26.6) at follow-up. Likewise the acetabular roof obliquity angle improved significantly with a mean of 21.2 (95% CI: 19.7; 22.6) preoperatively to 8.7 (95% CI: 7.1; 10.4) at follow-up. Eleven out of 127 hips had conversion to THA. The 11.7 years cumulated hip joint survival rate was 85% (95% CI: 0.753; 0.945). Significant predictors of converting to THA were preoperative high grade of OA and postoperative high degree of acetabular roof obliquity angle. An improvement was found in Harris Hip Score pain score after receiving a PAO (p = 0.01). CONCLUSIONS: Our results, with almost 12 years survival data, are comparable with the literature. PAO is considered as an effective treatment for young adults with painful hip dysplasia, especially when preoperative criteria for conversion to THA are highlighted. PMID- 24817398 TI - A new technique for closed reduction of traumatic posterior dislocations of the hip: the 'PGI technique'. AB - Many techniques have been described for closed reduction of posterior hip dislocations, but most require forceful and sustained traction, assistants to stabilise the pelvis and awkward positioning of the surgeon and/or the patient. We describe a new technique of closed reduction that does not need traction countertraction or special positioning and can be safely and effectively performed by one surgeon.Fifteen patients, mean age 36.4 years, were subjected to reduction. There were five type I, four type II and six type III dislocations; ipsilateral injuries included one knee dislocation with patellar fracture, and two cases of tibia fracture. Closed reduction was achieved in 14 (93.3%) hips, with single attempt successful in 13 cases, while one needed two attempts. One hip could not be reduced due to incarceration of a posterior wall fragment and was managed by open reduction and internal fixation.Our new technique has proved to be a reliable, safe and effective alternative for closed reduction of posterior hip dislocations. It can be carried out by one surgeon, does not need traction and can be especially beneficial in polytrauma patients and also in those patients who have pelvic fractures and ipsilateral lower limb injuries. PMID- 24817399 TI - Hip muscle strength recovery after hip arthroscopy in a series of patients with symptomatic femoroacetabular impingement. AB - PURPOSE: The aim of the study was to prospectively evaluate hip muscle strength in a series of patients with symptomatic FAI after hip arthroscopy. METHODS: Hip muscle strength of eight patients (age: 29 +/- 10 years) was evaluated preoperatively and 2.5 years after hip arthroscopy, and was compared to eight matched controls. Maximal voluntary contraction (MVC) strength was measured for all hip muscle groups. At follow-up, we used the symptom-specific well-being outcome to assess the acceptability of the health state related to the hip. RESULTS: Patients showed MVC strength increases for all hip muscles (9-59%, P<.05). At follow-up, only hip flexor MVC strength was lower for patients than controls (-18%, P<.05). At follow-up, four patients (out of eight) were "neither satisfied nor dissatisfied" with the health state of their operated hip. CONCLUSIONS: Patients with symptomatic FAI recovered their hip muscle strength to normal levels 2.5 years after hip arthroscopy, except for hip flexors. Although all patients showed good hip muscle strength at follow-up, half of them were not completely satisfied with their health state related to the hip. PMID- 24817400 TI - Acetabular component orientation in total hip arthroplasty: the impact of obesity. AB - INTRODUCTION: Acetabular component position can be an important determinant of joint stability and bearing surface wear after THA. Nonetheless, the incidence of malpositioning is high. Patient obesity, low surgeon volume, and minimally invasive approaches are known risk factors for malposition. As the incidence of obesity continues to increase, it is important to recognise its effect on intraoperative component positioning in THA. OBJECTIVES: Our goal was to assess the impact of obesity on component position for a high-volume surgeon using a standard postero-lateral approach. METHODS: A consecutive series of 120 obese (BMI >30, mean BMI 34.4) and 120 non-obese patients (mean BMI 25.4), who had undergone primary THA by a single surgeon, were included in our retrospective study. AP pelvis and cross-table radiographs obtained at the first postoperative visit were analysed using EBRA software to determine inclination and anteversion angles. Optimal position was defined as 30-45o of inclination and 5-25o of anteversion. RESULTS: Mean inclination and anteversion were 40.6 (+/-5.4o) and 16.6 (+/-5.5o) respectively, in the obese group and 39o (+/-5.0o) and 16.2o (+/ 7.5o) in the non-obese group. In the obese group 89 (74%) patients were within the desired range for both measurements, 31 (26%) were out of range in at least one, compared to 91 (76%) and 29 (24%) in the non-obese group, respectively. The overall incidence of malpositioning was 25% for both groups. Among outliers, mean deviation from the optimal range was <=3.8o in both groups. CONCLUSIONS: The risk of component malpositioning in THA may be reduced when surgery is performed by an experienced, high volume surgeon utilising a standard posterolateral approach. In this setting the deleterious effect of obesity may be overcome. PMID- 24817401 TI - A two-year radiostereometric follow-up of the first generation Birmingham mid head resection arthroplasty. AB - During the first decade of the 21st century, metal-on-metal hip resurfacing became one of the main treatment options for younger, more active patients with osteoarthritis. However, as a result of the reported failure rate of both total hip replacement (THR) and resurfacing in patients with considerable loss of bone stock in the femoral head (e.g., in extensive avascular necrosis), other solutions have been sought for these patients. The short-stemmed Birmingham Mid Head Resection prosthesis (BMHR) combines a metal-on-metal articulation and a femoral neck preserving feature. In this study, radiostereometric analysis (RSA) was used to study migration of the BMHR femoral component in 13 hips. Translations and rotations were measured up to two years. Relative values showed no statistically significant migration. Absolute values demonstrated settling in occurring between zero and two months postoperatively in all directions studied. From two months to two years no significant migration occurred except for rotation around the x-axis of the femoral segment (p = 0.049). After initial settling-in, absolute values were low, indicating that there was no evidence of early migration or loosening of the components. PMID- 24817402 TI - Osteochondral lesion of the hip treated with partial femoral head resurfacing. Case report and six-year follow-up. AB - INTRODUCTION: This case describes a case of an osteochondral lesion in the femoral head and its treatment by partial resurfacing of the femoral head using the HemiCAP (Contoured Articular Prosthetic) hip resurfacing system. CASE HISTORY: A 19-year-old patient who complained of 15 months of worsening left hip pain. X-rays and MR scan revealed a large osteochondral lesion. SURGERY: A Ganz approach to the hip in the lateral position was used. The osteochondral lesion was identified, lying superiorly and centrally on the head, in the weight bearing zone. The osteochondral fragment was removed and HemiCAP prosthesis applied. OUTCOME: At six-year follow-up the patient remains pain free clinically. And radiographic follow-up shows no evidence of loosening. CONCLUSION: There are multiple methods of treatment described in the literature for osteochondral lesions; but treatments for defects of the femoral head are few. We conclude that partial hip resurfacing using the HemiCAP prosthesis is an effective treatment for osteochondral defects of the femoral head. PMID- 24817403 TI - The number of scholarly documents on the public web. AB - The number of scholarly documents available on the web is estimated using capture/recapture methods by studying the coverage of two major academic search engines: Google Scholar and Microsoft Academic Search. Our estimates show that at least 114 million English-language scholarly documents are accessible on the web, of which Google Scholar has nearly 100 million. Of these, we estimate that at least 27 million (24%) are freely available since they do not require a subscription or payment of any kind. In addition, at a finer scale, we also estimate the number of scholarly documents on the web for fifteen fields: Agricultural Science, Arts and Humanities, Biology, Chemistry, Computer Science, Economics and Business, Engineering, Environmental Sciences, Geosciences, Material Science, Mathematics, Medicine, Physics, Social Sciences, and Multidisciplinary, as defined by Microsoft Academic Search. In addition, we show that among these fields the percentage of documents defined as freely available varies significantly, i.e., from 12 to 50%. PMID- 24817404 TI - Hand bacterial communities vary across two different human populations. AB - This study utilized pyrosequencing-based phylogenetic library results to assess bacterial communities on the hands of women in Tanzania and compared these communities with bacteria assemblages on the hands of US women. Bacterial population profiles and phylogenetically based ordinate analysis demonstrated that the bacterial communities on hands were more similar for selected populations within a country than between the two countries considered. Organisms that have commonly been identified in prior human skin microbiome studies, including members of the Propionibacteriaceae, Staphylococcaceae and Streptococceacea families, were highly abundant on US hands and drove the clustering of US hand microbial communities into a distinct group. The most abundant bacterial taxa on Tanzanian hands were the soil-associated Rhodobacteraceae and Nocardioidaceae. These results help to expand human microbiome results beyond US and European populations, and the identification and abundance of soil-associated bacteria on Tanzanian hands demonstrated the important role of the environment in shaping the microbial communities on human hands. PMID- 24817405 TI - Initiated chemical vapor deposition and light-responsive cross-linking of poly(vinyl cinnamate) thin films. AB - The first vapor-phase deposition of poly(vinyl cinnamate) (PVCin) is reported. Initiated chemical vapor deposition (iCVD) is used to synthesize PVCin thin films with an average thickness of 100 nm. Free radical polymerization and cyclization reactions compete during the deposition process, with approximately 45% of the repeat units undergoing cyclization. Exposure to UV light (lambda = 254 nm) induces dimerization (cross-linking) of the PVCin, which is quantified using spectroscopic techniques. Approximately 90% of the free cinnamate moieties are dimerized at a UV dose of 300 mJ cm(-2) . PVCin is also incorporated into a copolymer with N-isopropylacrylamide, which exhibits a characteristic change in hydrophilicity with temperature. The copolymer is selectively cross-linked through a mask, and reversible swelling of patterns with 30 MUm resolution is demonstrated by submerging the film in water. PMID- 24817406 TI - Cyclobutadiene automerization and rotation of ethylene: energetics of the barriers by using spin-polarized wave functions. AB - Spin-projected spin polarized Moller-Plesset and spin polarized coupled clusters calculations have been made to estimate the cyclobutadiene automerization, the ethylene torsion barriers in their ground state, and the gap between the singlet and triplet states of ethylene. The results have been obtained optimizing the geometries at MP4 and/or CCSD levels, by an extensive Gaussian basis set. A comparative analysis with more complex calculations, up to MP5 and CCSDTQP, together with others from the literature, have also been made, showing the efficacy of using spin-polarized wave functions as a reference wave function for Moller-Plesset and coupled clusters calculations, in such problems. PMID- 24817407 TI - Benchmarking of trauma care worldwide: the potential value of an International Trauma Data Bank (ITDB). AB - BACKGROUND: National trauma registries have helped improve patient outcomes across the world. Recently, the idea of an International Trauma Data Bank (ITDB) has been suggested to establish global comparative assessments of trauma outcomes. The objective of this study was to determine whether global trauma data could be combined to perform international outcomes benchmarking. METHODS: We used observed/expected (O/E) mortality ratios to compare two trauma centers [European high-income country (HIC) and Asian lower-middle income country (LMIC)] with centers in the North American National Trauma Data Bank (NTDB). Patients (>=16 years) with blunt/penetrating injuries were included. Multivariable logistic regression, adjusting for known predictors of trauma mortality, was performed. Estimates were used to predict the expected deaths at each center and to calculate O/E mortality ratios for benchmarking. RESULTS: A total of 375,433 patients from 301 centers were included from the NTDB (2002-2010). The LMIC trauma center had 806 patients (2002-2010), whereas the HIC reported 1,003 patients (2002-2004). The most important known predictors of trauma mortality were adequately recorded in all datasets. Mortality benchmarking revealed that the HIC center performed similarly to the NTDB centers [O/E = 1.11 (95% confidence interval (CI) 0.92-1.35)], whereas the LMIC center showed significantly worse survival [O/E = 1.52 (1.23-1.88)]. Subset analyses of patients with blunt or penetrating injury showed similar results. CONCLUSIONS: Using only a few key covariates, aggregated global trauma data can be used to adequately perform international trauma center benchmarking. The creation of the ITDB is feasible and recommended as it may be a pivotal step towards improving global trauma outcomes. PMID- 24817408 TI - Pyruvate kinase M2 regulates apoptosis of intestinal epithelial cells in Crohn's disease. AB - BACKGROUND: Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, is involved in multiple cellular processes including apoptosis. Recently increased fecal PKM2 has been found in Crohn's disease (CD), but little is known regarding its function in the pathophysiology of the disease. AIM: The intestinal expression of PKM2 and its involvement in CD was investigated. METHODS: Pyruvate kinase M2 expression in mucosal biopsies from patients with CD and normal controls was detected by immunohistochemistry. A murine model of colitis induced by trinitrobenzenesulphonic acid (TNBS) was established and expression of PKM2, B cell lymphoma-extra large (Bcl-xl), active caspase-3 as well as cleaved poly (ADP ribose) polymerase (PARP) was examined for association of PKM2 with intestinal epithelial cell (IEC) apoptosis. Furthermore, we treated human IEC line HT-29 by tumor necrosis factor-alpha (TNF-alpha) and used RNA interference to analyze the role of PKM2 in IEC apoptosis. RESULTS: Intestinal expression of PKM2 was higher in patients with CD compared with normal controls mainly locating in IECs. In TNBS-induced colitis, up-regulation of PKM2 was accompanied by the elevated expression of Bcl-xl, active caspase-3, and cleaved PARP. PKM2 was co-localized with active caspase-3 in IECs marked by E-cadherin, suggesting its role in IEC apoptosis. Expression of PKM2 and Bcl-xl in TNF-alpha-induced HT-29 cells was increased, while TNF-alpha had no effect on cellular localization of PKM2. Furthermore, knockdown of PKM2 by siRNA could inhibit expression of Bcl-xl but enhance apoptosis in TNF-alpha-treated HT-29 cells. CONCLUSION: The up-regulation of PKM2 might protect IECs against apoptosis possibly through Bcl-xl in CD, indicating its important role in the pathophysiology of CD. PMID- 24817409 TI - Cholecystokinin mediates progression and metastasis of pancreatic cancer associated with dietary fat. AB - BACKGROUND: Obesity and dietary fat are associated with increased risk of several malignancies including pancreatic cancer. The incidence of pancreatic cancer is increased in countries that consume diets high in fat. AIM: The purpose of this study was to assess the relationship and mechanism of action between dietary fat and endogenous cholecystokinin (CCK) on pancreatic tumor growth and metastasis in an immunocompetent animal model. METHODS: C57BL/6 mice were placed on regular, low-fat, or high-fat diets for 8 weeks before establishment of Panc-02 orthotopic pancreatic tumors. Mice were then treated with a CCK-A receptor antagonist, devazepide, or vehicle for an additional 2.5 weeks. Pancreas tumors were weighed and metastases counted. Blood CCK levels were measured by radioimmunoassay (RIA). Tissues were examined histologically and studied for genes associated with metastasis by RT-PCR array. Effects of the CCK antagonist on Panc-02 cells invasiveness was assessed in a Matrigel invasion assay. RESULTS: Mice that received the high-fat diet had larger tumors and tenfold higher serum CCK levels by RIA compared to normal diet controls (p < 0.01). Pancreatic tumors in high-fat diet mice treated with the antagonist had fewer intravascular tumor emboli and metastases compared to controls. The reduction in tumor emboli correlated with decreased vascular endothelial growth factor-A (VEGF-A) expression in tumors (p < 6 * 10(-9)). In vitro invasiveness of Panc-02 cells also was reduced by CCK-A receptor antagonist treatment (p = 1.33 * 10(-6)). CONCLUSION: CCK is a mediator of dietary fat-associated pancreatic cancer. CCK is also involved in the invasiveness of pancreatic tumors through a mechanism involving VEGF-A. PMID- 24817410 TI - Painful micturition in a small child: an unusual clinical picture of paroxysmal extreme pain disorder. AB - BACKGROUND: Paroxysmal extreme pain disorder (PEPD) is a rare autosomal dominant pain disorder linked to a mutation in the SCN9A gene, which encodes voltage-gated sodium channel Nav1.7. Abnormal pain sensitivity occurs because of changes in the properties of voltage-gated sodium channels. Different mutations in SCN9A and a spectrum of clinical expressions have been described. CASE-DIAGNOSIS/TREATMENT: Here we describe a 3-year-old child with a rare clinical picture of PEPD. Extremely painful voiding had been present since the child's birth. The diagnosis was confirmed by the detection of a heterozygous pathogenic mutation in the SCN9A gene, c.554G>A (p.Arg185His) inherited paternally. The same mutation was also found in the girl's father, who has occasionally had some pain in his jaw while yawning since childhood. Significant reduction of the pain was achieved with carbamazepine. CONCLUSIONS: The case is interesting because the same mutation as that found in the girl and her father has been found in patients with small fiber sensory neuropathy. These data do not correlate with the clinical picture of our case and her father, but intra- and interfamily phenotypic diversity in symptoms associated with a gain-of-function variant of Na(V)1.7 are also described and may explain our case. PMID- 24817411 TI - Phase behavior and microstructures in a mixture of anionic Gemini and cationic surfactants. AB - We report in this work the phase behavior and microstructures in a mixture of an anionic Gemini surfactant, sodium dilauramino cystine (SDLC), and a conventional cationic surfactant, dodecyl trimethyl ammonium chloride (DTAC). Observation of the appearance shows that the phase behavior of the SDLC-DTAC mixed cationic surfactant system transforms from an isotropic homogeneous phase to an aqueous surfactant two-phase system (ASTP) and then to an anisotropic homogeneous phase with the continuous addition of DTAC. The corresponding aggregate microstructures are investigated by rheology, dynamic light scattering, transmission electron microscopy and polarization microscopy. It has been found that a wormlike micelle, in the isotropic homogeneous phase, occurs linear to the branch growth. The aggregate microstructures in the ASTP lower and upper phases are branched wormlike micelles and vesicles, respectively. The micelle transformed into a vesicle upon varying the phase volume percentage until a lamellar liquid crystal formed in the anisotropic homogeneous phase. The macroscopic phase behavior and microscopic aggregate structure are related to the understanding of the possible mechanisms for the above phenomena. PMID- 24817412 TI - Changes in floral bouquets from compound-specific responses to increasing temperatures. AB - We addressed the potential effects of changes in ambient temperature on the profiles of volatile emissions from flowers and tested whether warming could induce significant quantitative and qualitative changes in floral emissions, which would potentially interfere with plant-pollinator chemical communication. We measured the temperature responses of floral emissions of various common species of Mediterranean plants using dynamic headspace sampling and used GC-MS to identify and quantify the emitted terpenes. Floral emissions increased with temperature to an optimum and thereafter decreased. The responses to temperature modeled here predicted increases in the rates of floral terpene emission of 0.03 1.4-fold, depending on the species, in response to an increase of 1 degrees C in the mean global ambient temperature. Under the warmest projections that predict a maximum increase of 5 degrees C in the mean temperature of Mediterranean climates in the Northern Hemisphere by the end of the century, our models predicted increases in the rates of floral terpene emissions of 0.34-9.1-fold, depending on the species. The species with the lowest emission rates had the highest relative increases in floral terpene emissions with temperature increases of 1-5 degrees C. The response of floral emissions to temperature differed among species and among different compounds within the species. Warming not only increased the rates of total emissions, but also changed the ratios among compounds that constituted the floral scents, i.e. increased the signal for pollinators, but also importantly altered the signal fidelity and probability of identification by pollinators, especially for specialists with a strong reliance on species-specific floral blends. PMID- 24817413 TI - Drug interactions and protease inhibitors used in the treatment of hepatitis C: how to manage? AB - PURPOSE: The first-generation protease inhibitors (PI) boceprevir and telaprevir combined with pegylated interferon have revolutionized the treatment of type-1 hepatitis C by increasing the rates of sustained virologic response. However, they induce drug interactions, and their clinical relevance is difficult to predict. This review compiles available data on drug-drug interactions (DDI) based on their pharmacokinetic and pharmacodynamic properties with the aim of assisting clinicians in managing DDI METHODS: PubMed, drug interaction databases and hepatology and infectious disease conference abstracts were systematically searched using the key search terms "interaction", "hepatitis C", "telaprevir" and "boceprevir". All known interactions were compiled and reclassified according to their pharmacokinetic and pharmacodynamic mechanisms. The state of knowledge of interaction mechanisms are reported and a therapeutic approach is proposed. RESULTS: Boceprevir and telaprevir are both substrates and potent inhibitors of cytochrome P450 3A4 and the drug transporter P-glycoprotein. They induce overdosage but can sometimes decrease the effect of other drugs by inducing other cytochromes. Overdosage or low dosage mainly affects drugs with a narrow therapeutic range, such as immunosuppressants or antiretrovirals. The distribution and elimination of PI are unaffected by interactions. In terms of pharmacodynamic interactions, PI can trigger drug-induced QT interval prolongation, which means that clinicians should manage such risk factors as potassium/magnesium levels or avoid other QT-prolonging drugs. CONCLUSIONS: Management of hepatitis C therapy is complex. The key to interpreting DDI data is a solid understanding of the pharmacokinetic and pharmacodynamic profiles of the drugs involved. Their ability to inhibit cytochrome P450 3A4 and prolong the QT interval can have significant clinical consequences. This review provides a practical guide to the safe and effective management of therapy with boceprevir and telaprevir. PMID- 24817414 TI - Homocysteine induces procoagulant activity of red blood cells via phosphatidylserine exposure and microparticles generation. AB - Increased homocysteine (Hcy) levels in plasma correlate with the risk of thromboic events. Red blood cells (RBCs), the most abundant blood cells in circulation, also play an active role in the process of thrombus formation. However, the effect of Hcy on procoagulant activity (PCA) of RBCs is unclear. In the present study, RBCs from healthy adults were treated with Hcy (8, 20, 80, 200, 800 MUmol/L) for 24 h. Phosphatidylserine (PS) exposure of RBCs and red blood cell-derived microparticles (RMPs) release were detected using Alexa Fluor 488-lactadherin. PCA was assessed by coagulation time and purified clotting complexes testes. We found that Hcy treatment dose dependently enhanced PS exposure and consequent PCA of RBCs. Hcy also elevated the formation of procoagulant RMPs, with statistical significance at 800 MUmol/L of Hcy. Moreover, 128 nmol/L lactadherin inhibited about 90% PCA of RBCs and RMPs. Our data suggest that PS exposure and RMPs shedding are key sources for Hcy-induced PCA of RBCs. Lactadherin could be used to modulate the anticoagulant and procoagulant balance in this process. PMID- 24817415 TI - Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. AB - OBJECTIVES: Immunological events in the lungs might trigger production of anti citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA. PATIENTS AND METHODS: Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA. RESULTS: Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA. CONCLUSIONS: Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link. PMID- 24817416 TI - Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. AB - OBJECTIVES: We examined the utility of circulating total and IgG4+ plasmablasts as biomarkers of diagnosis and disease activity in IgG4-related disease (IgG4 RD). MATERIALS METHODS: We evaluated patients with active, untreated, biopsy proven IgG4-RD affecting various organs. Flow cytometry was used to measure total plasmablast and IgG4+ plasmablast counts by gating peripheral blood for CD19lowCD38+CD20-CD27+ cells and CD19lowCD38+CD20-CD27+IgG4+ cells. Serum IgG4 concentrations were measured by nephelometry. We compared 37 IgG4-RD patients to 35 controls, including healthy individuals (n=14) and patients with other inflammatory diseases before treatment (n=21). RESULTS: The IgG4-RD patients' mean age was 59, and 68% were male. Fourteen patients (38%) had three or more organs involved. The IgG4-RD patients had substantially elevated total plasmablast counts (median 4698/mL, range 610-79524/mL) compared to both untreated disease controls (median 592/mL, range 19-4294/mL; p < 0.001) and healthy controls (median 94/mL, range 1-653/mL; p < 0.001). Thirteen IgG4-RD patients (36%) had normal serum IgG4 concentrations (mean 60 mg/dL, range 5-123 mg/dL, normal <135 mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations (3784/mL) compared to those with elevated serum IgG4 (5155/mL) (p = 0.242). Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6356/mL (range 1123-41589/mL), declining to 1419/mL (range 386/mL-4150/mL) during remission (p < 0.01). CONCLUSIONS: Circulating plasmablasts are elevated in active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the appropriate time for re-treatment. PMID- 24817418 TI - Preference for a propellane motif in pure silicon nanosheets. AB - Free standing silicene nanosheets remain elusive presumably due to the instability associated with sp(2) hybridized silicon atoms. Here we show that silicon prefers nanosheets based on the non-classical Si5 unit with a [1.1.1] propellane motif that has two inverted tetrahedral atoms bridged by three tetrahedral atoms. DFT calculations show that nanosheets constructed exclusively from propellane building blocks are consistently more stable than those with sp(2) silicon atoms or their hybrids. These nanosheets also exhibit a narrow but definite band gap, unlike those reported earlier. PMID- 24817417 TI - Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial. AB - AIM: To test the efficiency of tumour necrosis factor blockers (adalimumab) in patients with painful refractory (non-responders to analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)) hand osteoarthritis (OA). METHODS: We performed a randomised, double-blind, placebo-controlled, parallel group, multicentre study. Patients were randomised to: 1/1 adalimumab 40 mg for two subcutaneous injections at a 15-day interval or placebo and monitored for 6 months. The primary outcome was the percentage of patients with an improvement of more than 50% in global pain (Visual Analogue Scale) between week 0 (W0) and week 6 (W6). Secondary outcomes included the number of painful joints, swollen joints, morning stiffness duration, patient and practitioner global assessments, functional indexes for hand OA, and consumption of analgesics. Analysis on the mean primary outcome measure was done on patients who received at least one injection. RESULTS: 99 patients were recruited and 85 patients were randomised. Among them, 37 patients in the placebo group and 41 in the adalimumab group received at least one injection and were evaluated at W6 (n=78) on the main efficacy outcome. Mean age was 62 years, 85% were women, and mean level of pain was 62 mm at W0. At W6, 35.1% in the adalimumab group versus 27.3% in the placebo group had a pain reduction >=50% (RR 1.12 (95% CI 0.82 to 1.54; p=0.48). There were no statistical differences for all secondary end points. The rate of adverse events was similar in the two groups. CONCLUSIONS: Adalimumab was not superior to placebo to alleviate pain in patients with hand OA not responding to analgesics and NSAIDs. TRIALS REGISTRATION NUMBER: NCT00597623. PMID- 24817419 TI - Sequential multimodal microscopic imaging and biaxial mechanical testing of living multicomponent tissue constructs. AB - Understanding relationships between mechanical stimuli and cellular responses require measurements of evolving tissue structure and mechanical properties. We developed a 3D tissue bioreactor that couples to both the stage of a custom multimodal microscopy system and a biaxial mechanical testing platform. Time dependent changes in microstructure and mechanical properties of fibroblast seeded cruciform fibrin gels were investigated while cultured under either anchored (1.0:1.0 stretch ratio) or strip biaxial (1.0:1.1) conditions. A multimodal nonlinear optical microscopy-optical coherence microscopy (NLOM-OCM) system was used to delineate noninvasively the relative spatial distributions of original fibrin, deposited collagen, and fibroblasts during month long culture. Serial in-culture mechanical testing was also performed to track the evolution of bulk mechanical properties under sterile conditions. Over the month long time course, seeded cells and deposited collagen were randomly distributed in equibiaxially anchored constructs, but exhibited preferential alignment parallel to the direction of the 10% stretch in constructs cultured under strip biaxial stretch. Surprisingly, both anchored and strip biaxial stretched constructs exhibited isotropic mechanical properties (including progressively increasing stiffness) despite developing a very different collagen microstructural organization. In summary, our biaxial bioreactor system integrating both NLOM-OCM and mechanical testing provided complementary information on microstructural organization and mechanical properties and, thus, may enable greater fundamental understanding of relationships between engineered soft tissue mechanics and mechanobiology. PMID- 24817420 TI - Mathematical modelling of the pathogenesis of multiple myeloma-induced bone disease. AB - Multiple myeloma (MM) is the second most common haematological malignancy and results in destructive bone lesions. The interaction between MM cells and the bone microenvironment plays an important role in the development of the tumour cells and MM-induced bone disease and forms a 'vicious cycle' of tumour development and bone destruction, intensified by suppression of osteoblast activity and promotion of osteoclast activity. In this paper, a mathematical model is proposed to simulate how the interaction between MM cells and the bone microenvironment facilitates the development of the tumour cells and the resultant bone destruction. It includes both the roles of inhibited osteoblast activity and stimulated osteoclast activity. The model is able to mimic the temporal variation of bone cell concentrations and resultant bone volume after the invasion and then removal of the tumour cells and explains why MM-induced bone lesions rarely heal even after the complete removal of MM cells. The behaviour of the model compares well with published experimental data. The model serves as a first step to understand the development of MM-induced bone disease and could be applied further to evaluate the current therapies against MM-induced bone disease and even suggests new potential therapeutic targets. PMID- 24817421 TI - Inclusion of weaning management group as a random effect in the genetic evaluation of postweaning traits in Nellore cattle. AB - The objective of this study was to evaluate the impact of including weaning management group (WMG) as an uncorrelated random effect in the genetic evaluation of postweaning traits. Data from 186,507 Nellore animals' sons to 1,734 sires and 75,016 cows were analyzed. Three single-trait models were studied. These models included the contemporary group (CG) as a fixed effect and age of animal at measurement and age of dam at calving as covariates, in addition to the direct additive breeding value as random effect. The CGs for postweaning traits varied between models which included or not WMG as part of the concatenation of fixed effects. In the model in which WMG was not part of the CG, the trait was included as an uncorrelated random effect. The results suggest that although no significant effects were observed on genetic parameter estimates or animal ranking, the inclusion of WMG as an uncorrelated random effect increased the number of observations per CG and contributed to maintaining animals in the analysis that would be discarded because they were in a CG with a small number of observations. This model could therefore be recommended for the genetic evaluation of this Nellore population. PMID- 24817422 TI - Pre-breeding blood urea nitrogen concentration and reproductive performance of Bonsmara heifers within different management systems. AB - This study investigated the association between pre-breeding blood urea nitrogen (BUN) concentration and reproductive performance of beef heifers within different management systems in South Africa. Bonsmara heifers (n = 369) from five herds with different estimated levels of nitrogen intake during the month prior to the commencement of the breeding season were sampled in November and December 2010 to determine BUN concentrations. Body mass, age, body condition score (BCS) and reproductive tract score (RTS) were recorded at study enrolment. Trans-rectal ultrasound and/or palpation was performed 4-8 weeks after a 3-month breeding season to estimate the stage of pregnancy. Days to pregnancy (DTP) was defined as the number of days from the start of the breeding season until the estimated conception date. Logistic regression and Cox proportional hazards survival analysis were performed to estimate the association of pre-breeding BUN concentration with subsequent pregnancy and DTP, respectively. After stratifying for herd and adjusting for age, heifers with relatively higher pre-breeding BUN concentration took longer to become pregnant when compared to those with relatively lower BUN concentration (P = 0.011). In the herd with the highest estimated nitrogen intake (n = 143), heifers with relatively higher BUN were less likely to become pregnant (P = 0.013) and if they did, it was only later during the breeding season (P = 0.017), after adjusting for body mass. These associations were not present in the herd (n = 106) with the lowest estimated nitrogen intake (P > 0.500). It is concluded that Bonsmara heifers with relatively higher pre-breeding BUN concentration, might be at a disadvantage because of this negative impact on reproductive performance, particularly when the production system includes high levels of nitrogen intake. PMID- 24817423 TI - Prevalence of bovine tuberculosis in slaughtered cattle identified by nested-PCR in abattoirs from two dairy areas of Ecuador. AB - Bovine tuberculosis (bTB) is a chronic granulomatous disease that primarily affects lung tissue and lymph nodes (LN) in cattle, with economic impact on their productivity. Furthermore, it is potential zoonoses that may cause public health hazard. In this study, we evaluated the presence of bTB in two abattoirs: Cayambe and Pelileo countries located in the Ecuadorian provinces of Pichincha and Tungurahua, respectively. In total, 578 cattle were sampled (Cayambe 271 and Pelileo 307): 1,156 LN and 578 lung tissue samples were collected to apply in vitro culture and nested-PCR, respectively. The results determined a total apparent prevalence of 4.33%, with 4.06% at Cayambe's abattoir and 4.56% at Pelileo's abattoir. Additionally, the Bayesian analysis showed a total true prevalence of 2.51%, with 89.7% of sensitivity and 97.6% of specificity. The risk factors were evaluated by the use of simple logistic regressions with and without the random effect of places of origin. Associations of the origin of cattle in the selected slaughterhouses were found. The results showed an efficient method for the detection of bTB, which could identify a large number of infected animals, and the usefulness of lung tissue samples for early diagnosis of the disease was demonstrated in this study. PMID- 24817424 TI - Detection and molecular characterization of naturally transmitted sheep associated malignant catarrhal fever in cattle in India. AB - Malignant catarrhal fever (MCF) is a fatal herpesvirus infection of domestic and wild ruminants, with a short and dramatic clinical course characterized primarily by high fever, severe depression, swollen lymph nodes, salivation, diarrhea, dermatitis, neurological disorders, and ocular lesions often leading to blindness. In the present study, fatal clinical cases of sheep associated malignant catarrhal fever (SA-MCF) were identified in cattle in the state of Karnataka. These cases were initially presented with symptoms of diarrhea, respiratory distress, conjunctivitis, and nasal discharges. Laboratory diagnosis confirmed the detection of ovine herpesvirus-2 (OvHV-2) genome in the peripheral blood samples of two ailing animals. The blood samples collected subsequently from sheep of the neighboring areas also showed presence of OvHV-2 genome indicating a nidus of infection in the region. The positive test results were further confirmed by nucleotide sequencing of the OIE approved portion of tegument gene as well as complete ORF8 region of the OvHV-2 genome. Phylogenetic analysis based on the sequence of the latter region indicated close genetic relationship with other OvHV-2 reported elsewhere in the world. PMID- 24817425 TI - Field trapping of the flathead oak borer Coroebus undatus (Coleoptera: Buprestidae) with different traps and volatile lures. AB - The flathead oak borer Coroebus undatus F. (Coleoptera: Buprestidae) is one of the primary pests of cork oak Quercus suber L. in the Mediterranean region causing great economic losses to the cork industry. Very little is known about its biology and behavior and, so far, no control measures have been established. We present the results of a pilot study aimed to develop an efficient trapping method for monitoring this harmful pest. In a 3-year field study, purple-colored prism traps baited with a mixture of green leaf volatiles (GLVs) from the host have been shown the most effective combination to catch C. undatus adults (solely females) compared to other trap and lure types tested. Wavelength and reflectance measurements revealed that purple traps exhibit reflectance peak values similar to those found in the abdominal and elytral cuticle of both sexes, suggesting the involvement of visual cues for mate location in this species. The data presented are the first to demonstrate captures of adults of the genus Coroebus by an attractant-based trapping method. PMID- 24817426 TI - Baseline abdominal lipid partitioning is associated with the metabolic response to bariatric surgery. AB - BACKGROUND: The purpose of this study was to compare the effects of two bariatric procedures on abdominal lipid partitioning and metabolic response. METHODS: Fifty one patients (RYGB 31(11 M/20 F); (SG) 20(8 M/12 F)) who met the criteria of metabolic syndrome before the operation were followed following Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Visceral and subcutaneous abdominal fat depots were assessed by CT before, 6 months, and 12 months following the operation. RESULTS: Patients undergoing both procedures did not differ in baseline body mass index (BMI) (42.84 +/- 4.65 vs. 41.70 +/- 4.68 kg/m(2)) or abdominal lipid depots. BMI at 12 months post-op was similar (29.44 +/- 3.35 vs 30.86 +/- 4.31 kg/m(2) for RYGB and SG, respectively). Both procedures led to a significant reduction in visceral and subcutaneous fat at 6 months (p < 0.001 for both). The visceral-to-subcutaneous fat ratio was comparable at 6 months vs. baseline yet was lower at 12 months vs. baseline for both procedures (p < 0.01). In patients who lost the diagnosis of metabolic syndrome, baseline visceral/subcutaneous fat was the only predictor of recovery (p < 0.005). No difference was detected between procedures in dynamics of abdominal fat depots or remission of cardiovascular risk factors. CONCLUSIONS: RYGB and SG induce a similar effect on abdominal fat mobilization. The metabolic effects in individual patients are mostly determined by their baseline abdominal lipid partitioning. PMID- 24817427 TI - Upper gastrointestinal series after Roux-en-Y gastric bypass for morbid obesity: effectiveness in leakage detection. a systematic review of the literature. AB - The aim of this study is to evaluate the results of routine and selective postoperative upper gastrointestinal series (UGIS) after Roux-en-Y gastric bypass (RYGB) for morbid obesity in different published series to assessing its utility and cost-effectiveness. A search in PubMed's MEDLINE was performed for English spoken articles published from January 2002 to December 2012. Keywords used were upper GI series, RYGB, and obesity. Only cases of anastomotic leaks were considered. A total of 22 studies have been evaluated, 15 recommended a selective use of postoperative UGIS. No differences in leakage detection or in clinical benefit between routine and selective approaches were found. Tachycardia and respiratory distress represent the best criteria to perform UGIS for early diagnosis of anastomotic leak after a RYGB. PMID- 24817428 TI - Translation, adaptation and validation of a Portuguese version of the Moorehead Ardelt Quality of Life Questionnaire II. AB - The prevalence of obesity has increased worldwide. An assessment of the impact of obesity on health-related quality of life (HRQoL) requires specific instruments. The Moorehead-Ardelt Quality of Life Questionnaire II (MA-II) is a widely used instrument to assess HRQoL in morbidly obese patients. The objective of this study was to translate and validate a Portuguese version of the MA-II.The study included forward and backward translations of the original MA-II. The reliability of the Portuguese MA-II was estimated using the internal consistency and test retest methods. For validation purposes, the Spearman's rank correlation coefficient was used to evaluate the correlation between the Portuguese MA-II and the Portuguese versions of two other questionnaires, the 36-item Short Form Health Survey (SF-36) and the Impact of Weight on Quality of Life-Lite (IWQOL Lite).One hundred and fifty morbidly obese patients were randomly assigned to test the reliability and validity of the Portuguese MA-II. Good internal consistency was demonstrated by a Cronbach's alpha coefficient of 0.80, and a very good agreement in terms of test-retest reliability was recorded, with an overall intraclass correlation coefficient (ICC) of 0.88. The total sums of MA-II scores and each item of MA-II were significantly correlated with all domains of SF-36 and IWQOL-Lite. A statistically significant negative correlation was found between the MA-II total score and BMI. Moreover, age, gender and surgical status were independent predictors of MA-II total score.A reliable and valid Portuguese version of the MA-II was produced, thus enabling the routine use of MA-II in the morbidly obese Portuguese population. PMID- 24817429 TI - Sociodemographic differences and time trends of bariatric surgery in Sweden 1990 2010. AB - BACKGROUND: The aim of the present study was to examine demographic and socioeconomic differences and time trends of bariatric surgery in Sweden during 1990-2010. METHODS: An open cohort of all individuals aged 20-64 years was followed between 1990 and 2010. Socioeconomic differences were examined during two periods: 1990-2005 and 2006-2010 using cumulative rates in a closed cohort. Hazard ratios (HRs) of bariatric surgery were calculated in these two periods using Cox regression models. RESULTS: A majority of the 22,198 individuals that underwent bariatric surgery were women (76.3 %). Women were more likely to undergo surgery in younger ages (30-39 years), while men were more likely to undergo surgery around 10 years later (40-49 years). The number of surgeries increased substantially during the second period. During the whole period, the dominating surgical method was gastric bypass contributing to 69.4 % of the procedures. HRs for bariatric surgery were highest for individuals with intermediate educational level and intermediate-low income in both periods. For married/cohabiting and/or employed individuals, the HRs were highest during the first period whereas an opposite pattern was seen in the second period. CONCLUSIONS: Individuals in the lowest socioeconomic groups undergo bariatric surgery less often than those with intermediate income and educational level, although previous research has shown that those with low socioeconomic status have the highest rates of morbid obesity. The failure to identify eligible individuals for surgery may result in negative effects on those individuals with the largest need for weight loss. PMID- 24817430 TI - Current diagnosis and management of simple hepatic cysts detected prenatally and postnatally. AB - PURPOSE: The optimal management of simple hepatic cysts (SHCs) remains controversial. A retrospective review was carried out to evaluate the clinical presentation and surgical consideration of children with SHCs and outcome of management at our institution. METHODS: We performed a retrospective review of all patients diagnosed with SHCs between January 1993 and May 2013. Patient variables included prenatal findings, age, gender, presenting symptoms, signs and diagnostic modality. Operative management and nonoperative follow-up were abstracted. RESULTS: The 67 patients comprised 42 females and 25 males: 16 had prenatally detected, and 51 had postnatally detected hepatic cysts with a mean follow-up of 3.2 years (10 months-12 years). The average age was 5.9 years (0-17 years). Ten patients (six females and four males) were treated surgically. Fifty seven asymptomatic patients were observed. Of those 57 patients, 9 (17%) had enlarged cysts, and 1 (2%) had clinical signs. The average enlargement time was 36 months (6-67 months). The cysts occurred in the right lobe in 47 patients, in the left lobe in 17 patients and in both lobes in 3 patients. The median cyst size for the asymptomatic cases was 2.1 cm (1.5-6 cm) and 13.7 cm (8-25 cm) for the surgery group. A statistically significant difference in cyst size was found between these two groups (p < 0.05). Prenatally detected cysts (n = 5) were subjected to surgery postnatally at an average age of 1.5 months (1 week-6 months). The main indication was the compressive effect of the cyst on the surrounding area. There was one case of hepatomegaly found to be causing pressure symptoms, two cases of respiratory distress, one case of hydroureteronephrosis, and one case of jaundice due to compression of the biliary system. Five patients underwent surgery in the postnatally detected group, and the main indication was a complication of the cyst or progressive enlargement. Symptoms included abdominal discomfort and pain in all five patients: one case exhibited a hemorrhage within the cyst, one case displayed a rupture with possible peritonitis, one case had a 25-cm cyst leading to secondary infection, and two cases were admitted with progressive enlargement with clinical symptoms. CONCLUSION: Conservative management of SHCs is practical. Surgical excision is recommended in patients with larger cysts, causing pressure symptoms, or if the cyst size does not seem to involute with intractable abdominal pain or becomes complicated in the follow-up period. PMID- 24817431 TI - Free perforator flap transfer for reconstruction of skull base defects after resection of advanced recurrent tumor. AB - BACKGROUND: Skull base reconstruction is challenging due to its proximity to important anatomical structures. This report evaluates the use of perforator flaps for reconstruction of skull base defects after advanced recurrent tumor resection. METHODS: Fourteen free perforator flaps were transferred to reconstruct skull base defects in 14 consecutive patients, from October 2004 to May 2011. All patients had advanced recurrent neoplasms that were previously treated with either radiation therapy or surgery. The surgical defects were reconstructed using various perforator flaps mainly the deep inferior epigastric artery perforator flaps, anterolateral thigh (ALT) flaps, or thoracodorsal artery perforator flaps. The outcomes following reconstruction and associated complications were evaluated. RESULTS: The overall free flap success rate was 93% (13/14). One ALT flap was lost. Three patients (20%) had a cerebrospinal fluid fistula, and two of them developed meningitis. No complications were observed at the donor site. CONCLUSIONS: The use of perforator flaps may be a viable option for reconstruction of skull base defects after the resection of advanced recurrent tumor. PMID- 24817432 TI - Mixed solvents for the optimization of morphology in solution-processed, inverted type perovskite/fullerene hybrid solar cells. AB - We investigate mixed solvents of N,N-dimethylformamide (DMF) and gamma butyrolactone (GBL) to produce the smooth surface of a perovskite film and uniform crystal domains. This ideal morphology from mixed solvents enhances the power conversion efficiency to over 6% by improving the exciton dissociation efficiency and reducing the recombination loss at both interfaces of PEDOT:PSS/perovskite and perovskite/PCBM. PMID- 24817433 TI - The Red Queen in a potato field: integrated pest management versus chemical dependency in Colorado potato beetle control. AB - Originally designed to reconcile insecticide applications with biological control, the concept of integrated pest management (IPM) developed into the systems-based judicious and coordinated use of multiple control techniques aimed at reducing pest damage to economically tolerable levels. Chemical control, with scheduled treatments, was the starting point for most management systems in the 1950s. Although chemical control is philosophically compatible with IPM practices as a whole, reduction in pesticide use has been historically one of the main goals of IPM practitioners. In the absence of IPM, excessive reliance on pesticides has led to repeated control failures due to the evolution of resistance by pest populations. This creates the need for constant replacement of failed chemicals with new compounds, known as the 'insecticide treadmill'. In evolutionary biology, a similar phenomenon is known as the Red Queen principle - continuing change is needed for a population to persevere because its competitors undergo constant evolutionary adaptation. The Colorado potato beetle, Leptinotarsa decemlineata (Say), is an insect defoliator of potatoes that is notorious for its ability to develop insecticide resistance. In the present article, a review is given of four case studies from across the United States to demonstrate the importance of using IPM for sustainable management of a highly adaptable insect pest. Excessive reliance on often indiscriminate insecticide applications and inadequate use of alternative control methods, such as crop rotation, appear to expedite evolution of insecticide resistance in its populations. Resistance to IPM would involve synchronized adaptations to multiple unfavorable factors, requiring statistically unlikely genetic changes. Therefore, integrating different techniques is likely to reduce the need for constant replacement of failed chemicals with new ones. PMID- 24817434 TI - Phyllanthin inhibits CCl4-mediated oxidative stress and hepatic fibrosis by down regulating TNF-alpha/NF-kappaB, and pro-fibrotic factor TGF-beta1 mediating inflammatory signaling. AB - Hepatic fibrosis is an important outcome of chronic liver injury and results in excess synthesis and accumulation of extracellular matrix (ECM) components. Phyllanthin (PLN) isolated from Phyllanthus amarus exhibits strong antioxidative property and protects HepG2 cells from carbon tetrachloride (CCl4)-induced experimental toxicity. The present study reports the antifibrotic potential of PLN. The in vivo inhibitory effect of PLN on CCl4-mediated lipid peroxidation and important profibrotic mediator transforming growth factor beta1 and on predominant ECM components collagen and fibronectin were also studied. The results show that PLN acts by suppressing the expression of inflammatory cytokine tumor necrosis factor-alpha and prevents activation of nuclear factor-kappaB in hepatic tissue. Our study highlights the molecular mechanism responsible for the antifibrotic efficacy of PLN. PMID- 24817435 TI - Compliance after switching from branded to generic statins. AB - PURPOSE: The purpose of this study was to evaluate the impact of switching from branded to generic statins on medication compliance. METHODS: In this historic cohort study, we identified patients taking branded statins between January 2003 and December 2012 from Sutter Health's electronic health records in Northern California. Patients with >=2 consecutive pharmacy claims for generic statins after initiating branded statins were classified as switchers. Switchers and non switchers were matched 1:1 on the propensity for switching. Medication possession ratio (MPR) was calculated as the sum of days supply of therapy divided by treatment duration. We assessed between-group differences in compliance (MPR >= 0.80) by logistic regression. RESULTS: Among 16,364 patients meeting eligibility criteria, 8470 were retained in the matched cohort. No significant differences in compliance with statin therapy were observed for non-switchers versus switchers, overall, or versus patients switched from a branded to generic statin of the same agent (generic substitutions). Patients switched from a branded to generic statin of a different agent (therapeutic substitutions) more frequently received less potent statin dosing relative to those with generic substitutions (42.2% vs. <2%, respectively) and were significantly less compliant with statin therapy in the first 6 months after switching (73.9% vs. 77.6%; p = 0.011); however, compliance significantly improved among patients with therapeutic substitutions relative to generic substitutions more than 12 months after switching (66.2% vs. 61.3%; p = 0.021). CONCLUSIONS: Compliance with statin therapy was largely similar among patients who switch to generic statins and those remaining on branded statins. Dosing should be reviewed when changing therapy to optimize clinical outcomes. PMID- 24817436 TI - Analysis of the interaction between experimental and applied behavior analysis. AB - To study the influences between basic and applied research in behavior analysis, we analyzed the coauthorship interactions of authors who published in JABA and JEAB from 1980 to 2010. We paid particular attention to authors who published in both JABA and JEAB (dual authors) as potential agents of cross-field interactions. We present a comprehensive analysis of dual authors' coauthorship interactions using social networks methodology and key word analysis. The number of dual authors more than doubled (26 to 67) and their productivity tripled (7% to 26% of JABA and JEAB articles) between 1980 and 2010. Dual authors stood out in terms of number of collaborators, number of publications, and ability to interact with multiple groups within the field. The steady increase in JEAB and JABA interactions through coauthors and the increasing range of topics covered by dual authors provide a basis for optimism regarding the progressive integration of basic and applied behavior analysis. PMID- 24817437 TI - Fixed-point bifurcation analysis in biological models using interval polynomials theory. AB - The paper proposes a systematic method for fixed-point bifurcation analysis in circadian cells and similar biological models using interval polynomials theory. The stages for performing fixed-point bifurcation analysis in such biological systems comprise (i) the computation of fixed points as functions of the bifurcation parameter and (ii) the evaluation of the type of stability for each fixed point through the computation of the eigenvalues of the Jacobian matrix that is associated with the system's nonlinear dynamics model. Stage (ii) requires the computation of the roots of the characteristic polynomial of the Jacobian matrix. This problem is nontrivial since the coefficients of the characteristic polynomial are functions of the bifurcation parameter and the latter varies within intervals. To obtain a clear view about the values of the roots of the characteristic polynomial and about the stability features they provide to the system, the use of interval polynomials theory and particularly of Kharitonov's stability theorem is proposed. In this approach, the study of the stability of a characteristic polynomial with coefficients that vary in intervals is equivalent to the study of the stability of four polynomials with crisp coefficients computed from the boundaries of the aforementioned intervals. The efficiency of the proposed approach for the analysis of fixed-point bifurcations in nonlinear models of biological neurons is tested through numerical and simulation experiments. PMID- 24817438 TI - Comparison of the incidence between tuberculosis and nontuberculous mycobacterial disease after gastrectomy. AB - PURPOSE: Gastrectomy is a well-known risk factor for tuberculosis (TB). However, little data are available regarding the relationship between gastrectomy and the risk of nontuberculous mycobacterial (NTM) disease. Here, we investigated the incidence of TB and NTM lung disease in gastrectomized patients. METHOD: New cases of TB and NTM lung infection or disease were examined among patients who had undergone gastrectomy due to gastric cancer from 2003 to 2009 at a tertiary referral hospital in South Korea. Annualized incidence rates for cases were compared with those of the general population. RESULTS: This study included a total of 2,684 patients. New mycobacterial cases were found in 41 patients. Cases of TB and NTM lung infection were 35 (85 %) and 6 (15 %) including 2 NTM lung disease cases, respectively. Annualized crude incidence rates for TB, NTM lung infection, and NTM lung disease were 327/100,000, 56/100,000, and 19/100,000, respectively. The age-standardized incidence rate of TB was significantly higher in gastrectomized patients than in the general population. However, the standardized incidences of NTM lung infection and disease were not significantly different from those of non-gastrectomized patients. Patients with NTM lung infection frequently exhibited comorbid chronic lung disease, while those with TB were more frequently found to have fibronodular lesions on preoperative chest radiography. CONCLUSIONS: Gastrectomy does not appear to increase the risk of NTM lung disease. However, NTM lung infection or disease should be considered as a differential diagnosis of pulmonary TB in gastrectomized patients accompanying chronic lung disease. PMID- 24817439 TI - Fluorescence sensors for selective detection of Hg2+ ion using a water-soluble poly(vinyl alcohol) bearing rhodamine B moieties. AB - The novel water-soluble poly(vinyl alcohol) with pendant rhodamine B moiety as colorimetric and fluorescene chemosensor for Hg(2+) ions was prepared by grafting poly(vinyl alcohol) using rhodamine B hydrazide and hexamethylenediisocyanate as fluorescent dye and coupling agent, respectively. Because of their good water solubility, the polymers binding rhodamine B can be used as chemosensors in aqueous media. With the addition of Hg(2+) ions into the aqueous solution, visual color changes and fluorescence enhancements were detected. In addition, we also noticed that other metal ions such as Ag(+), Cd(2+), Co(2+), Cu(2+), K(+), Mg(2+), Ba(2+), Fe(2+), Ni(2+), Pb(2+), Cr(3+), Fe(3+) and Zn(2+) cannot induce obvious changes to the fluorescence spectra of the polymer chemosensors. The combination of water solubility and positive fluorescence response as well as color change are hence particularly promising for the practical utility of the sensors. PMID- 24817440 TI - Personality characteristics of depressed and non-depressed patients with Parkinson's disease. AB - Depression and a specific personality profile are often outlined as premorbid characteristics of Parkinson's disease (PD). However, few studies have explored possible relations between personality and depression in PD despite research in non-parkinsonian samples identifying specific personality traits as risk factors for depression. The personality profiles of 290 non-depressed and 119 depressed patients with PD were compared. The depressed patients were characterized by elevated neuroticism, reduced extroversion, and reduced conscientiousness and less convincing findings of reduced openness and agreeableness. The largest unique contribution to a regression analysis predicting depression was greater number of motor symptoms, increased neuroticism, and reduced extroversion. PMID- 24817442 TI - Cardiac resynchronisation therapy in populations underrepresented in randomised controlled trials. PMID- 24817441 TI - The separate and combined effects of adiposity and cardiometabolic dysfunction on the risk of recurrent cardiovascular events and mortality in patients with manifest vascular disease. AB - OBJECTIVES: A remarkable variation exists in the cardiometabolic consequences of obesity. We evaluated the separate and combined effects of adiposity and cardiometabolic dysfunction on the occurrence of cardiovascular events and mortality in patients with vascular disease. METHODS: We prospectively followed 5231 patients with a history of clinical cardiovascular disease without diabetes from the Second Manifestations of ARTerial disease (SMART) study. Patients were classified according to body mass index and cardiometabolic function. The presence of cardiometabolic dysfunction was defined as >=3 of the modified National Cholesterol Education Program (NCEP) metabolic syndrome criteria (waist circumference replaced by elevated C-reactive protein). Cox proportional-hazards analysis was used to estimate HRs for cardiovascular events and mortality. RESULTS: The prevalence of cardiometabolic dysfunction was 40% in normal weight, 58% in overweight and 75% in obese patients. During a median follow-up of 6.1 years, 769 patients died and 705 patients experienced a major cardiovascular event. In the absence of cardiometabolic dysfunction, overweight (HR 1.18, 95% CI 0.90 to 1.55) and obese patients (HR 0.93, 95% CI 0.53 to 1.64) were not at increased risk of recurrent major cardiovascular events compared with normal weight patients without cardiometabolic dysfunction. An increased cardiovascular risk was observed in patients with cardiometabolic dysfunction and normal weight (HR 1.58, 95% CI 1.23 to 2.04), overweight (HR 1.35, 95% CI 1.07 to 1.70) and obesity (HR 1.50, 95% CI 1.12 to 2.00) compared with normal weight patients without cardiometabolic dysfunction. A similar pattern was observed for vascular and all-cause mortality. CONCLUSIONS: In patients with vascular disease, the cardiometabolic consequences of adiposity rather than adiposity per se increase the risk of recurrent cardiovascular events and mortality. PMID- 24817443 TI - Antithrombotic activities of sulforaphane via inhibiting platelet aggregation and FIIa/FXa. AB - Sulforaphane (SFN), a natural isothiocyanate that is present in cruciferous vegetables such as broccoli and cabbage, is effective in preventing carcinogenesis, diabetes and inflammatory responses. Here, the anticoagulant activities of SFN were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time, and the activities of thrombin (Factor IIa, FIIa) and activated factor X (FXa). And, the effects of SFN on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor-alpha activated human umbilical vein endothelial cells (HUVECs). Treatment with SFN resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, SFN inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. SFN also elicited anticoagulant effects in mice. In addition, treatment with SFN resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, SFN possesses antithrombotic activities and offers a basis for development of a novel anticoagulant. PMID- 24817444 TI - Tuning thiophene with phosphorus: synthesis and electronic properties of benzobisthiaphospholes. AB - 1,4-Dimercapto-2,5-diphosphinobenzene and 3,6-bis(hexyloxy)-1,4-dimercapto-2,5 diphosphinobenzene were synthesized and combined with various acid chlorides to obtain a series of benzobisthiaphospholes. Electrochemical and photophysical properties of the substituted benzobisthiaphospholes have been evaluated, and the observed reductions are more facile than the related benzothiaphospholes and 2,6 diphenylbenzobisthiazole. A benzobisthiaphosphole with C6H4-p-CN substituents was reduced at E(1/2)=-1.08 V (vs. saturated calomel electrode (SCE)). X-ray diffraction data for several of these phosphorus heterocycles has been obtained, and DFT calculations at the B3LYP level have been performed. PMID- 24817445 TI - One-pot enantioselective construction of indoloquinolizidine derivatives bearing five contiguous stereocenters using aliphatic aldehydes, nitroethylenes, and tryptamine. AB - An organocatalytic cascade reaction was established for the construction of indoloquinolizidine derivatives bearing five contiguous stereocenters from readily available aliphatic aldehydes, nitroethylenes, and tryptamine. This one pot process gave 30-55% overall yields with excellent d.r. (>20 : 1 in all cases) and ee (91-98%). Additionally, quaternary stereogenic carbon center-containing indoloquinolizidines were prepared through NBS-mediated cyclization of one of the intermediates. PMID- 24817446 TI - Arteriovenous access for hemodialysis: preoperative assessment and planning. AB - Longevity in end-stage renal disease (ESRD) is dependent on adequacy of renal replacement therapy. Over 85% of the global ESRD population is hemodialysis dependent. Preoperative evaluation is the cornerstone of vascular access planning. The goal of preoperative evaluation is to design a sequence of options that can be used to provide vascular access throughout the life span of an ESRD patient. The intention should be to provide a durable vascular access in a timely fashion that needs few interventions, while refraining from jeopardizing future needs. PMID- 24817447 TI - Intraoperative assessment of vascular access. AB - PURPOSE: The intraoperative quality assessment of the arteriovenous fistula for hemodialysis is an essential process to limit early failure due to technical problems or inadequate vascular quality. This step is not clearly defined in the literature with no recommendations. METHODS: We selected published articles related to the topic of intraoperative quality control of the vascular access for hemodialysis. RESULTS: The intraoperative blood flow measurement greater than 120 ml/min in autologous fistula and less than 320 ml/min in arteriovenous graft was described as predictive factors for early failure. CONCLUSIONS: The blood flow measurement should be performed after the confection of the anastomosis. When blood flow is limited, fistulography is an essential step to assess patency. PMID- 24817448 TI - Postoperative assessment of vascular access. AB - Vascular access problems lead to increased patient morbidity and mortality. Autologous arteriovenous fistulas (AVFs) are preferred over grafts. An increase in utilization of AVFs results in an increased incidence of early AVF failure and nonmaturation. A thorough evaluation of a new AVF after 4-6 weeks after creation should be considered mandatory. Experienced persons can examine AVF and predict its utility as a dialysis access. Detailed physical examination of the access performed by educated and trained staff can provide, in most cases, adequate information about the main causes for AVF dysfunction in case of nonmaturation or in case of late access complications. Physical examination has been shown to be very accurate in assessing fistula and is not difficult to learn. Doppler ultrasound (DU) is an additional diagnostic method to predict the ultimate maturation of newly created AVFs and is also very useful in further defining problems that have been detected by physical examination. DU also provides additional information that is of the utmost importance for the surgical or interventional treatment.In this review, basic principles of physical examination and of DU examination of early and late AVF/graft complications are shown. PMID- 24817449 TI - Why vascular access trials on flow surveillance failed. AB - INTRODUCTION: Since the introduction of access flow surveillance technology for routine patient screening in 1995, more than 30 clinical trials have been presented in peer reviewed journals. Despite overall positive outcomes, some trials, including randomized control trials (RCTs), failed to produce positive outcomes for access surveillance. The purpose of this study is to analyze published data related to the main component of access surveillance--adequate increase of access flow after percutaneous transluminal angioplasty (PTA). RESULTS: A total of nine studies for arteriovenous grafts (AVGs) that include 350 accesses and nine studies for arteriovenous fistula (AVF) that included 503 accesses were considered for analysis from 14 publications. Practically, all reference data find high sensitivity (>90%) of access flow measurement to predict 50% stenosis. Mean access flow increase after PTA in AVGs was 319 ml/min (from 238 to 524 ml/min). Mean access flow increase in AVFs was 331 ml/min (from 195 to 402 ml/min). Relative flow increase in AVFs was 1.6 times greater than in AVGs. The authors of failed RCT for AVGs either did not select patients for PTA based on KDOQI guidelines and did not provide/analyze PTA flow results data, or reveal data that obviously show failure of PTA to adequately improve access flow. SUMMARY: Access flow surveillance successfully identifies patients with hemodynamically significant stenosis. PTA performed on AVFs produce better hemodynamic results than in AVGs. Inadequate flow increases during PTA and not following KDOQI guidelines are major contributing factors for failed AVG randomized tails. Radiologists should use objective means for flow evaluation during PTA. PMID- 24817450 TI - Clinical access assessment. AB - BACKGROUND: Vascular access guidelines recommend routine screening for the timely detection of stenosis using noninvasive methods, including clinical assessment (monitoring) and device-based surveillance relying on access blood flow (Qa) and static intra-access pressure (sVPR, static venous pressure ratio) measurements and duplex ultrasound (DU). METHODS: We reviewed the literature to see how monitoring compares with surveillance in terms of compliance with the World Health Organization's criteria for screening tests. RESULTS: The fundamental element of monitoring, physical examination (PE), has a fair-to-good performance in detecting stenosis in both fistulas and grafts, similar to the Qa criteria recommended in the guidelines. In fistulas, the "or" combination of a positive PE with a Qa <900 mL/min or sVPR >0.5 is more sensitive in detecting stenosis (in up to 98% of cases), making it as good as DU. In grafts, PE performed significantly less well in diagnosing stenosis than sVPR or DU.In randomized controlled trials on fistulas, Qa surveillance enables a significant halving of the risk of thrombosis and access loss by comparison with monitoring alone when Qa criteria highly sensitive to stenosis are considered. In grafts, neither Qa nor DU nor sVPR is able to reduce thrombosis or access loss rates by comparison with monitoring alone. CONCLUSIONS: Our analysis indicates that regular monitoring should be the backbone of any vascular access stenosis screening program (possibly associated with Qa and sVPR surveillance for fistulas), and PE should be part of every teaching program for caregivers involved in hemodialysis. PMID- 24817451 TI - Surveillance of arteriovenous accesses with the use of duplex Doppler ultrasonography. AB - Stenosis is the most frequent vascular access complication and is responsible for access thrombosis and thus long-term patency limitation. Regular arteriovenous graft (AVG) examination by ultrasonography and preemptive balloon angioplasty prolong AVG cumulative patency according to some, but by far not all trials. This was why the routine use of ultrasound surveillance is not recommended recently.In this review we show huge differences in the definition of stenosis significance among the trials and other probable factors, which may have caused the contradiction of the results. Without precise definition of stenosis significance, many AVGs have been undergoing unnecessary balloon interventions with high morbidity, high cost and low benefit. PMID- 24817452 TI - Radiological assessment of vascular access in haemodialysis patients. AB - Clinical examination is still the most important diagnostic tool and duplex ultrasonography is the imaging method of first choice. Radiological assessment of vascular access for haemodialysis includes preoperative analysis of vessel anatomy and postoperative surveillance for access maturation as well as diagnosis in vascular access insufficiency. Compared to ultrasonography digital subtraction angiography is superior for the evaluation of the central veins and allows diagnosis and treatment in one session. Computed tomography should only be used in patients with inconclusive ultrasonography results, for example, for the assessment of the central veins and visualization of the vascular tree. Gadolinium-enhanced magnetic resonance imaging is no longer recommended in dialysis patients, because it may trigger nephrogenic systemic fibrosis. In patients with a history of previous central venous catheters additional preoperative imaging of the central veins should be performed. In this article we review the different radiological imaging methods for preoperative assessment and suspected vascular access dysfunction. PMID- 24817453 TI - Anesthesia for vascular access surgery. AB - The type of anesthesia chosen is an integral part of the decision-making process for arteriovenous access construction. We discuss the different types of anesthesia used, with emphasis on brachial plexus block, which is potentially safer than general anesthesia in this fragile patient population with end-stage renal disease. Brachial plexus block is superior to local anesthesia and enables the use of a tourniquet to minimize potential damage to the blood vessels during anastomosis using microsurgery techniques, and does not lead to the vasospasm that may be seen with local anesthesia. Regional anesthesia has a beneficial sympathectomy-like effect that causes vasodilation with increased blood flow during surgery and in the fistula postoperatively that may prevent early thrombosis and potentially improve outcome. PMID- 24817454 TI - Tips and tricks in creation of forearm arteriovenous fistulae. AB - Forearm arteriovenous fistula (AVF) is a direct anastomosis between the radial artery and the cephalic vein or the ulnar artery and the basilic vein, which are small-caliber vessels. The surgical technique must be precise to avoid postoperative stenosis of the anastomosis which may result in early thrombosis or nonmaturation. In our experience, microsurgery and preventive hemostasis are two major contributions to creation of forearm AVF. Using these techniques, construction of a radial-cephalic fistula was possible in 78% of children in our hospital, with 60% secondary patency rates at 4 years. In a personal unpublished series, 69% of the first arteriovenous angioaccess of adult patients were forearm fistulae, with 63% and 91% primary and secondary 1-year patency rates, respectively. Finally, 68% primary patency and 96% secondary patency rates at 1 year were reported by Pirozzi et al. in adults with an internal diameter of <1.6 mm in the radial artery. PMID- 24817455 TI - Elbow arteriovenous fistulae. AB - Multiple superficial veins in different anatomical configurations exist in the elbow. The resulting variety of elbow arteriovenous fistulae (AVFs) is described in this paper. A classification of elbow AVF in nontransposed AVF, transposed AVF and multiple outflow AVF is proposed. The nontransposed brachiocephalic AVF has the lowest primary failure rate and a good medium-term survival particularly in the elderly. The simplest technique is an end-to-side anastomosis of the median cubital vein to the brachial artery. In cases of small upper arm veins, a perforating vein AVF, using multiple outflow tracts, may be helpful to lower primary failure risk. In the era of vein mapping with portable ultrasound elbow AVF should be made when forearm veins are exhausted or too small. A side-to-side AVF in order to enhance retrograde flow in the median forearm vein seems rarely indicated, in particular considering the greater risk of steal and venous hypertension. A transposed brachiobasilic AVF is a tertiary access procedure after the simpler alternatives have been exhausted. There is conflicting evidence of the benefits of one-stage versus two-stage procedures. Therefore, the type of operation should be tailored to the individual patient. PMID- 24817456 TI - Mechanical enhancement of AVF maturation. AB - A native arteriovenous fistula (AVF) should be systematically evaluated at 4 to 6 weeks after creation. Any clinical indications of nonmaturation should be promptly followed up and confirmed by detailed duplex ultrasonography looking for a deep vein or inadequate access flow due to stenoses. Once vein depth has been ruled out, a significant stenosis is invariably identified and should therefore be operated on or dilated. Predilation angiography should be performed preferably through the brachial artery. Arterial lesions are frequent causes of nonmaturation of forearm AVFs and should therefore be dilated. The best results are obtained when the juxta-anastomotic vein and the feeding artery are dilated with 6 and 4 mm dilation balloons, respectively. Our opinion is that there is no or only the very rare indication for ligation or embolization of collaterals. Rupture of the weak venous or arterial wall is common (15% of cases), the majority of which can be managed with prolonged balloon tamponade. Nonmaturing AVFs are ideally needled only 7 to 14 days after successful dilation to allow hematomas caused by cannulation and local anesthesia to resorb. Including initial failures, 1-year primary and secondary patency rates reported by interventional radiologists range from 34% to 39% and 68% to 79%, respectively. Results after dilation of diseased radial arteries feeding normal veins are even better, with primary patency rates ranging for 65% to 83%, and secondary patency rates of over 90%. Using an aggressive and multidisciplinary treatment strategy, nonmaturing dialysis fistulas can be identified, evaluated and salvaged with angioplasty. PMID- 24817457 TI - Pre-operative ultrasonography and arteriovenous fistulae maturation. AB - BACKGROUND: Arteriovenous fistulae (AVF) are preferred for haemodialysis access, but maturation is unpredictable. RESULTS: Clinical examination alone is unreliable for AVF planning. Duplex ultrasonography may provide useful anatomical and physiological data to allow more accurate prediction of likely AVF success. CONCLUSION: Selective use of duplex ultrasonography appears to enhance AVF success rates, but there are insufficient data to recommend routine duplex screening of AVF candidates. Agreed vessel criteria are needed. PMID- 24817458 TI - Computational model for prediction of fistula outcome. AB - BACKGROUND: The creation and management of an autologous arteriovenous fistula (AVF) as vascular access (VA) for hemodialysis patients is still a critical procedure. The placement of a functional and long-lasting VA derives from adequate planning of the surgical procedure based on physical examination, vascular mapping and selection of the best modality for arteriovenous anastomosis. The risk of AVF non-maturation and early failure is high, even when all precautions are taken to minimize these events. In addition, AVF surgery may develop very high blood flow exposing the patient to the risk of heart failure or hand ischemia. METHODS: The choices of the surgeons on the modalities to perform a surgical intervention for AVF should take into consideration several factors including patient clinical condition, arterial and venous vessel sizes and elasticity. However, these evaluations cannot give direct indication on VA outcome in terms of blood flow after AVF maturation. We then took advantage of theoretical models of vascular network hemodynamics and of computational fluid dynamics to develop a numerical tool for the prediction of potential blood flow of a planned VA surgery on the basis of preoperative ultrasound evaluation of arterial and venous sizes and blood flow. RESULTS: Here we present the numerical model, previously developed and tested, and we describe the web-based application that has been developed to help during surgical planning. CONCLUSIONS: The use of this tool in the clinical setting should allow to reduce the incidence of AVF non maturation as well as incidence of VA complications. PMID- 24817459 TI - Anatomical vascular variations and practical implications for access creation on the upper limb. AB - BACKGROUND: A profound knowledge of vascular anatomy and an understanding of vascular access functionality with respect to possible complications are critical in selecting the site for arteriovenous anastomosis. METHODS: Outline of vasculature variations of the upper limb with prevalence reported in literature of at least 1%, which may affect access creation, is depicted in this review. RESULTS: Over a dozen arterial anatomical anomalies of the upper limb, the most common is "high origin" of the radial artery (12-20%). Superficial positions of brachial, ulnar and radial artery as well as accessory brachial are another possible anatomic variants (0.5-7%). The most variable venous layout on the upper arm is seen in the anatomy of the brachial vein and the basilic vein forming the axillary vein. Three types of basilic vein course on upper arm have been described. CONCLUSIONS: The mapping technique to assess vascular variants facilitate site selection for AVF creation even in cases with previously attempted failed access (misdiagnosed vascular variant could force to secondary options). Thus, a thorough understanding and evaluation of anatomy, taking into consideration the possible vascular variations of the forearm and upper arm, are necessary in the planning of AVF creation and increase the success of AVF procedures. PMID- 24817460 TI - Which accesses should be abandoned or revised? AB - This review considers the factors in deciding whether to abandon a functioning access. Strong indications for ligation or excision of an access are infection or severe early-onset steal. Access ligation may also be required for central vein occlusion or high-output cardiac failure. In general, a failing or thrombosed access should be restored to function unless it is no longer required. For failing or thrombosed distal arteriovenous fistulas, it may be easiest to abandon it and create a new fistula a few centimetres proximally rather than perform angioplasty, which is likely to require repeating. Other accesses may be abandoned after repeated treatment of the same stenosis over a short period provided other options exist. PMID- 24817461 TI - Basilic vein transposition: review of different techniques. AB - This is a review of the basilic vein procedure and changes that have evolved to improve outcomes. This includes reviewing data on the one-stage vs. two-stage technique as well as elevation for the basilic vein. The review discusses data that help the surgeon decide which technique he should evaluate. PMID- 24817462 TI - Which cannulation technique for which patient. AB - Cannulation of arteriovenous (AV) access is a crucial part of vascular access management in hemodialysis patients. It can significantly affect survival of the AV access, and consequently, it probably influences patient survival. The best type of cannulation technique, rotating site versus constant site (or buttonhole), is currently debated, but the increase in infectious complications observed with the buttonhole technique suggests a prudent use of this technique, restricting it to specific patients. Even in cases with a specific indication, the balance between advantages of the constant site needling and the potentially severe consequences of access related systemic infection should be considered. Educational efforts in improving cannulation skills of dialysis staff are important for improving outcomes, as the proper use of the rotating site technique might still be the best approach to cannulation. PMID- 24817463 TI - Managing 'buttonhole' complications. AB - Cannulation problems in vascular access can be a cause for significant morbidity, mortality and risk loss of access site. Buttonhole cannulation has been promoted as a method of arteriovenous fistula (AVF) cannulation that has fewer complications and is more patient friendly (1, 2). Widespread use of this technique has resulted in several publications raising concerns about the complications associated with this technique. This article attempts to understand the anatomic and physiologic basis for this technique and may provide explanations for some of these complications. A clear understanding of the mechanism of function of this technique might help mitigate some of the complications and help devise techniques to reduce others. It focuses on evaluation of the buttonhole to identify the infectious problems that may predispose to bleeding and their management. PMID- 24817464 TI - Endovascular techniques for cannulation difficulties in dialysis access. AB - Although the arteriovenous fistula (AVF) is the access of choice for dialysis, its success as an access is limited by its high rate of failing to mature and its development of venous stenoses. This makes cannulation difficult or even impossible for dialysis staff. A variety of endovascular techniques exist for improving cannulation rates in AVFs. These include coil embolization of tributaries and balloon-assisted maturation in immature fistulae and fistuloplasty, stents and thrombus removal in mature failing access. This article aims to discuss the methods and evidence related to these techniques. PMID- 24817465 TI - Using tunneled femoral vein catheters for "urgent start" dialysis patients: a preliminary report. AB - BACKGROUND: Multiple benefits of arteriovenous fistulas (AVF) and arteriovenous grafts (AVGs) exist over catheters. As part of a strategy to preserve thoracic venous sites and reduce internal jugular (IJ) vein catheter use, we inserted tunneled femoral vein catheters in incident "urgent start" dialysis patients while facilitating a more appropriate definitive dialysis access. METHODS: "Urgent start" dialysis patients between January 15, 2013 and January 15, 2014 who required chronic dialysis, and did not have prior modality and vascular access plans, had tunneled femoral vein catheters inserted. We determined the femoral vein catheter associated infections rates, thrombosis, and subsequent dialysis access. Eligible patients were surveyed on their femoral vein catheter experience. RESULTS: Twenty-two femoral vein catheters were inserted without complications. Subsequently, one catheter required intraluminal thrombolytic locking, while all other catheters maintained blood flow greater than 300 ml/min. There were no catheter-related infections (exit site infection or bacteremia). Six patients continued to use their tunneled catheter at report end, one transitioned to peritoneal dialysis, thirteen to an arteriovenous graft, and two to a fistula. One patient received a tunneled IJ vein catheter. Of the patients who completed the vascular access survey, all indicated satisfaction with their access and that they had minimal complaints of bruising, bleeding, or swelling at their access sites. Pain/discomfort at the exit site was the primary complaint, but they did not find it interfered with activities of daily living. CONCLUSIONS: Femoral vein tunneled catheters appear to be a safe, well tolerated, and effective temporary access in urgent start dialysis patients while they await more appropriate long-term access. PMID- 24817466 TI - Long segment recanalization and dedicated central venous stenting in an ultimate attempt to restore vascular access central vein outflow. AB - PURPOSE: Maintaining vascular access in patients undergoing chronic hemodialysis is a challenging process, especially in patients enduring multiple central line placements and in whom peripheral options have been exhausted. CASE: We present a case of a 60-year-old male without options for peripheral vascular access due to multiple failed arteriovenous fistulas for hemodialysis. Furthermore, bilateral subclavian, brachiocephalic veins and iliac veins were occluded or significantly obstructed. After long segment central vein recanalization, an upper arm loop arteriovenous graft was implanted. The recanalized segment was stented with a 12 mm dedicated venous nitinol stent. CONCLUSION: Chronic central vein obstructions demand stents with both high radial force and flexibility. We recommend dedicated venous stents to improve technical success and reduce stent-related complications like early re-occlusion due to fracturing, kinking or straightening. PMID- 24817467 TI - Treatment of hemodialysis vascular access arteriovenous graft failure by percutaneous intervention. AB - A patent vascular access is the lifeline of end-stage renal disease patients depending on hemodialysis treatment. Once a functioning vascular access has been established, maintaining its patency is of utmost importance. During the last decades percutaneous techniques became increasingly important for the treatment of hemodialysis vascular access graft failure. In this review, the role of percutaneous balloon angioplasty and stent implantation is evaluated for different clinical scenarios, based on the available evidence. PMID- 24817468 TI - Aneurysm formation and infection in AV prosthesis. AB - In contrast to autogenous arteriovenous (AV) fistulae where true aneurysms are the most frequent type, aneurysms in prosthetic AV grafts are mostly false aneurysms and less frequently anastomotic ones. Indications for repair comprise false aneurysms exceeding twofold the graft diameter, those with rapid enlargement or with skin thinning or erosion, the ruptured, those causing pain or severely limiting the cannulable area and the infected ones. They can be managed either with conventional surgery or with endovascular techniques; However, conventional surgery represents the current standard treatment consisting of either aneurysm resection and interposition graft in situ or resection/exclusion and bypass via a new route to avoid a potentially contaminated area. PMID- 24817469 TI - Extra- and intrathoracic access. AB - The most complex patients requiring vascular access are those with bilateral central vein occlusions. Endovascular repair of the central lesions when feasible allow upper extremity use for access. When endovascular repair is not feasible, femoral vein transposition should be the next choice. When lower limb access sites have been exhausted or are contraindicated as in obese patients and in patients with peripheral arterial obstructive disease, a range of extrathoracic "exotic" extra-anatomic access procedures as the necklace cross-chest arteriovenous (AV) grafts, the ipsilateral axillo-axillary loops, the brachial jugular AV grafts, the axillo-femoral AV grafts or even intra-thoracic ones as the right atrial AV bypasses represent the vascular surgeon's last resort. The selection among those extra-anatomical chest-wall procedures should be based upon each patient's anatomy or patient-specific factors. PMID- 24817470 TI - Lower limb access. AB - Lower limb vascular access is used as an access site in patients in whom all upper limb possibilities for arteriovenous access creation are exhausted or with bilateral upper limb central vein occlusions. Autologous arteriovenous fistulae (AVF) using the greater saphenous vein have disappointing results apart from the isolated success. Autologous AVF using the femoral vein transposition have good results both in terms of long-term patency and are associated with a 10-fold reduction in infection risk compared with arteriovenous grafts (AVGs). However, a femoral vein transposition is a major undertaking and is associated with an increased risk of ischaemic complications. It is not a good option for patients with established peripheral arterial disease, but may be a good alternative for the younger patient with a high infection risk. The type of lower-extremity vascular access should be carefully tailored to the individual patient. PMID- 24817471 TI - Complex central venous catheter insertion for hemodialysis. AB - Despite the introduction of payment by results in the UK, there has been no decrease in central venous catheter (CVC) use. In part, this may relate to a requirement to dialyse through a CVC while autogenous access matures. Mortality data have improved in parallel and patients on hemodialysis live longer, which may lead to an increased exposure to CVCs.Exposure to CVCs carries a significant risk of infection and occlusion requiring their repositioning or exchange. The mid to long-term sequelae of CVC use is central venous occlusion leaving clinical teams with an ever increasing challenge to find adequate venous access.In this article, we will discuss the challenges faced by operators inserting CVCs into the hemodialysis-dependent patient who has exhausted more tradition insertion sites. These include translumbar caval catheters, transocclusion and transcollateral catheters, transjugular Inferior Vena Cava catheter positioning, and transhepatic catheters. We will demonstrate the techniques employed, complications, and anticipated longevity of function. PMID- 24817472 TI - Dialysis central venous catheter types and performance. AB - The choice of both short-term (nontunneled) and long-term (tunneled) central venous catheters (CVCs) for hemodialysis is a difficult one, due to the large number of available catheters, with very different characteristics and cost.CVC related complications (in particular infections, thrombosis and inefficient dialysis) can determine ominous consequences and death, with extremely elevated costs due to prolonged hospitalization and expensive procedures. Thus, the correct balance between cost and quality of CVC is required when deciding which kind of CVC should be adopted.In this regard, the design of CVCs has become a very active area of industrial and clinical research, with the ultimate goal of improving the long-term function of the catheter and of reducing complication rates, because even small improvements in the complication or reintervention rates have a positive impact on individual patient care and cost to society. In this article we review the general features of CVCs, including differences between tunneled and nontunneled CVCs, materials and their compatibility with lock solutions, the implications of straight versus precurved design in nontunneled CVCs, lumen and tip features with their clinical implications, catheter coatings and their effect on infection and thrombosis. PMID- 24817473 TI - One-stage and two-stage designs for phase II clinical trials with survival endpoints. AB - This work is motivated by trials in rapidly lethal cancers or cancers for which measuring shrinkage of tumours is infeasible. In either case, traditional phase II designs focussing on tumour response are unsuitable. Usually, tumour response is considered as a substitute for the more relevant but longer-term endpoint of death. In rapidly lethal cancers such as pancreatic cancer, there is no need to use a surrogate, as the definitive endpoint is (sadly) available so soon. In uveal cancer, there is no counterpart to tumour response, and so, mortality is the only realistic response available. Cytostatic cancer treatments do not seek to kill tumours, but to mitigate their effects. Trials of such therapy might also be based on survival times to death or progression, rather than on tumour shrinkage. Phase II oncology trials are often conducted with all study patients receiving the experimental therapy, and this approach is considered here. Simple extensions of one-stage and two-stage designs based on binary responses are presented. Outcomes based on survival past a small number of landmark times are considered: here, the case of three such times is explored in examples. This approach allows exact calculations to be made for both design and analysis purposes. Simulations presented here show that calculations based on normal approximations can lead to loss of power when sample sizes are small. Two-stage versions of the procedure are also suggested. PMID- 24817474 TI - Laparoscopic or SILS liver resection for hepatic left lateral sectionectomy? PMID- 24817476 TI - Site-directed analysis on protein hydrophobicity. AB - Hydrophobicity of a protein is considered to be one of the major intrinsic factors dictating the protein aggregation propensity. Understanding how protein hydrophobicity is determined is, therefore, of central importance in preventing protein aggregation diseases and in the biotechnological production of human therapeutics. Traditionally, protein hydrophobicity is estimated based on hydrophobicity scales determined for individual free amino acids, assuming that those scales are unaltered when amino acids are embedded in a protein. Here, we investigate how the hydrophobicity of constituent amino acid residues depends on the protein context. To this end, we analyze the hydration free energy-free energy change on hydration quantifying the hydrophobicity-of the wild-type and 21 mutants of amyloid-beta protein associated with Alzheimer's disease by performing molecular dynamics simulations and integral-equation calculations. From detailed analysis of mutation effects on the protein hydrophobicity, we elucidate how the protein global factor such as the total charge as well as underlying protein conformations influence the hydrophobicity of amino acid residues. Our results provide a unique insight into the protein hydrophobicity for rationalizing and predicting the protein aggregation propensity on mutation, and open a new avenue to design aggregation-resistant proteins as biotherapeutics. PMID- 24817475 TI - Efficacy and safety of vitamin K-antagonists (VKA) for atrial fibrillation in non dialysis dependent chronic kidney disease. AB - BACKGROUND: Essential information regarding efficacy and safety of vitamin K antagonists (VKA) treatment for atrial fibrillation (AF) in non-dialysis dependent chronic kidney disease (CKD) is still lacking in current literature. The aim of our study was to compare the risks of stroke or transient ischemic attack (TIA) and major bleeds between patients without CKD (eGFR >60 ml/min), and those with moderate (eGFR 30-60 ml/min), or severe non-dialysis dependent CKD (eGFR <30 ml/min). METHODS: We included 300 patients without CKD, 294 with moderate, and 130 with severe non-dialysis dependent CKD, who were matched for age and sex. Uni- and multivariate Cox regression analyses were performed reporting hazard ratios (HRs) for the endpoint of stroke or TIA and the endpoint of major bleeds as crude values and adjusted for comorbidity and platelet inhibitor use. RESULTS: Overall, 6.2% (45/724, 1.7/100 patient years) of patients developed stroke or TIA and 15.6% (113/724, 4.8/100 patient years) a major bleeding event. Patients with severe CKD were at high risk of stroke or TIA and major bleeds during VKA treatment compared with those without renal impairment, HR 2.75 (95%CI 1.25-6.05) and 1.66 (95%CI 0.97-2.86), or with moderate CKD, HR 3.93(1.71-9.00) and 1.86 (95%CI 1.08-3.21), respectively. These risks were similar for patients without and with moderate CKD. Importantly, both less time spent within therapeutic range and high INR-variability were associated with increased risks of stroke or TIA and major bleeds in severe CKD patients. CONCLUSIONS: VKA treatment for AF in patients with severe CKD has a poor safety and efficacy profile, likely related to suboptimal anticoagulation control. Our study findings stress the need for better tailored individualised anticoagulant treatment approaches for patients with AF and severe CKD. PMID- 24817477 TI - Elastic-viscoplastic modeling of soft biological tissues using a mixed finite element formulation based on the relative deformation gradient. AB - The characteristic highly nonlinear, time-dependent, and often inelastic material response of soft biological tissues can be expressed in a set of elastic viscoplastic constitutive equations. The specific elastic-viscoplastic model for soft tissues proposed by Rubin and Bodner (2002) is generalized with respect to the constitutive equations for the scalar quantity of the rate of inelasticity and the hardening parameter in order to represent a general framework for elastic viscoplastic models. A strongly objective integration scheme and a new mixed finite element formulation were developed based on the introduction of the relative deformation gradient-the deformation mapping between the last converged and current configurations. The numerical implementation of both the generalized framework and the specific Rubin and Bodner model is presented. As an example of a challenging application of the new model equations, the mechanical response of facial skin tissue is characterized through an experimental campaign based on the suction method. The measurement data are used for the identification of a suitable set of model parameters that well represents the experimentally observed tissue behavior. Two different measurement protocols were defined to address specific tissue properties with respect to the instantaneous tissue response, inelasticity, and tissue recovery. PMID- 24817478 TI - The effect of non-genetic factors on the reproductive performance of Sanga and Friesian * Sanga crossbred dairy cattle breeds kept under hot and humid environment. AB - A study was conducted to assess the effect of non-genetic factors on the reproductive performance of Sanga and Friesian * Sanga crossbred dairy cattle kept at Amrahia Dairy Farm, Ghana. Records on 66 crossbred Friesian * Sanga and 105 purebred Sanga cattle from 2005 to 2012 were used. The effect of sex of calf (male or female), season of calving (major, minor and dry), year of calving (2005 2012) and parity (first to third) on birthweight, calving interval and age at first calving were determined. The data were analyzed using the general linear model procedures of GenStat (Discovery Edition). The effect of parity of dam, year of calving, season of calving and sex of calf were considered as fixed effects for evaluating the different reproductive traits. Data on calving and conception rates over the period were 74.3 and 76.1%, respectively. The overall mean values for birthweight, age at first calving and calving interval obtained were 23.9 +/- 1.5 and 22.8 +/- 1.4 kg, 38.8 +/- 2.5 and 40.2 +/- 2.4 months and 390.8 +/- 12.5 and 413.6 +/- 12.1 days for the crossbred and Sanga, respectively. It was observed that all the major determinants of reproductive performance studied apart from birthweight were significantly influenced by year of birth, parity, season of calving and sex. PMID- 24817479 TI - Detection of enteric pathogens in Turkey flocks affected with severe enteritis, in Brazil. AB - Twenty-two flocks of turkeys affected by enteric problems, with ages between 10 and 104 days and located in the Southern region of Brazil, were surveyed for turkey by PCR for turkey astrovirus type 2 (TAstV-2), turkey coronavirus (TCoV), hemorrhagic enteritis virus (HEV), rotavirus, reovirus, Salmonella spp., and Lawsonia intracellularis (Li) infections. Eleven profiles of pathogen combination were observed. The most frequently encountered pathogen combinations were TCoV Li, followed by TCoV-TAstV-2-Li, TCoV-TastV-2. Only TCoV was detected as the sole pathogen in three flocks. Eight and 19 flocks of the 22 were positive for TAstV-2 and TCoV, respectively. Six were positive for Salmonella spp. and L. intracellularis was detected in 12 turkey flocks. Reovirus and HEV were not detected in this survey. These results throw new light on the multiple etiology of enteritis in turkeys. The implications of these findings and their correlation with the clinical signs are comprehensively discussed, illustrating the complexity of the enteric diseases. PMID- 24817480 TI - Ureaplasma diversum as a cause of pustular vulvovaginitis in bovine females in Vale Guapore, Mato Grosso State, Brazil. AB - Ureaplasma diversum has been associated with various reproductive problems in cattle that include granular vulvovaginitis, weak calves, and abortion. This study was conducted in a beef herd situated in the Middle-West region of Brazil, and the objectives were to verify the presence of U. diversum and to elucidate its possible relationships with independent variables in this bovine herd population. A total of 134 vaginal mucous swabs were taken for polymerase chain reaction (PCR). Of these, 51 (38 %) were PCR positive for U. diversum. Of the 58 heifers with vulvovaginal lesions characterized by hyperemia, granulated lesions, and edema distributed throughout the vulvar mucosa, 37 (64 %) were U. diversum positive; of the 76 heifers without reproductive lesions, 14 (18 %) were U. diversum positive. All tested samples were negative for bovine herpesvirus 1 (BoHV-1). Multivariate logistic regression revealed that the following two variables were significantly associated with the presence of U. diversum: the presence of vulvar lesions (p = 0.001) and the presence of a progesterone (P4) device (p = 0.001). These findings indicate that U. diversum should be considered a pathogen that is associated with pustular vulvovaginitis in heifers from the Mato Grosso state and that additional studies of the risk factors associated with intravaginal P4 device transmission should be performed. PMID- 24817482 TI - Functional communication training in the treatment of problem behavior maintained by access to rituals. AB - This study evaluated the assessment and treatment of problem behaviors related to rituals for children with autism. After functional analyses, we used a multiple probe design to examine the effects of functional communication training (FCT) plus extinction and schedule thinning as a treatment package for problem behavior and appropriate communication for 3 children. Results of the functional analyses suggested that problem behavior was maintained by reinstatement of the interrupted routine for all participants, and the treatment package reduced problem behavior. Generalization across activities was observed for 1 participant. PMID- 24817481 TI - The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice. AB - Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option. PMID- 24817483 TI - Improved allometric models to estimate the aboveground biomass of tropical trees. AB - Terrestrial carbon stock mapping is important for the successful implementation of climate change mitigation policies. Its accuracy depends on the availability of reliable allometric models to infer oven-dry aboveground biomass of trees from census data. The degree of uncertainty associated with previously published pantropical aboveground biomass allometries is large. We analyzed a global database of directly harvested trees at 58 sites, spanning a wide range of climatic conditions and vegetation types (4004 trees >= 5 cm trunk diameter). When trunk diameter, total tree height, and wood specific gravity were included in the aboveground biomass model as covariates, a single model was found to hold across tropical vegetation types, with no detectable effect of region or environmental factors. The mean percent bias and variance of this model was only slightly higher than that of locally fitted models. Wood specific gravity was an important predictor of aboveground biomass, especially when including a much broader range of vegetation types than previous studies. The generic tree diameter-height relationship depended linearly on a bioclimatic stress variable E, which compounds indices of temperature variability, precipitation variability, and drought intensity. For cases in which total tree height is unavailable for aboveground biomass estimation, a pantropical model incorporating wood density, trunk diameter, and the variable E outperformed previously published models without height. However, to minimize bias, the development of locally derived diameter-height relationships is advised whenever possible. Both new allometric models should contribute to improve the accuracy of biomass assessment protocols in tropical vegetation types, and to advancing our understanding of architectural and evolutionary constraints on woody plant development. PMID- 24817484 TI - Experiences with the use of varenicline in daily practice in the Netherlands: a prospective, observational cohort study. AB - BACKGROUND: Although a concise overview of adverse drug reactions (ADRs) to varenicline is available, little is known about the use of varenicline in daily practice and time-related information about ADRs. OBJECTIVE: The aim of this study was to gain insight in the safety and use of varenicline in daily practice. METHODS: A prospective, observational, non-interventional cohort study was performed. The study population was defined as first-time users recruited through participating pharmacies between 1 December 2008 and 31 March 2012. Patients could sign up for the study on a dedicated website. Web-based questionnaires were sent after 1, 2 and 6 weeks, 3 months and 4 months after patients started to use varenicline. Questions were asked about drug use and ADRs. Information about the ADR, its seriousness and the action taken when experiencing an ADR was gathered. RESULTS: A total of 1,418 patients signed up for the study. The response rates for the various questionnaires varied from 31.3 to 62.5 %. At least one ADR was reported by 58.8 % of the patients. The most frequently reported ADRs were nausea (30.8 %), abdominal pain (11.2 %) and abnormal dreaming (10.4 %). Most patients did not stop taking varenicline when they experienced these ADRs. The median latency times for ADRs reported more than 50 times were 3-7 days, with an exception for depressed mood, which had a latency time of 10 days. CONCLUSION: This prospective cohort study has given insight into latency time and action taken with varenicline when ADRs occur during treatment with varenicline in daily practice. It confirms the ADR pattern detected prior to marketing of the drug. PMID- 24817485 TI - Stratum corneum molecular mobility in the presence of natural moisturizers. AB - The outermost layer of the skin, the stratum corneum (SC), is a lipid-protein membrane that experiences considerable osmotic stress from a dry and cold climate. The natural moisturizing factor (NMF) comprises small and polar substances, which like osmolytes can protect living systems from osmotic stress. NMF is commonly claimed to increase the water content in the SC and thereby protect the skin from dryness. In this work we challenge this proposed mechanism, and explore the influence of NMF on the lipid and protein components in the SC. We employ natural-abundance (13)C solid-state NMR methods to investigate how the SC molecular components are influenced by urea, glycerol, pyrrolidone carboxylic acid (PCA), and urocanic acid (UCA), all of which are naturally present in the SC as NMF compounds. Experiments are performed with intact SC, isolated corneocytes and model lipids. The combination of NMR experiments provides molecularly resolved qualitative information on the dynamics of different SC lipid and protein components. We obtain completely novel molecular information on the interaction of these NMF compounds with the SC lipids and proteins. We show that urea and glycerol, which are also common ingredients in skin care products, increase the molecular mobility of both SC lipids and proteins at moderate relative humidity where the SC components are considerably more rigid in the absence of these compounds. This effect cannot be attributed to increased SC water content. PCA has no detectable effect on SC molecular mobility under the conditions investigated. It is finally shown that the more apolar compound, UCA, specifically influences the mobility of the SC lipid regions. The present results show that the NMF components act to retain the fluidity of the SC molecular components under dehydrating conditions in such a way that the SC properties remain largely unchanged as compared to more hydrated SC. These findings provide a new molecular insight into how small polar molecules in NMF and skin care products act to protect the human skin from drying. PMID- 24817487 TI - Toward in silico modeling of palladium-hydrogen-carbon nanohorn nanocomposites. AB - We present the first in silico modeling of the Pd-H-single-walled carbon nanohorn nanocomposites. Temperature-quench Monte Carlo simulations are used to generate the most stable morphologies of Pd81 clusters (cluster sizes of ~2 nm) deposited inside the morphologically defective single-walled carbon nanohorns (S. Furmaniak, A. P. Terzyk, K. Kaneko, P. A. Gauden, P. Kowalczyk, T. Itoh, Phys. Chem. Chem. Phys., 2013, 15, 1232-1240). The optimized Pd81-single-walled carbon nanohorn nanocomposites are next used in calculating the H binding energy distributions at 300 K. The most stable positions of H impurity in confined Pd81 clusters are identified, showing subsurface character of H absorption from the dilute H2 gas at 300 K. The H binding energy distribution on the Pd(100) open surface at 300 K is computed and compared with those corresponding to Pd81-single walled carbon nanohorn nanocomposites. Finally, the impact of the Pd-H short range order on the H binding energy is explored and critically discussed. PMID- 24817486 TI - Potential use of NOACs in developing countries: pros and cons. AB - PURPOSE: Although vitamin K antagonists (VKAs) are effective for long-term thromboprophylaxis in atrial fibrillation (AF), their limitations have led to widespread underutilisation, especially in the developing world. Novel oral anticoagulants (NOACs) have emerged as promising alternatives to VKAs, although there are some particular considerations and challenges to their introduction in developing countries. This review summarises the current state of antithrombotic management of AF in the developing world, explores the early evidence for the NOACs and describes some of the special considerations that must be taken into account when considering the role of the NOACs within developing countries' health care systems. METHODS: A literature search was conducted via PubMed and Google Scholar to find articles published in English between the years 2000 to 2014. Search terms used were "atrial fibrillation", "oral anticoagulants", "warfarin", "NOACs", "dabigatran", "rivaroxaban", "apixaban", "edoxaban", "time in therapeutic range", "International Normalized Ratio" "cost-effectiveness", "stroke", "adverse-drug reactions" and "drug-drug interactions", together with the individual names of developing countries as listed by the World Bank. We reviewed the results of randomized clinical trials, relevant retrospective and prospective studies, case-studies and review articles. RESULTS: Many developing countries lack or have sporadic data on the quality of AF management, making it difficult to anticipate the potential impact of NOACs in these settings. The utilisation of anticoagulants for AF appears highly variable in developing countries. Given the issues associated with VKA therapy in many developing countries, NOACs offer some potential advantages; however, there is insufficient evidence to advocate the widespread replacement of warfarin at present. VKAs may continue to have a role in selected patients or countries, especially if alternative monitoring strategies can be utilised. CONCLUSION: The evaluation of the introduction of NOACs should consider safety, budget concerns and the quality of oral anticoagulation care achieved by each country. Prospective registries will be important in developing countries to better elucidate the comparative safety, efficacy and cost-effectiveness of NOACs and VKAs as NOACs are introduced into practice. PMID- 24817489 TI - Hierarchical 3D TiO2@Fe2O3 nanoframework arrays as high-performance anode materials. AB - Hierarchical 3D TiO2@Fe2O3 nanoframework arrays grown on a Ti substrate are synthesized via a facile hydrothermal reaction. As the synergetic effect of this hybrid material, the TiO2@Fe2O3 electrode shows superior rate capability and cycling performance to bare TiO2 and Fe2O3 electrodes. PMID- 24817488 TI - A frequency-tagging electrophysiological method to identify central and peripheral visual field deficits. AB - BACKGROUND: The aim of this study was to develop a fast and efficient electrophysiological protocol to examine the visual field's integrity, which would be useful in pediatric testing. METHODS: Steady-state visual-evoked potentials (ssVEPs) to field-specific radial checkerboards flickering at two cycle frequencies (7.5 and 6 Hz for central and peripheral stimulations, respectively) recorded at Oz were collected from 22 participants from 5 to 34 years old and from 5 visually impaired adolescents (12-16 years old). Responses from additional leads (POz, O1, O2), and the impact of gaze deviation on the signals, were also investigated in a subgroup of participants. RESULTS: Steady state visual-evoked potentials responses were similar at all electrode sites, although the signal from the central stimulation was significantly higher at Oz and was highly sensitive in detecting gaze deviation. No effect of age or sex was found, indicating similar ssVEP responses between adults and healthy children. Visual acuity was related to the central signal when comparing healthy participants with four central visual impaired adolescents. Clinical validation of our electrophysiological protocol was also achieved in a 15-year-old adolescent with a severe peripheral visual deficit, as assessed with Goldmann perimetry. CONCLUSIONS: A single electrode over Oz is sufficient to gather both central and peripheral visual signals and also to control for gaze deviation. Our method presents several advantages in evaluating visual fields integrity, as it is fast, reliable, and efficient, and applicable in children as young as 5 years old. However, a larger sample of healthy children should be tested to establish clinical norms. PMID- 24817490 TI - Identification of climate-resilient integrated nutrient management practices for rice-rice cropping system--an empirical approach to uphold food security. AB - Yield datasets of long-term experiments on integrated nutrient management in rice rice cropping systems were used to investigate the relationship of variability in rainfall, temperature, and integrated nutrient management (INM) practices in rice rice cropping system in three different agroecological regions of India. Twelve treatments with different combinations of inorganic (chemical fertilizer) and organic (farmyard manure, green manure, and paddy straw) were compared with farmer's conventional practice. The intraseasonal variations in rice yields are largely driven by rainfall during kharif rice and by temperature during rabi rice. Half of the standard deviation from the average monthly as well as seasonal rainfall during kharif rice and 1 degrees C increase or decrease from the average maximum and minimum temperature during rabi rice has been taken as the classification of yield groups. The trends in the date of effective onset of monsoon indicate a 36-day delay during the 30-year period at Rajendranagar, which is statistically significant at 95 % confidence level. The mean annual maximum temperature shows an increasing trend in all the study sites. The length of monsoon also showed a shrinking trend in the rate of 40 days during the 30-year study period at Rajendranagar representing a semiarid region. At Bhubaneshwar, the application of 50 % recommended NPK through chemical fertilizers and 50 % N through green manure resulted in an overall average higher increase of 5.1 % in system productivity under both excess and deficit rainfall years and also during the years having seasonal mean maximum temperature >=35 degrees C. However, at Jorhat, the application of 50 % recommended NPK through chemical fertilizers and 50 % N through straw resulted in an overall average higher increase of 7.4 % in system productivity, while at Rajendranagar, the application of 75 % NPK through chemical fertilizers and 25 % N through green manusre resulted in an overall average higher increase of 8.8 % in system productivity. This study highlights the adaptive capacity of different integrated nutrient management practices to rainfall and temperature variability under a rice-rice cropping system in humid, subhumid, and semiarid ecosystems. PMID- 24817491 TI - Dengue transmission based on urban environmental gradients in different cities of Pakistan. AB - This study focuses on the dengue transmission in different regions of Pakistan. For this purpose, the data of dengue cases for 2009-2012 from four different cities (Rawalpindi, Islamabad, Lahore, and Karachi) of the country is collected, evaluated, and compiled. To identify the reasons and regions of higher risk of Dengue transmission, land use classification, analysis of climate covariates and drainage patterns was done. Analysis involves processing of SPOT 5 10 m, Landsat TM 30 m data sets, and SRTM 90 m digital elevation models by using remote sensing and GIS techniques. The results are based on the change in urbanization and population density, analysis of temperature, rainfall, and wind speed; calculation of drainage patterns including stream features, flow accumulation, and drainage density of the study areas. Results suggest that the low elevation areas with calm winds and minimum temperatures higher than the normal, rapid increase in unplanned urbanization, low flow accumulation, and higher drainage density areas favor the dengue transmission. PMID- 24817492 TI - Change in tibiofemoral rotational alignment during total knee arthroplasty. AB - BACKGROUND: Rotational mismatch between femoral and tibial components has been recognized as a risk factor of unsuccessful total knee arthroplasty (TKA), but a main cause of rotational mismatch is uncertain. This study aims to evaluate rotational alignment of the knee by measuring both component rotation and version of the knee in TKA. METHOD: Fifty-one TKAs (mean age 73.7 years) were included in this study. The three dimensional, weight-bearing knee alignment was measured before and after TKA. A transepicondylar axis was referenced to femoral component rotation, and an anteroposterior axis of the tibia (middle of posterior cruciate ligament attachment to medial border of patella tendon attachment) was referenced to tibial component rotation. Knee rotational angle was defined as the angle between these two axes. RESULT: The mean preoperative knee rotation angle of 9.7 degrees (+/-8.5 degrees ) internal rotation was significantly reduced to 1.8 degrees (+/-7.3 degrees ) external rotation after TKA. Twenty-one of 51 knees (41%) exhibited rotational mismatch (>10 degrees ) preoperatively, and this number was reduced to eight knees (16%) post-TKA. The femoral component was rotationally aligned within 5 degrees of neutral in all knees, while rotational alignment of the tibial component showed a high degree of variability (range 20.7 degrees internal rotation to 17.2 degrees external rotation). CONCLUSION: Rotational malposition of the tibial component was considered to be a main factor of rotational mismatch of the knee after TKA. PMID- 24817493 TI - Femoral and sciatic nerve block for hindfoot and ankle surgery. AB - BACKGROUND: The use of regional anesthesia, such as ankle block or sciatic nerve block, has gained in popularity due to considerations of patient comfort and safety in foot and ankle surgery. However, if the operation extends above the midfoot or if a thigh tourniquet is required, general or spinal anesthesia is needed. The authors aimed to determine by prospective study whether a 'double block', involving femoral and sciatic nerve blocks, is advantageous under such conditions. MATERIALS AND METHODS: The effectiveness of a preoperative double block was prospectively evaluated in 26 consecutive patients undergoing a variety of foot and ankle procedures, compared with 32 patients with sciatic nerve block alone. Time of analgesia onset, length of block coverage, and complications were noted. Degree of pain was measured using VAS (Visual Analog Scale) scores at the operation, just after surgery, and at 2 h, 1 day, and 2 days after surgery. RESULTS: The surgical procedures performed under double block were ankle arthroscopy and medial ankle ligament reconstruction, and Achilles tendon repair, and the following conditions were treated; surgery for medial ankle fracture, ankle fusion, subtalar fusion, and surgery for hindfoot diseases, such as, talocalcaneal coalition. The average time required to analgesia onset was 63 min for a double block and 61 min for sciatic nerve block alone. Analgesia time lasted 12.0 h for a double block and 12.4 h for sciatic nerve block alone. Average VAS scores at the operation and immediately after the operation were 0.03 (range 0-1) and 0.16 (range 0-2) for sciatic nerve block, and 0.35 (range, 0-4), 0.31 (range 0-2) for double block. Average VAS scores at 2 h, 1 day, and 2 days postoperatively were 0.28 (range, 0-2), 2.16 (range 0-6), and 1.63 (range 0-5) for sciatic nerve block, and 0.42 (range 0-5), 2.27 (range 0-7), and 1.72 (range 0-8), respectively, for double block. CONCLUSION: The results of this prospective study suggest that double block provides good surgical anesthesia and good postoperative pain control for hindfoot and ankle surgery. PMID- 24817494 TI - New classification system for ossification of the posterior longitudinal ligament using CT images. AB - BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) is most frequently seen in the cervical spine. The types of cervical OPLL are classified into continuous, mixed, segmental, and other based on plain lateral X-ray. Computed tomography (CT) imaging is often used in clinical practice for evaluating ossified lesions as it can detect their precise location, size, and shape. However, to date, no CT classification of OPLL lesions has been proposed. METHODS: One hundred and forty-four patients diagnosed with cervical OPLL by plain radiograph were included in this study. Sagittal and axial CT images of the cervical spine were obtained. We propose three classification systems: A, B, and axial. Classification A comprises two lesion types: bridge and nonbridge. Classification B requires examiners to describe all vertebral and intervertebral levels where OPLL exits in the cervical spine. Axial classification comprises central and lateral lesions identified on axial CT images. Seven observers evaluated CT images using this classification system, and intra- and interrater reliability were examined. RESULTS: Averaged Fleiss' kappa coefficient of interrater agreement was 0.43 +/- 0.26 among the seven observers, averaged intrarater reliability for the existence of OPLL was 72.4 +/- 8.8% [95% confidence interval (CI) 67.5-76.8]. Fifty-four patients (37.5%) had the bridge type and 90 the nonbridge type according to Classification A; 102 (70.8%) had central and 42 (29.2%) lateral OPLL in the axial classification. Four representative cases defined according to the three classification types are reported here. CONCLUSION: Subcommittee members of the Investigation Committee on the Ossification of the Spinal Ligaments of the Japanese Ministry of Public Health and Welfare propose three new classification systems of cervical OPLL based on CT imaging: A, B, and axial. PMID- 24817495 TI - The short-term effect after a single injection of high-molecular-weight hyaluronic acid in patients with enthesopathies (lateral epicondylitis, patellar tendinopathy, insertional Achilles tendinopathy, and plantar fasciitis): a preliminary study. AB - BACKGROUND: Hyaluronic acid (HA) with a high molecular weight of 2700 kDa is approved in Japan to treat osteoarthritis of the knee, periarthritis scapulohumeralis, and knee pain associated with rheumatoid arthritis. The purpose of this preliminary study was to investigate the short-term efficacy, safety, and injectable volume of HA in the treatment of enthesopathies. METHODS: A total of 61 patients (16 with lateral epicondylitis, 14 with patellar tendinopathy, 15 with insertional Achilles tendinopathy, and 16 with plantar fasciitis) were each administered a single injection of HA (up to 2.5 ml). Efficacy and safety were assessed by comparing the visual analog scale (VAS) for pain and local symptoms before injection (baseline) and at 1 week after injection. We also investigated the injectable volume by means of the difference in syringe weight before and after injection and by the judgment of the administering investigator. RESULTS: The injection of HA resulted in a change in VAS (mean +/- SD) of -2.20 +/- 2.26 cm for the four sites overall and -2.55 +/- 2.43 cm for lateral epicondylitis, 2.01 +/- 2.16 cm for patellar tendinopathy, -1.80 +/- 1.91 cm for insertional Achilles tendinopathy, and -2.38 +/- 2.61 cm for plantar fasciitis. The injection of HA also improved local symptoms in each site. It was also determined that 2.5 ml of HA can be injected in each of the four sites. CONCLUSION: A single injection of HA resulted in similar improvements of pain in each of the four enthesopathies (lateral epicondylitis, patellar tendinopathy, insertional Achilles tendinopathy, and plantar fasciitis). These results suggest that HA could be clinically effective in the treatment of enthesopathies. PMID- 24817496 TI - The Dark Side of Authenticity: Feeling "Real" While Gambling Interacts with Enhancement Motives to Predict Problematic Gambling Behavior. AB - Engaging in activities that make people feel authentic or real is typically associated with a host of positive psychological and physiological outcomes (i.e., being authentic serves to increase well-being). In the current study, we tested the idea that authenticity might have a dark side among people engaged in an addictive or risky behavior (gambling). To test this possibility, we assessed gamblers (N = 61) who were betting on the National Hockey League playoff games at a sports bar. As predicted, people who felt authentic when gambling reported behavior associated with problem gambling (high frequency of betting) as well as problematic play (a big monetary loss and a big monetary win). Moreover, such behavior and gambling outcomes were particularly high among people who were motivated to gamble for the purpose of enhancement. The interaction of feeling authentic when betting and gambling for purposes of enhancing positive emotions proved especially troublesome for problematic forms of play. Implications of authenticity as a potential vulnerability factor for sports betting and other types of gambling are discussed. PMID- 24817497 TI - Design of a score to identify hospitalized patients at risk of drug-related problems. AB - PURPOSE: The potential impact of drug-related problems (DRP) on morbidity and mortality is a serious concern in hospitalized patients. This study aimed to design a risk score to identify patients most at risk of a DRP. METHODS: Data from patients admitted to a tertiary university hospital between January and August 2009 were used to design the risk score (training set). DRP were detected through a pharmacy warning system integrated in the computerized medical history. The variables associated with developing a DRP were identified through a binary multivariate logistic regression analysis and were used to compute the DRP risk score, which was subsequently validated in patients admitted between September and December 2009 (validation set). RESULTS: Of the 8713 patients included in the training set, at least one DRP was detected in 2425 (27.8%). Prescription of a higher number of drugs, higher comorbidity, advanced age, certain groups of the Anatomical Therapeutic Chemical classification system, and some major diagnostic categories were associated with risk of DRP. These variables were used to compute the DRP risk score. The area under the receiver operator characteristic curve was 0.778 (95%CI [0.768, 0.789]). Of the 4058 admissions included in the validation set, at least one DRP was detected in 876 (21.6%). The area under the receiver operator characteristic curve was 0.776 (95%CI [0.759, 0.792]). CONCLUSIONS: Knowledge of the variables associated with DRP could aid their early detection in at-risk patients. The use of an application that can be continually updated in daily clinical practice helps to optimize resources. PMID- 24817499 TI - Effects of radiation therapy on postoperative complications and adverse events in patients with head and neck reconstruction with flaps. AB - BACKGROUND: Radiation therapy is an essential treatment for head and neck cancer. However, the condition of the operative field is entirely altered after radiation therapy. This study aimed to examine the effects of preoperative radiation therapy on complications in patients who underwent head and neck reconstruction with flaps. METHODS: We retrospectively reviewed 252 instances of head and neck reconstruction with flaps in 240 patients between October 2000 and May 2011 at Okayama University Hospital. Of the participants, 51 had preoperative radiation exposure (21.3%) and 189 had no radiation exposure (78.7%). Postoperative complications were divided into three categories: minor complications that healed with conservative medical treatment within 4 weeks without a need for surgery; major complications requiring reoperation within 1 week after surgery (reoperation); and major complications needing additional operation later than 1 week after surgery (additional operation). RESULTS: Preoperative radiation therapy was only associated with major complications requiring reoperation later than 1 week after surgery (P < 0.001), open cervical wounds (P = 0.0030), and skin grafting for cervical skin necrosis (P = 0.0031) when compared to no radiation exposure. The results of flap failure were not significantly different between both groups (P = 0.3820). CONCLUSIONS: Minor complications and reoperation in the early postoperative period were not influenced by radiation exposure. The complications of radiation tend to be protracted and associated with additional operation later than 1 week after the initial surgery. It was thought that shortening of the duration of treatment was successful when we needed to perform early additional operations. PMID- 24817498 TI - A new approach to measuring partnership concurrency and its association with HIV risk in couples. AB - Empirical estimates of the association between concurrent partnerships (CP) and HIV risk are affected by non-sampling errors in survey data on CPs, e.g., because respondents misreport the extent of their CPs. We propose a new approach to measuring CPs in couples, which permits assessing how respondent errors affect estimates of the association between CPs and HIV risk. Each couple member is asked (1) to report whether s/he has engaged in CPs and (2) to assess whether his/her partner has engaged in CPs, since their couple started. Cross-tabulating these data yields multiple classifications (with varying combinations of sensitivity/specificity) of the CPs of each couple member. We then measure the association between CPs and HIV outcomes according to each classification. The resulting range of estimates is an indicator of the uncertainty associated with respondent errors. We tested this approach using data on 520 matched couples drawn from the Likoma Network Study. Results suggest that existing tests of the concurrency hypothesis are affected by significant uncertainty. PMID- 24817500 TI - Incidence of cancer following bariatric surgery: systematic review and meta analysis. AB - Obesity is linked to the development of cancer. Previous studies have suggested that there is a relationship between bariatric surgery and reduced cancer risk. Data sources were from Medline, Embase, and Cochrane Library. From 951 references, 13 studies met the inclusion criteria (54,257 participants). In controlled studies, bariatric surgery was associated with a reduction in the risk of cancer. The cancer incidence density rate was 1.06 cases per 1000 person-years within the surgery groups. In the meta-regression, we found an inverse relationship between the presurgical body mass index and cancer incidence after surgery (beta coefficient -0.2, P < 0.05). Bariatric surgery is associated with reduced cancer risk in morbidly obese people. However, considering the heterogeneity among the studies, conclusions should be drawn with care. PMID- 24817501 TI - [Practical information on language acquisition]. PMID- 24817502 TI - [First language acquisition research and theories of language acquisition]. AB - BACKGROUND: In principle, a child can seemingly easily acquire any given language. First language acquisition follows a certain pattern which to some extent is found to be language independent. Since time immemorial, it has been of interest why children are able to acquire language so easily. Different disciplinary and methodological orientations addressing this question can be identified. METHODS: A selective literature search in PubMed and Scopus was carried out and relevant monographies were considered. RESULTS: Different, partially overlapping phases can be distinguished in language acquisition research: whereas in ancient times, deprivation experiments were carried out to discover the "original human language", the era of diary studies began in the mid 19th century. From the mid-1920s onwards, behaviouristic paradigms dominated this field of research; interests were focussed on the determination of normal, average language acquisition. The subsequent linguistic period was strongly influenced by the nativist view of Chomsky and the constructivist concepts of Piaget. Speech comprehension, the role of speech input and the relevance of genetic disposition became the centre of attention. The interactionist concept led to a revival of the convergence theory according to Stern. DISCUSSION: Each of these four major theories--behaviourism, cognitivism, interactionism and nativism--have given valuable and unique impulses, but no single theory is universally accepted to provide an explanation of all aspects of language acquisition. Moreover, it can be critically questioned whether clinicians consciously refer to one of these theories in daily routine work and whether therapies are then based on this concept. It remains to be seen whether or not new theories of grammar, such as the so-called construction grammar (CxG), will eventually change the general concept of language acquisition. PMID- 24817505 TI - Inflammatory markers as predictors of surgical site infection after elective colorectal surgery: authors' reply. PMID- 24817506 TI - Cues for lexical tone perception in children: acoustic correlates and phonetic context effects. AB - PURPOSE: The authors investigated the effects of acoustic cues (i.e., pitch height, pitch contour, and pitch onset and offset) and phonetic context cues (i.e., syllable onsets and rimes) on lexical tone perception in Cantonese speaking children. METHOD: Eight minimum pairs of tonal contrasts were presented in either an identical phonetic context or in different phonetic contexts (different syllable onsets and rimes). Children were instructed to engage in tone identification and tone discrimination. RESULTS: Cantonese children attended to pitch onset in perceiving similarly contoured tones and attended to pitch contour in perceiving different-contoured tones. There was a decreasing level of tone discrimination accuracy, with tone perception being easiest for same rime different syllable onset, more difficult for different rime-same syllable onset, and most difficult for different rime-different syllable onset phonetic contexts. This pattern was observed in tonal contrasts in which the member tones had the same contour but not in ones in which the member tones had different contours. CONCLUSION: These findings suggest that in addition to pitch contour, the pitch onset is another important acoustic cue for tone perception. The relative importance of acoustic cues for tone perception is phonetically context dependent. These findings are discussed with reference to a newly modified TRACE model for tone languages (TTRACE). PMID- 24817507 TI - Fe or Fe-NO catalysis? A quantum chemical investigation of the [Fe(CO)3(NO)](-) catalyzed Cloke-Wilson rearrangement. AB - A quantum chemical investigation of the Bu4N[Fe(CO)3(NO)]-catalyzed Cloke-Wilson rearrangement of vinyl cyclopropanes is reported. It was found that allylic C-C bond activation can proceed through a SN2' or SN2-type mechanism. The application of the recently reported intrinsic bond orbital (IBO) method for all structures indicated that one Fe-N pi bond is directly involved. Further analysis showed that during the reaction oxidation occurs at the NO ligand exclusively. PMID- 24817508 TI - Design, synthesis and insecticidal activity of novel 1,1-dichloropropene derivatives. AB - BACKGROUND: Pyridalyl is a highly active insecticide against lepidopterous larvae, with a novel chemical structure not related to any other existing insecticide. To discover new pyridalyl analogues with high activity against resistant pests, a series of 1,1-dichloropropene derivatives bearing structurally diverse substituted heterocycle rings in place of the pyridine ring of pyridalyl were designed and synthesised. RESULTS: All of the title compounds were confirmed by (1)H NMR, (13)C NMR and high-resolution mass spectra. Two representative compounds (Ic and IIa) were further characterised by X-ray diffraction analysis. In addition, bioassays showed that most of the newly synthesised compounds displayed good insecticidal activity against Prodenia litura. Further determination of LD50 values and field trials identified compound IIa as the most promising candidate, which produced a much better 14 day control effect against diamondback moths and longer duration of efficacy than pyridalyl, indicating its potential for further development as a new insecticide for the control of lepidopteran insects. CONCLUSION: Compound IIa has great potential for further development as a new insecticide for the control of lepidopteran insects. PMID- 24817509 TI - The "rescue operation" for patients with cloacal exstrophy and its variants. AB - INTRODUCTION: A common error in the initial operative management of patients with cloacal exstrophy is to create an ileostomy leaving the colon defunctionalized and connected to the urinary tract. These patients benefit from a "rescue operation" to give them the best opportunity to be future pull-through candidates. METHODS: Nineteen patients were identified who underwent an inadequate diversion during the newborn period, leaving a distal defunctionalized colon, and required a "rescue operation". A retrospective review of the medical records of these patients was performed. RESULTS: A piece of colon was disconnected from the urinary tract, rescued from the pelvis, and incorporated into the fecal stream. The original stoma was closed, and an end colostomy was created. Fifteen patients were females and four were males. The length of rescued colon ranged from 5.5 to 20 cm. Symptoms present before the operation included: hyperchloremic acidosis (6), urinary tract infections (6), failure to thrive (5), sepsis (1), dehydration (1), and TPN dependent (1). There was resolution of these symptoms post-operatively. On follow up, 10 patients still have their colostomies as we are waiting for continued colonic growth, 6 patients had a pull-through after responding to our bowel management program through the stoma, 2 patients have a permanent stoma, and one patient expired. CONCLUSION: When patients with cloacal exstrophy, or its variants, receive an ileostomy or proximal colostomy at birth, a rescue operation should be attempted. PMID- 24817510 TI - A novel low molecular weight endo-xylanase from Streptomyces sp. CS628 cultivated in wheat bran. AB - An extracellular low molecular weight xylanase (Xyn628) from Streptomyces sp. CS628 was isolated from Korean soil sample, produced in wheat bran medium, purified, and biochemically characterized. Xyn628 was purified 4.8-fold with a 33.78 % yield using Sepharose CL-6B column chromatography. The purified xylanase was ~18.1 kDa estimated by SDS-PAGE and xylan zymography. N-terminal amino acid sequences of Xyn628 were AYIKEVVSRAYM. The enzyme was found to be stable in a broad range of pH (5.0-13.0) and up to 60 degrees C and have optimal pH and temperature of pH 11.0 and 60 degrees C, respectively. Xyn628 activities were remarkable affected by various detergents, chelators, modulators, and metal ions. The xylanase produced xylobiose and xylotriose as principal hydrolyzed end products from the xylan. It was found to degrade agro-waste materials like corn cob and wheat bran by Xyn628 (20 U/g) as shown by electron microscopy. As being simple in purification, low molecular weight, alkaline, thermostable, and ability to produce xylooligosaccharides show that Xyn628 has potential applications in bioindustries as a biobleaching agent or/and xylooligosaccharides production with an appropriate utilization of agro-waste. PMID- 24817511 TI - In vitro propagation, encapsulation, and genetic fidelity analysis of Terminalia arjuna: a cardioprotective medicinal tree. AB - The present study described an improved and reproducible in vitro regeneration system for Terminalia arjuna using nodal segment explants obtained from a mature plant. Shoot tips excised from in vitro proliferated shoots were encapsulated in 3 % sodium alginate and 100 mM CaCl2[Symbol: see text]2H2O for the development of synthetic seeds which may be applicable in short-term storage and germplasm exchange of elite genotype. Shoot multiplication was significantly influenced by a number of factors, namely types and concentrations of plant growth regulators, medium composition, repeated transfer of mother explants, subculturing of in vitro regenerated shoot clumps, agar concentrations, and temperature. Maximum numbers of shoots (16.50 +/- 3.67) were observed on modified Murashige and Skoog (MMS) medium containing 0.5 mg l(-1) of benzylaminopurine (BAP) and 0.1 mg l(-1) of naphthalene acetic acid (NAA). To shortening the regeneration pathway, rooting of micropropagated shoots under in vitro condition was excluded and an experiment on ex vitro rooting was conducted and it was observed that the highest percentage of shoots rooted ex vitro when treated with indole-3-butyric acid (IBA, 250 mg l( 1)) + 2-naphthoxy acetic acid (NOA, 250 mg l(-1)) for 5 min. The well-developed ex vitro rooted shoots were acclimatized successfully in soilrite under greenhouse conditions with 80 % survival of plants. Randomly amplified polymorphic DNA (RAPD) analysis confirmed that all the regenerated plants were genetically identical to the mother plant, suggesting the absence of detectable genetic variation in the regenerated plantlets. To the best of our knowledge, this is the first report on synthetic seed production as well as ex vitro rooting and genetic fidelity assessment of micropropagated shoots of T. arjuna. PMID- 24817512 TI - Electrocatalytic hydrogen generation by a trithiolato-bridged dimanganese hexacarbonyl anion with a turnover frequency exceeding 40,000 s(-1). AB - An unusual ionic manganese model complex [Mn(bpy)3](+)[(CO)3Mn(MU-SPh)3Mn(CO)3]( )(bpy: 2,2'-bipyridine) has been synthesized, which bears some structural resemblance to the active site of [FeFe] hydrogenase. An overpotential of 0.61 V has been determined for the electrocatalytic proton reduction using this complex in CH3CN with CF3COOH as the proton source. A turnover frequency of 44,600 s(-1) is achieved at high scan rates and in the presence of a large amount of acid. PMID- 24817513 TI - Causal inference for community-based multi-layered intervention study. AB - Estimating causal treatment effect for randomized controlled trials under post treatment confounding, that is, noncompliance and informative dropouts, is becoming an important problem in intervention/prevention studies when the treatment exposures are not completely controlled. When confounding is present in a study, the traditional intention-to-treat approach could underestimate the treatment effect because of insufficient exposure of treatment. In the recent two decades, many papers have been published to address such confounders to investigate the causal relationship between treatment and outcome of interest based on different modeling strategies. Most of the existing approaches, however, are suitable only for standard experiments. In this paper, we propose a new class of structural functional response model to address post-treatment confounding in complex multi-layered intervention studies within a longitudinal data setting. The new approach offers robust inference and is readily implemented. We illustrate and assess the performance of the proposed structural functional response model using both real and simulated data. PMID- 24817514 TI - Antimicrobial prophylaxis for colorectal surgery. AB - BACKGROUND: Research shows that administration of prophylactic antibiotics before colorectal surgery prevents postoperative surgical wound infection. The best antibiotic choice, timing of administration and route of administration remain undetermined. OBJECTIVES: To establish the effectiveness of antimicrobial prophylaxis for the prevention of surgical wound infection in patients undergoing colorectal surgery. Specifically to determine:1. whether antimicrobial prophylaxis reduces the risk of surgical wound infection;2. the target spectrum of bacteria (aerobic or anaerobic bacteria, or both);3. the best timing and duration of antibiotic administration;4. the most effective route of antibiotic administration (intravenous, oral or both);5. whether any antibiotic is clearly more effective than the currently recommended gold standard specified in published guidelines;6. whether antibiotics should be given before or after surgery. SEARCH METHODS: For the original review published in 2009 we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (Ovid) and EMBASE (Ovid). For the update of this review we rewrote the search strategies and extended the search to cover from 1954 for MEDLINE and 1974 for EMBASE up to 7 January 2013. We searched CENTRAL on the same date (Issue 12, 2012). SELECTION CRITERIA: Randomised controlled trials of prophylactic antibiotic use in elective and emergency colorectal surgery, with surgical wound infection as an outcome. DATA COLLECTION AND ANALYSIS: Data were abstracted and reviewed by one review author and checked by another only for the single, dichotomous outcome of surgical wound infection. Quality of evidence was assessed using GRADE methods. MAIN RESULTS: This updated review includes 260 trials and 68 different antibiotics, including 24 cephalosporins and 43,451 participants. Many studies had multiple variables that separated the two study groups; these could not be compared to other studies that tested one antibiotic and had a single variable separating the two groups. We did not consider the risk of bias arising from attrition and lack of blinding of outcome assessors to affect the results for surgical wound infection.Meta-analyses demonstrated a statistically significant difference in postoperative surgical wound infection when prophylactic antibiotics were compared to placebo/no treatment (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.28 to 0.41, high quality evidence). This translates to a reduction in risk from 39% to 13% with prophylactic antibiotics. The slightly higher risk of wound infection with short-term compared with long-term duration antibiotic did not reach statistical significance (RR 1.10, 95% CI 0.93 to 1.30). Similarly risk of would infection was slightly higher with single-dose antibiotics when compared with multiple dose antibiotics, but the results are compatible with benefit and harm (RR 1.30, 95% CI 0.81 to 2.10). Additional aerobic coverage and additional anaerobic coverage both showed statistically significant improvements in surgical wound infection rates (RR 0.44, 95% CI 0.29 to 0.68 and RR 0.47, 95% CI 0.31 to 0.71, respectively), as did combined oral and intravenous antibiotic prophylaxis when compared to intravenous alone (RR 0.56, 95% CI 0.43 to 0.74), or oral alone (RR 0.56, 95% CI 0.40 to 0.76). Comparison of an antibiotic with anaerobic specificity to one with aerobic specificity showed no significant advantage for either one (RR 0.84, 95% CI 0.30 to 2.36). Two small studies compared giving antibiotics before or after surgery and no significant difference in this timing was found (RR 0.67, 95% CI 0.21 to 2.15). Established gold-standard regimens recommended in major guidelines were no less effective than any other antibiotic choice. AUTHORS' CONCLUSIONS: This review has found high quality evidence that antibiotics covering aerobic and anaerobic bacteria delivered orally or intravenously (or both) prior to elective colorectal surgery reduce the risk of surgical wound infection. Our review shows that antibiotics delivered within this framework can reduce the risk of postoperative surgical wound infection by as much as 75%. It is not known whether oral antibiotics would still have these effects when the colon is not empty. This aspect of antibiotic dosing has not been tested. Further research is required to establish the optimal timing and duration of dosing, and the frequency of longer term adverse effects such as Clostridium difficile pseudomembranous colitis. PMID- 24817515 TI - Rare variants and autoimmune disease. AB - The study of rare variants in monogenic forms of autoimmune disease has offered insight into the aetiology of more complex pathologies. Research in complex autoimmune disease initially focused on sequencing candidate genes, with some early successes, notably in uncovering low-frequency variation associated with Type 1 diabetes mellitus. However, other early examples have proved difficult to replicate, and a recent study across six autoimmune diseases, re-sequencing 25 autoimmune disease-associated genes in large sample sizes, failed to find any associated rare variants. The study of rare and low-frequency variation in autoimmune diseases has been made accessible by the inclusion of such variants on custom genotyping arrays (e.g. Immunochip and Exome arrays). Whole-exome sequencing approaches are now also being utilised to uncover the contribution of rare coding variants to disease susceptibility, severity and treatment response. Other sequencing strategies are starting to uncover the role of regulatory rare variation. PMID- 24817516 TI - Chronic pancreatitis with benign biliary obstruction: management issues. AB - BACKGROUND: Benign biliary obstruction (BBO) is an important complication in patients with advanced chronic pancreatitis (CP). Its presentation varies from an incidental finding to overt jaundice. Thus it presents certain management issues. The present study was therefore performed to analyze the clinical presentation and management of biliary obstruction in patients with CP. METHODS: Retrospective analysis was performed from a prospectively collected database of 155 CP patients managed at our institute from October 2003 to June 2012. RESULTS: Among 43 (28 %) CP patients with biliary obstruction, 3 patients had evidence of malignancy on follow-up examination and were excluded from the final analysis. The various presentations include chronic nonprogressive elevation of serum alkaline phosphatase (SAP) (n = 15), a progressive increase in SAP with episodes of jaundice (n = 17), and persistent jaundice (n = 8). Of 15 patients with chronic nonprogressive elevation of SAP, 5 were managed conservatively, and the remaining 10 underwent only a pancreatic drainage procedure. During a median follow-up of 41 months (range 11-90 months), none of the 15 patients developed complications related to biliary obstruction. All patients with progressive increase in SAP levels and persistent jaundice underwent the biliary drainage procedure [choledochojejunostomy (CDJ, n = 20) and choledochoduodenostomy (CDD, n = 3)]. During a median follow-up of 30 months (range 10-89 months), two patients died of unrelated causes and two patients had an asymptomatic elevation of SAP. CONCLUSIONS: BBO is common in patients with CP; however, biliary drainage is not indicated for chronic nonprogressive elevation of SAP. In patients with a progressive increase in SAP or persistent jaundice, both CDJ and CDD provide effective biliary drainage. PMID- 24817517 TI - Preoperative MRI of the breast (POMB) influences primary treatment in breast cancer: a prospective, randomized, multicenter study. AB - BACKGROUND: Breast magnetic resonance imaging (MRI) has shown high sensitivity in determining tumor extent, multifocality, and occult contralateral breast cancer. Low specificity, unnecessary mastectomies, and costs are arguments against MRI. The purpose of this study was to determine whether preoperative breast MRI would affect primary surgical management, reduce reexcision/reoperation procedures, and influence the choice of neoadjuvant treatment in patients with newly diagnosed breast cancer. METHODS: This prospective, randomized, multicenter study included 440 breast cancer patients younger than aged 56 years from three, Swedish, large volume breast units. Patients were randomly allocated on a 1:1 basis to either preoperative staging with breast MRI (n = 220) or no breast MRI (n = 220) (control group). Treatment planning of all patients was discussed at multidisciplinary team conferences. RESULTS: In patients randomized to the MRI group, who had an observed higher percentage of planned breast-conserving surgery (BCS) compared with the control group, a change from suggested breast conservation to mastectomy occurred in 23 of 153 (15 %) patients. Breast MRI provided additional information in 83 of 220 (38 %) patients, which caused a change in treatment plan in 40 (18 %). The breast reoperation rate was significantly lower in the MRI group: 11 of 220 (5 %) versus 33 of 220 (15 %) in the control group (p < 0.001). The number of mastectomies, axillary reoperations, and the number of patients receiving neoadjuvant chemotherapy after definitive treatment did not differ significantly between the groups. CONCLUSIONS: Preoperative staging with breast MRI in women younger than age 56 years altered the treatment plan in 18 % of the patients. Although a higher MRI-related conversion rate from breast conservation to mastectomy was found, the final numbers of mastectomies did not differ between the two groups. The breast reoperation rate in the MRI group was significantly reduced. PMID- 24817518 TI - Cuticles of European and American lobsters harbor diverse bacterial species and differ in disease susceptibility. AB - Diseases of lobster shells have a significant impact on fishing industries but the risk of disease transmission between different lobster species has yet to be properly investigated. This study compared bacterial biofilm communities from American (Homarus americanus) and European lobsters (H. gammarus), to assess both healthy cuticle and diseased cuticle during lesion formation. Culture-independent molecular techniques revealed diversity in the bacterial communities of cuticle biofilms both within and between the two lobster species, and identified three bacterial genera associated with shell lesions plus two putative beneficial bacterial species (detected exclusively in healthy cuticle or healing damaged cuticle). In an experimental aquarium shared between American and European lobsters, heterospecific transmission of potentially pathogenic bacteria appeared to be very limited; however, the claws of European lobsters were more likely to develop lesions when reared in the presence of American lobsters. Aquarium biofilms were also examined but revealed no candidate pathogens for environmental transmission. Aquimarina sp. 'homaria' (a potential pathogen associated with a severe epizootic form of shell disease) was detected at a much higher prevalence among American than European lobsters, but its presence correlated more with exacerbation of existing lesions rather than with lesion initiation. PMID- 24817519 TI - Characteristics, therapies, and factors influencing outcomes of hospitalized hypernatremic geriatric patients. AB - PURPOSE: Hypernatremia is a common electrolyte disorder associated with adverse outcomes such as increased length of stay and mortality due to a variety of factors. Our aim was to investigate known factors as well as other variables which we had identified in hospitalized hypernatremic geriatric patients and their relationship to patient outcomes. METHODS: A retrospective chart review of all adult hospitalized patients in a 4-month period with a serum sodium level >150 mmol/L was performed. Factors evaluated included use of a nephrology consultation, certain urine laboratory measures, fluids employed, rate of correction, and patient's level of care setting. Outcome measures included length of stay and mortality. RESULTS: The patient mortality rate was 52 %. Mean age was 79.6 years (n = 33), and mean initial sodium level was 152.6 mmol/L. Plasma and urine osmolality, and urine sodium concentration were checked in less than 25 % of patients. Fifteen of 18 patients in the ICU expired, whereas only 2 of 15 patients not in the ICU expired (p < 0.0004, OR 32.50, CI 95 % (4.68-225.54)). Of the 23 patients (70 %) who had their serum sodium level corrected, 11 were corrected in <=3 days and 12 in >3 days, but this difference did not affect mortality rate (45 vs. 50 %, p = 0.99). The mortality rate was similar (60 %, p = 0.52) for those whose serum sodium level never corrected suggesting that correction did not influence outcomes. The fluids chosen for therapy of the hypernatremia were appropriate to the patients volume status. Five of 15 patients who received a nephrology consultation survived, while 11 of 18 patients without a nephrology consultation survived (p = 0.12). The mean length of stay was 25.0 +/- 23.9 days and no different for those who expired versus those who survived (25.2 +/- 21.2 vs. 24.8 +/- 25.9 days, p = 0.96). CONCLUSIONS: Hypernatremia is associated with a poor prognosis, and outcomes are still disappointing despite appropriate rates of correction, intensive monitoring, and the involvement of a nephrologist. Strategies directed at avoidance of the development of hypernatremia and attention to concomitant disease may provide significant patient benefit. PMID- 24817520 TI - Low body mass index is associated with adverse oncological outcomes following radical prostatectomy in Korean prostate cancer patients. AB - PURPOSE: The purpose of this study was to determine the impact of obesity on clinicopathological features and biochemical recurrence (BCR) following radical prostatectomy (RP) in Korean prostate cancer (PCa) patients. METHODS: A single institutional retrospective analysis was performed on 880 PCa patients treated by RP without neoadjuvant therapy between July 2005 and December 2011. Patients were stratified according to body mass index (BMI) standards for Asian populations: obese (BMI >=25 kg/m(2)), overweight (BMI 23-24.9 kg/m(2)), or normal weight (BMI <23 kg/m(2)). For analysis, overweight and obese patients were combined (n = 592, BMI >=23 kg/m(2)) and compared with normal weight patients (n = 288, BMI <23 kg/m(2)). BCR was defined as prostate-specific antigen (PSA) >=0.2 ng/ml following RP. RESULTS: Normal weight patients tended to be classified into the higher D'Amico risk category with smaller prostate volumes compared with obese and overweight patients. Normal weight patients had higher pathological Gleason scores and were at higher risk of BCR during the mean follow-up of 58.2 months. This translated to a higher 5-year BCR-free survival rate for obese and overweight patients compared with normal weight patients (77.8 vs. 70.3 %; p = 0.017). On multiple Cox-proportional hazards regression analysis incorporating variables of BMI category, PSA, positive surgical margins, pathological T stage, and Gleason score, higher BMI category remained a significant predictor of a lower risk of BCR (HR = 0.634, p = 0.028). CONCLUSIONS: Obese and overweight Korean PCa patients have lower Gleason scores and a reduced risk of BCR compared with normal weight patients. These findings suggest that body fat influences pathological features and oncologic outcomes of PCa. PMID- 24817521 TI - Evaluating the presence versus absence of the reinforcer during extinction. AB - The purpose of this study was to assess the effects of extinction when the reinforcer was present versus absent. These effects were examined with 2 human operant procedures (i.e., a computer program and a mechanical apparatus) with college students as participants. Discriminable properties of the apparatus appeared to influence responding during extinction. In general, responding during extinction was less likely with the mechanical apparatus when the reinforcer was absent and more likely with the computer program. PMID- 24817522 TI - Long Live Love. The implementation of a school-based sex-education program in The Netherlands. AB - Implementation of health education programs is often inadequately considered or not considered at all in planning, developing and evaluating interventions. With the focus being predominantly on the adoption stage, little is known about the factors influencing the implementation and continuation stages of the diffusion process. This study contributes to the understanding of factors that promote or impede each stage of the diffusion process in the school setting using the sex education program Long Live Love (LLL) as an example. A survey integrating different diffusion-related concepts was completed by 130 teachers. Results showed that teacher curriculum-related beliefs were associated with all stages in the diffusion process. Although adoption of LLL was predominantly related to teacher curriculum-related beliefs, implementation completeness and fidelity and continued use of LLL were also enhanced by contextual factors, namely teacher training and interactive context variables (school policy, governing body support and student response), respectively. The results of this study can be used to optimize the adoption, implementation and continuation of school-based (sexual) health promotion programs. PMID- 24817524 TI - Dual aging behaviour in a clay-polymer dispersion. AB - Clay-polymer compounds have recently attracted increasing attention due to their intriguing physical properties in colloidal science and their rheological non trivial behaviour in technological applications. Aqueous solutions of Laponite clay spontaneously age from a liquid up to an arrested state of different nature (gel or glass) depending on the colloidal volume fraction and ionic strength. We have investigated, through dynamic light scattering, how the aging dynamics of Laponite dispersions at fixed clay concentration (Cw = 2.0%) is modified by the addition of various amounts of poly(ethylene oxide) (PEO) (CPEO = (0.05 / 0.50) %) at two different molecular weights (Mw = 100 kg mol(-1) and Mw = 200 kg mol( 1)). A surprising and intriguing phenomenon has been observed: the existence of a critical polymer concentration C that discriminates between two different aging dynamics. With respect to pure Laponite systems the aging will be assisted (faster) or hindered (slower) for PEO concentrations respectively lower (CPEO < C) or higher (CPEO > C) than the critical concentration. In this way a control on the aging dynamics of PEO-Laponite systems is obtained. A possible explanation based on the balance of competitive mechanisms related to the progressive saturation of the clay surface by polymers is proposed. This study shows how a real control on the aging speed of the PEO-Laponite system is at hand and renders possible a real control of the complex interparticle interaction potential. PMID- 24817523 TI - Oxygen-promoted C-H bond activation at palladium. AB - [Pd(P(Ar)(tBu)2)2] (1, Ar=naphthyl) reacts with molecular oxygen to form Pd(II) hydroxide dimers in which the naphthyl ring is cyclometalated and one equivalent of phosphine per palladium atom is released. This reaction involves the cleavage of both C-H and O-O bonds, two transformations central to catalytic aerobic oxidizations of hydrocarbons. Observations at low temperature suggest the initial formation of a superoxo complex, which then generates a peroxo complex prior to the C-H activation step. A transition state for energetically viable C-H activation across a Pd-peroxo bond was located computationally. PMID- 24817525 TI - Interaction in the indole...imidazole heterodimer: structure, Franck-Condon analysis and energy decomposition. AB - The complex of indole and imidazole has been studied using a combination of theoretical chemistry techniques, with the relevant calculations compared to existing experimental resonant two-photon ionisation data. Results of fitted multidimensional Franck-Condon simulations based on ground and excited state geometry optimizations and harmonic vibrational frequencies confirm that the V shaped herringbone structure is that observed by experiment. The ground state interaction energy of these important biomolecular building blocks has been evaluated at a benchmark quality level using explicitly correlated coupled cluster theory, and the V-shaped structure is shown to be approximately 2 kcal mol(-1) more strongly bound than other possible conformers. The non-covalent interaction energy is decomposed into physical components using symmetry-adapted perturbation theory and it can be seen that although electrostatics dominate the interaction, dispersion plays a vital role in determining the optimal geometry. PMID- 24817526 TI - Heavy metal concentrations in timberline trees of eastern Tibetan Plateau. AB - Concentrations of 14 heavy metals (Ag, As, Cd, Co, Cr, Cu, Hg, Mo, Ni, Pb, Sb, Tl, V, and Zn) in needles, twigs, bark and xylem of spruce and fir collected at the timberline of eight sites along the Hengduan Mountains, eastern Tibetan Plateau, are reported. Twigs had the highest concentration for most of elements, while xylem had the lowest concentration. The connections between elements in twigs were much richer than other organ/tissues. Pb, Ni, As, Sb, Co, Cd, Hg, Cr and Tl which are partly through anthropogenic sources and brought in by monsoon, have been accumulated in twigs and needles by wet or dry deposition in south and east sites where are within or near pollutant sources. Under moderate pollution situation, vegetation are able to adjust the nutrient element (Cu and Zn) cycle rate, thus maintain a stable concentration level. Seldom V, Ag, and Mo are from external anthropogenic sources. Needles and twigs can be used as biomonitors for ecosystem environment when needles can simply distinguish the origin of elements and twigs are more sensitive to extra heavy metal input. PMID- 24817527 TI - Liposome-containing polymer films and colloidal assemblies towards biomedical applications. AB - Liposomes are important components for biomedical applications. Their unique architecture and versatile nature have made them useful carriers for the delivery of therapeutic cargo. The scope of this minireview is to highlight recent developments of biomimetic liposome-based multicompartmentalized assemblies of polymer thin films and colloidal carriers, and to outline a selection of recent applications of these materials in bionanotechnology. PMID- 24817528 TI - Tolerance and physiological correlates of neuromuscular electrical stimulation in COPD: a pilot study. AB - RATIONALE: Neuromuscular electrical stimulation (NMES) of the lower limbs is an emerging training strategy in patients with COPD. The efficacy of this technique is related to the intensity of the stimulation that is applied during the training sessions. However, little is known about tolerance to stimulation current intensity and physiological factors that could determine it. Our goal was to find potential physiological predictors of the tolerance to increasing NMES stimulation intensity in patients with mild to severe COPD. METHODS: 20 patients with COPD (FEV1 = 54+/-14% pred.) completed 2 supervised NMES sessions followed by 5 self-directed sessions at home and one final supervised session. NMES was applied simultaneously to both quadriceps for 45 minutes, at a stimulation frequency of 50 Hz. Spirometry, body composition, muscle function and aerobic capacity were assessed at baseline. Cardiorespiratory responses, leg discomfort, muscle fatigue and markers of systemic inflammation were assessed during or after the last NMES session. Tolerance to NMES was quantified as the increase in current intensity from the initial to the final NMES session (DeltaInt). RESULTS: Mean DeltaInt was 12+/-10 mA. FEV1, fat-free-mass, quadriceps strength, aerobic capacity and leg discomfort during the last NMES session positively correlated with DeltaInt (r = 0.42 to 0.64, all p<=0.06) while post/pre NMES IL-6 ratio negatively correlated with DeltaInt (r = -0.57, p = 0.001). FEV1, leg discomfort during last NMES session and post/pre IL-6 ratio to NMES were independent factors of variance in DeltaInt (r2 = 0.72, p = 0.001). CONCLUSION: Lower tolerance to NMES was associated with increasing airflow obstruction, low tolerance to leg discomfort during NMES and the magnitude of the IL-6 response after NMES. TRIAL REGISTRATION: ClinicalTrials.gov NCT00809120. PMID- 24817529 TI - Analysis of photosynthetically active radiation in Northwest China from observation and estimation. AB - Photosynthetically active radiation (PAR) observed at Fukang, China from 2005 to 2012 was used to investigate PAR variability and its relationship with global solar radiation (G) under various sky conditions in Northwest China. Clearness index (K t) was used for characterizing the sky conditions and model development; it was discovered that daily PAR/G (F p) generally increased from 1.79 +/- 0.016 mol MJ(-1) in November to 1.95 +/- 0.004 mol MJ(-1) in July with annual average being about 1.89 mol MJ(-1); F p generally decreased with sky conditions changing from overcast skies to clear skies in each month. Meanwhile, an efficient all-sky PAR model under any sky conditions has been proposed by investigating the dependence of hourly PAR on K t and cosine of solar zenith angle MU. The model was assessed through the statistical indices: mean bias error (MBE), mean absolute error (MAE), and root-mean-square error (RMSE) whose values were only 0.34% (-1.75%), 3.62% (3.47%), and 5.52% (4.79 %), respectively, at hourly (daily) basis. The model has also been tested at three other four sites with distinctly different climates in China. Finally, PAR values during 1961-2012 in Northwest China were reconstructed and annual mean daily PAR was 29.25 mol m(-2) d(-1). PAR decreased at 0.18 mol m(-2) d(-1) per decade during 1961-2012, and the decreases were sharpest in spring (0.63 mol m(-2) d(-1) per decade). The possible reasons for the long-term variability have also been analyzed, which will lay foundations for cloud effect study in the near future. PMID- 24817530 TI - Formal thought disorder in autism spectrum disorder predicts future symptom severity, but not psychosis prodrome. AB - Formal thought disorder (FTD) is a disruption in the flow of thought, which is inferred from disorganisation of spoken language. FTD in autism spectrum disorders (ASD) might be a precursor of psychotic disorders or a manifestation of ASD symptom severity. The current longitudinal study is a seven-year follow-up of 91 individuals aged 5-12 years with ASD. We tested (1) whether childhood FTD predicted prodromal symptoms of psychosis in adolescence and (2) whether childhood FTD was associated with greater ASD symptom severity in adolescence. ASD symptom severity was assessed in childhood (T1) and 7 years later (T2), using the autism diagnostic observation schedule (ADOS). At T1, the Kiddie-Formal Thought Disorder Rating Scale (KFTDS) was used to measure symptoms of FTD. At T2, the prodromal questionnaire (PQ) was used to assess prodromal symptoms of psychosis. FTD at T1 did not predict prodromal symptoms of psychosis at T2 in children with ASD. FTD symptoms at T1, namely illogical thinking, predicted ASD symptom severity at T2 and this effect remained significant after controlling for T1 ASD symptom severity. In children with ASD, illogical thinking predicts severity of ASD symptoms in adolescence, but FTD does not predict prodromal symptoms of psychosis. PMID- 24817532 TI - Integrating incomplete fossils by isolating conflicting signal in saturated and non-independent morphological characters. AB - Morphological characters are indispensable in phylogenetic analyses for understanding the pattern, process, and tempo of evolution. If characters are independent and free of systematic errors, then combining as many different kinds of characters as are available will result in the best-supported phylogenetic hypotheses. But since morphological characters are subject to natural selection for function and arise from the expression of developmental pathways, they may not be independent, a situation that may amplify any underlying homoplasy. Here, we use new dental and multi-locus genetic data from bats (Mammalia: Chiroptera) to quantify saturation and similarity in morphological characters and introduce two likelihood-based approaches to identify strongly conflicting characters and integrate morphological and molecular data. We implement these methods to analyze the phylogeny of incomplete Miocene fossils in the radiation of Phyllostomidae (New World Leaf-nosed Bats), perhaps the most ecologically diverse family of living mammals. Morphological characters produced trees incongruent with molecular phylogenies, were saturated, and showed rates of change higher than most molecular substitution rates. Dental characters encoded variation similar to that in other morphological characters, while molecular characters encoded highly dissimilar variation in comparison. Saturation and high rates of change indicate randomization of phylogenetic signal in the morphological data, and extensive similarity suggests characters are non-independent and errors are amplified. To integrate the morphological data into tree building while accounting for homoplasy, we used statistical molecular scaffolds and combined phylogenetic analyses excluding a small subset of strongly conflicting dental characters. The phylogenies revealed the Miocene nectar-feeding ?Palynephyllum nests within the crown nectar-feeding South American subfamily Lonchophyllinae, while the Miocene genus ?Notonycteris is sister to the extant carnivorous Vampyrum. These relationships imply new calibration points for timing of radiation of the ecologically diverse Phyllostomidae. [Chiroptera; conflict; dentition; morphology; Phyllostomidae; saturation; scaffold; systematic error.]. PMID- 24817533 TI - 8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases. AB - 8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1 /A2A adenosine receptor antagonists were identified. Several compounds showed triple-target inhibition; one of the best compounds was 8-(2,4-dichloro-5-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1 f]purine-2,4(1H,3H)-dione (72) (human AR: Ki A1 217 nM, A2A 233 nM; IC50 MAO-B: 508 nM). Dichlorinated compound 36 [8-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9 tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione] was found to be the best triple target drug in rat (Ki A1 351 nM, A2A 322 nm; IC50 MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics. PMID- 24817534 TI - Characterization of methicillin-resistant coagulase-negative staphylococci in milk from cows with mastitis in Brazil. AB - Staphylococci are one of the most prevalent microorganisms in bovine mastitis. Staphylococcus spp. are widespread in the environment, and can infect animals and humans as opportunistic pathogens. The objective of this study was to determine the frequency of methicillin-resistance (MR) among coagulase-negative staphylococci (CoNS) previously obtained from milk of mastitic cows in Brazil and to characterize the antimicrobial resistance phenotype/genotype and the SCCmec type of MRCoNS isolates. Identification of MRCoNS was based on both biochemical and molecular methods. Susceptibility testing for eleven antimicrobials was performed by disk-diffusion agar. Antimicrobial resistance genes and SCCmec were investigated by specific PCRs. Twenty-six MRCoNS were detected (20 % of total CoNS), obtained from 24 animals, and were identified as follows: S. epidermidis (7 isolates), S. chromogenes (7), S. warneri (6), S. hyicus (5) and S. simulans (1). All MRCoNS isolates carried mecA while the mecC gene was not detected in any CoNS. The SCCmec IVa was demonstrated in nine MRCoNS, while the remaining 17 isolates harbored non-typeable SCCmec cassettes. In addition to oxacillin and cefoxitin resistance, MRCoNS showed resistance to tetracycline (n = 7), streptomycin (n = 6), tobramycin (n = 6), and gentamicin (n = 4), and harbored the genes tet(K) (n = 7), str (n = 3), ant(4') (n = 6) and aac(6')-aph(2") (n = 4), respectively. In addition, seven strains showed intermediate resistance to clindamycin and two to streptomycin, of which two harboured the lnu(B) and lsa(E) genes and two the aad(E) gene, respectively. One isolate presented intermediate erythromycin and clindamycin resistance and harbored an erm(C) gene with an uncommon 89-bp deletion rendering a premature stop codon. MRCoNS can be implicated in mastitis of cows and they constitute a reservoir of resistance genes that can be transferred to other pathogenic bacteria. PMID- 24817536 TI - Preface to the special issues. PMID- 24817535 TI - Rapid expansion of mycotic aneurysm of left coronary sinus of Valsalva causing myocardial ischemia: report of a case. AB - We described a 71-year-old female of aneurysm of the left sinus of Valsalva from mycotic origin. She underwent aortic valve replacement 11 years ago. Repeated CT scans showed rapidly growing aneurysm below the left coronary ostium. On sixth day after the admission, she suddenly developed myocardial ischemia complicated with ventricular fibrillation. The patient was treated with emergent aortic root replacement and she recovered. We recommend emergent surgical repair of mycotic saccular aneurysm of the left sinus of Valsalva because a delay of surgery could be fatal. PMID- 24817537 TI - [New options in the treatment of acute heart failure]. AB - Acute heart failure is defined as the acute onset of symptoms due to hear failure necessitating emergency therapy. The in-hospital mortality rate ranges up to 10 % and in cardiogenic shock is 50-70 %. In acute heart failure, rapid diagnosis and causal therapy are necessary to avoid cardiogenic shock. In cases of acute coronary syndromes, primary percutaneous intervention should be performed immediately. Medical and apparative treatment strategies focus on decreasing pulmonary congestion, afterload, and neurohormonal activation in order to improve hemodynamics and reduce symptoms of dyspnea. In contrast to chronic heart failure, no medical therapy has been able to reduce mortality rates in acute heart failure. However, new medical therapies should at least improve clinical symptoms of congestion and favorably reduce cardiovascular events, re hospitalization, and mortality rates. PMID- 24817538 TI - [Exercise training in heart failure]. AB - Exercise training in patients with chronic stable heart failure (HF) is a recommended and broadly accepted treatment strategy that is an integral part of an evidence-based management involving pharmacological and non-pharmacological therapies. There is ample scientific evidence that exercise training in HF with reduced (HFrEF) and with preserved ejection fraction (HFpEF) improves exercise capacity, HF symptoms and quality of life. This is due to an improvement of central hemodynamics, endothelial function, neurohumoral activation, skeletal muscle structure and function as well as a decrease in inflammatory markers. The largest randomized, controlled HF-ACTION study (Heart Failure-A Controlled Trial Investigating Outcomes of exercise TraiNing) demonstrated that exercise training results in a modest improvement of all-cause mortality and hospitalizations in HFrEF, depending on adequate compliance. Outcome data in HFpEF are lacking. Besides compliance, efficacy of exercise training is dependent on the intensity and type of exercise. Resistance and high intensity endurance training in addition to a standard aerobic exercise seem to be superior in improving the clinical status of HF patients. In the future, individualized exercise programs will help to improve long-term adherence to exercise training. PMID- 24817539 TI - [Joint swelling, reversible arm paresis, and elevated serum IgG4 in a 55-year-old man]. AB - Only described in the last 10 years, IgG4-related disease is a fibroinflammatory disorder characterized by tumorous lesions with dense lymphoplasmacytic infiltration by IgG4-positive plasma cells and often elevated concentration of serum IgG4. In this paper, we present a male patient with this disease involving the lymph nodes and possibly the joints and kidneys. Infiltration of lymph node tissue with IgG4-positive plasma cells was demonstrated. The general condition of the patient improved considerably by immunosuppressive therapy. PMID- 24817540 TI - [Cardiovascular effects of a lifestyle intervention in type 2 diabetes. The Look AHEAD (Action for Health in Diabetes) study]. PMID- 24817531 TI - Risk of Guillain-Barre syndrome following pandemic influenza A(H1N1) 2009 vaccination in Germany. AB - PURPOSE: A prospective, epidemiologic study was conducted to assess whether the 2009 pandemic influenza A(H1N1) vaccination in Germany almost exclusively using an AS03-adjuvanted vaccine (Pandemrix) impacts the risk of Guillain-Barre syndrome (GBS) and its variant Fisher syndrome (FS). METHODS: Potential cases of GBS/FS were reported by 351 participating hospitals throughout Germany. The self controlled case series methodology was applied to all GBS/FS cases fulfilling the Brighton Collaboration (BC) case definition (levels 1-3 of diagnostic certainty) with symptom onset between 1 November 2009 and 30 September 2010 reported until end of December 2010. RESULTS: Out of 676 GBS/FS reports, in 30 cases, GBS/FS (BC levels 1-3) occurred within 150 days following influenza A(H1N1) vaccination. The relative incidence of GBS/FS within the primary risk period (days 5-42 post vaccination) compared with the control period (days 43-150 post-vaccination) was 4.65 (95%CI [2.17, 9.98]). Similar results were found when stratifying for infections within 3 weeks prior to onset of GBS/FS and when excluding cases with additional seasonal influenza vaccination. The overall result of temporally adjusted analyses supported the primary finding of an increased relative incidence of GBS/FS following influenza A(H1N1) vaccination. CONCLUSIONS: The results indicate an increased risk of GBS/FS in temporal association with pandemic influenza A(H1N1) vaccination in Germany. PMID- 24817541 TI - Micrometastasis of hypopharyngeal cancer. AB - PURPOSE: The aim of this study is to estimate the incidence and clinical impact of lymph node micrometastases in hypopharyngeal squamous cell cancer (HSCC). MATERIALS AND METHODS: In this retrospective study, we enrolled 58 patients who have undergone surgery for HSCC (between January 2004 and January 2011). Pharyngolaryngectomy and oesophagectomy with selective bilateral neck dissection was performed in all patients. Based on standard histological examination, 17 patients met N0 and 8 patients met N1 criteria and were further evaluated for the presence of micrometastases and isolated tumour cells (ITC). Following immunohistochemical analysis, the patients were grouped according to the presence of micrometastases and ITCs. RESULTS: In the pN0 group, cytokeratin-positive cells were detected in five patients, and they were marked as N0/CK+. Among these five patients, two were found to harbour micrometastases and ITCs, whilst in three, only ITCs were found. Two patients (11.75 %) were upstaged to pN1. The patients marked as N0/CK+ had a statistically significant worse overall survival rates than pN0 patients with tissue samples read as negative for cytokeratin immunostaining (p = 0.019, p < 0.05). In the pN1 group, cytokeratin-positive cells were detected in two patients, with one patient showing micrometastases and ITC, and the other showing ITC only. One patient was upstaged to pN2. CONCLUSION: Patients with lymph node micrometastases and ITC had worse overall survival rates, which may indicate that more aggressive post-operative treatment regimens should be considered for these HSCC patients. PMID- 24817543 TI - Wearing Different Hats. PMID- 24817542 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in recurrent epithelial ovarian cancer with peritoneal metastases: a single centre experience. AB - BACKGROUND: This investigation aims to assess morbidity, mortality and postoperative outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer (REOC) with peritoneal metastases (PM). METHODS: Consecutive patients with radiographic evidence of REOC with PM were scheduled for CRS and HIPEC at the Comprehensive Cancer Center, University Hospital Tubingen, Germany. Clinical data were retrospectively analyzed. RESULTS: In total, 90 patients were analyzed. Complete cytoreduction and HIPEC could be performed in 69 % of patients. When categorizing patients with respect to the completeness of cytoreduction (CC-0/1 vs CC-2/3), there was no difference considering baseline demographic characteristics. Cumulative morbidity was 42 %. Morbidity rates did not statistically differ between CC-0/1 patients with HIPEC and CC-2/3 patients without HIPEC. No surgery-related and 90-day postoperative mortality was observed. In CC-0/1 patients, median overall survival was 35 months as opposed to 14 months in CC-2/3 patients. There was no difference in survival with respect to the peritoneal carcinomatosis index (PCI) as long as complete cytoreduction could be achieved. CONCLUSIONS: CRS and HIPEC can be performed with acceptable morbidity and low mortality in specialized centres. Our data do not suggest that HIPEC necessarily increases the risk of postoperative adverse events. PMID- 24817544 TI - Attachment and penetration of acyclovir-resistant herpes simplex virus are inhibited by Melissa officinalis extract. AB - Medicinal plants are increasingly of interest as novel source of drugs for antiherpetic agents, because herpes simplex virus (HSV) might develop resistance to commonly used antiviral drugs. An aqueous extract of Melissa officinalis and the phenolic compounds caffeic acid, p-coumaric acid and rosmarinic acid were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) acyclovir-sensitive and clinical isolates of acyclovir-resistant strains in vitro. When drugs were added during the intracellular replication of HSV-1 infected cells, no antiviral effect was observed by plaque reduction assay. However, Melissa extract interacted directly with free viral particles of two acyclovir-resistant HSV strains at low IC50 values of 0.13 and 0.23 ug/mL and high selectivity indices of 2692 and 1522, respectively. The Melissa extract and rosmarinic acid inhibited HSV-1 attachment to host cells in a dose-dependent manner for acyclovir-sensitive and acyclovir-resistant strains. These results indicate that mainly rosmarinic acid contributed to the antiviral activity of Melissa extract. Penetration of herpes viruses into cells was inhibited by Melissa extract at 80% and 96% for drug-sensitive and drug-resistant viruses, respectively. Melissa extract exhibits low toxicity and affects attachment and penetration of acyclovir-sensitive and acyclovir-resistant HSVs in vitro. PMID- 24817546 TI - A model framework for identifying genes that guide the evolution of heterochrony. AB - Heterochrony, the phylogenic change in the time of developmental events or rate of development, has been thought to play an important role in producing phenotypic novelty during evolution. Increasing evidence suggests that specific genes are implicated in heterochrony, guiding the process of developmental divergence, but no quantitative models have been instrumented to map such heterochrony genes. Here, we present a computational framework for genetic mapping by which to characterize and locate quantitative trait loci (QTLs) that govern heterochrony described by four parameters, the timing of the inflection point, the timing of maximum acceleration of growth, the timing of maximum deceleration of growth, and the length of linear growth. The framework was developed from functional mapping, a dynamic model derived to map QTLs for the overall process and pattern of development. By integrating an optimality algorithm, the framework allows the so-called heterochrony QTLs (hQTLs) to be tested and quantified. Specific pipelines are given for testing how hQTLs control the onset and offset of developmental events, the rate of development, and duration of a particular developmental stage. Computer simulation was performed to examine the statistical properties of the model and demonstrate its utility to characterize the effect of hQTLs on population diversification due to heterochrony. By analyzing a genetic mapping data in rice, the framework identified an hQTL that controls the timing of maximum growth rate and duration of linear growth stage in plant height growth. The framework provides a tool to study how genetic variation translates into phenotypic innovation, leading a lineage to evolve, through heterochrony. PMID- 24817545 TI - Inter- and intraspecies phylogenetic analyses reveal extensive X-Y gene conversion in the evolution of gametologous sequences of human sex chromosomes. AB - It has long been believed that the male-specific region of the human Y chromosome (MSY) is genetically independent from the X chromosome. This idea has been recently dismissed due to the discovery that X-Y gametologous gene conversion may occur. However, the pervasiveness of this molecular process in the evolution of sex chromosomes has yet to be exhaustively analyzed. In this study, we explored how pervasive X-Y gene conversion has been during the evolution of the youngest stratum of the human sex chromosomes. By comparing about 0.5 Mb of human chimpanzee gametologous sequences, we identified 19 regions in which extensive gene conversion has occurred. From our analysis, two major features of these emerged: 1) Several of them are evolutionarily conserved between the two species and 2) almost all of the 19 hotspots overlap with regions where X-Y crossing-over has been previously reported to be involved in sex reversal. Furthermore, in order to explore the dynamics of X-Y gametologous conversion in recent human evolution, we resequenced these 19 hotspots in 68 widely divergent Y haplogroups and used publicly available single nucleotide polymorphism data for the X chromosome. We found that at least ten hotspots are still active in humans. Hence, the results of the interspecific analysis are consistent with the hypothesis of widespread reticulate evolution within gametologous sequences in the differentiation of hominini sex chromosomes. In turn, intraspecific analysis demonstrates that X-Y gene conversion may modulate human sex-chromosome-sequence evolution to a greater extent than previously thought. PMID- 24817547 TI - GAGA protein is essential for male germ cell development in Drosophila. AB - The Drosophila Trithorax-like (Trl) gene encodes a GAGA factor which regulates a number of developmentally important genes. In this study, we identify a new function for Drosophila GAGA factor in male germ cell development. Trl mutants carrying strong hypomorphic alleles display loss of primordial germ cells during their migration in embryogenesis and severe disruption in mitochondria structure during early spermatogenesis. The mutation resulted in small testes formation, a deficit of germ cells, abnormal mitochondrial morphogenesis, spermatocyte death through autophagy, and partial or complete male sterility. Pleiotropic mutation effects can be explained by the misexpression of GAGA factor target genes, the products of which are required for germ cell progression into mature sperm. PMID- 24817548 TI - Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management. AB - Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports. PMID- 24817549 TI - Prognostic impact of the serum heart-type fatty acid-binding protein (H-FABP) levels in patients admitted to the non-surgical intensive care unit. AB - BACKGROUND: Biomarkers predicting adverse outcomes in non-surgical intensive care patients have not been reported. METHODS AND RESULTS: Data for 1,006 emergency department patients were prospectively analyzed. The serum heart-type fatty acid binding protein (s-H-FABP) level was measured within 10 min of admission. The patients were assigned to intensive care (n = 835) or other departments (n = 171). The intensive care patients were divided into survivors (n = 745) and non survivors (n = 90) according to the in-hospital mortality and assigned to four groups according to the quartiles of s-H-FABP (Q1, Q2, Q3 and Q4). The s-H-FABP levels were significantly higher in the intensive care patients (12.7 [6.1-38.8] ng/ml versus 5.3 [3.1-9.4] ng/ml) and in the non-survivors (44.9 [23.2-87.6] ng/ml versus 11.5 [5.6-32.6] ng/ml). A Kaplan-Meier curve showed a significantly higher survival rate in Q3 than in Q1 and Q2 and in Q4 than in the other groups. The multivariate Cox regression model identified Q3 (HR 4.646, 95 % CI 1.526 14.146) and Q4 (HR 9.483, 95 % CI 3.152-28.525) as independent predictors of 90 day mortality. The sensitivity and specificity of H-FABP for in-hospital mortality were 81.1 and 66.0 % (AUC 0.775) at 20.95 ng/ml. The in-hospitality rate was significantly higher in the high s-H-FABP patients than in the low s-H FABP patients in each etiology group. CONCLUSIONS: The s-H-FABP level is an effective biomarker for risk stratification in non-surgical intensive care patients. PMID- 24817550 TI - Case report: Recurrent non-ST-elevation myocardial infarction caused by a compression of left internal mammary artery graft by transvenous pacemaker lead. PMID- 24817552 TI - Testing hypothesized predictors of immune activation in Tanzanian infants and children: community, household, caretaker, and child effects. AB - OBJECTIVES: There is increasing interest in the epidemiology of immune activation among young children because of the links with mortality and growth. We hypothesized that infant and child inflammation, as measured by elevated C reactive protein (CRP), would be associated with household assets, household size, measures of sanitation, and food insecurity. We also hypothesized that children in the poorest households and with elevated CRP would show evidence of growth faltering. METHODS: A nationally representative cross-sectional study of Tanzania children 6-59 months of age. Survey data, anthropometrics, and dried blood spots were available for 1,387 children. Measures of elevated CRP (CRP >= 1.1 mg/l) were used to assess inflammation. RESULTS: Fifty-four percent of the sample had CRP >= 1.1 mg/l. In bivariate analyses, several measures of sanitation were associated with elevated CRP but in multiple regression models only age, sex, literacy, maternal reports of illness, household size, and living in the wealthiest households predicted CRP. There were no associations between elevated CRP and any measure of child growth. CONCLUSIONS: Among children in Tanzania, a single elevated CRP does not predict poor growth functioning. Elevated CRP is associated with individual, caretaker, household, and community-level variables. Future work should strive to measure local biologies in more nuanced ways. PMID- 24817553 TI - Tantalum electrodes modified with well-aligned carbon nanotube-Au nanoparticles: application to the highly sensitive electrochemical determination of cefazolin. AB - Carbon nanotube/nanoparticle hybrid materials have been proven to exhibit high electrocatalytic activity suggesting broad potential applications in the field of electroanalysis. For the first time, modification of Ta electrode with aligned multi-walled carbon nanotubes/Au nanoparticles introduced for the sensitive determination of the antibiotic drug, cefazolin (CFZ). The electrochemical response characteristics of the modified electrode toward CFZ were investigated by means of cyclic and linear sweep voltammetry. The modified electrode showed an efficient catalytic activity for the reduction of CFZ, leading to a remarkable decrease in reduction overpotential and a significant increase of peak current. Under optimum conditions, the highly sensitive modified electrode showed a wide linear range from 50 pM to 50 MUM with a sufficiently low detection limit of 1 +/ 0.01 pM (S/N = 3). The results indicated that the prepared electrode presents suitable characteristics in terms of sensitivity (458.2 +/- 2.6 MUAcm(-2)/MUM), accuracy, repeatability (RSD of 1.8 %), reproducibility (RSD of 2.9 %), stability (14 days), and good catalytic activity in physiological conditions. The method was successfully applied for accurate determination of trace amounts of CFZ in pharmaceutical and clinical preparations without the necessity for samples pretreatment or any time-consuming extraction or evaporation steps prior to the analysis. PMID- 24817554 TI - Utilization of agricultural residues of pineapple peels and sugarcane bagasse as cost-saving raw materials in Scenedesmus acutus for lipid accumulation and biodiesel production. AB - The aim of this study is to optimize the lipid accumulation in microalgae by using two agricultural residues of pineapple peels and sugarcane bagasse as low cost organic carbon sources. Green microalgae Scenedesmus acutus was isolated and selected for cultivation. Effects of three initial sugar concentrations and the stage for adding sugar during cultivation on biomass and lipid production were investigated. The results clearly showed that two-stage cultivation is more suitable than one-stage. The maximum biomass concentration and productivity were obtained at 3.85 g/L and 160.42 mg/L/day when sugarcane bagasse was used. The highest lipid content and lipid yield was reached at 28.05 % and 0.93 g/L when pineapple peels were used, while in the case of sugarcane bagasse, 40.89 % and 1.24 g/L lipid content and yield were obtained. Lipid content was found in normal condition (autotrophic) at 17.71 % which was approximately 2.13-fold lower than when sugarcane bagasse was used (40.89 %). Biodiesel production via in situ transesterification was also investigated; the main fatty acids of palmitic acid and oleic acid were found. This work indicates that using agricultural residues as organic carbon sources could be able to increase lipid content and reduce the cost of biofuel production. PMID- 24817551 TI - Clinical significance of Helicobacter pylori infection in patients with acute coronary syndromes: an overview of current evidence. AB - Although Helicobacter pylori (Hp) primarily colonizes gastric mucosa, it can occasionally inhabit in atherosclerotic plaques. Both forms of Hp infection may be involved in the pathogenesis of atherosclerosis via activation of a systemic or local inflammatory host reaction and induction of plaque progression and/or instability, possibly leading to coronary syndromes. The association between Hp infection and cardiovascular endpoint prevalence remains uncertain; however, it has been reported in many epidemiological investigations and may be reasonably explained by pathophysiological mechanisms. Besides the inflammatory pathway, Hp infection may trigger acute coronary syndromes by enhanced platelet reactivity and increased risk of gastrointestinal bleeding (type 2 myocardial infarction). The former seems to be predominantly related to the stimulatory effect of Hp infection on von Willebrand factor-binding and P-selectin activation, and the latter results from cytotoxic bacteria properties and aggravation of digestive tract injury related to aspirin or dual antiplatelet therapy. Despite these premises, the role of Hp infection in cardiovascular syndromes should still be recognized as controversial and requiring randomized, controlled trials to evaluate the outcome of Hp eradication in both cardiac and gastroenterological endpoints. Such need is also justified by potential bias of previous studies resulting from (1) using different diagnostic methods for identification of Hp infection, since only a small number of studies required confirmation of active Hp infection; and from (2) common lack of adjustment for important confounders such as socioeconomic status, smoking and effectiveness of eradication therapy, as well as the genetic characteristics of both the host and the bacterium. PMID- 24817555 TI - Organosilane surfactant-directed synthesis of hierarchical porous SAPO-34 catalysts with excellent MTO performance. AB - Using an organosilane surfactant as the mesopore director, hierarchical porous silicoaluminophosphate SAPO-34 is obtained as an assembly of nanocrystallites intergrown into cubic micrometer-sized crystals, which show excellent performance in MTO reactions with a remarkably prolonged catalyst lifetime and enhanced selectivity of ethylene and propylene compared to the conventional microporous SAPO-34. PMID- 24817556 TI - A Bayesian design for phase II clinical trials with delayed responses based on multiple imputation. AB - Interim monitoring is routinely conducted in phase II clinical trials to terminate the trial early if the experimental treatment is futile. Interim monitoring requires that patients' responses be ascertained shortly after the initiation of treatment so that the outcomes are known by the time the interim decision must be made. However, in some cases, response outcomes require a long time to be assessed, which causes difficulties for interim monitoring. To address this issue, we propose a Bayesian trial design to allow for continuously monitoring phase II clinical trials in the presence of delayed responses. We treat the delayed responses as missing data and handle them using a multiple imputation approach. Extensive simulations show that the proposed design yields desirable operating characteristics under various settings and dramatically reduces the trial duration. PMID- 24817557 TI - Anogenital distance in male and female fetuses at 20 to 35 weeks of gestation: centile charts and reference ranges. AB - OBJECTIVES: In pediatrics, anogenital distance (AGD) serves as a bioassay of normal phenotypic androgen action on the external genitalia. Recently, hypospadias and cryptorchidism were reported to be associated with reduced AGD. No normal reference ranges exist for fetuses throughout gestation. This study defines the normal centile chart of the AGD, in male and female fetuses, between 20 and 35 weeks of gestation. METHODS: Participants were low-risk pregnant women, 20 to 35 weeks of gestation. All fetuses were singleton, with normal anatomic scan and appropriate fetal biometry for gestational age. Fetal AGD was measured by transabdominal ultrasound. The perineum was assessed in the axial plane. The distance was measured from the center of the anus to the posterior convergence of the fourchette in female fetuses and to the posterior base of the scrotum in male fetuses. Statistical analysis included the construction of the normal, modeled, centile, and standard deviation range, for each gestational age. Intraobserver and interobserver variability was assessed by the interclass correlation and Bland-Altman plot. RESULTS: Adequate measurements were obtained for 218 female and 206 male fetuses. For 17 cases, measurements were not possible because of fetal lie. AGD increased linearly throughout gestational age (GA) (r(2) = 0.808) for both sexes and was expressed by the following regression equation: for male fetuses, -12.348 + 1.075*GA, and for female fetuses, -3.179 + 0.513*GA, where GA is gestational age. The normal centiles, means, and standard deviations, per week, are presented. CONCLUSION: AGD measurement in utero is feasible. These measurements assess the normality of the perineal region and may assist in the detection of genital anomalies. PMID- 24817558 TI - Inhaled hyperosmolar agents for bronchiectasis. AB - BACKGROUND: Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients.Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation. OBJECTIVES: To determine whether inhaled hyperosmolar substances are effective in the treatment of bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, trials registries, and the reference lists of included studies and review articles. Searches are current up to April 2014. SELECTION CRITERIA: Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies for suitability. We used standard methods recommended by The Cochrane Collaboration. MAIN RESULTS: Eleven studies met the inclusion criteria of the review (1021 participants).Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health related quality of life (mean difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive.Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available. AUTHORS' CONCLUSIONS: There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function.It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease. PMID- 24817559 TI - Preliminary embryological study of the radiological concept of retroperitoneal interfascial planes: what are the interfascial planes? AB - PURPOSE: Recently, the radiological concept of retroperitoneal interfascial planes has been widely accepted to explain the extension of retroperitoneal pathologies. This study aimed to explore embryologically based corroborative evidence, which remains to be elucidated, for this concept. METHODS: Using serial or semi-serial transverse sections from 29 human fetuses at the 5th-25th week of fetal age, we microscopically observed the development of the retroperitoneal fasciae and other structures in the retroperitoneal connective tissue. A hypothesis for the formation of the interfascial planes was generated from the developmental study and analysis of retroperitoneal fasciae in computed tomography images from 224 patients. RESULTS: Whereas the loose connective tissue was uniformly distributed in the retroperitoneum by the 9th week, the primitive renal and transversalis fasciae appeared at the 10th-12th week, as previous research has noted. By the 23rd week, the renal fascia, transversalis fascia, and primitive adipose tissue of the flank pad emerged. In addition, the primitive lateroconal fascia, which runs parallel to and close to the posterior renal fascia, emerged between the renal fascia and the adipose tissue of the flank pad. Conversely, pre-existing loose connective tissue was sandwiched between the opposing fasciae and was compressed and narrowed by the developing organs and fatty tissues. CONCLUSION: Through this developmental study, we provided the hypothesis that the compressed loose connective tissue and both opposed fasciae compose the interfascial planes. Analysis of the thickened retroperitoneal fasciae in computed tomography images supported this hypothesis. Further developmental or histological studies are required to verify our hypothesis. PMID- 24817560 TI - Bilateral symmetrical supernumerary heads of biceps brachii with rare pectoralis major insertion. AB - During a routine dissection of a 51-year-old Caucasian male cadaver, bilateral symmetrical supernumerary heads (SH) of the biceps brachii muscles with insertion into the pectoralis major (PM) muscles were discovered. Multiple case reports have documented supernumerary heads for the biceps brachii; however, none have shown bilateral insertion into the pectoralis major. This study describes a previously undocumented variation of the SH that has potential for clinical impact. Healthcare providers could be confounded by patients presenting with shoulder pain or muscle tears as a result of the anomaly. Furthermore, MRI studies on patients with possible shoulder muscle tears could reveal unexpected results. Such cases would warrant consideration of SH anomaly and treatment should be adjusted accordingly. The significant bulk and angle of the SH insertion on the PM we observed changes force vectors which would have an unknown effect in performance, surgical interventions and pain syndromes. A second biceps brachii anomaly was observed on the left brachium in addition to the bilateral SH. We postulate that these variants provide the potential for clinical complications regarding muscular injury to these aforementioned muscle groups. PMID- 24817561 TI - Double mandibular foramen leading to the accessory canal on the mandibular ramus. AB - PURPOSE: The knowledge of the variation in the mandibular foramen and canal is clinically significant in surgical procedures of the mandible. This study aims to evaluate the anatomical characteristics of double mandibular foramen leading to the accessory canal on the mandibular ramus using cone beam CT. METHODS: The sagittal, cross-sectional, and three-dimensional images of cone beam CT data from 446 patients were evaluated in the presence of double mandibular foramen and the accessory canal passing through the foramen. The accessory canals were classified into two types according to the configuration (forward and retromolar type), and the location of double mandibular foramen was recorded. RESULTS: The eight double mandibular foramina leading to the accessory canals were observed in six patients out of 446 patients (1.35 % of population). Regarding the configuration of the accessory canal, there were two forward types and six retromolar types. All double mandibular foramina were located above the mandibular foramina on the medial aspect of the mandibular ramus. CONCLUSION: Three-dimensional images of cone beam CT data are useful in confirming the presence of double mandibular foramen leading to the accessory canal. The variation may cause failure in the routine mandibular nerve block anesthesia and it is often vulnerable during surgical procedures involving the mandibular ramus. Also, double mandibular foramen is considered as an easy route for tumor cell to spread following the radiotherapy. Therefore, the variation should be carefully investigated using reconstructed cone beam CT images in planning of dental surgery or radiotherapy in the mandible. PMID- 24817562 TI - New targets for increasing endogenous testosterone production: clinical implications and review of the literature. AB - Over the past several decades, our understanding of the regulatory mechanisms of testosterone production has increased significantly. Concurrently, the medical treatment of hypogonadism, particularly in the ageing male has increased. This review article consolidates some of our insights into the regulatory mechanisms of endogenous testosterone production and examines promising new targets that may allow endogenous production of testosterone to be re-established in males with primary hypogonadism. We examined the published scientific literature regarding regulatory mechanisms of testosterone biosynthesis with a focus on Leydig cell physiology and small-molecule regulation that resulted in increased testosterone production. We identified several pathways that have been manipulated pharmacologically to increase Leydig cell testosterone production, including phosphodiesterases, the cholesterol translocator protein, the electron transport chain of mitochondria, cyclooxygenases and osteocalcin. Manipulation of these pathways with small molecules has helped further our understanding of the regulatory pathways of testosterone biosynthesis. Herein, we identified five future targets that might promote increased endogenous testosterone production through the Leydig cell instead of relying on exogenous testosterone administration. PMID- 24817563 TI - Comparison of novel and familiar commercial kits for detection of C-reactive protein levels. AB - In this study, randomized patient sera were used to simultaneously evaluate an automated C-reactive protein (CRP) assay and a commercial semi-automated microCRP assay with respect to correlation, linearity, and accuracy. Patient specimens were analyzed; two independent assay runs were performed on i-CHROMA (Boditech Med Inc., Korea) and IMMAGE 800 (Beckman Coulter Inc., USA) analyzers to estimate the between- and within-run precision. All systems were calibrated, and quality control materials were analyzed according to the manufacturer's instructions. The results using the control materials were within the respective manufacturers' specified limits. The comparison studies were designed using the CLSI EP9-2A guidelines. The mean serum CRP concentrations were 123.2 +/- 123.5 mg/L (95 % confidence of interval (CI) 97.9-148.3) using the CRP assay and 130.1 +/- 109.3 mg/L (95 % CI 107.9-152.4) using the microCRP assay. The variance values were sigma = 15,252.6 and 11,935.8 for the CRP and microCRP assays, respectively. The concordance correlation coefficient value was calculated as 0.8314 (95 % CI 0.7594-0.8833). There was a significant correlation between the CRP and microCRP assays: r = 0.8392 and 95 % CI 0.7675-0.8902 (p < 0.0001). The CRP and microCRP detection methods were well correlated. The i-CHROMA has many advantages over the IMMAGE 800 with respect to space required, analysis time, and system setup/application costs in a laboratory. It may be an attractive instrument for small and intermediate medical centers. PMID- 24817564 TI - Biodiversity of Lactobacillus plantarum from traditional Italian wines. AB - In this study, 23 samples of traditional wines produced in Southern Italy were subjected to microbiological analyses with the aim to identify and biotype the predominant species of lactic acid bacilli. For this purpose, a multiple approach, consisting in the application of both phenotypic (API 50CHL test) and biomolecular methods (polymerase chain reaction-denaturing gradient gel electrophoresis and 16S rRNA gene sequencing) was used. The results showed that Lactobacillus plantarum was the predominant species, whereas Lb. brevis was detected in lower amount. In detail, out of 80 isolates 58 were ascribable to Lb. plantarum and 22 to Lb. brevis. Randomly amplified polymorphic DNA-polymerase chain reaction was used to highlight intraspecific variability among Lb. plantarum strains. Interestingly, the cluster analysis evidenced a relationship between different biotypes of Lb. plantarum and their origin, in terms of wine variety. Data acquired in this work show the possibility to obtain several malolactic fermentation starter cultures, composed by different Lb. plantarum biotypes, for their proper use in winemaking processes which are distinctive for each wine. PMID- 24817565 TI - Evaluation of the preschool life skills program in Head Start classrooms: a systematic replication. AB - In an attempt to address risk factors associated with extensive nonfamilial child care, we implemented the preschool life skills (PLS) program (Hanley, Heal, Tiger, & Ingvarsson, 2007) in two community-based Head Start classrooms. A multiple baseline design across classrooms, repeated across skills, showed that the program resulted in a 5-fold increase in PLS and an accompanying reduction in problem behavior, replicating the effects observed by Hanley et al. (2007). PMID- 24817566 TI - SpyTag/SpyCatcher cyclization confers resilience to boiling on a mesophilic enzyme. AB - SpyTag is a peptide that spontaneously forms an amide bond with its protein partner SpyCatcher. SpyTag was fused at the N terminus of beta-lactamase and SpyCatcher at the C terminus so that the partners could react to lock together the termini of the enzyme. The wild-type enzyme aggregates above 37 degrees C, with irreversible loss of activity. Cyclized beta-lactamase was soluble even after heating at 100 degrees C; after cooling, the catalytic activity was restored. SpyTag/SpyCatcher cyclization led to a much larger increase in stability than that achieved through point mutation or alternative approaches to cyclization. Cyclized dihydrofolate reductase was similarly resilient. Analyzing unfolding through calorimetry indicated that cyclization did not increase the unfolding temperature but rather facilitated refolding after thermal stress. SpyTag/SpyCatcher sandwiching represents a simple and efficient route to enzyme cyclization, with potential to greatly enhance the robustness of biocatalysts. PMID- 24817567 TI - A multi-Poisson dynamic mixture model to cluster developmental patterns of gene expression by RNA-seq. AB - Dynamic changes of gene expression reflect an intrinsic mechanism of how an organism responds to developmental and environmental signals. With the increasing availability of expression data across a time-space scale by RNA-seq, the classification of genes as per their biological function using RNA-seq data has become one of the most significant challenges in contemporary biology. Here we develop a clustering mixture model to discover distinct groups of genes expressed during a period of organ development. By integrating the density function of multivariate Poisson distribution, the model accommodates the discrete property of read counts characteristic of RNA-seq data. The temporal dependence of gene expression is modeled by the first-order autoregressive process. The model is implemented with the Expectation-Maximization algorithm and model selection to determine the optimal number of gene clusters and obtain the estimates of Poisson parameters that describe the pattern of time-dependent expression of genes from each cluster. The model has been demonstrated by analyzing a real data from an experiment aimed to link the pattern of gene expression to catkin development in white poplar. The usefulness of the model has been validated through computer simulation. The model provides a valuable tool for clustering RNA-seq data, facilitating our global view of expression dynamics and understanding of gene regulation mechanisms. PMID- 24817568 TI - Mechanical characterization of cross-linked serum albumin microcapsules. AB - Controlling the deformation of microcapsules and capsules is essential in numerous biomedical applications. The mechanical properties of the membrane of microcapsules made of cross-linked human serum albumin (HSA) are revealed by two complementary experiments in the linear elastic regime. The first provides the surfacic shear elastic modulus Gs by the study of small deformations of a single capsule trapped in an elongational flow: Gs varies from 0.002 to 5 N m(-1). The second gives the volumic Young's modulus E of the membrane by shallow and local indentations of the membrane with an AFM probe: E varies from 20 kPa to 1 MPa. The surfacic and volumic elastic moduli increase with the size of the capsule up to three orders of magnitude and with the protein concentration of the membrane. The membrane thickness is evaluated from these two membrane mechanical characteristics and increases with the size and the initial HSA concentration from 2 to 20 MUm. PMID- 24817570 TI - Private funding for molecular evolution. PMID- 24817569 TI - Breakthrough pain in elderly patients with cancer: treatment options. AB - The prevalence of pain is high in the elderly and increases with the occurrence of cancer. Pain treatment is challenging because of age-related factors such as co-morbidities, and over half of the patients with cancer pain experience transient exacerbation of pain that is known as breakthrough pain (BTP). As with background pain, BTP should be properly assessed before being treated. The first step to be taken is optimizing around-the-clock analgesia with expert titration of the painkiller. Rescue medication should then be provided as per the requested need, while at the same time preventing identified potential precipitating factors. In the elderly, starting treatment with a lower dose of analgesics may be justified because of age-related physiological changes such as decreased hepatic and renal function. Whenever possible, oral medication should be provided prior to a painful maneuver. In the case of unpredictable BTP, immediate rescue medication is mandatory and the subcutaneous route is preferred unless patient controlled analgesia via continuous drug infusion is available. Recently, transmucosal preparations have appeared in the medical armamentarium but it is not yet known whether they represent a truly efficient alternative, although their rapid onset of activity is already well recognized. Adjuvant analgesics, topical analgesics, anesthetic techniques and interventional techniques are all valid methods to help in the difficult management of pain and BTP in elderly patients with cancer. However, none has reached a satisfying scientific level of evidence as to nowadays make the development of undisputed best practice guidelines possible. Further research is therefore on the agenda. PMID- 24817571 TI - Electrochemical CO2 reduction on Cu2O-derived copper nanoparticles: controlling the catalytic selectivity of hydrocarbons. AB - The catalytic activity and hydrocarbon selectivity in electrochemical carbon dioxide (CO2) reduction on cuprous oxide (Cu2O) derived copper nanoparticles is discussed. Cuprous oxide films with [100], [110] and [111] orientation and variable thickness were electrodeposited by reduction of copper(ii) lactate on commercially available copper plates. After initiation of the electrochemical CO2 reduction by these oxide structures, the selectivity of the process was found to largely depend on the parent Cu2O film thickness, rather than on the initial crystal orientation. Starting with thin Cu2O films, besides CO and hydrogen, selective formation of ethylene is observed with very high ethylene-to-methane ratios (~8 to 12). In addition to these products, thicker Cu2O films yield a remarkably large amount of ethane. Long term Faradaic efficiency analysis of hydrocarbons shows no sign of deactivation of the electrodes after 5 hours of continuous experiment. Online mass spectroscopy studies combined with X-ray diffraction data suggest the reduction of the Cu2O films in the presence of CO2, generating a nanoparticulate Cu morphology, prior to the production of hydrogen, CO, and hydrocarbons. Optimizing coverage, number density and size of the copper nanoparticles, as well as local surface pH, may allow highly selective formation of the industrially important product ethylene. PMID- 24817572 TI - Geochemistry, mineralogy, solid-phase fractionation and oral bioaccessibility of lead in urban soils of Lisbon. AB - An urban survey of Lisbon, the largest city in Portugal, was carried out to investigate its environmental burden, emphasizing metallic elements and their public health impacts. This paper examines the geochemistry of lead (Pb) and its influence on human health data. A total of 51 soil samples were collected from urban recreational areas used by children to play outdoors. The semi-quantitative analysis of Pb was carried out by inductively coupled plasma mass spectrometry after an acid digestion. X-ray diffraction was used to characterize the soil mineralogy. The solid-phase distribution of Pb in the urban soils was investigated on a subset of 7 soils, out of a total of 51 samples, using a non specific sequential extraction method coupled with chemometric analysis. Oral bioaccessibility measurements were obtained using the Unified BARGE Method developed by the Bioaccessibility Research Group of Europe. The objectives of the study are as follows: (1) investigation of Pb solid-phase distribution; (2) interpretation of Pb oral bioaccessibility measurements; (3) integration of metal geochemistry with human health data; and (4) understanding the influence of geochemistry and mineralogy on oral bioaccessibility. The results show that the bioaccessible fraction of Pb is lower when major metal fractions are associated with less soluble soil phases such as Fe oxyhydroxides, and more increased when the metal is in the highly soluble carbonate phase. However, there is some evidence that the proportion of carbonates in the soil environment is also a key control over the oral bioaccessibility of Pb, irrespective of its solid-phase fractionation. PMID- 24817573 TI - Facile synthesis of TiN decorated graphene and its enhanced catalytic effects on dehydrogenation performance of magnesium hydride. AB - TiN@rGO nanohybrids were successfully synthesized by a simple "urea glass" technique. Experimental results demonstrated that TiN nanocrystals, with an average particle size of 20 nm, were uniformly anchored onto highly reduced graphene nanosheets. The as-synthesized TiN@rGO nanohybrids showed a porous planar-like structure, which had a large surface area of 177 m(2) g(-1). More importantly, the as-prepared TiN@rGO hybrids showed enhanced catalytic effects on the dehydrogenation of MgH2. The dehydrogenation thermodynamics and kinetics of the MgH2-TiN@rGO composites were systematically investigated and some significant improvements were confirmed. It was found that the 10 wt% TiN@rGO doped MgH2 sample started to release hydrogen at about 167 degrees C, and roughly 6.0 wt% hydrogen was released within 18 min when isothermally heated to 300 degrees C. In contrast, the onset dehydrogenation temperature of the pure MgH2 sample was about 307 degrees C, and only 3.5 wt% hydrogen was released even after 120 min of heating under identical conditions. In addition, the catalytic mechanism of TiN@rGO on the dehydrogenation of MgH2 was discussed using the Johnson-Mehl Avrami (JMA) model and X-ray diffraction equipment. PMID- 24817574 TI - Calpain inhibition reduces ataxin-3 cleavage alleviating neuropathology and motor impairments in mouse models of Machado-Joseph disease. AB - Machado-Joseph Disease (MJD) is the most prevalent autosomal dominantly inherited cerebellar ataxia. It is caused by an expanded CAG repeat in the ATXN3 gene, which translates into a polyglutamine tract within the ataxin-3 protein. Present treatments are symptomatic and do not prevent disease progression. As calpain overactivation has been shown to contribute to mutant ataxin-3 proteolysis, translocation to the nucleus, inclusions formation and neurodegeneration, we investigated the potential role of calpain inhibition as a therapeutic strategy to alleviate MJD pathology. For this purpose, we administered orally the calpain inhibitor BDA-410 to a lentiviral mouse model of MJD. Western-blot and immunohistochemical analysis revealed the presence of N- and C-terminal mutant ataxin-3 fragments and the colocalization of large inclusions with cleaved caspase-3 in the mice brain. Oral administration of the calpain inhibitor BDA-410 decreased both fragments formation and full-length ataxin-3 levels, reduced aggregation of mutant ataxin-3 and prevented cell injury and striatal and cerebellar degeneration. Importantly, in correlation with the preserved cerebellar morphology, BDA-410 prevented motor behavioural deficits. In conclusion, BDA-410 alleviates Machado-Joseph neuropathology and may therefore be an effective therapeutic option for MJD. PMID- 24817576 TI - Relationships between children's exposure to ethnic produce and their dietary behaviors. AB - The current study examined relationships between children's ethnic produce exposure and healthy dietary practices among Latino, Hmong and non-Hispanic white children. One hundred Latino, 100 Hmong, and 92 non-Hispanic white parents of children ages 5-8 years old in northern California completed a cross-sectional survey. Children's exposure to ethnic produce from Hmong and Latino cultures, overall fruit and vegetable consumption, and fast food and ethnic restaurant use were measured. The Kruskal-Wallis and Mann-Whitney tests were used to compare variables across different ethnic groups. Spearman's correlation was used to assess the relationship between variables. Children's overall ethnic produce exposure, as well as exposure to produce from other cultures, was significantly correlated with overall fruit and vegetable consumption. There was a marginal (p = 0.053) negative association between ethnic produce exposure and fast food restaurant use among Latino children. These findings suggest that promoting ethnic produce is an effective strategy for enhancing healthy dietary practices among children. PMID- 24817575 TI - Bridging cross-cultural gaps: monitoring herbal use during chemotherapy in patients referred to integrative medicine consultation in Israel. AB - INTRODUCTION: The high prevalence of the use of traditional herbs among patients with cancer is a cause for concern with regard to potentially adverse interactions with conventional oncology treatments. In this study, we explore herbal use among patients with cancer in northern Israel who are referred by their health care providers to complementary and traditional medicine (CTM) consultations provided to them within the conventional oncology department. The study's objectives were to identify which herbs patients use and to examine the scope of current research on the efficacy and safety regarding the identified herbs. PATIENTS AND METHODS: Herbal use by patients receiving oncology care was assessed prospectively from July 2009 to July 2012 by integrative physicians (IPs) trained in herbal medicine. Historical, ethnobotanical, basic research, and clinical data regarding the identified herbs were explored by using a keyword search in PubMed and Middle Eastern ethnohistorical literature. RESULTS: Disclosure of herbal use was reported by 154 of the 305 patients (50.5 %) interviewed by IPs. The use of 85 single herbs and 30 different herbal formulas was documented during the initial or follow-up IP assessments. Patients reported 14 quality of life-associated indications for herbal use. The ten most prevalent herbs displaying in vitro/in vivo anticancer activity and nine other herbs were preliminarily assessed concerning potential risks, safety, and interaction with chemotherapy. CONCLUSIONS: Herbal use by patients with cancer in northern Israel is widespread and calls for further study in order to address issues of safety and effectiveness. We recommend constructing a multinational and multidisciplinary team of researchers with ethnopharmacological and clinical expertise that will explore the use of herbs among patients with cancer in a cross-cultural perspective attuned with patients' affinity to traditional herbal medicine. PMID- 24817577 TI - Adverse effects of benfluorex on heart valves and pulmonary circulation. AB - Benfluorex is responsible for the development of restrictive valvular regurgitation due to one of its metabolites, norfenfluramine. The 5-HT2B receptor, expressed on heart valves, acts as culprit receptor for drug-induced valvular heart disease (VHD). Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways. Valve lesions essentially involve the mitral and/or aortic valves. The randomised prospective REGULATE trial shows a threefold increase in the incidence of valvular regurgitation in patients exposed to benfluorex. A cross-sectional trial shows that about 7% of patients without a history of VHD previously exposed to benfluorex present echocardiographic features of drug-induced VHD. The excess risks of hospitalisation for cardiac valvular insufficiency and of valvular replacement surgery were respectively estimated to 0.5 per 1000 and 0.2 per 1000 exposed patients per year. Recent data strongly suggest an aetiological link between benfluorex exposure and pulmonary arterial hypertension (PAH). The PAH development may be explained by serotonin, which creates a pulmonary vasoconstriction through potassium-channel blockade. Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects. PMID- 24817578 TI - Paenibacillus quercus sp. nov., isolated from rhizosphere of Quercus aliena var. acuteserrata. AB - A Gram-positive, spore-forming, rod-shaped and motile bacterium, designated strain 1-25(T), was isolated from the rhizosphere of Quercus aliena var. acuteserrata in Taibai Mountain, Shaanxi Province, China. 16S rRNA gene sequence analysis showed that strain 1-25(T) belongs to the genus Paenibacillus. Strain 1 25(T) was found to be closely related to Paenibacillus harenae and Paenibacillus castaneae with 96.0 and 95.9 % 16S rRNA gene sequence similarities, respectively. The strain was observed to grow optimally at 28 degrees C and pH 7.5. The major isoprenoid quinone was found to be menaquinone-7. The dominant cellular fatty acids were identified as anteiso-C15:0 and iso-C15:0. The diagnostic diamino acid in the cell-wall peptidoglycan was found to be meso-diaminopimelic acid. The DNA G+C content was determined to be 41.6 mol%. On the basis of phenotypic characteristics and molecular properties, strain 1-25(T) is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus quercus sp. nov. is proposed. The type strain is 1-25(T) (=CCTCC AB2013265(T) = KCTC 33194(T)). PMID- 24817579 TI - Endospore surface properties of commonly used Bacillus anthracis surrogates vary in aqueous solution. AB - The hydrophobic character and electrophoretic mobility (EPM) of microorganisms are vital aspects of understanding their interactions with the environment. These properties are fundamental in fate-and-transport, physiological, and virulence studies, and thus integral in surrogate selection. Hydrophobic and electrostatic forces are significant contributors to particle and microorganism mobility in the environment. Herein, the surface properties of commonly used Bacillus anthracis surrogate endospores were tested under comparable conditions with respect to culture, endospore purification, buffer type and strength. Additionally, data is presented of endospores suspended in dechlorinated tap water to evaluate the surrogates in regard to a breach of water infrastructure security. The surface properties of B. anthracis were found to be the most hydrophobic and least electronegative among the six Bacillus species tested across buffer strength. The effect of EPM on hydrophobicity varies in a species-specific manner. This study demonstrates that surrogate surface properties differ and care must be taken when choosing the most suitable surrogate. Moreover, it is shown that Bacillus thuringensis best represents Bacillus anthracis-Sterne with respect to both EPM and hydrophobicity across all test buffers. PMID- 24817580 TI - Novel Au/La-SrTiO3 microspheres: superimposed effect of gold nanoparticles and lanthanum doping in photocatalysis. AB - Novel multielement Au/La-SrTiO(3) microspheres were synthesized by a solvothermal method using monodisperse gold and La-SrTiO(3) nanocrystals as building blocks. The porous Au/La-SrTiO(3) microspheres had a large surface area of 94.6 m(2) g( 1). The stable confined Au nanoparticles demonstrated strong surface plasmon resonance effect, leading to enhanced absorption in a broad UV/Vis/NIR range. Doping of rare-earth metal La also broadened the absorption band to the visible region. Both the conduction and valence bands of Au/La-SrTiO(3) microspheres thus show favorable potential for proton reduction under visible light. The superimposed effect of Au nanoparticles and La doping in Au/La-SrTiO(3) microspheres led to high photocurrent density in photoelectrochemical water splitting and good photocatalytic activity in photodegradation of rhodamine B. The photocatalytic activities are in the order of the following: Au/La-SrTiO(3) microspheres>Au/SrTiO(3) microspheres>La-SrTiO(3) microspheres>SrTiO(3) microspheres. PMID- 24817583 TI - Detection of extracellular matrix degradation in intervertebral disc degeneration by diffusion magnetic resonance spectroscopy. AB - PURPOSE: To investigate whether diffusion magnetic resonance spectroscopy (MRS) can detect the extracellular matrix (ECM) degradation during intervertebral disc degeneration (IVDD) by the increased mobility of ECM macromolecules such as proteoglycans and collagens. METHODS: Fresh bovine intervertebral discs were injected with papain solution to induce ECM degradation. The apparent diffusion coefficients (ADCs), T2 values, and contents of ECM macromolecules and water resonances were measured longitudinally in the nucleus pulposus. RESULTS: The macromolecule ADCs increased drastically at day 1 after papain injection, and continued increasing for 5 days. In contrast, the proteoglycan content exhibited a small and slow decrease after injection while the macromolecule T2 values, water T2, ADC, and content showed slight increase or no change. The protein gel electrophoresis analysis confirmed the gradually increased ECM fragmentation in accordance with the observed macromolecule ADC increases. CONCLUSION: Diffusion MRS provides a new method to characterize the ECM degradation processes directly and sensitively. Macromolecule ADCs offer a potentially more sensitive and earlier marker for ECM degradation than the proteoglycan content and T2, and water MR properties during early IVDD. Such diffusion approach offers the possibility to directly monitor ECM integrity and degradation processes in vivo at molecular and microstructural levels in both preclinical and clinical settings. PMID- 24817581 TI - A network pharmacology study of Chinese medicine QiShenYiQi to reveal its underlying multi-compound, multi-target, multi-pathway mode of action. AB - Chinese medicine is a complex system guided by traditional Chinese medicine (TCM) theories, which has proven to be especially effective in treating chronic and complex diseases. However, the underlying modes of action (MOA) are not always systematically investigated. Herein, a systematic study was designed to elucidate the multi-compound, multi-target and multi-pathway MOA of a Chinese medicine, QiShenYiQi (QSYQ), on myocardial infarction. QSYQ is composed of Astragalus membranaceus (Huangqi), Salvia miltiorrhiza (Danshen), Panax notoginseng (Sanqi), and Dalbergia odorifera (Jiangxiang). Male Sprague Dawley rat model of myocardial infarction were administered QSYQ intragastrically for 7 days while the control group was not treated. The differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with QSYQ, followed by constructing a cardiovascular disease (CVD)-related multilevel compound-target-pathway network connecting main compounds to those DEGs supported by literature evidences and the pathways that are functionally enriched in ArrayTrack. 55 potential targets of QSYQ were identified, of which 14 were confirmed in CVD-related literatures with experimental supporting evidences. Furthermore, three sesquiterpene components of QSYQ, Trans-nerolidol, (3S,6S,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol and (3S,6R,7R)-3,7,11-trimethyl-3,6-epoxy-1,10-dodecadien-7-ol from Dalbergia odorifera T. Chen, were validated experimentally in this study. Their anti inflammatory effects and potential targets including extracellular signal regulated kinase-1/2, peroxisome proliferator-activated receptor-gamma and heme oxygenase-1 were identified. Finally, through a three-level compound-target pathway network with experimental analysis, our study depicts a complex MOA of QSYQ on myocardial infarction. PMID- 24817584 TI - Constitutive notch signaling in adult transgenic mice inhibits bFGF-induced angiogenesis and blocks ovarian follicle development. AB - Notch signaling is important in angiogenesis during embryonic development. However, the embryonic lethal phenotypes of knock-out and transgenic mice have precluded studies of the role of Notch post-natally. To develop a mouse model that would bypass the embryonic lethal phenotype and investigate the possible role of Notch signaling in adult vessel growth, we developed transgenic mice with Cre-conditional expression of the constitutively active intracellular domain of Notch1 (IC-Notch1). Double transgenic IC-Notch1/Tie2-Cre embryos with endothelial specific IC-Notch1 expression died at embryonic day 9.5. They displayed collapsed and leaky blood vessels and defects in angiogenesis development. A tetracycline inducible system was used to express Cre recombinase postnatally in endothelial cells. In adult mice, IC-Notch1 expression inhibited bFGF-induced neovascularization and female mice lacked mature ovarian follicles, which may reflect the block in bFGF-induced angiogenesis required for follicle growth. Our results demonstrate that Notch signaling is important for both embryonic and adult angiogenesis and indicate that the Notch signaling pathway may be a useful target for angiogenic therapies. PMID- 24817585 TI - Identification and functional characterization of sorbitol-6-phosphate dehydrogenase protein from rice and structural elucidation by in silico approach. AB - The sorbitol-6-phosphate dehydrogenase (S6PDH) is a key enzyme for sorbitol synthesis and plays an important role in the alleviation of salinity stress in plants. Despite the huge significance, the structure and the mode of action of this enzyme are still not known. In the present study, sequence analysis, cloning, expression, activity assays and enzyme kinetics using various substrates (glucose-6-phosphate, sorbitol-6-phosphate and mannose-6-phosphate) were performed to establish the functional role of S6PDH protein from rice (Oryza sativa). For the structural analysis of the protein, a comparative homology model was prepared on the basis of percentage sequence identity and substrate similarity using the crystal structure of human aldose reductase in complex with glucose-6-phosphate and NADP(+) (PDB ID: 2ACQ) as a template. Molecular docking was performed for studying the structural details of substrate binding and possible enzyme mechanism. The cloned sequence resulted into an active recombinant protein when expressed into a bacterial expression system. The purified recombinant protein was found to be active with glucose-6-phosphate and sorbitol-6-phosphate; however, activity against mannose-6-phosphate was not found. The K m values for glucose-6-phosphate and sorbitol-6-phosphate were found to be 15.9 +/- 0.2 and 7.21 +/- 0.5 mM, respectively. A molecular-level analysis of the active site of OsS6PDH provides valuable information about the enzyme mechanism and requisite enantioselectivity for its physiological substrates. Thus, the fundamental studies of structure and function of OsS6PDH could serve as the basis for the future studies of bio-catalytic applications of this enzyme. PMID- 24817586 TI - Ergosterol concentration and variability in genotype-by-pathogen interaction for grain mold resistance in sorghum. AB - A lack of understanding of host-by-pathogen relations can hinder the success of breeding for resistance to a major disease. Fungal strain pathogenicity has to be understood from the virulence it can cause on susceptible genotypes and host resistance indicates which genotypes have resistance genes. Where the two worlds meet lies the place where researchers match the prevalent pathogen in the area of production with resistant varieties. This paper uses ergosterol concentration analysis as a measure of fungal biomass accumulation to assess levels of resistance in host genotypes. 11 sorghum genotypes were inoculated with 5 strains of fungi that are known to be associated with grain mold disease of sorghum. The resulting interaction was analyzed using GGE Biplot analysis and Cluster analysis which showed that none of the genotypes were resistant to Phoma sorghina and Curvularia lunata. Three genotypes were resistant to Fusarium thapsinum. One fungal strain (Alternaria alternata) does not contribute any significant damage in the grain mold disease. Fusarium graminearum causes very little grain mold disease. There was no correlation between the fungal strains. Visual scoring did not correlate with ergosterol accumulation. Resistance to grain mold in sorghum is shown to be due to vertical or specific resistance genes. Sorghum breeders should, therefore, identify predominant fungal strains in their localities and then locate and tag these resistance genes in their germplasm and pyramid them in commercial varieties. PMID- 24817587 TI - Blue-light regulation of ZmPHOT1 and ZmPHOT2 gene expression and the possible involvement of Zmphot1 in phototropism in maize coleoptiles. AB - MAIN CONCLUSION: ZmPHOT1 and ZmPHOT2 are expressed differentially in maize coleoptiles and leaves, with Zmphot1 possibly involved in first-positive phototropic curvature of red-light-adapted maize coleoptiles exposed to pulsed low-fluence blue light. Unilateral blue-light perception by phototropin(s) is the first event of phototropism, with the subsequent signal causing lateral transport of auxin at the coleoptile tip region of monocots. In this study, we analyzed the behavior of two maize phototropin genes: ZmPHOT1 and ZmPHOT2, the latter identified from the maize genome database and newly characterized. Quantitative real-time PCR analysis demonstrated that ZmPHOT1 was abundantly expressed in etiolated coleoptiles, while lower expressions of both ZmPHOT1 and ZmPHOT2 were observed in young leaves. Interestingly, these genes were not specifically expressed in the coleoptile tip region, a key position for photoperception in phototropism. Exposure to pulsed low-fluence blue light (LBL) (0.33 umol m(-2) s( 1) * 8 s) and continuous high-fluence blue light (HBL) (10 umol m(-2) s(-1)) rapidly decreased ZmPHOT1 gene expression in coleoptiles, with levels of ZmPHOT2 not significantly altered in that tissue. In young leaves, no drastic expression changes were induced in either ZmPHOT1 or ZmPHOT2 by LBL or HBL irradiation. The Zmphot1 protein was investigated by Western blot analysis with anti-Osphot1 antibodies. Zmphot1 was detected in microsomal fractions, with higher levels in coleoptiles than in leaves. HBL caused rapid phosphorylation of the protein, whereas no phot1 phosphorylation was induced by LBL. The involvement of Zmphot1 in LBL-induced phototropic curvature of maize coleoptiles is discussed. PMID- 24817588 TI - Power spectrum, growth velocities and cross-correlations of longitudinal and transverse oscillations of individual Nicotiana tabacum pollen tube. AB - We report on our results concerning growth rate and oscillation modes of the individual pollen tube apex. The observed volumetric growth and growth rate periodicity in the longitudinal (axial) direction are accompanied by transverse oscillations with similar frequencies but higher energies than the axial modes. Examination of the time-domain coherence between oscillations in mutually perpendicular directions revealed minimal energy dissipation in the unperturbed (isotonic) case, opposite to the two remaining cases (hypertonic, hypotonic) with notable correlations. We conjecture that the minimal energy loss is therefore optimal in the natural growth conditions. The longitudinal growth velocity is also found to be the fastest in the unperturbed case. As a result, the isolated system (pollen tube tip) is conserving energy by transforming it from elastic potential energy of extending apical wall to the kinetic energy of periodical motion. The energy dissipation is found to be about 20 % smaller in axial direction than in lateral one, indicating that the main energy consumption is dedicated to the elongation. We further observe that the hypertonic spectrum is shifted towards lower and the hypotonic towards higher frequencies with respect to the isotonic spectrum. In consequence, the turgor pressure inside the growing cell influences monotonically the frequency of both modes of oscillations. The calculated power spectrum seen as a measure of the overall energy efficiency of tip growth under hypertonic, hypotonic and isotonic conditions implies that the biochemistry has been fine tuned to be optimal under normal growth conditions, which is the developmental implication of this work. A simple theoretical extension of the Ortega equation is derived and analysed with respect to its contribution to power spectrum. We show that the plastic term, related to the effective turgor pressure, with maximum contribution at frequency f = 0 is responsible for the steady growth. In turn, the elastic contribution dependent on the time derivative of pressure fluctuations tends to move the system into oscillatory mode (f > 0). None of those mechanisms is privileged over another. The coupling mechanism is naturally generated through a convolution of those two terms and will decide about the overall character of the growth for each particular case. PMID- 24817590 TI - Antiinflammatory effects and chemical constituents of Veronicastrum axillare. AB - Our study aims to ascertain the antiinflammatory activity of Veronicastrum axillare and characterize the bioactive constituents. Antiinflammatory activity of the total extract and different fractions from V. axillare was investigated by employing the xylene-induced mouse ear edema model. As a result, the ethyl acetate (EtOAc) fraction showed the highest antiinflammatory activity in vivo. From the EtOAc fraction and the inactive dichloromethane fraction, a total of five new compounds, axillasides A-C and axillactones A and B, together with four known compounds, procumboside A, buergeriside C1 , indole-3-carboxylic acid and apigenin, were isolated and identified. Their structures were elucidated on the basis of spectroscopic analysis and by comparison of their nuclear magnetic resonance data with those reported in the literature. Procumboside A, a major constituent in EtOAc fraction, showed significant antiinflammatory activity in vivo. Further studies revealed that procumboside A was a potent COX-2 inhibitor, significantly reducing the COX-2 protein level in lipopolysaccharide-stimulated RAW 264.7 macrophages. PMID- 24817591 TI - Effect of young extrinsic environment stimulated by hypoxia on the function of aged tendon stem cell. AB - Tendon stem cells (TSCs), recently identified as tendon cells, play an important role in maintaining the homeostasis of tendon tissue. Age-related decrease in the function of TSCs has been reported. Recent reports demonstrated that hypoxic condition is advantageous for efficient expansion of TSCs. Moreover, the impaired function of aged stem cells could be modulated by exposing them to a young environment. Therefore, we investigated the effects of hypoxic-conditioned culture medium (HCCM) from young TSCs on the proliferation, migration, senescence, and tenocyte phenotype of aged TSCs. TSCs were isolated, and the conditioned medium was collected. There were 4 groups: young TSCs, aged TSCs, aged TSCs + aged HCCM, and aged TSCs + young HCCM. The proliferative capacity, migration, beta-galactosidase activity, and tenogenic differentiation potential of TSCs were assessed. Our results showed that HCCM enhanced the proliferation and migration potential of aged TSCs. Moreover, the senescence-associated beta galactosidase activity of aged TSCs was decreased by young HCCM. After being cultured in the young HCCM, the expressions of tenocyte-related genes in aged TSCs were significantly enhanced. Together, results of this study indicate that HCCM from young TSCs may represent an effective strategy to improve the impaired function of aged TSCs. PMID- 24817589 TI - Spatial X-ray fluorescence micro-imaging of minerals in grain tissues of wheat and related genotypes. AB - MAIN CONCLUSION: Wheat and its related genotypes show distinct distribution patterns for mineral nutrients in maternal and filial tissues in grains. X-ray based imaging techniques are very informative to identify genotypes with contrasting tissue-specific localization of different elements. This can help in the selection of suitable genotypes for nutritional improvement of food grain crops. Understanding mineral localization in cereal grains is important for their nutritional improvement. Spatial distribution of mineral nutrients (Mg, P, S, K, Ca, Fe, Zn, Mn and Cu) was investigated between and within the maternal and filial tissues in grains of two wheat cultivars (Triticum aestivum Cv. WH291 and WL711), a landrace (T. aestivum L. IITR26) and a related wild species Aegilops kotschyi, using micro-proton-induced X-ray emission (u-PIXE) and micro-X-ray fluorescence (u-XRF). Aleurone and scutellum were major storage tissues for macro (P, K, Ca and Mg) as well as micro (Fe, Zn, Cu and Mn) nutrients. Distinct elemental distribution patterns were observed in each of the four genotypes. A. kotschyi, the wild relative of wheat and the landrace, T. aestivum L. IITR26, accumulated more Zn and Fe in scutellum and aleurone than the cultivated wheat varieties, WH291 and WL711. The landrace IITR26, accumulated far more S in grains, Mn in scutellum, aleurone and embryo region, Ca and Cu in aleurone and scutellum, and Mg, K and P in scutellum than the other genotypes. Unlike wheat, lower Mn and higher Fe, Cu and Zn concentrations were noticed in the pigment strand of A. kotschyi. Multivariate statistical analysis, performed on mineral distribution in major grain tissues (aleurone, scutellum, endosperm and embryo region) resolved the four genotypes into distinct clusters. PMID- 24817592 TI - Non-linear associations between stature and mate choice characteristics for American men and their spouses. AB - OBJECTIVES: Although male height is positively associated with many aspects of mate quality, average height men attain higher reproductive success in US populations. We hypothesize that this is because the advantages associated with taller stature accrue mainly from not being short, rather than from being taller than average. Lower fertility by short men may be a consequence of their and their partner's lower scores on aspects of mate quality. Taller men, although they score higher on mate quality compared to average height men, may have lower fertility because they are more likely to be paired with taller women, who are potentially less fertile. METHODS: We analyzed data from The Integrated Health Interview Series (IHIS) of the United States (N = 165,606). Segmented regression was used to examine patterns across the height continuum. RESULTS: On all aspects of own and partner quality, shorter men scored lower than both average height and taller men. Height more strongly predicted these aspects when moving from short to average height, than when moving from average to taller heights. Women of a given height who scored lower on mate quality also had shorter partners. CONCLUSIONS: Shorter men faced a double disadvantage with respect to both their own mate quality and that of their spouses. Scores of taller men were only marginally higher than those of average height men, suggesting that being tall is less important than not being short. Although effect sizes were small, our results may partly explain why shorter and taller men have lower fertility than those of average stature. PMID- 24817593 TI - Predictors of coronary artery aneurysms in Kawasaki disease. AB - Kawasaki disease (KD) is a common cause of cardiovascular morbidity in young children. No study has attempted to stratify risk factors for coronary artery involvement in Indian children. We attempted to study prospectively the risk factors for coronary involvement in children with KD in a tertiary care hospital between October 2009 and November 2011. The clinical details and investigations for all children admitted with KD were tabulated, and echocardiography was performed; 37 children were admitted with KD; and 8 children (21%) had coronary artery abnormalities. Prolonged fever, wider dispersion of symptoms, and pyuria were significantly associated with the development of coronary lesions. Clinical factors such as wider dispersion of symptoms and prolonged fever along with presence of pyuria can increase the risk of coronary lesions. The presence of these factors may help direct aggressive management and prevent loss of precious time. PMID- 24817594 TI - Discreet and indiscreet barriers to adolescent health-seeking efforts. PMID- 24817595 TI - Visible light induced fast synthesis of protein-polymer conjugates: controllable polymerization and protein activity. AB - Herein visible light is used to induce RAFT polymerization from protein for preparing protein-polymer conjugates at ambient temperature. Polymerization is fast and can be conveniently controlled with irradiation time. By site-specific polymerization of NIPAm to protein, the protein activity is maintained and in certain cases it presents an efficient on-off-switchable property. PMID- 24817598 TI - Sample-size calculation and reestimation for a semiparametric analysis of recurrent event data taking robust standard errors into account. AB - In some clinical trials, the repeated occurrence of the same type of event is of primary interest and the Andersen-Gill model has been proposed to analyze recurrent event data. Existing methods to determine the required sample size for an Andersen-Gill analysis rely on the strong assumption that all heterogeneity in the individuals' risk to experience events can be explained by known covariates. In practice, however, this assumption might be violated due to unknown or unmeasured covariates affecting the time to events. In these situations, the use of a robust variance estimate in calculating the test statistic is highly recommended to assure the type I error rate, but this will in turn decrease the actual power of the trial. In this article, we derive a new sample-size formula to reach the desired power even in the presence of unexplained heterogeneity. The formula is based on an inflation factor that considers the degree of heterogeneity and characteristics of the robust variance estimate. Nevertheless, in the planning phase of a trial there will usually be some uncertainty about the size of the inflation factor. Therefore, we propose an internal pilot study design to reestimate the inflation factor during the study and adjust the sample size accordingly. In a simulation study, the performance and validity of this design with respect to type I error rate and power are proven. Our method is applied to the HepaTel trial evaluating a new intervention for patients with cirrhosis of the liver. PMID- 24817596 TI - Effect of chicken, fat and vegetable on glycaemia and insulinaemia to a white rice-based meal in healthy adults. AB - PURPOSE: White rice is the main staple for the majority in the world. The effects of protein, fat and vegetables on the glycaemic and insulinaemic responses to a white rice-based meal have not been reported. The aim of this study was to determine the effect of co-ingesting a high-protein food (breast chicken), a fat (ground nut oil), a leafy vegetable or all three on the glycaemic and insulinaemic responses of white rice in healthy adults. METHODS: This was a randomized crossover trial conducted at the Clinical Nutrition Research Centre in Singapore. Twelve healthy volunteers were given five test meals (white rice alone, white rice with chicken, white rice with oil, white rice with vegetable and white rice with chicken, oil and vegetable) once and the reference food (glucose solution) three times in a random order at 1-week intervals. Capillary blood samples were then drawn serially for 3 h, and glucose and insulin were analysed. RESULTS: The glycaemic response (GR) to white rice with chicken breast, ground nut oil and vegetable was significantly lower than to white rice alone. The glycaemic index (GI) of pure white rice was 96, whereas combined with chicken breast, ground nut oil and vegetable, it was 50. The addition of oil delayed the peak glucose response and reduced the iAUC, resulting in a GI value of 67. The addition of chicken and vegetable resulted in a GI value of 73 and 82, respectively. The insulinaemic index (II) of the white rice-based meals varied between 54 and 89. Chicken breast in the meal increased the insulinaemic response and decreased the GR. White rice II was lower than the glucose control, which indicated that the former was not as insulinogenic as the latter. White rice with vegetable had the lowest II. CONCLUSIONS: Co-ingesting chicken, oil or vegetable with white rice considerably influences its glycaemic and insulinaemic responses. Co-ingesting white rice with all three components attenuates the GR to a greater degree than when it is eaten with any single one of them, and that this is not at the cost of an increased demand for insulin. PMID- 24817599 TI - First-trimester hand measurements in euploid and aneuploid human fetuses using virtual reality. AB - OBJECTIVE: Although second-trimester and third-trimester reference curves for human fetal hand growth allow for identification of several genetic syndromes, little is known about first-trimester hand growth. We investigated first trimester hand growth in euploid and aneuploid fetuses. METHOD: Between 9 and 12 weeks' gestational age (GA), wrist width, hand width, hand length, and hand index were measured in three-dimensional (3D) ultrasound datasets of 112 euploid and 65 aneuploid pregnancies. We constructed reference curves for these measurements in euploid pregnancies and calculated z-scores for measurements in aneuploid pregnancies. Reproducibility was established in a subset of 20 datasets. RESULTS: While wrist width, hand width, and hand length increased with gestational age, hand index decreased. Intraobserver and interobserver intraclass correlation coefficient values were >0.97. In trisomy 21 cases, wider wrists and hands were observed compared with euploid pregnancies (mean z-scores 1.06, SD 2.04, p < 0.001 and 1.16, SD 1.30, p < 0.001, respectively). Trisomy 18 cases showed narrower and shorter hands (mean z-scores -0.74, SD 1.20, p = 0.009 and -0.97, SD 0.86, p = 0.005, respectively). In trisomy 13 cases, no differences were observed. CONCLUSION: Reference values are available for first-trimester studies on human hand development. First-trimester hand measurements in trisomies 21 and 18 differ significantly from those in euploid pregnancies and may be useful for early identification of abnormal development. PMID- 24817600 TI - Absorption, distribution, metabolism, and excretion (ADME) of 14C-sonidegib (LDE225) in healthy volunteers. AB - PURPOSE: The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects. METHODS: Six subjects received a single oral dose of 800 mg 14C-sonidegib (74 kBq, 2.0 uCi) under fasting conditions. Blood, plasma, urine, and fecal samples were collected predose, postdose in-house (days 1-22), and during 24-h visits (weekly, days 29-43; biweekly, days 57-99). Radioactivity was determined in all samples using accelerator mass spectrometry (AMS). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine concentrations of sonidegib and its main circulating metabolite in plasma. Metabolite profiles and structures were determined in pooled plasma, urine, and fecal samples using high-performance LC-AMS and LC-MS/MS, respectively. RESULTS: A single dose of 14C-sonidegib was well tolerated in healthy subjects. Unchanged sonidegib and total radioactivity reached peak concentration in plasma by 2 and 3 h, respectively, and demonstrated similarly long half-lives of 319 and 331 h, respectively. Absorbed sonidegib (estimated 6-7 %) was extensively distributed, and the approximate terminal volume of distribution was 2,500 L. Unchanged sonidegib and a metabolite resulting from amide hydrolysis were the major circulating components (36.4 and 15.4 % of radioactivity area under the curve, respectively). Absorbed sonidegib was eliminated predominantly through oxidative metabolism of the morpholine part and amide hydrolysis. Unabsorbed sonidegib was excreted through the feces. Metabolites in excreta accounted for 4.49 % of the dose (1.20 % in urine, 3.29 % in feces). The recovery of radioactivity in urine and feces was essentially complete (95.3 +/- 1.93 % of the dose in five subjects; 56.9 % of the dose in one subject with incomplete feces collection suspected). CONCLUSIONS: Sonidegib exhibited low absorption, was extensively distributed, and was slowly metabolized. Elimination of absorbed sonidegib occurred largely by oxidative and hydrolytic metabolism. PMID- 24817601 TI - Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia. AB - PURPOSE: We evaluated the population pharmacokinetics (PPK) and exposure-response relationship of imatinib mesylate in Iranian patients with chronic myeloid leukemia (CML).This study was designed to assess steady state (SS) imatinib trough concentrations (Cmin) and pharmacokinetics parameters of imatinib in patients with CML in chronic phase after at least 12-month treatment. METHODS: Plasma concentrations from a randomized controlled trial consist of 61 patients who received oral imatinib at doses ranged between 300 and 800 mg in various dosing interval, which were quantified using a validated reversed-phase high performance liquid chromatographic method with UV detection method on different occasions at SS and evaluated using PPK model. RESULTS: A one-compartment model with zero-order absorption and a lag time was sufficient in describing the concentration-time profile. Inter-individual variability (IIV) was modeled for all parameters. Oral clearance (CL/F) and the volume of distribution (V/F) were estimated to 10.8 L/h with 30 % IIV and 265 L with 53 % IIV, respectively. Inter occasion variability (IOV) was included in CL/F (17 %) and V/F (22 %).The proportional residual error of the model was 8 %. CONCLUSIONS: Simulation analysis from individual parameters shows exposure to imatinib is highly variable among patients. Imatinib trough plasma levels <1,257 ng/mL were associated with lower rates of major molecular response. Because of the wide IIV compared with IOV with imatinib in our study, trough levels may play a role in investigating instances of suboptimal response. PMID- 24817602 TI - High liposomal doxorubicin tumour tissue distribution, as determined by radiopharmaceutical labelling with (99m)Tc-LD, is associated with the response and survival of patients with unresectable pleural mesothelioma treated with a combination of liposomal doxorubicin and cisplatin. AB - BACKGROUND: There are currently no available biomarkers for advanced pleural mesothelioma that determine which patients could benefit from a specific chemotherapy regimen. METHODS: Based on the results of a previously published phase II study, we associated the (99m)Technetium-labelled liposomal doxorubicin ((99m)Tc-LD) uptake value (75 % cut-off) with the response rate, progression-free survival and overall survival of patients treated with a combination of liposomal doxorubicin and cisplatin. RESULTS: Patients with tumours exhibiting increased (99m)Tc-LD uptake showed better response rates, progression-free survival and overall survival than those exhibiting lower uptake 73.3 versus 15 % (p < 0.001); 6.9 versus 3.2 months (p = 0.033) and 23 versus 6.6 months (p = 0.001), respectively. CONCLUSION: (99m)Tc-DL uptake in tumour tissue could define a set of patients who would benefit from this chemotherapy regimen. PMID- 24817603 TI - Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma. AB - PURPOSE: Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy. METHODS: Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two stage design, after 14 of planned 21 subjects were enrolled. RESULTS: Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) >=16 weeks was observed in 57 % patients, including three patients with SD lasting >=1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance. CONCLUSIONS: Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration. PMID- 24817604 TI - Vicilin-like peptides from Capsicum baccatum L. seeds are alpha-amylase inhibitors and exhibit antifungal activity against important yeasts in medical mycology. AB - The objective of this study was to isolate antimicrobial peptides from Capsicum baccatum seeds and evaluate their antimicrobial activity and inhibitory effects against alpha-amylase. Initially, proteins from the flour of C. baccatum seeds were extracted in sodium phosphate buffer, pH 5.4, and precipitated with ammonium sulfate at 90% saturation. The D1 and D2 fractions were subjected to antifungal tests against the yeasts Saccharomyces cerevisiae, Candida albicans, Candida tropicalis, and Kluyveromyces marxiannus, and tested against alpha-amylases from Callosobruchus maculates and human saliva. The D2 fraction presented higher antimicrobial activity and was subjected to further purification and seven new different fractions (H1-H7) were obtained. Peptides in the H4 fraction were sequenced and the N-terminal sequences revealed homology with previously reported storage vicilins from seeds. The H4 fraction exhibited strong antifungal activity and also promoted morphological changes in yeast, including pseudohyphae formation. All fractions, including H4, inhibited mammalian alpha-amylase activity but only the H4 fraction was able to inhibit C. maculatus alpha-amylase activity. These results suggest that the fractions isolated from the seeds of C. baccatum can act directly in plant defenses against pathogens and insects. PMID- 24817605 TI - Fungicide resistance of Botrytis cinerea in tomato greenhouses in the Canary Islands and effectiveness of non-chemical treatments against gray mold. AB - Tomato greenhouses in the Canary Islands, Spain, were surveyed to estimate frequencies of resistance to benzimidazoles, dicarboximides, anilinopyrimidines and N-phenylcarbamates in Botrytis cinerea. Resistance to carbendazim, iprodione, pyrimethanil and diethofencarb was found in 74.2, 86.4, 28.8 and 31.8% of isolates, respectively. Benzimidazole- and anilinopyrimide-resistant isolates were highly resistant, showing EC50 values above 500 ug/ml carbendazim and a mean EC50 value of 28.42 ug/ml pyrimethanil, respectively. By contrast, a low level of resistance was observed among dicarboximide-resistant isolates (mean EC50 value of 1.81 ug/ml iprodione). Phenotypes with double resistance to carbendazim and iprodione, and triple resistance to carbendazim, iprodione and pyrimethanil were the most common, occurring in 36.4 and 28.8% of isolates. The surveyed greenhouses had never been treated with fenhexamid and SignumTM (pre-packed mixture of boscalid and pyraclostrobin), and baseline sensitivities of B. cinerea isolates to these fungicides were determined. The EC50 values were within the range of 0.009-0.795 ug/ml fenhexamid and of 0.014-0.48 ug/ml Signum. In addition, available formulations based on elicitors of plant defense response and biocontrol agents were evaluated against B. cinerea in tomato plants under semi controlled greenhouse conditions, the yeast Candida sake CPA-1 being able to reduce gray mold significantly when it was applied on petiole wounds and the plants were inoculated 24 h later. Likewise, C. sake was effective against B. cinerea in harvested tomato fruits, yeast-treated tomatoes showed a 70.66 and 30.31% reduction in the diameters of decay lesions compared with controls after 10 days of storage at 20 and 9 degrees C, respectively. PMID- 24817606 TI - MicroRNA-101 suppresses liver fibrosis by targeting the TGFbeta signalling pathway. AB - Transforming growth factor-beta (TGFbeta) is crucial for liver fibrogenesis and the blunting of TGFbeta signalling in hepatic stellate cells (HSCs) or hepatocytes can effectively inhibit liver fibrosis. microRNAs (miRNAs) have emerged as key regulators in modulating TGFbeta signalling and liver fibrogenesis. However, the regulation of TGFbeta receptor I (TbetaRI) production by miRNA remains poorly understood. Here we demonstrate that the miR-101 family members act as suppressors of TGFbeta signalling by targeting TbetaRI and its transcriptional activator Kruppel-like factor 6 (KLF6) during liver fibrogenesis. Using a mouse model of carbon tetrachloride (CCl4 )-induced liver fibrosis, we conducted a time-course experiment and observed significant down-regulation of miR-101 in the fibrotic liver as well as in the activated HSCs and injured hepatocytes in the process of liver fibrosis. Meanwhile, up-regulation of TbetaRI/KLF6 was observed in the fibrotic liver. Subsequent investigations validated that TbetaRI and KLF6 were direct targets of miR-101. Lentivirus mediated ectopic expression of miR-101 in liver greatly reduced CCl4 -induced liver fibrosis, whereas intravenous administration of antisense miR-101 oligonucleotides aggravated hepatic fibrogenesis. Mechanistic studies revealed that miR-101 inhibited profibrogenic TGFbeta signalling by suppressing TbetaRI expression in both HSCs and hepatocytes. Additionally, miR-101 promoted the reversal of activated HSCs to a quiescent state, as indicated by suppression of proliferation and migration, loss of activation markers and gain of quiescent HSC specific markers. In hepatocytes, miR-101 attenuated profibrogenic TGFbeta signalling and suppressed the consequent up-regulation of profibrogenic cytokines, as well as TGFbeta-induced hepatocyte apoptosis and the inhibition of cell proliferation. The pleiotropic roles of miR-101 in hepatic fibrogenesis suggest that it could be a potential therapeutic target for liver fibrosis. PMID- 24817607 TI - Spontaneous biomimetic formation of (+/-)-dictazole B under irradiation with artificial sunlight. AB - Guided by biosynthetic considerations, the total synthesis of dictazole B is reported for the first time. Experimental evidence for an easy access to challenging cyclobutane alkaloids of marine origin, which are often postulated to be biosynthetic precursors of more complex structures, is provided. PMID- 24817608 TI - The influence of particle size and residual charge on electrostatic interactions between charged colloidal particles at an oil-water interface. AB - Electrostatic repulsive interaction forces between charged spherical colloidal particles at an oil-water interface are numerically studied by solving the standard three-dimensional Poisson-Nernst-Planck model. We directly compute the electrostatic force on a finite-size spherical particle and our results are applicable to all inter-particle distances without distinguishing short ranges and long ranges. The model successfully captures the scaling relationship of the force and the separation distance (d) between two charged particles at both short ranges (exponential dependence) and long ranges (~d(-4)). The model also bridges these two ranges and provides quantitative information in the middle range. In addition, by assuming that there is a small residual electric charge at the particle-oil interface, the standard model is capable of quantitatively predicting the repulsive particle-particle interaction force over a large range of the separation distance between two particles. The favorable agreement between experiments and theoretical predictions also leads one to conclude that the standard model adequately describes the particle-particle interactions trapped at the oil-water interface. PMID- 24817610 TI - Bayesian inference of local trees along chromosomes by the sequential Markov coalescent. AB - We propose a genealogy-sampling algorithm, Sequential Markov Ancestral Recombination Tree (SMARTree), that provides an approach to estimation from SNP haplotype data of the patterns of coancestry across a genome segment among a set of homologous chromosomes. To enable analysis across longer segments of genome, the sequence of coalescent trees is modeled via the modified sequential Markov coalescent (Marjoram and Wall, Genetics 7:16, 2006). To assess performance in estimating these local trees, our SMARTree implementation is tested on simulated data. Our base data set is of the SNPs in 10 DNA sequences over 50 kb. We examine the effects of longer sequences and of more sequences, and of a recombination and/or mutational hotspot. The model underlying SMARTree is an approximation to the full recombinant-coalescent distribution. However, in a small trial on simulated data, recovery of local trees was similar to that of LAMARC (Kuhner et al. Genetics 156:1393-1401, 2000a), a sampler which uses the full model. PMID- 24817609 TI - Short-term heat acclimation training improves physical performance: a systematic review, and exploration of physiological adaptations and application for team sports. AB - BACKGROUND: Studies have demonstrated that longer-term heat acclimation training (>=8 heat exposures) improves physical performance. The physiological adaptations gained through short-term heat acclimation (STHA) training suggest that physical performance can be enhanced within a brief timeframe. OBJECTIVE: The aim of this systematic review was to determine if STHA training (<=7 heat exposures) can improve physical performance in healthy adults. DATA SOURCES: MEDLINE, PubMed, and SPORTDiscusTM databases were searched for available literature. STUDY SELECTION: Studies were included if they met the following criteria: STHA intervention, performance measure outcome, apparently healthy participants, adult participants (>=18 years of age), primary data, and human participants. STUDY APPRAISAL: A modified McMaster critical appraisal tool determined the level of bias in each included study. RESULTS: Eight papers met the inclusion criteria. Studies varied from having a low to a high risk of bias. The review identified aerobic-based tests of performance benefit from STHA training. Peak anaerobic power efforts have not been demonstrated to improve. LIMITATIONS: At the review level, this systematic review did not include tolerance time exercise tests; however, certain professions may be interested in this type of exercise (e.g. fire-fighters). At the outcome level, the review was limited by the moderate level of bias that exists in the field. Only two randomized controlled trials were included. Furthermore, a limited number of studies could be identified (eight), and only one of these articles focused on women participants. CONCLUSIONS: The review identified that aerobic-based tests of performance benefit from STHA training. This is possibly through a number of cardiovascular, thermoregulatory, and metabolic adaptations improving the perception of effort and fatigue through a reduction in anaerobic energy release and elevation of the anaerobic threshold. These results should be viewed with caution due to the level of available evidence, and the limited number of papers that met the inclusion criteria of the review. STHA training can be applied in the team-sport environment during a range of instances within the competitive season. A mixed high-intensity protocol may only require five sessions with a duration of 60 min to potentially improve aerobic-based performance in trained athletes. PMID- 24817611 TI - Bacterial diversity of extremely alkaline bauxite residue site of alumina industrial plant using culturable bacteria and residue 16S rRNA gene clones. AB - Bauxite residue (red mud), generated during the extraction of alumina from bauxite ore is characterized by high pH, high concentrations of soluble ions with low or virtually no organic matter. These extreme conditions along with numerous nutrient deficiencies, limit the microbial growth and vegetation establishment. In the present study, diversity of both cultivable and non-cultivable bacteria present in the red mud was investigated by 16S rDNA sequence analyses. The cultivable bacteria were identified as Agromyces indicus, Bacillus litoralis, B. anthracis, Chungangia koreensis, Kokuria flava, K. polaris, Microbacterium hominis, Planococcus plakortidis, Pseudomonas alcaliphila and Salinococcus roseus based on their 16S rDNA sequence analysis. These isolates were alkali tolerant, positive for one or more of the enzyme activities tested, able to produce organic acids and oxidize wide range of carbon substrates. For non-cultivable diversity of bacteria, DNA was extracted from the bauxite residue samples and 16S rDNA clone library was constructed. The 16S rDNA clones of this study showed affiliation to three major phyla predominant being betaproteobacteria (41.1%) followed by gammaproteobacteria (37.5%) and bacteroidetes (21.4%). We are reporting for the first time about the bacterial diversity of this unique and extreme environment. PMID- 24817612 TI - Electrochemical tuning of oxygen-containing groups on graphene oxides: towards control of the performance for the analysis of biomarkers. AB - Graphene materials are very popular in the field of biosensing owing to their distinctive characteristics. However, oxygen-containing groups are known to exist intrinsically in graphene-related materials. These groups influence the electrochemical properties of graphene materials and therefore affect the sensing performance of graphene-based electrodes when used to detect redox active biomarkers. A well-defined carbon/oxygen (C/O) ratio can be obtained upon applying different reduction potentials to graphene oxide (GO) films for a controlled removal of redox active oxygen functionalities. Here, we show that a precise control of the oxygen functionalities on the graphene oxide films allows the tuning of the biosensing capabilities of the electrodes for the analysis of two significant biomarkers, uric acid and ascorbic acid, as well as two DNA bases, guanine and adenine. Both the catalytic properties and the sensitivity of the reduced GO film electrodes (ERGOs) are evaluated by measuring the oxidation potential and the peak current, respectively. We demonstrate that each biomarker requires different optimal conditions which can be easily matched by varying the electrochemical pre-treatment of the sensing GO film. PMID- 24817613 TI - Endocrine-disrupting chemicals in the Pearl River Delta and coastal environment: sources, transfer, and implications. AB - A study was conducted to investigate the occurrence and behavior of six endocrine disrupting chemicals (EDCs) in sewage, river water, and seawater from the Pearl River Delta (PRD). The six EDCs under study were 4-nonylphenol (NP), bisphenol A (BPA), 17alpha-ethynylestradiol (EE2), estrone (E2), 17beta-estradiol (E2), and estriol (E3). These EDCs, predominated by BPA, were found in high levels in the influents and the effluents of sewage treatment plants in the area. The relatively high concentrations (0.23-625 ng/L) of the EDCs detected in the receiving river water suggested that the untreated sewage discharge was a major contributor. The EDCs detected in eight outlets of the Pear River and the Pear River Estuary were in the ranges of 1.2-234 and 0.2-178 ng/L, respectively. The estrogen equivalents in the aquatic environments under study ranged from 0.08 to 4.5 ng/L, with E1 and EE2 being the two predominant contributors. As the fluxes of the EDCs from the PRD region to the nearby ocean are over 500 tons each year, the results of this study point to the potential that Pearl River is a significant source of the EDCs to the local environment there. PMID- 24817614 TI - Evaluation of geochemical characteristics and health effects of some geophagic clays southern Nigeria. AB - The geochemical characteristics of geophagic clays from Calabar and Okon-Eket, southern Nigeria were evaluated to determine their quality and the possible health effects of their consumption. The study involved the measurement of the pH, electrical conductivity (EC) and total dissolved solids (TDS) of the slurried clay samples soaked in distilled water for 48 h using digital multi-parameters probe as well as the elemental and mineralogical analyses of twenty geophagic clay samples for elemental and mineralogical constituents using both the ICP-MS and XRD, respectively. Medical data were also mined from medical facilities within the area in addition to the administering of questionnaire to adults involved in the geophagic practices in order to determine their justification for the practice as well as their and clay preferences. Results of physicochemical measurement revealed that the pH range of the samples ranges from 3.9 to 6.9 and 6.5 to 7.0; EC 0.3-377.7 and 0.12-82.38 uS/cm; TDS 1.98-2,432.65 and 0.08-52.95 mg/L for consumed and non-consumed clay, respectively. The elemental analyses revealed that the concentration of some potential harmful elements, PHEs, exceeded the recommended dietary intake by humans. This is especially true for Cu (9.1-23 ppm), Pb (16.7-55.6 ppm), Zn (13-148 ppm), Ni (11.1-46.4 ppm), Co (1.8 21.7 ppm), Mn (16-338 ppm), As (BDL-15 ppm) and Cd (BDL-0.2 ppm). The predominant phases established in the clay samples are quartz and kaolinite, while the minor minerals were montmorillonite and muscovite in all the clay samples. Respondents revealed that capacity for relief from gastrointestinal problems believes in the curative power to cure skin infections and cultural reasons as main justification for the geophagic practices. This is, however, not in conformity with information gleaned from the medical records which still indicated that the prevalent diseases in the area still include gastrointestinal problems in addition to malaria, hypertension and cardiac failure with minor cases of respiratory tract infections. The high concentrations of the PHEs may be responsible for or contribute in part to the prevalence of hypertension, cardiac failures and gastrointestinal problems within the study areas. Though the kaolinite present in the geophagic clays makes them suitable for use as traditional antacids; however, the toxic trace element concentrations and significant quartz content will most likely mask the beneficial effects of such kaolinite. PMID- 24817615 TI - Linear {NiII-LnIII-NiII} complexes containing twisted planar Ni(MU-phenolate)2 Ln fragments: synthesis, structure, and magnetothermal properties. AB - Sequential reaction of a multisite LH(4) ligand {2-[2-hydroxy-3-(hydroxymethyl)-5 methylbenzylideneamino]-2-methylpropane-1,3-diol} with appropriate lanthanide salts followed by the addition of Ni(NO(3))(2)?6 H(2)O in a 4:1:2 stoichiometric ratio in the presence of triethylamine afforded four heterobimetallic trinuclear complexes [Ni(2)Gd(LH(3))(4)]?3NO(3)?3 MeOH?H(2)O?CH(3)CN (1), [Ni(2)Tb(LH(3))(4)]?(3 )NO(3)?3 MeOH?CH(3)CN (2), [Ni(2)Dy(LH(3))(4)]?3 NO(3)?3 MeOH?H(2)O?CH(3)CN (3), and [Ni(2)Ho(LH(3))(4)]?3 NO(3)?3 MeOH?H(2)O?CH(3)CN (4). Complexes 1-4 possess linear trimetallic cores with a central lanthanide ion. Magnetic studies revealed a predominant ferromagnetic interaction between the Ni and Ln centers. Alternating current susceptibility measurements of complex 3 showed a small frequency dependence of the out-of-phase signal, chi''(M), under zero direct current field, but without achieving a net maximum above 2 K. Magnetic studies on 1 revealed that it has a significant magnetocaloric effect. PMID- 24817616 TI - Active treatment given in the last weeks of life: poor quality cancer care or justifiable behavior? AB - PURPOSE: Chemotherapy near the end of life is frequently considered as an indicator of inappropriate aggressiveness. We were interested in revising our prescribing habits and in analyzing the reasons for offering active treatment to patients with advanced cancer. METHODS: We examined the electronic medical records of all the cancer patients died in the Italian Region of Valle d'Aosta in a 1-year period and extracted all the available clinical data. From the 350 deceased patients, we selected the 141 to whom active treatment had been given during the natural history of their disease. RESULTS: Among the patients undergoing any active treatment, the median number of days from the last administration to death was 75. Thirty-seven patients (26.2 %) had their last treatment administration during the 4 weeks before death and 20 (14.2 %) during the last 2 weeks. Fourteen patients (9.9 %) started treatment during the last 4 weeks. When the patients undergoing treatment in the last 4 weeks of life were compared with those subject to earlier withdrawal, only age and pretreatment were statistically significantly different. Most of the treatment choices were considered appropriate, and earlier treatment withdrawal could have been advised only in a minority of the cases. CONCLUSIONS: Our data were at the lower range when compared with the available literature. Uncertainties in prognostication and the possibility of response to treatment can justify chemotherapy prescriptions in selected cases. We suggest that the focus should move to the provision of adequate and timely supportive care. PMID- 24817618 TI - Assessing the effect of laser beam width on quantitative evaluation of optical properties of intraocular lens implants. AB - The design and manufacture of intraocular lenses (IOLs) depend upon the identification and quantitative preclinical evaluation of key optical properties and environmental parameters. The confocal laser method (CLM) is a new technique for measuring IOL optical properties, such as dioptric power, optical quality, refractive index, and geometrical parameters. In comparison to competing systems, the CLM utilizes a fiber-optic confocal laser design that significantly improves the resolution, accuracy, and repeatability of optical measurements. Here, we investigate the impact of changing the beam diameter on the CLM platform for the evaluation of IOL dioptric powers. Due to the Gaussian intensity profile of the CLM laser beam, the changes in focal length and dioptric power associated with changes in beam diameter are well within the tolerances specified in the ISO IOL standard. These results demonstrate some of the advanced potentials of the CLM toward more effectively and quantitatively evaluating IOL optical properties. PMID- 24817617 TI - Desire for children, difficulties achieving a pregnancy, and infertility distress 3 to 7 years after cancer diagnosis. AB - PURPOSE: The aim was to investigate desire for children, difficulties achieving a pregnancy, and infertility distress among survivors 3 to 7 years after cancer treatment in reproductive age. METHODS: Cancer survivors were identified in national population-based cancer registries. Eligible subjects presented with selected cancer diagnoses between 2003 and 2007 between the ages of 18 to 45. A postal questionnaire including study-specific questions, the Short-Form 36 Health Survey and the Fertility Problem Inventory, was sent to 810 survivors, and 484 participated (60 % response). RESULTS: Most survivors who had a pretreatment desire for children still wanted children 3-7 years after treatment, and this group was characterized by young age and being childless at diagnosis. In addition, a substantial group of survivors (n = 55, 17 %) that did not have a pretreatment desire for children had changed their mind about wanting children after treatment. About a third of the survivors with a desire to have children had experienced difficulties achieving a pregnancy after the cancer treatment, and an unfulfilled desire to have children was associated with worse mental health. Survivors presently facing difficulties achieving a pregnancy reported moderate levels of infertility distress and expressed low interest in using gamete donation. CONCLUSIONS: Health professionals in cancer care need to be aware that patients' plans for future children may change, particularly if they are young and childless. All patients of reproductive age should be provided with adequate information about the impact of cancer treatment on future fertility and fertility preservation. PMID- 24817619 TI - Simultaneous imaging of cellular morphology and multiple biomarkers using an acousto-optic tunable filter-based bright field microscope. AB - An acousto-optic tunable filter (AOTF)-based multispectral imaging microscope system allows the combination of cellular morphology and multiple biomarker stainings on a single microscope slide. We describe advances in AOTF technology that have greatly improved spectral purity, field uniformity, and image quality. A multispectral imaging bright field microscope using these advances demonstrates pathology results that have great potential for clinical use. PMID- 24817620 TI - Fast spatiotemporal image reconstruction based on low-rank matrix estimation for dynamic photoacoustic computed tomography. AB - In order to monitor dynamic physiological events in near-real time, a variety of photoacoustic computed tomography (PACT) systems have been developed that can rapidly acquire data. Previously reported studies of dynamic PACT have employed conventional static methods to reconstruct a temporally ordered sequence of images on a frame-by-frame basis. Frame-by-frame image reconstruction (FBFIR) methods fail to exploit correlations between data frames and are known to be statistically and computationally suboptimal. In this study, a low-rank matrix estimation-based spatiotemporal image reconstruction (LRME-STIR) method is investigated for dynamic PACT applications. The LRME-STIR method is based on the observation that, in many PACT applications, the number of frames is much greater than the rank of the ideal noiseless data matrix. Using both computer-simulated and experimentally measured photoacoustic data, the performance of the LRME-STIR method is compared with that of conventional FBFIR method followed by image domain filtering. The results demonstrate that the LRME-STIR method is not only computationally more efficient but also produces more accurate dynamic PACT images than a conventional FBFIR method followed by image-domain filtering. PMID- 24817621 TI - Optoacoustic characterization of prostate cancer in an in vivo transgenic murine model. AB - Optoacoustic (OA) imaging was employed to distinguish normal from neoplastic tissues in a transgenic murine model of prostate cancer. OA images of five tumor bearing mice and five age-matched controls across a 14 mm * 14 mm region of interest (ROI) on the lower abdomen were acquired using a reverse-mode OA imaging system (Seno Medical Instruments Inc., San Antonio, Texas). Neoplastic prostate tissue was identified based on the OA signal amplitude in combination with spectral analysis of the OA radio frequency (RF) data. Integration of the signal amplitude images was performed to construct two-dimensional images of the ROI. The prostate tumors generated higher amplitude signals than those of the surrounding tissues, with contrast ratios ranging from 31 to 36 dB. The RF spectrum analysis showed significant differences between the tumor and the control mice. The midband fit was higher by 5 dB (62%), the intercept higher by 4 dB (57%) and the spectral slope higher by 0.4 dB/MHz (50%) for neoplastic prostate tissue compared to normal tissues in the control mice. The results demonstrate that OA offers high contrast imaging of prostate cancer in vivo. PMID- 24817622 TI - Monitoring brain temperature by time-resolved near-infrared spectroscopy: pilot study. AB - Mild hypothermia (HT(32 degrees C-33 degrees C)) is an effective neuroprotective strategy for a variety of acute brain injuries. However, the wide clinical adaptation of HT(32-33 degrees C) has been hampered by the lack of a reliable noninvasive method for measuring brain temperature, since core measurements have been shown to not always reflect brain temperature. The goal of this work was to develop a noninvasive optical technique for measuring brain temperature that exploits both the temperature dependency of water absorption and the high concentration of water in brain (80%-90%). Specifically, we demonstrate the potential of time-resolved near-infrared spectroscopy (TR-NIRS) to measure temperature in tissue-mimicking phantoms (in vitro) and deep brain tissue (in vivo) during heating and cooling, respectively. For deep brain tissue temperature monitoring, experiments were conducted on newborn piglets wherein hypothermia was induced by gradual whole body cooling. Brain temperature was concomitantly measured by TR-NIRS and a thermocouple probe implanted in the brain. Our proposed TR-NIRS method was able to measure the temperature of tissue-mimicking phantoms and brain tissues with a correlation of 0.82 and 0.66 to temperature measured with a thermometer, respectively. The mean difference between the TR-NIRS and thermometer measurements was 0.15 degrees C +/- 1.1 degrees C for the in vitro experiments and 0.5 degrees C +/- 1.6 degrees C for the in vivo measurements. PMID- 24817623 TI - Illicit drug detection with laser 1: investigation of optimal parameters in stomach tissue. AB - The main purpose of this study is to establish radiation-safe scanning of passersby at high security areas, such as airports and customs. The stomach was selected as the organ to be analyzed. In order to determine whether a substance found inside a human body as wrapped in a plastic bag is filled narcotics or not, many substances in white powder form including morphine-HCL were inspected. Inspection was carried out with on-ionizing radiation by irradiating stomach tissue with laser light. Optical transmittance of lamb stomach tissue was analyzed at different wavelengths. We showed that detection by 650-nm diode laser irradiation would be suitable for such a radiation-safe scan. Different materials were also investigated for absorptive properties, and closed system Raman studies were performed. The spectrum of a molecule found inside white powder placed behind the lamb stomach tissue was detected as a fingerprint. This allowed the detection of target substances without any physical contact or damage to the biological tissue. PMID- 24817624 TI - Parental stress predicts functional outcome in pediatric cancer survivors. AB - BACKGROUND: Childhood cancer survivors are at risk for long-term neurocognitive and psychosocial morbidities. Research has seldom examined the relationship between these morbidities; thus, little empirical evidence exists concerning overall salience and how morbidities converge to impair day-to-day functioning. An increased understanding of functional impairment resulting from the pediatric cancer experience can inform early risk identification as well as sources for intervention. The purpose of this study was to characterize the frequency/severity of functional impairment and identify significant neurocognitive and psychosocial determinants of functional impairment. METHODS: Fifty child-parent dyads were enrolled. Children were aged 7-19 years who were at least 2 years postdiagnosis with leukemia/lymphoma and were recruited through a pediatric oncology late effects clinic. Parents completed questionnaires, rating their own adjustment to their child's illness as well as their child's level of functional impairment, while a brief neuropsychological exam was administered to children. RESULTS: Twenty-six percent of the sample evidenced clinically significant functional impairment. Regression analyses indicated that neurocognitive deficits did not predict functional impairment, whereas parental stress was a significant predictor. CONCLUSIONS: Although children demonstrated both neurocognitive deficits and functional impairments, results favor psychosocial factors, such as parental stress, as a predictor of overall functional impairment. The implications of this study suggest that late effects aggregate to impact day-to-day functioning in pediatric cancer survivor populations and parental stress may serve as a marker for heightened risk. The results suggest that broader functional domains, especially school and self-care domains, should be evaluated and considered when identifying potential targets for psychosocial interventions. PMID- 24817626 TI - Impedance spectroscopic analysis on effects of partial oxidation of TiN bottom electrode and microstructure of amorphous and crystalline HfO2 thin films on their bipolar resistive switching. AB - The electrical resistance switching (RS) properties of amorphous HfO2 (a-HfO2) and crystalline HfO2 (c-HfO2) thin films grown on a TiN substrate via atomic layer deposition were examined using DC current-voltage (I-V) sweep and AC impedance spectroscopic (IS) analyses. The rapid thermal annealing of the a-HfO2 film at 500 degrees C under a N2 atmosphere for 5 min crystallized the HfO2 film and induced an interfacial TiON barrier layer. The a-HfO2 sample showed fluent bipolar RS performance with a high on/off ratio (~ 500), whereas the c-HfO2 sample showed a much lower on/off ratio (<~ 10), but its switching uniformity was better than that of a-HfO2. Such critical differences can be mainly attributed to the absence and presence of the TiON barrier layer in the a-HfO2 and c-HfO2 samples, respectively. The AC IS especially enabled the resistance states of the HfO2/Pt interface and the HfO2/TiN interface to be separately examined during one complete switching cycle of each sample. Although the Pt/c-HfO2 interface has a Schottky barrier in the pristine state, it disappeared once the c-HfO2 was electroformed and was not recovered even after the reset step. In contrast, the Pt/a-HfO2 interface partly recovered the Schottky barrier after the reset. PMID- 24817625 TI - Evaluation of an implementation model: a national investigation of VA residential programs. AB - This national investigation utilizes qualitative data to evaluate an implementation model regarding factors influencing provider use of two evidence based treatments for posttraumatic stress disorder (PTSD). Semi-structured qualitative interviews with 198 mental health providers from 38 Department of Veterans Affairs' (VA) residential treatment programs were used to explore these issues regarding prolonged exposure (PE) and cognitive processing therapy (CPT) in VA residential PTSD programs. Several unique and some overlapping predictors emerged. Leadership was viewed as an influence on implementation for both CPT and PE, while a lack of dedicated time and resources was viewed as a deterrent for both. Compatibility of CPT with providers' existing practices and beliefs, the ability to observe noticeable patient improvement, a perceived relative advantage of CPT over alternative treatments, and the presence of a supportive peer network emerged as influential on CPT implementation. Leadership was associated with PE implementation. Implications for the design and improvement of training and implementation efforts are discussed. PMID- 24817627 TI - Understanding cancer screening service utilization by Somali men in Minnesota. AB - This study examined factors that influence use of cancer screening by Somali men residing in Minnesota, USA. To better understand why recent immigrants are disproportionately less likely to use screening services, we used the health belief model to explore knowledge, beliefs, and attitudes surrounding cancer screening. We conducted a qualitative study comprised of 20 key informant interviews with Somali community leaders and 8 focus groups with Somali men (n = 44). Somali men commonly believe they are protected from cancer by religious beliefs. This belief, along with a lack of knowledge about screening, increased the likelihood to refrain from screening. Identifying the association between religion and health behaviors may lead to more targeted interventions to address existing disparities in cancer screening in the growing US immigrant population. PMID- 24817628 TI - Regulation of SRC kinases by microRNA-3607 located in a frequently deleted locus in prostate cancer. AB - Genomic studies suggest that deletions at chromosome (chr) 5q region (particularly chr5q14-q23) are frequent in prostate cancer, implicating this region in prostate carcinogenesis. However, the genes within this region are largely unknown. Here, we report for the first time the widespread attenuation of miR-3607, an miRNA gene located at chr5q14 region, in prostate cancer. Expression analyses of miR-3607 in a clinical cohort of prostate cancer specimens showed that miR-3607 is significantly attenuated and low miR-3607 expression is correlated with tumor progression and poor survival outcome in prostate cancer. Our analyses suggest that miR-3607 expression may be a clinically significant parameter with an associated diagnostic potential. We examined the functional significance of miR-3607 in prostate cancer cell lines and found that miR-3607 overexpression led to significantly decreased proliferation, apoptosis induction, and decreased invasiveness. Furthermore, our results suggest that miR-3607 directly represses oncogenic SRC family kinases LYN and SRC in prostate cancer. In view of our results, we propose that miR-3607 plays a tumor-suppressive role in prostate cancer by regulating SRC kinases that in turn regulates prostate carcinogenesis. To our knowledge, this is the first report that: (i) identifies a novel role for miR-3607 located in a frequently deleted region of prostate cancer and (ii) defines novel miRNA-mediated regulation of SRC kinases in prostate cancer. Because SRC kinases play a central role in prostate cancer progression and metastasis and are attractive targets, this study has potential implications in the design of better therapeutic modalities for prostate cancer management. PMID- 24817629 TI - EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. AB - Advanced tumors produce an excessive amount of transforming growth factor beta (TGFbeta), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFbeta therapeutics for cancer. We synthesized a novel small-molecule TGFbeta receptor I kinase (activin receptor like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6 methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/TGFbeta signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFbeta-treated breast cancer cells and 4T1 orthotopic grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy. PMID- 24817630 TI - Functional outcomes and quality of life following surgical treatment of aneurysmal bone cysts of the pelvis in children. AB - BACKGROUND: Aneurysmal bone cysts (ABCs) are a benign aggressive tumor that occurs rarely in the pelvis in the pediatric population. Pelvic ABCs may involve the triradiate cartilage and/or the acetabulum, which increases the technical difficulty of surgical treatment and has potential implications on the growth and development of the hip joint. This study examines the clinical presentation, rate of surgical complications, and recurrence rate, as well as, long-term clinical and functional outcomes of children with pelvic ABCs treated at a single institution by a single treatment modality. METHODS: Between 1988 and 2008, 142 children with histologically confirmed ABCs were treated at our institution. Seventeen (12 %) tumors were located in the pelvis. A total of 13 pelvic ABCs (5 ilium-periacetabular, 4 pubic, 3 ilium-iliac wing, and 1 ischium) were included in this study. There were eight male and five female patients with a mean age of 12.9 years (range 4.1-17.5 years) at the time of surgery. The Toronto Extremity Salvage Score (TESS), the Musculoskeletal Tumor Society 1993 (MSTS'93) score, and the Short Form Health Survey Sf-36 were obtained at a minimum 5-year follow-up in all patients (mean follow-up 11.5 years, range 5.5-19.8 years). The mean age at follow-up was 24.3 years (range 14.6-32.6 years). RESULTS: All patients were treated surgically with intralesional curettage extended with a high-speed burr and bone grafting. Eight patients received adjunctive therapy with phenol. Five patients had preoperative selective arterial embolization. Of the 13 patients, 1 had a local recurrence diagnosed at 6 months after surgery. The only complication in the cohort was a superficial wound infection. At the latest follow-up, all patients were free of disease. The mean TESS score was 95 and the mean MSTS'93 score was 93 %. The mean self-rated general health score, according to the SF-36 was 87 % of total points possible. CONCLUSIONS: Extended curettage and bone grafting of pelvic ABCs in the pediatric population can yield high clinical and functional scores at an average of 11 years follow-up with a low rate of complications and recurrence. LEVEL OF EVIDENCE: IV, case series. PMID- 24817631 TI - Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes. AB - High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed. PMID- 24817634 TI - Differential distribution of Y-box-binding protein 1 and cold shock domain protein A in developing and adult human brain. AB - The two cold shock domain containing proteins, Y-box-binding protein-1 and cold shock domain protein A were immunolocalized in developing and adult human brain. With the exception of a small population of hypothalamic astrocytes, brain Y-box binding protein-1 was predominantly found in multiple neurons in the mature human CNS, which might be related to its involvement in neurotransmission and other neuron-associated functions. Cold shock domain protein A was typically observed in astrocytes, oligodendrocytes, choroid plexus epithelia and nerve fibers. However, in circumscribed brain regions as hypothalamus, habenula, and cerebellum, this protein was also expressed in neurons. In the prenatal brain, both proteins were found to be abundantly expressed in radial glial cells, neuroblasts and neurons, which might be an anatomical correlate of the proposed roles of both proteins in cell proliferation and differentiation. In addition, Y box-binding protein-1 was identified in cultured, lipopolysaccharide-stimulated microglial cells, which underscores its putative role as a mediator in immune and inflammatory processes. PMID- 24817635 TI - Development of the blood-brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess. AB - The blood-brain barrier (BBB) is a critical contributor to brain function. To understand its development and potential function in different brain regions, the postnatal (P) BBB was investigated in the mouse cortex (CTX), lateral hypothalamus, and paraventricular nucleus of the hypothalamus (PVN). Brains were examined on postnatal days (P)12, P22 and P52 for BBB competency and for pericytes as key cellular components of the BBB demarcated by immunoreactive desmin. Glucocorticoid influences (excess dexamethasone; dex) during prenatal development were also assessed for their impact on the blood vessels within these regions postnatally. At P12, there was significantly more extravascular leakage of a low molecular weight dye (fluorescein isothiocyanate) in the CTX than within hypothalamic regions. For pericytes, there were low levels of desmin immunoreactivity at P12 that increased with age for all regions. There was more desmin immunoreactivity present in the PVN at each age examined. Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20. In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence. Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders. PMID- 24817636 TI - [Simultaneous EEG-fMRI measurements: insights in applications and challenges]. AB - BACKGROUND: The following article presents an introduction to simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) measurements which have undergone a huge development during the last few years. OBJECTIVES: The idea behind combining both non-invasive methods is to join the excellent temporal resolution of EEG (ms) together with the superior spatial resolution of fMRI (mm). In this article the status quo of the method and perspectives regarding multimodal imaging are discussed. MATERIAL AND METHODS: Simultaneous EEG-fMRI measurements are affected by scanner and cardioballistic artifacts. We present common artifact subtraction methods in order to achieve a feasible data quality and outline what to consider when planning and recording EEG and fMRI simultaneously. Moreover, we discuss different analysis strategies. RESULTS: Combined EEG-fMRI measurements have already increased our knowledge about the underlying relationships between the blood oxygenation level-dependent (BOLD) response and the EEG signal and are applied to answer widespread research questions. Simultaneous measurements are an essential part of multimodal imaging in investigating the underlying processing mechanisms of the brain as well as in advancing our understanding of neuropsychiatric diseases. CONCLUSIONS: Current developments in multimodal imaging focus on the combination of electrophysiological and MRI parameters within ultra-high field MRI as well as on positron emission tomography (PET) in a trimodal approach. PMID- 24817637 TI - [Coping with multiple sclerosis in partnerships: a systematic review of the literature]. AB - BACKGROUND: As with other chronic diseases, multiple sclerosis (MS) is not only experienced by the persons suffering from the disease but also their partners. OBJECTIVE AND METHOD: To explore the current level of knowledge on dealing with MS in relationships and to obtain indications of factors that have a positive impact on the way of coping with the disease, studies on this topic were sought in the databases of Cinahl, Medline and PsycINFO using the following keywords: multiple sclerosis, spouses, couples, married couple, dyadic system, dyadic systems and dyads. The results were interpreted in the context of "Developmental contextual model of couples coping with chronic illness across the adult life span". RESULTS: Systematic allocation of the study results found in this way created a comprehensive image of the coping process. The results clearly showed that both partners experience difficult feelings such as uncertainty, fear, depression and distress. Coping in a relationship with the often continuously changing situations and the associated stress is done best by couples who consistently exchange their mutual perceptions, inform one another of the mental and physical strains in open discussions and synchronise their ideas regarding the generation of the meaning and satisfaction with life. CONCLUSION: Targeted support for dyadic coping can lead to stress reduction and higher relationship satisfaction of couples living with MS. PMID- 24817638 TI - Alpha-B-crystallin expression in human laryngeal squamous cell carcinoma tissues. AB - BACKGROUND: Laryngeal squamous cell carcinoma (SCC), being an aggressive malignancy, is one of the most commonly diagnosed malignant types of head and neck SCC worldwide. The recent studies suggested that alphaB-crystallin might play an important role in tumorigenesis. The purpose of this study was to investigate the alphaB-crystallin expression level in metastatic and nonmetastatic laryngeal SCC tissues and to determine its prognostic significance. METHODS: Alpha-B-crystallin expression status in metastatic, nonmetastatic laryngeal SCC, and normal tissue samples was investigated by quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: We demonstrated that the expression of alphaB-crystallin was significantly upregulated in laryngeal SCC tumor tissue samples in comparison with the corresponding normal tissues (p < .001), although no significant association has been found between alphaB crystallin expression and either the metastatic potential or the T classification of the specimens. CONCLUSION: Although expression of alphaB-crystallin is not statistically correlated with neck metastases, we demonstrated that alphaB crystallin is significantly overexpressed in laryngeal cancer. PMID- 24817639 TI - Determination of micronutrients and oxidative stress status in the blood of STZ induced experimental diabetic rat models. AB - This study aims to research the effect of streptozotocin (STZ) at different doses on the serum micronutrients and oxidative stress status in diabetic rat models. Twenty male rats averaged 250 g and 3-4 months old were used as experimental models. They were put in four groups composed of five rats each. Diabetic was induced by administering STZ 55 and 65 mg/kg intraperitonally. The serum micronutrients including minerals and vitamins (Cu, Zn, Mg, Fe, vitamins D, E, and C) and oxidative stress (malondialdehyde, MDA) were determined. Cu, Zn, and Vitamin D3 levels were found to increase significantly in STZ groups (p < 0.005). Retinol levels decreased significantly in STZ groups (p < 0.005). In the groups administered 55 mg/kg STZ ferrum and vitamin C levels were found significantly lower than the other groups (p < 0.005). In the group given 65 mg/kg STZ alpha tocopherol levels were highest (p < 0.005) among other groups. There was not any difference between the groups for MDA, Cu/Zn, and Mg. For both doses, oxidative stress status was not significantly affected within 48 h of the application, however, some micronutrients were affected significantly. PMID- 24817640 TI - Nicotine promotes late endothelial progenitor cells functional activity in a PI 3 kinase-dependent manner. AB - Recent studies have shown that endothelial progenitor cells (EPCs) participated in angiogenic effects of nicotine and nicotine dose dependently increased the functional activity of early EPCs. The effects of nicotine on late EPCs remain to be determined. Therefore, we investigated whether nicotine had influences on the functional activity of late EPCs. Late EPCs were isolated from human umbilical cord blood and characterized. Late EPCs of 3-5 passages were treated for 32 h with either vehicle or nicotine. The proliferative, migratory, and in vitro vasculogenesis activities of late EPCs were assayed with 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay, modified Boyden chamber assay, and in matrigel, respectively. Late EPCs adhesion assay was performed by replating cells on fibronectin-coated dishes, and then adherent cells were counted. Nicotine enhanced proliferative, migratory, adhesive, and in vitro vasculogenesis capacities of late EPCs. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitor. PMID- 24817641 TI - An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex. AB - Fanconi anemia (FA) is an autosomal recessive human disease characterized by genomic instability and a marked increase in cancer risk. The importance of FANCD1 gene is manifested by the fact that deleterious amino acid substitutions were found to confer susceptibility to hereditary breast and ovarian cancers. Attaining experimental knowledge about the possible disease-associated substitutions is laborious and time consuming. The recent introduction of genome variation analyzing in silico tools have the capability to identify the deleterious variants in an efficient manner. In this study, we conducted in silico variation analysis of deleterious non-synonymous SNPs at both functional and structural level in the breast cancer and FA susceptibility gene BRCA2/FANCD1. To identify and characterize deleterious mutations in this study, five in silico tools based on two different prediction methods namely pathogenicity prediction (SIFT, PolyPhen, and PANTHER), and protein stability prediction (I-Mutant 2.0 and MuStab) were analyzed. Based on the deleterious scores that overlap in these in silico approaches, and the availability of three dimensional structures, structure analysis was carried out with the major mutations that occurred in the native protein coded by FANCD1/BRCA2 gene. In this work, we report the results of the first molecular dynamics (MD) simulation study performed to analyze the structural level changes in time scale level with respect to the native and mutated protein complexes (G25R, W31C, W31R in FANCD1/BRCA2-PALB2, and F1524V, V1532F in FANCD1/BRCA2-RAD51). Analysis of the MD trajectories indicated that predicted deleterious variants alter the structural behavior of BRCA2-PALB2 and BRCA2-RAD51 protein complexes. In addition, statistical analysis was employed to test the significance of these in silico tool predictions. Based on these predictions, we conclude that the identification of disease-related SNPs by in silico methods, in combination with MD approach has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases. The methods reviewed here generated a considerable amount of valuable data, but also the need for further validation. PMID- 24817642 TI - Mobile phone radiation alters proliferation of hepatocarcinoma cells. AB - This study investigated the effects of intermittent exposure (15 min on, 15 min off for 1, 2, 3, or 4 h, at a specific absorption rate of 2 W/kg) to enhanced data rates for global system for mobile communication evolution-modulated radiofrequency radiation (RFR) at 900- and 1,800-MHz frequencies on the viability of the Hepatocarcinoma cells (Hep G2). Hep G2 cell proliferation was measured by a colorimetric assay based on the cleavage of the tetrazolium salt WST-1 by mitochondrial dehydrogenases in viable cells. Cell injury was evaluated by analyzing the levels of lactate dehydrogenase (LDH) and glucose released from lysed cells into the culture medium. Morphological observation of the nuclei was carried out by 4',6-diamidino-2-phenylindole (DAPI) staining using fluorescence microscopy. In addition, TUNEL assay was performed to confirm apoptotic cell death. It was observed that cell viability, correlated with the LDH and glucose levels, changed according to the frequency and duration of RFR exposure. Four hour exposure produced more pronounced effects than the other exposure durations. 1,800-MHz RFR had a larger impact on cell viability and Hep G2 injury than the RFR at 900 MHz. Morphological observations also supported the biochemical results indicating that most of the cells showed irregular nuclei pattern determined by using the DAPI staining, as well as TUNEL assay which shows DNA damage especially in the cells after 4 h of exposure to 1,800-MHz RFR. Our results indicate that the applications of 900- and 1,800-MHz (2 W/kg) RFR cause to decrease in the proliferation of the Hep G2 cells after 4 h of exposure. Further studies will be conducted on other frequency bands of RFR and longer duration of exposure. PMID- 24817643 TI - A pedigree with pulmonary alveolar microlithiasis: a clinical case report and literature review. AB - Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease characterized by the presence of innumerable calcium phosphate microliths in the alveoli. Clinical-radiological dissociation is an important hallmark of this disease. Most PAM patients are asymptomatic and pulmonary tissue changes are discovered incidentally. PAM is pathologically attributable to the formation and aggregation of calcium phosphate microliths in the alveoli after mutations in the SLC34A2 gene (the type IIb sodium-phosphate cotransporter gene) coding NaPi-IIb. In the clinical work, we discovered an inbred pedigree with PAM, which include four PAM siblings. We performed a sequence analysis of the SLC34A2 gene in all members of this PAM pedigree and found that a homozygous mutation c.575C > A (p.T192 K) in exon 6 was involved. To the best of our knowledge, this study was the first to discover nucleotide mutations in exon 6 in Asians. PMID- 24817644 TI - Three-dimensional inversion recovery manganese-enhanced MRI of mouse brain using super-resolution reconstruction to visualize nuclei involved in higher brain function. AB - The visualization of activity in mouse brain using inversion recovery spin echo (IR-SE) manganese-enhanced MRI (MEMRI) provides unique contrast, but suffers from poor resolution in the slice-encoding direction. Super-resolution reconstruction (SRR) is a resolution-enhancing post-processing technique in which multiple low resolution slice stacks are combined into a single volume of high isotropic resolution using computational methods. In this study, we investigated, first, whether SRR can improve the three-dimensional resolution of IR-SE MEMRI in the slice selection direction, whilst maintaining or improving the contrast-to-noise ratio of the two-dimensional slice stacks. Second, the contrast-to-noise ratio of SRR IR-SE MEMRI was compared with a conventional three-dimensional gradient echo (GE) acquisition. Quantitative experiments were performed on a phantom containing compartments of various manganese concentrations. The results showed that, with comparable scan times, the signal-to-noise ratio of three-dimensional GE acquisition is higher than that of SRR IR-SE MEMRI. However, the contrast-to noise ratio between different compartments can be superior with SRR IR-SE MEMRI, depending on the chosen inversion time. In vivo experiments were performed in mice receiving manganese using an implanted osmotic pump. The results showed that SRR works well as a resolution-enhancing technique in IR-SE MEMRI experiments. In addition, the SRR image also shows a number of brain structures that are more clearly discernible from the surrounding tissues than in three-dimensional GE acquisition, including a number of nuclei with specific higher brain functions, such as memory, stress, anxiety and reward behavior. PMID- 24817645 TI - Chiral squaramide-catalyzed asymmetric synthesis of pyranones and pyranonaphthoquinones via cascade reactions of 1,3-dicarbonyls with Morita-Baylis Hillman acetates of nitroalkenes. AB - Cascade reactions of 1,3-dicarbonyls with Morita-Baylis-Hillman acetates of nitroalkenes using a quinine derived chiral squaramide organocatalyst led to the formation of pyranones and pyranonaphthoquinones in good to excellent yields and high diastereo- and enantioselectivities. Representative examples of the reaction scale-up with a much lower catalyst loading without an appreciable loss of selectivities and synthetic transformations of the products are also reported here. The compounds described herein for the first time were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, since the structures are related to bioactive alpha-lapachones. PMID- 24817646 TI - Effect of walnut oil on hyperglycemia-induced oxidative stress and pro inflammatory cytokines production. AB - PURPOSE: In this study, we focused on the effect of hyperglycemia on the generation of reactive oxygen species and on the release of pro-inflammatory cytokines in the human monocytic cell line (U937). We also monitored potential anti-inflammatory effects of walnut oil as well as its protective effect against oxidative damage to biopolymers (DNA and proteins). METHODS: We cultured U937 cells under normoglycemic or hyperglycemic conditions for 72 h, in the absence or presence of walnut oil. We detected cell proliferation by the MTT test. To determine the antioxidant status of cells, we used the trolox equivalent antioxidant capacity method. We determined the activity of superoxide dismutase (SOD) spectrophotometrically, the oxidative damage to DNA by an enzyme-modified comet assay, and the oxidative damage to proteins by the marker-protein carbonyls and the levels of pro-inflammatory cytokines by the ELISA method. RESULTS: Hyperglycemia reduced the antioxidant capacity of cells, induced oxidative damage to DNA, and increased the release of pro-inflammatory cytokines. It had no effect on cell proliferation, SOD activity, nor oxidative damage to proteins. Walnut oil significantly increased the antioxidant capacity of cells as well as SOD activity on the second and third day of incubation, but had no effect on cell proliferation and showed no protective effect against oxidative damage to DNA and proteins. The walnut oil showed both anti-inflammatory and pro-inflammatory properties depending on its concentration and time of its incubation with the monocytic cell line. CONCLUSION: Our in vitro results indicate that walnut oil can diminish oxidative stress with its antioxidant properties. However, we could not confirm its protective effect against oxidative damage to DNA and proteins. PMID- 24817647 TI - Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. AB - PURPOSE: This study evaluated the preclinical pharmacokinetics (PK) and disposition of fruquintinib (HMPL-013), a small molecule vascular endothelial growth factor receptors inhibitor. METHODS: In vitro and in vivo PK/ADME assays were conducted. Allometry and PK modeling/simulation were conducted to predict human PK parameters and the time course profiles. RESULTS: HMPL-013 has high permeability without efflux. It shows moderate oral bioavailability of 42-53 % and Tmax < 4 h in mouse, rat, dog and monkey, with exposure-dose linearity proved in rats and dogs. No significant food effect is on dog PK. HMPL-013 has moderately high tissue distribution. It majorly distributes in gastrointestinal tract, liver, kidney, adrenal and adipose. The plasma protein binding fraction is 88-95 % in mouse, rat, dog and human, invariable up to 10 uM. The in vivo clearance of HMPL-013 is low, consistent with the in vitro scaling. Three major oxidative metabolites were identified in liver microsomes of mouse, rat, dog, monkey and human. Dog is mostly similar to human regarding in vitro metabolism. Demethylation, hydroxylation and sequential glucuronidation are the major in vivo metabolic reactions. Direct urinary and biliary excretion of HMPL-013 is negligible. Metabolizing to M1 (demethylation), sequentially glucuronidating, followed by biliary excretion, and to a less extent, by urinary excretion, are important elimination pathways for HMPL-013 in rats. HMPL-013 has low risk of drug-drug interaction. It is predicted to have favorable human PK properties and low efficacious dose. CONCLUSION: HMPL-013 demonstrates good preclinical PK and enables successful human PK and dose projection. It is valuable for further clinical development. PMID- 24817648 TI - Non-standard intracranial connections and alternative pathways between dural venous sinuses and cerebral veins in the rat. AB - The aim of this study was to describe the uncommon intracranial venous connections and vein structures that may play a role in the redirection of cerebral blood drainage. The study was carried out on 35 adult Wistar rats. Corrosion casts were prepared from the cerebral venous system and Spofacryl(r) was used as a casting medium. The highest prevalence of non-standard connections and variations was noted in the region of sinus petrosus dorsalis (SPD) (31.2 %) and v. cerebri magna (VCM) (28.5 %). SPD established a non-standard anastomosis with sinus petrosus ventralis in 8.6 % of cases, with sinus interperiopticus in 2.8 % of cases, with sinus sigmoideus in 5.7 % of cases and with confluens sinuum (CS) in 2.8 % of cases, where higher prevalence was observed on the left side of the brain. In 11.4 % of cases VCM formed a secondary connection between CS and sinus rectus leading to the formation of the loop. In a similar manner, VCM entered the sinus transversus in 8.6 % of cases, while in 5.7 % of cases VCM merged with SPD and formed an unusual connection among dorsal and ventral systems of sinuses. Several sinuses were observed as inconsistent, including sinus occipitalis (14.3 %), sinus intercavernosus rostralis (22.8 %) and sinus interbasilaris (14.3 %). The hypoplastic posterior and anterior anastomotic vein did not reach one another in 20 % of observed cases. Anatomical information concerning different drainage pathways are important in preoperative planning and can provide necessary understanding in experimental studies, including cerebral vein occlusion, venous infarction, or experimentally induced cerebral venous obstruction. PMID- 24817649 TI - Metabolism of Nomega -methylserotonin, a serotonergic constituent of black cohosh (Cimicifuga racemosa, L. (Nutt.)), by human liver microsomes. AB - The roots/rhizomes of black cohosh (Cimicifuga racemosa L. (Nutt.) (syn. Actaea racemosa L.) are a popular dietary supplements among women for management of menopausal symptoms. Although not estrogenic, Nomega -methylserotonin has been identified in black cohosh as a potent agonist of serotonin 5-HT1A and 5-HT7 receptors. In the present study, in vitro metabolism of Nomega -methylserotonin was investigated to gain insights into aspects of the bioavailability of this compound. The major metabolic pathway was determined to be conversion into 5 hydroxyindole acetaldehyde catalyzed by the monoamine oxidase A (MAO-A). 5 Hydroxyindole acetaldehyde could be further oxidized to form 5-hydroxyindole acetic acid by the action of microsomal aldehyde dehydrogenase or reduced to 5 hydroxy tryptophol by the action of aldehyde reductase. The cytochrome P450 enzymes had only a minor role in the metabolism of Nomega -methylserotonin and then only when MAO-A was inhibited. In many aspects, the metabolism of Nomega methylserotonin was similar to the metabolism of serotonin, suggesting that this compound is unlikely to elicit CNS effects due to rapid metabolism by the widely distributed MAO-A. PMID- 24817650 TI - Solutions to shortage of liver grafts for transplantation. PMID- 24817651 TI - Donor age as a risk factor in donation after circulatory death liver transplantation in a controlled withdrawal protocol programme (Br J Surg 2014; 101: 784-792). PMID- 24817652 TI - Failure to rescue as a source of variation in hospital mortality after hepatic surgery (Br J Surg 2014; 101: 836-846). PMID- 24817653 TI - Performance of prognostic scores in predicting long-term outcome following resection of colorectal liver metastases. AB - BACKGROUND: Ten-year survival appears to define cure following resection of colorectal liver metastases (CRLMs). Various scores exist to predict outcome at 5 years. This study applied several scores to a patient cohort with 10 years of actual follow-up to assess their performance beyond 5 years. METHODS: The study included consecutive patients who underwent liver resection at a single institution between 1992 and 2001. The ability of eight prognostic scoring systems to predict disease-free (DFS) and disease-specific (DSS) survival was analysed using the C-statistic. RESULTS: Among 286 patients, the 1-, 3-, 5- and 10-year actual DSS rates were 86.6, 58.3, 39.5 and 24.5 per cent respectively. Seventy patients underwent 105 further resections for recurrent disease, of which 84.8 per cent were within 5 years of follow-up. Analysis of C-statistics showed only one score--the Rees postoperative index--to be a significant predictor of DFS and DSS at all time points. The remaining scores performed less well, and regularly showed no significant improvement in predictive accuracy over what would be expected by chance alone. No score yielded a C-statistic in excess of 0.8 at any time point. CONCLUSION: Although available risk scores can predict DFS and DSS, none does so with sufficient discriminatory accuracy to identify all episodes of recurrent disease. A non-negligible proportion of patients develop recurrent disease beyond 5 years of follow-up and so surveillance beyond this point may be advantageous. PMID- 24817655 TI - Authors' reply: Systematic review and meta-analysis of predictors of post thyroidectomy hypocalcaemia (Br J Surg 2014; 101: 307-320). PMID- 24817656 TI - Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia (Br J Surg 2014; 101: 307-320). PMID- 24817654 TI - Multicentre propensity score-matched analysis of conventional versus extended abdominoperineal excision for low rectal cancer. AB - BACKGROUND: Abdominal perineal excision (APE) was originally described with levator ani removal for rectal cancer. An even wider, more aggressive extralevator resection for APE has been proposed. Although some surgeons are performing a very wide 'extralevator APE (ELAPE)', there are few data to recommend it routinely. This multicentre study aimed to compare outcomes of APE and ELAPE. METHODS: A multicentre propensity case-matched analysis comparing two surgical approaches (APE and ELAPE) was performed. All patients who underwent abdominoperineal resection of a rectal tumour were considered for the analysis. Tumour height was defined by magnetic resonance imaging measurement and patients with stage II-III tumours had neoadjuvant radiochemotherapy. Involvement of the circumferential resection margin (CRM) and intraoperative tumour perforation were the main outcome measures. A logistic regression model was used to study the relationship between the surgical approaches and outcomes. RESULTS: From January 2008 to March 2013 a total of 1909 consecutive patients underwent APE or ELAPE, of whom 914 matched patients (457 in each group) formed the cohort for analysis. Intraoperative tumour perforation occurred in 7.9 and 7.7 per cent of patients during APE and ELAPE respectively (P = 0.902), and there was CRM involvement in 13.1 and 13.6 per cent (P = 0.846). There were no differences between APE and ELAPE in terms of postoperative complication rates (52.3 versus 48.1 per cent; P = 0.209), need for reoperation (7.7 versus 7.0 per cent; P = 0.703), perineal wound problems (26.0 versus 21.9 per cent; P = 0.141), mortality rate (2.0 versus 2.0 per cent; P = 1.000) and local recurrence rate at 2 years (2.7 versus 5.6 per cent; P = 0.664). CONCLUSION: ELAPE does not improve rates of CRM involvement, intraoperative tumour perforation, local recurrence or mortality. PMID- 24817659 TI - IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria. AB - The recent recognition of receptor-mediated ATP signalling as a pathway of epithelial pro-inflammatory cytokine release challenges the ubiquitous role of the TLR4 pathway during urinary tract infection. The aim of this study was to compare cellular responses of renal epithelial cells infected with uropathogenic Escherichia coli (UPEC) strain IA2 to stimulation with ATP-gamma-S. A498 cells were infected or stimulated in the presence or absence of apyrase, that degrades extracellular ATP, or after siRNA-mediated knockdown of ATP-responding P2Y2 receptors. Cellular IL-8 release and global gene expression were analysed. Both IA2 and A498 cells per se released ATP, which increased during infection. IA2 and ATP-gamma-S caused a ~5-fold increase in cellular release of IL-8 and stimulations performed in the presence of apyrase or after siRNA knockdown of P2Y2 receptors resulted in attenuation of IA2-mediated IL-8 release. Microarray results show that both IA2 and ATP-gamma-S induced marked changes in gene expression of renal cells. Thirty-six genes were in common between both stimuli, and many of these are key genes belonging to classical response pathways of bacterial infection. Functional analysis shows that 88 biological function annotated cellular pathways were identical between IA2 and ATP-gamma-S stimuli. Results show that UPEC-induced release of IL-8 is dependent on P2Y2 signalling and that cellular responses elicited by UPEC and ATP-gamma-S have many identical features. This indicates that renal epithelial responses elicited by bacteria could be mediated by bacteria- or host-derived ATP, thus defining a key role of ATP during infection. PMID- 24817660 TI - Silica nanoparticles as tracers of the gelation dynamics of a natural biopolymer physical gel. AB - The gelation of methylcellulose in water has been studied by X-ray photon correlation spectroscopy, electrophoresis and rheological measurements by looking into the dynamics of silica nanoparticles as tracers in the polymer matrix. The temperature and scattering vector dependence of the structural relaxation time is investigated at the nanometric length scale during the formation of the strong gel state. We find a stress-dominated dynamics on approaching the gel state, characterized by a hyper-diffusive motion of the silica particles. These results support the idea of a unifying scenario for the dynamics of complex out of equilibrium soft materials. PMID- 24817661 TI - Determination of urinary lithogenic parameters in murine models orthologous to autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease caused by mutations in PKD1 or PKD2 genes, is associated with a high prevalence of nephrolithiasis. The underlying mechanisms may encompass structural abnormalities resulting from cyst growth, urinary metabolic abnormalities or both. An increased frequency of hypocitraturia has been described in ADPKD even in the absence of nephrolithiasis, suggesting that metabolic alterations may be associated with ADPKD per se. We aimed to investigate whether non-cystic Pkd1-haploinsufficient (Pkd1(+/-)) and/or nestin-Cre Pkd1-targeted cystic (Pkd1(cond/cond):Nestin(cre)) mouse models develop urinary metabolic abnormalities potentially related to nephrolithiasis in ADPKD. 24-h urine samples were collected during three non consecutive days from 10-12 and 18-20 week-old animals. At 10-12 weeks of age, urinary oxalate, calcium, magnesium, citrate and uric acid did not differ between test and their respective control groups. At 18-20 weeks, Pkd1(+/-) showed slightly but significantly higher urinary uric acid vs. controls while cystic animals did not. The absence of hypocitraturia, hyperoxaluria and hyperuricosuria in the cystic model at both ages and the finding of hyperuricosuria in the 18-20 week-old animals suggest that anatomic cystic distortions per se do not generate the metabolic disturbances described in human ADPKD-related nephrolithiasis, while Pkd1 haploinsufficiency may contribute to this phenotype in this animal model. PMID- 24817662 TI - Photochemistry of supramolecular systems and nanostructured assemblies. In memory of Professor Nick Turro (1938-2012). PMID- 24817664 TI - Prediction on miscibility of silicone and gasoline components by Monte Carlo simulation. AB - The miscibility behavior between silicone materials and mixed gasoline components was explored via Monte Carlo simulation. The variation of energy of mixing and Gibbs energy of mixing between silicone and gasoline components shifted with temperature was calculated. The findings indicated that the miscibility of gasoline components was exceptional in silicone 2 and the selectivity of thiophene was superior to that of other silicones, which resulted from the ester groups and methyl side chains. The density of methyl side chains in silicone 2 was significantly higher than other silicones; therefore, it could explain the lower energy of mixing and higher selectivity concerning silicone 2 and thiophene. The energy of mixing between silicone 2 and gasoline components declined with the increasing temperature (300-500 K). Nevertheless, the more increased the temperature, the more decreased the selectivity of thiophene. At 350 K, it was essential for us to research the miscibility between silicone 2 and gasoline components further. The value of Gibbs energy of mixing for silicone 2 was considerably smaller than that of the hydrocarbons at 350 K. It could be demonstrated that the miscibility between silicone 2 and thiophene was better than that of hydrocarbons. Accordingly, we should attach importance to silicone 2 in the gasoline desulfurization process. PMID- 24817665 TI - Conformational behaviors of trans-2,3- and trans-2,5-dihalo-1,4-diselenanes. A complete basis set, hybrid-density functional theory study and natural bond orbital interpretations. AB - Complete basis set CBS-4, hybrid-density functional theory (hybrid-DFT: B3LYP/6 311+G**) based methods and natural bond orbital (NBO) interpretations have been used to examine the contributions of the hyperconjugative, electrostatic, and steric effects on the conformational behaviors of trans-2,3-dihalo-1,4-diselenane [halo = F (1), Cl (2), Br (3)] and trans-2,5-dihalo-1,4-diselenane [halo = F (4), Cl (5), Br (6)]. Both levels of theory showed that the axial conformation stability, compared to its corresponding equatorial conformation, decreases from compounds 1 -> 3 and 4 -> 6. Based on the results obtained from the NBO analysis, there are significant anomeric effects for compounds 1-6. The anomeric effect associated with the electron delocalization is in favor of the axial conformation and increases from compounds 1 -> 3 and 4 -> 6. On the other hand, dipole moment differences between the axial and equatorial conformations [Delta(MU(eq)-MU(ax)] decrease from compounds 1 -> 3. Although Delta(MU(eq)-MU(ax)) parameter decreases from compound 1 to compound 3, the dipole moment values of the axial conformations are smaller than those of their corresponding equatorial conformations. Therefore, the anomeric effect associated with the electron delocalizations (for halogen-C-Se segments) and the electrostatic model associated with the dipole-dipole interactions fail to account for the increase of the equatorial conformations stability on going from compound 1 to compound 3. Since there is no dipole moment for the axial and equatorial conformations of compounds 4-6, consequently, the conformational preferences in compounds 1-6 is in general dictated by the steric hindrance factor associated with the 1,3-syn axial repulsions. Importantly, the CBS-4 results show that the entropy difference (?S) between the equatorial axial conformations increases from compounds 1 -> 3 and 4 -> 6. This fact can be explained by the anomeric effect associated with the electron delocalization which affects the C2-Se bond orders and increase the rigidity of the corresponding rings. The Gibbs free energy difference values between the axial and equatorial conformations (i.e. DeltaG(ax-ax) and DeltaG(eq eq)) of compounds 1 and 4, 2 and 5 and also 3 and 6 have been calculated. The correlations between the anomeric effect, electrostatic model, DeltaG(eq-ax), DeltaG(ax-ax), DeltaG(eq-eq), bond orders, dipole-dipole interactions, structural parameters and conformational behaviors of compounds 1-6 have been investigated. PMID- 24817666 TI - Probing the geometries, relative stabilities, and electronic properties of neutral and anionic Ag(n)S(m) (n + m <= 7) clusters. AB - The geometry structures, relative stabilities, and electronic properties of neutral and anionic Ag(n)S(m) (n + m <= 7) clusters have been investigated systematically by means of density function theory (DFT). The results of geometry optimization show that the most stable configurations of binary Ag(n)S(m)0/- clusters have an early appearance of 3D structure at n = 3, m = 1, differing from those of pure silver and sulfur clusters. Moreover, the ground-state structures prefer low spin multiplicity (singlet or doublet) except for S2, Ag2S3, Ag2S4, Ag4S3, and Ag2S5. The calculated electron detachment energies (both vertical and adiabatic) are in good agreement with experimental data. This further lends considerable credence for the lowest-energy structures and the chosen computational method. By calculating the binding energies, fragmentation energies, second-order difference of energies and HOMO-LUMO energy gaps of neutral and anionic Ag n S m clusters, the relative stability and electronic property as a function of cluster size are discussed in detail. Further, in order to understand the nature of the bond in doped clusters and pure clusters, we have performed the contour maps of their HOMOs and analyzed their composition. PMID- 24817667 TI - Self-assembly of five 8-hydroxyquinolinate-based complexes: tunable core, supramolecular structure, and photoluminescence properties. AB - Five new Zn(II) complexes, namely [Zn(3)(L)(6)] (1), [Zn(2)(Cl)(2)(L)(2) (py)(2)] (2), [Zn(2)(Br)(2) (L)(2)(py)(2)] (3), [Zn(L)(2)(py)] (4), and [Zn(2)(OAc)(2)(L)(2)(py)(2)] (5), were prepared by the solvothermal reaction of ZnX(2) (X(-) =Cl(-), Br(-), F(-), and OAc(-)) salts with a 8-hydroxyquinolinate ligand (HL) that contained a trifluorophenyl group. All of the complexes were characterized by elemental analysis, IR spectroscopy, and powder and single crystal X-ray crystallography. The building blocks exhibited unprecedented structural diversification and their self-assembly afforded one mononuclear, three binuclear, and one trinuclear Zn(II) structures in response to different anions and solvent systems. Complexes 1-5 featured four types of supramolecular network controlled by non-covalent interactions, such as pi???pi-stacking, C H???pi, hydrogen-bonding, and halogen-related interactions. Investigation of their photoluminescence properties exhibited disparate emission wavelengths, lifetimes, and quantum yields in the solid state. PMID- 24817668 TI - Skeletal muscle depletion is an independent prognostic factor for hepatocellular carcinoma. AB - BACKGROUND: Skeletal muscle depletion or sarcopenia has been identified as a poor prognostic factor for various diseases. The aim of this study is to determine whether muscle depletion is a prognostic factor for hepatocellular carcinoma (HCC). METHODS: We evaluated 217 consecutive patients with primary HCC. The skeletal muscle cross-sectional area was measured by computed tomography at the third lumbar vertebra (L3), from which the total body fat-free mass (FFM) and L3 skeletal muscle index (L3 SMI) were obtained. The factors contributing to overall survival (OS) were analyzed by univariate and multivariate Cox proportional hazards model. RESULTS: In univariate analysis, FFM (P = 0.0422), Child-Pugh classification (P = 0.0058), serum albumin level (P < 0.0001), serum AFP level (P < 0.0001), serum proteins induced by vitamin K absence or antagonist-II level (P < 0.0001), cancer stage (P < 0.0001), and curability of the initial treatment (P < 0.0001) were significantly associated with the prognosis of HCC. Multivariate analysis indicated that FFM (P = 0.0499), albumin level (P = 0.0398), and curability of the initial treatment (P = 0.0008) were independent prognostic factors. Sarcopenia was defined as an L3 SMI value of <=29.0 cm(2)/m(2) for women and <=36.0 cm(2)/m(2) for men, and 24 patients (11.1%) have sarcopenia. Sarcopenic patients showed a significantly lower OS than those without sarcopenia (P = 0.0043). Sarcopenic patients who were overweight (BMI >22) died earlier (P = 0.0129). CONCLUSIONS: Skeletal muscle depletion is an independent prognostic factor. Intervention to prevent muscle wasting might be an effective strategy for improving the outcome of HCC. PMID- 24817669 TI - Psychological, demographic, illness and treatment risk factors for emotional distress amongst paediatric oncology patients prior to reaching 5-year survivorship status. AB - OBJECTIVES: Studies assessing emotional distress severity of paediatric oncology patients prior to reaching 5-year survivorship status have produced inconsistent findings. This cross-sectional multi-centre study aimed to determine psychological, demographic, illness and treatment risk factors for emotional distress in this population. METHODS: Paediatric oncology patients (n = 74), aged 12-18 years, completed the Paediatric Index of Emotional Distress, Self Description Questionnaire and Paediatric Quality of Life Inventory. Seventy-two parents provided background information regarding demographics, diagnoses and treatment protocols in addition to appropriate proxy ratings. RESULTS: Hierarchical multiple regression analyses demonstrated that demographic, illness and treatment factors explained little variance in emotional distress. Global self-concept, global-generic and cancer-specific health-related quality of life (HRQOL) were significant predictors. Provisional multiple regression analyses indicated that pain/hurt, illness-related worries, communication difficulties and negative self-views in relation to math abilities, parent relations and opposite sex peer relations were risk factors for emotional distress in this sample. Paired-sample t-tests and Pearson's moment-correlation coefficients showed patient and parent reports of patients' self-concepts and HRQOL were highly consistent. CONCLUSIONS: This study empirically identified modifiable psychological risk factors for emotional distress prior to 5-year survivorship status and provided guidance for future interventions. Furthermore, findings suggest that parent reports can provide reliable estimates of patients' self concepts and HRQOL. Generalizability of the findings was enhanced by the diversity of the sample studied, in terms of diagnosis and treatment exposure, and the multi-centre recruitment strategy employed. Nevertheless, the findings should be corroborated by larger, longitudinal studies. PMID- 24817670 TI - Response to "De novo mutation of the TGFB3 latency-associated peptide domain in a patient with overgrowth and Loeys-Dietz syndrome features". PMID- 24817671 TI - (Non-)Arguments in Long-Distance Extractions. AB - Previous research has shown that in fully grammatical sentences, response time increases and acceptability decreases when the filler in a long-distance extraction is incompatible with the matrix verb. This effect could potentially be due to a difference between argument and adjunct extraction. In this paper we investigate the effect of long extraction of arguments and adjuncts where incompatibility is kept constant. Based on the results from two offline surveys and an online experiment, we argue that the argument/adjunct asymmetry in terms of acceptability is due to differences in processing difficulty, but that both types of extraction involve the same intermediate attachment sites in the online processing. PMID- 24817672 TI - The synthetic NCAM mimetic peptide FGL mobilizes neural stem cells in vitro and in vivo. AB - The neural cell adhesion molecule (NCAM) plays a role in neurite outgrowth, synaptogenesis, and neuronal differentiation. The NCAM mimetic peptide FG Loop (FGL) promotes neuronal survival in vitro and enhances spatial learning and memory in rats. We here investigated the effects of FGL on neural stem cells (NSC) in vitro and in vivo. In vitro, cell proliferation of primary NSC was assessed after exposure to various concentrations of NCAM or FGL. The differentiation potential of NCAM- or FGL-treated cells was assessed immunocytochemically. To investigate its influence on endogenous NSC in vivo, FGL was injected subcutaneously into adult rats. The effects on NSC mobilization were studied both via non-invasive positron emission tomography (PET) imaging using the tracer [(18)F]-fluoro-L-thymidine ([(18)F]FLT), as well as with immunohistochemistry. Only FGL significantly enhanced NSC proliferation in vitro, with a maximal effect at 10 MUg/ml. During differentiation, NCAM promoted neurogenesis, while FGL induced an oligodendroglial phenotype; astrocytic differentiation was neither affected by NCAM or FGL. Those differential effects of NCAM and FGL on differentiation were mediated through different receptors. After FGL-injection in vivo, proliferative activity of NSC in the subventricular zone (SVZ) was increased (compared to placebo-treated animals). Moreover, non invasive imaging of cell proliferation using [(18)F]FLT-PET supported an FGL induced mobilization of NSC from both the SVZ and the hippocampus. We conclude that FGL robustly induces NSC mobilization in vitro and in vivo, and supports oligodendroglial differentiation. This capacity renders FGL a promising agent to facilitate remyelinization, which may eventually make FGL a drug candidate for demyelinating neurological disorders. PMID- 24817673 TI - Quantification of homoegonol in rat plasma using liquid chromatography-tandem mass spectrometry and its pharmacokinetics application. AB - Homoegonol is a biologically active neolignan isolated from Styrax species with cytotoxic, antimicrobial, anti-inflammatory and anti-asthma activities. For the quantification of homoegonol in rat plasma, a selective and sensitive liquid chromatography-tandem mass spectrometric method was developed and validated for the first time using protein precipitation with methanol as a sample clean-up procedure. The analytes were separated in an Atlantis dC18 column using a gradient elution of methanol and 0.1% formic acid, and mass-to-charge ratios were determined in selective reaction monitoring mode using tandem mass spectrometry with m/z 343.12 > 296.97 for homoegonol and m/z 517.30 > 282.90 for udenafil (internal standard). The standard curve was linear over the concentration ranges of 1 - 500 ng/mL using a 30 MUL rat plasma sample. The coefficient of variation and relative error for intra- and inter-assay at four quality control levels were 3.9-10.0 and -3.3-2.7%, respectively. The overall recovery of homoegonol from rat plasma using protein precipitation was 99.7 +/- 7.7%. The pharmacokinetics parameters of homoegonol were dose-independent after both intravenous (1, 2.5 and 5 mg/kg doses) and oral (5, 10 and 20 mg/kg doses) administration in male Sprague Dawley rats. PMID- 24817675 TI - 'Exercise snacks' before meals: a novel strategy to improve glycaemic control in individuals with insulin resistance. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate whether small doses of intense exercise before each main meal ('exercise snacks') would result in better blood glucose control than a single bout of prolonged, continuous, moderate intensity exercise in individuals with insulin resistance. METHODS: Nine individuals completed three exercise interventions in randomised order. Measures were recorded across 3 days with exercise performed on the middle day, as either: (1) traditional continuous exercise (CONT), comprising 30 min moderate-intensity (60% of maximal heart rate [HRmax]) incline walking before dinner; (2) exercise snacking (ES), consisting of 6 * 1 min intense (90% HRmax) incline walking intervals 30 min before each meal; or (3) composite exercise snacking (CES), encompassing 6 * 1 min intervals alternating between walking and resistance-based exercise, 30 min before meals. Meal timing and composition were controlled within participants for exercise interventions. RESULTS: ES attenuated mean 3 h postprandial glucose concentration following breakfast (by 1.4 +/- 1.5 mmol/l, p = 0.02) but not lunch (0.4 +/- 1.0 mmol/l, p = 0.22), and was more effective than CONT following dinner (0.7 +/- 1.5 mmol/l below CONT; p = 0.04). ES also reduced 24 h mean glucose concentration by 0.7 +/- 0.6 mmol/l (p = 0.01) and this reduction persisted for the subsequent 24 h (lower by 0.6 +/- 0.4 mmol/l vs CONT, relative to their baselines; p = 0.01). CES was just as effective as ES (p > 0.05 for all glycaemic variables) at improving glycaemic control. CONCLUSIONS/INTERPRETATION: Dosing exercise as brief, intense 'exercise snacks' before main meals is a time-efficient and effective approach to improve glycaemic control in individuals with insulin resistance. PMID- 24817676 TI - Wall shear stress calculations based on 3D cine phase contrast MRI and computational fluid dynamics: a comparison study in healthy carotid arteries. AB - Wall shear stress (WSS) is involved in many pathophysiological processes related to cardiovascular diseases, and knowledge of WSS may provide vital information on disease progression. WSS is generally quantified with computational fluid dynamics (CFD), but can also be calculated using phase contrast MRI (PC-MRI) measurements. In this study, our objectives were to calculate WSS on the entire luminal surface of human carotid arteries using PC-MRI velocities (WSSMRI ) and to compare it with WSS based on CFD (WSSCFD ). Six healthy volunteers were scanned with a 3 T MRI scanner. WSSCFD was calculated using a generalized flow waveform with a mean flow equal to the mean measured flow. WSSMRI was calculated by estimating the velocity gradient along the inward normal of each mesh node on the luminal surface. Furthermore, WSS was calculated for a down-sampled CFD velocity field mimicking the MRI resolution (WSSCFDlowres ). To ensure minimum temporal variation, WSS was analyzed only at diastole. The patterns of WSSCFD and WSSMRI were compared by quantifying the overlap between low, medium and high WSS tertiles. Finally, WSS directions were compared by calculating the angles between the WSSCFD and WSSMRI vectors. WSSMRI magnitude was found to be lower than WSSCFD (0.62 +/- 0.18 Pa versus 0.88 +/- 0.30 Pa, p < 0.01) but closer to WSSCFDlowres (0.56 +/- 0.18 Pa, p < 0.01). WSSMRI patterns matched well with those of WSSCFD. The overlap area was 68.7 +/- 4.4% in low and 69.0 +/- 8.9% in high WSS tertiles. The angles between WSSMRI and WSSCFD vectors were small in the high WSS tertiles (20.3 +/- 8.2 degrees ), but larger in the low WSS tertiles (65.6 +/- 17.4 degrees ). In conclusion, although WSSMRI magnitude was lower than WSSCFD , the spatial WSS patterns at diastole, which are more relevant to the vascular biology, were similar. PC-MRI-based WSS has potential to be used in the clinic to indicate regions of low and high WSS and the direction of WSS, especially in regions of high WSS. PMID- 24817677 TI - Seromucinous hamartoma in the nasal cavity medial to the middle turbinate: report of 2 cases and review of the literature. AB - BACKGROUND: Seromucinous hamartoma, a type of epithelial hamartoma, is a rare benign glandular proliferation of the sinonasal tract and nasopharynx. Herein, we present 2 rare cases of seromucinous hamartoma arising in the nasal cavity medial to the middle turbinate. METHODS AND RESULTS: This is a case report of 2 patients diagnosed with seromucinous hamartoma of the nasal cavity and a review of the literature. CONCLUSION: Seromucinous hamartoma of the nasal cavity is an exceedingly rare diagnosis but should be included in the differential diagnosis of a posterior nasal tumor. Most cases arise from the posterior nasal cavity medial to the middle turbinate rather than lateral to the middle turbinate. PMID- 24817678 TI - Strengthen the collaboration between the River Basin Management Organization of China and International Environmental Specimen Bank Group. AB - Several types of emerging organic contaminants were investigated in many recent researches, such as persistent toxic substance (PTS), persistent organic pollutants (POPs), endocrine disrupters (EDs), and volatile organic compounds (VOCs). But the Chinese country standard detection methods of emerging organic pollutants were not developed with the dramatic increasing of the organic substances production. Hence, it is necessary to obtain the latest informations about the long-term storage of representative environmental specimens, which could provide scientific basis for environmental management and environmental decision-making of the water resources protection and management organization. As the significant water resource conservation organization, the Water Environment Monitoring Center of Yangtze River Basin is experienced in water environmental monitoring and records many useful water resources and environment informations. It is also our responsibility to monitor all the pollutants in water environment of the Yangtze River valley, especially the emerging organic contaminants. Meanwhile, the International Environmental Specimen Bank (IESB) accumulates lots environmental organic pollution specimens and plays a significant role in environmental monitoring. Thus, the collaboration between the two parties will be greatly helpful for each further researches and monitoring work of organic contaminants in Yangtze River Basin. PMID- 24817674 TI - Tobacco use and cessation for cancer survivors: an overview for clinicians. AB - Approximately 30% of all cancer deaths in the United States are caused by tobacco use and smoking. Cancers of eighteen sites have been causally linked to smoking, the most common of which are the lung, head and neck, bladder, and esophagus. While quit rates and quit attempt rates are relatively high shortly after a cancer diagnosis, the recidivism rates are also high. Therefore, screening, treating, and preventing relapse to tobacco use is imperative among patients with and survivors of cancer. To date, research has consistently shown that a combination of pharmacologic and behavioral interventions is needed to achieve the highest smoking cessation rates, with a recent emphasis on individualized treatment as a most promising approach. Challenges in health care systems, including the lack of appropriate resources and provider training, have slowed the progress in addition to important clinical considerations relevant to the treatment of tobacco dependence (eg, a high degree of comorbidity with psychiatric disorders and other substance use disorders). However, continued tobacco use has been shown to limit the effectiveness of major cancer treatments and to increase the risk of complications and of developing secondary cancers. The authors recommend that oncology providers screen all patients for tobacco use and refer users to specialized treatment when available. Alternatively, oncology clinicians can provide basic advice on tobacco use cessation and pharmacotherapy and/or referral to outside resources (eg, quitlines). Herein, the authors summarize the current knowledge on tobacco use and its treatment, with a focus on the related available evidence for patients with and survivors of cancer. PMID- 24817679 TI - Health risk assessment of odors emitted from urban wastewater pump stations in Tianjin, China. AB - In order to evaluate the potential adverse health effects of odor emissions from wastewater pump stations (WWPSs) to human, a health risk assessment was performed to study the odors emitted from an urban WWPS in a residential area, Tianjin (in North China). First, 15 types of volatile organic compounds in the WWPS were collected and analyzed using gas chromatography-mass spectrometry. Next, Monte Carlo probabilistic modeling was applied to evaluate the potential health effects of four odors (chlorobenzene, dichloromethane, hydrogen sulfide, and carbon disulfide), which had higher concentrations. The results revealed that the 95th percentile of the total non-carcinogenic risk was approximately 1.73, which poses a threat to human health. In addition, hydrogen sulfide had the highest non carcinogenic risk value of the four; the hazard quotient of hydrogen sulfide was estimated to be 1.60 at the 95th percentile, higher than the upper confidence limit (1.0). The 95th percentile of the carcinogenic risk was approximately 5.47E 08, much lower than the maximum acceptable level (1.0E-06). Finally, the influence of the input variables on the output was evaluated using sensitivity analysis, and contaminant concentration, reference concentration, and inhalation unit risk were the most influential variables. PMID- 24817680 TI - Slow adaptation of ventricular repolarization as a cause of arrhythmia? AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Studying Cardiovascular and Respiratory Systems". BACKGROUND: Adaptation of the QT interval to changes in heart rate reflects on the body-surface electrocardiogram the adaptation of action potential duration (APD) at the cellular level. The initial fast phase of APD adaptation has been shown to modulate the arrhythmia substrate. Whether the slow phase is potentially proarrhythmic remains unclear. OBJECTIVES: To analyze in-vivo human data and use computer simulations to examine effects of the slow APD adaptation phase on dispersion of repolarization and reentry in the human ventricle. METHODS: Electrograms were acquired from 10 left and 10 right ventricle (LV/RV) endocardial sites in 15 patients with normal ventricles during RV pacing. Activation-recovery intervals, as a surrogate for APD, were measured during a sustained increase in heart rate. Observed dynamics were studied using computer simulations of human tissue electrophysiology. RESULTS: Spatial heterogeneity of rate adaptation was observed in all patients. Inhomogeneity in slow APD adaptation time constants (Deltatau(s)) was greater in LV than RV (Deltatau(s)(LV) = 31.8 +/- 13.2, Deltatau(s)(RV) = 19.0 +/- 12.8 s , P< 0.01). Simulations showed that altering local slow time constants of adaptation was sufficient to convert partial wavefront block to block with successful reentry. CONCLUSIONS: Using electrophysiological data acquired in-vivo in human and computer simulations, we identify heterogeneity in the slow phase of APD adaptation as an important component of arrhythmogenesis. PMID- 24817681 TI - Transvenous hepatic biopsy in stable Fontan patients undergoing cardiac catheterization. AB - Liver pathology complicates Fontan palliation. Previous reports established that both hepatic sinusoidal and portal fibrosis occur in patients after Fontan procedures. Past studies predominantly included symptomatic patient cohorts. Thus, the authors of this study aimed to characterize hepatic pathology via transvenous hepatic biopsies in 21 asymptomatic patients at the time of elective cardiac catheterization. Seven of these patients (33 %) were accompanied by an interventional procedure. Hepatic biopsies showed evidence of either sinusoidal or portal fibrosis or both in all but one patient. The findings showed a statistically significant (p = 0.005) moderately strong positive correlation between fibrosis scores and time since Fontan surgery. Additionally, no significant correlation was found between fibrosis scores and inferior vena cava pressure, pulmonary vascular resistance, platelet counts, or serum laboratory testing of hepatic function. PMID- 24817682 TI - Phosphoramidates as novel activity-based probes for serine proteases. AB - Activity-based probes (ABPs) are small molecules that exclusively form covalent bonds with catalytically active enzymes. In the last decade, they have especially been used in functional proteomics studies of proteases. Here, we present phosphoramidate peptides as a novel type of ABP for serine proteases. These molecules can be made in a straightforward manner by standard Fmoc-based solid phase peptide synthesis, allowing rapid diversification. The resulting ABPs covalently bind different serine proteases, depending on the amino acid recognition element adjacent to the reactive group. A reporter tag enables downstream gel-based analysis or LC-MS/MS-mediated identification of the targeted proteases. Overall, we believe that these readily accessible probes will provide new avenues for the functional study of serine proteases in complex proteomes. PMID- 24817683 TI - Dual association modes of the 2,5,8-tris(pentafluorophenyl)phenalenyl radical. AB - The 2,5,8-tris(pentafluorophenyl)phenalenyl radical was obtained by a straightforward synthesis in 11 steps from 2,7-dibromonaphthalene. This radical crystallized as a sigma dimer from a solution in MeCN and as a pi-stack from a melted liquid. The pi stack was not confined to dimerization, but extended into a uniform 1D stack with an interplanar distance of 3.503 A. This unique duality in association mode arose from the thermodynamic stability of the phenalenyl moiety. PMID- 24817684 TI - Discharges of aortic and carotid sinus baroreceptors during spontaneous motor activity and pharmacologically evoked pressor interventions. AB - Our laboratory has demonstrated that the cardiomotor component of aortic baroreflex is temporarily inhibited at the onset of spontaneous motor activity in decerebrate cats, without altering carotid sinus baroreflex. A reason for this dissociation may be attributed to a difference in the responses between aortic nerve activity (AoNA) and carotid sinus nerve activity (CsNA) during spontaneous motor activity. The stimulus-response curves of AoNA and CsNA against mean arterial blood pressure (MAP) were compared between the pressor interventions evoked by spontaneous motor activity and by intravenous administration of phenylephrine or norepinephrine, in which the responses in heart rate (HR) were opposite (i.e., tachycardia vs. baroreflex bradycardia), despite the identical increase in MAP of 34-40 mmHg. In parallel to the pressor response, mean AoNA and CsNA increased similarly by 78-81 and by 88 % of the baseline control, respectively, irrespective of whether the pressor response was evoked by spontaneous motor activity or by a pharmacological intervention. The slope of the stimulus-response curve of the mean AoNA became greater (P < 0.05) during spontaneous motor activity as compared to the pharmacological intervention. On the other hand, the stimulus-response curve of the mean CsNA and its slope were equal (P > 0.05) between the two pressor interventions. Furthermore, the slopes of the stimulus-response curves of both diastolic AoNA and CsNA (defined as the minimal value within a beat) exhibited a greater increase during spontaneous motor activity. All differences in the slopes of the stimulus-response curves were abolished by restraining HR at the intrinsic cardiac frequency. In conclusion, mean mass activities of both aortic and carotid sinus baroreceptors are able to encode the beat-by-beat changes in MAP not only at rest but also during spontaneous motor activity and spontaneous motor activity-related reduction of aortic baroreceptor activity is denied accordingly. PMID- 24817685 TI - Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling. AB - AIMS: We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post myocardial infarction model. METHODS AND RESULTS: We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca(2+)-induced permeability transition and cytochrome c release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load. CONCLUSIONS: Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients. PMID- 24817686 TI - Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria. AB - AIMS: Small-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a functional role in human atria. METHODS AND RESULTS: Quantitative real-time PCR analyses showed higher transcript levels of SK2 and SK3 than that of the SK1 subtype in human atrial tissue. SK2 and SK3 were reduced in chronic atrial fibrillation (AF) compared with sinus rhythm (SR) patients. Immunohistochemistry using confocal microscopy revealed widespread expression of SK2 in atrial myocytes. Two SK channel inhibitors (NS8593 and ICAGEN) were tested in heterologous expression systems revealing ICAGEN as being highly selective for SK channels, while NS8593 showed less selectivity for these channels. In isolated atrial myocytes from SR patients, both inhibitors decreased inwardly rectifying K(+) currents by ~15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue. CONCLUSIONS: SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy. PMID- 24817687 TI - Genetic association of the tachykinin receptor 1 TACR1 gene in bipolar disorder, attention deficit hyperactivity disorder, and the alcohol dependence syndrome. AB - Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (TACR1) are nominally associated with bipolar affective disorder (BPAD) in a genome-wide association study and in several case-control samples of BPAD, alcohol dependence syndrome (ADS) and attention-deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 * 10(-3)), ADS (P = 2.0 * 10(-3)) and BPALC (P = 6.0 * 10(-4)) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1-susceptibility haplotypes identified 19 SNPs in the promoter region, 5' UTR, exons, intron/exon junctions and 3' UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10 fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders. PMID- 24817690 TI - Apathy in Parkinson's disease is associated with nucleus accumbens atrophy: a magnetic resonance imaging shape analysis. AB - Apathy is characterized by lack of interest, loss of initiative, and flattening of affect. It is a frequent, very disabling nonmotor complication of Parkinson's disease (PD). The condition may notably occur when dopaminergic medications are tapered after the initiation of subthalamic stimulation and thus can be referred to as "dopaminergic apathy." Even in the absence of tapering, some patients may develop a form of apathy as PD progresses. This form is often related to cognitive decline and does not respond to dopaminergic medications (dopa resistant apathy). We aimed at determining whether dopa-resistant apathy in PD is related to striatofrontal morphological changes. We compared the shape of the striatum (using spherical harmonic parameterization and sampling in a three dimensional point distribution model [SPHARM-PDM]), cortical thickness, and fractional anisotropy (using tract-based spatial statistics) in 10 consecutive patients with dopamine-refractory apathy, 10 matched nonapathetic PD patients and 10 healthy controls. Apathy in PD was associated with atrophy of the left nucleus accumbens. The SPHARM-PDM analysis highlighted (1) a positive correlation between the severity of apathy and atrophy of the left nucleus accumbens, (2) greater atrophy of the dorsolateral head of the left caudate in apathetic patients than in nonapathetic patients, and (3) greater atrophy in the bilateral nucleus accumbens in apathetic patients than in controls. There were no significant intergroup differences in cortical thickness or fractional anisotropy. Dopa resistant apathy in PD was associated with atrophy of the left nucleus accumbens and the dorsolateral head of the left caudate. PMID- 24817689 TI - MicroRNA expression signatures and their correlation with clinicopathological features in glioblastoma multiforme. AB - The increasing interest in identifying molecular biomarkers to determine patient prognosis in glioblastoma multiforme (GBM) has resulted in several microRNA (miRNA)-based signatures able to predict progression-free and overall survival. However, the coherency between these signatures is small, and correlations to clinicopathological features other than survival are seldom seen. The aim of this study was to identify any significant relationship between miRNA signatures and clinicopathological data by combining pathological features with miRNA and mRNA analysis in fourteen GBM patients. In total, 161 miRNAs were shown to cluster the GBM tumor samples into long- and short-term-surviving patients. Many of these miRNAs were associated with differential expression in GBM, including a number of miRNAs shown to confer risk or protection with respect to clinical outcome and to modulate the mesenchymal mode of migration and invasion. An inverse relationship between miR-125b and nestin expression was identified and correlated with overall survival in GBM patients, eloquently illustrating how clinicopathological findings and molecular profiling may be a relevant combination to predict patient outcome. The intriguing finding that many of the differentially expressed miRNAs contained exosome-packaging motifs in their mature sequences suggests that we must expand our view to encompass the complex intercellular communication in order to identify molecular prognostic biomarkers and to increase our knowledge in the field of GBM pathogenesis. PMID- 24817691 TI - Identification of human papillomavirus status specific biomarker in head and neck cancer. AB - BACKGROUND: In an attempt to improve the prognosis of patients with head and neck cancer, it could be necessary to identify biomarkers in homogeneous subgroups of patients with head and neck cancer. METHODS: We explored the necessity of human papillomavirus (HPV) status-specific biomarkers in patients with head and neck cancer and identified an HPV status-specific gene set. The identified gene set was validated with the external microarray datasets. For this purpose, we used 4 microarray datasets obtained from a public database. One dataset was used for identifying the HPV status specific gene set, and the other datasets were used for validation. RESULTS: The identified gene set for distinguishing head and neck cancer from head and neck normal, did not accurately discriminate the HPV specific patients with head and neck cancer from the head and neck normal group. Also, it was demonstrated that some HPV-positive (HPV+) head and neck cancer specific genes may not be significant in HPV-negative (HPV-) head and neck cancer patients. The identified HPV specific gene sets showed good performance in validation datasets. The HPV+ head and neck cancer-specific gene set included various metabolism-related pathways, and the HPV- head and neck cancer-specific gene set included several pathways; fibroblast, collagen degradation, actin binding, and actin cytoskeleton. CONCLUSION: The identification of HPV status specific significant gene set was necessary. It is expected that HPV status specific biomarkers can be helpful in deciding therapeutic methods for patients with head and neck cancer, after biological validation and large prospective trials. PMID- 24817692 TI - DNMT3a epigenetic program regulates the HIF-2alpha oxygen-sensing pathway and the cellular response to hypoxia. AB - Epigenetic regulation of gene expression by DNA methylation plays a central role in the maintenance of cellular homeostasis. Here we present evidence implicating the DNA methylation program in the regulation of hypoxia-inducible factor (HIF) oxygen-sensing machinery and hypoxic cell metabolism. We show that DNA methyltransferase 3a (DNMT3a) methylates and silences the HIF-2alpha gene (EPAS1) in differentiated cells. Epigenetic silencing of EPAS1 prevents activation of the HIF-2alpha gene program associated with hypoxic cell growth, thereby limiting the proliferative capacity of adult cells under low oxygen tension. Naturally occurring defects in DNMT3a, observed in primary tumors and malignant cells, cause the unscheduled activation of EPAS1 in early dysplastic foci. This enables incipient cancer cells to exploit the HIF-2alpha pathway in the hypoxic tumor microenvironment necessary for the formation of cellular masses larger than the oxygen diffusion limit. Reintroduction of DNMT3a in DNMT3a-defective cells restores EPAS1 epigenetic silencing, prevents hypoxic cell growth, and suppresses tumorigenesis. These data support a tumor-suppressive role for DNMT3a as an epigenetic regulator of the HIF-2alpha oxygen-sensing pathway and the cellular response to hypoxia. PMID- 24817693 TI - Solution conditions determine the relative importance of nucleation and growth processes in alpha-synuclein aggregation. AB - The formation of amyloid fibrils by the intrinsically disordered protein alpha synuclein is a hallmark of Parkinson disease. To characterize the microscopic steps in the mechanism of aggregation of this protein we have used in vitro aggregation assays in the presence of preformed seed fibrils to determine the molecular rate constant of fibril elongation under a range of different conditions. We show that alpha-synuclein amyloid fibrils grow by monomer and not oligomer addition and are subject to higher-order assembly processes that decrease their capacity to grow. We also find that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total number of aggregates, are undetectable. At pH values below 6, however, the rate of secondary nucleation increases dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, for example, that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates is much faster than at normal physiological pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of alpha-synuclein aggregation and aggregate spreading in the context of Parkinson disease. PMID- 24817694 TI - A mobile phone intervention increases physical activity in people with cardiovascular disease: Results from the HEART randomized controlled trial. AB - AIM: To determine the effectiveness and cost-effectiveness of a mobile phone intervention to improve exercise capacity and physical activity behaviour in people with ischaemic heart disease (IHD). METHODS AND RESULTS: In this single blind, parallel, two-arm, randomized controlled trial adults (n = 171) with IHD were randomized to receive a mobile phone delivered intervention (HEART; n = 85) plus usual care, or usual care alone (n = 86). Adult participants aged 18 years or more, with a diagnosis of IHD, were clinically stable as outpatients, able to perform exercise, able to understand and write English, and had access to the Internet. The HEART (Heart Exercise And Remote Technologies) intervention involved a personalized, automated package of text messages and a secure website with video messages aimed at increasing exercise behaviour, delivered over 24 weeks. All participants were able to access usual community-based cardiac rehabilitation, which involves encouragement of physical activity and an offer to join a local cardiac support club. All outcomes were assessed at baseline and 24 weeks and included peak oxygen uptake (PVO2; primary outcome), self-reported physical activity, health-related quality of life, self-efficacy and motivation (secondary outcomes). Results showed no differences in PVO2 between the two groups (difference -0.21 ml kg(-1)min(-1), 95% CI: -1.1, 0.7; p = 0.65) at 24 weeks. However significant treatment effects were observed for selected secondary outcomes, including leisure time physical activity (difference 110.2 min/week, 95% CI: -0.8, 221.3; p = 0.05) and walking (difference 151.4 min/week, 95% CI: 27.6, 275.2; p = 0.02). There were also significant improvements in self-efficacy to be active (difference 6.2%, 95% CI: 0.2, 12.2; p = 0.04) and the general health domain of the SF36 (difference 2.1, 95% CI: 0.1, 4.1; p = 0.03) at 24 weeks. The HEART programme was considered likely to be cost-effective for leisure time activity and walking. CONCLUSIONS: A mobile phone intervention was not effective at increasing exercise capacity over and above usual care. The intervention was effective and probably cost-effective for increasing physical activity and may have the potential to augment existing cardiac rehabilitation services. PMID- 24817695 TI - Antioxidants improve vascular function in children conceived by assisted reproductive technologies: A randomized double-blind placebo-controlled trial. AB - AIMS: Children conceived by assisted reproductive technology (ART) display vascular dysfunction. Its underlying mechanism, potential reversibility and long term consequences for cardiovascular risk are unknown. In mice, ART induces arterial hypertension and shortens the life span. These problems are related to decreased vascular endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) synthesis. The aim of this study was to determine whether ART-induced vascular dysfunction in humans is related to a similar mechanism and potentially reversible. To this end we tested whether antioxidants improve endothelial function by scavenging free radicals and increasing NO bioavailability. METHODS AND RESULTS: In this prospective double-blind placebo controlled study in 21 ART and 21 control children we assessed the effects of a four-week oral supplementation with antioxidant vitamins C (1 g) and E (400 IU) or placebo (allocation ratio 2:1) on flow-mediated vasodilation (FMD) of the brachial artery and pulmonary artery pressure (echocardiography) during high-altitude exposure (3454 m), a manoeuver known to facilitate the detection of pulmonary vascular dysfunction and to decrease NO bioavailability by stimulating oxidative stress. Antioxidant supplementation significantly increased plasma NO measured by ozone based chemiluminescence (from 21.7 +/- 7.9 to 26.9 +/- 7.6 uM, p = 0.04) and FMD (from 7.0 +/- 2.1 to 8.7 +/- 2.0%, p = 0.004) and attenuated altitude-induced pulmonary hypertension (from 33 +/- 8 to 28 +/- 6 mm Hg, p = 0.028) in ART children, whereas it had no detectable effect in control children. CONCLUSIONS: Antioxidant administration to ART children improved NO bioavailability and vascular responsiveness in the systemic and pulmonary circulation. Collectively, these findings indicate that in young individuals ART-induced vascular dysfunction is subject to redox regulation and reversible. PMID- 24817696 TI - Non-fasting triglycerides predict incident acute myocardial infarction among those with favourable HDL-cholesterol: Cohort Norway. AB - AIMS: to prospectively evaluate the risk of acute myocardial infarction (AMI) associated with non-fasting triglyceride levels. METHODS: a health survey of 140,790 Norwegians free of known coronary heart disease at baseline (1994-2003) were followed through December 2009 via record linkages to the Cause of Death Registry and hospital discharge diagnoses in the CVDNOR project, and evaluated in Cox proportional hazards analyses. RESULTS: a total of 3219 (4.8%) men and 1434 (1.9%) women developed an AMI. Women had a steeper gradient risk with increasing triglyceride decile than men, where the highest (>=2.88 mmol/l) compared to the lowest decile (<0.7 mmol/l) was associated with an age-adjusted 4.7-fold excess risk in women in contrast to a 2.8-fold excess risk in men (interaction term, p < 0.001). A significant at-risk HDL-C (<1.0 mmol/l for men and <1.3 mmol/l for women) by triglyceride interaction term was observed. HRs increased with increasing triglyceride quartile in participants with a favourable HDL-C after multivariable adjustment (p for trend <0.001), but triglycerides did not significantly predict AMI among those with low HDL-C. For those with favourable HDL-C, net reclassification index identified a 10% and 14% improvement in classification for men and women, respectively. CONCLUSION: non-fasting triglyceride levels among individuals with favourable HDL-C may help identify a subset of individuals at risk for CHD. Further research is warranted in evaluating non-fasting triglycerides in CHD prediction. PMID- 24817697 TI - Time-dependent relation between smoking cessation and improved exercise tolerance in apparently healthy middle-age men and women. AB - BACKGROUND: Smoking is an independent cardiovascular risk factor and correlates with reduced exercise tolerance. However, data on the time dependent effect of smoking cessation on exercise tolerance are limited. DESIGN AND METHODS: We investigated 17,115 men and women who were annually screened at the Institute for Medical Screening of the Chaim Sheba Medical Centre. All subjects had their smoking status documented and performed an exercise stress testing (EST) according to Bruce protocol at each visit. Subjects were divided at baseline into four groups: active smokers (N = 2858), recent quitters (smoking cessation <=2 years before baseline EST; N = 861), remote quitters (smoking cessation >2 years before the baseline EST; N = 3856) and never smokers (N = 9810). Baseline and follow up EST duration were compared among the four groups. RESULTS: Recent quitters demonstrated a 2.4-fold improvement in their EST duration compared with active smokers (improvement of 24 +/- 157 vs. 10 +/- 157 s, respectively, p = 0.02). Multivariate logistic regression showed that recent quitters were 26% more likely to improve their exercise tolerance compared with active smokers (95% confidence interval (CI) 1.08-1.47, p = 0.003). Assessing smoking status as a time-dependent covariate during four consecutive visits demonstrated that recent quitters were 17% more likely to improve their exercise tolerance compared with active smokers (95% CI 1.02-1.34, p = 0.02), with a less pronounced benefit among remote quitters (hazard ratio = 1.11, 95% CI 1.02-1.21; p = 0.01). CONCLUSIONS: Smoking cessation is independently associated with improved exercise tolerance. The benefits of smoking cessation are evident within the first two years of abstinence. PMID- 24817698 TI - Structure-based approach to the prediction of disulfide bonds in proteins. AB - Protein engineering remains an area of growing importance in pharmaceutical and biotechnology research. Stabilization of a folded protein conformation is a frequent goal in projects that deal with affinity optimization, enzyme design, protein construct design, and reducing the size of functional proteins. Indeed, it can be desirable to assess and improve protein stability in order to avoid liabilities such as aggregation, degradation, and immunogenic response that may arise during development. One way to stabilize a protein is through the introduction of disulfide bonds. Here, we describe a method to predict pairs of protein residues that can be mutated to form a disulfide bond. We combine a physics-based approach that incorporates implicit solvent molecular mechanics with a knowledge-based approach. We first assign relative weights to the terms that comprise our scoring function using a genetic algorithm applied to a set of 75 wild-type structures that each contains a disulfide bond. The method is then tested on a separate set of 13 engineered proteins comprising 15 artificial stabilizing disulfides introduced via site-directed mutagenesis. We find that the native disulfide in the wild-type proteins is scored well, on average (within the top 6% of the reasonable pairs of residues that could form a disulfide bond) while 6 out of the 15 artificial stabilizing disulfides scored within the top 13% of ranked predictions. Overall, this suggests that the physics-based approach presented here can be useful for triaging possible pairs of mutations for disulfide bond formation to improve protein stability. PMID- 24817699 TI - CD70-expressing CD4 T cells produce IFN-gamma and IL-17 in rheumatoid arthritis. AB - OBJECTIVE: CD70-expressing CD4 T cells are enriched in RA and promote autoimmunity via co-stimulatory CD70-CD27 interaction. This study aimed to explore the phenotype and cytokine production of CD70(+) CD4 T cells in RA. METHODS: Peripheral blood mononuclear cells from 32 RA patients were isolated and frequencies of CD70(+) cells within different CD4 T subsets were analysed using flow cytometry. IFN-gamma and IL-17 production were compared between the CD70(+) and CD70(-) cells. Expression of master transcription factors T-bet, GATA3 and retinoic acid-related orphan receptor gamma t (RORgammat) were examined by real time PCR. Results are presented as mean (s.e.m.). RESULTS: CD4 T cells of healthy controls rarely expressed CD70 as compared with CD4 T cells of RA patients [mean 0.9% (s.e.m. 0.3%) vs 7.6 (0.6), P < 0.001]. In RA, CD70(+) cells were present within all CD4 T cell subsets, i.e. CD45RA(+)CCR7(+) naive, CD45RA(-)CCR7(+) central memory, CD45RA(-)CCR7(-) effector memory and CD45RA(+)CCR7(-) terminally differentiated effector memory T cells with a mean frequency of 3.9% (s.e.m. 1.1%), 4.0 (0.5), 4.2 (0.7) and 9.4 (4.3), respectively. As compared to CD70(-) CD4 T cells, CD70(+) CD4 T cells produced significantly more IFN-gamma and IL-17 after short activation. CD70(+) CD4 T cells preferentially expressed transcription factor RORgammat. CONCLUSION: CD70(+) CD4 T cells are enriched in RA and may directly contribute to RA pathogenesis by producing IFN-gamma and IL 17. Targeting CD70(+) CD4 T cells might offer new therapeutic opportunities in RA. PMID- 24817700 TI - Serum 25-hydroxyvitamin D and the risk of knee and hip osteoarthritis leading to hospitalization: a cohort study of 5274 Finns. AB - OBJECTIVE: The aim of this study was to investigate whether low levels of serum 25-hydroxyvitamin D [25(OH)D] predicts the development of knee or hip OA. METHODS: The cohort consisted of 5274 participants in a national health examination survey who had no knee or hip OA at baseline. Information about the incidence of OA was drawn from the National Health Care Register. During the follow-up of 10 years (50 134 person-years), 127 subjects developed incident, physician-diagnosed OA in the knee and 45 in the hip joint. The information on covariates, including age, sex, education, BMI, work load, leisure time physical activity, smoking history, knee or hip complaint during the past month and previous injuries, was gathered at baseline. Serum 25(OH)D concentrations were determined from baseline serum samples. RESULTS: After adjustment for age and gender, serum 25(OH)D showed statistically significant associations with known risk factors for OA except injuries. In the fully adjusted model, low serum 25(OH)D concentration did not predict increased incidence of knee and hip OA. CONCLUSION: The results do not support the hypothesis that low levels of serum 25(OH)D contribute to the development of knee or hip OA. PMID- 24817703 TI - The Cys78-Asn88 loop region of the Campylobacter jejuni CstII is essential for alpha2,3-sialyltransferase activity: analysis of the His85 mutants. AB - CstII is a bifunctional sialyltransferase from Campylobacter jejuni that is active as a tetramer. CstIIs from different strains show substantial differences in enzyme activities (mono- versus bi-functional) and kinetic parameters. Crystal structures of CstII show that His85, conserved in CstIIs from different strains is part of an 11-residue loop that abuts the extended acceptor-binding site and is also part of the subunit interface. In this study, the role of His85 in the activity of CstII has been investigated by mutating it to Ala, Phe, Trp or Tyr. His85 is found to be essential for alpha2,3-sialyltransferase activity but not alpha2,8-sialyltransferase activity. Although no gross changes are observed in secondary and tertiary structures, thermal stability is affected by His85 mutation. MD simulations show changes in the flexibility of the loop regions including those in the binding site. PMID- 24817701 TI - Adjustments, extinction, and remains of selenocysteine incorporation machinery in the nematode lineage. AB - Selenocysteine (Sec) is encoded by an UGA codon with the help of a SECIS element present in selenoprotein mRNAs. SECIS-binding protein (SBP2/SCBP-2) mediates Sec insertion, but the roles of its domains and the impact of its deficiency on Sec insertion are not fully understood. We used Caenorhabditis elegans to examine SBP2 function since it possesses a single selenoprotein, thioredoxin reductase-1 (TRXR-1). All SBP2 described so far have an RNA-binding domain (RBD) and a Sec incorporation domain (SID). Surprisingly, C. elegans SBP2 lacks SID and consists only of an RBD. An sbp2 deletion mutant strain ablated Sec incorporation demonstrating SBP2 essentiality for Sec incorporation. Further in silico analyses of nematode genomes revealed conservation of SBP2 lacking SID and maintenance of Sec incorporation linked to TRXR-1. Remarkably, parasitic plant nematodes lost the ability to incorporate Sec, but retained SecP43, a gene associated with Sec incorporation. Interestingly, both selenophosphate synthetase (SPS) genes are absent in plant parasitic nematodes, while only Cys-containing SPS2 is present in Sec-incorporating nematodes. Our results indicate that C. elegans and the nematode lineage provide key insights into Sec incorporation and the evolution of Sec utilization trait, selenoproteomes, selenoproteins, and Sec residues. Finally, our study provides evidence of noncanonical translation initiation in C. elegans, not previously known for this well-established animal model. PMID- 24817704 TI - Rapid identification of bacteria in blood cultures by mass-spectrometric analysis of volatiles. PMID- 24817705 TI - Value of antibodies to free light chains in immunoperoxidase studies of renal biopsies. AB - AIMS: Because immunoglobulin abnormalities may affect the kidney, investigation of renal biopsies requires immunohistological study of light chains. A problem is that most antibodies to light chains react with whole immunoglobulins as well as free light chains, and there are generally many more whole immunoglobulins than free light chains. The usefulness of antibodies that only detected free light chains was investigated. METHODS: Antibodies to free light chains were used in an immunoperoxidase method on paraffin sections of 198 renal biopsies, and compared with conventional antibodies against light chains examined by immunofluorescence on 13 frozen sections and by immunoperoxidase on 46 paraffin sections. RESULTS: Immunofluorescence and immunoperoxidase were concordant on 10 of 13 biopsies. Immunofluorescence detected slight deposition of light chains in three biopsies not shown by immunoperoxidase, of undetermined clinical significance. Using immunoperoxidase, the free light chain antibodies were more sensitive than conventional antibodies, giving much cleaner staining and better detection of deposits in AL amyloid, light chain deposition disease and cryoglobulinaemic glomerulonephritis. The free light chain antibodies showed discordance or ambiguity between immunohistological and clinical findings in seven (4%) of 185 patients with known immunoglobulin status. These included two of 28 cases of AL amyloid that showed no light chain deposition. The method was not designed for detection of light chain restriction in neoplastic plasma or lymphoplasmacytic cells. CONCLUSIONS: Polyclonal antibodies to free light chains are an improvement on conventional antibodies in immunoperoxidase study of paraffin sections of renal biopsies and are useful in everyday practice. PMID- 24817706 TI - Isolated gastric crystal-storing histiocytosis: a rare marker of occult lymphoproliferative disorders. PMID- 24817707 TI - Validation of a population coronary disease predictive system: the CASSANDRA model. PMID- 24817708 TI - Applications of the second virial coefficient: protein crystallization and solubility. AB - This article begins by highlighting some of the ground-based studies emanating from NASA's Microgravity Protein Crystal Growth (PCG) program. This is followed by a more detailed discussion of the history of and the progress made in one of the NASA-funded PCG investigations involving the use of measured second virial coefficients (B values) as a diagnostic indicator of solution conditions conducive to protein crystallization. A second application of measured B values involves the determination of solution conditions that improve or maximize the solubility of aqueous and membrane proteins. These two important applications have led to several technological improvements that simplify the experimental expertise required, enable the measurement of membrane proteins and improve the diagnostic capability and measurement throughput. PMID- 24817709 TI - Structure of the Arabidopsis thaliana TOP2 oligopeptidase. AB - Thimet oligopeptidase (TOP) is a zinc-dependent metallopeptidase. Recent studies suggest that Arabidopsis thaliana TOP1 and TOP2 are targets for salicylic acid (SA) binding and participate in SA-mediated plant innate immunity. The crystal structure of A. thaliana TOP2 has been determined at 3.0 A resolution. Comparisons to the structure of human TOP revealed good overall structural conservation, especially in the active-site region, despite their weak sequence conservation. The protein sample was incubated with the photo-activated SA analog 4-azido-SA and exposed to UV irradiation before crystallization. However, there was no conclusive evidence for the binding of SA based on the X-ray diffraction data. Further studies are needed to elucidate the molecular mechanism of how SA regulates the activity of A. thaliana TOP1 and TOP2. PMID- 24817710 TI - Structure of catabolite activator protein with cobalt(II) and sulfate. AB - The crystal structure of cyclic AMP-catabolite activator protein (CAP) from Escherichia coli containing cobalt(II) chloride and ammonium sulfate is reported at 1.97 A resolution. Each of the two CAP subunits in the asymmetric unit binds one cobalt(II) ion, in each case coordinated by N-terminal domain residues His19, His21 and Glu96 plus an additional acidic residue contributed via a crystal contact. The three identified N-terminal domain cobalt-binding residues are part of a region of CAP that is important for transcription activation at class II CAP dependent promoters. Sulfate anions mediate additional crystal lattice contacts and occupy sites corresponding to DNA backbone phosphate positions in CAP-DNA complex structures. PMID- 24817711 TI - Structure determination of a sugar-binding protein from the phytopathogenic bacterium Xanthomonas citri. AB - The uptake of maltose and related sugars in Gram-negative bacteria is mediated by an ABC transporter encompassing a periplasmic component (the maltose-binding protein or MalE), a pore-forming membrane protein (MalF and MalG) and a membrane associated ATPase (MalK). In the present study, the structure determination of the apo form of the putative maltose/trehalose-binding protein (Xac-MalE) from the citrus pathogen Xanthomonas citri in space group P6522 is described. The crystals contained two protein molecules in the asymmetric unit and diffracted to 2.8 A resolution. Xac-MalE conserves the structural and functional features of sugar-binding proteins and a ligand-binding pocket with similar characteristics to eight different orthologues, including the residues for maltose and trehalose interaction. This is the first structure of a sugar-binding protein from a phytopathogenic bacterium, which is highly conserved in all species from the Xanthomonas genus. PMID- 24817712 TI - A structural characterization of the isoniazid Mycobacterium tuberculosis drug target, Rv2971, in its unliganded form. AB - Aldo-keto reductases (AKR) are a large superfamily of NADPH-dependent oxidoreductases and play a role in detoxification of toxic metabolites. Rv2971, an AKR in Mycobacterium tuberculosis, has recently been identified as a target of isoniazid, a key first-line drug against tuberculosis. Here, the cloning, expression, purification, crystallization and structural characterization of Rv2971 are described. To gain insight into its function, the crystal structure of Rv2971 was successfully determined to 1.60 A resolution in its unliganded form. The structure exhibits a TIM-barrel fold typical of AKRs, revealing structural characteristics essential for function and substrate specificities, allowing a structural comparison between Rv2971 and other mycobacterial AKRs. PMID- 24817713 TI - Crystallization and preliminary crystallographic analysis of human muscle phosphofructokinase, the main regulator of glycolysis. AB - Whereas the three-dimensional structure and the structural basis of the allosteric regulation of prokaryotic 6-phosphofructokinases (Pfks) have been studied in great detail, knowledge of the molecular basis of the allosteric behaviour of the far more complex mammalian Pfks is still very limited. The human muscle isozyme was expressed heterologously in yeast cells and purified using a five-step purification protocol. Protein crystals suitable for diffraction experiments were obtained by the vapour-diffusion method. The crystals belonged to space group P6222 and diffracted to 6.0 A resolution. The 3.2 A resolution structure of rabbit muscle Pfk (rmPfk) was placed into the asymmetric unit and optimized by rigid-body and group B-factor refinement. Interestingly, the tetrameric enzyme dissociated into a dimer, similar to the situation observed in the structure of rmPfk. PMID- 24817714 TI - Structure of tyrosine aminotransferase from Leishmania infantum. AB - The trypanosomatid parasite Leishmania infantum is the causative agent of visceral leishmaniasis (VL), which is usually fatal unless treated. VL has an incidence of 0.5 million cases every year and is an important opportunistic co infection in HIV/AIDS. Tyrosine aminotransferase (TAT) has an important role in the metabolism of trypanosomatids, catalyzing the first step in the degradation pathway of aromatic amino acids, which are ultimately converted into their corresponding L-2-oxoacids. Unlike the enzyme in Trypanosoma cruzi and mammals, L. infantum TAT (LiTAT) is not able to transaminate ketoglutarate. Here, the structure of LiTAT at 2.35 A resolution is reported, and it is confirmed that the presence of two Leishmania-specific residues (Gln55 and Asn58) explains, at least in part, this specific reactivity. The difference in substrate specificity between leishmanial and mammalian TAT and the importance of this enzyme in parasite metabolism suggest that it may be a useful target in the development of new drugs against leishmaniasis. PMID- 24817715 TI - Purification, crystallization and preliminary crystallographic analysis of a ribosome-recycling factor from Thermoanaerobacter tengcongensis (TteRRF). AB - Ribosome-recycling factor (RRF) plays an essential role in the fourth step of protein synthesis in prokaryotes. RRF combined with elongation factor G (EF-G) disassembles the post-termination ribosome complex and recycles the protein synthesis machine for the next round of translation. A reductive-methylation modified RRF from Thermoanaerobacter tengcongensis (TteRRF) has been crystallized using the vapour-diffusion method. The crystal grew in a condition consisting of 0.1 M citric acid pH 3.5, 3.0 M NaCl and 50 mg ml(-1) methylated protein solution at 289 K. A complete data set was collected from a crystal to 2.80 A resolution using synchrotron radiation at 100 K. The crystal belonged to space group P6122/P6522 with unit-cell parameters a = b = 103.26, c = 89.17 A. The asymmetric unit was estimated to contain one molecule of TteRRF. PMID- 24817716 TI - Crystallization and preliminary X-ray analysis of the cardiac transcription factor complex of NKX2.5 and TBX5 with DNA. AB - Heart development depends on timely expression of genes regulated by combinatorial interactions of master cardiac transcription factors. To elucidate the molecular basis of their interactions, a ternary complex of cardiac transcription factors, NKX2.5 and TBX5, and their target DNA was studied using X ray crystallography. Here, the purification, crystallization and preliminary X ray crystallographic analyses of the NKX2.5 homeodomain and TBX5 DNA-binding domain complex with a DNA element from the -252 promoter region of the atrial natriuretic factor are reported. The crystal diffracted to 2.88 A resolution and belonged to space group P21, with unit-cell parameters a = 69.30, b = 77.78, c = 77.60 A, beta = 108.31 degrees . Two sets of ternary complexes are present in an asymmetric unit with a solvent content of 54%. PMID- 24817717 TI - Expression, purification, crystallization and preliminary crystallographic study of the cytoplasmic domain of the mitochondrial dynamics protein MiD51. AB - Mitochondria play central roles in many cellular and physiological processes. They are highly dynamic organelles and continually undergo fusion and fission. Mitochondrial dynamics protein 51 kDa (MiD51), an integral mitochondrial outer membrane protein, recruits dynamin-related protein 1 (Drp1; a mitochondrial fission protein) to mitochondria and facilitates Drp1-directed mitochondrial fission. In this study, the cytoplasmic domain of MiD51 was overexpressed in Escherichia coli, purified and crystallized. An X-ray diffraction data set was collected to a resolution of 3.1 A and the crystal belonged to space group P41212, with unit-cell parameters a = b = 90.1, c = 124.7 A, alpha = beta = gamma = 90 degrees . The asymmetric unit had the highest probability of containing one molecule, with a Matthews coefficient of 3.32 A(3) Da(-1) and a solvent content of 63.0%. PMID- 24817718 TI - Cloning, expression, crystallization and preliminary X-ray diffraction studies of staphylococcal superantigen-like protein 1 (SSL1). AB - Staphylococcus aureus produces a family of exotoxins which are structural homologues of superantigens and thus are called staphylococcal superantigen-like proteins (SSLs). Amongst the 14 SSL genes, ssl1 (SAOUHSC_00383) has been cloned in the pQE30 expression vector, overexpressed in Escherichia coli M15 (pREP4) cells and the protein purified to homogeneity. The protein was crystallized using 6% Tacsimate pH 6.0, 0.1 M MES pH 6.0, 25%(w/v) polyethylene glycol 3350, 100 mM NDSB 256 at 298 K by the sitting-drop vapour-diffusion method. The crystals belonged to space group P21, with unit-cell parameters a = 77.9, b = 70.5, c = 126.5 A, beta = 106.2 degrees . X-ray diffraction data were collected and processed to a maximum resolution of 2.5 A. The crystal contains six molecules in the asymmetric unit. PMID- 24817719 TI - Crystallization and preliminary X-ray crystallographic analysis of the XoGroEL chaperonin from Xanthomonas oryzae pv. oryzae. AB - Along with the co-chaperonin GroES, the chaperonin GroEL plays an essential role in enhancing protein folding or refolding and in protecting proteins against misfolding and aggregation in the cellular environment. The XoGroEL gene (XOO_4288) from Xanthomonas oryzae pv. oryzae was cloned and the protein was expressed, purified and crystallized. The purified XoGroEL protein was crystallized using the hanging-drop vapour-diffusion method and a crystal diffracted to a resolution of 3.4 A. The crystal belonged to the orthorhombic space group P212121 with 14 monomers in the asymmetric unit, with a corresponding VM of 2.7 A(3) Da(-1) and a solvent content of 54.5%. PMID- 24817720 TI - Crystallization and preliminary X-ray characterization of the dephospho-CoA kinase from Legionella pneumophila. AB - Dephospho-CoA kinases (DPCKs) are members of the kinase family that catalyze the final step in CoA biosynthesis. Their function is phosphorylation of the 3 hydroxyl group of the ribose using ATP as a phosphate donor. Structural changes induced by ATP binding play an important role during the DPCK catalytic cycle. In this work, DPCK from Legionella pneumophila was overexpressed in Escherichia coli. The purification, crystallization and preliminary X-ray analysis of crystals of this protein are described. The protein was crystallized in space group P21212, with unit-cell parameters a = 36.29, b = 82.20, c = 81.80 A, using the hanging-drop vapour-diffusion method. Diffraction data were collected at 100 K and the phases were determined using the molecular-replacement method. PMID- 24817721 TI - Purification, crystallization and preliminary X-ray data collection of the N terminal domain of the 26S proteasome regulatory subunit p27 and its complex with the ATPase domain of Rpt5 from Mus musculus. AB - The protein 26S proteasome regulatory subunit p27 is one of the four chaperones that help in the assembly of the 19S regulatory particle (RP) of the 26S proteasome. In the present work, the N-terminus of p27 (residues 1-128) from Mus musculus was cloned, expressed, purified and crystallized alone and in complex with the C-terminal ATPase domain of Rpt5 (residues 173-442). The crystals of p27((1-128)) diffracted to 1.7 A resolution and belonged to space group P212121, with unit-cell parameters a = 26.79, b = 30.39, c = 145.06 A. Resolution dependent Matthews coefficient probability analysis suggested the presence of only one molecule per asymmetric unit, with 40.5% solvent content and a VM value of 2.02 A(3) Da(-1). The crystal of the p27((1-128))-Rpt5((173-442)) complex diffracted to 4 A resolution and belonged to space group P222, with unit-cell parameters a = 75.93, b = 76.08, c = 336.85 A. The presence of four heterodimers in the asymmetric unit with 53.2% solvent content and a VM value of 2.63 A(3) Da( 1) or five heterodimers in the asymmetric unit with 41.5% solvent content and a VM value of 2.10 A(3) Da(-1) is assumed. PMID- 24817722 TI - Crystallization and preliminary X-ray crystallographic analysis of a novel alpha L-arabinofuranosidase (CtGH43) from Clostridium thermocellum ATCC 27405. AB - The truncated carbohydrate-active enzyme belonging to family 43 glycoside hydrolase from Clostridium thermocellum (CtGH43) is an alpha-L arabinofuranosidase that in combination with endoxylanase leads to complete breakdown of L-arabinosyl-substituted xylans. The recombinant enzyme CtGH43 from C. thermocellum was overexpressed in Escherichia coli and purified by immobilized metal-ion affinity chromatography. The recombinant CtGH43 has a molecular mass of 35.86 kDa. Preliminary structural characterization was carried out on CtGH43 crystallized from different conditions, which gave either cube-shaped or brick shaped crystals. These diffracted to a resolution of 1.65 A for the cubic form and 1.1 A for the monoclinic form. Molecular replacement was used to solve the CtGH43 structure. PMID- 24817723 TI - Expression, purification and crystallization of the SKICH domain of human TAX1BP1. AB - TAX1BP1 is a highly conserved, pleiotropic protein that plays many essential functions in human cells, including negative regulation of inflammatory and antimicrobial responses mediated by NF-kappaB and IRF3 signaling, inhibition of apoptosis, transcriptional coactivation and autophagy etc. TAX1BP1 contains a SKICH domain at the N-terminus, three coiled-coil domains in the middle and two ubiquitin-binding zinc-finger motifs at the C-terminus. The SKICH domain and the linker sequence between the SKICH domain and the coiled-coil region mediate interaction with ubiquitin-like proteins of the LC3/GABARAP family, which are autophagosome markers. For structure determination of the SKICH domain of TAX1BP1, a protein construct (amino acids 15-148) corresponding to the SKICH domain plus the linker region was expressed, purified and crystallized. A native diffraction data set has been collected to 1.9 A resolution. A molecular replacement solution has been found by using the structure of the SKICH domain of NDP52, a paralog of TAX1BP1. PMID- 24817724 TI - Expression, crystallization and preliminary crystallographic data analysis of PigI, a putative L-prolyl-AMP ligase from the prodigiosin synthetic pathway in Serratia. AB - Prodigiosin, a member of the prodiginines, is a tripyrrole red pigment synthesized by Serratia and some other microbes. A bifurcated biosynthesis pathway of prodigiosin has been proposed in Serratia in which MBC (4-methoxy-2,2' bipyrrole-5-carbaldehyde) and MAP (2-methyl-3-N-amyl-pyrrole) are synthesized separately and then condensed by PigC to form prodigiosin. The first step for the synthesis of MBC is the activation of L-proline by PigI, but its catalytic mechanism has remained elusive. To elucidate its mechanism, recombinant PigI was purified and crystallized. Crystals obtained by the sitting-drop method belonged to space group P1 and diffracted to 2.0 A resolution, with unit-cell parameters a = 51.2, b = 62.8, c = 91.3 A, alpha = 105.1, beta = 90.1, gamma = 92.2 degrees . Matthews coefficient analysis suggested two molecules in the asymmetric unit, with a VM of 2.6 A(3) Da(-1) and a solvent content of 52.69%. PMID- 24817725 TI - Expression, purification and preliminary crystallographic analysis of the N terminal domain of Trypanosoma brucei BILBO1. AB - Trypanosoma brucei is a unicellular parasite that causes sleeping sickness in sub Saharan Africa. It has a unique flagellar pocket (FP) at the base of the single flagellum. The FP is the sole site for endocytosis and exocytosis activity and plays crucial roles in the defence of the cell against the host immune response. In the neck region of the FP is an electron-dense material termed the flagellar pocket collar (FPC). T. brucei BILBO1 (TbBILBO1) was the first cytoskeletal protein to be characterized in the FPC. This protein is highly conserved among trypanosomatids and is essential for FP biogenesis. Structural information is needed to better understand the molecular mechanism of TbBILBO1 function in the cell. Here, the expression, purification and preliminary crystallographic analysis of the N-terminal domain of TbBILBO1 are reported. The protein was overexpressed in Escherichia coli strain BL21 (DE3), purified by multi-step chromatography and crystallized using the vapour-diffusion method. The crystal diffracted to 1.69 A resolution and belonged to space group P21, with unit-cell parameters a = 29.69, b = 50.80, c = 37.22 A, beta = 94.61 degrees . There was one molecule in the asymmetric unit. PMID- 24817726 TI - Purification, crystallization and preliminary X-ray diffraction analysis of GatD, a glutamine amidotransferase-like protein from Staphylococcus aureus peptidoglycan. AB - Amidation of peptidoglycan is an essential feature in Staphylococcus aureus that is necessary for resistance to beta-lactams and lysozyme. GatD, a 27 kDa type I glutamine amidotransferase-like protein, together with MurT ligase, catalyses the amidation reaction of the glutamic acid residues of the peptidoglycan of S. aureus. The native and the selenomethionine-derivative proteins were crystallized using the sitting-drop vapour-diffusion method with polyethylene glycol, sodium acetate and calcium acetate. The crystals obtained diffracted beyond 1.85 and 2.25 A, respectively, and belonged to space group P212121. X-ray diffraction data sets were collected at Diamond Light Source (on beamlines I02 and I04) and were used to obtain initial phases. PMID- 24817727 TI - Crystallization and preliminary X-ray diffraction analysis of a novel beta-L arabinofuranosidase (HypBA1) from Bifidobacterium longum. AB - The beta-L-arabinofuranosidase (HypBA1) from Bifidobacterium longum JCM 1217 hydrolyzes the beta-1,2-linked arabinofuranose disaccharide to release L arabinoses. HypBA1 was classified into glycoside hydrolase family 127 (GH127) by the CAZy website (http://www.cazy.org/). The enzyme was expressed in Escherichia coli and the purified recombinant protein was crystallized. Crystals belonging to the primitive hexagonal space group P3x21, with unit-cell parameters a = b = 75.9, c = 254.0A, were obtained by the sitting-drop vapour-diffusion method and diffracted to 2.78A resolution. A BLASTP search (http://blast.ncbi.nlm.nih.gov/) of the Protein Data Bank did not reveal any similar crystal structures. Structural determination by using SeMet MAD and MIR methods is in progress. PMID- 24817728 TI - Expression, crystallization and preliminary X-ray crystallographic analysis of DNA-directed RNA polymerase subunit L from Thermococcus onnurineus NA1. AB - RNA polymerase (RNAP) plays a crucial role in gene expression in all organisms. It is a multiprotein complex that produces primary transcript RNA. Generally, the basal transcription apparatus in archaea is simpler than the eukaryotic RNA polymerase II counterpart. To understand the structure and function of archaeal RNAP, the TON-0309 gene encoding DNA-directed RNA polymerase subunit L (ToRNAP_L) from Thermococcus onnurineus NA1 was cloned and the protein was overexpressed in Escherichia coli, purified and crystallized. The purified protein was crystallized using the hanging-drop vapour-diffusion method and the crystal diffracted to 2.10 A resolution. The crystal belonged to the hexagonal space group P6122, with unit-cell parameters a = b = 42.3, c = 211.2 A. One molecule was present in the asymmetric unit, with a corresponding VM of 2.5 A(3) Da(-1) and a solvent content of 50.0%. PMID- 24817729 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of N-acetylmannosamine kinase from methicillin-resistant Staphylococcus aureus. AB - N-Acetylmannosamine kinase (EC 2.7.1.60) is involved in the catabolism of sialic acid for many bacterial pathogens implicated in human disease such as Escherichia coli, Staphylococcus aureus, Vibrio cholerae and V. vulnificus. Interestingly, some human commensals and bacterial pathogens can scavenge sialic acids from their surrounding environment and degrade them as a source of carbon, nitrogen and energy. This process requires a cluster of genes known as the 'Nan-Nag cluster', which have proven to be essential for S. aureus growth on sialic acids, suggesting that the pathway is a viable antimicrobial drug target. The enzyme N acetylmannosamine kinase is involved in the catabolism of sialic acid, transferring a phosphate group from adenosine-5'-triphosphate to the C6 position of N-acetylmannosamine to generate N-acetylmannosamine-6-phosphate. The gene was cloned into an appropriate expression vector; recombinant protein was expressed in E. coli BL21 (DE3) cells and purified via anion-exchange chromatography, hydrophobic interaction chromatography and size-exclusion chromatography. Purified N-acetylmannosamine kinase was screened for crystallization. The best crystal diffracted to a resolution of beyond 2.6 A in space group P2. Understanding the structural nature of this enzyme from methicillin-resistant S. aureus will provide insights necessary for the development of future antimicrobials. PMID- 24817730 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of N-acetylmannosamine-6-phosphate 2-epimerase from methicillin-resistant Staphylococcus aureus. AB - Sialic acids are one of the most important carbohydrate classes in biology. Some bacterial pathogens can scavenge sialic acids from their surrounding environment and degrade them as a source of carbon, nitrogen and energy. This sequestration and subsequent catabolism of sialic acid require a cluster of genes known as the 'Nan-Nag' cluster. The enzymes coded by these genes are important for pathogen colonization and persistence. Importantly, the Nan-Nag genes have proven to be essential for Staphylococcus aureus growth on sialic acids, suggesting that the pathway is a viable antibiotic drug target. The enzyme N-acetylmannosamine-6 phosphate 2-epimerase is involved in the catabolism of sialic acid; specifically, the enzyme converts N-acetylmannosamine-6-phosphate into N-acetylglucosamine-6 phosphate. The gene was cloned into an appropriate expression vector, and recombinant protein was expressed in Escherichia coli BL21 (DE3) cells and purified via a three-step procedure. Purified N-acetylmannosamine-6-phosphate 2 epimerase was screened for crystallization. The best crystal diffracted to a resolution of beyond 1.84 A in space group P21212. Understanding the structural nature of this enzyme from methicillin-resistant S. aureus will provide us with the insights necessary for the development of future antibiotics. PMID- 24817731 TI - Purification, crystallization and preliminary X-ray characterization of the third ScaB cohesin in complex with an ScaA X-dockerin from Acetivibrio cellulolyticus. AB - Interactions between cohesin and dockerin modules are critical for the formation of the cellulosome, which is responsible for the efficient degradation of plant cell-wall carbohydrates by anaerobes. Type I dockerin modules found in modular enzymatic components interact with type I cohesins in primary scaffoldins, enabling the assembly of the multi-enzyme complex. In contrast, type II dockerins located in primary scaffoldins bind to type II cohesins in adaptor scaffoldins or anchoring scaffoldins located at the bacterial envelope, contributing to the cell surface attachment of the entire complex. Acetivibrio cellulolyticus possesses an extremely complex cellulosome arrangement which is organized by a primary enzyme binding scaffoldin (ScaA), two anchoring scaffoldins (ScaC and ScaD) and an unusual adaptor scaffoldin (ScaB). An ScaA X-dockerin mutated to inactivate one of the two putative cohesin-binding interfaces complexed with the third ScaB cohesin from A. cellulolyticus has been purified and crystallized and data were collected to a resolution of 2.41 A. PMID- 24817732 TI - Purification, crystallization and phase determination of the DR1998 haem b catalase from Deinococcus radiodurans. AB - The protective mechanisms of Deinococcus radiodurans against primary reactive oxygen species involve nonenzymatic scavengers and a powerful enzymatic antioxidant system including catalases, peroxidases and superoxide dismutases that prevents oxidative damage. Catalase is an enzyme that is responsible for the conversion of H2O2 to O2 and H2O, protecting the organism from the oxidative effect of H2O2. This study reports the purification and crystallization of the DR1998 catalase from D. radiodurans. The crystals diffracted to 2.6 A resolution and belonged to space group C2221, with unit-cell parameters a = 97.33, b = 311.88, c = 145.63 A, suggesting that they contain four molecules per asymmetric unit. The initial phases were determined by molecular replacement and the obtained solution shows the typical catalase quaternary structure. A preliminary model of the protein structure has been built and refinement is currently in progress. PMID- 24817733 TI - The purification, crystallization and preliminary X-ray diffraction analysis of two isoforms of meso-diaminopimelate decarboxylase from Arabidopsis thaliana. AB - Diaminopimelate decarboxylase catalyses the last step in the diaminopimelate biosynthetic pathway leading to S-lysine: the decarboxylation of meso diaminopimelate to form S-lysine. Lysine biosynthesis occurs only in microorganisms and plants, and lysine is essential for the growth and development of animals. Thus, the diaminopimelate pathway represents an attractive target for antimicrobial and herbicide treatments and has received considerable attention from both a mechanistic and a structural viewpoint. Diaminopimelate decarboxylase has only been characterized in prokaryotic species. This communication describes the first structural studies of two diaminopimelate decarboxylase isoforms from a plant. The Arabidopsis thaliana diaminopimelate decarboxylase cDNAs At3g14390 (encoding DapDc1) and At5g11880 (encoding DapDc2) were cloned from genomic DNA and the recombinant proteins were expressed and purified from Escherichia coli Rosetta (DE3) cells. The crystals of DapDc1 and DapDc2 diffracted to beyond 2.00 and 2.27 A resolution, respectively. Understanding the structural biology of diaminopimelate decarboxylase from a eukaryotic species will provide insights for the development of future herbicide treatments, in particular. PMID- 24817734 TI - Expression, purification and crystallization of MnSOD from Arabidopsis thaliana. AB - Manganese superoxide dismutase (MnSOD) is an essential primary antioxidant enzyme. MnSOD plays an important role in plant tolerance to abiotic stress and is a target candidate for increasing stress tolerance in crop plants. Although the structure and kinetic parameters of MnSODs from several organisms have been determined, this information is still lacking for plant MnSODs. Here, recombinant MnSOD from Arabidopsis thaliana (AtMnSOD) was expressed, purified and crystallized. A nearly complete data set could only be obtained when a total rotation range of 180 degrees was imposed during data collection, despite the seemingly tetragonal metric of the AtMnSOD crystal diffraction. The data set extended to 1.95 A resolution and the crystal belonged to space group P1. Molecular-replacement calculations using an ensemble of homologous SOD structures as a search model gave a unique and unambiguous solution corresponding to eight molecules in the asymmetric unit. Structural and kinetic analysis of AtMnSOD is currently being undertaken. PMID- 24817735 TI - Expression, purification, crystallization and preliminary X-ray diffraction analysis of the C-terminal NHL domain of human TRIM2. AB - The tripartite motif-containing protein 2 (TRIM2) functions as an E3 ubiquitin ligase. Loss of function of TRIM2 has been shown to result in early-onset axonal neuropathy. As a member of the TRIM-NHL family of proteins, TRIM2 has a conserved modular architecture that includes N-terminal RING finger and B-box domains, a middle coiled-coil domain and a C-terminal NHL domain. To characterize the functional role of its NHL domain from the perspective of structural biology, a truncation of human TRIM2 (residues 465-744) was expressed, purified and crystallized. Rod-shaped crystals were obtained that diffracted X-rays to 1.7 A resolution. The crystals belonged to space group P21, with unit-cell parameters a = 43.6, b = 76.4, c = 107.4 A, alpha = 90.0, beta = 94.0, gamma = 90.0 degrees . A Matthews coefficient of 1.97 A(3) Da(-1), corresponding to a solvent content of 37.6%, indicated the presence of three molecules per asymmetric unit, which was further confirmed by the phasing solution from molecular replacement. PMID- 24817736 TI - Crystallization and preliminary X-ray analysis of the ergothioneine-biosynthetic methyltransferase EgtD. AB - Ergothioneine is an amino-acid betaine derivative of histidine that was discovered more than one century ago. Despite significant research pointing to a function in oxidative stress defence, the exact mechanisms of action of ergothioneine remain elusive. Although both humans and bacterial pathogens such as Mycobacterium tuberculosis seem to depend on ergothioneine, humans are devoid of the corresponding biosynthetic enzymes. Therefore, its biosynthesis may emerge as potential drug target in the development of novel therapeutics against tuberculosis. The recent identification of ergothioneine-biosynthetic genes in M. smegmatis enables a more systematic study of its biology. The pathway is initiated by EgtD, a SAM-dependent methyltransferase that catalyzes a trimethylation reaction of histidine to give N(alpha),N(alpha),N(alpha) trimethylhistidine. Here, the recombinant production, purification and crystallization of EgtD are reported. Crystals of native EgtD diffracted to 2.35 A resolution at a synchrotron beamline, whereas crystals of seleno-L-methionine labelled protein diffracted to 1.75 A resolution and produced a significant anomalous signal to 2.77 A resolution at the K edge. All of the crystals belonged to space group P212121, with two EgtD monomers in the asymmetric unit. PMID- 24817737 TI - SPINE-compatible 'carboloops': a new microshaped vitreous carbon sample mount for X-ray and neutron crystallography. AB - A novel vitreous carbon mount for macromolecular crystallography, suitable for neutron and X-ray crystallographic studies, has been developed. The technology described here is compatible both with X-ray and neutron cryo-crystallography. The mounts have low density and low background scattering for both neutrons and X rays. They are prepared by laser cutting, allowing high standards of production quality, the ability to custom-design the mount to specific crystal sizes and large-scale production. PMID- 24817739 TI - A close look at cornea. PMID- 24817740 TI - Short wavelength automated perimetry can detect visual field changes in diabetic patients without retinopathy. AB - PURPOSE: The purpose of the following study is to compare short wave automated perimetry (SWAP) versus standard automated perimetry (SAP) for early detection of diabetic retinopathy (DR). MATERIALS AND METHODS: A total of 40 diabetic patients, divided into group I without DR (20 patients = 40 eyes) and group II with mild non-proliferative DR (20 patients = 40 eyes) were included. They were tested with central 24-2 threshold test with both shortwave and SAP to compare sensitivity values and local visual field indices in both of them. A total of 20 healthy age and gender matched subjects were assessed as a control group. RESULTS: Control group showed no differences between SWAP and SAP regarding mean deviation (MD), corrected pattern standard deviation (CPSD) or short fluctuations (SF). In group I, MD showed significant more deflection in SWAP (-4.44 +/- 2.02 dB) compared to SAP (-0.96 +/- 1.81 dB) (P = 0.000002). However, CPSD and SF were not different between SWAP and SAP. In group II, MD and SF showed significantly different values in SWAP (-5.75 +/- 3.11 dB and 2.0 +/- 0.95) compared to SAP ( 3.91 +/- 2.87 dB and 2.86 +/- 1.23) (P = 0.01 and 0.006 respectively). There are no differences regarding CPSD between SWAP and SAP. The SWAP technique was significantly more sensitive than SAP in patients without retinopathy (p), but no difference exists between the two techniques in patients with non-proliferative DR. CONCLUSION: The SWAP technique has a higher yield and efficacy to pick up abnormal findings in diabetic patients without overt retinopathy rather than patients with clinical retinopathy. PMID- 24817741 TI - Comparison of the antimicrobial effect of heavy silicone oil and conventional silicone oil against endophthalmitis-causing agents. AB - PURPOSE: To conduct an in vitro experimental study comparing the effectiveness of conventional silicone oil and heavy silicone oil against endophthalmitis-causing agents. MATERIALS AND METHODS: The antimicrobial activity of conventional silicone oil (RS OIL 5000) and heavy silicone oil (heavySil 1500) was tested. The antimicrobial effects of both silicone oils were determined by the growing capability of the microorganism. RESULTS: The number of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans decreased to zero levels at the second day of inoculation in heavy silicone oil. In conventional silicone oil, the microorganisms survived longer than in heavy silicone oil. CONCLUSION: Heavy silicone oil seems to be more effective than conventional silicone oil against endophthalmitis-causing agents. PMID- 24817742 TI - Modified deep anterior lamellar keratoplasty for the treatment of advanced keratoconus with steep corneal curvature to help in eliminating the wrinkles in the Descemet's membrane. AB - AIMS: To determine the clinical efficacy of modified deep anterior lamellar keratoplasty (DALK) for the treatment of advanced-stage keratoconus with steep curvature. MATERIALS AND METHODS: In this interventional, non-comparative case series, 30 patients with advanced stages of keratoconus and curvature of more than 60 D underwent a modified DALK procedure. In this technique, after big bubble formation, posterior stromal lamella was cut and removed 5 mm centrally (baring Descemet's membrane completely) with posterior stromal layer remaining peripherally. RESULTS: The study included 30 eyes (30 patients with a mean +/- SD age of 25 +/- 5.4 years). The follow-up examination was performed for all participants up to 12 months after the surgery. The mean uncorrected visual acuity (UCVA) increased from 20/800 before the surgery to a subsequent 3/10 (P = 0.12). Likewise, best spectacle corrected visual acuity (BSCVA) improved, reaching 6/10 postoperatively (former quantity 20/200) (P = 0.18). In addition, mean keratometry and keratometric astigmatism managed to achieve considerable improvement, from 58.8 +/- 5.4 D to 46.5 +/- 2.1 D and 7.8 +/- 2.1 to 4.54 +/- 1.54 D, respectively (P = 0.52). Descemet's membrane wrinkling was not seen in any patient postoperatively. CONCLUSIONS: This technique is effective in restoring acceptable vision and corneal regularity in advanced cases of keratoconus with a curvature more than 60 D who are also at risk of Descemet's membrane wrinkling after DALK. Therefore, this procedure could prevent from Descemet membrane wrinkling in such cases. PMID- 24817743 TI - Use of subjective and objective criteria to categorise visual disability. AB - CONTEXT: Visual disability is categorised using objective criteria. Subjective measures are not considered. AIM: To use subjective criteria along with objective ones to categorise visual disability. SETTINGS AND DESIGN: Ophthalmology out patient department; teaching hospital; observational study. MATERIAL AND METHODS: Consecutive persons aged >25 years, with vision <20/20 (in one or both eyes) due to chronic conditions, like cataract and refractive errors, were categorized into 11 groups of increasing disability; group-zero: normal range of vision, to group X: no perception of light, bilaterally. Snellen's vision; binocular contrast sensitivity (Pelli-Robson chart); automated binocular visual field (Humphrey; Esterman test); and vision-related quality of life (Indian Visual Function Questionnaire-33; IND-VFQ33) were recorded. STATISTICAL ANALYSIS: SPSS version 17; Kruskal-wallis test was used to compare contrast sensitivity and visual fields across groups, and Mann-Whitney U test for pair-wise comparison (Bonferroni adjustment; P < 0.01). One-way ANOVA compared quality of life data across groups; for pairwise significance, Dunnett T3 test was applied. RESULTS: In 226 patients, contrast sensitivity and visual fields were comparable for differing disability grades except when disability was severe (P < 0.001), or moderately severe (P < 0.01). Individual scales of IND-VFQ33 were also mostly comparable; however, global scores showed a distinct pattern, being different for some disability grades but comparable for groups III (78.51 +/- 6.86) and IV (82.64 +/- 5.80), and groups IV and V (77.23 +/- 3.22); these were merged to generate group 345; similarly, global scores were comparable for adjacent groups V and VI (72.53 +/- 6.77), VI and VII (74.46 +/- 4.32), and VII and VIII (69.12 +/- 5.97); these were merged to generate group 5678; thereafter, contrast sensitivity and global and individual IND-VFQ33 scores could differentiate between different grades of disability in the five new groups. CONCLUSIONS: Subjective criteria made it possible to objectively reclassify visual disability. Visual disability grades could be redefined to accommodate all from zero-100%. PMID- 24817744 TI - Retinal nerve fiber layer thickness in normal Indian pediatric population measured with optical coherence tomography. AB - PURPOSE: To measure the peripapillary retinal nerve fiber layer (RNFL) thickness in normal Indian pediatric population. SUBJECTS AND METHODS: 120 normal Indian children ages 5-17 years presenting to the Pediatric Clinic were included in this observational cross-sectional study. RNFL thickness was measured with stratus optical coherence tomography (OCT). Children with strabismus or amblyopia, with neurological, metabolic, vascular, or other disorders and those with abnormal optic discs were excluded. One eye of each subject was randomly selected for statistical analysis. The effect of age, refraction and gender on RNFL thickness was investigated statistically. RESULT: OCT measurements were obtained in 120 of 130 (92.3%) subjects. Mean age was 10.8 +/- 3.24 years (range 5-17). Average RNFL thickness was (+/- SD) 106.11 +/- 9.5 MUm (range 82.26-146.25). The RNFL was thickest inferiorly (134.10 +/- 16.16 MUm) and superiorly (133.44 +/- 15.50 MUm), thinner nasally (84.26 +/- 16.43 MUm), and thinnest temporally (70.72 +/- 14.80 MUm). In univariate regression analysis, age had no statistical significant effect on RNFL thickness (P = 0.7249) and refraction had a significant effect on RNFL thickness (P = 0.0008). CONCLUSION: OCT can be used to measure RNFL thickness in children. Refraction had an effect on RNFL thickness. In normal children, variation in RNFL thickness is large. The normative data provided by this study may assist in identifying changes in RNFL thickness in Indian children. PMID- 24817745 TI - Anatomic study of the lacrimal fossa and lacrimal pathway for bypass surgery with autogenous tissue grafting. AB - PURPOSE: To study the microsurgical anatomy of the lacrimal drainage system and to provide anatomical evidence for transnasal endoscopic lacrimal drainage system bypass surgery by autogenous tissue grafting. MATERIALS AND METHODS: A total of 20 Chinese adult cadaveric heads in 10% formaldehyde, comprising 40 lacrimal ducts were used. The middle third section of the specimens were examined for the following features: the thickness of the lacrimal fossa at the anterior lacrimal crest, vertical middle line, and posterior lacrimal crest; the cross section of the upper opening, middle part, and lower opening of the nasolacrimal canal; the horizontal, 30 degrees oblique, and 45 degrees oblique distances from the lacrimal caruncle to the nasal cavity; the distance from the lacrimal caruncle to the upper opening of the nasolacrimal duct; and the included angle between the lacrimal caruncle-nasolacrimal duct upper opening junction and Aeby's plane. RESULTS: The middle third of the anterior lacrimal crest was significantly thicker than the vertical middle line and the posterior lacrimal crest (P > 0.05). The horizontal distance, 30 degrees oblique distance, and 45 degrees oblique distance from the lacrimal caruncle to the nasal cavity exhibited no significant differences (P > 0.05). The included angle between the lacrimal caruncle and the lateral wall middle point of the superior opening line of the nasolacrimal duct and Aeby's plane was average (49.9 degrees +/- 1.8 degrees ). CONCLUSION: The creation of the bony tunnel should start from the middle or posterior middle part of the lacrimal fossa, extending toward the anterior inferior region with an optimal downward oblique angle of 45 degrees . PMID- 24817746 TI - Effects of triamcinolone acetonide on human trabecular meshwork cells in vitro. AB - AIM: To study the effects of triamcinolone acetonide (TA) on cultured human trabecular meshwork (HTM) cells. MATERIALS AND METHODS: HTM cells were cultured and treated with 125, 250, 500 and 1000 MUg/mL concentration of TA for 24 h. The cells were treated with both crystalline TA (TA-C) (commercial preparation) and solubilized TA (TA-S). Cell viability was measured by a trypan blue dye exclusion test. The activity of caspse-3/7 was measured by a fluorescence caspase kit and DNA laddering was evaluated by electrophoresis on 3% agarose gel. Levels of lactate dehydrogenase (LDH) were assessed with LDH cytotoxicity assay kit-II. RESULTS: Mean cell viabilities of HTM cells after 24 h exposure to TA-C 125, 250, 500, and 1000 MUg/mL were 75.4 +/-2.45% (P < 0.0001), 49.43 +/- 1.85% (P < 0.0001), 17.07 +/- 2.39% (P < 0.0001), and 3.7 +/- 0.9% (P < 0.0001), respectively, compared with the untreated HTM cells 92.49 +/- 1.21%. The mean cell viabilities with 125, 250, 500, and 1000 MUg/mL of TA-S were 94.47 +/- 1.60% (P > 0.05), 90.13 +/- 0.40% (P < 0.01), 85.57 +/- 0.47% (P < 0.001), and 71.67 +/ 3.30% (P < 0.0001), respectively, compared to DMSO-equivalent cultures. Untreated HTM control had a cell viability of 96.57 +/- 1.98%. DMSO-treated controls of 125, 250, 500, and 1000 MUg/mL had a cell viability of 94.73 +/- 0.57%, 96.97 +/- 1.08%, 93.97 +/- 1.85%, and 97.27 +/- 1.15%, respectively. There was no increase of caspase-3/7 activity in cultures treated with either TA-C or TA-S. DNA laddering showed no bands in the TA-C or TA-S treated cultures. There were significantly higher LDH release rates at all concentrations of TA-C compared to TA-S. CONCLUSIONS: Results show that the effect of TA-C and TA-S on HTM cells is due to cell death by necrosis at all concentrations except 125 MUg/mL of TA-S. Elevated levels of LDH confirmed necrotic cell death. Our study also infers the relative safety of TA-S over TA-C. PMID- 24817747 TI - Benign fibrous histiocytoma. AB - Fibrous histiocytomas (FHs) are mesenchymal tumors that may be benign or malignant. Ocular involvement by FHs is infrequent and primarily limited to the orbit. Rarely, FHs can also involve the conjunctiva and perilimbal area. We report the case of a 38-year-old male with lid, conjunctival, and neck FHs. The diagnosis was confirmed by histopathology. PMID- 24817749 TI - Awareness, knowledge, and practice: a survey of glaucoma in north Indian rural residents. AB - BACKGROUND: Studies done on the prevalence of glaucoma have reported a high proportion of undiagnosed patients. Late diagnosis is related to increased risk of glaucoma associated with visual disability. Lack of awareness and non availability of appropriate screening procedures are among the major reasons for non-diagnosis or late diagnosis of glaucoma. The present study has been undertaken to evaluate the level of awareness about glaucoma among the North Indian rural population. MATERIALS AND METHODS: A group-administered, questionnaire-based survey, involving 5000 rural residents (aged 20 and above) was conducted through random sampling. The questionnaire was structured to evaluate the level of awareness and knowledge about glaucoma and the effect of gender, education status, and glaucoma diagnosis was also studied. The source of awareness about glaucoma was also questioned. RESULTS: Of the 5000 individuals enrolled for the survey, responses from 4927 (98.5%; 95% Confidence Interval (CI): 98.2 - 98.9) participants, including 3104 males (63%; 95% CI: 61.7 - 64.3) and 1823 females (37%; 95% CI: 35.7 - 38.3) were evaluated. A total of 409 (~8.3%; 95% CI: 7.6 - 9.14) respondents were aware about glaucoma and only 93 (1.89%; 95% CI: 1.55 - 2.31) were qualified as having knowledge about glaucoma as per the set questionnaire. Education was the only variable significantly correlated (P value < 0.001) with the awareness and knowledge of glaucoma out of the parameters included in this study. Close acquaintance with a glaucoma patient was the most common source of information. CONCLUSIONS: There is a lack of awareness about glaucoma among the rural residents of North India. The study findings stress the need to spread awareness about glaucoma for prevention of glaucoma-related blindness. PMID- 24817750 TI - Anterior chamber fixation of a posterior chamber intraocular lens: a novel technique. AB - We aimed to evaluate the implantation of a posterior chamber intraocular lens (IOL) in the anterior chamber (AC) with the haptics passing through two iridectomies to the posterior chamber. A total of 33 eyes of 33 patients with inadequate posterior capsular support due to either previous aphakia or posterior capsular rupture during cataract extraction were included in the study. A double iridectomy was performed on all patients using a vitrectomy probe on the midperiphery of the iris. IOLs were implanted in the AC, and the haptics were passed through the iridectomies to the posterior chamber. The mean follow-up time was 25.3 months. AC hemorrhage occurred in five patients during the iridectomy procedure. Corneal edema was detected in eight of 14 patients with primary IOL insertions. Haptic dislocation was detected in only one patient. This technique may be a good alternative to scleral-fixated IOL implantation in eyes with aphakia. PMID- 24817748 TI - Ophthalmic masquerades of the atherosclerotic carotids. AB - Patients with carotid atherosclerosis can present with ophthalmic symptoms. These symptoms and signs can be due to retinal emboli, hypoperfusion of the retina and choroid, opening up of collateral channels, or chronic hypoperfusion of the globe (ocular ischemic syndrome). These pathological mechanisms can produce many interesting signs and a careful history can bring out important past symptoms pointing toward the carotid as the source of the patient's presenting symptom. Such patients are at high risk for an ischemic stroke, especially in the subsequent few days following their first acute symptom. It is important for clinicians to be familiar with these ophthalmic symptoms and signs caused by carotid atherosclerosis for making an early diagnosis and to take appropriate measures to prevent a stroke. This review elaborates the clinical features, importance, and implications of various ophthalmic symptoms and signs resulting from atherosclerotic carotid artery disease. PMID- 24817751 TI - Multiple extra macular branch retinal vein occlusions in hyperhomocysteinemia. AB - Hyperhomocysteinemia is a well-known modifiable risk factor for thromboembolism. Retinal vascular occlusion in patients having hyperhomocysteinemia is a known entity, particularly in young patients. However, multiple extra macular branch retinal vein occlusion (BRVO) is a rare condition, which can be a presentation of this disease. We present a patient who had multiple extra macular BRVO; on complete systemic workup, he was found to have raised homocysteine levels. PMID- 24817752 TI - Medial canthus retiform hemangioendothelioma. AB - Retiform hemangioendothelioma (RH) is a distinct entity in the spectrum of vascular tumors with a high local recurrence rate. It is considered a low-grade, well-differentiated cutaneous angiosarcoma with low metastatic potential. We report here for the first time a case of medial canthus recurrent RH. It may be helpful in our practice to include RH as a differential diagnosis of eyelid lesions. It is noteworthy that the progressive course and recurrence tendency of RH might be misdiagnosed as angiosarcoma or basal cell carcinoma (BCC), if not expected and carefully evaluated by the pathologist. PMID- 24817753 TI - An unusual cause of optic atrophy in a child. AB - A 13-year-old child presenting with gross visual impairment was diagnosed as a case of optic atrophy. However, radiological investigations revealed osteopetrosis, which, though rare, can result in optic atrophy. The aim of this case report is to highlight this possibility while evaluating cases of optic atrophy in young patients. PMID- 24817754 TI - An unusual complication of blunt ocular trauma: a horseshoe-shaped macular tear with spontaneous closure. AB - A case of horseshoe-shaped macular tear after blunt trauma with the course of the tear and the relevant findings obtained by spectral-domain optical coherence tomography (SD-OCT) is described. A 21-year-old man who had suffered blunt trauma 5 days previously visited our clinic complaining of vision loss in his left eye. Ophthalmic examination and SD-OCT images revealed a horseshoe-shaped macular tear. A month later at the second visit, the macular tear was found to have spontaneously closed. There have been many cases reported previously of the spontaneous closure of traumatic macular holes. A horseshoe-shaped macular tear is an atypical clinical presentation. However, the mechanism of spontaneous closure is hypothetically as same as that for a macular hole. High-resolution images and three-dimensional maps taken with SD-OCT can provide more details on macular diseases and are more useful than time-domain OCT images. PMID- 24817755 TI - Current topics on genetic researches using Drosophila as a model system. PMID- 24817756 TI - New horizons in genome engineering of Drosophila melanogaster. AB - Drosophila melanogaster has the longest history as a genetic model system and even in the present day remains the front runner in diverse fields of biology. However, lack of a convenient method to make specified modifications to endogenous genes has been a pain in the neck for many fly geneticists for decades. Synthetic nuclease technologies, especially the CRISPR/Cas9 system, hold great promise for a breakthrough. Synthetic nucleases are programmable nucleases that can be directed to cleave a specified sequence in the genome. Deleterious mutations can be efficiently induced by expression of a synthetic nuclease that targets a gene of interest. Precise modification of the target site, such as a reporter gene knock-in, is also possible by simultaneous delivery of a synthetic nuclease and a targeting vector. Here I summarize recent advances in synthetic nuclease technologies and discuss their possible applications to Drosophila genetics. PMID- 24817757 TI - Cell surface control of the layer specific targeting in the Drosophila visual system. AB - To achieve the precise wiring of axons in the brain required to form a fine architecture, a molecular level interaction between axons and their targets is necessary. The Drosophila visual system has a layered and columnar structure which is often found in the brain of vertebrates. With powerful genetic tools for its analysis, the Drosophila visual system provides a useful framework to examine the molecular mechanisms of axon targeting specificity. The medulla is the second optic ganglion in the Drosophila optic lobe, and is subdivided into ten layers. Among the eight photoreceptor types, R7 and R8 pass through the first optic ganglion lamina and innervate the medulla. In the medulla, R7 and R8 axons grow in a distinct manner to reach their final target layers: M6 and M3, respectively. The axons from R7 and R8 take characteristic steps to extend toward their target layer. In this review, we discuss the formation of the Drosophila optic lobe and the molecular mechanisms of layer specific targeting of R8 axons in the medulla. Fundamental and comprehensive understanding of the crosstalk of growing axons and target regions in the Drosophila optic lobe will elucidate the general principles applicable to more complex nervous systems. PMID- 24817758 TI - Development of olfactory projection neuron dendrites that contribute to wiring specificity of the Drosophila olfactory circuit. AB - The antennal lobe (AL) of Drosophila is the first olfactory processing center in which olfactory input and output are spatially organized into distinct channels via glomeruli to form a discrete neural map. In each glomerulus, the axons of a single type of olfactory receptor neurons (ORNs) synapse with the dendrites of a single type of projection neurons (PNs). The AL is an ideal place to study how the wiring specificity between specific types of ORNs and PNs is established during development. During the past two decades, the involvement of diverse molecules in the specification and patterning of ORNs and PNs has been reported. Furthermore, local interneurons-another component of glomeruli-have been recently catalogued and their functions have been gradually dissected. Although there is accumulating knowledge about the involvement of these three cell types in the wiring specificity of the olfactory system, in this review, we focus especially on the development of PN dendrites. PMID- 24817759 TI - Neural control of steroid hormone biosynthesis during development in the fruit fly Drosophila melanogaster. AB - The insect steroid hormone ecdysteroid plays pivotal roles in the temporal coordination of development, represented by molting and metamorphosis. During the larval stages, ecdysteroid is biosynthesized from dietary cholesterol by several ecdysteroidogenic enzymes in the specialized endocrine organ called the prothoracic gland (PG). As ecdysteroid biosynthesis in the PG is affected by several environmental cues, such as photoperiod and nutrition, a fundamental question is how the ecdysteroid biosynthesis pathway is controlled in response to environmental cues. In this review, we briefly summarize recent topics on the regulatory mechanisms of ecdysteroid biosynthesis, especially the neuronal regulatory mechanism, in the fruit fly Drosophila melanogaster. The implications from studies with other insects are also discussed. PMID- 24817760 TI - Development and characterization of 14 microsatellite markers for Buergeria japonica (Amphibia, Anura, Rhacophoridae). AB - Buergeria japonica is a common frog species distributed throughout almost all islands in Ryukyu Archipelago. Because of their exceptionally wide distribution and higher physiological tolerance comparing to the other anurans, their demographic history and formation of distribution are intrinsic topics in the herpetological fauna of Ryukyu. Microsatellite marker is ideal genetic marker for such studies at inter- and intra-population level. We therefore developed microsatellite markers of B. japonica utilizing Ion PGMTM sequencing. As a result of the screening, we developed a total of 14 polymorphic markers. To test availabilities of these markers, we genotyped four island populations. The total number of alleles and expected hetelozygosities per locus ranged from 4 to 21 and 0.00 to 0.864, respectively. The phylogenetic relationship among the four populations based on the genetic distances of these markers was congruent with general divergence pattern of amphibians and reptiles in Ryukyu area. These markers developed in this study are considered to be useful for future studies about phylogeography and demography of this species. PMID- 24817761 TI - Upper limit of vulnerability during defibrillator implantations predicts the occurrence of appropriate shock therapy for ventricular fibrillation. AB - BACKGROUND: The utility of the upper limit of vulnerability (ULV) test in patients undergoing defibrillator implantation has been reported, so the purpose of this study was to evaluate the difference in the clinical outcomes between patients with ULV <=15 J or >15 J. METHODS AND RESULTS: A total of 165 patients receiving an implantable cardioverter-defibrillator underwent a vulnerability test. At the time of the implantation, we delivered a 15-J shock on the T-peak and +/-20 ms later to cover the most vulnerable part of the cardiac cycle. The clinical outcomes were prospectively analyzed. A 15-J shock induced ventricular fibrillation (VF) in 30 patients (ULV >15 J) and did not in 135 (ULV <=15 J). The characteristics of the 2 groups were comparable. After a mean follow-up of 757 days, Kaplan-Meier curve analysis showed that the ULV <=15 J group experienced less VF than the ULV >15 J group (log-rank P=0.003). The occurrence of ventricular tachycardia was similar between the 2 groups (P=0.140). Furthermore, the effectiveness of ATP was comparable. After adjusting for other known predictors of shock therapy, a ULV >15 J was independently associated with the occurrence of VF (hazard ratio: 6.25; 95% confidence interval: 1.913-20.40; P<0.01). CONCLUSIONS: A high ULV value was associated with a high incidence of VF, which suggests that cardiac vulnerability to electrical shock may be linked to electrical instability. PMID- 24817762 TI - Positron emission tomography-computed tomography for imaging of inflammatory cardiovascular diseases. AB - Inflammation is a determinant of atherosclerotic plaque rupture, the event usually responsible for myocardial infarction and stroke. Possible causes of inflammatory cardiomyopathy include myocarditis, eosinophilic disease, and sarcoidosis. Although conventional imaging techniques can identify the site and severity of luminal stenosis, they do not provide information regarding inflammatory status. (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for imaging of inflammatory cardiovascular diseases has been rapidly evolving. Integrated PET/computed tomography (CT) is becoming the method of choice for quantification of arterial inflammation across multiple vessels. Moreover, PET/CT provides information about the activation status of inflammatory cells in the vessel wall, thus allowing early diagnosis and risk stratification of patients. The Japanese health insurance system approved reimbursement for FDG PET use to detect inflammation sites in cardiac sarcoidosis as of April 2012. This approval has necessitated a more detailed assessment of the clinical value of FDG-PET. Standardized preparation, imaging, and image interpretation protocols should be established to sufficiently suppress physiological FDG uptake in the normal myocardium, and thereby facilitate detection of early-stage cardiac inflammatory lesions with more favorable specificity. This review summarizes the background, clinical utility, state-of-the-art advances, and potential future applications of FDG-PET for imaging inflammatory cardiovascular diseases including cardiac sarcoidosis, large-vessel arteritis, and atherosclerosis. PMID- 24817763 TI - Left atrial volume is superior to the ratio of the left atrium to aorta diameter for assessment of the severity of patent ductus arteriosus in extremely low birth weight infants. AB - BACKGROUND: This study was undertaken to establish the appropriate correction of left atrial volume (LAV) to body surface area (BSA) to provide reference values and to assess the hypotheses that LAV is useful for assessing patent ductus arteriosus (PDA) severity in extremely low birth weight infants (ELBWI) and could overcome the limitations of the LA-to-aortic dimension ratio (LA/Ao). METHODS AND RESULTS: Echocardiograms with 318 data points from 53 consecutive ELBWIs were assessed. PDA surgery was performed within the first 2 weeks in 6 patients. LAV was measured using the biplane (LAV) and single-plane (LAV(4CV)) area-length methods. The allometric model was used to correlate LAV to BSA. LAV(4CV) had a good correlation with LAV (R=0.93). Although LAV/BSA(1) had a residual relationship with BSA, LAV/BSA(1.54) (23.5+/-9.3 ml/m(3.08)) and LAV(4CV)/BSA(1.52) (21.4+/-9.4 ml/m(3.04)) did not. Receiver-operating characteristic analysis to detect hemodynamic status just before PDA surgery showed the superiority of LAV/BSA(1.54) (area under the curve (AUC) 0.97) and LAV(4CV)/BSA(1.52) (AUC 0.98) over LA/Ao (AUC 0.92). Moreover, LAV/BSA(1.54) and LAV(4CV)/BSA(1.52) were better correlated with left pulmonary arterial end diastolic velocity than was LA/Ao. CONCLUSIONS: This study provided appropriate BSA correction of LAV and its reference values in ELBWIs. LAV indices may be superior to LA/Ao for PDA severity assessment. Measurement of single-plane LAV is easy, with similar usefulness to biplane LAV. PMID- 24817764 TI - Synthesis and characterization of novel elastomeric poly(D,L-lactide urethane) maleate composites for bone tissue engineering. AB - Here, we report the synthesis and characterization of a novel 4-arm poly(lactic acid urethane)-maleate (4PLAUMA) elastomer and its composites with nano hydroxyapatite (nHA) as potential weight-bearing composite. The 4PLAUMA/nHA ratios of the composites were 1:3, 2:5, 1:2 and 1:1. FTIR and NMR characterization showed urethane and maleate units integrated into the PLA matrix. Energy dispersion and Auger electron spectroscopy confirmed homogeneous distribution of nHA in the polymer matrix. Maximum moduli and strength of the composites of 4PLAUMA/nHA, respectively, are 1973.31 +/- 298.53 MPa and 78.10 +/- 3.82 MPa for compression, 3630.46 +/- 528.32 MPa and 6.23 +/- 1.44 MPa for tension, 1810.42 +/- 86.10 MPa and 13.00 +/- 0.72 for bending, and 282.46 +/- 24.91 MPa and 5.20 +/- 0.85 MPa for torsion. The maximum tensile strains of the polymer and composites are in the range of 5% to 93%, and their maximum torsional strains vary from 0.26 to 0.90. The composites exhibited very slow degradation rates in aqueous solution, from approximately 50% mass remaining for the pure polymer to 75% mass remaining for composites with high nHA contents, after a period of 8 weeks. Increase in ceramic content increased mechanical properties, but decreased maximum strain, degradation rate, and swelling of the composites. Human bone marrow stem cells and human endothelial cells adhered and proliferated on 4PLAUMA films and degradation products of the composites showed little-to-no toxicity. These results demonstrate that novel 4-arm poly(lactic acid urethane) maleate (4PLAUMA) elastomer and its nHA composites may have potential applications in regenerative medicine. PMID- 24817765 TI - Impact of Analog IC Impairments in SiPM Interface Electronics. AB - The recent realization of Silicon Photomultiplier (SiPM) devices as solid-state detectors for Positron Emission Tomography holds the promise of improving image resolution, integrating a significant portion of the interface electronics, and potentially lowering the power consumption. Our lab has previously reported on novel board-level readout electronics for an 8*8 silicon photomultiplier (SiPM) array featuring row/column summation technique to reduce the hardware requirements for signal processing and is currently working on taking the next step by implementing a monolithic CMOS chip which is based on the row-column architecture. To date, relatively little modeling has been done to understand the impact of analog non-idealities associated with the front-end electronics, on SiPM-based PET systems. This paper focuses on various analog impairments associated with PET scanner readout electronics. Matlab was used as a simulation platform to model the noise, linearity and signal bandwidth of the frontend electronics with the measured SiPM pulses as the input. PMID- 24817766 TI - Estimation of 6-Degree-of-Freedom (6-DOF) Rigid-Body Patient Motion From Projection Data by the Principal-Axes Method in Iterative Reconstruction. AB - We developed a unique method for estimating and compensating rigid-body translations and rotations from scatter and-attenuation-compensated projection data in iterative reconstruction when multiple projection angles are acquired at the same time. During reconstruction, both the non-attenuated and attenuated line integrals are calculated. Their ratios are then multiplied to the scatter corrected projection data to estimate scatter-and-attenuation- compensated projection data. At the end of each iteration, the sets of compensated projection data for the angles acquired at the same time are employed to calculate the center-of mass and the inertia tensor, which are used to estimate the location and orientation of the imaging object by the principle-axes method. The estimated motion is applied in the next iteration to reposition the estimated slices and attenuation map in the projector and back-projector to match the pose of the patient at time the projections were acquired. To evaluate our method, we simulated an acquisition of the MCAT phantom with a 3-head SPECT system and imaged the Data Spectrum anthropomorphic phantom on a 3-head IRIX SPECT system. In simulations the phantom translated and rotated by the same amount 9 times. A numerical projector modeling the motion, attenuation, and distance-dependent blurring was used to generate the projection data. Poisson noise was added and 30 noise-realizations were generated. In the experiment with the anthropomorphic phantom, four 360-degree acquisitions were performed with the phantom translated or rotated beforehand. A motion-present dataset was made by mixing the 4 acquisitions. For both the MCAT phantom simulations and anthropomorphic phantom experiment, the motion-present data were reconstructed with 10 iterations of the OSEM which estimates and corrects the motion as described above. Our method obtained visually artifact-free reconstructions, while the reconstruction with no motion correction showed severe artifacts. The motion estimated from our method was in good agreement with the motion simulated. We determined in MCAT simulated and actual phantom acquisitions that our data-driven approach was effective reducing motion artifacts. PMID- 24817768 TI - Small meteoroids' major contribution to Mercury's exosphere. AB - The contribution of the meteoroid population to the generation of Mercury's exosphere is analyzed to determine which segment contributes most greatly to exospheric refilling via the process of meteoritic impact vaporization. For the meteoroid data, a differential mass distribution based on work by Grun et al. (Grun, E., Zook, H.A., Fechtig, H., Giese, R.H. [1985]. Icarus 62(2), 244-272) and a differential velocity distribution based on the work of Zook (Zook, H.A. [1975]. In: 6th Lunar Science Conference, vol. 2. Pergamon Press, Inc., Houston, TX, pp. 1653-1672) is used. These distributions are then evaluated using the method employed by Cintala (Cintala, M.J. [1992]. J. Geophys. Res. 97(E1), 947 974) to determine impact rates for selected mass and velocity segments of the meteoroid population. The amount of vapor created by a single meteor impact is determined by using the framework created by Berezhnoy and Klumov (Berezhnoy, A.A., Klumov, B.A. [2008] Icarus, 195(2), 511-522). By combining the impact rate of meteoroids with the amount of vapor a single such impact creates, we derive the total vapor production rate which that meteoroid mass segment contributes to the Herman exosphere. It is shown that meteoroids with a mass of 2.1 * 10-4 g release the largest amount of vapor into Mercury's exosphere. For meteoroids in the mass range of 10-18 g to 10 g, 90% of all the vapor produced is due to impacts by meteoroids in the mass range 4.2 * 10-7 g <= m <= 8.3 * 10-2 g. PMID- 24817767 TI - MRI Investigation of the Linkage Between Respiratory Motion of the Heart and Markers on Patient's Abdomen and Chest: Implications for Respiratory Amplitude Binning List-Mode PET and SPECT Studies. AB - Respiratory motion of the heart impacts the diagnostic accuracy of myocardial perfusion emission-imaging studies. Amplitude binning has come to be the method of choice for binning list-mode based acquisitions for correction of respiratory motion in PET and SPECT. In some subjects respiratory motion exhibits hysteretic behavior similar to damped non-linear cyclic systems. The detection and correction of hysteresis between the signals from surface movement of the patient's body used in binning and the motion of the heart within the chest remains an open area for investigation. This study reports our investigation in nine volunteers of the combined MRI tracking of the internal respiratory motion of the heart using Navigators with stereo-tracking of markers on the volunteer's chest and abdomen by a visual-tracking system (VTS). The respiratory motion signals from the internal organs and the external markers were evaluated for hysteretic behavior analyzing the temporal correspondence of the signals. In general, a strong, positive correlation between the external marker motion (AP direction) and the internal heart motion (SI direction) during respiration was observed. The average +/- standard deviation in the Spearman's ranked correlation coefficient (rho) over the nine volunteer studied was 0.92 +/- 0.1 between the external abdomen marker and the internal heart, and 0.87 +/- 0.2 between the external chest marker and the internal heart. However despite the good correlation on average for the nine volunteers, in three studies a poor correlation was observed due to hysteretic behavior between inspiration and expiration for either the chest marker and the internal motion of the heart, or the abdominal marker and the motion of the heart. In all cases we observed a good correlation of at least either the abdomen or the chest with the heart. Based on this result, we propose the use of marker motion from both the chest and abdomen regions when estimating the internal heart motion to detect and address hysteresis when binning list-mode emission data. PMID- 24817770 TI - Marriage and Offending among a Cohort of Disadvantaged African Americans. AB - OBJECTIVES: Drawing on Sampson and Laub's age-graded theory of informal social control, this research tests the generalizability of the marriage effect on desistance from crime. Specifically, do urban African American men and women living in the United States benefit from marriage similarly to Whites? METHODS: The authors use hierarchical linear modeling (HLM) to analyze the relationship between marriage and official arrest counts among African American male and female first graders from Woodlawn, an inner-city community in Chicago, first assessed in 1966 and followed up at three time points (ages 16, 32, and 42). RESULTS: The authors find strong evidence of a marriage effect for the males across crime type, with a reduction in offending between 21 percent and 36 percent when in a state of marriage. The findings for females were less consistent across crime type, a 10 percent reduction in the odds of a property arrest and a 9 percent increase in the odds of a drug arrest when in a state of marriage. CONCLUSIONS: Their findings provide evidence in favor of the generality of Sampson and Laub's theory, at least for males. However, the authors were not able to evaluate the mechanisms of desistance and identify this as an area of future research. PMID- 24817769 TI - Non-linear micromechanics of soft tissues. AB - Microstructure-based constitutive models have been adopted in recent studies of non-linear mechanical properties of biological soft tissues. These models provide more accurate predictions of the overall mechanical responses of tissues than phenomenological approaches. Based on standard approximations in non-linear mechanics, we classified the microstructural models into three categories: (1) uniform-field models with solid-like matrix, (2) uniform-field models with fluid like matrix, and (3) second-order estimate models. The first two categories assume affine deformation field where the deformation of microstructure is the same as that of the tissue, regardless of material heterogeneities; i.e., they represent the upper bounds of the exact effective strain energy and stress of soft tissues. In addition, the first type is not purely structurally motivated and hence cannot accurately predict the microscopic mechanical behaviors of soft tissues. The third category considers realistic geometrical features, material properties of microstructure and interactions among them and allows for flexible deformation in each constituent. The uniform-field model with fluid-like matrix and the second-order estimate model are microstructure-based, and can be applied to different tissues based on micro-structural features. PMID- 24817771 TI - FOLLOWING IN THE FOOTSTEPS OF CHRIST: TEXT AND CONTEXT IN THE VITA MILDRETHAE. PMID- 24817772 TI - The Cluster Elastic Net for High-Dimensional Regression With Unknown Variable Grouping. AB - In the high-dimensional regression setting, the elastic net produces a parsimonious model by shrinking all coefficients towards the origin. However, in certain settings, this behavior might not be desirable: if some features are highly correlated with each other and associated with the response, then we might wish to perform less shrinkage on the coefficients corresponding to that subset of features. We propose the cluster elastic net, which selectively shrinks the coefficients for such variables towards each other, rather than towards the origin. Instead of assuming that the clusters are known a priori, the cluster elastic net infers clusters of features from the data, on the basis of correlation among the variables as well as association with the response. These clusters are then used in order to more accurately perform regression. We demonstrate the theoretical advantages of our proposed approach, and explore its performance in a simulation study, and in an application to HIV drug resistance data. Supplementary Materials are available online. PMID- 24817773 TI - Nickel-Catalyzed Cross-Coupling of Aryl Halides with Alkyl Halides: Ethyl 4-(4-(4 methylphenylsulfonamido)-phenyl)butanoate. PMID- 24817774 TI - A Comparison of two Case-crossover Methods for Studying the Dose-Response Relationship Between Alcohol and Injury. AB - BACKGROUND: This study compares dose-response injury risk estimates for two control periods defined as the same 6-hour period the week prior and the set of all non-sleeping 6-hour periods over the past year. METHOD: Dose-response injury risk estimates for the multiple match controls are generated via the application of a maximum-likelihood approach. RESULTS: Injury risk associated with any (i.e., 1 drink or more) drinking 6 hours prior to injury was similar for the two control choices (last week and usual frequency). For 1-4 drinks, risk estimates were similar across control period definitions; for 5+ drinks, risk using the week prior as the control was nearly double that using the past 12 months as the control. CONCLUSIONS: Although studies with smaller ns may benefit from the increase in precision from the use of the multiple control periods, results indicate that heavy drinking injury risk estimates should be used with caution. PMID- 24817775 TI - A Multimodal Nanocomposite for Biomedical Imaging. AB - A multimodal nanocomposite was designed, synthesized with super-paramagnetic core (CoFe2O4), noble metal corona (Au), and semiconductor shell (TiO2). The sizes of core, core-corona, and core-corona-shell particles were determined by TEM. This multimodal nanocrystal showed promise as a contrast agent for two of the most widely used biomedical imaging techniques: magnetic resonance imaging (MRI) and X ray computed tomography (CT). Finally, these nanocomposites were coated with a peptide SN-50. This led to their ready uptake by the cultured cells and targeted the nanocomposites to the pores of nuclear membrane. Inside cells, this nanocomposite retained its integrity as shown by X-ray fluorescence microscopy (XFM). Inside cells imaged by XFM we found the complex elemental signature of nanoconjugates (Ti-Co-Fe-Au) always co-registered in the 2D elemental map of the cell. PMID- 24817776 TI - Translating Social Motivation into Action: Contributions of Need for Approval to Children's Social Engagement. AB - This research examined how children's need for approval (NFA) from peers predicted social behavior (prosocial behavior, aggression, social helplessness) and peer responses (acceptance, victimization, exclusion). Children (N = 526, M age = 7.95, SD = .33) reported on need for approval and teachers reported on social engagement. Approach NFA (motivation to gain approval) predicted more positive engagement and less conflictual engagement and disengagement. Conversely, avoidance NFA (motivation to avoid disapproval) predicted less positive engagement and more conflictual engagement and disengagement. Some results differed by gender. This study suggests that social motivation contributes to children's peer relationships, providing a specific target for interventions to optimize social health. PMID- 24817777 TI - Toward a cumulative ecological risk model for the etiology of child maltreatment. AB - The purpose of the current study was to further the integration of cumulative risk models with empirical research on the etiology of child maltreatment. Despite the well-established literature supporting the importance of the accumulation of ecological risk, this perspective has had difficulty infiltrating empirical maltreatment research and its tendency to focus on more limited risk factors. Utilizing a sample of 842 mother-infant dyads, we compared the capacity of individual risk factors and a cumulative index to predict maltreatment reports in a prospective longitudinal investigation over the first sixteen years of life. The total load of risk in early infancy was found to be related to maternal cognitions surrounding her new role, measures of social support and well-being, and indicators of child cognitive functioning. After controlling for total level of cumulative risk, most single factors failed to predict later maltreatment reports and no single variable provided odd-ratios as powerful as the predictive power of a cumulative index. Continuing the shift away from simplistic causal models toward an appreciation for the cumulative nature of risk would be an important step forward in the way we conceptualize intervention and support programs, concentrating them squarely on alleviating the substantial risk facing so many of society's families. PMID- 24817778 TI - "That's what friends do": Informal caregiving for chronically ill midlife and older lesbian, gay, and bisexual adults. AB - This study examines the relationships between friends; a caregiver who provides care to a care recipient, who is a lesbian, gay, or bisexual (LGB) adult over age 50 in need of assistance due to chronic physical or mental health conditions. Using a sample of 18 care pairs (n = 36), this work examines qualitative interview data. Findings from the study include: (a) both the care recipient and the caregiver receive benefits from the friendship; (b) caregiving alters and challenges the friendship; and (c) friends assume differential levels of commitment and responsibility in providing care. Studying this population of LGB adults expands our knowledge about the diversity of care arrangements and needs within a relational context. PMID- 24817779 TI - How Can the Comorbidity with ADHD Aid Understanding of Language and Speech Disorders? AB - This paper serves to provide a background for the topic of comorbidity than extends through this issue. Comorbidity is common within developmental disorders. It is shown that there are many possible reasons for comorbidity. Some of these can be viewed as artifacts as simple as chance occurrence or because of the way that the research participants were sampled. If these artifacts are eliminated, then comorbidity can be informative with respect to possible causes of the disorders that are comorbid. Several possible etiologic models are presented along with a general framework for considering levels of causality in developmental disorders. PMID- 24817780 TI - Absence of correlation between IL-28B gene polymorphisms and the clinical presentation of chronic hepatitis B in an Amazon Brazilian population. AB - OBJECTIVE: The present study investigated the prevalence of the IL-28B polymorphisms rs12979860 and rs8099917 in chronic hepatitis B patients from a case study in Eastern Amazonia. METHODS: In total, 65 chronically infected HBV patients and 97 healthy subjects who were anti-HBc and anti-HBs positive (control group) were evaluated between May 2011 and December 2012. The groups of patients were designated as inactive carriers, chronic hepatitis without cirrhosis, and chronic hepatitis with cirrhosis based on clinical, pathological, biochemical, hematological, and virological variables. The patients were genotyped using quantitative real-time PCR. RESULTS: The frequencies of the rs12979860 polymorphism were similar between the infected group (32.3% CC, 41.5% CT, and 26.2 TT) and the control population (35% CC, 47.4% CT, and 17.6% TT), and the frequencies of the rs8099917 polymorphism (7.7% GG, 35.4% GT, and 56.9% TT versus 7.2% GG, 35.1% GT, and 57.7% TT) were also similar in both groups. The associations between the rs12979860 and rs8099917 polymorphisms and the clinical manifestations were not statistically significant. CONCLUSION: In conclusion, these polymorphisms had a similar distribution between infected and control groups, indicating that they were not associated with susceptibility and the clinical evolution of hepatitis B in the examined population. PMID- 24817782 TI - Modelling the surface free energy parameters of polyurethane coats-part 2. Waterborne coats obtained from cationomer polyurethanes. AB - Polyurethane cationomer coats were synthesised on the basis of typical diisocyanates, properly selected polyether polyols, HO-tertiary amines and HCOOH as quaternisation reagents. The values of their surface free energy (SFE) parameters were obtained by the van Oss-Good method, with the use of the contact angle values which had been found by the goniometric method. Based on the obtained findings, empirical models were developed which made it possible to anticipate the effects of the raw material types on the SFE values of the produced coats. The possibility was noted to adjust the SFE values within 25-50 mJ/m2 by selecting carefully suitable parent substances. The principal consequences for the formation of improved hydrophobicity coats, applicable inter alia specialised protective coatings, were found to come not only from diisocyanate and polyol types but also from the alkylammonium cation structure which results from the use of different tertiary amines. The fundamental SFE lowering effect was noted when tertiary amines with 0-15 % of the 2,2,3,3 tetrafluoro-1,4-butanediol as a fluorinated chain extender was incorporated into polymer chains. PMID- 24817781 TI - MicroRNA-224 suppresses colorectal cancer cell migration by targeting Cdc42. AB - The metastatic spread of tumor cells is the major risk factor affecting the clinical prognosis of colorectal cancer (CRC) patients. The metastatic phenotype can be modulated by dysregulating the synthesis of different structural and functional proteins of tumor cells. Micro(mi)RNAs are noncoding RNAs that recognize their cognate messenger (m)RNA targets by sequence-specific interactions with the 3' untranslated region and are involved in the multistep process of CRC development. The objective of this study was to investigate the expression and biological roles of miR-224 in CRC. The miR-224 expression level was assessed by a quantitative real-time PCR in 79 CRC and 18 nontumor tissues. Expression levels of miR-224 in CRC tissues were significantly lower than those in nontumor tissues. Its expression level was associated with the mutation status of the APC gene. Ectopic expression of miR-224 suppressed the migratory ability of CRC cell line, but cell proliferation was less affected. Increased miR-224 diminished Cdc42 and SMAD4 expressions at both the protein and mRNA levels and inhibited the formation of actin filaments. Overall, this study indicated a role of miR-224 in negatively regulating CRC cell migration. The expression level of miR-224 may be a useful predictive biomarker for CRC progression. PMID- 24817783 TI - Variations in Quercus sp. pollen seasons (1996-2011) in Poznan, Poland, in relation to meteorological parameters. AB - The aim of this study is to supply detailed information about oak (Quercus sp.) pollen seasons in Poznan, Poland, based on a 16-year aerobiological data series (1996-2011). The pollen data were collected using a volumetric spore trap of the Hirst design located in Poznan city center. The limits of the pollen seasons were calculated using the 95 % method. The influence of meteorological parameters on temporal variations in airborne pollen was examined using correlation analysis. Start and end dates of oak pollen seasons in Poznan varied markedly from year-to year (14 and 17 days, respectively). Most of the pollen grains (around 75 % of the seasonal pollen index) were recorded within the first 2 weeks of the pollen season. The tenfold variation was observed between the least and the most intensive pollen seasons. These fluctuations were significantly related to the variation in the sum of rain during the period second fortnight of March to first fortnight of April the year before pollination (r = 0.799; p < 0.001). During the analyzing period, a significant advance in oak pollen season start dates was observed (-0.55 day/year; p = 0.021), which was linked with an increase in the mean temperature during the second half of March and first half of April (+0.2 degrees C; p = 0.014). Daily average oak pollen counts correlated positively with mean and maximum daily temperatures, and negatively with daily rainfall and daily mean relative humidity. PMID- 24817784 TI - Lunasin in cereal seeds: What is the origin? AB - Lunasin is a peptide from soybean seeds which has been demonstrated to have anticancer properties. It has also been reported in cereal seeds: wheat, rye, barley and Triticale. However, extensive searches of transcriptome and DNA sequence databases for wheat and other cereals have failed to identify sequences encoding either the lunasin peptide or a precursor protein. This raises the question of the origin of the lunasin reported in cereal grain. PMID- 24817786 TI - Effect of Tissue-Culture Substratum and Extracellular Matrix Overlay on Liver Selective and Xenobiotic Inducible Gene Expression in Primary Rat Hepatocytes. AB - In a previous study (Sidhu et al., 1993), we demonstrated that a combination of certain cell culture media, hormone addition, and extracellular matrix (ECM) overlay coordinately modulated the expression of certain liver-selective genes in primary rat hepatocyte cultures, including the responsiveness of genes to phenobarbital. However, little is known about the interactions between the type of substratum upon which hepatocytes are adhered and the ECM overlay, as codeterminants of liver-selective gene expression. The present study was undertaken to compare specific substrata, including tissue culture-grade plastic, Primaria, and type 1 collagen-coated plastic, in combination with the presence or absence of standard ECM or a growth-factor-reduced ECM overlay. Hepatocyte cultures were assessed either as control cultures or subsequent to treatment for 24 h with phenobarbital (0.1 or 1 mM), or beta-naphthoflavone (22 MUM), to monitor responses of hepatocytes to two prototypic gene-inducing agents. Analyses of maintenance and induction of cytochrome P450 and liver-selective gene expression included measures of mRNA levels using Northern blot and slot-blot hybridization and single cell immunofluorescence assays to measure levels of specific cytochrome P450 proteins. The results of these experiments demonstrated that hepatocyte-selective expression, including the absolute level of induction response (relative to those observed in the rat liver in vivo) was highly dependent on the presence of ECM overlay but independent of the substratum employed. As studied herein, the establishment of optimal conditions for primary hepatocyte culture, enabling reproduction of responses observed in vivo, is important to further prospects for in vitro toxicity testing and for investigating molecular mechanisms of phenobarbital-mediated gene regulation. PMID- 24817787 TI - Experiences of Marriage and Family Therapists Working with Intimate Partner Violence. AB - The purpose of our study was to explore the experiences of marriage and family therapists in working with violent couples. In particular, we focused on therapists' questions and feelings of competency pertaining to violence assessment and treatment, the difficulties they face during their practices, and the factors that affect their practice. Data for this study was collected via a focus group that lasted approximately an hour. The participants included five marriage and family therapists. A set of questions were used to explore experiences of therapists who were working with clients who are experiencing domestic violence. The research team recorded the answers to these questions as well as associated discussion. A grounded theory approach was used to analyze the data. Six themes were derived from the coded data: acknowledgment and reliance on systemic foundations, therapist factors, assessment, treatment considerations, sex of batterers, and training in Marriage and Family Therapy programs. PMID- 24817785 TI - Cognitive Consequences of Aging with HIV: Implications for Neuroplasticity and Rehabilitation. AB - Combination active antiretroviral therapy prevents HIV from replicating and ravaging the immune system, thus allowing people to age with this disease. Unfortunately, the synergistic effects of HIV and aging can predispose many to become more at-risk of developing cognitive deficits which can interfere with medical management, everyday functioning, and quality of life. The purpose of this article is to describe the role of cognitive reserve and neuroplasticity on cognitive functioning in those aging with this disease. Specifically, the role of environment and the health of these individuals can compromise cognitive functioning. Fortunately, some cognitive interventions such as prevention and management of co-morbidities, cognitive remediation therapy, and neurotropic medications may be of value in preventing and rehabilitating the cognitive consequences of aging with HIV. Novel approaches such as cognitive prescriptions, transcranial direct stimulation, and binaural beat therapy may also be considered as possible techniques for cognitive rehabilitation. PMID- 24817788 TI - Changes in parotid gland morphology and function in patients treated with intensity-modulated radiotherapy for nasopharyngeal and oropharyngeal tumors. AB - OBJECTIVE: To evaluate the morphological changes of the parotid glands in patients treated with intensity-modulated radiotherapy (IMRT) for nasopharyngeal and oropharyngeal tumors and the correlations with parotid function. METHODS: Ten patients with nasopharyngeal and oropharyngeal tumors treated with IMRT between May 2009 and January 2010 at Hokkaido University Hospital were included in this study. In the morphological assessment of the parotid glands, the sizes and computed tomography (CT) numbers of the bilateral parotid glands before and after IMRT with CT were calculated. For functional assessment of the parotid glands, we conducted the Saxon test and used a visual analog scale (VAS) for xerostomia evaluation. RESULTS: Reductions in saliva secretion were observed in the patients treated with IMRT for nasopharyngeal and oropharyngeal tumors, and there was a significant correlation between the reduction in saliva secretion and the VAS. The reductions in the parotid gland size and CT number were larger on the ipsilateral side than on the contralateral side. The reduction in saliva secretion was not significantly correlated with the reduction in parotid gland size, but was significantly correlated with the reduction in CT number. CONCLUSIONS: Morphological and functional changes of the parotid glands were observed after IMRT for nasopharyngeal and oropharyngeal tumors, and preservation of the contralateral parotid glands was only partly achieved. Among the morphological changes of the parotid glands, the CT number may be considered a predictor of parotid function after radiotherapy. PMID- 24817789 TI - The utility of repeated computed tomography to track a foreign body penetrating the esophagus to the level of the thyroid gland. AB - OBJECTIVE: Foreign body (FB) ingestion is a common problem in otolaryngology. One uncommon complication of FB ingestion is penetration to the level of the thyroid gland. To our knowledge, only 21 such cases have been reported in the literature. Here, we report a case of an esophageal FB penetrating to the level of the right thyroid gland. CASE REPORT: The patient was a 38-year-old woman in whom an esophageal FB penetrated to the level of the right thyroid gland. We traced the path to the thyroid gland using repeated computed tomography (CT) scans and demonstrated the importance of multiplanar reconstruction in locating the FB and formulating a precise surgical plan. CONCLUSIONS: To our knowledge, this is the first report of repeat CT scans being used to demonstrate the migratory route, over time, of a FB penetrating through the esophagus to the level of the thyroid gland. Our results suggest that multiplanar reconstruction may play a key role in the precise diagnosis of a FB at the level of the thyroid gland and may help surgeons choose the best approach for removal. PMID- 24817790 TI - What Drives the Formation of Trophectoderm During Early Embryonic Development? AB - In the mouse, the lineages of cells that give rise to trophectoderm and ICM are generally held to arise between the 8-cell and 16-cell stage of development. This model assumes that all blastomeres have essentially equivalent potential in terms of their fate through the first three rounds of cell division. There is, however, accumulating evidence that the blastomeres of 2-cell stage conceptuses may be compositionally different and contribute unequally to trophectoderm and ICM of the blastocyst. Here, we evaluate these competing points of view relating to when commitment to the trophectoderm lineage occurs in mammals, describe some of the genes that drive trophectoderm specification, and discuss the implications of the two hypotheses in relation to outcomes in commonly used reproductive technologies. Much of what is presently known has been derived from studying the mouse, but where information is available from other species, and particularly from cattle, it has been included. PMID- 24817791 TI - Dyscalculia, dysgraphia, and left-right confusion from a left posterior peri insular infarct. AB - The Gerstmann syndrome of dyscalculia, dysgraphia, left-right confusion, and finger agnosia is generally attributed to lesions near the angular gyrus of the dominant hemisphere. A 68-year-old right-handed woman presented with sudden difficulty completing a Sudoku grid and was found to have dyscalculia, dysgraphia, and left-right confusion. Magnetic resonance imaging (MRI) showed a focus of abnormal reduced diffusivity in the left posterior insula and temporoparietal operculum consistent with acute infarct. Gerstmann syndrome from an insular or peri-insular lesion has not been described in the literature previously. Pathological and functional imaging studies show connections between left posterior insular region and inferior parietal lobe. We postulate that the insula and operculum lesion disrupted key functional networks resulting in a pseudoparietal presentation. PMID- 24817793 TI - Sitagliptin prevents inflammation and apoptotic cell death in the kidney of type 2 diabetic animals. AB - This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and blood HbA1c levels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-alpha, IL-1beta, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c (by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1beta and TNF-alpha levels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti inflammatory and antiapoptotic properties. PMID- 24817795 TI - Inhibition of age-related cytokines production by ATGL: a mechanism linked to the anti-inflammatory effect of resveratrol. AB - Ageing is characterized by the expansion and the decreased vascularization of visceral adipose tissue (vAT), disruption of metabolic activities, and decline of the function of the immune system, leading to chronic inflammatory states. We previously demonstrated that, in vAT of mice at early state of ageing, adipocytes mount a stress resistance response consisting in the upregulation of ATGL, which is functional in restraining the production of inflammatory cytokines. Here, we found that, in the late phase of ageing, such an adaptive response is impaired. In particular, 24-months-old mice and aged 3T3-L1 adipocytes display affected expression of ATGL and its downstream PPARalpha-mediated lipid signalling pathway, leading to upregulation of TNFalpha and IL-6 production. We show that the natural polyphenol compound resveratrol (RSV) efficiently suppresses the expression of TNFalpha and IL-6 in an ATGL/PPARalpha dependent manner. Actually, adipocytes downregulating ATGL do not show a restored PPARalpha expression and display elevated cytokines production. Overall the results obtained highlight a crucial function of ATGL in inhibiting age-related inflammation and reinforce the idea that RSV could represent a valid natural compound to limit the onset and/or the exacerbation of the age-related inflammatory states. PMID- 24817794 TI - ADAM metallopeptidase domain 33 (ADAM33): a promising target for asthma. AB - Over the last few years, a significant progress has been made in understanding the role of a disintegrin and metalloproteinase 33 (ADAM33) in asthma. The previous observations for the association with asthma have been replicated in over 33 different population samples worldwide. We and others have performed association analysis and meta-analysis and provided further evidence that several polymorphisms in the ADAM33 are risk factors for asthma, especially in the Asian population. Further, several studies have suggested that alterations in epigenetic marks alter the patterns of DNA methylation of ADAM33 and result in potentially adverse biological effects. Finally, while the biological activities of ADAM33 are as yet unknown, ADAM33 may play a possible role in airway remodeling because of its high expression in epithelium, myo/fibroblasts, and airway smooth muscle cells (ASMCs) and its role in promoting angiogenesis and stimulating cell proliferation and differentiation. Thus, ADAM33 represents a promising target for asthma. However, further investigations are clearly needed to discover functional ADAM33 gene polymorphisms and the role of genetic/epigenetic factors in conferring genetic susceptibility to environmental exposure induced asthma as well as biological function in asthma. This, in turn, will unlock the possibility of ADAM33 as a target for asthma therapy. PMID- 24817796 TI - Determinants of Infant Mortality in a Developing Region in Rural Andhra Pradesh. AB - INTRODUCTION: BACKGROUND & OBJECTIVES: Despite several interventions implemented for the improvement of infant survival, the pace of decline in infant mortality in the State of Andhra Pradesh during the last two decades has been rather slow. This paper examines determinants of infant mortality in a rural population of about 45000 in Medchal region of Andhra Pradesh, India. METHODS: Data obtained through continuous (longitudinal) enumeration of household population and also from the cross-sectional survey of households carried out during 2008-09 in the study area were analyzed. A univariate analysis was carried out and followed by an application of binary logistic regression model to identify significant factors associated with infant mortality. RESULTS: Despite a substantial increase in institutional deliveries in the study area, infant mortality rate remained relatively constant at 43+/-1. Socioeconomic variables such as education and household economic status and environmental variables such as access to safe drinking water and sanitation facility and use of clean cooking fuel emerged as significant predictors of infant survival. INTERPRETATION & CONCLUSIONS: Promoting institutional deliveries by providing cash assistance to women by itself cannot be expected to bring down infant mortality to a low level in the absence of an improvement in socioeconomic and environmental conditions of the households. PMID- 24817797 TI - SEMIPARAMETRIC ROC ANALYSIS USING ACCELERATED REGRESSION MODELS. AB - The Receiver Operating Characteristic (ROC) curve is a widely used measure to assess the diagnostic accuracy of biomarkers for diseases. Biomarker tests can be affected by subject characteristics, the experience of testers, or the environment in which tests are carried out, so it is important to understand and determine the conditions for evaluating biomarkers. In this paper, we focus on assessing the effects of covariates on the performance of the ROC curves. In particular, we develop an accelerated ROC model by assuming that the effect of covariates relates to rescaling a baseline ROC curve. The proposed model generalizes the accelerated failure time model in the survival context to ROC analysis. An innovative method is developed to construct estimation and inference for model parameters. The obtained parameter estimators are shown to be asymptotically normal. We demonstrate the proposed method via a number of simulation studies, and apply it to analyze data from a prostate cancer study. PMID- 24817792 TI - Oral complications in hematopoietic stem cell recipients: the role of inflammation. AB - Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis. PMID- 24817798 TI - The double-helix point spread function enables precise and accurate measurement of 3D single-molecule localization and orientation. AB - Single-molecule-based super-resolution fluorescence microscopy has recently been developed to surpass the diffraction limit by roughly an order of magnitude. These methods depend on the ability to precisely and accurately measure the position of a single-molecule emitter, typically by fitting its emission pattern to a symmetric estimator (e.g. centroid or 2D Gaussian). However, single-molecule emission patterns are not isotropic, and depend highly on the orientation of the molecule's transition dipole moment, as well as its z-position. Failure to account for this fact can result in localization errors on the order of tens of nm for in-focus images, and ~50-200 nm for molecules at modest defocus. The latter range becomes especially important for three-dimensional (3D) single molecule super-resolution techniques, which typically employ depths-of-field of up to ~2 MUm. To address this issue we report the simultaneous measurement of precise and accurate 3D single-molecule position and 3D dipole orientation using the Double-Helix Point Spread Function (DH-PSF) microscope. We are thus able to significantly improve dipole-induced position errors, reducing standard deviations in lateral localization from ~2x worse than photon-limited precision (48 nm vs. 25 nm) to within 5 nm of photon-limited precision. Furthermore, by averaging many estimations of orientation we are able to improve from a lateral standard deviation of 116 nm (~4x worse than the precision, 28 nm) to 34 nm (within 6 nm). PMID- 24817799 TI - Real-time dynamic range and signal to noise enhancement in beam-scanning microscopy by integration of sensor characteristics, data acquisition hardware, and statistical methods. AB - Despite the ubiquitous use of multi-photon and confocal microscopy measurements in biology, the core techniques typically suffer from fundamental compromises between signal to noise (S/N) and linear dynamic range (LDR). In this study, direct synchronous digitization of voltage transients coupled with statistical analysis is shown to allow S/N approaching the theoretical maximum throughout an LDR spanning more than 8 decades, limited only by the dark counts of the detector on the low end and by the intrinsic nonlinearities of the photomultiplier tube (PMT) detector on the high end. Synchronous digitization of each voltage transient represents a fundamental departure from established methods in confocal/multi-photon imaging, which are currently based on either photon counting or signal averaging. High information-density data acquisition (up to 3.2 GB/s of raw data) enables the smooth transition between the two modalities on a pixel-by-pixel basis and the ultimate writing of much smaller files (few kB/s). Modeling of the PMT response allows extraction of key sensor parameters from the histogram of voltage peak-heights. Applications in second harmonic generation (SHG) microscopy are described demonstrating S/N approaching the shot-noise limit of the detector over large dynamic ranges. PMID- 24817800 TI - Dose Reduction in Fluoroscopic Interventions Using a Combination of a Region of Interest (ROI) X-Ray Attenuator and Spatially-Different, Temporally-Variable Temporal Filtering. AB - A novel dose reduction technique for fluoroscopic interventions involving a combination of a material x-ray region of interest (ROI) attenuator and spatially different, temporally variable ROI temporal recursive filter, was used to guide the catheter to the ROI in three live animal studies, two involving rabbits and one involving a sheep. In the two rabbit studies presented, a catheter was guided to the entrance of the carotid artery. With the added ROI attenuator the image under the high attenuation region is very noisy. By using temporal filtering with a filter weight of 0.6 on previous frames, the noise is reduced. In the sheep study the catheter was guided to the descending aorta of the animal. The sheep offered a relatively higher attenuation to the incident x-rays and thus a higher temporal filter weight of 0.8 on previous frames was used during the procedure to reduce the noise to levels acceptable by the interventionalist. The image sequences from both studies show that significant dose reduction of 5-6 times can be achieved with acceptable image quality outside the ROI by using the above mentioned technique. Even though the temporal filter weighting outside the ROI is higher, the consequent lag does not prevent perception of catheter movement. PMID- 24817801 TI - Updates in the real-time Dose Tracking System (DTS) to improve the accuracy in calculating the radiation dose to the patients skin during fluoroscopic procedures. AB - We have developed a dose-tracking system (DTS) to manage the risk of deterministic skin effects to the patient during fluoroscopic image-guided interventional cardiac procedures. The DTS calculates the radiation dose to the patient's skin in real-time by acquiring exposure parameters and imaging-system geometry from the digital bus on a Toshiba C-arm unit and displays the cumulative dose values as a color map on a 3D graphic of the patient for immediate feedback to the interventionalist. Several recent updates have been made to the software to improve its function and performance. Whereas the older system needed manual input of pulse rate for dose-rate calculation and used the CPU clock with its potential latency to monitor exposure duration, each x-ray pulse is now individually processed to determine the skin-dose increment and to automatically measure the pulse rate. We also added a correction for the table pad which was found to reduce the beam intensity to the patient for under-table projections by an additional 5-12% over that of the table alone at 80 kVp for the x-ray filters on the Toshiba system. Furthermore, mismatch between the DTS graphic and the patient skin can result in inaccuracies in dose calculation because of inaccurate inverse-square-distance calculation. Therefore, a means for quantitative adjustment of the patient-graphic-model position and a parameterized patient graphic library have been developed to allow the graphic to more closely match the patient. These changes provide more accurate estimation of the skin-dose which is critical for managing patient radiation risk. PMID- 24817802 TI - Quantitative Evaluation of Treatment Related Changes on Multi-Parametric MRI after Laser Interstitial Thermal Therapy of Prostate Cancer. AB - Laser interstitial thermal therapy (LITT) has recently shown great promise as a treatment strategy for localized, focal, low-grade, organ-confined prostate cancer (CaP). Additionally, LITT is compatible with multi-parametric magnetic resonance imaging (MP-MRI) which in turn enables (1) high resolution, accurate localization of ablation zones on in vivo MP-MRI prior to LITT, and (2) real-time monitoring of temperature changes in vivo via MR thermometry during LITT. In spite of rapidly increasing interest in the use of LITT for treating low grade, focal CaP, very little is known about treatment-related changes following LITT. There is thus a clear need for studying post-LITT changes via MP-MRI and consequently to attempt to (1) quantitatively identify MP-MRI markers predictive of favorable treatment response and longer term patient outcome, and (2) identify which MP-MRI markers are most sensitive to post-LITT changes in the prostate. In this work, we present the first attempt at examining focal treatment-related changes on a per-voxel basis (high resolution) via quantitative evaluation of MR parameters pre- and post-LITT. A retrospective cohort of MP-MRI data comprising both pre- and post-LITT T2-weighted (T2w) and diffusion-weighted (DWI) acquisitions was considered, where DWI MRI yielded an Apparent Diffusion Co efficient (ADC) map. A spatially constrained affine registration scheme was implemented to first bring T2w and ADC images into alignment within each of the pre- and post-LITT acquisitions, following which the pre- and post-LITT acquisitions were aligned. Pre- and post-LITT MR parameters (T2w intensity, ADC value) were then standardized to a uniform scale (to correct for intensity drift) and then quantified via the raw intensity values as well as via texture features derived from T2w MRI. In order to quantify imaging changes as a result of LITT, absolute differences were calculated between the normalized pre- and post-LITT MRI parameters. Quantitatively combining the ADC and T2w MRI parameters enabled construction of an integrated MP-MRI difference map that was highly indicative of changes specific to the LITT ablation zone. Preliminary quantitative comparison of the changes in different MR parameters indicated that T2w texture may be highly sensitive as well as specific in identifying changes within the ablation zone pre- and post-LITT. Visual evaluation of the differences in T2w texture features pre- and post-LITT also appeared to provide an indication of LITT related effects such as edema. Our preliminary results thus indicate great potential for non-invasive MP-MRI imaging markers for determining focal treatment related changes, and hence long- and short-term patient outcome. PMID- 24817803 TI - Transillumination and reflectance probes for in vivo near-IR imaging of dental caries. AB - Previous studies have demonstrated the utility of near infrared (NIR) imaging for caries detection employing transillumination and reflectance imaging geometries. Three intra-oral NIR imaging probes were fabricated for the acquisition of in vivo, real time videos using a high definition InGaAs SWIR camera and near-IR broadband light sources. Two transillumination probes provide occlusal and interproximal images using 1300-nm light where water absorption is low and enamel manifests the highest transparency. A third reflectance probe utilizes cross polarization and operates at >1500-nm, where water absorption is higher which reduces the reflectivity of sound tissues, significantly increasing lesion contrast. These probes are being used in an ongoing clinical study to assess the diagnostic performance of NIR imaging for the detection of caries lesions in teeth scheduled for extraction for orthodontic reasons. PMID- 24817804 TI - Monitoring the inhibition of erosion by a CO2 laser with OCT. AB - Since optical coherence tomography (OCT) is well suited for measuring small dimensional changes on tooth surfaces, OCT has great potential for monitoring tooth erosion. Previous studies have shown that enamel areas ablated by a carbon dioxide laser manifested lower rates of erosion compared to the non-ablated areas. The purpose of this study was to develop a model to monitor erosion in vitro that could potentially be used in vivo. Teeth surfaces were irradiated with a carbon dioxide laser at low sub-ablative fluence to create an acid-resistant reference layer without damaging the enamel. The laser treated areas were compared with the unprotected areas using OCT during exposure to a pH cycling model for up to 6 days. The laser treated areas markedly reduced the rate of erosion. PMID- 24817805 TI - Enhancing the detection of hidden occlusal caries lesions with OCT using high index liquids. AB - In a previous study, we investigated the influence of several high refractive index fluids on the performance of polarization sensitive optical coherence tomography (PS-OCT). That study showed that these liquids can increase the effective imaging depth and lesion contrast. Other in vitro and in vivo studies have shown that OCT can be used to show whether occlusal lesions have penetrated to the dentinal-enamel junction (DEJ) and spread laterally under the enamel. The purpose of this study was to determine if high index fluids can enhance the ability of OCT to detect hidden occlusal lesions and show if these lesions have penetrated through the enamel into the underlying dentin. Ten extracted teeth with occlusal lesions were imaged using OCT after the application of water, glycerol, BABB (33% Benzyl Alcohol + 67% Benzyl Benzoate) and a Cargille Liquid (Cedar Grove, NJ) (hydrogenated terphenyl 1-bromo-naphthalene) with a refractive index of 1.61. The intensity of the reflectance from the underlying lesion area for each sample was compared with the reflectance of the sound tooth surface for each fluid. The use of high index fluids significantly (P< 0.0001) increased the reflectivity of subsurface occlusal lesions under the surrounding sound enamel. PMID- 24817806 TI - Near-IR imaging of cracks in teeth. AB - Dental enamel is highly transparent at near-IR wavelengths and several studies have shown that these wavelengths are well suited for optical transillumination for the detection and imaging of tooth decay. We hypothesize that these wavelengths are also well suited for imaging cracks in teeth. Extracted teeth with suspected cracks were imaged at several wavelengths in the near-IR from 1300 1700-nm. Extracted teeth were also examined with optical coherence tomography to confirm the existence of suspected cracks. Several teeth of volunteers were also imaged in vivo at 1300-nm to demonstrate clinical potential. In addition we induced cracks in teeth using a carbon dioxide laser and imaged crack formation and propagation in real time using near-IR transillumination. Cracks were clearly visible using near-IR imaging at 1300-nm in both in vitro and in vivo images. Cracks and fractures also interfered with light propagation in the tooth aiding in crack identification and assessment of depth and severity. PMID- 24817807 TI - Near-IR imaging of demineralization under sealants. AB - Previous studies have shown that near-IR reflectance and transillumination imaging can be used to acquire high contrast images of early caries lesions and composite restorative materials. The aim of the study was to determine the optimum near-IR wavelengths for imaging demineralized areas under dental sealants. Fifteen natural human premolars and molars with occlusal lesions were used in this in vitro study. Images before and after application of sealants were acquired using near-IR reflectance and near-IR transillumination at wavelengths of 1300 nm, 1460 nm, and 1500 - 1700 nm. Images were also acquired using polarization sensitive optical coherence tomography for comparison. The highest contrast for near-IR reflectance was at 1460 nm and 1500 - 1700 nm. These near-IR wavelengths are coincident with higher water absorption. The clear Delton sealant investigated was not visible in either co-polarization or cross-polarization OCT images. The wavelength region between 1500-1700-nm yielded the highest contrast of lesions under sealants for near-IR reflectance measurements. PMID- 24817808 TI - Shape-Constrained Multi-Atlas Segmentation of Spleen in CT. AB - Spleen segmentation on clinically acquired CT data is a challenging problem given the complicity and variability of abdominal anatomy. Multi-atlas segmentation is a potential method for robust estimation of spleen segmentations, but can be negatively impacted by registration errors. Although labeled atlases explicitly capture information related to feasible organ shapes, multi-atlas methods have largely used this information implicitly through registration. We propose to integrate a level set shape model into the traditional label fusion framework to create a shape-constrained multi-atlas segmentation framework. Briefly, we (1) adapt two alternative atlas-to-target registrations to obtain the loose bounds on the inner and outer boundaries of the spleen shape, (2) project the fusion estimate to registered shape models, and (3) convert the projected shape into shape priors. With the constraint of the shape prior, our proposed method offers a statistically significant improvement in spleen labeling accuracy with an increase in DSC by 0.06, a decrease in symmetric mean surface distance by 4.01 mm, and a decrease in symmetric Hausdorff surface distance by 23.21 mm when compared to a locally weighted vote (LWV) method. PMID- 24817809 TI - Statistical label fusion with hierarchical performance models. AB - Label fusion is a critical step in many image segmentation frameworks (e.g., multi-atlas segmentation) as it provides a mechanism for generalizing a collection of labeled examples into a single estimate of the underlying segmentation. In the multi-label case, typical label fusion algorithms treat all labels equally - fully neglecting the known, yet complex, anatomical relationships exhibited in the data. To address this problem, we propose a generalized statistical fusion framework using hierarchical models of rater performance. Building on the seminal work in statistical fusion, we reformulate the traditional rater performance model from a multi-tiered hierarchical perspective. This new approach provides a natural framework for leveraging known anatomical relationships and accurately modeling the types of errors that raters (or atlases) make within a hierarchically consistent formulation. Herein, we describe several contributions. First, we derive a theoretical advancement to the statistical fusion framework that enables the simultaneous estimation of multiple (hierarchical) performance models within the statistical fusion context. Second, we demonstrate that the proposed hierarchical formulation is highly amenable to the state-of-the-art advancements that have been made to the statistical fusion framework. Lastly, in an empirical whole-brain segmentation task we demonstrate substantial qualitative and significant quantitative improvement in overall segmentation accuracy. PMID- 24817810 TI - Robust Optic Nerve Segmentation on Clinically Acquired CT. AB - The optic nerve is a sensitive central nervous system structure, which plays a critical role in many devastating pathological conditions. Several methods have been proposed in recent years to segment the optic nerve automatically, but progress toward full automation has been limited. Multi-atlas methods have been successful for brain segmentation, but their application to smaller anatomies remains relatively unexplored. Herein we evaluate a framework for robust and fully automated segmentation of the optic nerves, eye globes and muscles. We employ a robust registration procedure for accurate registrations, variable voxel resolution and image field-of-view. We demonstrate the efficacy of an optimal combination of SyN registration and a recently proposed label fusion algorithm (Non-local Spatial STAPLE) that accounts for small-scale errors in registration correspondence. On a dataset containing 30 highly varying computed tomography (CT) images of the human brain, the optimal registration and label fusion pipeline resulted in a median Dice similarity coefficient of 0.77, symmetric mean surface distance error of 0.55 mm, symmetric Hausdorff distance error of 3.33 mm for the optic nerves. Simultaneously, we demonstrate the robustness of the optimal algorithm by segmenting the optic nerve structure in 316 CT scans obtained from 182 subjects from a thyroid eye disease (TED) patient population. PMID- 24817811 TI - A brain MRI atlas of the common squirrel monkey, Saimiri sciureus. AB - The common squirrel monkey, Saimiri sciureus, is a New World monkey with functional and microstructural organization of central nervous system similar to that of humans. It is one of the most commonly used South American primates in biomedical research. Unlike its Old World macaque cousins, no digital atlases have described the organization of the squirrel monkey brain. Here, we present a multi-modal magnetic resonance imaging (MRI) atlas constructed from the brain of an adult female squirrel monkey. In vivo MRI acquisitions include T2 structural imaging and diffusion tensor imaging. Ex vivo MRI acquisitions include T2 structural imaging and diffusion tensor imaging. Cortical regions were manually annotated on the co-registered volumes based on published histological sections. PMID- 24817812 TI - Rural Neighborhood Context, Child Care Quality, and Relationship to Early Language Development. AB - RESEARCH FINDINGS: Prior research with older urban children indicates that disadvantaged neighborhood context is associated with poorer early development, including poorer verbal ability, reading recognition, and achievement scores among children. Neighborhood disadvantage in rural communities and at younger age levels may also be related to development; however this relationship has received little examination. In this study we utilize data from the Family Life Project, a representative sample of babies born to mothers in poor rural counties in North Carolina and Pennsylvania, to address questions related to the relationship between neighborhood context (disadvantage and safety) and children's early language development. We examine mediation of this relationship by child care quality. We also examine geographic isolation and collective socialization as moderators of the relationship between neighborhood context and child care quality. Results indicated that while neighborhood disadvantage did not predict children's development or child care quality, neighborhood safety predicted children's receptive language, with child care quality a partial mediator of this relationship. Collective socialization but not geographic isolation moderated the relationship between neighborhood safety and child care quality. PRACTICE OR POLICY: Implications for policy, practice, and future research are discussed, including improving community safety through community policing, neighborhood watch, and social networks and increasing access to quality child care. PMID- 24817813 TI - Non-Local Euclidean Medians. AB - In this letter, we note that the denoising performance of Non-Local Means (NLM) can be improved at large noise levels by replacing the mean by the Euclidean median. We call this new denoising algorithm the Non-Local Euclidean Medians (NLEM). At the heart of NLEM is the observation that the median is more robust to outliers than the mean. In particular, we provide a simple geometric insight that explains why NLEM performs better than NLM in the vicinity of edges, particularly at large noise levels. NLEM can be efficiently implemented using iteratively reweighted least squares, and its computational complexity is comparable to that of NLM. We provide some preliminary results to study the proposed algorithm and to compare it with NLM. PMID- 24817814 TI - Effect of Rock Cover on Small Mammal Abundance in a Montana Grassland. AB - We examined the influence of rock cover, as an indicator of presumable retreat site availability on the abundance of deer mice (Peromyscus maniculatus) and prevalence of Sin Nombre virus (SNV) using long-term live trapping and habitat data from three live trapping grids and a short-term (three month), spatially replicated study across three slopes in Cascade County, Montana. In our long-term study, we found that deer mice were more abundant at a live-trapping grid with greater rock cover, than two grids with less rock cover. There was a non significant trend(P = 0.053) for deer mice to be more abundant in rocky sites in the short term study. In the long-term study, average SNV antibody prevalence among deer mice was slightly greater (5.0 vs. 3.5 % on average) at the live trapping grid with more rock cover, than the grid with less rock cover. We were unable to demonstrate differences in SNV antibody prevalence among treatments in the short-term study. Further studies are needed to elucidate the multiple determinants of deer mouse abundance and SNV prevalence in grassland ecosystem and other habitat types. PMID- 24817815 TI - Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome. AB - Depression, type 2 diabetes (T2D), and metabolic syndrome (MetS) are often comorbid. Depression per se increases the risk for T2D by 60%. This risk is not accounted for by the use of antidepressant therapy. Stress causes hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, by triggering the hypothalamic corticotropin-releasing hormone (CRH) secretion, which stimulates the anterior pituitary to release the adrenocorticotropin hormone (ACTH), which causes the adrenal secretion of cortisol. Depression is associated with an increased level of cortisol, and CRH and ACTH at inappropriately "normal" levels, that is too high compared to their expected lower levels due to cortisol negative feedback. T2D and MetS are also associated with hypercortisolism. High levels of cortisol can impair mood as well as cause hyperglycemia and insulin resistance and other traits typical of T2D and MetS. We hypothesize that HPA axis hyperactivation may be due to variants in the genes of the CRH receptors (CRHR1, CRHR2), corticotropin receptors (or melanocortin receptors, MC1R-MC5R), glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), and of the FK506 binding protein 51 (FKBP5), and that these variants may be partially responsible for the clinical association of depression, T2D and MetS. In this review, we will focus on the correlation of stress, HPA axis hyperactivation, and the possible genetic role of the CRHR1, CRHR2, MCR1-5, NR3C1, and NR3C2 receptors and FKBP5 in the susceptibility to the comorbidity of depression, T2D, and MetS. New studies are needed to confirm the hypothesized role of these genes in the clinical association of depression, T2D, and MetS. PMID- 24817816 TI - Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. AB - Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder characterized by the triad of eczema, thrombocytopenia, and severe and often recurrent infections. Despite the rarity of this disorder, our understanding of the molecular and cellular pathogenesis of WAS has continued to increase. Advances in the use of diagnostic tools, the provision of supportive care, and improvements in allogeneic hematopoietic stem cell transplantation have significantly reduced the morbidity and mortality associated with this disorder. Exciting advancements in the care of patients with WAS have also occurred, including the successful application of autologous gene-modified hematopoietic stem cell transplantation. PMID- 24817817 TI - Overview of the genetic determinants of primary aldosteronism. AB - Primary aldosteronism is the most common cause of secondary hypertension. The syndrome accounts for 10% of all cases of hypertension and is primarily caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma. Over the last few years, the use of exome sequencing has significantly improved our understanding of this syndrome. Somatic mutations in the KCNJ5, ATP1A1, ATP2B3 or CACNA1D genes are present in more than half of all cases of aldosterone-producing adenoma (~40%, ~6%, ~1% and ~8%, respectively). Germline gain-of-function mutations in KCNJ5 are now known to cause familial hyperaldosteronism type III, and an additional form of genetic hyperaldosteronism has been reported in patients with germline mutations in CACNA1D. These genes code for channels that control ion homeostasis across the plasma membrane of zona glomerulosa cells. Moreover, all these mutations modulate the same pathway, in which elevated intracellular calcium levels lead to aldosterone hyperproduction and (in some cases) adrenal cell proliferation. From a clinical standpoint, the discovery of these mutations has potential implications for patient management. The mutated channels could be targeted by drugs, in order to control hormonal and overgrowth-related manifestations. Furthermore, some of these mutations are associated with high cell turnover and may be amenable to diagnosis via the sequencing of cell-free (circulating) DNA. However, genotype-phenotype correlations in patients harboring these mutations have yet to be characterized. Despite this recent progress, much remains to be done to elucidate the yet unknown mechanisms underlying sporadic bilateral adrenal hyperplasia. PMID- 24817818 TI - Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients. AB - BACKGROUND: The aim of this study was to investigate the effect of two genetic polymorphisms in the coding regions (exon 3 and exon 4) of the EPHX1 gene, ie, 337T>C and 416A>G, respectively, on the metabolism of carbamazepine (CBZ) 10,11 epoxide (the active metabolite of CBZ) by evaluating the variation in serum CBZ 10,11-epoxide levels 4 hours after administration of the drug. Moreover, we reported the genotype frequencies of the CYP3A4*22 (rs 35599367, C>T) variant and its influence on the metabolism of CBZ. METHODS: The analysis was performed in 50 patients receiving CBZ as monotherapy. DNA was extracted from leukocytes using a commercially available kit. Serum CBZ 10,11-epoxide levels were measured by high performance liquid chromatography. Allelic discrimination was performed using polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis of the difference in mean values for CBZ 10,11-epoxide levels according to genotype was performed using the Student's t-test with Statistical Package for the Social Sciences version 13 software. RESULTS: Fourteen percent of the study group were CC, 42% were CT, and 44% were TT for the EPHX1 337T>C variant. No GG homozygote was identified for the EPHX1 416A>G variant; 64% were AA and 36% were AG. When we compared serum CBZ 10,11-epoxide levels 4 hours after drug administration, we found no statistically significant difference between the 337 CC, CT, and TT genotypes. Similarly, no difference in serum CBZ 10,11-epoxide levels was found between 416A>G AA and AG. Genotype frequencies for the CYP3A4*22 (rs 35599367 C>T) allelic variant were 94% for CC and 6% for CT, with no statistically significant difference in serum CBZ 10,11-epoxide levels between these genotypes 4 hours after administration of the drug (2.6+/-1.3 MUg/MUL and 2.5+/-1.2 MUg/MUL, respectively). CONCLUSION: Although there is some evidence of involvement of these polymorphisms in enzyme activity in vitro, we found no interference with CBZ metabolism in vivo. PMID- 24817819 TI - Perineural but not systemic low-dose dexamethasone prolongs the duration of interscalene block with ropivacaine: a prospective randomized trial. AB - PURPOSE: To determine the effects of intravenous and perineural dexamethasone on the duration of interscalene brachial plexus block (ISB) with ropivacaine in patients undergoing arthroscopic shoulder surgery. PATIENTS AND METHODS: In this prospective, randomized, placebo-controlled trial, patients presenting for arthroscopic shoulder surgery with an ISB were randomized to receive ropivacaine 0.75% (group C), ropivacaine 0.75% plus perineural dexamethasone 4 mg (group Dperi), or ropivacaine 0.75% plus intravenous dexamethasone 4 mg (group Div). The primary outcome was the duration of analgesia, defined as the time between performance of the block and the first request for analgesic. RESULTS: Thirty nine patients were randomized. The median times of sensory block in groups C, Dperi, and Div were 11.2 hours (interquartile range [IQR] 8.0-15.0 hours), 18.0 hours (IQR 14.5-19.0 hours), and 14.0 hours (IQR 12.7-15.1 hours), respectively. Significant differences were observed between groups Dperi and C (P=0.001). Kaplan-Meier analysis for the first analgesic request showed significant differences between groups Dperi and C (P=0.005) and between groups Dperi and Div (P=0.008), but not between groups C and Div. CONCLUSION: Perineural but not intravenous administration of 4 mg of dexamethasone significantly prolongs the duration of effective postoperative analgesia resulting from a single-shot ISB with ropivacaine 0.75%. PMID- 24817820 TI - Women's Awareness of Periconceptional Use of Folic Acid Before and After Their Antenatal Visits. AB - OBJECTIVE: The aim of this study is to assess women's awareness of the benefit and use of folic acid during pregnancy and to assess whether their knowledge has improved following hospital visits. METHOD: This is a prospective survey conducted in a large teaching hospital in the UK. The survey questionnaire consisted of 28 questions about demographic variables, behavioral variables, and knowledge about folic acid and neural tube defects (NTDs). RESULT: A total of 603 women participated in this study. Some of them attended for the first time and others had more than one visit, either in their current or previous pregnancies. In about 25% of cases, the pregnancy was not planned. Between 14 and 19% of the women of First and Two+ Visit groups consulted their doctor or other healthcare professional before conception. Nearly 98% of the women stated that they had heard of folic acid, but only 42-52% knew the medical condition it protects against. The main sources of information for women who were aware of folic acid were midwives and general practitioners. Nearly 90% of women who attended their first antenatal visit were taking folic acid. However, only 40% of women knew that they should take it before pregnancy, and only between 36 and 46% knew the dietary sources of folic acid, although about 84% know the foods that should be avoided during pregnancy. This study found that attending antenatal clinic has not increased women's awareness about folic acid. CONCLUSION: There is still a high proportion of women who do not know that folic acid should be taken before pregnancy and continued for the first three months of pregnancy. School education, primary care team, and family planning service should take the lead in providing information to women about folic acid. PMID- 24817821 TI - Reply to letter to the editor: "JC viremia and multiple sclerosis" by Focosi et al. PMID- 24817822 TI - Motivational Interviewing (MI) to Change Type 2DM Self Care Behaviors: A Nursing Intervention. AB - AIMS: This paper evaluates a novel nursing intervention designed to improve physical and psychological outcomes for adult patients with Type 2 DM. BACKGROUND: Self care behaviors are an important component of diabetes treatment, yet for many reasons, patients do not adhere to suggested plans. Motivational Interviewing (MI) is a patient centered strategy that helps overcome ambivalence to change. Nurses, who frequently educate patients with diabetes about self care, can use MI as a way to improve health behaviors. METHODS: As a component of a large RCT, focus groups were used to evaluate the impact of an MI nursing intervention. Nineteen patients (8% of treatment group) participated in four different groups. IPA was used to explore patient response to the intervention. RESULTS/FINDINGS: Patients were able to reflect on and identify responses to sessions with the study nurses that differed from "typical" health care provider visits. Many of their descriptions captured the essence of MI practice. CONCLUSION: MI is a viable and useful technique for nurses to use in educating and caring for persons with Type 2 DM. PMID- 24817823 TI - The joint graphical lasso for inverse covariance estimation across multiple classes. AB - We consider the problem of estimating multiple related Gaussian graphical models from a high-dimensional data set with observations belonging to distinct classes. We propose the joint graphical lasso, which borrows strength across the classes in order to estimate multiple graphical models that share certain characteristics, such as the locations or weights of nonzero edges. Our approach is based upon maximizing a penalized log likelihood. We employ generalized fused lasso or group lasso penalties, and implement a fast ADMM algorithm to solve the corresponding convex optimization problems. The performance of the proposed method is illustrated through simulated and real data examples. PMID- 24817824 TI - #nowplaying Madonna: a large-scale evaluation on estimating similarities between music artists and between movies from microblogs. AB - Different term weighting techniques such as [Formula: see text] or BM25 have been used intensely for manifold text-based information retrieval tasks. Their use for modeling term profiles for named entities and subsequent calculation of similarities between these named entities have been studied to a much smaller extent. The recent trend of microblogging made available massive amounts of information about almost every topic around the world. Therefore, microblogs represent a valuable source for text-based named entity modeling. In this paper, we present a systematic and comprehensive evaluation of different term weighting measures, normalization techniques, query schemes, index term sets, and similarity functions for the task of inferring similarities between named entities, based on data extracted from microblog posts. We analyze several thousand combinations of choices for the above mentioned dimensions, which influence the similarity calculation process, and we investigate in which way they impact the quality of the similarity estimates. Evaluation is performed using three real-world data sets: two collections of microblogs related to music artists and one related to movies. For the music collections, we present results of genre classification experiments using as benchmark genre information from allmusic.com. For the movie collection, we present results of multi-class classification experiments using as benchmark categories from IMDb. We show that microblogs can indeed be exploited to model named entity similarity with remarkable accuracy, provided the correct settings for the analyzed aspects are used. We further compare the results to those obtained when using Web pages as data source. PMID- 24817826 TI - One-pot Solvothermal Synthesis of Well-ordered Layered Sodium Aluminoalcoholate Complex: A Useful Precursor for the Preparation of Porous Al2O3 Particles. AB - One-pot solvothermal synthesis of a robust tetranuclear sodium hexakis(glycolato)tris(methanolato)aluminate complex Na3[Al4(OCH3)3(OCH2CH2O)6] via a modified yet rigorous base-catalyzed transesterification mechanism is presented here. Single crystal X-ray diffraction (SCXRD) studies indicate that this unique Al complex contains three penta-coordinate Al3+ ions, each bound to two bidentate ethylene glycolate chelators and one monodentate methanolate ligand. The remaining fourth Al3+ ion is octahedrally coordinated to one oxygen atom from each of the six surrounding glycolate chelators, effectively stitching the three penta-coordinate Al moieties together into a novel tetranuclear Al complex. This aluminate complex is periodically self-assembled into well-ordered layers normal to the [110] axis with the intra-/inter-layer bindings involving extensive ionic bonds from the three charge-counterbalancing Na+ cations rather than the more typical hydrogen bonding interactions as a result of the fewer free hydroxyl groups present in its structure. It can also serve as a valuable precursor toward the facile synthesis of high-surface-area alumina powders using a very efficient rapid pyrolysis technique. PMID- 24817825 TI - The Association of Tobacco Use and Gender to Cardiac Rehabilitation Outcomes: A Preliminary Investigation. AB - INTRODUCTION: Cardiac rehabilitation (CR) outcomes are measured in terms of cardiovascular disease (CVD) risk factor reductions, and these predict long-term cardiac status. This report examines whether reported tobacco use has differential effects on successful cardiovascular risk factor modification, especially for women who have greater smoking-related CVD consequences than men. METHODS: A retrospective cohort analysis was conducted on 1138 adults (74% male) with diagnosed CVD who participated in >=7 weeks of a comprehensive CR program. Eleven CVD risk factors were assessed at CR entry and completion. Tobacco use was assessed by self-report at CR entry. The primary outcomes were attainment of goal levels for each risk factor. RESULTS: Fewer current and former tobacco users reached the preset goal for Maximal Exercise Capacity. Fewer women than men reached the preset goal for HDL. Women who were current or former tobacco users were less likely to meet the target goals for Triglycerides and more likely to meet target goals for Total Cholesterol and Non-HDL Cholesterol. CONCLUSIONS: This preliminary study suggests the importance of identifying the effect of tobacco use and gender on CR outcomes and the need to evaluate modification of key cardiovascular risk factors for subgroups of cardiac patients. PMID- 24817827 TI - The use of VivaSightTM single lumen endotracheal tube in morbidly obese patients undergoing laparoscopic sleeve gastrectomy. AB - BACKGROUND: The population of obese patients is progressively growing and bariatric operations are becoming increasingly common. Morbidly obese patients require special anesthetic care and are often considered to be difficult to ventilate and intubate. The VivaSightTM Single Lumen tube is an endotracheal tube with a camera embedded in its tip. The view from the tip appears continuously on a monitor in the anesthesiologist's vicinity. The aim of this study was to assess the VivaSightTM in comparison with conventional endotracheal tube as an aid in the intubation and surveillance of tube position during surgery of obese patients. METHODS: This is a prospective study of 72 adult obese patients who underwent laparoscopic sleeve gastrectomy. The patients were randomly assigned to be intubated by either the VivaSightTM (40 patients, test group) or a conventional endotracheal tube (32 patients, control group). Data on the patients, the pre-operative airway evaluation, the endotracheal intubation and the post-operative outcome were collected and compared. RESULTS: The Mallampati scores were significantly higher in the test group than in the control group. Endotracheal intubation took 29 +/- 10 and 24 +/- 8 seconds using the VivaSightTM and a conventional tube respectively (p = 0.02). Three of the patients in the control group, while none of those in the test group, had soft tissue injury (p < 0.05). CONCLUSION: We found the VivaSightTM SL to be helpful in the endotracheal intubation and continuous surveillance of tube position in morbidly obese patients undergoing laparoscopic sleeve gastrectomy. PMID- 24817828 TI - Diagnostic testing managed by hematopathology specialty and other laboratories: costs and patient diagnostic outcomes. AB - BACKGROUND: Successful management of patients with hematologic malignancies depends upon accurate and timely diagnosis, which frequently requires integration and interpretation of multiple tests. Our retrospective analysis compared diagnostic uncertainty, resource utilization, and costs for patients with diagnostic bone marrow (BM) tests managed by commercial laboratories. METHODS: Patients with BM biopsies and suspected hematologic cancer/condition were identified from claims (2005-2011) within a large US health plan (coverage >=6 pre- and >=3-months post-biopsy). Cohorts defined by laboratories performing BM morphologic assessment/directing testing sequence: Genoptix (GX, specialty hematology-testing laboratory), large commercial laboratories (LL), other laboratories (OL). One-year post-biopsy changes in diagnosis or treatments, tests performed, and diagnostic/treatment medical costs (measured as per-patient-per month [PPPM]) were examined. RESULTS: The study population included 1,387 GX, 4,162 LL, and 19,115 OL patients with suspected hematologic malignancy/disease and BM morphology assessment. GX had lower diagnostic uncertainty measured between 2 time periods by diagnostic stability (no conditions the same; 6.16% GX, 8.04% LL, 9.73% OL; p < 0.001) and changes (>=1 condition different; 7.88% GX, 11.19% LL, and 14.08% OL; p < 0.001), fewer repeat BM biopsies, and fewer chemotherapy changes (30-days and 60-days post-initiation). One-year PPPM costs adjusted for patient characteristics differences were $8,202 GX, $7,711 LL, and $10,302 OL (p < 0.05); adjusted PPPM costs (excluding testing period) were $6,019 GX, $6,649 LL, and $7,801 OL (p < 0.05). CONCLUSIONS: Our data suggests that a hematopathology specialty laboratory may result in earlier final diagnosis, fewer subsequent diagnosis changes, reduced need for follow-on testing requiring repeat biopsy procedures, and may result in lower downstream healthcare costs. Further evaluations using medical chart abstractions or registries will be valuable. PMID- 24817829 TI - Applying Quantitative Approaches to the Formative Evaluation of Antismoking Campaign Messages. AB - This article shares an in-depth summary of a formative evaluation that used quantitative data to inform the development and selection of promotional ads for the antismoking communication component of a social marketing campaign. A foundational survey provided cross-sectional data to identify beliefs about quitting smoking that campaign messages should target, as well as beliefs to avoid. Pretesting draft ads against quantitative indicators of message effectiveness further facilitated the selection and rejection of final campaign ads. Finally, we consider lessons learned from the process of balancing quantitative methods and judgment to make formative decisions about more and less promising persuasive messages for campaigns. PMID- 24817830 TI - The Organization of Wariness of Heights in Experienced Crawlers. AB - Most infants with more than 6 weeks of crawling experience completely avoid the deep side of a visual cliff (Campos et al., 1992; Gibson & Walk, 1960). However, some experienced crawlers do move onto the transparent surface suspended several feet above the ground. An important question is whether these non-avoiders lack wariness of heights or whether they have a qualitatively different way of showing their wariness than do avoiders of the deep side. The current study addressed this question by measuring heart rate (HR) acceleration upon being lowered on the deep and shallow sides of the visual cliff, latency to crawl toward the mother, and tactile exploration of the cliff surface. Non-avoiders and avoiders had indistinguishable patterns of HR acceleration, showing greater HR acceleration when lowered onto the deep than when lowered onto the shallow side of the cliff. Non-avoiders also showed more tactile exploration and longer latencies than did a comparable group of infants tested on the shallow side. This study illustrates how the same emotion, wariness of heights, can be shown by qualitatively different behaviors, all serving the same function of protecting the individual from falling over a drop-off. PMID- 24817831 TI - A simple epidemiological model for populations in the wild with Allee effects and disease-modified fitness. AB - The study of the dynamics of human infectious disease using deterministic models is typically carried out under the assumption that a critical mass of individuals is available and involved in the transmission process. However, in the study of animal disease dynamics where demographic considerations often play a significant role, this assumption must be weakened. Models of the dynamics of animal populations often naturally assume that the presence of a minimal number of individuals is essential to avoid extinction. In the ecological literature, this a priori requirement is commonly incorporated as an Allee effect. The focus here is on the study disease dynamics under the assumption that a critical mass of susceptible individuals is required to guarantee the population's survival. Specifically, the emphasis is on the study of the role of an Allee effect on a Susceptible-Infectious (SI) model where the possibility that susceptible and infected individuals reproduce, with the S-class the best fit. It is further assumed that infected individuals loose some of their ability to compete for resources, the cost imposed by the disease. These features are set in motion in as simple model as possible. They turn out to lead to a rich set of dynamical outcomes. This toy model supports the possibility of multi-stability (hysteresis), saddle node and Hopf bifurcations, and catastrophic events (disease induced extinction). The analyses provide a full picture of the system under disease-free dynamics including disease-induced extinction and proceed to identify required conditions for disease persistence. We conclude that increases in (i) the maximum birth rate of a species, or (ii) in the relative reproductive ability of infected individuals, or (iii) in the competitive ability of a infected individuals at low density levels, or in (iv) the per-capita death rate (including disease-induced) of infected individuals, can stabilize the system (resulting in disease persistence). We further conclude that increases in (a) the Allee effect threshold, or (b) in disease transmission rates, or in (c) the competitive ability of infected individuals at high density levels, can destabilize the system, possibly leading to the eventual collapse of the population. The results obtained from the analyses of this toy model highlight the significant role that factors like an Allee effect may play on the survival and persistence of animal populations. Scientists involved in biological conservation and pest management or interested in finding sustainability solutions, may find these results of this study compelling enough to suggest additional focused research on the role of disease in the regulation and persistence of animal populations. The risk faced by endangered species may turn out to be a lot higher than initially thought. PMID- 24817833 TI - Researching and Respecting the Intricacies of Isolated Communities. AB - PURPOSE: Conducting research in a rural area can be challenging for nurses for a variety of different reasons. The task at hand can be especially difficult when it involves discussing a sensitive topic, such as Human Papillomavirus (HPV) vaccination. This study was conducted to describe parental perceptions of the HPV vaccine in rural areas, while simultaneously describing a method for engaging in successful nursing research in rural areas. METHODS: A team of nurse researchers completed a planned process to first understand rural culture in southeastern Georgia, and then more specifically, the families living in these three separate counties. This process initially involved developing a connection and working relationship with key community leaders, such as school principals. Following this, researchers worked on establishing rapport and trust with local parents and research participants themselves. Qualitative methods were then used to collect focus group and interview data on parental views of HPV, HPV vaccination, and HPV related cancers. FINDINGS: Results indicated that parents had little knowledge of the HPV vaccine in rural Georgia, including misconceptions that the vaccine is for females only. In addition, many parents continually voiced the concern that the HPV vaccine would promote promiscuity in their children. CONCLUSIONS: Providing consistent, timely, and open communication with the community members was crucial throughout the entire research process. This focused approach with respect to total community, culture, and religious value is essential in conducting research. Future studies conducted in rural areas should focus on specific intervention points that improve Parental HPV knowledge. PMID- 24817832 TI - Increasing Outreach, Connection, and Services to Low-Income Non-Custodial Fathers: How Did We Get Here and What Do We Know. AB - This paper documents a model for outreaching, connecting, and serving low-income, ethnically diverse, non-custodial fathers. Men are engaged "where they are" by building their strengths and addressing their needs. The Male Involvement Network's (MIN) collaborative model was created in Connecticut to help fathers become positive and healthy role models by increasing their attachment to their children and families (Smith, 2003). This clinically informed, case management model addresses their physical, emotional, mental, economic and spiritual health needs. Through a relational approach and social modeling it includes skill development in education, economic stability, family/child support, and mental and physical health. Implications for testing this approach are suggested. PMID- 24817834 TI - Breast Cancer and DNA Repair Capacity: Association With Use of Multivitamin and Calcium Supplements. AB - CONTEXT: Breast cancer (BC) is the most common cancer in women, with over 1 million new cases diagnosed every year worldwide. Over recent decades, considerable interest has emerged regarding whether vitamins and/or other supplements can lower the risk of BC. However, previous epidemiologic studies that investigated the association between intake of multivitamin and supplements of single vitamins and minerals and BC risk have reported conflicting results. Whether vitamins can actually reduce BC risk is still controversial. OBJECTIVE: This study examined whether multivitamin and calcium use was associated with BC incidence and DNA repair capacity (DRC). DESIGN: The research team designed an observational, case-control study. SETTING: All work was performed at the Ponce School of Medicine and Health Sciences under the direct supervision of principal investigator Dr Jaime Matta. PARTICIPANTS: Participants were 836 women recruited primarily from the private practices of oncologists, gynecologists, and surgeons in Puerto Rico. INTERVENTIONS: A total of 312 individuals in the breast cancer (BC) group and 524 individuals in the control group were compared for their multivitamin and calcium intake, DRC levels, and other covariates. OUTCOME MEASURES: Odds ratios (OR), adjusted using both crude analysis and multiple logistic regression, were used as measures of association between BC and DRC and other selected variables. RESULTS: The BC group had 30% reduced odds of taking multivitamins and calcium as compared to controls: (1) OR = 0.7 (95% CI, 0.4-1.0; P = .073) for multivitamins and (2) OR = 0.7 (95% CI, 0.4-1.2; P = .167) for calcium. Women with low DRC had 50% lower odds of taking calcium and 30% lower odds of currently taking vitamins OR = 0.5 (95% CI, 0.4-0.7; P = .001) for calcium and (2) OR = 0.7 (95% CI, 0.5-0.9.1; P = .047) for vitamins. CONCLUSIONS: Although this study is a case-control study in which the risk of BC could not be assessed, results suggest that vitamin supplementation could be an independent protective factor for BC. Calcium intake appears to affect DRC in a positive way, because it was associated with a high DRC level, which in turn is associated with low odds for BC. PMID- 24817835 TI - Access to HIV Care and Support Services for African American Transwomen Living with HIV. AB - Low access to HIV care and support has led to survival rates for transwomen that are half that of other populations at risk for HIV. Within the population, HIV disproportionately impacts African American transwomen. Interventions to increase access to HIV care and support are needed to better serve those most affected and vulnerable within the population. We conducted a study of barriers and facilitators to care and support services for African American transwomen to fill a gap in the literature to improve access for this particularly impacted population. A total of 10 in-depth interviews were conducted with African American transwomen living with HIV who lived outside the metro area of San Francisco. Three overarching thematic topics emerged-gender stigma, peer, and institutional distrust - giving insight into African American transwomen's barriers to HIV care and support services. A number of factors within these themes impacted access, such as whether organizations offered gender-related care, the geography of organizations as it relates to safe transportation and location, confidentiality and trust of peers and organizations, and trauma. Specific instrumental, institutional and emotional supports are provided that that may increase access to care and support services for African American transwomen living with HIV. PMID- 24817836 TI - Syntheses, Characterization, Thermal, and Antimicrobial Studies of Lanthanum(III) Tolyl/Benzyldithiocarbonates. AB - Lanthanum(III) tris(O-tolyl/benzyldithiocarbonates), [La(ROCS2)] (R = o-, m-, p CH3C6H4 and C6H5CH2), were isolated as yellow solid by the reaction of LaCl3 .7H2O with sodium salt of tolyl/benzyldithiocarbonates, ROCS2Na (R = o-, m-, p CH3C6H4 and C6H5CH2), in methanol under anhydrous conditions in 1 : 3 molar ratio. These complexes have formed adducts with nitrogen and phosphorus donor molecules by straightforward reaction of these complexes with donor ligands, which have the composition of the type [La(ROCS2)3 .nL] (where n = 2, L = NC5H5 or P(C6H5)3 and n = 1, L = N2C12H8 or N2C10H8). Elemental analyses, mass, IR, TGA, and heteronuclear NMR ((1)H, (13)C and (31)P) spectroscopic studies indicated bidentate mode of bonding by dithiocarbonate ligands leading to hexacoordinated and octacoordinated geometry around the lanthanum atom. Antimicrobial (antifungal and antibacterial) activity of the free ligands and some of the complexes have also been investigated which exhibited significantly more activity for the complexes than the free ligands. PMID- 24817837 TI - Inverted bulk-heterojunction solar cell with cross-linked hole-blocking layer. AB - We have developed a hole-blocking layer for bulk-heterojunction solar cells based on cross-linked polyethylenimine (PEI). We tested five different ether-based cross-linkers and found that all of them give comparable solar cell efficiencies. The initial idea that a cross-linked layer is more solvent resistant compared to a pristine PEI layer could not be confirmed. With and without cross-linking, the PEI layer sticks very well to the surface of the indium-tin-oxide electrode and cannot be removed by solvents used to process PEI or common organic semiconductors. The cross-linked PEI hole-blocking layer functions for multiple donor-acceptor blends. We found that using cross-linkers improves the reproducibility of the device fabrication process. PMID- 24817838 TI - Mapping the distribution of the main host for plague in a complex landscape in Kazakhstan: An object-based approach using SPOT-5 XS, Landsat 7 ETM+, SRTM and multiple Random Forests. AB - Plague is a zoonotic infectious disease present in great gerbil populations in Kazakhstan. Infectious disease dynamics are influenced by the spatial distribution of the carriers (hosts) of the disease. The great gerbil, the main host in our study area, lives in burrows, which can be recognized on high resolution satellite imagery. In this study, using earth observation data at various spatial scales, we map the spatial distribution of burrows in a semi desert landscape. The study area consists of various landscape types. To evaluate whether identification of burrows by classification is possible in these landscape types, the study area was subdivided into eight landscape units, on the basis of Landsat 7 ETM+ derived Tasselled Cap Greenness and Brightness, and SRTM derived standard deviation in elevation. In the field, 904 burrows were mapped. Using two segmented 2.5 m resolution SPOT-5 XS satellite scenes, reference object sets were created. Random Forests were built for both SPOT scenes and used to classify the images. Additionally, a stratified classification was carried out, by building separate Random Forests per landscape unit. Burrows were successfully classified in all landscape units. In the 'steppe on floodplain' areas, classification worked best: producer's and user's accuracy in those areas reached 88% and 100%, respectively. In the 'floodplain' areas with a more heterogeneous vegetation cover, classification worked least well; there, accuracies were 86 and 58% respectively. Stratified classification improved the results in all landscape units where comparison was possible (four), increasing kappa coefficients by 13, 10, 9 and 1%, respectively. In this study, an innovative stratification method using high- and medium resolution imagery was applied in order to map host distribution on a large spatial scale. The burrow maps we developed will help to detect changes in the distribution of great gerbil populations and, moreover, serve as a unique empirical data set which can be used as input for epidemiological plague models. This is an important step in understanding the dynamics of plague. PMID- 24817839 TI - Efficient uranium immobilization on red clay with phosphates. AB - Uranium is a very toxic and radioactive element. Removal of uranium from wastewaters requires remediation technologies. Actual methods are costly and ineffective when uranium concentration is very low. Little is known about the enhancement of sorption of uranyl ions by phosphate ions on aluminosilicates. Here, we studied sorption of uranyl acetate on red clay in the presence of phosphates. The concentration of U(VI) ranged 0.0001-0.001 mol/L, whereas the concentration of PO43- was constant at 0.0001 mol/L. We designed a new method for the analysis of ternary surface complexes. We observed for the first time a remarkable improvement of U(VI) sorption on red clay under the influence of phosphates. We also found that at least two different ternary surface complexes U(VI)-phosphate-clay are formed in the sorbent phase. The complexation of UO22+ cations by phosphate ligands in the sorbent phase was confirmed by the X-ray photoelectron spectra of U 4f electrons. PMID- 24817840 TI - Gender-typical olfactory regulation of sexual behavior in goldfish. AB - It is known that olfaction is essential for the occurrence of sexual behavior in male goldfish. Sex pheromones from ovulatory females elicit male sexual behavior, chasing, and sperm releasing act. In female goldfish, ovarian prostaglandin F2alpha (PGF) elicits female sexual behavior, egg releasing act. It has been considered that olfaction does not affect sexual behavior in female goldfish. In the present study, we re-examined the involvement of olfaction in sexual behavior of female goldfish. Olfaction was blocked in male and female goldfish by two methods: nasal occlusion (NO) which blocks the reception of olfactants, and olfactory tract section (OTX) which blocks transmission of olfactory information from the olfactory bulb to the telencephalon. Sexual behavior of goldfish was induced by administration of PGF to females, an established method for inducing goldfish sexual behavior in both sexes. Sexual behavior in males was suppressed by NO and OTX as previously reported because of lack of pheromone stimulation. In females, NO suppressed sexual behavior but OTX did not affect the occurrence of sexual behavior. Females treated with both NO and OTX performed sexual behavior normally. These results indicate that olfaction is essential in female goldfish to perform sexual behavior as in males but in a different manner. The lack of olfaction in males causes lack of pheromonal stimulation, resulting in no behavior elicited. Whereas the results of female experiments suggest that lack of olfaction in females causes strong inhibition of sexual behavior mediated by the olfactory pathway. Olfactory tract section is considered to block the pathway and remove this inhibition, resulting in the resumption of the behavior. By subtract sectioning of the olfactory tract, it was found that this inhibition was mediated by the medial olfactory tracts, not the lateral olfactory tracts. Thus, it is concluded that goldfish has gender-typical olfactory regulation for sexual behavior. PMID- 24817841 TI - Histamine: a new immunomodulatory player in the neuron-glia crosstalk. AB - Histamine is an amine acting as a major peripheral inflammatory mediator. In the brain, histamine was initially viewed as a neurotransmitter, but new evidences support its involvement in the modulation of innate immune responses. Recently, we showed that histamine modulates microglial migration and cytokine release. Its pleiotropic actions, ranging from neurotransmission to inflammation, highlight histamine as a key player in a vast array of brain physiologic activities and also in the pathogenesis of several neurodegenerative diseases. Herein, we emphasize the role of histamine as a modulator of brain immune reactions, either by acting on invading peripheral immune cells and/or on resident microglial cells. We also unveil the putative involvement of histamine in the microglial neuronal communication. We first show that histamine modulates the release of inflammatory mediators, namely nitric oxide, by microglia cells. Consequently, the microglia secretome released upon histamine stimulation fosters dopaminergic neuronal death. These data may reveal important new pharmacological applications on the use histamine and antihistamines, particularly in the context of Parkinson's disease. PMID- 24817842 TI - Synchrony can destabilize reward-sensitive networks. AB - When exposed to rewarding stimuli, only some animals develop persistent craving. Others are resilient and do not. How the activity of neural populations relates to the development of persistent craving behavior is not fully understood. Previous computational studies suggest that synchrony helps a network embed certain patterns of activity, although the role of synchrony in reward-dependent learning has been less studied. Increased synchrony has been reported as a marker for both susceptibility and resilience to developing persistent craving. Here we use computational simulations to study the effect of reward salience on the ability of synchronous input to embed a new pattern of activity into a neural population. Our main finding is that weak stimulus-reward correlations can facilitate the short-term repetition of a pattern of neural activity, while blocking long-term embedding of that pattern. Interestingly, synchrony did not have this dual effect on all patterns, which suggests that synchrony is more effective at embedding some patterns of activity than others. Our results demonstrate that synchrony can have opposing effects in networks sensitive to the correlation structure of their inputs, in this case the correlation between stimulus and reward. This work contributes to an understanding of the interplay between synchrony and reward-dependent plasticity. PMID- 24817843 TI - Enhancement for well-being is still ethically challenging. PMID- 24817844 TI - Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. AB - Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB support neuronal survival during development and promote connectivity and plasticity in the adult brain. Decreased BDNF signaling is associated with the pathophysiology of depression and the mechanisms underlying the actions of antidepressant drugs (AD). Several transgenic mouse models with decreases or increases in the amount of BDNF or the activity of TrkB signaling have been created. This review summarizes the studies where various mouse models with increased or decreased BDNF levels or TrkB signaling were used to evaluate the role of BDNF signaling in depression-like behavior. Although a large number of models have been employed and several studies have been published, no clear-cut connections between BDNF levels or signaling and depression-like behavior in mice have emerged. However, it is clear that BDNF plays a critical role in the mechanisms underlying the actions of AD. PMID- 24817845 TI - Contrasting losses and gains increases the predictability of behavior by frontal EEG asymmetry. AB - Frontal asymmetry measured at rest using EEG is considered a stable marker of approach-avoidance behaviors and risk taking. We examined whether without salient cues of attention in the form of losses, predictability is reduced. Fifty-seven participants performed an experiential decision task in a gain-only, loss-only, and mixed (gains and losses) condition. Increased risk taking on the part of individuals with relatively high left frontal activation, as denoted by the Alpha band, was only observed in the task involving both gains and losses. Event related potential analysis sheds light on the processes leading to this pattern. Left-frontal dominant individuals had increased fronto-central P300 activation following risky compared to safe outcomes, while right-frontal dominant individuals did not show a P300 difference following safe and risky outcomes. This interaction also only emerged when losses were contrasted with gains. The findings highlight the sensitivity of behavioral predictability to cues of valence. PMID- 24817846 TI - Creative brains: designing in the real world. AB - The process of designing artifacts is a creative activity. It is proposed that, at the cognitive level, one key to understanding design creativity is to understand the array of symbol systems designers utilize. These symbol systems range from being vague, imprecise, abstract, ambiguous, and indeterminate (like conceptual sketches), to being very precise, concrete, unambiguous, and determinate (like contract documents). The former types of symbol systems support associative processes that facilitate lateral (or divergent) transformations that broaden the problem space, while the latter types of symbol systems support inference processes facilitating vertical (or convergent) transformations that deepen of the problem space. The process of artifact design requires the judicious application of both lateral and vertical transformations. This leads to a dual mechanism model of design problem-solving comprising of an associative engine and an inference engine. It is further claimed that this dual mechanism model is supported by an interesting hemispheric dissociation in human prefrontal cortex. The associative engine and neural structures that support imprecise, ambiguous, abstract, indeterminate representations are lateralized in the right prefrontal cortex, while the inference engine and neural structures that support precise, unambiguous, determinant representations are lateralized in the left prefrontal cortex. At the brain level, successful design of artifacts requires a delicate balance between the two hemispheres of prefrontal cortex. PMID- 24817848 TI - Clarifying the interaction types in two-person neuroscience research. PMID- 24817847 TI - Temporal dysfunction in traumatic brain injury patients: primary or secondary impairment? AB - Adequate temporal abilities are required for most daily activities. Traumatic brain injury (TBI) patients often present with cognitive dysfunctions, but few studies have investigated temporal impairments associated with TBI. The aim of the present work is to review the existing literature on temporal abilities in TBI patients. Particular attention is given to the involvement of higher cognitive processes in temporal processing in order to determine if any temporal dysfunction observed in TBI patients is due to the disruption of an internal clock or to the dysfunction of general cognitive processes. The results showed that temporal dysfunctions in TBI patients are related to the deficits in cognitive functions involved in temporal processing rather than to a specific impairment of the internal clock. In fact, temporal dysfunctions are observed when the length of temporal intervals exceeds the working memory span or when the temporal tasks require high cognitive functions to be performed. The consistent higher temporal variability observed in TBI patients is a sign of impaired frontally mediated cognitive functions involved in time perception. PMID- 24817849 TI - The Insight ToolKit image registration framework. AB - Publicly available scientific resources help establish evaluation standards, provide a platform for teaching and improve reproducibility. Version 4 of the Insight ToolKit (ITK(4)) seeks to establish new standards in publicly available image registration methodology. ITK(4) makes several advances in comparison to previous versions of ITK. ITK(4) supports both multivariate images and objective functions; it also unifies high-dimensional (deformation field) and low dimensional (affine) transformations with metrics that are reusable across transform types and with composite transforms that allow arbitrary series of geometric mappings to be chained together seamlessly. Metrics and optimizers take advantage of multi-core resources, when available. Furthermore, ITK(4) reduces the parameter optimization burden via principled heuristics that automatically set scaling across disparate parameter types (rotations vs. translations). A related approach also constrains steps sizes for gradient-based optimizers. The result is that tuning for different metrics and/or image pairs is rarely necessary allowing the researcher to more easily focus on design/comparison of registration strategies. In total, the ITK(4) contribution is intended as a structure to support reproducible research practices, will provide a more extensive foundation against which to evaluate new work in image registration and also enable application level programmers a broad suite of tools on which to build. Finally, we contextualize this work with a reference registration evaluation study with application to pediatric brain labeling. PMID- 24817850 TI - Structure-centered portal for child psychiatry research. AB - The real world needs of the clinical community require a domain-specific solution to integrate disparate information available from various web-based resources for data, materials, and tools into routine clinical and clinical research setting. We present a child-psychiatry oriented portal as an effort to deliver a knowledge environment wrapper that provides organization and integration of multiple information and data sources. Organized semantically by resource context, the portal groups information sources by context type, and permits the user to interactively "narrow" or "broaden" the scope of the information resources that are available and relevant to the specific context. The overall objective of the portal is to bring information from multiple complex resources into a simple single uniform framework and present it to the user in a single window format. PMID- 24817851 TI - Safety of liposome extended-release bupivacaine for postoperative pain control. AB - BACKGROUND: Ideal postoperative pain management requires a multidisciplinary approach in combination with a variety of dosage regimens. Approximately 21-30% of patients experience moderate to severe pain in the postoperative period, which may have a significant impact on recovery rate, standard of living, psychological health, and postoperative complications. OBJECTIVE: Analysis of the incidence and characterization of reported adverse effects with DepoFoam bupivacaine compared to conventional bupivacaine or placebo. METHODS: A systematic review of prospective studies on the use of DepoFoam versus bupivacaine or placebo was performed in order to answer the clinically relevant question: is DepoFoam a safer formulation in place of bupivacaine single injection or continuous local infusion techniques for postoperative pain management? Inclusion criteria required randomized, controlled, double-blind trials in patients 18 years old or older, single dose used for postoperative pain control, and a primary procedure performed. RESULTS: Six studies fitted the inclusion criteria for analysis, DepoFoam bupivacaine used in therapeutic doses was well-tolerated, had a higher safety margin, and showed a favorable safety profile compared to bupivacaine and control groups. CONCLUSION: Extended drug delivery system DepoFoam bupivacaine is a promising drug formulation that may significantly improve postoperative care and pain control in surgical patients. PMID- 24817853 TI - From the heart to the mind: cardiac vagal tone modulates top-down and bottom-up visual perception and attention to emotional stimuli. AB - The neurovisceral integration model (Thayer and Lane, 2000) posits that cardiac vagal tone, indexed by heart rate variability (HRV), can indicate the functional integrity of the neural networks implicated in emotion-cognition interactions. Our recent findings begin to disentangle how HRV is associated with both top-down and bottom-up cognitive processing of emotional stimuli. Higher resting HRV is associated with more adaptive and functional top-down and bottom-up cognitive modulation of emotional stimuli, which may facilitate effective emotion regulation. Conversely, lower resting HRV is associated with hyper-vigilant and maladaptive cognitive responses to emotional stimuli, which may impede emotion regulation. In the present paper, we recapitulate the neurovisceral integration model and review recent findings that shed light on the relationship between HRV and top-down and bottom-up visual perception and attention to emotional stimuli, which may play an important role in emotion regulation. Further implications of HRV on individual well-being and mental health are discussed. PMID- 24817854 TI - Observer efficiency in free-localization tasks with correlated noise. AB - The efficiency of visual tasks involving localization has traditionally been evaluated using forced choice experiments that capitalize on independence across locations to simplify the performance of the ideal observer. However, developments in ideal observer analysis have shown how an ideal observer can be defined for free-localization tasks, where a target can appear anywhere in a defined search region and subjects respond by localizing the target. Since these tasks are representative of many real-world search tasks, it is of interest to evaluate the efficiency of observer performance in them. The central question of this work is whether humans are able to effectively use the information in a free localization task relative to a similar task where target location is fixed. We use a yes-no detection task at a cued location as the reference for this comparison. Each of the tasks is evaluated using a Gaussian target profile embedded in four different Gaussian noise backgrounds having power-law noise power spectra with exponents ranging from 0 to 3. The free localization task had a square 6.7 degrees search region. We report on two follow-up studies investigating efficiency in a detect-and-localize task, and the effect of processing the white-noise backgrounds. In the fixed-location detection task, we find average observer efficiency ranges from 35 to 59% for the different noise backgrounds. Observer efficiency improves dramatically in the tasks involving localization, ranging from 63 to 82% in the forced localization tasks and from 78 to 92% in the detect-and- localize tasks. Performance in white noise, the lowest efficiency condition, was improved by filtering to give them a power-law exponent of 2. Classification images, used to examine spatial frequency weights for the tasks, show better tuning to ideal weights in the free-localization tasks. The high absolute levels of efficiency suggest that observers are well-adapted to free-localization tasks. PMID- 24817855 TI - Patterns of empathy as embodied practice in clinical conversation-a musical dimension. AB - Cognitive linguistics and conversation analysis (a) converge in the analysis of category bound activities and (b) in viewing thinking and talking as embodied activities. The first aim of this paper is to outline these powerful theories as useful tools for the analysis of enacting empathy. The second aim is to outline these theories as useful tools for the analysis of how empathy is co-enacted in clinical conversation documented in transcripts. Cognitive Linguistics and Conversation Analysis converge in detecting patterns of I-You-relationships with roots in early preverbal embodied protoconversation continuing to more symbolic conversational level. The paper proposes to describe this continuity of empathic conversation in musical metaphors like balance, rhythm and resonance. In a first section transcripts from therapeutic sessions are presented. In a second section linguistic and other research data are presented in order to bring empirical data to this new conception of how empathy can be understood, how it is done and how two participants cooperate to enact empathy. Ideas for further research are outlined. PMID- 24817856 TI - The interaction between stimulus factors and cognitive factors during multisensory integration of audiovisual speech. PMID- 24817852 TI - Gene regulation, alternative splicing, and posttranslational modification of troponin subunits in cardiac development and adaptation: a focused review. AB - Troponin plays a central role in regulating the contraction and relaxation of vertebrate striated muscles. This review focuses on the isoform gene regulation, alternative RNA splicing, and posttranslational modifications of troponin subunits in cardiac development and adaptation. Transcriptional and posttranscriptional regulations such as phosphorylation and proteolysis modifications, and structure-function relationships of troponin subunit proteins are summarized. The physiological and pathophysiological significances are discussed for impacts on cardiac muscle contractility, heart function, and adaptations in health and diseases. PMID- 24817857 TI - Opponent left-handedness does not affect fight outcomes for Ultimate Fighting Championship hall of famers. PMID- 24817858 TI - Inhibitory processes in toddlers: a latent-variable approach. AB - The aim of this study was to investigate the nature of inhibitory processes in early childhood. A confirmatory factor analysis was used to examine the latent structure of inhibitory processes in day-care center children aged 24-32 months and in preschool children aged 36-48 months. The best fit to the data for the younger sample was a single undifferentiated inhibition factor model; in older children, a two-factor model was differently identified in which response inhibition and interference suppression were distinguished. PMID- 24817860 TI - Picturing perspectives: development of perspective-taking abilities in 4- to 8 year-olds. AB - Although the development of perspective taking has been well researched, there is no uniform methodology for assessing this ability across a wide age span when frames of reference conflict. To address this gap, we created scenes of toy photographers taking pictures of layouts of objects from different angles, and presented them to 4- to 8-year-olds (N = 80). Children were asked to choose which one of four pictures could have been taken from a specific viewpoint. Results showed that this new technique confirmed the classic pattern of developmental progress on this kind of spatial skill: (1) 4-year-olds responded near chance level, regardless of layout complexity, (2) there was a growing ability to inhibit egocentric choices around age 6 with layouts of low complexity (one object), (3) performance increased and egocentric responses decreased dramatically around age 7, (4) even at age 8, children still showed considerable individual variability. This perspective taking task can thus be used to address important questions about the supports for early spatial development and the structure of early intellect. PMID- 24817859 TI - Reactive control processes contributing to residual switch cost and mixing cost across the adult lifespan. AB - In task-switching paradigms, performance is better when repeating the same task than when alternating between tasks (switch cost) and when repeating a task alone rather than intermixed with another task (mixing cost). These costs remain even after extensive practice and when task cues enable advanced preparation (residual costs). Moreover, residual reaction time mixing cost has been consistently shown to increase with age. Residual switch and mixing costs modulate the amplitude of the stimulus-locked P3b. This mixing effect is disproportionately larger in older adults who also prepare more for and respond more cautiously on these "mixed" repeat trials (Karayanidis et al., 2011). In this paper, we analyze stimulus locked and response-locked P3 and lateralized readiness potentials to identify whether residual switch and mixing cost arise from the need to control interference at the level of stimulus processing or response processing. Residual mixing cost was associated with control of stimulus-level interference, whereas residual switch cost was also associated with a delay in response selection. In older adults, the disproportionate increase in mixing cost was associated with greater interference at the level of decision-response mapping and response programming for repeat trials in mixed-task blocks. These findings suggest that older adults strategically recruit greater proactive and reactive control to overcome increased susceptibility to post-stimulus interference. This interpretation is consistent with recruitment of compensatory strategies to compensate for reduced repetition benefit rather than an overall decline on cognitive flexibility. PMID- 24817861 TI - Interrelationships between negative mood and clinical constructs: a motivational systems approach. AB - A series of three experiments was designed to test predictions from a motivational systems approach to understanding the role of clinical constructs in anxiety-based problems. Negative mood, inflated responsibility, and intolerance of uncertainty (IU) were separately manipulated within analog samples to examine their effect on the other two factors. In the first experiment (n = 59) the negative mood group scored significantly higher in terms of inflated responsibility than the positive mood group. In the second experiment (n = 63) the high responsibility group scored significantly higher in terms of both negative mood and IU than the low responsibility group. In the third experiment (n = 61) the high IU group scored significantly higher in terms of negative mood than the low IU group. Tests of indirect effects revealed an indirect effect of IU on inflated responsibility through negative mood and an indirect effect of negative mood on IU through inflated responsibility, suggesting all three constructs are causally interrelated. The findings are consistent with contemporary transdiagnostic views of clinical constructs, and support a view of anxiety that is underpinned by a coordinated and interdependent motivational system evolved to manage threat. PMID- 24817862 TI - KIR4.1 Antibodies as Biomarkers in Multiple Sclerosis. PMID- 24817863 TI - Brain tissue oxygenation and cerebral metabolic patterns in focal and diffuse traumatic brain injury. AB - INTRODUCTION: Neurointensive care of traumatic brain injury (TBI) patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted protocols. There are reasons to believe that knowledge of brain tissue oxygenation (BtipO2) would add information with the potential of improving patient outcome. The aim of this study was to examine BtipO2 and cerebral metabolism using the Neurovent-PTO probe and cerebral microdialysis (MD) in TBI patients. METHODS: Twenty-three severe TBI patients with monitoring of physiological parameters, ICP, CPP, BtipO2, and MD for biomarkers of energy metabolism (glucose, lactate, and pyruvate) and cellular distress (glutamate, glycerol) were included. Patients were grouped according to injury type (focal/diffuse) and placement of the Neurovent-PTO probe and MD catheter (injured/non-injured hemisphere). RESULTS: We observed different patterns in BtipO2 and MD biomarkers in diffuse and focal injury where placement of the probe also influenced the results (ipsilateral/contralateral). In all groups, despite fairly normal levels of ICP and CPP, increased MD levels of glutamate, glycerol, or the L/P ratio were observed at BtipO2 <5 mmHg, indicating increased vulnerability of the brain at this level. CONCLUSION: Monitoring of BtipO2 adds important information in addition to traditional ICP and CPP surveillance. Because of the different metabolic responses to very low BtipO2 in the individual patient groups we submit that brain tissue oximetry is a complementary tool rather than an alternative to MD monitoring. PMID- 24817864 TI - Bacteriophages of leuconostoc, oenococcus, and weissella. AB - Leuconostoc (Ln.), Weissella, and Oenococcus form a group of related genera of lactic acid bacteria, which once all shared the name Leuconostoc. They are associated with plants, fermented vegetable products, raw milk, dairy products, meat, and fish. Most of industrially relevant Leuconostoc strains can be classified as either Ln. mesenteroides or Ln. pseudomesenteroides. They are important flavor producers in dairy fermentations and they initiate nearly all vegetable fermentations. Therefore, bacteriophages attacking Leuconostoc strains may negatively influence the production process. Bacteriophages attacking Leuconostoc strains were first reported in 1946. Since then, the majority of described Leuconostoc phages was isolated from either dairy products or fermented vegetable products. Both lytic and temperate phages of Leuconostoc were reported. Most of Leuconostoc phages examined using electron microscopy belong to the Siphoviridae family and differ in morphological details. Hybridization and comparative genomic studies of Leuconostoc phages suggest that they can be divided into several groups, however overall diversity of Leuconostoc phages is much lower as compared to, e.g., lactococcal phages. Several fully sequenced genomes of Leuconostoc phages have been deposited in public databases. Lytic phages of Leuconostoc can be divided into two host species-specific groups with similarly organized genomes that shared very low nucleotide similarity. Phages of dairy Leuconostoc have rather limited host-ranges. The receptor binding proteins of two lytic Ln. pseudomesenteroides phages have been identified. Molecular tools for detection of dairy Leuconostoc phages have been developed. The rather limited data on phages of Oenococcus and Weissella show that (i) lysogeny seems to be abundant in Oenococcus strains, and (ii) several phages infecting Weissella cibaria are also able to productively infect strains of other Weissella species and even strains of the genus Lactobacillus. PMID- 24817865 TI - Safeguard against DNA sensing: the role of TREX1 in HIV-1 infection and autoimmune diseases. AB - Innate immune recognition is crucial for host responses against viral infections, including infection by human immunodeficiency virus 1 (HIV-1). Human cells detect such invading pathogens with a collection of pattern recognition receptors that activate the production of antiviral proteins, such as the cytokine interferon type I, to initiate antiviral responses immediately as well as the adaptive immune response for long-term protection. To establish infection in the host, many viruses have thus evolved strategies for subversion of these mechanisms of innate immunity. For example, acute infection by HIV-1 and other retroviruses have long been thought to be non-immunogenic, signifying suppression of host defenses by these pathogens. Studies in the past few years have begun to uncover a multifaceted scheme of how HIV-1 evades innate immune detection, especially of its DNA, by exploiting host proteins. This review will discuss the host mechanisms of HIV-1 DNA sensing and viral immune evasion, with a particular focus on TREX1, three prime repair exonuclease 1, a host 3' exonuclease (also known as DNase III). PMID- 24817866 TI - The distribution and impact of viral lineages in domains of life. PMID- 24817867 TI - Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms. AB - T cell activation, initiated by T cell receptor (TCR) mediated recognition of pathogen-derived peptides presented by major histocompatibility complex class I or II molecules (pMHC), shows exquisite specificity and sensitivity, even though the TCR-pMHC binding interaction is of low affinity. Recent experimental work suggests that TCR pre-clustering may be a mechanism via which T cells can achieve such high sensitivity. The unresolved stoichiometry of the TCR makes TCR-pMHC binding and TCR triggering, an open question. We formulate a mathematical model to characterize the pre-clustering of T cell receptors (TCRs) on the surface of T cells, motivated by the experimentally observed distribution of TCR clusters on the surface of naive and memory T cells. We extend a recently introduced stochastic criterion to compute the timescales of T cell responses, assuming that ligand-induced cross-linked TCR is the minimum signaling unit. We derive an approximate formula for the mean time to signal initiation. Our results show that pre-clustering reduces the mean activation time. However, additional mechanisms favoring the existence of clusters are required to explain the difference between naive and memory T cell responses. We discuss the biological implications of our results, and both the compatibility and complementarity of our approach with other existing mathematical models. PMID- 24817868 TI - Immersing undergraduate students into research on the metagenomics of the plant rhizosphere: a pedagogical strategy to engage civic-mindedness and retain undergraduates in STEM. PMID- 24817869 TI - Endoplasmic reticulum-mediated protein quality control in Arabidopsis. AB - A correct three-dimensional structure is crucial for the physiological functions of a protein, yet the folding of proteins to acquire native conformation is a fundamentally error-prone process. Eukaryotic organisms have evolved a highly conserved endoplasmic reticulum-mediated protein quality control (ERQC) mechanism to monitor folding processes of secretory and membrane proteins, allowing export of only correctly folded proteins to their physiological destinations, retaining incompletely/mis-folded ones in the ER for additional folding attempts, marking and removing terminally misfolded ones via a unique multiple-step degradation process known as ER-associated degradation (ERAD). Most of our current knowledge on ERQC and ERAD came from genetic and biochemical investigations in yeast and mammalian cells. Recent studies in the reference plant Arabidopsis thaliana uncovered homologous components and similar mechanisms in plants for monitoring protein folding and for retaining, repairing, and removing misfolded proteins. These studies also revealed critical roles of the plant ERQC/ERAD systems in regulating important biochemical/physiological processes, such as abiotic stress tolerance and plant defense. In this review, we discuss our current understanding about the molecular components and biochemical mechanisms of the plant ERQC/ERAD system in comparison to yeast and mammalian systems. PMID- 24817870 TI - Post-fertilization expression of FLOWERING LOCUS T suppresses reproductive reversion. AB - FLOWERING LOCUS T (FT) encodes a systemic signal communicating the perception of long day photoperiod from leaves to the shoot apex to induce the floral transition. Transient expression of FT in the phloem companion cells of rosette leaves for one to several days was previously shown to be sufficient to commit plants to flowering. Here we show that partial commitment results in pleiotropic inflorescence meristem reversion phenotypes. FT expression is much stronger in organs formed after the floral transition such as cauline leaves, sepals, and developing siliques. We show that expression of FT and its paralog TWIN SISTER OF FT (TSF) after the floral transition plays a role in inflorescence meristem stabilization even if plants flower very late in development. CONSTANS (CO), the major activator of FT, is not required to prevent late reproductive reversion. The requirement for FT is temporal since reproductive reversion to a vegetative state occurs only in recently formed inflorescence meristems. Unlike for the expression of FT in leaves, neither the distal putative FT enhancer nor long-day photoperiod is required for FT expression in developing siliques. Expression of FT in developing siliques and their supporting stems is sufficient to stabilize flowering during the sensitive developmental window indicating that fruit generated FT participates in inflorescence stabilization. PMID- 24817871 TI - The CUC1 and CUC2 genes promote carpel margin meristem formation during Arabidopsis gynoecium development. AB - Carpel margin meristems (CMMs), a pair of meristematic tissues present along the margins of two fused carpel primordia of Arabidopsis thaliana, are essential for the formation of ovules and the septum, two major internal structures of the gynoecium. Although a number of regulatory factors involved in shoot meristem activity are known to be required for the formation of these gynoecial structures, their direct roles in CMM development have yet to be addressed. Here we show that the CUP-SHAPED COTYLEDON genes CUC1 and CUC2, which are essential for shoot meristem initiation, are also required for formation and stable positioning of the CMMs. Early in CMM formation, CUC1 and CUC2 are also required for expression of the SHOOT MERISTEMLESS gene, a central regulator for stem cell maintenance in the shoot meristem. Moreover, plants carrying miR164-resistant forms of CUC1 and CUC2 resulted in extra CMM activity with altered positioning. Our results thus demonstrate that the two regulatory proteins controlling shoot meristem activity also play critical roles in elaboration of the female reproductive organ through the control of meristematic activity. PMID- 24817873 TI - Phytochrome-dependent coordinate control of distinct aspects of nuclear and plastid gene expression during anterograde signaling and photomorphogenesis. AB - Light perception by photoreceptors impacts plastid transcription, development, and differentiation. This photoreceptor-dependent activity suggests a mechanism for photoregulation of gene expression in the nucleus and plastid that serves to coordinate expression of critical genes of these two organelles. This coordinate expression is required for proper stoichiometric accumulation of components needed for assembly of plastids, photosynthetic light-harvesting complexes and components such as phytochromes. Chloroplast-targeted sigma factors, which function together with the plastid-encoded RNA polymerase to regulate expression of plastid-encoded genes, and nuclear-encoded plastid development factors, such as GLK1 and GLK2, are targets of phytochrome regulation. Such phytochrome dependent functions are hypothesized to allow light-dependent regulation, and feasibly tuning, of plastid components and function in response to changes in the external environment, which directly affects photosynthesis and the potential for light-induced damage. When the size and protein composition of the light harvesting complexes are not tuned to the external environment, imbalances in electron transport can impact the cellular redox state and cause cellular damage. We show that phytochromes specifically regulate the expression of multiple factors that function to modulate plastid transcription and, thus, provide a paradigm for coordinate expression of the nuclear and plastid genomes in response to changes in external light conditions. As phytochromes respond to changes in the prevalent wavelengths of light and light intensity, we propose that specific phytochrome-dependent molecular mechanisms are used during light-dependent signaling between the nucleus and chloroplast during photomorphogenesis to coordinate chloroplast development with plant developmental stage and the external environment. PMID- 24817872 TI - bZIPs and WRKYs: two large transcription factor families executing two different functional strategies. AB - bZIPs and WRKYs are two important plant transcription factor (TF) families regulating diverse developmental and stress-related processes. Since a partial overlap in these biological processes is obvious, it can be speculated that they fulfill non-redundant functions in a complex regulatory network. Here, we focus on the regulatory mechanisms that are so far described for bZIPs and WRKYs. bZIP factors need to heterodimerize for DNA-binding and regulation of transcription, and based on a bioinformatics approach, bZIPs can build up more than the double of protein interactions than WRKYs. In contrast, an enrichment of the WRKY DNA binding motifs can be found in WRKY promoters, a phenomenon which is not observed for the bZIP family. Thus, the two TF families follow two different functional strategies in which WRKYs regulate each other's transcription in a transcriptional network whereas bZIP action relies on intensive heterodimerization. PMID- 24817874 TI - Monitoring protein turnover during phosphate starvation-dependent autophagic degradation using a photoconvertible fluorescent protein aggregate in tobacco BY 2 cells. AB - We have developed a system for quantitative monitoring of autophagic degradation in transformed tobacco BY-2 cells using an aggregate-prone protein comprised of cytochrome b5 (Cyt b5) and a tetrameric red fluorescent protein (RFP). Unfortunately, this system is of limited use for monitoring the kinetics of autophagic degradation because the proteins synthesized before and after induction of autophagy cannot be distinguished. To overcome this problem, we developed a system using kikume green-red (KikGR), a photoconvertible and tetrameric fluorescent protein that changes its fluorescence from green to red upon irradiation with purple light. Using the fusion protein of Cyt b5 and KikGR together with a method for the bulk conversion of KikGR, which we had previously used to convert the Golgi-localized monomeric KikGR fusion protein, we were able to monitor both the growth and de novo formation of aggregates. Using this system, we found that tobacco cells do not cease protein synthesis under conditions of phosphate (Pi)-starvation. Induction of autophagy under Pi starvation, but not under sugar- or nitrogen-starvation, was specifically inhibited by phosphite, which is an analog of Pi with a different oxidation number. Therefore, the mechanism by which BY-2 cells can sense Pi-starvation and induce autophagy does not involve sensing a general decrease in energy supply and a specific Pi sensor might be involved in the induction of autophagy under Pi starvation. PMID- 24817875 TI - Role and regulation of autophagy in heat stress responses of tomato plants. AB - As sessile organisms, plants are constantly exposed to a wide spectrum of stress conditions such as high temperature, which causes protein misfolding. Misfolded proteins are highly toxic and must be efficiently removed to reduce cellular proteotoxic stress if restoration of native conformations is unsuccessful. Although selective autophagy is known to function in protein quality control by targeting degradation of misfolded and potentially toxic proteins, its role and regulation in heat stress responses have not been analyzed in crop plants. In the present study, we found that heat stress induced expression of autophagy-related (ATG) genes and accumulation of autophagosomes in tomato plants. Virus-induced gene silencing (VIGS) of tomato ATG5 and ATG7 genes resulted in increased sensitivity of tomato plants to heat stress based on both increased development of heat stress symptoms and compromised photosynthetic parameters of heat stressed leaf tissues. Silencing of tomato homologs for the selective autophagy receptor NBR1, which targets ubiquitinated protein aggregates, also compromised tomato heat tolerance. To better understand the regulation of heat-induced autophagy, we found that silencing of tomato ATG5, ATG7, or NBR1 compromised heat induced expression of not only the targeted genes but also other autophagy related genes. Furthermore, we identified two tomato genes encoding proteins highly homologous to Arabidopsis WRKY33 transcription factor, which has been previously shown to interact physically with an autophagy protein. Silencing of tomato WRKY33 genes compromised tomato heat tolerance and reduced heat-induced ATG gene expression and autophagosome accumulation. Based on these results, we propose that heat-induced autophagy in tomato is subject to cooperative regulation by both WRKY33 and ATG proteins and plays a critical role in tomato heat tolerance, mostly likely through selective removal of heat-induced protein aggregates. PMID- 24817876 TI - MicroRNA as a novel player in atrial fibrillation. PMID- 24817877 TI - CARF and WYL domains: ligand-binding regulators of prokaryotic defense systems. AB - CRISPR-Cas adaptive immunity systems of bacteria and archaea insert fragments of virus or plasmid DNA as spacer sequences into CRISPR repeat loci. Processed transcripts encompassing these spacers guide the cleavage of the cognate foreign DNA or RNA. Most CRISPR-Cas loci, in addition to recognized cas genes, also include genes that are not directly implicated in spacer acquisition, CRISPR transcript processing or interference. Here we comprehensively analyze sequences, structures and genomic neighborhoods of one of the most widespread groups of such genes that encode proteins containing a predicted nucleotide-binding domain with a Rossmann-like fold, which we denote CARF (CRISPR-associated Rossmann fold). Several CARF protein structures have been determined but functional characterization of these proteins is lacking. The CARF domain is most frequently combined with a C-terminal winged helix-turn-helix DNA-binding domain and "effector" domains most of which are predicted to possess DNase or RNase activity. Divergent CARF domains are also found in RtcR proteins, sigma-54 dependent regulators of the rtc RNA repair operon. CARF genes frequently co-occur with those coding for proteins containing the WYL domain with the Sm-like SH3 beta-barrel fold, which is also predicted to bind ligands. CRISPR-Cas and possibly other defense systems are predicted to be transcriptionally regulated by multiple ligand-binding proteins containing WYL and CARF domains which sense modified nucleotides and nucleotide derivatives generated during virus infection. We hypothesize that CARF domains also transmit the signal from the bound ligand to the fused effector domains which attack either alien or self nucleic acids, resulting, respectively, in immunity complementing the CRISPR-Cas action or in dormancy/programmed cell death. PMID- 24817879 TI - Estimating heritability of complex traits from genome-wide association studies using IBS-based Haseman-Elston regression. AB - Exploring heritability of complex traits is a central focus of statistical genetics. Among various previously proposed methods to estimate heritability, variance component methods are advantageous when estimating heritability using markers. Due to the high-dimensional nature of data obtained from genome-wide association studies (GWAS) in which genetic architecture is often unknown, the most appropriate heritability estimator model is often unclear. The Haseman Elston (HE) regression is a variance component method that was initially only proposed for linkage studies. However, this study presents a theoretical basis for a modified HE that models linkage disequilibrium for a quantitative trait, and consequently can be used for GWAS. After replacing identical by descent (IBD) scores with identity by state (IBS) scores, we applied the IBS-based HE regression to single-marker association studies (scenario I) and estimated the variance component using multiple markers (scenario II). In scenario II, we discuss the circumstances in which the HE regression and the mixed linear model are equivalent; the disparity between these two methods is observed when a covariance component exists for the additive variance. When we extended the IBS based HE regression to case-control studies in a subsequent simulation study, we found that it provided a nearly unbiased estimate of heritability, more precise than that estimated via the mixed linear model. Thus, for the case-control scenario, the HE regression is preferable. GEnetic Analysis Repository (GEAR; http://sourceforge.net/p/gbchen/wiki/GEAR/) software implemented the HE regression method and is freely available. PMID- 24817878 TI - Analysis pipeline for the epistasis search - statistical versus biological filtering. AB - Gene-gene interactions may contribute to the genetic variation underlying complex traits but have not always been taken fully into account. Statistical analyses that consider gene-gene interaction may increase the power of detecting associations, especially for low-marginal-effect markers, and may explain in part the "missing heritability." Detecting pair-wise and higher-order interactions genome-wide requires enormous computational power. Filtering pipelines increase the computational speed by limiting the number of tests performed. We summarize existing filtering approaches to detect epistasis, after distinguishing the purposes that lead us to search for epistasis. Statistical filtering includes quality control on the basis of single marker statistics to avoid the analysis of bad and least informative data, and limits the search space for finding interactions. Biological filtering includes targeting specific pathways, integrating various databases based on known biological and metabolic pathways, gene function ontology and protein-protein interactions. It is increasingly possible to target single-nucleotide polymorphisms that have defined functions on gene expression, though not belonging to protein-coding genes. Filtering can improve the power of an interaction association study, but also increases the chance of missing important findings. PMID- 24817880 TI - MRI Volume Fusion Based on 3D Shearlet Decompositions. AB - Nowadays many MRI scans can give 3D volume data with different contrasts, but the observers may want to view various contrasts in the same 3D volume. The conventional 2D medical fusion methods can only fuse the 3D volume data layer by layer, which may lead to the loss of interframe correlative information. In this paper, a novel 3D medical volume fusion method based on 3D band limited shearlet transform (3D BLST) is proposed. And this method is evaluated upon MRI T2* and quantitative susceptibility mapping data of 4 human brains. Both the perspective impression and the quality indices indicate that the proposed method has a better performance than conventional 2D wavelet, DT CWT, and 3D wavelet, DT CWT based fusion methods. PMID- 24817881 TI - Radix Astragali Improves Dysregulated Triglyceride Metabolism and Attenuates Macrophage Infiltration in Adipose Tissue in High-Fat Diet-Induced Obese Male Rats through Activating mTORC1-PPAR gamma Signaling Pathway. AB - Increased levels of free fatty acids (FFAs) and hypertriglyceridemia are important risk factors for cardiovascular disease. The effective fraction isolated from radix astragali (RA) has been reported to alleviate hypertriglyceridemia. The mechanism of this triglyceride-lowering effect of RA is unclear. Here, we tested whether activation of the mTORC1-PPAR gamma signaling pathway is related to the triglyceride-lowering effect of RA. High-fat diet induced obese (DIO) rats were fed a high-fat diet (40% calories from fat) for 9 10 weeks, and 4 g/kg/d RA was administered by gavage. RA treatment resulted in decreased fasting triglyceride levels, FFA concentrations, and adipocyte size. RA treated rats showed improved triglyceride clearance and fatty acid handling after olive oil overload. RA administration could also decrease macrophage infiltration and expression of MCP-1 and TNF alpha , but it may also increase the expression of PPAR gamma in epididymal adipose tissue from RA treated rats. Consistently, expressions of PPAR gamma and phospho-p70S6K were increased in differentiated 3T3 L1 adipocytes treated with RA. Moreover, RA couldnot upregulate the expression of PPAR gamma at the presence of rapamycin. In conclusion, the mTORC1-PPAR gamma signaling pathway is a potential mechanism through which RA exerts beneficial effects on the disturbance of triglyceride metabolism and dysfunction of adipose tissue in DIO rats. PMID- 24817882 TI - Decrease of PPARdelta in Type-1-Like Diabetic Rat for Higher Mortality after Spinal Cord Injury. AB - Changes in the peroxisome proliferator-activated receptors- delta (PPAR delta ) expression in rats after spinal cord injury (SCI) have been previously reported. Diabetic animals show a higher mortality after SCI. However, the relationship between the progress of diabetes and PPAR delta in SCI remains unknown. In the present study, we used compressive SCI in streptozotocin-(STZ-) induced diabetic rats. GW0742, a PPAR delta agonist, was used to evaluate its merit in STZ rats after SCI. Changes in PPAR delta expression were detected by Western blot. Survival rates were also estimated. A lower expression of PPAR delta in spinal cords of STZ-diabetic rats was observed. In addition, the survival times in two week induction diabetes were longer than those in eight-week induction group, which is consistent with the expression of PPAR delta in the spinal cord. Moreover, GW0742 significantly increased the survival time of STZ rats. Furthermore, their motor function and pain response were attenuated by GSK0660, a selective PPAR delta antagonist, but were enhanced by GW0742. In conclusion, the data suggest that higher mortality rate in STZ-diabetic rats with SCI is associated with the decrease of PPAR delta expression. Thus, change of PPAR delta expression with the progress of diabetes seems responsible for the higher mortality rate after SCI. PMID- 24817883 TI - Coronary artery disease detection using a fuzzy-boosting PSO approach. AB - In the past decades, medical data mining has become a popular data mining subject. Researchers have proposed several tools and various methodologies for developing effective medical expert systems. Diagnosing heart diseases is one of the important topics and many researchers have tried to develop intelligent medical expert systems to help the physicians. In this paper, we propose the use of PSO algorithm with a boosting approach to extract rules for recognizing the presence or absence of coronary artery disease in a patient. The weight of training examples that are classified properly by the new rules is reduced by a boosting mechanism. Therefore, in the next rule generation cycle, the focus is on those fuzzy rules that account for the currently misclassified or uncovered instances. We have used coronary artery disease data sets taken from University of California Irvine, (UCI), to evaluate our new classification approach. Results show that the proposed method can detect the coronary artery disease with an acceptable accuracy. Also, the discovered rules have significant interpretability as well. PMID- 24817884 TI - Overexpression of aquaporin 1 in the tunica vaginalis may contribute to adult onset primary hydrocele testis. AB - To investigate the cause of the adult-onset primary noncommunicating hydrocele testis, protein expressions of water channel aquaporins (AQPs) 1 and 3 in the tunica vaginalis were assessed. Frozen tunica vaginalis specimens from patients with adult-onset primary hydrocele testis and control male nonhydrocele patients were subjected to Western blot analysis for the detection of AQP1 and AQP3 proteins. Paraffin-embedded sections of tunica vaginalis specimens were histochemically stained with anti-AQP1 and anti-AQP3 antibodies as well as an anti-podoplanin antibody to stain lymphatic endothelia. Hydrocele fluid was subjected to biochemical analysis. AQP1 protein expression in the tunica vaginalis was significantly higher in patients with adult-onset hydrocele testis than in the controls. The AQP3 protein was not detected in the tunica vaginalis. Histochemically, AQP1 expression in the tunica vaginalis was localized in vascular endothelial and smooth muscle cells. The densities of AQP1-expressing capillaries and lymphatic vessels were similar between the tunica vaginalis of the controls and those of hydrocele patients. Sodium levels were higher in the hydrocele fluid than in the serum. In conclusion, overexpression of the AQP1 protein in individual capillary endothelial cells of the tunica vaginalis may contribute to the development of adult-onset primary noncommunicating hydrocele testis as another aquaporin-related disease. PMID- 24817885 TI - Efficacy and safety of sitagliptin for the treatment of new-onset diabetes after renal transplantation. AB - New-onset diabetes after transplantation (NODAT) is a common comorbidity after renal transplantation. Though metformin is the first-line agent for the treatment of type 2 diabetes, in renal transplant recipients, metformin is frequently avoided due to concerns about renal dysfunction and risk for lactic acidosis. Therefore, alternative first-line agents for the treatment of NODAT in renal transplant recipients are needed. Sitagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, has a low incidence of hypoglycemia, is weight neutral, and, in a small study, did not affect immunosuppressant levels. However, long-term sitagliptin use for the treatment of NODAT in kidney transplant recipients has not been studied. We retrospectively analyzed renal transplant recipients diagnosed with NODAT and treated with sitagliptin to assess safety and efficacy. Twenty-two patients were started on sitagliptin alone. After 12 months of followup, 19/22 patients remained on sitagliptin alone with a significant improvement in hemoglobin A1c. Renal function and immunosuppressant levels remained stable. Analysis of long-term followup (32.5 +/- 17.8 months) revealed that 17/22 patients remained on sitagliptin (mean hemoglobin A1c < 7%) with 9/17 patients remaining on sitagliptin alone. Transplant-specific adverse events were rare. Sitagliptin appears safe and efficacious for the treatment of NODAT in kidney transplant recipients. PMID- 24817886 TI - Adrenal incidentalomas: should we operate on small tumors in the era of laparoscopy? AB - Tumor size smaller than 4 cm as an indication for surgical treatment of incidentaloma is still a subject of discussion. Our aim was the estimation of the incidence of malignancy and analysis of treatment outcomes in patients with incidentaloma smaller than 4 cm in comparison to bigger lesions. 132 patients who underwent laparoscopic adrenalectomy for nonsecreting tumors were divided into two groups: group 1 (55 pts., size < = 40 mm) and group 2 (77 pts., size > 40 mm). Operation parameters and histopathological results were analyzed. No differences in group characteristics, mean operation time, and estimated blood loss were noted. Complications in groups 1 and 2 occurred in 3.6% and 5.2% of patients, respectively (P = 0.67). Malignancy in groups 1 and 2 was present in 1 and 6 patients, respectively (P = 0.13). Potentially malignant lesions were identified in 4 patients in group 1 and 4 patients in group 2 (P = 0.39). The results do not allow for straightforward recommendations for surgical treatment of smaller adrenal tumors. The safety of laparoscopy and minimal, but impossible to omit, risk of malignancy support decisions for surgery. On the other hand, the risk of malignancy in smaller adrenal tumors is lower than surgical complications, which provides an important argument against surgery. PMID- 24817887 TI - Role of serum fibrinogen levels in patients with rotator cuff tears. AB - Although rotator cuff (RC) tendinopathy is a frequent pathology of the shoulder, the real understanding of its aetiopathogenesis is still unclear. Several studies showed that RC tendinopathy is more frequent in patients with hyperglycemia, diabetes, obesity, or metabolic syndrome. This paper aims to evaluate the serum concentration of fibrinogen in patients with RC tears. Metabolic disorders have been related to high concentration of serum fibrinogen and the activity of fibrinogen has been proven to be crucial in the development of microvascular damage. Thus, it may produce progression of RC degeneration by reducing the vascular supply of tendons. We report the results of a cross-sectional frequency matched case-control study comparing the serum concentration of fibrinogen of patients with RC tears with that of a control group of patients without history of RC tears who underwent arthroscopic meniscectomy. We choose to enrol in the control group patients with pathology of the lower limb with a likely mechanic, not metabolic, cause, different from tendon pathology. We found no statistically significant differences in serum concentration of fibrinogen when comparing patients with RC tears and patients who underwent arthroscopic meniscectomy (P = 0.5). Further studies are necessary to clarify the role of fibrinogen in RC disease. PMID- 24817890 TI - Chronic maxillary rhinosinusitis of dental origin: a systematic review of 674 patient cases. AB - Objectives. The aim of this systematic review is to study the causes of odontogenic chronic maxillary rhinosinusitis (CMRS), the average age of the patients, the distribution by sex, and the teeth involved. Materials and Methods. We performed an EMBASE-, Cochrane-, and PubMed-based review of all of the described cases of odontogenic CMRS from January 1980 to January 2013. Issues of clinical relevance, such as the primary aetiology and the teeth involved, were evaluated for each case. Results. From the 190 identified publications, 23 were selected for a total of 674 patients following inclusion criteria. According to these data, the main cause of odontogenic CMRS is iatrogenic, accounting for 65.7% of the cases. Apical periodontal pathologies (apical granulomas, odontogenic cysts, and apical periodontitis) follow them and account for 25.1% of the cases. The most commonly involved teeth are the first and second molars. Conclusion. Odontogenic CMRS is a common disease that must be suspected whenever a patient undergoing dental treatment presents unilateral maxillary chronic rhinosinusitis. PMID- 24817889 TI - Small G Proteins Dexras1 and RHES and Their Role in Pathophysiological Processes. AB - Dexras1 and RHES, monomeric G proteins, are members of small GTPase family that are involved in modulation of pathophysiological processes. Dexras1 and RHES levels are modulated by hormones and Dexras1 expression undergoes circadian fluctuations. Both these GTPases are capable of modulating calcium ion channels which in turn can potentially modulate neurosecretion/hormonal release. These two GTPases have been reported to prevent the aberrant cell growth and induce apoptosis in cell lines. Present review focuses on role of these two monomeric GTPases and summarizes their role in pathophysiological processes. PMID- 24817891 TI - Maternal Characteristics of Women Exposed to Hypnotic Benzodiazepine Receptor Agonist during Pregnancy. AB - Background. There is little knowledge regarding the characteristics of women treated with hypnotic benzodiazepine receptor agonists (HBRAs) during pregnancy. In this large Danish cohort study, we characterize women exposed to HBRA during pregnancy. We determined changes in prevalence of HBRA use from 1997 to 2010 and exposure to HBRAs in relation to pregnancy. Methods. We performed a retrospective cohort study including 911,017 pregnant women in the period from 1997 to 2010. Information was retrieved from The Danish Birth Registry and The Registry of Medicinal Product Statistics to identify pregnant women redeeming a prescription of HBRAs. Results. We identified 2,552 women exposed to HBRAs during pregnancy, increasing from 0.18% in 1997 to 0.23% in 2010. Compared to unexposed women, exposed women were characterized by being older, with higher BMI, in their third or fourth parity, of lower income and education level, more frequently smokers, and more likely to be comedicated with antipsychotic, anxiolytic, or antidepressant drugs (P < 0.0001). Conclusion. Women using HBRAs during their pregnancy differ from unexposed women in socioeconomic factors and were more likely to receive comedication. The consumption of HBRAs was reduced during pregnancy compared to before conception. PMID- 24817892 TI - Mesenchymal stromal cells: novel methods for characterization, understanding differentiation, and function. PMID- 24817888 TI - Trends in computer-aided manufacturing in prosthodontics: a review of the available streams. AB - In prosthodontics, conventional methods of fabrication of oral and facial prostheses have been considered the gold standard for many years. The development of computer-aided manufacturing and the medical application of this industrial technology have provided an alternative way of fabricating oral and facial prostheses. This narrative review aims to evaluate the different streams of computer-aided manufacturing in prosthodontics. To date, there are two streams: the subtractive and the additive approaches. The differences reside in the processing protocols, materials used, and their respective accuracy. In general, there is a tendency for the subtractive method to provide more homogeneous objects with acceptable accuracy that may be more suitable for the production of intraoral prostheses where high occlusal forces are anticipated. Additive manufacturing methods have the ability to produce large workpieces with significant surface variation and competitive accuracy. Such advantages make them ideal for the fabrication of facial prostheses. PMID- 24817893 TI - Evidence of HLA-DQB1 Contribution to Susceptibility of Dengue Serotype 3 in Dengue Patients in Southern Brazil. AB - Dengue infection (DI) transmitted by arthropod vectors is the viral disease with the highest incidence throughout the world, an estimated 300 million cases per year. In addition to environmental factors, genetic factors may also influence the manifestation of the disease; as even in endemic areas, only a small proportion of people develop the most serious form. Immune-response gene polymorphisms may be associated with the development of cases of DI. The aim of this study was to determine allele frequencies in the HLA-A, B, C, DRB1, DQA1, and DQB1 loci in a Southern Brazil population with dengue virus serotype 3, confirmed by the ELISA serological method, and a control group. The identification of the HLA alleles was carried out using the SSO genotyping PCR program (One Lambda), based on Luminex technology. In conclusion, this study suggests that DQB1*06:11 allele could act as susceptible factors to dengue virus serotype 3, while HLA-DRB1*11 and DQA1*05:01 could act as resistance factors. PMID- 24817894 TI - Diagnosis of asthma in primary health care: a pilot study. AB - Some patients with an asthma diagnosis have a poor controlled asthma. One explanation may be an incorrect diagnosis. Aim. The aim of the study was to diagnose and classify patients with non-infectious lower respiratory tract problems in primary health care using internationally applied diagnostic criteria and diagnostic tests. Patients and Methods. New adult patients visiting a primary health care centre due to lower airway problems were included. The diagnostic tests included FEV1, FVC, PEF, two questionnaires, methacholine test, and skin prick test. Results. The patients (n = 43) could be divided into four groups: asthma (28%), asthma-like disorder (44%), idiopathic cough (12%), and a nonreversible bronchial obstructive group (16%). The asthma and asthma-like groups showed similar patterns of airway symptoms and trigger factors, not significantly separated by a special questionnaire. Phlegm, heavy breathing, chest pressure/pain, cough, and wheezing were the most common symptoms. Physical exercise and scents were the dominating trigger factors. Conclusions. Nonobstructive asthma-like symptoms seem to be as common as bronchial asthma in primary health care. Due to the similarities in symptoms and trigger factors the study supports the hypothesis that asthma and nonobstructive asthma-like disorders are integrated in the same "asthma syndrome," including different mechanisms, not only bronchial obstruction. PMID- 24817895 TI - Leukotriene receptor antagonists for chronic urticaria: a systematic review. AB - A significant proportion of patients with chronic urticaria respond inadequately to first line treatment with antihistamines. Leukotreine receptor antagonists (LTRA) are also used for chronic urticaria, although firm recommendations on their use are lacking. We performed a systematic review of randomised trials to determine the role of LTRA in treatment of chronic urticaria. A search of PUBMED, EMBASE, SCOPUS, LILACS, the Cochrane Central Register of Controlled Trials, and the Web of Science for relevant randomized control trials or cross over studies yielded 10 eligible studies. The heterogeneity of trials were high, preventing valid meta-analysis of data. Most trials indicated that LTRA are not superior to placebo or antihistamine therapy, while combination therapy of LTRA and antihistamines appear to be more efficacious compared to antihistamine alone. The side effect profile and tolerability of this group of drugs is acceptable. The use of LTRA as monotherapy cannot be recommended. LTRA are effective add-on therapy to anti-histamines, and their use in patients responding poorly to antihistamines is justifiable. Further well designed randomized controlled trials with clear and standardized outcome measures are needed to determine the role of LTRA in chronic urticaria. PMID- 24817896 TI - Arts therapies for anxiety, depression, and quality of life in breast cancer patients: a systematic review and meta-analysis. AB - Background. Breast cancer is one of the most common types of cancer. However, only a few trials assess the effects of arts therapies. Material and Methods. We searched the Cochrane Central Register of Controlled Trials, PubMed, and Google Scholar from their start date to January 2012. We handsearched reference lists and contacted experts. All randomized controlled trials, quasi-randomized trials, and controlled clinical trials of art interventions in breast cancer patients were included. Data were extracted and risk of bias was assessed. Meta-analyses were performed using standardized mean differences. Results. Thirteen trials with a total of 606 patients were included. Arts therapies comprised music therapy interventions, various types of art therapy, and dance/movement therapies. The methodological quality ranged from poor to high quality with the majority scoring 3 of 4 points on the Jadad scale. Results suggest that arts therapies seem to positively affect patients' anxiety (standardized mean difference: -1.10; 95%, confidence interval: -1.40 to -0.80) but not depression or quality of life. No conclusion could be drawn regarding the effects of arts therapy on pain, functional assessment, coping, and mood states. Discussion. Our review indicates that arts interventions may have beneficial effects on anxiety in patients with breast cancer. PMID- 24817897 TI - Complementary and alternative medicine for cancer pain: an overview of systematic reviews. AB - Background and Objective. Now with more and more published systematic reviews of Complementary and Alternative Medicine (CAM) on adult cancer pain, it is necessary to use the methods of overview of systematic review to summarize available evidence, appraise the evidence level, and give suggestions to future research and practice. Methods. A comprehensive search (the Cochrane Library, PubMed, Embase, and ISI Web of Knowledge) was conducted to identify all systematic reviews or meta-analyses of CAM on adult cancer pain. And the evidence levels were evaluated using GRADE approach. Results. 27 systematic reviews were included. Based on available evidence, we could find that psychoeducational interventions, music interventions, acupuncture plus drug therapy, Chinese herbal medicine plus cancer therapy, compound kushen injection, reflexology, lycopene, TENS, qigong, cupping, cannabis, Reiki, homeopathy (Traumeel), and creative arts therapies might have beneficial effects on adult cancer pain. No benefits were found for acupuncture (versus drug therapy or shame acupuncture), and the results were inconsistent for massage therapy, transcutaneous electric nerve stimulation (TENS), and Viscum album L plus cancer treatment. However, the evidence levels for these interventions were low or moderate due to high risk of bias and/or small sample size of primary studies. Conclusion. CAM may be beneficial for alleviating cancer pain, but the evidence levels were found to be low or moderate. Future large and rigor randomized controlled studies are needed to confirm the benefits of CAM on adult cancer pain. PMID- 24817898 TI - Time-Course of the Effects of QSYQ in Promoting Heart Function in Ameroid Constrictor-Induced Myocardial Ischemia Pigs. AB - We aim to investigate the therapeutic effects of QSYQ on a pig myocardial ischemia (MI) model and to determine its mechanism of action. The MI model was induced by Ameroid constriction of the left anterior descending coronary (LAD) in Ba-Ma miniature pigs. Four groups were created: model group, digoxin group, QSYQ group, and sham-operated group. Heart function, Ang II, CGMP, TXB2, BNP, and cTnT were evaluated before (3 weeks after operation: 0 weeks) and at 2, 4, and 8 weeks after drug administration. After 8 weeks of administration, the pigs were sacrificed for cardiac injury measurements. Pigs with MI showed obvious histological changes, including BNP, cTnT, Ang II, CGRP, TXB2, and ET, deregulated heart function, and increased levels of apoptotic cells in myocardial tissue. Treatment with QSYQ improved cardiac remodeling by counteracting those events. The administration of QSYQ was accompanied by a restoration of heart function and of the levels of Ang II, CGRP, TXB2, ET BNP, and cTnT. In addition, QSYQ attenuated administration, reduced the apoptosis, and decreased the level of TNF- alpha and active caspase-3. In conclusion, administration of QSYQ could attenuate Ameroid constrictor induced myocardial ischemia, and TNF- alpha and active caspase-3 seemed to be the critical potential target of QSYQ. PMID- 24817899 TI - Irritant contact dermatitis risk of common topical traditional chinese medicines used for skin-lightening: a pilot clinical trial with 30 volunteers. AB - Topical traditional Chinese medicine- (TTCM-) related contact dermatitis is not uncommon but ignored. Patch and photopatch tests using 6 individual herbal ingredients and Bai-Zhi-Kao (BZK; ), a skin-lightening TTCM preparation, were conducted on 30 participants. Twenty-five subjects showed at least 1 positive reaction, including 6 (20.0%) participants who reacted to BZK. The majority reacted to Radix Ampelopsis japonica (Bai-Lian; ) (60.0%), whereas few reacted to Rhizoma Bletilla striata (Bai-Ji; ) (16.7%), Rhizoma Atractylodis macrocephalae (Bai-Zhu; ) (10.0%), Radix Angelicae dahuricae (Bai-Zhi; ) (3.3%), and Herba asari (Xi-Xin; ) (3.3%). In the photopatch test, 3 participants (10.0%) reacted positively to BZK and 10 to >=1 constituent; however, all reacted to Radix Angelicae dahuricae (26.7%), Radix Ampelopsis japonica (13.3%), and Rhizoma Bletilla striata (3.3%). In contrast, no subjects showed positive reactions to Sclerotium Poria cocos (Bai-Fu-Ling; ). Thus, BZK and its constituents might present potential latent risk of contact dermatitis owing to the possible presence of Radix Ampelopsis japonica and Radix Angelicae dahuricae. Furthermore, TTCMs, particularly cosmetic products, must be used carefully, with ample warning of potential contact dermatitis risk. PMID- 24817900 TI - Yangjing Capsule Extract Promotes Proliferation of GC-1 Spg Cells. AB - Objective. To investigate the effect of Yangjing Capsule (YC) extract on proliferation of GC-1 spermatogonia (spg) cells and the mechanism. Methods. GC-1 spg cells were treated with 0.01, 0.1, and 1 mg/mL YC extract. MTT assay was performed to detect the cell viability. Flow cytometry was used to measure the cell cycle and apoptosis of GC-1 spg cells. Real-time PCR and western blot were applied to determine the mRNA and protein expression of Oct-4 and Plzf. Gfr alpha 1 knockdown and LY294002 (PI3K inhibitor) were applied to explore the underlying mechanism. Results. After 48 h treatment of YC, the viability of GC-1 spg cells increased significantly and the ratio of apoptotic cells reduced significantly. The increased mRNA and protein expression of Oct-4 and Plzf suggested YC promoted self-renewal of GC-1 spg cells. Both Gfr alpha 1 siRNAs and LY294002 treatments held back YC extract's stimulation effects on mRNA and protein expression of Oct 4 and Plzf and consequently inhibited the proliferation of GC-1 spg cells induced by YC extract. Conclusion. YC extract could stimulate the proliferation of GC-1 spg cells. Partly via Gfr alpha 1, YC extract is able to trigger the activation of PI3K pathway and finally lead to self-renewal of GC-1 spg cells. PMID- 24817902 TI - Decaffeinated green coffee bean extract attenuates diet-induced obesity and insulin resistance in mice. AB - This study investigated whether decaffeinated green coffee bean extract prevents obesity and improves insulin resistance and elucidated its mechanism of action. Male C57BL/6N mice (N = 48) were divided into six dietary groups: chow diet, HFD, HFD-supplemented with 0.1%, 0.3%, and 0.9% decaffeinated green coffee bean extract, and 0.15% 5-caffeoylquinic acid. Based on the reduction in HFD-induced body weight gain and increments in plasma lipids, glucose, and insulin levels, the minimum effective dose of green coffee bean extract appears to be 0.3%. Green coffee bean extract resulted in downregulation of genes involved in WNT10b- and galanin-mediated adipogenesis and TLR4-mediated proinflammatory pathway and stimulation of GLUT4 translocation to the plasma membrane in white adipose tissue. Taken together, decaffeinated green coffee bean extract appeared to reverse HFD-induced fat accumulation and insulin resistance by downregulating the genes involved in adipogenesis and inflammation in visceral adipose tissue. PMID- 24817901 TI - Cinnamon: a multifaceted medicinal plant. AB - Cinnamon (Cinnamomum zeylanicum, and Cinnamon cassia), the eternal tree of tropical medicine, belongs to the Lauraceae family. Cinnamon is one of the most important spices used daily by people all over the world. Cinnamon primarily contains vital oils and other derivatives, such as cinnamaldehyde, cinnamic acid, and cinnamate. In addition to being an antioxidant, anti-inflammatory, antidiabetic, antimicrobial, anticancer, lipid-lowering, and cardiovascular disease-lowering compound, cinnamon has also been reported to have activities against neurological disorders, such as Parkinson's and Alzheimer's diseases. This review illustrates the pharmacological prospective of cinnamon and its use in daily life. PMID- 24817903 TI - Nautical officers at sea: emergency experience and need for medical training. AB - BACKGROUND: On merchant ships, the medical treatment including emergency interventions on the high seas are carried out by nautical officers who have to pass a forty hours medical refresher course every five years in order to meet international requirements. This study aims to show the most frequent kinds of medical emergencies on the high seas and to assess the seafarers' knowledge about their treatment. METHODS: 465 nautical officers who participated in the medical refresher course at the Institute for Occupational and Maritime Medicine in Hamburg, within the period from 2006 to 2013, were interviewed about their experience of serious diseases and accidents on board, which had led to an emergency port call, a course deviation or an evacuation. Furthermore, prior to the course the officers were asked to answer 18 basic medical questions about common medical issues on board. RESULTS: 133 seafarers (28.6%) reported that they had been confronted with at least one serious medical emergency at sea. These emergencies encompassed trauma (37.9%), cardiovascular diseases (18.2%), severe gastrointestinal diseases (15.9%), serious skin or pulmonary infections (9.8%), neurological (9.1%) and urological diseases (4.5%) as well as burns (4.5%). With regards to the basic medical questions, an average of 70.7% of the total score had been achieved (from 26.8% to 100%). On average, 65.5% of internal and 65.6% of surgical questions had been answered correctly. Proper answers to toxicological and infectious questions had been given by 93.3% and 94.1% respectively and to topics of hypothermia and medical treatment by 59.4% and 61.0%. In total, a significant number of younger seafarers answered the questions correctly (p = 0.001). CONCLUSIONS: According to this study, serious emergencies on board are most frequently related to trauma or cardiovascular diseases. Taking into account the acquired medical knowledge, there seems to be a need to train deck officers within these fields more intensively. Considering the knowledge of seafarers about medical issues directly before attending their medical refresher course, the 5 years interval without any form of refresher course appears to be too long to guarantee adequate medical treatment by the lay persons on board. PMID- 24817904 TI - Use of CHAID decision trees to formulate pathways for the early detection of metabolic syndrome in young adults. AB - Metabolic syndrome (MetS) in young adults (age 20-39) is often undiagnosed. A simple screening tool using a surrogate measure might be invaluable in the early detection of MetS. Methods. A chi-squared automatic interaction detection (CHAID) decision tree analysis with waist circumference user-specified as the first level was used to detect MetS in young adults using data from the National Health and Nutrition Examination Survey (NHANES) 2009-2010 Cohort as a representative sample of the United States population (n = 745). Results. Twenty percent of the sample met the National Cholesterol Education Program Adult Treatment Panel III (NCEP) classification criteria for MetS. The user-specified CHAID model was compared to both CHAID model with no user-specified first level and logistic regression based model. This analysis identified waist circumference as a strong predictor in the MetS diagnosis. The accuracy of the final model with waist circumference user specified as the first level was 92.3% with its ability to detect MetS at 71.8% which outperformed comparison models. Conclusions. Preliminary findings suggest that young adults at risk for MetS could be identified for further followup based on their waist circumference. Decision tree methods show promise for the development of a preliminary detection algorithm for MetS. PMID- 24817906 TI - Brace treatment in juvenile idiopathic scoliosis: a prospective study in accordance with the SRS criteria for bracing studies - SOSORT award 2013 winner. AB - BACKGROUND: The Juvenile idiopathic scoliosis by age of onset, severity and evolutivity is source of great doubts concerning the purpose and use of conservative treatment. The different clinical experiences leave unsolved the question that arises in applying a conservative treatment when the patients are effectively forward a long growing period, in scoliosis characterized by inevitable evolutivity. The purpose of the present prospective study was to determine the effectiveness of conservative treatment in Juvenile idiopathic scoliosis. METHODS: From 1238 patients treated for idiopathic scoliosis between 1995 and 2012 fulfill the inclusion criteria 163 patients treated with PASB, Lyon brace and Milwaukee. Of these, 113 patients had a definite outcome, 27 have abandoned treatment e 23 are still in treatment. The minimum follow-up was 24 months. Radiographs were used to estimate the curve magnitude (CM) and the torsion of the apical vertebra (TA) at 5 time points: beginning (t1), 6 months after the beginning (t2), intermediate time between t1 and t4 (t3), end of weaning (t4), 2-years minimum follow-up (t5). Three outcomes were distinguished in agreement with SRS criteria: correction, stabilization and progression. RESULTS: The results from our study showed that of the 113 patients with a definite outcome CM mean value was 29.6 +/- 7.5 SD at t1 and 16.9 +/- 11.1 SD at t5. TA was 13.5 +/- 5.4 SD at t1 and 8.5 +/- 5.6 at t5. The variations between CM t5-t1 and TA t5-t1 were statistically significantly different. Curve correction was accomplished in 88 patients (77.8%), stabilization was obtained in 18 patients (15.9%). 7 patients (6.19%) have a progression and 4 of these were recommended for surgery. Of 26 patients who abandoned the treatment, at the time of abandonment (12.5 age) have achieved curve correction in 19 cases (70.0%), stabilization in 5 cases (19%) and progression in 3 cases (11%). Of these patients, reviewed at the end of growing, four have been operated on. CONCLUSIONS: Our study confirmed that conservative treatment with brace is highly effective in treating juvenile idiopathic scoliosis, in particular most patients reaching a complete curve correction and only 4.9% of patients need surgery. PMID- 24817905 TI - Structure-functional prediction and analysis of cancer mutation effects in protein kinases. AB - A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal "low" activity state to the "active" state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes. PMID- 24817907 TI - Right diaphragmatic injury and lacerated liver during a penetrating abdominal trauma: case report and brief literature review. AB - INTRODUCTION: Diaphragmatic injuries are rare consequences of thoracoabdominal trauma and they often occur in association with multiorgan injuries. The diaphragm is a difficult anatomical structure to study with common imaging instruments due to its physiological movement. Thus, diaphragmatic injuries can often be misunderstood and diagnosed only during surgical procedures. Diagnostic delay results in a high rate of mortality. METHODS: We report the management of a clinical case of a 45-old man who came to our observation with a stab wound in the right upper abdomen. The type or length of the knife used as it was extracted from the victim after the fight. CT imaging demonstrated a right hemothorax without pulmonary lesions and parenchymal laceration of the liver with active bleeding. It is observed hemoperitoneum and subdiaphragmatic air in the abdomen, as a bowel perforation. A complete blood count check revealed a decrease in hemoglobin (7 mg/dl), and therefore it was decided to perform surgery in midline laparotomy. CONCLUSION: In countries with a low incidence of inter-personal violence, stab wound diaphragmatic injury is particularly rare, in particular involving the right hemidiaphragm. Diaphragmatic injury may be underestimated due to the presence of concomitant lesions of other organs, to a state of shock and respiratory failure, and to the difficulty of identifying diaphragmatic injuries in the absence of high sensitivity and specific diagnostic instruments. Diagnostic delay causes high mortality with these traumas with insidious symptoms. A diaphragmatic injury should be suspected in the presence of a clinical picture which includes hemothorax, hemoperitoneum, anemia and the presence of subdiaphragmatic air in the abdomen. PMID- 24817908 TI - An overview of Ghana's mental health system: results from an assessment using the World Health Organization's Assessment Instrument for Mental Health Systems (WHO AIMS). AB - BACKGROUND: This survey provides data on the Mental Health System in Ghana for the year 2011. It supplies essential planning information for the implementation of Ghana's new Mental Health Act 846 of 2012, a renewal of the Ghana 5 year plan for mental health and it contributes to international knowledge base on mental health. It provides a baseline from which to measure future progress in Ghana and comparison data for use in other countries. In addition to reporting our findings we describe and analyse deficiencies and strengths of the Ghana mental health system. METHODS: We used the World Health Organization's Assessment Instrument for Mental Health Systems (WHO-AIMS) to collect, analyse, and report data on the mental health system and services for all districts of the ten regions of Ghana. Data was collected in 2012, based on the year 2011. RESULTS: In 2011, Ghana was a lower middle income country with a population of approximately 25 million. A mental health policy, plan and legislation were in place. Mental health legislation was outdated and no longer in line with best practice standards. Services were significantly underfunded with only 1.4% of the health expenditure going to mental health, and spending very much skewed towards urban areas. There were 123 mental health outpatient facilities, 3 psychiatric hospitals, 7 community based psychiatric inpatient units, 4 community residential facilities and 1 day treatment centre, which is well below what would be expected for Ghana's economic status. The majority of patients were treated in outpatient facilities and psychiatric hospitals and most of the inpatient beds were provided by the latter. There were an estimated 2.4 million people with mental health problems of which 67,780 (ie 2.8%) received treatment in 2011. The were 18 psychiatrists, 1,068 Registered Mental Nurses, 19 psychologists, 72 Community Mental Health Officers and 21 social workers working in mental health which is unbalanced with an unbalanced emphasis on nurses compared to what would be expected. CONCLUSIONS: The main strength of the mental health system was the presence of a long established service with staff working across the country in outpatients departments and hospitals. The main weakness was that government spending on mental health was very low and the bulk of services, albeit very sparse, were centred around the capital city leaving much of the rest of the country with almost no provision. Service provision was dominated by nurses with few other professions groups present. PMID- 24817909 TI - Straight proximal humeral nails are surrounded by more bone stock in comparison to bent nails in an experimental cadaveric study. AB - BACKGROUND: In the management of proximal humeral fractures intramedullary implants with bent and straight shape of the proximal part of nail are available. Based on data from previous studies on bone distribution in the humeral head, we hypothesized, that higher densities might exist in the bone stock surrounding straight nails in comparison to their angulated counterparts. With a known positive correlation between bone density and mechanical stability, this could indicate potentially higher rigidity of osteosyntheses done with straight implants. METHODS: We performed high resolution peripheral quantitative computed tomographies of the potential straight and bent implant bearing regions of 27 cadaveric proximal humeri. The acquired data were analyzed for differences between straight and bent Volumes of Interest as well as intra- and interindividual bone stock distribution. RESULTS: For both straight and bent volumes of interest a considerably declining bone mineral density was found in craniocaudal direction. Mean densities of bent volumes were significantly lower in comparison to their corresponding straight counterparts (p < 0.01) Intra individual comparison yielded high bivariate correlations of the corresponding Volumes of Interest of the right and the left side (p < 0.01). CONCLUSIONS: Based on the volumetric data a statistically relevant biomechanical superiority of straight shaped implants can be assumed. Since we found a rapid decrease of bone density in cranio-caudal direction, intramedullary implants should be anchored as proximally in the subcortical area as possible to minimize the risk of displacement or cutout. The high correlation between the Volumes of Interest of the corresponding right and left sides could aid in preoperative planning when considering an intra- or extramedullary approach. PMID- 24817910 TI - "The National Surgery Quality Improvement Project" (NSQIP): a new tool to increase patient safety and cost efficiency in a surgical intensive care unit. AB - BACKGROUND: The "National Surgical Quality Improvement Program" (NSQIP) is a nationally validated, risk-adjusted database tracking surgical outcomes. NSQIP has been demonstrated to decrease complications, expenses, and mortality. In the study institution, a high rate of nosocomial pneumonia (PNEU) and prolonged ventilator days >=48 hours (V48) was observed on the surgical service. METHODS: The hospital studied is a 500 bed university-affiliated teaching hospital performing approximately 20,000 surgical operations per year. A multidisciplinary team was formed and a series of interventions were implemented to address high pneumonia rates and prolonged intubation. Specific interventions included enforcement of protocols and adherence to the Institute for Healthcare Improvement (IHI) ventilator bundles, including head of bed elevation, sedation holidays, extubate when ready, and early nutrition. NSQIP collected pre-operative through 30-day postoperative data prospectively on 1,081 surgical patients in the intensive care unit from January 1, 2010 - July 31, 2012. The variables pneumonia and V48 undergo logistic regression and risk adjusted results of observed versus expected are calculated. Mean and confidence intervals are represented in caterpillar charts and bar graphs. Statistical analysis was via Fisher exact t test. RESULTS: Progressive improvements were observed over a two-year period via three semiannual reports (SAR). Corrective measures showed a decrease in V48 with an observed to expected odds ratio (O: E) improving from 1.5 to 1.04, or 1.9% ( 7/368 patients) July 31, 2011 to 1.11% (12/1080 patients) July 31, 2012 respectively. Similarly, pneumonia rates decreased 1.36% (5/368 patients) July 31, 2011 to 1.2% ( 13/1081 patients) July 31, 2012 with O: E = 1.4 and 1.25 respectively. Statistical significance was achieved (p < .05). CONCLUSION: Given an estimated annual volume of 20,000 cases per year with a cost of $22,097 per episode of pneumonia and $27,654 per episode of prolonged intubation greater than 48 hours; a projected 32 avoided episodes of pneumonia and 160 avoided episodes of V48 could be realized with potential savings exceeding $5,000,000. PMID- 24817911 TI - A study to assess the feasibility of Text Messaging Service in delivering maternal and child healthcare messages in a rural area of Tamil Nadu, India. AB - BACKGROUND: Mobile text messaging is a potentially powerful tool for behaviour change because it is widely available, inexpensive, and instant. AIMS: To evaluate whether mobile Text Messaging Service is a feasible mode of raising knowledge regarding maternal and child health (MCH) and to explore issues related to mobile text messages as a mode of health education. METHOD: A community-based intervention study was conducted from January to June 2013 in six randomly selected villages of Vellore district, Tamil Nadu. A multi-stage sampling technique was followed: 120 individuals from 120 households (30 clusters in six villages) were contacted. Data was collected using a pretested questionnaire by house-to-house visits in three phases: 1) baseline assessment of aptitude towards text messages; 2) intervention: sending MCH-related text messages; and 3) end line assessment to evaluate the increase in knowledge level. Qualitative data regarding mobile text messages as a mode of health education was explored. Quantitative data was analysed using SPSS version 17.0 and qualitative data by Anthropac software. RESULTS: Of the individuals surveyed, 69.17 per cent and 52.5 per cent were "able to read" and "type and send" text messages, respectively. Seventy per cent of individuals were willing to receive health information via text messages, and 98.33 per cent believed text messages could effectively spread health messages. A significant increase in knowledge was observed following text messages. Male gender and subjects' ability to read text messages were significantly associated. Factors related to mobile phone use include minimum economic burden, easy availability, portability, and ease of use. Factors related to mobile text messages as a mode of health message delivery include direct receipt of information, mass reach, the absence of regional language font in many handsets, and illiterate individuals being unable to read messages. CONCLUSION: In rural areas, mobile text messages have the potential to deliver health messages regarding MCH. PMID- 24817912 TI - Malignant melanoma of soft parts with osteoclast-rich giant cells: A rare tumour of the jejunum. AB - Malignant melanoma of soft parts (MMSP), first described by Franz M. Enzinger, is a rare tumour of unknown cell origin. We describe a case of a 45-year-old male who presented with a one-year history of abdominal pain, weakness, and anaemia. Computerised tomography enteroclysis showed a mass in the jejunum that was suggestive of a gastrointestinal stromal tumour. An ulceroinfiltrative lesion measuring 6.5 x 4 x 2cm was identified. Microscopy revealed typical features of MMSP with numerous osteoclasts-like giant cells. The diverse histomorphology and immunohistochemical characteristics of this case involving a rare tumour at a rare site is presented. PMID- 24817913 TI - A study of antibiogram of Salmonella enterica serovar Typhi isolates from Pondicherry, India. AB - BACKGROUND: Enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi) is an important public health problem in developing countries like India.1 The emergence of resistance to fluoroquinolones has reduced the therapeutic options available. Currently, the uniform laboratory interpretation of ciprofloxacin and azithromycin susceptibility remains unclear. AIMS: To study the antibiogram of S. Typhi isolates with special emphasis on in-vitro activity of ciprofloxacin and azithromycin. METHOD: We evaluated the antimicrobial susceptibility pattern of 16 S. Typhi isolates from January 2012 to June 2013. We also determined by Epsilometer-test (E-test) method, the minimum inhibitory concentration (MIC) of ciprofloxacin and azithromycin against these isolates and compared them with their corresponding disc diffusion sizes. RESULTS: Fifteen (93.75 per cent) isolates were sensitive to chloramphenicol, 14 (87.5 per cent) were sensitive to cotrimoxazole. All isolates were resistant to nalidixic acid. MICs for ciprofloxacin ranged from 6MUg/ml to 15MUg/ml and corresponding zone diameters ranged from 15mm to 26mm. MIC and zone diameters for ciprofloxacin had significant negative correlation. MICs for azithromycin ranged from 3MUg/ml to 24MUg/ml, corresponding zone diameters ranged from 13mm to 19mm. However, MIC and zone diameters for azithromycin had no significant negative correlation. CONCLUSION: The widespread emergence of resistance to fluoroquinolones and reappearance of sensitivity to firstline drugs has reinforced the need for antibiotic recycling. There is a need to have uniform laboratory testing guidelines for testing susceptibility to ciprofloxacin and azithromycin for S. Typhi isolates. PMID- 24817914 TI - Need for involving consumers in Nepal's pharmacovigilance system. AB - In Nepal, reporting of adverse drug reactions (ADRs) occurs on a voluntary basis by doctors, pharmacists, nurses, health assistants, and other healthcare professionals. The country's pharmacovigilance program is still in its infancy; it has limited coverage and underreporting is common. This major limitation could be reduced with consumer involvement. This report examines the necessity and benefits of consumer involvement in Nepal's existing pharmacovigilance program, reflecting on existing examples of consumer pharmacovigilance in different countries to highlight the necessity for such a framework in Nepal. PMID- 24817915 TI - Culture, law, ethics, and social implications: Is society ready for advanced genomic medicine? PMID- 24817916 TI - Training School Mental Health Providers to Deliver Cognitive-Behavioral Therapy. AB - Anxiety disorders are among the most prevalent mental health difficulties experienced by youth. A well-established literature has identified cognitive behavior therapy (CBT) as the gold-standard psychosocial treatment for youth anxiety disorders. Access to CBT in community clinics is limited, but a potential venue for the provision of CBT for child anxiety disorders is the school setting. The present study examined a subset of data from a larger study in which therapists from a variety of settings, including schools, were trained in CBT for child anxiety (N = 17). The study investigated the relationship between provider- and organizational-level variables associated with training and implementation among school mental health providers. The present findings indicate a positive relationship between provider attitudes and adherence to CBT. Self-reported barriers to implementation were also identified. Integrating CBT into school mental health providers' repertoires through training and consultation is a critical step for dissemination and implementation of empirically supported psychosocial treatments. PMID- 24817917 TI - AORTIC PULSE WAVE VELOCITY MEASURED BY PULSE WAVE IMAGING (PWI): A COMPARISON WITH APPLANATION TONOMETRY. AB - BACKGROUND: Arterial stiffness is a well-established indicator of cardiovascular disease outcome. Pulse Wave Velocity (PWV) is a surrogate for arterial stiffness that is measured either globally using carotid to femoral applanation tonometry or locally using biomedical imaging methods. Pulse Wave Imaging (PWI) is an ultrasound-based method for both qualitative visualisation of pulse wave propagation and quantitative estimation of arterial stiffness. The objective of this study is to assess the PWI performance in PWV estimation by comparing local abdominal aortic PWV values obtained by PWI to the carotid-femoral PWV measured by applanation tonometry. METHODS: A total of 18 subjects (age 18-66, 32.5+/ 14.5) with no history of cardiovascular disease were consecutively tested by both PWI and tonometry. RESULTS: The correlation coefficient r between values found by the two methods was found to be equal to 0.68. A linear regression yielded PWVPWI = 1.02* PWVtonometry +0.15. Tukey mean-difference plots indicated that PWVPWI was significantly lower than PWVtonometry (-0.3 m/s) at lower PWV values (PWV<=7 m/s), whereas PWVPWI was significantly higher (+1.4 m/s) than PWVtonometry at higher PWV values (PWV>7 m/s). CONCLUSIONS: Despite the regional nature of the PWVPWI measurements, as opposed to the global PWVtonometry measurements, abdominal PWVPWI and carotid-femoral PWVtonometry values were found to be similar, with an average bias equal to 0.25 m/s. Such a bias and its variation with PWV may be partially explained by both physiological variations of PWV along the arterial tree and by the increasing uncertainty of the PWV estimate by PWI as PWV increases. PMID- 24817918 TI - 'Skin Trade': Genealogy of Anti-ageing 'Whiteness Therapy' in Colonial Medicine. AB - This article investigates the extent to which the emerging trend of do-it yourself anti-ageing skin-whitening products represents a re-articulation of Western colonial concerns with environmental pollution and racial degeneracy into concern with gendered vulnerability. This emerging market is a multibillion dollar industry anchored in the USA, but expanding globally. Do-it-yourself anti ageing skin-whitening products purport to address the needs of those looking to fight the visible signs of ageing, often promising to remove hyper-pigmented age spots from women's skin, and replace it with ageless skin, free from pigmentation. In order to contextualize the investigation of do-it-yourself anti ageing skin-whitening practice and discourse, this article draws from the literature in colonial commodity culture, colonial tropical medicine, the contemporary anti-ageing discourse, and advertisements for anti-ageing skin whitening products. First, it argues that the framing of the biomedicalization of ageing as a pigmentation problem caused by deteriorating environmental conditions and unhealthy lifestyle draws tacitly from European colonial concerns with the European body's susceptibility to tropical diseases, pigmentation disorders, and racial degeneration. Second, the article argues that the rise of do-it-yourself anti-ageing skin-whitening commodities that promise to whiten, brighten, and purify the ageing skin of women and frames the visible signs of ageing in terms of pigmentation pathology. PMID- 24817919 TI - The role of Wnt signaling pathway in carcinogenesis and implications for anticancer therapeutics. AB - The Wnt proteins are a family of 19 secreted glycoproteins that occupy crucial roles in the regulation of processes such as cell survival, proliferation, migration and polarity, cell fate specification, body axis patterning and self renewal in stem cells. The canonical pathway has been implicated in a variety of cancers. As such, it is only fair to conclude that therapies targeting the Wnt pathway may play an essential role in the future of anticancer therapeutics, both alone or in conjunction with traditional therapies. PMID- 24817920 TI - Two-micron (Thulium) Laser Prostatectomy: An Effective Method for BPH Treatment. AB - The two-micron (thulium) laser is the newest laser technique for treatment of bladder outlet obstruction resulting from benign prostatic hyperplasia (BPH). It takes less operative time than standard techniques, provides clear vision and lower blood loss as well as shorter catheterization times and hospitalization times. It has been identified to be a safe and efficient method for BPH treatment regardless of the prostate size. PMID- 24817921 TI - Elucidating Oxygen Reduction Active Sites in Pyrolyzed Metal-Nitrogen Coordinated Non-Precious-Metal Electrocatalyst Systems. AB - Detailed understanding of the nature of the active centers in non-precious-metal based electrocatalyst, and their role in oxygen reduction reaction (ORR) mechanistic pathways will have a profound effect on successful commercialization of emission-free energy devices such as fuel cells. Recently, using pyrolyzed model structures of iron porphyrins, we have demonstrated that a covalent integration of the Fe-N x sites into pi-conjugated carbon basal plane modifies electron donating/withdrawing capability of the carbonaceous ligand, consequently improving ORR activity. Here, we employ a combination of in situ X-ray spectroscopy and electrochemical methods to identify the various structural and functional forms of the active centers in non-heme Fe/N/C catalysts. Both methods corroboratively confirm the single site 2e- * 2e- mechanism in alkaline media on the primary Fe2+-N4 centers and the dual-site 2e- * 2e- mechanism in acid media with the significant role of the surface bound coexisting Fe/Fe x O y nanoparticles (NPs) as the secondary active sites. PMID- 24817922 TI - Probing the Quenching of Quantum Dot Photoluminescence by Peptide-Labeled Ruthenium(II) Complexes. AB - Charge transfer processes with semiconductor quantum dots (QDs) have generated much interest for potential utility in energy conversion. Such configurations are generally nonbiological; however, recent studies have shown that a redox-active ruthenium(II)-phenanthroline complex (Ru2+-phen) is particularly efficient at quenching the photoluminescence (PL) of QDs, and this mechanism demonstrates good potential for application as a generalized biosensing detection modality since it is aqueous compatible. Multiple possibilities for charge transfer and/or energy transfer mechanisms exist within this type of assembly, and there is currently a limited understanding of the underlying photophysical processes in such biocomposite systems where nanomaterials are directly interfaced with biomolecules such as proteins. Here, we utilize redox reactions, steady-state absorption, PL spectroscopy, time-resolved PL spectroscopy, and femtosecond transient absorption spectroscopy (FSTA) to investigate PL quenching in biological assemblies of CdSe/ZnS QDs formed with peptide-linked Ru2+-phen. The results reveal that QD quenching requires the Ru2+ oxidation state and is not consistent with Forster resonance energy transfer, strongly supporting a charge transfer mechanism. Further, two colors of CdSe/ZnS core/shell QDs with similar macroscopic optical properties were found to have very different rates of charge transfer quenching, by Ru2+-phen with the key difference between them appearing to be the thickness of their ZnS outer shell. The effect of shell thickness was found to be larger than the effect of increasing distance between the QD and Ru2+ phen when using peptides of increasing persistence length. FSTA and time-resolved upconversion PL results further show that exciton quenching is a rather slow process consistent with other QD conjugate materials that undergo hole transfer. An improved understanding of the QD-Ru2+-phen system can allow for the design of more sophisticated charge-transfer-based biosensors using QD platforms. PMID- 24817923 TI - Olfactory Neuron Patterning and Specification. PMID- 24817924 TI - Screening, management and surveillance for the sessile serrated adenomas/polyps. AB - The incidence and mortality rates from right-sided colorectal cancers (CRCs) have not decreased, compared with the significant reduction of CRCs in the left colon in recent years. It is likely that a significant proportion of right-sided CRCs evolve from undetected sessile serrated adenomas/polyps (SSA/Ps) in the primary colonoscopy. Increasing evidences suggest that SSA/Ps are high-risk lesions, with 15% of the SSA/P patients developing subsequent CRCs or adenomas with high-grade dysplasia. However, there are many issues in the screening, management and surveillance of SSA/Ps. Based on new evidences, this review addresses major issues in the diagnostic criteria for the serrated polyps of the colorectum, new endoscopic techniques (high-resolution magnifying endoscopy, narrow-band imaging, autofluorescence imaging, confocal laser endoscopy, and endocytoscopy) for the realtime identification of SSA/Ps, and the management of SSA/Ps by endoscopic mucosal resection, endoscopic sub-mucosal dissection or surgical resection in practice. PMID- 24817925 TI - Long non-coding RNAs as novel biomarkers and therapeutic targets in head and neck cancers. AB - Long non-coding RNAs (lncRNAs) are generally defined as RNA molecules greater than 200 nt in length and without protein-coding property that different from housekeeping RNAs such as tRNAs, rRNAs, and snRNAs, and independent from small RNAs with specific molecular processing machinery such as micro- or piwi-RNAs. LncRNAs are a novel class of mRNA-like transcripts which contribute to cancer development and progression and accelerate cancer cells proliferation, invasion, metastasis, and apoptosis. These research results indicate the potential of lncRNAs as prospective novel biomarkers for diagnosis, therapeutic targets and prognosis for cancers. In this review, we synthesize present study results to highlight aberration of lncRNAs in various types of head and neck cancers, and try to clarify the molecular mechanisms of lncRNAs affecting the oncogenesis and progression of head and neck cancer, as well as pay particular attention to provide a new avenue to the diagnosis and treatment strategy. PMID- 24817926 TI - Clarifying the nomenclature of intervertebral disc degeneration and displacement: from bench to bedside. AB - As a significant determinant of low back pain, intervertebral disc degeneration (IDD) has attracted more and more attention of both investigators and physicians. Disc herniation, termed as intervertebral disc displacement, is amongst the most prevalent spinal diseases closely linked with IDD. Due to the same origins and similar pathophysiology, the ambiguity regarding the similarity and difference of IDD and intervertebral disc displacement thus remains. The aim of this study was to clarify the nomenclature of IDD and disc herniation in terms of molecular etiology, pathophysiology, nature history and clinical outcomes. Collectively, IDD is a type of multifaceted, progressive spinal disease with or without clinical symptoms as back pain, characterized by extracellular matrix and the integrity of NP and AF lost, fissures formation. Disc herniation (termed as intervertebral disc displacement) is a type of spinal disease based on IDD or not, with local pain and/or sciatica due to mechanical compression and autoimmune cascades upon the corresponding nerve roots. Clarifying the nomenclature of intervertebral disc degeneration and displacement has important implications both for investigators and for physicians. PMID- 24817927 TI - Valproic acid overcomes transforming growth factor-beta-mediated sorafenib resistance in hepatocellular carcinoma. AB - Sorafenib is a multi-kinase inhibitor approved for hepatocellular carcinoma, but rarely causes tumor regression in patients with chronic liver diseases. To investigate whether growth factor-mediated signaling is involved in sorafenib resistance, HepG2 and PLC/PRF/5 hepatoma cells were exposed to epidermal growth factor (EGF), hepatocyte growth factor (HGF) or transforming growth factor-beta (TGF-beta) prior to treatment with sorafenib. Furthermore, to identify an effective combination treatment with sorafenib, growth factor-sensitized cells were treated with sorafenib alone or in combination with celecoxib, lovastatin or valproic acid (VPA). Trypan blue staining and Annexin V assays showed that the cytotoxic effect of sorafenib was inhibited by 15-54% in cells sensitized to TGF beta (P<0.05). Western blotting analysis showed that TGF-beta significantly activated extracellular signal-regulated kinase (ERK)-mediated AKT signaling, and sorafenib failed to suppress both ERK and AKT in TGF-beta-sensitized cells. The decreased anti-tumor effect of sorafenib was rescued by chemical inhibition of ERK and AKT. When TGF-beta-sensitized cells were treated with sorafenib plus VPA, the levels of phosphorylated ERK and AKT were considerably suppressed and the numbers of dead cells were increased by 3.7-5.7-fold compared with those exposed to sorafenib alone (P<0.05). Moreover, low dose sorafenib-induced cell migration was effectively suppressed by combination treatment with sorafenib and VPA. Collectively, TGF-beta/ERK/AKT signaling might play a critical role in sorafenib resistance in hepatoma cells, and combination treatment with VPA may be effective against this drug resistance. PMID- 24817928 TI - Cardiac troponin I is abnormally expressed in non-small cell lung cancer tissues and human cancer cells. AB - Cardiac troponin I (cTnI) is the only sarcomeric protein identified to date that is expressed exclusively in cardiac muscle. Its expression in cancer tissues has not been reported. Herein, we examined cTnI expression in non-small cell lung cancer (NSCLC) tissues, human adenocarcinoma cells SPCA-1 (lung) and BGC 823 (gastric) by immunohistochemistry, western blot analysis and real-time PCR. Immunopositivity for cTnI was demonstrated in 69.4% (34/49) NSCLC tissues evaluated, and was strong intensity in 35.3% (6/17) lung squamous cell carcinoma cases. The non-cancer-bearing lung tissues except tuberculosis (9/9, 100%) showed negative staining for cTnI. Seven monoclonal antibodies (mAbs) against human cTnI were applied in immunofluorescence. The result showed that the staining pattern within SPCA-1 and BGC 823 was dependent on the epitope of the cTnI mAbs. The membrane and nucleus of cancer cells were stained by mAbs against N-terminal peptides of cTnI, and cytoplasm was stained by mAbs against the middle and C terminal peptides of cTnI. A ~25 kD band was identified by anti-cTnI mAb in SPCA 1 and BGC 823 extracts by western blot, as well as in cardiomyocyte extracts. The cTnI mRNA expressions in SPCA-1 and BGC 823 cells were about ten thousand times less than that in cardiomyocytes. Our study shows for the first time that cTnI protein and mRNA were abnormally expressed in NSCLC tissues, SPCA-1 and BGC 823 cells. These findings challenge the conventional view of cTnI as a cardiac specific protein, enabling the potential use of cTnI as a diagnostic marker or targeted therapy for cancer. PMID- 24817929 TI - Expression profiling of long noncoding RNAs and the dynamic changes of lncRNA NR024118 and Cdkn1c in angiotensin II-treated cardiac fibroblasts. AB - A growing body of evidence shows that long non-coding RNAs (lncRNAs) are involved in multiple human diseases than previously realized. However, no information is available now about lncRNAs in cardiac fibroblasts. The expression profile of lncRNAs was analyzed in Ang II-treated cardiac fibroblasts using lncRNAs arrays. The analysis showed that 282 of 4376 detected lncRNAs demonstrated >2-fold differential expression in response to the treatment with Ang II (100 nm) for 24 h. Among of them, 22 lncRNAs showed a greater than 4-fold changes. Meanwhile, Ang II also induced a widely expression changes in protein-coding genes in cardiac fibroblasts. Quantitative real time PCR confirmed the changes of six lncRNAs (AF159100, BC086588, MRNR026574, MRAK134679, NR024118, AX765700) and mRNAs (IL6, RGS2, PRG4, TIMP1, Cdkn1c, TIMP3, Col I, Col III and Fibronectin) in cardiac fibroblasts. Bioinformatic analysis indicated the process of cell proliferation. Further studies revealed that the down-regulating of Ang II on the expression of lncRNA-NR024118 was time-dependent, that the level of NR024118 was lowest at 24 h and back at 48 h. Ang II also dynamically down regulated the expression of Cdkn1c in cardiac fibroblasts. Ang II at a range from 10(-9) M to 10(-6) M induced a decrease of NR024118 and Cdkn1c in cardiac fibroblasts. In conclusion, the expression profile of lncRNAs was significantly altered in the Ang II-treated cardiac fibroblasts and Ang II dynamically regulated the expression of lncRNA NR024118 and Cdkn1c in cardiac fibroblasts, indicating the potential role of NR024118 in cardiac fibroblasts. PMID- 24817930 TI - Increasing the cytotoxicity of doxorubicin in breast cancer MCF-7 cells with multidrug resistance using a mesoporous silica nanoparticle drug delivery system. AB - Resistance to cytotoxic chemotherapy is the main cause of therapeutic failure and death in women with breast cancer. Overexpression of various members of the superfamily of adenosine triphosphate binding cassette (ABC)-transporters has been shown to be associated with multidrug resistance (MDR) phenotype in breast cancer cells. MDR1 protein promotes the intracellular efflux of drugs. A novel approach to address cancer drug resistance is to take advantage of the ability of nanocarriers to sidestep drug resistance mechanisms by endosomal delivery of chemotherapeutic agents. Doxorubicin (DOX) is an anthracycline antibiotic commonly used in breast cancer chemotherapy and a substrate for ABC-mediated drug efflux. In the present study, we developed breast cancer MCF-7 cells with overexpression of MDR1 and designed mesoporous silica nanoparticles (MSNs) which were used as a drug delivery system. We tested the efficacy of DOX in the breast cancer cell line MCF-7/MDR1 and in a MCF-7/MDR1 xenograft nude mouse model using the MSNs drug delivery system. Our data show that drug resistance in the human breast cancer cell line MCF-7/MDR1 can be overcome by treatment with DOX encapsulated within mesoporous silica nanoparticles. PMID- 24817931 TI - SERPINA3 promotes endometrial cancer cells growth by regulating G2/M cell cycle checkpoint and apoptosis. AB - Endometrial carcinoma (EC) is the most common gynecologic cancer worldwide and is one of the leading causes of death in women. Therefore, it is urgent to elucidate the pathological mechanisms of EC. SERPINA3 is a member of the serpin super family of protease inhibitors. Its aberrant expression has been observed in various tumor cells. However, its clinical significance and biological function in endometrial cancer remains unknown. In the present study, we demonstrated that SERPINA3 expression was significantly up-regulated in EC samples and was closely correlated with lower differentiation, higher stage, positive lymph node or vascular thrombosis and negative estrogen receptor (ER), indicating a poor prognosis. We then demonstrated that SERPINA3 promoted EC cells proliferation by regulating G2/M checkpoint in cell cycle and inhibited cells apoptosis, and we further uncovered that the pro-proliferative effect of SERPINA3 on EC was likely ascribed to the activation of MAPK/ERK1/2 and PI3K/AKT signaling. The results of our study may provide insight into the application of SERPINA3 as a novel predictor of clinical outcomes and a potential therapeutic target of EC. PMID- 24817932 TI - WNT3A gene expression is associated with isolated Hirschsprung disease polymorphism and disease status. AB - WNT3A has been regarded as an activator of the canonical Wnt signaling pathway. It has been found Wnt signaling pathway is closely related with embrionic development and Hirschsprung disease (HSCR). A common haplotype consisting of minor SNPs alleles located in the WNT3A gene has been described as a risk factor for various genetic disorders. However, whether WNT3A contributes to the onset of HSCR has not been identified. The present study aims to detect the interactions of genetic variations in the WNT3A gene and examine the biological expression levels with Hirschsprung disease (HSCR) in the Chinese people. We analyzed WNT3A gene (rs61743220, rs192966556 and rs145882986) variants in the whole blood samples from HSCR patients and normal children (control groups). WNT3A expression was also examined by quantitative real-time PCR (qRT-PCR), western blotting and immunostaining. Consequently, when rs192966556 and rs145882986 alleles of the WNT3A gene lack the SNPs, they are especially associated with a greater risk of HSCR (OR [95% confidence interval]=1.791, p=0.001; OR [95% confidence interval]=1.556, p=0.003, respectively). The mRNA and protein expressions of WNT3A were higher in the aganglionic colon segment tissues than in the normal ganglionic segments tissues. Immunostaining indicates that the staining of WNT3A was much stronger (brown) in the aganglionic colon segment tissues than that in the normal ganglionic colon segment tissues (colorless or light yellow) in the mucous layer and muscular layer. Although preliminary, these results suggest that WNT3A may play an important role in the pathogenesis of HSCR. PMID- 24817933 TI - Early articular cartilage degeneration in a developmental dislocation of the hip model results from activation of beta-catenin. AB - Developmental dislocation or dysplasia of the hip (DDH) is one of the most common deformities in children. Osteoarthritis (OA) is the most frequent long-term complication. The molecular mechanism of early articular cartilage degeneration in DDH is still unclear. It is well known that beta-catenin plays a crucial role in articular cartilage degeneration. The objective of this study was to verify the relationship between beta-catenin and DDH cartilage degeneration. We used a DDH model that was established by modification of swaddling position in newborn Wistar rats. The hips were isolated from the DDH model rats and untreated control group at the age of 2, 4, 6 and 8 weeks. beta-Catenin gene and protein were investigated by quantitative (q)RT-PCR and immunohistochemistry. Collagen X and matrix metalloproteinase (MMP)-13, markers of early cartilage degeneration, were assessed by qRT-PCR. Primary chondrocytes were cultured from cartilage of two groups at the age of 8 weeks. Expression of beta-catenin, collagen X and MMP-13 was detected. Continued high expression of beta-catenin was observed in cartilage from DDH model rats. mRNA and protein expression of beta-catenin was significantly increased in primary chondrocytes of the DDH model compared with the control group. Collagen X and MMP-13 expression was higher in the cartilage and chondrocytes from DDH model rats than the control group. Our findings suggest that early cartilage degeneration in DDH may result from activation of beta catenin signaling. PMID- 24817934 TI - Cyclosporine A improves adhesion and invasion of mouse preimplantation embryos via upregulating integrin beta3 and matrix metalloproteinase-9. AB - Our previous study has demonstrated cyclosporin A (CsA) promotes the migration and invasiveness of human first-trimester trophoblast cells in vitro. Here, we further investigated the effect of CsA on the early implantation in vitro of mouse embryo. Female C57 mice were superovulated and mated, and then two-cell embryos were harvested from the oviducts and sequentially cultured in vitro in G1 and G2 media with 0, 0.1, 1.0 or 10 MUM of CsA. Blastocyte formation, blastocyte cell number and apoptosis, embryo hatching were assessed in 4-6 dpc. The adhesion and stretching growth of hatched embryos in laminin coated dishes were evaluated from 5 dpc to 8 dpc, and the expressions of implantation serine proteinase 1 (ISP1), integrin (itg) beta3 and matrix metalloproteinase (MMP)-9 were determined by real time PCR and immunofluorescence, respectively. We showed there was no significant difference in blastocyst formation rates, hatching rates, number of whole embryonic cells, apoptotic cells, and distribution of inner cell masses (ICMs) and trophoblasts (TB) between the CsA- and control-treated groups. Expression of ISP1 mRNA was unaffected on 5 dpc. After hatching, adhesion rate of 7 dpc significantly increased in 0.1 and 1.0 MUM of CsA treatment, and embryo area of 8 dpc stretch growing on laminin were increased in 1.0 MUM of CsA. The mRNA and protein expression of itgbeta3 and MMP-9 on 7 dpc blastocyst were up regulated. In conclusion, CsA in low dosage up-regulates itgbeta3 and MMP-9 expression, and enhances embryonic adhesion and invasion, which is beneficial to the embryo implantation. PMID- 24817935 TI - Heterogeneity of microRNAs expression in cervical cancer cells: over-expression of miR-196a. AB - In recent years, the study of microRNAs associated with neoplastic processes has increased. Patterns of microRNA expression in different cell lines and different kinds of tumors have been identified; however, little is known about the alterations in regulatory pathways and genes involved in aberrant set of microRNAs. The identification of these altered microRNAs in several cervical cancer cells and potentially deregulated pathways involved constitute the principal goals of the present study. In the present work, the expression profiles of cellular microRNAs in Cervical Cancer tissues and cell lines were explored using microRNA microarray, Affymetrix. The most over-expressed was miR 196a, which was evaluated by real time PCR, and HOXC8 protein as potential target by immunohistochemistry assay. One hundred and twenty three human microRNAs differentially expressed in the cell tumor, 64 (52%) over-expressed and 59 (48%) under-expressed were observed. Among the microRNAs over-expressed, we focused on miR-196a; at present this microRNA is poorly studied in CC. The expression of this microRNA was evaluated by qRT-PCR, and HOXC8 by immunohistochemistry assay. There is not a specific microRNA expression profile in the CC cells, neither a microRNA related to HPV presence. Furthermore, the miR-196a was over-expressed, while an absence of HOXC8 expression was observed. We suggest that miR-196a could be played as oncomiR in CC. PMID- 24817936 TI - NCAM and FGFR1 coexpression and colocalization in renal tumors. AB - Neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor (FGFR) have a role in epithelial-mesenchymal transformation during tumor genesis. Interplay between both molecules activates FGFR signaling and it could be responsible for tumor development. Renal epithelial tumors were analyzed for FGFR1 and NCAM coexpression by immunohistochemistry and for colocalization of these molecules on the particular tumor cells by triple immunofluorescence. Detection of NCAM isoforms in renal tumors was evaluated by RT-PCR. Applying immunohistochemistry we revealed that the majority of analyzed renal neoplasms, including renal cell carcinoma (RCC) and oncocytoma coexpressed NCAM and FGFR1. Triple immunofluorescent technique confirmed that both markers are commonly colocalized on the same tumor cells. Interestingly, it seemed that different position of NCAM and FGFR1 expression on renal tumor cells is related to renal tumor type or grade: exclusively membranous FGFR1/NCAM expression occurred in low grade clear cell RCC (cRCC); cytoplasmatic and membranous expression was present in high grade cRCC and other RCC types; oncocytoma showed only cytoplasmatic staining of both markers. NCAM-140 and NCAM-120 were detected in almost all analyzed renal neoplasms. Expression of both molecules on different cell compartments in various kidney tumors indicated that NCAM/FGFR1 interaction could play distinct roles in renal tumor genesis. PMID- 24817937 TI - Comparison of the efficacy of bone marrow mononuclear cells and bone mesenchymal stem cells in the treatment of osteoarthritis in a sheep model. AB - OBJECTIVE: To evaluate the therapeutic efficacy of uncultured bone marrow mononuclear cells (BMMCs) and bone mesenchymal stem cells in an osteoarthritis (OA) model of sheep. METHODS: Induction of sheep OA was performed surgically through anterior cruciate ligament transection and medial meniscectomy. After 12 weeks, concentrated BMMCs obtained from autologous bone marrow harvested from anterior iliac crest or a single dose of 10 million autologous bone mesenchymal stem cells (BMSCs) suspended in phosphate-buffered saline (PBS) was delivered to the injured knee via direct intra-articular injection. Animals of the PBS group received vehicle alone. The contra-lateral joints were selected randomly as the control group. Knees of the four groups were compared macroscopically and histologically, and glycosaminoglycan (GAG) contents normalized to cartilage wet weight were measured at lesions of cartilage from medial condyle of the femur head. Gene expression levels of type II collagen (Col2A1), Aggrecan and matrix metalloproteinase-13 (MMP-13) in cartilage were measured based on RT-PCR and prostaglandin E2 (PGE2), Tumor Necrosis Factor-alpha (TNF-alpha) and Transforming Growth Factor beta (TGF-beta) concentrations in synovial fluid were determined with ELISA assays at 8 weeks after injection. RESULTS: At 8 weeks post cell transplantation, partial cartilage repair was observed in the cell therapy, but not the PBS group (P<0.05). The BMSCs group showed higher regeneration of cartilage and lower proteoglycan loss than the BMMCs group (P<0.05). Concentrated BMMCs injection led to a weaker treatment effect, but also inhibited PGE2, TNF alpha and TGF-beta levels in synovial fluid and promoted higher levels of Aggrecan and Col2A1 and downregulation of MMP-13 in sheep chondrocytes in a similar manner to BMSCs, compared with the PBS group. CONCLUSIONS: Bone marrow cells showed therapeutic efficacy in a sheep model of OA. Despite similar therapeutic potential, the easier and faster process of collection and isolation of BMMCs supports their utility as an effective alternative for OA treatment in the clinic. PMID- 24817938 TI - Pregnancy-associated plasma protein A up-regulated by progesterone promotes adhesion and proliferation of trophoblastic cells. AB - Embryo implantation and development is a complex biological process for the establishment of the successful pregnancy. Progesterone is a critical factor in the regulation of embryo adhesion to uterine endometrium and proliferation. Although it has been reported that pregnancy-associated plasma protein A (PAPPA) is increased in pregnant women, the relationship between progesterone and PAPPA, and the effects of PAPPA on embryo adhesion and proliferation are still not clear. The present results showed that the serum level of progesterone and PAPPA was closely correlated by ELISA assay (p<0.01). PAPPA was detected in the villi of early embryo by RT-PCR, Western blot, immunohistochemistry and immunofluorescent staining. Moreover, PAPPA was significantly up-regulated by progesterone in trophoblastic (JAR) cells by Real-time PCR and ELISA assay (p<0.01); while the expression was decreased by the progesterone receptor inhibitor RU486. The down-regulation of PAPPA by siRNA transfection or up regulation of PAPPA by progesterone treatment significantly decreased or increased the adhesion rate of trophoblastic cells to human uterine epithelial cell lines (RL95-2 and HEC-1A), respectively (p<0.01), as well as the proliferation of trophoblastic cells. In conclusion, PAPPA is up-regulated by progesterone, which promotes the adhesion and proliferation potential of trophoblastic cells. PMID- 24817939 TI - Features of gastric glomus tumor: a clinicopathologic, immunohistochemical and molecular retrospective study. AB - Glomus tumor (GT) of the stomach is a rare mesenchymal tumor. There have been few detailed studies on these tumors. A total of 1894 cases of resected gastric mesenchymal tumors were collected and eleven confirmed gastric GTs were studied. The clinical, pathological, immunohistochemical, ultrastructural and molecular characteristics of the tumors were analyzed through a retrospective study. Histologically, most tumors had gastric smooth muscle immediately adjacent and surrounding the tumor. Tumor cells around blood vessels were small, uniform, and round. Foci of hyaline and myxoid changes were observed. Prominent clear cell features were observed in two tumors. Positive expression of alpha-smooth muscle actin (alpha-SMA), laminin, collagen type IV, and vimentin was detected by immunohistochemical analysis in all patients. However, in clear cell areas the expression of alpha-SMA, laminin, and type IV collagen were mild, while Syn was positive. Moreover, myofibrils and neuroendocrine granules were also present in the cytoplasm of these cells. No C-kit or PDGFR-alpha genetic mutations were detected in all patients. To conclude, Our results show that GTs in the stomach are histologically and immunophenotypically fully comparable with the glomus tumors of peripheral soft tissues. Neuroendocrine granules and neuroendocrine differentiation were identified in some of the gastric GT cells. Thus, a novel subtype of gastric glomus tumor expressing neuroendocrine cell markers may exist. PMID- 24817940 TI - AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel. AB - Paclitaxel (PTX) has shown encouraging activity in the treatment of advanced gastric cancer (GC). However, the fact that more than half of GC patients respond poorly to PTX-based chemotherapies demonstrates the urgent need for biomarkers of PTX sensitivity in GC patients. In the present work, three GC cell lines (BGC 823, HGC-27 and NCI-N87) with different sensitivities to PTX were subjected to DNA microarray analysis. The significantly differentially expressed genes and microRNAs (miRs) were identified and pathway signatures for PTX sensitivity were proposed. Ingenuity Pathway Analysis results showed that the differentially expressed genes were mainly enriched in the ErbB signaling pathway and other pathways. Additionally, the AKT/ERK signaling pathway, which is the pathway downstream of ErbB, was predicted to be active in PTX-resistant GC cell lines. ErbB3 overexpression and AKT/ERK activation in PTX-resistant cell lines were validated, respectively, by quantitative PCR and immunoblotting. Furthermore, 10 miRs were dramatically differently expressed in the three GC cell lines, and a miR-gene network was constructed from these data. Our work uncovered a reliable signature for PTX sensitivity in GC and potential therapeutic targets for GC treatments. PMID- 24817941 TI - Lepidic and micropapillary growth pattern and expression of Napsin A can stratify patients of stage I lung adenocarcinoma into different prognostic subgroup. AB - Histologic categories and related growth pattern proposed by IASLC/ATS/ERS classification has been reported to be prognostically important in lung adenocarcinoma. Thyroid transcription factor-1 (TTF1) and Napsin A have been investigated as potential prognostic parameters with conflicting results. A total of 211 cases with stage I lung adenocarcinoma were analyzed according to the IASLC/ATS/ERS classification with slight modifications. Expression levels of TTF1 and Napsin A were evaluated by immunohistochemistry. In univariate analyses, we found female sex (p=0.009), lepidic growth pattern (P=0.011) and lack of micropapillary pattern (P=0.048) were favorable predictor significantly associated with disease-free survival (DFS). Lack of mitosis (P=0.044) and Napsin A expression (P=0.031) were favorable predictors for overall survival (OS). Tumors with a maximum diameter<=2 cm had both longer DFS (P=0.008) and OS (P=0.020). Negative TTF1 expression indicated increased risk of death, but failure in statistical significance (P=0.215). After multivariate analysis, histologic subtype, tumor size and gender were identified as independent predictor for DFS (RR: 0.343, 3.697, 0.494; P=0.006, 0.029, 0.019), no feature was found as an independent predictor for overall survival (P>0.05). To conclude, lepidic growth pattern, female sex and tumor size<=2 cm are independent favorable predictors for tumor recurrence, tumors with more than 5% percentage of lepidic growth pattern will have a better prognosis than absence, in early-stage lung adenocarcinoma. PMID- 24817942 TI - Ultrastructural features of endometrial-myometrial interface and its alteration in adenomyosis. AB - The endometrial-myometrial interface (EMI) is a specific functional region of uterus. However, our knowledge on EMI ultrastructure both in normal uterus and adenomyosis is far from enough to understand its pathology. In this study, used the samples of EMI and outer myometrium (OM) from the adenomyosis hysterectomy specimens and the subjects from the control uteri, we prospectively compared the ultrastructure of myocytes from EMI and OM, the ultrastructural changes of EMI between the proliferative and secretory phases, and the ultrastructural difference of EMI between adenomyosis and the control group. In both adenomyosis and control group, there were differences in ultrastructure between myocytes from EMI and OM. Specifically, the myocytes from EMI were rich in organelles. In contrast, the myocytes from OM had abundant contractile structural components. In the proliferative phase, the myocytes from EMI in adenomyosis had significantly smaller cell and nucleus diameter than those from the control group, but in the secretory phase, the difference was not significant. In the control group, the various ultrastructural features of myocytes from EMI including the mean diameter of cell and nuclei and the myofilaments/cytoplasm ratio exhibited cyclical changes, but in adenomyosis, the normal cyclical changes were absent. In conclusions, there are significant ultrastructural differences between the myocytes from EMI and OM. The myocytes in women with adenomyosis were significantly different to the control subjects, primarily because the normal cyclical changes were absent. PMID- 24817943 TI - Directed differentiation of skin-derived precursors into fibroblast-like cells. AB - Skin-derived precursors (SKPs), which are located at skin's dermis, display multi lineage potential and can produce both neural and mesodermal progeny in vitro. SKPs are considered to take part in dermal reconstruction and may be an important source of fibroblast during wound repairing. To explore the possibility of differentiation of SKPs into fibroblasts, the 3(rd) passage SKPs were treated with 0, 20, 40, 100, or 500 ng/ml human recombinant connective tissue growth factor (CTGF) for 48 h or treated with 100 ng/ml CTGF for 0, 24, 48, 72, or 96 h. Subsequently, a series of methods were to be used to observe cells immunocytochemistry changes under fluorescence microscope, to validate the mRNA expression change of collagen I, collagen III, fibroblast-specific protein 1 (FSP 1) and alpha smooth muscle actin (alpha-SMA) by quantitative real-time reverse transcriptase polymerase chain reaction (QRT-PCR), to analyze the expression of collagen I and collagen III protein by Enzyme-linked immunosorbent assay (ELISA), to semiquantitatively measure the expression of FSP-1 and alpha-SMA by western blot. After differentiation, cells showed that positively staining for collagen I, collagen III, alpha-SMA, and FSP-1, which are markers for fibroblasts, but negative expression for neural precursors. The effects of CTGF on collagen I, collagen III, FSP-1 and alpha-SMA in SKPs were detected both on the transcriptional and posttranscriptional levels. These findings indicate that SKPs can be induced to differentiate into fibroblast-like cells with CTGF treatment that may be a key source of fibroblast in wound healing. PMID- 24817944 TI - Bumetanide protects focal cerebral ischemia-reperfusion injury in rat. AB - OBJECTIVE: Bumetanide has been reported to attenuate ischemia-evoked cerebral edema. However, whether bumetanide can protect cerebral ischemia-reperfusion injury (IRI) in vivo is unclear. In the present study, we aim to determine whether intravenously injection bumetanide can attenuate cerebral IRI and if its protection effect might be related to the modification of cerebral NKCC1 and KCC2 protein expression. METHODS: Focal cerebral ischemia was induced by occluding the right middle cerebral artery (MCAO) for 2-h, followed by 3-h, 24-h or 48-h of reperfusion respectively. Brain edema, neurological deficits, and infarction volume were determined by (wet weights-dry weights)/dry weights*100, 5-point neurological function score evaluation system, and TTC staining, respectively. The expression levels of NKCC1 and KCC2 were determined by immunohistochemical staining. RESULTS: Reperfusion increased brain edema, neurological deficits, and infarction volume. Bumetanide decreased brain edema, attenuated the neurological defects and reduced post-ischemic cerebral infarction. Cerebral ischemia reperfusion injury increased NKCC1 expression level and decreased KCC2 expression level. Interestingly, bumetanide down-regulated the NKCC1 protein expression level without changing the KCC2 protein expression level in rat brain cortex. CONCLUSION: These results suggest that bumetanide protects focal cerebral ischemia-reperfusion injury in rat, which might through the inhibition of NKCC1. PMID- 24817945 TI - Acute and subacute toxicity study of 1,8-cineole in mice. AB - The effects of acute and subacute toxicity of 1,8-cineole in Kunming mice were studied. After acute oral administration, the LD50 value (95% CL) was 3849 mg/kg (3488.8~4247.1 mg/kg). In the subacute toxicity study, there were no significant differences in body weight and relative organ weight between the control group and 1,8-cineole treatment groups. The histopathological examinations showed that granular degeneration and vacuolar degeneration appeared in liver and kidney tissue after administration of high dose of 1,8-cineole. Under electron microscopy, a series of ultrastructural changes were observed: The electron microscopy assays indicated that the influence of 1,8-cineole on the target organ at the subcellular level were mainly on the mitochondria, endoplasmic reticulum and other membrane type structure of liver and kidney. PMID- 24817946 TI - Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma. AB - Cisplatin resistance is a major problem affecting ovarian carcinoma treatment. NF E2-related factor 2 (Nrf2), a nuclear transcription factor, plays an important role in chemotherapy resistance. However, the underlying mechanism by which Nrf2 mediates cisplatin chemoresistance is unclear. METHODS: The human ovarian carcinoma cell line, A2780, and its cisplatin-resistant variant, A2780cp were cultivated. Cell viability was determined with WST-8 assay. Western blot was applied to detect the expression of Nrf2, Nrf2 target genes, and autophagy related proteins. RNA interference was used to knock down target genes. Annexin V and propidium iodide (PI) staining was utilized to quantify apoptosis. The ultrastructural analysis of autophagosomes was performed by transmission electron microscopy (TEM). RESULTS: Nrf2 and its targeting genes, NQO1 and HO-1, are overexpressed in A2780cp cells compared with A2780 cells. Knocking down Nrf2 sensitized A2780cp cells to cisplatin treatment and decreased autophagy-related genes, Atg3, Atg6, Atg12 and p62 in both mRNA and protein levels. Furthermore, we demonstrated that in both cell lines cisplatin could induce the formation of autophagosomes and upregulate the expression of autophagy-related genes Atg3, Atg6 and Atg12. Treatment with an autophagy inhibitor, 3-Methyladenine (3-MA), or beclin 1 siRNA enhanced cisplatin-induced cell death in A2780cp cells, suggesting that inhibition of autophagy renders resistant cells to be more sensitive to cisplatin. Taken together, Nrf2 signaling may regulate cisplatin resistance by activating autophagy. CONCLUSIONS: Nrf2-activated autophagy may function as a novel mechanism causing cisplatin-resistance. PMID- 24817947 TI - DNA microarray reveals ZNF195 and SBF1 are potential biomarkers for gemcitabine sensitivity in head and neck squamous cell carcinoma cell lines. AB - Gemcitabine is a potential chemotherapy drug for treatment of head and neck squamous cell carcinoma (HNSCC), however, the poor or partial response of HNSCC patients to gemcitabine demonstrated the urgent need for gemcitabine biomarkers to improve the therapy. In present work, 10 HNSCC cell lines were employed to figure out the biomarkers for gemcitabine sensitivity. The sensitivities of these 10 cell lines to gemcitabine and the basal expression of these cell lines was investigated, the correlation between gemcitabine response (IC50 dose) and gene expression was investigated by Pearson correlation and FDR estimation. The top seven positive genes responsible for gemcitabine sensitivity were validated by qPCR in these 10 HNSCC cell lines, while only two genes (SBF1 and ZNF195) were expression-correlated to gemcitabine response. Furthermore, ZNF195 expression was closely associated with gemcitabine sensitivity in the subsequent independent validation in cell lines from various types of cancer. Our work might provide potential biomarkers for gemcitabine sensitivity in HNSCC and various type of cancer. PMID- 24817948 TI - RNA-seq reveals determinants of sensitivity to chemotherapy drugs in esophageal carcinoma cells. AB - Chemotherapy remains the mainstay of treatment for patients with incurable disease of esophageal carcinoma. Most patients respond poorly to chemotherapy, it is necessary to figure out biomarkers for chemotherapy sensitivity or resistance to perform the individualized therapy. In present work, the sensitivities of two ESCC cell lines to 9 chemotherapy drugs were identified and the transcriptome of these two cell lines were investigated by RNA-seq, the correlation between the sensitivity to drugs and expression of some genes was attempted to construct. Eca 1 was more resistant to most of the chemotherapy drugs than Eca-109 cell line. RNA-seq results showed that there is dramatic difference in the basal expression between these two ESCC cell lines. Pathway analysis demonstrated that these differentially expressed genes were mainly enriched in Galphai signaling, calcium signaling, cAMP-mediated signaling, G-protein coupled receptor signaling and actin cytoskeleton signaling pathways. The molecules in Galphai signaling (ADCY1 and SSTR3) and actin cytoskeleton signaling (MYH6 and MYH7) were highly expressed in multidrug-resistant Eca-1 cells, which were validated by quantitative PCR. Activation of these two pathways results in the upregulation of downstream signaling, PKA signaling and Src-STAT3, and downregulation of RAF-ERK signaling, which was validated by immunoblotting experiments. Our work proposed that activation of Galphai signaling or actin cytoskeleton signaling may confer ESCC cells resistance to most chemotherapy drugs. Our work might provide potential biomarkers and therapeutic targets for treatment of EC patients. PMID- 24817949 TI - FOXL2 suppresses proliferation, invasion and promotes apoptosis of cervical cancer cells. AB - FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which give rise to the blepharophimosis ptosis epicanthus inversus syndrome (BPES), often associated with premature ovarian failure. Recently, its mutations have been found in ovarian granulosa cell tumors (OGCTs). In this study, we measured the expression of FOXL2 in cervical cancer by immunohistochemistry and its mRNA level in cervical cancer cell lines Hela and Siha by RT-PCR. Then we overexpressed FOXL2 in Hela cells and silenced it in Siha cells by plasmid transfection and verified using western blotting. When FOXL2 was overexpressed or silenced, cells proliferation and apoptosis were determined by Brdu assay and Annexin V/PI detection kit, respectively. In addition, we investigated the effects of FOXL2 on the adhesion and invasion of Hela and Siha cells. Finally, we analyzed the influences of FOXL2 on Ki67, PCNA and FasL by flow cytometry. The results showed that FOXL2 was highly expressed in cervical squamous cancer. Overexpressing FOXL2 suppressed Hela proliferation and facilitated its apoptosis. Silencing FOXL2 enhanced Siha proliferation and inhibited its apoptosis. Meanwhile, silencing FOXL2 promoted Siha invasion, but it had no effect on cells adhesion. In addition, overexpressing FOXL2 decreased the expression of Ki67 in Hela and Siha cells. Therefore, our results suggested that FOXL2 restrained cells proliferation and enhanced cells apoptosis mainly through decreasing Ki67 expression. PMID- 24817950 TI - Expression of Hsp90alpha and cyclin B1 were related to prognosis of esophageal squamous cell carcinoma and keratin pearl formation. AB - Hsp90alpha (heat shock protein 90alpha), one of the important molecular chaperones in cancer cell signal transduction, has been a new candidate target for cancer therapy. Cyclin B1, the client protein of Hsp90alpha, plays a key role as a mitotic cyclin in the G2-M phase transition during the cell cycle progression. However, the relationship between the level of HSP90alpha and cyclin B1, the location of Hsp90alpha and cyclin B1 in prognosis of esophageal squamous cell carcinoma (ESCC) has not been examined. Here, we demonstrate that the diagnostic significance of Hsp90alpha and cyclin B1 by immunohistochemistry and the association of Hsp90alpha and cyclin B1 expression in ESCC. In the specimens from 105 ESCC patients (81 stained with Hsp90alpha antibody by Immunohistochemistry, 65 with cyclin B1 antibody, and among them, 41 paired specimens were stained with Hsp90alpha and cyclin B1 respectively, and then checked for the correlation of the level and location of Hsp90alpha and cylcin B1. The positivity rate of Hsp90alpha and cyclin B1 expression were 96.3% (78 of 81) and 84.6% (55 of 65) respectively. Both of them, the expression levels are associated with the clinical pathological stage (Hsp90alpha, p=0.027; cyclin B1, p=0.007). No association was found between Hsp90alpha or cyclin B1 and gender, age, tumor location. As to TMN stage, there is no association with the level of Hsp90alpha, However, cyclin B1 expression is significantly related to tumor status (p=0.002). Interestingly, Hsp90alpha expression was negatively correlated to cyclin B1 expression (Gamma=-0.692, p=0.007) in the keratin pearls though there is a positive correlation in the other areas of tumor (Gamma=0.503, p=0.015), which suggest Hsp90alpha might play diverse roles in the cyclin B1 expression and cyclin B1 related cell cycle regulation in the different area of tumor. These findings demonstrated that the expression of Hsp90alpha, cyclin B1 protein is associated with tumor malignancy and prognosis for patients with human esophageal squamous cell carcinoma, and Hsp90alpha might be involved in cyclin B1 expression regulation and cell cycle regulation in keratin peal formation of ESCC. PMID- 24817951 TI - Enhanced serum methylated p16 DNAs is associated with the progression of gastric cancer. AB - OBJECTIVE: The present study is to evaluate the effect of methylated p16 on the progression in patients with gastric cancer (GC), and develop a useful biomarker for predicting patient's prognosis. DESIGN AND METHODS: Methylation status of p16 in GC, their corresponding para-cancerous histological normal tissues (PCHNTs), preoperative peritoneal washes (PPWs) and serum were assessed using real-time methylation specific-PCR (MSP). RESULTS: The frequency of p16 methylation was significantly higher in GC tissues (85.9%; 79/92) than that in paired PCHNTs (12.0%; 11/92) (P<0.0001). p16 methylation correlated closely with lymph node metastasis, peritoneal metastasis, TNM stage, et al (all P<0.05). Both frequency of p16 methylation in PPWs and serum were 79.7% (63/92). The Azeta value of the receiver-operator characteristic curve for methylated p16 was 0.899 for serum and PPWs, compared to that in GC tissues. The patients with elevated methylated p16 levels in tumor tissues had poorer disease-free survival (DFS) rates than those without (P=0.042). There is a narrow significant difference in median survival time of more than 30 months between patients with and without preoperatively detectable methylated p16 in serum (P=0.057). Methylated p16 in PPWs revealed no significant association with survival (P=0.129). Cox regression analysis showed that serum methylated p16 DNAs was an independent risk factor for GC patients, with a remarkable decrease in DFS 30 months after surgical resection of the gastric tumor. CONCLUSIONS: Serum methylated p16 DNAs might serve as a potential biomarker for the progression and a prognostic factor in gastric cancer patients. PMID- 24817952 TI - Generation of homologous cell pairs using the oral lymphatic system. AB - The purpose of this study is to establish in vivo and in vitro models for studying lymphatic metastasis of squamous cell carcinoma (SCC). Three cell lines CAL-27, Tca-83, and HeLa were injected into the tongue of nude mice. Forty days after injection, we could isolate cells of 2 homologous cell lines LN-CAL-27 and LN-HeLa from lymph node metastasis lesions. Then, the homologous cell pairs were compared by the CCK-8 assay, wound healing assay, real-time PCR, western blot, and animal experiments. The results showed that all the three cell lines could be used to establish lymphatic metastasis animal models, and the lymphatic metastasis process was observed clearly. In addition, the homologous cell pairs performed differently from parent lines with respect to biological behavior and lymphatic metastasis-related gene and protein expression. In conclusion, CAL-27, Tca-83, and HeLa cells could be used to simulate the lymphatic metastasis process of oral cancer in vivo. Furthermore, the homologous cell pairs (CAL-27 and LN-CAL 27; HeLa and LN-HeLa) are potential tools for in vitro investigation of the mechanisms underlying metastasis. PMID- 24817953 TI - Lgr5 over-expression is positively related to the tumor progression and HER2 expression in stage pTNM IV colorectal cancer. AB - Recent studies display that Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) appears to involve the initiation of colorectal cancer (CRC). However, its role in the progression of CRC is not clear at present. In the present study, the expression of Lgr5, HER2, VEGF, and Ki-67 was detected by immunohistochemistry in primary cancer tissue and the matched normal mucosa, metastatic lymph node and distant metastatic tissues in 42 CRC cases staged as pTNM IV. The correlation of Lgr5 over-expression with the CRC progression, survival time, and expression of HER2, VEGF, and Ki-67 was evaluated. Moreover, the Lgr5 expression at the invasive front or residual cancer cells around coagulation necrosis was compared with that at the center of CRC in 51 paraffin embedded tissues. The results revealed that Lgr5 over-expression was more frequently found in the metastatic tissues of both lymph nodes and distant area when compared with primary CRC tissue (P<0.05). Additionally, cancer cells in the invasive front and residual cancer cells around or among the coagulation necrosis presented stronger Lgr5 immunoreactivity than that at tumor center (P<0.05), and strong positive staining was often observed in tumor budding cells. While, HER2 over-expression was detected in 28.9% (IHC 3+) and 42.1% (IHC 3+/2+) of CRC patients, neither Lgr5 nor HER2 expression was significantly related to the prognosis of CRC patients, though there was a positive correlation between Lgr5 and HER2 (P<0.05) or Ki-67 expression (P<0.05). In conclusions, Lgr5 over expression might involve the proliferation, invasion, and distant and regional metastasis of CRC cells, and has potential positive relation to HER2 expression. PMID- 24817954 TI - Hyperlipidemia compromises homing efficiency of systemically transplanted BMSCs and inhibits bone regeneration. AB - PURPOSE: Mesenchymal stem cells (MSCs) can selectively home to bone defects and play an essential role in promoting bone regeneration. As an adverse effect factor for bone metabolism, hyperlipidemia significantly impairs bone regeneration. In this study, bone marrow stromal cells (BMSCs) were systemically transplanted into a hyperlipidemic mouse model to explore the effect of hyperlipidemia on stem cell recruitment and bone regeneration. METHODS: Hyperlipidemia was established in ApoE-/- mice (on C57BL/6J background) fed with a high fat diet (HFD) for five weeks. C57BL/6 mice fed with the same diet served as controls. BMSCs labeled with the green fluorescent protein (GFP) were then injected via the tail vein and bone defects were created in the mandibles. The animals were sacrificed at weeks 1, 2 and 4 after surgery, and the fate of the transplanted BMSCs was monitored with a fluorescence microscope and immunohistochemical analysis. After hematoxylin and eosin (HE) staining and Masson's Trichrome (MT) staining, histomorphometric analysis was performed to evaluate bone regeneration. RESULTS: In both groups transplanted with BMSCs, the number of GFP-positive BMSCs detected in the bone defects reached its peak at 1 week after surgery and was decreased thereafter. However, at all time points, less GFP+ cells were detected in the ApoE-/- mice than in the corresponding control mice. BMSCs transplantation significantly enhanced new bone formation, but to a lesser degree in the ApoE-/- mice when compared with the control mice. CONCLUSIONS: Hyperlipidemia compromises homing efficiency of systemically transplanted BMSCs and inhibits bone regeneration. PMID- 24817955 TI - Metadherin contribute to BCR signaling in chronic lymphocytic leukemia. AB - We have reported Metadherin (MTDH) was proven to be overexpression and involved in malignance of chronic lymphocytic leukemia (CLL) via Wnt signaling pathway. In this study, we further investigate the role of MTDH in regulation of BCR signaling pathway in CLL. Six CLL samples whose cells were proliferation after BCR activation were chosen from patients with unmutated IgVH. CCK-8 method used to evaluate the proliferation rate. MTDH expression was measured by quantitative PCR and Western blot. After BCR activation, there exist upregulation of MTDH expression in mRNA and protein level in all six CLL patients (P<0.05). In cell line MEC-1, we observed the same pro-proliferation effect accompanying with elevated MTDH expression. The proliferation effects of BCR activation to MEC-1 can be inhibited by MTDH interference. The results of this study indicate that MTDH involved in the pro-proliferation effect of BCR activation in CLL. And the results imply that MTDH can be a potential therapy target of CLL. PMID- 24817956 TI - Increased Tbx1 expression may play a role via TGFbeta-Smad2/3 signaling pathway in acute kidney injury induced by gentamicin. AB - T-box 1 (Tbx1) gene is closely involved in embryonic kidney development. To explore the role of Tbx1 in acute kidney injury (AKI) and the underlying mechanism, we detected the expression of Tbx1 and components of transforming growth factor-beta (TGF-beta) signaling pathways including TGF-beta, phosphorylated Smad2/3 (p-Smad2/3) and phosphorylated Smad1/5/8 (p-Smad1/5/8) in kidney tissues derived from a rat model for AKI induced by gentamicin (GM). Apoptosis of renal cells was assessed by terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL), along with the expression of two essential genes involved in apoptosis, caspase-3 and Bcl-2. Correlation between Tbx1 expression and the number of TUNEL-positive cells was analyzed by a Spearman test. Expression of TGF-beta, p-Smad2/3 and p-Smad1/5/8 in Tbx1-knockdown NRK cells was also analyzed by real-time RT-PCR and Western blotting. Markedly increased Tbx1 expression was found in the injured kidney tissues, which has activated the TGFbeta-Smad2/3 pathway whilst suppressed Smad1/5/8 expression. Conversely, decreased TGF-beta and p-Smad2/3 levels, and elevated p-Smad1/5/8 levels were detected in Tbx1-knockdown NRK cells. More apoptotic cells were detected in the injured kidneys, which has well correlated with the expression of Tbx1. Expression of caspase-3 was markedly increased, while Bcl-2 was decreased in the injured kidney tissues. Above findings suggested that activation of Tbx1 is involved in AKI through the TGFbeta-Smad2/3 pathway. Tbx1 expression may therefore serve as a marker for AKI, and Tbx1-blocking therapies may provide an option for treating GM-induced nephropathy. PMID- 24817957 TI - Overexpression of GEFT, a Rho family guanine nucleotide exchange factor, predicts poor prognosis in patients with rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is one of the most common soft-tissue sarcomas in children and adolescents with poor prognosis. Yet, there is lack of effective prognostic biomarkers for RMS. The present study, therefore, aimed to explore potential biomarkers for RMS based on our previous findings using array comparative genomic hybridization. We investigated guanine nucleotide exchange factor, GEFT, at expression level in 45 RMS patients and 36 normal striated muscle controls using immunohistochemistry using tissue microarrays. The expression rate of GEFT in RMS samples (42/45, 93.33%) was significantly higher (P<0.05) than that in normal controls (5/36, 13.89%). Moreover, the overexpression rate of GEFT in RMS (31/45, 68.89%) was also significantly higher (P<0.05) than that in normal controls (0/36, 0.00%). Increased expression of GEFT correlated significantly with advanced disease stages (stages III/IV) (P=0.001), lymph node metastasis (P=0.019), and distant metastasis (P=0.004), respectively, in RMS patients. In addition, RMS patients having overexpressed GEFT experienced worse overall survival (OS) than those having low levels of GEFT (P=0.001). GEFT overexpression was determined to be an independent prognostic factor for poor OS in RMS patients (hazard ratio: 3.491, 95% confidence interval: 1.121-10.871, P=0.004). In conclusion, these observations provide the first evidence of GEFT overexpression in RMS and its correlations with disease aggressiveness and metastasis. These findings suggest that GEFT may serve as a promising biomarker predicting poor prognosis in RMS patients, thus implying its potential as a therapeutic target. PMID- 24817958 TI - Retrospective analysis of 80 cases with uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma in China, 1988-2007. AB - OBJECTIVE: Uterine sarcomas are rare gynecological malignancies with poor prognosis and high mortality. We provides clinical information of uterine sarcoma patients at Changhai Hospital of Secondary Military Medical University in Shanghai, China, over a 20-year period. DESIGN AND METHODS: Satisfied the criteria for the study, a total of 80 female patients with uterine sarcomas were retrospectively evaluated. Overall survival was analyzed by Kaplan-Meier method. MAIN OUTCOME MEASURES: The following information was extracted from our medical records: age, presentations, blood types, stages, ultrasonographic results, therapies and follow-up. RESULTS: Of the 80 patients, the mean age of onset was 57.3+/-2.03 years, and the highest frequency occurred in 51-60 age group. Endometrial stromal sarcoma was the most common histological type (47.5%). Even population of these patients presented was with early stage (I&II) and advanced stages (III&IV). Among 79 patients underwent primary surgery, 74 cases was hysterectomy and bilateral salping-ooophorectomy. Equal to disease-specific survival, overall survival rates at 1-, 3- and 5-year were 81.3%, 62.5% and 40% respectively. Age, menopausal status, blood type, stage, and pathologic types were all proved to be correlated with the survival. CONCLUSION: Our retrospective data in part reflect clinical characteristics of uterine sarcoma in China, and form the basis for further concerning researches. PMID- 24817959 TI - Expression of stabilin-1 in M2 macrophages in human granulomatous disease and melanocytic lesions. AB - Stabilin-1 is an endocytotic scavenger receptor, specifically expressed by non continuous sinusoidal endothelial cells in the liver, spleen and lymph nodes and by M2 or alternatively activated macrophages in human malignancies. We analysed paraffin-embedded tissue of melanocytic lesions and granulomatous diseases for stabilin-1 expression, using the human/murine RS1 antibody. The specificity of the RS1 staining was confirmed in a knockout model, as only M2-like tumor associated macrophages and vessels of a B16F10 melanoma in wild type mice stained positive; while staining of tumor-associated macrophages and vessels originating from stabilin-1 deficient mice remained negative for stabilin-1 specific antibody RS1. In human specimens, the RS1 antibody stained tumor-associated macrophages in all pathological stages of melanoma. In addition, five cases of juvenile xanthogranulomas and one case of necrobiotic xanthogranuloma were strongly stabilin-1 positive, while Th-1 cytokine dominated granulomatous diseases such as sarcoidosis and granulomatous leprosy were negative. Stabilin-1 positive vessels were found in all analysed non-Langerhans cell histiocytoses and melanocytic lesions. No stabilin-1 positive vessels were present in any other granulomatous diseases. PMID- 24817960 TI - Characterization of the pathologic and endoscopic measurements of colorectal polyp sizes with a focus on sessile serrated adenoma and high-grade dysplasia. AB - BACKGROUND: The characteristics of pathologically measured (PMS) and endoscopically measured sizes (EMS) of the colorectal polyps (CRPs) is poorly understood, particularly in polypoid unremarkable mucosa (PUM), sessile serrated adenoma (SSA), and high-grade dysplasia (HGD). METHODS: To characterize the discordance and correlation between the PMS and EMS of CRPs including PUM, SSA, HGD, hyperplastic polyp (HP) and adenomas, we conducted this prospective observational study on the polyps collected between August 2012 and December 2013. RESULTS: PMS was significantly smaller than EMS in the 497 qualified CRPs regardless of the sites (left, transverse and right colorectum) or EMS (>=1 cm and <1 cm) subgroups. The PMS and EMS discordance was associated with a diagnosis of HP and adenoma (versus PUM, SSA or HGD), single fragment (versus multiple), 3 of the 8 endoscopists and PMS<1 cm (versus >=1 cm). Despite a good correlation between EMS and PMS in the adenomas (K=0.626, 95% confidence intervals [CI], 0.505-0.746) and a moderate correlation in the serrated polyps (SPs) including HP and SSA, (K=0.424, 95% CI, 0.244-0.604), 40.4% (23/57) of the adenomas and 63.6% (21/33) of the SPs with EMS>=1 cm might warrant longer follow-up intervals since their PMS were <1 cm. The PMS and EMS had linear correlations except in CRPs with HGD or EMS>=1 cm. CONCLUSIONS: The discordance between PMS and EMS is associated with the pathologic diagnosis, fragment number, endoscopists and PMS, and may lead to different follow-ups in a considerable portion of adenomas and SPs. PMID- 24817961 TI - Enhancement of interaction of BSEP and HAX-1 on the canalicular membrane of hepatocytes in a mouse model of cholesterol cholelithiasis. AB - We induced gallstones in C57L mice fed with a high cholesterol diet and examined the expression of bile salt export pump (BSEP) on the canalicular membrane of hepatocytes and its relation with PKCalpha and HAX-1.Twenty-four gallstone-prone C57L mice were randomly assigned to receive a high cholesterol diet or a regular diet. Gallstone formation was recorded. BSEP, PKCalpha and phospho-PKCalpha expression was examined by immunoblotting assays. Co-expression of BSEP and HAX-1 was studied by immunofluorescent microscopy and immunoprecipitations. Gallstones were formed in all 12 mice fed with the high cholesterol diet. In Gallstone group, BSEP levels on the canalicular membrane of hepatocytes were markedly lower while a significant increase was observed in phosphorylated PKCalpha. Immunofluorescent microscopy showed that BSEP and HAX-1 were co-localized on the canalicular membrane, which was apparently enhanced by feeding with the high cholesterol diet. The immunoprecipitation assays further demonstrated that BSEP and HAX-1 showed enhanced interaction in the hepatocytes of mice fed with the high cholesterol diet. Cholesterol gallstone formation is associated with downregulation of BSEP expression on the canalicular membrane of hepatocytes with increased phosphorylation of PKCalpha. BSEP and HAX-1 show enhanced interaction with one another on the canalicular membrane during gallstone formation. PMID- 24817963 TI - Applicability of next-generation sequencing to decalcified formalin-fixed and paraffin-embedded chronic myelomonocytic leukaemia samples. AB - Decalcified formalin-fixed and paraffin-embedded (dFFPE) bone marrow trephines remain the primary source of gDNA in hematopathological diagnostics. Here, we investigated the applicability of next-generation sequencing (NGS) to dFFPE samples. Chronic myelomonocytic leukaemia (CMML) is a haematopoietic stem cell malignancy delineated by genetic heterogeneity. Recently characteristic mutations have been identified for this entity in a distinct group of genes (TET2, CBL, KRAS). We comparatively investigated DNA extracted from fresh mononuclear cells as well as dFFPE samples from four CMML patients employing a commercially available primer set covering the above mentioned and well characterized mutational hotspots in CMML followed by an amplicon based next-generation deep sequencing (NGS) approach. As we observed high quality run data as well as complete concordance between both sample types in all cases, we further validated the potential of NGS in hematopathology on a larger cohort of CMML patients (n=39), detecting sequence variations in 84.6% of patients. Sequence analysis revealed 92 variants, including five known polymorphisms, ten silent mutations, 36 missense mutations, 14 nonsense mutations, 24 frame shift mutations and three potential splice site mutations. Our findings ultimately demonstrate the applicability of NGS to dFFPE biopsy specimen in CMML and thus allowing the pathologist to evaluate prognostically relevant mutations at a high resolution and further contribute to risk stratification for the individual patient. PMID- 24817962 TI - Co-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma. AB - The aim of this study was to investigate the association of CD147 and GLUT-1, which play important roles in glycolysis in response to radiotherapy and clinical outcomes in patients with locally advanced cervical squamous cell carcinoma (LACSCC). The records of 132 female patients who received primary radiation therapy to treat LACSCC at FIGO stages IB-IVA were retrospectively reviewed. Forty-seven patients with PFS (progression-free survival) of less than 36 months were regarded as radiation-resistant. Eighty-five patients with PFS longer than 36 months were regarded as radiation-sensitive. Using pretreatment paraffin embedded tissues, we evaluated CD147 and GLUT-1 expression by immunohistochemistry. Overexpression of CD147, GLUT-1, and CD147 and GLUT-1 combined were 44.7%, 52.9% and 36.5%, respectively, in the radiation-sensitive group, and 91.5%, 89.4% and 83.0%, respectively, in the radiation-resistant group. The 5-year progress free survival (PFS) rates in the CD147-low, CD147 high, GLUT-1-low, GLUT-1-high, CD147- and/or GLUT-1-low and CD147- and GLUT-1- dual high expression groups were 66.79%, 87.10%, 52.78%, 85.82%, 55.94%, 82.90% and 50.82%, respectively. CD147 and GLUT-1 co-expression, FIGO stage and tumor diameter were independent poor prognostic factors for patients with LACSCC in multivariate Cox regression analysis. Patients with high expression of CD147 alone, GLUT-1 alone or co-expression of CD147 and GLUT-1 showed greater resistance to radiotherapy and a shorter PFS than those with low expression. In particular, co-expression of CD147 and GLUT-1 can be considered as a negative independent prognostic factor. PMID- 24817964 TI - NOD1, RIP2 and Caspase12 are potentially novel biomarkers for oral squamous cell carcinoma development and progression. AB - Although increasing studies have indicated that Nucleotide-oligomerization domain containing protein 1 (NOD1) signaling could play an important role in gastrointestinal tumorigenesis, the protein expression and function of NOD1 signaling have not been understood well in oral squamous cell carcinoma (OSCC) progression. The objective of this study is, thus, to examine protein expression of NOD1 signaling immunohistochemically in normal, premalignant and malignant specimens of oral cavity, and to take insights into the association between the protein expression of NOD1 signaling pathway and OSCC precession. In this study immunohistochemical expression of NOD1, Receptor-interacting protein 2 (RIP2), Caspase12, human beta Defensin1, 2 and 3 (hBD1, 2, 3) was examined in 15 normal controls, 30 cases of oral leukoplakia (OLK) and 60 cases of OSCC. The immunostaining score was assessed by 2 pathologists, respectively. We found that the expression of NOD1, RIP2, Caspase12, hBD1, 2, and 3 decreased along with the progression of OSCC. NOD1 expression was correlated significantly to tumor differentiation, lymph node metastasis, and tumor size. Our results also showed the correlation of hBD2, 3 to lymph node metastasis of OSCC. These results suggest that the dysfunction of NOD1 signaling pathways could be associated with OSCC development and progression. NOD1, RIP2 and Caspase12 could be used as potentially novel biomarkers for oral carcinogenesis. PMID- 24817965 TI - Estrogen-mimicking isoflavone genistein prevents bone loss in a rat model of obstructive sleep apnea-hypopnea syndrome. AB - OBJECTIVE: Intermittent hypoxia was introduced to mimic obstructive sleep apnea hypopnea syndrome (OSAHS) in rats. Then, bone mass, bone strength and bone turnover were evaluated, and the influence of genistein on bone mass reduction was investigated in these rats. METHODS: OSAHS animal model was established via chronic intermittent hypoxia, and genistein (2.5 mg/kg/day) was used to treat OSAHS rats. The bone mineral density (BMD), bone Histomorphometric indicators, bone biomechanics and expressions of genes related to bone formation and resorption (Runx2, Col I, ALP, Osteocalcin, OPG, RANKL and TRAP-5b) were measured after treatment. RESULTS: The BMD in OSAHS+OVX group was significantly lower than that in OVX group (P<0.05). The BMD in OSAHS+OVX+Genistein group was markedly increased when compared with OSAHS+OVX group (P<0.05), accompanied by partial improvement of the OSAHS induced damage to the lumbar biomechanics. In OSAHS+OVX group, the expressions of Runx2, Col I, ALP and Osteocalcin were significantly reduced when compared with OVX group, and rats in OSAHS+OVX+Genistein group had significantly higher expressions of Runx2, Col I, ALP and Osteocalcin and reduced TRAP-5b expression as compared to OSAHS+OVX group (P<0.05). CONCLUSIONS: Genistein can improve the reduction in bone mass and bone strength due to OSAHS in OVX rats, which may be attributed to the increase in bone formation and inhibition of bone resorption. Our findings suggest that genistein may be used to treat and prevent osteoporosis in postmenopausal women with OSAHS. PMID- 24817966 TI - SKIP expression is correlated with clinical prognosis in patients with bladder cancer. AB - The Ski-interacting protein (SKIP) is a transcriptional cofactor distinct from other cofactors and is involved in regulation of many cancer-related proteins. However, its distribution and clinical significances in bladder cancer remains poorly understood. In this study, Quantitative real-time PCR and immunohistochemistry were performed to detect the expression of SKIP in clinical bladder cancer samples. In addition, the correlation of SKIP expression and clinicopathological features and clinical outcomes were analyzed. The expression levels of SKIP in clinical bladder cancer were much higher than that in paired adjacent noncancerous tissues. High expression of SKIP was closely related with histological grades and the poor prognosis of bladder cancer. Based on our data, we speculated that SKIP may be a potential prognostic marker in bladder cancer. PMID- 24817967 TI - Dysregulation of microRNA biosynthesis enzyme Dicer plays an important role in gastric cancer progression. AB - BACKGROUND AND AIM: Dicer is one of the most important components in microRNA biogenesis. Although studies have revealed the aberrantly expression of Dicer in types of cancer, the results were greatly controversial. Here we aimed to study the expression of Dicer in gastric cancer (GC) and further explored the possible roles of Dicer in cancer progression. METHODS: The alteration of Dicer-expression in GC and its clinical significance was retrospectively studied with immunohistochemical analyses on 377 cases of cancer tissues using tissue microarray (TMA). Dicer mRNA and protein levels were also examined in 8 paired of GC tissues and non-neoplastic surrounding gastric epithelium with real time RT PCR and western blot. RESULTS: We found that Dicer was reduced in GC tissues in both mRNA and protein levels. Moreover, down-regulation of Dicer was correlated highly with tumor differentiation (P<0.05) and lymph node invasion (P<0.05) in GC tissues, which suggested an essential role of Dicer in cancer invasion. CONCLUSIONS: Considering that Dicer might be closely related to progression of GC, we proposed that Dicer might offer a promising target for prevention of metastatic progression in GC. PMID- 24817968 TI - Frequency of activating mutations in FGFR2 exon 7 in bladder tumors from patients with early-onset and regular-onset disease. AB - The FGF/FGFR-system plays an important role in embryogenesis, tissue homeostasis and carcinogenesis. Mutational activation of FGFR2 resulting in aberrant FGFR2 signaling activation is known from both hereditary germ line alterations and somatic mutations in various malignancies (e.g. breast, gastric or ovarian cancer). FGFR2 mutations are mainly located within the hinge between Ig-like domains (exon 7), around the 3rd Ig-like domains and within the kinase domain. For bladder cancer only sparse data on FGFR2 mutations are available. Most interestingly a case of early-onset papillary carcinoma of the bladder showing a FGFR2 p.Pro253Arg mutation in exon 7 in a patient with Apert Syndrome was reported recently. To further evaluate the importance of FGFR2 exon 7 alterations in bladder cancer a cohort of 254 bladder tumors (cohort 1: unselected cases: n=139; cohort 2: early-onset bladder cancer cases (age at time of diagnosis<=45 years): n=115) was analyzed. Sections from formalin-fixed, paraffin-embedded bladder tumors were used for DNA isolation. After precise microdissection exon 7 of the FGFR2 gene was analyzed by direct Sanger sequencing. All cases could be analyzed successfully. Mutations in exon 7 of FGFR2 could not be detected in any of the cases. All tumors showed wild type sequence. Our data demonstrate that the recently reported association between early-onset papillary carcinoma of the bladder with germ line FGFR2 p.Pro253Arg mutation could not be found in our cohorts of sporadic bladder tumors. These results indicate that FGFR2 gene mutations might only play a minor role in bladder carcinogenesis. PMID- 24817969 TI - Alpha-synuclein immunohistochemistry of gastrointestinal and biliary surgical specimens for diagnosis of Lewy body disease. AB - In Lewy body disease, Lewy pathology (LP: the accumulation of alpha-synuclein in neuronal perikarya and processes as Lewy bodies and Lewy neurites and dots, respectively) is observed in the central and peripheral nervous systems. Previous autopsy or biopsy studies of individuals with Lewy body diseases (LBDs) indicated that LP could be observed in the peripheral nerves of the gastrointestinal (GI) systems. The aim of this study is to clarify whether examination of GI and biliary surgical specimens would be useful for diagnosing LBD. We analyzed eight patients diagnosed clinically with LBD and with medical histories of GI or biliary surgery at our hospital. LP was identified by using alpha-synuclein immunohistochemistry in GI and biliary surgical specimens obtained before, at or after the clinical onset of LBD. LP was frequently observed in Auerbach's plexus, Meissner's plexus and the subserosal nerve fascicles within the GI and biliary surgical specimens. LP was observed in the specimens obtained 7 years before the onset of LBD. Our approach does not require any invasive procedures for patients. The immunohistochemical analysis of anti- alpha-synuclein antibody to archival GI or biliary surgical specimens from patients with clinically suspected LBD may contribute to clinical diagnosis of LBD. PMID- 24817970 TI - Clinical relevance of tag single nucleotide polymorphisms within the CAT gene in patients with PTSD in the Chongqing Han population. AB - BACKGROUND: Free radical-induced oxidative damage of the brain has been implicated in a number of psychiatric disorders, including post-traumatic stress disorder (PTSD). Catalase (CAT) is a major antioxidant enzyme and a number of polymorphisms in CAT have been shown to be associated with several diseases, including hypertension, diabetes mellitus, Alzheimer's disease, and vitiligo. The aim of this study was to evaluate the association of CAT gene polymorphisms with PTSD in a case-control study. MATERIALS AND METHODS: A total of 460 unrelated adult Chinese Han adults, including 287 healthy volunteers and 173 patients with PTSD. Six tag single-nucleotide polymorphisms (tSNPs) were selected from the entire CAT gene through construction of haplotype bins, and they were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. Allelic frequencies and clinical characteristics were compared in two independent Chinese Han populations. RESULTS: Six tag SNPs were identified in the Chinese Han population and all were common SNPs. However, we could detect no evidence of genetic association between six tag SNPs in the CAT gene and PTSD in the Chinese Han population. CONCLUSIONS: This result suggests that six tag SNPs of the CAT gene may not be associated with PTSD, and that CAT gene might not influence the development of PTSD in patients following exposure to a traumatic event, also may be the sample sizes too small to allow a meaningful test. PMID- 24817971 TI - Staphylococcus pseudintermedius for CAMP-test. AB - CAMP test reliably detects Listeria monocytogenes (Lm) and Streptococcus agalactiae (group B streptococcus, GBS); it is traditionally performed streaking the tested isolate perpendicularly to Staphylococcus aureus (Sa), provided that reference Sa strains (that produce beta-hemolysin) are used. In a zone of beta hemolysin activity, in fact, GBS and Lm form typical arrow-shaped hemolytic areas. While Sa production of the toxin is strain-dependent, however, that of Staphylococcus pseudintermedius (Sp), a pet-owner colonizer and an emerging human pathogen, is constitutive, then observed in all clinical isolates. Therefore, Sp may indeed represent a valid alternative to perform the assay. PMID- 24817972 TI - Primary cutaneous anaplastic large cell lymphoma occurring in an atopic dermatitis patient: a case report with review of the literature with emphasis on their association. AB - Although the risk of malignant lymphoma in patients with atopic dermatitis (AD) remains controversial, an increased risk of malignant T-cell lymphoma in patients with AD has been reported. Primary cutaneous anaplastic large cell lymphoma (C ALCL) is a relatively common distinct clinicopathological entity. However, occurrence of C-ALCL in patients with AD has been rarely reported. Herein, we describe the 5(th) reported case of C-ALCL occurring in a patient with AD and review the clinicopathological features. A 30-year-old Japanese male with a long standing history of AD presented with a gradually enlarged nodular lesion in the right abdominal wall, which had spontaneously regressed without therapy. Two years later, multiple nodular lesions appeared in his trunk, and swelling of multiple lymph nodes was also detected. Histopathological studies demonstrated diffuse proliferation of large-sized lymphocytes with large convoluted nuclei containing conspicuous nucleoli and relatively rich cytoplasm in the skin and lymph node. Immunohistochemically, these lymphocytes were positive for CD30, CD8, and MUM1, and negative for CD3, CD4, and ALK1. Accordingly, a diagnosis of primary C-ALCL was made. The patient died of disease after various courses of chemotherapy. Our clinicopathological review revealed that the prognosis of C ALCL occurring in patients with AD is poor because two of 5 patients died of disease. Therefore, albeit extremely rare, AD patients with C-ALCL should be monitored closely, and additional clinicopathological studies are needed to clarify the pathogenesis of C-ALCL occurring in patients with AD. PMID- 24817973 TI - Diffuse alveolar damage in a patient with Epstein Barr virus (EBV)-positive diffuse large B-cell lymphoma,severely low serum folate, and megaloblastic anemia: a case report of autopsy. AB - We report a case of a 49-year-old Japanese man, who was admitted to our hospital because of severe dyspnea. He was found to have severely low serum folate and megaloblastic anemia, which was at first suspected to cause his dyspnea. It was assumed that severely low serum folate might be related to his malnutrition, probably caused by habitual alcohol consumption. He died in several days because of acute respiratory distress syndrome. Autopsy revealed diffuse alveolar damage (DAD) in the lungs and systemic lymph node swelling by EBV-positive diffuse large B-cell lymphoma, in addition to megaloblastic anemia in the bone marrow. Together with histological hemophagocytosis and high level of serum iron and ferritin, DAD was considered to be caused by hypercytokinemia triggered by the presence of EBV positive diffuse large B-cell lymphoma. On the other hand, pathological findings suggestive of habitual alcohol consumption were not apparent. We considered that low serum folate in this case was not by the low intake but by increased consumption of folate by rapid progression of the lymphoma. PMID- 24817974 TI - Occurrence of Epstein-Barr virus-associated plasmacytic lymphoproliferative disorder after antithymocyte globulin therapy for aplastic anemia: a case report with review of the literature. AB - It is well established that patients with immunosuppression have a higher risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with development of LPDs. Aplastic anemia (AA) is an immune mediated hematological disorder, and immunosuppression therapy (IST), such as antithymocyte globulin (ATG), is widely used for treatment of AA. However, occurrence of LPD without bone marrow transplantation has been extremely rarely documented in patients with IST for AA. Herein, we report the 6th documented case of EBV-associated LPD after IST for AA and review the clinicopathological features of this extremely rare complication. A 46-year-old Japanese female was admitted for evaluation of progressive pancytopenia. Bone marrow biopsy revealed fatty marrow with marked decrease of trilineage cells, and bone marrow aspiration demonstrated no dysplastic changes. IST with rabbit ATG was administered, after which, she developed high fever. Bone marrow aspiration showed increase of atypical plasma cells with mildly enlarged nuclei and irregular nuclear contour. These atypical plasma cells were EBER-positive. Accordingly, a diagnosis of EBV positive plasmacytic LPD was made. Most cases of LPDs are B-cell origin, and plasmacytic LPD is a rare subtype. The current report is the second case of plasmacytic LPD in patients with IST for AA. Therefore, detailed histopathological and immunohistochemical analyses are needed for correct diagnosis and treatment, and additional studies are needed to clarify the clinicopathological features of EBV-LPD after IST for AA. PMID- 24817975 TI - Clear cell adenocarcinoma present exclusively within endometrial polyp: report of two cases. AB - Endometrial polyp is a common benign lesion that protrudes into the endometrial surface. The incidence of carcinoma within endometrial polyp is thought to be low, however, postmenopausal women with endometrial polyps are at an increased risk. Endometrial clear cell adenocarcinoma is a distinct and relatively rare subtype of endometrial carcinoma, and recent studies have proposed putative precursor lesions of clear cell adenocarcinoma, namely clear cell endometrial glandular dysplasia (EmGD) and clear cell endometrial intraepithelial carcinoma (EIC). Herein, we describe two cases of clear cell adenocarcinoma present exclusively within endometrial polyp and discuss the association of its precursor. Two postmenopausal Japanese females, 66-year-old (Case 1) and 54-year old (Case 2) presented with abnormal genital bleeding. Cytological examination of both cases revealed adenocarcinoma, thus, hysterectomy was performed. Histopathological studies demonstrated clear cell adenocarcinoma within exclusively endometrial polyp in both cases. The peculiar finding in Case 1 was presence of atypical glandular cells with large round to oval nuclei and clear cytoplasm within the atrophic endometrial glands in the surrounding endometrial tissue, which corresponded to clear cell EIC. A recent study showed that 33% of uteri had at least one focus of clear cell EmGD in endometrial polyps. Accordingly, clear cell adenocarcinoma and clear cell EmGD can occur in association with endometrial polyps more frequently than previously thought. Therefore, detailed histopathological examination is important in diagnosis of endometrial polyps, especially in the postmenopausal women, moreover cytological examination is a useful tool in the postmenopausal women with endometrial polyps. PMID- 24817976 TI - A young man with primary prostatic extra-gastrointestinal stromal tumor: a rare case report and review of the literature. AB - Mounting evidence demonstrates the presence of extragastrointestinal stromal tumor (EGIST) which originates from tissues outside the gastrointestinal (GI) tract and shares overlapping immunohistological features with gastrointestinal stromal tumor (GIST). GIST emanating from prostate is extremely rare. To our knowledge, there are only 3 definitely reported cases of primary prostatic EGIST. Herein, we report a case of prostatic EGIST in 31-year-old man with low urinary tract symptoms who was initially misdiagnosed as sarcoma of prostate. Imaging studies assist in determining the origin and location of EGIST. Immunohistochemical assessment (DOG-1, CD117, and CD34) helps in differentiating such lesion from other stromal tumors and in addressing an appropriate and optimal therapeutic strategy. PMID- 24817977 TI - Primary neuroendocrine tumor of the testis: a study of clinicopathological features. AB - This study aimed to explore the clinicopathological characteristics and differential diagnosis of primary neuroendocrine tumor (G1) of the testis. In this paper, we analyze the clinical, histomorphological and immunohistochemical findings, treatment and prognosis of a patient with primary neuroendocrine tumor of the testis, and discuss the relevant literature. A 52-year-old man presented with a painless testicular swelling since 6 months. Histopathological examination showed that the tumor cells were arranged in island and beam patterns. The tumor cells were uniform, polygonal and had moderately eosinophilic cytoplasm and fine granular nuclear chromatin. Immunohistochemical staining showed that the tumor cells were positive for cytokeratin, CD56, synaptophysin and chromogranin A, and negative for inhibin, placental alkaline phosphatase and alpha-fetoprotein. Primary neuroendocrine tumor of the testis is a rare tumor with characteristic imaging features. Its accurate diagnosis depends on the morphological and immunohistochemical findings. These tumors should be differentiated from metastatic neuroendocrine carcinomas, teratomas with carcinoid, seminomas, Sertoli cell tumors and granulosa cell tumors. The treatment of most primary neuroendocrine tumors involves surgical resection combined with other therapies and usually results in a good prognosis. PMID- 24817978 TI - Sporadic hemangioblastoma of the retroperitoneum. AB - Hemangioblastoma is a rare neoplasm occurred in soft tissue. Herein, we present an intriguing case of sporadic hemangioblastoma in the retroperitoneum occurring in a 59-year-old male. The tumor was characterized by an alternation of cellular and paucicellular areas surrounded by a thick fibrous capsule. The stromal cells showed a pale cytoplasm exhibiting occasional lipid droplets and hyperchromatic, irregularly nuclei. CD56, NSE, a-inhibin and S100 were positive in tumor cells. This is the third reported case of a hemangioblastoma in the retroperitoneum. Based on clinical examination, computed tomography imaging, surgical operation, and histopathologic studies, a definitive diagnosis was made. Further characteristic images and pathology of this disease are discussed. PMID- 24817979 TI - Coexistent loss of INI1 and BRG1 expression in a rhabdoid renal cell carcinoma (RCC): implications for a possible role of SWI/SNF complex in the pathogenesis of RCC. AB - In this study, we analyzed the immunohistochemical and molecular profiles of an unusual RCC showed coexistent absence of INI1 and BRG1 expression, rhabdoid morphology, and poor prognosis. Histologically, the tumor had rhabdoid features, which were demonstrated by large round to polygonal cells with eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm varying from abundant to scanty. Immunohistochemically, the tumor were positive for BRM, PBRM1, ARID1A, CD10, CKpan, Vimentin, carbonic anhydrase IX (CA-IX), and P504S (AMACR) but negative for INI1, BRG1, HMB45, melan A, CK7, CD117, Ksp-cadherin, TFEB, TFE3, and Cathepsin K. We detected all three exons status of the VHL gene of the tumor and observed 1 somatic mutations in 1st exon. Chromosome 3p deletion, coupled with polysomy of chromosome 3 was also found. Based on these findings, it is further indicated that in some cases, rhabdoid RCC may arise from clear cell RCC. SWI/SNF chromatin remodeling complex may be an attractive candidate for being the "second hit" in RCCs and may play an important role during tumor progression. The role of SWI/SNF complex in rhabdoid RCC should be further studied on a larger number of cases. PMID- 24817980 TI - Breast carcinoma with osteoclastic giant cells: case report and review of the literature. AB - Breast carcinoma with osteoclastic giant cells (OGCs) are uncommon. Here, we report a 46-year-old woman with a painless lump in her left breast that has been proved clinically and radiographically. Microscopical examination showed OGCs accompanying invasive ductal carcinoma. Immunohistochemical assay revealed that OGCs derived from macrophages. Despite positive lymph node metastasis, the patient has been well without evidence of recurrence or metastasis one year after the operation. To date, the influence of OGCs on the prognosis of patients is still controversial. Our case may provide insights into further understanding beast carcinoma with OGCs. PMID- 24817981 TI - Small cell type neuroendocrine carcinoma colliding with squamous cell carcinoma at esophagus. AB - Collision tumor is an extremely rare tumor which defined as the concrescence of two distinct primaries neoplasms. We report here a case of collision tumor at lower third esophagus composed of small cell type neuroendocrine carcinoma (NEC), which is an very rare, highly aggressive and poorly prognostic carcinoma and squamous cell carcinoma (SqCC). In our case, pathologically, the small cell carcinoma display the characteristic of small, round, ovoid or spindle-shaped tumor cells with scant cytoplasm, which colliding with a moderately differentiated squamous cell carcinoma. Immunohistochemical staining demonstrated positive activities for CD56, synaptophysin, 34betaE12, CK 5/6, ki-67 (70%-80%), but negative for CD99, chromogranin A, and TTF-1. Accurate diagnosis was made base on these findings. PMID- 24817982 TI - Secondary oligodendroglioma after postoperative irradiation for medulloblastoma: a case report and review of the literature. AB - Medulloblastoma, a malignant, invasive embryonal tumor of the cerebellum, occurs most often in children. It has high metastatic potential and is usually treated by aggressive multimodal therapy, including surgery, chemotherapy and craniospinal irradiation. Multiple secondary tumors have been reported following craniospinal irradiation. It is rare with the occurrence of oligodendroglioma after irradiation. In this report, we described a patient with secondary oligodendroglioma after postoperative craniospinal irradiation for medulloblastoma. PMID- 24817983 TI - Therapy-related B lymphoblastic leukemia with t(4;11)(q21;q23)/AF4-MLL in a patient with mantle cell lymphoma after recent aggressive chemotherapy: a unique case report. AB - Mantle cell lymphoma (MCL) is a mature B-cell lymphoma associated with the hallmark translocation t(11;14)(q13;32), which involves the cyclin D1 (CCND1) and immunoglobin heavy chain (IgH) genes. It may transform to a more aggressive blastoid or pleomorphic variant, with or without acquisition of chromosomal abnormalities. MCL could also present with a leukemic phase with marked lymphocytosis. A literature search did not reveal any prior reports of MCL transforming to or followed by a B-cell lymphoblastic leukemia (B-ALL). PMID- 24817984 TI - Secondary intestinal amyloidosis presenting intractable hematochezia: a case report and literature review. AB - Amyloidosis is characterized by an extracellular deposition of insoluble fibrils. Amyloid deposition caused various clinical symptoms associated with affected organs. Secondary amyloidosis without renal involvement and chronic inflammatory conditions is rarely reported. We experienced a case of secondary intestinal amyloidosis presented with recurrent hematochezia and abdominal pain in a 54-year old male. Sigmoidoscopy and abdominal computed tomography (CT) presented ischemic colitis and necrosis of whole colon. On microscopically, pinkish amorphous materials were infiltrated in the lamina propria and the thickened submucosal vessel walls in colon. The apple-green birefringence with polarized light on Congo red stain was demonstrated in the lamina propria and submucosal vessel walls. The deposits were positive for amyloid A and kappa and negative for lambda. The echocardiography and cardiac MRI findings showed infiltratives cardiomyopathy involving amyloidosis. Despite of conservative treatment, ischemic colitis and hemorrhage were aggravated and the patient expired. PMID- 24817985 TI - Adenosquamous carcinoma of the tongue: a case report with review of the literature. PMID- 24817986 TI - Tissue Micro Arrays for immunohistochemical detection of inflammatory infiltrates in renal cell carcinoma. PMID- 24817987 TI - Ectopic respiratory mucosa in the rectum: the second documented case with discussion of its histogenesis. PMID- 24817988 TI - Epidermal cyst of the skin with ossification: report of two cases. PMID- 24817990 TI - Spatial specificity and sensitivity of passive cavitation imaging for monitoring high-intensity focused ultrasound thermal ablation in ex vivo bovine liver. AB - Passive cavitation images (PCIs) generated from scattered acoustic waves are a potential technique for monitoring lesion formation during high-intensity focused ultrasound (HIFU) thermal ablation. HIFU lesion prediction by PCIs was assessed in ex vivo bovine liver samples (N=14) during 30-s sonications with 1.1-MHz continuous-wave ultrasound (1989 W/cm^2 estimated spatial-peak intensity). Treated samples were sectioned, optically scanned, and the HIFU lesions segmented based on tissue discoloration. During each insonation, a 192-element, 7-MHz linear array (L7/Iris 2, Ardent Sound) passively recorded emissions from a plane containing the HIFU propagation axis oriented parallel to the image azimuth direction. PCIs were formed from beamformed A-lines filtered into fundamental, harmonic, ultraharmonic, and inharmonic frequency bands. Lesion prediction was tested using binary classification of local tissue ablation based on thresholded PCIs, with spatial specificity and sensitivity of lesion prediction quantified by the area under receiver operating characteristic curves (AUROC). Tadpole-shaped lesions were best predicted by harmonic emissions (AUROC=0.76), prefocal lesions were best predicted by harmonic or ultraharmonic emissions (AUROC=0.86), and cigar-type focal lesions were best predicted by fundamental and harmonic emissions (AUROC=0.65). These results demonstrate spatial specificity and sensitivity when predicting HIFU lesions with PCIs. PMID- 24817989 TI - Genetic alterations in quadruple malignancies of a patient with multiple sclerosis: their role in malignancy development and response to therapy. AB - Multiple cancers represent 2.42% of all human cancers and are mainly double or triple cancers. Many possible causes of multiple malignancies have been reported such as genetic alterations, exposure to anti-cancer chemotherapy, radiotherapy, immunosuppressive therapy and reduced immunologic response. We report a female patient with multiple sclerosis and quadruple cancers of different embryological origin. Patient was diagnosed with stage III (T3, N1a, MO) medullary thyroid carcinoma (MTC), multicentric micropapillary thyroid carcinoma, scapular and lumbar melanomas (Clark II, Breslow II), and lobular invasive breast carcinoma (T1a, NO, MO). All tumors present in our patient except micropapillary thyroid carcinomas were investigated for gene alterations known to have a key role in cancer promotion and progression. Tumor samples were screened for the p16 alterations (loss of heterozygosity and homozygous deletions), loss of heterozygosity of PTEN, p53 alterations (mutational status and loss of heterozygosity) and mutational status of RET, HRAS and KRAS. Each type of tumor investigated had specific pattern of analyzed genetic alterations. The most prominent genetic changes were mutual alterations in PTEN and p53 tumor suppressors present in breast cancer and two melanomas. These co-alterations could be crucial for promoting development of multiple malignancies. Moreover the insertion in 4(th) codon of HRAS gene was common for all tumor types investigated. It represents frameshift mutation introducing stop codon at position 5 which prevents synthesis of a full-length protein. Since the inactivated RAS enhances sensitivity to tamoxifen and radiotherapy this genetic alteration could be considered as a good prognostic factor for this patient. PMID- 24817991 TI - The Emerging Role of Health Care Supervisors in Assisted Living. AB - Historically, the assisted living (AL) industry has promoted a social, non medical model of care. Rising health acuity of residents within AL, however, has brought about the need for providing increased health care services. This article examines the key staff role related to health care provision and oversight in AL, described as the health care supervisor. It briefly describes individuals in this role (N = 90) and presents their perspectives regarding their roles and responsibilities as the health care point person within this non-medical environment. Qualitative analyses identified four themes as integral to this position: administrative functions, supervision of care staff, provision of clinical and direct care, and clinical care coordination and communication. The article concludes with recommendations for AL organizations and practice of the emerging health care supervisor role in AL. PMID- 24817992 TI - Subsequent Adenomas of Ileal Pouch and Anorectal Segment after Prophylactic Surgery for Familial Adenomatous Polyposis. AB - : Familial adenomatous polyposis (FAP) is an autosomally dominant disease characterized by the early development of colorectal adenomas and carcinoma in untreated patients. Patients with FAP may develop rectal cancer at their initial presentation (primary) or after prophylactic surgery (secondary). Controversies exist regarding which surgical procedure represents the best first-line treatment. The options for FAP are ileorectal anastomosis (IRA) or a restorative proctocolectomy (RPC) with either a handsewn or a stapled ileal pouch-anal anastomosis (IPAA), with or without mucosectomy. The purpose of these surgeries is to stop progression to an adenoma-cancer sequence by eradicating the colon, a disease prone organ. Unfortunately, these surgical procedures, which excise the entire colon and rectum while maintaining transanal fecal continence, do not guarantee that patients still won't develop adenomas. Based on the available literature, we therefore reviewed reported incidences of pouch-related adenomas that occurred post prophylactic surgery for FAP. The review consists of a collection of case, descriptive, prospective and retrospective reports. OBJECTIVES: To provide available data on the natural history of subsequent adenomas after prophylactic surgery (by type) for FAP. METHODS: A review was conducted of existing case, descriptive, prospective and retrospective reports for patients undergoing prophylactic surgery for FAP (1975 - August, 2013). In each case, the adenomas were clearly diagnosed in one of the following: the ileal pouch mucosa (above the ileorectal anastomosis), within the anorectal segment (ARS) below the ileorectal anastomosis, or in the afferent ileal loop. RESULTS: A total of 515 (36%) patients with pouch-related adenomas have been reported. Two hundred and eleven (211) patients had adenomas in the ileal pouch mucosa, 295 had them in the ARS and in 9 were in the afferent ileal loop. Patients with pouch adenomas without dysplasia or cancer were either endoscopically polypectomized or were treated with a coagulation modality using either a Nd:Yag laser or argon plasma coagulation (as indicated). Patients with dysplastic pouch adenomas or pouch adenomas with cancer had their pouch excised (pouchectomy). CONCLUSION: In patients with FAP treated with IRA or RPC with IPAA, the formation of adenomas in the pouch-body mucosa or ARS/anastomosis and in the afferent ileal loop is apparent. Because of risks for adenoma recurrence, a life time endoscopic pouch surveillance is warranted. PMID- 24817994 TI - Restricted Stimulus Control in Stimulus Control Shaping with a Capuchin Monkey. AB - Teaching the first instances of arbitrary matching to sample to nonhumans can prove difficult and time consuming. Stimulus control relations may develop that differ from those intended by the experimenter - even when stimulus control shaping procedures are used. This paper reports efforts to identify sources of shaping program failure with a capuchin monkey. Procedures began with a baseline of identity matching. During subsequent shaping trials, compound comparison stimuli had two components - one identical to and another different from the sample. The identical component was eliminated gradually by removing portions across trials (i.e., subtracting stimulus elements). The monkey performed accurately throughout shaping. At a late stage in the program, probe tests were conducted: (1) arbitrary matching trials that had all elements of the identical comparison removed and (2) other trials that included residual elements. During the test, the monkey performed at low levels on the former trials and higher levels on the latter. These results suggested that higher accuracy was due merely to continued control by the residual elements: the target arbitrary matching relations had not been learned. Thus, it appears that procedures that gradually transform identity matching baselines into arbitrary matching can fail by inadvertently shaping restricted control by residual elements. Subsequent probes at the end of the shaping series showed a successful transfer of stimulus control from identity to arbitrary matching after further programming steps apparently overcame the restricted stimulus control. PMID- 24817993 TI - Endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes its subendothelial retention in vascular wall. AB - Oxidized low density of lipoprotein (oxLDL) is the major lipid found in atherosclerotic lesion and elevated plasma oxLDL is recognized to be a risk factor of atherosclerosis. Whether plasma oxLDL could be transported across endothelial cells and initiate atherosclerotic changes remains unknown. In an established in vitro cellular transcytosis model, the present study found that oxLDL could traffic across vascular endothelial cells and further that the regulation of endogenous ceramide production by ceramide metabolizing enzyme inhibitors significantly altered the transcytosis of oxLDL across endothelial cells. It was found that acid sphingomyelinase inhibitor, desipramine (DES), and de novo ceramide synthesis inhibitor, myriocin (MYR), both decreasing the endogenous ceramide production, significantly inhibited the transcytosis of oxLDL. Ceramidase inhibitor, N-oleoylethanolamine (NOE), and sphingomyelin synthase inhibitor, O-Tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt (D609), both increasing the endogenous ceramide production, significantly upregulated the transcytosis of oxLDL. In vivo, injection of fluorescence labeled oxLDL into mice body also predisposed to the subendothelial retention of these oxidized lipids. The observations provided in the present study demonstrate that endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes the initiating step of atherosclerosis-the subendothelial retention of lipids in vascular wall. PMID- 24817995 TI - Endodontic management of a mandibular first molar with four canals in a distal root by using cone-beam computed tomography: a case report. AB - BACKGROUND: Aberrations in the root canal anatomy are clinically challenging for clinicians. Mandibular first molars usually have 2 roots and 3 or 4 canals, but various combinations may exist. A distal root with three canals is rare and its incidence in literature is about 0.2 - 3%. As a diagnostic tool, cone-beam computed tomography (CBCT) may be a better choice for diagnosis of extra roots or canals comparing to conventional radiography. METHODS: An endodontic management of a mandibular first molar with six canals was performed. CBCT was used to confirm the diagnosis and to understand the morphology of the canals. RESULTS: Evaluation of the axial and coronal slices of CBCT images confirmed the presence of 2 roots and 6 canals. The distal root had four distinct root canal orifices with two apical foramens, being described as type XIV canal configuration. CONCLUSIONS: Dentists should be aware of unexpected canal morphology when performing endodontic treatment. The present case demonstrated the use of CBCT in diagnosis and negotiation of extra canals in a mandibular first molar. PMID- 24817996 TI - Desiccation plasticity in the embryonic life histories of non-annual rivulid species. AB - BACKGROUND: Diapause is a developmental arrest present in annual killifish, whose eggs are able to survive long periods of desiccation when the temporary ponds they inhabit dry up. Diapause can occur in three different developmental stages. These differ, within and between species, in their responsiveness to different environmental cues. A role of developmental plasticity and genetic assimilation in diapause evolution has been previously suggested but not experimentally explored. We investigated whether plastic developmental delays or arrests provoked by an unusual and extreme environment could be the ancestral condition for diapause. This would be in agreement with plasticity evolution playing a role in the emergence of diapause in this group. We have used a comparative experimental approach and exposed embryos of non-annual killifish belonging to five different species from the former genus Rivulus to brief periods of desiccation. We have estimated effects on developmental and mortality rates during and after the desiccation treatment. RESULTS: Embryos of these non-annual rivulids decreased their developmental rates in early stages of development in response to desiccation and this effect persisted after the treatment. Two pairs of two different species had sufficient sample sizes to investigate rates of development in later stages well. In one of these, we found cohorts of embryos in the latest stages of development that did not hatch over a period of more than 1 month without mortality. Several properties of this arrest are also used to characterize diapause III in annual killifish. Such a cohort is present in control conditions and increases in frequency in the desiccation treatment. CONCLUSIONS: The presence of plasticity for developmental timing and a prolonged developmental arrest in non-annual rivulids, suggest that a plastic developmental delay or diapause might have been present in the shared ancestor of annual and non-annual South American killifish and that the evolution of plasticity could have played a role in the emergence of the diapauses. Further comparative experimental studies and field research are needed to better understand how diapause and its plasticity evolved in this group. PMID- 24817997 TI - Types of sensitization to aeroallergens: definitions, prevalences and impact on the diagnosis and treatment of allergic respiratory disease. AB - The type of allergic sensitization is of central importance in the diagnosis and treatment of respiratory allergic diseases. At least 10% of the general population (and more than 50% of patients consulting for respiratory allergies) are polysensitized. Here, we review the recent literature on (i) the concepts of polysensitization, paucisensitization, co-sensitization, co-recognition, cross reactivity, cross-sensitization, and polyallergy, (ii) the prevalence of polysensitization and (iii) the relationships between sensitization status, disease severity and treatment strategies. In molecular terms, clinical polysensitization can be divided into cross-sensitization (also known as cross reactivity, in which the same IgE molecule binds to several allergens with common structural features) and co-sensitization (the simultaneous presence of different IgEs binding to allergens that may not necessarily have common structural features). There is a strong overall association between sensitization in skin prick tests and total IgE values but there is debate as to whether IgE thresholds are useful guides to the presence or absence of clinical symptoms in individual cases. Molecular information from component-resolved techniques appears to be of value for diagnosis and treatment decisions. Polysensitization develops over time and is a risk factor for respiratory allergy (being associated with disease severity) and therefore has clinical relevance for treatment decisions. The subterm polysensitization has been defined as polysensitization to between two and four allergens. Polyallergy is defined as clinically confirmed allergy to two or more allergens. Single-allergen grass pollen allergen immunotherapy (AIT) is safe and effective in polysensitized patients, whereas multi-allergen AIT requires more supporting evidence. Given that AIT may be more efficacious in moderate-to-severe disease than in mild disease, polysensitization could be an indication for this type of treatment. There is a need for flowcharts or decision trees for choosing the allergens for AIT in polysensitized patients and polyallergic patients. PMID- 24817999 TI - Angiogenic properties of dehydrated human amnion/chorion allografts: therapeutic potential for soft tissue repair and regeneration. AB - BACKGROUND: Chronic wounds are associated with a number of deficiencies in critical wound healing processes, including growth factor signaling and neovascularization. Human-derived placental tissues are rich in regenerative cytokines and have been shown in randomized clinical trials to be effective for healing chronic wounds. In this study, PURION(r) Processed (MiMedx Group, Marietta, GA) dehydrated human amnion/chorion membrane tissue allografts (dHACM, EpiFix(r), MiMedx) were evaluated for properties to support wound angiogenesis. METHODS: Angiogenic growth factors were identified in dHACM tissues using enzyme linked immunosorbent assays (ELISAs), and the effects of dHACM extract on human microvascular endothelial cell (HMVEC) proliferation and production of angiogenic growth factors was determined in vitro. Chemotactic migration of human umbilical vein endothelial cells (HUVECs) toward pieces of dHACM tissue was determined using a standard in vitro transwell assay. Neovascularization of dHACM in vivo was determined utilizing a murine subcutaneous implant model. RESULTS: Quantifiable levels of the angiogenic cytokines angiogenin, angiopoietin-2 (ANG 2), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), heparin binding epidermal growth factor (HB-EGF), hepatocyte growth factor (HGF), platelet derived growth factor BB (PDGF-BB), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) were measured in dHACM. Soluble cues promoted HMVEC proliferation in vitro and increased endogenous production of over 30 angiogenic factors by HMVECs, including granulocyte macrophage colony stimulating factor (GM-CSF), angiogenin, transforming growth factor beta3 (TGF beta3), and HB-EGF. 6.0 mm disks of dHACM tissue were also found to recruit migration of HUVECs in vitro. Moreover, subcutaneous dHACM implants displayed a steady increase in microvessels over a period of 4 weeks, indicative of a dynamic intra-implant neovascular process. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS DEMONSTRATE THAT DHACM GRAFTS: 1) contain angiogenic growth factors retaining biological activity; 2) promote amplification of angiogenic cues by inducing endothelial cell proliferation and migration and by upregulating production of endogenous angiogenic growth factors by endothelial cells; and 3) support the formation of blood vessels in vivo. dHACM grafts are a promising wound care therapy with the potential to promote revascularization and tissue healing within poorly vascularized, non-healing wounds. PMID- 24817998 TI - A new look at cerebrospinal fluid circulation. AB - According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation. PMID- 24818001 TI - Resin supported acyl carrier protein labeling strategies. AB - The post-translational modifying enzymes phophopantetheinyl transferase and acyl carrier protein hydrolase have shown utility in the functional modification of acyl carrier proteins. Here we develop these tools as immobilized biocatalysts on agarose supports. New utility is imparted through these methods, enabling rapid and label-independent protein purification. Immobilization of acyl carrier protein is also demonstrated for rapid activity assays of these 4' phosophopantetheine modifying enzymes, displaying a particular advantage in the case of phosphopantetheine removal, where few orthogonal techniques have been demonstrated. These tools further enrich the suite of functional utility of 4' phosophopantetheine chemistry, with applications to protein functionalization, materials, and natural product biosynthetic studies. PMID- 24818000 TI - Materials innovation for co-delivery of diverse therapeutic cargos. AB - Co-delivery is a rapidly growing sector of drug delivery that aspires to enhance therapeutic efficacy through controlled delivery of diverse therapeutic cargoes with synergistic activities. It requires the design of carriers capable of simultaneously transporting to and releasing multiple therapeutics at a disease site. Co-delivery has arisen from the emerging trend of combination therapy, where treatment with two or more therapeutics at the same time can succeed where single therapeutics fail. However, conventional combination therapy offers little control over achieving an optimized therapeutic ratio at the target site. Co delivery via inclusion of multiple therapeutic cargos within the same carrier addresses this issue by not only ensuring delivery of both therapeutics to the same cell, but also offering a platform for control of the delivery process, from loading to release. Co-delivery systems have been formulated using a number of carriers previously developed for single-therapeutic delivery. Liposomes, polymeric micelles, PLGA nanoparticles, and dendrimers have all been adapted for co-delivery. Much of the effort focuses on dealing with drugs having dissimilar properties, increasing loading efficiencies, and controlling loading and release ratios. In this review, we highlight the innovations in carrier designs and formulations to deliver combination cargoes of drug/drug, drug/siRNA, and drug/pDNA toward disease therapy. With rapid advances in mechanistic understanding of interrelating molecular pathways and development of molecular medicine, the future of co-delivery will become increasingly promising and prominent. PMID- 24818002 TI - Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets. AB - Heterogeneous loss of function mutations in the vitamin D receptor (VDR) interfere with vitamin D signaling and cause hereditary vitamin D-resistant rickets (HVDRR). HVDRR is characterized by hypocalcemia, secondary hyperparathyroidism and severe early-onset rickets in infancy and is often associated with consanguinity. Affected children may also exhibit alopecia of the scalp and total body. The children usually fail to respond to treatment with calcitriol; in fact, their endogenous levels are often very elevated. Successful treatment requires reversal of hypocalcemia and secondary hyperparathyroidism and is usually accomplished by administration of high doses of calcium given either intravenously or sometimes orally to bypass the intestinal defect in VDR signaling. PMID- 24818003 TI - Vitamin D and bone health: Epidemiologic studies. AB - Allelic variation in the vitamin D receptor was the first non-structural gene to be associated with osteoporosis, and together with the effects of the vitamin D system on bone homeostasis, suggested that this vitamin might have a strong role in bone health. However, controversy exists regarding what level of serum 25 hydroxyvitamin D (25(OH)D) is optimal. Current data from biochemical, observational and randomized controlled trials (RCTs), indicate serum 25(OH)D levels of at least 50 nmol l(-1) are required for normalization of parathyroid hormone (PTH) levels, to minimize the risk of osteomalacia and for optimal bone cell function. The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone turnover and bone loss and an increased risk of minimal trauma fractures. In large scale epidemiological studies, serum 25(OH)D levels are associated with bone mineral density in both men and women. However, there is mixed evidence on the effectiveness of optimizing serum 25(OH)D levels for the prevention of bone loss and minimal trauma fractures in postmenopausal women and older men. There may be some benefit on primary fracture prevention for those who have inadequate serum levels of 25(OH)D, particularly in institutionalised elderly patients, but only when combined with calcium supplements. For optimal bone health, evidence from RCTs suggests vitamin D may be considered a threshold nutrient with few further bone benefits observed at levels of 25(OH)D above which PTH is normalized. An adequate calcium intake is also imperative to gain optimum benefit from an improved vitamin D status in those with insufficient 25(OH)D levels, with an increased calcium intake being associated with suppression of PTH levels. PMID- 24818004 TI - Vitamin D supplements with or without calcium to prevent fractures. AB - Vitamin D deficiency is associated with fractures. This relationship is biologically plausible. The results of 19 randomized clinical trials with vitamin D with or without calcium show varying results: a decreased fracture incidence in 7, neutral in 10 trials, whereas 2 trials with a high dose of vitamin D once per year showed an increased fracture incidence. In three out of four well-powered trials that used recommended doses of vitamin D 700-1000 IU per day, vitamin D supplementation did not significantly influence fracture risk. In one of these trials, a statistically significant fracture reduction was observed in nursing home residents having severe vitamin D deficiency, low calcium intake and good compliance. Thirteen meta-analyses were done, and 11 of these showed a significantly decreased fracture incidence in the supplemented groups. Vitamin D alone was not effective, studies combining vitamin D and calcium showed inconsistent results. Analyses for vertebral fractures were negative in all cases. In conclusion, a vitamin D supplement of 800 IU per day in combination with calcium may decrease the incidence of non-vertebral fractures, especially in persons in the older age groups having low-baseline vitamin D status and low calcium intake and showing good compliance. PMID- 24818005 TI - Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol. AB - Eldecalcitol [1alpha,25-dihydroxy-2beta-(3-hydroxypropyloxy)vitamin D3] is an analog of 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], bearing a hydroxypropyloxy residue at the 2beta position. In preclinical studies, eldecalcitol suppressed bone resorption to a greater extent than alfacalcidol but had a similar effect on bone formation and Ca metabolism, resulting in a greater increase in bone mineral density (BMD) in ovariectomized (OVX) rats. Histological analysis in OVX rats immediately after ovariectomy revealed that eldecalcitol reduced osteoclast number and bone resorption parameters with a decrease in bone formation parameters. Eldecalcitol also promoted focal bone formation independent of bone resorption, a process known as bone minimodeling. In clinical studies, eldecalcitol showed stronger effects than alfacalcidol in increasing BMD and reducing bone resorption markers in osteoporotic patients under vitamin D supplementation. A 3-year randomized, double-blind, active-comparator clinical trial demonstrated that once-daily 0.75 MUg eldecalcitol reduced vertebral fracture incidence by 26% compared with 1.0 MUg alfacalcidol. Eldecalcitol also reduced the incidence of wrist fractures by 71% compared with alfacalcidol. Although this may be due to the previously reported effect of vitamin D in reducing the incidence of falls, it is not known whether eldecalcitol has a stronger effect in preventing falls than alfacalcidol. Because eldecalcitol stimulates intestinal Ca absorption and improves Ca balance in addition to its skeletal effects, combination treatment with antiresorptive agents may be able to show better effects than native vitamin D and Ca supplementation in preventing fractures in osteoporotic patients. Further studies are warranted to clarify these issues. PMID- 24818006 TI - The development of a bone- and parathyroid-specific analog of vitamin D: 2 methylene-19-Nor-(20S)-1alpha,25-dihydroxyvitamin D3. AB - The goal of synthetic chemists in the vitamin D field has been to produce an analog(s) of 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) that is selective for a specific function. The accumulation of structure/function information has led to the synthesis of two analogs that are both selective and more potent than 1,25 (OH)2D3, that is, 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD) and 2alpha-methyl-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2AMD). In vivo, the efficacy of 2MD is approximately equal to that of 1,25-(OH)2D3 in intestinal calcium transport but is 30- to 100-fold more active in bone mobilization. In vitro, 2MD supports new bone synthesis at 10(-12) M, whereas 1,25-(OH)2D3 is active at 10(-8) M. Similarly, 2MD is two orders of magnitude more potent than 1,25-(OH)2D3 in stimulating osteoclastogenesis and osteoclastic bone resorption. 2MD also markedly increases bone mass and bone strength of ovariectomized female rats. In postmenopausal women, 2MD significantly increases markers of both bone formation and resorption but has minimal effect on bone mass. Thus, in patients who are undergoing primarily remodeling rather than modeling (rat), the increased resorption largely counteracts the increased bone formation. So far, 2MD has not been tested for reduction of fractures in this population. However, its selectivity includes the parathyroid gland. Thus in the 5/6-nephrectomy model of chronic renal failure, 2MD is much more potent than currently available vitamin D compounds used to suppress secondary hyperparathyroidism of renal failure without causing hypercalcemia. It is currently in phase 2B trials in patients on dialysis. PMID- 24818008 TI - Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets. AB - This review describes the pathogenesis, clinical presentation and biochemical perturbations found in privational (nutritional) rickets and pseudo-vitamin D deficiency rickets (PDDR), an autosomal recessive condition with loss of function mutations in CYP27B1. It may seem strange to combine a discussion on privational rickets and PDDR as a single topic, but privational rickets and PDDR present with similar clinical signs and symptoms and with similar perturbations in bone and mineral metabolism. Of interest is the characteristic lack of features of rickets at birth in infants with PDDR, a finding which has also been reported in infants born to vitamin D-deficient mothers. This highlights the independence of the fetus and neonate from the need for vitamin D to maintain calcium homeostasis during this period. The variable roles of vitamin D deficiency and dietary calcium deficiency in the pathogenesis of privational rickets are discussed and the associated alterations in vitamin D metabolism highlighted. Although PDDR is a rare autosomal recessive disorder, results of long-term follow-up are now available on the effect of treatment with calcitriol, and these are discussed. Areas of uncertainty, such as should affected mothers breastfeed their infants, are emphasized. PMID- 24818009 TI - Responses to increasing exercise upon reaching the anaerobic threshold, and their control by the central nervous system. AB - The anaerobic threshold (AT) has been one of the most studied of all physiological variables. Many authors have proposed the use of several markers to determine the moment at with the AT is reached. The present work discusses the physiological responses made to exercise - the measurement of which indicates the point at which the AT is reached - and how these responses might be controlled by the central nervous system. The detection of the AT having been reached is a sign for the central nervous system (CNS) to respond via an increase in efferent activity via the peripheral nervous system (PNS). An increase in CNS and PNS activities are related to changes in ventilation, cardiovascular function, and gland and muscle function. The directing action of the central command (CC) allows for the coordination of the autonomous and motor systems, suggesting that the AT can be identified in the many ways: changes in lactate, ventilation, plasma catecholamines, heart rate (HR), salivary amylase and muscular electrical activity. This change in response could be indicative that the organism would face failure if the exercise load continued to increase. To avoid this, the CC manages the efferent signals that show the organism that it is running out of homeostatic potential. PMID- 24818010 TI - Use of adjuvant sorafenib in liver transplant recipients with high-risk hepatocellular carcinoma. AB - The efficacy of liver transplantation (LT) for hepatocellular (HCC) is limited by tumor recurrence rates of 10-15%. We undertook this pilot study to examine the use of sorafenib as adjuvant therapy in high-risk LT recipients. Methods. We prospectively enrolled patients transplanted for HCC into a treatment protocol utilizing sorafenib if their explant examination showed evidence of viable tumor exceeding Milan criteria. We utilized as historical controls patients transplanted previously, whose explant tumor characteristics exceeded Milan criteria, but who were not "preemptively" treated with sorafenib. Wilcoxon two sample test and Fisher's exact test were used to compare survival and recurrence rates between the two groups. Results. Seven patients were treated with sorafenib and compared to 12 historical "controls." Two of 7 treated patients suffered from HCC recurrence. Of the comparison group, 9 experienced HCC recurrence and all succumbed to disease. Dose reduction improved tolerance of drug. The overall rate of HCC recurrence was decreased in the adjuvant therapy group compared to historical controls (29% versus 75%, P = 0.07). Disease free 1-year survival for the treated versus untreated group was 100% versus 66%, respectively. Conclusion. Adjuvant use of sorafenib is safe and decreases risk of HCC recurrence in high risk LT recipients. PMID- 24818011 TI - Identification and preservation of intestinal parasites using methylene blue glycerol mount: a new approach to stool microscopy. AB - We have tried a new approach to routine stool microscopy by using a combination of methylene blue and glycerol in wet mount preparation of fresh faecal samples for the demonstration of medically important intestinal parasites. This combination was evaluated for finding differences in the details and clarity of morphology and internal structures of parasites under low- and high-power microscopy as compared to iodine and saline mount. It was further evaluated to estimate the time taken by methylene blue-glycerol mount to dry up as compared to iodine and saline wet mount. PMID- 24818012 TI - Immobilization of a Plant Lipase from Pachira aquatica in Alginate and Alginate/PVA Beads. AB - This study reports the immobilization of a new lipase isolated from oleaginous seeds of Pachira aquatica, using beads of calcium alginate (Alg) and poly(vinyl alcohol) (PVA). We evaluated the morphology, number of cycles of reuse, optimum temperature, and temperature stability of both immobilization methods compared to the free enzyme. The immobilized enzymes were more stable than the free enzyme, keeping 60% of the original activity after 4 h at 50 degrees C. The immobilized lipase was reused several times, with activity decreasing to approximately 50% after 5 cycles. Both the free and immobilized enzymes were found to be optimally active between 30 and 40 degrees C. PMID- 24818013 TI - A cDNA Cloning of a Novel Alpha-Class Tyrosinase of Pinctada fucata: Its Expression Analysis and Characterization of the Expressed Protein. AB - Tyrosinase plays an important role in the formation of the shell matrix and melanin synthesis in mollusks shells. A cDNA clone encoding a 47 kDa protein was isolated from the pearl oyster Pinctada fucata. The cDNA was 1,957 base pairs long and encodes a 417 residue protein that has extensive sequence identity with tyrosinase (polyphenol oxidase: EC 1.14.18.1). This tyrosinase-like protein, termed PfTy, contains an N-terminal signal sequence and the two copper-binding domain signatures (CuA and CuB), suggesting that PfTy belongs to the alpha subclass of type-3 copper proteins. Enzyme activity of PfTy was examined by a spectrophotometric method using the translation product derived from an S30 T7 high-yield protein expression system. Tyrosinase activity was seen in this recombinant product. RT-PCR analysis showed that PfTy mRNA was expressed in the mantle pallial, but not in the mantle edge. Therefore, PfTy may participate in insoluble shell matrix formation of the nacreous layer. PfTy expression was also observed in the foot, liver, and adductor muscle, suggesting that PfTy participates in the synthesis of melanins, which are effective scavengers of free radicals formed in multiple intracellular oxidative processes. This is the first report of a novel alpha -class tyrosinase from the pearl oyster P. fucata. PMID- 24818014 TI - A tandem repeat in decay accelerating factor 1 is associated with severity of murine mercury-induced autoimmunity. AB - Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA). Daf1, located within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reduced Daf1 transcription in lupus-prone mice was not associated with a reduction in the Daf1 transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2 Hmr1 locus suggested that Daf1 expression was controlled by the host genome and not the Hmr1 locus. A unique pentanucleotide repeat variant in the second intron of Daf1 in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis of Hmr1 congenics indicated that this most likely reflected the presence of autoimmunity predisposing genetic variants within the Hmr1 locus or that Daf1 expression is mediated by the tandem repeat in epistasis with other genetic variants present in autoimmune-prone mice. These studies argue that the effect of DAF on autoimmunity is complex and may require multiple genetic elements. PMID- 24818015 TI - Effect on blood pressure of daily lemon ingestion and walking. AB - Background. Recent studies suggest that the daily intake of lemon (Citrus limon) has a good effect on health, but this has not been confirmed in humans. In our previous studies, it was observed that people who are conscious of their health performed more lemon intake and exercise. An analysis that took this into account was required. Methodology. For 101 middle-aged women in an island area in Hiroshima, Japan, a record of lemon ingestion efforts and the number of steps walked was carried out for five months. The change rates (Delta%) of the physical measurements, blood test, blood pressure, and pulse wave measured value during the observation period were calculated, and correlations with lemon intake and the number of steps walked were considered. As a result, it was suggested that daily lemon intake and walking are effective for high blood pressure because both showed significant negative correlation to systolic blood pressure Delta%. Conclusions. As a result of multiple linear regression analysis, it was possible that lemon ingestion is involved more greatly with the blood citric acid concentration Delta% and the number of steps with blood pressure Delta%, and it was surmised that the number of steps and lemon ingestion are related to blood pressure improvement by different action mechanisms. PMID- 24818016 TI - Hematological indices for differential diagnosis of Beta thalassemia trait and iron deficiency anemia. AB - Background. The two most frequent types of microcytic anemia are beta thalassemia trait ( beta -TT) and iron deficiency anemia (IDA). We retrospectively evaluated the reliability of various indices for differential diagnosis of microcytosis and beta -TT in the same patient groups. Methods. A total of 290 carefully selected children aged 1.1-16 years were evaluated. We calculated 12 discrimination indices in all patients with hemoglobin (Hb) values of 8.7-11.4 g/dL. None of the subjects had a combined case of IDA and beta -TT. All children with IDA received oral iron for 16 weeks, and HbA2 screening was performed after iron therapy. The patient groups were evaluated according to red blood cell (RBC) count; red blood distribution width index; the Mentzer, Shine and Lal, England and Fraser, Srivastava and Bevington, Green and King, Ricerca, Sirdah, and Ehsani indices; mean density of hemoglobin/liter of blood; and mean cell density of hemoglobin. Results. The Mentzer index was the most reliable index, as it had the highest sensitivity (98.7%), specificity (82.3%), and Youden's index (81%) for detecting beta -TT; this was followed by the Ehsani index (94.8%, 73.5%, and 68.3%, resp.) and RBC count (94.8%, 70.5%, and 65.3%). Conclusion. The Mentzer index provided the highest reliabilities for differentiating beta -TT from IDA. PMID- 24818017 TI - Implementing a collaborative sepsis protocol on the time to antibiotics in an emergency department of a saudi hospital: quasi randomized study. AB - Background. The objective of this study is to evaluate the impact of an ED sepsis protocol on the time to antibiotics for emergency department (ED) patients with severe sepsis. Methods. Quasiexperimental prospective study was conducted at the emergency department. Consecutive patients with severe sepsis were included before and after the implementation of a sepsis protocol. The outcome measures were time from recognition of severe sepsis/septic shock to first antibiotic dose delivery and the appropriateness of initial choice of antibiotics based on the presumed source of infection. Results. There were 47 patients in preintervention group and 112 patients in postintervention group. Before implementation, mean time from severe sepsis recognition to delivery of antibiotics was 140 +/- 97 minutes. During the intervention period, the mean time was 68 +/- 67 minutes, with an overall reduction of 72 minutes. The protocol resulted in an overall improvement of 37% in the compliance, as 62% received appropriate initial antibiotics for the presumed source of infection as compared to 25% before the start of protocol. Conclusion. Implementation of ED sepsis protocol improved the time from recognition of severe sepsis/septic shock to first antibiotic dose delivery as well as the appropriateness of initial antibiotic therapy. PMID- 24818018 TI - Organizational culture shapes the adoption and incorporation of simulation into nursing curricula: a grounded theory study. AB - Purpose. To create a substantive mid-range theory explaining how the organizational cultures of undergraduate nursing programs shape the adoption and incorporation of mid-to high-level technical fidelity simulators as a teaching strategy within curricula. Method. A constructivist grounded theory was used to guide this study which was conducted in Ontario, Canada, during 2011-12. Semistructured interviews (n = 43) with participants that included nursing administrators, nursing faculty, and simulation leaders across multiple programs (n = 13) informed this study. Additionally, key documents (n = 67) were reviewed. Purposeful and theoretical sampling was used and data were collected and analyzed simultaneously. Data were compared among and between sites. Findings. The organizational elements that shape simulation in nursing (OESSN) model depicts five key organizational factors at the nursing program level that shaped the adoption and incorporation of simulation: (1) leaders working in tandem, (2) information exchange, (3) physical locale, (4) shared motivators, and (5) scaffolding to manage change. Conclusions. The OESSN model provides an explanation of the organizational factors that contributed to the adoption and incorporation of simulation into nursing curricula. Nursing programs that use the OESSN model may experience a more rapid or broad uptake of simulation when organizational factors that impact adoption and incorporation are considered and planned for. PMID- 24818019 TI - Treatment of early-stage pressure ulcers by using autologous adipose tissue grafts. AB - Assessing pressure ulcers (PUs) in early stages allows patients to receive safer treatment. Up to now, in addition to clinical evaluation, ultrasonography seems to be the most suitable technique to achieve this goal. Several treatments are applied to prevent ulcer progression but none of them is totally effective. Furthermore, the in-depth knowledge of fat regenerative properties has led to a wide use of it. With this study the authors aim at introducing a new approach to cure and prevent the worsening of early-stage PUs by using fat grafts. The authors selected 42 patients who showed clinical and ultrasonographic evidence of early-stage PUs. Values of skin thickness, fascial integrity, and subcutaneous vascularity were recorded both on the PU area and the healthy trochanteric one, used as control region. Fat grafting was performed on all patients. At three months, abnormal ultrasonographic findings, such as reduction of cutaneous and subcutaneous thickness, discontinuous fascia, and decrease in subcutaneous vascularity, all were modified with respect to almost all the corresponding parameters of the control region. Results highlight that the use of fat grafts proved to be an effective treatment for early-stage PUs, especially in the care of neurological and chronic bedridden patients. PMID- 24818020 TI - Is hippocampus susceptible to antinociceptive tolerance to NSAIDs like the periaqueductal grey? AB - Emotional distress is the most undesirable feature of painful experience. Numerous studies have demonstrated the important role of the limbic system in the affective-motivational component of pain. The purpose of this paper was to examine whether microinjection of nonsteroidal anti-inflammatory drugs (NSAIDs), Clodifen, Ketorolac, and Xefocam, into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats. We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the tail-flick (TF) and hot plate (HP) tests compared to controls treated with saline into the DH. Subsequent tests on consecutive three days, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and posttreatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models. Our data indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance. PMID- 24818021 TI - The Beliefs of Third-Level Healthcare Students towards Low-Back Pain. AB - Objectives. Beliefs held by healthcare providers are part of the complex recovery of a patient with low-back pain (LBP). The aim of this study was to investigate the attitudes and beliefs of Irish university healthcare students towards LBP. Methods. Physiotherapy (n = 107), medicine (n = 63), nursing, and midwifery (n = 101) students completed the survey. Demographic data, LBP related beliefs [Back Beliefs Questionnaire (BBQ) and the Fear Avoidance Beliefs Questionnaire physical subsection (FABQ-PA)] were collected. Results. Two hundred and seventy-one students responded (response rate 29%). Student physiotherapists had significantly lower FABQ (P < 0.001) scores than medical (95% CI [-5.492, 1.406]) and nursing students (95% CI [-7.718, -22.307]). Physiotherapy students had significantly higher BBQ scores (P < 0.0001) than medical (95% CI [1.490, 5.406]) and nursing students (95% CI [6.098, 11.283]). Beliefs of physiotherapy and medical students were significantly better among fourth-year year than first year students (P < 0.0001) but were not significantly different for nursing students (P = 0.820 for FABQ and P = 0.810 for BBQ). Conclusions. Physiotherapy students had more positive beliefs towards LBP than medical and nursing students. Physiotherapy and medical students' beliefs towards LBP significantly improved over the course of their studies. PMID- 24818022 TI - A postauthorization survey to document the therapeutic management of oxaliplatin as a first-line chemotherapy regimen in South Africa in patients with metastatic colorectal cancer. AB - Oxaliplatin is a standard first-line treatment for metastatic colorectal cancer. The objectives were to document the therapeutic management of oxaliplatin in South Africa, determine the incidence and severity of sensory neuropathy, and record the 2-year survival rate. Meccelox was a prospective, noncontrolled, open label, multicentre, observational survey of adult patients with stage IV metastatic colorectal cancer treated with oxaliplatin-based chemotherapeutic regimens. The study was conducted from August 2007 to November 2011 in 29 sites in South Africa by 66 participating treating physicians. Among the 195 enrolled patients, 61% were treated with FOLFOX regimen (5-fluorouracil/folinic acid plus oxaliplatin) for an average of 12 cycles and 32% patients were treated with XELOX (capecitabine plus oxaliplatin) for an average of 6-8 cycles, with the main reason for discontinuation being completion of the preplanned prescribed regimen. In Meccelox survey, 80% of patients were treated with intent of palliation. Overall 64% of patients reported symptoms of sensory neuropathy. The 2-year survival rate was 30%. Conclusions. Patients received a specified preplanned number of chemotherapy cycles rather than being treated until disease progression or toxicity. Both the incidence of neuropathy and the 2-year survival rate were less than previous reports. PMID- 24818023 TI - Salivary creatinine estimation as an alternative to serum creatinine in chronic kidney disease patients. AB - Context. Sampling blood for serum analysis is an invasive procedure. A noninvasive alternative would be beneficial to patients and health care professionals. Aim. To correlate serum and salivary creatinine levels and evaluate the role of saliva as a noninvasive alternative to serum for creatinine estimation in chronic kidney disease patients. Study Design. Case-control study. Methods. Blood and saliva samples were collected from 37 healthy individuals and 105 chronic kidney disease patients. Serum and salivary creatinine levels were estimated using automatic analyser. Statistical Analysis. The serum and salivary creatinine levels between controls and cases were compared using t-test. Correlation between serum and salivary creatinine was obtained in controls and cases using Pearson correlation coefficient. Receiver operating characteristic analysis was done to assess the diagnostic performance of salivary creatinine. Cut-off values were established for salivary creatinine. Results. Serum and salivary creatinine levels were significantly higher in CKD patients than controls. The correlation was negative in controls and positive in cases. Area under the curve for salivary creatinine was found to be 0.967. A cut-off value of 0.2 mg/dL gave a sensitivity of 97.1% and specificity of 86.5%. Conclusion. Saliva can be used as a noninvasive alternative to serum for creatinine estimation. PMID- 24818024 TI - Identification and Characterization of TEX101 in Bovine Epididymal Spermatozoa. AB - Several studies exhibit the presence of Ricinus Communis Agglutinin I (RCA) binding glycocalyx in mammalian spermatozoa. However, the molecular characterization of RCA binding glycocalyx in sperm membranes and its mechanism of action are poorly understood. The objective of the study was to identify and to characterize RCA binding glycoprotein of the bovine sperm plasma membranes (PM). Lectin blots of caput and cauda sperm PM revealed a 38 kDa polypeptide exhibiting the highest affinity to RCA among the several major RCA binding polypeptides. The 38 kDa RCA binding polypeptide of cauda sperm PM was purified and exhibited a charge train of three distinct spots with isoelectric points (pH 5.3 and 5.8). Proteomic identification yielded ten peptides that matched the sequence of Testis Expressed 101 protein (TEX101). Western blots data revealed that bovine sperm TEX101 is present in both testicular and epididymal sperm PM fractions. The native TEX101 polypeptide contains ~17 kDa N-linked oligosaccharides and the polypeptide is anchored to sperm membrane via a glycosylphosphatidylinositol lipid linkage. Immunofluorescence staining of sperm with anti-TEX101 demonstrated that the polypeptide is localized at the head of cauda sperm. Our biochemical results provide evidence on the presence of TEX101 in bovine epididymal sperm plasma membranes and may have a potential role in sperm-egg interaction. PMID- 24818025 TI - Roles of the Oxidative Stress and ADMA in the Development of Deep Venous Thrombosis. AB - Venous thromboembolism has multifactorial origin and occurs in the context of complex interactions between environmental and genetic predisposing factors. Oxidative stress plays an important role in the physiopathology of venous thrombosis. Current study examined the role of oxidative stress and asymmetric dimethylarginine in the development of DVT with the parameters such as serum malondialdehyde (MDA), glutathione peroxidase (GSH-Px), catalase, ADMA, homocysteine, folic acid, vitamin B6, and vitamin B12 levels. Serum MDA levels were found significantly (P < 0.005) high in patients with DVT compared with control group. Additionally, serum B6 levels were found significantly (P < 0.009) low in patients with DVT compared with healthy volunteers. There were no significant differences between the groups in terms of the other parameters (P > 0.05). This study showed that patients with DVT have increased oxidative stress compared with the healthy volunteers whereas there was no significant difference between the groups in terms of serum ADMA levels. Thus serum ADMA levels seemed to be not related with development of DVT. PMID- 24818026 TI - The thoracic shape of hominoids. AB - In hominoids, the broad thorax has been assumed to contribute to their dorsal scapular position. However, the dorsoventral diameter of their cranial thorax was found in one study to be longer in hominoids. There are insufficient data on thoracic shape to explain the relationship between broad thorax and dorsal scapular position. The current study presents data on multilevel cross-sectional shape and volume distribution in a range of primates. Biplanar radiographs of intact fluid-preserved cadavers were taken to measure the cross-sectional shape of ten equally spaced levels through the sternum (called decisternal levels) and the relative volume of the nine intervening thoracic segments. It was found that the cranial thorax of hominoids is larger and broader (except in the first two decisternal levels) than that of other primates. The cranial thorax of hominoids has a longer dorsoventral diameter because the increase in dorsoventral diameter caused by the increase in the volume of the cranial thorax overcompensates for the decrease caused by the broadening of the cranial thorax. The larger and broader cranial thorax in hominoids can be explained as a locomotor adaptation for scapular gliding and as a respiratory adaptation for reducing the effects of orthograde posture on ventilation-perfusion inequality. PMID- 24818027 TI - Hepatitis C among Egyptian Patients Referred for Bone Marrow Examination: Seroprevalence and Analysis of Hematological Findings. AB - Hepatitis C is a significant public health problem in Egypt where the highest prevalence (14.7%) of hepatitis C virus (HCV) exists. HCV prevalence is even higher among clinical populations and groups at risk of exposure to infection. Chronic HCV infection is associated with several hematological complications that may necessitate bone marrow (BM) examination. The aim of this study is to estimate HCV prevalence among patients referred for BM examination and to explore hematological and BM findings among HCV positive patients. One hundred adult patients referred for BM examination were included in the study and screened for HCV antibodies. Patients' clinical, hematological, and BM findings were recorded. The seroprevalence of HCV among patients referred for BM examination was 42%. The most common indication for BM examination among HCV positive patients was peripheral cytopenias (88.1%). The most common cytopenia detected was thrombocytopenia (85.7%). The most common diagnosis among HCV positive patients was hypersplenism (52.4%) followed by B-lymphoproliferative disorders (19%) and then immune thrombocytopenic purpura (11.9%). In conclusion, HCV prevalence among patients referred for BM examination is higher than that estimated in the general population. Patients with unexplained peripheral cytopenias should be tested for HCV. PMID- 24818028 TI - Dental Sealants: Knowledge, Value, Opinion, and Practice among Dental Professionals of Bathinda City, India. AB - Objective. The purpose of the study was to assess the knowledge, value, opinion, and practice regarding use of dental sealants among private dental practitioners in Bathinda City, Punjab, India. Materials and Methods. A cross-sectional survey was conducted among all private dental practitioners in Bathinda City, Punjab. A self-administered structured questionnaire consisting of 28 items was used to assess their knowledge, value, opinion, and practice regarding dental sealants. One-way analysis of variance, independent sample t-test, and multivariate regression analysis were utilized for statistical analysis. Confidence level and level of significance were set at 95% and 5%, respectively. Results. The mean scores for knowledge, value, opinion, and practice were 41.8 +/- 3.7, 18.7 +/- 2.8, 18.1 +/- 1.4, and 12.9 +/- 2.3, respectively. Analysis revealed that qualification was statistically significant among all dependent variables (P <= 0.05); work experience was significantly associated with both knowledge and opinion means scores (P <= 0.05). Conclusion. The results suggest that dental practitioners had sufficient knowledge about dental sealants. They also acknowledge the importance of use of dental sealants. Practice of dental sealants in clinics was found adequate but they were not following the specific guidelines and standardized procedures. PMID- 24818029 TI - Large complex odontoma of mandible in a young boy: a rare and unusual case report. AB - Odontomas are the most common odontogenic tumors. They are broadly classified in to Compound Odontoma and Complex Odontoma. Among them complex odontoma is a rare tumor. Occasionally this tumor becomes large, causing expansion of bone followed by facial asymmetry. Otherwise these tumors are asymptomatic and are generally diagnosed on radiographic examination. We report a rare case of complex odontoma of mandible in a young boy. The tumor was treated by surgical excision under general anesthesia. PMID- 24818030 TI - Metastases to the thyroid presenting as a metabolically inactive incidental thyroid nodule with stable size in 15 months. AB - Though the thyroid gland has a rich vascular supply, incidence of metastatic disease from distant organs is rare. Here we present an unusual case of metastases to the thyroid with several interesting features. A 63-year-old male with history of adenocarcinoma of the right lobe lung (5 years prior to presentation), treated with surgery and chemotherapy, followed by new adenosquamous lung cancer in the left lobe of the lung (one year prior to presentation), treated surgically followed by adjuvant chemotherapy, was referred to Endocrinology section for evaluation of an incidental thyroid nodule on CT chest. Ultrasound (US) of the thyroid revealed a complex, predominantly hypoechoic lesion measuring 1.8 cm within the lower pole of the right thyroid lobe and a subcentimeter lesion in the left lobe of the thyroid. Review of prior CT chests showed that the lesion in the right lobe was stable for 15 months, with no evidence of a hypermetabolic lesion on PET scan. The subcentimeter lesion was not seen on prior CT scans. US guided fine needle aspiration (FNA) and pathology of the lobectomy of the thyroid confirmed adenosquamous carcinoma. Interesting features in this case are that the thyroid metastases occurred without any evidence of synchronous lesions elsewhere, the size was stable over 15 months, and the lesions were metabolically inactive. PMID- 24818031 TI - Ependymoma and carcinoid tumor associated with ovarian mature cystic teratoma in a patient with multiple endocrine neoplasia I. AB - Ovarian teratomas rarely undergo new neoplastic transformation and account for a small percentage of malignant ovarian germ cell neoplasms. Here we report a case of a 51-year-old woman with multiple endocrine neoplasia type I (MEN I) who was found to have an ependymoma and neuroendocrine tumor (trabecular carcinoid) associated with mature cystic teratoma of her left ovary. The ependymoma component displayed cells with round nuclei and occasional small nucleoli which were focally arranged in perivascular pseudorosettes and true rosettes. Rare mitoses were identified. No necrosis was present. Immunohistochemical staining was positive for S-100 and GFAP. The Ki67 proliferation index was very low (2 3%). In contrast, the endocrine tumor component was composed of small uniform cells with eosinophilic cytoplasm, round nuclei, and speckled chromatin. Immunohistochemical staining was positive for synaptophysin and focally positive for chromogranin. This rare case illustrates that MEN I may have an influence on the pathogenesis of ovarian teratomas as they undergo malignant transformation. PMID- 24818032 TI - Unusual dermoid cyst in oral cavity. AB - Dermoid cysts in oral cavity are unusual lesions. Their etiology is not yet clear and can be associated with trapped cells as a result of the inclusion error resulting in the development into the ectoderm, mesoderm, and endoderm tissues. The aim of this case report is to evidence the presence of a dermoid cyst in the floor of mouth surgically removed. In the present case, the lesion showed soft consistency, floating, regular borders, smooth surface, and the same color as the adjacent mucosa, asymptomatic and measuring 4.5 * 5.5 cm in its greatest diameter. The initial diagnostic was ranula in consequence of the similarity with clinical characteristics and localization. After surgical removal lesion, a fibrotic capsule was identified with a friable material with intensive yellow color. The microscopic exam showed cystic lesion with cavity lined by squamous stratified epithelium hyperorthokeratinized. Cutaneous attachments, such as sebaceous glands and hair follicles, were present in connective adjacent tissue. Surgical intervention is elective in these situations. All dentists must have a thorough knowledge of this unusual lesion. PMID- 24818033 TI - Tackling negative symptoms of schizophrenia with memantine. AB - We present a case of a 52-year-old male patient suffering from chronic schizophrenia stabilized on risperidone long-acting injection (37,5 mg/2 weeks) and biperiden 4 mg/day. Residual symptoms are affective flattening, alogia, avolition, and asociality. Memantine 10 mg/day was added. After 1.5 months, the patient spontaneously referred to "feel better being in company of my relatives." The following scales have been completed: the Scale for the Assessment of Negative Symptoms (96), the Scale for the Assessment of Positive Symptoms (3), the Mini Mental Scale Examination (26), and the Calgary Depression for Schizophrenia Scale (2). Memantine was increased to 20 mg/day and biperiden was decreased to 2 mg/day. Two months later, apathy and asociality considerably improved and affective flattening, alogia, and attention slightly got better (SANS 76, SAPS 1, MMSE 26, and CDSS 1). After two more months, the improvement continued in the same domains (SANS: 70, SAPS: 1 MMSE: 27, and CDSS: 1). Positive symptoms remained in full remission. It has been hypothesized that one of the causes of schizophrenia is glutamate excitotoxicity. Memantine, a glutamate receptor antagonist, could possibly ameliorate schizophrenia symptoms, the negative ones among them, used as add-on therapy to atypical antipsychotics. Memantine could be of potential help in schizophrenia patients with severe residual negative symptoms. PMID- 24818034 TI - A case of psychosis in disulfiram treatment for alcoholism. AB - Background. Disulfiram, a drug used in the treatment of alcohol dependence, is an inhibitor of dopamine- beta -hydroxylase causing an increase in the concentration of dopamine in the mesolimbic system. In addition to the physical symptoms associated with concomitant use of alcohol, disulfiram may lead to adverse events, when used alone, including psychosis. Aims. To report a case of a rare complication when using disulfiram for alcoholism treatment in a patient in alcoholic abstinence. Case Report. We describe the case of a 42-year-old male patient, who developed psychotic symptoms 3 weeks after initiating treatment with disulfiram for alcohol dependency. The patient had a history of chronic alcoholism for 12 years and was under disulfiram treatment (250 mg/day) for 1 month, with no other past history of psychiatric illness. The symptoms worsened after he initiated alcohol consumption, while taking disulfiram. The patient was hospitalized and disulfiram was suspended. After 4 days he was asymptomatic and at 6-week follow-up remained asymptomatic. Conclusion. Treatment with disulfiram can lead to the appearance of psychosis in patients with increased vulnerability. In clinical practice, psychosis in the context of alcoholism with disulfiram therapy is often neglected and should be taken into account. PMID- 24818035 TI - Myelofibrosis-related arthritis successfully treated with hydroxyurea. AB - A 62-year-old woman suffering from one-year lasting, nonerosive peripheral arthritides with general health impairment and high acute-phase reactant levels was admitted to rheumatology department. The patient had suffered from chronic polyarthralgia and a thrombocytosis had been discovered 9 years before, with a recent increase in platelet count. All immunological blood tests were negative. Corticosteroid and methotrexate treatments improved pain, swollen joint count, and systemic inflammation. However, joints remained stiff and painful with two swollen wrists and persistent thrombocytosis. An iliac bone marrow biopsy was performed, showing primary myelofibrosis. Hydroxyurea treatment (500 mg per day) allowed to achieve complete and prolonged clinical and biological remission. After 6 months, a new disease flare occurred. The patient reached remission again after hydroxyurea dose increased to 1500 mg per day. This supports the hypothesis of idiopathic myelofibrosis-associated seronegative polyarthritis. This is the first reported case in which haemopathy-targeted treatment using hydroxyurea induced arthritis remission. PMID- 24818036 TI - Concurrent hepatic artery and portal vein thrombosis after orthotopic liver transplantation with preserved allografts. AB - In contrast to early HAT, late HAT has an insidious clinical presentation. Nevertheless, biliary and vascular reconstructions in this late setting are unlikely to improve outcome. Patent portal flow makes an important contribution to the viability of liver in case of late HAT while the allograft reconstitutes intrahepatic arterial flow through neovascularization. Concurrent HAT with PVT without immediate graft necrosis is extremely rare, and allograft and patient survival are seemingly impossible without retransplantation. In fact, hepatopetal arterial and portal venous neovascularization are known albeit obscure phenomena that can preserve posttransplant hepatic function under the extenuating circumstances of complete interruption of blood flow to the graft. We describe two such cases that developed combined HAT and PVT more than six months after OLT with perfect preservation of graft function. The survival of allografts in our cases was due to extensive hepatopetal arterial and portal venous collateralization. Simultaneous HAT and PVT after OLT are rare events and almost uniformly fatal, if they occur early. Due to paucity of such cases, however, underlying mechanisms and etiology remain elusive, and despite radiological diagnosis of these complications, there is no way to predict these events in the wake of stable graft function. PMID- 24818037 TI - Amiodarone induced hyponatremia masquerading as syndrome of inappropriate antidiuretic hormone secretion by anaplastic carcinoma of prostate. AB - Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hyponatremia. The usual causes are malignancies, central nervous system, pulmonary disorders, and drugs. Amiodarone is a broad spectrum antiarrhythmic agent widely used in the management of arrhythmias. The different side effects include thyroid dysfunction, visual disturbances, pulmonary infiltrates, ataxia, cardiac conduction abnormalities, drug interactions, corneal microdeposits, skin rashes, and gastrointestinal disturbances. SIADH is a rare but lethal side effect of amiodarone. We describe a 62-year-old male who was suffering from advanced prostatic malignancy, taking amiodarone for underlying heart disease. He developed SIADH which was initially thought to be paraneoplastic in etiology, but later histopathology refuted that. This case emphasizes the importance of detailed drug history and the role of immunohistochemistry in establishing the diagnosis and management of hyponatremia due to SIADH. PMID- 24818038 TI - Feasibility of dual-task gait training for community-dwelling adults after stroke: a case series. AB - This case series explored the feasibility and efficacy of cognitive-motor dual task gait training in community-dwelling adults within 12 months of stroke. A secondary aim was to assess transfer of training to different dual-task combinations. Seven male participants within 12 months of stroke participated in 12 sessions of dual-task gait training. We examined single and dual-task performance in four different dual-task combinations at baseline, after 6 and 12 sessions, and if possible, at 1-month followup. Feasibility was assessed by asking participants to rate mental and physical fatigue, perceived difficulty, anxiety, and fear of falling at the end of each session. Five of the seven participants demonstrated reduced dual-task cost in gait speed in at least one of the dual-task combinations after the intervention. Analysis of the patterns of interference in the gait and cognitive tasks suggested that the way in which the participants allocated their attention between the simultaneous tasks differed across tasks and, in many participants, changed over time. Dual-task gait training is safe and feasible within the first 12 months after stroke, and may improve dual-task walking speed. Individuals with a combination of physical and cognitive impairments may not be appropriate for dual-task gait training. PMID- 24818039 TI - Validation of a real time PCR for classical Swine Fever diagnosis. AB - The viral disease classical swine fever (CSF), caused by a Pestivirus, is one of the major causes of economic losses for pig farming. The aim of this work was to validate a RT-qPCR using Taqman for detection of CSF in swine tissues. The parameters for the validation followed the specifications of the Manual of Diagnostic Tests and Vaccines for Terrestrial Animals of the World Organization for Animal Health (OIE) and the guide ABNT NBR ISO/IEC 17025:2005. The analysis of the 5'NTR region of CSF virus was performed in 145 samples from 29 infected pigs and in 240 samples from 80 pigs originated in the Brazilian CSF-free zone. The tissues tested were spleen, kidney, blood, tonsils, and lymph nodes. Sequencing of the positive samples for 5'NTR region was performed to evaluate the specificity of the RT-qPCR. Tests performed for the RT-qPCR validation demonstrated that the PCR assay was efficient in detecting RNA from CSF virus in all materials from different tissues of infected animals. Furthermore, RNA from CSF virus was not detected in samples of swine originated from the Brazilian CSF free zone. Hence, it is concluded that RT-qPCR can be used as a complementary diagnostic for CSF. PMID- 24818040 TI - Autophagy in macrophages: impacting inflammation and bacterial infection. AB - Macrophages are on the front line of host defense. They possess an array of germline-encoded pattern recognition receptors/sensors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and which activate downstream effectors/pathways to help mediate innate immune responses and host defense. Innate immune responses include the rapid induction of transcriptional networks that trigger the production of cytokines, chemokines, and cytotoxic molecules; the mobilization of cells including neutrophils and other leukocytes; the engulfment of pathogens by phagocytosis and their delivery to lysosome for degradation; and the induction of autophagy. Autophagy is a catabolic process that normally maintains cellular homeostasis in a lysosome-dependent manner, but it also functions as a cytoprotective response that intersects with a variety of general stress-response pathways. This review focuses on the intimately linked molecular mechanisms that help govern the autophagic pathway and macrophage innate immune responses. PMID- 24818041 TI - Distinct functions of specialized dendritic cell subsets in atherosclerosis and the road ahead. AB - Atherosclerotic vascular disease is modulated by immune mechanisms. Dendritic cells (DCs) and T cells are present within atherosclerotic lesions and function as central players in the initiation and modulation of adaptive immune responses. In previous years, we have studied the functional contribution of distinct DC subsets in disease development, namely, that of CCL17-expressing DCs as well as that of plasmacytoid DCs that play specialized roles in disease development. This review focuses on important findings gathered in these studies and dissects the multifaceted contribution of CCL17-expressing DCs and pDCs to the pathogenesis of atherosclerosis. Furthermore, an outlook on future challenges faced when studying DCs in this detrimental disease are provided, and hurdles that will need to be overcome in order to enable a better understanding of the contribution of DCs to atherogenesis are discussed, a prerequisite for their therapeutic targeting in atherosclerosis. PMID- 24818042 TI - Medical Decisions Made by Surrogates for Persons with Advanced Dementia within Weeks or Months of Death. AB - BACKGROUND: Surrogates make all medical decisions for persons with advanced dementia. This study describes the types of medical decisions that surrogates faced prior to the person's death and their perceived difficulty and satisfaction with those decisions. METHODS: Seventy-six surrogates of nursing home residents meeting hospice criteria for dementia were followed longitudinally and interviewed following the death of the person with dementia. RESULTS: The most common decisions made were related to transfer to hospital, diagnostic testing, and placement of a feeding tube. Surrogates perceived decisions to not treat to be more difficult than decisions to treat. CONCLUSIONS: Surrogates frequently are faced with making medical decisions for persons with advanced dementia near the end of life. Clinicians can help surrogates by acknowledging the difficulty of making decisions to not treat. PMID- 24818043 TI - Durotomy repair in minimally invasive transforaminal lumbar interbody fusion by nonpenetrating clips. AB - BACKGROUND: Closure of the dura defect may be easy to perform in open lumbar surgery but could be difficult in minimally invasive transforaminal lumbar interbody fusions (MIS-TLIF) since MIS-TLIF was done through a small tube, which limited the use of standard dural repair instruments. We used nonpenetrating titanium clips that were originally designed for the vascular anastomoses to repair the dura defect, which is never described in the literature. METHODS: We presented a case of spinal stenosis with incidental durotomy while performing MIS TLIF. We closed the dura laceration with three medium-sized nonpenetrating titanium clips (AnastoClip Vessel Closure System, LeMaitre Vascular, Inc., Burlington, MA). RESULTS: Nonpenetrating titanium clips have the benefits of being technically easy to use, reduced durotomy repair time, decreased bed rest due to related medical complications, superior postoperation with immediate hydrostatic strength, and better reapproximation if it fails to clip successfully. As for the postoperation follow up, clips are tiny and reveal no obvious artifact, especially in cases where the pedicle screws are already causing much artifact. CONCLUSION: Primary dural closure during MIS-TLIF with clips is an effective way in cases that involve limited tubular space. PMID- 24818044 TI - Os odontoideum in identical twins: Comparative gene expression analysis. AB - BACKGROUND: Os odontoideum is a well identified anomaly of the craniovertebral junction. Since its initial description, there has been a continuous debate regarding the nature of its etiology: Whether congenital or traumatic. We sought to compare the gene expression profiles in patients with congenital os odontoideum, those with traumatic os odontoideum and controls. METHODS: We have evaluated a pair of identical twins both with os odontoideum. We identified two additional patients with and four subjects without os odontoideum. We analyzed the gene expression profiles in these patients using a custom TaqMan microarray and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The relative gene expression profiles in the two identical twins, the two nontwin patients with os odontoideum and the controls were assessed. RESULTS: A total of 213 genes with significantly different expression between the twin os odontoideum patients and the subjects without os odontoideum were detected. CACNG6, PHEX, CACNAD3, IL2, FAS, TUFT1, KIT, TGFBR2, and IGF2 were expressed at levels greater than 100-fold more in the twins. There were six genes with significantly different expression profiles in the twins as compared with the nontwin os odontoideum patients: CMK4, ATF1, PLCG1, TAB1, E2F3, and ATF4. There were no statistically significant differences in gene expression in the four patients with os odontoideum and the subjects without. Trends, however, were noted in MMP8, KIT, HIF1A, CREB3, PWHAZ, TGFBR1, NFKB2, FGFR1, IPO8, STAT1, COL1A1, and BMP3. CONCLUSIONS: Os odontoideum has multiple etiologies, both traumatic and congenital and perhaps some represent a combination of the two. This work has identified a number of genes that show increased expression in a pair of twins with congenital os odontoideum and also demonstrates trends in gene expression profiles between a larger group of os odontoideum patients and non-os patients. A number of these genes are related to bone morphogenesis and maintenance. PMID- 24818045 TI - RE: The risks of epidural and transforaminal steroid injections in the spine: Commentary and a comprehensive review of the literature. PMID- 24818046 TI - An overview of the current surgical options for pineal region tumors. AB - BACKGROUND: The list of pineal region tumors comprises an extensive array of pathological entities originating within one of the most complex areas of the intracranial cavity. With the exception of germ cell tumors, microsurgical excision is still nowadays the mainstay of management for most pineal region tumors. METHODS: A search of the medical literature was conducted for publications addressing surgical options for management of pineal region tumors. RESULTS: The infratentorial supracerebellar and the occipital transtentorial approaches are currently the most frequently used approaches for pineal region tumors. Endoscopic tumor biopsy with simultaneous endoscopic third ventriculostomy has emerged as a minimally invasive and highly effective strategy for initial management since it addresses the issue of tissue diagnosis and offers a solution for the associated hydrocephalus frequently encountered in these patients. Endoscope-assisted microsurgery and purely endoscopic excision have been reported in few reports and are likely to be more utilized in the future. CONCLUSION: Preoperative planning is very crucial and should most importantly be individualized according to the anatomical features of the lesion and structures encountered during the procedure. PMID- 24818047 TI - Is surgical spinal decompression for supratentorial GBM symptomatic drop down metastasis warranted? A case report and review of literature. AB - BACKGROUND: Symptomatic spinal metastasis from an intracranial primary glioblastoma multiforme (GBM) is very rare. Our literature search identified a total of 42 such patients of which 11 were treated with surgical decompression for spinal metastasis with only one such report from the pediatric age group. Previous studies have reported variable outcomes after surgical management. CASE DESCRIPTION: We report the case of a 16-year-old boy who underwent surgical spinal decompression for spinal metastasis after intracranial GBM. The patient regained motor and autonomic function following surgery and reported improvement in pain. We also present findings from a literature review using the PubMed database from 1985 to June 2013 on this subject and compare radiation therapy with surgical decompression as palliative modalities in such patients. CONCLUSION: There are no evidence-based guidelines available on the subject and no treatment regimen has yet demonstrated survival benefit in these patients. Surgical decompression may be a better option for patients with focal resectable lesions and who are medically stable to tolerate the procedure. PMID- 24818048 TI - Surgical management of large scalp infantile hemangiomas. AB - BACKGROUND: Infantile Hemangiomas (IH) are the most common benign tumor of infancy, occurring in over 10% of newborns. While most IHs involute and never require intervention, some scalp IHs may cause severe cosmetic deformity and threaten tissue integrity that requires surgical excision. CASE DESCRIPTION: We present our experience with two infants who presented with large scalp IH. After vascular imaging, the patients underwent surgical resection of the IH and primary wound closure with excellent cosmetic outcome. We detail the surgical management of these cases and review the relevant literature. CONCLUSION: In some cases the IHs leave behind fibro-fatty residuum causing contour deformity. Surgery is often required for very large lesions causing extensive anatomical and/or functional disruption. The goal of surgical intervention is to restore normal anatomic contour and shape while minimizing the size of the permanent scar. PMID- 24818049 TI - Delayed rebleeding of a spontaneously thrombosed aneurysm after subarachnoid hemorrhage. AB - BACKGROUND: This report provides a rare documentation of spontaneous thrombosis of a ruptured aneurysm followed by delayed recanalization and subsequent rerupture. CASE DESCRIPTION: A 47-year-old female presented with spontaneous subarachnoid hemorrhage (SAH). Four aneurysms were identified on CT angiogram including a basilar apex aneurysm, considered source of bleeding. Cerebral angiogram on postbleed day (PBD) #1 showed spontaneous thrombosis of basilar apex aneurysm. The patient was discharged to a nursing home on PBD #18 after two subsequent studies showed no recanalization of the basilar aneurysm. The patient returned on PBD #26 with a second episode of spontaneous SAH. The previously thrombosed basilar aneurysm had recanalized and reruptured, which was now treated with coil embolization. CONCLUSION: We are not aware of a previous report of saccular cerebral aneurysm documenting spontaneous thrombosis after SAH and recanalization with second hemorrhage. This occurrence presents a dilemma regarding the timing and frequency of subsequent cerebrovascular imaging and treatment. PMID- 24818050 TI - Trigeminocardiac reflex: Some thought to the definition. PMID- 24818051 TI - A tribute to atos de sousa, MD. PMID- 24818052 TI - A rare giant scalp dermatofibrosarcoma protuberans. AB - BACKGROUND: Giant dermatofibrosarcoma protuberans (DFSP) of the scalp is a rare case, which is an intermediate grade soft tissue neoplasm originating from the dermal layer of the skin, which usually occurs in adults. CASE DESCRIPTION: We describe such a case in a 26-year-old male. A wide local excision of the tumor with a generous tissue margin was performed; microscopic and immunohistochemical findings established the diagnosis of recurrent DFSP. CONCLUSION: Our case is unique in that it is presented as a dermatofibrosarcoma protuberans of the scalp, which is an extremely rare clinical entity, and the patient remains well after 14 months with no further treatment, without any tumor recurrence. PMID- 24818053 TI - Evaluation of an intraoperative ultrasound training model based on a cadaveric sheep brain. AB - BACKGROUND: The present study evaluates the effectiveness of an ultrasound (US) practice course based on a sheep brain cadaver. Neurosurgical education is considerably restrained following patient safety objections and work time restrictions. It is therefore of vital importance to offer residents an opportunity to practice certain US techniques in a controlled environment without ethical or legal restrictions. We developed an US training model based on a sheep brain cadaver in order to demonstrate the feasibility of such a model, facilitate crucial anatomic knowledge, and demonstrate a learning curve from it. METHODS: Over the course of 2 months from December 2012-January 2013, a total of 13 residents took part in a three part training session, each consisting of 20-30 min of individual US-training and performance evaluation based on a biological phantom. The first cadaver was a physiologic sheep brain. After initial familiarization with the US, the residents performed an US on a second cadaveric brain and tried to find a 0.5 cm big (in diameter) echogenic structure. In a third brain they were asked to identify a cyst (Fogarty catheter filled with water). RESULTS: Thirteen neurosurgical residents participated in the study. After the first training session, the learning curve improved significantly in the second and the third session. The ability to actuate the US device, the time needed to display crucial anatomic landmarks, and to locate the two different artificial masses increased, and respectively decreased remarkably by up to 80%. CONCLUSION: After 2 months and three training sessions, the handling of the US from the residents was excellent in the operating room. The accuracy and the dexterity in use of the US improved significantly. The participants found the model to be realistic and agreed on the need for further promotion of such courses. PMID- 24818054 TI - Preliminary study on safe thresholds for temporary internal carotid artery occlusion in aneurysm surgery based on motor-evoked potential monitoring. AB - BACKGROUND: The study aims were to clarify safe duration for temporary vessel occlusion of the internal carotid artery (ICA) during aneurysm surgery as exactly as possible. We examined safe time duration (STD), where brain tissue exposed to ischemia will never fall into even the ischemic penumbra using intraoperative motor-evoked potential (MEP). METHODS: In 45 patients, temporary occlusion of the ICA was performed with MEP. We measured STD as the duration of temporary vessel occlusion during which MEP changes did not occur. To estimate average STD, we calculated the 95% confidence interval for the population mean from sample data for STD in patients with MEP changes and in patients without changes. RESULTS: In the proximal-control group, 4 of 38 patients (10.5%) developed intraoperative MEP changes. In 4 patients, the time to MEP change (i.e. STD) was 6.0 +/- 2.5 min. STD was 3.8 +/- 1.6 min in the 34 patients without changes. The average STD was 4.0 +/- 0.6 min. In the trap group (proximal and distal flow control), five of seven patients (60.0%) experienced intraoperative MEP changes (STD, 2.3 +/- 1.0 min). All patients in the trap group who developed MEP changes showed involvement of the anterior choroidal artery (AchA) in the trapped segment. Average STD was 2.3 +/- 1.1 min when trapping involving the AchA. CONCLUSIONS: Although the study is preliminary based on the limited number of the patients, the 95% upper confidence limit for average STD was 4.6 min when the ICA was occluded proximal to the aneurysm, 3.4 min when the ICA was trapped involving the AchA. PMID- 24818055 TI - Use of Dyna CT in evaluation and treatment of pseudoaneurysm secondary to craniofacial tumor resection: Case report and diagnostic implications. AB - BACKGROUND: Digital subtraction angiography (DSA) is considered the gold standard for the evaluation of head and neck vascular abnormalities. It serves as a useful diagnostic and, in many cases, therapeutic tool for treatment of acute head and neck bleeding. CASE DESCRIPTION: We report the case of a patient who presented with life threatening, uncontrollable epistaxis several weeks after resection of a large recurrent chondrosarcoma of the nasal cavity and anterior skull base. A DSA study, with an adjunctive C-arm computed tomography (CT) (Dyna CT), was ultimately helpful in revealing and precisely localizing a large anterior ethmoidal artery pseudoaneurysm adjacent to the tumor resection cavity. CONCLUSION: This additional information helped define the arterial anatomy in postoperative region, allowed precise localization and direct ligation of the pseudoaneurysm to resolve the bleeding with a favorable patient outcome. PMID- 24818056 TI - Urgent treatment of severe symptomatic direct carotid cavernous fistula caused by ruptured cavernous internal carotid artery aneurysm using high-flow bypass, proximal ligation, and direct distal clipping: Technical case report. AB - BACKGROUND: Direct carotid cavernous fistula (CCF) secondary to ruptured carotid cavernous aneurysms (CCAs) is rare, but patients with this condition who develop acutely worsening and severe neuro-ophthalmic symptoms require urgent treatment. Endovascular methods are the first-line option, but this modality may not be available on an urgent basis. CASE DESCRIPTION: In this article, we report a 45 year-old female with severe direct CCF due to rupture of the CCA. She presented with intractable headache and acute worsening of double vision and visual acuity. Emergent radiographic study revealed high-flow fistula tracked from the CCA toward the contralateral cavernous sinus and drained into the engorged left superior orbital vein. To prevent permanent devastating neuro-ophthalmic damages, urgent high-flow bypass with placement of a radial artery graft was performed followed by right cervical internal carotid artery (ICA) ligation and the clipping of the ICA at the C3 portion, proximal to the ophthalmic artery. In the immediate postoperative period, her symptoms resolved and angiography confirmed patency of the high-flow bypass and complete occlusion of the CCF. CONCLUSION: With due consideration of strategy and techniques to secure safety, open surgical intervention with trapping and bypass is a good treatment option for direct severe CCF when the endovascular method is not available, not possible, or is unsuccessful. PMID- 24818057 TI - Giant Intradiploic Angiolipoma of the skull. Report of the first case with MR and histopathological characteristics reported in the literature and a review. AB - BACKGROUND: Intraosseous Angiolipoma of the skull bone (IOAL) is a very rare bony lesion of the calvarium. This lesion occurs most commonly in the soft, subcutaneous tissue of the trunk. Only a single case of angiolipoma of the skull has been previously reported. The authors report the first case of giant IOAL of the calvarium evaluated by 3D CTS, MRI and full histopathological staining in a young lady treated surgically and with 23 months of follow up. CASE DESCRIPTION: A 41-year-old female was admitted because of a prominent bulging on her right parietal region. Three dimensional CT and CT angiographic reconstruction of the cranium elucidated the geographical pattern of the lesion. MRI revealed a huge intraosseous right frontotemporoparietooccipital expansile lesion, nonhomogeneous but mostly hyperintense, in T1W images. In T2W images, the lesion was nonhomogeneously hyperintense and trabeculated with no perilesional edema. In the FLAIR-images, the lesion was trabeculated and nonhomogeneously hypointense. The lesion was excised totally followed by skull reconstruction and no recurrence after 23 months. CONCLUSION: We hypothesize that the possible pathogenesis of IOAL may be a kind of mutation or dedifferentiation of either a primary intradiploic hemangioma or lipoma changing its growth pattern with possibly more aggressive behavior. PMID- 24818058 TI - Endoscopic endonasal skull base approach for parasellar lesions: Initial experiences, results, efficacy, and complications. AB - BACKGROUND: Endoscopic surgery is suitable for the transsphenoidal approach; it is minimally invasive and provides a well-lit operative field. The endoscopic skull base approach through the large opening of the sphenoid sinus through both nostrils has extended the surgical indication for various skull base lesions. In this study, we describe the efficacy and complications associated with the endoscopic skull base approach for extra- or intradural parasellar lesions based on our experiences. METHODS: Seventy-four cases were treated by an endoscopic skull base approach. The indications for these procedures included 55 anterior extended approaches, 10 clival approaches, and 9 cavernous approaches. The operations were performed through both the nostrils using a rigid endoscope. After tumor removal, the skull base was reconstructed by a multilayered method using a polyglactin acid (PGA) sheet. RESULTS: Gross total resection was achieved in 82% of pituitary adenomas, 68.8% of meningiomas, and 60% of craniopharyngiomas in anterior extended approach and in 83.3% of chordomas in clival approach, but only in 50% of the tumors in cavernous approach. Tumor consistency, adhesion, and/or extension were significant limitations. Visual function improvements were achieved in 37 of 41 (90.2%) cases. Cerebrospinal fluid (CSF) leakage (9.5%), infections (5.4%), neural injuries (4.1%), and vascular injuries (2.7%) were the major complications. CONCLUSIONS: Our experiences show that the endoscopic skull base approach is a safe and effective procedure for various parasellar lesions. Selection of patients who are unlikely to develop complications seems to be an important factor for procedure efficacy and good outcome. PMID- 24818059 TI - Cranio cervical tuberculous hypertrophic pachymeningitis. AB - BACKGROUND: Hypertrophic pachymeningitis is a unique clinical entity characterized by fibrosis and thickening of dura mater resulting in neurological dysfunction. It could be idiopathic or due to variety of inflammatory and infectious conditions. Tuberculous hypertrophic pachymeningitis involving cranio cervical region is rarely reported. CASE DESCRIPTION: A 50-year-old female presented with history of progressive quadriparesis and stiffness of neck for 2 years, dysphagia to liquid for past 3 months. Her condition rapidly deteriorated when another physician prescribed her corticosteroid. Physical examination revealed high cervical compressive myelo-radiculopathy with lower cranial nerve palsy and neck rigidity. Series of serum analysis, cerebrospinal fluid (CSF) study and contrast magnetic resonance imaging (MRI) clinched the diagnosis. She improved on antitubercular treatment. CONCLUSION: In case of multilevel cervical compressive myelo-radiculopathy with lower cranial involvement, possibility of hypertrophic pachymeningitis should be kept in mind. Before diagnosing it as idiopathic, infectious causes should be excluded otherwise prescription of corticosteroid will flare up the disease process. PMID- 24818060 TI - Acute posttraumatic pediatric cerebral venous thrombosis: Case report and review of literature. AB - BACKGROUND: Pediatric cerebral venous thrombosis (CVT) is a common sequelae of infection, coagulopathies, and dehydration in the pediatric population. Acute posttraumatic CVT is an uncommon etiology of pediatric CVT that presents a unique management challenge. There are no established guidelines outlining the treatment of this small subset of patients. CASE DESCRIPTION: We present a case of a 12 year-old boy with posttraumatic CVT who was safely treated with anticoagulation therapy, and had resolution of his symptoms and radiographic improvement within 3 days of therapy. The relevant literature is reviewed. CONCLUSION: Anticoagulation therapy may be safely used in the treatment of acute posttraumatic CVT in pediatric patients, and may reduce the incidence of clot propagation, hospitalization time, and cost of treatment. PMID- 24818061 TI - What do hotels and hospitals have in common? How we can learn from the hotel industry to take better care of patients. AB - Despite widely divergent public perceptions and goals, hotels and hospitals share many core characteristics. Both serve demanding and increasingly well-informed clienteles, both employ a large hierarchy of workers with varying levels of responsibility, and both have payments that are increasingly tied to customer/patient evaluations. In the hotel industry, decades of management experience and market research have led to widespread improvements and innovations that improve customer satisfaction. But there has been incredibly little cross-fertilization between the hotel and hospital industries. In this paper, we first consider the changes in the healthcare system that are forcing hospitals to become more concerned with patient satisfaction. We discuss the similarities and differences between the hotel and hospital industries, and then outline several of the unique challenges that neurosurgeons face in taking care of patients and increasing their comfort. We cite specific lessons from the hotel industry that can be applied to patients' preadmission, check-in, hospital stay, discharge planning, and poststay experiences. We believe that hospitals can and should leverage the successful advances within the hotel industry to improve patient satisfaction, without having to repeat identical research or market experimentation. We hope this will lead to rapid improvements in patient experiences and overall wellbeing. PMID- 24818062 TI - Markov chains and semi-Markov models in time-to-event analysis. AB - A variety of statistical methods are available to investigators for analysis of time-to-event data, often referred to as survival analysis. Kaplan-Meier estimation and Cox proportional hazards regression are commonly employed tools but are not appropriate for all studies, particularly in the presence of competing risks and when multiple or recurrent outcomes are of interest. Markov chain models can accommodate censored data, competing risks (informative censoring), multiple outcomes, recurrent outcomes, frailty, and non-constant survival probabilities. Markov chain models, though often overlooked by investigators in time-to-event analysis, have long been used in clinical studies and have widespread application in other fields. PMID- 24818063 TI - Recrudescent Wave of A/H1N1pdm09 Influenza Viruses in Winter 2012-2013 in Kashmir, India. AB - Some parts of world, including India observed a recrudescent wave of influenza A/H1N1pdm09 in 2012. We undertook a study to examine the circulating influenza strains, their clinical association and antigenic characteristics to understand the recrudescent wave of A/H1N1pdm09 from November 26, 2012 to Feb 28, 2013 in Kashmir, India. Of the 751 patients (545 outpatient and 206 hospitalized) presenting with acute respiratory infection at a tertiary care hospital in Srinagar; 184 (24.5%) tested positive for influenza. Further type and subtype analysis revealed that 106 (58%) were influenza A (H1N1pdm09 =105, H3N2=1) and 78 (42%) were influenza B. The influenza positive cases had a higher frequency of chills, nasal discharge, sore throat, body aches and headache, compared to influenza negative cases. Of the 206 patients hospitalized for pneumonia/acute respiratory distress syndrome or an exacerbation of an underlying lung disease, 34 (16.5%) tested positive for influenza (22 for H1N1pdm09, 11 for influenza B). All influenza-positive patients received oseltamivir and while most patients responded well to antiviral therapy and supportive care, 6 patients (4 with H1N1pdm09 and 2 with influenza B) patients died of progressive respiratory failure and multi-organ dysfunction. Following a period of minimal circulation, H1N1pdm09 re-emerged in Kashmir in 2012-2013, causing serious illness and fatalities. As such the healthcare administrators and policy planners need to be wary and monitor the situation closely. PMID- 24818064 TI - A Prospective Study of the Outcome of Patients with Limb Trauma following the Haitian Earthquake in 2010 at One- and Two- Year (The SuTra2 Study). AB - Background Severe limb trauma is common in earthquake survivors. Overall medium term outcomes and patient-perceived outcomes are poorly documented. Methods and Findings The prospective study SuTra2 assessed the functional and socio-economic status of a cohort of patients undergoing surgery for limb injury resulting in amputation (A) or limb preservation (LP) one year and two years after the 2010 Haiti earthquake. 305 patients [A: n=199 (65%), LP: n=106 (35%)] were evaluated. Their characteristics were: 57% female; mean age 31 years; 74% of principal injuries involved the lower limb; 46% of patients had an additional severe injury; 60% had fractures, of which two-thirds were compound or associated with severe soft tissue damage; 15% of amputations were traumatic. At 2 years, 51% of patients were satisfied with the functional outcome (A: 52%, LP: 49%, ns). Comparison with the 1-year status indicates a worsening of the perceived functional status, significantly more pronounced in amputees, and an increase in pain complaints, mainly in amputees (62% and 80% of pain in overall population at 1- and 2-year respectively). Twenty eight percent (28%) of LP and 66% of A considered themselves as "cured". 100% of LP and 79% of A would have chosen a conservative approach if an amputation was medically avoidable. Two years after the earthquake, 23.5 % of patients were still living in a tent, 30% were working, and 25.5% needed ongoing surgical management. Conclusions Only half the patients with severe limb injuries, whether managed with amputation or limb preservation, deemed their functional status satisfactory at 2 years. The patients' perspective, clearly favors limb conservative management whenever possible. Prolonged care and rehabilitation are needed to optimize the outcome for earthquake survivors with limb injuries. Humanitarian respondents to catastrophes have professional and ethical obligations to provide optimal immediate care and ensure scrupulous attention to long-term management. Keywords Haiti earthquake, limb injury, two-year outcome, patients' perspective, amputation, limb salvage. PMID- 24818065 TI - Origin Detection During Food-borne Disease Outbreaks - A Case Study of the 2011 EHEC/HUS Outbreak in Germany. AB - The key challenge during food-borne disease outbreaks, e.g. the 2011 EHEC/HUS outbreak in Germany, is the design of efficient mitigation strategies based on a timely identification of the outbreak's spatial origin. Standard public health procedures typically use case-control studies and tracings along food shipping chains. These methods are time-consuming and suffer from biased data collected slowly in patient interviews. Here we apply a recently developed, network theoretical method to identify the spatial origin of food-borne disease outbreaks. Thereby, the network captures the transportation routes of contaminated foods. The technique only requires spatial information on case reports regularly collected by public health institutions and a model for the underlying food distribution network. The approach is based on the idea of replacing the conventional geographic distance with an effective distance that is derived from the topological structure of the underlying food distribution network. We show that this approach can efficiently identify most probable epicenters of food-borne disease outbreaks. We assess and discuss the method in the context of the 2011 EHEC epidemic. Based on plausible assumptions on the structure of the national food distribution network, the approach can correctly localize the origin of the 2011 German EHEC/HUS outbreak. PMID- 24818066 TI - The Prevalence of Sexual Violence among Female Refugees in Complex Humanitarian Emergencies: a Systematic Review and Meta-analysis. AB - IMPORTANCE: Refugees and internally displaced persons are highly vulnerable to sexual violence during conflict and subsequent displacement. However, accurate estimates of the prevalence of sexual violence among in these populations remain uncertain. OBJECTIVE: Our objective was to estimate the prevalence of sexual violence among refugees and displaced persons in complex humanitarian emergencies. DATA SOURCE: We conducted systematic review of relevant literature in multiple databases (EMBASE, CINAHL, and MEDLINE) through February 2013 to identify studies. We also reviewed reference lists of included articles to identify any missing sources. STUDY SELECTION: Inclusion criteria required identification of sexual violence among refugees and internally displaced persons or those displaced by conflict in complex humanitarian settings. Studies were excluded if they did not provide female sexual violence prevalence, or that included only single case reports, anecdotes, and those that focused on displacement associated with natural disasters. After a review of 1175 citations 19 unique studies were selected. DATA EXTRACTION: Two reviewers worked independently to identify final selection and a third reviewer adjudicated any differences. Descriptive and quantitative information was extracted; prevalence estimates were synthesized. Heterogeneity was assessed using I2. MAIN OUTCOMES: The main outcome of interest was sexual violence among female refugees and internally displaced persons in complex humanitarian settings. RESULTS: The prevalence of sexual violence was estimated at 21.4% (95% CI, 14.9-28.7; I2=98.3%), using a random effects model. Statistical heterogeneity was noted with studies using probability sampling designs reporting lower prevalence of sexual violence (21.0%, 95% CI, 13.2-30.1; I2=98.6%), compared to lower quality studies (21.7%, 95% CI, 11.5-34.2; I2=97.4%). We could not rule out the presence of publication bias. CONCLUSIONS: The findings suggest that approximately one in five refugees or displaced women in complex humanitarian settings experienced sexual violence. However, this is likely an underestimation of the true prevalence given the multiple existing barriers associated with disclosure. The long-term health and social consequences of sexual violence for women and their families necessitate strategies to improve identification of survivors of sexual violence and increase prevention and response interventions in these complex settings. PMID- 24818067 TI - L1 retrotransposition: The snap-velcro model and its consequences. AB - LINE-1 (L1) elements are the only active and autonomous transposable elements in humans. The core retrotransposition machinery is a ribonucleoprotein particle (RNP) containing the L1 mRNA, with endonuclease and reverse transcriptase activities. It initiates reverse transcription directly at genomic target sites upon endonuclease cleavage. Recently, using a direct L1 extension assay (DLEA), we systematically tested the ability of native L1 RNPs to extend DNA substrates of various sequences and structures. We deduced from these experiments the general rules guiding the initiation of L1 reverse transcription, referred to as the snap-velcro model. In this model, L1 target choice is not only mediated by the sequence specificity of the endonuclease, but also through base-pairing between the L1 mRNA and the target site, which permits the subsequent L1 reverse transcription step. In addition, L1 reverse transcriptase efficiently primes L1 DNA synthesis only when the 3' end of the DNA substrate is single-stranded, suggesting so-far unrecognized DNA processing steps at the integration site. PMID- 24818068 TI - Reasons for Divorce and Recollections of Premarital Intervention: Implications for Improving Relationship Education. AB - The study presents findings from interviews of 52 divorced individuals who received the Prevention and Relationship Enhancement Program (PREP) while engaged to be married. Using both quantitative and qualitative methods, the study sought to understand participant reasons for divorce (including identification of the "final straw") in order to understand if the program covered these topics effectively. Participants also provided suggestions based on their premarital education experiences so as to improve future relationship education efforts. The most commonly reported major contributors to divorce were lack of commitment, infidelity, and conflict/arguing. The most common "final straw" reasons were infidelity, domestic violence, and substance use. More participants blamed their partners than blamed themselves for the divorce. Recommendations from participants for the improvement of premarital education included receiving relationship education before making a commitment to marry (when it would be easier to break-up), having support for implementing skills outside of the educational setting, and increasing content about the stages of typical marital development. These results provide new insights into the timing and content of premarital and relationship education. PMID- 24818069 TI - Marital Processes, Neuroticism, and Stress as Risk Factors for Internalizing Symptoms. AB - OBJECTIVE: Marital discord has a robust association with depression, yet it is rarely considered within broader etiological frameworks of psychopathology. Further, little is known about the particular aspects of relationships that have the greatest impact on psychopathology. The purpose of the present study was to test a novel conceptual framework including neuroticism, specific relationship processes (conflict management, partner support, emotional intimacy, and distribution of power and control), and stress as predictors of internalizing symptoms (depression and anxiety). METHOD: Questionnaire and interview data were collected from 103 husbands and wives 5 times over the first 7 years of marriage. RESULTS: Results suggest that neuroticism (an expression of the underlying vulnerability for internalizing disorders) contributes to symptoms primarily through high levels of non-marital stress, an imbalance of power/control in one's marriage, and poor partner support for husbands, and through greater emotional disengagement for wives. CONCLUSIONS: Marital processes, neuroticism, and stress work together to significantly predict internalizing symptoms, demonstrating the need to routinely consider dyadic processes in etiological models of individual psychopathology. Specific recommendations for adapting and implementing couple interventions to prevent and treat individual psychopathology are discussed. PMID- 24818070 TI - Genetic and Environmental Influences on the Association between Subjective Well Being and Marital Adjustment. AB - This study was conducted to estimate the magnitude of genetic and environmental influences on the association between three indices of subjective well-being (i.e., life satisfaction, positive affect, negative affect) and positive and negative components of marital adjustment (i.e., spousal support, spousal strain) in a sample of adult married twin pairs (N = 453 pairs). Results indicated that subjective well-being and marital adjustment were significantly associated (particularly in women), that there were gender differences in the magnitude of genetic and environmental influences on this covariation, and that this association was largely influenced by genetic factors in women and genetic and nonshared environmental factors in men. These findings highlight the importance of using genetically informed research to evaluate the genetic and environmental influences on the covariation between marital adjustment and individual outcomes such as subjective well-being. PMID- 24818071 TI - Dairy and Cardiovascular Disease: A Review of Recent Observational Research. AB - The consumption of dairy, including milk, cheese and yogurt, has been associated with better quality of diet and reduced risk of cardiovascular disease, the leading cause of death globally. The purpose of this review is to examine recent literature on the relationship between dairy consumption and risk of cardiovascular disease incidence and mortality. Eighteen observational studies were reviewed, the results of which indicate that total dairy intake does not contribute to cardiovascular disease incidence or death. Based on available data, it appears that milk, cheese, and yogurt are inversely associated with cardiovascular disease risk. Data pertaining to dairy fat were inconclusive, but point to a potential protective effect of full-fat milk, cheese, and yogurt on risk of cardiovascular disease. Currently, there is a need to study specific well defined foods, as opposed to calculating nutrients, in order to better understand these relationships. Future research need not replicate the body of literature on total dairy consumption and associated risk of disease, but rather should focus on the effects of individual dairy foods on cardiovascular events in male and female populations. PMID- 24818072 TI - A Systematic Review of Obesity Prevention Intervention Studies among Immigrant Populations in the US. AB - The aim of this review was to systematically assess the effectiveness of obesity prevention and control interventions in US immigrant populations across the life course, from preschool-age to adults. A systematic review of relevant studies was undertaken and eligible articles included. The initial search identified 684 potentially relevant articles, of which only 20 articles met the selection criteria, representing 20 unique studies. They were divided into interventions that targeted adults (n=7), interventions that targeted children (n=5) and pilot studies (n=8). The majority of interventions targeted Latinos, predominately Mexican-origin populations. Among the interventions targeting adults, five had an effect on obesity related outcomes. However, they tended to use less rigorous study designs. Among the interventions that targeted children, three had a positive effect on obesity-related outcomes. Three of the eight pilot studies had an effect on obesity-related outcomes. There is a paucity of data on effective interventions but a great need to address obesity prevention to help inform health policies and programs to reduce migration-related obesity inequalities. PMID- 24818073 TI - Does IRISIN Have a BRITE Future as a Therapeutic Agent in Humans? AB - The epidemic of obesity has contributed to the rapid rise in comorbid conditions such as cardiovascular disease, type 2 diabetes, sleep apnea, and hypertension among others. Therefore, there is a critical need to develop therapeutic strategies to reduce the prevalence of the disease. Skeletal muscle cells secrete signaling cytokines/peptides (referred to as myokines) that act in autocrine, paracrine, and endocrine fashion. Myokines have been hypothesized to contribute to the immediate and chronic benefits of exercise and may thus serve as attractive therapeutic agents for the treatment of obesity. The recent discovery of the irisin, a proposed myokine, has gained much attention over the last two years as a potential therapeutic agent. Preliminary studies demonstrated that irisin has the potential to induce "browning" of white adipocytes in mice. If these findings in mice could be translated to humans, irisin could be a potential therapeutic agent for the treatment of obesity. Limitations with the available antibodies, however, have raised concerns regarding the detectability of irisin in circulation. Moreover, the gene encoding irisin, FNDC5, is expressed robustly not only in muscle but also in various white adipose tissues (WAT) in humans, raising the possibility for increased thermogenesis through autocrine mechanisms. Here we will discuss the browning of WAT, the discovery of irisin, and its potential role in improving metabolic health in humans. PMID- 24818074 TI - Depressive symptoms and neuroanatomical structures in community-dwelling women: A combined voxel-based morphometry and diffusion tensor imaging study with tract based spatial statistics. AB - Depressive symptoms, even at a subclinical level, have been associated with structural brain abnormalities. However, previous studies have used regions of interest or small sample sizes, limiting the ability to generalize the results. In this study, we examined neuroanatomical structures of both gray matter and white matter associated with depressive symptoms across the whole brain in a large sample. A total of 810 community-dwelling adult participants underwent measurement of depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D). The participants were not demented and had no neurological or psychiatric history. To examine the gray and white matter volume, we used structural MRI scans and voxel-based morphometry (VBM); to examine the white matter integrity, we used diffusion tensor imaging with tract-based spatial statistics (TBSS). In female participants, VBM revealed a negative correlation between bilateral anterior cingulate gray matter volume and the CES-D score. TBSS showed a CES-D-related decrease in fractional anisotropy and increase in radial and mean diffusivity in several white matter regions, including the right anterior cingulum. In male participants, there was no significant correlation between gray or white matter volume or white matter integrity and the CES-D score. Our results indicate that the reduction in gray matter volume and differences in white matter integrity in specific brain regions, including the anterior cingulate, are associated with depressive symptoms in women. PMID- 24818075 TI - Altered resting-state functional connectivity in patients with chronic bilateral vestibular failure. AB - Patients with bilateral vestibular failure (BVF) suffer from gait unsteadiness, oscillopsia and impaired spatial orientation. Brain imaging studies applying caloric irrigation to patients with BVF have shown altered neural activity of cortical visual-vestibular interaction: decreased bilateral neural activity in the posterior insula and parietal operculum and decreased deactivations in the visual cortex. It is unknown how this affects functional connectivity in the resting brain and how changes in connectivity are related to vestibular impairment. We applied a novel data driven approach based on graph theory to investigate altered whole-brain resting-state functional connectivity in BVF patients (n= 22) compared to age- and gender-matched healthy controls (n= 25) using resting-state fMRI. Changes in functional connectivity were related to subjective (vestibular scores) and objective functional parameters of vestibular impairment, specifically, the adaptive changes during active (self-guided) and passive (investigator driven) head impulse test (HIT) which reflects the integrity of the vestibulo-ocular reflex (VOR). BVF patients showed lower bilateral connectivity in the posterior insula and parietal operculum but higher connectivity in the posterior cerebellum compared to controls. Seed-based analysis revealed stronger connectivity from the right posterior insula to the precuneus, anterior insula, anterior cingulate cortex and the middle frontal gyrus. Excitingly, functional connectivity in the supramarginal gyrus (SMG) of the inferior parietal lobe and posterior cerebellum correlated with the increase of VOR gain during active as compared to passive HIT, i.e., the larger the adaptive VOR changes the larger was the increase in regional functional connectivity. Using whole brain resting-state connectivity analysis in BVF patients we show that enduring bilateral deficient or missing vestibular input leads to changes in resting-state connectivity of the brain. These changes in the resting brain are robust and task-independent as they were found in the absence of sensory stimulation and without a region-related a priori hypothesis. Therefore they may indicate a fundamental disease-related change in the resting brain. They may account for the patients' persistent deficits in visuo-spatial attention, spatial orientation and unsteadiness. The relation of increasing connectivity in the inferior parietal lobe, specifically SMG, to improvement of VOR during active head movements reflects cortical plasticity in BVF and may play a clinical role in vestibular rehabilitation. PMID- 24818076 TI - Validating computationally predicted TMS stimulation areas using direct electrical stimulation in patients with brain tumors near precentral regions. AB - The spatial extent of transcranial magnetic stimulation (TMS) is of paramount interest for all studies employing this method. It is generally assumed that the induced electric field is the crucial parameter to determine which cortical regions are excited. While it is difficult to directly measure the electric field, one usually relies on computational models to estimate the electric field distribution. Direct electrical stimulation (DES) is a local brain stimulation method generally considered the gold standard to map structure-function relationships in the brain. Its application is typically limited to patients undergoing brain surgery. In this study we compare the computationally predicted stimulation area in TMS with the DES area in six patients with tumors near precentral regions. We combine a motor evoked potential (MEP) mapping experiment for both TMS and DES with realistic individual finite element method (FEM) simulations of the electric field distribution during TMS and DES. On average, stimulation areas in TMS and DES show an overlap of up to 80%, thus validating our computational physiology approach to estimate TMS excitation volumes. Our results can help in understanding the spatial spread of TMS effects and in optimizing stimulation protocols to more specifically target certain cortical regions based on computational modeling. PMID- 24818077 TI - Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology. AB - The relationships between clinical phenotype, beta-amyloid (Abeta) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Abeta deposition measured by ((11)C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Abeta deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA-AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.0 +/- 7.7, Mini Mental State Examination 22.0 +/- 4.8). Patients were subclassified based on their cognitive profiles into an amnestic/dysexecutive group (AD-memory; n = 27), a language-predominant group (AD-language; n = 10) and a visuospatial-predominant group (AD-visuospatial; n = 9). All patients were required to have evidence of amyloid deposition on PiB-PET. To capture the spatial distribution of Abeta deposition and glucose metabolism, we employed parallel independent component analysis (pICA), a method that enables joint analyses of multimodal imaging data. The relationships between PET components and clinical group were examined using a Receiver Operator Characteristic approach, including age, gender, education and apolipoprotein E epsilon4 allele carrier status as covariates. Results of the first set of analyses independently examining the relationship between components from each modality and clinical group showed three significant components for FDG: a left inferior frontal and temporoparietal component associated with AD language (area under the curve [AUC] 0.82, p = 0.011), and two components associated with AD-visuospatial (bilateral occipito-parieto-temporal [AUC 0.85, p = 0.009] and right posterior cingulate cortex [PCC]/precuneus and right lateral parietal [AUC 0.69, p = 0.045]). The AD-memory associated component included predominantly bilateral inferior frontal, cuneus and inferior temporal, and right inferior parietal hypometabolism but did not reach significance (AUC 0.65, p = 0.062). None of the PiB components correlated with clinical group. Joint analysis of PiB and FDG with pICA revealed a correlated component pair, in which increased frontal and decreased PCC/precuneus PiB correlated with decreased FDG in the frontal, occipital and temporal regions (partial r = 0.75, p < 0.0001). Using multivariate data analysis, this study reinforced the notion that clinical phenotype in AD is tightly linked to patterns of glucose hypometabolism but not amyloid deposition. These findings are strikingly similar to those of univariate paradigms and provide additional support in favor of specific involvement of the language network, higher-order visual network, and default mode network in clinical variants of AD. The inverse relationship between Abeta deposition and glucose metabolism in partially overlapping brain regions suggests that Abeta may exert both local and remote effects on brain metabolism. Applying multivariate approaches such as pICA to multimodal imaging data is a promising approach for unraveling the complex relationships between different elements of AD pathophysiology. PMID- 24818078 TI - Impact of neonate haematocrit variability on the longitudinal relaxation time of blood: Implications for arterial spin labelling MRI. AB - BACKGROUND AND PURPOSE: The longitudinal relaxation time of blood (T 1b) is influenced by haematocrit (Hct) which is known to vary in neonates. The purpose of this study was threefold: to obtain T 1b values in neonates, to investigate how the T 1b influences quantitative arterial spin labelling (ASL), and to evaluate if known relationships between T 1b and haematocrit (Hct) hold true when Hct is measured by means of a point-of-care device. MATERIALS AND METHODS: One hundred and four neonates with 120 MR scan sessions (3 T) were included. The T 1b was obtained from a T 1 inversion recovery sequence. T 1b-induced changes in ASL cerebral blood flow estimates were evaluated. The Hct was obtained by means of a point-of-care device. Linear regression analysis was used to investigate the relation between Hct and MRI-derived R1 of blood (the inverse of the T 1b). RESULTS: Mean T 1b was 1.85 s (sd 0.2 s). The mean T 1b in preterm neonates was 1.77 s, 1.89 s in preterm neonates scanned at term-equivalent age (TEA) and 1.81 s in diseased neonates. The T 1b in the TEA was significantly different from the T 1b in the preterm (p < 0.05). The change in perfusion induced by the T 1b was 11% (sd 9.1%, p < 0.001). The relation between arterial-drawn Hct and R1b was R1b = 0.80 * Hct + 0.22, which falls within the confidence interval of the previously established relationships, whereas capillary-drawn Hct did not correlate with R1b. CONCLUSION: We demonstrated a wide variability of the T 1b in neonates and the implications it could have in methods relying on the actual T 1b as for instance ASL. It was concluded that arterial-drawn Hct values obtained from a point-of-care device can be used to infer the T 1b whereas our data did not support the use of capillary-drawn Hct for T 1b correction. PMID- 24818079 TI - Automated delineation of stroke lesions using brain CT images. AB - Computed tomographic (CT) images are widely used for the identification of abnormal brain tissue following infarct and hemorrhage in stroke. Manual lesion delineation is currently the standard approach, but is both time-consuming and operator-dependent. To address these issues, we present a method that can automatically delineate infarct and hemorrhage in stroke CT images. The key elements of this method are the accurate normalization of CT images from stroke patients into template space and the subsequent voxelwise comparison with a group of control CT images for defining areas with hypo- or hyper-intense signals. Our validation, using simulated and actual lesions, shows that our approach is effective in reconstructing lesions resulting from both infarct and hemorrhage and yields lesion maps spatially consistent with those produced manually by expert operators. A limitation is that, relative to manual delineation, there is reduced sensitivity of the automated method in regions close to the ventricles and the brain contours. However, the automated method presents a number of benefits in terms of offering significant time savings and the elimination of the inter-operator differences inherent to manual tracing approaches. These factors are relevant for the creation of large-scale lesion databases for neuropsychological research. The automated delineation of stroke lesions from CT scans may also enable longitudinal studies to quantify changes in damaged tissue in an objective and reproducible manner. PMID- 24818080 TI - Amygdala hyperactivation during symptom provocation in obsessive-compulsive disorder and its modulation by distraction. AB - Anxiety disorders have been linked to a hyperactivated cortico-amygdalar circuitry. Recent findings highlight the amygdala's role in mediating elevated anxiety in obsessive-compulsive disorder (OCD). However, modulation of amygdala hyperactivation by attentional distraction - an effective emotion regulation strategy in healthy individuals - has not yet been examined. While undergoing functional magnetic resonance imaging twenty-one unmedicated OCD patients and 21 controls performed an evaluation and a distraction task during symptom provocation with individually tailored OCD-relevant pictures. To test the specificity of responses, additional aversive and neutral stimuli were included. Significant group-by-picture type interactions were observed within fronto striato-limbic circuits including the amygdala. In these regions patients showed increased BOLD responses during processing of OCD triggers relative to healthy controls. Amygdala hyperactivation was present across OCD symptom dimensions indicating that it represents a common neural correlate. During distraction, we observed dampening of patients' amygdala hyperactivity to OCD-relevant stimuli. Augmented amygdala involvement in patients during symptom provocation, present across OCD symptom dimensions, might constitute a correlate of fear expression in OCD linking it to other anxiety disorders. Attentional distraction seemed to dampen emotional processing of disorder-relevant stimuli via amygdala downregulation. The clinical impact of this strategy to manage anxiety in OCD should be further elucidated. PMID- 24818081 TI - fMRI resting state networks and their association with cognitive fluctuations in dementia with Lewy bodies. AB - Cognitive fluctuations are a core symptom in dementia with Lewy bodies (DLB) and may relate to pathological alterations in distributed brain networks. To test this we analysed resting state fMRI changes in a cohort of fluctuating DLB patients (n = 16) compared with age matched controls (n = 17) with the aim of finding functional connectivity (FC) differences between these two groups and whether these associate with cognitive fluctuations in DLB. Resting state networks (RSNs) were estimated using independent component analysis and FC between the RSN maps and the entirety of the brain was assessed using dual regression. The default mode network (DMN) appeared unaffected in DLB compared to controls but significant cluster differences between DLB and controls were found for the left fronto-parietal, temporal, and sensory-motor networks. Desynchronization of a number of cortical and subcortical areas related to the left fronto-parietal network was associated with the severity and frequency of cognitive fluctuations. Our findings provide empirical evidence for the potential role of attention-executive networks in the aetiology of this core symptom in DLB. PMID- 24818082 TI - Functional connectivity of neural motor networks is disrupted in children with developmental coordination disorder and attention-deficit/hyperactivity disorder. AB - Developmental coordination disorder (DCD) and attention deficit/hyperactivity disorder (ADHD) are prevalent childhood disorders that frequently co-occur. Evidence from neuroimaging research suggests that children with these disorders exhibit disruptions in motor circuitry, which could account for the high rate of co-occurrence. The primary objective of this study was to investigate the functional connections of the motor network in children with DCD and/or ADHD compared to typically developing controls, with the aim of identifying common neurophysiological substrates. Resting-state fMRI was performed on seven children with DCD, 21 with ADHD, 18 with DCD + ADHD and 23 controls. Resting-state connectivity of the primary motor cortex was compared between each group and controls, using age as a co-factor. Relative to controls, children with DCD and/or ADHD exhibited similar reductions in functional connectivity between the primary motor cortex and the bilateral inferior frontal gyri, right supramarginal gyrus, angular gyri, insular cortices, amygdala, putamen, and pallidum. In addition, children with DCD and/or ADHD exhibited different age-related patterns of connectivity, compared to controls. These findings suggest that children with DCD and/or ADHD exhibit disruptions in motor circuitry, which may contribute to problems with motor functioning and attention. Our results support the existence of common neurophysiological substrates underlying both motor and attention problems. PMID- 24818083 TI - Urine lipoarabinomannan testing for diagnosis of pulmonary tuberculosis in children: a prospective study. AB - BACKGROUND: Urine tests for mycobacterial lipoarabinomannan might be useful for point-of-care diagnosis of tuberculosis in adults with advanced HIV infection, but have not been assessed in children. We assessed the accuracy of urine lipoarabinomannan testing for the diagnosis of pulmonary tuberculosis in HIV positive and HIV-negative children. METHODS: We prospectively recruited children (aged <= 15 years) who presented with suspected tuberculosis at a primary health care clinic and paediatric referral hospital in South Africa, between March 1, 2009, and April 30, 2012. We assessed the diagnostic accuracy of urine lipoarabinomannan testing with lateral fl ow assay and ELISA, with mycobacterial culture of two induced sputum samples as the reference standard. Positive cultures were identified by acid-fast staining and tested to confirm Mycobacterium tuberculosis and establish susceptibility to rifampicin and isoniazid. FINDINGS: 535 children (median age 42.5 months, IQR 19.1 - 66.3) had urine and two induced specimens available for testing. 89 (17%) had culture confirmed tuberculosis and 106 (20%) had HIV. The lateral fl ow lipoarabinomannan test showed poor accuracy against the reference standard, with sensitivity of 48.3% (95% CI 37.6 - 59.2), specificity of 60.8% (56.1 - 65.3), and an area under the receiver operating characteristic curve of 0.53 (0.46 - 0.60) for children without HIV and 0.64 (0.51 - 0.76) for children with HIV. ELISA had poor sensitivity in children without HIV (sensitivity 3.0%, 95% CI 0.4 - 10.5) and children with HIV (0%, 0.0 - 14.3); overall specificity was 95.7% (93.4 - 97.4). INTERPRETATION: Urine lipoarabinomannan tests have insufficient sensitivity and specificity to diagnose HIV-positive and HIV-negative children with tuberculosis and should not be used in this patient population. PMID- 24818084 TI - Preparedness of Tanzanian health facilities for outpatient primary care of hypertension and diabetes: a cross-sectional survey. AB - BACKGROUND: Historically, health facilities in sub-Saharan Africa have mainly managed acute, infectious diseases. Few data exist for the preparedness of African health facilities to handle the growing epidemic of chronic, noncommunicable diseases (NCDs). We assessed the burden of NCDs in health facilities in northwestern Tanzania and investigated the strengths of the health system and areas for improvement with regard to primary care management of selected NCDs. METHODS: Between November, 2012, and May, 2013, we undertook a cross-sectional survey of a representative sample of 24 public and not-for profit health facilities in urban and rural Tanzania (four hospitals, eight health centres, and 12 dispensaries). We did structured interviews of facility managers, inspected resources, and administered self-completed questionnaires to 335 health care workers. We focused on hypertension, diabetes, and HIV (for comparison). Our key study outcomes related to service provision, availability of guidelines and supplies, management and training systems, and preparedness of human resources. FINDINGS: Of adult outpatient visits to hospitals, 58% were for chronic diseases compared with 20% at health centres, and 13% at dispensaries. In many facilities, guidelines, diagnostic equipment, and fi rst-line drug therapy for the primary care of NCDs were inadequate, and management, training, and reporting systems were weak. Services for HIV accounted for most chronic disease visits and seemed stronger than did services for NCDs. Ten (42%) facilities had guidelines for HIV whereas three (13%) facilities did for NCDs. 261 (78%) health workers showed fair knowledge of HIV, whereas 198 (59%) did for hypertension and 187 (56%) did for diabetes. Generally, health systems were weaker in lower-level facilities. Front line health-care workers (such as non-medical-doctor clinicians and nurses) did not have knowledge and experience of NCDs. For example, only 74 (49%) of 150 nurses had at least fair knowledge of diabetes care compared with 85 (57%) of 150 for hypertension and 119 (79%) of 150 for HIV, and only 31 (21%) of 150 had seen more than fi ve patients with diabetes in the past 3 months compared with 50 (33%) of 150 for hypertension and 111 (74%) of 150 for HIV. INTERPRETATION: Most outpatient services for NCDs in Tanzania are provided at hospitals, despite present policies stating that health centres and dispensaries should provide such services. We identifi ed crucial weaknesses (and strengths) in health systems that should be considered to improve primary care for NCDs in Africa and identified ways that HIV programmes could serve as a model and structural platform for these improvements. PMID- 24818085 TI - Gates Grand Challenges Explorations award: Endectocides for Controlling Transmission of Mosquito-borne Diseases. PMID- 24818086 TI - Eating everything except food (PICA): A rare case report and review. AB - PICA is an act or habit of eating non-food items such as stone, bricks, chalk, soap, paper, soil etc., It occurs in children who actually start seeing the world through the oral cavity. There are many theories behind it such as iron and zinc deficiency etc., We as dentists should be able to diagnose and treat such conditions, as they may cause ill-effects to the developing dentition. This case report attempt to highlights the importance of proper diagnosis and treatment of pica. PMID- 24818087 TI - Risk of tumor cell seeding through biopsy and aspiration cytology. AB - Cancer cells, besides reproducing uncontrollably, lose cohesiveness and orderliness of normal tissue, invade and get detached from the primary tumor to travel and set up colonies elsewhere. Dislodging neoplastically altered cells from a tumor during biopsy or surgical intervention or during simple procedure like needle aspiration is a possibility because they lack cohesiveness, and they attain the capacity to migrate and colonize. Considering the fact that, every tumor cell, is bathed in interstitial fluid, which drains into the lymphatic system and has an individualized arterial blood supply and venous drainage like any other normal cell in our body, inserting a needle or a knife into a tumor, there is a jeopardy of dislodging a loose tumor cell into either the circulation or into the tissue fluid. Tumor cells are easier to dislodge due to lower cell-to cell adhesion. This theory with the possibility of seeding of tumor cells is supported by several case studies that have shown that after diagnostic biopsy of a tumor, many patients developed cancer at multiple sites and showed the presence of circulating cancer cells in the blood stream on examination. In this review, we evaluate the risk of exposure to seeding of tumor cells by biopsy and aspiration cytology and provide some suggested practices to prevent tumor cell seeding. PMID- 24818088 TI - Evaluation of nickel ion release from various orthodontic arch wires: An in vitro study. AB - AIM: The high incidence of nickel (Ni) allergy and the increasing use of Ni containing dental biomaterials have been of growing concern. The purpose of this investigation was to analyze and evaluate the rate of Ni ion release from different types arch wires used in orthodontics. MATERIALS AND METHODS: Four groups of arch wires (nickel titanium [NiTi], SS, Cu NiTi and ion implanted NiTi) with twelve samples were stored in artificial saliva with a pH 5.6-7.0 thermostated at (36.5 degrees C) and tested at different intervals i.e., 7(th) day, 14(th) day, and 21(st) day. The amount of Ni and Ti ions released from the sample were evaluated using an atomic adsorption spectrophotometer. The solution was replaced with a fresh bottle to avoid sediments. RESULTS: Statistical analysis was performed by nonparametric tests (Student's paired t-test, one-way analysis of variance and multiple comparison test by Tukey "Honestly significant difference"). The statistical package SPSS PC plus (version 4.0.1) was used for data processing and statistical analysis. Results showed significantly statistical influence on the release amount of Ni and Ti ions. Large variation in concentration of Ni released from brackets and bands combined. However, the amount of Ni ions released in all test solutions diminished with time and was below the critical value necessary to induce allergy and below daily dietary intake level. CONCLUSIONS: The daily release of NiTi, SS, Cu NiTi and ion implanted NiTi by an orthodontic appliance in acid pH, particularly favorable to corrosion, was well below that ingested with a normal daily diet. It is therefore concluded that the quantities of metal ions released in our experimental conditions should not be cause for concern in utilizing the appliance. PMID- 24818089 TI - A survey of dental students on global oral health issues in Nigeria. AB - OBJECTIVES: This study seeks to investigate to what extent are students conversant with global oral health initiatives and policies, students' willingness to volunteer service at international setting or developing countries and the need for global oral health course in Nigeria. METHODS: Final year dental students in two Nigerian Universities were surveyed for this study. The students voluntarily completed the global oral health information questionnaire in a classroom before a scheduled lecture. The collected data were analyzed using IBM SPSS Statistic 20. RESULTS: All the final year students participated in the survey. All the students agreed that they need to be taught course on global oral health and would consider volunteering their dental skills and expertise in an international setting or developing country. Only 4.5% of the students knew the meaning of the basic package of oral care (BPOC) and none of the surveyed students could correctly name the three components of BPOC. Whereas only 18.2% could identify World Dental Federation and World Health Organization as the bodies that developed global oral health goals for the year 2000, none of the students could correctly list the three components of global oral health goals for the year 2000. CONCLUSION: This study concludes that a gap exists in the knowledge of students on global oral health matters and recommends that the curricula of schools be constantly reviewed in line with current trends in policies and practices. PMID- 24818090 TI - Effect of two different finishing systems on surface roughness of feldspathic and fluorapatite porcelains in ceramo-metal restorations: Comparative in vitro study. AB - OBJECTIVE: The objective of present study was to qualitatively and quantitatively evaluate and compare the effect of two ceramic finishing systems and diamond polishing paste on surface texture of two ceramic materials. METHODOLOGY: The 40 test specimens were randomly divided into two main groups (Group I and Group II). Which were subsequently veneered with feldspathic porcelain and fluorapatite leucite porcelain systems respectively. The samples in Test group I and Test group II were subjected to different abrasion and finishing systems (Soft Lex and White silicon and grey rubber respectively). The surface roughness of all the four groups was assessed qualitatively using the scanning Electron Microscope and profilometer. RESULTS: The surface roughness of Feldspathic and fluorapetite porcelain increased after abrasion and finishing as compared to auto-glazed porcelin. The surface roughness was more in grey rubber disc group (Gp Ib) as compared to the soft lex disc groups. After polishing with the diamond paste, there was reduction in the surface roughness of both the disc groups. The Mean Ra values of the Feldspathic porcelain at three intervals were 0.52 +/- 0.06, 0.54 +/- 0.06, 0.32 +/- 0.06 and 0.50 +/- 0.04, 1.25 +/- 0.10, 0.45 +/- 0.6 respectively for grey rubber disc and soft lex groups. The Mean Ra values of Fluorapetite porcelain at three intervals were 0.40 +/- 0.06, 0.52 +/- 0.06, 0.30 +/- 0.03 and 0.41 +/- 0.04, 1.17 +/- 0.09, 0.39 +/- 0.07 respectively for grey rubber disc and soft lex groups. DISCUSSION AND CONCLUSION: The surface roughness was less in the polished samples as compared to the auto-glazed porcelain. The findings were more reinforcing in the soft lex group as compared to the white/grey rubber disc group. Between the two porcelain systems, the Fluorapatite leucite porcelain specimens exhibited better surface smoothness than feldspathic porcelain. PMID- 24818091 TI - Knowledge and attitude about computer and internet usage among dental students in Western Rajasthan, India. AB - BACKGROUND: Internet is a useful tool to update the knowledge. The aim of the present study was to assess the current level of knowledge on the computer and internet among under graduate dental students. MATERIALS AND METHODS: The study consists of self-administered close ended questionnaire survey. Questionnaires were distributed to undergraduate dental students. The study was conducted during July to September 2012. RESULTS: In the selected samples, response rate was 100%. Most (94.4%) of the students had computer knowledge and 77.4% had their own computer and access at home. Nearly 40.8% of students use computer for general purpose, 28.5% for entertainment and 22.8% used for research purpose. Most of the students had internet knowledge (92.9%) and they used it independently (79.1%). Nearly 42.1% used internet occasionally whereas, 34.4% used regularly, 21.7% rarely and 1.8% don't use respectively. Internet was preferred for getting information (48.8%) due to easy accessibility and recent updates. For dental purpose students used internet 2-3 times/week (45.3%). Most (95.3%) of the students responded to have computer based learning program in the curriculum. CONCLUSION: Computer knowledge was observed to be good among dental students. PMID- 24818092 TI - Self-reported and clinically diagnosed dental needs among institutionalized adults in Vijayawada: A cross-sectional study. AB - BACKGROUND: Frail and functionally dependent elderly people, living in institutions, have difficulties in accessing dental care. Hence, the present study aims to determine the relationship between subjective need and the equivalent clinical findings in an attempt to understand the factors that contribute to individual's perception of the need for dental care among institutionalized adults in Vijayawada. MATERIALS AND METHODS: A cross-sectional study is conducted in all old age homes in Vijayawada. A total of 182 subjects were interviewed with a questionnaire consisting of demographic details, dental behavior (last visit, reason for the last visit), and self-rating of oral health and impact of oral problems, followed by the clinical examination for oral mucosal condition, dentition status and treatment needs, prosthetic status and treatment needs, and periodontal status by using World Health Organization proforma. RESULTS: Results showed that normative needs of subjects are significantly more than the self-perceived needs. Response of subjects regarding their present condition of mouth and teeth is 65.4% of subjects reported good and 0.5% reported poor, with respective to perceived oral symptoms 61.9% of subjects' complaints of hypersensitivity and 23.1% of subjects were having toothache and 80.5% subjects are having difficulty in eating. The overall prevalence of complete Edentulous and require complete denture was 12.1%, and 60.4% required partial denture. CONCLUSION: About half of the participants confirmed need for problem-oriented dental care. The main reason for the problems faced by the institutionalized people is due to lack of teeth which could be prevented by appropriate care. PMID- 24818093 TI - Assessment of caries prevalence among children below 5 years old. AB - CONTEXT: In the current scenario of developing countries, dental caries has been a long-standing challenge in the oral health issue and still on the rise. AIM: The aim of the following study is to estimate the caries prevalence in the primary dentition among children below 5 years of age. MATERIALS AND METHODS: [corrected] Study population included both boys and girls below 5 years old attending KGF Dental College and Hospital, Karnataka. A simple random sampling method was used. A total of 672 children were examined under headlamp illumination using mouth mirror and probe according to World Health Organization (WHO) criteria. A questionnaire was used to elicit information from the attendants regarding general health, intra oral examination and caries experience was recorded using WHO 1997 proforma. The data were computerized and analyzed applying the Statistical Package for the Social Sciences program. RESULTS: Prevalence of dental caries was 44.34%. Caries prevalence was higher in the boys than the girls and it was statistically significant (P < 0.05). It was also found that primary second molars were the highest carious tooth. CONCLUSION: The prevalence of dental caries was high among children below 5 years old. The present study was undertaken to obtain baseline data for planning preventive programs. Untreated caries indicates subsequent steps toward preventive and restorative care should be initiated. In order to reduce the caries prevalence, there is a need for continuous monitoring and health education to the children and parents, guardians. PMID- 24818094 TI - Evaluation of awareness regarding orthodontic procedures among a group of preadolescents in a cross-sectional study. AB - OBJECTIVE: This study was carried out to know the level of awareness regarding orthodontic procedures among preadolescents as there is very high prevalence of malocclusion. METHODS: This cross-sectional study was conducted among a sample of 1010 subjects with a mean age of (in years) was 13.02 +/- 2.146. A self administered structured questionnaire proforma was used. Pilot study was done to validate the questionnaire, which was constituted of nine items. The Student's t test and ANOVA test along with stepwise multiple linear regression were applied for the statistical evaluation of means. The level of significance was set at 0.05. RESULTS: The overall awareness of orthodontist among the school going children was 45.1%. The knowledge of orthodontic procedures was significantly higher among girls (4.46 +/- 1.671) when compared to boys (4.00 +/- 1.489). When the results were compared according to the area of location most of the students in the urban areas gave a positive response regarding awareness when compared to children in the rural community. CONCLUSION: This group of preadolescents showed moderate level of awareness regarding orthodontic procedures as they mentioned that it helps in esthetics, better oral hygiene, mastication, and healthy lifestyle. PMID- 24818095 TI - The importance of dental aesthetics among dental students assessment of knowledge. AB - OBJECTIVE: The aim of this study is to assess the dental esthetics awareness among dental students in a private university in Chennai as none is available in Chennai, Tamil Nadu. MATERIALS AND METHODS: The dental esthetics awareness questionnaire consisting of a battery of 19 questions under five aspects that is, physical, functional, social, knowledge, and psychological aspects was administered to a sample of 100 dental college students aged between 18 and 27 years in a private college in Chennai, India. Gender variations on the responses of their effects and the impact on dental esthetics awareness had been analyzed using a Chi-square test. RESULTS: With respect to physical aspects, pigmentation shows more significance as students want to get treated for their pigmentation of lips and gums. With respect to functional aspects, eating shows more significance as students have difficulty while eating. In social aspects, habits show more significance as it affects their esthetics. With respect to psychological aspects, mental depression shows more significance as students feel more deprived due to their unesthetic appearance. CONCLUSION: This study shows a high level of self-consciousness and the findings of the studies prove that even the slightest of variations have a greater impact on the above-mentioned dimensions in particular to psychological, functional, and physical aspects. PMID- 24818096 TI - Prevalence of dental caries among school children of Bharatpur city, India. AB - BACKGROUND: Healthy teeth and oral tissues and the need for oral health care are important for any section of society. Dental caries is an infectious microbial disease of multifactorial origin in which diet, host, and microbial flora interacts over a period of time in such a way so as to encourage demineralization of the tooth enamel with resultant caries formation. Dental caries, the product of man's progress towards civilization, has a very high morbidity potential and thus, is coming into focus of the mankind. AIMS AND OBJECTIVES: To assess the prevalence of dental caries among 12-15 year old government and private school children of Bharatpur city. MATERIALS AND METHODS: This was a cross-sectional study carried out on total 1400 school children, of which 700 school children were from government schools and 700 were from private schools. Simple random sampling methodology was used to select the sample. The subjects were examined for dental caries according to WHO 1997 assessment form. Significant Caries Index was also used to assess the prevalence of dental caries. RESULTS: The prevalence of dental caries was found higher among government school children, that is, 53%, when compared to private school children, that is, 47% and this difference was found to be statistically significant. The mean decayed, missing, and filled teeth were found to be higher in government school children (7.61 +/- 2.86) as compared to private school children (4.76 +/- 2.42). CONCLUSION: Dental caries was found to be the major public health problems among both the government and private school children of Bharatpur city, which need immediate attention. Regular dental checkups and practice of routine oral hygiene procedures will enable them to lead a healthier life. PMID- 24818097 TI - In vitro evaluation of antibacterial efficacy of calcium hydroxide in different vehicles. AB - AIM: This study was aimed to evaluate the antibacterial effect of calcium hydroxide (CH) in different vehicles in an in vitro model. MATERIALS AND METHODS: Calcium hydroxide paste prepared with two conventionally used vehicles namely, camphorated monochlophenol, distilled water and propylene glycol. The antibacterial activity of these paste were tested against five micro-organisms that can commonly occur in the infected root canals. RESULTS: The results of this study indicate that a paste of CH made with propylene glycol exerts significant antibacterial action. Hence, it can be recommended for use as an intracanal medicament in preference to a paste prepared with a tissue toxic phenolic compound like camphorated monochlorophenol. PMID- 24818098 TI - Analysis of human papilloma virus in oral squamous cell carcinoma using p16: An immunohistochemical study. AB - AIMS: The aim of this study is to evaluate the expression of human papilloma virus (HPV) in oral squamous cell carcinoma (OSCC) and to correlate the association of HPV in histological grades of OSCC using p16 (p16INK4a) immunohistochemistry (IHC). SUBJECTS AND METHODS: This study consists of 30 histological diagnosed cases of OSCC (10-well-differentiated oral squamous cell carcinoma [WDOSCC], 10-moderately differentiated oral squamous cell carcinoma [MDOSCC] and 10-poorly differentiated oral squamous cell carcinoma [PDOSCC]). The sections were subjected to IHC procedure using p16. Two parameters in immunohistochemical p16 expression were evaluated by 3 observers based on the criteria by Galgano M. Tetal (2010) (a) percentage of p16 positive cases (b) pattern of p16 staining in various grades of OSCC. STATISTICAL ANALYSIS USED: Kappa test. RESULTS: Totally, 30 samples of 0SCC, p16 positivity was noted in 26/30 (86.66%). Of 26 positive cases, p16 staining was positive in 7/10 (70%) of WDOSCC, 9/10 (90%) in MDOSCC and, 10/10 (100%) PDOSCC. Incidentally, we also found single dispersed cell staining in WDOSCC, patchy staining in MDOSCC and more diffuse staining pattern predominant in PDOSCC. CONCLUSIONS: Our study revealed an association between HPV and OSCC. Diffuse staining pattern was noted in PDOSCC, which in turn depicts the increase viral overload, which might have an influence on its aggressive behavior. PMID- 24818099 TI - Unilateral condylar hyperplasia: A case report and review of literature. AB - Condylar hyperplasia is (CH) an uncommon malformation of the mandible involving change in size and morphology of the condylar neck and head. CH is an anomaly that usually occurs unilaterally and equally affects in both men and women. Hyperplasia of the condyle 'differentiated into hemimandibular hyperplasia, hemimandibular elongation and CH. Here, we are presenting a case of 17-year-old male patient with unilateral CH and its review of the literature. PMID- 24818100 TI - Orthokeratinized odontogenic cyst of the mandible: A rare case report with a systematic review. AB - Orthokeratinized odontogenic cyst (OOC) is an odontogenic cyst was initially termed as the uncommon orthokeratinized type of odontogenic keratocyst by the World Health Organization. It usually occurs in mandible. Various studies have shown that OOC has typical characteristic clinicopathologic features when compared to other developmental odontogenic lesions such as dentigerous cyst and the keratocystic odontogenic tumor (KCOT). Rare recurrence was noted after surgical removal of the lesion. The purpose of this article is to present a case of OOC arising in the posterior mandible and emphasize on differentiating it from the KCOT and dentigerous cyst. PMID- 24818101 TI - The Role of STAT1 for Crosstalk between Fibroblasts and Colon Cancer Cells. AB - Signaling between tumor cells and the associated stroma has an important impact on cancer initiation and progression. The tumor microenvironment has a paradoxical role in tumor progression and fibroblasts, a major component of the tumor stroma, have been shown to either inhibit or promote cancer development. In this study, we established that normal intestinal fibroblasts activate STAT1 signaling in colon cancer cells and, in contrast to cancer-associated fibroblasts, inhibit growth of tumor cells. Treatment of 18Co fibroblasts with the proinflammatory cytokine TNFalpha interfered with their ability to trigger STAT1 signaling in cancer cells. Accordingly, intestinal myofibroblasts isolated from patients with ulcerative colitis or Crohn's disease, which are activated and produce high levels of TNFalpha, failed to stimulate STAT1 signaling in tumor cells, demonstrating that activated myofibroblasts lose the ability to trigger growth-inhibitory STAT1 signaling in tumor cells. Finally, we confirmed that silencing of STAT1 in tumor cells alters the crosstalk between tumor cells and fibroblasts, suggesting STAT1 as a novel link between intestinal inflammation and colon cancer. We demonstrated that normal fibroblasts restrain the growth of carcinoma cells, at least in part, through the induction of STAT1 signaling in cancer cells and showed that changes in the microenvironment, as they occur in inflammatory bowel disease, alter the crosstalk between carcinoma cells and fibroblasts, perturb the homeostasis of intestinal tissue, and thereby contribute to tumor progression. PMID- 24818102 TI - Effect of integrated pest management on controlling zoonotic cutaneous leishmaniasis in Emamzadeh Agha Ali Abbas (AS) District, Isfahan province, 2006 2009. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is still considered as a health problem in the world. Several methods of control in different regions, together with obtaining integrated information on its natural foci, are needed to decrease its prevalence. This study was designed to evaluate the effects of simultaneous interventions on CL control. MATERIALS AND METHODS: A standard questionnaire was used to identify patients among pilgrims to Emamzadeh Agha Ali Abbas (Isfahan Province, Iran). Subsequently, three methods of controlling the disease, including, spraying residential buildings with Baygon, baiting with zinc phosphide poisons, changing the vegetative cover of the region, improving the environment, and mounting a mesh on all doors and windows of buildings in residential areas were used. The control measures were then evaluated by comparing the number of pilgrims affected by CL after and before the interventions. RESULTS: While 23 pilgrims (1.4%) were affected with CL before the intervention (pretest), five (0.3%) persons were found to have CL after taking control measures. The Chi-square test did not indicate any significant difference in the relative frequency of CL (P = 0.731). CONCLUSION: The only scientific method for preventing and controlling zoonotic CL (ZCL) is a combination of the control methods (improving the environment and fighting off the disease districts and vectors) together with changing the vegetative cover of the region. Any measure for controlling this disease must be taken and programmed in accordance with the relevant experts' views, in coordination with the participation of other organizations and the society. PMID- 24818103 TI - Breast carcinoma in young females below the age of 40 years: A histopathological perspective. AB - BACKGROUND: Breast cancer among young women is a rare pathology, but is known to have a more aggressive behavior and poorer outcome. AIMS: The objective of this study was to evaluate the clinicopathological characteristics of breast carcinoma below 40 years in comparison to that over 40 years in Manipur, India. SETTINGS AND DESIGN: This retrospective study from the period of January 2005-December 2010 was conducted in the Department of Pathology, Regional Institute of Medical Sciences, Imphal, Manipur. MATERIALS AND METHODS: All cases of mastectomy specimens of carcinoma breast from the period of January 2005-December 2010 were included in the study. Clinical and histopathological data of all cases were reviewed and correlated. RESULTS: A total of 507 mastectomy specimens were received, among which, 160 cases (31.56%) were below 40 years; whereas 347 cases (68.44%) were above 40 years of age. Stage III was the commonest stage (47% versus 18%) in the younger group; while in the older group, Stage II was the commonest (64% versus 34%). CONCLUSION: This study shows that young females with breast cancer have higher stage of tumor. PMID- 24818104 TI - Age at diagnosis of female breast cancer in Oman: Issues and implications. AB - INTRODUCTION: Female breast cancer (BC) is the most frequent malignancy diagnosed globally, about 23% of the diagnosed cancers. BC incidence varies geographically, highest in Western Europe and lowest in Africa. BC in females is strongly correlated to age, the highest incidence rate amongst older women reinforcing the importance of hormonal status. BC in young females has an aggressive phenotype. There is a shared observation amongst practicing oncologists that BC in Middle East and the developing world presents at an earlier age. AIM AND OBJECTIVE: The aims of this study are to evaluate the age at presentation of female BC in Oman, and to compare our data with international and regional published data. It discusses the impact of young age Breast Cancer. MATERIALS AND METHODS: All diagnosed female BC cases registered from 1996-2010 all over the country, were retrieved from the National Cancer Registry, Ministry of Health. BC cases were analyzed with respect to age at presentation. The data were compared with regional and international data. RESULTS: A total of 14,109 cancer cases were recorded during the period of study. BC was the leading malignancy as 1,294 cases (9.1%). Female BC patients were 1,230; denoting 19.2% of all female cancers. 53.5% of female BC presented below 50 years of age. Male BC constituted 5% of total, with 67% of male BC occurring over 50 years of age. Compared with data from Oman, the highest rates in UK and other Western countries are above 50 years of age. These rates are four to 10 times higher than local in different age groups. Interestingly, these rates increase with increasing age in UK from 40-45 to up to 85+, keep on increasing and go up to four times higher with higher age. This phenomenon, of increasing incidence rates with age, is not observed in our local population. DISCUSSION: BC is significantly correlated to age as reported from Western population. BC is reported at a younger age from developing and Arab World, which need to be further studied and validated. This phenomenon of BC in younger age may have significant implications and effects ranging from screening, diagnosis, management, prognosis, and cost of treatment. CONCLUSION: The impact on young women diagnosed with BC is enormous, ranging from psychosocial to healthcare services and economics. There is a need to study it further in depth in developing World. PMID- 24818105 TI - Evaluation of protective effect of myricetin, a bioflavonoid in dimethyl benzanthracene-induced breast cancer in female Wistar rats. AB - BACKGROUND: Breast cancer is one of the most common cancers worldwide. Alarmingly, the incidence of breast cancer is rising rapidly in India. AIM: The present research was focused to assess the role of myricetin; a bioflavonoid in 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer in female Wistar rats. MATERIALS AND METHODS: A total of 36 female Wistar rats (total 6 groups, n = 6 per group) 6 - 8 weeks old, weighing 150 gm were used in the study. DMBA was given at the dose of 7.5 mg/kg subcutaneously in the mammary region once a week for 4 consecutive weeks in group 2. Vincristine was given in the dose of 500 MUg/kg intraperitonially every week for 4 consecutive weeks in group 3. Myricetin was given orally in a dose of 50, 100, and 200 mg/kg in group 4, 5, and 6 respectively. The statistical significance of the data was determined using one way analysis of variance and Duncan's multiple range test. RESULTS: The result showed that myricetin increased the antioxidant levels in plasma, erythrocyte lysate, and breast tissue and was effective in preventing the oxidative damage induced by the carcinogen DMBA. Myricetin 50, 100, and 200 mg/kg/oral for 120 days treated animal resulted comparable results to that of standard vincristine and control groups. CONCLUSIONS: Myricetin was found to be either equieffective or more effective than vincristine in all the parameters studied. Myricetin proved the capacity of flavonols to act as antioxidant in cells represents a potential treatment in the field of oncology. PMID- 24818106 TI - Late effects of cancer treatment in breast cancer survivors. AB - Postoperative radiation therapy (RT) and chemotherapy,both reduces the risk of local recurrence and extends overall survival in patients with breast cancer (BC). Concerns have, however, been raised about the risk of acute and chronic side effects in breast cancer survivors as the number of treated individuals is large and their expected survival is long compared to most patients with other malignant diseases. Cardiac toxicity, reproductive dysfunction, pneumonitis (RP),arm lymph edema, neuropathy, skin changes are examples of the wide range of complications that has been associated with adjuvant treatment. PMID- 24818107 TI - Breaking bad news of cancer diagnosis - Perception of the cancer patients in a rural community in Malaysia. AB - CONTEXT: Breaking of bad news is an important component in the management of cancer patients. AIMS: This study aimed to assess the perceptions of breaking bad news of cancer diagnosis. SETTINGS AND DESIGN: It was a cross-sectional study using Breaking Bad News Assessment Schedule (BAS) questionnaire on cancer patients in Serian district. MATERIALS AND METHODS: Using snowballing sampling method, a total of 134 patients were interviewed face-to-face after the consent was obtained from each of the respondents. STATISTICAL ANALYSIS USED: Data was entered and analyzed using SPSS version 19.0. RESULTS: Majority were comfortable with the current method of breaking bad news. The main aspects found to be the areas of concern were the importance of the usage of body language, management of time and identifying patients' key area of concerns. There were significant difference between sex and "information giving" (P = 0.028) and "general consideration" (P = 0.016) and also between "the age and setting the scene" (P = 0.042). Significant difference was also found between the types of cancer and "the setting of scene" (P = 0.018), "breaking bad news technique" (P = 0.010), "eliciting concerns" (P = 0.003) and "information giving" (P = 0.004). CONCLUSION: Good and effective communication skill of breaking bad news is vital in the management of cancer patients. As the incidence of new cases of cancer increase every year, breaking of bad news has become a pertinent to the medical professionals' role. Specific aspects of communication skills based on local characteristics should be more emphasized in the formulation of training for doctors. PMID- 24818108 TI - Barriers for early detection of cancer amongst Indian rural women. AB - CONTEXT: Breast and cervical cancer are the most common causes of cancer mortality among women worldwide, but actually they are largely preventable diseases. Healthcare providers in developing countries regularly see women with advanced, incurable cancers. Health of a rural Indian women and her access to health facility is compromised due to sociocultural, economical, and environmental factors. AIMS: To know the problems associated with early detection of cancers in rural women. SETTINGS AND DESIGN: Rural area and cross-sectional. SUBJECTS AND METHODS: STUDY SUBJECT: Women of 35 years and above. EXCLUSION CRITERIA: Not willing to participate. SAMPLE SIZE: All eligible women of selected villages. SAMPLING TECHNIQUE: Random selection of villages. Study duration: 2 months. Study tools: Pretested questionnaire. STATISTICAL ANALYSIS USED: Percentages, chi(2) test, analysis of variance (ANOVA), multivariate analysis. RESULTS: Awareness about symptoms, possibility of early detection, available tests, possibility of cure of disease was low. Main barrier for screening was cognitive, that is, 'don't know' answer by 83.99% women for cancer cervix, 84.93%, for cancer breast, and 67.26% for oral cancer. Awareness score was significantly associated with age (chi(2) = 17.77, P = 0.001), education (chi(2) = 34.62, P = 0.000), and income (chi(2) = 16.72, P = 0.002); while attitude score with age (chi(2) = 16.27, P = 0.012) and education (chi(2) = 25.16, P = 0.003). Practice score was significantly associated with age (chi(2) = 11.28, P = 0.023), education (chi(2) = 32.27, P = 0.003), and occupation (chi(2) = 10.69, P = 0.03). Awareness, attitude, and practice score of women having history of cancer in family or relative was significantly high than women without history. CONCLUSIONS: Cognitive barrier was the important barrier which has to be taken care of. PMID- 24818109 TI - Afro Middle East Asian symposium on cancer cooperation. AB - This manuscript captures the discussion and recommendations that came out of a special Afro Asian symposium involving 13 countries. Unmet needs and cost effective solutions with special emphasis on training form the backbone of practical next steps. PMID- 24818110 TI - Ramosetron hydrochloride for the prevention of cancer chemotherapy induced nausea and vomiting: The Indian experience. AB - BACKGROUND: Despite the advent of 5-HT3 antagonists, control of delayed gastrointestinal adverse events with cancer chemotherapy is still not optimal. This open label, active controlled, multicentric clinical trial was undertaken to assess the comparative efficacy and safety of ramosetron with ondansetron for the prevention of acute and delayed nausea and vomiting associated with emetogenic cancer chemotherapy in adult patients in India. MATERIALS AND METHODS: Enrolled patients received treatment with ramosetron hydrochloride 0.1 mg or ondansetron hydrochloride 4 mg tablets once daily in the morning for 5 days starting 1 h before the start of chemotherapy. Severity grades of nausea and vomiting were recorded on a daily basis for a period of 5 days and complete response rate (CRR) and effective rate (ER) were calculated. Clinical adverse events were recorded and hematological and biochemical investigations were performed for safety assessment. RESULTS: A total of 114 patients in ramosetron group and 100 patients in ondansetron group completed the study and were eligible for efficacy and safety analysis. CRR and ERs show that while ramosetron is non-inferior to ondansetron in the control of early nausea and vomiting (occurring during the first 24 h) after the treatment with emetogenic chemotherapy, it is superior to ondansetron in the control of delayed nausea and vomiting (occurring after the first 24 h). The proportion of patients achieving a cumulative complete response (for the entire study period) is significantly greater in ramosetron group as compared to ondansetron group (27.2% vs. 7.0%; P < 0.001). Ramosetron was well tolerated by all the study participants. CONCLUSIONS: Ramosetron is significantly more effective than ondansetron for the control of delayed nausea and vomiting induced by emetogenic cancer chemotherapy. PMID- 24818111 TI - Role of Crizotinib in previously treated non-small-cell lung cancer. PMID- 24818112 TI - Myeloma and diabetes mellitus. PMID- 24818113 TI - Tuberculosis and lung cancer. PMID- 24818114 TI - Are results from dosimetric studies sufficient enough to determine the quality of treatment techniques in radiation therapy? PMID- 24818115 TI - Finding for epitope within egg shell protein of human liver fluke: A clue for cholangiocarcinoma vaccine development. PMID- 24818116 TI - NK cell therapy for end-stage cancerous patient: A case study. PMID- 24818117 TI - Health care in rural India: A lack between need and feed. PMID- 24818118 TI - Choriocarcinomatous differentiation in rectal adenocarcinoma: A rare occurrence. PMID- 24818119 TI - Mucosa-associated lymphoid tissue lymphoma of the ileum in a child presenting as intussusception. PMID- 24818120 TI - Severe neurotoxicity due to Vinblastine in Hodgkin lymphoma. PMID- 24818122 TI - Barium aspiration in an infant: a case report and review of management. AB - We describe a case of bilateral inhalation of barium in an infant following a barium swallow for investigation of dusky spells associated with feeds. A bronchoscopy subsequently revealed the presence of a mid-tracheal tracheo esophageal cleft. To date, little has been reported on barium aspiration in children and there is no consensus for management. We review the literature on barium aspiration, its consequences, and make recommendations for management. PMID- 24818121 TI - Pediatric critical care: grand challenges for a glowing future. PMID- 24818123 TI - The multimodal concept of hemodynamic stabilization. AB - Hemodynamic instability often leads to hypoperfusion, which has a significant impact on outcome in both medical and surgical patients. Measures to detect and treat tissue hypoperfusion early by correcting the imbalance between oxygen delivery and consumption is of particular importance. There are several studies targeting different hemodynamic endpoints in order to investigate the effects of goal-directed therapy on outcome. A so-called multimodal concept putting several variables in context follows simple logic and may provide a broader picture. Furthermore, rather than treating population based "normal" values of certain indices, this concept can be translated into the individualized patient care to reach adequate oxygen supply and tissue oxygenation in order to avoid under, or over resuscitation, which are equally harmful. The purpose of this review is to give an overview of current data providing the basis of this a multimodal, individualized approach of hemodynamic monitoring and treatment. PMID- 24818124 TI - Electrochemical sensors and devices for heavy metals assay in water: the French groups' contribution. AB - A great challenge in the area of heavy metal trace detection is the development of electrochemical techniques and devices which are user-friendly, robust, selective, with low detection limits and allowing fast analyses. This review presents the major contribution of the French scientific academic community in the field of electrochemical sensors and electroanalytical methods within the last 20 years. From the well-known polarography to the up-to-date generation of functionalized interfaces, the different strategies dedicated to analytical performances improvement are exposed: stripping voltammetry, solid mercury-free electrode, ion selective sensor, carbon based materials, chemically modified electrodes, nano-structured surfaces. The paper particularly emphasizes their advantages and limits face to the last Water Frame Directive devoted to the Environmental Quality Standards for heavy metals. Recent trends on trace metal speciation as well as on automatic "on line" monitoring devices are also evoked. PMID- 24818125 TI - Insights on the role of antimicrobial cuffed endotracheal tubes in preventing transtracheal transmission of VAP pathogens from an in vitro model of microaspiration and microbial proliferation. AB - We developed an in vitro model to evaluate the effect of different cuffed endotracheal tubes (ETTs) on transtracheal transmission of ventilator-associated pneumonia (VAP) pathogens along external surfaces of ETTs. The model independently assessed the relative contributions of microbial proliferation to the distal tip and microaspiration of contaminated secretions past the cuff by testing in three modes: microaspiration only, microbial proliferation only, and simultaneous microaspiration and microbial proliferation. We evaluated transmission of methicillin resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (PA) in the presence of a standard ETT; a soft, tapered cuff ETT with subglottic suctioning; and a novel antimicrobial gendine (combination of gentian violet and chlorhexidine) ETT in the model. In the microaspiration only mode, when leakage past the cuff occurred quickly, no ETT prevented transmission. When microaspiration was delayed, the gendine ETT was able to completely disinfect the fluid above the cuff and thereby prevent transmission of pathogens. In microbial proliferation only mode, the gendine ETT was the sole ETT that prevented transmission. With both mechanisms simultaneously available, transmission was dependent on how long microaspiration was delayed. Potent antimicrobial ETTs, such as a gendine ETT, can make unique contributions to prevent VAP when microaspiration is gradual. PMID- 24818126 TI - Association of immunological cell profiles with specific clinical phenotypes of scleroderma disease. AB - This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4(+) and CD8(+) T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. PMID- 24818127 TI - Phylogenetic analysis of Stenotrophomonas spp. isolates contributes to the identification of nosocomial and community-acquired infections. AB - Stenotrophomonas ssp. has a wide environmental distribution and is also found as an opportunistic pathogen, causing nosocomial or community-acquired infections. One species, S. maltophilia, presents multidrug resistance and has been associated with serious infections in pediatric and immunocompromised patients. Therefore, it is relevant to conduct resistance profile and phylogenetic studies in clinical isolates for identifying infection origins and isolates with augmented pathogenic potential. Here, multilocus sequence typing was performed for phylogenetic analysis of nosocomial isolates of Stenotrophomonas spp. and, environmental and clinical strains of S. maltophilia. Biochemical and multidrug resistance profiles of nosocomial and clinical strains were determined. The inferred phylogenetic profile showed high clonal variability, what correlates with the adaptability process of Stenotrophomonas to different habitats. Two clinical isolates subgroups of S. maltophilia sharing high phylogenetic homogeneity presented intergroup recombination, thus indicating the high permittivity to horizontal gene transfer, a mechanism involved in the acquisition of antibiotic resistance and expression of virulence factors. For most of the clinical strains, phylogenetic inference was made using only partial ppsA gene sequence. Therefore, the sequencing of just one specific fragment of this gene would allow, in many cases, determining whether the infection with S. maltophilia was nosocomial or community-acquired. PMID- 24818128 TI - Detection of food spoilage and pathogenic bacteria based on ligation detection reaction coupled to flow-through hybridization on membranes. AB - Traditional culturing methods are still commonly applied for bacterial identification in the food control sector, despite being time and labor intensive. Microarray technologies represent an interesting alternative. However, they require higher costs and technical expertise, making them still inappropriate for microbial routine analysis. The present study describes the development of an efficient method for bacterial identification based on flow through reverse dot-blot (FT-RDB) hybridization on membranes, coupled to the high specific ligation detection reaction (LDR). First, the methodology was optimized by testing different types of ligase enzymes, labeling, and membranes. Furthermore, specific oligonucleotide probes were designed based on the 16S rRNA gene, using the bioinformatic tool Oligonucleotide Retrieving for Molecular Applications (ORMA). Four probes were selected and synthesized, being specific for Aeromonas spp., Pseudomonas spp., Shewanella spp., and Morganella morganii, respectively. For the validation of the probes, 16 reference strains from type culture collections were tested by LDR and FT-RDB hybridization using universal arrays spotted onto membranes. In conclusion, the described methodology could be applied for the rapid, accurate, and cost-effective identification of bacterial species, exhibiting special relevance in food safety and quality. PMID- 24818129 TI - Development of an open-heart intraoperative risk scoring model for predicting a prolonged intensive care unit stay. AB - BACKGROUND: Based on a pilot study with 34 patients, applying the modified sequential organ failure assessment (SOFA) score intraoperatively could predict a prolonged ICU stay, albeit with only 4 risk factors. Our objective was to develop a practicable intraoperative model for predicting prolonged ICU stay which included more relevant risk factors. METHODS: An extensive literature review identified 6 other intraoperative risk factors affecting prolonged ICU stay. Another 168 patients were then recruited for whom all 10 risk factors were extracted and analyzed by logistic regression to form the new prognostic model. RESULTS: The multivariate logistic regression analysis retained only 6 significant risk factors in the model: age >= 60 years, PaO2/FiO2 ratio <= 200 mmHg, platelet count <= 120,000/mm(3), requirement for inotrope/vasopressor >= 2 drugs, serum potassium <= 3.2 mEq/L, and atrial fibrillation grading >= 2. This model was then simplified into the Open-Heart Intraoperative Risk (OHIR) score, comprising the same 6 risk factors for a total score of 7-a score of >= 3 indicating a likely prolonged ICU stay (AUC for ROC of 0.746). CONCLUSIONS: We developed a new, easy to calculate OHIR scoring system for predicting prolonged ICU stay as early as 3 hours after CPB. It comprises 6 risk factors, 5 of which can be manipulated intraoperatively. PMID- 24818130 TI - Suppressive effects of D-glucosamine on the 5-HT sensitive nociceptive units in the rat tooth pulpal nerve. AB - It is well known that D-glucosamine hydrochloride (DGL) has a variety of biological activities and is regarded as a nutritional supplement effective in improving various disorders, including osteoarthritis and atherosclerosis. Although it has been reported that DGL has a significant pain relief effect in treating osteoarthritis, little is known about the characteristics of the effects of this compound on dental pain. The present study was undertaken to evaluate the applicability of DGL as a medicament to control pulpalgia. Using an in vitro rat mandible-inferior alveolar nerve preparation (jaw-nerve preparation), we evaluated the effects of DGL on 5-hydroxytryptamine (5-HT) sensitive nociceptive responses in the tooth pulpal nerve. 5-HT-induced nociceptive responses were fairly suppressed by direct application of DGL, suggesting that DGL have a pain relief effect on patients with dental pain. PMID- 24818131 TI - Characterization of silk fibroin modified surface: a proteomic view of cellular response proteins induced by biomaterials. AB - The purpose of this study was to develop the pathway of silk fibroin (SF) biopolymer surface induced cell membrane protein activation. Fibroblasts were used as an experimental model to evaluate the responses of cellular proteins induced by biopolymer material using a mass spectrometry-based profiling system. The surface was covered by multiwalled carbon nanotubes (CNTs) and SF to increase the surface area, enhance the adhesion of biopolymer, and promote the rate of cell proliferation. The amount of adhered fibroblasts on CNTs/SF electrodes of quartz crystal microbalance (QCM) greatly exceeded those on other surfaces. Moreover, analyzing differential protein expressions of adhered fibroblasts on the biopolymer surface by proteomic approaches indicated that CD44 may be a key protein. Through this study, utilization of mass spectrometry-based proteomics in evaluation of cell adhesion on biopolymer was proposed. PMID- 24818132 TI - Extracts from glioma tissues following cryoablation have proapoptosis, antiproliferation, and anti-invasion effects on glioma cells. AB - OBJECTIVE: This study is to investigate the in vivo apoptotic processes in glioma tissues following cryoablation and the effects of glioma tissue extracts on GL261 glioma cells in vitro. METHODS: TUNEL and flow cytometry analysis were performed to detect the apoptotic processes in the glioma tissues following cryoablation and in the GL261 cells treated with cryoablated tumor extracts. The scratch assay, the transwell assay, and Western blot analysis were carried out to evaluate the effects of cryoablated tumor extracts on the migration, invasion, and proliferation of tumor cells. RESULTS: Our in vivo results indicated that the rapid-onset apoptosis was induced via the intrinsic pathway and the delayed apoptosis was triggered through the extrinsic pathway. The in vitro results showed that extracts from glioma tissues following cryoablation induced apoptosis via extrinsic pathways in GL261 glioma cells. Furthermore, cryoablated tumor extracts significantly inhibited the migration and proliferation of these cells, which would be related to the inhibition of ERK1/2 pathway and the activation of P38 pathway. CONCLUSION: Glioma cells surviving in cryoablation undergo intrinsic or extrinsic apoptosis. Augmenting the induction of apoptosis or enhancing the cryosensitization of tumor cells by coupling cryoablation with specific chemotherapy effectively increases the efficiency of this therapeutic treatment. PMID- 24818133 TI - Role of PET and SPECT in the study of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis has been defined as a "heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord." A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals. PMID- 24818134 TI - Mitochondrial aging and age-related dysfunction of mitochondria. AB - Age-related changes in mitochondria are associated with decline in mitochondrial function. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to accumulation of mutations and oxidative damage induced by reactive oxygen species (ROS). In aged subjects, mitochondria are characterized by impaired function such as lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, significant increase in ROS generation, and diminished antioxidant defense. Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells. However, implementation of strategies such as caloric restriction and regular physical training may delay mitochondrial aging and attenuate the age-related phenotype in humans. PMID- 24818135 TI - Gene expression correlation for cancer diagnosis: a pilot study. AB - Poor prognosis for late-stage, high-grade, and recurrent cancers has been motivating cancer researchers to search for more efficient biomarkers to identify the onset of cancer. Recent advances in constructing and dynamically analyzing biomolecular networks for different types of cancer have provided a promising novel strategy to detect tumorigenesis and metastasis. The observation of different biomolecular networks associated with normal and cancerous states led us to hypothesize that correlations for gene expressions could serve as valid indicators of early cancer development. In this pilot study, we tested our hypothesis by examining whether the mRNA expressions of three randomly selected cancer-related genes PIK3C3, PIM3, and PTEN were correlated during cancer progression and the correlation coefficients could be used for cancer diagnosis. Strong correlations (0.68 <= r <= 1.0) were observed between PIK3C3 and PIM3 in breast cancer, between PIK3C3 and PTEN in breast and ovary cancers, and between PIM3 and PTEN in breast, kidney, liver, and thyroid cancers during disease progression, implicating that the correlations for cancer network gene expressions could serve as a supplement to current clinical biomarkers, such as cancer antigens, for early cancer diagnosis. PMID- 24818136 TI - Interactions of neuropathogenic Escherichia coli K1 (RS218) and its derivatives lacking genomic islands with phagocytic Acanthamoeba castellanii and nonphagocytic brain endothelial cells. AB - Here we determined the role of various genomic islands in E. coli K1 interactions with phagocytic A. castellanii and nonphagocytic brain microvascular endothelial cells. The findings revealed that the genomic islands deletion mutants of RS218 related to toxins (peptide toxin, alpha -hemolysin), adhesins (P fimbriae, F17 like fimbriae, nonfimbrial adhesins, Hek, and hemagglutinin), protein secretion system (T1SS for hemolysin), invasins (IbeA, CNF1), metabolism (D-serine catabolism, dihydroxyacetone, glycerol, and glyoxylate metabolism) showed reduced interactions with both A. castellanii and brain microvascular endothelial cells. Interestingly, the deletion of RS218-derived genomic island 21 containing adhesins (P fimbriae, F17-like fimbriae, nonfimbrial adhesins, Hek, and hemagglutinin), protein secretion system (T1SS for hemolysin), invasins (CNF1), metabolism (D-serine catabolism) abolished E. coli K1-mediated HBMEC cytotoxicity in a CNF1-independent manner. Therefore, the characterization of these genomic islands should reveal mechanisms of evolutionary gain for E. coli K1 pathogenicity. PMID- 24818137 TI - Quantitative assessment of heteroplasmy of mitochondrial genome: perspectives in diagnostics and methodological pitfalls. AB - The role of alterations of mitochondrial DNA (mtDNA) in the development of human pathologies is not understood well. Most of mitochondrial mutations are characterized by the phenomenon of heteroplasmy which is defined as the presence of a mixture of more than one type of an organellar genome within a cell or tissue. The level of heteroplasmy varies in wide range, and the expression of disease is dependent on the percent of alleles bearing mutations, thus allowing consumption that an upper threshold level may exist beyond which the mitochondrial function collapses. Recent findings have demonstrated that some mtDNA heteroplasmic mutations are associated with widely spread chronic diseases, including atherosclerosis and cancer. Actually, each etiological mtDNA mutation has its own heteroplasmy threshold that needs to be measured. Therefore, quantitative evaluation of a mutant allele of mitochondrial genome is an obvious methodological challenge, since it may be a keystone for diagnostics of individual genetic predisposition to the disease. This review provides a comprehensive comparison of methods applicable to the measurement of heteroplasmy level of mitochondrial mutations associated with the development of pathology, in particular, in atherosclerosis and its clinical manifestations. PMID- 24818138 TI - Urinary angiotensinogen is elevated in patients with nephrolithiasis. AB - BACKGROUND: Elevated urinary angiotensinogen (UA) was identified as novel prognostic biomarker capable of predicting chronic kidney disease, and in the present study, we will investigate the diagnostic value of UA in the patients of nephrolithiasis. METHODS: Urine angiotensinogen levels and alpha 1-microglobulin were measured by enzyme-linked immunosorbent assay (ELISA) in 60 patients presenting with nephrolithiasis and 50 sex- and age-matched healthy volunteers. Estimated glomerular filtration (eGFR) was calculated and, by simple regression analysis, the correlation of UA/ alpha 1-microglobulin levels and the decline of eGFR were analyzed as well. RESULTS: Median UA levels was significantly increased in the nephrolithiasis patients compared with normal control (1250.78 +/- 439.27 versus 219.34 +/- 45.27 pg/mL; P < 0.01). The mean serum creatinine levels in patients with higher UA levels (>1250 pg/mL) was significantly higher than those with lower UA levels (<1250 pg/mL) [92.23 +/- 18.13 MUmol/L versus 70.07 +/- 11.17 MUmol/L; P < 0.05]. According to the single variate analysis, UA levels were significantly and positively correlated with urinary alpha 1-microglobulin (r = 0.733; P = 1.33 * 10(-15)), while they were significantly and negatively correlated with eGFR (r = -0.343; P = 1.03 * 10(-4)). CONCLUSION: Urinary UA is a novel biomarker for patients with nephrolithiasis, which indicates renal tubular injury. Further study on the molecular pathogenic mechanism of UA and larger scale of clinical trial is required. PMID- 24818139 TI - A novel algorithm for detecting protein complexes with the breadth first search. AB - Most biological processes are carried out by protein complexes. A substantial number of false positives of the protein-protein interaction (PPI) data can compromise the utility of the datasets for complexes reconstruction. In order to reduce the impact of such discrepancies, a number of data integration and affinity scoring schemes have been devised. The methods encode the reliabilities (confidence) of physical interactions between pairs of proteins. The challenge now is to identify novel and meaningful protein complexes from the weighted PPI network. To address this problem, a novel protein complex mining algorithm ClusterBFS (Cluster with Breadth-First Search) is proposed. Based on the weighted density, ClusterBFS detects protein complexes of the weighted network by the breadth first search algorithm, which originates from a given seed protein used as starting-point. The experimental results show that ClusterBFS performs significantly better than the other computational approaches in terms of the identification of protein complexes. PMID- 24818141 TI - Antioxidants, phytochemicals, and cytotoxicity studies on Phaleria macrocarpa (Scheff.) Boerl seeds. AB - In recent years, the utilization of certain medicinal plants as therapeutic agents has drastically increased. Phaleria macrocarpa (Scheff.) Boerl is frequently used in traditional medicine. The present investigation was undertaken with the purpose of developing pharmacopoeial standards for this species. Nutritional values such as ash, fiber, protein, fat, and carbohydrate contents were investigated, and phytochemical screenings with different reagents showed the presence of flavonoids, glycosides, saponin glycosides, phenolic compounds, steroids, tannins, and terpenoids. Our results also revealed that the water fraction had the highest antioxidant activity compared to the methanol extract and other fractions. The methanol and the fractionated extracts (hexane, chloroform, ethyl acetate, and water) of P. macrocarpa seeds were also investigated for their cytotoxic effects on selected human cancer cells lines (MCF-7, HT-29, MDA-MB231, Ca Ski, and SKOV-3) and a normal human fibroblast lung cell line (MRC-5). Information from this study can be applied for future pharmacological and therapeutic evaluations of the species, and may assist in the standardization for quality, purity, and sample identification. To the best of our knowledge, this is the first report on the phytochemical screening and cytotoxic effect of the crude and fractionated extracts of P. macrocarpa seeds on selected cells lines. PMID- 24818142 TI - Subchronic toxicity study in rats of two new ethyl-carbamates with ixodicidal activity. AB - Female and male Wistar rats were used to determine the subchronic oral toxicities of two new ethyl-carbamates with ixodicidal activities (ethyl-4-bromphenyl carbamate and ethyl-4-chlorphenyl-carbamate). The evaluated carbamates were administered in the drinking water (12.5, 25 and 50 mg/kg/day) for 90 days. Exposure to the evaluated carbamates did not cause mortality or clinical signs and did not affect food consumption or weight gain. However, exposure to these carbamates produced alterations in water consumption, hematocrit, percentages of reticulocytes, plasma proteins, some biochemical parameters (aspartate aminotransferase, gamma-glutamyl transpeptidase, cholinesterase, and creatinine activities), thiobarbituric acid reactive substances, and the relative weight of the spleen. Histologically, slight pathological alterations were found in the liver that were consistent with the observed biochemical alterations. The nonobserved adverse effect levels (NOAELs) of the evaluated carbamates were 12.5 mg/kg/day for both the female and male rats. The low severity and reversibility of the majority of the observed alterations suggest that the evaluated carbamates have low subchronic toxicity. PMID- 24818140 TI - Physical exercise-induced adult neurogenesis: a good strategy to prevent cognitive decline in neurodegenerative diseases? AB - Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain. PMID- 24818144 TI - Improving the diagnosis of bloodstream infections: PCR coupled with mass spectrometry. AB - The reference method for the diagnosis of bloodstream infections is blood culture followed by biochemical identification and antibiotic susceptibility testing of the isolated pathogen. This process requires 48 to 72 hours. The rapid administration of the most appropriate antimicrobial treatment is crucial for the survival of septic patients; therefore, a rapid method that enables diagnosis directly from analysis of a blood sample without culture is needed. A recently developed platform that couples broad-range PCR amplification of pathogen DNA with electrospray ionization mass spectrometry (PCR/ESI-MS) has the ability to identify virtually any microorganism from direct clinical specimens. To date, two clinical evaluations of the PCR/ESI-MS technology for the diagnosis of bloodstream infections from whole blood have been published. Here we discuss them and describe recent improvements that result in an enhanced sensitivity. Other commercially available assays for the molecular diagnosis of bloodstream infections from whole blood are also reviewed. The use of highly sensitive molecular diagnostic methods in combination with conventional procedures could substantially improve the management of septic patients. PMID- 24818143 TI - Neural regulation of cardiovascular response to exercise: role of central command and peripheral afferents. AB - During dynamic exercise, mechanisms controlling the cardiovascular apparatus operate to provide adequate oxygen to fulfill metabolic demand of exercising muscles and to guarantee metabolic end-products washout. Moreover, arterial blood pressure is regulated to maintain adequate perfusion of the vital organs without excessive pressure variations. The autonomic nervous system adjustments are characterized by a parasympathetic withdrawal and a sympathetic activation. In this review, we briefly summarize neural reflexes operating during dynamic exercise. The main focus of the present review will be on the central command, the arterial baroreflex and chemoreflex, and the exercise pressure reflex. The regulation and integration of these reflexes operating during dynamic exercise and their possible role in the pathophysiology of some cardiovascular diseases are also discussed. PMID- 24818145 TI - Quantitative diagnosis of colorectal polyps by spectral domain optical coherence tomography. AB - The principal aim of this study is to investigate the scattering coefficient of colorectal polyp tissues using an optical coherence tomography (OCT) technique. It combines the existing scattering coefficient model and spectral domain OCT to achieve method of early diagnosis of colorectal polyp in hospitals. Seventeen patients were studied, and a total of 1456 data points were extracted by curve fitting the OCT signals into a confocal single-backscattering model. The results show that the mean scattering coefficient value for colorectal polyps is 1.91 mm( 1) (std: +/- 0.54 mm(-1)), which is between the values for normal and malignant tissues. In addition, we studied the difference between adenomatous polyps (n = 15) and inflammatory polyps (n = 2) quantitatively and found that the adenomatous tissues had lower scattering coefficients than the inflammatory ones. The quantitative measurements confirmed that OCT can be used in primary diagnosis to compensate for the deficiencies in methods of pathological diagnosis, with a great potential for early diagnosis of tissues. PMID- 24818146 TI - Potential therapeutic effects of neurotrophins for acute and chronic neurological diseases. AB - The neurotrophins (NTs) nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5 are proteins that regulate cell proliferation, differentiation, and survival in both the developing and mature central nervous system (CNS) by binding to two receptor classes, Trk receptors and p75 NTR. Motivated by the broad growth- and survival-promoting effects of these proteins, numerous studies have attempted to use exogenous NTs to prevent the death of cells that are associated with neurological disease or promote the regeneration of severed axons caused by mechanical injury. Indeed, such neurotrophic effects have been repeatedly demonstrated in animal models of stroke, nerve injury, and neurodegenerative disease. However, limitations, including the short biological half-lives and poor blood-brain permeability of these proteins, prevent routine application from treating human disease. In this report, we reviewed evidence for the neuroprotective efficacy of NTs in animal models, highlighting outstanding technical challenges and discussing more recent attempts to harness the neuroprotective capacity of endogenous NTs using small molecule inducers and cell transplantation. PMID- 24818147 TI - Effect of Toona microcarpa Harms leaf extract on the coagulation system. AB - Toona microcarpa Harms is a tonic, antiperiodic, antirheumatic, and antithrombotic agent in China and India and an astringent and tonic for treating diarrhea, dysentery, and other intestinal infections in Indonesia. In this study, we prepared ethyl-acetate extract from the air-dried leaves of Toona microcarpa Harms and investigated the anticoagulant activities in vitro by performing activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) assays. Antiplatelet aggregation activity of the extract was examined using adenosine diphosphate (ADP), collagen, and thrombin as agonists, and the inhibitions of factor Xa and thrombin were also investigated. Bleeding and clotting times in mice were used to determine its anticoagulant activities in vivo. It is found that Toona microcarpa Harms leaf extract (TMHE) prolonged APTT, PT, and TT clotting times in a dose-dependent manner and significantly inhibited platelet aggregation induced by thrombin, but not ADP or collagen. Clotting time and bleeding time assays showed that TMHE significantly prolonged clotting and bleeding times in vivo. In addition, at the concentration of 1 mg/mL, TMHE inhibited human thrombin activity by 73.98 +/- 2.78%. This is the first report to demonstrate that THME exhibits potent anticoagulant effects, possibly via inhibition of thrombin activity. PMID- 24818148 TI - Apoptotic and inhibitory effects on cell proliferation of hepatocellular carcinoma HepG2 cells by methanol leaf extract of Costus speciosus. AB - Costus speciosus is a medicinal plant commonly known as wild ginger distributed in South and Southeast Asian countries. Leaves of this plant are used for ayurvedic treatment regimes in malignancies and mental illness. Rhizome extract from the plant is used to treat malignancies, pneumonia, urinary disorders, jaundice, rheumatism, and diabetes. The goal of this study was to investigate the effects of methanol extract of leaves of C. speciosus on the growth of human hepatocellular carcinoma (HepG2) cells and understand possible mechanisms of its action. Viability of HepG2 cells were measured by MTS assay after 24 h and 48 h treatment with extracts of 1, 10, 50, 100, and 200 MUg/mL concentrations. Cell cycle analysis and apoptosis were evaluated by flow cytometry and caspase-3 induction. HepG2 cells treated with 100 MUg/mL methanol leaf extract for 24 h displayed a significant reduction in cell viability (P <= 0.05). The methanol extract perturbed cell cycle progression, modulated cell cycle and regulated, signal molecules were involved in induction of apoptosis in HepG2 cells. Our findings indicate that phytochemicals of leaves of C. speciosus shows potential for natural therapeutic product development for hepatocellular carcinoma. This is the first report to demonstrate in vitro anticancer activity of leaf extract of C. speciosus in relation to liver cancer. PMID- 24818149 TI - Pomegranate fruit as a rich source of biologically active compounds. AB - Pomegranate is a widely used plant having medicinal properties. In this review, we have mainly focused on the already published data from our laboratory pertaining to the effect of methanol extract of pericarp of pomegranate (PME) and have compared it with other relevant literatures on Punica. Earlier, we had shown its antiproliferative effect using human breast (MCF-7, MDA MB-231), and endometrial (HEC-1A), cervical (SiHa, HeLa), and ovarian (SKOV3) cancer cell lines, and normal breast fibroblasts (MCF-10A) at concentration of 20-320 MUg/mL. The expressions of selected estrogen responsive genes (PR, pS2, and C-Myc) were downregulated by PME. Unlike estradiol, PME did not increase the uterine weight and proliferation in bilaterally ovariectomized Swiss-Albino mice models and its cardioprotective effects were comparable to that of 17 beta -estradiol. We had further assessed the protective role of PME on skeletal system, using MC3T3-E1 cells. The results indicated that PME (80 MUg/mL) significantly increased ALP (Alkaline Phosphatase) activity, supporting its suggested role in modulating osteoblastic cell differentiation. The antiosteoporotic potential of PME was also evaluated in ovariectomized (OVX) rodent model. The results from our studies and from various other studies support the fact that pomegranate fruit is indeed a source of biologically active compounds. PMID- 24818150 TI - Progesterone and mental rotation task: is there any effect? AB - Mental rotation task (MRT) incorporates elements of spatial abilities, important in many professions, with people of both genders involved. Importantly, these are the areas where spatial tasks might be performed for long time periods; thus adverse effects of mental fatigue are highly unwanted. Substantial variation of MRT performance in relation to estrogen levels has been observed in many studies, whereas the role of progesterone remains elusive. Here we aimed to elucidate the effect of progesterone level on the long-duration (1.5 hours) performance of MRT. We included three groups of subjects: a group of males as a control, a group of females in their follicular phase (low progesterone) and a group of females in their luteal phase (high progesterone), MRT accuracy and response time, subjective fatigue ratings and cardiovascular measures together with 17 beta estradiol and progesterone concentrations were analyzed. We found that subjective ratings of fatigue increased, performance accuracy increased, and mean response times decreased during the task in all groups. Females in luteal phase were significantly slower not only than men, but also than females in their follicular phase. An increase in subjective fatigue ratings was positively related to progesterone level-at higher progesterone levels, females felt more tired. PMID- 24818151 TI - Distinct characteristics of mandibular bone collagen relative to long bone collagen: relevance to clinical dentistry. AB - Bone undergoes constant remodeling throughout life. The cellular and biochemical mechanisms of bone remodeling vary in a region-specific manner. There are a number of notable differences between the mandible and long bones, including developmental origin, osteogenic potential of mesenchymal stem cells, and the rate of bone turnover. Collagen, the most abundant matrix protein in bone, is responsible for determining the relative strength of particular bones. Posttranslational modifications of collagen, such as intermolecular crosslinking and lysine hydroxylation, are the most essential determinants of bone strength, although the amount of collagen is also important. In comparison to long bones, the mandible has greater collagen content, a lower amount of mature crosslinks, and a lower extent of lysine hydroxylation. The great abundance of immature crosslinks in mandibular collagen suggests that there is a lower rate of cross link maturation. This means that mandibular collagen is relatively immature and thus more readily undergoes degradation and turnover. The greater rate of remodeling in mandibular collagen likely renders more flexibility to the bone and leaves it more suited to constant exercise. As reviewed here, it is important in clinical dentistry to understand the distinctive features of the bones of the jaw. PMID- 24818152 TI - The antihyperglycemic effects of Rhizoma Coptidis and mechanism of actions: a review of systematic reviews and pharmacological research. AB - Rhizoma Coptidis (Huang Lian in Chinese pinyin) is among the most widely used traditional Chinese herbal medicines and has a profound history of more than 2000 years of being used as a therapeutic herb. The antidiabetic effects of Rhizoma Coptidis have been extensively investigated in animal experiments and clinical trials and its efficacy as a promising antihyperglycemic agent has been widely discussed. In the meantime, findings from modern pharmacological studies have contributed the majority of its bioactivities to berberine, the isoquinoline alkaloids component of the herb, and a number of experiments testing the antidiabetic effects of berberine have been initiated. Therefore, we conducted a review of the current evidence profile of the antihyperglycemic effects of Rhizoma Coptidis as well as its main component berberine and the possible mechanism of actions, in order to summarize research evidence in this area and identify future research directions. PMID- 24818153 TI - Rapid degradation of Hfq-free RyhB in Yersinia pestis by PNPase independent of putative ribonucleolytic complexes. AB - The RNA chaperone Hfq in bacteria stabilizes sRNAs by protecting them from the attack of ribonucleases. Upon release from Hfq, sRNAs are preferably degraded by PNPase. PNPase usually forms multienzyme ribonucleolytic complexes with endoribonuclease E and/or RNA helicase RhlB to facilitate the degradation of the structured RNA. However, whether PNPase activity on Hfq-free sRNAs is associated with the assembly of RNase E or RhlB has yet to be determined. Here we examined the roles of the main endoribonucleases, exoribonucleases, and ancillary RNA modifying enzymes in the degradation of Y. pestis RyhB in the absence of Hfq. Expectedly, the transcript levels of both RyhB1 and RyhB2 increase only after inactivating PNPase, which confirms the importance of PNPase in sRNA degradation. By contrast, the signal of RyhB becomes barely perceptible after inactivating of RNase III, which may be explained by the increase in PNPase levels resulting from the exemption of pnp mRNA from RNase III processing. No significant changes are observed in RyhB stability after deletion of either the PNPase-binding domain of RNase E or rhlB. Therefore, PNPase acts as a major enzyme of RyhB degradation independent of PNPase-containing RNase E and RhlB assembly in the absence of Hfq. PMID- 24818155 TI - Reproducibility of the optical Biometer OA-1000 (Tomey). AB - AIM: The OA-1000 (Tomey, Japan) is a new optical biometer, which measures axial length (AL), anterior chamber depth (ACD), and central corneal thickness (CT) utilizing optical interference technology. The aim of this study was to prove the reproducibility which is considered fundamental for other clinical investigations. METHODS: 55 healthy volunteers were enrolled in this study. For each measurement of AL, ACD, and CT the biometer is grabbing a sequence of 10 shots and mean value (mean) and standard deviation (SD) are displayed. Five consecutive measurements were performed and average and standard deviation were assessed. Cronbach's alpha was derived as a quality measure for reproducibility. RESULTS: For AL measurement Cronbach's alpha was 1.000, for CT 0.999, and for ACD 0.979, respectively. Mean value for AL was 23.36 +/- 1.03 mm, for ACD it was 3.60 +/- 0.687 mm, and for CT it was 552.08 +/- 29.70 MUm, respectively. Standard deviation for AL was 0.013 +/- 0.022 mm, for ACD 0.09 +/- 0.11 mm, and for CT 2.18 +/- 1.75 MUm. One correlation was found between mean values for AL and ACD (R = 0.388, P = 0.005); no other correlations were found between mean values or values of standard deviation of AL, ACD, or CT. CONCLUSION: The OA-1000 shows an excellent reproducibility for measurement of AL, ACD, and CT and can be used in clinical practice. PMID- 24818154 TI - Impact of clipping versus coiling on postoperative hemodynamics and pulmonary edema after subarachnoid hemorrhage. AB - Volume management is critical for assessment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This multicenter prospective cohort study compared the impact of surgical clipping versus endovascular coiling on postoperative hemodynamics and pulmonary edema in patients with SAH. Hemodynamic parameters were measured for 14 days using a transpulmonary thermodilution system. The study included 202 patients, including 160 who underwent clipping and 42 who underwent coiling. There were no differences in global ejection fraction (GEF), cardiac index, systemic vascular resistance index, or global end-diastolic volume index between the clipping and coiling groups in the early period. However, extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were significantly higher in the clipping group in the vasospasm period. Postoperative C-reactive protein (CRP) level was higher in the clipping group and was significantly correlated with postoperative brain natriuretic peptide level. Multivariate analysis found that PVPI and GEF were independently associated with high EVLWI in the early period, suggesting cardiogenic edema, and that CRP and PVPI, but not GEF, were independently associated with high EVLWI in the vasospasm period, suggesting noncardiogenic edema. In conclusion, clipping affects postoperative CRP level and may thereby increase noncardiogenic pulmonary edema in the vasospasm period. His trial is registered with University Hospital Medical Information Network UMIN000003794. PMID- 24818156 TI - D-glucosamine conjugation accelerates the labeling efficiency of quantum dots in osteoblastic cells. AB - Quantum dots (QDs) are useful imaging tools in the medical and biological fields due to their optical properties, such as a high fluorescence intensity, remarkable resistance to photobleaching, broad absorption spectra, and narrow emission spectra. This is the first study to investigate the uptake of carboxylated QDs conjugated with D-glucosamine (core size: approximately 3 nm, final modified size: 20-30 nm) into cultured osteoblastic cells. The QDs attached to the cell surface and were transported into the cytoplasm within approximately three hours of culture, whose process was clearly demonstrated using specific fluorescent staining of the cell membrane. Although the intranuclear distribution was not observed, a dramatic decrease in the transfer of quantum dots into the cytoplasm was recognized after approximately seven days of culture. Other interesting phenomena include the escape of the quantum dots from lysosomes in the cytoplasm, as confirmed by the merging of both QD fluorescence and specific fluorescent staining of lysosomes in the cytoplasm. These findings suggest that D glucosamine conjugation enhances proton absorption in acid organelles and promotes the lysosomal escape of QDs. PMID- 24818157 TI - Generation of insulin-producing cells from human bone marrow-derived mesenchymal stem cells: comparison of three differentiation protocols. AB - INTRODUCTION: Many protocols were utilized for directed differentiation of mesenchymal stem cells (MSCs) to form insulin-producing cells (IPCs). We compared the relative efficiency of three differentiation protocols. METHODS: Human bone marrow-derived MSCs (HBM-MSCs) were obtained from three insulin-dependent type 2 diabetic patients. Differentiation into IPCs was carried out by three protocols: conophylline-based (one-step protocol), trichostatin-A-based (two-step protocol), and beta -mercaptoethanol-based (three-step protocol). At the end of differentiation, cells were evaluated by immunolabeling for insulin production, expression of pancreatic endocrine genes, and release of insulin and c-peptide in response to increasing glucose concentrations. RESULTS: By immunolabeling, the proportion of generated IPCs was modest ( ? 3%) in all the three protocols. All relevant pancreatic endocrine genes, insulin, glucagon, and somatostatin, were expressed. There was a stepwise increase in insulin and c-peptide release in response to glucose challenge, but the released amounts were low when compared with those of pancreatic islets. CONCLUSION: The yield of functional IPCs following directed differentiation of HBM-MSCs was modest and was comparable among the three tested protocols. Protocols for directed differentiation of MSCs need further optimization in order to be clinically meaningful. To this end, addition of an extracellular matrix and/or a suitable template should be attempted. PMID- 24818158 TI - Outer electrospun polycaprolactone shell induces massive foreign body reaction and impairs axonal regeneration through 3D multichannel chitosan nerve guides. AB - We report on the performance of composite nerve grafts with an inner 3D multichannel porous chitosan core and an outer electrospun polycaprolactone shell. The inner chitosan core provided multiple guidance channels for regrowing axons. To analyze the in vivo properties of the bare chitosan cores, we separately implanted them into an epineural sheath. The effects of both graft types on structural and functional regeneration across a 10 mm rat sciatic nerve gap were compared to autologous nerve transplantation (ANT). The mechanical biomaterial properties and the immunological impact of the grafts were assessed with histological techniques before and after transplantation in vivo. Furthermore during a 13-week examination period functional tests and electrophysiological recordings were performed and supplemented by nerve morphometry. The sheathing of the chitosan core with a polycaprolactone shell induced massive foreign body reaction and impairment of nerve regeneration. Although the isolated novel chitosan core did allow regeneration of axons in a similar size distribution as the ANT, the ANT was superior in terms of functional regeneration. We conclude that an outer polycaprolactone shell should not be used for the purpose of bioartificial nerve grafting, while 3D multichannel porous chitosan cores could be candidate scaffolds for structured nerve grafts. PMID- 24818159 TI - Determinants of disability in multiple sclerosis: an immunological and MRI study. AB - Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity. PMID- 24818160 TI - Distinct action of flavonoids, myricetin and quercetin, on epithelial Cl- secretion: useful tools as regulators of Cl- secretion. AB - Epithelial Cl(-) secretion plays important roles in water secretion preventing bacterial/viral infection and regulation of body fluid. We previously suggested that quercetin would be a useful compound for maintaining epithelial Cl(-) secretion at a moderate level irrespective of cAMP-induced stimulation. However, we need a compound that stimulates epithelial Cl(-) secretion even under cAMP stimulated conditions, since in some cases epithelial Cl(-) secretion is not large enough even under cAMP-stimulated conditions. We demonstrated that quercetin and myricetin, flavonoids, stimulated epithelial Cl(-) secretion under basal conditions in epithelial A6 cells. We used forskolin, which activates adenylyl cyclase increasing cytosolic cAMP concentrations, to study the effects of quercetin and myricetin on cAMP-stimulated epithelial Cl(-) secretion. In the presence of forskolin, quercetin diminished epithelial Cl(-) secretion to a level similar to that with quercetin alone without forskolin. Conversely, myricetin further stimulated epithelial Cl(-) secretion even under forskolin-stimulated conditions. This suggests that the action of myricetin is via a cAMP-independent pathway. Therefore, myricetin may be a potentially useful compound to increase epithelial Cl(-) secretion under cAMP-stimulated conditions. In conclusion, myricetin would be a useful compound for prevention from bacterial/viral infection even under conditions that the amount of water secretion driven by cAMP stimulated epithelial Cl(-) secretion is insufficient. PMID- 24818161 TI - Clinical and structural features of sperm head vacuoles in men included in the in vitro fertilization programme. AB - The human sperm head vacuoles and their role in male infertility are still poorly understood. The aim of this study was to identify the clinical and ultrastructural features of human sperm head vacuoles in men included in the in vitro fertilization programme: men with normal (normozoospermia) and impaired sperm morphology (teratozoospermia). The sperm samples were observed under 6000 time magnification using motile sperm organelle morphology examination (MSOME). The proportion of sperm with head vacuoles was evaluated and related to the outcome of in vitro fertilization. The sperm of men with impaired sperm morphology was characterized by a higher proportion of sperm head vacuoles. The sperm head vacuoles were related to impaired semen quality (sperm concentration, motility, and morphology) but were not influenced by male factors (semen volume, height, age, weight, or body mass index). Moreover, sperm head vacuoles were related to impaired fertilization rate merely after classical in vitro fertilization (IVF), while there was no relation to pregnancy. In a subgroup of men, the sperm was fixed and observed by transmission electron microscopy (TEM). The ultrastructural study revealed that sperm head vacuoles are large nuclear indentations of various sizes and positions, packed with membranous material organized in membrane whorls (MW). PMID- 24818162 TI - Arrabidaea chica hexanic extract induces mitochondrion damage and peptidase inhibition on Leishmania spp. AB - Currently available leishmaniasis treatments are limited due to severe side effects. Arrabidaea chica is a medicinal plant used in Brazil against several diseases. In this study, we investigated the effects of 5 fractions obtained from the crude hexanic extract of A. chica against Leishmania amazonensis and L. infantum, as well as on the interaction of these parasites with host cells. Promastigotes were treated with several concentrations of the fractions obtained from A. chica for determination of their minimum inhibitory concentration (MIC). In addition, the effect of the most active fraction (B2) on parasite's ultrastructure was analyzed by transmission electron microscopy. To evaluate the inhibitory activity of B2 fraction on Leishmania peptidases, parasites lysates were treated with the inhibitory and subinhibitory concentrations of the B2 fraction. The minimum inhibitory concentration of B2 fraction was 37.2 and 18.6 MUg/mL for L. amazonensis and L. infantum, respectively. Important ultrastructural alterations as mitochondrial swelling with loss of matrix content and the presence of vesicles inside this organelle were observed in treated parasites. Moreover, B2 fraction was able to completely inhibit the peptidase activity of promastigotes at pH 5.5. The results presented here further support the use of A. chica as an interesting source of antileishmanial agents. PMID- 24818163 TI - Lipoprotein-associated phospholipase A2 mass level is increased in elderly subjects with type 2 diabetes mellitus. AB - OBJECTIVE. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is extensively expressed by advanced atherosclerotic lesions and may play a role in plaque instability. We selected a group of elderly subjects that underwent transcatheter aortic valve implantation (TAVI) or balloon angioplasty (BA) and separated them into two groups, diabetic and nondiabetic, to compare the level of Lp-PLA2 mass between them. METHODS. 44 patients aged 79.6 +/- 5.6 years with symptomatic severe aortic valve stenosis underwent TAVI (n = 35) or BA (n = 9). 21 subjects had confirmed type 2 diabetes mellitus. Lp-PLA2 mass was measured using an enzyme linked immunosorbent assay kit (USCN Life Science, China) before and 3 days after the procedure. RESULTS. Lp-PLA2 mass was significantly elevated in this population (1296 +/- 358 ng/mL before TAVI; 1413 +/- 268 ng/mL before BA) and further increased after TAVI (1604 +/- 437 ng/mL, P < 0.01) or BA (1808 +/- 303 ng/mL, P < 0.01). Lp-PLA2 mass was significantly increased on the diabetic group before these interventions. CONCLUSION. Lp-PLA2 may be a novel biomarker for the presence of rupture-prone atherosclerotic lesions in elderly patients. Levels of Lp-PLA2 in diabetic patients may accompany the higher amount of small dense LDL particles seen in these subjects. PMID- 24818165 TI - Evaluation of serum fibrinogen, plasminogen, alpha2-anti-plasmin, and plasminogen activator inhibitor levels (PAI) and their correlation with presence of retinopathy in patients with type 1 DM. AB - BACKGROUND. Diabetic retinopathy (DR) is the leading cause of blindness in the world. Retinopathy can still progress despite optimal metabolic control. The aim of the study was to determine whether different degrees of DR (proliferative or nonproliferative) were associated with abnormally modulated hemostatic parameters in patients with T1DM. METHOD. 52 T1DM patients and 40 healthy controls were enrolled in the study. Patients were subdivided into three categories. Group I was defined as those without retinopathy, group II with NPRP, and group III with PRP. We compared these subgroups with each other and the control group (Group IV) according to the serum fibrinogen, plasminogen, alpha2-anti-plasmin ( alpha2-anti plasmin), and PAI. RESULTS. We detected that PAI-1, serum fibrinogen, and plasminogen levels were similar between the diabetic and control groups (P = 0.209, P = 0.224, and P = 0.244, resp.), whereas alpha2-anti-plasmin was higher in Groups I, II, and III compared to the control group (P < 0.01, P < 0.05, and P < 0.001, resp.). There was a positive correlation between serum alpha2-anti plasmin and HbA1c levels (r = 0,268, P = 0.031). CONCLUSION. To our knowledge there is scarce data in the literature about alpha2-anti-plasmin levels in type 1 diabetes. A positive correlation between alpha2-anti-plasmin with HbA1c suggests that fibrinolytic markers may improve with disease regulation and better glycemic control. PMID- 24818164 TI - Management of cardiorenal metabolic syndrome in diabetes mellitus: a phytotherapeutic perspective. AB - Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS. PMID- 24818166 TI - The role of PAM4 in the management of pancreatic cancer: diagnosis, radioimmunodetection, and radioimmunotherapy. AB - PAM4, a new monoclonal antibody (MAb) known as clivatuzumab, is highly reactive with pancreatic cancer and precursor lesions. It is absent from the normal tissues and has limited reactivity with nonpancreatic cancer. The detailed characteristic of the PAM4 epitope is unknown but recent studies have shown that it is dependent on MUC1 glycosylation status. The limited PAM4 expression pattern makes it an attractive candidate for management of pancreatic adenocarcinoma. In addition, PAM4 is a serum biomarker for diagnosis of pancreatic cancer. Several different radiolabeled immunodiagnostic and immunotherapeutic agents of PAM4 have been developed and some are being evaluated in preclinical and/or clinical studies. The review will focus on PAM4 and its potential utility for the diagnosis, radioimmunodetection, and radioimmunotherapy of pancreatic cancer. PMID- 24818167 TI - Renal transplantation dramatically reduces IgA anti-beta-2-glycoprotein I antibodies in patients with endstage renal disease. AB - IgA anti-beta-2-glycoprotein I (aB2GPI) antibodies have been related to vascular pathology in the general population and mainly in hemodialyzed patients (prevalence 33%) in whom an elevated incidence of thrombosis and mortality is found. In this paper we have studied the presence of IgA aB2GPI antibodies at pretransplant and their evolution after transplantation with a cross-sectional based follow-up study of a cohort of 288 endstage renal disease (ESRD) patients treated with kidney transplantation. Pretransplant IgA aB2GPI levels were elevated 31.7 +/- 4.2 U/mL without differences in age or type of dialysis. Patients with different etiologies of ESRD showed higher levels of IgA aB2GPI than blood donors, except the groups of non-IgA glomerular disease and systemic erythematosus lupus, whose nonsignificant differences were observed. IgA aB2GPI antibodies dropped immediately after transplantation (10.7 +/- 1.0 U/mL, P < 0.0001), coinciding with a high degree of immunosuppression, and remained significantly lower than that observed in pretransplant status. Prevalence of patients with elevated antibodies was also less in transplanted patients (8.9% versus 30.4%, P < 0.0001). Among, positivity for IgA aB2GPI was higher than in patients who had received their first transplant that those were retransplanted. This finding could have important clinical implications and can suggest new therapeutic strategies in patients with IgA aB2GPI antibodies. PMID- 24818170 TI - Daytime Sleepiness, Circadian Preference, Caffeine Consumption and Khat Use among College Students in Ethiopia. AB - OBJECTIVES: To estimate the prevalence of daytime sleepiness and circadian preferences, and to examine the extent to which caffeine consumption and Khat (a herbal stimulant) use are associated with daytime sleepiness and evening chronotype among Ethiopian college students. METHODS: A cross-sectional study was conducted among 2,410 college students. A self-administered questionnaire was used to collect information about sleep, behavioral risk factors such as caffeinated beverages, tobacco, alcohol, and Khat consumption. Daytime sleepiness and chronotype were assessed using the Epworth Sleepiness Scale (ESS) and the Horne & Ostberg Morningness /Eveningness Questionnaire (MEQ), respectively. Linear and logistic regression models were used to evaluate associations. RESULTS: Daytime sleepiness (ESS>=10) was present in 26% of the students (95% CI: 24.4-27.8%) with 25.9% in males and 25.5% in females. A total of 30 (0.8%) students were classified as evening chronotypes (0.7% in females and 0.9% in males). Overall, Overall, Khat consumption, excessive alcohol use and cigarette smoking status were associated with evening chronotype. Use of any caffeinated beverages (OR=2.18; 95%CI: 0.82-5.77) and Khat consumption (OR=7.43; 95%CI: 3.28 16.98) increased the odds of evening chronotype. CONCLUSION: The prevalence of daytime sleepiness among our study population was high while few were classified as evening chronotypes. We also found increased odds of evening chronotype with caffeine consumption and Khat use amongst Ethiopian college students. Prospective cohort studies that examine the effects of caffeinated beverages and Khat use on sleep disorders among young adults are needed. PMID- 24818169 TI - Targeted inhibition of mTOR signaling improves sensitivity of esophageal squamous cell carcinoma cells to cisplatin. AB - mTOR is an evolutionarily conserved serine-threonine kinase with a central role in cell growth, invasion, and metastasis of tumors, and is activated in many cancers. The aims of this study were to investigate the expression of mTOR in ESCC tissues and its relationship with progression of ESCC and measure the changes of sensitivity of ESCC cells to cisplatin after cells were treated with mTOR siRNA by WST-8 assays, TUNEL, RT-PCR, and western blots in vitro and in vivo. The results showed that the expression of mTOR was higher in ESCC specimens than that in normal esophageal tissues and its expression was closely correlated with the TNM stage of ESCC. mTOR siRNA significantly increased the sensitivity of the EC9706 cells to cisplatin at proliferation in vitro and in vivo. The growth of ESCC xenografts was significantly inhibited by mTOR siRNA or cisplatin, and the cell number of apoptosis was obviously increased after xenografts were treated with mTOR siRNA or cisplatin alone, especially when mTOR siRNA combined with cisplatin. The present study demonstrates that the expression of mTOR has important clinical significance and inhibition of mTOR pathway by mTOR siRNA can improve the sensitivity of ESCC cells to cisplatin. PMID- 24818171 TI - Evaluation of Genomic Evidence for Oxidative Stress in Experimental Radiation Nephropathy. AB - BACKGROUND: Chronic persistent oxidative stress has been proposed as a mechanism for late radiation injury to normal tissue. Using biochemical, histological, and pharmacological techniques, we have not been able to confirm this hypothesis for late renal radiation injury. Gene expression may be more revealing, especially since the initial effects of radiation are to damage DNA. METHODS: Gene array studies were done using kidney tissue from irradiated rats, with particular attention to genes pertinent to oxidative stress. The time points were from 1 to 49 days after irradiation. Cellular RNA and mitochondrial DNA were isolated, for gene expression analysis and common deletion testing, respectively. RESULTS: For the gene expression studies, and from over 30,000 transcripts, only nine related to oxidative stress had 1.4 fold or greater changes in expression. Mitochondrial DNA showed no changes in the common deletion. CONCLUSION: These studies do not support the hypothesis of chronic oxidative stress as a mechanism for radiation nephropathy. PMID- 24818168 TI - Some basic aspects of HLA-G biology. AB - Human leukocyte antigen-G (HLA-G) is a low polymorphic nonclassical HLA-I molecule restrictively expressed and with suppressive functions. HLA-G gene products are quite complex, with seven HLA-G isoforms, four membrane bound, and other three soluble isoforms that can suffer different posttranslational modifications or even complex formations. In addition, HLA-G has been described included in exosomes. In this review we will focus on HLA-G biochemistry with special emphasis to the mechanisms that regulate its expression and how the protein modifications affect the quantification in biological fluids. PMID- 24818174 TI - White matter structure assessment from reduced HARDI data using low-rank polynomial approximations. AB - Assessing white matter fiber orientations directly from DWI measurements in single-shell HARDI has many advantages. One of these advantages is the ability to model multiple fibers using fewer parameters than are required to describe an ODF and, thus, reduce the number of DW samples needed for the reconstruction. However, fitting a model directly to the data using Gaussian mixture, for instance, is known as an initialization-dependent unstable process. This paper presents a novel direct fitting technique for single-shell HARDI that enjoys the advantages of direct fitting without sacrificing the accuracy and stability even when the number of gradient directions is relatively low. This technique is based on a spherical deconvolution technique and decomposition of a homogeneous polynomial into a sum of powers of linear forms, known as a symmetric tensor decomposition. The fiber-ODF (fODF), which is described by a homogeneous polynomial, is approximated here by a discrete sum of even-order linear-forms that are directly related to rank-1 tensors and represent single-fibers. This polynomial approximation is convolved to a single-fiber response function, and the result is optimized against the DWI measurements to assess the fiber orientations and the volume fractions directly. This formulation is accompanied by a robust iterative alternating numerical scheme which is based on the Levenberg-Marquardt technique. Using simulated data and in vivo, human brain data we show that the proposed algorithm is stable, accurate and can model complex fiber structures using only 12 gradient directions. PMID- 24818172 TI - Coupling Mass Spectrometry-Based "Omic" Sciences with Bioguided Processing to Unravel Milk's Hidden Bioactivities. AB - Many of milk's functional molecules could not be discovered until the right concordance of novel separation and analytical technologies were developed and applied. Many health-promoting components still await discovery due to technical challenges in their identification, isolation and testing. As new analytical technologies are assembled, new functional milk molecules will be discovered. Bovine milk is a source of a wide array of known bioactive compounds from a variety of molecular classes, including free glycans, lipids, glycolipids, peptides, proteins, glycoproteins, stem cells and microRNA. Because milk is such a complex mixture, when analyzed without fractionation or purification, many components mask the analytical signal of others, so some components cannot be detected. Modern analytics allow for the discovery and characterization of hundreds of novel milk compounds with high-resolution and high-accuracy. Liquid chromatography paired with electrospray ionization allows the separation of peptides, glycans and glycolipids for improved mass spectrometric detection. Target proteins and glycoproteins can now be purified from intact milk or other dairy streams by chromatography in order to better characterize these proteins for new bioactivities. The combination of advanced analytics with the new engineering capabilities will allow for high molecular resolution and separation techniques that can be scaled-up to semi-industrial and industrial scale for translation of lab-based discoveries. Bioguided analysis and design of dairy processing side streams will result in the transformation of waste into isolated functional ingredients to add value to dietary products. PMID- 24818173 TI - Challenges in the Treatment of Triple Negative and HER2-Overexpressing Breast Cancer. AB - While the 5-year survival rate of breast cancer is at an all-time high of 90%, this disease remains the second most common cause of cancer-related death, surpassed only by lung cancer in the US. The reasons for this discrepancy stem from cancer subtypes which become resistant to current therapies. These subtypes: "Triple negative" and ErbB2-overexpressing, are discussed in this review. PMID- 24818175 TI - Field therapy in the treatment of actinic keratosis. PMID- 24818176 TI - Is the Sunshine Act worthy of concern? PMID- 24818177 TI - Cutaneous manifestations of injectable drug use: hidden secrets. AB - Abscesses related to drug use are the most common cutaneous manifestations among injection drug users, often occurring when the veins become less accessible. In these cases, other techniques may be used to administer drugs, such as skin popping (subcutaneous injection) or muscle popping (intramuscular injection). The main risk factors for abscess formation include skin popping, use of unsterilized needles, and injection of speedball (a mixture of cocaine and heroin). We present a case of recurrent abscesses accompanied by fever, hypersomnia alternating with insomnia, diaphoresis, fatigue, recent weight loss, and agitation following subcutaneous injection of a tramadol, opipramol, and clonazepam mixture. Differential diagnoses included pyoderma gangrenosum on the basis of hepatitis C virus, skin lesions connected with human immunodeficiency virus infection, vasculitis, endocarditis, and serotonin syndrome. The patient was treated with oral antibiotics, surgical incision, and drainage of the abscesses, with consequent improvement. PMID- 24818178 TI - Pulsed dye laser for the treatment of macular amyloidosis: a case report. AB - Macular amyloidosis causes an eruption of brown pigment in the skin when keratin is altered. The resulting hyperpigmentation, which often leads to patient distress, generally has unsatisfactory treatment options. Among the treatment modalities that have been used for amyloidosis, the pulsed dye laser (PDL) has shown success in the treatment of nodular amyloidosis, and the Q-switched Nd:YAG laser has reduced the appearance of amyloid plaques in macular amyloidosis. We investigated the effects of repeated PDL treatments in a 57-year-old man with recalcitrant macular amyloidosis. The patient was treated with 3 treatment sessions of PDL at 2-week intervals. Based on patient self-assessment and our own photographic analysis, improvement of the lesions was noted with each treatment. Macular amyloidosis can be successfully treated using the PDL, which decreases amyloid aggregation and skin hyperpigmentation. This effect from a decrease in collagen and dermatan sulfate synthesis is similar to the mechanism behind the reduction of size of hypertrophic scars using PDL. PMID- 24818180 TI - Familial confluent and reticulate papillomatosis successfully treated with minocycline. AB - Confluent and reticulate papillomatosis (CRP) is an idiopathic disorder characterized by persistent patches and plaques that are centrally confluent and peripherally reticulate. Although CRP primarily occurs sporadically, there may be a familial predisposition to the development of CRP. Minocycline has been reported as effective in the treatment of CRP, seemingly due to its antimicrobial and anti-inflammatory activity. We describe a case of familial CRP involving 2 brothers who were successfully treated with minocycline. PMID- 24818179 TI - Palmoplantar keratoderma with progressive gingivitis and recurrent pyodermas. AB - Papillon-Lefevre syndrome (PLS) is a rare inherited palmoplantar keratoderma (PPK) that is associated with progressive gingivitis and recurrent pyodermas. We present a case exhibiting classic features of this autosomal-recessive condition and review the current understanding of its pathophysiology, diagnosis, and treatment. Additionally, a review of pertinent transgredient PPKs is undertaken, with key and distinguishing features of each syndrome highlighted. PMID- 24818181 TI - Primary cutaneous Candida tropicalis infection in a patient with B-cell lymphoma. AB - We report the case of a 61-year-old man with diffuse large B-cell lymphoma who presented with a tender skin lesion on the left side of the flank of 5 weeks' duration after undergoing myeloablative chemotherapy. Prior treatment with intravenous vancomycin showed minimal response. Clinical examination revealed a tender, indurated, erythematous plaque on the left side of the flank. A skin biopsy demonstrated a lymphohistiocytic and neutrophilic infiltrate with deep dermal necrosis and fungal forms in the dermis and subcutis. A tissue culture grew Candida tropicalis; however, blood cultures remained negative for yeast. A diagnosis of primary cutaneous candidiasis was made based on the lack of response to antibiotics, tissue evidence of C tropicalis, and negative blood cultures. Although rare, primary cutaneous candidiasis should be considered in immunocompromised patients presenting with cellulitis or an abscess that is unresponsive to treatment. PMID- 24818182 TI - A cohort study on a ceramide-containing cleanser and moisturizer used for atopic dermatitis. AB - Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder. In this cohort study, we evaluated the effectiveness of a twice-daily regimen of a ceramide-containing cleanser and moisturizer in men, women, and children with AD (N=151). The treatment period was 6 weeks. Participants were evaluated at baseline (day 0) and at the end of treatment (day 42) using clinical photographs, the SCORAD (SCORing of Atopic Dermatitis) index, and quality of life (QOL) assessment. Participants were randomly selected and were allocated to 1 of 2 groups: group 1 with participants 12 years and older (n=118) and group 2 with participants younger than 12 years (n=33). At day 42, SCORAD scores for group 1 showed significant improvement (t115=18.33, P=.0001). Skin condition in group 2 was evaluated by the participants' guardians. At day 42, SCORAD scores for group 2 showed significant improvement (t27=5.38, P=.0001). Sim-ilar effects were observed for itching, with scores that improved from very itchy to itching only when the skin was wet (t27=5.38, P=.0001). No adverse events were reported during the 6-week evaluation period. The study results indicate that the ceramide containing cleanser and moisturizer regimen substantially improved skin condition and clinical outcomes related to AD severity as well as QOL aspects. PMID- 24818183 TI - Giant cell tumor of the tendon sheath. PMID- 24818184 TI - What is your diagnosis? subacute cutaneous lupus erythematosus. PMID- 24818185 TI - Indurated thigh plaque with associated lymphadenopathy. PMID- 24818186 TI - Osteomyelitis in association with pyoderma gangrenosum and ulcerative colitis. PMID- 24818187 TI - Simplifying sun safety: a guide to the new FDA sunscreen monograph. AB - Dermatologists are instrumental in educating their patients about safe sun practices. As residents, we should begin to instill this teaching point into our daily patient encounters. The new US Food and Drug Administration sunscreen guidelines, instituted fully in December 2012, help consumers make more educated decisions about sunscreens they purchase but also introduce new classifications and claims with which dermatologists should be intimately familiar. This article aims to concisely summarize the revisions as well as any continued controversies with the guidelines. PMID- 24818188 TI - Cutaneous metastasis of a perivascular epithelioid cell tumor. PMID- 24818189 TI - Erythematous friable papules on the flank. PMID- 24818190 TI - Recurrent Stevens-Johnson syndrome secondary to Mycoplasma pneumoniae infection. PMID- 24818191 TI - Cutaneous metastasis from primary gastric cancer: a case report and review of the literature. AB - Cutaneous metastases of internal neoplasms are uncommon. They can be metachronous or synchronous to the primary tumor and typically appear late in the course of advanced malignant disease. Gastric cancer rarely is reported as a cause of cutaneous metastasis; the most common metastatic sites are the liver, peritoneal cavity, and lymph nodes. We report a case of cutaneous metastasis from a primary gastric tumor that had been treated 6 years prior. There was no visceral invasion. The patient was treated successfully via a relaparotomy to exclude any macroscopic abdominal recurrence and complete excision of the lesion with a plastic flap to compensate for the tissue lost in the resection. Treatment plans vary depending on the diameter and number of lesions, the presence of visceral metastases, and the physical status of the patient. Therapy generally includes local excision, irradiation, or chemotherapy. PMID- 24818192 TI - Time to bid adieu to removable dental prostheses. PMID- 24818193 TI - Elevation forces and resilience of the sinus membrane during sinus floor elevation: preliminary measurements using a balloon method on ex vivo pig heads. AB - PURPOSE: Because the maxilla and its alveolar process are prone to resorption after tooth loss, it is often necessary to perform a bone augmentation procedure to successfully carry out implant treatment in that region. The aim of this study was to determine the adhesive force between the sinus membrane and the osseous sinus floor that occurs during sinus floor elevation with a balloon lift system. MATERIALS AND METHODS: Twenty-two ex vivo pig heads were used for this study. Access to the maxillary sinus was gained via the lateral sinus wall. Sinus elevation was performed using an inflatable balloon, which was consecutively filled with 3 mL of a radiopaque fluid. Pressure was monitored directly and continuously during the elevation procedure with an electronic pressure gauge. The integrity of the membrane was checked microscopically and macroscopically. RESULTS: The average adhesion force of the sinus membrane was found to be 748 +/- 65.56 mmHg. On microscopic and macroscopic inspection, no mucosal tearing occurred during sinus floor elevation. Underwood septa, when present, did not significantly influence the adhesion forces. CONCLUSIONS: The balloon system allowed for reproducible real-time measurement of the elevation forces and soft tissue resilience of the sinus membrane during the elevation process in this animal model. No mucosal ruptures were caused with this technical setup, in which effective elevation pressure ranging from 660 to 880 mmHg was not exceeded. A possible transfer of this technical setup to clinical procedures in humans requires investigation. PMID- 24818194 TI - Osteotome-mediated sinus floor elevation: a systematic review and meta-analysis. AB - PURPOSE: The objectives of this study were to systematically review the literature regarding sinus floor elevation using osteotomes with respect to the timing of implant placement, implant characteristics, grafting materials, and intraoperative and postoperative complications and to perform a meta-analysis to determine the influence of initial residual bone height (RBH) on implant success. MATERIALS AND METHODS: A systematic search of articles was conducted on MEDLINE and manually to identify studies of sinus floor elevation using osteotomes. Strict inclusion criteria were applied. The mean observation period was >= 1 year after functional loading of implants. The quality of the included papers was assessed using the Newcastle-Ottawa Scale for observational studies and the PEDro Scale for randomized clinical trials, and the heterogeneity of the papers included in the meta-analysis was evaluated. The statistical accuracy was tested using the Cochran C test, and the relationship between initial RBH and implant success was analyzed using the Student t test Welch variant. RESULTS: Twenty-five studies published over a period of 13 years met the inclusion criteria; 15 were retrospective, 9 were prospective, and 1 was a randomized controlled trial. The included articles comprised 3,092 inserted implants with a failure rate of 3.85%. Of the 25 included studies, 8 were selected for the meta-analysis. RBH > 4 mm did not influence implant success/failure; however, there was a significant difference between the success/failure rates of implants, inserted in combination with sinus floor elevation using osteotomes, when the initial RBH was < 4 mm. CONCLUSION: Initial RBH of less than 4 mm influenced the success rates of implants inserted in combination with sinus floor elevation using osteotomes. PMID- 24818195 TI - Three-dimensional accuracy of plastic transfer impression copings for three implant systems. AB - PURPOSE: The purpose of this study was to compare the three-dimensional accuracy of indirect plastic impression copings and direct implant-level impression copings from three implant systems (Nobel Biocare [NB], Biomet 3i [3i], and Straumann [STR]) at three interimplant buccolingual angulations (0, 8, and 15 degrees). MATERIALS AND METHODS: Two-implant master models were used to simulate a three-unit implant fixed partial denture. Test models were made from Impregum impressions using direct implant-level impression copings (DR). Abutments were then connected to the master models for impressions using the plastic impression copings (INDR) at three different angulations for a total of 18 test groups (n = 5 in each group). A coordinate measuring machine was used to measure linear distortions, three-dimensional (3D) distortions, angular distortions, and absolute angular distortions between the master and test models. RESULTS: Three way analysis of variance showed that the implant system had a significant effect on 3D distortions and absolute angular distortions in the x- and y-axes. Interimplant angulation had a significant effect on 3D distortions and absolute angular distortions in the y-axis. Impression technique had a significant effect on absolute angular distortions in the y-axis. With DR, the NB and 3i systems were not significantly different. With INDR, 3i appeared to have less distortion than the other systems. Interimplant angulations did not significantly affect the accuracy of NBDR, 3iINDR, and STRINDR. The accuracy of INDR and DR was comparable at all interimplant angulations for 3i and STR. For NB, INDR was comparable to DR at 0 and 8 degrees but was less accurate at 15 degrees. CONCLUSIONS: Three dimensional accuracy of implant impressions varied with implant system, interimplant angulation, and impression technique. PMID- 24818196 TI - Effect of abutment screw surface treatment on reliability of implant-supported crowns. AB - PURPOSE: To evaluate and compare the reliability of implant-supported single crowns cemented onto abutments retained with coated (C) or noncoated (NC) screws and onto platform-switched abutments with coated screws. MATERIALS AND METHODS: Fifty-four implants (DT Implant 4-mm Standard Platform, Intra-Lock International) were divided into three groups (n = 18 each) as follows: matching-platform abutments secured with noncoated abutment screws (MNC); matching-platform abutments tightened with coated abutment screws (MC); and switched-platform abutments secured with coated abutment screws (SC). Screws were characterized by scanning electron microscopy and x-ray photoelectron spectroscopy (XPS). The specimens were subjected to step-stress accelerated life testing. Use-level probability Weibull curves and reliability for 100,000 cycles at 200 N and 300 N (90% two-sided confidence intervals) were calculated. Polarized light and scanning electron microscopes were used for fractographic analysis. RESULTS: Scanning electron microscopy revealed differences in surface texture; noncoated screws presented the typical machining grooves texture, whereas coated screws presented a plastically deformed surface layer. XPS revealed the same base components for both screws, with the exception of higher degrees of silicon in the SiO2 form for the coated samples. For 100,000 cycles at 300 N, reliability values were 0.06 (0.01 to 0.16), 0.25 (0.09 to 0.45), and 0.25 (0.08 to 0.45), for MNC, MC, and SC, respectively. The most common failure mechanism for MNC was fracture of the abutment screw, followed by bending, or its fracture, along with fracture of the abutment or implant. Coated abutment screws most commonly fractured along with the abutment, irrespective of abutment type. CONCLUSION: Reliability was higher for both groups with the coated screw than with the uncoated screw. Failure modes differed between coated and uncoated groups. PMID- 24818197 TI - Diagnostic accuracy of cone beam computed tomography for dimensional linear measurements in the mandible. AB - PURPOSE: To compare linear measurements made on cone beam computed tomography (CBCT) images to direct measurements in ex vivo porcine mandibles. MATERIALS AND METHODS: Six cross-sectional planes were defined by gutta-percha-filled cavities in seven mandibles. The mandibles were scanned in a CBCT apparatus and later sectioned, using a band saw, through the gutta-percha markers. Next, four direct (DIR) linear measurements were performed for each section with a handheld digital caliper, using the gutta-percha markers as reference points. The corresponding radiographic (RAD) cross sections were then measured using dedicated software. A total of 168 sites were measured. Differences between RAD and DIR measurements [Delta (RAD - DIR)] were calculated for each pair individually. RESULTS: Mean Delta (RAD - DIR) was -0.17 +/- 0.53 mm (range, -1.42 to 1.09 mm). CBCT overestimated direct measurements at 36% of the sites; 8% of sites (95% confidence interval, 3.8% to 12.2%) showed errors between +0.5 and +1 mm, and 1.8% (95% confidence interval, -0.2% to 3.9%) showed errors greater than +1 mm. CONCLUSIONS: Good correlation was found between CBCT and direct measurements. However, the significant percentage of sites with overestimation of at least 0.5 mm indicates a need for safety margins to be maintained when CBCT is used to plan surgical interventions such as dental implant therapy. PMID- 24818198 TI - Economic evaluation of single-tooth replacement: dental implant versus fixed partial denture. AB - PURPOSE: This study assessed the cost-effectiveness from a societal perspective of a dental implant compared with a three-unit tooth-supported fixed partial denture (FPD) for the replacement of a single tooth in 2010. MATERIALS AND METHODS: A decision tree was developed to estimate cost-effectiveness over a 10 year period. The survival rates of single-tooth implants and FPDs were extracted from a meta-analysis of single-arm studies. Medical costs included initial treatment costs, maintenance costs, and costs to treat complications. Patient surveys were used to obtain the costs of the initial single-tooth implant or FPD. Maintenance costs and costs to treat complications were based on surveys of seven clinical experts at dental clinics or hospitals. Transportation costs were calculated based on the number of visits for implant or FPD treatment. Patient time costs were estimated using the number of visits and time required, hourly wage, and employment rate. Future costs were discounted by 5% to convert to present values. RESULTS: The results of a 10-year period model showed that a single dental implant cost US $261 (clinic) to $342 (hospital) more than an FPD and had an average survival rate that was 10.4% higher. The incremental cost effectiveness ratio was $2,514 in a clinic and $3,290 in a hospital for a prosthesis in situ for 10 years. The sensitivity analysis showed that initial treatment costs and survival rate influenced the cost-effectiveness. If the cost of an implant were reduced to 80% of the current cost, the implant would become the dominant intervention. CONCLUSION: Although the level of evidence for effectiveness is low, and some aspects of single-tooth implants or FPDs, such as satisfaction, were not considered, this study will help patients requiring single tooth replacement to choose the best treatment option. PMID- 24818199 TI - Implications of implant framework misfit: a systematic review of biomechanical sequelae. AB - PURPOSE: The objective of this study was to review all biomechanical investigations that have evaluated the implications of implant framework misfit with fixed prostheses. MATERIALS AND METHODS: A detailed electronic search was conducted of PubMed (MEDLINE), Google Scholar, and Cochrane Library with the aid of Boolean operators to combine relevant key words. The search was confined to articles published in English through April 2013. The literature search was enlarged by manual searches of the peer-reviewed literature and the reference lists of the selected articles. RESULTS: A total of 633 articles were retrieved from the initial search; however, only 28 articles met the determined inclusion criteria of the review. According to the study design, the selected articles were classified into two categories: laboratory studies (finite element analyses, actual model analyses, and screw stability analyses) and animal studies. The studies evaluated the effects of alterations in the magnitude and configuration of misfit, framework rigidity, type of retaining screws, and implant loading time. In addition to a lack of clear criteria of what constitutes an accurate implant framework fit, the biomechanical implications of framework misfit are unclear. CONCLUSIONS: Although implant framework misfit alters the biomechanical situation, negative biomechanical sequelae could not be confirmed from the included studies. Biologically, bone resorption cannot develop as a result of framework misfit. From a mechanical perspective, the framework stresses and screw stresses and instability increase with misfit, but the clinical significance of this remains unclear. PMID- 24818200 TI - Assessment of relationships between implant insertion torque and cortical shape of the mandible using panoramic radiography: preliminary study. AB - PURPOSE: To assess the relationship between mandibular cortical bone status as determined with panoramic radiography and insertion torque (IT) in implant treatment. MATERIALS AND METHODS: Using panoramic radiographs, two dental radiologists assessed patients' mandibular cortical bone status and classified them into two groups-normal or abnormal (mildly, moderately, or severely resorbed)-based on morphologic features of the mandibular cortical bone margins. Kappa coefficients between the two dental radiologists were calculated to determine interexaminer variability. Included patients underwent implant placement and surgery, during which IT was measured. Patients were classified into three groups based on these measurements: 15 Ncm or lower, between 15 and 35 Ncm, and 35 Ncm or higher. Correlations between mandibular cortical bone morphology and measured IT were assessed and analyzed statistically. RESULTS: Ninety-six patients (34 men, 62 women; mean age 59.1 years) were included in this study; 73 (76.0%) displayed a normal cortex and 23 (24.0%) had an abnormal cortex. In patients with a normal cortex, 13 (8.6%) had IT measurements of 15 Ncm or lower, 42 (27.6%) between 15 and 35 Ncm, and 97 (63.8%) of 35 Ncm or higher. In patients with an abnormal cortex, 3 (4.9%) had IT of 15 Ncm or lower, 35 (57.4%) between 15 and 35 Ncm, and 23 (37.7%) of 35 Ncm or higher. IT values were significantly lower in patients with an abnormal cortex compared to those with a normal cortex. A significant correlation between morphology of the mandibular cortex and IT was observed. CONCLUSION: The mandibular cortical bone status assessed on panoramic radiographs correlates with implant IT, suggesting that panoramic radiographs may be used effectively to determine bone density before implant treatment. PMID- 24818201 TI - Determination of implant position for immediate implant placement in maxillary central incisors using palatal soft tissue landmarks. AB - PURPOSE: The aim of this study was to suggest a clinical guideline to properly position immediate implant placement in the anterior maxillary area. MATERIALS AND METHODS: The computed tomography (CT) records of 250 patients (125 males, 125 females; mean age 49.5 years) were evaluated, and the relationship of the sagittal root positions of the maxillary central incisor teeth to their respective alveolar bony housing was classified as buccal (B), medial (M), or palatal (P). Then, the clinical guideline was suggested based on the implications derived from the classification. In the second investigation, the validity of the clinical guideline was confirmed by CT analysis. First, a reference line was defined using soft tissue landmarks. Then, a virtual rectangle representing the dental implant was created and merged on the CT image, symbolizing the space where the dental implant would be positioned. The rectangular frame was positioned on the image in accordance with the guideline. The frame on the image was thoroughly assessed to detect the possibility of perforation of the labial plate. The location of the initial drilling access on the respective crown was determined by extending the longitudinal axis of the frame in a coronal direction. RESULTS: Of the 250 samples, 94.0% were classified as type B. Type M and P represented 5.6% and 0.4% of the samples, respectively. In 82.0% of the samples, the frame was safely positioned, not contacting the labial or palatal cortical plate in the alveolar bony housing. Moreover, when a frame representing a tapered implant form with an apical diameter of 3.5 mm was applied, 98.8% of samples were positioned safely in the alveolar bony housing. The longitudinal axis of the frame crossed the respective crown at the incisal tip in 54.4% of the cases. It crossed the labial side of the crown and cingulum of the crown in 42.0% and 3.6% of the cases, respectively. CONCLUSIONS: The root of the maxillary central incisor teeth tended to be positioning labially in the alveolar bony housing. The result of the CT analysis confirms the clinical guideline as a dependable clinical reference in immediate implant placement. PMID- 24818202 TI - Buccal bone resorption around posterior implants after surgery: a 1-year prospective study. AB - PURPOSE: This prospective study aimed to examine postoperative dimensional changes in the buccal bone and mucosa around single-stage implants placed in the posterior region. MATERIALS AND METHODS: The dimensions of peri-implant tissue around screw-type implants placed in the posterior region were examined at surgery (baseline) and 6 months and 1 year after surgery. The lateral contour of the buccal bone and mucosa was horizontally measured at five vertical heights at 1-mm intervals (+1 to -3 mm from the implant platform) using custom-designed instruments. Bone resorption on the proximal sides was assessed on radiographs. Mucosal recession was measured on plaster casts of the dentition. RESULTS: Sixty six implants placed in 30 patients were examined. All implants were clinically osseointegrated and stable throughout the study period. The buccal bone exhibited horizontal resorption throughout the study period, even at the most apical height measured. Assessed at each height, thicker bone (> 2 mm thick) tended to exhibit horizontal resorption during the first 6 months after surgery. However, the bone resorbed horizontally by approximately 0.4 mm during the final 6 months, irrespective of its contour. Vertical resorption of the buccal marginal bone was approximately 1 mm during the period from 6 months to 1 year. The bone-retaining group at the 1-year time point was found to have thicker bone walls at baseline compared with the bone-loss group. The thickness of the buccal mucosa showed little change. There was no obvious correlation between buccal bone resorption and mucosal recession. CONCLUSIONS: The buccal bone exhibited both horizontal and vertical resorption over the year after surgery. The initial contour of the bone was significantly associated with bone retention or loss at 1 year. However, mucosal recession was not directly affected by buccal bone resorption. PMID- 24818203 TI - Three-year follow-up of immediately loaded implants in the edentulous atrophic maxilla: a study in patients with poor bone quantity and quality. AB - PURPOSE: Immediate loading of implants in the edentulous maxilla has previously been successfully performed and reported. Severe resorption of the maxillary alveolar crest presents a more demanding situation for the restorative team. Thus, it would be valuable to assess outcomes for this immediate loading treatment protocol in subjects with marked maxillary alveolar crest atrophy. This study evaluated the 3-year results of dental implants that were immediately restored with provisional fixed prostheses in atrophic maxillae without previous augmentation. MATERIALS AND METHODS: Two centers enrolled subjects with resorbed edentulous maxillae (Lekholm and Zarb quality 3 or 4 and quantity C, D, or E). Six implants were placed in each subject and restored with screw-retained fixed provisionals within 24 hours. Impressions were taken for definitive restorations, which were placed 20 to 24 weeks later. Radiographs were used to analyze marginal bone level changes throughout the study. RESULTS: Fifty-one patients received 306 implants. Forty-five patients remained in the study at the 3-year follow-up visit and successfully used their definitive prostheses. Sixty-two percent of the implants were placed in bone quantity C and quality 3 or 4, and 38% were placed in quantity D and quality 3 or 4 bone. Thirteen implants in six subjects were lost, resulting in a cumulative survival rate of 96% after 3 years. The mean marginal bone loss during the first year was -0.4 +/- 0.8 mm (255 implants); at 3 years it was -0.6 +/- 1.1 mm (253 implants). CONCLUSION: Data from the first 3 years of this study revealed good clinical outcomes. Careful selection of patients and planning by the restorative team can enable successful treatment outcomes for patients presenting with marked resorption of the edentulous maxilla. PMID- 24818204 TI - Flapless dental implant surgery: a retrospective study of 1,241 consecutive implants. AB - PURPOSE: The purpose of this study was to identify retrospectively the predictors of implant survival when the flapless protocol was used in two private dental practices. MATERIALS AND METHODS: The collected data were initially computer searched to identify the patients; later, a hand search of patient records was carried out to identify all flapless implants consecutively inserted over the last 10 years. The demographic information gathered on statistical predictors included age, sex, periodontal and peri-implantitis status, smoking, details of implants inserted, implant locations, placement time after extraction, use of simultaneous guided hard and soft tissue regeneration procedures, loading protocols, type of prosthesis, and treatment outcomes (implant survival and complications). Excluded were any implants that required flaps or simultaneous guided hard and soft tissue regeneration procedures, and implants narrower than 3.25 mm. RESULTS: A total of 1,241 implants had been placed in 472 patients. Life table analysis indicated cumulative 5-year and 10-year implant survival rates of 97.9% and 96.5%, respectively. Most of the failed implants occurred in the posterior maxilla (54%) in type 4 bone (74.0%), and 55.0% of failed implants had been placed in smokers. CONCLUSION: Flapless dental implant surgery can yield an implant survival rate comparable to that reported in other studies using traditional flap techniques. PMID- 24818205 TI - Implant treatment in atrophic posterior mandibles: vertical regeneration with block bone grafts versus implants with 5.5-mm intrabony length. AB - PURPOSE: To retrospectively compare the outcomes of implants placed in posterior mandibles vertically regenerated with onlay autogenous block bone grafts and short dental implants. MATERIALS AND METHODS: Consecutive patients with vertical bone atrophy in edentulous mandibular posterior regions (7 to 8 mm of bone above the inferior alveolar nerve) were treated with either implants placed in regenerated bone using autologous block bone grafts (group 1) or short implants (with 5.5-mm intrabony length) in native bone (group 2) between 2005 and 2010 and followed for 12 months after loading. The procedure used was the established treatment protocol for this type of patient at the Oral Surgery Unit (University of Valencia, Spain) at the time of surgery. All grafts were obtained using piezosurgery. The outcomes assessed were: complications related to the procedure, implant survival, implant success, and peri-implant marginal bone loss. Statistical analysis was done using the Fisher exact test and the Mann-Whitney test. RESULTS: Thirty-seven patients were included, 20 (45 implants) in group 1 and 17 (35 implants) in group 2. In group 1, 13 implants were less than 10 mm long (2 were 7 mm and 11 were 8.5 mm), and 32 were 10 mm or longer; the diameter was 3.6 mm in 6 implants, 4.2 mm in 31, and 5.5 mm in 8. In group 2 all implants were 7 mm long; the diameter measured 4.2 mm in 14 implants and 5.5 mm in 21 implants. Complications related to the block bone grafting procedure were temporary hypoesthesia in one patient, wound dehiscence with graft exposure in three patients, and exposure of the osteosynthesis screw without bone graft exposure in one patient. After 12 months, implant survival rates were 95.6% in group 1 and 97.1 % in group 2; success rates were 91.1% and 97.1%, respectively. The average marginal bone loss was 0.7 +/- 1.1 mm in group 1 and 0.6 +/- 0.3 mm in group 2. CONCLUSIONS: When residual bone height over the mandibular canal is between 7 and 8 mm, short implants (with 5.5-mm intrabony length) might be a preferable treatment option over vertical augmentation, reducing chair time, expense, and morbidity. PMID- 24818206 TI - Diagnostic performance of mandibular bone density measurements in assessing osteoporotic status. AB - PURPOSE: The study evaluated the diagnostic performance of computed tomography (CT) bone density measurements (in Hounsfield units [HU]) in assessing the osteoporotic status of edentulous subjects (21 men, 40 women) scheduled to receive mandibular implant-supported overdentures. MATERIALS AND METHODS: Density (in HU) of 61 left and 61 right mandibular canine sites was measured. Each subject was also subject to body bone mineral density measurements (dual-energy x ray absorptiometry). Bone density T-score values of total hip, femoral neck, spine (L1 to L4), and total body were assessed. Pearson correlations were conducted between HU of each mandibular bone site and the subject's T-score values. Sensitivity/specificity and receiver operating characteristic curve analyses were used to assess the diagnostic performance of HU in detecting subjects who were, based on each of the four T-scores: (1) "not osteonormal", ie, with a T-score at or below -1.0; or (2) osteoporotic, ie, with a T-score at or below -2.5. RESULTS: HU measurements of mandibular bone sites were found to have modest but significant correlations with each bone density T-score value (total hip, femoral neck, spine, total body). CT mandibular site HU measurement has diagnostic value in detecting a "not osteonormal" condition when total hip, spine, or total body T-scores were used, but not when femoral neck T-score was used. CONCLUSIONS: Based on the limited sample size, optimal HU cutoff values of ~530, ~600, and ~640 HU for total hip, spine, or total body T-scores, respectively, were proposed. CT mandibular site HU measurement had diagnostic value in detecting osteoporosis when spine T-score was used but not when total hip, femoral neck, and total body T-scores were used. An optimal HU cutoff value of ~460 HU for spine T-score was proposed. PMID- 24818207 TI - Comparison of two different abutment designs on marginal bone loss and soft tissue development. AB - PURPOSE: To assess the response of soft tissues around two different abutment designs in healed sites in the esthetic zone. MATERIALS AND METHODS: Twenty-six subjects received two endosseous implants in healed, bilateral implant sites in the esthetic zone in the maxilla or the mandible. After 17 to 19 weeks and left/right randomization, the implants were restored with either a conventional (control) or curved (experimental) titanium abutment and a provisional crown. Eight weeks after abutment placement, definitive crowns were cemented (T0). Soft tissue development was assessed based on peri-implant bone loss, Pink Esthetic Score (PES), and probing depths immediately after placement of the definitive crown and after 1 year (T12) and compared between sites. Possible confounding variables (abutment angle, plaque presence, gingival bleeding, width of attached mucosa) were also documented at T0 and T12. RESULTS: The mean peri-implant marginal bone loss from T0 to T12 was 0.00 +/- 0.37 mm in the experimental group and 0.12 +/- 0.27 mm in the control group. Differences were not statistically significant (P = .25). At T12, the curved abutment scored a mean PES of 10 +/- 2.3 and the straight abutment scored 9.7 +/- 2.3. The difference was not significant (P = .46)). Probing depths were also not significantly different between the two groups (P = .85). Correlation and regression analysis showed no hints of predictive behavior for the possible confounding variables. CONCLUSION: A titanium abutment with a circumferential curved design is of no additional benefit to soft tissue development and preservation of marginal bone compared to a conventional straight abutment design for the restoration of single-tooth implants in the esthetic zone. PMID- 24818208 TI - Implant survival and crestal bone loss around extra-short implants supporting a fixed denture: the effect of crown height space, crown-to-implant ratio, and offset placement of the prosthesis. AB - PURPOSE: To determine the effect of crown height space, crown-to-implant ratio, and offset placement of a prosthesis on implant survival, crestal bone loss, and prosthetic complications; and to determine whether detrimental values for crown height space and crown-to-implant ratio exist for implant-supported restorations. MATERIALS AND METHODS: Extra-short implants (length <=6.5 mm) supporting a fixed denture in the posterior mandible and followed for at least 12 months were analyzed. Radiographic and clinical examinations were conducted to retrieve data about patients' dental and medical history, prosthetic complications, antagonist type, crown height space, crown-to-implant ratio, offset placement of the prosthesis, crestal bone loss, and implant failure. RESULTS: Thirty-four patients (mean age, 60 +/- 10 years) with 45 extra-short implants participated in this study. Patients were followed for up to 4 years (mean, 2 years) and no implants were lost. The mean crown-to-implant ratio was 2.4 (range, 1.5 to 3.69). Mean crown height space was 17.05 +/- 3.05 mm, and 65.4% of the implants had a crown height space in the range of 15 to 20 mm. About 90% of the implants had a distal or mesial offset placement greater than 1 mm. The type of antagonist significantly affected marginal bone loss around extra-short implants: bone loss was greatest for implants opposing a partial denture (mean, 1.28 +/- 1.09 mm) and was lower for implants opposing a natural dentition (mean, 0.73 +/- 0.60 mm) or a complete denture (mean, 0.89 +/- 0.60 mm). Analysis of marginal bone loss and the factors crown-to-implant ratio, crown height space, and offset placement according to antagonist dentition indicated a significant positive correlation only between bone loss and crown height space. CONCLUSIONS: When an increased crown-to-implant ratio is present, crown height space may influence crestal bone loss more significantly. PMID- 24818210 TI - Tissue remodeling after bone expansion in grafted and ungrafted sockets. AB - PURPOSE: The aim of this clinical study was to assess horizontal width changes in grafted and ungrafted sites after bone expansion and implant placement. MATERIALS AND METHODS: Twenty-three patients were included in this prospective study. Each patient required extraction of two teeth and replacement with implants. After dental extraction in 23 alveoli (group 1), a collagen sponge was used to cover fresh sockets, and the remaining 23 alveoli (group 2) were grafted with corticocancellous porcine bone. Three months after extraction, bone expansion was performed in each site, and 46 dental implants were placed. To evaluate tissue volume changes, the variations in width of the buccal ridge were recorded with a periodontal probe immediately after tooth extraction, 3 months later (before implant placement), and 3 months after implant placement. RESULTS: In group 1, at 3 months after implant placement, mean volume changes of +1.6 +/- 0.8 mm for incisors and canines, +1.4 +/- 0.5 mm for premolars, and +0.8 +/- 0.5 mm for molars were seen. In group 2, mean changes of +1.5 +/- 0.8 mm for incisors and canines, +1.3 +/- 0.3 mm for premolars, and +2.8 +/- 0.6 mm for molars were observed. Statistically significant differences were found only for molars. CONCLUSIONS: In both groups, incisor, canine, and premolar sites showed no differences in volume changes, but statistically significant differences were found between molars in the two groups; the biomaterial graft prevented collapse of the large defects and significant volume loss. PMID- 24818209 TI - Patient-reported outcomes of immediate versus conventional loading with fixed full-arch prostheses in the maxilla: a nonrandomized controlled prospective study. AB - PURPOSE: To compare patient satisfaction and postoperative pain and swelling for immediate versus conventional loading in partially edentulous patients requiring extraction of the remaining maxillary dentition and rehabilitation with fixed full-arch prostheses. MATERIALS AND METHODS: This prospective, controlled, nonrandomized study with 12-month follow-up included 30 consecutive patients scheduled for fixed full-arch implant-supported maxillary rehabilitation. Fifteen patients were treated with conventional loading (control group) and the next 15 with immediate loading (test group). Ten-centimeter visual analog scales were used as assessment tools. Patient overall satisfaction and specific satisfaction with esthetics, chewing, speaking, comfort, self-esteem, ease of cleaning, and treatment duration were assessed preoperatively and at 3 and 12 months postoperatively. Postoperative pain and swelling levels were recorded daily during the first week. Statistical analysis was performed using Mann-Whitney and Wilcoxon rank sum tests, alpha = .05. RESULTS: One test group patient was excluded, so the final sample included 29 patients. Between baseline and 3 months, in the test group general satisfaction and all specific satisfactions increased significantly with the exception of speech; in the control group overall satisfaction and self-esteem did not change, satisfaction with esthetics increased significantly, and satisfaction with speech, chewing, and comfort decreased significantly. After 12 months, satisfaction was significantly higher in the test group with the exception of ease of cleaning. Between 3 and 12 months, satisfaction improved in both groups but to a greater degree in the control group. After 12 months, there were no differences in satisfaction. No differences were found in either mean postoperative pain/swelling or maximum pain/swelling at the studied time points. CONCLUSIONS: Patient satisfaction for immediate loading was significantly higher than for conventional loading during the osseointegration period. After 12 months, when final prosthetic rehabilitations had been in function for some time, differences had disappeared. No differences were found between loading protocols in postoperative pain or swelling. PMID- 24818211 TI - Nasal floor elevation combined with dental implant placement: a long-term report of up to 86 months. AB - PURPOSE: The aim of this paper is to present a large-scale long-term follow-up of dental implants placed simultaneously with nasal floor augmentation using osteoconductive bovine bone substitutes. MATERIALS AND METHODS: Patients who received dental implants combined with nasal floor elevation in three dental centers between 2006 and 2012 were included in this report. Preoperative available bone height was measured on computed tomographic scans. Implant parameters as well as implant survival rates were recorded. The cohort consisted of long-term follow-up of this previously reported cohort, combined with a cohort of newly treated patients. RESULTS: Overall, 67 patients were included in this study. Cigarette smoking was reported by 16 patients. Two hundred three implants were inserted in combination with nasal floor elevation. No nasal mucosa perforations were observed. The mean follow-up periods were 65.93 +/- 13.2 months (range, 33 to 86 months) for the original cohort and 23.14 +/- 9.4 months (range, 7 to 44 months) for the newly treated patients. The available bone height prior to bone augmentation was 8.89 +/- 1.1 mm (range, 5 to 11.2 mm) and a mean of 3.65 +/- 0.9 mm (range, 1.1 to 7 mm) of additional height was achieved with nasal floor elevation. During the follow-up period, no implants were lost, resulting in a 100% survival rate. CONCLUSION: Nasal floor augmentation, as shown in this report, might serve as a reliable method for reconstruction of the anterior atrophic maxilla when residual height is insufficient. PMID- 24818212 TI - Immediate provisionalization of dental implants placed in healed alveolar ridges and extraction sockets: a 5-year prospective evaluation. AB - PURPOSE: This 5-year prospective multicenter study compared implant survival and success, peri-implant health and soft tissue responses, crestal bone level stability, and complication rates following immediate loading of single OsseoSpeed implants placed in anterior maxillary healed ridges or extraction sockets. MATERIALS AND METHODS: Individuals requiring anterior tooth replacement with single implants were treated and immediately provisionalized. Definitive all ceramic crowns were placed at 12 weeks. Implant survival, bone levels, soft tissue levels, and peri-implant health were monitored for 5 years. RESULTS: One hundred thirteen patients received implants in fresh sockets (55) and healed ridges (58). After 5 years, 45 and 49 patients remained for evaluation, respectively. During the first year, three implants failed in the extraction socket group (94.6% survival) and one implant failed in the healed ridge group (98.3% survival); this difference was not significant. No further implant failures were recorded. After 5 years, the interproximal crestal bone levels were located a mean of 0.43 +/- 0.63 mm and 0.38 +/- 0.62 mm from the reference points of implants in sockets and healed ridges (not a significant difference). In both groups, papillae increased over time and peri-implant mucosal zenith positions were stable from the time of definitive crown placement in sockets and healed ridges. Compared to flap surgery for implants in healed ridges, flapless surgery resulted in increased peri-implant mucosal tissue dimension (average, 0.78 +/- 1.34 mm vs 0.19 +/- 0.79 mm). CONCLUSION: After 5 years, the bone and soft tissue parameters that characterize implant success and contribute to dental implant esthetics were similar following the immediate provisionalization of implants in sockets and healed ridges. The overall tissue responses and reported implant survival support the immediate provisionalization of dental implants in situations involving healed ridges and, under ideal circumstances, extraction sockets. PMID- 24818213 TI - Perforation of the sinus membrane during sinus floor elevation: a retrospective study of frequency and possible risk factors. AB - PURPOSE: To analyze the frequency of perforation of the sinus membrane during maxillary sinus floor elevation (SFE) and to assess possible risk factors. MATERIALS AND METHODS: Seventy-seven cases of SFE performed with a lateral window approach were evaluated retrospectively. Clinical and radiographic variables potentially influencing the risk of sinus membrane perforation were evaluated and divided into patient-related factors (age, sex, smoking habit); surgery-related factors (type of surgical approach, side, units, sites, and technique of osteotomy); and maxillary sinus-related factors (presence and height of septum, height of residual ridge, thickness of lateral sinus wall, width of antrum, and thickness and status of sinus membrane). RESULTS: The following factors presented with at least a 10% difference in rates of perforations: smokers (46.2%) versus nonsmokers (23.4%), simultaneous (32%) versus staged (18.5%) approach, mixed premolar-molar sites (41.2%) versus premolar-only sites (16.7%) versus molar-only sites (26.2%), presence of septa (42.9%) versus no septa (23.8%), and minimum height of residual ridge <=4 mm (34.2%) versus > 4 mm (20.5%). These same parameters, except minimum height of residual ridge, also showed an odds ratio above 2. However, none of the comparisons reached statistical significance. CONCLUSION: The present study failed to demonstrate any factor that statistically significantly increased the risk of sinus membrane perforation during SFE using the lateral window approach. PMID- 24818214 TI - Effects of taurolidine and chlorhexidine on SaOS-2 cells and human gingival fibroblasts grown on implant surfaces. AB - PURPOSE: The purpose of the study was the evaluation of possible cytologic effects of taurolidine to fibroblasts and osteoblast-like cells. MATERIALS AND METHODS: Human gingival fibroblasts and SaOS-2 cells were seeded on samples with sand-blasted and acid-etched surfaces. Both groups were treated with taurolidine, chlorhexidine, and pure water with three different treatment times. Three dates of measurements were set to evaluate cell viability, cytotoxicity, and apoptosis. RESULTS: Highest cytotoxicity was measured in both cell lines in the groups treated with chlorhexidine, while cell viability was lower than in the corresponding taurolidine and pure water groups; on days 3 and 6 these differences were significant. Taurolidine showed similar results to the pure water groups. CONCLUSION: The results of this study indicate that taurolidine is biocompatible and gentle to the tested human cells for the application time of a mouthrinse. PMID- 24818217 TI - Acquisition of reproducible transmission near-infrared (NIR) spectra of solid samples with inconsistent shapes by irradiation with isotropically diffused radiation using polytetrafluoroethylene (PTFE) beads. AB - A bead-incorporated transmission scheme (BITS) has been demonstrated for collecting reproducible transmission near-infrared (NIR) spectra of samples with inconsistent shapes. Isotropically diffused NIR radiation was applied around a sample and the surrounding radiation was allowed to interact homogeneously with the sample for transmission measurement. Samples were packed in 1.40 mm polytetrafluoroethylene (PTFE) beads, ideal diffusers without NIR absorption, and then transmission spectra were collected by illuminating the sample-containing beads using NIR radiation. When collimated radiation was directly applied, a small portion of the non-fully diffused radiation (NFDR) propagated through the void space of the packing and eventually degraded the reproducibility. Pre diffused radiation was introduced by placing an additional PTFE disk in front of the packing to diminish NFDR, which produced more reproducible spectral features. The proposed scheme was evaluated by analyzing two different solid samples: density determination for individual polyethylene (PE) pellets and identification of mining locality for tourmalines. Because spectral collection was reproducible, the use of the spectrum acquired from one PE pellet was sufficient to accurately determine the density of nine other pellets with different shapes. The differentiation of tourmalines, which are even more dissimilar in appearance, according to their mining locality was also feasible with the help of the scheme. PMID- 24818215 TI - Effect of direct current on surface structure and cytocompatibility of titanium dental implants. AB - PURPOSE: A low direct current can be used to disinfect dental titanium implants in simulated physiologic environments. The aim of this study was to determine whether this treatment affects implant surface structure and cytocompatibility. MATERIALS AND METHODS: Titanium test disks with a sandblasted, acid-etched, large grit (SLA) surface were placed as anodes in an electrolytic bath with physiologic saline and treated with 15 mA of current for 15 minutes. Surfaces were analyzed by light and electron microscopy and contact angle measurement. Depth profile analyses of SLA disks were run at subsurface levels from 0 to 1,000 nm. The proliferation and viability of preosteoblastic cells and human foreskin fibroblasts on implant surfaces were assessed. Alkaline phosphatase (ALP) activity was determined with and without exposure to bone morphogenetic protein-2 (BMP-2). Mineralization was determined after 4 weeks. RESULTS: A blue discoloration was observed after treating the SLA disks, but no damage was recognized microscopically. An oxidation layer formed on the surface and the wettability of the disks increased significantly. Cell proliferation and initial maturation were not affected by the treatment. Mineralization and ALP activity of BMP-exposed cells, however, were slightly but significantly reduced on test disks. CONCLUSIONS: The current study showed that the alterations in implant color after electrochemical treatment did not reflect significant surface changes, which would preclude cell adhesion and growth or have a major impact on osteoblastic differentiation or maturation. PMID- 24818216 TI - A novel technique to prevent the loss of graft material through the antrostomy after sinus surgery: technical note. AB - Maxillary sinus surgery has been shown to be a reliable procedure for increasing vertical bone height prior to implant placement. A variety of grafting materials have been proposed, with particulate bone substitutes showing similar clinical results to autogenous bone when rough surfaces implants are used. A barrier membrane is usually placed external to the grafted sinus, covering the antrostomy. In this technical report, the membrane is placed over the window and its borders gently tucked between the inner side of the bony wall and the graft material. This procedure stabilizes the membrane without tacks and prevents graft dislodgement through the antrostomy. PMID- 24818218 TI - A Pd/CNT-SiC monolith as a robust catalyst for Suzuki coupling reactions. AB - A novel Pd/CNT-SiC monolith catalyst has been prepared by a simple two-step approach. The as-synthesized Pd/CNT-SiC monolith afforded high activity and stability for the Suzuki coupling reactions. In particular, it can be easily separated from reaction mixtures, showing its potential application in liquid phase reactions. PMID- 24818219 TI - Red electroluminescence of ruthenium sensitizer functionalized by sulfonate anchoring groups. AB - We have synthesized five novel Ru(ii) phenanthroline complexes with an additional aryl sulfonate ligating substituent at the 5-position [Ru(L)(bpy)2](BF4)2 (1), [Ru(L)(bpy)(SCN)2] (2), [Ru(L)3](BF4)2 (3), [Ru(L)2(bpy)](BF4)2 (4) and [Ru(L)(BPhen)(SCN)2] (5) (where L = 6-one-[1,10]phenanthroline-5-ylamino)-3 hydroxynaphthalene 1-sulfonic, bpy = 2,2'-bipyridine, BPhen = 4,7-diphenyl-1,10 phenanthroline), as both photosensitizers for oxide semiconductor solar cells (DSSCs) and light emitting diodes (LEDs). The absorption and emission maxima of these complexes red shifted upon extending the conjugation of the phenanthroline ligand. Ru phenanthroline complexes exhibit broad metal to ligand charge transfer centered electroluminescence (EL) with a maximum near 580 nm. Our results indicated that a particular structure (2) can be considered as both DSSC and OLED devices. The efficiency of the LED performance can be tuned by using a range of ligands. Device (2) has a luminance of 550 cd m(-2) and maximum efficiency of 0.9 cd A(-1) at 18 V, which are the highest values among the five devices. The turn on voltage of this device is approximately 5 V. The role of auxiliary ligands in the photophysical properties of Ru complexes was investigated by DFT calculation. We have also studied photovoltaic properties of dye-sensitized nanocrystalline semiconductor solar cells based on Ru phenanthroline complexes and an iodine redox electrolyte. A solar energy to electricity conversion efficiency (eta) of 0.67% was obtained for Ru complex (2) under standard AM 1.5 irradiation with a short-circuit photocurrent density (Jsc) of 2.46 mA cm(-2), an open-circuit photovoltage (Voc) of 0.6 V, and a fill factor (ff) of 40%, which are all among the highest values for ruthenium sulfonated anchoring groups reported so far. Monochromatic incident photon to current conversion efficiency was 23% at 475 nm. Photovoltaic studies clearly indicated dyes with two SCN substituents yielded a higher Jsc for the cell than dyes with a tris-homoleptic anchor substituent. PMID- 24818220 TI - Rapid synthesis, structure and photocatalysis of pure bismuth A-site perovskite of Bi(Mg3/8Fe2/8Ti3/8)O3. AB - Bi(Mg3/8Fe2/8Ti3/8)O3, a member of a small group of pure Bi(3+) A site perovskites, exhibiting a high ferroelectric Curie point (Tc), was rapidly synthesized by a sample method of molten salt synthesis. The purity of Bi(Mg3/8Fe2/8Ti3/8)O3 samples is directly affected by the reaction conditions such as the soaking temperature, and the heating and cooling rates. The as prepared Bi(Mg3/8Fe2/8Ti3/8)O3 particles are well-formed, cube-shaped single crystals with sizes ranging from 200-300 nm. The chemical states of Bi and Fe ions are Bi(3+) and Fe(3+) in Bi(Mg3/8Fe2/8Ti3/8)O3. UV-vis diffuse reflectance spectra and preliminary photocatalytic experiments indicate that the pure Bi(3+) A site perovskite of Bi(Mg3/8Fe2/8Ti3/8)O3 has a suitable energy bandgap (1.86 eV) and shows obvious photocatalytic activity for the decolorization of methyl blue under visible-light irradiation. The present work suggests potential future applications of Bi(Mg3/8Fe2/8Ti3/8)O3 in photocatalysis and ferroelectric photovoltaic effects. PMID- 24818221 TI - Microwave-assisted synthesis of arene ruthenium(II) complexes [(eta6-RC6H5)Ru(m MOPIP)Cl]Cl (R = -H and -CH3) as groove binder to c-myc G4 DNA. AB - Two arene Ru(II) complexes coordinated by 2-(3-methoxyphenyl)imidazole[4,5 f][1,10]phenanthroline, [(eta(6)-RC6H5)Ru(m-MOPIP)Cl]Cl (R = H, ; R = CH3, 2), have been prepared under microwave irradiation; the crystal structure of 2 exhibits a typical "piano stool" conformation, with bond angles for N1-Ru1-Cl1 86.02 (14) degrees and N2-Ru1-Cl1 84.51 (14) degrees . The Ru-C distance for the Ru atom bound to the benzene ring is about 0.2178(8) nm, and the average Ru-N distance for Ru atom to the two chelating N atoms is about 0.2092(4) nm. The evaluation of in vitro anticancer activities revealed that these synthetic Ru(II) complexes selectively inhibited the growth of HepG2 hepatocellular carcinoma cells, with low cytotoxicity toward LO2 human normal liver cells. The results demonstrated that the complexes exhibited great selectivity between human cancer and normal cells by comparing with the ligand m-MOPIP. Furthermore, complexes 1 and 2 could bind to c-myc G4 DNA in groove binding mode in promising affinity, and the insertion of the methyl groups in the arene ligand contributed to strengthen the binding affinity. This was also confirmed by molecular docking calculation and (1)H NMR analysis which showed that both 1 and 2 can bind in the loop constructed by A6-G9 and G21-A25 base pairs in c-myc G4 DNA to block the replication of c-myc oligomer. Taken together, these results suggest that arene Ru(II) complexes display application potential as small molecule inhibitors of c myc G4 DNA. PMID- 24818222 TI - Protective effects of diphenylheptanes from Curcuma phaeocaulis Val. on H2O2 induced cell injury. AB - Curcuma phaeocaulis Val. has been used as a health food in China for a long time. This research aimed to isolate and identify its active compounds with protective effects against hydrogen peroxide-induced PC12 cell death. 70% ethanol extracts of C. phaeocaulis were re-extracted and three fractions of water, petroleum ether and ethyl acetate were obtained. Three diphenylheptane compounds from the ethyl acetate fraction were identified for the first time from C. phaeocaulis, and compound III was considered to be a new structure. All of the three compounds displayed certain protective effects against toxicity in PC12 cells. For all concentrations, compound III displayed a more significant protective effect than ethanol extracts, the ethyl acetate fraction, and the other two compounds. At a concentration of 50 MUg mL(-1), the survival rate of damaged PC-12 cells treated with compound III reached 84.7%. Diphenylheptanes were concluded to be the main compounds responsible for the health effects of C. phaeocaulis. PMID- 24818223 TI - The editorial scope tightrope. PMID- 24818224 TI - CRISPR snapshots of a gene-editing tool. PMID- 24818225 TI - Making protein crystals fly. PMID- 24818226 TI - Fishing for fas ter findings. PMID- 24818227 TI - Single cells make the tissue. PMID- 24818228 TI - Interspecies systems biology (a.k.a. interspecies genetics). PMID- 24818229 TI - Stress and myocardial infarction. AB - People's perception of the effect of stress on their health is linked to risk of myocardial infarction according to a study. PMID- 24818230 TI - Another step on the road to a European Council for Health Research. AB - The Alliance for Biomedical Research in Europe, co-founded by the European Society of Cardiology, has persuaded the European Parliament to move towards European Union-wide means of better directing and coordinating biomedical research, from the laboratory bench to the marketplace. PMID- 24818231 TI - India's blood pressure skyrockets. Rural-to-urban migrants are at especially high risk. PMID- 24818232 TI - Stopping the leaks: new insights into C4 photosynthesis at low light. PMID- 24818233 TI - Interaction between salt and heat stress: when two wrongs make a right. PMID- 24818234 TI - [Infections and oncology: viruses as a cause of colorectal cancer]. PMID- 24818235 TI - Trade-offs between constitutive and induced defences drive geographical and climatic clines in pine chemical defences. AB - There is increasing evidence that geographic and climatic clines drive the patterns of plant defence allocation and defensive strategies. We quantified early growth rate and both constitutive and inducible chemical defences of 18 Pinaceae species in a common greenhouse environment and assessed their defensive allocation with respect to each species' range across climatic gradients spanning 31 degrees latitude and 2300 m elevation. Constitutive defences traded-off with induced defences, and these defensive strategies were associated with growth rate such that slow-growing species invested more in constitutive defence, whereas fast-growing species invested more in inducible defence. The position of each pine species along this trade-off axis was in turn associated with geography; moving poleward and to higher elevations, growth rate and inducible defences decreased, while constitutive defence increased. These geographic patterns in plant defence were most strongly associated with variation in temperature. Climatic and geographical clines thus act as drivers of defence profiles by mediating the constraints imposed by trade-offs, and this dynamic underlays global patterns of defence allocation.